Mild and Chemoselective Triethylsilane-Mediated Debenzylation for Phosphate Synthesis

Abstract

The synthetic utility of tetrabenzyl pyrophosphate for achieving chemoselective phosphorylation of phenols, as well as primary, secondary, and tertiary alcohols, is reported here. Additionally, we introduce a rapid, mild, and chemoselective debenzylation procedure, enabling access to phosphates in the presence of redox sensitive groups. Finally, stoichiometrically controlled monodebenzylation provides a versatile platform for late-stage divergent synthesis of phosphodiester and phosphoramidate chemical libraries.

Figure 1

Synthetic limitations of cannabidiol and the incompatible commonly employed phosphorylation methods.

Figure 2

Scope of TBPP-based phosphorylation and triethylsilane-mediated debenzylation. Unless otherwise stated, condition a denotes dibenzyl phosphate, condition b denotes fully debenzylated phosphate, and condition c denotes monobenzyl phosphate derivative. Blue represents installed phosph(on)ates, green redox sensitive/benzyl protecting groups, orange competitive nucleophiles, and red problematic functionalities. ^an-BuLi was used as the base. ^bDeprotection results in compound degradation. ^cSynthesized from (S)-(−)-perillyl alcohol over two steps. ^dSynthesized from 6-(bromomethyl)-2H-chromen-2-one. ^eWith 4 equiv of Et₃SiH. ^fIsolated as a crude Et₃N salt. ^gIsolated as a HCl salt. ^hWith 8 equiv of Et₃SiH. ⁱLDA was used as the base. ^jIsolated as an ammonium salt. ^kSynthesized from cinnamyl bromide.

Scheme 1. Monodebenzylation-Mediated Phosphodiester and Phosphoramidate Synthesis