Development of a 2-aza-cope-[3 + 2] dipolar cycloaddition strategy for the synthesis of quaternary proline scaffolds

Article abstract of DOI:10.1021/ol101606v

A one-pot multicomponent procedure for the synthesis of highly functionalized pyrrolidine rings through a domino 2-aza-Cope-[3 + 2] dipolar cycloaddition sequence has been demonstrated. This protocol was found to be both high-yielding and stereoselective for the endo cycloadduct.

Full text of DOI:10.1021/ol101606v

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3906-3909
Development of a 2-Aza-Cope-[3 + 2]
Dipolar Cycloaddition Strategy for the
Synthesis of Quaternary Proline
Scaffolds
Michael P. McCormack,† Tamila Shalumova,‡ Joseph M. Tanski,‡ and
Stephen P. Waters*,†
Department of Chemistry, The UniVersity of Vermont, 82 UniVersity Place,
Burlington, Vermont 05405, and Department of Chemistry, Vassar College,
Poughkeepsie, New York 12604
stephen.waters@uVm.edu
Received July 12, 2010
ABSTRACT
A one-pot multicomponent procedure for the synthesis of highly functionalized pyrrolidine rings through a domino 2-aza-Cope-[3 + 2] dipolar
cycloaddition sequence has been demonstrated. This protocol was found to be both high-yielding and stereoselective for the endo cycloadduct.
The pyrrolidine ring represents a prevalent scaffold for many
compounds of pharmaceutical interest, as well as a structural
element common to the Amaryllidaceae and Erythrina
alkaloids.1 The development of mild, efficient, and opera-
tionally simple methods for their construction continues to
warrant interest. As chemical synthesis places an ever-
increasing emphasis on concise molecular assembly, pro-
cesses that rapidly assemble complex structures in a stere-
ocontrolled fashion are highly desirable. Toward these ends,
multicomponent reactions have played an important role.2
The orchestration of two or more distinct chemical events
involving multiple components permits a magnification of
structural complexity in a minimal number of synthetic
steps.3 In the context of heterocyclic chemistry, strategic
extensions of the 2-aza-Cope rearrangement could potentially
meet these criteria. Specifically, the merging of the 2-aza-
Cope rearrangement with a [3 + 2] dipolar cycloaddition
reaction could provide new and more concise routes to a
variety of pyrrolidine-containing targets.
† The University of Vermont.
‡ Vassar College.
(1) For reviews of these alkaloid classses, see: (a) Lewis, J. R. Nat.
Prod. Rep. 1993, 10, 291–299. (b) Martin, S. F. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1987; Vol. 30, p 252. (c) Tsuda, Y.;
Sano, T. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1996; Vol. 48, p 239. For selected syntheses, see: (d) Jin, J.; Weinreb, S. M.
J. Am. Chem. Soc. 1997, 119, 2050–2051. (e) Overman, L. E.; Shim, J. J.
Org. Chem. 1993, 58, 4662–4672. (f) Ishizaki, M.; Hoshino, O.; Iitaka, Y.
Tetrahedron Lett. 1991, 32, 7079–7082. (g) Pansare, S. V.; Lingampally,
R.; Kirby, R. L. Org. Lett. 2010, 12, 556–559. (h) Jones, M. T.; Schwartz,
B. D.; Willis, A. C.; Banwell, M., G. Org. Lett. 2009, 11, 3506–3509. (i)
Yamada, K.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.; Tomioka, K.
Org. Lett. 2009, 11, 1631–1633.
(2) (a) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (b) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(3) (a) Parsons, J. P.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96,
195–206. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115–136.
10.1021/ol101606v  2010 American Chemical Society
Published on Web 08/03/2010

The 2-aza-Cope rearrangement affords imine or iminium
products, which could in principle be used directly for
additional carbon-carbon bond-forming events. A classic
example of this strategy is well illustrated by Overman’s aza-
Cope-Mannich reaction (Scheme 1).4 In this powerful
Condensation of a homoallylic amine with a glyoxylate ester
would provide imine I (Scheme 1), which after thermody-
namically driven 2-aza-Cope rearrangement would afford
imine II. The addition of a metal/amine base pair would
result in the formation of a metalated azomethine ylide for
subsequent [3 + 2] dipolar cycloaddition with a wide range
of dipolarophiles.8
Central to our plans was the need for stereocontrol.
Cycloaddition could potentially generate up to four stereo-
genic centers, with at least one quaternary, within the proline
cycloadduct. Predictions as to which stereoisomers will
dominate would require analyses of both azomethine ylide
geometry as well as endo versus exo approach of the
dipolarophile. Cognizant that imines bearing electron-
withdrawing groups (e.g., II) lead to metalated azomethine
ylides with rigid geometries,9 more accurate predictions
regarding the stereochemical outcome should be possible.
As a result, the 2-aza-Cope-[3 + 2] dipolar cycloaddition
sequence should stereoselectively generate functionalized
proline scaffolds bearing a quaternary center.
Scheme 1. Applications of the 2-Aza-Cope Rearrangement
Our survey of substrates centered on homoallylamines
1a-e (Figure 1),10 ethyl glyoxylate (2) as the aldehyde
variant, a charge-accelerated cationic 2-aza-Cope rearrange-
ment affords an iminium ion having an enol moiety correctly
positioned for Mannich cyclization. The utility of this process
has been amply demonstrated by Overman5 and others6 in
many elegant total syntheses. Bennett and others have used
a 2-aza-Cope-iminium ion solvolysis protocol to prepare
allylglycine derivatives.7
Inspired by these advancements, we took interest in
developing conceptually new unions of the 2-aza-Cope
rearrangement with other carbon-carbon bond-forming
reactions. We first envisioned that the 2-aza-Cope rearrange-
ment could be used to prepare azomethine ylide precursors
for direct use in [3 + 2] dipolar cycloadditions. Such a
strategy would capitalize on the considerable bond-reorga-
nization properties of the Cope rearrangement, as well as
the diversity and facility of azomethine ylide cycloaddition.
Figure 1. Survey of amine, aldehyde, and alkene components.
component, and dipolarophiles 3a-c. For our initial opti-
mization studies, homoallylic primary amine 1a, ethyl
glyoxylate (2), and N-phenyl maleimide (3a) were selected,
1
and each step of the process was monitored via H NMR
analysis of sequential aliquots. Condensation of 1a and 2
was rapid (15 min) at rt in toluene (concentration 0.33 M)
to afford an imine product of type I (Scheme 1).11 Bringing
the mixture to reflux for 2 h effected clean 2-aza-Cope
rearrangement, determined to be complete and quantitative
(8) (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106,
4484–4517. (b) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765–2809.
(c) Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150.
(9) (a) Grigg, R.; Sridharan, V. In AdVances in Cycloaddition; Curran,
D. P., Ed.; JAI Press: London, 1993; Vol. 3, p 161. (b) Grigg, R.;
Montgomery, J.; Somasunderam, A. Tetrahedron 1992, 48, 10431–10442.
(c) Grigg, R.; Gunaratne, H. Q. N. Chem. Commun. 1982, 384–386. (d)
Grigg, R.; Kemp, J.; Malone, J.; Tangthongkum, A. Chem. Commun. 1980,
648–650.
(4) For a recent perspective, see: Overman, L. E. Tetrahedron 2009,
65, 6432–6446. For earlier accounts, see: (a) Overman, L. E. Acc. Chem.
Res. 1992, 25, 352–359. (b) Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am.
Chem. Soc. 1988, 110, 4329–4336.
(5) For selected examples, see: (a) Martin, C. L.; Overman, L. E.; Rohde,
J. M. J. Am. Chem. Soc. 2008, 130, 7568–7569. (b) Dunn, T. B.; Ellis,
J. M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett. 2009, 11,
5658–5661. (c) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem.
Soc. 1995, 117, 5776–5788.
(10) Preparation of 1a, 1b, and 1e: (a) Hart, D. J.; Kanai, K.; Thomas,
D. G.; Yang, T. K. J. Org. Chem. 1983, 48, 289–294. Preparation of 1d:
(b) McCoy, C. P.; Morrow, R. J.; Edwards, C. R.; Jones, D. S.; Gorman,
S. P. Bioconjugate Chem. 2007, 18, 209–215. (c) Felpin, F. X.; Girard, S.;
Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.; Lebreton, J. J. Org. Chem. 2001,
66, 6305–6312. For the preparation of 1c, see Supporting Information.
(6) (a) Brummond, K. M.; Hong, S. J. Org. Chem. 2005, 70, 907–916.
(b) Agami, C.; Cases, M.; Couty, F. J. Org. Chem. 1994, 59, 7937–7940.
(7) (a) Bennett, D. J.; Hamilton, N. M. Tetrahedron Lett. 2000, 41, 7961–
7964. (b) Agami, C.; Couty, F.; Lin, J.; Mikeaeloff, A.; Poursoulis, M.
Tetrahedron 1993, 49, 7239–7250.
Org. Lett., Vol. 12, No. 17, 2010
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1
by H NMR, to furnish a new imine of type II. When the
dipolarophile (1.5 equiv), AgOAc (1.5 equiv), and Et3N (2.0
equiv) were added to the reaction mixture and stirred at rt,
azomethine ylide formation and [3 + 2] dipolar cycloaddition
occurred within 6 h to provide 2-allyl proline 4a (entry 1,
Table 1) in 84% yield. Stereochemical analysis of 4a by 1-D
Table 1. Exploring the Substrate Scope of the 2-Aza-Cope-[3 +
2] Dipolar Cycloaddition: Homoallylamines 1a-e and
Maleimide 3aa
Figure 2. NOE enhancements and X-ray crystal structure of 4a.
by 1H NMR analysis of the reaction mixtures. Each product
(4a-e) displayed NOE enhancements consistent with the
stereoisomer expected to result from cycloaddition of a
W-shaped azomethine ylide through endo approach of the
dipolarophile, as drawn in Scheme 1. The only other
compounds observed in the reaction mixtures were variable
amounts of unreacted imine after 2-aza-Cope rearrangement.
The overall yields were generally good and, as anticipated,
appeared to be dependent on the electronic characteristics
of the aromatic moiety. Electron-deficient p-trifluorometh-
ylbenzyl amine 1c gave a higher yield (97%) than electron-
rich p-methoxybenzyl amine 1b (70% yield), likely attrib-
utable to increased acidity and therefore more facile
azomethine ylide formation in the case of substrates bearing
electron-withdrawing groups. Gratifyingly, 3-pyridinyl amine
1d also underwent the transformation in good yield (87%).
Overall, furanylamine 1e was the only difficult substrate as
the 2-aza-Cope rearrangement required an additional 1 h and
the resultant imine did not readily undergo either azomethine
ylide formation or [3 + 2] dipolar cycloaddition even after
14 h of stirring at rt (entry 5, Table 1).
We also investigated the reactivities of two other dipo-
larophiles, dimethyl maleate (3b) and dimethyl fumarate (3c,
Table 2). For each homoallylamine substrate (1a-e) ex-
plored, the overall yields were good and were generally found
to parallel those observed with N-phenyl maleimide (3a),
with yields somewhat better for reactions with fumarate 3c
(entries 6-10, Table 2) than maleate 3b (entries 1-5). The
relative stereochemistries of the isolated 2-allyl prolines 4f-o
once again proved to be those consistent with [3 + 2] dipolar
cycloaddition via an endo transition state maleate with a
W-shaped azomethine ylide.
a Reaction conditions: homoallylic amine 1a-e (1.0 mmol), ethyl
glyoxylate (2, 1.0 mmol), 4 Å MS, toluene (3 mL), reflux, 2-3 h; then add
N-phenyl maleimide (3a, 1.5 mmol), AgOAc (1.5 mmol), Et3N (2.0 mmol),
rt, 6 h. b Isolated yields after flash column chromatography on silica gel or
recrystallization.
In summary, we demonstrate here the first examples of a
one-pot domino 2-aza-Cope-[3 + 2] dipolar cycloaddition
for the synthesis of functionalized 2-allyl proline derivatives.
The resultant allyl and ester moieties provide convenient
points for additional structural elaboration. Importantly, the
multicomponent nature of the protocol is evident as a wide
variety of amine, glyoxylic ester, and dipolarophile compo-
nents could potentially be used. The reaction stereoselectively
generates four new chiral centers and one quarternary carbon
NOE enhancement experiments revealed that the cycload-
dition exhibited endo-selectivity as evidenced from through-
space coupling of the protons indicated below (Figure 2),
which was unambiguously confirmed via X-ray crystal-
lographic analysis.
The scope of the 2-aza-Cope-[3 + 2] dipolar cycloaddition
was next extended to other homoallyl amine substrates (Table
1). For all cases, only the endo cycloadducts were detected
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Org. Lett., Vol. 12, No. 17, 2010

Table 2. Extending the Substrate Scope of the 2-Aza-Cope-[3 + 2] Dipolar Cycloaddition with Dimethyl Maleate and Dimethyl
Fumaratea
a Reaction conditions: homoallylic amine 1a-e (1.0 mmol), ethyl glyoxylate (2, 1.0 mmol), 4 Å MS, toluene (3 mL), reflux, 2-3 h; then add 3b or 3c
(1.5 mmol), AgOAc (1.5 mmol), Et3N (2.0 mmol), rt, 6 h. b Isolated yields after flash column chromatography on silica gel or recrystallization.
with a high degree of functionalization around a pyrrolidine
ring, and we anticipate applying this strategy toward the
synthesis of alkaloid natural products. Our route to azome-
thine ylide precursors via the 2-aza-Cope rearrangement is
complementary to the condensation of aldehydes with
allylglycine derivatives and may afford azomethine ylides
not accessible by other means. The transition to nonbenzylic
homoallylic amine components, monoactivated dipolaro-
philes, and catalytic asymmetric variants12 are all important
avenues currently under investigation.
also generously supported by the Vermont Genetics
Network through Grant No. P20 RR16462 from the
INBRE Program of the National Center for Research
Resources (NCRR), a component of the National Institutes
of Health (NIH). X-ray facilities at Vassar College were
provided by the U.S. National Science Foundation (Grant
No. 0521237 to J.M.T.). We thank Vic Parcell and Dr.
Lynn Teesch at the High Resolution Mass Spectrometry
Facility at the University of Iowa for obtaining high-
resolution mass spectra.
Acknowledgment. We gratefully acknowledge the Uni-
versity of Vermont for financial support. This work was
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. X-ray crystallographic information for 2-allyl
proline 4a in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) We found it convenient to conduct the reactions in the presence of
4 Å molecular sieves, thereby reducing the possibility of byproduct
formation from competing processes with water.
(12) (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400–13401. (b) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem.
Soc. 2003, 125, 10174–10175. (c) Zeng, W.; Zhou, Y. G. Org. Lett. 2005,
7, 5055–5058.
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