An efficient enantioselective synthesis of 1α,25-dihydroxyvitamin D3 A-ring synthon

Article abstract of DOI:10.1016/S0040-4039(00)00170-2

The asymmetric synthesis of the A-ring of 1α,25-dihydroxyvitamin D₃, (Z)-2, from 5-tert-butyldimethylsiloxy-2-cyclohexenone [(S)-1], is described where an intramolecular lactonization using cat. scandium triflate is the key reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00170-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2389–2390
An efficient enantioselective synthesis of 1α,25-
dihydroxyvitamin D3 A-ring synthon
Masakazu Koiwa, Georges P. J. Hareau and Fumie Sato ∗
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 13 December 1999; revised 17 January 2000; accepted 21 January 2000
Abstract
The asymmetric synthesis of the A-ring of 1α,25-dihydroxyvitamin D3, (Z)-2, from 5-tert-butyldimethylsiloxy-
2-cyclohexenone [(S)-1], is described where an intramolecular lactonization using cat. scandium triflate is the key
reaction. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; cyclization; scandium and compounds; vitamins.
Optically active 5-tert-butyldimethylsiloxy-2-cyclohexenone [(R)- and (S)-1], prepared in our labora-
tory, has proved to be an efficient chiral building block in the synthesis of natural products.1 As reported in
the preceding paper,2 we have succeeded in synthesizing the A-ring precursor of 1α,25-dihydroxyvitamin
D3, (E)-2, starting from (S)-1 via the intermediates 3, 4 and 5 (Scheme 1).
Scheme 1.
According to the protocol reported by the Hoffmann–La Roche group,3 (E)-2 can be converted to (Z)-
2, to allylic alcohol 6 and then to (Z)-allylic phosphine oxide 7 (A-ring portion) which, in turn, affords
1α,25-dihydroxyvitamin D3 through Horner–Wittig coupling with the bicyclic ketone 8 (C,D-ring
portion). As the isomerization of (E)-2 to (Z)-2 remains difficult to achieve without photoisomerization,
we continued our efforts to prepare (Z)-2 directly from (S)-1, and we report the results here (Scheme 2).
Initially, we investigated a lactonization of 4 which would enable the (Z)-geometry of the double
bond, together with a selective protection of one hydroxy group in 4. However, the lactonization under
∗
Corresponding author: Tel: +81 45 924 5787; fax: +81 45 924 5826; e-mail: fsato@bio.titech.ac.jp (F. Sato)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00170-2
tetl 16450

2390
Scheme 2.
various conditions furnished only small amounts of the desired compound since the retroaldolization
to 3 competed with the cyclization. During the course of this investigation, we fortunately found that
treatment of 5 with neat acetic anhydride in the presence of catalytic amounts of Sc(OTf)3 (3 mol%)4 at
rt for 12 h gave the bicyclic diacetate 9 cleanly in 65% yield and in a >95:<5 diastereoisomeric ratio.
This unexpected result encouraged us to try to take advantage of the bicyclic moiety 9 where the β-
elimination of the acetate group would fix the (Z)-geometry of the trisubstituted double bond. To our
satisfaction, the reaction of 9 with DBU in CH2Cl2 at rt for 0.5 h gave 10 smoothly. Saponification of 10
with K2CO3/MeOH at rt, followed by treatment with ethyl iodide in DMF for 4 h at rt, yielded 11 in 87%
overall yield from 9. Finally, the methylenation of 11 to (Z)-25 was achieved by using the Tebbe reagent
in 48% yield (Scheme 3).
Scheme 3. Reagents and conditions: (a) Ac2O (neat), 3 mol% Sc(OTf)3 (0.25 M in MeCN), rt, 12 h; (b) DBU (1.5 equiv.),
CH2Cl2, rt, 30 min; (c) K2CO3 (20 equiv.), MeOH, rt, 1 h; (d) C2H5I (3 equiv.), K2CO3 (5 equiv.), DMF, rt, 4 h; (e) Tebbe
reagent (1.1 equiv.), 1 mol% Pyr, THF, rt 20 min
References
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Hanazawa, T.; Sato, F. Tetrahedron Lett. 1999, 40, 7493.
2. Hareau, G. P. J.; Koiwa, M.; Sato, F. Tetrahedron Lett. 2000, 41, 2385.
3. (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Uskokovic, M. R. J. Am. Chem. Soc. 1982, 104, 2945. (b) Baggiolini
E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098.
4. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 4413.
5. For preparation of (Z)-2 without isomerization of (E)-2, see: (a) Kobayashi, S.; Shibata, J.; Shimada, M.; Ohno, M.
Tetrahedron Lett. 1990, 31, 1577. (b) Nagasawa, K.; Ishihara, H.; Zako, Y.; Shimizu, I. J. Org. Chem. 1993, 58, 2523.