Journal of the American Chemical Society
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was obtained in 48% yield with 91% ee. Thus, aldol 5 is not
stable under the reaction conditions, but is an intermediate
of the catalytic cycle. Together, these findings support the
three-step, one-pot pathway proposed in Figure 1b.19
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Figure 3. Mechanistic supports.
In conclusion, we developed a catalytic enantioselective
method for the introduction of ketones to hemiaminals. This
is the first catalytic enantioselective method for introducing
various ketones to N-heterocycles with differing ring sizes (5-,
6-, and 7-membered ring). The process comprises three dis-
tinct steps in one pot, all of which are promoted by the chiral
copper(I)-conjugated Brønsted base catalyst. This method
offers
general
and
straightforward
access
to
enantiomerically-enriched versatile precursors for alkaloid
and drug syntheses, including pyrrolidines, piperidines,
indolizidines, quinolizidines, tetrahydroisoquinolines, and
tetrahydrobenzazepines, starting from stable and easily
available substrates.
Supporting Information
Experimental details including procedures, synthesis and
characterization of all new products, and supporting data for
mechanistic insights. This material is available free of charge
AUTHOR INFORMATION
(17) This finding indicates that 11 was the kinetic product, and
epimerization proceeded selectively at the benzylic position through
an iterative retro-aza-Michael reaction and aza-Michael reaction,
affording thermodynamically more favorable 12.
(18) (a) Mancheño, O. G.; Arrayás, R. G.; Adrio, J.; Carretero, J. C. J.
Org. Chem. 2007, 72, 10294–10297. (b) Pilli, R. A.; Dias, L. C.;
Maldaner, A. O. J. Org. Chem. 1995, 60, 717–722. (c) Shan, Z.-H.; Liu,
J.; Xu, L.-M.; Tang, Y.-F.; Chen, J.-H.; Yang, Z. Org. Lett. 2012, 14,
3712–3715. (d) Weymann, M.; Pfrengle, W.; Schollmeyer, D.; Kunz H.
Synthesis 1997, 1151–1160.
Corresponding Author
ACKNOWLEDGMENTS
This work was supported by ERATO from JST. S.S. thanks
JSPS for the fellowship.
REFERENCES
(19) For a proposed catalytic cycle, please see SI.
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