American Chemical Society
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Synthesis of Boronic Acid Analogues of α-Amino Acids by Introducing Side Chains as Electrophiles

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journal contribution
posted on 2001-08-22, 00:00 authored by Sharada Jagannathan, Timothy P. Forsyth, Charles A. Kettner
A synthetic route has been developed which has allowed us to prepare novel α-aminoboronic acids as inhibitors of serine proteases. These compounds were prepared to study the roles of proteases in biological systems. This methodology affords α-aminoboronic acids with the general formula R‘-NHCH(R)BO2-pinanediol, where R = −CH2CHF2, −CH2CO2tBu, and −(CH2)2CO2Me 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, respectively. Following acylation of the amino group, the side chain tert-butyl ester of boroaspartic acid was removed by treatment with TFA. Boroglutamic acid was obtained as the free boronic acid by hydrolysis with HCl. Prior syntheses of α-aminoboronic acids involve the initial addition of an organometallic reagent to a trialkyl borate ester. These conditions do not allow the preparation of compounds with functionalities that are not stable to the strongly basic reaction conditions. The methodology described here allows the preparation of α-aminoboronic acids by introducing side chains as electrophiles. This is particularly advantageous for side chains which are prone to elimination or unwanted enolate formation. Specifically, BrCH2CHF2, BrCH2COOtBu, and CH2CHCOOMe were allowed to react with the stabilized anion of (phenylthio)methane boronate, PhSCH2BO2C6H12, to give the substituted boronate. The substituted (phenylthio)methane boronate was converted to the corresponding sulfonium ion by treatment with methyl iodide and subsequently displaced with iodide. The α-iodo derivative was converted to the amine by conventional methods.