Depsipeptides synthesis

A distinct group of synthetic depsipeptides comprises of compounds that do not originate from natural product biodiversity several artificial substrates of peptidases and esterases belong to this group, as well as polydepsipeptides that are considered as potentially biodegradable polymeric materials. A specific feature of depsipeptide synthesis is the necessity to acylate a hydroxy acid component, which requires stronger activation of the amino acid component in comparison to normal peptide synthesis. Otherwise, the main principles of depsipeptide synthesis are similar to those of peptides. Frequently, formation of the ester... 

Some of the versions of the mixed anhydride technique discussed may involve components other than a-hydroxy acids. Therefore, the resultant products cannot be considered as main-chain modified peptidomimetics. However, on many grounds these methods are of general importance in depsipeptide synthesis. For example the classical peptide reagent isobutyl chloroformate appears to be suitable for ester bond formation through the corresponding mixed anhydride with Boc- or Z-protected amino acids and the Thr (3-hydroxy group in the synthesis of a number of natural peptide lactones.145 7 ... 

Table 4 Yields and Reaction Conditions for Depsipeptide Synthesis Using the Mitsunobu Reaction198 "1011...

Mitsunobu activation of a hydroxy group has been successfully utilized for the construction of depsipeptide units in only a limited number of published synthetic works. Nevertheless, this procedure might be considered as an effective and promising approach to depsipeptide synthesis even in complicated cases due to its simplicity, mild conditions, and absence of racemization. 

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. 

Boc-Ala-O-Gly-OBzl General Procedure for Depsipeptide Synthesis through Active Esters 1 041... 

In addition to the more or less popular methods of depsipeptide synthesis discussed vide supra, there are also a limited number of complementary and effective synthetic procedures that have been described for this purpose. Among these, the well-known method of symmetric anhydrides from N-protected amino acids has to be considered. This method has found successful use in the esterification of hydroxy acids in the presence of some catalyst additives. Initially, the addition of pyridine11091 or 1-hydroxybenzotriazole in pyridine1 101 to a symmetric anhydride was utilized for ester bond formation. As an example, Katakai has prepared a number of didepsipeptides in 85-96% yield by means of a 2-nitrophenylsulfenyl /V-carboxy anhydride with lactic acid derivatives in the presence of pyridine.1 09 ... 

Stawikowski, M., and Cudic, P. (2006) Depsipeptide synthesis, in Peptide Characterization and Application Protocols (Fields, G. B., ed.), Humana Press, Totowa, NJ, pp. 321-339. 

Table 18.1 Cycles performed in a depsipeptide synthesis (see text for details).

Zocher R, Keller U, Kleinkauf H. Enniatin synthetase, a novel type of multifunctional enzyme catalyzing depsipeptide synthesis in FusoWum oxysporum. Biochemistry 1982 21 43-48. 

Zocher R, Keller U, Kleinkauf H. Enniatin synthetase, a novel type of multifunctional enzyme catalyzing depsipeptide synthesis in Fusarium oxysporum. Biochem 1982 21 43-48. Zocher R, Nihira T, Paul E, Madry N, Pecters H, Kleinkauf H. Keller U. Biosynthesis of cyclosporin A Partial purification and properties of a mulcifunctional enzyme from Tolypocla-diutn mjkitum. Biochem 1986 25 550-553. 

Wilson B.J., Ramstad, E., Jansson, I. and Orrenius, S. (1971) Conversion of agroclavine by mammalian cytochrome P450. Biochim. Biophys. Acta, 252, 348-356. Zocher, R., Keller, U. and Kleinkauf, H. (1982) Enniatin synthetase, a novel type of multifunctional enzyme catalyzing depsipeptide synthesis in Fusarium oxysporum. Biochemistry, 21,43—48. 

Ethylene derivatives from halides) CGl>Hal —, aromatization by — 19, 975 —, preferential 19, 971 0-Demesylation —, stereospecific 19, 4 Depsipeptides, synthesis, acid chloride method 19, 517 0-Depyranylation, selective 19, 10... 

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]. 

Application of the bromine substitution reaction allows the synthesis of aminoamides, alkoxyamides of simple alcohols and sugars, depsipeptides and (NH) pseudopeptides, C2 symmetric compounds. 

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]. 

Cabaret, D. Adediran, S. A. Garcia Gonzalez, M. J. Pratt, R. F. Wakselman, M. Synthesis and reactivity with P-lactamases of penicillin-like cyclic depsipeptides. J. Org. Chem. 1999, 64, 713-720. 

As an example for the synthesis of a 14C-labeled depsipeptide from 14C-glycine and serine by the imidazolide method, see reference [78]. 

TE-catalyzed cyclization is not limited to the synthesis of macrocyclic peptides by catalyzing the formation of aC N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a di-domain excised from fengycin synthase was... 

Initially PDPs were synthesized by stepwise polycondensation of linear activated depsipeptide [93]. In 1985, Helder, Feijen and coworkers reported the synthesis of PDPs by ROP of a morpholine-2,5-dione derivative (cyclic dimer of ot-hydroxy- and a-amino acid cyclodepsipeptide, cDP) [94, 95]. The ROP method gives an alternative type of PDP by homopolymerization and also allows the copolymerization with other monomers (lactones and cyclic diesters) including LA, GA, and CL to give a wide variety of functional biodegradable materials. The synthesis of PDPs as functional biomaterials has been recently reviewed [17]. 

Fig. 4 Synthesis of polydepsipeptides and poly(depsipeptide-co-lactide)s having reactive side-chain groups...

Narita K, Kikuchi T, Watanabe K, Takizawa T, Oguchi T, Kudo K, Matsuhara K, Abe H, Yamori T, Yoshida M, Katoh T. (2(X)9) Total synthesis of the bicyclic depsipeptide HD AC inhibitors spiruchostatins A and B, 5"-ep(-spiruchostatin B, FK228 (FR901228) and preUminary evaluation of their biological activity. Chem Ear J15 11174-11186. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

It should be noted that TE-catalyzed cyclization is not Umited to the synthesis ofmacrocycUc peptides by catalyzing the formation of a C—N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a didomain excised from fengydn synthase was able to catalyze the formation of a macrolactone through the formation of a C—O bond [39]. Several cyclases from PKSs have also been characterized to be functional. For example, when a TE from picromycin synthase was fused to an erythromycin module (DEBS module 3), the resulting hybrid was able to convert a diketide and 2-methylmalonyl-CoA to a triketide ketolactone (Scheme 7.12) [40]. However, their in vitro activity is in... 

Fiuorotris(trimethyisiiyi)methane addition reactions. Synthesis of fiuorooiefin depsipeptide precursor (27)... 

A kinetically controlled Negishi palladium-catalyzed coupling reaction was used in a highly stereospecific synthesis of (E)- or (Z)-a-fluoro-a,/(-unsaturated ketone (29), an intermediate to the above described depsipeptides [54], Reaction of E/Z gem-bromofluoroolefin (30) and alkoxyvinylzinc species (31) yielded (Z)-29 in 70-99% yields. When the unreacted (Z) bromo, fluoroolefin was allowed to react in tetrahydrofuran (THF) under reflux, (E)-29 was formed in up to 98% yield (Scheme 9). 

The antibiotic viscosin from Pseudomonas viscosa (Scheme 8) is a cyclo-depsipeptide acyl-ated at the N-terminus with D-3-hydroxydecanoic add.[103 112] The C-terminal carboxy group is esterified with the hydroxy group of the Thr3 residue. The synthesis of this natural product presents the problem of an ester ring closure and was performed in two steps with initial solid-phase synthesis of the Thr3-0-branched linear intermediate followed by ring closure with formation of the amide bond.1 131... 

---