A simple, enantiospecific approach to both enantiomers of 1α,25- dihydroxyvitamin D3 A-ring precursors from R-carvone

Article abstract of DOI:10.1016/S0040-4039(00)00325-7

A simple and direct approach to both enantiomeric series of A-ring derivatives of 1α,25-dihydroxyvitamin D₃ and the corresponding 1α,3α- derivatives, starting from the abundantly available R-carvone, is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00325-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3177–3180
A simple, enantiospecific approach to both enantiomers of
1α,25-dihydroxyvitamin D3 A-ring precursors from R-carvone†
A. Srikrishna,∗ Santosh J. Gharpure and P. Praveen Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 January 2000; accepted 21 February 2000
Abstract
A simple and direct approach to both enantiomeric series of A-ring derivatives of 1α,25-dihydroxyvitamin D3
and the corresponding 1α,3α-derivatives, starting from the abundantly available R-carvone, is described. © 2000
Elsevier Science Ltd. All rights reserved.
Research activity in the synthesis of vitamin D3 (1) and its analogues has grown exponentially owing to
the discovery that 1α,25-dihydroxyvitamin D3 (calcitriol, 2), the hormonally active metabolite of vitamin
D3, and its analogues have a much broader spectrum of activity than originally thought, in addition to
the classical roles of regulating calcium and phosphorous metabolism.1 Calcitriol 2 and its derivatives
have been used recently in treating a diverse range of human diseases such as osteoporosis, cancer,
AIDS and psoriasis. An attractive convergent synthetic approach to vitamin D3 analogues is based on the
coupling of a CD-ring fragment with a suitable A-ring fragment,2 as originally developed by Lythgoe.1
The palladium(II)-mediated coupling of the A-ring synthon enyne 1S,5R-3 with an enol triflate of the CD
ring fragment has become one of the most convenient methods for the large scale generation of 1α,25-
dihydroxyvitamin D3 analogues. Several research groups3 have employed S-carvone as the chiral starting
material for the synthesis of enyne derivatives 1S,5R-3. Herein, we report a simple and straightforward
enantiospecific approach to both enantiomeric forms of the A-ring 3 of 1α,25-dihydroxyvitamin D3 and
its analogues starting from the more abundantly available R-carvone.
∗
†
Corresponding author. E-mail: ask@orgchem.iisc.ernet.in (A. Srikrishna)
Chiral synthons from carvone. Part 40. For part 39, see: Srikrishna, A.; Dinesh, C. Indian J. Chem. 1999, 38B, 1151; Part 38
see: Srikrishna, A.; Gharpure, S. J. Tetrahedron Lett. 1999, 40, 1035.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00325-7
tetl 16605

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To begin with, we have addressed the synthesis of the 1R,5S enantiomeric enyne, Scheme 1. It was
anticipated that the isopropenyl group could serve as the masked hydroxy group corresponding to the C-3
hydroxy of vitamin D3. The acetylenic side chain was conveniently introduced employing a 1,3-enone-
transposition methodology.4 Thus, sonochemical irradiation of a solution of R-carvone (4) and lithium
acetylide–ethylenediamine complex in THF yielded the tertiary alcohol 5, which on oxidation with
24
pyridinium chlorochromate (PCC) and silica gel in methylene chloride furnished the enynone 6, [α]
D
40.3 (c 3.6, CHCl3). Regio- and stereoselective reduction of the enone 6 with lithium aluminium hydride
in ether furnished the syn-allylic alcohol 1S,5S-7, [α]25 22.2 (c 5.4, CHCl3), whose stereochemistry was
D
based on the well established reduction of carvone derivatives.5 For the conversion of the alcohol 7 into
1R,5S-3, inversion at the C-1 carbon atom is required in addition to degradation of the isopropenyl group.
A Mitsunobu reaction6 was contemplated for simultaneous inversion and protection of the alcohol group.
Thus, reaction of the alcohol 7 with diethyl azodicarboxylate (DEAD), triphenylphosphine and benzoic
acid in THF furnished the benzoate 1R,5S-8, [α]25 125.5 (c 10, CHCl3). Finally, controlled ozonolysis in
D
a methylene chloride–methanol medium followed by Criegee rearrangement7 using acetic anhydride and
triethylamine in the presence of a catalytic amount of N,N-dimethylaminopyridine (DMAP) in refluxing
benzene transformed the benzoate 8 into the calcitriol analogue A-ring 1R,5S-enantiomeric synthon 9.8‡
In another direction, instead of the Mitsunobu inversion, protection of the alcohol in 7 with benzoyl
‡
All the compounds exhibited spectral data consistent with their structures. Yields refer to isolated and chromatographically
pure compounds and are not optimised. Selected spectral data for the acetoxy benzoate 9: [α]2D4 13.0 (c 1.0, CHCl3). IR (neat):
ν
max/cm−1 3280, 1735, 1715. 1H NMR (300 MHz, CDCl3+CCl4): δ 8.07 (2H, d, J 7.5 Hz), 7.61 (1H, t, J 7.5 Hz), 7.44 (2H, t,
J 7.5 Hz), 5.73 (1H, t, J 4.8 Hz), 5.20 (1H, m), 3.14 (1H, s), 2.72 (1H, dd, J 17.4 and 3.9 Hz), 2.26 (1H, dd, J 17.4 and 7.8 Hz),
2.20–2.00 (2H, m), 2.05 (3H, s), 1.97 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4, DEPT): δ 170.1 (C), 165.9 (C), 139.5 (C),
133.1 (CH), 130.1 (C), 129.9 (2 C, CH), 128.5 (2 C, CH), 116.7 (C), 82.4 (C), 81.7 (CH), 70.6 (CH), 66.4 (CH), 35.1 (CH2),
33.6 (CH2), 21.2 (CH3), 18.5 (CH3). For the syn-acetoxy benzoate 11: [α]2D5 −63.0 (c 1.27, CHCl3). IR (neat): νmax/cm−1 3270,
1720. 1H NMR (300 MHz, CDCl3+CCl4): δ 8.04 (2H, d, J 7.5 Hz), 7.55 (1H, t, J 7.5 Hz), 7.43 (2H, t, J 7.5 Hz), 5.68 (1H, t,
J 4.0 Hz), 5.15 (1H, m), 3.13 (1H, s), 2.59 (1H, d with fine splitting, J 16.8 Hz), 2.45–2.00 (3H, m), 1.99 (3H, s), 1.96 (3H, s).
13C NMR (75 MHz, CDCl3+CCl4, DEPT): δ 169.7 (C), 165.5 (C), 139.9 (C), 133.0 (CH), 130.1 (C), 129.7 (2 C, CH), 128.3 (2
C, CH), 115.6 (C), 82.4 (C), 81.7 (CH), 69.9 (CH), 65.9 (CH), 34.9 (CH2), 33.0 (CH2), 21.1 (CH3), 18.0 (CH3). For the acetate
13: [α]2D0 30.7 (c 1.14, CHCl3). IR (neat): νmax/cm−1 3300, 1740. H NMR (300 MHz, CDCl3+CCl4): δ 4.87 (1H, m), 4.29
1
(1H, m), 3.02 (1H, s), 2.49 (1H, dd, J 16.2 and 4.2 Hz), 2.35–2.10 (2H, m), 2.04 (3H, s), 1.90 (3H, s), 1.72 (1H, d of t, J 11.7
and 9.3 Hz), 0.90 (9H, s), 0.10 (3H, s), 0.09 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4, DEPT): δ 170.1 (C), 145.3 (C), 112.6
(C), 83.1 (C), 80.3 (CH), 69.9 (CH), 67.2 (CH), 38.1 (CH2), 35.4 (CH2), 25.9 (3 C, CH3), 21.3 (CH3), 18.2 (C), 17.9 (CH3),
−4.1 (CH3), −4.8 (CH3). For the benzoate 15: m.p. 98–99°C. [α]2D3 −41.7 (c 1.15, CHCl3). IR (neat): νmax/cm−1 3300, 1720.
1H NMR (300 MHz, CDCl3+CCl4): δ 8.01 (2H, d, J 7.5 Hz), 7.54 (1H, t, J 7.5 Hz), 7.43 (2H, t, J 7.5 Hz), 5.41 (1H, m), 4.31
(1 H, m), 3.03 (1H, s), 2.73 (1H, d with fine splitting, J 18.0 Hz), 2.35 (1H, dd, J 18.0 and 6.0 Hz), 2.05–1.95 (2H, m), 1.98
(3H, s), 0.93 (9H, s), 0.12 (6H, s). 13C NMR (75 MHz, CDCl3+CCl4, DEPT): δ 165.6 (C), 143.9 (C), 132.8 (CH), 130.6 (C),
129.7 (2 C, CH), 128.3 (2 C, CH), 113.2 (C), 83.2 (C), 80.3 (CH), 68.8 (CH), 67.5 (CH), 37.0 (CH2), 35.2 (CH2), 25.9 (3 C,
CH3), 18.9 (CH3), 18.2 (C, SiC(CH3)3), −4.2 (CH3), −4.7 (CH3).

3179
24
D
chloride, pyridine and DMAP in methylene chloride led to the benzoate 10, [α] 18.4 (c 2.5, CHCl3),
m.p. 74°C, which on ozonolysis followed by Criegee rearrangement furnished the diastereomeric A-ring
synthon 1S,5S-11.8‡
Scheme 1. Reagents, conditions and yields:‡ (a) HC≡C–Li·ethylenediamine, THF, sonification, 1.5 h; (b) PCC, silica gel,
CH2Cl2, 10 h; 70%; c) LAH, Et2O, −40°C, 1 h, 98%; (d) Ph3P, PhCOOH, DEAD, THF, rt, 10 h, 97%; (e) (i) O3/O2,
CH2Cl2:MeOH (5:1), NaHCO3, −70°C; (ii) Ac2O, Et3N, DMAP, C6H6, 1 h rt, 6 h reflux; 37%;8 (f) PhCOCl, DMAP, Py,
CH2Cl2, rt, 10 h, 98%; (g) same as (e), 33%8
After successfully developing a short route to the calcitriol A-ring synthon 9, attention was turned
to the natural series 1S,5R-3, Scheme 2. Even though repetition of the same sequence with S-carvone
will provide the shortest route to the A-ring synthon 1S,5R-9, we have conceived a strategy from R-
carvone itself via inversion at C-5 instead of at C-1. Consequently, reaction of the alcohol 7 with t-
butyldimethylsilyl chloride and imidazole in the presence of a catalytic amount of DMAP in methylene
chloride furnished the TBDMS ether 12, [α]21 32.0 (c 1.0, CHCl3). As earlier, ozonolysis in a methylene
D
chloride–methanol medium followed by Criegee rearrangement using acetic anhydride and triethylamine
in the presence of a catalytic amount of DMAP in refluxing benzene transformed the TBDMS ether
12 into the acetate 1S,5S-13.8‡ Hydrolysis of the acetate in 13 using potassium carbonate in methanol
22
D
furnished the alcohol 14, [α] −25.0 (c 1.24, CHCl3), m.p. 81–82°C. Finally, Mitsunobu reaction of
the alcohol 14 using triphenylphosphine and DEAD in the presence of benzoic acid furnished the A-ring
1S,5R-15‡ of calcitriol (2), in which the two hydroxy groups are differentially protected.
Scheme 2. Reagents, conditions and yields:‡ (a) TBDMSCl, imidazole, DMAP, CH2Cl2, 4 h, rt, 96%, (b) (i) O3/O2,
CH2Cl2:MeOH (5:1), NaHCO3, −70°C; (ii) Ac2O, Et3N, DMAP, C6H6, 1 h rt, 6 h reflux; 38%;8 (c) K2CO3, MeOH, rt, 2
h, 92%; (d) Ph3P, PhCOOH, DEAD, THF, rt, 4 h, 80%
In conclusion, we have developed a short and simple enantiospecific approach to both enantiomeric
forms of 9 and 15 building blocks to 1α,25-dihydroxyvitamin D3 analogues and also the corresponding
1α,3α-derivatives 11, 13 and 14.

3180
Acknowledgements
We thank the D. S. T., New Delhi for financial support and the C. S. I. R., New Delhi for the award of
a research fellowship to S.J.G.
References
1. For excellent reviews, see: Dai, H.; Posner, G. H. Synthesis 1994, 1383; Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95,
1877.
2. (a) Harrison, R. G.; Lythgoe, B.; Wright, P. W. J. Chem. Soc., Perkin Trans. 1 1974, 2654. For recent reports on the synthesis
of A-ring of vitamin D3 and its analogues, see: (b) Knölker, H.-J.; Ecker, A.; Struwe, P.; Steinmeyer, A.; Müller, G.; Neef, G.
Tetrahedron 1997, 53, 91. (c) 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. (d) Courtney, L. F.; Lange, M.; Uskokovic, M. R.; Wovkulich,
P. M. Tetrahedron Lett. 1998, 39, 3363. (e) Ishikawa, T.; Ikeda, S.; Ibe, M.; Saito, S. Tetrahedron 1998, 54, 5869. (f) Gotor-
Fernández, V.; Ferrero, M.; Fernández, S.; Gotor, V. J. Org. Chem. 1999, 64, 7504. (g) Anné, S.; Yong, W.; Vandewalle, M.
Synlett 1999, 1435.
3. (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; (b) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Uskokovic, M. R. J. Am. Chem. Soc. 1982, 104, 2945; (c)
Baggiolini, E. G.; Hennessy, B. M.; Iacobelli, J. A.; Uskokovic, M. R. Tetrahedron Lett. 1987, 28, 2095; (d) Mascarenas, J.
L.; Sarandeses, L. A.; Castedo, L.; Mourino, A. Tetrahedron 1991, 47, 3485; (e) Castedo, L.; Mascarenas, J. L.; Mourino, A.
Tetrahedron Lett. 1987, 28, 2099. (f) Aurrecoechea, J. M.; Okamura, W. H. Tetrahedron Lett. 1987, 28, 4947. (g) Okamura,
W. H.; Aurrecoechea, J. M.; Gibbs, R. A.; Norman, A. W. J. Org. Chem. 1989, 54, 4072.
4. Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021; Srikrishna, A.; Sharma, G. V. R.; Doss, S. D.; Hemamalini, P. J. Chem.
Soc., Perkin Trans. 1 1996, 1305.
5. Garver, L.; van Eikeren, P.; Byrd, J. E. J. Org. Chem. 1976, 41, 2773.
6. Hughes, D. L. Org. React. 1992, 42, 335.
7. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363; Criegee, R. Ber. Bunsenges. Phys. Chem. 1944, 77, 722.
8. In addition to the Criegee product, varying amounts of starting material and 10–20% of simple ozonolysis products (easily
separable) were also obtained.