Conformation and reactivity in dibenzocyclooctadienes (DBCOD). A general approach to the total synthesis of fully substituted DBCOD lignans via borostannylative cyclization of α,ω-diynes

Abstract

Dibenzocyclooctadienes (DBCOD) are a class of plant-derived natural products that exhibit a broad range of biological activities. These include cytotoxicity, anti-hepatitis-B activity, inhibition of HIV replication and of NO production and activity. None of the fully substituted DBCODs have been prepared before. 2,2′-Dipropargylbiphenyls undergo highly regio- and atropselective cyclizations mediated by a [B-Sn]-reagent, 1-trimethylstannyl-2,5-diazaborolidine (Me₃Sn–B[–N(Me)CH₂CH₂(Me)N–], in the presence of Pd(II)-catalysts, to give highly functionalized DBCOD precursors. The configuration of the newly created, axially chiral, 1,2-bis-alkylidene moiety is controlled by the resident chirality of the starting biphenyls and the configurations of the benzylic positions. New chemistry of the bis-alkylidenes described in this paper enables the first total syntheses of a wide variety of DBCOD natural products, fully functionalized at the cyclooctadiene ring. These include ananolignans B, C, D, F, interiotherin C, kadsuralignan B, tiegusanin D and schizanrin F. Revision of the structure of a key natural product, ananolignan B, is also reported. Key steps in the syntheses exploits the conformational features of the various DBCOD intermediates as revealed by NMR spectroscopy and X-ray crystallography.