Competition-driven selection in covalent dynamic networks and implementation in organic reactional selectivity

Article abstract of DOI:10.1039/c5sc04924e

Competition among reagents in dynamic combinatorial libraries of increased complexity leads to reactional self-sorting (improved regioselectivity) in mixtures of aldehydes and oligoamines. High selectivity of a given library component is transferred to a

Full text of DOI:10.1039/c5sc04924e

Chemical
Science
View Article Online
View Journal
EDGE ARTICLE
Competition-driven selection in covalent dynamic
networks and implementation in organic reactional
selectivity†
Cite this: DOI: 10.1039/c5sc04924e
P. Kovarıcek,‡ A. C. Meister,§ K. Flıdrova, R. Cabot,{ K. Kovarıckovak and J.-M. Lehn*
ˇ´ˇ
´
´
ˇ´ˇ
´
Competition among reagents in dynamic combinatorial libraries of increased complexity leads to reactional
self-sorting (improved regioselectivity) in mixtures of aldehydes and oligoamines. High selectivity of a given
library component is transferred to a different reacting component of low selectivity through a network of
underlying equilibrating reactions which provide component exchange between all species. The selectivity
of various carbonyl compounds in reactions with amines was also assessed towards the formation of
defined sequences of residues along oligoamine chains. The approach was further exploited for defining
selective dynamic protecting groups (DPGs), based on the reversible linkage between the substrate and
the protecting group. They represent an intermediate approach between the conventional protecting
groups and the protecting-group-free approach in organic synthesis. Removal of the protecting group is
effected via dynamic exchange trapping by formation of a more stable product. The establishment of
equilibrium eliminates the need for isolation and purification of the dynamically protected intermediate(s)
and enables as well the selective sequential derivatisation of oligoamines. The DPG concept can be
generalised to other reversible reactions and can thus represent a valuable alternative in the design of
total synthesis of complex molecules.
Received 24th August 2015
Accepted 3rd February 2016
DOI: 10.1039/c5sc04924e
www.rsc.org/chemicalscience
2,27–32
the search for biologically active compounds.
“
In fact, only
virtual presence” of, i.e. access to, all combinations is required
are formed by reversible as the amplied species can be formed upon the application of
Introduction
1
1
–11
Dynamic covalent libraries (DCLs)
combinatorial linkage of molecular components generating an the stimulus – in the terms of the “lock and key” principle, one
equilibrium mixture of constituents under thermodynamic may say that the lock assembles its key.
control. The reversibility of the linkage allows for constitutional
Imines, resulting from the reversible condensation of
exchange giving access to all possible combinations of compo- a carbonyl component with an amine, are of particular interest
nents. By application of a stimulus, the DCL is able to undergo for setting up DCLs, due to the ease of formation and exchange,
constitutional adaptation whereby some species are amplied usually under mild conditions. The heteroatomic imine bond is
33–36
at the expense of others that are depleted. These features make also satisfactorily orthogonal
to many other reversible
dynamic covalent chemistry (DCC) attractive for application in bonds and its dynamic nature can be “frozen” by reduction or
1
2–20
21
37
material science,
architectures,
surface modication, synthesis of nano- other transformations. Simplication of the complex mixture
2
2–25
7
26
design of receptors and sensors as well as in of species in the library is achieved through adaptive sort-
38–41 42–44 45
ing,
for example in course of crystallisation,
oxidation,
46,47
48–52
distillation
or coordination.
Institut de Science et d'Ing ´e nierie Supramol ´e culaires, Universit ´e de Strasbourg, 8 all ´e e
Gaspard Monge, 67000 Strasbourg, France. E-mail: lehn@unistra.fr
Herewith we report the operation of a reactional self-sorting
process in DCLs of imines of increasing complexity, driven by
competition among the reagents in mixtures of aldehydes and
oligoamines components and leading to improved selectivity in
product formation and/or in site of reaction. The aldehydes in
†
Electronic supplementary information (ESI) available: Experimental details,
NMR spectra, synthetic protocols and mathematical model for formal dynamic
combinatorial library description. See DOI: 10.1039/c5sc04924e
‡
Current address: Department of Low-dimensional Systems, J. Heyrovsky
Institute of Physical Chemistry, Dolej ˇs kova 2155/3, 18223 Prague 8, Czech the studied DCLs are moderately selective in reactions with
Republic.
Current address: Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt,
Germany.
Current address: Department of Chemistry, University of Cambridge, Lenseld
different amines to form various products such as imines,
§
aminals or amino-lactones in the case of o-carboxy-
53,54
benzaldehyde.
Competition between an increasing number
{
of aldehydes for a given mixture of amines leads to increased
selectivity of each of them. It leads to a simplication of the
nal composition resulting from the complexity of the DCL and
Road, CB2 1EW Cambridge, United Kingdom.
k Current address: Institute of Chemical Technology Prague, Department of
´
Research and Development, Technicka 5, 160 00 Prague, Czech Republic.
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
its collapse into a system of reduced multiplicity (and lower pairs”, effecting reactional recognition, like supramolecular
4,57
entropy), amounting to a state that may be termed “simplexity” systems effect interactional recognition (Fig. 1).
in a process of general type from chemical to biological
55,56
systems.
In fact, any recognition process, be it reactional or
interactional (see Fig. 3 in ref. 57) results in the reduction of the [2 ꢀ 2] aldehyde–amine mixtures
complexity of a mixture, of its simplication, through the
Selection by preferential imine/lactone formation. In order
to explore selection in a [2 ꢀ 2] competition, the case of
a mixture of the two aldehydes SALAL–CAXAL and the two
amines IPA–PIP was examined in detail.
Checking rst the combinations opposite to the “matching
pairs” (see above) showed that both aldehydes reacted with both
amines: when CAXAL was mixed with 1 eq. of IPA, equilibrium
was reached almost instantaneously giving a dynamic mixture
of the imine and lactone formed with IPA (details in ESI, Section
operation of competitive selection. On the supramolecular/
interactional level it is expressed in the “instructed mixture
paradigm”, whereby the behaviour of mixtures is driven by the
instructions (molecular information) present in its members
5
8
resulting in self-recognition (or self-sorting), a self-process,
belonging to the general phenomenon of self-organization.
9
,59
The term “simplexity” does not carry the meaning that the
system in itself is less complex, as there is in fact an increased
complexity (increased number of reacting species) underlying
and resulting in the simplication (increased selectivity)
observed. We also propose a formal approach for the repre-
sentation and comparison of DCLs (see below and ESI†) which
has been used for evaluating the efficiency of selection in the
self-sorting processes investigated here within the realm of
3.2†); on the other hand, SALAL reacted with PIP in approxi-
mately 30% conversion to the aminal formed from two amine
molecules and one aldehyde. In subsequent experiments, the
propensity towards the formation of the “matching pair”
product was tested in presence of a competing amine, i.e. each
aldehyde was reacted with an equimolar mixture of the two
amines. SALAL showed a very high preference for imine
formation reacting solely with IPA and leaving PIP unreacted in
the solution. However, the conversion of the aldehyde in this
case was not complete, approximately 10% remaining unreac-
ted. In contrast, CAXAL under the same reaction conditions
provided two products: the lactone on the PIP ring was formed
in about 39% yield and the dynamic imine–lactone product
from IPA was present in about 61% yield (details in the ESI,
Section 3.2†). Finally, the full [2 ꢀ 2] library was considered:
SALAL and CAXAL were mixed with both IPA and PIP in equi-
molar amounts and the resulting product mixture was exam-
ined using NMR spectroscopy. Equilibrium was reached aer 5
hours and the mixture contained only the two “matching pair”
species, the imine SALAL–IPA and the lactone CAXAL–PIP, both
in quantitative conversion.
1
–5,28–30,57
dynamic covalent chemistry (DCC).
Aldehyde–amine dynamic covalent
libraries
In view of the ubiquity of amines and imines in organic
chemistry and in biochemistry, as well as the ability to control
each partner in the reaction, condensations between aldehydes
and amines were taken as model reactions in order to probe
reaction selectivity in competitive dynamic reversible systems.
At rst, different aldehydes were reacted with different
amines in order to test their differences in reactivity and the
nature of the product formed. Salicylaldehyde (SALAL), pyri-
dine-2-carboxaldehyde (PYRAL) and 2-carboxy-benzaldehyde
(
CAXAL) were selected as prototypical aldehydes. On the other
0
hand, isopentylamine (IPA), N,N -dimethyl-1,3-diaminopropane
(
Me PDA) and piperidine (PIP) were selected as their amine
2
6 2
counterparts. As solvent a mixture of d -DMSO with 1% of D O
was used to guarantee solubility of all partners, in which the
water addition maintains constant water content during the
aldehyde–amine condensation. On the basis of previous
studies, differences in reaction outcome was expected for the
53
various aldehyde–amine pairs, anticipating that: (a) SALAL
53
would have a preference for primary amines to form imines,
b) PYRAL would react with diamines to provide a cyclic ami-
(
53
nal and (c) CAXAL would react with secondary amines to afford
amino-lactones through trapping of the intermediary iminium
54
by the neighbouring carboxylate group. These anticipated
selectivities towards formation of different condensation
products were veried in separate experiments: SALAL reacted
with IPA to provide the expected imine, PYRAL gave the six-
membered cyclic aminal with Me PDA, and CAXAL indeed
reacted with PIP to form the amino-lactone. These reactions
proceeded with quantitative conversion and the resulting pref-
2
Fig. 1 Schemes of anticipated reaction outcome of different alde-
hydes and amines with their acronyms used in the study. SALAL forms
preferentially imines and PYRAL cyclic aminals. CAXAL is capable of
erentially formed products may be considered as “matching reacting at a secondary amine site with formation of a lactone ring.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Edge Article
Chemical Science
This remarkable simplicity achieved in the comparatively the corresponding aminals in high conversion (about 90% for
complex mixture, contrasts with the ability of both aldehydes to SALAL and quantitative for CAXAL). Libraries similar to the
react with both amines, and vice versa each amine with the two previous one were examined using PYRAL and its matching
aldehydes. It demonstrates the occurrence of a selectivity diamine (Me EDA and Me PDA) combined either with the
2
2
enhancement of a poor selector by competition with a strong SALAL–IPA or the CAXAL–PIP pair. The experiments (described
selector. Specically, a species reacting non-selectively with in detail in the ESI, Section 3.2 and 3.3†) revealed that although
several compounds is brought to become selective towards all aldehyde–amine combinations were forming efficiently, high
a given product, when put in presence of a competing species of selectivity for the matching pairs was observed when all
high selectivity which monopolises one of the components. The constituents of the library were mixed in equimolar ratio. In
process amounts to a competitive selectivity enhancement. The particularly, for the SALAL–PYRAL–IPA–Me PDA mixture the
2
formation of the matching pair products can also be seen as SALAL–IPA imine and the PYRAL–Me PDA aminal were
2
9,57
resulting from agonist amplication
component exchange through an underlying network of equil- SALAL–Me
ibrating reactions (Fig. 2). the PYRAL–CAXAL–Me
by competition via formed in 80% conversion (and the non-matching pairs
PDA and PYRAL–IPA in 20%), while in the case of
EDA–PIP mixture the PYRAL–Me EDA
2
2
2
Stoichiometry is of course a crucial parameter providing the aminal and the CAXAL–PIP lactone were present in 97% conver-
enhanced selection of the inherent self-sorting process. In the sion (and the non-matching pairs were formed only in 3%).
present case, the components react in 1 : 1 ratio to form the
Selection in extended aldehyde–amine dynamic combina-
preferred product. Therefore, the initial mixture must contain torial libraries. The three [2 ꢀ 2] libraries described above form,
the components in this ratio so that the condensation of the when combined, a [3 ꢀ 3] dynamic library composed of three
matching pair in quantitative conversion depletes all of aldehydes and three amine partners. In this vein, a mixture of
the starting materials, which in turn do not interfere with the SALAL, PYRAL and CAXAL was combined with a mixture of IPA,
2
formation of the second matching pair in the complex system. Me PDA and PIP (all equimolar) and the NMR spectra were
This is clearly demonstrated by the fact that whereas the recorded (Fig. 3). Equilibration of the mixtures was accelerated
ꢁ
aforementioned mixture SALAL–CAXAL–IPA–PIP can give, in by heating at 60 C overnight. The equilibrated samples con-
principle, 14 products (accounting for 2 imines, 4 homo- and 2 tained the imine of SALAL and IPA in 88% conversion and the
heteroaminals, 4 hemiaminals and 2 lactones), only two prod- aminal of SALAL and Me PDA in 12%, whereas the imine to
2
ucts are observed in the mixture containing all four species in aminal ratio of PYRAL was exactly the opposite, and CAXAL
equimolar amounts.
provided quantitatively the lactone with PIP. The system thus
Selection by aminal formation. PYRAL offers the opportunity displayed selectivity in product formation in each case as well as
of considering selection by the formation of aminal species, a remarkable selectivity inversion when comparing the two
different from imine and lactone. Indeed, PYRAL efficiently cases, which display imine/aminal ratios of 88/12 ¼ 7.
0
forms both ve- and six-membered-ring aminals with N,N -
As the nal concentration of species can play a role in the
0
60
dimethyl-1,2-diaminoethane (Me
2
EDA) or N,N -dimethyl-1,3- selection process, we repeated the library experiments at
diaminopropane (Me PDA), reaching quantitative conversion several concentrations: 4, 10, 20, 60 and 100 mM of the
2
when reacted separately with either of the two diamines. On the components. The equilibrium composition of the library in this
other hand, when it was reacted with an equimolar mixture of range was constant showing no concentration dependency.
Me
preferentially (77% conversion to the aminal of Me
SALAL and CAXAL reacted as well with these diamines giving
2
EDA and Me
2
PDA, the ve-membered ring was formed
2
EDA). Both
Fig.
2 Schematic representation of the process of competitive
amplification (enhanced selection) induced by increasing the
complexity of the mixture: while A is capable of reacting with both B
0
0
0
0 0
and B , addition of A leads to enforced formation of the A B product
0
which traps the B component and therefore depletes the AB
constituent. Due to the underlying network of equilibrating reactions
this also leads to amplified formation of the AB constituent in a type of
agonist amplification process of AB by the formation of A B . The Fig. 3 H-NMR spectrum of the [3 ꢀ 3] aldehyde–amine library with
amplified agonistic species are represented by thick lines on the assignment of the peaks. Three major species are formed: the imine of
0
0
1
vertices of the square while the depleted species are denoted by the SALAL and IPA, the aminal of PYRAL and Me
2
PDA, and the lactone of
striped diagonals.
CAXAL and PIP, the latter being the only product of this aldehyde.
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
The library was also assessed for the effect of pH. To this end,
the pre-equilibrated library was examined on addition up to 4
equivalents of acid (MeSO H) or up to 2 eq. of base (t-BuOK).
3
Addition of 1 eq. of acid leads to almost complete hydrolysis of
the aminals of both SALAL and PYRAL, while on addition of the
3
second equivalent of MeSO H the imine hydrolysis reached
60%. Continued titration by acid led to complete hydrolysis of
the imines and extensive hydrolysis of the CAXAL derived
lactone, nally giving only the hydrolysed products, aer addi-
tion of 4 equivalents of acid. In contrast, upon titration by base,
disappearance of the lactone signals was observed. Interest-
ingly, this lactone depletion was not accompanied by the
emergence of the aldehyde peak of CAXAL, but rather of a new
imine of CAXAL with IPA and liberation of SALAL was observed.
This example clearly displays the operation of the underlying
network of interconnected equilibrating reactions which leads
to the complex adaptation of the dynamic library to a stimulus.
The selectivity enhancement displayed here for [n ꢀ n] Chart 1 Relative percentage of the imine formed by the reaction of
SALAL + IPA plotted as a function of time. The rate is significantly lower
when CAXAL is added to the mixture as a result of competition of two
aldehydes for one amine. Interestingly, when PIP is also added, the rate
is higher than the previous two rates, indicating catalysis due to PIP.
dynamic libraries represents a process of competitive selection,
whereby simplication results from competition within the set
of equilibrating constituents undergoing component exchange.
This behaviour relates also to the process of co-evolution in
Kinetic experiments were performed in solution 20 mM for each
-DMSO + 1% D O with 0.8 M triethanolamine buffer.
a dynamic library, leading to the synergistic expression of given compound in d
6
2
9,61
constituents.
We have developed a formal method for quantication of
selection in dynamic combinatorial libraries and especially for Finally, when the experiment was performed in presence of 1
self)-sorting processes which involve coupled reactions. It is eq. of both CAXAL and PIP, forming the corresponding lactone,
(
based on a matrix representation of the combinatorial library the original SALAL conversion of 90% was restored and the rate
ꢂ1 ꢂ1
including the particular case of the selection induced by of formation was even accelerated (k ¼ 0.03 M
s ) due
64
increased complexity of the mixture (see ESI, Section 2,† for probably to the catalytic effect of the secondary amine. Thus,
detailed description).
as expected, on the way towards the simplexity state, the
evolution of the fractions of the different library constituents
depends on the kinetics until equilibrium has been reached.
Kinetics in dynamic reaction selectivity
The key aspect of the eld of dynamic covalent chemistry (DCC)
is that it is governed by thermodynamics and therefore relates
Reactional organization along oligoamine amine chains
to the equilibrium composition. However, the equilibration of Selection in aldehyde–amine DCLs described above arises from
the mixture proceeds via component exchanges, each with the preference of a given aldehyde for its matching amine
a given rate constant, and the equilibrium is thus established partner through equilibration involving reaction both with
when the sum of all reaction rates is zero. Kinetics are therefore different amines and with different sites in an oligo(poly)amine.
intimately involved in the status of the composition of Combining different amine structural motives within one
62
a dynamic set at a given time. It is in particular the case when molecule opens the way to intramolecularly organise aldehyde
considering the vastly different rates of C]N double bond residues along an oligo(poly)amine chain in a given sequence.
formation between different carbonyl groups and different Thus, using the described “matching pairs” a multivalent
63
types of amino compounds. Such kinetic features can be polyamine molecule containing both primary amine end groups
briey illustrated on the library consisting of SALAL, CAXAL, and secondary amines along the chain could serve as the
IPA and PIP.
organisational scaffold for the positioning of aldehyde residues
under functional recognition (Fig. 4).
In the simplest case of N-benzylethylenediamine (BnEDA),
4,57,65
When SALAL was reacted with IPA (20 mM, buffered d
DMSO, see ESI, Section 3,† for details) the formation of the
6
-
imine followed second order kinetics with the rate constant of the chain has one primary and one secondary nitrogen, ex-
ꢂ1 ꢂ1
0.01 M
s
and 90% overall conversion to the imine (note that pected to represent the reactivity of both IPA and PIP respec-
in the reaction without a buffer the conversion was quantita- tively. When an equimolar mixture of SALAL and CAXAL was
tive). When the experiment was repeated in presence of 1 eq. of reacted with 1 eq. BnEDA the dominant species in the solution
ꢂ1 ꢂ1
CAXAL, signicantly slower rate (k ¼ 0.001 M
s ) and only (70%) was the expected imine–lactone: the imine of SALAL
7
7% conversion of SALAL was observed (Chart 1), showing that formed on the primary nitrogen and the lactone of CAXAL
competition of the two aldehydes for one amine affects both the closed on the secondary nitrogen (Fig. 5, see ESI, Section 3.5,†
equilibrium (conversion) and the kinetics (rate of formation). for details). This predominant formation of a single product is
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Edge Article
Chemical Science
The non-symmetric triamines en-prN
3
and spermidine were
also examined in the reaction with the two aldehydes. When
en-prN was reacted with 1 eq. of PYRAL and 1 eq. of SALAL the
3
desired imine–aminal species with ve membered aminal ring
formed in 85% conversion, with trace amounts of six-
membered isomer. When spermidine was reacted under the
same conditions, only one size of the aminal ring can be formed
as seven-membered rings are much more difficult to form
compared to the six-membered ones, and indeed the NMR
spectrum revealed that the six-membered PYRAL aminal
bearing the SALAL-imine on the C -arm was formed in overall
4
conversion of 71% (Fig. 7a, see ESI, Section 3.5,† for details).
Fig. 4 Structures and acronyms of polyamines used in the multi-
valency-based sorting experiments.
In a further extension to four amino sites, the reaction of
triethylenetetramine (en
a complex mixture of products: four different imine signals
three sharp and one broad) and three aminal peaks were
3 4
N ) with 2 equivalents of SALAL gave
(
observed in the NMR spectrum, corresponding to all possible
combinations of imine–aminal structures formed in an essen-
tially statistical fashion. However, when 1 equivalent of PYRAL
was added to the mixture, preferential formation of its aminal
on the middle secondary amino groups enhanced the formation
of the imines of SALAL at the extremities leading to an equi-
librium conversion of about 60% (Fig. 7c).
Fig. 5 Simultaneous reaction of BnEDA with the imine-forming SALAL
and the lactone-forming CAXAL with formation of the expected
imine–lactone product in about 70% conversion. The imine is formed
on the primary amine group and the lactone on the secondary one.
These experiments clearly demonstrate that despite the
ambiguous reactivity of both the amine sites and the aldehydes
(imine–aminal-lactone equilibria), the system of higher
complexity involving all components led to a pronounced
competition-enhanced selectivity towards a preferred species,
as compared to less complex mixtures. These results provide
a remarkable illustration of selectivity amplication, i.e.
simplication induced by an increase in complexity.
remarkable given the fact that the mixture can in principle
generate a large number of other species.
With extended chains with three nitrogen sites, such as
diethylenetriamine (en
2
N
3
)
or bis(3-aminopropyl)amine
(
pr ), selective formation of aminals with PYRAL can be
2 3
N
Selective dynamic protection of amino
groups by reaction with aldehydes
assessed. Closure of the aminal ring bridges two nitrogen sites,
terminal and central, while the third one, the other primary
amine, is available for imine formation. Thus, when either of
the triamines was reacted with 2 eq. of PYRAL, the imine–
aminal was the major product formed. In contrast, when the
triamines were reacted with 2 eq. of SALAL, the terminal bis-
imine was the only product. Remarkably, reaction of the two
aldehydes mixed in 1 : 1 ratio with the two triamines, resulted
in selective formation of the expected products, the SALAL-
imine and PYRAL-aminal, with respectively 77% and 84%
conversion for en N and pr N (Fig. 6).
Specic reversible reaction of different carbonyl reagents with
different amino groups may offer a strategy that can be exploi-
ted for the selective dynamic protection of amines. The
synthesis of complicated multifunctional molecules oen
requires to perform a selective reaction with a given functional
group in presence of other similar groups. Such specic
addressing of a given group in complex molecules is enabled by
66,67
the use of protecting groups (PG).
However, introduction
2
3
2 3
and removal of a PG necessitates two more synthetic steps
Fig. 6 Selective intramolecular organization of two aldehyde residues via imine formation of SALAL and aminal formation of PYRAL affording the
imine–aminal (bottom). Similar results are obtained with ethylene or propylene spacers between nitrogen atoms.
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Fig. 7 Reactional selectivity with multivalent polyamines: (a) reaction of en-prN
3
with a mixture of SALAL and PYRAL (1 eq. each) gave a mixture
3 4
of two imine–aminal isomers; (b) spermidine afforded the expected imine–aminal in 71% conversion; (c) en N gave with about 60% conversion,
the product bearing imines at the termini of the chain, accompanied by the aminal of PYRAL bridging the two central secondary amine sites.
accompanied by purication procedures. It is therefore of much Selective derivatisation of amines
interest to develop “protecting-group-free” synthetic method-
Selective dynamic protection of primary amino groups.
68,69
ologies.
Selective dynamic protecting groups (DPGs) could in
Common amine protection groups such as Boc, Cbz, Fmoc, etc.
are introduced by reactions presenting oen low selectivity
among different amine sites using the corresponding chlor-
oformate or anhydride. A selective version of this protocol
principle offer an attractive intermediate approach whereby the
desired functional group would be protected directly in the
reaction mixture under thermodynamic control without isola-
tion and purication, yet the dynamic nature provides revers-
ibility for comparatively easy dynamic deprotection, for
instance via transimination. Selective DPGs can be fully
89
employs triuoroacetate protection of primary amine, but
3
removal of the CF CO group may be problematic and therefore
lowers overall yields in these reactions. To explore the applica-
tion of a DPG strategy, we rst examine the case of N-methyl-1,3-
diaminopropane (MeDAP). It contains both a primary and
a secondary amino group and can, in principle, form aminal
with an aldehyde thus comprising possible challenges in
selective derivatisation of polyamines. Previous results have
shown that SALAL forms selectively imines as the thermody-
namic product with primary amines, as was conrmed also for
MeDAP (quantitative conversion in less than 2 hours). The
imine formation strongly differentiates the two nitrogen sites in
their reactivities: while the secondary amino group is not
altered, the primary one is engaged in the imine, which presents
in addition a hydrogen bond with the neighbouring OH group.
As a result, only the secondary amino group is free to react
effectively with electrophiles such as acyl chlorides or
66
complementary to traditional PGs in organic synthesis as
there are several types of dynamic linkages which have been
3
3–36,70
shown to be orthogonal to each other,
thus providing
7
1,72
a pool of reagents for different functional groups.
Together
45
with dynamic kinetic resolution, the present work demon-
strates the contribution that the implementation of Dynamic
Covalent Chemistry (DCC) can make to the eld of organic
synthesis.
Amine protection with carbonyl compounds enables C-
7
3–76
77,78
alkylations,
O-alkylations
or C]C double bond dihy-
7
9
80–83
droxylation. As protecting aldehydes, salicylaldehyde
and
84–86
formaldehyde
have been used for selective imine or aminal
formation respectively followed by the typical acidic hydrolysis
7
3–76
work up.
Deprotection can be effected by transimination on
87
82,88
application of hydrazides or hydroxylamine derivatives.
Fig. 8 Illustration of the use of the DPG strategy for selective derivatization. Selective acylation of MeDAP is enabled by the selective imine
formation using SALAL to protect the primary amine in presence of a secondary one. The reaction is under thermodynamic control which
eliminates the need for purification of the protected intermediate. The dynamic nature of the imine bond also allows for easy protecting group
removal and the resulting mono-derivatised A1–4 can be reacted “one pot” with a second electrophile to give doubly derivatized products B1–6.
The imine formation of SALAL directs the selectivity of the first acylation and thus the reaction sequence. Complete conversion of the imine
exchange reaction (used in the deprotection step) provides acylhydrazone and oxime derivatives of SALAL, which are under given conditions
benign byproducts. The sequence of operations allows in principle for multi-step reaction performed “one pot” and requiring purification only
after the last step.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Edge Article
Chemical Science
Table 1 Products and isolated yields of the selective derivatisation of MeDAP using SALAL as protecting group for the primary amine group.
Deprotection was effected by imine exchange and the reactions were conducted in “one pot” fashion followed by a single isolation and puri-
0
fication step. Cbz-GlyONp ¼ N-benzyloxycarbonyl-glycine-p-nitrophenyl ester; Boc-LeuOSu ¼ N-t-butyloxycarbonyl-leucine-N -hydroxy-
0
succinimide ester; Boc-AlaOSu ¼ N-t-butyloxycarbonyl-alanine-N -hydroxysuccinimide ester; CbzCl ¼ benzyl chloroformate
Ref.
Electrophile 1
Cbz-GlyONp
Electrophile 2
Solvent
Deprotecting agent
Yield
A1
A2
A3
A4
B1
B2
B3
B4
B5
B6
—
—
—
—
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
BnONH
BnONH
3
Cl
Cl
82%
69%
70%
86%
78%
83%
82%
75%
71%
82%
pNO
Ph NCOCl
PhNCO
pNO PhCOCl
2
PhCOCl
3
2
PhCONHNH
BnONH Cl
2
3
2
Cbz-GlyONp
Boc-LeuOSu
Boc-AlaOSu
PhCOCl
PhNCO
CbzCl
PhCONHNH
PhCONHNH
PhCONHNH
2
2
2
Cbz-GlyONp
Cbz-GlyONp
Ph
2
NCOCl
EtOH
CH CN
EtOH
BnONH
PhCONHNH
BnONH Cl
3
Cl
CbzCl
PhNCO
3
2
3
isocyanates giving the corresponding amides or ureas while the reaction was performed without the addition of SALAL, it
imine function is not affected. afforded 85% isolated yield of a product consisting of a mixture
The dynamic nature of the reversible imine bond forming of regioisomers due to unsufficient difference in reactivity of the
reaction gives the opportunity for facile protecting group two nitrogen atoms. The regioisomers were present in 2 : 1 ratio
removal in conditions which do not affect acylated amines or in favour of the product of acylation on the secondary amine.
similar derivatives. Imine hydrolysis under acidic conditions The product of double acylation of MeDAP was isolated as well
can be replaced by much milder thermodynamically driven in about 6% yield. We explored the versatility of the protocol by
imine exchange. To this end, addition of a hydrazine, a hydra- varying the reagents, the solvent and also the nature of the
zide or an alkoxyamine leads to cleavage of the imine to give deprotecting agent. The results are summarized in Table 1
a hydrazone, an acylhydrazone or an oxime (respectively) of the (entries A1–A4). Good isolated yields in the range of 69–86% of
carbonyl partner in quantitative conversion with liberation of the desired products were obtained aer the complete three-
the free primary amino group. The double implementation of step reaction sequence.
the features of DCC gives the advantage to perform the three-
The operation of DCC under thermodynamic control has
step reaction sequence, protection–derivatisation–depro- been exploited here for the protection and deprotection steps.
tection, in a “one pot” fashion without the need for isolation The establishment of equilibrium offers the possibility to
and purication of the intermediates (Fig. 8). A number of such perform sequences of reactions in systems of increasing
processes have been explored (Fig. 8; Table 1). To be successful, complexity. Thus, the equilibrium mixtures in the previous
this selective DPG approach requires of course high imine experiments before isolation of products consist of the oxime or
formation, high transimination on deprotection, as well as acylhydrazone of SALAL together with a MeDAP derivative dis-
stability of the imine in the conditions used for the derivatiza- playing a free primary amino group (complete conversion in
tion. Comprehensive method optimisation, synthetic details deprotection). We have therefore investigated the possibility to
and full characterisation of all products are provided in the ESI, perform a controlled sequential derivatisation in a “one pot”
Section 4.† In the following text, the reported yields represent fashion (Fig. 8), in which the imine formation by SALAL directs
isolated amount of pure products.
the sequence of derivatization to give products bearing the
In the reaction of MeDAP with the p-nitrophenyl activated residue introduced rst on the secondary amine group and the
ester of protected glycine (Cbz-GlyONp) using dynamic protec- second one on the primary amine site. The reaction was
tion by 1 eq. SALAL, the N-Cbz-glycyl substituent was introduced repeated for various combinations of electrophiles, in two
on the secondary amine, giving isolated yield of 82% for the full solvents and with two deprotecting agents giving yields of the
three-step one-pot reaction sequence. Importantly, when the desired products in the range of 71–83% (92–95% per step,
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
acylation leads to a regioselectivity opposite to that obtained
when SALAL is used, resulting in an opposite sequence of acyl
groups in the case of sequential double acylation. Such
a process has been performed with MeDAP as shown in Fig. 9.
When PYRAL was mixed with MeDAP, efficient formation of
the aminal within 2 hours was conrmed by NMR. The equili-
brated solution was then treated with phenyl isocyanate form-
ing the urea moiety and the protecting group was removed by
the exchange reaction with O-benzylhydroxylamine which
converts the aminal of PYRAL completely to the corresponding
oxime. The resulting product C1 was isolated in 74% yield,
accompanied with 2% of the opposite regioisomer (Table 2). It
is thus possible to perform a double derivatisation of the
diamine in a “one pot” fashion by addition of a second elec-
Fig. 9 Representation of the generation of opposite sequences of
substitution on consecutive double acylation of MeDAP when either
SALAL or PYRAL is used as dynamic protecting group. Opposite trophile aer deprotection. To this end, we have used phenyl
regioisomers are obtained as a result of the preferential formation of isocyanate as the rst electrophile and the activated ester of
imine and aminal condensation products by SALAL and PYRAL
N-protected phenylalanine or benzyl chloroformate in the
respectively. Both imines and aminals are formed reversibly which
second acylation (isolated yields 76 and 74%, respectively),
allows for mild deprotection with hydroxylamine or hydrazide
demonstrating the potential of the approach implementing
derivatives.
dynamic protecting groups and mild deprotection procedures
compared to conventional protecting groups used in peptide
synthesis.
Table 1 entries B1–B6). In contrast, when the reaction was
The reaction employing PYRAL protection via aminal
performed in absence of the SALAL-imine protecting group
formation was studied with several different electrophiles used
using N,N-diphenylcarbamoyl chloride and benzoyl chloride as
electrophiles, a mixture of all four possible products was ob-
tained in yields from 16 to 34% (details in the ESI, Section
in the rst acylation, but the isolated product always consisted
of the diamine derivatised on the secondary amine (due to
aminal–imine equilibrium, see above). Even aer extensive
optimisation of reaction conditions (details in the ESI, Section
4.1.1.9†).
Inverted sequence of derivatisation. In contrast to SALAL,
4.1.3†) and replacement of PYRAL with formaldehyde, reported
which yields selectively imines, PYRAL preferentially gives
8
4,85
53
in the literature as aminal forming reagent,
the terminal
aminals.
Aminal formation between
a
primary and
regioisomer was only obtained with phenyl isocyanate. Litera-
ture reports describe the use of aminal forming aldehyde to
drive the selectivity of the Michael addition of acrylonitrile to
a secondary amine site transforms the latter into a tertiary
amine and the former into a secondary amine site, which thus is
available for reaction with an electrophile. As a consequence,
85,90
polyamines.
In this vein, MeDAP was reacted rst with 1 eq.
of PYRAL (or SALAL) and then 1 eq. of acrylonitrile was added.
Formation of the product of Michael addition (Fig. 10a) was
Table 2 Inverted selectivity of derivatisation of MeDAP. Formation of
the six-membered aminal ring by the condensation with PYRAL leaves followed by NMR (at r.t. in d
-methanol) revealing that the
4
only the terminal amino group available for the reaction with electro-
reaction time in presence of PYRAL was much longer (35%
conversion aer 24 hours) than in the case of SALAL protected
version (quantitative in 24 hours). Moreover, while SALAL drove
the reaction with full selectivity for the addition on the
secondary nitrogen, the reaction mixture with PYRAL consisted
philes. Isolated yields for one pot multi-step procedures. Boc-PheOSu ¼
0
N-t-butyloxycarbonyl-phenylalanine-N -hydroxysuccinimide
CbzCl ¼ benzyl chloroformate
ester;
Deprotecting
agent
Ref.
Reagent 1
Reagent 2
Solvent
Yield Fig. 10 (a) Michael addition of acrylonitrile proceeds faster on the
primary amino group. Selective reaction of the secondary amino group
C1
C2
C3
PhNCO
PhNCO
PhNCO
—
CbzCl
Boc-PheOSu
CH
CH
CH
3
3
3
CN
CN
CN
BnONH
BnONH
BnONH
3
Cl
3
Cl
3
Cl
74%
74%
76%
can be achieved by protection with SALAL. (b) Double Michael reaction
of acrylonitrile (2 eq.) with 1,3-diaminopropane proceeds with
complete selectivity on primary amino groups in full conversion
without any protecting group.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Edge Article
Chemical Science
of both regioisomers in ratio 1 : 2.5 in favour of the same
product as with SALAL (due to the aminal–imine dynamic
interconversion). When the acrylonitrile Michael addition was
repeated without any protecting aldehyde, again a mixture of
products was obtained, but in this case favouring the addition
on the primary amine. This nding indicates kinetic resolution
between primary and secondary amines in the acrylonitrile
Michael addition, which was supported by the reaction of 1,3-
diaminopropane with 2 eq. of acrylonitrile providing a quanti-
Fig. 12 Selective derivatisation of oligo(poly)amines is enabled by
0
tative yield of the N,N -bis(2-cyanoethyl)-1,3-diaminopropane preferential product formation of a given aldehyde with the amine
91
(
Fig. 10b, details in the ESI, Section 4.4†). In conclusion, the under thermodynamic control. Mild deprotection by imine exchange
reaction, again thermodynamically driven, allows performing
a sequence of three derivatisation steps without isolation and purifi-
cation of intermediates.
PYRAL protection is a suitable approach in the case of highly
reactive isocyanate species, presumably because it reacts faster
than is the rate of intramolecular aminal–imine interconver-
sion. In the case of acyl chlorides this equilibrium, although
strongly shied towards the aminal, leads to non-selective
derivatisation of both amino groups. Acrylonitrile, reacts pref-
erentially with primary amines and SALAL protection is needed
to achieve the selective reaction on the secondary nitrogen.
with protection by 1 eq. of PYRAL forming the aminal and thus
leaving only one primary amino group available for the subse-
quent reaction with the activated ester of an amino acid (Cbz-
GlyONp). The protecting group was removed by exchange
reaction with benzyloxyamine and without isolation, the
subsequent protection by 1 eq. of SALAL was introduced. The
Selective derivatisation of oligoamines
2
selective imine formation at the other terminal NH group of
Selective dynamic protection of amino groups was further
explored with challenging polyamine substrates. To demon-
strate the principle and to draw a comparison with known
alternative protocols, we have examined the monoderivatisation
of diethylenetriamine en N at the central secondary amine
the starting polyamine le the central secondary amine free,
thus allowing for selective derivatisation in the middle of the
chain by benzyl chloroformate. Deprotection was again per-
formed by imine exchange with benzyloxyamine and the last
remaining nitrogen atom was thereaer derivatized using
p-nitrobenzoyl chloride (Fig. 12). This 7-step, one-pot reaction
sequence performed at r.t. under ambient atmosphere afforded
aer a single purication step the desired triply derivatized
product in 31% yield (85% calc. per step), demonstrating the
potential of dynamic selective protecting groups in organic
synthesis.
The presented strategy of selective DPGs showed remarkable
versatility when SALAL was used as the protecting agent. On the
other hand, inverted sequence of derivatisation by employing
PYRAL was limited to cases in which the acylating reagent reacts
faster than the rate of equilibration of the protecting group
between several species. These two approaches are thus
complementary and when combined, provide a powerful tool
to perform selective and/or sequential functionalization of
polyamines.
2
3
group. The traditional protection/reaction/deprotection
89
approach employs triuoroacetyl protection of the terminal
NH functions, followed by reaction with Boc O and removal of
2
2
the triuoroacetate groups by reux in ammonia solution with
overall 63% yield including at least two chromatographic puri-

cation steps. In the present case, SALAL is used as the pro-
tecting agent (2 eq.) and the reaction is performed at room
temperature, in “one pot” fashion, with a single isolation and
purication step giving the desired product in an overall yield of
8
0% (see ESI for the synthetic protocol†). Selective DPGs offer
large versatility which is not easily available with conventional
protecting groups. If pr is protected by 1 eq. of PYRAL
2 3
N
forming the aminal and then reacted with an electrophile,
selective monoderivatisation of one of the termini is achieved in
good yields (70%, Fig. 11, see ESI, Section 4.5,† for synthetic
details). In this case, the PYRAL protection is crucial since
reproducing the reaction without the protecting aldehyde led to
a complex mixture of all possible products in essentially
statistic ratio.
Conclusions
Finally, the sequential derivatisation shown above for Dynamic covalent chemistry (DCC) operates at thermodynamic
diamines was also investigated with the biologically relevant equilibrium achieved by component exchange through rever-
triamine spermidine. In this case, the reaction sequence started sible covalent reactions. The condensation of carbonyl
2 3 2 3
Fig. 11 Selective derivatisation of polyamines in the case of pr N . en N gives similar results. (Right) End-capping of the polyamine chain with
SALAL protection drives the reaction to the central secondary nitrogen, whereas (left) linking two nitrogens in the aminal form of PYRAL leads to
selective derivatisation of only one of the terminal primary amine.
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
compounds with amines is of special interest as it can result in
the formation of N–C–N aminals in addition to the usual C]N
imines, depending on the nature of the carbonyl component. It
offers thus a richer palette of constituents that may be exploited
towards the design of selective reaction pathways of interest for
organic synthetic strategies. It allows for substrate selectivity in
mixtures of amines as well as for the programming of reaction
sequences towards the control of regioselective positioning of
carbonyl residues along an oligo(poly)amine chain. These
features lead to the concept of selective dynamic protecting
groups, whereby primary and secondary amine functional
3 P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor,
J. K. M. Sanders and S. Otto, Chem. Rev., 2006, 106, 3652–
3711.
4 J.-M. Lehn, Chem. Soc. Rev., 2007, 36, 151–160.
5 S. Ladame, Org. Biomol. Chem., 2008, 6, 219–226.
6 R. A. R. Hunt and S. Otto, Chem. Commun., 2011, 47, 847–858.
7 S. R. Beeren and J. K. M. Sanders, J. Am. Chem. Soc., 2011,
133, 3804–3807.
8 S. Hamieh, V. Saggiomo, P. Nowak, E. Mattia, R. F. Ludlow
and S. Otto, Angew. Chem., Int. Ed., 2013, 52, 12368–12372.
9 J.-M. Lehn, Angew. Chem., Int. Ed., 2013, 52, 2836–2850.
groups may be reversibly derivatized in processes presenting 10 S. P. Black, J. K. M. Sanders and A. R. Stefankiewicz, Chem.
selectivity between different amine compounds as well as Soc. Rev., 2014, 43, 1861–1872.
between different amino sites within a polyamine via a network 11 J.-M. Lehn, Angew. Chem., Int. Ed., 2015, 54, 3276–3289.
of underlying equilibrating reactions.
12 C. Wang, G. Wang, Z. Wang and X. Zhang, Chem.–Eur. J.,
2011, 17, 3322–3325.
The selective DPG concept has been exploited towards the
regioselective derivatization of various amines with different 13 D. N. Bunck and W. R. Dichtel, J. Am. Chem. Soc., 2013, 135,
reagents ranging from isocyanates to activated esters of amino 14952–14955.
acids. The establishment of equilibrium in the reaction of the 14 J.-M. Lehn, Prog. Polym. Sci., 2005, 30, 814–831.
substrate with the protecting group as well as in the depro- 15 E. Moulin, G. Cormos and N. Giuseppone, Chem. Soc. Rev.,
tection step eliminates the need for isolation and purication of
intermediates and allows to run reactions in “one-pot” fashion. 16 T. Aida, E. W. Meijer and S. I. Stupp, Science, 2012, 335, 813–
Furthermore, the thermodynamic control over the reversible 817.
condensations opens the possibility to perform sequences or 17 J. Li, J. M. A. Carnall, M. C. A. Stuart and S. Otto, Angew.
networks of reactions in systems of increasing complexity, as it Chem., Int. Ed., 2011, 50, 8384–8386.
was shown in the case of selective sequential derivatisation of 18 T. Ono, S. Fujii, T. Nobori and J.-M. Lehn, Chem. Commun.,
polyamines. Exploitation of other reversibly formed species, 2007, 4360–4362.
such as acetals or boroxines, can provide useful alternatives in 19 T. Ono, S. Fujii, T. Nobori and J.-M. Lehn, Chem. Commun.,
total synthesis of complex products. Altogether the present 2007, 46–48.
work represents an extension of the thermodynamically driven 20 C. B. Minkenberg, F. Li, P. van Rijn, L. Florusse,
2012, 41, 1031–1049.
DCC, implementing dynamic organic reactivity, into the tradi-
tionally kinetically governed realm of organic synthesis and
provides ground for further exploration of its potential.
J. Boekhoven, M. C. A. Stuart, G. J. M. Koper, R. Eelkema
and J. H. van Esch, Angew. Chem., Int. Ed., 2011, 50, 3421–
3424.
Finally, in a broad perspective, the data presented provide 21 A. Ciesielski, M. El Garah, S. Haar, P. Kova ˇr ´ı ˇc ek, J.-M. Lehn
a remarkable illustration of simplication within a given
and P. Samor `ı , Nat. Chem., 2014, 6, 1017–1023.
constitutional dynamic library, induced by an increase in 22 A. Granzhan, T. Riis-Johannessen, R. Scopelliti and
complexity, which leads to enhanced competition within the set K. Severin, Angew. Chem., Int. Ed., 2010, 49, 5515–5518.
of equilibrating constituents undergoing component exchange 23 K. Acharyya, S. Mukherjee and P. S. Mukherjee, J. Am. Chem.
via a network of interconnected reactions engaged in agonistic Soc., 2013, 135, 554–557.
and antagonistic relationships with feedback loops. In general 24 F. B. L. Cougnon, N. Ponnuswamy, N. A. Jenkins,
terms, higher complexity results in simplication through
competition.
G. D. Panto ¸s and J. K. M. Sanders, J. Am. Chem. Soc., 2012,
134, 19129–19135.
2
2
5 S. J. Rowan and J. F. Stoddart, Org. Lett., 1999, 1, 1913–1916.
6 G. J. Mohr, C. Demuth and U. E. Spichiger-Keller, Anal.
Chem., 1998, 70, 3868–3873.
Acknowledgements
2
2
2
7 T. Hotchkiss, H. B. Kramer, K. J. Doores, D. P. Gamblin,
N. J. Oldham and B. G. Davis, Chem. Commun., 2005, 4264–
We thank the ERC Advanced grant “SUPRADAPT” for nancial
support. A. C. M. thanks the French Embassy in Berlin for
a post-doctoral fellowship. P. K. thanks the Universit ´e de
Strasbourg for a doctoral fellowship. K. K. thanks the Erasmus
exchange programme for an international internship.
4266.
8 Dynamic combinatorial chemistry in drug discovery, bioorganic
chemistry, and materials science, ed. B. L. Miller, Wiley,
Hoboken, N.J, 2010.
9 M. Hochg u¨ rtel and J.-M. Lehn, in Fragment-based Approaches
in Drug Discovery, ed. W. Jahnke and D. A. Erlanson, Wiley-
VCH Verlag GmbH & Co. KGaA, 2006, pp. 341–364.
Notes and references
1
2
J.-M. Lehn, Chem.–Eur. J., 1999, 5, 2455–2463.
O. Ramstrom and J.-M. Lehn, Nat. Rev. Drug Discovery, 2002, 31 S. Duan, W. Yuan, F. Wu and T. Jin, Angew. Chem., Int. Ed.,
, 26–36. 2012, 51, 7938–7941.
30 A. Herrmann, Chem. Soc. Rev., 2014, 43, 1899–1933.
1
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Edge Article
Chemical Science
3
3
3
3
3
3
3
3
4
4
4
4
4
2 J. D. Cheeseman, A. D. Corbett, J. L. Gleason and
R. J. Kazlauskas, Chem.–Eur. J., 2005, 11, 1708–1716.
increased complexity in self-sorting, see: K. Mahata and
M. Schmittel, Beilstein J. Org. Chem., 2011, 7, 1555–1561.
3 V. Goral, M. I. Nelen, A. V. Eliseev and J.-M. Lehn, Proc. Natl. 57 J.-M. Lehn, in Constitutional Dynamic Chemistry, ed. M.
Acad. Sci. U. S. A., 2001, 98, 1347–1352. Barboiu, Springer, Berlin Heidelberg, 2012, pp. 1–32.
4 M. Schmittel and K. Mahata, Angew. Chem., Int. Ed., 2008, 47, 58 J.-M. Lehn, Supramolecular chemistry: concepts and
284–5286. perspectives, VCH, Weinheim, 1995.
5 A. Wilson, G. Gasparini and S. Matile, Chem. Soc. Rev., 2014, 59 J.-M. Lehn, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 4763–4768.
3, 1948–1962. 60 I. Saur and K. Severin, Chem. Commun., 2005, 1471–1473.
6 M. L. Saha, S. De, S. Pramanik and M. Schmittel, Chem. Soc. 61 S. Ulrich and J.-M. Lehn, J. Am. Chem. Soc., 2009, 131, 5546–
Rev., 2013, 42, 6860–6909. 5559.
7 L. A. Wessjohann, D. G. Rivera and F. Le ´o n, Org. Lett., 2007, 62 C. Bohne, Chem. Soc. Rev., 2014, 43, 4037–4050.
, 4733–4736. 63 M. Chaur, S. Kulchat, J.-M. Lehn, and work in progress.
8 J.-B. Lin, X.-N. Xu, X.-K. Jiang and Z.-T. Li, J. Org. Chem., 64 M. Ciaccia, R. Cacciapaglia, P. Mencarelli, L. Mandolini and
008, 73, 9403–9410. S. Di Stefano, Chem. Sci., 2013, 4, 2253–2261.
9 Q. Ji, R. C. Lirag and O. S. Miljanic, Chem. Soc. Rev., 2014, 43, 65 C. Fasting, C. A. Schalley, M. Weber, O. Seitz, S. Hecht,
5
4
9
2
ˇ
´
1
873–1884.
0 Y.-M. Legrand, A. van der Lee and M. Barboiu, Inorg. Chem.,
007, 46, 9540–9547.
1 M. L. Saha and M. Schmittel, Org. Biomol. Chem., 2012, 10,
651–4684.
B. Koksch, J. Dernedde, C. Graf, E.-W. Knapp and R. Haag,
Angew. Chem., Int. Ed., 2012, 51, 10472–10498.
66 P. G. M. Wuts and T. W. Greene, Greene's protective groups in
organic synthesis, Wiley-Interscience, Hoboken, N.J, 4th edn,
2007.
2
4
2 C.-F. Chow, S. Fujii and J.-M. Lehn, Chem. Commun., 2007, 67 K. C. Nicolaou, Classics in total synthesis: targets, strategies,
363–4365. methods, VCH, Weinheim, New York, 1996.
3 P. N. W. Baxter, J.-M. Lehn and K. Rissanen, Chem. Commun., 68 P. S. Baran, T. J. Maimone and J. M. Richter, Nature, 2007,
997, 1323–1324. 446, 404–408.
4
1
4 M. Hutin, C. J. Cramer, L. Gagliardi, A. R. M. Shahi, 69 K. C. Nicolaou, J. Org. Chem., 2009, 74, 951–972.
G. Bernardinelli, R. Cerny and J. R. Nitschke, J. Am. Chem. 70 C.-H. Wong and S. C. Zimmerman, Chem. Commun., 2013,
Soc., 2007, 129, 8774–8780.
49, 1679–1695.
4
4
5 K. Osowska and O. S. Miljani ´c , J. Am. Chem. Soc., 2011, 133, 71 Y. Li and X. Liu, Chem. Commun., 2014, 50, 3155–3158.
7
24–727.
6 K. Osowska and O. S. Miljanic, Angew. Chem., Int. Ed., 2011,
0, 8345–8349.
72 S. Mundinger, U. Jakob and W. Bannwarth, Chem.–Eur. J.,
ˇ
´
2014, 20, 1258–1262.
5
73 P. Bey and J. P. Vevert, Tetrahedron Lett., 1977, 18, 1455–
ˇ
´
4
4
7 Q. Ji and O. S. Miljanic, J. Org. Chem., 2013, 78, 12710–12716.
1458.
8 S. De, K. Mahata and M. Schmittel, Chem. Soc. Rev., 2010, 39, 74 B. W. Metcalf and P. Casara, Tetrahedron Lett., 1975, 16,
555–1575. 3337–3340.
9 K. Mahata and M. Schmittel, J. Am. Chem. Soc., 2009, 131, 75 R. Polt and M. A. Peterson, Tetrahedron Lett., 1990, 31, 4985–
6544–16554. 4986.
0 M. Schmittel and K. Mahata, Chem. Commun., 2008, 2550– 76 J. M. Hornback and B. Murugaverl, Tetrahedron Lett., 1989,
552. 30, 5853–5856.
1 I. Kocsis, D. Dumitrescu, Y.-M. Legrand, A. van der Lee, 77 M. Bergmann and L. Zervas, Ber. Dtsch. Chem. Ges. B, 1931,
1
4
5
5
1
2
I. Grosu and M. Barboiu, Chem. Commun., 2014, 50, 2621–
623.
2 J. R. Nitschke and J.-M. Lehn, Proc. Natl. Acad. Sci. U. S. A.,
003, 100, 11970–11974.
3 P. Kova ˇr ´ı ˇc ek and J.-M. Lehn, J. Am. Chem. Soc., 2012, 134,
446–9455.
4 P. Kova ˇr ´ı ˇc ek and J.-M. Lehn, Chem.–Eur. J., 2015, 21, 9380–
384.
5 (a) For general considerations on the notion of “simplexity”
64, 975–980.
2
78 M. A. Peterson and R. Polt, J. Org. Chem., 1993, 58, 4309–
4314.
79 E. J. Corey, A. Guzman-Perez and M. C. Noe, J. Am. Chem.
Soc., 1995, 117, 10805–10816.
80 J. N. Williams Jr and R. M. Jacobs, Biochem. Biophys. Res.
Commun., 1966, 22, 695–699.
81 J. C. Sheehan and V. J. Grenda, J. Am. Chem. Soc., 1962, 84,
2417–2420.
5
5
5
5
2
9
9
in particular in a biological context, see A. Berthoz, La 82 A. R. Khomutov, A. S. Shvetsov, J. J. Veps ¨a l ¨a inen and
simplexit ´e , Odile Jacob, 2009; (b) For an elaboration in the
A. M. Kritzyn, Tetrahedron Lett., 2001, 42, 2887–2889.
context of organic synthesis, see: Ph. Compain, L'actualit ´e 83 J. D. Prugh, L. A. Birchenough and M. S. Egbertson, Synth.
Chimique, 2003, april-may issue, 129–134. Commun., 1992, 22, 2357–2360.
6 (a) For an early case, see the competitive selection in the 84 J. S. McManis and B. Ganem, J. Org. Chem., 1980, 45, 2041–
generation of double and triple helicates in an 2042.
5
interconverting set of ligands and metal ions: see 85 B. Ganem, Acc. Chem. Res., 1982, 15, 290–298.
R. Kr ¨a mer, J.-M. Lehn and A. Marquis-Rigault, Proc. Natl. 86 J. C. Bradley, J. P. Vigneron and J. M. Lehn, Synth. Commun.,
Acad. Sci. U. S. A., 1993, 90, 5394–5398; (b) For the effect of
1997, 27, 2833–2845.
This journal is © The Royal Society of Chemistry 2016
Chem. Sci.

View Article Online
Chemical Science
Edge Article
8
8
8
7 D. R. Mootoo and B. Fraser-Reid, Tetrahedron Lett., 1989, 30, 90 B. Frydman, S. Bhattacharya, A. Sarkar, K. Drandarov,
2
363–2366.
S. Chesnov, A. Guggisberg, K. Popaj, S. Sergeyev,
A. Yurdakul, M. Hesse, H. S. Basu and L. J. Marton, J. Med.
Chem., 2004, 47, 1051–1059.
8 K.-J. Fasth, G. Antoni and B. Langstr ¨o m, J. Chem. Soc., Perkin
Trans. 1, 1988, 3081–3084.
9 S. Srinivasachari, Y. Liu, G. Zhang, L. Prevette and 91 S. K. Sharma, Y. Wu, N. Steinbergs, M. L. Crowley,
T. M. Reineke, J. Am. Chem. Soc., 2006, 128, 8176–8184.
A. S. Hanson, R. A. Casero and P. M. Woster, J. Med.
Chem., 2010, 53, 5197–5212.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2016