Simple and Diastereoselective Synthesis of an A-Ring Precursor of Dihydroxyvitamin D₃ (Calcitriol) by Photooxygenation

Abstract

A convenient synthesis of a racemic A-ring precursor of dihydroxyvitamin D₃ (calcitriol) is described. The key step involves the singlet oxygen ene reaction of the Lythgoe lactone, which proceeds with excellent regio- and good diastereoselectivities. Strong polar interactions are operative during the attack of ¹O₂ to the double bond, which is important for the mechanism of such reactions.

Key words

diastereoselectivity - ene reactions - photooxidation - stereoselective synthesis - vitamins

References

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11

A solution of 415 mg (3.00 mmol) of lactone rac-6 and 2 mg of tetraphenylporphin (TPP) in 6 mL of CHCl₃ was photooxygenated by passing a slow stream of dry oxygen gas through the solution at -30 °C. The mixture was externally irradiated with two 250 W sodium lamps for 3 d. The hydroperoxides were directly reduced to the corresponding alcohols by adding a solution of 800 mg (3.05 mmol) of PPh₃ in 3 mL of CH₂Cl₂. The solvent was removed at 35 °C and the residue was purified by silica gel column chromatography (petroleum ether-EtOAc 50:50) to afford 270 mg (58%) of trans-7 (R _f = 0.21) as a white solid, mp 89-90 °C and 110 mg (24%) of cis-7 (R _f = 0.16) as a colorless oil. Lactone trans-7: ¹H NMR (600 MHz, CDCl₃): δ = 1.58 (dd, J = 13.3, 9.8 Hz, 1 H, 2-H), 1.93 (d, J = 11.6 Hz, 1 H, 6-H), 2.50 (dddd, J = 11.6, 5.5, 4.8, 1.8 Hz, 1 H, 6′-H), 2.63 (dddd, J = 13.3, 7.4, 4.8, 1.8 Hz, 1 H, 2′-H), 2.77 (d, J = 6.0 Hz, 1 H, OH), 3.31 (d, J = 4.8 Hz, 1 H, 5-H), 4.42 (ddd, J = 9.8, 7.4, 6.0 Hz, 1 H, 3-H), 4.92 (dd, J = 5.8, 4.8 Hz, 1 H, 1-H), 5.05, 5.20 (2 s, 2 H, 7-H). ¹³C NMR (151 MHz, CDCl₃): δ = 38.4, 39.0 (2 t, C-2, C-6), 47.3 (d, C-5), 66.8 (d, C-3), 77.9 (d, C-1), 109.5 (t, C-7), 144.8 (s, C-4), 176.4 (s, C-8). Anal. Calcd for C₈H₁₀O₃: C, 62.33; H, 6.54. Found: C, 62.17; H, 6.32. Lactone cis-7: ¹H NMR (600 MHz, CDCl₃): δ = 1.90 (d, J = 11.6 Hz, 1 H, 6-H), 2.00 (ddd, J = 15.2, 6.0, 1.8 Hz, 1 H, 2-H), 2.10 (br s, 1 H, OH), 2.29 (ddd, J = 15.2, 3.5, 2.3 Hz, 1 H, 2′-H), 2.56 (dddd, J = 11.6, 5.6, 5.1, 2.3 Hz, 1 H, 6′-H), 3.19 (d, J = 5.1 Hz, 1 H, 5-H), 4.49 (ddd, J = 6.0 Hz, 1 H, 3-H), 4.90 (ddd, J = 5.6, 3.5, 1.8 Hz, 1 H, 1-H), 5.10, 5.11 (2 s, 2 H, 7-H). ¹³C NMR (151 MHz, CDCl₃): δ = 36.3, 37.8 (2 t, C-2, C-6), 45.4 (d, C-5), 69.0 (d, C-3), 76.9 (d, C-1), 114.6 (t, C-7), 145.2 (s, C-4), 176.6 (s, C-8). Anal. Calcd for C₈H₁₀O₃: C, 62.33; H, 6.54. Found: C, 62.09; H, 6.46.