retrosynthetic analysis of...
TRANSCRIPT
Retrosynthetic Analysis of
Alsmaphorazine E
1
David Daniels, Robert Pullin and Christian Winter(Team 6)
SCI’s Young Chemist’s 1st National Retrosynthesis Competition 29th February 2012
Alsmaphorazine E
2Isolation: Koyama, K. et. al., Tetrahedron 2012, 68, 1502
Key structural considerations:
• hexahydropyrrolo[2,3-b]pyrrole subunit• diazabicyclo[3.3.1]nonane• 6 contiguous stereocenters• benzylic tertiary alcohol
Alstonia pneumatophora
A monoterpene-indole alkaloid, isolated from the leaves of Alstoniapneumatophora.
Proposed Retrosynthesis
NN
HHO
H
O
HO
MeO
MeO2C
Alsmaphorazine E
ConjugateAddition
N
OMe
HO
O
HN
CO2Me
II
3
N
OMe
O
HO PGN
OMe
O
OIII
Forward Synthesis
4Ref. 1: Aikawa, K., Mimura, S., Numata, Y. and Mikami, K. Eur. J. Org. Chem. 2011, 62
Palladium-Catalyzed Enantioselective Addition to Isatins:
Forward Synthesis
5Ref. 2: Campi, E. M., Fallon, G. D., Jackson, W. R., and Nilsson, Y., Aust. J. Chem. 1992, 45, 1167.Ref. 3: Pelletier, G., Bechara, W. S. and Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817.
i. DIBAL-H, PhMe
ii. Fmoc-Cl, iPr2EtN
Forward Synthesis
5Ref. 2: Campi, E. M., Fallon, G. D., Jackson, W. R., and Nilsson, Y., Aust. J. Chem. 1992, 45, 1167.Ref. 3: Pelletier, G., Bechara, W. S. and Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817.
i. DIBAL-H, PhMe
ii. Fmoc-Cl, iPr2EtN
Forward Synthesis
HN
NBS
0 °C N
N
O
CO2Me
HO
MeOBr
DBUor NEt3
6
N
OMe
O
HONH
OMe
O
O
N
OMe
HO
O
O CO2Me
HN
N
OMe
HO
O
CO2Me
N
work-up
-H2O
H+
in situ Fmocdeprotection
N
N
O
CO2Me
HO
MeO
I
Forward Synthesis - Backup
7
A
B
Forward Synthesis
H2OTi
MeiPrOiPrO
Ti(OiPr)4iPrMgCl
Ref . 4
8
Ref. 4: Urabe, H., Suzuki, K. and Sato F., J. Am. Chem. Soc. 1997, 119, 10014.Sato, F., Urabe, H. and Okamoto, S., Synlett 2000, 6, 753.
Titanium-Mediated Intramolecular Cyclization of Enynoates:
[Ti]
N
N
O
HO
MeO
CO2Me
N
N
O
HO
HMeO
[Ti]
OMe
O
Summary
Key Features:
Early-stage enantioselective Palladium-catalyzed generation of tertiary alcohol:
9
12 steps (LLS)
Titanium-mediated intramolecular cyclization to construct final ring and control alkene geometry:
Supplementary I
Addition of primary amines to tert-butyl thioesters:
10
Supplementary II
Selective reduction of amides:
O
O
NH
O
N
O
N
O
HO
O
O
NH
O
N
O
N
HO
BH3•THF
THF
92%
Slough G A Han F and Lee B H Tetrahedron Lett 1999 40 3851
11
Slough, G. A., Han, F. and Lee, B. H., Tetrahedron Lett. 1999, 40, 3851Pharmacia and Upjohn Company, Patent: EP1400523 A2, 2004, pg. 15
NHO
O
N
O
NHO
O
NDIBAL-H
toluene0 °C to rt
82%
Fukuyama, T. and Liu, G., J. Am. Chem. Soc. 1996, 118, 7426.
Supplementary III
Selective triflation in the presence of tertiary alcohols:
12
Supplementary IV
Acylation of amides in the presence of tertiary alcohols:
13
Supplementary V
Enolate condensation with amides:
NS
O
O O
NS
O O
OMe
O
KOtBu
tBuOH
53%OMe
O
14
N
O
OPO(OEt)2
OEt
O
N
O
OEtO
NaH
THF
43%
Cholleton, N., Gauthier-Gillaizeau, I., Six, Y. and Zard, S. Z., Chem. Commun. 2000, 7, 535.
Jakopin, Z. and Sollner-Dolenc, M., Synth. Comm. 2010, 40, 2464.
Supplementary VI
In situ bromination/nucleophilic attack (with O) of β-amino-α,β-unsaturated esters:
N
O
MeO
O
HO
OMe
OAr
N
OMe
OAr
Br
MeOO
O
O
N
HBr3
CH2Cl20 °C
15
O OAr OArO
Ar = m-NO2-C6H487%
Goerlitzer, K. and Roth, A., Pharmazie 1995, 50, 681.
NH
N
NH
O
tBuO
H H
C9H19NH
N
NH
H H
C9H19
O
tBuOBrO
AcOAcONBS
MeOH
Cohen, F. and Overman, L. E., J. Am. Chem. Soc. 2006, 128, 2594.
Supplementary VII
Elimination from α-bromo esters:
BrO
MeO
O
MeOquinoline
96%
16
O
OO
O
BrBr
H
H
O
OO
O
H
BrLiCO3
DMF
Ando, M., Wada, T. and Isogai, K., J. Org. Chem. 1991, 56, 6235.
Lange, G. L. and Otulakowski, J. A., J. Org. Chem. 1982, 47, 5093.
94%