Catalytic Enantioselective [2+2] Cycloaddition of α-Halo Acroleins: Construction of Cyclobutanes Containing Two Tetrasubstituted Stereocenters

Article abstract of DOI:10.1002/anie.202008465

A catalytic enantioselective formal [2+2] cycloaddition between α-halo acroleins and electronically diverse arylalkenes is described. In the presence of (S)-oxazaborolidinium cation as the catalyst, densely functionalized cyclobutanes containing two vicin

Full text of DOI:10.1002/anie.202008465

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Accepted Article
Title: Catalytic Enantioselective [2+2] Cycloaddition of α-Halo
Acroleins: Construction of Cyclobutanes Containing Two
Quaternary Stereocenters
Authors: Lizhu Gao, Lei Zeng, Jingjing Xu, Dongsheng Zhang,
Zhongliang Yan, Guolin Cheng, and Weidong Rao
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10.1002/anie.202008465
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COMMUNICATION
Catalytic Enantioselective [2+2] Cycloaddition of -Halo
Acroleins: Construction of Cyclobutanes Containing Two
Tetrasubstituted Stereocenters
Lei Zeng,[a] Jingjing Xu,[a] Dongsheng Zhang,[a] Zhongliang Yan,[a] Guolin Cheng,[a] Weidong Rao,[b]
Lizhu Gao*[a]
Abstract: A catalytic enantioselective formal [2+2] cycloaddition
between -halo acroleins and electronically diverse arylalkenes is
described. In the presence of (S)-oxazaborolidinium cation as the
catalyst, densely functionalized cyclobutanes containing two vicinal
tetrasubstituted stereocenters were produced in high yields and high
diastereoselectivities with excellent enantioselectivities. Mechanistic
studies revealed that the cis isomer could be transformed into the
trans isomer via an enantiocontrolled process. A gram-scale reaction
of this catalytic method was used to demonstrate its synthetic
potential.
photochemical [2+2] reactions involving radical intermediates.[5]
Thus, in enantioselective [2+2] reactions, alkenes with two same
geminal substituents have always been utilized.[7-11] To our
knowledge, only one example has reported [2+2] cycloaddition
between acyclic asymmetrical 1,1-disubstituted activated olefins
and acyclic asymmetrical 1,1-disubstituted alkenes using a
photochemical reaction.[7f] To realize Lewis-acid-catalyzed
version of such reaction is important, because the resulting
cyclobutanes contain two vicinal tetrasubstituted stereocenters.
Second, in order to trigger nucleophilic addition, most reactions
require the use of highly polarized alkenes with S, O, or N atoms
attached to the double bond (Scheme 1a).[9a-j] With exceptions,
two examples using highly-activated p-methoxyl styrenes were
reported.[9k-m] In 2015, Tang et al. reported an impressive Cu-
catalyzed reaction by reacting a variety of styrenes with
The cyclobutane ring is an important structural motif in natural
products and pharmaceutical molecules, and many biologically-
active compounds contain a cyclobutane ring.[1] Driven by the
relief of inherent ring strain, they can also undergo broad
synthetic transformations, which enable the development of new
synthetic methods,[2,3] and often act as key intermediates in
synthetic routes to obtain structurally complex targets.[4] [2+2]
Cycloaddition reactions represent the most straightforward and
atom-economical approach for constructing cyclobutanes, and
considerable efforts have been devoted to accomplish this
transformation.[5,6] Although recent advances have given rise to
elegant enantioselective methods, the enantioselective
synthesis of cyclobutanes is still challenging.[7-12]
Among the established methods, Lewis-acid-catalyzed [2+2]
cycloaddition between activated olefins and alkenes is
particularly interesting because the resulting donor-acceptor
cyclobutanes can behave as 1,4-zwitterionic synthons in
chemical transformations.[3] In 1989, the Narasaka group
reported the first catalytic enantioselective [2+2] cycloadditions
methylidenemalonate
in
high
yield
and
excellent
enantioselectivity.[9m] These reactions are only applicable to p-
methoxyl styrenes and the reaction of 2-substituted
methylidenemalonate gave the product in poor diastero- and
enantioselectivity (Scheme 1b). Further, in the realm of [2+2]
cycloaddition reactions, the utilization of electron-deficient
styrene substrates is challenging.[9k,l,13] In view of the
aforementioned challenging questions, to develop a new and
efficient catalytic protocol to enlarge the scope of methodologies
that can be applied would be highly desirable and valuable. Here,
we disclose an oxazaborolidinium-ion-catalyzed formal [2+2]
cycloaddition of -halo acroleins with electronically diverse
arylalkenes that can be used to construct cyclobutanes with high
diastereoselectivities. The resulting cyclobutanes bearing two
using
a Ti-TADDOL complex as the catalyst with 1,1-
bis(methylthio)ethylene as the substrate, and the reaction
provided excellent enantioselectivity.[9a] Since then, several
catalytic asymmetric reactions have been developed.[9b-n]
Despite these advances, significant limitations remain. First, due
to the formation of dipolar intermediate in transition state, acyclic
asymmetrical 1,1-disubstituted olefins or alkenes would
generate cyclobutanes with low diastereoselectivities.[9e-g] This is
a
common challenge in [2+2] cycloadditions, including
[a]
L. Zeng, J. Xu, D. Zhang, Z. Yan, Prof. G. Cheng, Prof. L. Gao
College of Materials Science and Engineering, Huaqiao University
No.668 Jimei Avenue, Xiamen, Fujian, China
E-mail: lizhugao@hqu.edu.cn
[b]
Prof. W. Rao
Jiangsu Key Laboratory of Biomass-Based Green Fuels and
Chemicals, College of Chemical Engineering, Nanjing Forestry
University, Nanjing, China
Scheme 1. Chiral Lewis Acid-Catalyzed Asymmetric [2+2] Cycloadditions.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.202008465
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COMMUNICATION
adjacent tetrasubstituted stereocenters[14] and multiple functional
groups that facilitate late-stage modifications (Scheme1c).
with pure cis-2 (Scheme 2). Racemic cis-2 was subjected to the
optimized conditions for 30 min, and trans-2 was formed in 35%
yield, along with recovered cis-2 and some unidentified
decomposition products. Interestingly, this process involved
enantioconversion, and the enantiomeric excess of trans-2 and
recovered cis-2 were 88% and 78%, respectively. A similar
experiment using isolated racemic trans-2 was also carried out.
In contrast to the result of cis-2, trans-2 was recovered in 91%
yield and 2% ee, without the formation of cis-2, according to the
crude 1H NMR analysis. These results indicated that neither
isomer was stable and both decomposed, but the ring of cis-2
was more easily opened, which allowed some to be converted
into trans-2. Thus, careful control of the reaction temperature
and time is crucial to obtain high yields and high
diastereoselectivities.
Initially, the enantioselective [2+2] cycloaddition between -
bromo acrolein and -methyl styrene was carried out using 20
mol % of catalyst 1a at −78 °C in toluene. After 30 min, the
resulting optically active trans-cyclobutane 2[15] was isolated in
30% yield and 51% ee, with a similar amount of the cis isomer
(Table 1, entry 1). Under the same reaction conditions, catalyst
1b with a phenyl group attached to the boron provided slightly
better results (entry 2). To improve the enantioselectivity,
sterically hindered 3,5-dimethylphenyl was used as the Ar
substituent in 1c, and the enantiomeric excess substantially
increased to 89% (entry 3). The yield and diastereoselectivity
dramatically increased with the temperature (entries 4 and 5).
When the reaction was carried out at −45 oC, the yield and
diastereoselectivity increased to 77% and 15:1, respectively. In
o
another experiment at −25 C, the yield decreased to 43%, but
the dr increased to 20:1 (entry 6). The effect of the solvent was
also examined using catalyst 1c. Dichloromethane provided
inverse diastereoselectivity and decreased the ee, while polar
butyronitrile afforded a complex mixture (entries 7 and 8). To
further investigate the catalytic performance, we performed a
reaction using -methyl styrene as the limiting reactant. Using
o
1c as the catalyst in toluene at −45 C, the desired cyclobutane
2 was produced in 83% yield and 93% ee with a 14:1
diastereoselectivity (entry 9).[16]
Table 1. Optimization of the Reaction Conditions.[a]
Me
Ph
Ph
CHO
Br
Me
Ph
CHO
Br
Br
CHO
1 (20 mol %)
Me
+
+
30 min
trans-2
cis-2
Scheme 2. Mechanistic Considerations.
Ar
1a: Ar = phenyl, R = o-tolyl
1b: Ar = phenyl, R = phenyl
Ar
N
O
1c: Ar = 3,5-dimethylphenyl, R = phenyl
1d: Ar = 3,5-ditbutylphenyl, R = phenyl
B
TfO
Based on the preliminary mechanistic investigation and with
the optimal reaction conditions determined, we investigated this
catalytic system using a broad range of arylalkenes. As depicted
in Table 2, various para halogenated styrenes reacted quite well
with -bromo acrolein and generated optically-active
cyclobutanes 3-5 in high yields with high diastereomeric ratios.
The absolute configuration of 3 was determined to be (1S,2R)
based on X-ray crystallographic analysis. Electron-poor styrenes
were suitable for this transformation, delivering products 6 and 7
in excellent ee values, albeit moderate yields and
diastereoselectivities. Highly reactive p-Me and p-OMe
substituted styrenes furnished 8 and 9 in moderate yields. n-
Propyl and n-heptyl substituted styrene gave higher yields than
the corresponding -methyl styrene (10 and 11). Disubstituted
phenyl styrene worked well, and products 12 and 13 were
obtained in high yields with consistently high enantiomeric
excesses. Naphthyl alkene and indene were highly active
substrates and provided products 14 and 15 at −65 °C in high
yields with excellent diastero- and enantioselectivities.
Compound 15 was not sufficiently stable for isolation by silica
gel chromatography, thus it was converted to alcohol 16 by
adding NaBH4 and menthol to the crude reaction mixture (see
SI). The absolute configuration of 16 was confirmed based on X-
ray crystallographic analysis. To our delight, (E)-2-Phenyl-2-
butene could react fast and provided cyclobutane 17 in good
diastereoselectivity and excellent enantioselectivity. Application
H
R
entry
cat.
T (oC)
−78
−78
−78
−60
−45
−25
−45
−45
−45
solvent
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
trans/cis[b]
1.1:1
1.5:1
1.4:1
4:1
yield (%)[c]
30/26
33/20
35/26
52
ee (%)[d]
51/47
59/41
89/43
90/35
92
1
2
1a
1b
1c
1c
1c
1c
1c
1c
1c
3
4
5
15:1
77
6
20:1
43
88
7
0.5:1
22/43
trace
83
60/60
8
butyronitrile
toluene
9[e]
14:1
93
[a] Unless noted, the reaction of -bromo acrolein (0.27 mmol) with -methyl
styrene (0.41 mmol) was performed with 20 mol % of catalyst 1, for 30 min in
1.0 mL of solvent. [b] Determined by 1H NMR analysis of the crude reaction
mixture. [c] Isolated yield of the trans/cis isomer. [d] The ee of trans/cis isomer
was determined by chiral HPLC. [e] -Bromo acrolein (0.41 mmol) and -
methyl styrene (0.27 mmol).
Based on the significant effect of reaction temperature on
the yield and diastereoselectivity, we envisioned that the cis
isomer could be transformed into the trans isomer in the reaction
system. To verify this speculation, we carried out experiments
2
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10.1002/anie.202008465
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of 1,1-dialkyl alkenes in this reaction did not provide cyclobutane
product.
good yields and excellent ee (20, 22-24). Application of (E)--
bromo--methyl acrolein in reaction, result was exactly the same
with reaction of (Z)--bromo--methyl acrolein, as the (E)-isomer
was isomerized into (Z)-isomer quickly in the presence of
catalyst.To improve the diastereoselectivity, control experiments
were performed at higher temperatures. However, in this case,
the cis isomers were not converted into trans isomers, and both
isomers decomposed into other products. The absolute
stereochemistry was determined to be (1S,2R,4S) by the
reduction of product 20 and X-ray analysis of the corresponding
alcohol 21. To investigate the functional group tolerance of the
reaction, bromo and ester groups were introduced into the
substrates. They reacted cleanly and afforded 26 and 27 in high
yields with good diastereoselectivities and excellent
enantiomeric excess. Unfortunately, -bromo--phenyl acrolein
provided the product in low yield under the current reaction
conditions.
Given the good results shown in Table 2, the substrate
scope with respect to various acroleins was examined. As
described in Table 3, -chloro and -iodo acroleins reacted well
with -methylstyrene to give highly enantiomerically enriched
cyclobutanes 18 and 19 in high yields with high diastereomeric
ratios. For -disubstituted (Z)-acroleins, however, the optimal
catalyst 1c for monosubstituted acroleins was not suitable for
disubstituted (Z)-acroleins. The use of a more hindered catalyst
1d with Ar = 3,5-ditbutyl, was found to be more effective for
Table 2. Evaluation of the Substrate Scope Using Different Arylalkenes.[a]
R1
Ar
R2
Br
R1
1c (20 mol %)
Br
CHO
CHO
R2
toluene, -45 oC, 30 min
+
Ar
Br
CHO
Br
Table 3. Evaluation of the Substrate Scope Using Different Acroleins.[a]
CHO
Br
R2
Ph
Halo
Halo
R1
CHO
R2
1d (20 mol %)
2
3
+
CHO
R1
toluene, -60 o
C
83%, dr = 14:1, 93% ee
88%, dr = 16:1, 98% ee
Ph
CCDC 1941029
Br
Br
Br
CHO
CHO
CHO
Cl
CHO
I
Br
F3C
Cl
F
CHO
CHO
6[b]
4
5
Me
78%, dr = 12:1, 97% ee
75%, dr = 9:1, 96% ee 49/21%, dr = 2.4:1, 96/81% ee
18[b] (30 min)
19[b] (30 min)
82%, dr = 12:1, 92% ee
20[c] (48 h), dr = 4:1
Br
85%, dr = 20:1, 94% ee
76/19%, 97/89% ee
Br
CHO
Br
CHO
CHO
Me
MeO
nHep
Br
CHO
Me
Br
Br
7[c]
8[d]
9[e]
CH2OH
57/20%, dr = 2.8:1, 95/44% ee 63%, dr > 20:1, 92% ee
53%, dr = 15:1, 98% ee
Me
Br
nHep
Br
CHO
22 (60 h), dr = 3.8:1
78/18%, 95/78% ee
21
CHO
Br
CHO
(derived from 20)
CCDC 1978557
nHep
nHep
Br
CHO
Br
CHO
Et
11[f]
12[d]
Br
10
85%, dr = 12:1, 96% ee
87%, dr = 10:1, >99% ee
72%, dr > 20:1, 90% ee
CHO
Ph
Br
Et
Br
Br
CHO
23[c] (60 h), dr = 4:1
CHO
24 (72 h), dr = 3.8:1
76/20%, 91/77% ee
25 (6 days), dr = 3:1
70/22%, 90/82% ee
CHO
75/19%, 93/73% ee
F
nHep
Br
CHO
nHep
Br
CHO
14[d]
15[d]
13
71%, dr = 13:1, 90% ee
62%, dr > 20:1, 91% ee
Br
COOMe
Br
Br
26 (96 h), dr = 5:1
81/15%, 94/75% ee
27 (96 h), dr = 7:1
84%, 92% ee
CHO
CH2OH
16 (derived from 15)
85%, dr = 19:1, 99% ee
17
[a] Unless otherwise noted, the reaction was performed with -bromo acrolein
(0.41 mmol), arylalkene (0.27 mmol), and catalyst 1d (20 mol %) in toluene
(1.0 mL) at −60 °C for the indicated time. Yields are of the isolated trans/cis
product, the ee was determined by HPLC analysis, and the dr was determined
by 1H NMR analysis of the crude reaction mixture. [b] Reaction was conducted
at −45 °C with catalyst 1c. [c] Yield was calculated from 1H NMR analysis of
the isolated isomer mixture, and the ee was determined after reduction to the
corresponding alcohol.
70/22%, dr = 3:1, 98/24% ee
CCDC 1978556
[a] Unless otherwise noted, the reaction was performed with -bromo acrolein
(0.41 mmol), arylalkene (0.27 mmol), and catalyst 1c (20 mol %) in toluene
(1.0 mL) for 30 min. The reported yields are of the isolated trans/cis product,
the ee was determined by HPLC analysis, and the dr was determined by 1H
NMR analysis of the crude reaction mixture. [b] 30 mol % of catalyst at 0 °C for
15 min. [c] 30 mol % of catalyst for 1 h. [d] 10 mol % of catalyst at −65 °C. [e]
10 mol % of catalyst at −95 °C in 3 mL of toluene for 1 h. [f] The ee was
determined after reduction to the corresponding alcohol.
The observed stereochemistry of the asymmetric
cyclobutanantion reaction using oxazaborolidinium ion catalyst
1c can be rationalized using the transition state model shown in
Figure 1. The coordination mode of acrolein to 1c was the same
as has been previously observed in cyclopropanation
reactions.[17] In the pre-transition-state assembly (28 in Figure 1),
producing a higher enantiomeric excess. Using 1d as the
catalyst, -bromo--methyl, -bromo--ethyl, and -bromo--
phenylethyl acroleins reacted effectively with -propyl and -
heptyl styrenes, affording the corresponding cyclobutanes in
3
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10.1002/anie.202008465
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COMMUNICATION
the double bond of the acrolein is situated above the 3,5-
dimethylphenyl group, which effectively shields the re face
(back) of the acrolein from attack by styrene. Because of the
steric repulsion between the bromo group and the large phenyl
ring of styrene, as well as attractive π−π interactions between
the aldehyde group and the phenyl ring of styrene, the styrene
likely approached the double bond of acrolein to undergo
nucleophilic addition with the phenyl group oriented away from
the bromo group. This facilitated the 1,4-addition of styrene from
the si face (front) of the acrolein, leading to intermediate 29,
which then cyclized to form trans-(1S,2R)-cyclobutane as the
major enantiomer for 2 and trans-(1S,2R,4S)-cyclobutane for 20.
In summary, the first example of a Lewis-acid-catalyzed
enantioselectivie
[2+2]
cycloaddition
between
acyclic
asymmetrical 1,1-disubstituted olefin and acyclic asymmetrical
1,1-disubstituted alkene was accomplished. The reaction
produced cyclobutanes with two vicinal tetrasubstituted
stereocenters and multiple functional groups in high yields and
excellent enantiomeric excess. The absolute stereochemistry of
the cyclobutanes predicted by the transition-state model is
shown in Figure 1. The cyclobutane products could be prepared
at the gram scale, and the densely-functionalized compounds
readily underwent late-stage derivatization.
Acknowledgements
This work was supported by the Scientific Research Funds and
Subsidized Project for Postgraduates’ Innovative Fund in
Scientific Research of Huaqiao University. We also thank the
Instrumental Analysis Center of Huaqiao University for their kind
help.
Keywords: Asymmetric synthesis • Chirality • [2+2]
Cycloaddition • Cyclobutane • Tetrasubstituted stereocenter
Figure 1. Transition State Model for [2+2] Cycloaddition Reaction.
[1]
[2]
[3]
a) J.-S. Li, K. Gao, M. Bian, H.-F. Ding, Org. Chem. Front. 2020, 7, 136;
b) M. A. Beniddir, L. Evanno, D. Joseph, A. Skiredj, E. Poupon, Nat.
Prod. Rep. 2016, 33, 820.
To demonstrate the scalability and practicality of this
catalytic protocol, a 5-mmol-scale reaction was conducted using
only 7 mol % of catalyst 1c to afford isolated cyclobutane 2 in
85% yield and 95% ee. Additional transformations are illustrated
in Scheme 3. In the presence of Ti(OiPr)4, cyclobutane 2
reactedwith benzylamine, followed by reduction with NH3BH3 to
afford -benzyl amino cyclobutane 30 in 95% yield.[18]
Debromination proceeded effectively using Et3B as a radical
initiator at −40 oC and furnished product 31 in 88% isolated yield
of the cis isomer.[19] Reduction of 2 with NaBH4 in MeOH
followed by treatment with KOtBu resulted in an intramolecular
SN2-type substitution that provided the inverted spiro-epoxide 32
in 85% yield with ee retention.[20]
a) J. C, Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485; b) T.
Seiser, T. Saget, D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011,
50, 7740; Angew. Chem. 2011, 123, 7884.
Recent examples on donor-acceptor cyclobutane reactions, see: a) H.-
U. Reissig, R. Zimmer, Angew. Chem. Int. Ed. 2015, 54, 5009; Angew.
Chem. 2015,127,5093; b) S. Wei, L. Yin, S.-R. Wang, Y. Tang, Org.
Lett. 2019, 21, 1458; c) A. Levens, A. Ametovski, D. W. Lupton, Angew.
Chem. Int. Ed. 2016, 55, 16136; Angew. Chem 2016, 128, 16370; d) D.
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Eur. J. 2019, 25, 15244.
[4]
[5]
a) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003, 103, 1449; b) T. Bach,
P. Hehn, Angew. Chem. Int. Ed. 2011, 50, 1000; Angew. Chem. 2011,
123, 1032.
For reviews, see: a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem.
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1310; d) Y. Xu, M. L. Conner, M. K. Brown, Angew. Chem. Int. Ed.
2015, 54, 11918; Angew. Chem. 2015, 127, 12086.
[6]
Selected papers on cyclobutene synthesis via Lewis acid-catalyzed
[2+2] cycloaddition, see: a) Y.-B. Bai, Z. Luo, Y. Wang, J.-M. Gao, L.
Zhang, J. Am. Chem. Soc. 2018, 140, 5860; b) C. García-Morales, B.
Ranieri, I. Escofet, L. López-Suarez, C. Obradors, A. I. Konovalov, A. M.
Echavarren, J. Am. Chem. Soc. 2017, 139, 13628; c) T. Kang, S. Ge, L.
Lin, Y. Lu, X. Liu, X. Feng, Angew. Chem. Int. Ed. 2016, 55, 5541;
Angew. Chem. 2016, 128, 5631. d) C. Schotes, A. Mezzetti, Angew.
Chem. Int. Ed. 2011, 50, 3072; Angew. Chem. Int. Ed. 2011, 123, 3128;
e) L. Shen, K. Zhao, K. Doitomi, R. Ganguly, Y. X. Li, Z. L. Shen, H.
Hirao, T. P. Loh, J. Am. Chem. Soc. 2017, 139, 13570; f) E K. Enomoto,
H. Oyama, M. Nakada, Chem. Eur. J. 2015, 21, 2798.
[7]
For photochemical [2+2] cycloaddition reactions, see: a) R. Brimioulle,
T. Bach, Science 2013, 342, 840; b) J. Du, K. L. Skubi, D. M. Schultz, T.
P. Yoon, Science 2014, 344, 392; c) M. E. Daub, H. Jung, B. J. Lee, J.
Won, M. H. Baik, T. P. Yoon, J. Am. Chem. Soc. 2019, 141, 9543; d) N.
Hu, H. Jung, Y. Zheng, J. Lee, L. Zhang, Z. Ullah, X. Xie, K. Harms, M.-
H. Baik, E. Meggers, Angew. Chem. Int. Ed. 2018, 57, 6242; Angew.
Chem. 2018, 130, 6350; e) S. Poplata, A. Bauer, G. Storch, T. Bach,
Chem. Eur. J. 2019, 25, 8135. f) X. Huang, T. R. Quinn, K. Harms, R. D.
Webster, L. Zhang, O. Wiest, E. Meggers, J. Am. Chem. Soc. 2017,
Scheme 3. Scale Up of the Reaction and Derivatizations.
4
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10.1002/anie.202008465
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COMMUNICATION
139, 9120; g) H. Yu, S. Dong, Q. Yao, L, Chen, D. Zhang, X. Liu, X.
Feng, Chem. Eur. J. 2018, 24, 19361.
[16] Relationship between stereoselectivities of compound 2 and reaction
time was investigated, see SI.
[8]
For Lewis acid-catalyzed racemic [2+2] cycloaddition between activated
olefins and alkenes, see: a) K. Inanaga, K. Takasu, M. Ihara, J. Am.
Chem. Soc. 2005, 127, 3668; b) K. Takasu, M. Ueno, K. Inanaga, M.
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[15] The trans geometry means bromo and Ar ring groups are directed trans
to each other in the cyclobutane.
5
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10.1002/anie.202008465
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[2+2] Cycloaddition reaction of electronically diverse arylalkenes with -bromo acroleins provided highly functionalized cyclobutanes
bearing two adjacent tetrasubstituted stereocenters. Mechanistic studies revealed cis-cyclobutane could be enantioselectively
transformed into the trans isomer in reaction system.
6
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