Synthesis of Optically Active Prostaglandin-J₂ and 15-Deoxy-Δ^12,14-prosta-glandin-J₂

Abstract

An efficient route to optically pure prostaglandin-J₂ compounds has been discovered: ent-PGJ₂ is shown to display anti-viral activity against Sendai virus with a similar potency to the natural enantiomer.

Key words

prostaglandin-J₂ - 15-deoxy- ^12,14-prostaglandin-J₂ - lipase-catalysed resolutions

References

• 1a Roberts SM. Santoro MG. Sickle ES. J. Chem. Soc., Perkin Trans 1.  2002,  1735 
• 1b Straus DS. Glass CK. Med. Res. Rev.  2001,  21:  185 
• 1c Santoro MG. Roberts SM. Drug News Perspect.  1999,  12:  395 
• 2 Santoro MG. Trends in Microbiology  1997,  5:  276 
• 3a Söderström M. Wigren J. Surapureddi S. Glass CK. Hammarström S. Biochim. Biophys. Acta  2003,  1631:  35 
• 3b Forman BM. Tontonoz P. Chen J. Brun RP. Spielgelman BM. Evans RM. Cell  1995,  83:  803 
• 3c Kliewer SA. Lenhard JM. Wilson TM. Patel I. Morris DC. Lehmann JM. Cell  1995,  83:  813 
• 4a Ricote M. Li AC. Wilson TM. Kelly CJ. Glass CK. Nature (London)  1998,  391:  79 
• 4b Jiang C. Ting AT. Seed B. Nature (London)  1998,  391:  82 
• 5a Suguira S. Toru T. Tanaka T. Hazato A. Okamura N. Bannai K. Manabe K. Kurozumi S. Noyori R. Chem. Pharm. Bull.  1984,  32:  4658 
• 5b Kato T. Fukushima M. Kurozumi S. Noyori R. Cancer Res.  1986,  46:  3538 
• 6 Fitzpatrick FA. Wynalda MA. J. Biol. Chem.  1983,  258:  713 
• 7 Wakatsuki H, Yamoto T, and Hashimoto S. inventors; Eur. Pat. Appl.,  EP97023. 
• 8 Baxter AD. Binns F. Javad T. Roberts SM. Sadler P. Scheinmann F. Wakefield BJ. Lynch M. Newton RF. J. Chem. Soc., Perkin Trans. 1  1986,  889 
• 10a Jacob J. Espenson JH. Jensen JH. Gordon MS. Organometallics  1998,  17:  1835 
• 10b Espenson JH. Chem. Commun.  1999,  479 

9

Preparation of 7-(1′-Hydroxyoct-2′-enyl)bicyclo[2.2.1]hepta-2,5-diene 7. 4,4′-Di-tert-butyl-biphenyl (DTBB) (8.40 g, 31.6 mmol) was added to a stirred suspension of lithium granules (11.25 g, 1.61 mol) in dry THF (300 mL) under an atmosphere of dry argon gas. After 30 min the resultant dark green solution was cooled to -78 °C and 7-chloronorbornadiene 4 (26.70 g, 0.21 mol) added followed by trans-2-octenal (31.40 mL, 0.21 mol) after a further 30 min. After 1 h, the excess lithium was removed by filtration and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica using ethyl acetate in hexane (1:10) as eluent to afford the title compound 7 (44.91 g, 90%) as a straw yellow oil; R_f = 0.15 (ethyl acetate/hexane, 1:6); IR (film/cm^-1) 3332, 2926, 2856, 1466, 1309; ¹H NMR (CDCl₃, 400 MHz) δ 6.85 (2 H, m, H-2 and H-3), 6.62 (2 H, m, H-5 and H-6), 5.56 (1 H, dt, J = 15.4 Hz, 6.8 Hz, H-3′), 5.36 (1 H, ddt, J = 15.4 Hz, 7.4 Hz, 1.3 Hz, H-2′), 3.93 (1 H, dd, J = 9.3 Hz, 7.4 Hz, H-1′), 3.64 (1 H, m, H-1), 3.25 (1 H, m, H-4), 2.41 (1 H, d, J = 9.3 Hz, H-7), 2.00 (2 H, m, 2 × H-4′), 1.32 (6 H, m, 2 × H-5′, 2 × H-6′ and 2 × H-7′), 0.89 (3 H, t, J = 6.8 Hz, 3 × H-8′); ¹³C NMR (CDCl₃; 75.4 MHz) δ 145.07, 144.64, 140.58, 140.55, 133.08, 132.16, 91.49, 73.39, 52.16, 52.05, 32.59, 31.75, 29.26, 22.85, 14.38; HRMS (CI, NH₃): calcd for [M + H]⁺ C₁₅H₂₂O: 219.1749; found: 219.1751.

11

Preparation of {5-[1′-(Dimethyl-t-butylsilyloxy)oct-2′-enyl]-4-hydroxycyclopent-2-enyl}acetaldehyde 9. Oxone (2.32 g, 3.77 mmol) was added in one portion to a suspension of NaHCO₃ (0.63 g, 7.50 mmol) in acetone (30 mL) and water (30 mL) stirred at 0 °C. After 10 min, a solution of 7-[1′-(dimethyl-t-butylsilyloxy)oct-2′-enyl]bicyclo[2.2.1]hepta-2,5-diene (0.25 g) in acetone (30 mL) was added and the solution stirred for a further 1.5 h. The resultant solution was diluted with ethyl acetate (100 mL) and washed with water (2 × 100 mL) and brine (100 mL), dried (MgSO₄) and the solvent removed by distillation under reduced pressure. The residue was diluted with CH₂Cl₂ (10 mL) and a 2 M aqueous solution of HCl (10 mL) and stirred slowly for 5 d and the organic portion separated, dried (MgSO₄) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica using ethyl acetate in hexane (1:3) as eluent to afford the title compound 9 (0.13 g, 48%) as a straw yellow oil; R_f = 0.25 (ethyl acetate/hexane); NMR (CDCl₃, 400 MHz, 1:2 mixture of diastereoisomers) δ 9.75 (2 H, t, J = 1.3 Hz, CHO), 9.72 (1 H, t, J = 1.3 Hz, CHO), 5.73 (6 H, s, H-2 and H-3), 5.60 (3 H, m, H-3′), 5.38 (3 H, m, H-2′), 4.70 (1 H, dd, J = 4.8 Hz, 1.0 Hz, H-4), 4.61 (2 H, d, J = 4.6 Hz, H-4), 4.15 (3 H, m, H-1′), 2.89 (2 H, m, H-1), 2.79 (1 H, m, H-1), 2.75 (2 H, ddd, J = 17.7 Hz, 5.3 Hz,1.3 Hz, CHCHO), 2.66 (1 H, ddd, J = 18.0 Hz, 5.8 Hz, 1.3 Hz, CHCHO), 2.53 (2 H, ddd, J = 17.7 Hz, 8.1 Hz, 1.3 Hz, CHCHO), 2.47 (1 H, ddd, J = 18.0 Hz, 8.0 Hz, 1.3 Hz, CHCHO), 2.00 (6 H, m, H-4′), 1.82 (3 H, m, H-5), 1.36-1.23 (18 H, m, H-5′, H-6′ and H7′), 0.85 [36 H, m, CH₃ and (CH₃)₃], 0.02 [18 H, m, Si(CH₃)₂]; ¹³C NMR (CDCl₃; 75.4 MHz, 1:2 mixture of diastereoisomers) δ 201.88 and 201.73, 135.71 and 135.35, 133.01and 132.97, 132.96 and 132.90, 131.58 and 131.18, 79.82 and 79.19, 76.23 and 75.66, 60.71 and 60.53, 50.02 and 49.57, 40.94 and 40.66, 32.12 and 32.08, 31.39 and 31.38, 28.82 and 28.73, 25.83 and 25.82, 22.43, 18.01, 14.01 and 14.00, -3.75 and -3.92, -4.81 and
-4.86; HRMS (CI, NH₃): calcd for [M + H]⁺ C₂₁H₃₉O₃Si: 367.2669; found: 367.2675.

12

Enantiomeric excesses were determined to be >99% by synthesis and analysis of the Mosher ester derivatives.

13

Compounds gave satisfactory NMR (¹H and ¹³C) and mass spectral data in accord with the literature. Specific rotations were (+)-PGJ₂ 1, [α]_D +175.9 (c 1.1, CHCl₃); (+)-15-epi-PGJ₂, [α]_D +168.0 (c 1.2, CHCl₃); (-)-PGJ₂, [α]_D -171.7 (c 1.4, CHCl₃); (-)-15-epi-PGJ₂, [α]_D -171.7 (c 1.1, CHCl₃).

14

Compound (+)-2 gave satisfactory NMR (¹H) and mass spectral data in accord with the literature; [α]_D +194.3 (c 0.7, CHCl₃); ¹³C NMR (CDCl₃; 75.4 MHz) δ 197.45, 178.86, 160.75, 146.98, 135.15, 134.85, 131.83, 131.23, 125.89, 125.50, 43.43, 33.44, 33.34, 31.37, 30.63, 28.42, 26.55, 24.42, 22.45, 13.99.

15

Lipase Resolution of 7-(1′-Hydroxyoct-2′-enyl)bicyclo[2.2.1]hepta-2,5-diene 7. Lipase A from Candida antarctica (0.77 g) was added to a slowly stirred solution of the alcohol 7 (1.99 g, 9.14 mmol) in vinyl acetate (1.6 mL, 173.76 mmol) and toluene (25 mL). After 20 h the mixture was filtered through a glass sinter and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica using ethyl acetate in hexane (1:50) as eluent to afford the acetate 12 (0.97 g, 41%) as a clear colourless oil. Further elution using ethyl acetate in hexane (1:10) as eluent afforded the alcohol (+)-7 (0.817 g, 41%) as a clear colourless oil; [α]_D+22.5 (c 1.5, CHCl₃). Potassium carbonate (5.04 g, 36.49 mmol) was added to a stirred solution of the acetate 12 (0.968 g, 3.72 mmol) in methanol (20 mL) and water (10 mL). After 20 h the mixture was diluted with CH₂Cl₂ (50 mL) and washed with a 10% aqueous solution of citric acid (2 × 25 mL) and brine (25 mL), dried (MgSO₄) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica using ethyl acetate in hexane (1:10) as eluent to afford the alcohol (-)-7 (0.67 g, 83%) as a clear colourless oil; [α]_D -21.2 (c 1.5, CHCl₃). Enantiomeric excesses were determined to be >99% by synthesis and analysis of the Mosher ester derivatives of aldehydes 9.

16

Crystal data (Figure [3] ). C₂₉H₃₂Br₂O₅, M = 620.37, T = 100(2)K, crystal dimensions = 0.25 × 0.05 × 0.02 mm, Spacegroup P21, a = 5.0940(11), b = 16.480(3), c = 16.695(3) Å, β = 98.689(4)°, U = 1385.4(5) ų, µ(Mo-Kα) = 1.487 mm^-1, 5565 reflections measured, 3004 unique (R_int = 0.0413). R1 = 0.1634, wR2 = 0.4116 (all data); Crystals consisted of fine hairy needles of low scattering power and high mosaicity, which contributed to the high R-value. However, the model refined well and allowed the determination of the molecular connectivity. The absolute configuration could not be determined.