Enantiopure 2,3-Dihydro-4-pyridones as Synthetic Intermediates: A Concise Asymmetric Synthesis of (+)-Allopumiliotoxin 267A

Article abstract of DOI:10.1021/ol0069709

(Matrix Presented) A concise asymmetric synthesis of (+)-allopumiliotoxin 267A has been accomplished using an enantiopure dihydropyridone building block. The synthesis is highly stereoselective and requires 10 steps from readily available material.

Full text of DOI:10.1021/ol0069709

ORGANIC
LETTERS
2001
Vol. 3, No. 3
469-471
Enantiopure 2,3-Dihydro-4-pyridones as
Synthetic Intermediates: A Concise
Asymmetric Synthesis of
(+)-Allopumiliotoxin 267A
Daniel L. Comins,* Shenlin Huang, Cheryl L. McArdle, and Charles L. Ingalls
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received December 6, 2000
ABSTRACT
A concise asymmetric synthesis of (+)-allopumiliotoxin 267A has been accomplished using an enantiopure dihydropyridone building block.
The synthesis is highly stereoselective and requires 10 steps from readily available material.
The skin secretions of neotropical frogs of the family
Dendrobatidae have been a fruitful source of biologically
active indolizidine alkaloids.1 One group of these alkaloids,
the allopumiliotoxins, has stimulated considerable synthetic
efforts due to their unique structures and biological activities.2
These studies have resulted in numerous new synthetic
methodologies and novel strategies for the construction of
indolizidines.
core 2 which is Overman’s intermediate2a for the preparation
of various allopumiliotoxins. The key intermediate 3 was to
Scheme 1
In our laboratories we have been exploring the utility of
enantiopure N-acyl-2,3-dihydro-4-pyridones as chiral build-
ing blocks for the stereocontrolled synthesis of various
alkaloids.3 As part of this program, we developed a novel
strategy (Scheme 1) for a concise synthesis of the indolizidine
(1) For reviews, see: (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1999; Vol. 13, Chapter 1. (b) Daly, J. W. J. Nat. Prod.
1998, 61, 162. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F. Alkaloids
1993, 43, 185-288.
(2) (a) Franklin, A. S.; Overman, L. E. Chem. ReV. 1996, 96, 505-522.
(b) Okamoto, S.; Iwakubo, M.; Kobayashi, K.; Sato, F. J. Am. Chem. Soc.
1997, 119, 6984. (c) Tan, C.-H.; Stork, T.; Feeder, N.; Holmes, A. B.
Tetrahedron Lett. 1999, 40, 1397. (d) Tang, X.-Q.; Montgomery, J. J. Am.
Chem. Soc. 2000, 122, 6950.
(3) (a) Huang, S.; Comins, D. L. Chem. Commun. 2000, 569. (b) Kuethe,
J. T.; Comins, D. L. Org. Lett. 2000, 2, 855 and references therein.
10.1021/ol0069709 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/10/2001

be prepared in six steps from readily available pyridine 5. It
was anticipated that 3 could be converted to known 2 in two
steps. Our strategy proved successful, and we now report a
concise and highly stereocontrolled asymmetric synthesis of
2 and (+)-allopumiliotoxin 267A (1).
Preliminary studies indicated that incorporation of the C-8
methyl group late in the synthesis would be problematic.
To circumvent this potential problem, the needed methyl
group was introduced during the first step as shown in
Scheme 2. Methylation at the C-5 position of 4-methoxy-
intermediate enol ether during workup. With the TIPS group
protecting the enone system, catalytic hydrogention of 7 gave
8 in quantitative yield. Treatment of 8 with lithium methoxide
(MeOH, reflux, 18 h) effected removal of the chiral auxiliary
(95% recovery) and cyclization to afford indolizidinone 9
as an 8:1 mixture of diastereomers. Acetoxylation of mixture
9 proceeded in a stereocontrolled manner on treatment with
Pb(OAc)4 in refluxing AcOH/m-hexafluoroxylene to give
10.9 The stereoselectivity can be explained by invoking an
intramolecular acetate transfer from an enol-lead triacetate
intermediate (Figure 1). Because of stereoelectronic control,10
Scheme 2
Figure 1. Axial acetoxylation of 9 with Pb(OAc)4. The hydrogens
have been removed for clarity.
3-(triisopropylsilyl)pyridine4 occurred via lithiation with
mesityllithium5 (THF, -23 °C, 3 h) and treatment with
methyl iodide to give 6. To a 1-acylpyridinium salt, prepared
in situ from 6 and (+)-TCC chloroformate,6 was added
lithiated ethyl propiolate7 (THF, -78 °C) followed by acidic
workup to provide dihydropyridone 7 in 70% yield. The
diastereoselectivity of this reaction was determined to be
>96% by HPLC and NMR analysis of the crude product.
The stereochemistry at C-2 of 7 was assigned R by analogy
to similar reactions reported from these laboratories.4 The
configuration at C-3 was determined to be R on the basis of
1H NMR coupling constants (JH2-3 ) 5.5 Hz; calcd cis JH2-3
) 3.8 Hz, trans JH2-3 ) 1.0 Hz).8 The observed stereo-
chemistry at C-3 is likely a result of axial protonation of the
the acetate transfer occurs from the axial direction to maintain
a chairlike transition state. Protodesilylation of 10 using
formic acid (reflux, 2 h) provided a 93% yield of enantiopure
3 (Scheme 3). A one-pot reduction using K-Selectride
followed by LiAlH4 gave diol 11 in high yield. The reduction
was completely stereoselective at C-7, providing the equato-
rial alcohol (JH7-6 ) 11.0, 5.1 Hz). Oxidation under Swern
conditions11 afforded Overman’s intermediate 2 which was
converted in 48% overall yield to (+)-allopumiliotoxin 267A
using a modified literature procedure.12 Lithiation of 2 with
trityllithium (2.0 equiv), addition of chiral aldehyde 12 (1.2
equiv), and dehydration was effected by a one-pot process
(9) For acetoxylation of C-3 unsubstituted N-acyl-2,3-dihydro-4-pyridones
with Pb(OAc)4, see: Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle,
C. L. Tetrahedron Lett. 1998, 39, 5693.
(10) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983; Chapter 6. (b) Brown, J. D.; Foley, M.
A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110, 0. 7445.
(11) (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
43, 2480. (b) The C-7 epimer of 11 has been oxidized to 2 under Swern
conditions, see ref 2c.
(4) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
(5) For lithiation of methoxypyridines with mesityllithium, see: Comins,
D. L.; LaMunyon, D. H. Tetrahedron Lett. 1998, 29, 773.
(6) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(7) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28.
(8) Calculations of coupling constants were performed using PCMODEL
(v 7.0), Serena Software, Bloomington, IN.
(12) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org. Chem.
1992, 57, 1179.
470
Org. Lett., Vol. 3, No. 3, 2001

A concise and highly stereocontrolled asymmetric syn-
thesis of (+)-allopumiliotoxin 267A (1) has been carried out
in 10 steps from readily available materials. Key steps in
the synthesis include (1) a regio- and stereospecific addition
of an alkynyllithium to a 1-acylpyridinium salt of trisubsti-
tuted pyridine 6, (2) an axial acetoxylation of indolizidinone
9 with Pb(OAc)4, and (3) a one-pot reduction of intermediate
3 to provide diol 11. Our synthesis compliments earlier work
in this area1,2 and expands the considerable utility of
enantiopure N-acyl-2,3-dihydro-4-pyridones as synthetic
intermediates.
Scheme 3
Acknowledgment. We express appreciation to the Na-
tional Institutes of Health (Grant GM 34442) for financial
support of this research. We are grateful to Dr. A. Holmes
for useful experimentals and spectral data of intermediate
2. NMR and mass spectra were obtained at NCSU instru-
mentation laboratories, which were established by grants
from the North Carolina Biotechnology Center and the
National Science Foundation (Grants CHE-9121380 and
CHE-9509532).
Supporting Information Available: Characterization
data for compounds 1-3, 6-11, and 13 and comparison
tables of NMR data for synthetic 1. 1H and 13C NMR spectra
of 3, 8, and 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
to give keto alcohol 13. Reduction with Me4NBH(OAc)3
OL0069709
1
provided the natural product 1 in excellent yield. The H
and 13C NMR data and the optical rotation of 1 [[R]2D5
+30.0 (c 0.50, CHCl3)] are in agreement with literature
values.12,13
(13) 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.
Org. Lett., Vol. 3, No. 3, 2001
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