Communications
DOI: 10.1002/anie.201106024
Heterocycles
Skeletal Fusion of Small Heterocycles with Amphoteric Molecules**
Lawrence L. W. Cheung, Zhi He, Shannon M. Decker, and Andrei K. Yudin*
Small heterocycles provide the core structure of a vast range
of modern pharmaceuticals. The so-called privileged motifs
have been the engine of drug discovery and molecular probe
development.[1] During a discovery campaign, functional
groups designed to interact with biological targets of interest
are commonly built off electrophilic sites on the heterocyclic
scaffolds. Despite the commercial availability of a wide range
of nucleophilic reagents, this general strategy has a significant
shortcoming: introduction of an electrophilic handle such as
an acrylate, an epoxide, or an aziridine[2] often requires
methods with low functional group tolerance, which limits the
effectiveness of late-stage, diversity-oriented approaches.[3,4]
Amphoteric aziridine aldehydes, developed in our laboratory,
facilitate chemoselective transformations and can circumvent
Scheme 1. Examples of connectivity in amphoteric molecule-induced
transformations.
protecting-group manipulations.[5] These molecules have led
us to consider processes that are characterized by high bond-
forming efficiency[6] and result in rapid synthesis of privileged
heterocyclic frameworks by “skeletal fusion”. The method
presented here demonstrates how we have reached this goal
by preparing and elaborating medicinally important tem-
plates that can be employed for the presentation of cis-amide
bonds.[7] Our method of fusing small heterocycles should
facilitate diversity-oriented synthesis of other stereochemi-
cally rich motifs.
Isocyanides, first synthesized in 1859, are the best known
amphoteric reagents. Two of the most widely used multi-
component reactions, the Passerini reaction and the Ugi four-
component condensation,[8] owe their efficiency to the
amphoteric nature of the isocyanideꢀs terminal carbon.
Isocyanides are (1,1) amphoteric molecules because the a-
carbon center can establish a connection with both nucleo-
phile and electrophile (for a conceptual representation, see
Scheme 1A). Our continuing efforts to expand the scope of
synthetically useful amphoteric molecules have led us to
examine systems in which the electrophilic and nucleophilic
nodes of reactivity are separated by one or more atoms. Of
particular interest are (1,3) systems exemplified by the
unprotected a-amino aldehydes in which NH aziridine, a
well-established precursor to complex amines, plays a pivotal
role.[4] We recently initiated a search for two-atom p-electro-
philic reaction partners for amphoteric aziridine aldehydes.
The goal was to build a bridge between the “Nu” and “E”
nodes, resulting in a net [3+2] annulation (Scheme 1B). To
the best of our knowledge, no such reactions of amphoteric
molecules have been reported.
We envisioned that aziridine aldehydes would act as
three-atom “connectors”, engaging the p-system of isocya-
nates in a [3+2] fashion. This fusion was projected to supply a
hydantoin scaffold equipped with a strategically placed
reduced imide bond and an electrophilic aziridine function-
ality suitable for further chemical modifications (Scheme 2).
Scheme 2. Construction of the reduced-hydantoin scaffold by using
aziridine aldehydes.
Hydantoins are well represented in the structures of natural
products and synthetic bioactive compounds. Examples of
therapeutic agents containing the hydanoin core include
phosphenytoin, phenytoin, and ethotoin, to name a few. The
rigid and planar hydantoin group provides an excellent means
of presenting cis-amide bond conformers. This feature is the
main reason for sustained interest in this small heterocycle.
For instance, spirohydantion undergoes little loss of confor-
mational energy on binding to glycogen phosphorylase
glucopyranose.[9] The cis-amide group of spirohydantoin is
the determinant of both specificity and affinity by virtue of
hydrogen bonding to the protein core. Common methods of
[*] Dr. L. L. W. Cheung, Z. He, S. M. Decker, Prof. Dr. A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George St., Toronto, ON, M5S 3H6 (Canada)
E-mail: ayudin@chem.utoronto.ca
[**] The authors thank the Natural Science and Engineering Research
Council (NSERC) and the Canadian Institutes of Health Research
(CIHR) for financial support.
Supporting information for this article is available on the WWW
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11798 –11802