Syntheses of Norstatine, Its Analogs, and Dipeptide Isosteres by Means of -Lactam Synthon Method

Nonprotein amino acids are the amino acids that are not found in protein-main chains and mostly originate in plants, microorganisms, and marine products. Certain nonprotein amino acids exhibit biological activities by themselves, and many of them are important constituents of biologically active compounds of medicinal interest. For this reason, in addition to the naturally occurring nonprotein amino acids, synthetic nonprotein amino acids have been studied extensively, especially in connection with the design and synthesis of various enzyme inhibitors. Indeed, statine, norstatine, and their analogs, as well as a variety of dipeptide isosteres, have been developed and incorporated in various inhibitors of enzymes such as renin and HIV-1 protease with great success (
1
). These amino acid residues and their isosteres provide effective transition-state mimics of the substrates for peptidases that bind to these enzymes tightly and inhibit their actions. Although a number of methods has been reported for the synthesis of statine and its analogs (
2
–
7
), to date, only a few synthetic methods are available for norstatine and its analogs (
8
–
12
). The β-lactam synthon method developed by these laboratories (
13
–
17
) can be effectively applied to the asymmetric synthesis of norstatine and its analogs, as well as various dipeptide isosteres. In this chapter, the preparation of 3-siloxy-β-lactams will be described first, followed by those of norstatine and its analogs, as well as dihydroxyethylene, hydroxyethylamine and other dipeptide isosteres.