5,5'-Diamino-BIPHEP ligands bearing small selector units for non-covalent binding of chiral analytes in solution

Article abstract of DOI:10.1039/c5cc06306j

A dynamic axially chiral BIPHEP-ligand with 3,5-dichlorobenzoyl amide selector units for non-covalent binding of phenylalanine derivatives has been developed. Interaction studies in solution were performed with rhodium(i) complexes under exclusion of the metal being involved in binding. (R_ax, S^Phe) and (S_ax, S^Phe) adducts were observed as significantly separated species in NMR spectroscopy.

Full text of DOI:10.1039/c5cc06306j

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5,50-Diamino-BIPHEP ligands bearing small
selector units for non-covalent binding of chiral
Cite this:DOI: 10.1039/c5cc06306j
analytes in solution†
Received 28th July 2015,
G. Storch, M. Siebert, F. Rominger and O. Trapp*
Accepted 4th September 2015
DOI: 10.1039/c5cc06306j
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A dynamic axially chiral BIPHEP-ligand with 3,5-dichlorobenzoyl racemic ligands in combination with enantiopure diamine or
amide selector units for non-covalent binding of phenylalanine biphenol co-ligands as efficient catalytic systems for asymmetric
derivatives has been developed. Interaction studies in solution were activation.11,12 Faller et al. used a similar approach with racemic
performed with rhodium(I) complexes under exclusion of the metal rhodium complexes and chiral phosphorous ligand additives.13,14
being involved in binding. (Rax, SPhe) and (Sax, SPhe) adducts were
Since free coordination sites are blocked by the aligning ligands,
they often have to be cleaved off prior to catalysis.15 Brown et al. and
Mikami et al. reported a strategy to overcome this limitation by using
elaborated enantiopure chiral COD-analogues that are cleaved
off under catalysis conditions for alignment of dynamic chiral
ligands.16,17 Another approach focused on the use of chiral ionic
liquids with free amino functionalities for metal coordination.18,19
However, the common ground of all these findings is that a chiral
analyte is introduced via metal coordination. Not only does this render
the metal centre a prerequisite for the concept to work; it also often
limits further catalytic applications at the metal centre. Furthermore,
all mentioned examples share the requirement of the analyte to bind
to the specific metal, e.g. via free amines or phosphines, which
intrinsically excludes analytes without these groups. Our investigations
were focused on changing this principle and introducing selector
groups for non-covalent analyte binding. We consider this new
concept as highly promising, because no metal vacancy is blocked
by coordination and thus can be utilised for further purposes (Fig. 1).
We focused on the synthesis of a 5,50-diamino functionalised
BIPHEP ligand enabling selector bonding. Although axially chiral
BINAP ligands bearing methylamino20 or amino21 groups in the
backbone are known in literature, these molecules were not suitable
for our purpose for several reasons: methylamino groups were
considered to be too flexible, thus direct bonding of the NH2-
moiety was considered to be a more promising approach because
the enhanced rigidity should have a beneficial effect on analyte
binding. Since future studies will aim at controlling the axial
stereochemistry, the tropos nature of BIPHEP-type ligands was also
advantageous. Modification of BIPHEP-ligands in the 6-position
leads to atropos ligands as it is the case for the widely used MeO-
BIPHEP ligand family. In contrast, the 3-position directs the selector
to close proximity of the diphenylphosphino groups potentially
making substrate coordination difficult due to additional steric
repulsion. Little is known about effects of substitution at the
observed as significantly separated species in NMR spectroscopy.
Interactions between chiral substances represent a fundamental
principle in chiral amplification, self-organisation and chirality
sensing. This requires covalent, coordinative or non-covalent binding
of the chiral molecules. Impressive examples of enantioselective self-
assembly1 and binding of chiral compounds2 have been reported in
supramolecular chemistry for capsules and clusters.
On a molecular level, it has been shown that metal complexes
are able to differentiate between enantiomers in a quite effective
way. One interesting field of application is the sensing of
enantiomeric excesses of small chiral molecules by complexation
to transition metals bearing chiral ligands. Canary et al.3,4 and
Anslyn et al.3,5 reported copper complexes with chiral ligands for
direct enantiomeric excess determination via CD spectroscopy or
colorimetric analysis. Wolf et al.6 demonstrated palladium
complexes with dynamic chiral ligands for this purpose.
The formation of diastereomeric substrate–catalyst adducts that
occur in metal catalyzed enantioselective hydrogenation (re or si
coordination) represents a related case of asymmetric recognition.7
The vice versa process of metal-coordinated and (ꢀ)-menthol
functionalised substrates, selectively coordinating one additional
phosphine ligand enantiomer upon addition of a racemic ligand
mixture, has been shown as well.8
Impressive results in enantioselective catalysis have been shown
by Mikami et al. utilizing chiral diamines as aligning ligands for the
control of a dynamic chiral phosphine ligand.9,10 Previously, Mikami
and Noyori reported ruthenium and titanium complexes bearing
¨
Organisch-Chemisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer
Feld 270, 69120 Heidelberg, Germany. E-mail: trapp@oci.uni-heidelberg.de
† Electronic supplementary information (ESI) available: Full experimental data and
characterisation for all compounds. CCDC 1415494. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c5cc06306j
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glycine derivative 4. In even closer analogy to HPLC stationary phases,
reaction with isocyanates resulted in urea derivative 5 (Fig. 2B).
Selective reduction of the phosphine oxides was achieved with
PhSiH3. Subsequent coordination to the metal precursor [Rh(COD)2]-
(BF4) led to the corresponding rhodium(I) complex (Fig. 3A). X-ray
crystallographic investigation25 illustrates the twisted biphenyl core
with metal coordinated diphenylphosphino groups on one and the
rigid 3,5-dichlorobenzoyl amides on the other side (Fig. 3B).
Reduction and coordination was investigated for selector modified
BIPHEP oxides 3 and 4. However, it was found that the reduction
product of 4 gives rise to very broad signals in the NMR-spectra in
non-polar solvents rendering interaction studies almost impossible.
Since very sharp signals were observed in case of complex 6, we
focused on this derivative in the current study.
Fig. 1 Previous investigations of complexes bearing chiral or dynamic
chiral ligands in binding of chiral analytes. The fundamental concept of our
new strategy is depicted centred.
We subsequently investigated derivatives of the amino acid
phenylalanine as interacting small chiral analytes. Derivatives
of phenylalanine are of great pharmaceutical importance, e.g.
in the case of Parkinson’s drug L-3,4-dihydroxyphenylalanine
(L-DOPA). Besides, they represent the product of enantioselective
catalyses, thus samples of varying enantiomeric excess are often
analysed. Phenylalanine bears good hydrogen bond donor and
acceptor properties and derivatives can easily be obtained by
modification of the amino and carboxy functionalities.
4-position,22 however, it can be assumed that substituents in this
position will have less influence on the axial stereochemistry of
the BIPHEP-ligand. Therefore, we decided to develop a synthetic
strategy for the 5-substituted derivative (Fig. 2) in line with our
previously investigated hydroxy functionalised BIPHEPs.23
The synthetic procedure starts with nitration of commercially
available ortho-biphenol24 and selective crystallisation of the 5,50-
dinitro derivative. Conversion of the phenol groups into triflates and
reduction of the nitro groups yielded 1. N-Boc-protection allowed for
subsequent palladium catalysed C–P-coupling with HP(O)Ph2. Acidic
cleavage thus led to 2 which can easily be isolated as hydrogen
chloride salt (Fig. 2A).
Several types of selector units can be attached to ligand
backbone 2. We chose state of the art chiral HPLC column selectors,
i.e. interacting sites of amylose and cellulose CSPs (Chiralpak IC/IE
series) as model and focused on the 3,5-dichlorophenyl moiety
attached to the ligand core via carboxylic acids or isocyanates. The
resulting amide or urea NH and CO functionalities as well as the
electron deficient aromatic rings are known for efficient binding of
analytes in HPLC stationary phase design. Reaction with acyl
chlorides readily yielded the corresponding amides exemplified by
the preparation of 3. Amide bond formation can also be applied to
the established coupling of diamides with EEDQ as it was shown for
Complex 6 was dissolved in CDCl3 and NMR spectra were
recorded with two, five and ten equivalents of (S)-phenylalanine (SPhe
)
derivative. We were interested in signal splitting due to dynamic
formation of (Rax, SPhe) and (Sax, SPhe) adducts. (S)-Acetylphenylalanine
methyl ester 7 was the first derivative to be investigated. While no
interaction was detected with two or five equivalents of substrate, a
1
small splitting (9 ppb) of the complex’s NH-groups in H-NMR was
observed in the case of ten equivalents amidoester (Table 1).
With this result, we implemented electron rich aromatic sub-
stituents to the amino acid in order to potentially improve substrate
binding efficiency. We thus studied amide bond formation products
Fig. 2 Synthetic overview of selector modified BIPHEP oxides. (A) Preparation
of the ligand backbone: (i) HOAc, HNO3, 16%, (ii) Tf2O, pyridine, 85%, (iii) Fe, aq.
HCl, 84%, (iv) Boc2O, 84%, (v) Pd2(dba)3, dppb, DIPEA, HP(O)Ph2, 26%, (vi) HCl
in 2-propanol, 93%; (B) modification of 2 with various types of selectors:
(vii) 3,5-dichlorobenzoyl chloride, pyridine, 92%, (viii) N-3,5-dichlorobenzoyl
glycine, EEDQ, 60%, (ix) 3,5-dichlorophenyl isocyanate, 52%.
Fig. 3 Synthesis and characterization of rhodium(I)-complex 6. (A) Reduction
of phosphine oxide 3 and subsequent coordination to a rhodium(I)-precursor:
(i) PhSiH3, 70%; (ii) [Rh(COD)2](BF4), 88%; (B) X-ray crystallographic investigation
of 6. The depicted structure represents the view along the central biphenyl C–C
ꢀ
bond. Hydrogen atoms and the BF4 counter anion are omitted for clarity.
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Table 1 Non-covalent interaction of complex 6 with various derivatives of (S)-phenylalanine in solution: The Dd values are shown for the amide NH
signal of 6 in 1H-NMR and the phosphorous resonance (in brackets) in 31P{1H}-NMR
2 eq.a Dppb 1H (NH), [31P]
5 eq.a Dppb 1H (NH), [31P]
10 eq.a Dppb 1H (NH), [31P]
7
8
—, [—]
—, [—]
9, [—]
—, [—]
92, [—]b
—, [12]
—, [—]
—, [—]
9
146, [—]b
9, [25]b
171, [—]c
22, [37]c
10
11
12
10, [12]b
57, [27]
27, [25]c
26, [26]c
107, [49]
406, [18]
117, [51]c
13
322, [10]
445, [27]b
a
b
c
6.7 mM 6 in dry degassed CDCl3. Diamide concentration was varied. Substrate dissolves completely upon warming. Incomplete dissolution of
substrate.
from piperonyloyl chloride (8) and 3,4-(dioxymethylene)aniline (9). 3,5-dichlorobenzoyl HAr signals (see ESI†). This supports our initial
Interestingly, no interaction took place in case of 8 while a splitting idea of amide hydrogen bonding and p-stacking of the 3,5-dichloro-
of 92 ppb (1H-NMR, amide NH of 6) was already observed in the benzoyl fragment being the predominant interaction sites.
presence of two equivalents of 9.
It has to be noted that binding of the analyte to the metal
Next, we aimed at increasing the steric demand at the amino centre can be excluded because control experiments with
group of 9 by replacing the acetyl moiety by benzoyl (10) and [(BIPHEP)Rh(COD)](BF4) did not show any splitting even with
1-naphthoyl (11) groups. These enlarged derivatives should ten equivalents of 12 or 13 (Fig. 4D and ESI†). Besides, adding
potentially lead to increasing repulsion with the diphenylphos- ten equivalents of 13 to the free ligand results in splitting of
phino groups. Although 10 and 11 were only moderately soluble signals as well (see ESI†).
in CDCl3 (saturated solutions were obtained with less than
Next, we verified that the two species observed correspond to the
10 equivalents), both showed splitting of the JP–Rh doublet in adducts (Rax, SPhe) and (Sax, SPhe). Thus, we repeated the interaction
31P{1H}-NMR (Table 1) for the first time.
experiment using two equivalents of racemic 13. This led to observa-
1
At this point, we concluded that the most crucial part for strong tion of one single species in the NMR spectrum without any signal
non-covalent binding would be the presence of two amide bonds. It splitting. In contrast, signal splitting was observed when adding 13
seemed reasonable to include the methylamide analogues of 7 and 8. with 50% ee but the Dppm value was significantly smaller compared
Both can easily be obtained by aminolysis of the corresponding methyl to enantiopure 13 (Fig. 4B). It has to be noted, that the two NH-
esters. N-Piperonyloyl derivative 12 was found to lead to significant signals do not correspond to RPhe and SPhe, as it would be the case
splitting in 1H-NMR and remarkable splitting of 0.05 ppm in for common chiral shift reagents, thus their relative intensity does
31P{1H}-NMR. Intriguingly, the small acetyl derivative 13 gives the not change with different ee values of the analyte. Splitting is the
1
highest values regarding splitting in H-NMR. The two adducts of result of the complex sensing the chirality of the analyte through
(Rax, SPhe) and (Sax, SPhe) are separated by 0.45 ppm (NH signal) in non-covalent coordination to the selector units forming two pairs of
1H-NMR spectra with 10 equivalents of diamide (Table 1 and Fig. 4A). adducts: (Rax, SPhe) and (Sax, SPhe). These adducts are diastereomeric
In all cases, the splitting effect is not limited to the NH signal in and thus are observed at different chemical shifts in NMR spectra.
1H-NMR and can also be observed, for example, when analysing the Coordination and de-coordination can occur rapidly in solution.
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found to be dependent on its enantiomeric excess. This makes ee
determination possible.
Our study represents the first example of non-covalent and
non-coordinative binding of chiral analytes with a selector
modified transition metal complex in solution. These findings
open up the perspective of developing self-recognising stereo-
dynamic systems applicable in catalysis and beyond.
Generous financial support by the European Research Council
(ERC) for a Starting Grant (No. 258740, AMPCAT) is gratefully
acknowledged. G.S. acknowledges the Fonds der Chemischen
Industrie for a Ph.D. fellowship.
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