ABSTRACT:The cyclic dodecapeptides wewakazole and wewakazole B have been synthesized by a divergent strategy via a common tris-proline containing oxazole octapeptide and two separate bisoxazole containing tetrapeptide units, followed by peptide coupling and macrocyclization. The three oxazole amino acid fragments are readily accessible by rhodium(II)-catalysed amide N-H insertion of diazocarbonyl compounds, or by the cycloaddition of rhodium carbenoids with nitriles.Wewakazole 1 was isolated from the cyanobacterium Lyngbya majuscula off the coast of Papua New Guinea in 2003, and assigned a modified cyclododecapeptide structure incorporating three prolines, and in which one threonine and two serine residues had been cyclized to form oxazoles. 1 Although no biological activity was reported, subsequent studies showed that it was active against non-small cell lung cancer H-460 cells. 2 Thirteen years later, the structurally related wewakazole B 2 was reported from a different genus of cyanobacteria, Moorea producens, in the Red Sea. 3 Wewakazole B was of particular interest, given its reported anticancer activity (IC 50 0.58 µM against MCF7 breast cancer cells), 3 and the scarcity of material for further biological evaluation. Although two total syntheses of wewakazole B have recently been reported, 4,5 its mode of action remains unknown. Given our previous work in the synthesis of post-translationally modified peptides, and particularly those containing azoles, 6-10 these two structures caught our attention as attractive targets for total synthesis. The two wewakazole structures differ only by the presence or absence of a methyl group on one oxazole and the identity of two of the peptide residues: the 5-unsubstituted oxazole, phenylalanine and valine present in wewakazole are replaced with a 5-methyloxazole, alanine and phenylalanine in wewakazole B. As all these variations are found within one portion of the structures, a divergent strategy for the synthesis of the two compounds presented itself, whereby the common octapeptide 3 could be synthesized and coupled to the two bis-oxazole containing tetrapeptide units 4 and 5. An additional advantage of this approach is that macrocyclization can be carried out by amide coupling of the N-terminal to a Cterminal glycine, reducing the steric bulk around the reactive center and minimizing the risk of epimerization in what will inevitably be a highly dilute, and hence slow, macrocyclization step. We have previously reported the use of rhodium(II)-catalyzed amide N-H insertion of diazocarbonyl compounds for
The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)‐catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis.
The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)‐catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis.
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