Vinyl imidates in cycloaddition reactions: Synthesis of (±)-alloyohimbane

Article abstract of DOI:10.1016/S0040-4039(00)01093-5

The intramolecular Diels-Alder reaction of N-acylvinyl imidates provides a rapid entry into cis-fused hexahydroisoquinolones. This methodology has been used in a concise synthesis of the yohimbine alkaloid (±)-alloyohimbane. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01093-5

Tetrahedron Letters 41 (2000) 6721±6724
Vinyl imidates in cycloaddition reactions: synthesis of
(þ)-alloyohimbane
Steven M. Sparks and Kenneth J. Shea*
Department of Chemistry, University of California, Irvine, California 92697, USA
Received 13 June 2000; accepted 29 June 2000
Abstract
The intramolecular Diels±Alder reaction of N-acylvinyl imidates provides a rapid entry into cis-fused
hexahydroisoquinolones. This methodology has been used in a concise synthesis of the yohimbine alkaloid
(þ)-alloyohimbane. # 2000 Elsevier Science Ltd. All rights reserved.
The intramolecular Diels±Alder cycloaddition of trienes incorporating nitrogen in the tether
joining the diene and dienophile has become an important methodology for the synthesis of
highly functionalized nitrogen carbocycles. This approach has been successfully employed in the
synthesis of hydroindole, hydroisoindole, hydroquinoline, and hydroisoquinoline heterocycles.1
Application of these methods have been realized in the synthesis of alkaloid natural products
including members of the yohimbine alkaloid family.2
We have been developing the chemistry of N-acylvinyl imidates for the synthesis of nitrogen
heterocycles.3 The intramolecular Diels±Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates
provides a rapid entry into the DE rings of yohimbinoid alkaloids (Eq. (1)). The cycloaddition
a€ords a high level of the cis-fused hexahydroisoquinolone 1 in good yield. Subsequent
reduction of the cycloadduct provides a direct entry into the cis-fused isoquinol-3-one ring
system (2). We now wish to report the successful utilization of this methodology for the
synthesis of (þ)-alloyohimbane (3).
ꢀ1†
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01093-5

6722
Analysis of (þ)-alloyohimbane (3) is shown in Scheme 1. Disconnection of the C-ring leads to
indole 4, an intermediate that has previously been transformed into alloyohimbane.4 The key
intermediate 4 would arise by N-alkylation of amide 6 with a substituted indoline. Lactam 6
would be prepared via the cycloaddition of N-3,5-hexadienoyl ethyl acrylimidate (7).
Scheme 1.
The synthesis of the DE rings of (þ)-alloyohimbane begins with the deconjugation of sorbic
acid which was achieved by treatment of sorbic acid with 2.2 equivalents of LDA followed by an
acid quench (Scheme 2).5 The deconjugated acid was converted directly to the acid chloride.
Coupling of acid chloride 8 with 2-ethoxy-1-aza-1,3-butadiene (9)3 produced Diels±Alder
precursor 7, which was not isolated but diluted in benzene and heated to e€ect conversion to
cycloadduct 10. The cycloadduct was then treated with NaBH4 and NaCNBH3 in ethanol
followed by subsequent addition of TFA to a€ord lactam 6. The three-step sequence of coupling/
cycloaddition/reduction provided isoquinolone 6 in 53% overall yield and set the cis-ring fusion
required for (þ)-alloyohimbane.
Scheme 2.
E€orts to couple lactam 6 with various 3-(2-substituted) ethylindole electrophiles furnished
3-vinylindole as the major product via an E2 elimination pathway.6 The elimination pathway,
endemic to substitution reactions of 3-(2-haloethyl)indoles with amides, could be bypassed by
employing an indoline electrophile which could subsequently be oxidized to the required indole.
The need for an indoline provided an opportunity to establish a radical based approach for the
synthesis of the desired electrophile.7

6723
This strategy was accomplished starting from o-bromoaniline (Scheme 3). Alkylation of o-
bromoaniline with methyl 4-bromocrotonate provided radical precursor 11 required for the
5-exo-trig radical cyclization. In the event, treatment of a dilute solution of bromide 11 with
catalytic AIBN (5 mol%) and tributyltin hydride in re¯uxing benzene e€ected the cyclization to
provide indoline 12 in 80% yield. The synthesis of the indoline electrophile was completed by
protection of the nitrogen as the benzyl amine followed by LAH reduction to alcohol 13.
Mesylation of alcohol 13 provided the desired indoline 14 in ®ve steps from o-bromoaniline in
60% overall yield.
Scheme 3.
With the indoline electrophile in hand, the alkylation of lactam 6 was investigated (Scheme 4).
Treatment of lactam 6 with sodium hydride in DMF at room temperature followed by addition
of mesylate 14 a€orded tertiary lactam 15 in 76% yield as a diastereomeric mixture at the 3
position of the indoline. Hydrogenation of the C16±C17 ole®n (alloyohimbane numbering)
occurred concomitantly with hydrogenolysis of the benzylamine to deliver the fully saturated DE
ring lactam needed to complete the synthesis. Oxidation of the indoline was accomplished by
treatment with DDQ (1 equiv.) at room temperature to furnish indole 4. The synthesis was
completed via the previously reported sequence of Bischler±Naperalski cyclization followed by
reduction to form the C-ring and set the C3 stereocenter and deliver (þ)-alloyohimbane.4,6
Scheme 4.

6724
In summary, a concise synthesis of (þ)-alloyohimbane has been accomplished which demonstrates
the utility of the intramolecular Diels±Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates to
provide the cis-fused isoquinolone ring system required for the DE rings of yohimbine alkaloids.
A radical based strategy has been developed for the synthesis of the indoline electrophiles which
allows for the synthesis of substituted indolines from o-bromoaniline derivatives. Further
applications of the intramolecular Diels±Alder reaction of N-acylvinyl imidates toward
substituted yohimbine alkaloids will be reported in due course.
Acknowledgements
We are grateful to the National Institutes of Health for ®nancial support. S.M.S. also wishes to
acknowledge Pharmacia Upjohn for a graduate fellowship.
References
1. (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10. (b) Ciganik, E. Org. React. 1984, 32, 1. (c) Fallis, A. G.
Can. J. Chem. 1984, 62, 183. (d) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon: Oxford, 1991; pp. 513. (e) Martin, S. F. J. Heterocyclic Chem. 1994, 31, 679.
2. (a) Aube, J.; Ghosh, S.; Pearson, W. H., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 3, pp. 99±150. (b) Baxter, E. W.;
Mariano, P. S.; Pelletier, S. W., Ed.; Springer-Verlag: New York, 1992; Vol. 8, pp. 197±319. (c) Martin, S. F.;
Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org. Chem. 1983, 48, 5170. (d) Martin, S. F.; Rueger, H.;
Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109, 6124. (e) Wender, P. A.; Smith, T. E. J. Org.
Chem. 1996, 61, 824. (f) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. J. Org. Chem. 1991, 56, 2960.
3. (a) Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem. 1989, 54, 4335. (b) Shea, K. J.; Svoboda, J. J.
Tetrahedron Lett. 1986, 27, 4837.
4. Aube, J.; Wang, Y. G.; Hammond, M.; Tanol, M.; Takusagawa, F.; Vandervelde, D. J. Am. Chem. Soc. 1990,
112, 4879.
5. Martin, S. F.; Tu, C.; Chou, T. J. Am. Chem. Soc. 1980, 102, 5274.
6. Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237.
7. For related aryl radical cyclizations, see: (a) Boger, D. L.; Garbaccio, R. M.; Jin, Q. J. Org. Chem. 1997, 62, 8875.
(b) Patel, V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D. A.; Kennedy, J. H.; Mohamadi, F.; Schultz, R. M.;
Soose, D. J.; Spees, M. M. J. Org. Chem. 1997, 62, 8868.