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.

diastereoselectivity - ene reactions - photooxidation - stereoselective synthesis - vitamins

References

1a Friedrich W. Vitamins   Walter de Gruyter; Berlin / New York: 1988.  p.141-216  

1b Vitamin D   Feldman D. Glorieux FH. Pike JW. Academic Press; NewYork: 1997. 

Recent reviews on dihydroxyvitamin D₃:

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

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

2c Posner GH. Kahraman M. Eur. J. Org. Chem.  2003,  3889 

Recent examples:

3a Kittaka A. Suhara Y. Takayanagi H. Fujishima T. Kurihara M. Takayama H. Org. Lett.  2000,  2:  2619 

3b Miyazawa N. Tosaka A. Hanada K. Ogasawara K. Heterocycles  2003,  59:  491 

3c Hanazawa T. Koyama A. Wada T. Morishige E. Okamoto S. Sato F. Org. Lett.  2003,  5:  523 

3d Hanazawa T. Koyama A. Nakata K. Okamoto S. Sato F. J. Org. Chem.  2003,  68:  9767 

4a Harrison RG. Lythgoe B. Wright PW. Tetrahedron Lett.  1973,  3649 

4b Harrison RG. Lythgoe B. Wright PW. J. Chem. Soc., Perkin Trans. 1  1974,  2654 

4c Kocienski PJ. Lythgoe B. J. Chem. Soc., Perkin Trans. 1  1980,  1400 

4d Lythgoe B. Waterhouse I. J. Chem. Soc., Perkin Trans. 1  1980,  1405 

5a Linker T. Fröhlich L. Angew. Chem., Int. Ed. Engl.  1994,  33:  1971 

5b Linker T. Fröhlich L. J. Am. Chem. Soc.  1995,  179:  2694 

6a Jacobsen O. Ber. Dtsch. Chem. Ges.  1883,  16:  1962 

6b Bruck PR. Clark RD. Davidson RS. Günther WHH. Littlewood PS. Lythgoe B. J. Chem. Soc. C  1967,  2529 

6c Dixon J. Lythgoe B. Siddiqui IA. Tideswell J. J. Chem. Soc. C  1971,  1301 

Reviews:

7a Schultz AG. Acc. Chem. Res.  1990,  23:  207 

7b Rabideau PW. Marcinow Z. Org. React.  1992,  42:  1 

7c Schultz AG. Chem. Commun.  1999,  1263 

Reviews on stereoselective ene reactions:

8a Griesbeck AG. Adam W. In Houben-Weyl, Methods of Organic Chemistry   Vol. E21e:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Georg Thieme Verlag; Stuttgart: 1995.  p.4928 

8b Prein M. Adam W. Angew. Chem., Int. Ed. Engl.  1996,  35:  477 

8c Adam W. Krebs O. Chem. Rev.  2003,  103:  4131 

9 Rabideau PW. The Conformational Analysis of Cyclohexenes, Cyclohexadienes, and Related Hydroaromatic Compounds   VCH; Weinheim: 1989.  p.91 

10 Vorndran K. Linker T. Angew. Chem. Int. Ed.  2003,  42:  2489 

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.

12 Peters K. Peters E.-M. Linker T. Z. Kristallogr. - New Cryst. Struct.  2004,  219:  in press

13a Dussault PH. Han Q. Sloss DG. Symonsbergen DJ. Tetrahedron  1999,  55:  11437 

13b Adam W. Peters K. Peters E.-M. Schambony SB. J. Am. Chem. Soc.  2000,  122:  7610 

13c Adam W. Bosio SG. Turro NJ. J. Am. Chem. Soc.  2002,  124:  8814