Flexible and Convergent Total Synthesis of Cyclotheonamide B

• Published in: Journal of organic chemistry Vol. 62; no. 12; pp. 3880 - 3889
• Main Authors: Bastiaans, Harold M. M, van der Baan, Juul L, Ottenheijm, Harry C. J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.06.1997; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; PROTECTED AMINO-ACIDS; TRANSFORMATION; PEPTIDES; REAGENTS; POTENT THROMBIN INHIBITORS; KETO ESTER DERIVATIVES; ALPHA-DIKETONE
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo961447m

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 ). 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-(1H-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(PPh3)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.