total synthesis of (+)- crotogoudin - portal
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Total Synthesis of (+)-Crotogoudin
Simon Breitler and Erick M. Carreira
ETHZ, Switzerland
Angew. Chem. Int. Ed. 2013, 52, 1-5.
Me
OO
Me
O
Introduction – Crotogoudin
2
• Isolated in 2010 by a Madagascan-French research group
• Two closely related cytotoxic diterpenes were isolated, crotogoudin 1 and crotobarin 2
• Both 1 and 2 belongs to the rare 3,4-seco atisane family of diterpenoids
• Novel diterpenes (C20) contains a polycyclic ring system with four contiguous stereocenters, where a six-membered ring is fused to a bicylco[2.2.2]octane subunit
Me
OO
Me X
OMe
Me
H
MeMe
3 4
9
oxidative cleavage
oxidationH: crotogoudin (1)OAc: crotobarin (2)
X =atisane family
Proposed Biosynthesis
3
OPP
enz-H+
Henz
OPP
H H
H
1,3-hydrideshift
H1,2 shift
H
geranylgeranyl diphosphate copalyl diphosphate primaren-8-yl carbocation
beyeran-16-yl carbocation beyeran-12-yl carbocation
– H+
atisirene
oxidative cleavage
HHO2C
H H
O
O
O
crotogoudin (1)
JACS 2007, 41, 12453
Retrosynthetic Analysis
4
Me
OO
Me
O
crotogoudin (1)
Me
OO
Me
OPG OPGO
O
Me
X
Me10
5
1610
3 4
O OH
Me
Me5
OtBu
O
OMe
Me 6 7
+OBn
O
• Late-stage introduction of enone at C(16) • Cyclopropane opening and cyclization cascade (annulative
cascade) • Const ruct ion of lactone and cyclopropane f rom
hydroxyketone 5 • Bicyclo[2.2.2]octane 5 could be obtained from β-ketoester 6
and enal 7
Synthesis of Lactone 15
5
OtBu
O
OMe
Me 6 7
+OBn
O
1.) DBU, 0 - 80 °C2.) LiCl, 160 °C
60% for 2 steps
O
OBn
Me
Me 8
OMe
Me 9
3.) Na, NH3 (l)4.) (COCl)2, DMSO, EtN3
5.) 2M HCl6.) DMP O
Me
Me 10
O
54% for 4 steps
7.) baker's yeast, sugar O
Me
Me(–)-5
>99% ee
OH77% (87% brsm)
8.)
LaCl3 . 2 LiClMgBr
OR
Me
Me
Me
OH
11: R = H12: R = TBS
9.)TBSOTf
88%
98%
10.) 13, Rh2(esp)2
OTBSMe
Me
OH
Me
MeO2CMeO2C
144.4:1 d.r.
66%
IPhMeO2C
MeO2C 13
OTBS
MeMe
Me
MeO2C
15
OO
11.) aq. sat. NaHCO3
O
quantitative
Annulative Cascade
6
Trisubstituted olefin would serve as nucleophile (e.g. X = H, SiMe3) in the opening of the electrophilic cyclopropane in 15 to deliver tetracyclic product 17
OTBSO
O
MeMe
XMeO2C
10 Me
OO
Me
OTBS
10
5
1715 : X = H or Si3Me
MeO2C
Lewis acids
Reversal of reactivity, wherein the alkene would serve as an acceptor to a reactive, nucleophilic species at C(10) derived from reductive opening of the cyclopropane
Annulative Cascade
7
Speculation: offering the radical at C(4) a suitable leaving group (X) would enable a favorable termination pathway, leading to increased product formation?!?
OTBSO
O
MeMe
MeO2C
10 Me
OO
Me
OTBS
10
5
17a
MeO2C
SmI2 (2.5 equiv.)THF/DMPU 9:10 °C to RT
SmI2reductive
CP-opening
radicalannulation
Me
O
Me
OTBSMeO2C
Me
OOSmIII
Me
OTBSMeO2C
I IIOSmIII
15
Me
OO
Me
OTBS
10
5
17b
MeO2C
+
disproportionation
low yield (<10%)X
X X
X = H
SmI2-Promoted Anion Radical Alkylation
8
J. Inanaga et al. Tet. Lett. 1989, 30, 2837.
MeO2CO OO
HO
BOMO
H OSEMSmI280%
OO
HBOMO
H OSEM
OH
BOMO BOMO
K. C. Nicolaou et al. Angew. Chem. Int. Ed. 2008, 47, 8605.
Total Synthesis of Vannusal B
Annulative Cascade
9
OTBSO
O
MeMe
XMeO2C
10 Me
OO
Me
OTBS
10
5
177.7:1 d.r.
15: X = H 16: X = OPiv
MeO2C
SmI2 (2.5 equiv.)THF/DMPU 9:10 °C to RT
a.) SeO2, tBuO2H then NaBH4, 74%b.) Me3COCl, 95%
a, b
SmI2 SmI2reductive
CP-openingreduction &elimination
radicalannulation
Me
O
Me
OTBSMeO2C
Me
OOSmIII
Me
OTBSMeO2C
I IIOSmIII
X X
80%
Me
O
Me
OTBSMeO2C O
side-product from 1,5-H-abstraction
from I (14%)
Completion of the Synthesis
10
Me
OO
Me
OTBSMeO2C
17
Me
OO
Me
O
(+)-crotogoudin (1)
Me
OO
Me
OH
18
LiCl, Δthen 5M HCl
96%DMP93%
Me
OO
Me
O
19
iPr3SiOTf, NEt3then HMDS, 20then MeIthen basic Al2O3
54%
N I20
Eschenmoser's salt
Conclusion
11
• All spectroscopic and physical data were in full agreement with already reported ones, except the optical rotation
• Synthetic: [α]D20 = + 29.6 (c = 0.4, CHCl3); Reported: [α]D
20 = + 7 (c = 0.4, CHCl3)
à re-measurement of the optical rotation (à [α]D20 =
– 25.2 (c = 0.4, CHCl3) for 1) • Natural product is (–)-crotogoudin with (R,R)-
configuration
Me
H
H
Me Me
Me
ent-atisane
O
O
Me
Me
O
(+)-crotogoudin (1)
(S,S)(R,R)
Preparation of Starting Materials 6+7
12
O
OtBu
OBr+
NaH, nBuLithen bromide
O
OtBu
O
21 22 681%
• Weiler dianion alkylation (JACS 1970, 92, 6702.)
• A. Córdova et al. Eur. J. Org. Chem. 2012, 398.
HO OH23
BnBr, NaH
71%BnO OH
24
a.) (COCl)2, DMSO, EtN3b.) Ph3P=CHCO2Me
90%
BnO25
CO2Mec.) DIBALd.) (COCl)2, DMSO, EtN3
BnO7
CHO81%