Enantioselective Synthesis of Cyclohexenol Derivatives from ?-Aryl-Substituted Enals via an Organocatalyzed Three-Component Reaction

Article abstract of DOI:10.1021/acs.orglett.9b03532

A three-component reaction between ?-aryl-substituted α,β-unsaturated aldehydes and nitroalkenes was realized by using cinchona alkaloid-derived (thio)ureas and squaramides via the dienolate intermediates. This unprecedented 1,3- A nd 1,5-reactivity of dienolates of the ?-aryl-α,β-unsaturated aldehydes led to the formation of cyclohexenol derivatives with four contiguous stereogenic centers and a chiral substituent at C2 with good diastereoselectivities and high ee values. Such reactivities of the dienolates are totally different from those of the corresponding dienamine intermediates.

Full text of DOI:10.1021/acs.orglett.9b03532

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of Cyclohexenol Derivatives from γ‑Aryl-
Substituted Enals via an Organocatalyzed Three-Component
Reaction
Debashis Majee, Satish Jakkampudi, Hadi D. Arman, and John C.-G. Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, United States
S
* Supporting Information
ABSTRACT: A three-component reaction between γ-aryl-substituted α,β-unsaturated aldehydes and nitroalkenes was realized
by using cinchona alkaloid-derived (thio)ureas and squaramides via the dienolate intermediates. This unprecedented 1,3- and
1,5-reactivity of dienolates of the γ-aryl-α,β-unsaturated aldehydes led to the formation of cyclohexenol derivatives with four
contiguous stereogenic centers and a chiral substituent at C2 with good diastereoselectivities and high ee values. Such
reactivities of the dienolates are totally different from those of the corresponding dienamine intermediates.
α,β-Unsaturated aldehydes are versatile substrates in amine-
mediated organocatalysis.1,2 In fact, the activation of these
substrates via the formation of iminium intermediates with the
amine catalysts was recognized in the beginning of organo-
catalysis,3 and many useful synthetic methodologies based on
this activation mode have been established since then.1,2,4 In
recent years, activation of enolizable α,β-unsaturated aldehydes
via the formation of dienamine intermediates with the amine
catalysts has also received considerable attention (Scheme
1).5,6 The dienamine intermediate may have 1,3- (i.e., α-
Scheme 2. Comparison of Dienamine- and Dienolate-
Mediated Reactions of 1a and 2a [Ar = 3,5-(CF3)2C6H3-]
Scheme 1. Formation of Dienamine and Dienolate
Intermediates of an Enolizable α,β-Unsaturated Aldehyde
enolizable α,β-unsaturated aldehyde was essentially unrecog-
nized in organocatalysis. The single example that we found in
the literature is the formation of dienolates from α,γ-diphenyl-
substituted enals as reported by Xu and co-workers.7 During
our recent study of a reaction between 1a and 2a catalyzed by
the modularly designed organocatalyst (MDO) self-assembled
from quinidine thiourea (5a) (Figure 1) and L-proline,8 the
formation of an unexpected product 4a was observed, albeit in
very low yield (Scheme 2, lower equation). Subsequent control
experiments revealed that the reaction was not catalyzed by the
functionalization), 1,5- (i.e., γ-functionalization), 2,5- (i.e., [4 +
2] cycloadditions), or 4,5-reactivity (i.e., [2 + 2], [2 + 3], and
[2 + 4] cycloadditions) depending on the electrophile or the
catalyst.5,6 For example, Jørgensen and co-workers reported
that the dienamine of trans-4-phenylbut-2-enal (1a) reacts with
trans-β-nitrostyrene (2a) to give the [2 + 2] cycloaddition
product 3a (Scheme 2, upper equation).6d Nonetheless, the
reactivity of the corresponding dienolate intermediate of the
Received: October 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Catalyst Screening and Optimization of the
a
Conditions for the Three-Component Reaction
b
c
d
entry
catalyst
solvent
THF
THF
THF
THF
THF
THF
THF
1,4-Dioxane
Ether
Toluene
Benzene
CH2Cl2
CHCl3
CH3CN
MeOH
THF
THF
THF
THF
yield (%)
dr
ee (%)
53
64
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
41
53
0
60:40
65:35
−
e
−
51
34
80
75
62
46
40
60
42
40
72
36
62
70
21
34
79:21
70:30
88:12
81:19
78:22
81:19
83:17
82:18
88:12
82:18
85:15
54:46
85:15
85:15
82:18
87:13
95
97
99
e
97
98
97
97
97
99
98
98
97
96
99
98
99
10
11
12
13
14
15
f
16
g
17
18
h
i
19
a
Unless otherwise indicated, all of the reactions were carried out with
1a (0.20 mmol), 2a (0.60 mmol), and catalyst 5 (0.04 mmol, 20 mol
%) in the specified solvent (0.7 mL) at room temperature for 72 h.
Figure 1. Structures of selected catalysts employed in this study [Ar =
3,5-(CF3)2C6H3-].
b
Yields of the isolated products after column chromatography.
c
1
Determined by H NMR analysis of the crude reaction mixtures.
d
e
Determined by HPLC analysis. The opposite enantiomer was
f
MDO but instead that 5a was solely responsible for the
formation of this product. Most likely, product 4a is formed
through a three-component reaction between 1a and 2a (two
molecules of 2a are involved) via domino9 1,3- and 1,5-
dialkylation of the dienolate intermediate by the nitroalkene
followed by an intramolecular Henry reaction. Herein we
report a highly diastereo- and enantioselective three-
component reaction between γ-aryl-substituted α,β-unsatu-
rated aldehydes and nitroalkenes that uses a cinchona alkaloid-
derived (thio)urea or squaramide as the catalyst.
While catalyst 5a led to the formation of 4a, the yield, dr,
and ee obtained for this product were low (Table 1, entry 1).
In order to find an optimal catalyst for this reaction, many
cinchona alkaloid-derived (thio)urea and squaramide catalysts
were screened. The results for some representative catalysts
(Figure 1) are collected in Table 1 (for more details, see Table
S-1). As shown in Table 1, quinine-derived thiourea 5b also led
to low yield and stereoselectivities of 4a (entry 2). Using urea
instead of thiourea, changing the hydrogen-bonding capability
of the (thio)urea moiety, or increasing the steric hindrance on
the thiourea moiety of the catalyst all failed to improve the
stereoselectivities of this reaction (for details, see the
Supporting Information). On the other hand, the 6′-thiourea
catalyst 5c failed to catalyze the desired reaction completely
(entry 3). Improved diastereoselectivity (79:21) and much
improved enantioselectivity (95% ee) were obtained when the
quinidine-derived squaramide catalyst 5d was employed (entry
4). These results indicate that a squaramide moiety at C9 is
more effective in stereocontrol than a thiourea moiety at the
same location. Previously, Jacobsen and co-workers showed
that the introduction of a secondary hydrogen-bonding site
with a chiral substituent on the thiourea moiety is helpful for
improving the stereoselectivities,10 and therefore, we synthe-
obtained as the major product. The solvent amount was 1.2 mL.
The solvent amount was 0.5 mL. The reaction was carried out at 0
°C. The catalyst loading was 10 mol %.
g
h
i
sized several new cinchona alkaloid squaramide catalysts
containing a secondary hydrogen-bonding site and a chiral
substituent, such as 5e, 5f, and 5g (Figure 1). When the
quinidine-derived squaramide 5e was applied, the product
enantioselectivity was slightly increased to 97% ee, but the
product yield was much lower than that with 5d, and the
diastereoselectivity was also slightly inferior (entry 5). To our
pleasure, when the 3,5-bis(trifluoromethyl)benzyl group on the
amide moiety of the catalyst was replaced by a benzyl group, as
in catalyst 5f, the product yield increased to 80% with a dr of
88:12 and 99% ee (entry 6). In addition, when quinine-derived
5g was applied, the opposite enantiomer of 4a was obtained in
good yield with similarly high ee (entry 7). Thus, this
screening identified the quinidine-derived squaramide catalyst
5f as the best catalyst for obtaining the three-component
reaction product 4a. Its enantiomer may be obtained by using
catalyst 5g. From the screening results, it is also obvious that
the reaction, especially the reactivity, is highly sensitive to
subtle changes in the catalyst structure.
Next, some common organic solvents were screened. As the
results in Table 1 show, the enantioselectivity of the reaction
was not much changed when different solvents were used,
including polar and protic solvents (entries 8−15). However,
the product yield and diastereoselectivity were more
susceptible to the solvent used (entries 8−15), with methanol
giving the lowest yield and diastereoselectivity of 4a (entry
15). Of all the solvents screened, THF (entry 6) produced the
highest yield and stereoselectivities for 4a. We also found that
B
DOI: 10.1021/acs.orglett.9b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the product yield was very sensitive to the concentration of the
starting materials. The latter also affected the stereo-
selectivities, albeit to a much lesser extent (entries 16 and
17). The optimal loading of THF was 0.7 mL for a 0.20 mmol
loading of 1a (entry 6). Both a higher and a lower amount of
solvent led to inferior product yields and stereoselectivities
(entries 16 and 17 vs entry 6). Furthermore, carrying out the
reaction at 0 °C (entry 18) or with a reduced catalyst loading
(i.e., 10 mol %; entry 19) led to much lower product yields.
Once the reaction conditions were optimized, the scope of
this three-component reaction was evaluated. As the results in
Table 2 show, besides trans-β-nitrostyrene (2a) (entry 1),
substituent on the phenyl ring of the enal has a negligible
influence on the reactivity and stereoselectivities of this
reaction. However, no reaction was observed when an alkyl-
substituted enal was applied (entry 15). The reaction carried
out on a 1.0 mmol scale of enal 1a yielded the desired product
4a with similar stereoselectivities and yield (entry 16).
The absolute stereochemistry of the major product was
determined by X-ray crystallographic analysis of compound 4a
(for details, see the Supporting Information).
In order to understand the reaction mechanism, we
synthesized cyclobutane derivative 3a using the reported
method6d and attempted the reaction of 3a with 2a using 5f as
the catalyst under the optimized conditions. Nonetheless, no
reaction between 3a and 2a was observed (Scheme 3). This
Table 2. Substrate Scope of the Three-Component
a
Reaction
Scheme 3. Control Reaction Conducted with Compound 3a
negative result rules out the possible involvement of 3a as an
intermediate of this reaction. We previously demonstrated that
cinchona alkaloid (thio)ureas can be used as organocatalysts to
deprotonate weakly acidic substrates,11 such as α-styrylaceta-
te.11f Xu and co-workers also demonstrated that cinchona
alkaloid derivatives can deprotonate α,γ-diphenyl-substituted
enals.7 On the basis of these results, we believe that the
reaction proceeds through the enolate mechanism via
consecutive α-functionalization (i.e., 1,3-reaction) and γ-
functionalization (i.e., 1,5-reaction). As shown in Scheme 4,
enal 1a is enolized by catalyst 5f to form dienolate 8, which is
associated with the catalyst via ionic interactions. The reaction
of 8 with 2a yields intermediate 9, which is an α-
functionalization (i.e., 1,3-reaction) product, via a transition
state similar to the one proposed for the formation of
intermediate 11 (Scheme 4, bottom). Intermediate 9 is again
enolized to form dienolate 10 by catalyst 5f. According to the
double-bond stereochemistry in the final product, this
dienolate most likely adopts an s-cis conformation (10) instead
of the s-trans conformation (12). The reaction of 10 with 2a
yields the γ-functionalization (i.e., 1,5-reaction) product 11 via
the proposed transition state (Scheme 4, bottom), in which the
Si−Si attack of the dienolate to the nitrostyrene leads to the
observed stereochemistry of the major stereoisomer. Finally, an
intramolecular Henry reaction yields the desired product 4a.
Alternatively, the reaction can also proceed with the γ-
functionalization first and then the α-functionalization (for
details, see the Supporting Information). According to this
mechanism, the failure of the 4-isopropyl-substituted enal to
participate in this reaction (Table 2, entry 15) most likely
occurs because this substrate cannot be enolized by 5f.
The obtained cyclohexenol product 4a can be readily
converted to the corresponding O-acetyl derivative 6 and the
enone derivative 7 in high yields with complete retention of
the stereochemistry (Scheme 5).
b
c
d
entry
R1
R2
4/yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a/80
4b/73
4c/70
4d/70
4e/75
4f/65
4g/68
4h/68
0
4i/68
4j/63
4k/61
4l/62
4m/65
0
88:12
84:16
80:20
78:22
85:15
76:24
80:20
92:8
99
99
98
99
99
98
98
98
−
99
95
98
99
99
−
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
3-BrC6H4
2-Thiophenyl
i-Pr
−
10
11
12
13
14
15
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
i-Pr
Ph
Ph
Ph
Ph
85:15
80:20
84:16
85:15
80:20
−
4-BrC6H4
Ph
e
16
Ph
Ph
4a/70
87:13
99
a
Unless otherwise indicated, all of the reactions were carried out with
1 (0.20 mmol), 2 (0.60 mmol), and catalyst 5f (0.04 mmol, 20 mol
b
%) in THF (0.7 mL) at room temperature for 72 h. Yields of the
c
1
isolated products after column chromatography. Determined by H
d
NMR analysis of the crude reaction mixtures. Determined by HPLC
analysis. Carried out with 1.0 mmol of 1a, 3.0 mmol of 2a, and 0.20
e
mmol of 5f (20 mol %) in THF (3.5 mL).
substituted trans-β-nitrostyrenes are also good substrates for
this reaction, and the desired products (4b−g) were obtained
in good yields and diastereoselectivities with excellent
enantioselectivities (entries 2−7). The electronic nature of
the substituent and its location on the phenyl ring have only
minimal influence on the stereoselectivity of this reaction. A
heteroaryl-substituted (2-thiophenyl) nitroalkene also led to
the formation of the expected product 4h with excellent
diastereoselectivity and enantioselectivity (entry 8). However,
an alkyl-substituted nitroalkene failed to react under the
optimized conditions (entry 9). On the other hand, different
aryl-substituted enals participated in the desired reaction and
led to the formation of the expected products (4i−m) in good
yields and diastereoselectivities with excellent enantioselectiv-
ities (entries 10−14). Again, the electronic nature of the
In summary, we have discovered a distinct reactivity of the
dienolates of γ-aryl-substituted enals catalyzed by cinchona
alkaloid-derived thioureas and squaramides, which participate
in three-component reactions with nitroalkenes via an α,γ-
dialkylation and ensuing intramolecular Henry reaction. When
squaramide 5f is used as the catalyst, the reaction yields the
C
DOI: 10.1021/acs.orglett.9b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Scheme 4. Proposed Reaction Mechanism
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cong.zhao@utsa.edu.
ORCID
John C.-G. Zhao: 0000-0001-7174-5956
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The generous financial support of this research from the Welch
Foundation (Grant AX-1593) and the National Science
Foundation (Grant CHE-1664278) is gratefully acknowledged.
The authors also thank Drs. Manisha Bihani and Sharada
Swain for conducting some initial experiments.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03532.
Detailed experimental procedures, ORTEP drawing of
compound 4a, compound characterization data, and
copies of NMR spectra and HPLC chromatograms of
the reaction products (PDF)
Accession Codes
CCDC 1883852 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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