A novel entry to the vitamin D triene system

Article abstract of DOI:10.1016/S0040-4039(00)60832-8

The application of Negishi's cyclization methodology to the synthesis of (Z)-1-iodo-1,3-bis-exocyclic-dienes from acyclic precursors is described. This kind of compounds can be used for the preparation of conjugated systems such as the triene of vitamin D

Full text of DOI:10.1016/S0040-4039(00)60832-8

Tetrahedron
in
Vol. 33. No. 49.
55.00 +
A Novel Entry to the Vitamin D Triene System
L. Mascareiias,
Luis
and Antonio Mouriiio*
Departamento de
y
de Alcaloides
CSIC, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain.
The application of Negishi’s cyclixation methodology to the synthesis of
bisexocyclic-dienes from acyclic precursors is described. This kind of compounds can be used for
the preparation of conjugated systems such us the
of vitamin D.
The discovery that
the hormonally active form of vitamin
plays an
important function in a number of fundamental cell processes (including cell differentiation and proliferation) in
addition to its classical role in calcium homeostasisl has renewed interest in the synthesis of analogues with
potential therapeutical utility in the treatment of proliferative disorders, or which can be used to investigate the
Among the reported synthetic approaches to the triene system
hormone.
molecular mechanism of action of the
of vitamins D, those based on convergent strategies have been shown to be the most useful and versatile since
they allow for separate elaboration of the C/D-side chain and ring A fragments.3 There have recently been
published several elegant routes to the alcohol
coupling of its phosphme oxide derivative 3b with the corresponding upper part ketone 2 (route a, scheme
Although this strategy is highly efficient for the synthesis of a variety of chain analogues of the hormone
a fragment required for the synthesis of 1 by Wittig-Homer
1, it seems less suitable for the preparation of derivatives with a modified ring A and/or triene
b
a
5

We hypothesized that these latter analogues might be more accessible via a palladium catalyzed coupling
between suitably prepared (Z )-vinyliodides, like 5, and fragments of type 4 or others), i.e.
route of Scheme I.7 Here we report the results of our initial efforts towards this goal, the stereoselective
synthesis of 1-iodovinyl from readily available acyclic precursors
triene system present in vitamin D.
=
and their coupling with the model vinylstannane 9 to give the
The synthesis is based on the previously described zirconium-promoted cyclization of
The
required enyne precursor 6b (Scheme II) was prepared by treatment of enyne
with methyllithium and
trapping of the resulting acetylide with
Under previously described conditions for the cyclization-
iodonolysis sequence [(a)
THF. (b)
compound 7a was obtained in 55% yield
(87% based on recovered starting material). Other iodinatlng agents
and
did not provide better yields. The stereochemistry was assigned on the basis of previously reported data for
compound
The absence of observable
lying equatorial9
NMR coupling between H-l and H-10 (steroidal numbering) is
consistent with
X
R
H
RI
OR
The exocyclic double bond was efficiently introduced by treatment of 7a with DBU in
3
in DMF
of
days, 90%
and the trimethylsilyl group was smoothly removed by reaction of with
12 h, 84 yield). Compound was alternatively obtained by inverting the procedure: initial
7a with
in DMF (or stirring with KF in
to remove the trimethylsilyl group, and subsequent
elimination with DBU in
(82% yield for both steps). Most importantly, compound 7a can be
transformed in a one-pot reaction to the requited vinyliodide by treatment with TBAF (3 equiv) in THF at
room temperature (83% yield). The Q-stereochemistry of compound was by NOE NMR
Silylation imidazole, afforded a compound that was spectroscopically identical
obtained by the above procedures. To test whether these iodovinyl compounds can be used to
prepare the conjugated system of vitamins D, the cross-coupling reaction of with the vinyhributyltin
to compound

7591
in
derivative
under Stille conditions was performed. Stirring a solution of compound
and 9 (2
DMF and in the presence of
(5% for two days at room temperature followed by
afforded a compound whose NMR is identical to that of (53% over the two
obtained by direct coupling between 9 and under the
Work to prepare the required true upper fragment 4, and
desilylation
steps, unoptimized yield). This compound was
same reaction conditions (50% unoptimized yield).
optically active ring A derivatives, is underway.
Acknowledgements. Support for this research under Grants
gratefully acknowledged. A. M. G.. thanks the Xunta de
and
(M.E.C., Spain) is
for a fellowship.
References and Notes
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PC Model, this conformation is energetically
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All new compounds gave satisfactory
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(Received in UK 8 September 1992)