Metalation of N-Boc-pyrrole (I) with the lithium amide of tetramethylpiperidine, followed by boronation with triethyl borate and acidic work-up leads to the pyrroleboronic acid (II). Subsequent catalytic hydrogenation over Pt/C provides the racemic pyrrolidineboronic acid (III). Alternatively, protection of pyrrolidine (IV) with Boc2O affords (V). After metalation of N-Boc-pyrrolidine (V) with s-butyllithium, treatment with triethyl borate gives rise to the boronic acid (III). Condensation of the racemic boronic acid (III) with (+)-pinanediol (VI) furnishes the corresponding mixture of diastereoisomeric pinanediol boronates, from which the desired isomer (VII) can be isolated by column chromatography. Further removal of the N-Boc protecting group under acidic conditions yields the pyrrolidineboronic ester (VIII). Coupling of pyrrolidine (VIII) with N-Boc-L-valine (IX) produces amide (X). The N-Boc group is then cleaved with HCl in Et2O to afford the deprotected amine (XI). Finally, removal of the pinanediol moiety by transesterification of the boronic ester (XI) with phenylboronic acid provides the desired boronic dipeptide
In a related synthetic procedure, N-trifluoroacetyl-L-valine (I) is activated as the corresponding acid chloride (II) by treatment with the Vilsmeier reagent in cold EtOAc. Coupling of (II) with the pyrrolidineboronic ester (III) yields amide (IV). The trifluoroacetyl protecting group is then removed by alkaline hydrolysis to produce (V). Finally, deprotection of the boronic acid moiety of (V) with concomitant recycling of the (+)-pinanediol chiral auxiliary is achieved by transesterification with N-Boc-2-pyrrolidineboronic acid (VI) in the presence of methanesulfonic acid to furnish the pinanediol boronate (VII) along with the title compound