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The preparation of four key building blocks is described for the total synthesis of psymberin and its C4 epimer. High-yielding syntheses are developed for pyran core, natural side chain, 4-epi side chain, and aryl fragments of the molecule.

A route to spiroisoxazolinopiperidinylbenzamides has been developed. N-Boc-4-piperidone underwent a Wittig olefination and Boc-deprotection followed by a nucleophilic substitution reaction with 4-fluoro-3-nitrobenzoic acid to yield the starting scaffold 3 in excellent yields. Diversification of the acid with primary amines, followed nitrile oxide formation in situ (aryl oximes treated with bleach) and subsequent 1,3-dipolar cycloaddition to the exo�methylene moiety delivered the spiroisoxazolinopiperdines. Reduction of the arylnitro group followed by acylation with acid chlorides or reductive amination with aldehydes yielded the spiroisoxazolinopiperidinylbenzamide library. [ABSTRACT FROM AUTHOR]

An efficient, multigram synthesis of a spiroisoxazolinoproline-based amino acid, 7, requiring minimal purification, delivering good cis:trans diastereoselectivity (approximately 1:4), and providing good yields is reported. Surface-bound studies of the reduction of an arylnitro group in the presence of an isoxazoline ring with tin(II) dichloride dihydrate were undertaken to confirm the stability of the isoxazoline ring. Full derivitization of this spiroisoxazolinoproline-based amino acid scaffold was performed during the synthesis of a sample library with high yields and high purity that validated the efficiency of the chemistry that was employed in resin-bound library synthesis. A 129,600 member one-bead-one-compound (OBOC) library based on the scaffold 7 was synthesized utilizing a dual amino acid encoding method and bifunctionalization of TentaGel resin.