Asymmetric Total Synthesis of (-)-Swainsonine from Inexpensive and Commercially Available Starting Material, Ascorbic Acid

Zheng Yang Lee¹, Mohd Fazli Mohammat², Agustono Wibowo³, and Jhi Biau Foo^1,4*

Abstract

Introduction: Swainsonine is a natural and synthetic alpha-mannosidase II inhibitor which has been shown to inhibit various types of cancer growth in vitro and in vivo. Our initial study was to synthesise (-)-swainsonine from commercially available D-isoascorbic acid, yet unsuccessful, although following published protocol. Hence, we envisioned this challenge associated with aldehyde-lactol tautomerism by exploiting another novel route. Methods: Acetonide protected diol 1 was first prepared from D-isoascorbic acid via a three-step procedure. It was then selectively acetylated, and further Swern oxidation yielded aldehyde 2. Wittig olefination was carried out to afford olefinic ester 3 with ease. Subsequent deacetylation and azide substitution gave imino ester 6, which readily produces (-)-swainsonine in 4 steps. Purification of the products was carried out using the classical column chromatography Si-gel G60 (230-400 mesh, Merck). The ¹H and ¹³C NMR spectra were registered in CDCl₃ with Joel Resonance ECZ400S 400 MHz (¹H) and 100 MHz (¹³C) using TMS as the internal standard. Results: The imino ester 6 was obtained as a colourless oil with an overall yield of 2% from D-isoascorbic acid. Conclusion: The present study illustrated the total synthesis route of (-)-swainsonine. 

Keywords: Swainsonine, Cancer, Swern oxidation, Wittig olefination, Aldehyde-lactol tautomerism

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