Bi-aryl rotation in phenyl-dihydroimidazoquinoline catalysts for kinetic resolution of arylalkyl carbinols

Article abstract of DOI:10.1039/c3cy00904a

Chiral nucleophilic catalysts, 6-aryl-phenyl-dihydroimidazoquinolines (PIQs), were designed, synthesised and applied to the kinetic resolution of arylalkyl carbinols with very high selectivity (S) factors (up to 530). Density functional theory calculations indicate that multiple noncovalent interactions play a key role in chiral recognition between 6-aryl-PIQ catalysts and chiral secondary alcohol substrates. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cy00904a

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Jiagao Cheng, Wei-Ping Deng et al.
Bi-aryl rotation in phenyl-dihydroimidazoquinoline catalysts for kinetic
resolution of arylalkylcarbinols

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Bi-aryl rotation in phenyl-dihydroimidazoquinoline
catalysts for kinetic resolution of arylalkyl carbinols†
Cite this: Catal. Sci. Technol., 2014,
4, 1909
a
Zheng Wang,a Jinjin Ye,a Rui Wu,a Yang-Zi Liu,a John S. Fossey,ab Jiagao Cheng
*
a
*
and Wei-Ping Deng
Received 8th November 2013,
Accepted 3rd December 2013
DOI: 10.1039/c3cy00904a
www.rsc.org/catalysis
Chiral nucleophilic catalysts, 6-aryl-phenyl-dihydroimidazoquinolines
(PIQs), were designed, synthesised and applied to the kinetic
resolution of arylalkyl carbinols with very high selectivity (S) fac-
tors (up to 530). Density functional theory calculations indicate
that multiple noncovalent interactions play a key role in chiral
recognition between 6-aryl-PIQ catalysts and chiral secondary
alcohol substrates.
combines aspects from Fu's and Birman's catalysts to deliver
high selectivity factors in the kinetic resolution of bulky
alkyl-containing arylalkyl carbinols (S up to >1800). However,
our Fc-PIP system did not give such impressive selectivity
factors for arylalkyl carbinols with less sterically demanding
alkyl groups. In order to overcome this shortcoming, a new
catalyst design concept is required.
Herein, we report a variant of the PIQ core structure with
aryl groups at position 6 of the PIQ backbone (Fig. 2). By
comparing phenyl, naphthyl and anthracenyl derivatives, the
role of semi-stable atropisomers was revealed, permitting
access to greatly improved selectivity factors for most arylalkyl
carbinols (S up to 530).
The catalytically active Fc-PIP diastereoisomer utilises
matched central and planar chiral stereochemical elements
with phenyl and metallocene fragments on the same face of
the molecule to create a highly selective catalyst, whereas the
alternative diastereoisomer with the opposite sense of planar
chirality (not drawn) was completely inactive as a kinetic
resolution catalyst.12
Introduction
Nucleophilic acyl transfer catalysts,1 such as chiral phos-
phines and chiral DMAP derivatives, have attracted much
attention since the early work of Vedejs2 on catalytic,
nonenzymatic secondary alcohol kinetic resolution (KR).
Fu and co-workers introduced planar chiral DMAP equiva-
lents (p-DMAP) delivering a step change in effectiveness with
selectivity factors (S) ranging from 32 to 200.3 Thereafter,
numerous scalemic DMAP-like catalysts integrating elements
of central,4,5 axial,6 helical7 and planar8 chirality have been
developed, showing similar selectivity factors to those of
ferrocene-containing planar chiral DMAP derivatives. Birman
and coworkers9 have described a class of amidine-based nucle-
ophiles,10 such as CF3-PIP,9a Cl-PIQ9b and BTM,9c offering
higher selectivity factors (S up to 355). The higher selectivity
factors were rationalised as resulting from π–π and π–cation
interactions between the aromatic ring of the N-acylated
catalysts and the aromatic rings of the arylalcohol substrates.
In 2010, we reported a new class of hybrid planar chiral
ferrocene nucleophilic catalyst, Fc-PIP (Fig. 1),11 which
a Shanghai Key Laboratory of New Drug Design, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: weiping_deng@ecust.edu.cn, jgcheng@ecust.edu.cn
b School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
B15 2TT, UK. E-mail: j.s.fossey@bham.ac.uk
† Electronic supplementary information (ESI) available: Synthetic procedures
and characterisation for nucleophilic catalysts 1; HPLC data analysis for all
kinetic resolutions of rac-2; computational studies. See DOI: 10.1039/
c3cy00904a
Fig. 1 DMAP and examples of previously reported chiral nucleophilic
catalysts for secondary alcohol kinetic resolution.
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optimized reaction conditions (in toluene at 0 °C). Therefore,
the 1 : 1 ratio of diastereoisomers of Np-PIQ was used for the
KR of secondary alcohols (see the ESI† for details).
Encouraged by the good stereoselectivity factors obtained
when using Np-PIQ as catalyst, we further screened the reac-
tion conditions with Np-PIQ (see the ESI† for full screening).
Gratifyingly, the KR proceeded smoothly with a selectivity
factor of S = 89 under optimal resolution conditions (Table 1,
entry 1; versus S = 41 obtained with Cl-PIQ).
Next, the generality and scope of substrates were examined;
the results are summarised in Table 1. The newly developed
catalyst 1c displayed excellent chiral recognition ability. The
kinetic resolution proceeded smoothly under the optimal
reaction conditions for all arylalkyl carbinols tested. Selec-
tivity factors15 ranged from 43 to 456 and ee values for the
corresponding unreacted alcohols were up to >99.5% (see
the ESI†). The S factors for arylalkyl carbinols with small
alkyl groups were higher than those achieved with Cl-PIQ
and Fc-PIP (Table 1, entries 1–3, 5–9, 13–14). Notably, bulky
(hetero) arylalkyl carbinols were also well accommodated as
substrates, and Np-PIQ also exhibited a wider substrate
scope, with higher S values in many cases (entries 4, 15–18).
The highest S factor (S = 456) was observed in the case of
using a p-methyl phenyl butyl carbinol (2p), much higher
than that achieved with Fc-PIP (entry 16).
Density functional theory (DFT) calculations were per-
formed to better understand the role of naphthyl groups
appended to PIQ catalysts. At first, the origin of enantio-
selectivity in the acylation of 1-phenyl-1-propanol (2a) was
analysed using B97D/TZVP.16 Two competing diastereomeric
transition states were constructed and optimised for each
catalyst examined.17 Corresponding transition state geometries
were verified by frequency analysis and intrinsic reaction coor-
dinate (IRC) calculation. Since a mixture of diastereoisomers
exists in equilibrium due to a somewhat hindered rotation
about an Ar–Ar bond, N-acetyl-6-naphthyl-PIQ was divided into
two categories, one with the naphthyl group on the upper face
of PIQ and the other with the naphthyl group under the plane
of PIQ, marked respectively as 1c–2a-A and 1c–2a-B.
Fig. 2 Design of Ar–Ar PIQ derivatives.
Results and discussion
We wished to investigate the potential of metallocene-free
(organo) catalysts, and drawing on knowledge learned from
our earlier investigations, we hypothesised that a group
orthogonal to the catalyst plane may be required for the
improvement of enantioselectivity. By introducing phenyl,
1-naphthyl and 9-anthryl groups at the 6-position of the
catalyst core, we could observe the effects of small, medium
and large orthogonal aryl groups (see the ESI† for details of
the synthesis of these 6-aryl-PIQs). A 1-naphthyl substituent
offers a diversity potential in that rotational diastereoisomers,
perhaps via a chiral relay effect,13 may be exploited in catalysis.
Racemic 2a was then chosen as the model substrate to
investigate the catalytic asymmetric resolution capability14 of
different PIQ catalysts (1a–1d) under a previously reported
regime9b (Scheme 1). It should be pointed out that the
Np-PIQ was found to give one set of 1H NMR spectrum;
however, the chiral HPLC gave two diastereoisomeric peaks
in a 1 : 1 ratio. Further preparative chiral HPLC separation
gave two diastereoisomers in high diastereomeric purities,
but they can slowly epimerize in the HPLC eluent as well as
during the evaporation under reduced pressure. Further
investigation showed that 1c can also slowly epimerize under
For all calculated transition state structures, the free
energy for the reaction with the (S)-enantiomer of the alcohol
was lower than its (R)-enantiomer counterpart, consistent with
the absolute sense of enantioselection of KR. Unexpectedly,
the free energy differences between stacked and splayed transi-
tion states of 1c–2a-A and 1c–2a-B were 5.22 kcal mol−1 and
3.65 kcal mol−1, respectively, which indicated that the naphthyl
group points towards the same face as the approaching
arylalkyl carbinol substrates in the energetically favoured
transition state. Interestingly, it was found that the transition
state geometries of the fast-reacting enantiomer were stabilised
by dispersion and electrostatic interactions between the
naphthyl group and the phenyl ring of alcohol substrates when
the naphthyl group was located at the upper face of PIQ
(Fig. 3, TS-1c–(S)-2a-A, see the ESI† for details).
Based on this finding, we further speculated that the
selectivity factors of KR could be further improved by using
Scheme 1 Comparison of different PIQ catalysts for the KR of rac-2a.
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Table 1 Scope and generality of the Np-PIQ catalysed KRa
R1/R2
CHPLC (%)/t (h)
S
Fc-PIPc
Cl-PIQd
b
Entry
1e
2
Ph/Et (2a)
Ph/Me (2b)
Ph/iPr (2c)
Ph/tBu (2d)
48.9/10
47.4/10
49.1/15
40.6/35
45.1/12
49.8/10
42.3/10
50.0/10
51.0/10
53.9/10
49.5/10
49.0/10
49.8/10
49.9/10
51.5/48
43.3/48
49.9/50
52.5/51
89
43
124
450
95
70
68
73
85
95
91
95
88
113
152
456
258
118
53
31
84
534
—
44
35
41
37
—
41
33
59
117
60
—
—
—
—
—
—
—
55
74
—
—
—
—
3e
4e
5
2-MePh/Me (2e)
3-MeOPh/Me (2f)
4-MeOPh/Me (2g)
4-ClPh/Me (2h)
4-BrPh/Me (2i)
4-NO2Ph/Me (2j)
4-MePh/Me (2k)
2,4-DimethylPh/Me (2l)
1-Naphthyl/Me (2m)
2-Naphthyl/Me (2n)
4-ClPh/tBu (2o)
4-MePh/tBu (2p)
2-Naphthyl/tBu (2q)
4-(2-ClPy)/tBu (2r)
6
7
8
9
10
11
12
13
14
15
16
17
18
—
—
47
—
118
61
142
74
a
b
Conditions: substrate concentration 0.1 M, (EtCO)2O 0.75 equiv., iPr2NEt 0.75 equiv., catalyst 5 mol%. Calculated from the ee of the ester
c
d
and unreacted alcohol, see ref. 15. The S factors given by Fc-PIP in previous reports. The S factors given by Birman and co-workers.
e
The experiment was carried out in duplicate and relatively low S values were reported herein (see the ESI† for details).
Table 2 KR of secondary alcohols using An-PIQ 1da
Entry R1/R2
t (h) CHPLC (%)
S
S (Np-PIQ)
1
2
Ph/Et (2a)
Ph/Me (2b)
Ph/iPr (2c)
Ph/tBu (2d)
2-MePh/Me (2e)
3-MeOPh/Me (2f)
4-MeOPh/Me (2g)
4-BrPh/Me (2i)
2,4-DimethylPh/Me (2l) 10
1-Naphthyl/Me (2m)
2-Naphthyl/Me (2n)
10
10
17
46
13
10
10
10
46.4
46.2
51.1
48.0
49.2
48.4
48.4
51.7
46.6
43.5
52.0
118
76
174 124
530 450
178
102
105
110
114
54
89
43
3
4b
5
95
70
68
85
95
88
6
7
8
9
10
11
10
10
72 113
a
Conditions: 0.1 M of substrate concentration, 0.75 equiv. (EtCO)2O,
b
0.75 equiv. iPr2NEt, 5 mol% An-PIQ 1d. The experiment was carried
out in duplicate and relatively lower S values were reported herein
(see the ESI† for details).
Fig. 3 Free energy calculation for possible transition states of Np-PIQ
(1c)-catalysed acylation of 1-phenylpropanol (rac-2a).
the 6-anthryl-PIQ (An-PIQ). To our delight, An-PIQ catalysed
KR of phenyl alkyl carbinols proceeded smoothly with higher
S values up to 530 under the optimal condition (Table 2,
entries 1–9). However, a dramatic drop of S value was found
when naphthyl methyl carbinol (2m and 2n, entries 10–11)
was employed, compared with those catalysed by Np-PIQ.
This observation might be ascribed to the steric repulsion
between the extended aromatic ring of the substrates and the
anthryl group in the favoured transition state.
Scheme 2 Larger scale catalytic KR of racemic 2r.
In order to demonstrate the utility of 6-aryl-PIQ catalysts,
catalyst Np-PIQ (3 mol%) was applied to the kinetic
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resolution on a reasonable scale (800 mg) of substrate 2r.
The reaction proceeded smoothly to afford unreacted alcohol
2r in 99.0% ee with good selectivity factor S = 61 and in
44.5% yield (Scheme 2). Besides, the catalyst could be readily
recovered (88%).
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Conclusions
In conclusion, we have developed remarkably effective chiral
6-aryl PIQ catalysts (Np-PIQ/An-PIQ) for the enantioselective
acyl transfer of secondary alcohols to achieve selectivity
factors up to S = 530. Notably, the newly designed catalysts
Np-PIQ/An-PIQ are useful for the catalytic KR of arylalkyl
carbinols with both small alkyl and bulky groups with excellent
S factors much higher than those achieved using the parent
Cl-PIQ and our previously reported Fc-PIP catalyst. Theoretical
calculations supported the hypothesis that selectivity in
kinetic resolution is induced by a chiral relay effect of PIQ cata-
lysts through multiple noncovalent interactions.18 Besides
classic cation–π19 and π–π interactions, secondary interac-
tions, mainly dispersion and electrostatic interactions, are
complimentary to each other, further enhancing enantio-
discrimination, which is evident in a calculated favoured
transition state between the aromatic substituent and the
phenyl fragment of alcohol.
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Acknowledgements
12 Whilst only one diastereoisomer of Fc-PIP was catalystically
active, both diastereoisomers of Fc-PIP functioned compara-
bly as chiral sensors of chiral acids, see: S.-Y. Xu, B. Hu,
S. E. Flower, Y.-B. Jiang, J. S. Fossey, W.-P. Deng and
T. D. James, Chem. Commun., 2013, 49, 8314–8316.
13 S. D. Bull, S. G. Davies, D. J. Fox and T. G. R. Sellers,
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This work was supported by the Fundamental Research
Funds for the Central Universities, the Shanghai Committee
of Science and Technology (no. 11DZ2260600) and the Natural
Science Foundation of China (no. 21172068; 21372074).
Notes and references
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14 Enantioselectivity in KR of racemic mixtures is expressed in
terms of a selectivity factor (S) defined as the ratio of
reaction rates of the fast- and the slow-reacting enantio-
mers of the starting material: S = kfast/kslow. Kagan's equa-
tions are used to calculate it from the ee values of the
product and the unreacted starting material: conversion
C = eeSM/(eeSM + eePR); selectivity factor S = ln[(1 − C)(1 − eeSM)]/
ln[(1 − C)(1 + eeSM)]. See reference: C.-S. Chen, S.-H. Wu,
G. Girdaukas and C. J. Sih, J. Am. Chem. Soc., 1982, 104,
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3 (a) J. C. Ruble, H. A. Latham and G. C. Fu, J. Am. Chem. Soc.,
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15 Due to the calculation error associated with high ee's, large
S values should be viewed as approximate.
16 Geometry optimizations were performed with B97D,
a
dispersion-corrected density functional and TZVP basis set.
Solvation effect was considered by the SMD solvent model in
toluene. Frequency calculation was carried out to confirm
the true stationary points.
17 Transition state structures of were also calculated (see ESI†)
and the free energy difference was 3.19 kcal mol−1
,
indicating the asymmetric induction ability of 1c should be
much better than that of 1a, which was exactly in accord
with the experimental finding.
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18 For examples, see: (a) S. J. Zuend and E. N. Jacobsen, J. Am.
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19 S. Yamada and J. S. Fossey, Org. Biomol. Chem., 2011, 9,
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