Flexible and Convergent Total Synthesis of Cyclotheonamide B

Abstract

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.

Synthesis and Evaluation of Acyl Protein Thioesterase 1 (APT1) Inhibitors

“…Starting from (2S,3)-diaminopropionic acid hydrochloride (1), allyl ester 2 was prepared following a known procedure. [29] Then, the b-amino functionality was converted into a hexadecyl sulfonamide; subsequently the allyl group was removed leading to free acid 4. Additionally, the known bishydrotosylate 5 could be easily transformed into amine 6.…”

Luminescent Homo- and Heteropolynuclear Platinum(II) Chalcogenido Aggregates Based on [Pt2E2(P^N)4] Units (E=S, Se)

“…Synthesis of tri‐ and pentapeptide analogues : For the synthesis of the tri‐ and pentapeptide analogues, the two diaminopropionic acid derivatives 4 and 6 had to be generated (Scheme ). Starting from (2 S ,3)‐diaminopropionic acid hydrochloride ( 1 ), allyl ester 2 was prepared following a known procedure 29. Then, the β‐amino functionality was converted into a hexadecyl sulfonamide; subsequently the allyl group was removed leading to free acid 4 .…”

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

“…Initial attempts to remove the Boc protecting group of 15 using TFA resulted in the cleavage of the pyridyl ether. Eventually, the deprotection was successfully carried out using trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine in DCM at -40 °C [26] to provide Compound 8. A very similar protocol was employed for the preparation of 4-iodo-3-hydroxypyridyl nisoxetine derivative 10 from the known 4-iodo-3-hydroxypyridine 17 [27].…”