Michel Bénéchie

Further Insight from Model Experiments into a Possible Scenario Concerning the Origin of Manzamine Alkaloids

The common source of this new class of alkaloids and the structural similarities of these compounds suggest the existence of a unique biosynthetic pathway, in a particularly striking example of “nature diversity-oriented synthesis”. The biosynthetic pathway is unknown to date; however, in 1992, Baldwin and Whitehead put forward the hypothesis that dihydropyridinium salts 1 formed through the condensation of aminoaldehydes with acrolein may serve as key intermediates(Scheme 2). This hypothesis was tested experimentally and, remarkably, provided access to keramaphidin B. However, the efficiency of this kind of strategy was limited as a result of a competing dihydropyridine redox process. Furthermore, the model proposed by Baldwin and Whitehead did not permit access to the manzamine skeleton. Studies towards the synthesis of cyclostellettamines led us to propose an alternate scenario based upon the chemistry of aminopentadienal species 2, which could be formed from malonaldehyde instead of acrolein. This modification of the initial proposal is summarized in Scheme 2. Experimental studies revealed that only regioisomers of aminopentadienals 2 were available (isomers 14, see Scheme 5), but that these regioisomers do add to salts 1 to deliver the AB ring system of halicyclamine A (via analogues of 3), whereas the condensation of aminopentadienoic esters enabled the synthesis of analogues of the AB ring system of manzamine A (via analogues of 4). Herein, we report further results related to the chemistry depicted in Scheme 2. We describe a new method based on the original proposal of Baldwin and Whitehead for the preparation of salts 1, as well as a Chichibabin-like process for the formation of a common intermediate, which, depending on the reaction conditions, rearranges to give a ring system equivalent to the AB ring system of 3 or the AB ring system of 4. To our knowledge, the condensation of an unsaturated aldehyde, such as acrolein, with aldehydes and amines to give dihydropyridinium salts 1 has no equivalent in the literature. However, as acrolein can be viewed as the aldol-condensation product of acetaldehyde and formaldehyde, the reaction could be considered to be related to the Chichibabin synthesis of pyridines. Indeed, this multicomponent procedure, known as early as the beginning of the 20th century, involves the condensation of three equivalents of an aldehyde with ammonia at high temperature to give 2,3,5-trisubstituted pyridines (Scheme 3, R=H). If R is an alkyl group, the reaction produces the corresponding pyridinium salts. In fact, the intermediates of this reaction are believed to be dihydropyridinium salts 7, or even dihydropyridines 8, which are oxidized spontaneously under the rather harsh and acidic reaction conditions. The initial main drawbacks of this process were the necessary use of the same aldehyde, which does not allow variation of the R groups, and the difficulty in stopping the reaction at the dihydropyridinium stage. The selective synthesis of salts 1 by the route proposed in Scheme 2 could thus be viewed as a useful modified Chichibabin synthesis of six-membered nitrogen heterocycles. After some unsuccessful attempts, we have now found a sequence that mimics this process (Scheme 4). The Strecker Scheme 1. Some natural products representative of the manzamine family of alkaloids.

Studies related to the synthesis of maytansinoids.

Two approaches to the partial synthesis of C1–C5 of a bis-nor maytansinoid 1 have been investigated starting on the one hand with (S)-(−)-malic acid and on the other, with D-(+)-ribonolactone.

The opening of trans-2-3-epoxy-1-butanol derivatives with organometallic reagents

Abstract The opening of trans -2-3-epoxy-butan-1-ol derivatives with various organometallic reagents was studied to find the best conditions necessary to obtain convenient yields and regioselectivities for their application in natural product synthesis.

From disubstituted acetylenes to trisubstituted olefins. An application

Abstract The transformation of disubstituted acetylenes to trisubstituted olefins was studied in order to obtain precursors of the north-eastern part of maytansine. Depending on the starting material, a trans or a cis stannylation reaction could lead to the olefin of the desired stereochemistry

Stereoselective allylic transposition by means of allylic n-pentenyl ethers

Abstract Stereospecific formation of optically active tetrahydrofurans and dihydropyrans was obtained via an allylic rearrangement by means of allylic n-pentenyl ethers.

Total synthesis of maytansinoids. Approach to 4,6-bisdemethylmaytansine and 4-demethylmaytansine

Abstract A convergent strategy was elaborated to synthesize maytansine 1 and maytansinoids modified on the carbon skeleton, especially 4-demethylmaytansine 2, 6-demethylmaytansine 3, 4,6-bisdemethylmaytansine 4. In this paper, the feasibility of the project was verified by the preparation of key intermediates for the synthesis of 4, 6-bisdemethylmaytansine and 6-demethylmaytansine. The C-1-N open chain compound 18 in the 4,6-bisdemethyl series was obtained.

Stereoselective allylic transposition by means of allylic n-pentenyl ethers. Part 2: Synthesis of nitrogen heterocycles

Abstract Stereospecific synthesis of optically active substituted pyrrolidines, and piperidines was studied via an intramolecular allylic rearrangement by means of allylic n-pentenyl ethers as leaving groups when reacting with halonium ions.