Highly Enantioselective Semisynthesis of (+)/(-)-Gossypol Schiff Base Derivatives from Ground Plant Material.

We have recently developed a one-pot process for simultaneous extraction and chemical modification (SECheM) on Cienfuegosia digitata, a Mauritanian Malvaceae called locally "Izide". On the basis of this innovative methodology that consisted of using ground plant roots as starting material in gossypol Schiff base semisynthesis, we now report how this concept can be used to access enantiomerically pure Schiff base atropisomer derivatives of gossypol in only two steps. This study has been envisioned since enantiomerically pure Schiff base atropisomer derivatives of gossypol are generally more potent biologically when compared to racemic gossypol Schiff bases.

Development of SECheM Concept for Isolation and Chemical Modification of Gossypol Directly from Cienfuegosia digitata.

INTRODUCTION: Gossypol is an axially chiral natural polyphenol classically extracted from the Malavaceae family. Nevertheless, its extraction and isolation from a plant can be quite complicated and extremely time-consuming since gossypol is known to be sensitive to degradation under solvents, high temperature and light action. Moreover, its purification over column chromatography is a challenging problem due to its ability to oxidise and the existence of various tautomer forms. OBJECTIVE: To develop an efficient "one-step" strategy for simultaneous extraction and semi-synthesis by short-circuiting critical gossypol isolation and purification steps. METHODOLOGY: Gossypol was first isolated from Cienfuegosia digitata roots, characterised (by 1D and 2D NMR) and quantified (by UV spectrophotometry). Thus, aniline was selected to test the "one-step" in situ trapping of freshly extracted gossypol leading to a Schiff base analogue. After screening solvents and extraction times on this model reaction, the "SECheM" (simultaneous extraction and chemical modification) concept was successfully extended to other amines, underlining the efficiency and the robustness of the strategy. RESULTS: After having shown that gossypol occurred as a major compound in C. digitata roots, different experimental procedures using Soxhlet extraction in the presence of aniline pointed out the best conditions for the SECheM concept (7 h of reaction and extraction time in ether as solvent). Ultimately, the concept has been generalised to 17 other amines. CONCLUSION: This is a report of the first semi-synthesis that allows: (1) "in situ" preparation of more stable gossypol Schiff base derivatives directly from ground plant material and (2) circumvention of gossypol extraction and purification problems. Copyright © 2017 John Wiley & Sons, Ltd.