Asymmetric Construction of Cyclobutanes via Direct Vinylogous Michael Addition/Cyclization of β,γ-Unsaturated Amides

Article abstract of DOI:10.1021/acs.orglett.0c02488

The construction of cyclobutanes has attracted much attention because of its unique four-membered ring skeleton. Herein, we report the highly enantioselective direct vinylogous Michael reaction of β,γ-unsaturated pyrazole amides and nitroolefin using a squaramide catalyst. Cyclobutane derivatives were obtained by subsequent cyclization in good yields (up to 85%) with excellent enantioselectivities (up to 99% ee). Importantly, the large-scale reaction experiment confirmed the reliability of the vinylogous reaction. Furthermore, the synthetic utility of the vinylogous adducts and cyclobutane derivatives has been realized.

Full text of DOI:10.1021/acs.orglett.0c02488

pubs.acs.org/OrgLett
Letter
Asymmetric Construction of Cyclobutanes via Direct Vinylogous
Michael Addition/Cyclization of β,γ-Unsaturated Amides
Yuzhen Chen, Yichen Wang, Shuzhong Wang, Yan-Yan Ma, Deng-Gao Zhao, Ruoting Zhan,
and Huicai Huang*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02488
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The construction of cyclobutanes has attracted much attention because of its unique four-membered ring skeleton.
Herein, we report the highly enantioselective direct vinylogous Michael reaction of β,γ-unsaturated pyrazole amides and nitroolefin
using a squaramide catalyst. Cyclobutane derivatives were obtained by subsequent cyclization in good yields (up to 85%) with
excellent enantioselectivities (up to 99% ee). Importantly, the large-scale reaction experiment confirmed the reliability of the
vinylogous reaction. Furthermore, the synthetic utility of the vinylogous adducts and cyclobutane derivatives has been realized.
atural products containing a cyclobutane skeleton are
Nwidely distributed, and many of them have significant
biological activities such as anticancer and antibacterial activity.1
For example, a series of alkaloid pipercyclobutanamides
containing a four-membered ring were isolated from the
branches of the pepper. The dipiperamide A has been identified
to have potent activity of cytochrome P450 (CYP) 3A4, an
important enzyme in the body (Figure 1).1c
was used in the construction of cyclobutanes. In 2012,
Jørgensen’s group used a bifunctional catalyst that simulta-
neously activates aldehydes and nitroolefins through the
formation of dienamines and hydrogen bonding to give
cyclobutane products (Scheme 1a).8 Subsequently, Vicario
and co-workers reported a [2 + 2] annulation/hemiacetal
reaction of α-hydroxymethylnitroolefin and α,β-unsaturated
aldehyde by cooperative dienamine/hydrogen-bonding catalysis
(Scheme 1b).9 Recently, Hong’s group reported a highly
enantioselective [2 + 2] annulation of allyl ketones and α-
substituent nitroalkenes for the synthesis of cyclobutane
derivatives under bifunctional catalysis (Scheme 1c).10
Compared with unsaturated aldehydes or ketones,7 β,γ-
unsaturated amides with potential enolization were less explored
as active nucleophiles in the vinylogous reaction.11 In previous
work, we investigated a dienolate-mediated asymmetric inverse-
electron-demand oxa-Diels−Alder reaction of β,γ-unsaturated
pyrazole amides with β,γ-unsaturated α-ketoesters.12 Subse-
quently, a regiodivergent vinylogous cyclization reaction of β,γ-
unsaturated pyrazole amides was demonstraed.13 Furthermore,
pyrazole as a good leaving group can be easily derivatized to
esters, amides, and alcohols under simple conditions.14 Inspired
Figure 1. Natural products containing chiral cyclobutane units.
Cyclobutane is a highly strained skeleton, and stereoselective
transformations involving this interesting molecule are mainly in
the field of photocatalysis2 and metal catalysis.3 There are a few
examples of the organocatalytic synthesis of chiral cyclobutane
derivatives.4 In 2007, the Ishihara group reported the first
organocatalytic enantioselective [2 + 2] cycloaddition reaction
of olefins and α-acyloxyacroleins to obtain cyclobutane
derivatives through iminium catalysis.5 It is noteworthy that
several groups discovered cyclobutane intermediates in the
Michael reaction of aldehydes with nitroolefins.6 Furthermore,
the strategy of the organocatalytic vinylogous Michael reaction7
Received: July 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02488
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Vinylogous Reaction of Nitroolefin Access to
Table 1. Optimization of Reaction Conditions
Enantioenriched Cyclobutanes
b
c
d
entry catalyst
solvent
time (h) yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C3
C3
C3
C3
C3
C3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
PhCF3
CH3CN
toluene
toluene
toluene
12
12
12
12
12
48
24
24
24
24
60
72
41
19
80
51
42
15
55
66
58
72
81
85
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
−90
94
94
−95
−92
93
96
98
98
98
98
by the above work on synthesizing cyclobutane derivatives, we
envision that a direct vinylogous Michael addition/cyclization of
β,γ-unsaturated pyrazole amides can be used for the
construction of cyclobutanes. Herein, we report a direct
vinylogous Michael reaction of β,γ-unsaturated pyrazole amides
with nitroalkenes by employing a squaramide organocatalyst and
further study the vinylogous Michael products to construct
chiral cyclobutane compounds with excellent stereoselectivities.
Our screening started with trans-nitrostyrene 1a and β,γ-
unsaturated pyrazole amide 2a in the presence of 10 mol % of
bifunctional organocatalysts (Table 1, entries 1−6). With
cinchona-alkaloid-derived thioureas C1 and C2 as catalysts,
the direct vinylogous Michael reaction proceeded smoothly,
affording 3a with high enantioselectivity but in a low yield (95%
ee and −90% ee, entries 1 and 2). Compared to those of the
thiourea catalyst, quinine-derived squaramide catalyst15 C3 has
a better yield and enantioselectivity (entry 3). Encouraged by
the results, we used squaramide catalyst C4 for this reaction, but
no improvement of yield was found (entry 4). The reaction was
also carried out with Takemoto’s catalyst C5 and tertiary amine
thiourea C6; unfortunately, lower yields were afforded (42 and
15%, entries 5 and 6). Then more reaction media were
investigated with catalyst C3. Among the different kinds of
solvents (entries 7−10), toluene was an effective solvent
considering the yield and enantioselectivity of 3a. Subsequently,
the yield was increased to 81% while the reaction was carried out
using 1.5 equiv of 2a (entry 11). Further optimization of the
reaction parameters, such as increasing the amount of catalyst
and prolonging the time, could increase the yield to 85% while
maintaining the enantioselectivity (entry 12). In other pyrazole
amide groups, neither pyrazole nor diphenylpyrazole can obtain
a single pure product.12,13
9
10
11
12
e
f
a
Unless otherwise noted, the reactions were performed with 1.0 equiv
of 1a (0.10 mmol), 1.2 equiv of 2a (0.12 mmol), and catalyst C (10
b
c
mol %) in 1.0 mL of solvent at rt. Yield of the isolated product. The
dr was determined by 1H NMR analysis of the crude product.
d
e
Determined by chiral HPLC analysis. The reaction was carried out
f
using 1.5 equiv of 2a (0.15 mmol). Catalyst C3 (15 mol %) and 2a
(0.15 mmol) were used in the reaction.
nitroalkenes were converted into desired products 3a−3g and
3h−3i in good yields (57−85%) with excellent enantioselectiv-
ities (94−99% ee). In the ortho-position of aromatic rings,
halogen-substituted products 3j−3l were obtained in good
yields (76−82%) with excellent enantioselectivities (95−97%
ee); the yield decreased slightly for the substrate with a methoxy
substituent on the phenyl moiety, but product 3m still
maintained excellent stereoselectivity (98% ee, >20:1 dr).
Moreover, the double substituent could also be suitable, and
product 3n was afforded in 70% yield with high enantiose-
lectivity (94% ee). The naphthyl 1o was also compatible under
standard reaction conditions, generating the desired product in
moderate yield (51%). It is noteworthy that aromatic hetero-
cycle-substituted nitroalkenes (such as thiophene and furan)
were also proven to be suitable substrates, and the
corresponding products 3p and 3q were afforded with good
yields (72 and 78%) and excellent enantioselectivities (>99%
ee). A phenethyl-substituted nitroalkene 1r reacted with 2a to
access product 3r with excellent enantioselectivity (98% ee) but
in lower yield.
Under this optimized condition, we explored the scope of the
different substituted nitroalkenes 1; the results are summarized
in Scheme 2. To our delight, all tested nitroalkene substrates
could be smoothly converted to the corresponding products
(3a−3r) with excellent stereoselectivities (94−99% ee and
>20:1 dr). For instance, with electron-donating and electron-
withdrawing groups (such as halogen, methoxy, methyl,
trifluoromethyl, and nitro groups) at the para- or meta-positions,
In the course of further studies, the scope of various β,γ-
unsaturated pyrazole amides was evaluated (Scheme 3).
Satisfyingly, the reaction proceeded smoothly to obtain products
4 whether there was an electron-donating or electron-with-
B
https://dx.doi.org/10.1021/acs.orglett.0c02488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
ities (97−98% ee). In addition, 2-naphthyl and heteroaromatic
allylic amides also gave the desired products 4f and 4g in
moderate to good yields (67 and 75%) with excellent
stereoselectivities (up to >99% ee), but the diastereoselectivity
is poor for furyl-substituted product 4h. Note that the meta-
substituent on the phenyl of aromatic nitroalkene has almost no
effect on the reaction (4i, >99% ee, >20:1 dr). Unfortunately,
aliphatic-substituted β,γ-unsaturated pyrazole amides (methyl
or benzyl) were not suitable in this reaction, and almost no
product was observed. Meanwhile, a preparative-scale experi-
ment was performed with (E)-1-methyl-4-(2-nitrovinyl)-
benzene 1f and β,γ-unsaturated pyrazole amide 2a, and the
direct vinylogous Michael reaction occurred smoothly to afford
the corresponding product 3f in 70% yield with 98% ee under
the optimized condition (Scheme 4).
Scheme 2. Scope of Nitroalkenes
Scheme 4. Preparative-Scale Synthesis
After obtaining the vinylogous Michael adducts, we further
investigated the synthesis of cyclobutanes. Varieties of bases and
solvents were used to investigate the screening of cyclization
conditions (for more details, see the Supporting Information).
Eventually, dealing with tetramethylguanidine in chloroform at
room temperature for 4 h, intramolecular nitro-Michael
cyclization reaction proceeded well and cyclobutane products
5a−5f were obtained in good yields (70−85%) with excellent
enantioselectivities (95−99% ee). As shown in Scheme 5, both
the electron-donating and electron-withdrawing substituents
with regard to vinylogous Michael products 3 and 4 were
tolerated. The reaction was not affected by the position of
substituents on the aromatic ring. The absolute configurations of
a
All reactions were carried out using 1 (0.20 mmol), 2a (0.30 mmol),
and catalyst C3 (15 mol %) in toluene (2.0 mL) at rt for 72 h. Yield of
the isolated product after flash column chromatography. The ee
values were determined by HPLC analysis on a chiral column. The dr
1
was determined by H NMR analysis of the crude product.
a
Scheme 3. Scope of β,γ-Unsaturated Pyrazole Amides
a
Scheme 5. Synthetic Cyclization
a
Unless otherwise noted, all reactions were carried out using 1.0 equiv
of 1a (0.20 mmol), 1.5 equiv of 2 (0.30 mmol), and catalyst C3 (15
mol %) in 2.0 mL of toluene for 72 h. Yield of the isolated product
after flash column chromatography. The ee values were determined by
1
HPLC analysis on a chiral column. The dr was determined by H
NMR analysis of the crude product.
a
The reactions were carried out using 1.0 equiv of 3 (0.10 mmol) and
0.2 equiv of TMG (0.02 mmol) in 1.0 mL of CHCl3. Yield of the
isolated product after flash column chromatography. The ee values
were determined by HPLC analysis on a chiral column. The dr was
determined by 1H NMR analysis of the crude product. TMG: 1,1,3,3-
tetramethylguanidine.
drawing substituent on the phenyl moiety. In view of the results,
for different substituents at the para-, meta-, and ortho-positions
or double substitution, the corresponding products 4a−4e were
obtained in moderate to good yields with high enantioselectiv-
C
https://dx.doi.org/10.1021/acs.orglett.0c02488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
4i and 5c were confirmed by an X-ray crystallography study
(Figure 2).
Figure 2. X-ray crystallographic structures of 4i and 5c.
Based on the above results, a possible catalytic transition state
Figure 4. Transformation of products. Reaction conditions: (a)
MeOH, 60 °C, 60 h; (b) MeOH, 60 °C, 48 h; (c) BnNH2, THF, 50
°C, 5 h; (d) NaBH4, THF/H2O, 0 °C to rt, 2 h.
was proposed10 in Figure 3. The dienolates were formed by β,γ-
yields with excellent stereoselectivities. Importantly, this
method of asymmetric vinylogous Michael reaction and
subsequent cyclization will be a useful contribution to chemical
synthesis. Further biological activity evaluation of these
compounds is being carried out in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02488.
Experimental procedures and spectroscopic data for
adduct compounds (PDF)
Figure 3. Synthesis of cyclobutanes.
Accession Codes
CCDC 1971730 and 1971733 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
unsaturated amides 2 with catalyst C3 through the α-position
deprotonation. At the same time, nitroalkene was activated by
squaramide hydrogen bonding. The conjugate addition of the
enolized substrates 2 and the nitroalkenes 1 gave the vinylogous
Michael addition products 3 or 4, which were then subjected to
intramolecular cyclization under the action of TMG to obtain
the cyclobutane products 5.
As a good leaving group, 3,5-dimethylpyrazole could be
substituted by nucleophiles simply and effectively (Figure 4).
For example, alcoholysis of vinylogous Michael adduct 3f and
cyclobutane derivative 5b with methanol gave ester products 6
and 7, while retaining excellent enantioselectivitives (97 and
98% ee) and high yields (89 and 93%). Aminolysis of
cyclobutane derivative 5a with benzylamine gave amide 8 in
high yield (86%) with retention of the stereochemistry (95%
ee). In addition, after treatment of the N-acylpyrazole group
with NaBH4 in H2O/THF, cyclobutane 5a was reduced to the
corresponding alcohol 9 in 72% yield and 98% ee.
AUTHOR INFORMATION
Corresponding Author
■
Huicai Huang − Research Center of Chinese Herbal Resource
Science and Engineering, Key Laboratory of Chinese Medicinal
Resource from Lingnan, Ministry of Education, Guangzhou
University of Chinese Medicine, Guangzhou 510006, China;
orcid.org/0000-0002-8813-1499; Email: huanghc@
gzucm.edu.cn
Authors
Yuzhen Chen − Research Center of Chinese Herbal Resource
Science and Engineering, Key Laboratory of Chinese Medicinal
Resource from Lingnan, Ministry of Education, Guangzhou
University of Chinese Medicine, Guangzhou 510006, China
Yichen Wang − Research Center of Chinese Herbal Resource
Science and Engineering, Key Laboratory of Chinese Medicinal
In summary, not only have we reported a direct vinylogous
Michael reaction between β,γ-unsaturated pyrazole amides and
nitroolefins but we have also developed a new strategy for
construction of cyclobutanes. The desired vinylogous Michael
products and cyclobutanes were afforded in moderate to good
D
https://dx.doi.org/10.1021/acs.orglett.0c02488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Resource from Lingnan, Ministry of Education, Guangzhou
University of Chinese Medicine, Guangzhou 510006, China
Shuzhong Wang − Research Center of Chinese Herbal Resource
Science and Engineering, Key Laboratory of Chinese Medicinal
Resource from Lingnan, Ministry of Education, Guangzhou
University of Chinese Medicine, Guangzhou 510006, China
Yan-Yan Ma − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
Deng-Gao Zhao − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Ruoting Zhan − Research Center of Chinese Herbal Resource
Science and Engineering, Key Laboratory of Chinese Medicinal
Resource from Lingnan, Ministry of Education, Guangzhou
University of Chinese Medicine, Guangzhou 510006, China
pubs.acs.org/OrgLett
Letter
Rh-catalyzed bicyclobutanation/Cu catalysed Homoconjugate Addi-
tion. J. Am. Chem. Soc. 2013, 135, 9283−9286. (c) Suarez-Pantiga, S.;
Hernandez-Díaz, C.; Rubio, E.; Gonzalez, J. M. Intermolecular [2 + 2]
Reaction of N-allenylsulfonamides With Vinylarenes: Enantioselective
Gold(i)-Catalyzed Synthesis of Cyclobutane Derivatives. Angew.
Chem., Int. Ed. 2012, 51, 11552−11555. (d) Conner, M. L.; Xu, Y.;
Brown, M. K. Catalytic Enantioselective Allenoate-Alkene [2 + 2]
Cycloadditions. J. Am. Chem. Soc. 2015, 137, 3482−3485.
(4) (a) Duan, G.-J.; Ling, J.-B.; Wang, W.-P.; Luo, Y.-C.; Xu, P.-F.
Organocatalytic Formal [2 + 2] Cycloaddition Initiated by Vinylogous
Friedel-Crafts Alkylation: Enantioselective Synthesis of Substituted
Cyclobutane Derivatives. Chem. Commun. 2013, 49, 4625−4627.
(b) Nielsen, A. J.; Jenkins, H. A.; McNulty, J. Asymmetric Organo-
catalytic Stepwise [2 + 2] Entry to Tetra-Substituted Heterodimeric
and Homochiral Cyclobutanes. Chem. - Eur. J. 2016, 22, 9111−9115.
(c) Gutekunst, W.; Baran, P. Total Synthesis and Structural Revision of
the Piperarborenines via Sequential Cyclobutane C-H Arylation. J. Am.
Chem. Soc. 2011, 133, 19076−19079.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02488
(5) Ishihara, K.; Nakano, K. Enantioselective [2 + 2] Cycloaddition of
Unactivated Alkenes with Alpha-Acyloxyacroleins Catalyzed by Chiral
Organoammonium Salts. J. Am. Chem. Soc. 2007, 129, 8930−8931.
(6) (a) Bures, J.; Armstrong, A.; Blackmond, D. G. Mechanistic
Rationalization of Organocatalyzed Conjugate Addition of Linear
Aldehydes to Nitro-Olefins. J. Am. Chem. Soc. 2011, 133, 8822−8825.
(b) Bures, J.; Armstrong, A.; Blackmond, D. G. Curtin-Hammett
Paradigm for Stereocontrol in Organocatalysis by Diarylprolinol Ether
Catalysts. J. Am. Chem. Soc. 2012, 134, 6741−6750.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Guangzhou University of Chinese
Medicine, Pearl River Talents Recruitment Program of
Guangdong Province (2017GC010361), Department of Edu-
cation of Guangdong Province (2016KCXTD015), and Jiang-
men Program for Innovative Research Team
(2018630100180019806).
(7) For reviews about vinylogous Michael addition, see: (a) Chen, P.-
Q.; Xiao, Y.-C.; Yue, C.-Z.; Chen, Y.-C. Trienamine catalysis with linear
deconjugated 3,5-dienones. Org. Chem. Front. 2014, 1, 490−493.
(b) Schneider, C.; Abels, F. Catalytic, enantioselective vinylogous
Michael reactions. Org. Biomol. Chem. 2014, 12, 3531−3543. (c) Yin,
L.; Jiang, Z. Organocatalytic Asymmetric Vinylogous Michael
Reactions. ChemCatChem 2017, 9, 4306−4318. For selected examples,
see: (d) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen, Y.-C.; Wu, Y.;
Zhu, J.; Deng, J.-G. Organocatalytic and direct asymmetric vinylogous
Michael addition of α,α-dicyanoolefins to α,β-unsaturated aldehydes.
Chem. Commun. 2006, 14, 1563−1565. (e) Huang, H.; Yu, F.; Jin, Z.;
Li, W.; Wu, W.; Liang, X.; Ye, J. Asymmetric vinylogous Michael
reaction of α, β-unsaturated ketones with γ-butenolide under
multifunctional catalysis. Chem. Commun. 2010, 46, 5957−5959.
(f) Huang, H.; Jin, Z.; Zhu, K.; Liang, X.; Ye, J. Highly diastereo-and
enantioselective synthesis of 5-substituted 3-pyrrolidin-2-ones: Vinyl-
ogous Michael addition under multifunctional catalysis. Angew. Chem.,
Int. Ed. 2011, 50, 3232−3235. (g) Gu, Y.; Wang, Y.; Yu, T.-Y.; Liang, Y.-
M.; Xu, P.-F. Rationally Designed Multifunctional Supramolecular
Iminium Catalysis: Direct Vinylogous Michael Addition of Unmodified
Linear Dienol Substrates. Angew. Chem., Int. Ed. 2014, 53, 14128−
14131. (h) Guo, Q.; Fraboni, A. J.; Brenner-Moyer, S. E. Direct
Diastereo- and Enantioselective Vinylogous Michael Additions of
Linear Enones. Org. Lett. 2016, 18, 2628−2631. (i) Iriarte, I.; Olaizola,
O.; Vera, S.; Gamboa, I.; Oiarbide, M.; Palomo, C. Controlling the a/γ-
Reactivity of Vinylogous Ketone Enolates in Organocatalytic
Enantioselective Michael Reactions. Angew. Chem., Int. Ed. 2017, 56,
8860−8864.
(8) Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.;
Davis, R. L.; Jørgensen, K. A. Asymmetric Organocatalytic Formal [2 +
2]-cycloadditions via Bifunctional H-bond Directing Dienamine
Catalysis. J. Am. Chem. Soc. 2012, 134, 2543−2546.
(9) Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo, L. Cooperative
Dienamine/Hydrogen-Bonding Catalysis: Enantioselective Formal [2
+ 2] Cycloaddition of Enals with Nitroalkenes. Angew. Chem., Int. Ed.
2012, 51, 4104−4107.
(10) Akula, P. S.; Hong, B.-C.; Lee, G.-H. Catalyst- And Substituent-
Controlled Switching of Chemoselectivity for the Enantioselective
Synthesis of Fully Substituted Cyclobutane Derivatives via [2 + 2]
Annulation of Vinylogous Ketone Enolates and Nitroalkene. Org. Lett.
2018, 20, 7835−7839.
REFERENCES
■
(1) For selected examples, see: (a) Hu, J.-L.; Feng, L.-W.; Wang, L.;
Xie, Z.; Tang, Y.; Li, X. Enantioselective Construction of Cyclobutanes:
A New and Concise Approach to the Total Synthesis of
(+)-Piperarborenine B. J. Am. Chem. Soc. 2016, 138, 13151−13154.
̈
(b) Poplata, S.; Troster, A.; Zou, Y.-Q.; Bach, T. Recent Advances in the
Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition
Reactions. Chem. Rev. 2016, 116, 9748−9815. (c) Takahashi, M.;
Ichikawa, M.; Aoyagi, S.; Kibayashi, C. Total Synthesis of Dipiperamide
A and Revision of Stereochemical Assignment. Tetrahedron Lett. 2005,
46, 57−59. (d) Gutekunst, W.; Baran, P. Applications of C−H
Functionalization Logic to Cyclobutane Synthesis. J. Org. Chem. 2014,
79, 2430−2452. (e) Chapman, L.; Beck, J.; Wu, L.; Reisman, S.
Enantioselective Total Synthesis of (+)-Psiguadial B. J. Am. Chem. Soc.
2016, 138, 9803−9806. (f) Schmitz, A.; Ricke, A.; Oschmann, M.;
Verho, O. Convenient access to chiral cyclobutanes with three
contiguous stereocenters from verbenone enabled by directed
C(sp3)−H arylation. Chem. - Eur. J. 2019, 25, 5154−5157.
̈
(2) For selected examples, see: (a) Troster, A.; Alonso, R.; Bauer, A.;
Bach, T. Enantioselective Intermolecular [2 + 2] Photocycloaddition
Reactions of 2(1H)-Quinolones Induced by Visible Light Irradiation. J.
Am. Chem. Soc. 2016, 138, 7808−7811. (b) Coote, S. C.; Bach, T.
Enantioselective Intermolecular [2 + 2] Photocycloadditions of
Isoquinolone Mediated by a Chiral Hydrogen-Bonding Template. J.
Am. Chem. Soc. 2013, 135, 14948−14951. (c) Miller, Z. D.; Lee, B. J.;
Yoon, T. P. Enantioselective Crossed Photocycloadditions of Styrenic
Olefins by Lewis Acid Catalyzed Triplet Sensitization. Angew. Chem.,
Int. Ed. 2017, 56, 11891−11895. (d) Alonso, R.; Bach, T. A Chiral
Thioxanthone as an Organocatalyst for Enantioselective [2 + 2]
Photocycloaddition Reactions Induced by Visible Light. Angew. Chem.,
Int. Ed. 2014, 53, 4368−4371.
(3) For selected examples, see: (a) Yang, X.; Shan, G.; Yang, Z.;
Huang, G.; Dong, G.; Sheng, C.; Rao, Y. One-pot Synthesis of
Quaternary Carbon Centered Cyclobutanes via Pd(ii)-catalyzed
Cascade C(sp3)-H Activations. Chem. Commun. 2017, 53, 1534−
1537. (b) Panish, R.; Chintala, S. R.; Boruta, D. T.; Fang, Y.; Taylor, M.
T.; Fox, J. M. Enantioselective Synthesis of Cyclobutanes via Sequential
E
https://dx.doi.org/10.1021/acs.orglett.0c02488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(11) For selected examples, see: (a) Li, T.-Z.; Jiang, Y.; Guan, Y.-Q.;
Sha, F.; Wu, X.-Y. Direct Enantioselective Vinylogous Aldol-
Cyclization Cascade Reaction of Allyl Pyrazoleamides with Isatins:
Asymmetric Construction of Spirocyclic Oxindole-Dihydropyranones.
Chem. Commun. 2014, 50, 10790−10792. (b) Li, T.-Z.; Xie, J.; Jiang, Y.;
Sha, F.; Wu, X.-Y. Enantioselective Vinylogous Michael/Cyclization
Cascade Reaction of Acyclic β,γ-Unsaturated Amides with Isatylidene
Malononitriles: Asymmetric Construction of Spirocyclic Oxindoles.
Adv. Synth. Catal. 2015, 357, 3507−3511. (c) Jiang, Y.; Fu, J. H.; Li, T.
Z.; Sha, F.; Wu, X.-Y. Enantioselective direct vinylogous aldol-
cyclization cascade reaction between β,γ-unsaturated amides and o-
quinones. Org. Biomol. Chem. 2016, 14, 6435−6441. (d) Zhong, F.;
Yue, W.-J.; Zhang, H.-J.; Zhang, C.-Y.; Yin, L. Catalytic Asymmetric
Construction of Halogenated Stereogenic Carbon Centers by Direct
Vinylogous Mannich-Type Reaction. J. Am. Chem. Soc. 2018, 140,
15170−15175.
(12) Qin, J.; Zhang, Y.; Liu, C.; Zhou, J.; Zhan, R.; Chen, W.; Huang,
H. Asymmetric Inverse-Electron-Demand Diels−Alder Reaction of β,γ-
Unsaturated Amides through Dienolate Catalysis. Org. Lett. 2019, 21,
7337−7341.
(13) Zhang, Y.; Lu, X.; Wang, Y.; Xu, H.; Zhan, R.; Chen, W.; Huang,
H. Regiodivergent Vinylogous-Cyclization Reactions of Cyclic α-
Amide Enone Acceptors: Synthesis of Highly Enantioenriched
Heterobicyclic Structures. Org. Lett. 2019, 21, 10069−10074.
(14) Zhang, H.-J.; Shi, C.-Y.; Zhong, F.; Yin, L. Direct Asymmetric
Vinylogous and Bisvinylogous Mannich-Type Reaction Catalyzed by a
Copper(I) Complex. J. Am. Chem. Soc. 2017, 139, 2196−2199.
(15) For reviews about squaramide catalysis, see: (a) Storer, R. I.;
Aciroa, C.; Jones, L. H. Squaramides: physical properties, synthesis and
applications. Chem. Soc. Rev. 2011, 40, 2330−2346. (b) Held, F. E.;
Tsogoeva, S. B. Asymmetric cycloaddition reactions catalyzed by
bifunctional thiourea and squaramide organocatalysts: recent advances.
Catal. Sci. Technol. 2016, 6, 645−667. For selected examples, see:
(c) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide
Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am.
Chem. Soc. 2008, 130, 14416−14417. (d) Zhu, Y.; Malerich, J. P.;
Rawal, V. H. Squaramide-Catalyzed Enantioselective Michael Addition
of Diphenyl Phosphite to Nitroalkenes. Angew. Chem., Int. Ed. 2010, 49,
153−156. (e) Jiang, H.; Paixao, M. W.; Monge, D.; Jørgensen, K. A.
̃
Acyl Phosphonates: Good Hydrogen Bond Acceptors and Ester/Amide
Equivalents in Asymmetric Organocatalysis. J. Am. Chem. Soc. 2010,
132, 2775−2783. (f) Manoni, F.; Connon, S. J. Catalytic Asymmetric
Tamura Cycloadditions. Angew. Chem., Int. Ed. 2014, 53, 2628−2632.
(g) Orue, A.; Uria, U.; Reyes, E.; Carrillo, L.; Vicario, J. L. Catalytic
Enantioselective [5 + 2] Cycloaddition between Oxidopyrylium Ylides
and Enals under Dienamine Activation. Angew. Chem., Int. Ed. 2015, 54,
3043−3046. (h) Li, X.; Yan, J.; Qin, J.; Lin, S.; Chen, W.; Zhan, R.;
Huang, H. Enantioselective Synthesis of Benzofuran-Fused N-Hetero-
cycles via Chiral Squaramide Catalyzed [4 + 2] Cyclization of
Azadienes with Azlactones. J. Org. Chem. 2019, 84, 8035−8045.
(i) Wang, Y.; Chen, Y.; Li, X.; Mao, Y.; Chen, W.; Zhan, R.; Huang, H.
Enantioselective synthesis of pyrano[2,3-c]pyrrole via an organo-
catalytic [4 + 2] cyclization reaction of dioxopyrrolidines and
azlactones. Org. Biomol. Chem. 2019, 17, 3945−3950.
F
https://dx.doi.org/10.1021/acs.orglett.0c02488
Org. Lett. XXXX, XXX, XXX−XXX