WOODWARD Peptide synthesis

WOODWARD Peptide synthesis Peptide synthesis mediated by N-ethyl 5-phenylisoxazoilum-3,-suifonate 3... 

WOODWARD Peptide synthesis 428 Woodward 305 WURTZ Coupling 429... 

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

For a synthesis of Cephalosporin C Woodward and co-workers required a protecting group that could be removed under mild and highly specific conditions. From this work, the 2,23-trichloroethyl (TCE) group was bom and its specific removal on treatment with zinc in acetic acid was the concluding step to their pioneering synthesis.193 More recently, zinc and 1 M ammonium acetate in THF has also be used.194 The group is still employed extensively in peptide synthesis as shown in a late step in a synthesis of the bacterial siderophore Alterobactin A [Scheme 6.83].195... 

Peptide synthesis. Izumiya and Muraoka1 examined the extent of isomerization with commonly used coupling reagents (isobutyl chloroformate, DCC, N-ethyl-5-phenylisoxazolium-3 -sulfonate, and EEDQ) and of these found that EEDQ caused the least racemization (0.2%) in the particular test chosen. The next most satisfactory was N-ethyl-5-phenylisoxazolium-3 -sulfonate (Woodward s Reagent K, 1.7-1.8%). 

The amino add analysis of all peptide chains on the resins indicated a ratio of Pro Val 6.6 6.0 (calcd. 6 6). The peptides were then cleaved from the resin with 30% HBr in acetic acid and chromatogra phed on sephadex LH-20 in 0.001 M HCl. 335 mg dodecapeptide was isolated. Hydrolysis followed by quantitative amino acid analysis gave a ratio of Pro Val - 6.0 5.6 (calcd. 6 6). Cycll2ation in DMF with Woodward s reagent K (see scheme below) yielded after purification 138 mg of needles of the desired cyc-lododecapeptide with one equiv of acetic add. The compound yielded a yellow adduct with potassium picrate, and here an analytically more acceptable ratio Pro Val of 1.03 1.00 (calcd. 1 1) was found. The mass spectrum contained a molecular ion peak. No other spectral measurements (lack of ORD, NMR) have been reported. For a thirty-six step synthesis in which each step may cause side-reaaions the characterization of the final product should, of course, be more elaborate. 

The smooth conversion of the enol acetate (151) into an A -acyl derivative (152) under extremely mild conditions points to the high acylating capacity of these esters. This cleavage of isoxazolium salts is also caused by other anions of carboxylic acids, and thus they can be readily converted to reactive enol esters. A very convenient and specific synthesis of peptides due to Woodward et is based on... 

Several different metltods were used to couple muramic acid with the peptide moiety. In the first synthesis of MDP, N-ethyl-5-phenyl-is-oxazolium-3 -sulfonate (Woodward s reagent K) was used (50). This condensing reagent had been applied in earlier preparations of various N-acetyl-muramyl-peptides (8, 39). A mixture of acetonitrile-dimethyl-formamide (2 1), is used as solvent but the protected muramic acid derivative is poorly soluble and the reaction does not always proceed well. 

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