Solid-Phase Total Synthesis of Bacitracin A

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Abstract
An efficient solid-phase method for the total synthesis of bacitracin A is reported. This work was undertaken in order to provide a general means of probing the intriguing mode of action of the bacitracins and exploring their potential for use against emerging drug-resistant pathogens. The synthetic approach to bacitracin A involves three key features: (1) linkage to the solid support through the side chain of the l-asparaginyl residue at position 12 (l-Asn12), (2) cyclization through amide bond formation between the α-carboxyl of l-Asn12 and the side chain amino group of l-Lys8, and (3) postcyclization addition of the N-terminal thiazoline dipeptide as a single unit. To initiate the synthesis, Fmoc l-Asp(OH)-OAllyl was attached to a PAL resin. The chain of bacitracin A was elaborated in the C-to-N direction by sequential piperidine deprotection/HBTU-mediated coupling cycles with Fmoc d-Asp(OtBu)-OH, Fmoc l-His(Trt)-OH, Fmoc d-Phe-OH, Fmoc l-Ile-OH, Fmoc d-Orn(Boc)-OH, Fmoc l-Lys(Aloc)-OH, Fmoc l-Ile-OH, Fmoc d-Glu(OtBu)-OH, and Fmoc l-Leu-OH. The allyl ester and allyl carbamate protecting groups of l-Asn12 and l-Lys8, respectively, were simultaneously and selectively removed by treating the peptide-resin with palladium tetrakis(triphenylphosphine), acetic acid, and triethylamine. Cyclization was effected by PyBOP/HOBT under the pseudo high-dilution conditions afforded by attachment to the solid support. After removal of the N-terminal Fmoc group, the cyclized peptide was coupled with 2-[1‘(S)-(tert-butyloxycarbonylamino)-2‘(R)-methylbutyl]-4(R)-carboxy-Δ2-thiazoline (1). The synthetic peptide was deprotected and cleaved from the solid support under acidic conditions and then purified by reverse-phase HPLC. The synthetic material exhibited an ion in the FAB-MS at m/z 1422.7, consistent with the molecular weight calculated for the parent ion of bacitracin A (MH+ = C73H84N10O23Cl2, 1422.7 g/mol). It was also indistinguishable from authentic bacitracin A by high-field 1H NMR and displayed antibacterial activity equal to that of the natural product, thus confirming its identity as bacitracin A. The overall yield for the solid-phase synthesis was 24%.