Enantioselective Synthesis of Axially Chiral Biaryls by Diels-Alder/Retro-Diels-Alder Reaction of 2-Pyrones with Alkynes

Article abstract of DOI:10.1021/jacs.1c04759

The enantioselective synthesis of axially chiral biaryls by a copper-catalyzed Diels-Alder/retro-Diels-Alder reaction of 2-pyrones with alkynes is reported herein. Using electron-deficient 2-pyrones and electron-rich 1-naphthyl acetylenes as the reaction partners, a broad range of axially chiral biaryl esters are obtained in excellent yields (up to 97% yield) and enantioselectivities (up to >99% ee). DFT calculations reveal the reaction mechanism and provide insights into the origins of the stereoselectivities. The practicality and robustness of this reaction are showcased by gram-scale synthesis. The synthetic utilizations are demonstrated by the amenable transformations of the products.

Full text of DOI:10.1021/jacs.1c04759

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Enantioselective Synthesis of Axially Chiral Biaryls by Diels−Alder/
Retro-Diels−Alder Reaction of 2‑Pyrones with Alkynes
Meng-Meng Xu, Xin-Yu You, Yu-Zhen Zhang, Yang Lu, Kui Tan, Limin Yang,* and Quan Cai*
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ABSTRACT: The enantioselective synthesis of axially chiral biaryls by a copper-catalyzed Diels−Alder/retro-Diels−Alder reaction
of 2-pyrones with alkynes is reported herein. Using electron-deficient 2-pyrones and electron-rich 1-naphthyl acetylenes as the
reaction partners, a broad range of axially chiral biaryl esters are obtained in excellent yields (up to 97% yield) and
enantioselectivities (up to >99% ee). DFT calculations reveal the reaction mechanism and provide insights into the origins of the
stereoselectivities. The practicality and robustness of this reaction are showcased by gram-scale synthesis. The synthetic utilizations
are demonstrated by the amenable transformations of the products.
xially chiral biaryls are highly important structural motifs
in natural products,1 pharmaceuticals,2 privileged chiral
1b, 45% yield, 78% ee).16 Despite this great achievement, a
direct catalytic asymmetric Diels−Alder/retro-Diels−Alder
reaction of 2-pyrones with alkynes has yet to be realized. As
part of our continuous interest in the development of
enantioselective inverse-electron-demand Diels−Alder reac-
tions of 2-pyrones,17−20 we now report the first examples of
Diels−Alder/retro-Diels−Alder reaction of 2-pyrones with
alkynes by copper catalysis (Scheme 1c). By changing the
electron-deficient 2-pyrone and electron-rich naphthylalkyne
substrates, this method provides a general platform for the
stereoselective synthesis of diverse, axially chiral naphthyl aryl
esters with multiple substituents. DFT calculations reveal an
intriguing mechanism, involving a vinylidene-quinone methide
(VQM)-like intermediate21 with allene-axial chirality and a
lactone intermediate with alkene-axial chirality. The details of
this study are reported herein.
Initially, 3-carbomethoxyl-2-pyrone 1a and 2-methoxy-1-
(pent-1-yn-1-yl)naphthalene 2a were selected as model
substrates to evaluate the Diels−Alder/retro-Diels−Alder
reaction. To our delight, in the presence of 10 mol%
Cu(OTf)2 and 12 mol% bis(oxazoline) (BOX) ligand L1,
the reaction did occur to afford the desired chiral biaryl 3a with
moderate yield and enantioselectivity (Table 1, entry 1, 37%
yield, 66% ee). Further evaluation of various Lewis acids
(Table S1) revealed that the utilization of Cu(ClO4)2·6H2O
increased the yield to 61% (Table 1, entry 2, 64% ee).
Recently, the group of Tang has proved that the side arms of
BOX ligands played a pivotal role in tuning both the reactivity
and stereocontrol.22 Consequently, a series of BOX ligands
with different substituents and side arms were explored. After
A
ligands,3 and catalysts.4 Therefore, extensive efforts have been
made over the past decade for the synthesis of atropisomeric
biaryls by asymmetric catalysis.5−10 Among those reported
examples, the atroposelective construction of aryl rings from
readily available starting materials has emerged as a
straightforward and versatile approach.11−14 One of the earliest
and most successful methods is the transition-metal-catalyzed
enantioselective [2+2+2] cyclotrimerization of alkynes.11 By
mimicking the aromatic polyketide biosynthesis, Sparr et al.
developed an innovative method for the synthesis of axially
chiral biaryls by organocatalytic aldol condensation.12 Very
recently, the N-heterocyclic carbene (NHC)-catalyzed arene
formation has been demonstrated as a powerful method for the
construction of axially chiral biaryls by Lupton,13a Zhu,13b and
Ye.13c Despite these achievements, due to the challenges in
atroposelective formation of inert arenes, the reaction types of
current methods are still limited,11−14 especially when
considering the functionality compatibilities and substitution
patterns on aromatic rings. Thus, the development of new
methods for atroposelective arene formation is highly
desirable.
The sequential Diels−Alder reaction of 2-pyrones with
alkenes or alkynes followed by retro-Diels−Alder extrusion of
CO2 under thermal reaction conditions has been proved an
efficient method for the synthesis of substituted benzenes
(Scheme 1a).15 In general, owing to the semi-aromaticity of 2-
pyrones, these reactions are often conducted at high
temperatures. Thus, the catalytic asymmetric Diels−Alder/
retro-Diels−Alder reaction of 2-pyrones is scarcely utilized for
the atroposelective synthesis of chiral arenes. To the best of
our knowledge, only one case has been reported to date. In
2014, in the total synthesis of (+)-cavicularin, Beaudry et al.
developed a thiourea-catalyzed sequential intramolecular
normal-electron-demand Diels−Alder reaction/elimination/
retro-Diels−Alder reaction of 2-pyrone with vinylsulfone to
construct the distorted phenyl ring atroposelectively (Scheme
Received: May 7, 2021
Published: June 9, 2021
https://doi.org/10.1021/jacs.1c04759
J. Am. Chem. Soc. 2021, 143, 8993−9001
© 2021 American Chemical Society
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Scheme 1. Enantioselective Synthesis of Axially Chiral
Biaryls by Diels−Alder/Retro-Diels−Alder Reaction of 2-
Pyrones
Table 1. Optimization of the Reaction Conditions
a
b
c
entry
Lewis acid
Cu(OTf)2
ligand
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
L1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
37
61
47
47
35
40
46
72
61
88
91
97
66
64
−34
79
74
75
82
89
93
95
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
d
11
e
DCE
DCE
96
96
12
a
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), Lewis acid (10
b
mol%), and ligand (12 mol%) in solvent (1.0 mL) at 25 °C. Isolated
yield of 3a. Determined by HPLC analysis. 5 Å MS (25 mg) was
added. 1a (0.2 mmol), 2a (0.3 mmol), Cu(ClO4)2·6H2O (5 mol%),
c
d
e
L8 (6 mol%), and 5 Å MS (50 mg) in DCE (1.0 mL). Abbreviations:
DCM, dichloromethane; DCE, 1,2-dichloroethane; MS, molecular
sieves.
afford the corresponding biaryls 3e−3h in good yields and
enantioselectivities (72%−96% yields, 92%−95% ee). More-
over, 2-pyrones bearing a methyl, phenyl, or bromide group on
the C5 position were also tolerated, giving biaryls 3i−3k in
good yields but with slightly decreased enantioselectivities
(66%−82% yields, 72%−82% ee). This is probably due to the
steric effect caused by the C5-substituent of 2-pyrone and the
arylalkyne. Furthermore, when 6-phenyl-substituted 2-pyrone
1l was used as the substrate, no desired product was obtained.
Next, the scope with respect to arylalkynes was investigated.
As shown in Table 2, an array of arylalkynes bearing various
primary alkyl groups on the terminus of alkynes, including
methyl, ethyl, n-butyl, and benzyl groups, were investigated,
giving 3m−3p in excellent yields and ee (75%−92% yields,
95%−96% ee). Furthermore, alkynes bearing secondary alkyl
groups with significant steric effects, such as cyclopropyl,
cyclopentyl, cyclohexyl, and isopropyl groups, were well
tolerated in this reaction (3q−3t, 81%−95% yields, 95%−
96% ee). The arylalkyne with a more sterically hindered tert-
butyl group showed relatively low reactivity but afforded 3u
with 37% yield and 94% ee. However, when a phenyl group
was installed on the terminus of alkyne 2k, the reactivity was
decreased distinctly, and the corresponding product 3v was
obtained in only 16% yield. It is worth mentioning that
bromoarylacetylene 2l and silylarylacetylene 2m worked very
well in this reaction, affording products 3w and 3x with
excellent yields and ee (84% yield and 94% ee, 89% yield and
considerable experimentation (Table 1, entries 3−9, see the
Supporting Information for details), it was found that ligand
L7 bearing a 3,5-dimethoxybenzyl side arm group dramatically
enhanced the yield and enantioselectivity (Table 1, entry 8,
72% yield, 89% ee). The introduction of two 3,5-dimethox-
ybenzyl side arm groups on the ligand (L8) further improved
the enantioselectivity but with slightly decreased yield (Table
1, entry 9, 61% yield, 93% ee). Further reaction optimization
revealed significant solvent effects (Table S3 in the Supporting
Information), and dichloroethane was optimal, affording 3a in
88% yield and 95% ee (Table 1, entry 10). Then, the effect of
additives was investigated. The addition of 5 Å molecular
sieves gave better results (Table 1, entry 11, 91% yield, 96%
ee). Of particular note, lower catalyst loading [5 mol%
Cu(ClO4)2·6H2O and 6 mol% L8] was also compatible, giving
3a in 97% yield and 96% ee (Table 1, entry 12).
After the optimized reaction conditions were established, the
reaction scope was investigated. A variety of 2-pyrones were
evaluated (Table 2). The reaction was applicable to 2-pyrones
with different ester groups, including methyl (3a), ethyl (3b),
phenylethyl (3c), and benzyl (3d) examples (73%−97% yields,
94%−96% ee). Notably, various C4-alkyl- and C4-aryl-
substituted 2-pyrones underwent the reaction smoothly to
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a b c
, ,
Table 2. Substrate Scope
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Cu(ClO4)2·6H2O (5 mol%), L8 (6 mol%), and 5 Å MS (50 mg) in DCE (1.0 mL) at 25 °C.
b
c
d
e
Isolated yields of 3 are given. The ee was determined by HPLC analysis. Cu(ClO4)2·6H2O (10 mol%) and L8 (12 mol%) were used. The
absolute configuration of 3w was determined by X-ray crystallographic analysis (CCDC 2054016).
94% ee, respectively). The bromo and silyl substituents on the
biaryl scaffolds could serve as handles for further functionaliza-
tion, thus dramatically enhancing the synthetic potential of the
products. Moreover, naphthalenes substituted with a variety of
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Figure 1. DFT calculations. (a) DFT-optimized transition structures and relative free energies. (b) Calculated free energy profile for pathways A
and B.
functional groups such as methyl, phenyl, bromo, and alkoxyl
groups on various positions were accommodated, affording the
products 3y−3ag in good yields and enantioselectivities.
Replacement of the 2-methoxyl group with other alkoxyl
groups (e.g., EtO-, iPrO-, and BnO-) gave the corresponding
products 3ah−3aj with comparable yields and ee. To
demonstrate the key role of the 2-alkoxyl group on
naphthalenes, substrates without an alkoxyl group (2z) or
with a 2-hydroxyl group (2aa) were evaluated. The desired
product was not observed (3ak) or was afforded with
diminished yield and enantioselectivity (52% yield and 32%
ee for 3al). Furthermore, the double Diels−Alder/retro-Diels−
Alder reactions of 2-pyrone 1a with diyne 2ab were also
performed (Table 2). Remarkably, the desired product 3am,
possessing two stereogenic axes, was obtained in 51% yield
with excellent enantioselectivity (>99% ee) and diastereo-
selectivity (19:1 dr).
To explore the reaction mechanism and the origins of the
stereoselectivities, DFT calculations were conducted on the
reaction of 2-pyrones 1a and arylalkyne 2b catalyzed by
Cu(II)/L1. Figure 1 shows the free energy surface starting
from the malonate model complex for the BOX ligand used in
the experiments. According to the different approaching faces
of 2-pyrone and arylalkyne, there should be four possible
reaction pathways (A, B, C, and D) for the Diels−Alder
reaction. We carried out DFT calculations on the correspond-
ing transition states and intermediates, which showed that the
Diels−Alder reaction is stepwise, with the first step as the rate-
determining step. The four stereoisomeric transition structures
are shown in Figure 1a. TS1-A, leading to the major axially
enantiomeric biaryl product, is energetically more favored than
TS1-B by 1.0 kcal/mol, leading to the minor axially
enantiomeric biaryl product. The enantioselectivity is also
determined at this stage in accordance with the experimental
observations (68% ee in calculation vs 64% ee in
experimental). The major difference between the two
transition structures lies in the relative positions of the
methoxyl group on the arylalkyne substrate and the phenyl ring
on the ligand. In the TS1-A structure, the distance between the
C−H on the methoxyl group and the center of the phenyl ring
is 2.58 Å. In contrast, in the TS1-B structure, the methoxyl
group on arylalkyne is deviated away from the phenyl ring.
These results might suggest that the energy difference between
the two transition structures originates from the C−H···π
interaction and decreasing energy of the favored transition
structure TS1-A. Similar interactions may also be observed
with arylalkynes carrying other alkoxyl groups such as EtO-,
iPrO-, and BnO-, thus leading to the corresponding products
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with comparable yields and ee (3ah−3aj). In the calculated
free energy profile for the reaction (Figure 1b), the catalyst−
substrate complex IN0 associated with arylalkyne 2b results in
an unstabilized complex IN1 due to the unfavorable entropy of
association. In the TS1 structure, the carbon−carbon triple
bond is broken and the naphthyl ring is dearomatized, resulting
in a chiral VQM-like21 transition structure. Meanwhile, a chiral
carbon center is formed on pyrone. In the structure of TS1-A,
the dihedral angle between pyrone and alkyne (highlighted in
Figure 1a) is 149° (deviated from 180°); therefore, an
intermediate IN2-A is formed which is responsible for the
stepwise Diels−Alder reaction mechanism. The lower energy
transition state TS1-A, with the first forming bond length of
2.10 Å, has a barrier of 23.1 kcal/mol compared with IN0,
while the transition state for the second step of the Diels−
Alder reaction (TS2-A) has a barrier of 17.5 kcal/mol
compared with IN0, with the second forming bond length of
2.55 Å. In this step, the naphthyl ring is regenerated, and the
axial chirality of the allene intermediate IN2-A is transferred to
the nascent alkene, affording bridged-lactone cycloadduct P1-A
with two chiral carbon centers and one stereogenic axis
(alkene-aryl axial chirality). The adduct P1-A then undergoes
retro-Diels−Alder extrusion of CO2 in a concerted mechanism
via TS3-A with a barrier of 13.9 kcal/mol.
noting that the bromide of 3w could be easily converted to
various types of functionalities by palladium-catalyzed cross-
couplings. For instance, the Suzuki reactions of 3w gave 3v
(90% yield, 95% ee) and 4 (43% yield, 95% ee); the
carbonylation of 3w gave diester 5 (83% yield, 95% ee); the
Heck reaction gave α,β-unsaturated ester 6 (97% yield, 95%
ee); and the Buchwald−Hartwig amination afforded amino-
biaryl 7 (71% yield, 95% ee). All of these transformations went
on smoothly with high yields and maintained enantio-
selectivities. Furthermore, the ester group of 3v was also
amenable to be transformed (Scheme 2c): the chiral aldehyde
8 was obtained via sequential reduction and oxidation (86%
yield, 95% ee); the chiral carboxylic acid 9 was obtained by
hydrolysis (91% yield, 96% ee); and then the chiral amine 10
was obtained by Curtius rearrangement of 9 (75% yield, 96%
ee).
In summary, we have disclosed the first copper-catalyzed
enantioselective sequential Diels−Alder/retro-Diels−Alder
reaction of 2-pyrones and alkynes. Under mild reaction
conditions, this reaction enables the synthesis of a wide
range of axially chiral biaryl esters with excellent yields and
enantioselectivities. DFT calculations reveal the Diels−Alder
reaction involves a stepwise mechanism, and provide insights
into the origins of the stereoselectivities. The obtained
products are amenable to being transformed to other valuable
axially chiral biaryl scaffolds. It is anticipated that this reaction
will become a new strategy for stereoselective arene formation.
Further investigations of this strategy are ongoing in our
laboratory.
To showcase the practicability of this method, a large-scale
reaction was conducted. As illustrated in Scheme 2a, the gram-
scale reaction of 1a and brominated alkyne 2l proceeded
uneventfully to give the product 3w without loss of yield and
enantiopurity (1.60 g, 87% yield, 94% ee). The product 3w was
amenable for further transformations (Scheme 2b). It is worth
ASSOCIATED CONTENT
■
sı
* Supporting Information
Scheme 2. Gram-Scale Synthesis and Synthetic
Transformations
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04759.
Experimental procedures and spectra data for all new
compounds (PDF)
Accession Codes
CCDC 2054016 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Quan Cai − Department of Chemistry, Fudan University,
Shanghai 200433, China; orcid.org/0000-0002-8493-
3267; Email: quan_cai@fudan.edu.cn
Limin Yang − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; orcid.org/0000-0003-1021-3942;
Email: myang@hznu.edu.cn
Authors
Meng-Meng Xu − Department of Chemistry, Fudan
University, Shanghai 200433, China
Xin-Yu You − Department of Chemistry, Fudan University,
Shanghai 200433, China
Yu-Zhen Zhang − Department of Chemistry, Fudan
University, Shanghai 200433, China
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Xiang, S.-H.; Li, S.; Ye, L.; Tan, B. Recent Advances in Catalytic
Asymmetric Construction of Atroisomers. Chem. Rev. 2021, 121 (8),
4805−4902.
Yang Lu − Department of Chemistry, Fudan University,
Shanghai 200433, China
Kui Tan − Department of Chemistry, Fudan University,
Shanghai 200433, China
(6) For recent examples involving oxidative coupling, transition-
metal-catalyzed cross-coupling, and aromatic substitution, see: (a) Jia,
Z.-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick, A. P.;
Waldmann, H. General Enantioselective C−H Activation with
Efficiently Tunable Cyclopentadienyl Ligands. Angew. Chem., Int.
Ed. 2017, 56, 2429−2434. (b) Qi, L.-W.; Mao, J.-H.; Zhang, J.; Tan,
B. Organocatalytic asymmetric arylation of indoles enabled by azo
groups. Nat. Chem. 2018, 10, 58−64. (c) Qi, L.-W.; Li, S.; Xiang, S.-
H.; Wang, J.; Tan, B. Asymmetric construction of atropisomeric
biaryls via a redox neutral cross-coupling strategy. Nat. Catal. 2019, 2,
314−323. (d) Tian, J.-M.; Wang, A.-F.; Yang, J.-S.; Zhao, X.-J.; Tu, Y.-
Q.; Zhang, S.-Y.; Chen, Z.-M. Copper-Complex-Catalyzed Asym-
metric Aerobic Oxidative Cross-Coupling of 2-Naphthols: Enantio-
selective Synthesis of 3,3′-Substituted C1-Symmetric BINOLs. Angew.
Chem., Int. Ed. 2019, 58, 11023−11027. (e) Shen, D.; Xu, Y.; Shi, S.-
L. A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst Enables
Highly Enantioselective Suzuki−Miyaura Cross-Coupling Reactions
for the Synthesis of Biaryl Atropisomers. J. Am. Chem. Soc. 2019, 141,
14938−14945. (f) Yang, H.; Sun, J.; Gu, W.; Tang, W.
Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-
Substituted Biaryls and Asymmetric Synthesis of Gossypol. J. Am.
Chem. Soc. 2020, 142, 8036−8043. (g) Qiu, H.; Shuai, B.; Wang, Y.-
Z.; Liu, D.; Chen, Y.-G.; Gao, P.-S.; Ma, H.-X.; Chen, S.; Mei, T.-S.
Enantioselective Ni-Catalyzed Electrochemical Synthesis of Biaryl
Atropisomers. J. Am. Chem. Soc. 2020, 142, 9872−9878. (h) Liu, Z.-
S.; Hua, Y.; Gao, Q.; Ma, Y.; Tang, H.; Shang, Y.; Cheng, H.-G.;
Zhou, Q. Construction of axial chirality via palladium/chiral
norbornene cooperative catalysis. Nat. Catal. 2020, 3, 727−733.
(7) For selected examples involving the modification of prochiral or
racemic biaryls, see: (a) Gustafson, J. L.; Lim, D.; Miller, S. J.
Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-
Catalyzed Asymmetric Bromination. Science 2010, 328, 1251−1255.
(b) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka, M.;
Akiyama, T. Enantioselective Synthesis of Multisubstituted Biaryl
Skeleton by Chiral Phosphoric Acid Catalyzed Desymmetrization/
Kinetic Resolution Sequence. J. Am. Chem. Soc. 2013, 135, 3964−
3970. (c) Cheng, D.-J.; Yan, L.; Tian, S.-K.; Wu, M.-Y.; Wang, L.-X.;
Fan, Z.-L.; Zheng, S.-C.; Liu, X.-Y.; Tan, B. Highly Enantioselective
Kinetic Resolution of Axially Chiral BINAM Derivatives Catalyzed by
a Brønsted Acid. Angew. Chem., Int. Ed. 2014, 53, 3684−3687.
(d) Zheng, J.; You, S.-L. Construction of Axial Chirality by Rhodium-
Catalyzed Asymmetric Dehydrogenative Heck Coupling of Biaryl
Compounds with Alkenes. Angew. Chem., Int. Ed. 2014, 53, 13244−
13247. (e) Ramírez-López, P.; Ros, A.; Romero-Arenas, A.; Iglesias-
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (Grant No. 21801043, 22071030), the Natural Science
Foundation of Zhejiang Province (ZJNSF) (Grant No.
LY20B020010), the “1000-Youth Talents Plan”, and Fudan
University (start-up grant) for financial support.
REFERENCES
■
(1) For selected reviews, see: (a) Bringmann, G.; Gulder, T.; Gulder,
T. A. M.; Breuning, M. Atroposelective Total Synthesis of Axially
Chiral Biaryl Natural Products. Chem. Rev. 2011, 111, 563−639.
(b) Zask, A.; Murphy, J.; Ellestad, G. A. Biological Stereoselectivity of
Atropisomeric Natural Products and Drugs. Chirality 2013, 25, 265−
274. (c) Smyth, J. E.; Butler, N. M.; Keller, P. A. A twist of nature−
the significance of atropisomers in biological systems. Nat. Prod. Rep.
2015, 32, 1562−1583.
(2) For selected reviews, see: (a) Clayden, J.; Moran, W. J.; Edwards,
P. J.; LaPlante, S. R. The Challenge of Atropisomerism in Drug
Discovery. Angew. Chem., Int. Ed. 2009, 48, 6398−6401. (b) LaPlante,
S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. Revealing
Atropisomer Axial Chirality in Drug Discovery. ChemMedChem 2011,
6, 505−513. (c) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.;
Fandrick, D. R.; Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J.
Assessing Atropisomer Axial Chirality in Drug Discovery and
Development. J. Med. Chem. 2011, 54, 7005−7022.
(3) For selected reviews, see: (a) Noyori, R.; Takaya, H. BINAP: an
efficient chiral element for asymmetric catalysis. Acc. Chem. Res. 1990,
23, 345−350. (b) Chen, Y.; Yekta, S.; Yudin, A. K. Modified BINOL
Ligands in Asymmetric Catalysis. Chem. Rev. 2003, 103, 3155−3211.
(4) For selected reviews, see: (a) Parmar, D.; Sugiono, E.; Raja, S.;
Rueping, M. Complete Field Guide to Asymmetric BINOL-
Phosphate Derived Brønsted Acid and Metal Catalysis: History and
Classification by Mode of Activation; Brønsted Acidity, Hydrogen
Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114,
9047−9153. (b) Shirakawa, S.; Maruoka, K. Recent Developments in
Asymmetric Phase-Transfer Reactions. Angew. Chem., Int. Ed. 2013,
52, 4312−4348.
(5) For selected reviews on the synthesis of axially chiral biaryls, see:
(a) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Atroposelective Synthesis of Axially Chiral
Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384−5427.
(b) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Total synthesis of
chiral biaryl natural products by asymmetric biaryl coupling. Chem.
Soc. Rev. 2009, 38, 3193−3207. (c) Wencel-Delord, J.; Panossian, A.;
Leroux, F. R.; Colobert, F. Recent advances and new concepts for the
synthesis of axially stereoenriched biaryls. Chem. Soc. Rev. 2015, 44,
3418−3430. (d) Zilate, B.; Castrogiovanni, A.; Sparr, C. Catalyst-
Controlled Stereoselective Synthesis of Atropisomers. ACS Catal.
2018, 8, 2981−2988. (e) Link, A.; Sparr, C. Stereoselective arene
formation. Chem. Soc. Rev. 2018, 47, 3804−3815. (f) Wang, Y.-B.;
Tan, B. Construction of Axially Chiral Compounds via Asymmetric
Organocatalysis. Acc. Chem. Res. 2018, 51, 534−547. (g) Metrano, A.
J.; Miller, S. J. Peptide-Based Catalysts Reach the Outer Sphere
through Remote Desymmetrization and Atroposelectivity. Acc. Chem.
Res. 2019, 52, 199−215. (h) Bao, X.; Rodriguez, J.; Bonne, D.
Enantioselective Synthesis of Atropisomers with Multiple Stereogenic
Axes. Angew. Chem., Int. Ed. 2020, 59, 12623−12634. (i) Cheng, J. K.;
Siguenza, J.; Fernández, R.; Lassaletta, J. M. Synthesis of IAN-type
̈
N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald−Hartwig
Amination. J. Am. Chem. Soc. 2016, 138, 12053−12056. (f) Yao, Q. J.;
Zhang, S.; Zhan, B.-B.; Shi, B.-F. Atroposelective Synthesis of Axially
Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination
Enabled by a Transient Chiral Auxiliary. Angew. Chem., Int. Ed. 2017,
56, 6617−6621. (g) Zhang, J.; Wang, J. Atropoenantioselective
Redox-Neutral Amination of Biaryl Compounds through Borrowing
Hydrogen and Dynamic Kinetic Resolution. Angew. Chem., Int. Ed.
2018, 57, 465−469. (h) Chen, G.-Q.; Lin, B.-J.; Huang, J.-M.; Zhao,
L.-Y.; Chen, Q.-S.; Jia, S.-P.; Yin, Q.; Zhang, X. Design and Synthesis
of Chiral oxa-Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric
Reduction of Bringmann’s Lactones with Molecular H2. J. Am. Chem.
Soc. 2018, 140, 8064−8068. (i) Zhan, B.-B.; Wang, L.; Luo, J.; Lin, X.-
F.; Shi, B.-F. Synthesis of Axially Chiral Biaryl-2-amines via Pd(II)-
Catalyzed Free Amine-Directed Atroposelective C-H Olefination.
Angew. Chem., Int. Ed. 2020, 59, 3568−3572. (j) Wang, Q.; Zhang,
W.-W.; Song, H.; Wang, J.; Zheng, C.; Gu, Q.; You, S.-L. Rhodium-
Catalyzed Atroposelective Oxidative C−H/C−H Cross-Coupling
Reaction of 1-Aryl Isoquinoline Derivatives with Electron-Rich
Heteroarenes. J. Am. Chem. Soc. 2020, 142, 15678−15685. (k) Liu,
W.; Jiang, Q.; Yang, X. A Versatile Method for Kinetic Resolution of
8998
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Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Protecting-Group-Free BINAMs and NOBINS through Chiral
Phosphoric Acid Catalyzed Triazane Formation. Angew. Chem., Int.
Ed. 2020, 59, 23598−23602.
Zheng, G.; Mi, R.; Huang, Z.; Zhu, X.; He, X.; Li, X. Rhodium(III)-
Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation
and Intermolecular Coupling with Sterically Hindered Alkynes.
Angew. Chem., Int. Ed. 2020, 59, 13288−13294. (j) Zhang, L.;
Shen, J.; Wu, S.; Zhong, G.; Wang, Y.-B.; Tan, B. Design and
Atroposelective Construction of IAN analogues by Organocatalytic
Asymmetric Heteroannulation of Alkynes. Angew. Chem., Int. Ed.
2020, 59, 23077−23082.
(8) For selected examples involving point-to-axial chirality transfer,
see: (a) Guo, F.; Konkol, L. C.; Thomson, R. J. Enantioselective
Synthesis of Biphenols from 1,4-Diketones by Traceless Central-to-
Axial Chirality Exchange. J. Am. Chem. Soc. 2011, 133, 18−20.
(b) Quinonero, Q.; Jean, M.; Vanthuyne, N.; Roussel, C.; Bonne, D.;
Constantieux, T.; Bressy, C.; Bugaut, X.; Rodriguez, J. Combining
Organocatalysis with Central-to-Axial Chirality Conversion: Atropo-
selective Hantzsch-Type Synthesis of 4-Arylpyridines. Angew. Chem.,
Int. Ed. 2016, 55, 1401−1405. (c) Raut, V. S.; Jean, M.; Vanthuyne,
N.; Roussel, C.; Constantieux, T.; Bressy, C.; Bugaut, X.; Bonne, D.;
Rodriguez, J. Enantioselective Syntheses of Furan Atropisomers by an
Oxidative Central-to-Axial Chirality Conversion Strategy. J. Am.
Chem. Soc. 2017, 139, 2140−2143. (d) Link, A.; Sparr, C. Remote
Central-to-Axial Chirality Conversion: Direct Atroposelective Ester to
Biaryl Transformation. Angew. Chem., Int. Ed. 2018, 57, 7136−7139.
(9) For selected examples of other methods, see: (a) Li, G.-Q.; Gao,
(11) For selected reviews about the enantioselective [2+2+2]
cyclotrimerization of alkynes, see: (a) Shibata, T.; Tsuchikama, K.
Recent advances in enantioselective [2+2+2] cycloaddition. Org.
Biomol. Chem. 2008, 6, 1317−1323. (b) Dominguez, G.; Perez-
Castells, J. Recent advances in [2+2+2] cycloaddition reactions.
Chem. Soc. Rev. 2011, 40, 3430−3444. (c) Pla-Quintana, A.; Roglans,
A. Chiral Induction in [2 + 2+2] Cycloaddition Reactions. Asian J.
Org. Chem. 2018, 7, 1706−1718. For selected examples: (d) Gutnov,
A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.;
Sundermann, B.; Sundermann, C. Cobalt(I)-Catalyzed Asymmetric
[2+2+2] Cycloaddition of Alkynes and Nitriles: Synthesis of
Enantiomerically Enriched Atropoisomers of 2-Arylpyridines. Angew.
Chem., Int. Ed. 2004, 43, 3795−3797. (e) Shibata, T.; Fujimoto, T.;
Yokota, K.; Takagi, K. Iridium Complex-Catalyzed Highly Enantio-
and Diastereoselective [2 + 2+2] Cycloaddition for the Synthesis of
Axially Chiral Teraryl Compounds. J. Am. Chem. Soc. 2004, 126,
8382−8383. (f) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K.
Enantioselective Synthesis of Axially Chiral Phthalides through
Cationic [RhI(H8-binap)]-Catalyzed Cross Alkyne Cyclotrimeriza-
tion. Angew. Chem., Int. Ed. 2004, 43, 6510−6512. (g) Nishida, G.;
Noguchi, K.; Hirano, M.; Tanaka, K. Asymmetric Assembly of
Aromatic Rings to Produce Tetra-ortho-Substituted Axially Chiral
Biaryl Phosphorus Compounds. Angew. Chem., Int. Ed. 2007, 46,
3951−3954. (h) Li, H.; Yan, X.; Zhang, J.; Guo, W.; Jiang, J.; Wang, J.
Enantioselective Synthesis of C−N Axially Chiral N-Aryloxindoles by
Asymmetric Rhodium-Catalyzed Dual C−H Activation. Angew.
Chem., Int. Ed. 2019, 58, 6732−6736.
(12) (a) Link, A.; Sparr, C. Organocatalytic Atroposelective Aldol
Condensation: Synthesis of Axially Chiral Biaryls by Arene
Formation. Angew. Chem., Int. Ed. 2014, 53, 5458−5461. (b) Lotter,
D.; Neuburger, M.; Rickhaus, M.; Häussinger, D.; Sparr, C.
Stereoselective Arene-Forming Aldol Condensation: Synthesis of
Configurationally Stable Oligo-1,2-naphthylenes. Angew. Chem., Int.
Ed. 2016, 55, 2920−2923. (c) Fäseke, V. C.; Sparr, C. Stereoselective
Arene-Forming Aldol Condensation: Synthesis of Axially Chiral
Aromatic Amides. Angew. Chem., Int. Ed. 2016, 55, 7261−7264.
(d) Witzig, R. M.; Lotter, D.; Fäseke, V. C.; Sparr, C. Stereoselective
Arene-Forming Aldol Condensation: Catalyst-Controlled Synthesis of
Axially Chiral Compounds. Chem. - Eur. J. 2017, 23, 12960−12966.
(e) Lotter, D.; Castrogiovanni, A.; Neuburger, M.; Sparr, C. Catalyst-
Controlled Stereodivergent Synthesis of Atropisomeric Multiaxis
Systems. ACS Cent. Sci. 2018, 4, 656−660. (f) Witzig, R. M.; Fäseke,
V. C.; Häussinger, D.; Sparr, C. Atroposelective synthesis of tetra-
ortho-substituted biaryls by catalyst-controlled non-canonical polyke-
tide cyclizations. Nat. Catal. 2019, 2, 925−930. (g) Castrogiovanni,
A.; Lotter, D.; Bissegger, F. R.; Sparr, C. JoyaPhos: An Atropisomeric
Teraryl Monophosphine Ligand. Chem. - Eur. J. 2020, 26, 9864−
9868.
H.; Keene, C.; Devonas, M.; Ess, D. H.; Kurti, L. Organocatalytic
̈
Aryl−Aryl Bond Formation: An Atroposelective [3,3]-Rearrangement
Approach to BINAM Derivatives. J. Am. Chem. Soc. 2013, 135, 7414−
7417. (b) Chen, Y.-H.; Cheng, D.-J.; Zhang, J.; Wang, Y.; Liu, X.-Y.;
Tan, B. Atroposelective Synthesis of Axially Chiral Biaryldiols via
Organocatalytic Arylation of 2-Naphthols. J. Am. Chem. Soc. 2015,
137, 15062−15065. (c) Wang, J.-Z.; Zhou, J.; Xu, C.; Sun, H.; Kurti,
̈
L.; Xu, Q.-L. Symmetry in Cascade Chirality-Transfer Processes: A
Catalytic Atroposelective Direct Arylation Approach to BINOL
Derivatives. J. Am. Chem. Soc. 2016, 138, 5202−5205. (d) Jolliffe, J.
D.; Armstrong, R. J.; Smith, M. D. Catalytic enantioselective synthesis
of atropisomeric biaryls by a cation-directed O-alkylation. Nat. Chem.
2017, 9, 558−562. (e) Zhao, K.; Duan, L.; Xu, S.; Jiang, J.; Fu, Y.; Gu,
Z. Enhanced Reactivity by Torsional Strain of Cyclic Diaryliodonium
in Cu-Catalyzed Enantioselective Ring-Opening Reaction. Chem.
2018, 4, 599−612. (f) Liang, Y.; Ji, J.; Zhang, X.; Jiang, Q.; Luo, J.;
Zhao, X. Enantioselective Construction of Axially Chiral Amino
Sulfide Vinyl Arenes by Chiral Sulfide-Catalyzed Electrophilic
Carbothiolation of Alkynes. Angew. Chem., Int. Ed. 2020, 59, 4959−
4964. (g) Zhao, K.; Yang, S.; Gong, Q.; Duan, L.; Gu, Z. Diols
Activation by Cu/Borinic Acids Synergistic Catalysis in Atropose-
lective Ring-Opening of Cyclic Diaryliodoniums. Angew. Chem., Int.
Ed. 2021, 60, 5788−5793.
(10) For selected examples about the atroposelective formation of
aromatic heterocycles, see: (a) Zhang, L.; Zhang, J.; Ma, J.; Cheng,
D.-J.; Tan, B. Highly Atroposelective Synthesis of Arylpyrroles by
Catalytic Asymmetric Paal−Knorr Reaction. J. Am. Chem. Soc. 2017,
139, 1714−1717. (b) Wang, Y.-B.; Zheng, S.-C.; Hu, Y.-M.; Tan, B.
Brønsted acid-catalysed enantioselective construction of axially chiral
arylquinazolinones. Nat. Commun. 2017, 8, 15489. (c) Zhao, C.; Guo,
D.; Munkerup, K.; Huang, K.-W.; Li, F.; Wang, J. Enantioselective [3
+ 3] atroposelective annulation catalyzed by N-heterocyclic carbenes.
Nat. Commun. 2018, 9, 611. (d) Zheng, S.-C.; Wang, Q.; Zhu, J.
Catalytic Atropenantioselective Heteroannulation between Isocya-
noacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially
Chiral 3-Arylpyrroles. Angew. Chem., Int. Ed. 2019, 58, 1494−1498.
(e) He, X.-L.; Zhao, H.-R.; Song, X.; Jiang, B.; Du, W.; Chen, Y.-C.
Asymmetric Barton−Zard Reaction to Access 3-Pyrrole-Containing
Axially Chiral Skeletons. ACS Catal. 2019, 9, 4374−4381. (f) Zheng,
S.-C.; Wang, Q.; Zhu, J. Catalytic Kinetic Resolution by
Enantioselective Aromatization: Conversion of Racemic Intermedi-
ates of the Barton−Zard Reaction into Enantioenriched 3-
Arylpyrroles. Angew. Chem., Int. Ed. 2019, 58, 9215−9219.
(g) Kwon, Y.; Li, J.; Reid, J. P.; Crawford, J. M.; Jacob, R.; Sigman,
M. S.; Toste, F. D.; Miller, S. J. Disparate Catalytic Scaffolds for
Atroposelective Cyclodehydration. J. Am. Chem. Soc. 2019, 141,
6698−6705. (h) Peng, L.; Li, K.; Xie, C.; Li, S.; Xu, D.; Qin, W.; Yan,
H. Organocatalytic Asymmetric Annulation of ortho-Alkynylanilines:
Synthesis of Axially Chiral Naphthyl-C2-indoles. Angew. Chem., Int.
Ed. 2019, 58, 17199−17024. (i) Wang, F.; Qi, Z.; Zhao, Y.; Zhai, S.;
(13) (a) Candish, L.; Levens, A.; Lupton, D. W. N-Heterocyclic
carbene catalysed redox isomerisation of esters to functionalised
benzaldehydes. Chem. Sci. 2015, 6, 2366−2370. (b) Xu, K.; Li, W.;
Zhu, S.; Zhu, T. Atroposelective Arene Formation by Carbene-
Catalyzed Formal [4 + 2] Cycloaddition. Angew. Chem., Int. Ed. 2019,
58, 17625−17630. (c) Zhang, C.-L.; Gao, Y.-Y.; Wang, H.-Y.; Zhou,
B.-A.; Ye, S. Enantioselective Synthesis of Axially Chiral Benzothio-
phene/Benzofuran-Fused Biaryls by N-Heterocyclic Carbene Cata-
lyzed Arene Formation. Angew. Chem., Int. Ed. 2021, 60, 13918−
13922.
(14) (a) Satoh, M.; Shibata, Y.; Kimura, Y.; Tanaka, K.
Atroposelective Synthesis of Axially Chiral All-Benzenoid Biaryls by
the Gold- Catalyzed Intramolecular Hydroarylation of Alkynones.
8999
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Communication
Eur. J. Org. Chem. 2016, 2016, 4465−4469. (b) Arae, S.; Beppu, S.;
Kawatsu, T.; Igawa, K.; Tomooka, K.; Irie, R. Asymmetric Synthesis of
Axially Chiral Benzocarbazole Derivatives Based on Catalytic
Enantioselective Hydroarylation of Alkynes. Org. Lett. 2018, 20,
4796−4800. (c) Xue, F.; Hayashi, T. Asymmetric Synthesis of Axially
Chiral 2-Aminobiaryls by Rhodium-Catalyzed Benzannulation of 1-
Arylalkynes with 2-(Cyanomethyl)phenylboronates. Angew. Chem.,
Int. Ed. 2018, 57, 10368−10372. (d) Shibata, T.; Sekine, A.; Mitake,
A.; Kanyiva, K. S. Intramolecular Consecutive Dehydro-Diels−Alder
Reaction for the Catalytic and Enantioselective Construction of Axial
chirality. Angew. Chem., Int. Ed. 2018, 57, 15862−15865. (e) Chen,
X.; Gao, D.; Wang, D.; Xu, T.; Liu, W.; Tian, P.; Tong, X. Access to
Aryl-Naphthaquinone Atropisomers by Phosphine-Catalyzed Atropo-
selective (4 + 2) Annulations of δ-Acetoxy Allenoates with 2-
Hydroxyquinone Derivatives. Angew. Chem., Int. Ed. 2019, 58,
15334−15338. (f) Jia, S.; Li, S.; Liu, Y.; Qin, W.; Yan, H.
Enantioselective Control of Both Helical and Axial Stereogenic
Elements though an Organocatalytic Approach. Angew. Chem., Int. Ed.
2019, 58, 18496−18501. (g) Takano, H.; Shiozawa, N.; Imai, Y.;
Kanyiva, K. S.; Shibata, T. Catalytic Enantioselective Synthesis of
Axially Chiral Polycyclic Aromatic Hydrocarbons (PAHs) via
Regioselective C−C Bond Activation of Biphenylenes. J. Am. Chem.
Soc. 2020, 142, 4714−4722. (h) Zhang, J.; Simon, M.; Golz, C.;
Alcarazo, M. Gold-Catalyzed Atroposelective Synthesis of 1,1′-
Binaphthalene-2,3′-diols. Angew. Chem., Int. Ed. 2020, 59, 5647−
5650. (i) Gicquiaud, J.; Abadie, B.; Dhara, K.; Berlande, M.;
Hermange, P.; Sotiropoulos, J.-M.; Toullec, P. Y. Brønsted Acid-
Catalyzed Enantioselective Cycloisomerization of Arylalkynes. Chem. -
Eur. J. 2020, 26, 16266−16271.
(15) For reviews, see: (a) Afarinkia, K.; Vinader, V.; Nelson, T. D.;
Posner, G. H. Dies-Alder Cycloadditions of 2-Pyrones and 2-
Pyridones. Tetrahedron 1992, 48, 9111−9171. (b) Cai, Q. The [4 +
2] Cycloaddition of 2-Pyrone in Total Synthesis. Chin. J. Chem. 2019,
37, 946−976. (c) Huang, G.; Kouklovsky, C.; de la Torre, A. Inverse-
Electron-Demand Diels−Alder Reactions of 2-Pyrones: Bridged
Lactones and Beyond. Chem. - Eur. J. 2021, 27, 4760−4778. For
selected examples, see: (d) Boger, D. L.; Mullican, M. D. Inverse
electron demand diels-alder reaction of 3-carbomethoxy-2-pyrones
with 1,1-dimethoxyethylene: a simple and mild method of aryl
annulation. Tetrahedron Lett. 1982, 23, 4551−4554. (e) Ireland, R. E.;
Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.;
Thaisrivongs, S.; Wilcox, C. S. The total synthesis of ionophore
antibiotics. A convergent synthesis of lasalocid A (X537A). J. Am.
Chem. Soc. 1983, 105, 1988−2006. (f) Kraus, G. A.; Riley, S.; Cordes,
T. Aromatics from pyrones: para-substituted alkyl benzoates from
alkenes, coumalic acid and methyl coumalate. Green Chem. 2011, 13,
2734−2736. (g) Lee, J.-H.; Cho, C.-G. Total Synthesis of (−)-Neo-
cosmosin A via Intramolecular Diels−Alder Reaction of 2-Pyrone.
Org. Lett. 2016, 18, 5126−5129. (h) Gan, P.; Smith, M. W.; Braffman,
N. R.; Snyder, S. A. Pyrone Diels−Alder Routes to Indolines and
Hydroindolines: Syntheses of Gracilamine, Mesembrine, and Δ7-
Mesembrenone. Angew. Chem., Int. Ed. 2016, 55, 3625−3630.
(i) Zhang, X.; Beaudry, C. M. Synthesis of Highly Substituted
Phenols and Benzenes with Complete Regiochemical Control. Org.
Lett. 2020, 22, 6086−6090. (j) Points, G. L., III; Stout, K. T.;
Beaudry, C. M. Regioselective Formation of Substituted Indoles:
Formal Synthesis of Lysergic Acid. Chem. - Eur. J. 2020, 26, 16655−
16658.
Lett. 1994, 35, 7541−7544. (c) Posner, G. H.; Dai, H.; Bull, D. S.;
Lee, J.-K.; Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr, S.
Lewis Acid-Promoted, Stereocontrolled, Gram Scale, Diels-Alder
Cycloadditions of Electronically Matched 2-Pyrones and Vinyl Ethers:
The Critical Importance of Molecular Sieves and the Temperature of
Titanium Coordination with the Pyrone. J. Org. Chem. 1996, 61,
671−676.
(18) (a) Markó, I. E.; Evans, G. R. Catalytic, Enantioselective,
Inverse Electron-Demand Diels−Alder (IEDDA) Reactions of 3-
Carbomethoxy-2-Pyrone (3-CMP). Tetrahedron Lett. 1994, 35,
2771−2774. (b) Markó, I. E.; Evans, G. R.; Declercq, J.-P. Catalytic
Asymmetric Diels−Alder Reactions of 2-Pyrone Derivatives. Tetrahe-
dron 1994, 50, 4557−4574. (c) Markó, I. E.; Warriner, S. L.;
Augustyns, B. Radical-Initiated, Skeletal Rearrangements of Bicy-
clo[2.2.2] Lactones. Org. Lett. 2000, 2, 3123−3125.
(19) (a) Shimizu, H.; Okamura, H.; Iwagawa, T.; Nakatani, M.
Asymmetric Synthesis of (−)- and (+)-Eutipoxide B Using a Base-
catalyzed Diels−Alder Reaction. Tetrahedron 2001, 57, 1903−1908.
(b) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L.
Asymmetric Diels−Alder Reactions of 2-Pyrones with a Bifunctional
Organic Catalyst. J. Am. Chem. Soc. 2007, 129, 6364−6365. (c) Singh,
R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L.
Enantioselective Diels−Alder Reaction of Simple α,β-Unsaturated
Ketones with a Cinchona Alkaloid Catalyst. J. Am. Chem. Soc. 2008,
130, 2422−2423. (d) Soh, J. Y.-T.; Tan, C.-H. Amino-Indanol
Catalyzed Enantioselective Reactions of 3-Hydroxy-2-Pyridones. J.
Am. Chem. Soc. 2009, 131, 6904−6905. (e) Bartelson, K. J.; Singh, R.
P.; Foxman, B. M.; Deng, L. Catalytic Asymmetric [4 + 2] Additions
with Aliphatic Nitroalkenes. Chem. Sci. 2011, 2, 1940−1944.
(f) Burch, P.; Binaghi, M.; Scherer, M.; Wentzel, C.; Bossert, D.;
Eberhardt, L.; Neuburger, M.; Scheiffele, P.; Gademann, K. Total
Synthesis of Gelsemiol. Chem. - Eur. J. 2013, 19, 2589−2591.
(g) Suzuki, T.; Watanabe, S.; Kobayashi, S.; Tanino, K.
Enantioselective Total Synthesis of (+)-Iso-A82775C, a Proposed
Biosynthetic Precursor of Chloropupukeananin. Org. Lett. 2017, 19,
922−925. (h) Shi, L.-M.; Dong, W.-W.; Tao, H.-Y.; Dong, X.-Q.;
Wang, C.-J. Catalytic Asymmetric Desymmetrization of Cyclo-
pentendiones via Diels−Alder Reaction of 3-Hydroxy-2-pyrones:
Construction of Multifunctional Bridged Tricyclic Lactones. Org. Lett.
2017, 19, 4532−4535. (i) Zhou, Y.; Zhou, Z.; Du, W.; Chen, Y.
Asymmetric Inverse-Electron-Demand Diels−Alder Reaction of 2-
Pyrone and 2,5-Dienones via HOMO-Activation. Huaxue Xuebao
2018, 76, 382−386. (j) Cole, C. J. F.; Fuentes, L.; Snyder, S. A.
Asymmetric pyrone Diels−Alder reactions enabled by dienamine
catalysis. Chem. Sci. 2020, 11, 2175−2180.
(20) (a) Liang, X.-W.; Zhao, Y.; Si, X.-G.; Xu, M.-M.; Tan, J.-H.;
Zhang, Z.-M.; Zheng, C.-G.; Zheng, C.; Cai, Q. Enantioselective
Synthesis of Arene cis-Dihydrodiols from 2-Pyrones. Angew. Chem.,
Int. Ed. 2019, 58, 14562−14567. (b) Si, X.-G.; Zhang, Z.-M.; Zheng,
C.-G.; Li, Z.-T.; Cai, Q. Enantioselective Synthesis of cis-Decalin
Derivatives by the Inverse-Electron-Demand Diels−Alder Reaction of
2-Pyrones. Angew. Chem., Int. Ed. 2020, 59, 18412−18417.
(21) For an excellent review about VQMs, see: (a) Rodriguez, J.;
Bonne, D. Enantioselective organocatalytic activation of vinylidene−
quinone methides (VQMs). Chem. Commun. 2019, 55, 11168−
11170. For selected examples, see: (b) Beppu, S.; Arae, S.; Furusawa,
M.; Arita, K.; Fujimoto, H.; Sumimoto, M.; Imahori, T.; Igawa, K.;
Tomooka, K.; Irie, R. Stereoselective Intramolecular Dearomatizative
[4 + 2] Cycloaddition of Linked Ethynylnaphthol−Benzofuran
Systems. Eur. J. Org. Chem. 2017, 2017, 6914−6918. (c) Wu, X.;
Xue, L.; Li, D.; Jia, S.; Ao, J.; Deng, J.; Yan, H. Organocatalytic
Intramolecular [4 + 2] Cycloaddition between In Situ Generated
Vinylidene ortho-Quinone Methides and Benzofurans. Angew. Chem.,
Int. Ed. 2017, 56, 13722−13726. (d) Jia, S.; Li, S.; Liu, Y.; Qin, W.;
Yan, H. Enantioselective Control of Both Helical and Axial
Stereogenic Elements though an Organocatalytic Approach. Angew.
Chem., Int. Ed. 2019, 58, 18496−18501. (e) Wang, Y.-B.; Yu, P.;
Zhou, Z.-P.; Zhang, J.; Wang, J.; Luo, S.-H.; Gu, Q.-S.; Houk, K. N.;
Tan, B. Rational design, enantioselective synthesis and catalytic
(16) Zhao, P.; Beaudry, C. M. Enantioselective and Regioselective
Pyrone Diels−Alder Reactions of Vinyl Sulfones: Total Synthesis of
(+)-Cavicularin. Angew. Chem., Int. Ed. 2014, 53, 10500−10503.
(17) (a) Posner, G. H.; Carry, J.-C.; Lee, J. K.; Bull, D. S.; Dai, H.
Mild, asymmetric Diels-Alder cycloadditions of electronically matched
2-pyrones and vinyl ethers. Tetrahedron Lett. 1994, 35, 1321−1324.
(b) Posner, G. H.; Eydoux, F.; Lee, J. K.; Bull, D. S. Binaphthol-
Titanium-Promoted, Highly Enantiocontrolled, Diels−Alder Cyclo-
additions of Electronically Matched 2-Pyrones and Vinyl Ethers:
Streamlined Asymmetric Synthesis of an A-ring Precursor to
Physiologically Active 1α-Hydroxyvitamin D3 Steroids. Tetrahedron
9000
https://doi.org/10.1021/jacs.1c04759
J. Am. Chem. Soc. 2021, 143, 8993−9001

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
applications of axially chiral EBINOLs. Nature Catalysis 2019, 2,
504−513.
(22) (a) Liao, S.; Sun, X.-L.; Tang, Y. Side Arm Strategy for Catalyst
Design: Modifying Bisoxazolines for Remote Control of Enantiose-
lection and Related. Acc. Chem. Res. 2014, 47, 2260−2272. For
selected examples, see: (b) Liu, Q.-J.; Zhu, J.; Song, X.-Y.; Wang, L.;
Wang, S. R.; Tang, Y. Highly Enantioselective [3 + 2] Annulation of
Indoles with Quinones to Access Structurally Diverse Benzofuroindo-
lines. Angew. Chem., Int. Ed. 2018, 57, 3810−3814. (c) Zhou, L.; Yan,
W.-G.; Sun, X.-L.; Wang, L.; Tang, Y. A Versatile Enantioselective
Catalytic Cyclopropanation Rearrangement Approach to the
Divergent Construction of Chiral Spiroaminals and Fused Bicyclic
Acetals. Angew. Chem., Int. Ed. 2020, 59, 18964−1896.
9001
https://doi.org/10.1021/jacs.1c04759
J. Am. Chem. Soc. 2021, 143, 8993−9001