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1421
1975
Synthesis of Active Forms of Vitamin D. Part 1X.l Synthesis of 1a,24Dihydroxycholecalciferol
Published on 01 January 1975. Downloaded by Lakehead University on 29/10/2014 23:29:44.
By Masuo Morisaki, Naoyuki Koizumi, and Nobuo Ikekawa,' Laboratory of Chemistry for Natural Products, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan Toru Takeshita and Sachio Ishimoto, Teijin Institute for Biomedical Research, Hino-shi, Tokyo, Japan 24-Oxocholesterol (1 ) (readily available from fucosterol) was converted by three steps into 1a,24E-dihydroxycholesterol (4). From the corresponding triacetate (5), 1a,24~-dihydroxycholecalciferol(9) was prepared via the 5,7-diene (8). The C-24 epimers of compound (4) were resolved by silica gel column chromatography of the monohydroxydibenzoates (7). and were separatelytransformed into the corresponding 1a.24-dihydroxycholecalciferol epimers.
VARIOUSmetabolites of vitamin D, have been isolated recently, some of which may be the biologically active forms of the vitamin.2 This has stimulated the synthesis of vitamin D analogues with hydroxy-groups at positions 25,3* 24 and 25,7*s25 and 26,9 la and 25,10911 and la, 24, and 25.l In addition to these metabolic products, artificial ' analogues such as la-,l2-17 4ct-,l8 22-, l 9 and 24-hydroxy- 2o and 20,25-dihydroxy- 21 cholecalciferol, as well as the 1a-hydroxy-3-deoxy-derivative 22*23 have been synthetic targets. We have synthesized several key intermediates 24-28 for the preparation of these compounds from fucosterol, a marine sterol which is abundant in brown algae.29 From one of these intermediates, the epimeric 24-hydroxycholecalciferols t,$
t The configuration at C-24 of 24-hydroxycholestero1has been determined by Klyne and Stokes.30 However, van Lier and Smith 3 1 suggested that this assignment should be reversed, and some uncertainty still remains. We will therefore retain the original nomenclature 32 for the present paper, referring to the epimers as 24E1- and 24E2-cholesterol(see Experimental section). $ Note added in proof: We have now determined the absolute configurations a t C-24 of 24-hydroxycholestero1 and related compounds. 24f' and 24E2 in this paper are 24s and 24R, respectively (N. Koizumi, M. Morisaki, N. Ikekawa, A. Suzuki, and T. Takeshita, Tetrahedron Letters, in the press).
were prepared, and were found to be active in stimulating intestinal calcium transport in rats deficient in vitamin D.20 A significant difference of biological activities was noted between the 2 4 - i ~ o m e r s . ~That ~ nephrectomy abolishes the intestinal calcium responses suggested that these compounds required a l-hydroxy-group for biological activity. We now report a synthesis of 1~,24~-dihydroxycholecalciferol. Both 24-epimers have also been prepared, in order to elucidate the effect of configuration on vitamin D activity. 24-Oxocholesterol (1), readily available from fucoster01,~'was oxidized with 3.3 equiv. of dichlorodicyanobenzoquinone (DDQ) 34 in refluxing dioxan to afford, the 1,4,6-triene-3,24-dione (2) in 52% yield. The same trienedione (2) was also prepared from 2koxocholestenone,,Z an ozonolysis product of fucostenone, by 16 C. Kaneko, S. Yamada, A. Sugimoto, Y.Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, 1974, 23, 75; Tetrahedron, 1974, 30, 2701. l7 A. Saiga, K. Bannai, M. Sawamura, J. Rubio-Lightbourn, T. Tachibana, N. Koizumi, M. Morisaki, N. Ikekawa, in preparation. l8 B. Pelc, J.C.S. Perkin I, 1974, 1436. 19 D. R. CrumD. D. H. Williams, and B. Pelc,. "T.C.S. PerRin I, 1973, 2731. 20 N. Ikekawa. M. Morisaki. N. Koizumi, M. Sawamura. Y. Tanaka, and H. F. DeLuca, Biochern. Biophys. Res. Cornm., 1975, 62, 485. 21 J . S. Bonetkoe, A. Wignall, M. P. Rappoldt, and J. R. Roborgh, Internat. J . Vitamin Res., 1970, 40,689. Z t H. Y. Lam, B. L. Onisko, H. K. Schnoes, and H. F. DeLuca, Biochem. Biophys. Res. Comm., 1974, 59, 846. 23 W. H. Okamura, M. N. Mitra, R. M. Wing, and A. W. Norman, Biochem. Biophys. Res. Comm., 1974,60, 179. zr M. Morisaki, 3. Rubio-Lightbourn, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 457. 25 M. Morisaki, K. Bannai, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1863. 26 J. Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Phavm. Bull. (Japan), 1973, 21, 1854. 27 M. Morisaki, J. Rubio-Lightbourn, N. Ikekawa, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1973, 21, 2568. 28 At. Seki, J. Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973,21,2783. 29 N. Ikekawa, N. Morisaki, K. Tsuda, and T. Yoshida, Steroids, 1968, 12,41. 30 TV. Klyne andW. M. Stokes, J . Chem. SOC.,1954, 1979. 31 J. E. van Lier and L. L. Smith, J . Pharm. Sci., 1970, 59, 719. a2 A. Ercoli and P. deRuggieri, J . Amer. Chem. Soc., 1953, 75, 3284. 33 Y. Tanaka, H. Frank, H. F. DeLuca, N. Koizumi, and N. Ikekawa, Biochemistry, in the press. 34 A. B. Turner, J . Chem. SOC. ( C ) , 1968, 2568. 1.-
1 Part VIII, N. Ikekawa, M. Morisaki, N. Koizumi, Y . Kato, and T. Takeshita, Chem. and Phavm. Bull. ( J a p a n ) ,1975, 23, 695; The present paper is also Part XIX of the series ' Studies on Steroids;' Part XVIII, idem., ibid. 2 H. F. DeLuca, Amev. J . Med., 1974,57, 1. 3 J. W. Blunt and H. F. DeLuca, Biochemistry, 1969, 8, 671. * S. J. Halkes and N. P. van Vliet, Rec. Trav. chiln., 1969, 88, 1080. J. A. Campbell, D. M. Squires, and J. C. Babcock, Steroids, 1969, 13, 667. T. Suda, H. F. DeLuca, and R. B. Hallick, Biochemistry, 1971, 43, 139. 7 H-Yat Lam, H.K. Schnoes, H. F. DeLuca, and T. C . Chen, Biochemistry, 1973, 12,4851. M. Seki, N. Koizumi, M. Morisaki, and N. Ikekawa, Tetrahedron Letters, 1975, 16. J. Redel, P. Bell, F. Delbarre, and F. Kodicek, Compt. rend., 1973, 276D,2907. 10 E. J. Semmler, M. F. Holick, H. I
1421
1975
Synthesis of Active Forms of Vitamin D. Part 1X.l Synthesis of 1a,24Dihydroxycholecalciferol
Published on 01 January 1975. Downloaded by Lakehead University on 29/10/2014 23:29:44.
By Masuo Morisaki, Naoyuki Koizumi, and Nobuo Ikekawa,' Laboratory of Chemistry for Natural Products, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan Toru Takeshita and Sachio Ishimoto, Teijin Institute for Biomedical Research, Hino-shi, Tokyo, Japan 24-Oxocholesterol (1 ) (readily available from fucosterol) was converted by three steps into 1a,24E-dihydroxycholesterol (4). From the corresponding triacetate (5), 1a,24~-dihydroxycholecalciferol(9) was prepared via the 5,7-diene (8). The C-24 epimers of compound (4) were resolved by silica gel column chromatography of the monohydroxydibenzoates (7). and were separatelytransformed into the corresponding 1a.24-dihydroxycholecalciferol epimers.
VARIOUSmetabolites of vitamin D, have been isolated recently, some of which may be the biologically active forms of the vitamin.2 This has stimulated the synthesis of vitamin D analogues with hydroxy-groups at positions 25,3* 24 and 25,7*s25 and 26,9 la and 25,10911 and la, 24, and 25.l In addition to these metabolic products, artificial ' analogues such as la-,l2-17 4ct-,l8 22-, l 9 and 24-hydroxy- 2o and 20,25-dihydroxy- 21 cholecalciferol, as well as the 1a-hydroxy-3-deoxy-derivative 22*23 have been synthetic targets. We have synthesized several key intermediates 24-28 for the preparation of these compounds from fucosterol, a marine sterol which is abundant in brown algae.29 From one of these intermediates, the epimeric 24-hydroxycholecalciferols t,$
t The configuration at C-24 of 24-hydroxycholestero1has been determined by Klyne and Stokes.30 However, van Lier and Smith 3 1 suggested that this assignment should be reversed, and some uncertainty still remains. We will therefore retain the original nomenclature 32 for the present paper, referring to the epimers as 24E1- and 24E2-cholesterol(see Experimental section). $ Note added in proof: We have now determined the absolute configurations a t C-24 of 24-hydroxycholestero1 and related compounds. 24f' and 24E2 in this paper are 24s and 24R, respectively (N. Koizumi, M. Morisaki, N. Ikekawa, A. Suzuki, and T. Takeshita, Tetrahedron Letters, in the press).
were prepared, and were found to be active in stimulating intestinal calcium transport in rats deficient in vitamin D.20 A significant difference of biological activities was noted between the 2 4 - i ~ o m e r s . ~That ~ nephrectomy abolishes the intestinal calcium responses suggested that these compounds required a l-hydroxy-group for biological activity. We now report a synthesis of 1~,24~-dihydroxycholecalciferol. Both 24-epimers have also been prepared, in order to elucidate the effect of configuration on vitamin D activity. 24-Oxocholesterol (1), readily available from fucoster01,~'was oxidized with 3.3 equiv. of dichlorodicyanobenzoquinone (DDQ) 34 in refluxing dioxan to afford, the 1,4,6-triene-3,24-dione (2) in 52% yield. The same trienedione (2) was also prepared from 2koxocholestenone,,Z an ozonolysis product of fucostenone, by 16 C. Kaneko, S. Yamada, A. Sugimoto, Y.Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, 1974, 23, 75; Tetrahedron, 1974, 30, 2701. l7 A. Saiga, K. Bannai, M. Sawamura, J. Rubio-Lightbourn, T. Tachibana, N. Koizumi, M. Morisaki, N. Ikekawa, in preparation. l8 B. Pelc, J.C.S. Perkin I, 1974, 1436. 19 D. R. CrumD. D. H. Williams, and B. Pelc,. "T.C.S. PerRin I, 1973, 2731. 20 N. Ikekawa. M. Morisaki. N. Koizumi, M. Sawamura. Y. Tanaka, and H. F. DeLuca, Biochern. Biophys. Res. Cornm., 1975, 62, 485. 21 J . S. Bonetkoe, A. Wignall, M. P. Rappoldt, and J. R. Roborgh, Internat. J . Vitamin Res., 1970, 40,689. Z t H. Y. Lam, B. L. Onisko, H. K. Schnoes, and H. F. DeLuca, Biochem. Biophys. Res. Comm., 1974, 59, 846. 23 W. H. Okamura, M. N. Mitra, R. M. Wing, and A. W. Norman, Biochem. Biophys. Res. Comm., 1974,60, 179. zr M. Morisaki, 3. Rubio-Lightbourn, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 457. 25 M. Morisaki, K. Bannai, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1863. 26 J. Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Phavm. Bull. (Japan), 1973, 21, 1854. 27 M. Morisaki, J. Rubio-Lightbourn, N. Ikekawa, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1973, 21, 2568. 28 At. Seki, J. Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973,21,2783. 29 N. Ikekawa, N. Morisaki, K. Tsuda, and T. Yoshida, Steroids, 1968, 12,41. 30 TV. Klyne andW. M. Stokes, J . Chem. SOC.,1954, 1979. 31 J. E. van Lier and L. L. Smith, J . Pharm. Sci., 1970, 59, 719. a2 A. Ercoli and P. deRuggieri, J . Amer. Chem. Soc., 1953, 75, 3284. 33 Y. Tanaka, H. Frank, H. F. DeLuca, N. Koizumi, and N. Ikekawa, Biochemistry, in the press. 34 A. B. Turner, J . Chem. SOC. ( C ) , 1968, 2568. 1.-
1 Part VIII, N. Ikekawa, M. Morisaki, N. Koizumi, Y . Kato, and T. Takeshita, Chem. and Phavm. Bull. ( J a p a n ) ,1975, 23, 695; The present paper is also Part XIX of the series ' Studies on Steroids;' Part XVIII, idem., ibid. 2 H. F. DeLuca, Amev. J . Med., 1974,57, 1. 3 J. W. Blunt and H. F. DeLuca, Biochemistry, 1969, 8, 671. * S. J. Halkes and N. P. van Vliet, Rec. Trav. chiln., 1969, 88, 1080. J. A. Campbell, D. M. Squires, and J. C. Babcock, Steroids, 1969, 13, 667. T. Suda, H. F. DeLuca, and R. B. Hallick, Biochemistry, 1971, 43, 139. 7 H-Yat Lam, H.K. Schnoes, H. F. DeLuca, and T. C . Chen, Biochemistry, 1973, 12,4851. M. Seki, N. Koizumi, M. Morisaki, and N. Ikekawa, Tetrahedron Letters, 1975, 16. J. Redel, P. Bell, F. Delbarre, and F. Kodicek, Compt. rend., 1973, 276D,2907. 10 E. J. Semmler, M. F. Holick, H. I
