Sulfur-Facilitated Organic Synthesis - The Stoltz Group

Sulfur-Facilitated Organic SynthesisAndrew McCloryMonday March 16, 20098:00 pm, 147 Noyes

SSS

SSS'Attempts to make thioacetone by the cracking of trithioacetone gave rise to an offensive smell which spread rapidlyover a great area of the town causing fainting, vomiting and a panic evacuation'...'the laboratory work was abandoned.'-Researcher, Freiburg, 1889

SSS'Attempts to make thioacetone by the cracking of trithioacetone gave rise to an offensive smell which spread rapidlyover a great area of the town causing fainting, vomiting and a panic evacuation'...'the laboratory work was abandoned.'-Researcher, Freiburg, 1889'Recently we found ourselves with an odour problem beyond our worst expectations. During early experiments, astopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint ofnausea and sickness from colleagues working in a building two hundred yards away. Two of our chemists who haddone no more than investigate the cracking of minute amounts of trithioacetone found themselves the object ofhostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with adeodorant. The odours defied the expected effects of dilution since workers in the laboratory did not find theodours intolerable...and genuinely denied responsibility since they were working in closed systems. To convincethem otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of amile, and one drop of either acetone gem-dithiol or the mother liquors from crude thioacetone crystallizations wereplaced on a watch glass in a fume cupboard. The odour was detected downwind in seconds.'-Esso Researcher, Oxford, 1967

Seminar Overview1. Nomenclature2. Selected Properties3. EliminationA. BurgessB. MartinC. SulfoxideD. Chugaev4. Radical ReactionA. BartonB. Zard5. C-C Bond FormationA. Nature; FukuyamaB. Acyl Anion EquivalentsC. Sulfur YlidesE. Chiral Auxiliaries6. OlefinationA. JuliaB. Ramberg-BacklundC. EschenmoserD. Corey-WinterE. Nicolaou7. OxidationA. KornblumB. Moffatt-Swern8. FunctionalizationA. Mislow-EvansB. PummererC. DMTSFD. Diels-AlderE. Total Synthesis9. Allium Chemistry

Nomenclature of Organosulfur CompoundsRSHRS R'ROS R'O OR S R' R S S R'RSHRSR'SR NH 2Thiol(Mercaptan)Sulfide(Alkyl Mercaptan)Sulfoxide Sulfone DisulfideThioaldehydeThioketoneThioamideRSOR'ROSR'SSR SR' RO SR' RSOOSOSXO XSThionoesterThioesterDithioesterXanthate EsterSulfineSulfeneSulfonium SaltSulfoxonium SaltSOSSRSXOO O SSOOOH 2 N S RSulfonium ylideSulfoxonium YlideThiirane(Episulfide)Episulfonium SaltEpisulfoneSulfolaneSulfonamideRSSThioacetal(1,3-Dithiane)SRSKetene ThioacetalXSNRThiazolium SaltR S ClSulfenyl ChlorideRS OHSulfenic AcidRS OR'Sulfenate EsterR S S R'OR S S R'O ORSRNR'OR SClROS NR'OR S NH 2OR S OR'ThiosulfinateThiosulfonateSulfilimineSulfinyl ChlorideSulfinimineSulfinamideSulfinate Ester

Selected Properties of Organosulfur CompoundspKa Values (DMSO)OOSS SS SOH 2 OS45 3935 313125OSSHSNPhSHOPh S 7OHOPhOS OH181817101Bond Stengths (kcal/mol)Bond Lengths (A)A-Values (kcal/mol)C=S: 120C-S: 74S-H: 87S-S: 65C=O: 177C-O: 85O-H: 110O-O: 43C=S: 1.6C-S: 1.8S-H: 1.4S-S: 2.0S=O: 1.5C=O: 1.2C-O: 1.4O-H: 1.0O-O: 1.5Me: 1.7OMe: 0.6SMe: 0.7SOMe: 1.2SO 2 Me: 2.5

EliminationBurgess DehydrationOHMeO 2 CO ONSNEt 3Benzene25 -> 50 ºC60$ / gramSO 2Et 3 NHMeO 2 CO ONSOMeO 2 CNH 2HTESOOBOMTESOOBOMTBSOOOHOHOTMSMeO 2 CO ONSNEt 3(63% yield)TBSOOOHOH7 stepsTaxolOOAtkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744-4745.Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26-31.Holton, R. A. et al. J. Am. Chem. Soc. 1994, 116, 1599-1600.

EliminationMartin DehydrationF 3 COHF 3 CF 3 CPhOSOCF 3CF 3PhCHCl 3Ph Ph-50 ºC -> 25 ºC57$ / gramOCF 3OPh SPhPhPh O CF 3S O CF 3PhCF 3SCF 3O PhPh PhOHCF 3 HF 3 C OPhPhOHF 3 CF 3 CPhOSOPh PhCF 3CF 3CHClPh3 , 25 ºC(32% yield)Martin, J. C. Arnhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329.

EliminationSulfoxidePhRSOR'Benzene25 -> 80 ºCPhRSOR'HRR'O O OLiCA;PhSSPhSPhLDA;MeISPhOOmCPBA;PhCCl 4 , 70 ºCSOH(+/-)-AcorenoneTrost, B. M. Acc. Chem. Res. 1978, 11, 453-461.Oppolzer, W.; Mahalanabis, K. K.; Bättig, K. Helv. Chim. Acta. 1977, 60, 2388-2401.

EliminationXanthate EsterPhOHNaH, CS 2 ;MeIPhHSOSMe250 -> 300 ºCPhSCOMeSHMeSOHOONCbzNaH, THF,CS 2 ;then MeI, -30 ºC(92% yield)OOOSNCbzNaHCO 3Ph 2 O, 260 ºC(72% yield)OONCbzOOHHNCbz6 stepsHO 2 CHO 2 CHHNH(-)-Kainic AcidChugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332.Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181-3183.

Radical ReactionBartonROClNaONSROONSAIBN,Bu 3 SnHBenzene, 80 ºCRHNCNNCNCNH SnBu 3Bu3 SnROONSH SnBu 3RSnBu 3ROHNaH, CS 2 ;SMeI R OSMeAIBN,Bu 3 SnHBenzene, 80 ºCRCH 3Barton, D. H. R.; Serebryakov, E. P. Proc. Chem. Soc. 1962, 309.Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574-1585.

C-C Bond FormationNature - ThioesterNH 2OSHNOHNOOHOPOOOOPOOHHOONNHHOHNNOPOAcetyl CoAOOOOSCoAFatty Acids, PolyketidesHOHOHOOOHOHOOOHOSCoAOOSCoAAlkaloidsGlucosePyruvic AcidAcetyl CoAHO 2 CHOCO 2 HCO 2 HFADH 2NADHATP Synthesis

C-C Bond FormationFukuyama - ThioesterRCO 2 HiBuOCOClN-Methylmorpholine;EtSHROSEt10% Pd/CEt 3 SiH (2-3 equiv)Acetone, 25 ºC, 30 minRCHOOORR'Pd (0)RSEtOR' = H, RROPd SEtR Pd R' R'MMSEtOOOOOOHOHSEt1. 5% PdCl 2 (PPh 3 ) 2IZnToluene, 25 ºC, 5 min2. HCO 2 HOOOOOOHOHtBuO 2 C(78% yield)HO 2 CPhomoidride BFukuyama, T.; Lin, S-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050-7051.Hayashi, Y.; Itoh, T.; Fukuyama, T. Org. Lett. 2003, 5, 2235-2238.Fukuyama, T.; Tokuyama, H. Aldrich. Acta. 2004. 37, 87-96.

C-C Bond FormationAcyl Anion Equivalent - Thiazolium CatalystHOClSNNNHOSNClPhThiamine(Vitamin B 1 )NH 21.30 $ / gramHOSClO17%NPhOEt 3 N, EtOH80 ºC, 90 minOH(74% yield)HOSClOCN10%NEt 3 N, EtOH80 ºC, 16 hPhOCN(75% yield)Stetter, H.; Kuhlmann, H. Org. Syn. 1984, 62, 170.Stetter, H.; Kuhlmann, H.; Haese, W. Org. Syn. 1987, 65, 26.

C-C Bond FormationAcyl Anion Equivalent - Thiazolium CatalystROAcyl Anion = synthon exhibiting reversal of normal carbonyl group reactivityHOSClNPhO* PhPhOHHOSRNBnR'OPhOPhRRSR'SNBnROHPhNBnR'SOPhOHPhNBnSNCl6% yield52% eePhR'Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Sheehan, J.; Hunnemann, D. H. J. Am. Chem. Soc. 1966, 88, 3666-3667.Sheehan, J.; Hara, T. J. Org. Chem. 1974, 39, 1196-1199.

C-C Bond FormationAcyl Anion Equivalent - Thiazolium CatalystCNHCO 2 Me CHOHO S IN Ph2.3 equivEt 3 N, iPrOH, 80 ºC(67% yield)MeO 2 COCNHHO 2 CHH O(+/-)-Hirsutic AcidOHBzOOOHO10%S ClN PhEt 3 N, Dioxane, 70 ºCBzOOO(77% yield)N6 stepsNHOClOMeRoseophilinTrost, B. M.; Shuey, C. D.; DiNinno, F. J. Am. Chem. Soc. 1979, 101, 1284-1285.Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509-8514.

C-C Bond FormationAcyl Anion Equivalent - DithianeMeS SMe nBuLiRTHF, -78 ºCMeSRSMeRSMeSRSnBuLiTHF, -78 ºCSRSSRSCH 2 CH 2ROHSH SHnBuLiSBF 3 •Et 2 OE + PhI(CF 3 CO 2 ) 2S SS SSS SCHTHF, -78 ºC2 ClCH 3 CN, 25 ºC2 RRRR EROEElectrophiles (E + ): R' XR'OClR'OHR'OR''OR'OR'Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. Engl. 1965, 4, 1075-1077.Stork, G.; Zhao, K. A. Tetrahedron Lett. 1989, 30, 287-290.

C-C Bond FormationAcyl Anion Equivalent - DithianeSSTBStBuLi, Et 2 O-78 -> -45 ºC;BnOOBnOOSSTBSHMPABnOTBSOSSO(1 equiv)OTHF-78 ºC -> 25 ºC(2 equiv) (2 equiv)(59% yield)BnOTBSOSSOH HOSSOTBSOBn1. Me 2 C(OMe) 2PPTS2. TBAF3. Hg(ClO 4 ) 22,6-LutidineBnOHO O O O O OHOBn(62% yield)HO OH OH OH OH OHHOOHOO(+)-Mycoticin ASmith, A. B. III; Pitram, S. M. Org. Lett. 1999, 1, 2001-2004.Smith, A. B. III, Adams, C. M. Acc. Chem. Res. 2004, 37, 365-377.

S InBuLiTHF, -78 ºCSC-C Bond FormationSulfur Ylides -Epoxidation, CyclopropanationOSINaHDMSO, 25 ºCOSOOOABReagent Solvent Temperature Ratio (A/B)SOSTHFTHF0 ºC -> 25 ºC65 ºC87 : 130 : 100OAOBOReagent Solvent Temperature Ratio (A/B)SOSTHFDMSO0 ºC -> 25 ºC25 ºC -> 50 ºC100 : 00 : 100Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364.

C-C Bond FormationSulfur Ylides - Epoxidation, CyclopropanationIClPh 2 S, AgBF 4CH 3 NO 2 , 25 ºCPh 2 SBF 4ClNaHTHF, 25 ºCPh 2 SBF 4(99% yield)(83% yield)OPh 2 SBF 4KOHDMSO, 25 ºCO(75% yield)OPh 2 SBF 4KOHDMSO, 25 ºCOEu(fod) 3CDCl 3 , 37 ºC(80% yield)OONaOH, H 2 O 2OMeOH, H 2 O, 25 ºC(Quant.)Bogdanowicz, M. J.; Trost, B. M. Org. Syn. 1974, 54, 27.Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1971, 93, 3773-3774.Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5311-5321.Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5321-5334.

C-C Bond FormationSulfur Ylides - Epoxidation, CylopropanationOOHOPh 2 SBF 4KOHDMSO, 25 ºC(92% yield)OOHO1. (PhSe) 2 , NaBH 4DME, 60 ºC2. BSA(56% yield)TMSOTMSOOHOHFVT (610 ºC)HOOH(97% yield)OOH2:1 drHOHOHAphidicolinTrost, B. M.; Nishimura, Y.; Yamamoto, K.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1328-1330.

C-C Bond FormationSulfur Ylides - Epoxidation, CyclopropanationPhCH 2 BrPhCHO*R S R*BaseSolvent, 25 ºCPhOPhPhOPh*R S R*PhCH 2 BrPhCHOPhPh*R S R**R S R*KOHSMeOHSMeOHSArOHSPhOOHHHSOHOPhSHOOH PhPhFurukawa198943% eeDai199642% eeSaito200156% eeMetzner199985% eeGoodman200297% eeShimizu199948% ee

C-C Bond FormationSulfur Ylides - Epoxidation, CyclopropanationRCHO*RRSR*ML nPhNNNaTsor PhCHN 2PhOR'R* 2 SL n MPhN 2S5%ONaRCHO Ph N TsN1% Rh 2 (OAc) 410% BnEt 3 NClCH 3 CN, 40 ºCPhORR Yield (%) Trans/Cis ee (%)Ph8298:294Ph7098:2874675:2589Aggarwal, V. K. et al. J. Am. Chem. Soc. 2003, 125, 10926-10940.

C-C Bond FormationSulfur Ylides - Epoxidation, Cyclopropanation1. PPh 3 , H 2 OhνSH 2 , Pd/C/SSOSO 2 Cl2. K 2 CO 3 ,OClPhOPhSOSOOEtOH(4 steps - 48%)OPhOSR* 2HOPhOR'SPhHSHPhRHHRHSR* 2PhOOPhOSR* 2HOPhOHHRRHSR* 2PhR'Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747-5756.

C-C Bond FormationSulfur Ylides - Epoxidation, CyclopropanationOSBF 4 EtP 2OMe CH 2 Cl 2 , -78 ºC;OthenN(89% yield)CHONOOMeOtrans/cis 70:3098% eePhMgBr, CuITHF, -40 ºC(85% yield)OHOMeOMeO1. Et 3 N, MsClON2. Zn, HOAcN(80% yield)CDP-840S20%OOPhNNNaTs1% Rh 2 (OAc) 4 EtO 2 C N EtO 2 C NH 3 ClO 20% BnEt 3 NClNO 6N HCl (aq)OCO 2 EtDioxane, 40 ºC(55% yield)Ph7:1 dr91% ee(90% yield)Aggarwal, V. K. et al. Angew. Chem. Int. Ed. 2003, 42, 3274-3278.Aggarwal, V. K. et al. Angew. Chem. Int. Ed. 2001, 40, 1433-1436.Ph

C-C Bond FormationSulfur Ylides - [2,3]-Sigmatropic Rearrangement1. tBuOClSClNH 22.S3. Et 3 NORNHROtBuSNHSClRONH 2ROOOSNHSREt 3 NNHSRONHRGassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W. J. Am. Chem. Soc. 1974, 96, 5495-5508.

C-C Bond FormationSulfur Ylides - [2,3]-Sigmatropic RearrangementTMSOTBSOPh H SNBzOOPhhνOTBS(60% yield)TMSOTBSOPh H SNBzOTMSOTBSOPh H SNBzOOTBSTMSIOAcPh H SNHOTMSK 2 CO 3OCH 3 CN, 80 ºC PhHO (60% yield) NOHSOTMSPhHNHOAcOSOTMS1. Me 3 OBF 42. Zn, HOAc(92% yield)PhHNHOAcSMeOO1. mCPBA2. CaCO 3 , Xylenes, 140 ºC3. BF 3 •Et 2 O, HOAc, 0 ºC(73% yield)OAcPh H NOBzOCytochalasanVedejs, E.; Reid, J. G. J. Am. Chem. Soc. 1984, 106, 4617-4618.Vedejs, E. Acc. Chem. Res. 1984, 17, 358-364.

C-C Bond FormationChiral SulfoxidesR'SRCumene HydroperoxideTi(OiPr) 4 , (R,R)-DETiPrOH, CH 2 Cl 2R'OSROSOClHOP(OMe) 3pyridineOSORMgClOSRArO 2 SNSOOSOCl 23,5-LutidineTHF, -45 ºCNHSO 2 ArOHSOCl 22,6-Di-tBu-pyTHF, -45 -> -20 ºCArO 2 SNSOOEndo/Exo 97:3(80% yield)(82% yield)Exo/Endo 93:71. RMgCl2. R'MgCl1. RMgCl2. R'MgClOOR'SRR'SRZhao, S. H.; Samuel, O.; Kagan, H. B. Org. Syn. 1989, 68, 49-56.Andersen, K. K. Tetrahedron Lett. 1962, 3, 93.Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52, 2598-2602.Senanayake, C. H. et al. Aldrich. Acta. 2005, 38, 93-104.

C-C Bond FormationChiral SulfoxidespTolSNOMeO1. 5% Ni(acac) 2Ph 3 ZnMgClTHF, -25 ºC2. Zn, HOAcNOMeOO(90% yield)CDP-84092% eepTolOSOMgBrpTolOSOMgBrMeI, HMPAMeOTHF, -78 ºC-78 ºC -> 33 ºCMeO(42% yield)pTolOSOMe 2 CuLiEt 2 O, THF, 0 ºCOMBrCH 2 CO 2 MeMeO 2 COHMPA, 25 ºCMeOMeO(89% yield)MeOReider, P. J. et al. Tetrahedron Lett. 1997, 38, 7131-7134.Posner, G. H.; Mallamo, J. P.; Miura, K. J. Am. Chem. Soc. 1981, 103, 2886-2888.

C-C Bond FormationChiral SulfoxidespTolOSOArNMeO 2 CpTol OArSOLHMDSHNTHF, -78 ºC(90% yield)MeO 2 CH>20:1 dr; >20:1 Exo/EndoArHNMeO 2 COOOCO 2 EtCO 2 EtDBUToluene, -30 ºCOOCO 2 EtCO 2 EtAcOpTolSO(86% yield)pTolHSO>20:1 drOEtOOEtOOpTolSOCH 2 Cl 2 , -20 ºC(47% yield)OOO96% ee[α] D -1938(c 0.006, CHCl 3 )OEt4 equivOEtRuano, J. L. G. Tito, A.; Peromingo, M. T. J. Org. Chem. 2003, 68, 10013-10019.Lopez, F.; Castedo, L.; Mascarenas, J. L. J. Org. Chem. 2003, 68, 9780-9786.Carreno, M. C.; Conzalez-Lopez, M.; Urbano, A. Chem. Commun. 2005, 611-613.

C-C Bond FormationChiral SulfinamidesOOSOLHMDSthen NH 4 ClSNH 2ArO 2 SNSOEndo/Exo 97:3O1. tBuMgClTHF, -45 ºC2. LiNH 3 , THF, -78 ºC(97% yield)OtBu S NH 2ArO 2 SNSOOExo/Endo 93:71. tBuMgClTHF, -45 ºC2. LiNH 3 , THF, -78 ºC(90% yield)OtBu S NH 20.25%tBuNOHtBuOHtButBu S S tBu 0.25% VO(acac) 2H 2 O 2 , 20 ºCOtBu S S tBu91% eeLiNH 2NH 3 , THF, -78 ºC(2 steps - 78% yield)OtBu S NH 2Davis, F. A. et al. J. Org. Chem. 1999, 64, 1403-1406.Senanayake, C. H. et al. Aldrich. Acta. 2005, 38, 93-104.Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.

C-C Bond FormationChiral SulfinamidesOCuSO 4RCHOOTi(OEt) 4RCOR'OR'tBu S NR(79 - 100% yield)tBu S NH 2(63 - 89% yield)tBuS NRtBuOS NHRR'MgBrEt 2 O, CH 2 Cl 2-48 ºCtBuSHNO Mg RR'tBuOS NHHR'RHClH R'MeOH H 2 N R•HClR R' dr Addition Yield (%) Cleavage Yield (%)EtMe93:79697EtiPr98:29792EtPh96:4Quant.90PhMe97:39688Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.

C-C Bond FormationChiral SulfinamidestBuOS NR'RMe 3 Al, Toluenethen R"Li, -78 ºCtBuSR'NO Li RR''AlMe 3O R' R'' HClR' R''tBu S N R MeOH H 2 N RH•HClR R' R'' dr Addition Yield (%)iPrMenBu99:161iPrMePh97:393iPrnBuMe91:982CH 2 OTBSMenBu95:589O2.5% [Rh(OH)cod] 25% dppbenzEt 3 N (2 equiv)OHtBuS NKF 3 BDMF, H 2 O, 60 ºCtBu S NH(72% yield) 98:2 drEllman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.Brak, K.; Ellman, J. A. J. Am. Chem. Soc. asap.

C-C Bond FormationChiral SulfinamidesOtBu S NCO 2 EtPhMgBrBF 3 •Et 2 OTHF, -55 ºC(70% yield)F 3 BH CO 2 EtONBF 3tBuO PhtBu S NHCO 2 Et84:16 drHClPhEtOH H 2 N CO 2 Et•HClOEt 2 AlCNONCMe6N HClHO 2 CMetBuS NPhiPrOH, THF(56% yield)tBuS N PhH12:1 dr100 ºC(64% yield)H 2 N Ph•HCltButBuOS NOTi(OiPr) 3OSO PhOTiNPh tBu S OMeNTHF, -78 ºCHOOMe(81% yield)MeO Ph 91:9:0:0 drDavis, F. A.; McCoull, W. J. Org. Chem, 1999, 64, 3396-3397.Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704-8708.Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.

C-C Bond FormationChiral SulfinamidesLiBEt 3 H (2 equiv)tBuSHNOOHtBuN S OLDA, MgBr 2THF, -78 ºC;tBuSNOOHTHF, -78 ºC(69% yield)Ph99:1 drPhC 2 H 5 CHO(84% yield)Ph96:4 drOBHO(2 equiv)tBuSHNOOHTHF, -10 ºC(95% yield)Ph95:5 drKochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518-6519.

C-C Bond FormationChiral SulfinamidestButBuONN S OKHMDSTHF, -78 ºC;Br(82% yield)ONN S O>20:1 drMeLi, CeCl 3THF, -48 ºC(82% yield)tBuN S O2% Grubbs IItBuN S O1. Me 3 AlToluene, -78 ºC;LiH 2 N•HClCH 2 Cl 2 , 40ºC2. HCl, MeOH, 25 ºC(87% yield)(49% yield)>20:1 dr(6R,7S)-7-Amino-7,8-dihydro-α-bisaboleneKochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.

OlefinationJulianBuLi; R'CHORSO 2 Ph1. nBuLi; R'CHO2. Ac 2 O3. Na/Hg, MeOHRR'-AcOROHSO 2 PhR'Ac 2 OROSOOAcPhR'Na/HgRSOOOAcPhR'-PhSO 2ROAcR'Na/HgROAcR'ROS NONNNPhNaHMDSHMPA;R'CHORR'NaHMDS;R'CHO-SO 2 ; -ArOROS NONNNPhR'OOSOOPhNNNNJulia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833-4836.Kocienski, P. J. et al. Synlett. 1998, 26-28.

OlefinationJuliaNNNNPhSHHOHHHO1. PPh 3 , DEADTHF, 25 ºC2. H 2 O 2 , (NH 4 ) 6 Mo 7 O 24EtOH, H 2 O(82% yield)NNNPhNSO OHHHOOTBSOTBSOHCHOLHMDSDMF, HMPA-35 ºC -> 25 ºCTBDPSOTBDPSOOTBSOHOTBSHHHOCO 2 HOHOHOHHH(+)-AmbruticinHOLiu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772-10773.

OlefinationRamberg-BacklundOOKOtBuOOOOTHFIOSOSO OX-RayOSOClNCO 2 tBuKOtBuDMSO, 25 ºC10 minNCO 2 tBu97% yield)Ramberg, L.; Backlund, B. Arkiv. Kemi, Minerat. Geol. 1940, 13A, 50.MaGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060-1066.

OlefinationEschenmoser Sulfide ContractionPhNOMeOSSP PSS92 ¢ / gramOMeToluene110 ºCPhNSSOArPSPhNOPSArSPhNSOPSArArPSNBnS1. DABCOBrCH 2 CO 2 Me2. PPh 3NBnCO 2 MeBrCH 2 CO 2 MePh 3 P=SNBnSDABCOCO 2 MeNBnSCO 2 MeNBnSCO 2 MeLawesson, S. O.; Perregaad, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I. Bull Soc. Chim. Belg. 1977, 86, 679.Eschenmoser, A. Angew. Chem. Int. Ed. Engl. 1973, 12, 910.

OlefinationNicolaou Ring ContractionOHHOOOOHOLawesson's ReagentToluene, 110 ºC(78% yield)OHHSOOSHO1. Na•NaphthalenideTHF, -78 ºC2. MeI-78 ºC -> 25 ºC(80% yield)HSOHOAIBN, Bu 3 SnHHOHOOOSToluene, 110 ºC(99% yield)OOBnOHOOOTIPSOOHHOHHOHHOOOOHOHOHHOHOHHBrevetoxin BNicolaou, K. C. et al. J. Am. Chem. Soc. 1986, 108, 6800-6802.Nicolaou, K. C. et al. J. Am. Chem. Soc. 1990, 112, 3040-3054.

OlefinationCorey-WinterOHOH1. (Im) 2 C=S2. P(OMe) 3(75% yield)OOSP(OMe) 3OOP(OMe) 3OOP(OMe) 3SOOP(OMe) 3OONOHOHOH1. (Im) 2 C=S, Toluene2. TBSOTf, pyr, CH 2 Cl 22. P(OMe) 3(3 steps - 76% yield)OONOTBS1. H 2 , Pd/C, EtOAc2. TFA (aq)(83% yield)OHHO NHO(+)-SwainsonineCorey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677-2678.Corey, E. J., Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934-935.Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8565-8568.

OxidationKornblumOSCl Na 2 CO 3100 - 150 ºCO SCHOHO SNO 2NO 2NH 2- OOPO -OH OHOHNNHHHNNBrODMSO, DBUpH 4.525 ºC, 12 h(62% yield)OONO 2- OOPO -OH OHOHNNHHHNNKornblum, N. et al. J. Am. Chem. Soc. 1957, 79, 6562.Fischer, B.; Kabha, E.; Gendron, F-P.; Beaudoin, A. R. Nucleosides, Nucleotides & Nucleic Acids 2000, 19, 1033-1054.

OxidationMoffatt-SwernROHDMSO, (COCl) 2Et 3 NCH 2 Cl 2 , -78 ºC -> 25 ºCRCHOOOSClOClRHO SOROHOSOClClSRO SClCorey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586.Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480.Mancuso, A. J.; Swern, D. Synthesis. 1981, 161-185.

FunctionalizationMislow-Evans RearrangementS OSOP(OMe) 3OHMeOHpTolSTsTs pTolNa SNpTolSNTsNClHOnBuLi;HOHOOSPhLiNEt 2HMPA, THF;HOOSPhMe 2 NHHOHOPhSClOSPhMeIH 2 OHOBickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4869-4876.Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956-4957.

FunctionalizationPummerer RearrangementPhS OOAcAc 2 OCO 2 Et Ph SHCO 2 EtOAcPh S CO 2Et Ph S CO 2EtAcOOAcROOHTBHPTi(OiPr) 4(+)-DIPT(92% yield)ROOOHNaOH, PhSHH 2 O, tBuOH(71% yield)ROOHOROOHOHSPhROPOCl 3Me 2 C(OMe) 2ROOOSPh1. mCPBA, -78 ºC2. Ac 2 O, NaOAcROOOOAcSPhDIBALHCH 2 Cl 2 , -78 ºC(91% yield)OROOCHO(D)-HexosesK 2 CO 3MeOH, 25 ºC(100% yield)OOCHOPummerer, R. Chem. Ber. 1909, 42, 2282.Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A. III, Sharpless, K. B.; Walker, F. J. Science. 1983, 220, 949.

FunctionalizationDMTSFS S •BF 4MeSSMeOTMSDMTSF(2 equiv)DMTSFCH 2 Cl 2 , -20 ºC -> 0 ºC(63% yield)OSSSMeS S S SOTMSHSSSSOTMSOOTMSOMeSSMeSS•BF 4OTMSCH 2 Cl 2 , 25 ºCTrost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529-6530.

FunctionalizationDMTSFS S •BF 4DMTSFOSPh1.LiTHF, Et 2 O, -100 ºCTMSOSPhDMTSFSPh2. TMS-ImidazoleSPhCH 2 Cl 2 , -78 ºC(92% yield)(80% yield)OOHSPhAcOHHOHHShahamin KLebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851-4852.

FunctionalizationDMTSFSSMe[Me 2 S-SMe]BF 4NH 4 OHEpisulfoniumNH 2CH 3 CN, H 2 O, 25 ºC(92% yield)[Me 2 S-SMe]BF 4NaCNCH 3 CN, 25 ºCSMeCN(94% yield)SMe[Me 2 S-SMe]BF 4NaHCO 3OHCH 3 CN, H 2 O, 25 ºC(92% yield)[Me 2 S-SMe]BF 41-heptynenBuLi, Me 3 AlSMeSMeO[Me 2 S-SMe]BF 4DMSO;then iPr 2 NEt, 25 ºC(72% yield)DCE, THF, 80 ºC(88% yield)Trost, B. M.; Shibata, T. J. Am. Chem. Soc. 1982, 104, 3225-3228.Trost, B. M.; Shibata, T.; Martin, S. J. J. Am. Chem. Soc. 1982, 104, 3228-3230.Trost, B. M.; Martin, S. J. J. Am. Chem. Soc. 1984, 106, 4263-4265.

FunctionalizationDiels-Alder Controlling GroupMeOOMeOOOAcSO 2 PhOAcSO 2 PhPhSToluene110 ºC(75% yield)PhS5:1 regioselectivityCO 2 MeToluene110 ºC(65% yield)6:1 endo/exoCO 2 MeSO O18 ¢ / gramBrLHMDSTHF, -78 ºC(57% yield)SO OToluene, 110 ºC(80% yield)OZnCl 2CH 2 Cl 2 , 25 ºC(63% yield)HBF 3 •Et 2 OHOHToluene(63% yield)OHBuss, A. D.; Hirst, G. C.; Parsons, P. J. J. Chem. Soc. Chem. Commun. 1987, 18360-1837.Winkler, J. D.; Kim, H. S.; Kim, S. Tetrahedron Lett. 1995, 36, 687-690.

Sulfur-Templated Total SynthesisCantharidinHSCO 2 Me5 steps(26% yield)SOOOO(1.2 equiv)CH 2 Cl 215 kbar, 25 ºCOOSOO85:15 Exo / EndoRaney NiEtOAc, 78 ºC(63% yield - 2 steps)O OOOCantharidinCantharus vesicatoriaDauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 6893-6894.

Sulfur-Templated Total SynthesisJuvenile HormoneS1. MeMgClSOSS2. POCl 3 , py(90% yield)ODMSO(75% yield)OSS1. sBuLi, TMEDATHF, -20 ºCSSsBuLi, TMEDATHF, -50 ºC;O2. POCl 3 , py(90% yield)Cl(90% yield)OLiSSLiSHSHOHEtNH 2 , -70 ºCOH1. Raney Ni2. H 2 CrO 43. CH 2 N 2CO 2 MeOCO 2 Me(55% yield)(+/-)-Juvenile Hormone IKondo, K.; Negishi, A.; Matsui, K.; Tunemoto, D.; Masamune, S. J. Chem. Soc. Chem. Commun. 1972, 1311-1312.Stotter, P. L.; Hornish, R. E. J. Am. Chem. Soc. 1973, 95, 4444-4446.

Sulfur-Templated Total SynthesisColchicineMeOMeO 2 CNH 2ClSClMeO 2 CNS20 stepsMeOMeONSOOH1. NaOH (aq)Raney Ni2. NaBH 43. Ac 2 OMeOMeOMeOOHNHAcOMeOMeOMeOMeO(+/-)-ColchicineNHAcOWoodward, R. B. Harvey Lectures 1963, 59, 31-47.

Allium ChemistryGarlicOSHNH 2Alliin(allylic sulfoxide)CO 2 HAlliinaseNH 2CO 2 HOHSSHO(sulfenic acid)S N 2O HSSBOSSHOHSS[4+2]SSAllicin(thiosulfinate ester)antibiotic(thioacetal)platelet aggregation inhibitorBlock, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135-1178.

Allium ChemistryOnionOS[3+2]((Z)-sulfine)onion lachrymator factorOSOSSSOO(thiosulfonate ester)non-lachrymatorOSHNH 2CO 2 HIsoalliin(vinylic sulfoxide)AlliinaseNH 2CO 2 HHOSSHO(sulfenic acid)S N 2O HSSBSOSO[2+2] S [3,3] [Ox]SSSSSOO(thiosulfinate ester)trans-zwiebelane (thioaldehyde-sulfine)O OSS(thiosulfonate ester)smell of raw onionsBlock, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135-1178.

Organosulfur CompoundsOCH 3 SHmethylmercaptan(natural gas additive)MeSSMebis(methylthio)methane(black truffles)SH1-p-menthene-8-thiol(grapefruit)NHSOOsaccharin(sweetener)OHNNHH HSCO 2 HbiotinH 2 N SO 2 NH 2PhOHNOHNpenicillin G(antibiotic)SCO 2 HEtOOSNOHNONNNsulfanilamide(antibiotic)Viagra(erectile dysfunction)

SummaryNomenclatureEliminationRadical ReactionC-C Bond FormationOlefinationOxidationFunctionalizationAllium Chemistry