Synlett 2005(14): 2163-2166  
DOI: 10.1055/s-2005-872224
LETTER
© Georg Thieme Verlag Stuttgart · New York

Design and Synthesis of Novel 20-epi Analogues of Calcitriol with Restricted Side Chain Conformation

Carlos Fernándeza, Generosa Gómeza, Carmen Lagoa, Edelmiro Mománb, Yagamare Fall*a
a Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Spain
b Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland
Fax: +34(986)812262; e-Mail: yagamare@uvigo.es;
Further Information

Publication History

Received 31 May 2005
Publication Date:
20 July 2005 (online)

Abstract

The design and efficient preparation of two 20-epi analogues of calcitriol with restricted side chain conformation is described. The formation of the tetrahydropyran ring was achieved via zinc chloride mediated etherification of alcohols. Docking experiments show that these novel analogues could be interesting synthetic targets.

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All new compounds exhibited satisfactory 1H NMR and 13C NMR, analytical, and/or high-resolution mass spectral data.

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Compound 5a: 1H NMR (300 MHz, CDCl3): δ = 6.37 (1 H, d, J = 11.3 Hz, =CH-6 or =CH-7), 6.01 (1 H, d, J = 11.30 Hz, =CH-6 or =CH-7), 5.31 (1 H, s, CH2-19), 4.99 (1 H, s, CH2-19), 4.42 (1 H, dd, J = 7.69, 4.27 Hz, CHOH), 4.22 (1 H, m, CHOH), 3.66 (1 H, d, J = 11.52 Hz, CH2O), 3.47 (1 H, t, J = 11.38 Hz, CH2O), 2.82 (1 H, m), 2.59 (1 H, m), 2.31 (2 H, m), 1.18 (3 H, s, CH3-26 or CH3-27), 1.16 (3 H, s, CH3-26 or CH3-27), 0.81 (3 H, d, J = 6.80 Hz, CH3-21), 0.52 (3 H, s, CH3-18). 13C NMR (CDCl3): δ = 147.67 (C=), 143.08 (C=), 132.91 (C=), 125.15 (CH=), 117.20 (CH=), 111.90 (CH2=), 71.01 (C-25), 70.87 (CH), 66.87 (CH), 62.76 (CH2), 56.35 (CH), 53.50 (CH), 46.16 (C-13), 45.30 (CH2), 42.89 (CH2), 39.85 (CH2), 39.13 (CH), 37.89 (CH), 37.16 (CH2), 31.35 (CH3), 29.12 (CH2), 26.96 (CH2), 24.86 (CH2), 23.45 (CH2), 22.20 (CH2), 21.57 (CH3), 14.30 (CH3), 12.10 (CH3). HRMS: m/z calcd for C28H45O3: 429.3369; found: 429.3390.

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Compound 5b: 1H NMR (300 MHz, CDCl3): δ = 6.36 (1 H, d, J = 11.3 Hz, =CH-6 or =CH-7), 6.01 (1 H, d, J = 11.3 Hz, =CH-6 or =CH-7), 5.31 (1 H, s, CH2-19), 4.99 (1 H, s, CH2-19), 4.42 (1 H, dd, J = 8.0, 4.3 Hz, CHOH), 4.23 (1 H, m, CHOH), 3.53 (1 H, t, J = 11.3, CH2O), 3.43 (1 H, dd, J = 11.1, 3.0 Hz, CH2O), 2.82 (1 H, dd, J = 10.5, 3.7 Hz), 2.58 (1 H, dd, J = 9.9, 3.3 Hz), 2.30 (1 H, dd, J = 13.5, 6.4 Hz), 1.19 (3 H, s, CH3-26 or CH3-27), 1.17 (3 H, s, CH3-26 or CH3-27), 0.77 (3 H, d, J = 6.8 Hz, CH3-21), 0.54 (3 H, s, CH3-18). 13C NMR (CDCl3): δ = 147.67 (C=), 142.93 (C=), 132.99 (C=), 124.96 (CH=), 117.14 (CH=), 111.74 (CH2=), 71.35 (C-25), 70.82 (CH), 66.87 (CH), 65.85 (CH2), 56.38 (CH), 53.08 (CH), 46.02 (C-13), 45.27 (CH2), 42.89 (CH2), 39.80 (CH2), 38.70 (CH), 36.55 (CH2), 36.27 (CH), 31.34 (CH3), 29.69 (CH2), 27.25 (CH2), 23.52 (CH2), 22.12 (CH2), 21.51 (CH3), 19.73 (CH2), 14.39 (CH3), 11.89 (CH3). HRMS: m/z calcd for C28H45O3: 429.3369; found: 429.3377.