Vitamin D heterocyclic analogues; Part 2: Synthesis of the first vitamin D analogues with a tetrazole ring at the side chain

Article abstract of DOI:10.1055/s-0030-1260258

Access to the calcitriol analogues with a tetrazole ring at the side chain was very efficiently achieved using the Calverley-Choudhry approach instead of the Wittig-Horner method, which gave very low yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260258

PAPER
3887
Vitamin D Heterocyclic Analogues; Part 2: Synthesis of the First Vitamin D
Analogues with a Tetrazole Ring at the Side Chain
V
itamin D Hete
o
rocyclic Ana
i
loguesla Gándara, Pedro Lois Suárez, Maria González, Generosa Gómez,* Yagamare Fall*
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(98)6812262; E-mail: yagamare@uvigo.es; E-mail: ggomez@uvigo.es
Received 2 August 2011; revised 1 September 2011
Abstract: Access to the calcitriol analogues with a tetrazole ring at
the side chain was very efficiently achieved using the Calverley–
Choudhry approach instead of the Wittig–Horner method, which
gave very low yields.
OH
i
I
I
ii
H
H
H
Key words: 1a,25-dihydroxyvitamin D3, tetrazole, heterocycles,
azasteroids, Windhaus–Grundmann ketone
OH
OH
O
TBSO
6
7
5
O
OEt
N
OEt
+
N
1a,25-Dihydroxyvitamin D3 [1, 1a,25-(OH)2-D3, calcitri-
ol], the hormonally active form of vitamin D31 (2, chole-
calciferol) (Figure 1), is one of the most potent inducers of
calcitropic effects, notably intestinal calcium absorption
and bone calcium mobilization. Besides regulating the
metabolism of calcium and phosphorus, calcitriol pro-
motes cell differentiation, inhibits the proliferation of tu-
mor cells, and has certain indirect effects on the
immunological system.2 However, the clinical utility of
this hormone for treatment of cancers and skin disorders
is limited by its hypercalcemic effects. There is accord-
ingly much interest in the design and synthesis of ana-
logues of 1 having high cell-differentiating properties and
low or negligible calcemic effects.2
N–
N
Na
N
N
N
O
8
N
N
N
N
OEt
iii
N
H
9
TBSO
10
H
TBSO
iv
O
O
N
N
N
N
N
OEt
OEt
N
N
N
v
Despite the fact that azasteroids show noteworthy phar-
macological activity,3 very few aza-analogues of vitamin
D have been known.3,4 We report here a straightforward
access to the side chain of vitamin D analogues 3 and 4
bearing a tetrazole moiety (Figure 1). The synthesis of
analogue 3 is detailed in Scheme 1.
H
H
HO
O
11
12
Ph2PO
vi
TBSO
OTBS
N
13
Selective iodation of the primary alcohol of diol 5 gave io-
dide 65 in 96% yield. Protection of the secondary hydroxy
group of 6 (85%), followed by tetrazole displacement of
the C-22 primary iodide afforded tetrazoles 9 and 10 in
41% and 52% yield, respectively.
O
N
OEt
N
N
OH
N
N
H
Removal of the silyl protecting group of 10 by reaction
with HF in acetonitrile at room temperature, gave alcohol
11 in 93% yield. Oxidation of alcohol 11 with TPAP gave
ketone 12 in 88% yield, so setting the stage for the Wittig–
Horner reaction with phosphine oxide 13.6 The effect of
the scale of the coupling reaction on its effectiveness re-
ported by Posner et al.7 could explain the low yield ob-
tained. With key intermediate 14 in hand, its reaction with
MeLi was carried out followed by desilylation to afford
N
N
14
vii
H
TBSO
OTBS
3
HO
OH
Scheme 1 Reagents and conditions: (i) Ph3P, I2, imidazole, THF, 0
°C (90%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, –10 °C (85%); (iii) 8,
DMF, r.t. (9, 41%; 10, 52%); (iv) HF, MeCN, r.t. (93%); (v) TPAP,
NMO, CH2Cl2, r.t. (88%); (vi) 13, n-BuLi, THF, –78 °C (13%); (vii)
(a) MeLi, Et2O, –20 °C (b) TBAF, THF, r.t. (95%, two steps).
SYNTHESIS 2011, No. 23, pp 3887–3893
x
x.
x
x
.
2
0
1
1
Advanced online publication: 07.10.2011
DOI: 10.1055/s-0030-1260258; Art ID: Z76011SS
© Georg Thieme Verlag Stuttgart · New York

3888
Z. Gándara et al.
PAPER
OH
OH
N
N
N
N
R1
N
N
N
N
H
H
H
3
4
HO
OH
R2
HO
OH
HO
1 R1 = R2 = OH
2 R1 = R2 = H
Figure 1 tructures of 1a,25-dihydroxyvitamin D3 (1), cholecalciferol (2), and the tetrazole analogues 3 and 4
new vitamin D analogue 3 bearing a tetrazole ring at the tion and subsequent thermolysis of the sulfur dioxide
9b,c
side chain (95% yield for the two steps).
adducts of vitamin D2 seemed to us more appropriate
for a large scale synthesis of a late-stage intermediate such
as 15 (Scheme 2).
Reaction of iodide 7 with tetrazole 8 led to compounds 9
and 10 corresponding to N1 and N2 alkylation respective-
ly. NMR analyses were performed in order to determine Accordingly alcohol 15 was easily obtained using this
the regiochemistry of the alkylation.8 For tetrazole 9, a method and then led to target analogues 3 and 4 as depict-
15N-1H HMBC spectrum showed a correlation between ed in Scheme 3.
the C22-H2 group and N1 and N2. In the case of tetrazole
Tosylation of alcohol 15 gave tosylate 16 in 91% yield.
Displacement of the C-22 tosylate with tetrazole salt 8 af-
forded compounds 17 and 18 in 93% yield. Compounds
10 a 15N-1H HMBC spectrum showed a correlation be-
tween the C22-H2 group and N1, N2, and N3 (Figure 2).
17 and 18 were rather difficult to separate by column
O
H
O
H
OEt
chromatography, reason why the mixture was submitted
to the next reaction with methyllithium affording alcohols
19 and 20, which were easily separable by chromatogra-
phy. Nonetheless, for characterization purposes pure sam-
ples of 17 and 18 were isolated. Removal of the silyl
protecting groups of 19 and 20, followed by photosensi-
tized isomerization using anthracene as triplet sensitizer
afforded target compounds 3 and 4 in 88% and 71% over-
all yield, respectively, from 19 and 20.
1N
H
H
2N
3N
OEt
1 N
2 N
N
N
N
3
H
TBSO
H
TBSO
9
10
Figure 2 15N-1H HMBC correlations for 9 and 10
In summary, this is the first report on the synthesis of a vi-
tamin D analogue bearing a tetrazole moiety at the side
chain. The synthesis of the side chain is straightforward
using the Inhoffen–Lythgoe diol 5 easily obtained by deg-
radation of vitamin D2 and commercially available tetra-
zole 8. The synthesis of analogues 3 and 4 using the
Caverley approach proved to be in this case more efficient
than the Wittig–Horner approach. The synthesis of a se-
ries of analogues of 3 and 4 modified at C-25 using inter-
Due to the low yield obtained in the Wittig–Horner cou-
pling reaction towards the synthesis of analogue 3, we de-
cided to overcome this shortcoming by switching to a
totally different approach described some years ago by
Calverley9b and later modified by Choudhry.9c The use of
this strategy involved the concept of the triene system pro-
tection to allow chemical modification of the vitamin D
side chain. This concept received relatively little atten-
tion.9 Among the approaches, the one using the prepara-
OH
OH
N
OH
N
N
N
N
N
N
N
H
vitamin D2
H
H
3
4
15
TBSO
OTBS
HO
OH
HO
OH
Scheme 2
Synthesis 2011, No. 23, 3887–3893 © Thieme Stuttgart · New York

PAPER
Vitamin D Heterocyclic Analogues
3889
Preparation of 3 by Wittig–Horner Method
(1R,3aR,4S,7aR)-Octahydro-1-[(S)-1-iodopropan-2-yl]-7a-
methyl-1H-inden-4-ol (6)
OH
OTs
ii
To a solution of diol 5 (4.50 g, 21.23 mmol) in THF (90 mL) at –20
°C were added I2 (5.92 g, 23.34 mmol), Ph3P (6.68 g, 25.47 mmol),
and imidazole (4.33 g, 63.67 mmol). The reaction mixture was
stirred at –20 °C for 15 min, then allowed to reach r.t. After stirring
at r.t. for 1 h 30 min, the mixture was cooled to 0 °C before adding
sat. aq NaHCO3 (50 mL). The product was extracted with Et2O
(2 × 60 mL) and the combined organic phases washed with sat. aq
Na2S2O3 (20 mL) and H2O (15 mL), and dried (Na2SO4). Filtration
and solvent evaporation afforded a residue, which was chromato-
graphed on silica gel using 8% EtOAc–hexane as eluent giving 6.34
g (96%) of 6; white solid; mp 108 ° C; Rf = 0.66 (30% EtOAc–hex-
ane).
i
H
H
15
16
TBSO
OTBS
TBSO
OTBS
CO2Et
N
N
N
N
N
N
N
CO2Et
N
1H NMR (CDCl3): d = 4.09 (1 H, m, H-8), 3.32 (1 H, dd, J = 2.1, 9.5
Hz, H-22), 3.18 (1 H, dd, J = 4.8, 9.5 Hz, H-22), 185 (4 H, m), 1.45
(5 H, m), 1.15 (4 H, m), 1.00 (3 H, d, J = 5.5 Hz, CH3-21), 0.97 (3
H, s, CH3-18).
H
H
iii
+
17
18
13C NMR (CDCl3): d = 69.1 (CH-8), 55.9 (CH2), 52.3 (CH2), 42.23
(C-13), 40.49 (CH2-22), 36.74 (CH3-18), 33.94 (CH2), 26.93 (CH2),
22.79 (CH2), 21.73 (CH2), 21.07 (CH), 17.3 (CH2), 14.3 (CH-21).
TBSO
OTBS
TBSO
OTBS
HRMS: m/z calcd for C13H23IO: 322.0816; found: 322.0814.
OH
N
N
{(1R,3aR,4S,7aR)-Octahydro-1-[(S)-1-iodopropan-2-yl]-7a-
methyl-1H-inden-4-yloxy}(tert-butyl)dimethylsilane (7)
To a solution of iodide 6 (408 mg, 1.26 mmol) in anhyd CH2Cl2 (2
mL) at –10 °C was added 2,6-lutidine (0.3 mL, 2.54 mmol) and
TBSOTf (0.5 mL, 1.91 mmol). The mixture was stirred at this tem-
perature for 12 h, quenched with aq NaHCO3 (6 mL), and extracted
with Et2O (3 × 50 mL). The combined organic phases were washed
with aq 10% HCl (2 × 50 mL). After drying (Na2SO4) and solvent
evaporation, the residue was chromatographed on silica gel using
10% EtOAc–hexane as eluent to afford 437 mg (85%) of iodide 7;
colorless oil; Rf = 0.74 (50% EtOAc–hexane).
N
N
N
N
N
OH
N
iv
H
H
+
19
20
TBSO
OTBS
TBSO
OTBS
1H NMR (CDCl3): d = 4.00 (1 H, m, H-8), 3.34 (1 H, dd, J = 2.4,
7.12 Hz, H-22), 3.18 (1 H, dd, J = 4.4, 5.0 Hz, H-22), 2.85 (2 H, m),
2.65 (2 H, m), 1.35 (6 H, m), 1.00 (3 H, d, J = 5.8 Hz, H-21), 0.95
(3 H, s, H-18), 0.88 (9 H, s, t-C4H9), –0.01 (3 H, s, SiCH3), –0.02 (3
H, s, SiCH3).
OH
N
OH
N
N
N
N
N
N
N
13C NMR (CDCl3): d = 69.30 (CH-8), 55.99 (CH), 52.77 (CH),
42.08 (C-13), 40.38 (CH2-22), 36.442 (CH3-18), 34.31 (CH2), 26.66
(CH2), 25.65 [C(CH3)3], 22.89 (CH2), 21.40 (CH2), 20.72 (CH),
18.01 [C(CH3)3], 17.59 (CH2), 14.56 (CH3-21), –4.77 (SiCH3),
–5.05 (SiCH3).
H
H
4
3
HO
OH
HO
OH
Ethyl 1-((S)-2-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsi-
lyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}propyl)-1H-tetra-
zole-5-carboxylate (9) and Ethyl 2-((S)-2-{(1R,3aR,4S,7aR)-4-
[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-
1-yl}propyl)-2H-tetrazole-5-carboxylate (10)
Scheme 3 Reagents and conditions: (i) p-TsCl, DMAP, pyridine, 0
°C (91%); (ii) 8, DMF, 70 °C (93%); (iii) MeLi, Et2O, –10 °C (19,
65%; 20, 27%); (iv) (a) TBAF, THF, r.t.; (b) anthracene, Et3N, hn,
CH2Cl2, toluene (2 steps, 88% for 3; 71% for 4).
To a solution of iodide 7 (150 mg, 0.34 mmol) in anhyd THF (3 mL)
was added tetrazole salt 8 (113 mg, 0.69 mmol). The mixture was
stirred at r.t. for 12 h, and extracted with Et2O (3 × 30 mL). The
combined organic phases were washed with brine (40 mL) and
dried (Na2SO4). Filtration and solvent evaporation gave a residue,
which was chromatographed on silica gel using 10% EtOAc–hex-
ane as eluent, to afford 64 mg (41%) of tetrazole 9; yellow oil; Rf =
0.37(20% EtOAc–hexane) and 80 mg (51%) of tetrazole 10; yellow
oil; Rf = 0.49 (20% EtOAc–hexane).
mediates 17 and 18 is currently under way in our
laboratory with a view to their biological evaluation.
Solvents were purified and dried by standard procedures before use.
Melting points are uncorrected.
1H and 13C NMR spectra were recorded in a Bruker ARX-400 spec-
trometer (400 MHz for 1H, 100.61 for MHz 13C) using TMS as in-
ternal standard (chemical shifts in d values, J in Hz). Mass
spectrometry was carried out with a Hewlett Packard 5988A spec-
trometer. Flash chromatography (FC) was performed on silica gel
(Merck 60, 230–400 mesh); analytical TLC was performed on
plates precoated with silica gel (Merck 60 F254, 0.25 mm).
9
1H NMR (CDCl3): d = 4.77 (1 H, dd, J = 3.8, 9.3 Hz, H-22), 4.51 (2
H, q, J = 7.1 Hz, OCH2CH3), 4.39 (1 H, dd, J = 2.5, 10.3 Hz, H-22),
4.00 (1 H, d, J = 2.3 Hz, H-8), 2.07 (1 H, m, H-14), 1.90 (2 H, m),
Synthesis 2011, No. 23, 3887–3893 © Thieme Stuttgart · New York

3890
Z. Gándara et al.
PAPER
1.76 (1 H, td, J = 3.5, 6.3 Hz, H-17), 1.59 (2 H, m), 1.51 (1 H, m, H-
20), 1.46 (3 H, t, OCH2CH3), 1.37 (2 H, m), 1.32 (2 H, m), 1.27 (2
H, m), 0.93 (3 H, s, H-18), 0.87 (9 H, s, t-C4H9), 0.72 (3 H, d,
J = 10.4 Hz, H-21), 0.03 (3 H, s, CH3Si), 0.02 (3 H, s, CH3Si).
was stirred at r.t. for 12 h. The organic solvent was removed by ro-
tary evaporation and the residue was chromatographed on silica gel
using 43% EtOAc–hexane as eluent to afford 89 mg (88%) of ke-
tone 12; yellow oil; Rf = 0.42 (50% EtOAc–hexane).
13C NMR (CDCl3): d = 156.82 (C=O), 145.95 (NC=N), 69.19 (CH-
8), 63.46 (OCH2CH3), 54.81 (CH-14), 54.71 (CH2-22), 52.79 (CH),
42.62 (C-13), 40.50 (CH2), 37.18 (CH3-18), 34.28 (CH2), 26.71
(CH2), 25.80 [C(CH3)3], 23.09 (CH2), 18.92 [C(CH3)3], 17.50
(CH2), 16.25 (CH), 14.05 (OCH2CH3), 13.79 (CH3-21), –4.79
(SiCH3), –5.14 (SiCH3).
1H NMR (CDCl3): d = 4.67 (1 H, dd, J = 3.8, 9.4 Hz, H-22), 4.50 (3
H, m, H-22 and OCH2CH3), 2.46 (1 H, dd, J = 4.1, 7.5 Hz, H-14),
2.20 (6 H, m), 1.80 (2 H, m), 1.50 (4 H, m), 1.44 (3 H, t, J = 7.1 Hz,
OCH2CH3), 0.90 (3 H, d, J = 6.6 Hz, H-21), 0.67 (3 H, s, H-18).
13C NMR (CDCl3): d = 210.91 (C-8), 157.72 (C=O, NC=N), 62.63
(OCH2CH3), 61.44 (CH), 59.10 (CH2-22), 53.90 (CH), 49.82 (C-
13), 40.76 (CH2), 38.76 (CH2), 37.03 (CH3-18), 27.17 (CH2), 23.77
(CH2), 19.17 (CH2), 17.00 (CH), 14.14 (OCH2CH3), 12.56 (CH3-
21).
LRMS: m/z (%) = 451.26 [M+ + 1, (100)], 449.24 (9), 393.19 (8),
319.15 (6), 177.18 (33), 171.14 (11).
HRMS: m/z calcd for C23H43N4O3Si28: 451.3101; found: 451.3104.
LRMS: m/z (%) = 335.25 [M+ + 1, (100)], 334.25 [M+, (5)], 307.14
10
(13), 175.26 (8), 165.23 (5), 155.23 (18), 154.22 (54).
1H NMR (CDCl3): d = 4.63 (1 H, dd, J = 3.8, 9.4 Hz, H-22), 4.54 (2
H, q, J = 7.1 Hz, OCH2CH3), 4.40 (1 H, dd, J = 3.9, 9.3 Hz, H-22),
3.96 (1 H, m, J = 2.3 Hz, H-8), 2.17 (1 H, H-14), 1.90 (2 H, m, H-
9), 1.74 (1 H, m, H-17 or 20), 1.59 (2 H, m), 1.43 (3 H, t, J = 7.1 Hz,
OCH2CH3), 1.34 (1 H, m, H-20 or 17), 1.11 (2 H, m), 0.91 (3 H, s,
H-18), 0.83 (9 H, t-C4H9), 0.79 (3 H, d, J = 6.5 Hz, H-21), –0.03 (3
H, s, SiCH3), –0.04 (3 H, s, SiCH3).
13C NMR (CDCl3): d = 157.98 (C=O), 157.63 (NC=N), 69.14 (CH-
8), 62.60 (OCH2CH3), 59.48(CH2-22), 54.22 (CH-14), 52.75 (CH),
42.51 (C-13), 40.41 (CH2), 37.07 (CH3-18), 34.24 (CH2), 26.99
(CH2), 25.79 [C(CH3)3], 23.05 (CH2), 18.01 [C(CH3)3], 17.51
(CH2), 16.89 (CH), 14.19 (OCH2CH3), 13.80 (CH3-21), –4.79
(SiCH3), –5.15 (SiCH3).
HRMS: m/z calcd for C17H24N4O3: 335.2081; found: 335.2083.
Ethyl 2-{(S)-2-[(1R,3aS,7aR,E)-4-((Z)-2-{(3S,5R)-3,5-Bis[(tert-
butyldimethylsilyl)oxy]-2-methylenecyclohexylidene}eth-
ylidene)-7a-methyloctahydro-1H-inden-1-yl]propyl}-2H-tetra-
zole-5-carboxylate (14)
To a solution of phosphine oxide 13 (5 mL, 0.19 M in THF) at –78
°C was added n-BuLi (0.23 mL of a 2.5 M solution in hexane, 0.59
mmol). The deep red mixture was stirred for 2 h at –78 °C in the
dark. A solution of ketone 12 (82 mg, 0.24 mmol) in anhyd THF (2
mL) was then added via a canula. The mixture stirred at –78 °C for
5 h in the dark, quenched with aq NH4Cl (a few drops) and extracted
with EtOAc (2 × 20 mL). The combined organic phases were
washed with sat. aq NaHCO3 (2 × 10 mL). After solvent evapora-
tion, the residue was chromatographed on silica gel using 5–10%
EtOAc–hexane as eluent to afford 22 mg (13%) of 14; colorless oil;
Rf = 0.45 (50% EtOAc–hexane).
LRMS: m/z (%) = 451.23 [M+ + 1, (100)], 393.15 (14), 319.13 (8),
177.76 (27), 175.15 (9), 171.11 (11), 154.08 (14).
HRMS: m/z calcd for C23H43N4O3Si: 451.3106; found: 451.3104.
1H NMR (CDCl3): d = 6.22 and 6.02 (2 H, AB, J = 11.2 Hz, H-6 and
7), 5.17 (1 H, d, J = 1.67 Hz, H-19), 4.85 (1 H, d, J = 2.3 Hz, H-19),
4.67 (1 H, dd, J = 3.7, 9.5 Hz, H-22), 4.52 (2 H, q, J = 7.1 Hz,
CH2OAc), 4.44 (1 H, dd, J = 3.9, 9.17 Hz, H-22), 4.35 (1 H, m, H-
1), 4.17 (1 H, m, H-3), 2.80 (1 H, m), 2.44 (1 H, m), 2.19 (2 H, m),
2.03 (3 H, m), 1.95 (2 H, m), 1.66 (3 H, m), 1.45 (3 H, t, J = 7.1 Hz,
OCH2CH3), 1.30 (5 H, m), 0.86 (18 H, s, CH3-t-BuSi), 0.57 (3 H, s,
H-18), 0.05 (12 H, s, SiCH3).
13C NMR (CDCl3): d = 157,94 (C=O), 157.64 (NC=N), 148.16 (C-
10), 139.97 (C-8), 135.53 (C-5), 122.90 (CH-6), 118.36 (CH2-19),
72.06 (CH-1 or 3), 67.45 (CH-1 or 3), 62.69 (OCH2CH3), 59.44
(CH2-22), 55.92 (CH2), 53.87 (CH), 46.00 (CH2), 44.72 (CH2),
40.26 (CH2), 37.86 (CH), 28.69 (CH), 27.39 (CH2), 25.83
[C(CH3)3], 25.78 [C(CH3)3], 23.26 (CH2), 22.20 (CH2), 18.21
[C(CH3)3], 18.51 [C(CH3)3], 17.03 (CH3-21), 14.18 (OCH2CH3),
12.06 (CH3-18), –4.70 (SiCH3), –4.72 (SiCH3), –4.82 (SiCH3),
–5.08 (SiCH3).
Ethyl 2-{(S)-2-[(3R,3aR,7S,7aR)-Octahydro-7-hydroxy-3a-
methyl-1H-inden-3-yl]propyl}-2H-tetrazole-5-carboxylate (11)
To a solution of tetrazole 10 (0.13 g, 0.29 mmol) in anhyd MeCN
(15 mL) was added 48% aq HF (34 drops) and the mixture stirred at
r.t. for 3 h. Sat. aq NaHCO3 (14 mL) was added and the mixture
stirred for 40 min and extracted with Et2O (3 × 30 mL). The com-
bined organic phases were washed with brine (2 × 30 mL) and dried
(Na2SO4). After solvent evaporation, the residue was chromato-
graphed on silica gel using 30% EtOAc–hexane as eluent to afford
93 mg (93%) of alcohol 11; yellowish oil; Rf = 0.30 (35% EtOAc–
hexane).
1H NMR (CDCl3): d = 4.63 (1 H, dd, J = 3.8, 9.4 Hz, H-22), 4.50 (2
H, q, J = 7.1 Hz, OCH2CH3), 4.41 (1 H, dd, J = 4.0, 9.17 Hz, H-22),
4.05 (1 H, d, J = 2.47 Hz, H-8), 2.18 (1 H, m, H-14), 1.96 (2 H, m),
1.88 (2 H, m), 1.78 (1 H, m), 1.64 (4 H, m), 1.60 (3 H, t, J = 7.0 Hz,
OCH2CH3), 1.35 (1 H, m), 1.22 (2 H, m), 0.94 (3 H, s, H-18), 0.80
(3 H, d, J = 6.6 Hz, H-21).
13C NMR (CDCl3): d = 157.86 (C=O), 157.55 (NC=N), 68.83 (CH-
8), 62.54 (OCH2CH3), 59.29 (CH2-22), 53.98 (CH), 52.23 (CH),
42.17 (C-13), 40.06 (CH2), 40.06 (CH2), 36.92 (CH3-18), 33.47
(CH2), 26.78 (CH2), 22,48 (CH2), 17.23 (CH2), 16.73 (CH), 14.09
(OCH2CH3), 13.54 (CH3-21).
LRMS: m/z (%) = 336.22 [M+ + 1, (66)], 318.45 (23), 291.36 (15),
176.25 (24), 150.82 (13).
LRMS: m/z (%) = 699.49 [M+ + 1, (15)], 698.48 [M+, (14)], 567.41
(48), 379.25 (17), 248.16 (100), 221.13 (28), 207.09 (23).
HRMS: m/z calcd for C38H67N4O4Si2: 699.4724; found: 699.4701.
(1R,3S,5Z)-5-[(E)-2-((1R,3aS,7aR)-Hexahydro-1-{(S)-1-[5-(2-
hydroxypropan-2-yl)-2H-tetrazol-2-yl]propan-2-yl}-7a-meth-
yl-1H-inden-4(7aH)-ylidene)ethylidene]-4-methylenecyclohex-
ane-1,3-diol (3) (Wittig–Horner Method)
To a solution of alcohol 14 (13 mg, 0.02 mmol) in anhyd Et2O (1
mL) at 10 °C was added MeLi (0.06 mL, 1.5 M). The mixture was
stirred at this temperature in the dark for 5 h 30 min, then quenched
with H2O (few drops), and extracted with EtOAc (2 × 10 mL).The
combined organic phases were washed with H2O (10 mL) and dried
(Na2SO4). Filtration and solvent evaporation afforded a residue,
which was dissolved in anhyd THF (5 mL). TBAF (0.2 mL, 1.0 M)
HRMS: m/z calcd for C17H28N4O3: 336.2204; found: 336.2217.
Ethyl 2-{(S)-2-[(3R,3aR,7aR)-Octahydro-3a-methyl-7-oxo-1H-
inden-3-yl]propyl}-2H-tetrazole-5-carboxylate (12)
To a solution of alcohol 11 (101 mg, 0.30 mmol) in anhyd CH2Cl2
(5 mL) were added 4 Å molecular sieves (188 mg), NMO (73 mg,
0.64 mmol), and TPAP (catalytic amount). The reaction mixture
Synthesis 2011, No. 23, 3887–3893 © Thieme Stuttgart · New York

PAPER
Vitamin D Heterocyclic Analogues
3891
was added and the mixture stirred for 12 h at r.t., then quenched with
aq NH4Cl (1 mL), and extracted with EtOAc (2 × 10 mL). The com-
bined organic phases were washed with sat. aq NH4Cl (2 × 20 mL).
After drying (Na2SO4) and solvent evaporation, the residue was
chromatographed on silica gel using 20% EtOAc–hexane as eluent
to afford 12 mg (95%) of 3; colorless oil; Rf = 0.15 (30% EtOAc–
hexane).
Ethyl 2-{(S)-2-[(1R,3aS,7aR,E)-4-((E)-2-{(3S,5R)-3,5-Bis[(tert-
butyldimethylsilyl)oxy]-2-methylenecyclohexylidene}eth-
ylidene)-7a-methyloctahydro-1H-inden-1-yl]propyl}-2H-tetra-
zole-5-carboxylate (17) and Ethyl 1-{(S)-2-[(1R,3aS,7aR,E)-4-
((E)-2-{(3S,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-2-methyl-
enecyclohexylidene}ethylidene)-7a-methyloctahydro-1H-in-
den-1-yl]propyl}-1H-tetrazole-5-carboxylate (18)
To a solution of tosylate 16 (480 mg, 0.65 mmol) in anhyd DMF (6
mL) was added tetrazole salt 8 (430 mg, 2.62 mmol). The mixture
was heated at 70 °C for 8 h, then allowed to reach r.t., then quenched
with H2O (10 mL), and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (3 × 10 mL) and
dried (Na2SO4). The solvent was removed in vacuo and the crude
mixture was purified by flash column chromatography on silica gel
using 3% EtOAc–hexane to afford 418 mg of the mixture of tetra-
zoles 17 and 18 (93%).
1H NMR (CDCl3): d = 6.36 and 6.03 (2 H, AB, J = 11.1 Hz, H-6 and
7), 5.33 (1 H, br s, H-19), 4.99 (1 H, br s, H-19), 4.56 (1 H, dd,
J = 3.7, 9.5 Hz, H-22), 4.36 (1 H, br s, H-3 or 1), 4.33 (1 H, dd,
J = 4.1, 9.1 Hz, H-22), 4.22 (1 H, br s, H-1 or 3), 2.84 (1 H, m, H-
14), 2.81 (2 H, m), 2.31 (1 H, m), 2.06 (1 H, m), 2.01 (8 H, m), 1.62
[6 H, br s, (CH3)2COH], 1.26 (4 H, m), 0.91 (3 H, d, J = 6.3 Hz, H-
21), 0.60 (3 H, s, H-18).
13C NMR (CDCl3): d = 172.09 (NC=N), 147.65 (C-10), 142.21 (C-
8), 133.43 (C-5), 124.77 (CH-6), 117.48 (CH-7), 111.85 (CH2-19),
70.83 (CH-1 or 3), 68.69 (C–OH), 66.85 (CH-1 or 3), 58.64 (CH2),
56.01 (CH), 54.08 (CH), 46.10 (C-13), 45.26 (CH2), 42.88 (CH2),
40.23 (CH2), 37.66 (CH), 29.71 (CH3C–OH), 29.67 (CH3C–OH),
28.94 (CH2), 27.32 (CH2), 23.40 (CH2), 22.38 (CH2), 17.19 (CH3-
21), 12.10 (CH3-18).
17
White solid; mp 49–51 °C; Rf = 0.69 (30% EtOAc–hexane).
1H NMR (CDCl3): d = 6.38 (1 H, d, J = 11.3 Hz, H-6), 5.78 (1 H, d,
J = 11.3 Hz, H-7), 4.91 (1 H, s, H-19), 4.88 (1 H, s, H-19), 4.63 (1
H, dd, J = 3.6, 9.6 Hz, H-22), 4.47 (2 H, q, J = 7.1 Hz, OCH2CH3),
4.40 (2 H, m, H-1 and H-22), 4.16 (1 H, s, H-3), 2.77 (1 H, m), 2.45
(1 H, m), 2.22 (2 H, m), 2.05 (2 H, m), 1.55 (6 H, m), 1.39 (3 H, t,
J = 7.1 Hz, OCH2CH3), 1.15 (6 H, m), 0.85 (3 H, d, J = 7.4 Hz, H-
21), 0.83 (9 H, s, t-C4H9), 0.80 (9 H, s, t-C4H9), 0.54 (3 H, s, H-18),
0.00 (12 H, s, SiCH3).
LRMS: m/z (%) = 601.47 [M+ + 1, (5)], 505.42 (10), 410.27 (17),
394.29 (41), 282.15 (18), 264.12 (19), 250.11 (48).
HRMS: m/z calcd for C26H40N4O3: 457.3179; found: 457.3178.
Preparation of 3 by Calverley Method
13C NMR (CDCl3): d = 157.83, 157.59 (C=O, NC=N), 153.53 (C-
10), 142.06 (C-8), 135.92 (C-5), 121.39 (CH-6), 116.81 (CH-7),
106.56 (CH2-19), 70.06 (CH-1), 67.88 (CH-3), 67.12 (OCH2CH3),
59.30 (CH2-22), 55.97 (CH-14), 53.84 (CH-17), 46.09 (C-13),
43.83 (CH2), 40.10 (CH2), 37.32 (CH-20), 36.49 (CH2), 28.69
(CH2), 27.20 (CH2), 25.69 [C(CH3)3], 23.23 (CH2), 22.24 (CH2),
18.13 [C(CH3)3], 16.97 (CH3-18), 14.07 (OCH2CH3), 12.10 (CH3-
21), –4.98 (SiCH3).
(S)-2-[(1R,3aS,7aR,E)-4-((E)-2-{(3S,5R)-3,5-Bis[(tert-butyldi-
methylsilyl)oxy]-2-methylenecyclohexylidene}ethylidene)-7a-
methyloctahydro-1H-inden-1-yl]propyl 4-methylbenzene-
sulfonate (16)
To a solution of 15 (990 mg, 1.72 mmol) in pyridine (9 mL) at 0 °C
was added p-TsCl (660 mg, 3.44 mmol) and DMAP (cat.). The mix-
ture was stirred at this temperature for 9 h, quenched with aq NH4Cl
(10 mL), then allowed to reach r.t. The product was extracted with
EtOAc (3 × 15 mL). The combined organic phases were washed
with CuSO4 (3 × 20 mL). After drying (Na2SO4) and solvent evap-
oration, the residue was chromatographed on silica gel using 3%
EtOAc–hexane as eluent to afford 1.1 g (91%) of tosylate 16; white
solid; mp 50–53 °C; Rf = 0.87 (30% EtOAc–hexane).
LRMS: m/z (%) = 699.36 [(M + 1)+, (52)], 698.36 [M+, (53)],
697.36 [(M – 1)+, (60)], 567.31 (70), 301.12 (48), 251.1 (25),
248.12 (100).
HRMS: m/z calcd for C38H66N4O4Si2: 699.4701; found: 699.4724.
1H NMR (CDCl3): d = 7.72 (2 H, d, J = 8.2 Hz, Harom), 7.27 (2 H, d,
J = 8.0 Hz, Harom), 6.37 (1 H, d, J = 11.3 Hz, H-6), 5.74 (1 H, d,
J = 11.3 Hz, H-7), 4.91 (1 H, s, H-19), 4.88 (1 H, s, H-19), 4.48 (1
H, m, H-1), 4.45 (1 H, m, H-3), 3.92 (1 H, m, H-22), 3.90 (1 H, m,
H-22), 2.75 (1 H, m), 2.43 (1 H, m), 2.37 (3 H, s, ArCH3), 2.17 (1
H, m), 1.85 (3 H, m), 1.55 (5 H, m), 1.37 (3 H, m), 1.15 (3 H, m),
0.93 (3 H, d, J = 6.5 Hz, H-21), 0.84 (9 H, s, t-C4H9), 0.80 (9 H, s,
t-C4H9), 0.44 (3 H, s, H-18), 0.00 (12 H, s, SiCH3).
13C NMR (CDCl3): d = 154.00 (C-10), 144.97 (C-8), 142.92 (Carom),
136.09 (C-5), 133.60 (Carom), 130.17 (CHarom), 128.30 (CH-6),
121.98 (CH-7), 107.07 (CH2-19), 75.90 (CH2-22), 70.60 (CH-1),
67.20 (CH-3), 56.40 (CH-14), 52.62 (CH-17), 46.25 (C-13), 44.34
(CH2), 40.58 (CH2), 36.99 (CH-20), 36.93 (CH2), 29.23 (CH2),
27.31 (CH2), 26.33 [C(CH3)3], 26.28 [C(CH3)3], 26.20 [C(CH3)3],
23.78 (CH2), 22.60 (CH2), 22.03 (ArCH3), 18.63 [C(CH3)3], 18.45
[C(CH3)3], 17.39 (CH3-18), 12.37 (CH3-21), –4.36 (SiCH3), –4.47
(SiCH3), –4.50 (SiCH3).
18
White solid; mp 148–151 °C; Rf = 0.63 (30% EtOAc–hexane).
1H NMR (CDCl3): d = 6.38 (1 H, d, J = 11.1 Hz, H-6), 5.78 (1 H, d,
J = 11.5 Hz, H-7), 4.92 (1 H, s, H-19), 4.88 (1 H, s, H-19), 4.73 (1
H, dd, J = 3.1, 9.7 Hz, H-22), 4.47 (2 H, q, J = 7.0 Hz, OCH2CH3),
4.38 (2 H, m, H-1 and 22), 4.16 (1 H, m, H-3), 2.81 (1 H, m), 2.47
(1 H, m), 2.03 (1 H, m), 1.85 (6 H, m), 1.55 (5 H, m), 1.41 (3 H, t,
J = 7.0 Hz, OCH2CH3), 1.25 (3 H, m), 0.83 (9 H, s, t-C4H9), 0.80 (9
H, s, t-C4H9), 0.74 (3 H, d, J = 6.5 Hz, H-21), 0.52 (3 H, s, H-18),
0.00 (12 H, s, SiCH3).
13C NMR (CDCl3): d = 156.70 (C=O), 153.56 (C-10), 145.98
(NC=N), 142.29 (C-8), 135.89 (C-5), 121.52 (CH-6), 116.86 (CH-
7), 106.76 (CH2-19), 70.25 (CH-1), 67.19 (CH-3), 63.48
(OCH2CH3), 56.10 (CH-14), 54.74 (CH2-22), 54.43 (CH-17), 46.22
(C-13), 43.92 (CH2), 40.34 (CH2), 37.98 (CH-20), 36.63 (CH2),
28.83 (CH2), 27.08 (CH2), 25.85 [C(CH3)3], 23.35 (CH2), 22.37
(CH2), 18.24 [C(CH3)3], 16.48 (CH3-18), 14.04 (OCH2CH3), 12.11
(CH3-21), –4.75 (SiCH3).
LRMS: m/z (%) = 729.35 [(M + 1)+, (23)], 728.35 [M+, (22)],
727.34 [M+ – 1, (14)], 597.28 (32), 596.28 (46), 425.27 (35), 379.19
(16), 249.13 (47), 248.13 (100), 247.11 (33).
LRMS: m/z (%) = 699.41 [(M + 1)+, (26)], 698. 4 [M+, (22)], 697.40
[(M – 1)+, (25)], 566.33 (74), 435.23 (31), 301.11 (24), 275.0 (18),
249.12 (70), 248.12 (100), 229.08 (21), 217.09 (25), 209.12 (24).
HRMS: m/z calcd for C41H68O5Si2S: 729.4404; found: 729.4418.
HRMS: m/z calcd for C38H66N4O4Si2: 699.4701; found: 699.4702.
Synthesis 2011, No. 23, 3887–3893 © Thieme Stuttgart · New York

3892
Z. Gándara et al.
PAPER
2-(2-{(S)-2-[(1R,3aS,7aR,E)-4-((E)-2-{(3S,5R)-3,5-Bis[(tert-bu-
tyldimethylsilyl)oxy]-2-methylenecyclohexylidene}ethylidene)-
7a-methyloctahydro-1H-inden-1-yl]propyl}-2H-tetrazol-5-
yl)propan-2-ol (19) and 2-(1-{(S)-2-[(1R,3aS,7aR,E)-4-((E)-2-
{(3S,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-2-methylenecy-
clohexylidene}ethylidene)-7a-methyloctahydro-1H-inden-1-
yl]propyl}-1H-tetrazol-5-yl)propan-2-ol (20)
To a solution of the mixture of tetrazoles 17 and 18 (404 mg, 0.58
mmol) in Et2O (3 mL) at –10 °C was added MeLi (1.5 M, 2.0 mL,
2.89 mmol). The mixture was stirred at this temperature for 10 min,
then quenched with H2O (10 mL), and extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed with brine
(3 × 10 mL) and dried (Na2SO4). Filtration and solvent evaporation
gave a residue, which was chromatographed on silica gel using 5%
EtOAc–hexane as eluent, to afford 257 mg (65%) of tetrazole 19;
white solid; mp 41–43 °C; Rf = 0.38 (30% EtOAc–hexane)] and 107
mg (27%) of tetrazole 20; white solid; mp 63–65 °C; Rf = 0.22 (30%
EtOAc–hexane)].
mL), and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined extracts were washed with brine (3 × 10 mL), dried
(Na2SO4), and the solvent was evaporated. The resulting residue
was dissolved in CH2Cl2 (1 mL) and MeOH (5 mL), and catalytic
amounts of anthracene and Et3N were added. The mixture was irra-
diated with a lamp (200 W) for 2 h. The resulting mixture was then
diluted with CH2Cl2 (10 mL). The organic layer was washed with
brine (3 × 15 mL), and dried (Na2SO4). The solvent was removed in
vacuo and the crude mixture was purified by flash column chroma-
tography on silica gel using 50% EtOAc–hexane as eluent to afford
15.5 mg (88%) of tetrazole 3; white solid; mp 35–37 °C; Rf = 0.57
(EtOAc).
The spectral data were identical with that of 3 obtained by the
Wittig–Horner method (vide supra).
(1R,3S,5Z)-5-[(E)-2-((1R,3aS,7aR)-Hexahydro-1-{(S)-1-[5-(2-
hydroxypropan-2-yl)-1H-tetrazol-1-yl]propan-2-yl}-7a-meth-
yl-1H-inden-4(7aH)-ylidene)ethylidene]-4-methylenecyclohex-
ane-1,3-diol (4)
19
To a solution of tetrazole 20 (30 mg, 0.04 mmol) in anhyd THF (1.0
mL) was added TBAF (0.24 mL, 1.0 M, 0.24 mmol), and the mix-
ture stirred at r.t. for 48 h. The reaction was quenched with H2O (2
mL), and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined extracts were washed with brine (3 × 10 mL), dried
(Na2SO4), and the solvent was evaporated. The resulting residue
was dissolved in CH2Cl2 (1 mL) and MeOH (5 mL), and catalytic
amounts of anthracene and Et3N were added. The mixture was irra-
diated with a lamp (200 W) for 2 h. The resulting mixture was then
diluted with CH2Cl2 (10 mL). The organic layer was washed with
brine (3 × 15 mL) and dried (Na2SO4). The solvent was removed in
vacuo and the crude mixture was purified by flash column chroma-
tography on silica gel using 50% EtOAc–hexane as eluent, to afford
12.5 mg (71%) of tetrazole 4; white solid; mp 47–49 °C; Rf = 0.31
(10% MeOH–CH2Cl2).
1H NMR (CDCl3): d = 6.55 (1 H, d, J = 11.3 Hz, H-6), 5.89 (1 H, d,
J = 11.3 Hz, H-7), 5.12 (1 H, s, H-19), 4.97 (1 H, s, H-19), 4.56 (1
H, dd, J = 3.9, 9.4 Hz, H-22), 4.47 (1 H, m, H-1), 4.32 (1 H, m, H-
22), 4.15 (1 H, m, H-3), 2.77 (2 H, m), 2.15 (3 H, m), 2.00 (4 H, m),
1.77 (3 H, s, H-29 or 30), 1.74 (3 H, s, H-29 or 30), 1.55 (7 H, m),
1.20 (3 H, m), 0.84 (3 H, d, J = 6.5 Hz, H-21), 0.62 (3 H, s, H-18).
1H NMR (CDCl3): d = 6.43 (1 H, d, J = 11.5 Hz, H-6), 5.83 (1 H, d,
J = 11.4 Hz, H-7), 4.98 (1 H, s, H-19), 4.94 (1 H, s, H-19), 4.59 (1
H, m, H-1), 4.54 (1 H, dd, J = 3.9, 8.7 Hz, H-22), 4.33 (1 H, dd,
J = 3.9, 9.3 Hz, H-22), 4.22 (1 H, m, H-3), 2.77 (1 H, m), 2.55 (1 H,
m), 2.22 (1 H, m), 2.15 (1 H, m), 2.05 (2 H, m), 1.97 (2 H, m), 1.69
(6 H, s, CH3-29 and 30), 1.55 (6 H, m), 1.35 (3 H, m), 0.9 (3 H, d,
J = 7.7 Hz, H-21), 0.89 (9 H, s, t-C4H9), 0.60 (3 H, s, H-18), 0.06
(12 H, s, SiCH3).
13C NMR (CDCl3): d = 172.06 (NC=N), 153.65 (C-10), 142.39 (C-
8), 135.90 (C-5), 122.91 (CH-6), 116.85 (CH-7), 106.70 (CH2-19),
70.20 (CH-1), 68.70 (C-28), 67.23 (CH-3), 58.66 (CH2-22), 56.12
(CH-14), 54.11 (CH-17), 46.14 (C-13), 45.91 (CH2), 38.20 (CH-
20), 37.71 (CH2), 29.73 (CH3-29 or 30), 29.68 (CH3-29 or 30),
28.83 (CH2), 25.87 [C(CH3)3], 23.37 (CH2), 22.36 (CH2), 18.26
[C(CH3)3], 17.17 (CH3-18), 12.14 (CH3-21), –4.87 (SiCH3).
LRMS: m/z (%) = 685.79 [(M + 1)+, (64)], 684.81 [M+, (38)],
683.79 [(M – 1)+, (23)], 552 (66), 421.43 (50), 249.23 (68), 248.22
(100), 247.22 (37).
HRMS: m/z calcd for C38H68N4O3Si2: 685.4908; found: 685.4972.
20
13C NMR (CDCl3): d = 159.15 (NC=N), 151.62 (C-10), 144.32 (C-
8), 133.17 (C-5), 123.15 (CH-6), 116.33 (CH-7), 109.81 (CH2-19),
71.12 (CH-1), 69.57 (C-28), 65.94 (CH-3), 56.16 (CH-14), 54.80
(CH-17), 54.18 (CH2-22), 46.29 (C-13), 41.98 (CH2), 40.30 (CH2),
37.46 (CH-20), 36.76 (CH2), 30.59 (CH3-29 and 30), 29.68 (CH2),
28.97 (CH2), 27.08 (CH2), 23.38 (CH2), 23.38 (CH2), 22.39 (CH2),
16.79 (CH3-18), 12.26 (CH3-21).
1H NMR (CDCl3): d = 6.43 (1 H, d, J = 11.5 Hz, H-6), 5.83 (1 H, d,
J = 11.4 Hz, H-7), 4.98 (1 H, s, H-19), 4.94 (1 H, s, H-19), 4.59 (1
H, m, H-1), 4.54 (1 H, dd, J = 3.9, 8.7 Hz, H-22), 4.33 (1 H, dd,
J = 3.9, 9.3 Hz, H-22), 4.22 (1 H, m, H-3), 2.77 (1 H, m), 2.55 (1 H,
m), 2.22 (1 H, m), 2.15 (1 H, m), 2.05 (2 H, m), 1.97 (2 H, m), 1.69
(6 H, s, CH3-29 and 30), 1.55 (6 H, m), 1.35 (3 H, m), 0.9 (3 H, d,
J = 7.7 Hz, H-21), 0.89 (9 H, s, t-C4H9), 0.60 (3 H, s, H-18), 0.06
(12 H, s, SiCH3).
LRMS: m/z (%) = 457.19 [M+ + 1, (100)], 456.8 [M+, (10)], 455.18
[M+ – 1, (5)], 439.19 (17), 277.06 (11), 185.13 (93).
13C NMR (CDCl3): d = 172,06 (NC=N), 151.65 (C-10), 144.00 (C-
8), 133.38 (C-5), 122.91 (CH-6), 116.85 (CH-7), 106.70 (CH2-19),
70.20 (CH-1), 68.70 (C-28), 67.23 (CH-3), 58.66 (CH2-22), 56.12
(CH-14), 54.11 (CH-17), 46.14 (C-13), 45.91 (CH2), 38.20 (CH-
20), 37.71 (CH2), 29.73 (CH3-29 or 30), 29.68 (CH3-29 or 30),
28.83 (CH2), 25.87 [C(CH3)3], 23.37 (CH2), 22.36 (CH2), 18.26
[C(CH3)3], 17.17 (CH3-18), 12.14 (CH3-21), –4.87 (SiCH3).
LRMS: m/z (%) = 685.79 [(M + 1)+, (64)], 684.81 [M+, (38)],
683.79 [(M – 1)+, (23)], 552 (66), 421.43 (50), 249.23 (68), 248.22
(100), 247.22 (37).
HRMS: m/z calcd for C26H40N4O3: 457.3179; found: 457.3175.
Acknowledgment
This work was supported financially by the Spanish Ministry of
Foreign Affairs and Cooperation (PCI A/030052/10) and the Xunta
de Galicia (INCITE845B-2010/020, INCITE08PXIB314255PR).
The work of the NMR and MS divisions of the research support ser-
vices of the University of Vigo (CACTI) is also gratefully acknow-
ledged. Zoila Gándara thanks the Xunta de Galicia for an Angeles
Alvariño contract.
HRMS: m/z calcd for C38H68N4O3Si2: 685.4908; found: 685.4972.
Tetrazole 3 (Calverley Method)
References
To a solution of tetrazole 19 (30 mg, 0.04 mmol) in anhyd THF (1.0
mL) was added TBAF (0.24 mL, 1.0 M, 0.24 mmol), and the mix-
ture stirred at r.t. for 48 h. The reaction was quenched with H2O (2
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1995, 16, 200.
Synthesis 2011, No. 23, 3887–3893 © Thieme Stuttgart · New York

PAPER
(2) For general reviews on vitamin D chemistry and biology,
Vitamin D Heterocyclic Analogues
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Tetrahedron Lett. 2004, 45, 4619. (e) Sestelo, J. P.; de Uña,
O.; Mouriño, A.; Sarandeses, L. A. Synlett 2002, 719.
(f) Fernández-Gacio, A.; Mouriño, A. Eur. J. Org. Chem.
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see: (a) Vitamin D: Chemistry, Biology and Clinical
Applications of the Steroid Hormone; Norman, A. W.;
Bouillon, R.; Thomasset, M., Eds.; Vitamin D Workshop,
Inc.: Riverside (CA, USA), 1997. (b) Feldman, D.;
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1985, 98. (d) Dai, H.; Posner, G. H. Synthesis 1994, 1383.
(e) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
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