Vinyl imidates in cycloaddition reactions: a formal synthesis of (+/-)-reserpine.

Article abstract of DOI:10.1021/ol015988w

[reaction: see text] The intramolecular Diels-Alder reaction of N-acylvinylimidates provides an efficient entry into cis-fused perhydroisoquinoline ring systems. This is demonstrated by the preparation of isoquinoline 2, an intermediate, which has been pr

Full text of DOI:10.1021/ol015988w

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2265-2267
Vinyl Imidates in Cycloaddition
Reactions: A Formal Synthesis of
(±)-Reserpine
Steven M. Sparks and Kenneth J. Shea*
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
kjshea@uci.edu
Received April 16, 2001
ABSTRACT
The intramolecular Diels−Alder reaction of N-acylvinylimidates provides an efficient entry into cis-fused perhydroisoquinoline ring systems.
This is demonstrated by the preparation of isoquinoline 2, an intermediate, which has been previously transformed to reserpine.
The yohimbine alkaloids have attracted attention from
chemists for both their medicinal properties and intriguing
molecular structures.1 Reserpine (1), the most complex
member of the yohimbine family, contains five contiguous
asymmetric centers embedded in a cis-fused perhydroiso-
quinoline ring system. The challenges associated with the
construction of the stereochemically complex isoquino-
line ring system present in reserpine have stimulated the
development of a number of synthetic approaches which
have culminated in both total and formal syntheses of
reserpine.2 In this manner, reserpine has served as a
testing ground to evaluate the utility of synthetic methodol-
ogy.
Our laboratory has been involved in the utilization of
intramolecular Diels-Alder reactions for the preparation
of perhydroisoquinoline ring systems. Employing vinyl
imidates as the 2π electron component in intramolecular
Diels-Alder reactions allows for the synthesis of iso-
quinoline ring systems with considerable potential for stereo-
chemical control.3 As a demonstration of this potential,
we report the application of the intramolecular Diels-
Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates to
the synthesis of perhydroisoquinoline 2. This intermediate
contains five of the six asymmetric centers in reserpine and
constitutes its formal synthesis (Scheme 1).4 Compound 2
was envisioned to result from elaboration of N-acylimidate
3, which in turn arises from intramolecular cyclization of
N-acylvinylimidate 4. In this approach, all E-ring functional-
ity is confined to the diene fragment 5, which upon
(1) Woodson, R. E.; Youngken, H. W.; Schittler, E.; Schneider, J. A.
Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology; Little,
Brown and Co.: Boston, 1957.
(2) For recent reviews, see: (a) Baxter, E. W.; Mariano, P. S. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Springer-Verlag: New York, 1992; Vol 8, pp 197-319. (b) Sza´ntay, C.;
Honty, K. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; John Wiley
& Sons: Chinchester, 1994; Chapter 4, pp 161-216. (c) Hanessian, S.;
Pan, J.; Carnell, A.; Bouchard, H.; Lesage, L. J. Org. Chem. 1997, 62,
465.
(3) (a) Shea, K. J.; Svoboda, J. J. Tetrahedron Lett. 1986, 27, 4837. (b)
Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989, 54, 4335.
(c) Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721.
(4) (a) Wender, P. A.; Schaus, J. M.; White, A. W. J. Am. Chem. Soc.
1980, 102, 6157. (b) Wender, P. A.; Schaus, J. M.; White, A. W.
Heterocycles 1987, 25, 263.
10.1021/ol015988w CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/27/2001

Scheme 1. Retrosynthetic Analysis Employing the Intramolecular Diels-Alder Reaction of N-3,5-Hexadienoyl Ethyl Acrylimidates
cyclization in the tether endo mode establishes three of the
five asymmetric centers.
by 2-chloro-1-methylpyridinium iodide9 to afford N-acylvi-
nylimidate 4 (85% isolated yield, Scheme 3).10 Cycloaddition
This approach was reduced to practice in the following
manner (Scheme 2). Diene 5 was prepared starting with the
Scheme 3
Scheme 2
Stille coupling5 of vinylstannane 66 with methyl (3E)-
bromopropenoate (7)7 in the presence of Pd2(dba)3 (2 mol
%), tri-2-furylphosphine (TFP, 16 mol %), and copper(I)
iodide in N-methylpyrrolidine to afford diene 8 in high yield.
Kinetic deconjugation of 2,4-hexadienoic acid ester derivative
8 with LDA (1.2 equiv)/ DMPU/THF at -78 °C followed
by an acidic quench (10% HCl, -78 °C) afforded a single
product in 89% isolated yield.8 Both 1H NMR and subsequent
chemical studies established that the reaction gave exclu-
sively the 3E,5E dienoic acid ester. Saponification provided
diene 5 in high yield.
(CHCl3, 60 °C, 14 h) resulted in formation of two cycload-
ducts in a 6:1 ratio (95% yield).11 The major cycloadduct,
3, was assigned the cis-ring fusion on the basis of 1H NMR
(JH4a-H8a ) 5.5 Hz), corresponding to a tether-endo cycload-
dition. The cycloaddition step sets three of the five stereo-
centers required for the preparation of the DE isoquinoline
ring system in reserpine. N-Acylimidate reduction with
lithium aluminum hydride was followed by treatment with
methyl chloroformate to provide carbamates 11 and 12 (89%
yield, two steps), which were chromatographically separated
to afford cis-fused isoquinoline 11.
The Diels-Alder precursor was prepared by the coupling
of diene 5 with 1-aza-2-ethoxy-1,3-butadiene (9)3b mediated
(9) Bald, E.; Saigo, Z.; Mukaiyama, T. Chem. Lett. 1975, 1163.
(10) Under the coupling conditions, a minor amount (>5%) of cycload-
duct was observed. The origin of cycloadduct may result from an
intermediate N-acyliminium ion produced from the coupling reaction. This
raises the possibility of protonic or Lewis acid catalysis of the cycloaddition
step. This chemistry is currently being pursued.
(5) Farina, V.; Krishnamurthy, A.; Scott, W. J. Org. React. 1997, 50, 1.
(6) Paterson, I.; Feâner, K.; Finlay, M. R. V.; Jacobs, M. F. Tetrahedron
Lett. 1996, 37, 8803.
(7) Weir, J. R.; Patel, B. A.; Heck, R. F. J. Org. Chem. 1980, 45,
4926.
(8) Greico, P. A.; Yoshida, K.; He, A. Tetrahedron Lett. 1984, 25,
(11) Cycloaddition in refluxing benzene provided a lower endo/exo ratio
(4:1).
5715.
2266
Org. Lett., Vol. 3, No. 15, 2001

Completion of the DE isoquinoline ring system entailed
installation of the C6 methyl ether and transposition of the
benzyl groups for acetates (Scheme 4). This was ac-
Catalytic hydrogenolysis of the benzyl ethers (H2, 10%
Pd-C, 100%) proceeded smoothly to afford diol 14. The
stereochemistry of diol 14 was confirmed by spectroscopic
comparison with an authentic sample derived from (-)-
reserpine.4 Completion of the formal synthesis was ac-
complished by acetylation (Ac2O, DMAP, pyr, 55%) to
furnish hydroisoquinoline 2.
Scheme 4
In summary, the synthesis of perhydroisoquinoline 2, an
intermediate previously transformed to reserpine (1), has been
accomplished by employing the intramolecular Diels-Alder
cycloaddition of N-3,5-hexadienoyl ethyl acrylimidate 4. This
approach demonstrates the utility of vinyl imidates in
intramolecular cycloadditions for preparing stereochemically
complex isoquinoline ring systems.
Acknowledgment. This research was supported in part
by the National Institute of Health. S.M.S. was supported
by a graduate fellowship sponsored by Pharmacia. We would
like to thank Professor Paul Wender for providing us with
detailed procedures for the degradation of (-)-reserpine to
diol 14 and Dr. Arnold Gutierrez for preliminary experi-
mental results.
complished by hydroboration of olefin 11 with BH3‚THF
followed by oxidation (3 M NaOH, 30% H2O2) to afford a
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2 and 14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
single alcohol (80%). The stereochemistry of the newly
1
formed alcohol (C6) was secured by H NMR (JH5-H6
)
9.7 Hz, JH6-H7 ) 9.7 Hz, see 13). Methyl ether forma-
tion required forcing conditions12 (n-BuLi/THF/-78 °C;
MeOTf, 65%) due to steric hindrance about the secondary
alcohol.
OL015988W
(12) Baxter, E. W.; Labaree, D.; Ammon, H. L.; Mariano, P. S. J. Am.
Chem. Soc. 1990, 112, 7682.
Org. Lett., Vol. 3, No. 15, 2001
2267