The first synthesis and biological testing of the enantiomer of 1α,25-dihydroxyvitamin D3

Article abstract of DOI:10.1016/S0040-4039(01)00317-3

The 1α,25-dihydroxyvitamin D₃ enantiomer was synthesized and examined in biological tests. The ring A precursor was prepared from vitamin D₂ employing the Mitsunobu reaction for inversion of the configuration at C-3 and SeO₂ hydroxylation at C-1. The CD rings-side chain portion was synthesized from an optically active hexanoic acid derivative using diastereoselective tandem Mukaiyama-Michael addition and vinylsulfone reduction as the key steps. The ring A and CD rings building blocks were combined using the Julia alkenylation reaction. 1α,25-Dihydroxyvitamin D₃ enantiomer shows no significant affinity to the vitamin D receptor.

Full text of DOI:10.1016/S0040-4039(01)00317-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2891–2895
The first synthesis and biological testing of the enantiomer of
†
1a,25-dihydroxyvitamin D3
Barbara Achmatowicz,a Evgueni Gorobets,a Stanis*law Marczak,a Agnieszka Przezdziecka,a
Andreas Steinmeyer,b Jerzy Wichaa,* and Ulrich Zu¨gelb
aInstitute of Organic Chemistry, Polish Academy of Sciences, PO Box 58, 01-224 Warsaw 42, Poland
bSchering AG, Preclinical Drug Research, D-13342 Berlin, Germany
Received 8 January 2001; revised 15 February 2001; accepted 21 February 2001
Abstract—The 1a,25-dihydroxyvitamin D3 enantiomer was synthesized and examined in biological tests. The ring A precursor was
prepared from vitamin D2 employing the Mitsunobu reaction for inversion of the configuration at C-3 and SeO2 hydroxylation
at C-1. The CD rings-side chain portion was synthesized from an optically active hexanoic acid derivative using diastereoselective
tandem Mukaiyama–Michael addition and vinylsulfone reduction as the key steps. The ring A and CD rings building blocks were
combined using the Julia alkenylation reaction. 1a,25-Dihydroxyvitamin D3 enantiomer shows no significant affinity to the
vitamin D receptor. © 2001 Elsevier Science Ltd. All rights reserved.
A great deal of attention has been given to the synthesis
of 1a,25-dihydroxyvitamin D3, 1 (Scheme 1), which acts
as a hormone controlling calcium homeostasis and shows
a broad spectrum of biological activity.1 There is a
continuous search for analogues of 1 devoid of calcemic
activity but retaining cell differentiating and anti-prolif-
eration activities, suitable for treatment of cancer and
certain skin disorders in humans.2 Equally needed are
analogues which would selectively induce intestine or
bone calcium absorption thus providing a means to
mediate calcium transport disorders3 and analogues
suppressing immunological responses.4 In pursuit of new
types of biologically active compounds it appeared of
interest to synthesize and examine the enantiomer of
1a,25-dihydroxyvitamin D3 (ent-1) and some related
stereo-isomers with profound changes in molecular
geometry. Unnatural enantiomers of various natural
products have been synthesized.5 However, reports on
enantiomers of hormonally active compounds are scarce.
ent-Equilenin was synthesized and showed to have rather
low estrogenic activity.6 The prostaglandin E1 enantio-
mer exhibited small activity in certain tests.7 However,
Scheme 1. The target compound ent-1 and the general synthetic plan.
Keywords: enantioselective synthesis; Mukaiyama–Michael reaction; Mitsunobu reaction; vitamin D.
* Corresponding author. Fax: +4822 6326681; e-mail: jwicha@icho.edu.pl
†
This work was presented in part at the 18th Conference on Isoprenoids, Prachatice, the Czech Republic, 10–16 September 1999.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00317-3

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B. Achmatowicz et al. / Tetrahedron Letters 42 (2001) 2891–2895
prostaglandin analogues with inverted configuration at
all but one of the stereogenic centers show high and
specific activity.8 In principle, enantiomers may also
display activities which are not inherent in the parent
compounds.9
remaining hydroxyl groups,12 it was challenging to sub-
mit this acid labile triol to a regioselective configuration
inversion reaction. Our initial experiments with the
Mitsunobu reaction14 using p-nitrobenzoic acid as the
nucleophile provided dehydration products only. How-
ever, treatment of 7 with picolinic acid, Ph3P and DIAD
according to the procedure of Sammakia and Jacobs15
afforded picolate 8 in 36–39% yield, which was readily
purified by column chromatography.
In this communication we report the synthesis and the
results of some biological tests of ent-1a,25-dihydroxy-
vitamin D3 (ent-1, Scheme 1). The general plan of the
synthesis of compound ent-1 includes: (1) coupling of the
building blocks 2 and 3 using the Julia alkenylation
reaction,10 (2) preparation of the ring A building block
3 from inexpensive vitamin D2, 6, (Scheme 2) using the
Mitsunobu reaction for the inversion of configuration at
C-3 and allylic oxidation at C-1 as the key reactions, and
(3) a new enantioselective synthesis of the CD rings-side
chain building block 2 based upon 1,3-asymmetric
induction11 in the conjugate addition reaction of optically
active ketene acetal 4 and unsaturated ketone 5.
Compound 8 was subjected to SeO2 oxidation16 to give
the 1-hydroxy derivative 9 in a 20% yield along with
unreacted starting material. Although yields of the above
described transformations were rather low, the interme-
diate 9 was prepared form vitamin D2 in just three steps.
After protection of the 1-hydroxy group with the TBS
group, the picolate ester group in 10 was hydrolyzed in
a
mixture of chloroform and methanol using
CuOAc2·H2O as the catalyst.15 Alcohol 11 was trans-
formed into the derivative 12 in the usual way. Efficient
transformation of 9 into 11 suggests potential applica-
tions of the picolate ester moiety as a protective group.
Triol 7 (Scheme 2), which is readily accessible by KMnO4
dihydroxylation of vitamin D2 6, has served as a conve-
nient starting material for synthesis of numerous vitamin
D congeners.12,13 Since in the silylation reaction of 7, the
hydroxyl group at C-3 proved more reactive than the
Oxidative cleavage of the vicinal diol 12 followed by
reduction of the crude product17 and chromatography
Scheme 2. Synthesis of the ring A building block, 3.

B. Achmatowicz et al. / Tetrahedron Letters 42 (2001) 2891–2895
2893
afforded alcohol 13. Dess–Martin oxidation18 of 13
gave aldehyde 3 along with its dihydropyrone tautomer
diastereomers. After NaBH4–CeCl3 reduction21 of these
a,b-unsaturated ketones a crystalline material was
obtained, which was recrystallized to afford allylic alco-
hol 19 in a 53% yield from 17. The structure of 19 was
determined by X-ray analysis.11
1
3a in a ratio of 2:1, respectively (by H NMR). This
mixture was used for coupling with the CD rings-side
chain building block.
A new enantioselective synthesis of the building block 2
was developed based upon the asymmetric
Mukaiyama–Michael reaction.19 Optically active
thioester‡ 14 (96% ee, Scheme 3), was treated with LDA
and then with TMSCl to give ketene acetals 15. The
latter were allowed to react with enone 5 in the pres-
ence of 5 mol% of TrSbCl6. When the majority of the
reagents were consumed, the second Michael acceptor
16 was added.20 The reaction product consisted of three
diasteromers in a ratio of 85:11:4 (by HPLC). All our
attempts to separate the major component, to which
structure 17 was later assigned, failed. The mixture was
subjected to cyclization to give 18 along with minor
Compound 19 was transformed into the key building
block 2 using routine operations indicated in Scheme 3.
However, one or two brief comments are in order.
DIBAL-H which is the reagent of choice for reduction
of the thioester group could not be applied to 19 due to
susceptibility of the dioxolane ring to reductive open-
ing. Accordingly, 19 was reduced to the corresponding
diol using LiAlH4 in THF at reflux. Vinylsulfide 20 was
oxidized with m-CPBA to the corresponding vinylsul-
fone and this derivative was then treated with LiAlH4
in THF without purification. Reduction of the vinylsul-
fone moiety, the adjacent CꢀO bond22 and the tosyloxy
group at C-21 occurred simultaneously to afford the
Scheme 3. Synthesis of CD rings—side chain building block 2 and coupling of building blocks 2 and 3 to afford ent-1.
‡ This compound was prepared11 from methyl 5-methyl-hept-4-enoate using the Sharpless asymmetric dihydroxylation27 and the Weinreb ester
group interconversion.28

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B. Achmatowicz et al. / Tetrahedron Letters 42 (2001) 2891–2895
Figure 1. CD spectra of 1a,25-dihydroxyvitamin D3 (1) and its enentiomer (ent-1).
trans-hydrindane derivative 21. Ultimately, the key
building block 2 was obtained from thioester 14 in
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