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

Toshio Yamanaka; Mitsuru Ohkubo; Masayuki Kato; Yasufumi Kawamura; Akinori Nishi; Takahiro Hosokawa

doi:10.1055/s-2005-863719

LETTER

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

Toshio Yamanaka*^a,b, Mitsuru Ohkubo*^a, Masayuki Kato^a, Yasufumi Kawamura^b, Akinori Nishi^b, Takahiro Hosokawa^b
^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;

Abstract

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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

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References

<A NAME="RU33104ST-1">1</A> Hawiger J. Kloczewiak M. Bednarek MA. Timmons S. Biochemistry 1989, 28: 2909

For reviews, see:

<A NAME="RU33104ST-2A">2a</A> Agah R. Plow EF. Topol EJ. Platelets 2002, 769

<A NAME="RU33104ST-2B">2b</A> Scarborough RM. Gretler DD. J. Med. Chem. 2000, 43: 3454

<A NAME="RU33104ST-2C">2c</A> Mousa SA. Drug Discovery Today 1999, 4: 552 ; and references cited therein

<A NAME="RU33104ST-3">3</A> Yamanaka T. Ohkubo M. Takahashi F. Kato M. Tetrahedron Lett. 2004, 45: 2843

<A NAME="RU33104ST-4A">4a</A> Liu M. Sibi MP. Tetrahedron 2002, 58: 7991

<A NAME="RU33104ST-4B">4b</A> Chippindale AM. Davies SG. Iwamoto K. Parkin RM. Smethurst CAP. Smith AD. Rodriguez-Solla H. Tetrahedron 2003, 59: 3253

<A NAME="RU33104ST-4C">4c</A> Gardiner J. Anderson KH. Downard A. Abell AD. J. Org. Chem. 2004, 69: 3375

<A NAME="RU33104ST-4D">4d</A> Abell AD. Gardiner J. Org. Lett. 2002, 4: 3663

<A NAME="RU33104ST-4E">4e</A> Fustero S. Bartolomé A. Sanz-Cervera JF. Sánchez-Roselló M. Soler JG. Ramírez de Arellano C. Fuentes AS. Org. Lett. 2003, 5: 2523

<A NAME="RU33104ST-5A">5a</A> Lee DL. Morrow CJ. Rapoport H. J. Org. Chem. 1974, 39: 893

<A NAME="RU33104ST-5B">5b</A> Krogsgaard-Larsen P. Thyssen K. Schaumburg K. Acta Chem. Scand. Ser. B 1978, 32: 327

<A NAME="RU33104ST-6A">6a</A> Trnka TM. Grubbs RH. Acc. Chem. Res. 2001, 34: 18

<A NAME="RU33104ST-6B">6b</A> Fürstner A. Angew. Chem. Int. Ed. 2000, 39: 3021

<A NAME="RU33104ST-6C">6c</A> Connom SJ. Blechert S. Angew. Chem. Int. Ed. 2003, 42: 1900

<A NAME="RU33104ST-7">7</A> Evans DA. Ennis MD. Mathre DJ. J. Am. Chem. Soc. 1982, 104: 1737

<A NAME="RU33104ST-8">8</A> van Benthem RATM. Michels JJ. Hiemstra H. Speckamp WN. Synlett 1994, 368

Purchased from Tokyo Chemical Industry (TCI).

<A NAME="RU33104ST-10A">10a</A> Hong SH. Day MW. Grubbs RH. J. Am. Chem. Soc. 2004, 126: 7414

<A NAME="RU33104ST-10B">10b</A> Schmidt B. Synlett 2004, 1541

Purchased from Aldrich.

<A NAME="RU33104ST-12A">12a</A> Schöllkopf U. Tetrahedron 1983, 39: 2085

<A NAME="RU33104ST-12B">12b</A> Seebach D. Sting AR. Hoffmann M. Angew. Chem., Int. Ed. Engl. 1997, 35: 2708

<A NAME="RU33104ST-12C">12c</A> Job A. Janeck CF. Battray W. Peters R. Enders D. Tetrahedron 2002, 58: 2253

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).

<A NAME="RU33104ST-14A">14a</A> Hosokawa T. Yamanaka T. Itotani M. Murahashi S.-I. J. Org. Chem. 1995, 60: 6159

<A NAME="RU33104ST-14B">14b</A> Hosokawa T. Yamanaka T. Murahashi S.-I. J. Chem. Soc., Chem. Commun. 1993, 117

<A NAME="RU33104ST-15">15</A> Evans DA. Britton TC. Ellman JA. Tetrahedron Lett. 1987, 28: 6141

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).

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).

<A NAME="RU33104ST-18">18</A> Hashimoto N. Aoyama T. Shioiri T. Chem. Pharm. Bull. 1981, 29: 1475

<A NAME="RU33104ST-19">19</A> Garro-Helion F. Merzouk A. Guibé F. J. Org. Chem. 1993, 58: 6109

<A NAME="RU33104ST-20">20</A> Sibi MP. Deshpande PK. J. Chem. Soc., Perkin Trans. 1 2000, 1461

<A NAME="RU33104ST-21A">21a</A> Ohkubo M, Kuroda S, Nakamura H, Minagawa M, Aoki T, Harada K, and Seki J. inventors; Int. Patent WO 0160813. 2001; Chem. Abstr. 2001, 135, 180951

<A NAME="RU33104ST-21B">21b</A> Ohkubo M, Takahashi F, Yamanaka T, Sakai H, and Kato M. inventors; Int. Patent WO 9508536. 1995; Chem. Abstr. 1995, 123, 285788