NEW ORGANIC CHEMISTRY BASED ON THE PERICYCLIC REACTION OF SULFUR DIOXIDE Total Asymmetric Synthesis of Polyketides and Analogs of Biological Interest Spongistatins Oxo-polyene antibiotics (1,3-polyols) Ryfamycin S, Baconopyrone, Apoptolidin Polypropionates via new organic chemistry of sulfur dioxide
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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: 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%)
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
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.