SOLID-PHASE TOTAL SYNTHESIS OF BACITRACIN-A

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 path ogens. The synthetic approach to bacitracin A involves three hey featu res: (1) linkage to the solid support through the side chain of the L- asparaginyl residue at position 12 (L-Asn(12)), (2) cyclization throug h amide bond formation between the alpha-carboxyl of L-Asn(12) and the side chain amino group of L-Lys(8), and (3) postcyclization addition of the N-terminal thiazoline dipeptide as a single unit. To initiate t he synthesis, Fmoc L-Asp(OH)-OAllyl was attached to a PAZ, resin. The chain of bacitracin A was elaborated in the C-to-N direction by sequen tial piperidine deprotection/HBTU-mediated coupling cycles with Fmoc D -Asp(OtBu)-OH, Fmoc L-His(Trt)-OH, Fmoc D-Phe-OH, Fmoc L-ne-OH, Fmoc D -Om(Boc)-OH, Fmoc L-Lys(Aloc)-OH, Fmoc L-ne-OH, Fmoc D-Glu(OtBu)-OH, a nd Fmoc L-Leu-OH. The allyl ester and allyl carbamate protecting group s of L-Asn(12) and L-Lys(8), respectively, were simultaneously and sel ectively 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 affor ded by attachment to the solid support. After removal of the N-termina l Fmoc group, the cyclized peptide was coupled with '(R)-methylbutyl]- 4(R)-carboxy-Delta(2)-thiazoline (1). The synthetic peptide was deprot ected and cleaved from the solid support under acidic conditions and t hen purified by reverse-phase HPLC. The synthetic material exhibited a n ion in the FAB-MS at m/z 1422.7, consistent with the molecular weigh t calculated for the parent ion of bacitracin A (MH(+) = C73H84N10O23C l2, 1422.7 g/mol). It was also indistinguishable from authentic bacitr acin A by high-field H-1 NMR aad displayed. antibacterial activity equ al to that of the natural product, thus confirming its identity as bac itracin A. The overall yield for the solid-phase synthesis was 24%.