Stereoselective synthesis of 22-oxacalcitriol (OCT) and analogues modified at C25

Article abstract of DOI:10.1016/S0040-4039(01)02164-5

The stereoselective synthesis of 22-oxacalcitriol (OCT) has been achieved. The triene system was introduced using the Lythgoe-Hoffmann La Roche convergent Wittig-Horner approach to couple ketoester 7 with A ring phosphine oxide 8. The value of the resulting ester 6 for synthesis of C25-modified OCT analogues is exemplified by the synthesis of 5.

Full text of DOI:10.1016/S0040-4039(01)02164-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 427–429
Stereoselective synthesis of 22-oxacalcitriol (OCT) and
analogues modified at C25
Yagamare Fall,a,* Victoria Gonza´lez,a Beatriz Vidala and Antonio Mourin˜ob
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias. Universidad de Vigo, 36200 Vigo, Spain
bDepartamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 17 September 2001; accepted 13 November 2001
Abstract—The stereoselective synthesis of 22-oxacalcitriol (OCT) has been achieved. The triene system was introduced using the
Lythgoe–Hoffmann La Roche convergent Wittig–Horner approach to couple ketoester 7 with A ring phosphine oxide 8. The
value of the resulting ester 6 for synthesis of C25-modified OCT analogues is exemplified by the synthesis of 5. © 2002 Published
by Elsevier Science Ltd.
Vitamin D and its metabolites continue to attract a
great deal of interest owing to their potential for the
treatment of rickets, osteoporosis, psoriasis, renal
osteodystrophy, leukaemia, breast cancer, prostate can-
cer, Alzheimer’s disease and AIDS.1 1a,25-Dihydroxy-
vitamin D3 [1, 1a,25-(OH)2-D3, calcitriol], the hormon-
1a,25-dihydroxy-22-oxavitamin D3 (3, OCT)4 inhibits
the proliferation of certain cancers,5 is a potent
immunomodulator in vivo, and does not cause
hypercalcaemia.6
Surprisingly, although many synthetic approaches to
OCT have been developed,4,7 few OCT analogues have
been reported.7a,c This means that a synthesis of 3 that
is both convergent and flexible has been lacking.
2
ally active form of vitamin D3 (2a, cholecalcif-
erol), besides regulating the metabolism of calcium and
phosphorus, promotes cell differentiation, inhibits the
proliferation of tumour cells, and triggers certain bio-
logical functions related to the immunological system.3
However, the clinical utility of the hormone in the
treatment of cancers and skin disorders is limited by its
hypercalcaemic effects. Accordingly, chemists have pur-
sued the synthesis of analogues of 1 with high cell
differentiating ability and weak calcaemic effects;
known examples include 3 and 4 (Fig. 1). In particular,
We have previously published a method for construc-
tion of the 25-hydroxy-22-oxavitamin D3 side chain
that compares favourably with previous methods as
regards efficiency and rapidity.7b However, for the syn-
thesis of OCT analogues modified at C25 we needed to
develop another synthetic approach. This is outlined in
Scheme 1.
O
OH
O
OH
OH
H
H
H
H
HO
OH
HO
OH
HO
HO
OH
2a, R = H
1
3
4
2b, R = OH
Figure 1. The structures of 1a,25-dihydroxyvitamin D3 and some analogues with modified side chains.
* Corresponding author. Fax: 34 986 81 23 82; e-mail: yagamare@uvigo.es
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02164-5

428
Y. Fall et al. / Tetrahedron Letters 43 (2002) 427–429
OH
O
OH
CO2Et
O
R
O
CO2Et
OH
R
H
H
H
HO
TBSO
O
7
11
9
H
H
Ph2P(O)
HO
OH
CO2Et
TBSO
OTBS
10
3, R = Me
5, R = Ph
6
TBSO
OTBS
8
Scheme 1. Retrosynthetic plan.
The synthesis of key intermediate 6 is detailed in
Scheme 2. Diol 11 obtained by degradation of vitamin
affinity for VDR (0.5% that of calcitriol). Further
biological evaluation is currently underway.
8
D2 was converted to ester 12 using our previously
described procedure.7b Removal of the silyl protecting
group of 12 by reaction with HF in acetonitrile at room
temperature, gave alcohol 139 (90%). Finally, oxidation
of 13 with pyridinium dichromate afforded ketone 79
(95%), so setting the stage for the Wittig–Horner reac-
tion with phosphine oxide 8.10 This coupling reaction
between 7 and 8 created the labile triene unit, affording
key intermediate 611 in 93% yield.
In conclusion, we have developed a convergent synthe-
sis of key intermediate 6, which contains both the
vitamin D triene system and the OCT side chain skele-
ton. We are currently using compound 6 to prepare a
broad range of OCT analogues modified at C25 for
biological evaluation and SAR studies.
Acknowledgements
Reaction of 6 with MeLi at −78°C, followed by desily-
lation, afforded 22-oxacalcitriol (3)12 in good yield,
while its reaction with PhLi afforded the new OCT
derivative 5.13 Preliminary biological evaluation of this
new vitamin D3 analogue has shown it to have very low
This work was supported by a grant from the Vicerec-
torate for Research of the University of Vigo. We
thank the NMR service of the CACTI, University of
O
OH
O
CO2Et
CO2Et
ii
i
H
HO
H
H
TBSO
12
11
HO
13
O
OH
O
H
CO2Et
O
3
v
CO2Et
iii
H
iv
HO
OH
H
O
vi
6
O
7
OH
TBSO
OTBS
H
5
HO
OH
Scheme 2. Reagents and conditions: (i) see Ref. 7b; (ii) HF, CH3CN, rt (90%); (iii) PDC, CH2Cl2, rt (95%); (iv) 8; nBuLi, THF,
−78°C (93%); (v) (a) MeLi/THF, −78°C (80%) (b) nBu4NF, THF, rt (96%); (vi) (a) PhLi/THF, −78°C (b) nBu4NF, THF, rt
(73%).

Y. Fall et al. / Tetrahedron Letters 43 (2002) 427–429
429
1
Vigo, for NMR studies. We are also grateful to Solvay
Pharmaceuticals (Weesp, The Netherlands) for the gift
of starting materials.
[93%, Rf=0.72 (20% EtOAc/hexanes), colourless oil]. H
NMR (250 MHz, CD2Cl2): l 6.24 and 6.02 (2H, AB,
J=11.2, H-6 and 7), 5.18 (1H, br s, H-19), 4.83 (1H, br
s, H-19), 4.36 (1H, m), 4.17 (1H, m), 4.08 (2H, q, J=7.1,
OCH2
(1H, m), 2.44 (2H, t, J=6.3), 2.20 (1H, m), 1.22 (3H, t,
J=7.1, OCH2CH3), 1.12 (3H, d, J=6.01, CH3-21), 0.87
6 CH3), 3.78 (1H, m), 3.50 (1H, m), 3.25 (1H, m), 2.8
References
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(9H, s, t-BuSi), 0.86 (9H, s, t-BuSi), 0.48 (3H, s, CH3-18),
0.06 (6H, s Me2Si), 0.05 (6H, s, Me2Si); 13C NMR
(CD2Cl2): l 172.26 (CꢀO), 149.04 (Cꢀ), 141.24 (Cꢀ), 135.88
(Cꢀ), 123.55 (CHꢀ), 118.65 (CHꢀ), 111.59 (ꢀCH2), 78.54,
72.46, 68.05, 64.20 (CH2), 60.69 (CH2), 57.79, 56.63, 46.43
(CH2), 45.32 (CH2), 45.00 (C-13), 40.09 (CH2), 36.11
(CH2), 29.20 (CH2), 26.04 (CH3-tBu), 25.61 (CH2), 23.64
(CH2), 22.48 (CH2), 19.39, 18.54 (C), 18.43 (C), 14.44,
12.70, −4.57 (SiCH3), −4.68 (SiCH3), −4.92 (SiCH3).
HRMS calcd for C38H68O5Si2: 660.4605; found: 660.4622.
12. Compound 3 was prepared as follows: To a solution of 6
(50 mg, 0.076 mmol) in THF (3 ml) at −78°C was added
MeLi (0.142 ml, 0.228 mmol, 1.6 M in ether). The mixture
was stirred at −78°C for 1 h and allowed to reach room
temperature. The mixture was quenched with aqueous
NH4Cl solution and extracted with ether. The etheral
extracts were dried, filtered, and concentrated in vacuo.
The residue was dissolved in THF (3 ml) and treated with
tetrabutylammonium fluoride (1.5 ml, 1.5 mmol, 1 M in
THF). The mixture was stirred in the dark at rt overnight
and concentrated in vacuo. Flash chromatography of the
concentrate (1% EtOAc/hexanes) afforded 24 mg of 3 [77%
1
from 6, Rf=0.27 (20% EtOAc/hexanes)]. H NMR (300
MHz, CDCl3): l 6.31 and 5.98 (2H, AB, J=11.2, H-6 and
7), 5.28 (1H, br s, H-19), 4.94 (1H, br s, H-19), 4.38 (1H,
dd, J=7.4, 4.3, H-1), 4.17 (1H, m, H-3), 3.8 (1H, dt, J=9.2,
5.5, H-23), 3.44 (1H, dt, J=9.2, 5.5, H-23), 3.21 (1H, m,
H-20), 2.79 (1H, dd, J=12.1, 3.9, H-14), 2.55 (1H, m, H-9),
1.2 (6H, s, CH3-26 and CH3-27), 1.16 (3H, d, J=6.0,
CH3-21), 0.50 (3H, s, CH3-18); 13C NMR (CDCl3): l
147.58 (C-10), 142.33 (C-8), 133.23 (C-5), 124.79 (CH-6),
117.44 (CH-7), 111.91 (CH2-19), 78.74 (CH-20), 70.83
(CH-1), 70.52 (C-25), 66.82 (CH-3), 65.55 (CH2-23), 57.08
(CH-17), 56.06 (CH-14), 45.27 (CH2-4), 44.79 (C-13), 42.80
(CH2-2), 41.47 (CH2-24), 39.54 (CH2-12), 29.24 (CH3-26),
29.10 (CH3-27), 28.92 (CH2-9), 25.60 (CH2-16), 23.23
(CH2-11), 22.20 (CH2-15), 18.85 (CH3-21), 12.63 (CH3-18);
LRMS: m/z (I, %): 418 (M+, 21), 400 (11), 382 (31), 364
(10), 314 (20), 296 (19), 278 (13), 134 (73), 59 (84), 45 (100).
13. Compound 5 was prepared according to the same proce-
dure as above using PhLi (2 M in cyclohexane–Et2O)
instead of MeLi. [73% from 6, Rf=0.23 (40% EtOAc/hex-
anes)]. 1H NMR (300 MHz, CDCl3): l 7.15–7.45 (10H, m,
Ar), 6.35 and 6.02 (2H, AB, J=11.2, H-6 and 7), 5.33 (1H,
br s, H-19), 4.99 (1H, br s, H-19), 4.42 (1H, m), 4.22 (1H,
m), 3.68 (1H, m), 3.37 (1H, m), 3.11 (1H, m), 2.81 (1H, m),
1.02 (3H, d, J=6.0, CH3-21), 0.47 (3H, s, CH3-18)); 13C
NMR (CDCl3): l 147.59 (Cꢀ), 147.04 (Cꢀ), 142.30 (Cꢀ),
133.28 (Cꢀ), 128.47 (CHꢀ), 128.03 (CHꢀ), 126.52 (CHꢀ),
124.79 (CHꢀ), 117.48 (CHꢀ), 111.94 (CH2ꢀ), 78.83 (C-25),
77.23, 70.85, 66.83, 65.67 (CH2), 57.02, 56.07, 45.27 (CH2),
44.79 (C-13), 42.82 (CH2), 40.21 (CH2), 39.51 (CH2), 28.92
(CH2), 25.38 (CH2), 23.22 (CH2), 22.23 (CH2), 18.73, 12.58.
HRMS calcd for C36H46O4: 542.3396; found: 542.3412.
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11. Compound 6 was prepared as follows: A solution of
n-BuLi (2.25 M in hexane, 0.199 mL, 0.448 mmol) was
added dropwise via syringe to a solution of the phosphine
oxide 8 (0.436 mmol, 4.3 mL, 0.1 M) at −78°C. The
resulting deep red solution was stirred at −78°C for 1 h
followed by the slow addition of the ketone 7 (100 mg,
0.242 mmol) in THF (2 ml). The red solution was stirred
in the dark at −78°C for 3 h and then warmed to −40°C
over 2 h. The reaction was quenched with H2O. The
mixture was extracted with Et2O and the combined organic
fractions were washed with brine, dried, filtered, and
concentrated in vacuo. The residue was flash chro-
matographed (2% EtOAc/hexanes) to give 149 mg of 6