Novel synthetic approach to 19-nor-1α,25-dihydroxyvitamin D3 and its derivatives by Suzuki-Miyaura coupling in solution and on solid support

Article abstract of DOI:10.1021/ol016908r

equation presented 19-nor-1α,25-Dihydroxyvitamin D₃ was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 3, which was efficiently prepared from readily available 5-(tert-butyldimethylsilyl)oxycyclohex-2-enone (5), with the

Full text of DOI:10.1021/ol016908r

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3975-3977
Novel Synthetic Approach to
19-nor-1r,25-Dihydroxyvitamin D and
3
Its Derivatives by Suzuki−Miyaura
Coupling in Solution and on Solid
Support
Takeshi Hanazawa, Takeshi Wada, 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 October 15, 2001
ABSTRACT
19-nor-1r,25-Dihydroxyvitamin D was synthesized by the Suzuki−Miyaura coupling of the A-ring intermediate 3, which was efficiently prepared
3
from readily available 5-(tert-butyldimethylsilyl)oxycyclohex-2-enone (5), with the boronate compound of the C,D-ring portion. The method
could be applied to a solid-phase synthesis to prepare the des-C,D derivatives of 19-nor-1r,25-dihydroxyvitamin D .
3
1R,25-Dihydroxyvitamin D3 (1R,25-(OH)2VD3) is a hor-
monal, biologically active form of vitamin D3. Besides its
classical role in regulating calcium metabolism, its activities
in cellular differentiation, inhibition of tumor cell prolifera-
tion, and induction of functions related to the immunological
system have been established.1 In 1990, DeLuca et al.
reported that deletion of the 19-methylene group of 1R,25-
(OH)2VD3 increased significantly the stimulation of dif-
ferentiation 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 the compounds 1
and 2 (Ro 65-2299) shown in Scheme 1 have attracted much
interest as potential therapeutical agents.3
The synthesis of the 19-nor-VD3s having a C,D-ring
portion can be efficiently carried out by the Wittig olefination
reaction of the diphenylphosphine oxide of the corresponding
A-ring portion with the respective ketone through the
(3) Paricalcitol: (a) Graul, A.; Leeson, P. A.; Castaner, J. Drugs Future
1998, 23, 602. Compound 1: (b) U.S. Patent 5,969,190, 1998. Compound
2: (c) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681. (d) U.S. Patent
6,184,422, 1999. Other analogues: (e) 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. (f) Zhou, X.; Zhu, G.-D.;
Van Haver, D.; Vandewalle, M.; De Clercq, P. J.; Verstuyf, A.; Bouillon,
R. J. Med. Chem. 1999, 42, 3539. (g) 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. (h) Kubodera, N.; Okano,
T.; Nakagawa, K.; Ozono, K.; Mikami, K. Curr. Pharm. Des. 2000, 6(7),
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. Biochim. Biophys. Acta 1993,
1158, 279.
10.1021/ol016908r CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

Scheme 1
Scheme 2a
connection between the C-7 and C-8 positions (see Scheme
1), which proceeded with excellent stereoselectivity. How-
ever, in the preparation of des-C,D-19-nor-VD3s 1 and 2 via
a similar Wittig olefination, difficulty was incurred in co-
producing the stereoisomer in relation to the newly formed
olefin moiety.3b-d To overcome this drawback, preparation
of 2 via the connection between the C-5 and C-6 and the
C-6 and C-7 positions was pursued by the chemists of
Hoffmann-La Roche. They succeeded in the synthesis of 2
via the former connection pathway applying the Julia
coupling reaction. However, they gave up the synthesis via
the latter pathway by the Suzuki-Miyaura coupling using
the intermediate such as alkenylbromide 3 or alkenylboronate
4, because they failed to prepare 3 and could prepare 4 in
only very low yield.3c This approach, however, is very
attractive because it might not only provide another practical
approach to the known 19-nor-VD3s, including 1 and 2, but
also open up an entry to new 19-nor-VD3 derivatives that
are difficult to prepare through other pathways.4 Herein we
report an efficient and high-yield preparation of 3 and 4 and
their utilization for the synthesis of 19-nor-1R,25-(OH)2VD3
and its derivatives including 1 by the Suzuki-Miyaura
coupling under liquid- and/or solid-phase reaction conditions.
We recently reported a practical method for preparation
of optically active 5-(tert-butyldimethylsilyloxy)-2-cyclo-
hexenone (5) and showed that it works as a versatile chiral
building block for synthesizing optically active cyclohexane
derivatives.5 We have now found that 3 and 4 can be readily
synthesized from (S)-56 according to the procedure shown
in Scheme 2. Thus, the compound 5 was converted to
bromomethylidenecyclohexanol 7 in 71% overall yield by
the conventional reaction sequence, which involves stereo-
selective epoxidation of 5 using a H2O2/NaOH reagent,5h
Wittig olefination of the resulting epoxyketone7 with
a (i) Aqueous 30% H2O2, 3 N NaOH, MeOH; (ii) (Ph3P+CH2Br)-
Br-, KHMDS, toluene; (iii) DIBAL, hexanes; (iv) TBDMSCl,
imidazole, DMF; (v) t-BuLi, ether then B(O-i-Pr)3, pinacol.
(Ph3P+CH2Br)Br- and KHMDS, and epoxide-ring opening
of the diene monoepoxide 68 thus produced using i-Bu2AlH.
Silylation of 79 with TBDMSCl/imidazole afforded 3 in 93%
yield. The compound 3 thus obtained was readily converted
to boronate 4 in 90% yield by sequential treatment with
t-BuLi, B(O-i-Pr)3, aqueous NH4Cl, and pinacol. Because
all reagents used in the synthesis are readily available,
inexpensive and nontoxic and the yield is high (the overall
yields of 3 and 4 from 5 were 66% and 60%, respectively),
we believe that 3 and 4 can be easily prepared in quantity.
With the A-ring precursors 3 and 4 in hand, we carried
out the synthesis of 1 and/or 19-nor-1R,25-(OH)2VD3 by the
Suzuki-Miyaura coupling reaction10 (Scheme 3). Thus, the
coupling reaction of 3 with boronate 9, prepared by hy-
droboration of acetylene 8,11 in the presence of KOH and
PdCl2(dppf) (5 mol %) in aqueous THF furnished, after
desilylation, 1 in 86% yield. The 1H and 13C NMR analyses
of the crude product indicated that the reaction did not
produce the olefinic isomer of 1 at all.12 Similarly, 19-nor-
(5) (a) Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997,
38, 8299. (b) Hareau, G. P-J.; Hikichi, S.; Sato, F. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2099. (c) Hareau, G. P-J.; Koiwa, M.; Hikichi, S.; Sato,
F. J. Am. Chem. Soc. 1999, 121, 3640. (d) Hareau, G.; Koiwa, M.;
Hanazawa, T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493. (e) Hareau, G. P.
J.; Koiwa, M.; Sato, F. Tetrahedron Lett. 2000, 41, 2385. (f) Koiwa, M.;
Hareau, P. J.; Sato, F. Tetrahedron Lett. 2000, 41, 2389. (g) Hanazawa, T.;
Okamoto, S.; Sato, F. Tetrahedron Lett. 2001, 42, 5545. (h) Hanazawa, T.;
Inamori, H.; Masuda, T.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 2205.
(6) Prepared from (S)-epichlorohydrine with >99% enantiomeric excess
(ee).5g
(7) The reaction gave a mixture of the epoxyketone having the structure
shown in Scheme 2 and its diastereomer in a ratio of >96:4, recrystallization
of which from hexane provided the diastereomerically pure compound.
(8) Greater than 97% E.
(4) The synthesis of 19-nor-1R-hydroxyvitamin D3 via the carbon-
carbon bond formation between the C-6 and C-7 positions has been reported,
although the synthesis did not involve the Csp2-Csp2 coupling reaction
such as Suzuki-Miyaura coupling: Zhou, S.-Z.; Anne´, S.; Vandewalle,
M. Tetrahedron Lett. 1996, 37, 7637.
(9) The ee of 7 was confirmed by 1H NMR analyses, after converting to
the corresponding MTPA esters, to be >99%.
(10) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(11) See Supporting Information.
3976
Org. Lett., Vol. 3, No. 24, 2001

Scheme 3a
Scheme 4
a (i) (ipc)2BH, then CH3CHO, 2,2-dimethyl-1,3-propanediol, THF
(70% yield); (ii) t-BuLi, then B(O-i-Pr)3, aqueous NH4Cl, pinacol,
ether (79% yield); (iii) PdCl2(dppf) catalyst, KOH, THF/H2O; (iv)
aqueous 30% HF, THF.
1R,25-(OH)2VD3 was readily synthesized in 68% yield by
coupling reaction between 3 and 11, the latter of which was
prepared from bromide 1013 by a lithiation-transmetalation
reaction sequence. The Suzuki-Miyaura coupling reaction
of boronate 414 and bromide 10 also proceeded smoothly to
afford 19-nor-1R,25-(OH)2VD3 in 72% yield.
With the results shown in Scheme 3, we then devoted our
efforts to prepare 19-nor-VD3s in solid phase by utilizing 7.
Synthesis on solid support has recently played an important
role in parallel synthesis and combinatorial chemistry,
particularly in the area of medicinal chemistry.15 Our parallel
solid-phase synthesis of des-C,D-19-nor-VD3s shown in
Scheme 4 involves coupling of the resin-supported 7 with
ester boronate 13 and the following Grignard addition to the
ester group present in the resulting coupling product. Thus,
the compound 7 reacted with PS-DES-Cl16 in the presence
of imidazole to provide the resin 12.17 Treatment of the resin
12 thus prepared with boronate 1318 where X ) CH2 under
reaction conditions similar to those applied in Scheme 3
provided the corresponding coupling product, which in turn
was treated with an excess amount of MeMgCl or EtMgBr
and then aqueous HF to produce 1 and 14 in 94% and 96%
yield, respectively.19 It should be noted that the 26,27-
dimethyl-19-nor-VD3 derivative 1420 prepared here is a new
compound. Similarly, new des-C,D-19-nor-VD3 derivatives
15 and 16 were readily synthesized from 12 and 13 (X )
O)18 in 92% and 93% yield, respectively.19
In summary, we have succeeded in developing a new
efficient method for synthesizing 19-nor-VD3s, including
those that are difficult to access by other known methods,
such as 15 and 16,21 in solution and on solid support. We
believe that the present method can find utility in the fields
of drug discovery and manufacturing.
(12) Authentic sample of the cis isomer of 1 was prepared from 3 and
8, see Supporting Information.
(13) Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114,
9836.
(14) The corresponding alkenylstannane could be synthesized from 3
via transmetalation using Bu3SnCl instead of B(O-i-Pr)3 (Scheme 2) in 93%
yield, which might be useful for 19-nor-VD3 synthesis by Pd-catalyzed
coupling reactions: Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 3, 4, 6-9, 11, and 13-
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL016908R
(15) A leading reference for the Suzuki-Miyaura coupling on solid
phase: Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett. 2001, 3, 803. For
solid-phase synthesis of vitamin D3s, see: Doi, T.; Hijikuro, I.; Takahashi,
T. J. Am. Chem. Soc. 1999, 121, 6749. Hijikuro, I.; Doi, T.; Takahashi, T.
J. Am. Chem. Soc. 2001, 123, 3716.
(16) Prepared from PS-DES (Argonaut Technologies) by the reported
procedure: Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W.; Trost,
B. M. J. Org. Chem. 1998, 63, 4518.
(17) The loading was determined to be 0.738 mmol/g by cleavage with
HF-pyridine in THF from the resin and quantification of the resulting
5-bromocyclohexane-1,3-diol by 1H NMR analysis of the crude mixture
using an internal standard.11
(19) Chemical purity of the products 1 and 14-16 was determined by
1H NMR and HPLC analyses to be >95%.
(20) Several 26,27-dimethyl derivatives of 1R,25(OH)2VD3, i.e., the
compounds having a 25,25-diethyl structure, have shown a different
spectrum of biological activities compared with the corresponding 25,25-
dimethyl VD3s. Reviews on the synthesis and structure-function relationship
of vitamin D analogues: Bouillon, R.; Okamura, W. H.; Norman, A. W.
Endocr. ReV. 1995, 16, 200. Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995,
95, 1877. Dai, H.; Posner, G. H. Synthesis 1994, 1383. Uskokoovic, M.,
Ed. Bioorg. Med. Chem. Lett. 1993, 3(9), special issue.
(21) It appears difficult to synthesize 15 and 16 by the Julia coupling
method developed by Hilpert3c because the corresponding sulfone reagent
might undergo elimination of an alkoxy group by treatment with a base.
(18) Prepared from the corresponding terminal alkynes via hydroboration
reaction.11
Org. Lett., Vol. 3, No. 24, 2001
3977