Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids

Abstract

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (P^a AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all. Today, a variety of methods to access enantiopure α-aminophosphonic acids is known but none of the reported approaches can be generally applied for the synthesis of P^a AAs. Here we show that the phosphonic acid analogs of many (proteinogenic) α-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee) ≥ 98 %) α-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to α-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same α-oxo-phosphonates using deuterated formic acid (DCO₂ H).

Keywords: aminophosphonates; asymmetric transfer hydrogenation; deuteration; hydroxyphosphonates.