Anionic cyclizations of chiral 2,3-dihydro-4-pyridones: A five-step, asymmetric synthesis of indolizidine 209D

Full text of DOI:10.1021/ja9626446

12248
J. Am. Chem. Soc. 1996, 118, 12248-12249
Scheme 1
Anionic Cyclizations of Chiral
2,3-Dihydro-4-pyridones: A Five-Step, Asymmetric
Synthesis of Indolizidine 209D
Daniel L. Comins* and Yue-mei Zhang
Department of Chemistry, North Carolina State UniVersity
Raleigh, North Carolina 27695-8204
ReceiVed July 30, 1996
As part of a program directed at studying the synthesis and
synthetic utility of chiral dihydropyridones,1 we are investigating
annulation reactions of N-acyl-2,3-dihydro-4-pyridones of the
type 1 using the Heck and anionic cyclization methods.
Although the Heck reaction is effective,2 the anionic cyclization
appears to be of broader synthetic utility. To effect an anionic
cyclization of 1, lithium-halogen exchange in the presence of
the enaminone system was considered. Since the metal-
halogen exchange of an aryl iodide is extremely rapid, it will
tolerate certain carbonyl functions such as ketones, esters, and
amides.3 Although N-alkylenaminones have been reported to
undergo intermolecular 1,2- or 1,4-addition with Grignard or
organolithium reagents,4 the intramolecular anionic 1,4-addition
to N-acylenaminones of the type 1 was unexplored. In addition
to the possibility of competing 1,2- and 1,4-addition to the enone
of 1, the N-acyl group is quite reactive1 and attack at this
carbonyl would complicate the anionic cyclization step. A clean
conversion and a high degree of stereoselectivity during the
anionic cyclization would be required to make the method
attractive for use in natural product synthesis. Since N-acyl-
2,3-dihydro-4-pyridones of various structure are readily available,1b
we initiated a study to explore the potential of anionic
cyclizations of 1. Our preliminary results, and application of a
related anionic cyclization in a concise asymmetric synthesis
of indolizidine alkaloid 209D, are reported herein.
Table 1. Anionic Cyclizations of Dihydropyridones 1
entry
Ra
product
yield,b %
1
2
3
4
5
Ph
c-hex
vinyl
HCtC
C4H9CtC
2a
2b
2c
2d
2e
91
86
89
88
86
a The reactions were carried out on a 0.5 mmol scale in THF and
quenched at -78 °C with saturated aqueous NaHCO3. b Yield of product
obtained from radial preparative-layer chromatography (silica gel,
EtOAc/hexanes).
The required N-acyldihydropyridones 1 were prepared by
adding a Grignard reagent to 1-acylpyridinium salt 3, formed
in situ from 4-methoxypyridine and 2-iodobenzoyl chloride
(THF, -42 °C, 30 min), as shown in Scheme 1.2 The anionic
cyclization3 was carried out by adding 1.1 equiv of n-
butyllithium to the dihydropyridone 1 in THF at -78 °C. After
30 min, the reaction was quenched with aqueous sodium
bicarbonate to give high yields (86-91%) of trans-indolizidi-
nones 2 as shown in Table 1. The reactions appear by NMR
analysis to be completely stereoselective for the trans isomer
and free of byproducts resulting from n-butyllithium addition
to the dihydropyridone. The stereoselectivity of this reaction
is in contrast to, and therefore compliments, the intermolecular
polar addition to C-2 substituted N-acyl-2,3-dihydro-4-pyridones
which affords cis-2,6-disubsubstituted 4-piperidones. The
analogous cyclization of the N-benzyl derivative 5, prepared
from pyridinium salt 4, also occurred under similar conditions
to give 6 in 50% yield (Scheme 2). Again, none of the cis
diastereomer corresponding to 6 could be detected by 1H NMR
analysis. It is noteworthy that an analogous cyclization attempt
on 5 using a Heck reaction failed, and only dehalogenated
product was isolated.2 Also, radical cyclization of the bromide
Scheme 2
corresponding to 5 is reported to give poor diastereoselectivity
(3:1) in favor of 6.5
A dihydropyridone anionic cyclization of the type depicted
in Scheme 2 was utilized in a very concise synthesis of the
poison-dart frog alkaloid,6 (+)-indolizidine 209D (11), as shown
in Scheme 3. The 1-acylpyridinium salt, prepared in situ from
4-methoxy-3-(triisopropylsilyl)pyridine7 and (1S,2R,4S)-2-(1-
methyl-1-phenylethyl)-4-(2-propyl)cyclohexanol (CPC),8 was
(1) (a) Comins, D. L.; Guerra-Weltzien, L. Tetrahedron Lett. 1996, 37,
3807 and references cited therein. (b) Comins, D. L.; Joseph, S. P. In
AdVances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI Press, Inc.:
Greenwich, CT, 1996; Vol. 2, pp 251-294.
(2) Comins, D. L.; Joseph, S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37,
793.
(3) For a review on anionic cyclizations, see: Thebtaranonth, C.;
Thebtaranonth, Y. Cyclization Reactions; CRC Press, Inc.: London, 1994;
Chapter 4, pp 169-242.
(4) (a) For a review on the chemistry of enaminones, see: Greenhill, J.
V. Chem. Soc. ReV. 1977, 6, 277-294. (b) Shawe, T. T.; Landino, L. M.;
Ross, A. A.; Prokopowicz, A. S.; Robinson, P. M.; Cannon, A. Tetrahedron
Lett. 1996, 37, 3823 and references cited therein.
(5) Beckwith, A. L. J.; Joseph, S. P.; Mayadunne, T. A. J. Org. Chem.
1993, 58, 4198.
(6) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1993; Vol. 43, pp
185-288. (b) For an asymmetric synthesis of indolizidine 209D, see:
Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688.
S0002-7863(96)02644-3 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 48, 1996 12249
Scheme 3
Lithium-halogen exchange and subsequent anionic cyclization
occurred on addition of tert-butyllithium (1.1 equiv, THF, -78
°C, 1 h) to 9. In this case, tert-butyllithium was used in place
of n-butyllithium to avoid byproducts resulting from dehydro-
halogenation and alkylation by the in situ formed n-butyl iodide.
The intermediate ketone enolate was trapped with N-(5-chloro-
2-pyridyl)triflimide11 to provide an 80% yield of vinyl triflate
10, which was determined to be enantiomerically pure by chiral
column HPLC. The anionic cyclization was again highly
stereospecific as only the trans diastereomer 10 could be detected
by 1H NMR analysis. Catalytic hydrogenation directly reduced
24
10 to (+)-indolizidine 209D (11) in 79% yield [[R]D +10.1
(c 0.42, CH2Cl2)] [lit.4b [R]D + 8.0 (c 1.0, CH2Cl2)].12,13
In summary, a stereoselective anionic cyclization of 2-sub-
stituted 1-acyl- or 1-alkyl-2,3-dihydro-4-pyridones to give trans-
indolizidinones has been developed. The method was utilized
in a five-step, highly stereocontrolled asymmetric synthesis of
alkaloid 11, which was carried out with an overall yield of 35%.
Work is in progress on the enantioselective synthesis of other
indolizidine and related alkaloids using this concise, practical
strategy.
Acknowledgment. We express appreciation to the National Insti-
tutes of Health (Grant GM 34442) and the Petroleum Research Fund
(ACS-PRF #28394-AC) for financial support of this research. Y.Z.
also thanks the Burroughs Wellcome Fund for a graduate fellowship.
NMR and mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the North Carolina
Biotechnology Center and the National Science Foundation (Grant
CHE-9121380).
treated with n-hexylmagnesium bromide to give dihydropyridone
7 in 87% yield after chromatography (silica gel, 4% EtOAc/
hexane). HPLC analysis of the crude product showed that the
reaction proceeded in 92% diastereomeric excess. Removal of
the chiral auxiliary (>95% recovery) and the C-5 triisopropyl-
silyl group provided enantiopure 8 in 86% yield as an oil
Supporting Information Available: Experimental details for the
preparation of 2b and 7-11, physical properties and spectroscopic data
1
for 2b,d,e and 7-11, and H and 13C NMR spectra of 2d, 8-10 (20
pages). See any current masthead page for ordering information and
Internet access instructions.
24
[[R]D -336 (c 0.27, CH2Cl2)] via a one-pot reaction.9
N-Alkylation of 8 was effected in 74% yield by deprotonation
(NaHMDS, THF, -78 °C, 30 min) and addition of (Z)-1,3-
diiodopropene10 (-78 °C f 0 °C) to give vinyl iodide 9.
JA9626446
(10) (a) Meyer, C.; Marek, I.; Normant, J.-F. Synlett 1993, 386. (b) Sato,
Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371.
(11) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(12) The spectral properties of (+)-11 were in agreement with those
reported.6b See table of spectral data in the Supporting Information.
(13) All new compounds were spectroscopically characterized and
furnished satisfactory elemental analyses (C, H, N (0.4%) or high-resolution
mass spectra. Details are provided in the Supporting Information.
(7) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
(8) Comins, D. L.; Guerra-Weltzien, L.; Salvador, J. M. Synlett 1994,
972.
(9) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993,
58, 7732.