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Synlett 2002(2): 0239-0242
DOI: 10.1055/s-2002-19781
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Highly Selective EP2-Receptor Agonist

Kousuke Tani*a, Atsushi Naganawaa, Akiharu Ishidaa, Hiromu Egashiraa, Yoshihiko Odagakia, Toru Miyazakia, Tomoyuki Hasegawab, Yasufumi Kawanakab, Hisao Nakaia, Shuichi Ohuchidaa, Masaaki Todaa
a Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan
Fax: +81(75)9629314; e-Mail: k.tani@ono.co.jp;
b Fukui Research Institute, Ono Pharmateutical Co., Ltd., Mikuni, Sakai, Fukui 913-8538, Japan
Further Information

Publication History

Received 17 November 2001
Publication Date:
02 February 2007 (online)

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Abstract

A practical method for the synthesis of the prostanoid EP2-receptor agonist 1 was developed. This method includes magnesium-mediated Julia olefination of aldehyde 2 with the optically active sulfone 3, which was prepared from allylic alcohol 4 using the Sharpless asymmetric epoxidation procedure.

Key words

prostaglandins - asymmetric synthesis - Julia olefination - magnesium - EP2-receptor agonist

    References

  • 1a Tani K. Naganawa A. Ishida A. Egashira H. Sagawa K. Harada H. Ogawa M. Maruyama T. Ohuchida S. Nakai H. Kondo K. Toda M. Bioorg. Med. Chem. Lett.  2001,  11:  2025 
    CrossrefSearch in Google Scholar
  • 1b

    Tani, K.; Naganawa, A.; Ishida, A.; Sagawa, K.; Harada, H.; Ogawa, M.; Maruyama, T.; Ohuchida, S.; Nakai, H.; Kondo, K.; Toda, M. Bioorg. Med. Chem., in press.
    Crossref
  • 1c

    Tani, K.; Naganawa, A.; Ishida, A.; Egashira, H.; Sagawa, K.; Harada, H.; Ogawa, M.; Maruyama, T.; Ohuchida, S.; Nakai, H.; Kondo, K.; Toda, M. Bioorg. Med. Chem., in press.
    Crossref
  • 2 Gardiner PJ. Br. J. Pharmac.  1986,  87:  45 
    Search in Google Scholar
  • 3 Nials AT. Vardey CJ. Denyer LH. Thomas M. Sparrow SJ. Shepherd GD. Coleman RA. Cardiovascular Drug Review  1993,  11:  165 
    Search in Google Scholar
  • 4 Lee GH. Lee HK. Choi EB. Kim BT. Pak CS. Tetrahedron Lett.  1995,  36:  5607 
    Search in Google Scholar
  • 9 Hayashi M. Arai Y. Wakatsuka H. Kawamura M. Konishi Y. Tsuda T. Matsumoto K. J. Med. Chem.  1980,  23:  525 
    CrossrefSearch in Google Scholar
  • 10 Corey EJ. Schaaf TK. Huber W. Koelliker U. Weinshenker NM. J. Am. Chem. Soc.  1970,  92:  397 
    CrossrefSearch in Google Scholar
  • 11 Buchmann B. Skuballa W. Vorbruggen H. Tetrahedron Lett.  1990,  31:  3425 
    CrossrefSearch in Google Scholar
  • 15 Kiriyama M. Ushikubi F. Kobayashi T. Hirata M. Sugimoto Y. Narumiya S. Br. J. Pharmac.  1997,  122:  217 
    Search in Google Scholar
5

The α,β-unsaturated ester was prepared by Horner-Emmons reaction of triethyl phosphono acetate with 2,2-(trimethylene)butanal, the preparation of which was described in ref. [1b] of this report.

6

Spectrum data of compound 7: IR(neat): 3441, 2962, 1584, 1481, 1439, 1310, 1272, 1071, 1026, 737, 690 cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.40-7.10 (m, 5 H), 3.80-3.65 (m, 1 H), 3.28-2.94 (m, 2 H), 2.00-1.20 (m, 11 H), 0.88 (t, J = 7.5 Hz, 3 H); TLC: Rf = 0.52 (n-hexane/AcOEt = 4:1).

7

Spectrum data of compound 8: IR(neat): 3525, 2963, 2936, 2878, 1447, 1304, 1148, 1087, 1072, 748, 689, 599, 533 cm-1; 1H NMR (200 MHz, CDCl3): δ = 8.00-7.90 (m, 2 H), 7.70-7.50 (m, 3 H), 3.66-3.55 (m, 1 H), 3.50-3.10 (m, 2 H), 2.00-1.30 (m, 11 H), 0.88 (t, J = 7.5 Hz, 3 H); TLC: Rf = 0.32 (n-hexane/AcOEt = 2:1). The optical purity of compound 8 was determined based on the result of HPLC analysis of its benzoyl derivative 9.

8

Spectrum data of compound 3: IR(neat): 2939, 2864, 1446, 1305, 1150, 1075, 1031, 987 cm-1; 1H NMR (200 MHz, CDCl3): δ = 8.00-7.90 (m, 2 H), 7.70-7.50 (m, 3 H), 4.40 (m, 1 H), 3.94-3.70 (m, 1 H), 3.62-3.28 (m, 3 H), 3.17-3.04 (m, 1 H), 2.24-1.20 (m, 16 H), 0.85 (t, J = 7.4 Hz, 3 H); TLC: Rf = 0.42 and 0.37 (n-hexane/AcOEt = 4:1).

12

Spectrum data of compound 2: IR(neat): 2947, 2868, 2736, 1439, 1352, 1323, 1247, 1201, 1154, 1133, 1077, 1034, 1021, 970 cm-1; 1H NMR (200 MHz, CDCl3): δ = 9.76 and 9.73 (2 × d, J = 2.0 Hz, 1 H), 5.60-5.30 (m, 2 H), 4.65-4.50 (m, 2 H), 4.15-3.95 (m, 1 H), 3.90-3.70 (m, 1 H), 3.67 (s, 3 H), 3.60-3.40 (m, 1 H), 2.80-1.40 (m, 18 H); TLC: Rf = 0.60 (n-hexane/AcOEt = 2/1).

13

Typical Experimental Procedure for the Synthesis of 14 from 2 and 3: To a stirred solution of 3 (19.8 g, 54.0 mmol) in dry THF (125 mL) was added n-butyllithium (1.6 M in hexane, 33.8 mL, 54.0 mmol) at -78 ºC under an argon atmosphere. The reaction mixture was stirred for 1 h at -78 ºC and then added to a stirred solution of 2 (16.0 g, 41.5 mmol) in 125 mL of dry THF (125 mL) at -78 ºC. After stirring for 1 h at -78 ºC, the resulting mixture was treated with acetic anhydride (7.85 mL, 83.0 mmol) and allowed to warm up to ambient temperature over 1 h. The reaction mixture was treated with sat. aq ammonium chloride and extracted with EtOAc repeatedly. The combined organic layers were washed with water, then brine, dried over anhyd magnesium sulfate, and concentrated in vacuo to afford a crude acetoxy sulfone (40.1 g) as a dark-brown viscous oil. TLC: Rf = 0.41 (n-hexane/EtOAc = 3:1); IR(neat): 2943, 2863, 1740, 1447, 1371, 1307, 1228, 1150, 1131, 1075, 1031 cm-1; 1H NMR (200 MHz, CDCl3): δ = 8.00-7.45 (m, 5 H), 5.70-5.20 (m, 2 H), 5.00-3.20 (m, 14 H), 2.60-1.20 (m, 37 H), 1.10-0.80 (m, 3 H).
To a stirred solution of the crude acetoxy sulfone (10.6 g, 11.0 mmol) in 100 mL of methanol was added powdered magnesium (-50 mesh, 2.40 g, 100 mmol) under an argon atmosphere. The mixture was again stirred (15 min), and a catalytic amount of chloro trimethylsilane (0.1 mL) was added. After stirring for 1 h at ambient temperature, the reaction mixture was poured into ice-cold aq ammonium chloride and extracted with EtOAc. The organic layer was washed with water, then brine, dried over anhyd magnesium sulfate, and concentrated in vacuo to afford a crude oil, which was purified by column chromatography on silica gel to give a mixture of 13E- (compound 14) and 13Z-olefinic compounds (3.0 g, 47% yield from aldehyde 2) as a pale yellow oil (E/Z = 5:1). The undesired Z isomer was easily removed by silica gel column chromatography after deprotection. TLC: Rf = 0.66 (n-hexane/EtOAc = 3:1); IR(neat): 2942, 2875, 1741, 1440, 1352, 1200, 1115, 1077, 1032, 977 cm-1; 1H NMR (200 MHz, CDCl3): δ = 5.80-5.25 (m, 4 H), 4.60 (m, 2 H), 4.15-3.75 (m, 4 H), 3.57 (s, 3 H), 3.55-3.35 (m, 3 H), 2.50-1.40 (m, 34 H), 1.00-0.85 (m, 3 H).

14

X-Ray analysis (Figure)of the salt 1Ly consisting of a 1/1 molar ratio of 1 and l-lysine was conducted. The absolute configuration of the 16-OH was determined to be an S-form based on its configuration relative to the absolute configuration of l-lysine in the crystal lattice. Lattice Parameters: a = 32.91(2) Å, b = 5.91(2) Å, c = 17.64(2) Å, β = 112.52(6)°V = 3169(10) Å3. Space Group: C2. Cu-Kα radiation (λ = 1.54178 cm-1) graphite monochromated was used for data collection. 1307 Reflections with I > 3σ (I) was used for final structure factor calculations. R = Σ||Fobs|-|Fcalc||/Σ|Fobs| = 0.104. Rw = ((Σw(|Fobs|-|Fcalc|)2/ΣwFobs 2)1/2 = 0.119, where w = 1/σ 2(Fobs).