Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

doi:10.1016/j.tet.2008.02.008

Tetrahedron

Volume 64, Issue 17, 21 April 2008, Pages 3629-3641

https://doi.org/10.1016/j.tet.2008.02.008 Get rights and content

Abstract

An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in 11 steps from a commercially available starting material.

Graphical abstract

Introduction

Stemofoline (1, Fig. 1) was first isolated from the stems and leaves of Stemona japonica by Irie and co-workers in 1970.¹ X-ray crystallographic analysis of the hydrobromide salt of 1 revealed a pyrrolizidine ring system containing a two-carbon bridge connecting C7 and C9a and an angular butyl side chain at C3. Stemofoline also contains a spiroketal functionality at C8 and a (Z)-olefin bridge from a tetrahydrofuran ring to a conjugated butenolide moiety. The rigid pentacyclic core of 1 possesses three heteroatoms and seven contiguous stereogenic centers.2, 3

Of the 11 members of the stemofoline alkaloids which have been reported to date,4, 5, 6, 7, 8 most differ only in the oxidation state of the C3 chain (cf. 1 vs 2 or 3) or the (E)-configuration versus (Z)-configuration of the C11–C12 alkene (1 vs 4). Notably, Sekine and co-workers reported isolation of 2, which they named asparagamine A, from the roots of Asparagus racemosus.⁴ Later studies suggested that Sekine and co-workers had actually isolated 2 from Stemona collinsae, which is commonly confused with A. racemosus.⁵ Parallel studies found 2 to be a major component of the ethanolic extracts of S. collinsae,⁶ along with 19-(S)-hydroxystemofoline (3).⁵ Since it appears to have no connection to the Asparagus plant genus, 2 is now commonly referred to as didehydrostemofoline.

The Thai plant from which Sekine and co-workers isolated didehydrostemofoline (2) had traditionally been administered to pregnant women to arrest premature uterine contractions, and it was hypothesized that 2 was the active agent. Indeed, 2 was found not only to inhibit oxytocin-induced labor in pregnant rats but also to exhibit dose-dependent in vivo activity against Kato-III human gastric carcinoma cells.⁹ More recent explorations have focused on the potential of Stemona alkaloids as natural insecticides, as 1–3 were found to exhibit insecticidal and growth-inhibitory activity against the neonate larvae of Spodoptera littoralis.5, 10 Additionally, 1 and 2 have shown insecticidal and antifeedant activity against the larvae of the diamondback moth, a vegetable crop pest.⁶

Owing to their complex molecular architecture and intriguing biological activity, the stemofoline alkaloids have attracted considerable synthetic attention,11, 12, 13, 14 culminating in two racemic total syntheses.15, 16 The studies reported herein comprise the first non-racemic synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids.

Section snippets

Results and discussion

The utility of azomethine ylide [3+2] cycloadditions for the construction of highly substituted pyrrolidine rings has been demonstrated by its implementation in the total synthesis of numerous alkaloid natural products.17, 18, 19, 20, 21 Non-stabilized azomethine ylides are often generated by desilylation of iminium salts derived from the O-activation of amides17, 22 or the N-alkylation of vinylogous imidates.²³ In a related strategy, we recently reported the use of N-(trimethylsilyl)methyl

Conclusion

A key observation regarding the dependence of α-stereochemistry in the azomethine ylide generation and intramolecular dipolar cycloaddition of vinylogous amide 44 led to the development of a successful non-racemic synthesis of the bridged pyrrolizidine core of the stemofoline alkaloids.

General

All reactions were performed in flame-dried modified Schlenk (Kjeldahl shape) flasks fitted with a glass stopper under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe. Organic solutions were concentrated by rotary evaporation below 30 °C. Flash column chromatography was performed employing 230–400 mesh silica gel. Thin-layer chromatography (analytical and preparative) was performed using glass plates pre-coated

Acknowledgements

This research was supported by the NIH-NIGMS (GM67659) and Merck. MTE thanks NSF and AstraZeneca for predoctoral fellowships.

References and notes (26)

S. Jiwajinda et al.
Phytochemistry
(2001)
E. Kaltenegger et al.
Phytochemistry
(2003)
A. Padwa et al.
Tetrahedron Lett.
(1983)
X.Q. Feng et al.
Tetrahedron: Asymmetry
(1999)
H. Irie et al.
J. Chem. Soc., Chem. Commun.
(1970)
C. Seger et al.
Chem. Biodivers.
(2004)
T. Sekine et al.
Chem. Pharm. Bull.
(1994)
B. Brem et al.
J. Agric. Food Chem.
(2002)
P. Mungkornasawakul et al.
J. Nat. Prod.
(2004)

T. Sastraruji et al.

J. Nat. Prod.

(2005)

T. Sekine et al.

J. Chem. Soc., Perkin Trans. 1

(1995)

R.L. Beddoes et al.

J. Chem. Soc., Chem. Commun.

(1992)

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Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

Acknowledgements

Phytochemistry

Phytochemistry

Tetrahedron Lett.

Tetrahedron: Asymmetry

J. Chem. Soc., Chem. Commun.

Chem. Biodivers.

Chem. Pharm. Bull.

J. Agric. Food Chem.

J. Nat. Prod.

J. Nat. Prod.

J. Chem. Soc., Perkin Trans. 1

J. Chem. Soc., Chem. Commun.