d- and l-Serine, useful synthons for the synthesis of 24-hydroxyvitamin D3 metabolites. A formal synthesis of 1α,24R,25-(OH)3-D3, 24R,25-(OH)2-D3 and 24S,25-(OH)2-D3

Article abstract of DOI:10.1016/j.tetlet.2007.02.027

d- and l-Serine have been used for the enantioselective synthesis of tosylates 7a and 7b, useful building blocks for the synthesis of triols 5a and 5b which have already been obtained via a diastereoselective synthesis and used for the synthesis of 2a, 2b and 2c. We have thus performed a formal synthesis of 24S,25-(OH)₂-D₃, 24R,25-(OH)₂-D₃ and 1α,24R,25-(OH)₃-D₃.

Full text of DOI:10.1016/j.tetlet.2007.02.027

Tetrahedron Letters 48 (2007) 2939–2942
D- and L-Serine, useful synthons for the synthesis of
24-hydroxyvitamin D3 metabolites. A formal synthesis
of 1a,24R,25-(OH)3-D3, 24R,25-(OH)2-D3 and 24S,25-(OH)2-D3
a
a
a
´
´
Carlos Fernandez, Zoila Gandara, Generosa Gomez,
Berta Covelob and Yagamare Falla,*
aDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
bServicio Determinacio´n Estructural y Proteo´mica, CACTI, Universidad de Vigo, 36310 Vigo, Spain
Received 16 January 2007; revised 31 January 2007; accepted 7 February 2007
Available online 13 February 2007
Abstract—D- and L-Serine have been used for the enantioselective synthesis of tosylates 7a and 7b, useful building blocks for the
synthesis of triols 5a and 5b which have already been obtained via a diastereoselective synthesis and used for the synthesis of 2a,
2b and 2c. We have thus performed a formal synthesis of 24S,25-(OH)2-D3, 24R,25-(OH)2-D3 and 1a,24R,25-(OH)3-D3.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1a,25-Dihydroxyvitamin D3 (1a, calcitriol) (Fig. 1) is the
hormonally active form of vitamin D3 (1b). Besides
regulating calcium homeostasis, it is also involved in other
cellular processes, including cell differentiation, immune
system regulation and gene transcription.1 The latter
function, mediated by the nuclear vitamin D receptor
(found in more than thirty different tissues and cancer cell
lines), raises the possibility of developing 1a,25-(OH)2-
D3 analogues for specific therapeutic applications.
min D3 (1b). However, the biological activity of vitamin
D has generally been attributed to calcitriol leaving
secalciferol’s functions relatively unexplored. In the last
25 years, a great deal of effort has been devoted to the
elucidation of the biological function of secalciferol,
and as a consequence more than 350 papers have been
published about the biological activity of this metabo-
lite.2 Most of the available syntheses of secalciferol use
the lengthy and less efficient steroidal biomimetic route,3
and consequently the price of secalciferol is rather
high (450 €/lg). Recently, Sarandeses and co-workers
described a stereoselective convergent synthesis of
1a,25-(OH)2-D3 (1a, calcitriol) and 24R,25-(OH)2-D3
(2a, secalciferol) are the major active metabolites of vita-
R1
R2
R2
OH
H
H
2a: R = R1 = H; R2 = OH; 24R,25-(OH)2-D3
2b: R = R2 = H; R1 = OH; 24S,25-(OH)2-D3
2c: R = R2 = OH; R1 = H; 1α,24R,25-(OH)3-D3
1a, R1 = R2 = OH
1b, R1 = R2 = H
HO
R1
HO
R
1
2
Figure 1.
Keywords: Vitamin D; Calcitriol; Secalciferol; Aminoacid; Enantioselective synthesis.
*
Corresponding author. Fax: +34 986 81 22 62; e-mail: yagamare@uvigo.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.027

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C. Fernandez et al. / Tetrahedron Letters 48 (2007) 2939–2942
24-substituted metabolites and analogues of vitamin D
in which the stereogenic centre at C-24 was generated
through ultrasonically induced conjugate addition of
an iodide to a dioxolanone4 (Scheme 1).
R2 R1
I
R2 R1
24
OH
24
OH
4
H
HO
H
H
+
HO
O
O
5a: R1 = H; R2 = OH
5b: R1 = OH; R2 = H
O
O
HO
R
O
O
2a: R = R1 = H; R2 = OH; 24R,25-(OH)2-D3
2b: R = R2 = H; R1 = OH; 24S,25-(OH)2-D3
(-)-3
(+)-3
2c: R = R2 = OH; R1 = H; 1α,24R,25-(OH)3-D3
Scheme 1.
CN
R2 R1
OH
8
H
HO
R2 R1
H
HO
R2 R1
HO
COOH
TsO
5a: R1 = H; R2 = OH
5b: R1 = OH; R2 = H
OH
6a: R1 = H; R2 = NH2
6b: R1 = NH2; R2 = H
7a: R1 = H; R2 = OH
7b: R1 = OH; R2 = H
Scheme 2. Retrosynthetic analysis for 5a and 5b.
R2 R1
R2 R1
HO
NaNO2, H2SO4, H2O, -5 ºC
47%
MeOH, HCl gas
94%
HO
COOH
COOH
9a: R1 = H; R2 = OH
9b: R1 = OH; R2 = H
6a: R1 = H; R2 = NH2
6b: R1 = NH2; R2 = H
O
O
COOMe
R2 R1
MeLi, Et2O
-78 ºC
Me2C(OMe)2, H2SO4, Acetone
11a
HO
COOMe
O
10a: R1 = H; R2 = OH
10b: R1 = OH; R2 = H
17% from 9
(3 steps)
O
COOMe
11b
O
O
R2 R1
HO
p-TsCl, pyr, 0 ºC to rt
70%
OH
OH
12a
AcOH 5%, 60-65 ºC
89%
O
13a: R1 = H; R2 = OH
13b: R1 = OH; R2 = H
O
OH
12b
OH
OH
TsO
TsO
7a
OH
OH
7b
Scheme 3. Synthesis of tosylates 7a and 7b.

C. Fernandez et al. / Tetrahedron Letters 48 (2007) 2939–2942
2941
This approach clearly improves the so far available syn-
theses of secalciferol, but since it is a diastereoselective
approach (5a and 5b are obtained as a mixture of diaste-
reoisomers albeit with a high de), this means that an
enantioselective, flexible and convergent synthesis of
secalciferol is still in need. In Scheme 2 is depicted the
enantioselective synthesis of 5a and 5b from commer-
cially available amino acids D- and L-serine 6a and 6b
and nitrile 8.5
11b with methyllithium afforded alcohols 12a and 12b,
which on reaction with acetic acid gave triols 13a and
13b. Selective tosylation of 13a and 13b afforded the
desired tosylates 7a and 7b (the yields obtained for both
enantiomers were similar).
It is worth mentioning that the first step of this reaction
sequence occurs with retention of configuration as
depicted in the following mechanism (Scheme 4).5
Tosylates 7a and 7b were obtained as depicted in
Scheme 3. Nitrous desamination of 6a and 6b gave acids
9a and 9b which were esterified using methanol and HCl
gas to provide ester diols 10a and 10b, which were pro-
tected as acetonides 11a and 11b. Reaction of 11a and
With tosylates 7a and 7b in hand, the stage was set for
their coupling with nitrile 8 using our previously de-
scribed methodology.6 Nitrile 8 was deprotonated with
2 equiv of LDA in THF at À78 ꢁC and reacted with
tosylates 7a and 7b to afford a diastereoisomeric mixture
-
O
OH
OH
O
R
HNO2
SN2
SN2
R
R
R
O
O
O
O
H
Inversion
H
H
+
N2
H
HO
H2N
Inversion
H2O:
16
14
17
15
Scheme 4. Reaction mechanism of a-amino acids with HNO2.
NC
R2 R1
CN
OH
K, HMPA
LDA / THF
t-BuOH
Et2O, 0 ºC
R2 R1
8
H
H
HO
HO
TsO
18a: R1 = H; R2 = OH (62%)
18b: R1 = OH; R2 = H (45%)
OH
7a: R1 = H; R2 = OH
7b: R1 = OH; R2 = H
OH
OH
OH
OH
5b
5a
H
H
HO
HO
Scheme 5. Synthesis of triols 5a and 5b from nitrile 8.
Figure 2. X-ray structure of 5b.

2942
C. Fernandez et al. / Tetrahedron Letters 48 (2007) 2939–2942
Y.; Taguchi, T. Biochemistry 1984, 23, 5041–5048; (c)
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1976, 727–731; (d) Takayama, H.; Ohmori, M.; Yamada, S.
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1688.
of nitriles 18, which upon treatment with potassium
metal in portions provided triols 5a (39%) and 5b
(33%)7 (Scheme 5).
Triols 5a and 5b have been previously synthesized by
Sarandeses and co-workers and were used for the con-
vergent synthesis of 2a, 2b and 2c via a Wittig–Horner
coupling with the corresponding ring A phosphine
oxide.4 We have thus performed a formal synthesis of
24S,25-(OH)2-D3, 24R,25-(OH)2-D3 and 1a,24R,25-
(OH)3-D3.
4. (a) Cornella, I. Ph.D. Thesis, University of Santiago de
Compostela, 2001; (b) Cornella, I.; Suarez, R. M.;
Mourino, A.; Sestelo, J. P.; Sarandeses, L. A. J. Steroid
˜
Biochem. Mol. Biol. 2004, 89–90, 19–23.
5. Yokokawa, F.; Inaizumi, A.; Shioiri, T. Tetrahedron 2005,
61, 1459–1480.
Compounds 5a and 5b have been synthesized through
an enantioselective route starting from a chiral amino
acid, hence their structure is unambiguous. Neverthe-
less, recrystallization of triol 5b in hexane and ethyl ace-
tate afforded crystals which were subjected to X-ray
crystallographic analysis,8 thus confirming its structure
to be that shown in Figure 2.
6. (a) Fall, Y.; Torneiro, M.; Castedo, L.; Mourino, A.
˜
Tetrahedron Lett. 1992, 33, 6683–6686; (b) Fall, Y.;
Torneiro, M.; Castedo, L.; Mourino, A. Tetrahedron
˜
1997, 53, 4703–4714; (c) Torneiro, M.; Fall, Y.; Castedo,
L.; Mourino, A. Tetrahedron 1997, 53, 10851–10870.
˜
1
7. Compound 5a: H NMR (CDCl3, d): 4.06 (1H, br s, H-8),
3.32 (1H, m, H-24), 2.01 (2H, m), 1.88 (1H, m), 1.79 (2H,
m), 1.2 (3H, s, H-26 or 27), 1.15 (3H, s, H-26 or 27), 0.92
(3H, s, H-18), 0.89 (3H, d, J = 6.47 Hz, H-21); 13C NMR
(CDCl3, d): 78.74 (CH-24), 73.18 (C-25), 69.39 (CH-8),
56.61 (CH-17), 52.56 (CH-14), 41.86 (C-13), 40.37 (CH2),
35.10 (CH-20), 33.55 (CH2), 32.65 (CH2), 28.06 (CH2),
27.21 (CH2), 26.57 (CH3-26 or 27), 23.22 (CH3-26 or 27),
22.49 (CH2), 18.39 (CH3-21), 17.41 (CH2), 13.54 (CH3-18);
HRMS (FAB): calcd for C18H34O3Na: 321.2400; found:
321.2407. Compound 5b: 1H NMR (CDCl3, d): 4.05 (1H, br
s, H-8), 3.27 (1H, d, J = 9.29 Hz, H-24), 1.98 (1H, d,
J = 13.22 Hz, H-14), 1.19 (3H, s, H-26 or 27), 1.14 (3H, s,
H-26 or 27), 1.89 (6H, m, H-18 and 21); 13C NMR (CDCl3,
d): 79.96 (CH-24), 73.66 (C-25), 69.77 (CH-8), 56.94 (CH-
17), 52.97 (CH-14), 42.25 (C-13), 40.78 (CH2), 35.88 (CH-
20), 33.94 (CH2), 33.46 (CH2), 28.74 (CH2), 27.53 (CH2),
26.89 (CH3-26 or 27), 23.57 (CH3-26 or 27), 22.90 (CH2),
17.82 (CH2), 14.57 (CH3-21), 13.93 (CH3-18); HRMS
(FAB): calcd for C18H34O3Na: 321.2400; found: 321.2410.
8. X-ray crystal structure analysis of 5b: Bruker Smart
In conclusion, we have performed a formal asymmetric
synthesis of secalciferol and 24-substituted metabolites
and analogues of vitamin D. Tosylates 7a and 7b are
useful building blocks easily obtained from commer-
cially available amino acids. Further investigations on
the synthesis of novel vitamin D thia-analogues using
these synthons will be reported in due course.9
Acknowledgements
This work was supported by a grant from the Xunta de
Galicia (PGIDIT04BTF301031PR). The CACTI NMR
and X-ray services of the University of Vigo are grate-
fully acknowledged.
References and notes
˚
CCD diffractometer, Mo-Ka-radiation (k = 0.71073 A), T
1. (a) For a general review on the chemistry and/or biochem-
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Clinical Applications of the Steroid Hormone; Norman, A.
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3. (a) Lam, H.-Y.; Schnoes, H. K.; DeLuca, H. F.; Chen, T.
C. Biochemistry 1973, 12, 4851–4855; (b) Perlman, K.;
Schnoes, H. K.; Tanaka, Y.; DeLuca, H. F.; Kobayashi,
293(2) K. Crystal size: 0.26 · 0.24 · 0.22 mm3, colourless
irregular prism, space group C2, monoclinic, a = 13.401(2),
˚
b = 25.538(4),
c = 12.2778(19) A,
b = 117.714(3)ꢁ,
V = 3720.0(10) A , Z = 8, qcal = 1.082 g/cm3, h range =
1.59–28.08ꢁ, 10,228 reflections collected, 6938 independent
(Rint = 0.0673), 402 parameters, final R indices [I > 2r],
R = 0.0486, wR = 0.0940, GOF = 0.735. Structure solu-
tion: direct methods (SHELXS97), refinement on F2
(SHELXL97). H atoms were calculated. Crystallographic
data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Centre No. CCDC 240720.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge
CB21EZ (fax: (+44) 1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk).
3
˚
´
9. Gandara, Z. Ph.D. Thesis, University of Vigo, 2006.