12-substituents of cordypyridones A and B have opposite
stereochemistry to that reported in pyridoxatin.
Scheme 2. Racemic Synthesis of the Cyclic Vinyl Ketones
Although the total synthesis of (()-pyridoxatin (2) has
been reported by Snider and Lu in as early as 1994,7 the
approach cannot be readily applied to the synthesis of the
cordypyridones. In addition, although the methodology as
reported was elegant in design, the reported synthetic route
is not amenable to the rapid synthesis of related compound
libraries of related structures. To this end, the objective of
our work reported here is to develop a convergent synthetic
route to the cordypyridones A and B, structuring the route
for maximum flexibility for future forays into analogue
synthesis. Our study also constitutes the first reported total
synthesis of cordypyridones A and B.
Our retrosynthetic analysis of cordypyridones A and B is
shown in Scheme 1. The key step in the synthesis would
utilize the nucleophilic attack of a pyridyl anion 8 onto the
appropriately functionalized cyclohexanone 7, with removal
of the superfluous hydroxyl group being effected diastereo-
selectivity. The brevity of this analysis along with the
structural simplicity of the precursors makes this route
attractive for implementation.
spontaneously tautomerises to form the meso-ketone 9 as a
single diastereoisomer (Scheme 2). With the meso-ketone
in hand, the installation of the vinyl substituent at the
R-position to the ketone functionality can be easily achieved.
By using methodology that has been established for cyclo-
hexanones,10 the vinyl substituent can be installed syn to the
methyl substituents on the cyclohexane ring by coupling the
corresponding silyl enol ether 10 with ethynyltrimethylsilane
in the presence of gallium trichloride. In his paper, Yamagu-
chi describes the mechanism of such systems in which
gallium, after migration to R-carbon, favors an equatorial
position with insertion of the vinyl substituent proceeding
with retention of configuration.10 This gave a mixture of
diastereomers (>9:1) in favor of the desired vinyl ketone 7.
The epimeric vinyl compound can also be synthesized
from the meso ketone 9 and hence this provides access to
8-epi-cordypyridones A and B. Aldol reaction of 9 with
acetaldehydeledtothealcohol11withthenewcarbon-carbon
bond installed anti to the methyl substituents on the cyclo-
hexanone ring. The relative stereochemistry observed in 11
occurs due to the steric effect of the 4,6-dimethyl groups,
which directs the attack of the chelated acetaldehyde to occur
from the less sterically hindered face. This stereochemistry
was confirmed through single crystal structural analysis as
shown in Figure 2. Elimination of the hydroxyl group in 11
can be effected efficiently with both Martin’s sulfurane as
well as under basic conditions via the corresponding mesylate
or tosylate.
Scheme 1. Retrosynthetic Analysis of Cordypyridones A and B
The total synthesis of (()-cordypyridones A and B
commenced with the preparation of 2,4,6-trimethylcyclo-
hexanone (9). This meso-ketone had been synthesized
previously by Mori et al. in two steps by hydrogenation of
the commercially available phenol 5 with Raney nickel and
subsequent oxidation of the cyclohexanol with Jones’ re-
agent.8 In our laboratories, we had previously developed a
zeolite-supported rhodium catalyst for applications in hy-
drogenation reactions.9 To our delight, the use of this
heterogeneous catalyst in the reduction of 5 gave the meso-
cyclohexanone 9 directly in 82% yield. This presumably
arises from the “controlled” reduction (as opposed to the
over-reduction) of 5 to the cyclohexenol, which then
With the cyclohexanone fragment in hand, we turned our
attention to the synthesis of the pyridine 13. This was readily
(9) Synthesis of the Rhodium Catalyst. Rhodium trichloride (0.38 g)
in ultrapure water (4.0 mL) was added to ꢀ-H 75 zeolite (5.00 g) suspended
in ultrapure water (8 mL). The resulting slurry was stirred at room
temperature for 10 h to achieve a uniform dispersion after which the water
was removed under reduced pressure. The solid residue was calcinated in
a Carbolite Furnace (CWF-1200), using the following temperature program
with a temperature rate increase of 2 °deg/min: (a) hold at 200 °C for 2 h;
(b) hold at 400 °C for 2 h; (c) hold at 500 °C for 8 h. The calcinated material
was powdered and further dried in an oven at 90 °C for 5 h.
(6) Jegorov, A.; Matha, V.; Husak, M.; Kratochvil, B.; Stuchilik, J.;
Sedmera, P.; Havlicek, V. J. Chem. Soc., Dalton Trans. 1993, 1287.
(7) Snider, B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065.
(8) Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5545.
(10) Arisawa, M.; Miyagawa, C.; Yamaguchi, M. Synthesis 2002, 138.
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