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

alpha-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 alpha-aminocarboxylic acids (PaAAs) 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 a-aminophosphonic acids is known but none of the reported ap- proaches can be generally applied for the synthesis of PaAAs. Here we show that the phosphonic acid analogs of many (proteinogenic) alpha-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of alpha-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee)>= 98%) alpha-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to a-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same aoxo-phosphonates using deuterated formic acid (DCO2H).

Automated summary

alpha-Aminophosphonic acids have a wide range of bioactivity and can serve as highly efficient transition state mimics. Although various methods for accessing enantiopure a-aminophosphonic acids have been reported, none of them can be applied universally for the synthesis of PaAAs. By using catalytic, stereoselective asymmetric transfer hydrogenation, phosphonic acid analogs of many alpha-amino acids can be obtained, which are important pharmaceutical building blocks and can be easily converted to a-aminophosphonic acids in most cases.