this isoxazolidine was confirmed by NMR and X-ray
analysis. In addition to adduct 14, an impure chromatographic
fraction was isolated which contained the bridged cycload-
duct 15, but despite some effort, this compound could not
be obtained in pure form for full characterization. However,
heating the fraction containing 15 in toluene at 115 °C for
24 h produced the linear adduct 14, increasing the overall
yield to 76%. This process undoubtedly involves a well-
precedented thermal retrocycloaddition of the bridged adduct
15 to starting nitrone 13.4,5 In view of these results, the
cycloaddition was conducted in toluene-d8 in an NMR tube
and was periodically monitored. It was found that bridged
cycloadduct 15 is the kinetic product of the reaction and over
time is converted to the more stable linear adduct 14. For
preparative purposes, it proved most convenient to heat the
nitrone 13 in toluene solution in an oil bath maintained at
130 °C for 45 h, which provided the desired adduct 14 in
73% isolated yield after chromatography.
corresponding free amine, which could be successfully
alkylated to yield diene amine 20. Reintroduction of the TFA
protecting group gave the desired metathesis substrate 21 in
high overall yield. Unfortunately, all attempts to effect ring-
closing metathesis of 21 to produce indenotetrahydropyridine
22 failed despite screening a number of catalysts. In most
cases, only the starting diene 21 was recovered. We believe
the problem here is steric in origin because based on our
earlier work it appears that the nonchlorinated olefin must
initially form a metal carbene species for this RCM process
to occur as desired.6
Because the metathesis strategy proved untenable, we
turned to what proved to be a shorter and more convergent
approach for introducing both the tetrahydropyridine and
A-rings. It was possible to couple amine 17 with known
phenylacetic acid 23,12 leading to amide 24 (Scheme 5).
Scheme 5
As noted above, our original intent was to construct a
functionalized tetrahydropyridine ring potentially useful for
the haouamines via a ring-closing metathesis of a vinyl
chloride.6 Toward this end, isoxazolidine 14 was first
hydrogenated with Pearlman’s catalyst to afford amino
alcohol 16 (Scheme 4). Protection of this alcohol as the TBS
Scheme 4
Removal of the silyl protecting group of 24 with TBAF
followed by Dess-Martin oxidation10 of the resulting
primary alcohol afforded aldehyde 25. In a key transforma-
tion, it was found that warming aldehyde amide 25 in warm
methanol in the presence of potassium carbonate effects an
aldol condensation/dehydration to produce the desired pen-
tacyclic lactam 26 in high yield. To complete the synthesis,
lactam 26 was reduced with lithium aluminum hydride/zinc
chloride to give the Baran pentacycle 3 in good yield.13 This
compound has spectral data identical to those previously
reported.3
ether 17, followed by conversion of the amine to the
trifluoroacetamide and removal of the silyl group, led to
alcohol 18. Dess-Martin oxidation10 of alcohol 18 to the
corresponding aldehyde and subsequent Peterson olefination
then afforded intermediate 19. All attempts to directly
N-alkylate the anion derived from trifluoroacetamide 19 with
3-iodo-2-chloropropene failed.11 Therefore, it was necessary
to first remove the trifluoroacetyl group to generate the
In conclusion, we have developed a convergent synthesis
of the Baran pentacycle 3 which requires 13 steps and
(11) Nordlander, J. E.; Catalane, D. B.; Eberlein, T. H.; Farkas, L. V.;
Howe, R. S.; Stevens, R. M.; Tripoulas, N. A. Tetrahedron Lett. 1978, 4987.
(12) Lebegue, N.; Bethegnies, G.; Berthelot, P. Synth. Commun. 2004,
34, 1041.
(13) Van der Veken, P.; Kertesz, I.; Senten, K.; Haemers, A.; Augustyns,
K. Tetrahedron Lett. 2003, 44, 6231.
Org. Lett., Vol. 8, No. 11, 2006
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