Synthesis of cyclic hexapeptide core of antifungal drug candidates

摘要: The major objective of the antifungal drug program at Abbott Laboratories was to develop a non-toxic drug, superior amphotercin B, which could be used treat life threatening fungal infections. One such candidate (I) originated from highly functionalized natural product echinocandins [1,2]. It showed high activity with least toxicity. key components this are cyclic hexapeptide core and lipophilic side chain (R). An efficient synthesis has been developed for purpose preparing multigram quantities SAR studies. is composed (2S, 4S)-4-amino-proline (Amp), two threonines, 4-hydroxyproline, homotyrosine (hTyr) ornithine. segments selected were Boc-Orn-Thr-Hyp-OH (II) Fmoc-hTyr-Thr-AzP-OMe (III). Strategically, these because they contain C-terminal proline derivatives, known less sensitive racemization during segment condensation. In synthetic scheme 4-amino-proline introduced as 4-azido-proline (Azp). Homotyrosine, now it commercially available, prepared by literature procedure [3,4] converted Fmoc-hTyr-OH standard procedure. Boc-Azp-OMe starting Boc-Hyp-OMe. Boc-Hyp-OMe mesyl derivative treatment MS-Cl/pyridine. then sodium azide in DMF. Now also available commercially. Segment II stepwise approach Hyp-OBzl. HypOBzl coupled Z-Thr-OH utilizing EDC/HOBt method yield ZThr-Hyp-OBzl solid material. This dipeptide on hydrogenation coupling Boc-Orn(Fmoc)-OSu gave crude II. peptide purified silica gel chromatography give pure crystalline III Azp-OMe. Z-Thr-Azp-OMe obtained Boc-Thr-OH Azp-OMe EDC/HOBt. Boc group removed resulting using yielding removal Fmoc followed EEDQ produced linear hexapeptide, chromatography.