Efficient convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling.

Article abstract of DOI:10.1021/ol0274007

[reaction: see text] 1alpha,25-Dihydroxyvitamin D(3) was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 1, which was efficiently prepared from readily available 1,7-enyne 2, with the corresponding boronate compound of the C,D-ring portion. The method was applied to prepare des-C,D analogues of 1alpha,25-dihydroxyvitamin D(3).

Full text of DOI:10.1021/ol0274007

ORGANIC
LETTERS
2003
Vol. 5, No. 4
523-525
Efficient Convergent Synthesis of
1r,25-Dihydroxyvitamin D and Its
3
Analogues by Suzuki−Miyaura Coupling
Takeshi Hanazawa, Akiko Koyama, Takeshi Wada, Eiko Morishige,
Sentaro Okamoto, and Fumie Sato*
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received December 4, 2002
ABSTRACT
1r,25-Dihydroxyvitamin D was synthesized by the Suzuki−Miyaura coupling of the A-ring intermediate 1, which was efficiently prepared from
3
readily available 1,7-enyne 2, with the corresponding boronate compound of the C,D-ring portion. The method was applied to prepare des-C,D
analogues of 1r,25-dihydroxyvitamin D .
3
1R,25-Dihydroxyvitamin D3 [1,25-(OH)2-VD3], which plays
an important role in human physiology, has attracted
substantial interest in its pharmacology and therapeutic
potential.1 The chemical synthesis of 1,25-(OH)2-VD3 and
its analogues, therefore, has been the subject of much
research because organic synthesis is the only means of
supplying sufficient quantities and creating more effective
compounds.2 Recently, we synthesized 19-nor-1R,25-(OH)2-
VD3 by the Suzuki-Miyaura coupling3 between the corre-
sponding A-ring and C,D-ring parts.4 Herein we report a new
efficient synthetic method of 1,25-(OH)2-VD3 that involves,
as shown in Scheme 1, by a retrosynthetic pathway, the
synthesis of A-ring portion 1 from the known starting
compound 1,7-enyne 25 by Ti(II)-mediated cyclization reac-
tion6 and its coupling with C,D-ring unit 3 by the Suzuki-
Miyaura coupling.
removing the trimethylsilyl group, for producing 1,25-(OH)2-
VD3 by a Pd-catalyzed tandem carbometalation-cyclization
reaction (Trost method).8 The conversion of 2 to [(3S)-
(1Z,3R,5â)]-[2-[3,5-bis[[(1,1-dimethyl)dimethylsilyl]oxy]-2-
methylenecyclohexylidene]ethyl]diphenylphosphine oxide,
the A-ring intermediate for synthesizing 1,25-(OH)2-VD3 by
the Horner-Wittig reaction (Lythgoe-Roche method9) was
also reported.5,10
Preparation of 2 from optically active epichlorohydrin (4)
was carried out in 45% overall yield according to the
(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) Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877.
(3) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(4) Hanazawa, T.; Wada, T.; Masuda, T.; Okamoto, S.; Sato, F. Org.
Lett. 2001, 3, 3975.
(5) Tazumi, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1994,
1903.
(6) Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7329.
(7) Garc´ıa, A. M.; Mascaren˜as, J. L.; Castedo, L.; Mourin˜o, A. J. Org.
Chem. 1997, 62, 6353.
(8) (a) Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114,
9836. (b) Trost, B. M.; Hanson, P. R. Tetrahedron Lett. 1994, 35, 8119.
A similar coupling approach to 1,25-(OH)2-VD3 using the
Stille coupling and/or Negishi coupling was proposed by
Mourin˜o and co-workers; however, they only synthesized
3-deoxy-1-hydroxyvitamin D3 by this approach.7 It is also
noteworthy that the starting enyne 2 can be utilized, after
10.1021/ol0274007 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/28/2003

methoxyethoxy)-aluminum hydride (Red-Al) provided (E)-
allyl alcohol 9 in 97% overall yield. Preparation of 2 from
9 was carried out in 78% overall yield by the conventional
reaction sequence, which involves Sharpless catalytic asym-
metric epoxidation (Ti(O-i-Pr)4, L-(+)-DIPT, TBHP, CH2Cl2,
-20 °C), conversion of the hydroxy group to iodide, and
reductive opening of the epoxy iodide moiety.5
Scheme 1
The titanacyclization of 2 mediated by a divalent titanium
reagent, Ti(O-i-Pr)4/2i-PrMgX, and the following reaction
with NBS afforded dibromo compound 10 in 88% yield.6,12
Although the stereochemistry of the bromomethyl moiety
of 10 could not be assigned by the 1H NMR analysis, it was
tentatively assigned as depicted in Scheme 3 on the basis of
Scheme 3
procedure shown in Scheme 2. Thus, 4 was converted to
epoxide 5 according to the procedure reported by Ogasawara
Scheme 2
our previous results of the cyclization of similar com-
pounds.6 After protection of the hydroxyl group of 10 as
tert-butyldimethylsilyl ether, the resulting 11 was treated with
DBU in CH2Cl2 and then Cs2CO3 in DMF to provide 1 in
excellent yield.7 Thus, 1 could be obtained in 76% overall
yield from 2.
With the A-ring unit 1 in hand, we carried out the synthesis
of 1,25-(OH)2-VD3 by the Suzuki-Miyaura coupling reac-
tion. Thus, the reaction of 1 with 34 in the presence of KOH
and PdCl2(dppf) (8 mol %) in aqueous THF furnished, after
desilylation, 1,25-(OH)2-VD3 in 82% yield (Scheme 4).
Among the analogues of 1,25-(OH)2-VD3, those which
lack the C,D-ring have recently attracted much interest as
potentially therapeutic compounds.13 The present method for
synthesizing 1,25-(OH)2-VD3 using 1 is also very efficient
for synthesizing such compounds as exemplified by the
synthesis of Retiferol.13a Thus, as also shown in Scheme 4,
the coupling of 1 with 12, which was prepared from the
corresponding alkyne by hydroboration reaction,4 afforded,
after desilylation, Retiferol in 78% overall yield.14
with minor modifications.5,11 Epoxide ring-opening of 5 with
alkynyllithium 6 in the presence of boron trifluoride etherate
provided, after hydrolysis, diol 7 in 82% yield. Selective
acylation of the primary hydroxyl group of 7 to 8 was
attained by treatment with vinyl acetate in the presence of
porcine pancreatic lipase (PPL) in 96% yield. Protection of
the secondary hydroxy group of 8 as tert-butyldimethylsilyl
ether, and the following treatment with sodium bis(2-
(12) Review for synthetic reactions mediated by a Ti(O-i-Pr)4/2 i-PrMgCl
reagent: Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835.
Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343, 759. Sato, F.; Urabe,
H. In Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 319-354.
(13) (a) Kutner, A.; Zhao, H.; Fitak, H.; Wilson, S. R. Bioorg. Chem.
1995, 23, 22. (b) Wirz, B.; Iding, H.; Hilpert, H. Tetrahedron: Asymmetry
2000, 11, 4171. (c) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681. (d)
U.S. Patent 5,969,190, 1998. (e) U.S. Patent 6,184,422, 1999.
(9) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.;
Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098 and references
therein.
(10) Vrielynck, S.; Vandewalle, M. Tetrahedron Lett. 1995, 36, 9023.
(11) Subburaj, K.; Okamoto, S.; Sato, F. J. Org. Chem. 2002, 67, 1024.
524
Org. Lett., Vol. 5, No. 4, 2003

Scheme 4
Scheme 5a
a Reaction conditions: (a) allylmagnesium chloride, cat. CuCN
(77%). (b) (i) Ti(O-i-Pr)4, 2i-PrMgCl, NBS; (ii) TBSCl, imidazole
(59% for two steps). (c) (i) DBU, CH2Cl2; (ii) Cs2CO3, DMF (74%
for two steps). (d) Pd(dppf)Cl2 (8 mol %), KOH, THF-H2O, 60
°C. (e) TBAF, THF (74% for two steps). (f) t-BuLi, then B(O-i-
Pr)3, aqueous NH4Cl, pinacol, ethyl acetate (76%).
derivatives that involves, as a key reaction, the coupling of
the A-ring and C,D-ring portions by Suzuki-Miyaura
coupling. Especially noteworthy is the efficient synthesis of
1 that allows easy access to 1,25-(OH)2-VD3 and its des-
C,D analogues. Thus, in addition to the Trost8 and Lythgoe-
Roche9 methods, another practical entry to 1,25-(OH)2-VD3
and its derivatives has now been established.
As the synthesis of vitamin D3 has also attracted much
interest, we synthesized vitamin D3 by a strategy similar to
that mentioned above. Epoxide ring-opening reaction of 5
with allylmagnesium bromide in the presence of a catalytic
amount of CuCN provided 1,7-enyne 13, which in turn was
converted to 14, as shown in Scheme 5, according to a
procedure similar to the synthesis of 1 from 2. The Suzuki-
Miyaura coupling reaction of 14 with 16, prepared from 15,
provided vitamin D3 in 74% yield after deprotection.
In summary, we have developed a new synthetic meth-
odology for synthesizing VD3, 1,25-(OH)2-VD3, and their
Acknowledgment. T.H. thanks the Japan Society for the
Promotion of Science for financial support.
Supporting Information Available: Experimental pro-
cedure and spectral data for compounds 1, 2, 7-11, 13-15,
and the final products as shown in Schemes 4 and 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) For the synthesis of des-C,D-VD3 analogues by the Lythgoe-Roche
method, see ref 13. Synthesis of des-C,D-VD3 analogues by the Trost
method was not reported.
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