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. Especially the phosphonic acid analogues to α‐aminocarboxylic acids (PaAAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolutions, 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 are known but none of the reported approaches can be generally applied for the synthesis of PaAAs. Here we show that the phosphonic acid analogues to many (proteinogenic) α‐amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α‐oxo‐phosphonates. The obtained highly enantioenriched α‐hydroxyphosphonates (enantiomeric excess [ee] ≥ 98%) are important pharmaceutical building blocks themselves and could be easily converted to α‐aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogues became easily accessible from the same α‐oxo‐phosphonates using formic acid (DCO2H).