2] cycloaddition reaction of azomethine ylides with alkenes
has been developed in the past years mainly using optically
pure dipolarophiles8 and more recently by using metal
complexes. After the pioneering work by Grigg et al. on the
use of chiral transition metal complexes, which required a
stoichiometric amount of the metal complex,9 a relatively
limited number of procedures that employ substoichiometric
amounts of a chiral metal complex have been reported. Zhang
et al. reported the cycloaddition of methylglycine imines with
different dipolarophiles catalyzed by Ag(I) complexes with
chiral diphosphines,10 obtaining good enantioselectivities with
doubly deactivated alkenes but modest selectivity with
methyl acrylate. We described at the same time the use of
chiral Zn(II)-bisoxazoline complexes as catalysts for the
enantioselective cycloaddition of methylglycine esters to
acrylates as a simple approach to optically active proline
derivatives.11 Schreiber et al. used the combination of silver
acetate and P,N ligands12 to give good yields and stereose-
lectivities of the expected endo-adducts. On the other hand,
Komatsu et al.13 have reported the use of chiral phosphine-
copper triflate complexes yielding the exo-adducts as the
predominant products in the cycloaddition of azomethine
ylides and N-phenylmaleimide; however, moderate enanti-
oselectivity was obtained. Although some of these procedures
afford the corresponding cycloadducts in good yields and
high enantioselectivities, they normally require preformation
of the catalysts, dry and deoxygenated solvents, and glovebox
techniques. Also, the reactions must be carried out under an
inert atmosphere, which may limit their application from a
practical point of view. Therefore, the development of new
procedures that effect this 1,3-dipolar cycloaddition with high
yields and diastereo- and enantioselectivities under more
convenient reaction conditions is an important challenge.
In this communication we present a new catalytic asym-
metric strategy for the 1,3-dipolar cycloaddition of azome-
thine ylides with alkyl acrylates, which does not require
special precautions with regard to drying, degasifying
solvents, or using an inert atmosphere and which therefore
presents several advantages from a practical point of view
with regards to the previously described metal-complex-
catalyzed procedures.
metallo-azomethine ylide-chiral base ion pair. This species
would then react with the dipolarophile in a chiral environ-
ment to afford the expected cycloadduct stereoselectively
(Scheme 1).
Scheme 1. 1,3-Dipolar Cycloaddition of Azomethine Ylides,
Activated by a Metal Salt and a Chiral Base, and Alkenes
The 1,3-dipolar cycloaddition reaction of methyl N-(4-
methylbenzylidene) glycinate 1a and methyl acrylate 2a in
the presence of a cinchona alkaloid14 as the chiral base
(Figure 1) and a metal salt was used for the screening process
(Scheme 2). Some representative results are summarized in
Table 1.
Figure 1. Cinchona alkaloids screened in this work.
Our strategy is based on the use of a metal salt and a chiral
base, both in catalytic amount. We envisioned that chelation
of the metal to the iminoester followed by deprotonation by
a cinchona alkaloid, acting as the chiral base, would form a
For the screening of metal salts, lithium, zinc, and silver
salts were explored. The reaction yielded almost exclusively
the endo-adduct 3a in all cases. With the exception of AgCl,
silver salts were superior to lithium15 and zinc salts (Table
1, entries 1-4 and 14). We believe the low solubility of AgCl
in the reaction solvent reduces its efficacy. AgNO3 and AgF
gave similar results with cinchonine in toluene (Table 1,
entries 3 and 4), but AgF gave better conversions and more
reproducible results. We therefore chose AgF for the rest of
the screening. Cinchonine and quinine (entries 4 and 5) gave
similar results when used as chiral bases, but they lead to
different enantiomers, as usually happens when comparing
reactions catalyzed by this pair of cinchona alkaloids. They
gave also better conversions and enantioselectivites than other
cinchona alkaloid derivatives (entries 6, 7, and 13). Several
solvents were tested using the combination AgF-cinchonine;
(8) (a) Copper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P. Redpath,
J. Tetrahedron 1995, 51, 7791-7808. (b) Grigg, R. Tetrahedron: Asym-
metry 1995, 6, 2475-2486. (c) Kanemasa, S.; Hayashi, T.; Tanaka, J.;
Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473-4481. (d) Galley,
G.; Liebscher, J.; Pa¨tzel, M. J. Org. Chem. 1995, 60, 5005-5010. (e) Garc´ıa-
Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981-
987.
(9) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5871-5820.
(10) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
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(11) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236-4238.
(12) (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174-10175. (b) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971-5793. (c) Stohler,
R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431-1436.
(13) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata,
S.; Komatsu, M. Org. Lett. 2003, 5, 5043-5046.
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