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 2. Selected Properties 3. Elimination
A. Burgess B. Martin C. Sulfoxide D. Chugaev

6. Olefination
A. Julia B. Ramberg-Backlund C. Eschenmoser D. Corey-Winter E. Nicolaou

7. Oxidation
A. Kornblum B. Moffatt-Swern

4. Radical Reaction
A. Barton B. Zard

8. Functionalization
A. Mislow-Evans B. Pummerer C. DMTSF D. Diels-Alder E. Total Synthesis

5. C-C Bond Formation

A. Nature; Fukuyama B. Acyl Anion Equivalents C. Sulfur Ylides E. Chiral Auxiliaries

9. Allium Chemistry

Nomenclature of Organosulfur Compounds

O RSH Thiol (Mercaptan) S R OR' R R S R' R S R' O R S O R' R S S R' R H R R' R NH2 Thioaldehyde Thioketone Thioamide S S S

Sulfide (Alkyl Mercaptan) O SR' R S

Sulfoxide

Sulfone

Disulfide

S SR' RO SR' R

O S S O

O X S Sulfoxonium Salt O O S H2N R Sulfonamide

Thionoester

Thioester O

Dithioester

Xanthate Ester R S S

Sulfine

Sulfene

Sulfonium Salt O O S

S Sulfonium ylide

O X S

S Sulfoxonium Ylide

Thiirane (Episulfide) X

Episulfonium Salt

Episulfone

Sulfolane

S R S R

S S

S N

Cl

OH

OR'

Thioacetal (1,3-Dithiane)

Ketene Thioacetal

R Thiazolium Salt R N O R S Cl

Sulfenyl Chloride

Sulfenic Acid

Sulfenate Ester

S O

R'

S O

R' O

S R

R'

O R S N R' R

O S NH2 R

O S OR'

Thiosulfinate

Thiosulfonate

Sulfilimine

Sulfinyl Chloride

Sulfinimine

Sulfinamide

Sulfinate Ester

Selected Properties of Organosulfur Compounds

pKa Values (DMSO)
O S 45 O S S 39 S SH N 18 17 Ph SH Ph S S 35 O S 31 O H2O 31 O S 7 OH

S 25

O Ph S 1

O OH

18

10

Bond Stengths (kcal/mol)

C=S: 120 C-S: 74 S-H: 87 S-S: 65 C=O: 177 C-O: 85 O-H: 110 O-O: 43

Bond Lengths (A)

C=S: 1.6 C-S: 1.8 S-H: 1.4 S-S: 2.0 S=O: 1.5 C=O: 1.2 C-O: 1.4 O-H: 1.0 O-O: 1.5

A-Values (kcal/mol)
Me: 1.7 OMe: 0.6 SMe: 0.7 SOMe: 1.2 SO2Me: 2.5

Elimination
Burgess Dehydration
O O MeO2C S N NEt3

OH

Benzene 25 -> 50 C SO2

60$ / gram
MeO2CNH2

Et3NH

O O MeO2C S N O H

TESO

OBOM O O MeO2C S N NEt3 (63% yield) TBSO

TESO

OBOM 7 steps Taxol OH

TBSO O O H O OTMS OH

O O

H 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 F3C Ph

CF3 CF3 Ph CHCl3 -50 C -> 25 C O

Ph Ph

57$ / gram
F3C CF3 O Ph Ph Ph S Ph OH F3C O CF3 CF3 Ph CF3 O Ph Ph S O H O CF3 CF3 Ph S

Ph

Ph

OH

F3C F3C Ph

CF3 CF3 Ph CHCl3, 25 C (32% yield)

Ph Ph

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

Elimination
Sulfoxide

Ph R

O Benzene 25 -> 80 C

Ph R

O H R' R R'

R'

O LiCA; PhSSPh

O LDA; SPh MeI

O SPh

O Ph S O

mCPBA;
CCl4, 70 C H

(+/-)-Acorenone

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

Elimination
Xanthate Ester
S O SMe 250 -> 300 C Ph S C O MeSH

Ph

OH

NaH, CS2; MeI Ph

MeS HO O O N Cbz NaH, THF, CS2; then MeI, -30 C (92% yield) O O N Cbz O S NaHCO3 Ph2O, 260 C (72% yield)

H O O N Cbz 6 steps O O N H Cbz HO2C HO2C

N 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 R Cl NaO N R S O AIBN, Bu3SnH N S Benzene, 80 C

RH

H SnBu3 NC N N CN CN

Bu3Sn

H SnBu3

O R O N S SnBu3

OH

NaH, CS2; MeI R

S O

SMe

AIBN, Bu3SnH Benzene, 80 C

RCH3

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

O O

O Fatty Acids, Polyketides SCoA

HO HO HO

O O OH OH Glucose O Pyruvic Acid OH

O SCoA Acetyl CoA

O SCoA Alkaloids

HO2C

CO2H HO CO2H

FADH2

NADH

ATP Synthesis

C-C Bond Formation

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

RCHO

O R R' Pd (0) R

O SEt

O R Pd R'

R' = H, R R

O Pd SEt

MSEt O

R'M O

O O

O O

1. 5% PdCl2(PPh3)2 SEt H Toluene, 25 C, 5 min 2. HCO2H (78% yield) IZn O O

O O

tBuO2C

HO2C

Phomoidride B

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
HO Cl N N N NH2 Thiamine (Vitamin B1)
HO S N Cl Ph

HO

S N

Cl Ph

1.30 $ / gram

17% Et3N, EtOH 80 C, 90 min (74% yield)

OH

HO

S N

Cl Ph

O CN

10% Et3N, EtOH 80 C, 16 h (75% yield)

O CN

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 N Cl Ph

O Ph * Ph OH R R' S Ph NBn

S OH N

Cl

HO S R R'

Ph Ph R

S NBn R'

Ph 6% yield 52% ee

NBn O OH S O Ph R R' NBn Ph

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 N I Ph

CN H CO2Me CHO 2.3 equiv

CN H MeO2C O HO2C H

H OH

Et3N, iPrOH, 80 C (67% yield)

(+/-)-Hirsutic Acid

O BzO O

HO

S N

Cl Ph

O O BzO

10% Et3N, Dioxane, 70 C (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 R SMe

nBuLi
THF, -78 C

MeS R

SMe

SMe

nBuLi
S R S THF, -78 C S R S

S R

CH2CH2

SH O R H

SH

BF3Et2O CH2Cl2

nBuLi
S R S THF, -78 C

S R

S R

E+ S R S E

PhI(CF3CO2)2 CH3CN, 25 C R

O E

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

O H R'

O R''

O R'

O 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 (1 equiv) S S THF -78 C -> 25 C (59% yield)

tBuLi, Et2O -78 -> -45 C;

S S BnO (2 equiv) O BnO TBS (2 equiv)

HMPA S S TBS BnO

TBSO

TBSO BnO

OH HO

OTBS OBn

1. Me2C(OMe)2 PPTS 2. TBAF 3. Hg(ClO4)2 2,6-Lutidine (62% yield) BnO

HO

OH OBn

HO

OH

OH

OH

OH

OH

HO HO (+)-Mycoticin A

O O

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.

nBuLi
THF, -78 C S

C-C Bond Formation

Sulfur Ylides Epoxidation, Cyclopropanation
O O A Reagent S O S THF 65 C 0 : 100 Solvent Temperature Ratio (A/B)

O S

NaH DMSO, 25 C O

O S

THF

0 C -> 25 C

87 : 13

O A Reagent S O S DMSO Solvent

O B Ratio (A/B)

Temperature

THF

0 C -> 25 C 25 C -> 50 C

100 : 0 0 : 100

Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364.

C-C Bond Formation

Sulfur Ylides - Epoxidation, Cyclopropanation
Ph2S, AgBF4 I Cl CH3NO2, 25 C (99% yield) Ph2S BF4 Cl NaH THF, 25 C (83% yield) Ph2S BF4

BF4 Ph2S O

KOH DMSO, 25 C (75% yield) O

O Ph2S

BF4

KOH DMSO, 25 C (80% yield)

Eu(fod)3 CDCl3, 37 C O

O NaOH, H2O2 MeOH, H2O, 25 C (Quant.) O

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 BF4 Ph2S O O H KOH DMSO, 25 C (92% yield) O O

1. (PhSe)2, NaBH4 DME, 60 C 2. BSA

(56% yield)

OH TMSO TMSO FVT (610 C) O O (97% yield) O O H 2:1 dr H HO HO H Aphidicolin OH

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* Base PhCH2Br PhCHO Solvent, 25 C Ph

Ph

O Ph PhCHO

Ph *R S R* PhCH2Br

Ph *R S R* *R S

Ph R*

KOH

Ph Ar OH SMe Furukawa 1989 43% ee Dai 1996 42% ee Saito 2001 56% ee Metzner 1999 85% ee SMe OH OH S S O

O HH O

Ph O

H O O S H Ph Ph

Goodman 2002 97% ee

Shimizu 1999 48% ee

C-C Bond Formation

Sulfur Ylides - Epoxidation, Cyclopropanation
R RCHO *R O R' Ph
S

Na S R* MLn Ph N N Ts or PhCHN2

R*2S

LnM Ph

N2

5% O

Na RCHO Ph N N Ts

1% Rh2(OAc)4 10% BnEt3NCl CH3CN, 40 C Trans/Cis 98:2 98:2 75:25 Ph

O R

R Ph Ph

Yield (%) 82 70 46

ee (%) 94 87 89

Aggarwal, V. K. et al. J. Am. Chem. Soc. 2003, 125, 10926-10940.

C-C Bond Formation

Sulfur Ylides - Epoxidation, Cyclopropanation

1. PPh3, H2O 2. K2CO3, O SO2Cl Ph O Cl O Ph S O

h O O

H2, Pd/C/S EtOH (4 steps - 48%) O

Ph Ph S O H O Ph H S H Ph R

SR*2 H

H R

Ph Ph

O R'

H SR*2

SR*2 R

H R

Ph Ph

O 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
BF4 O S OMe O EtP2 CH2Cl2, -78 C;
CHO

OMe O O N trans/cis 70:30 98% ee OMe (85% yield) PhMgBr, CuI THF, -40 C

then

(89% yield) OH OMe O N 1. Et3N, MsCl 2. Zn, HOAc (80% yield) N

CDP-840

20% O O Na Ph N N Ts 1% Rh2(OAc)4 20% BnEt3NCl Dioxane, 40 C (55% yield) EtO2C N O Ph 7:1 dr 91% ee (90% yield) 6N HCl (aq) EtO2C NH3Cl

O CO2Et

Ph

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
1. tBuOCl NH2 2. S O R N H S

3. Et3N Cl OtBu

S N H S O O R N H S N H Et3N S Cl O NH2 R

O R

S R O NH

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

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

TMS O Ph H N H O

TMS OAc Ph O H N H O

S O

TMS 1. Me3OBF4 2. Zn, HOAc (92% yield) Ph H N H O OAc 1. mCPBA 2. CaCO3, Xylenes, 140 C 3. BF3Et2O, HOAc, 0 C O (73% yield) Ph OAc H N Bz O O

SMe

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

R'

iPrOH, CH2Cl2

O S

O Cl HO

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

ArO2S N S O

SOCl2 3,5-Lutidine THF, -45 C (80% yield)

NHSO2Ar OH

ArO2S SOCl2 2,6-Di-tBu-py THF, -45 -> -20 C (82% yield) N S O

Endo/Exo 97:3 1. RMgCl 2. R'MgCl O R' S R

Exo/Endo 93:7 1. RMgCl 2. R'MgCl O R' S 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 OMe 1. 5% Ni(acac)2 Ph3ZnMgCl THF, -25 C 2. Zn, HOAc (90% yield) OMe O CDP-840 92% ee

pTol

S O

O O O S MeO MgBr THF, -78 C MeO

OMgBr MeI, HMPA -78 C -> 33 C (42% yield)

pTol

pTol

O Me2CuLi Et2O, THF, 0 C

pTol

OM BrCH2CO2Me HMPA, 25 C MeO2C

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
O O Ar N MeO2C LHMDS THF, -78 C H (90% yield) MeO2C >20:1 dr; >20:1 Exo/Endo O DBU Toluene, -30 C S O EtO O O O 96% ee O CH2Cl2, -20 C O OEt 4 equiv (47% yield) OEt O O []D -1938 (c 0.006, CHCl3) S (86% yield) O S O H >20:1 dr CO2Et CO2Et MeO2C

pTol O Ar S O
HN

Ar HN

pTol

CO2Et CO2Et O

AcO

pTol
OEt

pTol

pTol

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 LHMDS then NH4Cl S NH2

O S

ArO2S N S O Endo/Exo 97:3

ArO2S 1. tBuMgCl THF, -45 C 2. Li NH3, THF, -78 C (97% yield)

tBu

N NH2

S O

1. tBuMgCl THF, -45 C

O S NH2

tBu

tBu 2. Li NH3, THF, -78 C

(90% yield)

Exo/Endo 93:7

0.25%
tBu

N OH

OH

tBu

tBu

tBu

0.25% VO(acac)2 H2O2, 20 C

tBu

tBu

LiNH2 NH3, THF, -78 C (2 steps - 78% yield)

tBu

NH2

91% ee

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
O CuSO4 RCHO N R (79 - 100% yield) Ti(OEt)4 RCOR' NH2 (63 - 89% yield) tBu O S N R' R

tBu

tBu

H N R

H R'MgBr Et2O, CH2Cl2 -48 C

H R' N H R

tBu

tBu S N

R Mg O R'

tBu

HCl MeOH

H R' H2N R HCl

R Et Et Et Ph

R' Me iPr Ph Me

dr 93:7 98:2 96:4 97:3

Addition Yield (%) 96 97 Quant. 96

Cleavage Yield (%) 97 92 90 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' N R Me3Al, Toluene then R"Li, -78 C S

tBu

tBu S N R O Li R'' AlMe3

O R' S tBu N H

R'' R

HCl MeOH

R'

R''

H2N R HCl

R' Me Me

R''

dr 99:1 97:3 91:9 95:5

Addition Yield (%) 61 93 82 89

iPr iPr iPr

CH2OTBS

nBu
Ph Me

nBu
Me

nBu

2.5% [Rh(OH)cod]2 5% dppbenz Et3N (2 equiv) N KF3B DMF, H2O, 60 C (72% yield)

H N H 98:2 dr

tBu

tBu

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 CO2Et F3B O N BF3 tBu

PhMgBr BF3Et2O N CO2Et THF, -55 C (70% yield)

Ph N H CO2Et

tBu

tBu

HCl EtOH

Ph H2N CO2Et HCl

84:16 dr

Et2AlCN N Ph iPrOH, THF (56% yield)

tBu

O NC Me S tBu N Ph H 12:1 dr

6N HCl 100 C (64% yield)

HO2C Me H2N Ph HCl

tBu
O OTi(OiPr)3 N Ph OMe THF, -78 C (81% yield) MeO Ph O S O Ti N O Ph S tBu N H O OMe

tBu

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
LiBEt3H (2 equiv) THF, -78 C S O HN OH Ph 99:1 dr

tBu
N Ph S O LDA, MgBr2 THF, -78 C; C2H5CHO (84% yield) Ph

tBu
S O N OH

(69% yield)

O 96:4 dr O (2 equiv) THF, -10 C (95% yield) Ph 95:5 dr BH

tBu
S O HN OH

Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518-6519.

C-C Bond Formation

Chiral Sulfinamides

tBu
N N O (82% yield) S O KHMDS THF, -78 C; N Br O N

tBu
S O MeLi, CeCl3 THF, -48 C (82% yield) >20:1 dr

tBu
N S O 2% Grubbs II CH2Cl2, 40C (87% yield) N

tBu
S O

1. Me3Al Toluene, -78 C;

Li

HCl H2N

2. HCl, MeOH, 25 C (49% yield) >20:1 dr (6R,7S)-7-Amino-7,8dihydro--bisabolene

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

Olefination
Julia
R SO2Ph 1. nBuLi; R'CHO 2. Ac2O 3. Na/Hg, MeOH R R' -AcO

nBuLi; R'CHO

OH R Ac2O R' SO2Ph R

OAc Na/Hg R' O S O R

OAc OAc R' Ph -PhSO2 R R' Na/Hg OAc R R'

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

NaHMDS HMPA; R'CHO

R'

-SO2; -ArO

O O N N N N

S O O N N Ph N N

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

Olefination
Julia
Ph HO N SH H H H O 1. PPh3, DEAD THF, 25 C 2. H2O2, (NH4)6Mo7O24 EtOH, H2O (82% yield)

N N N

N N N N

Ph H S O O H H O

OTBS OTBS O TBDPSO CHO LHMDS DMF, HMPA -35 C -> 25 C

OTBS OTBS O TBDPSO H H O CO2H

OH OH O H H O

H (+)-Ambruticin

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

Olefination
Ramberg-Backlund

O KOtBu THF

I O

S O O

S O X-Ray

O S O Cl

NCO2tBu

KOtBu DMSO, 25 C 10 min 97% yield)

NCO2tBu

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 N Ph S Ar P S N Ph S O Ar P S O S P Ar S Ar O MeO P S S P OMe Toluene 110 C N Ph O P S

S 92 / gram

N Ph

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

CO2Me

Ph3P=S DABCO

N Bn

S CO2Me

N Bn

S CO2Me

S N Bn 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 O O O O H (78% yield) H H S O O O S H O Lawesson's Reagent Toluene, 110 C O H S O O S H O 1. NaNaphthalenide THF, -78 C 2. MeI -78 C -> 25 C (80% yield) H AIBN, Bu3SnH Toluene, 110 C O (99% yield) BnO H O H H O OTIPS H O O

O H

O O O O H

O O

O H H Brevetoxin B

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 OH 1. (Im)2C=S 2. P(OMe)3 (75% yield) P(OMe)3 O S O O P(OMe)3

O S O

P(OMe)3

O O

P(OMe)3

OH OH O O N OH 1. (Im)2C=S, Toluene 2. TBSOTf, pyr, CH2Cl2 2. P(OMe)3 (3 steps - 76% yield) O O N

OTBS 1. H2, Pd/C, EtOAc 2. TFA (aq) HO (83% yield) HO

OH

(+)-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 Cl Na2CO3 100 - 150 C CHO

H O S O S

NO2

NO2

NH2 N O
-O

N N

N H O H H OH H H

P O O-

Br O DMSO, DBU pH 4.5 25 C, 12 h (62% yield) O O

NO2 O
-O

N N H O H H OH H H N

P O O-

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 CH2Cl2, -78 C -> 25 C

RCHO

O O S Cl O Cl R H O S

R O O S Cl O Cl

OH Cl S R O

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

P(OMe)3 MeOH

OH

Ts

pTol

Ts N

Na Cl

pTol

pTol

Ts

HO HO HO

nBuLi;
PhSCl HO O S Ph

HO LiNEt2 S Ph HMPA, THF; MeI

O S Ph Me2NH H2O

HO

HO

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
O Ph S CO2Et OAc Ac2O Ph S H CO2Et OAc Ph S CO2Et Ph S CO2Et OAc

AcO

RO

TBHP Ti(OiPr)4 (+)-DIPT OH (92% yield)

RO

O OH

NaOH, PhSH H2O, tBuOH (71% yield)

OH RO O RO

OH SPh OH RO

DIBALH RO POCl3 O Me2C(OMe)2 O SPh 1. mCPBA, -78 C 2. Ac2O, NaOAc O O K2CO3 MeOH, 25 C (100% yield) O O RO CH2Cl2, -78 C OAc SPh RO (91% yield) O O

CHO

(D)-Hexoses

CHO

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
DMTSF
MeS SMe OTMS DMTSF (2 equiv) CH2Cl2, -20 C -> 0 C O S S S SMe OTMS H O S S S S S (63% yield) S

S BF4 DMTSF

TMSO

TMSO

MeS

SMe

S BF4

TMS

CH2Cl2, 25 C

Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529-6530.

Functionalization
DMTSF
S

S BF4 DMTSF

O SPh SPh

Li THF, Et2O, -100 C 2. TMS-Imidazole (92% yield)

1.

TMSO SPh SPh DMTSF CH2Cl2, -78 C (80% yield)

O O AcO H SPh H H Shahamin K H H O

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

Functionalization
DMTSF

S SMe NH2 [Me2S-SMe]BF4 NH4OH CH3CN, H2O, 25 C (92% yield) CH3CN, 25 C (94% yield) SMe OH [Me2S-SMe]BF4 NaHCO3 CH3CN, H2O, 25 C (92% yield) [Me2S-SMe]BF4 1-heptyne nBuLi, Me3Al DCE, THF, 80 C (88% yield) O then iPr2NEt, 25 C (72% yield) CN Episulfonium [Me2S-SMe]BF4 NaCN

SMe

SMe

SMe

[Me2S-SMe]BF4 DMSO;

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 MeO PhS Toluene 110 C (75% yield) MeO PhS

OAc SO2Ph CO2Me Toluene 110 C (65% yield)

OAc SO2Ph CO2Me 6:1 endo/exo

5:1 regioselectivity

Br LHMDS O S O THF, -78 C (57% yield) O S O Toluene, 110 C (80% yield)

O ZnCl2 CH2Cl2, 25 C (63% yield)

18 / gram

H BF3Et2O Toluene H O (63% yield)

H 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 5 steps HS CO2Me (26% yield) O S O

O (1.2 equiv) CH2Cl2 15 kbar, 25 C

O O O S Raney Ni EtOAc, 78 C (63% yield - 2 steps)

O O O

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 2. POCl3, py (90% yield) O S DMSO (75% yield) O S

S O

1. sBuLi, TMEDA THF, -20 C 2. POCl3, py (90% yield)

sBuLi, TMEDA THF, -50 C;

Cl

OLi

(90% yield)

S OH

Li EtNH2, -70 C

SH

SH OH

1. Raney Ni 2. H2CrO4 3. CH2N2 (55% yield) CO2Me

CO2Me (+/-)-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 NH2 MeO2C Cl N S Cl MeO2C OH N S 20 steps MeO MeO O S

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

MeO NHAc MeO MeO O MeO (+/-)-Colchicine

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

Allium Chemistry
Garlic

B O S H NH2 CO2H NH2 CO2H

Alliinase

OH S S HO (sulfenic acid)

SN2

O S

H S

Alliin (allylic sulfoxide)

O S S

OH S S

[4+2]

S S

Allicin (thiosulfinate ester) antibiotic

(thioacetal) platelet aggregation inhibitor

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

Allium Chemistry
Onion
O O S S ((Z)-sulfine) onion lachrymator factor [3+2] S O O S O S (thiosulfonate ester) non-lachrymator

O S

H H NH2 CO2H NH2 CO2H

B O S S HO SN2 O S H S

Alliinase

Isoalliin (vinylic sulfoxide)

(sulfenic acid)

S [2+2] S O trans-zwiebelane

O S

O [3,3] S S O S [Ox] S

O O S S (thiosulfonate ester) smell of raw onions

(thiosulfinate ester) (thioaldehyde-sulfine)

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

Organosulfur Compounds

O CH3SH methylmercaptan (natural gas additive) MeS SMe S O SH 1-p-menthene-8-thiol (grapefruit) O HN H S biotin NH H CO2H Ph O O penicillin G (antibiotic) H2N SO2NH2 sulfanilamide (antibiotic) H N H S N CO2H O S N O N Viagra (erectile dysfunction) EtO HN O N N NH O

bis(methylthio)methane (black truffles)

saccharin (sweetener)

Summary

Nomenclature Elimination Radical Reaction C-C Bond Formation Olefination Oxidation Functionalization Allium Chemistry