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

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.

Key words

synthesis - vitamin D - analogues - nitriles - diols - drugs

References

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10

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

15

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.

16

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.