Total Synthesis of cis,cis-Ceratospongamide, a Bioactive Thiazole-Containing Cyclic Peptide from Marine Origin

Abstract

Abstract:The first total synthesis of cis,cis-ceratospongamide (1a), isolated from marine source, was accomplished via thiazole synthesis using CMD methodology, DEPC-mediated peptide coupling, macrolactamization, and cyclodehydration. Comparison of the cyclization sites and coupling reagents in the macrolactamization step was also investigated.Key words: ceratospongamide, chemical manganese dioxide (CMD), macrolactamization, cyclic peptide, total synthesis Ceratospongamide is a bioactive thiazole-containing cyclic heptapeptide isolated by Gerwick and co-workers from the Indonesian red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica.1 This peptide consists of two L-phenylalanine residues, one (L-isoleucine)-L-methyloxazoline residue, one L-proline residue, and one (L-proline)thiazole residue. Interestingly, ceratospongamide is able to be isolated as two stable isomers, which are assigned as cis,cis-and trans,trans-isomers (1a, 1b) of the two proline amide bonds by Gerwick and co-workers (Figure 1). Both compounds show moderate potency in the brine shrimp toxicity assay (LD 50 = 13-19 mM). In addition, trans, exhibits potent inhibition of the expression of a key enzyme in the inflammatory cascade, secreted phospholipase A 2 (sPLA 2 ) with an ED 50 of 32 nM, whereas the cis,cis-conformer (1a) is inactive. As a part of our program toward the total synthesis of marine natural products, 2 we have embarked on the total synthesis of ceratospongamide. 3Our retrosynthetic analysis of ceratospongamide is shown in Scheme 1. As the oxazoline ring is sensitive under acidic conditions, we used allo-L-threonine as a precursor of the oxazoline and postponed the cyclodehydration of the threonine residue to the final stage of the total synthesis for reducing the risk of racemization at the chiral center attached to the heterocycle. 4 For the synthesis of the macrocycle 2, a [5+2] convergent strategy was adopted to give the pentapeptide segment 3 and dipeptide segment 4. Because the thiazole and L-proline residues located on the Cterminus in peptide coupling would be tolerant of racemization, the segment condensation and macrocyclization at the thiazole/L-phenylalanine and L-proline/L-isoleucine amide bonds were chosen among the six amide bonds.For the preparation of the thiazole amino acid fragment 8, we applied our CMD (chemical manganese dioxide) oxidation for the conversion of thiazolidine to thiazole (Scheme 2).3b,5 Coupling of Boc-protected L-proline with N,O-dimethylhydroxylamine using DEPC (diethyl phosphorocyanidate) 6 afforded the amide 5 in 88% yield. After reduction of the amide 5 with lithium aluminum hydride, 7 the resulting aldehyde 6 was condensed with L-cysteine methyl ester to give the thiazolidine 7 as a diastereomeric N

Marine natural products

“…201 The total synthesis of cis,cis-ceratospongamide 293 from the red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica 202 has been reported. 203 Hymenamide C 294 from Hymeniacidon sp. 204 has been synthesised using solid support methodology.…”

The cyclization of peptides and depsipeptides

“…Ceratospongamide (27) in its cis, cis form at the acyl-prolyl bonds, has been synthesized [180] using a (5 + 2) convergent strategy to form a linear precursor which allowed cyclization by activation of the triazole carboxyl group. Macrocyclization with DPPA gave a 31% yield while FDPP gave 63%, with cyclization to form the oxazoline kept to the last step using bis (2-methoxyethyl)amino sulfur trifluoride.…”

Oxidation of heterocyclic compounds by manganese dioxide (Review)*

“…Dehydrogenation with MnO 2 was also realized successfully in five-membered heterocycles with two heteroatoms: The dihydro derivatives of pyrazoles [59,60], imidazoles [61], isoxazoles [62], and thiazoles [63,64] and also tetrahydrothiazoles [63][64][65][66].…”