J. CHEM. soc. PERKIN TRANS. I 1995 (I?)-(+ )-3-Amino-2-phenylpropanoic Acid: a Revised Absolute Configuration based on an Enantioselective Synthesis and an X-Ray Crystal Structure of the Salt with (1S)-( +)-Camphor-l O-sulfonic Acid Alice A. D'Souza, Majid Motevalli, Andrew J. Robinson and Peter B. WyatttDepartment of Chemistry, Queen Mary and Westfield College, University of London, Mile End Road, London El 4NS, UK ~ Amidoalkylation of the lithium enolate of (4S,5R) -4-methyl- 5-phenyl-3- (phenylacetyl) oxazolidin- 2-one 5 by 1-(N-benzyloxycarbonylaminomethyl)benzotriazole 2c. followed by cleavage of the oxazolidinone chiral auxiliary and of the N-benzyloxycarbonyl group, gave (R)-( +) -3-amino-2-phenylpropanoic acid 1, the absolute configuration of which was determined by X-ray crystallography on the salt 8 with (1S)-(+)-camphor-I O-sulfonic acid.Derivatives of 3-amino-2-phenylpropanoicacid 1, an isomer of 62% yield by refluxing 1-(hydroxyrnethyl)benzotriazole and phenylalanine, are of biological interest. For example, (-)-1 is benzyl carbamate with a catalytic amount of toluene-4-sulfonic the side chain in the semisynthetic penicillin betacine,' whereas acid in toluene, using a Dean-Stark trap. the ethyl ester of ( k)-1 has neurological activity.2 The amino The lithium enolate of the 3-(phenylacety1)oxazolidinone 5 acid 1has been resolved via its camphor-lO-sulfonate salt and was generated (LDA-THF, -78 "C) and then treated with 4c. (+)-1 has been assigned the S-configuration by a chemical The mixture was allowed to warm up to +20 "C over 5 h, and correlation with ( +)-(S)-1 -amino-2-phenylbutane and by ORD then maintained at this temperature for 1 h before being studies;3 however, no previous asymmetric synthesis of 1 has quenched with saturated NH,Cl (aq.) and subjected to an been reported. We chose 1 as a target in order to explore the aqueous work up.A 250 MHz 'H NMR spectrum of the crude stereoselective aminomethylation of chiral enolates. organic product was consistent with the formation of the Evans et a/. have reported that the titanium enolate of the protected amino acid 6 and the deacylated oxazolidinone 7 as acyloxazolidinone2a reacts with N-(chloromethy1)benzamide3 the principal products in a ca. 3 :1 molar ratio: presumably 7 to give the amidoalkylation product 2b,stereoselectively and in arises by decomposition of the enolate of 5 at the relatively high high yield.4 However, the reagent 3deteriorates on storage and temperatures needed for the amidoalkylation. Flash chromato- the ultimate removal of the N-benzoyl group would normally graphy, using EtOAc-light petroleum (b.p.40-60 "C) as eluent, require heating with mineral acid, conditions under which an gave 6 as a foam, [a]D +84 (c 1.1 in EtOAc), in 65% yield.$ acid such as 1might be expected to racemize. The chiral auxiliary was then removed hydrolytically and the Z 1-(Aminomethyl)benzotriazolesand their N-acyl derivatives group was hydrogenolysed to give, after recrystallisation from can also function as aminomethylating agents.6 Recent work by aqueous ethanol, (+)-3-amino-2-phenylpropanoicacid 1(68% Page and co-workers7 has shown that the reagents 4a and 4b yield from 6).9 may be used to effect the stereoselective aminoalkylation of ketone enolates containing the 1,3-dithiane 1-oxide auxiliary.We reasoned that 1-(N-benzyloxycarbonylaminomethy1)-benzotriazole 4c would be a particularly useful aminomethyl- 'kPhating agent because the benzyloxycarbonyl group could readily i, ii, iii iv,v be removed by catalytic hydrogenolysis. The stable, crystalline Ph-N)f'o -reagent 4c, m.p. 119-120 "C (from toluene),$ was prepared in 00 00 5 6 Scheme 1 Reagents and conditions: i, LDA, THF, -78 "C; ii, 4c; iii,H3N+i warm to 20 "C;iv, LiOH, H,O,, H,O, 0 "C, 1 h, then H+;v, H, (3 atm), Ph*C02-L( R Pd-C, AcOH CH2Ph 1 2a R=H 2b R=CH$JHCOPh It was expected that the amidomethylation would occur selectively on the less hindered, siface of the chelated, Z form of the enolate of 5, which is the preferred site for alkylation of this CICH2NHCOPh C , N type of en~late,~ thus leading to the synthesis of (R)-1; yet the 3 'N [a]D data in ref.3 implied that the S-enantiomer had been produced. In order to resolve this inconsistency, (+)-1 was'NHP treated with (lS)-( +)-camphor-lO-sulfonic acid to give the salt 4a P=CH2Ph 8, which after crystallisation from EtOH-Et20 had [alD +614b P = COPh (c 0.5 in H,O) {lit.,' [alD +63 (c 0.5 in H,O)} and for which 4c P=Z t E-mail: p.b.wyatt@qmw.ac.uk. 0Data for (+)-I: m.p.222-224 "C (decomp.), [alD +94 (c 0.2 in $ Compounds 4c and 6 had spectroscopic and high resolution mass H,O) {lit.,3 m.p. 224-225 "C (decomp.), [alDfor (S)-1 +95 (c 0.2 in spectrometric data in full agreement with the structures proposed; a H,O)}; 6,(250 MHz, D20)3.30 (1 H, dd, J 12 and 7 Hz), 3.49 (1 H, satisfactory microanalysis was also obtained for 4c. dd, J 12 and 7 Hz), 3.81 (1 H, t, J7 Hz) and 7.3-7.5 (5 H, m). 2 J. CHEM. SOC. PERKIN TRANS. I 1995 Fig. 1 X-Ray crystal structure of compound 8 the R-configuration of the amino acid 1 was proved by a single crystal X-ray structure determination (Fig. 1).* Thus, we have shown that the reagent 4c does deliver a conveniently N-protected aminomethyl group to the enolate of the N-acyloxazolidinone 5, in the same stereochemical sense as has been observed for simple alkylations.We have also shown * Crystal Structure Determination for Compound 8.-Data were collected at 293 K on an Enraf-Nonius CAD-4 diffractometer. C,H,,NO,+ CloH1,SO4-, M 397.48, monoclinic, space group P2,, a = 6.280(2), h = 11.563(4), c = 13.804(3) A, U = 987.6(5) A3, F(OO0) = 424; Z = 2, D, = 1.337 g ~m-~,Mo-Ka, 1 = 0.710 69 A, ,u(Mo-Kcr) = 0.199 mm-', 2503 independent reflections. The structure was solved by direct methods using SHELXS-86 lo and refined on F2 by full matrix, least-squares techniques using SHELXL-93.' All atoms were refined isotropically, except 0 and S atoms. H atoms were placed at calculated positions using the AFIX command in SHELXL-93.Displacement parameters of H atoms were kept fixed at the isotropic values of parent atoms. The absolute configuration was confirmed by the Flack factor,' x = -0.3(2), in SHELXL-93. Atomic coordinates, bond lengths and angles, and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre. See 'Instructions for Authors (1994)', J. Chem. Soc., Perkin Trans. 1, 1995, Issue 1. The final residuals for reflections with I > 20 (0 were R, = 0.0557, wR, = 0.1096. "SHP" HNKo0 7 8 that the absolute configuration of 1was incorrectly assigned in ref. 3. Acknowledgements We thank the EPSRC (formerly SERC) for studentships (A. A. D. S. and A. J. R.). We also thank Miss J. Isaacs, Mr. P.Cook and Mr. G. Coumbarides for measuring spectra. References 1 E. Testa, G. Cignarella, G. Pifferi, S. Furesz, M. T. Timbal, P. Schiatti and G. Maffii, I1Farmaco (Sci. Ed.), 1964, 19, 895. 2 F. Leonard, A. Wajngurt, M. Klein and C. M. Smith, J. Org. Chem., 1961,26,4062. 3 J. A. Garbarino and 0. Nufiez, J. Chem. Soc., Perkin Trans. I, 1981,906. 4 D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark and M. T. Bilodeau, J. Am. Chem. Soc., 1990,112,8215. 5 J. J. Getz, R. J. Prankerd and K. B. Sloan,J. Org. Chem., 1992,57,1702. 6 A. R. Katritzky, X. Lan and W.-Q. Fan, Synthesis, 1994,445. 7 P. C. B. Page, S. M. Allin, E. W. Collington and R. A. E. Carr, J. Org. Chem., 1993,58, 6902. 8 K. Fries, H. Guterbock and H. Kuhn, Annalen, 1934,511, 213. 9 D. A. Evans, M. D. EnnisandD. J. Mathre, J. Am. Chem. SOC., 1982, 104,1737. 10 G. M. Sheldrick, SHELXS-86 Program for structure solution, Acta Crystallogr., Sect. A, 1990,46,467. 11 G. M. Sheldrick, Program for crystal structure refinement, J. Appl. Crystallogr., in preparation. 12 H. D. Flack, Acta Crystallogr., Sect. A, 1983,39, 876. Paper 4/06444E Received 21st October 1994 Accepted 3rd November 1994