Sulfur-Facilitated Organic Synthesis

Andrew McClory Monday March 16, 2009 8:00 pm, 147 Noyes S

S S S

S S

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

-Researcher, Freiburg, 1889 S

S S

'Attempts to make thioacetone by the cracking of trithioacetone gave rise to an offensive smell which spread rapidly over 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, a stopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nausea and sickness from colleagues working in a building two hundred yards away. Two of our chemists who had done no more than investigate the cracking of minute amounts of trithioacetone found themselves the object of hostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with a deodorant. The odours defied the expected effects of dilution since workers in the laboratory did not find the odours intolerable...and genuinely denied responsibility since they were working in closed systems. To convince them otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of a mile, and one drop of either acetone gem-dithiol or the mother liquors from crude thioacetone crystallizations were placed on a watch glass in a fume cupboard. The odour was detected downwind in seconds.'

-Esso Researcher, Oxford, 1967 Seminar Overview

1. Nomenclature 6. Olefination

2. Selected Properties A. Julia B. Ramberg-Backlund 3. Elimination C. Eschenmoser D. Corey-Winter A. Burgess E. Nicolaou B. Martin C. Sulfoxide 7. Oxidation D. Chugaev A. Kornblum 4. Radical Reaction B. Moffatt-Swern

A. Barton 8. Functionalization B. Zard A. Mislow-Evans 5. C-C Bond Formation B. Pummerer C. DMTSF A. Nature; Fukuyama D. Diels-Alder B. Acyl Anion Equivalents E. Total Synthesis C. Sulfur Ylides E. Chiral Auxiliaries 9. Allium Chemistry Nomenclature of Organosulfur Compounds

O O O S S S S S S S R' RSH R R' R R' R S R R' R H R R' R NH2 Thiol Sulfide Sulfoxide Sulfone Disulfide Thioaldehyde Thioketone Thioamide (Mercaptan) (Alkyl Mercaptan)

O S O S S S O X O X S S S R OR' R SR' R SR' RO SR' R O Thionoester Thioester Dithioester Xanthate Ester Sulfine Sulfene Sulfonium Salt Sulfoxonium Salt

O O O R O O O O S S S S S X S S H2N R

Sulfonium ylide Sulfoxonium Ylide Thiirane Episulfonium Salt Episulfone Sulfolane Sulfonamide (Episulfide)

S S X R S S S S R S S R Cl R OR' N R OH Thioacetal Ketene Thioacetal R Sulfenyl Chloride Sulfenic Acid Sulfenate Ester (1,3-Dithiane) Thiazolium Salt

O O S R' S R' R N O O R S R S S R' S S S S R NH R OR' O O O R R Cl R N R' 2 Thiosulfinate Thiosulfonate Sulfilimine Sulfinyl Chloride Sulfinimine Sulfinamide Sulfinate Ester Selected Properties of Organosulfur Compounds

pKa Values (DMSO)

O O O S S S S S S H2O

45 39 35 31 31 25

S O O SH O O S N SH S S Ph Ph OH Ph OH

18 18 17 10 7 1

Bond Stengths (kcal/mol) Bond Lengths (A) A-Values (kcal/mol)

C=S: 120 C=O: 177 C=S: 1.6 C=O: 1.2 Me: 1.7 C-S: 74 C-O: 85 C-S: 1.8 C-O: 1.4 OMe: 0.6 S-H: 87 O-H: 110 S-H: 1.4 O-H: 1.0 SMe: 0.7 S-S: 65 O-O: 43 S-S: 2.0 O-O: 1.5 S=O: 1.5 SOMe: 1.2 SO2Me: 2.5 Elimination Burgess Dehydration

O O OH MeO2C S N NEt3 Benzene 25 -> 50 ºC 60$ / gram

SO2

MeO2CNH2 O O Et3NH MeO2C S N O H

TESO TESO OBOM OBOM

O O 7 steps TBSO MeO2C S TBSO Taxol N NEt3 OTMS OH H H O OH O O (63% yield) O O O

Atkins, 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. Elimination Martin Dehydration

OH F3C O O CF3 F C S CF 3 3 CHCl3 Ph Ph Ph Ph -50 ºC -> 25 ºC 57$ / gram O

CF3 S F3C O Ph Ph

Ph Ph O CF3 CF Ph O 3 Ph S CF3 S CF3 O Ph Ph Ph OH CF3 H F3C O

Ph

F C CF OH 3 O O 3 F C S CF 3 3 CHCl , 25 ºC Ph Ph Ph Ph 3 (32% yield)

Martin, J. C. Arnhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329. Elimination Sulfoxide

Ph O Ph O S S R' H R R Benzene R 25 -> 80 ºC R' R'

O O O LiCA; LDA; SPh SPh PhSSPh MeI

O O mCPBA; Ph S CCl , 70 ºC 4 O H (+/-)-Acorenone

Trost, B. M. Acc. Chem. Res. 1978, 11, 453-461. Oppolzer, W.; Mahalanabis, K. K.; Bättig, K. Helv. Chim. Acta. 1977, 60, 2388-2401. Elimination Xanthate Ester

S SMe S NaH, CS2; H OH C MeSH Ph O Ph 250 -> 300 ºC MeI Ph O

MeS

HO S O NaH, THF, CS ; NaHCO O 2 3 O N then MeI, -30 ºC Ph2O, 260 ºC O Cbz N (92% yield) O Cbz (72% yield)

H H 6 steps O HO C O 2 N N HO C N O Cbz Cbz 2 O H H H (-)-Kainic Acid

Chugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181-3183. Radical Reaction Barton

O AIBN, O Bu SnH N 3 R Cl NaO N RH R O Benzene, 80 ºC S S

H SnBu3 NC Bu3Sn H SnBu3 N N CN CN

O R N R O S SnBu3

AIBN, S SMe NaH, CS ; Bu SnH R OH 2 3 RCH3 MeI R O Benzene, 80 ºC

Barton, 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 Formation Nature - Thioester

NH2 N N O OH O O H H N N P P N N S O O O H H O O O O O H H O OH O P O Acetyl CoA O

O O Fatty Acids, Polyketides O SCoA

O HO O O O O OH HO Alkaloids HO OH SCoA SCoA OH O Glucose Pyruvic Acid Acetyl CoA

HO2C CO2H FADH2 NADH ATP Synthesis HO CO2H C-C Bond Formation Fukuyama - Thioester

iBuOCOCl 10% Pd/C O N-Methylmorpholine; Et3SiH (2-3 equiv) RCO2H RCHO EtSH R SEt Acetone, 25 ºC, 30 min

O O Pd (0) R R' R SEt

R' = H, R O O R' SEt R Pd R Pd

MSEt R'M

O O O H O H 1. 5% PdCl (PPh ) O O O O 2 3 2 SEt O O O O IZn O H O H Toluene, 25 ºC, 5 min 2. HCO2H

HO2C Phomoidride B tBuO2C (78% yield)

Fukuyama, 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 Formation Acyl Anion Equivalent - Thiazolium Catalyst

Cl HO S N HO S Cl N N N Ph

NH2 Thiamine 1.30 $ / gram (Vitamin B1)

HO S Cl N Ph 17% O O

Et3N, EtOH 80 ºC, 90 min OH

(74% yield)

HO S Cl N Ph O O 10% CN CN Et3N, EtOH 80 ºC, 16 h

(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 Formation Acyl Anion Equivalent - Thiazolium Catalyst O

R Acyl Anion = synthon exhibiting reversal of normal carbonyl group reactivity

HO S Cl N Ph

O O * Ph Ph S R Ph OH NBn S Cl R' OH N HO Ph S S Ph Ph R 6% yield R NBn NBn O 52% ee OH R' R' S Ph R O NBn

Ph R'

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 Formation Acyl Anion Equivalent - Thiazolium Catalyst

HO S I CN CN N Ph H 2.3 equiv OH H H HO2C Et3N, iPrOH, 80 ºC MeO2C O CO Me CHO O H 2 (67% yield) (+/-)-Hirsutic Acid

O HO S Cl O O N Ph 10% O BzO BzO Et3N, Dioxane, 70 ºC

(77% yield)

N 6 steps NH O

Cl OMe Roseophilin

Trost, 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 Formation Acyl Anion Equivalent - Dithiane

MeS SMe nBuLi MeS SMe R SMe THF, -78 ºC R R

nBuLi S S S S S S CH2CH2 THF, -78 ºC R R R

SH SH + O O nBuLi S E PhI(CF3CO2)2 BF3•Et2O S S S S S S S R E R H CH Cl THF, -78 ºC CH3CN, 25 ºC 2 2 R R E R R

O O O O O Electrophiles (E+): R' X R' Cl R' H R' R'' R' R'

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 Formation Acyl Anion Equivalent - Dithiane

O O tBuLi, Et2O -78 -> -45 ºC; O HMPA TBSO (1 equiv) S S S S S S O BnO BnO THF BnO TBS TBS -78 ºC -> 25 ºC (2 equiv) (2 equiv) (59% yield)

1. Me2C(OMe)2 PPTS TBSO OH HO OTBS 2. TBAF HO O O O O OH S S S S BnO OBn BnO OBn 3. Hg(ClO4)2 2,6-Lutidine

(62% yield)

HO OH OH OH OH OH

HO O

HO O (+)-Mycoticin A

Smith, 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. C-C Bond Formation O nBuLi O I I NaH S S Sulfur Ylides - S S THF, -78 ºC Epoxidation, Cyclopropanation DMSO, 25 ºC

O O O

A B

Reagent Solvent Temperature Ratio (A/B)

S THF 0 ºC -> 25 ºC 87 : 13 O S THF 65 ºC 0 : 100

O O O A B

Reagent Solvent Temperature Ratio (A/B)

S THF 0 ºC -> 25 ºC 100 : 0 O S DMSO 25 ºC -> 50 ºC 0 : 100

Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364. C-C Bond Formation Sulfur Ylides - Epoxidation, Cyclopropanation

BF4 BF Ph2S, AgBF4 NaH 4 Ph S I Cl Ph2S Cl 2 CH3NO2, 25 ºC THF, 25 ºC

(99% yield) (83% yield)

BF4 KOH Ph2S DMSO, 25 ºC O O (75% yield)

O BF4 O KOH Eu(fod)3 Ph2S DMSO, 25 ºC CDCl3, 37 ºC (80% yield) O O NaOH, H2O2 O

MeOH, H2O, 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 Formation Sulfur Ylides - Epoxidation, Cylopropanation

O O BF4 1. (PhSe)2, NaBH4 KOH DME, 60 ºC Ph2S DMSO, 25 ºC 2. BSA O O H H (92% yield) (56% yield) O O

OH TMSO TMSO OH

FVT (610 ºC) H O O HO H (97% yield) H H O O 2:1 dr HO Aphidicolin

Trost, B. M.; Nishimura, Y.; Yamamoto, K.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1328-1330. C-C Bond Formation Sulfur Ylides - Epoxidation, Cyclopropanation

S *R R* O Base Ph PhCH2Br PhCHO Solvent, 25 ºC Ph

O Ph S *R R* PhCH2Br Ph

PhCHO Ph Ph

S S *R R* *R R*

KOH

Ph Ph O HH O H O Ar SMe OH O O O OH OH S S S S Ph H SMe H H Ph

Furukawa Dai Saito Metzner Goodman Shimizu 1989 1996 2001 1999 2002 1999 43% ee 42% ee 56% ee 85% ee 97% ee 48% ee C-C Bond Formation Sulfur Ylides - Epoxidation, Cyclopropanation

R Na Ph N Ts RCHO ML N S n or PhCHN2 *R R*

O R' LnM R*2S N2 Ph Ph

S

5% O

1% Rh (OAc) Na 2 4 O R 10% BnEt3NCl RCHO Ph N Ts N CH3CN, 40 ºC Ph

R Yield (%) Trans/Cis ee (%)

Ph 82 98:2 94

Ph 70 98:2 87

46 75:25 89

Aggarwal, V. K. et al. J. Am. Chem. Soc. 2003, 125, 10926-10940. C-C Bond Formation Sulfur Ylides - Epoxidation, Cyclopropanation

S S 1. PPh3, H2O hν H2, Pd/C/S

2. K2CO3, O O EtOH O O O S O O S SO2Cl (4 steps - 48%) Cl Ph Ph

O O Ph SR*2 H Ph O R'

Ph H R H R H H Ph SR*2 S H S Ph

O O O O H Ph O Ph SR*2

H R R H Ph R' H SR*2

Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747-5756. C-C Bond Formation Sulfur Ylides - Epoxidation, Cyclopropanation

BF 4 EtP2 OMe OMe CH2Cl2, -78 ºC; PhMgBr, CuI S O O CHO O THF, -40 ºC O then N N trans/cis 70:30 (89% yield) 98% ee (85% yield)

OMe OMe OH

O 1. Et3N, MsCl O N 2. Zn, HOAc N

(80% yield) CDP-840

S

20% O O

1% Rh (OAc) Na 2 4 EtO2C N EtO2C NH3Cl O O 20% BnEt3NCl 6N HCl (aq) Ph N Ts N O N Dioxane, 40 ºC CO2Et Ph Ph (55% yield) 7:1 dr (90% yield) 91% ee

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. C-C Bond Formation Sulfur Ylides - [2,3]-Sigmatropic Rearrangement

S 1. tBuOCl

2. R NH2 S N R H O 3. Et3N Cl OtBu

S Cl R N H O R NH2 S O O O S

R R Et3N R S S O N N NH H H

Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W. J. Am. Chem. Soc. 1974, 96, 5495-5508. C-C Bond Formation Sulfur Ylides - [2,3]-Sigmatropic Rearrangement

TMS TMS TMS OTBS OTBS OTBS hν O O O S H S H S H Ph Ph Ph O O O N OTBS N N OTBS Bz O Ph Bz Bz (60% yield)

TMS TMS TMS I OAc K2CO3 O OAc H S H S H S Ph CH3CN, 80 ºC Ph Ph O O O N O (60% yield) N O N H H H O

TMS

1. mCPBA 1. Me OBF OAc 3 4 OAc 2. CaCO3, Xylenes, 140 ºC H SMe H 2. Zn, HOAc Ph Ph 3. BF3•Et2O, HOAc, 0 ºC O O N N O (92% yield) H O (73% yield) Bz Cytochalasan

Vedejs, E.; Reid, J. G. J. Am. Chem. Soc. 1984, 106, 4617-4618. Vedejs, E. Acc. Chem. Res. 1984, 17, 358-364. C-C Bond Formation Chiral Sulfoxides

Cumene Hydroperoxide O Ti(OiPr)4, (R,R)-DET S S R' R R' R iPrOH, CH2Cl2

O O O O S P(OMe)3 RMgCl S Cl S R HO pyridine O

ArO2S ArO2S O NHSO Ar O N SOCl2 2 SOCl2 N S 3,5-Lutidine 2,6-Di-tBu-py S OH O O THF, -45 ºC THF, -45 -> -20 ºC

(80% yield) (82% yield) Endo/Exo 97:3 Exo/Endo 93:7

1. RMgCl 1. RMgCl 2. R'MgCl 2. R'MgCl O O S S R' R R' R

Zhao, 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 Formation Chiral Sulfoxides N N 1. 5% Ni(acac)2 OMe OMe Ph3ZnMgCl THF, -25 ºC pTol O S O 2. Zn, HOAc

O (90% yield) CDP-840 92% ee

O OMgBr O S O MgBr pTol pTol S MeI, HMPA THF, -78 ºC -78 ºC -> 33 ºC MeO MeO (42% yield)

O O OM O pTol S Me2CuLi MeO C BrCH CO Me 2 Et2O, THF, 0 ºC 2 2 HMPA, 25 ºC

MeO MeO (89% yield) MeO

Reider, 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 Formation Chiral Sulfoxides

pTol O O Ar O Ar S O Ar O pTol S LHMDS N HN HN THF, -78 ºC MeO C H 2 (90% yield) MeO2C MeO2C >20:1 dr; >20:1 Exo/Endo

O CO2Et O CO Et CO2Et 2 DBU O O CO2Et Toluene, -30 ºC

AcO (86% yield) H S S pTol pTol >20:1 dr O O

OEt EtO O O O S 96% ee pTol O O [ ] -1938 CH2Cl2, -20 ºC O α D (c 0.006, CHCl3) O (47% yield) 4 equiv OEt OEt

Ruano, 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 Formation Chiral Sulfinamides

O O S LHMDS S O NH2 then NH4Cl

ArO2S ArO2S N O 1. tBuMgCl N O 1. tBuMgCl S O S O THF, -45 ºC THF, -45 ºC O S O S 2. Li tBu NH2 2. Li tBu NH2 NH3, THF, -78 ºC NH3, THF, -78 ºC Endo/Exo 97:3 Exo/Endo 93:7 (97% yield) (90% yield)

tBu 0.25% N OH

tBu OH

tBu O O 0.25% VO(acac) LiNH2 S tBu 2 S tBu S tBu S tBu S tBu NH2 H O , 20 ºC NH3, THF, -78 ºC 2 2 91% ee (2 steps - 78% yield)

Davis, 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 Formation Chiral Sulfinamides

CuSO Ti(OEt) O 4 O 4 O R' RCHO RCOR' S S S tBu N R tBu N R (79 - 100% yield) tBu NH2 (63 - 89% yield)

H O H R' O H R'MgBr HCl H R' S S tBu N R S tBu N R Mg tBu N R MeOH H2N R Et2O, CH2Cl2 O R' H -48 ºC •HCl

R R' dr Addition Yield (%) Cleavage Yield (%)

Et Me 93:7 96 97

Et iPr 98:2 97 92

Et Ph 96:4 Quant. 90

Ph Me 97:3 96 88

Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995. C-C Bond Formation Chiral Sulfinamides

R' O R' O Me Al, Toluene S R' R'' HCl R' R'' 3 tBu N R S Li S tBu N R then R"Li, -78 ºC O R'' tBu N R MeOH H2N R H AlMe3 •HCl

R R' R'' dr Addition Yield (%)

iPr Me nBu 99:1 61

iPr Me Ph 97:3 93

iPr nBu Me 91:9 82

CH2OTBS Me nBu 95:5 89

2.5% [Rh(OH)cod]2 5% dppbenz O O Et3N (2 equiv) H S S tBu N KF3B DMF, H O, 60 ºC tBu N 2 H (72% yield) 98:2 dr

Ellman, 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 Formation Chiral Sulfinamides

H CO Et PhMgBr 2 O Ph Ph O BF •Et O HCl 3 2 O S S F3B N tBu N CO2Et EtOH H2N CO2Et tBu N CO2Et THF, -55 ºC BF H 3 •HCl tBu (70% yield) 84:16 dr

O O NC Me HO2C Me Et2AlCN 6N HCl S S tBu N Ph H N Ph tBu N Ph iPrOH, THF H 100 ºC 2 •HCl (56% yield) 12:1 dr (64% yield)

tBu S O OTi(OiPr)3 O O Ph O O N S Ti S tBu N Ph OMe tBu N OMe THF, -78 ºC H MeO (81% yield) Ph 91:9:0:0 dr

Davis, 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 Formation Chiral Sulfinamides

tBu S O LiBEt3H (2 equiv) HN OH

THF, -78 ºC Ph tBu tBu (69% yield) 99:1 dr S O S LDA, MgBr2 N O THF, -78 ºC; N OH

C H CHO Ph Ph 2 5 O (84% yield) 96:4 dr BH tBu O S O (2 equiv) HN OH

THF, -10 ºC Ph 95:5 dr (95% yield)

Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518-6519. C-C Bond Formation Chiral Sulfinamides

tBu tBu S S N O N O KHMDS THF, -78 ºC; MeLi, CeCl3 N N THF, -48 ºC Br O O (82% yield) (82% yield) >20:1 dr

1. Me3Al tBu Toluene, -78 ºC; tBu •HCl S Li N O S H2N 2% Grubbs II N O

CH2Cl2, 40ºC 2. HCl, MeOH, 25 ºC

(87% yield) (49% yield) >20:1 dr

(6R,7S)-7-Amino-7,8- dihydro-α-bisabolene

Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652. Olefination Julia

R 1. nBuLi; R'CHO R R' SO Ph 2. Ac2O 2 3. Na/Hg, MeOH nBuLi; R'CHO -AcO

OAc OAc OH OAc OAc Ac2O R Na/Hg R Na/Hg R R' R' R R R' R' R' S S SO2Ph O Ph O Ph -PhSO O O 2

R NaHMDS S N HMPA; O R O N R' R'CHO N N Ph

NaHMDS; -SO ; -ArO R'CHO 2 R' R O O S O O N O S N O N N N N N N Ph Ph

Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833-4836. Kocienski, P. J. et al. Synlett. 1998, 26-28. Olefination Julia

Ph H 1. PPh3, DEAD N N THF, 25 ºC N HO O H 2. H O , (NH ) Mo O N SH H 2 2 4 6 7 24 EtOH, H2O

(82% yield)

Ph OTBS N N H OTBS N LHMDS N S O H DMF, HMPA O O H O CHO -35 ºC -> 25 ºC H TBDPSO

OTBS OH OTBS OH H H

O O O O H H H H H CO H H TBDPSO 2 (+)-Ambruticin

Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772-10773. Olefination Ramberg-Backlund

O O O O O O KOtBu THF I S S O O O O X-Ray

O KOtBu S NCO2tBu NCO2tBu O DMSO, 25 ºC Cl 10 min 97% 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. Olefination Eschenmoser Sulfide Contraction

S S MeO P P OMe S N O N S Toluene S 110 ºC Ph Ph 92 ¢ / gram S O P P Ar S Ar S O O N Ar N P S P Ar S Ph S Ph S

1. DABCO BrCH2CO2Me CO2Me N S N Bn 2. PPh3 Bn

BrCH2CO2Me Ph3P=S

DABCO S S N S N N CO Me Bn Bn Bn 2 CO2Me CO2Me

Lawesson, 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. Olefination Nicolaou Ring Contraction

H H O 1. Na•Naphthalenide O O H S H O THF, -78 ºC O Lawesson's Reagent O 2. MeI O Toluene, 110 ºC -78 ºC -> 25 ºC O O S O H H (78% yield) (80% yield)

H H S O O H H O AIBN, Bu3SnH O

O Toluene, 110 ºC O O S O (99% yield)

BnO

OTIPS H O O H H H O O H H H H O O O O H Brevetoxin B O O H H O O O O H H H

Nicolaou, 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. Olefination Corey-Winter

OH 1. (Im)2C=S

OH 2. P(OMe)3 (75% yield)

P(OMe)3 O O

S P(OMe)3 O O

P(OMe)3 O P(OMe)3 O S O O

OH OTBS OH OH 1. (Im)2C=S, Toluene 2. TBSOTf, pyr, CH2Cl2 1. H2, Pd/C, EtOAc O HO N O N N OH 2. P(OMe)3 2. TFA (aq) O O HO (3 steps - 76% yield) (83% yield) (+)-Swainsonine

Corey, 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. Oxidation Kornblum O S CHO Cl Na2CO3

100 - 150 ºC

H S S O O

NO2 NO2

NH2 N N Br O NO2 N O N N N DMSO, DBU - pH 4.5 O P O H O H O O N N O- - 25 ºC, 12 h O P O H O H H H O- OH H (62% yield) O H H OH H

Kornblum, 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. Oxidation Moffatt-Swern

DMSO, (COCl)2 Et3N R OH RCHO CH2Cl2, -78 ºC -> 25 ºC

O Cl O Cl H S O S R O

R OH O Cl O Cl S S O S R O Cl

Corey, 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. Functionalization Mislow-Evans Rearrangement

O S S O P(OMe)3 OH MeOH

Ts pTol Ts pTol N S Ts S Na S pTol N N Cl

HO HO O O HO HO HO LiNEt2 nBuLi; S S Ph HMPA, THF; Ph Me2NH PhSCl MeI H2O O S HO HO Ph

Bickart, 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. Functionalization Pummerer Rearrangement

OAc O S CO Et Ac2O 2 S CO2Et S CO2Et Ph S CO2Et Ph Ph Ph OAc H OAc AcO

TBHP Ti(OiPr)4 OH OH (+)-DIPT O NaOH, PhSH RO RO RO RO OH OH SPh H2O, tBuOH O (92% yield) OH (71% yield)

RO

DIBALH CHO O CH2Cl2, -78 ºC RO RO O OAc (91% yield) POCl3 1. mCPBA, -78 ºC (D)-Hexoses O SPh O SPh Me2C(OMe)2 O 2. Ac2O, NaOAc O RO

K2CO3 CHO O MeOH, 25 ºC O (100% yield)

Pummerer, 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. Functionalization S S DMTSF •BF4 DMTSF DMTSF MeS SMe OTMS (2 equiv)

CH2Cl2, -20 ºC -> 0 ºC O S (63% yield) S

S S S OTMS S SMe H

O S S S S

O TMSO

O S TMSO S MeS SMe •BF4

CH2Cl2, 25 ºC TMS

Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529-6530. Functionalization S S DMTSF •BF4 DMTSF

1. O Li TMSO SPh THF, Et2O, -100 ºC SPh DMTSF CH Cl , -78 ºC SPh 2. TMS-Imidazole SPh 2 2 (92% yield) (80% yield)

O

AcO O O H SPh H H

H

H

Shahamin K

Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851-4852. Functionalization DMTSF

S

Episulfonium SMe [Me2S-SMe]BF4 NH4OH [Me S-SMe]BF NH CH3CN, H2O, 25 ºC 2 4 SMe 2 NaCN (92% yield) CH3CN, 25 ºC CN (94% yield) [Me S-SMe]BF SMe 2 4 NaHCO3

CH CN, H O, 25 ºC OH 3 2

(92% yield) [Me2S-SMe]BF4 1-heptyne SMe nBuLi, Me3Al

[Me2S-SMe]BF4 DCE, THF, 80 ºC SMe DMSO; (88% yield) then iPr2NEt, 25 ºC O (72% 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. Functionalization Diels-Alder Controlling Group

O O OAc OAc MeO MeO SO2Ph SO2Ph

Toluene PhS CO Me Toluene PhS 110 ºC 2 110 ºC CO2Me 5:1 regioselectivity 6:1 endo/exo (75% yield) (65% yield)

Br O LHMDS ZnCl2 S THF, -78 ºC S Toluene, 110 ºC CH Cl , 25 ºC O O 2 2 O O (57% yield) (80% yield) 18 ¢ / gram (63% yield)

H H BF3•Et2O

Toluene H H O (63% yield) O

Buss, 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 Synthesis Cantharidin

O O O O O O 5 steps (1.2 equiv) O Raney Ni O HS CO2Me S O (26% yield) CH2Cl2 O EtOAc, 78 ºC O 15 kbar, 25 ºC O S (63% yield - 2 steps) 85:15 Exo / Endo Cantharidin

Cantharus vesicatoria

Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 6893-6894. Sulfur-Templated Total Synthesis Juvenile Hormone O S S 1. MeMgCl S S 2. POCl , py DMSO 3 O O (90% yield) (75% yield)

1. sBuLi, TMEDA sBuLi, TMEDA S S THF, -20 ºC S S THF, -50 ºC;

2. POCl3, py Cl O OLi (90% yield) (90% yield)

S S Li SH SH

OH EtNH2, -70 ºC OH

1. Raney Ni 2. H CrO 2 4 O CO2Me CO2Me 3. CH2N2

(55% yield) (+/-)-Juvenile Hormone I

Kondo, 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 Synthesis Colchicine

MeO N NH2 S N 20 steps MeO S S MeO MeO C 2 Cl Cl MeO C 2 O OH

MeO MeO NHAc NHAc 1. NaOH (aq) MeO Raney Ni MeO MeO MeO 2. NaBH4 O 3. Ac2O O MeO OH (+/-)-Colchicine

Woodward, R. B. Harvey Lectures 1963, 59, 31-47. Allium Chemistry Garlic

B H O OH H NH2 O Alliinase SN2 S S S CO2H S S HO Alliin NH2 (allylic sulfoxide) (sulfenic acid) CO2H

O H OH [4+2] S S S S S S

Allicin (thioacetal) (thiosulfinate ester) platelet aggregation inhibitor antibiotic

Block, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135-1178. Allium Chemistry Onion O O O S [3+2] S O O S S S ((Z)-sulfine) (thiosulfonate ester) onion lachrymator factor non-lachrymator

B H H O O H NH2 O Alliinase SN2 S S S CO2H S S HO Isoalliin NH2 (vinylic sulfoxide) (sulfenic acid) CO2H

S O O O O S [Ox] [2+2] S [3,3] S S S S S S S O O (thiosulfinate ester) (thiosulfonate ester) smell of raw onions trans-zwiebelane (thioaldehyde-sulfine)

Block, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135-1178. Organosulfur Compounds

O

MeS CH3SH SMe NH S methylmercaptan bis(methylthio)methane O (natural gas additive) (black truffles) O SH saccharin 1-p-menthene-8-thiol (sweetener) (grapefruit)

O

HN NH H H O H H S CO H N 2 N Ph S EtO HN biotin N O N O CO2H penicillin G (antibiotic) S O N H2N SO2NH2 O N

sulfanilamide Viagra (antibiotic) (erectile dysfunction) Summary

Nomenclature

Elimination

Radical Reaction

C-C Bond Formation

Olefination

Oxidation

Functionalization

Allium Chemistry