The 'azirine/oxazolone approach' to the synthesis of Aib-Pro endothiopeptides

The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-L-prolinate (2a) with thiobenzoic acid at room temperature gave the endothiopeptide Bz-Aib psi[CS]-Pro-OMe (7) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)-protected proline was tranformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z-Pro-Aib psi[CS]-Pro-Ome (12). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H2S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro2 was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe OMe and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-1H-benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer Bz psi[CS]-Aib-Pro-Aib psi[CS]-N(Mc)Ph (21) was achieved via isomerization of 7 to Bz psi[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1a), The structures of 12 and 21 were established by X-ray cyrstallography.