Application of ring-closing metathesis to the synthesis of 19-functionalized derivatives of 1α-hydroxyvitamin D3

Article abstract of DOI:10.1021/ol052856k

The synthesis of the 19-functionalized derivative of vitamin D₃ based on ring-closing metathesis (RCM) is presented.

Full text of DOI:10.1021/ol052856k

ORGANIC
LETTERS
2006
Vol. 8, No. 5
839-842
Application of Ring-Closing Metathesis
to the Synthesis of 19-Functionalized
Derivatives of 1r-Hydroxyvitamin D3
Agnieszka Wojtkielewicz and Jacek W. Morzycki*
Institute of Chemistry, UniVersity of Bialystok, al. Pilsudskiego 11/4,
15-443 Bialystok, Poland
morzycki@uwb.edu.pl
Received November 25, 2005
ABSTRACT
The synthesis of the 19-functionalized derivative of vitamin D3 based on ring-closing metathesis (RCM) is presented.
A hormonally active metabolite of vitamin D3, 1R,25-
dihydroxyvitamin D3, exhibits, besides the regulation of
calcium and phosphorus homeostasis, a variety of biological
activities such as cell differentiation and proliferation.1 Since
this discovery, extensive studies to find analogues with
selective activity profiles as potential therapeutic agents have
been undertaken. Over the past two decades many vitamin
D derivatives containing modification in A, C, or D rings as
well as in the side chain have been synthesized.2 However,
only a few methods of synthesis of 19-functionalized
compounds have been described so far.3
The discovery of olefin metathesis and development of
well-defined ruthenium and molybdenum alkylidene cata-
lysts4 has provided a very convenient synthetic route to
complex olefins. The preparation of 19-functionalized de-
rivatives of vitamin D based on cross metathesis (CM)
seemed to be the shortest and most straightforward way. We
have undertaken efforts to synthesize such analogues of
vitamin D in our laboratory. The reactions of vitamin D3
(1) with various olefins, such as 1-heptene, allyl alcohol,
trans-3-hexenedinitrile, and allyl cyanide, were examined.
Unfortunately, the CM reactions of vitamin D3 with these
alkenes in the presence of 20 mol % of Grubbs or Hoveyda
second generation catalysts in dichloromethane did not work
and the starting material was recovered in all cases. There
was no reaction even under more drastic conditions (80 °C,
30 mol % of catalyst).
(1) Holick, M. F., Ed. Vitamin D: Physiology, Molecular Biology and
Clinical Aplications; Humana Press: Totowa, NJ, 1999.
(2) (a) Bouillon, R. M.; Okamura, W. H.; Norman, A. W. Endocr. ReV.
1995, 16, 200. (b) Muralidharan, K. R.; De Lera, A. R.; Isaeff, S. D.;
Norman, A. W.; Okamura, W. H. J. Org. Chem. 1993, 58, 1895. (c) Perlman,
K. L.; Sicinski, R. R.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett.
1990, 31, 1823. (d) Kanzler, S.; Halkes, S.; van de Velde, J. P.; Reischel,
W. Bioorg. Med. Chem. Lett. 1996, 6, 1865. (e) Kroszczynski, W.;
Morzycka, B.; Morzycki, J. W. Wiad. Chem. 2002, 56, 793.
(3) (a) Yamada, S.; Nakayama, K.; Takayama, H.; Itai, A.; Iitaka, Y. J.
Org. Chem. 1983, 48, 3477. (b) Yamada, S.; Suzuki, T.; Takayama, H. J.
Org. Chem. 1983, 48, 3483. (c) Addo, J. K.; Ray, R. Steroids 1998, 63,
218. (d) Swamy, N.; Addo, J. K.; Ray, R. Bioorg. Med. Chem. Lett. 2000,
10, 361. (e) Addo, J. K.; Swamy, N.; Ray, R. Bioorg. Med. Chem. Lett.
2002, 12, 279. (f) Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.; Malagu,
K.; Procopiou, P. A. Org. Lett. 2003, 5, 669.
A failure of the CM approach caused alteration of the
synthetic strategy and ring-closing metathesis (RCM) was
used instead in the next experiments, as an alternative method
for the preparation of 19-functionalized derivatives of vitamin
(4) (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (b) Deiters, A.; Martin,
S. F. Chem. ReV. 2004, 104, 2199. (c) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900.
10.1021/ol052856k CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/01/2006

Scheme 1
D3. According to the synthetic plan, the 3-hydroxyl group
obtained in the 5,6-trans-vitamin D3 series. The 5,6-trans-
vitamin D3 did not undergo the CM reactions, while the
corresponding esters (5) yielded the SM products only.
Presumably, the failure of ring closure is due to the lack
of sufficient conformational flexibility in ring A, as well as
the steric hindrance (5,6-cis compounds) caused by the CD
ring fragment of the molecule. Additionally, molecular
modeling reveals that the cyclization requires the change of
A ring conformation from the favored chair to the boat
conformation.
In the next attempts, the same approach was applied for
1R-hydroxyvitamin D3 derivatives. The 3-TBS-ether of 1R-
hydroxy-5,6-trans-vitamin D3 (6) obtained by a known
method6 was analogously transformed into 3-butenoate 7,
which theoretically allows for closure of a six-membered
ring in the RCM reaction. In this case the desired cyclic
product 8 was obtained in 70% yield with use of 20 mol %
of Hoveyda second generation catalyst (worked slightly better
than the Grubbs catalyst): dilution, Cm ) 0.5-1.5 mM, 80
°C.5 The most important factor for successful RCM proved
to be reaction temperature. At 40-70 °C the main product
appeared to be a dimer 9, as a result of SM. The higher
temperature favored the RCM reaction. Such an effect of
in vitamin D3 was esterified with carboxylic acid containing
the terminal double bond (4-pentenoic, 5-hexenoic, 6-hep-
tenoic, and 10-undecenoic acid). The esterification was
performed with the DCC method with DMAP as catalyst.
The products 2 were obtained in high yields. The esters 2
appeared to be rather unstable and therefore were im-
mediately subjected to RCM reaction.5 Although there are
many reports of successful application of RCM to the
synthesis of medium sized rings,4 in the case of metathesis
of vitamin D3 esters, the only products were dimers 3, as a
result of self-methatesis (SM). Despite the change of the
reaction conditionsshigher temperature (80 °C), more second
generation catalyst (Grubbs or Hoveyda, 30 mol %), higher
dilution, and slow addition of reagentssthe desired RCM
products were not formed.
Compound 4 with inverted configuration at C-3 (synthe-
sized from vitamin D3 via the Mitsunobu reaction) did not
afford the RCM product either. The same results were
(5) General procedure for RCM reaction: To the solution (2 mM) of
20 mol % of Grubbs (or Hoveyda) second generation catalyst in dry toluene
in oven-dried Schlenk flask was added the solution (0.5-1.5 mM) of vitamin
D3 (or 1R-hydroxyvitamin D3) ester in dry toluene dropwise over 2 h. The
reaction mixture was stirred at 80 °C for 4 h under argon atmosphere. Then
the reaction mixture was concentrated in vacuo and purified by silica gel
column chromatography.
(6) Marshall, J. A.; Grote, J.; Shearer B. J. Org. Chem. 1986, 51, 1635.
Org. Lett., Vol. 8, No. 5, 2006
840

Scheme 2
temperature was not reported earlier for phoshonate or silic
steric hindrance caused by the CD ring fragment of the
molecule because of the cis configuration of the 5,6 double
bond in this compound.
The lactone 8 appeared to be rather unstable, and to avoid
its decomposition, it was converted into the corresponding
diol 12. Subsequent photoisomerization of the 19-hydroxy-
ethyl derivative of 1R-hydroxy-5,6-trans-vitamin D3 (12) in
analogues of 1R-hydroxy-5,6-trans-vitamin D2.3f The influ-
ence of other reaction conditions (type of catalyst, dilution,
mode of reagent addition) proved much less important. The
RCM reaction was not observed (even at higher temperature)
for 3-butenoate of 1R-hydroxyvitamin D derivatives (e.g. for
compound 11). The reason for that is presumably the greater
Scheme 3
Org. Lett., Vol. 8, No. 5, 2006
841

the presence of anthracene as triplet sensitizer7 in degassed
and dry benzene at 0-5 °C afforded the desired cis isomer
13. The almost complete conversion to vitamin D3 analogue
was observed within 15 min (5 × 3 min) of irradiation with
a UV lamp. The two isomers (5E and 5Z) were distinguished
In conclusion, a new synthetic strategy for the preparation
of 19-functionalized derivatives of 1R-hydroxyvitamin D was
elaborated. In the methodology developed, the synthesis of
a cyclic analogue proceeds through RCM of the 1R-hydroxy-
trans-vitamin D3 vinylacetyl derivative. Subsequent reduction
of the obtained RCM product followed by photochemical
isomerization afforded the 19-functionalized analogue.
1
on the basis of their H NMR spectra. The position of two
doublets of 6-H and 7-H was diagnostic: for the 5,6-trans
isomer these signals appeared at 6.46 and 5.89 ppm, while
in the case of the 5,6-cis compound the first signal was
shifted upfield to 6.30 ppm, the second one downfield to
5.91 ppm. Thus the distance between the doublets of 6-H
and 7-H in the trans isomer is about 0.2 ppm larger than
that between analogous signals for the cis isomer, what is
typical for the cis/trans series of vitamin D derivatives.8
Acknowledgment. This work was supported by the State
Committee for Scientific Research (Grant No. 3 T09A 013
27). We also thank Professor A. Kutner and Dr. M.
Chodyn˜ski from the Pharmaceutical Institute in Warsaw for
a gift of some vitamin D derivatives.
Supporting Information Available: Details of the ex-
periments and characterization of compounds 7, 8, 12, and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
(7) Gielen, J. W. J.; Koolstra, R. B.; Jacobs, H. J. C.; Havinga, E. J. R.
Neth. Chem. 1980, 99, 306.
(8) Paaren, H. E.; DeLuca, H. F.; Schnoes, H. K. J. Org. Chem. 1980,
45, 3253.
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Org. Lett., Vol. 8, No. 5, 2006