Synthesis of (-)-Conduramine A1, (-)-Conduramine A2 and (-)-Conduramine E2 in Six Steps from Cyclohexa-1,4-diene

Solange Da Silva Pinto; Stephen G Davies; Ai M Fletcher; Paul M Roberts; James E Thomson

doi:10.1021/acs.orglett.9b02914

Synthesis of (-)-Conduramine A1, (-)-Conduramine A2 and (-)-Conduramine E2 in Six Steps from Cyclohexa-1,4-diene

Org Lett. 2019 Oct 4;21(19):7933-7937. doi: 10.1021/acs.orglett.9b02914. Epub 2019 Sep 13.

Authors

Solange Da Silva Pinto¹, Stephen G Davies¹, Ai M Fletcher¹, Paul M Roberts¹, James E Thomson¹

Affiliation

¹ Department of Chemistry, Chemistry Research Laboratory , University of Oxford , Mansfield Road , Oxford OX1 3TA , United Kingdom.

PMID: 31518146
DOI: 10.1021/acs.orglett.9b02914

Abstract

A method to enable the synthesis of conduramines and their N-substituted derivatives (enantiopure or racemic form) in six steps (five steps for N-substituted derivatives) from cyclohexa-1,4-diene is reported. Key features of this reaction sequence include a preparation of benzene oxide that is amenable to multigram scale, and its efficient ring-opening upon treatment with a primary amine. Epoxidation of the resultant amino alcohols (40% aq HBF₄ then m-CPBA) is accompanied by hydrolytic ring-opening in situ to give the corresponding N-substituted conduramine derivatives directly. These may undergo subsequent N-deprotection to give the parent conduramines, as demonstrated by the preparation of enantiopure (-)-conduramine A1, (-)-conduramine A2, and (-)-conduramine E2 (the latter two for the first time). The selectivity of the epoxidation reaction is proposed to be the result of competitive ammonium-directed and hydroxyl-directed epoxidation processes, followed by either direct (S_N2-type) or conjugate (S_N2'-type) ring-openings of the intermediate epoxides.