Synthesis of the Dipeptide Hydroxyethylene Isostere of Leu-Val, a Transition State Mimic for the Control of Enzyme Function

Article abstract of DOI:10.1021/jo00254a016

Dipeptide isosteres have recently begun to attract attention because of their ability to mimic the transition states of proteolytic enzymes or to alter or enhance the function of regulatory peptides.We have developed a general approach that may be used to prepare a diverse array of dipeptide hydroxyethylene isosteres.As an example we have prepared a mimic of Leu-Val, the cleavage site of the enzyme renin.The sequence begins with leucinal 8. which is converted to the aldehyde 15ct by addition of vinylmagnesium bromide to form an allylic alcohol.This is converted to the acetonide, ozonized, and equilibrated to give the trans aldehyde 15t as the primary product.A Wadsworth-Emmons olefination fallowed by hydrogenation affords the ester 30 as a mixture of isomers.Hydrolysis of the acetonide and purification gives the desired lactone 26β in 23percent overall yield from BOC-leucinol.