Synthesis of depsipeptides

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Arthur, M. Molinas, C. Courvalin, P. The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J. Bacteriol., 174, 2582-2591 (1992)... 

In summary, among the carbodiimide-based methods only the carbodiimide/dialkyl-aminopyridine technique has been widely used in the synthesis of depsipeptides. It usually affords the desired products in moderate or high yield and has good potential for routine use in the esterification of urethane-protected amino acids or peptide fragments even in the case... 

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. 

Most commonly, the carboxylate anion is treated directly with an alkyl halide to give the corresponding ester212,371-373. A variety of metal counterions have been used to influence the yield, depending upon the substrates being used. Silver oxide has been used to assist this process in the synthesis of depsipeptide analogues from 2-bromocarboxamides and N-protected amino acids (equation 46)374. 

The acid chloride method has been successfully used for the synthesis of depsipeptides by O-acylation of hydroxy acids. Although Fmoc amino acid chlorides were recommended for such reactions, and can be used for the introduction of the first amino acid onto hydroxy resins for SPPS, oxazol-5(4//)-one formation promoted by the presence of the required tertiary amine leads to relatively low yields compared to other activation methods such as those involving UNCA groups. ... 

Synthesis of depsipeptides by the Fmoc/tBu strategy presents some limitations because of the potential lability of the ester bond in response to piperidine exposure, and to the formation of DKP after the deprotection of the second amino acid after the ester bond. 

Spengler and coworkers [173] have used p-nitromandelic acid (Pnm) as a safety-catch linker for the synthesis of depsipeptides by Boc/Bzl chemistry. The hexafluo-roacetone (HFA)-protected Pnm is loaded on the resin with concomitant deprotection of the hydroxy unit. After the depsipeptide is constructed, reduction of the nitro group with 6M SnCl2/1.6mM HC1 gives the p-aminomandelic (Pam) linker, which can be cleaved in acidic media (5% TFA in dioxane, 50°C, lh), thereby obtaining the target depsipeptides in good yields and purities (Scheme 18.7). 

Total Synthesis of Depsipeptide HDAC Inhibitors - Routes to the fi-Hydroxy Acid Fragment... 

Compared to other classes of HDAC inhibitors, the depsipeptides exhibit two impressive features. Firstly, they are highly potent with IC50S in the low nanomolar range. Secondly, they are significantly more active against class I HDACs compared to class II HDACs. Fortuitously, it is the former that are more heavily implicated in cancer and cardiac hypertrophy. On the other hand, the depsipeptides are structurally the most complicated class of HDAC inhibitors. Their elaborate framework has apparently deterred the pharmaceutical industry from the preparation of unnatural analogs and the iterative improvement of their properties. The Fujisawa and Yamanouchi patents only cover the natural products and so far only academic groups have described the total synthesis of depsipeptides. 

DCC-DMAP has been used in the synthesis of depsipeptides. Macrocyclic lactones have been prepared by cyclization of hydroxy carboxylic acids with DCC-DMAP. The presence of salts of DMAP, such as its trifluoroacetate, is beneficial in such cyclizations, as shown for the synthesis of a (9. -dihydroerythronolide. Other macrolactonizations have been achieved using 2,4,6-Trichlorobenzoyl Chloride and DMAP in Triethylamine at rt or Di-2-pyridyl Carbonate (6 equiv) with 2 equiv of DMAP at 73 °C. ... 

It has been shown by Ojima in the synthesis of depsipeptides (see the last five lines in Table 6) that optical selectivities are much higher in the hydrosilylation reactions, where asymmetric induction by the chiral catalyst predominates over that of the chiral center already present in the N- (a- ketoacyO-a- aminoester substrates. 

Madry N, Zocher R, Kleinkauf H. Selective synthesis of depsipeptides by the immobilized multienzyme enniatin synthetase. Eur J Appl Microbiol Biotechnol 1983 17 75-79. 

Arthur Mi Molinas C, Depardieu F, Courvalin P Characterization ofTnl546, 9 Tn3-related transposon conferring glycopcptide resistance by synthesis of depsipeptide peptidoglycan precursors in Enterococcus/oecium BM4147. J Bacteriol 1993 175 117-121. 

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