Flexible and Convergent Total Synthesis of Cyclotheonamide B

A convergent approach using two key intermediates, segment A [a l -proline- l -α-hydroxy-β-homoarginine- d -phenylalanine (Pro-hArg- d -Phe) tripeptide] and segment B [a vinylogous l -tyrosine- l -2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheonamide B (Scheme 1). The starting compound for the preparation of the hArg moiety 7, the predominant part of segment A, was N α -(benzyloxycarbonyl)- N ω, N ω ‘-bis( tert -butyloxycarbonyl)-l-arginine methyl ester ( 15, Scheme 2), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a carboxylic acid anion equivalent. Coupling with properly protected Pro and d -Phe derivatives gave smoothly the desired Pro-hArg- d -Phe tripeptide derivative 24 . The key feature of segment B, i.e., the l -tyrosine-derived α,β-unsaturated γ-amino acid 4, was prepared by a Wadsworth−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 aryl 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. Coupling of the key intermediates 24 and 34 using 2-(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protected linear pentapeptide 35 in high yield (Scheme 4). Treatment of 35 with Pd(PPh 3 ) 4 /morpholine resulted in simultaneous removal of the C -terminal allyl group and the N -terminal allyloxycarbonyl group to yield 36 . Ring closure was effected under dilution conditions by treatment with TBTU/1-hydroxybenzotriazole/4-(dimethylamino)pyridine and gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group with Dess−Martin periodinane (24 h, 40 °C) in the presence of tert -butyl alcohol gave 38, which was then subjected to O,N -deprotection with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.