5 SYNTHETIC STUDY OF LEUPEPTINS AND THEIR ANALOGS

Abstract

Leupeptin Ac-LL (1) and Pr-LL (2), metabolites of various species of Actinomycetes, was found to have an interesting anti-plasmin activity and their synthesis was already reported. This communication deals with their alternate synthesis. N^α-Cbz-N^G-NO_2-L-Arginine (3) was converted into its imidazolide (4) and reduced with LiAlH_4 to give N^α-Cbz-N^G-NO_2-argininal (5) in a good yield. The aldehyde (5) was converted into N^G-NO_2-argininal semicarbazone (8) which was coupled with an active ester of Ac-Leu-LeuOH and followed by deprotection, giving Leupeptin Ac-LL (1) in a good yield. Leupeptin Pr-LL (2) and other acyl argininals were also synthesized in a similar manner. In addition, N^α-(Ac-Leu-Leu)-N^G-Cbz-L-arginine δ-lactam (22) was treated with LiAlH_4 to give the corresponding aldehyde (23), which were deprotected, affording 1 in a good yield. Leupeptins (1 and 2) thereby obtained exhibited antiplasmin activities similar to the samples of natural origin. On the other hand, Ac-Leu-Leu-D-argininal, which was analogously synthesized from N^α-Cbz-N^G-NO_2-D-arginine, the enantiomer of 3, was found to have practically no activity.