Pergamon zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Appl. Radial. Isor. Vol. 45, No. 3, pp. 361-369, 1994 Elsevier Science Ltd Printed in Great Britain 0969-8043/94 $6.00 + 0.00 Enantioselective Syntheses of n.c.a. (S)-L-[/? -“Cl-4-Chlorophenylalanine and (S)-~-(a -Methyl)-[P -“Cl-4-Chlorophenylalanine ALAIN PLENEVAUX, M. J. AL-DARWICH, CHRISTIAN LEMAIRE, GUY DELFIORE and DOMINIQUE COMAR Cyclotron Research Center, Liege University, B-4000 Liege, Belgium (Received 12 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML July 1993) The radiolabeling of (S)-L-4chlorophenylalanine and (S)-L-(a-methyl)-4-chlorophenylalanine were real- ized with carbon-l 1 at position fi through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chioro[a-“C]benzyc bromide and the lithium enoiate-of (S)-l-(t-butyloxycarbonyl)- 2-(t-butyl)-3-methvl-I,3-imidazolidine-4-one for (S)-L-IS-“Cl-4-chloroohenvlalanine and of (2S,5S)-l- (t-butylbxycarbon~l)-2-(t-butyl)-3,5-dimethyl-l,~-~midazolidine-4-one for-(S)-L-(a-methyl)-b-“Cl-4- chlorophenylalanine. Quantities of about 25-35 mCi were obtained at the end of synthesis, ready for injection, after hydrolysis and HPLC purification with a radiochemical yield of 19% corrected to EOB within 45 min. The enantiomeric excesses were shown to be 397% for both molecules without chiral separation. The radiochemical and the chemical purities of the final compounds were 298% and the specific activity at the end of synthesis ranged between 25OG800 mCi/pmol. Introduction L-4-Chlorophenylalanine (PCPA) has been demon- strated to produce a long-lasting depletion of cerebral serotonin (5-HT) in several species (Koe and Weiss- man, 1966; Weitzman et al., 1968) and is known to be an irreversible inhibitor of tryptophan hydroxylase (TpOH) activity, the rate limiting enzyme in the synthesis of S-HT (Jequier et al., 1967). Another interesting property is that no such effect was ob- served on tyrosine hydroxylase presumably due to the very poor affinity of PCPA for this enzyme (Gal et al., 1970). More recent work has shown that a single injection of PCPA totally blocked the TpOH protein synthesis in the rat raphe dorsalis nucleus which is the brain region displaying the greatest population of serotonin-containing cells (Richard et al., 1990; Weissman et al., 1990). As the concentration of the neurotransmitter 5-HT is lower in the brain of patients with certain mental disorders than in normal brain (Gaillard and Tissot, 1979), the cerebral metabolism of 5-HT must be considered as a topic of importance. In the continu- ing search for a specific tool to study this neurotrans- mission system in uiuo with positron emission tomography (PET), PCPA appeared to be a potential radiopharmaceutical. Nonproteinogenic, unnatural a-amino acids have increasingly attracted the attention of numerous dis- ciplines including enzyme inhibitor synthesis, phar- maceutical chemistry and the study of enzymatic reaction mechanisms. As a consequence, numerous and versatile approaches to the synthesis of natural and unnatural amino acids in optically active form have been reported (Barrett, 1985; Williams, 1989; O’Donnell, 1988; Coppola and Schuster, 1987; Oppolzer, 1987; Seebach er al., 1989). The present study deals with the enantioselective syntheses of (S)-L-[@-“Cl-4-chlorophenylalanine and (S)- L- (a- methyl)-[P-“Cl-4-chlorophenylalanine. The synthesis of the a-methyl substituted analog of PCPA was considered because this type of compound has been the subject of several studies (O’Donnell and Wu, 1992 and references cited therein) and that an inter- esting property of the a-methyl substituted amino acids is that they show some potential as inhibitors of decarboxyl-ase and hydroxylase enzymes (Moore and Jerome, 1971; Coenen, 1993). Experimental Instrumentation and methods Melting points were measured with a Fisher-Johns apparatus and are uncorrected. ‘H-NMR spectra were recorded on a Brucker 400 MHz instrument in CDCl, or in D,O/DCI, the chemical shifts were reported in parts per million (6) downfield from tetramethylsilane or from 3-(trimethylsilyl)-l- propanesulfonic acid sodium salt (DSS) as internal reference. Mass spectra were obtained with a VG 361