Synthesis of boronic acid analogues of alpha-amino acids by introducing side chains as electrophiles

A synthetic route has been developed which has allowed us to prepare novel alpha -aminoboronic acids as inhibitors of serine proteases. These compound s were prepared to study the roles of proteases in biological systems. This methodology affords a-aminoboronic acids with the general formula R ' -NHC H(R)BO2-pinanediol, where R = -CH2CHF2, -CH(2)CO(2)tBu, and -(CH2)(2)CO2Me and R '= either H or C(O)R ". The latter two compounds are the boronic acid analogues of the natural amino acids aspartic acid and glutamic acid with the side chain carboxylate protected as a tert-butyl or a methyl ester, res pectively. Following acylation of the amino group, the side chain tert-buty l ester of boroaspartic acid was removed by treatment with TFA. Boroglutami c acid was obtained as the free boronic acid by hydrolysis with HCL Prior s yntheses of alpha -aminoboronic acids involve the initial addition of an or ganometallic reagent to a trialkyl borate ester. These conditions do not al low the preparation of compounds with functionalities that are not stable t o the strongly basic reaction conditions. The methodology described here al lows the preparation of alpha -aminoboronic acids by introducing side chain s as electrophiles. This is particularly advantageous for side chains which are prone to elimination or unwanted enolate formation. Specifically, BrCH 2CHF2, (BrCH2COOBu)-Bu-t, and CH2=CHCOOMe were allowed to react with the st abilized anion of (phenylthio)methane boronate, PhSCH2BO2C6H12, to give the substituted boronate. The substituted (phenylthio)methane boronate was con verted to the corresponding sulfonium ion by treatment with methyl iodide a nd subsequently displaced with iodide. The a-iodo derivative was converted to the amine by conventional methods.