Approach to the Homoerythrina Alkaloids Using a Tandem N ...ccc.chem.pitt.edu/wipf/Current...
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Approach to the Homoerythrina Alkaloids Using a Tandem N-Alkylation/Azomethine Ylide Cycloaddition Pearson, W. H.; Kropf, J. E.; Choy, A. L.; Lee, I. Y.; Kampf, J. W. J. Org. Chem.; 2007; 72(11); 4135-4148. Wipf group Current lit 08-18-07 Akira Nakamura Akira Nakamura @ Wipf Group 1 10/29/2007
Transcript of Approach to the Homoerythrina Alkaloids Using a Tandem N ...ccc.chem.pitt.edu/wipf/Current...
Approach to the Homoerythrina Alkaloids Using a Tandem N-Alkylation/Azomethine Ylide Cycloaddition
Pearson, W. H.; Kropf, J. E.; Choy, A. L.; Lee, I. Y.; Kampf, J. W.J. Org. Chem.; 2007; 72(11); 4135-4148.
Wipf group Current lit 08-18-07Akira Nakamura
Akira Nakamura @ Wipf Group 1 10/29/2007
Background
CurarelikeHypnoticSedativeHypotensiveNeuromuscular blockingCNS
Activities
Akira Nakamura @ Wipf Group 2 10/29/2007
-Isolated from D. lenticellare Gillespie grown in the Fiji Islands in 1983.-There are no reports on pharmacological effect either 1 or 2.-Isolated alkaloids from D. lentivellare which include 3 are shown to have both cardiac effects in rats and molluscicidal activity. J. Nat. Prod. 1987, 50, 1041., Phytochemistry 1988, 27,3789.
Target Alkaloids
Akira Nakamura @ Wipf Group 3 10/29/2007
Padwa, A. Org. Lett. 2006, 8, 601.
78%
N
OMe
OMe
OMe
OMeO
N3
OMe
OMe
MsO
NaN3
TMSO
TFA, DCM
81%
O
J.d’Angelo, J. J. Org. Chem. 1993, 58, 2933
Construction of the erythrinan ring system
Akira Nakamura @ Wipf Group 4 10/29/2007
Retrosynthetic sequence
Akira Nakamura @ Wipf Group 5 10/29/2007
a
a
Starting material synthesis
Akira Nakamura @ Wipf Group 6 10/29/2007
b
b
Synthesis
Akira Nakamura @ Wipf Group 7 10/29/2007
Key cycloaddition test
Akira Nakamura @ Wipf Group 8 10/29/2007
2nd Retrosynthetic sequence
Akira Nakamura @ Wipf Group 9 10/29/2007
c
c
1.
2nd Key cycloaddition test
Akira Nakamura @ Wipf Group 10 10/29/2007
OH
CHO 58%
Synthesis
Akira Nakamura @ Wipf Group 11 10/29/2007
OH
CHO 58%
Synthesis
Akira Nakamura @ Wipf Group 12 10/29/2007
NTs
OAcAr
H
NTs
OAcAr
HHO
SeO2, dioxane
reflux
86%
Mori, M. J. Org. Chem. 1998, 63, 7586-7587.
OOt-Bu
tBuOOH
Pd(OAc)2, K2CO3
DCM
62%
Corey, E. J. Org. Lett. 2002, 4, 2727-2730.
Allilic oxidation
(1) Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845.(2) Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.(3) Hoekstra, W. J. In EROS; Paquette, L. A., Ed.: Wiley: Chicester,UK, 1995; Vol. 6, p 4437.(4) Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(1) (2) (3) (4)
Akira Nakamura @ Wipf Group 13 10/29/2007
1) HOCH2CH2OH TsOH, benzene
2) tBuOH 82%
EtCH2CNLDA, THF
88%
LDA, THF
then 1-bromo- 3-chloropropane96%
DIBAL-HDCM
thenoxalic acid82%
H2NCH2CO2HCSA, toluene
heat79%
HCl/THF
89%
1) PhNHNH2 benzene
2) AcOH3) LiAlH4, THF 42% over 3 steps
Aspidospermidine
N
HH
CO2H
OO
Iain. Coldham, Angew. Chem., 2007, 119, 6271
Successful example of [3 + 2] Cycloaddition
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Conclusion
- A tandem N-alkylation/azomethine ylide [3 + 2] cycloaddition provides a rapid access to tricyclic amines from acyclic precursors.
-Two separate model systems guided to improve yields of the key step.
- Allilic oxidation was unsuccessful.
Akira Nakamura @ Wipf Group 15 10/29/2007
