Tandem driven dynamic combinatorial resolution via Henry-iminolactone rearrangement

Article abstract of DOI:10.1039/b716521h

An unexplored type of tandem reaction is used to kinetically resolve a dynamic combinatorial library resulting in quantitative amplification of an interesting 3-substituted isoindolinone. The Royal Society of Chemistry.

Full text of DOI:10.1039/b716521h

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COMMUNICATION
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Tandem driven dynamic combinatorial resolution via Henry–
iminolactone rearrangement{
Marcus Angelin, Pornrapee Vongvilai, Andreas Fischer and Olof Ramstro¨m*
Received (in Cambridge, UK) 26th October 2007, Accepted 28th November 2007
First published as an Advance Article on the web 14th December 2007
DOI: 10.1039/b716521h
The concept is displayed in Fig. 1: a dynamic library from sets of
An unexplored type of tandem reaction is used to kinetically
resolve a dynamic combinatorial library resulting in quantita-
tive amplification of an interesting 3-substituted isoindolinone.
components A and B is allowed to form by reversible bond
formation. A specific constituent can subsequently react further in
a consecutive reaction to form a kinetically stable product. The
thermodynamically controlled process will simultaneously undergo
continuous re-equilibration, and a clear amplification of the
coupled tandem reaction product will be observed.
Dynamic combinatorial chemistry is an emerging approach for
efficient generation of molecular diversity and rapid identification
of ligands and receptors for a large variety of target species.1 This
approach relies on constitutional dynamic exchange of kinetically
labile entities, where dynamic combinatorial libraries (DCLs) are
formed through reversible bonds between participating compo-
nents. Due to the dynamic nature of DCLs, they can adapt in
response to system constraints and selection pressures. To date,
applications of DCLs have mainly exploited their potential to
adapt to external selection pressures. Molecular targets,2,3 or
external stimuli,4 have then been used to install secondary
processes leading to the amplification of certain library members.
The possibility of controlling a DCL by an internal kinetic
selection pressure is a hitherto unexplored approach. In this
communication, we demonstrate an example of this sequential
approach, where a DCL is influenced and strongly driven by an
internal selection pressure. By coupling a thermodynamically
controlled DCL to a kinetically controlled sequential intramole-
cular reaction, a library could be quantitatively resolved into one
product. We have recently proposed a dynamic combinatorial
resolution process (DCR), where DCLs are kinetically resolved by
enzyme-catalyzed reactions,2a,2b,5 but in the present study, we have
taken advantage of the properties of individual library members,
creating an internal selection pressure without an external
biocatalyst. This represents a highly straightforward one-pot
process to selective product formation from a pool of candidates,
without the addition of intervening external factors.
We based our system on the nitroaldol or Henry reaction, a very
powerful C–C bond forming reaction with a long history and
numerous applications within synthetic organic chemistry.6–10
Recently, it has also shown great potential in the DCC field where
it has been successfully coupled to an enzymatic secondary
process.2a The robust nature of this transformation, and its
potential for handling structural diversity, makes it a good
candidate for exploring tandem driven DCLs. Considering these
features, a conceptual nitroaldol library was designed (Fig. 2). Five
benzaldehyde derivatives (1–5), all with a unique substitution
pattern, were chosen in order to make library generation and
analysis clear and simple. A 2-CN substituted benzaldehyde was
also included in order to provide a possible candidate for
tandem cyclization following dynamic formation of the nitroalco-
hols (6–10). A resulting 5-exo-dig type cyclization of a hydro-
xynitrile to the corresponding iminolactone is an expected,11,12
albeit unexplored,13–16 intramolecular reaction, and would lead to
kinetic resolution of the library. Library generation was initially
tested on a reference library (DCL-A), containing one equivalent
each of aldehydes 2–5 and nitroethane in acetonitrile. To initiate
equilibration, triethylamine was added and the mixture was
monitored by frequent 1H-NMR analysis. Although catalytic
amounts of base proved sufficient, the reaction rate was increased
by adding an excess of base. Under these conditions, equilibrium
was reached within three hours (Fig. 3a). Following this, a target
Fig. 1 Concept of tandem driven, internal DCR. A dynamic library is
formed from i components A and j components B. A specific combination
An–Bm subsequently undergoes the selective formation of kinetically stable
product Cnm
.
KTH – Royal Institute of Technology, Stockholm, Sweden.
E-mail: ramstrom@kth.se; Fax: +46 (0)8 7912333
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b716521h
Fig. 2 Tandem driven dynamic nitroaldol library resulting in complete
amplification and selection of product 12 (X-ray structure lower right).
768 | Chem. Commun., 2008, 768–770
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unusually high shift for the carbon in the benzylic position was
observed, suggesting possible lactam formation. Intrigued by this,
single crystals were produced,17 and subsequent X-ray diffraction
analysis proved the compound to be lactam 12 (Fig. 2).{
Following these surprising results, the literature was probed for
similar transformations. Observations where cyanoalcohols were
transformed to lactams were found,18–20 however in all cases
requiring a partly different mechanistic route in order to form the
final product. These routes also resulted in products that, despite
their heterocyclic complexity, are of limited synthetic utility. The
3-substituted isoindoline-1-one represents an interesting motif
present in a variety of natural products and drug compounds.21
Furthermore, compound 12 belongs to a group of synthetic
precursors to 1,2-diamines. Reduction of the nitro group and
further hydrolysis of the lactam, would lead to these structures
which are of broad utility, reaching from antitumor reagents to
ligands in stereoselective organic synthesis.22–24
More detailed time-dependent NMR-studies of the process with
aldehyde 1 were subsequently performed in order to evaluate the
tandem reaction (Fig. 4). The experimental data fitted the
consecutive reversible/irreversible model well,25 suggesting that
the final rearrangement step is fast compared to the proposed
iminolactone formation step. The studies also revealed that the
forward nitroaldol formation and the consecutive tandem-cycliza-
tion step proceed at comparable rates. The reverse nitroaldol
reaction rate was however comparatively low under the present
conditions.
In conclusion, we have formulated and demonstrated the
concept of intramolecular dynamic combinatorial resolution.
From a prototype dynamic nitroaldol library, internal selection
pressure from a consecutive intramolecular tandem reaction
influenced the thermodynamically controlled process and caused
a quantitative amplification effect. Further investigation also
showed that the tandem reaction was followed by an unexplored
type of intramolecular rearrangement, affording an interesting
nitrosubstituted isoindolinone structure. This concept has intri-
guing potential applications: For example, it provides a possible
route to systematization of reaction discovery,26,27 where novel
reactions could be identified from amplification effects due to
unexpected coupled reactions occurring in dynamic libraries.
Tandem reactions could also be a tool for controlling dynamic
combinatorial systems, and to demonstrate dynamics in biased
equilibria.28
Fig. 3 1H-NMR spectra for selected DCLs. Enlarged areas display
protons marked in the scheme. (a) Reference library DCL-A at
equilibrium (t 5 24 h). (b) Full compound tandem driven DCL-B at
t 5 t0. (c) DCL-B at t 5 30 min. (d) DCL-B after completed tandem
reaction (t 5 24 h). *, #, and fl indicate the signals of 1, nitroethane and
12, respectively.
library (DCL-B) was constructed analogously, this time including
aldehyde 1. Initially, the 1H-NMR analysis displayed a similar
pattern, with different nitroalcohols forming competitively.
However, as the time approached thirty minutes, an amplification
of what was assumed to be the cyclic iminolactone (11) was
observed (Fig. 3c). This internal amplification process then
gradually proceeded until all previously formed nitroalcohols, as
well as all nitroethane, had been consumed (Fig. 3d).
Upon successful demonstration of our tandem driven dynamic
library, the amplified reaction product was isolated and further
characterized. During evaluation of the 13C-NMR spectrum, an
Fig. 4 Reaction composition followed over time (aldehyde 1 (&),
nitroalcohol intermediate 6 (#) and product 12 (n)). Lines represent fitted
data from kinetic model.25
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J.-M. Lehn, Chem.–Eur. J., 2006, 12, 1715; (c) N. Giuseppone and J. M.
Oscar Norberg is gratefully acknowledged for artwork assis-
tance. This study was supported by the Swedish Research Council.
MA gratefully acknowledges financial support from the Royal
Institute of Technology’s Excellence Award.
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{ CCDC 665392. For crystallographic data in CIF format see DOI:
10.1039/b716521h
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770 | Chem. Commun., 2008, 768–770
This journal is ß The Royal Society of Chemistry 2008