IMDA/retro-Mannich approach to cis-perhydroquinoline Lycopodium alkaloids: Asymmetric synthesis of (+)-luciduline

Article abstract of DOI:10.1021/ol990028j

(equation presented) The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished. Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich r

Full text of DOI:10.1021/ol990028j

ORGANIC
LETTERS
1999
Vol. 1, No. 2
229-231
IMDA/Retro-Mannich Approach to
cis-Perhydroquinoline Lycopodium
Alkaloids: Asymmetric Synthesis of
(+)-Luciduline
Daniel L. Comins,* Clinton A. Brooks, Rima S. Al-awar, and R. Richard Goehring
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received April 9, 1999
ABSTRACT
The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished.
Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich ring opening, and a novel cationic reductive
cyclization reaction.
The Lycopodium alkaloids are diverse in structure and have
provided challenging targets for total synthesis.1 Luciduline
(1) is a cis-perhydroquinoline alkaloid isolated from Lyco-
podium lucidulum.2 The presence of a cyclohexanone ring
in its skeleton makes 1 unique among this group of naturally
occurring alkaloids. Four racemic syntheses2 of 1, and one
enantioselective route3 starting from (+)-pulegone, have
appeared in the literature. We report in this Letter the first
chiral auxiliary mediated asymmetric synthesis of (+)-
luciduline, which features new strategies and methods for
the stereoselective construction of cis-perhydroquinoline-
containing alkaloids.
1-acylpyridinium salt 2, would be converted to 1,2-dihydro-
pyridine 4. Intramolecular Diels-Alder (IMDA) and sub-
Scheme 1
Our strategy for the total synthesis of 1 is shown in Scheme
1. The enantiopure dihydropyridone 3, prepared from chiral
(1) (a) Ayer, W. A.; Trifonov, L. S. The Alkaloids; Cordell, G. A., Brossi,
A., Eds.; Academic Press: San Diego, 1994; Vol. 45, pp 233-274. (b)
Blumenkopf, T. A.; Heathcock, C. H. Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp
185-240.
(2) (a) Schumann, D.; Naumann, A. Liebigs Ann. Chem. 1984, 1519.
(b) Szychowski, J.; MacLean, D. B. Can. J. Chem. 1979, 57, 1631. (c)
Scott, W. L.; Evans, D. A. J. Am. Chem. Soc. 1972, 94, 4779. (d) Oppolzer,
W.; Petrzilka, M. J. Am. Chem. Soc. 1976, 98, 6722.
(3) Oppolzer, W.; Petrzilka, M. HelV. Chim. Acta 1978, 61, 2755.
10.1021/ol990028j CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/11/1999

sequent reduction leads to 5, which after retro-Mannich ring
opening is converted to enecarbamate 6. Completion of the
synthesis requires a novel tandem cationic alkylation/
reduction cyclization reaction.
The enantiopure Grignard reagent 74 was added to
1-acylpyridinium salt 2, prepared in situ from 4-methoxy-
3-(triisopropylsilyl)pyridine5 and the chloroformate of (+)-
trans-2-(R-cumyl)cyclohexanol (TCC),6,7 to give N-acyldihy-
dropyridone 8 in 80% yield8 (Scheme 2). One-pot removal
yield of intermediate 3. Oxidative cleavage of the terminal
alkene in 3 and subsequent Horner-Wadsworth-Emmons
olefination provided ester 10. The 1,2-dihydropyridine 4 was
efficiently prepared in two steps (98%) by Luche reduction
of 10 and subsequent dehydration with Furukawa’s9 reagent.
Intramolecular Diels-Alder reaction of 4 in refluxing xylene
provided an 86% yield of the tricyclic carbamate 11.10
Catalytic hydrogenation of 11 gave a near quantitative yield
of amino ester 5. The structure of 5 was confirmed by single-
crystal X-ray analysis. On the basis of our model studies,10
ring opening of 5 was anticipated to occur on treatment with
excess base (i.e., LDA) as depicted in Scheme 3. Retro-
Scheme 2
Scheme 3
Mannich ring opening (10 LDA, 10 i-Pr2NH, THF, -50 °C)
and quenching with chlorotrimethylsilane provided a crude
mixture of polysilylated derivatives 14 (Scheme 4). Without
purification, the mixture was N-acylated with benzyl chlo-
roformate in refluxing methylene chloride to give the
enecarbamate 15 in 51% yield. Completion of the synthesis
required a cyclization at the â-position of the enecarbamate
Scheme 4
of the chiral auxiliary and TIPS group provided a high yield
of enantiopure dihydropyridone 9 with 95% recovery of the
chiral auxiliary, (+)-TCC. Deprotonation with n-BuLi and
addition of benzyl chloroformate gave a near quantitative
(4) The Grignard reagent was prepared from the chloride, which was
derived from the known enantiopure alcohol, see: Evans, D. A.; Bender,
S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506.
(5) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
(6) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(7) The (+)- and (-)-TCC alcohols are available from Aldrich Chemical
Co.
(8) The yield is for diastereomerically pure 8 isolated by radial preparative
layer chromatography. The stereoselectivity ranged from 85 to 90%.
230
Org. Lett., Vol. 1, No. 2, 1999

olefin. After several unsuccessful attempts at intramolecular
acylations, the ester 15 was reduced to the aldehyde 6 with
DIBAL. The desired ring formation was obtained via a
cationic reductive cyclization reaction. On treatment of 6 with
SnCl4 in the presence of triethylsilane, a 61% yield of alcohol
16 was obtained. The reactive N-acyliminium ion formed
during the cyclization step is rapidly reduced by triethylsilane
to give the desired tricyclic carbamate. The ketone 17 was
obtained from 16 in near quantitative yield using Dess-
Martin oxidation. Finally, deprotection and reductive meth-
ylation were carried out using a one-pot procedure11 to give
(+)-luciduline (1) in high yield [[R23D] +85.3 (c 0.15,
MeOH); lit4 [RD] +87 (c 2.05, MeOH)]. Our synthetic 1 is
identical in all respects to the natural material.4
In summary, the first chiral auxiliary mediated asymmetric
synthesis of (+)-luciduline has been accomplished from
readily available materials in 14 steps (10% overall) with a
high degree of stereocontrol.12 The IMDA/retro-Mannich
strategy should be amenable to the synthesis of other cis-
decahydroquinoline alkaloids, and work is in progress toward
this goal.
Acknowledgment. We express appreciation to the Na-
tional Institutes of Health (Grant GM 34442) for financial
support of this research. C.B. and R.A. also thank the
Burroughs Wellcome Fund for graduate fellowships.
(9) Furukawa, J.; Morisaki, N.; Kobayashi, H.; Iwasaki, S.; Nozoe, S.;
Okuda, S. Chem. Pharm. Bull. 1985, 33, 440.
(10) Onyl a single Diels-Alder product was observed. For model studies
on related IMDA reactions and subsequent ring opening, see: Comins, D.
L.; Al-awar, R. S. J. Org. Chem. 1992, 57, 4098.
(11) Rosenberg, S. H.; Spina, K. P.; Condon, S. L.; Polakowski, J.; Yao,
Z.; Kovar, P.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.; Egan,
D. A.; Tricarico, K. A.; Perun, T. J.; Baker, W. R.; Kleinert, H. D. J. Med.
Chem. 1993, 36, 460.
(12) The structure assigned to each new compound is in accord with its
IR and 1H and 13C NMR spectra and elemental analysis or high-resolution
mass spectra.
Supporting Information Available: Characterization
data for compounds 1, 3-6, 8-11, and 15-17 and X-ray
data for 5 . This material is available free of charge via the
Internet at http://pubs.acs.org.
OL990028J
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