Inducing Enantioselectivity in a Dynamic Catalyst by Supramolecular Interlocking

Article abstract of DOI:10.1002/anie.201901175

The design of a new class of fluxional biphenyl bisphosphinite (BIBIPHOS) ligands decorated with amino acid-based diamide interaction sites is reported that undergo spontaneous desymmetrization. Hydrogenation of prochiral alkenes using Rh-BIBIPHOS results

Full text of DOI:10.1002/anie.201901175

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Accepted Article
Title: Inducing Enantioselectivity in a Dynamic Catalyst by
Supramolecular Interlocking
Authors: Oliver Trapp and Jan Felix Scholtes
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901175
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10.1002/anie.201901175
Angewandte Chemie International Edition
COMMUNICATION
Inducing Enantioselectivity in a Dynamic Catalyst by
Supramolecular Interlocking
Jan Felix Scholtes[a,b] and Oliver Trapp*[a,b]
Abstract: Supramolecular ligands offer a variety of possibilities to control selectivity in catalysis due to their non-covalent interactions with other
molecules. Conceptionally, enantioselectivity can be induced by interaction of chiral additives or products with the interaction sites of a
supramolecular catalyst. However, the design of such catalysts is very challenging due to the complex fusion of recognition sites and catalytically
active center. Here, we report the design of a new class of fluxional biphenyl bisphosphinite (BIBIPHOS) ligands decorated with amino acid-
based diamide interaction sites that undergo spontaneous desymmetrization. Hydrogenation of prochiral alkenes using Rh-BIBIPHOS results
in enantiomeric ratios of up to 96:4 (R/S). This stereoconvergent behavior of the fluxional BIBIPHOS ligand is triggered by pronounced
intermolecular interlocking of the recognition sites, leading to the formation of a supramolecular assembly, where the axial orientation of the
biphenyl ligand backbone is governed by the chirality of the amino acid moieties. Stereoinduction during catalysis is decoupled from this process
and occurs as an immediate consequence of the ligands’ emergent behavior. This supramolecular system is very robust and has the potential
be adopted for other ligand designs in enantioselective catalysis.
Enantioselective interactions between molecules play a pivotal
role in a wide range of natural processes. While this interaction is
of non-covalent nature, it is the basis for molecular recognition
and chirality transfer, processes believed to be deeply rooted in
natural chiral replication.[ 1 ] Understanding how non-covalent
interactions can be used to exert enantiocontrol over chemical
reactions promises far-reaching possibilities for the future design
of chiral catalysts. Therefore, great efforts have been made to find
ways to enable enantiocontrol at the molecular level.
mediated alkylation of 5-pyrimidinecarbaldehydes[10]. Similarly,
non-covalent interactions of a catalyst with the targeted reaction
product can control selectivity in an autoinductive way to amplify
a sense of chirality.[11] This has been demonstrated by Wynberg
and Feringa in oxidative couplings of phenols and camphor to
[
12 ]
obtain homochiral dimers.
Other examples include
enantioselective hydrocyanation reactions reported by Danda et
al.[13] and Shvo et al.[14] as well as a self-amplifying hydrogenation
reaction by our own group. [15]
The classical supramolecular approach aims at the stabilization
of a molecular skeleton by non-covalent interaction, which ideally
results in catalysts with a certain selectivity.[2] Much less prevalent
are examples where the nature of the chiral element is determined
by the interaction itself. Inspired by nature, nucleobase-derived
Another form of chiral amplification, referred to as the “sergeant-
soldier principle” relies on the self-organizational ability of
supramolecular systems. [16] Most commonly found in larger self-
assembling structures[17] or helical polymers, [18] it is based on
chirality transfer along a chain of subunits where only few chiral
“sergeants” are needed to align a much greater number of achiral
“soldiers” in order to build structures with a high degree of
stereoselectivity.
3
]
ligands[
as well as ligands bearing amino acid-derived
interaction site[ 4 ] have been reported, that mimic naturally
occurring hydrogen bonding patterns in DNA or in proteins to
enantioselectively generate self-assembled ligands with chiral
axes. Other examples were reported where chiral molecules were
capable of controlling the stereodynamic element of a catalyst[5]
such as its helicity[ 6 ] or a chiral axis[ 7 ] through non-covalent
bonding.
Combining some of these approaches, we developed a strategy
19
]
to introduce
a
highly selective receptor group[
for
a
enantioselective recognition into the backbone of
stereodynamic biphenyl ligand.[20] Because of the C2-symmetry of
the ligand core, we expected a homochiral alignment of the
ligands that would have a stereodirecting effect on the ligand’s
rotamer distribution and would allow to reinforce stereo-alignment
through cooperative interaction.
A more elaborate feature that results from intermolecular
interactions between different components of a catalytic system,
i.e. different catalyst molecules, ligands or reagents, is that
formation of aggregates can cause the emergence of nonlinear
effects such as the amplification of asymmetric processes.[ 8 ]
Particularly intriguing are autocatalytic reactions[9] where this is
induced by the product of the catalysis, as most impressively
demonstrated by Soai et al. during their investigations of the Zn-
We synthesized
a set of biphenyl bisphosphinite ligands
(BIBIPHOS) with low rotational barriers resulting in high
stereodynamic flexibility (see Figure 1). Interestingly, all ligands
(and their phenol precursors) were found to adapt a single well-
defined structure in solution, that rendered both molecular halves
unsymmetrical as apparent by two sets of signals of equal
intensity in all 1H, 13C and 31P NMR spectra. Furthermore, no
interconverting ligand rotamers were observed which indicates a
full diastereomeric enrichment of one ligand rotamer. This
intriguing behavior prompted a comprehensive investigation of
the ligand structure.
[a]
J. F. Scholtes, Prof. Dr. O. Trapp
Department of Chemistry
Ludwig - Maximilians - University Munich
Butenandtstr. 5-13
81377 Munich (Germany)
The 31P NMR spectrum of each compound showed two distinct
singlet peaks. Similarly, both 1H and 13C NMR spectra contain two
sets of signals with identical intensity which were assigned by 2D
NMR spectroscopy to the same molecular scaffold. Analysis of 1H
NMR signals of amide protons revealed a very strong downfield
shift as found in peptide bonds that engage in strong and steady
hydrogen bonding. [21]
E-mail: oliver.trapp@cup.uni-muenchen.de
[b]
Max-Planck-Institute for Astronomy
Königstuhl 17
69117 Heidelberg (Germany)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901175
Angewandte Chemie International Edition
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The complex is divided into an inner sphere part, where two
selectors align in a [b²]-turn forming two hydrogen bonds and an
outer sphere part where the remaining two selectors engage in a
“tweezer”-like assembly by forming two additional hydrogen
bonds with the back-side of the inner sphere selector of the
respective
other
ligand
molecule.
This
results
in
desymmetrization of the two subunits. This is in line with the
aforementioned observation of an additional signal set for each of
these compounds. It also becomes apparent that the spatial
arrangement of the glycine moieties does not allow the formation
of dimers with different axial chirality. For ligands 4a-c with chiral
selectors, only one of two possible isomers S,S,Rax/S,S,Rax or
S,S,Sax/S,S,Sax is observed, which leads to the conclusion that
the chiral information in the amide linker determines the axial
chirality of the biphenyl backbone in the dimer and only one
rotamer is present in solution. By conducting hydrogenation
experiments (see below) and comparing the obtained selectivities
to those of similar ligand structures with known chirality, we
established that all ligands transform into their respective Rax
isomers.
Figure 1: Biphenyl bisphosphinite (BIBIPHOS) synthesis i) PhI(OAc)2, 51%,
ii) KOH, 97%, iii) amide selector hydrochloride, EDCI·HCl, HOBt, DIPEA, then
excess Me2NCH2CH2NH2, 89% a; 51% b, 91% c, 80% d, iv) PPh2Cl, 1,4-
diazabicyclo[2.2.2]octane, 49% a, 53% b, 83% c, 53% d.
Signals for compound 4a were observed at 9.43, 9.12, 8.11 and
7.56 ppm and those for ligands 4b, c and d were found between
10.22 and 7.44 ppm. When 31P NMR spectra of 4a were collected
at various temperatures between -40 and 100 °C, significant line
broadening was observed at 80 °C. At 40 °C, new singlet species
appeared, which was only stable at elevated temperatures and
vanished again when returning to room temperature (see SI for
spectral data). These findings indicate that ligand behavior is
governed by strong hydrogen bonding of the compound’s selector
moieties with supramolecular interactions fading at elevated
temperatures. It also signifies that the dimeric complex retains
enough dynamic to disengage and to undergo chemical exchange
with other complexes.
We obtained an X-ray structure of ligand 4d with glycine-derived
selectors. The structure shows a C2-symmetric dimer comprising
two Rax rotamers (see Figure 2).
Figure 3: 31P NMR spectra (a) of individual ligands 4a and 4b and (b) of an
equimolar mixture of 4a and 4b, where four additional signals of equal intensity
arise. With a total of eight peaks, four of them represent the original two ligand
dimers. Remaining signals display formation of a supramolecular heterodimer
comprising both ligands, which contains four diastereotopic phosphorus atoms.
Figure 2: Representation of the supramolecular arrangement of 4d, which is
based on the single crystal X-ray structure obtained for this compound. Two
molecules form a supramolecular C2-symmetric dimer of C1-symmetric subunits.
One selector of each subunit engages in -turn-like, two-fold hydrogen bonding
in the center (inner sphere), while the two remaining selector moieties form two
more hydrogen bonds each with the inner sphere selector of the respective
other molecule (outer sphere).
To corroborate that the supramolecular structure is still conserved
in solution, crossover experiments were conducted. When mixing
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10.1002/anie.201901175
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ligands 4a and 4b, which differ with respect to the terminal amide
substituent, formation of an additional species was observed.
While the phosphorus atoms of the individual compounds show
two signals each (see Figure 3a), the 31P NMR spectrum of a 1:1
mixture comprised eight different peaks of identical intensity (see
Figure 3b). We conclude from preceding experiments that the four
additional signals belong to a heterodimeric species where all four
phosphorus atoms are diastereotopic. A 2:1 mixture of the two
ligands resulted in a similar spectrum with a 4:4:1 distribution of
the three species, indicating a statistical distribution of dimers (for
spectral data and kinetic considerations see SI). It should be
stressed that the ligand mixture exhibits identical behavior
compared to the pure ligand. All amide protons show low-field
NMR shifts in the same range as the individual pure ligands. 31P
NMR spectra measured at elevated temperatures exhibit line
broadening along with formation symmetric species like those
found for the pure ligand, which also vanish again when the
spectrum is re-measured at room temperature afterwards. These
findings provide the definite proof for dimer formation in solution
and demonstrate intermolecular nature of the hydrogen bonding
that cause the C1-symmetric appearance of the ligands and the
energetic differences among rotamers.
H9 and H8’, and for H9 and H10’, which both accounts for the
interaction between inner and outer sphere selector protons.
This remarkable stereoconvergent behavior of the fluxional
BIBIPHOS ligands, triggered by pronounced intermolecular
interlocking of the recognition sites, leading to the formation of a
defined supramolecular assembly is a promising approach to
generate selectivity in asymmetric catalysis. Consequently,
BIBIPHOS ligands 4a-c were employed in Rh-catalyzed
hydrogenation experiments (see Figure 5). All three ligands
exhibited high to very high enantioselectivities with phenyl alanine
ligand 4c performing slightly better than the valine-based ligands
4a and b. The former was found to convert methyl 2-
acetamidoacrylate 5 with the best enantiomeric ratio observed
(96.0:4.0 R:S), followed by dimethyl-2-methyl succinate 7 with a
ratio of 94.9:5.1 (S:R) and N-acetylphenylalanine methyl ester 6
with 94.5:5.5 (R:S).
Figure 4: Model of the calculated structure of ligand Rax/Rax-4a with annotated
atomic distances for protons what show strong NOE-based cross peaks. The
initial structure for optimization was based on the crystal structure of 4d and was
optimized at the B3LYP/(aug)-cc-pvdz level of theory. To improve clarity, only
annotated hydrogen atoms are shown and OPPh2 moieties are abstracted as
orange placeholder atoms. The two molecular subunits of the dimer are colored
in light and dark grey. Nitrogen = blue, oxygen = red, OPPh2 moiety = orange.
Figure 5: Results for the enantioselective hydrogenation of substrates 5-8 using
BIBIPHOS ligands 4a-c. Detailed experimental procedures can be found in the
SI.
For enamide 8, a selectivity of 93.7:6.3 (R:S) was obtained. These
results also allowed us to corroborate our assumption of all
ligands being diastereomerically pure Rax isomers by comparing
obtained selectivities to those of similar, earlier reported systems.
[22] We also conducted experiments with various catalyst loadings
and und lower hydrogen pressure (see SI) yielding identical
outcomes. These experiments were designed to show that the
selectivity is independent of the turnover number thus excluding
selective catalyst activation or temporal change of the catalyst as
a source of selectivity. The catalysis was also performed in THF
and MeOH to evaluate solvent effects. While THF, a weakly
To corroborate the structure of the supramolecular complex,
NOESY spectra of compound 4a were collected. The most
prominent signals are illustrated in Figure 4. The structure of 4a
is based on the crystal structure of glycine derivative 4d and was
optimized using DFT calculations on the B3LYP/(aug)-cc-pvdz
level of theory. Cross peaks indicate proximity between protons
H4 and H6’. Comparing atomic distances in the model structure
suggests that corresponding atoms within the same molecule are
too far away to give a strong coupling signal. Intermolecular
coupling, however, seems likely. Coupling was also observed for
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10.1002/anie.201901175
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coordinating solvent, gave comparable results for hydrogenation
of methyl 2-acetamidoacrylate 5 using ligand 4c (95.2:4.8 R:S)
compared to those in CDCl3, employment of methanol as reaction
solvent led to a significant drop in selectivity (80.8:19.2 R:S), most
likely attributed to the solvent inhibiting ligand-ligand interaction
that drive the rotameric enrichment.
In summary, we have shown that the fluxional ligands 4a-c, all of
which contain chiral (S)-amino acid derived 5,5’–diamide selector
moieties, form well-defined supramolecular dimers by
intermolecular interlocking. Due to the bias of the chiral selectors,
a complete transformation into a single Rax rotamer is achieved.
The diastereomeric enrichment is based on a process of
supramolecular, cooperative self-recognition, where diamide
asymmetric transformation. It is important to point out, that chiral
induction during catalysis is conceptually decoupled from the
alignment of the ligands. Cooperative chiral induction that results
from the self-recognition properties of the selector units evokes a
stereoconvergent response from the dynamic ligand core, a bias
which is further relayed during catalysis. The presented system
yields a predictable core structure that has the potential to be
combined with other biaryl-based ligand types to yield self-
recognizing enantioselective catalysts for a number of different
transformations.
Experimental Section
moieties diastereoselectively lock the rotamers through
a
“tweezer”-like network of hydrogen bonds into a preferential axial
conformation. The ligands were employed in Rh-catalyzed,
enantioselective hydrogenation experiments. All ligands showed
high to very high enantioselectivities with various prochiral olefins.
The best performance was observed with phenylalanine-based
ligand 4c which converted methyl 2-acetamido acrylate 5 with an
er of 96.0:4.0 (R:S). The catalytic experiments could also be used
to ascertain the axial chirality of the ligands and to verify the
diastereomeric purity of the ligand and the stereomeric integrity of
the catalyst over the course of the reaction.
Supporting information for this article is available on the WWW under XXX
Acknowledgements
Generous financial support by the European Research Council
(ERC) for a Starting Grant (No. 258740, AMPCAT) and the Max-
Planck-Society is gratefully acknowledged. We thank Dr. Peter
Mayer for the X-ray structure analysis.
To the best of our knowledge, this is the first example where the
concepts of stereodynamic ligands and supramolecular
assemblies are combined to generate a diastereomerically pure
compound that can convey very high enantioselectivity in an
Keywords: supramolecular chemistry • self-recognition •
stereodynamics • asymmetric catalysis • ligand design
[1] a) R. G. Cooks, D. Zhang, K. J. Koch, F. C. Gozzo, M. N. Eberlin, Anal.
Chem. 2001, 73, 3646-3655; b) P. D. Bailey, J. Chem. Soc., Chem.
Commun. 1995, 1797-1798; c) A. Saghatelian, Y. Yokobayashi, K. Soltani,
M. R. Ghadiri, Nature 2001, 409, 797-801.
[10] K. Soai, T. Kawasaki, A. Matsumoto, Acc. Chem. Res. 2014, 47, 3643-
3654.
[11] A. H. Alberts, H. Wynberg, J. Am. Chem. Soc. 1989, 111, 7265-7266.
[12] a) H. Wynberg, B. Feringa, Tetrahedron 1976, 32, 2831-2834; b) B.
Feringa, H. Wynberg, J. Am. Chem. Soc. 1976, 98, 3372-3373.
[13] H. Danda, H. Nishikawa, K. Otaka, J. Org. Chem. 1991, 56, 6740-6741.
[14] Y. Shvo, M. Gal, Y. Becker, A. Elgavi, Tetrahedron: Asymmetry 1996, 7,
911-924.
[2] a) S. Carboni, C. Gennari, L. Pignataro, U. Piarulli, Dalton Trans. 2011, 40,
4355-4373; b) M. Raynal, P. Ballester, A. Vidal-Ferran, P. W. N. M. van
Leeuwen, Chem. Soc. Rev. 2014, 43, 1660-1733.
[3] a) M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc. 2006, 128,
4188-4189; b) J. Wieland, B. Breit, Nat Chem 2010, 2, 832-837; c) W. K.
Marie, L. L. Günter, B. Bernhard, Angew. Chem. Int. Ed. 2018, 57, 5100-
5104; Angew. Chem. 2018, 130, 5194-5198.
[15] G. Storch, O. Trapp, Nature Chem. 2017, 9, 179-187.
[16] M. M. Green, M. P. Reidy, R. D. Johnson, G. Darling, D. J. O'Leary, G.
Willson, J. Am. Chem. Soc. 1989, 111, 6452-6454.
[17] a) L. J. Prins, P. Timmerman, D. N. Reinhoudt, J. Am. Chem. Soc. 2001,
123, 10153-10163; b) A. R. A. Palmans, J. A. J. M. Vekemans, E. E.
Havinga, E. W. Meijer, Angew. Chem. Int. Ed. 1997, 36, 2648-2651;
Angew. Chem. 1997, 109, 2763-2765; c) L. Brunsveld, A. P. H. J.
Schenning, M. A. C. Broeren, H. M. Janssen, J. A. J. M. Vekemans, E. W.
Meijer, Chem. Lett. 2000, 29, 292-293; d) L. J. Prins, J. Huskens, F. de
Jong, P. Timmerman, D. N. Reinhoudt, Nature 1999, 398, 498-502.
[18] a) B. M. W. Langeveld-Voss, R. J. M. Waterval, R. A. J. Janssen, E. W.
Meijer, Macromolecules 1999, 32, 227-230; b) Y. Nagata, T. Nishikawa, M.
Suginome, ACS Macro Lett. 2016, 5, 519-522.
[4] a) Z. Kokan, S. I. Kirin, Eur. J. Org. Chem. 2013, 2013, 8154-8161; b) Z.
Kokan, Z. Glasovac, M. Majerić Elenkov, M. Gredičak, I. Jerić, S. I. Kirin,
Organometallics 2014, 33, 4005-4015; c) A. C. Laungani, B. Breit, Chem.
Commun. 2008, 844-846.
[5] a) V. Blanco, A. Leigh, V. Marcos, Chem. Soc. Rev. 2015, 44, 5341-
5370; b) M. Vlatković, B. S. L. Collins, B. L. Feringa, Chem. Eur. J. 2016,
22, 17080-17111; c) G. Romanazzi, L. Degennaro, P. Mastrorilli, R.
Luisi, ACS Catal. 2017, 7, 4100-4114.
[6] a) P. Dydio, C. Rubay, T. Gadzikwa, M. Lutz, J. N. H. Reek, J. Am. Chem.
Soc. 2011, 133, 17176-17179; b) T. Yamamoto, R. Murakami, S. Komatsu,
M. Suginome, J. Am. Chem. Soc. 2018, 140, 3867-3870; c) J. M. Zimbron,
X. Caumes, Y. Li, C. M. Thomas, M. Raynal, L. Bouteiller, Angew. Chem.
Int. Ed. Engl. 2017, 56, 14016-14019, Angew. Chem. 2017, 129, 14204-
14207.
[19] a) W. H. Pirkle, P. G. Murray, S. R. Wilson, J. Org. Chem. 1996, 61,
4775-4777; b) H. Frank, G. J. Nicholson, E. Bayer, Angew. Chem. Int.
Ed. Engl. 1978, 17, 363-365; Angew. Chem. 1978, 90, 396-398; c) G.
Storch, M. Siebert, F. Rominger, O. Trapp, Chem. Commun. 2015, 51,
15665-15668; d) G. Storch, M. Haas, O. Trapp, Chem. Eur. J. 2017, 23,
5414-5418.
[7] a) F. Maier, O. Trapp, Angew. Chem. Int. Ed. Engl. 2014, 53, 8756-8760;
Angew. Chem. 2014, 126, 8901-8905; b) G. Storch, O. Trapp, Chirality
2018, 30, 1150-1160.
[20] F. Maier, O. Trapp, Angew. Chem. Int. Ed. 2012, 51, 2985-2988; Angew.
Chem. 2012, 124, 3039-3043.
[8] T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int. Ed. 2009,
48, 456-494; Angew. Chem. 2009, 121, 464-503; b) C. Girard, H. B.
[21] H. Kessler, Angew. Chem. Int. Ed. Engl. 1982, 21, 512-523; Angew. Chem.
1982, 94, 509-520.
Kagan, Angew. Chem. Int. Ed. 1998, 37, 2922-2959.
[9] M. H. Todd, Chem. Soc. Rev. 2002, 31, 211-222
[22] a) J. Yu, T. V. RajanBabu, J. R. Parquette, J. Am. Chem. Soc. 2008, 130,
7845-7847; b) Y.-G. Zhou, X. Zhang, Chem. Commun. 2002, 1124-1125.
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Entry for the Table of Contents
COMMUNICATION
Emergence in Chiral Induction:
Intermolecular interaction of fluxional
biphenyl bisphosphinite (BIBIPHOS)
ligands decorated with amino acid-
based diamide selectors undergo
spontaneous deracemization.
Hydrogenation of prochiral alkenes
using Rh-BIBIPHOS results in
enantiomeric ratios of up to 96:4
(R/S).
Jan Felix Scholtes and Oliver Trapp*
Page No. – Page No.
Inducing Enantioselectivity in a
Dynamic Catalyst by Supramolecular
Interlocking
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