Pergamon Tetrahedron: Asymmetry, Vol. 7, No. 5, pp. 1267-1268, 1996 Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0957-4166/96 $15.00 + 0,00 S0957-4166(96)00139-5 First Asymmetric Synthesis of (-)- (2S, 3R)-Methanoproline Alain Hercouet*, Bernard Bessi~res and Maurice Le Corre. Laboratoire de Syntla~se Organique, Associ~ au CNRS. Universit6 de Rennes I. Avenue du GfnOal Leclerc, 35042 Rennes Cedex, France. Abstract: The title amino acid was synthesized in enantiomerically pure form, starting from (S)-(-)-butanetriol 1, by condensation of cyclic sulfate 3 with methyl benzylideneglycinate. Copyright © 1996 Elsevier Science Ltd The potential value of 2,3-methanoaminoacids as enzyme inhibitors or in the synthesis of conformationally constrained peptidomimetics was recognized some years ago I. During the course of our studies toward the synthesis of cyclopropane aminoacids 2,3, we recently reported the synthesis of (-)-(IS, 2R)- allonorcoronamic acid using a chiral cyclic sulfate as precursor 3. We now wish to report the first asymmetric synthesis of (-)-(2S, 3R)-methanoproline 7, a known ethylene biosynthesis inhibitor which has already been prepared by Stammer 4 in the racemic form, and then resolved a few years later 5. Thus (S)-(-)-butanetriol 6 1 was converted to chlorosulfite 2 7 which was purified by flash chromatography (Scheme 1). The following oxidation, using the Sharpless procedure 8, gave sulfate 3. Scheme 1 o, ° o s-o s-o . ~o v v -o. -~ °r "--/~t~-cl NaIO~= , 1,," RuC13, O~C 1 (S)-(-)-I 2 3 Z(cid:127).... CO2Me NaH/DME ~ ~" "v PhCH=N-CH2CO2M~ N---CHPh .> CI" 4 ~t C02Me "~ NH ~kCO2Me HCI IN= ~,~ .or/NH3 +CI - CI 5 ~tCO 2" I°)HCI 6N ~ g~. + 2°)Dowex 50X8 NH 2 (2S, 3R)-7 1267
`
`SAXA-DEF-00440
`
`Page 1 of 2
`
`AstraZeneca Exhibit 2040
` Mylan v. AstraZeneca
` IPR2015-01340
`
`

`
`1268 A. HERCOUET et al. Condensation of this sulfate on methyl benzylideneglycinate 9, at room temperature in DME in the presence of two equivalents of sodium hydride, was achieved following the procedure recently reported 3, to give the alkylated imine 4 in quantitative yield. This reaction is diastereospecific, only the Z isomer is obtained. Hydrolysis of the amino protective group by 1 N HCI gave the hydrochloride 510 in 80% yield, that cyclized to the desired aminoester 6 when treated with K2CO3. Hydrolysis of the ester group was realized by refluxing in 6 N HCI. The aminoacid zwitterion 7 II was then quantitatively obtained using Dowex 50X8. This new synthesis can be perform on a multigram scale with 43% overall yield from 2 and without purification of intermediates. Spectral data and specific rotation of aminoacid 7 are in accordance with those obtained by Stammer 5. Acknowledgement: We are grateful to the Conseil R~gional de Bretagne for a doctoral fellowship to B. B.. R EFERI,?,N C ES 1. For recent reviews see: (a), Stammer C. H., Tetrahedron, 1990, 46, 2231. (b) Alami A., Calmes M., Daunis J. and Jacquier R., Bull. Soc. Chim. Fr., 1993, 130, 5. (c) Burgess K., Ho K. K. and Moye-Sherman D., Synlett, 1994, 575. 2. Le Corre M., Hercourt A. and Bessi~res B., Tetrahedron: Asymmetry, 1995, 6, 683. 3. Hercou~t A., Bessi&es B. and Le Corre M., Tetrahedron: Asymmetry, 1996, 7, 283. 4. Switzer F. L., Van Halbeek H., Holt E. M., Stammer C. H. and Salveit M. E., Tetrahedron, 1989, 45, 6091. 5. Matsui S., Srivastava V. P., Holt E. M., Taylor E. W. and Stammer C. H., Int. J. Peptide Protein Res., 1991, 37, 306. 6. Hanessian S., Ugolini A., Dub6 D. and Glamyan A., Can. J. Chem., 1984, 62, 2146. 7. 4-chloroethyl-2-oxo-1,3,2-dioxathiolane 2. SOC12 (21.3 mL, 300 retool) is added dropwise to a solution of I (10.61 g, 100 retool) in CCI4 (100 mL) and the solution is refluxed for 3h° The solvent is evaporated and the resulting oil is chromatographied over SiOg, eluting with Et20 to yield the two diastereomers (50:50) of 2 (11.76 g, 69 mmol, 69%). IH NMR (300 MHz, CDC13) ~ 2.06-2.48 (m, 4H); 3.65- 3.76 (m, 4H); 4.05-4.07 (m, IH), 4.38-4.44 (m, 1H), 4.53-4.58 (m, 1H); 4.76-4.81 (m, 2H) and 5.12-5.21 (m, 1H). 13C NMR (75.5 MHz, CDC13) i5 35.45 and 36.61; 40.25 and 40.77; 70.43 and 71.26; 77.48 and 80.42. 8. Gao Y. and Sharpless K. B., J. Am. Chem. Sot., 1988. 110, 7538. 9. Stork G., Leong A. Y. W. and Touzin A. M., J. Org. Chem., 1976, 41, 3491. 10. NMR of crude 5 : IH (300 MHz, CDC13) 5 1.62-1.74 (m, 2H), 1.98-2.05 (m, 1H), 2.19-2.26 (m, 1H), 2.41-2.46 (m, IH), 3.67-3.82 (m, 2H), 3.78 (s, 3H) and 9.14 (br s, 3H). J3C (75.5 MHz, CDCI3) ~ 19.26, 24.19, 30.03, 38.40, 44.05, 53.38 and 169.73. 20 11. (-)-(2S, 3R)-Methanoproline 7 : M.p. 217°C (dec) (Litt. 5 M.p. 215°C (dec)), let],, -51.2 (c 1, MeOH) (Litt. 5 [ct]~ ° -48.2 (c 1, MeOH). 1H NMR (300 MHz, D20)8 1.27-1.31 (m, 1H), 1.44-1.49 (m, IH), 2.03-2.21 (m, 3H), 2.86-2.91 (m, 1H) and 3.39-3.46 (m, 1H). 13C NMR (75.5 MHz, D20) 15.57, 27.28, 27.31, 45.40, 51.16 and 176.81. (Received in UK 8 March 1996)
`
`SAXA-DEF-00441
`
`Page 2 of 2