APPLICATION S OF CHIRAL ALUMINUM AND BORON CATALYSTS IN ASYMMETRIC SYNTHESIS By Li Zheng A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry Doctor of Philosophy 20 20 ABSTRACT APPLICATION S OF CHIRAL ALUMINUM AND BORON CATALYSTS IN ASYMMETRIC SYNTHESIS By Li Zheng A potent chiral aluminum catalyst has been developed for asymmetric MPV reduction of ketones with broad substrate scope and excellent yields and enantiomeric induction s . The catalyst consists an aluminum core, a VANOL - derived chiral ligand and an isopropoxy group. Different ligands have be en screened and reaction parameters have been optimized. A variety of aromatic (both electron - poor and electron - rich) and aliphatic ketones were converted to chiral alcohols in good yields with high enantioselectivities (26 examples, 70 - 98% yield and 82 - 99 % ee ). This method operates under mild conditions ( 10 ºC) and low catalyst loading (1 10 mol%). Furthermore, this process is catalyzed by the earth - abundant main group element aluminum and employs inexpensive and environmentally benign 2 - propanol as hydride source. This catalyst has also been employed in resolution of racemic alcohols. The kinetic resolution of alcohols by Oppenauer oxidation has been achieved with moderate results. The formal dynam ic kinetic resolution via Oppenauer oxidation/ MPV reduction sequence has also been examined and discussed, which avoided acylation and the use of enzymes. A highly efficient asymmetric heteroatom Diels - Alder reaction between diene and aldehydes for the co nstruction of 6 - membered heterocycles catalyzed by chiral boron catalysts has been developed. A BINOL - derived propeller borate is found to be effective cataly zing the reaction of aromatic aldehyde s. A VANOL - derived meso - borate is found to be able to cataly ze the reaction of both aromatic and aliphatic aldehydes with high asymmetric inductions . Excellent yields and enantioselectivities have been achieved after optimization. Furthermore, the skeleton of 6 - carbon saccharides is synthesized in the reaction of 2 - hydoxyace t aldehyde with different protecting groups , which can be derivatized into many saccharide analogs. The mechanism of this reaction is proposed to be concerted based on experi ments involving different methods for the reaction quench. A reversal of direction of the asymmetric induction by switching boron to aluminum has been observed. Computational studies show that catalysts derived from boron and aluminum have different geomet ries at the Lewis acid center. Copyright by L I ZHENG 20 20 v This thesis is dedicated to my parents, my wife , and my cats . vi ACKNOWLEDGMENTS First and foremost, I would like to thank my advisor Dr. Wulff. I am so grateful to have him as my mentor and w ords are never enough to tell how much I have lea r nt from him. Besides his extensive knowledge, his passion in chemistry inspired me the most. Once I asked him that why he did not t ake a vacation during Christmas, and he said that He is a great scientist and a patient teacher who devotes his whole life into chemistry . I thank him so much for explaining me different reaction mechanisms ; for listening to me carefully when we have different opinions ; for giving me advices whenever I meet problems; for letting me work on projects that I am interested in; for his wine, cheese and fun stories during the post - group meetings; and for his warm support and encouragement in lab and in life . I am so proud to be part of the Wulff group. I would also like to thank Professor Borhan for being my second reader of my thesis. He is a good teacher and a very nice frien in the first one to two years of my PhD. I felt like he was so smart that just by looking into my eyes he pressure from him made me highly motivated and I th ought that if I were not hard - working enough, horrible thing s would happen during my first committee meeting/ seminar/ second - year oral exam / defen se . He was qualified PhD. I would like to thank my committee member Professor Tepe and Professor Beck for their guidance in my research. Professor Tepe taught m e to pay attention vii to the replicability of reactions and Professor Bec k encouraged me to learn computational chemistry . Their suggestions helped me a lot towards the completion of my PhD projects. I would also like to thank Professor Huang, Professor Maleczka, Professor Jackson and Professor Smith for their fantastic lectures. The knowledge they delivered and the problem - solving skills that I learn t from them are truly valuable. I would like to thank Dr. Azadnia for being my advisor in teaching for 5 years. I really enjoy being a teaching assistant for CEM 14 3, 252, 255, 355 and 356 under his supervision . And I will always remember the help from Dr. Holmes and Dr. Xie for their patient NMR training, as well as the help from Dr. Staples for solving the crystal structures of my samples. I also thank Professor Jo nes, Professor Sun and Dr. Chen for their assistance on Mass Spectrometry. I am so proud to be the last PhD in the Wulff group and I will never forget those days I spent with all the senior lab members. I need to thank Dr. Xin Zhang first for his email bef ore I came to US. In the email he described Dr. Wulff to be the I am so glad nd every day in the past five years proves that Xin did not lie to me . I thank Dr. Yubai Zhou , a crazy cat lover, for being a great friend. I miss the many poker game Boy never won. I also thank Dr. Yijing Dai, a much better p oker player, for beating me and Yubai every single time. I want to thank Dr. Xiaopeng Yin, my lab mentor, for teaching me how to conduct researc h and helping me patiently whenever I met a problem. He helped me a lot through my second - year seminar and oral exam. Without his mentorship and friendship, my PhD would be a lot harder. I would like viii to thank Dr. Aliakbar Mohammadlou , a brilliant and hard - working chemist, for his company and support during the five years. He taught me a lot of chemistry as well as experimental technics and was always there to help. I thank several undergraduates in our group, Emily, Brendyn, Brian and Ryan for their help in the lab. I would also like to thank Dr. Yu Zhang, Dr. Hong Ren, Dr. Yong Guan and Dr. Wenjun Zhao, former mem bers from the Wulff group, for their help and support in my research and life . I would like to thank Hadi, Yi, Wei, Ding, Jun, Aritra, Debarshi, Saeedeh, Rahele and many other people from the Borhan group for their help and scientific advices during my Ph D. I thank Dr. Tayeb Kakeshpour very much for teaching me how to run DFT calculations and explaining computational concepts to me . I also , Jun, Dan, Chenjia, Nate, Daoyang, Eli, Jia, Kunli, Zhen, Yuhan, Qianyi and Guangyao for those wonderful games we played together . I would like to thank Yiqing, Ke, Badru - Deen, Shuang, Zibin, Zhilin, Qianjie, Tian and other friends for all the wonderful moments we s hared together. Finally, I would like to give special thanks to my wife Xiaojing. It is so beautiful that we fell in love in college and g o t married in graduate school. Thank you so much for your endless support and encouragement over the years, and that is the most precious gift for me throughout my PhD journey. ix TABLE OF CONTENTS LIST OF TABLES ................................ ................................ ................................ x i LIST OF FIGURES ................................ ................................ ............................. xi i LIST OF SCHEMES ................................ ................................ ........................... xi ii CHAPTER ONE ASYMMETRIC CATALYTIC MEERWEIN - PONNDORF - VERLEY REDUCTION S IN THE LITERATURE ................................ ................... 1 1.1 Introduction ................................ ................................ .............................. 1 1.2 Catalytic MPV reduction s ................................ ................................ ......... 2 1.3 Asymmetric catalytic MPV reductions ................................ ...................... 8 1.4 Aluminum - catalyzed asymmetric MPV reductions ................................ . 12 1. 5 Summary ................................ ................................ ............................... 15 REFERENCES ................................ ................................ ................................ ... 17 CHAPTER TWO ASYMMETRIC CATALYTIC MEERWEIN - PONNDORF - VERLEY REDUCTION OF KETONES WITH ALUMINUM( III ) - VANOL C ATALYSTS ................................ ................................ ................................ ... 24 2.1 Introductio n ................................ ................................ ............................ 24 2.2 Initial study: Is switching BINOL to VANOL a way out? ......................... 25 2.3 Reaction optimizations ................................ ................................ ........... 27 2. 3 .1 L igand screening ................................ ................................ ............. 2 7 2. 3 .2 P reliminary optimization of reaction parameters ............................. 31 2.3.3 Further optimizations on the reduction of 2 - bromoacetophenone ... 33 2.3. 4 - bromoacetophenone .............. 40 2. 4 Substrate scope for aromatic ketones ................................ ................... 42 2. 5 Substrate scope for aliphatic ketones ................................ .................... 48 2. 6 Scale up synthesis with 1 mol% catalyst loading ................................ .. 5 1 2. 7 Reaction mechanism and computational study ................................ ..... 5 2 2.7.1 Mechanism of MPV reduction of ketones ................................ ........ 5 2 2.7.2 Computational study ................................ ................................ ........ 5 3 2. 8 Formal dynamic kinetic resolution of racemic alcohols via Oppenauer oxidation/MPV reduction ................................ ................................ .............. 60 2.8.1 Introduction ................................ ................................ ..................... 60 2.8.2 Oxidative kinetic resolution of racemic alcohols with aluminum - VANOL catalysts ................................ ................................ ...................... 6 4 2.8. 3 Tentative formal dynamic kinetic resolution of racemic alcohols with aluminum - VANOL catalysts ................................ ................................ ..... 6 6 2.9 Conclusion ................................ ................................ ............................. 6 9 REFERENCES ................................ ................................ ................................ ... 71 x CHAPTER THREE ENANTIOSELECTIVE HETEROATOM DIELS - ALDER REACTION OF ALDEHYDES CATALYZED BY CHIRAL BORATE CATALYSTS ................................ ................................ ................................ ... 7 6 3.1 Introduction ................................ ................................ ............................ 7 6 3.1.1 Synthetic applications of heteroatom Diels - Alder reactions ............ 7 6 3.1.2 Chiral borates in asymmetric reactions ................................ ........... 9 9 3.2 Initial study ................................ ................................ ........................... 1 0 5 3.3 NMR study on catalysts ................................ ................................ ....... 1 11 3.4 Optimization and substrate scope with catalysts 216 .......................... 11 4 3.5 Optimi zations of asymmetric HDA reaction with catalyst 249 .............. 11 7 3.6 Substrate scope of asymmetric HDA reaction with catalyst 249 .......... 1 21 3. 7 - alkoxyacetaldehyde ............. 1 2 4 3. 8 Reaction mechanism and computational study ................................ .... 1 30 3 . 8 .1 Is the asymmetric HDA reaction catalyzed by VANOL borate complex concerted or stepwise? ................................ ............................ 1 30 3 . 8 .2 Reversal of asymmetric induction ................................ ................. 1 32 3. 9 Conclusion ................................ ................................ ........................... 1 3 4 REFERENCES ................................ ................................ ................................ . 1 3 6 CHAPTER FOUR EXPERIMENTAL SEC TION ................................ ................ 1 4 5 4.1 General information ................................ ................................ ............. 1 4 5 4.2 Experimental information for c hapter two ................................ ............. 1 47 4.2.1 General procedure for catalytic asymmetric MPV reduction of aromatic ketones ................................ ................................ .................... 1 47 4.2.2 General procedure for catalytic asymmetric MPV reduction of aliphatic ketones ................................ ................................ ......................... 170 4.2.3 Procedure for gram scale s ynthesis ................................ .............. 174 4.2.4 Procedure for resolution of racemic alcohols ................................ 176 4.2.5 Computational study ................................ ................................ ...... 178 4.3 Experimental information for chapter three ................................ .......... 21 5 4.3.1 General procedure for preparing diene 93 ................................ .... 21 5 4.3.2 General procedure for preparing aldehyde 231w .......................... 21 6 4.3.3 General procedure for preparing aldehyde 231 y ........................... 21 8 4.3.4 General procedure for preparation of catalysts ............................. 2 20 4.3.5 General procedure for asymmetric HDA reaction .......................... 22 6 4.3.6 Computational study ................................ ................................ ...... 2 46 REFERENCES ................................ ................................ ................................ . 2 51 xi LIST OF TABLES Table 2.1 Screening of ligands for the MPV reduction of 2 - bromoacetophenone ................................ ................................ ................................ ............................ 3 0 Table 2.2 Preliminary optimization of reaction conditions ................................ ... 3 2 Table 2.3 Solvent screening for the MPV reduction of 2 - bromoacetophenone ... 3 3 Table 2.4 Study on different methods of preparing catalysts .............................. 3 4 Table 2.5 Concentration effect for the MPV reduction of 2 - bromoacetophenone ................................ ................................ ................................ ............................ 3 6 Table 2.6 Test of replicability ................................ ................................ .............. 3 7 Table 2.7 Al cohol Screening for the MPV reduction of 2 - bromoacetophenone .. 3 8 Table 2.8 Further optimizations with L21 as ligand ................................ ............ 3 9 Table 2.9 - bromoacetophenone ................. 40 Table 2.10 - bromoacetophenone with different ligands .............. 42 Table 2.11 Optimization on the reduction of 3 - phenyl - 2 - butanone ..................... 49 Table 2.12 Free energy differences at transition state with 30 ligands ............... 55 Table 4.1 Free energy differences by HF/3 - 21G* in vacu um ............................ 1 80 Table 4.2 Free energy differences by B3LYP/6 - 31G(d) in vacuum .................. 184 Table 4.3 Free energy differences by B3LYP/6 - 31G(d) in toluene ................... 188 Table 4.4 Free energy differences by B3LYP/6 - 31G(d) in n - pentane ............... 19 3 Table 4.5 Free energy differences by B3LYP/6 - 31G(d) in 2 - propanol .............. 19 7 Table 4.6 - 21G* in vacuum for 2 - bromoacetophenone 55g ................................ ................................ ................................ .......................... 201 xii LIST OF FIGURES Figure 1.1 Aluminum complexes as catalysts for the MPV reduction ................... 4 Figure 2.1 The use of BINOL derivatives as common solu tion .......................... 2 5 Figure 2.2 Ligands that were tested for MPV re action ................................ ....... 28 Figure 2.3 Computational study with 30 ligands ................................ ................. 54 Figure 2.4 Transition states with ( S ) - L21 in 2 - propanol ................................ ..... 57 Figure 2.5 Transition states with ( S ) - L21 in the reduction of 2 - bromoacetophenone ................................ ................................ ................................ ............................ 59 Figure 3.1 Six - membered heterocycles in natural products ............................... 77 Figure 3.2 Selected Lewis acid catalysts for asymmetric HDA reactions ........... 90 Figure 3.3 Chiral organocatalysts in asymmetric HDA reactions ....................... 91 Figure 3.4 Selected chiral boron catalysts ................................ ....................... 100 Figure 3.5 Ligands screened ................................ ................................ ............ 124 Figure 3.6 Boron and aluminum catalysts prepared from VANOL .................... 133 xiii LIST OF SCHEMES Scheme 1.1 Classic MPV reduction of carbonyl compounds ............................... 2 Scheme 1.2 Addition of protic acid in MPV reduction/Oppenauer oxidation ........ 3 Scheme 1.3 Alkali metal alkoxides in quinine oxidation and quininone reduction 6 Scheme 1.4 Inorganic bases in MPV reduction ................................ .................... 7 Scheme 1.5 Asymmetric MPV reduction with chiral alcohols ............................... 9 Scheme 1.6 Asymmetric MPV reductions with chiral catalysts .......................... 10 Scheme 1.7 Asymmetric MPV reduction of glyoxylates ................................ ..... 1 2 Scheme 1.8 Asymmetric catalytic MPV reductions with aluminum - BINOL catalysts ................................ ................................ ................................ ............................ 13 Scheme 1.9 Asymmetric MPV reductions with aluminum - calixaren e catalysts .. 14 Scheme 2.1 Switching BINOL to VANOL ................................ ........................... 2 6 Scheme 2.2 Substrate scope for aromatic ketones I ................................ .......... 4 3 Scheme 2.3 Substrate scope for aromatic ketones II ................................ ......... 45 Scheme 2.4 Limitations on substrate scope ................................ ....................... 48 Scheme 2.5 Substrate scope for aliphatic ketones ................................ ............. 51 Scheme 2.6 Scale up synthesis ................................ ................................ ......... 52 Scheme 2.7 Mechanism of MPV reduction of ketones ................................ ....... 5 3 Scheme 2. 8 Explanation of stereo outcome ................................ ....................... 58 Scheme 2. 9 Kinetic resolution and dynamic kinetic resolution ........................... 61 Scheme 2.1 0 Alcohol racemizations with ruthenium catalyst ............................. 62 Scheme 2.1 1 Chemo - enzymatic dynamic kinetic resolution of alcohols ............ 62 xiv Scheme 2.1 2 Non - enzymatic dynamic kinetic resolution of alcohols ................. 6 3 Scheme 2.1 3 Oxidative kinetic resolution of racemic alcohols .......................... 66 Scheme 2.1 4 Formal dynamic kinetic resolution of racemic alcohols ................. 68 Scheme 3.1 Normal HDA reaction and inverse electron - demand HDA re action 78 Scheme 3.2 Aldehyde as dienophile of HDA reactions in total syntheses .......... 79 Scheme 3.3 ........... 80 Scheme 3.4 Constructing aromatic heterocycles by HDA reactions ................... 82 Scheme 3.5 Inverse electron - demand HDA reactions in total syntheses ........... 85 Scheme 3.6 HDA reactions in the construction of spiro compounds .................. 86 Scheme 3.7 HDA reactions with uncommon dienophiles in total sy ntheses ...... 88 Scheme 3.8 Chromium catalyst 147 with alkynals in total syntheses ................. 92 Scheme 3.9 Chromium catalyst 147 with aldehyde 170 in total syntheses ........ 94 Scheme 3.10 Asymmetric HDA reactions with chiral aldehydes or dienes ......... 96 Scheme 3.11 Rhodium - catalyzed asymmetric HDA reactions in total syntheses ................................ ................................ ................................ ............................ 97 Scheme 3.12 Copper - catalyzed asymmetric HDA reactions in total syntheses . 98 Scheme 3.13 Chiral borate catalysts in asy mmetric Diels - Alder reaction ......... 101 Scheme 3.14 Chiral spiro - borate catalysts ................................ ....................... 102 Scheme 3.15 Chiral boroxinate in asymmetric catalysis ................................ .. 104 Scheme 3.16 Oxa - Diels - Alder reaction with BOROX catalysts ........................ 106 Scheme 3.17 Oxa - Diels - Alder reaction with BLA catalyst 222 ......................... 107 Scheme 3.18 Optimization of the ligand and the temperature .......................... 108 Scheme 3.19 Control experiments and screening of the boron source ............ 109 xv Scheme 3.20 Can the same syringe be used for two injections of BH 3 2 S? 112 Scheme 3.21 Catalyst prepared from BINOL ................................ ................... 114 Scheme 3.22 Optimizations with catalyst 216 ................................ .................. 11 6 Scheme 3.23 Substrate scope of asymmetric HDA reaction with catalyst 216 11 7 Scheme 3.24 Optimization of the HDA reaction of benzaldehyde with catalyst 249 ................................ ................................ ................................ .......................... 11 9 Scheme 3.25 The optimization of aliphatic aldehyde with catalyst 249 ............ 1 20 Scheme 3.26 Substrate scope with catalyst 249 ................................ .............. 1 21 Scheme 3.27 Failed substrates with catalyst 249 ................................ ............ 1 23 Scheme 3.28 Attempts at optimizations of aldehyde 231f ................................ 1 25 Scheme 3.29 Optimization of aldehyde 231w in the reaction with diene 93 ..... 1 27 Scheme 3.30 Optimizations on aldehyde 231x ................................ ................ 1 28 Scheme 3.31 Optimizations of aldehyde 231y ................................ ................. 1 29 Scheme 3.32 Two possible pathways ................................ .............................. 1 30 Scheme 3.33 Different quenching methods ................................ ..................... 1 31 Scheme 3.34 Asymmetric HDA reaction with boron and aluminum catalysts .. 1 32 1 CHAPTER ONE ASYMMETRIC CATALYTIC MEERWEIN - PONNDORF - VERLEY REDUCTION S IN THE LITERATURE 1.1 Introduction The reduction of carbonyl compounds is one of the most important functional group manipulation s in organic chemistry. 1 Amont various methods developed during the past century, t he Meerwein - Ponndorf - Verley (MPV) reaction holds a prominent and historical position . In 1925, the reduction of carbonyl compounds with aluminum ethoxide (Al(OEt) 3 ) and ethanol was discovered independently by Meerwein and Schmidt 2 , and by Verley 3 . Aldehydes and a few ketones were reduced to their corresponding alcohols at the expense of one equivalent of ethanol that is oxidized to acetaldehyde. The reaction is reversible, but the equilibrium can be shifted to the completion of reduction by removal of acetaldehyde with a dry hydrogen or nitrogen stream. 4 In 1926, Ponndorf established an efficient method with the use of aluminum isopropoxide (Al(O i Pr) 3 ) and isopropanol. Aldehydes as well as ketones were reduced satisfactorily, with the acetone f or med being removed by distillation . 5 Futhermore, the reversible nature of the Me erwein - Ponndorf - Verley reaction was employed to achieve oxidation of alcohols with aluminum t - butoxide (Al(O t Bu) 3 ) in the presence of a large excess of acetone, known as the Oppenauer oxidation. 6 ,7 Th e Meerwein - Ponndorf - Verley reaction utilizes inexpensive 2 - propanol as reducing agent to generate primary or secondary alcohols from aldehydes or ketones that are activated though coordination to a Lewis acidic aluminum center. 8 2 The mechanism involves the hydride transfer from 2 - propanol to carbonyl compounds via a six - membered ring transition state (Scheme 1.1) . 9 The classic MPV reduction of ketones is relatively slow, so it usually requires more than stoichiometric amounts of aluminum isopropoxide (Al(O i Pr) 3 ) to achieve a sati sfactory yield. 10 Therefore, it was largely replaced by methods using boron and aluminum hydrides after 1950. 11 However, efforts to improve the MPV reduction never diminished since the use of 2 - propanol as hydride source is very attractiv e. Sch eme 1.1 Classic MPV reduction of carbonyl compounds 1. 2 Catalytic MPV reductions have been established. Rathke and co - workers 1 2 initially discovered rate enhancement with addition of protic acid in 197 7 . They found that the oxidation of cyclohexanol by benzaldehyde could be dramatically improved with the addition of 3 trifluoroacetic acid (TFA) or hydrochloric acid (HCl) in presence of a catalytic amount (5 mol%) of Al(O t Bu) 3 (Scheme 1.2) . In 1995, Akamanchi et al. 13 employed 8.2 mol% Al(O i Pr) 3 with 0.32 mol% TFA as co - catalyst to achieve catalytic reduction of carbonyl compounds with 1 equivalent of isopropanol at room temperature. The reduction of aldehydes was carried out in 15 min to 4 hours with 61 to 100% conversion, while lower conversion and longer reaction time s were observed for ketones (44% conversion in 22 hours for acetopheno ne). Scheme 1.2 Addition of protic acid in MPV reduction/Oppenauer oxidation As solid Al(O i Pr) 3 is known to be in a high aggrega t ion state as indicated in 14 with isopropoxy as bridging units 14 , it was proposed that the protic acid additive 4 could replace some of the alkoxy groups and generate a new aluminum species 15 that is more electronegtive. Therefore, the catalyst bec o me s more Lewis acidic and the coordination between a carbonyl substrate and aluminum was enhanced, which increased the overall reactivity of the catalyst. 15 The aluminum alkoxide/protic acid combination is the first example of a catalytic MPV reduction/Oppena uer oxidation catalyzed by aluminum. However, this combination is also found to be a potent catalyst for the undesired aldol condensation as a side self condensed with 90% yield in 5 minutes in the presence of 5 mol% Al(O t Bu) 3 and 2.5 mol% TFA. 12 Therefore, the applications of this method in organic synthe sis are limited. Figure 1.1 Aluminum complexes as catalyst s for the MPV reduction Replacement of aluminum isopropoxide with other aluminum complexes that are coordinated to multidentate ligand s can make the catalytic reduction highly efficient (Figure 1.1) . In 1988, Inoue and co - workers 16 found that aluminum 5 porphyrin 16 showed novel catalytic prowess with 20 mol% catalyst loading in the reduction of aldehydes or ketones with alcohols as reducta nt. High ster e oselectivities were observed with the reduction of 2 - methylcyclohexanone, which gave up to a 93:7 trans to cis ratio in the corresponding product. Bidentate aluminum alkoxides 17 have been found as eff i cient catalysts for the MPV reduction of aldehydes and ketones with 5 mol% catalyst loading and one equivalent of isopropanol. 17 The catalyst 17 bearing two aluminum s in one molecule were able to capture both of the oxygen lone pairs simu l taneously, which enables double activati on of the carbonyl group. 10 Dimeric biphenoxyalkoxide 18 could catalyze the reduction of aldehydes with 2 equivalent s of isopropanol at ambient conditions. 18 Aluminum sulfonamide 19 could readily reduce various ketones under mild conditions owing to its high Lewis acidity. 19 A sterically overloaded siloxide - supported aluminum species 20 was found to be cap a ble of reducing a wide range of aldehydes and ketones with very low catalyst loading (0.05 mol% to 0.7 mol%). 20 Bidentate N,O - aluminum complex 21 and tridentate imino - phenolate aluminum complex 22 also showed catalytic activity in MPV reductions. 21,22 It has been shown that reducing the aggregation state of aluminum alkoxides leads to enhancement of catalytic prope rties. The use of Al(O t Bu) 3 instead of Al(O i Pr) 3 was found to accelerate ketone reductions 23 because its favorable dimeric structure in benzene ha s more exchang e able ligands compared with the tetrameric structure of Al(O i Pr) 3 . 24 Nguyen and co - workers demonstrated that low - aggregated Al(O i Pr) 3 freshly prepared from AlMe 3 and 2 - propanol was 6 essential to achieve high catalytic activity in the MPV reduction of aldehydes and ketones . 25 Scheme 1.3 Alkali metal alkoxides in quinine oxidation and quininone reduction s MPV reductions with isopropanol could also be catalyzed by other metals. In 1945, Woodward and co - workers 26 first discovered the use of alkali metal alkoxides in the so - 9 Quinine was not oxidized by Oppenauer method using aluminum t - butoxide and phenoxide as catalysts and a variety of ketones as oxidants (Scheme 1.3) , proba bly due to the basicity of nitrogen that binds to aluminum and kill the catalysts. The use of 2.5 7 equivalent of freshly prepared potassium t - butoxide and 5 equivalent of benzophenone successfully oxidized quinine to quininone in quantitative yield. Further more, quininone was reduced to quinine and quinidine with sodium isopropoxide and isopropanol. Although these methods required f a r more than stoichiometric amount s of metal alkoxides, it indicate s that alkali metal alkoxides can be possible catalysts in MP V reductions. Scheme 1.4 Inorganic bases in MPV reduction Recently, the use of i norganic bases such as sodium hydroxide (NaOH) 27 , potassium hydroxide (KOH) 28 , and potassium phosphate (K 3 PO 4 ) 29 have been found to be effective in aldehyde and ketone reductions ( Scheme 1.4 ) . Catalytic 8 amount s of NaOH, KOH and the weaker base K 3 PO 4 c an reduce aldehydes and ketones with isopropanol as solvent. The active catalytic species was proposed to be an in - situ generat ed sodium or potassium isopropoxide and a novel six - membered ring transition state 26 was proposed by Chuah 29 . Garg and co - workers 30 employed K 3 PO 4 and alcohol 27 instead of isopropanol to achieve ketone reductions for many heterocycles. The reduction of ketones with isopropanol catalyzed by transition metal systems have also been reported and include samarium 31 , ruthenium 32 ,33 , rhodium 3 4 , tin 35 , zirconium 36 - 40 , indium 22,41 , ytterbium 42 and yttrium 43 . However, some of these ketone reductions catalyzed by transition metals via the transfer hydrogenation from alcohols are not considered as MPV reductions by some 44 . With metal - hydride species as the real catalyst in these reaction s , the most common hydride source is formic acid instead of isopropanol . 45 ,46 1. 3 Asymmetric c atalytic MPV reductions The asymmetric MPV reduction of ketones can be achieved by two strategies. One is the use of chiral alcohol s as sacrificial hydride source instead of 2 - propanol, which requires far more than stoichiometric amount s of enantiopure reagent. 47 The first asymmetric MPV reduction induced by chiral alcohols was reported by Doering and Young in 1950 with the use of aluminum alkoxides as catalysts. 48 Maruoka and co - workers 17 employed 5 mol% catalyst 17 and 1 equivalent of enantiopure alcohol ( R ) - 30 as sacrificial hydride source to achieve enantio en riched alcohol 29 from ketone 28 in 51% yield and 82% ee . Other chiral alcohols such as ( R ) - sec - phenethyl alcohol ( R ) - 31 gave lower asymmetric 9 inductions. Nguyen et al. also found that the same reaction could be achieved without the use of a ligand on aluminum. 25 With 10 mol% trimethylaluminum as pre - catalyst and 1 equivalent of ( R ) - 3 1 , ketone 28 was reduced in 70% ee but no reported yield. For using 1 equivalent of ( R ) - 30 , a range of 86 to 81% ee was observed. The enantioselectivity of product 29 decreased slowly over time, because of the reversible nature of this reaction. Scheme 1.5 Asymmetric MPV reduction with chiral alcohol s 10 Scheme 1.6 Asymmetric MPV reductions with chiral catalysts The other strategy for asymmetric MPV reaction s employs a chiral Lewis acid complex as catalyst and achiral 2 - propanol as reductant to achieve the prochiral ketone reduction . Evans and co - workers 31 in 1993 reported an asymmetric ketone reduction with a Samarium - based chiral catalyst. The C 2 - symmetric samarium catalyst 32 could catalyze the reduction of aromatic ketones 11 in 36 - 96% yield and 68 - 97% ee . The hydrogen atoms at the two tertiary carbons next to oxygen in the chiral ligand did not participate in the MPV reduction as hydride source (Scheme 1.6) . The samarium - iodide bond was found to be essential in the system. Furthermore, a non - linear effect was observed, giving the alcohol product in 95% ee while using a ligand that was 80% ee . Huskens et al. in 1994 studied lanthanide alkoxide catalyzed asymmetric MPV reduction of acetophenone 35 with the chiral ligand 37 , h owever, only 10% yield was obtained after six days. 49 Krohn et al. employed zirconium t - butoxide and chiral diol 40 to asymmetrically reduce ketone 38 in 99% yield and 62% ee with 3 equivalent s of alcohol 27 as hydride source. 50,51 Kellogg et al. reported the reduction of acetophenone 35 catalyzed by erbium isopropoxide and chiral diol 41 in moderate yield and ee . 52 Wu and co - workers 53 used samarium catalyst 42 that is derived from 1,1' - bi - 2 - naphthol (BINOL) 54 to achieve asymmetric reduction of acetophenone 35 . However, the enantioselectivity was not as good as samarium catalyst developed by Evans. Notably, BINOL has been used in asymmetric reduction of ketones with stoichiometric amount of lithium aluminum hydride . 55 - 61 Other than s imple ketones, glyoxylates could also be reduced with isopropanol as hydride source. In 2017, Feng, Lin and co - workers 43 developed an asymmetric MPV reduction of glyoxylates 44 to get access to a variety of optically active - hydroxyester s 45 in high yield and ee . The co - catalyst system with 50 mol% Al(O t Bu) 3 , 10 mol% Y(OTf) 3 and 10 mol% chiral N,N - dioxide ligand 62 43 were found to be essential for good results, giving 20 - hydroxyesters 45 in 98 - 99% yield and 84 - 92% ee . Other transition meta ls like scandium and zirconium instead 12 of yttrium did not work, while in the absence of Al(O t Bu) 3 or molecular sieves a drop in yield and ee were observed . The good enantioselectivity observed resulted from the multidentate nature of glyoxylates, which was proposed in the paper. Under the same conditions, simple ketones gave low enantioselectivity or no reactivity. Only 2 - bromoacetophenone, which can bind t o metals in two points, gave a 95% yield and 81% ee . Scheme 1.7 Asymmetric MPV reduction of glyoxylates 1. 4 Aluminum - catalyzed asymmetric MPV reductions In 2002, Nguyen and co - workers established the first catalytic enantioselective MPV reduction with an aluminum catalyst. 63 C atalyst 48 was generated in - situ from trimethylaluminum (AlMe 3 ), BINOL and 2 - propanol as shown in Scheme 1 .8 . After 16 h at room temperature chiral 1 - phenylethanol was obtained in 5 8 % yield and 28 % ee . Only ketones capable of 2 - point binding to aluminum, such as 2 - haloacetophenones, were reduced to alcohols with excellent 13 yield (99% yield) and good enantioselectivity (80 - 83% ee ) . Except for 2 - haloacetophenone, other substrates all gave moderate yield an d ee ( 20 - 95% yield, 8 - 61% ee ). Increasing the loading of 2 - propanol from 4 equivalent s to 15 equivalent s led to higher yield but lower ee . They proposed that 2 - propanol kicked out some of BINOL ligands and formed Al(O i Pr) 3 as an achiral catalyst for the MPV reduction . It has been studied by the same group that MPV reduction of ketones could be achieved with aluminum alkoxide catalyst freshly prepared from trimethylaluminum and 2 - propanol. 25 Scheme 1.8 Asymmetric catalytic MPV reductions with aluminum - BINOL catalysts D ensity functional theory (DFT) was employed to study the mechanism computationally. 64 The direct hydrogen transfer from 2 - propanol to ketone substrate via a six - member ring transition state was supported by calculations. In 14 the reduction of acetophenone with 2 - propanol catalyzed by catalyst 48 , the n the two transition states towards ( R ) - 1 - phenylethanol and ( S ) - 1 - phenylethanol have been calculated as 0.5 kcal/mol, which is not large enough to give good enantioselectivity and is consistent with the experimental result ( 28 % ee ). They believe that the small energy difference between two transition states is due to the similar structures in both transition states, which means that the asymmetrical discrimination brought by the chiral ligand BINOL is not enough. In their subsequen t mechanistic studies, 6 5 it was - disubstituted BINOL derived catalysts 49 and 50 gave lower asymmetric induction under the same conditions. Catalyst 48 has also been used in the MPV reduction of imines. 66 However, the catal yst did not turn over and 1.2 equivalent of 48 was required to achieve completion of the imine reduction. Scheme 1.9 Asymmetric MPV reductions with aluminum - calixarene catalysts The only other example to date in aluminum - catalyzed asymmetric MPV reduction was developed by Nandi, Katz and coworkers . 67 They have developed a calix[4]arene phosphite ligand 68 for an aluminum - catalyzed MPV re du ction with 15 excellent enantioselectivity (Scheme 1 .9 ). Unfortunately, the scope of this method was limited t o ketones with two binding sites such as 2 - fluorobenzophenone 52 . 1.5 Summary In this chapter, the development of catalytic asymmetric Meerwein - Ponndorf - Verley reduction s of carbonyl compounds has been discussed. While this reaction first developed in the mid 1920s employs stoichiometric amount s of an aluminum alkoxide, a lot of effort ha s been taken to make the MPV reduction catalytic. Efficient solutions include the addition of protic acid to increase the Lewis acidity of aluminum, and the use of ligand s to prevent the aggregation of the aluminum alkoxide. Som e alkali metals and transition metals have been found to be capable of catalyzing ketone reductions with 2 - propanol as hydride source , either via a classic MPV reduction or a transfer hydrogenation mechanism . Previous asymmetric MPV reductions employ a chi ral alcohol as sacrificial reductant, while modern asymmetric MPV reductions could be carried out catalytically with chiral metal complexes. Many chiral transition metal complexes have been studied and the best asymmetric inductions are given by a chiral s amarium complex developed by Evans, and a chiral yttrium - aluminum complex developed by Feng and Lin. However, the former is limited to aromatic ketones and the latter is limited to glyoxylates. T wo examples of asymmetric MPV reduction of ketones catalyzed by aluminum catalysts have been reported. However, h igh enantioselectivities are only observed for ketones with two binding sites. To date, there is no aluminum catalyst that can catalyze the asymmetric MPV reduction of simple aromatic and aliphatic keton es with high asymmetric 16 inductions. Considering the advantages that includ e the use of the non - transition metal aluminum as catalyst, and the use of inexpensive and environmentally benign 2 - propanol as hydride source , it is very attractive to develop a highly applicable aluminum - catalyzed MPV reduction for the synthesis of enantioenriched chiral alcohols. In chapter two we will discuss the development of enantioselective MPV reduction of ketones catalyzed by aluminum - VANOL catalysts. 17 REFERENCES 18 REFERENCES 1. Nishide, K.; Node, M. Recent development of asymmetric syntheses based on the Meerwein - Ponndorf - Verley reduction. Chirality 2002 , 14 , 759 - 767. 2. Meerwein, H.; Schmidt, R. Ein neues Verfahren zur Reduktion von Aldehyden und Ketonen. Justus Liebigs Ann. Chem. 1925 , 39 , 221 - 238. 3. Passage des cétones aux alcohols et inversement. 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Catal. 2011 , 284 , 42 - 49. 24 CHAPTER TWO ASYMMETRIC CATALYTIC MEERWEIN - PONNDORF - VERLEY REDUCTION OF KETONES WITH ALUMINUM( III ) - VANOL CATALYSTS 2.1 Introduction The many advantages of the aluminum mediated MPV reduction of ketones include mild conditions, inexpensive reagents, ease of operation and the fact that desirable to develop a catalytic asymmetric MPV reaction with a chiral aluminum catalyst that gave consistently high yields and asymmetric inductions. Considering that - BINOL catalyst 11 is easy to prepare but gives modest enantioselectivities for most of substrates, we want to see if we can enhance its chiral environment by using different chiral ligands. We have developed a class of vaulted biaryl ligands that include VAPOL and VANOL fo r use in reactions where the BINOL ligand is not suitable. 1 The idea was that when VANOL and VAPOL are bound to a catalytic center via the phenol functions, the bulk of the space that is asymmetrically discriminated around the active site would be greater than it would be for BINOL catalysts. The vaulted biaryl ligands VANOL and VAPOL have been demonstrated to be useful in a variety of asymmetric reactions. 2 - 9 In this work, we describe the discovery of aluminum - VANOL catalysts that are the first aluminum M PV catalysts that can reduce a 25 variety of aromatic and aliphatic ketones to chiral alcohols with excellent yields and enantioselectivities. 10 2.2 Initial study: I s s witching BINOL to VANOL a way out ? In some reactions, BINOL as ligand provides modest asymm etric induction because its chiral pocket is far away from its active site (Figure 2.1). Adding - positions of BINOL is a common solution to increase the asymmetric induction, which brings the chiral pocket close r to the active site (Figure 2.1). Figure 2.1 The use of BINOL derivatives as common solution Thus, it is easy to assume that by replacing BINOL with other bulkier ligands - disubstituted BINOL might dramatically improve the enantioselectivity of th e MPV re du - Me 2 - Et 2 BINOL to construct the chiral aluminum complex as catalyst and tried these two catalysts in the reduction of 2 - bromoacetophenone 55 g . 11 - 13 Surprisingly, under 26 the same condition as using ( S ) - BINOL as ligand, using ( S ) - - Me 2 BINOL and ( S ) - - Et 2 BINOL as ligands gave only 50% ee and 26% ee respectively (Scheme 2. 1 ). Compared with the result using BINOL without any substituent (83% ee ), - positions of BINOL actually decreased the asymmetric induction. Therefore, their attempt to obtain high enantioselectivity by - disubst ituted BINOL was not successful. Scheme 2. 1 Switching BINOL to VANOL 27 Our initial study started with switching BINOL to VANOL. As a control we first carried out the reaction with ( S ) - BINOL. With 4 equivalents of 2 - propanol and 20 mol% catalyst generated from ( S ) - BINOL and trimethylaluminum, 2 - bromoacetophenone 55 g was reduced to the corresponding alcohol ( R ) - 56 g in 72% yield and 76% ee (Scheme 2.1) . It should be noted that these conditions were slightly different from those reported by Nguyen. By comparison, the catalyst 57 made from ( S ) - VANOL catalyzed the reduction of 2 - bromoacetophenone 55 g with 75% yield and 56% ee (Scheme 2.1). These results ( ee for BINOL is 20% h igher than that for VANOL) were opposite to what we expected, as we thought that the asymmetric discrimination brought by VANOL should be greater than BINOL. We then tested VANOL derivatives with substituents at the - positions, which were thought to pr ovide a better chiral environment around the reactive site and were - substituted BINOL derivatives . To our delight, a different trend for enantioselectivities was found. Catalyst 58 made from - Me 2 VANOL gave 74% ee and catalyst 59 made from - Et 2 VANOL gave 80% ee (Scheme 2.1) , which indicates that increasing the bulkiness of VANOL suc c essfully increased the asymme tric induction. With this finding, we were glad to see that w hile making derivatizations on BINOL failed to enhance the enantioselectivity , switching BINOL to VANOL is a way out. 2.3 Reaction optimization s 2.3.1 Ligand screening The initial study revealed that adding substituents on VANOL has positive effect on the asymmetric induction, which encouraged us to screen more 28 derivatives of vaulted biaryl ligands. We selected 2 - bromoacetophenone 55 g as the model substrate for the scree n of various ligands in the MPV reduction since it was the best substrate for the BINOL catalyst (Scheme 1.8 ) . Figure 2.2 Ligands that were tested for MPV reaction 29 We first tried c atalyst made from bulky va u lted biaryl ligand VAPOL ( L2 ) as it was assum ed that increasing the bulkiness of the ligand would enhance enantioselectivity. However, a 24% yield and 61% ee ( Table 2. 1 , entry 2) was obtained for VAPOL ( L2 ) and no conversion was ob s erved for its derivative L3 ( Table 2.1 , entry 3). L4 as an isomer of L2 gave 70% yield and 62% ee while VANOL ( L5 ) gave 75% yield and 56% ee ( Table 2.1 , entr ies 4 - 5). Considering that VAPOL catalysts gave much slower reactions than that of VANOL and derivitization of iso VAPOL is not as easy as it is with VANOL, we decided to screen a large number of VANOL ligands that we have previously prepared (Figure 2.2) . 1 4 We started with catalysts generated from the ligands L6 to L10 (Table 2.1) that are derivatives of VANOL - positions in the VANOL backbone . The idea of screening these types of ligands is that a change in the dihedral angle between the naphthalenes in these ligands might enhance the asymmetric inductions , but to no avail. Moderate to good yields with 43 - 55% ee were obtained (entry 6 - 9) for those with deriv a tization on the phenyl groups in the - positions , while none of them gave higher ee than VANOL. L10 with a cyclohexyl group ins tead of phenyl group at the - positions did not wor k (entry 10), probably because of the destruction of the - system in the VANOL skeleton. The results obtained from the C 1 - symmetrical ligands L11 and L12 did not lead to any significantly enhanced resul ts (entry 11 - - substituted VANOL L13 increased the ee to 78% with good yield, indicating that changes made on naphthalene rings were more efficient than those on the backbone of the ligands (entry 13 vs entries 6 - - diphenyl 30 VANOL L14 was used, presumably due to th e steric bulk near the active site which m ight have either slowed down the reaction or hindered the formation of catalyst . Table 2.1 Screening of ligands for the MPV reduction of 2 - brom oacetophenone - positions of VANOL gave promising results especially for those with aliphatic substituents (entry 15 - 28) . L15 and L16 bearing fluorine and chlorine a nd thus electron - deficient ligands showed neither accel e ration of reaction s nor notable enhancement of asymmetric inductions (entry 31 15 - 16). Wh en - positions of VANOL, significant improvement s in the enantioselectivity wa s observed from methyl groups (74% ee , entry 17), ethyl groups (80% ee , entry 18) to n - butyl groups (85% ee , entry 19). The l onger substituent ( n - hexyl ) led to a drop in ee ( 79% ee , entry 20 ) , which stopped us from making any longer groups, but rather turned to bulkier groups . However, t - butyl groups decreased the ee to 62% (entry 22) and adamantyl groups resulted in both low conversion and low ee (entry 23) , which indicated that tertiary groups might be too bulky. Unsurprisingly, L21 with second ary cyclohexyl groups were found to have the best size and won the championship with 86% yield and 92% ee (entry 21). Further investigation found that various aryl and heteroaryl groups as well as silyl groups were not nearly as effective, giving either lo w conversion or modest enantioselectivities (entry 24 - 28). 2. 3.2 P reliminary optimization of reaction parameters After ligand screening, L22 - t Bu 2 VANOL) was chosen as the ligand to do further optimization on various reaction parameters because of its ready availability and because it only had a moderate asymmetric induction. The precatalyst was prepared by addition of trimethylaluminum into L22 toluene solution at room temperature . Stirring for 5 min gave lower yield and ee than stirring for 1 h (Table 2.2, entr ies 1 - 2). Then the reaction solution was charged with 2 - propanol and 2 - bromoacetophenone 55 g to initiate the asymmetric MPV reduction. Changing the ligand/ trimethylaluminum ratio led to a drop in yield and no improvement in ee , no matter whether excess trimethyl aluminum or excess ligand was used (entr ies 3 - 6). Changing the loading of 2 - propanol to 2 equival ents 32 decreased the yield while the use of 3 or 5 equivalent s of 2 - propanol had no significant differences from 4 equivalents (entry 7 - 9). T he t emperature effect was stud i ed and the finding was that lower temperature s helped obtain higher asymmetric inducti on (entr ies 10 - 14). However, the reaction slowed down dramatically at 40 C, and gave only a 23% isolated yield after 48 hours. Table 2.2 Preliminary optimization of reaction conditions 33 2.3.3 Further optimizations on the reduction of 2 - bromoacetophenone Table 2.3 Solvent screening for the MPV reduction of 2 - bromoacetophenone When the reduction of 2 - bromoacetophenone 55 g was screened in different solvent s with a constant amount of 2 - propanol (4 equiv.) , it was found that strongly coordinating solvents such as THF and diethyl ether resulted in a dramatic drop in yield (Table 2.3, entr ies 1 - 2). This is presumably due to the coordination of solvent 34 to the aluminum preventing the coordination of the ketone and the formation of the proper 4 or 5 coordinate aluminum tran sition state. 1 3 The w eakly coordinating solvent anisole and the polar solvent s dichloromethane and 1,2 - dichloroethane gave both lower yield and ee compared non - polar solvents such as toluene, benzene and cyclohexane (entr ies 3 - 12 ). The highest asymmetric induction was achieved with n - pentane, which has the lowest dielectric constant among common organic solvents (entry 12). Table 2.4 Study on different methods of preparing catalysts 35 In previous experiments, 2 - propanol and 2 - bromoacetophenone 55 g were added to the reaction solution containing the precatalyst at the same time (Table 2.4, method A). So once the active catalyst was in - situ generated, it would start catalyzing the reduction of ketones. It was important to see if forming the active cat alyst before adding ketones would make any difference. T herefore, t he active catalyst was prepared according to method B (Table 2.4). A solution of the ligand (0.2 equiv.) and trimethylaluminum (0.2 equiv.) was stirr ed for 0.5 h before the addition of 2 - pr opanol (0.2 equiv.). After another 0.5 h, ketone (1 equiv.) and the rest of 2 - propanol (3.8 equiv.) were charged into the reaction solution. Toluene, n - pentane and mesitylene were used as solvent to study the difference between method A and B, but no signi ficant change in yield and ee was observed (entry 1 - 6). Therefore, method A was still employed for following studies. Then the concentration effect was studied by changing the amount of solvent used in the reaction. Notably, lowering the concentration of the reaction had significant impact on the enantioselectivities. When toluene was used as solvent, a 15% increase in ee was achieved by diluting the reaction from 0.6 M to 0.1 M (Table 2.5, entr ies 1 - 4). Further dilution failed to give bet ter results (entr ies 5 - 6). Same trends were observed while using mesitylene (7% ee increase upon diluting from 0.3 M to 0.1 M, entr ies 8 - 10) and n - pentane (10% ee increase upon diluting from 0.3 M to 0.1 M, entr ies 11 - is probably due to the aggregation of the aluminum complex at higher concentration. It has been shown that aluminum alkoxides c an dimerize (A l (O t Bu) 3 ) or tetramerize (Al(O i Pr) 3 ) in solution. 15 36 Table 2. 5 Concentration effect for the MPV reduction of 2 - bromoacetophenone T o make sure that the results obtained during the optimization process were reliable, the replicability of this MPV reduction was tested. Under the same conditions, 2 - bromoacetophenone 55 g was reduced to the corresponding alcohol on different dates with different batch es of trimethylaluminum, toluene and 2 - propanol (Table 2.6). Consistent results were obtained as 72 - 83% yield and 61 - 63% ee with an average of 77% yield and 62% ee from 4 runs. The ± 6% yield and 37 ± 1% ee were in reasonable ranges to be consi dered as systematic errors, which revealed satisfactory reproducibility on this asymmetric MPV reaction. Table 2.6 Test of replicability Some other alcohols as hydride source instead of 2 - propanol were screened. Since the MPV reduction first employed ethanol as hydride source 1 6,17 , we started with the screening of primary alcohols. However, none of these primary alcohols worked (Table 2. 7 , entr ies 1 - 9). Secondary alcohols like cyclohexanol, 2 - butanol, 2 - hexanol and 3,3 - dimethyl - 2 - butanol all work ed but were not as good as 2 - propanol (entries 11, 14 - 17 ) , the 2 3 - pentanol and 2,4 - dimethyl - 3 - pentanol gave low induction and opposite stereo chemical outcome compared with 2 - p ropanol (entr ies 1 2 - 1 3 ). Two diols with bidentate properties were also tested but both failed (entr ies 18 - 19). 38 Table 2. 7 Alcohol Screening for the MPV reduction of 2 - bromoacetophenone 39 After the study of the reaction parameters with L22 , we have a better understanding about how those conditions influence the yield and enantio selectivity of this asymmetric MPV reduction. And then L21 , which was harder to synthesize but gave the best result during ligand screening, was employed in further optimizations (Table 2.8) . It was possible to reduce the c atalyst loading to 5 mol% without erosion of asymmetric induction while using n - pentane as solvent (entr ies 1 - 3) . Shortening the reaction time to 6 h ours ha d no significant impact on yield while lowering the temperature to 0 C increased the ee to 94% (entr y 4 - 5). Table 2.8 Further optimization s with L21 as ligand 40 2.3.4 Optimization s on - bromoacetophenone Considering that 2 - bromoacetophenone 55 g is the best substrate in - BINOL system owing to its bidentate nature, it was important to study how the current catalyst works on other ketones without the 2 - halo function al group. Therefore, f - bromoacetophenone 5 5u , which gave the alcohol 5 6u in 70% yield with 30% ee with the BINOL catalyst 48 in toluene under the conditions in Scheme 1 .8. Table 2.9 Optimization s on - bromoacetophenone 41 With 5 mol% catalyst prepared from ( S ) - L21 - Cy 2 VANOL), the corresponding alcohol ( S ) - 5 6u was obtained in 76% yield and 85% ee at room temperature in n - pentane (Table 2.9, entry 1). Lowering the temperature to 0 ºC increased the induction to 92% ee but the yield dropped to 48% (entry 2). However, if the amount of 2 - propanol was increased from 4 equivalents to 80 equivalents, the yield was greatly improve d from 48% to 91% at the same reaction time without erosion of enantioselectivity (entr ies 2 - 6). It was not surprising that the yield was improved since increasing the loading of 2 - propanol helps drive the reaction forward. Nguyen and co - workers have demon strated that higher loading of 2 - propanol resulted in a drop of enantioselectivities, 11 which was not observed in our VANOL catalysts. Notably, the catalyst loading could be reduced to 2 mol%, providing 5 6u with 81% yield and 93% ee after 24 hours (entry 8 ). The best result (94% yield and 96% ee) was obtained while running the reaction at 10 ºC with the addition of 4 Å molecular sieves (entry 11). Under the optimal conditions in Table 2.9 (entry 11), other ligands were examined to compare with the results from L21 . The use of L29 - i Pr 2 VANOL, Table 2.10, entry 2) and L30 - isopentyl 2 VANOL, entry 3) gave no better yield or ee than that of L21 , while L31 - (3 - penylpropyl) 2 VANOL, entry 4) showed low conversion. It was observed that reactions with VANOL ( L5 ) and BINOL ( L1 ) catalysts under the same conditions gave less than 1 - 2% of the reduced product 5 6u (entr ies 5 - 6), indicating the importance of attaching proper substituents at the - positions of the VANOL ligand. It is possible that one role of the cyclohexyl groups helps to prevent aggregation or oligomerization of the catalyst. 42 Table 2.10 - bromoacetophenone with different ligands 2.4 Substrate scope for aromatic ketones Under the optimal conditions established above, a variety of aromatic ketones were examined . Acetophenone 55a was reduced in 88% yield and 94% ee (Scheme 2. 2) to the alcohol 56a by the catalyst prepared from L21 , whereas the reduction with BINOL catalyst 48 11 gave 58% yield and 28% ee (Scheme 1 .8 ). Likewise, 2 - aceto naph thanone 55 b and 1 - acetonaphthanone 55 c were reduced to the corresponding alcohols 56 b and 56 c in 78% yield, 91% ee and 95% yield, 98% ee respectively. Ketones with 2 - halo methyl groups were the only type of ketones that gave high asymmetric inductions .8 ) , possibly because the coordination 43 between 2 - halo substituent and the carbonyl oxygen with the aluminum center g ave a penta - coordinated aluminum species in the transition state . Scheme 2.2 Substrate scope for aromatic ketones I A number of acetophenone derivatives with halogens at the 2 - positon were tested with the catalyst prepared from L21 . H igh yields with excellent enantioselectivities were obtained under optimal conditions for 2,2,2 - trifluoro , 2 - chloro, 2,2 - dichloro, 2 - bromo and 2 - bromo - - nitro acetophenones. Electron - deficient penta - fluoroacetophenone 55i was reduced in 80% yield and 99% ee . 44 However, low conversion was observed when propiophenone 55j was reduced under the same conditions, however a 57% yield and 74% ee was obtained by running the reaction at room temperature. The absolute configurations of the products were confirmed by comparing their opt ical rotations with literature values, and in addition, the absolute configuration of 56h was confirmed by its crystal structure. It is obvious that the electron density of the substrate will have significant impact on the reactivity of these ketone reductions. Thus, a wide range of acetophenone derivatives were examined with both electron - rich and electron - poor substituents at the ortho , meta and para positions of phenyl group ( Scheme 2.3). Ortho - substituted acetophenones with electron - withdrawing groups such as chloro, bromo and iodo as well as electron - donating groups such as methoxy were all reduced in excellent yields and excellent enantioselectivities. The reduction of - me thylacetophenone 55n gave lower conversion at standard conditions, but 94% yield and 96% ee was achieved by increasing the catalyst loading to 10 mol%. - methoxyacetophenone 55o was reduced - methylacet ophenone 55n with 5 mol% catalyst loading, considering that the former is more electron - rich, which should be disfavored in reduction of ketones. An explanation might be that the oxygen at ortho - position could coordinate to the aluminum center, serving a s imilar role as the 2 - halo functional groups. In the meta positions, the electron - withdrawing group bromine gave 91% yield and 97% ee . Electron - releasing groups as methyl and methoxy gave slower reduction under the standard conditions. Increasing catalyst l oading to 10 mol% 45 - methylacetophenone 55q resulted in 82% yield and 90% ee , while increasing both the catalyst loading and reaction temperature gave 84% yield and 88% ee on - methoxyacetophenone 55r . Scheme 2.3 Substrate scope for aromatic ketones II 46 As for the para positions, a number of electron - withdrawing groups did not seem to - nitroacetophenone 55s - trifluoromethylacetophenone 55t - bromoacetophenone 55u - iodoacetophenone 55v , where 89 - 94% yield and 93 - 97% ee were observed. - methylacetophenone 55w can be reduced effectively with 10 mol% catalyst loading , the 4 - methoxyacetophenone 55x is not reduced at all. I t is possible that the oxygen at the ortho - position coordinate s t o the aluminum while the oxygen at the para - position is too far away to form a penta - coordinated aluminum species. Another possibility is that ortho - substitution resulted in poor delocalization due to the steric hindrance that the carbonyl group and phenyl group are not on the same plane. The electron density of 55o is lower than t hat of 55x and thus 55o showed higher reactivity. It is interesting to observe that the presence of a bromo group alpha to the ketone can largely offset the effect of the 4 - methoxy group , with 71% yield and 83% ee achieved on the reduction of 2 - bromo - - methoxyacetophenone 55y . There are also limitations on the substrate scope of this asymmetric MPV reduction (Scheme 2.4). Penta - methylacetophenone 5a was not reduced under the s t andar d conditions, which might result from its steric bulkiness that prevents the coordination with aluminum and also its electron density that makes the carbonyl less reactive. It was previously shown that propiophenone 55j gave lower yield and asymmetric induction ( Scheme 2.2 ) . Increasing t he bulkiness of the ketone substituent to n - propyl and phenyl shut s down the reaction as observed for 5b and 5c . Therefore, this catalytic system is limited to the reduction of methyl 47 ketones. Enone 5d and ynone 5 e were also tested but failed. A f ree hydro xy group and amin o group on the acetophenone in the ortho - position were not tolerated, probably because they could kill the catalyst by binding to the aluminum and replace the VANOL ligand or an isopropoxide ( 5f - g ) . An acetoxy group is not tolerated either, possibly due to competition between the acetoxy and acetyl carbonyls in coordinating to the catalyst ( 5h ) . Unfortunately, ketones bearing a heterocycle were not reduced. The basicity of pyridyl group might kill the catalyst and the high e lectron density of pyrrolyl, thiophenyl and furyl groups might be responsible for their low reactivit ies ( 5i - l) . Des p ite the se limitation s in the substrate scope, the present aluminum - VANOL catalyst is far superior to previously reported aluminum catalys ts for MPV reduction. 11,18 Their systems only gave high asymmetric inductions on ketones with two binding sites, such as 2 - haloacetophenone, while our aluminum - VANOL catalysts gave high yield and enantioselectivities on many simple aromatic ketones with di fferent electron densities that have only one binding site. With many excellent results gained from aryl alkyl ketones, we learned that the catalyst has great ability in distinguishing sp 3 carbons from sp 2 carbons. Our attention was turned to the more chal lenging task of distinguishing sp 3 carbons from other sp 3 carbons. 48 Scheme 2.4 Limitations on substrate scope 2.5 Substrate scope for aliphatic ketones The asymmetric reduction of simple dialkyl ketones with a chiral aluminum catalyst has never been reported. Thus, i t is important to examine the ability of our catalyst in the reduction of aliphatic ketones. The substrate we chose for further optimization was 3 - phenyl - 2 - butanone 57a , which bears a phenyl group that is not in conjugation with the carbonyl group. The rea son 57a was chosen is that it has 49 good UV absorption at 210 nm, so the corresponding alcohol 58a can be detected on chiral HPLC to measure its enantioselectivity without derivatization . Under the optimal conditions for aromatic ketones, the ketone 57a was reduced in 84% yield and 74% ee (Table 2.11, entry 7). Screening catalysts prepared from other ligands (entr ies 8 - 10) - i pentyl 2 VANOL L30 gave the best asymmetric induct ion (entr ies 1 - 6) . Changing the temperature to 20 C gave the reduction product 58a in 91% yield and 82% ee , while increasing or decreasing the temperature resulted in a drop in both yield and ee (entry 4 ). Table 2.11 Optimization on the reduction of 3 - phenyl - 2 - butanone 50 Anticipating that the degree of asymmetric induction would correlate with the steric differential of the two alkyl groups o n the ketone, t wo other ketones bearing a 2 cyclohexyl group 57b and a 3 adamantyl group 57c were examined (Scheme 2.5). Due to the lack of chromophore for these two substrates, the yield and ee were determined after making the corresponding 4 - fluorobenzoic ester of the alcohol products. The most difficult substrate in terms of steric differentia l between the two alkyl groups was 3 - phenyl - 2 - butanone 57a with 91% yield and 82% ee , which has a methyl group and an unbranched alkyl group to be distinguished by the catalyst. Better results were obtained on substrate 57b at 10 C, which has a methyl gr oup and a cyclohexyl group on the ketone. After derivatizing to the corresponding 4 - fluorobenzoic ester, 81% yield and 88% ee were observed. Unsurprisingly, the ketone 57c with the bulkiest substituent gave the highest stereochemical outcome of 94% ee in 8 4% yield. This study illustrates the first examples of aluminum - catalyzed asymmetric reduction of aliphatic ketones. 51 Scheme 2.5 Substrate scope for aliphatic ketones 2.6 Scale up synthesis with 1 mol% catalyst loading The scalability of this MPV reduction was examined on a 32 - fold increase in scale of the reduction of 2 - bromoacetopheone 55 g (Scheme 2.6). On an 8 mmol scale the re duction proceeded smoothly with the catalyst loading reduced to 1 mol% catalyst to give the alcohol 56 g in 90% yield and 97% ee . This result is essentially unchanged from the 0.25 mmol scale reaction at 5 mol% catalyst (Scheme 2.2). The corresponding alcoh ol ( (S) - 56 g ) was then treated with potassium carbonate to give chiral epoxide 5 9 with retention of enantiomeric purity (Scheme 2.6 ). 52 Scheme 2.6 Scale up synthesis 2.7 Reaction mechanism and computational study 2.7.1 Mechanism of MPV reduction of ketones The mechanism of the MPV has long been thought to involve a four - coordinate aluminum transition state with an intramolecular transfer of hydride from an isopropoxy substituent on aluminum to a molecule of ketone coordinated to the aluminum as indicated in Scheme 2.7 a . 12 In the particular case of the BINOL aluminum catalyst 48 developed by Nguyen , the mechanism of reduction was explored by DFT analysis and this direct transfer was found to be more energetically favorable that either a radical mechanism or a hydride mechanism involving an aluminum hydride (Scheme 2.7b) . 12 In the case of the substrate 55 g , a transition state for direct transfer with a five - coordinate aluminum was proposed (Scheme 2.7c) . 1 3 53 Scheme 2.7 Mechanism of MPV reduction of ketones 2.7.2 Computational study During the discovery of this MPV reduction methodology , a lot of effort was expended to predict the best ligand for this reaction employing computational study . Over 2000 t ransition state energies with 30 different ligands have been calculated and analyzed. Twelve of these ligands ( L5 - L31 ) ha ve been synthesized and screened in this asymmetric MPV re action , while the other eighteen ligands ( L32 - L49 ) were designed and studied by computational modelling only (Figure 2.3) . The transition state with a six - member ring hydride transfer on the reduction of 54 acetophenone 55a was modeled a s shown in Figure 2.3 . With all ligands being S , TS - S is the transition state towards the formation of S product ( S ) - 1 - phenyl - ethanol and TS - R is the transition state towards the formation of R product ( R ) - 1 - phenyl - ethanol. Transition state energies (electronic energies, enthalpies and free energies) for both TS - S and TS - R have been calculated to elucidate and predict the enantioselectivity of the asymmetric reduction. Figure 2.3 Computational study with 30 ligands Computation s have been achieved with both Hartree - Fock and density functional theory in Gaussian 16 19 . Geometry optimizations were carried out at 55 HF/3 - 21G* or B3LYP/6 - 31G(d) level of theory in vacuum . Transition states of this asymmetric MPV reduction of acetophenone were simulated at HF/3 - 21G* or B3LYP/6 - 31G(d) level in vacuum and in three solvent: tolue ne, n - p entane and 2 - propanol with CPCM as solvation method. The free energy difference s between TS - S and TS - R have been calculated TS - R ) TS - S )) and analyzed in Table 2.12 for 30 different ligands. Table 2.12 Free energy differences at t ransition state with 30 ligands 56 Table 2.12 Experimentally, the best ligand was found to be L21 in the reduction of aromatic ketones. Although the free energy differences ( were not large enough (0.383 to 0.823 kcal/mol) to match the induction observed (94% ee at ), they all favored TS - S leading to the correct enantiomer produced (Table 2.12, entry 9) . The transition state geometries with ( S ) - L21 in the reduction of acetophenone 55a are shown as an example in Figure 2.4, w ith DFT/B3LYP/6 - 31G(d) level of calculation and CPCM as solvation method in 2 - propanol . A tetra - coordinated aluminum center with a six - member ring hydride transfe r was shown, supporting the previously proposed mechanism . 11 The interaction between - positions of naphthalene was observed, which is in correlation with the experimental results showing that replacing phenyl with cyclohexyl groups shut s down the reaction (Table 2.1, entry 10) . Substituents at the - positions o f the ligand provide a better chiral environment around the active site of the catalyst compared with other positions, and thus was supported by observations during ligand screening process (Table 2.1) . Steric e ffect s seem to be responsible for the asymmetric discrimination between TS - S and TS - R . 57 Figure 2.4 Transition states with ( S ) - L21 in 2 - propanol According to the computational model s , an explanation of the stereo chemical outcome is indicated in Scheme 2. 8 . With ( S ) - L21 as ligand and acetophenone as substrate, TS - R is disfavored due to the steric interaction between the cyclohexyl group on catalyst complex and the phenyl group on the ketone. Therefore, distinguishing the small group (methyl) and large group (phenyl) o n the ketone is the key to achieve high asymmetric inductions. Unsurprisingly, replacement of the methyl group by a n ethyl group on the ketone resulted in a drop in ee in the reduction of propiophenone 55j ( 94% to 74% ee , Scheme 2.2). Meanwhile, the steric hindrance between ligand and 2 - propanol is observed on both TS - S and TS - R , which is consistent with the finding that any alcohol bigger than 2 - propanol led to worse results (Table 2.7) . TS - R - L21 - p TS - S - L21 - p 58 Scheme 2. 8 Explanation of stereo outcome As for the reduction of 2 - haloacetophenone s , a penta - coordinated aluminum in the transition state has been proposed for BINOL catalyst (Scheme 2.7). To understand the behavior of VANOL catalyst in the reduction of 2 - bromoacetophenone 55g , calculations have been completed under HF/3 - 21G* level of theory in vacuum. The transition states with ligand ( S ) - L21 are shown in Figure 2.5 as examples. The geometries are very similar to those w hen acetophenone is used as substrate, with a tetra - coordinated aluminum and six - member ring hydri de transfer. Steric interaction between cyclohexyl group on the ligand and the p he nyl g r oup on the ketone is still the key to the ster e o chemical 59 outcome, and the bromine at the 2 - position of the ketone barely changes the geometry of the transition states. A higher TS - S and TS - R with the reduction of 2 - bromoacetophenone has been observed in the for acetophenone reduction. Figure 2. 5 Transition states with ( S ) - L21 in the reduction of 2 - br omo acetophenone The proposed coordination between aluminum and bromine is not found, with the distance between aluminum and bromine being 3.97 Å ( TS - S ) and 3.66 Å ( TS - R ) . It is too early to exclude the existence of a penta - coordinated aluminum before running more calculat ions at a higher level of theory. However, it is not surprising that a similar transition state was found, given that a bidentate ketone is 60 not required in our aluminum - VANOL system since simple monodentate ketones also g i ve excellent results. 2.8 Formal d ynamic kinetic resolution of racemic alcohols via Oppenauer oxidation/MPV reduction 2.8.1 Introduction Chiral catalysts can be used in the kinetic resolution of racemic compounds, due to the fact that enantiomers undergo reactions with different rates in a chiral environment. W hen exposed to chiral reagents or catalysts, one enantiomer of the substrate can react faster than the other. In Scheme 2. 9 a this is illustrated for situation where the ( S ) - substrate reacts faster than ( R ) - substrate (K S >K R ). Usually, this process would lead to the formation of enantioenriched ( S ) - product and recovery of unreacted ( R ) - Substrate. The enanti opurity of the ( S ) - product and ( R ) - Substrate is highly dependent on the rate difference (K S /K R ) , which result s from the asymmetric discrimination of the chiral environment. With reliance on a significant technology with enzymes as well as the development of many chiral reagents/ catalysts, kinetic resolution of racemic compounds has been one of the most important a pproach es to obtain enantiopure species, especially in industry. 20 However, an inherent drawback o f kinetic resolution is that the theoretical maximum yield for kinetic resolution is 50%. This situation changes when the ( S ) - Substrate and ( R ) - Substrate can undergo fast in tercon version with each other (Scheme 2. 9 b) . The simplest example is that of a substrate bears a labile stereogenic center that is capable of undergoing epimerization during the reaction. 21 .22 When the rate of epimerization is higher than the rate of reaction for 61 the slow enantiomer (K inv >K R ), in principle, enantioenriched ( S ) - Product can be produced in 100% yield instead of 50% . 22 This process couples the epimeri zation of substrate and the subse q uential kinetic resolution t o convert both ( R ) - and ( S ) - Substrate into a single product with a 100% theoretical yield, which is called dynamic kinetic resolution. 23 A variety of enzymatic and non - enzymatic methods for dynamic kinetic resolution have been developed for the preparation of chiral compounds. 24 - 26 Scheme 2. 9 Kinetic resolution and dynamic kinetic resolution During the past decades, the dy n a m ic kinetic resolution of racemic alcohols have been explored by several groups. 27 The general approach includes a metal - catalyzed racemization of alcohols and an enzymatic kinetic resolution. Some transitio n metal s such as rhodium and ruthenium were found to be effective in catalyzing alcohol racemization. A simplified mechanism for alcohol racemization 62 with ruthenium catalysts is shown in Scheme 2.1 0 27 . The racemization occurs via ketone 67 as intermediate with a transfer hydrogenation mechanism. 28 Sometimes undesired ketone 67 was isolate d , resulting in a drop in yield in the desired alcohol product. 27 Scheme 2.1 0 Alcohol racemizations with ruthenium catalyst Scheme 2.1 1 Chemo - enzymatic dynamic kinetic resolution of alcohols 63 In 1997, B ä ckvall and co - workers reported an efficient method for the dynamic kinetic resolution of alcohols via this chemo - enzymatic approach. 29 As shown in Scheme 2.1 1 , catalyst 68 and 1 equivalent of acetoph enone as hydride acceptor. The acylation was catalyzed by e n zyme CALB ( Candida antarctica lipase B, immobilized; Novozym 435) with the use of para - chlorophenyl acetate 69 as acyl donor. Optically pure (>99.5% ee ) acylation product ( R ) - 70 was obtained in 92% yield after 87 hours. The substrate scope of this method has been ex t en d ed to other aromatic and aliphatic alcohols. 30 Scheme 2.1 2 Non - enzymatic dynamic kinetic resolution of alcohols The first non - enzymatic dynamic kinetic resolution of secondary alcohols was illustrated by Fu and co - workers in 2012. 31 T hey employed ruthenium catalyst 71 to achieve racemization of the alcohol and t he plan a r chiral ferrocene catalyst 64 72 to complete the acylation. While acetic anhydride as acyl source failed to give any product, the use of acetyl isopropyl carbonate 73 as acyl donor is the key as it av oids the deactivation of the ruthenium catalyst by acetate coordination. 32 A variety of aromatic carbinols with different electron densities as well as aromatic allylic alcohols were well tolerate d in this protocol. 2.8.2 Oxidative k inetic resolution of racemic alcohols with aluminum - VANOL catalysts Since the O ppenauer oxidation is the reverse reaction of the MPV reduction, the transition state in O ppenauer oxidation should be the same as i t in MPV reduction. Gi ven that excellent enantioselectivities have been observed in our asymmetric MPV reduction with aluminum - VANOL catalyst s , we know that the products are high enough to give satisfa c tory asymmetric inductions. Therefore, we first tried a n oxidative kinetic resolution of racemic alcohols using Oppenauer oxidation catalyzed by the same aluminum - VANOL catalyst . As shown in Scheme 2.1 3 , racemic alcohol 56a was treated with 10 mol% ( S ) - catalyst that was used in the MPV reductions. We first used cyclohexan one instead of acetone as oxidant because it is harder to make acetone anhydrous. W ith 2 equivalent s of cyclohexanone at 10 C , all of the alcohol 56a was oxidized to ketone 55a after 10 hours (entry 1) . Reducing the reaction time to 4 hours gave 7% of recovered ( R ) - 56a in 84% ee while reducing the loading of cyclohexanone to 1 equivalent gave ( R ) - 56a 15% in 76% ee (entry 3). Yield of ( R ) - 56a could be increased by cutting the reaction time, lowering the r eaction temperature and the use of 0.5 65 equivalent of cyclohexanone. However, ee drop p ed dramatically with the increase of yield ( entr ies 4 - 7). Due to the unsatisfactory enantioselectivity, we turned to employ acetone instead of cyclohexanone as the oxidant, which is supposed to give better induction since 2 - propanol is better than cyclohexanol in the MPV reduction with same catalyst. With 1 equiv alent of acetone, a 40% yield of ( R ) - 56a in 49% ee was obtained while the use of 0.5 equivalent of acetone gave 53% ( R ) - 56a in 66% ee (entr ies 8 - 9). Switching the ligand from ( S ) - L22 to ( S ) - L21 with 0.6 equivalent of acetone improved the results to 46% rec overy in 83% ee (entry 10). In this case, the selectivity factor of this oxidative kinetic resolution method is calculated to be s = 14.8 (using s = ln[(1 - C)(1 - ee )]/ln[(1 - C)(1+ ee )] where C is the conversion of ketone 55a ). 33 66 Scheme 2.1 3 Oxidative k inetic resolution of racemic alcohols 2.8. 3 Tentative formal dynamic kinetic resolution of racemic alcohols with aluminum - VANOL catalysts T o take advantage of the reversible nature of MPV reduction s , a formal dynamic kinetic resolution of racemic alcohols via Oppenauer oxidation/ MPV reduction sequ ence is proposed. A single aluminum - VANOL catalyst is responsible for both oxidation and reduction. This method starts with an aluminum - catalyzed Oppenauer oxidation of racemic alcohols with a ketone oxidant, followed 67 by the addition of 2 - propanol as reduc tant to accomplish the in - situ MPV reduction with the same aluminum catalyst, giving enantioenriched alcohol product in theoretical 100% yield. It is not a real dynamic kinetic resolution, since there is no racemization of substrates. However, this method has the potential to give optically active chiral alcohol s from racemic alcohols in a stepwise/one - pot process , and most importantly, with a single catalyst. According to the kinetic resolution attempts that we have done so far , 2 equivalent s of cyclohexanone is capable of oxidi zi ng both enantiomers of racemic alcohols in 10 hours at 10 C (Scheme 2.1 3 , entry 1). Further experiments revealed that the use of 2 equivalent s of acetone or cyclohexanone could fully oxidize alcohol 56a to ketone 55 a in one hour at room temperature. We first tried to add 2 equivalent s of acetone and 80 equivalent s of 2 - propanol at the same time to avoid the stepwise process (Scheme 2.1 4 , entry 1). However, the kinetic resolution product ( R ) - 56a instead of the dynamic resolution product ( S ) - 56a was formed even with a large excess of 2 - propanol as reductant. A stepwise procedure gave desired isomer ( S ) - 56a in 10% yield and 10% ee (entry 2) , while s witch ing from acetone to cyclohexanone increased yield to 44% (entry 3). Using 1 instead of 2 equivalent s of ketone improved ee to 39% (entry 4). After changing the loading of 2 - propanol to 4 equivalents , a 61% yield and 32% ee was obtaine d (entr ies 4 - 8 ). Best result was obtained with the use of ( S ) - L21 with 1.2 equivalent of cyclohexanone at 10 C, where 79% yield and 73% ee was observed (entry 11) . 68 Scheme 2.1 4 Formal dynamic kinetic r esolution of racemic alcohols Further optimizations o f the reaction temperature, solvent and concentration failed to improve the selectivity of this process. However, this novel employment of the Oppenauer oxidation/ MPV reduction sequence in resolution of racemic alcohols provides a new strategy for accessing ch iral alcohols, which avoids the use of enzymes and the acylation of substrates . 69 2. 9 Conclusion Motivated by the unsatisfactory enantioselectivities observed in the on the developm ent of VANOL catalysts. While adding substituents on the BINOL ligand - disubstituted VANOL ligands dramatically improved the results. After screening different ligands and optimizing reaction parameters, the substrate scope has been extensively studied. Computational stud ies on the transition state has been carried out with Gaussian 16 and reaction mechanism has been discussed. A tentative formal dynamic kinetic resolution of racemic alcohols has been proposed and preliminarily examined . In conclusion, it is reported here the development of the first highly enantioselective aluminum catalyzed MPV reduction of ketones to access chiral alcohols. Aromatic ketones with different electron densities and substituents are well - tolerated and most o f them can be reduced with >90% yield and >90% ee . Notably, aliphatic ketones were also addressed with good to excellent enantioselectivity for the first time. The aluminum catalyst generated from - dicyclohexyl substituted VAN OL ligand L21 is very efficient giving high yields and enantioselectivities of the reduced products under the same conditions where the VANOL ligand without the cyclohexyl groups gives no product at all (<2%). It is possible that the presence of the cycloh exyl groups helps to prevent aggregation or oligomerization of the catalyst. Computational study suggests that the steric interactions between the cyclohexyl group on the 70 ligand and ketone is the key to achieve high asymmetric inductions. The present chira l aluminum catalyst is far superior to previously reported aluminum catalysts for the MPV reduction. 1 0,18 Given that this catalyst gives high asymmetric induction at 1 - 10 mol% catalyst loading, it is on par with the previously reported best systems with sa marium 34 and ruthenium 35 catalysts and in addition gives good to excellent inductions for dialkyl ketones. 71 REFERENCE S 72 REFERENCES 1. Bao, J.; Wulff, W. D.; Dominy J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S. - M.; Ostrander, R. L.; Rheingold, A. L. Synthesis, - - Biphenanthrol (VAPOL). J. Am. Chem. Soc. 1996 , 118 , 3392 - 3405. 2. Bao, J.; Wulff, W. D.; Rheingold, A. L. Vaulted biaryls as chiral ligands for asymmetric catalytic Diels - Alder reactions. J. Am. Chem. Soc. 1993 , 115 , 3814 - 3815. 3. Antilla, J. C.; Wulff, W. D. C atalytic Asymmetric Aziridination with a Chiral J. Am. Chem. Soc. 1999 , 121 , 5099 - 5100. 4. Desai, A. A.; Wulff, W. D. 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Soc. 1995 , 117 , 7562 - 7563. 76 CHAPTER THREE ENANTIOSELECTIVE HETEROATOM DIELS - ALDER REACTION OF ALDEHYDES CATALYZED BY CHIRAL BORATE CATALYSTS 3.1 Introduction 3.1.1 Synthetic applications of h eteroatom Diels - Alder reactions The Diels - Alder reaction has been one of the most fundamental transformations in chemistry since its discovery in 1928 by Otto Diels and Karl Alder. 1 The construction of six - membered rings with 100% atom economy makes it extremely popular in organic synthe sis. 2 The h eteroatom Diels - Alder (HDA) reaction is one of the most important variants of the Diels - Alder reaction, as it constructs six - membered heterocycles that widely exist in natural products or bioactive compounds. 3 S ome examples o f natural products containing six - membered heterocycle skeletons are shown in Figure 3.1 , such as bistramide A, polycavernoside A, phyllanthine , luotonin A and pederin . 4 To construct these six - membered heterocycles using HDA reactions, a carbon on either th e dienophile or the diene is replaced by a heteroatom such as oxygen or nitrogen. Similar to the classic Diels - Alder reaction, the normal HDA reaction employs an electron - poor - rich diene (Scheme 3.1a), which is fa vored because of the better overlap between the lower LUMO of dienophile and the higher HOMO of diene. 5 The i nverse electron - demand HDA reaction usually employs an electron - poor , - unsaturated species as the diene and an electron - rich alkene as the dienophile, in which the interaction between the L U MO of the 77 diene and the HOMO of the dienophile is favored (Scheme 3.1b). 5 Except for the popular use of carbonyl compounds , 6 many other heteroatomic substrates have been used as dienophiles such as n itroso compounds, 7 nitriles, 8 imines, 9 az o dicarboxylates, 10 singlet oxygen, 11 and sulfur dioxide. 12 Figure 3.1 Six - membered heterocycles in natural products 78 S chem e 3.1 Normal HDA reaction and inverse electron - demand HDA reaction 5 During the past several decades, heteroatom Diels - Alder reaction s ha ve been widely used in the total synthesis of natural products. For example, the first total synthesis of (+) - keto - deoxyoctulosonate 89 was achieved by Danishefsky and coworkers, with the HDA reaction as the key cyclization to construct the saccharide skeleton. 13 The reaction between - selenoaldehyde 85 and highly functionalized diene 86 was activated by Lewis acid BF 3 Et 2 O and followed by acidic cleavage of the silyl group, to g ive the cyclized product s 87 and 88 in a 5:1 ratio. The favored endo product 87 was then derivatized into (+) - keto - deoxyoctuloso nate (Scheme 3.2 a ) . Rawal et al. has employed the HDA reaction in the total synthesis of pederin, a vesicant natural product isolated from beetles. 14 Aldehyde 90 and diene 91 were transformed into pyrone 92 catalyzed by various Lewis acids. Using 2 equivalent s of BF 3 Et 2 O as the Lewis acid gave the undesired isomer as the major product. The use of TiCl 4 (2 equivalents) gave the desired isomer 92 ( syn ) but with only 79 60:40 diastereomeric ratio. The b est diastereoselectivity (dr = 92:8) was produced by the addition of an aluminum catalyst (20 mol%) and TMSOTf (200 mol%) , in wh ere the activation of the aluminum alkoxide with TMSOTf was essential for success. These reactions both employed very electron - r ich dienes bearing a siloxy group and a methoxy group, which synergistically enhanced the reactivity and stereoselectivity. Scheme 3.2 Aldehyde as dienophile of HDA reactions in t otal synthes e s 80 Scheme 3.3 HDA reactions in total synthes e s The simplest diene 93 with oxygen substituents in the 1,3 - positions was developed for the Diels - Alder reaction of activated alkenes by Danishefsky in 1974. 15 After acidic hydrolysis of silyl enol ether and then elimination of the methoxy group, cyclic - unsaturated ketone was obtained. Diene 93 has subsequently widely u sed in HDA reactions with aldehydes and imines owing to its high reactivity. In the total synthesis of (+) - aspergillide C 97 , Waters and co - workers employed diene 93 and ( S ) - glyceraldehyde acetonide 94 , prepared from 81 (+) - arabinose, to construct the dihydro pyran skeleton in (+) - aspergillide C. 16 The reaction was catalyzed by zinc chloride and a single diastereomer 95 was obtained in 71% yield. The carbonyl group was then reduced, acylated, and then displaced in a S N a side chain next to the oxygen (Scheme 3.3a). Diene 93 has also been used to react with an imine in the total synthesis of phyllanthine 75 by Weinreb and co - workers. 17 Imine 98 , prepared from the corresponding tosyl amine, was employed as dienophile in the HDA reaction to construct the piperidine skeleton in phyllanthine 75 . While a variety of common Lewis acid catalysts (SnCl 4 , TiCl 4 et al.) resulted in low yield due to the destruction of the sensitive ketal and silyl either groups, dihydropyridone 99 was o btained in 81% yield with 22 mol% Yb(OTf) 3 as catalyst. It was also found that this HDA reaction could be completed at high pressure without any catalyst (71% yield, 12 kbar). The structure of 99 was confirmed by X - ray crystallography, indicating that the desired exo product was formed in the reaction. This is not surprising because imine 98 has bulky groups next to carbon nitrogen double bond, which favors the attack of diene from less hindered exo side, and also it lacks a - system to provide orbital over lap, making the endo attack less favored. After reduction, deprotection, Julia olefination and further derivatizations, the first total synthesis of natural product 75 phyllanthine was achieved (Scheme 3.3b). 82 Scheme 3.4 Constructing aromatic heterocycles by HDA reactions HDA reactions have also been used to synthesize aromatic rings. Due to the lack of proper degree of unsaturation in the product wh en using dienophile with double bond s , triple bond ed species such as alkynes and nitriles have been used as dienophiles in the HDA reaction for the purpose of accessing aromatic heterocycles. Boger et al. employed an intramolecular HDA reaction between an ox ime ether moiety as the diene and an alkyne moiety as dienophile to build up the pyridine skeleton in the total synthesis of rubrolone aglycone. 18 Heating oxime ester 101 in 1,3,5 - triisopropylbenzene (TIB) at 175 C for 36 hours afforded the in - situ aromatized product 103 via intermediate adduct 102 by the loss of methanol (Scheme 3.4a). The attachment of the methyl ether on the nitrogen was proposed 83 to be the key in achieving this HDA reaction, as it injected sufficient electron density into the diene moiety. 3 In the total synthesis of luotonin A by Nomura and co - workers, an intramolecular HDA reaction between a cyanide and a tautomerized amide led to the formation of luotonin A after aromatization (Scheme 3.4b). 19 These examples further establis hed the significance for intramolecular HDA reactions in the synthesis of polycyclic compounds. The inverse electron - demand strategy has often been employed using an - unsaturated ketone or imine as diene, taking advantage of the electron deficient nature of these compounds. A tandem Knoevenagel condensation - intramolecular inverse electron - demand HDA reaction was used in the total synthesis of leporin A by Snider and Lu. 20 Pyridone 106 and dienal 107 underwent Knoevenagel condensation in the presence of triethylamine, giving intermediate 108 . The enone moiety was then attacked by the double bond to achieve an intramolecular inverse electron - demand HDA reaction. This one pot process afforded tricyclic adduct 109 in 35% yield. Further hydroxylation and methylation completed the total synthesis of leporin A 110 (Scheme3.5a). A biomimic total synthesis of variecolortide A using a late - stage HDA reaction was developed by Zipse and Trauner et al. 21 . The HDA reaction between enone 111 and dienophile 112 under thermal conditions followed by aromatization - induced 1,5 - hydrogen shift and oxidation afforded variecolortide A 113 in 48% yield in one step (Scheme 3.5b) . DFT calculations supported that the cyclization step was concerted instead of stepwise. Rizzacasa et al. applied the HDA reaction to build up the key spiroketal fragment in the total synthesis of ( ) - reveromycin A 117 . 22 Enone 114 and 84 methylene pyran 115 underwent HDA cyclization thermally t o produce spiroketal 116 as single diastereomer in 26% yield in the absence of a catalyst . The stereochemistry of the spiro core was set by an axial approach of the carbonyl group in the transition state. They later improved this step by using a Lewis acid to promote the inverse electron - demand HDA reaction. 23 Siproketal 116 was obtained in 86% yield in the presence of Eu(fod) 3 (Sch eme 3.5c). Another example of using the HDA reaction to construct spiroketal s was presented by Tietze et al. in the total synthesis of mycotoxin ( ) - talaromycin B. 24 Enone 118 reacted with methylene pyran 119 to generate siprokital 120 via an inverse electron - demand HDA reaction. Reduction of acid and deprotection of the alcohol led to the synthesis of ( ) - talaromycin B 121 (Scheme 3.6a). 25 Other spiro - fused rings could also be built up by the HDA reaction, as illustrated in the total synthesis of antiviral spirooliganone A and B by Tong and co - workers. 26 Spiro - adduct 124 was formed in 79% with a 1:1 diastereomeric ratio. The two isomer s of 124 w ere separately derivatized into spirooliganone A 125 and B 126 (Scheme 3.6b). 85 Scheme 3.5 Inverse electron - demand HDA reactions in total syntheses 86 Scheme 3.6 HDA reactions in the construction of spiro compound s HDA reactions with other uncommon dienophiles have been used in total synthesis, either to construct important skeletons or to generate important synth etic intermediates. In the total synthesis of agelastatin A by Weinreb and co - workers, N - sulfinylmethylcarbamate 127 was employed as dienophile to produce adduct 129 with cyclopentadiene 128 via a HDA reaction. 27 Subsequent Grignard addition, [2,3] - sigmatropic rearrangement and carbamate formation led to bicyclic 132 , which is the precursor to agelastatin A (Scheme 3.7a) . 3 In the total synthesis of fasicularin and lepadiformine, Kibayashi and co - workers employed an intramolec ular HDA reaction with an N - acylnitroso moiety as dienophile. 28 87 Oxidation of previously prepared chiral substrate 134 using NaIO 4 in aqueous media in situ generated N - acylnitroso compound 135 , which in - situ proceeded to undergo the intramolecular HDA reaction with the diene moiety giving bicyclic trans - adduct 136 as major product , which was taken on to lepadiformine 138 . With modification o f substrate 134 that led to the formation of the cis - adduct, access was also proceeded to fasicularin 137 (Scheme 3.7b) . The use of an a llene as dienophile in the HDA reaction was explored in the total synthesis of zincophorin by Hsung and co - workers. 29,3 0 Chiral enone 139 was prepared from commercially available chiral hydroxy ester and chiral allene 140 was synthesized from ephedrine and urea followed by propargylation and isomerization. The HDA reaction of 139 and 140 under thermal conditions g ave methylene pyran adduct 141 i n 85% yield and 95:5 diastereomeric ratio . Subsequent hydrogenation of the exo - cyclic olefin with palladium on carbon established the desired stereochemistry, which was then derivatized into zincophorin 142 (Scheme 3.7c). 88 Scheme 3.7 HDA reactions with uncommon dienophiles in total syntheses 89 Because of the usefulness of HDA reactions in the total synthesis of natural products and bioactive molecules as discussed above, there is a high demand for the development of asymmetric HDA reactions that allow access to optically pure six - membered heterocycles. 31 Some of examples illustrated above employed chiral diene s or dienophile s , in which the ste reochemistry was determined by previously installed chiral moieties. A more efficient way to control the stereo chemical outcome of reaction s is to develop enantioselective reactions with chiral catalysts , which allows the direct formation of chiral heterocycles from achiral substrate s with sub - stoichiometric amount of chiral material s . 32 Since Lewis acids c an promote both normal HDA reaction s and inverse electron - demand HDA reaction s by lowering the corresponding LUMO orbitals, many chiral Lewis aci d catalysts have been developed during the past several decades as shown in Figure 3.2 . Danishefsky et al. in 1983 employed Eu(hfc) 3 143 as a chiral catalyst in the HDA reaction with diene bearing chiral auxiliaries. 33 Yamamoto and co - workers in 1988 established the first efficient asymmetric HDA reaction catalyzed by a chiral organoaluminum catalyst 144 . 34 The catalyst 144 diene. Another aluminum catalyst 145 with a hyper - coordinating nature was developed by Jørgensen and gave up to 97% yield and >99% ee in enantioselective HDA reaction s . 35 Chromium catalysts such as 146 (Cr - salen) and 147 (Cr - Schiff base) were developed by Jacobson et al. and have been applied to many total syntheses of natural products. 36,37 These chromium - catalyzed HDA reactions were found to proceed through a concerted mechanism, while chiral 90 oxazaborolidine 148 catalyzed the HDA reaction via the Mukaiyama aldol pathway. 38 Many other Lewis acid catalysts derived from chiral ligands and transition metals such as zirconium 39 , rhodium 40 , titanium 41,42 and copper 43 have been found to be effective in the asymmetric HDA reactions. Figure 3.2 Selected L ewis acid catalysts for asymmetric HDA reactions 91 Chiral organocatalysts (Figure 3.3) have also been used in the asymmetric HDA reactions, in which the substrates are activated via hydrogen - bonding to catalysts. Rawal et al. in 2003 employed TADDOL derivative 154 as hydrogen - bond donor to catalyze the reaction between diene s an d aldehydes with excellent enantioselectivities. 44 Ding and co - workers in 2004 found that BINOL - derived hydrogenphosphate 155 could activate carbonyl groups and catalyze the asymmetric HDA reaction between diene s and glyoxylates. 45 Chiral disulfonimide 156 93 and aldehyde s with high asymmetric inductions developed by List et al. in 2012. 46 Figure 3.3 Chiral organocatalysts in asymmetric HDA reactions Among these chiral Lewis acid catalysts and organocatalysts, chromium catalyst 147 plays a predominant role in the total synthesis of natural products. The asymmetric HDA reactions between diene s and alk ynal s catalyzed by 147 produced enantioenriched alkynyl dihydropyran species, which w ere used in the 92 enantioselective total synthesis of aphadilactone A - D 47 , GEX1Q1 48 , an g uinomycin C and D 49 ( Scheme 3.8 ) . Excellent asymmetric inductions were observed. Scheme 3.8 Chromium catalyst 147 with alkynals in total syntheses 93 The asymmetric HDA reaction between a diene and an acetaldehyde that bears oxygen substituents at - position has drawn a lot of attention from chemists, as it allows for the construct ion of hexose skeleton with designed stereochemistry. The enantioselective HDA reactions of ( tert - butyldimethylsilyloxy)acetaldehyde 170 and various diene s catalyzed by chromium catalyst 147 have been studied and applied in the total synthes e s of many natural products (Scheme 3.9) . In 2012, Sasaki and co - workers employed the catalytic asymmetric HDA reaction of aldehyde 170 and diene 17 1 to build up the key tetrahydropyran structure in the total synthesis of ( ) - polycavernoside A. 50 With 3 mol% of catalyst 147 , two chiral centers in the target were realized and endo - adduct 172 was produced as single diastereomer in 60% yield and 96% ee . F ollowing derivatizations such as hydrogenation o f the tetrahydropyran ring set up additional stereo centers based on the existing chiral environment . T hus , the enantioselective total synthes i s of polycavernoside A could be accomplished by taking advantage of the catalytic asymmetric HDA reactions in an early stage of the synthesis . Asymmetric HDA reactions between aldehyde 170 and different dienes catalyzed by the chromium complex 147 led to the construction of various enantioenriched cycloadducts as key building blocks, which have been used in total synthesis of neosidomycin, 51 dactylolide, 52 leucascandrolide A, 53 and lasonolide A. 54 Endo - cyclization products were generally favored and high diastereomeric ratio were observed with excel lent enantioselectivities (94 - 99% ee ). The r egiochemistry could be programmed by changing the position of the electron - donating groups on the diene. With sil yl oxy group at the 2 - posit i on, diene 171 gave adduct 172 with the aldehyde oxygen being 94 connected with the carbon at 4 - position of diene , while with methoxy group at 1 - position, opposite regiochemistry was observed. Scheme 3.9 Chromium catalyst 147 with aldehyde 170 in total syntheses 95 Some total syntheses have employed asymmetric HDA reaction s between chiral aldehyde s or chiral diene s . The potent catalyst 147 was able to control the stereo chemical outcome of cycloadduct in high diastereomeric ratio, regardless of the chirality previously installed i n the aldehyde or the diene (Scheme 3.10) . In the enantioselective total synthesis of neopeltolide 185 by Ghosh et al., diene 183 with three chiral centers was reacted with aldehyde 182 in the presence of 10 mol% catalyst 147 . 55 After acidic work up, the silyl protecting groups were removed and adduct 184 was formed in 83% yield with diastereomeric ratio of 97:3. The tosyla te moiety on 184 was then replaced by a cyano group followed by hydrolysis and macrolactonization. The carbonyl group was reduced and a subsequent Mitsunobu esterification installed the side chain and completed the total synthesis of neopeltolide 185 . Anot her total synthesis of neopeltolide was developed by Paterson et al., who utilized aldehyde 186 instead of diene 183 with the proper chiral centers in the asymmetric HDA reaction catalyzed by 147 . 56 It was not surprising to find that the HDA reaction between the two bulky substrates 186 and 187 required a prolonged reaction time (8 days) , compared with the reaction of the less sterically hindered aldehyde 182 . In the total synthesis of bistramide A by Floreancig, both aldehyde 189 and diene 190 have chiral centers. 57 It was confirmed that the use of achiral aldehyde and diene analogs produced adducts with same stereochemistry. Oxidation of the silyl enol ether adduct by DDQ gave dihydropyrone, which was attacked by the oxygen on th e side chain after acidic work up. S piroketal 191 was achieved in 58% yield in a one - pot process , which is the precursor of bistramide A 74 . 96 Scheme 3.10 A symmetric HDA reaction s with chiral aldehydes or dienes 97 Scheme 3.11 Rhodium - catalyzed a symmetric HDA reactions in total synthes e s Second to the most popular chromium catalyst 147 , are rhodium (Scheme 3.11) catalyzed asymmetric HDA reactions , which have also been employed in total synthes e s. In the total synthesis of azadirachtin 194 by Ley and co - workers, 58 the 192 was utilized to build up the tetrahydropyran moiety with a tethered alkynyl group. 59 Many catalysts were inappropriate for this transformation while the rhodi um 98 catalyst 150 was found to be effective, giving adduct 193 in 77% yield and 90% ee . The same catalyst was also useful in the reaction between diene 195 and alkynal 196 , which tied into the total synthesis of centrolobine 198 . 60,61 Scheme 3.12 Copper - catalyzed asymmetric HDA reactions in total syntheses 99 Examples of copper - catalyzed asymmetric HDA reactions in total syntheses are shown in Scheme 3.12. Cu - BOX catalyst 153 was used in the reaction between cyclic diene 199 and glyoxylate 200 , giving the bicyclic adduct 201 in 88% yield and 99% ee . After hydrolysis, rearrangement and elimination, actinidiolide 202 was synthesized from 201 . 62 An i nverse electron - demand HDA reaction catalyzed by 153 was used to construct the hexose skeleton in the total synthesis of ethyl - D - manno - pyranoside tetraac etate 206 . 63 The use of electron - deficient diene 203 and electron - rich dienophile 204 created adduct 205 with high asymmetric induction. A s imilar reaction was employed in the total synthesis of azaspiracid - 1 210 to construct the middle tetrahydropyran rin g, as illustrated by Evans and co - workers in 2008. 64 3.1.2 Chiral borates in asymmetric reactions Boron species are one of the most important Lewis acids among all main group elements owing to its electron - deficient nature. Many c hiral boron catalysts (Figure 3.4) have been developed since Mamedov first employed BF 3 menthol OEt in the asymmetric Diels - Alder reaction in 197 6 . 65 Some c hiral oxazaborolidine catalysts were found to be effective in a number of asymmetric reactions with carbonyl compounds, such as CBS reduction, 66 Diels - Alder reaction, 67 cyclopropanation 6 8 and Roskamp reaction. 69 In 1988, Yamamoto and co - workers reported an asymmetric Diels - Alder reaction with excellent enantioselectivity catalyzed by a chiral acyloxyborane (CAB) catalyst 213 that is derived from tartaric acid. 70 They later employed this type of catalyst in asymmetric aldol reactio n s , 71 aldehyde allylation s 72 and aza - Diels - Alder reaction s . 73 The CAB catalysts were 100 proposed to be a Br ø nsted acid assisted Lewis acid, known as BLA catalyst. 7 4 The hydrogen bonding between carboxylic acid and the oxygen on the oxazoborolidine enhanced the Lewis acidity of the boron by reducing electron density on the oxygen next to boron. Figu re 3.4 Selected chiral boron catalysts Kaufmann et al. in 1990 reported the first chiral borate - catalyzed asymmetric Diels - Alder reaction. 75 By reacting 3 equivalent of BINOL with 2 equivalent of H 2 BrB SMe 2 , a propeller - like borate species 216 was generated and utilized as a catalyst in reaction between methacrolein 214 and cyclopentadiene 128 . Exo - adduct 215 was formed in 85% yield and 99% ee after 2 days at 78 . BLA catalyst 217 developed by Yamamoto was found to be effective in the same asymmetric Diels - Alder reaction , which reduced reaction time to 4 hours . 76 To investigate the importance of the hydrogen bonding in 217 to activate the Lewis acidic boron center in the BLA cataly st , the free phenolic group was protected with benzyl giving catalyst 218 . Unsurprisingly, t he use of 218 as catalyst, which lacks hydrogen bonding donor to enhance the Lewis acidity, resulted in lower enantioselectivity. 76 BLA catalysts 219 and 220 were d erived from boronic acids with a chiral triol. 77,78 While both catalysts were efficient in the asymmetric Diels - 101 Alder reaction, catalyst 219 with boron connected to two oxygens on the chiral ligand gave higher yield, regioselectivity and enantioselectivity (Scheme 3.13) . Scheme 3.13 Chiral borate catalysts in asymmetric Diels - Alder reaction A spiro - borate catalyst 221 has been developed by Yamamoto and co - workers in the asymmetric HDA reaction between an 102 diene (Scheme 3.14) . 79 It was deprotonated by imine substrates and the structure was confirmed by X - ray crystallography, which could be classif ied as one of the earliest examples of asymmetric counterion directed catalysis. 80 However, due to the higher basicity of adduct 224 , no catalyst turnover was observed and a stoichiometric amount of 221 was required. One equivalent of catalyst 221 has also been used in the Mannich reaction to give the - amino ester 227 . 81 It has been shown that a catalytic amount of 221 was able to catalyze an asymmetric aziridination reaction with moderate yield and low ee . 82 Scheme 3.14 Chiral spiro - borate catalysts 103 A VANOL - derived borate 22 2 has been shown to be involved in an asymmetric epoxidation reaction between an aldehyde and diazo compound (Scheme 3.14) . 83 The substrates were not basic enough to deprotonate the catalyst , thus a Lewis acid behavior was proposed. In 11 B NMR, catalyst 22 2 showed a broad peak a t ~20 ppm, supporting the existence of a tri - covalent borate species. After adding 1 equivalent of imine to 22 2 , a sharp peak at 9 ppm was observed, indicating the deprotonated spiro - borate species. Hydrogen bonding between free hydroxy group and an oxygen on the other ligand was found in DFT calculation, suggesting that 22 2 is a BLA catalyst. 84 The Wulff group has developed a novel boroxinate catalyst 234 (BOROX) derived from 1 equivalent of VANOL or VAPOL ligand and 3 equivalent s of boron. The catalyst was first applied to asymmetric cis - aziridination in 1999, 85 but the structure of 234 was not confirmed until 2010, when the crystal structure 235 was obtained. 86 The BOROX species consists of one tetra - covalent borate and two tri - covalent bor ates. This unique feature provides multiple Lewis acidic boron centers and a chiral anion that directs imin ium substrates and other hydrogen bond donors to the chiral pocket formed from VANOL/VAPOL ligand. A number of BOROX - catalyzed asymmetric reactions u sing imine as substrate have been developed by Wulff and co - workers in the past two decades, such as trans - aziridination, 87 aza - Diels - Alder reaction, 88 aza - Cope rearrangement, 89 and three - component Ugi reaction . 9 0 Notably, an orthogonal dual catalyst system with BOROX 234 and triphenylborate was established in the catalytic asymmetric aza - Diels - Alder 104 reaction to solve the turnover problem presented by the fact that adduct 240 is more basic than starting material 236 . 88 Scheme 3.15 Chiral boroxinate in asymmetric catalysis 105 3.2 Initial study The BOROX catalyst 234 was prepared by mixing 1 equivalent of VAPOL and 3 equivalents of B(OPh) 3 during the development of aza - Diels - Alder reaction and the catalysts was proposed to be a Lewis acid species since the structure of catalyst has not determined at that time. 88 An ox a - Diels - Alder reaction between 93 has been reported under the same condition as used in the aza - Diels - Alder reaction , and a 67% yield with 28% ee was obtained 84 (Scheme 3.16b) . The research on oxa - Diels - Alder reaction was not further pursued until the structure of BOROX catalyst was determined, which revealed that a Lewis base such as an imine is required to form the boroxinate skeleton. It is not surprising that this catalyst system failed to promote the HDA reaction w ith aldehydes, because the carbonyl species is not basic enough to form the BOROX catalyst . To expand the use of BOROX in asymmetric reaction of aldehydes, a breakthrough was made in the development of an asymmetric epoxidation reaction between aldehydes a nd diazo compound by using basic additives, such as DMSO. 83 It was found that catalytic amount of DMSO successfully generated BOROX catalyst. The activation of aldehydes by the catalyst was probably the Lewis acid - Lewis base interaction between the sulfur on protonated DMSO and carbonyl on aldehydes. The same strategy was employed in the asymmetric HDA reaction with 10 mol% DMSO as additive, however, low conversion (<20% conv.) was observed (Scheme 3.16c) . 84 The other catalyst used in the asymmetric epoxidation reaction is BLA catalyst 222 , and it has been found that the direct activation of aldehydes by Lewis acidic borate 222 was successful. 106 Therefore, 10 mol% catalyst 222 was employed in the oxa - Diels - Alder reactio n . It was pleasing to find that t he reaction in toluene at room temperature after 24 hours gave adduct 248 b in 79% yield and 62% ee (Scheme 3.1 7 ). 84 Scheme 3.16 Oxa - Diels - Alder reaction with BOROX catalysts 107 Scheme 3.17 Oxa - Diels - Alder reaction with BLA catalyst 222 The catalyst 222 was prepared by heating 2 equivalents of ( S ) - VANOL ( L5 ) and 1 equivalent of BH 3 2 S ( borane dimethylsulfide ) in toluene for 0.5 hour followed by pumping off solvent and volatiles. diene 93 and para - bromobenzaldehyde 231b was achieved in 79% yield and 62% ee with 10 mol% catalyst loading. The use of ( S ) - BINOL ( L1 ) as ligand improved results to 94% yield and 83% ee (Scheme 3.18, entry 2). Using VAPOL ( L2 ) as ligand failed to give any product (entry 3) , probably because the steric bulkiness of VAPOL hindered the formation of the 2:1 borate catalyst and a similar fai lure has been observed in the asymmetric epoxidation reaction. 83 Surprisingly, the use of another bulky ligand - t Bu 2 VANOL ( L22 ) gave adduct 248b in 90% yield and 64% ee (entry 4) . Further study showed that the reaction is much faster than expected, wit h completion in 1 hour at room temperature. 108 Scheme 3.18 Optimization o f the ligand and the temperature It was interesting to find that decreasing the reaction temperature to 40 C improved the ee by 21% and 22% for VANOL ( L5 - t Bu 2 VANOL ( L22 ) 109 respectively, while only a 3% improvement was observed for BINOL ( L1 ) (Scheme 3.18, entr ies 5 - 7). Further lowering temperature to 60 C gave 77% yield and 88% - t Bu 2 VANOL ( L22 ) but a lower yield and ee for BINOL ( L1 ) (entr ies 8 - 9). Scheme 3.19 Control experiment s and screening o f the boron source C ontrol experiments were carried out to determine the optimal boron source. T he addition of only ligand or only triphenylborate (B(OPh) 3 ) resulted in no product being observed i n both cases (Scheme 3.19, entr ies 1 - 2). When ligand L22 and 110 B(OPh) 3 were used together, adduct 248b was obtained in 95% yield and 38% ee (entry 3) . The reason that B(OPh) 3 was chosen as catalyst in those control experiment s is that it has three phenolic ligands at the boron center, which is similar to the structure of catalyst 222 (Scheme 3.17) . Considering that the electronic nature of VANOL is close to that of phenol, the much higher reactivity observed for VANOL could be attributed to the intramolecular hydrogen bonding that makes it a BLA catalyst (Br ø nsted acid assisted Lewis acid). The hydrogen bonding reduces the Lewis basicity of the accepting oxygen, and as a result the Lewis acidity on boron center is enhanced . Therefore, the activation of aldehyde by BLA catalyst 222 is better than it by B(OPh) 3 . While screening other boron source s , BH 3 2 S was found to be more efficient than B(OPh) 3 , probably because of the water residue in commercial B(OPh) 3 that generates B - O - H bonds (entr ies 3 - 6) . 86 Another possibility is that the free phenols in the system compete with VANOL ligand in binding to boron center, and B(OPh) 3 itself has been proven to be not able to catalyze the HDA reactions. BH 3 as boron source was also tested. Studies have been per formed on preparing the catalyst at different temperature , but no better results were obtained compared with the use of BH 3 Me 2 S (entr ies 7 - 10) . Therefore, BH 3 Me 2 S as optimal boron source was used in the following asymmetric HDA reactions . 3.3 NMR study on catalysts The BH 3 2 S used in this reaction was purchased from Alfa Aesar as a 2 M solution in toluene. During catalyst preparation, BH 3 2 S was injected into the reaction solution containing the ligand via a 111 the oven for over 24 hours and flushed with nitrogen before use. Usually, two reactions were carried out at the same time and one syringe was responsible for two injections. After the first injection, the syringe was le ft on the bench (the needle ha d not been touched) for less than 10 seconds before the next measurement and injection. The preparation of the catalyst was studied using NMR. After pumping off the volatiles, Ph 3 CH as internal standard was added to the catalyst, which was then dissolved in CDC l 3 for the NMR study. - positions of - t Bu 2 VANOL ligands in the catalyst 249 were integrated and t he NMR yields of the catalyst were calculated and shown in Scheme 3.20. A total of 12 reactions were carried out in six pairs . For each pair, the same one syringe was used for the measurements and injections of BH 3 2 S . For example, entry 1 and 2 were carried out at the same time . The reaction in entry 1 was treated with BH 3 2 S via a syringe (taken out from oven and flushed with nitrogen) . W hile for reaction in entry 2 , BH 3 2 S was added using the same syringe used in entry 1. Interestingly, a statistical difference in results between odd entries and even entries was observed (75% average yield and 63% average yield) . 112 Scheme 3.20 Can the same syringe be used for two injections of BH 3 2 S ? Since all other conditions are identical except for the addition of borane, it indicates that the order of adding borane matters. Obviously, the use of the same syringe for two injections of BH 3 2 S should be questioned. After the first injection, the BH 3 2 S residue in the needle is exposed to air because a dry box is not employed. Due to the moisture sensitivity of BH 3 2 S, it is possible that hydrolysis occurs on the residue in the needle and leads to the formation of boric acid that is injected into the second reaction as an impurity. In methodology development, 113 running multiple reactions at the same time and using the same sy ringe to measure the same compounds are typically considered expedient . It was found here that using the same syringe for multiple injections of air - sensitive compounds outside a dry box might be risky. The simplest solution to this finding is to use a new syringe for each injection. This strategy has been employed in all following reactions when air - sensitive compounds , suc h as borane, trimethylaluminum and TMSCl , were measured out via syringes. i The structure of the catalyst prepared from BINOL ( L1 ) under our conditions was first thought to be a 2:1 borate ester 250 (structure proposed by Yamamoto 79 ), similar to catalyst 249 (Scheme 3.20) - t Bu 2 VANOL ( L22 ) and catalyst 222 (Scheme 3.17) from VANOL ( L5 ). However, in this work the 1 H NMR study revealed that propeller borate 216 , a known species developed by Kaufmann 75 , was obtained as the sole product under our standard conditions . The structure of 216 was confirmed by comparing the 1 H NMR spectrum with the previously reported data . 82 O nly the free ligand (BINOL) and 216 were observed in the reaction mixture as indicated by 1 H NMR spectrum. Increasing the borane loading from 0.5 equivalent to 1 equivalent and 4 equivalents also gave 216 as single product in higher yield (Scheme 3.21) . Notably, i t is the first time that the propeller i Paying attention to details like this may not increase the yield of product dramatically, but it will definitely make results more reliable. During the long journey of optimizing reactions, I never felt upset by getting bad results because bad results woul d tell me where to go. I was disappointed only when a result could not be reproduced, as it indicated that at least one of the results was not reliable. Recalling the five years in my PhD career, I have spent months figuring out why inconsistent results were obtained. Sometimes it was because of an old bottle of reagent or a not fully dried solvent, and sometimes it was because of the use of one syringe in two injections. What I have l earned is that paying 100% attention to every single detail and questioning myself in every single step while running a reaction will make results more reliable and avoid lots of detours in chasing the truth. 114 borate 216 has been employed in the asymmetric HDA reaction. Even though 216 and 249 displayed a similar capacity in catalyzing diene 93 and para - bromobenzaldehyde 231b (Scheme 3.19 , entries 5 and 6 ), they gave different responses to chan ges in the reaction paramet ers . Therefore, optimizations on catalyst 216 and 249 wer e performed separately. Scheme 3.21 Catalyst prepared from BINOL 3.4 O ptimization and substrate scope with catalysts 2 16 The r eaction parameters of the asymmetric HDA reaction between diene 93 and aldehyde 231a catalyzed by BINOL - derived propeller borate 216 have been studied. While moderate yield and ee were obtained with t he reaction concentration at 0.25 M, diluting the reaction to 0.05 M gave adduct 248a in an 115 improved 91% ee (Scheme 3.22, entr ies 1 - 4). Previous results by Dr. Xiaopeng Yin showed that the non - polar solvent toluene is superior to other polar solvent s such as CH 2 Cl 2 and THF. 84 Inspired by the success of using n - pentane as solvent in MPV reduction (Table 2.3) , the asymmetric HDA reaction in n - pentane was carried out, but low conversion was observed (entry 7). This is possibly because of the low solubility of the catalyst in n - pentane. After the preparation of catalyst and pumping off volatiles, solvent s and substrates were added to the flask containing th e catalyst. It was observed that the catalyst stayed on the inner side of flask as a white powder and did not go into the reaction mixture wh en using n - pentane as solvent . Therefore, to decrease the polarity of the reaction, a mixture of toluene and n - pentane as co - solvent were employed. Toluene was added into the flask first to fully dissolve the catalyst, and then n - pentane was added . Using toluene/ n - pentane in 1:4 ratio improved the results to 90% yield and 94% ee (entry 5). Notably, e ven though the catalyst cr a shed out after the addition of n - pentane and the reaction turned cloudy (more precipitates were observed after cooling to 40 C), high conversion and asymmetric induction were obtained. The reason that the heterogeneous mixture showed good results is not clear. It is possible that the concentration of active catalyst in solution remained constant owing to the low solubility of catalyst, which might contribute to a better reaction. D iluting the reaction to 0.025 M with toluene/ n - pentane in 1:9 ratio gave lower yield and slightly lower ee (entry 6). Lowering the reaction temperature to 60 C resulted in a slower reaction (entry 8). 116 Scheme 3.22 Optimizations with catalyst 216 With optimal conditions in hand, the substrate scope of the asymmetric HDA reaction catalyzed by propeller borate 216 was studied. Aromatic aldehydes were tolerated well, but aliphatic al dehydes were not (Scheme 3.23). No product was observed when aldehyde 231f was used and only 25% yield and 59% ee was 117 obtained from the reaction of cyclohexanecarboxaldehyde 231e . Despite the failure with aliphatic aldehydes, this is the first example of using the propeller catalyst 216 in asymmetric HDA reaction of aromatic aldehydes. Scheme 3.23 Substrate scope of asymmetric HDA reaction with catalyst 216 3.5 Optimization s of asymmetric HDA reaction with catalyst 249 Due to the limitation in the scope with the asymmetric HDA reaction catalyzed by the propeller borate 216 , our attention was turned to the use of borate ester 249 as catalyst. The effect of c oncentration was first studied and 0.05 M was 118 found to be optimal, with higher concentration s causing lower ee and further dilution causing lower yield s (Scheme 3.24, ent r ies 1 - 4). The use of Et 2 O as solvent gave adduct 248a in only 37% yield, probably due to the coordination between the Lewis basic oxygen on ether and boron catalyst (entry 5) . Polar solvent CH 2 Cl 2 resulted in lower yield and ee compared with non - polar solvent toluene (entr ies 3 vs 6). T he use of toluene/ n - pentane as co - solvent decreased the polarity and increased enantioselectivity (entr ies 7 - 8) . Unlike propeller borate 216 , the catalyst 249 could be dissolved by n - pentane at ro om temperature. The high solubility is presumably aided by the tert - - t Bu 2 VANOL ligand . Without those tert - butyl groups, the catalyst 222 prepared from VANOL displayed poor solubility in n - pentane. Unsurprisingly, using n - pentane as the sole solvent increased the result s to 96% yield and 88% ee (entry 9). It is noteworthy that some of catalyst 249 still precipitated out when the reaction w as run at 40 C, but the heterogeneous mixture gave excellent results . Lowering the temperature to 60 C gave adduct 248a in 93% yield and 91% ee (entry 10). Running the reaction at 78 C slowed down the reaction and did not improve the enantioselectivity (entry 11). The use of 20 mol% DMSO or benzoic acid as additive shut down the reaction, perhaps because of the destruction of catalyst (entr ies 12 - 13). Adding molecular sieves failed to enhance the results (entry 14). By cutting the catalyst loading to 5 mol%, a 90% yield and 9 3 % ee was achieve d (entry 15). 119 Scheme 3.2 4 O ptimization of the HDA reaction of benzaldehyde with catalyst 249 120 Catalyst 249 was also studied in the reaction between diene 93 and the aliphatic aldehyde 231e . This reaction catalyzed by the propeller borate 216 gave 248w in only 25% yield and 59% ee . To our delight, catalyst 249 was very effective with cyclohexanecarboxaldehyde 231e . With t oluene as solvent and with a concentration of 0.1 M , the adduct 248e was obtained in 82% yield and 88% ee (Scheme 3.25, entry 1). Additional improvement was observed when a two - fold dilution and co - solvent was employe d (entry 2). With 5 mol% catalyst loading and reaction running in n - pentane at 60 C, a 97% yield and 98% ee of 248e was accomplished (entry 3). This exciting finding indicated that the optimiz ed conditions for benzaldehyde w ere also suitable for aliphatic aldehydes. Therefore, the substrate scope of the asymmetric HDA reaction catalyzed by borate 249 was studied under the se optimal conditions. Scheme 3.25 The o ptimization of aliphatic aldehyde with catalyst 249 121 3.6 Substrate scope of asymmetric HDA reaction with catalyst 249 Scheme 3.26 Substrate scope with catalyst 249 122 The substrate scope of the asymmetric HDA reaction between aldehydes and diene 93 catalyzed by borate ester 249 has been studied under the optimal conditions shown in en try 3 of Scheme 3.25 . Gratefully, a broad scope was found as shown in scheme 3.26 . Aromatic aldehydes such as benzaldehyde 231a and 2 - naphthaldehyde 231d gave the corresponding adducts with excellent asymmetric inductions. Changing the e lectron density on the aromatic rings showed little impact on enantioselectivities. Both electron - withdrawing substituents such as bromo ( 231b ) and nitro ( 231c ) , and electron - donating group methoxy ( 231g ) at para - position were tolerated well, giving 78 - 94% yield a nd 91 - 92% ee . A m ethyl group and a chloride as substituents at ortho - and meta - positions gave 88 - 96% yield and 90 - 95% ee ( 231h - k ). Heterocycles such as furan ( 231l ), thiophene ( 231m ) and Boc - protected pyrrole ( 231n ) were also well tolerated. The reaction of 2 - thiophenecarboxaldehyde 231m in n - pentane was unsuccessful due to the poor solubility of the aldehyd. Changing n - pentane to toluene gave adduct 248m in 72% yield and 85% ee . Aliphatic aldehydes other than cyclohexanecarboxaldehyde 231e were also tested. Branched aldehyde 231o (isobutyraldehyde) and unbranched aldehyde 231p (butyraldehyde) both gave high yield and ee . To our delight, an 81% yield and 87% ee was achieved for ad duct 248f - siloxyacetaldehyde 231f was used. Aldehyde 231f is one of the most important substrates, because it constructs the hexose skeleton in this asymmetric HDA reaction. Further derivatization of adduct 248f could lead to a variety of saccharide analogs . Moreover, the chiral center installed on 248f would help achieve - alkylation, ketone reduction and 123 dihydroxylation to build up more chiral centers on the six - membered ring. The asymmetric HDA reaction s o f aldehyde 231f have been used in total synthesis of neosidomycin, 51 dactylolide, 52 leucascandrolide A, 53 and lasonolide A 54 as shown in scheme 3.9. Scheme 3.2 7 Failed substrates with catalyst 249 There are also some aldehydes that are not tolerated in this asymmetric HDA reaction catalyzed by borate 249 , as shown in Scheme 3.27. Substrates with unprotected N - H bond s such as pyrrole ( 231q ) and indole ( 231r ) were not reactive under standard condition s. Aldehyde s bearing strong base moieties such as 124 pyridinecarboxaldehyde 231s - t and para - dimethylaminobenzaldehyde 231u were not tolerated, possibly due to the deprotonation of catalyst 249 generating spiro - borate anion that is no longer has the Lewis acid i ty to activate the aldehyde. A ldehyde s 231v gave less than 1% yield, perhaps due to its steric bulkiness that hinder s the Lewis acid - Lewis base interaction between the aldehyde and catalyst. In spite of these limitations, borate 249 has shown superior capability over borate 216 in catalyzing the asymmetric HDA reaction between aldehydes and 3. 7 Study on asymmetric HDA reaction of - alkoxyacetaldehyde Figure 3.5 Ligands screened Most of aldehydes underwent asymmetric HDA reaction catalyzed by borate 249 in high yields and excellent asymmetric inductions. However, the reaction of 125 the - siloxyacetaldehyde 231f gave the important adduct 248f and 87% ee (Scheme 3.26). Driven by the significance and potential application s of this reaction, further stud ies on asymmetric HDA reaction of - alkoxyacetaldehyde s were performed. The optimization of asymmetric HDA reaction between diene 93 and aldehyde 231f is shown in Scheme 3.28. Scheme 3.28 Attempts at o ptimizations o f aldehyde 231 f 126 The use of catalyst (R,R) - 249 generated from ( R ) - L22 gave adduct 248 f in 71% yield and 84% ee at 40 C (Scheme 3.28, entry 1) . Lowering the temperature to 60 C and 78 C slowed down the reaction but increased enantioselectivity (entr ies 2 - 3). The l ess bulky ligand ( R ) - L21 and ( S ) - L29 resulted in lower conversion and a drop of ee (entry 4 - 5). BINOL ( L1 - diphenylVANOL ( L14 , entry 8) gave no product under the standard conditions. O ther - disubstituted VANOL as ligands were found to be not as good as ( R ) - L22 and g ave lower asymmetric inductions (entr ies 9 - 13) . Thus, the best that was achieved in the formation of adduct 248 f was 88% ee , which is not satisfactory, especially considering its significant application in synthetic chemistry. During the ligand screening we found that bulkier ligands usually gave better yields a nd asymmetric inductions , which implied that aldehyde 231 f might not be b ulky enough with the TBS group . Therefore, it was proposed that by switching the TBS group on the aldehyde to TBDPS, a bulkier protecting group, a better asymmetric discrimination in the transition stat es might be realized . A ldehyde 231w was synthesized by mono - protection of ethylene glycol followed by Swern oxidation. Screening of ligands for the asy mmetric HDA reaction between aldehyde 231w and diene 93 was performed and results are shown in Scheme 3.29. The c atalyst prepared from BINOL ( L1 ) gave no product as expected from the results in Scheme 3.23 ( Scheme 3.29, entry 1) , and the use of iso VAPOL ( L4 ) and VANOL ( L5 ) gave adduct 248w in good to high yield and moderate ee (entr ies 2 - 3). - position of VANOL did not change the e e significantly with adduct 248w formed in 127 70 - 90% yield and 75 - 82% ee ( entr ies 4 - 8 ) . The b est enantioselectivity , but with lower yield , was obtained when - TBDPS 2 VANOL ( L25 ) was used as ligand, giving adduct 248w in 51% yield and 88% ee (entry 9). Due to the unsatisfactory - sil oxyacetaldehyde, other protecting groups were explored . Scheme 3.2 9 Optimization o f aldehyde 231w in the reaction with diene 93 the asymmetric HDA reaction between diene 93 and aldehyde 231x that has benzyl as protecting group was studied and the results are shown in scheme 3.30. The reactions were first conducted in n - pentane but low conversions were observed (entr ies 1 - 3), and this is probably because of the poor miscibility between 128 aldehyde 231x and solvent. When toluene was employed as solvent, reactions with different ligands proceeded well and gave adduct 248x in high yields. However, only moderate enantioselectivities were observed for all of the ligands screened. We proposed that the lack of asymmetric induction resulted from less bulky benzyl substituent in aldehyde 231x . T herefore, a much bigger protecting group triphenylmethyl (trityl) was installed on the aldehyde. Scheme 3.30 Optimizations on aldehyde 231x 129 Scheme 3.31 Optimizations o f aldehyde 231y The aldehyde 231y was synthesized from triphenylmethylchloride and allylic alcohol followed by ozonolysis and was prepared as a stock solution in toluene before use. After ligand screening with toluene as solvent , the - i Pr 2 VANOL ( L29 ) was found to be most effective in the asymmetric HDA reaction between diene 93 and aldehyde 231y , giving adduct 248y in 91% yield and 82% ee ( Scheme 3.31, entry 6 ). The use of toluene/ n - pentane in 1:10 ratio as co - solvent 130 and running reaction at 78 C f or 12 hours successfully gave adduct 248y in 90% yield and 93% ee (entry 10, average of two runs). Finally, t he achievement of excellent yield and excellent asymmetric induction for the HDA reaction on aldehyde 231y provided a n effective approach in the asymmetric synthesis of hexose skeleton, which potentially could le a d to a variety of saccharide analogs. 3.8 Reaction mechanism and computational study 3.8.1 Is the asymmetric HDA reaction catalyzed by VANOL borate complex conce rted or stepwise? Scheme 3.32 Two possible pathways Two mechanistic pathways of the HDA reaction between aldehydes and previously been proposed and studied (Scheme 3.32). 91,38,36 The first one is a concerted [4+2] cycloaddition pathway that is similar to the traditional Diels - Alder reaction. The second one is a stepwise pathway, undergoing Mukaiyama aldol reaction first followed by acid - promoted cyclization. It was determined by D anishefsky in 1985 that different catalysts c an result in 131 different pathways in the same reaction. 91 Corey and co - workers have isolated the Mukaiyama aldol product 252 in a reaction catalyzed by a titanium - BINOL catalyst, with cyclization occur ing after acidic treatment, which is evidenced that the reaction under goes a stepwise pathway. 38 chromium catalyst, no Mukaiyama aldol product 252 was detected. The intermediate 252 was synthesized independently and treated with the chromium catalyst under the same conditions, but no cyclization product was obtained. 36 Therefore, a concerted mechanism was suggested for this reaction. Scheme 3.33 Different quenching methods I n our bor ate catalyzed asymmetric HDA reaction, a concerted mechanism was proposed and evidence was obtained for this by changing the quenching method. The addition of strong acid s such as TFA or 1 M HCl in MeOH/H 2 O (1:1) into the solution to quench the reaction was employed under standard conditions 132 (Scheme 3.33, entr ies 1 - 2) . However, without acid, using ethanol/water mixture to quench the reaction also gave adduct 248b in high yield and ee (entry 3). 252 would undergo cyclization only with acid promotion . 38 Therefore, t he mechanism in our system is thought to be a concerted pathway, since no acid is required to achieve cyclization to the product 248 . 3.8.2 Reversal of asymmetric induction Scheme 3.34 Asymmetric HDA reaction with boron and aluminum catalysts The catalyst made from aluminum instead of boron has also been investigated in the asymmetric HDA reaction between aldehyde 231a and diene 93 . A very interesting finding is that boron and aluminum catalysts made from the 133 same ligands gave the opposite chiral outcome, in other words, a reversal of direction of asymmetric induction was observed (Scheme 3.34). With the VANOL ligand ( S ) - L5 and - t Bu 2 VANOL ligand ( S ) - L22 were used to prepared boron catalyst, ( S ) - 248a was generated as the major enantiomer. However, when reactions were catalyzed by aluminum catalysts prepared from ( S ) - L5 and ( S ) - L22 with trimethylaluminum, ( R ) - 248a was formed as major enantiomer. Figure 3.6 Boron and aluminum catalysts prepared from VANOL A similar reversal has been observed in asymmetric epoxidation reaction, where aluminum - VANOL catalyst and boron - VANOL catalyst led to different chiral outcome s in the epoxide. 92 However, the reason why the reversal occurs is not clear. In order to have some preliminary insights on understanding the behaviors of boron and aluminum catalysts, a computational study was perfor m ed and the structures of catalysts were optimi zed by DFT calculations as shown in Figure 3.6. Geometry optimizations were carried out in Gaussian 16 under DFT B3LYP 6 - 31g(d) level. 93 As for boron catalyst 222 , three oxygens of the ligands are bound 134 to a planar boron center with B - O distance s of 1.36 - 1 .38 Å . The fourth oxygen is not coordinating to the boron as indicated by its B - O distance at 3.48 Å . The hydrogen bonding between free OH group and an oxygen on the other ligand was observed, evidenced by the O - H distance at 2.08 Å. These feat ure s make the borate 222 a BLA catalyst, with enhancement of Lewis acidity on boron. As for aluminum catalyst 253 , the aluminum has bonds to all four oxygens in close to a tetrahedron geometry. Three of the oxygens are bound to aluminum at 1.74 - 1.75 Å and the fourth oxygen is coordinating to aluminum with an Al - O distance of 1.93 Å. A hydrogen bonding interaction between the OH and an oxygen on the other ligand is found at 2.59 Å, which is weaker than that observed in the boron catalyst 222 . In general, the aluminum catalyst 253 is symmetrical with the aluminum bound to four oxygens, while the boron cat alyst 222 is twisted and only three oxygens are b ound to boron. Certainly, the geometry of the ligand and catalyst will change after interact ing with the substrates (aldehydes and dienes), but the very different geometries between the boron and aluminum ca talysts might be responsible for the observed asymmetric induction reversal, especially when it is considered that aluminum can be five or six coordinat e but boron can be four coordinate at maximum . 3.9 Conclusion In this chapter, the significance of the heteroatom Diels - Alder reaction has been illustrated by its synthetic applications. Previously developed catalysts in asymmetric HDA reactions and the ir applications in total synthesis of natural 135 products have been discussed. The development of chiral borate catalysts in the asymmetric HDA reaction between diene s and aldehydes has been presente d. In conclusion, a highly efficient asymmetric heteroatom Die ls - Alder reaction between diene s and aldehydes for the construction of 6 - membered heterocycles catalyzed by chiral bor ate catalysts has been developed. A BINOL - derived propeller borate 216 was found to be effective in catalyzing the reaction of aromatic al dehydes. A VANOL - derived borate ester 249 was found to be able to catalyze the reaction of a variety of common aromatic and aliphatic aldehydes as well as some heterocycl ic aldehydes . Excellent yields and enantioselectivities have been achieved after subst antial optimization. Furthermore, the 6 - carbon skeleton of saccharides has been synthesized in the reaction of - oxyacetaldehyde with different protecting groups, which can be derivatized into many saccharide analogs. The mechanism of this reaction is prop osed to be concerted based on experiments involving different methods for the reaction quench . 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L.; Williams - Young , D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Hon da, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendel l, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2016. 145 CHAPTER FOUR EXPERIMENTAL SECTION 4.1 General information All reactions were carried out in round bottom flasks with argon balloons unless otherwise indicated. Unless otherwise specified, all solvents used in reactions were strictly dried before use: dichlorometh ane and 1,2 - dichloroethane were distilled over calcium hydride under nitrogen; tetrahydrofuran, ether, and toluene were distilled from sodium and benzophenone under nitrogen; n - pentane, hexanes, cyclohexane, benzene, m - xylene, mesitylene, and anisole were distilled from sodium under nitrogen; 2 - propanol was distilled over calcium oxide under nitrogen. Hexanes and ethyl acetate for column chromatography were ACS grade and used as purchased. Commercially available ketones and aldehydes and other reagents were purchased from Sigma - Aldrich, Alfa - Aesar, Combi - Blocks or Oakwood and were purified by distillation or sublimation unless otherwise indicated. AlMe 3 was purchased from Sigma - Aldrich as a 2 M solution in toluene and wa s used as received. Borane dimethylsulfide ( BH 3 2 S) was purchased from Alfa - Aesar as a 2 M solution in toluene and was used as received. VANOL, VAPOL and their derivatives were made according to known procedures. 1 - 4 Melting points were recorded on a Thom as Hoover capillary melting point apparatus and are uncorrected. The 1 H NMR , 11 B NMR and 13 C NMR spectra were recorded on a Varian Unity Plus 500 MHz spectrometer using CDC l 3 as solvent (unless otherwise noted). The residual peak of CDC l 3 or TMS was used as the 146 internal standard for both 1 H NMR ( = 7.26 ppm for CDC l 3 or = 0 ppm for TMS) and 13 C NMR ( = 77.0 ppm). The 11B NMR spectra were done in a Norell® quartz NMR tube a nd referenced to external standard BF 3 2 O ( = 0 ppm). Chemical shifts were reported in parts per million (ppm). Analytical thin - layer chromatography (TLC) was performed on Silicycle silica gel plates with F - 254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol. Column chromatography was performed with silica gel 60 (230 450 mesh). HPLC analyses were performed using Agilent 1100 or 1260 HPLC System with CHIRA LCEL® OJ - H , OD and OD - H or CHIRALPAK® AD - H, AS - H and IA columns. HPLC grade hexanes (mixture of isomers) and 2 - propanol were used for HPLC analyses. Optical rotations were obtained at a wavelength of 589 nm (sodium D line) using a 1.0 decimeter cell with a total volume of 1.0 mL . Specific rotations are reported in degrees per decimeter at 20 °C and the concentrations are given in gram per 100 mL in chloroform unless otherwise noted. IR spectra were recorded on NaCl disc (for liquids) on a Nicolet IR/42 spec trometer. High Resolution Mass Spectrometry was performed in the Department of Chemistry at Michigan State University Mass Facility. 147 4.2 Experimental information for chapter two 4.2.1 General procedure for catalytic asymmetric MPV reduction of aromatic ketones Procedure A illustrated for acetophenone 55a (R) - 1 - phenylethanol 56 a : To a 5 mL flame - dried round bottom flask equipped with a stir bar was charged ( R ) - L21 (( R ) - - Cy 2 VANOL , 9.8 mg, 0.01625 mmol), 4 Å molecular sieves (25.0 mg, activated), and dry pentane (1 mL ). Then a rubber septum stopper and argon balloon were attached. While s tirring at was added to the reaction flask. After 1 hour, the flask containing the precatalyst was charged with dry 2 - propanol (1.5 mL , 20 mmol) and chilled to e mixture was added acetophenone 55 a - syringe and the resulting mixture was stirred for 24 hours at by the addition of 2 M HCl (1 mL ) and then was warmed to room temperature. The mixture was t ransferred into a 60 mL separatory funnel and added 15 mL water before extracted with CH 2 Cl 2 (15 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Purification of the crude product by silica gel chromatography (15 m m × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56 a as a colorless oil in 88% isolated yield 148 (26.8 mg, 0.22 mmol); The optical purity of 56 a was determined to be 94% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1 mL /min); retention times: R t = 16.7 min (major enantiomer, 56 a ) and R t = 24.0 min (minor enantiomer, ent - 56 a ). Each enantiomer was obtained and confirmed by reducing the keto ne with sodium borohydride in methanol. Spectral data for 56 a : R f = 0.18 ( CH 2 Cl 2 ); = +47.9 ( c =1.0 in CHCl 3 ) 94% ee ( R ) (lit. 5 = +49.0 ( c =1.0 in CHCl 3 ) 98% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.04 (s, 1H), 4.90 (q, J = 6.5, 1H), 7.27 7.32 (m, 1H), 7.34 7.41 (m, 4H); 13 C NMR (126 MHz, CDC l 3 127.47, 128.50, 145.80. These spectral data match those previously reported for this compound. 5 (R) - 1 - (2 - naphthyl)ethanol 56 b : Ketone 55 b was reduced according to procedure A with 10 mol% precatalyst. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56 b as a white solid (m.p. 65 - (33.8 mg, 0.20 mmol); The optical purity of 56 b was determined to be 91% ee by HPLC (CHIRALCEL® OJ - H column, 95:5 hexanes/2 - propanol at 220 nm, flow - rate: 1 mL /min); retention times: R t = 38.5 min (mi nor enantiomer, ent - 56 b ) and R t = 149 52.1 min (major enantiomer, 56 b ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56 b : R f = 0.18 ( CH 2 Cl 2 ); = +40.2 ( c =1.0 in CHCl 3 ) 91% ee ( R ) (lit. 6 = +43.1 ( c =1.2 in CHCl 3 ) 93% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 1.96 (s, 1H), 5.09 (d, J = 6.5, 1H), 7.45 7.55 (m, 3H), 7.80 7.89 (m, 4H); 13 C NMR (126 MHz, CDC l 3 123.81, 125.81, 126.16, 127.68, 127.93, 128.33, 132.91, 133.30, 143.16. These spectral data match those previously reported for this compound. 7 (R) - 1 - (1 - naphthyl)ethanol 56 c : Ketone 55 c was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56 c as a white solid (m.p. 62 - optical purity of 56 c was determined to be 98% ee by HPLC (CHIRALCEL® OD - H column, 90:10 hexanes/2 - propanol at 210 nm, flow - rate: 0.8 mL /min); retention times: R t = 7.0 min (minor enantiomer, ent - 56 c ) and R t = 11.1 min (major enantiomer, 56 c ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. 150 Spectral data for 56 c : R f = 0.18 ( CH 2 Cl 2 ); = +74.5 ( c =1.0 in CHCl 3 ) 98% ee ( R ) (lit. 6 = +69.7 ( c =1.1 in Et 2 O) 90% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.22 (s, 1H), 5.66 (q, J = 6.5, 1H), 7.45 7.58 (m, 3H), 7.68 (dt, J = 7.1, 1.0, 1H), 7.80 (dt, J = 8.1, 1.0, 1H), 7.90 (dd, J = 8.0, 1.7, 1H), 8.07 8.13 (m, 1H); 13 C NMR (126 MHz, CDC l 3 123.18, 125.55, 125.56, 126.04, 127.93, 128.90, 130.26, 133.79, 14 1.38. These spectral data match those previously reported for this compound. 7 (S) - 2,2,2 - trifluoro - 1 - phenylethanol 56d : Ketone 55d was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56d as a colorless oil in 71% isolated yield (31.2 mg, 0.18 mmol); The optical purity of 56d was determined to be 96% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 33.2 min (major enantiomer, 56d ) and R t = 43.3 min (minor enantiomer, ent - 56d ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56d : R f = 0.16 ( CH 2 Cl 2 ); = +23.4 ( c =1.0 in CHCl 3 ) 96% ee ( S ) (lit. 8 = +28.4 ( c =1.3 in CHCl 3 ) 95% ee ( S )). 1 H NMR (500 MHz, 151 CDC l 3 J = 6.8, 1H), 7.44 (dd, J = 5.0, 2.0, 3H), 7.49 (dd, J = 6.9, 3.0, 2H); 13 C NMR (126 MHz, CDC l 3 J = 32.0), 124.22 (q, J = 282.2), 127.46, 128.65, 129.60, 133.90. These spectral data match tho se previously reported for this compound. 8 (S) - 2 - chloro - 1 - phenylethanol 56e : Ketone 55 e was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 h exanes/ EtOAc as eluent) afforded pure alcohol 56 e as a colorless oil in 98% isolated yield (38.5 mg, 0.24 mmol); The optical purity of 56 e was determined to be 99% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 18.6 min (major enantiomer, 56 e ) and R t = 23.5 min (minor enantiomer, ent - 56 e ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56 e : R f = 0.17 ( CH 2 Cl 2 ); = +53.8 ( c =1.0 in CHCl 3 ) 99% ee ( S ) (lit. 5 = +51.5 ( c =1.1 in cyclohexane) 95% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 11.3, 8.8, 1H), 3.76 (dd, J = 11.3, 3.4, 1H), 4.92 (dd, J = 8.9, 3.4, 1H), 7.32 7.43 (m, 5H); 13 C NMR (126 MHz, CDC l 3 ) 152 These spectral data match those previously reported for this compound. 9 (S) - 2,2 - dichloro - 1 - phenylethanol 56 f : Ketone 55 f was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pu re alcohol 56 f as a colorless oil in 94% isolated yield (44.8 mg, 0.24 mmol); The optical purity of 56 f was determined to be >99% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 31.9 min (sole enantiomer, 56 f ). Both 56 f and its enantiomer ent - 56 f were obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56 f : R f = 0.17 ( CH 2 Cl 2 ); = +27.2 ( c =1.0 in CHCl 3 ) >99% ee ( S ) (lit. 10 = - 21.7 ( c =1.0 in CHCl 3 ) >99% ee ( R ) ). 1 H NMR (500 MHz, CDC l 3 J = 5.4, 1H), 5.83 (d, J = 5.4, 1H), 7.35 7.46 (m, 5H); 13 C NMR (126 MHz, CDC l 3 These spectral d ata match those previously reported for this compound. 10 153 (R) - 2 - bromo - 1 - phenylethanol 56 g : Ketone 55 g was reduced according to procedure A with ( S ) - L21 silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56 g as a yellow oil in 87% isolated yield (43.5 mg, 0.22 mmol); The optical purity of 56 g was determined to be 97% ee by HPLC (CHIRALCEL® OD - H column, 98:2 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: 13.0 min (minor enantiomer, ent - 56 g ) and R t = 15.8 min (major enantiomer, 56 g ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56 g : R f = 0.17 ( CH 2 Cl 2 ); = - 40.1 ( c =1.0 in CHCl 3 ) 97% ee ( R ) (lit. 8 = +42.3 ( c =1.5 in CH 2 Cl 2 ) 97% ee ( S ) ). 1 H NMR (500 MHz, CDC l 3 J = 10.5, 9.0, 1H), 3.63 (dd, J = 10.5, 3.3, 1H), 4.91 (dd, J = 9.0, 2.6, 1H), 7.28 7.42 (m, 5H); 13 C NMR (126 MHz, CDC l 3 40.27, 73.81, 125.96, 128.48, 128.70, 140.24. These spectral data match those previously reported for this compound. 8 154 (S) - 2 - bromo - 1 - (4 - nitrophenyl)ethanol 56h : Ketone 55h was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforde d pure alcohol 56h as a white solid (m.p. 94 - (58.1 mg, 0.24 mmol); The optical purity of 56h was determined to be 98% ee by HPLC (CHIRALCEL® OJ - H column, 90:10 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention tim es: R t = 28.0 min (minor enantiomer, ent - 56h ) and R t = 30.3 min (major enantiomer, 56h ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. The Crystal structure of 56h was solved and absolute configuration was confirmed. C CDC 1903110 contains details for it and could be found from The Cambridge Crystallographic Data Centre via www.c cdc .cam.ac.uk/structures. Spectral data for 56h : R f = 0.16 ( CH 2 Cl 2 ); = +31.4 ( c =1.0 in CHCl 3 ) 98% ee ( S ) (lit. 6 = +29.6 ( c =1.1 in CHCl 3 ) 90% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 3.6, 1H), 3.53 (dd, J = 10.6, 8.4, 1H), 3.68 (dd, J = 10.6, 3.4, 1H), 5.05 (s, 1H), 7.55 7.63 (m, 2H), 8.21 8.28 (m, 2H); 1 3 C NMR (126 MHz, CDC l 3 data match those previously reported for this compound. 17 155 (R) - 1 - (pentafluorophenyl)ethanol 56i : Ketone 55i was reduced according to procedure A with 10 mol% precatalyst. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtO Ac as eluent) afforded pure alcohol 56i as a colorless oil in 80% isolated yield (42.4 mg, 0.20 mmol); The optical purity of 56i was determined to be 99% ee by HPLC (C HIRALPAK ® AD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 0.8 mL /min); retenti on times: R t = 19.4 min (minor enantiomer, ent - 56i ) and R t = 24.0 min (major enantiomer, 56i ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56i : R f = 0.16 ( CH 2 Cl 2 ); = +13.6 ( c =1.0 in CHCl 3 ) 99% ee ( R ) (lit. 11 = +13.0 ( c =1.1 in CHCl 3 ) >99% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.8, 0.8, 3H), 2.68 (d, J = 6.8, 1H), 5.24 (t, J = 6.8, 1H); 13 C NMR (126 MHz, CDC l 3 144.57 (m). These spectral data match those previously reported for this co mpound. 11 156 (R) - 1 - (2 - chlorophenyl)ethanol 56k : Ketone 55k was reduced according to procedure A after 16 hours. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56k as a colorless oil in 96% isolated yield (37.7 mg, 0.24 mmo l); The optical purity of 56k was determined to be 99% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 12.0 min (major enantiomer, 56k ) and R t = 13.2 min (minor enantiomer, ent - 56k ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56k : R f = 0.17 ( CH 2 Cl 2 ); = +60.7 ( c =1.0 in CHCl 3 ) 99% ee ( R ) (lit. 9 = +61.4 ( c =1.0 in CHCl 3 ) 94% ee ( R )). 1 H NMR (500 MHz, CDC l 3 1.52 (m, 3H), 2.17 (s, 1H), 5.30 (q, J = 6.4, 1H), 7.21 (td, J = 7.6, 1.7, 1H), 7.28 7.36 (m, 2H), 7.60 (dd, J = 7.8, 1.7, 1H); 13 C NMR (126 MHz, CDC l 3 These spectral data match those previously reported for this compound. 9 157 (R) - 1 - (2 - bromophenyl)ethanol 56l : Ketone 55l was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56l as a colorless oil in 90% isolated yield (45.1 mg, 0.22 mmol); The optical purity of 56l was determined to be 99% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 11.8 min (major enantiomer, 56l ) and R t = 13.6 min (minor enantiomer, ent - 56l ). Each en antiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56l : R f = 0.17 ( CH 2 Cl 2 ); = +47.0 ( c =1.0 in CHCl 3 ) 99% ee ( R ) (lit. 8 = +50.8 ( c =2.4 in CH 2 Cl 2 ) 83% ee ( R )). 1 H NMR (500 MHz, CDC l 3 ) J = 6.4, 3H), 2.26 (s, 1H), 5.24 (q, J = 6.4, 1H), 7.13 (td, J = 7.6, 1.7, 1H), 7.35 (td, J = 7.7, 1.2, 1H), 7.52 (dd, J = 8.0, 1.2, 1H), 7.59 (dd, J = 7.8, 1.7, 1H); 13 C NMR (126 MHz, CDC l 3 121.69, 126.66, 127.85, 128.77, 132.64, 144.59. These spectral data match those previously reported for this compound. 8 158 (R) - 1 - (2 - iodophenyl)ethanol 56m : Ketone 55m was reduced accordi ng to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56m as a white solid (m.p. 68 - optical purity of 56m was determined to be 99% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 12.8 min ( major enantiomer, 56m ) and R t = 14.6 min (minor enantiomer, ent - 56m ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56m : R f = 0.17 ( CH 2 Cl 2 ); = +67.0 ( c =1.0 in CHCl 3 ) 99% ee ( R ) (lit. 12 = +43.9 ( c =0.5 in CHCl 3 ) 99% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.4, 3H), 2.29 (s, 1H), 5.06 (q, J = 6.4, 1H), 6.93 7.01 (m, 1H), 7.38 (td, J = 7.5, 1.2, 1H), 7.56 (dd, J = 7.8, 1.7, 1H), 7.80 (dd, J = 7.9, 1. 2, 1H); 13 C NMR (126 MHz, CDC l 3 139.30, 147.45. These spectral data match those previously reported for this compound. 13 159 (S) - 1 - (2 - methylphenyl)ethanol 56n : Ketone 55n was reduced according to procedure A with 10 mol% precatalyst made from ( S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5 :1 hexanes/ EtOAc as eluent) afforded pure alcohol 56n as a colorless oil in 94% isolated yield (32.1 mg, 0.24 mmol); The optical purity of 56n was determined to be 96% ee by HPLC (C HIRALPAK ® AD - H column, 98:2 hexanes/2 - propanol at 210 nm, flow - rate: 0.8 m L /min); retention times: R t = 15.7 min (minor enantiomer, ent - 56n ) and R t = 17.8 min (major enantiomer, 56n ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56n : R f = 0.18 ( CH 2 Cl 2 ); = - 54.1 ( c =1.0 in CHCl 3 ) 96% ee ( S ) (lit. 13 = +56.9 ( c =0.41 in EtOH) 94% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.4, 3H), 1.76 (s, 1H), 2.36 (s, 3H), 5.15 (q, J = 6.4, 1H), 7.13 7.21 (m, 2H), 7.23 7.28 (m, 1H), 7.50 7.56 (m, 1H); 13 C NMR (126 MHz, CDC l 3 3.82. These spectral data match those previously reported for this compound. 13 160 (R) - 1 - (2 - methoxyphenyl)ethanol 56o : Ketone 55o was reduced according to procedure A after 16 hours. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56o as a colorless oil in 93% isolated yield (35.5 mg, 0.23 mmo l); The optical purity of 56o was determined to be 94% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 17.8 min (minor enantiomer, ent - 56o ) and R t = 19.2 min (major enantiomer, 56o ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56o : R f = 0.18 ( CH 2 Cl 2 ); = +28.1 ( c =1.0 in CHCl 3 ) 94% ee ( R ) (lit. 13 = +24.8 ( c =2.0 in CHCl 3 ) 90% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.77 (s, 1H), 3.87 (s, 3H), 5.11 (d, J = 6.5, 1H), 6.90 (dd, J = 8.2, 1.0, 1H), 6.98 (td, J = 7.5, 1.0, 1H), 7.24 7.29 (m, 1H), 7.36 (dd, J = 7.5, 1.7, 1H); 13 C NMR (126 MHz, CDC l 3 1, 110.40, 120.79, 126.09, 128.29, 133.41, 156.52. These spectral data match those previously reported for this compound. 13 161 (R) - 1 - (3 - bromophenyl)ethanol 56p : Ketone 55p was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure a lcohol 56p as a colorless oil in 91% isolated yield (45.5 mg, 0.23 mmol); The optical purity of 56p was determined to be 97% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 17.6 min (minor enantiomer, ent - 56p ) and R t = 19.5 min (major enantiomer, 56p ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol. Spectral data for 56p : R f = 0.17 ( CH 2 Cl 2 ); = +46.5 ( c =1.0 in CHCl 3 ) 97% ee ( R ) (lit. 14 = +45.0 ( c =1.0 in CHCl 3 ) 96% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.21 (s, 1H), 4.84 (q, J = 6.5, 1H), 7.21 (t, J = 7.7, 1H), 7.28 (dt, J = 7.7, 1.4, 1H), 7.40 (ddd, J = 7.8, 2.0, 1.2, 1H), 7.53 (t, J = 1.9, 1H); 13 C NMR (126 MHz, CDC l 3 130.45, 148.10. These spectral data match those previously reported for this compound. 14 162 (S) - 1 - (3 - methylphenyl)ethanol 56q : Ketone 55q was reduced according to procedure A with 10 mol% precatalyst made from ( S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56q as a colorless oil in 82% isolated yield (27.8 mg, 0.20 mmol); The optical purity of 56q was determined to be 9 0% ee by HPLC (CHIRALCEL® OD - H column, 98:2 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 9.0 min (minor enantiomer, ent - 56q ) and R t = 12.4 min (major enantiomer, 56q ). Each enantiomer was obtained and confirmed by reducing th e ketone with sodium borohydride in methanol. Spectral data for 56q : R f = 0.17 ( CH 2 Cl 2 ); = - 35.9 ( c =1.0 in CHCl 3 ) 90% ee ( S ) (lit. 15 = - 29.2 ( c =0.5 in EtOH) 74% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.06 (s, 1H), 2.38 (d, J = 0.7, 3H), 4.87 (q, J = 6.5, 1H), 7.11 (ddt, J = 7.4, 1.8, 0.9, 1H), 7.15 7.22 (m, 2H), 7.26 (t, J = 7.5, 1H); 13 C NMR (126 MHz, CDC l 3 138.15, 145.80. These spe ctral data match those previously reported for this compound. 15 163 (S) - 1 - (3 - methoxyphenyl)ethanol 56r : Ketone 55r was reduced according to S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56r as a colorless oil in 84% isolated yield (32.0 mg, 0.21 mmol); The optical purity of 56r was determined to be 8 8% ee by HPLC (CHIRALCEL® OD - H column, 98:2 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 18.6 min (minor enantiomer, ent - 56r ) and R t = 24.1 min (major enantiomer, 56r ). Racemic product was prepared from reducing the ketone wi th sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retention time with racemic product under sam e HPLC conditions. Spectral data for 56r : R f = 0.18 ( CH 2 Cl 2 ); = - 40.1 ( c =1.0 in CHCl 3 ) 88% ee ( S ) (lit. 13 = +38.1 ( c =1.0 in CHCl 3 ) 96% ee ( R )). 1 H NMR (500 MHz, CDC l 3 ) J = 6.4, 3H), 2.06 (s, 1H), 3.82 (s, 3H), 4.87 (q, J = 6.5, 1H), 6.82 (ddd, J = 8.2, 2.5, 1.1, 1H), 6.93 6.97 (m, 2H), 7.27 (t, J = 8.1, 1H); 13 C NMR (126 MHz, CDC l 3 These spectral dat a match those previously reported for this compound. 13 164 (S) - 1 - (4 - nitrophenyl)ethanol 56s : Ketone 55s was reduced according to procedure A with ( S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) af forded pure alcohol 56s as a colorless oil in 92% isolated yield (38.5 mg, 0.23 mmol); The optical purity of 56s was determined to be 97% ee by HPLC (CHIRALPAK® AS - H column, 90:10 hexanes/2 - propanol at 254 nm, flow - rate: 1.0 mL /min); retention times: R t = 18.6 min (minor enantiomer, ent - 56s ) and R t = 21.5 min (major enantiomer, 56s ). Racemic product was prepared from reducing the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched p roduct. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retention time with racemic product under same HPLC conditions. Spectral data for 56s : R f = 0.15 ( CH 2 Cl 2 ); = - 31.8 ( c =1.0 in CHCl 3 ) 97% ee ( S ) (lit. 8 = +27.1 ( c =2.2 in CH 2 Cl 2 ) 98% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.04 2.25 (m, 1H), 5.02 (q, J = 6.5, 1H), 7.49 7.59 (m, 2H), 8.17 8.24 (m, 2H); 13 C NMR (126 MHz, CDC l 3 123.76, 126.12, 147.13, 153. 09. These spectral data match those previously reported for this compound. 8 165 (R) - 1 - (4 - trifluoromethylphenyl)ethanol 56t : Ketone 55t was reduced according to procedure A. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56t as a colorless oil in 91% isolated yield (43.2 mg, 0.23 mmol); The optical purity of 56t was determined to be 97% ee by HPLC (CHIRALCEL® OJ - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 20.3 min (minor enantiomer, ent - 56t ) and R t = 22.7 min (major enantiomer, 56t ). Racemic product was prepared from reducing the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retentio n time with racemic product under same HPLC conditions. Spectral data for 56t : R f = 0.16 ( CH 2 Cl 2 ); = +25.4 ( c =1.0 in CHCl 3 ) 97% ee ( R ) (lit. 13 = +17.9 ( c =0.5 in CHCl 3 ) 94% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 2.23 (s, 1H), 4.95 (q, J = 6.5, 1H), 7.45 7.51 (m, 2H), 7.58 7.63 (m, 2H); 13 C NMR (126 MHz, CDC l 3 J = 273), 125.42 (q, J = 3.8), 125.63, 129.58 (q, J = 32.4), 149.66. These spectral data match those previously r eported for this compound. 13 166 (R) - 1 - (4 - bromophenyl)ethanol 56u : Ketone 55u was reduced according to procedure A after 6 hours. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) a fforded pure alcohol 56u as a colorless oil in 94% isolated yield (47.0 mg, 0.23 mmol); The optical purity of 56u was determined to be 96% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 16.9 min (minor enantiomer, ent - 56u ) and R t = 18.7 min (major enantiomer, 56u ). Racemic product was prepared from reducing the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retention time with racemic product under same HPLC conditions. Spectral data for 56u : R f = 0.17 ( CH 2 Cl 2 ); = +35.1 ( c =1.0 in CHCl 3 ) 96% ee ( R ) (lit. 8 = +36.0 ( c =1.7 in CH 2 Cl 2 ) 95% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.5, 1.0, 3H), 2.20 (s, 1H), 4.84 (q, J = 6.4, 1H), 7.23 (d, J = 8.1, 2H), 7.46 (d, J = 7.4, 2H); 13 C NMR (126 MHz, CDC l 3 121.12, 127.15, 131.52, 144.76. These spectral data match those previously reported for this compound. 8 167 (S) - 1 - (4 - iodophenyl)ethanol 56v : Ketone 55v was reduced according to procedure A with 10 mol% precatalyst made from ( S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56v as a yellow solid (m.p. 46 - 89% isolated yield (54.9 mg, 0.22 mmol); The optical purity of 56v was det ermined to be 93% ee by HPLC (CHIRALCEL® OD - H column, 98:2 hexanes/2 - propanol at 220 nm, flow - rate: 0.8 mL /min); retention times: R t = 14.7 min (major enantiomer, 56v ) and R t = 15.6 min (minor enantiomer, ent - 56v ). Racemic product was prepared from reducin g the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retention time with racemic pr oduct obtained under same HPLC conditions. Spectral data for 56v : R f = 0.17 ( CH 2 Cl 2 ); = - 37.0 ( c =1.0 in CHCl 3 ) 93% ee ( S ) (lit. 12 = +25.3 ( c =0.6 in CHCl 3 ) 99% ee ( R )). 1 H NMR (500 MHz, CDC l 3 J = 6.6, 1.4, 3H), 1.94 (s, 1H), 4.85 (d, J = 6.4, 1H), 7.13 (dd, J = 8.3, 1.6, 2H), 7.68 (dd, J = 8.3, 1.5, 2H); 13 C NMR (126 MHz, CDC l 3 168 69.85, 92.73, 127.41, 137.52, 145.44. These spectral data match those previously reported for this compound. 16 (S) - 1 - (4 - methylphenyl)ethanol 56w : Ketone 55w was reduced according to procedure A with 10 mol% precatalyst made from ( S ) - L21 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56w as a colorless oil in 70% isola ted yield (23.7 mg, 0.17 mmol); The optical purity of 56w was determined to be 92% ee by HPLC (CHIRALCEL® OJ - H column, 95:5 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 10.2 min (major enantiomer, 56w ) and R t = 12.5 min (mino r enantiomer, ent - 56w ). Racemic product was prepared from reducing the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantio mer was confirmed by comparing the retention time with racemic product under same HPLC conditions. Spectral data for 56w : R f = 0.17 ( CH 2 Cl 2 ); = - 42.3 ( c =1.0 in CHCl 3 ) 92% ee ( S ) (lit. 16 = - 33.4 ( c =1.0 in EtOH) 81% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 6.6, 3H), 2.40 (s, 3H), 2.62 (s, 1H), 4.84 (d, J = 6.5, 1H), 7.19 (d, J = 7.9, 2H), 7.28 (d, J = 7.9, 2H); 13 C NMR (126 MHz, CDC l 3 169 25.14, 70.11, 125.43, 129.13, 137.00, 143.02. These spectral data match those previously reported for this compound. 16 (S) - 2 - bromo - 1 - (4 - methoxyphenyl)ethanol 56y : Ketone 55y was reduced according to procedure A with 10 mol% preca talyst. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 56y as a colorless oil in 71% isolated yield (40.8 mg, 0.18 mmol); The optical purity of 56y was determined t o be 83% ee by HPLC (CHIRALCEL® OD - H column, 95:5 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 9.6 min (minor enantiomer, ent - 56y ) and R t = 11.9 min (major enantiomer, 56y ). Racemic product was prepared from reducing the ketone with sodium borohydride in methanol. Purification of the crude racemic product was the same as it for enantioenriched product. HPLC for racemic product was obtained. Each enantiomer was confirmed by comparing the retention time with racemic product under same HPLC conditions. Spectral data for 56y : R f = 0.17 ( CH 2 Cl 2 ); = +26.6 ( c =1.0 in CHCl 3 ) 83% ee ( S ) (lit. 6 = +36.7 ( c =1.0 in CHCl 3 ) 98% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 10.4, 9.0, 1H), 3.60 (dd, J = 10.4, 3.5, 1H), 3.81 (s, 3H), 4.88 (dd, J = 9.0, 3.4, 1H), 6.88 6.93 (m, 2H), 7.28 7.34 (m, 2H); 170 13 C NMR (126 MHz, CDC l 3 159.65. These spectral data match those previously reported for this compound. 6 4.2.2 General procedure for catalytic asymmetric MPV reduction of aliphatic ketones Procedure B illustrated for 1 - adamantyl methyl ketone 57c (S) - 1 - (1 - adamantyl)ethyl 4 - fluorobenzoate S1c : To a 5 mL flame - dried round bottom flask equipped with a stir bar was charged ( S ) - L30 (( S ) - - i Pentyl 2 VANOL , 9.4 mg, 0.01625 mmol), 4 Å molecular sieves (25.0 mg, activated), and dry pentane (1 mL ). Then a rubber septum stopper and argon balloon were attached. While stirring at room temperature, trimethylaluminum as added to the reaction flask. After 1 hour, the flask containing the precatalyst was charged with dry 2 - propanol (1.5 171 mL , 20 mmol) and chilled to - adamantyl methyl ketone 57c (44.6 mg, 0.25 mmol) and the resulting mixtur e was stirred for 24 hours at mL ) and then was warmed to room temperature. The mixture was transferred into a 60 mL separatory funnel and added 15 mL water before extracted with CH 2 Cl 2 (15 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol 58c . Then to another 5 mL fla me - dried round bottom flask equipped with a stir bar was charged 58c mmol) and dry CH 2 Cl 2 (2.5 mL ). Then a rubber septum stopper and argon balloon were attached. While stirring at room tempe rature, 4 - fluorobenzoyl chloride (35.5 12 h at room temperature before quenched by 2 mL water. The mixture was transferred into a 60 mL separatory funnel and added 15 mL wa ter before extracted with CH 2 Cl 2 (15 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, hexanes as eluent) afforded pure chiral e ster S1c as a colorless oil in 84% yield over two steps (63.3 mg, 0.21 mmol). The optical purity of S1c was determined to be 94% ee by HPLC (CHIRALPAK® IA column, 100% hexanes at 220 nm, flow - rate: 1.0 mL /min); retention times: R t = 12.7 min (minor enantiomer, ent - S1c ) and R t = 13.8 min (major enantiomer, S1c ). 172 Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol followed by making its 4 - fluorobenzoate derivative. Spectral data for S1c : R f = 0.30 (hexanes); = +38.9 ( c =1.0 in CHCl 3 ) 94% ee ( S ); 1 H NMR (500 MHz, CDC l 3 J = 6.5, 3H), 1.59 1.69 (m, 9H), 1.71 1.79 (m, 3H), 1.98 2.06 (m, 3H), 4.78 (d, J = 6.5, 1H), 7.10 7.15 (m, 2H), 8.03 8.12 (m, 2H); 13 C NMR (126 MHz, CDC l 3 37.09, 38.05, 78.62, 115.43 (d, J = 21.9), 127.20 (d, J = 2.9), 132 .01 (d, J = 9.1), 165.25, 165.60 (d, J = 253.26); IR (NaCl): - 1 ; HRMS (ESI - TOF) m/z 325.1581 [(M - Na + ); calcd. for C 19 H 23 FNaO 2 : 325.1580]. (S) - 1 - cyclohexylethyl 4 - fluorobenzoate S1b : Crude chiral ester S1b was achieved according to procedure B. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, hexanes as eluent) afforded pure 173 chiral ester S1b as a colorless oil in 81% yield over two steps (50.4 mg, 0.20 mmol). The optical purity of S1b was determined to be 88% ee by HPLC (CHIRALPAK® IA column, 99.9:0.1 hexanes/2 - propanol at 220 nm, flow - rate: 1.0 mL /min); retention times: R t = 9.4 min (minor enantiomer, ent - S1b ) and R t = 10.0 min (major enantiomer, S1b ). Each enantiomer was obtained and confirmed by reducing the ketone with sodium borohydride in methanol followed by making its 4 - fluorobenzoate derivative. Spectral data for S1b : R f = 0.30 (hexanes); = +21.5 ( c =1.0 in CHCl 3 ) 88% ee ( S ); 1 H NMR (500 MHz, CDC l 3 1.25 (m, 5H), 1.27 (d, J = 6.4, 3H), 1.51 1.61 (m, 1H), 1.61 1.87 (m, 5H), 4.96 (t, J = 6.3, 1H), 7.04 7.13 (m, 2H), 8.01 8.08 (m, 2H); 13 C NMR (126 MHz, CDC l 3 26.37, 28.44, 28.65, 42.74, 75.39, 115.31 (d, J = 21.9), 127.14 (d, J = 2.9), 131.97 (d, J = 9.4), 165.10, 165.58 (d, J = 253.26); IR (NaCl): 2852 (s), 1716 (s), 1603 (s), 1275 (s), 1237 (s) cm - 1 ; HRMS (ESI - TOF) m/z 273.1265 [(M - Na + ); calcd. for C 15 H 13 FNaO 2 : 273.1267]. (S) - 4 - phenyl - butan - 2 - ol 58a : Ketone 57a was reduced according to S ) - L30 . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 5:1 hexanes/ 174 EtOAc as eluent) afforded pure alcohol 58a as a colorless oil in 91% isolated yield (34.0 mg, 0.23 mmol); The optical purity of 58a was determined to be 8 2% ee by HPLC (CHIRALCEL® OD - H column, 97:3 hexanes/2 - propanol at 210 nm, flow - rate: 1.0 mL /min); retention times: R t = 8.8 min (minor enantiomer, ent - 58a ) and R t = 13.8 min (major enantiomer, 58a ). Each enantiomer was obtained and confirmed by reducing th e ketone with sodium borohydride in methanol. Spectral data for 58a : R f = 0.16 ( CH 2 Cl 2 ); = +20.4 ( c =1.0 in CHCl 3 ) 82% ee ( S ) (lit. 18 = +7.9 ( c =1.0 in CHCl 3 ) 33% ee ( S )). 1 H NMR (500 MHz, CDC l 3 J = 6.2, 3H), 1.61 (s, 1H), 1.79 (m, 2H), 2.70 (dd, J = 9.4, 6.9, 1H), 2.76 (dd, J = 9.5, 6.1, 1H), 3.79 3.90 (m, 1H), 7.17 7.25 (m, 3H), 7.31 (td, J = 7.3, 1.4, 2H); 13 C NMR (126 MHz, CDC l 3 125.83, 128.41, 142.06 (one sp 2 carbon not located). These spectral data match those previously reported for this compound. 18 4.2.3 Procedure for gram scale synthesis (S) - 2 - bromo - 1 - phenylethanol (S) - 56g : To a 100 mL flame - dried round bottom flask equipped with a stir bar was charged ( R ) - L21 (( R ) - - Cy 2 VANOL , 62.7 mg, 0.104 mmol), 4 Å molecular sieves (800 mg, activated), and dry pentane (16 mL ). Then a rubber septum s topper and argon balloon were attached. While 175 toluene) was added to the reaction flask. After 1 hour, the flask containing the precatalyst was charged with dry 2 - propanol (2 4 mL , 320 mmol) and chilled to 0 - bromoacetophenone 55g (1.59 g, 8 mmol) and by the addition of 2 M HCl (30 mL ) and then was warmed to room temp erature. The mixture was transferred into a 250 mL separatory funnel and added 30 mL water before extracted with CH 2 Cl 2 (60 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Purification of the crude product by silica gel chromatography (30 mm × 200 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure alcohol ( S ) - 56g as a pale yellow oil in 90% isolated yield (1.44 g, 7.2 mmol); The optical purity of ( S ) - 56g was determined to be 97% ee by HPLC (CHIRALCEL® OD - H column, 98:2 hexanes/2 - propanol at 210 nm, flow - rate: 1 mL /min); retention times: R t = 12.9 min (major enantiomer, ( S ) - 56g ) and R t = 16.1 min (minor enantiomer, ( R ) - 56g ). Spectral data for ( S ) - 56g : = +37.4 ( c =1.0 in CHCl 3 ) 97% ee ( S ) (lit. 8 = +42.3 ( c =1.5 in CH 2 Cl 2 ) 97% ee ( S ) ); NMR spectra are the same as its enantiomer ( R ) - 56g . (S) - styrene oxide 59 : To a 100 mL flame - dried round bottom flask equipped with a stir bar was added (S) - 56g (1.44 g, 7.2 mmol), anhydrous potassium carbonate (1.49 g, 10.8 mmol) and dry THF (40 mL ). Then an oven - dried 176 condenser was attached and the mixture was refluxed and stirred for 24 hours in room temperature and added 50 mL water. The mixture was transferred into a 250 mL separatory funnel and was extracted with diethyl ether (60 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Purification of the crud e product by silica gel chromatography (30 mm × 200 mm column, 10:1 hexanes/ EtOAc as eluent) afforded pure epoxide 59 as a colorless oil in 86% isolated yield (0.75 g, 6.2 mmol); The optical purity of 59 was determined to be 97% ee by HPLC (CHIRALCEL® OD - H column, 99.9:0.1 hexanes/2 - propanol at 210 nm, flow - rate: 1 mL /min); retention times: R t = 8.1 min (major enantiomer, 59 ) and R t = 8.9 min (minor enantiomer, ent - 59 ). Spectral data for 59 : R f = 0.6 ( CH 2 Cl 2 ); = +25.7 ( c =1.0 in CHCl 3 ) 97% ee ( S ) (lit. 19 = - 24 ( c =1.0 in CHCl 3 ) >99% ee ( R )). 1 H NMR (500 MHz, CDC l 3 ) J = 5.5, 2.6, 1H), 3.15 (dd, J = 5.5, 4.1, 1H), 3.89 (dd, J = 4.1, 2.5, 1H), 7.31 7.43 (m, 5H); 13 C NMR (126 MHz, CDC l 3 128.23, 128.56 , 137.75. These spectral data match those previously reported for this compound. 19 4.2.4 Procedure for resolution of racemic alcohols 177 Procedure C Oxidative kinetic resolution of racemic 56a (R) - 1 - phenylethanol 56a : To a 5 mL flame - dried round bottom flask equipped with a stir bar was charged ( S ) - L21 (( S ) - - Cy 2 VANOL , 19.6 mg, 0.0 325 mmol), and dry pentane ( 2.5 mL ). Then a rubber septum stopper and argon balloon were attached. While stirring at room temperature, trimethylaluminum solution ( 12 . 4 25 mmol, 2 M in toluene) was added to the reaction flask. After 1 hour, the flask containing the precatalyst was charged with racemic 56a ( 0.25 mmol , ) and chilled to 4 ne ( 11 0. 1 5 mmol) via micro - syringe and the resulting mixture was stirred for 24 hours at 4 mL ) and then was warmed t o room temperature. The mixture was transferred into a 60 mL separatory funnel and added 15 mL water before extracted with CH 2 Cl 2 (15 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Triphenylmethane was added as internal standard to determine NMR yield and 46% 56a with 54% 55a was observed. The optical purity of 56a was determined to be 83 % ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1 mL /min); retention times: R t = 16.7 min (major enantiomer, 56a ) and R t = 24.0 min (minor enantiomer, ( S ) - 56a ). Procedure D Formal dynamic kinetic resolution of racemic 56a 178 (S) - 1 - phenylethanol ( S ) - 56a : To a 5 mL flame - dried round bottom flask equipped with a stir bar was charged ( S ) - L21 (( S ) - - Cy 2 VANOL , 19.6 mg, 0.0325 mmol), and dry pentane (2.5 mL ). Then a rubber septum stopper and argon balloon were attached. While stirring at room temperature, trimethylaluminum 1 h our, the flask containing the precatalyst was charged with racemic 56a (0.25 cyclohexan one ( 3 3 mmol) via micro - syringe and the resulting mixture was stirred for 1 hour at room temperature . The reaction mixtu re was then chilled to - propanol (1 stirring for 24 hours t he reaction was quenched by the addition of 2 M HCl (1 mL ) and then was warmed to room temperature. The mixture was transferred into a 60 mL separator y funnel and added 15 mL water before extracted with CH 2 Cl 2 (15 mL × 3). Combined organic layer was concentrated under vacuum to afford the crude product. Triphenylmethane was added as internal standard to determine NMR yield and 79 % 56a was observed. The optical purity of 56a was determined to be 7 3% ee by HPLC (CHIRALCEL® OD - H column, 99:1 hexanes/2 - propanol at 210 nm, flow - rate: 1 mL /min); retention times: R t = 16.7 min (m in or enantiomer, ( R ) - 56a ) and R t = 24.0 min (m aj or enantiomer, ( S ) - 56a ). 4.2.5 Computational study Computations have been achieved with both Hartree - Fock and density functional theory in Gaussian 16 20 . Geometry optimizations were carried out at 179 HF/3 - 21G* or B3LYP/6 - 31G(d) level of theory in vacuum. Transition states of this asymmetric MPV reduction of acetophenone 55a and 2 - bromoacetophenone 55g were simulated at HF/3 - 21G* or B3LYP/6 - 31G(d) level in vacuum and in three solvent: toluene, n - pentane and 2 - propanol with CPCM as solvation method. The conf ormation of alkyl groups on ligands is considered. For example, two calculations (TS - R - Me and TS - S - - Me 2 VANOL ( L17 ), with each calculation shows the transition state towards R or S product. - Et 2 VANOL ( L18 ), four calculations of different conformers (from the rotation of two ethyl group s ) towards each product have been done . For each TS - S or TS - R, t he one with lowest energy was chosen as real transition state . The free energy - S and TS - R - R) - S)) and analyzed for 30 different ligands shown in Figure 2.3. The simulations in the reduction of acetophenone 55a have been achieved and analyzed in Table 4.1 to Table 4.5. Table 4.1 shows free energies calc ulated under HF/3 - 21G* level in vacuum. Table 4.2 shows free energies calculated under B3LYP/6 - 31G(d) level in vacuum. Table 4.3 shows free energies calculated under B3LYP/6 - 31G(d) level in toluene with CPCM as solvation method. Table 4.4 shows free energies calculated under B3LYP/6 - 31G(d) level in n - pentane with CPCM as solvation method. Table 4.5 shows free energies calculated under B3LYP/6 - 31G(d) level in 2 - propanol with CPCM as s olvation method. Results obtained in the reduction of 2 - bromoacetophenone 55g under HF/3 - 21G* level in vacuum are shown in Table 4.6. 180 Table 4. 1 Free energy differences by HF/3 - 21G* in vacuum 181 Table 4.1 182 Table 4.1 183 Table 4.1 184 Table 4.1 Table 4. 2 Free energy differences by B3LYP/6 - 31G(d) in vacuum 185 Table 4. 2 186 Table 4. 2 187 Table 4. 2 188 Table 4. 2 Table 4. 3 Free energy differences by B3LYP/6 - 31G(d) in toluene 189 Table 4. 3 190 Table 4. 3 191 Table 4. 3 192 Table 4. 3 193 Table 4. 3 Table 4. 4 Free energy differences by B3LYP/6 - 31G(d) in n - pentane 194 Table 4. 4 195 Table 4. 4 196 Table 4. 4 197 Table 4. 4 Table 4. 5 Free energy differences by B3LYP/6 - 31G(d) in 2 - propanol 198 Table 4. 5 199 Table 4. 5 200 Table 4. 5 201 Table 4. 5 Table 4.6 by HF/3 - 21G* in vacuum for 2 - bromoacetophenone 55g 202 Table 4. 6 203 Table 4. 6 204 Table 4. 6 205 Table 4. 6 206 Table 4. 6 In the reduction of acetophenone 55a with catalyst prapared from ( S ) - L21 , t he transition state geometries calculated under DFT/B3LYP/6 - 31G(d) level with CPCM as solvation method in 2 - propanol are shown in Figure 2.4 . TS - R - L21 - p Coordinate: 1 H 0.290 - 3.977 - 0.459 2 C - 0.208 - 3.622 - 1.688 3 C 0.729 - 3.708 0.742 4 Al - 0.09 6 - 1.200 - 0.244 5 O - 1.456 - 0.449 0.580 6 O 0.905 0.097 - 0.877 7 O - 0.532 - 2.351 - 1.542 8 O 0.724 - 2.376 0.811 9 C 5.030 2.157 1.132 10 C 3.973 2.928 1.558 11 C 2.640 2.626 1.168 12 C 2.421 1.493 0.330 TS - R - L21 - p TS - S - L21 - p 207 13 C 3.533 0.712 - 0.085 14 C 4.827 1.024 0.293 15 H 1.694 4.189 2.316 16 H 6.038 2.418 1.443 17 H 4.147 3.788 2.201 18 C 1.527 3.383 1.606 19 C 1.082 1.188 - 0.081 20 C 0.006 2.002 0.281 21 C 0.238 3.088 1.201 22 C - 1.354 1.780 - 0.310 23 C - 2.046 0.592 - 0.071 24 C - 1.993 2.809 - 1.094 25 C - 3.418 0.432 - 0.462 26 C - 3.311 2.659 - 1.483 27 C - 4.151 - 0.744 - 0.162 28 C - 4.059 1.499 - 1.160 29 H - 3.780 3.426 - 2.093 30 C - 5.481 - 0.886 - 0.523 31 C - 5.419 1.336 - 1.535 32 C - 6.105 0.183 - 1.223 33 H - 5.914 2.141 - 2.073 34 H - 7.148 0.082 - 1.516 35 C - 1.260 4.013 - 1.584 36 C - 1.842 5.289 - 1.499 37 C - 0.015 3.895 - 2.229 38 C - 1.204 6.409 - 2.033 39 H - 2.797 5.403 - 0.994 40 C 0.624 5.014 - 2.763 41 H 0.444 2.917 - 2.328 42 C 0.034 6.277 - 2.667 43 H - 1.673 7.386 - 1.949 44 H 1.582 4.897 - 3.263 45 H 0.533 7.149 - 3.082 46 C - 0.875 3.872 1.812 47 C - 0.804 5.274 1.887 48 C - 1.975 3.232 2.411 49 C - 1.798 6.012 2.533 50 H 0.032 5.788 1.421 51 C - 2.969 3.969 3.056 52 H - 2.040 2.149 2.386 53 C - 2.886 5.362 3.119 54 H - 1.723 7.095 2.572 55 H - 3.805 3.451 3.518 56 C - 0.339 - 4.379 1.600 57 H - 0.426 - 5.449 1.408 58 H - 0.066 - 4.236 2.652 59 H - 1.308 - 3.902 1.431 60 C 2.095 - 4.344 0.706 61 C 2.243 - 5.739 0.625 62 C 3.241 - 3.536 0.743 63 C 3.513 - 6.312 0.593 64 H 1.370 - 6.382 0.575 65 C 4.510 - 4.113 0.717 66 H 3.129 - 2.459 0.807 67 C 4.651 - 5.501 0.643 68 H 3.615 - 7.391 0.530 69 H 5.391 - 3.478 0.758 70 H 5.640 - 5.949 0.621 71 C - 1.373 - 4.584 - 1.802 72 H - 2.140 - 4.357 - 1.058 73 H - 1.818 - 4.457 - 2.798 74 H - 1.050 - 5.623 - 1.702 208 75 C 1.014 - 3.904 - 2.538 76 H 1.852 - 3.267 - 2.239 77 H 1.312 - 4.953 - 2.481 78 H 0.763 - 3.669 - 3.580 79 H - 3.661 5.935 3.620 80 H 3.347 - 0.142 - 0.728 81 H - 3.640 - 1.536 0.376 82 C 6.002 0.187 - 0.184 83 C 6.954 0.986 - 1.105 84 C 6.795 - 0.445 0.984 85 H 5.590 - 0.640 - 0.782 86 C 8.123 0.124 - 1.605 87 H 7.351 1.850 - 0.553 88 H 6.388 1.391 - 1.954 89 C 7.963 - 1.307 0.481 90 H 7.189 0.351 1.632 91 H 6.118 - 1.045 1.607 92 C 8.898 - 0.510 - 0.440 93 H 8.795 0.730 - 2.226 94 H 7.731 - 0.674 - 2.254 95 H 8.522 - 1.713 1.334 96 H 7.565 - 2.171 - 0.071 97 H 9.698 - 1.156 - 0.822 98 H 9.388 0.285 0.143 99 C - 6.275 - 2.139 - 0.188 100 C - 5.694 - 3.407 - 0.855 101 C - 6.418 - 2.356 1.337 102 H - 7.289 - 2.000 - 0.590 103 C - 6.527 - 4.657 - 0.530 104 H - 4.662 - 3.558 - 0.504 105 H - 5.636 - 3.259 - 1.941 106 C - 7.250 - 3.606 1.661 107 H - 5.417 - 2.461 1.781 108 H - 6.871 - 1.468 1.794 109 C - 6.674 - 4.860 0.985 110 H - 6.068 - 5.541 - 0.991 111 H - 7.525 - 4.552 - 0.981 112 H - 7.302 - 3.749 2.748 113 H - 8.283 - 3.452 1.316 114 H - 7.311 - 5.730 1.192 115 H - 5.688 - 5.082 1.417 END 209 TS - S - L21 - p Coordinate: 1 H - 0.303 - 3.991 - 0.575 2 C - 0.731 - 3.481 - 1.786 3 C 0.174 - 3.885 0.633 4 Al 0.138 - 1.227 - 0.315 5 O - 0.519 - 2.185 - 1.673 6 O 0.516 - 2.599 0.747 7 O - 0.973 - 0.127 0.492 8 O 1.494 - 0.262 - 0.878 9 C 5.957 0.338 1.347 10 C 5.175 1.384 1.784 11 C 3.833 1.525 1.342 12 C 3.313 0.551 0.438 13 C 4.143 - 0.517 0.012 14 C 5.454 - 0.639 0.445 15 H 3.360 3.253 2.547 16 H 6.983 0.252 1.697 17 H 5.578 2.119 2.477 18 C 2.985 2.568 1.791 19 C 1.961 0.690 - 0.022 20 C 1.170 1.776 0.356 21 C 1.685 2.698 1.339 22 C - 0.169 2.002 - 0.279 23 C - 1.195 1.068 - 0.123 24 C - 0.438 3.207 - 1.023 25 C - 2.530 1.340 - 0.568 26 C - 1.723 3.474 - 1.462 27 C - 3.594 0.423 - 0.360 28 C - 2.794 2.576 - 1.228 29 H - 1.915 4.372 - 2.042 30 C - 4.885 0.694 - 0.777 31 C - 4.123 2.839 - 1.660 32 C - 5.133 1.930 - 1.440 33 H - 4.331 3.777 - 2.170 34 H - 6.139 2.1 63 - 1.780 35 C 0.639 4.161 - 1.422 36 C 0.456 5.547 - 1.277 37 C 1.821 3.710 - 2.036 38 C 1.420 6.451 - 1.724 39 H - 0.445 5.915 - 0.794 40 C 2.785 4.613 - 2.484 41 H 1.974 2.645 - 2.180 42 C 2.591 5.988 - 2.328 43 H 1.257 7.518 - 1.595 44 H 3.688 4.241 - 2.962 45 H 3.343 6.691 - 2.676 46 C 0.838 3.756 1.965 47 C 1.327 5.064 2.122 48 C - 0.428 3.454 2.498 49 C 0.578 6.039 2.782 50 H 2.298 5.320 1.707 51 C - 1.178 4.428 3.158 52 H - 2.151 4.169 3.568 53 H - 0.817 2.445 2.410 54 C - 0.680 5.725 3.302 55 H - 1.266 6.483 3.815 56 H 0.976 7.045 2.885 57 C - 2.180 - 3.922 - 1.745 58 H - 2.708 - 3.449 - 0.913 59 H - 2.655 - 3.598 - 2.680 60 H - 2.269 - 5.008 - 1.671 210 61 C 0.195 - 4.218 - 2.734 62 H 1.234 - 3.9 16 - 2.578 63 H 0.101 - 5.301 - 2.630 64 H - 0.087 - 3.945 - 3.759 65 C 1.374 - 4.823 0.565 66 H 2.107 - 4.432 - 0.146 67 H 1.839 - 4.856 1.557 68 H 1.101 - 5.840 0.276 69 C - 1.011 - 4.321 1.459 70 C - 1.413 - 5.666 1.505 71 C - 1.740 - 3.367 2.188 72 C - 2.511 - 6.050 2.272 73 H - 0.876 - 6.420 0.937 74 C - 2.837 - 3.755 2.957 75 H - 1.436 - 2.327 2.159 76 C - 3.226 - 5.096 3.002 77 H - 2.810 - 7.094 2.300 78 H - 3.387 - 3.008 3.523 79 H - 4.080 - 5.396 3.602 80 H - 3.375 - 0.508 0.153 81 H 3.723 - 1.241 - 0.678 82 C 6.349 - 1.778 - 0.019 83 C 5.812 - 3.165 0.407 84 C 6.600 - 1.748 - 1.545 85 H 7.325 - 1.646 0.472 86 C 6.743 - 4.301 - 0.043 87 H 4.816 - 3.316 - 0.034 88 H 5.679 - 3.189 1.496 89 C 7.531 - 2.885 - 1.993 90 H 5.638 - 1.8 38 - 2.070 91 H 7.022 - 0.776 - 1.829 92 C 6.998 - 4.258 - 1.557 93 H 6.317 - 5.270 0.245 94 H 7.703 - 4.212 0.488 95 H 7.660 - 2.855 - 3.083 96 H 8.529 - 2.729 - 1.556 97 H 7.701 - 5.049 - 1.847 98 H 6.056 - 4.465 - 2.087 99 C - 6.007 - 0.299 - 0.531 100 C - 7.105 0.271 0.398 101 C - 6.636 - 0.820 - 1.845 102 H - 5.566 - 1.166 - 0.017 103 C - 8.219 - 0.754 0.662 104 H - 7.541 1.168 - 0.063 105 H - 6.653 0.594 1.344 106 C - 7.751 - 1.844 - 1.578 107 H - 7.051 0.026 - 2.411 108 H - 5.854 - 1.264 - 2.475 109 C - 8.831 - 1.274 - 0.647 110 H - 8.996 - 0.306 1.295 111 H - 7.803 - 1.601 1.228 112 H - 8.196 - 2.166 - 2.528 113 H - 7.313 - 2.742 - 1.117 114 H - 9.591 - 2.037 - 0.435 115 H - 9.349 - 0.448 - 1.157 EN D 211 In the reduction of acetophenone 55g with catalyst prapared from ( S ) - L21 , the transition state geometries calculated under HF/3 - 21G* level in vacuum are shown in Figure 2.5. TS - R - L21 - 55g Coordinate: 1 H 0.007 - 3.767 0.784 2 C 0.340 - 3.248 1.905 3 C - 0.413 - 3.578 - 0.507 4 Al 0.177 - 0.925 0.322 5 O 1.386 0.008 - 0.490 6 O - 1.051 0.195 0.814 7 O 0.672 - 1.983 1.631 8 O - 0.451 - 2.281 - 0.654 9 C - 5.340 1.687 - 1.246 10 C - 4.403 2.570 - 1.673 11 C - 3.054 2.460 - 1.253 12 C - 2.707 1.406 - 0.399 13 C - 3.703 0.495 0.026 14 C - 4.99 9 0.620 - 0.373 15 H - 2.291 4.094 - 2.419 16 H - 6.356 1.800 - 1.569 17 H - 4.672 3.372 - 2.333 18 C - 2.045 3.347 - 1.690 19 C - 1.359 1.286 0.047 20 C - 0.419 2.222 - 0.292 21 C - 0.767 3.242 - 1.235 22 C 0.944 2.211 0.328 23 C 1.797 1.165 0.126 24 C 1.390 3.323 1.119 212 25 C 3.149 1.213 0.570 26 C 2.675 3.373 1.563 27 C 4.036 0.149 0.306 28 C 3.597 2.339 1.272 29 H 2.992 4.191 2.180 30 C 5.334 0.189 0.717 31 C 4.946 2.367 1.700 32 C 5.782 1.330 1.429 33 H 5.29 9 3.222 2.243 34 H 6.802 1.368 1.758 35 C 0.446 4.386 1.579 36 C 0.753 5.729 1.407 37 C - 0.709 4.043 2.272 38 C - 0.080 6.712 1.914 39 H 1.631 5.999 0.856 40 C - 1.541 5.025 2.777 41 H - 0.948 3.010 2.417 42 C - 1.229 6.363 2.600 43 H 0.168 7.745 1.770 44 H - 2.428 4.746 3.310 45 H - 1.875 7.123 2.992 46 C 0.267 4.139 - 1.837 47 C 0.086 5.515 - 1.857 48 C 1.378 3.595 - 2.471 49 C 1.001 6.335 - 2.496 50 H - 0.757 5.940 - 1.353 51 C 2.291 4.415 - 3.107 52 H 1.519 2.534 - 2.467 53 C 2.106 5.787 - 3.122 54 H 0.852 7.397 - 2.500 55 H 3.144 3.982 - 3.593 56 C 0.686 - 4.327 - 1.255 57 H 0.821 - 5.326 - 0.886 58 H 0.401 - 4.354 - 2.297 59 C - 1.727 - 4.295 - 0.449 60 C - 1.814 - 5.651 - 0.152 61 C - 2.879 - 3.570 - 0.705 62 C - 3.044 - 6.275 - 0.123 63 H - 0.933 - 6.220 0.071 64 C - 4.11 1 - 4.201 - 0.681 65 H - 2.804 - 2.527 - 0.929 66 C - 4.195 - 5.550 - 0.392 67 H - 3.108 - 7.319 0.109 68 H - 4.998 - 3.639 - 0.889 69 H - 5.150 - 6.036 - 0.373 70 C 1.491 - 4.143 2.328 71 H 2.296 - 4.072 1.615 72 H 1.849 - 3.786 3.289 73 H 1.169 - 5.170 2.433 74 C - 0.946 - 3.414 2.697 75 H - 1.749 - 2.852 2.240 76 H - 1.230 - 4.453 2.781 77 H - 0.774 - 3.008 3.688 78 H 2.816 6.421 - 3.616 79 H - 3.410 - 0.286 0.696 80 H 3.651 - 0.687 - 0.237 81 C - 6.070 - 0.335 0.127 82 C - 7.072 0.386 1.057 83 C - 6.830 - 1.023 - 1.029 84 H - 5.578 - 1.110 0.709 85 C - 8.137 - 0.589 1.594 86 H - 7.561 1.182 0.504 213 87 H - 6.531 0.844 1.878 88 C - 7.889 - 2.005 - 0.490 89 H - 7.324 - 0.272 - 1.635 90 H - 6.124 - 1.540 - 1.671 91 C - 8.883 - 1.280 0.437 92 H - 8.840 - 0.056 2.226 93 H - 7.654 - 1.344 2.210 94 H - 8.419 - 2.467 - 1.317 95 H - 7.39 7 - 2.798 0.068 96 H - 9.611 - 1.983 0.828 97 H - 9.424 - 0.532 - 0.136 98 C 6.295 - 0.957 0.437 99 C 5.849 - 2.253 1.152 100 C 6.454 - 1.216 - 1.078 101 H 7.271 - 0.683 0.829 102 C 6.829 - 3.410 0.880 103 H 4.862 - 2.529 0.795 104 H 5.769 - 2.067 2.218 105 C 7.433 - 2.375 - 1.349 106 H 5.485 - 1.463 - 1.501 107 H 6.798 - 0.310 - 1.564 108 C 6.971 - 3.659 - 0.634 109 H 6.484 - 4.311 1.377 110 H 7.803 - 3.163 1.294 111 H 7.511 - 2.549 - 2.417 112 H 8.422 - 2.103 - 0.990 113 H 7.676 - 4.464 - 0.817 114 H 6.010 - 3.966 - 1.037 115 Br 2.397 - 3.419 - 1.173 END TS - S - L21 - 55g Coordinate: 1 H - 0.203 - 3.820 - 0.584 2 C - 0.761 - 3.389 - 1.687 3 C 0.363 - 3.540 0.610 4 Al 0.042 - 0.954 - 0.500 5 O - 0.486 - 2.088 - 1.733 6 O 0.566 - 2.247 0.590 7 O - 1.200 - 0.080 0.346 8 O 1.203 0.207 - 1.031 9 C 5.523 1.338 1.177 10 C 4.625 2.232 1.661 11 C 3.277 2.219 1.223 12 C 2.895 1.256 0.281 13 C 3.851 0.336 - 0.207 14 C 5.143 0.362 0.218 15 H 2.569 3.780 2.517 16 H 6.536 1.367 1.525 17 H 4.923 2.964 2.387 18 C 2.296 3.100 1.734 19 C 1.546 1.219 - 0.166 20 C 0.626 2.130 0.273 21 C 1.011 3.065 1.289 22 C - 0.75 3 2.178 - 0.311 23 C - 1.616 1.127 - 0.161 24 C - 1.202 3.347 - 1.007 25 C - 2.978 1.229 - 0.560 26 C - 2.497 3.446 - 1.412 214 27 C - 3.887 0.166 - 0.343 28 C - 3.425 2.408 - 1.168 29 H - 2.818 4.310 - 1.960 30 C - 5.193 0.260 - 0.712 31 C - 4.786 2.489 - 1.556 32 C - 5.637 1.456 - 1.335 33 H - 5.134 3.388 - 2.029 34 H - 6.663 1.544 - 1.635 35 C - 0.254 4.427 - 1.415 36 C - 0.533 5.758 - 1.136 37 C 0.875 4.119 - 2.166 38 C 0.302 6.763 - 1.594 39 H - 1.390 6.000 - 0.541 40 C 1.709 5.122 - 2.621 41 H 1.091 3.095 - 2.393 42 C 1.425 6.448 - 2.337 43 H 0.077 7.787 - 1.366 44 H 2.575 4.870 - 3.200 45 H 2.073 7.225 - 2.692 46 C 0.010 3.939 1.973 47 C 0.226 5.306 2.087 48 C - 1.10 5 3.381 2.588 49 C - 0.657 6.101 2.799 50 H 1.072 5.745 1.599 51 C - 1.987 4.176 3.296 52 H - 2.842 3.732 3.766 53 H - 1.273 2.327 2.512 54 C - 1.766 5.539 3.405 55 H - 2.450 6.154 3.955 56 H - 0.479 7.156 2.875 57 C - 2.214 - 3.739 - 1.422 58 H - 2.591 - 3.195 - 0.568 59 H - 2.785 - 3.436 - 2.294 60 H - 2.342 - 4.800 - 1.264 61 C - 0.063 - 4.241 - 2.732 62 H 0.997 - 4.049 - 2.724 63 H - 0.254 - 5.292 - 2.567 64 H - 0.460 - 3.958 - 3.701 65 C 1.615 - 4.409 0.538 66 H 2.068 - 4.415 1.518 67 H 1.403 - 5.412 0.220 68 C - 0.725 - 4.031 1.521 69 C - 0.968 - 5.384 1.728 70 C - 1.513 - 3.083 2.161 71 C - 1.981 - 5.784 2.577 72 H - 0.380 - 6.130 1.233 73 C - 2.527 - 3.490 3.009 74 H - 1.338 - 2.041 1.989 75 C - 2.761 - 4.837 3.221 76 H - 2.161 - 6.828 2.736 77 H - 3.130 - 2.755 3.503 78 H - 3.545 - 5.149 3.881 79 H - 3.516 - 0.716 0.134 80 H 3.525 - 0.388 - 0.923 81 C 6.153 - 0.647 - 0.303 82 C 7.380 0.031 - 0.951 83 C 6.605 - 1.614 0.814 84 H 5.661 - 1.239 - 1.070 85 C 8.372 - 1.017 - 1.491 86 H 7.885 0.646 - 0.213 87 H 7.04 9 0.685 - 1.751 88 C 7.604 - 2.659 0.278 215 89 H 7.074 - 1.046 1.612 90 H 5.733 - 2.107 1.230 91 C 8.822 - 1.973 - 0.369 92 H 9.233 - 0.521 - 1.926 93 H 7.893 - 1.592 - 2.280 94 H 7.926 - 3.309 1.085 95 H 7.108 - 3.280 - 0.463 96 H 9.505 - 2.718 - 0.764 97 H 9.357 - 1.407 0.388 98 C - 6.159 - 0.887 - 0.467 99 C - 7.316 - 0.473 0.471 100 C - 6.725 - 1.450 - 1.790 101 H - 5.608 - 1.686 0.023 102 C - 8.270 - 1.655 0.732 103 H - 7.873 0.339 0.015 104 H - 6.906 - 0.105 1.405 105 C - 7.679 - 2.632 - 1.529 106 H - 7.26 5 - 0.666 - 2.312 107 H - 5.905 - 1.761 - 2.428 108 C - 8.827 - 2.211 - 0.592 109 H - 9.083 - 1.337 1.376 110 H - 7.731 - 2.443 1.252 111 H - 8.079 - 2.998 - 2.469 112 H - 7.125 - 3.447 - 1.070 113 H - 9.480 - 3.056 - 0.397 114 H - 9.423 - 1.444 - 1.079 115 Br 2.936 - 3.671 - 0.677 END 4. 3 Experimental information for chapter three 4. 3 .1 General procedure for preparing diene 93 4 - Methoxy - 2 - trimethylsilyloxy - 1,3 - butadiene 93 : To a 250 mL oven - dried round bottomed flask was added anhydrous zinc chloride (16 3 mg, 1.2 0 mmol) to freshly distilled triethylamine (1 2 .2 mL , 8 8 .0 mmol), and a argon balloon with septum was attached and the mixture was stirred for 1 h at room temperature until the salt was suspended in the triethylamine . To this mixture was added (E) - 4 - methoxyb ut - 3 - en - 2 - one S2 (4. 07 mL , 40 .0 mmol) in dry benzene ( 2 0 mL ) in one portion. Then trimethylchlorosilane (10.2 mL , 80.0 mol) was injected 216 in to the reaction dropwise over 30 minutes at room temperature while stirring . The reaction mixture was then heated at 40 ºC and stirred in oil bath for 24 hours . The reaction mixture was quenched by the addition of diethyl ether (1 5 0 mL ) and filtered through a pad of C elite. The filtrate and combined ethereal washings were concentr ated by rotavapor . Purification by vacuum distillation ( 9 mm Hg, 59 ºC) gave 4 - methoxy - 2 - trimethylsilyloxy - 1,3 - butadiene 93 ( 3.81 g, 22.1 mmol) as a colorless liquid in 55 % yield. Spectral data for 93 : 1 H NMR (500 MHz, CDC l 3 9 H), 3.59 (s, 3H), 3.96 4.21 (m, 2H), 5.36 (d, J = 12.4, 1H), 6.83 (d, J = 12.3, 1H). These spectral data match those previously reported for this compound 21 . 4. 3 . 2 General procedure for preparing aldehyde 2 31 w 2 - ((tert - butyldi phen ylsilyl)oxy) ethan - 1 - ol S3 : To a stirring mixture of sodium hydride ( 1.2 g, 30 mmol, 60% w/w in mineral oil ) in 5 0 mL of freshly distilled THF at 0 ethylene glycol ( 1.7 mL , 30 mmol ) and the resulting solution was warmed up to room temperature and stirred for 1 hour . Then a solution of tert - b utyl(chloro)diphenylsilane ( TB DP SCl , 30 mmol, 7.8 mL ) in 20 mL THF was added to the stirring solution at 0 a rming up the reaction mixture to room temperature and stirring for another 1 h. The reaction was quenched by dilution of 100 mL diethyl e ther and slow addition of 50 mL water. Then the separated organic layer was washed twice with 50 mL brine and dried over Na 2 SO 4 . After removing 217 the solvent under reduced pressure, the crude product was purified via column chromatography ( 30 x 250 mm, 10: 1 hexane / EtOAc as eluent ) and the desired product S3 (13.0 mmol, 3.9 1 g) was obtained as a light - yellow oil in 43 % isolated yield. Spectral data for S3 : R f = 0. 15 ( 10: 1 hexane: ethyl acetate ); 1 H NMR (500 MHz, CDC l 3 4 ( s , 9 H), 3.7 1 3.74 ( m , 2 H), 3.79 - 3.8 4 ( m, 2 H), 7.4 0 7.50 ( m , 6 H), 7.7 1 7.77 ( m , 4 H) ; 13 C NMR (126 MHz, CDC l 3 19.28, 26.91, 63.73, 65.08, 127.82, 129.84, 133.32, 135.58 . These spectral data match those previously reported for this compound 2 2 . 2 - ((tert - butyld iphen ylsilyl)oxy) acetaldehyde 231w : In a n oven dried 25 0 mL round bottom flask under argon , oxalyl chloride ((COCl) 2 , 2 3 .4 mmol, 1.98 mL ) and C H 2 Cl 2 ( 50 mL ) were added. Then the reaction flask was cooled down to - and a solution of DMSO ( 31.2 mmol, 2.2 2 mL ) in 10 mL CH 2 Cl 2 was added dropwise . After 10 minutes, alcohol S3 (1 3.0 mmol, 3.9 1 g) solution in 20 mL of CH 2 Cl 2 was added slowly and the reaction mixture was stirred at - The reaction was w a rmed up to room temperature and stirred for 1 h after the addition of Et 3 N ( 65 .0 mmol, 9 .06 mL ) and it was quenched by the slow addition of saturated aq NH 4 Cl solution . The organic layer was separated and washed with brine and dried over Na 2 SO 4 . After removing the solvent under reduced pressure, the crude product was purified via co lumn chromatography ( 30 x 2 5 0 mm, 10: 1 218 hexane / EtOAc as eluent ) and the desired product 231w (11 .0 mmol, 3.29 g) was obtained as a light - yellow oil in 85 % isolated yield. Spectral data for 231w : R f = 0. 2 ( 10: 1 hexane: ethyl acetate ); 1 H NMR (500 MHz, CDC l 3 2 ( s , 9 H), 4.23 ( s , 2 H), 7. 39 7. 43 ( m , 4 H), 7. 44 7. 48 ( m , 2 H) , 7. 65 7.69 ( m , 4 H) , 9.74 (s, 1H) ; 13 C NMR (126 MHz, CDC l 3 19. 3 , 26.8, 70.0, 127.7, 130.1, 132.5, 135.7, 2 01.7 . These spectral data match those previously reported for this compound 22 . 4. 3 . 3 General procedure for preparing aldehyde 2 31 y allyl triphenylmethyl ether S4 : In a n oven dried 10 0 mL round bottom flask was added triphenylmethyl chloride (5.58 g, 20 .0 mmol), allyl alcohol (6.8 mL , 0.10 mol) and pyridine (9.7 mL , 0.12 mol). The reaction mixture was stirred for 6 days at room temperature before the precipitate was filtered off and washed with diethyl ether. The combined organic layer was washed with water and brine and was then dried over Na 2 SO 4 . After removing the solvent under reduced pressure, the crude product was purified via column chromatography ( 25 x 2 0 0 mm, 8: 1 hexane / CH 2 Cl 2 as eluent ) and the desired product S4 (19.1 mmol, 5.74 g) was obtained as a white solid in 96 % isolated yield. 219 Spectral data for S4 : R f = 0. 25 ( 8: 1 hexane: CH 2 Cl 2 ); 1 H NMR (500 MHz, CDC l 3 J = 4.8, 1.7, 2H), 5.1 7 5.21 ( m, 1H), 5.4 2 5.48 ( m, 1H), 5.90 6.01 (m, 1H), 7.22 7.29 (m, 3H), 7.29 7.36 (m, 6H), 7.45 7.51 (m, 6H). These spectral data match those previously reported for this compound 2 3 . 2 - ( trityl oxy) acetaldehyde 231y : Ozone was bubbled through a pre - chill ed solution at 78 °C of allyl tri phenylmethyl ether S4 ( 2.1 g, 7 .0 mmol) in 50 mL CH 2 Cl 2 containing NaHCO 3 ( 0.6 g, 7 mmol) until the pale blue color persisted. Excess ozone was flushed off with nitrogen gas and Me 2 S ( 2.6 mL , 35 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h before the addition of 50 mL water. The organic layer was separated and washed with brine and dried over Na 2 SO 4 . After removing the solvent under reduced pressure, the crude pro duct was purified via column chromatography ( 30 x 2 5 0 mm, 1: 1 hexane / CH 2 Cl 2 as eluent ) and the desired product 231 y (4.95 mmol, 1.50 g) was obtained as a colorless oil in 71 % isolated yield. Spectral data for 231y : R f = 0. 2 ( 1 : 1 hexane: CH 2 Cl 2 ); 1 H NMR (500 MHz, CDC l 3 s , 2 H ), 7.27 7.40 (m, 9 H), 7.49 7.55 (m, 6 H) , 9.53 (s, 1H) . These spectral data match those previously reported for this compound 2 4 . 220 4. 3 . 4 General procedure for preparation of catalysts Procedure E preparation of the BINOL - propeller catalyst 216 : A 50 mL flamed dried Schlenk flask was equipped with a stir bar and connected to vacuum followed by flush ing with nitrogen gas. To the flask was added ( S ) - BI NOL ( 7.2 mg, 0.0 25 mmol) and freshly distilled toluene (1. 5 mL ) with nitrogen flow via the side arm. After all solids were dissolved, BH 3 2 S ( 6. 3 0.0 1 3 mmol , as 2 M solution in toluene) was added via an oven - dried 50 syringe and the Schlenk flask was sealed and heated in an oil bath at 100 ºC . After 0.5 hour, the side arm of the Schlenk flask was connected to vacuum (1 mm Hg) and the Teflon cap was carefully loosened to apply vacuum to the solution in the flask. After the removal of solvent, white solids cr a shed out and the flask was kept in oil bath at 100 ºC for another 0.5 hours with vacuum. The flask containing BINOL - propeller catalyst 216 was allowed to cool to room temperature after 0.5 hours and flushed with nitrogen gas. NMR study revealed that the use of different equivalents of BH 3 2 S ( 6.3 to 50 125 to 0.1 mmol , 0.5 to 4 equivalents, as 2 M solution in toluene) led to the sam e product 216 . The 1 H NMR spectrum of 216 221 (with unreacted BINOL and toluene as impurity) is shown below. 1 H NMR (500 MHz, CDC l 3 6.62 6.68 (m, 12 H), 7. 03 ( d , J = 8.2, 6 H) , 7.23 7.27 (m, 6 H) , 7.43 7.47 (m, 6 H) , 7. 72 ( d , J = 8.2, 6 H) . These spectral data match those previously reported for this compound 33 . 1 H NMR Spectrum for 216 1 H NMR Spectrum for 216 (aromatic region) 222 The 1 H NMR spectrum of L 1 (BINOL) is shown below. 1 H NMR Spectrum for BINOL Procedure F preparation of the borate ester catalyst 249 : 223 A 50 mL flame dried Schlenk flask was equipped with a stir bar and connected to vacuum followed by flushed with nitrogen gas. To the flask was added ( S ) - - t Bu 2 VANOL ( 13.8 mg, 0.0 25 0 mmol) and freshly distilled toluene (1.5 mL ) with nitrogen flow via the side arm. After all solids were dissolved, BH 3 2 S ( 6.3 1 3 mmol , as 2 M solution in toluene) was added via an oven - dried 50 syringe and the Schlenk flask was sealed and heated in an oil bath at 100 ºC . After 0.5 hours, the side arm of the Schlenk flask was connected to vacuum (1 mm Hg) and the Teflon cap was carefully loosened to apply vacuum to the solution in the flask. After the removal of solvent, white solids cr a shed out and the flask was kept in oil bath at 100 ºC for another 0.5 hour with vacuum. The flask containing borate ester catalyst 249 was allowed to cool to room temperature after 0.5 hour and flushed with nitrogen gas. The 1 H NMR spectrum of 2 49 (with unreacted L22 as impurity) is shown below. The four tert - butyl groups of 249 shows the same signal as a singlet at 1.31 ppm, while the tert - butyl groups of the free ligand L22 shows a singlet at 1.50 ppm. 1 H NMR (500 MHz, CDC l 3 1.31 (s, 36 H , proton - t Bu ), 6.58 6.61 (m, 8 H , proton - Ph ), 6.97 (dd, J = 8.7, 6.8, 8 H , proton - Ph ), 7.10 7.14 (m, 4 H , proton - Ph ) , 7.39 (s, 4H , proton - D ), 7.61 (dd, J = 8.6, 2.0, 4 H , proton - B ) , 7.74 (d, J = 8.6, 4 H , proton - C ), 8.78 (d, J = 2.0, 4 H , proton - A ) . 224 1 H NMR Spectrum for 249 1 H NMR Spectrum for 249 (aromatic region) 225 The 1 H NMR spectrum of L22 - t Bu 2 VANOL) is shown below . 1 H NMR Spectrum for L22 ( - t Bu 2 VANOL ) 1 H NMR Spectrum for L22 ( aromatic region ) 226 Procedure G preparation of the VANOL - aluminum catalyst 253 : To a 10 mL oven - dried round bottom flask equipped with a stir bar was charged ( S ) - L 5 (( S ) - VANOL , 22.0 mg, 0.0 5 0 mmol) and freshly distilled toluene (1 mL ). Then a rubber septum stopper and argon balloon were attached. While stirring at room temperature, trimethylaluminum solution ( 1 3 L , 0.025 mmol, 2 M in toluene) was added to the reaction flask. The stock solution of VANOL - aluminum catalyst 253 in toluene was achieved a fter stirring the mixture at room temperature for 1 hour . 4. 3 . 5 General procedure for asymmetric HDA reaction Procedure H illustrated for the reaction of benzaldehyde 231a : 227 (R) - 2 - phenyl - 2,3 - dihydro - 4H - pyran - 4 - one 248a : T he catalyst 249 was prepared according to p rocedure F. To the Schlenk flask containing catalyst 249 with nitrogen flow was added 5 mL freshly distilled n - pentane and was swirled until all solids were dissolved. The flask was cooled to 60 °C for 10 minutes in a chiller with an ethanol cold bath followed by the addition of benzaldehyde 231a (26 L , 0.25 mmol) and diene 93 (97 L , 0.5 0 mm ol) with nitrogen flow through the side arm. The reaction was stirred at 60 °C for 4 hours before quenching with 2 mL 1 M HCl in MeOH/H 2 O (1:1). The mixture was allowed to warm to room temperature and stirred for another 1 hour before the addition of 10 mL diethyl ether and 10 mL water, and then the layers were separated. The aqueous layer was extracted with diethyl ether ( 5 mL × 3). The c ombined organic layer was dried over Na 2 SO 4 and concentrated under vacuum to afford the cru de product. Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure a dduct 248 a as a colorless oil in 90 % isolated yield ( 39.3 mg, 0.22 6 mmol); The optical purity of 248a was determined to be 9 3 % ee by HPLC (CHIRALCEL® OD column, 9 5 : 5 hexanes/2 - propanol at 2 54 nm, flow - rate: 1 mL /min); retention times: R t = 1 7.4 min (m in or enantiomer, ( S ) - 248a ) and R t = 2 0.7 min ( majo r enantiomer, ( R ) - 248a ) . The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 a : R f = 0. 2 8 ( CH 2 Cl 2 ); = 112 ( c =1.0 in CHCl 3 ) 9 3 % ee ( R ) (lit. 25 = +103.2 ( c = 0.5 in CHCl 3 ) 9 7 % ee ( S )) ; 1 H NMR (500 MHz, CDC l 3 J = 16.9, 3.5, 1H), 2.92 (dd, J = 16.9, 14.5, 1H), 5.44 (dd, J = 14.5, 3.4, 1H), 5.54 (d, J = 6.0, 1H), 7.38 7.45 (m, 5H), 7.49 (d, J = 6.0, 1H) ; 13 C 228 NMR (126 MHz, CDC l 3 129.0, 137.8, 163.3, 192.3 . These spectral data match those previously reported for this compound. 25 2 - (4 - bromo phenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248b : T he catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248b was obtained according to procedure H with the use of aldehyde 231b ( 46.3 mg, 0.25 0 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (15 mm × 200 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure a dduct 248b as a yellow solid (m.p. 68 - 70 C) in 94 % isolated yield ( 59.2 mg, 0.2 3 4 mmol); The optical purity of 248 b was determined to be 9 1 % ee by HPLC (CHIRALCEL® OD column, 95:5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 8.3 min (m ajor enantiomer) and R t = 2 2.2 min (m inor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . The absolute configuration of 248b was assumed to be S , homochiral with other products from same procedure, which configuration s ha ve been confirmed. Spectral data for 248 b : R f = 0.2 5 ( CH 2 Cl 2 ); = +131 ( c =1.0 in CHCl 3 ) 9 1 % ee ; 1 H NMR (500 MHz, CDC l 3 J = 16.8, 3.5, 1H), 2.85 (dd, J = 229 16.8, 14.4, 1H), 5.40 (dd, J = 14.4, 3.5, 1H), 5.54 (d, J = 6.0, 1H), 7.24 7.32 (m, 2H), 7.47 (d, J = 6.0, 1H), 7.53 7.57 (m, 2H) ; 13 C NMR (126 MHz, CDC l 3 80.3, 107.5, 122.9, 127.7, 132.0, 136.9, 163.0, 191.7. These spectral data match those previously reported for this compound. 2 6 (R) - 2 - (4 - nitro phenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248c : T he catalyst 249 was prepared from ( S ) - L22 according to procedure F and adduct 248 c was obtained according to procedure H with the use of aldehyde 231 c (37.8 mg, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 0 mm × 15 0 mm column, 5 :1 hexanes/ EtOAc as eluent) afforded pure a dduct 248c as a yellow solid (m.p. 96 - (5 1.1 mg, 0.23 3 mmol); The optical purity of 248c was determined to be 9 2 % ee by HPLC (CHIRALCEL® OD - H column, 80 : 20 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 3 . 7 min (major enantiomer) and R t = 1 6.5 min (minor enantiomer). 230 Spectral data for 248 c : R f = 0. 21 ( CH 2 Cl 2 ); = 71 ( c =1.0 in CHCl 3 ) 9 2 % ee ; ) (lit. 2 5 = + 58. 3 ( c = 1.0 in CH 2 Cl 2 ) 9 4 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) J = 16.9, 3.7, 1H), 2.85 (dd, J = 16.8, 14.2, 1H), 5.53 5.62 (m, 2H), 7.53 (d, J = 6.0, 1H), 7.57 7.64 (m, 2H), 8.28 8.34 (m, 2H); 13 C NMR (126 MHz, CDC l 3 These spectral data match those pr eviously reported for this compound. 33 (R) - 2 - (2 - naphthyl) - 2,3 - dihydro - 4H - pyran - 4 - one 248d : The catalyst 249 was prepared from ( S ) - L22 according to procedure F and adduct 248d was obtained according to procedure H with the use of aldehyde 231d (39.0 mg, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (10 mm × 150 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure a dduct 248d as a white solid (m.p. 57 - in 89 % isolated yield ( 49.7 mg, 0.2 2 2 mmol); The optical purity of 248 d was determined to be 9 0 % ee by HPLC (CHIRALCEL® OD column, 80 : 20 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 5.7 min (m in or enantiomer) and R t = 2 3.5 min (m aj or enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . 231 Spectral data for 248 d : R f = 0.12 ( 4 :1 hexane/ EtOAc); = 164 ( c =1.0 in CHCl 3 ) 9 0 % ee ; ) (lit. 27 = + 95.8 ( c =1.03 in CHCl 3 ) 9 6 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 J = 16.9, 3.5 , 1H), 3.02 (dd, J = 16.9, 14.4, 1H), 5.57 (d, J = 6.0 , 1H), 5.60 (dd, J = 14.4, 3.5, 1H), 7.47 7.57 (m, 4H), 7.84 7.89 (m, 3H), 7.91 (d, J = 8.5, 1H) ; 13 C NMR (126 MHz, CDC l 3 123.5, 125.4, 126.6, 126.7, 127.8, 128.2, 128.8, 133.1, 133.4, 135.7, 164.1, 192.9. These spectral data match those previously reported for this compound. 2 8 ( S ) - 2 - ( 4 - methoxyphenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 g : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 g was obtained according to procedure H with the use of aldehyde 231 g (30.4 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (10 mm × 150 mm column, 5:1 hexanes/ EtOAc as eluent) afforded pure adduct 248 g as a yellow oil in 78 % isolated yield ( 40.0 mg, 0. 19 6 mmol); The optical purity of 248 g was determined to be 9 2 % ee by HPLC (CHIRALCEL® OD - H column, 95 : 5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 6.1 min (m ajo r enantiomer) and R t = 18.3 min 232 (m in or enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 g : R f = 0.1 3 ( 4 :1 hexane/ EtOAc ); = + 95 ( c =1.0 in CHCl 3 ) 9 2 % ee ; ) (lit. 27 = + 121 ( c = 1.04 in CHCl 3 ) 9 9 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 2.67 (m, 1H), 2.93 (dd, J = 16.9, 14.5, 1H), 3.83 (s, 3H), 5.38 (dd, J = 14.5, 3.4, 1H), 5.52 (d, J = 6.0, 1H), 6.87 6.98 (m, 2H), 7.29 7.37 (m, 2H), 7.46 (d, J = 6.0, 1H) ; 13 C NMR (126 MHz, CDC l 3 107.3, 114.2, 127.8, 129.8, 160.1, 163.3, 192.5. These spectral data match those previously reported for this compound. 2 8 ( S ) - 2 - ( 2 - meth yl phenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 h : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 h was obtained according to procedure H with the use of aldehyde 231 h (28.9 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 h as a colorless oil in 91 % isolated yield ( 4 2.8 mg, 0. 2 27 mmol); The optical purity of 248 h was determined to be 9 3 % ee by HPLC 233 (CHIRALCEL® OD column, 95:5 hexanes/2 - propanol at 254 nm, fl ow - rate: 1 mL /min); retention times: R t = 1 5.2 min (major enantiomer) and R t = 22.1 min (minor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 h : R f = 0. 28 ( CH 2 Cl 2 ); = + 34 ( c =1.0 in CHCl 3 ) 9 3 % ee ; ) (lit. 2 5 = + 40.6 ( c = 0.5 in CHCl 3 ) 9 2 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) J = 17.0, 3.3, 1H), 2.89 (dd, J = 16.9, 14.7, 1H), 5.54 (d, J = 6.0, 1H), 5.64 (dd, J = 14.7, 3.2, 1H), 7. 19 7. 24 ( m , 1H), 7.27 7.31 (m, 2H), 7.45 7.49 (m, 1H), 7.51 (d, J = 6.0, 1H) ; 13 C NMR (126 MHz, CDC l 3 78.5, 107.3, 125.7, 126.5, 128.8, 130.9, 135.1, 135.9, 163.5, 192.4. These spectral data match those previously reported for this compo und. 2 5 ( S ) - 2 - ( 2 - chlorophenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 i : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 i was obtained according to procedure H with the use of aldehyde 231 i (28.2 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure a dduct 248 i as a colorless oil in 94 % isolated yield ( 49.2 mg, 234 0. 2 36 mmol); The optical purity of 248 i was determined to be 9 3 % ee by HPLC (CHIRALCEL® OD column, 9 7 : 3 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 25.6 min (major enantiomer) and R t = 31.7 min (minor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 i : R f = 0. 27 ( CH 2 Cl 2 ); = 68 ( c =1.0 in CHCl 3 ) 9 0 % ee ; ) (lit. 2 9 = 127 ( c = 0.24 in CHCl 3 ) 9 8 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) J = 16.9, 14.1, 1H), 2.80 (dd, J = 16.9, 3.8, 1H), 5.56 (d, J = 6.0, 1H), 5.83 (dd, J = 14.1, 3.8, 1H), 7.32 (td, J = 7.6, 1.8, 1H), 7.36 (td, J = 7.5, 1.5, 1H), 7.40 (dd, J = 7.8, 1.5, 1H), 7.52 (d, J = 6.1, 1H), 7.60 (dd, J = 7.7, 1.8, 1H) ; 13 C NMR (126 MHz, CDC l 3 (x2) , 131.7, 136.7, 162.6, 191.7 . These spectral data match those previously reported for this compound. 34 ( S ) - 2 - ( 3 - methylphenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 j : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 j was obtained according to procedure H with the use of aldehyde 231 j (29.5 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by 235 silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 j as a colorless oil in 9 6 % isolated yield ( 4 5.0 mg, 0. 2 39 mmol); The optical purity of 248 j was determined to be 9 5 % ee by HPLC (CHIRALCEL® OD column, 95:5 hexanes/2 - propanol at 254 nm, fl ow - rate: 1 mL /min); retention times: R t = 1 4.6 min (major enantiomer) and R t = 18.2 min (minor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 j : R f = 0. 28 ( CH 2 Cl 2 ); = + 69 ( c =1.0 in CHCl 3 ) 9 5 % ee ; ) (lit. 2 5 = + 89.8 ( c = 0. 4 5 in CHCl 3 ) 9 2 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) J = 16.9, 3.4, 1H), 2.92 (dd, J = 16.9, 14.5, 1H), 5.39 (dd, J = 14.5, 3.4, 1H), 5.53 (d, J = 6.0, 1H), 7.17 7.25 (m, 3H), 7.32 (t, J = 7.6, 1H), 7.48 (d, J = 6.0, 1H) ; 13 C NMR (126 MHz, CDC l 3 123 .2, 126.8, 128.8, 129.7, 137.8, 138.7, 163.2, 192.3. These spectral data match those previously reported for this compound. 2 5 2 - ( 3 - chlorophenyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 k : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 k was 236 obtained according to procedure H with the use of aldehyde 231 k (28.3 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 k as a colorless oil in 88 % isolated yield ( 46.1 mg, 0. 22 1 mmol); The optical purity of 248 k was determined to be 9 0 % ee by HPLC (CHIRALCEL® OD column, 9 8 : 2 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 26.5 min (major enantiomer) and R t = 37.9 min (minor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . The absolute configu ration of 248 k was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. Spectral data for 248 k : R f = 0. 2 6 ( CH 2 Cl 2 ); = + 52 ( c =1.0 in CHCl 3 ) 9 0 % ee ) ; 1 H NMR (500 MHz, CDC l 3 J = 16.8, 3.5, 1H), 2.86 (dd, J = 16.8, 14.4, 1H), 5.41 (dd, J = 14.4, 3.5, 1H), 5.54 (d, J = 6.0, 1H), 7.2 4 7. 29 ( m , 1H), 7.33 7.38 (m, 2H), 7.40 7.45 (m, 1H), 7.48 (d, J = 6.0, 1H) ; 13 C NMR (126 MHz, CDC l 3 . These spectral data match th ose previously reported for this compound. 30 237 ( S ) - 2 - ( 2 - furyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 l : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 l was obtained according to procedure H with the use of aldehyde 231 l (20.7 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 l as a yellow solid (m.p. 66 - 67 C) in 86 % isolated yield ( 35.4 mg, 0. 2 16 mmol); The optical purity of 248 l was determined to be 9 4 % ee by HPLC (CHIRALCEL® OD column, 95:5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 6.4 min (m in or enantiomer) and R t = 1 7.9 min (m ajor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with r acemic L22 . Spectral data for 248 l : R f = 0. 2 6 ( CH 2 Cl 2 ); = + 126 ( c =1.0 in CHCl 3 ) 9 4 % ee ; ) (lit. 2 5 = + 255.4 ( c = 0.5 in CHCl 3 ) 67 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) J = 16.9, 3.9, 1H), 3.09 (dd, J = 16.9, 12.9, 1H), 5.45 5.49 (m, 1H), 5.50 (d, J = 6.1, 1H), 6.41 (dd, J = 3.4, 1.8, 1H), 6 .4 4 6 .4 6 ( m , 1H), 7.37 (d, J = 6.0, 1H), 7 .4 7 7.48 ( m , 1H) ; 13 C NMR (126 MHz, CDC l 3 109.7, 110.6, 143.6, 150.0, 162.4, 191.3 . These spectral data match those previously reported for this compound. 2 5 238 2 - ( 2 - thiopheny l ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 m : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 m was obtained according to procedure H with the use of aldehyde 231 m (23.4 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Toluene as solvent instead of n - pentane was employed. Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 m as a yellow oil in 72 % isolated yield ( 3 2.6 mg, 0. 18 1 mmol); The optical purity of 248 m was determined to be 85 % ee by HPLC (CHIRAL PAK ® A D column, 9 9 : 1 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 39.9 min (m in or enantiomer) and R t = 46.4 min (m ajor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . The abs olute configuration of 248 m was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. Spectral data for 248 m : R f = 0. 2 5 ( CH 2 Cl 2 ); = + 12 5 ( c =1.0 in CHCl 3 ) 85 % ee ); 1 H NMR (500 MHz, CDC l 3 J = 16.8, 3.7 , 1H), 3.03 (dd, J = 16.8, 13.3, 1H), 5.53 (d, J = 6.1, 1H), 5.68 (dd, J = 13.2, 3.7, 1H), 7.04 (dd, J = 5.1, 3.5, 1H), 7.12 (d, J = 3.7, 1H), 7.37 7.45 (m, 2H) ; 13 C NMR (126 MHz, CDC l 3 43.1, 76.5, 107.6, 126.3, 126.7, 126.9, 140.3, 162.7, 191.4. These spectral data match those previously reported for this compound. 2 7 239 N - Boc - 2 - ( 2 - pyrrol) - 2,3 - dihydro - 4H - pyran - 4 - one 248 n : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 n was obtained according to procedure H with the use of aldehyde 231 n (48.8 mg, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure a dduct 248 n as a yellow oil in 92 % isolated yield ( 60.4 mg, 0. 2 29 mmol); The optical purity of 248 n was determined to be 93 % ee by HPLC (CHIRAL CEL ® OJ - H column, 9 5 : 5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 16.6 min (m in or enantiomer) and R t = 21.5 min (m ajor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . The absolute configuration of 248 n was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. 240 Spectral data for 248 n : R f = 0. 2 7 ( CH 2 Cl 2 ); = + 1 14 ( c =1.0 in CHCl 3 ) 93 % ee ); 1 H NMR (500 MHz, CDC l 3 J = 16.7, 4.1 , 1H), 2.93 (dd, J = 16.6, 12.4, 1H), 5.49 (d, J = 6.0, 1H), 6.10 (dd, J = 12.4, 4.1, 1H), 6.19 (t, J = 3.4, 1H), 6.39 (dd, J = 3.5, 1.8, 1H), 7.32 (dd, J = 3.3, 1.7, 1H), 7.40 (d, J = 6.0, 1H) ; 13 C NMR (126 MHz, CDC l 3 113.6, 123.3, 130 .6, 148.7, 162.9, 192.4 ; HRMS (ESI - TOF) m/z 2 64.1236 [(M - H + ); calcd. for C 1 4 H 1 8 NO 4 : 2 64.1236 ]. ( S ) - 2 - cyclohexyl - 2,3 - dihydro - 4H - pyran - 4 - one 248 e : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 e was obtained according to procedure H with the use of aldehyde 231 e (30.3 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 5 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 e as a colorless oil in 97 % isolated yield ( 43.6 mg, 0. 2 4 2 mmol); The optical purity of 248 e was determined to be 9 8 % ee by HPLC (CHIRALCEL® OD column, 9 9 : 1 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 4.6 min (m aj or enantiomer) and R t = 1 6.4 min 241 (m in or enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 e : R f = 0. 19 ( 4 :1 hexane/ EtOAc ); = + 1 30 ( c =1.0 in CHCl 3 ) 9 8 % ee ; ) (lit. 2 5 = + 112 ( c = 0. 1 in CHCl 3 ) 6 8 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 1.91 (m, 11 H), 2.38 (dd, J = 16.7, 3.3, 1H), 2.55 (dd, J = 16.7, 14.5, 1H), 4.16 (ddd, J = 14.5, 5.8, 3.3, 1H), 5.39 (d, J = 5.9, 1H), 7.37 (d, J = 5.9, 1H) ; 13 C NMR (126 MHz, CDC l 3 84.2, 106.8, 164.8, 193.9 . These spectral data match those previously reported for this compound. 2 5 2 - ( iso - propyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 o : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 o was obtained according to procedure H with the use of aldehyde 231 o (23.0 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Toluene as solvent instead of n - pentane was employed. Purification of the crude product by silica gel chromatography (1 0 mm × 2 5 0 mm column, 4 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 o as a colorless oil in 81 % isolated yield ( 28.3 mg, 0. 20 2 mmol); The optical purity of 248 o was determined to be 89 % ee by HPLC (CHIRAL CEL ® O D - H column, 242 9 9 .5 : 0.5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 10.3 min (m aj or enantiomer) and R t = 11.4 min (m in or enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . The absolute configuration of 248b was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. Spectral data for 248 o : R f = 0. 2 5 ( CH 2 Cl 2 ); = + 82 ( c =1.0 in CHCl 3 ) 8 9 % ee ); 1 H NMR (500 MHz, CDC l 3 J = 11.4, 6.8, 6 H), 1.94 2.03 (m, 1H), 2.39 (dd, J = 16.7, 3.3, 1H), 2.54 (dd, J = 16.6, 14.6, 1H), 4.12 4.19 (m, 1H), 5.37 5.42 (m, 1H), 7.38 (d, J = 6.0, 1H) . These spectral data match those previously reported for this compound. 3 5 ( R ) - 2 - (n - propyl) - 2,3 - dihydro - 4H - pyran - 4 - one 248 p : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 p was obtained according to procedure H with the use of aldehyde 231 p (22.5 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 5 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 p as a colorless oil in 9 5 % isolated yield ( 33.2 mg, 0. 2 37 mmol); The optical purity of 248 p was determined to be 9 0 % ee by HPLC 243 (CHIRALCEL® OD column, 9 9 : 1 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 1 4. 1 min (m aj or enantiomer) and R t = 1 5.3 min (m inor enantiomer). The retention time for e ach enantiomer was confirmed by running the reaction with racemic L22 . Spectral data for 248 p : R f = 0. 2 5 ( CH 2 Cl 2 ); = + 75 ( c =1.0 in CHCl 3 ) 9 0 % ee ; ) (lit. 3 2 = 78.4 ( c = 0.1 in CHCl 3 ) 94 % ee ( S )); 1 H NMR (500 MHz, CDC l 3 ) 0.99 (m, 3 H), 1. 4 3 1.69 (m, 4H), 2.43 (dd, J = 16.8, 3.8, 1 H), 2.52 (dd, J = 16.7, 13.5, 1H), 4.37 4.44 (m, 1H), 5.38 5.42 (m, 1H), 7.36 (d, J = 5.8, 1H) . These spectral data match those previously reported for this compound. 32 2 - ( tert - butyldimethylsiloxymethyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 f : The catalyst (R,R) - 249 was prepared from ( R ) - L22 according to procedure F and adduct 248 f was obtained according to procedure H with the use of aldehyde 231 f (48.0 L, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Catalyst loading was 10 mol%. Purification of the crude product by silica gel chromatography (1 5 mm × 20 0 mm column, 5 :1 hexanes/ Et OAc as eluent) afforded pure adduct 248 f as a colorless oil in 81 % isolated yield ( 49.3 mg, 0. 20 3 mmol); The optical purity of 248 f was determined to be 8 7 % ee by HPLC (CHIRAL CEL ® O D column, 9 9.5 : 0.5 244 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 14.8 min (m aj or enantiomer) and R t = 17.3 min (m inor enantiomer). The absolute configuration of 248 f was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. Spectral data for 248 f : R f = 0. 20 ( 4 :1 hexane/ EtOAc ); = + 26 ( c =1.0 in CHCl 3 ) 8 7 % ee ); 1 H NMR (500 MHz, CDC l 3 (dd, J = 16.9, 3.7, 1H), 2.73 (dd, J = 16.9, 14.0, 1H), 3.81 (dd, J = 11.4, 4.6, 1H), 3.90 (dd, J = 11.4, 3.9, 1H), 4.46 (ddt, J = 14.1, 4.6, 3.8, 1H), 5.40 (d, J = 6.1, 1H), 7.36 (d, J = 6.0, 1H); 13 C NMR (126 MHz, CDC l 3 5.4, 18.8, 25.8, 38.1, 64.2, 80.9, 106.9, 163.0, 191.8 ; HRMS (ESI - TOF) m/z 2 43.1422 [(M - H + ); calcd. for C 1 2 H 2 3 O 3 Si : 243.1416 ]. 2 - ( triphenylmethoxymethyl ) - 2,3 - dihydro - 4H - pyran - 4 - one 248 y : The catalyst was prepared from ( R ) - L2 9 according to procedure F and adduct 248 y was obtained according to procedure H with the use of aldehyde 231 y (75.6 mg, 0.250 mmol) and diene 93 (0.50 mmol, 97 L) . Catalyst loading was 10 mol% and solvent was toluene/ n - pentane (1:10). Purification of the crude product by silica gel 245 chromatograph y (1 5 mm × 20 0 mm column, 5 :1 hexanes/ EtOAc as eluent) afforded pure adduct 248 y as a colorless oil in 92 % isolated yield ( 8 5.0 mg, 0. 2 29 mmol); The optical purity of 248 y was determined to be 93 % ee by HPLC (CHIRAL CEL ® OD - H column, 9 5 : 5 hexanes/2 - propanol at 254 nm, flow - rate: 1 mL /min); retention times: R t = 8.6 min (m aj or enantiomer) and R t = 13 .2 min (m inor enantiomer). The absolute configuration of 248 y was assumed to be S , homochiral with other products from same procedure, which configurations have been confirmed. Spectral data for 248 y : R f = 0. 18 ( 4 :1 hexane/ EtOAc ); = + 57 ( c =1.0 in CHCl 3 ) 93 % ee ); 1 H NMR (500 MHz, CDC l 3 J = 16.9, 3.6, 1H), 2.79 (dd, J = 16.9, 14.1, 1H), 3.30 3.46 (m, 2H), 4.56 (ddt, J = 13.9, 5.0, 3.8, 1H), 5.44 (d, J = 6.0, 1H), 7.24 7.29 (m, 3H), 7.30 7.36 (m, 6H), 7.42 (d, J = 6.0, 1H), 7.44 7.49 (m, 6H) ; 13 C NMR (126 MHz, CDC l 3 127.3, 127.9, 1 28.6, 143.5, 162.0, 193.0 ; HRMS (ESI - TOF) m/z 371.1645 [(M - H + ); calcd. for C 2 5 H 2 3 O 3 : 371.1647 ]. 246 4. 3 . 6 Computational study Computations have been achieved with density functional theory in Gaussian 16 20 . Geometry optimizations of boron catalyst 222 and aluminum catalyst 253 were carried out at B3LYP/6 - 31G(d) level of theory in vacuum. 222 Coordinate: 1 C 2.140 5.770 1.606 2 C 3.257 5.026 1.296 3 C 3.131 3.716 0.761 4 C 1.825 3.183 0.546 5 C 0.689 3.974 0.862 6 C 0.847 5.239 1.385 7 H 5.240 3.394 0.455 8 H 2.249 6.770 2.017 9 H 4.253 5.431 1.454 10 C 4.255 2.940 0.386 11 C 1.731 1.862 0 .024 12 H - 0.303 3.574 0.685 13 C 2.830 1.065 - 0.246 14 C 4.140 1.662 - 0.125 15 C 2.654 - 0.361 - 0.654 16 C 1.819 - 0.678 - 1.713 17 C 3.358 - 1.438 - 0.002 18 C 1.768 - 1.971 - 2.305 19 C 3.324 - 2.701 - 0.559 20 C 0.963 - 2.26 7 - 3.435 21 C 2.581 - 2.995 - 1.730 22 H 3.836 - 3.515 - 0.053 23 C 0.978 - 3.531 - 3.984 24 H 0.346 - 1.483 - 3.858 25 C 2.564 - 4.288 - 2.317 26 C 1.785 - 4.549 - 3.422 27 H 3.177 - 5.070 - 1.875 28 H 1.782 - 5.542 - 3.863 247 29 O 0.963 0.276 - 2.256 30 O 0.436 1.397 - 0.178 31 C 4.020 - 1.266 1.321 32 C 5.286 - 1.821 1.572 33 C 3.348 - 0.631 2.380 34 C 5.864 - 1.740 2.838 35 H 5.827 - 2.295 0.758 36 C 3.927 - 0.550 3.645 37 H 2.354 - 0.225 2.215 38 C 5.188 - 1.102 3.880 39 H 6.848 - 2.170 3.008 40 H 3.387 - 0.061 4.452 41 H 5.639 - 1.039 4.867 42 C 5.382 1.001 - 0.620 43 C 6.557 1.029 0.150 44 C 5.439 0.424 - 1.900 45 C 7.749 0.500 - 0.342 46 H 6.524 1.448 1.1 51 47 C 6.631 - 0.107 - 2.391 48 H 4.549 0.408 - 2.520 49 C 7.791 - 0.072 - 1.615 50 H 8.644 0.527 0.275 51 H 6.654 - 0.542 - 3.387 52 H 8.720 - 0.486 - 1.999 53 O - 1.261 0.794 - 1.706 54 O - 0.763 - 0.210 1.842 55 C - 2.242 1.390 - 0.923 56 C - 1.515 - 1.143 1.176 57 C - 2.874 0.649 0.062 58 C - 2.613 2.724 - 1.256 59 C - 1.240 - 2.502 1.517 60 C - 2.527 - 0.795 0.290 61 C - 3.936 1.275 0.808 62 C - 1.988 3.465 - 2.294 63 C - 3.673 3.325 - 0.509 64 C - 2.0 43 - 3.523 0.924 65 C - 0.208 - 2.863 2.421 66 C - 3.308 - 1.837 - 0.318 67 C - 4.305 2.572 0.511 68 C - 4.671 0.562 1.895 69 C - 2.387 4.755 - 2.568 70 H - 1.203 3.000 - 2.881 71 C - 4.054 4.658 - 0.816 72 C - 1.783 - 4.877 1.264 73 C - 3.064 - 3.156 0.012 74 C 0.017 - 4.187 2.730 75 H 0.404 - 2.082 2.858 76 C - 4.404 - 1.540 - 1.287 77 H - 5.100 3.041 1.086 78 C - 6.068 0.445 1.827 79 C - 4.007 0.056 3.024 80 C - 3.426 5.359 - 1.820 81 H - 4.858 5.114 - 0.242 82 C - 0.779 - 5.203 2.149 83 H - 2.394 - 5.654 0.811 84 H - 3.655 - 3.939 - 0.455 85 C - 5.709 - 1.985 - 1.023 86 C - 4.157 - 0.870 - 2.497 87 C - 6.784 - 0.168 2.856 88 H - 6.589 0.820 0.951 89 C - 4.725 - 0.553 4.053 90 H - 2.929 0. 153 3.103 248 91 H - 3.729 6.378 - 2.046 92 H - 0.592 - 6.243 2.400 93 C - 6.740 - 1.762 - 1.937 94 H - 5.914 - 2.494 - 0.085 95 C - 5.188 - 0.650 - 3.410 96 H - 3.149 - 0.541 - 2.729 97 C - 6.114 - 0.669 3.973 98 H - 7.865 - 0.255 2.782 99 H - 4.195 - 0.936 4.921 100 C - 6.483 - 1.093 - 3.134 101 H - 7.745 - 2.111 - 1.711 102 H - 4.976 - 0.136 - 4.344 103 H - 6.670 - 1.147 4.776 104 H - 7.284 - 0.919 - 3.847 105 B 0.060 0.822 - 1.373 106 H - 0.758 0.624 1.340 107 H - 0.028 5.836 1.626 108 H 0.363 - 3.750 - 4.852 109 H - 1.904 5.312 - 3.366 110 H 0.812 - 4.454 3.421 END 2 53 Coordinate: 1 C 2.538 5.817 0.669 2 C 3.575 5.062 0.167 3 C 3.453 3.652 0.037 4 C 2.230 3.029 0.429 5 C 1.175 3.831 0.936 6 C 1.328 5.195 1.057 7 H 5.380 3.338 - 0.885 8 H 2.646 6.894 0.765 9 H 4.506 5.534 - 0.137 10 C 4.487 2.850 - 0.503 11 C 2.116 1.608 0.307 12 H 0.249 3.350 1.230 13 C 3.179 0.820 - 0.131 14 C 4.371 1.477 - 0.608 15 C 3.131 - 0.680 - 0.055 16 C 2.223 - 1.422 - 0.810 17 C 4.086 - 1.390 0.761 18 C 2.327 - 2.846 - 0.925 19 C 4.173 - 2.767 0.682 20 C 1.472 - 3.595 - 1.774 21 C 3.336 - 3.523 - 0.175 22 H 4.878 - 3.293 1.319 23 C 1.611 - 4.963 - 1.877 24 H 0.720 - 3.068 - 2.349 25 C 3.440 - 4.935 - 0.290 26 C 2.600 - 5.640 - 1.124 27 H 4.205 - 5.450 0.287 28 H 2.699 - 6.719 - 1.210 29 O 1.212 - 0.821 - 1.509 30 O 0.922 1.042 0.673 31 C 4.949 - 0.698 1.763 32 C 6.317 - 1.004 1.858 33 C 4.405 0.204 2.693 34 C 7.115 - 0.427 2.845 249 35 H 6.757 - 1.683 1.133 36 C 5.202 0.781 3.680 37 H 3.347 0.442 2.649 38 C 6.561 0.469 3.761 39 H 8.172 - 0.674 2.894 40 H 4.759 1.474 4.391 41 H 7.182 0.922 4.529 42 C 5.470 0.737 - 1.293 43 C 6.811 0.969 - 0.944 44 C 5.203 - 0.139 - 2.358 45 C 7.850 0.345 - 1.634 46 H 7.034 1.629 - 0.110 47 C 6.241 - 0.763 - 3.048 48 H 4.175 - 0.315 - 2.659 49 C 7.570 - 0.526 - 2.688 50 H 8.880 0.535 - 1.342 51 H 6.011 - 1.433 - 3.872 52 H 8.378 - 1.014 - 3.226 53 O - 1.241 0.765 - 1.480 54 O - 0.899 - 0.906 0.716 55 C - 2.237 1.405 - 0.815 56 C - 2.122 - 1.563 0.362 57 C - 3.161 0.698 - 0.043 58 C - 2.338 2.826 - 0.974 59 C - 2.111 - 2.975 0.478 6 0 C - 3.183 - 0.799 - 0.080 61 C - 4.149 1.425 0.715 62 C - 1.455 3.549 - 1.816 63 C - 3.364 3.525 - 0.270 64 C - 3.309 - 3.653 0.094 65 C - 1.006 - 3.726 0.958 66 C - 4.344 - 1.517 - 0.553 67 C - 4.230 2.797 0.585 68 C - 5.051 0.765 1.703 69 C - 1.584 4.914 - 1.955 70 H - 0.686 3.007 - 2.354 71 C - 3.463 4.933 - 0.427 72 C - 3.364 - 5.067 0.216 73 C - 4.381 - 2.894 - 0.435 74 C - 1.097 - 5.096 1.065 75 H - 0.085 - 3.219 1.223 76 C - 5.481 - 0.840 - 1.239 77 H - 4.953 3.346 1.182 78 C - 6.421 1.078 1.732 79 C - 4.556 - 0.116 2.678 80 C - 2.594 5.612 - 1.253 81 H - 4.241 5.465 0.115 82 C - 2.284 - 5.773 0.696 83 H - 4.275 - 5.580 - 0.081 84 H - 5.252 - 3.427 - 0.805 85 C - 6.806 - 1.147 - 0.888 86 C - 5.259 0.045 - 2.307 87 C - 7.263 0.529 2.699 88 H - 6.827 1.739 0.973 89 C - 5.396 - 0.667 3.645 90 H - 3.497 - 0.356 2.694 91 H - 2.683 6.689 - 1.368 9 2 H - 2.337 - 6.854 0.786 93 C - 7.877 - 0.584 - 1.582 94 H - 6.993 - 1.812 - 0.051 95 C - 6.330 0.607 - 2.999 96 H - 4.242 0.276 - 2.609 250 97 C - 6.755 - 0.347 3.659 98 H - 8.320 0.783 2.697 99 H - 4.986 - 1.341 4.393 100 C - 7.643 0.296 - 2.639 101 H - 8.895 - 0.830 - 1.290 102 H - 6.137 1.284 - 3.827 103 H - 7.410 - 0.776 4.413 104 H - 8.477 0.735 - 3.180 105 Al 0.102 0.127 - 0.569 106 H - 0.874 - 0.557 1.626 107 H 0.512 5.799 1.447 108 H 0.956 - 5.526 - 2.536 109 H - 0.903 5.458 - 2.603 110 H - 0.242 - 5.663 1.423 END 251 REFERENCES 252 REFERENCES 1. 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