Asymmetric conjugate addition of benzofuran-2-ones to alkyl 2-phthalimidoacrylates: Modeling structure-stereoselectivity relationships with steric and electronic parameters

Article abstract of DOI:10.1002/anie.201601028

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3-substituted benzofuranones and alkyl 2-phthalimidoacrylates is described. As predicted, new 3,5-bis(trifluoromethyl)benzyl- and methyl-substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α-amino acid derivatives with 1,3-nonadjacent stereogenic centers. A predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of the title reaction is described. As predicted, 3,5-bis(trifluoromethyl)benzyl- and methyl-substituted tertiary amine thioureas turned out to be highly suitable catalysts.

Full text of DOI:10.1002/anie.201601028

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International Edition: DOI: 10.1002/anie.201601028
German Edition: DOI: 10.1002/ange.201601028
Asymmetric Catalysis
Asymmetric Conjugate Addition of Benzofuran-2-ones to Alkyl
-Phthalimidoacrylates: Modeling Structure–Stereoselectivity
2
Relationships with Steric and Electronic Parameters
Chen Yang, En-Ge Zhang, Xin Li,* and Jin-Pei Cheng*
Abstract: A highly predictive model to correlate the steric and
electronic parameters of tertiary amine thiourea catalysts with
the stereoselectivity of Michael reactions of 3-substituted
benzofuranones and alkyl 2-phthalimidoacrylates is described.
As predicted, new 3,5-bis(trifluoromethyl)benzyl- and methyl-
substituted tertiary amine thioureas turned out to be highly
suitable catalysts for this reaction and enabled the synthesis of
enantioenriched a-amino acid derivatives with 1,3-nonadjacent
stereogenic centers.
B
enzofuran-2(3H)-ones with quaternary stereogenic centers
at the 3-position are very important structural motifs of
[1]
Scheme 1. Catalyst screening for the Michael addition of 3-substituted
benzofuranones and alkyl 2-phthalimidoacrylates by FER analysis.
biologically interesting compounds and frequently utilized
as versatile chiral building blocks for asymmetric synthesis.
Accordingly, various methods have been well established for
[2]
[
3]
the synthesis of these compounds. The generation of chiral
benzofuranones with one quaternary stereogenic center or
two adjacent stereogenic centers has been frequently docu-
mented. However, in sharp contrast, highly diastereo- and
enantioselective syntheses of chiral benzofuran-2-ones with
nonadjacent stereogenic centers in the 1- and 3-position have
not been achieved. One conceivable strategy to solve this
problem might be the conjugate addition of 3-substituted
benzofuran-2-ones to a-branched Michael acceptors. This
process has been considered to be a great challenge as it
proceeds by tandem conjugate addition–protonation and
requires the simultaneous controlled formation of two
separated stereogenic centers (Scheme 1).
Chiral bifunctional thioureas with tertiary amine substitu-
ents have received particular attention owing to their ability
to activate several functionalities, enabling a great variety of
asymmetric reactions. However, the dependence of the
stereoselectivity of such reactions on the catalyst structure has
not be carefully elucidated thus far. The use of free energy
have made remarkable contributions in finding correlations
between the outcomes of asymmetric reactions and two-,
three-, or multiple dimensional models by employing a set of
[
7]
steric, electronic, and molecular vibration parameters.
Although the increased research activity in this area is
reflected by a number of recent investigations, reports that
focus on organocatalysis and on bifunctional thiourea cata-
[6c,e–g,o,7d,e,j]
lysts in particular are still limited.
Herein, we report the highly stereoselective Michael
addition of 3-substituted benzofuranones to alkyl 2-phthali-
midoacrylates that is catalyzed by new bifunctional tertiary
amine thioureas with two simple alkyl substituents, which
could be applied to synthesize a-amino acid derivatives with
tetrasubstituted g-carbon atoms. The discovery of the new
catalysts was based on a FER analysis to determined the
catalytic performance of bifunctional thioureas; this approach
is completely different from the traditional catalyst screening
process (Scheme 1).
[
4]
Taking the addition of 3-benzylbenzofuranone (1a) to
2-phthalimidoacrylate 2a as the model reaction, we con-
ducted an FER analysis to investigate the effect of structural
parameters, that is, steric and electronic factors, on the
stereoselectivity achieved with a particular catalyst. (S,S)-
Cyclohexane-1,2-diamine-based tertiary amine thiourea cat-
alysts with different substituents were evaluated first (Table 1,
entries 1–9). The choice of proper steric parameters is very
[
5]
relationship (FER) analyses in the realm of asymmetric
catalysis has provided some understanding in recent years,
which has greatly promoted the rational design of new
catalysts and enabled reasonable predictions of new chemical
[
6,7]
transformations.
In this context, Sigman and co-workers
[
*] C. Yang, E.-G. Zhang, Prof. X. Li, Prof. J.-P. Cheng
State Key Laboratory of Elemento-organic Chemistry
Department of Chemistry, Nankai University, and Collaborative
Innovation Center of Chemical Science and Engineering
Tianjin 300071 (China)
[
7h]
important to quantify the correlation. The extensively used
Charton values were unsuitable for our steric analysis
(Supporting Information, Figure S1) because they consider
the substituents to be spherical. On the other hand, the
E-mail: xin_li@nankai.edu.cn
[8]
multifaceted Sterimol parameters (B , B , L) have been
chengjp@nankai.edu.cn
1
5
shown to be more robust in the description of steric effects in
recent correlative steric analyses. We thus applied this set of
parameters in the following analysis.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
[9]
1
002/anie.201601028.
6
506
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[
a]
Table 1: Catalyst optimization.
predicted and experimental diaste-
reoselectivities provided a slope of
.94, indicating that the predictive
power of Eq. (3) is also rather high
Figure 1b). Of particular note is
0
(
that the observed correlation
between the diastereoselectivity
and the steric parameters enriched
the scope of quantitative structure–
selectivity analyses for the first
time. Collectively, the analyses of
the stereoselectivity suggest that
methyl, ethyl, and benzyl substitu-
ents, with minimum widths and
lengths, should be considered for
further optimization.
[
b]
[c]
¼6
[d]
[e]
¼6
[d]
Entry
R
Cat.
Yield [%]
d.r.
DDG (d.r.)
e.r.
DDG (e.r.)
1
2
3
4
5
6
7
8
9
Me
Et
iPr
Bn
cHex
Ph
tBu
CEt3
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
99
99
92
99
89
79
70
57
93
96
97
98
99
99
99
93
82
6.71
5.58
3.07
4.47
2.20
3.67
2.00
1.05
4.82
4.26
4.89
5.80
5.07
4.28
3.66
3.62
4.61
1.12
1.02
0.66
0.89
0.47
0.77
0.41
0.03
0.93
0.86
0.94
1.04
0.96
0.86
0.77
0.76
0.90
13.07
10.28
5.32
11.44
4.72
4.60
2.76
1.69
9.67
11.04
13.74
14.86
16.27
18.53
15.67
12.02
8.09
1.52
1.38
0.99
1.44
0.92
0.89
0.60
0.31
1.34
1.42
1.55
1.60
1.65
1.73
1.63
1.47
1.24
iBu
We tried to further modify these
promising candidates by electronic
perturbation (Table 1, entries 10–
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
4-MeC H CH
2
4-ClC H CH
2
4-CF C H CH
2
3,4,5-F C H CH
2
3,5-(CF ) C H CH
CF CH
C F CH
2
3,5-(CF
6
4
6
4
3
6
4
1
6). The benzyl-substituted thio-
3
6
2
urea was chosen as the starting
point rather than the optimal cata-
lyst 4a because it is much easier to
tune its electronic properties by
3
2
6
3
2
3
2
2
5
3
)
2
C
6
H
3
[
a] The reactions were conducted with 1a (0.1 mmol), 2a (0.15 mmol), and 10 mol% of the catalyst in introducing substituents on the
toluene (0.5 mL) at RT for 3 days. [b] Yield of isolated product as the average of three runs.
[
R=0.001986 kcalK mol , T=298.15 K. [e] For the major diastereomer, determined by HPLC analysis
on a chiral stationary phase, averaged over three runs.
benzyl ring. Interestingly, even
though benzyl-substituted squara-
mide catalysts have been used for
¼
6
c] Determined by HPLC analysis, averaged over three runs. [d] DDG =RTln(d.r. or e.r.),
À1
À1
[10]
a long time,
thioureas have never been de-
modified benzyl
[11]
According to Eq. (1), the dependence of the stereoselec-
scribed (entries 10–14).
A very
¼6
tivity (DDG ) on steric effects can be evaluated, and the
coefficients can be determined by performing a stepwise
regression (for details, see the Supporting Information).
6¼
DDG ¼ a B þb B þc Lþd
ð1Þ
ð2Þ
ð3Þ
1
5
6¼
DDG ðe:r:Þ ¼ À0:73 B À0:13 Lþ3:2
1
6¼
DDG ðd:r:Þ ¼ À0:62 B À0:12 Lþ2:5
1
For the enantioselectivity, the best fit [Eq. (2)] included B
and L terms with R = 0.92 and p = 1.7 ” 10 with a confidence
1
2
À3
level of 95% (determined by an f-test, similarly hereinafter).
¼6
A plot of the predicted and experimentally measured DDG
values shows a very good linear correlation with a slope of
2
0
.92, a y intercept at 0.076, and R = 0.92 (Figure 1a). The
slope is close to 1.0, and the intercept value is very small,
indicating the high predictive power of Eq. (2), which was
corroborated by the analysis of additional data (Table 1,
entry 9). The negative coefficients of the B and L parameters
1
indicated that a substituent with minimum width and length
should be optimal to induce high enantioselectivity. Based on
similar principles, we conducted a quantitative analysis of the
diastereoselectivity. It was found that the same terms (B and
1
L) are statistically significant for the diastereoselectivity with
2
À3
R = 0.94 and p = 1.0 ” 10 [Eq. (3)]. Good diastereoselectiv-
ity should thus be achieved with substituents similar required
to those for high enantioselectivity. Comparison of the
Figure 1. FER analysis of steric effects.
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¼6
good linear FER was found between the DDG (e.r.) values
and the Hammett constants for a set of benzyl thioureas
(
Figure 2). As expected, the introduction of more electron-
Figure 2. FER analysis of the electronic effects of benzyl-substituted
thioureas.
withdrawing groups improved the enantioselectivity. Simi-
larly, catalysts with fluorinated ethyl and propyl substituents
also followed this rule (entries 15 and 16). The 3,5-bis(tri-
fluoromethyl)benzyl-substituted tertiary amine thiourea
[
12]
4
n,
which had never been synthesized and applied in
asymmetric catalysis, was calculated to be a favorable catalyst
for the current Michael addition. It is noteworthy that the
Figure 3. FER analysis for all catalysts.
[12,13]
performance of the Takemoto catalyst 4q
worse than that of the new catalyst 4n.
(entry 17) is
[
14]
at À308C, which gave 3a in 99% yield, > 19:1 d.r., and 97:3
e.r.
Furthermore, we noted that the model considering only
steric parameters cannot be compatible with R groups that
induce electronic perturbation (Figure S2). We then tried to
develop a new model to unite steric and electronic effects by
With the optimized reaction conditions in hand, we
subsequently evaluated the substrate scope of the addition
reaction of 3-substituted benzofuran-2-ones to 2-phthalimi-
doacrylates. As shown in Table 2, at a catalyst loading of
3 mol%, electron-withdrawing and -donating groups at the 2-,
[15–17]
introducing IR vibrations and NBO charges (Table S2).
After a stepwise regression analysis, Eq. (4) and Eq. (5) were
obtained. The good correlation between the predicted and
experimental stereoselectivities indicates that these models
can handle cases where both steric and electronic parameters
play a role (Figure 3) as the equations delineated the
activation of substrates by hydrogen bonds and the disadvan-
tages of repulsive interactions. An inspection of the corre-
sponding parameters revealed that this model also indicates
that the introduction of small electron-withdrawing groups
will generate high enantioselectivities as the aforementioned
two-step analysis did.
2
3- and 4-position of the benzyl substituent R of substrate
1 were tolerated, and their addition to ethyl and methyl
2-phthalimidoacrylates proceeded to give the corresponding
products 3a–3o in excellent yields (up to 99%) with excellent
diastereoselectivities (> 19:1 d.r.) and enantioselectivities
(96:4–98.5:1.5 e.r.). Different benzyl 2-phthalimidoacrylates
were also investigated. As expected, these 1,3-conjugate
addition reactions catalyzed by 4n under the standard
conditions proceeded smoothly, and afforded the desired
products 3p–3r in high yields (up to 96% yield) and
stereoselectivities (up to > 19:1 d.r. and 95:5 e.r.). Our further
exploration of the reaction scope focused on methyl- and
ethyl-substituted benzofuran-2-ones. Whereas the catalyst
loading had to be increased to 5 mol% to maintain acceptable
reactivities, the diastereo- and enantioselectivities of the
desired products 3s and 3t were still very good. Under
modified reaction conditions (Table S8), 3-aryl-substituted
benzofuranones can also be employed in this conjugate
addition strategy, and the Michael products 3u–3w were
obtained in high yields and stereoselectivities.
6¼
DDG1 ðe:r:Þ ¼ À0:40 B
1
þ0:0076 vN2ÀH2þ35 NBON1À4:0
ð4Þ
ð5Þ
6¼
DDG1 ðd:r:Þ ¼ À0:085 Lþ44 NBO N2þ75 NBON1ÂH1þ27
C*
The screening of several widely used bifunctional organo-
catalysts under identical conditions confirmed the conclusion
drawn from our free-energy analysis (Table S6), namely that
4
n performs best in terms of both catalytic reactivity and
stereoselectivity. With 4n as the optimal catalyst, a further
screen of the reaction conditions, including solvent, temper-
ature, and additive and catalyst loadings (Table S7), revealed
the most suitable reaction conditions to entail the use of 4n
It is noteworthy that whereas large substituents are
generally employed in ligand and catalyst design to achieve
better stereoselectivities, our steric analysis showed that the
smallest, methyl-substituted catalyst 4a gave 3a with the best
(
3 mol%) and 3 Š molecular sieves (40 mg) in chlorobenzene
6
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[
a]
Table 2: Substrate scope.
Scheme 2. Catalytic performance of methyl catalyst 4a. Reaction con-
ditions: 1 (0.1 mmol), 2 (0.15 mmol), 4a (5 mol%), 3 Š molecular
sieves (40 mg), chlorobenzene (1.0 mL), À308C, 5 days.
study and previous computational mechanistic studies on the
[19]
activation model of tertiary amine thiourea catalysts,
a preliminary mechanism was proposed (Figure S6).
[20]
In summary, the free-energy relationships between the
stereoselectivities and the properties of tertiary amine
thiourea catalysts were investigated by combining steric and
electronic parameters for the first time. Thioureas with small,
strongly electron-withdrawing N substituents were shown to
be optimal catalysts for the Michael addition of 3-substituted
benzofuranones and alkyl 2-phthalimidoacrylates. As a result,
the methyl- and 3,5-bis(trifluoromethyl)benzyl-substituted
tertiary amine thioureas identified during the free-energy
analysis were successfully applied for the synthesis of a-amino
acid derivatives with a benzofuran-2-one in the g-position and
1
,3-nonajacent stereogenic centers in high yields and stereo-
selectivities. Comprehensive studies of the mechanism are
ongoing in our laboratory.
Acknowledgements
This work was supported by the National Basic Research
Program of China (2012CB821600) and the National Natural
Science Foundation of China (21390400 and 21421062). We
thank Prof. S. Z. Luo (ICCAS), Dr. L. Zhang (ICCAS), and
Dr. S. S. Hu (UC Berkeley) for helpful discussions.
Keywords: amino acids · asymmetric catalysis ·
[
a] Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), 4n (3 mol%), 3 Š
molecular sieves (40 mg), chlorobenzene (1.0 mL), À308C, 5 days. The
enantioselectivity · free-energy relationships · hydrogen bonds
[
18]
absolute configuration was determined by X-ray analysis. Yields of
isolated products are given. The stereoselectivities were determined by
HPLC analysis on a chiral stationary phase. [b] 4n (5 mol%). [c] In
chlorobenzene/toluene (6:4, 1.0 mL).
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6506–6510
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[
Received: January 29, 2016
Revised: February 29, 2016
Published online: April 15, 2016
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