An efficient solid-phase synthesis of the vitamin D3 system [2]

Full text of DOI:10.1021/ja990739c

J. Am. Chem. Soc. 1999, 121, 6749-6750
6749
carbonyl group, Horner-Wittig reaction of an A-ring moiety to
the polymer-supported 8-keto CD-ring is performed initially,
giving rise to the triene system of the vitamin D3 in the presence
of a tosylate. Alkylation of a tosyl group at the 22-position of
the polymer-support with a Grignard reagent will afford the
vitamin D3 system,9 if it can be performed at sufficiently low
temperature to avoid isomerization of the triene system. ED-71
(2) which has three hydroxy units on the A-ring is a promising
candidate for osteoporosis therapy10 and has regulatory activities
for calcium metabolism. Contemplating the construction of a big
library of A-ring analogues by changing either the alkoxy group
or the stereogenic centers, we attempted solid-phase syntheses
of 11-hydroxylated ED-71 analogue 3a and 1R,25-(OH)2-vitamin
D3 analogue 3b.
An Efficient Solid-Phase Synthesis of the Vitamin D3
System
Takayuki Doi, Ichiro Hijikuro, and Takashi Takahashi*
Department of Chemical Engineering
Tokyo Institute of Technology
2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
ReceiVed March 8, 1999
1R,25-Dihydroxyvitamin D3 (calcitriol) (1) is well-known as
the hormonally active form of vitamin D3, whose physiological
activities include regulation of cell differentiation and prolifera-
tion, intestinal calcium absorption, bone mobilization, and bone
formation.1 These properties have stimulated significant efforts
toward the synthesis of various calcitriol analogues having
modified side chains and having some A-ring derivatives.2
However, there is no report of a convenient method for the
preparation of a library of vitamin D3 analogues having modified
side chains and modified A-ring moieties at the same time.3 We
anticipated that a key component for constructing a library of
vitamin D3 analogues is the ability to simply and efficiently couple
A-ring moieties, CD-rings, and side chains. The combination of
a variety of these three components could provide a large array
of analogues if this can be performed on solid-phase resins.
Recently, solid-phase synthesis has become a powerful tool for
the preparation of not only oligopeptides and oligonucleotides
but also small molecule libraries.4 We report here the novel solid-
phase synthesis of the vitamin D3 system, obtained by efficient
coupling of the solid-supported CD-ring with modified A-ring
moieties, followed by immediate alkylation with a side chain.
The 11-hydroxy CD-ring 8 is a key intermediate, and our
strategy is outlined in Scheme 1. The hydroxy group at the 11-
position is used for loading to the polymer resin and the attached
group should not affect the subsequent two steps, that is:5 (i)
Horner-Wittig reaction of A-ring moieties 5 to the polymer-
supported 8-keto CD-ring 4,6-8 (ii) alkylation of the polymer-
supported tosylate at the 22-position with the Grignard reagent
6. The trialkylsilane linker was chosen to attach the polymer
support because silyl protection has proven to be effective in the
synthesis of various vitamin D3 analogues and is readily cleaved
smoothly even in the presence of the unstable triene moiety. To
avoid facile epimerization at the 14-position adjacent to the
The A-ring moiety 5a was prepared as follows. Nitrile 9 was
synthesized according to our previously reported procedure.11
Protection of the hydroxy group of 9 by TBS, followed by DIBAL
reduction of the nitrile afforded an aldehyde, which was oxidized
to acid 10. Acid 10 was treated with carbonyl diimidazole,
followed by the addition of magnesium ethyl malonate, to provide
â-keto ester 11.12 The (Z)-enolate13 formed by the treatment of
11 with sodium hydride was trapped as a triflate, and the ethyl
ester was reduced with DIBAL to yield alcohol 12. Palladium-
(0)-catalyzed cyclization was carried out as previously reported.14
The reaction proceeded smoothly at room temperature to furnish
cyclized (Z)-diene 13 in 87% yield, exclusively, without formation
of (E)-diene.13 Dienyl alcohol 13 was chlorinated (MsCl/LiCl/
DMF), and was converted to the phosphine oxide 5a according
to the literature procedure6-8,15 (Scheme 2).
The â-hydroxyketone 8 was prepared from the Inhoffen-
Lythgoe diol,16,17 and was loaded on chlorinated PS-DES resin
(0.74 mmol/g).18 The loading yield was determined to be 66%
by cleavage with HF‚Py in THF from the solid support.19 Horner-
Wittig reaction of resin 4 with lithiated 5a in THF at -78 °C to
-40 °C yielded triene 14. Acid cleavage gave the corresponding
11-hydroxy compound, whose characterization showed exclusive
formation of the triene system and no epimerization at the 14-
position. Coupling of tosylate 14 with Grignard reagent 6 at -10
(9) In most of precedent syntheses of vitamin D3 derivatives, Grignard
coupling reaction was initially carried out with a CD-ring that possesses not
8-keto but 8-hydroxy group. Then, the hydroxy group was oxidized to provide
an 8-keto compound, which underwent Horner-Wittig olefination leading to
the vitamin D3 system. There are only a few examples for alkylation of tosylate
at the 22-position in the presence of triene system with Grignard reagent.
Especially, few examples of alkylation have been reported using 3-alkoxy-
3-methylbutyl Grignard reagent for the direct formation of the side chain of
vitamin D3 system; see: Andrews, D. R.; Barton, D. H. R.; Hesse, R. H.;
Pechet, M. M. J. Org. Chem. 1986, 51, 4819.
(10) Okano, T.; Tsugawa, N.; Masuda, S.; Takeuchi, A.; Kobayashi, T.;
Takita, Y.; Nishii, Y. Biochem. Biophys. Res. Commun. 1989, 163, 1444;
Tobayashi, T.; Okano, T.; Tsugawa, N.; Murano, M.; Masuda, S.; Takeuchi,
A.; Sato, K.; Nishii, Y. Bioorg. Med. Chem. Lett. 1993, 3, 1815; Tsurukami,
H.; Nakamura, T.; Suzuki, K.; Sato, K.; Higuchi, Y.; Nishii, Y. Calcif. Tissue.
Int. 1994, 54, 142.
(11) Takahashi, T.; Nakazawa, M. Synlett 1993, 37; Takahashi, T.;
Nakazawa, M.; Sakamoto, Y.; Houk, K. N. Tetrahedron Lett. 1993, 34, 4075.
(12) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int. Ed.
Engl. 1979, 18, 72.
(13) NOE (9%) was observed between H4 and H6.
(14) Yokoyama, H.; Takahashi, T. Synlett 1997, 187.
(15) An acetonide group was cleaved under the reported chlorination
conditions.
(1) Norman, A. W., Bouillon, R., Thomasset, M., Eds.; Vitamin D: Gene
Regulation, Structure Function Analysis and Clinical Application; Walter de
Gruyter and Co.: Berlin; 1991.
(2) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. ReV. 1995, 16,
200.
(3) Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877. For recent
reports of the preparation of the A-ring moieties, see: Sicinski, R. R.; Prahl,
J. M.; Smith, C. M.; DeLuca, H. F. J. Med. Chem. 1998, 41, 4662. Posner, G.
H.; Lee, J. K.; White, M. C.; Hutchings, R. H.; Dai, H.; Kachinski, J. L.;
Dolan, P.; Kensler, T. W. J. Org. Chem. 1997, 62, 3299. Hatakeyama, S.;
Ikeda, T. Maeyama, J. Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawase, A.;
Kubodera, N. Bioorg. Med. Chem. Lett. 1997, 7, 2871.
(4) For a review, see: Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 17.
(5) C-11 R-substituted analogues are suitable for the triene formation rather
than C-11 â-substituted derivatives in the Horner-Wittig olefination, see:
D’Halleweyn, C.; Van Haver, D.; Van der Eycken, J.; De Clercq, P.;
Vandewalle, M. Bioorg. Med. Chem. Lett. 1992, 2, 477. Other examples of
C-11 substituted 1R,25-(OH)2D3, see: Bouillon, R.; Allewaert, K.; van
Leeuwen, J. P. T. M.; Tan, B.-K.; Xiang, D. Z.; De Clercq, P.; Vandewalle,
M.; Pols, H. A. P.; Bos, M. P.; Van Baelen, H.; Birkenha¨ger, J. C. J. Biol.
Chem. 1992, 267, 3044; Torneiro, M.; Fall, Y.; Castedo, L.; Mourino, A.
Tetrahedron Lett. 1992, 33, 105; Zhu, G.-D., Van Haver, D.; Jurriaans, H.;
De Clercq, P. J. Tetrahedron 1994, 50, 7049.
(16) Inhoffen, H. H.; Quinkert, G.; Schuetz, S.; Friedrich, G.; Tober, E.
Chem. Ber. 1958, 91, 781; Lythgoe, B.; Roberts, D. A.; Waterhouse, I. J.
Chem. Soc., Perkin Trans. 1 1977, 2608.
(17) Details of the preparation of 8 were presented in the Supporting
Information.
(6) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Tideswell, J.; Wright,
P. W. J. Chem. Soc., Perkin Trans. I 1978, 590.
(7) Toh, H. T.; Okamura, W. H. J. Org. Chem. 1983, 48, 1414.
(8) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.;
Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098.
(18) Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W.; Trost, B.
M. J. Org. Chem. 1998, 63, 4518.
(19) The resin 4 was identified by IR absorption, 1714 (CdO), 1174 (OTs)
cm-1, whose bands completely disappeared after acid cleavage.
10.1021/ja990739c CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

6750 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Communications to the Editor
Scheme 1
Scheme 2a
Scheme 3a
a (a) TBSCl, imidazole, 98%; (b) DIBAL, 83%; (c) NaClO4, NaH2PO4,
2-methyl-2-butene, 100%; (d) CDI, (EtOCOCH2CO2)2Mg, 99%; (e) NaH,
Tf2NPh, THF, 63%; (f) DIBAL, 96%; (g) Pd(OAc)2 (10 mol %), PPh3
(20 mol %), NEt3 (2 equiv), DMF, rt, 87%; (h) MsCl, LiCl, lutidine,
85%; (i) n-BuLi, Ph2PH, THF; 5% H2O2, 81%.
°C led to the alkylation product 15.20 Finally, treatment of 15
with HF‚Py in THF at room temperature for 24 h released the
desired vitamin D3 system 3a (Scheme 3). Simple filtration
through silica gel provided a white powder 3a in 62% overall
yield from 4. The purity of the final product, judging by HPLC
analysis, was high, and there is no epimerization at the 14-position
of ketone 4 and no triene isomerization under these conditions.
This procedure could also be applied to an activated vitamin D3
analogue. Starting from 5b,7,8 the solid-phase synthesis described
above (Horner-Wittig reaction with 4, alkylation with Grignard
reagent 6, and the cleavage from the resin) afforded 3b (>95%
pure) in 61% overall yield.
We have demonstrated an efficient and general strategy for
the solid-phase synthesis of vitamin D3 systems. This strategy
promises to overcome the required two carbon-carbon bond-
forming steps on the solid-phase, resulting in the consecutive
coupling of the CD-ring with the A-ring and side-chain moieties.
a (a) 1,3-Dichloro-5,5-dimethylhydantoin (3 equiv), CH2Cl2, rt, 1 h;
(b) 8 (4 equiv), imidazole (4.5 equiv), CH2Cl2, rt, 6 h (66%); (c) 5a (8
equiv), n-BuLi (7.5 equiv), THF -78 to -40 °C, 4 h; (d) 6 (30 equiv,
0.45 M), CuBr‚Me2S (3 equiv), THF, -10 °C, 6 h; (e) HF‚Py, THF, rt,
24 h, 62% (from resin 4).
This solid-phase synthesis will be a powerful method for the
preparation of a variety of vitamin D3 derivatives.
Acknowledgment. We gratefully acknowledge Argonaut Technolo-
gies (U.S.A.) for helpful advice and the supply of PS-DES resin.
Supporting Information Available: Experimental information,
including experimental procedures for 5a, 3a, and 3b, 270 MHz 1H NMR
and 67.8 MHz 13C NMR spectra of 3a, 3b, 5a, 9-13, IR spectra of resins
4, 14, and 15, and details of the preparation of 8 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) The alkylation by means of the chloride salt of the Grignard reagent
instead of the bromide salt 6 was unsuccessful. There are few reports using
an alkoxy Grignard reagent in the alkylation at the 22-position on the steroid
system, see: Nakagawa, M. Ph.D. thesis, University of Tokyo, 1993 and ref
9.
JA990739C