Carbene-Catalyzed Atroposelective Annulation and Desymmetrization of Urazoles

Article abstract of DOI:10.1021/acs.orglett.1c01191

An NHC-catalyzed atroposelective reaction between ynals and urazoles is disclosed. The reaction establishes a chiral C-N axis via an atroposelective [3 + 2] annulation/desymmetrization process. Our reaction allows efficient access to axially chiral and heteroatom-rich urazole derivatives with potential applications in bioactive molecules and catalysis.

Full text of DOI:10.1021/acs.orglett.1c01191

pubs.acs.org/OrgLett
Letter
Carbene-Catalyzed Atroposelective Annulation and
Desymmetrization of Urazoles
Jiamiao Jin,⊥ Xuan Huang,⊥ Jun Xu,⊥ Tingting Li, Xiaolin Peng, Xun Zhu, Junmin Zhang, Zhichao Jin,
and Yonggui Robin Chi*
Cite This: Org. Lett. 2021, 23, 3991−3996
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ABSTRACT: An NHC-catalyzed atroposelective reaction be-
tween ynals and urazoles is disclosed. The reaction establishes a
chiral C−N axis via an atroposelective [3 + 2] annulation/
desymmetrization process. Our reaction allows efficient access to
axially chiral and heteroatom-rich urazole derivatives with potential
applications in bioactive molecules and catalysis.
razole is a heteroatom-rich five-membered heterocycle
atroposelective thiol-addition/lactam formation process for
Ubearing three nitrogen and two oxygen atoms. This access to axially chiral thiazine derivatives with high optical
purities.9
unique structural motif has received considerable interest in
Here we disclose an NHC-catalyzed oxidative atroposelec-
tive [3 + 2] annulation and desymmetrization of 4-arylurazoles
(Figure 1b). The key step in this process involves
atroposelective addition of a nitrogen atom of urazole to an
ynal-derived acetylenic acylazolium intermediate (I).9,10 The
final products bearing a urazole moiety and a chiral C−N axis
were obtained with excellent yields and optical purities.
developing bioactive molecules as potential medicines (Figure
1a).1 For example, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-
dione (APTD) is in clinical studies as a potential
hypolipidemic medicine.1a Ferroptocide bearing a urazole
moiety incorporated in a chiral scaffold possesses promising
anticancer activity.1h In the area of bioactive molecule
development, it has been long-established that the chirality
of the molecules, including axial chirality, can have profound
influence on the activities (Figure 1a).2 Given the wide
presence of nitrogen atoms, molecules bearing a chiral C−N
axis is of particular interest.3 For instance, the (S)-enantiomer
of the p38α kinase antagonist is 100 times more reactive than
the (R)-enantiomer.3c The (S)-AMPA receptor antagonist has
shown more efficient anticonvulsant activity than its (R)-
enantiomer.3a Phosphoinositide 3-kinase (PI3K) β inhibitor is
an atropisomeric compound bearing the chiral C−N axis with
significantly different pharmacological and pharmacokinetic
profiles: the active (S)-PI3K β inhibitor (IC50 = 2 nM) has
better metabolic stability than the inactive (R)-enantiomer
(IC50 > 1000 nM).3e
As part of our programs in developing novel chiral molecules
for both human and agricultural uses, we therefore feel it will
be meaningful to prepare axially chiral4 and urazole-containing
molecules with high optical purities. The nitrogen atom in
urazole is an excellent point of connection for introducing
chiral C−N axis.5 N-Heterocyclic carbene (NHC) catalysis6
explored in our laboratories can likely provide excellent
chirality control. It is worth noting that the limited success
in using NHC for axial chirality control has been realized only
in very recent years, as reported by Zhao, Wang, Zhu and
others.7 In 2019, we observed low axial chirality control in an
NHC-catalyzed cascade reaction between a dialdehyde and a
pro-chiral maleimide.8 Very recently, we developed an
The NHC precatalysts that are derived from chiral
aminoindanol scaffolds were evaluated for the atroposelective
reaction between the ynal 1a and the 4-arylurazole 2a in the
presence of the DQ oxidant11 and Cs2CO3 (Table 1, entries 1
to 6). The NHC precatalysts bearing electron-rich N-aryl
groups12 could efficiently promote this reaction even at −20
°C, with the target product 3a afforded in good to excellent
yields and promising enantioselectivities (entries 1, 2, and 4).
In contrast, the NHC precatalyst C13 bearing an electron-
deficient N−C6F5 group could only give a trace amount of the
desired product 3a (entry 3). To our delight, installing a NO2
group on the aminoindanol motif of the NHC precatalyst A
(to afford E)14 could further increase the reaction yield and
enantioselectivity (entry 5). Switching the conjugate anion of
the NHC precatalyst E from BF4− to Cl− (to afford F)15 led to
drops in the product yield and optical purity (entry 6).
Replacing the Cs2CO3 with various organic bases would
decrease the product yield and er value (e.g., entries 7 to 8).
But the use of Na2CO3 instead of the Cs2CO3 as the base
Received: April 7, 2021
Published: May 12, 2021
https://doi.org/10.1021/acs.orglett.1c01191
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3991−3996
3991

Organic Letters
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a
Table 1. Optimization of Reaction Conditions
yield
b
c
entry NHC
base
solvent
(%)
er
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
E
E
E
E
E
E
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
THF
THF
THF
THF
THF
THF
THF
THF
91
89
<5
93
94
61
78
24
93
68
42
0 or <5
91:9
35:65
−
90:10
92:8
88:12
90:10
89:11
95:5
88:12
81:19
−
DBU
Na2CO3 THF
Na2CO3 C2H5OAc
Na2CO3 toluene
Na2CO3 CH2Cl2/MeCN/dioxane/
TBME
d
10
11
12
e
13
E
Na2CO3 THF
74
92:8
a
Unless otherwise specified, the reactions were carried using 1a (0.15
Figure 1. Bioactive molecules and atroposelective access to urazole
derivatives with chiral C−N axes.
mmol), 2a (0.10 mmol), DQ (0.15 mmol), NHC (0.02 mmol), base
(0.02 mmol), solvent (2.0 mL) at −20 °C for 24 h. The absolute
configurations of the products were estimated based on the X-ray
b
analysis on the single crystals of 3a (CCDC 2062393). Isolated yield
could give the desired axially chiral product 3a with an
improved enantioselectivity without much erosion on the
reaction yield (entry 9). Solvents also had significant impacts
on the reaction outcome (entries 10 to 12). Although the
reaction went on smoothly in a variety of organic solvents such
as C2H5OAc and toluene, the target product 3a could only be
afforded in moderate yields and optical purities (entries 10 to
11). No or trace amount of product 3a was observed when
carrying out the reaction in the solvent of CH2Cl2, MeCN,
dioxane, or TBME (entry 12). Decreasing the NHC catalyst
loading resulted in decreases in both the product yield and
optical purity (entry 13).
With optimized reaction conditions in hand, we next
examined the reaction scope using ynal substrates 1 bearing
different substituents and substitution patterns (Scheme 1).
Electron-donating substituents and halogen atoms could be
installed on the 2-position of the phenyl group of 1a, with the
target products afforded in good to excellent yields and
enantioselectivities (3b to 3e). Strong electron-withdrawing
substituents existing at this position led to decreases in both
the product yields and optical purities (e.g., 3f). Ynal substrates
bearing both electron-donating and electron-withdrawing
groups on the 3-position of the benzene rings worked
smoothly in this transformation and gave the corresponding
products in moderate to good yields with good to excellent er
values (3g to 3i). Electron-withdrawing groups existing at the
4-position of the ynal benzene rings resulted in decreased
product yields and er values (3j and 3k), while electron-
donating groups at this position could give the desymmetrized
c
of 3a. The er values were determined via UPLC on chiral stationary
d
phase. 1a (0.15 mmol), 2a (0.10 mmol), DQ (0.15 mmol), E (0.02
e
mmol), Na2CO3 (0.02 mmol), THF (2.0 mL), −20 °C, 24 h. 10 mol
% of E was used.
pyrazolo[1,2-a]triazole products in almost quantitative yields
with excellent optical purities (3l and 3m). The β-phenyl
group on the ynal substrate 1a could be switched to 1- or 2-
naphthalene groups, with the desired products afforded in
good to excellent yields and er values (3n and 3o). Note that
the aliphatic linear ynal could also be used in this NHC-
catalyzed atroposelective annulation reaction, although the
desymmetrized product 3p could only be afforded in a
moderate yield and enantioselectivity under the current
reaction conditions.
The 4-arylurazole substrate 2 could also tolerate various
substituents at different positions (Scheme 2). Urazole
substrates bearing various p-substituents on the 4-aryl groups
worked well in this atroposelective [3 + 2] annulation reaction,
with the final products afforded in good to excellent yields and
er values regardless of their electronic properties (3q to 3t).
With a strong electron-withdrawing group installed at the 5′-
position of the urazole phenyl ring, the desired product 3u
could be afforded in an excellent yield, although the er value
was slightly dropped. Incorporating a methyl group at the
other o-position of the 4-aryl ring led to the formation of the
axially chiral product 3v in 83% yield without much erosion on
the reaction enantioselectivity. The o-tBu group on the N-
3992
https://doi.org/10.1021/acs.orglett.1c01191
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a
a
Scheme 1. Scope of Ynals 1
Scheme 2. Scope of 4-Arylurazoles 2
a
Reaction conditions as stated in Table 1, entry 9. Yields are isolated
yields after purification by column chromatography. Er values were
determined via UPLC on chiral stationary phase.
Scheme 3. Applications of Bromoenals in the
Atroposelective Desymmetrization Reaction
a
Reaction conditions as stated in Table 1, entry 9. Yields are isolated
yields after purification by column chromatography. Er values were
b
determined via UPLC on chiral stationary phase. 1a (0.15 mmol), 2a
(0.10 mmol), DQ (0.15 mmol), D (0.02 mmol), Na2CO3 (0.02
mmol), THF (2.0 mL), −20 °C, 24 h.
phenyl ring of urazole substrate 2 was crucial for the
stereochemical stabilities of the axially chiral products. For
instance, the product 3w bearing 2-Br-6-CH3 groups on its N-
phenyl ring can only be afforded in a moderate 85:15 er value.
The product 3x with the o-tBu group on the N-phenyl ring
replaced with an o-iPr group appears to be achiral at ambient
temperature. This might be due to the significant drop in the
energy barrier to rotation caused by the o-iPr group.
Figure 2. Evaluation of the stereochemical stability of 3a.
The α- and β-bromoenals are also promising precursors for
the generation of the reactive acetylenic acylazolium
intermediates. Therefore, we have examined the bromoenals
1b and 1c in this transformation under oxidative conditions at
a higher temperature (Scheme 3). Interestingly, the α-
bromoenal 1b cannot give the target product 3a with the
catalysis of the NHC catalyst E, while the β-bromoenal 1c can
lead to the formation of the desired product 3a in a low yield
with moderate enantioselectivity.
The stereochemical stability of the axially chiral pyrazolo-
[1,2-a]triazole product 3a (95:5 er) was evaluated at different
temperatures (Figure 2). The er value of 3a was not changed
after stirring for 12 h at 75 °C in mesitylene. But the er value
decreased to 61:39 after stirring for 12 h at 100 °C and the
product 3a became nearly racemic when the reaction
temperature was increased to 125 °C. Therefore, the barrier
to rotation of the axially chiral compound 3a was examined at
125 °C based on the changing rate of its er values (ΔG‡ = 29.8
kcal/mol).16
The atroposelective synthesis of 3a can be carried out at
gram scales with little erosion of the product yield and optical
purity (Figure 3a). The optically enriched 3a can be
brominated by NBS under mild conditions to give 4 in a
good yield with retention of the optical purity.9 The nitro
group of 3u can be efficiently reduced to give the axially chiral
aniline product 5, which can be transformed to the urea 6 in a
3993
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Org. Lett. 2021, 23, 3991−3996

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Letter
Chemistry, School of Physical & Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore; orcid.org/0000-0003-0573-257X;
Email: robinchi@ntu.edu.sg
Authors
Jiamiao Jin − State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang 550025, China
Xuan Huang − International Joint Research Center for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, China
Jun Xu − School of Pharmacy, Guizhou University of
Traditional Chinese Medicine, Guiyang 550025, China
Tingting Li − State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang 550025, China
Xiaolin Peng − State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang 550025, China
Xun Zhu − State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang 550025, China
Junmin Zhang − International Joint Research Center for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, China;
orcid.org/0000-0003-4061-8350
Figure 3. Gram-scale synthesis of 3a and synthetic applications of the
axially chiral products.
good yield with slight erosion of the product optical purity
(Figure 3b).17
In summary, we have disclosed an atroposelective [3 + 2]
annulation reaction for desymmetrization of 4-arylurazoles.
The C−N axis that is remote to the NHC catalyst moiety of
the reaction intermediates is efficiently established. Axially
chiral pyrazolo[1,2-a]triazole derivatives bearing various
substituents and substitution patterns are afforded as the
final products in good to excellent yields and enantioselectiv-
ities. The stereochemical stability of the axially chiral products
is evaluated via thermal dynamic methods. Versatile functional
molecules bearing chiral C−N axes can be obtained from the
pyrazolo[1,2-a]triazole products in good yields with excellent
enantioselectivities. Investigations on novel molecular scaffolds
bearing heteroatom-rich moieties and stereogenic axis for
applications in medicines and plant protections are in progress
in our laboratories.
Zhichao Jin − State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Guiyang 550025, China;
orcid.org/0000-0003-3003-6437
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01191
Author Contributions
⊥J.J., X.H., and J.X. contributed equally to this work.
Notes
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01191.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Experimental procedures and spectral data for all new
compounds (PDF)
■
We acknowledge financial support from the National Natural
Science Foundation of China (21772029, 21801051,
21961006, 22001173), The 10 Talent Plan (Shicengci) of
Guizhou Province ([2016]5649), the Guizhou Province
Returned Oversea Student Science and Technology Activity
Program [(2014)-2], the Science and Technology Department
of Guizhou Province ([2018]2802, [2019]1020, Qiankehe-
jichu-ZK[2021]Key033), the Program of Introducing Talents
of Discipline to Universities of China (111 Program, D20023)
at Guizhou University, Frontiers Science Center for Asym-
metric Synthesis and Medicinal Molecules, Department of
Education, Guizhou Province [Qianjiaohe KY (2020)004], the
Basic and Applied Research Foundation of Guangdong
Province (2019A1515110906), the Guizhou Province First-
Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-
GNYL(2017)008], Guizhou University of Traditional Chinese
Medicine, and Guizhou University (China). Singapore Na-
Accession Codes
CCDC 2062393 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 Author
■
Yonggui Robin Chi − State Key Laboratory Breeding Base of
Green Pesticide and Agricultural Bioengineering, Key
Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University,
Guiyang 550025, China; Division of Chemistry & Biological
3994
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Letter
R.; Wang, W. Green Synth. Catal. 2020, 1, 83. (n) Ong, J. Y.; Ng, X.
Q.; Lu, S.; Zhao, Y. Org. Lett. 2020, 22, 6447. (o) Yang, G.-H.; Zheng,
H.; Li, X.; Cheng, J.-P. ACS Catal. 2020, 10, 2324.
(5) For an excellent example on the preparation of urazole-
containing molecules bearing stereogenic axes, see: Zhang, J.-W.; Xu,
J.-H.; Cheng, D.-J.; Shi, C.; Liu, X.-Y.; Tan, B. Nat. Commun. 2016, 7,
10677.
tional Research Foundation under its NRF Investigatorship
(NRF-NRFI2016-06), the Ministry of Education, Singapore,
under its MOE AcRF Tier 1 Award (RG108/16, RG5/19,
RG1/18), MOE AcRF Tier 3 Award (MOE2018-T3-1-003),
the Agency for Science, Technology and Research (A*STAR)
under its A*STAR AME IRG Award (A1783c0008,
A1783c0010), GSK-EDB Trust Fund, and Nanyang Research
Award Grant, Nanyang Technological University.
(6) For selected reviews on NHC organocatalysis, see: (a) Enders,
D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182.
(c) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (d) Cohen,
D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53. (e) Grossmann, A.;
Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (f) Ryan, S. J.;
Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906.
(g) Connon, S. J. Angew. Chem., Int. Ed. 2014, 53, 1203.
(h) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
2014, 510, 485. (i) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res.
2014, 47, 696. (j) Flanigan, D. M.; Romanov-Michailidis, F.; White,
N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (k) Menon, R. S.; Biju,
A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040. (l) Wang, M. H.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (m) Zhang, C.;
Hooper, J. F.; Lupton, D. W. ACS Catal. 2017, 7, 2583. (n) Murauski,
K. J. R.; Jaworski, A. A.; Scheidt, K. A. Chem. Soc. Rev. 2018, 47, 1773.
(o) Chen, X.; Wang, H.; Jin, Z.; Chi, Y. R. Chin. J. Chem. 2020, 38,
1167.
(7) (a) Zhao, C.; Guo, D.; Munkerup, K.; Huang, K.-W.; Li, F.;
Wang, J. Nat. Commun. 2018, 9, 611. (b) Lu, S.; Ong, J.-Y.; Yang, H.;
Poh, S. B.; Liew, X.; Seow, C. S. D.; Wong, M. W.; Zhao, Y. J. Am.
Chem. Soc. 2019, 141, 17062. (c) Xu, K.; Li, W.; Zhu, S.; Zhu, T.
Angew. Chem., Int. Ed. 2019, 58, 17625. (d) Zhu, T.; Xu, K.; Wang, Z.
Synlett 2020, 31, 925. (e) Zhang, C.-L.; Gao, Y.-Y.; Wang, H.-Y.;
Zhou, B.-A.; Ye, S. Angew. Chem., Int. Ed. 2021 DOI: 10.1002/
anie.202103415.
(8) Zhuo, S.; Zhu, T.; Zhou, L.; Mou, C.; Chai, H.; Lu, Y.; Pan, L.;
Jin, Z.; Chi, Y. R. Angew. Chem., Int. Ed. 2019, 58, 1784.
(9) (a) Li, T.; Mou, C.; Qi, P.; Peng, X.; Jiang, S.; Hao, G.; Xue, W.;
Yang, S.; Hao, L.; Chi, Y. R.; Jin, Z. Angew. Chem., Int. Ed. 2021, 60,
9362. (b) Barik, S.; Shee, S.; Das, S.; Gonnade, R. G.; Jindal, G.;
Mukherjee, S.; Biju, A. T. Angew. Chem., Int. Ed. 2021 DOI: 10.1002/
anie.202016938.
(10) (a) Lu, Y.; Tang, W.; Zhang, Y.; Du, D.; Lu, T. Adv. Synth.
Catal. 2013, 355, 321. (b) Zhang, Y.; Lu, Y.; Tang, W.; Lu, T.; Du, D.
Org. Biomol. Chem. 2014, 12, 3009. (c) Cao, J.; Sun, K.; Dong, S.; Lu,
T.; Dong, Y.; Du, D. Org. Lett. 2017, 19, 6724. (d) Mou, C.; Wu, J.;
Huang, Z.; Sun, J.; Jin, Z.; Chi, Y. R. Chem. Commun. 2017, 53,
13359. (e) Sun, K.; Jin, S.; Zhu, J.; Zhang, X.; Gao, M.; Zhang, W.;
Lu, T.; Du, D. Adv. Synth. Catal. 2018, 360, 4515. (f) Xie, Y.; Wang, J.
Chem. Commun. 2018, 54, 4597. (g) Sun, K.; Jin, S.; Fang, S.; Ma, R.;
Zhang, X.; Gao, M.; Zhang, W.; Lu, T.; Du, D. Org. Chem. Front.
2019, 6, 2291. (h) Li, J.-H.; Duan, X.-Y.; Tian, Z.-H.; Zheng, Y.-F.;
Qi, J. Asian J. Org. Chem. 2020, 9, 385.
REFERENCES
■
(1) (a) Hall, I. H.; Simlot, R.; Day, P.; Wong, O. T.; ElSourady, H.;
Izydore, R. A. Pharm. Res. 1993, 10, 1206. (b) Martinez, A.; Alonso,
M.; Castro, A.; Dorronsoro, I.; Gelpi, J. L.; Luque, F. J.; Perez, C.;
Moreno, F. J. J. Med. Chem. 2005, 48, 7103. (c) Adibi, H.; Abiri, R.;
Mallakpour, S.; Zolfigol, M. A.; Majnooni, M. B. J. Rep. Pharm. Sci.
2012, 1, 87. (d) Saluja, P.; Khurana, J. M.; Nikhil, K.; Roy, P. RSC
Adv. 2014, 4, 34594. (e) Saluja, P.; Khurana, J. M.; Sharma, C.; Aneja,
K. R. Aust. J. Chem. 2014, 67, 867. (f) Pelit, E.; Oikonomou, K.; Gul,
M.; Georgiou, D.; Szafert, S.; Katsamakas, S.; Hadjipavlou-Litina, D.;
Elemes, Y. C. R. Chim. 2017, 20, 424. (g) Varmaghani, F.; Hassan, M.;
Nematollahi, D.; Mallakpour, S. New J. Chem. 2017, 41, 8279.
(h) Llabani, E.; Hicklin, R. W.; Lee, H. Y.; Motika, S. E.; Crawford, L.
A.; Weerapana, E.; Hergenrother, P. Nat. Chem. 2019, 11, 521.
(i) Xin, X.; Zimmermann, S.; Flegel, J.; Otte, F.; Knauer, L.;
Strohmann, C.; Ziegler, S.; Kumar, K. Chem. - Eur. J. 2019, 25, 2717.
(2) For selected reviews, see: (a) Santos, A. R. d.; Pinheiro, A. C.;
Sodero, A. C. R.; Cunha, A. S. d.; Padilha, M. C.; Sousa, P. M. d.;
Fontes, S. P.; Veloso, M. P.; Fraga, C. A. M. Quim. Nova 2007, 30,
125. (b) LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.;
Hucke, O. ChemMedChem 2011, 6, 505. (c) Zask, A.; Murphy, J.;
Ellestad, G. A. Chirality 2013, 25, 265. (d) Gustafson, J.; Nalbandian,
C.; Hecht, D. Synlett 2016, 27, 977. (e) Glunz, P. W. Bioorg. Med.
Chem. Lett. 2018, 28, 53. (f) Toenjes, S. T.; Gustafson, J. L. Future
Med. Chem. 2018, 10, 409. (g) Mancinelli, M.; Bencivenni, G.;
Pecorari, D.; Mazzanti, A. Eur. J. Org. Chem. 2020, 2020, 4070.
(3) (a) Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.;
Pagnozzi, M. J.; Kelly, K.; Seymour, P. A.; Guanowsky, V.; Guhan, S.;
Guinn, M. R.; Critchett, D.; Lazzaro, J.; Ganong, A. H.; DeVries, K.
M.; Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11,
177. (b) Takahashi, H.; Wakamatsu, S.; Tabata, H.; Oshitari, T.;
Harada, A.; Inoue, K.; Natsugari, H. Org. Lett. 2011, 13, 760. (c) Xing,
L.; Devadas, B.; Devraj, R. V.; Selness, S. R.; Shieh, H.; Walker, J. K.;
Mao, M.; Messing, D.; Samas, B.; Yang, J. Z.; Anderson, G. D.; Webb,
E. G.; Monahan, J. B. ChemMedChem 2012, 7, 273. (d) Hasegawa, F.;
Kawamura, K.; Tsuchikawa, H.; Murata, M. Bioorg. Med. Chem. 2017,
25, 4506. (e) Chandrasekhar, J.; Dick, R.; Van Veldhuizen, J.;
Koditek, D.; Lepist, E. I.; McGrath, M. E.; Patel, L.; Phillips, G.;
Sedillo, K.; Somoza, J. R.; Therrien, J.; Till, N. A.; Treiberg, J.;
Villasenor, A. G.; Zherebina, Y.; Perreault, S. J. Med. Chem. 2018, 61,
6858.
(11) (a) De Sarkar, S.; Grimme, S.; Studer, A. J. Am. Chem. Soc.
2010, 132, 1190. (b) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed.
2010, 49, 9266.
(12) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298. (b) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem.
Soc. 2006, 128, 8418. (c) Cardinal-David, B.; Raup, D. E. A.; Scheidt,
K. A. J. Am. Chem. Soc. 2010, 132, 5345.
(13) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.
(14) Zhao, C.; Li, F.; Wang, J. Angew. Chem., Int. Ed. 2016, 55, 1820.
(15) Lu, H.; Tan, C.-Y.; Zhang, H.-X.; Zhang, J.-L.; Liu, J.-Y.; Li, H.-
Y.; Xu, P.-F. J. Org. Chem. 2018, 83, 15245.
(16) (a) Reist, M.; Testa, B.; Carrupt, P.-A.; Jung, M.; Schurig, V.
Chirality 1995, 7, 396. (b) Curran, D. P.; Liu, W.; Chen, C. H.-T. J.
Am. Chem. Soc. 1999, 121, 11012. (c) Shirakawa, S.; Liu, K.; Maruoka,
K. J. Am. Chem. Soc. 2012, 134, 916. (d) Ma, C.; Sheng, F.-T.; Wang,
H.-Q.; Deng, S.; Zhang, Y.-C.; Jiao, Y.; Tan, W.; Shi, F. J. Am. Chem.
Soc. 2020, 142, 15686. (e) Wang, Q.; Zhang, W.-W.; Song, H.; Wang,
J.; Zheng, C.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2020, 142, 15678.
(4) For selected reviews on the preparation of axially chiral
molecules, see: (a) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.;
Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005,
44, 5384. (b) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.;
Colobert, F. Chem. Soc. Rev. 2015, 44, 3418. (c) Bonne, D.;
Rodriguez, J. Chem. Commun. 2017, 53, 12385. (d) Bonne, D.;
Rodriguez, J. Eur. J. Org. Chem. 2018, 2018, 2417. (e) Bao, X.;
Rodriguez, J.; Bonne, D. Angew. Chem., Int. Ed. 2020, 59, 12623.
(f) Bertuzzi, G.; Corti, V. Synthesis 2020, 52, 2450. For selected
examples, see: (g) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.;
Overgaard, J.; Jorgensen, K. A. Chem. - Eur. J. 2006, 12, 6039.
(h) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006,
128, 4586. (i) Hasegawa, F.; Kawamura, K.; Tsuchikawa, H.; Murata,
M. Bioorg. Med. Chem. 2017, 25, 4506. (j) Li, S.-L.; Yang, C.; Wu, Q.;
Zheng, H.-L.; Li, X.; Cheng, J.-P. J. Am. Chem. Soc. 2018, 140, 12836.
(k) Zilate, B.; Castrogiovanni, A.; Sparr, C. ACS Catal. 2018, 8, 2981.
(l) Lu, S.; Ng, S. V. H.; Lovato, K.; Ong, J. Y.; Poh, S. B.; Ng, X. Q.;
Kurti, L.; Zhao, Y. Nat. Commun. 2019, 10, 3061. (m) Dong, Y.; Liu,
3995
https://doi.org/10.1021/acs.orglett.1c01191
Org. Lett. 2021, 23, 3991−3996

Organic Letters
pubs.acs.org/OrgLett
Letter
(17) (a) Koketsu, M.; Ishihara, H. Curr. Org. Synth. 2006, 3, 439.
(b) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(c) Fang, X.; Wang, C.-J. Chem. Commun. 2015, 51, 1185. (d) Jagtap,
A.; Kondekar, N.; Sadani, A.; Chern, J.-W. Curr. Med. Chem. 2017, 24,
622. (e) Brullo, C.; Rapetti, F.; Bruno, O. Molecules 2020, 25, 3457.
3996
https://doi.org/10.1021/acs.orglett.1c01191
Org. Lett. 2021, 23, 3991−3996