Model studies toward the total synthesis of the Lycopodium alkaloid spirolucidine

Article abstract of DOI:10.1021/ol016556o

(figure presented) A strategy for the synthesis of the spirocyclic core of spirolucidine was explored through a model study. The diene 4a was prepared and photolyzed to give the desired [2 + 2] photoadduct 17 containing the correct relative stereochemistr

Full text of DOI:10.1021/ol016556o

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3217-3220
Model Studies toward the Total
Synthesis of the Lycopodium Alkaloid
Spirolucidine
Daniel L. Comins* and Alfred L. Williams
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received August 9, 2001
ABSTRACT
A strategy for the synthesis of the spirocyclic core of spirolucidine was explored through a model study. The diene 4a was prepared and
photolyzed to give the desired [2 + 2] photoadduct 17 containing the correct relative stereochemistry corresponding to spirolucidine.
Spirolucidine (1) was isolated from Lycopodium lucidulum
by Ayer and co-workers, and the relative stereochemistry
of the alkaloid was determined by chemical, spectroscopic,
and X-ray studies.1 No biological or synthetic studies have
been previously reported on this complex natural product.
As part of our program directed at developing N-acyl-2,3-
dihydro-4-pyridones as chiral building blocks for alkaloid
synthesis,2,3 we have been exploring strategies for the
construction of spirolucidine. Herein is reported a model
study of a photochemical approach to the spirocyclic core
of 1.
arise from an intramolecular [2 + 2] photocyclization of
dihydropyridone 3 (Scheme 1). To determine the feasibility
Scheme 1
One potential route to 1 involves the preparation and
cyclobutane ring opening of intermediate 2, which would
10.1021/ol016556o CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

of the key photocyclization step, a model study was carried
out.
Scheme 4
Dihydropyridone 4a was chosen as a model photosubstrate
that would mimic 3 in the photocycloaddition step. The
synthesis of 4a was accomplished by the coupling of 6-iodo-
2,3-dihydro-4-pyridone 5 with alkyne 6 followed by selective
reduction and desilylation (Scheme 2).
Scheme 2
steps as previously described.5 Regioselective reduction of
10 with phenyl chloroformate and tributyltin hydride6
provided a 75% yield of the 1,2-dihydropyridine 11. The
next step in the synthesis required a regioselective function-
alization at C-3 of 11. The Vilsmeier-Haack reaction
afforded the desired aldehyde 12 in 80% yield. In the absence
of a C-5 TIPS group, this type of 1,2-dihydropyridine
formylates regioselectively at C-5.5,7 Luche reduction of the
aldehyde, regioselective catalytic hydrogenation of the 3,4-
double bond, and Swern oxidation provided aldehyde 13.
The desired alkyne intermediate 6 was prepared by adding
13 to the Seyfert-Gilbert reagent7 and t-BuOK in THF at
-78 °C.
Intermediate 5 was prepared using 1-acylpyridinium salt
chemistry.2 Treatment of 4-methoxypyridine with phenyl
chloroformate and isobutylmagnesium chloride provided a
crude 1-phenoxycarbonyl-1,2-dihydropyridine that was con-
verted to the Boc derivative 7 with t-BuOK in THF.4a The
overall yield for the two-step process was 95% (Scheme 3).
Scheme 3
The two heterocycles, 5 and 6, were joined using a
Sonogashira reaction.9 In the presence of palladium(II)
iodide, triphenylphosphine, and copper(I) iodide, cross-
coupling occurred to give an 87% yield of diastereomers 14
(Scheme 5). With the TIPS group still protecting its appended
double bond, chemoselective reduction of the alkyne could
be carried out. Catalytic hydrogenation of 14 gave dihydro-
(3) For recent and leading references, see: (a) Comins, D. L.; Zhang,
Y. J. Am. Chem. Soc. 1996, 118, 12248. (b) Comins, D. L.; Chen, X.;
Morgan, L. A. J. Org. Chem. 1997, 62, 7435. (c) Comins, D. L.; LaMunyon,
D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182. (d) Comins, D. L.; Green,
G. M. Tetrahedron Lett. 1999, 40, 217. (e) Comins, D. L.; Libby, A. H.;
Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64, 2184. (f) Comins, D.
L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org. Lett. 1999, 1, 229.
(g) Comins, D. L.; Zhang, Y.; Joseph, S. P. Org. Lett. 1999, 1, 657. (h)
Comins, D. L.; Fulp, A. B. Org. Lett. 1999, 1, 1941. (i) Kuethe, J. T.;
Comins, D. L. Org. Lett. 2000, 2, 855. (j) Huang, S.; Comins, D. L. J.
Chem. Soc., Chem. Commun. 2000, 7, 569. (k) Comins, D. L.; Huang, S.;
McArdle, C. L.; Ingalls, C. L. Org. Lett. 2001, 3, 469. (l) Comins, D. L.;
Sandelier, M. J.; Abad Grillo, T. J. Org. Chem. In press.
Directed lithiation of dihydropyridine 7 with n-BuLi, addition
of iodine, and workup with oxalic acid afforded the 6-iodo-
2,3-dihydro-4-pyridone 8 in 75% yield. A carbamate
exchange4b was effected in two steps by removal of the
N-Boc group with TMSI to give 9. Deprotonation and re-
acylation with phenyl chloroformate provided intermediate
5.
(4) (a) Comins, D. L.; Weglarz, M. A.; O’Connor, S. Tetrahedron Lett.
1988, 29, 1751. (b) The N-Boc group was necessary to effect the directed
lithiation of 7; however, subsequent carbamate exchange, 8 f 5, was needed
to provide easily purified intermediates and crystalline photocycloaddition
products.
(5) Comins, D. L.; Myoung, Y. C. J. Org. Chem. 1990, 55, 292.
(6) Tributyltin hydride has been used to reduce N-acylisoquinolinium
salts to dihydroisoquinolines, see: Yamaguchi, R.; Hamasaki, T.; Utimoto,
K. Chem. Lett. 1988, 913.
(7) (a) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993,
58, 7732. (b) Comins, D. L.; Herrick, J. J. Heterocycles 1987, 26, 2159.
(8) (a) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 48, 4155.
(b) Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois, R. G.;
Hoye, T. R. J. Org. Chem. 1996, 61, 2540.
The alkyne 6 was prepared as depicted in Scheme 4. The
silylpyridine 10 was prepared from 2-chloropyridine in two
(1) Ayer, W. A.; Ball, L. F.; Browne, L. M.; Tori, M.; Delbaere, L. T.
J.;Silverberg, A. Can. J. Chem. 1984, 62, 298.
(2) (a) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen Hetero-
cycles; Moody, C. J., Ed.; JAI Press Inc.; Greenwich, CT, 1996; Vol. 2, pp
251-294. (b) Comins, D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic
Chemistry, 2nd ed.; McKillop, A., Ed.; Pergamon Press: Oxford, England,
1996; Vol. 5, pp 37-89.
(9) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 2.4.
3218
Org. Lett., Vol. 3, No. 20, 2001

Scheme 5
Scheme 6
In an attempt to prevent the secondary cyclization, the
photocycloaddition was repeated using a Vycor filter (>210
nm). After 2 h, the starting material was gone, and only one
product was observed by TLC. Chromatographic purification
afforded a 55% yield of the photoadduct as a white solid,
mp 152-3 °C. Single-crystal X-ray analysis confirmed that
the reaction proceeded in the desired manner with complete
control of stereochemistry to provide tetracyclic ketone 17.
The observed facial selectivity was anticipated on the basis
of our earlier photochemical studies of 2,3-dihydro-4-
pyridones.13 Due to A(1,3) strain, the isobutyl group of 4a
occupies an axial orientation, and cyclization takes place on
the more accessible alkene face opposite the large C-2
substituent.
This successful model study lends credence to our
proposed plan for the total synthesis of spirolucidine (1).
Although the cyclobutane cleavage of 17 was not investi-
gated, the required regioselective ring opening of similar ring
systems has been carried out in our laboratories.13 Further
synthetic studies toward 1 are underway and will be reported
in due course.14
pyridones 15a and 15b which were separated by radial PLC
(silica gel, EtOAc/hexanes). The TIPS group was now
removed with TFA/CHCl3 to afford the corresponding
intermediates 4a and 4b in 64% and 56% yields, respectively.
The stereochemical assignments for diastereomers 15 and 4
were tentative initially, but they were confirmed through the
results obtained from the subsequent photochemical studies.10
Acknowledgment. We express appreciation to the Na-
tional Institutes of Health (Grant GM 34442) for financial
support of this research. A.W. also thanks the NIH for a
Irradiation of photosubstrate 4a in acetonitrile (450-W
Hanovia Hg lamp, 8 h)11 gave a 25% yield of a white solid,
mp 125-6 °C (Scheme 6). Single-crystal X-ray analysis
showed that the photocycloaddition did not proceed to give
the desired product but instead provided the pentacyclic
cyclopropanol 16. Examination of the literature indicated that
the cyclopropane ring formation probably resulted from a
secondary photoinitiated reaction on the primary adduct.12
(12) Related photochemical cyclopropanol syntheses have been reported,
see: (a) Henning, H. G.; Haber, H.; Buchholz, H. Pharm. 1981, 36, 160.
(b) Henning, H. G.; Berlinghoff, R.; Hahlow, A.; Koeppl, H. J. Prakt. Chem.
1981, 323, 914. (c) Wyss, C.; Batra, R.; Lehmann, C.; Sauer, S.; Giese, B.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2529. (d) Sauer, S.; Schumacher,
A.; Barbosa, F.; Giese, B. Tetrahedron Lett. 1998, 39, 3685. (e) Boyle, P.
H.; Nelson, P. H.; Sunder-Plassmann, P.; Crabbe, P.; Edwards, J. A.; Green,
D.; Iriarte, J.; Murphy, J. W.; Zderic, J.; Fried, J. H. Proc. Int. Symp. Drug
Res. 1967, 206-16.
(13) (a) Comins, D. L.; Zheng, X. J. Chem. Soc., Chem. Commun. 1994,
2681. (b) Comins, D. L.; Lee, Y. S.; Boyle, P. D. Tetrahedron Lett. 1998,
39, 187. (c) Comins, D. L.; Zhang, Y.-M.; Zheng, X. J. Chem. Soc., Chem.
Commun. 1998, 2509.
(10) Under the conditions used for the photocyclization of 4a, irradiation
of 4b gave only recovered starting material.
(11) For recent reviews of [2 + 2] photocycloaddition, see: (a) Schuster,
D. I.; Lem, G.; Kaprinidis, N. A. Chem. ReV. 1993, 93, 3-22. (b) De
Keukeleire, D.; He, S.-L. Chem. ReV. 1993, 93, 359-380. (c) Crimmins,
M. T.; Reinhold, T. L. Org. React. 1993, 44, 297-588. (d) Winkler, J. D.;
Bowen, C. M.; Liotta, F. Chem. ReV. 1995, 95, 2003-2020.
(14) The structure assigned to each new compound is in accordance with
its IR, 1H NMR, and 13C NMR spectra and elemental analysis or high-
resolution mass spectra.
Org. Lett., Vol. 3, No. 20, 2001
3219

Minority Graduate Research Assistantship. The authors thank
Dr. Paul Boyle for X-ray crystallographic analyses of 16 and
17. NMR and mass spectra and X-ray data were obtained at
NCSU instrumentation laboratories, which were established
by grants from the North Carolina Biotechnology Center and
the National Science Foundation (Grants CHE-9509532,
CHE-0078253, CHE-9509532).
Supporting Information Available: Characterization
data for compounds 4-6, 8-9, and 11-17, 1H and 13C NMR
spectra of 4-6, 13, 16, and 17, and ORTEP plots and X-ray
crystal data (cif format) for 16 and 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016556O
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