Stereoselective synthesis of lupin alkaloids: total synthesis of (+)-ß-isosparteine and (–)-epilupinine

Abstract

The first stereoselective total synthesis of the tetracyclic lupin alkaloid (+)-ß-isosparteine (+)-1.4 hasbeen achieved in 15% yield over 4 steps using a two-directional, syn-selective, double imino-aldolreaction between diphenyl glutarate 2.1 and tert-butanesulfinimine 1.205. The chiral auxiliary, tertbutyl sulfinamide 2.9, was used to control the stereoselectivity of imino-aldol reaction. Thismethodology was applied to access diastereomerically pure product, introducing 4 stereogeniccentres in a single step. In addition, the minor diastereoisomers from double imino-aldol reactionhave been identified and used to synthesise (–)-sparteine (–)-1.3 and (–)-10,17-dioxo-β–isosparteine ((–)-1.43). The stereochemistry of intermediates (+)-10,17-dioxo-ß-isosparteine ((+)-1.33), and (–)-10,17-dioxo-ß-isosparteine were confirmed by single crystal X-ray structuredetermination. A short total synthesis of the bicyclic lupin alkaloid (–)-epilupinine (–)-1.1 has alsobeen achieved in 31% yield over 2 steps from halo imine 1.205. Formation of mono cyclised iminoaldol adduct 2.13 was obtained from reaction of the dianion of diphenyl glutarate 2.1 with oneequivalent of halo tert-butanesulfinimine 1.205. The stereochemistry of cyclised 2.13 anduncyclised 2.16 mono syn imino-aldols were confirmed by single crystal X-ray structuredetermination. As a part of synthetic studies towards (+)-allomatridine (+)-1.5, total synthesis ofthe bicyclic lupin alkaloid (–)-epilupinine ((–)-1.1) was completed in 55% overall yield over 6 stepsusing single imino-aldol reaction between phenyl ester 1.173 and unsaturated tertbutanesulfinimine 1.208. The stereochemistry of unsaturated quinolizidinone 2.30 and tricyclicimide 2.40 were confirmed by single crystal X-ray structure determination

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ORCID for Richard C.D. Brown: orcid.org/0000-0003-0156-7087

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