Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Synthesis of (-)-Slaframine

Article abstract of DOI:10.1021/ol991083v

(matrix presented) (-)-slaframine An asymmetric synthesis of (-)-slaframine and N-acetylslaframine has been accomplished starting from an enantiopure dihydropyridone building block. The oxygen-carbon bond at C-1 was incorporated with complete stereoselect

Full text of DOI:10.1021/ol991083v

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1941-1943
Enantiopure N-Acyldihydropyridones as
Synthetic Intermediates: Asymmetric
Synthesis of (−)-Slaframine
Daniel L. Comins* and Alan B. Fulp
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received September 23, 1999
ABSTRACT
An asymmetric synthesis of (−)-slaframine and N-acetylslaframine has been accomplished starting from an enantiopure dihydropyridone building
block. The oxygen−carbon bond at C-1 was incorporated with complete stereoselectivity by using an efficient phenylselenocyclocarbamation
reaction.
The synthetic transformation of readily available chiral
building blocks is an attractive method for the preparation
of enantiopure natural products and bioactive compounds.1
N-Acyldihydropyridones 1 are easily prepared as either
antipode using chiral 1-acylpyridinium salt chemistry.2 As
part of a program directed at expanding the scope of
heterocycles 1 as synthetic intermediates, we began a study
on the total synthesis of the indolizidine alkaloid (-)-
slaframine (2). Alkaloid 2 is a metabolite of the fungus
Rhizoctonia leguminicola, which can infest ruminant for-
ages.3 Due to the presence of slaframine, excessive salivation
in animals occurs after consumption of the infested vegeta-
tion. The biological activity of (-)-slaframine may make it
clinically useful for the treatment of disease arising from
chlolinergic dysfunctions,4 and slaframine has been proposed
as a possible drug candidate for treatment of the symptoms
of cystic fibrosis sufferers.5 The alkaloid’s biological activity
has stimulated considerable synthetic effort.6 Herein we
describe a novel asymmetric synthesis of 2 that utilizes an
enantiopure N-acyl-2,3-dihydro-4-pyridone as a chiral build-
ing block.
The synthesis proceeded as shown in Scheme 1. The
alkenylcuprate 3 was added to a mixture of 4-methoxy-3-
(triisopropylsilyl)pyridine7 and the chloroformate of (-)-
(1) (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis; Wiley:
New York, 1987. (b) Ager, D. J.; East, M. B. Asymmetric Synthetic
Methodology; CRC Press: New York, 1995.
(2) Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am. Chem.
Soc. 1999, 121, 2651 and references therein.
(3) Harris, C. M.; Schneider, M. J.; Ungemach, F. S.; Hill, J. E.; Harris,
T. M. J. Am. Chem. Soc. 1988, 110, 940 and references therein.
(4) For a review, see: Croom, W. J.; Hagler, W. M.; Froetschel, M. A.;
Johnson, A. D. J. Anim. Sci. 1995, 73, 1499.
(5) Aust, S. D. Biochem. Pharmacol. 1969, 18, 929.
(6) (a) Sibi, M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434. (b)
Knight, D. W.; Sibley, A. W. J. Chem. Soc., Perkin Trans. 1 1997, 2179
and references therein.
(7) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
10.1021/ol991083v CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

provided bromovinyl triflate 8. At this stage, the synthetic
plan called for incorporation of a C-1 acetoxy precursor with
control of stereochemistry. This was accomplished by using
a phenylselenocyclocarbamation reaction.12 Addition of
PhSeCl to 8 gave a 70% yield of carbamate 9. The reaction
appears to be completely stereoselective as no other isomers
were found on purification. The stereochemistry of 9 was
tentatively assigned as shown on the basis of 1H NMR data
and transition state analysis. Oxidation of 9 with hydrogen
peroxide gave the alkene 10 in excellent yield. The stereo-
chemical assignment was confirmed by reducing 10 to the
known cyclic carbamate 11.13 Hydroboration-oxidation of
the terminal olefin in 10 provided the alcohol 12 (Scheme
2). Prior to hydrolysis of the cyclic carbamate, the labile
Scheme 1
Scheme 2
TCC8 to give N-acyldihydropyridone 4 in 61% yield.9 One-
pot removal of the chiral auxiliary and TIPS group provided
enantiopure dihydropyridone 5 in 75% yield along with 95%
recovery of the chiral auxiliary (-)-TCC. Deprotonation with
n-BuLi and addition of benzyl chloroformate gave a 94%
yield of intermediate 6. In preparation for the eventual
introduction of the required C-6 amino group of slaframine,
the C-5 position of dihydropyridone 6 was functionalized.
Treatment of 6 with NBS gave bromide 7 in high yield.10
Conjugate reduction of 7 with L-Selectride and trapping the
intermediate enolate with N-(5-chloro-2-pyridyl) triflimide11
(8) (a) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(b) Both (+)- and (-)-TCC alcohols are available from Aldrich Chemical
Co.
(9) The yield is of diastereomerically pure 4 isolated by radial preparative
layer chromatography. The reaction proceeded in 87% de.
(10) (a) Comins, D. L.; Chen, X.; Morgan, L. A. J. Org. Chem. 1997,
62, 7435. (b) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett.
1995, 36, 9141.
(11) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299.
bromovinyl triflate11 needed to be selectively reduced to a
vinyl bromide. After considerable effort, a modification of
Kotsuki’s procedure14 for reduction of enol triflates was
found to effect the required transformation. Treatment of 12
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Org. Lett., Vol. 1, No. 12, 1999

with triethylsilane in the presence of a catalytic amount of a
palladium catalyst (10% Pd(OAc)2, 10% dppf) gave a 11:1
mixture of the desired vinyl bromide 13 and over-reduced
alkene 14. After conversion of 13 to chloride 15, hydrolysis
with NaOH, in situ cyclization, and subsequent acylation
provided indolizidine 16. Several attempts to convert the
vinyl bromide moiety of 16 to a ketone were unsuccessful;
however, reaction with freshly prepared CuOAc15 in N-
methylpyrrolidone at 202 °C gave the diacetate 17 in good
yield.16 The diacetate 17 could be converted directly to oxime
18 under mild conditions. The oxime 18 is an intermediate
in previous slaframine syntheses; a highly stereoselective
reduction via catalytic hydrogenation gives slaframine.17 One
attempt at this known conversion on a small scale afforded
a mixture of (-)-slaframine (2) and deacetylslafamine 19.
The crude mixture was acylated with acetic anhydride and
purified to yield N-acetylslaframine 20. Our synthetic 20
exhibited spectral data in agreement with reported data for
authentic material.18 The optical rotation [[R]25 -10.0 (c
D
0.06, EtOH)] also agrees with the literature value [[R]25
D
-11.2 (c 1.45, EtOH)].18
An asymmetric synthesis of (-)-slaframine and N-acetyl-
slaframine has been carried out starting from an enantiopure
dihydropyridone building block.19 Although the synthetic
route is not as short as some others,6 it is highly stereo-
controlled and represents the first asymmetric synthesis of
slaframine using a recyclable chiral auxiliary. Key transfor-
mations in the synthesis include (1) a highly stereoselective
phenylselenocyclocarbamation reaction to give 9, (2) a
chemoselective reduction of a 1,2-bromovinyl triflate to
provide vinyl bromide 13, and (3) the use of CuOAc to
convert 16 in two steps to known slaframine intermediate
17. The phenylselenocyclocarbamation reaction of dihydro-
pyridone derivatives should be useful for the synthesis of
other hydroxyindolizidines and related biologically active
alkaloids.
(12) For other examples of phenylselenocyclocarbamation reactions,
see: (a) Berkowitz, D. B.; Pedersen, M. L.; Jahng, W. Tetrahedron Lett.
1996, 37, 4309. (b) Takano, S.; Hatakeyama, S. Heterocycles 1982, 19,
1243.
(13) This conversion was carried out on racemic 10. The product 11
exhibited NMR spectra in agreement with literature values, see: Kano, S.;
Yokomatsu, T.; Yuasa, Y.; Shibuya, S.; Heterocycles 1986, 24, 621.
(14) Kotsuki, H.; Datta, P. K.; Hayakawa, H.; Suenaga, H. Synthesis
1995, 1348.
(15) Edwards, D. A.; Richards, R. J. Chem. Soc., Dalton Trans. 1973,
2463. Method g was used to prepare fresh copper(I) acetate.
(16) For previous preparations of vinyl acetates from vinyl bromides
using copper(I) acetate, see: (a) Klumpp, G. W.; Bos, H.; Schakel, M.;
Schmitz, R. F.; Vrielink, J. J. Tetrahedron Lett. 1975, 16, 3429. (b) Lewin,
A. H.; Goldberg, N. L. Tetrahedron Lett. 1972, 13, 491.
(17) (a) Gensler, W. J.; Hu, M. W. J. Org. Chem. 1973, 38, 3843. (b)
Wasserman, H. H.; Vu, C. B. Tetrahedron Lett. 1994, 35, 9779.
(18) Pearson, W. H.; Bergmeier, S. C.; Williams, J. P. J. Org. Chem.
1992, 57, 3977.
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. H. Wasserman
for an 1H NMR spectrum of a slaframine intermediate. 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 (Grants CHE-9121380 and CHE-9509532).
Supporting Information Available: Characterization
data for compounds 4-10, 12-18, and 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) 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.
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