Structural verification via convergent total synthesis of dipeptide–lipids isolated from Porphyromonas gingivalis

Abstract

A periodontal pathogen, Porphyromonas gingivalis, produces two serine dipeptide lipid classes that we labeled lipid 654 and lipid 430, and both contain l-serine as the terminal amino acid. The lipid 654 and lipid 430 classes are each comprised of three species with differing fatty acid substitutions, but the most abundant species demonstrate unit masses of either 654 or 430, respectively. Recently we observed that the lipid 654 can be hydrolyzed by specific lipases to lipid 430. However, a substantial percentage of the naturally occurring lipid 654 cannot be enzymatically hydrolyzed to lipid 430. The observed partial hydrolysis could be due to the presence of a mixture of stereoisomers. Testing this theory requires structural verification of our so-called 654 and 430 by total synthesis. We present herein details of the convergent synthesis of lipids 430 and 654, which confirm the proposed structure of P. gingivalis lipid 654 to be (3R and 3S)-l-serine-2. The bis(fatty acid) (3R)-l-serine-2 was prepared as well as the synthetic precursor, serine dipeptide mono-fatty acid (3R)-l-serine-1, which is the structure of lipid 430. We also synthesized the (3S)-l-serine-2 diastereomer as well as (3S)-l-serine-1. Using these synthetic standards, we confirmed that PLA2-mediated hydrolysis of lipid 654 is enantioselective in that only the (3R)-l-serine-2, but not (3S)-l-serine 2 is enzymatically hydrolyzed.