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I ... a... ‘..1....l Q... . r. ... 0.. C II . . . .. ' .... .. v. . . I ...\.,\-\‘0QP\I. o. r I . . - - - ' II‘I ll . |\(. l I | I.\I| | ll‘l‘l’ - Ill.“ 'I‘I‘II' )LHO LIBRARY Michigan State University This is to certify that the dissertation entitled SYNTHETIC APPROACH TO AUTOLYTIMYCIN & RELATED SYNTHETIC ENDEAVORS presented by ANNA MONICA NORBERG has been accepted towards fulfillment of the requirements for the Doctoral I degree in Chemistry W? \M LQQ (iLQN Maj r Professor’s Sign‘atbre V , 330, “lo I D Date MSU is an Affinnative Action/Equal Opportunity Employer PLACE IN RETURN BOX to remove this checkout from your record. To AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 5103 KIProj/Am‘PndCIRCIDdoDumIndd SYNTHETIC APPROACH TO AUTOLYTIMYCIN & RELATED SYNTHETIC ENDEAVORS BY Anna Monica Norberg A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2010 ABSTRACT SYNTHETIC APPROACH TO AUTOLYTIMYCIN & RELATED SYNTHETIC ENDEAVORS BY Anna Monica Norberg Autolytimycin, isolated in 2000 as a new geldanamycin member of the ansamycin superfamily, inhibits the oncostatin M signaling pathway and heat shock protein 90. Other members of the geldanamycin family are geldanamycin, herbimycin, macbecin and reblastatin, which also show cytotoxicity and anticancer activity. Along with other ansamycins, autolytimycin contains a 1,3,5- trisubstituted aromatic core with all substituents electron-donating. This substitution pattern, with ortho-/para-directing groups meta to each other, is . difficult to access with conventional aromatic substitution chemistry. However, through the use of an iridium catalyst, our group has shown that arenes can undergo C-H activation/borylation to afford boronic esters with substitution patterns that are primarily governed by steric and not electronic factors. This methodology enables several one-pot functionalizations of the crude boronic esters without the isolation of any intermediates. One of these sequences is the C-H activation/borylation/amidation/oxidation, which provides substituted amidophenols with the regiochemistry desired for molecules such as the natural product autolytimycin. Contributions made toward the development of this methodology, as well as our findings and progress in the total synthesis of this interesting natural product, will be presented and discussed. To showcase the utility of our aforementioned methodology, we have successfully demonstrated the large scale feasibility of the CH activation/borylation protocol for several arenes on multi-gram scale. Additionally, the one-pot C-H activation/borylation/oxidation sequence to form the 3,5- disubstituted phenols, compounds difficult to obtain with traditional synthetic methods, was also demonstrated to proceed efficiently on large scales. To ease the purification and isolation of these phenols, an alternative oxidation and isolation method was developed using hydrogen peroxide as the oxidant. This modification resulted into not only a simpler, but also a more environmentally benign C-H activation/borylation/oxidation methodology. An interesting observation made in a crude 1H NMR spectrum, during one of the reaction steps in the total synthesis towards autolytimycin, culminated in a study of cation-n interactions between ammonium salts and amidophenols. These interactions were shown to significantly alter the chemical shifts of the arenes. The implifications of this study for the use of ammonium salts as chemical shift reagents, and those for the use of 1H NMR analysis in organic synthesis will be discussed as well. H'ut I". w “399.05 rwmmlna ' am mop;- ' . . . , - - . .. .-°r.-,.':.i.-;‘.-' of my I?» for five ‘r. , ' 4i ‘..'f T H“ Ir -dWhICIH,:-.‘. ~. ".m' -.- f'w‘sgs. 08948 There l~4 . . 3r??? ' i - '. ’ ' J-‘hfé \.;:;}:l.'oi“ If: 9: .4 lot.- » ,5 . . ,. “an... \':r:en l? 5.“ fl; ' it J’IJ' ‘v' - i ' '2 M37! 'lrl' Irl‘f'. you . 5" .-Tha 5,0,...0,‘ N U , . . .. . . -,, . Human I: , Jr. Wit? . n .. - - ~ : - ~ .'n-.\.'ar-«;t-m I _' =b01h €le ‘ 'u' , l .. ° . -' ‘ ‘ T" NW" 790 'f_ . times. t'w . .- - “N" ”9”“; . — ,. He haigut a“. ' . ' “ "h“: M to '3 - q—r . -+ - quest“ , '- u1 not“ being a .. mar-m -- _--.... ... . Vt .' .4 \‘ . k .M also one u .. .. - ---~vr:imw 'WRSmw. wt: .4. ..., . . vu- .r-V'wamfl .51}, L ' &' . V‘ I 2k .0 Wu. '3 c L , K x u ". , ‘ x...' 5“— 45:.1 “ ' I 'm M Iflaifihy '3qu OYN" I '2, H's-tw-‘upg ,1}! 1-3,. .... 1 ‘13.. 1.2“ \\_-. . -~.\~‘, ' q a 1: F1.“ \Jru‘. VI ..1 ‘ 1.. I , . J . .' :24- ‘n - V *. c “I'. o g ‘2‘. nr‘; 49 ' ,. - a 7 ,', . _I ‘-, r' ~.._~ ' ' - “ . '..XJ_.._& - l .: ' :‘m‘Q‘r-"h\u— ls. bili- ACKNOWLEDGEMENTS Well, another chapter of my life is written. This Ph.D. thesis represents in a way so much more than just the work in it; it was the majority of my life for five years, of which only about four have been documented within these pages. There are many people that I should acknowledge, both for guidance and support in the world of chemistry, but also for keeping things outside the lab at ease. A Ph.D. is not a day job, it is not something that you can leave and walk away from when it gets dark at night. It follows you wherever you may go during the entire time you are in graduate school. It was my only life in many ways. The person I should thank first is my advisor, Professor Robert E. Maleczka, Jr. Without his guidance, encouragement, support, and understanding, during both the successful and bright days as well as during the dark and doubtful times, there would have been little chance of this Ph.D. thesis ever being completed. He helped me navigate through the world of chemistry, taught me to ask the right questions and to question the answers. I thank him for both being a good advisor and an excellent teacher. I would also like to thank our collaborator and my committee member Professor Milton R. Smith, III for putting things in perspective and for pushing me to work hard. He has literally taught me the meaning of “Do not judge a book by its cover”. For my two other committee members, Professor Babak Borhan and my second reader Professor William D. Wulff, I also hold great gratitude. Both of them have supported and encouraged my learning of chemistry and its applications: To Professor Wulff for introducing me to retrosynthetic analysis and total synthesis, and to Professor Borhan for teaching the greatest class of my chemistry career. Several additional people have made this endeavor of my Ph.D. possible and pleasurable. I would like to thank all Maleczka group members, past and present, for making valuable suggestions and important remarks about my results and research; and also for widening my general knowledge and interest in chemistry. There are especially two fellow group members that I should mention, Luis Sanchez and now Doctor Feng Shi. Luis has been my partner in crime since the first day in the Maleczka group. We jointly took on the task of the C-H activation/borylation chemistry and the endeavor of autolytimycin. I would like to thank him for his optimism and faith in chemical transformations, which have long been unfruitful. Doctor Feng Shi, whose project we took over, initially taught me all he knew about our total synthesis and our methodology, as well as teaching me important hands-on techniques and procedures. There is an additional member of the Maleczka group I should personally mention, Luis Mori-Quiroz, who has been a very close lab-mate and friend for the past four years. I would like to thank him for always being there when I needed support and physical help; or an extra TLC plate, pipet and what not. vi iv.--v Since my project was in collaboration with the Smith group, I need to acknowledge them as well as my own group. In a way, they too were my group, the boron group. We endured group meetings and projects together. They helped me with the glovebox, the GC and whatever else I needed to get the borylation chemistry to work, for all of which I am thankful. Several other people in this department have made my stay here at Michigan State pleasurable and possible. I would especially like to thank some of- them: Professor Gary J. Blanchard, the associate chair for the graduate program, and Debbie Roper in the graduate office. Without their help and support I would not have graduated, I will be forever grateful. I would also like to acknowledge Dr. Daniel Holmes, he has taught me how to use the NMR machines and its methods, some of which I used every day. He has always been helpful, suggesting how to improve the spectral data or fishing out lost NMR experiments from the sea of spectra that I accumulated over the years. Thus far I have thanked several doctors, but there are still many left. I would like to acknowledge a few more, who most other people would also call doctors. This Ph.D. has been a physical roller coaster and I would like to thank all the people involved in keeping my brain working and me physically on my feet. Special thanks go to Dr. Krystal Kempf, Dr. Sunita Yedavally, Dr. Timothy Hellman, Dr. James Herman, Dr. Tom Mikkelsen, Dr. Jack Flock, and Dr. Giuseppe Stragiotto. My thanks also go to all the nurses, secretaries and other vii personnel that I encountered during my countless doctor’s appointments and hospital visits during the last couple of years. However, I would not be here if not for two very special people in my life, my beloved parents. I am forever grateful for everything they have done for me, and for all their support over the years. They have encouraged me to seek, explore, and widen my horizon, sometimes maybe beyond their intentions. I also would like to acknowledge my big little brother, who I have fought with through the years over all things imaginable. He still loves to tease me, but he is always there if I really need something as the big brother that he is. Some of the best friends I have made have been in the lab. This is true for both my undergraduate at KT H as well as here at Michigan State University. I will first thank my three former lab-mates, who are still some of my closest friends to this day. Asa, Maria and Kristin have encouraged me to pursue my dreams. Asa told me during our first organic lab that I would go to graduate school; she was right. I would also like to include here my new gained “lab” friends, the people that have made the long hard Ph.D. days worthwhile. A very special thank you to the Crunchy’s crew: Aman, Allison, Luis MQ, Hovig, Maryam and Borzoo; the friends that have nothing against singing good songs badly in public. I will miss you guys and our loud nights together. Well, five pages later, my last but not least acknowledgement and thank you goes to my very best friend, soon to be Doctor Aman Desai. He is another dear friend found amongst the chemicals in the lab. He is not only a great and viii inspiring chemist, he is the most supporting person I know. Aman has helped and encouraged me in my research and thesis writing; and has been an enormous support and aid for my entire wellbeing. Well, I guess I should thank one more being. Wall-E, without him I would not have made it all the way through. Sometimes, what people say is true, “Every cloud has a silver lining.” ix TABLE OF CONTENTS LIST OF TABLES .................................................................................. xiii LIST OF FIGURES ............................................................................... xiv LIST OF SCHEMES .............................................................................. xv CHAPTER 1 INTRODUCTION ................................................................................... 1 1.1 Autolytimycin — The Target Natural Product ................................... 1 1.2 Geldanamycin Family Members and Their Total Syntheses .............. 5 1.2.1 Total Synthesis of Reblastatin .......................................... 7 1.2.2 Total Synthesis of Geldanamycin ..................................... 8 1.2.3 Total Synthesis of Macbecin i ........................................ 10 1.2.4 Total Synthesis of Herbimycin A ..................................... 15 1.3 Our Retrosynthetic Analysis of Autolytimycin ................................ 18 CHAPTER 2 C-H ACTIVATION/BORYLATION ............................................................ 21 2.1 C-H Activation/Borylation/Amidation/Oxidation .............................. 21 2.2 C-H Activation/Borylation, C-H Activation/Borylation/Amldation/ Oxidation and C-H Activation/Borylation/Amidation/Oxidation — Scale Up Studies ............................................................................ 22 CHAPTER 3 OXIDATION OF BORONIC ESTERS TO PHENOLS .................................... 28 3.1 3,5-Disubstituted Phenols ......................................................... 28 3.2 Oxidation of Boronic Esters ...................................................... 29 3.3 Oxidation of Boronic Esters with Hydrogen Peroxide ...................... 29 CHAPTER 4 PROGRESS IN THE TOTAL SYNTHESIS OF AUTOLYTIMYCIN - THE RIGHT HALF AMIDE 1.5 ................................................................................... 37 4.1 Preparation of the Right-Hand Segment - Amide 1.5 ..................... 37 4.2 Alternative Routes to Amide 1.5a ............................................... 45 CHAPTER 5 PROGRESS IN THE TOTAL SYNTHESIS OF AUTOLYTIMYCIN - THE LEFT HALF BORON ADDUCT 1.2 ................................................................... 52 5.1 The Left-Hand Segment — Boron Adduct1.2 ................................. 52 CHAPTER 6 GENERATION OF AUTOLYTIMYCIN’S AROMATIC CORE WITH THE FULLY ELABORATED PIECES ......................................................................... 58 6.1 C-H Activation/Borylation/Amidation/Oxidation of Amide 1.5a ........... 58 6.2 Redesign in the Synthesis of Autolutimycin’s Aromatic Core ............ 61 6.3 Attempted Suzuki Couplings and Model Studies ........................... 64 6.4 TIPS Deprotection of Allylic Alcohol 6.13 ..................................... 69 6.5 Preparation of the Demethylated Right-Half Amide ......................... 72 6.6 Preparation of the Saturated Right-Half Amide .............................. 78 CHAPTER 7 OXIDATIVE CLEAVAGE OF OLEFINS ..................................................... 84 7.1 Oxidations of Olefins with 0504 ................................................. 84 7.2 Observed Selectivities in the Oxidation of Olefins with 0304 ............ 85 CHAPTER 8 EVIDENCE FOR CATION-rt INTERACTIONS BETWEEN TBAF AND SMALL AROMATIC MOLECULES — IMPLICATIONS FOR CRUDE 1H NMR ANALYSIS IN ORGANIC SYNTHESIS ..................................................................... 92 8.1 Initial Observations .................................................................. 92 8.2 NMR Shift Reagents and Cation-3t Interactions of Quaternary Ammonium Salts .................................................................... 98 8.3 Probing the Cation-n: Interactions for Arene 6.17 .......................... 103 CHAPTER 9 SUMMARY AND FUTURE DIRECTIONS ................................................ 115 9.1 Total Synthesis of Autolytimycin ............................................... 115 9.2 C-H Activation/Borylation and Functionalization ........................... 115 9.3 Selective Oxidative Cleavage of Olefins .................................... 116 9.4 Cation-n Interactions between Ammonium Salts and Amidophenols ...................................................................... 1 17 APPENDIX 1 EXPERIMENTAL ................................................................................ 119 1.1 General Materials and Methods ............................................... 119 1.2 General Starting Materials, Reagents and Methods ...................... 120 1.3 Experimental for Chapter 2 ..................................................... 124 1.4 Experimental for Chapter 3 ..................................................... 132 1.5 Experimental for Chapter 4 ..................................................... 141 1.6 Experimental for Chapter 6 ..................................................... 163 1.7 Experimental for Chapter 7 ..................................................... 195 1.8 Experimental for Chapter 8 ..................................................... 203 1.9 Experimental for Chapter 9 ..................................................... 236 xi ‘I‘: , 1 ‘>“ I. I$I5I 'Iv -‘ " 9v“ ., .(— " '21-», -'.' , .'f7°::j. I A 1' ,. 2 *1 SPECTRA FOR APPENDIX 1.8.. 241 - V. I. ‘9....0.0.0CC......‘OCCCCOC......OOOCOCCOOC.0.........CCOOOD......‘...............m 0 . .,. 4 .’ c‘ _-’ (‘ ' A ~- \ .. ‘. o 0 . ‘- - -I o I ... -1 ‘ O I ,r T‘. U l- ‘J h l O I. I " a C . . a ' o c o ‘0 . O ‘. ‘ 1‘, . ' .‘x’ .7 T, - ‘ -- I‘ " C I; ~- ‘II _"Q | %Q.".' ")w't‘. ‘ l‘- -) 1 A“. ,. ts. .. -.~. ,-. u_ . t; . . ‘ ‘ v n. .‘V - J “‘4 ‘I' - '2 . . . \§‘ fit" - I. . _\ .-' -‘ v - . ’\‘ ’ ¥ 1 LIST OF TABLES Table 2.1 Multi-gram C-H activation/borylations .......................................... 23 Table 2.2 Multi-gram C-H activation/borylation/oxidations ............................. 25 Table 3.1 Oxidation with H202 vs. oxone ................................................... 30 Table 3.2 Oxidation with H202 in MeOH and EtOl-l ....................................... 32 Table 3.3 Oxidation of the crude boronic ester 2.1a with H202 ........................ 33 Table 4.1 Optimization of vinyl addition to epoxide 4.9 ................................. 41 Table 6.1 Effect of concentration and additives in the Suzuki coupling ............. 66 Table 6.2 TIPS deprotection of the Suzuki precursor 6.5 ............................... 70 xiii LIST OF FIGURES Figure 1.1 Autolytimycin and reblastatin ...................................................... 2 Figure 1.2 The geldanamycin family members .............................................. 6 Figure 8.1 1H NMR spectrum of 6.17 ........................................................ 92 Figure 8.2 1H NMR spectra of 6.17, crude product at rt vs. at 60 °C ................ 93 Figure 8.3 1H NMR spectra of 6.17, crude product vs. isolated product ............ 94 Figure 8.4 1H NMR spectra of 6.17, “crude” product vs. reisolated product ....... 96 Figure 8.5 Cation-n interactions between circumtrindene and tetramethyl ammopictrate ....................................................................................... 99 Figure 8.6 1H NMR spectra, TBAF and TBAF + amide 6.17 ......................... 103 Figure 8.7 1H NMR spectra, “dried” TBAF and “dried” TBAF + arene 6.17 ....... 104 Figure 8.8 NOE of “dried” TBAF + arene 6.17 ........................................... 105 Figure 8.9 1H NMR spectra, arene 6.5 and (n-Bu),,NPF6 + arene 6.5 .............. 106 Figure 8.10 1H NMR spectra, amide 6.14 and TBAF + amide 6.14 ................ 107 Figure 8.11 ‘H NMR spectra, phenol 8.3 and phenol 8.3 + TBAF .................. 109 Figure 8.12 ‘H NMR spectra, arene 6.17, arene 6.17 + 0.1 equiv TBAI and arene 6.17 + 1 equiv TBAI ............................................................................ 111 Figure 9.1 Examples of substrates for studying the rate of oxidative cleavage ........................................................................................... 117 Figure 9.2 Interesting compounds for further studying the cation-n interactions ....................................................................................... 1 17 xiv LIST OF SCHEMES Scheme 1.1 Smith’s preparation of the aromatic core of trienomycins A and F....3 Scheme 1.2 Synthesis of trienomycins A and F ............................................ 4 Scheme 1.3 Synthesis of trienomycin analogs ............................................. 4 Scheme 1.4 Retrosynthesis of reblastatin by Panek and co-workers ................. 7 Scheme 1.5 Retrosynthesis of geldanamycin by Panek and co-workers ............ 8 Scheme 1.6 Retrosynthesis of geldanamycin by Andrus and co-workers ........... 9 Scheme 1.7 Retrosynthesis of macbecin l by Baker and co-worker ................. 10 Scheme 1.8 Formal synthesis of macbecin I by Martin and co-workers ............ 12 Scheme 1.9 Retrosynthesis of macbecin l by Evans and co-workers ............... 13 Scheme 1.10 Retrosynthesis of macbecin I by Panek and co-workers ............. 13 Scheme 1.11 Retrosynthesis of macbecin l by Micalizio and co-workers .......... 14 Scheme 1.12 Retrosynthesis of herbimycin A by Tatsuta and co-workers ......... 16 Scheme 1.13 Retrosynthesis of herbimycin A by Panek and co-workers .......... 17 Scheme 1.14 Retrosynthesis of herbimycin A by Cossy and co-workers .......... 17 Scheme 1.15 Retrosynthetic analysis of autolytimycin .................................. 18 Scheme 1.16 Retrosynthesis of autolytimycin by Panek and co-workers .......... 20 Scheme 2.1 Three-step, one-pot synthesis of 5-substituted-3-amidophenols....21 Scheme 2.2 Scalable ipso-substitution of chloro- and fluorobenzenes ............. 26 Scheme 3.1 Oxidation with H202 of boronic ester 2.2b ................................. 31 Scheme 3.2 30 mmol alkaline oxidation with H202 ....................................... 31 Scheme 3.3 26 mmol oxidation of the crude boronic ester 3.1 with H202...........34 Scheme 3.4 Multi-gram C-H activation/borylation/oxidation of 3-chlorobenzonitrile 3.5 ......................................... . .......................................................... 36 Scheme 4.1 Sub-targets in the retrosynthesis of autolytimycin ....................... 37 Scheme 4.2 Retrosynthetic analysis of amide 1.5 ....................................... 38 Scheme 4.3 Preparation of methyl ester 4.3 from vitamin C ........................... 38 Scheme 4.4 Formation of olefin 4.6 from a-hydroxy ester 4.3 ........................ 39 Scheme 4.5 Preparation of epoxide 4.9 from 4.6 ......................................... 39 Scheme 4.6 Initial route to aldehyde 4.12 .................................................. 40 Scheme 4.7 The new retrosynthesis of aldehyde 4.12 .................................. 42 Scheme 4.8 New route to aldehyde 4.12 ................................................... 43 Scheme 4.9 Deoxygenation of epoxide 4.9 ................................................ 43 Scheme 4.10 Completion of amide 1.5a .................................................... 44 Scheme 4.11 Retrosynthesis of epoxide 4.9 — the first alternative approach......45 Scheme 4.12 Preparation and epoxidation of diene 4.18 .............................. 46 Scheme 4.13 Sharpless asymmetric epoxidation of diene 4.18 ...................... 46 Scheme 4.14 Retrosynthesis of epoxide 4.9 — the second alternative approach ............................................................................................ 46 Scheme 4.15 Oxidation of R-glycidol 4.22 ................................................. 47 Scheme 4.16 Retrosynthesis of epoxide 4.9 — the third alternative approach....48 Scheme 4.17 Favorskii rearrangement of mesityl oxide 4.26 ......................... 48 Scheme 4.18 Reduction of crude esters 4.25 and 4.27 ................................. 49 Scheme 4.19 Favorskii rearrangement and subsequent reduction of 4.26 ........ 50 Scheme 4.20 Sharpless asymmetric epoxidation of alcohol 4.24 .................... 50 xvi Scheme 4.21 Payne rearrangement of epoxy alcohol 4.23a .......................... 51 Scheme 5.1 Sub-targets of autolytimycin ................................................... 52 Scheme 5.2 Retrosynthesis of boron adduct 1.2 ......................................... 53 Scheme 5.3 Preparation of Evan’s chiral auxiliary and subsequent allylation ..... 54 Scheme 5.4 Chiral auxiliary removal and asymmetric dihydroxylation of 5.7 ...... 54 Scheme 5.5 Reduction and ring opening of 5.98 ......................................... 55 Scheme 5.6 Conversion of the undesired 5.9a to the desired alcohol 5.118....55 Scheme 5.7 Crotylation of 5.2 with Roush’s cis-boronate 5.14 ....................... 56 Scheme 5.8 Formation of alkyl iodide 5.1 .................................................. 56 Scheme 6.1 Amidation with amide 1.5a under modified conditions ................. 59 Scheme 6.2 C-H activation/borylation/amidation/oxidation with amide 1 .5a ...... 60 Scheme 6.3 Preparation of the TIPS-protected 3-bromo-5-chlorophenol 6.1 ..... 61 Scheme 6.4 Amidation of the TIPS-protected phenol 6.1 in an open system.....62 Scheme 6.5 Amidation of the PMB-protected phenol 6.4 in a closed system.....63 Scheme 6.6 PMB protection of amidophenol 1.3a ....................................... 63 Scheme 6.7 Suzuki coupling with octylmagnesium chloride 6.7 ...................... 65 Scheme 6.8 Suzuki cross-coupling with the PMB protected aryl chloride 6.11...67 Scheme 6.9 Successful Suzuki coupling with the fully elaborated amide 6.5 ..... 68 Scheme 6.10 Desilylation of the Suzuki product 6.13 under optimal conditions ........................................................................................... 71 Scheme 6.11 Attempted RCM of MOM-protected RCM precursor 6.13a ......... 71 Scheme 6.12 RCM reaction explored computationally .................................. 72 xvii Scheme 6.13 Attempted RCM reaction by Hiersemann and Helmboldt ............ 73 Scheme 6.14 RCM of the demethylated system by Hiersemann and Helmboldt ........................................................................................... 74 Scheme 6.15 Preparation of the demethylated epoxide 6.21 from ester 4.4 ...... 75 Scheme 6.16 Preparation and oxidation of diene 6.23 .................................. 75 Scheme 6.17 Preparation of the demethylated aryl amide 6.26 ...................... 76 Scheme 6.18 Suzuki cross-coupling of the demethylated aryl amide 6.26.........77 Scheme 6.19 Ring-closing metathesis of Suzuki-product 1.1 .......................... 78 Scheme 6.20 Asymmetric Evans aldol of aldehyde 4.12 with oxazolidinone 6.28a ................................................................................................. 79 Scheme 6.21 Removal of chiral auxiliary and generation of amide 6.31 ........... 79 Scheme 6.22 Amidation coupling with amide 6.31 ....................................... 80 Scheme 6.23 Amidation coupling with amide 6.31 under modified conditions....81 Scheme 6.24 Suzuki coupling of saturated amide 6.32 .................................. 82 Scheme 7.1 Contradictory selectivity in the oxidative cleavage of diene 4.13....84 Scheme 7.2 Oxidation of 4.13 to the carboxylic acid 7.1 with 0504 and oxone..86 Scheme 7.3 Formation and oxidation of the methyl protected diene 7.4 ........... 86 Scheme 7.4 Oxidation of 4.11 to the carboxylic acid 7.6 with 0304 and oxone...87 Scheme 7.5 Oxidation of ester 4.16 with 0304, NaIO4, and 2,6-Iutidine ............ 88 Scheme 7.6 Oxidation of ester 4.16 with 0804 and oxone in DMF .................. 88 Scheme 7.7 Direct oxidation of dienol 7.3 with 0304 and oxone in DMF ........... 89 Scheme 8.1 Desilylation of arene 6.5 with TBAF ......................................... 92 Scheme 8.2 Desilylation of TIPS-protected butanol 8.1 in presence of 6.17 ...... 95 xviii L. figaflesllyletlon of the unprotected arene 13.108 QMIation of the fully protected amidophenol 8. 4112 '1Lszfidg‘ ‘.0 ..I uh ”I: 9‘13;th '. ... ' I ...,”1 #2 ‘E’f" :4 :o Orv/{,1 .-.. l' n . I , . ‘ “3' r . ._ ..\ O- ‘ %Y_fytirny.flr. I" I . - .-( 0n- 0 a 0' G r: 7. O O J ..‘I‘ ’D «.../u I . . . I - . . - + p . _ l ' us“. :f ,r‘} : r- - .I-If . ‘ .o L 55‘ | V . 1 O L c aII""~"’- m ‘ . r .f.. a." . ::-.:5:s:*.,«'4fzt‘.\~. \ '..4- '. ..., Chapter 1. lntroductlon 1.1 Autolytimycin - The Target Natural Product Over the last few decades, several natural products from the ansamycin superfamily have been isolated. Ansamycins are antibiotics possessing an aromatic or a quinone core with a non-adjacent aliphatic ansa-bridge. Some of the family members are the geldanamycins,"4 the macbecinsf"6 the trienomycins}8 and the herbimycinsf'” many of which exhibit significant cytotoxic and anti-cancer activity through inhibiting heat shock protein 90 (HSP90), a chaperone protein that is essential for the non-covalent folding and unfolding of several growth proteins.3'15 Autolytimycin is a relatively new ansamycin family member; it was first isolated in 2000 from the fermentation broth of Streptomyces sp. 86699, together with the already known reblastatin.1 It was isolated again in 2001, this time from Streptomyces Auto/yticus JX-47, and was given the name autolytimycin.2 Autolytimycin has been shown to inhibitit the oncostatin M signaling pathway that promotes cartilage degradation, which is known to induce arthritis in mice, and along with other ansamycin family members, also inhibits heat shock protein 90 (Hsp90).‘-“'16 Structurally autolytimycin consist of a disubstituted phenolic core, with an unsaturated amide in the three-position and an aliphatic chain in the five position. These together form the 19-membered macro-lactam, which is referred to as the ansa-bridge (Figure 1.1). The ansa-bridge has stereocenters at carbons 6, 7, 10, 11, 12, and 14. These six stereocenters consist of two methyls, two methoxys, one hydroxyl and one carbamide functionality. Other than the E—unsaturated amide, autolytimycin contains an additional site of unsaturation, the trisubstituted E-olefin between carbons 8 and 9. Autolytimycin has the same stereochemistry in the ansa-bridge, as its family member reblastatin. These two natural products differ only by a methoxy substituent on the aromatic core, Fi‘ (Figure 1.1). The stereochemistry of reblastatin was confirmed by total synthesis, reported by Panek and co-workers in 2005.17 Flgure 1.1 Autolytimycin and reblastatin R1 = H autolytimycin R1 = OMe reblastatin Autolytimycin, as mentioned, has an aromatic core with three ortho/para- directing groups, meta to each other. This is a structural motif difficult to obtain through conventional aromatic chemistry. Other ansamycin family members, also containing this structural motif, are the trienomycins A-E, which were isolated from the culture broth of Streptomyces sp. No. 83-16 in 1985.8 The most active of the trienomycins, trienomycin A, shows cytotoxicity against several cell lines and was synthesized together with trienomycin F7 by Smith and co-workers in 1996.1"'19 Scheme 1.1 Smith’s preparation of the aromatic core of trienomycins A and F N02 0M6 OH LiOMe acetic acid, HBr I :L HMPA,98%V L 1 o. 7 J: 1 H020 No2 H020 N02 79/ H020 N02 OH OH BH3-THF CBr4, PPh3 PhSOzNa _——_—.p > > THF, 60% HO THF, 85% gr DMF, 60°C N02 N02 75% OH OBPS \D BPSCI \0 H2. Pd/C PhOZS N02 imidazole,DMF Ph02S N02 won, 100% 95% o OBPS #0 OBPS MeO = Y PhOZS NH2 AIM:%.°§36H6 PhOQS fi/lKA/OH o In Smith’s total syntheses of trienomycins A and F, the aromatic core, with the amide in place, was prepared from the commercially available 3,5- dinitrobenzoic acid in eight steps (Scheme 1.1).""20 This accounts for approximately one third of the total linear steps, in the otherwise efficient total syntheses of trienomycins A and F (Scheme 1.2). Scheme 1.2 Syntheses of trienomycins A and F N02 8 steps H020 N02 —————>PhOQS OH R = / NH HO O Ro" \ \ \ 0M9 R = OBPS O OMe 14 steps ——> N OH ———> H O 0.1,, W H (+)-trienomycin A O W H (+)-trienomycin F The same method to generate this aromatic core was later used by Blagg and Peng in their preparation of derivatives of the trienomycins.21 Their aim was to develop a library of trienomycin analogs, which could be used to investigate structure/activity relationships. However, amongst the eight examples of macrocycle formation in their study, only one contained the phenolic core (Scheme 1.3). Scheme 1.3 Synthesis of trienomycin analogs OBn Grubb's first 7 generation catalyst Grubb's first ' generation catalyst \ cisrtrans, 1 :1 mixture of isomers (39%) mixture of isomers (37%) OBn OBn NH + \ 0 cisztrans, 1 :1 (19%) NH NH 0 + \ o cisztrans, 1 :1 (26%) \ Many other ansamycin analogs have been prepared for structure/activity relationship studies towards anti-cancer activity, some of which have progressed it to clinical trial lll.‘5'2"’-"26 Most of the efforts to study the biological activity of these molecules have been for the inhibition of HSP90, however macbecin | and II, geldanamycin, and geldanamycin derivatives have also been investigated as Met receptor signal transduction pathway inhibitors.27 Genetic engineering of cell lines producing these HSP90 inhibitors has been a common method to access many derivativeSF’e“29 Progress towards compounds with lower hepatotoxicity than geldanamycin has been made."-4 The benzoquinone core of geldanamycin is believed to be the cause of this hepatotoxicity. Analogs with a phenolic or hydroquinone core have been made and studied for their HSP90 inhibition, some of which show stronger binding than geldanamycin.15 The ansamycin family of natural products has shown important biological activity in the treatment of cancer and tumor growth. It is thus important to be able to readily access this family of compounds and their derivatives. In addition to their biological significance, these complicated natural product represent a considerable challenge for their total syntheses, and opportunities to demonstrate the utility of synthetic methodology on advanced systems. 1.2 Geldanamycin Family Members and Their Total Syntheses As mentioned previously, autolytimycin belongs to the geldanamycin family, a sub-family of the ansamycin superfamily. In addition to autolytimycin and geldanamycin, the geldanamycin family also consists of the herbimycins, the macbecins and reblastatin, all of which are structurally very similar (Figure 1.2). Figure 1.2 The geldanamycin family members R1 = H autolytimycin OMe Me OMe herbimycin A OMe H OMe herbimycin B OMe herbimycin C R1 = OMe reblastatin OMe Me Me macbecin l IIIII i OMe Me Me macbecin Il (hydroquinone) OMe H H OMe geldanamycin A common feature of these natural products is a phenolic or benzoquinolic core with a 19-membered ansa-bridge in meta position to each other. Geldanamycin, the herbimycins and the macbecins contain a doubly unsaturated E,Z-amide and a benzoquinone core, except for macbecin II, which has a hydroquinone core. Geldamycin, as well as reblastatin, contain an additional methoxy group on the aromatic core, R‘. The substituents on the ansa-bridge at carbons 6, 11 and 15 differ between hydrogen, methoxy, methyl and hydroxy groups in these natural products. However, the stereochemistry at these carbons is assumed to be the same. Several of the ansamycin family members have succumbed to total synthesis by different groups.‘30 1.2.1 Total Synthesis of Reblastatin Reblastatin, which is structurally most similar to autolytimycin, has one reported total synthesis, published in 2005 by Panek and co-workers. The aromatic core was obtained in several steps from 2,3-dihydroxybenzaldehyde. The amide functionality on the aromatic core and the closure of the 19- membered macrolactam was to be established in the end of the synthesis through a copper(I)-mediated amidation (Scheme 1.4). Scheme 1.4 Retrosynthesis of reblastatin by Panek and co-workers copper(l)-mediated 0H amidation MeO BO 1 / C:>crotylation , ,1/ —’ OPG MeO 11’ H O crotylation 1":\ To assemble the E—trisubstituted olefin, a stereoselective zirconium E-vinyl zirconium coupling coupling between the methyl alkyne and the aldehyde was intended. The stereochemistry of carbon 6 was obtained from the chiral pool, more specifically from L-glutamic acid.31 The stereochemistry at carbon 14 was to be set with a crotylsilane32 and at carbon 12 with a substrate controlled hydroboration. The last two stereocenters at carbon 10 and 11 were to be set simultaneously through a crotylation with a crotylboronate.33 The total synthesis of reblastatin by Panek and co-workers, is significantly different in its approach, than that of many of its family members. Two elaborate pieces were prepared and assembled together late in the synthesis. Several of the reported total syntheses of reblastatin’s family members suffer from linearity in the preparation and installation of the ansa-bridge. 1.2.2 Total Synthesis of Geldanamycin Geldanamycin was isolated in 1970 from Streptomyces hygroscopicus and is a heat shock protein 90 (Hsp90) inhibitor."3 Inhibition leads to cell cycle disruption. Therefore, geldanamycin and its analogs are interesting targets for total synthesis. However, only two total syntheses of geldanamycin have been reponed. Scheme 1.5 Retrosynthesis of geldanamycin by Panek and co-workers OPG copper(l)-mediated amidation MeO l tion 0 annu 3‘“ Br 0 I W] l:> “vii + ROMS OPG \5 alkynation and M90 11; \ reduction 4;..VerHO OCONH2 crotylation OPG Panek and Oin recently reported the second total synthesis of geldanamycin.34 This enantioselective synthesis was reported in 2008 and is synthetically similar to their synthesis of reblastatin (vide supra). The amide and the macro cycle were installed in the same way, through a copper(l)-mediated coupling (Scheme 1.5). The stereocenter at carbon 6 was set through a zinc- mediated addition to an alkyne. A crotyI-silane, similar to the one used for reblastatin was used here also to set the stereocenters at carbons 7, 10 and 11. For the stereocenters at carbons 12 and 14 another crotyl-silane was used for a [4+2]-annulation with 3-bromo-2,5-isopropoxy-6-methoxybenzaldehyde, which was obtained from the commercially available 2-methoxyhydroquinone in three steps. The first total synthesis of geldanamycin was reported in 2002 by Andrus and co-workers with a demethylation quinone-forming oxidation as a last step to obtain the aromatic core, which started from 2,5-dimethoxy anisole.35'36 Key steps in this linear synthesis were a macrolactam formation and two glycolate aldol reactions to install the stereochemistry of the ansa-bridge (Scheme 1.6). Scheme 1.6 Retrosynthesis of geldanamycin by Andrus and co-worker macrolactam formation H0201 anti-glycolate aldol The stereochemisty at carbons 6 and 7 was installed through a syn- glycolate aldol reaction, using a norephedrine ester.37 Another glycolate aldol reaction, an anti-glycolate aldol reaction with bisaryldioxanone was used to install the stereochemistry at carbons 11 and 12.3”9 The other two stereocenters, 10 and 14, were installed through a substrate directed hydroboration and an Evans’ asymmetric alkylation, respectively. 1.2.3 Total Synthesis of Macbecin l Macbecin l was isolated almost three decades ago from the culture broth of Nocardia sp. No. C-14919."o It is structurally very similar to geldanamycin with its quinone core and 19 membered lactam. Differences between the two natural products are that macbecin I lack the methoxy substituent on the aromatic core, though it has an additional methoxy on carbon 15. Another difference is the presence of a methoxy substituent at carbon 11, where geldanamycin has a hydroxyl group. Since its isolation in 1980, macbecin I has succumbed four total syntheses and two formal syntheses reported by different groups. The first total synthesis was reported in 1989 by Baker and Castro."‘-"2 Their synthesis uses para- methoxyphenol as the starting material for the aromatic core and installs the nitrogen at position 2 as a nitro-group and the carbon substituent at position 6 as an aldehyde. Scheme 1.7 Retrosynthesis of macbecin l by Baker and co-worker l l bl:\> koreoms OMe\ + macrolactam formation OMe I TBDMSO Evans €10 aldol I... cuprate mediated Sharpless asymmetric epoxide opening epoxidation A key step in Baker’s synthesis is the late stage macrolactam formation between an aniline derivative and the tethered carboxylic acid, a very similar 10 approach to the lactam formation used by Andrus in the total synthesis of geldanamycin. However, to reduce the linearity of the synthesis, Baker successfully brought together two elaborate segments to form the ansa-bridge with a higher order cyano-cuprate mediated addition of a vinyl iodide and an epoxide (Scheme 1.7). The epoxide was generated through a Sharpless asymmetric epoxidation, setting the stereochemistry at carbons 10 and 11. The other stereocenters at carbons 6, 7, 12, 14 and 15 were set with the aid of Evans’ chiral auxiliaries. An Evans’ aldol reaction was used for the formation of the carbon 6-7 and 14-15 bonds, thus setting the stereochemistry of the methyls, methoxy and the carbamate. An a-hydroxylation of 2-benzenesulphonyl-3- phenyloxaziridine was used to bring in and set the stereochemistry of the oxygen at carbon 12. Shortly after Baker’s total synthesis of macbecin I, an approach to its ansa-bridge was reported by Kallmerten and co-workers.43 In their racemic synthesis, the stereocenters at carbons 10, 11 and 14 were set with two [2,3]- Wittlg rearrangements, both with high diasterioselectivity. This method was used to synthesize a late stage intermediate reported in Baker’s total synthesis, thus completing Kallmerten’s formal synthesis of macbecin l. Another late stage intermediate in Baker’s synthesis was in 1992 synthesized by Martin and co-workers."""’5 This linear approach to the ansa-brige involved a substrate directed oxidation of a chiral furan to a hydropyranone, albeit with a low 3:1 diastereoselectivity (Scheme 1.8). Even though the fl-diastereomer 11 could be recycled, this synthesis has other selectivity problems. The reduction of the ketone at carbon 12 provided the wrong diastereomer of the alcohol. Alternative conditions for a Mitsunobu reaction were explored using p- nitrobenzoic acid to invert the alcohol. The desired alcohol was then obtained in 80% yield and could be transformed over several steps to a late stage 41.42 intermediate reported by Baker and co-workers. Scheme 1.8 Formal synthesis of macbecin l by Martin and co-workers 0 O / 5‘ x 5' x (Mm 1) Br2, aq. MeCN‘ 12 N MezCuLi, TMSCI‘ 12 N - O O 7 O O 2) TBDMS-OTf 3 97% ‘ 2,6-lutidine OTBDMS OTBDMS 67°/o OMe OH 1)NaBH4,CSA 12 9 __. - -——> ' O OH —-> 2) DlBAL-H , 71% OTBDMS ii OTBDMS Me Ph The second total synthesis of macbecin l was reported by Evans and co- workers.“"’7 As in Baker’s synthesis they established their aromatic core from 2,5-dimethoxy-3-nitrobenzaldehyde and used a macrolactamization to form the amide bond Other key transformations used, were their own aldol-chemistry and a Horner-Emmons olefination (Scheme 1.9). 12 Scheme 1 .9 Retrosynthesis of macbecin l by Evans and co-workers OMe Evans macro- lactamization aldol MeO — Horner- ______ x o Elmgnons 14 ‘ 1 oeI nation ‘ P OCH CF M /:> O OMejOMeo/ILH/Vg ( 2 3)? "I- N O OMe T880 0 . I H «=- - Me \ Evans \ Evans aldol aldol Panek and co-workers reported a linear total synthesis of macbecin l in 1995, where they used p-methoxyphenol as the starting material for the aromatic core. As most previous syntheses they used a macro-lactamization to close the 19-membered macrocycle (Scheme t.10).“’-"9 Six of the seven stereocenters were installed through chiral crotylation chemistry. The seventh stereocenter at carbon 12 was installed through a substrate directed hydroboration. Scheme 1.10 Retrosynthesis of macbecin l by Panek and co-workers OMe O macrolactamization chiral crotylation M o Wittig \? ..... olefination l 5 OCONH Chll'al/ \L5/ 2 crotylation 0 pM BO 5— chiral crotylation The most recent total synthesis of macbecin l was reported in 2008 by Micalizio and Belardi.50 The quinone core was generated through a late stage 13 CAN (cerium ammonium nitrate) oxidation of a dimethylated hydroquinone core, which was obtained from 4-methoxy-2-nitrophenol and installed as reported by Cossy and Tatsuta in their total synthesis of herbimycin A (vide infra).51 As in many other total syntheses of macbecin and its family members the unsaturated amide and the macrocycle were generated through a late stage macro- lactamization between an aniline moiety and the tethered carboxylic acid (Scheme 1.11). Scheme 1.11 Retrosynthesis of macbecin l by Micalizio and co-workers 0 macrolactamization 0M9 Sonogashira 0 coupling MeO 7 O NH2 H ,/ :> Myers , OMe + \ ~,\ 1 OMe alkylation ‘ x- , Mex/nit..— OCONH2 .2Nropargylatlon — \‘ \ titanium-mediated \8 reductive coupling In their synthesis Micalizio brought together two relatively elaborate pieces through a titanium-mediated reductive coupling of a substituted alkyne and an aldehyde to form the trisubstituted E—alkene. The left-half, containing carbons 8 through 15 of the ansa-bridge, was linearly constructed before coupling with the aromatic core. The stereocenter at carbon 12 was installed through a Myers alkylation, forming the carbon 12—13 bond.52 The carbon 10-11 bond was formed through a diastereoselective propargylation with a chiral allenyl stannane, simultaneously setting those stereocenters, albeit with low 4:1 diastereoselectivity. The stereocenter at carbon 6 in the right-half was installed 14 A through a palladium-catalyzed asymmetric propargylation between a chiral alkyne and a a-silyloxy acetaldehyde (d.r. 5:1 antizsyn). A Sonogashira coupling, followed by Lindlar reduction was used to form the two conjugated olefins and the carbon 3-4 bond. 1.2.4 Total Synthesis of Herbimycin A Herbimycin A is structurally very similar to macbecin l, except for a methoxy at carbon 6 instead of a methyl group (Figure 1.2, vide supra). It was isolated in 1979 from the fermentation broth of Streptomyces hydroscopicus strain AM-3672.13 Herbimycin A is, as other members of the geldanamycin family, an inhibitor of Hsp 90. Since its isolation, herbimycin A has succumbed to three total syntheses. In 1991, Tatsuta and co-workers reported the asymmetric total synthesis of herbimycin A starting from D-mannopyranoside for the ansa-bridge and 3- bromo-2,5-dimethoxyaniline for the aromaticcore.”54 In their linear synthesis, the 19-membered macrocycle was envisioned to be closed through yet again a macro-lactamization of an amino acid derivative, and the ansa-bridge would be installed through a substrate controlled addition of the lithiated arene (Scheme 1.12). Carbon 10-15 of the ansa-bridge and the stereocenters at carbons 11, 12, and 14 were to be obtained from the starting material, o-mannopyranoside. The other three stereocenters at carbons 6, 7, and 10 were to be set with an asymmetric allylation and a stereoselective hydroboration, respectively. The hydroboration gave higher diastereoselectivity when BHa-SMe2 was used instead 15 of an alkylated borane reagent. The trisubstituted double bond was to be installed through a Corey-Schlessinger olefination.55'56 Scheme 1.12 Retrosynthesis of herbimycin A by Tatsuta and co-workers OMe Cram- selective addition 0 macrolactamization /o Wittig Jam olefination Br NHTr M60 [\5/ OMe ' I’ ’ ’ ‘_—_4> l Brown's e MeO g/allylation Corey-Schlessinger olefination More than a decade after Tatsuta’s synthesis, the second total synthesis of herbimycin A was reported by Panek in 2004.57 Panek’s synthesis is very similar to their previously reported total syntheses of the geldanamycin family (Scheme 1.13). As with macbecin I, p-methoxyphenol was used as the starting material for the aromatic core. The ansa-bridge was installed through a chiral crotylation and the macrocycle was closed with a macro-lactamization. The carbon 6-7 bond and its stereochemistry was installed through Brown’s allylation; this methodology was also used in Tatsuta’s synthesis of the same molecule. 16 Scheme 1.13 Retrosynthesis of herbimycin A by Panek and co-workers OMe . ' chiral 0 macrolactamizatIon crotylation VI—O MeO Horner—Emmons \ _ _ - - MeO ‘ M olefination - \ - J--/ :> s" I 5 M90 . OMe , OCONH2 chiral / | \ j\/O é crotylatIon ‘. ’ pM BO \.5_ Brown's allylation The most recent total synthesis of herbimycin A was reported in 2007 by Cossy and co-workers.51 To construct the aromatic core, they started with the commercially available 4-methoxy-2-nitrophenol and used the same methods as Tatsuta to attach the ansa-bridge, close the 19-membered macrocycle, install the stereochemistry at carbons 6-7, and the trisubstituted double bond (Scheme 1.14). Carbons 13-15 and the stereochemistry at carbon 14 were obtained from the Roche ester starting material. Carbon 12 was stereoselectively installed through an allyI-titanation, and the Z—double bond of the dienoate was obtained through a ring-closing metathesis (RCM). Scheme 1.14 Retrosynthesis of herbimycin A by Cossy and co-workers OMe O macrolactamization steregsielective _ a d tion \ Wittig olefination ...}. K Br N1‘\1“fi RCM OMe Brown's . 14 o H _ __1_/ I allylation 5 I: > OMelV‘eo OMe Meo‘» 7 14 11' . [7/751/KOTBDMS :1 MeO \5 crotylation OCONH2 o’ Corey-Schlesslnger olefination 17 Many of the syntheses of the geldanamycin family members feature similar methodologies to build the ansa-bridge and to establish the stereochemistry. Several of these syntheses suffer from linearity, and therefore, lack of efficiency and the opportunity to easily alter the synthesis and the structural features of the molecule. 1.3 Our Retrosynthetic Analysis of Autolytimycin To design an efficient and non-linear synthesis of autolytimycin, we needed late-stage couplings of highly elaborated segments. To do this, we planed to utilize the C—H activation/borylation/amidation/oxidation methodology56 developed in our laboratories (vide infra) as the key step in forming the aromatic core of autolytimycin. Scheme 1.15 Our retrosynthetic analysis of autolytimicin 0P63 0 Suzuki / Coupling MeO 5 \ OPG2 autolytimycin 1.1 OPG 3 o O \ C-H H2N / 14 GOMG X1 N / activation/ .. H 5 borylation/ MeO 5 ’0PG1 + Mac I > 0 + amidation/ X1 X2 \ OPG2 ,. \ OPGz oxidation 1,4 1.5 1.3 18 In our retrosynthetic analysis, we envisioned that a ring-closing metathesis59 (RCM) could close the macrocycle and simultaneously form the E- trisubstituted olefin from acyclic precursor 1.1 (Scheme 1.15). A late-stage Suzuki cross-coupling60 between the sp3-boronate 1.2 and a suitable aryl electrophile 1.3 could bring the two halves of autolytimycin together. The aromatic core in 1.3 could be accessed through the C-H activation/borylation/amidation/oxidation sequence from the dihalogenated arene 1.4 and amide 1.5. The left side-chain of the molecule 1.2 was to be installed after the one-pot sequence since the amidation has been shown to work best for electron deficient arenes.58 Our approach could thus generate the aromatic core of autolytimycin in only four steps; three of which would take place during the one-pot borylation/amidation/oxidation sequence. The total synthesis of autolytimycin was started by Dr. Feng Shi in our laboratory and continued together with Mr. Luis Sanchez. Although Dr. Shi had previously synthesized amide 1.5,61 a shorter and more efficient route was developed in this work, in addition to an investigation of other routes to amide 1.5. The strategy of these efforts and the subsequent findings will be discussed in this dissertation. It was very unfortunate that during the course of these endeavors, the first total syntheses of autolytimycin was reported by Panek and co-workers in April 2010.62 However, they again utilized the same approach towards autolytimycin (Scheme 1.16) as they had for their total synthesis of reblastatin (Scheme 1.4). 19 These two compounds only differ by a methoxy substituent on the aromatic ring. In the total synthesis of reblastatin, Panek and co-workers synthesized the aromatic core from 2,3-dihydroxybenzaldehyde.62 For autolytimycin the aromatic core was prepared from 3,5-dibromophenol. Scheme 1.16 Retrosynthesis of autolytimycin by Panek and co-workers copper(l)-mediated OH amidation OPG Wittig — O 0 1.1/ E101 "s’ 1 / crotylation ’,-— Br ‘ — ...v + 5 5 :> . 14 MeO 11 7 M60 LPG H o , OCONH2 :‘37 \crotylation E-vinyl zirconium coupling 20 Chapter 2. C-H Actlvation/Borylatlon 2.1 C-H Activation/Borylatlon/Amldatlon/Oxldatlon As mentioned earlier, to accomplish the total synthesis of autolytimycin, we plan to install the aromatic core via the iridium-catalyzed borylation of a 3,5- disubstituted arene. In 2006 our group reported a one-pot C-H activation/borylation/amidation/oxidation sequence, which provided access to 5- substituted amidophenols in three steps without isolation of any intermediates.58 In that report, it was shown that 3-substituted aryl bromides could be borylated in the 5-position and subsequently undergo a Pd(O)-mediated amidation at the bromide, followed by an oxidation of the boronic ester to the phenol (Scheme 2.1). Scheme 2.1 Three-step, one-pot synthesis of 5-substituted-3-amidophenols (lnd)Ir(COD), dmpe Bpin ' ji ' R \ ll HBpIn or 11 R R 3' [Ir(OMe)(COD)]2 R Br Pd2d%:3'ggmph°s t . 2 3 d bpy, HBpIn Bpin OH O O 1) filtration Q 0 R NJLR" 2) oxone, NalO4 Fl NJLFI" R' B' NC£EHLNNNZ N£EHLN° :5“ FC£:HLNJOL JLNBN2 C,£O:LN° £1/A 82 % 46 % 55% 66% 21 Autolytimycin contains an unsaturated amide; the use of an unsaturated amide in the amidation step in the above sequence has previously been shown to proceed in good yields (Scheme 2.1).58 At the inception of this project, autolytimycin had never been obtained through total synthesis, nor had our three- step sequence been used in a total synthesis of a natural product. Our goal, thus, was to develop a total synthesis of autolytimycin, using our C-H activation/borylation/amidation/ oxidation protocol as a key step. 2.2 C-H Activation/Borylatlon, C-H Activation/Borylatlon/Oxldatlon and C-H Activation/Borylation/Amldation/Oxldation - Scale Up Studies Boronic esters are frequently used reagents in organic chemistry. They are commonly used in different C-C bond formations through direct cross- coupling reactions.63 They can also be transformed into more reactive boron species for cross-coupling reactions.“65 Additionally, they can form C-Halogen bonds,66 C-N bonds,67 and C-O bonds such as aryl ethers67 or alcohols?" To showcase the utility of our C-H activation/borylation methods, it was desired to perform these reactions on a larger scale than on our standard 2 mmol scale. Initially we wanted to demonstrate that our protocols: The C-H activation/borylation“, the one-pot C-H activation/borylation/oxidation’a, the one- pot C-H activation/borylation/amination’7 and the one-pot C-H activation/borylation/amidation/oxidation58 worked on a 10 gram scale under the previously reported conditions. 22 Table 2.1 Multi-gram C-H activation/borylations l (lnd)Ir(COD), dmpe HBPin, 150 °C or ll (lnd)Ir(COD), dppe BPin \ HBPin, 100 °C or \ Q t > |// R III [lr(OMe)COD]2, d bpy R 2-1 pentane or o-hexane, rt 2-2 HBPin or B2Pin2 Entry Substrate Scale Product Method Time Yield (%)8‘ BPin 1 D 10 9 D I 6 h 91 81' (59 mmol) 81' 2.18 2.28 BPin Br Br (24 mmol) Br Br I l 2.1b 2.2b BPin 3 O 10 g D II 36 h 84 Br Br (42 ”117101) Br Br 2.1c 2.2c BPin i3 CI 2.1d 10 g 0 l 12 h 79 0M9 (70 mmol) Cl 0M6 2.211 10 g mBPin 111° 1.5 h 96 (75 mmol) S 2.19 2.2a 0'1 03; g Reaction conditions: Method I) To a solution of lnd(lr)COD (0.02 equiv) and HBPin (1.5-2 equiv), dmpe (0.02 equiv) and arene (1 equiv) were added. The reaction was heated under nitrogen in an oil bath at 150 °C. Method II) To a solution of lnd(lr)COD (0.02 equiv) and HBPin (2 equiv), dppe (0.02 equiv) and arene (1 equiv) were added. The reaction was heated under nitrogen in an oil bath at 100 °C. Method I”) To a solution of [lr(OMe)COD]2 (0.01 equiv) and BzPinz (1 equiv) or HBPin (1.2 equiv) in cyclohexane or pentane, dtbpy (0.02 equiv) and arene (1 equiv) were added. The reaction was stirred under nitrogen at room temperature. 8 Isolated product on a single run. b) BzPinz in ohexane was used. c) HBPin in pentane was used. One problem here was that the reported conditions for several of the borylation reactions used a closed system; a closed air-free flask heated at 100 °C or 150 °C in an oil bath (Table 2.1, method I and II). These methods create pressure in the reaction vessel, which is not ideal at large scale. The initial plan was to use [lr(OMe)COD]2 and d‘bpy (Table 2.1, method III), instead of (lnd)Ir(COD) as the catalyst and dmpe or dppe as the ligand, which were used in the reported system, but run the reaction in cyclohexane and under a nitrogen atmosphere at 80 °C. Under these conditions the borylation of 3- bromotoluene proceeded with long reaction times, incomplete conversion and therefore, a low isolated yield. Thus, we went back to the initially reported conditions, only changing the fact that on large scale the reactions were run under nitrogen atmosphere in a three-necked round-bottom flask equipped with a reflux condenser. Under these conditions, good to excellent yields were obtained (Table 2.1). The reactions heated at 150 °C in an oil bath, were actually refluxed in HBPin (bp~130 °C). The scale up of the one-pot borylation/oxidation reactions was performed as described above for the borylation step. The oxidation was subsequently performed with oxone as previously reported.76 All phenols were isolated in moderate to good yields (Table 2.2). 24 Table 2.2 Multi-gram C-H activation/borylation/oxidations l (lnd)Ir(COD), dmpe HBPin, 150 °C or BPin OH ll (lnd)Ir(COD), dppe oxone 0 HBPin, 100 °C or A I \ acetone/H20 ‘ I \ FI// III [lr(OMe)COD]2, dtbpy // rt, 7-10 min // 2 1 BzPinQ, c-hexane, rt R 2.2 R 2 3 Entry Substrate Scale Product Method Time Yielg (mmol) (34.) OH 1 D 14 g D I 6 h 81 Br (82 mmol) 2.1a 2.3a 8' OH 2 13 9 III 3 h 74 Br Br (35 mmol) Br Br I 2.1b 2"!” OH 3 O 14 g D II 36 h 69 Br Br (60 mmol) 2.1c Br 2 3c Br OH 4 O 14 g D I 9 h 71 ' 2.3d OH 27 5 19 g l 13 h (2.3f’) C1 Cl (109 mmol) C1 Cl OMe 55 OH H 201' R = H, 2.3fl (203‘ ) R = Me, 2.31" Reaction conditions: Method I) To a solution of lnd(lr)COD (0.02 equiv) and HBPin (1.5-2 equiv), dmpe (0.02 equiv) and arene (1 equiv) were added. The reaction was heated under nitrogen In an oil bath at 150 °C. Method II) To a solution of lnd(lr)COD (0.02 equiv) and HBPin (2 equiv), dppe (0.02 equiv) and arene (1 equiv) were added. The reaction was heated under nitrogen in an oil bath at 100 °C. Method lll) To a solution of [lr(OMe)COD]2 (0.01 equiv) and BzPinz (1 equiv) in cyclohexane, dtbpy (0.02 equiv) and arene (1 equiv) added were. The reaction was stirred under nitrogen at room temperature. When the borylation was complete, the volatiles were removed under reduced pressure. The crude boronic ester was dissolved in acetone and an aqueous solution of oxone (1 equiv) was slowly added. The resulting slurry was stirred for 7-10 min at room temperature open to air. a Isolated product on a single run. 25 The C-H borylation/oxidation of 2,6-dichl0roanisole 2.1f (Table 2.2, Entry 5) gave us two products: The expected diol 2.31” as the minor product and anisole 2.3 ” as the major product, where the methoxy group was still intact. It was observed while performing the borylation step that two products were formed, which were the corresponding boronic esters. Unfortunately, these boronic esters were inseparable by silica gel column chromatography. Although the reported one-pot C-H activation/borylation/oxidation protocol proved to be scalable, an alternative to oxone as the oxidant of the boronic ester products was desirable. This is due to the salt stream, subsequent tedious work- up, and the large solvent volumes generated with oxone. Studies towards oxone alternatives will be discussed later in this dissertation. - Scheme 2.2 Scalable ipso-substitution 0f chloro- and fluorobenzenes Ci OPMB OH t TFA, toluene BuOK, PMB-OH 1,3-dimethoxybenzene Cl CN NM P, 40-50 °c is. cm 50-70 °C 7 c. CN 2.4 25 2.6 75% F OPMB OH MsOH, toluene ‘BuOK, PMB-OH 1,3-dlmethoxybenzene Y Br THF, 50-60 °C Y Br 5 °C Y Br 2.7 Y = CI 2.9 Y =, CI, 93% 2.11 Y = Cl, 81% 2.8 Y = Br 2.10 Y = Br, 93% 2.12 Y = Br, 84% Since this scale-up study, Cooper and co-worker reported the ipso- substitution of 3,5-disubstututed chloro- and fluorobenzenes (Scheme 2.2).78 In their report, they stated the need for 3.5-disubstituted phenols such as 2.6, 2.11, and 2.12, and referring to our work as “A recent report describing the 26 preparations of 2.1279 by C-H activation has also surfaced. Notwithstanding, experimental details for larger scale synthesis, and more generally, descriptions of synthetic approaches readily amenable to scale-up are quite limited”. The reported reactions were performed on kilogram scale and afforded the desired phenol in high yield (>75%). However, only four examples were provided, all with electron withdrawing groups and the reaction conditions are harsh. in addition, the use of strong base limits the functional group tolerance. Despite the need for continued improvement to the oxidation step, the scalability of the C-H activation/borylation/oxidation was deemed successful enough to explore the full C—H activation/borylation/amida-tion/oxidation sequence at scale. However, performing the one-pot C—H activation/borylation/amida-tion/oxidation sequence on a larger scale has not yet been successful. All attempts to run the amidation on a 1-gram scale with 3- bromotoluene 2.1a or 3-bromobenzonitrile (56 mmol) and acetamide failed, even when a Fisher-Porter bottle was used to recreate the pressure obtained in the originally reported amidation procedure.58 These multi-gram amidation reactions were very sluggish and afforded mixtures of products that were difficult to separate. The origin of these setbacks are unknown at this time, however, in the originally reported conditions distilled HBpin was used. For the multi-gram reactions HBPin stabilized with 1% TEA was used. It is possible that the residues of TEA complicate the amidation step of this sequence. Further exploration of this reaction is needed to fully understand the influence of the TEA. 27 Chapter 3. Oxidation of Boronlc Esters to Phenols 3.1 3,5-Dlsubstltuted Phenols 3,5-Disubstituted phenols are, as previously mentioned, difficult to obtain through conventional electrophilic aromatic substitution chemistry, especially with ortho/para directing substituents. Successful systems that provide access to these phenols are very rare in the literature. 3-Bromo-5-chlorophenol for example, can been obtained from the ipso-substitution of 3-chloro-5- flourobromobenzenem-E’O'81 or from the bromination/de-bromination of 3- chlorophenol.82 To the best of our knowledge, there is only one other general procedure for obtaining 3,5-dihalophenols, which was reported in 1926, started with trinitrotoluene (TNT) and required 10 steps.83 in 2003, our group reported a one-pot C-H activation/borylation/oxidation sequence, which provided access to such 3,5—disubstituted phenols in an efficient manner.76 Later, Botting and co-workers reported the formation of electron rich 3,5-disubstituted phenols from resorcinol derivatives.84 They used a protocol very similar to our one-pot C-H activation/borylation/oxidation sequence, with [lr(OMe)(COD)]2, d'bpy, and BzPinz for the borylation step, and oxone for the oxidation of the boronic ester to the phenol. This system is not different than ours, and no significant improvements have been made. Additionally, they run these reactions in sealed air-free flasks at 110 °C. Although the oxidation of the boronic ester with oxone on large scales was successful (Chapter 2, section 2.2), the work-up was very tedious (vide supra). 28 Therefore, we became interested in other oxidants for this transformation. The requirements here were that the oxidant should not only provide for a more efficient work-up than that with oxone, but it should also be compatible with the one-pot C-H activation/borylation sequence. 3.2 Oxidation of Boronlc Esters The oxidation of boronic esters with oxone was initially reported in 1995 by Webb and Levy,68 and was shown in our group to be compatible with our one-pot C-H activation/borylation protocol.76 Other reagents that oxidize boronic esters or acids have also been reported in the literature. Hydroxylamine,69 sodium perborate,7°-71 copper sulfate85 and hydrogen peroxide”74 have all been used to oxidize boronic esters to the corresponding phenols. 3.3 Oxidation of Boronlc Esters with Hydrogen Peroxide As previously reported by Webb and Levy, oxone is an alternative to the alkaline hydrogen peroxide oxidation of boranes.68 However, hydrogen peroxide had never been tested in our system. Therefore, we were interested to see its compatibility with our one-pot C-H activation/borylation chemistry, and see if it was an attractive alternative for multi-gram oxidations. l-le2 was thus used as the oxidant for the boronic esters under a variety of conditions; several alkaline and non-alkaline oxidations were performed (Table 3.1). 29 Table 3.1 Oxidations with H202 vs. oxone BPin OH H202 Br solvent, rt Br 2.2a (1.7 mmol) 2.3a Entry Oxidant Solvent Base Time Ylelds(%)° 1 Oxone acetoneb ' 7 min 90 THF N H 10 m'n 92 2 H202 80 l N 1 ' 92 3 H202 acetone aOH 0 min H2028 acetone - 10 h 83 Reaction conditions: Unless otherwise specified all reactions were performed on a 1.7 mmol scale of 2.2a in 2.7 mL solvent with 1.1 equiv of H202 or 1 equiv of oxone and with 1.1 equiv of base. The reactions were stirred at room temperature open to air for the time specified. a) 2 equiv of oxidant were used. 5.4 mL of solvent was used. c) Isolated yields after column chromatography on a single run. Oxidations with oxone or H202 and NaOH were both fast, and high yielding (Table 3.1, Entry 1-3). However, without base, H202 oxidized the boronic ester in acetone very slowly and afforded a slightly lower yield even when 2 equivalents of of oxidant were used (Table 3.1, Entry 4). With the standard 1.1 equivalents of oxidant, the oxidation in acetone without base did not proceed to completion within 24 h. Acetone was first believed to be a better solvent than THF due to the possible formation of unstable and explosive tetrahydrofuryl hydroperoxide products.”87 The optimal conditions were then used for the oxidation of another halogenated boronic ester 2.2b, and the corresponding phenol was isolated in excellent yield (Scheme 3.1). 30 Scheme 3.1 Oxidation with H202 of boronic ester 2.2b BPin NaOH (1.1 equiv) 0” H202 (1.1 equiv) Br Br acetone, rt, 10 min Br Br I 920/0 I 2.2b 2.3b However, these alkaline oxidations had only so far been performed on small scales. To test the multi-gram feasibility of this process and to obtain larger quantities of 3-bromo-5-chlorophenol, which was being used in the ongoing total synthesis of autolytimycin, the arylboronic ester 3.1 (30 mmol) was oxidized with alkaline H202 in acetone (Scheme 3.2). Unfortunately, this resulted in a yield of only 36% for the corresponding phenol 3.2. Scheme 3.2 30 mmol alkaline oxidation with H202 BPin NaOH (1.3 equiV) OH H202 (1.3 equiV) Cl Br acetone, rt. 17 min Cl Br 36% 3.1 3.2 During the addition of H202 to the multi-gram oxidation the reaction turned hot due to the highly exothermic reaction. As a result the acetone started refluxing and by-products were formed. Thus a low isolated yield of the desired phenol 3.2 was obtained. As such, it became clear that a low boiling solvent, such as acetone is undesirable, particularly if the reaction is to be performed similarly on large scale. Therefore, other solvents were evaluated. Methanol can be used as a solvent during oxidations with H202,88 These reactions are often performed without base. When methanol was used in our 31 system, the reaction was very slow with the standard 1.1 equivalents of the H202 (Table 3.2, Entry 1). Increasing the amount of H202 to 2 equivalents gave full conversion within three hours and also afforded an excellent isolated yield of 94% (Table 3.2, Entry 2). In order to make a direct comparison, a reaction with H202 loadings of 1.1 equivalents was quenched after three hours (Table 3.2, Entry 3). The ‘H NMR of the crude product revealed 89% conversion to the phenol (84% of phenol 2.3a could be isolated). Usefully, employment of the “greener” solvent ethanol, proved to be equally efficient (Table 3.2, Entry 3). Table 3.2 Oxidations with H202 in MeOH and EtOH BPin OH H202 Dar solvent, rt 7 DBr 2.2a (1.7 mmol) 2.3a Entry H202(equlv) Solvent Time Yields (%)a 1 1.1 MeOH 17 h 94 2 2 MeOH 3 h 94 4 2 EtOH 3 h 92 Reaction conditions: Unless otherwise specified all reactions were performed on a 1.7 mmol scale of 2.2a in 7.5 mL solvent with H202. The reactions were stirred at room temperature open to air for the time specified. a) Isolated yields after column chromatography on a single run. ) 89% conversion after 3h by 1H NMR of the crude product. An advantage of oxone was that the oxidation could be performed on the crude boronic ester in the presence of iridium. Therefore, we examined the possibility of using H202 for the oxidation of the crude boronic ester. We tried three working H2O2 oxidation conditions: H202 with NaOH in acetone, in MeOH 32 and in EtOH. In all the three cases, the corresponding phenol was isolated in good yields (Table 3.3). Fortunately, no significant deborylation was seen, even with methanol, which has previously been seen to deborylate boronic esters in our group.89 Table 3.3 Oxidation of the crude boronic ester 2.1a with H202 HBPin (1.55 equiv) Bpin OH (lnd)Ir(COD) 2% D - dmpe 2°/o 0 H202 Br 150 °C,14 h Br solvent, base, rt Br closed system 2.1 a (1.7 mmol) 2.2a 2.3a Entry H202(equlv) Solvent Baseb Time Yleld(%)° 1 1.1 acetonea NaOH 10 min 74 2 2 MeOH - 2 h 78 3 . 2 EtOH - 2 h 78 Reaction conditions: Unless otherwise specified all reactions were performed in a sealed air-free flask on a 1.7 mmol scale of 2.1a neat with lnd(lr)COD (0.02 equiv), HBPin (1.55 equiv), and dmpe (0.02 equiv). The reaction was heated in an oil bath at 150 °C for 14 hours. The volatiles were removed under reduced pressure before the oxidation, which was performed in 7.5 mL solvent with H202 and base. The oxidations were stirred at room temperature open to air for the time specified. a) 2.7 mL of acetone was used. b) 1.1 equiv. of base was used. b) Isolated yields after column chromatography for a single run. To test the multi-gram feasibility of this one-pot C-H activation/boryla- tion/oxidation protocol, 3-bromo-5-chlorophenol 3.2 was generated on a 5 9 scale starting from 3-chlorobromobenzene 3.3 (Scheme 3.3). The reaction was performed in a three-necked round bottom flask under a nitrogen atmosphere. The crude reaction mixture from the borylation step was subjected to solvent removal under reduced pressure before the oxidation. The desired phenol 3.3 was thus isolated in an excellent yield (92%). 33 Scheme 3.3 26 mmol oxidation of the crude boronic ester 3.1 with H202 HBpin (1.25 equiv) ' OH [lr(MeO)COD] 0.50/o BP'" d’bpy 1% D H202 (2 equiv) 0 Cl Br c-hexane, 60 °C, 6 h Cl Br EtOH, rt, 45 min Cl Br 3.3 3.1 3.2 5 9 scale 92 % over two steps (26 mmol) To further ease the preparation of these phenols, we have also made improvements in the isolation process. It was noted that the pinacol by-products could be removed with just a simple water wash. This eliminated the need for column chromatography during the purification step, making the process faster and easier, as well as more environmentally friendly. In addition to the development of an easier work-up, it was also noted that the multi-gram borylation reactions were not as sensitive as previously thought. The reagents could be used as received and weighed out in air; not even the solvents had to be distilled and dried before use, regular reagent grade solvent could be used. As previously described, Cooper and co-workers recently reported a multi- gram protocol to generate 3,5-disubstituted phenols through the ipso-substitution of the corresponding 3.5-disubstituted chloro- or flouro-benzenes.78 To make a direct comparison to their chemistry, we applied our one-pot C-H activation/borylation/oxidation chemistry to one of their targets, 3-chloro-5- hydroxybenzonitrile 3.4 (Scheme 3.4), which they obtained in 75% yield over 2 steps on a 4.4 kg, 25 mol scale. Additionally, we decided to see if we could use the water wash as the only purification method. We initially started with a 19 (7.3 34 mmol) scale of the starting material, 3-chlorobenzonitrile 3.5. The borylation step was performed with 1.5% [lr(OMe)(COD)]2, 3% d'bpy, and 1 equiv B2Pin2, all of which were weighed out in air, and the 3-chlorobenzonitrile 3.5 was used as received. Hexanes was the solvent of choice and used right out of the squirt bottle. The reaction was monitored as before with GC, and it reached full conversion within 3 hours. The volatiles were then removed under reduced pressure and the oxidation was performed as before with 2 equiv of H202 in EtOH. The crude phenol was washed with water and recrystallization was attempted. However, this only resulted in brownish solids, which had to be filtered through a pad of silica gel to obtain phenol 3.4 as an off-white solid (50% yield). To ease the purification in the second attempt, again on a 1 gram scale, a quick filtration of the crude boronic ester 3.6 was performed to remove the iridium before the oxidation. The crude phenol was simply stirred in water, filtered and air dried, the pure phenol 6.4 could thus be obtained in 66% yield. The quick filtration of the crude boronic ester made the isolation of the phenol very easy, as compared to the previous attempt. Therefore, this method was used for the subsequent multi-gram reaction. A 15 g (109 mmol) quantity of 3- chlorobenzonitrile 3.5 was borylated, filtered, oxidized and washed with water to provide phenol 3.4 in 80% yield over the three steps (Scheme 3.4). We were pleased that we could isolate the desired pure phenol 3.4 on a multi-gram scale after only a water wash and filtration, minimizing the use of organic solvents and silica gel column chromatography. 35 Scheme 3.4 Multi-gram C-H activation/borylation/oxidation of 3-chloro- benzonitrile 3.5 dtbpy 3% _ B2Pir‘2 (1 EQUIV) BP'” 1) concentrated OH O ["(M90)COD]2 1-5°/° O and filtered 0 CI CM hexanes' 60 °C cu CN 2) H202 (2 equiv) CI CN open system EtOH rt 3.5 110 min 3.6 100 '. 3.4 159 scale m'” 80% over two steps (109mmol) Throughout the study discussed in this Chapter, it was found that the oxidations of the boronic esters could be performed with H2O2 in excellent yields in both MeOH and EtOH; this eliminated the need for tedious work-ups and large solvent volumes. Most importantly, the crude boronic ester could also be oxidized on a multi-gram scale and the corresponding phenol could be obtained in good yields after just a simple water wash. This new one-pot C-H activation/b0rylation/oxidation protocol provides a very simple and green method to access 3,5-disubstituted phenols in an efficient manner. 36 Chapter 4. Progress in the Total Synthesis of Autolytimycin - The Right Half Amide 1.5 After advancement of our C-H activation/borylation methodology we were now ready to apply it to the total synthesis of the natural product autolytimycin. From our retrosynthetic analysis presented in Chapter 1 for the synthesis of autolytimycin, we had envisioned two equally elaborate pieces, 1.2 and 1.5 (Scheme 4.1). The first goal of the synthesis was to synthesize these two sub- targets. Then, we would explore the one-pot C-H activation/borylation/amidation/oxidation sequence with this elaborate amide 1.5 and a suitable aryl halide 1.4. Thus, amide 1.5 had to be synthesized. Scheme 4.1 Sub-targets in the retrosynthesis of autolytimycin \ opcz autolytimycin 1-5 4.1 Preparation of the Right-Hand Segment - Amide 1.5 To install the stereochemistry at carbon 6 and 7 in amide 1.5, we turned to the chiral pool. L-Threonic acid contains two oxygenated stereocenters, with the required stereochemistry for carbon 6 and 7 of amide 1.5. L-Threonic acid can in turn be readily accessed from vitamin C (Scheme 42).”93 37 Scheme 4.2 Retrosynthetic analysis of amide 1.5 OH OH HO HO 76 6 HO r::{> Ho 7 OH I:> \ 0 OPGQ 0 HO O L—theonlc acid vitamin C We were able to generate the potassium salt of 3,4-isopropylidene L- threonic acid 4.2 in two steps from vitamin C (Scheme 4.3).61 Subsequent alkylation, performed on the crude product, gave the methyl ester 4.3 in good yield. Scheme 4.3 Preparation of methyl ester 4.3 from vitamin C OH +0 ’ H0 00% X AcCl 0 H202, K2003 j Mel o 0 HO ———>H ———> \ O acetone \ 0 H20 0°C tort >OIK 0%?09 MeCN, reflux M60” rt, 85% L0 90% 2 steps HO 0 HO 0 OH vitamin C 4.1 4.2 4.3 Methyl ester 4.3 was then taken on further into the synthesis. The secondary alcohol in 4.3 was protected with a TIPS group to afford 4.4 (Scheme 4.4). TBS was initially used as the protecting group, but was replaced with TIPS as TBS caused problems further on in the synthesis.61 Ester 4.4 was then subjected to a methyl Grignard addition, which was followed by dehydration using thionyl chloride in pyridine to form the 1,1-disubstituted olefin 4.6 in good yields. 38 Scheme 4.4 Formation of olefin 4.6 from a-hydroxy ester 4.3 >4O MeMgl o TIPS-Cl, DMAP 0 M90” DMF, rt, ON, 90% ’ M90” ether, 45 °C, , 40 min, 88% 0 OH 0 OTIPS 4.3 4.4 0X0 SOCI2, pyridine 0X0 HO} 2 rt, 75 min, 86% 7 M OTIPS OTIPS 4.5 4.6 Acidic conditions (TFA in methanol) removed the acetonide and revealed diol 4.7 (Scheme 4.5). Crude product 4.5 from the Grignard addition to ester 4.4 (Scheme 4.4) could be directly dehydrated and then subjected to the acetonide deprotection step without any purification of the intermediates, affording the desired diol 4.7 in 70% yield over the three steps on a 8.80 mmol scale, in comparison to the 64% if each intermediate product was purified and isolated. Scheme 4.5 Preparation of epoxide 4.9 from 4.6 0X0 TFA/MeOH HO OH TEA: 730' rt, 1 h, 85% 7 Ms CHZCIQ, 0°c—»rt’ OTIP o OTIPS 15 h, 90/o 4.6 4.7 HO OTs K2003 o MeOH, 0 °c, 3 h M OTIPS 94% OTIPS 4.8 4.9 The elimination of the tertiary alcohol in 4.5 and the acetonide deprotection of 4.6, were attempted as a single step by using the same acidic 39 conditions (TFA and methanol). However, no desired product was obtained; only deprotection of the diol appeared to have occurred. The primary alcohol in 4.7 was successfully converted to the corresponding tosylate 4.8, which under basic conditions afforded the terminal epoxide 4.9 in excellent yield (Scheme 4.5). The elimination step to form the. epoxide could also be performed on the crude product of 4.8 obtained from the tosylation of 4.7. In this way, the epoxide 4.9 was obtained in 89% yield over the two steps on a 16 mmol scale, compared to 85% if the steps were run separately. Unfortunately, deprotection of the acetonide in 4.6 could not be successfully combined with the tosylation and the epoxidation steps. This could possibly be due to the formation of an unidentified salt in the deprotection to diol 4.6. This salt, if not removed, seemed to affect the outcome of the tosylation/epoxidation sequence. Scheme 4.6 Initial route to aldehyde 4.12 o M VMQCLCUCN ”0 \ KHMDS,MeOTf THF, - 40 °C, 30 min toluene, -78 °c-.n ‘7 OTIPS -25 °C,16 h, 93% mpg 16 h, 94% 4.9 4.10 o H MeO \ 1) hydroboration MeO ................ ’ OTIPS 2) oxrdatlon OTIPS 4.11 4.12 The initial route to the aldehyde 4.12 was envisioned to proceed through a vinyl Grignard addition to the epoxide 4.9 in the presence of copper to afford alcohol 4.10 (Scheme 4.6). The homoallylic alcohol was successfully methylated 40 with MeOTf and KHMDS. Previously we used methyl iodide and sodium hydride for this methylation, however, this afforded 19% of silylmigrated product and only 78% of the desired methylated product 4.11.61 "A hydroboration/oxidation sequence could afford aldehyde 4.12.‘51 In practice though, this route to the aldehyde was problematic. Table 4.1 Optimization of vinyl addition to epoxide 4.9 0 HO \ M VMgX OT'PS : OTIPS 4.9 4.10 Entry Copper Grignard Temp (°C) Time (h) Yield (%) SM (%) 1 CuCN Br -40 _. ~20 17 71 25 2 CuCN Br -10 16 ' 61 35 3 Cul Br -78 —> O 1.25 75 2 4 CuCN Cl -40 —+~ -25 16 93 0 5a CuCN Cl -40 —- ~25 16+2 74 21 6 CuCN CI -40 —r -25 16 94 4 7 - Cl -40 _. -25 16 - 96 8 - Cl 0 -+ rt 17 Trace by TLC - 9b - Cl 55 8+2 Mixtures 32 Representative reaction conditions, entry 4: to a stirred solution of THF (5 mL), CuCN (16.4 mg, 0.18 mmol, 0.17 equiv), and 4.9 (290 mg, 1.07 mmol, 1 equiv) at -40°C was vinyl magnesium halide (1.7 mL, 2.72 mmol, 2.5 equiv) added. The reaction was stirred at -40°C for 30 min then at -25°C for 16 h. 8‘) Another equivalent of Grignard was added was added after 16 h, and the reaction was stirred for another two hours. b) After 8 h, 2 more equiv of Grignard were added and the reaction was stirred for another two hours. 41 The nucleophilic Grignard attack on epoxide 4.9 did not proceed to completion when vinyl magnesium bromide was used (Table 4.1, Entry 1-3). However, if vinyl magnesium chloride was used, the desired alcohol 4.10 could be isolated in 93% yield (Table 4.1, Entry 4). The epoxide opening with vinyl magnesium halides was found to be very sensitive (Table 4.1, Entry 46). The reaction was slow and had to be performed at a low temperature. Changes in the temperature or the copper gave low conversions and a sluggish reaction. We then became interested in an alternative route to aldehyde 4.12. A different Grignard, such as an allyl magnesium halide was considered for the addition to epoxide 4.9. This would add two carbons (carbons 3 and 4) and provide an aldehyde precursor, the mono-substituted double bond (Scheme 4.7). Scheme 4.7 The new retrosynthesis of aldehyde 4.12 M60 5% OTIPS O'll'lPS OTIPS 4.12 4.13 Osmylation, followed by oxidative cleavage of the primary double bond in diene 4.13 could provide the desired aldehyde 4.12. To do this, we would have to cleave the mono-substituted olefin in 4.13 in the presence of a 1,1-disubstututed olefin; a task which might seem difficult since the selectivities in these oxidative cleavages generally favor the more electron rich double bond. 42 Scheme 4.8 New route to aldehyde 4.12 O M WMQC' ”0 KHMDS, MeOTf THF, 0 °C—-rt r toluene, -78 °C—urt 7 OTIPS 2 h, 98% OTIPS 14 h, 92% 4-9 4.14 M O — 0804 H 0 e . . NalO4, 2,6—Iutidlne = MeO dioxane/HZO OTIPS ' ° 40 min, 80 /o OTIPS 4.13 4.12 To explore this new route, epoxide 4.9 was opened with allylmagnesium chloride to afford alcohol 4.14 in excellent yield after only two hours at rt (Scheme 4.8). Interestingly, if the epoxide 4.9 was opened with the same allyl magnesium chloride in the presence of copper, as was done, previously with the vinyl Grignard (Scheme 4.6), some of the epoxide was reduced to the olefin 4.15 (Scheme 4.9). Such deoxygenation of epoxides in the presence of copper and magnesium has previously been observed.94 Scheme 4.9 Deoxygenation of epoxide 4.9 MgCl __ O A HO M CUCN )4: > + THF, rt, 30 min OTIPS OT'PS OTIPS 4.9 4.14 69% 4.15 21% Methylation of alcohol 4.14 proceeded in excellent yield with KMHDS and MeOTf in toluene (Scheme 4.8). No TIPS migration was observed here either in comparison to the previous system of sodium hydride and methyl iodide in THF.61 However, if the reaction was performed in THF, 32% of TIPS migration was 43 isolated in addition to 47 % of the desired product. With diene 4.13 in hand, a selective oxidative cleavage of the mono-substituted olefin in presence of the 1,1- disubstituted olefin was desired, as this would afford aldehyde 4.12. Using 0304 and NaIO4 in the presence of 2,6—Iutidine,95 the oxidative cleavage of the mono- substituted olefin was obtained, furnishing the desired product in good yield and with excellent regioselectivity (Scheme 4.8). This result initially surprised us since, as previously mentioned, electron rich olefins are generally known to react faster in osmylations than the electron deficient olefins. The selectivity of oxidation with 0304 will further be discussed in Chapter 7. Scheme 4.10 Completion of the amide 1.5a 0 BO 0 H2N O o PPh3 H Etc)? \ NH4CI, AlMe3 \ MeO > MeO = MeO toluene, 110 °C benzene, 50 °C, 22 h 15 h. 95%. 92 (1531) 76% E over 2 steps OTIPS OTIPS OTIPS 4.12 4.16 1.58 A Wittig olefination of aldehyde 4.12 gave inseparable isomers of the (1,6- unsaturated ester 4.16 in a 15:1 E:Z ratio (Scheme 4.10). A subsequent Weinreb amidation96 with ammonium chloride and trimethylaluminium completed the synthesis of amide 1.5a and the desired E-amide was isolated in 76% over two steps. Thus, amide 1.5a could be isolated in 26% overall yield from vitamin C in 14 steps. Several of the crude materials could be used in the next step without purification and isolation of intermediate products. 44 4.2 Alternative Routes to Amide 1.5a Other efforts toward epoxide 4.9 were pursued in an attempt to develop an overall shorter and more efficient synthesis for amide 1.5a. It was anticipated that these alternative syntheses also would open up more options to access the right half of the molecule in the unfortunate event that we would have to change the route to autolytimycin. Three retrosynthetic analyses were made. Unfortunately, none of these proved to be successful in the forward direCtion. The first route considered involved a Sharpless asymmetric epoxidation (SAE)97 of the known diene 4.1898'99 (Scheme 4.11). Because our system was a mis-matched case with respect to the desired stereochemistry for both the epoxide and the alcohol, the thought was that a Mitsunobu reaction could be used to invert the stereochemistry of the alcohol, if we could get reagent control, and the correct stereochemistry during epoxidation. Scheme 4.11 Retrosynthesis of epoxide 4.9 - the first alternative approach o Sharpless M Mitsunobu \HJOED epoxidation:> \n/c‘); : > i OTIPS O I 4.9 4.17 4.18 Diene 4.18 was generated from vinyl magnesium chloride and methacrylein 4.19 in moderate yield, and than the Sharpless asymmetric epoxidation was attempted (Scheme 4.12). After 24 h the reaction was stopped, this was at about 50% conversion. Unfortunately, the major product obtained was the wrong regioisomer, epoxide 4.20, only trace of amount of what was believed to be the desired epoxide was observed. 45 Scheme 4.12 Preparation and epoxidation of diene 4.18 0 0H Ti(Ol-Pr)4, (—)-DEI’ 0H \[fiLH WMgCI % cumene hydroperoxide EI/H THF. 0 °(Z I 4 A MS,CH2CI2 O I 4.19 40 mm' 58 A 4.18 '35 °C» 24 h: 29% 4.20 The epoxidation of diene 4.18 via the Sharpless asymmetric epoxidation showed very poor selectivity for the desired regioisomer 4.17a. Even if the reaction was allowed to go to completion, only a small amount of the desired epoxide 4.17a was observed (Scheme 4.13). This approach was thus deemed unfeasible as a method to obtain the desired epoxide 4.9. Scheme 4.13 Sharpless asymmetric epoxidation of diene 4.18 OH TiIOi-Pr)4 OH OH \rk (-)-DET, t-BuOOH TH fl : + II CHZCIZ, 4 AMS, -20 °C, 2 d O I O 4.18 ~50%, (7:1, 4.20:4.17a) 4.20 4.17a The second alternative route explored to access epoxide 4.9 was envisioned to occur through a chelation controlled nucleophilic attack of glycidal 4.21100103 (Scheme 4.14). Sato and co-workers have previously shown that (1,6- epoxy aldehydes can undergo chelation-controlled syn-additions with dialkylzincs.104 However, a simple substrate such as glycidal was not used. Scheme 4.14 Retrosynthesis of epoxide 4.9 — the second alternative approach 0 M :> 0%) OTIPS 4.9 4.21 Exploration of this route began with the oxidation of Fl-glycidol 4.22 under Doss-Martin periodate (DMP) conditions to provide the desired aldehyde, glycidal 46 4.21, in moderate yields (Scheme 4.15). Oxidation under Swern’s conditions105 or with IBX106 both failed. Scheme 4.15 Oxidation of R-glycidol 4.22 o DMP, CH2C|2 (292m M TISP-Cl, DMAP M ”CK/u n 25h , Ova CHZClz, 78°C OH DMF, rt, 2d, 36% 4.17a OTIPS 53% 4 21 30 min, 28% (1: 1. 7, syn: anti) 4'22 (1 :2, synzanti) Subsequent addition of isopropenyl magnesium bromide or isopropenyl zinc (prepared from ZnCl2 and isopr0penyl magnesium bromide solution)” to aldehyde 4.21 generated the corresponding alcohol 4.17a with low syn/anti selectivities in a complex mixture of products. If the magnesium salt was crystallized out of the generated isopropenyl zinc solution with 1,4-dioxane and only the supernatant was used,”8 the by-product formation decreased. Although changing the solvent from THF to CHQCI2 seemed to increase the selectivity for the desired syn-isomer, the reaction was still sluggish and gave a 2:1 ratio of antizsyn as an unseparable mixture (Scheme 4.15). The diasteriomers were assigned after TIPS protection and comparison with “H NMR spectrum of the desired epoxide 4.9. Due to the low yields and selectivity for the desired isomer this alternative route was also abandoned. The third and last effort to obtain epoxide 4.9 was envisioned to be from the Payne or Payne-like rearrangement of epoxy alcohol 4.23, which would be obtained from the allylic alcohol 4.24 through a Sharpless asymmetric epoxidation (Scheme 4.16). Alcohol 4.24 was to be obtained from the reduction 47 of the known dienate 4.25, which in turned could be obtained from a Favorskii rearrangement of mesityl oxide 4.26. Scheme 4.16 Retrosynthesis of epoxide 4.9 — the third alternative approach 0 o 0 OH O I OMe fist—79 IE“ r::{> I:> | dfi 4.9 4.24 4.25 4.26 The first step of this sequence, the Favorskii rearrangement of mesityl oxide 4.26, proceeded through the tri-brominated ketone 4.28, using neat bromine at 0 °C, followed by reacting the crude mixture immediately with sodium methoxide in methanol to form the Z-esters 4.25 and 4.27 in a 1:1 ratio (Scheme 4.17).“"3'110 Attempts to use a solvent in the reactionas Engler and co-workers did,"‘ resulted with reduced reaction rates. Separation and purification of the 1:1 mixture of esters (4.25 and 4.27) through fractional distillation was unsuccessful. Therefore, reduction of the crude ester mixture was tested using both LiAIH4 and DIBAL. Scheme 4.17 Favorskii rearrangement of mesity oxide 4.26 0 Br 0 o Br2 O NaOCH3 | OMe | OMe = = + fi 0 °C, 30 min 5’ CH3OH, 0 °C, 2 h Br 1:1 OMe 4.26 4.28 4.25 4.27 The ester mixture (1:1, 4.25:4.27) obtained from the Favorskii rearrangement (Scheme 4.17) was divided into two batches: one was reduced with LiAIH4 and the other with DIBAL (Scheme 4.18). The reduction with DIBAL 48 gave higher yields, though the isolated products contained more impurities than the products isolated from the corresponding LiAlH4 reduction. Gratifyingly, the corresponding alcohols 4.24 and 4.29 were easily separated by silica gel chromatography. Scheme 4.18 Reduction of the crude esters 4.25 and 4.27 O O OMe OMe LIAIH4 I OH I OH I . I 2 . ago, -78 °C, 2h OMe OMe 4.25 4.27 4.24 28% 4.29 36% O O DIBAL OMe OMe _ OH OH I + I _ v I + I EtZO, -78 °C, 40 min OMe OMe 4.25 4.27 4.24 41% 4.29 44% The desired product 4.25 from the Favorskii rearrangement is relatively unstable and was, as previously mentioned, not successfully separated from the side product, ester 4.27. Therefore, a quick distillation of the crude product mixture of 4.25 and 4.27 was performed to clean up the reaction mixture before the subsequent reduction to the alcohols 4.24 and 4.29 with DIBAL. The entire route to alcohol 4.24 from mesityl oxide 4.26 is shown in Scheme 4.19. 49 Scheme 4.19 Favorskii rearrangement and subsequent reduction of 4.26 0 3,2 Br 0 NaOCH3 ———D = fi 0 .C 3W CH3OH, 0 °c Br (1 :1.5, 2.44:2.46) ~22% 2.41 2.45 O O OMe OMe DIBAL OH OH I + I 4' I + I CHZCIQ, -78 ° OMe (1 :1, 2.43:2.47) OMe 2.44 2.46 "67 /° 2.43 2.47 7% from 2.41 8% from 2.41 From the allylic alcohol 4.24, it was believed that the epoxy alcohol 4.23 could be obtained through a Sharpless asymmetric epoxidation.”113 Both enantiomers of the epoxyalcohol 4.23 were desired depending upon the route that would be used in the subsequent step, a regular Payne-rearrangement114 or a Payne-like rearrangement (mesyl chloride, perchloric acid, and potassium carbonate).115 Scheme 4.20 Sharpless asymmetric epoxidation of alcohol 4.24 TIN-PTO)4 OH (—)-DET, i-BuOOH ,. OH I > o... CH20I2, MW -20 °c, 2.5 d, ~57% 4.24 4.23a The original Payne-rearrangement would provide for a shorter route, thus the stereochemistry for the epoxyalcohol 4.23 was set through the Sharpless asymmetric epoxidation using (-)-diethyltartrate (Scheme 4.20). However, the desired epoxyalcohol 4.23a was obtained in moderate yield only and was inseparable from impurities such as diethyltartrate, among others. Nevertheless, 50 this material was taken on to the subsequent Payne-rearrangement. The original aqueous conditions‘“ for the rearrangement afforded low conversion to the desired rearranged product 4.30 (Scheme 4.21). Under non-aqueous conditions,116 the desired product was only seen in trace amounts by 1H NMR analysis. of the crude reaction mixture. Scheme 4.21 Payne rearrangement of epoxy alcohol 4.23a 0 OH NaOH (1 N) A... rt, 1.5h (5:,1 4.23a,.430) 4.23a 64% 4. 23a Due to these problems of low conversions, isolations and purifications mentioned above, in addition to the significant amounts of side-product 4.27 formed in the Favorskii rearrangement, this route for the epoxide 4.9 was also abandoned. The original route, although maybe lengthy, offers the option of performing several steps on crude reaction products, thus providing the desired epoxide 4.9 in an efficient and clean manner. 51 Chapter 5. Progress in the Total Synthesis of Autolytimycin — The Left Half Boron Adduct 1.2 As mentioned in previous chapters, we were to explore the utility of our one-pot C-H activation/borylation/amidation/oxidation method in the total synthesis of autolytimycin; this would provide the right half (1.3) of autolytimycin (Scheme 5.1). Boron adduct 1.2 was envisioned to be combined with the right half 1.3 through a Suzuki cross coupling. A RCM was to be used to close the 19- membered macocycle. Scheme 5.1 Sub-targets of autolytimycin OPG3 MeO \ 7 OPG2 autolytimycin 1.3 5.1 The Left-Hand Segment - Boron Adduct 1.2 To form the nucleophilic coupling partner (boron-adduct 1.2) we envisioned starting with a suitable halide, such as the alkyl iodide 5.1 (Scheme 5.2). The boronate could be installed through a lithium-halogen exchange. Carbons 8-10 of 5.1 and the stereochemistry of carbons 10 and 11 were to be installed through an asymmetric crotylation117 of 5.2. This would also provide the terminal olefin, which later would be used for the ROM to close the 19-membered macrocycle of autolytimycin. The two adjacent oxygens at carbons 11 and 12 in 52 5.2 were to be installed through a Sharpless asymmetric dihydroxylation118 of olefin 5.3. This would also provide the stereochemistry of carbon 12. The double bond and carbons 11 -13 in 5.3 were to be brought in through an Evans’s enolate allylation119 of 5.4. This would simultaneously set the stereocenter of carbon 14. Compound 5.4 is readily available from (+)-norephedrine. Scheme 5.2 Retrosynthesis of boron adduct 1.2 The synthesis of boronate 1.2 was performed by Mr. Luis Sanchez and started with the preparation of Evans’ chiral auxiliary 5.6 from norephedrine 5.5 and carbonyl diimidazole (CDl) (Scheme 5.3).120 The desired product 5.6 was isolated in good yield. After acylation of 5.6, Evan’s allylation with allyl iodide provided the desired product 5.3 in excellent yield and diastereoselectivity. 53 Scheme 5.3 Preparation of Evan’s chiral auxiliary and subsequent allylation o o o o / o (300)20 I/V HO NH2 00' O/lLNH DMAP,NEt3 OJLN LIHMDS OXNJW r r 7 “T '3' 011ch2 5%, THF 4” ‘ ' THF I “'0, Ph 87% Ph 97% Ph 91 % Ph 5.5 5.6 5.4 5.3 Evans’ chiral auxiliary in 5.3 was subsequently removed with benzyl alcohol under basic conditions to provide ester 5.7 in high yield (Scheme 5.4). In addition to the product, the chiral auxiliary 5.6 was also successfully isolated in quantitative yield from the reaction. Sharpless asymmetric dihydroxylation of the terminal olefin in 5.7 provided the in situ generated lactone 5.8 with a low 3:1 cisztrans ratio. After TIPS protection of the primary alcohol in 5.8, the previously inseparable diastereomers were now separated and the desired (ii-isomer 5.98 could be isolated in 64% yield. The undesired a-isomer 5.901 was isolated in 21% yield.121 Scheme 5.4 Chiral auxiliary removal and asymmetric dihydroxylation of 5.7 XNW ©/\ = BnOW ADmix-O..N3HCO3= O : ~ 3 \J, = "BUUOTHF = HZO/tBuOH .r 89 /° 80% (3:1, bza) Ph 5.3 5.7 TIPSCI, DMAP owes OH H o o H CH20I2 > 0% 64°/o 5.9b, 21°/o 5.93 . ‘ 5.8 5.9b Treatment of 5.96 with lithium borohydride reduced and opened the lactone to provide dioI 5.108 in quantitative yield (Scheme 5.5). The primary 54 alcohol in 5.108 was selectively protected with a trityl group, followed by a methylation of the secondary alcohol to provide intermediate 5.12. Scheme 5.5 Reduction and ring-opening of 5.98 TIPS . TrtCl, DMAP O H O L'BH4 OH OTIPS pyridine ‘ ‘ Tr , MeOH,THF H 81 % (98% brsm) 7 ~" quantitative O 5.9b 5.106 OTrt OTIPS KHMDS,MeOTf OTrt OTIPS a toluene - OH 90% - OCH3 5.116 5.12 Luckily, the undesired lactone 5.9a could also be transformed to the desired alcohol 5.118 (Scheme 5.6). After similar reduction and tritylation steps as shown for the desired lactone 5.98 in Scheme 5.5, a Mitsunobu reaction was used to invert the stereochemistry of secondary alcohol in 5.1141. Scheme 5.6 Conversion of the undesired 5.901 to the desired alcohol 5.118 OTIPS . o o I} L'BH4 9H OT'PS TrtCI, DMAP , MeOH, THF i pyridine , 4". quantitative ' OH 82% -l- 5% SM 5.98 5.108 1) p-nitrobencoic acid OTrt OTIPS PPh3, DIAD, THF OTrt OTIPS I 2 W 2) LiBH4, MeOH, THF _ ' 0H 77% (two steps) ' 0H 5.11s 5.11b The TIPS protected primary alcohol in 5.12 was desilylated with TBAF and then oxidized under Swern’s conditions to aldehyde 5.2 (Scheme 5.7). With aldehyde 5.2 in hand, we were ready for the crotylation with Roush’s cis boronate 55 5.14117 to install the stereochemistry at carbon 12. The desired product 5.15 was isolated in 75% yield. Scheme 5.7 Crotylation of 5.2 with Roush’s cis-boronate 5.14 é THF, 95°/o 5 NEt3, CH2CI2 7 ' OCH3 ' OCH3 quantitative 5.12 5.13 0&0 (S) O é OCH3 4A MS : OCH3 2. N80H(aq) 2M 75% MOM protection of the formed alcohol in 5.15 provided 5.16 in high yield, which was then subjected to detritylation with PPTS (pyridinium p- toluenesulfonate) to provide alcohol 5.17 (Scheme 5.8). Halogenation of the primary alcohol in 5.17 with iodine in the presence of triphenyl phosphine and imidazole afforded the desired alkyl iodide 5.1. The iodination was performed in the absence of light to minimize side reactions. Scheme 5.8 Formation of alkyl iodide 5.1 MOMCI,DMAP 0T” OMOM PPTS MeOH W TBAl,iPr2NEt W 85% " 00113= 88°/o ’ OCH3' 5.15 5.16 i imidazole W ' OCHaé 77% "' 500H3' 5.17 56 Alkyl iodide 5.1 was found to be unstable, and was, therefore, stored as its precursor alcohol 5.17. This alkyl iodide 5.1 is one step away from the desired left half coupling partner, the boron adduct 1.2 (Scheme 5.1 and Scheme 5.2), which is prepared in situ. Thus, when the boron adduct 1.2 was needed for the Suzuki coupling, it was generated in sifu from the freshly prepared alkyl iodide 5.1. 57 Chapter 6. Generation of Autolytimycln’s Aromatic Core with the Fully Elaborated Pieces 6.1 C-H Actlvatlon/Borylatlon/Amldatlon/Oxldatlon of Amide 1.5a With amide 1.5a in hand (Chapter 4), we were now ready for the one-pot C-H activation/borylation/amidation/oxidation reaction. Would the reaction work on such an elaborated amide? We have already demonstrated the C-H activation/borylation/amidation/oxidation with a unsaturated amide (Chapter 2, Scheme 2.1), where 1-bromo-3-chlorobenzene 3.3 was amidated and the corresponding amidophenol was isolated in good yield. This became our starting point for the amidation with the fully elaborated amide.58 1-Bromo-3- chlorobenzene 3.3, which was used as the coupling partner for tiglic amide, was thus thought to be a suitable coupling partner for the amide1.5a as well. It was previously shown by Dr. Feng Shi in our group, that the isolated boronic ester 3.1 could be amidated with 1.58 and directly oxidized under modified conditions to provide product 1.3a in 73% isolated yield over the two steps (Scheme 6.1).61 A Suzuki coupling side-product was also obtained in 16% yield, where the boronic ester of the intermediate product 1.3b cross coupled with the bromine of another molecule of 3.1. Three modifications had been made in the reaction conditions: 1) An excess of boronic ester was used, 1.5 equivalents of boronic ester 3.1 to 1 equivalent of amide 1.5a, 2) the amount of oxone was also increased from 1 to 1.5 equivalents, and 3) the reaction time was increased from 10 to 40 minutes for the oxidation step.61 However, the originally reported 58 reaction conditions,58 where the amidation was performed on the crude boronic ester with an excess of amide, had not been attempted on the fully elaborated amide 1.5a. Scheme 6.1 Amidation with amide 1.58under modified conditions H2N 0 _ r BPin \ M80 0 BPin 1.58 CI m I OTIPS Cl Br Pd2db83 2%, xantphos 6% 7 M90 . CS CO 1.4 uiv 3.1 (1.5 equrv) 2DM%,(95 $8 I . OTIPS I— - 1.3b OH 1: ° + Cl N H | Oxone (2.2 equiv) '7' MeO HZO/acetone n' 73% f OTIPS 1.38 Therefore, borylation of 1-bromo-3-chlorobenzene 3.3 was performed as reported, with [lnd(lr)COD], dmpe and HBpin neat at 150 °C in a closed air free flask (Scheme 6.2).76 After removal of all volatiles from the crude reaction mixture, the amidation was performed with an excess of amide 1.58. A slightly larger excess of amide 1.58 (1.5 equivalent as compared to the reported 1.1 equivalent) was used with respect to 1 equivalent of the aryl 3.3. This was done with the hope of decreasing the undesired Suzuki-coupling. It was believed that 59 the excess amide 1.5a could be isolated back from the reaction mixture in the end. Scheme 6.2 C-H activation/borylation/amidation/oxidation with amide 1.58 CI’ : Br 3.3 _ CI [lnd(lr)COD] 2% . 1.58 (1.5 equiv) 39'” 032C03(1.4 equiv) Bpin 150 °C, 6 h N H I MeO YOTIPS—J 1.3b dmpe 2%, HB pin (2 equiv) D Pd2dba3 1%, xantphos 3% Cl Br DME, 100 °C, 4.5 h 3.1 OH 1) filtration 2) oxone (1.5 equiv) 0 acetone/water, rt 40 min 0' ‘ 7' i2 3 NalO 1 uiv )rt,1h4( 99 ) M80 57% over 3 steps OTIPS (73% BRSM) 1.38 For the oxidation step, the modified reaction conditions with an excess of oxone and a longer reaction time were used to insure complete oxidation of the boronic ester to the phenol. The desired amido phenol 1.3a could then be isolated in a moderate yield, 57% over the three steps. 48% of the amide 1.5a was also recoverd from the reaction mixture. So, based on the recovered amide, the yield of the desired product was 73% over the three steps, which was the same as that obtained previously by Dr. Feng Shi in the two step amidation reaction (Scheme 6.1). Only about 6% of the undesired Suzuki-coupling product was observed. However, the isolation of the amidophenol 1.38 and the recovery of the unreacted amide 1.58 in the above reaction (Scheme 6.2) were relatively tedious 6O and difficult. Even though the yield of the desired product was acceptable, alternative routes to access larger quantities of amidophenol 1.38 were subsequently pursued. 6.2 Redesign In the Synthesis of Autolytimycln’s Aromatic Core To make the isolation of the desired amidophenol 1.3a easier, we looked into the cause of the isolation problem and the side reactions. To solve these problems, we decided to switch our C-H activation/borylation/amidation/oxidation reaction sequence to the amidation of the TIPS protected 3-bromo-5- chlorophenol 6.1 (Scheme 6.3). This would provide a product that would be less polar than 1.3a. Additionally, by following this route, the undesired Suzuki- coupling product could be avoided, together with any pinacol by-products. Scheme 6.3 Preparation of the TIPS-protected 3-bromo-5-chlorophenol 6.1. BPin OH TIPS-CI OTIPS H202, NaOH 0 DMAP, TEA Cl Br acetone, rt, 15 min Cl Br CHZCI2, rt, 6h Cl Br 95°/o 98°/o 3.1 3.2 6.1 The first attempt in this respect was the amidation of the TIPS protected 3-bromo-5-chlorophenol 6.1, which was obtained from the oxidation of the boronic ester 3.1, followed by TIPS protection (Scheme 6.3)‘22. Thus, the amidation of 6.1 was performed in refluxing DME under a N2 atmosphere (Scheme 6.4). The desired amide 6.2 was formed, along with the deprotected amidophenol 1.3a, in a ratio of 1:1 as determined by 1H NMR analysis of the crude reaction mixture. The desired product 6.2 was inseparable from another by-product, which was believed to be the dechlorinated product 6.3. 61 Scheme 6.4 Amidation of the TIPS-protected phenol 6.1 in an open system OR OTIPS O O O O H2N I 6.1 (1.2 equiv) CI n l H n I Pd2db83 1%, xantphos 3 % M90 . = MeO + MeO 052C03 (1.4 equrv) OTIPS DME, H, 21 h OTIPS OTIPS 1.58 R = TIPS, 6.2 6.3 R = H, 1.38 Since changing the protecting group on the phenol in the Suzuki coupling (Chapter 6, section 6.3, Scheme 6.8) had proved to be beneficial to prevent dechlorination, the TIPS group on the phenol in 6.1 was thus changed to a PMB (p-methoxybenzyl) group. Therefore, phenol 3.2 was protected with PMB-Cl in the presence of 052003 in DMF; the desired PMB protected phenol 6.4 was isolated in good yields (Scheme 6.5). The amidation was performed under a closed system in an air-free flask with twice the catalyst loading, 2% szdba3 and 6 % xantphos; this resulted in the formation of the desired product 6.5 in 82% isolated yield. When the same reaction was performed in an open system, a 73% yield of an impure product was obtained. The impurity was again believed to be the dechlorinated product. 62 Scheme 6.5 Amidation of the PMB-protected phenol 6.4 in a closed system OPMB O OH OPMB Pd2db83 2°/o, CI n I xantphos 6% PMBCI, (382003 C52C03 (1.4 equiv) > 3 M60 Cl Br DMF, rt, 17 h Cl Br amide 1.58 (1 equiv) 3 2 88% DME, 95 °C, 36 h OTIPS ' 6'4 closed system, 82% 6.5 Amidophenol 6.5 could also be obtained from the PMB protection of phenol 1.3a (Scheme 6.6). The reaction conditions used here were the same as those used for the preparation of the PMB-protected phenol 6.4, 1.3 equiv of PMB-Cl and 3 equiv of CS2CO3 in DMF at room temperature. However, due to the excess PMB-Cl (0.3 equiv), 30% of the di-PMB protected amide 6.6 was also isolated, in addition to 63% of the desired amide 6.5. Scheme 6.6 PMB-protection of amidophenol 1.3a OH OPMB OPMB £10 1:0 (1° CI N PMBCI Cl N CI N H I 062003 _ H | PMB l MeO " DMF, rt, 2 d MeO + MeO OTIPS OTIPS OTIPS 1.38 55 63% 6.6 30% The most efficient route to the protected amidophenol 6.5 so far was thus the amidation of the PMB protected bromochlorophenol 6.4 under a closed 63 system (Scheme 6.5). This reaction could be performed on a 1.5 mmol scale and a good isolated yield (82%) of the desired product 6.5 could be obtained. 6.3 Attempted Suzuki Couplings and Model Studies With the protected amidophenol 6.5 in hand, we were now ready for the Suzuki coupling with the left half, boronate precursor 5.1 (Chapter 5, Scheme 5.7). It was believed that the B-alkyl-BBN coupling partner 1.2 could be prepared in situ from the corresponding alkyl iodide 5.1 through a halogen lithium exchange followed by addition of 9-OMe-9-BBN. Unfortunately, the Suzuki cross- coupling between the boron adduct 1.2 and the aryl chloride 6.5 failed under numerous conditions; mostly dechlorination was seen in these reactions.61 Aryl chlorides are known to be difficult to use in cross-coupling reactions, and they have been shown to undergo reductive hydrodechlorination side reactions.123 However, FIJrstner and co—workers have shown that Grignard reagents can be used as coupling partners in Suzuki cross-coupling reactions, if they are first transformed with 9-MeO-9-BBN to the corresponding boron-adducts.124 To explore the feasibility of such a method in our studies, we used n- octylmagnesium chloride 6.7 and the TIPS-protected amidophenol 6.9 as a model system. The Grignard 6.7 was generated from the corresponding n- octylchloride and reacted with 9-MeO-9-BBN in situ to form the alkyl-boronate coupling partner 6.8 (Scheme 6.7). The desired Suzuki coupling product 6.10 was then obtained in a good yield (74%) after 12 h. However, in addition to the use of excess alkyl coupling partner (4 equiv), this reaction also suffered from 64 another drawback, which was the formation of a by-product that was believed to be the dechlorinated amidophenol.123 Scheme 6.7 Suzuki coupling with octylmagnesium chloride 6.7 I- —I 1) 9-MeO-9-BBN (4 equiv) V THF, rt, 30 min n-octylMgCl = MQC' . B. 6.7 (4 equiv) 2) DMF' degas tWIce n-octyl/e OMe® 6.8 (4 equiv) OTIPS D 0 OTIPS 6.9 H Q t n-octyl N / Pd(OAc)2 10%, S-Phos 20% H 110 °c, 12 h, 74% 6.10 Lowering the stoichiometry of Grignard reagent 6.7 from 4 to 1.5 equivalents resulted in a lower yield and lower conversion; 43% of a mixture of product and starting material in a 1:1 ratio was isolated. The main concerns here were the yield and the concentration of the Grignard reagent 6.7 that was being generated. Originally, when one equivalent of magnesium was used per equivalent of halide to generate Grignard 6.7, it was assumed that the consumption of the magnesium indicated completion of the reaction with 100% conversion of the alkyl halide to the Grignard. However, to be certain of the concentration when the fully elaborated amide 1.38 was used, the Grignard solution was titrated prior to use.125 The titer showed a much lower concentration of active Grignard than was initially assumed. The chloride and the bromide Grignard were obtained in 0.37 M and 0.25 M respectively, instead of the 65 evaluated concentration of 0.5 M. It was also noted that the alkyl chloride gave a higher and more reproducible yield of the Grignard reagent as compared to the corresponding alkyl bromide. Table 6.1 Effect of concentration and additives in the Suzuki coupling OTIPS D O OTIPS 1) 9-MeO-9-BBN Cl NJWA THF, rt, 30 min 6 9 H O n-octyIMgCI > ' = 2) DMF, degas twice Pd(OAc)2 (10%), S-Phos (20%) rroctyl ” / 5-7 110°C,12h 610 additive ' Entry Concentration Grignard 6.7 Additive Yield (%)!) Ratio (M) (equiv) (6.9:6.10) 1a 0.05 2 - 75 1:7.3 2«'1 0.05 1.1 - 42 127.8 3 0.1 1.5 - 50 125.5 4 0.1 1.5 DMSO (4 equiv) 68 0:1 5 0.1 1.5 K3PO4'H H20 (2 SQUIV) 22 124.5 Reaction conditions: Unless otherwise specified all reactions were performed on a 0.26 mmol scale of 6.9 in DMF at the specified concentrations with freshly titrated octylmagnesium chloride (0.3-0.4 M in THF), B-MeO-QBBN (1 equiv with respect to grignard), Pd(OAc)2 (0.10 equiv), and S—Phos (0.20 equiv). The reaction was heated in under nitrogen in an oil bath at 110 °C for 12 hours. 8 Reaction performed on 0.2 mmol of 6.9. b) Isolated yield of 6.9:6.10 after column chromatography. The ratio was determined by 1H NMR analysis. With the accurate concentrations of the Grignard reagent in hand, the equivalents of the Grignard reagent were then decreased from the assumed 4.0 equivalents to 2.0 and 1.1 equivalents, with respect to equivalent of the aryl chloride 6.9 (Entry1 and 2, Table 6.1) resulted in lower yields and incomplete 66 conversions. However, using additives and increasing the concentration of the reaction from 0.05 M to 0.1 M provided encouraging results. In all the above Suzuki reactions, dechlorination was always observed during the 1H NMR analysis of the crude reaction mixture. The reaction with no additive gave a poor yield and did not go to completion (Entry 3, Table 6.1), and the addition of K3PO,-n H20 gave mostly dechlorination (Entry 5, Table 6.1). However, the addition of 4 equivalents of distilled DMSO to the reaction furnished full conversion and 68% of the desired Suzuki product 6.10 could be isolated (Entry 4, Table 6.1). The use of DMSO to stabilize palladium catalysts has been previously reported by Sanford and co-workers.126 Scheme 6.8 Suzuki cross coupling with the PMB protected aryl chloride 6.11 OPMB D O OPMB 1) 9-MeO-9-BBN 0' ”V o (1.5 equiv) 6.11 moctylMgCl . = = ”0ch N JHA 6.7 (1.5 equiv) THF. rt. 30 min Pd(OAc)2 10%, S—Phos 20% H 2) DMF, degas twice 110 °C, 12 h 6.12 DMSO full conversion no de-chlortnation During the study of the Suzuki cross-coupling, other protecting groups on the phenol were also evaluated. When PMB was used as the protecting group, we had not seen any dechlorination of the aryl chloride. Therefore, the Suzuki cross-coupling of the PMB protected aryl chloride 6.11 was performed with DMSO and alkylmagnesium chloride 6.7 (Scheme 6.8). To our delight, this gave full conversion and no dechlorination; however, the desired product 6.12 was contaminated with a 9-BBN side-product. Finally, with a working model system in 67 hand, we needed to be able to generate the alkyl Grignard on a small scale for the coupling reaction with the fully elaborated amide 6.5. The Grignards for the model systems in the initial runs had been generated on about 10 mmol scales; generating the same Grignard reagent (6.7) on a 1 mmol scale was more difficult than anticipated. The magnesium was initially activated with 1,2-dibromoethane. Other magnesium activation methods127 were also explored, both with chloro- and bromo octane as the starting material for the alkyl Grignard. However, none were effective on that scale. At the same time, we had also been investigating the Suzuki coupling where the borane-adduct was generated from a halogen lithium exchange of the alkyl iodide.128 Through adjusting the solvents and the concentrations in the individual reaction steps, conditions that could reliably provide the desired Suzuki product 6.13 in excellent yields were obtained (Scheme 6.9). Scheme 6.9 Successful Suzuki coupling with the fully elaborated amide 6.5 1) OPMB / I 0 CI \ N I H OPMB 1) f—BuLi (3.2 equiv) ether (0.1 M) M90 -78 °C, 3 min I OPMB 2) BOMe-9-BBN OTIPS I i (3.5 equiv) 6.5 “... THF. -78 °c —- rt , KsPO4-nH20 (2 equiv) 7 0MB 10 min + 1 h degas thrice Me 5.18 1.6 e uiv 3) nitrogen gas flow 2) Pd(OAc)2 10% ( q ) to evaporate the S—Phos 20 mol % OT'PS solvent (pre-mixed in THF, degas thrice) 3) 85 °C, 12 h, 90% 68 With 6.13 in hand, we began to investigate the RCM59 (ring closing metathesis) between the two terminal olefins. This would form the requisite tri- substituted double bond in autolytimycin and simultaneously close the 19- membered macrocycle. Thus far, all attempts to do this have failed. One of the reasons for these failures was thought to be the steric hindrance from the TIPS protecting group on the allylic alcohol. It was also thought that forming the free allylic alcohol would increase the reactivity of the 1,1-disubstituted olefin for the ROM by allowing coordination of the catalyst to the alcoholic oxygen. Therefore, we explored the deprotection of the allylic alcohol to remove the TIPS group from 6.13. 6.4 TIPS Deprotection of Allylic Alcohol 6.13 The initial attempts at the TIPS deprotection of the allylic alcohol 6.13 gave a very low isolated yield of the desired product. Therefore, we decided to use the Suzuki precursor 6.5 as a model system. Different flouride sources and reaction conditions were evaluated. As seen from the results in Table 6.2, attempts at desilylation with either HF or HF-pyridine gave poor results. A double deprotection was seen in the case where HF was used (Entry 1, Table 6.2), and an incomplete reaction was obtained using HF-pyridine (Entry 2, Table 6.2). However, using 10 equivalents of a stronger fluoride source, TBAF, at 0 °C gave excellent results; 98% isolated yield of the desired allylic alcohol 6.14 was obtained (Entry 3, Table 6.2). When the amount of TBAF was reduced from 10 equivalents to 5 equivalents, a longer 69 reaction time was required; it resulted in a sluggish reaction and a lower isolated yield (Entry 4, Table 6.2). Table 6.2 TIPS deprotection of the Suzuki precursor 6.5 OPMB OPMB O 0 Cl N Cl N H I TIPS deprotection‘ H I M80 M80 OTIPS OH 6.5 6.14 Entry Flourlde Source Additive Solvent Temperature Time Yields (%)a 1b 48% HFaq (400 equiv) ' CH3CN ” 15 h Mixturec 2d HFopyridine (500 equiv) pyridine THF rt 72 h 446 3 TBAF (10 equiv) - THF 0 °c 1.5 h 98 4f TBAF (5 equiv) - THF 0 °C 4 h 44 Reaction conditions: The reactions were performed on 0.48 mmol scales of 6.5 in THF (0.02 mM) under the specified reaction conditions. a) Isolated yields after column chromatography on a single run. b) The reaction performed on a 0.12 mmol scale of 6.5, according to Schreiber and co-workers.129 c) Mixtures of products were isolated, including PMB deprotection. d) The reaction was performed on a 0.07 mmol scale of 6.5, according to Panek and co-workers.17 6) 23% recovered 6.5. I) 0.16 mmol scale of 6.5 in THF (0.04 mM). During the TIPS deprotection of 6.5 (Table 6.2), it was noted that the aromatic region in the 1H NMR of the crude product did not match that in the 1H NMR of the isolated product. If the isolated product was re-submitted to the same reaction conditions, the 1H NMR of the crude product looked similar to that of the crude product from the real deprotection reaction. This strange phenomenon was further studied and will be discussed in Chapter 8. 70 Scheme 6.10 Desilylation of the Suzuki product 6.13 under optimal conditions OPMB OPMB | TBAF (10 equiv) 7 THF, 0 °C, 2 h 71 % OTIPS 6.13 The TIPS deprotection of the Suzuki product 6.13 under these optimal conditions could afford the desired product 6.15 in 71% isolated yield (Scheme 6.10).130 Unfortunately, even with the allylic alcohol free in 6.15, the RCM proved to be sluggish. Although the 1,1-disubstituted olefin did react through an intramolecular metathesis, the major product seemed to be the six-membered ring formed from the 1,1-disubstituted olefin and the unsaturated amide in the right half of the molecule. If the left half of the molecule was protected with a MOM-group, the RCM precursour 6.13a provided 37% of the chopped product 6.16 (Scheme 6.11). Scheme 6.11 Attempted RCM of MOM-protected RCM precursour 6.138 OPMB OPMB O 50 % Grubbs' 2nd .v H benzene, 80 °C, 10 h ’OMOM 37% M90 OTIPS 6.16 71 It was believed that the steric effects of both the eventual tri-substituted double bond in the desired product and the PMB protecting group on the homo- allylic alcohol were causing these problems. However, the reaction proved to be complicated by more than the sterics of the protecting groups. The enthalpy for the RCM reaction of model compound 1.1, where all the protecting groups were replaced with hydrogen, was evaluated computationally (Scheme 6.12).131 The low energy conformers for the starting material and RCM product were identified with Monte Carlo searches.132 The enthalpies of these compounds and ethylene were calculated using DFT (B3LYP functional with a 63119 basis set).133 Unfortunately, the reaction was found to be endothermic (AH = 13.5 kcaI/mol). Scheme 6.12 RCM reaction explored computationally 6.5 Preparation of the Demethylated Right-Half Amlde So far, the desired RCM product had neither been observed nor isolated. It was thought that these failures might be due to the two side-chains being too far apart and the closing being conformationaly prohibitive; and/or that the trisubstituted double bond was too sterically hindered to be formed through the RCM. 72 Scheme 6.13 Attempted RCM reactions by Hiersemann and Helmboldt ROO \ RCM ———> No RCM product RO / 0 6.178 6.178 We decided to focus on the second possibility, where it was thought that the trisubstituted double bond was too sterically hindered to be formed. Hiersemann and Helmboldt have previously reported an interesting study during the total synthesis towards the jatrophane diterpenes.134 In their synthesis, they encountered similar problems in closing 6.168 to form a 12-membered ring with a tri-substituted E—olefin (Scheme 6.13). In spite of trying several different catalysts and conditions for the RCM, their reactions always failed. Only different amounts of starting material were recovered from the reaction mixtures. Just as in our study, changing protecting groups or using a relay-chain did not improve the results.128 Utilizing a relay chain on the 1,1-disubstituted olefin (6.16b) provided no desired product, only ring closing of the relay chain and generation of 6.168 was seen (Scheme 6.13). 73 After the failures of the RCM and the RRCM (relay ring closing metathasis) Hiersemann and Helmboldt reasoned that it might be due to the steric strain caused by the methyl group on the 1,1-disubstituted olefin. Therefore, a new RCM precursor 6.17 was made, this time without the methyl group on the 1,1-disubstituted olefin (Scheme 6.14). When this new molecule 6.17 was subjected to Grubb’s second-generation catalyst, 44% of the desired product 6.18 was isolated in an isomeric mixture. Optimization of the reaction conditions gave an increased yield; 75% of the desired product 6.18 was eventually isolated (Scheme 6.14). Scheme 6.14 RCM of the demethylated system by Hiersemann and Helmboldt 12.5% Grubbs' 2nd 1 ,2-dichloroethane 60°C, 6 1'1 75°/o 6.117c 6.18 Drawing inspiration from this study, a demethylated version of autolytimycin was prepared. The synthesis for the right-half coupling partner (i.e. amide 1.58) was revised only for two steps during the initial stages to prepare the analogous demethylated amide. The methylester 4.4 was reduced with DIBAL to the corresponding aldehyde, which was directly subjected to an in situ Wittig- olefination to form the mono-substituted olefin 6.19 (Scheme 6.15). From then on, the synthesis of the desired demethylated amide was similar to that of the original amide 1.58. The acetonide 6.19 was deprotected under acidic conditions 74 in excellent yield, and the subsequent epoxide formation was performed in two steps without purification of the intermediate tosylate. Scheme 6.15 Preparation of the demethylated epoxide 6.21 from ester 4.4 ,4, 1) DIBAL 0 M90 0 o toluene, -78 °C 0 TFA/MeOH (1 :3) > / > O 2) CH2PPh3, THF rt, 1.5 h, 91% OTIPS -73 cc _. 50 .C OT'PS 4.4 20 h, 71% 6.19 OH 1) TSCI, TEA, CHZCI2 OH 0 °c -+ rt, 18 h 0 / 2) K co M OH = / 2 3. e OTIPS 0 °c, 3 h, 77% OTIPS 6.20 6.21 Epoxide 6.21 was then opened with an allyl Grignard to form the corresponding alcohol 6.22, which was subsequently methylated with methyltriflate under the same conditions used for the original methylated version (Scheme 4.8). This set the stage for the crucial step of selectively oxidizing a mono-substituted olefin in diene 6.23 in the presence of another mono- substituted olefin. Scheme 6.16 Preparation and oxidation of diene 6.23 O /‘(z_\ AMQBI “0 KHMDS. MeOTf / THF, rt, 2.5 h 7 toluene, ~78 °C—vrt V OTIPS 91% / OTIPS 17 h, 90% 6.21 6.22 O —" 0804 H MeO NalO4, 2,6-iutidine MeO / dioxane/HZO, 40 min OTIPS 64% / OTIPS 6.23 6.24 75 We had anticipated that the TIPS-protecting group would provide enough steric bulk to differentiate between these two double bonds. Fortunately, this anticipation was borne out when the desired aldehyde 6.24 was isolated in a moderate yield (Scheme 6.16). Scheme 6.17 Preparation of the demethylated aryl amide 6.26 O OPMB 1) PPh OPMB 130ka 3 H N o o O 2 H toluene, 110 °C \ Cl Br CI u I 18 h 6.6 M90 = MeO Pd dba antphos= Q 2 31 x Me / 2) ti;lH,,c1, AlMe§ 09.2003, DME OTIPS enzene, 50 C / 100 °C 15 h \ 24 h, 74% OTIPS 98% OTIPS 6.24 6.25 6.26 Thus, there were only two steps left to obtain the desired demethylated amide 6.25. Both these steps, the Wittig-olefination and the amide formation proceeded as expected (Scheme 6.17). Amide 6.25 was then coupled under the previously used Pd-catalyzed conditions with 6.6 to form the PMB protected phenol 6.26 (Scheme 6.17). With aryl amide 6.26 in hand, the left half 5.1a could be introduced through the Suzuki coupling. With the same reaction conditions that had been used for the original methylated version, the Suzuki- cross coupling was performed with the de-methylated right half 6.26 and the same alkyl halide 5.18. The desired product 6.27 was isolated in 86% yield (Scheme 6.18).128 76 Scheme 6.18 Suzuki-cross coupling of the demethylated aryl amide 6.26 OPMB 1) O 0' 8 I OPMB 1) l-BuLi (3.2 equiv) other (0.1 M) -78 °C, 3 min MeO l OPMB 2) B-OMe-9-BBN \ I i (3.5 equiv) 6.26 OTIPS .1‘" E i THF, -78 °C _. rt K PO -nH20 (2 equiv) OMe 10 min + 1 h dggas4thrice MeO 5.1a (1.6 equiv) 3) nitrogen gas flow 2) Pd(OAc)2 10% to evaporate the S—Phos 20 mol % solvent (pre-mixed in THF, degas thrice) 3) 85 °C, 12 h, 86% Several RCM conditions were then applied to 6.27, without any encouraging results.128 Subsequently, to increase the reactivity for the RCM, the allylic alcohol in 6.27 was desilylated under the standard conditions128 and subjected to the RCM conditions, once again without positive results. It was then thought that the PMB group might be causing considerable steric hindrance during the RCM. Therefore, the PMB group was removed128 with DDQ and the product was again subjected to the RCM. Unfortunately again, no desired RCM product was observed. Several other protecting group combinations have been used for Suzuki-product 1.1, as well as solvents (CH2Cl2, benzene, toluene, hexafluorobenzene, octafluorotoluene, acetic acid, and ionic licuid (BMlM-PF6)) and catalysts (Grubbs 2"“, Neolyst M2, Hoveyda-Grubbs 2"“, and o-toluyl variant of Hoveyda-Grubbs 2"“) (Scheme 6.19). However, none of these reaction conditions have thus far provided the desired RCM product. 77 Scheme 6.19 Ring-closing metathesis of Suzuki-product 1.1 1.1 no RCM product seen R1 = H, TIPS, CONH2 R2 = H, MOM, PMB R3=PMB 6.6 Preparation of the Saturated Right-Half Amide Yet another attempt for the ROM was subsequently made. It was thought that maybe the unsaturated amide in the RCM precursor made the molecule too constrained for the RCM and the formation of the 19-membered macro-lactam was therefore difficult. To explore this possibility, we needed a functional group in the position of the olefin that we could easily and stereoselectivly regenerate the E-olefin after the RCM. A stereoselective “hydration” of the unsaturated amide 1.58 would fulfill these criteria. This stereospecific “hydration” was accomplished through an asymmetric Evans-aldol‘35‘137 of aldehyde 4.12 with the acylated oxazolidinone 6.288 in good yield (Scheme 6.20). 78 Scheme 6.20 Asymmetric Evans-aldol of aldehyde 4.12 with oxazolidinone 6.288 c 8(qu OTIPS °>= F °>=oI ONYIT O Bn’EN 0 BuzBOTf,TEA‘ 8n’EN “2 0M9 “0 ’ CH Cl 78°C 15h; MeO ° \ 2 2’ - ' ' oh CHZC'Q’ O C B02B0}\\ -50°C,1.5 h then 40 min - slowly heated to 0°C 6.288 6.29 80% OTIPS 6.30 The desired amide 6.31 was then obtained in good yield after removal of the chiral auxiliary with M8,),AINH2 (Scheme 6.21).138 The chiral auxiliary, the oxazolidinone 6.28b was also recovered from the reaction mixture in excellent yields.128 Fortunately, the synthesis of the desired unsaturated amide 6.31 was easily accomplished by minor alterations to our original approach. Scheme 6.21 Removal of chiral auxiliary and generation of amide 9.31 O Bn’q ’KO o)\/ 0 HO MegAlNHg “0 ._ 0 M80 > MeO + BHI k0 CHZCI2/toluene n OTIPS ri- 7h OTIPS 6 28b 970/ 6.30 6.31 71 % With the amide 6.31 in hand, the installation of the aromatic core with the same PMB-protected bromochlorophenol 6.6 was pursued next. The same reaction conditions as for the amidation with the unsaturated amide 1.58 (Scheme 6.5) were used, 4% szdbaa, 12% xantphos and 1.4 equiv 052003 in DME at 100°C. However, only about 22% of the desired arylamide 6.32 was 79 obtained, and a large amount of what was believed to be the retro-aldol product was observed. In the possibility that this failure was due to the DME139 solvent, another common solvent (1,4-dioxane) was tried. Performing the same reaction in dioxane afforded the desired product 6.32 in 56% isolated yield along with a 6% yield of the oxidized product, ketone 6.33, which was obtained as a 1:1 mixture of diastereomers. Oxidation of alcohols in the presence of palladium has been reported in several “borrowing hydrogen” reactions.“‘°'141 Additionally, 30% of the unreacted starting material 6.31 was also recovered from the reaction. Scheme 6.22 Amidation coupling with amide 6.31 OPMB OPMB o o o 6.6 (1.2 equiv) , H2N Pd2dba3 4% Cl C. N N H O xantphos 12% H H > HO + O MeO C82C03 (1.4 equiv) M80 M80 dioxane, 100 °C OTIPS 15 h, closed system OTIPS OTIPS 6.31 6.32 71 % 6.33 6% (1 :1) It was believed that the incomplete amidation reaction was due to amide 6.31 being less reactive than the previously used amides 1.58 and 6.25. Therefore, the amount of arene 6.6 was increased from 1 equivalent to 1.2 equivuivalents thus affording 71% of the desired amidated arene 6.32 and 6% of the oxidized side-product 6.33, in addition to 16% unreacted starting material (Scheme 6.22). Further increasing the amount of arene 6.6 to 1.5 equiv provided full conversion, but it did not improve the yield of the desired amidophenol 6.32, which was obtained in 68% yield. The oxidized side-product 6.33 was formed in 80 19% yield. In an attempt to increase the formation of ketone 6.33, the reaction time was increased, as well as the catalyst loading to 8% szdba3 and 24% xantphos, and the reaction was diluted by half. Under these modified conditions, the reaction had reached full conversion after 24 h and 44% of the ketone 6.33 in a 1:1 diastereomeric mixture was be isolated, in addition to 54% of amide 6.32 (Scheme 6.23). The exact reason for the formation of by-product 6.33 is unknown at this time. Scheme 6.23 Amidation coupling with amide 6.31 under modified conditions OPMB OPMB O . O O O O 6.6 (1.2 equw) "'2N Pdgdba3 8% CI N c) N HO xantphos 24% H H 4, HO + 0 M90 Cs2003 (1.4 equiv) Meow/I M90 dioxane, 100 °C I OTIPS 24 h, closed system YOTlPS OTIPS 6.31 6.32 54% 6.33 44% (1:1) As for the amidation reaction, the Suzuki coupling of the saturated amide 6.32 was also found to be problematic.128 Using the original conditions gave an unseparable mixture of products. Therefore, the catalyst loading was increased from 5% to 15 % Pd(OAc)2, and the formed Suzuki product was directly subjected to desilylation with 10 equiv of TBAF in THF at 0°C (Scheme 6.24). However, only about 30% of prouct was obtained in an unseparable mixture (4:1) of desired product 6.34 and an unidentified “elimination” product. Additionally, a trace of the dechlorinated product was observed. 81 Scheme 6.24 Suzuki coupling of saturated amide 6.32 OPMB 1) 6.32 (1 equiv) in THF 2) evaporation in of 1) t-BuLi (3.6 equiv) solveniwiih N2 I OPMB ether (0.1 M) 3) K3PO4-nH20 (2 equiv) ' ~78 °C, 3 min 4) degassed 3 times , , \ > = 2) BOMe-9-BBN 5) Pd(OAc) 15% OMe . 2 (4 equ1v) o S-Phos 30% OTIPS 6.14 (1.6 equiv) 15”?” 31" “ (premixed in THF, min + degassed 3 times) , 6) 85 °C, 8 h mixture of unseparable products OPMB \‘W TBAF (10 equiv) THF, 0°C, 2 h 6.34 ~30% (4:1) The undesired amidation product, ketone 6.33 was also of interest for the subsequent RCM reaction. However, when ketone 6.33 was subjected to the Suzuki coupling under the same reaction conditions as for 6.32, with the corresponding MOM protected alkyl iodide, only a minor amount of the desired coupling product was observed. The reaction did not proceed to completion and a mixture of products was formed; about 40% of an unpure product mixture was obtained. Only the saturated amide 6.34 has so far been subjected to the RCM.128 Different catalysts have been tried (second generation Grubbs, second generation Hoveyda-Grubbs with o-tolyl ligand, and Neolyst M2) under different reaction conditions. However, the previously seen isomerization of the 82 monosubstituted homoallylic alcohol on left side chain of the RCM precursor could be minimized in these RCM reactions with acetic acid.“143 Thus far, all attempts to obtain the 19-membered macro-lactam via the RCM reaction have failed. It is believed that the problem is in bringing the two olefins in close proximity of each other. Work towards solving this problem is currently in progress. 83 Chapter 7. Oxidative Cleavage of Olefins As described in Chapter 4, the selectivity seen in the oxidation of diene 4.13 to the corresponding aldehyde 4.12 was somewhat surprising (Scheme 7.1). The general tendency of 030, is to oxidize electron rich olefins faster than those that are electron deficient. After obtaining this contradictory selectivity in our system, where the monosubstituted olefin in 4.13 was selectively oxidized over the more electron rich disubstituted olefin, we decided to investigate this phenomenon further. Scheme 7.1 Contradictory selectivity in the oxidative cleavage of diene 4.13 0804 10/0 O — NaIO4 (4 equiV) H MeO 2,6-lutidine (2 equiV) MeO dioxane/I120 (3:1) * OTIPS 40 min. 82% OTIPS 4.13 4.12 7.1 Oxidations of Olefins with 0504 The oxidation of carbon-carbon multiple bonds with stoichiometric or catalytic 0504 to the corresponding cis-diol is a rather common transformation in organic chemistry.144 Chiral ligands have successfully rendered OsO4 dihydroxylation into a reliable source of asymmetry from prochiral alkenes.“‘5'147 The diols formed trom the OsO4 mediated dihydroxilation can easily undergo further oxidative cleavage to generate the corresponding aldehydes. According to the Sharpless dihydroxylation conditions, under which OsO4 is used as the oxidant, 1,1-disubstituted olefins were shown to react 1.2 to 3.7 times faster than the corresponding monosubstituted olefins, depending on the ligands used.“""149 84 Sharpless and co-workers have also shown that the more electron rich olefins in dienes and polyenes were preferentially oxidized in the presence of the more electron deficient ones.149 However, it has been shown that using AD-mix-ot or AD-mix-8, and increasing the steric bulk around allylic silyl ethers can reverse the regiochemistry and result in oxidation of the more sterically accessible olefins.150 Several research groups have used this to their advantage in synthesis, and selectively cleaved an electron deficient olefin in the presence of an electron rich olefin, using OsO4 under different reaction conditions.‘5"153 7.2 Observed Selectivities in the Oxidation of Olefins wlth OsO,| A reversed regioselectivity of the osmylation in our system was initially observed in the oxidative cleavage of olefin 4.13, using conditions developed by Borhan and co-workers.154 The monosubstituted olefin in 4.13 was oxidatively cleaved to the carboxylic acid 7.1 in a moderate yield (Scheme 7.2). Excess oxone (4 equivalents) was used as the co-oxidant; when only 1 equivalent of oxone was used, the hydroxyketone 7.2 (13%) was also isolated in addition to the desired acid 7.1 (20%). Additives, such as amines are commonly used in OsO4 mediated oxidations. In these reactions the co-oxidant is oxone, a triple salt, which might also act as an additive. We were interested to see if oxone provides the same selectivities as seen with the'amine additives. 85 Scheme 7.2 Oxidation of 4.13 to the carboxylic acid 7.1 with 050., and oxone _ -— M —- 0804 1°/o . HO O HO O 80 oxone (4 equrvL MeO MeO DMF, rt, 50 min ' OTIPS 50°/o OTIPS OTIPS 4.13 7-1 - 7'2 ‘ The selectivity observed here was thought to be due to the steric bulk of the TIPS protecting group, an observation as has been previously reported by others for OsO, mediated oxidations.‘5""‘"-‘55'157 To investigate this hypothesis, the TIPS protecting group was removed from diene 4.13 and replaced with the smaller methyl group to afford diene 7.4 (Scheme 7.3). Scheme 7.3 Formation and oxidation of the methyl-protected diene 7.4 M90 TBAF M90 KHMDS, MeOTf THF, rt, 100 min ' toluene, ~78 °C—~rt' OTIPS 88% OH on, 68% 4.13 7.3 OH — OsO4 1% 0 M90 oxone (4 equiv) M90 DM F, rt, 75 min OMe 51% (crude) 0M6 7.4 7.5 This diene 7.4 was then subjected to the same oxidative reaction conditions as those applied to diene 4.13, 1% OsO4 and 4 equivalents of oxone in DMF. The reaction was carefully monitored by TLC and quenched with N82303 when the starting material was consumed. To our surprise, the same selectivity was obtained; no vinyl protons were seen in the 1H NMR spectrum of the crude product. 1H NMR, 13C NMR, as well as the DEPT spectral analysis of the crude 86 product indicated the formation of acid 7.5, albeit in a reduced yield (51% crude yield). Furthermore, a similar substrate to the TIPS protected diene 4.13, diene 4.11 was also subjected to these oxidation conditions (Scheme 7.4). As compared to diene 4.13, 4.11 has some additional sterics around the monosubstituted double bond, due to the lack of a methylene between the olefin and the methoxy substituent. The reaction was carefully monitored by TLC until full consumption of starting material was observed. The 1H NMR spectrum of the crude product showed no vinyl protons, however, two new sets of peaks were seen in a ratio of about 3:1. This crude mixture was separated by silica gel column chromatography to afford two slightly impure products. 38 % of the expected acid 7.6 and about 5% of the a-hydroxyketone 7.7 was obtained (Scheme 7.4). Scheme 7.4 Oxidation of 4.11 to the carboxylic acid 7.6 with 030,, and oxone \ OsO4 1% Ho HO M90 oxone (4 equiv) M80 0 MeO O = + DMF, rt, 70 min OTIPS OTIPS OTIPS 4.11 7.6 38% 7.7 5% Initially, in our total synthesis towards autolytimycin, we had thought of an alternative route for preparing the demethylated amide 6.25, which was needed for the ring closing metathesis study described in Chapter 6. It was thought that the olefin in the unsaturated ester 4.16 was too electron deficient, so that the 1,1- disubstituted olefin could be oxidized in its presence to afford compound 7.8. This 87 route would provide the demethylated amide 6.25 without significant changes to the synthesis of the original amide 1.58. To our disappointment and surprise, we saw cleavage of the electron deficient unsaturated ester olefin in 4.16 instead of the more electron rich 1,1—disubstituted olefin (Scheme7.5). The 1H NMR analysis of the crude product mixture indicated the absence of the olefinic proton of the ester, and the known aldehyde 4.12 was isolated in low yield. Scheme 7.5 Oxidation of ester 4.16 with 0804, NalO4, and 2,6-lutidine O O O H N O 2 E“) 03041 % E‘O \ \ 232C314 (4(univ) ) \ H , ~ ti ine equiv M80 M80 :> MeO “ _ MeO + dioxane/H20 (3:1) OTIP 7 8 OTIPS OTIPS OTIPS 6.25 4.16 4.12 1 6% not observed This result made us test the oxidation of 4.16 under our previously used OsO4 and oxone conditions in DMF. Borhan and co-workers had previously reported conditions to oxidatively cleave a 1,1-disubstituted olefin in the presence of an 01,8-unsaturated ketone.154 In the reported experiment, only 2 equivalents of oxone were used to prevent oxidation of the a,8-unsaturated ketone. Scheme 7.6 Oxidation of ester 4.16 with OsO4 and oxone in DMF BO 0 EtO O \ 0804 1°/o O HO O oxone (2 equiv) HO = MeO = M60 + MeO DMF, rt, 3 h OTIPS OTIPS OTIPS 4.16 7.9 35 % 7.1 14 % 88 The a,8~unsaturated ester 4.16 was thus subjected to the oxidative cleavage under the reported conditions (Scheme 7.6). The reaction was carefully monitored by TLC and quenched when the starting material was fully consumed. Surprisingly, the olefinic proton of the 01,8-unsaturated ester was absent in the 1H NMR analysis of the crude product mixture. After purification by silica gel column chromatography, two major products were isolated in modest yields, the known carboxylic acid 7.1 and the ot-hydroxy-8-ketoester 7.9, which was isolated in a 1 :1 mixture of diastereomers at the ot—hydroxyl center. Scheme 7.7 Directed oxidation of dienol 7.3 with OsO4 and oxone in DMF _ __ O 0 M80 M80 H0 0504, oxone > + MeO + O DMF, rt, 2 h “0 OH O OH OMe 7.3 7.10 7.11 ~2-6% 7.12 ~6-7% not observed Additionally, we were curious to see if we could direct the oxidation by having the allylic alcohol unprotected (7.3) and obtain oxidation at the 1,1- disubstituted olefin. Several conditions for directed osmylation of olefins have been reported, both for stereoselective‘sii'162 and regioselective163 dihydroxylations.164 Therefore we anticipated oxidative cleavage of the 1,1- disubstituted olefin in 7.3. This would generate an or-hydroxy-acid, which would further be oxidized to form acid 7.10.165 Disappointingly, subjecting the free alcohol 7.3 to the oxidation conditions only lead to trace amounts of products (Scheme 7.7). No vinyl protons were seen in the 1H NMR analysis of the crude product mixture. Impure carboxylic acid 7.11 89 (2—6%) and the cyclized product, lactone 7.12 (6-7%) were isolated in low yields. Different quenching methods were subsequently used for the workup, due to that the commonly seen color changes, when the previous reactions were quenched, were not observed for this reaction. Normally these oxidation reactions attain a pale yellow color during the course of the reaction and turn dark brown when quenched. In the reaction of 7.3, this color change to dark brown was only seen when sodium sulfate and water were used for quenching, and not when solid sodium sulfate or solid sodium bisulfate were used. Even then, however, the mass recovery in the crude product corresponded to less than 50% of the mass of the initial starting material. One of the possible reasons for this might be that both the olefins in 7.3 were getting oxidatively cleaved, the corresponding diacid would be formed, a glutaric acid derivative, which would probably be lost during the aqueous work-up. If this were the case, then it would imply that the 1,1- disubstituted olefin in 7.3 was getting oxidized almost at the same rate as the monosubstituted olefin. Whether, this could be due to a directing effect or a steric effect is not clear at this time. From the handful of substrates in this study, it is difficult to determine the relative reactivity of two different olefins for the OsO,/oxone mediated oxidations in DMF. What has, however, become apparent from this study is that steric effects can significantly change the reactivity of an electron rich double bond for oxidative cleavage. In their review on osmylation,151 Haudrechy and co-workers presented several examples of selective osmylation of electron deficient olefins in 90 the presence of electron rich olefins, which is the reverse of the commonly expected regioselectivity in these reactions. Clearly, the selectivity in osmylation reactions is not as straightforward as is commonly thought. 91 Chapter 8. Evidence for Cation-11: Interactions Between TBAF and Small Aromatic Molecules — Implications for Crude 1H NMR Analysis in Organic Synthesis 8.1 Initial Observations Scheme 8.1 Desilylation of arene 6.5 with TBAF OPMB OPMB o o TBAF N . I N H | (10 equw) § H I THF, 0 °C M90 1.5 h, 98 % M90 OTIPS OH 6.5 6.17 autolytimycin Figure 8.1 1H NMR spectra of 6.17 (500 MHz, CDCI3) b e l OMe O k f C O k I p Cl N d I H89 0 IMeO r/r' h/h' m jOHn q 6.17 i q p hh, j m 0 /I n rr L. I d“ , -, , , ..-...,....,....,....,....,... 6.0 5 0 4.0 3.0 2.0 ppm 92 As mentioned In Chapter 6, an interesting phenomenon was observed during the TIPS deprotection of arene 6.5 enroute in the total synthesis of autolytimycin (Scheme 8.1). When arene 6.5 was treated with 10 equivalents of TBAF at 0°C for 1.5 hours, the desired arene 6.17 was isolated In excellent yield. Figure 8.2 1H NMR spectra of 6.17 (500 MHz, CDCls). crude product at rt (front) vs. at 60 °C (back), for assignment see Figure 8.1 OPMB 0 Cl N H I MeO OH 6.17 1"" 60 °C *“‘--‘~ ~ ‘~“ ~‘ w 25 °C fi‘ ‘“ mmwmmmfij-WWW 7.8 7.4 7.0 6.6 6.2 ppm The aromatic region of the 1H NMR spectrum for the crude product 6.17 showed the presence of two species in a ratio of 6.821 (Figure 8.2, front). The crude reaction mixture was then heated subjected to VT-NMR at 60 °C. This caused the two sets of peaks to coalesce (Figure 8.2, back). However, when the crude NMR sample was cooled down again, it did not revert back to the two species, which would be expected if the two species were originally rotamers. Instead, the coalesced NMR spectrum remained, which indicated the presence of 93 two different compounds or complexes in the crude reaction mixture that decomposed or reorganized upon heating. Notably, the methylenes adjacent to the nitrogen of TBAF showed a small down field shift at elevated temperature. After column chromatography however, the product (isolated in 98% yield) provided a different 1H NMR spectrum (Figure 8.3, back) with significant chemical shift changes as compared to the 1H NMR of the crude reaction mixture (Figure 8.3, front). These chemical shift changes were especially prominent for the aromatic protons the amide proton, and the vinyl proton of the unsaturated amide. Only minor changes were seen for the rest of the molecule and the PMB protecting group. Figure 8.3 1H NMR spectra of 6.17 (500 MHz, CDCla). crude product (front) vs. isolated product (back), for assignment see Figure 8.1 OPMB 1 C 0 C003 Cl N d Hag] MeO OH 6.17 I. I . , a u I "9 ...~ isolated ... J _...._~J AILJI 1 ....,....,....,....,.........,....,....,....,....,....,....l....,-...,....,....,....,....,....,.m1 7.8 7.4 7.0 6.6 6.2 ppm 94 These chemical shift changes were quite puzzling and initially not understood by us. Therefore, we decided to investigate the origin of these chemical shift changes a bit further. Scheme 8.2: Desilylation of TIPS protected butanol 8.1 in the presence of 6.17 OPMB 0 Cl N H I 10 equiv TBAF M80 1 equiv amide 6.17 MOTIPS 4.. /\/\OH + THF, 0 °C, 1.5 h OH 8.1 8.2 6.17 Initially we wanted to confirm that it was indeed something in the reaction medium that was causing these chemical shift changes. Toward this end, 1 equivalent of the isolated arene 6.17 was included in the desilylation reaction of the TIPS protected 1-butanol 8.1, under the same reaction conditions as in the original deprotection of arene 6.5, viz. 10 equivalents of TBAF at 0°C for 1.5 h (Scheme 8.2). The reaction was quenched and worked up in the same manner as before, and the 1H NMR spectrum of the “crude” product 6.17 was taken. Although slightly differently shifted from the 1H NMR spectrum of the crude product obtained from the original deprotection of arene 6.5, this spectrum showed again two different sets of peaks, which coalesce when the sample was heated and it did not revert back, even after several hours in the freezer. The 1H NMR spectrum of the reisolated pure product 6.17 was significantly different than that of the “crude” product, although the same as the before the reaction. Thus, 95 the TIPS deprotection reaction conditions certainly contained something that caused chemical shift changes in the 1H NMR spectrum of arene 6.17. Next we wanted to ascertain whether it was the TBAF or the silylether by- product that was the cause of these chemical shift changes. Thus, the isolated pure arene 6.17 was subjected to 10 equivalents of TBAF in THF at 0°C for 1.5 h. After the aqueous work up, the 1H NMR spectrum of the crude product was taken (Figure 8.4, front). It showed similar chemical shift changes as the previous two reactions. As expected, upon isolation by column chromatography, the reisolated arene 6.17 provided again the same spectrum as the initial starting material (Figure 8.4, back). Figure 8.4 1H NMR spectra of 6.17 (CDCI3, 500 MHz), “crude" product (front) vs. reisolated product (back), for assignment see Figure 8.1 OPMB 0 CI N H I MeO 6.17 I ~ isolated IIE‘Lj W ... “crude" - TYYIIIII'YIIVT'VrIII'YY'YVIIIYV'Y—rTVT—TTIIl'li'YIlI'VIIIYYW’IIUII'UTIVTTIIIII'IIIVTUUrrVIIIIYTUIIri‘j 7.8 7.4 7.0 6.6 6.2 ppm 96 It thus seemed likely that the major cause of these chemical shift changes was the presence of TBAF. Since 10 equivalents of TBAF had been added to 6.17 in the previous experiment, which was the same amount used in the original desilylation reaction. Lowering the equivalents of TBAF to 1 equivalent resulted in similar but smaller chemical shift changes. The use of 0.1 equivalent of TBAF consequently resulted in no chemical shift changes in the 1H NMR spectrum of the crude product. But this spectrum also did not show any presence of TBAF residue, indicating that the TBAF must have been lost in the aqueous work up. To confirm this, 0.1 equivalent of TBAF was added to a separate solution of arene 6.17 in CDCI3, and sure'enough, similar chemical shift changes were observed again. These studies again indicated to us that TBAF was the cause of these chemical shift changes. TBAF is a very commonly used reagent in organic synthesis; indeed, it has been employed in countless total syntheses. For TBAF to cause significant chemical shift changes in the 1H NMR spectrum of a crude product, as compared to the isolated pure product, is somewhat worrisome. This is especially true since 1H NMR analysis of crude reaction mixtures is frequently used in organic synthesis to determine the chemical outcome of a reaction in terms of the conversions, selectivities, and such. To investigate this phenomenon further, we started looking for prior reports in the literature for the use of ammonium salts as chemical shift reagents. 97 8.2 NMR Shift Reagents and Cation-1r Interactions of Quaternary Ammonium Salts Lanthanides metals are commonly used chemical shift reagents for resolving NMR spectra.““‘*“58 Generally, these chemical shift reagents coordinate to a hard Lewis basic moiety in the host molecule. Thus, alcohols, carbonyls, or amines need to be present in the host molecule for resolution to occur. Binuclear lanthanide reagents containing lsilver have been shown to cause chemical shift changes of weaker nucleophiles such as olefins and aromatics, as well as halogen containing alkanes.‘66"69"7" Interactions between the silver ion and the 11- electrons of unsaturated hydrocarbons in the absence of any lanthanides have also been reported.175 The strength of the interactions between rt-donors and silver has been studied; electron poor rt-systems and steric hindrance decreased the interactions.‘73'175 Arenes showed weaker Interactions with silver than terminal double bonds. Systems with more than one binding site showed multiple interactions, though not independent of each other.175 Furthermore, the solvent is important for chemical shift reagents. Wenzel and Sievers reported the chemical shift changes for 4~methylstyrene with a binuclear complex from Eu(fod)3 and Ag(fod) in chloroform and carbon tetrachloride.171 In the same study, benzene-d6, acetone-d6, acetonitriIe-da, and dimethyl sulfoxide-d6 showed small or no shifts at all. lmportantly, all these solvents can themselves be chelated to the lanthanide or the silver. Additionally, it is commonly known that the change in solvent alone, without the presence of 98 any shift reagent, can change the chemical shifts of a compound. This is especially prominent with a change to aromatic solvents; their anisotropic nature can change the environment of the compound?”-177 Other means to change the chemical shifts of a compound have been reported. Ammonium salts have been used for the 1H NMR spectrum determination of the corresponding amine through addition of hydrochloride.‘7"'179 Hence, in this case the proton is the chemical shift reagent. Also, cyclodextrins have been shown to resolve the spectra of p-cumene and other mono- and di- substituted arenes?”-181 Flgure 8.5 Cation-rt interactions between circumtrindene and tetramethyl ammonium pictrate Ansems and Scott showed that both silver and tetramethyammonium ions can bind to the rt-electrons of circumtrindene, a bowl shaped polycyclic arene, through what was described as rt-cation interactions (Figure 8.5).‘82 As mentioned previously, silver has been shown by others to act as a chemical shift reagent, alone or in combination with lanthanides. Thus, silver can induce chemical shift changes and coordinate with rt-electrons through rt-cation interactions. In analogy to this, Ansems and Scott showed that tetramethyammonium ions also can interact through n-cation complexation, this 99 raises the question: could tetraalkylammonium salts induce chemical shift changes as well. To the best of our knowledge, ammonium salts have never been used as chemical shift reagents. Cation-rt interactions are seen for side-chains of amino acids with a positive charge, which are commonly positioned directly over the face of an aromatic residue in proteins.183 In this way, lysine and arginine have been found to coordinate to the aromatic moiety of phenylalanine, tryptophan, and tyrosine.184 This non-covalent interaction, important for the secondary structure of proteins, is commonly referred to as a cation-1r interaction. It provides stability and specificity, to the peptides and is important for biological recognition."’~’*187 Cationic metals, and protonated and quaternary amines are common cations that interact through cation-rt interactions. These interactions have been studied in biological systems as well as in host-guest chemistry. Among the techniques used for studying these interactions are mass spectroscopy, NMR, crystallography and computational methods.”194 The edge of a benzene ring bears a partial positive charged and the face bears a partial negative charged. This gives benzene and other aromatic systems a large quadropole moment.195 Therefore, it is possible for cations to complex to the negative face of aromatic systems. The cation-rt interactions compete with aqueous phases for the binding of highly solvated cations. Computational studies have shown that the cation-11: complexation can overcome the aqueous solvation energies of the cation.‘93 Cation-1r interactions are not only 100 limited to aromatic systems. Deakyne and Meot—Ner have observed cation-rt complexation between ammonium cations and other rr-donors such as olefins.‘96"97 The chromodomain of the HP1 (heterochromatin-associated protein 1) family recognizes histone tails with specifically methylated lysines.198 The methylation of lysine is essential for the binding. No detectible binding was seen without the methylation. Protonated amines bind less well due to their increased water solubility.199 The hydrophobic property is increased through the methylation; this also favors the Van der Waal’s interactions. The polarization of the C-N bond leads to a more cationic character and stabilizes the cation-1t interactions of the aromatic cage in the protein.198 Cation-rt interactions in host—guest chemistry have been studied by several groups.“204 The binding of several ammonium ions to different cyclic and bowl shaped hosts has been investigated in aqueous and Iipophilic media. The ammonium ion 1H NMR signals show upfield shifts when bound to the host. However, the chemical shift changes of the host are not mentioned. The interactions between the cation and the aromatic walls of the host have been shown to be both anion and host dependent.‘88'"“’2'Z"""2"5'207 In some cases, the anion can inhibit the binding of the cation to the host. Bartoli and Roelens showed that the picrate ion was the most suitable counterion for tetramethylammonium to bind to their cyclophane host in CDCI3.205 In that study, 101 addition of dimethyl- or dibutyI-tin dichloride was shown to increase the binding of tetramethylammonium chloride to the host. Alkylations and dealkylations, using cation-rt interactions as means of catalysis, have been studied by McCurdy and co-workers.195 Cyclophane hosts were shown to be effective catalysts for both the methylation of quinoline structures and the dealkylation of sulfonium salts. The alkylation was performed with methyl iodide and the dealkylation with thiocyanate to produce sulfides. The major factor for the catalysis in these systems was proposed to be the recognition by the host of the developing positive charge at the transition state. This produces a preferential binding at the transition state and thus catalysis. Intermolecular and intramolecular rt-cation interactions with ammonium derivatives have been used in several cases in organic synthesis to generate small molecules."’°"-209 Pyridinium salts, possessing an amide derivative with a it- electron containing side-chain, have been used to stereoselectively generate 1,4- dihydropyridines, cyclopropanes, and also catalytically desymmetrize alcohols.208 Hydroxyalkyl azides with an aromatic substituent have been shown to stereoselectivly ring expand clue to an intramolecular rt-cation stabilization between the aryl moiety and the diazonium cation.“210 NMR, as mentioned before, is a commonly used method to study the cation-rt interactions between a host and a guest. Waters and Tatko have reported the impact of diagonal cation-11: interactions of ,B-hairpin peptides.“’*""211 The chemical shift changes were examined, as well as the NOE of the doubly 102 mutated peptides. Both the upfield chemical shift (up to 0.39 ppm) and the NOE of the methylene adjacent to the ammonium cation indicated a cation-rt interaction between the lysine and the aromatic residue of either phenylalanine or tryptophane. 8.3 Probing the Cation-1r Interactions for Arene 6.17 We started to suspect that the chemical shift changes that we observed during the TIPS deprotection of arene 6.17 were due to a cation-1t interaction between the tetrabutylammonium cation of TBAF and the rt-system of the aromatic core of arene 6.17. Thus, to examine this hypothesis, we looked for an upfield shift in the 1H NMR for the TBAF protons, similar to the shifts reported by Waters and Tatako in their study of cation-11: interactions In biological systems ( vide supra).“’5-211 Figure 8.6 1H NMR spectra (CDCI3, 500 MHz), TBAF (front) and TBAF + amide 6.17 (back) F. N+’\|/\ ai-Lcr C. W 103 Therefore, 4.4 umol of TBAF (1.0 M in THF) was added to 0.5 mL of CDC13 in a NMR-tube and the 1H NMR spectrum was taken (Figure 8.6, front). Thereafter, 10 equivalents of the arene 6.17 (20.3 mg, 43 umol) were added to 0.5 mL of CDCI3; this solution was then added to the same NMR tube containing TBAF and the 1H NMR spectrum was taken again (Figure 8.6, back). Comparing the two 1H NMR spectra, we could clearly see the upfield shift of the tetrabutylammonium proton signals. The methylenes Ha. gave an upfield shift from 3.34 ppm to 3.16 ppm, 8 change of 0.18 ppm. That the 1H NMR signals for the TBAF protons were also shifted on interaction with arene 6.17, strongly suggest the existence of a cation-rt interaction between TBAF and arene 6.17. Figure 8.7 1H NMR spectra (CDCI3, 500 MHz), “dried” TBAF (front), “dried” TBAF + arene 6.17 (back) x F- \/\/N+ I fla- c. I) #WM _J"~__.l. ' I T I U I ‘ V V V l I U I I' l V I 1 V I Y I U V 1 U I I I I T l ‘I I I V V V 17‘ 3.5 2.5 1 .5 0.5 ppm The interaction between arene 6.17 and TBAF was further studied by NOE (Nuclear Overhauser Effect) NMR. TBAF is commonly available as a solution in 104 THF; to make sure that THF did not interact with the system, it was removed from TBAF under reduced pressure. The 1H NMR spectrum of this “dried” TBAF was taken in a 60 8M solution of CDCI3 (Figure 8.7, front), 1 equivalent of arene 6.17 was then added to the NMR tube and the 1H NMR spectrum was taken again (Figure 8.7, back). This was followed by the NOE experiments, where first the aromatic proton Hc on arene 6.17 was irradiated. Weak correlations with the TBAF protons, Ha, Ho, Ho, and Hd. were observed, in addition to correlation with HD, H,, and Hi of arene 6.17 itself (Figure 8.8, spectrum iii). Figure 8.8 NOE (CDCI3, 500 MHz) of “dried” TBAF + arene 6.17 12%(b') 4% (c’) , . , 0.10/0 (C) l) Irradiatlng Ha. l0.2% (d) 100% t 1% (d’) 0.2°/o (b’) 20/0 (0') .. . . 0.4% ’ ' . ll) Irradiatlng HC, 100% (a)\ /0'2% (d) ' 3°/ (0 L10 0273‘”) 0.2%(c) . . 0 ° -4% a’ / 0.2% (d’) Ill) Irradiating Hc 1004/. 221 _JI .22 ./ 25L - ./ ‘ . , d, l C cd L a' b’ II _I_tIvA I l LIL. L__J_ .,.........,....,....,....,....,.-e.,....,.2-.,....,.. 10 8 6 4 2 ppm On irradiating proton Hd on arene 6.17, again correlations with all the TBAF protons, Ha, Hb, HC, and H. were observed, as well as with Hf on the 105 aromatic core (Figure 8.8, spectrum ii). Lastly, the methylene protons Ha. on TBAF were irradiated (Figure 8.8, spectrum i) and as anticipated, correlations with the arene 6.17 protons H6 and Hd were clearly seen, indicating a complexation of TBAF with the aromatic ring. This irradiating of Ha. also showed correlations to the other methylenes of TBAF, HU, Hc., and HG. Thus, this NOE experiments provided correlations between the aromatic protons of arene 6.17 and the TBAF protons, demonstrating that the two molecules are in close proximity of each other and this is indicative of a cation-rt complexation. Figure 8.9 1H NMR spectra (CDCI3, 500 MHz), arene 6.5 (back) and (ri-Bu),,NPF6 + arene 6.5 (front) OPMB 0 CI N H I MeO OTIPS 6.5 __w/o (n-Bu)4NPF6 - w/ (n-Bu)4NPF5 ... IYITV 7.8 7.4 7.0 6.6 6.2 ppm We then decided to check whether the free hydroxyl group in arene 6.17 had any role in causing these interactions with TBAF. A convenient probe for this was the original TIPS-protected arene 6.5; this was subjected to a similar study with 1 equiv of (n-Bu),,NPF6 instead of TBAF, since arene 6.5 would be reactive 106 toward TBAF. On comparing the 1H NMR spectrum of arene 6.5 complexed with (n-Bu),,NPF6 (Figure 8.9, front), with that of 6.5 alone (Figure 8.9, back), as expected, similar chemical shift changes were observed in the aromatic region, albeit smaller than those previously observed. Likewise, the methylene adjacent to the ammonium nitrogen of (r1-Bu),,NPF6 showed a minor upfield shift of 0.02 ppm in the presence of arene 6.5. These results thus implied that the free hydroxyl group in arene 6.17 had no role in causing this phenomenon. Figure 8.10 1H NMR spectra (CDCI3, 500 MHz), amide 6.14 (front) and TBAF + arene 6.14 (back) OPMB O 01/ i \N)\( H I 6.14 -.....u (.4 MI. - L; A. _ '_- w/oTBAF ITYIIVTVIIYVYTITUYIIII'V'VT'IIIVIIIYVY'IWTrrTrYIIIIIUFII'VV‘I'I’TW'ijYI‘UT'j—VTT‘TTIVIIIY VIII'VIVUIVI 7.8 7.4 7.0 6.6 6.2 ppm We were also interested to see if other arenes, structurally similar to arene 6.17, would also give us similar chemical shift changes with TBAF. The PMB protected tiglic arene 6.14 (Figure 8.10), which had been used as a model 107 system for the Suzuki cross coupling reactions discussed in Chapter 6, was thus subjected to 1 equivalent of TBAF (1.0 M in THF) in 8 NMR solution of CDCI3 and the 1H NMR spectrum was taken (Figure 8.10, back). On comparing this spectrum with that of the pure arene 6.14 (Figure 8.10, front), as expected, we saw significant changes in the chemical shifts of the aromatic protons of arene 6.14. Additionally, an upfield shift of 0.16 ppm for the methylenes adjacent to the ammonium nitrogen, H,- of TBAF was also seen. The results with arene 6.14 suggested that this phenomenon was not specific for the original arene 6.17 only, but rather was general for other structurally similar compounds. Arene 6.14 does not possess a tethered free hydroxyl group as arene 6.17, and that it still exhibits these chemical shift changes, again discounts any interactions between the hydroxyl of 6.17 and TBAF as the cause of this phenomenon. This in turn lends further support to our proposal that a cation-11: interaction between TBAF and these arenes is the causative factor here. Scheme 8.3 Desilylation of the unprotected arene 1.3a OH OH 0 o C' I“) | 10 equiv TBAF C' E | THF,0°C,1.5h 7 MeO 56% M80 138 OTIPS 83 OH Furthermore, we were interested to see if the PMB group on the phenol in arene 6.17 was important for the TBAF interaction. Therefore, the unprotected 108 arene 1.38 was desilylated under the same reaction conditions as those for arene 6.5 with 10 equivalents of TBAF at 0 °C for 1.5 h (Scheme 8.3). The desired phenol 8.3 was isolated in a moderate yield. The 1H NMR spectrum of this crude reaction mixture was compared to that of the isolated phenol 8.3 after column chromatography. As previously observed for these systems, significant chemical shifts changes were again seen in the aromatic region for the two samples. Figure 8.11 1H NMR spectra (CDCI3, 500 MHz), phenol 8.3 (front) and phenol 8.3 + TBAF (back) OH 0 ° Cl N H I MeO I OH 8.3 l -w/TBAF :7— fi . — - ~ vow/o TBAF :7 1.- 5-2. ..-.,....T...4,....,....,....,....4....,....,...rr.........,...-,.........,....,....,....,....,...-, 7.8 7.4 7.0 6.6 6.2 ppm For a more quantitative study, the isolated phenol 8.3 was subjected to 1 equivalent of TBAF in a 56 mM NMR solution of CDCI3 and the 1H NMR spectrum was taken (Figure 8.11, back). Comparing this spectrum with that of the pure product 8.3 (Figure 8.11, front), similar chemical shift changes for the aromatic protons were again observed. Additionally, the signal from the methylenes 109 adjacent to the ammonium nitrogen, Ha. of TBAF was also shifted upfield by 0.35 ppm, again in accordance with the previous experiments. Thus far, four arenes, 6.17, 6.5, 6.14 and 8.3, had been studied, all with the same structural core of an unsaturated 1,3,5-trisubstituted amidophenol. All of these arenes, in the presence of a tetrabutylammonium salt, exhibited significant changes in the 1H NMR chemical shifts for the protons in the aromatic region. Furthermore, the 1H NMR signal for the methylenes, Ha. adjacent to the ammonium nitrogen in TBAF was also shifted upfield in the presence of the arenes. The NOE studies with the original arene 6.17 showed weak interactions between the methylenes on TBAF and the aromatic protons, Hc and HC, on arene 6.17. Also, in the case of arene 6.17, it even seemed to afford two different complexes on interacting with the tetrabutylammonium cation (Figure 8.2, front). All these observations support the existence of a unique rt-cation interaction between the tetrabytylammonium cation and the arene substrates. To see if this phenomenon was general for other ammonium ions, the study was expanded to include other ammonium salts as well. Another tetrabutyl ammonium salt that was investigated for these cation-rt interactions with arene 6.17 was TBAI (tetrabutyl ammonium iodide). When 0.1 equiv of solid TBAI was added to a 43 mM NMR solution of arene 6.17 in CDCI3 (Figure 8.12, middle), 8 very small chemical shift change was observed on comparing this 1H NMR spectrum with the 1H NMR spectrum of the pure arene 6.17 (Figure 8.12, front). Therefore, an additional 0.9 equivalent of TBAI was added (1 equivalent total) 110 and larger chemical shift changes in the aromatic region were seen (Figure 8.12, back). The methylene protons adjacent to the ammonium nitrogen of TBAI also showed a small upfield shift of 0.04 ppm, from 3.34 to 3.30 ppm. This smaller chemical shift Is in analogy with that Iodide is a weaker anion than fluoride. Chemical shift changes from rt-cation interactions are anion dependent, with stronger anions providing larger chemical shifts.188 Figure 8.12 1H NMR spectra (CDCI3, 500 MHz), arene 6.17 (front), arene 6.17 + 0.1 equiv TBAI (middle) and arene 6.17 + 1 equiv TBAI (back) (for assignment see figure 8.1) OPMB 0 CI N H I MeO 6.17 1.0 equiv TBAI 0.1 equiv TBAI 0.0 equiv TBAI le'r'Y ITI'I’IITII'IIYUITWVIIIITVIIIII'V IUIYIIY—[TVrFIII'Ilr'YTIUVIFIYY'YITYfYIIIIII’U'VYj , .. 7.8 7.4 7.0 6.6 6.2 ppm Other tetrabutylammonium salts with less coordinating counteranions were 1" II also investigated. Both (n-Bu),,NPF6 and (n-Bu)4NBF,, on complexation with arene 6.17, resulted in chemical shift changes for the aromatic protons of arene 6.17; these changes were smaller as compared to those obtained with TBAF. Moreover, the methylenes adjacent to the ammonium nitrogen in (n-Bu),,NPF6 111 were shifted upfield by 0.03 ppm, from 3.14 ppm to 3.11 ppm. The corresponding methylenes shift for (n-Bu),NBF4 was also 0.03 ppm, from 3.17 ppm to 3.14 ppm. Additionally, no NOE signals were seen between the methylenes of (n-Bu),,NBF4 and the arene 6.17, when either the aromatic protons of arene 6.17 or the methylenes adjacent to the nitrogen in (n-Bu),,NBF4 were irradiated. Scheme 8.4 Desilylation of the fully protected amidophenol 8.4 OPMB OPMB o o 0' 8MB | 10 equiv TBAF C' 8MB | THF,O°C,1.5h 7 MeO 71% M80 OTIPS OH 8.4 8.5 To investigate the importance of hydrogen bonding between the counteranion of the ammonium salt and the NH of the amide in arene 6.17, we decided to subject a fully protected version of arene 6.17 to the study. During the PMB protection of 1.38 (Chapter 6, Scheme 6.6), we had observed some di- protection, where both the phenol and the amide nitrogen had been protected with a PMB group to afford the fully protected amidophenol 8.4. After desilylation of amidophenol 8.4 (Scheme 8.4), the resulting arene 8.5 was subjected to 1 equivalent of TBAF, and the 1H NMR spectrum was studied for any chemical shift changes. However, no chemical shift changes were observed, neither for the ammonium methylenes nor the arene signals. It was thought that the doubly protected arene 8.5 might be too sterically hindered to interact with the tetrabutyl ammonium cation. Therefore, smaller ammonium salts were tried. Unfortunately, 112 both Me,,NBF4 and Me4NBr were insoluble in CDCI3, which had been the NMR solvent of choice for our study. Several other common NMR solvents (THF, MeOH, H20, CHaCN) were then tried to solubilize smaller ammonium salts such as Me4NBr, Me,.NBF4 and Me4NCl. Methanol and water were determined to be unsuitable for this NMR study due to their high solvation energies. Me,,NBF4 was soluble in CD3CN. Therefore, we decided to use this combination to study the it- cation interactions with arene 8.5. One equivalent of Me,,NBF4 was added to a 57 (M solution of arene 8.5 in CDaCN, and the 1H NMR spectrum was taken. On comparing this with the 1H NMR spectra of only arene 8.5 or only M8,,NBF4 in CD3CN, no chemical shift changes for either compound were observed. This was suspected to be due to the high solvation energy of the ammonium salt in CD3CN. Therefore, 0.5 mL CDCI3 was added to the NMR solution, to hopefully favor the it-cation complexation. However, there were still no chemical shift changes for either the arene 8.5 or the tetramethylammonium. Additionally, no NOE correlations were observed between arene 8.5 and the ammonium cation. All these results suggested that there was no its-cation interaction between the two molecules.- Thus, the study with arene 8.5 seems to suggest that the NH hydrogen bond of arene 6.17 is important for the cation-rt interactions between arene 6.17 and tetraalkylammonium salts. While this beneficial influence of H-bonding for cation- rt interactions has been documented in the literature,‘““-212 it can very well be that 113 in our study, the doubly protected arene 8.5 is just too sterically hindered to offer any opportunity for cation-rt: complexation with tetraalkylammonium salts. In summary, we have provided evidence for cation-1t interactions between tetrabutylammonium salts and small aromatic molecules. Several structurally similar arenes have been investigated with a number of tetraalkylammonium salts, most of which offered evidence for cation-rt interactions. These interactions lead to significant chemical shift changes in the 1H NMR spectra for both the arenes and the ammonium salts. We have thus shown that tetraalkylammonium salts can behave as chemical shift reagents. Among the factors found to be important for these cation-rt interactions were the strength of the counteranion to the ammonium, as well as possibility for H-bonding with the arene substrates. We believe that the wider implications from this study are those for the use of 1H NMR analysis of the crude reaction mixture in organic synthesis. 1H NMR analysis of crude reaction mixtures is often employed to determine the reaction outcome, conversions, diastereoselectivities, side products, and yields etc. Tetraalkylammonium salts such as TBAF are common reagents, and are widely used in organic synthesis; for them to induce considerable chemical shift changes in the‘H NMR is, in our opinion, a matter of concern for the wider synthetic community. 114 Chapter 9. Summary and Future Directions Four major projects have been discussed in this dissertation, some of which had satisfying conclusions. During the course of the synthetic efforts towards autolutimycin, two new projects were initiated and explored, the selectivity in the oxidative cleavage of olefins ‘with 0604 and the cation-11 interactions between substituted amidophenols and ammonium salts. 9.1 Total Synthesis of Autolytimycin The two side chains of autolytimycin were efficiently synthesized. We showed that we could access the aromatic core of the natural product in an efficient manner through our one-pot C-H activation/borylation/amidation/ oxidation protocol, using an elaborate amide. Additionally, we were also able to install the left side chain of autolytimycin as planned through a late stage Suzuki cross-coupling between an aryl chloride and a spa-hybridized in situ generated boronate species. Both of these steps were part of the initial retrosynthetic analysis. However, the subsequent RCM has proven to be problematic and has thus far been unfruitful. Through further studies of the RCM methodology and/or alteration of the route to autolytimycin, we anticipate to complete this total synthesis. 9.2 C-H Activation/Borylatlon and Functionallzation Through the C-H activation/borylation methodology we have shown that we can access functionalized arenes in an efficient manner. Both the C-H activation/borylation and the one-pot C-H activation/borylation/oxidation have 115 proven feasible on large scales, generating multi-gram quantities of the corresponding boronic esters and phenols, respectively. Oxone could be replaced with H202 as the oxidant of the boronic esters; this made the work-up and the isolation of the phenols not only easier but also more environmentally friendly. Additionally, H202 was also shown to be compatible with our one-pot sequence. The large-scale reactions were shown to be robust and straightforward; the reagents could be used as received, weighed out in air and solvents could be used straight from the squirt-bottle. 9.3 Selective Oxidative Cleavage of Olefins The unexpected selectivity seen in the initial oxidative cleavage of an intermediate diene towards the total synthesis of autolytimycin was further explored. However, the results revealed a more complicated system that seemed to be driven both by steric and electronic effects. Additionally, the formation of the ot-hydroxy ketone side-product, and the difficult isolation and purification, made this selectivity study difficult. To thoroughly understand this reaction and the obtained selectivities, one should identify all the possible products the formed from each olefin. The ratio of formed products should be determined from the crude reaction mixture before work-up, because it was evident from the mass recovery of the crude reaction mixture that material had been lost in the aqueous work-up. However, the selectivity in these reactions can though be further studied by studying the relative rates of only one olefin at a time, where substituents 116 close to the olefin could be varied such as in the substrates 9.1, 9.2 and 9.3 (Figure 9.1). It would also be important to select substrates where the formed acid is not water soluble, so that accurate mass recovery could be made. Figure 9.1 Examples of substrates for studying the rate of oxidative cleavage OH OMe OTIPS 9.1 9.2 9.3 9.4 Cation-rt Interactions between Ammonium Salts and Amidophenols The chemical shift changes that were seen in the 1H NMR spectrum of the crude product mixture from the desilylation reaction with TBAF were due to cation-1t interactions. The 11: electrons of the arene were interacting with the positively charged ammonium cation, thus resulting into both chemical shift changes for both the arene as well as the methylenes of the ammonium ion. This phenomenon was found to be general for structurally similar amidophenols and tetrabutyl ammonium salts. However, it was noted for these cation-1t interactions that the strength of the counter anion was important and possibly brought about by intermolecular hydrogen bonding. Figure 9.2 Interesting compounds for further studying the cation-rt interactions 1:0 00 Me ”V Me ”k 9.4 9.5 To determine the generality of these cation-rt: interactions with small aromatic compounds, it would be interesting to see if there would be an 117 interaction between ammonium salts and simple substrates such as 9.4 or 9.5 (Figure 9.2). Substrate 9.5 would provide information on the importance of the unsaturated amide, which has always been present in our study. 118 Appendix 1. Experimental Appendix 1.1 General Materials and Methods All starting materials were used as received, unless otherwise stated. Diethyl ether and tetrahydrofuran were distilled from sodium and benzophenone under nitrogen. Dichloromethane, toluene, benzene and triethylamine were distilled from calcium hydride. DMF was distilled over magnesium sulfate and stored in amber flask over 4 A molecular sieves under nitrogen. All arenes and solvents used for borylations were purified before use. Liquids and solvents were distilled over sodium or calcium hydride and then degassed, except pinacolborane (HBPin), which was used as received or distilled under reduced pressure. Solvents should pass the Na-benzophenone test inside the glove box. Solid substrates were sublimed under vacuum, including bis(pinacolato)diboron (BzPinz). I All reactions were carried out in oven dried or flame dried glassware, with distilled solvents and under nitrogen atmosphere, unless otherwise stated. All borylation and amidation reactions were set up in the glovebox. Borylation and amidation reactions were monitored by GC-FID. All other reactions were monitored by thin layer chromatography, using pre-coated silica gel aluminum plates and developed with uv and/or phosphomolybdeneic acid. Column chromatography was performed on 60 A silica gel (230-400 Mesh). NMR spectroscopic data was recorded on either Varian VXR-500 or 300 MHz instruments. Chemical shifts are reported relative to the residue peaks of 119 solvent CDCI3 (6 7.24 ppm for 1H and 77 ppm for 13C), acetone-d6 (6 2.04 ppm for 1H and 29.8 ppm for 13C). For B11 NMR, BF3- EtZO was used as standard and referenced to 0 ppm. Melting points were measured on a capillary melting point apparatus and are uncorrected. IR spectra were taken on a Nicolet IR/42 spectrometer on sodium chloride plates. Appendix 1.2 General Starting Materials, Reagents and Methods Br’ ; Br 1,3-Dibromo-2-lodobenzenezz“3'215 To 2,6-dibromoaniline (10.49 g, 41.8 mmol) was concentrated HCI (17.5 mL, 209.6 mmol) added, followed by water (78 mL) and ice (~ 80 g). No dried equipment needed. The mixture was cooled in an icebath while NaNO2 (3.46 g, 50.17 mmol) in water (78 mL) was slowly added and stirred for 30 minutes. Ice was continuously added to the reaction flask. To this slurry, still kept cold, urea was added in small portion until gas evolution seized. A cold solution of Kl (13.88 g, 83.61 mmol) in water (26 mL) was slowly added to the ice slurry, which was kept cold during the addition. The resulting slurry was stirred for 75 min at rt, forming a brown solution with off-white solids on top. The solids were filtered off, dissolved in ether and washed with saturated aqueous NaHSOa, followed by NaOH (3.0 M in H20) and water. The organic layer was dried over MgSO,, filtered and concentrated to afford 13.85 g the desired product as an orange solid (92%). The product was further purified by sublimation (0.005 torr, 85 °C, static vacuum) to provide 12.52 g of the product as 120 a light orange solid (84%). Mp 95-97 °C (lit.215 98-99 °C); 1H NMR (500 MHz, CDCla) 6 (ppm) 7.53 (d, .1.-. 7.9 Hz, 2 H), 7.04 (t, J: 7.8 Hz, 1 H); 13c NMR (126 MHz, CDCI3) 6 (ppm) 131.3, 131.1, 130.3, 109.3. OMe MO 4-Methoxybenzyl chloride:216 In a 500 mL round bottom flask, an open air solution of p-methoxybenzylalcohol (33 mL, 265 mmol) and 12M HCI (38 mL, 456 mmol) was stirred at rt for 3 h. The reaction was diluted with 200 mL CH2CI2 and 100 mL water. After separation of the layers, the aqueous layer was extracted once with 100 mL CHZCIz. The combined organic layers were washed with brine, dried over M9804, filtered, and concentrated to afford 39.45 g of the desired product as a light yellow oil. Full conversion, was confirmed by 13C NMR. 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.30 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.56 (s, 2 H), 3.80 (s, 3 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 159.7, 130.0, 129.4, 114.1, 55.3, 46.3. CH CL 0 Cl ”M H i‘ Tlglic amidophenol:58 In a glovebox, 3-bromochlorobenzene (118 pl, 1.00 mmol), HBPin (244 (II, 1.68 mmol), (lnd)Ir(COD) (8.3 mg, 0.02 mmol), dmpe (3.2 mg, 0.02 mmol) and n-hexane (0.5 mL) were charged into an air-free flask. The flask was removed from the glovebox and heated at 150 °C in an oil bathfor 3.5 h, then pumped down under high vacuum overnight. The flask was again 121 transferred to the glovebox and charged with szdbaa (9.2 mg, 0.01 mmol), xantphos (17.4 mg, 0.03 mmol), CsCO3 (450 mg, 1.38 mmol), tiglic amide (108 mg, 1.09 mmol) and THF (3 mL). The flask was removed from the glovebox, heated at 100 °C for 1.5 h, cooled to rt, after which the resulting mixture was filtered through a pad of silica (1.5 cm, Q = 3 cm) and eluted with acetone until no uv activity was seen by TLC. The filtrate was concentrated and then redissolved to a homogenous solution in acetone (about 3 mL). Oxone (615 mg, 1.00 mmol) dissolved in water (3 mL) was slowly added. The resulting slurry was stirred open to air for 10 min, before a suspention of NalO, (2.14 mg, 1.00 mmol) in water (2 mL) was added followed by acetone (2 mL). The resulting mixture was stirred at rt opened to air for 1 h, then extracted twice with ethyl acetate. Upon addition of solid NaHSO3 to the aqueous layer the mixture turned dark, additional NaHSO3 was added until the solution turned pale in color. The aqueous was then extraction twice with ethyl acetate. The combined organic layers were dried over M9804, filtered and concentrated. The crude product was purified by flash silica gel chromatography (CHZCIZIethyI acetate, 7:1) to provided 103 mg (46%) of the desired product as an off-white solid, mp 130-132 °C (small impurities by NMR) (lit.58 131 .5-133.5 °C) TLC analysis (CHZCIZIethyl acetate, 7:1), R, = 0.38; 1H NMR (500 MHz, Aceton-Ds) 6 (ppm) 8.93 (bs, 1 H), 8.68 (s, 1 H), 7.32 (t, J = 2.0 Hz, 1 H), 7.29 (t, J: 2.0 Hz, 1 H), 6.56 (t, J: 2.0 Hz, 1 H), 6.47 (qq, J: 1.3, 6.8 Hz, 1 H), 1.86 (m, 3 H), 1.76 (dq, J: 1.2, 6.8 Hz, 3 H); 13C NMR (126 MHz, Aceton-ds) 122 6 (ppm) 168.7, 159.4, 142.7, 134.9, 134.0, 131.5, 111.8, 111.3, 106.2, 14.1, 12.6. Grlgnard titration:125 LiCI (434 mg, 10 mmol) was dried at 140-145 °C under vacuum for 4 h, allowed to cool down to rt, and then dissolved in THF (20 mL). The mixture was stirred for 1 day at rt to form a clear solution, 0.5 M LiCi in THF. To each of three dry 5 mL round bottom flasks, l2 (65.1 mg, 0.257 mmol; 32.9 mg, 0.130 mmol; and 32.7 mg, 0.129 mmol, respectively) was added. The flasks were flushed with nitrogen, before addition of 1.5 mL of the LiCI solution. The resulting brown/yellow solutions were cooled to 0 °C in an ice-bath and the Grignard reagent to be titrated (octylmagnesium bromide in THF) was added dropwise until the solutions turned clear (1.06 mL, 0.50 mL and 0.50 mL respectively). The color change indicates the titer. The volume added contains the same amount of the active Grignard reagent as the amount of |2 in the flasks. The average value from the three titrations provided the concentration of the Grignard reagent ((0.242+0.259+0.258)/3 = 0.253 M). Dllsopropenylzlncflmt108 ZnCl2 (410.0 mg, 3.01 mmol) was heated in oil bath at 130 °C under reduced pressure (0.1 mm Hg) for 2 h. CH,_,C|2 (3 mL) was added and the mixture was stirred for 30 min at rt. lsopropenyi magnesium bromide (12 mL, 6 mmol, 0.5 M in THF) was slowly added, dissolving the ZnCIz; the resulting solution was stirred for 2 h at rt before freshly distilled 1.4-dioxane (1.8 mL) was added to the solution and stirred for an additional 45 min at rt. The mixture was cooled in icebath for 4 h without stirring and left overnight at rt during which the 123 formed solids was allowed to settle. The supernatant was syringed off and used directly. Appendix 1.3 Experimental for Chapter 2 Large-scale C-H Activation/Borylation and C-H Activation/Borylation] Oxidation BPin Br 2.28 2-(3-Bromo-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dloxaborolane, 2.2a: in a glovebox dmpe (195 pl, 1.17 mmol) and 3-bromotoluene (7.10 mL, 58.5 mmol) was added to a three-neck round-bottom flask containing a solution of lnd(lr)COD (486 mg, 1.17 mmol) in HBPin (13.2 mL, 91.0 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 150 °C in oil bathfor 6 h. The reaction was cooled down and concentrated to afford 19.35 g crude product. The crude boronic ester was purified by a short silica gel column (300 mL silica gel, 100% CHZCIZ). This provided 15.8 g of the desired product as a white solid (91%). Mp 73-76 °C; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.71 (t, J: 1.0 Hz, 1 H), 7.51 (t, J = 0.6 Hz, 1 H), 7.40 (m, 1 H), 2.31 (d, J: 0.5 Hz, 3 H), 1.32 (s, 12 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 139.5, 134.8, 134.4, 133.8, 122.3, 84.1, 24.8, 20.9; IR (neat) 3054, 2994, 2926, 1599, 1437, 1372, 1348, 1267, 1210, 1140, 1043, 964, 851 cm“; HRMS m/e calcd for [C,\.,H,,,BBr02+H]+ 297.0661, found 297.0670. 124 BPin Br Br i 2.2b 2-(3,5-leromo-4-lodophenyI)-4,4,5,5-tetramethyl-1,3,2-dloxaboroiane, 2.2b: in a glovebox was [ir(OMe)COD]2 (243 mg, 0.37 mmol) added together with cyclohexane (100 mL) to a round-bottom flask with sublimed B2Pin2 (6.20 g, 24.4 mmol), followed by addition of d‘bpy (196 mg, 0.73 mmol) and 1,3-dibromo-2- iodobenzene (8.83 g, 24.4 mmol). The reaction, covered in aluminum foil, was stirred at rt inside the glovebox for 6.5 h. The volatiles were removed under reduced pressure and the crude mixture was further pumped down under high vaccum overnight to afford 13.26 g of the crude product. The crude boronic ester was purified by a shot silica gel column (300 mL silica, 100% CHZCI2) to provide 11.21 g of the desired product as a off-white solid (94%). Mp 114-116 °C; TLC analysis (CHzclz), R: 0.78; lFi (neat) 2978, 1576, 1362, 1341, 1144, 1121, 843 cm"; 1H NMR (500 MHz, CDCl3) 6 (ppm) 7.89 (s, 2 H), 1.31 (s, 12 H); “’0 NMR (126 MHz, CDCIS) 6 (ppm) 136.6, 131.2, 112.9, 84.7, 24.8; HRMS m/e calcd for [C,2H,,Bo,,er2l+H]+ 486.8577, found 486.8563. BPin Br Br 2.2c 2-(3,5-Dibromophenyl)-4,4,5,5-tetramethyl-1,3,2-dloxaborolane, 2.2c: In a glovebox dppe (338 mg, 0.848 mmol) and 1,3-dibromobenzene (5.10 mL, 42.2 125 mmol) were added to a three-neck round-bottom flask containing a solution of lnd(lr)COD (352 mg, 0.847 mmol) and HBPin (12.5 mL, 85.9 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 100 °C in an oil bath for 36 h. The reaction solution was concentrated to afford 21.4 g crude product as brown solid. The crude boronic ester was purified by a short silica gel column (100% CHZCIZ) to provide 12.84 g of the desired product as a off-white solid (84%). Mp 69-72 °C; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.82 (d, J: 1.8 Hz, 2 H), 7.72 (t, J: 1.9 Hz, 1 H), 1.32 (s, 12 H); 13C NMR (126 MHz, CDCls) 6 (ppm) 136.5, 136.0, 122.9, 84.5, 24.8; IR (neat) 3063, 2992, 2930, 1584, 1435, 1372, 1339, 1265, 1148, 1022, 963, 864 cm“; HRMS m/e calcd for [C12H15BBr202+HCOZ]‘ 406.8856, found 406.8865. BPin Ci OMe 2.2d 2-(3-Chloro-5-methoxyphenyi)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2.2d:217 in a glovebox dmpe (234 pl, 1.4 mmol) and 3-chloroanisole (8.6 mL, 70.1 mmol) were added to a three-neck round-bottom flask containing a solution of lnd(lr)COD (583 mg, 1.4 mmol) and HBPin (20 mL, 137.5 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 150 °C in an oil bath for 12 h. The reaction was cooled down and concentrated to afford 27.8 9 orange oil as crude product. The crude boronic ester was purified by a short silica gel column (300 mL, 100% 126 CHZCIZ) to afford 14.95 g of clear oil (79%). 1H NMR (500 MHz, 000,) 6 (ppm)7.35 (dd, J: 0.6, 2.0 Hz, 1 H), 7.17 (dd, J: 0.5, 2.4 Hz, 1 H), 6.97 (dd, J: 2.2, 2.3 Hz, 1 H), 3.80 (s, 3H), 1.32 (s, 12 H); 13C NMR (126 MHz, CDCIa) 6 (ppm)159.9, 134.6, 126.9, 117.7, 117.4, 84.2, 55.5, 24.8. mBPin S 2.2a 2-(Benzolblthlophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2.2a:218 To a solution of [lr(OMe)COD]2 (741 mg, 1.12 mmol) and HBPin (13.0 mL, 89.6 mmol), was d‘be (600 mg, 2.24 mmol) added. The resulting red solution was stirred for 10 min, before pentane (100 mL) and benzothiophene (10.0 g, 74.5 mmol) was added. The reaction was stirred for 1.5 h at rt in the glove box before it was concentration to afford 32.53 g crude product. The crude boronic ester was purified by a short silica gel column (300 mL silica gel, 100% CHzclz) to provide 18.6 g of the desired product as a white solid (96%). Mp 68-70 °C (lit.218 72-74 °C); 1H NMR (500 MHz, CDCIa) 6 (ppm) 7.90-7.83 (m, 3 H), 7.37-7.32 (m, 2 H), 1.36 (s, 12 H); 13C NMR (126 MHz, CDCla) 6 (ppm)143.7, 140.4, 134.5, 125.3, 124.4, 124.1, 122.5, 84.4, 24.8. OH 0.. 2.3a 3-Bromo-5-methyiphenol, 2.3a:76 in a glovebox dmpe (275 pl, 1.65 mmol) and 3-bromotoluene (10.0 mL, 82.4 mmol) was added to a three-neck round-bottom 127 flask containing a solution of lnd(lr)COD (685 mg, 1.65. mmol) and HBPin (18.0 mL, 124.0 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 150 °C in oil bath for 6 h. The reaction was cooled down, concentrated and redissolved in acetone (264 mL). To the resulting solution oxone (50.7 g, 82.4 mmol) dissolved in water (264 mL) was added slowly over 25 minutes. The resulting grey slurry was stirred for an additional 7 minutes open to air then quenched with saturated aqueous NaHSO3 (100 mL). After extraction with CHZCIZ, the combined organic layers were washed with brine, followed by water, and concentrated to afford 25.9 g crude product as dark orange oil. The crude phenol was purified by a short silica gel column (300 mL silica gel, 100% CHZCiz) then washed with hexane to provide 12.56 g of the desired product as a off—white solid (81%). Mp 56-57 °C (lit.76 55-57 °C); TLC analysis (CHQCIZ), R, = 0.39; 1H NMR (500 MHz, CDCI3) 6 (ppm) 6.90 (m, 1 H), 6.80 (m, 1 H), 6.56 (m, 1 H), 4.78 (bs, 1 H), 2.26 (d, J: 0.6 Hz, 3 H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 155.9, 141.4, 124.8, 122.4, 115.8, 115.0, 21.1; HRMS m/e calcd for [C,3H,8BBrOZ+H]* 297.0661, found 297.0670. OH Br‘ : Br I 2.3b 3,5-leromo-4-iodophenol, 2.3b:2‘9-22° In a glovebox [ir(OMe)COD]2 (344 mg, 0.52 mmol) was added together with cyclohexane (90 mL) to a round-bottom flask containing sublimed B2Pin2 (8.79 g, 34.6 mmol), followed by addition of 128 d'bpy (279 mg, 1.04 mmol) and 1,3—dibromo-2-iodobenzene (12.52 g, 34.6 mmol). The reaction, covered in aluminum foil, was stirred at rt inside the glovebox for 3 h. The reaction was removed from the clovebox and concentrated under reduced pressure. The crude boronic ester was dissolved in acetone (110 mL) and a solution of oxone (21.3 g, 34.6 mmol) in water (110 mL) was added dropwise. The reaction was stirred open to air for 10 minutes, then quenched with saturated aqueous NaHSO3 and extracted with ether. The combined organic layers were washed with brine, followed by water and concentrated to afford 18.54 g crude product. The crude phenol was purified by a shot silica gel column (300 mL silica, hexaneszether, 2:1) then wash with hexane to provide 9.67 g of the desired product as a light orange solid (74%), which contained a small amount of ether that could not be removed. Mp 142-146 °C (turned to a dark red liquid, lit.2‘9153.5-153.9 °C); 1H NMR (500 MHz, CDCla) 6 (ppm 7.12 (s, 2 H), 4.94 (bs, 1 H); 13C NMR (126 MHz, CDCIa) 6 (ppm) 156.3, 131.1, 119.1, 98.3. OH Br’ i 'Br 2.3c 3,5-leromophenol, 2.3c:7"'221 in a glovebox dppe (479 mg, 1.2 mmol) and 1,3- dibromobenzene (7.3 mL, 60.4 mmol) was added to a three-neck round-bottom flask containing a solution of lnd(lr)COD (499 mg, 1.2 mmol) and HBPin (17.4 mL, 119.9 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 100 °C in an oil bath for 36 h. The reaction was cooled down, concentrated and redissolved 129 in acetone (193 mL). To the resulting solution, oxone (37.15 g, 60.4 mmol) dissolved in water (193 mL) was added slowly over 25 minutes. The resulting slurry was stirred for an additional 7 minutes at rt opened to air before quenching with saturated aqueous NaHSO3 (100 mL). After extraction with CHZCIQ, the combined organic layers were washed with brine, followed by water, and concentrated to afford 15.13 g crude product as brown solid. The crude boronic ester was purified by a short silica gel column (100% CHZCI2) then recrystallized from hexane to provide 10.53 g of the desired product as a off—white solid (69%). Mp 78-79 °C (lit.76 78-80 °C); 1H NMR (500 MHz, CDCla) 6 (ppm) 7.23 (t, J = 1.5 Hz, 1 H), 6.94 (d, J: 1.5 Hz, 2H), 4.86 (bs, 1H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 156.6, 126.8, 123.2, 117.9. OH Cl’ : OMe 2.3d 3-Chloro—5-methoxyphenol, 2.3d?6 In a glovebox dmpe (326 pl, 1.95 mmol) and 3-chloroanisole (12.0 mL, 98.0 mmol) was added to a three-neck round- bottom flask containing a solution of lnd(lr)COD (814 mg, 1.96 mmol) and HBPin (28.0 mL, 192.9 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 150 °C in oil bath for 9 h. The reaction was cooled down, concentrated and redissolved in acetone (314 mL). To the resulting solution, oxone (60.3 g, 98.0mmol) dissolved in water (314 mL) was added slowly over 25 minutes. The resulting slurry was stirred for an additional 7 minutes at rt opened to air then quenched with 130 saturated aqueous NaHSO3 (100 mL). After extraction with CHZCIZ, the combined organic layers were washed with brine, followed by water, and concentrated to afford crude product as orange solid. The crude phenol was purified by filtration through a silica gel plug and eluted with CHZCIZ, then washed with hexane to provide 10.99 g of the desired product as a light orange solid (71 %). Mp 94-96 °C (lit.76 94-96 °C); 1H NMR (500 MHz, 000,) 6 (ppm) 6.49 (dd, J = 2.0, 2.2 Hz, 1 H), 6.44 (dd, 1.7, 2.2 Hz, 1 H), 6.27 (dd, J = 2.2, 2.4 Hz, 1H), 4.85 (bs, 1H), 3.75 (s, 3H); 130 NMR (126 MHz, CDCla) 6 (ppm) 161.3, 156.9, 135.35, 108.6, 107.3, 100.3, 55.5. OH OH Cl/QCI CIQCI OH OMe 2.3f' 2.3f" 2,6-Dichloro-4-hydroxyphenoi, 2.3f’ and 3,5-dlchloro-4-methoxyphenol, 2.3f”:76 in a glovebox, dmpe (364 pl, 2.18 mmol) and 2,6-dichloroanisole (15 mL, 109.4 mmol) was added to a tound-bottom flask containing a solution of lnd(lr)COD (909 mg, 2.19 mmol) and HBPin (40 mL, 275.6 mmol). The flask was sealed, removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated at 150 °C in an oil bath for 13 h. The reaction was cooled down, concentrated and redissolved in acetone (350 mL). To the resulting solution, oxone (67.3 9, 109.4 mmol) dissolved in water (350 mL) was added slowly over 25 minutes. The resulting slurry was stirred for an additional 7 minutes at rt opened to air before being quenched with saturated aqueous 131 NaHSO3 (100 mL). After extraction with CHzclz, the combined organic layers were washed with brine, followed by water, and concentrated to afford 69.31 g crude product, which was purified by flash silica gel chromatography (pentanezether, 3:1—e2:1) to afford 11.5 g of 2.3f” as a white solid (55%) and 5.28 g of 2.3f’ as a white solid (27%) after CH2CI2 wash. For 2.3f’:76 Mp 160-161 °C (lit.76 160-161 °C); 1H NMR (500 MHz, acetone-d6) 6 (ppm) 8.23 (bs, 2H), 6.83 (s, 2 H); 13C NMR (126 MHz, acetone-d6) 6 (ppm) 151.5, 143.2,123.1,116.3. For 2.31”:_Mp 119-121 °C; 1H NMR (500 MHz, CDCIS) 6 (ppm) 6.79 (s, 2 H), 4.76 (s, 1 H), 3.82 (s, 3 H); 13C NMR (126 MHz, CDCIa) 6 (ppm) 151.8, 146.4, 129.5, 116.0, 60.9; IR (neat): 3297, 3085, 2921, 1603, 1580, 1482, 1447, 1428, 1223, 1186, 1071, 986; HRMS (ESI) m/e calcd for [C7HGC|202-H]‘ 190.9653, found 190.9667. Appendix 1.4 Experimental for Chapter 3 Oxidation of Boronlc Esters to Phenols BPin OH I \ [0] _ / Br Br 2.28 2.33 Oxone — Entry 1, Table 3.1: To a stirred solution of boronic ester 2.2a (500 mg, 1.68 mmol) in acetone (5.4 mL), a solution of oxone (1.033 g, 1.68 mmol) and water (5.4 mL) was added dropwise. Upon complete addition, the reaction stirred for 7 min open to air and was then quenched with saturated aqueous NaHSOa. 132 After extraction with CHZCIZ, the combined organic layers were washed with water followed by brine and concentrated to afford 450.8 mg of crude product. The crude phenol was purified by flash silica gel chromatography (CHZCIZ) to provide 289.4 mg of 2.3a as a white solid (90%). For characterization see Appendix 1.3. THF/ HZOJNaOH - Entry 2, Table 3.1: To a stirred solution of boronic ester 2.2a (500 mg) in THF (2.7 mL), NaOH (0.62 mL, 1.86 mmol, 3.0 M in H20) was added, followed by H202 (0.19 mL, 1.86 mmol, 30% in H20). The reaction was stirred open to air for 10 minutes, quenched with saturated NaHSO3 and then stirred for an additional 15 minutes. After separation of layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 514.7 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CHZCIQ) to provide 289.4 mg of 2.3a as a white solid (92%). For characterization see Appendix 1.3. Acetone/HzogNaOH - Entry 3, Table 3.1: To a stirred solution of boronic ester 2.2a (500 mg) in acetone (2.7 mL), NaOH (0.62 mL, 1.86 mmol, 3.0 M in H20) was added, followed by H202 (0.19 mL, 1.86 mmol, 30% in H20). The reaction was stirred open to air for 10 minutes, quenched with saturated NaHSO3 and then stirred for an additional 15 minutes. After separation of layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 133 477.1 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CHZCIZ) to provide 289.1 mg of 2.3a as a white solid (92%). For characterization see Appendix 1.3. Acetone/H202 - Entry 4, Table 3.1: To a stirred solution of boronic ester 2.2a (500 mg) in acetone (2.7 mL), H202 (0.34 mL, 3.33 mmol, 30% in H20) was added. The reaction was stirred open to air for 10 h, quenched with saturated NaHSO3 and then stirred for an additional 15 minutes. After separation of layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 495.2 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CHZClz) to provide 261.3 mg of 2.3a as a white solid (83%). For characterization see Appendix 1.3. OH Br’ : Br i 2.313 3,5-leromo-4-lodophenol, 2.3b: To a stirred solution of boronic ester 2.2b (500 mg, 1.03 mmol) in acetone (5.5 mL), NaOH (0.38 mL, 1.14 mmol, 3.0 M in H20) was added, followed by H202 (0.12 mL, 1.17 mmol, 30% in H20). The reaction was stirred open to air for 10 minutes, quenched with saturated NaHSO3 and then stirred for an additional 15 minutes. After separation of layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and 134 concentrated to afford 367.0 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CHZCIZ) to provide 357.5 mg of 2.3b as a white solid (92%). For characterization see Appendix 1.3. MeOH/i-lZO2 - Entry 1, Table 3.2: To a suspension of boronic ester 2.2a (500 mg, 1.68 mmol) in MeOH (7.5 mL), H202 (0.19 mL, 1.86 mmol, 30% in H20) was added. The reaction was stirred for 17 h at rt open to air, quenched with saturated aqueous NaHSOa, and then stirred for an additional 15 min. After dilution with EtOAc and water, the layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 487.2 mg of the crude product as yellow oil. The crude phenol was purified by flash silica gel chromatography (CH2Cl2) to provide 296.9 mg of 2.3a as a white solid (94%). For characterization see Appendix 1.3. MeOH/H202 - Entry 2, Table 3.2: To a suspension of boronic ester 2.2a (500 mg, 1.68 mmol) in MeOH (7.5 mL), H202 (0.35 mL, 3.43 mmol, 30% in H20) was added. The reaction was stirred for 3 h at rt open to air, quenched with saturated aqueous NaHSOa, and then stirred for an additional 15 min. After dilution with EtOAc and water, the layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 487.2 mg of the crude product as yellow oil. The crude phenol was purified by flash 135 silica gel chromatography (CHQCIZ) to provide 296.9 mg of 2.3a as a white solid (94%). For characterization see Appendix 1.3. MeOH/Inigo2 - Entry 3, Table 3.2: To a suspension of boronic ester 2.2a (500 mg, 1.68 mmol) in MeOH (7.5 mL), H202 (0.19 mL, 1.86 mmol, 30% in H20) was added. The reaction was stirred for 3 h at rt open to air, quenched with saturated aqueous NaHSOa, and then stirred for an additional 15 min. After dilution with EtOAc and water, the layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2304, filtered and concentrated to afford 457.1 mg of the crude product as yellow oil. . The 1H NMR of the crude product showed a 1:78 ratio of the starting material 2.2a to product 2.3a. The crude phenol was purified by flash silica gel chromatography (CH20l2) to provide 263 mg of 2.3a as a white solid (84 %). For characterization see Appendix 1.3. EtOH/H202 - Entry 4, Table 3.2: To a suspension of boronic ester 2.2a (500 mg, 1.68 mmol) in EtOH (7.5 mL), H202 (0.35 mL, 3.43 mmol, 30 % in H20) was added. The reaction was stirred for 3 h at rt open to air, quenched with saturated aqueous NaHSO3 solution and then stirred for an additional 15 min. After dilution with EtOAc and water, the layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over NaQSO4, filtered and concentrated to afford 584.7 mg of the crude product as yellow oil. The crude phenol was purified by 136 flash silica gel chromatography (CHZCIQ) to provide 288.6 mg of 2.3a as a white solid (92 %). For characterization see Appendix 1.3. One-pot C-H activatlon/borylatlon/oxidatlon with Acetone/Hzoz/NaOH - Entry 1, Table 3.3: in a glovebox, a solution of lnd(lr)COD (14 mg, 0.03 mmol) and HBPin (370 (ii, 2.55 mmol) was added to a testtube with dmpe (5 mg, 0.03 mmol). The resulting solution was transferred to an airfree flask containing 3- bromotoluene 2.1a (204 pl, 1.68 mmol). The flask was closed, removed from the glovebox and heated at 150 °C in oil bath for 14 h. The reaction was cooled down, transferred to a round-bottom flask and concentrated. Acetone (2.7 mL) was added, followed by NaOH (0.62 mL, 1.86 mmol, 3.0 M in H20) and H202 (0.19 mL, 1.86 mmol, 30% in H20). The reaction was stirred open to air for 10 minutes, quenched with saturated NaHSO3 and then stirred for an additional 15 minutes. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 519.5 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CHQClz) to provide 232.9 mg of 2.3a as a white solid (74%). For characterization see Appendix 1.3. One-pot C-H activation/b0rylatlon/oxldatlon with MeOH/H202 — Entry 2, Table 3.3: In a glovebox, a solution of lnd(lr)COD (14 mg, 0.03 mmol) and HBPin (370 (ii, 2.55 mmol) was added to a testtube with dmpe (5 mg, 0.03 mmol). The resulting solution was transferred to an airfree flask containing 3-bromotoluene 137 2.16 (204 pl, 1.68 mmol). The flask was closed, removed from the glovebox and heated at 150 °C in oil bath for 14 h. The reaction was cooled down, transferred to a round-bottom flask and concentrated. Methanol (7.5 mL) was added to the flask, followed by H202 (0.35 mL, 3.43 mmol). The reaction was stirred for 2 h at rt before 2 mL of saturated aqueous solution of NaHSO3 was added and then stirred for additionally 15 min. After dilution with EtOAc and water, the layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over NaZSO4, filtered and concentrated to afford 620.7 mg of the crude product as yellow oil. The crude phenol was purified by flash silica gel chromatography (CHZCIZ) to provide 245.0 mg of 2.3a as a white solid (78%). For characterization see Appendix 1.3. One-pot C—H activation/borylatlon/oxldatlon with EtOH/H202 - Entry 3, Table 3.3: In a glovebox, a solution of lnd(lr)COD (14 mg, 0.03 mmol) and HBPin (370 pl, 2.55 mmol) was added to a testtube with dmpe (5 mg, 0.03 mmol). The resulting solution was transferred to an airfree flask containing 3-bromotoluene 2.16 (204 (ii, 1.68 mmol). The flask was closed, removed from the glovebox and heated at 150 °C in oil bath for 14 h. The reaction was cooled down, transferred to a round-bottom flask and concentrated. Ethanol (7.5 mL) was added to the flask, followed by H202 (0.35 mL, 3.43 mmol). The reaction was stirred for 2 h at rt before 2 mL of saturated aqueous solution of NaHSO3 was added and then stirred for additionally 15 min. After dilution with EtOAc and water, the layers 138 were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, followed by water, dried over Na2804, filtered and concentrated to afford 558 mg of the crude product. The crude phenol was purified by flash silica gel chromatography (CH20I2) to provide 247.0 mg of 2.3a as a white solid (78%). For characterization see Appendix 1.3. OH Cl’ : Br 3.2 3-Bromo-5-chlorophenol, 3.2:76'7‘3'80'83 In a glovebox, a solution of [lr(MeO)(COD)]2 (87 mg, 0.13 mmol) and HBPin (2 mL, 13.8 mmol, 1% TEA) was stirred at rt in a 100 mL 3 necked round bottom for 5 min, before dtbpy (71 mg, 0.26 mmol) was added together with more HBPin (1 mL, 6.9 mmol, 1% TEA). The resulting deep red solution was stirred for an additional 5 minutes, before 3.1 (5.05 g, 26.38 mmol) together with additional HBPin (1.8 mL, 12.4 mmol, 1% TEA) and cyclohexane (5 mL) were added. The flask was sealed, removed from the box, and connected to a reflux condenser under N2 flow. The reaction was heated at 60 °C in oil bath for 6 h. After cooling to rt, the dark brown solution was transferred to a round bottom flask with CH2CI2 and concentrated. EtOH (100 mL) was added to the reaction mixture, followed by H202 (5.4 mL, 52.8 mmol, 30% in H20). The reaction was left stirring open to air at rt for 45 min before saturated aqueous NaHSO3 solution was added and stirred for an additional 15 minutes. After dilution with water and EtOAc, the layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed 139 with brine, followed by water, dried over Na2804, filtered and concentrated to afford 8.44 g of the crude product. The crude phenol was purified by flash silica gel chromatography (CHZCIZ) to provide 5.02 g of 2.25 as a white solid (92%). Mp 67-68 °C (lit.76 66-68 °C); 1H NMR (500 MHz, CDCIS) 6 (ppm) 7.08 (t, J = 1.7 Hz, 1 H) 6.89 (dd, J: 1.6, 2.3 Hz, 1 H), 6.78 (dd, J: 1.7, 2.3 Hz, 1 H), 4.88 (bs, 1 H); 13C NMR (126 MHZ, CDCI3) 6 (ppm) 156.6, 135.7, 124.1, 122.9, 117.4, 115.0. OH NO f CI 3.4 3-Chloro-5-hydroxybenzonltrlle, 3.4:78 B,Pin2 (27 g, 106 mmol, used as received), [ir(OMe)COD]2 (1.10 g, 1.7 mmol), d‘bpy (885 mg, 3.3 mmol) and 3- dibromo-benzonitrile (15 g, 109 mmol) was‘weighed in the air and transferred to a dry 250 mL round bottom flask. After being flushed with nitrogen, hexanes (140 mL, used as received) were added. The reaction was heated in an oil bath at 55 °C for 110 min. After concentration under reduced pressure, the crude boronic ester was dissolved in CH2CI2 and silica gel was added to quench the remaining HBpin. The slurry was added to a pad of dry silica (Q = 8.5 cm, h = 4 cm) and eluated with CHZCIQ. The resulting red oil was dissolved in EtOH (75 mL, 100%) and cooled in an ice-bath. H202 (23 mL, 225 mL, 30% in water) was added over 25 minutes. The reaction mixture was stirred in the ice-bath for an additional 10 minutes before the ice-bath was removed and the reaction was stirred at rt for 100 minutes. After concentration under reduced pressure, the orange solids 140 were stirred in water (300 mL) overnight. The solids were filtered off, washed with water and air dried to afford 13.41 g of the desired phenol as an off-white solid with a trace of pinacol by-product. Mp 166-167°C (lit.78 165-166 °C); 1H NMR (500 MHz, DMSO) 6 (ppm) 10.71 (bs, 1 H), 7.40 (t, J = 1.7 Hz, 1 H), 7.14-7.12 (m, 2 H) "‘0 NMR (126 MHz, DMSO) 6 (ppm) 158.8, 134.6, 122.2, 120.5, 117.7, 117.5, 113.4. Appendix 10.5 Experimental for Chapter 4 Progress in the Total Synthesis of Autolytimycin - The Right Half >L o o MeO 0 OTIPS 4.4 (R)-Methyl-2-((S)-2,2-dimethyI-1 ,3-dloxolan-4-yI)-2-((triIsopropylsilyl)oxy) acetate, 4.4: To a solution of alcohol 4.3 (5.57 g, 29.3 mmol) and DMAP (10.7 g, 87.8 mmol) in dry DMF (80 mL) at rt, TIPS-Ci (12.5 mL, 58.4 mmol“) was added over a few minutes. The reaction was stirred for 20 h at rt and then quenched with half saturated NaHCO3 and ether (160 mL). After dissolving the formed solids in water, the layers were separated and the aqueous layer was further extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (hexanes/ether, 6:1) to provide 9.17 g (90%) of 4.4 as clear oil. TLC analysis (hexanes/ether, 6:1, R, = 0.31); [3]?"D +11.0° (c 1.195, EtOH); 1H NMR (300 MHZ. CDC'a) 6 (ppm) 4-41 (d. J = 5-5 Hz. 141 1H), 4.25 (q, J= 6.3 Hz, 1H) 4.01 (m, 2H), 3.69 (8, 3H), 1.32 (S, 3H), 1.28 (s, 3H), 1.12-0.94 (m, 21 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 171.5, 109.7, 77.1, 73.2, 65.1, 51.7, 26.1, 25.0, 17.74, 17.70, 12.1. >L 00 HO OTIPS 4.5 (R)-1-((S)-2,2-DlmethyI-1 ,3-dloxolan-4-yl)-2-methyl-1-((trilsopropylsllyl)oxy) propan-2-ol, 4.5: To a solution containing methyl magnesium iodide (3.0 M in THF, 40 mL, 120 mmol) and ether (30 mL) in a three necked round bottom equipped with a reflux condenser at rt, a solution of 4.4 (4.29 g) in 30 mL ether added via cannula, another 10 mL ether was used to rinse the flask. The resulting solution was heated in an oil bath at 45 °C for 40 min, cooled down and quenched with water. The formed slurry was stirred at rt with saturated sodium potassium tartrate solution until the solids were dissolved. The layers were separated, rnore saturated sodium potassium tartrate solution was added to the aqueous layer to dissolve the last the solids, and the white aqueous layer was extracted with ether. The combined organic layers were dried over M9304 and concentrated. The crude alcohol was purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide 4.5 as white crystals 3.76 g (88%). Mp 74-75 °C (lit.61 74-75.5 °C); TLC analysis (hexanes/ether, 1:1), R, = 0.37, [ot]2°D -5.9° (c 1.17, EtOH), 1H NMR (500 MHz, CDCI3) 6 (ppm) 4.030-3.95 (m, 2 H), 3.65-3.59 (m, 2 H), 2.19 (bs, 1 H), 1.37 (S, 3 H), 1.31 (8,3 H), 1.22-1.14 (m, 3H), 1.19 (S, 3 142 H), 1.16(s, 3 H), 1.08 (d, J: J: 2.1 Hz, 9 H), 1.06 (d, J: 2.1 Hz, 9 H); ”C NMR (126 MHz, CDCla) 6 (ppm) 107.7, 80.8, 77.5, 72.3, 66.9, 26.6, 25.4, 25.3, 16.4, 13.4. >L O O M OTIPS 4.6 (((S)-1-((S)-2,2-DlmethyI-1 ,3-dloxolan-4-yi)-2-methylalIyl)oxy)trllsopropyl silane, 4.6: To a solution of 4.5 (3.53 g, 10.2 mmol) and pyridine (80 mL) at 0 °C, SOCI2(1.5 mL, 20.6 mmol) was added dropwise over 15 min, after 5 min at 0 °C, the reaction was stirred at rt for 75 min. The dark orange solution was quenched at 0 °C with saturated Na2003 solution until no more gas evolved. Half saturated Na?_CO3 and ether was added till the solids were dissolved into three layers. The two organic layers (ether and pyridine) were washed with water. The two aqueous layers were both extracted with ether. The combined organic layers were washed once with water followed by 5% CuSO, until the dark blue color had changed to a light blue color and once more with water. The organic layer was dried over M9804 and concentrated. The crude olefin was purified by flash silica gel chromatography (hexanes/methylene chloride, 3:2) to provide 4.6 as clear oil 2.87 g (86%). TLC analysis (hexanes/methylene chloride, 3:2), R, = 0.38, [011200 - 20° (01.15, EtOH); 1H NMR (300 MHz, CDCI3) 6 (ppm) 4.91 (bs, 1 H), 4.86 (bs, 1 H), 4.21-4.10 (m, 2 H), 3.83 (dd, J: 6.3, 8.5 Hz, 1 H), 3.62 (t, J: 7.7 Hz, 1H), 1.73 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H), 1.16-0.98 (m, 21 H); 130 NMR (126 MHz, 143 CDCI3) 6 (ppm) 144.8, 113.3, 109.4, 78.6, 78.4, 65.9, 26.5, 25.4, 18.3, 17.99, 17.98, 12.4. HO OH M OTIPS 4.7 (2S,3S)-4-Methyl-3-((triIsopropyisllyl)oxy)pent-4-ene-1,2-dlol, 4.7: To a stirred solution of 4.6 (2.32 g, 7.06 mmol) in methanol (42 mL, used as received) at 0 °C, TFA (14.0 mL) was added dropwise. After 5 min at 0 °C, the reaction was stirred open to air at rt for 1 h. Saturated aqueous Nazco3 solution was then added until no more gas evolved. The resulting mixture was partitioned between saturated aqueous NaHCOa, water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were. dried over MgSO,,, filtered and concentrated. The crude diol was purified by flash silica gel chromatography (hexanes/ethyl acetate, 3:2) to provide 4.7 as clear oil 1.74 g (85%). TLC analysis (hexanes/ethyl acetate, 3:2), Ft, = 0.47; [01]?"D - 92° (01.13, EtOH); 1H NMR (300 MHz, CDCI3) 6 (ppm) 4.97 (m, 1 H), 4.92 (m, 1 H), 4.19 (d, J: 6.6 Hz, 1 H), 3.65-3.58 (m, 2 H), 3.49 (dd, J = 5.5, 11.2 Hz, 1 H) 2.70 (bd, J: 2.4 Hz, 1 H), 2.03 (bs, 1 H), 1.73 (dd, J: 0.9, 2.2 Hz, 3 H), 1.13-1.03 (m, 21 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 144.6, 114.3, 77.5, 73.5, 62.9, 18.00, 17.95, 17.6, 12.4. 144 HO OTs OTIPS 4.8 (2S,3S)-2-Hydroxy-4-methyl-3-((trllsopropylslIyl)oxy)pent-4-en-1-yl 4-methyl benzenesulfonate, 4.8: To a stirred solution of 4.7 (1.71 g, 5.93 mmol), CHZCI2 (20 mL) and EtaN (8 mL, 57.7 mmol) at 0 °C, tosylchloride (1.26 g, 6.61 mmol) was added in one batch. The ice in icebath was allowed te melt and the reaction slowly reached rt. After 15 h the reaction was quenched with saturated aqueous NaHCO3 solution and diluted with CHZCIZ. After separation of layers, the aqueous layer was extracted with CHzClz. The combined organic layers were dried over MgSO,, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/ethyl acetate, 6:1) to provide 4.8 as clear oil 2.36 g (90%). TLC analysis (hexanes/ethyl acetate, 6:1) R, = 0.37; [OJZOD -24.8° (01.15, EtOH); 1H NMR (300 MHz, CDCIS) 6 (ppm) 7.79-7.76 (m, 2 H), 7.33-7.31 (m, 2 H), 4.94 (m, 1 H), 4.90 (m, 1 H), 4.18 (cl, .1: 5.7 Hz, 1 H), 4.05 (dd, J: 4.3, 10.3 Hz, 1 H), 3.94 (dd, J: 6.0, 10.1 Hz, 1 H), 3.73 (m, 1 H), 2.54 (d, J: 4.5 Hz, 1 H), 2.43 (d, J: 0.2 Hz, 3 H), 1.68 (dd, J: 0.9, 1.3 Hz, 3 H), 1.05-0.98 (m, 21 H); ”C NMR (126 MHz, CDCI3) 6 (ppm) 144.8, 143.9, 132.8, 129.8, 128.0, 114.5, 76.2, 71.1, 70.2, 21.6, 17.98, 17.95, 12.4. 145 O M OTIPS 4.9 Trllsopropyl(((.S‘)-2-methyl-1-((S)-oxlran-2-yl)allyl)oxy)sllane, 4.9: To a stirred solution of 4.8 (22.33 g, 5.26 mmol) in methanol (used as received, 26 mL) at 0 °C, K2003 (1.23 g, 8.90 mmol) was added in one portion. The reaction was stirred open to air for 3 h at 0 °C and then poured into half saturated NH,CI and on0|,, (1 :1). The layers were separated and the aqueous layer was extracted with CHZCIZ. The combined organic layers were dried over MgSO,,, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/ CHzclz, 3:2) to provide 4.8 as clear oil 1.34 g (94%). TLC analysis (hexanes/ CHZCIZ, 3:2), R, = 0.33; [01]”D -9.8 (c1.13, EtOH); 1H NMR (500 MHz, CDCI3) 6 (ppm) 4.98 (m, 1 H), 4.85 (t, J: 1.5 Hz, 1 H), 3.81 (d, J: 6.3 Hz, 1 H), 3.00 (m, 1 H), 2.75 (dd, J: 4.2, 4.5 Hz, 1H), 2.56 (dd, J: 2.9, 5.1 Hz, 1 H), 1.77 (s, 3 H), 1.11-1.03 (m, 21 H) ‘30 NMR (126 MHz, 600,) 6 (ppm) 144.8, 112.1, 78.7, 55.9, 44.7, 18.6, 17.9, 17.9, 12.3. OTIPS 4.10 (3S,4S)-2-MethyI-3-((trllsopropylsllyl)oxy)hepta-1,6-dlen-4-ol, 4.10: To a stirred solution of 4.9 (290 mg, 1.07 mmol) and CuCN (16 mg, 0.18 mmol) in THF (5 mL) at -40 °C vinyl magnesium chloride was added slowly. After 30 min at -40 146 °C, the reaction was allowed to warm up to -25 °C and was then stirred for another 16 h, before being quenched with saturated aqueous N628203 solution. Saturated aqueous Na2003 and ether were added until most solids were dissolved. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were over M9804, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexane/CHZCIQ, 2:1) to provided 298 mg (93%) 4.10 as clear oil. TLC analysis (hexanes/ CHZCIZ, 3:2), Ft, = 0.35; [01]?“D = -19.7 (c = 1.16, EtOH); NMR (500 MHz, CDCIS) 6 (ppm) 5.88 (m, 1 H), 5.09-5.03 (m, 2 H), 4.93 (m, 1 H), 4.89 (m, 1 H), 4.01 (d, J: 7.1 Hz, 1 H), 3.57 (m, 1 H), 2.55 (d, J: 2.7 Hz, 1 H), 2.27-2.22 (m, 1 H), 2.05 (m, 1 H), 1.71 (dd, J: 0.7, 1.2 Hz, 1 H), 1.12-1.02 (m, 21H) 13C NMR (126 MHz, CDCI3) 6 (ppm) 144.8, 135.2, 116.8, 114.4, 60.5, 72.6, 37.0, OTIPS 16.1, 16.0, 17.6, 12.5. 4.11 Trllsopropyl(((3S,4.S)-4-methoxy-2-methylhepta-1 ,6-dlen-3-yl)oxy)sllane, 4.11:61 To a stirred solution of 4.10 (292.6 mg, 0.980 mmol) in dry toluene (5 mL) at -78 °C, KHMDS (5.9 mL, 2.95 mmol, 0.5M in toluene) was added at a rate of 1 mL/min. After 30 minutes, MeOTf (0.55mL, 4.96 mmol) was added slowly. The reaction mixture was allowed to slowly warm up to rt. After 16h it was quenched with saturated aqueous NaHCO3 solution. The layers were separated and the 147 aqueous layer was extracted with ether. The combined organic layers were dried over MgSO,,, filtered and concentrated. The crude product, 410 mg yellow oil was purified by flash silica gel chromatography (hexanes/CHZCIZ, 5:1) to provide 4.11 as clear oil 287 mg (94%). TLC analysis (hexanes/CHZCI2, 5:1), R, = 0.35; [01]?"D - 1.1 (01.207, EtOH); 1H NMR (500 MHz, CDCI3) 6 (ppm) 5.86 (dddd, J: 7.1, 7.1, 10.3, 17.3 Hz, 1 H), 5.04 (dq, J: 1.5, 17.1 Hz, 1 H), 5.01-4.98 (m, 1 H), 4.94 (m, 1 H), 4.87 (m, 1 H), 4.26 (d, J: 6.1 Hz, 1 H), 3.42 (s, 3 H), 3.22 (ddd, J: 2.9, 6.1, 8.8 Hz, 1 H), 2.33-2.27 (m, 1 H), 2.01-1.94 (m, 1H), 1.73 (t, J: 0.98 Hz, 3 H), 1.12-0.95 (m, 21 H); 130 NMR 6 (ppm) 145.0, 136.0, 116.2, 113.1, 84.5, 76.9, 58.8, 34.7, 18.9, 18.1, 18.0, 12.4. HO OTIPS 4.14 (3S,4S)-2-Methyl-3-((trilsopropylsllyl)oxy)octa-1,7-dlen-4-ol, 4.14: To a stirred solution of 4.9 (484 mg, 1.79 mmol) in THF (9 mL) at 0 °C, allyl magnesium chloride (2.0 M in THF, 2.7 mL, 5.4 mmol) was added. Upon completed addition the ice bath was removed. After 2 h the reaction was quenched with water, then stirred with saturated aqueous Na2003 solution until a white slurry formed. After dilution with ether, the layers were separated and the aqueous layer was back extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude alcohol was purified by flash silica gel chromatography (hexanes/ CH2012, 3:1) to provide 2.18 as clear oil 547 mg 148 (98%). TLC analysis (hexanes! CHZClz, 3:1), Ft, = 0.24; [012% + 1.7 (c 1.16, CHzClz); lR (neat) 3586, 3488, 3077, 2946, 2894, 2889, 1642, 1464, 1088, 1063 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.60 (ddd, J: 6.8, 13.4, 17.1 Hz, 1 H), 5.01 (qd J: 1.7, 18.8 Hz, 1 H), 4.94-4.92 (m, 2 H), 4.88 (t, J: 1.7 Hz, 1 H), 3.96 (d, J: 7.1 Hz, 1 H), 3.49 (ddd, J: 2.9, 7.1, 10.0 Hz, 1 H), 2.53 (dd, J: 0.7, 2.0 Hz, 1 H), 2.27 (m, 1 H), 2.11 (m, 1 H), 1.69 (s, 3 H), 1.52-1.46 (m, 1 H), 1.40-1.34 (m, 1 H), 1.12-1.00 (m, 21 H); 130 NMR (126 MHz, CDCIS) 6 (ppm) 144.9, 138.5, 114.6, 114.4, 61.4, 72.3, 31.6, 30.0, 18.1, 18.0, 17.5, 12.4; HRMS (El) m/e calcd for [C,8H36028i+H]* 313.2563, calcd 313.2563. MeO OTIPS 4.13 TrlIsopropyl(((3S,4S)-4-methoxy-2-methylocta-1 ,7-dlen-3-yl)oxy)sllane, 4.13: To a stirred solution of 4.12 (792mg, 2.53 mmol) in dry toluene (16 mL) at -78 °C, KHMDS (15 mL, 7.5 mmol) was added at a rate of 1 mL/min. Upon completed addition the reaction was stirred for 30 minutes. MeOTf (1 .45mL, 12.8 mmol) was then added slowly. The resulting reaction mixture was allowed to slowly reach rt. After 14h the reaction was quenched with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/CHZCIZ, 5:1) to provide 4.13 as clear oil 758 mg (92%). TLC analysis (hexanes/CHzclz, 149 5:1), R, = 0.32; [(11200 -13.5 (c 1.09, CHzclz); IR (neat) 3077, 2946, 2894, 2869, 1642, 1464, 1383, 1370, 1111, 1067, 903, 884 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.76 (ddd, J: 6.3, 13.2, 17.1 Hz, 1 H), 4.99 (qd, J: 1.5, 17.1 Hz, 1 H), 4.93-4.86 (m, 3 H), 4.26 (d, J: 6.1 Hz, 1 H), 3.44 (s, 3H), 3.16 (ddd, J: 3.7, 6.1, 9.0 Hz, 1 H), 2.20 (m, 1 H), 2.07 (m, 1 H), 1.72 (s, 3 H), 1.61-1.54 (m, 1H), 1.33- 1.25 (m, 1 H), 1.11-1.02 (m, 21 H); "*0 NMR (126 MHz, CDCla) 6 (ppm) 145.2, 138.9, 114.5, 112.8, 83.9, 77.2, 58.9, 30.1, 29.6, 19.0, 18.09, 18.05, 12.5; HMBC and H800 analysis indicated the above connectivity; HFtMS (El) m/e calcd for [C19H38028HH]+ 327.2712, calcd 327.2719. TIPSO _ OMe TIPS migration TIPS migration of 4.13: To a stirred solution of 4.12 (387 mg, 1.24 mmol) in dry THF (8 mL) at -78 °C, KHMDS (7.5 mL, 3.75 mmol) was added at a rate of 1 mL/min. Upon completed addition the reaction was stirred for 15 minutes. MeOTf (0.7 mL, 6.19 mmol) was then added slowly. The resulting reaction mixture was allowed to slowly reach rt. After 13h the reaction was quenched with saturated aqueous NaHCO3 solution, forming a gel type solution, which was diluted with ether, water and brine to form a homogeneous mixture, which separated over time. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried over MgSO,,, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes) to 150 provide 4.13 as clear oil 192 mg (47%), further purified by flash silica gel chromatography (hexanes) to provide the TIPS migrated product as clear oil 131 mg (32%). TLC analysis (hexanes/ CHZCIQ, 5:1) R, = 0.59; [01]”: +102 (0: 1.00, CHzCiz); IR 3077, 2944, 2889, 2822, 1653, 1559, 1464, 1379, 1103, 1017, 907, 884 cm“; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.78 (m, 1 H), 4.98-4.88 (m, 4 H), 3.85 (m, 1 H), 3.36 (d, J: 7.8 Hz, 1 H), 3.13 (s, 3 H), 2.15 (m, 2H), 1.61 (m, 3H), 1.51 (m, 1 H), 1.37 (m, 1 H), 1.15-1.00 (m, 21 H); 13C NMR (126 MHz, CDCia) 6 (ppm) 142.5, 139.2, 115.5, 114.1, 90.0, 72.9, 55.7, 33.3, 28.8, 18.32, 18.31, 17.3, 13.0; HRMS (El) m/e calcd for [C,9H3802$i+H]* 327.2714, calcd 327.2719. 4.15 (R)-Trllsopropyl((2-methylpenta-1,4-dlen-3-yl)oxy)sllane, 4.15: To a stirred solution of epoxide 4.9 (1.409, 5.18 mmol) and CuCN (79.1mg, 0.883 mmol) in 25 mL THF at 0 °C, allylmagnesium chloride was added dropwise. Upon complete addition, the icebath was removed and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous N62820:, affording a dark green slurry, which was diluted with ether and saturated aqueous N62003. The layers were separated and the organic phase was extracted 3 times with ether, dried over M9804 and concentrated. The crude product was purified by gradient flash silica gel chromatography (hexanes to hexane/dichloromethane, 3:1) to provided 954mg (69%) of 4.14 and 282mg (21 %) of 4.15 as clear oil. 151 For 4.15: TLC analysis (hexanes), R, = 0.76; [01]“), = +202 (0 = 1.12, CHZCIZ); lR (neat) 3077, 2946, 2894, 2869, 1642, 1464 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 5.75 (ddd, J: 5.6, 10.5, 17.1 Hz, 1 H), 5.24 (dt, J: 1.7, 17.31 Hz, 1 H), 5.05 (dt, J: 1.7, 10.3 HZ, 1 H), 4.97 (m, 1 H), 4.77 (t, J: 1.5 HZ, 1 H), 4.59 (d, J = 5.4 Hz, 1 H), 1.65 (t, J: 1.0, 1.2 Hz, 3 H), 1.11-0.99 (m, 21 H) ”C NMR (126 MHZ, CDCI3) 6 (ppm) 147.0, 140.5, 113.8, 110.3, 77.7, 18.02, 18.00, 17.2, 12.3; HRMS (El) m/e calcd for [C,5H30OSI+H]+ 255.2141, calcd 255.2144. O H MeO OTIPS 4.12 (4S,SS)-4-Methoxy-6-methyl-5-((trllsopropylsllyl)oxy)hept-6-enal, 4.12: To a stirred of 4.13 (2.11 g, 6.46 mmol), in dioxane/water (12 mL, 3:1), 2,6-lutidine223 (1.5 mL, 12.88 mmol) was added, followed by OsO4 (2.5 wt% in isopropanol, 0.81 mL, 0.065 mmol) and NaiO4 (5.53 g, 25.84 mmol). A white slurry resulted. After 40 minutes, the reaction was diluted with water and CHZCIZ. The layers were separated and the aqueous layer was extracted with CHZCIZ. The combined organic layers were dried over M9804, filtered and concentrated. The crude aldehyde was purified by flash silica gel chromatography (hexanes/ethyl acetate, 15:1) to provide 4.12 as light yellow oil 1.70 g (80%). TLC analysis (hexanes/ethyl acetate, 10:1), R, = 0.32; [(11200 = -26.5 (c = 1.21, acetone); 1H NMR (500 MHz, CDCI3) 6 (ppm) 9.69 (t, J = 1.95 Hz, 1H), 4.95 (m, 1 H), 4.90 (m, 1 H), 4.27 (d, J: 6.1 Hz, 1H), 3.38 (S, 3 H), 3.16 ddd, J: 3.2, 5.9, 9.0 Hz, 1 H), 152 2.45 (m, 2 H), 1.87 (m, 1 H), 1.73 (bs, 3 H), 1.57 (m, 1 H), 1.09-1.01 (m, 21 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 202.6, 144.8, 113.2, 83.8, 76.9, 58.7, 40.6, 23.1, 19.0, 18.1, 18.0, 12.4. BO 0 \ MeO OTIPS 4.16 (6S,7S,E)-Ethyl-6-methoxy-2,8-dlmethyl-7-((trllsopropylslIyl)oxy)nona-2,8— dienoate, 4.16: To a stirred solution of 4.12 (1.94 g, 5.90 mmol) in toluene (50 mL) at rt, 1-carbethoxyethylidenethriphenylphosphorane was added (2.78 mg, 7.68 mmol). The flask was equipped with a reflux condenser and heated at reflux (oil bath at 110 °C) overnight (15 h). After cooling down to rt, the solution was filtered and the resulting solids were washed with hexanes. The filtrate was concentrated to afford 3.67 mg of a oil containing white solids. The products were present as a 15:1 E/Z ratio as determined by 1H NMR of the crude product. The crude product was purified by flash silica gel chromatography (hexanes/ethyl acetate, 15:1) to provide 4.16 (mixture of E and Z, 15:1) as clear oil 2.35 mg (96%). TLC analysis (hexanes/ethyl acetate) 15:1, R, = 0.38; [01]"‘0D = -10.6° (c 1.08, EtOH); Spectra assign for major isomer.‘H NMR (500 MHz, CDCIa) 6 (ppm) 6.72 (qt, J: 1.5, 7.1 Hz, 1 H), 4.94 (m, 1 H), 4.66 (quintet, J: 1.7 Hz, 1 H), 4.30 (d, J: 5.6 Hz, 1 H), 4.16 (q, J: 7.5 Hz, 2 H), 3.43 (s, 3 H), 3.15 (ddd, J: 1.7, 5.6, 9.0 HZ, 1 H), 2.31-2.19 (m, 2 H), 1.81 (d, J: 1.3 HZ, 3 H), 1.72 (s, 3 H), 153 1.67-1.60 (m, 1 H), 1.39-1.29 (m, 1 H), 1.27 (t, J: 7.1 Hz, 3 H), 1.10-1.01 (m, 21 H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 168.2, 145.0, 142.1, 127.9, 112.9, 84.1, 76.3, 60.3, 58.7, 28.8, 25.0, 19.2, 18.1, 18.0, 14.3, 12.4, 12.3. HQN O \ MeO OTI PS 1 .58 (63,7S,E)-6-Methoxy-2,8-dimethyl-7-((trllsopropylsllyl)oxy)nona-2,8- dlenamlde, 1.56: To a suspension of NH,CI (913 mg, 17.07 mmol) in benzene (14 mL) at 0 °C, AlMe3 (2.0 M in toluene, 8.5 mL, 17.00 mmol) was added via syringe. (More AlMe3 can be added if not all crystals dissolve.) After a few minutes at 0 °C, the mixture was allowed to warm it rt and stirred until no more gas evolved and a clear solution formed. This solution was transferred through cannola to a solution containing, 4.16 (15:1, E/Z, 2.35 g, 5.69 mmol) in benzene (50 mL). The resulting solution was heated to 50 °C for 7 h. After which another batch of NH4CI and AlMe3 in benzene was added. After another 15 h, the solution was cooled down, quenched with HCI (1 M) and stirred over saturated aqueous sodium potassium tartrate solution for 1.5 h. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over NaSO4, filtered and concentrated. The crude amide, 1.45 g was purified by flash silica gel chromatography (hexanes/ethyl acetate, 1:1) to provide 1.5a E as a white solid 1.72 g (79%). 154 For 1.5a E: Mp 61-62 °C (lit.6‘62-65 °C); TLC analysis (hexanes/ethyl acetate, 1:1) F1, = 0.27; [01120D = -13.5 (c = 1.06, acetone); 1H NMR (500 MHz, CDCIa) 6 (ppm) 6.37 (qt, J = 1.3, 7.8 Hz, 1 H), 5.49 (bs, 2 H), 4.93 (m, 1 H), 4.87 (t, J = 1.7 Hz, 1 H), 4.32 (d, J= 5.7 Hz, 1 H), 3.46 (s, 3 H), 3.15 (ddd, J= 2.8, 5.7, 8.8 Hz, 1 H), 2.31-2.15 (m, 2 H), 1.84 (d, J=1.2 Hz, 3 H), 1.72 (s, 3 H), 1.66-1.59 (m, 1 H), 1.36-1.29 (m, 1 H), 1.10-1.00 (m, 21 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 171.2, 144.9, 137.7, 130.0, 112.9, 84.2, 76.4, 58.8, 29.0, 24.9, 19.1, 18.1, 18.0, 12.7, 12.4. The Z isomer of 1.5a was difficult to obtain pure and was isolated as a slightly impure as a clear oil: TLC analysis (hexanes/ethyl acetate, 1:1, R, = 0.35), 1H NMR (300 MHz, CDCI3) 6 (ppm) 5.84 (bs, 1 H), 5.56 (m, 1 H), 5.38 (bs, 1H), 4.93 (bs, 1 H), 4.88 (bs, 1 H), 4.30 (d, J: 5.86 Hz, 1 H), 3.41 (s, 3 H), 3.20 (m, 1 H), 2.44-2.32 (m, 2 H), 1.89 (d, J: 1.2 Hz, 3 H), 1.71-1.57 (m, 4 H), 1.40-1.28 (m, 1 H), 1.10-0.98 (m, 21 H); 130 NMR (126 MHz, CDCI3) 6 (ppm) 172.0, 144.9, 134.6, 131.0, 113.0, 83.7, 76.3, 58.2, 29.2, 25.7, 20.9, 19.0, 18.03, 18.01, 12.4. OH 161 4.16 2-Methylpenta-1,4-dlen-3-ol, 4.18:9”24 To a stirred solution of methacrylein (706mg, 10 mmol) in THF (25 mL) at '0 °C, vinyl magnesium chloride (1.6M in THF, 9.0 mL, 14 mmol) was added dropwise. After 40 min at 0 °C, the reaction was quenched with saturated aqueous NH4CI solution, diluted with water until all solids dissolved and the layers were separated. The aqueous layer was extracted 155 with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude alcohol was purified by kugelrohr distillation (20 torr, 50- 60 °C) to provide 4.18 as clear oil 559.1 mg (58%). 1H NMR (500 MHz, CDCla) 6 (ppm) 5.84 (ddd, J: 6.0, 10.4, 17.1 Hz, 1 H), 5.29 (dt, J: 1.5, 17.2 Hz, 1 H), 5.16 (dt, J: 1.3, 10.4 Hz, 1 H), 5.02 (m, 1 H), 4.86 (m, 1 H), 4.53 (d, J: 6.1 Hz, 1 H), 1.71 (m, 3 H), 1.66 (bs, 1 H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 146.1, 138.9,115.6,111.1,76.8,18.1. OH m 4.20 1-(2-Methylox|ran-2-yl)prop-2-en-1-ol, 4.20: 4 A M5 (20 mg), Ti(OiPr),, (16 pl, 54 umol) and (—)-DET (12 pl, 70 umol) were stirred for 30 min in CHZCI2 (1.5 mL) at -35 °C before 4.18 (52mg, 0.54 mmol) was added, followed by cumenehydroperoxide (80%, 0.2 mL, 1.08 mmol). The resulting solution was stirred for 24 h at -35 °C, quenched with 0.5 mL of saturated aqueous NaZSO, and stirred for another 3 h, before being diluted with water. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried over NaZSO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/ethyl acetate, 4:1) to provide 4.20 as clear oil 17mg (29%) containing a 9:1 ratio of 4.20 to 4.17a. TLC analysis (hexanes/ethyl acetate, 3:1) R, = 0.34; 1H NMR (500 MHz, CDCI3) 6 (ppm) 5.79 (ddd, J = 6.6, 10.5, 17.1 Hz, 1 H), 5.39 (dt, J = 1.5, 17.3, Hz, 1 H), 5.3 (dt, J: 1.2, 10.3 Hz, 1 H), 4.11 (d, J: 5.6 Hz, 1 H), 2.90 (d, J: 4.9 Hz, 156 1 H), 2.60 (d, J: 4.9 Hz, 1 H), 2.15 (d, J: 1.7 Hz, 1 H), 1.34 (s, 3 H); ‘30 NMR (126 MHz, 000,) 6 (ppm) 135.9, 116.1, 73.4, 58.6, 50.1, 17.9. OH OH + m W0 4.20 4.17a 1-(2-Methyloxlran-2-yl)prop-2-en-1-ol, 4.20 and 2-methyi-1-(oxlran-2-yl)prop- 2-en-1-ol, 4.17a: To a solution of Ti(OiPr)4 (0.31 mL, 1.05 mmol) in methylene chloride (6 mL) with 4 A Ms (250 mg) at -20 °C, (—)-DET (0.21 mL, 1.23 mmol) was added. After 30 min, t-BuOOH (1.2 mL, 4.32 mmol, 3.6 M in toluene) was added and after an additional 30 min diene (199.3mg, 2.07 mmol) was added. The reaction was stirred at -20 °C for 40 h and then quenched with 2 mL saturated Na2804 solution. The resulting mixture was stirred at rt for 4 h. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over NaZSO4 and concentrated. The crude product, 714.9 mg of yellow oil with 4.20 and 4.17a in a ratio of 6 to1 by 1H NMR, was purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide 118.1 mg of 4.20 and 4.17a (7:1) as clear oil (50%). o o§/l—\- 4.21 (R)-Glycldal, 4.21:100 DMP (2.40 g, 5.66 mmol) in CHzcl2 (57mL) was stirred for 10 min, and then (R)-glycidol 4.22 (250 pl, 3.77 mmol) in CHZCI2 (15 mL) was added slowly. The resulting mixture was stirred at rt for 2.5 h then poured onto a silica gel column (2:25 cm, 80 mL silica), that was buffered with 1 % TEA in 157 CH2CI2. The product was eluted with 100 % CHZCI2 and concentrated to provide 146 mg (53 %) 4.21 as light yellow oil, 155 mg contaminate with 9 mg CH2CI2 (7 wt%). TLC analysis (TLC pretreated with 1 % TEA in CHZClz, 100 % CHQClz), R, = 0.47; [01]?"D = -169.6° (c= 1.01, CHZCIZ); 1H NMR (500 MHz, CDCI3) 6 (ppm) 8.94 (d, J: 6.3 Hz, 1 H), 3.33 (m, 1 H), 3.12 (m, 1H), 3.01 (dd, J: 2.4, 5.4 Hz, 1 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 198.0, 53.0, 44.5. (k/loA (A220 : M 4.21 4.17a Representative procedure of alkenylzlnc addition to 4.21: To a stirred solution of 4.21 (40.6 mg, 0.526 mmol, 93.4 wt%), in CH2CI2 (5.3 mL) at -78 °C, diisopropenylzinc (prepared as described above) was slowly added. The reaction was stirred at -78 °C for 30 min then quenched at -78 °C with sat. NH,,CI and stirred at rt until all solids were dissolved. After dilution with CHZClz, the layers were separated. The aqueous layer was extracted with CHZClz, dried over Na2804, filtered and concentrated to afford 95 mg oil of the crude product (1:2.1, syn:anti determined by 1H NMR analysis). The crude epoxides were purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide16.7 mg of the epoxyalcohol 4.17a (~28%, 1:2.3 diastereomeric ratio) as clear oil. TLC analysis (hexanes/ether, 1:1), Ft, = 0.30. 158 O O xxx-MM: OH OTIPS 4.17a 4.96 General procedure for TIPS protection of 4.17a: To a flask containing DMAP (54.5 mg, 0.446 mmol), a solution of 31 (16.7 mg, 0.146 mmol) in DMF (1 mL) was added. After all DMAP had dissolved, TIPS-Cl (62.5 ul, 0.292 mmol) was added and the reaction was stirred at rt for 2 days. The reaction was quenched with half saturated aqueous NaHCO3 solution. Ether was added and layers were separated. The aqueous layer was extracted with ether. Combined organic layers were dried over MgSO4, filtered and concentrated to afford 188 mg of orange oil (1 :1.7 syn/anti). The crude product was purified by flash silica gel chromatography (hexanes/ CHZCIZ, 2:1) to provide the product as clear oil 14.2 mg (~36 %, 1:1.6 syn/anti). TLC analysis (hexanes/ CHZCIZ, 3:2, R, = 0.33); NMR containing two diastereomers in 1:1.6 ratio. 1H NMR (300 MHz, CDCIa) 6 4.99- 4.95 (m, 2.6 H), 4.90-4.85 (m, 2.6 H), 4.19 (d, J: 3.9 Hz, 1.6 H), 3.61 (d, J: 6.1 Hz, 1 H), 3.00 (m, 1 H), 2.93 (m, 1.6 H), 2.79-2.74 (m, 2.6 H), 2.70 (dd, J: 3.9, 5.6 Hz, 1.6 H), 2.56 (dd, J: 2.7, 4.9 Hz, 1 H), 1.77-1.76 (m, 7.7 H), 1.11-0.98 (m, 54 H). 159 O O OMe OMe l + l OMe 4.25 4.27 (Z)-Methyl 4-methylpenta-2,4-dlenoate, 4.25 and (Z)-methyl 4-methoxy-4- methylpent-Z-enoate, 4.27909"111 To stirred mesityl oxide 4.26 (4.9 g, 49.8 mmol) at 0 °C, Br2 (16 g, 99.5 mol) was added dropwise via an addition funnel over 30 min, after complete addition the solution was stirred for an additional 30 min at 0 °C. The resulting tribromide 4.28 was used directly. To a stirred solution of NaOMe (45.5 mL, 199 mmol, 25 wt% in MeOH) in MeOH (45.5 mL, used as received) at 0 °C, 4.28 (49.8 mmol) was added dropwise over 30 min. The resulting reaction was stirred for an additional 2 h at 0 °C, before being poured over ice and extracted with pentanes. The combined organic layers were dried over MgSO.1 and concentrated. The crude mixture, containing a 1:1 mixture of 4.25 and 4.27, was purified through Kugelrhor distillation (aspirator, ~20 mm Hg, 80 °C), affording a 2.11 g, 22 % (1 :1.5 ratio of 4.25:4.27), together with some impurities and 25 wt% CHzClz. This mixture was used in the following step without further purification. OH OH I , l OMe 4.24 4.29 (Z)-4-Methylpenta-2,4-dlen-1-ol, 4.24 and (Z)-4-methoxy-4-methylpent-2-en- 1-ol, 4.29: To a stirred solution 4.25 and 4.27 (2.08 g, 11.0 mmol, 1:1.5, 160 4.25:4.27) in CHZCI2 (73 mL) at -78 °C, DIBAl-H (22 mL, 27.1 mmol, 20 wt% in toluene) was added. After 40 min, the reaction was quenched with MeOH at -78 °C. Saturated aqueous NaCl solution and ether were added and the mixture was stirred for 40 min, before NaK-tartrate was added to dissolve the solids. EtOAc was added and the layers were separated. The aqueous layer was extracted once more with EtOAc; this second organic layer was filtered to remove the resulted gel-like suspension. The combined organic layers were washed with saturated aqueous NaCI solution, dried over N32804, filtered and concentrated. The crude product mixture was purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide 355 mg of 4.24 (~86%, calculated from initial ratio) and 494.4 mg of 4.29 (~56%, calculated from the initial ratio), yield based on initial ratio of the esters. NMR showed impurities, which could not be removed by further purification by column. For 4.24: TLC analysis (hexanes/ether, 1:1), Fl, = 0.39; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.93 (dd, J: 1.2, 11.7); 5.60 (dt, J= 6.3, 12.0 Hz, 1H), 4.99 (t, J = 1.5 H, 1H), 4.74 (s, 1H), 4.36 (dd, J= 1.7, 6.3 Hz, 2H), 1.83 (s, 3H), 1.58 (bs, 1H); 130 NMR (126 MHz, CDCI3) 6 (ppm) 141.0, 132.7, 130.3, 116.4, 59.7, 22.9. For 4.29: TLC analysis (hexanes/ether, 1:1), R, = 0.20; 1H NMR (500 MHz, CDCI3) 6 (ppm) 5.59 (dt, J: 5.5, 12.3 Hz, 1 H), 5.36 (dt, 1.8, 12.2 Hz, 1 H), 4.26 (dd, J: 1.7, 5.5 Hz, 2 H), 3.21 (s 3 H), 1.31 (s, 6 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 135.2, 130.4, 75.9, 59.7, 50.3, 27.2. 161 OH “Cr 4.23a ((2R,3S)-3-(Prop-1-en-2-yl)oxiran-2-yl)methanol, 4.23a: To a solution of Ti(OiPr),, (115.2 mg, 0.41 mmol) in CHZClz (3 mL) with 4 A Ms (110 mg) at -20 °C, (-)-DET (0.08 mL, 0.47 mmol) was added. After 20 min t-BuOOH (0.44 mL, 1.58 mmol, 3.6 M in toluene) was added and after an additional 20 min 4.24 (78.5 mg, 0.81 mmol) was added. The reaction was stirred at -20 °C for 63 h, then quenched with 2 mL saturated NaZSO4 solution. The resulting mixture was stirred at rt for 1 h. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated. The crude product (209.2 mg yellow oil) was purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide 52.0 mg of epoxide as clear oil (57%). A small amount of tartrate was detectable by NMR. TLC analysis (hexanes/ ether, 1:1), Ft, = 0.22; 1H NMR (500 MHz, CDCIS) 6 (ppm) 4.98 (s, 1H), 4.96 (m, 1H), 3.68 (m, 1H), 3.569 (m, 1H), 3.45 (dt, J: 0.7, 4.4 Hz, 1H), 3.28 (dt, J= 4.6, 6.8 Hz, 1H) 1.77 (ddd, J= 0.7, 1.0 Hz, 3H) 1.55 (bs, 1H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 136.1, 112.3, 60.2, 582,576, 19.7. o . OH OH rt, 1.5 h Ho“ (5:1, 4.23a,4.30) 4.23a 64% 4.23a 4-30 Payne rearrangement of 4.23a: To a flask containing epoxide 4.236 (57 mg, 0.5 mmol), aqueous NaOH (1 mL, 0.5 mmol) was added and the reaction was stirred 162 at 0 °C for 1.5h. After saturation with (NH,)ZSO4, the aqueous layer was extracted with methylenechloride (3x4 mL). The combined organic layers were washed with half saturated (NH,,)2SO4 aqueous solution, dried over M9804 and concentrated. The crude product 36.4 light mg yellow oil (64%) showed by NMR analysis a ratio of 5:1, 4.23a/4.30. Appendix 1.6 Experimental for Chapter 6 Generation of the Aromatic Core with the Fully Elaborate Pieces OH 0 CI N H MeO OTIPS 1.3a (65,7S,E)-N-(3-Chloro-5-hydroxyphenyi)-6-methoxy-2,8-dlmethyl-7- ((trllsopropylsllyl)oxy)nona-2,8-dlenamlde, 1.5a:61 In the glovebox, a dry airfree flask was charged with arene 3.3 (118 pl, 1.00 mmol) followed by a premixed solution of [lnd(lr)COD] (8.3 mg, 0.02 mmol), dmpe (3 mg, 0.02 mmol) and distilled l-prin (290 (ii, 2.00 mmol). (The premixed catalyst solution mixture was prepared by the addition of HBpin to [lnd(lr)COD], followed by dmpe in HBpin). The flask was sealed, removed from the glovebox and heated at 150°C in an oil bath. The reaction was followed by GC-FID until consumption of SM (< 3%). After 5 h the dark yellow brownish oil was put under vacuum for several hours to remove volatiles. It was then returned to the glovebox. The air free flask 163 was charged with amide 1.5a (576 mg, 1.50 mmol), szdba3 (9.2 mg, 0.01 mmol), xantphos (17.4 mg, 0.03 mmol), C52003 (456 mg, 1.40 mmol), and DME (3 mL). The flask was closed, brought out of the glovebox and the yellow suspension was heated in an oil bath at 100 °C for 5h or until judged complete by GC-FID, 3.5h. After being cooled to room temperature, the reaction was filtered through a pad of silica (1 cm, Q = 3 cm) and eluted with acetone until no more uv activity was detected. The reaction was concentrated, redissolved in acetone (6.7 mL) and a solution of oxone (923 mg, 1.50 mmol) in water (4.4 mL) was added dropwise. The resulting slurry was stirred at rt, open to air, for 40 minutes before a suspention of NalO4 (214 mg, 1.00 mmol) in 1 mL water was added, followed by an additional 1 mL of acetone. The reaction was stirred for an additional 60 min at rt, before being diluted with EtOAc (40 mL). After separation of the layers, the aqueous layer was extracted twice with EtOAc (15 mL), solid NaHSO3 was then added until color appeared and diminished. This aqueous layer was by back-extracted twice with EtOAc (15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO,, filtered and concentrated to afford 806 mg of brown oil. The crude amide was purified flash silica gel chromatography (CH2Cl22EtOAc, 12:1—>3:1) to provide 291 mg (57%) of the desired product 1.3a as a light orange solid, 34.5 mg (6%) of unpure Suzuki product 2.23, and 292 mg of the starting material, amide 1.5a was also recovered as _a brown solid, which was further purified by flash silica gel chromatography (hexaneszEtOAc, 1:1) to provide 273 mg (48%) of amide 1.5a as a white solid. 164 For 1.3a: Mp 105.5-107.5°C (lit.61 106.5-108°C); TLC analysis (CHzclzzEtOAc, 9:1), R,= 0.41; [01]”D -12.9 (61.13, acetone); 1H NMR (500 MHz, CDCI3) 6 (ppm) 6.77 (bs, 1H), 7.66 (t, J: 2.1 Hz, 1H), 7.46 (bs, 1H), 6.62 (t, J: 2.0 Hz, 1H) 6.34 (tq, J: 1.2, 7.3) 4.96 (s, 1H), 4.90 (t, J: 1.6 Hz, 1 H), 4.31 (d, J: 5.6 Hz, 1 H), 3.46 (S, 3 H), 3.20 (ddd, J: 2.7, 5.9, 8.8 Hz, 1 H), 2.35-2.3 (m, 2 H), 1.92 (S, 3 H), 1.74 (S, 3 H), 1.68 (dddd, J= 2.9, 7.3, 10.0, 16.6 HZ, 1 H), 1.37 (dddd, J: 5.9, 8.5, 14.4, 20.0) 1.11-1.01 (m, 21 H); 13C NMR (126 MHZ, CDCIS) 6 (ppm) 169.4, 158.7, 144.9, 139.1, 138.1, 134.7, 131.6, 113.0, 112.5, 110.7, 105.9, 84.2, 76.4, 58.8, 28.9, 25.1, 19.1, 18.1, 18.0, 12.9, 12.4. For the Suzuki product: TLC analysis (CH20I2:EtOAc, 12:1), R,= 0.43; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.6 (dd, J: 1.7, 1.7 Hz, 1 H), 7.57 (bs, 1H), 7. 50 (dd, J=1.8,2.0 Hz, 1 H), 7.18 (dd, J: 1.7, 1.7 HZ, 1H), 7.02 (dd, J: 1.6, 1.7 HZ, 1 H), 6.84 (dd, J: 1.6, 2.2 Hz, 1H), 6.81 (dd, J: 1.8, 2.2 Hz, 1 H), 6.44 (dq, J: 1.2, 7.6 Hz, 1 H), 6.23 (bs, 1H), 4.96 (t, J: 1.0 HZ, 1 H), 4.90 (t, J: 1.6 Hz, 1 H), 4.32 (d, J: 5.7 Hz, 1 H), 3. 46 (s, 3 H), 3.20 (ddd, J: 2.7, 5.7, 6.6 Hz, 1 H), 2.38- 2.24 (m, 2 H), 1.94 (s, 3 H), 1.74-1.66 (m, 4 H), 1.41-1.34 (m, 1H), 1.11-1.02 (m, 21 H); ‘30 NMR (126 MHz, CDCI3) 6 (ppm) 166.0, 157.0, 144.9, 142.0, 141.9, 139.2, 138.0, 135.2, 135.0, 131.4, 123.0, 119.6, 119.4, 117.1, 115.5, 113.0, 112.7, 84.4, 76.3, 58.8, 29.0, 25.2, 19.2, 18.1, 18.0, 12.7, 12.4. 165 OTPS Cl Br 6A (3-Bromo-5-chIorophenoxy)trlIsopropylsllane, 6.1: To a stirred solution of phenol 3.2 (2.20 g, 10.6 mmol) and DMAP (259 mg, 2.12 mmol) in CHZCI2 (18 mL) at 0 °C, distilled TEA (1.6 mL, 11.5 mmol) was added, followed by TIPSCI (2.5 mL, 11.7 mmol). The ice bath was removed and the reaction was stirred at rt. After 6 h it was partitioned between half saturated NaHCO,3 and EtOAc. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2804, filtered and concentrated to afford 3.26 g of crude product as yellow oil. The crude product was purified flash silica gel chromatography (100% hexane), to provide 3.77 g (98%) of the desired product 6.1 as clear oil. TLC analysis (hexane), R, = 0.61; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.08 (t, J: 2.0 Hz, 1 H), 6.91 (dd, J = 1.7, 2.2 Hz, 1 H), 6.79 (t, J : 2.0 Hz, 1 H), 1.26-1.19 (m, 3 H), 1.09-1.07 (m, 16 H); 1so NMR (126 MHz, CDCI3) 6 (ppm) 157.4, 135.2, 124.2, 122.5, 121.7, 119.3, 17.8, 12.6. OPMB Cl Br 6.4 1-Bromo-3-chloro-5-((4-methoxybenzyl)oxy)benzene, 6.4:?25 To a stirred slurry of bromochlorophenol 3.2 (1.29 g, 6.22 mmol) and dried 032003 (6.08 g, 18.7 mmol) in DMF (6.5 mL), PMB-Cl (1.46 g, 9.32 mmol) was added. The reaction was stirred for 17 h at rt before being diluted with half saturated brine 166 solution and EtOAc. After separation of the layers, the organic layer was washed with water. The combined aqueous layers were back extracted once with EtOAc. The combined organic layers were dried over Na2804, filtered and concentrated to afford 2.40 g of the crude product as yellow oil. The crude product was purified by flash silica gel chromatography (hexane:CH2Cl2, 2:1) to provide 1.79 g of the desired product 6.4 as a white solid (88%). Mp 49-50.5 °C (lit.225 49-50 °C); 1H NMR (500 MHz, CDCla) 6 (ppm) 7.30 (d, J= 8.8 Hz, 2 H), 7.09 (t, J= 1.7 Hz, 1 H), 7.00 (dd, J: 1.7, 2.2 Hz, 1 H), 6.91 (d, J= 8.8 Hz, 2 H), 6.89 (t, J= 1.7 Hz, 1 H), 4.93 (s, 2 H), 3.81 (s, 3 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 159.9, 159.7, 135.5, 129.3, 127.8, 123.9, 122.8, 116.9, 114.5, 114.1, 70.4, 55.3; IR (neat) 3083, 3002, 2934, 2836, 1613, 1588, 1564, 1516, 1250, 1036, 1009, 828 cm". OPMB CI IZ MeO OTIPS 6.4 (6S,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-6-methoxy-2,8- dlmethyI-7-((trllsopropylsllyl)oxy)nona-2,8-dlenamlde, 6.5:128 in a glovebox, a dry airfree flask was charged with amide 1.5a (576 mg, 1.50 mmol), aryl 6.4 (492 mg, 1.50 mmol), szdba3 (30 mg, 0.03 mmol), xantphos (54 mg, 0.09 mmol), and DME (6 mL). The flasked was closed, brought out of the glovebox and heated in an oil bath at 100 °C for 36 h. The reaction was cooled to rt, filtered through 167 celite, eluated with CH20I2 and concentrated to afford 1.57 mg of the crude product as orange solid. The crude amide was purified by flash silica gel chromatography (hexanezEtOAc, 8:1 ), followed by hexane wash to provide 777.5 mg of the desired product 6.5 as a white solid (82%). Mp 93-94 °C; TLC analysis (hexanezEtOAc, 5:1), R, = 0.30; [(11200 = -8.9 (c = 1.10, CHzclz); 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.36 (s, 1 H), 7.31 (d, J: 8.7 Hz, 2 H), 7.29 (t, J: 2.1 Hz, 1 H), 7.07 (t, J: 1.8 Hz, 1 H), 6.89 (d, J= 8.8 Hz, 2 H), 6.70 (t, J: 2.1 Hz, 1 H), 6.35 (qt, J: 1.3, 7.7 Hz, 1 H), 4.95-4.89 (m, 4 H), 4.31, (CI, J= 5.6 Hz, 1 H), 3.80 (s, 3 H), 3.45 (s, 3 H), 3.18 (ddd, J: 2.8, 5.7, 8.8 Hz, 1 H), 2.34-2.21 (m, 1 H), 1.91 (d, J: 1.0 Hz, 3 H), 1.73 (s, 3 H), 1.67 (m, 1 H), 1.36 (m, 1 H), 1.10-1.03(m, 21 H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 167.5, 159.9, 159.5, 144.9, 139.9, 137.1, 134.9, 131.8, 129.3, 128.3, 114.0, 112.9, 112.3, 111.4, 104.6, 84.3, 76.3, 70.1, 58.7, 55.3, 29.0, 25.1, 19.2, 18.1, 18.0, 12.7, 12.4. OPMB OTIPS 6.6 (6S,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyI)-6-methoxy-N-(4- methoxybenzyl)-2,8-dlmethyl-7-((trilsopropylslIyl)oxy)nona-2,8-dIenamlde, 6.6: To a stirred solution of PMB-Cl (70 (ii, 0.52 mmol) in DMF (0.5 mL), amide 1.3a (200 mg, 0.39 mmol) and dried 032003 (383 mg, 1.18 mmol) were added. 168 The reaction was stirred for 2 days at rt before being diluted with half saturated brine solution and EtOAc. After separation of layers, the aqueous layer once extracted with EtOAc. The combined organic layers were washed with water, dried over N32804, filtered and concentrated to afford 298 mg of yellow solids. The crude product was purified by flash silica gel chromatography (hexanezEtOAc, 5:1) to provide 156 mg of the desired product 6.6 as a white solid (63%) and 88 mg 016.5 as thick oil (30%). For 6.5: TLC analysis (hexanezEtOAc, 5:1) R, = 0.18; [01]”D = -11.4 (c = 1.167, CHZCIZ); 1l-l NMR (500 MHz, CDCla) 6 (ppm) 7.24 (d, J: 8.8 Hz, 2 H), 7.10 (d, J= 8.8 Hz, 2 H), 6.88 (d, J= 8.8 Hz, 2 H), 6.78 (d, J= 8.8 Hz, 2 H), 6.75 (t, J= 2.2 Hz, 1 H), 6.53 (t, J: 2.0 Hz, 1 H), 6.38 (t, J= 2.2 Hz, 1 H), 5.56 (qt, J= 1.2, 7.6 Hz, 1 H) 6.66 (m, 1H), 4.63 (m, 1 H), 4.61 (s, 4 H), 4.18 (d, J: 6.1 Hz, 1 H), 3.60 (s, 3 H), 3.76 (s, 3 H), 3.36 (s, 3 H), 3.02 (ddd, J: 2.9, 6.1, 9.0 Hz, 1 H), 2.05- 1.97 (m, 1 H), 1.94-1.86 (m, 1 H), 1.66 (s, 3 H), 1.61 (s, 3 H), 1.32-1.26 (m, 1 H), 1.09-0.96 (m, 21 H); 13C NMR (126 MHz, CDCIa) 6 (ppm) 172.8, 159.7, 159.4, 158.9, 145.6, 144.9, 136.1, 134.7, 131.4, 129.7, 129.6, 129.1, 127.9, 120.1, 114.1, 113.8, 113.6, 113.0, 112.6, 84.3, 77.2, 70.2, 58.9, 55.3, 55.2, 52.5, 28.9, 24.3, 18.8, 18.1, 18.0, 14.3, 12.4; IR (neat) 3079, 2940, 2867, 1653, 1588, 1514, 1456, 1250, 1173, 1105 cm"; HRMS (TOF MS ES+) m/e calcd for [C4,H60No,ol+H]+750.3957, found 750.3955. 169 n-octylMgCI 6.7 n-Octylmagneslum chloride, 6.7: To stirred magnesium metal (272.3 mg, 11.2 mmol) at rt, dibromoethane (9 (ii, 0.10 mmol) was added, followed by 0.5 mL. of a solution of 1-chlorooctane in THF (1.7 mL, 10.0 mmol chloride in 20 mL THF). The resulting mixture was heated with a heat gun until gas evolved from the surface of the metal. The remaining chloride solution was slowly added and the subsequent reaction mixture was stirred at rt until the magnesium dissolved (about 3 days). The Grignard titrated to 0.37 M (74%) and was used without further purification. OTIPS -£?l*n (E)-N-(3-Chloro-5-((trllsopropylsllyl)oxy)phenyl)-2—methylbut-2-enamlde, 6.9:61 To a stirred solution of tiglic amidophenol (791.0 mg, 3.51 mmol) in DMF (12 mL) was DMAP (642.3 mg, 5.26 mmol) added, followed by slow addition of TIPS-Cl (0.83 mL, 3.88 mmol) when DMAP was dissolved. The reaction was stirred overnight then partitioned between half saturated NaHCOa and EtOAc. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to afford 5.51 g of crude product as yellow oil. The crude amide was purified by flash silica gel chromatography (hexanezether, 6:1), followed by a hexane wash to provide 943 mg (70%) of the desired product 6.9 as a white solid. Mp 87-88 °C 170 (lit.61 82-83 °C). TLC analysis (hexanezEtOAc, 8:1), R: 0.31; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.27 (bs, 1 H), 7.14 (t, J: 2.2 Hz, 1 H), 7.09 (t, J: 2.0 Hz, 1 H), 6.60 (t, J: 1.7 Hz, 1 H), 6.48 (qq, J: 1.5, 6.8 Hz, 1 H), 1.91(dq, J: 1.2, 1.2 Hz, 3 H), 1.80 (dq, J: 7.1, 1.2 Hz, 3 H), 1.30-1.21 (m, 3 H), 1.09-1.08 (m, 18 H); 13C NMR (126 MHz, cook) 6 (ppm) 167.42, 157.2, 139.6, 134.6, 132.8, 131.6, 115.9, 112.5, 109.7, 17.9, 14.1, 12.6, 12.5. OTIPS _ D / n octyl H M 6.10 (E)-2-Methyl-N-(3-octyl-5-((trlIsopropylsllyl)oxy)phenyl)but-2-enamlde, 6.10: To as stirred solution of B-MeO-9BBN (1.51 mL, 1.51 mmol, 1 M in hexanes) at - 78 °C, freshly made octylmagnesium chloride 6.7 (2.25 mL, assumed 1.51 mmol, 0.67 M in THF, used without titration) was added slowly. Upon complete addition, the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (10 mL) was added followed by freeze-degas-thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride (144.5 mg, 0.38 mmol), l=’d(OAc)2 (8.5 mg, 0.038 mmol) and S-Phos (30.9 mg, 0.075 mmol). The flask containing the now orange solution was topped with a reflux condenser and heated under nitrogen at 110 °C for 12 h. After the reaction was cooled to rt, it was filtered through celite. To the organic phase 70 mL water was added. After separation of the layers, the aqueous layer was extracted 3 times with 10 mL EtOAc. The combined organic layers were washed with 5 mL brine, dried over 171 NaSO4 and concentrated to afford 1.48 g of an orange oil. The crude product was purified by flash silica gel chromatography (100% methylenechloride) to provide 128.1 mg (74%) of the desired product 6.10 as light yellow oil. TLC analysis (methylenechloride), R,= 0.70; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.27 (bs, 1H), 7.05 (t, J= 2.0 Hz, 1 H), 6.86 (s, 1H), 6.47 (dq, 1.5, 6.8 H, 1H), 6.44 (t, 1.5 H, 1H), 2.49 (t, J: 7.7 Hz, 2H), 1.91 (t, 1.2 Hz, 3H), 1.78 (dd, J= 1.2, 8.1 Hz, 3H), 1.54 (m, 2H), 1.28-1.20 (m, 13H), 1.08 (d, J: 2.7 Hz, 18 H), 0.86 (t, J: 7.0 Hz, 3H); 13C NMR (126 MHz, CDCla) 6 (ppm) 167.4, 156.3, 144.7, 138.8, 132.9, 131.0, 115.8, 112,5, 108.8, 35.9, 31.9, 31.2, 29.5, 29.3, 29.2, 22.7, 17.9, 14.10, 14.07, 12.6, 12.5; IR (neat) 3305, 3152, 3032, 2926, 2867, 1665, 1632, 1611, 1595, 1547, 1462, 1431, 1288, 1183, 1017, 884 cm"; HRMS (ESI) m/e calcd for [C-,,,,H,,9NOZSi+H]+ 460.3622, found 460.361 1 . Entry 1, Table 6.1 — 2 equiv of Grignard: To a stirred solution of B-MeO-9BBN (0.4 mL, 0.40 mmol, 1 M in hexanes) at -78 °C, freshly titrated octylmagnesium chloride 6.11 (1.2 mL, 0.40mmol, 0.33 M in THF, titrated) was added slowly. Upon complete addition, the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (4 mL) was added followed by freeze-degas-thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride 6.9 (76.6 mg, 0.20 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S- Phos (16.5 mg, 0.04 mmol). The flask was topped with a reflux condenser and heated under nitrogen at 110 °C for 12 h. After the reaction was cooled to rt, it was filtered through celite. To the organic phase water was added. After 172 separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated to afford 620.7 mg of an orange oil. The crude product was purified by flash silica gel chromatography (100% methylenechloride) to provide 81.7 mg (75%) clear oil of the desired product 6.11 and starting material 6.9 in a 7.321 ratio as determined by 1H NMR of the isolated mixture. Entry 2, Table 6.1 — 1.1 equiv of Grignard: To as stirred solution of B-MeO- 9BBN (0.22 mL, 0.22 mmol, 1 M in hexanes) at -78 °C, freshly titrated octylmagnesium chloride 6.11 (0.67 mL, 0.22 mmol, 0.33 M in THF, titrated) was added slowly. Upon complete addition, the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (4 mL) was added followed by freeze- degas-thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride 6.9 (76.6 mg, 0.20 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S-Phos (16.5 mg, 0.04 mmol). The flask was topped with a reflux condenser and heated under nitrogen at 110 °C for 12 h. After the reaction was cooled to rt, it was filtered through celite. To the organic phase water was added. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated to afford 617.1 mg of an orange oil. The crude product was purified flash silica gel chromatography (100% methylenechloride) to provide 37.5 mg (42%) clear oil of the desired product 6.11 and starting material 6.9 in a 7.8:1 ratio as determined by 1H NMR of the isolated mixture. 173 Entry 3, Table 6.1 — 1.5 equiv of Grignard, no additives: To a stirred solution of B-MeO-9BBN (0.39 mL, 0.39 mmol, 1 M in hexanes) at -78 °C, freshly titrated octylmagnesium chloride 6.11 (1 mL, 0.39mmol, 0.39 M in THF, titrated) was added slowly. Upon complete addition the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (2.5 mL) was added followed by freeze- degas-thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride 6.9 (100 mg, 0.26 mmol), Pd(OAc)2 (5.9 mg, 0.026 mmol), and S-Phos (21.5 mg, 0.052 mmol). The flask containing the now orange solution was topped with a reflux condenser and the reaction was heated under nitrogen at 110 °C for 12 h. After the reaction was cooled to rt, it was filtered through celite. To the organic phase water was added. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated with MeOH overnight to afford 194.4 mg of a yellow oil. The crude product was purified by flash silica gel chromatography (100% methylenechloride) to provide 58.5 mg (42%) clear oil of the desired product 6.11 and starting material 6.9 in a 5.5:1 ratio as determined by 1H NMR of the isolated mixture. Entry 4, Table 6.1 — 1.5 equiv of Grignard and DMSO: To a stirred solution of B-MeO-9BBN (0.39 mL, 0.39 mmol, 1 M in hexanes) at -78 °C, freshly titrated octylmagnesium chloride 6.11 (1 mL, 0.39mmol, 0.39 M in THF) was added slowly. Upon complete addition the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (2.5 mL) was added followed by freeze-degas- 174 thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride 6.9 (100 mg, 0.26 mmol), Pd(OAc)2 (5.9 mg, 0.026 mmol), S-Phos (21.5 mg, 0.052 mmol) and DMSO (75 ul, 1.06 mmol). The flask containing the now orange solution was topped with a reflux condenser and the reaction was heated under nitrogen at 110 °C for 12 h. After the reaction had cooled down to rt, it was filtered through celite. To the organic phase water was added. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated with MeOH overnight to afford 214.8 mg as a yellow oil. The crude product was purified by flash silica gel chromatography (100% methylenechloride) to provide 81.7 mg of the desired product 6.11 as clear oil (68 %). Entry 5, Table 6.1 — 1.5 equiv of Grignard and KaPO,,-n H20: To a stirred solution of B-MeO-9BBN (0.39 mL, 0.39 mmol, 1 M in hexanes) at -78 °C, freshly titrated octylmagnesium chloride 6.11 (1 mL, 0.39mmol, 0.39 M in THF) was added slowly. Upon complete addition the cooling-bath was removed and the mixture was stirred at rt for 30 min. DMF (2.5 mL) was added followed by freeze- degas-thaw twice. After the solution reached rt, the reaction mixture was charged with arylchloride 6.9 (100 mg, 0.26 mmol), Pd(OAc)2 (5.9 mg, 0.026 mmol), S- Phos (21.5'mg, 0.052 mmol) and K3PO4-n H20 ( 110.4 mg, 0.52 mmol). The flask was topped with a reflux condenser and the reaction was heated under nitrogen at 110 °C. After 20 min the reaction turned green. The reaction was heated at 175 110 °C for totally 12 h and then cooled to rt, it was filtered through celite. To the organic phase water was added. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated with MeOH overnight to afford 185.8 mg crude product, mostly declorination was seen in the 1H NMR of the crude product. The arene was purified by flash silica gel chromatography (100% methylenechloride) to provide 25 mg (22%) clear oil of the desired product 6.11 and starting material 6.9 in a 4.5:1 ratio as determined by 1H NMR of the isolated mixture. OPMB CI 322 M60 6.17 (6S,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyI)-7-hydroxy-6- methoxy-2,8-dImethylnona-2,8-dienamlde, 6.17: To a stirred solution of amide 6.5 (300 mg, 0.476 mmol) in THF (25 mL) at 0 °C, TBAF (4.8 mL, 4.8 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over NaQSO4 and concentrated to afford 553.1 mg of the crude alcohol as an orange oil. The crude product was purified by flash silica 176 gel chromatography (hexanes:EtOAc, 1:1) to provide 221.1 mg (98%) of the desired product 6.17 as an opaque oil, which solidified after several days at rt. TLC analysis (hexanes:EtOAc, 1:1), R, = 0.25; [ot]"’°D = +154 (0 = 1.147, CHZCIZ); IR (neat) 3328, 3079, 2930, 2841, 1663, 1590, 1516, 1455, 1426, 1250, 1189, 1034 "cm; 1H NMR (500 MHz, CDCla) 6 (ppm) 7.37 (bs, 1 H), 7.32 (d, J = 8.8 Hz, 2 H), 7.28 (t, J: 2.1 Hz, 1 H), 7.08 (t, J= 1.7 Hz, 1 H), 6.89 (d, J: 8.8 Hz, 2 H), 6.71 (t, J= 1.8 Hz, 1 H), 6.38 (qt, J: 1.3, 7.3 Hz, 1 H), 5.03 (m, 1 H), 4.95 (s, 3 H), 3.97 (d, J: 6.5 HZ, 1 H), 3.80 (s, 3 H), 3.43 (s, 3 H), 3.26 (dt, J= 4.6, 6.3 Hz, 1 H), 2.52 (bs, 1 H), 2.27 (q, J: 7.6 Hz, 2 H), 1.92 (d, J: 1.2 Hz, 3 H), 1.75 (t, J = 1.0 Hz, 3 H), 1.72-1.56 (m, 2 H); 13C NMR (126 MHz, CDCIa) 6 (ppm) 167.3, 159.9, 159.6, 144.3, 139.8, 136.7, 135.0, 131.9, 129.3, 128.3, 114.0, 113.9, 112.4, 111.4, 104.7, 81.6, 77.1, 70.1, 58.3, 55.3, 29.1, 23.9, 18.0, 12.8; HRMS (ESI) m/e calcd for [CQGHSZNOSCHNar 496.1867, found 496.1867. DFT calculations of ROM reaction with B3LYP functional with a 6-311g basis set 177 They xyz coordinates for the optimized structure of 1.1. Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z 1 6 0 4.819445 2.349770 -0.567303 2 6 0 3.580071 2.945587 -0.320618 3 6 0 2.579796 2.159868 0.258158 4 6 0 2.833456 0.820533 0.602287 5 6 0 4.059370 0.224751 0.312427 6 6 0 5.068025 1.006682 -0.274730 7 1 0 3.410453 3.976762 -0.575804 8 1 0 2.042170 0.230786 1 .042996 9 1 0 6.033719 0.568444 -0.502027 10 7 0 1 .257555 2.608420 0.496259 1 1 6 0 0.671226 3.818024 0.205553 12 1 0 0.658350 1.913878 0.912611 13 8 0 1.309521 4.818587 -0.194603 14 6 0 -0.817358 3.875482 0.426317 15 6 0 -1.598919 2.824251 0.114038 16 1 0 -1.128924 1.948200 -0.328697 17 6 0 -1.308627 5.211817 0.922215 18 1 0 -1.019199 5.377365 1.964338 19 1 0 -0.834380 6.000601 0.337771 20 1 0 -2.388062 5.318318 0.843187 21 6 0 -3.096176 2.718009 0.285031 178 22 23 24 25 26 27 26 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43 44 45 46 47 46 49 50 51 52 53 54 55 56 57 56 59 60 61 62 63 64 65 d—A—‘AQ—Lm—témmmm—L-Lm-Amd_.LAGAO—Lm—L—iéo—memmdm—Lm—L—Lw—Ld OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO -3.607121 -3.429671 -3.561 724 -2.721 858 -4.298567 -4.147704 -3.469632 -4.456029 -4.8351 58 -5.361 574 -5.488860 -3.220308 -2.520657 -2.91 1258 -2.880206 -3.788906 -2.487599 -2.142797 -1 .21 8988 -1 .325807 -0.071072 -0.379834 -0.926302 -0.789535 -1 .758606 -0.026072 1 .309221 1 .734540 2.235525 2.028823 1 .934442 0.13741 7 1 .13641 5 3.763848 4.250579 5.31 1 196 3.729403 5.792183 6.626127 -6.430467 -7.249491 -6.757594 -6.129806 4.227929 3.029765 3.40641 2 1 .277894 0.70221 7 1 .305455 0.5061 10 0.55241 6 -0.9921 17 -1 .055932 1 .14671 1 -1 .474854 -1 .87761 0 -2.202997 -1 .871 190 -2.336227 -2.6901 10 -1 .521 105 -3.136301 -2.998789 -3.913445 -2.1 90087 -1 .935185 -3.371830 -2.474563 -3.940979 -3.975180 -2.867143 -2.971831 -2.08271 8 -2.481 632 -1 .035671 -0.935779 -4.1 96421 -2.1 54754 -1 .259498 -1 .470249 -1 .557199 3.1 75141 2.697703 1 .492529 1 .837239 0.62801 9 2.298085 -1 .742891 179 -0.632970 1 .062584 0.636307 1 .032861 1 .442605 -0.548379 -1 .401 072 -0.221 662 0.803759 -1 .093662 -1 .1 23354 -0.346096 0.755927 1 .71 6220 -1 .743082 -2.227528 -2.360462 -1 .745749 0.830542 0.240968 0.1 70447 -0.845977 2.296773 2.902273 2.71 4864 2.399086 0.068250 1 .071 053 -0.88141 1 -1 .878230 -0.894003 0.91 8536 -0.542438 -0.63071 7 0.553227 0.71 8069 1 .468350 -1 .1 37922 -1 .281 460 -0.1 57495 -0.781 953 0.424207 0.51 31 45 -1 .534747 66 67 68 69 70 71 72 73 74 75 ..L—L—A—L—Lm—L-L‘O) OOOOOOOOOO 4.284028 3.954720 3.927643 5.376464 1 .200746 1 .99281 0 0.251 695 1 .430331 -0.734872 -5.864562 -3.594504 -4.031 954 -4.237247 -3.61 0888 -5.368974 -5.2761 23 -5.565528 -6.203429 -0.52481 0 -0.698599 -0.463896 0.481 909 -1 .269282 -0.467282 0.309492 1 .058024 0.81 2495 -0.348873 ‘1 .063902 -1 .587037 The xyz coordinates for the optimized structure of ROM Product. Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z 1 6 0 4.223577 4.136263 0.295140 2 6 0 2.834853 4.078272 0.293802 3 6 0 2.195543 2.960032 -0.260002 4 6 0 2.950984 1.915260 -0.813080 5 6 0 4.352605 1.973791 -0.794247 6 6 0 4.985488 3.095187 -0.237890 7 1 0 2.277822 4.896278 0.729570 8 1 0 2.442798 1.070765 -1.242166 9 1 0 6.067681 3.154707 -0.228162 10 7 0 0.775235 2.965539 -0.257883 11 6 0 -0.082060 1.892425 -0.383244 180 12 13 14 15 16 17 16 19 20 21 22 23 24 25 26 27 26 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43 44 45 46 47 46 49 50 51 52 53 54 55 mmmdAmdmdédm‘mémédémdmmmm‘mdm.A-Lmddmd—L—La—LQmm—L OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO 0.359499 0.336750 -1 .548994 -2.3921 86 -1 .926241 -1 .979984 -3.062725 -1 .596657 -1 .638627 -3.892837 -4.230859 -4.297427 -4.474489 -4. 1 31 235 -4.095702 -6.009393 -6.394054 -6.627703 -6.097488 -6.479795 -6.322639 -8.1 18030 1 .533883 1 .77641 5 -8.61 0764 -8.143626 -8.343484 -9.691 61 2 1 .560838 1 .371 558 2.93621 4 3.1 1381 9 0.4551 27 0.573074 -0.527539 0.504769 4.1 43945 4.3081 69 4.024745 3.687839 3.236498 2.880466 5.3201 87 5.327659 3.867183 0.71 6684 2.220096 1 .188065 0.221776 3.650834 3.741028 4.039939 4.318121 1 .192213 0.938184 2.182923 0.1 63155 -0.842492 0.396538 0.14581 1 1 .169505 -0.558573 -0.236209 -0.634232 -1 .991833 -0.354501 -2.680769 -3.503192 -0.968005 -0.490963 -2.025102 -0.873707 -3.017156 -2.107686 -3.56831 5 -4.504895 -4.040858 -4.957144 -3.622388 -4.301563 -2.643173 -2.546887 -1 .268164 -1 .415330 -0.719194 -3.868477 -3.319479 -0.439161 181 -0.094030 -0.527772 -0.3371 44 -0.528236 -0.6951 21 -0.097905 -0.059256 0.850836 -0.895795 -0.535400 -1 .5471 78 -0.31 5567 0.463636 0.21 6059 1 .461 333 0.503202 0.583894 -0.71 4640 -1 .61 2880 1 .655230 -0.624790 -0.952596 1 .798422 2.471 149 -2.242591 -3.1 10875 -2.279924 -2.344756 0.323647 -0.250792 -0.094527 0.454589 -0.021 299 0.565352 0.1 9941 0 -1 .076444 0.1621 20 1 .239054 -0.494532 -1 .5231 1 0 0.024293 -1 .520982 -0.4361 59 -0.50401 6 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 Adm—Ldméd—A—‘AG‘AAG‘A—L—Lmém—L—Am OOOOOOOOOOOOOOOOOOOOOOOOOO 5.185648 4.769727 6.1 92328 4.799031 5.769389 -6.430643 -6.8581 70 -5.407060 -7.026292 6.08281 5 5.840668 5.098598 6.081 188 6.751682 6.01 041 7 6.372893 5.373566 6.857452 3.79961 7 -6.571907 1 .1 98826 1 .1 6681 9 0.936085 -8.934398 -8.598691 -9.988595 0.846819 0.552682 1 .226350 5.278996 5.242318 0.0261 1 1 -0.674285 0.262105 0.945013 -1 .052769 -0.1 13352 0.445623 -1 .022890 0.489330 -4.258986 -3.760495 -5.100963 -4.630126 -4.022815 -2.273731 -1 .492937 -1.321 1 14 -0.659095 0.285302 0.698730 0.399779 -1.3781 11 -2.346251 -1 .575725 0.856779 0.82691 2 2.943945 3.655767 3.244898 2.936577 -1 .001 672 0.909875 1 .484054 1 .462967 0.86621 2 0.430220 1 .333883 0.71 5723 -0.1 40877 -1 .81 4638 0.277586 2.307230 3.376549 1 .666558 -0.1 08798 0.830893 -0.330064 The xyz coordinates for the optimized structure of ethylene. Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z 1 6 0 0.000000 0.665637 0.000000 2 6 0 0.000000 -0.665637 0.000000 3 1 0 -0.919057 1 .239135 0.000000 4 1 0 0.919057 1 .239135 0.000000 5 1 0 0.919057 -1.239135 0.000000 6 1 0 -0.919057, -1.239135 0.000000 delta H delta H RCM Product 1.1 ethylene (hartrees) (kcal/mol) -1638.162081 -1559.548845 -78.5917766 0.0214594 13.46596663 182 04: OTIPS 6.19 / (((S)-1-((S)-2,2-DImethyl-1 ,3-dloxolan-4-yl)allyl)oxy)trllsopropylsllane, 6.19: To a 0 °C stirred suspension of BrCHaPPh3 (1.62 g, 4.53 mmol) in THF (4 mL) , NaHMDS (4.5 mL, 4.50 mmol, 1.0 M in THF) was added and the resulting reaction was stirred for 2.75 h. in a separate flask, DIBAIH (3.1 mL, 3.10 mmol, 1.0 M in hexanes) was added to a stirred solution of ester 4.4 (1.05 g, 3.03 mmol) and toluene (10 mL) at -78 °C. The reduction was stirred at -78 °C for 1 h before the ylide was added. The cooling bath was removed and the reaction was allowed to reach rt over 30 minutes before being heated in an oil bath at 50 °C for 22 h. After being cooled to rt, Rochell salt and EtOAc were added to the reaction and the alyers were separated. The aqueous layer was extracted three times with EtOAc. Combined organic layers were dried over Na2804, filtered and concentrated. The crude product, 1.74 g of an orange oil containing white solids was purified by flash silica gel chromatography (hexanes/CHZCI2, 2:1) to provide 637.6 mg (67% over the two steps) of olefin 6.19 as clear oil. TLC analysis (hexanes/CHZCIZ, 2:1), R, = 0.24; [(11200 = -31.9 (c = 1.093, CHZCIZ); IR (neat) 3083, 2946, 2869, 1464, 1381, 1370, 1260, 1214, 1142, 1067, 884 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 5.84 (ddd, J = 5.7, 10.5, 17.2 Hz, 1 H); 5.31 (td, J: 1.6, 17.2 Hz, 1 H), 5.20 (td, J 1.3, 10.5 Hz, 1 H), 4.38 (tt, J: 1.3, 5.5 Hz, 1 H), 4.15 (q, J: 6.3 HZ, 1 H), 3.92 (dd, J= 6.7, 8.5 Hz, 1 H), 3.81 (dd, J: 6.2, 8.5 Hz, 183 1 H), 1.36 (s, 3 H), 1.31 (s, 3 H), 1.11-1.02 (m, 21 H); “’0 NMR (126 MHz, CDCl3) 6 (ppm) 136.5, 116.7, 109.3, 78.4, 74.0, 65.1, 26.3, 25.1, 18.0, 12.4; HRMS (ES) m/e calcd for [C,7H34038i+Na]*337.2175, found 337.2174. OH OH / OTIPS 6.20 (25,3S)-3-((TrlIsopropylsllyl)oxy)pent-4-ene-1,2-dlol, 6.19: To a stirred solution of the acetonide 6.19 (1.91 g, 6.07 mmol) in MeOH (30 mL) at 0 °C, TFA (10 mL) was added. Upon complete addition, the ice bath was removed and the reaction was stirred at rt for 1.5 h. The reaction was quenched with saturated aqueous INIaZSO4 and diluted with EtOAc and water. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined the organic layers were dried over Na2804, filtered and concentrated. The crude product, 7.08 mg of a white oil was purified by flash silica gel chromatography (hexanes/EtOAc, 2.5:1) to provide 1.51 g (91 %) of the diol 6.20 as clear oil. TLC analysis (hexanes/EtOAc, 2.521), R, = 0.26; [(11200 = -0.3 (c = 1.12, CHZCIQ) IR (neat) 3397, 3090, 2946, 2869, 1653, 1464, 1086, 1032, 884 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 5,84 (ddd, J= 7.8, 10.4, 18.1 Hz, 1 H), 5.27 (ddd, J= 1.1, 1.5, 17.3 Hz, 1 H), 5.21 (ddd, J= 0.9, 1.5, 10.4 Hz, 1 H), 4.25 (m, 1 H), 3.70 (m, 1 H), 3.58-3.53 (m, 2 H), 2.72 (bs, 1 H), 2.04 (bs, 1 H), 1.12-1.01 (m, 21 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 137.9, 117.9, 75.4, 74.7, 62.7, 18.05, 17.99, 12.3; HRMS: m/e calcd for [C,,,H3,,O,,Si+Na]+ 297.1862, found 297.1869. 184 O / OTI PS 6.21 Trllsopropyl(((S)-1-((S)-oxlran-2-yl)allyl)oxy)sllane, 6.21: To a stirred solution of diol 6.20 (1.38 g, 5.03 mmol) and TEA (7 mL, 50.5 mmol) in GHQCI2 (17 mL) at 0 °C, TsCl (1 .05 g, 5.51 mmol) was added in one batch. The reaction was stirred overnight, letting the ice slowly melt and the reaction reach rt. After 18 h, NaHCO3 and CHZCI2 were added and the layers were separated. The aqueous layer was extracted three times CHZCIZ. The combined organic layers were dried over Na2804, filtered, and concentrated. The crude product, 3.04 g was dissolved in MeOH (22 mL) and cooled to 0 °C in an ice bath. To the resulting mixture, K2003 (1.18 g, 8.54 mmol) was added in one batch. The reaction was stirred at 0 °C for 3 h under nitrogen atmosphere and then poured into half saturated aqueous NH4CI and CHZCI2 (1:1). After separation of layers, the aqueous layer was extracted three times with CHQCIZ. The combined organic layers were dried over M9804, filtered and concentrated. The crude product, 1.96 g was purified by flash silica gel chromatography (hexanes/CHZCIQ, 2:1) to provide the desired epoxied 6.21, 0.99 g (77 %) as a clear oil. TLC analysis (hexanes/CHZCIZ, 2:1), R, = 0.26; [00200 = -28.6 (c = 1.08, CHzClz) lR (neat) 3050, 2946, 2869, 1464, 1254, 1142, 1096, 1034, 926, 664 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.62 (ddd, J: 5.6, 10.5, 17.3 Hz, 1 H), 5.33 (td, J=1.7, 17.1 Hz, 1 H), 5.16 (td, J: 1.5, 10.5 Hz, 1 H), 3.98 (tt, J = 1.5, 5.6 Hz, 1 H), 2.97 (ddd, J = 2.7, 4.2, 6.8 Hz, 1 H), 2.75, (dd, J: 4.2, 4.9 Hz, 1 H), 2.58 (dd, J: 2.7, 4.9 HZ, 1 H), 1.14-1.03 (m, 21 H); 13C 185 NMR (126 MHz, CDCI3) 6 (ppm) 136.9, 116.0, 75.5, 55.7, 44.2, 18.0, 17.9, 12.4; HRMS: m/e calcd for [C,,,H2,,OQSi+Na]+ 279.1756, found 279.1753. HO / OTIPS 6.22 (3S,4S)-3-((Trilsopropylsllyl)oxy)octa-1,7-dlen-4-ol, 6.22: To a stirred solution of epoxide 6.21 (682.3 mg, 2.66 mmol) in THF (10 mL) at 0 °C, allylmagnesium bromide (8 mL, 8 mmol, 1.0 M in ether) was added slowly. Upon complete addition the ice bath was removed and the reaction was stirred at rt for 4 h. The reaction was quenched with saturated aqueous NaHCO3 solution, diluted with water and ether. After separation of the layers, the aqueous layer was extracted with ether. The combined organic layers were dried over MgSO,,, filtered and concentrated. The crude product, 0.96 g as a clear oil was purified by flash silica gel chromatography (hexanes/CHZCIZ, 1:1) to provide the alcohol 6.21, 717.7 mg (90 %) as clear oil. TLC analysis (hexanes/CH2Cl2, 1:1), R, = 0.32; [01]?"D = -4.1 (c = 0.7909, CHZCIZ); IR (neat) 3584, 3465, 3079, 2946, 2894, 2869, 1642, 1464, 1094, 1065, 920, 884 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.85-5.76 (m, 2 H), 5.20 (td, J: 1.5, 17.3 Hz, 1 H), 5.17 (dd, J: 1.0, 10.5 Hz, 1 H), 5.02 (qd, 1.7, 17.1 Hz, 1 H), 4.94 (tdd, J: 1.2, 2.2, 10.3 Hz, 1 H), 4.00 (t, J: 6.8 Hz, 1 H), 3.42 (m, 1 H), 2.49 (d, J= 4.2 Hz, 1 H), 2.27 (m, 1 H), 2.12 (m, 1 H), 1.60 (m, 1 H), 1.40 (m, 1 H), 1.13-0.96 (m, 21 H); 130 NMR (126 MHZ, CDCI3) 6 (ppm) 138.6, 186 138.5, 117.5, 114.6, 78.6, 74.3, 31.7, 30.1, 18.1, 18.0, 12.4; HRMS: m/e calcd for [C,7H3,,OQSi+Li]+ 305.2488, found 305.2482. MeO / OTIPS 6.23 Trllsopropyl(((3S,4S)-4-methoxyocta-1,7-dlen-3-yl)oxy)sllane, 6.23: To a stirred solution of alcohol 6.22 (208.2 mg, 0.697 mmol) in toluene (4.5 mL) at -78 °C, KHMDS (2 mL, 1 mmol, 0.5M in toluene) was added slowly, then stirred at - 78 °C for 30 min before MeOTf (153 11.1, 1.34 mmol) was added. The reaction was stirred overnight, letting the dry ice melt and the reaction slowly reach rt. After 17 h, the reaction was quenched with saturated aqueous NaHCOa solution, diluted with water and ether. After separation of the layers, the aqueous layer was extracted three times with ether. The combined organic layers were dried over NaZCOS, filtered and concentrated. The crude product, 314.4 mg of a clear oil containing white solids was purified by ilash silica gel chromatography (hexanes/CHZCIQ, 2:1) to provide the alcohol 6.23, 188.7 mg (87 %) as a clear oil. TLC analysis (hexanes/CHZClz, 2:1), R, = 0.31; [or]2°D= -45.9 (c = 1.007, CH2CI2); lR (neat) 3079, 2946, 2869, 1653, 1642, 1464, 1142, 1109, 920, 884 cm"; 1H NMR (500 MHz, CDCIa) 6 (ppm) 5.88-5.75 (m, 2 H), 5.24 (td, J= 1.5, 17.3 Hz, 1 H), 5.15 (td, J= 1.5, 10.7 Hz, 1 H), 5.00 (qd, J= 1.7, 17.3 Hz, 1 H), 4.93 (m, 1 H), 4.23 (m, 1 H), 3.42 (s, 3 H), 3.18 (ddd, J= 2.7, 4.9, 9.8 Hz, 1 H), 2.22 (m, 1 H), 2.07 (m, 1 H), 1.68 (m, 1 H), 1.34 (m, 1 H), 1.11-1.01 (m, 21 H); 13C NMR (126 187 MHz, CDCIS) 6 (ppm) 138.9, 137.5, 115.6, 114.5, 84.0, 73.1, 58.3, 30.4, 28.6, 18.08, 18.06, 12.4; HRMS: m/e calcd for [C,,,H3,,OZSi+Li]+ 319.2645, found 319.2650. 0. M90 / OTIPS 6.24 (4S,SS)-4-Methoxy-5-((trllsopropylsllyl)oxy)hept-6-enal, 6.24: To a stirred solution of diene 6.23 (450.5 mg, 1.44 mmol) in dioxane (9 mL) and water (3 mL), 2,6-lutidine (0.34 mL, 2.92 mmol), OsO4 (180 pl, 0.014 mmol, 2.5 wt% in t- BuOH), and NalO4 (1.23 g, 5.75 mmol) was added. The resulting white slurry was stirred at rt open to air for 40 min. The reaction was carefully monitored by TLC and diluted with water and CH2CI2 after the SM was consumed. After separation of layers, the aqueous layer was extracted three times with CHzclz. The combined organic layers were dried over Na2804, filtered and concentrated. The crude product, 4.15 g of a clear oil containing white solids”6 was purified by flash silica gel chromatography (CHZCIZ) to provide the aldehyde, 289.2 mg (64 %) as clear oil. TLC analysis (CHZCla), R, = 0.36; [01]”,D = -61.1 (c = 1.225, CHZCIZ); IR (neat) 2944, 2894, 2869, 2720, 1728, 1464, 1138, 1098, 884 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 9.69 (t, J: 2.0 Hz, 1 H), 5.65 (ddd, J: 5.6, 10.5, 17.1 Hz, 1 H), 5.27 (td, J: 1.7, 17.3 Hz, 1 H), 5.19 (td, J: 1.5, 10.7 Hz, 1 H), 4.45 (m, 1 H), 3.37 (s, 3 H), 3.17 (ddd, J= 2.9, 4.6, 9.5 Hz, 1 H), 2.46 (tt, J= 2.4, 7.1 Hz, 2 H), 1.94 (m, 1 H), 1.65 (m, 1 H), 1.13-1.01 (m, 21 H); 13C NMR (126 MHz, CDCI3) 188 6 (ppm) 202.6, 137.0, 116.1, 84.0, 72.9, 58.1, 40.9, 22.4, 18.1, 18.0, 12.3; HRMS: m/e calcd for [C,7H3,,038i+Na]+ 337.2175, found 337.2179. 0 M60 OTIPS 6.25 (6S,7S,[:‘)-6-Methoxy-2-methyl-7-((trllsopropylsllyl)oxy)nona-2,8-dlenamlde, 6.25: To a stirred solution of aldehyde 6.24 (255.7 mg, 0.813 mmol) in toluene (8 mL) at rt, 1-carbethoxyethylidenethriphenylphosphorane (441 mg, 1.22 mmol) was added. The flask was equipped with a reflux condenser and the reaction was heated to 110 °C overnight. After cooling to rt and then in an icebath, the white precipitate was filtered off over; celite and washed with hexanes. The filtrate was concentrated to afford the crude product, 605.3 mg of a yellow oil containing white solids. The crude product was purified by flash silica gel chromatography (hexanes/EtOAc, 15:1, R, = 0.35) to provide 318.4 mg (98%) of the desired ester”7 as a clear oil, which was used without further purification in the following step. To a stirred suspension of NH,Cl (128 mg, 2.4 mmol) in benzene (2 mL) at 0 °C, AlMe3 (1.2 mL, 2.4 mmol, 2.0 M in toluene) was added slowly. The icebath was removed and the reaction was stirred at rt for 30 min, before being added to a stirred solution of the ester (318.4 mg, 0.799 mmol) in benzene (8 mL). The reaction was heated at 50 °C in an oil bath for 6 h before another batch of NH,CI 189 (128 mg, 2.4 mmol) and AIMe3 (1.2 mL, 2.4 mmol, 2.0 M in toluene) in benzene (2 mL), prepared the same way, was added. After another 18 h at 50 °C, the reaction was cooled to rt and quenched with 1 M HCI until no more bubbles were seen. Na-K-tartrate was added and the mixture was stirred at rt until solids dissolved. After separation of the layers, the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaZSO,,, filtered and concentrated to afford the crude product as yellow oil, 398.3 mg. The crude amide was purified by flash silica gel chromatography (hexanezEtOAc, 1:1) to afford the desired product, amide 6.25 as a white solid, 221.9 mg (73% over two steps). Mp 42.5-45 °C; TLC analysis (hexanezEtOAc, 1:1), R, = 0.18; [01]”D = - 41.5 (c = 1.05, CHZCIZ); IR (neat) 3348, 3200, 3090, 2944, 2869, 1669, 1636, 1603, 1464, 1379, 1094, 884 cm"; 1H NMR (500 MHz, CDCia) 6 (ppm) 6.37 (tq, J = 1.2, 7.8 Hz, 1 H), 5.83 (ddd, J: 5.9, 10.7, 17.3 Hz, 1 H), 5.51 (bs, 2 H), 5.25 (td, J: 1.5, 17.3 Hz, 1 H), 5.16 (td, J: 1.5, 10.5 HZ, 1 H), 4.45 (m, 1 H), 3.42 (s, 3 H), 3.16 (ddd, J: 2.4, 4.6, 9.5 Hz, 1 H), 2.32-2.17 (m, 2 H), 1.84 (d, J= 1.0 Hz, 3 H), 1.72 (m, 1 H), 1.38 (m, 1 H), 1.12-0.97 (m, 21 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 171.2, 137.4, 137.1, 130.2, 115.8, 84.2, 72.7, 58.3, 28.3, 25.2, 18.1, 18.0, 12.6, 12.3; HRMS: m/e calcd for [02,,H39NO;,Si+Na]+ 392.2597 found 392.2594. 190 OPMB 0 Cl N H l MeO \ 6.26 OTIPS (65,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-6-methoxy-2- methyl-7-((trlisopropylsllyl)oxy)nona—2,8—dlenamlde, 6.25: In a glovebox, an airfree flask was charged with amide 6.25 (156.6 mg, 0.42 mmol), aryl 6.6 (138 mg, 0.42 mmol), Pd2dba3 (7.7 mg, 0.008 mmol), xantphos (14.5 mg, 0.025 mmol), and DME (2 mL). The flask was closed, brought out of the glovebox and heated in an oil bath at 100 °C for 15 h. The reaction was cooled to rt, filtered through celite, eluated with EtOAc and concentrated to afford 292.8 mg of the crude product as an orange solid. The crude amide was purified by flash silica gel chromatography (hexanezEtOAc, 5:1) to afford 253.7 mg (98%) of aryl amide 6.26 as ayellow solid. Aryl amide 6.26 was further purified with a hexane wash to afford a 163.8 mg off-white solid (63%). Mp 70-72 °C; TLC analysis (hexanezEtOAc, 5:1), R,= 10.27; [002% = -27.7 (c = 1.20, CHZCIQ); IR (neat) 3316, 3085, 2944, 2867, 1661, 1603, 1516, 1458, 1250, 1171, 1034 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.33 (bs, 1 H), 7.32 (d, J= 8.8 Hz, 2 H), 7.30 (t, J: 2.0 Hz, 1 H), 7.07 (t, J: 1.7 Hz, 1 H), 6.90 (d, J= 8.8 Hz, 2 H), 6.7 (t, J= 2.2 Hz, 1 H), 6.36 (t, 6.8 Hz, 1 H), 5.84 (ddd, J: 5.9, 10.7, 17.3 Hz, 1 H), 5.27 (td, J: 1.5, 17.1 Hz, 1 H), 5.28 (bd, J= 10.7 Hz, 1 H), 4.95 (s, 2 H), 4.48 (t, 5.4 Hz, 1 H), 3.80 (S, 3 H), 3.44 (S, 3 H), 3.29 (ddd, J: 2.7, 4.6, 9.5 Hz, 1 H), 2.36-2.22 (m, 2 191 H), 1.91 (s, 3 H), 1.75 (m, 1 H), 1.41 (m, 1 H), 1.12-1.02 (m, 21 H); 13C NMR (126 MHZ, CDCIS) 6 (ppm) 167.5, 159.9, 159.6, 140.0, 137.1, 136.9, 135.0, 132.0, 129.3, 128.4, 115.9, 114.0, 112.4, 111.4, 104.7, 84.2, 72.6, 70.1, 58.3, 55.3, 28.3, 25.3, 18.07, 18.06, 12.7, 12.4; HRMS: m/e calcd for [C34H50CINOSSi+H]* 616.3224 found 616.3225. OPMB CI IZ MeO OTIPS 6.32 (25,3R,6$,7S)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-3-hydroxy-6- methoxy-2,8-dlmethyl-7-((trllsopropylsllyl)oxy)non-8-enamlde, 6.32: In a glovebox, an airfree flask was charged with amide 6.31 (100 mg, 0.249 mmol), aryl 6.6 (100 mg, 0.305 mmol), Pdgdba3 (9.2 mg, 0.01 mmol), xantphos (17.2 mg, 0.03 mmol), 09,003 (114 mg, 0.35 mmol) and 1,4-dioxane (1 mL). The flask was closed, brought out of the glovebox and heated in an oil bath at 100 °C for 17 h. The reaction was cooled to rt, filtered through celite, eluated with EtOAc and concentrated to afford 251 mg of the crude product as a green oil. The crude amide was purified by flash silica gel chromatography (hexanezEtOAc, 4:1—>0:1) to afford 144 mg of 6.32 as a thick light yellow oil, 10 mg (6%) of ketone 6.33 and 23 mg of the starting amide 6.31. The starting material 6.31 was recrystalized from hexanes and CH,,CI2 to afford 16 mg (16%). The desired arene 6.32 was 192 further purified by flash silica gel chromatography (hexanezEtOAc, 4:1) to afford 119.5 mg (71%) of 6.32 as a thick pale yellow oil. TLC analysis (hexanezEtOAc, 4:1), R, = 0.19; [0.]200 = +128 (0 = 0.79, EtOAc); iR (neat) 3308, 2944, 2867, 1669, 1591, 1545, 1516, 1458, 12501101, 1036, 824 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 8.63 (bs, 1 H), 7.32 (d, J: 8.8 Hz, 2 H), 7.29 (t, J= 2.0 Hz, 1 H), 7.03 (t, J= 2.0 Hz, 1 H), 6.89 (d, J= 8.8 Hz, 2 H), 6.67 (t, J: 2.0 Hz, 1 H), 4.94 (s, 2 H), 4.87 (d, J: 1.0 Hz, 1 H), 4.84 (t, J: 1.7 Hz, 1 H), 4.29 (d, J= 6.6 Hz, 1 H), 4.21 (d, J: 2.4 Hz, 1 H), 3.84-3.74 (m, 1 H), 3.78 (s, 3 H), 3.48 (s, 3 H), 3.24 (dt, J= 2.9, 6.8 Hz), 2.61 (dq, J= 2.9, 7.1 Hz, 1 H), 1.78-1.71 (m, 1 H), 1.70 (s, 3 H), 1.59-1.52 (m, 1 H, overlapping with water), 1.45-1.39 (m, 1 H)1.18 (d, J = 7.3 Hz, 3 H), 1.09-1.00 (m, 21 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 173.4, 159.9, 159.6, 144.5, 140.1, 134.9, 129.3, 128.4, 114.0, 113.7, 112.2, 110.9, 104.5, 84.7, 76.8 (overlapping with 0001,, found in DEPT), 72.8, 70.1, 58.6, 55.3, 46.1, 28.9, 26.2, 18.4, 18.1, 18.0, 12.4, 11.9; HRMS: m/e calcd for [C35H5,,CINO,,Si+H]* 648.3487 found 648.3488. OPMB 0 Cl IZ MeO OTIPS 6.33 (6S,75)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-6-methoxy-2,8- dlmethyI-3-oxo-7-((trllsopropylsllyl)oxy)non-8-enamlde, 6.33: In a glovebox, 193 an airfree flask was charged with amide 6.31 (25 mg, 0.062 mmol), aryl 6.6 (32 mg, 0.098 mmol), Pd2dba3 (4.6 mg, 0.005 mmol), xantphos (8.6 mg, 0.015 mmol), Cs2003 (28 mg, 0.086 mmol) and 1,4-dioxane (0.5 mL). The flasked was closed, brought out of the glovebox and heated in an oil bath at 100 °C for 24 h. The reaction was cooled to rt, filtered through celite, eluated with EtOAc and concentrated to afford 60.2 mg of the crude product as a green oil. The crude amide was purified by flash silica gel chromatography (hexane:EtOAc, 4:1) to afford 21.7 mg (54%) of 6.32 as thick pale yellow oil and 17.7 mg (44%) of ketone 6.33 as a 1 :1 mixture of diastereomers. For 6.33: TLC analysis (hexane:EtOAc, 4:1), R, = 0.25; IR (neat) 3310, 2944, 2867, 1717, 1663, 1607, 1593, 1510, 1458, 12550, 1096, 1036 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 8.61( bs, 0.5 H), 8.54 (bs, 0.5 H), 7.31 (b, J = 18.5 Hz, 2 H), 7.22 (bs, 0.5 H), 7.20 (bs, 0.5 H), 7.101 (s, 0.5 H), 7.097 (s, 0.5 H), 6.96.90 (d, J: 9.2 Hz, 2 H), 6.700 (s, 0.5 H), 6.697 (s, 0.5 H), 4.96 (d, J: 8.5 Hz, 1 H), 4.94 (s, 2 H), 4.90 (d, J: 8.8 Hz, 1 H), 4.27 (d, J: 6.3 Hz, 0.5 Hz), 4.26 (d, J: 6.3 Hz, 0.5 Hz), 3.60 (s, 3 H), 3.59 (q, J: 7.3 Hz, 0.5 H), 3.56 (q, J: 7.3 Hz, 0.5 H), 3.37 (s, 1.5 H), 3.31 (s, 1.5 H), 3.17 (m, 1 H), 2.69-2.53 (m, 2 H), 1.92-1.83 (m, 1 H), 1.73 (s, 1.5 H), 1.72 (s, 1.5 H), 1.62-1.51 (m, 1 H), 1.46 (d, J: 7.3 Hz 1.5 H), 1.46 (d, J = 7.3 Hz 1.5 H), 1.10-0.97 (m, 21 H); 13C NMR (126 MHz, CDCI3) 6 (ppm) 211.44, 211.36, 167.9, 167.7, 159.64, 159.63, 159.6, 144.8, 144.7, 139.6, 139.4, 135.0, 129.3, 128.33, 128.32, 114.0, 113.3, 113.2, 112.4, 112.3, 111.5, 111.4, 104.7, 104.6, 83.9, 83.4, 77.1, 76.6, 70.12, 70.11, 58.9, 194 58.7, 55.3, 54.1, 53.2, 39.1, 38.5, 29.7, 24.8, 24.4, 19.1, 18.9, 18.1, 18.03, 18.02, 16.5, 16.3, 12.4 (silicon grease at 1.01 ppm); HRMS: m/e calcd for [C35H52CINOSSi+H]* 646.3331 found 646.3328. Appendix 1.7 Experimental for Chapter 7 Oxidative Cleavage of Olefins O HO MeO OTIPS 7.1 (4S,5S)-4-Methoxy-6-methyI-5-((trllsopropylsllyl)oxy)hept-6-enolc acid, 7.1: To a stirred solution of 4.13 (80 mg, 0.24 mmol) in DMF (1.2 mL) at rt, OsO, (50 mg/mL in toluene, 12 (ii, 2.4 umol) was added. After 5min, oxone (600 mg, 0.98 mmol) was added in one batch. The reaction was stirred at rt for 50 min, quenched with Na2803 (476 g, 6 eq w/w) and stirred for 2 h. EtOAc and 1 N HCI were added and the layers were separated. The organic layer was washed 3 times with 25 mL 1 N HCI, dried Na2804, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexane/ethyl acetate, 4:1, with 1% acetic acid) to provided 42 mg (50%) of 7.1 as a clear oil. TLC analysis (hexanes/ethyl acetate, 4:1, with 1% acetic acid), R, = 0.34; 1H NMR (500 MHz, CDCI3) 6 (ppm) 4.95 (m, 1 H), 4.89 (m, 1 H), 4.26 (d, J = 6.1 Hz, 1 H), 3.44 (s, 3 H), 3.21 (ddd, J: 3.2, 6.1, 9.3 Hz, 1 H), 2.45-2.42 (m, 2H), 1.87 (m, 1 H), 1.72 (bs, 3 H), 1.51 (m, 1 H), 1.06-1.02 (m, 21H) 130 NMR (126 MHz, 0001,) 195 6 (ppm) 179.3, 144.8, 113.2, 83.6, 77.1, 59.0, 30.3, 25.3, 18.8, 18.1, 18.0, 12.4; HRMS: m/e calcd for [C,,,H3,,O,Si]+ 344.2383 found 344.2375. HO O MeO OTIPS 7.2 (5S,6S)-1 -Hyd roxy-5-methoxy-7-methyl-6-((trllsopropylsllyl)oxy)oct-7-en-2- one, 7.2: To a stirred solution of 4.13 (285 mg, 0.87 mmol) in DMF at rt, OsO, (2.5 wt% in isopropanol, 110 (ii, 8.8 umol) was added. After 5 min, oxone (536 mg, 0.87 mmol) was added in one batch. The reaction was stirred at rt for 9 h, quenched with Na2803 (1.7 g, 6 eq w/w) and stirred for 1 h. EtOAc and 1 N HCI were added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried Na2804, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexane/ethyl acetate, 5:1, with 1% acetic acid) to provide 61 mg (20%) of 7.1 as a clear oil and 41 mg (13%) of 7.2 as a clear oil. For 7.2: TLC analysis (hexanes/ethyl acetate, 5:1, with 1 % acetic acid), R, = 0.24; IR (neat) 3474, 2946, 2869, 1721, 1647, 1464, 1383, 1244, 1113, 1015, 884 "cm; 1H NMR (500 MHz, CDCI3) 6 (ppm) 4.94 (d, J: 1.0 Hz, 1 H), 4.89 (t, J :1.7, 1 H), 4.26 ( d, J: 5.6 Hz, 1 H ), 4.24 (cl, J: 18.6 Hz, 1 H), 4.19 (d, J: 18.6 Hz, 1 H), 3.38 (s, 3 H), 3.17 (ddd, J: 3.4, 6.1, 9.0 Hz, 1 H), 3.06 (bs, 1 H), 2.51-2.41 (m, 2 H), 1.90 (m, 1 H), 1.72 (S, 3 H), 1.54 (m, 1 H), 1.09-1.00 (m, 21 H); 13C NMR (126 MHZ, CDCIS) 6 (ppm) 209.7, 144.8, 113.2, 83.6, 76.9, 67.9, 196 58.8, 34.7, 24.3, 18.9, 18.1, 18.0, 12.4; HRMS: m/e calcd for [C,,,H,_,,,O,,Si+H]+ 359.2618 found 359.2608. MeO OH 7.3 (3S,4S)-4-Methoxy-2-methylocta-1,7-dlen-3-ol, 7.3:128 To a stirred solution of 4.13 (102.8 mg, 0.3148 mmol) in THF (0.8 mL) at rt, TBAF (0.63 mL, 0.63 mmol, 1.0 M in THF) was added dropwise. The resulting orange solution was stirred for 100 min at rt and then quenched with saturated aqueous NH,CI solution. The layers were separated; the aqueous was extracted with CHZCIZ. The combined organic layers were dried over Na,,SO4 and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/ether, 1:1) to provide 47.1 mg (88%) 7.3 as a clear oil. TLC analysis (hexanes/ether, 1:1), R, = 0.37; [(11200 = +303 (0 = 1.04, CHzClz); IR (neat) 3453, 3077, 2977, 2926, 1642, 1449, 1370, 1103, 907; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.79 (m, 1 H), 5.04-4.92 (m, 4 H), 3.92 (dd, J: 3.7, 6.3 Hz, 1 H), 3.41 (s, 3 H), 3.23 (m, 1 H), 2.56 (d, J: 3.9 Hz, 1 H), 2.15-2.10 (m, 2 H), 1.73 (t, J= 1.2 Hz, 3 H), 1.64-1.50 (m, 2 H); 13C NMR (75 MHz, CDCIs) 6 (ppm) 144.4, 138.3, 114.8, 113.7, 81.5, 77.2, 58.2, 29.5, 29.2, 17.9. 197 MeO OMe 7.4 (3S,4S)-3,4-Dimethoxy-Z-methylocta-1,7-dlene, 7.4: To a stirred solution of 7.3 (32.5 mg, 0.191 mmol) in toluene (1 mL) at -78 °C, KHMDS (1.2 mL, 0.60 mmol, 0.5 M in toluene) was added dropwise. After stirring for 30 min at -78 °C, MeOTf (110 pl, 0.973 mmol) was added. The reaction was allowed to slowly reach rt overnight and then quenched with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried over Na2804, filtered and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/ether, 4:1) to provide 23.8 mg (68%) 7.4 as a yellow oil. TLC analysis (hexanes/ether, 4:1), R, = 0.41; [0.]200 = +249 (0 = 1.02, CH,CI2); IR (neat) 3075, 2978, 2926, 2622, 1642, 1449, 1101 cm"; 1H NMR (500 MHz, CDCla) 6 (ppm) 5.77 (m, 1 H), 5.02-4.92 (m, 4 H), 3.49 (d, J: 7.1 Hz, 1 H), 3.44 (s, 3 H), 3.24-3.20 (m, 1H), 3.23 (s, 3 H), 2.20-2.04 (m, 2 H), 1.64 (m, 3 H), 1.53-1.36 (m, 2 H); 130 NMR (126 MHZ, CDCI3) 6 (ppm) 142.3, 138.6, 115.3, 114.6, 88.7, 81.3, 59.0, 56.5, 30.1, 29.4, 17.5. 198 OH 0 M90 OMe 7.5 (4S,5S)-4,5-Dimethoxy-6-methylhept-G-enolc acid, 7.5: To a stirred solution of 7.4 (51.9 mg, 0.2816 mmol) in DMF (1.4 mL) at rt, OsO, (35 pl, 0,0027 mmol, 2.5 wt% in t-BuOH) was added, followed after 5 min by oxone (695.0 mg, 1.13 mmol). The reaction was stirred at rt for 75 min and then quenched with Na?_SO3 (313.4 mg, 6 eq wat). The resulting mixture was stirred at rt for 3 h. EtOAc and 1 N HCI were added until the salt dissolved. The layers were separated. The organic layer was washed three times with 1 N HCI and once with brine, dried over Nazso, and concentrated to afford 29 mg (51 %) ’of crude 7.5 w as a clear oil. 1H NMR (500 MHz, CDCI3) 6 (ppm) 10.92 (bs, 1 H) 4.99 (m, 1 H), 4.94 (t, J= 1.0 Hz 1H), 3.48 (d, J: 7.1 Hz, 1 H), 3.45 (s, 3 H), 3.27 (ddd, J= 3.4, 7.1, 10.7 Hz, 1 H), 3.22 (s, 3H), 2.42 (t, J: 6.8 Hz, 2 H), 1.78 (m, 1 H), 1.64 (t, J= 1.0 Hz, 3 H) 1.61-1.54 (m, 1 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 179.1, 141.9, 115.8, 88.9, 81.0, 59.4, 56.3, 29.7, 25.9, 17.3. HO HO MeO O MeO O OTIPS OTIPS 7.6 7.7 (3S,4S)-3-Methoxy-5-methyl-4-((trllsopropylsllyl)oxy)hex-5-enolc acid, 7.6 and (4S,5.S)-1-hydroxy-4-methoxy-6-methyl-5-((trllsopropylsllyl)oxy)hept-6- 199 en-2-one, 7.7: To a stirred solution of 4.11 (100 mg, 0.32 mmol) in DMF (1.6 mL) at rt, 0304 (40111, 0.0032 mmol, 2.5 wt% in t-BuOH) was added, followed after 5 min by oxone (787 mg, 1.28 mmol). The reaction was stirred at rt for 70 min open to air and then quenched with Na,,SO3 (600 mg, 6 eq WWII) and water (1 mL). The resulting mixture was stirred at rt for 2 h. EtOAc and 1 N HCI were added until the salt was dissolved, the layers were separated. The organic layer was washed three times with 1 N HCI and once with brine, dried over NaZSO, and concentrated. The crude product, 110.8 mg of an oil, was purified by flash silica gel chromatography (hexanes/ether, 10:1, 1% acetic acid) to provide 40.1 mg (38%) of 7.6 as a white solid and about 6 mg (~5%) of unpure 7.7 was obtained as a clear oil. For 7.6: Mp 40-42 °C; TLC analysis (hexane:EtOAc, 10:1 and 1% acidic acid), R, = 0.25; [ot]"’°D = -16.4 (c = 1.085, CHQCIZ); lR (neat) 3076, 2916, 2889, 1713, 1464, 1101, 884 cm"; 1H NMR (500 MHz, CDCI3) 6 (ppm) 10.79 (bs, 1 H), 4.99 (t, J: 1.0 Hz, 1 H), 4.94 (t, J: 1.5 Hz, 1 H), 4.35 (d, J: 5.9 Hz, 1 H), 3.75 (ddd, J: 3.2, 5.6, 9.0 HZ, 1 H), 3.46 (s, 3 H), 2.62 (dd, J: 3.2, 16.1 Hz, 1 H), 2.30 (dd, J: 9.0, 16.1 Hz, 1 H), 1.74 (s, 3 H), 1.12-1.01 (m, 21 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 176.9, 144.3, 113.6, 81.1, 75.4, 58.8, 35.4, 19.4, 18.02, 17.99, 12.4; HRMS: m/e calcd for [0,7H3,,O,Si+H]+ 331.2305 found 331.2307. For 7.7: TLC analysis (hexanes/ether, 10:1, 1% acetic acid), R, = 0.18; Grease was present in both 1H NMR and 13C NMR spectra. 1H NMR (500 MHz, CDCIS) 6 (ppm) 4.78 (d, J= 1.0 Hz, 1 H), 4.94 (bs, 1 H), 4.36 (d, J: 5.4 Hz, 1 H), 4.4.24 200 (d, J= 19.0 Hz, 1 H), 4.20 (d, J= 19.0 Hz, 1 H), 3.83 (ddd, J: 2.9, 5.6, 9.0 Hz, 1 H), 3.39 (s, 1 H), 2.53 (dd, J: 2.4, 15.6 Hz, 1 H), 2.41 (dd, J= 9.3, 15.6 HZ, 1 H), 1.74 (s, 3 H), 1.12-1.03 (m, 21 H), the OH proton was missing; 13C NMR (126 MHz, CDCI3) 6 (ppm) 209.0, 144.6, 113.4, 80.7, 75.1, 69.0, 58.8, 39.5, 19.6, 18.0, 18.0, 12.3. EtO O O HO MeO OTIPS 7.9 (6S,7S)-Ethyl-2-hydroxy-6-methoxy-2,8-dImethyl-3-oxo-7—((trlIsopropylsllyl) oxy)non-8-enoate, 7.9: To a stirred solution of DMF (0.7 mL) and ester 4.16(12:1, E/Z, 54.7 mg, 0.133 mmol) at rt, OsO4 (17 pl, 0.0014 mmol, 2.5 wt% in t-BuOH) was added, followed by oxone (164 mg, 0.267 mmol). The reaction was stirred at rt for 3h, then quenched with NaZSO3 (164 mg, 6 eq wat). The resulting mixture was stirred at rt for 3 h. EtOAc and 1 N HCI were added until the salt dissolved. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed three times with 1 N HCI, dried over NaZSO, and concentrated overnight with EtOH. The crude product, 59.1 mg of a brown oil was purified by flash silica gel chromatography (hexanes/ether, 6:1) to provide 20.5 mg (35%) of a 1:1 mixture of diasteriomers of 7.9 as a clear oil and 6.4 mg (14%) 7.1. 201 For 7.9: (1 :1 mixture of diasteriomers) TLC analysis (Hexanes/EtOAc, 6:1), R, = 0.31; (6120,, : -17.0 (c : 1.025, on01,_); IR (neat) 3078, 2914, 2889, 2725, 1744, 1723, 1464, 1373, 1259, 1105, 1017, 884 "cm; 1H NMR (500 MHz, CDCI3) 6 (ppm) 4.93 (m, 1 H), 4.87 (m, 1 H), 4.24-4.18 (m, 4 H), 3.39 (s, 1.5 H), 3.37 (s, 1.5 H), 3.19-3.14 (m, 1 H), 2.75-2.58 (m, 2 H), 1.90-1.80 (m, 1 H), 1.72 (m, 3 H), 1.56 (s, 1.5 H), 1.55 (s, 1.5 H), 1.51-1.43 (m, 1 H), 1.26 (t, J: 7.2 Hz, 3 H), 1.10- 1.00 (m, 21 H); 130 NMR (126 MHz, CDCla) 6 (ppm) 207.4, 207.1, 171.5, 171.4, 144.90, 144.87, 113.21, 113.17, 83.34, 83.30, 80.9, 80.8, 77.3, 77.2, 62.49, 62.47, 58.9, 58.8, 32.6, 32.4, 24.2, 24.1, 21.92 21.91, 18.8, 18.7, 18.05, 18.01, 14.0, 12.4; HRMS: m/e calcd for [CmHMOSSHNar 467.2808, found 467.2805. 0 0 HO 1 MeO ‘ O 7.11 7.12 (4S,5.S')-5-Hydroxy-4-methoxy-6-methylhept-G-enolc acid, 7.11 and (5S,GS)-5- methoxy-6-(prop-1-en-2-yl)tetrahydro-2H-pyran-2-one, 7.12: To a stirred solution of diene (100 mg, 0.587 mmol) in DMF (2.9 mL) at rt, 030,, (74 pl, 0.0059 mmol, 2.5 wt% in t-BuOH) was added, followed after 5 min by oxone (1.44 g, 2.34 mmol). The reaction was stirred at rt for 2 h, then quenched with Na2503 (600 mg, 6 eq wat) and water (1 mL). The resulting mixture was stirred at rt for 2 h. EtOAc and 1 N HCI were added until the salt was dissolved. The layers were separated. The organic layer was washed three times with 1 N HCI and dried over NaZSO4 and concentrated to afford 28 mg of a yellow oil. The 202 crude product was purified by flash silica gel chromatography (hexane:EtOAc, 2:1 and 1% acidic acid) to afford 2.5 mg (~2%) of 7.11 and 7.3 mg (~7%) of 7.12, both of which were obtained unpure. For 7.11: TLC analysis (hexane:EtOAc, 2:1 and 1% acidic acid), R, = 0.27; 1H NMR (500 MHz, CDCI3) 6 (ppm) 8.11 (s, 1 H), 5.26 (d, J= 6.3 Hz, 1 H), 5.06 (bs, 1 H), 5.01 (bs, 1 H), 3.69 (s, 1 H), 3.45-3.41 (m, 1 H), 3.43 (s, 3 H), 2.47 (t, J= 7.1 Hz, 2 H), 1.86-1.79 (m, 1 H), 1.76 (s, 3 H), 1.74-1.64 (m, 1 H). For 7.12: TLC analysis (hexane:EtOAc, 2:1 and 1% acidic acid), R, = 0.17; 1H NMR (500 MHz, CDCIa) 6 (ppm) 5.14 (d, J = 0.7 Hz, 1 H), 5.02 (m, 1 H), 4.69 (bs, 1 H), 6.89 (m, 1 H), 3.34 (s, 3 H), 2.65 (ddd, J= 7.1, 11.0, 18.1 Hz, 1 H), 2.52 (ddd, J: 3.2, 7.1, 17.8 Hz, 1 H), 2.23 (m, 1 H), 1.91 (m, 1 H), 1.81 (t, J: 0.7 Hz, 3 H). Appendix 1.8 Experimental for Chapter 8 Evidence for Cation-tr Interactions Between TBAF and Small Aromatic Molecules — Implications for Crude 1H NMR Analysis In Organic Synthesis General Materials and Methods The NMR spectra were recorded on a Varian VXR-500 MHz NMR instrument. The NMR solvents were used as receive. CDCI3 was purchased from Cambrige Isotope Laboratories, inc. and stored over activated 4 A molecular sieves. CD30N was purchased from Cambrige Isotope Laboratories, inc. and stored in a desiccator over Drierite. Each spectrum was referenced by the solvent peak, 7.24 ppm for CDCI3 and 1.93 ppm for CDSCN. 203 OPMB OPMB o o 0' Q | TBAF (10 equiv) (3' fl l THF, 0 °o,1.5 h ' M90 98 <>/,3 MeO OTIPS OH 6.5 6.17 (65,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-7-hydroxy-6- methoxy-2,8-dImethylnona-2,8-dlenamlde, 6.17: To a stirred solution of amide 6.5 (300 mg, 0.476 mmol) in THF (25 mL) at 0 °C, TBAF (4.8 mL, 4.8 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over NaZSO, and concentrated to afford 553.1 mg of the crude alcohol as an orange oil. The 1H NMR spectrum of the crude reaction mixture was taken (Figure 10.1). The NMR sample was heated to 60 °C in the NMR spectrometer (Figure 10.2). After 90 minutes at room temperature, the 1H NMR of the same sample was taken again (Figure 10.3). The crude product was purified by flash silica gel chromatography (hexanes:EtOAc, 1:1) to provide 221.1 mg (98%) of the desired product 6.17 as an opaque oil (Figure 10.4). For characterization see Appendix 1.6. 204 Figure 10.1 1H NMR (500 MHz, CDCla) of crude arene 6.17 at rt (see Appendix 2 for full scale spectrum) TIYVYIITYUIITIII'FWIUIIIIUIIlr‘l1‘ITI'Y'UITT'I1YIIITjTYF 10 8 6 4 2 ppm Figure 10.2 1H NMR (500 MHz, CDCIS) of crude arene 6.17 at 60 °C (see Appendix 2 for full scale spectrum) 205 Figure 10.3 1H NMR (500 MHz, CDCla) of cooled crude arene 6.17 (see Appendix 2 for full scale spectrum) l ILA Ll Al I I I I r I l I I I I l I I I I I I I T I ' I I I I I I I l I I I ....., 6 4 2 ppm ..l O- m- Flgure 10.4 1H NMR (500 MHz, CDCla) of arene 6.17 (see Appendix 2 for full scale spectrum) 206 TBAF (10 equiv) amide 6.17 (1 equiv) MOTIPS /\/\OH THF, 0 °c, 1.5 h 8.1 3,2 Desilylation of 8.1 In presence of arene 6.17: To a stirred solution of 6.17 (32 mg, 0.068 mmol) and 8.1 (16 mg, 0.069 mmol) in THF (3.6 mL) at 0 °C, TBAF (0.69 mL, 0.69 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h and then quenched with NaHCOa. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na2003, filtered and concentrated to afford 158.6 mg of an orange oil (Figure 10.5). Figure 10.5 1H NMR (500 MHz, CDCI3) of “crude” arene 6.17 at rt (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 207 Figure 10.6 1H NMR (500 MHz, CDCI3) of “crude” arene 6.17 after 1.5 h at 50 °C (see Appendix 2 for full scale spectrum) u .11. ..L i_l .2 ”L ITIITIITII’IIITIIrTrrjI'IIII1IIIIIIIIIlfiTIYfilITIIrI’VIIlIT 10 8 6 4 2 ppm Figure 10.7 1H NMR (500 MHz, CDCI3) of cooled “crude” arene 6.17 (see Appendix 2 for full scale spectrum) ii .i J. 1 1i. i Y1fffIlIIIIFTIIIITIIYITTIIIIIIIIIITTIIIIIIIIIjlrITIwa 10 8 6 4 2 ppm 208 Figure 10.8 1H NMR (500 MHz, CDCIS) of reisolated arene 6.17 (see Appendix 2 for full scale spectrum) il l l A- I I I I I I I rrr'fiI I I l I I I I I I l I I I I I I I I I 1 10 8 6 4 2 ppm r I I I I I l I I I I I 1 I I I I I I I I I The NMR sample was heated in an oil bath at 50 °C for 1.5 h (Figure 10.6) and then stored in freezer overnight (Figure 10.7) and 6.17 was recovered by flash silica gel chromatography (hexanes:EtOAc, 1:1) 17.5 mg (50%). The reisolated product showed the same 1H NMR spectrum as the initial sample (Figure 10.8). OPMB OPMB | \_ o / 0' fl TBAF(10 equiv) 0' n | THF, 0 °C,1.5h 7 M90 OH 6.17 6.17 Resublectlng arene 6.17 to the desilylation condition with 10 equiv TBAF: To a stirred solution of 6.17 (20 mg, 0.042 mmol) in THF (2.25 mL) at 0 °C, TBAF (0.42 mL, 0.42 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C 209 for 1.5 h and then quenched with NaHCOa. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na2003, filtered and concentrated to afford 215.3 mg of an oil containing white solids (Figure 10.9). Compound 6.17 was recovered by flash silica gel chromatography (hexanes:EtOAc, 1:1) to afford 18.9 mg (95%). The reisolated product showed the same 1H NMR spectrum as the initial sample (Figure 10.10). Figure 10.9 1I-l NMR (500 MHz, CDCI3) of “crude” arene 6.17, 10 equiv TBAF (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 210 Flgure 10.10 1H NMR (500 MHz, CDCI3) of reisolated arene 6.17, 10 equiv TBAF (see Appendix 2 for full scale spectrum) ppm 10 OPMB o 0' TBAF (1 equiv) 0' Q | THF, 0 °C,1.5 h I MeO , OH 6.17 6.17 Resublecting arene 6.17 to the desilylation condition with 1 equiv TBAF: To a stirred solution of 6.17 (20.8 mg, 0.044 mmol) in THF (2.3 mL) at 0 °C, TBAF (0.44 mL, 0.44 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h and then quenched with NaHCOa. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic 211 layers were dried over NazCoa, filtered and concentrated to afford 50.3 mg of a clear oil (Figure 10.11). Flgure 10.11 1H NMR (500 MHz, CDCIS) of “crude" arene 6.17, 1 equiv TBAF (see Appendix 2 for full scale spectrum) Ail ll. 1i IL__UH.MJ.L_li_ IrrTIIIIIIIITIIIIIerTrIIIIIfi‘FIjIrrIIIIIIIIjITfIfIIIIfi 10 8 6 4 2 ppm Flgure 10.12 1H NMR (500 MHz, CDCI3) of reisolated arene 6.17, 1 equiv TBAF (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 212 Compound 6.17 was recovered by flash silica gel chromatography (hexanes:EtOAc, 1:1) to afford 19.8 mg (95%). The reisolated product showed same 1H NMR spectrum as the initial sample (Figure 10.12). OPMB OPMB O 0 Cl {5" I TBAF (0.1 equiv) 0' H i THF, 0 °C,1.5 h 7 M90 M90 OH OH 6.17 6.17 Resubjectlng arene 6.17 to the desilylation condition with 0.1 equiv TBAF: To a stirred solution of 6.17 (20.8 mg, 0.044 mmol) in THF (2.3 mL) at 0 °, TBAF (0.44 mL, 0.44 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h and then quenched with NaHCOa. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over NaZCOS, filtered and concentrated to afford 27 mg of a clear oil (Figure 10.13). Compound 6.17 was recovered by flash silica gel chromatography (hexanes:EtOAc, 1:1) to afford 20 mg (96%). The reisolated product showed same 1H NMR spectrum as the initial sample (Figure 10.14). 213 Flgure10.13 1H NMR (500 MHz, coon) of “crude” arene 6.17, 0.1 equiv TBAF (see Appendix 2 for full scale spectrum) —T fi—r I T I I I V I I I r I r I Y rj 1 I I I I jfi—I' I l I V V I I 1 I I I I I W I I I I I I T I I T T I I I I 10 8 6 4 2 ppm Flgure 10.14 1H NMR (500 MHz, CDCI3) of reisolated arene 6.17, 0.1 equiv TBAF (see Appendix 2 for full scale spectrum) 214 OPMB 0 Cl N H | F' MeO + W N{/:\/—\ OH NMR study of arene 6.17 wlth 0.1 equlv TBAF: TBAF (4.4 gal, 4.4 pmol, 1 M in THF) and arene 6.17 (20.9 mg, 44 umol) was dissolved in CDCI:3 (1 mL) and transferred to an NMR tube (Figure 10.15). compound 6.17 was recovered by flash silica gel chromatography (hexanes:EtOAc, 1 :1) to afford 20.3 mg (97%). The reisolated product showed same 1H NMR spectrum as the initial sample (Figure 10.16). Flgure 10.15 1H NMR (500 MHz, CDCIS) of arene 6.17, and 0.1 equiv TBAF (see Appendix 2 for full scale spectrum) 215 Flgure 10.16 1H NMR (500 MHz, CDCIa) of reisolated arene 6.17 (see Appendix 2 for full scale spectrum) Iilirlllliiil ltfiillfifij IIIIITIIIITT' lTI‘llrIllIr—T 10 8 6 4 2 ppm OPMB 15L ° Cl N H I F‘ NMR study of TBAF with 10 equiv of arene 6.17: TBAF (4.4 pl, 4.4 umol, 1 M in THF) was added to a NMR tube of CDCI3 (0.5 mL) (Figure 10.17). To the same NMR sample, arene 6.17 (20.3 mg, 27 pmol) in CDCI3 (0.5 mL) was added (Figure 10.18). 216 Flgure 10.17 1H NMR (500 MHz, CDCIa) of TBAF (see Appendix 2 for full scale spectrum) M ., din]. _..JJLLl__—.L__ VIIITIIfiTTIIIIlilTrl’lIrl’IYlI—FTI1IIIIIIWTIITII‘IrIIlTjTI 10 8 6 4 2 ppm Flgure 10.18 1H NMR (500 MHz, CDCla) of TBAF with 10 equiv of arene 6.17 (see Appendix 2 for full scale spectrum) 217 OPMB 0 Cl N H | F' W Nq: + MeO "dry" OH 6.17 NMR study of “dry” TBAF with 1 equiv of arene 6.17: TBAF (60 pl, 60 pmol, 1 M in THF) was dried under reduced pressure overnight before being dissolved in CDCI3 (1 mL) and transferred to an NMR tube (Figure 10.19). Arene 6.17 (25 mg, 60 pmol) was added to the same NMR tube (Figure10. 20). The NMR sample was spurged with nitrogen. The 90° pulse was determined before acquiring the NOE spectra. Three protons were irradiated, Ha. on TBAF (Figure 10.21), Hd on amide 6.17 (Figure 10.22), and Hc on amide 6.17 (Figure 10.23). Figure 10.19 1H NMR (500 MHz, CDCI3) of “dry” TBAF (see Appendix 2 for full scale spectrum) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Flgure 10.20 1H NMR (500 MHz, CDCla) of “dry” TBAF with 1 equiv of arene 6.17 (see Appendix 2 for full scale spectrum) A llLLh l J 1le L_J_ IIIIIII‘IrIITIfiIIIIIIIIIIIIIIIITIIIIIIIIII‘IIIIfiIIITIIT 10 8 6 4 2 ppm Flgure 10.21 NOE (500 MHz, CDCis) of “dry” TBAF with 1 equiv of arene 6.17, irradiating Ha. of TBAF (see Appendix 2 for full scale spectrum) .. 11 - _— . 1 .f 4%- J W W La 0.10 4.42 0.22 12.48 1.04 -100.00 U l ‘1 1L 1 Li AJbLJLJL—J— 10 8 6 4 2 ppm 219 Flgure 10.22 NOE (500 MHz, CDCIS) of “dry” TBAF with 1 equiv of arene 6.17, irradiating Hd of amide 6.17 (see Appendix 2 for full scale spectrum) ”‘u‘AM‘A +k A v -‘ A :J‘v—JJ A ‘ Lv‘ ‘ h:‘:._;uv‘; AH“ L‘“—“ LAWN-MW v ta ta L» v 0.23 0 07 0'35 0.20 0.24 -100.00 I I I I I I I I I I I I I I I I I I I T I I I I I I I‘I I I I I l I f I I I I I I I l I I I I 1 I I I I 1 I I 10 8 6 4 2 ppnt Flgure 10.23 NOE (500 MHz, CDCIa) of “dry" TBAF with 1 equiv of arene 6.17, irradiating Hc of amide 6.17 (see Appendix 2 for full scale spectrum) W - . - - _ ... ____ {‘%L wt.” ww— —‘ L... _—‘ ._ “... 7:74."? 4 —‘ ...:r 5—9 v v '14 “r‘ Hut» 54 0°11 0.18 0 15 o 33 3.40 0.10 0.15 -100.50 11 [11 IL 1 LJ. A_JJJKLLJL____i___ I T I I I I I r I fj rj' If I i I I I I I I I I I I I Ifi T T I I I I I I rI I I I I I I 1'1 I I I I I f 10 8 6 4 2 ppnt 220 OPMB 0 Cl N l H + PF6 OTIPS 1.3a NMR study of TIPS protected amlde 1.3a with 1 equiv Bu4NPF6: Bu.,NPF6 (19.5 mg, 50 umol) and amide 1.3a (31.5 mg, 50 umol) were added to an NMR tube, and dissolved in CDCI3 (1 mL) (Figure 10.24). Compound 1.5a was recovered by flash silica gel chromatography (hexanes:EtOAc, 5:1) to afford 30 mg (95%). The reisolated product showed same 1H NMR spectrum as the initial sample (Figure 10.25). Flgure 10.24 1H NMR (500 MHz, CDCIS) of TIPS protected amide 1.3a with 1 equiv of Bu,,NPF6 (see Appendix 2 for full scale spectrum) Y'IfillITTYIYIfi—T'lIYYYITYIYII II 1T1 II YTIYI FTIYYIITY—rrlfil 10 8 6 4 2 ppm 221 Flgure 10.25 1H NMR (500 MHz, CDCI3) of reisolated TIPS protected amide 1.3a (see Appendix 2 for full scale spectrum) OPMB Q 0 M m + WN+ Cl ”)KE \—\— 6.14 NMR study of arene 6.14 with 1 equiv TBAF: TBAF (20 pl, 20 pmol, 1 M in THF) was added to an NMR tube with tiglic amide 6.14 (6.8 mg, 20 umol) in CDCI3 (0.46 mL) (Figure 10.26). Compound 6.14 was recovered by flash silica gel chromatography (CHzclzzEtOAc, 95:5) to afford 6.4 mg (94%). The reisolated product showed same 1H NMR spectrum as the initial sample (Figure 10.27) 222 Flgure 10.26 1H NMR (500 MHz, CDCIa) of arene 6.14 with 1 equiv of TBAF (see Appendix 2 for full scale spectrum) uLLl l - . l VIYYIIIYYFfiVIIIIIYUTITIT'1YIIVII'I'IIIWrTTWfitrIIII'IITr 10 8 6 4 2 ppm Flgure 10.27 1H NMR (500 MHz, CDCla) of reisolated arene 6.14 (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 223 OH .0 ° N H l MeO 8.3 (6S,7S,E)-N-(3-Chloro-5-hydroxyphenyl)-7-hydroxy-6—methoxy-2,8- dlmethylnona-2,8-dlenamlde, 8.3:61 To a stirred solution of amide 1.3a (103.3 mg, 0.202 mmol) in THF (10.5 mL) at 0 °C, TBAF (2 mL, 2.0 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over NaZSO4 and concentrated to afford 181.6 mg of the crude alcohol as a brown oil. The crude product was purified by flash silica gel chromatography first with a gradient of CH2ClzzEtOAc, 3:2 to 100% EtOAc then with CHQClezEtOAc, 2:3 to provide 40.3 mg (56%) of the desired product 8.3 as a glass-like white solid (Figure 10.28). TLC analysis (CHZClzzEtOAc, 2:3 to), Fl, = 0.46; Mp 40-42 °C; [@200 = +2.2 (0 = 1.176, acetone); 1H NMR (500 MHz, CDCIS) 6 (ppm) 7.71 (t, J: 2.0 Hz, 1 H), 7.57 (bs, 1 H), 7.41 (bs, 1 H), 6.66 (t, J: 1.7 Hz, 1 H), 6.23 (t, J = 2.0 Hz, 1 H), 6.38 (qt, J = 1.5, 7.3 Hz, 1 H), 5.03 (quint. J = 0.7 Hz, 1 H), 4.95 (quint. J: 1.5 Hz, 1 H), 3.98 (dd, J: 3.7, 5.9 Hz, 1 H), 3.44 (s, 3 H), 2.28 (ddd, J: 4.6, 6.3, 6.3 Hz), 2.43 (d, J: 3.9 Hz, 1 H), 2.28 (q, J: 7.6 Hz, 1 H), 1.94 (d, J: 1.0 Hz, 3 H), 1.76 (3,3 H), 1.73-1.58 (m, 2 H); 13c NMR 224 (126 MHZ, CDCI3) 5 (ppm) 168.6, 158.1, 144.3, 139.3, 137.5, 134.9, 131.7, 113.9, 112.3, 111.1, 105.7, 81.6, 77.1, 58.4, 29.1, 24.0, 18.0, 12.9; IR (neat) 3303, 2924, 1659, 1597, 1547, 1536, 1483, 1428, 1289, 1096. Figure 10.28 1H NMR (500 MHz, CDCla) of isolated 8.3 (see Appendix 2 for full scale spectrum) Ill zL ll . 1___L I I I j r I7 I ‘fiI—r I I I1 rI I 10 8 6 4 2 ppm OH Q 0 Cl N H I F‘ MeO + WNqfllv: OH 8.3 NMR study of arene 8.3 with 1 equiv TBAF: To an NMR tube with 8.3 (19.9 mg, 56 pmol) and CDCl3 (1 mL), 1 equiv of TBAF (56 pl, 56 pmol, 1 M in THF) was added (Figure 10.29). 225 Flgure 10.29 1H NMR (500 MHz, CDCIS) of arene 8.3 with 1 equiv of TBAF (see Appendix 2 for full scale spectrum) . 1L1 LL _ ll 11 M; 'I' IW I'1 'I Ijvl I 1 I '1rf""I" 10 8 4 2 ppm OPMB 0 Cl N H | _L\ 1- M90 + WNQ OH , 6.17 NMR study of arene 6.17 with TBAI: To an NMR tube of 6.17 (12.9 mg, 27 pmol) and CDCI3 (0.63 mL) (Figure 10.30), 0.13 equiv of TBAI (1.3 mg, 3.5 pmol) was added (Figure 10.31). Another 0.87 equiv of TBAI (8.7 mg, 23.5 umol) was added (Figure 10.32). The NMR of only TBAI in CDCI3 was taken for comparison (Figure 10.33). 226 Flgure 10.30 1H NMR (500 MHz, CDCI3) of arene 6.17 (see Appendix 2 for full scale spectrum) IrTIYYF1TYjT1UUIVIYIYUIV‘YU'IY‘ITTYfijU'IIUT‘II‘UrTrUUIIVV 10 8 6 4 2 ppm Flgure10.31 1H NMR (500 MHz, CDCI3) of arene 6.17 with 0.1 equiv of TBAI (see Appendix 2 for full scale spectrum) _ Jeraldmu rtrr'lIIVYrI'WYU'I'UUIITUI'ITUIFTTIUUW'U'II'UIITITUUUIIf 10 8 6 4 2 ppm 227 Flgure 10.32 1H NMR (500 MHz, CDCla) of arene 6.17 with 1 equiv of TBAI (see Appendix 2 for full scale spectrum) I L L__.I_ TII'IYIIIVIIIIYI[YTFYTTT—Ifilfifi'UIll'rtlitr'l'trfliiIIlil 10 8 6 4 2 ppm Flgure 10.33 1H NMR (500 MHz, CDCIS) of TBAI (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 228 OPMB O ‘3' ii I + PF6 WNCC OTIPS 1.3a NMR study of arene 6.17 with Bu,NPF,: Bu4NPF6 (19.3 mg, 50 umol) (Figure 10.34) and 6.17 (20.6 mg, 50 pmol) were dissolved in CDCI3 (1 mL) and added to an NMR tube (Figure 10.35). Flgure 10.34 1H NMR (500 MHz, CDCI3) of Bu,,NPF6 (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 229 Flgure 10.35 1H NMR (500 MHz, CDCIS) of Bu,,NPF6 with 1 equiv of arene 6.17 (see Appendix 2 for full scale spectrum) LHLII 1 r _ L____L__ ..ji..fi..,. ... ,.. .., 2....rj- .., ... ,,. ... ,.. .., ... .,. ...,e.. 10 8 6 4 2 ppm OPMB O . 0' nkfl - + BF4 mas \o/~\/N“\‘/A\ \‘L OH 6J7 NMR study of arene 6.17 with Bu4NBF42 Bu,,NBF4 (16.4 mg, 50 pmol) (Figure 10.36) and 6.17 (20.6 mg, 50 pmol) were dissolved in CDCI3 (1 mL) and added to a NMR tube (Figure 10.37). 230 Flgure 10.36 1H NMR (500 MHz, CDCI3) of Bu4NBF4 (see Appendix 2 for full scale spectrum) I I I I I I I I I I I l I I I I I I I I I I I I I I l I I I I l I I I I 1 I I r r I I I I T l I 1 I I l I I 10 8 6 4 2 ppm Flgure 10.37 1H NMR (500 MHz, CDCIS) of Bu4NBF4 with 1 equiv of arene 6.17 (see Appendix 2 for full scale spectrum) 10 8 6 4 2 ppm 231 OPMB CI 3.5 (68,7S,E)-N-(3-Chloro-5-((4-methoxybenzyl)oxy)phenyl)-7-hydroxy-6- methoxy-N-(4-methoxybenzyl)-2,8-dlmethylnona-2,8-dlenamlde, 8.5: To a stirred solution of amide 6.6 (90.1 mg, 0.12 mmol) in THF (6 mL) at 0 °C, TBAF (1.2 mL, 1.2 mmol, 1 M in THF) was added. The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution. After separation of the layers, the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na2804 and concentrated to afford 351.8 mg of the crude alcohol as a brown oil. The crude product was purified by flash silica gel chromatography first with a gradient of hexanes:EtOAc, 1:1 to provide 50.9 mg (71%) of the desired product 8.8 as a white oil. TLC analysis (Hexanes:EtOAc, 1:1), R, = 0.32; [a]2°D = +132 (0 = 1.195, CDCla); 1H NMR (500 MHz, CDCI3) 6 (ppm) 7.24 (d, J = 8.8 Hz, 2 H, overlapping with CDCIS), 7.11 (d, J: 8.8 Hz, 2 H), 6.89 (d, J: 8.8 Hz, 2 H), 6.79-6.78 (m, 3 H), 6.54 (t, J: 1.8 Hz, 1 H), 6.40 (dd, J: 2.0, 2.2 Hz, 1 H), 5.56 (qt, J: 1.5, 7.3 Hz, 1 H), 4.94 (m, 1 H), 4.89 (m, 1 H), 4.83 (s, 2 H), 4.82 (s, 2 H), 3.84 (dd, J: 3.8, 6.6 Hz, 1 H), 3.80 (S, 3 H), 3.76 (s, 3 H), 3.32 (s, 3 H), 3.05 (m. 1 H), 2.45 (d, J: 3.5 Hz, 1 H), 1.94 (q, J: 8.3 Hz, 2 H), 1.68 (t, J: 1.3, 3 H), 1.61 (d, J=1.5 Hz, 3 232 “I?“ H), 1.34-1.19 (m, 2H, overlapping with grease at 1.23); 13C NMR (126 MHz, CDCIa) 6 (ppm) 172.6, 165.6, 159.7, 159.5, 158.9, 145.5, 144.2, 135.3, 134.7, 131.9, 129.7, 129.5, 129.2, 127.8, 120.1, 114.1, 113.9, 113.5, 112.8, 81 .6, 77.2, 70.2, 58.1, 55.3, 55.2, 52.4, 28.7, 23.1, 17.9, 14.3; IR (neat) 3449, 3080, 2924, 2838, 1636, 1613, 1586, 1514, 1456, 1375, 1304, 1250, 1173, 1111, 1034; HRMS (TOF MS ES+) m/e calcd for [C,.,,,H,,,NO,,CI]+ 594.2624, found 594.2622. 8.5 NMR study of arene 8.5wlth Me4NBF4: To a NMR solution of arene 8.5 (33.7 mg, 57 pmol) in CD30N (1 mL) (Figure 10.38), Me4NBF4 (9.3 mg, 57 pmol) was added (Figure 10.39). CDCI3 (0.5 mL) was added to the NMR sample (Figure 10.40), as well as to samples containing only arene 8.5 in CD3CN (Figure 10.41) and Me4NBF4 in CD3CN (Figure 10.42) for comparison. 233 Flgure 10.38 1H NMR (500 MHz, CDSCN) of arene 8.5 (see Appendix 2 for full scale spectrum) _. . . L JIL...Jl_lI___I,LL_ML.____ I7 TITI IIII IIfiI 'IIII IIIT IfiII IIII III—r TIFI VIII ‘TT I I I I I I I I T I I 10 8 6 4 2 ppm Flgure 10.39 1H NMR (500 MHz, CD3CN) of arene 8.5 with 1 equiv of Me4NBF4 (see Appendix 2 for full scale spectrum) IljfirIIlIIIIIIIIIIIIIIIIIII‘IIIIIIIIIrrITII'II‘IIIIIIII’rI 10 8 6 4 2 PP'“ 234 Flgure 10.40 1H NMR (500 MHz, CD3CN) of arene 6.17 with 1 equiv of Me,,NBF4 and addition of CDCI3 (see Appendix 2 for full scale spectrum) I 1 l_l_IIIl .. i FrTTrITTIrIIIII fill—rrrfirITIITIIIIIIIIIIIITfi r1 fiTTII'IIIII'TI 10 8 6 4 2 ppm Flgure 10.41 1H NMR (500 MHz, CDaCN) of arene 8.5 with addition of CDCI3 (see Appendix 2 for full scale spectrum) TWIIIITIIVIIIIIIII'IIIIIIIIIIITTIIIIIIIIIIIIiIIIlIrrTIII 10 8 6 4 2 ppm 235 Flgure 10.42 1H NMR (500 MHz, CDSCN) of Me,,NBF4 with addition of CDCI3 (see Appendix 2 for full scale spectrum) l 3.. ll - I'IIIflTIIIIIIIIIIIIIlI’III[IIIITr—ITIl—I’IfirI—TIIITIIIII1II 10 8 6 4 2 ppm Appendix 1.9 Experimental for Chapter 9 Summary and Future Directions OH 9.1 (R)-2-Methylundec-1-en-3-ol, 9.1:228 To a stirred solution of nananyl aldehyde (1.00 g, 7.03 mmol) in THF (70 mL) at 0 °C in a ice-bath, propenyl magnesium bromide (28 mL, 14 mmol, 0.5 M in THF) was added over five minutes. The reaction was stirred at 0 °C for 3 h before being quenched with saturated aqueous NaHCCS. Brine was added and the layers were separated. The aqueous layer was extracted three times with CHZCIQ. The combined organic 236 layers were dried over M9804, filtered and concentrated to afford 1.66 g of light yellow oil. The crude alcohol was purified by flash silica gel chromatography (100% CHQClz) to afford 712 mg (55%) of a clear oil containing a trace of THF. TLC analysis (100% CHQClz), R,= 0.26; (500 MHz, CDCIS) 6 (ppm) 4.91 (m, 1 H), 4.81 (m, 1 H), 4.03 (dt, J: 3.4, 6.6 Hz, 1 H), 1.70 (t, J: 1.2 Hz, 3 H), 1.56-1,47 (m, 2 H), 1.42 (d, 3.7 Hz, 1 H), 1.39-1.21 (m, 12 H), 0.86 (t, J: 6.8 Hz, 3 H); 13C NMR (126 MHz, CDCIS) 6 (ppm) 147.7, 110.9, 76.0, 35.0, 31.9, 29.6, 29.5, 29.3, 25.6, 22.7, 17.5, 14.1. OMe 9.2 (R)-3-Methoxy-2-methylundec-1-ene, 9.2: To a stirred slurry of alcohol 9.2 (200 mg, 1.09 mmol) and NaH (131 mg, 3.28 mmol, 60% in mineral oil) in THF (29 mL), Mel (0.41 mL, 6.59 mmol) was added, followed by TIBAI (24 mg, 0.065 mmol). The reaction was heated in an oil bath at 55 °C for 17 h before being quenched with saturated aqueous NH4CI. After separation of the layers, the aqueous layer was extracted once with ether. The combined organic layers were washed with brine, dried over M9804, filtered and concentrated to afford 346 mg of a yellow oil containing black solids. The crude ether was purified by flash silica gel chromatography (2:1, hexanes:CHQC|2) to afford a pink oil, which was diluted with CH20l2 and washed with 15 wt% Na,s,o, to remove iodine. The organic layer was dried over Na2804, filtered and concentrated to afford 197 mg (91%) 237 lrl‘ " T m 9.2 as a clear oil. TLC analysis (2:1, hexaneszCHZClz), R,= 0.31; IR (neat) 3074, 2928, 2855, 2818, 1653, 1456, 1098, 899 cm"; (500 MHZ, CDCIS) 6 (ppm) 4.90 (m, 1 H), 4.86 (m, 1 H), 3.46 (t, .1: 7.08 Hz, 1 H), 3.18 (s, 3 H), 1.161 (t, J: 1.0 H2, 3 H), 1.58-1.52 (m, 1 H), 1.46 (m, 1 H), 1.33-1.17 (m, 12 H) 0.86 (t, J: 6.8 Hz, 3 H); ‘30 NMR (126 MHz, 0001,) 5 (ppm) 144.6, 113.4, 85.9, 56.0, 33.5, 31.9, 29.6, 29.5, 29.3, 25.8, 22.7, 16.2, 14.1; HRMS m/e calcd for [C13H260+H]* 199.2062, found 199.2058. OTIPS 9.3 (R)-Trllsopropyl((2-methylundec-1-en-3—yl)oxy)sllane, 9.3: To a stirred solution of alcohol 9.1 (200 mg, 1.09 mmol), imidazole (222 mg, 3.27 mmol), and DMAP (2.5 mg, 0.02 mmol) in CH2C|2 (5 mL), TIPS-Cl (0.46 mL, 2.17 mmol) was added. The reaction was stirred at rt for 1.5 days, before another equivalent of TIPS-Cl (0.23 mL, 1.07 mmol) was added. After and additional 24 h, the reaction was concentrated, dissolved in ether (10 mL), washed with 5 mL 1 N HCI, dried over Na2804, filtered and concentrated to afford 747 mg of a clear oil. The crude silylether was purified by flash silica gel chromatography (100% hexanes) to provide 178 mg (48%) of the desired product 9.3 with trace impurities. TLC analysis (100% hexanes), R, = 0.73; IR (neat) 3073, 2930, 2867, 1653, 1464, 1086, 1065, 1013, 897, 884 cm“; (500 MHz, CDCIS) 6 (ppm) 4.81 (m, 1 H), 4.75 (m, 1 H), 4.12 (t, J: 6.3 Hz, 1 H), 1.65 (dd, J: 1.0, 1.2 Hz, 3 H), 1.56-1.45 (m, 2 238 H), 1.29-0.95 (m, 33 H), 0.86 (t, J: 6.8 Hz, 3 H); 13C NMR (126 MHz, CDCla) 6 (ppm) 147.3, 110.9, 76.9, 35.9, 31.9, 29.7, 29.6, 29.3, 25.0, 22.7, 18.11, 18.09, 16.8, 14.1, 12.4; HRMS m/e calcd for [Cz,H,,,OSi+H]+ 341.3240, found 341.3253. 0 ° Me ”J% 9.4 (E)-2-Methyl-N-(m-tolyl)but-2-enamlde, 9.4: In a glovebox, a three-neck round- bottom flask was charged with 3-bromotoluene 2.1a (354 pl, 2.92 mmol), szdba3 (27 mg, 0.03 mmol), xantphos (51 mg, 0.09 mmol), tiglic amide (318 mg, 3.21 mmol), 032003 (1.33 g, 4.08 mmol) and DME (9 mL). The flask was sealed and removed from the glovebox and connected to a condenser under nitrogen. The reaction was heated in an oil bath at 100 °C for 48 h. The crude reaction was filtered through a pad of silica, eluted with acetone and concentrated to afford 678.1 mg of a dark brown oil as crude product. The crude amide was purified by flash silica gel chromatography (hexanes:EtOAc, 4:1) to provide 468.9 mg of the desired product as white solid (85%). The amide was further purified through sublimation (0.3 torr, 60 °C, continuous vacuum) to provide 394.2 mg of 9.4 as a white solid (71%). Mp: 59-61 °C; TLC analysis (hexanes:EtOAc, 4:1), R, = 0.25; 1H NMR (500 MHz, acetone-d6) 6 8.79 (bs, 1 H), 7.54 (s, 1 H), 7.51 (d, J = 8.1 Hz, 1 H), 7.15 (dd, J: 7.6, 8.1 Hz, 1 H), 6.85 (dq, J: 7.6, 0.7 Hz, 1 H), 6.47 (qq, J: 1.2, 6.8 Hz, 1 H), 2.28 (s, 3 H), 1.88 (q, J: 1.2 Hz, 3 H), 1.75 (dq, J: 1.0, 6.8 Hz, 3 H); 13C NMR (126 MHz, acetone-d6) 6 168.3, 140.5, 138.9, 134.2, 130.6, 129.2, 124.8, 121.3, 117.8, 21.6, 14.0, 12.6; IR (neat) 3308, 3058, 2919, 239 2857, 1663, 1635, 1611, 1541, 1489, 1437, 1310,1258, 1179 cm“; HRMS (ESI) m/e calcd for [C,2H,5NO-1-H]+ 190.1229, found 190.1232. 240 Appendix 2. Reference Spectra for Appendix 1.8 Appendix 2 contains the fullpage spectra of the spectra shown in Appendix 1.8 as Figure 10.1 to Figure 10.42. For example, the spectrum shown here as Figure A10.1 corresponds to the spectum shown as Figure 10.1 in Appendix 1.8. 241 : a. :6 $pr 8:6 6 308 .sz 83 £22 I. 32 2:9“. and H a m 4 m p n m m S . _ _ . . 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IL! ,lrt LI!|»I|L||F-|rI Lui 5"; I» ||_v| .L'lLL LIIFI» 3 J1 g . M 283 References (1) (7) (8) Stead, P.; Latif, 8.; Blackaby, A. P.; Sidebottom, P. J.; Deakin, A.; Taylor, N. L.; Life, P.; Spaull, J.; Burrell, F.; Jones, R; Lewis, J.; Davidson, |.; Mander, T. J. Antibiot. 2000, 53, 657-663. Li, M. G.; Wu, 8. H.; Zhao, L. X.; Zhang, 0.; Li, W. J.; Cui, X. L.; Xu, L. H.; Wu, D. G.; Jiang, C. L. Chin. Chem. Lett. 2001, 12, 903-906. Rascher, A.; Hu, 2. H.; Buchanan, G. 0.; Reid, R.; Hutchinson, C. R. Appl. Environ. Microbiol. 2005, 71, 4862-4871. Onodera, H.; Kaneko, M.; Takahashi, Y.; Uochi, Y.; Funahashi, J.; Nakashima, T.; Soga, 8.; Suzuki, M.; lkeda, 8.; Yamashita, Y.; Rahayu, E. 8.; Kanda, Y.; lchimura, M. Bioorg. Med. Chem. Lett. 2008, 18, 1577- 80. Muroi, M.; Haibara, K.; Asai, M.; Kishi, T. Tetrahedron Lett. 1980, 21, 309-312. Muroi, M.; Haibara, K.; Asai, M.; Kamiya, K.; Kishi, T. Tetrahedron 1981, 37, 1123-1130. Smith, A. 8., ill; Wood, J. L.; Gould, A. 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