Organocatalyzed asymmetric 1,6-conjugate addition of para-quinone methides with dicyanoolefins

Article abstract of DOI:10.1021/acs.orglett.5b03471

A chiral thiourea catalyzed asymmetric 1,6-conjugate addition of para-quinone methides with dicyanoolefins has been developed. The reaction provided an efficient approach to the synthesis of chiral diarylmethine skeletons in good yields (up to 99% yield) with high diastereo- and enantioselectivity (>20:1 dr and up to 99.5:0.5 er), also on a gram scale. The preliminary mechanistic study showed that the remote stereocontrol was achieved through intermolecular hydrogen-bond interaction between the chiral thiourea catalyst and the para-quinone methides directly for the first time.

Full text of DOI:10.1021/acs.orglett.5b03471

Letter
pubs.acs.org/OrgLett
Organocatalyzed Asymmetric 1,6-Conjugate Addition of para-
Quinone Methides with Dicyanoolefins
Xuanyi Li, Xiuyan Xu, Weiwei Wei, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical
University, Nanjing, 210009, P. R. China
S
* Supporting Information
ABSTRACT: A chiral thiourea catalyzed asymmetric 1,6-
conjugate addition of para-quinone methides with dicyanoo-
lefins has been developed. The reaction provided an efficient
approach to the synthesis of chiral diarylmethine skeletons in
good yields (up to 99% yield) with high diastereo- and
enantioselectivity (>20:1 dr and up to 99.5:0.5 er), also on a
gram scale. The preliminary mechanistic study showed that the
remote stereocontrol was achieved through intermolecular hydrogen-bond interaction between the chiral thiourea catalyst and
the para-quinone methides directly for the first time.
iarylmethine stereogenic centers are important substruc-
tures found in pharmaceuticals and natural products,1
Scheme 1. Asymmetric 1,6-Conjugate Addition of p-QMs
D
such as (R)-tolterodine,1a COP-840,1b (−)-Schisandra lignan,1c
and (−)-kadangustin J1c (Figure 1). The development of
Figure 1. Selected bioactive compounds containing a chiral diary-
lmethine stereogenic center.
promising strategies for enantioselective synthesis of com-
pounds with a diarylmethine stereogenic center from simple
starting materials has attracted considerable attention in the
past decades.2 The asymmetric 1,6-conjugate addition of para-
quinone methides (p-QMs)3 provided an effective way to
achieve the skeleton. In 2013, Fan’s group reported chiral
quaternary ammonium salt-catalyzed asymmetric 1,6-conjugate
addition of p-QMs with malonates (Scheme 1a).4 In 2014,
Jørgensen’s group realized chiral secondary amine catalyzed
asymmetric 1,6-conjugate addition of p-QMs with aldehydes
through enamine catalytic mode (Scheme 1b).5 In 2015, Liao’s
group reported a copper-catalyzed 1,6-conjugate addition of p-
QMs with B2(pin)2, achieving chiral dibenzylic boronates
(Scheme 1c).6 In aforementioned works, the selectivity was
obtained from catalytically generated chiral nucleophiles rather
than the activation of the p-QMs directly. The stereoselectivity
induced by the activation of p-QMs directly is challenging,
Received: December 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
because of the increased distance between the catalyst
activation site of p-QMs (carbonyl) and the reaction center.
In 2015, Sun’s group reported chiral phosphoric acid catalyzed
1,6-conjugate addition of in situ generated p-QMs with 2-
methylpyrroles, realizing the first remote stereocontrol by
activating the p-QMs and nucleophiles simultaneously (Scheme
1d).7 In conjunction with our ongoing interest in p-QMs8 and
to explore a new asymmetric activation mode of p-QMs, herein,
we describe our results on the chiral thiourea catalyzed9 1,6-
conjugate addition of p-QMs with dicyanoolefins,10 affording
the diarylmethine stereogenic centers in good yields with good
to excellent enantioselectivity (up to 99.5:0.5 er) and high
diastereoselectivity (>20:1 dr). The preliminary mechanistic
study showed that the chiral thiourea catalyst catalyzed the p-
QMs directly through intermolecular hydrogen-bond inter-
action between the thiourea portion and the carbonyl of p-
QMs, thus leading to the remote stereocontrol.
screened, we found that toluene was better than others in terms
of yield, while from an er value standpoint the Et2O was the
best choice.
With the optimized conditions in hand, we tested an array of
substituted p-QMs and dicyanoolefins to explore the generality
of this asymmetric 1,6-conjugate addition reaction. The results
are summarized in Schemes 2 and 3. The substrates bearing a
methyl group at the 4-position of the arene afforded the
corresponding product 3ab in 84% yield with 91:9 er and 20:1
dr. The halogen (F, Cl, Br) substituted 2c−2e offered 3ac−3ae
in 81%−99% yields with 92:8−99.5:0.5 er. The absolute
configuration of 3ae was determined by X-ray crystal structure
analysis (Figure 2).12 Functional groups, such as the CF3 group,
a b
,
Scheme 2. Scope of the p-QMs
We started our investigation with the reaction between
dicyanoolefin (1a) and p-QM (2a). Compound 1a reacted with
2a, affording the desired product 3aa in 61% yield with 20:1 dr
as a racemic product under the catalysis of C1 in CH2Cl2 at
room temperature (Table 1, entry 1). To improve the
ab
,
Table 1. Optimization of Reaction Conditions
entry
cat.
t (°C)
solvent
CH2Cl2
yield (%)
dr
er
1
C1
C2
C3
C4
C5
C6
C6
C6
C6
C6
C6
C6
C6
rt
61
37
74
78
31
78
80
94
82
80
80
82
76
>20:1
>20:1
88:12
84:16
>20:1
88:12
>20:1
>20:1
>20:1
>20:1
>20:1
95:5
50:50
50:50
57:43
60:40
57:43
64:36
92:8
2
rt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
3
rt
4
rt
5
rt
6
rt
7
−40
−40
−40
−40
−40
−40
−40
8
95:5
9
mesitylene
chlorobenzene
m-xylene
DME
95:5
10
11
12
13
93:7
95:5
55:45
98:2
Et2O
>20:1
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0
equiv), catalyst (20 mol %), and Et3N (0.15 mmol, 1.5 equiv) in
b
solvent (1 mL). Isolated yield.
enantioselectivity, various catalysts were then evaluated
(Table 1, entries 2−6). The assessment of catalysts led to the
identification of C611 as the best catalyst, which furnished 3aa
with an enantiomeric ratio of 64:36. When the reaction was
performed at −40 °C, the enantiomeric ratio of 3aa was
increased to 92:8 (Table 1, entry 7). After solvents were
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.1 mmol, 1.0
equiv), C6 (20 mol %), Et3N (0.15 mmol, 1.5 equiv) in Et2O (1 mL)
b
at −40 °C for 48 h. Isolated yields.
B
DOI: 10.1021/acs.orglett.5b03471
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Organic Letters
Letter
a b
,
Next, we turned our attention to the dicyanoolefin scope. It
was found that the enantiomeric ratio of 3ca could be improved
from 83:17 to 93:7 when toluene was chosen as the solvent
instead of Et2O. As a consequence, we chose toluene as solvent
for the dicyanoolefin scope study. The substrates derived from
7-substituted 1-tetralone worked well and gave the correspond-
ing products 3ba−3da in 77%−98% yields with 86:14−93:7 er.
6-Substituted dicyanoolefins afforded 3ea−3fa in 87%−99%
yields with 93:7−96:4 er. The more flexible 2,2-dicyanoolefin
prepared from cyclohexanone was also tested, and 3ia could be
obtained in 99% yield and 20:1 dr with a low er value. When
the 2,2-dicyanoolefin derived from a seven-membered ring
ketone was tested, 3ja was obtained in 75% yield with 91:9 er.
When the dicyanoolefin derived from thiochroman-4-one was
tested, the desired product 3ka was obtained in 98% yield with
20:1 dr and 99:1 er. The acyclic dicyanoolefin (1l) could also
give the desired product 3la in 56% yield with 20:1 dr and
67:33 er.
Scheme 3. Scope of Dicyanoolefins
To test the synthetic utility of our method, 3ae was prepared
on a gram scale (Scheme 4). The reaction of 1a (2 mmol, 388.0
Scheme 4. Gram-Scale Synthesis of 3ae
a
mg) with 2e (2 mmol, 746.0 mg) under the optimal reaction
conditions afforded 3ae in 1.09 g (96% yield) maintaining the
dr and er values. Removal or functionalization of the tert-butyl
groups and dicyanoolefin could not be realized in our system at
the present stage.13
Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0
equiv), C6 (20 mol %), Et3N (0.15 mmol, 1.5 equiv) in toluene (1
b
c
mL) at −40 °C for 48 h. Isolated yields. Et2O (1 mL) as solvent.
To gain insight into the mechanism of our asymmetric 1,6-
conjugate addition, we carried out a series of mass
spectrometric studies,14 and a representative result is shown
in Scheme 5. When catalyst C6 was mixed with 1a, 2a, and
Et3N in Et2O for 40 min, a new peak characterized by m/z =
885.5 was detected and assigned to be C6 + 2a, which provided
evidence that the catalyst C6 activated 2a through intermo-
lecular hydrogen-bond interaction. The role of the phosphorus
atom in the catalytic cycle is unclear, but it may play a role as a
Lewis base to act on dicyanoolefin. Based on previous work10f
and our experimental clue, we propose an activation mode
between the catalyst and the two reactants as shown in Scheme
6. The dicyanoolefin was much more accessible to attack the
active p-QM from the Si face, affording the major stereoisomer.
In conclusion, we have developed the first example of chiral
thiourea catalyzed asymmetric 1,6-conjugate addition of p-QMs
with dicyanoolefins. This protocol provided facile access to
diarylmethine stereogenic centers in good yields, excellent
diastereoselectivity, and good to excellent enantioselectivity.
The preliminary mechanistic study showed that in our catalytic
system the remote stereocontrol was achieved through
intermolecular hydrogen-bond interaction between the chiral
thiourea catalyst and the p-QMs. Further reaction mechanistic
study is underway in our group.
Figure 2. X-ray structure of enantiopure 3ae. Thermal ellipsoids are
shown at 30% probability.
an ester group, a CN group, and a NO2 group, were all well
tolerated under the reaction conditions, leading to products
3af−3ai in 78%−91% yields with 93:7−99.5:0.5 er. Phenyl
group substituted p-QM provided the desired product 3aj in
94% yield with 90:10 er. Substrates with meta-substituents (Cl,
F, Br, Me) at benzene rings such as 2k, 2l, 2m, and 2n offered
the desired products 3ak−3an in 84%−92% yields with 96:4−
99:1 er. A substrate with an ortho-substituent at the phenyl ring
(2o) gave the desired product 3ao in 99% yield and 20:1 dr
while the er was low. Alkyl substituent p-QM was also
attempted, and the 1,6-conjugate addition product 3ap was
obtained in 47% yield with 53:47 er. Disubstituted p-QM was
also examined, and the product 3aq was obtained in 96:4 er.
C
DOI: 10.1021/acs.orglett.5b03471
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Organic Letters
Letter
Scheme 5. Species Detected by MS (ESI) Analysis of 1a and
2a after the Addition of Et3N and Catalyst C6
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(12) CCDC 1436969 contains the supplementary crystallographic
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03471.
■
S
1H and 13C NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 3ae (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) See Supporting Information for details of removal or
functionalization of the tert-butyl groups and dicyanoolefin.
(14) Shi, Y.; Lin, A.; Mao, H.; Mao, H.; Mao, Z.; Li, W.; Hu, H.; Zhu,
C.; Cheng, Y. Chem. - Eur. J. 2013, 19, 1914.
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), and the Foundation of State Key Laboratory
of Natural Medicines (ZZJQ201306) is gratefully acknowl-
edged.
D
DOI: 10.1021/acs.orglett.5b03471
Org. Lett. XXXX, XXX, XXX−XXX