The thioacetate approach to vitamin D analogues. Part 2: Synthesis of (25S)-23-thia-1α,25,26-trihydroxyvitamin D3

Article abstract of DOI:10.1016/j.tetlet.2007.07.086

(25S)-23-Thia-1α,25,26-trihydroxyvitamin D₃ (4) was prepared from alcohol 5 in 56% overall yield (five steps) using our previously developed methodology. Alcohol 5 was synthesized from commercially available vitamin D₂.

Full text of DOI:10.1016/j.tetlet.2007.07.086

Tetrahedron Letters 48 (2007) 6735–6737
The thioacetate approach to vitamin D analogues.
Part 2: Synthesis of (25S)-23-thia-1a,25,26-trihydroxyvitamin D3
a
b
a,
a,
*
*
´
´
Zoila Gandara, Ousmane Diouf, Generosa Gomez and Yagamare Fall
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
bLaboratoire de Chimie Inorganique, Departement de Chimie, Faculte´ des Sciences et Techniques,
Universite´ Cheikh Anta Diop de Dakar, Senegal
Received 15 June 2007; revised 9 July 2007; accepted 16 July 2007
Available online 21 July 2007
Abstract—(25S)-23-Thia-1a,25,26-trihydroxyvitamin D3 (4) was prepared from alcohol 5 in 56% overall yield (five steps) using our
previously developed methodology. Alcohol 5 was synthesized from commercially available vitamin D2.
Ó 2007 Elsevier Ltd. All rights reserved.
It has long been known that 1a,25-dihydroxyvitamin D3
(1a, calcitriol; see Fig. 1) is the hormonally active form
of vitamin D3 (1b). Besides regulating calcium homeo-
stasis, it is also involved in other cellular processes,
including cell differentiation, immune system regulation
and gene transcription.1 This has led to speculation that
1a might be an effective drug for the treatment of dis-
eases such as leukaemia and psoriasis. However, its ther-
apeutic utility is limited because effective doses have
calcaemic side effects. Much research has accordingly
been devoted to searching for analogues with high anti-
proliferation activity and low calcaemic activity, and
several antiproliferative analogues with little or no cal-
caemic activity have already been prepared.2
We recently started a research programme directed
towards the synthesis of thia analogues of calcitriol,3
which have been reported to be less calcaemic than cal-
citriol itself.4 In particular, we were interested in 23-thia
analogue 4 (Fig. 1), the similarly 26-hydroxylated ana-
logues 2 and 3 having been, respectively, reported to
have antiosteoporotic potential5 and to inhibit the bio-
synthesis of calcitriol.6 Scheme 1 indicates our approach
to 4 from commercially available vitamin D2 (7) and the
protected chiral epoxide 6. Vitamin D2 was used to pre-
pare alcohol 5 by the procedure described by Calverley,7
as modified by Choudhry et al.8 Compound 6 was
obtained by the protection of commercially available
(S)-2-methylglycidol.
S
R2
OH
OH
OH
OH
OH
OH
H
H
H
H
1a, R1 = R2 = OH
1b, R1 =, R2 = H
HO
R1
HO
OH
HO
OH
HO
OH
3
4
2
1
Keywords: Vitamin D; Calcitriol; Vitamin D thia analogues; Thioacetate; Vitamin D2.
*
Corresponding authors. Tel.: +34 986 81 36 79; fax: +34 986 81 22 62 (G.G.); tel.: +34 986 81 23 20; fax: +34 986 81 22 62 (Y.F.); e-mail addresses:
ggomez@uvigo.es; yagamare@uvigo.es
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.086

6736
Z. Ga´ndara et al. / Tetrahedron Letters 48 (2007) 6735–6737
OH
H
S
H
OH
OH
H
TBSO
OTBS
HO
5
7
+
HO
OH
O
4
OTBDPS
6
Scheme 1. Retrosynthetic analysis for 4.
Tosylation of alcohol 5, followed by the displacement of
thetosylategroupbypotassiumthioacetate,affordedthio-
acetate 9 in excellent yield (Scheme 2). Reaction of 9 with
chiral epoxide 6 using our previously described methodol-
ogy3 gave alcohol 10 in 83% yield, and removal of the silyl
groups of 10 gave 11.9 Finally, photosensitized isomeriza-
tion of 11 using anthracene as triplet sensitizer afforded
target compound 410 in 56% overall yield from alcohol 5.
O
S
OTs
OH
H
H
H
MeCOSK, DMF
98%
p-TsCl, DMAP, pyr
91%
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
8
9
5
NaOH, EtOH,NaBH4
S
S
OH
OTBDPS
OH
OH
O
OTBDPS
6
TBAF, THF
H
H
83%
87%
TBSO
OTBS
HO
OH
10
11
S
OH
OH
Anthracene, Et3N, hν, MeOH
87%
H
HO
OH
4
Scheme 2. Synthesis of (25S)-23-thia-1a,25,26-trihydroxyvitamin D3 (4).

Z. Ga´ndara et al. / Tetrahedron Letters 48 (2007) 6735–6737
6737
M.; Mori, T. Chem. Pharm. Bull. 1991, 39, 3221–3224; (c)
Calverley, M. J.; Grue-Soerensen, G.; Binderup, E. T.
PCT Int. Appl. WO 9115475, 1991; 64 pp; (d) Allewaert,
K.; Van Baelen, H.; Bouillon, R.; Zhao, X. Y.; De Clercq,
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1859–1862; (e) Grue-Sorensen, G.; Pedersen, H.; Bind-
erup, E. T.; Tranholm, M. PCT Int. Appl. WO 0156981,
2001; 50 pp.
In conclusion, (25S)-23-thia-1a,25,26-trihydroxyvitamin
D3 (4) can be synthesized straightforwardly from com-
mercially available vitamin D2 and (S)-2-methylglycidol.
Further results on the synthesis of novel thia analogues
of vitamin D will be reported in due course.
Acknowledgements
5. (a) Drezner, M. K.; Nesbitt, T. Metabolism 1990, 39, 18–
23; (b) Drezner, M. K.; Nesbitt, T.; Quarles, L. D. In
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Tetrahedron 1984, 40, 2283–2296.
This work was supported by grants from the Xunta de
Galicia (PGIDIT04BTF301031PR) and the Spanish
Ministry of Education and Science (CTQ2007-61788).
The work of the NMR, MS and X-ray divisions of the
research support services of the University of Vigo
(CACTI) is gratefully acknowledged.
References and notes
7. Calverley, M. J. Tetrahedron 1987, 43, 4609–4619.
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Maehr, H.; Manchand, P. S.; Serico, L.; Tang, R. T. J.
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1994, 1383–1398; (e) Zhu, G.-D.; Okamura, W. H. Chem.
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C.; Suda, T.; Nishii, Y. Endocrinology 1989, 124, 2645–
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9. Data for compound 11. White solid, mp 56–59 °C,
Rf = 0.45 (10% MeOH/CH2Cl2). 1H NMR (300 MHz,
CDCl3), d: 6.55 (1H, d, J = 11.5 Hz, H-6), 5.87 (1H, d,
J = 11.5 Hz, H-7), 5.11 (1H, s, H-19), 4.96 (1H, s, H-19),
4.88 (1H, m, H-1), 4.22 (1H, m, H-3), 3.55 (1H, s), 3.45
(1H, s), 2.87 (2H, m), 2.75 (2H, m), 2.55 (2H, m), 2.35 (3H,
m), 1.55 (11H, m), 1.21 (3H, s, H-26), 1.08 (3H, d,
J = 6.5 Hz, H-21), 0.56 (3H, s, H-18). 13C NMR (CDCl3),
d: 151.69 (C-10), 144.84 (C-8), 132.90 (C-5), 123.28 (CH-
6), 116.09 (CH-7), 109.71 (CH2-19), 72.50 (C-25), 71.13
(CH-1), 68.98 (CH2-27), 65.95 (CH-3), 56.34 (CH-14),
55.58 (CH-17), 46.08 (C-13), 42.80 (CH2), 42.24 (CH2),
41.99 (CH2), 37.33 (CH-21), 36.78 (CH2), 29.01 (CH2),
27.62 (CH2), 23.86 (CH3-26), 23.46 (CH2), 22.27 (CH2),
18.82 (CH3-18), 12.20 (CH3-21). MS (m/z, %): 451.29
[(M+1)+, (25)], 450.27 [M+, (32)], 362.23 (35), 309.07 (25),
284.23 (30), 190.17 (34), 185.12 (100). HRMS: calcd for
C26H42O4S, 450.2863; found, 450.2859.
10. Data for compound 4. Colourless oil, Rf = 0.45 (10%
MeOH/CH2Cl2). 1H NMR (300 MHz, CDCl3), d: 6.30
(1H, d, J = 10.9 Hz, H-6), 5.94 (1H, d, J = 11.3 Hz, H-7),
5.25 (1H, s, H-19), 4.93 (1H, s, H-19), 4.36 (1H, m, H-1),
4.16 (1H, m, H-3), 3.65 (1H, s), 3.45 (2H, s), 2.65 (6H, m),
2.25 (1H, m), 1.85 (6H, m), 1.35 (8H, m), 1.25 (3H, m),
1,15 (3H, s, H-26), 1.02 (3H, d, J = 6.5 Hz, H-21), 0.48
(3H, s, H-18). 13C NMR (CDCl3), d: 147.63 (C-10), 142.73
(C-8), 133.11 (C-5), 124.88 (CH-6), 117.20 (CH-7), 111.76
(CH2-19), 72.48 (C-25), 70.79 (CH-1), 68.96 (CH2-27),
66.86 (CH-3), 56.17 (CH-14), 55.54 (CH-17), 45.24 (CH2),
42.85 (CH2), 42.76 (CH2), 40.26 (CH2), 37.35 (CH-20),
29.70 (CH2), 29.00 (CH2), 27.62 (CH2), 23.85 (CH-26),
23.49 (CH2), 22.26 (CH2), 18.81 (CH3-18), 12.07 (CH3-21).
HRMS: calcd for C26H42O4S, 450.2863; found, 450.2859.
´
3. Fall, Y.; Diouf, O.; Gomez, G.; Bolano, T. Tetrahedron
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