A
Novel Strategy for the Synthesis of the Lupin Alkaloids - Cytisine,
Thermopsine, Anagyrine
Kowalski
Ester Homolgation - Application to the Synthesis of b-Aminoesters |
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NEWS:
Diane
Gray has recently completed the synthesis of (+)-cytisine (the unnatural
enantiomer) in a very direct and efficient manner, key features of which
are illustrated below.
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Cytisine
- Background
Cytisine
represents one of the key members of the lupin family of alkaloids.
This molecule, which is most often associated with the laburnum
tree - see left - was isolated in
pure form in 1862 but it took until 1931 for the structure of
cytisine to be correctly elucidated.
There
then followed a series of very elegant papers in the mid-1950s
from three separate groups - van Tamelen, Bohlmann, and Govindachari
- on the synthesis of cytisine.
However,
it was almost another 50 years before a renewed interest in the
synthesis of cytisine emerged. |
Two papers
then appeared, one each from the groups of Jotham Coe and Brian
O'Neill, both at Pfizer in Groton, which heralded a key role
for cytisine as a lead for drug discovery (B. T. O'Neill et
al. Org. Lett., 2000, 2,
4201; J. W. Coe, Org. Lett., 2000, 2,
4205.). This work has now led to a clinical candidate Varenicline
- see right and below - which is
in late-stage development for smoking cessation. Indeed Jotham
and colleagues at Pfizer have now just published their first
paper paper in this area (J. Med. Chem. 2005, 48,
3474 -3477). Many congratulations!
This therapeutic
application for cytisine is linked directly to the well-established
pharmacology of cytisine as a potent and selective agonist for
a4b2
nicotinic acetylcholine receptors. This
then links cytisine directly to our own
interest in the chemistry of nicotinic agonists.
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However,
our current targets include other lupin alkaloids, such as thermopsine,
anagyrine, sparteine, and aloperine. Our aim is to develop a generally
application approach to this category of important natural products.
CURRENT
WORK - The Synthesis of Cytisine and Other Lupin Alkaloids
Our
first generation approach to cytisine
is shown below. Our strategy, which is quite different to all of those
reported earlier, involves assembling the tricyclic skeleton by making
the central six-membered ring via (i) N-selective alkylation
of 6-bromopyridone and (ii) Pd-mediated intramolecular arylation of
lactam enolate.
This
approach has been realized but there are significant issues, some of
which have been addressed. The major issues are asymmetric assembly
of the piperidinone A
and the N-selective alkylation of A using
6-bromopyridone.
Both
aspects have been studied and A is now available in
high enantiomeric excess (unpublished) which provides us with
the most direct and efficient asymmetric entry to cytisine. The N-
vs. O-alkylation of 6-bromopyridone was also studied in depth.
This involved a close collaboration with GSK, and the application of
factorial experimental design methods. This took a very poor yielding
process – 22% of the desired N-alkylated adduct,
with O-alkylation and elimination of A being
the dominant processes – to a 60% yield of the N-alkylated
adduct as the major product. We are very grateful to Dr Martin Owen
and his colleagues at GSK for sharing their experience and for providing
invaluable advice.
A
second generation route has also been achieved and although essentially
the same strategy has been retained, this new (unpublished)
approach is not only much more efficient - no issues with N-
vs. O-alkylation of 6-bromopyridone - but also involves a new
and unprecedented transformation, and provides (+)-cytisine - see News
above.
The
synthesis of the tetracyclic variants (and isomers) themopsine
and anagyrine requires access to the quinolizidine
based bromides - B and C. The synthesis
of B has already been accomplished in a highly efficient
manner and a synthesis of thermopsine has
been accomplished. Making B also involved the application
of the elegant and underutilised ester ester homologation chemistry
that was discovered and developed so elegantly by Dr Conrad Kowalski
during the 1980s. This provides an effcient method for the homolgation
of a-amino esters to provide b-amino
esters with no loss of stereochemical
integrity.
On
a personal note: Sadly, Conrad
Kowalski passed away during late 2004. Conrad's career spanned both
academia and industry, and he was a valued and highly respected colleague.
Tim Gallagher
