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Synlett 2005(4): 631-634  
DOI: 10.1055/s-2005-863719
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthesis of Cyclic β-Amino Acid Derivatives as β-Turn Mimetics

Toshio Yamanaka*a,b, Mitsuru Ohkubo*a, Masayuki Katoa, Yasufumi Kawamurab, Akinori Nishib, Takahiro Hosokawab
a Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-Ku, Osaka 532-8514, Japan
b Department of Environmental Systems Engineering, Kochi University of Technology, Tosayamada, Kochi 782-8502, Japan
Fax: +81(6)63045435; e-Mail: toshio_yamanaka@po.fujisawa.co.jp;
Further Information

Publication History

Received 3 December 2004
Publication Date:
22 February 2005 (online)

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Abstract

Seven-, eight-, and nine-membered cyclic β-amino acids, precursors of platelet aggregation inhibitors, were synthesized for the first time starting from N-alkenyl amines and ethyl acrylate via ring-closing metathesis (RCM) as the key reaction. Synthesis of the corresponding enantiomerically pure β-amino acids was also accomplished in a similar manner using Evans’ asymmetric allylation.

Key words

cyclic β-amino acid - β-turn mimetics - ring-closing metathesis - asymmetric allylation - platelet aggregation inhibitor

9

Purchased from Tokyo Chemical Industry (TCI).

11

Purchased from Aldrich.

13

Procedure for the Preparation of 11a.
To a solution of 10a (735 mg, 1.72 mmol, >99% de) in anhyd CH2Cl2 (70 mL) was added Grubbs’ catalyst 6 (146 mg, 0.172 mmol). The mixture was refluxed under nitrogen atmosphere for 1.5 h. After cooling to r.t., solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:4) to give 11a (664 mg, 97%) as an amorphous solid. The diastereomeric purity of purified 11a was >99% de determined by HPLC analysis using CHIRALPAK AD (DAICEL) with hexane-i-PrOH (85:15). IR (KBr): 2976, 2929, 1772, 1697, 1684, 1456, 1051, 1020, 702 cm-1. 1H NMR (CDCl3; major rotamer): δ = 1.47 (s, 9 H), 2.38-2.58 (m, 2 H), 2.73-2.79 (m, 1 H), 3.28 (dd, J = 13.2, 3.3 Hz, 1 H), 3.65 (dd, J = 13.9, 8.0 Hz, 1 H), 3.79 (dd, J = 13.9, 6.8 Hz, 1 H), 3.85-4.06 (m, 2 H), 4.10-4.27 (m, 3 H), 4.58-4.82 (m, 1 H), 5.62-5.89 (m, 2 H), 7.20-7.36 (m, 5 H). HRMS: m/z calcd for C22H29N2O5 [M + H]+: 401.2076; found: 401.2069. [α]D 27 -42.0 (c 0.525, CHCl3).

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Procedure for the Preparation of 12a. To a solution of 11a (560 mg, 1.40 mmol) in THF (28 mL) and H2O (9 mL) were added 30% H2O2 (1.27 mL, 11.2 mmol, 8.0 equiv) and then 1 N aq LiOH solution (2.8 mL, 2.8 mmol, 2.0 equiv) under ice cooling. The reaction mixture was stirred at the same temperature for 30 min, then treated with 20% aq Na2S2O3 solution (55 mL) and stirred for further 5 min. It was extracted with Et2O. The aqueous phase was acidified to pH 2 with 10% aq KHSO4, and extracted with EtOAc twice. The extracts were combined and dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified with silica gel short column chromatography on silica gel (CH2Cl2-EtOAc = 1:1) to give 12a (295 mg, 87%) as an oil. The enantiomeric purity of purified 12a was >98% ee determined by HPLC analysis using CHIRALPAK AD column (DAICEL) (hexane-EtOH-TFA = 98:2:0.1). IR (neat): 2978, 2933, 2866, 1734, 1697, 1419, 1367, 1269, 1252, 1167, 891 cm-1. 1H NMR (CDCl3): δ = 1.47 (s, 9 H), 2.43-2.47 (m, 2 H), 2.80-3.15 (m, 1 H), 3.55-4.30 (m, 4 H), 5.55-5.85 (m, 2 H). HRMS: m/z calcd for C12H20NO4 [M + H]+: 242.1392; found: 242.1387. [α]D 26 -23.2 (c 1.01, CHCl3).

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Procedure for the Preparation of 13a.
To a solution of 12a (48 mg, 0.20 mmol) in MeOH (1.5 mL) was added 10% Pd/C (24 mg), and the mixture was stirred under H2 atmosphere (1 atm) at r.t. for 3 h. The catalyst was filtered off, and the filtrate was evaporated off to give 13a (48 mg, 100%) as a solid. The enantiomeric purity of purified 13a was >98% ee determined by HPLC analysis using CHIRALPAK AD column (DAICEL) with (hexane-EtOH-TFA = 98:2:0.1). IR (KBr): 2976, 2933, 2866, 1732, 1695, 1481, 1423, 1367, 1163 cm-1. 1H NMR (CDCl3; major rotamer): δ = 1.31-1.96 (m, 5 H), 1.48 (s, 9 H), 2.01-2.08 (m, 1 H), 2.86-2.93 (m, 1 H), 3.13-3.27 (m, 1 H), 3.52 (dt, J = 13.9, 5.1 Hz, 1 H), 3.60-3.70 (m, 2 H). HRMS: m/z calcd for C12H22NO4 [M + H]+: 244.1549; found: 244.1542. [α]D 26 -7.7 (c 0.74, CHCl3).