Vitamin D1

Article abstract of DOI:10.1039/b007191i

The X-ray crystallographic structure of vitamin D₁ reveals a sandwich-like 1:1 heterodimeric complex of lumisterol₂ and vitamin D₂ with the latter in its α-chair conformer.

Full text of DOI:10.1039/b007191i

Vitamin D1
Edwin S. Tan,† Fook S. Tham,‡ and William H. Okamura*
Department of Chemistry, University of California, Riverside, CA 92521 USA. E-mail: william.okamura@ucr.edu
Received (in Corvallis, OR, USA) 1st September 2000, Accepted 13th October 2000
First published as an Advance Article on the web 10th November 2000
The X-ray crystallographic structure of vitamin D
1
reveals a
and
2
isomorph revealed that the D was essentially the same as that
in the very interesting finding in 1976 by Hull et al. that the
8
sandwich-like 1+1 heterodimeric complex of lumisterol
2
vitamin D
2
with the latter in its a-chair conformer.
crystalline orthorhombic form of pure 1a (a feature also
9
characteristic of 1b, vitamin D
3
) exists as a pseudo-homo-
Vitamin D
1
, the very first anti-rachitic factor, which played a
dimer. What is novel about 1a (and also 1b) is that it crystallizes
as a 1+1 complex of a- and b-A-ring chairs (Fig. 2), the former
with an equatorial disposition of the C-3 hydroxy and the latter
with an axial orientation of the same hydroxy. Not surprising is
historical role in the development of the vitamin D field, was
1
discovered by Windaus with contributions from Askew and co-
workers2 and Reerink and Van Wijk3 in 1931. This sharp
melting, biologically active substance, produced photochem-
2
that in solution vitamin D exists as a dynamically equilibrating
ically from ergosterol (provitamin D
2
, 3a), was soon thereafter
mixture of the same a- and b-chairs and that this ratio is solvent
discovered to be a 1+1 crystalline heterodimer of lumisterol
2
dependent.10
1
(
4a) and vitamin D
2
(1a). This was all at a time when the
(2), pyrocalciferol (5) and
involvement of previtamin D
2
isopyrocalciferol (6) in the now well accepted scheme (Fig. 1)
4
was not yet recognized. Early unsuccessful attempts to obtain
2
the X-ray structure of crystalline, monoclinic D were reported
5
6
by Bernal in 1932 and by Bernal and Crowfoot in 1935, but
interestingly, the successful completion of the structure was not
7
completed until 1994! The X-ray structure of the monoclinic
Fig. 2
In light of these divergent solid state and solution structural
results for 1a, it became of interest to consider the structure of
the crystalline heterodimeric D , a complex of two seemingly
1
very structurally dissimilar molecules 4a and 1a. The former
possesses the steroid skeleton, but the latter exists in an
extended 6-s-trans conformation. It was intriguing to entertain
the possibility that D
and previtamin D , a substance related to vitamin D
a facile thermal [1,7]-sigmatropic shift. Alternatively, it was
considered possible that the D might exist in its 6-s-cis
conformation (not shown), thus rendering it, like the putative
previtamin D , better able to co-crystallize with the more
topologically similar lumisterol molecule. The purpose of this
communication is to report that in fact the single crystal X-ray
structure§ reveals that vitamin D is simply a 1+1 complex
containing lumisterol and vitamin D in its 6-s-trans conforma-
1
might in fact be a complex of lumisterol
2
2
2
by way of
2
2
2
1
2
2
tion, but with the A-ring in the a-chair conformation as
indicated in Fig. 3. It is interesting that the axial 3b-OH of
lumisterol
vitamin D
2
is hydrogen bonded to the equatorial 3b-OH of
2
in such a manner as to form a face to face sandwich-
like structure placing the two C18 angular methyl group carbons
in close proximity with one another.
Samples of vitamin D
mp, 119–121 °C; literature mp 124–125 °C) from a slowly
evaporating solution containing a 1+1 mixture of lumisterol
and vitamin D (acetone). Similar attempts to obtain crystalline
1
were prepared by collecting crystals
2
(
2
2
Fig. 1
Fig. 3
DOI: 10.1039/b007191i
Chem. Commun., 2000, 2345–2346
2345
This journal is © The Royal Society of Chemistry 2000

material from a 1+1 mixture of previtamin D
, lumisterol (4b) and vitamin D (1b), or previtamin D
and vitamin D failed. Lumisterol and previtamin D
prepared by photochemical irradiation of 3a (Hanovia 450 W
medium pressure mercury lamp, pyrex vessel, EtOH) followed
by HPLC purification (20% EtOAc–hexanes, silica column).
2
(2a) and vitamin
model the disorder, where the C–C and CNC–C single bond distances were
restrained to 1.53 and 1.51 Å, respectively. Full details have been deposited
at the Cambridge Crystallographic Data Centre, Cambridge, UK CB2 1EZ
D
2
3
3
3
(2b)
3
2
2
were
(CCDC 182/1825).
1
A. Windaus, A. Luttringhaus and M. Deppe, Liebigs Ann. Chem., 1931,
4
1
89, 252. See also: A. Windaus, Proc. R. Soc. London, Ser. B, 1931,
08, 568; A. Windaus, O. Linsert, A. Luttringhaus and G. Weidlich,
Previtamin D
vitamin D
followed by HPLC separation.11 Lumisterol
previtamin D were prepared in a similar way from 7-dehydro-
cholesterol or from vitamin D as appropriate. The X-ray
structures of pure lumisterol and lumisterol have been
previously reported12 as have vitamin D .7–9 Thus, the
and D
vitamin D result reported herein represents a unique combina-
2
could also prepared by thermal equilibration with
2
3
and
Liebigs Ann. Chem., 1932, 492, 226.
3
2 F. A. Askew, H. M. Bruce, R. K. Callow, J. St. L. Philpot and T. A.
Webster, Nature, 1931, 128, 758. See also: T. C. Angus, F. A. Askew,
R. B. Bourdillon, H. M. Bruce, R. K. Callow, C. F. Fischmann, J. St. L.
Philpot and T. A. Webster, Proc. R. Soc. London, Ser. B, 1931, 108, 340;
F. A. Askew, R. B. Bourdillon, H. M. Bruce, R. K. Callow, J. St. L.
Philpot and T. A. Webster, Proc. Royal Soc. B, 1932, 109, 488.
3
2
3
2
3
1
tion of these earlier crystallographic results.
3
4
5
6
E. H. Reerink and A. Van Wijk, Biochem. J., 1931, 25, 1001.
P. Karlson, Trends Biochem. Sci., 1981, 29.
J. D. Bernal, Nature, 1932, 129, 277.
This study was generously supported by grants from the NIH,
NSF, and the Committee on Research of the University of
California, Riverside. We also acknowledge generous supplies
of starting materials from Solvay Pharmaceuticals (Weesp, the
Netherlands).
J. D. Bernal and D. Crowfoot, Chem. Ind., 1935, 54, 701.
7 I. Leban, R. A. G. De Graaf, R. De Gelder, J. Turkenburg, K. S. Wilson
and Z. Dauter, The Collected Works of Dorothy Crowfoot Hodgkin:
Volume-III, General Crystallography and Essays, eds. G. G. Dodson,
J. P. Glusker, S. Ramaseshan and K. Venkateran, Interline Pub.,
Bangalore, India, 1994, pp. 43–51.
Notes and references
†
Undergraduate Honors Thesis Program Participant, University of Cal-
ifornia, Riverside.
Analytical Chemistry Instrumentation Facility located in the Department
8 S. E. Hull, I. Leban, P. Main, P. S. White and M. M. Woolfson, Acta
Cryst. B, 1976, 32, 2374.
9 Trinh-Toan, H. F. DeLuca and L. F. Dahl, J. Org. Chem., 1976, 41,
3476.
10 R. M. Wing, W. H. Okamura, M. R. Pirio, S. M. Sine and A. W.
Norman, Science, 1974, 186, 939; R. M. Wing, W. H. Okamura, A.
Rego, M. R. Pirio and A. W. Norman, J. Am. Chem.Soc., 1975, 97, 4980;
G. N. LaMar and D. L. Budd, J. Am. Chem. Soc., 1974, 96, 7317; B.
Helmer, H. K. Schnoes and H. F. DeLuca, Arch. Biochem. Biophys.,
1985, 241, 608; W. H. Okamura and G.-D. Zhu, Vitamin D, eds. D.
Feldman, F. H. Glorieux and J. W. Pike, Academic Press, San Diego,
1997, pp. 939–971.
‡
of Chemistry, College of Natural and Agricultural Sciences, University of
California, Riverside.
§
88 2
Crystal data: C56H O , M = 793.26, monoclinic, a = 20.1072(13), b =
7.2481(5), c = 35.858(3) Å, b = 94.091(2)°, V = 5212.6(6), T = 213(2)
21
K, space group C2, Z = 4, m(Mo-Ka) = 0.059 mm , 16502 reflections
measured, 9692 unique (Rint = 0.0262) which were in all calculations. The
final R indices [I > 2s(I)] were R1 = 0.0497, wR2 = 0.1147; R indices (all
data) were R1 = 0.0725, wR2 = 0.1249. There was one lumisterol
vitamin D molecule present in the asymmetry unit. The side chain attached
to C23A of vitamin D and C23 of lumisterol were refined as individual
disordered-side chains (the site occupancy ratio for disordered-side chains
was 56+44% and 52+48% for vitamin D and lumisterol , respectively). The
DELU, SIMU, and DFIX restrains (SHELXTL software) were used to
2
and one
2
2
2
11 W. H. Okamura, H. Y. Elnagar, M. Ruther and S. Dobreff, J. Org.
Chem., 1993, 58, 600.
12 D. C. Hodgkin and P. Sayre, J. Chem. Soc., 1952, 4561; A. J. De Kok
and C. Romers, Acta Cryst. B, 1974, 30, 1695.
2
2
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Chem. Commun., 2000, 2345–2346