6953
The second class of catalysts consists of compounds 15±18. These compounds were shown to
catalyze the transformation (1+2!3+4) but not the dehydration of 4 to 5. In independent assays,
these catalysts were active in the transformation of 3 to 4, where again formation of 5 was not
observed.9 Examination of the structure/activity relationships of the catalysts reported here,
suggests that chiral compounds containing a secondary amine of the pyrrolidine-type and a
carboxylate functionality are the most ecient catalysts of this asymmetric annulation reaction.
The carboxylic acid functionality appears to be key to the dehydration step, at least when the
reactions are performed at ambient temperatures.
In summary, chiral secondary amines, particularly pyrrolidine-like molecules are catalysts of
Michael and aldol reactions.10 We believe the potential of molecules such as these to act as
asymmetric organic catalysts has not been suciently exploited. Our proline-catalyzed direct
asymmetric aldol reaction,11 MacMillan's amine-catalyzed asymmetric Diels±Alder reaction,12
and the Robinson annulation reaction reported here are recent examples of asymmetric amine
catalysis facilitated by imine and enamine type reaction mechanisms. These results underscore an
interplay between mechanistic enzymology and asymmetric organic catalysis that may enable the
creation of diverse and ecient organocatalysts for a wide variety of reactions.13
Acknowledgements
This study was supported by the NIH (CA27489) and The Skaggs Institute for Chemical
Biology.
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