Palladium-Catalyzed [5 + 2] Annulation of Vinylethylene Carbonates with Barbiturate-Derived Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c02508

A palladium/XantPhos-catalyzed [5 + 2] annulation of VECs with electron-deficient alkenes having an isolated carbon-carbon double bond has been developed to afford spirobarbiturate-tetrahydrooxepines. This study provides an expedient assembly of biologically interesting spirobarbiturate-tetrahydrooxepines. The easy scalability and versatile transformability of the reaction products were also exhibited.

Full text of DOI:10.1021/acs.orglett.0c02508

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed [5 + 2] Annulation of Vinylethylene Carbonates
with Barbiturate-Derived Alkenes
Xing Gao, Dongyu Zhu, Yuehua Chen, Hao Deng, Feng Jiang, Wei Wang, Yongjun Wu,
and Hongchao Guo*
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ABSTRACT: A palladium/XantPhos-catalyzed [5 + 2] annulation of
VECs with electron-deficient alkenes having an isolated carbon−carbon
double bond has been developed to afford spirobarbiturate-tetrahy-
drooxepines. This study provides an expedient assembly of biologically
interesting spirobarbiturate-tetrahydrooxepines. The easy scalability and
versatile transformability of the reaction products were also exhibited.
Scheme 1. Palladium-Catalyzed Annulation Reactions of
VECs with Alkenes
inylethylene carbonates (VECs) have been demonstrated
Vas a versatile synthon for the construction of cyclic and
acyclic molecular scaffolds.1 On the one hand, VECs have been
used in allylic substitution reactions.2 On the other hand,
[3+n] and [5+n] cycloadditions of VECs are exceptional
synthetic tools that provide efficient avenues toward the rapid
synthesis of various cyclic molecules.3 A broad range of
substrates including aldehydes,3a alkenes,3b−d isocyanates,3e
imines,3f,g azadienes,3h azomethine imines,3i benzoxazinano-
nes,3j enals3k and electron-deficient conjugated 1,3-dienes3o,p
have been exploited as the electrophilic reagents in diverse Pd-
catalyzed annulation reactions of VECs. Among these
electrophilic coupling reagents, alkenes are particularly
fascinating for synthesis of oxygen-containing heterocycles
and have attracted much attention. In principle, all types of
electron-deficient alkenes can perform the cycloaddition
reaction with VECs under palladium catalysis. In previous
reports, electron-deficient alkenes having an isolated carbon−
carbon double bond such as methylenemalononitriles,3b 3-
cyanochromones,3c and β-nitroolefins3d have been used in Pd-
catalyzed [3 + 2] annulation reactions of VECs to construct
tetrahydrofuran derivatives (Scheme 1a). However, those
alkenes having an isolated carbon−carbon double bond have
not been successfully tamed in Pd-catalyzed [5 + 2]
cycloaddition of VECs to construct medium-ring heterocycles,
in which the zwitterionic palladium intermediates generated
from VECs through decarboxylation serve as 1,5-dipoles. Due
to their unfavorable transannular interactions4 as compounds
and competitive [3 + 2] annulation, Pd-catalyzed [5 + 2]
annulation of VECs and the isolated carbon−carbon double
bond represent a formidable challenge.3k In our previous work,
we realized a Pd-catalyzed [5 + 4] annulation of electron-
deficient conjugated 1,3-dienes with VECs via tandem [3 + 2]
cycloaddition/Cope rearrangement to achieve synthesis of
nine-membered cyclic compounds3p (Scheme 1b). Most
recently, Peng and Han reported [5 + 4] and [5 + 2]
annulations of VECs and conjugated 1,3-dienes for synthesis of
seven- and nine-membered rings3o (Scheme 1b and 1c). As our
continuous efforts on the cycloaddition reactions,5 we herein
describe an unprecedented palladium-catalyzed formal [5 + 2]
cycloaddition of barbiturate-derived alkenes (BDAs) with
VECs to synthesize functionalized spirobarbiturate-tetrahy-
drooxepines (Scheme 1d).
Received: July 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02508
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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As a readily accessible reaction partner6 and pharmaceuti-
cally interesting skeleton,7 barbiturate-derived alkenes were an
ideal target for the current work. We chose the VEC 1a with
BDA 2a as model reaction to investigate the optimal reaction
conditions (Table S1). After an extensive investigation of
reaction parameters, the optimal conditions for the [5 + 2]
cycloaddition reaction were ultimately identified as follows:
Pd2dba3·CHCl3 (2.5 mol %) as a catalyst and XantPhos (5.0
mol %) as a ligand in CHCl3 at room temperature.
With the optimized reaction conditions in hand, the scope of
VECs in this [5 + 2] annulation was examined first (Table 1).
It is worth pointing out that the [3 + 2] cycloaddition product
4 has not been observed in all the following cases (see below).
A wide range of substituted phenyl-VECs having different
electronic and steric properties were well-tolerated and a
number of spirobarbiturate-tetrahydrooxepines (3aa−3ua)
were readily constructed (entries 1−21). Obviously, the steric
hindrance makes much difference on the yield of correspond-
ing products. For example, the VECs 1b and 1i bearing o-
methyl- and o-fluorophenyl underwent the annulation reaction
to afford the products 3ba and 3ia in 52% and 63% yield,
respectively, in comparison, meta- and para-substituted
substrates provided the corresponding products in >80%
yield (entry 2 vs entries 3, 4 and entry 9 vs entries 10 and 11).
The installation of a heterocycle in the spiro compounds was
also workable (entry 24). The unsubstituted, methyl-, and tert-
butyl-substituted VECs did not react with alkene 2a (entries
25−27), probably due to instability of the corresponding
seven-membered ring of products. Interestingly, the annulation
product with a cyclohexyl group could be obtained in 65%
yield through using a higher catalyst loading (7.5 mol %
Pd2dba3·CHCl3) (entry 28). The vinyl-substituted VEC was
also proved to be reactive to afford the product in 94% yield
(entry 29). Additionally, the process also worked well for
substrate VEC having a methyl group at alkenyl motif to
furnish corresponding spiro compounds in 87% yield (entry
30). The structure of the product 3oa was unequivocally
determined through X-ray crystallographic data and that of
other products was established by analogy.
a
Table 1. Scope of [5 + 2] Cycloaddition of VECs
In order to further amplify the scope of the reaction, we then
systematically varied the BDAs to produce the annulation
products 3 (Table 2). The alkene bearing a phenyl group led
b
entry
R1
R2
time (h)
3
yield (%)
a
Table 2. Scope of [5 + 2] Cycloaddition of BDAs
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
36
36
36
36
36
80
46
24
70
36
36
60
72
25
36
42
52
48
36
48
49
72
36
12
93
93
72
72
4
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
99
52
99
96
99
78
82
86
63
99
85
97
83
97
99
83
94
99
99
86
84
55
90
99
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-t-BuC6H4
2-OMeC6H4
3-OMeC6H4
4-OMeC6H4
2-FC6H4
3-FC6H4
4-FC6H4
2,4-F2C6H3
2-ClC6H4
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-CNC6H4
4-PhC6H4
1-naphthyl
2-naphthyl
3-thienyl
H
b
9
entry
R
time (h)
3
yield (%)
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3ja
3ka
3la
1
2
3
4
5
6
7
8
Ph
48
48
42
42
48
48
48
48
48
48
23
23
48
48
17
43
23
12
24
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
37, 69
NR
cde
,
,
4-MeC6H4
4-OMeC6H4
3,4-(OMe)2C6H3
4-FC6H4
4-ClC6H4
2-naphthyl
2-pyridyl
3-pyridyl
4-pyridyl
2-furanyl
3-furanyl
e
35, 64
73
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
3ua
3va
3wa
3xa
ce
,
NR
NR
ce
,
c
NR, 43
ce
,
trace
trace, 88
c
9
3aj
3ak
3al
ce
,
10
11
12
13
14
15
16
17
18
NR
82
e
3am
3an
3ao
3ap
3aq
3ar
3as
3au
30, 64
ce
,
2-thienyl
3-thienyl
trace
91
3-Me-2-thienyl
5-Me-2-thienyl
5-Cl-2-thienyl
2-benzofuran
cyclohexyl
69
60
46
46
c
NR
Me
t-Bu
NR
NR
d
e
cyclohexyl
vinyl
3zc
3zd
3ze
65
19
63
94
87
a
Ph
72
Unless noted otherwise, the reaction of 1a (0.15 mmol), 2 (0.10
mmol), Pd2dba3·CHCl3 (2.5 mol %), and XantPhos (5.0 mol %) was
a
Unless noted otherwise, the reaction of 1 (0.15 mmol), 2a (0.10
performed in 1.0 mL of CHCl3 under the indicated reaction
b
c
mmol), Pd2dba3·CHCl3 (2.5 mol %), and XantPhos (5.0 mol %) was
performed in 1.0 mL of CHCl3 under the indicated reaction
conditions. Isolated yield. No reaction. The reaction was carried
out with 7.5 mol % of Pd2dba3·CHCl3 and 15 mol % of XantPhos.
conditions. Isolated yield. The reaction was performed with 5.0
mol % of Pd2dba3·CHCl3 and 20 mol % of PPh3 in 1.0 mL of CH2Cl2.
b
c
d
d
e
No reaction. 5.0 mol % of Pd2dba3·CHCl3 and 10 mol % of
XantPhos were used.
B
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to a 37% yield of the product (entry 1). In order to increase
the yield, many experiments were carried out to tune reaction
parameters. Out of various trials (see Table S2), the use of
PPh3 as ligand and dichloromethane as solvent led to an
appreciable conversion, affording 3ab in 69% isolated yield
(entry 1). Surprisingly, BDAs bearing methyl- or electron-
withdrawing substituents on the aromatic group failed to
provide the desired products (entries 2, 5, and 6). Conversely,
p-methoxyphenyl and 3,4-dimethoxyphenyl-substituted alkenes
2d and 2e were suitable for this transformation, delivering the
products 3ad and 3ae (entries 3 and 4), indicating that the
electron-rich group was beneficial to the reaction. Mean-
ingfully, alkene with naphthyl was effective for this trans-
formation (entry 7). Notably, the reaction of alkenes derived
from picolinaldehyde and isonicotinaldehyde led to a trace
amount of the seven-membered ring product, while the anti-
Knoevenagel condensation/allylic alkylation product 11 was
obtained as a major product (see Scheme S1). However, BDAs
containing 3-pyridyl and furanyl moieties were tolerated under
the reaction conditions to give the products in 64−88% yield
(entries 9, 11, and 12). The alkenes from 2-thiophene-
carboxaldehyde and benzofurancarboxaldehyde were also
suitable for this transformation, giving the products 3ao−3as
(entries 14−18), whereas 2-thienyl olefin 2n was unproductive
(entry 13). The alkene having an aliphatic substituent was
practicable, although a higher amount of Pd catalyst (5.0 mol
%) was necessary (entry 19).
Table 3. Scope of Cinnamaldehyde-Derived Alkenes for Pd-
Catalyzed [5 + 2] Cycloaddition of VECs
a
Following exploration of the substrate scope of olefins
derived from aromatic and aliphatic aldehydes, we attempted
to develop [5 + 2] annulation of cinnamaldehyde-derived
olefins to construct alkenyl-substituted spiro seven-membered
cyclic products and optimization was carried out (see Table
S3). To our delight, the [5 + 2] annulation reaction of VEC 1a
with styryl olefin 5a in the presence of Pd2dba3·CHCl3 at
ambient temperature proceeded smoothly to afford the
annulation product 6aa in 72% yield. As outlined in Table 3,
it can be seen that VECs with different electron-donating or
electron-withdrawing substituents worked well to give the
corresponding products in moderate to high yield (entries 2−4
and 9−18). When olefins 5d and 5e, which feature a methyl or
a methoxy on phenyl group, respectively, were used as the
material, the reaction failed to give the corresponding products
under standard conditions (entries 7 and 8). Contrary to the
results in Table 2, the electron-rich group in the substrate 5
was unfavorable for the reaction. Olefins bearing an electron-
withdrawing group and thienyl were both competent substrates
(entries 9−18). In addition, α-amylcinnamaldehyde-derived
alkene favorably produced 6ai in 98% yield (entry 19). We
clearly determined the structure of 6of by the single-crystal X-
ray analysis and assigned that of the other products by analogy.
Subsequently, we attempted to develop an asymmetric
variant of palladium-catalyzed [5 + 2] annulation reaction.
Although different palladium salts, ligands, solvents, reaction
temperatures, and substrates with different functional groups
had been screened, attempts to increase the yield and improve
enantioselectivity of the reaction failed and only trace amount
of the desired product was observed in most cases. Overall,
spiro seven-membered cyclic product 6aa was obtained in 17%
yield with 96% ee in the presence of Pd2dba3·CHCl3 (2.5 mol
%) and the chiral phosphoramidite L1 (10 mol %) (Scheme
2). The absolute configuration of the chiral product 6aa had
not been assigned. Since asymmetric annulation reaction gave
the higher ratio of [3 + 2] cycloadduct 7aa and
a
Unless noted otherwise, the reaction of 1 (0.15 mmol), 5 (0.10
mmol), Pd2dba3·CHCl3 (5.0 mol %), and XantPhos (10 mol %) was
stirred in 1.0 mL of CHCl3 under the indicated reaction conditions.
b
Isolated yield.
Scheme 2. Asymmetric Variant of [5 + 2] Annulation
spirotetrahydrofurans are also biologically important com-
pounds,8 optimization was performed to explore stereo-
selective [3 + 2] annulation of 1a and 5a (see Table S4).
Spiroketal-based diphosphine (SKP)9 was found to be the
optimal choice and afforded the product 7aa in 95% yield with
99/96% ee and 83:17 dr. The reaction of a series of alkenes 2
and a range of VECs 1 gave products 7 with moderate to good
yield with excellent enantioselectivity and good diastereose-
lectivity (see Table S5).
As shown in Scheme 3, to demonstrate the efficiency and the
usefulness of this catalytic process, a gram-scale reaction of
VEC 1a and olefin 2a was conducted under the optimized
reaction conditions, furnishing the seven-membered spirocyclic
product 3aa in 80% yield (0.95 g). Importantly, 3aa could
undergo 1,3-dipolar cycloaddition reaction with nitrile oxides,
producing a mixture of diastereoisomers of isoxazole-fused
C
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Authors
Scheme 3. Gram-Scale Reaction and Postfunctionalization
Xing Gao − Department of Chemistry and Innovation Center of
Pesticide Research, China Agricultural University, Beijing
100193, P.R. China; orcid.org/0000-0001-6254-2583
Dongyu Zhu − Department of Chemistry and Innovation Center
of Pesticide Research, China Agricultural University, Beijing
100193, P.R. China
Yuehua Chen − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China
Hao Deng − Department of Chemistry and Innovation Center of
Pesticide Research, China Agricultural University, Beijing
100193, P.R. China
Feng Jiang − Department of Chemistry and Innovation Center of
Pesticide Research, China Agricultural University, Beijing
100193, P.R. China
Wei Wang − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P.R. China
Yongjun Wu − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02508
Notes
spirobarbiturate-tetrahydrooxepines 8a and 8b in 99% yield
with the dr of 1:1. Furthermore, direct epoxidation of 6ah
provided 9 with two oxiranes ring in 48% yield with a single
diastereomer. Interestingly, bromination of the product 3 or 6
resulted in a 6,8-dioxabicyclo[3.2.1]octane derivatives 10a or
10b. The configurations of the derivatives were unambiguously
confirmed by single-crystal X-ray diffraction analysis.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the Natural Science Foundation of
China (No. 21871293) and Chinese Universities Scientific
Fund (Nos. 2018TC052, 2018TC055, and 2019TC085).
In conclusion, we have developed a palladium-catalyzed [5 +
2] annulation of VECs with electron-deficient alkenes having
an isolated carbon−carbon double bond, offering a useful tool
for the synthesis of spirobarbiturate-tetrahydrooxepines. A
broad range of VECs and BDAs were compatible in this
procedure and were converted into the corresponding spiro
seven-membered ring compounds in high yields. A gram-scale
reaction and a series of synthetic transformations of these
products were also demonstrated.
REFERENCES
■
́
(1) For a recent review of VECs, see: Guo, W.; Gomez, J. E.;
̀
̀
Cristofol, A.; Xie, J.; Kleij, A. W. Catalytic Transformations of
Functionalized Cyclic Organic Carbonates. Angew. Chem., Int. Ed.
2018, 57, 13735−13747.
(2) Selected examples: (a) Trost, B. M.; Aponick, A. Palladium-
catalyzed asymmetric allylic alkylation of meso- and dl-1,2-divinyl-
ethylene carbonate. J. Am. Chem. Soc. 2006, 128, 3931−3933.
(b) Zhang, Y. J.; Yang, J. H.; Kim, S. H.; Krische, M. J. anti-Diastereo-
and enantioselective carbonyl (hydroxymethyl)allylation from the
alcohol or aldehyde oxidation level: allyl carbonates as allylmetal
surrogates. J. Am. Chem. Soc. 2010, 132, 4562−4563. (c) Cai, A.; Guo,
W.; Martinez-Rodriguez, L.; Kleij, A. W. Palladium-Catalyzed Regio-
and Enantioselective Synthesis of Allylic Amines Featuring Tetrasub-
stituted Tertiary Carbons. J. Am. Chem. Soc. 2016, 138, 14194−
14197. (d) Guo, W.; Martinez-Rodriguez, L.; Kuniyil, R.; Martin, E.;
Escudero-Adan, E. C.; Maseras, F.; Kleij, A. W. Stereoselective and
Versatile Preparation of Tri- and Tetrasubstituted Allylic Amine
Scaffolds under Mild Conditions. J. Am. Chem. Soc. 2016, 138,
11970−11978. (e) Guo, W.; Martinez-Rodriguez, L.; Martin, E.;
Escudero-Adan, E. C.; Kleij, A. W. Highly Efficient Catalytic
Formation of (Z)-1,4-But-2-ene Diols Using Water as a Nucleophile.
Angew. Chem., Int. Ed. 2016, 55, 11037−11040. (f) Khan, A.; Khan,
S.; Khan, I.; Zhao, C.; Mao, Y.; Chen, Y.; Zhang, Y. J. Enantioselective
Construction of Tertiary C-O Bond via Allylic Substitution of
Vinylethylene Carbonates with Water and Alcohols. J. Am. Chem. Soc.
2017, 139, 10733−10741. (g) Miralles, N.; Gomez, J. E.; Kleij, A. W.;
Fernandez, E. Copper-Mediated SN2’ Allyl-Alkyl and Allyl-Boryl
Couplings of Vinyl Cyclic Carbonates. Org. Lett. 2017, 19, 6096−
6099. (h) Guo, W.; Kuniyil, R.; Gomez, J. E.; Maseras, F.; Kleij, A. W.
A Domino Process toward Functionally Dense Quaternary Carbons
through Pd-Catalyzed Decarboxylative C(sp(3))-C(sp(3)) Bond
Formation. J. Am. Chem. Soc. 2018, 140, 3981−3987. (i) Wang, H.;
Qiu, S.; Wang, S.; Zhai, H. Pd-Catalyzed Umpolung of π−
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Experimental procedure, characterization data, NMR
spectra, and X-ray crystallographic data (PDF)
Accession Codes
CCDC 1985800−1985805 and 1991932 contain the supple-
mentary crystallographic data for this paper. These data can be
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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.
AUTHOR INFORMATION
Corresponding Author
■
Hongchao Guo − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China; orcid.org/0000-0002-7356-
4283; Email: hchguo@cau.edu.cn
D
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Allylpalladium Intermediates: Assembly of All-Carbon α-Vinyl
Quaternary Aldehydes through C(sp3)−C(sp3) Coupling. ACS
Catal. 2018, 8, 11960−11965. (j) Khan, A.; Zhao, H.; Zhang, M.;
Khan, S.; Zhao, D. Regio- and Enantioselective Synthesis of Sulfone-
Bearing Quaternary Carbon Stereocenters by Pd-Catalyzed Allylic
Substitution. Angew. Chem., Int. Ed. 2020, 59, 1340−1345.
(5) (a) Wu, Y.; Yuan, C.; Wang, C.; Mao, B.; Jia, H.; Gao, X.; Liao,
J.; Jiang, F.; Zhou, L.; Wang, Q.; Guo, H. Palladium-Catalyzed [5 + 2]
Cycloaddition of Vinyloxiranes with Sulfamate-Derived Cyclic Imines
To Construct 1,3-Oxazepine Heterocycles. Org. Lett. 2017, 19, 6268−
6271. (b) Mao, B.; Zhang, J.; Xu, Y.; Yan, Z.; Wang, W.; Wu, Y.; Sun,
C.; Zheng, B.; Guo, H. Palladium-Catalyzed [3 + 2] Annulation of
Allenyl Carbinol Acetates with C,N-cyclic Azomethine Imines. Chem.
Commun. 2019, 55, 12841−12844. (c) Zhou, L.; Zeng, Y.; Gao, X.;
Wang, Q.; Wang, C.; Wang, B.; Wang, W.; Wu, Y.; Zheng, B.; Guo, H.
A Chiral Squaramide-Catalyzed Asymmetric Dearomative Tandem
Annulation Reaction through A Kinetic Resolution of MBH Alcohols:
Highly Enantioselective Synthesis of Three-Dimensional Heterocyclic
Compounds. Chem. Commun. 2019, 55, 10464−10467. (d) Zhou, L.;
Yuan, C.; Zeng, Y.; Wang, Q.; Wang, C.; Liu, M.; Wang, W.; Wu, Y.;
Zheng, B.; Guo, H. Direct Activation of Unmodified Morita-Baylis-
Hillman Alcohols through Phosphine Catalysis for Rapid Con-
struction of Three-Dimensional Heterocyclic Compounds. Org. Lett.
2019, 21, 4882−4886. (e) Shi, W.; Mao, B.; Xu, J.; Wang, Q.; Wang,
W.; Wu, Y.; Li, X.; Guo, H. Phosphine-Catalyzed Cascade Michael
Addition/[4 + 2] Cycloaddition Reaction of Allenoates and 2-
Arylidene-1,3-indanediones. Org. Lett. 2020, 22, 2675−2680. (f) Mao,
B.; Liu, H.; Yan, Z.; Xu, Y.; Xu, J.; Wang, W.; Wu, Y.; Guo, H.
Palladium-Catalyzed Asymmetric [4 + 2] Cycloaddition of 2-
Methylidenetrimethylene Carbonate with Alkenes: Access to Chiral
Tetrahydropyran-Fused Spirocyclic Scaffolds. Angew. Chem., Int. Ed.
2020, 59, 11316−11320.
(6) Selected examples: (a) Frankowski, S.; Gajda, T.; Albrecht, Ł.
Isothiocyanate Strategy for the Synthesis of Quaternary α-Amino
Acids Bearing a Spirocyclic Ring System. Adv. Synth. Catal. 2018, 360,
1822−1832. (b) Liu, H.; Liu, Y.; Yuan, C.; Wang, G.-P.; Zhu, S.-F.;
Wu, Y.; Wang, B.; Sun, Z.; Xiao, Y.; Zhou, Q.-L.; Guo, H.
Enantioselective Synthesis of Spirobarbiturate-Cyclohexenes through
Phosphine-Catalyzed Asymmetric [4 + 2] Annulation of Barbiturate-
Derived Alkenes with Allenoates. Org. Lett. 2016, 18, 1302−1305.
(c) Liu, Y.; Yang, W.; Wu, Y.; Mao, B.; Gao, X.; Liu, H.; Sun, Z.; Xiao,
Y.; Guo, H. Asymmetric Construction of Highly Functionalized
Spirobarbiturate-Cyclopentenes through Chiral Phosphine-Catalyzed
[3 + 2] Annulation of Morita−Baylis−Hillman Carbonates with
Barbiturate-Derived Alkenes. Adv. Synth. Catal. 2016, 358, 2867−
2872. (d) Gao, X.; Li, Z.; Yang, W.; Liu, Y.; Chen, W.; Zhang, C.;
Zheng, L.; Guo, H. Phosphine-catalyzed [3 + 2] and [4 + 2]
annulation reactions of ynones with barbiturate-derived alkenes. Org.
Biomol. Chem. 2017, 15, 5298−5307.
(3) Selected examples: (a) Khan, A.; Zheng, R.; Kan, Y.; Ye, J.; Xing,
J.; Zhang, Y. J. Palladium-catalyzed decarboxylative cycloaddition of
vinylethylene carbonates with formaldehyde: enantioselective con-
struction of tertiary vinylglycols. Angew. Chem., Int. Ed. 2014, 53,
6439−6442. (b) Khan, A.; Yang, L.; Xu, J.; Jin, L. Y.; Zhang, Y. J.
Palladium-catalyzed asymmetric decarboxylative cycloaddition of
vinylethylene carbonates with Michael acceptors: construction of
vicinal quaternary stereocenters. Angew. Chem., Int. Ed. 2014, 53,
11257−11260. (c) Khan, I.; Zhao, C.; Zhang, Y. J. Pd-Catalyzed
asymmetric decarboxylative cycloaddition of vinylethylene carbonates
with 3-cyanochromones. Chem. Commun. 2018, 54, 4708−4711.
(d) Liu, K.; Khan, I.; Cheng, J.; Hsueh, Y. J.; Zhang, Y. J. Asymmetric
Decarboxylative Cycloaddition of Vinylethylene Carbonates with β-
Nitroolefins by Cooperative Catalysis of Palladium Complex and
Squaramide. ACS Catal. 2018, 8, 11600−11604. (e) Khan, A.; Xing,
J.; Zhao, J.; Kan, Y.; Zhang, W.; Zhang, Y. J. Palladium-catalyzed
enantioselective decarboxylative cycloaddition of vinylethylene
carbonates with isocyanates. Chem. - Eur. J. 2015, 21, 120−124.
(f) Yang, L.; Khan, A.; Zheng, R.; Jin, L. Y.; Zhang, Y. J. Pd-Catalyzed
Asymmetric Decarboxylative Cycloaddition of Vinylethylene Carbo-
nates with Imines. Org. Lett. 2015, 17, 6230−6233. (g) Park, J.-U.;
Ahn, H.-I.; Cho, H.-J.; Xuan, Z.; Kim, J. H. Asymmetric Synthesis of
N-Fused 1,3-Oxazolidines via Pd-Catalyzed Decarboxylative (3 + 2)
Cycloaddition. Adv. Synth. Catal. 2020, 362, 1836−1840. (h) Yang, L.
C.; Rong, Z. Q.; Wang, Y. N.; Tan, Z. Y.; Wang, M.; Zhao, Y.
Construction of Nine-Membered Heterocycles through Palladium-
Catalyzed Formal [5 + 4] Cycloaddition. Angew. Chem., Int. Ed. 2017,
56, 2927−2931. (i) Yuan, C.; Wu, Y.; Wang, D.; Zhang, Z.; Wang, C.;
Zhou, L.; Zhang, C.; Song, B.; Guo, H. Formal [5 + 3] Cycloaddition
of Zwitterionic Allylpalladium Intermediates with Azomethine Imines
for Construction of N,O-Containing Eight-Membered Heterocycles.
Adv. Synth. Catal. 2018, 360, 652−658. (j) Das, P.; Gondo, S.;
Nagender, P.; Uno, H.; Tokunaga, E.; Shibata, N. Access to benzo-
fused nine-membered heterocyclic alkenes with a trifluoromethyl
carbinol moiety via a double decarboxylative formal ring-expansion
process under palladium catalysis. Chem. Sci. 2018, 9, 3276−3281.
(k) Singha, S.; Patra, T.; Daniliuc, C. G.; Glorius, F. Highly
Enantioselective [5 + 2] Annulations through Cooperative N-
Heterocyclic Carbene (NHC) Organocatalysis and Palladium
Catalysis. J. Am. Chem. Soc. 2018, 140, 3551−3554. (l) Wei, Y.;
Liu, S.; Li, M. M.; Li, Y.; Lan, Y.; Lu, L. Q.; Xiao, W. J.
Enantioselective Trapping of Pd-Containing 1,5-Dipoles by Photo-
generated Ketenes: Access to 7-Membered Lactones Bearing Chiral
Quaternary Stereocenters. J. Am. Chem. Soc. 2019, 141, 133−137.
(m) Zeng, R.; Li, J.-L.; Zhang, X.; Liu, Y.-Q.; Jia, Z.-Q.; Leng, H.-J.;
Huang, Q.-W.; Liu, Y.; Li, Q.-Z. Diastereoselective Construction of
6,8-Dioxabicyclo[3.2.1]octane Frameworks from Vinylethylene Car-
bonates via Palladium-Organo Relay Catalysis. ACS Catal. 2019, 9,
8256−8262. (n) An, X.-T.; Du, J.-Y.; Jia, Z.-L.; Zhang, Q.; Yu, K.-Y.;
Zhang, Y.-Z.; Zhao, X.-H.; Fang, R.; Fan, C.-A. Asymmetric Catalytic
[4 + 5] Annulation of ortho-Quinone Methides with Vinylethylene
Carbonates and its Extension to Stereoselective Tandem Rearrange-
ment. Chem. - Eur. J. 2020, 26, 3803−3809. (o) Zhang, X.; Li, X.; Li,
J.-L.; Wang, Q.-W.; Zou, W.-L.; Liu, Y.-Q.; Jia, Z.-Q.; Peng, F.; Han,
B. Regiodivergent construction of medium-sized heterocycles from
vinylethylene carbonates and allylidenemalononitriles. Chem. Sci.
2020, 11, 2888−2894. (p) Gao, X.; Xia, M.; Yuan, C.; Zhou, L.; Sun,
W.; Li, C.; Wu, B.; Zhu, D.; Zhang, C.; Zheng, B.; Wang, D.; Guo, H.
Enantioselective Synthesis of Chiral Medium-Sized Cyclic Com-
pounds via Tandem Cycloaddition/Cope Rearrangement Strategy.
ACS Catal. 2019, 9, 1645−1654.
(7) (a) Duan, J. J. W.; Chen, L.; Lu, Z.; Jiang, B.; Asakawa, N.;
Sheppeck, J. E.; Liu, R.-Q.; Covington, M. B.; Pitts, W.; Kim, S.-H.;
Decicco, C. P. Discovery of low nanomolar non-hydroxamate
inhibitors of tumor necrosis factor-alpha converting enzyme
(TACE). Bioorg. Med. Chem. Lett. 2007, 17, 266−271. (b) Girgis,
A. S.; Farag, H.; Ismail, N. S. M.; George, R. F. Synthesis, hypnotic
properties and molecular modeling studies of 1,2,7,9-tetraaza-
spiro[4.5]dec-2-ene-6,8,10-triones. Eur. J. Med. Chem. 2011, 46,
4964−4969.
(8) (a) Heindel, N. D.; Minatelli, J. A. Synthesis and Antibacterial
and Anticancer Evaluations of α-Methylene-γ-butyrolactones. J.
Pharm. Sci. 1981, 70, 84−86. (b) Lorente, A.; Lamariano-
́
Merketegi, J.; Albericio, F.; Alvarez, M. Tetrahydrofuran-Containing
Macrolides: A Fascinating Gift from the Deep Sea. Chem. Rev. 2013,
113, 4567−4610. (c) Taylor, R. D.; Maccoss, M.; Lawson, A. D. G.
Rings in Drugs. J. Med. Chem. 2014, 57, 5845−5859.
(9) (a) Ding, K.; Han, Z.; Wang, Z. Spiro Skeletons: A Class of
Privileged Structure for Chiral Ligand Design. Chem. - Asian J. 2009,
4, 32−41. (b) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Catalytic
Asymmetric Synthesis of Aromatic Spiroketals by SpinPhox/Iridium-
(I)-Catalyzed Hydrogenation and Spiroketalization of α,α′-Bis(2-
hydroxyarylidene) Ketones. Angew. Chem., Int. Ed. 2012, 51, 936−
940. (c) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.-J.; Liu, L.;
Wang, Z.; Ding, K. Aromatic Spiroketal Bisphosphine Ligands:
Palladium-Catalyzed Asymmetric Allylic Amination of Racemic
Morita−Baylis−Hillman Adducts. Angew. Chem., Int. Ed. 2012, 51,
(4) Modern Physical Organic Chemistry; Anslyn, E. V., Dougherty, D.
A., Eds.; Higher Education Press: Beijing, 2009; pp 63−140.
E
https://dx.doi.org/10.1021/acs.orglett.0c02508
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
9276−9282. (d) Wang, X.; Guo, P.; Wang, X.; Wang, Z.; Ding, K.
Practical Asymmetric Catalytic Synthesis of Spiroketals and Chiral
Diphosphine Ligands. Adv. Synth. Catal. 2013, 355, 2900−2907.
(e) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K.
Spiroketal-Based Diphosphine Ligands in Pd-Catalyzed Asymmetric
Allylic Amination of Morita−Baylis−Hillman Adducts: Exceptionally
High Efficiency and New Mechanism. J. Am. Chem. Soc. 2014, 136,
405−411. (f) Liu, J.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. Highly
Regio- and Enantioselective Alkoxycarbonylative Amination of
Terminal Allenes Catalyzed by a Spiroketal-Based Diphosphine/
Pd(II) Complex. J. Am. Chem. Soc. 2015, 137, 15346−15349. (g) Liu,
J.; Han, Z.; Wang, X.; Meng, F.; Wang, Z.; Ding, K. Palladium-
Catalyzed Asymmetric Construction of Vicinal Tertiary and All-
Carbon Quaternary Stereocenters by Allylation of β-Ketocarbonyls
with Morita-Baylis-Hillman Adducts. Angew. Chem., Int. Ed. 2017, 56,
5050−5054. (h) Wang, X.; Wang, X.; Han, Z.; Wang, Z.; Ding, K.
Palladium-Catalyzed Asymmetric Allylic AllylationofRacemic Mor-
ita−Baylis−HillmanAdducts. Angew. Chem., Int. Ed. 2017, 56, 1116−
1119. (i) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.; Ding,
K. Highly Stereoselective Olefin Cyclopropanation of Diazooxindoles
Catalyzed by a C2-Symmetric Spiroketal Bisphosphine/Au(I)
Complex. J. Am. Chem. Soc. 2013, 135, 8197−8200. (j) Wang, H.;
Yu, L.; Xie, M.; Wu, J.; Qu, G.; Ding, K.; Guo, H. Regio- and
Enantioselective Allylic Amination of Aliphatic MBH Adducts with N-
Heteroaromatics. Chem. - Eur. J. 2018, 24, 1425−1430.
F
https://dx.doi.org/10.1021/acs.orglett.0c02508
Org. Lett. XXXX, XXX, XXX−XXX