Synthesis of Allylic Isoprenoid Diphosphates by SN2 Displacement of Diethyl Phosphate

Abstract

Allylic polyenyl diphosphates such as geranyl and (E,E,E)-geranylgeranyl diphosphates are ubiquitous substrates for monoterpene and diterpene synthases and transferases in isoprenoid biosynthesis. These enzyme substrates were prepared in asymmetrically labeled form by reduction of 1-deuterio aldehyde precursors with (R)- and (S)-Alpine boranes®, conversion into diethyl phosphates, and SN2 displacements with tris(tetrabutylammonium) pyrophosphate which occurred slowly with essentially complete inversion of configuration over 2-5 days. The 8α- and 8β-hydroxy-17-nor analogs (13 and 14) of copalyl diphosphate as well as the (15R)-deuterium-labeled form of 13 were similarly prepared from nor-diols 11, (15S)-[15-2H1]-11, and 12 by means of regioselective phosphorylation of the allylic hydroxy groups and displacements with pyrophosphate anion. The configurations and enantiopurities of the deuterium-labeled geraniols, before and after the SN2 displacements, and the diastereopurity of the bicyclic keto alcohol intermediate (15S)-[15-2H1]-15 were determined by conversion into (1S)-camphanate esters and 1H-NMR analysis. Amino alcohol 18 was similarly converted into amino diphosphate 19, 15-aza-14,15-dihydro GGPP, a potential aza analog inhibitor for diterpene synthases which generate stereoisomeric forms of copalyl diphosphate.