mm 5 «v filt‘uuturdfif Equal: 32.1.: :m Mt... 7.3.... 3%.»! . , .n.wkwl...: r gar... .WQ .. I dun W. “a .II. '9 MW 5!."- n ‘ . ' ' u mvntfiul .9; a i. ‘33.: 4‘ .sn¥$ig...i . .. Gov :mmmm: ‘ (0‘ m. m. TIES“ ‘LIBRARY ”uohigan State a: iiniversity zoool This is to certify that the dissertation entitled DEVELOPMENT OF ONE-POT Pd-MEDIATED REACTIONS & A SYNTHETIC APPROACH TO MONOCILLIN I presented by KYOUNGSOO LEE has been accepted towards fulfillment of the requirements for the degree' m Chemistry ATM-ML am, am ProfessoVs Signature MW 7): 1009 Date MSU is an 'affinnative-action, equal~opportunity employer PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 5/08 K lProleccaPrelelRC/DateDue indd DEVELOPMENT OF ONE-POT Pd-MEDIATED REACTIONS & A SYNTHETIC APPROACH TO MONOCILLIN I By Kyoungsoo Lee A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2008 ABSTRACT DEVELOPMENT OF ONE-POT Pd-MEDIATED REACTIONS & A SYNTHETIC APPROACH TO MONOCILLIN I By Kyoungsoo Lee Our group has developed a one—pot Pd-catalyzed hydrostannation/Stille coupling catalytic tin sequence that use in situ generated tin hydride to reduce some of the toxicity, cost, and purification concerns associated with the use of organotins in Stille reactions. Previously we demonstrated that vinyl, aryl, and benzyl halides are all acceptable electrophiles for this sequence but acid chlorides. Efforts to develop a one-pot hydrostannation/Stille coupling protocol with acid chlorides as the electrophile have revealed that using MeasnF (better than BUSSnF) / PMHS as a tin hydride source and adding the acid chloride to the reaction mixture after the initial hydrostannation, allows for the formation of variety of a,[3-unsaturated ketones in a single pot in excellent yields. In case of bromo-substituted-benzoyl chloride, high chemoselectivity was observed. Despite two potential coupling sites (acid chloride and aryl bromide) this substrate chemoselectively reacted with the in situ generated vinyl stannane at the acid chloride site to afford the product in near quantitative yield. Then, without isolation, an additional allyl, vinyl or aryl stannane is reacted at the aryl bromide site to afford doubly coupled products in good overall yields. During this reaction, aldehyde was formed as by-product in the one-pot hydrostannation IStille coupling reaction. We examined how these aldehydes are formed. Finally, studies showed that PMHS in the presence of fluoride was leading to reduction of acid chlorides to aldehydes. Having developed several one-pot hydrostannation/Stille methods, we sought to validate their utility in the theater of target synthesis, then a total synthesis of monocillin l was attempted. The details of these studies will be descnbed. To My Lovely Family TABLE OF CONTENDS Abstract ............................................................................................................. ii List of Tables ................................................................................................... vii List of Schemes .............................................................................................. viii List of Abbreviation ........................................................................................... xi Chapter 1. Introduction ...................................................................................... 1 Chapter 2. One-pot Hydrostannation/Stille Reaction with Acid Chlorides as the Electrophiles ................................................... 5 21. Introduction ...................................................................................... 5 2-2. One-pot Sequence with Acid Chlorides ........................................... 5 2-3. One-Pot Hydrostannation/Stille Reaction With Acid Chlorides Using BuasnF .................................................................................... 7 2-4. One-Pot Hydrostannation/Stille Reaction With Acid Chlorides Using MeasnF .................................................................................... 9 2-5. One-Pot Sequence of Mono-substituted Alkynes With Acid Chlorides ......................................................................... 11 Chapter 3. One-Pot Multi-Component Stille Sequences .................................. 14 3-1. Introduction .................................................................................... 14 3-2. Chemoselective Coupling to Acid Chloride over Aryl Bromide ...... 15 3-3. One-Pot Multi-Component Stille Coupling Reactions ................... 17 3-4. Optimization of Reaction ................................................................ 18 1) Additional Fresh Pd Catalyst Loading ......................................... 18 2) Additional Different Pd Catalyst Loading ..................................... 19 3) Solvent and Temperature ............................................................ 20 3-5. Recycling of Tin in Multi Step Sequence ....................................... 22 Chapter 4. Pd (0)-Catalyzed PMHS Reductions of Aromatic Acid Chlorides to Aldehydes ........................................................................................ 27 4-1. Introduction .................................................................................... 27 4-2. Reductions of Acid Chlorides ......................................................... 27 4-3. Reductions with PMHS .................................................................. 28 4-4. Reductions of Electron Poor and Aliphatic Acid Chlorides ............ 32 Chapter 5. Application of One-pot Pd-mediated Reactions in Target Synthesis ......................................................................... 35 5-1. Introduction .................................................................................... 35 5-2. Prior Synthesis ............................................................................... 36 5-3. Our Retrosynthesis ....................................................................... 38 5-4. Synthesis of Vinyl Bromide 16 ...................................................... 39 5-5. Synthesis of Benzyl Bromide 19 ................................................... 42 5.6. Synthesis of the Diyne Moiety ....................................................... 44 5.6.1. Synthesis of Vinylstannane 42 from Silyldiyne 41 ................ 45 5.6.2. Synthesis of Vinylstannane 46 from Diyne 45 ....................... 46 5.7. Synthesis of the Terminal lkyne .................................................... 47 5.8. One-pot Sequence with real substrates ........................................ 50 Experimental Details ........................................................................................ 66 vi LIST OF TABLES Table 1. One-pot Hydrostannation/Stille with Acid Chlorides using BuasnF ........ 8 Table 2. One-pot Hydrostannation/Stille with Acid Chlorides using MeSSnFm 10 Table 3. Chemoselective One-pot Hydrostannation/Stille with Bromophenyl Acid Chlorides .................................................................. 16 Table 4. Multi One-pot Hydrostannation/Stille with Bromophenyl Acid Chlorides ................................................................................................ 21 Table 5. Multi One-pot Hydrostannation/ Stille with Recycling Tin ................... 25 Table 6. Pd-Mediated Reaction of Benzoyl Chloride to Benzaldehyde with in Situ Generated MeSnaH .............................................................. 29 Table 7. Various Acid Chlorides Reduction with Pd/PMHS/KF ........................ 31 Table 8. Non-aqueous Reduction of Electron Deficient Benzoyl Chlorides and Aliphatic Acid Chlorides ......................................................................... 34 Table 9. Search for the Stille Reaction Condition ............................................. 54 vii LIST OF SCHEMES Scheme 1. Stille Cross-Coupling Reaction of Vinylstannanes ........................... 1 Scheme 2. Stille Reaction Catalytic Tin ............................................................. 2 Scheme 3. One-pot Hydrostannation/Stille Sequence ....................................... 3 Scheme 4. Three Steps in One-pot Sequence .................................................. 3 Scheme 5. One-pot Hydrostannation/Stille Sequence ....................................... 5 Scheme 6. Outlined Route for One-pot Hydrostannation/Stille with Acid Chlorides .................................................................................. 6 Scheme 7. Preparation of Tin Hydride from Tin Fluoride ................................... 7 Scheme 8. Side Reactions in One-pot Sequence .............................................. 9 Scheme 9. One-pot Sequence of Mono-substituted Alkynes with Acid Chloride .................................................................................. 12 Scheme 10. Stille Reaction with Halo-substituted Benzoyl Chloride ............... 14 Scheme 11. Chemoselective Stille Reaction with 4-Bromo Benzoyl Chloride ............................................................. 15 Scheme 12. Chemoselective One-pot Sequence with 4-Bromo Benzoyl Chloride ............................................................. 15 Scheme 13. Our Strategy for Multi-Components Coupling .............................. 17 Scheme 14. Stepwise Multi-Coupling Reaction ............................................... 18 Scheme 15. Additional Fresh Pd Catalyst Loading ......................................... 19 Scheme 16. Additional Different Pd Catalyst Loading ..................................... 19 Scheme 17. Hydrostannation with szdbaalf-buaP ........................................... 20 Scheme 18. Hydrostannation in 1,4-Dioxane .................................................. 20 Scheme 19. Optimized Multi-Coupling Reaction ............................................. 21 viii Scheme 20. Scheme 21. Scheme 22. Scheme 23. Scheme 24. Scheme 25. Scheme 26. Scheme 27. Scheme 28. Scheme 29. Scheme 30. Scheme 31. Scheme 32. Scheme 33. Scheme 34. Scheme 35. Scheme 36. Scheme 37. Scheme 38. Scheme 39. Scheme 40. Scheme 41. Recycling Tin Multi-Coupling ....................................................... 22 Recycling Double Stille Reactions ............................................... 23 Over-Reduction with in situ Formed Tin Hydride ......................... 24 By-product Formation in One-pot Sequence with BuasnF ........... 27 Acid Chloride Reduction with Buaan under Pd Catalysis .......... 28 Acid Chloride Reduction with Pd/PMHS/KF ................................ 30 Fast Hydrolysis Reaction ............................................................. 32 Lett’s Retrosynthesis ................................................................... 36 Danishefsky’s Route l .................................................................. 37 Danishefsky’s Route ll using Diels-Alder Reaction ...................... 38 Our Retrosynthesis ...................................................................... 39 Lipase Resolution of (:)-17 ......................................................... 40 Synthesis of gem-Dibromide 23 .................................................. 41 (Z)-Vinyl Halide Preparation ........................................................ 42 Preparation of Compound 35 ...................................................... 42 Synthesis of 37 ............................................................................ 42 Stepwise Synthesis of 37 ............................................................ 43 PMHS/KF Dehydrohalogenation Catalyzed by Pd(OAc)2 ............ 44 TBS Protection and Benzylic Bromination ................................... 44 Approach to Synthesis of 15 ........................................................ 45 Synthesis of Diyne 41 .................................................................. 45 Hydrostannation of Diyne 41 ....................................................... 46 Scheme 42. Scheme 43. Scheme 44. Scheme 45. Scheme 46. Scheme 47. Scheme 48. Scheme 49. Scheme 50. Scheme 51. Scheme 52. Scheme 53. Scheme 54. Scheme 55. Scheme 56. Scheme 57. Scheme 58. Scheme 59. Scheme 60. Scheme 61. Scheme 62. Synthesis of Diyne 45 .................................................................. 46 Hydrostannation of Diyne 45 ....................................................... 47 New Route for the Preparation of Terminal Alkyne ..................... 48 Synthesis of y-Silyl Ethynyldithiane 48 ........................................ 48 Nucleophilic Addition of Dithiane to Benzyl Bromide ................... 48 Desilylation of Silyl Alkyne ........................................................... 49 Chemoselective Desilylation of 50 with Silver Nitrate .................. 50 Close to the End Game ............................................................... 50 One-pot Sequence with 28 and 47 .............................................. 51 Desilyation of 50 with TBAF ........................................................ 52 Construction of Diene through Our One-pot Sequence ............... 52 Hydrostannation of 51 ................................................................. 53 One-pot Sequence with B-Bromo Styrene ................................... 53 Our one-pot Sequence with simply Modified Vinylstannanes ...... 55 Furan Formation .......................................................................... 55 Furan Formation from 29 ............................................................. 56 The Proposed Mechanism for Furan Formation .......................... 56 Switch from Vinylstannane to Vinyl Iodide ................................... 57 Stannylation of Vinyl Iodide 28 to Vinylstannane ......................... 57 Preparation of (E)-Epoxy Vinyl Iodide. ....................................... 59 Stille Cross-Coupling Reaction of Mixture of the (E) and (Z)-Epoxy Vinyl Iodide ................................................. 59 Ac Acac AIBN AgNO3 aq BPS GHQCI2 CI CSA Cy DCC DBU DIAD DIBAL DMAP DME DMF DMSO El 99 FAB LIST OF ABBREVIATIONS acetyl acetylacetonate 2,2’-azobisisobutyronitriIe silver nitrate aqueous tert—butyldiphenyl dichloromethane chemical ionization camphorsulfonic acid cyclohexyl dicyclohexylcarbodiimide 1 ,8-diazabicyclo[5,4,0]undec-7-ene diisopropyl azodicarboxylate diisobutylaluminum hydride 4-(dimethylamino)pyridine dimethoxyethane N, N-dimethylformamide dimethyl sulfoxide electric ionization equaflon fast atom bombardment xi h HMPA HRMS HWE IMES-H2 KHMDS LiHMDS m-CPBA Mes mL mmol NaHMDS NBS NMP NOE Ph PMB RCM r.t. TBAF TBS THF hour hexamethyl phosphoramide high resolution mass spectrometry Horners-Wadsworth-Emmons reaction 4,5-dihydro-1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene potassium bis(trimethylsilyl)amide lithium bis(trimethylsilyl)amide m-chloroperbenzoic acid mesityl milliliter millimole sodium bis(trimethylsilyl)amide N-bromosuccinimide N-methyl-2-pyrrolidinone nuclear Overhauser effect phenyl p—methoxybenzyl ring closing metathesis room temperature tetrabutylammonium fluoride tert-butyldimethylsilyl tetrahydrofu ran xii TFP tri-2-furyl phosphine TMS trimethylsilyl PTSA p-toulenesulphonic acid xiii CHAPTER 1. Introduction Pd-catalyzed cross-coupling reactions have provided a simple, powerful and indispensable methodology for the construction of carbon—carbon o-bonds.1 Among those coupling reactions, the Stille reaction is convenient and widely used.2 It involves the Pd-catalyzed cross-coupling of organostannanes and various electrophiles, such as vinyl halides, aryl halides, benzyl halides or triflates and acid chlorides.3 (Scheme 1) Scheme 1. Stille Cross-Coupling Reaction of Vinylstannane Pd Catalyst msnBUS + R-X NR2 4» Bu3SnX R1 2 R1 R1 and R2 = many possibilities X = halogen, OTt, ONf, OAc Despite the well-established power of the Stille reaction, there are negative issues associated with handling the often unstable and/or toxic organostannanes used in these couplings.‘1 To obviate direct manipulation of the stannane coupling partners, procedures that promote the in situ generation of organotin species and their subsequent reactions have been explored. In 1996, Pattenden described a stepwise one—pot palladium catalyzed hydrostannation/Stille coupling.5 A one-pot hydrostannation/Stille coupling which does not require the isolation of the Vinylstannane can be advantageous when dealing with stannanes. From those previous works, it was envisioned that a Stille reaction catalytic in tin could be achieved it an organotin hydride could undergo an in situ chemoselective sequence of Pd(0)—catalyzed Vinylstannane formation followed by cross-coupling, and then regeneration from the organotin halide byproduct. (Scheme 2) Our group has developed a one-pot Pd-catalyzed hydrostannation/Stille coupling catalytic tin sequence6 that uses an in situ generated tin hydride to reduce some of the toxicity, cost, and purification concerns associated with the use of organotins in Stille reactions. Scheme 2. Stille Reaction Catalytic Tin x/VRZ +Pd<0> : H + R1’VSDR3 Pd(0) . vra 2 RSSn-Pd(ll)-H WM/R R1 H‘SDRS R3Sn-X "SI-F" KF Rasn'F PMHS/KP KX Making the Stille sequence catalytic in tin represented a significant “Greening” of the reaction. However, in practice for Stille reactions run at bench scale or with elaborate coupling partners the real advantage of the sequence is that it allows for multiple organostannane reactions to be telescoped into a single reaction vessel. With this in mind additional development of such one-pot reaction schemes is of value are they catalytic in tin or stoichiometric in tin. In the later case this would be especially true if the stoichiometric tin could be recycled in situ and used in multiple steps. (Scheme 3) Scheme 3. One-pot Hydrostannation/Stille Sequence (PPh3)2PdC|2 Pd2dbaa, TFP MeasnF, PMHS \ a Na + r _ Z Bu38nH (1) 1.5 equiv BuaanI, 4.0 equiv KF 2.5 equiv PMHS, 1 drop TBAF, X 0.01 equiv szdbaa, 0.04 equiv TFP /\/k (2) ¢ , Buasn \ THF, 2 h, rt 98% BU3SHF, PMHS cat. TBAF 1 mOIo/o (PPh3)2PdCI2 3 % Br / “ ( ) / + \/\ 7 M Snaus P“ THF / / Ph Previously we demonstrated that vinyl, aryl, and benzyl halides are all acceptable electrophiles for this sequence except acid chloride.6 Efforts to develop a one-pot hydrostannation/Stille coupling protocol with acid chlorides as the electrophile will be discussed in Chapter 2. CHAPTER 2. One-pot Hydrostannation/Stille Reaction with Acid Chlorides as the Electrophiles 2-1. Introduction As discussed in Chapter 1, our group has developed one-pot Pd-catalyzed hydrostannation /Stille coupling sequences that begin with the in situ generation of triorganotin hydrides to obviate negative issues associated with handling the often unstable and/or toxic organostannanes used in these couplings. The hydrides so formed react in situ with alkynes to form Vinylstannanes, which without isolation undergo Stille cross-coupling reactions.6 (Scheme 5) Scheme 5. One-pot Hydrostannation/Stille Sequence (PPh3)2PdC|2 szdbas, TFP MeasnF, PMHS + r - EtZO, 37 °c, 11 hr 88% \\< 2-2. One-pot Sequence with Acid Chlorides In the studies mentioned above, we showed that vinyl, aryl, and benzyl halides were all acceptable electrophiles for this sequence. Noticeably absent from this group of electrophiles were acid chlorides. We considered this omission problematic because acid chlorides represent an important class of Stille electrophiles.1o ln Stille’s earliest studies, he showed that reactions with these compounds could efficiently produce a,[3-unsaturated ketones. Thus, we sought to expand the scope of the one pot hydrostannation/ Stille protocol to include acid chlorides among the viable electrophiles. (Scheme 6) Scheme 6. Outlined Route for One-pot Hydrostannation/Stille with Acid Chlorides cat. Pd As it were, the prospect of adopting a straightforward extension of our existing methodology with acid chlorides exposed a number of uncertainties. Unlike previously used electrophiles, reactions with acid chlorides face a host of potential problems. For example, under our standard conditions the triorganotin hydrides used in the hydrostannation step are prepared by the reduction of organotin halides with polymethylhydrosiloxane (PMHS) in the presence of fluoride.11 Thus, we were confronted with the possibility of residual tin hydride or PMHS reducing the acid chloride12 or the a,B-unsaturated ketone products.13 In addition, while Suzuki reactions with acid chlorides have been done in water,14 we worried about acid chloride hydrolysis. Furthermore, adventitious formation of HCI from the acid chlorides could promote competitive protiodestannylation of the vinyltin intermediates.15 Lastly, decarbonylation16 of the palladium(ll) oxidative addition intermediate was also one of our concerns. Nonetheless, provided these problems could be defeated, achieving the synthesis of various afi- unsaturated ketones from alkynes and acid chlorides in a single pot using an organotin salt as the initial tin source, a single load of catalyst, and unpurified vinyltin intermediates would be attractive. 2-3. One-Pot Hydrostannation/Stille Reaction with Acid Chlorides using BuasnF In starting our exploration of this putative one-pot sequence, we opted to use an anhydrous variation for the in situ generation of tributyltin hydride. Thus, BuasnF, PMHS, and a catalytic amount of TBAF were reacted in the presence of an alkyne and an acid chloride. (Scheme 7) Scheme 7. Preparation of Tin Hydride from Tin Fluoride BuasnF + 1.1 equiv PMHS + cat.TBAF ———> Bu3SnH This procedure gave little of the desired a,B-unsaturated ketone as the acid chloride was consumed by the BuaSnF/PMHS/TBAF combination in advance of the cross-coupling. To avoid this trouble, we simply added the acid chloride (without any additional Pd-catalyst) after Vinylstannane formation was complete. Under this two-step one-pot procedure a variety of cuff-unsaturated ketones could be formed. (Table 1) This first generation study only employed alkynes that were tri-substituted at the propargylic position so that our evaluation of the process would not be complicated by the formation of regioisomers. The protocol proved workable with a variety of acid chlorides. Typically cross- couplings were achieved after 6-10 h at 65 °C and the yields could be very high. However, in some cases intrusive amounts of side products were observed. For example, reactions with either 4-trifluoromethylbenzoyl chloride (entry 3) or 2-chlorobenzoyl chloride (entry 4) witnessed the formation of the corresponding benzaldehydes and the decarbonylated coupling products (Scheme 8). Moreover, despite our best efforts at reaction optimization some of the product yields remained moderate at best. We attributed some of these problems to the relatively slow cross-coupling times. Table 1. One-pot Hydrostannation/Stille with Acid Chlorides using Bu3$nF17 1.5 equiv Bu3$nF, O 1.6 equiv PMHS, /U\ 1 mol % Pdgdba3, R' Cl X 4 mol % TFP, (1.3 equiv) // 0.8 mol% TBAF 9' 65 °C THF, 2 h, rt o \ I] entry R acid chloride Stille rxn time PIOGUCI yield a 1 CH3 cocr 6 h / 96% 2 CH(COgMe)2 6 h R 84% COCI O / 3 CH(COzMe)2 O 2 h OW 74%) b F30 F30 COCI \ 4 CH3 6 h 73% 0 CI CI O / \ o / \ O 5 CH3 a 6 h 0 / 63% COCI 7 CH3 10 h 8 CH3 COCI 10 h 9 CH(COgMe)2 ME 6 h a Average isolated yield over two runs. See experimental section for details. b The decarbonylated product (16%) was also observed. cThe decarbonylated product (73%) and aldehyde (32%) are obtained. 31 % O 91 % 58% Scheme 8. Side Reactions in One-pot Sequence Cl COCI 1 mol% szdbaa Cl CI 4 mol% TFP - \ CHO X 1.5 equrv Bu3SnF (1.3 equiv) M + 0 / 2.5 equiv PMHS 55 °C, 4 h r / 0.8 mol% TBAF 73% 32% THF, 2 h, r1 2-4. One-Pot Hydrostannation/Stille Reaction with Acid Chlorldes using MeasnF In our previously reported tin catalyzed hydrostannation/Stille sequence with other spZ—halides, switching from Buaanl to the less sterically demanding Meaanl gave faster reaction times and decreased byproduct formation.18 Looking for a similar outcome for the two-step one-pot acid chloride coupling sequence, the initial tin species was changed from BuasnF to MeQSnF. We were gratified to observe a significantly improved process. As illustrated in Table 2, using Me3SnF in place of BuasnF typically decreased cross-coupling times from 6 to 2 h. More importantly, the observed increases in reaction rates were generally met with substantially higher yields and fewer visible side reactions. For example, the previously failed coupling of 2-chlorobenzoylchloride (entry 3) could now be achieved in an over all yield of 86%. Other entries worthy of further comment include the reaction of 4-bromobenzoylchloride (entry 6). Table 2. One-pot Hydrostannation/Stille with Acid Chlorides using MeSSnF 1.5 equiv Me3SnF, 2.5 equiv PMHS 1mol% szdbag, 4 mol% TFP 0 8 |°/ TBAF Room 0 ' mo ° (1.3 equiv) /l< T ’ RMf-Bu // THF. 2 h, rt 65 °C 'll . Entry Acid Chloride sgeeg)" Product Yield (%) a 0 Q COCI 2 [ED/KAN?“ 94 0 M90 COCI MGOWt-Bu 96 Me OMe N O E N cocr . 0t 2 .. Cl cocr 4 CE 2 72b N02 NC cocr 5 U 2 98 cocr 6 0/ 4 98 Br 3 cocr 7 2 99 U o 0001 2 9 fig COCI 2 92 10 WGCOC' 2 90 cocr 11 >r 4 92 \ cocr 12 80 Q a Average isolated yield over two runs. See experimental section for details. b Decarbonylation occured even under CO atmosphere. See experimental section for details. 10 Despite its two potential coupling sites (acid chloride and aryl bromide) this substrate chemoselectively reacted with the in situ generated vinyl stannane at the acid chloride site to afford the product in near quantitative yield. Furthermore, that product did not suffer from any unwanted dehalogenation of the aryl bromide.19 Likewise, cinnamoyl chloride afforded the 1,4—diene-3-one in 81%. Unfortunately, even under these conditions not all substrates were universally accepted. As shown in entry 4 on Table 2, 2-nitrobenzoyl chloride still gave the decarbonylated coupling product, even when the reaction was run under an atmosphere of CO. 2-5. One-Pot Sequence of Mono-substituted Alkynes with Acid Chlorides Finally, we examined a reaction sequence that started with an alkyne that was not fully substituted at the propargylic position (Scheme 9). As previously mentioned such substrates afford measurable levels of the proximal Vinylstannanes under Pd-catalyzed conditions.20 Such vinyltins are known to be sluggish Stille partners.21 This is reflected in the slightly diminished yield (66%) of the cross-coupled product, which arose from the partially selective cross- coupling of the distal vinyltin intermediate with the benzoyl chloride.22 Furthermore, it must be noted that for this substrate we were also required to add an additional load of the palladium catalyst and extend the Stille reaction time to 8 h to achieve the reported yield. In an attempt to circumvent the distal/proximal regiochemical matter, we first looked at performing the Pd-catalyzed 11 hydrostannation step on the 1—bromoalkyne derivatives.5 However, for reasons that remain unclear, that substrate did not work well in the hydrostannation/cross- coupling sequence. Another option involved running the hydrostannation step under free radical conditions4 and then adding the acid chloride along with Pd- catalysts to carry out the second step. Scheme 9. One-Pot Sequence of Mono-substituted Alkynes with Acid Chlorides 1.5 equiv MegsnF, 2.5 equiv PMHS, 0.8 mol% TBAF, r 2 mol% (Ph3P)ZCl2Pd, THF, 2 h, rt; OTBS \\ 1.5 equiv Bu3$nF, 2.5 equiv PMHS, r cat. AIBN toluene, 70 °C, 2 h b ores“ BUasn \ + proximal vinyltinJ ores" Bu3Sn \ + Z-vinyltin then (1.3 equiv) benzoyl chloride, 2 mol% (PhaP)4Pd 65 °C, 8 h (71%) ll then (1.3 equiv) benzoyl chloride, 1 mol% (PhaP)2PdCI2 ‘ 65 °C, a h (42%) Owing to the volatility of Meaan, we chose to run the radical hydrostannation with Bu3SnH. While, this modified procedure was successful at eliminating the proximal isomer (at the cost of some Z-vinylstannane formation), recourse to the tributyltin again gave the a,(3-unsaturated ketone in only modest 12 average overall yield (42%). Usefully, the TBS ether survived the fluoride present throughout both successful sequences. In summary, we expanded the one-pot hydrostannation/Stille coupling method to allow acid chlorides to serve as the electrophilic coupling partner. Problems associated with the use of these reactive building blocks were avoided by adding the acid chloride to the reaction after the Vinylstannane was produced in situ from MessnF/PMHS generated Me3$nH and a corresponding alkyne. Both aliphatic and electronically varied aromatic acid chlorides could be employed in this one-pot synthesis of a,(3-unsaturated ketones. 13 CHAPTER 3. One-Pot Multi-Component Stille Sequences 3-1 . Introduction During our development of the one-pot hydrostannation/Stille sequence with acid chlorides as the electrophile, we found that halo-substituted benzoyl chlorides cross-coupled chemoselectively at the acid chloride site, keeping the aryl halide bonds in tact (Chapter 2). This was somewhat surprising since it is shown that when Stille coupling of 4-bromobenzoyl chloride with organotin compounds give reduced yields and a significant amount of the aryl bromide coupled byproduct.23 (Scheme 10) Moreover it was not until 2005 that Wolf’s group24 was able to define a set of generally chemoselective conditions for the Pd-catalyzed coupling of halo-bearing aryl acid chlorides with aryl/ vinyl stannanes. In these examples bis-(di-tert-butyl chloro phosphine) palladium(ll) dichloride catalyzed cross-coupling of acyl chlorides with organostannanes in refluxing acetonitrile provided a means to prepare aliphatic and aromatic ketones with aryl bromide tolerance. (Scheme 11) Scheme 10. Stille Reaction with Halo-substituted Benzoyl Chloride O o COCI 0.05 mol% PhCHgPd(PPh3)2CI O + SnMe4 = + B, . HMPA, 65 °C, (1.05 equrv) Br Me 67.5% 25.9% 14 Scheme 11. Chemoselective Stille Reaction with 4-Bromo Benzoyl Chloride t'B”, .f—Bu P; Cde. Cl COCI f-Bu“ _ (2.5 mol%) 0 + QSHBU3 tBU t O 3, \ / 82°C, 20h I / 3-2. Chemoselective Coupling to Acid Chloride over Aryl Bromide In light of these few previous reports, we were excited that our one-pot sequence not only afforded the chemoselective coupling reaction of 4-bromo benzoyl-chloride with the in situ formed Vinylstannane without unwanted cross coupling at the aryl bromide, but also in that the reaction product did not suffer from any unwanted dehalogenation of the aryl bromide. (Scheme 12) Scheme 12. Chemoselective One-pot Sequence with 4-Bromo Benzoyl Chloride szdbaa (1 mol %), l TFP (4 mol %), COC Me3$nF (1.5 equiv), 0 PMHS (2.5 equiv), Br / /]< TBAF (0.8 mol%), (1.2 equiv) é THF, rt. 2 h 65 °C, 4 h 2 3' 98% Of course, this was only a single example therefore we decided to subject an expanded set of bromo—containing acid chlorides to the reaction sequence. The results are shown below on Table 3. 15 Table 3. Chemoselective One-pot Hydrostannation/Stille with Bromophenyl Acid Chlorides szdbag TFP \ Me3SnF PMHS BrQWCOC'B; TBAF THF, rt, 2h = 65°C 4h t'Bu Entry Acid Chloride Product Yield(°/o) cocr 0 Br Br Br COCI O COCI 3 t-Bu 55 Br BfiCOC' 8W t-Bu 4 l COC / t—Bu 5 7 Br Br We found that 4-bromo benzoyl chloride undenrvent Pd-catalyzed ketone X— formation with in situ formed Vinylstannane to give 4-bromophenyl ketone in 98% yield. 3-Bromo benzoyl chloride reacted in just a little bit lower 80% yield. In the case of 2-bromo benzoyl chloride the yield dropped to 55% and some side reactions were observed, namely over-reduction of the olefin and decarbonylation. Even 4-bromo-phenyl aliphatic acid chlorides worked well to give moderate to good yield for the three consecutive reactions. 16 3-3. One-Pot Multi-Component Stille Coupling Reactions As the one-pot sequence afforded ketones containing an aryl bromide we asked if this reaction sequence could be subjected to a second Stille coupling at that aryl bromide site after adding another organostannane. Based on the previous results, the selective addition of two different kinds of organostannanes to halo-substituted acid chlorides to generate multi-component coupled products, without intermediate isolation, became our goal. Our strategy is shown on Scheme 13. Scheme 13. Our Strategy for Multi-Components Coupling szdba3, TFP Me3SnF, PMHS M S / —:—t-BU TBAF t 93 ”\At-BU] THF, rt, 2 h | \ BF‘T“ o / COCI 65 C.4h n (0:04) ll 0 R' : R'SnR3 Br-'-\ 0 n t‘BU‘ ............ / / t‘BU Of course there are potential problems in this sequence, including incomplete differentiation of the electrophilic sites and unwanted reactions between the first cross-coupled product or the lastly added stannanes and the reaction milieu. If these problems could be overcome, the formation of doubly- coupled a,B-unsaturated ketones in this manner would be advantageous in a number of ways. (1) No intermediate separation or isolation would be required. (2) Tin waste from all reactions could be removed in a single and final step. (3) 17 The protocol would allow for the rapid buildup of molecular complexity. (4) Such a sequence could be potentially adapted to automated and/or parallel syntheses. 3-4. Optimization of Reaction We first explored the proposed sequence by simply following the first one- pot hydrostannation/Stille reaction with the addition of allylSnBua. Unfortunately that reaction did not succeed as only trace amounts of product were collected. (Scheme 14) Obviously study would be needed to achieve the desired multi- component coupling sequence. Scheme 14. Stepwise Multi-Coupling Reaction Pdgdbaa (1 mol o/O), CI TFP (4 mol %), CO Me3SnF (1.5 equiv), PMHS (2.5 equiv), Br allyISnBu3 O /l< TBAF (0.8 mol%), (1.2 equiv) (1.2 equiv) / é THF, rt, 2 h 65 °C, 4 h 75 °C, 3 days trace 1) Additional Fresh Pd Catalyst Loading As simply adding the second organostannane after the first Stille reaction was unsuccessful, we hypothesized that the catalyst was dying prior to the second Stille reaction. Thus we looked at adding fresh Pd and trifuryl phosphine along with the allylSnBua. (Scheme 15) However, the reaction outcome did not get much better as we got just under 10% yield of the doubly coupled product. 18 Scheme 15. Additional Fresh Pd Catalyst Loading Pdgdbaa (1 mol %), TFP (4 mol %), COCI MeasnF (1.5 equiv), O 2 mol% szdba3, O PMHS (2.5 equiv), 8 mol% TFP / /k TBAF (0.8 mol%), (12 equiv) 1.2 equrv allylSnBu3 é THF, rt, 2 h 55 °c, 4 h 75 °C, 2 days \ <10% 2) Additional Different Pd Catalyst Loading. We next sought to overcome the sluggishness of the second Stille reaction by adding more reactive Pd/Iigand combination. The literature25 is rich with examples where Pd/t-Bu3P serves as a versatile catalyst for Stille reactions. This system represented the first general method for couplings of aryl chlorides and for room-temperature couplings of aryl bromides. Therefore we looked at replacing tri-2-furylphosphine (T FP) with t-Bu3P during the second Stille. This greatly improved the outcome of Scheme 16. After 2 days a 78% yield of the doubly-coupled product was obtained. Scheme 16. Additional Different Pd Catalyst Loading. szdea (1} mol o/o), TFP (4 mol %), COCI O Me3$nF (1.5 equiv), 2 mol% szdba3, PMHS (2.5 equiv), Br 8 mol% t-Bu3P / /‘< TBAF (1 drop), (1.2 equiv) 1.2 equiv allylSnBua é THF, rt, 2 h 7 65 °c, 4 h a 75 °C, 2 days 7 \ 78% We also examined the use of the more active tri-tert-butyl phosphine ligand during the first step with the hope that it would facilitate the second Stille reaction and simplify the sequence. Again though, lower yields and the over 19 reduced byproducts were observed at the first hydrostannation step. (Scheme 17) Scheme 17. Hydrostannation with szdbaslt-busP 0 Me3SnF (1.5 equiv) / PMHS (2.5 equiv) COCI 73% szdba3 (1 mol%) Br + t-Bu3P (4 mol%) Br cat. TBAF (1.2 equiv) O THF,2h,rt 65 °C,4h w 70/0 Br 3) Solvent and Temperature X Even though replacing TFP with t-Bu3P gave us better results, we were not fully satisfied with reaction conditions. It is well documented that high temperatures are sometimes needed in Stile couplings.4 However, the use of THF as solvent in the first step of the sequence limited how high the temperature could be raised. Therefore we investigated using the higher boiling solvent 1,4- dioxane at the beginning of the reaction. Unfortunately this change gave us lower yields and over-reduced byproduct during the hydrostannation/Stille reaction. (Scheme 18) Scheme 18. Hydrostannation in 1,4-Dloxane Me3SnF (1.5 equiv) CH0 PMHS (2.5 equiv) 20% szdba3 (1 mol%) COCI 0 Br TFP (4 mol%) 3 /k cat. TBAF Br w 0 // dioxane, 2 h, rt 65 °C- 4 h Br 0 6% 46 /0 Br 20 Scheme 19. Optimized Multi-Coupling Reaction Me3SnF (1.5 equiv) PMHS (2.5 equiv) 000' szdba3 (1 mol%) 0 szdbag (2 mol%) 0 TFP (4 mol%) Br t-Bu3P (8 mol%) / X cat. TBAF (1.2 equiv) allylSnBu3 (1.2 equiv) // THF, 2 h, rt 65 °C. 4 h 1,4-dioxane, 95 °C, 18 h \ 97% Table 4. Multi One-pot Hydrostannation/Stille with Bromophenyl Acid Chlorides MegsnF (1.5 equiv) PMHS (2.5 equiv) Br._ \ szdbag (1 mol%) ' / coc| szdba3 (2 mol%) TFP (4 mol%) n t-Bu3P (8 mol%) \ O X TBAF (0.8 mol%) (1.2 equiv) R'SnR3 (2.0 equiv) R'—:- / / F T T t-Bu // THF, 2 h, rt 65 °C. 4 h 1,4-dioxane, 90 °c ” (n=0~1) Entry Acid Chloride R'SnR3 rxn time (h) Product Yield (%) COCI WSDBU3 12 Wt-Bu 82 O That said, adding an equivalent volume of 1,4-dioxane to the THF reaction after the first in Stille reaction and increasing oil bath temperature to 90 °C during 21 the second Stille coupling met with big improvements in the yield affording the product almost quantitatively. (Scheme 19) With these conditions we examined the formation of a variety of doubly-coupled a,j3-unsaturated ketones. (Table 4) Bromo benzoyl chloride underwent the one-pot multi coupling reaction with vinyl, allyl, aryl stannanes to give corresponding multi-coupled ketones in yields up to 98%. 3-5. Recycling of Tin in Multi Step Sequence In Table 4, the second Stille was always performed with newly added organostannane. In an attempt to push the limit of our multi component sequence even further, we considered the possibility of generating the second organostannane in situ. Specifically we thought that it should be possible to recycle the trimethyltin chloride formed in the first one-pot hydrostannation/Stille. (Scheme 20) Scheme 20. Recycling Tin Multi Coupling COCI U 0 ° cat. Pd / X Me3SnH Br I w / , r / T [Br I MegsnF RI R'é MB3SUCI k 7 PMHS, TBAF KF(aq.) R,/\/SnMe3 22 If the trimethyltin chloride could be converted to trimethyltin hydride then addition of an alkyne would pave the way for an in situ hydrostannation where the newly formed vinyltin could participate in the second Stille reaction. Such a process is illustrated below. We began to explore this tin-recycling sequence by simply adding another terminal alkyne, PMHS, and KF after first hydrostannation/Stille coupling reaction, allowing 2 h for the second tin hydride formation and in situ formation of Vinylstannane. After the second hydrostannation, szdbaa, t-Bu3P and dioxane were added to the mixture, which was then stirred with heating to 90 °C for 12 h. (Scheme 21) Scheme 21. Recycling Double Stille Reaction Pdgdbaa (1 "10' °/o), TFP (4 mol %), COC' Me3SnF (1.5 equiv), O ' PMHS (2.5 equiv), Br / /l< TBAF (0.8 mol%), (1.2 equiv) é THF,rt,2h 7 65°C,4h V 3' 1' MeaanI J / PMHS (1.5 equiv), O 7 OH KF (aq.) (3.0 equiv), . TBAF (0.8 mol%) (5.0 SQUIV) rt 2 h ._ O _ \ 41% szdbaa (2 mol %), / OH t-Bu3P (16 mol %), O L Br dioxane, 90 °c, 12 h \ Measn NH 0 _ .J OH 27 /o 23 This procedure proved moderately successful. The reaction sequence afforded 27% of the anticipated doubly-coupled product. However, 41% of the over-reduced doubly-coupled product was also produced. This product results from some of the regenerated trimethyltin hydride and/or PMHS reducing the 6,6- unsaturated ketone. We probed this reduction by following the first Stille reaction with the addition of PMHS/KF in the absence of any alkyne. This resulted in formation of a 1:1 mixture of enone and saturated ketone.26 (Scheme 22) Scheme 22. Over-Reduction with in situ Formed Tin Hydride O szdbaa (1 mol %), COCI / TFP (4 mol %), \ o Me3SnF (1.5 equiv), 0 M60 40 /" PMHS (25 equiv). M60 3 equiv PMHS + TBAF (0.8 mol%), (1.3 equiv) 3 equiv KF(aq.) O X THF,rt,2h 65°C,4h 65°C,2h V 36% M60 To avoid the over-reduction problem we removed the offending alkene by running the first Stille reaction with arylstannanes instead of Vinylstannanes.3 To our satisfaction this change worked well. The one-pot Stille reaction/ hydrostannation/Stille reaction with recycled trimethyltin hydride afforded the multi-component products in up to 53% yields. (Table 5) This represents an average yield of up to 85% for each step. 24 Table 5. Multi One-pot Hydrostannation/Stille with Recycling Tin : R (3.0 equiv), o SnM63 COCI PMHS (3.0 equiv), Pdgdba3 (1 mol %), KF (aq.) (3.0 euiv), szdba3 (2 mol %), + TFP (4 mol %), TBAF (0.8 mol%) t-Bu3P (16 mol %), THF, 65 °C, 4 h "r 2 h dioxane. 90 °C I Br R Entry Alkyne Time (h) Product Yield (%) O a Alkyne byproduct and unreacted 1 >/ 12 O O 50 a intermediate were obtained in this / reaction. 0 ¢ 7% 2 ‘2 O O 53 O O OH 0 / OH 0 Br / / 13% gyros.» 00 OH site. In summary, we have expanded the one-pot hydrostannation/Stille coupling of aromatic acid chlorides for substrates containing a halo-substituent on the aryl ring. We showed that such acid chlorides chemoselectively react with the in situ generated Vinylstannane at the acid chloride site over the aryl bromide This selective addition enables the coupling of two different kinds of organostannanes to halo-substituted acid chlorides to generate multi-component coupled products without intermediate isolation. The tin byproduct of the first Stille reaction between an arylstannane and an acid chloride can be recycled for use in an in situ hydrostannation with an added alkyne and then the in situ 25 formed Vinylstannane can undergo the second Stille coupling. In these last examples it must be noted that, where possible, 1,4-reduction can be competing side reaction. 26 CHAPTER 4. Pd (0)-Catalyzed PMHS Reductions of Acid Chlorides to Aldehydes 4-1. Introduction As described in the Chapter 2, we have expanded the one-pot hydro- stannation/Stille coupling method to allow acid chlorides to serve as the electrophilic coupling partner.27 In the course of researching this one-pot sequence with acid chlorides as electrophiles, we obtained the intrusive amounts of aldehyde from the reduction of acid chloride. (Scheme 23) This finding prompted us to investigate this side reaction further. Scheme 23. By-product Formation in One-pot Sequence with BuasnF CI COCI 1 mOIO/o szdba3 CI Cl 4 mol% TFP . \ CHO X 1.5 equrv Bu3SnF (1.3 equiv) M + 6 / 2.5 equiv PMHS 65 °C, 4 h 7 / 0.6 mol% TBAF 71 % 32 % THF, 2 h, rt 4-2. Reductions of Acid Chlorides The reduction of acid chlorides to aldehydes is a basic and well-known functional group transformation and has been developed by various reaction conditions. Among those, reductions under Rosenmund conditions or by Li(t- BuO)3AlH are classic means for effecting the reaction.28 However, it was problematic due to the over-reduction to alcohols and intolerance of other 27 functional groups. Since that, the quest for greater selectivity and efficiency has long prompted the development of alternative methods. The effectively selective conversions from acid chloride to aldehyde have been explored including several complex metallic hydrides, and several hydride reagents.29 The palladium- mediated organotin hydride reductions invented by Guibé have proven particularly popular. 3° (Scheme 24) Scheme 24. Acid Chloride Reduction with Bu38nH under Pd Catalysis O 1 mol% Pd(PPh3)4 O 1.2 eq. Buaan Cl 5 H benzene, rt, 0.5 hr 95 % 4-3. Reductions with PMHS Of course, organotin reagents carry the baggage of being relatively toxic, expensive, unstable, etc.31 Thus, mindful of prior reactions made catalytic in tin through the use of polymethylhydrosiloxane (PMHS) as the stoichiometric t32 reductan we contemplated a tin-catalyzed version of Guibe's method for reducing acid chlorides to aldehydes. As a prelude to that goal, we examined the Pd-catalyzed reduction of benzoyl chloride with a stoichiometric amount of Meaan that was generated in situ by the reaction of Me3SnCl with PMHS in the presence of aqueous KF (entry 1, Table 6).7a Despite the potential for hydrolysis and unwanted reactions, this combination rapidly and quantitatively afforded benzaldehyde. We next looked to 28 make the reaction catalytic in tin. Needless to say, we were pleased when reactions with 30 mol% and then 10 mol% tin worked nearly as well as the stoichiometric variant (entries 2-3). That satisfaction turned to surprise when, after 1 h, a tin-free control experiment (entry 4) also gave 100% benzaldehydel Table 6. Pd-Mediated Reduction of Benzoyl Chloride to Benzaldehyde with in situ Generated Meaan Meaanl, 1.5 equiv PMHS, aq KF @000 0.8 mol% TBAF OCHO szdba3/TFP (1 :4), THF, rt entry Pd (0) Meaanl KF time yield 1 1 mol% 1.0 eqiuv 1.5 eqiuv 0.5 h 100% 2 1 mol% 0.3 eqiuv 1.5 eqiuv 0.5 h 100% 3 1 mol% 0.1 eqiuv 1.5 eqiuv 1.0 h 100% 4 1 mol% - 1.5 eqiuv 1.0 h 100% 5 1 mol% - - 24 h 12% 6 1.5 eqiuv 24 h 0% We were caught unawares by this result because, while organosilanes "33 it has been over have long been used to convert acid chlorides to aldehydes, 20 years since Keinan and Greenspoon reported that acid chlorides " nn t mducecLiust with PMHS/Pd(Pl’hfig'.34 Their observation was later supported by Crabtree, who found that colloidal. Pd formed from Pd(hfacac)2 and PMHS required the presence of H2 gas to reduce benzoyl chloride to benzaldehyde.35 29 In our system, it appeared that the presence of KF heightened the reactivity of the PMHS to where the acid chlorides can be converted to their aldehydes without the need for an additional reductant. This was supported by our own KF-free experiment (entry 5), which only gave 12% benzaldehyde after 24 h. That said, activation by KF is not sufficient to abolish the need for Pd catalysis (entry 6). We presume the fluoride activates PMHS by making it hyper-coordinate.36 Nonetheless, unlike acid chlorides, acid fluorides can be reduced by just PMHS/Pd(O).37 Therefore, we had to consider if benzoyl chloride was first converted to benzoyl fluoridea"3 and then reduced to benzaldehyde. However, GC monitoring never indicated the presence of benzoyl fluoride. Furthermore subjecting benzoyl fluoride to our reaction conditions failed to afford any benzaldehyde. (Scheme 25) Scheme 25. Acid Chloride Reduction with Pd/PMHS/KF O 3 equiv PMHS, 3 equiv KF(aq.) O 1 mol% szdbaa, 4 mol% TFP, Q/lLF 0.6 mol% TBAF ©/&H THF, 12 h, rt No reaction in GO monitoring With an acid fluoride intermediate ruled highly unlikely,39 this reduction represents a noteworthy refinement of the literature. Moreover, given that PMHS is mild, safe, and cheaps, these conditions may be attractive as a general way to convert acid chlorides to aldehydes. To assess this prospect, we tested a series of acid chlorides against the PMHS/KF/Pd(0)conditions. (Table 7.) 3O Table 7. Various Acid Chlorides Reduction with Pd/PMHS/KF O 3.0 equiv PMHS, 3.0 equiv KF(aq) O R/lLCI 1 mol % szdbaa, 4 mol % TFP, v R/lLH 0.8 mol % TBAF, THF, rt, 1 h Entry Acid Chloride Aldehyde Yield 1 benzoyl chloride benzaldehyde 99% Me Me cocr GHQ 83% Q Q. COCI f-Bu E: i> 3 t- BU CHO 99°/o COCI M60 CHO 910/0 9 M60 M90 5 OCOCI O—CHO 98% M60 M60 6 MeO—OCOCI MeOAOVCHO 82% M60 MeO COCI GHQ 86% 8 8 COCI GHQ 81 % 8 8 cocr 92% (D \ 0);] / \ (1);: / O I 0 cool CHO 68% 10 E: a: 31 We soon saw that not all substrates underwent complete reaction with 1.5 equiv of PMHS. In contrast, 3.0 equiv of PMHS and aqueous KF in the company of substoichiometric amounts of Pd(O), trifurylphosphine (TFP), and TBAF40 uniformly reduced a variety of electron-rich and neutral aryl acid chlorides (entries 1-8 in Table 7), including heterocyclic 2-thiophenoyl chloride (entry 9), to their aldehydes within 1 h at room temperature. Despite the ability of PMHS/Pd(O) to reduce aryl halides,‘9'41 4-bromobenzoyi chloride was selectively reduced to 4-bromobenzaldehyde and no benzaldehyde was detected by GC (entry 10). 4-4. Reductions of Electron Poor and Aliphatic Acid Chlorides As shown in Table 7, the previously described reduction conditions were not universally applicable. Neither electron deficient benzoyl chlorides nor aliphatic acid chlorides were efficiently reduced. Instead the water in the reactions rapidly hydrolyzed such substrates. (Scheme 26) Scheme 26. Fast Hydrolysis Reaction 0 3 equiv PMHS, 3 equiv KF O 1 mol% szdba3, 4 mol% TFP, CI 0.8 mol% TBAF OH OZN THF/H20, 1 min, rt 02N To expand this methodology to include electron deficient benzoyl chloride and aliphatic acid chloride, it was clear that water should be avoided. Among the reasons for the presence of water was the need to solubilize the potassium 32 fluoride. Thus an early idea was to simply replace KF with stoichiometric amounts of TBAF. Unfortunately such amounts of TBAF promote sol-gel formation upon reaction with the PMHS. We then looked at exchanging water with an aprotic organic solvent such as acetonitrile that could at least partially dissolve KF. Again we were disappointed when the reaction In acetonitrile did not go. Of course, we also knew that crown ethers could facilitate the movement of fluoride into other aprotic solvents. In fact coincident with these initial studies on anhydrous reduction conditions our lab established conditions for the non-aqueous hydrostannation of alkynes under Mo catalysis with Bu3$nC|/PMHS with dry KF and 18-crown-6 in THF.‘2 With this information in hand we thought to apply similar non-aqueous reaction conditions to the reduction of aliphatic and electron-deficient aromatic acid chlorides to aldehydes. As illustrated in Table 8, reduction of such substrates with 3 equivalents of both PMHS and KF along with 1 equivalent of 18-crown-6 afforded the corresponding aldehydes. These anhydrous reactions tended to take longer (6 hours) and yields tended to be lower (50 to 71%). However, hydrolysis was shut down with trace amount of over-reduced products as the only observable byproducts. 33 Table 8. Non-aqueous Reduction of Electron Deficient Benzoyl Chlorides and Aliphatic Acid Chlorides 3 equiv PMHS, 3 equiv KF, 1 equiv 18-crown-6 1 mol% szdbaa, 4 mol% TFP, o 0.8 mol% TBAF o R/lLCI THF, rt ' R/lLH Entry Acid Chloride rxn time (h) Product Yield (%) a 1 WCOCI 6 WCHO 71 HO 2 Macao/MCOC' 5 rilleozc’\i~i’3C 53 3 M000) 6 MCHO 50 o: O I O 3 COCI 4 ©/\/ OZN OZN 3 Average isolated yield over two runs. See experimental section for details. In summary, the presence of fluoride allows Pd(0)-catalyzed PMHS reductions of electron-rich and neutral aryl acid chlorides. Yields are generally high and reaction times short. Perhaps most importantly, these results amend the existing literature. Electron-rich and neutral aryl respond well to standard aqueous KF/PMHS conditions, but for electron poor or aliphatic acid chlorides KF/18-crown-6 needs to be used instead of aqueous KF to avoid acid chloride hydrolysis. 34 CHAPTER 5. Application of One-pot Pd-medlated Reactions in Target Synthesis 5-1. Introduction Having developed several one-pot hydrostannation/Stille methods, we sought to validate their utility in the theater of target synthesis. The molecule chosen for this task should meet several criteria. (1) The molecule should have been previously synthesized so as to allow us a direct evaluation of any efficiency gained via the employment of our chemistry. (2) Retrosynthetic analysis of the molecule should reveal multiple opportunities to showcase our methodology. (3) The synthesis of the chosen target molecule should be instructional beyond application of the one-pot hydrostannation/Stille sequence. We deemed monocillin I a molecule that satisfied these three conditions (Figure 1).43 Figure 1. The Structure of Monocillin I { . Monocillin l 35 5-2. Prior Synthesis Monocillin I is a resorcylic macrolide isolated from Monocil/ium nordinii.44 Monocillin l exhibits a variety of antifungal and antibiotic properties not shared by other members of this class of natural products. The structure of monocillin l was confirmed by its direct conversion into radicicol.45 Affirmation of these structures was achieved by their total synthesis by Lett46 and Danishefsky.47 Lett's retrosynthesis is shown in Scheme 27. Lett began with a condensation between the lithiated alkyne 1 and aldehyde 2, followed by the addition of RzBH to afford vinylborane 3. lsocoumarin 5 was obtained via a Suzuki-Miyaura coupling with allyl chloride 4. Macrolide 6 was synthesized via an intramolecular Mitsunobu reaction. The conjugated E, Z-diene was installed by elimination of the in situ generated mesylate with EtsN. Following deprotection, monocillin l was obtained in 15% overall yield from aldehyde 2 and TMS acetylene. Scheme 27. Lett’s Retrosynthesis monocillin l C: m + ' I: ' + TMS%U / CI 5 $\ TBSO 4 RZBMOMOM HA0 1 3 2 36 Danishefsky's retrosynthesis is outlined in Scheme 28. Danishefsky planned a convergent coupling sequence for three key intermediates. The first coupling was an esterification of benzoic acid 8 with the optically active secondary alcohol 9 containing all three stereogenic centers of monocillin I. The second coupling required a chemo- and regioselective addition of a masked acyl anion equivalent 10 to the benzyl chloride carbon in the presence of a vinyl epoxide. To complete the synthesis, 3 stereospecific ring-closing metathesis of 7 afforded the desired monocillin I. Scheme 28. Danishefsky’s Route I OH 0 g 0 II HO 0 “CM.” on o _ _ _ :9 OH :\ W R0 CI . S S Li 7 [/W 10 While most syntheses of these resorcylic macrolides had begun with an intact substituted aromatic ring, he approached this synthesis differently. He used the Diels-Alder reaction shown in Scheme 29 to construct the aromatic moiety. In this regard, macrolactone ring 12 was prepared from three key starting materials, then this alkynyl macrolactone served as the dienophile in the aforementioned Diels-Alder reaction. 37 Scheme 29. Danishefsky’s Route II using DieIs-Alder Reaction Cycloproparadicicol 11 5-3. Our Retrosynthesis Our own retrosynthetic examination of monocillin I suggested the newly developed one-pot hydrostannation/Stille chemistry described before could be applied to the formation of 01—02, 02—03, and/or C4—C5 In the end, it was decided that our first generation retrosynthesis involving the newly developed Stille chemistry would be applied to the construction of the 01-02 and C4-CS bonds. That retrosynthesis is outlined in Scheme 30. Retrosynthetic disassembly of monocillin I provided intermediate 14 as a precursor which could undergo an intramolecular Mitsunobu reaction. The diene moiety in monocillin I would be installed via a one-pot hydrostannation/Stille sequence between alkyne 15 and Z-vinyl bromide 16. The Z—vinyl bromide 16 could be obtained via routine synthetic operations starting from the commercially available 4—penten-2-ol 17. The one-pot Stille protocol would then be used to form alkyne 15 from benzyl bromide 19 and diyne 18. Benzyl bromide 19 could be synthesized via the commercially available methyl acetoacetate 20 and methyl crotonate 21. 38 Scheme 30. Our Retrosynthesis COZH go /' 5 monocillin I 14 TBSO C 22$ HO TBSO . r 17 16 \/ - \ OK4+ B/: 5 0 PG T880 0 /U\/CQZM9 ‘ 20 2' | r::> + 2| I 18 TBSO NCO2M9 21 5-4. Synthesis of Vinyl Bromide 16 The first building block to be assembled was vinyl bromide 16. Establishing the methyl group stereochemistry at what would become the C10 carbon of monocillin became our immediate goal. Towards this end optically active 17 would represent a good starting point. Although several asymmetric syntheses of 17 are known and a carbohydrate-based approach was previously developed,48 we chose the resolve racemic 17 by way of an enzyme catalyzed kinetic resolution.49 This decision was based on the realization that both 39 enantiomers could be used for the formation of the lactone through either Mitsunobu way or Yamaguchi esterifications. Scheme 31. Lipase Resolution of (1)-17 M OH LipaseB (S)-17:25%yield,99%ee / vinyl acetate 1' OA ° c (1)-17 25 C, 12h ? M 40% yield, 65% ee acetaldehyde THF, 0 °C, 2 h With this approach in mind (1)-17 was prepared via a Grignard reaction between allylmagnesium bromide and acetaldehyde.50 With racemate 17 in hand, various enzymes were explored for the desired kinetic resolution. From these experiments Novozyme emerged as the enzyme of choice. After column chromatography, (s)-17 was obtained in 25% yield with a 99%ee. (Scheme 31) The ease and cost of the protocol, as well as the high enantiomeric purity, warranted using this protocol in the total synthesis. In order to transform the newly resolved material into vinyl bromide 16, homoallylic alcohol (s)-17 was first protected as its corresponding tert-butyldiphenylsilyl ether 22. The alkene moiety was then subjected to a one-pot ozonolysis-Wittig olefination to afford ester 23 in 90% yield.51 DIBALH reduction of 23 gave the corresponding allylic alcohol 24 in 92% yield. Sharpless asymmetric epoxidation (D-DET) afforded the corresponding epoxy alcohol 25 in 85% yield. The alcohol was then oxidized52 with 803° py and EtaN to afford epoxy aldehyde 26 in 72% yield. (Scheme 32) 4O Scheme 32. Synthesis of gem-Dibromide 23 OH _ B'SSCII OBPS a) 03. ~78 °C to rt QBPS M "T" azoe : M CHZClz, 2h ‘ MCOZEt (5)47 DMF. 3.11 h 22 b) Et3N, 25 °C, 23 99 4 Ph 15 min _ _\ ._ Ph P=CHCO Et (BPS- t-Bu [SI ) 3 90% 2 Ph OBPS D-DET, Ti(I-PrO)4 QBPS 0'8““ 4 ; TBHP, 4AMs W CH CI -78 °c 6 hr W0” T OH 2 292% ’ 24 CHZCIZ, -30°C, 12h 25 85% SOa-py, Et3N QBPS o CHZCl2/DMSO (4:1)7 W0 0°C,1 h 26 72% Subjection of the epoxy aldehyde 26 to a modified Corey-Fuchs protocol was necessary so the epoxide moiety would remain intact.53 The use of Et3N was essential for the success of the reaction. This procedure produced gem- dibromide 27 in 85% yield. With gem-dibromide 27 in hand, the next step was to form the Z-vinyl bromide group. (Scheme 33) Per the literature treatment of 27 with 1.0 equiv of Bu3SnH in the presence of Pd(PPh3)4 should afford the desired Z—vinyl bromide 16.54 However, in our hands, this protocol did not give clean vinyl bromide. With the general dibromide approach to 16 failing, we considered alternative routes that would still use aldehyde 26 as a starting material. Among the routes consider the most successful involved construction of a (2)-vinyl iodide (28) through a setereoselective Wittig reaction with iodomethyltriphenyl- phOSphorane (PhaPCHzlz) to afford the vinyl halide with an E/Z ratio >921.55 41 Scheme 33. (2)-Vinyl Halide Preparation Pd(PPhaH)4 gaps o CBr4,Ph3P, QBPS Bu3SnH Caps 0 W ........... \ o EtN,CHCI, We CHCl, W 26 38 °c 22l12 22 2 16 Br 85% Ph3P-CH2l2, ears 0 NaN(TMS)2 QBPS o W : \ \o THF, -20 °C, 20 min W 26 72%(E/Z: >9:1) 28 | 55. Synthesis of Benzyl Bromide 19 With one electrophilic substrate for the proposed one-pot hydrostannation/ Stille sequence synthesized, our attention turned to the remaining electrophile, benzyl bromide 19. The key precursor to 19 was methyl orsellinate 37. Several routes to 37 were explored. Most of these began with a methanol solution of compounds 20 and 21 was being refluxed in the presence of NaOMe, to afford methyl dihydroorsellinate (35) in quantitative yield. (Scheme 34) Scheme 34. Preparation of Compound 35 O O NaOMe C0 Me + NCOzMe —————> 2 /u\/C02M9 MBOH, 21 reflux, 44 h HO quant 35 Scheme 35. Synthesis of 37 O Brz (3.0 equiv) B CH C O M . OH $6on6 AcOH, > r 2 6 Raney NI 002Me 25 °C, 12 h NaOH/H O HO qua", HO 2 HO - Br 35 36 37 complex mixture 42 Efficient and clean generation of methyl orsellinate (37) from methyl dihydro-orsellinate (35) proved difficult as shown in Scheme 35. While this gave the desired arene, yields were moderate and unidentifiable products contaminated the final product. Scheme 36. Stepwise Synthesis of 37 1) Br2 (1 equiv) Ac20 (3 equiv) AcOH OH 002Me reflux, 2 h 002MB 9, + unknown 2 HBr cat., HO 0 ) ( ) H01 1 water, reflux, 2 h 35 37 66% crude yield COzMe C5§2(‘12.Z‘L‘i'v)" OH 002Me HO O Solvent, Temp, time 7 H0 35 37 Entry Cqu MX Solvent Temp Time (h) Yield 1 Br LiBr CH3CN 65 °C 2 33% 2 Br LiBr DMF 100 °C 2 44% 3 Cl LiCl CH3CN 65 °C 5 33% 4 Cl LiCI DMF 100 °C 5 47% 5 Cl MgCl2 CH3CN 65 °C 12 47% Ultimately the solution to this problem would be a more stepwise approach to 36. Treatment of 35 with Br2 in AcOH gave dibromide 36. (Scheme 36) Although our initial efforts to dehalogenated 36 with Flaney nickel proved irreproducible, chemistry developed in our lab worked well at transforming 36 to 37. Specifically, we took advantage of our group’s a Pd catalyzed, PMHS/KF assisted dehalogenation procedure.19 This method had been shown to reduce a 43 variety of aryl and vinyl halides at room temperature. When 36 was treated with 5 mol% Pd(OAc)2, KF and PMHS in THF/H20 (5:2) at 25 °C for 24 h. Crude 1H NMR analysis indicated a 1.7:1.0 mixture of monobromide to 37. The reaction was extracted with ether and the water was removed. The organics were then filtered to remove all of the palladium. The filtrate was then concentrated and resubjected to the same conditions. After workup and column chromatography, methyl orsellinate 37 was obtained in 88% yield. (Scheme 37) Scheme 37. PMHS/KF Dehydrohalogenation Catalyzed by Pd(OAc)2 _ OH _ C02Me 0H Pd(OAc)2, (5mol%), H0 KF (4 equiv) OH Br 002Me . 37 same PMHS (3 equw), + conditions 002Me > ————> HO THF/H20 (5:2), OH 21 h, 25 °C 3, 24 h, 25 °c co M 88% HO 2 e 36 Br\|\ 37 HO / Treatment of 37 with TBSCI (2.0 equiv) and imidazole (5.0 equiv) in DMF at 25 °c for 2.5 h afforded the bis-TBS ether 38 in 99% yield.56 The desired benzyl bromide 19 was synthesized by treatment of 38 with NBS and catalytic AIBN in CCI4 at 80 °C for 4 h. (Scheme 38) Scheme 38. TBS Protection and Benzylic Bromination COQMe COzMe 002Me TBSO ”0 TBSCI (2.5 equiv) NBS (1.1 equiv) TBSO B, imidazole (5.0 equiv) AIBN (1 mol%) DMF, 25 °c, 2.5 h , ores och, so °c, 4 hfi' 37 OH 990/0 38 87°o 19 OTBS 44 5-6. Synthesis of the Diyne Moiety With both electrophiles in hand, the central mono-protected diyne needed to be made. In this regard, we explored several different protective groups with a focus on bulky substituents that would promote mono hydrostannation during the first of our two planed hydrostannation/Stille sequences. Scheme 39. Approach to Synthesis of 15 TBSO O TBSO O T530 0 OMe TBSO 1:::> TBSO + LL13 0 mreso 5-6-1. Synthesis of Vinylstannane 42 from Silyldiyne 41 We first investigated the unique Silyl-protecting group, biphenyldimethyl- chlorosilane (BDMSCI), owing to the ease with which its installation could be monitored and with which the final product could be isolated.57 Diyne 41 was prepared from hexachlorobutadiene with 4.0 equiv of n-BuLi and 1.0 equiv of BDMSCI in THF in 60% yieid.58 (Scheme 40) Scheme 40. Synthesis of Diyne 41 n-BuLi (4.0 eq.) Cl CI THF, -78 °c to 25 °c, 2 h : E—E—BDMS C' / / Cl then BDMSCI (1 .0 eq.) CI Cl THF, -78 °C to 25 °C, 5 h 41 60% With 41 in hand, hydrostannation of the diyne was investigated. When 41 was subject to the palladium catalyzed hydrostannation using the KF/PMHS 45 conditions described in Chapter 2, only the internal stannylenyne 42 was obtained, as was determined by ‘H NMR of a crude material. Unfortunately, all attempts to isolate this compound failed. (Scheme 41) With the undesired outcome using diyne 41, and alternative diyne was needed. Scheme 41. Hydrostannation of Diyne 41 S MegSnCl,KF,PMHS J\ 41 PdCl2(PPh3)2,THF M838" Q 25 °C,2h 42 inidcated by 1H NMR BDMS 5-6-2. Synthesis of Vinylstannane 46 from Diyne 45 We attributed the difficulties experienced with 41 to, or at least in part to, cleavage of the C-Si bond under the reaction conditions. Therefore a non-silicon containing protecting group would be needed. One simple and easily removable group would be acetone and for that reason diyne 45 was synthesized via the two-step protocol shown in Scheme 42. Scheme 42. Synthesis of Diyne 45 %r // // ' 90% HQNOH-HCI 43 nBuNHz, 30 min I I 65% OH OH 'Il'BS 44 First, 2-methyl-3-butyn-2-ol was converted into bromoalkyne 43. Using conditions developed by Marinof'9 bromoalkyne 43 was coupled with TBS- 46 acetylene to afford silyl diyne 44 in 65% yield. Subsequent treatment with TBAF removed the silyl group to afford diyne 45 in 90% yield. The isolation of this compound was tedious due to its volatility. Diyne 45 was then subjected to a palladium-catalyzed hydrostannation using the KF/PMHS protocol. After two hours, the desired internal stannylenyne 46 was obtained, but again, isolation was not successful. (Scheme 43) The lack of progress in manipulating the various diynes led us to reevaluate our retrosynthesis. Scheme 43. Hydrostannation of Diyne 45 _ _ Me3SnCl, KF, PMHS \> _ S _ — OH PdCl2(PPh3)2, THF ' Measn OH 45 25 °C, 2 h 46 inidcated by 1H NMR 5-7. Synthesis of the Terminal Alkyne In reevaluating our retrosynthesis we decided to forego the 01-02 Stille coupling. This would allow us to introduce the 02 carbon at the monocillin oxidation state. We viewed an alkynyl dithiane as a substrate that would still allow us to use compound 19, while providing us enough steric bulk for a regioselective hydrostannation. (Scheme 44) Admittedly this route held some uncertainty because we had no experience in using dithiane substrates in the one-pot hydrostannation/Stille reaction where sulfur might be problematic in Pd catalyzed coupling reaction.60 Nonetheless this route was otherwise attractive and therefore we targeted y-silyl ethynyldithiane 48 for synthesis. 47 Scheme 44. New Route for the Preparation of Terminal Alkyne OTBS COzMe ores COzMe S TBSO = + TMS{_< :> S TBSO S \ 48 47 {/8 \ 19 Br Scheme 45. Synthesis of y—Silyl Ethynyldithiane 48 SH SH Mg TMS—z DMF BF -OEt S EtBr e e > TMS : CHO——3-2—> TMS—3% :> THF EQO CHCI S . 55% ‘9 63%3 48 Ethyl magnesium bromide, prepared from Mg and ethyl bromide in THF, was added dropwise to a solution of trimethylsilylacetylene in THF. After refluxing for 5 min and the reaction mixture was added dropwise to a solution of DMF in THF. The solution was refluxed again for 5 min before dilute aqueous HCI was added. The resulting oil was purified by vacuum distillation to give the product in 56% yield. Conversion of 3-(trimethylsilyl)-propynal 49 to the corresponding dithiane 48 occurred in acceptable yield 63% under typical thioacetalization procedures with BF3- OEt2 and 1,3-propane dithiol. (Scheme 45) Scheme 46. Nucleophilic Addition of Dithiane to Benzyl Bromide s TMS—:—< 3 ores ores 48 S COzMe COaMe 1) nBuLi,THF -20 to -78 0c TBSO ' 2)-78°C,2h L/ \ 19 B' 82% 50 S \ TMS TBSO 48 Dithiane 48 underwent rapid and stoichiometric transmetalation in the presence of n-BuLi in THF solution. Disappointingly, the addition of solution 19 in THF to the lithiumated dithiane solution did not give coupled product, only complex mixture. Fortunately changing the order of addition improved things significantly. Thus, when thioacetal 48 was converted into its lithium salt by the addition of n-BuLi and was then added dropwise to a solution of benzyl bromide 19 in THF, the alkylated thioketal 50 was obtained in 82% yield. (Scheme 46) The selective desilylation of the Silyl alkyne was investigated next. When 50 was treated with 1.7 equiv of potassium hydroxide a mixture of mono-desilylated, di- desilylated and tri-desilylated products were obtained. We could simply remove three silyl groups with 6.7 equiv. of potassium hydroxide and then reprotect the two hydroxyl groups with TBSCI. (Scheme 47) Scheme 47. Desilylation of Silyl Alkyne OTBS OH COzMe _ CO Me 2.2 euiv TBSCI 6.7 eurv KOH 2 4.0 equiv imidazole OTBS COzMe TBSO S MeOH HO S DMF 7TBSO 8 £3 Q TMS72% E/S \\ 890/0 E/S \\ However this approach wasted reagents and lacked elegance. Thus we conducted additional experiments aimed at the desired selective desilylation.61 An interesting literature reaction involved the silver catalyzed desilylation of a silyl alkyne in the presence of a phenylsilylether. However, with compound 50 this procedure did not give good results. 49 Scheme 48. Chemoselective Desilylation of 50 with Silver Nitrate ores OTBS 002MB C02M6 AgNOa (10 equ) T830 5 H20/Acetone, rt, 7 1: TBSO S (91%) E/ \ \ \ LS TMS S \ 50 47 Instead the reaction was very slow and gave complex mixtures. It was assumed some of our problems might be coming from using only catalytic amounts of silver. Indeed we were glad to find that stoichiometric amount of silver chemoselectively desilylated product 47 with 91% yield in 7 h. (Scheme 48) 5-8. One-pot Sequence with Real Substrates We were now ready to explore the accessibility of one-pot sequence in the synthesis of monocillin l with substrates 28 and 47. Were we to be successful in our one-pot hydrostannation/Stille sequence, lactonization and deprotections were all that would be left for the end game of monocillin I. Scheme 49. Close to the End Game OTBS COZMG (P=BPS) 47 28 Exploration of the one-pot hydrostannation IStille reaction began with a look at the stepwise sequence. (Scheme 50) Hydrostannation of 47 with in Situ formed tin hydride from trimethyltin fluoride and PMHS under the presence of Pd catalysts was followed by the addition of vinyl iodide 28 and heating to 65 °C. After 2 days, Vinylstannane 47 was gone according to TLC monitoring. Scheme 50. One-pot Sequence with 28 and 47 T330 1 mol% szdbaa COzMe 4 mol% TFP 1.5 equiv MeasnF 28 (1.2 equiv) "330 S 2.5 equiv PMHS 65 °c, 2 days \ 0.8 mol% TBAF (P=BPS) 47 s \ THF, 2 h, rt no diene in NMR of crude Disappointingly though, only a complex mixture of products was obtained and none of the observed compounds exhibited NMR peaks that would indicate diene formation. Rather purification of crude reaction indicated that Significant amounts of desilylation had occurred among the byproducts, presumably due to the presence of fluoride during the hydrostannation. We decided to avoid this complication by removing the TBS protecting groups on the two phenols. The treatment of compound 50 with TBAF gave the unprotected diol terminal alkyne 51 in 91% yield. (Scheme 51) Compound 51 was then subjected to our standard one-pot hydrostannation/ Stille reaction conditions, but again there were no indications of diene formation by NMR of crude materials. (Scheme 52) 51 Scheme 51 . Desilyation of 50 with TBAF OTBS OH O COZMB . 3.1 equrv TBAF OMe TBSO S THF, 20 °c, 1 hr HO (/ 91°70 S \ \ so 5 \ TMS 51 £8 \ Scheme 52. Construction of Diene through Our One-pot Sequence 0H 1 mol% Pd2dba3 002Me 4 mol% TFP 1.5 equiv MeaSnF 28 (1.2 equiv) H0 3 2.5 equiv PMHS 65 °C. 2 days 0.8 mol% TBAF (P=BPS) 51 S % THF, 2 h, rt no diene in NMR of crude Frustrated by these failures we decide to study the individual steps of hydrostannation/Stille sequence. First, the in situ formation of the Vinylstannane was investigated. Compound 51 was tested to determine whether this substrate worked well in our standard hydrostannation protocol. A hydrostannation of 51 was setup. By TLC monitoring, the starting material was gone in 30 min and a clear new spot showed up. While the acidity of the phenols made isolation via column chromatography in the presence of triethylamine difficult, the Vinylstannane product 54 could be passed through the short column with 10% ethylacetate/hexane to afford pure material in 96% yield. This allowed us to conclude that the hydrostannation step with dithiane substrate 51 worked well (Scheme 53). 52 Scheme 53. Hydrostannation of 51 OH 0 OH 0 szdba3,TFP OMe MeasnF, PMHS OMe TBAF Ho 5 Ho 5 THF, rt, 30min 3 / 96 % M 51 {/3 \\ 54 E/S 3" 63 The next question became “Is the Stille coupling of in situ generated 54 problematic?” As mentioned earlier we had no prior experience with the cross- coupling of dithianes such as 51/54.62 With this in mind we looked into the one- pot hydrostannation/Stille coupling reaction of 51 with a Simple electrophile, B- bromo-(E)-styrene. Under tetrakistriphenyl-phosphine Pd catalysis, the Stille coupling step (Scheme 54) did not afford a high yield of the product, but 55 was generated in 48% yield. These experiments suggested that dithiane 51 was not inherently a bad substrate for our one-pot sequence. Scheme 54. One-pot Sequence with B-Bromo Styrene OH o 1 moi% szdbaa 3% Ph OH 4 mol% TFP 0M9 1.5 equiv Me3SnF Pd(PPh3)4 0M9 HO 8 2.5 equiv PMHS r 70 °C, 24 h 7 HO S 0.8 moi% TBAF 48 % / / pr. 51 s Q THF,2h,rt 55 8 Given the results described above, we concluded that the successful cross Coupling of our monocillin substrates, (2)-vinyl iodide 28 and Vinylstannane 54, would Simply require a thorough screening of various Stille conditions. Unfortunately this did not prove to be the case. 53 Table 9. Search for the Stille Reaction Condition OH O 0M9 Pd cat. Ho 3 + W H0 .. £3 / 22:35.22?” .. Entry Pd cat. solvent Aditives temp time Yield 1 PdCl2(CH30N)2 DMF rt 5 days no diene 2 PdCI2(CH3CN)2 NMP rt 2 days no diene 3 PdCl2(CH30N)2 NMP Cul(1.0 eq.) rt 2days no diene 4 szdba3/AsPh3 NMP LiCl(2.0 eq.) 60 °C 2 days no diene Table 9 showed some of the catalyst, solvent, additive, condition’s combinations studied. For these and all other variations tried NMR of the crude materials never suggested diene formation. Owing to all of the unsuccessful results plus the successful control experiment with 51/54, we began to suspect vinyl iodide substrate 28 as the cause of our problems. The literature does not offer any examples of a substrate bearing an epoxide group right next to a (2)- vinyl iodide participating in any Pd-catalyzed coupling reactions. Therefore we decided to investigate the coupling of substrate 28 with Simplified vinyltins. (Scheme 55) Again, we did not get the cross-coupled DTOducts. Instead NMR analysis of the crude reaction and TLC monitoring indicated consumption of the vinyl iodide plus homocoupling of stannane 62 and 64 .63 54 Scheme 55. Our One-pot Sequence with Simply Modified Vinylstannanes QBPS S S + \ = PhMSnMea H l DMF, rt, 2 days 28 62 No reaction 9% BPS? H O PdCI2(CH30N)2 HO / 3011493 1' \ % DMF, rt, 2 days 64 28 H I , HO No reaction %SnBua BPS? ';' o PdCl2(CH30N)2 + \ Ar 66 DMF, rt, 2 days 23 H I No reaction Somewhat surprisingly when we subjected alkyne 56 and substrate 28 to the full one-pot hydrostannation/Stille reaction sequence a new product was observed. (Scheme 56) Again this was not the expected cross-coupled product, but furan 58. Scheme 56. Furan Formation ph szdba3, TFP 26 (1.2 equiv) _ o Me3SnF, PMHS P S TBAF 2 mol% Pd(PPh3)4 + moeps Q’s \\ THF, rt, 30 min dioxane, 90 °C, 1 d L 58 (18 Cy) 56 57(not observed) 55 We wondered what among the reaction conditions led epoxy (2)-vinyl iodide 28 to be converted into the furan ring. When epoxy (2)-vinyl iodide 28 and (PPh3)4Pd were mixed in benzene, then heated at 80°C for 12 h, the mixture did not give any furan formation. However, we got furan product 58 in 62% yield from epoxy (2)-vinyl iodide 28 in presence of the tetrakis Pd catalyst and Hunig’s base. (Scheme 57) Presumably either the PMHS or TBAF was playing the role of the Hunig’s base during the reaction of Scheme 56. Scheme 57. Furan Formation from 29 1 mOIO/o Pd(PPh3)4 O 3.0 equiv i-PrNEt moans benzene, 80°C, 12 h 63 % Scheme 58. The Proposed Mechanism for Furan Formation — O QBPS ("NM 28 BPSO E’d\ O’BPS 0 / / P.“"° ’ | 59 BPSO HI Base Base While the furan formation mechanism has not been experimentally elUCidated, a putative mechanism is put forth in Scheme 58. After oxidative 56 addition by Pd into the vinyl iodide bond, the epoxide oxygen could coordinate after which epoxide opening would lead to cationic :lt allyl Pd. Base would promote formation of intermediate 61, which upon reductive elimination would afford the furan ring of 58. Assuming that our mechanistic picture was at least correct in oxidative addition initiating the furan forming sequence we considered switching the reactive ends of the Stille partners. While this switch would be incompatible with our goal of forming the C4-CS bond via our one-pot hydrostannation/Stille cross coupling sequence, the information gained by studying such a reaction would otherwise still be instructive. Scheme 59. Switch from Vinylstannane to Vinyl Iodide a)? 1.7 equiv l2 A / SnMe3 CH2Cl2, 10 min / l 81 % 68 69 Scheme 60. Stannylation of Vinyl Iodide 28 to Vinylstannane 2 mol% Pd(PPh3)4 QBPS 1.5 equiv (Measn)2 QBPS O o 0.3 equiv IPerEt 0 OBPS Mm‘E : M-“‘\I m PhH, 80°C 23 ' SW93 56 (50 °/) 70 (not observed) 0 1)1.5 equiv MeLi, Ergo, -40 °C to rt 9 S o -78 °c ? 0 MAE ; M‘\ complex mixture 28 I 3) 1.5 equiv Meaanl SnMe THF, -78 °c 3 70 (not observed) 57 The vinyl stannane easily was switched to the corresponding vinyl iodide with iodine in CH2Cl2 in 81% yield. (Scheme 59) Unfortunately converting vinyl iodide 28 into epoxy (2)-vinyl stannane 70 was not readily realized. (Scheme 60) Pd-catalyzed stannylation,64 intended to afford the Vinylstannane, did not provide any of the corresponding Vinylstannane, but again by-product, furan formation was witnessed in 50% yield. In another approach, lithiation of 23 with methyl lithium and then butyl lithium at -78 °C and subsequent treatment with trimethylstannyl chloride was also examined. This too did not afford epoxy (Z)- Vinylstannane but resulted in generating complex mixture. Because the Sn/l partner swap was as mentioned above outside the scope of our synthetic aim no additional effort was extended to the preparation of 70. We questioned if the geometry of the (2)-vinyl iodide was necessary for furan formation. To answer this query we sought to make and cross-coupled the (E)-epoxy vinyl iodide. Thus, the epoxy aldehyde in Scheme 61 was subjected to a diiodination. Then lithium-halogen exchange reactions gave us a mixture of diiodide, (E) and (2) vinyl iodides in a ratio of 1:1:0.6. (Scheme 61) Attempted Isolation of pure (E) vinyl iodide by column chromatography failed, but did allow for the removal of the diiodo compound. So, a 1:06 mixture of (E) and (Z) vinyl iodides was used and a Stille coupling with organostannane. (Scheme 62) The reaction was monitored by kinetic studies of 1H NMR. This NMR monitoring showed that (E)-vinyl iodide consumed and coupled with Vinylstannane with the diene formation. However (2)-vinyl iodide stayed un- 58 reactive. Through these experiments we concluded that the (Z) geometry is problematic. Scheme 61. Preparation of (E) Epoxy Vinyl lodide MeLi EtZO -100 °C, 2 h CHI3, Ph3P wk t-BUOK TBD O BPSO " " ———» PS ————> -o THF then MeOH BPSO 0 °C, 0.5 h l + 85% mixture l (SM:E:Z 9 =1 :1 :0.6) BPSO ' ' I Scheme 62. Stille Cross-Coupling Reaction of Mixture of the (E) and (2)-Epoxy Vinyl iodide 10 mol% Mess” / PdCl2(CH3CN)2‘ (2.0 eqiuv) OH DMF. rt Moreover the fact that the (2)-vinyl iodide epoxide was not viable as intermediate in our retrosynthetic scheme also forced us to acknowledge that demonstrating a successful one-pot hydrostannation/Stille sequence as part of the planned approach to monocillin would be unlikely. As a full reworking of the S)lnthetic approach to monocillin would extend beyond the scope of this dissertation, work in this area is concluded until it is taken up as part of a future dissertation project. 59 9. . (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771—1780. (b) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508—523. (c) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813—817. (d) Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1-652. . 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Catal. 1986, 37, 359—367. 62 35. Fowley, L. A.; Michos, D.; Luo, X.-L.; Crabtree, R. H. Tetrahedron Lett. 1993, 34, 3075—3078. 36. Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev. 1993, 93, 1371—1448. 37. Braden, R.; Himmler, T. J. Organomet. Chem. 1989, 367, 012—014. 38. Cuomo, J.; Olofson, R. A. J. Org. Chem. 1979, 44, 1016—1017. 39. We cannot rule out fluoride converting a RCO-Pd(ll)-Cl species to RCO- Pd(ll)-F. 40. TBAF presumably facilitates phase transfer. 41. Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Tetrahedron Lett. 2002, 43, 8823— 8826. 42. Banibrata Ghosh unpublished results, 2007. 43. This project was begun by William P. Galagher. (Gallagher, W. P. Stille Couplings Catalytic in Tin and Related Reactions Ph.D. Thesis, Michigan State University, East Lansing, MI, 2003) 44. Ayer, W. A.; Lee, S. P.; Tsuneda, A.; Hiratsuka, Y. Can. J. Microbiol. 1980, 26, 766. 45. Cutler, H. G.; Arrendale, R. F.; Springer, J. P.; Cole, P. D.; Roberts, R. G.; Hanlin, R. T. Agric. 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(a) Hon, Y. 8.; Lu, L. Tetrahedron 1995, 51, 7937-7942. (b) Hon, Y. 8.; Lu, L.; Chang, R. C.; Lin, 8. W.; Sun, P. F.; Lee, C. F. Tetrahedron 2000, 56, 9269—9279. 52. Parikh, V. E.; Doering, W. J. Am. Chem. Soc. 1967, 89, 5505-5507. 53. Gonzalez, l. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099—9108 and references cited. 54. This protocol has been investigated, see: Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1998, 63, 8965—8975. 55. (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b) Bestmann, H. J.; Rippel, H. C.; Dostalek, R. Tetrahedron Lett. 1989, 30, 5261. 56. Nomoto, S.; Mori, K. Liebigs Ann. 1997, 721—723. 57. Anthony, J.; Diederich, F. Tetrahedron Lett. 1991, 32, 3787—3790. 58. ljadi-Maghsoodi, 8.; Barton, T. J. Macromolecules 1990, 23, 4485—4486. 59. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841—6844. 60. Rahaim, R. J., Jr. Application of Palladium Nanoparticles in the Reduction of Organic Functional Groups Ph.D. Thesis, Michigan State University, East Lansing, MI, 2006 61. (a) Orsini, A.; Vitérisi, A.; Bodlenner, A.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2005, 46, 2259-2262. (b) Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem. 2005, 1859-1864. 62. (a) lchigea, T.; Kamimuraa, S.; Mayumia, K.; Sakamotoa, Y.; Terashita, S.; Ohtekia, E.; Kanoh, N.; Nakata, M. Tetrahedron Lett. 2005, 46, 1263-1267. (b) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865 -3868. (c) Hanessian, S.; Ma, J.; Wang W. J. Am. Chem. Soc. 2001, 123, 10200 -10206. 64 63. Homocoupling of 66 would produce butadiyne, which would be too volatile to observe. 64. Vanderwal, D. C.; Vosburg, A. D.; Sorensen, J. E. Org. Lett. 2001, 3, 4307- 4310. 65 Experimental Details Materials and Methods All reactions were carried out in oven-dried glassware, with magnetic stirring, and monitored by thin-layer chromatography with 0.25-mm precoated Silica gel plates or capillary GC, unless otherwise noted. All commercial reagents were used without purification. All solvents were reagent grade. Diethyl ether and THF were freshly distilled from sodium/benzophenone under nitrogen. Benzene, toluene, DMSO, diisopropyl-ethylamine and cyclohexane were freshly distilled from calcium hydride under nitrogen. Tetrahydrofuran was freshly distilled from sodium/benzophenone under nitrogen. TriS(dibenzylideneacetone)- dipalladium (0), dichlorobis(triphenyl- phosphine)palladium (ll), tetrakis(triphenyl- phosphine)palladium (0), anhydrous A.C.S grade potassium fluoride, polymethyl- hydrosiloxane (PMHS), tetrabutylammonium fluoride (1M solution in THF), and 3,3-dimethyl-1-butyne were purchased and used without purification unless otherwise mentioned. 2-Thiophenecarbonyl chloride, 2-furoyl chloride, 3,4,5- trimethoxybenzoyl chloride, and 2-nitrobenzoyl chloride, were prepared following literature procedures and used after distillation. The remaining acid chlorides were purchased and used without purification. Flash chromatography was performed with silica gel 60 A (particle size 230-400 mesh ASTM). High performance liquid chromatography (HPLC) was performed with Ranin component analytical/ semiprep system. Yields refer to chromatographically and spectrosc0pically pure compounds unless otherwise 66 stated. Melting points were determined on a Thomas-Hoover Apparatus, uncorrected. Infrared spectra were recorded on a Nicolet lR/42 spectrometer. Proton and carbon NMR spectra were recorded on a Varian Gemini-300, VXR 500 or lNOVA 600 spectrometer. Chemical shifts for 1H NMR and 13C NMR are reported in parts per million (ppm) relative to CDCl3 (6 = 7.24 ppm for 1H NMR or 6 = 77.0 ppm for 13C NMR). Optical rotations were measured with a Perkin-Elmer Model 341 polarimeter. High resolution mass spectra (HRMS) data were obtained at either the Michigan State University Mass Spectrometry Service Center or at the Mass Spectrometry Laboratory of the University of South Carolina, Department of Chemistry & Biochemistry. GC/MS were performed with a fused silica column (30 m by 0.25 mm i.d.). lCP analysis was performed on a Micromass Platform Inductively Coupled Plasma-Mass Spectrometer at the ICP- Hex-MS Laboratory at the department of Geological Sciences at Michigan State University. 67 Chapter 2. One-pot Hydrostannation/Stille Reaction with Acid Chlorides as the Electrophiles Procedure for the Preparation of Tri-2—furylphosphlne (TFP): CeCl3-7H20 (60 g, 161 mmol) was placed into a 3 neck 1-L flask containing a stir bar. The flask was places into a 150 °C oil bath and was then places under vacuum (~1 mmHg) until a fine powder was obtained. The flask was then cooled to 25 °C under N2 and THF (200 mL) was added. In a separate flask, a solution of furan (20 g, 294 mmol) in THF (100 mL) was cooled to 0 °C. To this solution was added n-BuLi (100 mL of a 1.6 M solution in hexanes, 160 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 h. The flask containing the dried CeCl3 in THF was cooled to —78 °C and then the a-furyl lithium solution was added via cannula. Once the addition was complete, the solution was allowed to stir at —78 °C for 1 h and then PCI3 (3.50 mL, 40.1 mmol) was added and the cold bath was removed. The mixture was then allowed to warm to 25 °C overnight with stirring. The mixture was then poured into sat. aq. NH4CI (300 mL). The layers were separated and the aqueous layer was extracted with EtZO. The combined organics were dried (M9804), filtered and concentrated (not to dryness). The residue was purified by column chromatography [silica; 90:10 hexane/EtOAc] to afford tri-2-furylphosphine (5.36 g, 58%) as a white crystalline solid (mp 64 °C; lit.1 mp 59-64 °C). The product 68 could also be recrystallized from hexanes (3x). All Spectral data match those reported in the literature.2 Preparation of Trimethyltin Fluoride: THF (30 mL) was placed in a 250 mL flask and KF (150 mmol, 8.71 9) dissolved in H20 (20 mL) was added. Meaanl 1 M solution in THF (50 mL) was added with vigorous stirring. During this time the exothermicity of the reaction made the flask warm to touch. The reaction was stirred for 2 h, at which time then flask was no longer warm to touch. The reaction was filtered and the white solid was washed with H20 and EtZO. After air-drying, the remaining volatiles were removed by drying the solid dried under high vacuum to afford the MeasnF as a white solid in quantitative yield.3 General Procedure for the One-pot Hydrostannation/Stille Reaction using Me,SnF: szdba3 (0.01 mmol, 9.2 mg) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, 3,3- dimethyl 1-butyne (1 mmol, 0.125 mL), MeasnF (1.5 mmol, 274 mg), PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. The acid chloride (1.3 mmol) was then added and the mixture was allowed to reflux (~65 °C) until the cross- coupling was judged complete by TLC (2—4 h). At that time, the reaction was 69 diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with 3,0 and H20 and the aqueous phase was back extracted with EtZO. The combined organics were dried over MgSO,,, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the corresponding (MB-unsaturated ketone. 7 o ‘ (E)-4,4-Dimethyl-1-phenylpent-2-en-1-one: Subjection / w of benzoyl chloride (1.3 mmol, 0.15 mL) to the general (Table 2, Entry 1) procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.179 g (95%) of (E)-4,4-dimethyl-1-phenylpent-2-en- tone as a colorless oil. Second run gave 93% yield. IR (neat) 2963, 1669, 1620, 1304 cm“; 1H NMR (300 MHz, CDCIa): 6 = 7.90 (dd, J = 6.9, 1.6 Hz, 2H), 7.52—7.41 (m, 3H), 7.06 (cl, J = 15.7 Hz, 1H), 6.78 (d, J: 15.7 Hz, 1H,), 1.12 (s, 9H) ppm; 1to NMR (75 MHz, CDCI3): o = 191.4, 159.5, 138.2, 132.4, 128.4, 121.0, 34.1, 28.7 ppm; HRMS (El) m/z 189.1279 [(M+H), calcd. for C,3H,7O 189.1285] Physical and spectral data were consistent with those previously reported.4 0 ‘ (E)-1-(3,4,5-Trimethoxyphenyl)-4,4-dlmethylpent- MeO / 2-en-1-one: Subjection of 3,4,5-trimethoxybenzoyl MeO OMe chloride (1.3 mmol, 0.3 g) to the general procedure (Table 2, Entry 2) afforded after column chromatography (silica gel, 70 hexane/EtOAc: 90/10) 0.267 g (97%) of (E)-1-(3,4,5-trimethoxyphenyl)-4,4- dimethylpent-2-en-1-one as a white solid. Second run gave 95% yield. mp 57— 58 °C. IR (KBr) 2963, 1665, 1582, 1414 cm"; 1H NMR (300 MHz, CDCI3): 6 = 7.12 (S, 2H), 7.00 (d, J: 15.7 Hz, 1H), 6.67 (d, J: 15.9 Hz, 1H), 3.86 (s, 9H), 1.10 (s, 9H); 13C NMR (75 MHz, CDCIa) ppm: 6 = 190.3, 159.2, 152.9, 142.2, 133.3, 120.6, 106.2, 60.7, 56.2, 34.0, 28.6 ppm; HRMS (El) m/z 279.1596 [(M+H), calcd. for 0,6H230, 279.1574] , 1 (E)-1-(2-Chlorophenyl)—4,4-dimethylpent-2-en-1-one: w Subjection of 2-chlorobenzoyl chloride (1.3 mmol, 0.17 CI mL) to the general procedure afforded after column (Table 2, Entry 3) chromatography (Silica gel, hexane/EtOAc: 90/10) 0.203 g (91%) of (E)-1-(2-chlorophenyl)-4,4-dimethylpent-2-en-1-one as a colorless liquid. Second run gave 81% yield. IR (neat) 1667, 1618, 1300 cm"; 1H NMR (300 MHz, CDCla): 6 = 7.40—7.22 (m, 4H), 6.69 (d, J = 16.2 Hz, 1H), 6.38 (d, J: 15.9 Hz, 1H), 1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCIa): 6 = 194.6, 161.4, 138.8, 130.8, 129.8, 128.9, 126.4, 125.2, 33.8, 28.2 ppm; HRMS (El) m/z 223.0896 [(M+H), calcd. for C,3H,BCIO 223.0890] 71 r m 1-((&3,3-Dimethylbut-1—enyl)-2-nltrobenzene: \ (>ka Subjection of 2-nitrobenzoyl chloride (1.3 mmol, 0.17 mL) NO 2 to the general procedure afforded after column (Table 2, Entry 4) chromatography (silica gel, hexane/EtOAc: 90/10) 0.152 g (74%) of 1-((E)-3,3-dimethylbut-1-enyl)-2-nitrobenzene as a yellow liquid along with a trace amount of the corresponding enone. IR (neat) 2963, 1524, 1346 cm"; ‘H NMR (300 MHz, CDCI3): 6 = 7.84 (d, J = 8.2 Hz, 1H), 7.56—7.45 (m, 2H), 7.31-7.26 (t, J = 6.6 Hz, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.22 (d, J: 15.9 Hz, 1H), 1.10 (s, 9H) ppm; ‘30 NMR (75 MHz, CDCla): 6 = 147.1, 133.6, 132.7, 128.4, 1272,1242, 120.2, 33.6, 29.2 ppm 2 , Reaction under CO Atmosphere: C(Vk 1-((E)-3,3-Dlmethylbut-1-enyI)-2-nitrobenzene: NO 2 Subjection of 2-nitrobenzoyl chloride (1.3 mmol, 0.17 mL) (Table 2, Entry 4) to the general procedure with CO gas bubbling to the reaction mixture afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.152 g (74%) of 1-((E)-3,3-dimethylbut-1-enyI)-2- nitrobenzene as a yellow liquid along with a trace amount of the corresponding enone. 72 f o 1 3-( E)-4,4-Dimethylpent-2-enoyl)benzonitrlle: ”Cw Subjection of 3-cyanobenzoyl chloride (1.3 mmol, 0.216 t h nrlr r ffr ftr lumn (Table 2’ Entry 5) g) o t e ge ea pocedue a oded a e co L chromatography (silica gel, hexane/EtOAc: 90/10) 0.2119 (99%) of 3-((E)-4,4-dimethylpent-2-enoyl) benzonitrile as a white crystalline solid. Second run gave 97% yield. mp 74—75 °C. IR (KBr) 2230, 1678, 1612 cm"; 1H NMR (300 MHz, CDCI3): 6 = 8.14 (s, 1H), 8.11 (d, J: 7.7 Hz, 1H), 7.80 (d, J: 7.7 Hz, 1H), 7.59 (t, J: 7.14 Hz, 1H), 7.09 (d, J: 15.7 Hz, 1H), 6.72 (d, J: 15.7 Hz, 1H), 1.12 (s, 9H) ppm; ”C NMR (75 MHZ, CDCI3): 6 = 189.1, 161.5, 138.9, 135.4, 132.4, 132.0, 129.5, 119.9, 118.0, 112.9, 34.3, 28.5 ppm (E)-1-(4-Bromophenyl)—4,4-dimethylpent-2-en-1- W one: Subjection of 4-bromobenzoyl chloride (1.3 mmol, Br 0.216 g) to the general procedure afforded after 4 h (Table 2, Entry 6) Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 02649 (99%) of (E)-1-(4-bromophenyl)-4,4-dimethylpent- 2-en-1-one as a white crystalline solid. mp 43—44 °C. Second run gave 97% yield. IR (KBr) 1671, 1620, 1580, 1108, 1004 cm"; 1H NMR (300 MHz, CDCIS): 6 = 7.77 (d, J: 8.5 Hz, 2H), 7.58 (d, J: 8.9 Hz, 2H), 7.06 (d, J: 15.7 Hz, 1H), 6.72 (d, J = 15.7 Hz, 1H), 1.13 (s, 9H) ppm; 130 NMR (75 MHz, CDCI3): 6 190.3, 160.2, 73 136.9, 131.7, 130.0, 127.6, 120.5, 34.2, 26.7 ppm; HRMS (El) m/z 267.0375 [(M+H), calcd. for C,3H,sBrO 267.0385] / \ s 0 (Table 2, Entry 7) 1 (E)-4,4-Dimethyl-1-(thlophen-2—yl)pent-2-en-1-one: Subjection of 2-thiophenoyl chloride (1.3 mmol, 0.14 mL) to the general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.1939 (99%) of (E)-4,4-dimethyl-1-(thiophen-2-yl)pent-2-en-1-one as a bright yellow liquid. Second run gave 99% yield. IR (neat) 1659, 1617, 1414, 723 cm"; 1H NMR (300 MHz, 000,): 6 = 7.72 (dd, J = 3.6, 1.1 Hz, 1H), 7.59 (dd, J: 4.9, 1.1 Hz, 1H), 7.10—7.04 (m, 2H), 6.67 (d, J: 15.7 Hz, 1H), 1.09 (s, 9H) ppm; 13C NMR (75 MHz, CDCla): 6 = 182.8, 158.6, 145.2, 133.5, 131.7, 128.0, 120.3, 33.9, 28.6 ppm; HRMS (El) m/z 195.0846 [(M+H), calcd. for C,,H,,OS 195.0844] /\ o 0 (Table 2, Entry 8) j (E)-1-(Furan-2-yl)-4,4-dimethylpent-2-en-1 -one: Subjection of 2-furanoyl chloride (1.3 mmol, 0.13 mL) to the general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 01719 (96%) of (E)-1-(furan-2-yl)-4,4-dimethylpent-2-en-1-one as a dark brown liquid. Second run gave 94% yield. 74 IR (neat) 1667, 1616, 1468 cm"; 1H NMR (300 MHZ, CDCI3): 6 = 7.55 (S, 1H), 7.18 (d, J: 3.6 Hz, 1H), 7.11 (d, J: 15.9 HZ, 1H), 6.67 (d, J: 15.7 Hz, 1H), 6.49 (m, 1H), 1.07 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): 6 178.5, 158.6, 153.3, 146.3, 119.8, 117.3, 112.2, 33.9, 28.5 ppm; HRMS (El) m/z 179.1074 [(M+H), calcd. for C,,H,,.,O2 179.1072] (E).4,4-Dlmethyl-1-(naphthalen-S-yl)pent-2-en-1- one: Subjection of 2-furanoyl chloride (1.3 mmol, 0.2 mL) to the general procedure afforded after column (Table 2, Entry 9) chromatography (silica gel, hexane/EtOAc: 90/10) 0.216 g (93%) of (E)-4,4-dimethyl-1-(naphthalen-5-yl)pent-2-en-1-one as a bright brown crystalline solid. Second run gave 91% yield. mp 37—38 °C. IR (neat) 1669, 1615, 1508, 1298, 775 cm"; ‘H NMR (300 MHz, CDCI3): 6 = 8.26 (d, J: 8.0 Hz, 1H), 7.96 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.1 Hz, 1H), 7.66 (d, J: 6.9 Hz, 1H), 7.56-7.46 (m, 3H), 6.88 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H), 1.11 (s, 9H) ppm; 13C NMR (75 MHz, CDCIa): 6 = 196.7, 161.1, 137.0, 133.7, 131.3, 130.5, 128.3, 127.2, 127.1, 126.3, 126.1, 125.6, 124.4, 34.1, 28.6 ppm; HRMS (El) m/z 239.1436 [(M+H), calcd. for c,,H,,,o 239.1442] O MW (E)-6,6-Dimethylhept-4-en-3-one: Subjection of 1- 6 octanoyl chloride (1.3 mmol, 0.22 mL) to the general (Table 2, Entry 10) procedure afforded after column chromatography (silica 75 gel, hexane/EtOAc: 90/10) 0.1899 (90%) of (E)-6,6-dimethylhept-4-en-3-one as a bright brown liquid. Second run gave 90% yield. IR (neat) 1676, 1626 cm"; 1H NMR (300 MHz, CDCI3): 6 = 6.80 (d, J = 16.2 Hz, 1H), 5.99 (d, J = 16.2 Hz, 1H), 2.50 (t, J: 7.7 Hz, 2H), 1.59 (m, 2H), 1.24 (brs, 8H), 1.04 (s, 9H), 0.84 (brs, 3H) ppm; 13C NMR (75 MHz, CDCI3): 6 201.5, 156.7, 125.4, 40.3, 33.6, 31.7, 29.2, 29.1, 28.7, 24.3, 22.6, 14.0 ppm; HRMS (El) m/z 211.2053 [(M+H), calcd. for C1,,H27O 211.2062] r— J 0 (E)-2,2,6,6-Tetramethylhept-4-en-3-one: Subjection of M trimethylacetyl chloride (1.3 mmol, 0.16 mL) to the general (Table 2, Entry 11) procedure afforded after 4 h Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.155 g (92%) of (E)-2,2,6,6- tetramethylhept-4-en-3-one as a bright brown crystalline solid. Second run gave 92% yield. mp 42 °C. (lit. 42—43°C)5 IR (KBr) 1688, 1628, 1086 cm"; 1H NMR (300 MHz, CDCI3) 6 = 6.92 (d, J: 15.4 Hz, 1H), 6.38 (d, J: 15.7 Hz, 1H), 1.12 (s, 9H), 1.04 (s, 9H) ppm; "‘C NMR (75 MHz, CDCla): 6 = 204.8, 157.2, 119.0, 43.0, 33.7, 28.8, 26.3 ppm; HRMS (El) m/z 169.1592 [(M+H), calcd. for c,,H,,o 169.1592] Physical and spectral data were consistent with those previously reported.6 76 r— 1 (1 E,4E)-6,6-Dimethyl-1-phenylhepta—1 ,4-dien-3-one O W : Subjection of cinnamoyl chloride (1.3 mmol, 0.217 g) to the general procedure afforded after 4 h Stille (Table 2, Entry 12) reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.1739 (81%) of (1E,4E)-6,6-dimethyl-1-phenylhepta-1,4- dien-3-one as a bright brown liquid. Second run gave 79% yield. IR (neat) 1659, 1628, 1601 cm"; 1H NMR (300 MHz, CDCla): 6 = 7.65 (d, 1H), 7.55 (m, 2H), 7.36 (m, 3H), 7.00 (d, J: 15.9 Hz, 2H), 6.34 (d, J: 15.9 Hz, 1H), 1.12 (s, 9H) ppm; 13C NMR (75 MHz, CDCI3): 6 = 189.7, 157.8, 142.9, 134.8, 130.3, 128.8, 128.2, 124.8, 124.4, 33.9, 28.7 ppm; HRMS (El) m/z 215.1436 [(M+H), calcd. for C,5H,90 215.1423] Physical and spectral data were consistent with those previously reported.7 ' 01.381 (E)-6-(tert-Butyldimethylsilyloxy)-1-phenylhex-2-en- Ph \ 1-one: 5-(tert-Butyldimethylsilyloxy)-1-pentyne (199 mg, 0 (SCth9 9) 1.0 mmol), MeSSnF (1.5 mmol, 274 m9), (PPh3)2Cl2Pd (0.02 mmol, 14.0 mg), PMHS (1.5 mmol, 0.09 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added to 3,0 (5 mL) and the resulting mixture was stirred at rt for 2 h, at which time the hydrostannation was complete by TLC. Then (PPh3)4Pd (11.3 mg, 0.01 mmol) and benzoyl chloride (0.15 mL, 1.3 mmol) in THF (5 mL) was added and the mixture was allowed to reflux (~65 °C) until the cross-coupling was judged complete by TLC (8 h). At that time, the 77 reaction was diluted with saturated aq. KF (2 mL) and stirred for 10 min. The reaction was extracted with EtZO and H20 and the aqueous phase was back extracted with EtzO. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by column chromatography (silica gel, hexane/EtOAc: 90/10) to afford 0.219 g (71%) of (E)-6-(tert- butyldimethylsilyloxy)-1-phenylhex-2-en-1-one along with a trace of the ot-isomer as a bright yellow liquid as a colorless oil. IR (neat) 1672, 1622,1099, 835 cm"; 1H NMR (300 MHz, CDCIS): 6 = 7.91 (d, J: 6.9 Hz, 2H), 7.54—7.39 (m, 3H), 7.08—7.01 (m, 1H), 6.89 (d, J: 15.4 Hz, 1H), 3.64 (t, J = 6.0 Hz, 2H), 2.40 (overlapping q, J: 7.1 Hz, 2H), 1.76 (quint, J: 6.3 Hz, 2H) 0.88 (s, 9H), 0.04 (s, 6H) ppm; 1"C NMR (75 MHz, CDCla): 6 = 190.7, 149.4, 138.0, 132.5, 128.4, 126.1, 62.1, 31.2, 29.2, 25.9, 18.2, -5.4 ppm Procedure for the One-pot Radical Hydrostannation/Stille Reaction: A round-bottom flask containing a solution of 5-(tert-butyldimethylsilyloxy)—1- pentyne (199 mg, 1.0 mmol), Buaanl (0.33 mL, 1.2 mmol), aq. KF (175 mg, 3.0 mmol; 0.25 mL H20), PMHS (0.07 mL, 1.2 mmol), and AIBN (8 mg, 0.05 mmol) in toluene (5 mL) was immersed in a preheated (~75 °C) oil bath for 10 min. After Stirring for 2 h at this temperature, the reaction mixture was cooled, then (PPh3)4Pd and distilled benzoyl chloride (0.15 mL, 1.3 mmol) were added. The mixture was allowed to stir at reflux (~75 °C) until the cross-coupling was judged complete by TLC (2.5 h). At that time, the reaction was diluted with saturated aq. 78 KF (2 mL) and stirred for 10 min. The reaction was extracted with 3,0 and H20 and the aqueous phase was back extracted with EtZO. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by column chromatography (silica gel, hexane/EtOAc: 90/10) to afford 0.128 g (42%) of (E)-6-(tert-butyldimethylsilyloxy)-1-phenylhex-2-en-1-one as a colorless oil. For spectroscopic data see above. 79 Chapter 3. One-pot Multi-Component Stille Sequences General Procedure for the One-pot Hydrostannation/Stille Reaction using Me,SnF: szdba3 (0.01 mmol, 9.2 mg) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, 3,3- dimethyl 1-butyne (1 mmol, 0.125 mL), MeasnF (1.5 mmol, 274 mg), PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. The acid chloride (1.3 mmol) was then added and the mixture was allowed to reflux (~65 °C) until the cross- coupling was judged complete by TLC (2—4 h). At that time, the reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with EtZO and H20 and the aqueous phase was back extracted with Et20. The combined organics were dried over MgSO,, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the corresponding a,B-unsaturated ketone. o 1 (E)-1-(4-BromophenyI)-4,4-dlmethylpent-z-en-1-one: / OW Subjection of 4-bromobenzoyl chloride (1.3 mmol, 0.216 Br ”ab"? 35'1"“) g) to the general procedure afforded after 4 h Stille 80 reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.264 g (99%) of (E)-1-(4-bromophenyI)-4,4-dimethylpent-Z-en-1-one as a white crystalline solid. mp 43—44 °C. IR (KBr) 1671, 1620, 1580, 1108, 1004 cm"; 1H NMR (300 MHz, CDCla): 6 = 7.77 (d, J: 8.5 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.06 (d, J: 15.7 Hz, 1H), 6.72 (d, J = 15.7 Hz, 1H), 1.13 (s, 9H) ppm; 13C NMR (75 MHz, CDCIS): 6 = 190.3, 160.2, 136.9, 131.7, 130.0, 127.6, 120.5, 34.2, 28.7 ppm; HRMS (El) m/z 267.0375 [(M+H), calcd. for C,3H,eBrO 267.0385] 0 ‘ (EH'(3'3romophenleA-dlmethylpent-z-en-1-one: Br / w Subjection of 3-bromobenzoyl chloride (1.3 mmol, 0.216 g (T able 3, Entry 2) g) to the general procedure afforded after 4 h Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.2119 (80%) of (E)-1-(3-bromophenyI)-4,4-dimethylpent-2-en-1-one as a bright brown liquid. IR (neat) 3068, 2960, 1687, 1568, 1312, 1260 cm“; 1H NMR (300 MHz, CDCI3): 6 = 6.01 (t, J: 1.9 Hz, 1H), 7.60 (dt, J: 8.0 and 1.1 Hz, 1H), 7.64 (dq, J: 8.0 and 1.1 Hz, 1H), 7.31(t, J: 8.0 Hz, 1H), 7.05 (d, J: 15.7 Hz, 1H), 6.69 (d, J: 15.7 Hz, 1H), 1.13 (s, 9H) ppm; 13C NMR (75 MHz, CDCla): 6 = 190.0, 160.6, 140.0. 135.4, 131.5, 130.1, 127.0, 122.8, 120.5, 34.3, 28.7 ppm. 81 ( o ‘ (E)-1-(2-Bromophenyl)-4,4-dlmethylpent-2-en-1-one: / w Subjection of 2-bromobenzoyl chloride (1.3 mmol, 0.216 9) Br (Table 3, Entry 3) to the general procedure afforded after 4 h Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.1479 (55%) of (E)-1-(2-bromophenyl)-4,4-dimethylpent-2-en-1-one as a bright brown liquid and a trace amount of the decarbonylated byproduct was observed. IR (neat) 3056, 2961, 1660, 1616, 1298 cm"; 1H NMR (300 MHz, CDCla): 6 = 7.56 (d, J: 8.0 Hz, 1H), 7.23-7.36 (m, 3H), 6.63 (d, J: 15.7 Hz, 1H), 6.32 (d, J = 15.7 Hz, 1H), 1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCla): 6 = 195.5, 161.9, 141.1, 133.2, 131.0, 128.9, 127.1, 125.3, 119.2, 34.1, 28.4 ppm * (E)—1-(4-Bromophenyl)-5,5-dimethylhex-3-en-2-one: \ B W Subjection of 2-(4-bromophenyl) acetyl chloride (1.3 , (Table 3, Entry 4) mmol, 0.306 g) to the general procedure afforded after 4 h Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.1779 (63%) of (E)-1-(4-bromophenyl)-5,5-dimethylhex-3-en-2-one as a white crystalline solid. mp 69—70 °C. IR(PTFE) 2957, 1696, 1672, 1629, 1487 cm"; ‘H NMR (500 MHz, CDCIa): 6a 7.43 (d, .1: 6.5 Hz, 2H), 7.07 (d, J: 8.3 Hz, 2H), 6.90 (d, J: 16.1 Hz, 1H), 6.05 (d, J: 16.1 Hz, 1H), 3.78 (s, 2H), 1.06 (s, 9H) ppm; 13C NMR (125 MHz, CDCI3): 6 = 197.4, 156.4, 133.5, 131.7, 131.2, 124.5, 120.9, 46.7, 33.9, 26.6 ppm 82 o ‘ (E)-1-(4-Bromophenyl)-6,6-dimethylhept-4-en-3- / W one: Subjection of 3-(3-bromophenyl) propanoyl Br (Table 3, Entry 5) chloride (1.3 mmol, 0.322 g) to the general procedure afforded after 4 h Stille reaction and column chromatography (silica gel, hexane/EtOAc: 90/10) 0.2159 (73%) of (E)-1-(4-bromophenyl)-6,6-dimethylhept- 4-en-3-one as a white crystalline solid. mp 156—157 °C IR(KBr) 3041, 3024, 2962, 1696, 1671, 1626, 1488, 1364, 1107, 1011, 811 cm"; 1H NMR (500 MHz, CDCI3): 6 = 7.37 (d, J = 8.5 Hz, 2H), 7.06 (d, J: 8.2 Hz, 2H), 6.78 (d, J: 15.8 Hz, 1H), 5.99 (d, J: 16.2 Hz, 1H), 2.84 (m, 4H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCIS): 6 199.6, 157.4, 140.3, 131.5, 130.2, 15.3, 119.8, 41.5, 33.7, 29.4, 28.6 General Procedure for the Multiple Hydrostannation/Stille Reaction: szdbaa (0.01 mmol, 9.2 m9) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, 3,3- dimethyl 1-butyne (1 mmol, 0.125 mL), MeasnF (1.5 mmol, 274 mg), PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. The bromo benzoyl chloride (1.3 mmol) was then added and the mixture was allowed to reflux (~65 °C) until the cross-coupling was judged complete by TLC (2—4 h). At that time, szdbaa, t- BuaP, organostannanes (2.0 equiv) and 1,4-dioxane (5 mL) were added and 83 refluxed at ~90 °C until the cross-coupling was judged complete by TLC. The reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with 8,0 and H20 and the aqueous phase was back extracted with EtzO. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the corresponding cup-unsaturated ketone. T o ‘ (E)-1-(Biphenyl-4-yl)-4,4-dimethylpent-2-en-1-one: / w Subjection of MeasnPh (2.0 mmol, 0.36 mL) to the Ph (Table 4. Enid/1) general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.233 g (88%) of (E)-1- (biphenyl-4-yl)-4,4-dimethylpent-2-en-1-one as a white crystal. mp 127—129 °C lR (PTFE) 1661, 1614, 1600, 1303 cm"; 1H NMR (500 MHz, CDCI3): 6 = 8.00 (d, J: 8.6 Hz, 2H), 7.68 (d, J: 8.7 Hz, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.47 (t, J: 8.0 Hz, 2H), 7.39 (t, J: 7.7 Hz, 1H), 7.09 (d, J: 15.6 Hz, 1H), 6.62 (d, J: 15.7 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (125 MHz, CDCI3): 6 = 191.0, 159.5, 145.3, 140.0, 136.9, 129.1, 128.9, 128.1, 127.3, 127.2, 120.9, 34.2, 28.8 ppm; HRMS (El) m/z 264.1516 [(M+), calcd. for C,9HZOO 264.1514] 84 ' 0 ‘ (E)-1-(4-Allylphenyl)—4,4-dlmethylpent-2-en-1-one: / m Subjection of allylSnBu3 (2.0 mmol, 0.16 mL) to the (Table 4. Entry 2) general procedure afforded after column chromatography (Silica gel, hexane/EtOAc: 90/10) 0.222 g (97%) of (E)-1-(4- allylphenyI)-4,4-dimethylpent-Z-en-1-one as a colorless liquid. IR (neat) 1667, 1618, 1300 cm"; 1H NMR (500 MHz, CDCIS): 6 = 7.86 (d, J: 8.3 Hz, 2H), 7.28 (d, J: 8.1 Hz, 2H), 7.04 (d, J: 15.6 Hz, 1H), 6.77 (d, J: 15.6 Hz, 1H), 5.97 (m, 1H), 5.11 (s, 1H), 5.09 (d, J: 7.6 Hz, 1H), 3.44 (d, J: 6.6 Hz, 2H), 1.13 (s, 9H) ppm; 130 NMR (125 MHz, coma): 6 = 191.1, 145.2, 136.4, 136.3, 128.8, 128.7, 121.0, 116.5, 40.1, 34.1, 28.8 ppm; HRMS (El) m/z 228.1511 [(M+), calcd. for C,6HZOO 228.1514] f o ‘ (E)-1-(BiphenyI—3-yI)-4,4-dimethylpent-2-en-1-one: Ph / W Subjection of MeasnPh (2.0 mmol, 0.36 mL) to the (“9'9 4. 5910/3) general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.214 g (81%) of (E)-1- (biphenyl-3-yl)-4,4—dimethylpent-2-en-1-one as a liquid. IR (neat) 3060, 3031, 2960, 1669, 1618, 1309, 1206 cm"; 1H NMR (500 MHz, CDCI3): 6 = 8.12 (s, 1H), 7.88 (d, J: 7.8 Hz, 1H) 7.77 (d, J: 7.8 HZ, 1H) 7.62 (d, J: 7.8 HZ, 1H) 7.54(t, J: 7.6 Hz, 1H) 7.47 (d, J: 8.1 HZ, 2H), 7.38 (d, J: 7.6 Hz, 1H), 7.10 (d, J: 15.9 Hz, 1H), 6.62 (d, J: 15.9 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (125 MHZ, CDCIS): 6 = 191.5, 159.8, 141.6, 140.3, 138.8, 131.2, 85 126.9(2), 127.7, 127.3, 127.2(2), 121.1, 34.2, 26.7 ppm; HRMS (El) m/z 264.1514 [(M+), calcd. for C19H200 264.1514] f 0 ‘ (E)-1-(3-Allylphenyl)—4,4-dimethylpent-2-en-1-one: / W Subjection of allylSnBu3 (2.0 mmol, 0.16 mL) to the , (Table 4. Entry 4) general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.187 g (82%) of (E)-1-(3- allylphenyl)-4,4-dimethylpent-Z-en-1-one as a liquid. IR (neat) 1667, 1618, 1300 cm"; 1H NMR (300 MHz, CDCI3): 6 = 8.12 (s, 1H), 7.88 (d, J: 7.6 Hz, 1H) 7.77 (d, J: 7.6 Hz, 1H) 7.62 (d, J: 7.6 Hz, 1H) 7.54(t, J = 7.6 Hz, 1H) 7.47 (d, J: 8.1 Hz, 2H), 7.38 (d, J: 7.6 Hz, 1H), 7.10 (d, J: 15.9 Hz, 1H), 6.82 (d, J: 15.9 Hz, 1H), 1.16 (s, 9H) ppm; HRMS (El) m/z 228.1513 [(M+), calcd. for C,6HZOO 228.1514] ' o ‘ (E)—1-(2-Allylphenyl)-4,4-dimethylpent-2-en-1-one: / w Subjection of allylSnBua (2.0 mmol, 0.16 mL) to the \ (Table 4, Entry 5) general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 90/10) 0.105 g (46%) of (E)-1-(2- allylphenyI)-4,4-dimethylpent-2-en-1-one as a liquid. IR (neat) 3067, 2960, 2924, 2853, 1653, 1616, 1297, 1019 cm"; 1H NMR (500 MHz, 0001,): 6 = 7.38—7.20 (m, 4 H), 6.69 (d, J: 16.0 Hz, 1H), 6.36 (d, J: 15.9 Hz, 1H), 5.96—5.83 (m, 1 H), 5.01-4.93 (m, 2 H), 3.47 (d, J: 6.6 Hz, 1 H), 1.11 86 (s, 9 H) ppm; 130 NMR (125 MHz, CDCla): 6 = 197.6, 161.2, 139.3, 136.5, 137.1, 130.4, 130.2, 128.0, 126.1, 125.7, 116.0, 37.3, 34.0, 28.6 ppm \ L 0 (Table 4, Entry 6) (E)-5,5-Dimethyl-1-(4-vinylphenyl)hex-3-en-2- one: Subjection of vinylSnBua (2.0 mmol, 0.16 mL) to the general procedure afforded after column chromatography (Silica gel, hexane/EtOAc: 90/10) 0.107 g (47%) of (E)-5,5- dimethyl-1-(4-vinylphenyl)hex-3-en-2-one as a liquid. IR (neat) 3064, 2960, 1694, 1280 cm"; ‘H NMR (500 MHz, CDCla): 6 = 7.36 (d, J = 8.2 HZ, 2 H), 7.17 (d, J: 8.0 HZ, 2 H), 6.73 (dd, J: 17.6, 6.6 HZ, 1H), 6.07 (d, J: 16.2 HZ, 1H) 5.74 (d, J: 17.6 Hz, 1 H), 5.23 (d, J: 10.7 Hz, 1H), 3.81 (8, 2H), 1.05 (s, 9H) ppm; 13C NMR (125 MHZ, CDCIa): 6 = 197.8, 157.9, 136.4, 136.1, 134.1, 129.5, 126.4, 124.4, 113.5, 47.2, 33.7, 28.5 ppm \ OH (Scheme 22) 1 (E)-1-(4-((E)-3-Hydroxy-3-methylbut-1-enyl)- phenyl)-4,4-dimethylpent-2-en-1-one: szdbaa (0.01 mmol, 9.2 mg) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, 3,3-dimethyl 1-butyne (1 mmol, 0.125 mL), MeasnF (1.5 mmol, 274 m9). PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. The 87 bromo benzoyl chloride (1.3 mmol) was then added and the mixture was allowed to reflux (~65 °C) until the cross-coupling was judged complete by TLC (4 h). At that time, alkyne (3 mmol), PMHS (3.0 mmol, 0.18 mL), and potassium fluoride (3 mmol in 1ml H20) TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. Then, szdbaa, t-Bu3P and 1,4- dioxane were added and refluxed at ~90 °C until the cross-coupling was judged complete by TLC. The reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with EtZO and H20 and the aqueous phase was back extracted with 3,0. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by Silica gel chromatography (silica gel, hexane/EtOAc: 90/10) to afford the inseparable mixture of product (27%) and corresponding 1,4-reduction byproduct (41%). T o ‘ Procedure for the Reduction after One-pot Meow Sequence with 4-Methoxybenzoyl Chloride: szdbaa (smeme 22) (0.01 mmol, 9.2 mg) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, 3,3-dimethyl 1-butyne (1 mmol, 0.125 mL), MeasnF (1.5 mmol, 274 mg), PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. The 4- Methoxybenzoyl Chloride (1.3 mmol) was then added and the mixture was 88 allowed to reflux (~65 °C) until the cross-coupling was judged complete by TLC (4 h). At that time, PMHS (3.0 mmol, 0.18 mL), and potassium fluoride (3 mmol in 1mL H20) TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at 65 °C for 2 h, at which time the reduction did not go further by TLC. The reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with 3,0 and H20 and the aqueous phase was back extracted with EtZO. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the product (40%) and corresponding 01, B-unsaturated ketone (38%). mp 63—66 °C. IR (KBr) 3074, 2948, 2865, 2841, 1668, 1605, 1260, 1032, 837 cm"; 1H NMR (500 MHz, CDCI3): 6 = 7.93 (m, 2 H), 6.92 (m, 2 H), 3.65 (s, 3 H), 2.66 (m, 2 H), 1.61 (m, 2 H), 0.94 (s, 9 H) ppm; 13C NMR (125 MHz, CDCIa): 6 = 163.3, 130.3, 130.2, 113.7, 55.4, 38.4, 34.0, 30.2, 29.2 ppm , 4 IR (neat) 3071, 2960, 2905, 2866, 2840, 1667, W 1617, 1600, 1260, 1169, 1024, 832 cm"; 1H NMR ““0 (Scheme 22) (500 MHz, 000,): 6 = 7.96 (dd, J = 6.8, 2.2 Hz, 2 H), 7.06 (d, J: 15.6 Hz, 1 H), 6.96 (dd, J: 6.9, 2.2 HZ, 2 H), 6.81 (d, J: 15.7 Hz, 1 H), 3.88 (S, 3 H), 1.16 (s, 9 H) ppm; 13C NMR (125 MHZ, CDCIS): 6 = 189.7, 163.2, 158.5, 131.1, 130.8, 120.5, 113.7, 55.4, 34.0, 28.8 ppm General Procedure for the Multiple Hydrostannation/Stille Reaction Recycling Tin: Typical reaction procedure: szdba3 (0.01 mmol, 9.2 mg) and 89 TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, PhSnMe3 and 4-Br-benzoyl chloride were added successively. The reaction was then allowed to stir at 65 °C for 4 h, at which time the coupling reaction was complete by TLC. At that time, alkyne (3 mmol), PMHS (3.0 mmol, 0.18 mL), and potassium fluoride (3 mmol in 1mL H20) TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. At that time, szdbas, t-BuaP and 1,4- dioxane were added and refluxed at ~90 °C until the cross-coupling was judged complete by GC. The reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with 3,0 and H20 and the aqueous phase was back extracted with 8,0. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by Silica gel chromatography to afford the corresponding cup-unsaturated ketone. (E)-(4-(3,3-Dimethylbut-1-enyl)phenyl)- (phenyl)methanone: Subjection of 3,3-dimethylbut- (Table 5’ Entry 1) 1-yne (3.0 mmol, 0.25 mL) to the general procedure afforded after column chromatography (silica gel, hexane/EtOAc: 80l20) 0.132 9 (50%) of (E)-(4-(3,3-dimethylbut-1-enyl)phenyl)(phenyl)methanone as a liquid with inseparable byproduct. 90 (EH4-(3-Hydroxy-3-methylbut-1-enyl)phenyl)- o O O (phenyl)methanone: Subjection of 2-methylbut-3- / OH (Tables Entry 2) yn-2-ol (3.0 mmol, 0.29 mL) to the general L procedure afforded after column chromatography (silica gel, hexane/EtOAc: 80/20) 0.141 g (53%) of (E)-(4-(3-hydroxy-3-methylbut-1-enyl)phenyl)(phenyl)- methanone as a liquid. IR (neat) 3448 (br), 3058, 2972, 1652, 1600, 1316, 1281 cm"; 1H NMR (500 MHz, CDCI3): 6 = 7.77 (m, 4H), 7.56 (m, 1H) 7.47 (m, 4H) 6.66 (d, J = 16.1 Hz, 1H) 6.49(t, J: 16.1 Hz, 1H) 1.43 (s, 6H) ppm; 13C NMR (125 MHz, CDCI3): 6 = 196.1, 141.2, 140.4, 137.8, 136.2, 132.2, 130.6, 129.9, 128.2, 126.2, 125.5, 71.1, 29.9 ppm l “ (E)-(4-(3-Hydroxy-3-methylpent-1-nyl)phenyl)- (phenyl)methanone: Subjection of 3-methylpent-1- _ (Tab'e 5' Entry 3) yn-3-ol (3.0 mmol, 0.34 mL) to the general procedure afforded after column chromatography (silica gel.) hexane/EtOAc: 80/20) 0.112 g (40%) of (E)-(4-(3-hydroxy-3-methylpent-1-nyl)phenyl)(phenyl) methanone as a liquid. IR (neat) 3466 (br), 3059, 2967, 1652, 1600, 1446, 1316, 1281 cm"; 1H NMR (500 MHz, CDCIa): 6 = 7.76 (m, 4H), 7.57 (m, 1H) 7.46 (m, 4H) 6.67 (d, J: 16.1 HZ, 1H) 6.41 (t, J: 16.1 HZ, 1H) 1.73 (m, 3H), 1.42 (s, 3H), 0.98 (t, J: 7.3 HZ, 91 3H) ppm; 1ac NMR (125 MHz, 0001,): 6 = 196.1, 141.3, 139.4, 137.6, 136.1, 132.2, 130.6, 129.9, 128.2, 126.4, 126.1, 73.5, 35.3, 27.7, 8.2 ppm 92 Chapter 4. Pd (0)-Catalyzed PMHS Reductions of Aromatic Acid Chlorides to Aldehydes General Procedure for Reductions with MeaanIIPMHS/KF/Pdm): szdba3 (0.01 mmol, 9.2 mg) and TFP (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at it for 15 min. At that time, acid chloride (1 mmol), MesanI (0.1—1.0 mmol), PMHS (1.5 mmol, 0.09 mL), aq. KF (1.5 mmol, 87.3 mg in 1 mL H20) and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt until the reduction was judged complete by GC (~05 to 1 h). At that time, the reaction was diluted with saturated aq. KF (3 mL) and stirred for 0.5 h. The reaction was then extracted with EtZO and the aqueous phase was back extracted with 3,0. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (10% EtZO/pentane) to afford the aldehyde. General Procedure for Reductions with PMHS/KF/Pd(0): szdba3 (0.01 mmol, 9.2 mg) and trifurylphosphine (T FP) (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, acid chloride (1 mmol), PMHS (3.0 mmol, 0.18 mL), aq. KF (3.0 mmol, 174.5 mg in 1 mL H20) and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt until the reduction was complete by GC monitoring (~1 h). At that time, the reaction was extracted 93 with EtZO and the aqueous phase back extracted with EtZO. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (10% EtzO/pentane) to afford the aldehyde. ‘ Benzaldehyde: Subjection of benzoyl chloride (1.0 mmol, @010 (Table 7, Entry 1) 0.141 mg) to the general procedure afforded after column chromatography (silica gel, 10% EtQO/pentane) 0.105 g (99%) of benzaldehyde as a colorless liquid. 1H NMR (300 MHz, CDCIS): 6 = 9.96 (s, 1H), 7.85 (dd, J: 8.0, 1.1 Hz, 2H), 7.62 (m, 1H), 7.51 (m, 2H) ppm; 13C NMR (75 MHz, CDCIa): 6 = 192.2, 136.3, 134.3, 129.6, 128.9 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. i 2-Methylbenzaldehyde: Subjection of 2-methyl-benzoyl < g—CHO chloride (1.0 mmol, 0.155 mg) to the general procedure (Table 7, Entry 2) afforded after column chromatography (silica gel, 10% EtZO/pentane) 0.100 g (83%) of 2-methyl-benzaldehyde as a colorless liquid. 1H NMR (300 MHz, CDCIS): 6 = 10.24 (s, 1H), 7.78 (d, J: 7.4 Hz, 1H), 7.48 (m, 1H), 7.35 (m, 1H), 7.23 (d, J: 7.4 Hz, 1H), 2.64 (s, 3H) ppm; 13C NMR (75 MHz, CDCIa): 6 = 192.8, 140.6, 134.2, 133.6, 132.0, 131.7, 126.3, 19.5 ppm. Physical 94 and spectral data were consistent with those obtained from a commercial sample. ‘ 4-tert-Butylbenzaldehyde: Subjection of 4-tert-butyl- t-BUAQ—CHO benzoyl chloride (1.0 mmol, 197 mg) to the general (Table 7, Entry 3) procedure afforded after column chromatography (silica gel, 10% EtZO/pentane) 0.161 g (99%) of 4-tert-butylbenzaldehyde as a colorless liquid. 1H NMR (300 MHz, .CDCla): 6 = 9.96 (s, 1H), 7.81 (d, J: 8.5 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 1.32 (s, 9H) ppm; 13C NMR (75 MHz, CDCI3): 6 = 191.9, 158.4, 134.1, 129.6, 125.9, 35.3, 31.0 ppm. Physical and Spectral data were consistent with those obtained from a commercial sample. ‘ 4-Methoxybenzaldehyde: Subjection of 4-methoxy- benzoyl chloride (1.0 mmol, 0.171 mg) to the general (Table 7, Entry 4) procedure afforded after column chromatography (silica gel, 10% Et20/pentane) 0.124 9 (91%) of 4-methoxybenzaldehyde as a colorless liquid. 1H NMR (300 MHz, CDCI3): 6 = 9.64 (s, 1H), 7.61 (d, J: 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H) ppm; 13C NMR (75 MHz, CDCIa): 6 = 190.7, 164.6, 131.9, 129.9, 114.3, 55.5 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. 95 CH0 3-Methoxybenzaldehyde: Subjection of 3-methoxy-benzoyl MeO chloride (1.0 mmol, 0.171 mg) to the general procedure (Table 7, Entry 5) afforded after column chromatography (silica gel, 10% EtZO/pentane) 0.133 g (98%) of 3-methoxybenzaldehyde as a colorless liquid. ‘H NMR (300 MHz, CDCI3): 6 = 9.92 (s, 1H), 7.40 (m, 2H), 7.33 (s, 1H), 7.14 (m, 1H), 3.61 (s, 3H) ppm; 130 NMR (75 MHz, CDCI3): 6 = 192.0, 160.1, 137.7, 129.9, 123.4, 121.4, 112.0, 55.3 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. ’ MeO ‘ 3,4,5-Trimethoxybenzaldehyde: Subjection of 3,4,5- MeO‘Q'CHO trimethoxybenzoyl chloride (1.0 mmol, 231 mg) to the MeO general procedure afforded after column chromatography (Table 7, Entry 6) (Silica gel, 10% EtZO/pentane) 0.160 g (82%) of 3,4,5- trimethoxybenzaldehyde as a white crystal. 1H NMR (300 MHz, CDCI3): 6 = 9.84 (s, 1H), 7.01 (s, 2H), 3.91 (s, 3H), 3.90 (s, 6H,) ppm; 13C NMR (75 MHz, CDCI3): 6 = 191.0, 153.6, 143.7, 131.7, 106.7, 61.0, 56.3 ppm; mp 71—72 °C. Physical and spectral data were consistent with those obtained from a commercial sample. ’ CH0 ‘ 1-Naphthaldehyde: Subjection of 1-naphthoyl chloride (1.0 mmol, 0.191 mg) to the general procedure afforded after L (Table 7, Entry 7) column chromatography (silica gel, 10% EtZO/pentane) 0.134 g (86%) of 1- naphthaldehyde as a colorless liquid. 1H NMR (300 MHz, CDCI3): 6 96 = 10.36 (s, 1H), 9.25 (d, J: 8.5 Hz, 1H), 8.06 (d, J: 8.2 Hz, 1H), 7.95 (d, J: 8.2 Hz, 1H), 7.90 (d, J: 8.5 Hz, 1H), 7.67 (t, J: 8.5 Hz, 1H), 7.59 (m, 2H) ppm; 13C NMR (75 MHz, CDCla): 6 = 193.3, 136.5, 135.1, 133.6, 131.3, 130.4, 128.9, 128.4, 126.8, 124.7 (20) ppm. Physical and spectral data were consistent with those obtained from a commercial sample. 2-Naphthaldehyde: Subjection of 2-naphthoyl chloride (1.0 CHO‘ mmol, 0.191 mg) to the general procedure afforded after (Table 7, Entry 8) column chromatography (silica gel, 10% EtZO/pentane) 0.126 g (81%) of 2- naphthaldehyde as a white crystal. 1H NMR (300 MHz, CDCIa): 6 = 10.12 (s, 1H), 8.30 (s, 1H), 7.95-7.85 (m, 4H), 7.63-7.52 (m, 2H) ppm; 1"0 NMR (75 MHz, CDCI3): 6 = 191.6, 136.1, 134.1, 133.7, 132.3, 129.1, 128.7 (20), 127.7, 126.7 ppm, 122.4; mp 57—58 °C. Physical and spectral data were consistent with those obtained from a commercial sample. ‘ 2-Thlophenecarboxaldehyde: Subjection of 2-thiophene- Us... 8 (Table 7, Entry 9) carbonyl chloride (1.0 mmol, 0.147 mg) to the general procedure afforded after column chromatography (silica gel, 10% EtZO/pentane) 0.103 g (92%) of 2-thiophenecarboxaldehyde as a colorless liquid. 1H NMR (300 MHz, CDCIS): 6 = 9.90 (s, 1H), 7.75 (m, 2H), 7.19 (m, 1H) ppm; 130 NMR (75 MHz, 0001,): 6 = 162.9, 144.0, 136.2, 135.0, 126.2 ppm. 97 Physical and spectral data were consistent with those obtained from a commercial sample. ‘ 4-Bromobenzaldehyde: Subjection of 4-bromo-benzoyl (Table 7, Entry 10) chloride (1.0 mmol, 220 mg) to the general procedure afforded after column chromatography (silica gel, 10% EtzO/pentane) 0.126 g (68%) of 4-bromo-benzaldehyde as a white crystal. mp 54—56 °C 1H NMR (300 MHz, CDCIS): 6 = 9.93 (s, 1H), 7.72 (d, J: 8.5 Hz, 2H), 7.65 (d, J: 8.5 Hz, 2H) ppm; 13C NMR (75 MHz, CDCI3): 6 = 190.9, 135.0, 132.4, 130.9, 129.7 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. General Procedure for Reductions with PMHS/KF/18-crown-6/Pd(0): szdbaa (0.01 mmol, 9.2 mg) and trifurylphosphine (T FP) (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting mixture was stirred at rt for 15 min. At that time, acid chloride (1 mmol), PMHS (1.5 mmol, 0.09 mL), aq. KF (2.0 mmol, 174.5 mg), 18-crown-6 (1mmol, 260 mg) and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt until the reduction was complete by GC monitoring. At that time, the reaction was filtered through cotton and evaporated. The resulting 98 residue was purified by silica gel chromatography (10% EtZO/pentane) to afford the aldehyde. CH0 ‘ Stearaldehyde: Subjection of stearoyl chloride (1.0 mmol, \MI/SV (Table 8, Entry 1) 303 mg) to the general procedure afforded after column chromatography (silica gel, 10% EtZO/pentane) 180 mg (67%) of stearaldehyde as a white crystal. mp 42—43 °C. IR (KBr) 2952, 1737, 1437 cm"; 1H NMR (500 MHz, CDCI3) 6 = 9.75 (s, 6 H), 2.42 (m, 2 H), 1.23 (m, 30 H), 0.86 (m, 3H) ppm; 13C NMR (125 MHz, CDCIa) 6 = 203.0, 43.9, 31.9, 29.69, 29.65, 29.63, 29.57, 29.42, 28.36, 29.16, 22.69, 22.07, 14.12 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. Methyl 6-Oxobutanoate: Subjection of methyl 6-chloro-6- Meozc/Nvlq,CH0 (Table 8, Entry 2) oxohexanoate (1.0 mmol, 179 mg) to the general procedure afforded after column chromatography (silica gel, 10% EtZO/pentane) 77 mg (53%) of methyl 6-oxohexanoate as colorless liquid. IR (neat) 2952, 2725, 1737, 1196 cm-1; 1H NMR (500 MHz, CDCIa): 6 = 9.74 (m, 1H), 3.64 (s, 3 H), 2.44 (m, 2 H), 2.31 (m, 2 H), 1.64 (m, 4 H) ppm; “’0 NMR (125 MHz, 000l3): 6 = 202.0, 173.7, 51.5, 43.5, 33.7, 24.3, 21.4 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. 99 ‘ Undec-10-enal: Subjection of undec-10-enoyl chloride (1.0 Mom (Table B’Emry 3) mmol, 203 mg) to the general procedure afforded after column chromatography (Silica gel, 10% EtZO/pentane) 84 mg (50%) of undec-lO-enal as colorless liquid. IR (neat) 3076, 2927, 2716, 1727, 1640 cm-1; ‘H NMR (500 MHz, CDCI3): 6 = 9.74 (S, 1 H), 5.82—5.74 (m, 1 H), 4.99-4.89 (m, 2 H), 2.41 (dt, J: 7.3, 1.9 Hz, 2 H), 2.03 (m, 2 H), 1.61 (m, 2 H), 1.29 (m, 10 H); 13C NMR (125 MHz, CDCI3): 6 = 202.9, 139.1, 114.1, 43.8, 33.7, 29.26, 29.22, 29.1, 29.0, 28.8, 22.0 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. ‘ 3-Phenylpropanal: Subjection of 3-phenylpropanoyl CHO ©/\/ chloride (1.0 mmol, 169 mg) to the general procedure (Table 8. Entry 4) afforded after column chromatography (silica gel, 10% EtZO/pentane) 95 mg (71%) of 3-phenylpropanal as colorless liquid. IR (KBr) 3027, 2927, 1723, 1496, 1453, 699 cm-1; 1H NMR (300 MHZ, CDCIa): 6 = 9.81 (m, 1 H), 7.30—7.18 (m, 4H), 2.95 (t, J: 7.6 Hz, 2 H), 2.78 (m, 2 H); ”C NMR (75 MHz, CDCla): 6 = 201.7, 140.3, 126.6, 128.3, 126.3, 45.2, 26.1 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. 100 4-Nitrobenzaldehyde: Subjection of 4-nitrobenzoyl chloride oCHO 02N (1.0 mmol, 186 mg) to the general procedure afforded after (Table 8, Entry 5) column chromatography (Silica gel, 10% EtZO/pentane) 77 mg (51%) of 4-bromo-benzaldehyde as a white crystal. mp 102—103 °C IR (KBr): 3107, 1709, 1606, 1536, 1347 cm-1; 1H NMR (300 MHz, CDCIS): 6 = 10.14 (s, 1H), 8.39 (m, 2 H), 8.07 (m, 2 H) ppm; 13C NMR (75 MHz, CDCla): 6 = 190.3, 140.0, 130.5, 124.3 ppm. Physical and spectral data were consistent with those obtained from a commercial sample. 101 CHAPTER 5. Application of One-pot Pd-mediated Reactions in Target Synthesis OH Preparation of (+/-)-4-Penten-2-ol: A flask was charged with M9 M turnings (110 g, 4.5 mol) and dry 3,0 (187 mL). While this 17 mixture was stirring, a solution of allyl bromide (173 mL, 2.0 mol) in 8,0 (1.0 L) was added slowly so as to keep the reaction temperature ~30 °C. Once the addition was complete, the solution was allowed to stir for 1 h. The solution of allylmagnesium bromide was cooled with an ice bath and a solution of acetaldehyde (100 mL, 1.8 mol) in EtZO (100 mL) was added via an addition funnel. Once the addition was complete, the reaction was refluxed for 3 h. The reaction was then poured into ice water and quenched by the addition of dilute H2804. The mixture was then extracted with Et20. The organics were dried (M9804), filtered and concentrated (NO HEAT on rotovap). The resulting residue was purified by distillation [bp 112-116 °C @ 760 mmng to afford (+/-)-4-penten- 2-ol (170 g, 98%) as a clear liquid. Spectra matched those of commercial material. 0H AcO ‘ Preparation of (S)-4-Penten-2-ol and (RM- ? + M M Penten-2—yl Acetate: (+/-)-4-Penten-2-ol (77.86 g, (S)-17 904 mmol) was dissolved into freshly distilled vinyl acetate (83.3 mL, 904 mmol) and Novozyme 435 (8.22 g) was added. This slurry 102 was stirred at room temperature for ~12 h. The reaction was then filtered and the filtrate was loaded onto a column of silica and was eluted with 90:10 Pentane/EtZO and once the acetate was off, 70:30 pentane/Et20 was used to obtain the (S)-alcohol. The relevant fractions were rotovaped (NO HEATIIII) to afford (5')-4-penten-2-ol (19.49 g, 25%; 99% ee) and (R)-4-penten-2-yl acetate (46 g, 40%; 65 % ee). 1H NMR (300 MHz, C00,) 6 = 1.18 (d, J = 6.2 Hz, 3H), 1.97 (bs, 1H), 2.09-2.21 (m, 2H), 3.68 (m, 1H), 5.04-5.08 (m, 2H), 5.72-5.81 (m, 1H) ppm; 13C (75 MHz, CDCI3) 6 = 22.6, 43.6, 66.8, 117.9, 134.7 ppm Spectra matched those of commercial material. QTBDPS Preparation of (S)-tert-Butyl(pent-4-en-2-yloxy)diphenyl- M 22 slIane: (S)-4-Penten-2-ol (11.97 g, 139 mmol) was dissolved into DMF (140 mL) and imidazole (20.82 g, 306 mmol) was added followed by TBDPSCI (35.8 mL, 138 mmol). After stirring at room temperature for 10 h, the reaction was poured into sat. aq. NH,,CI and then was extracted with 3,0. The combined organics were dried (M9804), filtered and concentrated. The resulting residue was purified by column chromatography [silica; hexanes] to afford (S)-tart-butyl(pent-4-en-2-yloxy)diphenylsilane (44.95 g, 99%) as a clear oil. IR (neat) 3072 cm"; 1H NMR (500 MHz, 000;) 6 = 1.10 (m, 12 H), 2.24 (m, 2 H), 3.95 (m, 1 H), 4.96-5.03 (m, 2 H), 5.74-5.86 (m, 1 H), 7.35-7.48 (m, 6 H), 7.69- 103 7.75 (m, 4 H) ppm; 130 NMR (125 MHz, 00013) 6 = 19.3, 22.8, 27.0, 43.9, 69.2, 116.7, 127.4, 127.5, 129.4, 129.5, 134.5, 134.8, 135.1, 135.8, 135.9 ppm; [011023 = + 16.8 (c = 2.07, CHZCIZ) All data matched those of the literature.8 Preparation of Ph, =CHC02Et. Ethyl-2-bromoacetate (111 mL, 1 mol), was added dropwise during 30 min to a stirred solution of PPh3 (262 g, 1 mol) in benzene at 25 °C. This mixture was stirred for 5 h and then was allowed to stand overnight. The precipitate was filtered off and was successively washed with benzene and hexanes and then dried in vacuo to yield the corresponding bromide. This solid was then dissolved into cold water and 2 N NaOH was added dropwise until the mixture was alkaline to phenolphthalein. The precipitate was filtered off and air-dried to give the phosphorane as a white solid (312 g, 90%). OTBDPS ‘ Preparation of (SHE-Ethyl 5-(tert-Butyldiphenyl- ‘ E WW" I slloxy)-2-hexenoate: (S)-tert-Butyl(pent-4-en-2-yloxy) 23 diphenylsilane (1.0 g, 3.08 mmol) was dissolved into CH2CI2 (15 mL). This solution was then purged with N2 and then cooled to -78 °C. 03 was bubbled through the solution at -78 °C until a blue color persisted. The excess 03 was removed by purging the solution with N2. The reaction was then allowed to warm to room temperature and a condenser was added. Once at room temperature, a solution of Et3N (0.47 mL, 3.4 mmol) and Ph3P=CHCOZEt (1.18 g, 3.4 mmol) in CHZCI2 (15 mL) was added to the solution. Once the 104 addition was complete, the mixture was stirred for 20 min. The reaction was then concentrated and purified by column chromatography [silica; 95:5 hexane/EtOAc] to afford (S)-(E)-ethyl 5-(tert-butyldiphenylsiloxy)-2-hexenoate (1.10 g, 90%) of light yellow oil. IR (neat) 3071, 3049, 2963, 1721, 1656, 1427, 1264, 1175 cm"; 1H NMR (500 MHz, CDCI3) 6 = 7.67 (d, J = 7.7 Hz, 4 H), 7.47—7.27 (m, 6 H), 6.99—6.89 (m, 1 H), 5.60 (dd, J: 15.7, 1.4 Hz, 1 H), 4.23—4.15 (q, J: 7.1 Hz, 2 H), 4.00—3.94 (m, 1 H), 2.35 (m, 2 H), 1.29 (t, J: 7.1 Hz, 3 H), 1.07 (s, 9 H) ppm; 1"C (125 MHZ, CDCIa) 6 = 166.4, 145.5, 135.8, 134.3, 133.9, 129.65, 129.56, 127.57, 127.49, 123.4, 66.5, 60.1, 42.1, 26.9, 23.2, 19.2, 14.2 ppm; [0.]025 = -34.2 (c = 0.67, CHZCIZ) All data matched those of the literature.9 QTBDPS ‘ Preparation of (S)-(E)-5-(tert-Butyldlphenylsiloxy)hex-2- Wort en-1-ol: (S)-(E)-Ethyl 5-(tert-butyldiphenylsiloxy)-2- 24 hexenoate (44.57 g, 113 mmol) was dissolved into CH2CI2 (560 mL) and the solution was cooled to —78 °C. DIBALH (236 mL of a 1M solution in hexanes, 236 mmol) was added dropwise via an addition funnel. Once the addition was complete, the reaction was allowed to stir for 6 h at —78 °C. The reaction was quenched by the addition of water and Rochelle’s salt. The reaction was then allowed to warm to room temperature for several hours (overnight if needed). The phases were separated and the aqueous phase was 105 extracted with CHZCI2 (4x). The combined organics were dried (Na2804), filtered and concentrated. The residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford (S)-(E)-5-(tert-butyldiphenylsiloxy)-hex-2-en-1-ol (36.64 g, 92%) as a colorless oil. IR (neat) 3320(br), 3070, 2963, 2857, 1427, 1110 cm"; 1H NMR (500 MHz, CDCla) 6 = 7.69—7.65 (m, 4 H), 7.42—7.33 (m, 6 H), 5.59—5.55 (m, 2 H), 4.00 (m, 2 H), 3.90 (Q, J: 6.0 Hz, 1 H), 2.18 (m, 2 H), 1.05 (s, 9 H) ppm; 13C (125 MHz, CDCI3) 6 163.2, 135.9, 134.6, 134.4, 131.3, 129.53, 129.48, 129.38, 127.5, 127.4, 69.2, 63.7, 42.2, 27.0, 23.1, 23.1, 19.2 ppm; HRMS (El) m/z 355.2093 [(M+), calcd. for CZZH3,OZSI 355.2113]; [or]"""D = -21.5 (c = 0.67, CHZCIZ) All data matched those of the literature.”11 Procedure for the Preparation of Anyhydrous tert-Butylhydrogen Peroxide (TBHP) in Toluene. To 1 L sep. funnel was added 360 mL of TBHP (30% aqueous solution) and 440 mL of toluene. The solution was swirled, not shaken. The aqueous phase was separated and the organic phase was transferred to a 1 L flask equipped with a Dean-Stark trap and reflux condenser. Boiling chips were added and the solution was refluxed for 4 h; during which ~120 mL of distillate was removed. The head temperature was ~80 °C. After cooling, the remaining TBHP/toluene solution was transferred to a brown glass bottle and stored at 25 °C over activated 4A MS. 106 P ti 1 S, R, 3-2-trt-B ldih lil 9TBDPS repara on o ( R)—( ( (e uty p enys oxy)— WOH propyl)oxiran-2-yl)methanol: To a suspension of 4A MS 25 (4 g) in CHZCI2 (125 mL) at —30 °C was added in sequential fashion: D-DET (0.73 mL, 4.22 mmol), Ti(i-PrO)4 (1.03 mL, 3.52 mmol) and dropwise addition of TBHP (14 mL of a 3.86 M solution in toluene, 54 mmol). After stirring at —30 °C for 30 min, a solution of (S)-(E)-5-(tert— butyldiphenylsiloxy)-hex-2-en-1-ol (12.47 g, 35.2 mmol) in CHZCI2 (18 mL) was added via a syringe so as to keep the reaction temperature at —30 °C. Once the addition was complete, stirring was stopped and the mixture was left at —30 °C for 12 h. The reaction was then warmed to —20 °C and quenched by the addition of 10% NaOH/brine (25 mL). Upon further warming to —10 °C, the reaction was diluted with EtZO and MgSO, (15 g) and celite (4.0 g) were added and this mixture was stirred for 20 min. The reaction was then allowed to settle for ~1 h before filtering through celite. The filter cake was rinsed with EtZO and the filtrate was concentrated. The residue was purified by column chromatography [silica; 80:20 to 70:30 hexane/EtOAc] to afford (S, R, R)-(3-(2-(tert-butyldiphenylsiloxy)- propyl)oxiran-2-yl)methanol (11.12 g, 85%) as a clear oil. IR (neat) 3430(br), 3070, 2931, 2657, 1472, 1427, 1110 cm"; 1H NMR (500 MHz, CDCI3) 6 = 7.68 (m, 4 H), 7.40 (m, 6 H), 4.08 (m, 1 H), 3.82 (m, 1 H), 3.54 (m, 1H), 3.04 (m, 1 H), 2.81 (m, 1 H), 1.76 (m, 2 H), 1.62 (m, 1 H), 1.11 (d, J: 6.1 Hz, 3 H), 1.05 (S, 9 H); 1"C NMR (125 MHZ, CDCIa) 6 = 1.9.2, 23.8, 26.9, 41.6, 107 53.2, 58.7, 61.5, 67.6, 127.5, 129.6, 134.3, 135.8 ppm; HRMS (El) m/z 371.2042 [(M+H), calcd. for CZZH3,O;,Si 371.2050]; [91250: + 2.0 (c = 0.76, CHZClz) All data matched those of the literature.11 9TBDPS ‘ Preparation of 3-(2—(tert-Butyldiphenylslloxy)-propyl)- , 0 W0 oxirane-2-carbaldehyde: A solution of (S, R. R)-(3-(2- 26 (tert-butyldiphenylsiloxy)-propyl)oxiran-2-yl)methanol (10.66 g, 28.77 mmol) and EtaN (20 mL, 141 mmol) in 4:1 mixture of CHZCl2/DMSO (300 mL) at 0 °C was treated with SOatpy (16.08 g, 101 mmol) and this mixture was stirred at room temperature for 1 h. The reaction was then diluted with EtOAc, washed with water, sat. aq. NaHCOa, brine, dried (M9804), filtered and concentrated. The residue was purified by column chromatography [silica; 95:5 hexane/EtOAc] to afford 3-(2-(tert-butyldiphenylsiony)-propyl)oxirane-2- carbaldehyde (7.68 g, 72%) as a yellow oil. IR (neat) 3071, 2931, 2857, 1730, 1427, 1110 cm"; 1H NMR (500 MHZ, CDCla) 6 = 8.91 (d, J = 6.3 Hz, 1 H), 7.69-7.65 (m, 4 H), 7.44—7.36 (m, 6 H), 4.14-4.09 (m, 1 H), 3.28 (m, 1 H), 3.03 (dd, J = 6.3, 2.0 Hz, 1 H), 1.85—1.79 (m, 1 H), 1.66— 1.61 (m, 1 H), 1.14 (d, J: 6.3 Hz, 3 H), 1.06 (S, 9 H); 13C NMR (125 MHz, CDCI3) 6 = 198.1, 135.81, 135.77, 134.12, 133.76, 129.77, 129.67, 127.68, 127.55, 67.4, 59.3, 54.1, 41.1, 26.9, 23.7, 19.2 ppm [01250: -42.0 (c = 1.12, 0H20l2) All data matched those of the literature.11 108 r o OTBDPS‘ Preparation of 2-(2,2-Dibromovinyl)-3-(2-(tert- B’ / i ’ butyl-diphenylsiloxy)propyl)oxirane. Br t 27 To a mixture of CBr, (14.51 g, 43.76 mmol) in CHZCI2 (120 mL) at 0 °C under Ar was added a solution of PPh3 (22.96 g, 87.53 mmol) in CHZCI2 (40 mL). After 20 min at 0 °C, the solution was cooled to —78 °C and EtaN (3.2 mL, 22.92 mmol) was added. A solution of 3-(2-(tert—butyldiphenylsiloxy)- propyl)oxirane-2-carbaldehyde (7.68 g, 20.84 mmol) in CHZCI2 (70 mL) was added dropwise over 10 min. After 2 h, hexanes (120 mL) were added and the mixture was allowed to stir for 1 h. Filtering and concentration afforded a mixture of bromohydrin and epoxy dibromide. This mixture was then dissolved into THF (100 mL) and treated with TBAF (22 mL of a 1M solution in THF, 22 mmol) and stirred for 1 min at room temperature. The mixture was then washed with water, brine, dried (M9804), filtered and concentrated to afford 2-(2,2-dibromovinyI)-3- (2-(tert-butyldiphenylsiloxy)propyl)oxirane (9.25 9,85%) as a yellow oil. Data for bromohydrin: [01250: -77.8 (c = 1.12, CHCI3) IR (neat) 3458 cm"; 1H NMR (500 MHz, CDCI3) 6 1.10 (m, 9 H), 1.18 (d, J: 6.2 Hz, 3 H), 1.62 (m, 2 H), 3.13 (m, 1 H), 4.18 (m, 1 H), 4.62 (m, 1 H), 6.80 (d, J: 10.2 Hz, 1 H), 7.34-7.52 (m, 6 H), 7.64-7.79 (m, 4 H); 13C (125 MHz, CDCIa) 6 19.1, 23.0, 27.0, 41.8, 56.2, 67.7, 71.1, 95.1, 127.6, 127.8, 129.8, 129.9, 133.3, 133.7, 134.6, 135.8, 135.9; HRMS (El) m/z 601.9492 [(M“), calcd. for 0,,H,,Br,o,Si 601.9487]. 109 Data for epoxy dibromide: [01250: -7.6 (c = 1.08, CHCla); IR (neat) 3071 cm"; 1H NMR (300 MHz, CDCla) 6 1.6 (m, 9 H), 1.11 (d, J: 6.2 Hz, 3 H), 1.58-1.80 (m, 2 H), 3.00 (td, J: 2.1, 6.2 Hz, 1 H), 3.27 (dd, J: 2.1, 7.8 Hz, 1 H), 4.07 (m, 1 H), 6.06 (d, J: 10.2 Hz, 1 H), 7.33-7.47 (m, 6 H), 7.64-7.74 (m, 4 H); 13c (75 MHz, CDCI3) 6 19.2, 23.8, 25.9, 26.5, 26.9, 41.6, 56.7, 57.8, 67.4, 93.4, 127.5, 127.6, 127.7, 129.5, 129.6, 129.7, 133.8, 134.3, 134.7, 135.7, 135.8; HRMS (El) m/z 522.0222 [(M+), calcd. for 0,,H,,Br,o,Si 522.0225]. o OTBDPSj Preparation of tert-Butyl((S)-1-((2R,3R)-3-((Z)-2- / ’ lodovinyl)oxlran-2-yl)propan-2-yloxy)diphenylsilane. l L 28 To a suspension of iodomethyltriphenylphosphonium iodide (0.65 mmol, 345 mg) in THF/DMF (2 mU2 mL) at -20 °C was slowly added sodium bis-(trimethylsilyl)amide (0.65 mmol, 0.65 mL) in THF. After stirring for 5 min the solution was cooled to -20 °C and the aldehyde (0.5 mmol, 185 mg) in THF (1 ml) was added. The reaction was maintained at -20 °C for 25 min. The reaction mixture was diluted with EtOAc and workup with water and brine. The combined organics were dried over NaZSO,. Removal of solvent in vacuo afforded the crude product, which was purified by flash chromatography (95:5 hex/EtOAc) to afford product (dr: Z/E= >9/1) in 72% yield. IR (neat) 3070, 2930, 1427, 1111 cm"; 1H NMR (500 MHz, CDCI3) 6 = 7.66 (m, 4H), 7.43-7.37 (m, 6H), 6.46 (d, J: 7.8 Hz, 1 H), 5.94 (t, J: 7.8 Hz, 1 H), 4.12— 4.06 (m, 1 H), 3.32 (d, J: 7.6 Hz, 1 H), 3.04 (m, 1 H), 1.82-1.77 (m, 1H), 1.70— 110 1.63 (m, 1H), 1,13(d, J: 6.1 Hz, 3 H), 1.06 (S, 9H) ppm; 13C (125 MHz, CDCIa) 6 = 138.3, 135.83, 135.82, 134.4, 134.0, 129.7, 129.6, 127.6, 127.5, 84.6, 67.6, 60.7, 56.7, 41 .7, 27.0, 23.6, 19.2 ppm; [01250: -28.7 (c = 2.15, CHCIS) Preparation of Methyl 2,4-Dihydroxy-6-methylbenzoate: Methyl acetoacetate (5.2 mL, 48 mmol) and 030 (2.73 g, 48.7 mmol) were dissolved in THF (35 mL) under nitrogen and then were heated to 50 °C for 1 h. Diketene (stabilized with CuSO,,) (3.70 mL, 4.04 mmol) was added dropwise while the mixture was being cooled with a water bath to keep the temperature between 30-40 °C. Once the addition was complete, the reaction was refluxed for 8 h and then cooled to room temperature. The THF was removed (rotovap) and ether (50 mL) was added followed by enough 2 M HCI to dissolve the residual CaO in the mixture. After extracting with ether (3x), water was added and the aqueous phase was adjusted to pH 6.0 with 10% NaOH and then the mixture was extracted with ether (3x). The solvent was removed to provide a complex mixture of products that were not identifiable. ’ o 1 Preparation of Methyl Dlhydroorselllnate: Na (18.4 g, COzMe 800 mmol) was added with stirring in small pieces to dry HO , 35 MeOH (275 mL). After the reaction had subsided, methyl acetoacetate (86 mL, 800 mmol) was added dropwise followed by the dropwise addition of methyl crotonate (85 mL, 800 mmol). After the addition was complete, 111 the reaction was refluxed for 44h. At this time the MeOH was carefully removed in the original flask with the rotovap. The resulting residue was then cooled to 0 °C and ether (400 mL) was added with stirring. The solid formed was then removed by filtration and the filter cake was then washed with ether (100 mL). The solid was hen dissolved into water (275 mL), cooled to 0 °C, and then concentrated HCI was added until the aqueous phase turned the pH paper red (pH 3). This solution was then allowed to Sit in the ice bath for ~1 h. The white solid was then filtered and washed with ice water (300 mL). This solid was then dried under vacuum for ~1 day to afford methyl dihydroorsellinate (120 g, 82%) as a white solid (mp 125-127 °C)."" ’ 0H 1 Procedure using BrJAc,O/AcOH and Catalytic HBr COzMe 1:]: -Preparation of Methyl 2,4-Dihydroxy-6-methylbenzo- HO L 37 ate: Methyl dihydroorsellinate (18.42 g, 100 mmol) was dissolved in a mixture of AcOH (60 mL) and A020 (30 mL) by warming and once dissolved cooled to 0 °C (ice bath). A solution of Br2 (5.12 mL, 100 mmol) in AcOH (10 mL) was added dropwise at 0 °C. A stream of N2 was allowed to bubble through the solution as the temperature was brought to reflux (~125 °C). This mixture was then allowed to reflux for 2h. The authors suggest bubbling N2 through the mixture during reflux, but this has to be watched carefully! The solution was then cooled to 25 °C and water (60 mL) was added followed by the addition of 48% HBr (1 mL). This solution was then refluxed for 2 h. After 112 cooling, the mixture was poured into water and extracted with ether (7x). The organics were washed with water, sat. aq. NaHCOa, water, dried (M9804), filtered and concentrated. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6- methylbenzoate (12.05 g, 66%) as a white solid contaminated with an unknown product. mp 138 °C (lit. 136—138 °C)‘3 All spectroscopic data matched those of the literature. ’ OH R Procedure for the Use of CuBr2 and LiBr1s - COzMe Preparation of Methyl 2,4-Dihydroxy-6-methylbenzoate HO _ 37 Methyl dihydroorsellinate (1.84 g, 10 mmol), CuBr2 (4.46 g, 20 mmol) and LiBr (0.86 g, 10 mmol) were dissolved into CHacN (20 mL). This mixture was then refluxed for 2 h. After cooling to 25 °C, the reaction was poured into a solution of 10% HCI (50 mL) and ether (100 mL). The layers were separated and the aqueous phase was extracted with ether (2x). The combined organics were dried (M9804), filtered and concentrated. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6-methylbenzoate (600 mg, 33%) as a white solid.“ IR (KBr) 3366, 3311, 1641, 1445, 1326, 1266, 1159 cm"; 1H NMR (500 MHz, DMSO-d6) 6 = 10.75 (brs, 1H),.6.17 (m, 2H), 3.78 (s, 3H), 2.27 (s, 3H) ppm; 13C NMR (125 MHz, DMSO-d6) 6 170.4, 161.4, 161.3, 141.1, 110.4, 107.5, 100.6, 51.9, 22.2 ppm 113 5 OH ‘ fiCOZMe HO L 37 Procedure for the Use of CuBr2 and LiBr using DMF as Solvent15 - Preparation of Methyl 2,4-DIhydroxy-6- methylbenzoate: Applying the above conditions except this entry used DMF (20 mL) as solvent at 100 °C. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6-methylbenzoate (800 mg, 44%) as a white solid. OH H0 37 V j Procedure for the Use of CuCI2 and LiCI15 in CH3CN - Preparation of Methyl 2,4-Dihydroxy-6- methylbenzoate: Methyl dihydroorsellinate (10.0 g, 54.3 mmol), CuCI2 (29.20 g, 217 mmol) and LiCl (4.60 g, 109 mmol) were dissolved into CHacN (200 mL). This mixture was then refluxed for 5 h. After cooling to 25 °C, the reaction was poured into a solution of 10% HCI (50 mL) and ether (100 mL). ether (2x). The layers were separated and the aqueous phase was extracted with The combined organics were dried (M9804), filtered and concentrated. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6-methylbenzoate (3.30 g, 33%) as a white solid. COzme HO 37 F OH ‘ Procedure for the Use of CuCI2 and LICI‘5 in DMF - Preparation of Methyl 2,4-Dihydroxy-6- methylbenzoate Applying the above conditions using 114 DMF as the solvent at 100 °C for 5 h after column chromatography [silica; 80:20 hexane/EtOAc] afforded methyl 2,4-dihydroxy-6-methylbenzoate (4.47 g, 47%) as a white solid. ’ 0H 1 Procedure for the Use of CuCI2 and MgCl,” - COzMe Preparation of Methyl 2,4-Dihydroxy-6- H0 37 methylbenzoate: Methyl dihydroorsellinate (5.0 g, 27.15 mmol), CuClz-ZHZO (9.26 9, 54.30 mmol) and MgClz-GHZO (2.76 g, 13.60 mmol) were dissolved into CHSCN (30 mL). This mixture was then refluxed for 12 h. After cooling to 25 °C, the reaction was poured into a solution of 10% HCI (50 mL) and ether (100 mL). The layers were separated and the aqueous phase was extracted with ether (2x). The combined organics were dried (M9804), filtered and concentrated. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6-methylbenzoate (3.0 g, 60%) contaminated with an unknown product. F 0... ‘ Preparation of Methyl 3,5-Dibromo-2,4-dihydroxy-6- Bf COQMB methyl-benzoate: Br2 (56 mL, 1090 mmol) was added to a HO 3, solution of methyl dihydroorsellinate (66.35 g, 360 mmol) in 36 AcOH (212 mL) at such a rate to keep the temperature between 40-45 °C. This mixture was allowed to stir for ~1 h and then allowed to stand for ~10 h. Water was then added to this mixture and the solid was 115 collected by filtration (course glass frit) and was washed with copious amounts of water. The white solid obtained was dried to afford methyl 3,5-dibromo-2,4- dihydroxy-6-methyI—benzoate (142 g, 93%) as a white solid (mp 106 °C, lit 112— 114 °C)‘5”. IR (neat) 3619, 3425, 2957, 1652, 1588, 1404, 1320, 1252 cm"; 1H NMR (500 MHz, CDCla) 6 = 12.16 (s, 1H), 6.46 (s, 1H), 3.97 (s, 3H), 2.65 (s, 3H) ppm; ‘30 NMR (125 MHz, CDCla) 6 = 171.2, 159.4, 153.8, 140.4, 107.5, 105.4, 96.3, 52.8, 23.2 ppm All spectros00pic data matched those of the literature.16 l OH ‘ Procedure for PMHS/KP Dehydrohalogenation CO Me a 2 catalyzed by Pd(OAc)2 - Preparation of Methyl 2,4- H0 3" Dihydroxy-6-methylbenzoate: Methyl 3,5-dibromo-2,4- dihydroxy-6-methyl-benzoate (117 g, 345 mmol) was dissolved into THF (1725 mL) and was purged with N2. Pd(OAc)2 (3.87 g, 17.25 mmol), KF (80.18 g, 1380 mmol) and H20 (~690 mL) were all added under N2. PMHS (166 mL, 2760 mmol) was then slowly added (add the PMHS via an additional funnel and allow the PMHS to flow as a thin stream while using a mechanical stirrer. Also use a reflux condenser as the reaction is exothermic) and once the addition was complete, the reaction was allowed to stir at 25 °C for 24 h. Crude 1H NMR analysis indicated a 1.7:1.0 ratio of product to monobromide. This reaction was then diluted with EtZO and the layers were separated. The aqueous portion was 116 extracted with EtZO (3x). The combined organics were then concentrated to about 1/2 volume. This solution was then filtered through a pad of silica gel with celite on top. The filter cake was rinsed with EIZO until TLC analysis (80:20 hexane/EtOAc) showed no product. The filtrate was then concentrated to dryness. This residue was then dissolved into THF (1725 mL) and was purged with N2. Pd(OAc)2 (3.87 g, 17.25 mmol), KF (80.18 g, 1380 mmol) and H20 (~690 mL) were all added under N2. PMHS (166 mL, 2760 mmol) was then slowly added and this mixture was allowed to stir at 25 °C for 21 h. Crude 1H NMR analysis indicated that the reaction was complete. After diluting with 3,0, the reaction was allowed to stand overnight (~10 h). The layers were separated and the aqueous portion was extracted with E120. The combined organics were dried (M9804), filtered through celite and then concentrated. The resulting residue was purified by column chromatography [silica; 80:20 hexane/EtOAc] to afford methyl 2,4-dihydroxy-6-methylbenzoate (55.3 g, 88%) of a white solid. ( OTBS fl Preparation of Methyl 2,4-DI-(t-butyldlmethylsiloxy)- 002MB 6-methylbenzoate. Methyl 2,4-dihydroxy-6- TBSO 33 methylbenzoate (15.73 g, 86.35 mmol) was dissolved into DMF (130 mL). lmidazole (29.40 g, 432 mmol) was added followed by TBSCI (32.54 g, 216 mmol). The reaction was then allowed to stir at 25 °C fro 2.5 h. The reaction was then poured into water and then extracted with EtOAc. The combined organics were washed with sat. aq. NaHCOa, sat. aq. NH4CI, 117 brine, dried (MgSO4), filtered and concentrated. The resulting residue was purified by column chromatography [silica; 98:2 hexane/EtOAc] to afford methyl 2,4-di-(t-butyldimethylsiloxy)-6-methylbenzoate (35.01 g, 99%) as a clear oil. IR (neat) 2957 cm"; 1H NMR (500 MHz, CDCIa) 6 = 0.18 (s, 6 H), 0.20 (s, 6 H), 0.96 (s, 9 H), 0.97 (S, 9 H), 2.22 (s, 3 H), 3.82 (s, 3 H), 6.16 (s, 1 H), 6.29 (s, 1 H); 13C NMR (125 MHZ, CDCI3) 6 = -4.4, 18.0, 18.2, 19.7, 25.5, 25.6, 51 .7, 108.5, 114.9, 119.8, 137.9, 153.8, 156.9, 168.8; HRMS (El) 410.2305 m/z 410.2305 [(M’), calcd. for C21 H380,Si 410.2309. l OTBS B Preparation of Methyl 2-(Bromomethyl)-4,6-dI-(t- 002MB . butyldimethylslloxyybenzoate: Methyl 2,4-dl-(t— TBSO 19 B, butyldimethyl siloxy)-6-methylbenzoate (1.0 g, 2.44 mmol), NBS (477 mg, 2.68 mmol) and AIBN (4 mg, 0.024 mmol) were added to freshly distilled CCI4 (20 mL). This mixture was gently refluxed for 3.5 h. The reaction was then filtered, while still warm, through a pad of celite and the filtrate was concentrated. The resulting residue was purified by column chromatography [silica; 95:5 hexane/EtOAc] to afford methyl 2-(bromomethyl)-4,6-di-(t-butyldimethylsiloxy)-benzoate (1.03 g, 87%) as an oil. IR (neat) 2957 cm"; 1H NMR (500 MHz, CDCIa) 6 = 0.18 (s, 6 H), 0.20 (s, 6 H), 0.96 (s, 9 H), 0.97 (s, 9 H), 2.22 (s, 3 H), 3.82 (s, 3 H), 6.16 (s, 1 H), 6.29 (s, 1 H); 130 NMR (125 MHz, 000,) 6= 44, 18.0, 16.2, 19.7, 25.5, 25.6, 30.5, 51.7, 118 111.2, 115.1, 136.0, 154.5, 156.9, 167.7; HRMS (El) m/z 466.1410 [(M+), calcd. for 0,,H,,Bro,Si 466.1414. “Note: If this compound is left to stand for a long period of time, another product forms. The product has been identified as 5,7-bis(tert-butyldimethylsiloxy)- isobenzofuran-1 (3H)-one. ' OTBS O ‘ Data for 5,7-Bis(tert-butyldimethylsiloxy)-isobenzofuran- O 1(3H)-one: 1H NMR (500 MHZ, CDCIa) 6 = 0.23 (s, 6 H), TBSO L _ 0.26 (s, 6 H), 0.98 (s, 9 H), 1.04 (S, 9 H), 5.09 (S, 2 H), 6.29 (s, 1 H), 6.45 (s, 1H); 130 NMR (125 MHz, 000l,) 6 = -4.4, 18.2, 25.6, 66.1, 106.4, 109.7, 112.5, 150.5, 156.2, 162.5, 166.4; HRMS (El) m/z 394.1990 [(M+), calcd. for 02,,H3,O.,Si2 394.1996]. Procedure for the Preparation of Biphenyldlmethylsllyl Ph~©~s:,i-C| Chloride (BDMSCI). To a solution of 4-bromobiphenyl (50 g, 215 mmol) in dry Et20 (200 mL) at 0 °C was added n- BuLi (135 mL of a 1.6 M solution in hexanes, 215 mmol). After stirring at 0 °C for 20 min., the mixture was warmed to room temperature and stirred for another 30 min. The resulting 4-lithiobiphenyl was then added via cannula to a precooled (0 °C) solution of Me,.SiCl2 (25.83 mL, 215 mmol) in dry 3,0 (300 mL). This mixture was then left stirring for ~14 h at 25 °C. The solution was then filtered and the filtrate was concentrated to afford biphenyldimethylsilyl chloride (46.30 g, 87%) as a white solid. 119 1H NMR (500 MHz, CDCla) 6 = 0.74 (s, 6 H), 7.34-7.42 (m, 1 H), 7.42-7.50 (m, 2 H), 7.57-7.69 (m, 4 H), 7.70-7.75 (m, 2 H) ppm; ”C NMR (125 MHz, CDCIS) 6 = 2.1, 126.8, 127.2, 127.7, 128.8, 133.6, 134.8, 140.6, 143.1 Physical and spectral data were consistent with those obtained from a commercial sample. Preparation of (Buta-1,3-diynyl)dimethyl(4-blphenyl)- Z—E—BDMS 41 sllane: Hexachlorobutadiene (1.9 mL, 12.16 mmol) was added dropwise to a solution of n-BuLi (30.5 mL of a 1.6 M solution in hexanes, 49 mmol) at -78 °C in THF (15 mL). After the addition was complete, the mixture was allowed to warm to room temperature and then was stirred for 2 h. The solution was then recooled to —78 °C and BDMSCl (3.0 g, 12.16 mmol) was added dropwise as a solution in THF (5 mL). After the addition, the reaction was allowed to warm to room temperature and the mixture was stirred for 5 h. The reaction was then washed with 1M HCI and extracted with EtZO. The combined organics were washed with brine, dried (M9804), filtered and concentrated to afford a dark oil. The resulting residue was purified by column chromatography [silica; Pentane] to afford (buta-1,3-diynyl)dimethyl(4- biphenyl)silane (1.84 g, 60%) as a white solid. mp 77 °C (lit. mp 77°C)17 IR (neat) 3323 cm“; 1H NMR (500 MHz, CDCIS) 6 = 0.50 (s, 6 H), 2.16 (s, 1 H), 7.32-7.40 (m, 1 H), 7.42-7.50 (m, 2 H), 7.55-7.65 (m, 4 H), 7.66-7.72 (m, 2 H) ppm; 130 NMR (125 MHz, CDCI3) 6 = -1.3, 67.2, 66.3, 62.6, 66.9, 126.8, 127.2, 120 127.5, 128.8, 134.2, 140.9, 142.6; HRMS (El) m/z 260.1029 [(M”), calcd. for 0,,H,,Si 260.1021] ‘ Procedure for the Hydrostannation of the %SnMea BDMS Silyldiyne: (Buta-1.3-diynyl)dimethyl(4-biphenyl)silane 42 (1.84 g, 7.07 mmol) was dissolved into THF (30 mL). MeSSnCl (8.5 mL of a 1M solution in THF, 8.5 mmol), KF (1.23 g, 21.21 mmol), water (5-10 mL), PMHS (0.64 mL, 10.61 mmol) and PdCl2(PPh3)2 (50 mg, 0.07 mmol) were all added. After 2 h of stirring at room temperature, the phases were separated and the organics were dried (M9804), filtered and concentrated. 1H NMR analysis of the crude reaction indicated only the formation of internal terminal Vinylstannane. All attempts to isolate this compound failed. Preparation of 4-Bromo-2-methyl-3-butyn-2-ol: A 1L 3- H0 : Br neck flask was charged with KOH (89.2 g, 1600 mmol) and water (350 mL). This mixture was cooled with an ice bath followed by the addition of Br2 (110 mL, 200 mmol) dropwise. Once the dark red color discharged, the reaction was allowed to stir for 15 min. To this solution was added 2-methyl-3-butyn-2-ol (26.75 mL, 276 mmol) in hexanes (40 mL) via an addition funnel. Once the addition was complete, the reaction was allowed to stir for 15 min. A white solid could be seen floating on the surface of the colorless solution. The reaction was diluted with 3,0, and washed with water. The 121 organics were dried (M9804), filtered and concentrated. The resulting residue was purified by distillation [bp 68 °C @ 12 mmng to afford 4-bromo-2-methyl-3- butyn-2-ol (32.60 g, 100%) as a clear liquid.18 Preparation of 6-(tert-ButyldlmethylsinI)-2- \/I—:TBS H0 44 methylhexa-3,5-diyn-2-ol. CuCl (120 mg, 1.2 mmol) was added to a 30% aq. n- BuNH, solution (50 mL) which turned blue. A few crystals of NH20H-HCI were added to discharge the color. TBS acetylene (13.37 mL, 71.3 mmol) was added to the solution in one portion. The now yellow mixture was cooled with an ice bath. At this point, 4-bromo-2-methyl-3-butyn-2-ol (9.68 g, 60 mmol) was added in one portion with vigorous stirring. If at any time during this addition the solution turned blue or green, a few crystals of NHZOH-HCI were added immediately. The reaction turned from red to a rusty color that denotes the reaction was complete. The mixture was extracted with EtZO (3x), dried (M9804), filtered and concentrated to afford 6-(tert-butyldimethylsiIyl)-2-methylhexa-3,5- diyn-2-ol (6.67 g, 50%) of a white solid. mp 75-76 °C (lit. 80—81 °C)” IR (KBr) 3395 cm"; 1H NMR (300 MHz, CDCI3) 6 = 0.12 (s, 6 H), 0.94 (s, 9 H), 1.52 (s, 6 H), 2.08 (br s, 1 H) ppm; 13C NMR (75 MHz, CDCI3) 6 = -4.9, 16.7, 25.9, 31.0, 65.5, 67.5, 81.4, 86.4, 87.8 ppm; HRMS (El) m/z 222.1436, [(M“), calcd. for 0,,H,,OSi 222.1440] 122 Preparation of 2-Methylhexa-3,5-dlyn-2-ol: 6-(tert- Butyldimethylsilyl)-2-methylhexa-3,5-diyn-2-ol (6.67 g, 30 mmol) was dissolved into THF (50 mL) and this solution was cooled with an ice bath. TBAF (45 mL of a 1M solution in THF, 45 mmol) was added dropwise. After 5 h, the reaction was concentrated and the residue was purified by column chromatography [silica; 90:10 pentane/EtZO] to afford 2- methylhexa-3,5-diyn-2-ol (3.24 g, 100%) as a clear liquid.20 ‘ Procedure for the Hydrostannation of the Diyne: 2- %SnMe3 Methylhexa-3,5-diyn-2-ol (765 mg, 7.07 mmol) was OH 45 dissolved into THF (30 mL). Meaanl (8.5 mL of a 1M solution in THF, 8.5 mmol), KF (1.23 g, 21.21 mmol), water (5-10 mL), PMHS (0.64 mL, 10.61 mmol) and PdCl.,,(PPh,,)2 (50 mg, 0.07 mmol) were all added. After 2 h of stirring at room temperature, the phases were separated and the organics were dried (M9804), filtered and concentrated. 1H NMR analysis of the crude reaction indicated only the formation of internal terminal Vinylstannane. All attempts to isolate this compound failed. 49 Peatio of3-TI thlill illh TMS : CHO r p ra n ( rme ys y)propoade yde from Ethynyltrlmethylsilane: To prepare EtMgBr, syringe pump- dropwise (20 mL/h) bromoethane (10.9 g, 100 mmol) into 100 mL THF and 2.43 9 Mg then stir an hour at rt. Cool the reaction to 0 °C then dropwise add 123 ethynyltrimethylsilane (14.2 mL, 100 mmol). The reaction mixture was heated for an hour at 50—60 °C, cooled and transferred to a dropwise funnel. A flask was charged with 21 g dimethylformamide in 20 mL absolute ether, then with cooling to -25—30 °C ((trimethylsilyl)ethynyl)-magnesium bromide was added dr0pwise. The temperature of the reaction mixture was gradually raised to it and stirring continued for an hour. The content of the flask were cooled to -10 °C and poured into 5% H280, solution. After cooling to -5 °C, the mixture was stirred for an hour and set aside overnight. The next day the aqueous layer was separated and extracted with ether. The ethereal extracts were combined, dried with M9804, and purified through flash chromatography with pentane to afford product in 52— 65% yield. IR (KBr) 2963, 2165, 1723, 1252, 1211, 845 cm"; 1H NMR (500 MHz, CDCla) 6 = 9.13 (s, 1 H), 0.23 (s, 9 H) ppm; 13C NMR (125 MHz, CDCI3) 6 = 176.7, 103.0, 102.1, -1.0 ppm All spectroscopic data matched those of the literature.21 Preparation. of ((1,3-Dithlan-2-yl)ethynyl)trimethyl- s TMS————<: :> s ] sllane: BF3-Et20 (0.15 mL, 1.2 mmol), acetic acid (0.5 43 mL, 8.7 mmol) and 1,3-propanedithiol (0.12 mL, 1.2 mmol) were added to a stirring solution of 3-(trimethylsilyl)propiolaldehyde(130 mg, 1 mmol) in toluene (2 mL) in the ice bath. The progress of the reaction was followed by TLC. After completion, the reaction was quenched with water and 124 extracted with NaHCO3 (X3), 2 M NaOH (X2) dried with NaZSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography with 5%EtOAc/hexane to afford product in 62% yield. IR (KBr) 2957, 2164, 1423, 1248 cm"; 1H NMR (500 MHz, CDCI3) 6 = 0.18 (s, 9 H), 3.21 (m, 2 H), 2.73 (m, 2 H), 1.96—2.08 (m, 2 H), 4.52 (s, 1 H) ppm; 13C NMR (125 MHz, CDCla) 6 = 100.8, 90.9, 33.2, 27.5, 25.6 ppm. OTBS ‘ Preparation of Methyl 2,4-Bis(tert-butyldimethyl COzMe silonxy)-6-((2-((trlmethylsilyl)ethynyI)-1 ,3- TBSO S dithian-z-yl) methyl)benzoate: The ((1,3-dithian-2- £8 \\ TMS so yl)ethynyl)—trimethylsi|ane (0.342 g, 0.79 mmol) was added to a flame-dried flask equipped with a stir bar under Argone pressure. Anhydrous THF (8 mL) was added via cannula and the resulting solution was cooled to -20 °C. n-BuLi (1 mL, 1.6 mmol) was added in a steady stream and the resulting dark purple solution was stirred at -20 °C for an hour. The solution was cooled to -78 °C and cannulated into a solution of methyl 2-(bromomethyl)-4,6-di-(t-butyldimethylsiloxy)-benzoate (0.387 g, 0.79 mmol) in anhydrous THF (8 mL) at -78 °C. The resulting purple reaction was stirred 90 min at -78 °C before it was stored overnight in a -78 °C freezer. The reaction was then quenched by the addition of 1N HCI, extracted with CHZCIZ, and dried with NaZSO,. Evaporation of the solvents under reduced pressure followed by flash chromatography (silica gel, 10% EtOAc/hexane) afforded a product in 87% yield. 125 IR (KBr) 3021, 2953, 2928, 2856, 2155, 1733, 1597, 1472, 1430, 1252 cm"; 1H NMR (500 MHz, CDCI3) 6 = 6.80 (d, J = 2.2 Hz, 1 H), 6.22 (d, J = 2.2 Hz, 1 H), 3.82 (s, 3 H), 3.30 (s, 2 H), 3.26 (m, 2 H), 2.74 (m, 2 H), 2.06 (m, 1 H), 1.79 (m, 1 H), 0.94 (d, J: 4.2 Hz, 18 H), 0.17 (m, 21 H) ppm; 13C NMR (125 MHz, CDCI3) 6 = 168.7, 156.8, 154.0, 135.3, 121.0, 117.2, 110.3, 103.3, 93.8, 60.7, 52.3, 43.3, 29.1, 25.9, 25.7, 25.5, 18.5, 18.3, 0.4, -4.1(2) ppm; HRMS (El) m/Z 625.2693 [(M+H), calcd. for 03,,H53O.,SZSI3 625.2734] OTBS ‘ Preparation of Methyl 2,4-Bis(tert-butyldlmethyl- CO Me 2 sllyloxy)-6-((2-ethynyl-1 ,3-dithian-2-yl)methyl)benzo- T880 3 ate: Water (4 mL) and AgNO3 (0.35 g, 2.06 mmol) were L8 S 47 added to a solution of methyl 2,4-bis(tert-butyldimethyl L silyloxy)-6-((2-((trimethylsilyl)ethynyl)-1 ,3-dithian-2-yl) methyl)benzoate (2.06 mmol, 1.289 g) in acetone (20 mL) and the resulting mixture was stirred in the dark at the rt and for 7 h. The reaction was then poured into a saturated aqueous NaCl solution (20 mL) and extracted with EtzO (3x10 mL). The organic extract was washed with brine (2x10 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel in 91% yield. mp 83—85 °C IR (KBr) 3296, 2953, 2859, 2339, 1709, 1599, 1431, 1281, 1170 cm"; 1H NMR (500 MHz, CDCI3) 6 = 6.73 (d, J: 2.2 Hz, 1 H), 6.24 (d, J: 2.2 Hz, 1 H), 3.82 (s, 3 H), 3.38 (s, 2 H), 3.29 (td, J: 14.9, 2.5 Hz, 2 H), 2.86 (s, 1 H), 2.76 ((11, J: 126 14.2, 3.7 Hz, 2 H), 2.11 (m, 1 H), 1.81 (m, 1 H), 1.55 (s, 1 H), 0.94 (d, J: 2.6 Hz, 16 H), 0.17 (d, J = 2.4 Hz, 12 H) ppm; 130 NMR (125 MHz, CDCI3) 6 = 168.4, 156.7, 154.3, 134.9, 120.6, 116.9, 110.7, 62.3, 76.3, 51.8, 45.9, 43.4, 28.7, 25.6, 25.2, 18.2, -4.3 ppm f 0... o ‘ Preparation of Methyl 2-((2-Ethynyl-1,3-dithian-2- 0M9 yl)methyI)-4,6-dihydroxybenzoate: Methyl 2,4-bis(ten‘- C butyldimethyl Silyloxy)-6-((2-((trimethylsilyl)ethynyI)-1 ,3- S dithian-2-yl) methyl)benzoate (0.625 g, 1 mmol) was dissolved in THF (10 mL) and treated at -20 °C with a TBAF trihydrate solution (3 mL, 1M in THF, 3 mmol). The solution was allowed to warm up to 0 °C, stirred for 60 minutes and transferred into a cooled NH,,Cl-solution (10 mL, saturated). The organic layer was separated and the remaining aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with and purified by flash column chromatography (Silica gel, hexanes/ethyl acetate 3:1) to afford the pure alkyne as a colorless oil (702 mg, 2.84 mmol, 88%). mp 137—138 °C IR (KBr) 3365(br), 3276, 3039, 3001, 2949, 2914, 1651, 1579, 1432, 1322, 1262, 1199, 1171 cm"; 1H NMR (500 MHz, CDCI3): 6 = 11.45 (s, 1 H), 7.26 (s, 1 H), 6.48 (d, J: 2.8 Hz, 1 H), 6.42 (d, J: 2.8 Hz, 1 H), 3.94 (s, 3 H), 3.74 (s, 2 H), 3.33 (td, J: 2.8 Hz, 2 H), 2.88 (s, 1 H), 2.60 (m, 2 H) 2.18 (m, 1 H), 1.66 (m, 1 H) ppm; 13C NMR (125 MHZ, CDCI3): 6 = 172.0, 164.5, 159.5, 138.3, 113.6, 106.9, 103.4, 81.8, 76.3, 51 .7, 46.0, 45.6, 28.7, 25.3 ppm 127 f OH 0 ‘ Preparation of Methyl 2-((2-Ethynyl-1,3-dithian-2-yl) 0M9 methyI)-4,6-dihydroxybenzoate: Potassium carbonate C was added to a stirred solution of TMS-alkyne in methanol 8 at rt. After 10 min, the solution was filtered through a pad L 51 of celite, diluted with EtZO and poured into water. The solution was extracted into 3,0 and the combined organic layers were further treated with saturated NH4CI, saturated NaHCOa, and brine. The resulting ethereal solution was dried over NaZSO,, filtered through a plug of silica, and concentrated in vacuum to afford the product in 60% yield. f 0H 0 2 Preparation of (E)-Methyl 2,4-Dihydroxy-6-((2-(2- 0M9 (trimethylstannyl)vinyl)-1,3—dithlan-2-yl)methyl) HO 5 / benzoate: szdbas (0.02 mmol, 16.4 mg) and TFP E/S SnMe3 (0.08 mmol, 18.6 mg) were added to THF (5 mL) L 54 and the resulting mixture was stirred at rt for 15 min. At that time, methyl 2-((2- ethynyl-1,3-dithian-2-yl)methyl)-4,6-dihydroxybenzoate (1 mmol, 0.324 g), MessnF (1.5 mmol, 274 mg), PMHS (2.5 mmol, 0.15 mL), and TBAF (1 drop of a 1 M solution in THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by GC. At that time, the reaction was extracted with EtZO and H20 and the aqueous phase was back extracted with 3,0. The combined organics were 128 dried over M9804, filtered, and concentrated. The resulting residue was purified by short silica gel chromatography (30%EtOAc/hexane) to afford the corresponding Vinylstannane in 96% yield. IR (KBr) 3365 (br), 2952, 2913, 2852, 1653, 1616, 1272, 1117 cm“; 1H-NMR (500 MHz, CDCla): 6 = 11.30 (s, 1 H), 6.22 (d, J: 18.8 Hz, 1 H), 5.59 (d, J: 18.8 Hz, 1 H), 3.85 (s, 3 H), 3.55 (s, 2 H), 2.73 (m, 2 H), 2.57 (m, 2 H), 1.96 (m, 1H), 1.81 (m, 1H), 0.09 (s, 9H) ppm; 1a‘C-NMR (125 MHz, CDCI3): 6 = 171.7, 164.1, 160.1, 146.3, 139.0, 133.3, 114.0, 106.7, 102.8, 58.6, 51 .5, 46.9, 27.5, 25.3, -9.6 mm f 0H 0 ‘ Preparation of Methyl 2,4-DIhydroxy-6-((2- 0M9 ((1E,3E)-4-phenylbuta-1,3-dlenyI)-1 ,3-dlthlan—2- HO C / / Ph yl)methyl)benzoate: Pd2dbaa (0.002 mmol, 3.7 S 55 mg) and TFP (0.008 mmol, 9.3 mg) were added to L THF (2 mL) and the resulting mixture was stirred at rt for 15 min. At that time, methyl 2-((2-ethynyI-1,3-dithian-2-yl)methyl)-4,6-dihydroxybenzoate (0.2 mmol, 65 mg), MeSSnF (0.3 mmol, 55 m9), PMHS (0.5 mmol, 0.03 mL), and TBAF (1 drop of a 1 M solution In THF (~0.008 mmol)) were added successively. The reaction was then allowed to stir at rt for 2 h, at which time the hydrostannation was complete by TLC. The (E)-[3-bromo styrene (0.04 mL, 0.3 mmol) and Pd(PPha)4 (0.05 mmol, 7 mg) was then added and the mixture was allowed to reflux (~65 °C) until the cross-coupling was judged complete by TLC (8 h). At 129 that time, the reaction was diluted with saturated aq. KF (2 mL) and stirred for 0.5 h. The reaction was extracted with Et20 and H20 and the aqueous phase was back extracted with 3,0. The combined organics were dried over M9804, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the product in 48% yield. IR (KBr) 3363(br), 3023, 2163, 1656, 1249 cm"; 1H-NMR (500 MHz, CDCI3): 6 = 11.20 (s, 1 H), 7.38 (d, J: 7.1 Hz, 2 H), 7.32 (t, J: 7.8 Hz, 2 H), 7.23 (m, 1 H), 6.76 (dd, J: 15.1, 10.5 Hz, 1 H), 6.56 (d, J: 15.6 Hz, 1 H), 6.47 (dd, J: 14.9, 10.5 Hz, 1 H), 6.38 (d, J: 2.5 Hz, 2 H), 5.61 (d, J: 15.3 HZ, 1 H), 3.85 (s, 3 H), 3.64 (s, 2 H), 2.90 (m, 2 H), 2.62 (m, 2 H), 2.01 (m, 1 H), 1.83 (m, 1 H) ppm. 0 ‘ Preparation of ($)-tert-Butyl(1-(furan-2-yl)propan-2- m/OTBDPS yloxy)diphenylsilane: In a seal-tube were placed tert- 56 butyl((S)-1 -((2R,3R)-3-((Z)-2-iodovinyl)oxiran-2-yl)propan- 2-yloxy)diphenylsilane (0.2 mmol, 99 mg), Pd(PPha)4 (0.02 mmol, 23 mg) and N,N-diisopropylethylamine (0.4 mmol, 0.07 mL), and benzene (1 mL) were added. The reaction was stirred at 80 °C for 8 h. After TLC monitoring, the reaction was quenched with water. Extracted with EtOAc, then the combined organic extracts were washed with brine, dried over NaZSO,, and concentrated. Crude mixture was purified by column chromatography (10% EtOAclhexane) to afford product in 62% yield. 130 IR (neat) 3070, 3048, 2957, 2929, 2857, 1427, 1111, 725 cm"; 1H-NMR (500 MHz, CDCI3): 6 = 7.65 (m, 4 H), 7.39 (m, 6 H), 6.24 (s, 1 H), 5.94 (s, 1 H), 4.13 (m, 1 H), 2.82 (m, 1 H), 2.71 (m, 1 H), 1.02 (s, 9 H) ppm; 13C-NMR (125 MHz, CDCIS): 6 = 153.2, 140.9, 135.9, 135.8, 134.6, 134.2, 129.5(2), 127.5(2), 110.1, 106.7, 68.7, 38.2, 26.9, 23.2, 19.1 ppm. 131 (1) 2008~2009 Aldrich Chemical Catalog (2) For a prior preparation and spectral data see: Zapata, A. J.; Rondon, A. C. Org. Proc. Prep. Int. 1995, 27, 567—568. (3) Johnson, W. K. J. Org. Chem. 1960, 25, 2253—2254. (4) Chong, J. M.; Shen, L.; and Taylor, N. J. J. Am. Chem. Soc. 2000, 122, 1822— 1823. (5) Bowers, K. W.; Giese, R. W.; Grimshaw, J.; House, H. O.; Kolodny, N. H.; Kronberger, K.; Roe, D. K. J. Am. Chem. Soc. 1970, 92, 2783-2799. (6) Sparling, B. A., Moslin, R. M., and Jamison, T. F. Org. Lett. 2008, 10, 1291— 1294. (7) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007, 129, 2214~2215. (8) Gopal, V. R.; Jagadeesh, S. G.; Reddy, Y. K.; Bandyopadhyay, A.; Capdevilab, J. H. Falcka, J. R. Tetrahedron Lett. 2004, 45, 2563—2565. (9) Yoshino, T.; N9, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 14185— 14191. (10) Barluenga, S.; Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J. 2005, 11, 4935—4952. (11) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903-10908. (12) For spectroscopic data see: Piskov, V. B; Kasperovich, V. P. J. Org. USSR (Engl. Trans/.) 1985, 21 , 1088—1095. (13) Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72, 2068- 2076. (14) Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K. C.; Baudoin, 0.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095—3115. (15) Bondon, D.; Pietrasanta, Y.; Pucci, B. Tetrahedron Lett.1977, 18, 821—824. 132 (16) (a) Sargent, M. V.; Vogel, P.; Elix, J. A. J. Chem. 800., Perkin Trans. I 1975, 1986-1991. (b) Neelakantan, S.; Padmasani, R.; Seshadri, T. R., Indian J. Chem. 1964, 2, P78—84. (17) Gallagher, W. P. Stille Couplings Catalytic in Tin and Related Reactions Ph.D. Thesis, Michigan State University, East Lansing, MI, 2003 (18) Saalfrank, R. W.; Welch, A.; Haubner, M.; Bauer, U. Liebigs Ann. 1996, 2, 171-181. (19) Jiang, M. X. Rawat, M.; Wulff, W. D. J. Am. Chem. SOC. 2004, 126, 5970— 5971. (20) For a prior preparation and spectroscopic data see: Cannon, J. G.; Johnson, L. E. J. Med. Chem. 1974, 17, 355—358. (21) For a prior preparation and spectroscopic data see: (a) Sorg, A.; Siegel, K.; Briickner, R. Chem. Eur. J. 2005, 11, 1610—1624. (b) Harris, N. J.; Gajewski, J. J. J. Am. Chem. Soc. 1994,116, 6121—6129. 133