Communication
Enabling New Modes of Reactivity via Constrictive Binding in a
Supramolecular-Assembly-Catalyzed Aza-Prins Cyclization
David M. Kaphan, F. Dean Toste,* Robert G. Bergman,* and Kenneth N. Raymond*
Chemical Sciences Division, Lawrence Berkeley National Laboratory and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
up to 4 units upon encapsulation.7 Moreover, constrictive
binding8 within the cluster cavity lowers the entropic barrier to
ABSTRACT: Supramolecular assembly 1 catalyzes a
bimolecular aza-Prins cyclization featuring an unexpected
transannular 1,5-hydride transfer. This reaction pathway,
which is promoted by constrictive binding within the
supramolecular cavity of 1, is kinetically disfavored in the
absence of 1, as evidenced by the orthogonal reactivity
observed in bulk solution. Mechanistic investigation
through kinetic analysis and isotopic labeling studies
indicates that the rate-limiting step of the transformation is
the encapsulation of a transient iminium ion and supports
the proposed 1,5-hydride transfer mechanism. This
represents a rare example of such an extreme divergence
of product selectivity observed within a catalytic metal−
ligand supramolecular enzyme mimic.
reactions with constrained transition-state conformations and
enthalpically disfavors less compact transition-state conforma-
tions. These synergistic effects have been shown to promote a
variety of acid-catalyzed, as well as pericyclic, transformations.
Notably, the cluster catalyzes a Nazarov-like cyclization with up
to 106 fold rate acceleration as well as the Prins cyclization of
citronellal and related derivates.4,9 Cluster 1 is also capable of
stabilizing a number of high-energy species within its cavity
(e.g., quantitative iminium ion formation can be observed
within the cluster in aqueous media).10
We envisaged that the cluster’s propensity to effect
cyclizative reactivity and stabilize transient carbocations,
combined with its ability to promote iminium ion formation,
could facilitate an aza-Prins reaction, whereupon an amino
group tethered to a nucleophilic double bond would undergo
condensation with an aldehyde or ketone, followed by
cyclization and elimination or hydration of the resulting
carbocation. Unexpectedly, treatment of amine 2 with form-
aldehyde in the presence of 1 at ambient temperature afforded
substituted piperidine 3 as the main product, wherein
demethylation at nitrogen and reduction of the putative
carbenium generated by the cyclization of 2 had occurred
(Scheme 1). This stands in stark juxtaposition to the aza-Prins
cyclization of 2 in bulk solution, which required heating to
reflux in neat formic acid and afforded alcohol 4 as the product.
To understand this unusual result, we first prepared an
isotopically enriched analogue of the starting material (2-d3) in
an effort to elucidate the origin of the hydrogen of the isopropyl
methine in 3. 2-d3 was subjected to the cluster-catalyzed aza-
Prins cyclization conditions, followed by treatment with p-
nitrobenzenesulfonyl chloride, in order to facilitate purification.
The resulting sulfonamide, 5-d1, exhibited complete deuterium
incorporation at the isopropyl methine (Scheme 2). Con-
versely, reaction of unlabeled amine 2 under otherwise identical
conditions furnished nosylated product 5, which did not
incorporate any deuterium at the isopropyl methine.
(Deuterium exchange with the solvent mixture does not
explain the formation of 5-d1.)
nzymes have evolved over the course of millions of years
Eto facilitate biochemical transformations though selective
transition-state stabilization. In some cases, such as the skeletal
rearrangements in the formation of many complex natural
products, the enzymatic binding pocket is able to control the
reactivity of high-energy intermediates through a series of
cooperative noncovalent interactions and substrate preorgani-
zation in order to selectively form molecules that would be
difficult to access in bulk solution.1 The cavity of a
supramolecular capsule bears a strong resemblance to many
hydrophobic enzymatic active sites.1g,h The properties of such
capsules can be investigated to shed light on the nature of
analogous enzymatic catalysis as well as to develop highly
selective and specific synthetic catalysts.2
In emulation of its biological inspiration, the strategy of
catalysis within a supramolecular cluster cavity relies upon
controlled microenvironments and noncovalent interactions to
promote specific reactivity. Many supramolecular architectures
have shown high levels of catalytic activity. In particular,
specially designed molecular capsules have been shown to
accelerate reactions such as Diels−Alder cyclizations, con-
densations, and sigmatropic rearrangements, among other
transformations.3,4 Despite these accomplishments, complete
divergence of reactivity by selective stabilization of reaction
pathways too high in energy to be observed in bulk solution is
rare in catalytic supramolecular systems.5
Another observation that shed light on the mechanism of the
divergent reactivity of 2 came from the exposure of the N-
benzyl analogue of the starting material (2i) to cluster
cyclization conditions. Importantly, the identical dealkylated
The Raymond group has developed a metal−ligand capsule
of M4L6 stoichiometry (1).6 Previous studies have illustrated
the unique chemical microenvironment within the cluster. For
example, amines and phosphines exhibit an effective pKa shift of
Received: February 4, 2015
© XXXX American Chemical Society
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX