Divergent total synthesis and reactivity of 2,3-dihydroxypropylphosphonic acid dipeptides

2,3-Dihydroxypropylphosphonic acid (DHPPA) dipeptides, which are the proposed end products of the valinophos biosynthetic pathway, have not been detected in the culture extracts of a valinophos-producing Streptomyces strain. To facilitate structural and biosynthetic investigations, we developed a divergent synthetic route to six putative DHPPA dipeptides bearing Ala, Leu, Ile, Ser, Gln, or His as the N-terminal amino acid, based on substrate preferences previously reported for the biosynthetic ligase. The synthetic route starts from (R)-glycidol and proceeds via a common phosphonate intermediate, thereby enabling the divergent introduction of various N-terminal amino acids and efficient access to the target compounds. Notably, the synthesized DHPPA dipeptides were found to readily undergo 1,2-rearrangement and diketopiperazine (DKP) formation in polar solvents. This DKP-forming propensity may contribute to the apparent absence of DHPPA dipeptides in the culture extracts. These findings provide synthetic access to DHPPA dipeptides and reveal their previously unrecognized instability in solution.