3-(4-Hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis

A new safety catch linker, 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA), is described for use in solid phase peptide synthesis. The linker is readily synthesized from commercially available chemicals in a more cost efficient way compared to similar reported linkers. The HMPPA linker is easily attached to an amino derivatized solid support followed by on-resin oxidation of the thioether to sulfoxide, thereby making the linker very stable towards strong acid treatment. Final resin cleavage is performed by reductive acidolysis.     

Rapid, mild method for phosphonate diester hydrolysis: development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester

A rapid, low temperature hydrolysis of tenofovir diethyl ester mediated by TMSCl and NaBr was identified and demonstrated to be superior to the current production method, TMSBr-mediated hydrolysis. This mild phosphonate ester hydrolysis was then coupled to alkylation of the phosphonic acid, providing a one-pot procedure for formation of tenofovir disoproxil from tenofovir diethyl ester. The hydrolytic conditions developed here dramatically improve the synthesis of tenofovir disoproxyl and will lead to lower cost HIV/AIDS treatment in the developing world.     

Efficient synthesis of phosphonodepsipeptides derived from norleucine

In the present work, we describe in detail an efficient solution synthesis of norleucine-derived phosphonopeptides mimicking the peptide sequences Nle-Gly(Ala) and Nle-Gly(Ala)-Val. The most efficient strategy involved use of the benzyl group. The synthesis was achieved through BOP-catalysed coupling of the monobenzyl ester of the N-Cbz-protected phosphonate derivative of norleucine with the hydroxyl moieties of derivatised l-lactic or glycolic acid. Subsequently, complete deprotection of the products was achieved in good yields by one-step Pd-catalysed hydrogenolysis. We also prepared the Fmoc-Nle-Ψ[PO(OH)O]-CH₂-COOH synthon and demonstrated that this precursor is a suitable building block for the solid-phase synthesis of cysteine-containing phosphonopeptides.