Stereoselective synthesis of (22R)- and (22S)-22-methyl-1α,25-dihydroxy-vitamin D3

Article abstract of DOI:10.1055/s-2001-17446

An efficient, straightforward method for construction of the side chain of (22R)- and (22S)-22-alkyl-1α,25-dihydroxyvitamin D₃ is described. The title compounds were synthesized by Lythgoe's procedure.

Full text of DOI:10.1055/s-2001-17446

LETTER
1567
Stereoselective Synthesis of (22R)- and (22S)-22-Methyl-1 ,25-Dihydroxy-
vitamin D3
Stereoselective
Sy
a
nthesis of
(
g
R
)- and (2
a
2
S
)
-22-Me
t
m
hyl-1 ,25-Dihydrox
a
yvitamin re Fall,*a Carlos Fernandez,a Victoria González,a Antonio Mouriñob
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Ponte vedra, Spain
Fax +34(986)812382; E-mail: yagamare@uvigo.es
b
Departamento de Quimica Orgánica y Unidad Asociada al CSIC, Universidad de Santiago de Compostela, 15782 Santiago
de Compostela, Spain
Received 19 July 2001
2a and 2b, based on the retrosynthetic analysis depicted in
Scheme 1.
Abstract: An efficient, straightforward method for construction of
the side chain of (22R)- and (22S)-22-alkyl-1 ,25-dihydroxyvita-
min D3 is described. The title compounds were synthesized by Lyth-
goe’s procedure.
The synthesis of the key precursors bearing the 22 substi-
tuted side chains 7a and 7b is detailed in Scheme 2. Nitrile
Key words: 1 ,25-dihydroxyvitamin D3, stereoselective synthesis, 5,7 readily obtained from the Inhoffen–Lythgoe diol 8,
alkylations, nitriles, 22-substituted analogue
was deprotonated with 2 equivalents of LDA in THF at –
78 °C, a solution of bromide 48 in THF was added, and the
mixture was allowed to reach room temperature over-
night, affording the cyanoalcohol 99 (89%) as a mixture of
It is now well established that regulation of gene tran-
inseparable diastereoisomers. Reaction of 9 with DIBAH
in dichloromethane at –10 °C and subsequent acid work-
up afforded the corresponding aldehyde, which was taken
up in methanol and reacted with excess sodium borohy-
dride, giving a 2:1.5 mixture of alcohols 10 and 11. These
colorless oils were cleanly separated by flash chromatog-
raphy (15% EtOAc–hexanes) in yields of 40 and 24%, re-
spectively; the stereochemistry at C22 was determined by
X-ray crystallographic analysis of the triol resulting from
deprotection of the TES group of diol 10.9
scription is among the mechanisms of action of 1 ,25-di-
hydroxyvitamin D3 (calcitriol, 1) (Figure), the hormonally
1
active metabolite of vitamin D3. This multifunctional
hormone2 controls the expression of various genes in-
volved in calcium and phosphorus metabolism, cell differ-
entiation and regulation of the immune system,3
apparently by binding to the nuclear vitamin D receptor
(VDR)4.
R1 R2
R2
R1
Selective tosylation of the primary alcohols of 10 and 11
gave the corresponding tosylates 12 and 13 in 82% and
76% yield, respectively,10 and treatment of these tosylates
with LAH in ether at 0 °C to room temperature afforded
the 22-methylated alcohols 14a and 14b in 80% and 84%
yield, respectively. Pyridinium dichromate oxidation of
alcohols 14a and 14b then afforded the ketones 15a and
15b in 90% and 91% yield, respectively, so setting the
stage for the Wittig–Horner reaction with phosphine ox-
ide 6.11 This coupling reaction, followed by removal of the
silyl protecting groups, finally afforded the targets
2a12and 2b13 in 72% and 75% yield, respectively. In con-
clusion, we have developed a convergent route to (22R)-
OH
HO
OH
H
H
H
HO
OH
HO
OH
HO
OH
3a : R1 = Me, R2 = H
3b : R1 = H, R2 = Me
2a : R1 = Me, R2 = H
2b : R1 = H, R2 = Me
1
Figure
It is of crucial importance to find out the conformation
that calcitriol must adopt in order to bind to VDR and to
the equally vital transport protein, vitamin D binding pro-
tein (DBP). To that end, Yamada et al.5,6 designed and
synthesized analogues 2a, 2b, 3a and 3b. Structure-func-
tion studies of these compounds then showed that they are
not only useful for studying calcitriol binding, but may
also prove to be of therapeutical value. Yamada’s synthe-
sis of 2 and 3 was based on the stereoselective conjugate
addition of organocuprate to steroidal E- and Z-22-en-24-
ones, and suffers from the usual drawbacks of biomimetic
approaches. Here we describe a convergent synthesis of
R2
R1
R2
OTES
R1
CN
OH
H
O
7
H
H
HO
5
Ph2P(O)
Br
OTES
HO
OH
4
TBSO
OTBS
2a : R1 = Me, R2 = H
2b : R1 = H, R2 = Me
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1567,1568,ftx,en;D16801st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
6
Scheme 1

1568
Y. Fall et al.
LETTER
References and Notes
CN
OH
CN
(1) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. Rev.
1995, 16, 200.
(2) Reichel, H.; Koeffler, H. P.; Norman, A. W. N. Engl. J. Med.
1989, 320, 980.
OTES
i
ii
H
H
8
H
5
HO
HO
9
HO
OH
(3) Feldman, D.; Glorieux, F. H.; Pike, J. W. Vitamin D;
Academic Press: San Diego, 1997.
OH
(4) (a) Minghetti, P. P.; Norman, A. W. FASEB J. 1988, 2,
3043. (b) Deluca, H. F.; Krisinger, J.; Darwish, H. Kidney
Int. (Suppl.) 1990, 29S, 2.
(5) Yamamoto, K.; Takahashi, J.; Hamano, K.; Yamada, S.;
Yamaguchi, K.; Deluca, H. F. J. Org. Chem. 1993, 58, 2530.
(6) Yamamoto, K.; Yan Sun, W.; Ohta, M.; Hamada, K.;
Deluca, H. F.; Yamada, S. J. Med. Chem. 1996, 39, 2727.
(7) Fall, Y.; Torneiro, M.; Castedo, L.; Mouriño, A.
Tetrahedron 1997, 53, 4703.
OTES
OTES
iii
+
11
H
10
H
HO
HO
R2
R1
OTs
OTs
OTES
+
iv
OTES
OTES
12
H
13
14
HO
(8) Andrews, D. R.; Barton, D. H. R.; Hesse, R. H.; Pechet, M.
M. J. Org. Chem. 1986, 51, 4819.
a, R1 = Me, R2 = H
b, R1 = H, R2 = Me
R2
R1
(9) Fall, Y.; Fernandez, C.; Vitale, C.; Mouriño, A. Tetrahedron
Lett. 2000, 41, 7323.
OTES
vi
v
(10) All new compounds exhibited satifactory 1H and 13C NMR
spectra, analytical, and/or high resolution mass spectra.
(11) Mouriño, A.; Torneiro, M.; Vitale, C.; Fernandez, S.; Perez-
Sestelo, J.; Anne, S.; Gregorio, C. Tetrahedron Lett. 1997,
33, 4713.
2a, 2b
H
O
15
Scheme 2 (i) LDA, THF, –78 °C; 4 (89%); (ii) DIBAH, CH2Cl2, –
10 °C; HCl; NaBH4, MeOH (64% global yield 10+11, two steps); (iii)
TsCl, Pyr, 0 °C, 12 h; (iv) LiAlH4, Et2O, 0 °C to r.t.; (v) PDC, CH2Cl2,
r.t. 5 h; (vi) (a) 6; n-Buli, THF, –78 °C; (b) n-Bu4NF, THF, r.t.
(12) Compound 2a: 1H NMR (300 MHz, CDCl3), : 6.37 (1 H, d,
J = 11.20 Hz, H-6 or 7), 6.01 (1 H, d, J = 11.27 Hz, H-6 or
7), 5.32 (1 H, d, J = 1.47 Hz, H-19), 4.99 (1 H, s, H-19), 4.42
(1 H, dd, J = 7.76 and J = 4.21 Hz, H-1), 4.22 (1 H, m, H-3),
2.60 (1 H, m), 2.31 (1 H, m), 1.25 (3 H, s, CH3-26 or 27),
1.20 (3 H, s, CH3-26 or 27), 0.78 (3 H, d, J = 5.96 Hz, CH3-
22), 0.72 (3 H, d, J = 6.72 Hz, CH3-21), 0.54 (3 H, s, CH3-
18); 13C NMR (CD2Cl2), : 147.67 (C-10), 143.18 (C-8),
132.90 (C-5), 124.96 (CH-6), 117.00 (CH-7), 111.70 (CH2-
19), 71.12 (C-25), 70.78 (CH-3), 66.83 (CH-1), 56.37, 54.20
(CH),45.99 (C-13), 45.25, 42.87, 42.17, 40.62 (CH2), 39.00,
35.01 (CH), 30.25 (CH2), 29.67 and 29.27 (CH3-26 and 27),
29.10, 27.24, 23.62, 22.15 (CH2), 13.09 (CH3-18 or 21),
12.49 (CH3-22), 11.93 (CH3-18 or 21).
and (22S)-22-methyl-1 ,25-dihydroxyvitamin D3.14 The
new method is valid for multigram quantities and should
allow convergent synthesis of a large number of vitamin
D3 analogues with restricted side chain conformations.
Work is in progress for the synthesis of a series of such an-
alogues.
Acknowledgement
(13) Compound 2b: 1H NMR (300 MHz, CDCl3), : 6.38 (1 H, d,
J = 11.10 Hz, H-6 or 7), 6.03 (1 H, d, J = 11.15 Hz, H-6 or
7), 5.32 (1 H, s, H-19), 5.00 (1 H, s, H-19), 4.42 (1 H, m, H-
1), 4.23 (1 H, m, H-3), 2.84 (1 H, m)2.60 (1 H, m), 2.31 (1
H, m), 1.22 (3 H, s, CH3-26 or 27), 1.21 (3 H, s, CH3-26 or
27), 0.87 (3 H, d, J = 6.72 Hz, CH3-22), 0.72 (3 H, d,
J = 6.74 Hz, CH3-21), 0.54 (3 H, s, CH3-18); 13C NMR
(CD2Cl2), : 147.66 (C-10), 143.28 (C-8), 132.83 (C-5),
125.03 (CH-6), 116.97 (CH-7), 111.75 (CH2-19), 71.23 (C-
25), 70.83 (CH-3), 66.88 (CH-1), 56.31, 54.20 (CH),45.91
(C-13), 45.27, 42.87, 42.80 (CH2), 41.85 (CH), 40.58 (CH2),
35.21 (CH), 29.69 (CH2), 29.58 and 29.13 (CH3-26 and 27),
29.05, 27.38, 23.60, 22.20 (CH2), 18.95 (CH3-22), 13.17 and
11.93 (CH3-18 and 21).
We are grateful to the DGES (Spain, project PM97-0166) for finan-
cial support and to Solvay Pharmaceuticals (Weesp, The Nether-
lands) for the gift of starting materials.
(14) A few mgs of compounds 2a and 2b are available upon
request.
Synlett 2001, No. 10, 1567–1568 ISSN 0936-5214 © Thieme Stuttgart · New York