A R T I C L E S
Vongvilai and Ramstro¨m
These challenges prompted us to explore the potential of
generating complex dynamic systems using C-C bond-forming
reactions, amenable to exchange in more than one dimension
around a single chiral center. Furthermore, the use of mild
conditions that are compatible with both the selector entities
and applicable to a dynamic resolution process were addressed.
After surveying different possibilities, we chose the Strecker
reaction, in which, originally, R-aminonitriles were formed by
mixing an aldehyde, an ammonium salt, and a cyanide source
in water.31 This powerful C-C bond-forming reaction provides
chiral R-branched amine structures, which are common sub-
structures in many biologically active entities.32,33
Herein, we describe the generation of a multiple dynamic
covalent system based on the Strecker reaction, where tran-
simination is combined with imine cyanation, and the reaction
is carried out under mild conditions. This multilevel system
provided a vast range of substances from a small number of
starting compounds, yielding double dynamic covalent systems
of N-substituted R-aminonitriles. The resulting systems could
also be resolved through a coupled process in the form of a
kinetically controlled lipase-mediated amidation reaction. Am-
plification of specific chiral R-aminonitriles could in this case
be efficiently achieved in a one-pot process. Benefiting from
the self-screening process, high enantiomeric purities of acylated
N-substituted R-aminonitriles were thus obtained.
Figure 1. Double dynamic multicomponent resolution. A double dynamic
system is formed from i components A and j components B followed by k
components C. A specific constituent An-Bm-Cp is selectively recognized
by a selector (e.g., an enzyme), enabling the formation of specific product
Dnmp under kinetic control.
dolinone from the system pool.22,23 From these studies, dynami-
cally generated chirality, in combination with compact anatomy,
play important roles in creating structural diversity and asym-
metry. However, in both examples only one moiety, correlated
to the chiral center, can be changed due to limitation of the
reaction as well as type of the structure. Enhanced diversity of
the restricted structural element can conversely be expanded if
more than one axis at the same stereogenic center is exchange-
able. In this case, the 2D diversity is in principle extended into
3D, more efficiently covering the chemical space.24 This
generates maximum diversity around a minimal point of
attachment, resulting in complexity of the highest density. To
demonstrate this concept, novel types of reactions and structures
have to be investigated, and this has been the objective of the
present study (Figure 1).
One of the key challenges in dynamic covalent chemistry is
the development of efficient reversible reactions. Although
several chemistries have been exemplified, imine formation/
exchange and thiol-disulfide exchange are most often chosen
to form dynamic systems, as these processes have been most
developed in the systems studied.1-6 Nevertheless, one of the
most important reactions in organic chemistry, C-C bond
formation, is still quite rare in this matter and this is especially
the case when generation of chirality is involved in the system.2,3
Furthermore, dynamic systems based on a single reaction type
can in principle be constructed and controlled relatively easily,
where the reaction conditions form the constraints of the overall
system. When two or more chemistries are combined, this results
in additional complications in addressing the chemistries
independently.18,25-30 Thus, not many examples of systems
involving the multiple exchange process have been reported so
far, and especially examples where multiple exchange reactions
are performed simultaneously and continuously communicate
with each other during the process.25
Results and Discussion
Thermodynamic Studies of the Strecker Reaction and the
Double Dynamic Covalent Systems. The Strecker reaction of
preformed, or in situ generated, imines and hydrogen cyanide
is arguably the most important method for the synthesis of
R-amino acid precursors.32-36 The products, R-aminonitriles,
have furthermore a broad range of synthetic applications through
hydrolysis, reduction, or alkylation of the nitrile functionality.37-49
In addition, these transformations represent one of the simplest
and most economical methods on the laboratory scale as well
as on the technical scale. In principle, the cyanation reaction is
a reversible process but kinetic studies of the reaction in water
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