pvogel_polyketide
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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
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