Concise Modular Synthesis and NMR Structural Determination of Gallium Mycobactin T

A modular synthesis of mycobactin T and its N-acetyl analogue is reported in a route that facilitates permutation of the lipid tails. A key feature is the generation of N(alpha)-Cbz-N(epsilon)-benzyloxy-N(epsilon)-Boc-lysine (A4) with methyl(trifluoromethyl)-dioxirane in 59% yield. Selective hydroxamate N-acylation was achieved with acyl fluorides, enabling installation of lipids tails in the final step. O-Benzyl-dehydrocobactin T (B4) was prepared by modifying a known five-step sequence with an overall yield of 49%. 2-Hydroxyphenyl-4-carboxyloxazoline (C3) was prepared from 2-hydroxybenzoic acid and L-serine methyl ester in three steps with an overall yield of 55%. Ester coupling of A4 and B4 with EDCI afforded MbI-1 in 73% yield. Catalytic hydrogenation with Pd/BaSO4 and 50 psi of H-2 simultaneously effected alkene reduction and debenzylation to afford MbI-2 in 96% yield. Fragment C3 was converted into acyl fluoride C4, which coupled with MbI-2 to afford MbI-3 in 51% yield. Finally, Boc-removal with HCl/EtOAc and treatment of the resultant hydroxylamine with stearyl fluoride furnished mycobactin T in 65% yield. Overall, the yield is 4% over 14 steps. The gallium mycobactin T-N-acetyl derivative (GaMbT-NAc) structure was determined by H-1 NMR. The structure shows an octahedral Ga and two internal hydrogen bonds between peptidic N-Hs and two of the oxygen atoms coordinating Ga.