Total synthesis of ent-pavettamine.

Memory Zimuwandeyi,Manuel A Fernandes,Amanda L Rousseau,Moira L Bode

doi:10.3762/bjoc.17.99

Abstract

Pavettamine, a plant toxin first isolated from Pavetta harborii in 1995, was previously identified as a polyamine with C2 symmetry and a 1,3-syn-diol moiety on a C10 carbon backbone – one of very few substituted polyamines to be isolated from nature. Its absolute configuration was later established by our first reported total synthesis in 2010. Herein we report the first total synthesis of the enantiomer of pavettamine, ent-pavettamine. The symmetrical structure of the molecule allows for the synthesis of a common C5 fragment that can be divergently transformed into two synthons for later convergent coupling to furnish the target carbon framework. Based on the success of the protocol we employed for the synthesis of the naturally occurring pavettamine, (S)-malic acid was again the starting material of choice for the synthesis of the two individual C5 fragments, with strategic differences in terminal-group manipulation allowing for the synthesis of ent-pavettamine rather than pavettamine. Chain extension and stereoselective ketone reduction were achieved using the (R)-methyl p-tolyl sulfoxide chiral auxiliary to give the desired 1,3-syn-diol C5 unit. A protecting-group strategy was also developed for the orthogonal protection of the alcohol and amine functional groups as they were unveiled. The functionalized C5 fragments were coupled via reductive amination revealing the C10 carbon backbone. Deprotection of the alcohol and amine functional groups successfully provided ent-pavettamine as a TFA salt.

Highlights

The identification and first reported synthesis of pavettamine (1) heralded the arrival of a novel and uniquely hydroxylated polyamine (PA) (Figure 1) [1]
The elucidation of the structure of pavettamine revealed a new class of polyamines with a substituted methylene linkage
With the absolute stereochemistry of pavettamine having been established previously [1], this study focused on developing a route for the synthesis of enantiomer 2 by modification of the established protocol used for the synthesis of 1

Summary

Introduction

The identification and first reported synthesis of pavettamine (1) heralded the arrival of a novel and uniquely hydroxylated polyamine (PA) (Figure 1) [1]. The first step involved esterification of malic acid using methanol, followed by selective reduction of the resulting dimethyl ester using borane dimethyl sulfide (BMS) yielding diol 5 (Scheme 2) [1,14,15]. Our choice of the trityl protecting group was based on the fact that it could be Scheme 1: Established route for the synthesis of intermediate 4 [1].

Results

Conclusion