Pipecolic Acid → Malonic acid, diethyl-

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Reaction Steps

1H NMR spectra were recorded on Bruker AM 100 and Bruker AM 400 spectrometers. As an internal standard the residual solvent peak was used. Chemical shifts are given in part per million (ppm). Optical rotations were measured on a Perkin Elmer 241 polarimeter in a 10 cm cuvette at room temperature. Melting points were determined with a Büchi melting point apparatus (Tottoli). TLC was performed on Merck SILICAGEL 60F254 plates, and column chromatography on Merck KIESELGEL 60, 70-230 Mesh ASTM. Spots were detected by UV-fluorescence quenching, ninhydrine (free amino functions), chlorine/TDM (NH groups), Barton's—(hydrazides) and Sakaguchi's (arginine residues) reagent. Methanol was refluxed on magnesium turnings for two hours, distilled and stored on 3 Å molsieves. Pyridine was distilled over KOH pellets and stored on 4 Å molsieves. Boc-amino acids were synthesized by the method of Schnabel31. Their hydroxysuccinimide esters were prepared according to Anderson et al.32 Amino acid p-nitroanilides were prepared as described elsewere. The resolution of DL-pipecolic acid was carried out according to the method of Mende and Lukes et al.33 Malonic acid and dimethylmalonic acid were converted to their corresponding dimethyl esters by heating the dicarboxylic acid with an excess of methanol in the presence of concentrated sulfuric acid34. Dimethyl methylmalonate was prepared by generating the mono-sodio derivative of dimethyl malonate which reacts with methyl iodide via a SN2 mechanism34. The corresponding half esters were prepared by controlled partial hydrolysis of the diester with one equivalent of potassium hydroxide35. The monomethyl ester of diethylmalonic acid was obtained in a direct way by refluxing the acid in an excess of methanol with sulfuric acid as catalyst. Dimethylmalonic acid and DL-pipecolic acid were from Janssen, diethylmalonic acid and D(−)-tartaric acid were from Aldrich. Naphtalene-2-sulfonyl chloride, toluene-4-sulfonyl chloride and D-alanine were obtained from Fluka. Boc-Nle-OH, Boc-D-Val-ONSu and Fmoc-Orn(Boc)-OH were from Bachem. D-Phenylalanine was a generous gift of Dr. J. Kamphuis (DSM Research, Geleen, The Netherlands).

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