Synthesis of the First 24-Aminovitamin D₃ Derivatives by Diastereoselective Conjugate Addition to a Chiral Methyleneoxazolidinone in Aqueous Media

Abstract

The synthesis of the first 24-aminovitamin D₃ derivatives is reported. A stereoselective convergent synthetic approach was employed to prepare 24(S)-benzoylamino-25-hydroxyvitamin D₃ and 24(S)-benzoylamino-1α,25-dihydroxyvitamin D₃ in six steps from iodide 2 in 34% and 42% overall yields, respectively. The key step in the synthesis is a novel diastereoselective ultrasonically induced conjugate addition, promoted by the zinc-copper couple, of iodide 2 to methyleneoxazolidinone 4 in aqueous media. The conjugate vitamin D triene system was constructed using the Lythgoe approach.

Key words

aqueous media - Michael additions - stereoselective synthesis - vitamin D - zinc-copper couple

References

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Representative Experimental Procedure To a solution of methyleneoxazolidinone (-)-4 (102 mg, 0.39 mmol) and iodide 2 (254 mg, 0.78 mmol) in aq EtOH (5 mL, 70%) was added CuI (182 mg, 0.96 mmol) and Zn (188 mg, 2.88 mmol). The resulting black mixture was sonicated for 90 min until consumption of (-)-4 was complete (TLC test). The mixture was diluted with EtOAc (8 mL) and filtered through a short pad of Celite^®, washing the solids with EtOAc (3 × 15 mL). The organic phase was washed with brine (50 mL), dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexanes) to afford, after concentration and high vacuum drying, 127 mg of 9 (74%, 24R/24S = 17:83) as a white foam: IR(neat): 3500, 2940, 1790, 1670, 1340 cm^-1. (24S)-9: ¹H NMR (200 MHz, CDCl₃): δ = 0.84 (d, J = 6.8 Hz, 3 H), 0.93 (s, 3 H), 1.05 (s, 9 H), 3.83 (dd, J = 10.8 and 2.9 Hz, 1 H), 4.07 (m, 1 H), 6.06 (s, 1 H), 7.43 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 13.5 (CH₃), 17.4 (CH₂), 18.5 (CH₃), 22.4 (CH₂), 24.7 (CH), 25.2 (3 × CH₃), 27.1 (CH₂), 32.0 (CH₂), 32.4 (CH₂), 33.5 (CH₂), 34.6 (CH), 36.9 (C), 40.2 (CH₂), 41.7 (C), 52.5 (CH), 58.0 (CH), 69.2 (CH), 95.3 (CH), 126.5 (2 × CH), 128.8 (2 × CH), 130.6 (CH), 135.6 (C), 172.4 (C), 175.9 (C). (24R)-9: ¹H NMR (200 MHz, CDCl₃): δ = 0.62 (d, J = 6.4 Hz, 3 H) 0.84 (s, 3 H), 1.04 (s, 9 H), 4.05 (m, 1 H), 4.47 (m, 1 H), 6.18 (s, 1 H), 7.43 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 13.4 (CH₃), 17.3 (CH₂), 18.0 (CH₃), 22.4 (CH₂), 24.7 (3 × CH₃), 26.9 (CH₂), 28.2 (CH₂), 29.7 (CH₂), 33.5 (CH₂), 34.6 (CH), 39.8 (C), 40.2 (CH₂), 41.7 (C), 52.5 (CH), 55.6 (CH), 59.2 (CH), 69.2 (CH), 94.8 (CH), 127.5 (2 × CH), 128.9 (2 × CH), 132.1 (CH), 135.7 (C), 171.0 (C), 173.1 (C). MS (FAB): m/z (%) = 456(4) [M⁺], 441(12) [M⁺ - CH₃], 438(9) [M⁺ - H₂O], 105(100). HRMS (EI): m/z calcd for C₂₈H₄₁NO₄: 455.3036 [M⁺]; found: 455.3030.

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All new compounds gave satisfactory ¹H and ¹³C NMR spectra, and HRMS or microanalytical data.

16

Phosphine oxide 7 is obtained by degradation of vitamin D₃, see ref. 12.

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Compound 14: [α]_D ²⁵ +53.3 (c 0.3, MeOH). UV (MeOH): λ_max 264, 237, 218, 202 nm. ¹H NMR (200 MHz, CDCl₃):
d = 0.50 (s, 3 H), 0.94 (d, J = 5.9 Hz, 3 H), 1.23 (s, 6 H), 3.86 (m, 2 H), 4.77 (d, J = 2.4 Hz, 1 H), 5.02 (d, J = 2.9 Hz, 1 H), 6.00 and 6.21 (2 d, AB system, J = 11.2 Hz, 2 H), 6.22 (br s, 1 H), 7.60 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): d = 12.0 (CH₃), 19.2 (CH₃), 22.5 (CH₂), 23.9 (CH₂), 26.5 (2 × CH₃), 26.8 (CH₂), 28.0 (CH), 29.3 (CH₂), 30.0 (CH₂), 32.3 (CH₂), 33.4 (CH₂), 35.7 (CH₂), 36.7 (CH), 40.8 (CH₂), 46.1 (C), 46.3 (CH₂), 56.5 (CH), 59.6 (CH), 69.5 (CH), 73.6 (C), 112.4 (CH₂), 117.9 (CH), 122.5 (CH), 127.2 (2 × CH), 128.9 (2 × CH), 131.7 (CH), 135.3 (C), 135.8 (C), 142.3 (C), 145.8 (C), 168.5 (C); MS (EI): m/z (%) = 519(2) [M⁺], 501(6) [M⁺ - H₂O], 105(100). HRMS (EI): m/z calcd for C₃₄H₄₉NO₃: 519.3712 [M⁺]; found: 519.3715.

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Compound 16: Mp 116-118 °C. [α]_D ²³ +94.5 (c 0.15, MeOH). UV (MeOH): λ_max 266, 237, 217, 203 nm. ¹H NMR (200 MHz, CDCl₃): d = 0.56 (s, 3 H), 0.96 (d, J = 6.3 Hz,
3 H), 1.21 (s, 3 H), 1.25 (s, 3 H), 3.30 (br s, 1 H) 3.97 (m, 1 H), 4.12 (m, 1 H), 4.34 (t, J = 5.9 Hz, 1 H), 4.88 (d, J = 2.9 Hz, 1 H), 5.28 (d, J = 2.5 Hz, 1 H), 6.05 and 6.30 (2 d, AB system, J = 11.2 Hz, 2 H), 7.64 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 12.5 (CH₃), 19.1 (CH₃), 23.2 (CH₂), 24.6 (CH₂), 25.9 (CH₂), 26.4 (CH₃), 27.4 (CH₃), 28.6 (CH₂), 30.0 (CH₂), 33.6 (CH₂), 36.3 (CH), 41.9 (CH₂), 43.7 (CH₂), 46.1 (CH₂), 47.0 (C), 57.6 (CH), 58.1 (CH), 59.0 (CH), 67.4 (CH), 71.4 (CH), 73.9 (C), 112.0 (CH₂), 119.0 (CH), 124.9 (CH), 128.3 (2 × CH), 129.5 (2 × CH), 132.5 (CH), 135.6 (C), 136.2 (C), 142.5 (C), 149.8 (C), 170.9 (C); MS (EI): m/z (%) = 535(3) [M⁺], 517(5) [M⁺ - H₂O], 105(100). HRMS (EI): m/z calcd for C₃₄H₄₉NO₄: 535.3662 [M⁺]; found: 535.3657.

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These new vitamin D₃ analogues are available for biological evaluation upon request.