FLEXIBLE AND CONVERGENT TOTAL SYNTHESIS OF CYCLOTHEONAMIDE-B

A convergent approach using two key intermediates, segment A [a -L-alp ha-hydroxy-beta-homoarginine-D-phenylalanine (Pro-hArg-D-Phe) tripepti de] and segment B [a vinylogous L-tyrosine-L-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheona mide B (Scheme 1). The starting compound for the preparation of the hA rg moiety 7, the predominant part of segment A, was N-alpha-(benzyloxy carbonyl)-N-omega , N(omega)'bis(tert-butyloxycarbonyl)-l-arginine met hyl ester (15, Scheme 2), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a c arboxylic acid anion equivalent. Coupling with properly protected Pro and D-Phe derivatives gave smoothly the desired Pro-hArg-D-Phe tripept ide derivative 24. The key feature of segment B, i.e., the L-tyrosine- derived alpha,beta-unsaturated gamma-amino acid 4, was prepared by a W adsworth-Emmons olefination of the aldehyde 29 (Scheme 3) derived from N-(tert-butyloxycarbonyl), O-tert-butyl-L-tyrosine methyl ester (28). Selective N-(tert-butyloxycarbonyl) removal in the presence of the ar yl tert-butyl ether present in the fully protected segment B, i.e., 32 , was achieved by treatment with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield. Coupli ng of the key intermediates 24 and 34 using -(1H-benzotriazol-l-yl)-1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protect ed linear pentapeptide 35 in high yield (Scheme 4). Treatment of 35 wi th Pd(PPh3)(4)/morpholine resulted in simultaneous removal of the C-te rminal allyl group and the N-terminal allyloxycarbonyl group to yield 36. Ring closure was effected under dilution conditions by treatment w ith TBTU/1-hydroxybenzotriazole/4-(dimethylamino and gave the protecte d cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group w ith Dess-Rlartin periodinane (24 h, 40 degrees C) in the presence of t ert-butyl alcohol gave 38, which was then subjected to O,N-deprotectio n with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.