Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D(3) and its (13)C- or (2)H-labeled derivative.

Article abstract of DOI:10.1021/ol016052q

[reaction: see text] The A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D(3) (1) and its (13)C- or (2)H-labeled derivative were efficiently synthesized from readily available, optically active 5-(tert-butyldimethylsilyloxy)-2-cyclohexenone (2) thro

Full text of DOI:10.1021/ol016052q

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2205-2207
Efficient and Practical Synthesis of the
A-Ring Precursor of
19-nor-1r,25-Dihydroxyvitamin D and
3
2
Its 13C- or H-Labeled Derivative
Takeshi Hanazawa, Hajime Inamori, Tomoko Masuda, Sentaro Okamoto, and
Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received May 2, 2001
ABSTRACT
2
The A-ring precursor of 19-nor-1r,25-dihydroxyvitamin D (1) and its 13C- or H-labeled derivative were efficiently synthesized from readily
3
available, optically active 5-(tert-butyldimethylsilyloxy)-2-cyclohexenone (2) through a five-step reaction in 68% overall yield.
1R,25-Dihydroxyvitamin D3 [1R,25-(OH)2VD3], the biologi-
cally active form of vitamin D3, is a highly potent regulator
of calcium homeostasis, and more recently, its activity in
cellular differentiation, inhibition of tumor cell proliferation,
and induction of functions related to the immunological
system have been established.1 Many structural analogues
have been prepared and tested, and differentiation was made
of the respective activities. In 1990, DeLuca et al. reported
that deletion of the 19-methylene group of 1R,25-(OH)2VD3
increased significantly the stimulation of differentiation and
growth inhibition of tumor cells without a parallel increase
in hypercalcemia.2 With this finding, 19-nor-1R,25-(OH)2VD3
itself and also its derivatives having a different C,D-ring
portion such as paricalcitol or those lacking the C,D-ring
substructure such as Ro 65-2299 (Hoffmann La Roche) have
attracted much interest as potentially therapeutic agents.3
One efficient methods for synthesizing these compounds
involves a Wittig olefination of the diphenylphosphine oxide
derived from the allyl alcohol 1 via the chloride with the
corresponding carbonyl moiety, as exemplified by the
synthesis of 19-nor-1R,25-(OH)2VD3 as shown in Scheme
1.4 Considerable efforts, therefore, have been made toward
developing an industrially viable access to 1, the A-ring
precursor of 19-nor-1R,25-(OH)2VD3.
(3) Paricalcitol: (a) Graul, A.; Leeson, P. A.; Castaner, J. Drugs Future
1998, 23, 602. Ro 65-2299: (b) Hilpert, H.; Wirz, B. Tetrahedron 2001,
57, 681. Other analogues: (c) Mikami, K.; Osawa, A.; Isaka, A.; Sawa, E.;
Shimizu, M.; Terada, M.; Kubodera, N.; Nakagawa, K.; Tsugawa, N.;
Okano, T. Tetrahedron Lett. 1998, 39, 3359. (d) Zhou, X.; Zhu, G.-D.;
Van Haver, D.; Vandewalle, M.; De Clercq, P. J.; Verstuyf, A.; Bouillon,
R. J. Med. Chem. 1999, 42, 3539. (e) Verstuyf, A.; Verlinden, L.; Van
Baelen, H.; Sabbe, K.; D’hallewyn, C.; De Clercq, P. J.; Vandewalle, M.;
Bouillon, R. J. Bone Miner. Res. 1998, 13, 549. (f) Kubodera, N.; Okano,
T.; Nakagawa, K.; Ozono, K.; Mikami, K. Curr. Pharm. Design 2000, 6,
791.
(1) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J. W., Eds.; Academic
Press: New York, 1997. Bouillon, R.; Okamura, W. H.; Norman, A. W.
Endocr. ReV. 1995, 16, 200.
(2) (a) Perlman, K. L.; Sicinski, R. R.; Schnoes, H. K.; DeLuca, H. F.
Tetrahedron Lett. 1990, 31, 1823. (b) Perlman, K. L.; Swenson, R. E.;
Paaren, H. E.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett. 1991, 32,
7663. (c) Yang, S.; Smith, C.; DeLuca, H. F. Biochem. Biophys. Acta 1993,
1158, 279.
(4) For the synthesis of 19-nor-1R,25-(OH)2VD3 and its derivatives using
1, see refs 2b and 3b-e.
10.1021/ol016052q CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/20/2001

Scheme 1
Scheme 2
Five syntheses of 1 have been reported so far. DeLuca
prepared 1 starting from (-)-quinic acid via an eight-step
reaction in 16-20% overall yield.2b Vandewalle reported a
five-step synthesis with 15% overall yield starting from
optically active 1,2:4,5-diepoxypentane.5 Mikami3c and
Uskokovic6 independently accomplished the synthesis start-
ing from achiral acyclic precursors and using carbonyl-ene
cyclization as a key reaction in 11 steps in 9.7% and 20%
overall yield, respectively. Quite recently, Hilpert developed
an efficient approach to 1 starting from triacetate of trans-
cyclohexane-1,3,5-triol, which employs selective enzymatic
hydrolysis (63% overall yield).3b,7
We have recently developed optically active 5-(tert-
butyldimethylsilyloxy)-2-cyclohexenone (2) as a versatile
building block for synthesizing chiral cyclohexane deriva-
tives.8 The compound 2 can be readily prepared starting from
optically active ethyl 3-hydroxy-4-chlorobutyrate8a or epi-
chlorohydrin,8h both of which are commercially available.
In both synthetic approaches, all of the reagents used are
readily available, nontoxic, and inexpensive, and the overall
yield exceeds 50%. We believe, therefore, that 2 can be easily
prepared in quantity and thus might find industrial use. We
have, so far, revealed that 2 can be conveniently used as a
starting compound for synthesizing several natural products
such as penienone,8d penihydron,8d palitantin,8e and the A-ring
synthon of 1R,25-(OH)2VD3.8f,g Herein we report the syn-
thesis of 1 from (S)-2.
highly diastereoselective epoxidation of 2 to 3, Horner-
Wadsworth-Emmons olefination of 3 to 4, and regio-
selective reductive ring opening of the epoxide moiety of 4
to 5. Epoxidation of (S)-2 under various conditions was
examined. It was found that the use of H2O2/NaOH gives 3
in 87% yield with the highest diastereomeric ratio of 96:4.
Oxone at 0 °C (6 h) afforded 3 in 22% yield9 and 94% dr,
whereas TBHP/Triton-B (5 °C, 3 h) gave 3 in 70% yield10
and 85% d.r. It is noteworthy that m-CPBA failed to oxidize
2.
The Horner-Wadsworth-Emmons olefination reaction of
3 with (EtO)2(O)PCH2CO2Et afforded 4 in 94% yield, which
was obtained as a mixture of E- and Z-isomers and was used
for the following reactions without separation. The regio-
specific reductive epoxide ring opening of 4 to 5 was
effectively carried out with HCO2H in the presence of a
catalytic amount of Pd2(dba)3(CHCl3) (2.5 mol %).11 Protec-
tion of the newly formed hydroxy group as tert-butyldi-
methylsilyl ether followed by column chromatography
provided 612 in 90% overall yield from 4. The compound 1
([R]29D +17.8 (c 1.02, CHCl3), lit.3b [R]D +18.4 (1%, CHCl3))
was finally synthesized in 92% yield by reduction of 6 with
DIBAL-H,13 the spectral data of which were in good
agreement with those reported.3b,c Thus, the synthesis of 1
The synthesis can be accomplished according to the
reaction sequence shown in Scheme 2, which involves
(5) Zhou, S. Z.; Anne´, S.; Vandewalle, M. Tetrahedron Lett. 1996, 37,
7637.
(6) Courtney, L. F.; Lange, M.; Uskokovic, M. R.; Wovkulich, P. M.
Tetrahedron Lett. 1998, 39, 3363.
(7) Wirz, B.; Iding, H.; Hilpert, H. Tetrahedron: Asymmetry 2000, 11,
4171.
(8) (a) Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997,
38, 8299. (b) Koiwa, M.; Hareau, G. P-J.; Morizono, D.; Sato, F.
Tetrahedron Lett. 1999, 40, 4199. (c) Hareau, G. P-J.; Hikichi, S.; Sato,
F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2099. (d) Hareau, G. P-J.; Koiwa,
M.; Hikichi, S.; Sato, F. J. Am. Chem. Soc. 1999, 121, 3640. (e) Hareau,
G.; Koiwa, M.; Hanazawa, T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493.
(f) Hareau, G. P. J.; Koiwa, M.; Sato, F. Tetrahedron Lett. 2000, 41, 2385.
(g) Koiwa, M.; Hareau, P. J.; Sato, F. Tetrahedron Lett. 2000, 41, 2389.
(h) Hanazawa, T.; Okamoto, S.; Sato, F. Tetrahedron Lett., in press.
(9) Recovery of 2 was 75%.
(10) Phenol was coproduced in 30% yield.
(11) For reductive epoxide ring opening of diene monoepoxides with a
Pd(0)/HCO2H reagent, see: Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar,
M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280.
(12) [R]29 + 18.0 (c 0.26, CHCl3). Spectral data (1H NMR and IR)
D
were in good agreement with those reported.2b,3b
(13) The reduction of 6 to 1 with Red-Al was reported to proceed in
97% yield; see ref 3b.
2206
Org. Lett., Vol. 3, No. 14, 2001

Another attractive feature of the present approach is the
2
fact that it allows the synthesis of 1 labeled with 13C or H
(Figure 1). Thus, the use of (EtO)2(O)P-13CH2CO2Et15 instead
of (EtO)2(O)PCH2CO2Et for the conversion of 3 to 4 in
Scheme 2 provided 1 labeled with a 13C atom at the C-6
position (steroid numbering). Meanwhile, the use of DCO2D
instead of HCO2H for the conversion of 4 to 5 afforded a
2
mixture of 1 having a H atom on the cyclohexane ring at
the C-4 and C-10 positions.16
Figure 1.
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science and Technology (Japan) for financial
support.
from 2 was attained in five steps and in 68% overall yield.14
Although it is difficult to compare the present approach to 1
with the Hilpert method, which appears to be the most
practical approach known to date, because the starting
compounds and the reagents used for its synthesis are quite
different, we believe that this adds another industrially viable
approach to 1.
Supporting Information Available: Experimental pro-
cedure and spectral data for compounds 3-5 and 13C- or
2H-labeled 1. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL016052Q
(15) Purchased from Aldrich.
(14) Thus, 1 was obtained in 35% overall yield in 11 steps from ethyl
3-hydroxy-4-chlorobutyrate.
(16) Deuterium incorporation of the resulting 2H-1 was determined to
be >93% by GC/MS analysis.
Org. Lett., Vol. 3, No. 14, 2001
2207