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.

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

References

1a Vitamin D   Feldman D. Glorieux FH. Pike JW. Academic Press; New York: 1997. 

1b Calverley MJ. Jones J. In Antitumor Steroids   Blickenstaff RT. Academic Press; San Diego: 1992.  Chap. 7. p.193 

1c Norman AW. Litwack G. Hormones   Academic Press; San Diego: 1997. 

2a Dai H. Posner GH. Synthesis  1994,  1383 

2b Zhu G.-D. Okamura WH. Chem. Rev.  1995,  95:  1877 

2c Okamura WH. Zhu G.-D. In Vitamin D   Feldman D. Glorieux FH. Pike JW. Academic Press; New York: 1997.  p.939 

3a Okamura WH. Palenzuela JA. Plumet J. Midland MM. J. Cell. Biochem.  1992,  49:  10 

3b Bouillon R. Okamura WH. Norman AW. Endocr. Rev.  1995,  16:  200 

4 Beckman MJ. DeLuca HF. In Progress in Medicinal Chemistry   Vol. 35:  Ellis GP. Luscombe DK. Oxford AW. Elsevier; Amsterdam: 1998.  p.1 

5 Pérez Sestelo J. Cornella I. De Uña O. Mouriño A. Sarandeses LA. Chem.-Eur. J.  2002,  8: in press

6a Petrier C. Dupuy C. Luche JL. Tetrahedron Lett.  1986,  27:  3149 

6b Luche JL. Allavena C. Tetrahedron Lett.  1988,  29:  5369 

6c Luche JL. Allavena C. Petrier C. Dupuy C. Tetrahedron Lett.  1988,  29:  5373 

6d Dupuy C. Petrier C. Sarandeses LA. Luche JL. Synth. Commun.  1991,  21:  643 

6e Sarandeses LA. Mouriño A. Luche JL. J. Chem. Soc., Chem. Commun.  1992,  798 

7a Seebach D. Naef R. Calderari G. Tetrahedron  1984,  40:  1313 

7b Zimmermann J. Seebach D. Helv. Chim. Acta  1987,  70:  1104 

For previous applications of the sonochemical conjugate addition to the synthesis of vitamin D analogues see:

8a Castedo L. Mascareñas JL. Mouriño A. Sarandeses LA. Tetrahedron Lett.  1988,  29:  1203 

8b Mascareñas JL. Sarandeses LA. Castedo L. Mouriño A. Tetrahedron  1991,  47:  3485 

8c Mascareñas JL. Pérez Sestelo J. Castedo L. Mouriño A. Tetrahedron Lett.  1991,  32:  2813 

8d Pérez Sestelo J. Mascareñas JL. Castedo L. Mouriño A. J. Org. Chem.  1993,  58:  118 

8e Pérez Sestelo J. Mascareñas JL. Castedo L. Mouriño A. Tetrahedron Lett.  1994,  35:  275 

9a Beckwith ALJ. Chai CLL. J. Chem. Soc., Chem. Commun.  1990,  1087 

9b Axon JR. Beckwith ALJ. J. Chem. Soc., Chem. Commun.  1995,  549 

10a Seebach D. Naef G. Helv. Chim. Acta  1981,  64:  2704 

10b Seebach D. Fadel A. Helv. Chim. Acta  1985,  68:  1243 

11a Lythgoe B. Moran TA. Namburidy MEN. Ruston S. Tideswell J. Wright PW. Tetrahedron Lett.  1975,  3863 

11b Lythgoe B. Chem. Soc. Rev.  1980,  9:  449 

11c Baggiolini EG. Iacobelli JA. Hennessy BM. Batcho AD. Sereno JF. Uskokovic MR. J. Org. Chem.  1986,  51:  3098 

12 Sardina FJ. Mouriño A. Castedo L. J. Org. Chem.  1986,  51:  1264 

13 Beckwith ALJ. Pyne SG. Dickic B. Chai CLL. Gordon PA. Skelton BW. Tozer MJ. White AH. Aust. J. Chem.  1993,  46:  1425 

14

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.

18 Mouriño A. Torneiro M. Vitale C. Fernández S. Pérez Sestelo J. Anné S. Gregorio C. Tetrahedron Lett.  1997,  38:  4713 

19

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.