Supramolecular Interlocked Biphenyl Ligands for Enantioselective Ti-Catalyzed Alkylation of Aromatic Aldehydes

Article abstract of DOI:10.1021/acs.organomet.9b00262

The substitution of tropos 2,2′-biphenols with (S)-amino-acid-derived interaction sites in the 5,5′-position results in a spontaneous desymmetrization. This process is driven by well-defined intermolecular hydrogen bonding, which leads to diastereoselecti

Full text of DOI:10.1021/acs.organomet.9b00262

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Supramolecular Interlocked Biphenyl Ligands for Enantioselective
Ti-Catalyzed Alkylation of Aromatic Aldehydes
Jan Felix Scholtes†,‡ and Oliver Trapp*,†,‡
†
̈
̈
Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, 81377 Munich, Germany
‡Max-Planck-Institute for Astronomy, 69117 Heidelberg, Germany
S
* Supporting Information
ABSTRACT: The substitution of tropos 2,2′-biphenols with (S)-
amino-acid-derived interaction sites in the 5,5′-position results in a
spontaneous desymmetrization. This process is driven by well-
defined intermolecular hydrogen bonding, which leads to
diastereoselective interlocking of the interaction sites of two
biphenol units. The axial chirality of the subunits within the
supramolecular dimer is dictated by the chiral information in the
interacting selector units. The structure of the complex was
investigated by nuclear magnetic resonance spectroscopy, X-ray
crystallography, and hydrogen−deuterium exchange. Ligands were
successfully employed in the Ti-mediated asymmetric alkylation of
aromatic aldehydes.
detailed understanding of how noncovalent interactions
can be used to exert enantiocontrol over chemical
A
reactions promises far-reaching opportunities for the design
of chiral catalysts1−3 and the understanding of enantiodiscri-
minatory processes.4−7 Using the abundance of different
motives in functional groups available for interaction,
numerous new strategies have been devised to generate
enantioselectivity in a variety of transition-metal-catalyzed
transformations.8−10 Most of these systems rely on the
modification of well-established ligand motives such as
BINOL, where enantioselectivity is enhanced by the rigid-
ification of the complex geometry through noncovalent
interactions between ligands that already bear static chiral
information. Only a few examples exist where the chiral
information in the ligand itself is controlled by the
intermolecular interaction (e.g., a stabilized chiral axis or
helix).11−16
Figure 1. Stereodynamic biphenyl ligands interlock to form
supramolecular dimers when equipped with amino-acid-derived sites
for noncovalent interactions in the 5,5′-position. The diastereose-
lective nature of interactions induces stereoconvergent ligand
behavior during dimerization, and full transformation into the
diastereomerically pure Rax rotamer is observed. Ligand subunits are
depicted in red and blue, and hydrogen bonds are indicated as green
lines.
We recently reported the design of a novel core motif for
stereodynamic biphenyl-based ligands with chiral amino-acid-
derived diamide substituents (selectors) in the 5,5′-position.17
These compounds form dimeric supramolecular structures that
are stabilized by a network of hydrogen bonds between the
selector moieties. Diastereoselective interlocking of two ligand
units subsequently leads to complete transformation into the
diastereomerically pure Rax rotamer. We observed an analogous
behavior for their BIPOL precursor molecules 1a−c (see
Figure 1), which prompted us to investigate their stereo-
convergent behavior and their versatility as ligands. Diols like
these have found successful application as ligands in
homogeneous catalysis.18−20 Among the most prominent
examples is the Ti-catalyzed alkylation21 of aromatic aldehydes,
where Chan et al. pioneered the use of atropos (S)-BINOL to
convert a range of substrates with excellent selectivities.22,23 In
2018, Feringa and coworkers reported on a stereodynamic,
photoresponsive biphenol catalyst for a similar reaction.24
Characteristic analytical data that support the dimer
formation25 of BIPOLs 1a−c as well as an X-ray crystal
structure of O,O′-methylated BIPOL 1c could be obtained
(Me-1c; see the Supporting Information (SI)). The stability of
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
Received: April 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00262
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Article
Table 1. Estimated Half-Life Times and Exchange Rates for HD Exchange in Methanol
a
compound
diol 1c
diamide 2
Ha1c
Hb
Ha′1c
Hb′1c
Ha2
8 × 10−4
1.5 × 10−1
Hb
1c
2
b
t1/2 (102 min)
kex (s−1
slowdown factor
1.91
6.0 × 10−5
2554
253.3
4.6 × 10−7
−
1.80
6.4 × 10−5
2402
201.6
5.7 × 10−7
−
0.28
4.2 × 10−4
)
c
1
−
−
917
−
731
−
1
a
Experiments were conducted at room temperature with a 20 mM solution of 1c and a 40 mM solution of 2 in deuterated methanol. Atom
b
annotations X and X′ refer to core and peripheral amide protons, respectively. Complete exchange was already observed after 30 s when the first
c
spectrum was measured. Half-life time was therefore estimated (see the SI). Slowdown factor = kex(HX )/kex(HX1c).
2
the biphenols toward protic solvents allowed for further
experiments to ascertain that the structure found in the
crystalline state is retained in solution. Ligand 1c was chosen
for structural investigations because NMR spectra could
conveniently be recorded at ambient temperatures. Those for
compounds 1a and 1b had to be collected at −20 °C to obtain
sharp NMR signals, which indicates higher ligand dynamics,
residual axial rotation, and thus incomplete rotamer enrich-
ment of the Rax isomer due to weaker selector interlocking at
ambient temperatures.
calculated to align the exchange constants of diol 1c with those
of diamide 2 to directly compare the deceleration for each
individual amide proton. The difference between the factors
for protons Ha1c and Ha′1c (2554 and 2402) and protons Hb
1c
and Hb′1c (917 and 731) is comprehensively reflected in the
assumed binding model is shown in Table 1: Amide proton Ha,
which is located in the core of the complex, experienced the
biggest stabilization due to the chelating effect of all
surrounding hydrogen bonds and showed the strongest
exchange slowdown. Proton Ha′ benefited to a similar extent
but was deuterated slightly faster because of its peripheral
position. The exchange slowdown of the terminal amide
proton Hb was 2.5 times smaller, which is explained by the lack
of chelate stabilization. Proton Hb′ experienced the least
retardation of all protons due to the exposed position, and the
observed slowdown compared with model compound 2 can be
attributed to exchange and the rearrangement of the subunits.
Diol ligands 1a−c were employed in the enantioselective,
Ti-mediated alkylation of aromatic aldehydes. Using benzalde-
hyde, screening experiments were conducted by varying the
ligands and the reaction conditions such as temperature,
solvent, and reagent ratios, where the work of Chan and
coworkers was taken as a starting point (see Table 2). As
previously discussed, differences in the diols’ dynamics are
reflected in their enantioselectivities as ligands (entries 1−3).
More dynamic, valine-based compounds 1a and 1b gave
enantiomeric excesses below 40% as well as conversions below
62% at a reaction temperature of 0 °C after 16 h. In contrast,
phenylalanine-based ligand 1c gave 75.6% ee R and a
conversion of 92.7%. All further screening experiments were
consequently limited to this diol. Reaction temperature of 25
or −20 °C expectedly in- or decreased the yield, and,
surprisingly, both eroded the enantioselectivity significantly
(entries 4 and 5). This was also observed when the reaction
was run in higher concentration (entry 7), whereas a 6.5 times
more diluted setup gave almost no conversion but a slight
increase in selectivity (entry 6). As noted in literature, the ratio
of titanium precursor and ligand also has a strong impact on
the course of the catalysis.28 Decreasing the amount of ligand
(28:1 Ti(OiPr)4/ligand) deteriorated both the yield and the
selectivity, whereas an increased amount of diol (3.5:1
In a titration experiment, NMR spectra of diol 1c dissolved
in mixtures of CDCl3 and CD3OD with ratios of 99:1, 90:10,
50:50, and 0:100 (v/v) were collected. (See the SI for spectral
data.) In accordance with suggested bonding patterns, three
amide protons of each ligand subunit that engage in
intermolecular hydrogen bonding to form the dimer showed
only very small overall shift differences between δ −0.18 and
+0.20. The exposed, “unbonded” amide proton, however,
experienced a significant downfield shift of δ +1.97 due to the
increased interaction with solvent molecules. (See the dimer
structure in Figure 1 for a structural reference.) Next,
hydrogen−deuterium (HD) exchange rates in deuterated
methanol were investigated, which are known to be dependent
on both the substitution pattern and the electronics of the
amide and can be used to assess the degree of hydrogen
bonding in the solution.26,27 Deuteration rates of 1c were
compared with those of model compound 2, which provides a
similar structure compared to the selector moieties of 1c but
was considered to not engage in comparably strong self-
interaction due to the lack of a chelating effect. Analyte
solutions in CD3OD were prepared (20 mM for 1c, 40 mM for
2), and 1H NMR spectra were periodically collected to
monitor the decrease in the amide proton signals. Half-life
times t1/2 and corresponding exchange rates kex are shown in
Table 1. Model compound 2 was found to undergo deuterium
exchange significantly faster. Proton Ha2 had fully exchanged
2
before the first measurement after 30 s, and the signal for Hb
had vanished after 2 h. For diol 1c, however, full exchange of
amide protons took roughly 20 h for Ha1c/Ha′1c and about 9
weeks for Hb1c/Hb′1c, which was attributed to proton
immobilization by hydrogen bonding. Slowdown factors were
B
DOI: 10.1021/acs.organomet.9b00262
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Table 2. Condition Screening for the Enantioselective
Alkylation of Aromatic Aldehydes
Table 3. Enantioselective Alkylation of Different Aromatic
Aldehydes
a
product (%)
b
entry
solvent
lig.
ratio Ti/lig. temp. (°C) conv.
ee
1
2
3
4
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.4
1.4/0.05
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
1.4/0.2
0
0
0
25
−20
0
0
0
0
0
61.8
41.4
92.7
98.0
22.1
16.0
98.5
65.1
57.7
11.5
86.4
78.1
36.3
35.0
37.4 R
29.4 R
75.6 R
66.0 R
57.9 R
77.2 R
37.8 R
79.8 R
32.2 R
12.4 R
27.6 R
34.5 R
18.5 R
77.2 R
c
6
7
d
8
9
10
11
12
13
14
Tol
Et2O
MeCN
EtOAc
0
0
0
0
a
Conversion and ee were determined using chiral GC (Chirasil-β-
Dex29). Benzylic alcohol formed only in traces and was not
considered. Benzaldehyde/Ti(OiPr)4/ZnEt2 1.0:1.4:3.0 (molar
b
ratio) and 0.125 M solution with respect to substrate. All reactions
were stopped after 16 h. The detailed experimental procedure can be
c
d
found in the SI. 0.02 M solution with respect to substrate. 0.375 M
solution with respect to substrate.
a
Benzaldehyde/Ti(OiPr)4/ZnEt2/ligand 1.0:1.4:3.0:0.2 (molar ratio)
and 0.125 M solution with respect to substrate. The detailed
experimental procedure can be found in the SI. Unless otherwise
b
Ti(OiPr)4/ligand) gave a comparably good enantiomeric
excess to 79.8% ee R (entries 8 and 9). Finally, choosing
different solvents led to smaller yields in all cases, and only
ethyl acetate gave enantioselectivities comparable to those of
dichloromethane (entry 14).
stated, conversion and ee were determined using chiral GC (Chirasil-
c
β-Dex29). ee was determined by chiral HPLC (Chiracel OD-H).
was observed, and benzylic alcohol, a commonly observed side
product, formed only in traces.
Under these optimized reaction conditions, we tested a
variety of substituted aromatic aldehydes (see Table 3). Most
noticeable was the significant variation in conversion. Whereas
3-nitro-, 2-methoxy-, and α-naphthaldehyde (entries 7, 9, and
10) gave good to very good yields (94.7, 79.5, and 77.0%), p-
substituted aldehydes resulted in lower conversion in the range
of 19.3 (4-methoxybenzaldehyde, entry 5) to 56.7% (4-
fluorobenzaldehyde, entry 4). In terms of enantioselectivity, a
strong dependence on substrate sterics was observed. Whereas
most p-substituted aldehydes were generally alkylated with
similar, slightly lower enantiomeric excesses than benzalde-
hyde, the substitution of the o-position led to a decrease in
selectivity to ∼50% ee R. Only 4-fluorobenzaldehyde exceeded
the benchmark value, being alkylated with 76.9% ee (entry 4),
albeit with lower conversion. Altogether, the present system
satisfyingly reflects the trends previously found for benchmark
ligand (S)-BINOL by Chan et al.22 The decreased selectivity
can be attributed to the ligand’s fluxional character or to a
differing dihedral angle compared with atropos BINOL.
Furthermore, the spatial arrangement of the hydroxy groups
brings the active centers of two interlinked titanium complexes
close together, which leads to a further increase in steric
pressure when large substrates coordinate during the catalytic
cycle. All of these issues could potentially be addressed by
optimizing selector and biaryl substituents on the diol.
Moreover, a high selectivity for the formation of the product
In a final set of experiments, the origin of enantioselectivity
during the catalytic cycle was verified. It is well known that zinc
complexes of small, bifunctionalized molecules such as amino
alcohols or bis(sulphonamides) also catalyze the reaction with
high selectivities.30−32 A number of control experiments were
conducted to verify that selectivity during the catalysis was
indeed induced by the axial chirality of diastereoenriched
biphenol ligands and not by the simple coordination of the
chiral diamide selector groups to a catalytically active metal
center (see Table 4). The addition of a selector-type diamide 3
to the catalysis showed a strong, inhibiting effect, lowering
both conversion and selectivity (entry 1). In a second
experiment, a catalyst solution from racemic 2,2′-biphenol 4
and four equivalents of diamide 3 was prepared, which gave a
very low enantiomeric excess of 5% but not the expected
racemate (entry 2). Indeed, when increasing the incubation
time of additive 3, ligand 4, Ti(OiPr)4, and ZnEt2 before
substrate addition from 10 min to 2 h, an increased
enantioselectivity of 11.3% was observed (entry 3). Omitting
biphenol 4 gave an even higher enantiomeric excess of 38.5%
but only in the presence of the titanium precursor (entries 4
and 5). These experiments illustrate, that simple diamides can
coordinate to a titanium center under basic conditions
provided by the zinc organyl, forming a less active, less
selective, competing catalyst for the alkylation reaction. In a
C
DOI: 10.1021/acs.organomet.9b00262
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Article
and exemplifies a promising concept for stereoinduction for
the future development of stereodynamic ligands.
Table 4. Investigation about the Origin of Chiral Induction
EXPERIMENTAL SECTION
■
General Procedures and Materials. All reactions involving the
use of oxygen or moisture-sensitive substances were carried out in
heat-dried glassware under an atmosphere of nitrogen or argon using
standard Schlenk techniques. All chemicals were used as received
from suppliers without further purification. Column chromatography
was done using silica gel (technical grade, pore size 60 Å, 70−230
mesh, 63−200 μm) produced by Sigma-Aldrich Chemie. Thin layer
chromatography was performed on coated aluminum sheets
(Macherey-Nagel POLYGRAM SIL G/UV 254). Components were
visualized by fluorescence quenching during irradiation with UV light
(254 nm). Dry solvents were tapped from solvent purification system
MB SPS-800 and used immediately. Manual degassing of solvents, if
needed, was done by performing three consecutive freeze−pump−
thaw cycles. Oxygen-free solvents were then placed under an
atmosphere of argon.
a
product (%)
ligand
solute
reagents
NMR spectra were recorded on a Varian NMR system (300, 400,
and 600 MHz) and Bruker Avance III HD and DRX apparatuses
(300, 400, 600, and 800 MHz). NMR shifts are given in parts per
million (ppm) and are referenced to the residual proton or carbon
solvent signals.1 Couplings are termed as follows: s (singlet), bs
(broad singlet), d (doublet), t (triplet), sept (septet), dd (doublet of a
doublet), dt (doublet of triplet), tt (triplet of triplet), and m
(multiplet). Assignment was done by means of 2D experiments
b
entry
(0.2 equiv) (0.4 equiv) (Ti/Zn equiv) conv.
ee
1
2
1c
4
4
−
−
3
3
3
3
3
−
1.4/3.0
1.4/3.0
1.4/3.0
1.4/3.0
0.0/3.0
1.4/3.0
52.7
82.7
52.4
33.0
9.1
54.0
5.0
11.3
38.5
3.8
R
R
R
R
R
R
c
3
c
4
5
6
Me-1c
38.9
0.3
1
1
(1H-1H-COSY, H-13C-HSQC, H-13C-HMBC). Mass spectra were
acquired on a Thermo Finnigan LTQ FT Ultra FT-ICR apparatus
(ESI). For solid-state IR analysis, a Thermo Fisher Nicolet 6700 FT-
IR spectrometer was employed, and the wavenumber of reflectance
was measured with signals being denoted as s (strong), m (medium),
w (weak), and b (broad signal). Crystallographic data were collected
on Bruker APEX II Quazar area detector with Mo Kα radiation (λ =
0.71073 Å).
a
Conversion and ee were determined using chiral GC (Chirasil-β-
Dex29). Benzaldehyde/Ti(OiPr)4/ZnEt2 1.0:1.4:3.0 (molar ratio)
b
and 0.125 M solution with respect to substrate. The detailed
experimental procedure can be found in the SI. Biphenol, diamide,
and titanium precursor were incubated in the presence of ZnEt2 for 2
c
d
h prior to catalysis. 0.375 M solution with respect to substrate.
Synthesis of BIPOL Ligands. A detailed synthetic procedure for the
selector-modified biphenol ligands can be found in ref 17.
final experiment, however, we employed the “capped” ligand
with methylated hydroxy groups (Me-1c). This catalytic
mixture gave a full racemate (entry 6), proving that
interlocking of the ligand selectors prevents their coordination
to a Ti center. These experiments lead to the conclusion that
the obtained enantioselectivities indeed originate from the axial
chirality of the diol ligands 1a−c.
(S)-PhCO-Phe-NHtBu (2). (tert-Butoxycarbonyl)-S-phenylalanine
(5.00 g, 18.9 mmol, 1.00 equiv) was placed in a dried Schlenk flask
and dissolved in dry DMF (40 mL). NEtiPr2 (6.57 mL, 37.7 mmol,
2.00 equiv) and tert-butylamine (2.18 mL, 20.79 mmol, 1.10 equiv)
were added, and the clear solution was cooled in an ice bath. The
addition of COMU (8.88 g, 20.73 mmol, 1.10 equiv) gave a bright-
yellow solution that was left stirring to slowly warm to room
temperature overnight. For workup, the solution was diluted with
ethyl acetate (400 mL), and the organic layer was consecutively
washed with HCl solution (300 mL, 2 M, three times), saturated
NaHCO3 solution (300 mL, two times), and brine (300 mL, two
times), dried over sodium sulfate, and evaporated. Purification by
column chromatography (silica, pentane/diethyl ether 4:1, Rf = 0.14)
gave the BOC-protected amide as a white solid (5.75 g, 17.9 mmol,
95%). To ensure that no racemization occurred during amide
formation, ee was determined using chiral HPLC (Chiralpak IE,
hexane/isopropanol 95:5, 1 mL/min, 20 °C, tS = 11.9 min, tR = 14.6
min). 1H NMR (CDCl3, 400.33 MHz, 298 K): δ = 1.20 (s, 9H), 1.43
(s, 9H), 2.91 (dd, 1H, 3J(H,H) = 8.33 Hz, 2J(H,H) = 13.45 Hz), 3.10
In summary, we investigated a novel type of stereodynamic
BIPOL ligand equipped with chiral 5,5′-bis(diamido) inter-
action sites. These compounds undergo diastereoselective
interlocking through noncovalent interactions to form supra-
molecular dimers comprising exclusively Rax ligand rotamers.
The self-assembly was verified, inter alia, by X-ray analysis, by
solvent titration, and by the analysis of isotope exchange
kinetics, which allowed the verification of the chelate bonding
pattern. Supramolecular ligands were employed in titanium-
catalyzed alkylation reactions of aromatic aldehydes. The best
results for the conversion of benzaldehyde were obtained using
phenylalanine-based ligand 1c with a conversion of 92.7% and
an enantiomeric excess of up to 75.6% of the R enantiomer. A
series of differently substituted aromatic aldehydes were
subsequently converted with medium to good selectivities.
Overall, the trends were found to be similar to those of atropos
ligand BINOL, with the noteworthy difference that the system
investigated here generates selectivity solely through its
stereoconvergent behavior that results from diastereoselective,
supramolecular interlocking of the ligand’s interaction sites.
The chirality transfer in the ligand is decoupled from
stereoinduction in the subsequent catalysis. The presented
approach constitutes an intriguing example of chirality transfer
3
2
(dd, 1H, J(H,H) = 5.72 Hz, J(H,H) = 13.45 Hz), 4.14 (m, 1H),
5.16 (bs, 1H), 5.26 (bs, 1H), 7.20−7.21 (m, 3H), 7.28−7.32 (m,
2H). 13C{1H}-NMR (CDCl3, 100.66 MHz, 298 K): δ = 28.5, 28.7,
39.3, 51.4, 56.7, 80.2, 127.1, 128.8, 129.6, 137.3, 155.5, 170.1. HRMS
(ESI): m/z calcd for C36H56N4NaO6 [2M + Na]+: 663.4092; found:
663.4092. FTIR: ν = 696 (s), 1021 (m), 1170 (s), 1363 (s), 1539 (s),
̃
1653 (s), 2868 (w), 2931 (w), 2972 (m), 3066 (w), 3304 (bs) cm−1.
20
[α]D +8.7 (c 1%, CHCl3).
For the removal of the BOC group, the protected amide (4.80 g,
15.0 mmol, 1.00 equiv) was dissolved in THF (15 mL), and HCl in
isopropanol (30 mL, 5M, 10 equiv) was slowly added. The clear
solution was stirred at room temperature for 20 h. After all volatiles
were removed, the residual oil was stirred in diethyl ether (100 mL)
D
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Article
to give white solids that were filtered off, washed another two times
with diethyl ether (100 mL each), and finally dried in vacuo to give
the corresponding hydrochloride as a white, fluffy solid (3.35 g, 13.0
The temperature of the mixture was subsequently adjusted, the
substrate (125 μmol) was added, and stirring was continued for 16 h.
The reaction was stopped by the addition of saturated ammonium
chloride solution (3 mL), and the product was extracted with ethyl
acetate (2 × 3 mL). Combined organic layers were dried over sodium
sulfate, and conversion and enantioselectivity were determined by
chiral GC (Chirasil-β-Dex29) or HPLC (Chiracel OD-H). Retention
times and absolute configurations were assigned by comparison with
GC traces in the literature or with known compounds or by
identification with GC−MS.
1
mmol, 87%). H NMR (CDCl3, 150.93 MHz, 298 K): δ = 1.15 (s,
9H), 3.18−3.22 (m, 1H), 3.50−3.58 (m, 1H), 4.48−4.52 (m, 1H),
6.46 (s, 1H), 7.20−7.25 (m, 1H), 7.26−7.35 (m, 2H), 7.31−7.45 (m,
2H), 8.54 (bs, 3H). 13C{1H}-NMR (CDCl3, 100.66 MHz, 298 K): δ
= 28.6, 37.8, 52.1, 55.3, 127.6, 129.0, 130.1, 135.0, 167.1. HRMS
(ESI): m/z calcd for C13H21N2O [M − Cl]+: 221.1648; found:
221.1647. FTIR: ν = 698 (s), 740 (s), 1221 (s), 1456 (s), 1295 (s),
̃
20
1688 (s), 2899 (bs), 2969 (bs), 3209 (w), 3309 (w) cm−1. [α]D
+64.6 (c 1%, CHCl3).
ASSOCIATED CONTENT
* Supporting Information
■
In the last step, benzoyl chloride (100 μL, 854 μmol, 1.00 equiv)
and diisopropylethylamine (327 μL, 1.88 μmol, 2.20 equiv) were
mixed in dry DCM (5 mL) and cooled in an ice bath. The amine
hydrochloride (241 mg, 939 μmol, 1.10 equiv) was added as a solid,
and the clear mixture was subsequently stirred at room temperature
for 18 h. For workup, the clear solution was diluted in ethyl acetate
(40 mL), and the organic layer was washed with HCl solution (40
mL, 2 M, three times), saturated bicarbonate solution (40 mL, two
times), and brine (40 mL, once). Drying over sodium sulfate and
evaporation gave the diamide 2 as a white, fluffy solid (257 mg, 792
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00262.
NMR spectra of synthesized compounds, NMR data for
ligand dimer characterization, data for HD exchange
kinetics and titration experiment, crystal structure of
Me-1c, and chromatographic data for alkylation experi-
ments (PDF)
1
μmol, 93%). H NMR (CDCl3, 598.17 MHz, 298 K): δ = 1.19 (s,
9H), 2.96 (dd, 1H, 3J(H,H) = 9.3 Hz, 2J(H,H) = 13.4 Hz), 3.31 (dd,
Accession Codes
3
2
3
1H, J(H,H) = 5.2 Hz, J(H,H) = 13.4 Hz), 4.66 (ddd, 1H, J(H,H)
CCDC 1905601 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
= 9.3 Hz, 3J(H,H) = 7.3 Hz, 3J(H,H) = 5.2 Hz), 5.17 (s, 1H), 7.98 (d,
3
1H, J(H,H) = 7.3 Hz), 7.25−7.28 (m, 1H), 7.30−7.35 (m, 4H),
7.41−7.44 (m, 2H), 7.49−7.52 (m, 1H), 7.78−7.80 (m, 2H).
13C{1H}-NMR (CDCl3, 150.65 MHz, 298 K): δ = 28.6, 39.6, 51.6,
55.7, 127.2, 127.2, 128.7, 128.9, 129.7, 131.9, 134.1, 137.2, 166.9,
169.6. HRMS (ESI): m/z calcd for C20H23N2O2 [M − H]−:
323.17650; found: 323.17682. FTIR: ν = 687 (s), 1224 (m), 1543
̃
(s), 1636 (s), 2923 (w), 2970 (m), 3066 (bw), 3278 (bs) cm−1
[α]D +7.01 (c 1%, CHCl3).
.
AUTHOR INFORMATION
Corresponding Author
*E-mail: oliver.trapp@cup.uni-muenchen.de.
■
20
O,O′-Dimethyl Phenylalanine-Selector-Modified BIPOL (Me-1c).
Biphenol 1c (180 mg, 244 μmol, 1.00 equiv) was dissolved in dry
acetone (20 mL). Cesium carbonate (188 mg, 975 μmol, 4.00 equiv)
was added, and the mixture was cooled in an ice bath. The cool
solution was treated with iodomethane (303 μL, 4.87 mmol, 20.0
equiv) and turned into a gel-like mass. Stirring was continued at room
temperature, the gel dissolved over time, and solids formed. After 72
h, all volatiles were removed, and the crude mix was partitioned
between water and DCM (20 mL each). Layers were separated, and
the aqueous layer was extracted with DCM (20 mL) another two
times. Combined organic layers were subsequently washed with brine,
dried over sodium sulfate, and evaporated to give the methylated
ORCID
Oliver Trapp: 0000-0002-3594-5181
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the European Research Council
(ERC) for a Starting Grant (no. 258740, AMPCAT) and by
the Max-Planck-Society is gratefully acknowledged.
1
compound as a white solid (160 mg, 209 μmol, 86%). H NMR
(CDCl3, 600.24 MHz, 298 K): δ = 1.01 (s, 9H), 1.29 (s, 9H), 3.01
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2
3
■
(dd, 1H, J(H,H) = 13.6 Hz, J(H,H) = 10.0 Hz), 3.15−3.22 (m,
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