Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

Vinyl Sulfone: Preparation of Vinyl Sulfone:

A. Addtion-Elimination SO R 2 1. Good Micheal acceptor - ionic 2. 2$ partner in cycloaddtion, - radical ethylene, acetylene and ketene equivalent 3. nicely crystalline, ease of handling General Process: 4. ready removal (desulfonlation) 5. inhibitior of cysteine protease

pKa=25 PhSX [O] SO R Z SO2R 2 Proctect + - SO2R M R! X R ! Regenerate R ! PhSO2X O SPh

X-R" 1. PhSH [O] 2. [O]

X SO2R SO2Ph Eli. Eli. R R " SO2R 1,2-Elimination " SO R Nucleophilic R"# 2 SO2Ph OH or Radical R! R R! ! SPh SO Ph PhSCl 1. mCPBA, 99% 2 99% Stability of Vinyl Sulfone: 2. DBU, 97% Cl

Equilibrium between !,% and ",! unsaturated sulfones,

SO2Ar R SO R# 2 99:1 R SO2R# TL, 1988, 29, 1445 Chem. Rev. 1960, 60, 3840 1. PhSeSO2Ar, hv JOC, 1981, 46, 3249 Interconvension between !,% and ",! unsaturated sulfones 2. H O 2eq DBU 2 2 Et SO2Tol Et SO2Tol 94% JACS, 1964, 86, 3840

For comprehensive reviews: T, 1990, 46, 6951; MRR, 2006, 26, 793; Journal of Sulfur Chemistry, 2005, 26, 163; Phorsphorus, sulfur and silicon and related elements, 1994, 95, 1. 1 Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

B. Olefination D. Organometallic Reagents - Aldol, - Wittig, via organozirconium reagents - Peterson, Ph H - HWE Cp2Zr(H)Cl Ph SO2Ar JOC, 2003, 68, 1958 E+ E SO Ph Addtion of sulfonyl-stabilized carbanion to carbonly compound >70% 2 Ar Cp Zr(H)Cl Tf SO R 2 2 Ar Synlett., 1999, 3, 317 Ar"SO2Cl SO Ph R OH 78% 2 Tf SO2R K2CO3, (CHO)X 1 via organotellurides SO R R1 2 R SO2Ar" R SO2Ar" ArTeTeAr NaBH4 quantitative yield R R1 T.L., 1985, 26, 2849 Ar"SO2Na ArTe H AcOH, H O, 80°C H H 2 61% SO2Ph JOC, 2001, 60, 74 E via palladium catalysis 1. BuLi, ArCHO Ar SO2Ph 2. ClP(O)(OEt)2 SO Tol LHMDS OTf Pd2(dba)3 2 3. t-BuOK Ar Xantphos NMeBoc + 4. HCl NHMe E N CsCO3 Me TolSO Na + 81% 2 Toluene OL, 2005, 7, 4641 >80% 60°C 80% JOC, 2004, 69, 5608 C. Manipulation of acetylenic sulfone E. Miscellaneous Base, O O O TMS SO2Ph oxidize sulfone carbanion R then acid work up Al(Hg), 2 R2 R2 R1 R R Li 2 eq Cu(OAc) 1 1 R 2 73% SO2Ph R SO2Ph 3 R3 R3 R SO2Ph 60-85% SO2Ph Li 1 eq Cu(OTf) Phenyl trimethlsilyl ethynyl sulfone as vinyl cation sython, JOC, 1982, 47, 4713 R 2 R R TL, 1984, 25, 3203 PhSO Cl, AlCl SO2Ph >70% TMS TMS 2 3 C C SO Ph TMS SO2Ph ! 2

CAN Mediated Reaction Me Me CAN, TolSO2Na, NaI SO Ar SO2Ar SO2Ar 2 CH3CN, 0°C 83% SO2Tol EtAlCl3, benzene Me Me Synthesis, 2002, 2259 64% 21% JOC, 1980, 45, 5015

2 Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

Radical-Mediated Alkenylation OLi OH R SO2Me SO 1 Ph 2 1. CatBH R1 R2 JOC, 1980, 45, 4789 R3 R2 R3 100% SO Ph 55%-72% 2. PhO2S 2 R4 Ph SO2Ph OLi tBuON=NOtBu R4

R1 R1 R2 SO2Ph O JOC, 1984, 49, 3898 R R CatBH 1 2 CatBH R NOBn R3 3 R3 R R 2 PhO2S SO Ph R BnON 2 R SO Ph R4 1. SOCl2 R 4 2 HO HO Cl 4 tBuON=NOtBu tBuON=NOtBu 1. Δ, 95% 2. KOH SO Ph Ph SO Ph 2 SO Ph 2 pTolSO CN 2. BnBr, 79% SO2Ph 2 2 NH N N 2 Bn 94% Bn TMS SO2Ph R R 1 2 JOC, 2003, 68, 9389 LDA R R1 R2 3 R R 80% 1 2 R 3 SO Ph R3 2 R4 Ph N R4 R4 TMS Radical Addition N ACIEE, 2006, 45, 5847 SO2Et Bn O O Ph O I Ph O Olefin metathesis tBuOOtBu OTBS SO2Ph OTBS ACIEE, 1999, 38, 1943 57% SO2Ph TL, 42, 2001, 6425 Ph Grubbs II Ph O 55% R1 O SO2Tol O O Reactions of Vinyl Sulfones steps R1 O R1 O SO Tol SO2Tol 2 A. Michael Addtion R2 hv, AIBN R3 R - Hard nucleophiles: competing reaction between metalation and conjugatea addtion R2 2 R 80-90% X 4 H+, heat Y N O R1 R4 R1 R4

R2 R - Soft nucleophiles: sp3 functionalized nucleophiles, the trans product in excess R3 2 R3 sp functionalized anion, the cis product predominated Chem. Lett. , 1988, 813 X=NHY X=OH potassium anions were more reactive 3 Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

B. Cycloaddition D. Metallation - [2+2] - [2+3] Form the vinyl transition metal complex - [2+4] Et Cp TMS R R 1 3 Zr R1 R3 + R1 R3 Pd(PPh3)4, dppe H Cp E R 2 SO Ph THF, RT R2 SO2Ph 70% 2 ZrCp2SO2Ph R2 E PhO S OAc 2 75-90% H ACIEE, 2002, 41, 1410 JACS, 1982, 104, 3733 E. Miscellaneous

C. Asymmetric Reactions Ph

- Asymmetric Dihydroxylation, T, 2003, 59, 7973 Ph Ph Ph O nBuLi 81% Br SO2Tol TolO S -78°C to RT 2 O JACS, 2004, 126, 1624, OSiMe3 O N R2 N R2 + N LHMDS R1 R SiMe 1 3 S N SiMe O 3 2 Ph R2 R1 - Catalytic Enantioselective Reduction, ACIEE, 2007, 46, 5955 OL, 2003, 5, 2789

Desulfonlation of Vinyl sulfone

A. Reductive Desulfonylation General process: dissolving metal or metal amalgams, e.g. Al(Hg)

SO2Ph

2 mol% Ni(acac)2 R R T., 1987, 43,859 2 eq nBuMgCl R′ R′ SO2Ph Na2S2O4, DMF H Me H O, NaHCO T.L., 1982, 23, 3265 R 2 3 Me R

4 Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

B. Tin-based Methods S

SO2Ph SO2Ph SO2Ph SO2Ph S TBSO Bu3SnLi xylene SnBu R! R 3 1. MeI, CaCO R reflux R 2-lithiodithiane MeO 3 MeO O MeCN-H O O R 2 ! R! JCS, CC, 1983, 619 THF, -100°C 2. NaBH4 MeO 89% 3. TBSOTf MeO Addition functionality into the unsaturated product lutidine OMe 76% OMe SO2Ph 1. nBuLi, -100°C SO2Ph 70% 1. Bu3SnLi OMe veratraldehyde 2. Ac O, Py SnBu3 2 2. TMSCl TMS TMS SO2Ph OMe TBSO R R R HO 1. Mg, HgCl OAc Chem. Lett., 1983, 1457 2 EtOH MeO MeO 2. TBAF O O Ar C. Alkylative Desulphonlation 83% MeO MeO SO2Me nBu3B, THF, Bu OMe Reflux OMe Bull. Soc. Chem. Jpn., 1974, 47, 503 70% (±)-Magnofaragesin Ph Ph

1.8eq PhMgBr T.L., 1982, 23, 2469 Total Synthesis of dl-Morphine, JOC, 1988, 53, 4694 1% Fe(acac)3 tBuO2S Ph 60% OTBS OMe OH 1. nBu3P Br OMe DEAD, 85% Br Applications in Total Synthesis O Br 2. HF, 95% Br OH PhO S Total Synthesis of (±)-Magnofaragesin, OL, 2006, 8, 3659 SO Ph 2 2 H OH

nBu3Sn IPh(OTf) 2.2 nBuLi -78°C 45% SO2Ph

OMe OMe MeO MeO MeO 9 Steps O O O PhICN(OTf) PhSO2Na O OH MeO MeO O MeO DCM, RT OMe OMe OH OMe MeN 59% dl-Morphine SO2Ph

5 Baran Group Meeting Jun Shi Vinyl Sulfone in Synthesis 02/06/2008

Total Synthesis of dl-Cephalotaxine, JACS, 1990, 112, 9601

O SO2Ph 1. O O O O O O O O2S O O O

O then BrCH2CH=CH2 O Li HMPA 84% O

O tBuLi, -78°C to RT 77% O O O

N O O O 1. p-TsOH The synthesis of natural product is analogous to building a pyramid. One needs to forge 2. NH2OH, nBuNIO4 O O a strong base before being in a position to complete the structure. The analog extends to further to the merit of the excercise- those pyramids which have been carefully crafted will O 71% O provide further benefit to all who follow. Phillips. L. Fuchs O O O O O N O O O

O O O O O O 9 steps N O N O N O O O 40%

HO O O O O MeO dl-Cephalotaxine

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