Synthesis of allylic isoprenoid diphosphates by S(N)2 displacement of diethyl phosphate

Allylic polyenyl diphosphates such as geranyl and (E,E,E)-geranylgeranyl di phosphates are ubiquitous substrates for monoterpene and diterpene synthase s and transferases in isoprenoid biosynthesis. These enzyme substrates were prepared in asymmetrically labeled form by reduction of 1-deuterio aldehyd e precursors with (R)- and (S)-Alpine boranes(R) conversion into diethyl ph osphates, and S(N)2 displacements with tris(tetrabutylammonium) pyrophospha te which occurred slowly with essentially complete inversion of configurati on over 2-5 days. The 8 alpha- and 8 beta-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-H-2(1)]-11, and 12 by means of regioselective phosphorylation of the allylic hydroxy groups and d isplacements with pyrophosphate anion. The configurations and enantiopuriti es of the deuterium-labeled geraniols, before and after the S(N)2 displacem ents, and the diastereopurity of the bicyclic keto alcohol intermediate (15 S)-[15-H-2(1)]-15 were determined by conversion into (1S)-camphanate esters and H-1-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 dip hosphate.