Collective synthesis of natural products by means of organocascade catalysis

Abstract

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

Multi-Bond Forming Processes in Efficient Synthesis

“…[93] The approach involved the generation of key intermediate 17, from which no less than six structurally related natural products were synthesised. Tetracycle 17 was prepared by an 'organocascade' sequence, commencing with a catalytic enantioselective iminium-mediated Diels-Alder reaction, followed by a selenide elimination and terminated with an aza-Michael addition.…”

Asymmetric trapping of zwitterionic intermediates by sulphur ylides in a palladium-catalysed decarboxylation-cycloaddition sequence

“…Notably, trapping of these intermediates with electrophilic components for cycloaddition was hitherto unknown and remains a challenging goal in this field of Pd-catalysed DC reactions because, as Tunge concluded, ''ypalladium-polarized aza-ortho-xylylenes (D) (note: intermediate I here) prefer to react with electron deficient olefinsy'' 30 . More significantly, via this approach, an important indoline core that is ubiquitous in many biologically active natural and synthetic chemicals could be conveniently constructed in a highly enantioselective and diastereoselective manner [31][32][33] . The method described here is a complement to previous efficient protocols including kinetic resolutions of racemic indolines 34 , catalytic asymmetric hydrogenation of indoles 35 and de nevo construction of chiral indolines via formal [3 þ 2] cycoloaddions of anilines and olefins 36 .…”

Organocatalysis in Total Synthesis

“…One is the synthesis of (-)-aromadendranediol via a Mukaiyama-Michael-aldol condensation, through a triple-catalysis-cycle-specific mechanism involving cross-metathesis, iminium and enamine catalysis [58]. And others more recent are the total syntheses of six well-known alkaloids (strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine) based on the combination of collective synthesis of natural products and organocascade catalysis [59].…”