Depsipeptide methodology

Coin 1, Dolling R, Krause E, Bienert M, Beyermann M, Sferdean CD, Carpino LA. Depsipeptide methodology for solid-phase peptide synthesis circumventing side reactions and development of an automated technique via depsidipeptide units. J. Org. Chem. 

To overcome aggregation, stepwise elongation of large peptides requires not only potent coupling reagents but also additional tools. In recent years, beneficial results have been obtained by means of PEG resins, pseudoprolines (TPro) and O-acyl isopeptide or depsipeptide methodology. 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Benzenesulfonyl chloride in pyridine remains a powerful and facile method for the efficient synthesis of optically pure depsipeptides. Nevertheless, various new approaches based upon the mixed anhydride methodology have been introduced into depsipeptide chemistry. 

The active ester methodology, which is widely used in peptide chemistry, has found only limited application in depsipeptide synthesis. A more vigorous activation of the carboxy component is apparently required to form an ester bond compared to the peptide analogue. Nevertheless, active esters have been utilized for this purpose in combination with some catalyst additives. The first successful attempt in this direction was described by Mazur.1103 The modification of the 4-nitrophenyl ester procedure included addition of 1-10 equivalents of imidazole to the reaction mixture. This accelerated technique presumably involves formation of the highly reactive intermediate imidazolide. The reaction resulted in the preparation of model benzyloxycarbonyl didepsipeptide esters in good yields within several hours at room temperature from 4-nitrophenyl esters of Z-amino acids and the pentamethylbenzyl ester of glycolic acid, while in the absence of imidazole this reaction failed to give any product. 

Although oligomers of a-hydroxy acids (depsides) and mixed oligomers of cx-hydroxy and a-amino acids (depsipeptides) are found in nature (antibiotics, ion-transporters [249,250]), little solid-phase methodology has been developed for their preparation. One recent strategy is based on sequential acylation with THP-protected cx-hydroxy acids (DIC, DMAP, THF, 2 h see Entry 6, Table 13.13), followed by deprotection with TsOH/MeOH [249,251]. Under these conditions, no racemization was observed. A similar approach to the solid-phase synthesis of depsipeptides is outlined in Figure 16.24. 

The following general solid-phase synthetic protocol can be used for depside and depsipeptide bond formation using DIC/DMAP coupling methodology (64-66). 

Kuisle, O., Quinoa, E., and Riguera, R., (1999) A general methodology for automated solid-phase synthesis of depsides and depsipeptides. Preparation of a valinomycin analogue. J. Org Chem. 64, 8063-8075. 

Depsipeptide SPPS methodology, a method for SPPS applicable to difficult sequences arising from aggregation phenomena. It relies on the synthesis of Ser or Thr isopeptide intermediates with a final 0-N acyl migration step. The principle is identical to the O-acyl isopeptide method, also termed click peptide or switch peptide method that were developed independently by different groups. It was, for example, successfully employed to synthesize the extremely difficult WWDomain FBP28 [I. Coin et al.,/. Org. Chem. 2006, 71, 6171]. 

Zhu s group applied their synthetic methodology for 1675 analogs to the synthesis of macrocytic depsipeptides wherein an oxazole was the activating group... 

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