Access to Enantiopure Triarylmethanes and 1,1-Diarylalkanes by NHC-Catalyzed Acylative Desymmetrization

Article abstract of DOI:10.1002/chem.201605445

We present herein an unprecedented, efficient and enantioselective synthesis of triarylmethanes and 1,1-diarylalkanes through N-heterocyclic carbene-catalyzed acylative desymmetrization of bisphenols. This method utilizes readily available substrates, reagents and a simple procedure to deliver the valuable products in excellent enantiopurity. DFT calculations reveal that the selectivity is governed by the C?C bond cleavage step of the tetrahedral intermediate leading to the ester product. A transition state model featuring a combination of intramolecular hydrogen bond and steric effect is developed to explain the enantioselectivity.

Full text of DOI:10.1002/chem.201605445

A Journal of
Accepted Article
Title: Access to Enantiopure Triarylmethanes and 1,1-Diarylalkanes by
NHC-Catalyzed Acylative Desymmetrization
Authors: Yu Zhao, Shenci Lu, Xiaoxiao Song, Si Bei Poh, Hui Yang,
and Ming Wah Wong
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201605445
Link to VoR: http://dx.doi.org/10.1002/chem.201605445
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Access to Enantiopure Triarylmethanes and 1,1-Diarylalkanes by
NHC-Catalyzed Acylative Desymmetrization
Shenci Lu+, Xiaoxiao Song+, Si Bei Poh, Hui Yang, Ming Wah Wong, and Yu Zhao
1,1-diarylalkanes (Scheme 1d). This method, if successful, will
also represent an important advancement on controlling remote
prochiral stereogenic centers. It is noteworthy that the Miller
group reported a classical example of highly enantioselective
acylation of distant bisphenols catalyzed by a nucleophilic
peptide catalyst.[13] A bulky substituent such as t-butyl on the
substrate was required for achieving high enantioselectivity in
this system. Very recently, the Chi group also reported an
elegant example of NHC-catalyzed bisphenol desymmetrization
to access P-stereogenic phosphinates.[14] We report herein a
Abstract: We present here an unprecedented, efficient and
enantioselective synthesis of triarylmethanes and 1,1-diarylalkanes
through NHC-catalyzed acylative desymmetrization of bisphenols.
This method utilizes readily available substrates, reagents and a
simple procedure to deliver the valuable products in excellent
enantiopurity. DFT calculations reveal that the selectivity is governed
by the C-C bond cleavage step of the tetrahedral intermediate
leading to the ester product. A transition state model featuring a
combination of intramolecular hydrogen bond and steric effect is
developed to explain the enantioselectivity.
highly
efficient
and
general
desymmetrization
of
triarylmethanes/1,1-diarylalkanes by NHC-catalyzed acylation of
phenols.[14] This method utilizes readily available substrates,
reagents and a simple procedure to deliver the valuable
products in excellent enantiopurity. Further derivatization of the
products could lead to additional structural diversity of these
compounds. Experimental and DFT calculations have also
provided key information on the origin of stereoselectivity of this
catalytic system.
Introduction
Triarylmethanes and 1,1-diarylalkanes are highly valuable
structural motifs in pharmaceutical industry and material
science.[1-2] The development of efficient catalytic methods to
access these motifs in a stereoselective fashion has thus been
the focus of substantial studies in the past decade.[3] The most
established strategies for these efforts have focused on
substitution reactions of the central benzylic carbon. In particular,
transition metal-catalyzed cross coupling of a benzylic unit with
an aryl group has been accomplished in both enantiospecific
(using enantioenriched substrate)[4] and enantioselective[5]
fashion (Scheme 1a).[6] Transition metal-catalyzed addition of
aryl nucleophiles[7] or acid-catalyzed Friedel-Crafts reaction of
arenes to electron deficient alkenes including o-quinone methide
(Scheme 1b)[8] represents another successful type of reactions
to deliver these compounds in high enantioselectivities.[9]
As an intriguing alternative strategy, the desymmetrization of
achiral triarylmethanes and 1,1-diarylalkanes may enable
efficient access to new analogs of these valuable compounds in
an enantiopure form. Along these lines, the Yu group reported
an elegant Pd-catalyzed enantioselective C-H arylation (Scheme
1c).[10] In this system, however, pyridine is required as the
directing group on the substrate. A general preparation of
enantiopure triarylmethanes as well as diarylalkanes by
desymmetrization is still highly desired.
NHC-catalyzed conversion of aldehydes to activated
carboxylates has been developed into a powerful strategy for
enantioselective C-C bond formation[11] as well as kinetic
resolution of the alcohol counterpart.[12] Our group has
developed highly enantioselective acylative kinetic resolution of
oxindole-derived tertiary alcohols as well as axially chiral BINOL
and NOBIN analogs.[12e-g] We were curious whether NHC-
catalyzed enantioselective acylation of phenols could be applied
to the desymmetrization of a wide range of triarylmethanes and
Scheme 1. Different Approaches to Enantioenriched Triarylmethanes
Results and Discussion
We initiated our studies by testing the enantioselective
acylation of 1a by screening different aldehyde reagents and
chiral azolium salts as the pre-catalyst (Table 1). Excellent
reactivity could be achieved in this catalytic system, so only 1.0
equiv. of aldehyde was used. As it turned out, the use of a
bulkier aldehyde 2b vs. 2a led to the formation of 5a with a
higher ee of 93% (entry 2 vs. 1), while the leaving group on 2b
or 2c made no difference on the reaction outcome at all (entry 2
vs. 3). The stable and easier-to-handle aldehyde 2c was then
chosen for further optimization.[15] Azolium 3a remained as the
[*]
Dr. S. Lu[+], Dr. X. Song[+], S. B. Poh, Dr. H. Yang, Prof. M. W.
Wong, Prof. Y. Zhao
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543
E-mail: zhaoyu@nus.edu.sg; chmwmw@nus.edu.sg
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201605445
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optimal choice after further screening of other pre-catalysts
(entries 4-6). Fortunately, the screening of solvents identified
that toluene could improve the enantioselectivity of 5a to an
excellent 97% (entry 9 vs. 3).
With the optimal conditions in hand, we moved on to examine
the scope of this NHC-catalyzed acylative desymmetrization. It
is important to note that essentially all the prochiral substrates
(both triarylmethanes and 1,1-diarylalkanes) could be prepared
in a single step from commercial compounds (see SI for details).
The ready availability of substrates certainly renders this
catalytic method more attractive for practical application.
Table 1. Optimization of the Reaction Conditions[a]
entry
1
aldehyde
NHC
solvent
DCM
yield (%)[b]
ee (%)[c]
55
2a
3a
4a, 90
2
2b
3a
5a, 80
5a, 80
93
DCM
3
4
5
6
7
8
9
2c
2c
2c
2c
2c
2c
2c
3a
3b
3c
3d
3a
3a
3a
93
88
59
5
DCM
DCM
5a, 80
5a, 77
5a, 70
5a, 78
5a, 80
5a, 81
DCM
DCM
88
92
97
CH3CN
THF
toluene
[a] The reactions were carried out by mixing all reagents and catalysts under
N2. See supporting information for more details. [b] Isolated yield. [c]
Determined by chiral HPLC.
Scheme 2. Scope of Triarylmethanes[a]
The broad substrate scope of triarylmethanes prompted us to
examine the desymmetrization of 1,1-diarylalkanes under similar
conditions as well (Scheme 3). For 6a bearing a small methyl
substituent, we were excited to observe a high ee of 93% for 7a.
Clearly this catalytic system has a high degree of tolerance for
the steric size of the substituent on the benzylic carbon bearing
two phenol units. Various analogs bearing substituted aryl
groups including 7b to 7d were first examined. Good to high
level of enantioselectivity could be obtained. On the other hand,
1,1-diarylalkane 7e bearing a linear n-hexyl group could also be
obtained in a good 86% ee. t-Butyl-containing 7f could be
obtained in an excellent ee of 97%. Another intriguing triol
substate 6g was also examined. Again, acylation of the phenol
is favored over that of a primary alcohol to deliver 7g in high
yield with excellent ee. The absolute configuration of this series
of products was further confirmed by single crystal x-ray analysis
of 7f, which was consistent with that of the triarylmethane series.
As shown in Scheme 2, a range of substituted aryl groups
could be tolerated to deliver 5a to 5i in uniformly high yield and
excellent enantioselectivity (94-99% ee). In the case of 5h
bearing an ortho-substituted aryl group, the highest
enantioselectivity was obtained albeit at the cost of relatively low
yield. In addition, different substitution patterns on the bisphenol
units were also well-tolerated. Products 5j-5s were again
obtained in uniformly high efficiency and selectivity. More
importantly, various heteroarenes could serve as the substituent
as well. While the smaller furan group resulted in slightly
diminished enantioselectivity for 5t, 5u bearing an indole was
obtained in the standard level of 96% ee. Lastly, an interesting
trisphenol substrate was tested. Bisphenol 5v was obtained in
good yield and excellent ee. The chemoselectivity for the
synthesis of 5v is noteworthy: clearly the phenol on the para-
position is more accessible for acylation. However, the two
ortho-phenols seem to work in a cooperative fashion to result in
the acylation of the more sterically hindered phenol selectively.
The presence of the phenol units in the substrates provided
opportunities for further derivatization of the enantioenriched
products obtained from the NHC-catalyzed desymmetrization.
As shown in Scheme 4, gram-scale transformation of 1a to 5a
worked out similarly well. Conversion of the free phenol in 5b to
the corresponding triflate followed by reduction led to the
formation of 8 in good yield and excellent ee. Alternatively, 5a
could be converted to 9 by Suzuki coupling; the ester moiety
could be reduced to yield 10 in good yield and high ee. Further
derivatization of 10 is possible if desired. In this way, the
The absolute configuration of 5a was established
unambiguously by single crystal x-ray analysis and the
configuration of the other products was assigned by analogy.
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products in our studies can serve as a springboard for the
access to more diverse triarylmethanes and 1,1-diarylalkanes.
Scheme 5. Substrate Structure Alternation
To shed light on the origin of the stereoselectivity, DFT
calculations were carried out. A detailed computational study of
the mechanism of desymmetrization of triarylmethane 1a
through 3a-catalyzed acylation with aldehyde 2c was performed
(Scheme 6). Experimentally, the selectivity of this reaction was
shown not to be affected by the method of generating the key
acyl azolium intermediate A (entries 2 vs. 3, Table 1). Hence, we
only investigated the steps after the formation of A. Density
functional theory (DFT) calculations, using the Gaussian
programs,[16] were performed at M06-2X/6-311+G**//M06-2X/6-
31G* level.[17] Solvent effect was included using SMD implicit
solvation method[18] and with toluene as solvent for both
optimizations and single-point energy calculations. Unless
otherwise noted, calculated relative free energies at 298 K
(G298, in kJ/mol) were reported in the text. Images of reported
structures were rendered using CYLview.[19]
Scheme 3. Scope of 1,1-Diarylalkanes [a]
Scheme 6. Proposed Mechanism for NHC-Catalyzed Acylation of 1a and
Scheme 4. Access to More Diverse Triarylmethanes
calculated reaction profile. Calculated relative energies (ΔG298
) for the
desymmetrization of 1a are shown in kJ/mol in the parentheses.
In our reaction, a small amount of bisester products could be
obtained in some cases. When we tested the kinetic resolution
of racemic 5a (Scheme 5a), however, the NHC-catalyzed
acylation resulted in minimal level of enantioselectivity for this
process (S = 1.5). The enantioselectivity in our catalytic system,
therefore, only comes from the desymmetrization step. This
attempted kinetic resolution also provided further support for the
cooperativity of the diol functionality in this catalytic system. The
desymmetrization of a more distant bisphenol 12 was also
attempted (Scheme 5b). Much lower level of reactivity as well as
enantioselectivity was obtained for 13. The two phenols in this
substrate may be too distant for any effective cooperative
interaction.
Our proposed catalytic mechanism is illustrated in Scheme 6.
Since phenol and their derivatives are poor nucleophiles, they
need to be activated by a base before they can be used in
nucleophilic addition to acyl azolium. Thus, we first investigated
the deprotonation of 1a by a representative base DIPEA. The
proton transfer process is calculated to be quite facile, with a
small barrier of 7.8 kJ/mol (via transition state TS1), leading to
an ion pair complex (II) that is 14.9 kJ/mol higher in energy than
I (Scheme 6). The calculated result is typical of low-barrier
hydrogen bonds proposed for many important enzymatic
systems where the proton is shared between two heteroatoms
whose pKa’s are closely matched.[20] The presence of a low-
barrier hydrogen bond suggests that the base is not involved in
the stereo-determining step of the overall catalytic reaction.
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the large group (e.g. phenyl of 1a) on carbon C1, which will
become the stereogenic center of the product, is furthest away
from the catalyst moiety and the second phenol group forms an
important intramolecular hydrogen bond to the partially
negatively charged carbonyl oxygen (Model-TS-R). For
comparison, four possible low-lying S-inducing transition states
could be envisioned. Three of them, namely Model-TS-S1,
Model-TS-S3 and Model-TS-S4, while maintaining the critical
hydrogen bond, incur significant steric repulsion to the catalyst
moiety. Although the third S-inducing transition state, namely
Model-TS-S2, may also fit into the empty quadrant of the
catalyst moiety, it is proposed to have a weaker hydrogen bond
to the less negatively charged oxygen atom of the leaving ester.
To validate our proposed transition state model and to test its
predictability, we selected a few substrates in such a way that
their experimental ee’s gave a large range so as to reduce the
chance of false positive error. The various optimized TS
structures for substrate 1a and their relative enthalpies H≠298
are shown in Figure 2, while computational results for other
substrates are given in Table 2. These calculations lent strong
support to our hypothesis that only the leaving ester leading to
the R-ester product can fit into the empty quadrant and at the
same time maintain the crucial intramolecular hydrogen bond to
partially negatively charged oxygen atom (Figure S2 in SI). In
the case of 1a, the strength of the intramolecular hydrogen bond
is estimated to be ~50 kJ/mol in transition state 1a-TS-R (Figure
S3 in SI). There are two low-energy S-inducing transition states,
1a-TS-S1 and 1a-TS-S4, which are 9.4 and 12.3 kJ/mol higher
in energy, respectively. The other two S-inducing transition
states, namely 1a-TS-R2 and 1a-TS-R3 are both significantly
higher in energy, by 25.9 and 33.1 kJ/mol, respectively. Based
on these calculated results, we opted to focus on the lowest
energy TS 1a-TS-S1 to unravel the origin of enantioselectivity.
Overlay of the 1a-TS-R and the mirror image of the lowest S-
inducing transition state 1a-TS-S1 (Figure 2b) revealed that the
mesityl moiety of the catalyst and the acylated phenol moiety of
1a in 1a-TS-S1 are very close to each other. The closest C-
H···C distance between the two in 1a-TS-S1 was measured to
be 2.648 Å, shorter than sum of the van der Waals radii of 2.9 Å.
To give a semi-quantitative understanding of the interaction, we
performed NBO steric analysis[24] of 1a-TS-S1, which showed a
destabilizing interaction of 15.9 kJ/mol, suggesting the energy
difference between the two TSs is mostly due to this steric
interaction. To further support our transition state models, we
compared calculated ee, based on the energy difference
between 1a-TS-R and 1a-TS-S1, to experimental ee for 1a, and
they matched each other closely (entry 1, Table 2).
Figure 1. Proposed Transition State Models. The Newman Projection of
Model-TS-R is also shown.
The ion pair complex II can undergo an ion exchange with acyl
azolium A to yield another ion-pair intermediate III. However, we
were unable to locate a definite transition state (TS2) for the
subsequent C-O bond-forming step. Extensive potential energy
surface scans show that the potential energy surface is
extremely flat in the vicinity of the complex III, indicating it is only
tangibly stable and might not have a significant role for the
overall reaction dynamics. In other words, our calculations
suggest that the ion pair complex III would most likely collapse
instantly to form an oxyanion tetrahedral intermediate (IV), which
is 5.4 kJ/mol lower in energy, upon contact of each other. Similar
issue has been reported in DFT studies of NHC-catalyzed
annulation reaction and Michael addition.[21] In comparison, C-C
bond cleavage of the tetrahedral intermediate IV to yield the
ester product V and regenerate the NHC catalyst is calculated to
have a significant activation barrier of 16.9 kJ/mol, via transition
state TS3. Assuming there is a fast equilibrium between acyl
azolium A and the tetrahedral intermediate IV,[22] the C-C bond
cleavage step being irreversible, with product V being 67.2
kJ/mol lower in energy than the tetrahedral intermediate IV, and
Curtin-Hammett paradigm of stereocontrol,[23] we postulated that
the stereoselectivity of NHC-catalyzed desymmetrization of
triarylmethanes can be determined from the relative energy of
various TSs of the C-C bond cleavage step. Subsequently, we
examined various possible transition states (TS3) of this key
step to shed light on the origin of stereoselectivity.
(a)
Next, we constructed transition state models based on the
structures of the oxyanion intermediate IV, which is
characterized by a strong intramolecular hydrogen bond, and the
ester product, which adopts the Z conformation. The in situ
generated NHC catalyst in this study does not possess a
hydrogen bond donor or acceptor that can interact with either
the aldehyde or triphenyl moiety in the stereo-determining step.
Thus, the mode of chiral induction by the catalyst is likely of
steric interaction. To view the spatial arrangement of atoms of
the catalyst moiety, schematic representations in the stereo-
determining TS’s are shown in Figure 1. The vicinity of the
carbonic carbon atom of NHC in these TS’s can be divided into
four quadrants, three of which are crowded with phenyl and
mesityl groups of the catalyst moiety, leaving the quadrant
opposing the phenyl group relatively free of steric hindrance. We
hypothesized that the lowest energy R-inducing transition state
adopts a conformation (see Figure 1, Newman project) such that
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(b)
Conclusions
We have developed a highly efficient NHC-catalyzed acylative
desymmetrization of remote bisphenols that provides access to
a
wide range of enantioenriched triarylmethanes and
diarylalkanes. The simple procedure coupled with the uniformly
high enantioselectivity makes this method a useful tool in
organic synthesis. DFT calculations show that the selectivity is
governed by the C-C bond cleavage step of the tetrahedral
intermediate to yield the ester product. Transition state models
involving a key intramolecular hydrogen bond between the
tetrahedral intermediate oxygen and the remaining phenol and
steric control from the catalyst moiety were successfully
developed and generalized to desymmetrization of this important
class of bisphenols.
Figure 2. Optimized Transition State Geometries. Part a: optimized transition
state geometries for desymmetrization of 1a. Relative enthalpies (ΔΔH≠
)
298
were reported in kJ/mol. Part b: overlay of 1a-TS-R (white) and mirror image
of 1a-TS-S1 (red) showing the closeness between the mesityl moiety of the
catalyst and the acylated phenol moiety of 1a in 1a-TS-S1. Hydrogen atoms
are not shown for clarity.
Experimental Section
To a 4 mL vial was added 1 or 6 (0.075 mmol), triazolium salt 3a (0.0075
mmol) and 4Å MS (50 mg). The mixture was taken into the glovebox,
where aldehyde 2c (12 L, 0.075 mmol), anhydrous toluene (1.0 mL) and
DIPEA (36 L, 0.15 mmol) were added. The reaction mixture was taken
outside the glovebox. The vial was then sealed and the reaction mixture
was allowed to stir for 16 h. The crude reaction mixture was directly
purified by silica gel column chromatography with hexanes/ethyl acetate
(10:1 v/v) as eluent to afford the ester product.
Although we have established the importance of steric
interaction to the origin of enantioselectivity, we want to
emphasize that the role of intramolecular hydrogen bonds in TSs
should not be underestimated. They help to rigidify transition
state conformation by restricting rotation around the important
single bond between C2 and C1 (Figure 2) and thus limit the
number of accessible conformers, so that enantiomeric
discrimination could be possible. The large group on C1 could
help to further rigidify the TSs. Experimentally, when the large
group was changed from a methyl group to a t-butyl group,
entries 6 and 7 of Table 2, or from a phenyl group to an o-tolyl
group, entries 1 and 2 of Table 2, enantioselectivity increased.
The trend that bigger group on C1 gives higher enantioselectivity
was well reproduced by calculations using our transition state
Acknowledgements
We are grateful for the generous financial support from
Singapore National Research Foundation (R-143-000-477-281),
A*STAR SERC (R-143-000-648-305) and National University of
Singapore (R-143-000-555-112).
model.
Hence,
the
origin
of
stereoselectivity
for
desymmetrization of triarylmethanes is determined to be a
combination of conformational rigidity due to strong
intramolecular hydrogen bond and the steric requirement of the
large group on C1, and the resulting unfavorable steric
interaction between the mesityl group of the catalyst moiety and
the acylated phenol moiety in Model-TS-S1 (Figure S4 in SI).
Keywords: acylation • desymmetrization • triarylmethanes • 1,1-
diarylalkanes• N-heterocyclic carbene
[1]
For selected reviews on triarylmethanes, see: a) V. Nair, S. Thomas, S.
C. Mathew, K. G. Abhilash, Tetrahedron 2006, 62, 6731; b) S. Mondal,
G. Panda, RSC Adv. 2014, 4, 28317. For selected examples, see c) P.
Finocchiaro, D. Gust, K. Mislow, J. Am. Chem. Soc. 1974, 96, 3198; d)
H. W. Gibson, S.-H. Lee, P. T. Engen, P. Lecavalier, J. Sze, Y. X. Shen,
M. Bheda, J. Org. Chem. 1993, 58, 3748; e) M. K. Parai, G. Panda, V.
Chaturvedi, Y. K. Manju, S. Sinha, Bioorg. Med. Chem. Lett. 2008, 18,
Table 2. Predicted and Experimental Selectivitya
289.
[2]
For selected reports on the application of 1,1-diarylalkanes, see: a) C. J.
Hills, S. A. Winter, J. A. Balfour, Drugs 1998, 55, 813; b) W. E. Heydorn,
Expert Opin. Invest. Drugs 1999, 8, 417; c) A. L. McRae, K. T. Brady,
Expert Opin. Pharmacother. 2001, 2, 883; d) A. Abad, J. L. Lꢀpez-
Pꢁrez, E. del Olmo, L. F. García-Fernꢂndez, A. Francesch, C. Trigili, I.
Barasoain, J. M. Andreu, J. F. Díaz, A. San Feliciano, J. Med. Chem.
2012, 55, 6724.
For selected recent reviews, see: a) E. C. Swift, E. R. Jarvo,
Tetrahedron 2013, 69, 5799; b) A. H. Cherney, N. T. Kadunce, S. E.
Reisman, Chem. Rev. 2015, 115, 9587; c) M. Nambo, C. M. Crudden,
ACS catal. 2015, 5, 4734.
For examples on triarylmethanes, see: a) B. L. H. Taylor, M. R. Harris,
E. R. Jarvo, Angew. Chem. Int. Ed. 2012, 51, 7790; Angew. Chem.
2012, 124, 7910; b) M. R. Harris, L. E. Hanna, M. A. Greene, C. E.
Moore, E. R. Jarvo, J. Am. Chem. Soc. 2013, 135, 3303; c) Q. Zhou, H.
D. Srinivas, S. Dasgupta, M. P. Watson, J. Am. Chem. Soc. 2013, 135,
3307; d) S. C. Matthew, B. W. Glasspoole, P. Eisenberger, C. M.
Crudden, J. Am. Chem. Soc. 2014, 136, 5828. For examples on
entry
substrate
ΔΔH≠
9.4
calc ee (%)
expt ee (%)
1
2
3
4
5
6
7
1a
1h
1l
96
98
98
94
92
97
99
97
99
96
89
87
93
97
11.0
11.3
8.5
[3]
[4]
1m
1t
7.9
6a
6f
10.7
13.6
[a] Predicted ee calculated at M06-2X/6-311+G**//M06-2X/6-31G* level, using
a two-TS model, namely Model-TS-R and Model-TS-S1 (toluene solvent).
Relative enthalpies (H≠) were reported in kJ/mol.
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10.1002/chem.201605445
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diarylalkanes, see: e) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M.
Crudden, J. Am. Chem. Soc. 2009, 131, 5024; f) B. L. H. Taylor, E. C.
Swift, J. D. Waetzig, E. R. Jarvo, J. Am. Chem. Soc. 2011, 133, 389; g)
I. M. Yonova, A. G. Johnson, C. A. Osborne, C. E. Moore, N. S.
Morrissette, E. R. Jarvo, Angew. Chem. Int. Ed. 2014, 53, 2422; Angew.
Chem. 2014, 126, 2454; h) M. O. Konev, L. E. Hanna, E. R. Jarvo,
Angew. Chem. Int. Ed. 2016, 55, 6730; Angew. Chem. 2016, 128, 6842.
H.-Q. Do, E. R. R. Chandrashekar, G. C. Fu, J. Am. Chem. Soc. 2013,
135, 16288.
Sequential or synergistic bimetallic catalysis has also been reported for
these coupling reactions, see: a) Y. Lou, P. Cao, T. Jia, Y. Zhang, M.
Wang, J. Liao, Angew. Chem. Int. Ed. 2015, 54, 12134; Angew. Chem.
2015, 127, 12302; b) S. D. Friis, M. T. Pirnot, S. L. Buchwald, J. Am.
Chem. Soc. 2016, 138, 8372.
Yamada, J. Am. Chem. Soc. 2013, 135, 11485. For the kinetic
resolution of sulfoximines, see: i) S. Dong, M. Frings, H. Cheng, J. Wen,
D. Zhang, G. Raabe, C. Bolm, J. Am. Chem. Soc. 2016, 138, 2166. For
the kinetic resolution of cyclic secondary amines using the combination
of an achiral NHC catalyst and a chiral hydroxamic acids, see: j) M.
Binanzer, S.-Y. Hsieh, J. W. Bode, J. Am. Chem. Soc. 2011, 133,
19698; k) S. E. Allen, S.-Y. Hsieh, O. Gutierrez, J. W. Bode, M. C.
Kozlowski, J. Am. Chem. Soc. 2014, 136, 11783. For dynamic kinetic
resolution of pyranones and carboxylate esters, see: l) C. Zhao, F. Li, J.
Wang, Angew. Chem. Int. Ed. 2016, 55, 1820; Angew. Chem. 2016,
128, 1852; m) X. Chen, J. Z. M. Fong, J. Xu, C. Mou, Y. Lu, S. Yang,
B.-A. Song, Y. R. Chi, J. Am. Chem. Soc. 2016, 138, 7212. For
desymmetrization of 1,3-diol see: n) B.-S. Li, Y. Wang, R. S. J. Proctor,
Z. Jin, Y. R. Chi, Chem. Commun. 2016, 52, 8313.
[5]
[6]
[7]
[8]
a) J.-F. Paquin, C. Defieber, C. R. J. Stephenson, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 10850; b) Y. Huang, T. Hayashi, J. Am. Chem.
Soc. 2015, 137, 7556.
a) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He, S.-L. You, Eur. J. Org.
Chem. 2010, 47; b) M.-H. Zhuo, Y.-J. Jiang, Y.-S. Fan, Y. Gao, S. Liu,
S. Zhang, Org. Lett. 2014, 16, 1096; c) H.-H. Liao, A. Chatupheeraphat,
C.-C. Hsiao, I. Atodiresei, M. Rueping, Angew. Chem. Int. Ed. 2015, 54,
15540; Angew. Chem. 2015, 127, 15760.
For enantioselective hydrogenation and transfer hydrogenation of 1,1-
diarylalkenes, see: a) D. H. Woodmansee, A. Pfaltz, Chem. Commun.
2011, 47, 7912; b) P. Tolstoy, M. Engman, A. Paptchikhine, J.
Bergquist, T. L. Church, A. W.-M. Leung, P. G. Andersson, J. Am.
Chem. Soc. 2009, 131, 8855; c) Z. Wang, F. Ai, Z. Wang, W. Zhao, G.
Zhu, Z. Lin, J. Sun, J. Am. Chem. Soc. 2015, 137, 383.
[13] a) C. A. Lewis, A. Chiu, M. Kubryk, J. Balsells, D. Pollard, C. K. Esser,
J. Murry, R. A. Reamer, K. B. Hansen, S. J. Miller, J. Am. Chem. Soc.
2006, 128, 16454; b) C. A. Lewis, J. L. Gustafson, A. Chiu, J. Balsells,
D. Pollard, J. Murry, R. A. Reamer, K. B. Hansen, S. J. Miller, J. Am.
Chem. Soc. 2008, 130, 16358; c) J. L. Gustafson, M. S. Sigman, S. J.
Miller, Org. Lett. 2010, 12, 2794. For a recent desymmetrization by
Ullmann coupling, see: d) B. Kim, A. J. Chinn, D. R. Fandrick, C. H.
Senanayake, R. A. Singer, S. J. Miller, J. Am. Chem. Soc. 2016, 138,
7939.
[9]
[14] Z. Huang, X. Huang, B. Li, C. Mou, S. Yang, B.-A. Song, Y. R. Chi, J.
Am. Chem. Soc. 2016, 138, 7524.
[15] a) E. M. Phillips, M. Wadamoto, H. S. Roth, A. W. Ott, K. A. Scheidt,
Org. Lett. 2009, 11, 105; b) Y. Kawanaka, E. M. Phillips, K. A. Scheidt,
J. Am. Chem. Soc. 2009, 131, 18028; c) K. B. Ling, A. D. Smith, Chem.
Commun. 2011, 47, 373; d) J. E. Taylor, D. S. B. Daniels, A. D. Smith,
Org. Lett. 2013, 15, 6058.
[16] M. J. Frisch, G. W. Trucks, H. B. Schlegel, et al Gaussian 09, Revision
A.02, Gaussian, Inc., Wallingford CT, 2009.
[17] a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215; b) H.
Yang, M. W. Wong, J. Am. Chem. Soc. 2013, 135, 5808; c) B. Cho, C.-
H. Tan, M .W. Wong, J. Org. Chem. 2012, 77, 6553; d) C. W. Kee, M.
W. Wong, J. Org. Chem. 2016, 81, 7459.
[10] a) B.-F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. Int. Ed.
2008, 47, 4882; Angew. Chem. 2008, 120, 4960; b) L. Chu, X.-C.
Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu, J. Am. Chem. Soc. 2013,
135, 16344; c) B. N. Laforteza, K. S. L. Chan, J.-Q. Yu, Angew. Chem.
Int. Ed. 2015, 54, 11143; Angew. Chem. 2015, 127, 11295.
[11] For selected recent reviews, see: a) X. Bugaut, F. Glorius, Chem. Soc.
Rev. 2012, 41, 3511; b) J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A.
Scheidt, Angew. Chem. Int. Ed. 2012, 51, 11686; Angew. Chem. 2012,
124, 11854; c) J. Douglas, G. Churchill, A. D. Smith, Synthesis 2012,
2295; d) S. D. Sarkar, A. Biswas, R. C. Samanta, A. Studer, Chem.–Eur.
J. 2013, 19, 4664; e) S. J. Ryan, L. Candish, D. W. Lupton, Chem. Soc.
Rev. 2013, 42, 4906; f) M. N. Hopkinson, C. Ricter, M. Schedler, F.
Glorius, Nature, 2014, 510, 485; g) P. Chauhan, D. Enders, Angew.
Chem. Int. Ed. 2014, 53, 1485; Angew. Chem. 2014, 126, 1509; h) J.
Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696; i) D. M.
Flanigan, F. Romnov-Michailidis, N. A. White, T. Rovis, Chem. Rev.
2015, 15, 9307.
[12] For NHC catalyzed resolution of alcohol see: a) N. T. Reynolds, J.
Read de Alaniz, T. Rovis, J. Am. Chem. Soc. 2004, 126, 9518; b) A.
Chan, K. A. Scheidt, Org. Lett. 2005, 7, 905; c) B. E. Maki, A. Chan, E.
M. Phillips, K. A. Scheidt, Org. Lett. 2007, 9, 371; d) S. De Sarkar, A.
biswas, C. H. Song, A. Studer, Synthesis 2011, 12, 1974; e) S. Lu, S. B.
Poh, W.-Y. Siau, Y. Zhao, Angew. Chem. Int. Ed. 2013, 52, 1731;
Angew. Chem. 2013, 125, 1775; f) S. Lu, S. B. Poh, W.-Y. Siau, Y.
Zhao, Synlett 2013, 24, 1165; g) S. Lu, S. B. Poh, Y. Zhao, Angew.
Chem. Int. Ed. 2014, 53, 11041; Angew. Chem. 2014, 126, 11221; h) S.
Kuwano, S. Harada, B. Kang, R. Oriez, Y. Yamaoka, K. Takasu, K.-I.
[18] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009,
113, 6378.
[19] C. Y. Legault, 1.0 BETA ed.; Université de Sherbrooke, 2012.
[20] a) M. Nadal-Ferret, R. Gelabert, M. Moreno, J. M. Lluch, J. Am. Chem.
Soc. 2014, 136, 3542; b) W. W. Cleland, Adv. Phys. Org. Chem. 2010,
44, 1; c) W. W. Cleland, Science, 1994, 264, 1887.
[21] Similar issue has been reported in DFT studies of NHC-catalyzed
annulation reaction and Michael addition, see: a) L. Lyngvia, J. W.
Bode, F. Schoenebeck, Chem. Sci. 2012, 3, 2346; b) L. R. Domingo, J.
A. Sáezb, M. Arnó. Org. Biomol. Chem. 2014, 12, 895.
[22] a) J. Mahatthananchai, P. Zheng, J. W. Bode, Angew. Chem. Int. Ed.
2011, 50, 1673; Angew. Chem. 2011, 123, 1711; b) S. M. Langdon, C.
Y. Legault, M. Gravel, J. Org. Chem. 2015, 80, 3597.
[23] J. I. Seeman, Chem. Rev. 1983, 83, 83.
[24] J. P. Foster, F. Weinhold, J. Am. Chem. Soc. 1980, 102, 7211.
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10.1002/chem.201605445
Chemistry - A European Journal
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Shenci Lu, Xiaoxiao Song, Si Bei Poh, Hui
Yang, Ming Wah Wong, and Yu Zhao
Page No. – Page No.
Access to Enantiopure Triarylmethanes
and 1,1-Diarylalkanes by NHC-Catalyzed
Acylative Desymmetrization
We present here a general, efficient and enantioselective synthesis of triarylmethanes
and 1,1-diarylalkanes through NHC-catalyzed acylative desymmetrization of bisphenols.
This method utilizes readily available substrates, reagents and a simple procedure to
deliver the valuable products in excellent enantiopurity. DFT calculations provided a
transition state model featuring a combination of intramolecular hydrogen bond and steric
effect to explain the enantioselectivity.
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