Stereoselective synthesis of (22Z)-25-hydroxyvitamin D2 and (22Z)-1α,25-dihydroxyvitamin D2

Article abstract of DOI:10.1016/j.tetlet.2009.06.049

Two new vitamin D₂ analogues, (22Z)-25-(OH)-D₂ and (22Z)-1α,25-(OH)₂-D₂, were serendipitously synthesized from vitamin D₂ and using the Julia-Kocienski olefination.

Full text of DOI:10.1016/j.tetlet.2009.06.049

Tetrahedron Letters 50 (2009) 4874–4877
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Tetrahedron Letters
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Stereoselective synthesis of (22Z)-25-hydroxyvitamin D2 and (22Z)-1a,
25-dihydroxyvitamin D2
*
*
Zoila Gándara, Manuel Pérez, Xenxo Pérez-García, Generosa Gómez , Yagamare Fall
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new vitamin D2 analogues, (22Z)-25-(OH)-D2 and (22Z)-1a,25-(OH)2-D2, were serendipitously syn-
thesized from vitamin D2 and using the Julia–Kocienski olefination.
Received 5 May 2009
Revised 5 June 2009
Accepted 9 June 2009
Available online 13 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Vitamin D
Calcitriol
Vitamin D2
Stereoselective synthesis
The classical Julia olefination, also known as the Julia–Lythgoe
olefination, was first described in 1973 by Julia and Paris.1 Since
then a variant of this reaction, the modified or one-pot Julia olefin-
ation,2 also known as the Julia–Kocienski reaction, has emerged as
a very powerful method for olefin synthesis. The stereochemical
outcome of this reaction is generally predictable on the basis of
the substrates and reaction conditions,2c,3 although some excep-
tions have recently been reported.4
obu conditions7 followed by oxidation of intermediate 8 (Scheme
2). Coupling of 3a with aldehyde 4 gave exclusively Z olefin 5 in
75% yield.
This unexpected and unprecedented result prompted us to con-
sider the synthesis of 22Z vitamin D2 analogues. The analogue
(22Z)-25-OH-D2 was prepared as shown in Scheme 3 starting from
the Inhoffen–Lythgoe diol (9), which is easily obtained by degrada-
tion of vitamin D2.8 Protection of the hydroxyl groups of 9, fol-
lowed by selective deprotection of the primary alcohol, afforded
compound 10 in 79% overall yield; and TPAP oxidation9 of alcohol
10 then afforded aldehyde 4 in 93% yield. Julia–Kocienski olefin-
ation of 4 with sulfone 3a was best carried out in THF at À78 °C
using LiHMDS as base: under these conditions, the Z olefin 5 was
obtained in 75% yield. Reaction of 5 with methyllithium, followed
by removal of the silyl protecting group with TBAF, gave diol 11 in
78% overall yield; and TPAP oxidation of the C8 hydroxyl group,
followed by protection of the C25 hydroxyl with TMS, afforded ke-
tone 12 in 85% overall yield. Wittig–Horner coupling of ketone 12
with phosphine oxide 13,10 followed by removal of the silyl pro-
tecting group, then afforded the target vitamin D2 analogue 1411
in almost quantitative yield.
As part of our ongoing programme on the synthesis of vitamin D
and its analogues, we decided to prepare 25-hydroxyvitamin D2 (1)
and 1a,25-dihydroxy vitamin D2 (2) (Fig. 1); although considerable
effort has been devoted to the synthesis of vitamin D3 metabo-
lites,5 very few syntheses of 25-(OH)-D2 and 1
been reported to date.6
a,25-(OH)2-D2 have
Our approach was based on generation of the side chain by Ju-
lia–Kocienski reaction of an appropriate aldehyde with sulfones 3,
which bear a methyl ester group offering the possibility of easy
modification at C-25 (Scheme 1).
It was anticipated that coupling of sulfones 3 with aldehyde 4
would lead stereoselectively to the formation of the E olefin. Much
to our surprise, however, despite numerous changes in reaction
conditions (cf. Table 1), only the Z olefin 5 could be isolated.
The optimized reaction conditions to synthesize Z olefin 5 were
established to be reacting aldehyde 4 with sulfone 3a (1.45 equiv)
and LiHMDS (1.36 equiv) at À78 °C.
For the synthesis of (22Z)-1a,25-(OH)2-D2 (20) we decided to
start from alcohol 15 (Scheme 4), which is readily obtained in large
quantities from vitamin D2 using the procedures described by Cal-
verley12 and later modified by Choudhry.13
TPAP oxidation of 15 afforded aldehyde 16 in 95% yield, and
Julia–Kocienski olefination of 16 with sulfone 3a, gave a 65% yield
of ester 17, which upon reaction with methyllithium in ether at
À78 °C yielded alcohol 18. Removal of the silyl protecting groups
of 18 with TBAF in THF afforded a 93% yield of triol 19, and
Benzothiazole 3a was efficiently prepared from commercially
available alcohol 6 and 2-mercaptobenzothiazole (7) using Mitsun-
* Corresponding authors. Tel.: +34 986 812320; fax: +34 986 81 22 62 (Y.F.).
E-mail addresses: ggomez@uvigo.es (G. Gómez), yagamare@uvigo.es (Y. Fall).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.049

Z. Gándara et al. / Tetrahedron Letters 50 (2009) 4874–4877
4875
photoisomerization of 19 using anthracene as sensitizer finally
gave the target analogue 2014 in 85% yield.
In conclusion, we have synthesized two new vitamin D2 ana-
logues, (22Z)-25-OH-D2 (14) and (22Z)-1a,25-(OH)2-D2 (20), using
a Julia–Kocienski olefination with an unexpected stereoselectivity.
Compound 14 was synthesized from the Inhoffen–Lythgoe diol (9)
in 10 steps and 33% overall yield, and compound 20 from readily
accessible alcohol 15 in five steps and 41% overall yield. We are
currently using our method to synthesize new vitamin D2 ana-
logues with modifications at C-25 for biological evaluation and
SAR studies. Small samples of these new vitamin D2 analogues
(14 and 20) are available upon request for biological evaluation.
OH
OH
HO
H
H
OH
HO
1
2
Figure 1. Structures of 25-hydroxyvitamin D2 (1) and 1
a
,25-dihydroxyvitamin D2
(2).
O
S
O
3a
N
S
O
OMe
CO2Me
1) (Me3Si)2NM
O
S
O
N
N
N
N
O
O
2)
H
5
TESO
H
OMe
3b
4
H
TESO
Scheme 1.
Table 1
Entry
Solvent
M
Phenyltetrazole (PT)
% Yield 5
Benzothiazole (BT)
E:Z
% Yield 5
E:Z
1
2
3
4
5
THF
THF
THF
DME
DME
Li
K
Na
K
Na
35a
0b
0:100
75a
0:100
57a
4c
0:100
0:100
0b
Conditions: a Aldehyde 4 (1 equiv), sulfone (1.45 equiv), base (1.36 equiv), À78 °C; b aldehyde 4 (1.5 equiv), sulfone (1 equiv), base (1.1 equiv), À55 °C; c aldehyde 4 (1 equiv),
sulfone (1.45 equiv), base (1.36 equiv), À55 °C.
N
SH
S
7
DIAD, PPh3, THF,
0º C to rt
(NH4)6Mo7O2.4H2O, H2O2(30%)
EtOH, 0º C to rt
N
S
HO
O
S
O
94%
OMe
OMe
76%
6
8
LiHMDS, THF, -78º C
O
S
O
N
O
OMe
O
S
O
H
OMe
75%
3a
H
TESO
5
4
H
TESO
Scheme 2.

4876
Z. Gándara et al. / Tetrahedron Letters 50 (2009) 4874–4877
O
H
OH
OH
ii
i
10
9
H
H
H
4
TESO
HO
TESO
O
iii
iv
OMe
OH
H
5
H
11
TESO
HO
Ph2PO
vi
v
TBSO
OH
OTMS
13
H
H
12
O
14
HO
Scheme 3. Reagents and conditions: (i) (a) TESCl, imid, CH2Cl2, 0 °C (80%); (b) TBAF, THF (99%); (ii) TPAP, NMO, CH2Cl2 (93%); (iii) 3a, LiHMDS, THF, À78 °C (75%); (iv) (a)
MeLi, Et2O, À78 °C (79%); (b) TBAF, THF (99%); (v) (a) TPAP, NMO, CH2Cl2 (98%); (b) TMS-imidazole (87%); (vi) (a) 13, n-BuLi, THF, À78 °C (90%); (b) TBAF, THF (99%).
O
O
H
OH
OMe
H
ii
H
H
i
16
15
17
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
OH
OH
iv
OH
iii
v
H
H
H
20
18
19
HO
OH
TBSO
OTBS
HO
OH
Scheme 4. Reagents and conditions: (i) TPAP, NMO, CH2Cl2, molecular sieves (95%); (ii) 3a, LiHMDS, THF, À78 °C (65%); (iii) MeLi, Et2O, À78 °C (85%); (iv) TBAF, THF (93%); (v)
anthracene, Et3N, h , CH2Cl2, MeOH (85%).
m
Acknowledgements
Supplementary data
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de Galicia
(INCITE08PXIB314253PR, INCITE08ENA314019ES and INCITE08P-
XIB314255PR). The work of the NMR and MS divisions of the re-
search support services of the University of Vigo (CACTI) is also
gratefully acknowledged.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.049.
References and notes
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4877
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11.2 Hz, H-7), 5.19 (1H, dd, J = 2 Â 10.6 Hz, H-22 or 23), 5.09 (1H, dd, J =
2 Â 10.6 Hz, H-22 or 23), 4.92 (1H, s, H-19), 4.67 (1H, s, H-19), 3.78 (1H, m, H-
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69.5 (CH, C-3), 57.2 (CH, C-17), 56.7 (CH, C-14), 54.2 (CH2, C-1), 53.8 (CH, C-24),
46.4 (CH2), 43.2 (CH, C-20), 40.9 (CH2), 35.8 (CH2), 32.5 (CH2), 29.6(CH2), 28.1
(CH2), 27.8 (CH3, C-26 and 27), 24.0 (CH2), 22.6 (CH2), 21.5 (CH3, C-28), 16.5
(CH3, C-21), 12.5 (CH3, C-18); MS (FAB+) [m/z, (%)]: 412.32 ([M+], 100), 396.32
(22), 395.31 (68), 393.30 (20), 377.30 (17), 271.19 (19), 269.18 (33), 253.19
(28), 251.18 (10), 211,19 (11), 202.26 (19), 197.20 (10), 187.27 (15), 186.31
(61), 185.23 (12), 183.23 (15); HRMS (EI+): calcd for C28H44O2 412.3341, found
412.3330.
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EtOAc). 1H NMR (CDCl3, d): 6.35 (1H, d, J = 11.2 Hz, H-6), 6.00 (1H, d,
J = 11.6 Hz, H-7), 5.31 (2H, m, H-19 and H-22 or 23), 5.17 (1H, dd, J =
2 Â 10.6 Hz, H-22 or 23), 4.98 (1H, s, H-19), 4.41 (1H, m, H-1), 4.21 (1H, m, H-
3), 2.77 (1H, m), 2.45 (2H, m), 2.25 (1H, m), 1.85 (4H, m), 1.55 (5H, m), 1.45
(4H, m), 1.35 (4H, m), 1.17 (3H, s, H-26 or 27), 1.18 (3H, s, H-26 or 27), 0.98
(3H, d, J = 6.8 Hz, CH3-21 or 28), 0.94 (3H, d, J = 6.8 Hz, CH3-21 or 28), 0.57 (3H,
s, H-18); 13C NMR (CDCl3, d): 147.7 (C-10), 142.9 (C-8), 138.2 (C-5), 133.0 (CH-
23), 128.5 (CH-22), 124.9 (CH-6), 117.1 (CH-7), 111.7 (CH2-19), 72.7 (C-25),
70.8 (CH-1), 66.9 (CH-3), 56.7 (CH-14), 56.4 (CH-17), 45.3 (CH2), 45.9 (C-13),
42.8 (CH-24), 40.4 (CH2), 35.0 (CH-20), 29.1 (CH2), 27.7 (CH2), 27.0 (CH3-26 or
27), 26.7 (CH3-26 or 27), 23.6 (CH2), 22.3 (CH2), 21.3 (CH3-28), 16.4 (CH3-18),
12.4 (CH3-21); MS (EI+) [m/z, (%)]: 429.28 [(M+1)+, (6)], 428.27 [M+, (5)], 427.27
[(MÀ1)+, (3)], 411.27 (16), 277.09 (10), 269.14 (4), 230.20 (3), 199.15 (3);
HRMS (EI+): calcd for C28H44O3 429.3369, found 429.3363.
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