Central-to-Helical-to-Axial-to-Central Transfer of Chirality with a Photoresponsive Catalyst

Article abstract of DOI:10.1021/jacs.8b10816

Recent advances in molecular design have displayed striking examples of dynamic chirality transfer between various elements of chirality, e.g., from central to either helical or axial chirality and vice versa. While considerable progress in atroposelective synthesis has been made, it is intriguing to design chiral molecular switches able to provide selective and dynamic control of axial chirality with an external stimulus to modulate stereochemical functions. Here, we report the synthesis and characterization of a photoresponsive bis(2-phenol)-substituted molecular switch 1. The unique design exhibits a dynamic hybrid central-helical-axial transfer of chirality. The change of preferential axial chirality in the biaryl motif is coupled to the reversible switching of helicity of the overcrowded alkene core, dictated by the fixed stereogenic center. The potential for dynamic control of axial chirality was demonstrated by using (R)-1 as switchable catalyst to direct the stereochemical outcome of the catalytic enantioselective addition of diethylzinc to aromatic aldehydes, with successful reversal of enantioselectivity for several substrates.

Full text of DOI:10.1021/jacs.8b10816

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Article
Central-to-Helical-to-Axial-to-Central Transfer
of Chirality with a Photoresponsive Catalyst
Stefano F. Pizzolato, Peter Stacko, Jos C. M. Kistemaker,
Thomas van Leeuwen, Edwin Otten, and Ben L. Feringa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10816 • Publication Date (Web): 20 Nov 2018
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Central-to-Helical-to-Axial-to-Central Transfer of Chirality with
a Photoresponsive Catalyst
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Stefano F. Pizzolato, Peter Štacko, Jos C. M. Kistemaker, Thomas van Leeuwen, Edwin Otten and
Ben L. Feringa*
Center for Systems Chemistry, Stratingh Institute for Chemistry and Zernike Institute for Advanced Materials,
Faculty of Mathematics and Natural Sciences, University of Groningen, Nijenborgh 4, 9747 AG Groningen (The
Netherlands)
KEYWORDS. chirality transfer · molecular switches · photoisomerization · atropisomers · photoresponsive catalyst ·
dynamic selectivity control
ABSTRACT: Recent advances in molecular design have displayed striking examples of dynamic chirality transfer between
various elements of chirality, e.g. from central to either helical or axial chirality and vice versa. While considerable
progress in atroposelective synthesis has been made, it is intriguing
UV-light
to design chiral molecular switches able to provide selective and
dynamic control of axial chirality with an external stimulus to
modulate stereochemical functions. Here, we report the synthesis
HO
HO
OH
OH
1 = 365 nm
2 = 420 nm
and characterization of
a
photoresponsive bis(2-phenol)-
substituted molecular switch 1. The unique design exhibits a
dynamic hybrid central-helical-axial transfer of chirality. The
change of preferential axial chirality in the biaryl motif is coupled
to the reversible switching of helicity of the overcrowded alkene
core, dictated by the fixed stereogenic center. The potential for
dynamic control of axial chirality was demonstrated by using (R)-1
as switchable catalyst to direct the stereochemical outcome of the
catalytic enantioselective addition of diethylzinc to aromatic
1
1
(R,M,Ra)-
(R,P,Sa)-
Stable state (S)
Metastable state (MS)
P
M
h
coupled inversion
of helical and
axial chiraliy
HO
HO
OH
Sa
Ra
OH
aldehydes, with successful reversal of enantioselectivity for several substrates.
INTRODUCTION
motifs that feature axial chirality,12,13 helical chirality,14 and
planar chirality15,16 have been extensively investigated for
their potential use in synthesis, in asymmetric catalysis
and as chiral dopants. Compared with molecules that
feature fixed central chirality (i.e. point chirality), axially
chiral compounds may not comprise stereogenic center(s)
yet exist as enantiomers.17,18 Atropisomers belong to the
class of axially chiral compounds: in this case the
enantiomers exist due to the restricted rotation around a
single bond. The phenomenon of equilibration of
Chirality plays a fundamental role in a myriad of
biological processes, including information storage and
transmission, gene expression, energy production and
cellular motion.1–4 For instance, life has developed on
Earth by optimizing its biological functions using L-
amino acids as polypeptide building blocks and D-glucose
as chemical energy source. The chirality of D-deoxyribose
is amplified to the (almost) exclusively right handed
helices of DNA.5 The supreme control of directional
movement showcased by biological machine structures
like ATP synthase,6 proteasomes,7 ribosomes,8 myosin,9
kinesin10 and bacterial flagella11 are astonishing
demonstrations of how transfer of chiral information
leads to accurate control of metabolic functions and
motion in cells. None of these processes could take place
without precise propagation, amplification and coupling
of movement, from the very bottom scale of single
molecular chiral entities to the fine interplay of large
stereoisomers
about
a
rotational
axis
-
atropisomerization19 - has become a main topic of
investigation in organic,20 materials,21 and medicinal
chemistry.22 Despite a number of responsive molecular
devices based on reversible cis-trans isomerization of
double bonds,23–25 cyclizations,26 redox cycles27 and
rotation around single bonds,21,28 only scattered examples
of stimuli responsive systems featuring elements of axial
chirality have been reported.25,29–31 Focused efforts have
produced elegant systems displaying unidirectional aryl-
aryl bond rotation of biaryl structures via sequential
protein
stereochemistry mainly focused on point chirality, other
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sub-units.
While
early
research
on

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addition of chemical stimuli, overcoming the E-Z isomerization (PEZI) and thermal helix inversion
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atropisomerization energy barrier inherently featured by
the open structures via more flexible macrocyclic or
(THI) of the central alkene bond allows unidirectional
rotary motion controlled by a light- and heat-driven four-
stage cycle (Scheme 1). The combinations of an upper half
containing a six-membered ring and a lower half featuring
a five membered ring, are characterized by a high
activation energy for the thermal relaxation process and
have been recently reported as a new class of bi-stable
photoswitches.46–48 Due to the long half-life at room
temperature, i.e. high thermal stability, of their photo-
generated metastable isomers,47 they allow for the design
of systems capable of displaying dual stereocontrol while
retaining the desired configuration for extended time
intervals at elevated temperatures. This property,
combined with their unique dynamic helical chirality, is
highly desirable in the field of switchable asymmetric
catalysis.
tricyclic
intermediates.21,28,32–35
Solvent-dependent
atropisomerism of a flexible 2,2’-biphenol core bridged
tricyclic structure was reported by Reichert and Breit.36
However, a catalytic application in which the biphenol
acts as a responsive ligand was not shown. Therefore, the
major challenge remains to design chiral based molecular
switches able to selectively and dynamically generate and
harness biaryl axial chirality with an external stimulus.
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Combining dynamic chirality, chirality transfer, and
photoswitches, our group has previously achieved control
of activity and stereoselectivity by switchable catalysts29,37–
39
based on first generation molecular motors.40–44 These
responsive catalysts harness the intra- and intermolecular
transfer of chirality to ultimately control the
stereochemical outcome of a catalytic transformation via
photochemical E-Z isomerization and thermal helix
inversions of a functionalized unidirectional four-stage
rotary motor based on an overcrowded alkene core. By
combining the fixed point chirality originating from the
stereocenters in first generation molecular motors with
the dynamic alkene configuration and helical chirality,
the enantiomeric excess and configuration of the chiral
product can be reversibly controlled. However, out of the
four possible diastereoisomeric forms only the two
pseudoenantiomeric cisoid isomers exert significant
asymmetric induction via internal cooperative catalysis
while an exclusive light-driven switchable catalyst based
on these chiral motor remains elusive.
Scheme 1. Isomerization processes leading to
unidirectional rotation in second generation
molecular motor.
PEZI
rotor
h1
axle
h2
R
R'
R
R'
stator
S-(R)-(P)
THI
MS-(R)-(M)
THI


We anticipated that the development of new bis(2-
phenol)-functionalized switchable catalysts which
harness the pairing of hybrid helical-axial chiralities
within chiroptical switchable units could provide
unprecedented levels of dual stereoselectivity with non-
invasive control and high spatio-temporal resolution.
Here we report the photochemical control of axial biaryl
chirality in a light-responsive BINOL-type catalyst based
on a chiral molecular switch, which displays dual
stereocontrol in an asymmetric addition of organozinc
reagents to aromatic aldehydes. The bis(2-phenol) unit
operates as a chiral flexible bifunctional catalytic unit, the
conformation of which is dictated by the dynamic
stereochemistry of the central photoswitchable scaffold
via internal dynamic transfer of chirality. Moreover, the
catalyst described here benefits from a highly thermally
stable switch core unit which can be reversibly
PEZI
h1
R
R'
R
R'
h2
MS-(R)-(M)
S-(R)-(P)
Four-stage cycle with only two distinct stereoisomers in case
of symmetrically substituted lower half (here R = R’).
S = stable isomer, MS = metastable isomer.
We envisioned that merging a flexible 2,2’-biphenol
core with the rotor of a rigid second generation
overcrowded alkene scaffold would result in transfer of
chirality from the helical core of the overcrowded alkene
to the biphenyl unit by steric interactions (Scheme 2). We
expected the lower phenol group to remain parallel to the
fluorene half, as a consequence of the system’s tendency
to reduce steric hindrance between these two moieties. In
this way the distinctive dynamic helicity of the switch
unit and the conformational versatility of the substituted
biaryl motif are combined. The system described herein
features three stereochemical elements (Scheme 2). The
first element is the stereogenic center of the switch
(highlighted in red), which can exist with either the R or S
configuration. The second element is the helicity of the
overcrowded alkene (highlighted in blue), which is
photoisomerized
exclusively
between
two
pseudoenantiomeric forms.
RESULTS AND DISCUSSION
Design. Molecular motors of the second generation
are helical-shaped overcrowded alkenes consisting of a
symmetric tricyclic lower half and an asymmetric upper
half that features a single stereocenter (Scheme 1).45–47
Utilizing the hybrid chirality generated by the stereogenic
center and the helical structure during the photochemical
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controlled by the configuration at the stereogenic center
but can be inverted upon photoisomerization.
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Scheme 2. Design of photoswitchable 2,2’-biphenol- this work. So for isomer (R,P=,Pa,Sa)-1: R = configuration of
1
2
3
4
5
6
7
8
substituted overcrowded alkene 1.
stereogenic center, P= = helicity of alkene, Pa = helicity of
biaryl, Sa = axial chirality of biaryl (Figure 1a).
a)
Top-down schematic view
Front structural view
Flexible and
HO
Rigid chiral
photoresponsive
core
versatile
+
Ar
HO
2,2'-biphenol core
P=
Sa
Pa
R
HO
HO
=
HO
HO
biphenol axial
chirality: Sa
biphenol axial
chirality: Ra
9
Example: (R,P=,Pa,Sa)-1
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b)
h1
P=
OH
Sa
HO
OH
OH
Pa
R
R
+135°
HO
Sa
HO
+45°
h2
HO
HO
Ma
(R,P=,Pa,Sa)-1
(R,P=,Ma,Sa)-1
B
Photochemical
E-Z Isomerization
A
cw
1
1
(R,P,Sa)-
(R,M,Ra)-
rotation
of lower
phenol
Stable state (S)
Metastable state (MS)
The assigned descriptors are based on the structure of
compound (R)-1 (for explanation of the chiral descriptors,
vide infra). Axial helicity and chirality (green) of the 2,2’-
biphenol core are coupled to axial helicity (blue) and point
chirality (red) of the molecular switch scaffold. Two
diastereomers with opposite coupled helicity can be
selectively addressed by irradiation with UV-light: (R,P,Sa)-1
(S); (R,M,Ra)-1 (MS).
Ra
Ma
R
R
OH
Pa
Ra
-135°
-45°
HO
HO
OH
(R,P=,Ma,Ra)-1
(R,P=,Pa,Ra)-1
D
C
c)
O
More precisely, the more stable diastereoisomer (stable
isomer, S) of the R enantiomer will adopt a P helicity,
while the photo-generated diastereoisomer with higher
energy (metastable isomer, MS) will adopt an M helicity.
The axial chirality of the biaryl unit (highlighted in green)
is the third stereochemical element which can be assigned
either Ra or Sa according to the CIP rules.49,50 For
biphenyls with an average dihedral angle of 90°, such as
ortho substituted biphenyls, these stereochemistry
descriptors are interchangeably used with M and P,
respectively. Depending on the size of the groups and
substitution pattern at the ortho positions, the dihedral
angle can be smaller than 90°. Each rotamer with either
Ra or Sa absolute configuration possesses two
conformational helical geometries, also assigned as right-
handed (P) or left-handed (M) according to the CIP
rules.18
H
O
H
O
H
O
H
O
H
O
H
Sa
Ra
d)
Recently our group reported a study on the tidal locking
of an aryl moiety in a molecular motor, showing that
among the four theoretically possible conformations of a
biaryl unit, only conformations in which the non-
annulated aryl group was parallel to the fluorenyl lower
half were adopted.51 The other conformations with the
aryl orientated perpendicular with respect to the lower
half are expected to induce significant steric strain. With
such a diastereotopic constraint, the true helicity (Pa/Ma)
of the biaryl is inextricably connected to the helicity
(P=/M=) of the overcrowded alkene chromophore, and is
identical to it in each isomer (Figure 1b). Therefore, three
stereodescriptors (R/S, P/M and Ra/Sa) will be sufficient
for the assignment of any expected isomer reported in
Figure 1. a) Example of top-down schematic view and front
structural view of (R,P=,Pa,Sa)-1. Upper half ring (red, methyl
substituent omitted); fluorenyl lower half (blue); biaryl
moiety (black). Assigned stereodescriptors based on the
structure of compound (R)-1 (see main text for details). b)
Depiction of four conformations of the biaryl moiety as
viewed from the top along the central double bond and
biaryl single bond. c) Hydrogen-bonding assisted biaryl
rotation of 2,2’-biphenol with inversion of stereochemistry.
d) Schematic energy vs. biaryl torsional angle profile upon
clockwise rotation of lower phenol group around the biaryl
single bond in (R)-1.
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The asterisks at the stereodescriptors throughout the text the central overcrowded alkene in a syn conformation
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2
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4
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7
8
denote a racemic mixture of isomers with identical
relative stereochemistry (e.g. R*,P*,Sa* means a mixture of
R,P,Sa and S,M,Ra). The doubly expressed axial
stereodescriptor (Ra/Sa) throughout the text denotes a
with the upper phenol group.
In summary, our design is based on the following
elements: a) the selective and reversible photo-
isomerization of the overcrowded alkene scaffold between
only two states; b) the unique change in helicity of the
chiroptical switch governed by the fixed configuration of
the stereogenic center; c) the coupled change in axial
chirality of the biaryl core achieved via a central-to-
helical-to-axial transfer of chirality; d) the introduction of
the switchable chiral biphenol functionality with the
mixture
of
rotamers
with
identical
absolute
stereochemistry at the stereocenter and configurational
helicity but opposite axial chirality (e.g. R,P,Sa/Ra means a
mixture of atropisomers R,P,Sa and R,P,Ra). The inversion
of axial chirality in 2,2’-biphenols is likely to take place via
a coplanar transition state along the syn-periplanar
conformation of the phenol rings taking advantage of the
intramolecular hydrogen bonds between the hydroxyl
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potential
of
various
applications
in
catalytic
enantioselective transformations.
groups (Δ‡G° = 48.1 kJ mol-1 T = 298.15 K; Figure 1c), based
,
on a DFT study by Fujimura and co-workers.52 These
calculations support the proposal of reversible axial
chirality when applied to our system, as we expected the
syn- and anti-conformers (hydroxyl groups in proximity
or pointing away from each other, respectively) to be in
equilibrium in solution in the absence of metals or other
coordinating species. Recently our group has shown how
Scheme 3. Schematic representation of switching
process between the rotamers of stable and
metastable isomers of (R)-1.
Conformers of
Stable state (S)
Conformers of
Metastable state (MS)
h1
h2
the behavior of
molecular motor can be controlled via reversible covalent
and non-covalent schematic
modifications.53
a
related biphenol-functionalized
OH
OH
anti
syn
HO
A
OH
1
(R,P,Ra)-
1
(R,M,Ra)-
representation of four possible conformations of 1 upon
rotation of the aryl-aryl bond is presented in Figure 1b.
We expect conformations with matching helicities of
biaryl and overcrowded alkene units to be highly favored
(A and C), while the two conformers with the aryl
perpendicular to the lower half to experience steric
hindrance (B and D), as shown in the relative energy vs.
torsional angle profile plot (see Figure 1d) based on DFT
calculations (vide infra). Scheme 3 illustrates the delicate
interplay of dynamic stereochemical elements and the
switching process between the stable and metastable
isomers of (R)-1. The rotamers of the stable state (R,P,Ra)-
Atropisomerization
processes of Stable (left)
and Metastable states (right)
HO
hydrogen
bonding
OH
hydrogen
bonding
OH
OH
h1
h2
HO
HO
syn
HO
anti
OH
1
(R,P,Sa)-
1
(R,M,Sa)-
Proposed ground states of rotamers and transition states
(middle) of atropisomerization processes, as viewed from the
top along the axis given by the double bond. Top and bottom
left: rotamers of stable isomer (R,P,Sa/Ra)-1; top and bottom
right: metastable isomer (R,M,Ra/Sa)-1.
1
and (R,P,Sa)-1 interchange via atropisomerization
(Scheme 3, left equilibrium) presumably facilitated by
internal hydrogen bonding between the two phenolic
moieties.52 We envisioned that upon irradiation with UV-
light of a mixture of (R,P,Ra)-1 and (R,P,Sa)-1 brings about
isomerization into the corresponding conformers of the
metastable state (R,M,Ra)-1 and (R,M,Sa)-1 isomers,
respectively, during which the upper half containing the
biaryl motif rotates with respect to the fluorenyl lower
half yielding isomers with opposite helicity (P→M).
Notably, the metastable isomer was also expected to
display atropisomerization (Scheme 3, right equilibrium).
We undertook a theoretical study a priori to verify the
design as shown in Figure 1, with particular attention to
the barrier for biaryl rotation and the relative energy of
the four accessible conformers upon reversible
irradiation. The structures of the four ground states were
computed via DFT method calculations (see
Supplementary material for details), which suggested an
energetic preference in both biaryl rotation equilibria for
the conformers (R,P,Sa)-1 and (R,M,Ra)-1, respectively
(Scheme 3). These conformers are characterized by
having the lower hydroxyl substituent pointing away from
Synthesis. Key steps in the synthesis of 1 are the
Barton-Kellogg coupling of thioketone 7 and diazo-
derivative 6, followed by deprotection of the biphenol
moiety and chiral resolution of the target molecule 1 as
illustrated in Scheme 4. Commercially available 7-
methoxy-1-tetralone
was
brominated
with
N-
bromosuccinimide in acetonitrile to yield 2 (93%)54,
followed by Suzuki-Miyaura cross-coupling catalyzed by
Pd2dba3 and SPhos to provide the dimethoxy-biaryl motif
in ketone 3 (94%). α-Methylation provided ketone 4
(86%), which was converted to the corresponding
hydrazone 5 (75%) via condensation with hydrazine
monohydrate using Sc(OTf)3 as a catalyst. The diazo
coupling partner 6 was accessed via in situ oxidation with
[bis(trifluoroacetoxy)iodo]-benzene at low temperature.
Fluorene-9-thione 7, freshly synthesized by thionation of
9-fluorenone with Lawesson's reagent, was subsequently
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added to yield a variable mixture of episulfide 8 and
Page 6 of 17
1
2
3
overcrowded alkene 9.
Scheme 4. Synthesis and chiral resolution of 2,2'-biphenol molecular switch 1.
4
5
6
7
8
9
OMe
Pd2(dba)3 (1.5 mol%)
SPhos (6 mol%)
i-Pr2NH (1.3 equiv)
n-BuLi (1.25 equiv)
NBS
(1.35 equiv)
B(OH)2
K3PO4 (3 equiv)
MeI (1.5 equiv)
(2 equiv)
O
O
O
O
O
toluene
reflux, 16 h
94%
O
O
O
THF
-78 oC to rt, 1 h
86%
CH3CN
rt, 24 h
93%
O
Br
O
3
4
2
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S
Sc(Otf)3
(2.5 mol%)
(2.5 equiv)
PhI(OTf)2
(1.15 equiv)
N2H4 . H2O
O
O
7
O
+
O
O
O
O
S
N
DMF, DCM
- 60 oC to r.t, 16 h
O
N2
EtOH
reflux, 3 d
75%
DMF
- 60 oC, 3 min
NH2
5
6
8
9
i) MeMgI (5 equiv)
(3M in Et2O)
80 oC, 1 h
1
N+
Cl-
HO
HO
HO
P(NMe2)3 (2.2 equiv)
O
O
HO
HO
(R)-isomer
reported
toluene (press. tube)
140 oC, 72 h
ii) neat
165 oC, 5 h
84%
N
10 (0.5 equiv)
EtOAc
rt, 16h
85% over 3 steps
i) Solid: (S,M,Ra/Sa)-1, 40%, 94% ee
Solution: (R,P,Sa/Ra)-1, 60%, 54% ee
9
(R*,P*,Sa/Ra)-1
ii) Solid: (S,M,Ra/Sa)-1, 79%, >99% ee
Solution: (R,P,Sa/Ra)-1, 15%, 96% ee
Note on resolution of 1: i) result from first resolution; ii) (S,M,Ra/Sa)-1 obtained by second resolution of the solid fraction:
(8S,9R)-(−)-N-benzylcinchonidinium chloride 10 (0.9 equiv), 79% yield, >99% ee (solid); (R,P,Sa/Ra)-1 obtained by second
resolution of the residue from solution: 10 (0.3 equiv), 81% ee (residue from solution), followed by recrystallization from
EtOH/H2O = 1:1 of the residue from solution, 15% yield, 96% ee.
After separation, the remaining episulfide was
desulfurized by treatment with HMPT at elevated
temperature to provide 9 (85%, for the 3-step sequence).
The use of boron tribromide, widely applied for the
deprotection of methoxy-substituents, resulted in partial
decomposition of the overcrowded alkene and in an
inseparable mixture of target compound and side-
products. Successful deprotection was accomplished
using methyl magnesium iodide at 165 °C55 to afford
racemic (R*,P*,Sa/Ra)-1 (86%) as a mixture of two
atropisomers in their thermodynamic equilibrium ratio of
conformation of the lower aryl substituent to be parallel
to the fluorenyl lower half of the switch core (synclinal) in
the crystal lattice. The dihedral angle over the biaryl motif
determined from the X-ray structure in the solid state was
found to be +55.7° (+52.7° by calculation, vide infra).
1
60:40 (in CDCl3) according to H NMR analysis. Optical
resolution of 1 was accomplished by two-step resolution
with (8S,9R)-(−)-N-benzylcinchonidinium chloride (10) in
ethyl acetate.55 Both enantiomeric mixtures of conformers
were obtained in high optical purity: (R,P,Sa/Ra)-1 (96%
ee, 15%); (S,M,Ra/Sa)-1 (>99% ee, 31%). The structure of 1
was unequivocally proven by NMR spectroscopy (vide
infra), HRMS, as well as by single-crystal X-ray structure
analysis. By means of a high-brilliance Cu IμS microfocus
source (Cu Kα radiation wavelength = 1.54178 Å), the
absolute configuration of enantiomerically pure (R)-1 was
determined despite the absence of atoms that show
significant anomalous scattering.56–58 The reconstructed
unit cell of the lattice was shown to contain only the syn-
conformer (R,P,Sa)-1 (see Figure 2). The experimental data
confirmed the proposed model of coupled helical-to-axial
transfer of helicity, demonstrating the most favored
Figure 2. a) X-Ray structure of (R,P,Sa)-1. Left: front view;
right: top view. Ellipsoids set at 50% probability. Hydrogen
bond lengths (intra: H101–O1 1.874 Å, inter: H100–O1’ 1.826 Å)
and Oxygen-Oxygen distances (intra: O1–O2 2.629 Å, inter:
O1–O2’ 2.685 Å). b) Newman projections. Left: top view
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through overcrowded alkene bond. Right: top view through
aryl-aryl bond of biaryl unit. Torsional angles of alkene unit
(13.92°) and biaryl unit (55.71°) are shown
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atropisomers revealed a ratio of A:B = 67:33 [methyl
1
protons: δ 1.34 ppm (A), 1.22 ppm (B); proton H1 at the
stereogenic center: δ 3.95 ppm (A), 3.86 ppm (B); proton
H2 of fluorenyl substituent: δ 7.78 ppm (A), 7.70 ppm
(B)]. Based on calculated 1H NMR spectra (see Table S3-S4
and Figure S30 in Supporting material), we assigned the
experimental sets of absorptions A and B to the
atropisomers (R,P,Sa)-1 and (R,P,Ra)-1, respectively (Figure
3a, see Supporting material for atropisomer assignment
study). Similar behavior with minor variation in the ratio
was observed in other deuterated solvents (see
Supporting material for details). Based on our design, we
assumed the syn and anti atropisomers to equilibrate via
biaryl rotation (Scheme 3). Initial attempts to determine
the rate of the atropisomerization process via dynamic
NMR focused on the coalescence of the aforementioned
diagnostic absorption peaks in the aromatic region (see
Figure 3b).59–61 1H NMR spectra (400 MHz) of a sample of
stable isomer (R,P,Sa/Ra)-1 in toluene-d8, were recorded at
temperatures ranging from 50 to 100 °C.62 No coalescence
of the aforementioned diagnostic absorption peaks was
observed, suggesting the activation barrier for the biaryl
rotation process to be higher than typical exchange
processes usually determined via Dynamic NMR (see
Supporting material for details).63 Dynamic HPLC
(DHPLC) analysis was also considered, as it was
previously reported to allow for the successful
determination of rotational barriers for other substituted
biphenyl atropisomers.64–67 Despite the screening of
temperatures down to 0 °C, no splitting of the elution
peaks was observed, indicative of a relatively fast
equilibration process even at lower temperatures. The
rotational process was eventually demonstrated and
studied by one dimensional exchange spectroscopy
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Figure 3. a) Schematic representation of the photochemical
E-Z isomerization of stable atropisomers (R,P,Sa/Ra)-1 to
metastable atropisomers (R,M,Ra/Sa)-1. H NMR spectra of
(R)-1 (~5.0 mg, toluene-d8 (0.7 mL), 25 °C): b) stable state
(R,P,Sa/Ra)-1 (A:B = 67:33); c) after irradiation with UV light
(365 nm) of (R)-1 to the metastable state (R,M,Ra/Sa)-1 (~65%
of MS); d) metastable state (R,M,Ra/Sa)-1 (C:D = 58:42)
isolated by preparative HPLC from the irradiated mixture
(see Supplementary material for details).
1
1
(EXSY, H-1H nuclear Overhauser enhancement spectra).
The measurements were conducted in the temperature
range of 39.2–60.9 °C, consisting of an arrayed cluster of
multiple mixing times per temperature (see Supporting
material for details). Exponential curve fitting of the EXSY
traces provided the exchange constant (k) and associated
standard error (σk) for each temperature. Eyring analysis
of rate versus temperature afforded the Gibbs free energy
of activation for the isomerization of the major into the
minor atropisomer (∆‡ GBI at rt = 78.2±1.1 kJ mol−1). The
equilibration time at room temperature (20 °C) is
The angles found by calculation agree with those found
by X-Ray, and the small deviation between the two can be
explained by a packing effect in the crystal structure
which is expected to bring about small distortions with
respect to a free molecule in solution or gas phase.
extrapolated to be in order of minutes (t = 1.2±0.4 min),
½
Atropisomerization process. The chiral resolution
while the temperature at which t equals one hour is
½
1
and initial characterization of 1 by H NMR (Figure 3b)
calculated to be equal to -50.5 ± 0.5 °C. This analysis
explains why the isolation of atropisomers was not
successful, as well as the lack of coalescence in the
1H NMR spectrum even at higher temperatures and the
unresolved elution profile in the analytical HPLC
chromatograms. Notably, when the isolated metastable
isomer (R,M,Ra/Sa)-1 (via preparative HPLC, vide infra)
was subjected to the same EXSY experiments no exchange
was observed (measurement temperatures up to 60 °C).
This observation is in accordance with the larger elution
band of the metastable isomers fraction compared with
the elution band of the stable isomers observed in the
analytical HPLC analysis (see Supporting material for
disclosed a very interesting yet initially unexpected
phenomenon. Compound 1 was obtained from synthesis
as pure stable isomer and could be resolved in two
enantiomerically pure fractions, which by chiral HPLC
analysis appeared as single eluted fractions with sharp
symmetric peaks (see Supplementary material for details).
However, both racemic and enantiopure fractions
comprised two inseparable species, as displayed by
1H NMR spectroscopy analysis. We observed two sets of
absorptions in the 1H NMR spectra recorded with a
solution of stable (R)-1 in toluene-d8 (Figure 3b): the
relative integration of the best resolved peaks of the
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details), which suggests a lower atropisomerization rate
hence a slightly higher activation barrier for the biaryl
1
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Photochemical isomerization. The switching
properties of (R)-1 were monitored by UV-vis absorption
and circular dichroism (CD) spectroscopy (Figure 4). A
schematic representation of the reversible photochemical
E-Z isomerization process of (R)-1 is shown in Figure 4a. A
solution of stable (R,P,Sa/Ra)-1 (toluene, 4.5 10−5 M) in
quartz cuvettes was purged with argon and irradiated at
room temperature towards either the metastable isomer
using UV light (365 nm, Figure 4b, black to red gradient)
or the stable isomer using visible light (420 nm, Figure 4c,
red to blue gradient). The reversible photochemical E-Z
isomerization was found to be characterized by a clear
isosbestic point at 368 nm, indicating the absence of side
reactions. A bathochromic shift of the major absorption
band (π→ π*) of about 40 nm was observed, indicative of
an increase in alkene strain and consistent with other
second generation motors and switches as is expected for
the metastable form (R,M,Ra/Sa)-1.48 The sample was
subsequently subjected to irradiation cycles (see Figure S6
in Supporting material), displaying non-perfect switching
fatigue resistance with minor decomposition, as opposed
to the highly resistant unfunctionalized parent
compounds recently studied.48 However, upon addition of
the radical scavenger TEMPO (10−5 M) to a solution of
(R)-1 (toluene, 4.0·10−5 M), we observed no evidence of
degradation after six irradiation cycles (Figure 4d). This
observation suggests that radicals may be involved in the
decomposition process.68 Lastly, a solution of stable
(R,P,Sa/Ra)-1 (toluene, 4.5 10−5 M) was subjected to CD
spectroscopy in order to perform a qualitative analysis of
the change in its helical structure (Figure 4e). The CD
spectrum displayed a strong Cotton effect in the area of
320-370 nm. Upon irradiation with 365 nm light an
inversion of the absorption band was observed, which is
indicative of an inversion in helicity and shows that the
photochemical isomerization of the stable isomers
(R,P,Sa/Ra)-1 to the metastable isomers (R,M,Ra/Sa)-1 has
occurred. Upon irradiation with 420 nm light, the original
absorption band could be partially recovered. Chiral
HPLC analysis confirmed the presence of the metastable
species and allowed determining the S:MS ratio at the PSS
of the irradiated mixtures upon selection of detector
wavelength at the isosbestic point (368 nm, see
Supplementary material for details). An efficient
photoswitching process was observed upon irradiation
with 365 nm light, with a high ratio towards the
rotation process in the metastable isomers. As observed in
the X-ray structure analysis and based on the model
investigated by Fujimura and co-workers51, we propose a
thermodynamically favored cyclic seven-membered ring
conformation generated upon internal coordination via
hydrogen bonding of the two hydroxyl substituents (see
Scheme 3). Experimental evidence and calculation data
suggest that such a conformation provides access to a
9
transition state with
a relatively low barrier for
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atropisomerization, allowing for a fast exchange of two
conformers in solution at room temperature. In these two
‡
calculated transition states (TSBI-(R,P,Syn)-1
and TSBI-
‡
(R,M,Syn)-1 , see Figure S25 in Supplementary material)
the hydrogen bond between the two phenol moieties is
shorter than it is in any other conformation suggesting
additional stabilization of the transition state with respect
to its corresponding minima explaining the relatively low
barrier for atropisomerization. Moreover, the barrier for
biaryl rotation is sufficiently low to allow the desired syn
atropisomer to act as a thermodynamic sink upon its
depletion in a reaction selective for it, for instance by
bidentate coordination of the biphenol to a metal center
(vide infra, Scheme 5a). Such a complexation would
require a syn conformation of the biaryl motif and
concordant alkene and biaryl helicity, due to the system’s
tendency to reduce steric hindrance between the lower
phenol moiety and the fluorenyl lower half (Figure 1; vide
infra, Scheme 5b).
NMR spectroscopy. In order to investigate the
photochemical behavior of 1 in more detail, an NMR
sample of stable isomer (R,P,Sa/Ra)-1 in toluene-d8 was
irradiated with UV light (365 nm) for 30 min at room
1
temperature. H NMR spectra were taken before (Figure
3b) and after exposure (Figure 3c). Upon irradiation two
new sets of absorptions, C and D, with intensities
increasing over time were obtained [methyl protons: δ
1.22 ppm (C+D, peaks not resolved); proton H1 at the
stereogenic center: δ 3.75 ppm (C), 3.35 ppm (D); proton
H2 of fluorenyl substituent: δ 7.61 ppm (C), 7.47 ppm
(D)]. This is indicative of the photo-induced
isomerization to the metastable isomer (R,M,Ra/Sa)-1
comprising of two distinct atropisomeric species,
(R,M,Ra)-1 (C) and (R,M,Sa)-1 (D), respectively. The
relative integration revealed a final ratio in toluene-d8 of
(R,P,Sa/Ra)-1 (A+B) : (R,M,Ra/Sa)-1 (C+D) = 35:65, upon
irradiation over 30 min. It should be specified that the
PSS was not reached in order to avoid degradation upon
prolonged exposure. Due to the high thermal stability of
the metastable isomers [(R,M,Ra/Sa)-1], their isolation
from a crude mixture of an irradiated solution of (R)-1
was achieved by preparative HPLC (see Supplementary
metastable diastereoisomer (S:MS = 17:83) at the PSS365
.
However, the reverse process achieved upon irradiation at
420 nm light was found to be less selective, affording an
equimolar mixture of stable and metastable isomers
(S:MS = 50:50) at the PSS420
.
Switchable asymmetric catalysis. Having established
the reversible switching process between (R,P,Sa/Ra)-1 and
(R,M,Ra/Sa)-1, we investigated their abilities for dual
stereocontrol in a model asymmetric catalysis reaction.37
1
material for details). Analysis by H NMR revealed the
metastable isomer to comprise a mixture of atropisomers
(R,M,Ra)-1 (C) and (R,M,Sa)-1 (D) in a ratio of C:D = 58:42
(Figure 3d).
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Figure 4. a) Schematic representation of photochemical E-Z isomerization of stable isomer (R,P,Sa/Ra)-1 to metastable isomer
(R,M,Ra/Sa)-1. b) Experimental UV-vis absorption spectra of stable (R,P,Sa/Ra)-1 (toluene, 4.5·10−5 M, black) and upon irradiation
with UV-light (365 nm) of (R,P,Sa/Ra)-1 towards the metastable isomer affording a PSS365 mixture (S/MS = 17:83, red) with an
isosbestic point at 368 nm. c) Experimental UV-vis absorption spectra after irradiation of the PSS365 sample using visible light
(420 nm), resulting in reversed E-Z isomerization towards the stable isomer affording a new PSS420 mixture (S/MS = 50:50). d)
Irradiation cycles of (R)-1 (toluene, ~4.0·10−5 M) in the presence of TEMPO (~10−5 M) towards opposite PSS mixtures (red: 365
nm, 4 min; blue: 420 nm, 15 min). e) Experimental and calculated CD spectra of (R)-1 (toluene, 5.0·10−1 M): black, starting stable
isomer (R,P,Sa/Ra)-1; red: CD spectra of PSS365 mixture; blue: CD spectra of PSS420 mixture; cyan: metastable isomer (R,M,Ra/Sa)-1.
Note: PSS ratios determined by HPLC analysis of the irradiated solutions via quantitative analysis with PDA detector wavelength
set at the isosbestic point (368 nm).
As a proof of principle, we envisioned to use compound
(R)-1 as a switchable bidentate ligand, which could
coordinate a metal center and eventually be applied to an
switchable bidentate ligand in 1,2-additions of diethylzinc
to benzaldehydes. Numerous efforts have been devoted in
the past decades to develop new effective chiral ligands
for asymmetric addition of diethylzinc to benzaldehyde.73–
asymmetric transformation acting as
a
tunable
77
stereoselective catalyst (vide infra, Scheme 5). We
anticipated the isomers of 1 having an anti conformation
of the biphenol unit (torsion angle = ±90°–180°; hydroxyl
groups pointing away from each other) to be poor
bidentate ligands. Therefore only the isomers with syn
conformation (torsion angle = 0°–±90°; hydroxyl groups
in proximity) were expected to efficiently bind metal ions
in a bidentate fashions common to binaphthols (BINOL’s)
However, only few cases have been reported in which
dual stereocontrol was achieved by tuning the reaction
conditions. The switching of enantioselectivity in the
catalytic addition of diethylzinc to aldehydes was
obtained by changes in the reaction conditions (e.g.
solvent, temperature) while using the same chiral
additive.78–81 Alternatively, complementary catalytic
systems were developed by the use of distinct structural
derivatives from a common chiral catalyst scaffold to
access both enantiomers of the desired products.82–85 In
the representative reaction (see scheme in Table 1),
benzaldehyde 11a was added to a mixture of ligand (R)-1
and a solution of diethylzinc in toluene, yielding
secondary alcohol 12a and in an amount of the side-
product benzyl alcohol 13a. The latter is the product of
the aldehyde reduction, a known process occurring in the
case of a slow addition process and proposed to derive
from the β-hydride elimination of organozinc species and
subsequent reduction of the substrate in case of poorly
activated zinc complexes.86,87 As we anticipated, photo-
and successfully transfer the chirality within
a
catalytically active complex (Scheme 5a,b). Hence we
proposed that the tunable helicity (P or M) of the switch
core in turn would dictate the preferential axial
configuration (Ra or Sa) of the desirable syn conformation
of the biaryl moiety and eventually, for instance, the
configuration (R or S) of a newly formed stereogenic
center when applied to an enantioselective catalytic event
(Scheme 5c). Zn-BINOL-derived complexes have
previously been reported to successfully mediate the
catalytic asymmetric aldol69–71 and hetero-Diels-Alder72
reactions. We decided to use compound (R)-1 as a
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induced switching of ligand (R)-1 allowed successful
reversal of stereoselectivity in the 1,2-addition of
diethylzinc to benzaldehyde.
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Scheme 5. Schematic representation of mono- and aromatic aldehydes bearing electron-withdrawing or
1
2
3
4
5
6
7
8
bidentate coordination equilibrium upon reaction of
(R)-1 with organozinc reagents.
electron-donating groups were tested as substrates. In all
cases, when the stable form (R,P,Sa/Ra)-1 was used as a
catalyst, the preferred formation of the (R)-enantiomer of
secondary alcohols 12 was observed (Table 1, odd-number
entries), with ee’s up to 68% (entry 1).88 In sharp contrast,
upon use of the irradiated mixture of catalyst (R,P,Sa/Ra)-1
(365 nm light, PSS ratio S:MS = 17:83), the addition
proceeded with reversed enantioselectivity under the
same reaction conditions. Preferred formation of the (S)-
enantiomer of secondary alcohols 12 was also observed in
all cases after irradiation (even-number entries), with ee’s
up to 55% (entry 8). The difference in enantioselectivity
(∆ee) between non-irradiated and irradiated catalyst
solution was up to 113% (from 68% (R) to 45% (S),
comparison of entries 1-2). Notably, use of diisopropylzinc
led to no enantioselectivity in either case (entries 13-14).75
A control experiment was conducted by performing the
addition of diethylzinc in absence of (R)-1 , which
resulted in a marked decrease in conversion, as well as
lower addition vs. reduction selectivity and isolated yield
of 12a (entry 15).89 Addition of tetrabutylammonium
bromide did not improve the catalytic activity, as
otherwise observed in previously reported systems.90 It
should be emphasized that no decomposition,
racemization or significant thermal relaxation of the
recovered catalyst (90% average catalyst recovery) was
a)
biaryl
rotation
HO
HO
HO
-
OH
1
1
(R,P,Ra)-
(R,P,Sa)-
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ZnR2
2 ZnR2
ZnR2
O
O
O
RZn
Zn
O- ZnR
-ZnR2
1
1
Zn2R2-(R,P,Ra)-
Zn-(R,P,Sa)-
biaryl syn conformation allows
bidentate coordination of Zinc
yielding effective catalyst
biaryl anti conformation allows only
monodentate coordination of Zinc
yielding non-effective catalyst
b)
P=
P=
Pa
Pa
O
O
R
Sa
Ra
Zn
Zn R
Zn O
O
1
1
Zn-(R,P=,Pa,Sa)-
Sa-syn
Zn-(R,P=,Pa,Ra)-
Ra-anti
1
observed, as determined by H NMR and chiral HPLC
c)
analysis (see Supplementary material for details).
Moreover, in all cases the catalyst was recovered after an
experiment conducted using a non-irradiated catalyst
solution which was recycled to perform a subsequent
experiment with the same substrate after irradiation of
catalyst solution without notable loss of catalytic
performance (see Supplementary material for further
details). Point chirality of 1 governs the dynamic helical
chirality, which in turn is coupled to the axial chirality
resulting in a syn conformation in the catalytically active
ligand species. The inversion of enantioselectivity is an
indication of the reversed local chirality around the alkyl-
transferring zinc center and the coordinated aldehyde,
Stable isomer (S)
Metastable isomer (MS)
 = 365 nm
St:MS = 17:83
HO
HO
OH
OH
 = 420 nm
St:MS = 50:50
1
1
(R,P,Sa)-
(R,M,Ra)-
Zn2+
Zn2+
M
P
Dual stereocontrol via
reversible chirality transfer
in a catalyzed organometallic
transformation
O
O
Zn
Sa
Ra
Zn
O
O
achieved by using
a ligand with opposite chiral
a) Depiction of the possible mono-and bidentate
coordination species upon reaction of stable isomers of 1
with ZnR2. b) Only the isomers with a syn conformation
(torsion angle = 0°–±90°) were expected to efficiently bind a
metal center and successfully transfer the chirality within a
catalytically active complex. c) Light-assisted dual
induction.82–84 In this system we propose that upon
irradiation and subsequent inversion of the biaryl axial
chirality, the metastable isomer (R,M,Ra/Sa)-1 resembles
the enantiomer of the stable isomer (R,P,Sa/Ra)-1 (Scheme
5c). As the flexible biphenol unit is the chiral ligand for
zinc, tunable chiral induction can be achieved in the
proximity of the zinc- aldehyde substrate complex,
providing a novel approach for light-assisted dual
stereocontrol in catalysis.
stereocontrol could be achieved in
a
catalyzed
organometallic reaction upon photoisomerization of (R)-1
and internal transfer of chirality to the coordinated metal
site.
The results of the catalysis experiments are presented in
Table 1. 1H NMR analysis allowed determining the
conversion and selectivity of organozinc addition versus
aldehyde reduction to benzylic alcohol. The enantiomeric
excess (ee) of chiral secondary alcohols 12a-g was
determined by chiral HPLC or GC analysis. In addition to
benzaldehyde, several para- and ortho-substituted
CONCLUSIONS
The design, synthesis and resolution of
a
photoresponsive molecular switch featuring a versatile
2,2’-biphenol motif in which chirality is transferred across
three stereochemical elements is described.
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Table 1: Dynamic enantioselective addition of organozinc to aromatic aldehydes with (R)-1.
2
3
4
5
6
7
8
9
 = 365 nm
S:MS = 17:83
O
OH
*
OH
1
(R)- (10 mol%)
HO
HO
OH
OH
H
ZnR2
+
+
toluene
0 °C, 7 d
R
R
R
3 equiv
11
12
13
1
1
(R,P,Sa)-
(R,M,Ra)-
Stable isomer (S)
Metastable isomer (MS)
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Entrya
11
R
Catalyst
Conv. (%)b Yield of 12 (%)d ee of 12 (%)c
∆ee of 12 (%)c
12:13b
O
1
Et
Et
Et
(R)-1
>95
>95
94
86
87
80
68 (R)-12a
45 (S)-12a
35 (R)-12b
93:7
93:7
81:19
H
113
11a
2
3
(R)-1 + 365 nm
(R)-1
O
H
59
82
95
11b
Cl
4
Et
(R)-1 + 365 nm
>95
80
24 (S)-12b
81:19
O
5
6
7
Et
Et
Et
(R)-1
(R)-1 + 365 nm
(R)-1
94
>95
66
87
86
37
40 (R)-12c
42 (S)-12c
40 (R)-12d
89:11
88:12
62:38
H
11c
O
H
11d
O
8
Et
(R)-1 + 365 nm
>95
76
55 (S)-12d
97:3
O
9
10
11
Et
Et
(R)-1
(R)-1 + 365 nm
(R)-1
>95
>95
>95
>95
95
58
79
81
48 (R)-12e
50 (S)-12e
46 (R)-12f
31 (S)-12f
<5 (±)-12g
<5 (±)-12g
N.A.
63:37
85:15
89:11
83:17
41:59
58:42
80:20
H
98
77
11e
O
O
Et
H
11f
12
13
14
15
Et
(R)-1 + 365 nm
(R)-1
72
40
57
24
i-Pr
N.A
11a
i-Pr (R)-1 + 365 nm
Et
>95
59
/
a
General reaction conditions: 0.0125 mmol of (R,P,Sa/Ra)-1 in 0.5 mL of dry toluene at 0 °C; 0.375 mmol of R2Zn (Et2Zn,
1.0 M in hexane; i-Pr2Zn, 1.0 M in toluene) added dropwise and stirred over 10 min; 0.125 mmol of 11 added to the mixture.
Reaction mixture stirred for 7 d at 0 °C. Reaction with irradiated mixture of (R)-1: 0.00125 mmol of (R,P,Sa/Ra)-1 in 15 mL of
dry, degassed Et2O, irradiated with UV-light (365 nm) for 30 min until the PSS was reached (S:MS = 17:83). PSS ratio determined
b
1
c
by chiral HPLC analysis. Reaction procedure follows as described above. Determined by H NMR analysis of crude.
Determined by chiral GC or chiral HPLC analysis of isolated product. d Isolated yield. Abbreviations: N.A., Not Applicable.
The comparison of experimental and computational data
confirmed the proposed model of coupled central-to-
helical-to-axial transfer of chirality, demonstrating the
most favored conformation of the lower aryl substituent
of the biaryl unit to be parallel to the fluorenyl lower half
of the switch core. Compared with previously reported
molecular motor based systems, the reduction from four
to two isomerization stages featured by the biaryl-
functionalized design described herein provides a simple,
reusable and efficient dynamic responsive chiral core.
Extensive studies based on chiral HPLC analysis, 1H NMR,
UV-vis absorption and CD spectroscopy proved the
reversible photoswitching of 1, with no fatigue over
multiple cycles in presence of substoichiometric amount
of TEMPO. The chirality transfer was successfully applied
to creation of another stereogenic element as
demonstrated via dynamic central-to-helical-to-axial-to-
central transfer of chirality by using (R)-1 as switchable
catalyst in the enantioselective addition of diethylzinc to
various benzaldehydes. Reversal of enantioselectivity was
accomplished for each substrate, with ee values for12 up
to 68%, ∆ee’s up to 113% and yields up to 87%. These
results achieved in switchable asymmetric catalysis
highlight the proof-of principle of
a
two-stage
dynamically responsive chiral biaryl-functionalized switch
scaffold. The future development of analogous biaryl-
switch structures combined with the well-established role
of biaryls as privileged structures in asymmetric catalysis
may lead to the construction of
a
variety of
unprecedented switchable chiral catalysts that could
perform multiple enantioselective transformation in a
sequential manner. In addition, this chiral switch system
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has considerable potential as responsive chirality selector
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1
2
3
4
5
6
7
8
for a range of other applications beyond the field of
asymmetric catalysis, such as control of supramolecular
architecture, host-guest interaction, and polymer or
liquid crystal morphology.
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ASSOCIATED CONTENT
Experimental procedures, supporting characterization data,
crystallographic detail and data, supporting irradiation and
EXSY kinetic experiments, computational details, catalysis
9
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procedures, copies of the H and C NMR spectra and HPLC
chromatograms are presented in the Supporting material.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*b.l.feringa@rug.nl
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from The Netherlands Organization for
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Scientific
Research
(NWO-CW),
Foundation
for
Fundamental Research on Matter (FOM, a subsidiary of
NWO), the Zernike Institute for Advanced Materials, The
Royal Netherlands Academy of Arts and Sciences (KNAW),
The European Research Council (Advanced Investigator
Grant no 694345 to BLF), Ministry of Education, Culture and
Science (Gravitation program 024.001.035), and the
University of Groningen are acknowledged. The authors
would like to thank Ing. P. van der Meulen for the technical
support during the EXSY experiments.
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ABBREVIATIONS
PEZI, photochemical E-Z isomerization; THI, thermal helix
inversion; S, stable; MS, metastable; PSS, photostationary
state; CD, circular dichroism; DFT, density functional theory;
ee, enantiomeric excess.
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The same reaction catalyzed by (P)-3,3’-diphenyl BINOL
was reported to yield the product in 44% ee (see Ref. 82).
It should be noted that the quality of the commercial
diethylzinc solution had a large impact on the results of the
catalytic reactions, affording lower yields and selectivities
as degradation of the reagent progressed.
Zong, H.; Huang, H.; Bian, G.; Song, L. Synergistic effect of
achiral quaternary ammonium salt on asymmetric
additions of diethylzinc to aldehydes. Tetrahedron Lett.
2013, 54 (21), 2722–2725.
(77)
(78)
(86)
(87)
(79)
(80)
(81)
(88)
(89)
(90)
Shibata, T.; Tarumi, H.; Kawasaki, T.; Soai, K. Reversal in
enantioselectivity induced by achiral alcohols in
asymmetric autocatalysis in the presence of a chiral diol as
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1
2
3
4
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v
(Sa)
HO
(Ra)
OH
HO
OH
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
UV-light
HO
HO
OH
OH
1 = 365 nm
2 = 420 nm
1
1
(R,P,Sa)-
(R,M,Ra)-
Stable state (S)
Metastable state (MS)
R
h
P
M
R
HO
OH
coupled
inversion of
helical and
axial chiraliy
Sa
Ra
HO
OH
17
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