The Improved Synthesis of Boc-Abu(PO3Me2)-OH and Its Use for the Facile Synthesis of Glu-Abu(P)-Leu

Abstract

The improved synthesis of Boc -L-Abu(PO3Me2)-OH from Boc-Asp-Obut in 42% overall yield is described. This derivative was prepared in seven steps and involved initial sodium borohydride reduction of the isobutoxycarbonyl mixed anhydride of BOC-Asp-OBut and subsequent 2,2,6,6- tetramethylpiperidine-1-oxyl-catalysed sodium hypochlorite oxidation of the alcohol. The resultant aldehyde was phosphonylated by reflux with dimethyl trimethylsilyl phosphite and the trimethylsilyl group was then cleaved in situ by aqueous hydrolysis. The 4-hydroxy 4-dimethylphosphono derivative was converted into the Abu(PO3Me2) residue by reaction with thiocarbonyldiimidazole followed by radical deoxygenation of the thiocarbonylimidazolide with tributyltin hydride. The Boc and t-butyl groups were cleaved from BOC-Abu(PO3Me2)-OBut with trifluoroacetic acid and the Boc group was reintroduced to CF3CO2H.H-Abu(PO2Me2)-OH by using di-t-butyl dicarbonate to give Boc -Abu(PO3Me2)-OH as a clear oil. The optical purity of the Abu(PO3Me2) residue was established to be greater than 99.5% of the L-isomer by h.p.1.c. analysis of its L- Leu dipeptide. The protected derivative Boc-Abu(PO3Me2)-OH was used in the Boc mode of peptide synthesis for the preparation of Boc-Glu (OBz1)-Abu(PO3Me2)-Leu-OBzl in high yield, 40% CF3CO2H/CH2Cl2 being used for cleavage of the Boc group from intermediate peptides. The tripeptide was deprotected to CF3CO2H.H-Glu-Abu(P)- Leu -OH by a two-step procedure which involved initial hydrogenolytic cleavage of the benzyl groups in 50% CF3CO2H/CH3CO2H followed by cleavage of the methyl phosphate groups with either (A) 30% bromotrimethylsilane in acetonitrile, or (B) 1 M bromotrimethylsilane /l M thioanisole in trifluoroacetic acid; complete cleavage of the methyl groups was effected after 40 min and 12 h, respectively. In addition, the dipeptide Boc-Leu-Abu (P03Me2)- OBut was prepared from Boc-Abu(PO3Me2)-OBut in high yield and was readily deprotected by acidolytic cleavage of the t-butyl groups with trifluoroacetic acid followed by silylitic cleavage of the methyl phosphonate groups with 30% bromotrimethylsilane in acetonitrile, CF3CO2H.H-Leu-Abu(P)-OH being obtained in high yield.