Organocatalytic asymmetric synthesis of 1,1-diarylethanes by transfer hydrogenation

Article abstract of DOI:10.1021/ja510980d

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

Full text of DOI:10.1021/ja510980d

Article
pubs.acs.org/JACS
Organocatalytic Asymmetric Synthesis of 1,1-Diarylethanes
by Transfer Hydrogenation
Zhaobin Wang,† Fujin Ai,‡ Zheng Wang,† Wanxiang Zhao,† Guangyu Zhu,*,‡ Zhenyang Lin,*,†
and Jianwei Sun*,†
†Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
‡Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, China
S
* Supporting Information
ABSTRACT: A new organocatalytic transfer hydrogenation strategy for the
asymmetric synthesis of 1,1-diarylethanes is described. Under mild condi-
tions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or
indole unit could be obtained with excellent efficiency and enantioselectivity.
We also extended the protocol to an unprecedented asymmetric hydro-
arylation of 1,1-diarylalkenes with indoles for the synthesis of a range of
highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon
quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive
cytotoxicity against a number of human cancer cell lines. Preliminary mecha-
nistic studies combined with DFT calculations provided important insight
into the reaction mechanism.
protocols have been developed, among which C(sp2)−C(sp3)
INTRODUCTION
■
cross-coupling (Scheme 1a) and hydrogenation of 1,1-diaryl-
1,1-Diarylalkane is an important structural unit in numerous
alkenes (Scheme 1b) represent the two major strategies that
biologically active natural products and synthetic molecules,
have been pursued with general success. However, although
including a number of notable pharmaceuticals (e.g., tolter-
odine and sertraline).1,2 Among them, unsymmetrically substi-
significant progress has been achieved, additional new efficient
tuted 1,1-diarylethanes are particularly noteworthy because
of their versatile applications in potential treatment of a wide
range of diseases, such as insomnia, autoimmune disorders,
inflammation, cancers, obesity, etc. (representative structures
I−V shown Figure 1).2
Scheme 1. Typical Strategies for 1,1-Diarylmethine
Stereocenter Formation
As a result of the significance of these important diaryl-
methine pharmacophores, the development of efficient strate-
gies for their enantioselective synthesis has been the focus of
intense investigations.3−5 A variety of state-of-the-art catalytic
Received: October 25, 2014
Figure 1. Representative bioactive 1,1-diarylethanes.
© XXXX American Chemical Society
A
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a
catalytic systems remain in high demand. Of particular note is
the fact that the majority of these known strategies are based
on metal catalysis, and removal of trace metal residues in
pharmaceutical manufacturing processes is often tedious and
costly. Herein we report a metal-free asymmetric transfer hy-
drogenation strategy for the synthesis of 1,1-diarylethanes with
high efficiency and enantioselectivity (Scheme 1c) as well as the
identification of a lead compound with impressive inhibitory
activity against a number of cancer cell lines.
Table 1. Reaction Optimization
In the past decade, organocatalytic asymmetric transfer
hydrogenation (ATH) has evolved as an attractive metal-free
biomimetic alternative to the metal-based approaches.6
A
number of functional groups (e.g., ketimines, ketones, electron-
deficient olefins) can be smoothly reduced with high
enantioselectivity under mild conditions. A variety of elegant
cascade processes involving ATH have also been designed to
provide rapid access to highly enantioenriched heterocycles.
Nevertheless, there still remain challenges in this field. For
example, unactivated and electron-rich olefins have met with
limited success. Specifically, to our knowledge, the ATH of
1,1-diarylalkenes lacking an electron-withdrawing group has
not been realized in general. However, in contrast to metal-
catalyzed hydrogenation, where reactivity is generally trivial but
differentiation of the two aryl groups for chiral induction is
challenging, organocatalytic ATH in this scenario would require
solutions to both challenges (reactivity and chirality).
RESULTS AND DISCUSSION
■
To overcome the above challenges, we resorted to a possible
removable directing group on one of the two aryl groups.7 In
our initial study, a hydroxyl group was installed in the model
substrate 1a. Fortunately, with the Hantzsch ester 2a as the
hydride donor, the transfer hydrogenation of 1a in the presence
of a chiral phosphoric acid catalyst proceeded smoothly to pro-
vide the desired 1,1-diarylethane 3a in generally excellent yield
(Table 1).8 Moderate to good enantioselectivity was observed
with various chiral phosphoric acid catalysts. Among them, the
BINOL-derived acid A1 provided the best results.9 Other
Hantzsch esters and reaction solvents were also effective but
with either reduced yield or diminished enantioselectivity. The
use of 4 Å molecular sieves (MS) slightly increased the enan-
tioselectivity. Reduced loading of the catalyst (to 5 or 2.5 mol %)
or the hydride donor (to 1.5 equiv) did not result in significant
erosion of the reaction efficiency or enantioselectivity (entries
16−18).
With the established protocol, we next examined the reaction
scope. As shown in Scheme 2, a range of 1,1-diarylethylenes all
smoothly participated in the asymmetric transfer hydrogenation
to afford the corresponding 1,1-diarylethanes in high yield.
For easy purification, most of the products were protected with
a TMS group after treatment of the reaction mixture with
TMSCl and Et3N. It is noteworthy that the diarylmethine
tertiary stereocenters were mostly generated with excellent
stereocontrol. The mild conditions can tolerate a range of
functional groups, including silyl ethers, alkenes, alkynes, thio-
ethers, etc. It is also worth noting that the CC bonds in 3d
and 3j were not reduced under the standard conditions,
demonstrating chemoselectivity and highlighting the effect of
the directing group.
a
Reaction scale: 1a (0.1 mmol), 2 (2 equiv), catalyst (10 mol %),
b
solvent (2.0 mL), rt, 12 h. GC yields with n-decane as the internal
standard. Run with 4 Å MS as an additive. 5 mol % catalyst loading.
2.5 mol % catalyst loading. Run with 1.5 equiv of 2a.
c
d
e
f
subunits in numerous natural products and biologically active
molecules.10 However, under the standard conditions, the
reaction of 4a proceeded with disappointingly low enantiose-
lectivity (49% ee), although a clean conversion to the desired
transfer hydrogenation product 5a was observed. The enan-
tioselectivity could not be significantly improved simply by
lowering the reaction temperature (59% ee at −30 °C) or using
a different catalyst. In contrast to those substrates in Scheme 2,
4a does not have an o-hydroxy directing group, which is pre-
sumably the reason for the increased difficulty in stereocontrol.
Driven by the importance of this type of indole product, we
screened a wide range of conditions. After considerable effort,
we were pleased to find that with benzothiazoline 6 as the
reductant and A2 as the catalyst, the asymmetric transfer hydro-
genation of 4a proceeded with both high chemical efficiency
and excellent enantioselectivity (91% yield, 91% ee).11 This
new standard protocol is general for the synthesis of a range of
indole-substituted 1,1-diarylethanes (5b−e; Scheme 3). To the
best of our knowledge, general and efficient asymmetric hydro-
genation of indole-substituted 1,1-diarylalkenes of this type is
unknown.12
Furthermore, we were also interested in evaluating the gener-
ality of our protocol for indole-substituted 1,1-diarylethylenes
(e.g., 4a; Scheme 3), considering the fact that indole-containing
compounds are versatile synthetic building blocks and useful
As depicted in Scheme 4, we have proposed a possible
reaction mechanism. The electron-rich styrene substrate 1 is
B
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a
Scheme 2. Scope Study of the ATH Reaction
Scheme 3. Reactions of Indole-Substituted Olefins
a
Products 3 have Rf values very close to that of the pyridine byproduct
(from oxidation of 2a). To simplify purification, the reaction mixtures
were treated with TMSCl and Et3N upon completion. The
corresponding silyl ethers were obtained as the products (except for
Scheme 4. Possible Reaction Mechanism
b
3c, 3h, and 3i). Run at 60 °C for 5 days.
initially protonated by the catalyst to form the tertiary carbo-
cation intermediate IM-R1, in which the chiral phosphate anion
also interacts with the hydroxyl directing group via hydrogen
bonding. The ionic form has a neutral resonance structure
IM-R2, which is an activated o-quinone methide (o-QM) form.
The two resonance structures are the two extreme forms of the
actual intermediate regarding electron density distribution. Pre-
sumably the intermediate is more represented as the activated
o-QM form in nonpolar organic solvents (e.g., DCM). Sub-
sequent hydride addition forms the observed product and
regenerates the chiral acid catalyst.13 The stereochemistry is
controlled by the chiral anion (as in chiral ion-pairing catalysis)
or the chiral acid (as in hydrogen-bonding catalysis).
To gain further insight into the reaction mechanism, parti-
cularly on the major form of the intermediate and the absolute
stereocontrol, we carried out B3LYP-D3 density functional
theory (DFT) calculations.9 First of all, the simplified structures
of the possible intermediates (E)- and (Z)-IM′ employing a
biphenyl-based phosphoric acid were calculated (Figure 2). The
distinct bond lengths of the C−C bonds in the six-membered
ring clearly indicate that the intermediate should indeed be
more represented as an activated o-QM (IM-R2), in contrast to
the essentially equal bond lengths expected in the aryl ring of
the ionic form (IM-R1).
Figure 2. DFT-calculated structures of the simplified intermediate (IM′).
Notably, although the E isomer is more stable than the
Z isomer (+2.1 kcal/mol), the barrier for the formation of
(Z)-IM′ is lower than that for (E)-IM′ (ΔΔG⧧ = 2.0 kcal/mol).
More importantly, the first step (i.e., the formation of the QM
intermediate) is rate-determining, and the subsequent hydride
addition is a fast step. The results were also confirmed by
experiments. Indeed, kinetic studies indicated that the reaction
C
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Table 2. Other Substrates without an o-Hydroxy Group
Figure 3. Zeroth-order kinetics of Hantzsch ester 2a.
is zeroth-order in Hantzsch ester 2a (Figure 3). Isotope-labeling
experiments also showed that the first step is irreversible.9 Thus,
the Z isomer, though less stable, is preferentially generated for
subsequent rapid hydride addition.
DFT calculations also indicated that in the transition state of
the hydride addition, the Hantzsch ester N−H has a hydrogen-
bonding interaction with the catalyst phosphoryl oxygen, and
thus, the hydride is delivered to the side of the (Z)-o-QM plane
where the catalyst resides.14 This rationale is also consistent
with the observed absolute stereochemical outcome.15
To further probe the reaction mechanism, we performed
some control experiments. We protected the free o-hydroxyl
directing group and subjected the analogue 1h′ to the standard
conditions. No reaction was observed (eq 1), thereby confirming
a
The remainder of the mass balance is the styrene starting material or
the corresponding styrene from dehydration (entries 3 and 4). The
products from entries 1, 3, and 4 have Rf values very similar to those of
b
the remaining styrenes, so these yields are NMR yields. Isolated yield.
c
Run for 3 days.
identified that with catalyst A4, substrates with a p-hydroxyl
group could smoothly react to form the desired hydrogenation
products with good enantioselectivity (entries 1 and 2). Under
the same conditions, racemic tertiary alcohols 1q and 1r were
also suitable substrates. In view of the above mechanistic analysis,
we believe that these reactions might involve the intermediacy of
p-quinone methides (p-QMs). The observed low reaction rate in
these cases could be explained by the ineffective synergistic
activation and delivery of the Hantzsch ester nucleophile to the
remote δ position of the p-QMs, considering that the primary
activation by the bifunctional catalyst is located at the p-oxygen
moiety (carbonyl of the p-QM). However, the stereocontrol in
these cases remained reasonably good, particularly in view of the
remote control in the absence of an ortho anchoring group. It is
worth mentioning that catalytic asymmetric reactions of p-QMs
with high enantioselectivity are very scarce and remain chal-
lenging.17 In particular, those with δ,δ-disubstituted p-QMs are
essentially unknown. Finally, o-aminostyrene 1s could also
participate in the asymmetric transfer hydrogenation to form 3s
(entry 5).
Finally, in addition to the use of Hantzsch esters as the
reaction partners, we also evaluated indole nucleophiles, hoping
to achieve a formal asymmetric hydroarylation of the 1,1-
diarylethylenes. Gratifyingly, subjection of 1a and indole to the
standard conditions formed the desired triarylethane 8a, but
with a low reaction rate (∼50% conversion, 48 h) and moderate
enantioselectivity (76% ee) (Scheme 5). It is worth noting that
chiral 1,1,1-triarylalkanes represent another important family
of pharmacophores in medicinal chemistry, particularly with an
the importance of the free hydroxyl group that is required to
form the o-QM intermediate. Furthermore, we also employed
racemic tertiary alcohol 7 as the substrate, which can potentially
generate the common o-QM intermediate after protonation
followed by loss of a water molecule.16 Indeed, the same 1,1-
diarylethane 3a was generated under the standard conditions,
but the reaction proceeded with a much lower rate and the
enantioselectivity was also much lower (42% conversion,
46% ee; eq 2). We believe that the generation of the o-QM
intermediate is relatively slow compared with the situation
using 1a as the starting material. Moreover, in the first step, the
selectivity (barrier difference) for the formation of the (Z)-QM
and (E)-QM intermediates might not be as good as that with
1a, thereby compromising the product enantiomeric excess.
Aiming to further expand the scope of the reaction, we
examined additional substrates without an o-hydroxyl directing
group (Table 2). Although the previous standard conditions
could not be directly applied to achieve good enantioselectivity,
presumably because of the loss of the anchoring group for effec-
tive stereocontrol, subsequent extensive conditions optimization
D
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Scheme 5. Asymmetric Hydroarylation of 1,1-Diarylalkenes
1 with Indoles
Scheme 6. Transformations of the ATH Product 3a
a
overall yield with excellent enantioselectivity, demonstrating
the reliability of the protocol.
We were intrigued by the potential biological activities of
these diaryl- and triarylalkanes,2 and thus, we randomly selected
a number of our reaction products for the evaluation of
cytotoxicity in different human cancer cells, including A549
(lung cancer), HeLa (cervical cancer), and MCF-7 (breast
cancer). The results are summarized in Table 3. In human lung
Table 3. Cytotoxicities in Human Cancer Cells
a
IC50 (μM)
compound
A549
HeLa
MCF-7
nd
3d
3b
3j
32.6 4.6
25.9 2.8
35.1 1.5
42.0 4.2
33.2 2.6
7.5 0.6
nd
26.6 0.8
25.3 1.2
nd
nd
3l
nd
nd
3g
3m
8a
8c
8d
nd
nd
1.5 0.2
21.7 0.8
nd
5.9 0.7
19.3 6.4
nd
26.7 2.2
17.9 4.8
26.1 1.0
0.21 0.06
nd
nd
b
Dox
0.07 0.01
0.05 0.01
a
Run with 10 mol % (S)-B3 at 60 °C for 4 days.
a
IC50 values were measured by an MTT assay upon 72 h drug
treatment. Values were obtained through independent measurement of
b
cell viabilities. nd = not determined. Doxorubicin (Dox) was used as a
positive control.
indole moiety incorporated.10,18 Aiming to improve the reaction
results, we did some optimization of the reaction conditions and
finally found that the SPINOL-derived acid (S)-B2 could
catalyze the transformation with both excellent efficiency and
enantioselectivity (98% yield, 91% ee). Thus, the reaction
represents a new asymmetric alkene hydroarylation to form all-
carbon quaternary stereocenters.19,20 A brief scope study indi-
cated that the new conditions are general, and a range of highly
functionalized indole-containing triarylethanes were obtained
with excellent efficiency and enantioselectivity, including those
lacking a p-alkoxy group (8e and 8f) or an o-hydroxyl group (8k
and 8l).
cancer cells, most of the tested compounds exhibited cyto-
toxicity with median inhibitory concentration (IC50) values in
the micromolar range. Compounds 3b, 3m, and 8a also effec-
tively inhibited the proliferation of human cervical and breast
cancer cells. Notably, 3m showed impressive cytotoxicity in all
of these cancer cells with IC50 values in the low micromolar
range.21 The cell viability upon treatment with 3m is shown
in Figure 4. The results suggest that compound 3m and its
analogues might be promising anticancer agents for further
investigation.
We also carried out some derivatizations of the transfer
hydrogenation product 3a, particularly to verify the removable/
convertible feature of the hydroxyl directing group. 3a
could easily be converted to aryl triflate 9 (Scheme 6). Under
Pd-catalyzed hydrogenation conditions, the triflate moiety was
removed under mild conditions to form 10 in 85% yield. In
addition, the aryl triflate can undergo smooth cross-coupling
reactions to install an allyl or phenyl group with excellent
efficiency. Notably, in all of these transformations the diary-
lmethine stereocenter was essentially not touched. A gram-
scale two-step reaction from 1a also delivered triflate 9 in good
CONCLUSION
■
We have demonstrated a new organocatalytic transfer hydro-
genation strategy for the efficient asymmetric synthesis of 1,1-
diarylethanes, an important family of compounds with broad
medicinal and agricultural applications. With suitable design
of the substrates by employing a removable o-hydroxyl group,
we were able to achieve excellent reaction efficiency as well
as asymmetric induction under mild conditions. Preliminary
mechanistic studies confirmed the critical importance of the
free hydroxyl group, which is required for the in situ generation
E
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of the o-quinone methide intermediate. DFT calculations
provided important insight into the reaction mechanism. The
free hydroxyl group in the products can be easily removed or
converted to other useful functional groups. Furthermore, after
careful modifications of the reaction conditions, we also success-
fully extended the protocol to the asymmetric transfer hydro-
genation of a range of indole-substituted 1,1-diarylethylenes as
well as styrenes without a directing group. Further extension of
the protocol to asymmetric hydroarylation of 1,1-diarylalkenes
with indoles was also successfully achieved, featuring efficient
formation of the intermolecular C−C bonds and the challenging
acyclic all-carbon quaternary stereocenters with excellent stereo-
control. Finally, a preliminary biological study indicated that
the enantioenriched diaryl- and triarylalkanes obtained from our
reactions exhibit impressive cytotoxicity against a number of
human cancer cell lines. Further investigations of biological activi-
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ASSOCIATED CONTENT
* Supporting Information
Experimental and computational details, bioactivity study, and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
sunjw@ust.hk
■
(4) For leading reviews/highlights on asymmetric hydrogenation of
terminal diarylalkenes, see: (a) Besset, T.; Gramage-Doria, R.; Reek, J.
chzlin@ust.hk
guangzhu@cityu.edu.hk
Notes
N. H. Angew. Chem., Int. Ed. 2013, 52, 8795−8797. (b) Pam
Andersson, P. G.; Dieg
uez, M. Chem.Eur. J. 2010, 16, 14232−14240.
For representative leading references, see: (c) Mazuela, J.; Verendel, J.
J.; Coll, M.; Schaffner, B.; Borner, A.; Andersson, P. G.; Pamies, O.;
uez, M. J. Am. Chem. Soc. 2009, 131, 12344−12353. (d) Mazuela,
J.; Norrby, P.-O.; Andersson, P. G.; Pamies, O.; Dieguez, M. J. Am.
̀
ies, O.;
́
̀
̈
̈
The authors declare no competing financial interest.
Dieg
́
̀
́
ACKNOWLEDGMENTS
■
Chem. Soc. 2009, 131, 13634−13645. (e) Wang, X.; Guram, A.; Caille,
S.; Hu, J.; Preston, J. P.; Ronk, M.; Walker, S. Org. Lett. 2011, 13,
1881−1883. (f) Bess, E. N.; Sigman, M. S. Org. Lett. 2013, 15, 646−
649. (g) Caille, S.; Crockett, R.; Ranganathan, K.; Wang, X.; Woo, J. C.
S.; Walker, S. D. J. Org. Chem. 2011, 76, 5198−5206. (h) Wang, X.;
Guram, A.; Caille, S.; Hu, J.; Preston, J. P.; Ronk, M.; Walker, S. Org.
Lett. 2011, 13, 1881−1883.
Financial support was provided by Hong Kong RGC
(ECS605812, GRF604513, GRF603313, M-HKUST607/12)
and City University of Hong Kong (Project 7004024).
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Article
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Ed. 2014, 53, 13258−13263. It is worth mentioning that all of these
examples invole β-monosubstituted o-QMs. Asymmetric reactions with
β,β-disubstituted o-QMs remain challenging, and our reaction
represents an early example.
(14) A similar interaction has also been proposed before. See: Simon
́
,
L.; Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741−8747.
(15) Regarding the enantioselectivity drop with 1-naphthyl
substitution (3m′ in Scheme 2), a plausible explanation is as follows.
The naphthyl substituent further extends the conjugation of the o-QM
intermediate. As a result, the charge density in the o-QM is more
delocalized, which reduces the intermolecular interaction between the
o-QM and HA*, thereby diminishing the enantiomeric discrimination.
(16) In a parallel study in our lab, the asymmetric substitution of
such tertiary alcohols by indoles was achieved. See: Zhao, W.; Wang,
Z.; Chu, B.; Sun, J. Angew. Chem., Int. Ed. 2014, DOI: 10.1002/
anie.201405252.
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M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660−6662. For
various subsequent reports on ATH in this field (>50 papers), mostly
employing different imines, carbonyls, or their conjugated forms as
substrates or intermediates, see the reviews in ref 6a−e. For selected
relevant examples, see: (h) Martin, N. J. A.; List, B. J. Am. Chem. Soc.
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(17) We are aware of only one report on catalytic asymmetric
reactions of p-QMs with high enantioselectivity, which deals with δ-
monosubstituted p-QMs. See: Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao,
X.-H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan,
C.-A. Angew. Chem., Int. Ed. 2013, 52, 9229−9233. Examples involving
δ,δ-disubstituted p-QMs are essentially unknown.
(18) For selected reviews and reports on the utility of 1,1,1-
triarylalkanes, see: (a) Shchepinov, M. S.; Korshun, V. A. Chem. Soc.
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(20) Terada and co-workers pioneered asymmetric nucleophilic
addition to 3-vinylindoles to form indol-3-yl tertiary stereocenters.
See: Terada, M.; Moriya, K.; Kanomata, K.; Sorimachi, K. Angew.
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(21) We also evaluated the cytotoxicity of 3m in certain types of
normal mammalian cells and found that 3m is more active in the
cancer cells. See the Supporting Information for more details.
(7) For a review of substrate-directable reactions, see: Hoveyda, A.
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(9) See the Supporting Information for details.
(10) For reviews of indole in natural products and bioactive
molecules, see: (a) Sundberg, R. J. Indoles; Academic Press: London,
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(11) Benzothiazoline 6 was first introduced by Akiyama for
asymmetric transfer hydrogenation reactions. See: (a) Zhu, C.;
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Mori, K.; Akiyama, T. Org. Lett. 2012, 14, 3312−3315.
(12) There are a few approaches to access indole-substituted 1,1-
diarylalkanes (e.g., ref 1i), but they are not applicable to 1,1-
diarylethanes.
(13) o-QMs are important species in organic synthesis. For reviews,
see: (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367−5405. (b) Pathak, T. P.; Sigman, M. S. J. Org. Chem. 2011, 76,
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o-QMs, see ref 1i and: (d) Jensen, K. H.; Pathak, T. P.; Zhang, Y.;
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Lett. 2012, 14, 4074−4077. During the revision of this manuscript,
additional examples appeared. See: (g) El-Sepelgy, O.; Haseloff, S.;
G
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