NEW ORGANIC CHEMISTRY BASED ON

THE PERICYCLIC REACTION OF SULFUR DIOXIDE

Total Asymmetric Synthesis of Polyketides and Analogs of

Biological InterestSpongistatinsOxo-polyene antibiotics (1,3-polyols)Ryfamycin S, Baconopyrone,ApoptolidinPolypropionates via new organic

chemistry of sulfur dioxide

Pettit, G.R. et al. JOC 1993,58,1302

Kobayashi. M, et al. Chem. Pharm. Bull.1993, 41, 989

GI50 = 0.15 nM(inhibition of tubulin polymerization,

multidrug-resistant cancer cells)

macrolactonisation

Aldolisation

Wittig

D

C

B

A

F

E

O

O

O

O

O

O

Cl OHO

OAc

O

AcO

OH

HO

OH

OH H

HO

OMe

O

H

OH

Fusetani, N. et al. JACS 1993, 115, 397750 % inhibition of cellular growth:GI50: 0.03 nM (lung cancer cells)

Spongistatin 1 (Altohyrtin A)

Total SynthesesKishi, 1998 29 0.27 % 33 0.25 % 36 0.01 %

Eastern part Western part Total

Evans, 1999 21 5.2 % 21 10 % 32 0.9 %

Paterson, 2001 28 23 % 20 17 % 33 1 %

Smith, 2001, a: 39 1 % 31 0.3 % 44 0.1 %b: 22 4 %

Spongistatin 1: 23 stereogenic centersAbsolute and rel. configuration: Kitagawa, 1994Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243

Gerber, 2000 20(11) 2 %

Crimmins, 2002: other strategy, longest linear chain synth.: 36 0.1 %Nakata, 2003: formal synth. of Spongistain 2 ; Heathcock, 2003

Synthesis of the pyranose F-ring

S. Gerber-Lemaire, P. Vogel., J. Org. Chem. 2000, 65, 3346

O

O

MOMO

H

CO2Et

OH

MOMO

E

MOMO

OMOM OBn

E

OBnHO OBn

1. Swern2. (EtO)2P(O)CH2CO2Et

LiBr, NEt3, MeCN, RT80%

1. AD-mix β

2. MOMCl, iPr2NEt85%

syn / anti = 80 / 20

E

MOMO

OMOME

E = CO2Et

1. OsO4, NMO

2. HCl, THF96%

71%

46%

O

O

MOMO

HOH

MOMOCO2Et

OMOMO

H

CO2Et

OH

MOMO

OH

DIBAL-H

CH2Cl2, -78°C

80%

72%

O

OTBS

MOMO

H

CHO

OTBSMOMO

1. protection

2. reduction

HO OBn

13 steps, 27% overall yield

isolation of 5 intermediateproducts only

Synthesis of F-Ring

Synthesis of the methyl ketone

S. Gerber-Lemaire

OHC(CH2)4OPMB

O

C4H8OPMB

OTES

90%

MeMgCl, 0°CN

MeOO

C4H8OPMB

OTES

73%

68%2. TESCl, imidazole

THF, 0°C1. AlMe3, MeONHMe.HCl

NO

O

Bn

O

C4H8OPMB

OH

-78°C to 0°C

2.

NEt3, 0°C

1. Bu2BOTfNO

O

Bn

O

diastereoselective aldol

4 steps45% overall yield

O

OTBS

MOMO

HOTBS

MOMO

O OTES

C4H8OPMB

OTES

O

OTBS

MOMO

HOTBS

MOMO

OAc O

C4H8OPMB

OH

1. Et2BOMe-78°C

de > 95 / 5

O

OTBS

MOMO

HOTBS

MOMO

OAc O

C4H8OPMB

OTES

75%DMAP cat., 0C

3. Ac2O, pyridine

2.

1. LDA, -78°C

O

OTBS

MOMO

H

CHO

OTBSMOMO

O

C4H8OPMB

OH

HF.pyridine, -10°C90%

2. NaBH4OAc OH

C4H8OPMB

OH

80%56%

S. Gerber-Lemaire

OH

SiMe3

Cl

O

OP

PO

HOP

PO

O

C4H8OR

OPOP

F E

C-glycosidation

Introduction of the trienic side chain

CO2MeCl2, CHCl3, 0°C

selective chlorination70%

CO2MeCl

Cl

1. DIBAL-H, -78°C2. Dess-Martin

65%

CHOCl

Cl

Me3Si

Ph3Sn

Ti(OiPr)4, (S)-BINOL60%

ee = 90% (Mosher's esters)

Cl

Cl

OH

SiMe3

DBU, THF, 60°C

Cl

OH

SiMe3 allylsilane for the final C-glycosidation

absolute configuration proved by transformationinto L-(-)-malic acidchloro-diene moiety

O

OTBS

MOMO

HOTBS

MOMO

O OTES

C4H8OPMB

OTES O

OTBS

MOMO

HOTBS

MOMO

O

OAcOMe

C4H8OPMB

1. HF.pyridine

2. CSA, MeOH

77% 1. TBAF 1 eq, -30°C2. Ac2O, pyridine

O

OAc

MOMO

HOTBS

MOMO

O

OAcOMe

C4H8OPMB

75%

1. TMSOTf, -10°C, CD3NO2

Cl

Cl

OP

SiMe3

2.

3. DBU, THF, 50°C

OMOMO

HOTBS

MOMO

O

OAcOMe

C4H8OPMB

PMBzO

Cl

42%

α / β = 1 / 4

then Ac2O,pyr

S. Gerber-Lemaire

20 steps2% overall yield11 isolatedintermediates

S. Gerber-Lemaire,P. Vogel, J. Org. Chem.

2000, 65, 3346-3356

HO OBn

O

OTBS

MOMO

H

CHO

OTBSMOMO

NO

O

Bn

O

O

C4H8OPMB

OTES Cl

Cl

OH

SiMe3

CO2Me

OMOMO

HOTBS

MOMO

O

OAcOMe

C4H8OPMB

PMBzO

Cl

13 steps27 % yield 4 steps

45% yield

4 steps40% yield

Spongistatin 1 (Altohyrtin A)

Pettit, G.R. et al. JOC 1993,58,1302

Kobayashi. M, et al. Chem. Pharm. Bull.1993, 41, 989

GI50 = 0.15 nM(inhibition of tubulin polymerization,

multidrug-resistant cancer cells)

macrolactonisation

Aldolisation

Wittig

D

C

B

A

F

E

O

O

O

O

O

O

Cl OHO

OAc

O

AcO

OH

HO

OH

OH H

HO

OMe

O

H

OH

Fusetani, N. et al. JACS 1993, 115, 3977

50 % inhibition of cellular growth:GI50: 0.03 nM (lung cancer cells)

O

O

O

O

PO

OH

1

5

7

13

O

SeArOHOH OH

O

HO

OH

1

37

11 13

A

B

SeArOP'OP OP

P'O

OP

P'O

OP OP

OP'O

O O

O

Retrosynthesis for AB spiroketal

- double chain elongation startegy from meso bis-bicyclo adducts- molecular diversity to produce a large number of analogues

O O

O O

OOH O O

OCl

Cl

Cl

ClO+ threoCF3COOH

0oC, 24 h(70%)

1. Et3N, (CF3)2CHOH2. Cu/Zn/MeOH 20oC, 4 d (55%) :

OAc

PMBzO

OAc

OPMBz

OAc

PMBzO

OAc

OPMBz

Cl Cl

1. BCl3, CH2Cl2, -10oC2.

pyr. DMAP

MeOCl

O

Bu3SnH, AIBNtoluene, 80oC(100% meso)

(85%)

Long-Chain 1,3-Polyols from Furan and Furfurol

M.-E. Schwenter

OAc OAc

O O1. recrystallization from furan (erythro/threo 4:1)2. K-Selectride, THF, -78oC, 12 h3. Ac2O, CH2Cl2, DMAP, 20oC, 24 h

Desymmetrization: Sharpless DH

OAc

PMBzO

OAc

OPMBz

OAc

PO

OAc

OP

OHOH

+AD-mix-β, K3Fe(CN)6

K2CO3, (DHQD)2PHALK2OsO4⋅2 H2O

t-BuOH/H2O/MeCNMeSO2NH2

80% (e.e. 98.4%)

OAc

PO

OAc

OP

OHOH

+ ent.

20%

OHOH OPMBz

OPMBz

OH

OH

OHOH OPMBz

OPMBz

OH

OH

Et2BOMe, NaBH4THF, MeOH, Nasaraka

Me4NBH(OAc)3, AcOH20oC, 90 min, Evans

OO OPMBz

OPMBz

OH

OH

H

HO

OPMBzO

O

OPMBz

OH

1. Mg(OMe)2, MeOH2. NaIO4, dioxane H2O, 20°C, 15 h (74%)

M.-E. Schwenter

OH

OHOH OPMBz

OPMBz

OH

OH

OTIPSO OPMBz O O

OTIPSO OPMBz

OPMBz

O

OH

1. Me2C(OMe)2 PPTS2. TIPSCl imidazole DMF, 25oC (95%)

OOPMBz

1. NMO, OsO4 acetone, H2O, 20oC2. Pb(OAc)4, PhH 20oC (82%)

Bu4NBH4AcOH/MeCN

-50°C

OTIPSO OPMBz O OH

OH

OPMBzOH

anti,anti,syn,anti,anti-Pentadeca-1,3,5,7,9,11,13,15-octol

M.-E. Schwenter, P. Vogel, Chem. Eur. J. 2000, 6, 4091-4103

OOH OPMBz

OPMBz

O

OH

"Evans"

OTIPSO OPMBz O OH OPMBzOH

"Mitsunobu"

OTIPSO OPMBz O OP OPMBzOP

OP

OH

OOPMBz OH

OPMBz

O

OH

DBU, MeCN

80oC (70%)

"Mitsunobu"

OOPMBz OP

OPMBz

O

OH

"Evans"

OOPMBz OP O OH OH OPMBz

OH

Other Pentadeca-1,3,5,7,9,11,13,15-pentols

Vogel,P.; Gerber-Lemaire, S.; Carmona, A. T.; Meilert, K.T.; Schwenter, M.-E.; Pure Appl. Chem. 2005, 77, 131

Yield: 30% (98% ee) 10% (80% ee) 40% (98% ee)

+ +

(±)-threo (±)-threo

KBH(i-Bu)3

THF (95%) Candida cylindracealipase (2.4 U/mg)

OAc pure

O O

O O

Enzymatic Resolution

OH OH

O O

OH OH

O O1

3

5

OH OAc

O O

OAcOAc

OO

A. G. Csaky, P. Vogel, Tetrahedron Asymmetry 2000, 11, 4935-4944

Long-chain polyketides quickly with high stereodiversity ?

O O

O O

O O

OH OHKBH/i-Bu)3/THF endo/exo > 99:1 (> 95 %)SmI2/THF < 1:99 (> 60 %)

1.Ac2O/py

2. BCl3/CH2Cl2, - 10 oC3. BOM-Cl, Et3N, CH2Cl2

(60 %)

OAc OAc

BOMO

Cl Cl

OBOM

O

BOMO

OH OH OHOH

OH

OBOM

K. Meilert, S. Gerber-Lemaire

4. Me2NBH(OAc)3/ AcOH, 20 Co

1. Bu4SnH, AIBN/PhMe2. K2CO3/MeOH3. ozone, -78 C, Me2S4. Et2BOMe/THF/MeOH, NaBH4, O Co

o

O

BOMO

OH OH OHOH OBOM

OH(60 %)

Bu4NF, THF - 20 (100 %)

camphorsulfonic acid

oC

dec.

Sandrine Gerber-Lemaire

BOMO

OH

OBOM

OH

1. Et3SiCl, imidazole, DMF, 0 2. O3, CH2Cl2, - 78

oC

oCoC

3. Me2S 4. NaBH4, - 78 to - 10 ( 88 %)

O O

OH OHOTESTESO

OBOMBOMO

40 % aq. HFMeCN, - 10oC

( 60 % )O

OO

OH

OBOMBOMO

OH

O

OO

OH

OBOMBOMO

OH

OO

OBOM

OH

OBOM

OH

SEt

SEt1. 40 % aq. HF MeCN, - 40 C

2. BBr3, EtSH, CH2Cl2, 0 C

o

o

1. TBSOTf (1 equiv.) 2,6-lutidine, - 40 C (90 %)

o

2. Ac2O/Pyr, DMAP, 0 C (91%)

oO

O

OBOM

O OBOM

OTBS

OAc

Gerber-Lemaire, S.; Vogel.; Eur. J. Org. Chem. 2005

macrolactonisation

Aldolisation

Wittig

D

C

B

A

F

E

O

O

O

O

O

O

Cl OHO

OAc

O

AcO

OH

HO

OH

OH H

HO

OMe

O

H

OH

Spongistatin 1 (Altohyrtin A)

Can we do more ?

OH OH OH OH

O

O

OH

OH

OH

OH

1

13

27 17

Mycoticin A

Synthesis: Poss, C.S. ; Rychnovsky, S.D. Schreiber, S.L. JACS 1993, 115, 3360

OPMB

SO2Ph O O O O O

O

O

O

TBSO

H

O

OEt

OP(O)(OEt)2

Osada,H.;Kobinata,K.;Koshino,H.;Kudo,T.;Isono,K. J.Antibiot.

1993, 46, 1616Total Synthesis:

S.A.Burova,F.E.McDonald

JACS 2004,126,2495(C.Schneider et al.Synlett 2002, 2098)

OEt

OP(OEt)2O

OPMB

SO2Ph

OO O OO O O

OMe

OP

O

OH OH OHOH OH

O

O OH

RK-397OH

OH

O O

O O

O O

OH OH

THFSmI2

OAc OAc

BOMO

Cl Cl

OBOM2. BCl3/CH2Cl2, - 10 oC3. BOM-Cl, Et3N, CH2Cl2

(60 %)

1.Ac2O/py

1. Bu4SnH, AIBN/PhMe2. K2CO3/MeOH3. ozone, -78 C, Me2So

4. Me2NBH(OAc)3/ AcOH, 20 Co BOMO OH OHOH O

OH

OBOMHO

synanti

S. Gerber-Lemaire, A. T. Carmona-Asenjo

idem

5. NaBH4,MeOH r.T. (65 %) BOMO OH OHOH OH

HO

synantiOBOM

OH

BOMO OH OHOH OH

HO

synantiOBOM

OH

A. T. Carmona-Asenjo

kinetic resolution

homochiral allylationagent OBOM

O OO O OBOM

O

OH

BOMO O OO O

HO

OBOM

OHMe2C(OMe)2

TsOH

BOMO O OO O

O

OBOM

OSwernoxidation

New C-C Forming Reaction basedon Umpolung with Sulfur Dioxide

R

OTMS+

SO2 in excessLewis acid catalyst

CH2Cl2- 100 to -78 Co

R

O OR*B. DeguinJ.-M.RouletV.NarkevitchS. MegevandX. HuangM. TurksC. Craita

Polypropionate Fragments with three New Contiguous Stereogenic Centers in One-pot Operation

R*O

oC

The Expected Cheletropic Additions of SO2

OSiTBS

MeO

OSiTBS

MeOSO2

SO2

SO

O+ SO2

oC

+ 20

B. Deguin, P. Vogel, Tetrahedron Lett. 1993, 34, 6269

- 40

OSiTBS

MeO+ SO2excess)

OSiTBS

MeOS

O

O

The Unexpected Observation: Hetero-Diels-Alder Cycloaddition of SO2

- 50 oC

(

One single diastereomer

OMe

+ SO2S

O

OMe

O

LA LA

S

OLA

OMe

O

-

+

Ph

OSiMe3

OMe

Ph

O

SO2SiMe3

Oxyallylation of Ketones

Deguin, B.; Roulet, J-M.; Vogel, P.Tetrahedron Lett. 1997, 38, 6197

The reactions of silyl sulfinates

Ph

O OMe

Ph

O OMe

SO2NBu4

TBAF

SO2SiMe3

B.Deguin, J.-M. Roulet, P. Vogel, Tetrahedron Lett. 1997, 38, 6197J.-M. Roulet, G. Puhr, P. Vogel, Tetrahedron Lett. 1997, 38, 6201

Ph

O OMe

SMe

OO

S-Alkylation

+ MeI

Ph

O OMe

Ph

O OMe

SO MeO

two diastereomers

O-Alkylation NH4Cl/H2O

SO2H

CH2N2Ph

O OMe

+ SO2Retro-ene

One-pot, four-component sulfone synthesis

OSiMe3

R BnO SO2C

C

C

O OBn Me

R

+ +

1. Yb(OTf)3/CH2Cl2 , - 80o

o

2.Bu4NF, THF, -80 to 0o3. + Electrophile, 0 to 35

βε

SO2 NBu4

+ R'X

SO2R'

O OBn Me

R βε

Br BrBr

Cl

EtO C CH2

OBrMeI

E.g.:

R = Ph 45 50 49 52 82 %

R = Me 70 62 52 30 49 %

Huang, X.; Vogel, P. Synthesis 2002, 232

L. Bouchez, S. Reddy Dubbaka, X. Huang, J .Org. Chem. 2004, 69, 6413

Z

Y

R

SiMe3

+ SO2 +

R4

X

OR*

R2 LA

CH2Cl2/SO2

Z

Y

R

X

OR*

R2

SO2SiMe3R4

Z

Y

R

X

OR*

R2

SO2NR"R'R4Cl2 or NCSor Br2 or NCS

HNR"R'

X = H, OCORY = H, alkyl,arylZ = O, CH2R = H, MeR2, R4 = H, alkyl

One-pot, Four-component Synthesisof Polyfunctional Sulfonamides

+ CO

R-CO-R'

Stille cross-couplings of sulfonyl chlorides

R-SO2Cl + R'SnBu31.5 mol % Pd2dba3, 5 mol % (2-furyl)3P10 mol % CuBr.Me2STHF, reflux, 2- 4 h.

R-R' + SO2 + ClSnBu3

R' : aryl, heteroaryl, alkenyl, glycal-1-yl

Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15295

R-SO2Cl + R'B(OH)21.5 mol % Pd2dba3, 6 mol % ligand LNa2CO3, THF, reflux, 15 -35 h.

R-R' + SO2 + Na3BO3 + NaCl

R' : aryl, heteroaryl, alkenyl,

Suzuki-Miyaura Cross-couplings of Sulfonyl Chlorides

L : N N

HCl

ArN2X ArSO2Cl ArBr ArClArI

Dubbaka, S. R.; Vogel, Org. Lett. 2004, 6, 95

RSO2Cl + ArCH=CH2

[RhCl(C2H4)2]2 (1 mol %)m-xylene, reflux, 60 h

RAr + SO2

Phosphine- and Base-free DesulfitativeMizoroki-Heck Coupling

Dubbaka, S. R.; Vogel, P. Chem. Eur. J. 2005, 11, to appear

Stereoselective retro-ene elimination

SO2HO OH

O

H

Me

H

SOH

OMe

HO

O OHε

βγβ

β,γ-anti

J.-M. Roulet

HMe

Hypothesis of Mock and WeinrebCf.: J.Org. Chem. 1978, 43, 3433; Tetrahedron Lett. 1983, 24, 987Baudin, J. B.; Julia, S. Bull. Soc. Chim. Fr.1995, 132, 196-214

OSiMe3

Ph

ORPh OR OSO2 excess

catalyst / CH2Cl2

1.

-100 to -70 oC MeOH/NH4Cl2.

0 - 20 oC

+

chiral hplc

Cat.: BINOL + BCl3; BINOLateTiBr2, BINOLateYbOTf; TADDOLateTiClCpE.e.: 0 6 8 0 %

Cat.:BO

NR

PhHPh

N B

O

O

O2S Ar

)2BCl

((-)-Ipc)2BCl

E.e.: 0 0 15 %

*

Attempted asymmetric oxyallylations induced by homochiral Lewis acid catalysts

J.-M. Roulet, G. Puhr, P. Vogel, Tetrahedron Lett. 1997, 38, 6201

Oxyallylation of Enoxysilanes with only one Face:Three New Stereogenic Centers Stereoselectively in One-pot

O

OSiMe3BnO

+

OTBS

SO2/TBSOTf, -

MeOH/NH4Cl,

O

O

H

BnO

OTBS

**

*

oCoC

1.

2.

78

20

α,β-syn-Diastereoselectivity

OR*

+

OTMS 1. SO2, CH2Cl2,(CF3SO2)2NH

- 100 to - 78 oC2. Bu4F3. MeI

(85 %)

OSO2Me

OR*

major (X-Rays)

OTMS

OR*

+

OSO2Me

OR*

OSO2Me

OR*

idem +

ratio: 14/1

(X-Rays)

R* =H Me

V. Narkevitch, P. Vogel, K. Schenk, Helv. Chim. Acta 2002, 85, 1674

SO2SiMe3

H

HH

Me

Me

R

HO

Me

O

Me

Ar

H

(S)(R)

(S)

α,β-syn

α,ε-syn

S

H

H H

Me

Me

O

OLA

R HO MeMe3Si

O

H Me

Ar

β,ε-unlike

α,β-syn

MODEL: WORKING HYPOTHESIS

OR* OHOH OO

Rifamycin S

OR* OH OOO

TMSO OR' O+

O

ArH(R)

OO OR'O

Ar

H(S)

+OTMS

OHO

OO

O

NH

O

OMe

OHHOAcO

O

Make polypropionate fragments adding three contiguousstereogenetic centers in one single operation.

1. SO2•ΤΜSOTf-100°C

OSiMe3

OR*

+

silyl enol ether

Repeat ?

RifamycinWith the Greene’s chiral auxiliary

75 %, 4:1

OSO2TMS

OR*

αβ

Pd(OAc)2, Ph3P,K2CO3, MeCN,i-PrOH, 90 Co

X. Huang, C. Craita

It fails !

OR' O OR* OH

OH

O OR*

αβ

O OR*

αβ

OR R* : (R)-PhEtR : (S)-PhEt

But:

C. Craita, X. Huang

Sterichindrance

of MeOR

OTES OR*

αβ

+SO2

TBSOTf(60 %)

H

H

Combine with Mukaiyama cross-aldol reaction

H

BnO O BnO OH OOPh

OBzTiCl4, DIPEA

-78°C(57 %)

+

OSiMe3

OPhBzO

+

(S)

OOOBz

Ph

Tf2NH, -80°C

Pd(OAc)2, PPh3

CH3CN, i-PrOHd.r. 5:170%

CH2Cl2, SO2

O O OOBz

O1. Me4NBH(OAc)3, CH3CN, 78%

2. an. FeCl3, CH2Cl2, 0°C; dimethoxypropane, CH2Cl2, p-TSA, 0°C, 80% O O OO OH1. O3, ether, -78°C

2. BH3 Me2S, -78°C

80%

Nagaoka,H.; Kishi,T. Tetrahedron 1981, 37, 3873Chênevert,R.; Rose, Y.S.

J. Org. Chem. 2000, 65, 1707

Turks, M,; Huang, X.; Vogel, P.Chem. Eur. J. 2005, 11, 465

aldol

SO2 Umpolung

Isolated from SiphonariaBaconi

Manker,C.D,;,Faulkner,D.J.; Stout,J.T.; Clardy,J.

J. Org. Chem. 1989,54, 5371

O

AcylOPh

OTMS

OHMe

O

Me

MeOH

Me

+

OO

OHO OH O O

O

Rbaconipyrone A , R=Mebaconipyrone B, R=H

Maris Turks

O Ph

Et

i-PrCOO OPh

O

O

Tf2NTMS or Tf2NHSO2, -78°C

Et

O SiMe3

O Ph

O

i-Pr-COO SO2SiMe3

Et

i-PrCOO OPh

O1

23

4

O

Pd(OAc)2Ph3P

67 % 13 %

K2CO3MeCN,i-PrOH

OHMe

O

Me

MeOH

Me

Et

i-PrCOO O

Ph

O

1. Bu3SnOMe, 70 C ( 86 %)2. H2; Pd/C (100 %)

o

12

34

Turks, M.; Murcia, M.C.; Scopelliti, R.; Vogel, P.Org. Lett. 2004, 6, 3031

Me

H

H

Me

H

O

O O

Me

Bu3Sn

PhH

Me

OTMSOTMS

1. SO2, CH2Cl2,TBSOTf

CMe + - 100 to - 78 o

2. Bu4F3. 2,6-(NO2)2C6H3F

(85 %)

Et

O OHSO2Ar

(X-Ray)

αβ

ε

unlike

(Z)

Et

O OH

SO2

NO2

NO2

αβ

ε

like

(CF3SO2)2NH

(E)(62 %)

Role of the acid promoter and of the enoxysilane

Bouchez, L. C.; Craita, C. Org. Lett. 2005, 7

OTMSR

OTMS

R

O OHSO2SiTMS

αβ

ε

(Z)

OTMS

TMSOTfor Tf2NH

with Tf2NH only

OTMS

S

H

H

O OH

NTf2

OTMS

S

H

TMSO

O OH

NTf2

MeHR

TMSO

R

R

O OH

SO2TMSαβ

ε

(E)

OTMS

R

OTMS

R

OSO2R'

(Z)

1. SO2, TBSOTf2. Bu4F, R'X

3. TfOH

(0ne pot)

+

1. SO2, Tf2NHR

O

SO2R'αβ

ε

(E)

(E)

(E)2,3. idem

Stereoselective synthesis of (E,Z)- and (E,E)-2,4-dien-1-ones

Bouchez, L. C.; Craita, C.; Vogel, P. Org. Lett. 2005, 7

O

OH

O

O

O

HOO

HO H

OH

OMeO O

HOO

O OH

OMe

O

OH

MeO

HO

Apoptolidin

1

9

13

the top 0.1 % of most selective cytotoxic agents (NCI/NIH)http://dtp.nci.nih.gov

Isolated from Norcardiopsis sp.: Hayakawa et al. J. Antibiotics 1997, 50, 628.

Total Synthesis:Koert et coll. Tetrahedron Lett. 2000, 41, 621;

Angew. Chem. Int. Ed. 2001, 40, 2063;Angew. Chem. In. Ed. 2004, 43, 4597.

Nicolaou et coll. Chem. Commun. 2000, 307, Angew. Chem. Int. Ed. 2001, 40, 3849;

J. Am. Chem. Soc. 2003, 125, 15433; 15443.Sulikowski et coll. Org. Lett. 2000, 2, 1439;

Angew. Chem. Int. Ed. 2004, 43, 6673.Fuchs et coll. Org. Lett. 2002, 4, 3571.Wender et coll. Org. Lett. 2003, 5, 487, 2299.

See also: Toshima et al. Tetrahedron Lett. 2001, 42, 8873;

Loh. T.-P. Tetrahedron Lett. 2003, 44, 4997;

Paquette & coll. Org. Lett. 2004, 6, 103.

Me

OH

MeOHO

O

O

MeMeSO

MeO

ODS

OMeMe

OH

OHMe

Me

9

27

apoptolidin

Me

OH

MeOHO

O

O

MeMeSO

MeO

ODS

OMeMe

OH

OHMe

Me

9

27

apoptolidinY.Hayakawa et al. JACS 1998, 120, 3524C. Khosla et al. Chem. Biol. 2001, 8, 71

Me

OR

MeMe

OMe

OR'

O2SPO

L. Bouchez

++ SO2 +TBSO

I OTBS

X

TBSO

Me

Me

MeMe

OMe

OTBS

O2S

(62 %)

1. HNTf2, - 84 10 h.2. TBAF,HMPA

o

OTBS1. NaOH / Br2 dioxane/H2O

2. t-BuLi (3 equiv.), - 100 , THF 3. NCS (2 equiv.) - 100 to rt4. Al2O3/KOH, CH2Cl2, 2 days

oC

Me

OR

MeMe

OMe

OR'

O2S

OTBS

Me

OH

MeMe

OMe

OTBS

60%

O

H

OMe

O

TBSO

O

OMeTES

(Nicolaou's intermediate)

111

1

9

1. TBSOTf/Et3N2. TMSOTf

3. mCPBA, CH2Cl24. NaIO4, MeOH, H2O5. CH2N2

S OMe

O

OH

O O

62 % (one pot)

Laure Bouchez

OTBS

+

1. SO2/HNTf2 - 84 C/10h

2. TBAF/MeCNMOMO

I3. TsOH MeOH, reflux

SO

OH

O O

50 % (one pot)

oOTES

1. Dess-Martin, CH2Cl22. SiEt3Li ,THF

3. TBSCl/imidazole DMF

S OMe

O

OTBS

O OEt3Si

56 % (d.r.: 3:1)

Al2O3/KOH

CF2Br2CH2Cl2

OMe

OTBS

Et3Si

O72 % (E,E,E vs. E,E,Z: 12/1; ee: 99 %)Nicolaou: 11 steps

Me

OH

MeOHO

O

O

MeMeSO

MeO

ODS

OMeMe

OH

OHMe

Me

9

27

MeOTBSO

O

OH

OH

OMeMe

OH

OHMe

27

O

H

H

H

TBSOOMe OR*

OTBS

OO

H

OTMS

*RO++

MeOTBSO

O

OH

Me

OH

OHMe

27H

CHOTBSOOMe OR*OH

OTBS

O

OTBS

OTES

O

Ph

HMe

R+

1. SO2/Tf2NH (30 %), CH2Cl2, - 78 Co

2. Pd(OAc)2, PPh3, i-PrOH, K2CO3, 80 Co

(60 %)

OR*O

α:β syn/anti 3:1

1.TBSOTf, Et3N

2. mCPBA,CH2Cl2

OR*

OTBS

O

(70 %) TBSOOMe O

H

TBSOOMe OR*OH

OTBS

O

L-malic acid

BF3,CH2Cl2,- 78 Co

(73 %)

HOOH O

OMe

1. TBSCl, imidazolTHF,0 C, 92 %2. Proton Sponge Me3OBF4, CH2Cl23. DIBAL, - 78 C (60 %)

o

o

S.V.LeyOrg. Lett. 2003, 5, 4819

TBSOOMe OR*OH

OTBS

O O

O3, CH2Cl2- 78 C (62 %)o

H

Cotinica Craita

Polyketide chain of apoptolidinone

Cotinica Craita

Polyketide chain of apoptolidinone

TBSOOMe OR*OH

OTBS

O O

HMeO

TBSOO

OH

Me

OH

OR*Me

27H

OTBS(+)-Ipc2BAllyl

(55 %)

1.(DHDD)2PYROsO4 cat.

MeOTBSO

O

OH

Me

OH

OR*Me

27H

OTBS

OH

OMe

2. Me3OBF4 (t-Bu)2MePyr

Restricticin(Penicillium restrictum):Broad spectrumantifungal agentsR.E.Schwartz & coll., J. Antibiot.1991, 44, 463;S.Matsukuma et all. J. Antibiot.1992, 45, 151.

Synthesis:S.Jendrzejewski, P. Ermann, Tetrahedron Lett. 1993, 34, 615.I. Paterson, T. Nowak, Tetrahedron Lett. 1996, 37, 8243.A. G. M. Barrett & coll. J. Org. Chem. 1999, 64, 162.

O R

OO

O

R = H lanomycinR = Et restricticin

NH2

Laure Bouchez, Cotinica Craita

(one-pot)

SO OO

(one-pot 73 %)OTES

+OTMS

4.NaIO4/RuO3,MeOH3.NaBH42.mCPBA,CH2Cl21.TMSOTf/Et3N,CH2Cl2(40 %)

1. SO2, Tf2NH2. TBAF, Bu-I

3. TsOH, MeOH

O

OO

O

PMBO SOH

OBn

OH O O7 71

1

PMBOOBn

SO OO

H+PMBO

O

OMe

O

NH2 1. (c-Hex)2BCl/CH2Cl22. Me4NBH(AcO)3

I. Paterson

α,β,γ−anti,anti-Stereotriads

Maris Turks

O

O

ArS

OOTMS O O

ArOO

+

1. SO2,Tf2NH, toluene

2. Pd(OAc)2 Ph3P, i-PropOH K2CO3

(E)α

βγ

Ar = Ph α,β anti/syn 5.2:1 (80 %)Ar = Greene's 20.1:1 (81 %)

O OAr

O

α

βγ

OBz OH

syn,anti anti,syn

O

R

O OAr

OO

α

βγ

OBz OH

anti,anti syn,syn

Eight Stereotriads

Iterative oxy-allylations: long-chain polypropionates

Maris Turks

OAc

OBn

SiMe3

1. SO2, Tf2NH- 80 C, 24 h2. Et3NHTfO/MeOH, - 78 to - 30 Co

o

OBn

AcO

OBn

TMSO

MeLi, - 78 CEt3N,HMPATMSCl

(86%)

o

o

(68 %)

OBn

BzO

OBnO

OBz

OBn

SO2, Tf2NH- 80 C, 24 h

Maris Turks, Freddy Fonquerne

Two-directional chain elongation*RO

BzO

R SiBu3

1. SO2/tolueneTMSOTf

2.Pd-retroene

OBzO

R

OOBz

R

Ph Ph

OR*

BzO

R

SiBu3 SiBu3

1. SO2/tolueneTMSOTf+

2.Pd-retroene

R = H, Me

Low yield !

O

BzO

Ph

OAc

O

OAc

SiMe3

Ph

OBz1. SO2/CH2Cl2Tf2NSiMe3- 78 oC

2. MeOH/Et3NHTfO (71 %)

S

O

SiMe2Ph

Ph

OBz

(100 %)

(Me2PhSi)2Cu(CN)Li2

(Fleming, I. JCSP1, 1981,2527)

O

SiMe2Ph

Ph

OBzO

BzO

PhS

M.Turks,F.Fonquerne, P.VogelOrg. Lett. 2004, 6, 95-98

repeat

R

O

Ph

OBz

(62 %) R = Me

O

R

OBz

Ph

(81 % ) R = H

O

SiMe2Ph

Ph

OBz O

SiMe2Ph

PhOTBS

1. MeLi:LiBr (81 %) 2. L-Selectride (90 %)3. TBSOTf/Et3N (97 %)

Anti-HIVMaris Turks,José Esté, Badalona, Spain, TRIoH

O

BzO

PhS

OPh

OTBS O OBzPh

1.SO2; Tf2NH - 78 C, 24 h

2. Et3N, TMSOTf, MeOH, - 40 C, 3h3. NaHCO3, H2O

(one-pot)

(61 %)

OR*

BzOPhMe2Si SiMe2Ph

1. SO2/CH2Cl2 Tf2NTMS

+2. MeOH, Et3NH+TfO- (60 %)

OPh

OBz O OBzPh

1. MeLi LiBr, Et2O2.TMSOTf, Et3N3.IBX.MPO, DMSO4. PhSeH, Et3N (55 %)

OR*O OR* OSePh SePh

ClCl

Me2PhSiLi

OMe

O

1.R*OH, 20 mbar2. TMSOTf, Et3N3. BzF, Bu4NF

IO

O

O OH

IBX:

Santagostino et al., JOC 1999,64,4537

OR*O OR* OSePh SePh 1.B-Me(S)-CBS (0.5 eq.) BH3.Me2S, THF, - 30 to - 10 C

2. m-CBBA

o

OR*HO OR* OH 1. (isopinocampheyl)BH (1 eq.)

O O

OHC

*RO OR*

2. ozonolysis, H3O+

OH(desymmetrizationby chirality)

Spiroketals of the Spongistatins ?

Freddy Fonquerne

Alcohol silylation under neutral conditions,with no silyl group migration or exchange,

and volatile co-products

R'-OH + SO2SiR3 R'-OSiR3 + SO2 +or MeCN

CH2Cl2

primary secondary tertiary

TMS TES TBS

X. Huang

R'-OSi

H

O

S O R'-OSi

H

O

SO entropydriven

assistance to Si subst.by the S=O group ?

OO

OBOM

OH

OBOM

OH

SEt

SEt

OPh

OBz O OBzPh

OHO

OO

O

NH

O

OMe

OHHOAcO

O

MeOTBSO

O

OH

Me

OH

OR*Me

27H

OTBS

OH

OMe

OMe

OTBS

Et3Si

O

Ryfamycin SApoptolidinone

OO

OHO OH O O

O

R

Baconopyrone

OH OH OHOH OH

O

O OH

RK-397OH

OH

Spongistatins

O O

O O

O

Y

Ph

R

OTMS

R

O OPh

Y

+ α

βγSO2

acid

CONCLUSIONS:

O O

OHC

*RO OR*

OH

O 3 steps O+

OR*NCR* = (1S)-camphanoyl

O OR*

CN85 %, d.e. > 95 %

2

O

BnO

KOH/H2O, CH2O

HC(OMe)3/Montmor.BH3Me2SBnBr/NaH/Bu4NI

1.

2.3.4.

O

BnOOMe

OMe

O

BnO O

Nafion

OSiMe3

O

BnO OO

1. mCPBA2. LiHMDS/ MeI

O

OR

OBn

O

Polypropionates from acetone

A.-F. Sevin, P. Vogel, J. Org. Chem. 1994, 59, 5920;P. Kernen, P. Vogel, Helv. Chim. Acta 1995, 78, 301

New 9,12-Anhydroerythronilides

A. Morishita, S. Yaginuma,J.Antibiotics1992,45,613

O

HO O

O

O

O

HONMe2

OHOMe

O

O

HO

HO

Erythromycin A

O

O

O

OH

O

O

HO2C

HO

O

OR

CNO

O

O

R = (1S)-camphanoyl

S.W. Ainge, P. Vogel, Tetrahedron Lett. 1998, 39, 4039

OBn

OO

O

O

XO

O

O

O

HONMeR2

OHOR1

1

9

6

R1 = Me, R2 = Me, X = OH R1 = H, R2 = Me, X = OH R1 = Me, R2 = H, X = OH R1 = Me, R2 = Me, X = H

Sporeamycin ASporeamycin BSporeamycin C

12

C(1)-C(6)-Fragment

OBn

O 1. Sn(OTf)2, NEt3 CH2Cl2, -78°

2. CHO-78 to -50°

OH

O

OBn(87%)

1. Et2BOMe, NaBH4 THF/MeOH, -78°2. Me2C(OMe)2

pTsOH cat., CH2Cl23. O3, NaHCO3 CH2Cl2, -78°

(66%)

OO

OBn

Mulzer'sintermediate

J. Mulzer, H. M. Kirstein, J. Bushmann, C. Lehmann,P. Luger, J. Am. Chem. Soc. 1991, 113, 910

I. Paterson, R. D. Norcross, R. A. Ward, P. Romea,M. A. Lister, J. Am. Chem. Soc. 1994, 116, 11287

O

P. Kernen, S.W. Ainge, S. Gerber-Lemaire

O

O

OO

3 steps

(78%)

O

O

OO

1. (i-Pr)2NLi, Me3SiCl THF, -78°2. ICH2Cl, ZnEt2

Cl(CH2)2Cl, 0°3. FeCl3, pyridine DMF, 50°

(64%)

1. CuBr.Me2S, MeLi Et2O, -78°

2. Me3SiCl(100%)

O

OSiMe3

OO

O

O

OO

Pd(OAc)2 (cat), O2

DMSO, 40°

(quant.)

O

CN

OR*

OO

O OH

SPhO

O

O OTBS

SOPh

CH2Cl2

(PhS)2, P(Oct)3MeCN, 20°

(90%)

(t-Bu)Me2SiOTf2,6-lutidine

(99%)

123

4

56

7

89

1.

2. NaIO4/MeOH/H2O(95%)major (3:1)

O

O

O

O

Pd(PPh3)(OAc)2PPh3, ZnCl2

Ph2SiH2, CHCl3(50 %)

O

O

O

O

(Me3Si)2NLi, HMPAArNTf2, THF

1.

.Pd(PPh3)4 (cat.)LiCl, CH2=CHSnBu3,THF,

2

OO

OOO

O

H2NNH2, H2O2Cu(OAc)2 (cat)

MeOH(75 %)

1. O3, CH2Cl2MeOH, -78Me2S2.

NaBH43.(80 %)

1. Raney Ni, Et2O, EtOH2. Raney Ni, H2, EtOH3. DMSO, (COCl)2, NEt34. NaClO 2, NaH2PO 4 t-BuOH 2-methylbut-2-ene

(50%)

OO

O

COOH

O O

HO

OX

X = TBS

X = H

Bu4NF, THF-30° to 20°

(80%)

16

13

1. 2,4,6-trichlorobenzoyl chloride (i-Pr)2NEt, PhH, 20°

2. Me2Npyr, PhH, 80°3. CF3COOH, H2O, 20°

(55%)

C(6)-C(7)-Bond Formation & Macrolactonization

O

HO

HO

O

O

OHOH

OH1

3

56

810

1113

14

15

9

OO

O OTBS

SOPh123

4

56

7

89

OO

OS O O OBn

HO

OTBS

O Ph

1. (i-Pr)2NLi, TMEDA THF,-78°

2. + Mulzer's interm.

(40%), recovery of sulfoxide (35%)

S. Gerber-Lemaire, S. W. Ainge,C. Glanzmann, P. Vogel, Helv.

Chim. Acta 2002, 85, 417

J(8,9) = 11.1 Hz

J(2,3) = 10.7 Hz

SPARTAN

S.Gerber-Lemaire, K. Meilert

J(3,4) = 0 Hz

3

2

4

8

O

O

OHOTBSTBSO

TBSOOTBS

O

O

SO2TES

CH2Cl2, r. T24 h

5 equiv.

1.

2. MeOH

O

O

OTESOTBSTBSO

TBSOOTBS

O

OX. Huang, L. Awad

Friedel-Crafts sulfinylation

The Classical Organic Chemistry of SO2

The copolymerization of SO2 with alkenes and alkynes

R-metal + SO2 RSO2M

Ring opening of oxiranes and oxetanes polysulfites

Sulfone synthesis: RSO2M + R'X RSO2R'

Isomerization of alkenes

Cheletropic additions of dienes sulfolenes

Sulfolene alkylation cheletropic elimination1-substituted 1,3-dienes

Calculations: CSCS, MannoJ. A. Sordo & co-workers, Oviedo

X-Ray CrystallographyK. Schenk (UNIL),

R. Scopelliti,E. Solari

Swiss NSF, BernRoche Research Fondation

NovartisSocrates, OFES (COST D13)

ETH Zürich

SpongistatinsS.Gerber-LemaireK. Meilert

Sulfur DioxideB. DeguinJ.-M. RouletF. MonnatV. NarkevitchS. MegevandE. RoversiL. BouchezD. MarkovicS.R. Dubbaka

Long-chain 1,3-polyols, polyketidesM-E. SchwenterA.G. CsákÿS. Gerber-Lemaire A.T Carmona-AsenjoF. Fonquerne

PolypropionatesM. TurksX. HuangC. CraitaC. Murcia