An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure

Abstract

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product�along with a hypothesis about a biosynthetic relationship to related family members�inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama−Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C−N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

“…The second most widely used approach to prepare silyl enols is Mukaiyama-Michael addition. [42][43][44][45] For this purpose, preparation of Michael acceptor 10 was required (Scheme 4). Direct Mannich reaction of the ketone 7 was accompanied with a number of side processes, such as protective group cleavage, hydroxymethylation, etc.…”