Facile construction of the 7,8-olefin linkage in vitamin D3: A practical synthesis benefiting the vitamin D3 analog study

Article abstract of DOI:10.1080/00397910500503645

A facile procedure for construction of the 7,8-olefin linkage in vitamin D₃ is described. Treatment of a mixture of A-ring phosphine oxide and CD-ring ketone in THF with lithium hexamethyldisilazide (LHMDS) at -20°C followed by gradual heating

Full text of DOI:10.1080/00397910500503645

Synthetic Communicationsw, 36: 1141–1146, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500503645
Facile Construction of the 7,8-Olefin
Linkage in Vitamin D3: A Practical
Synthesis Benefiting the Vitamin D3
Analog Study
Yoshiyuki Ono, Hirotaka Kashiwagi,
and Tadakatsu Takahashi
Chemistry Research Dept. I, Chugai Pharmaceutical Co., Gotemba,
Shizuoka, Japan
Abstract: A facile procedure for construction of the 7,8-olefin linkage in vitamin D3 is
described. Treatment of a mixture of A-ring phosphine oxide and CD-ring ketone in
THF with lithium hexamethyldisilazide (LHMDS) at 2208C followed by gradual
heating to 508C gives the key intermediate of vitamin D3 analogs in excellent yield.
This simplified procedure makes possible small-scale synthesis benefiting the
vitamin D3 analog study.
Keywords: Horner–Wittig olefination, vitamin D3, vitamin D3 analog
INTRODUCTION
The active form of vitamin D3, 1a,25-dihydroxyvitamin D3 [1a,25(OH)2D3,
calcitriol] (1) has been identified as a highly potent and multifunctional
hormone (Figure 1). Therapeutic potential of calcitriol (1) for various
diseases, such as osteoporosis, cancer, secondary hyperparathyroidism, and
psoriasis, have been reported.[1] However, because of its hypercalcemic
effects, the use of calcitriol (1) in disease treatment is limited. In response
to this issue, various analogs of calcitriol (1) with attenuated calcemic
Received in Japan August 25, 2005
Address correspondence to Yoshiyuki Ono, Chemistry Research Dept. I, Chugai
Pharmaceutical Co., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Tel.: þ 81-550-87-6742; Fax: þ81-550-87-5326; E-mail: onoysy@chugai-pharm.co.jp
1141

1142
Y. Ono, H. Kashiwagi, and T. Takahashi
Figure 1. Structure of active vitamin D3.
effects and enforced desirable effects have been synthesized to obtain useful
medical candidates.[2–5]
In the vitamin D3 analog study, small-scale, micromolar synthesis is prefer-
able and efficient. This is because only a few micrograms of sample are required
for the preliminary biological assay.[6,7] Nevertheless, the small-scale synthesis
is impractical in the most typical synthetic strategy, the Horner–Wittig olefina-
tion. The Horner–Wittig olefination constructs the 7,8-olefin linkage in vitamin
D3 as follows: A-ring phosphine oxide (2) is treated with n-BuLi at 2788C to
produce a ylide (3); to the ylide, CD-ring ketone (4) is added at 2788C to
form the E-olefin (5) stereoselectively in good yield (Scheme 1).[8,9] In this
procedure, the reaction scale affects the yield significantly. It has been
reported that with reactions using 80–100 mg or more of A-ring phosphine
oxide, the yield is routinely excellent; on the other hand, small-scale
reactions of 10–20mg result in a very poor yield.[10] The reason for the low
yield in the small-scale reactions could be water contamination from
moisture, leading to disappearance of ylide. At the very low temperature of
2788C, the water contamination is inevitable, especially in small-scale
reactions. Therefore, a practical and facile procedure for small-scale synthesis
is desirable.
Scheme 1. Established procedure.

7,8-Olefin Linkage in Vitamin D
RESULTS AND DISCUSSION
1143
Presuming that the low temperature in the established procedure is caused by
the instability of the generated ylide and the prevention of the enolation of the
base-sensitive CD-ring ketone,[8] we treated a mixture of the phosphine oxide
(2) and the ketone (4) in THF with lithium hexamethyldisilazide (LHMDS) to
react the ylide with the existing ketone as soon as possible after its generation
from the phosphine oxide (Scheme 2). The reaction successfully occurred
when a mixture of 1.1 equivalents of A-ring phosphine oxide (2) and 1.0
equivalent of CD-ring ketone (4) was treated with 1.1 equivalents of
LHMDS in THF at 2208C followed by gradual heating to 508C. The
heating was required to complete the olefin formation with elimination of
diphenylphosphinic acid. Neither the Z-olefin nor the epimer of the CD-ring
was generated. Next, we were interested in utilization of this procedure for
various analog syntheses. All the reactions were tested on a small scale
using 13 mg (22 mmol) of A-ring phosphine oxide; the yields were satisfac-
tory, as shown in Table 1. The higher reaction temperature of 2208C and
the simpler addition procedure than the established procedure should
prevent water contamination from moisture and make the small-scale
reactions workable.
In conclusion, we developed a facile reaction procedure for the Horner–
Wittig olefination, which constructs the 7,8-olefin linkage in vitamin D3. The
procedure made small-scale synthesis possible, benefiting vitamin D3 analog
study. The procedure would also be beneficial to industrial-scale synthesis of
vitamin D3 analog because the procedure is simpler than the established
method and the low temperature of 2788C is not required.
Scheme 2. Improved procedure.
EXPERIMENTAL
Benzene and THF were obtained from Kanto Chemical Co., Inc., as dehy-
drated solvents (water content: ,0.005% for THF, ,0.003% for benzene)
and used without further purification. LHMDS (1 M in THF) was purchased
from Aldrich. Silica-gel preparative TLC was purchased from Merck (silica
gel 60 F254, 0.5 mm). 1H NMR spectra were recorded on a Jeol JNM-
EX270 spectrometer using CDCl3 as a solvent. Chemical shifts are reported
in parts per million (ppm) downfield from tetramethylsilane.

1144
Y. Ono, H. Kashiwagi, and T. Takahashi
Table 1. Wittig reaction using 13 mg (22 mmol) of phosphine oxide
Yield
(%)
Entry Phosphine oxide
Ketone
Product
1[11]
92
2[12]
3[12]
4[13]
87
91
62
95
5[7]
General Procedure
To a reaction vessel, 100 ml of 0.22 M solution of A-ring phosphine oxide
(22 mmol) in benzene and 66.7 ml of 0.3 M solution of CD-ring ketone

7,8-Olefin Linkage in Vitamin D
1145
(20 mmol) in benzene were added. The benzene was evaporated, and the
mixture was dried by vacuum pump for 3 h. The reaction vessel was sealed
with a septum and charged with dry nitrogen gas. The residue was
dissolved or suspended in 200 ml of THF. The mixture was cooled to
2208C, and 2 ml of LHMDS (1 M in THF) were added 11 times in 1-s
intervals (22 ml in total, 22 mmol), at 2208C; then the cooling bath was
removed. The mixture was warmed to room temperature gradually for
10 min, then heated and kept at a temperature of 508C for 16 h. The solvent
was evaporated, and the residue was purified by silica-gel preparative TLC
developed with hexane/ethyl acetate (20 : 1) to give the target product.
1H NMR Spectral Data
3b-tert-Butyldimethylsilyl-1a-tert-butyldimethylsilyloxy-22-oxa-25-
trimethylsilyloxyvitamin D3 (product of entry 1): 0.03–0.17 (m, 21H), 0.52
(s, 3H), 0.82–0.93 (m, 18H), 1.16 (d, 3H, J ¼ 5.9 Hz), 1.20 (s, 6H), 3.17–3.22
(m, 1H), 2.15–2.25 (m, 1H), 2.40–2.50 (m, 1H), 2.78–2.87 (m, 1H), 3.28–
3.36 (m, 1H), 3.60–3.70 (m, 1H), 4.17–4.23 (m, 1H), 4.35–4.40 (m, 1H),
4.86 (s, 1H), 5.18 (s, 1H), 6.02 (d, 1H, J ¼ 11.3 Hz), 6.22 (d, 1H, J ¼ 11.3 Hz).
3b-tert-Butyldimethylsilyl-1a-tert-butyldimethylsilyloxy-25-trimethylsi-
lyloxy(20S)-vitamin D3 (product of entry 2): 0.03–0.17 (m, 21H), 0.55
(s, 3H), 0.82–0.93 (m, 21H), 1.20 (s, 6H), 2.18–2.25 (m, 1H), 2.40–2.50
(m, 1H), 2.78–2.88 (m, 1H), 4.17–4.22 (m, 1H), 4.37–4.42 (m, 1H), 4.84
(s, 1H), 5.19 (s, 1H), 6.00 (d, 1H, J ¼ 11.5 Hz), 6.21 (d, 1H, J ¼ 11.5 Hz).
3b-tert-Butyldimethylsilyl-1a-tert-butyldimethylsilyloxy-24,25,26-
trihomo-22-oxa-25-trimethylsilyloxy-(20S)-vitamin D3 (product of entry
3): 0.03–0.17 (m, 21H), 0.55 (s, 3H), 0.79–0.90 (m, 27H), 1.07 (d, 3H,
J ¼ 5.8 Hz), 1.43–1.50 (m, 4H), 1.96–2.03 (m, 1H), 2.17–2.25 (m, 2H),
2.42–2.50 (m, 1H), 2.80–2.88 (m, 1), 3.10–3.20 (m, 1H), 3.20–3.30
(m, 1H), 3.50–3.60 (m, 1H), 4.13–4.21 (m, 1H), 4.34–4.40 (m, 1H), 4.86
(s, 1H), 5.19 (m, 1H), 6.00 (d, 1H, J ¼ 11.0 Hz), 6.24 (d, 1H, J ¼ 11.0 Hz).
3b-tert-Butyldimethylsilyl-1a-tert-butyldimethylsilyloxy-25-
trimethylsilyloxy-19-norvitamin D3 (product of entry 4): 0.05 (s, 9H), 0.11
(s, 12H), 0.54 (s, 3H), 0.82–0.90 (m, 18H), 0.93 (d, 3H, J ¼ 6.1 Hz), 1.20
(s, 6H), 2.88–3.83 (m, 1H), 4.01–4.10 (m, 2H), 5.80 (d, 1H, J ¼ 11.3 Hz),
6.16 (d, 1H, J ¼ 11.3 Hz).
3b-tert-Butyldimethylsilyl-1a-tert-butyldimethylsilyloxy-2-methylene-
25-trimethylsilyloxy-19-nor-(20S)-vitamin D3 (product of entry 5): 0.04–
0.15 (m, 21H), 0.54 (s, 3H), 0.82–0.95 (m, 21H), 1.20 (s, 6H), 2.12–2.20
(m, 1H), 2.30–2.38 (m, 1H), 2.42–2.58 (m, 2H), 2.78–2.88 (m, 1H), 4.34–
4.42 (m, 2H), 4.92 (s, 1H), 4.97 (s, 1H), 5.83 (s, 1H, J ¼ 11.2 Hz), 6.21
(s, 1H, J ¼ 11.2 Hz).

1146
Y. Ono, H. Kashiwagi, and T. Takahashi
ACKNOWLEDGMENTS
We thank Kunio Ogasawara, professor emeritus, Tohoku University, for his
helpful suggestions.
REFERENCES
1. Bouillon, R.; Okamura, W. H.; Norman, A. W. Structure–function relationships in
the vitamin D endocrine system. Endocr. Rev. 1995, 16, 200–257.
2. Kubodera, N. Development of OCT and ED-71. In Vitamin D; 2nd ed.; Elsiever
Academic Press: San Diego, 2005; Vol. 2, pp. 1525–1542.
3. Shevde, N. K.; Plum, L. A.; Clagett-Dame, M.; Yamamoto, H.; Pike, J. W;
DeLuca, H. F. A potent analog of 1a,25-dihydroxyvitatmin D3 selectively
induces bone formation. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13487–13491.
4. Slatopolsky, E.; Finch, J.; Brown, A. New vitamin D analogs. Kidney Int., Suppl.
2003, 85–87.
5. Fogh, K.; Kragballe, K. New vitamin D analogs in psoriasis. Curr. Drug Targets:
Inflammation Allergy 2004, 3, 199–204.
6. Ono, Y.; Watanabe, H.; Shiraishi, A.; Takeda, S.; Higuchi, Y.; Sato, K.;
Tsugawa, N.; Okano, T.; Kobayashi, T.; Kubodera, N. Synthetic studies of
vitamin D analogs. XXIV. Synthesis of active vitamin D3 analogs substituted at
the 2b-position and their preventive effects on bone mineral loss in ovariectomized
rats. Chem. Pharm. Bull. (Tokyo) 1997, 45, 1626–1630.
7. Sicinski, R.; Prahl, J. M.; Smith, C. M.; DeLuca, H. F. New 1a,25-dihydroxy-19-
norvitamin D3 compounds of high biological activity: Synthesis and biological
evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogs. J. Med.
Chem. 1998, 41, 4662–4674.
8. Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J. F.;
Uskokovic, M. R. Stereocontrolled total synthesis of 1a,25-dihydroxychole-
calciferol and 1a,25-dihydroxyergocalciferol. J. Org. Chem. 1986, 51,
3098–3108.
9. Zhu, G.-D.; Okamura, W. H. Synthesis of vitamin D (calciferol). Chem. Rev. 1995,
95, 1877–1952.
10. Posner, G. H.; Nelson, T. D.; Guyton, K. Z.; Kensler, T. W. New vitamin D3
derivatives with unexpected antiproliferative activity: 1-(Hydroxymethyl)-25-
hydroxyvitamin D3 homologs. J. Med. Chem. 1992, 35, 3280–287.
11. Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I. Synthetic
studies of vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues.
Chem. Pharm. Bull. (Tokyo) 1986, 34, 4410–4413.
12. Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.; Calverley, M.; Hansen, K.
20-Epi-vitamin D3 analogs: A novel class of potent regulators of cell growth
and immune responses. Biochem. Pharmacol. 1991, 42, 1569–1575.
13. Perlman, K. L.; Swenson, R. E.; Paarena, H. E.; Schnoes, H. K.; DeLuca, H. F.
Novel synthesis of 19-nor-vitamin D compounds. Tetrahedron Lett. 1991, 32,
7663–7666.