An expedited approach to the vitamin D trans-hydrindane building block from the Hajos dione

Article abstract of DOI:10.1021/ol060775y

Efficient and operationally simple synthesis of the key trans-hydrindane alcohol building block for the synthesis of calicitriol (1α,25- dihydroxyvitamin D₃) has been developed. Epoxy alcohol prepared almost quantitatively from the Hajos dione

Full text of DOI:10.1021/ol060775y

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2551-2553
An Expedited Approach to the Vitamin
D trans-Hydrindane Building Block from
the Hajos Dione
Paweł Chochrek and Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52,
01-224 Warsaw 42, Poland
jwicha@icho.edu.pl
Received March 31, 2006
ABSTRACT
Efficient and operationally simple synthesis of the key trans-hydrindane alcohol building block for the synthesis of calicitriol (1
dihydroxyvitamin D3) has been developed. Epoxy alcohol prepared almost quantitatively from the Hajos dione was reduced at the quaternary
carbon by the Hutchins procedure (NaBH3CN BF3 Et2O). The diol was selectively deoxygenized either using the Barton McCombie reaction
(with Bu3SnH AIBN) or via the respective iodohydrine (with LiAlH4).
r,25-
−
‚
−
−
The syntheses of calcitriol (1R,25-dihydroxyvitamin D3) 1
(Figure 1) and other derivatives of vitamin D3 have received
in biomedical research.2 The Hajos dione3 3, produced from
L-proline-catalyzed annulation of 2-methylcyclopentane-1,3-
dione with methyl vinyl ketone, presents a classic precursor
to the calcitriol CD ring building block4 2. However, methods
currently available for saturation of the double bond in 3 or
easily accessible derivatives as 4 and for transposition of
the oxygen substituent from C-5 to C-4 suffer from serious
drawbacks (e.g., catalytic hydrogenation of 3 or 4 affords
predominantly cis-hydrindan derivatives).
Reduction of the carbonyl group in 4 with the Luche
reagent5 affords the respective â-alcohol 6 (Scheme 1).
Ingenious methods6-8 have been developed for hydrogen
(2) (a) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endoc. ReV. 1995,
16, 200-257. (b) Beckman, M. J.; DeLuca, H. F. In Progress in Medicinal
Chemistry; Ellis, G. P., Luscombe, D. K., Oxford, A. W., Eds.; Elsevier:
Amesterdam, 1998; Vol. 35, pp 1-56. (c) Posner, G. H.; Kahraman, M.
Eur. J. Org. Chem. 2003, 3889-3895.
Figure 1. Structures of calcitriol 1, the Hajos dione 3, and selected
synthetic precursors to the calcitriol CD ring system.
(3) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239-3243.
Hajos, Z. G.; Parrish, D. R. Chem. Abstr. German Patent Appl. Jan 21,
1970; Chem. Abstr. 1971, 75, 129414r.
a great deal of attention1 due to their application for treatment
of various human metabolic diseases and their importance
(4) (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A.
D.; Sereno, J. F.; Uskokovic´, M. R. J. Org. Chem. 1986, 51, 3098-3108.
(b) Wovkulich, P. M.; Barcelos, F.; Batcho, A. D.; Sereno, J. F.; Baggiolini,
E. G.; Hennessy, B. M.; Uskokovic´, M. R. Tetrahedron 1984, 40, 2283-
2296.
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601-602.
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(7) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem.
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(1) (a) For a review, see: Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995,
95, 1877-1952. Recent works include: (b) Fernandez, C.; Diouf, O.;
Moman, E.; Gomez, G.; Fall, Y. Synthesis 2005, 1701-1705. (c) Rodriguez,
R.; Ollivier, C.; Santelli, M. Synlett 2006, 312-314. (d) Gomez-Reino, C.;
Vitale, C.; Maestro, M.; Mourino, A. Org. Lett. 2005, 7, 5885-5887. (e)
Pandey, G.; Raikar, S. B. Tetrahedron Lett. 2006, 47, 2029-2032.
10.1021/ol060775y CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/16/2006

Scheme 1
Figure 2. Structures of side products formed on tri(n-butyl)tin
hydride-AIBN reduction of the imidazolylthionocarbonyl deriva-
tive 10.
tive 11 (Figure 2) were formed along with an unstable tin-
containing derivative to which structure 12 was assigned (by
1H NMR) and the alcohol 9. Fragmentation of hemiacetal
12 provides a likely mechanism for reversion from 10 to
the starting alcohol 9. When the thionocarbamate 10 in
toluene containing AIBN was added to neat Bu3SnH at 120
°C, methoxy derivative 11 was obtained in 77% yield.
Reduction of 10 in dilute solutions but at a lower temperature
(80 °C) also gave considerable amounts of 11 and 12. These
results corroborate some earlier reported observations on tri-
n-butyltin hydride reduction of xanthate esters.15
atom delivery from the R-side in allylic alcohols related to
6 via “chirality transfer”. All of these methods lead to olefins
5 which have a lack of regiocontrolling factors for further
functionalization. Direct conjugate reduction of ketones 3
with DIBAL-cuprous iodide provides a short-step approach
to functionalized trans-hydrindane derivatives,9 but the fragile
nature of the intermediate copper hydride species may
obstruct large-scale preparations. More circumvent ap-
proaches to 2 starting from 3 or 4 have also been developed.10
We wish now to present a facile and operationally simple
method for transforming 4 into 2 via alcohol 6, epoxide 7,
and diol 8.
Although the overall yield of 2 compared rather well with
those attainable by other methods, other approaches to
selective removal of the C-5 hydroxyl group in diol 8 were
examined.
Allylic alcohol 6 was treated with m-CPBA to give
â-epoxide 7 quantitatively. Reduction of the epoxide 7 with
sodium cyanoborohydride-BF3‚Et2O in THF according to
the Hutchins protocol11 afforded diol 8 in 77% yield. Use
of Et2O12 as the solvent led to an increase of the product
yield to 86%.13 Diol 8 was transformed quantitatively into
the diacetate which by controlled hydrolysis and chroma-
tography afforded monoacetate 9 in 70% yield along with
unchanged diacetate (7%), isomeric monoacetate (7%), and
diol 8 (16%). The hydrolysis step was not optimalized
extensively since all side products could be easily recycled.
The monohydroxy derivative 9 was esterified with thiono-
carbonyl-1,1′-diimidazole (TCDI) in THF at reflux, and the
thionocarbonate 10 was reduced with tri(n-butyl)tin hydride-
2,2′-azobis(2-methylpropanenitrile) (AIBN).14 Chromatog-
raphy then gave the known4 derivative 2. The best yields of
2 (80% in two steps) were obtained when a solution of 10
containing AIBN (ca. 20 mol %) was added slowly with a
syringe pump to a dilute solution of Bu3SnH (4 molar equiv)
in toluene at reflux. At higher concentrations of tri(n-
butyltin)hydride substantial amounts of the methoxy deriva-
Figure 3. Structures of monotosylate 13 and of the product
obtained on its reduction with LiAlH4.
Monotosylate 13 (Figure 3) was obtained almost quanti-
tatively by treating 8 with 1.5 molar equiv of tosyl chloride
in pyridine. Upon reduction of tosylate 13 with LiAlH4 in
THF rearranged primary alcohol 14 was obtained. Anti-
periplanar disposition of the C-3a-C-4 bond and the tosyloxy
C-O bond explains the rearrangement (Figure 3, 13a).
Diol 8 when treated with TCDI produced cyclic thiono-
carbonate 15 (Scheme 2) quantitatively. Reduction of 15 with
tri-n-butyltin hydride-AIBN provided a complex mixture
of products. Gratifyingly, treatment of 15 with methyl
iodide16 at 40 °C (sealed ampule) provided crystalline and
stable iodohydrine derivative 16 (81% yield after chroma-
tography). The structure of 16 was confirmed by narrow
multiplets corresponding to equatorial protons at C-4 (δ 5.33
(8) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429-6431.
Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-4844.
(9) (a) Daniewski, A. R.; Kiegiel, J. J. Org. Chem. 1988, 53, 5534-
5535. (b) Daniewski, A. R.; Liu, W. J. Org. Chem. 2001, 66, 626-628.
(10) For a review, see: Jankowski, P.; Marczak, S.; Wicha, J. Tetrahe-
dron 1998, 54, 12071-12150.
(11) Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J. Org. Chem. 1981,
46, 5214-5215.
(12) Leyes, A. E.; Poulter, C. D. Org. Lett. 1999, 1, 1067-1070.
(13) In THF, partial gelling of the solvent occurred that complicated the
isolation procedure, especially on larger scale runs.
1
ppm) and C-5 (δ 4.63 ppm). An H NMR spectrum of the
(15) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983,
105, 4059-4065.
(16) (a) Vedejs, E.; Wu, E. S. C. J. Org. Chem. 1974, 39, 3641-3645.
(b) Barton, D. H. R.; Stick, R. V. J. Chem. Soc., Perkin Trans. 1 1975,
1773-1776.
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
2552
Org. Lett., Vol. 8, No. 12, 2006

of products from which epoxide 19 (27%), iodohydrine 20
(53%), and diene 18 (18%) were isolated by chromatography.
In summary, the synthetic route from R,â-unsaturated
ketone 4 to monoacetate 2 via thionoimidazolyl acetate
derivative (10) involved seven steps. The product was
obtained in 44% yield (neglecting recovery of some diol 8),
which compares rather well to those attainable by other
methods. The route via cyclic thionocarbonate (15) is one
step shorter and provides the product 17 (alcohol) in 51%
yield, which is self-indicative. The latter route also has other
advantages; namely, no chromatographic purification of
intermediates in all synthetic sequences was needed and only
the final product (17) was briefly filtered through a silica
gel column before crystallization.
Scheme 2
crude reaction product showed traces of contamination, most
likely the regioisomeric iodohydrine derivative.
Synthesis of other trans-hydrindane-based natural products
by these methods is in progress.
Reduction of 16 with LiAlH4 (4 molar equiv) in THF at
reflux gave alcohol 17 in 80-85% yield along with some
diene17 18, which was easily removed by chromatography
or by crystallization. It was found important that the solution
of 16 in THF was added dropwise to a refluxing LiAlH4
solution. Monitoring of the reaction by TLC suggested that
intermediates, most likely epoxide 19 and iodohydrine 20
were involved. Indeed, careful reduction of 16 at a room
temperature with LiAlH4 (1 molar equiv) afforded a mixture
Acknowledgment. We thank Dr. Milan R. Uskokovic´
of BioXell for the generous gift of the Hajos dione and Dr.
David M. Piatak for reading and commenting on the
manuscript.
Supporting Information Available: Experimental pro-
1
cedures, compound characterization, and copies of H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Tietze, L. F.; Subba Rao, P. S. V. Synlett 1993, 291-292.
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