Cofactor-Controlled Chirality of Tropoisomeric Ligand

Article abstract of DOI:10.1021/acs.organomet.6b00265

A new tropos ligand with an integrated anion receptor site has been prepared. Chiral carboxylate and phosphate anions that bind in the anion receptor unit proved capable of stabilizing chiral conformations of the achiral flexible bidentate biaryl phosphite ligand, as shown by variable temperature ¹H and ³¹P NMR spectroscopical studies of palladium(0) olefin complexes. Palladium allyl complexes of the supramolecular ligand-chiral cofactor assemblies catalyzed asymmetric allylic substitutions of rac-(E)-1,3-diphenyl-2-propenyl carbonate and rac-3-cyclohexenyl carbonate with malonate and benzylamine as nucleophiles to provide nonracemic products. Although moderate enantioselectivities were observed, (ee:s up to 66%), the results confirm the ability of the anionic guests to affect the conformation of the ligand.

Full text of DOI:10.1021/acs.organomet.6b00265

Article
pubs.acs.org/Organometallics
Cofactor-Controlled Chirality of Tropoisomeric Ligand
Laure Theveau,† Rosalba Bellini,† Paweł Dydio,‡ Zoltan Szabo,† Angela van der Werf,†,‡
́
Robin Afshin Sander,† Joost N. H. Reek,*,‡ and Christina Moberg*,†
†Department of Chemistry, Organic Chemistry, KTH Royal Institute of Technology, SE 10044 Stockholm, Sweden
‡van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: A new tropos ligand with an integrated anion
receptor site has been prepared. Chiral carboxylate and
phosphate anions that bind in the anion receptor unit proved
capable of stabilizing chiral conformations of the achiral
flexible bidentate biaryl phosphite ligand, as shown by variable
temperature 1H and 31P NMR spectroscopical studies of
palladium(0) olefin complexes. Palladium allyl complexes of
the supramolecular ligand-chiral cofactor assemblies catalyzed
asymmetric allylic substitutions of rac-(E)-1,3-diphenyl-2-
propenyl carbonate and rac-3-cyclohexenyl carbonate with malonate and benzylamine as nucleophiles to provide nonracemic
products. Although moderate enantioselectivities were observed, (ee:s up to 66%), the results confirm the ability of the anionic
guests to affect the conformation of the ligand.
chiral additive would facilitate structural variations and permit
efficient combinatorial catalyst screening.10
Encouraged by our previous observation that a chiral anion
resulted in enantio-differentiation of stereotopic nuclei in
palladium allyl complexes with a configurationally labile
bisazepine ligand, 1,2-bis[4,5-dihydro-3H-dibenzo[c-e]-
azepino]ethane (Figure 1),11 we decided to explore the use
INTRODUCTION
■
Metal complexes with chirally flexible, tropos, ligands are
known to induce high levels of enantioselectivity in a variety of
catalytic reactions.1 Such complexes are convenient to prepare
since no resolution or asymmetric synthesis is required. The
configuration is instead controlled by a chiral motif covalently
attached to the flexible function2 or present in a separate unit
bound to the metal center,3 and may as well be affected by the
substrate undergoing reaction.4 It has also been shown that
chiral ionic liquids are able to favor one enantiomeric
conformation of tropos ligands.5
An alternative way to control ligand conformation, which is
limited to charged complexes, is by means of a chiral
counterion.6 The axial chirality in a tropos biaryl (BIPHEP)
ligand has in this way been controlled by chiral anions capable
of ion pairing, thereby allowing the preparation of enantiomeri-
cally highly enriched gold complexes with either aR or aS
configuration7 and subsequent use of such ion pairs in
enantioselective hydroalkoxylation of allenes.8 In other
examples, one of the axially chiral atropos BINAP enantiomers
in a racemic mixture has been selectively activated by a chiral
borate anion.9
Configurational control in bidentate ligands containing two
tropos elements is more challenging than in ligands containing
a single tropos structural element since such ligands can adopt
up to four different geometries, with (aR,aR), (aR,aS), (aS,aR),
and (aS,aS) configurations. So far, control of the absolute
configuration of bistropos bidentate ligands has been achieved
by connecting the two flexible elements via a chiral back-
bone.2a,b,d The possibility to influence the stereochemistry by
instead relying on noncovalent interactions with an external
Figure 1. Bistropos ligand with chiral anion capable of enantio-
differentiation.
of supramolecular interactions for configurational control of
ligands with two stereochemically flexible units. Palladium-
catalyzed asymmetric allylic alkylation has proven to serve as a
useful probe for monitoring the stereochemistry of chirally
flexible ligands, since “broad” substrates, such as 1,3-
diphenylpropenyl acetate, prefer ligands with pseudo-C2
structure whereas “narrow” substrates like cyclohexenyl acetate
react with higher selectivity in the presence of a catalyst with
pseudo-Cs symmetry.11 This reaction was therefore selected as a
model reaction to study the influence of chiral additives on the
symmetry of self-adaptable ligands.
Received: April 4, 2016
© XXXX American Chemical Society
A
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Control of nucleophilic attack on η3-allyl palladium
Scheme 1. Preparation of Ligand 1
complexes by a chiral counteranion (A, Figure 2) was
Figure 2. (A): Cationic complex with chiral counteranion. (B):
Complex with cationic substituent and chiral counteranion. (C):
Achiral ligand with binding site for chiral anion.
considered inefficient since a neutral complex is formed along
the reaction coordinate, resulting in loss of ion pairing.
Furthermore, use of an anionic nucleophile may result in
replacement of the chiral counterion with the achiral
nucleophile. To circumvent this problem, Ooi and co-workers
used a ligand assembled from an achiral monodentate
phosphine equipped with an ammonium group and chiral
biphenolates or phosphates via electrostatic interactions (B,
Figure 2).12 An alternative approach, with more general
applications, consists of the use of cofactor-controlled ligands
containing a receptor unit13 capable of supramolecular
interaction with a chiral anion (C, Figure 2);14 such ligands
have been developed by some of us and successfully applied in
enantioselective catalysis.15 We anticipated that this strategy
could be efficient for conformational control of bistropos
ligands, which is demonstrated in studies presented here.
ligands containing the same biphenyl phosphite moiety, which
have inversion barriers around 10 kcal mol−1.17,18 An analogous
phosphine ligand has been found to have a considerably higher
barrier, 19.3 kcal mol−1 at 298 K;19 the ability to undergo rapid
configurational change might render flexible phosphites more
useful than their phosphine analogues for catalytic applications.
Catalytic Reactions. The ability of the chiral anions bound
to the DIM pocket to stabilize chiral conformations of the
ligand was first evaluated by analysis of the results of palladium-
catalyzed allylic alkylations. Allylic carbonates were chosen as
substrates for the catalytic experiments. As might be expected,
these substrates are more suitable than the allylic acetate
analogues, which release acetate anions during the catalytic
reaction. These achiral anions can displace the chiral anion
from the binding pocket of the catalyst, leading in consequence
to the formation of the racemic product. A range of chiral
anions were assessed in the reaction of rac-(E)-1,3-diphenyl-2-
propenyl carbonate 4 with sodium dimethyl malonate as the
nucleophile (see Supporting Information). In contrast to
previously studied catalytic reactions with cofactor-controlled
ligands, where the substrate has a direct interaction with the
chiral anion,15 the conformation of 1 relies solely on long
distance interactions between the tropos units and the chiral
cofactor. Among the anions evaluated, (S)-2-hydroxy-3-
methylbutyric carboxylate, obtained from 6 by treatment with
N,N-diisopropylethylamine (DIPEA), appeared as the most
promising chiral cofactor, resulting in a high yield of product
with 36% ee in CH2Cl2 (Table 1, entry 1). Optimization of the
reaction conditions by modification of the order of addition of
reagents, the solvent (entries 1−4), and the palladium to ligand
ratio (entries 4 and 5) led to somewhat improved selectivity
(46% ee, entry 5). Considering that nucleophilic attack might
be faster than the ability of the ligand to adapt its conformation
RESULTS AND DISCUSSION
■
Preparation and Properties of Cofactor Ligand. Ligand
1 was prepared and used for studies of the influence of chiral
anions on the atropisomeric behavior of a bidentate biaryl
phosphite. The ligand consists of a bis(indolylamide)methane
(DIM) unit, which is known to serve as an efficient anion
receptor,13 and which has also previously been used for the
preparation of cofactor-controlled ligands.15 The anion-binding
pocket is equipped with four N−H functions, suitably
positioned to allow all four of them to participate in hydrogen
bonding to oxyanions. The ligand was prepared by a method
analogous to that previously used for the preparation of a rigid
binaphthyl analogue,15c−e by reaction of the known phenolic
derivative 216 with chlorophosphite 317 (Scheme 1).
The time-averaged structure of 1 has a mirror plane (Cs
symmetry), and as a result of the low barrier to inversion of the
biphenyl units, pairwise identical NH signals were observed in
the 1H NMR spectrum and a single phosphorus signal appeared
in the 31P NMR spectrum collected at room temperature. Upon
cooling, the signals broadened but, whereas the central
methylene proton started to split at −79 °C (194 K), the
NH and phosphorus signals did not split even at this low
temperature, suggesting a barrier to inversion ≤10 kcal mol−1
(Figures S1 and S2). This behavior is similar to that of other
B
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Table 1. Asymmetric Allylic Alkylation of 4 Catalyzed by Pd-
1 in the Presence of 6, Optimization of Reaction
Conditions
Table 2. Asymmetric Allylic Alkylation of 4 Catalyzed by Pd-
1 in the Presence of BINOL-Derived Phosphate Cofactors
a
a
entry
[Pd]:1
solvent (ratio)
CH2Cl2
yield (%)
ee (%) (config)
b
1
2
3
4
5
6
7
1:1.5
1:1.5
1:1.5
1:1.5
1:1.1
1:1.1
1:1.1
89
36 (S)
entry
R (config)
H (R), 7a
yield (%)
ee (%) (config)
CH2Cl2/THF (2:1)
85
29 (S)
35 (S)
43 (S)
b
1
2
3
89
87
85
39 (R)
CH2Cl2/THF (1:2)
100
100
100
97
Ph (S), 7b
38 (S)
THF
THF
THF
THF
b
c
p-MeOC6H4 (S), 7c
28 (S)
46 (S)
d
a
57 (S)
Reactions were performed and analyzed as described in Table 1 but
e
the catalyst solution was prepared in CH2Cl2 since the phosphate was
insoluble in THF; solutions of 4 and sodium dimethyl malonate were
prepared separately in THF. The sodium dimethyl malonate solution
was added over 4 h. Full conversion of 4 was observed in all
98
57 (S)
a
Reaction conditions: 4 (0.055 mmol), [Pd(allyl)Cl]2 (5 mol %),
ligand 1 (5.5−7.5 mol %), cofactor 6 (0.9 equiv based on 4), DIPEA
(0.7 equiv), dimethyl malonate (3.6 equiv), NaH (3 equiv), solvent (1
mL), room temperature, 30 min. A solution of 4 and a solution of
sodium dimethyl malonate were prepared separately and added
successively to the catalyst mixture. Full conversion of 4 was observed
in all experiments. Yields and ee were determined by H NMR using
1-methoxynaphtalene as internal standard and by chiral HPLC,
respectively. A solution of the catalyst and 4 was added to the sodium
dimethyl malonate solution. Average of three experiments. The
b
experiments. Average of two or three experiments.
Table 3. Asymmetric Allylic Alkylation of 8 Catalyzed by Pd-
a
1
1 in the Presence of Different Chiral Cofactors
b
c
d
e
sodium dimethyl malonate solution was added over 4 h. The sodium
dimethyl malonate solution was added over 8 h.
to the substrate, slow addition of the nucleophile to the
catalyst/substrate mixture was thought to be beneficial for the
enantioselectivity of the reaction. Thus, different rates of
addition of the nucleophile to the catalyst/substrate mixture
were studied under the otherwise optimum reaction conditions.
Addition of the nucleophile to the catalyst/substrate mixture
over 4 h did indeed lead to improved results and afforded the
product with 57% ee and in excellent yield, whereas further
decrease of the rate had no effect (entries 6−7).
entry
cofactor
yield (%)
ee (%) (config)
b
,c
1
2
3
4
5
6
7
6
94
80
100
73
14
63
76
5 (S)
6 (S)
c
6
b
d
e
7a
7a
7a
7b
7c
15 (R)
43 (R)
35 (R)
20 (S)
d
19 (S)
−
a
Dihydrogen phosphate (H2PO4 ) has been shown to bind
Reactions were performed and analyzed as described in Table 2. Full
conversion of 8 was observed in all experiments. The sodium
dimethyl malonate solution was added in one portion. The catalyst
solution was prepared in THF. Average of two experiments. The
sodium dimethyl malonate solution was added over 8 h.
strongly to the DIM receptor,13b,15a,c and for this reason chiral
phosphates were considered as suitable cofactor candidates.
Several nonsubstituted, 3,3-, and 6,6′-disubstituted chiral
BINOL-derived phosphates20 were studied as chiral cofactors
(Table 2). Noteworthy, 3,3′-substituted chiral phosphates were
shown to be inefficient, presumably as a result of severe steric
hindrance, and slightly inferior enantioselectivities were
observed with this new class of chiral cofactors.
As a result of the different conformational preferences of
different types of substrates, it was assumed that different
cofactors might be preferred for different types of substrates. In
order to study the ability of the flexible ligand to adapt its
conformation to a different kind of substrate, rac-3-cyclo-
hexenyl carbonate 8 was also studied in the asymmetric
alkylation (Table 3). In contrast to carbonate 4, which is
considered as a “broad” substrate, carbonate 8 represents a
“narrow” substrate, and as such requires a different complex
geometry for efficient induction of selectivity. The highest
selectivity in reactions with this substrate was observed with
phosphate 7a (43% ee, entry 4). Notably, the reaction with
carbonate 8 in the presence of the anion of (S)-2-hydroxy-3-
b
c
d
e
methylbutyric acid 6 gave close to racemic product (entries 1
and 2), which is in sharp contrast to the reaction of carbonate
4, which in the presence of the same chiral anion occurred with
the highest selectivity. This demonstrates that the selectivity of
the same complex can be optimized for substantially different
substrates through the choice of an appropriate guest.
Finally benzylamine was used as the nucleophile in reactions
with both types of substrates, employing the reaction
conditions developed before (Scheme 2). The highest
selectivity, 66% ee, was observed in the reaction of rac-(E)-
1,3-diphenyl-2-propenyl carbonate 4, whereas reactions with
the cyclic substrate gave the product with low selectivity.
To evaluate the importance of the noncovalent interactions
between the receptor and the chiral anion, control experiments
were performed in which ligand 1 was replaced by 12, which
lacks the anion binding site. The ligand was prepared as shown
C
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a
Scheme 2. Use of Benzylamine as Nucleophile
Figure 3. Predicted structure of palladium olefin complex of ligand 1
in the presence of the anion of (S)-2-hydroxy-3-methylbutyric acid.
a
Reactions were performed and analyzed as described in Table 1. Full
b
conversion of 4 or 8 was observed in all experiments. The
benzylamine solution was added over 4 h. Average of two
experiments. The catalyst solution was prepared in CH2Cl2 since
c
d
the phosphate was insoluble in THF.
in Scheme 3 and used together with the silver salt of 7a in
reactions of rac-(E)-1,3-diphenyl-2-propenyl carbonate (4)
Scheme 3. Preparation of Ligand Devoid of Anion Binding
Site
1
Figure 4. Part of the H NMR spectra of ligand 1 in the absence and
in the presence of chiral cofactors 6 or 7a and DIPEA in CD2Cl2 (400
MHz) at 21 °C. Minor signals originate from impurities.
1
the H NMR spectrum; the largest separation of signals was
observed for the complex with 7a. In the 31P NMR spectra in
the presence of the chiral anions, the phosphorus nuclei
appeared at chemical shifts different from that of 1. In the
presence of 7a, two signals were observed as a result of the
absence of mirror symmetry, whereas in the presence of 6 only
one signal appeared at room temperature. In low temperature
NMR spectra of the complex with 7a no separation of signals
due to the presence of different isomers was observed (Figures
S5 and S6), but separate signals for free and bound phosphate
cofactor appeared; at room temperature the exchange between
free and bound cofactor was fast (Figure S6).
Palladium Olefin Complexes with Ligand 13. It is usually
assumed that the transition state in palladium-catalyzed
asymmetric allylic substitution has a structure closer to that
of the product olefin complex rather than that of the precursor
allyl complex,21 and analysis of the structure of Pd(0)-olefin
complexes of ligand 1 is therefore considered informative to
study the stereochemistry-determining step.11 Notably, pre-
vious work has demonstrated the tendency of palladium
complexes of bidentate tropos ligand to adapt their
conformation to linear and cyclic olefins with a structure with
C2 and Cs symmetry, respectively.11
with both sodium dimethyl malonate and benzylamine. In
both cases, racemic product was obtained, thus demonstrating
that anion binding to the ligand is crucial for configurational
control of the tropos moieties.
From previous studies it is known that allylic alkylation of
rac-4 in the presence of palladium complexes with rigid
binaphthyl analogues of 1,2-bis[4,5-dihydro-3H-dibenzo[c-e]-
azepino]ethane (Figure 1), containing nitrogen as well as
phosphorus donor atoms, with (S,S) configuration yield (S)-5
as the major product.4 Since a product with the same absolute
configuration was obtained from the complex containing (S)-2-
hydroxy-3-methylbutyric acid, it is assumed that the ligand in
the presence of this cofactor adopts (S,S) configuration in the
product olefin complex (Figure 3).
1H and 31P NMR Studies. Cofactor Complexes with
Ligand 1. In order to gain insight into the effect of chiral anions
on the conformation of ligand 1, its complexes with the most
efficient anions, 6 and 7a, were studied in detail by 31P and 1H
NMR spectroscopy (Figures 4, S3, and S4). Addition of anions
resulted in characteristic downfield shifts for the four NH
protons. The presence of chiral anions causes loss of the mirror
symmetry of the ligand, and as a result separate signals were
observed for diastereotopic NH indolyl and amide protons in
In order to mimic the transition states in reactions with linear
and cyclic allylic substrates, complexes with trans and cis
olefins, respectively, were studied. Initially, palladium com-
plexes of the previously reported ligand 13, which was used for
rhodium-catalyzed hydrogenation15b and hydroformylation,15a
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with acetate as the counterion and fumaronitrile as the olefin in
CD2Cl2 were studied (Figures S7 and S8).
just as with 13, coordinate in two different ways, giving rise to a
total of eight complexes with each olefin. For each olefin, four
of the complexes are interconvertable via flipping of the ligand,
whereas interconversion between the two sets of complexes
(coordinating with different faces of the olefin) requires
decoordination−recoordination of the olefin (Figure S30).
The 31P NMR spectrum of the Pd(0) fumaronitrile complex
of the phosphite ligand 1 containing acetate showed, as did the
spectrum with the corresponding triphenylphosphine ligand 13,
two doublets at δ = 137.8 and 142.2 with J = 41 Hz and four
N−H proton signals in the 1H NMR spectrum (Figures S9 and
S10). The 31P NMR pattern was unchanged upon cooling to
−90 °C but characteristic shifts to lower field were observed
and the signals gradually broadened; upon subsequent heating
to room temperature a spectrum identical to that recorded
before cooling was obtained, demonstrating that the processes
are reversible (Figures S11 and S12). This result is compatible
only with an enantiomeric mixture of complexes with
diastereotopic phosphorus atoms (Figure 7).
Coordination to the enantiotopic faces of the trans olefin is
expected to give rise to two enantiomeric complexes, each with
diastereotopic phosphorus centers (Figure 5). This was verified
Figure 5. (A) Two enantiomeric complexes with achiral ligand and
trans olefin. (B) Two diastereomeric meso complexes with cis olefin.
Cis and trans olefins are shown in red.
Figure 7. Enantiomeric complexes with symmetrically substituted
trans olefin.
by the presence of two doublets at δ = 24.05 and 24.25 ppm in
the 31P NMR spectrum and four signals for the pairwise
diastereotopic NH protons in the 1H NMR spectrum. In
contrast, coordination of the two faces of maleic anhydride
leads to two diastereomeric meso complexes, and the 31P NMR
spectrum accordingly showed two singlets at δ = 26.40 and
26.45 ppm with unequal intensity (3:2), and the H NMR
spectrum showed two sets of two NH protons (Figures S7 and
S8).
Palladium Olefin Complexes with Ligand 1. Ligand 1 can
adopt four different conformations, two achiral meso structures,
RsS and SrR, where r and s refer to pseudoasymmetric
centers,22 and two homochiral structures, with RR and SS
configuration, respectively (Figure 6). Each kind of olefin can,
In contrast, the 31P NMR spectrum of the analogous complex
with dimethyl fumarate showed two broad signals of equal
intensity at room temperature, which separated into two major
and two minor signals upon cooling (Figures S13 and S14). At
−30 to −40 °C the major signals appeared as doublets with J =
19 Hz. The original spectrum was restored upon subsequent
heating to room temperature. This result is compatible with the
presence of two complexes, which equilibrate rapidly at room
temperature (Figure 8).
1
Figure 8. Diastereomeric complexes with symmetrically substituted cis
olefin.
The NMR spectra of the complexes with maleic anhydride
are somewhat more complicated, probably due to ring opening
of the anhydride (Figures S15 and S16). At room temperature,
one major broad signal was observed in the 31P NMR spectrum.
At lower temperatures, this signal was split into several signals.
1
The H NMR spectrum showed two NH signals at room
temperature. Also these signals were split into several signals at
lower temperatures. These results indicate a flexible structure of
the complex at room temperature.
Palladium Olefin Complexes of 1 Binding Chiral Anions.
In order to study whether nonequal amounts of diastereomeric
complexes were formed in the presence of chiral cofactors,
further studies were performed with the anions that induced the
highest enantioselectivites in the catalytic experiments (Tables
1−3). The 31P and 1H NMR spectra of the Pd(0) fumaronitrile
Figure 6. Four conformations of ligand 1-Pd complex. Two have
achiral meso structures (RsS and SrR) and two are chiral (RR and SS).
E
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complex of ligand 1 containing deprotonated (S)-2-hydroxy-3-
methylbutyric acid 6 showed two sets of two doublets and two
sets of four N−H protons, respectively, corresponding to two
diastereoisomeric complexes (Figures 9, S17, and S18). The
Figure 10. 31P{1H} NMR spectra of the [Pd(fumaronitrile)1] complex
in the presence of chiral cofactors and DIPEA in CD2Cl2 (162 MHz).
(a) (S)-2-Hydroxy-3-methylbutyric acid 6; (b) N-boc-N-α-methyl-L-
isoleucine; (c) N-α−actetyl-L-valine; (d) (R)-1,1′-binaphthyl-2,2′-diyl
hydrogen phosphate 7a; (e) (S)-6,6′-bisphenyl-1,1′-binaphthyl-2,2′-
diyl-hydrogen phosphate 7b; (f) (S)-6,6′-bis(4-methoxyphenyl)-1,1′-
binaphthyl-2,2′-diyl-hydrogen phosphate 7c.
Figure 9. 31P{1H} NMR spectra of the [Pd(fumaronitrile)1] complex
in the presence of acetic acid or (S)-2-hydroxy-3-methylbutyric acid 6
and DIPEA in CD2Cl2 (162 MHz).
In order to compare the affinities of the different anions to
the binding pocket, one equivalent of the anion of (S)-2-
hydroxy-3-methylbutyric acid 6 was added to the Pd-
fumaronitrile complex of the ligand 1 containing the non-
substituted BINOL-based phosphate 7a. The NMR spectra
recorded at −50 °C showed complete displacement of the
phosphate from the DIM pocket by the carboxylate (Figures
S26 and S27).
two complexes were present in unequal amounts, according to
1H NMR spectrum in a ratio of approximately 1.5:1, thus
demonstrating the ability of the chiral anion to influence the
conformation of the flexible biaryl units. A NOESY experiment
confirmed the presence of two different complexes, which did
not undergo mutual exchange (Figure S19). No splitting of the
signals, which remained in the same ratio, was observed upon
cooling to −79 °C further supporting the presence of two
stable complexes (Figures S20 and S21). Moreover, broadening
of the isopropyl signals of the cofactor 6 at lower temperature
showed that free cofactor and cofactor bound in the DIM
pocket of the ligand, which are in fast exchange at room
temperature, are in slow exchange at these low temperatures
(Figure S20). These results are in accordance with the assumed
preference for homochiral structures of the ligand (RR and SS)
in the presence of a trans olefin, with one of the configurations
being slightly more stable due to coordination of the chiral
cofactor.
Pd(0) fumaronitrile complexes of ligand 1 with other chiral
cofactors were also studied (Figures 10, S22, and S23). As
observed with the anion of (S)-2-hydroxy-3-methylbutyric acid
6, the presence of chiral carboxylates of N-boc-N-α-methyl-L-
isoleucine and N-α−actetyl-L-valine led to the formation of two
diastereoisomeric complexes in unequal amounts (approx-
imately the same ratio as for (S)-2-hydroxy-3-methylbutyric
acid). Surprisingly, the presence of BINOL-derived phosphates
7a−c led to the formation of single complexes.
The nature of the Pd(0) cofactor complexes formed with a
cis olefin was then investigated. The Pd(0) diethyl maleate
complex of ligand 1 with acetate as the cofactor showed four
N−H signals (2 overlapped)two pairs of NH indole and NH
amide signals in a ratio of 1:1 and a broad signal at 143.21 ppm
1
in the H and 31P NMR spectra, respectively (Figures S28 and
S29). According to the result obtained with the Pd(0) cis olefin
complex of the corresponding phosphine ligand containing
acetate, those signals evidenced the formation of two
diastereoisomeric complexes from a meso conformation (RsS
or SrR) of the ligand coordinating two different faces of the
olefin. The Pd(0) diethyl maleate complex of 1 with (S)-2-
hydroxy-3-methylbutyric carboxylate (6) and BINOL-based
phosphate 7a showed eight N−H signals and two sets of broad
doublets in 1H and 31P NMR, respectively, with unequal
intensities showing the ability of chiral phosphate cofactor to
stabilize one conformation of the ligand.
CONCLUSIONS
■
A new tropos ligand (1) with an integrated anion receptor site
has been prepared with the aim to provide control over the
chirality of a metal complex formed by the binding of a chiral
Low temperature NMR of the Pd(0) fumaronitrile complex
of ligand 1 with the parent BINOL-derived phosphate 7a did
not show any splitting of neither the NH signals, nor the
phosphorus signal of the ligand (broadening of one of the two
P signals was observed) (Figures S24 and S25). However,
separate signals could be observed for the bound and unbound
phosphate cofactor at low temperature (−50 °C) by 31P NMR,
demonstrating that the phosphate cofactor is in fast exchange
with the DIM pocket of the ligand at room temperature.
cofactor in the binding pocket. H and 31P NMR studies of a
1
palladium(0) complex of ligand 1 with coordinated fumaroni-
trile, selected as a model for the E-olefin product obtained in
palladium-catalyzed substitution of (E)-1,3-diphenyl-2-propenyl
carbonate, and with acetate in the anion-binding pocket,
revealed the formation of a racemic mixture of complexes.
Replacement of acetate by (S)-2-hydroxy-3-methylbutyric
carboxylate resulted in the formation of two diastereomeric
F
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Organometallics
Article
another oven-dried Schlenk flask under argon was placed dry and
degassed THF (6 mL) and Et3N (333 μL, 2.39 mmol) and the mixture
was cooled to −78 °C before the dropwise addition of PCl3 (118 μL,
1.37 mmol) and then the 5,5′-dimethoxy-3,3′-di-tert-butylbiphenyl-
2,2′-diol solution prepared before. The reaction mixture was stirred at
the same temperature for 20 min, then allowed to reach room
temperature and stirred for another 45 min. Volatiles were evaporated
using the argon-vacuum dual manifold and, dry and degassed toluene
(3 mL) was added, and then the volatiles were evaporated again.
Compound 3 was finally dissolved in dry and degassed THF (9 mL)
under argon.
complexes with homochiral biaryl phosphite units in a ratio of
1.5:1, presumably with the (S,S)-isomer as the major isomer, as
judged by the absolute configuration of the product formed in
the catalytic reaction. In contrast, replacement of acetate with
(R)-binol phosphate 7a did not give rise to diastereomeric
complexes under the conditions of the NMR experiments. The
analogous maleic anhydride complex used to model the olefin
palladium complex from nucleophilic substitution of 3-cyclo-
hexenyl carbonate with acetate in the anion-binding cavity
appeared as a mixture of two diastereomeric meso compounds.
In the presence of chiral anions, a complex mixture of isomers
was observed.
The ability of the chiral anions to influence the conformation
of the chirally flexible biaryl phosphite units was also
demonstrated by the formation of nonracemic products from
palladium-catalyzed substitutions of allylic carbonates with
sodium dimethyl malonate and benzylamine.
The work described here demonstrates that the geometry of
metal complexes of tropos ligands can be controlled through
tailored noncovalent interactions with chiral guest molecules.
Considering the privileged nature of axially chiral ligands, the
rich chemistry of supramolecular receptors, and the ease of
preparation of wide libraries of chiral catalysts by the
methodology demonstrated here, that is, combinatorial mixing
of a metal precursor, a pool of tropos ligands equipped with a
receptor unit and a variety of potential chiral guests, this
methodology should seed the formation of many selective
catalysts for desired transformations.
Compound 2 (342 mg, 0.597 mmol) was placed in an oven-dried
Schlenk flask and put under argon. Dry and degassed toluene (3 mL)
was added and the volatiles were evaporated using the argon-vacuum
dual manifold. The solid was then dissolved in dry and degassed THF
(6 mL), Et3N (833 μL, 5.97 mmol) was added, and the solution was
cooled to −78 °C. The freshly prepared solution of compound 3 in
THF was then added dropwise, the reaction mixture was stirred at −78
°C for 30 min, and then allowed to progressively reach room
temperature overnight. Volatiles were evaporated using the argon-
vacuum dual manifold then dry and degassed THF (6 mL) and Et3N
(0.6 mL) were added. The solution was rapidly filtered under argon
through a short pad of oven-dried and degassed silica. The silica pad
was then washed with another portion of dry and degassed THF. The
combined organic fractions were concentrated to approximatively 3
mL of solution, using the argon-vacuum dual manifold, then dry and
degassed hexane (6 mL) was added before total evaporation of
volatiles. After drying under vacuum ligand 1·THF·C6H14 was
1
obtained as a pale yellow solid (444 mg, 55% yield). H NMR (400
MHz, CD2Cl2): δ = 9.44 (s, 2H, NH), 8.18 (s, 2H, NH), 7.74 (d, 4H, J
= 8.6 Hz), 7.38 (d, 2H, J = 7.5 Hz), 7.08−7.04 (m, 6H), 7.01 (d, 4H, J
= 3.1 Hz), 6.96 (d, 2H, J = 7.5 Hz), 6.75 (d, 4H, J = 3.1 Hz), 4.48 (t,
1H, J = 7.7 Hz), 3.81 (s, 12H), 2.30 (s, 6H), 2.23−2.16 (m, 2H), 1.43
(s, 36H), 1.00 (t, 3H (overlap with Et3N), J = 7.1 Hz). 13C NMR (100
MHz, CD2Cl2): δ = 165.4 (2 CO), 156.5 (4 COP), 155.6 (4 C), 143.1
(2 C), 141.4 (4 C), 136.3 (2 C), 134.0 (4 C), 132.4 (2 C), 130.3 (2
C), 129.6 (4 C−H), 128.1 (2 C), 122.4 (2 C), 120.5 (2 C−H), 120.4
(2 C−H), 119.3 (2 C−H), 116.2 (2 C−H), 114.9 (4 C−H), 113.9 (2
C−H), 113.4 (4 C−H), 108.3 (2 C), 56.0 (4 O−CH3), 37.2 (C−H),
35.8 (4 C-CH3), 31.2 (12 C-CH3), 27.8 (CH2), 12.6 (CH3), 8.9 (2
CH3). 31P{1H} NMR (162 MHz, CD2Cl2): δ = 138.4. HRMS (ESI-
Orbitrap) m/z: [M]+ calcd for C79H86N4O12P2 1344.5712, found
1344.5747.
EXPERIMENTAL SECTION
■
General Information. All commercially available reagents were
used as received, unless otherwise specified. Chiral carboxylic or
phosphoric acid-derived cofactors were obtained from chemical
suppliers or synthesized according to previously reported procedur-
es.15b,23 rac-(E)-1,3-Diphenylallyl methyl carbonate and rac-cyclohex-
2-en-1-yl methyl carbonate were synthesized according to previously
reported procedures.24 Dry CH2Cl2, THF, toluene, and hexane were
taken from a glass-contour solvent dispensing system. CD2Cl2 was
dried over 3 Å molecular sieves before use. Et3N, DIPEA, and
benzylamine were distilled from potassium hydroxide under nitrogen.
Dimethyl malonate was distilled under reduced pressure. Column
chromatography was performed using silica gel 40−63 μm (230−400
mesh). TLC was performed using TLC silica gel 60 F254 and products
Synthesis of Ligand 12. Ligand 12 was prepared according to a
procedure used for an analogous compound26 by the addition of a
solution of 5,5′-dimethoxy-3,3′-di-tert-butyl-2,2′diol (308.3 mg, 0.86
mmol) in THF (4.3 mL) to a solution of 1,2-(dichlorophosphino)-
ethane (65 μL, 0.43 mmol) and triethylamine (263 μL, 4.4 equiv) in
THF (3 mL) at −78 °C under Ar. The reaction mixture was allowed
to reach room temperature overnight, then THF (10 mL) was added
and the mixture filtered under Ar. The solvent was evaporated to give
revealed by UV irradiation (λ = 254 nm). 1H NMR, 13C NMR, and 31
P
NMR spectra were recorded at room temperature at 400 or 500 MHz,
1
100 MHz, and 162 or 202 MHz, respectively. Low temperature H
NMR and 31P NMR spectra were recorded at 400 and 162 MHz,
respectively. Chemical shifts (δ) are given in ppm relative to the
residual solvent peak. Splitting patterns are indicated as follows: br:
broad; s: singlet; d: doublet; t: triplet; dd: doublet of doublet; m:
multiplet. Yields were determined by 1H NMR using 1-methox-
ynaphtalene as internal standard and enantiomeric excesses were
measured by HPLC using a UV detector and a chiral column, Daicel
Chiralpak IC (0.46 cm × 25 cm) or Daicel Chiralcel OD-H (0.46 cm
× 25 cm), or by GC using a FID detector and a chiral column,
CYCLOSIL B (30 m × 0.25 mm × 0.25 μm).
1
288 mg (0.36 mmol, 84%) of 12. H NMR (400 MHz, C6D6): δ =
7.10 (d, 4H, J = 2.9 Hz), 6.63 (d, 4H, J = 2.9 Hz), 3.33 (s, 12H), 1.42
(s, 36H) 13C NMR (100 MHz, C6D6): δ = 157.0, 145.3, 143.2, 135.7,
115.5, 114.3, 55.8, 36.3, 32.1, 30.3. 31P NMR (162 MHz, C6D6): δ =
202.67 (t, J = 24.3 Hz).
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis of Ligand 1. Compound 2 was synthesized according
to a previously reported procedure.13b The final step affording ligand 1
was performed in analogy to the procedure described for a similar
compound.16 Chlorophosphite 3 was synthesized as follows and
engaged directly in the final step: 5,5′-Dimethoxy-3,3′-di-tert-
butylbiphenyl-2,2′-diol (428 mg, 1.19 mmol), synthesized according
to the procedure of Jana and Tunge,25 was placed in an oven-dried
Schlenk flask and put under argon. Dry and degassed toluene (3 mL)
was added and the volatiles were evaporated using an argon-vacuum
dual manifold before the addition of dry and degassed THF (6 mL). In
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00265.
Procedures for the preparation of phosphate anions and
palladium olefin complexes; procedures for catalytic
reactions; results from screening of chiral cofactors;
1
stereochemical analyses; and H, 13C, and 31P NMR
spectra (PDF)
G
DOI: 10.1021/acs.organomet.6b00265
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(15) (a) Dydio, P.; Dzik, W. I.; Lutz, M.; de Bruin, B.; Reek, J. N. H.
Angew. Chem., Int. Ed. 2011, 50, 396−400. (b) Dydio, P.; Rubay, C.;
Gadzikwa, T.; Lutz, M.; Reek, J. N. H. J. Am. Chem. Soc. 2011, 133,
17176−17179. (c) Dydio, P.; Detz, R. J.; Reek, J. N. H. J. Am. Chem.
Soc. 2013, 135, 10817−10828. (d) Dydio, P.; Reek, J. N. H. Angew.
Chem., Int. Ed. 2013, 52, 3878−3882. (e) Dydio, P.; Detz, R. J.; de
Bruin, B.; Reek, J. N. H. J. Am. Chem. Soc. 2014, 136, 8418−8429.
(f) Dydio, P.; Reek, J. N. H. Chem. Sci. 2014, 5, 2135−2145.
(16) Dydio, P.; Reek, J. N. H. Nat. Protoc. 2014, 9, 1183−1191.
(17) Whiteker, G. T.; Harrison, A. M.; Abatjoglou, A. G. J. Chem. Soc.,
Chem. Commun. 1995, 1805−1806.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: J.N.H.Reek@uva.nl.
*E-mail: kimo@kth.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Wenner-Gren Foundations (L.T.)
and from NRSCC (P.D). are gratefully acknowledged. Dr Anna
Laurell Nash contributed with skillful experimental work.
(18) Pastor, S. D.; Shum, S. P.; Rodebaugh, R. K.; Debellis, A. D.;
Clarke, F. H. Helv. Chim. Acta 1993, 76, 900−914.
(19) Zalubovskis, R.; Fjellander, E.; Szabo,
Chem. 2007, 2007, 108−115.
(20) (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047−9153. (b) Terada, M. Chem. Commun. 2008, 4097−
4112.
́
Z.; Moberg, C. Eur. J. Org.
REFERENCES
■
(1) (a) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M.
Synlett 2002, 1561−1578. (b) Aikawa, K.; Mikami, K. Chem. Commun.
2012, 48, 11050−11069.
(21) Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2108−2110.
(2) (a) Buisman, G. J. H.; van der Veen, L. A.; Klootwijk, A.; de
Lange, W. G. J.; Kamer, P. C. J; van Leeuwen, P. W. N. M.; Vogt, D.
Organometallics 1997, 16, 2929−2939. (b) Reetz, M. T.; Neugebauer,
T. Angew. Chem., Int. Ed. 1999, 38, 179−181. (c) Alexakis, A.; Rosset,
S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001,
2001, 1375−1378. (d) Dieguez, M.; Ruiz, A.; Claver, C. Tetrahedron:
Asymmetry 2001, 12, 2895−2900. (e) Monti, C.; Gennari, C.; Piarulli,
U.; de Vries, J. G.; de Vries, A. H. M.; Lefort, L. Chem. - Eur. J. 2005,
11, 6701−6717.
(22) Nourse, J. G. J. Am. Chem. Soc. 1975, 97, 4594−4601.
(23) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Kockritz,
̈
A.; Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316−1322.
(24) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.;
Yanagi, K. J. Am. Chem. Soc. 1989, 111, 6301−6311. (b) Gais, H.-J.;
Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe, G. Chem. -
Eur. J. 2003, 9, 4202−4221.
(25) Jana, R.; Tunge, J. A. J. Org. Chem. 2011, 76, 8376−8385.
(26) Adams, D. J.; Gudmunsen, D.; Hope, E. G.; Stuart, A. M.; West,
A. J. Fluorine Chem. 2003, 121, 213−217.
(3) (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham,
T.; Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495−497. (b) Mikami,
K.; Aikawa, K.; Korenaga, T. Org. Lett. 2001, 3, 243−245. (c) Mikami,
K.; Aikawa, K.; Yusa, Y.; Hatano, M. Org. Lett. 2002, 4, 91−9.
(4) (a) Stranne, R.; Moberg, C.; Vasse, J.-L. Org. Lett. 2001, 3, 2525−
2528. (b) Vasse, J.-L.; Stranne, R.; Zalubovskis, R.; Gayet, C.; Moberg,
C. J. Org. Chem. 2003, 68, 3258−3270.
(5) Schmitkamp, M.; Chen, D.; Leitner, W.; Klankermayer, J.;
Francio, G. Chem. Commun. 2007, 4012−4014.
(6) (a) Lacour, J.; Moraleda, D. Chem. Commun. 2009, 7073−7089.
(b) Phipps, R. J.; Hamilton, G. L.; Toste, F. T. Nat. Chem. 2012, 4,
603−614. (c) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52,
518−533. (d) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013,
52, 534−561.
(7) Aikawa, K.; Kojima, M.; Mikami, K. Angew. Chem., Int. Ed. 2009,
48, 6073−6077.
(8) Aikawa, K.; Kojima, M.; Mikami, K. Adv. Synth. Catal. 2010, 352,
3131−3135.
(9) (a) Chen, D.; Sundararaju, B.; Krause, R.; Klankermayer, J.;
Dixneuf, P. H.; Leitner, W. ChemCatChem 2010, 2, 55−57.
(b) Raskatov, J. A.; Thompson, A. L.; Cowley, A. R.; Claridge, T. D.
W.; Brown, J. M. Chem. Sci. 2013, 4, 3140−3147.
(10) (a) Breit, B. Angew. Chem., Int. Ed. 2005, 44, 6816−6825.
(b) Bellini, R.; van der Vlugt, J. I.; Reek, J. N. H. Isr. J. Chem. 2012, 52,
613−629. (c) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen,
P. W. N. M. Chem. Soc. Rev. 2014, 43, 1660−1733. (d) Meeuwissen, J.;
Reek, J. N. H. Nat. Chem. 2010, 2, 615−621.
(11) Zalubovskis, R.; Bouet, A.; Fjellander, E.; Constant, S.; Linder,
D.; Lacour, J.; Privalov, T.; Moberg, C.; Fischer, A. J. Am. Chem. Soc.
2008, 130, 1845−1855.
(12) Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T. Nat. Chem. 2012, 4,
473−477. Ohmatsu, K.; Hara, Y.; Ooi, T. Chem. Sci. 2014, 5, 3645−
3650.
(13) (a) Dydio, P.; Lichosyt, D.; Jurczak, J. Chem. Soc. Rev. 2011, 40,
2971−2985. (b) Dydio, P.; Lichosyt, D.; Zielínski, T.; Jurczak, J. Chem.
- Eur. J. 2012, 18, 13686−13701.
(14) The selectivity in palladium-catalyzed allylations mediated by
bidentate atropos phosphite ligands with the coordinating units linked
by polyether chains was recently shown to be affected by coordination
of metal ions to the polyether: Rovira, L.; Fernan
́ ́
dez-Perez, H.; Vidal-
Ferran, A. Organometallics 2016, 35 (4), 528−533.
H
DOI: 10.1021/acs.organomet.6b00265
Organometallics XXXX, XXX, XXX−XXX