This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical
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Supramolecularly Fine-Regulated Enantioselective Catalysts
a

a

a,b

Mónica Vaquero, Laura Rovira, and Anton Vidal-Ferran*
a

Institute of Chemical Research of Catalonia (ICIQ) & The Barcelona Institute of Science and Technology, Avgda. Països Catalans 16, 43007 Tarragona, Spain.
ICREA, Pg. Lluís Companys 23, 08010 Barcelona.
E-mail: avidal@iciq.cat
b

The use of supramolecular interactions in catalysis has undergone major growth in the last decade and has contributed to the major advances achieved in
the field of enantioselective catalysis. Of the various approaches that use supramolecular interactions in enantioselective catalysis, this article highlights
different supramolecular strategies to generate a set of enantiopure ligands (or enantioselective catalysts) that retain the majority of the backbone’s
structural features, yet at the same time incorporate subtle changes at its active site that depend on the structural characteristics of the regulation agent
(RA) employed.

1. Introduction
Enantioselective catalysis enables selective pathways for
converting simple compounds into enantiomerically pure
complex molecules. It has evolved greatly since the early 1970s
to now encompass nearly any transformation subject to three1
dimensional bias. The critical step in most enantioselective
processes is the assembly of a supramolecular system around
the catalytic site. This involves the substrate, the metal
precursor, if present, and an enantiopure molecule (the chiral
ligand). In metal-mediated transformations, the metal centre
provides a low-energy reaction pathway that enables catalysis,
whereas the enantiomerically pure ligand enables the
formation of enantiopure (or enantioenriched) products. In
metal-mediated asymmetric transformations, the metal centre
and ligand have the complementary functions indicated above,
whereas in organocatalysis, the enantiopure organic molecule
alone plays both roles by providing a low energy reaction
pathway and enabling the formation of enantiopure (or
2
enantioenriched) products. The first chiral ligands to be
employed in enantioselective catalysis were mostly derived
3
from the “chiral pool”. Practitioners of enantioselective
catalysis soon realised that, because of the limited structural
diversity among ligands derived from natural products, they
were unlikely to provide a satisfactory response to all
conceivable selectivity demands in catalysis (reactions,
substrates, reagents, etc.). Thus, researchers realised that they
needed to harness asymmetric synthesis to broaden the
repertoire of ligand scaffolds, to incorporate all types of
stereogenic elements in the ligand, and to functionalize ligands
with diverse functional groups that bind the desired metal
centre (in transition metal-based transformations) or interact
4
with the substrates/reagents (in organocatalysed processes).
The use of supramolecular interactions in catalysis has
undergone major growth in the last decade and has also
contributed to the major advances achieved in the field of
enantioselective catalysis. In addition to the situations in which
supramolecular interactions participate exclusively in a
5
catalytic event, supramolecular chemistry in enantioselective
catalysis has a range of other uses:

First and foremost, supramolecular interactions have been
widely used to construct the backbone of enantiopure ligands
by attaching suitably designed building blocks through noncovalent and metal-ligand interactions. The building blocks
contain the binding groups required for the desired catalysis as
well as the motifs necessary for supramolecular assembly. This
synthetic methodology has enabled libraries of structurally
diverse enantiopure ligands or catalysts to be synthesised with
greater ease than for standard covalent chemistry. The use of
supramolecular interactions to construct ligands for
enantioselective catalysis, or catalysts themselves, has been
6
widely reviewed and is outside the scope of this text.
Second, supramolecular interactions in enantioselective
catalysis have also been exploited by placing in the ligand or
catalyst well-designed functional groups capable of
supramolecularly interacting with the substrate. Substrate-,
chemo-, diastereo- and/or enantio-selectivities have been
improved using this strategy, which relies on the precise
positioning of the substrate relative to the catalytic site.
Reported examples encompass both transition-metal- and
metal-free catalysed enantioselective transformations and will
not be discussed in this text, as these have been recently
7
reviewed.
Encapsulation of the catalytic species in a molecular container
constitutes the third supramolecular strategy that has been
applied in catalysis. Amongst other advantages, encapsulating
the catalytic system has led to rate enhancement by increasing
the effective concentration of the reagents within a confined
space, to unusual selectivity within the molecular container
and to the stabilisation of otherwise unstable molecules within
the cavity. Many of these applications refer to achiral
transformations and there is very little literature providing
examples of enantioselective transformations within a
confined space. This topic has been the object of recent
8
reviews and is also outside the scope of this text.
The fourth and last supramolecular strategy that has been
implemented in enantioselective catalysis has sought to
override one of the intrinsic limitations of enantioselective
catalysts: their lack of generality. It is well known to

practitioners in the field that structural changes in the
substrate(s) and/or reagent(s) often translate to a loss of
enantioselectivity. A common strategy to improve the
generality of a catalyst is based on a modular ligand design and
9
ligand tuning. Libraries of structurally related ligands have
also been prepared (in many cases through parallel
10
synthesis ) and assessed by automated high-throughput
screening to rapidly identify high-performing catalysts for a
10,11
specific transformation and substrate.
With the aim of
reducing the synthetic efforts associated with the above
mentioned strategies, practitioners have also harnessed
supramolecular
chemistry
to
produce
libraries
of
enantioselective catalysts, whose members preserve the main
structural characteristics of the whole set but also incorporate
subtle geometrical differences at the catalytic site. Hence, the
members of these libraries of related catalysts are capable of
geometric adaptation to the requirements of a given substrate
for high enantioselectivity.
Two strategies have been developed to achieve these goals:
 Supramolecular regulation onto an already formed
enantioselective catalyst: this approach resembles allosteric
modulation or “allosterism”, which is one of Nature’s most
12
exquisite mechanisms of action in enzyme catalysis.
Allosteric modulation of a biocatalyst refers to the
modification of the biocatalyst’s active site when an effector
molecule binds at a distinct site on the same biocatalyst
(known as the allosteric site or regulation site).
Supramolecularly fine-regulated enantioselective catalysts
belonging to this category possess a catalytic site with a welldefined
three-dimensional
structure
suitable
for
enantioselective catalysis and a distal regulation site
containing a supramolecular motif capable of interacting with
a regulation agent (RA). In this way, the library of
enantioselective catalysts that results from the binding of an
array of geometrically diverse RAs to the regulation site not
only preserves most of the structural characteristics but also
incorporates structural peculiarities that depend on the size
and shape of the RA employed.
 Supramolecular regulation onto a pro-chiral ligand: the
principle of this approach is similar to that summarised above
with one crucial exception. The three-dimensional structure of
the catalytic site is not well defined in the absence of a
regulation agent. The addition of an enantiopure regulation
agent creates chirality and the size and shape of the RA
employed also determine the geometry of the catalytic site.
It should be recalled at this point that this feature article
focuses only on the progress on systems that fall within the
two aforementioned categories (supramolecular regulation of
enantioselective catalysts involving major alterations of the
principal structural features of the catalyst has been the object
13
of recent reviews and is outside the scope of this text).
Furthermore, it should be noted that this perspective article
highlights published pieces of work only when the authors
demonstrate the regulation ability of a set of RAs on an array
of substrates. Examples describing the use of only one RA for a
whole array of substrates have not been included in the
present article because the authors regard these examples as
6,13
referring to the construction of the catalyst
and not to the

regulation effects induced by the external molecule.
Analogously, the present article also excludes examples
describing an array of external molecules or RAs for only one
substrate.

2. Discussion
The discussion is divided into two sections corresponding to
the two aforementioned different strategies.
2.1. Supramolecular regulation
enantioselective catalyst

on

an

already

formed

In this strategy, regulation occurs when a catalytic site is
modified by the interaction of an external unit (regulation
agent; RA) with a distinct specific regulation site. The following
discussion is divided into different sections corresponding to
the different supramolecular motifs that have been employed
as regulation sites.
2.1.1. Catalytic systems regulated by interactions of a
regulation agent with an (aza-)crown-ether motif. Cyclic crownethers and their nitrogenated analogues form very stable
complexes with charged species (i.e. metal ions, halide anions,
14
carboxylates, etc.). Furthermore, crown-ethers have become
popular supramolecular motifs due to the ease with which their
size, shape and topology can be varied and the fact that synthetic
14
strategies for preparing them are well-established. Ito and co15
workers pioneered the field of supramolecularly fine-regulated
enantioselective catalysts for asymmetric allylic substitutions (AASs)
by incorporating an aza-crown-ether motif as a regulation site in
their bisphosphine ligand design (Fig. 1). The underlying principle in
the design of the catalyst consisted of introducing a secondary
16
interaction between the reacting nucleophile (enolates generated
from S1 or S2 by using alkali metal salts as bases) and the azacrown-ether motif. It was envisaged that the metal enolate would
form an inclusion complex with the aza-crown-ether. In doing so, it
was expected that the reacting nucleophile would be placed in close
proximity to the allyl group bound to the palladium centre with an
overall improvement in the reaction rate and in the stereocontrol of
the reaction by reducing the degrees of freedom in the intervening
transition states (TSs). Reactions of the enolates derived from S1 or
S2 with allyl acetate were carried out in the presence of in situ
formed palladium catalysts (equimolar amounts of Pd2(dba)3·CHCl3
and the corresponding ligand) and an array of alkali metal fluorides
(i.e. KF, RbF or CsF) as bases. The authors used an array of bases
because they believed that the size of the cation could

Fig. 1. Supramolecularly regulated ligand for AASs reported by Ito et al.

These results indicate that even for the same combination of
ligand and RA, the sign and magnitude of the regulation effects
depend on the substrate. Though the regulation effects were
small in magnitude, the authors demonstrated that a library of
bisphosphines could be easily generated with this strategy by
varying the regulation agent.

Table 1. Catalytic results obtained for AASs reported by Ito et al.

Entry
1
2
3
4
5
6
a

Carbanion
derived
from
S1
S1
S1
S2
S2
S2

RA

Yield
(%)

KF
RbF
CsF
KF
RbF
CsF

33
57
31
95
95
91

ee
(%, config.)
25 (R)
38 (R)
31 (R)
51 (R)
60 (R)
34 (R)

Regulation
effects in
eea (%)
+13
+6
+17
+26
-

Calculated with respect to the lowest ee described.

influence the relative arrangement of the attacking
nucleophile and the allyl group. The ability to modify the
arrangement of reactants through supramolecular interactions
constitutes the regulation mechanism in this catalytic system.
After an optimisation process, ligand L1 was found to be the
optimal one for achieving high ees in the AASs of allyl acetate
with the nucleophiles derived from S1 and S2. The authors also
found that the combined use of RbF with ligand L1 provided
the highest conversions and ees in both cases. The authors
reported that the affinity between RbF and the aza-crownether motif in ligand L1 was higher than those for KF and CsF.
The better complementarity between RbF and the aza-crownether motif translated into more efficient regulation effects in
terms of enantioselectivity for RbF than those observed for KF
(compare entries 2 with 1 for S1 and 5 with 4 for S2, in Table 1)
or CsF (compare entries 2, 3, 5 and 6 in Table 1).
Vidal-Ferran et al. reported the preparation of
bisphosphine ligand L2, which incorporates a crown-ether
motif as a regulation site, and its use in rhodium-mediated
17
asymmetric hydrogenations (AHs). The authors envisaged
that binding a regulation agent to the crown-ether motif could
modulate the catalyst performance by modifying the dihedral
angle  of the biaryl unit (see Fig. 2a for a general
representation of the regulation principle). The importance of
the geometrical parameter in the performance of a
transition metal-based catalyst is well documented in the
literature, as it is associated with the natural bite-angle  of a
18
ligand to the metal centre (see Fig. 2a). Rhodium complexes
derived from bisphosphine L2 were efficient catalysts in the
AH of S3 in terms of activity, though the ees remained
moderate (ees ranging from 56% to 62% in favour of (S)-P3
and from 26% to 30% for (S)-P4, see Table 2). In terms of the
AH of S3 in the presence of a set of RAs, small but noticeable
regulation effects on the ee were observed. The maximal
increment in the ee was observed using the enantiomerically
pure ammonium salt RA1 as the RA. In contrast, the best
enantioselectivity for S4 was obtained in the absence of an RA.

Fig. 2. (a) Ligand structure and regulation principle for AHs reported by Vidal-Ferran et
al.; (b) Ammonium salts employed as regulation agents.
Table 2. Catalytic results obtained for AHs reported by Vidal-Ferran et al.

Entry

Substrate

RA

ee
(%, config.)

1
2
3
4
5
6
7
8

S3
S3
S3
S3
S3
S4
S4
S4

NaBArF
CsBArF
RA1
RA2
NaBArF
CsBArF

60 (S)
56 (S)
60 (S)
62 (S)
61 (S)
30 (S)
27 (S)
26 (S)

Regulation
effects in ee
(%)a
-4
0
+2
+1
-3
-4

a

Calculated for each substrate with respect to the experiment in the absence of
an RA.
19

Recently, Wu and Li et al.
have designed a new
supramolecularly regulated biphosphine ligand containing
pyridyl-aza-crown-ether motifs to be applied in the AH of dehydroamino acid and quinoline derivatives. The new ligand
L3 incorporated two pyridyl-aza-crown-ether units (see Fig. 3
for the structure), which bind an array of BArF salts in a 1:2
19
relative stoichiometry between L3 and the BArF salt. The use
of an array of alkali metal BArF salts in the asymmetric
hydrogenation of -dehydroamino acid derivatives S5S7
mediated by rhodium complexes derived from L3 translated
into complete conversion and different enantioselectivities
depending on the RA used (NaBArF provided the highest ee,

entry 5 in Table 3). Of the various weakly coordinating anions
(WCA) constituting the RAs, the BArF anion provided the
highest regulation effects during the hydrogenation of S5 with
G = H (compare entries 5-7 in Table 3). The authors suggest
that the weaker coordinating ability of the BArF anion favours
strong binding of NaBArF to the crown ether motif. Binding
studies between a bulky ammonium BArF salt (i.e.
(nBu)4NBArF) and the crown ether motifs revealed a weak
interaction and the effects of (nBu)4NBArF on the performance
of the catalyst were also minimal (compare entries 1 and 8 in
Table 3). Furthermore, enhancements in the enantioselectivity
of up to 11% ee in the hydrogenation of S5 with G = H were
achieved when NaBArF was employed as the RA (compare
entries 1, 2 and 5 in Table 3; the reader is referred to the
original work for the whole set of results). The authors
expanded the scope of the reaction to a set of structurally
diverse -dehydroamino acid derivatives (see the scheme in
Table 3 and the original reference for the whole set of
19
substrates studied). The highest regulation effects were
observed for S5 with G = 2-F, for which NaBArF increased the
conversion by 62% and the enantioselectivity by 22% with
respect to the hydrogenation in the absence of an RA
(compare entries 11 and 12 in Table 3).
This supramolecular regulation approach was also applied to
the iridium-mediated asymmetric hydrogenation of quinolines.
The resulting hydrogenated products were obtained with
excellent enantioselectivities (90-97% ee, Table 4), but the
regulation effects were smaller than those obtained in
rhodium-mediated AHs of functionalised alkenes, with
enhancements of up to 10% (see entries 1 and 2 in Table 4).
In short, it is interesting to note that supramolecularly
regulated ligand L3 performs better in terms of
20
enantioselectivity in Rh- and Ir-mediated AHs, than the ligand
21
lacking the two crown ether motifs (i.e. Xyl-P-Phos ).
2.1.2. Catalytic systems containing a polyether linear chain as
the regulation site. Metallacrown-ethers are formed by combining
a metal precursor with a linear polyether chain containing
functional groups at the  and  positions capable of coordinating
22
23
to the metal centre. Fan et al. identified metallacrown-ethers as
ideal scaffolds for developing supramolecularly regulated
enantioselective catalysts: metallacrown derivatives simultaneously
contain a plausible catalytic group (the metal centre) and a
supramolecular motif capable of acting as a

Fig. 3. Supramolecularly regulated ligand for AHs reported by Wu and Li et al.

Table 3. Catalytic results obtained for Rh-mediated AHs reported by Wu and Li et
al.

Entry
1b
2b
3b
4b
5b
6b
7b
8b
9
10
11
12
13
14
15
16
17
18

Substrate

RA
(mol%)

S5, G = H
S5, G = H
NaBArF (2)
S5, G = H
LiBArF (2)
S5, G = H
KBArF (2)
S5, G = H
NaBArF (10)
S5, G = H
NaBF4 (10)
S5, G = H
NaPF6 (10)
S5, G = H
(nBu)4NBArF(10)
S5, G = 2-OMe
S5, G = 2-OMe
NaBArF (10)
S5, G = 2-F
S5, G = 2-F
NaBArF (10)
S5, G = 3-OMe
S5, G = 3-OMe
NaBArF (10)
S5, G = 4-F
S5, G = 4-F
NaBArF (10)
S6
NaBArF (10)
S7
NaBArF (10)

Conv.
(%)

ee (%,
config.)

>99
>99
>99
>99
>99
68
96
91
69
93
33
95
42
93
71
92
90
88

82 (R)
88 (R)
84 (R)
86 (R)
93 (R)
81 (R)
83 (R)
84 (R)
78 (R)
99 (R)
76 (R)
98 (R)
77 (R)
98 (R)
84 (R)
98 (R)
97 (R)
97 (R)

Regulation
effects in
ee (%)a
+6
+2
+4
+11
-1
+1
+2
+21
+22
+21
+14
-

a

Calculated for each substrate with respect to the experiment in absence of an
RA. b Reaction performed in DCM.

regulation site (polyether motif) by binding a complementary
external unit (RA). It should be noted at this point that, like
cyclic crown-ethers, linear polyether groups are also capable of
24
binding charged species such as metal ions, carboxylates, etc.
Fan et al. pioneered the use of supramolecularly regulated
polyether-based ligands for rhodium-mediated asymmetric
22
hydrogenations (AHs). These authors reported the first
example of rhodium complexes derived from bisphosphitepolyether ligands, whose catalytic performance in terms of
enantioselectivity in AH was enhanced by the addition of an
RA. Fan et al. first investigated the effect of the linker length
on the catalytic performance of the metallacrown-ether
catalyst. Ligands with five, six or seven ethyleneoxy units in the
polyether chain provided moderate enantioselectivities in the
absence of an RA, which were associated by the authors with
their high flexibility (although the results for ligand L4 (Fig. 4),
which contains six ethyleneoxy units, are indicated in Table 5,
22
the reader is referred to the original work for the results for
the other two ligands). The efficiency of L4 could be enhanced
by adding an RA (i.e. LiBArF, NaBArF or KBArF) capable of
interacting with the polyether chain.

Table 4. Catalytic results obtained for Ir-mediated AHs by Wu and Li et al.

Entry

Substrate

RA

ee (%,
config.)

1
2
3
4
5
6

S8, R1 = Me, R2 = H
S8, R1 = Me, R2 = H
S8, R1 = nPr, R2 = H
S8, R1 = nBu, R2 = H
S8, R1 = npentyl, R2 = H
S8, R1 = Me, R2 = F

NaBArF
NaBArF
NaBArF
NaBArF
NaBArF

87 (R)
97 (R)
97 (R)
96 (R)
96 (R)
90 (R)

Regulation
effects in
ee (%)a
+10
-

Fig. 4. Supramolecularly regulated ligand for AHs reported by Fan et al.
Table 5. Catalytic results obtained for AHs by Fan et al.

a

Calculated for each substrate with respect to the experiment in absence of an
RA.

Entry

NaBArF provided the highest increase in the enantioselectivity
of the AH of S5 with G = H (see entry 3 in Table 5; increase in
ee up to 11%). The authors suggested that the difference in
the abilities of ligand L4 to bind LiBArF, NaBArF or KBArF
translated into different regulation effects. A binding
competition experiment between 18-crown-6 ether, KBArF
and L4 helped to determine the role of the alkali-metal salts in
the regulation event. The higher affinity of 18-crown-6 for
KBArF with respect to L4 led to an enantioselectivity similar to
that obtained in the absence of an RA. Once the optimal
catalytic system had been identified, a series of dehydroamino acids were hydrogenated by employing Rhcomplexes derived from L4 as catalyst and NaBArF as RA. As
shown in Table 5, AHs proceeded efficiently with full
conversions, excellent enantioselectivities (ees ranged from
94% to 98% ee; see entries 5-8 in Table 5) and positive
regulation effects (increases in the ee ranging from 5% to 17%)
when NaBArF was used as the RA.
More recently, Fan and He et al. have reported the
preparation of supramolecularly regulated phosphinephosphite ligand L5 and its performance in rhodium-mediated
25
AHs (Fig. 5). The design principle was the same as for L4,
though metallacrown-ethers with different coordinating
groups at their  and  positions were unknown before the
study by Fan and He et al. The catalytic system that provided
higher enantioselectivities in the AH of -arylenamide S9 (G =
H) was derived from ligand L5. The use of KBArF as the RA
provided the highest enhancements in enantioselectivity for all
RAs assayed (ee enhancement up to 9% ee; see entry 4 in
Table 6 for all RAs studied).

Substrate

RA

ee
(%, config.)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

S5, G = H
S5, G = H
S5, G = H
S5, G = H
S5, G = 4-F
S5, G = 4-F
S5, G = 4-Cl
S5, G = 4-Cl
S5, G = 3-Cl
S5, G = 3-Cl
S5, G = 2-Cl
S5, G = 2-Cl
S5, G = 4-Me
S5, G = 4-Me
S5, G = 4-NO2
S5, G = 4-NO2
S4
S4

LiBArF
NaBArF
KBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF

84 (R)
87 (R)
95 (R)
94 (R)
83 (R)
95 (R)
84 (R)
96 (R)
82 (R)
95 (R)
84 (R)
94 (R)
86 (R)
94 (R)
79 (R)
96 (R)
93 (R)
98 (R)

Regulation
effects in
ee (%)a
+3
+11
+10
+12
+12
+13
+10
+8
+17
+5

a

Calculated for each substrate with respect to the experiment in absence of an
RA.

Fan and He et al. also reported that the addition of KBArF had
a rate accelerating effect on the AH, which indicated that the
addition of alkali metal salts also improved the activity of the
25
metallacrown catalyst.
The authors attributed the
differences in the regulation effects (or enhancements) on the
ee of the hydrogenated product to the differences in the
match of the RAs (i.e. LiBArF, NaBArF, KBArF or CsBArF) to the
metallacrown motif. A series of -arylenamides (S9 and S10)
were hydrogenated using the rhodium catalyst derived from L5
and KBArF as the RA. In general terms, the AHs of parasubstituted arylenamides proceeded with full conversions and
high enantioselectivities (from 94 to 99% ee; see entries 6 to
15 in Table 6). Lower ees were obtained for the ortho- and
meta-substituted analogues, although considerable regulation
effects (enhancements of up to +6% in the ee; see entry 17 in
Table 6) were observed.

Fig. 5. Supramolecularly regulated ligand for AHs reported by Fan and He et al.
Table 6. Catalytic results obtained for AHs of -arylenamides by Fan and He et al.

Entry

Substrate

RA

ee
(%, config.)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

S9, G = H
S9, G = H
S9, G = H
S9, G = H
S9, G = H
S9, G = 4-Me
S9, G = 4-Me
S9, G = 4-F
S9, G = 4-F
S9, G = 4-CF3
S9, G = 4-CF3
S9, G = 4-Cl
S9, G = 4-Cl
S9, G = 4-Br
S9, G = 4-Br
S9, G = 3-Cl
S9, G = 3-Cl
S9, G = 2-Cl
S9, G = 2-Cl
S10
S10

LiBArF
NaBArF
KBArF
CsBArF
KBArF
KBArF
KBArF
KBArF
KBArF
KBArF
KBArF
KBArF

84 (S)
89 (S)
91 (S)
93 (S)
92 (S)
84 (S)
96 (S)
85 (S)
94 (S)
92 (S)
99 (S)
94 (S)
99 (S)
93 (S)
98 (S)
81 (S)
87 (S)
66 (S)
70 (S)
50 (S)
58 (S)

Regulation
effects in
ee (%)a
+5
+7
+9
+8
+12
+9
+7
+5
+5
+6
+4
+8

a

Calculated for each substrate with respect to the experiment in absence of an
RA.

In between the publication dates of the studies on
supramolecularly regulated metallacrown-based catalysts by
22,25
Fan and He et al.,
Vidal-Ferran et al. reported the first
generation of supramolecularly regulated -bisphosphites
26
for asymmetric hydroformylations (AHFs). The design of the
ligand was similar to that of L4 but incorporated a
conformationally labile [1,1'-biphenyl]-2,2'-diol motif at the
regulation site. The supramolecularly regulated bisphosphite was successfully applied to the AHF of terminal
alkenes with highly positive regulation effects on the
enantioselectivity (increases of up to 62% ee for vinyl
26
acetate). Further optimization studies towards the optimal
supramolecularly regulated ligand for this chemistry (i.e.

optimal bisphosphite motif, optimal length of the polyether
chain, necessity or not of having a conformationally labile
[1,1'-biaryl]-2,2'-diol motif at the regulation site and the
nature of the anionic component of the RA) led to an improved
supramolecularly regulated catalytic system for the AHF of
27
terminal alkenes (see ligand L6 in Fig. 6). These studies
revealed that ligands with a conformationally labile [1,1'biaryl]-2,2'-diol motif at the regulation site led to lower
conversions in the AHF of the chosen model substrate (i.e.
vinyl acetate) and that phosphite groups derived from 3,3'bis(trimethylsilyl)-[1,1'-binaphthalene]-2,2'-diol provided the
28
highest ees in AHF. As regards the nature of the anionic
component of the RA, the weakly coordinating BArF anion
provided higher branched to linear (b/l) ratios for vinyl acetate
than those observed using other RAs containing the BF4 or
27
ClO4 ions. Furthermore, BArF salts were an attractive option
given their adequate solubility profile in solvents that are
suitable for AHFs (e.g. toluene containing a small amount of
THF).

Fig. 6. Supramolecularly regulated ligand for AHFs reported by Vidal-Ferran et al.

As a continuation of their catalytic studies, Vidal-Ferran et al.
became interested in evaluating the design principle—namely,
whether the addition of an RA in the reaction medium would
affect the catalytic activity of the rhodium complexes derived
from L6 (Fig. 6). Error! Reference source not found.
summarises the effects of different alkali metal and
ammonium salts on the catalytic activity. Of all the RAs tested
for the AHF of vinyl acetate (S11), RbBArF gave the best
results: full conversion, complete regioselectivity (> 99:1 in
favour of the branched product) and perfect enantioselectivity
(99% ee) were observed (see entry 4 in Error! Reference
source not found.). It should be noted that the addition of
RbBArF to the reaction mixture had the highest positive
regulation effect on the enantioselectivity of the AHF of S11
(enhancement of 64% in the ee). Interestingly, the use of
KBArF or CsBArF rather than RbBArF also provided very high
ees (98 and 96% ee, respectively; see entries 3 and 5 in Error!
Reference source not found.). In contrast, when
enantiomerically pure ammonium salts RA1 and RA2 were
used, the activity of catalysts derived from L6 worsened. As
summarised in Error! Reference source not found., 1 mol% of
catalyst (a substrate-to-catalyst [S/C] ratio of 100:1) was used
for all the assays. Interestingly, the amount of catalyst derived
from RbBArF·L6 could be reduced to 0.1 mol% (S/C = 1000)
with almost no decrease in the catalytic activity (99% conv., b/l
28
ratio > 99:1, and 97% ee in favour of (S)-P11). Furthermore,
the addition of RbBArF enhanced the catalytic activity of the
catalyst as evidenced by a ca. four-fold increase in the reaction

rate (TOF value with a S/C ratio = 1000 at 50% conversion (i.e.
TOF½) in

Table 7. Catalytic results obtained for AHFs by Vidal-Ferran et al.

Entry

Substrate

RA

b/l ratio

ee
(%, config.)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

S11
S11
S11
S11
S11
S11
S11
S12
S12
S13
S13
S14
S14
S15
S15

NaBArF
KBArF
RbBArF
CsBArF
RA1
RA2
RbBArF
RbBArF
RbBArF
RbBArF

90:10
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96:4
>99:1
98:2
>99:1
95:5
80:20
59:41
18:82

35 (S)
74 (S)
98 (S)
99 (S)
96 (S)
40 (S)
40 (S)
36 (S)
99 (S)
14 (S)
96 (S)
12 (S)
5 (S)
7 (S)
25 (S)

Regulation
effects in
ee (%)a
+39
+63
+64
+61
+5
+5
+63
+82
-7
+18

a

Calculated for each substrate with respect to the experiment in absence of an
RA.

the absence of RbBArF = 40 h ; TOF½ = 177 h in the presence
of the RA). With regard to the AHF of a wider array of terminal
alkenes, the addition of RbBArF significantly enhanced the ees
(up to 82%) of the AHFs of substrates S12, S13 and S15 (entries
9, 11 and 15 in Error! Reference source not found.) and it also
turned out to be the ideal RA for these substrates.
Unfortunately, the use of RAs led to lower regio- and enantioselectivities for styrene (S14; compare entries 12 and 13 in
Error! Reference source not found.).
Computational studies on the geometry of hydrido-dicarbonyl
Rh(I) complexes derived from L6 were carried out to gain
insight into the structural changes induced by the RA in the
catalytic site. These computational studies revealed that the
RA had an important effect on the PRhP bond angle of the
29
rhodium complexes (see Fig. 7). The trend observed was that
the size of the ionic radius in the RA cation correlated with the
width of the PRhP angle (from 113°, when no RA is present,
+
+
+
to ca. 122° for K , Rb and Cs ). Most interestingly, a plot of the
ee in the AHF of vinyl acetate as a function of the PRhP
bond angle revealed a maximum in the ee value around the
PRhP bond induced by RbBArF, which indicates that the
1

1

significant increase in the enantiomeric excess resulted from
adaptation of the PRhP angle (see Fig. 7). Rhodium
complexes derived from L6 failed to provide good selectivities
in the AHF of heterocyclic alkenes, even in the presence of
30a
RAs.
Ligand L7 incorporating a (Ra)-BINOL motif at the
regulation site and 3,3'-di-tbutyl-[1,1'-biphenyl]-2,2'-diolderived phosphite groups was developed (Fig. 8).Error!
b
Bookmark not defined.

Fig. 7. Rhodium-derived supramolecular complexes and representation of the ee values
versus calculated PRhP bond angle value.

Higher enantioselectivities were observed in the AHF of
heterocyclic olefins S16, S17 and S18 with L7 than those
a
obtained using L6.Error! Bookmark not defined. Interestingly,
regio- and enantio-selectivities were greatly enhanced by
choosing KBArF as the regulation agent. For instance, the AHF
of S16 showed full regioselectivity towards product P21 and
the use of KBArF as RA improved the conversion (not shown in
b
Table 8Error! Bookmark not defined. ) and the
enantioselectivity (compare entries 1 and 2 in Table 8). The
high catalytic activity of the rhodium complexes derived from
L7 and KBArF is reflected in the fact that the AHF of S16 could
be performed at room temperature without detrimental
effects on the conversion (conv. > 99%) and with excellent ees
(93% ee), which, to the best of our knowledge, is the highest
b
reported for this substrate.Error! Bookmark not defined.
Optimised AHF conditions leading to the highest possible
enantioselectivities for products P22 and P23 were identified
for dihydrofurans S17 and S18 employing KBArF as the RA (see
entries 4 and 6 in Table 8). It is interesting to note that aldehyde derivative P22 was obtained with higher
enantioselectivity than that for its parent -aldehyde

derivative P23 under all studied reaction conditions. The use of
KBArF as regulation agent, together with further adjustments
of the reaction conditions (5 bar of a 1.5:3.5 CO/H 2 gas
mixture), allowed the outcome of the reaction to be
exquisitely regulated by completely suppressing the formation
of the isomerization product of S18 (i.e. S17) and reversing the
regioselectivity of the hydroformylation reaction (see entry 8
in Table 8). In short, Vidal-Ferran et al. showed that the
inclusion of an enantiopure BINOL motif at the remote site
reinforces the regulation ability of the supramolecular
catalysts and led to efficient AHF catalysts for a number of
heterocyclic olefins.

Ratio
P22/P23

P22+P23
ee
(%)
(%, config.)

Entry

Substrate

RA

1b
2b
3c

S16
S16
S17

KBArF
-

1:1.77

86

4c

S17

KBArF

3.65:1

65

5d

S18

-

1:7.33

77

6d

S18

KBArF

1:1.31

60

7e

S18

-

0:1

83

8e

S18

KBArF

2.45:1

100

10 (-)
83 (+)
13 (S) P22
14 (S) P23
84 (R) P22
rac P23
rac P22
33 (R) P23
84 (R) P22
62 (S) P23
29 (R) P23
74 (R) P22
24 (S) P23

REs
in ee
(%)a
+93
+97
-14
+84
+95
+74
+53

a

Regulation effects (REs) calculated for each substrate with respect to the
experiment in absence of an RA. b As indicated in the reaction scheme. c With 5
bar of 3.5:1.5 CO/H2. d With 5 bar of 4:1 CO/H2. e With 5 bar of 1.5:3.5 CO/H2.

Fig. 8. Supramolecularly regulated ligand for the AHFs of heterocyclic alkenes reported
by Vidal-Ferran et al.

Table 8. Catalytic results obtained for AHFs by Vidal-Ferran et al.

Encouraged by the good levels of regulation and overall
performance achieved using polyether-based ligands in AHFs,
the same research group shifted their attention to developing
27
supramolecular ligands for asymmetric hydrogenations. After
a ligand screening process, Vidal-Ferran et al. identified the
rhodium(I) complexes derived from L8 (Fig. 9) without using a
RA (for substrates S3 and S5; see entries 1 and 3 in Table 9) or
in combination with ammonium derivative RA1 (for substrates
S4, S9 and S19; see entries 2, 4 and 5 in Table 9) or with
CsBArF (for substrate S20; see entry 6 in Table 9) as efficient
AH catalysts. As indicated in Table 9, regulation effects in AH
were minor (enhancements of up to 5% in the ee were
observed), as ligand L8 already provided very high
enantioselectivities. However, the use of RAs served to slightly
improve enantioselectivities by adapting the catalysts derived
from L8 to the geometry of the different substrates.

Fig. 9. Supramolecularly regulated ligand for AHs reported by Vidal-Ferran et al.

Table 9. Catalytic results obtained for AHs by Vidal-Ferran et al.

Table 10. Catalytic results obtained for asymmetric Henry reactions by Fan and He
et al.

Entry

Entry

Substrate

RA

ee
(%, config.)

1
2
3
4
5
6

S3
S4
S5
S9
S19
S20

RA1
RA1
RA1
CsBArF

97 (R)b
96 (S)
92 (S)b
93 (S)
95 (S)
78 (R)

Substrate

RA
(mol%)

ee (%)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-OMe
S21, R = 2-Br
S21, R = 2-Br
S21, R = 2-F
S21, R = 2-F
S21, R = 2-Cl
S21, R = 2-Cl
S21, R = 3-OMe
S21, R = 3-OMe
S21, R = 3-Cl
S21, R = 3-Cl
S21, R = 4-F
S21, R = 4-F
S21, R = 4-Cl
S21, R = 4-Cl

LiBArF (2)
NaBArF (2)
KBArF (2)
CsBArF (2)
KBArF (1)
KBArF (4)
KBArF (4)
KBArF (4)
KBArF (4)
KBArF (4)
KBArF (4)
KBArF (4)
KBArF (4)

87
89
89
91
89
90
93
77
86
81
90
80
96
53
84
66
84
77
85
74
83

Regulation
effects in
ee (%)a
+2
+3
+2
+5

a

Calculated for each substrate with respect to the experiment in absence of an
RA. b The highest ees were obtained in the absence of an RA.

As a continuation of their efforts in developing
supramolecularly regulated enantioselective catalysts, Fan and
He et al. described the first example of a regulated catalyst for
31
asymmetric Henry reactions. The designed catalyst was
derived from enantiopure ligand L9 and contained two
chromium(III)-salen moieties (salen = 2,2'-((1E,1'E)-(ethane1,2-diylbis(azanylylidene))bis(methanylylidene))diphenol; see
the red fragment in Fig. 10) separated by a polyether chain.
Fan and He et al. envisaged that supramolecular interactions
between the polyether chain of the ,bis(metallosalen)
derivative and a regulation agent (RA) would bring the two
chromium(III)-salen units together and convert the resulting
supramolecular

Fig. 10. Supramolecularly regulated ligand for asymmetric Henry reactions reported by
Fan and He et al.

Regulation
effects in
ee (%)a
+2
+2
+4
+2
+3
+6
+9
+9
+16
+31
+18
+8
+9

a

Calculated for each substrate with respect to the experiment in absence of an
RA.

complex into a suitable catalyst for transformations involving a
bimetallic cooperative catalysis mechanism, such as
asymmetric Henry reactions. Initially, the authors studied the
binding of KBArF, as a representative RA, to the polyether
chain of L9 and measured an association constant K = 79  12
-1
M in CDCl3 for a 1:1 binding process. The authors then
assessed the new catalyst in a benchmark asymmetric Henry
reaction using 2-methoxybenzaldehyde as a model substrate
and a set of alkali metal BArF salts as RAs. As reflected in Table
10, the size of the cation affected the catalytic activity with the
best results in terms of activity and enantioselectivity being
obtained with KBArF as the RA (compare entries 2-5 in Table
10). Moreover, by increasing the amount of KBArF to two
equivalents with respect to the amount of the ,bis(metallosalen) derivative, almost complete conversion and
an enhancement of up to 6% in the ee were observed
(compare entries 4, 6 and 7 in Table 10). With the optimised
reaction conditions in hand, Fan and He et al. expanded the
substrate scope of the reaction to an array of differently
substituted aromatic aldehydes. This study revealed that the
highest regulation effects in terms of both conversion and
enantioselectivity were observed for the meta-substituted
benzaldehydes (see entries 14-17 in Table 10; positive
regulation effects of up to 31% in the ee).

More recently, Vidal-Ferran et al. have used supramolecularly Table 11. Catalytic results obtained for AASs by Vidal-Ferran et al.
32
regulated catalysts in asymmetric allylic substitutions (AASs).
These authors envisaged that the combination of metal salts,
which could function both for the generation of the required
nucleophiles and for triggering the regulation mechanism, with
palladium complexes derived from the previously developed
ligands could mediate AASs. Initial catalytic studies aimed to
identify the optimal palladium precursor and ligand for this
28
chemistry on model substrate S22 (Fig. 11 and Table 11). Of
all the combinations tested, RbOAc•(ent-L8) and [PdCl2(cod)]
gave the best results in the AAS of substrate S22 with dimethyl
malonate (DMM); that is full conversion and 65% ee (increase
of 6% ee with respect to when no RA was used; compare
REs in
b/l
ee (%,
entries 1-10 in Table 11). The AAS of cinnamyl acetate S23 with Entry Subst.
RA
Ligand
Nu
ee
ratio config.)
DMM could also be supramolecularly regulated by employing
(%)a
3
ligand L10 and [Pd(-Cl)( -C3H5)]2 to achieve the highest
1b
S22
ent-L8 DMM
59 (R)
2b
S22
LiOAc
ent-L8 DMM
46 (R)
-13
enantioselectivity or the same catalytic system in the presence
3b
S22
NaOAc
ent-L8 DMM
62 (R)
+3
of Mg(OTf)2 to slightly improve the b/l ratio in favour of the
4b
S22
KOAc
ent-L8 DMM
63 (R)
+4
branched compound P28 (compare entries 11 and 12 in Table
5b
S22
RbOAc
ent-L8 DMM
65 (R)
+6
11). The outcome of the allylic amination of substrate S22 was
6b
S22
CsOAc
ent-L8 DMM
56 (R)
-3
also supramolecularly regulated using a similar approach. A
7b
S22
Mg(OTf)2
ent-L8 DMM
56 (R)
-3
low ee was obtained for benzylamine (BZA) as the nucleophile
8b
S22
Ba(OTf)2
ent-L8 DMM
4 (R)
-55
when no RAs were used (see entry 13 in Table 11). In contrast 9b
S22
La(OTf)3
ent-L8 DMM
3 (R)
-56
32
with the results observed with the Cnucleophile,
an 10b S22
Ho(OTf)3
ent-L8 DMM
rac
-59
improvement in the ee was observed by using group II or 11c S23
L10
DMM 12:88
60 (R)
lanthanide triflates as RAs (see entry 14 in Table 11).
12c
S23
Mg(OTf)2
L10
DMM 15:85
50 (R)
-10
In short, it has been described in this section how 13c S22
ent-L8
BZA
30 (S)
c
S22
Mg(OTf)2d ent-L8
BZA
46 (S)
+16
combinations of RAs and polyether based-ligands have been 14
used to supramolecularly regulate the outcome of AHs, AHFs, a Regulation effects (REs) calculated for each substrate with respect to the
asymmetric Henry reactions and AASs. The achievements experiment in absence of an RA. b [PdCl2(cod)] as precursor. c [Pd(-Cl)(3-C3H5)]2
summarised in this section demonstrate that this strategy can as precursor. d Ba(OTf)2, La(OTf)3 and Ho(OTf)3 had the same regulation effects.
be used to easily prepare libraries of enantiopure
supramolecular ligands (or catalytic systems). Furthermore,
appropriate combinations of ligands plus the corresponding
2.1.3. Catalytic systems containing complementary
regulation agents provided enantioselective catalysts that hydrogen-bonding motifs. Clarke and co-workers designed a
adapted to the specific geometry of the substrate of interest in supramolecularly regulated enantioselective catalyst formed
a given transformation.
by complementary hydrogen bonding between a first unit,
containing a substituted pyrrolidine ring responsible for
enantioselective catalysis (see L11 and L12 in Fig. 12), and a
second unit bearing an achiral additive to influence the steric
environment at the catalytic site (see the 1-(1H-imidazol-2yl)urea-containing structures RA3 and RA4 in Fig. 12).
Furthermore, this example is highly interesting because it
illustrates that supramolecular regulation strategies are not
limited to transition-metal catalysed reactions and can also be
used for organocatalysed processes such as the asymmetric
33
Michael addition of ketones to nitroalkenes. Clarke et al.
Fig. 11. Supramolecularly regulated ligand for AASs reported by Vidal-Ferran et al.
envisaged that enantiopure amidonaphtyridine motifs (present
in structures L11 and L12) and 3-substituted 1-(1H-imidazol-2yl)urea structures (present in RA3 and RA4) would be highly
complementary recognition motifs through hydrogen-bonding
interactions. Thus, they were chosen as the complementary
units for achieving precise self-assembly by hydrogen bonding
33
towards the target supramolecular catalysts (Fig. 12). Clarke
et al. observed that supramolecular assemblies arising from
the combination of ligands L11 or L12 and regulation agents
RA3 and RA4 were more efficient in mediating asymmetric
Michael reactions than catalysts L11 or L12 alone (compare

entries 1 with 2 and 5 with 6 in Table 12). For asymmetric
Michael additions of cyclohexanone S24 to nitroalkene S26, an
important enhancement in the diastereoselectivity (from a
26:1 to a 65:1 ratio in favour of the syn diastereoisomer) and
enantioselectivity (from 6 to 68% ee, compare entries 1 and 2
in Table 12) of the reaction was observed when the hydrogenbonding complementary regulation agent RA3 was used.

Entry
1
2
3
4
5
6

Substrates

Catalyst

S24, S26
(R)-L11, S24, S26 (R)-L11, RA3
S24, S27 (R)-L11, RA4
S24, S28 (R)-L11, RA4
S25, S26
(S)-L12, S25, S26 (S)-L12, RA3

Conv.
(%)
87
99
47
41
<5
95

dra
26:1
65:1
36:1
7:1
n.d.
12:1

eeb
(%, config.)
6 (R,S)
68 (R,S)
74 (R,S)
81 (R,S)
n.d.
rac

REs in
ee (%)c
+62
n.d.

a

syn:anti ratio. b ee of the syn product. The first stereochemical descriptor refers
to the carbon alpha to the C=O group and the second to the aryl-substituted one.
c
Regulation effects (REs) calculated for each substrate with respect to the
experiment in absence of an RA.

2.2. Supramolecular regulation on a pro-chiral ligand

Fig. 12. Supramolecularly regulated catalysts for asymmetric Michael additions
reported by Clarke et al.

Interestingly, a slightly modified regulation agent (the 4substituted 1-(1H-imidazol-2-yl)urea RA4) achieved the highest
diastereo- and enantio-selectivities in the asymmetric Michael
additions of cyclohexanone S24 to (E)-(2-nitrovinyl)benzenes
with substituents at the phenyl ring (S27 and S28; see entries 3
and 4 in Table 12). Asymmetric Michael additions of acyclic
aliphatic aldehyde S25 to nitroalkene S26 required the
combination of the regulation agent RA3 and a new aminocontaining unit ((S)-L12) as opposed to the original prolinecontaining one ((R)-L11) (see structures in Fig. 12). Acceptable
diastereoselectivities were obtained using the catalyst derived
from the aforementioned self-complementary units for
hydrogen bonding. Unfortunately, the final product obtained
was a racemic mixture (see entries 5 and 6 in Table 12).
Table 12. Catalytic results obtained for asymmetric Michael additions by Clarke et
al.

The principle of this approach is similar to that detailed in the
previous section: a regulation agent is employed to modify the
geometry of the catalytic site. However, the three-dimensional
structure of the catalytic site is not well defined in the absence
of the regulation agent and, upon addition of an enantiopure
regulation agent, chirogenesis processes mediated by the RA
lead to an asymmetric supramolecular assembly with a welldefined three-dimensional structure. Reek et al. have
published the only examples of this elegant approach for
generating libraries of enantioselective supramolecular
34,35
catalysts.
These authors have shown that the interaction of
an enantiopure regulation agent (called a “cofactor” by the
authors) with an achiral bisphosphine or bisphosphite metal
complex equipped with a binding site to recognise the RA,
efficiently led to the formation of an asymmetric
supramolecular assembly that was used as pre-catalyst in
34
35
AHs
or AASs.
With regard to the first asymmetric
transformation, initial studies aimed to identify a suitable
strategy that would facilitate the straightforward preparation
of libraries of enantioselective catalysts from ligand L13 (see
Fig. 13). This ligand contained a diamidodiindolylmethane
motif (as the binding site for the regulation agent) and
phosphine binding groups for the generation of rhodium
catalysts for AH. Reek et al. demonstrated that cationic ligand+
rhodium complexes [Rh(nbd)(L13)] were straightforwardly
formed by mixing stoichiometric amounts of ligand L13 and
the standard cationic rhodium precursor for AHs (i.e.
34
[Rh(nbd)2]BF4). Interestingly, the X-ray structure of the
resulting complexes [Rh(nbd)(L13)]BF4 showed that in the solid
state the BF4 anion was bound to the ligand’s
diamidodiindolylmethane motif, which acted as an efficient
receptor for this anion. Binding studies in solution
demonstrated that the BF4 anion was easily displaced by
regulation agents (or cofactors) with carboxylate groups, as
these proved to have a much higher affinity for the
diamidodiindolylmethane motif than the BF4 anion. The
authors exploited the high affinity of carboxylate anions
towards the diamidodiindolylmethane motif in ligand L13 (K >
5
1
10 M in dichloromethane) and the wide availability of
enantiomerically pure compounds containing a carboxylate
group to easily generate libraries of supramolecular
34
enantioselective catalysts using this strategy. Detailed NMR
studies confirmed chirogenesis in the supramolecular binding
event (i.e. chirality transfer from the regulation agent to the

carbon backbone of the rhodium complex through
supramolecular interactions). Subsequent studies aimed to
identify the optimal regulation agent that mediated the
highest enantioselectivity in the AH of functionalised alkenes.
34
The authors studied
a wide variety of enantiopure
carboxylate-containing derivatives in the AH of acylaminoacrylate S4 (see entry 1 in Table 13), with amino acid
derivatives as RAs providing the best results in terms of ees.
Reek et al. identified the substituents at the nitrogen group of
the amino acid derivative as the structural motif of the
regulation agent that had the greatest effect on the ees of the
AH, whereas varying the side chain of the amino acid
34
derivative had a smaller influence. The valine-derived RA
RA5, which incorporates a tbutylthiourea group at the
nitrogen group, was identified after an iterative deconvolution
catalyst screening strategy as the optimal RA for providing the
highest ees in the AH of -acylaminoacrylate S4 (full
conversion, 98% ee; entry 1 in Table 13). In an analogous
manner, the same regulation agent mediated the AH of acylaminoacrylate S29, arylenamide S9, itaconic acid derivative
S3 and 2-methylenepentanedioic acid derivative S32 (ees
ranging from 39 to 91% ee; see entries 2, 3, 6, and 7 in Table
13, respectively) with the highest ees. In contrast, valine
derivative RA6, which incorporates a tbutylcarbamoyl group at
the nitrogen group, was the RA of choice for the AH of
dihydronaphthalenyl acetamides S30 and S31 (see entries 4
and 5 in Table 13).

NMR spectra was attributed to a preferred stabilisation of one
of the two possible configurations of the carbon between the
two indole rings and one of those possible for the phosphite
35
3
groups. Catalysts derived from ligand L14 and [Pd(-Cl)( C3H5)]2 were applied to AASs on substrates S33 and S34 (see
the Scheme to Error! Reference source not found.). The
authors observed the formation of enantioenriched products
when enantiopure RAs were used. The substrates S33 and S34
were chosen as model substrates for the catalytic studies given
the different ligand requirements for achieving high ees in the
AASs on these two substrates: substrate S33 requires ligands
with pseudo-C2 symmetry, whilst ligands with pseudo-Cs
symmetry mediate AASs on S34 with higher ees. A library of
35
enantiopure acid derivatives was tested, from which RA7 and
RA8 provided the highest enantioselectivities. When
dimethylmalonate (DMM) was used, higher conversions and
ees were obtained by employing RA7 for the AASs on S33 (57%
ee, compare entries 1 and 2 in Error! Reference source not
found.). In contrast, higher regulation effects in the AASs on
S34 were obtained using RA8 (compare entries 3 and 4 in
Error! Reference source not found.). The highest ee was
obtained for S33 when benzylamine (BZA) was used as the
nucleophile and

Table 13. Catalytic results obtained for AHs by Reek et al.

Fig. 13. Supramolecularly regulated ligand and RAs by AH from Reek et al.

Following the same regulation strategy, Reek, Moberg et al.
described the application of the new bisphosphite ligand L14
to palladium-mediated AASs; see Error! Reference source not
35
found. and Error! Reference source not found.. The addition
of an enantiopure acid derivative as the RA (or “cofactor” as
referred to by the authors) broke the symmetry of the
diamidodiindolylmethane fragment in ligand L14 and
generated preferred conformations in the conformationally
labile phosphite groups. NMR spectroscopy studies showed
that hydrogen bonding between the NH groups in ligand L14
and the oxyanions was at the origin of the chirogenesis
processes taking place. A mixture of ligand L14 and an excess
of the enantiopure RAs (RA7 and RA8; see Error! Reference
source not found.) led to a splitting of the phosphorus and NH
31 1
1
signals in the P{ H} and H NMR spectra, respectively. The
presence of a major group of signals in the above mentioned

Entry

RA

Yield (%)

1
2
3
4
5
6
7
a

Substrate
S4
S29
S9
S30
S31
S3
S32

RA5
RA5
RA5
RA6
RA6
RA5
RA5

93
92
84
95
89
58
69

ee
(%, config.)
98 (R)
91a
82a
79a
43a
39a
50a

Configuration not provided.

RA7 (66% ee, entry 5 in Error! Reference source not found.),
but the AASs product derived from S34 and BZA was obtained
with low levels of enantioselectivity when either RA7 or RA8

was employed (see entries 7 and 8 in Error! Reference source
not found.).
34
35
In short, Reek’s and Reek’s & Moberg’s elegant approaches
for regulating the catalyst activity and stereoselectivity
demonstrate that efficient AH or AAS catalysts can be easily
obtained by the optimal choice of an enantiomerically pure RA
and achiral ligands L13 or L14, respectively.

Fig. 14. Supramolecularly regulated ligand and RAs for AASs reported by Reek and
Moberg et al.

Table 14. Catalytic results obtained for AASs by Reek and Moberg et al.

Entry

Substrate

RA

Nu

Yield (%)

1
2
3
4
5
6
7
8

S33
S33
S34
S34
S33
S33
S34
S34

RA7
RA8
RA7
RA8
RA7
RA8
RA7
RA8

DMM
DMM
DMM
DMM
BZA
BZA
BZA
BZA

97
89
94
73
85
87
85
89

ee
(%, config.)
57 (S)
39 (R)
5 (S)
43 (R)
66 (R)
57 (S)
4 (R)
12 (S)

3. Conclusions and outlook
This feature article highlights different supramolecular
strategies for generating a set of enantioselective catalysts
that retain most of the backbone’s structural features yet at
the same time incorporate subtle changes at their active sites
that are determined by the structural characteristics of the
external molecule (or regulation agent) that is employed. Two
different categories of supramolecularly fine-regulated
enantioselective catalytic systems have been developed.
The first type of catalytic system possesses a catalytic site with
a well-defined three-dimensional structure suitable for
enantioselective catalysis and a distal regulation site
containing a supramolecular motif capable of interacting with
the regulation agent. The interaction between cyclic (aza)crown-ether,
metallacrown-ether
and
polyether
supramolecular motifs with metal salts or ammonium
derivatives as RAs has been exploited by a number of research
groups for generating libraries of enantioselective catalysts,
which are capable of geometric adaptation to the
requirements of a given substrate for high enantioselectivity in
asymmetric hydrogenations, hydroformylations, Henry
reactions and allylic substitutions on an array of structurally
diverse substrates. This regulation concept at the active site of
the enantioselective catalyst has not been restricted to
transition metal-based transformations, such as those
previously mentioned. Researchers have also developed
supramolecularly regulated enantioselective organocatalysts
for asymmetric Michael addition reactions. In this case, the
regulation agent is attached to the unit that contains the
catalytic site by a highly efficient and precise hydrogenbonding-mediated assembly process.
The second type of supramolecularly fine-regulated catalytic
system is directly generated from a pro-chiral unit containing
the catalytic site. The three-dimensional structure of the
catalytic site is not well-defined in the absence of a regulation
agent, and in this elegant approach, the addition of an
enantiopure regulation agent triggers chirogenesis processes
from the regulation agent to the carbon backbone containing
the catalytic site. In this case, the authors demonstrated that
efficient asymmetric hydrogenation and allylic substitution
catalysts could be obtained with unprecedented ease just by
the optimal choice of an enantiopure regulation agent (or
“cofactor” as referred to by the authors).
The approaches reported in the present article for the fineregulation of the activity of an enantioselective catalyst
combine concepts from supramolecular and physical organic
chemistry with traditional approaches from enantioselective
catalysis. The potential for research and innovation is almost
unlimited, with ample scope for the development of practical
applications. Thus, one can only imagine that the near future
will witness new examples of successful application of fineregulation strategies to new enantioselective catalysts for
transformations of interest.

Acknowledgements

The authors would like to thank MINECO (CTQ2014-60256-P
and Severo Ochoa Excellence Accreditation 2014-2018 SEV2013-0319) and the ICIQ Foundation for financial support. Dr.
M. V. is grateful for the financial support received from the
CELLEX Foundation. L. R. thanks ICIQ for a pre-doctoral
fellowship. Dr. Héctor Fernández-Pérez is gratefully
acknowledged for proof-reading the manuscript and Dr. José
Luis Núñez-Rico for his support in the preparation of a few
graphics.

Notes and references
10
1

2
3
4
5

6

7

8

9

For general references on this topic, see for example: (a)
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In biocatalysis these two roles are played by the
biocatalyst (i.e. enzyme).
Chiral pool refers to the stock of readily available
enantiopure natural products.
Privileged Chiral Ligands and Catalysts, ed. Q.-L. Zhou,
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Any catalytic event involves supramolecular interactions,
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11
12

13

14

15
16
17
18

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