Asymmetric Synthesis of Axially Chiral Anilides via Organocatalytic Atroposelective N-Acylation

Article abstract of DOI:10.1021/acs.orglett.0c01581

A highly atroposelective N-acylation reaction of aniline-derived sulfonamides has been developed with chiral isothiourea as the catalyst. This approach provides a facile and efficient route to an array of atropoisomeric sulfonyl substituted anilide produc

Full text of DOI:10.1021/acs.orglett.0c01581

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Asymmetric Synthesis of Axially Chiral Anilides via Organocatalytic
Atroposelective N‑Acylation
Dawei Li, Sijing Wang, Shulin Ge, Shunxi Dong,* and Xiaoming Feng
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ABSTRACT: A highly atroposelective N-acylation reaction of
aniline-derived sulfonamides has been developed with chiral
isothiourea as the catalyst. This approach provides a facile and
efficient route to an array of atropoisomeric sulfonyl substituted
anilide products in good yields with high to excellent
enantioselectivities.
he nonbiaryl C−N axially chiral compounds1 are
straightforward strategies to access axially chiral anilides
(Scheme 1a, right). In this respect, enantioselective N-
allylation of achiral ortho-substituted NH-anilides, initially
reported by Curran and Taguchi,9h,i has been well-studied by
many other groups.9a−g In 2012, the group of Maruoka
described an elegant example of chiral quaternary ammonium
salt-catalyzed N-alkylation, various chiral o-iodoacrylanilides
and N-allyl-o-iodoanilides were afforded in good yield with
high enantioselectivity.9g On the other hand, a catalytic
asymmetric N-arylation reaction10 has also been explored for
the construction of atropoisomeric anilides by Taguchi,10c,d
Kitagawa,10b and Gu.10a Despite these significant advances,
there still leaves much room for improvement in terms of
synthetic strategies, catalysts and substrate generality.
T
frequently found in pharmaceuticals2 and bioactive
natural products3 as well as being used as chiral organic
catalysts or ligands (Scheme 1a, left).4 In particular,
Scheme 1. Selected Examples of Nonbiaryl C−N Axially
Chiral Compounds and Representative Methods for the
Asymmetric Synthesis of Atropoisomeric Anilides
The enantioselective acyl transfer reaction has been
extensively investigated as one of most important organic
transformations over the past several decades.14 Mechanisti-
cally, the acyl donor is first activated by a nucleophilic chiral
catalyst to generate a reactive intermediate, which subse-
quently transfers the acyl group to the nucleophilic substrate
with specific configuration (such as an alcohol, amine, etc.),
thus affording the corresponding chiral acylated product and
regenerating the catalyst. However, to the best of our
knowledge, an acyl transfer strategy has never been used for
the construction of axially chiral anilides.15 Motivated by
distinct properties of axially chiral anilides and inspired by the
high efficiency of isothiourea catalysts14a in an acyl transfer
reaction, we envisioned that the nucleophilic anilide anion with
sterically hindered ortho-substituents could be acylated in an
atroposelective manner by the in situ generated chiral
atropoisomeric anilides,1c pioneered by Curran and co-
workers,5 has attracted considerable attention due to their
intriguing biological activity6 and important application in the
field of synthetic chemistry7 and peptoid chemistry.8 During
the past two decades, tremendous endeavors have been
dedicated to the enantioselective syntheses of such architec-
ture.9−13 Among the established methods, the direct N-
functionalization9,10 of anilides represented one of most
Received: May 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01581
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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acylisothiouronium intermediates (Scheme 1b).16 If successful,
it would provide a feasible avenue to axially chiral anilides.
Herein, we wish to disclose our studies toward this end. A
highly atroposelective N-acylation of readily available aniline-
derived sulfonamides was realized under mild conditions by
employing homobenzotetramisole (HBTM) as the catalyst.
Various atropoisomeric sulfonyl substituted anilide products
were afforded in good yields with high to excellent
enantioselectivities.
In light of the fact that some enantioenriched sulfonamides
are pharmaceutically attractive compounds,2a,f,h and inspired
by Matsubara’s work,17 sulfonamide 1a with α,β-unsaturated
carbonic anhydride 2a were chosen as the model reaction
substrates to optimize the reaction conditions (Table 1). First,
solvents with low polarity. Toluene was the best choice, and
the corresponding chiral anilide 3a was obtained in 80% yield
with 81% ee (entry 6). Subsequent investigation of the base
(entries 6−9) implied that coordinating cations deteriorated
the ee considerably and neutral base DIPEA gave better results
than ionic bases (entry 9, 82% yield, 87% ee). When 3 Å M.S.
was used as the additive, the yield increased slightly to 91%
without influencing the enantiomeric excess (entry 10).20 To
improve the stereoselectivity, we next turned our attention to
evaluate the substituents at sulfonamide. Less bulky mesyl-
substituted substrate 1b gave a remarkable increase in the
enantioselectivity, but with a lower yield (entry 11, 56% yield,
95% ee). Careful analysis of reaction mixture by TLC indicated
that a side product was generated concurrently, which was
responsible for low isolated yield. This side product, arising
from the nucleophilic attach of anilide anion to isopropox-
a
Table 1. Optimization of the Reaction Conditions
1
ycarbonyl unit, was assigned to be compound 4b by H and
13C NMR spectra (see the Supporting Information for details).
Further optimization studies revealed that a higher yield (88%)
with maintained enantioselectivity (entry 12, 95% ee) was
delivered when the reaction was performed with 1b (0.1
mmol), 2a (1.5 equiv), HBTM C3 (10 mol %), and 3 Å M.S.
(15 mg). It should be noted that when N-heterocycle carbene
was used as acyl transfer catalyst with cinnamaldehyde under
oxidative conditions no desired product was detected.21
With the optimal reaction conditions in hand, a variety of
substituted α,β-unsaturated carbonic anhydrides 2 were
examined with sulfonamide 1b (Scheme 2). Overall, regardless
of the substituent pattern and the electronic property of the
aryl moiety, the corresponding axially chiral anilides (3b−m)
were afforded in good to excellent yields with high
enantioselectivities (93−97% ee). Generally, electron-deficient
substrates (2j−l) provided a higher yield than that of electron-
rich ones (2b−d). Notably, 1-naphthyl-substituted anhydride
2m as well as anhydrides 2n and 2o derived from heteroaryl-
substituted acrylic acids were compatible in current systems,
furnishing the desired products 3n−p in 74−86% yields with
uniformly high enantioselectivities (95−96% ee). Moreover,
the reactions of anhydrides with aliphatic substitution took
place as well, and the enantioenriched products (3q and 3r)
were obtained in good yield with high enantiomeric purity.
The absolute configuration of 3l was determined to be R by X-
ray diffraction analysis and the configurations of all other
examples were assigned by comparing their CD spectra with
that of 3l.
b
c
entry
cat.
sol
base
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
C1
C2
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
DCM
DCM
DCM
THF
Et2O
tol
tol
tol
tol
tol
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
LiOtBu
DIPEA
DIPEA
DIPEA
DIPEA
trace (3a)
NR (3a)
96 (3a)
72 (3a)
77 (3a)
67
35
57
81
60
0
87
87
95
95
80 (3a)
>95% (3a)
>95% (3a)
82 (3a)
91 (3a)
56 (3b)
88 (3b)
d
10
11
12
de
,
tol
tol
ef
,
a
Unless otherwise noted, all reactions were performed with catalyst
(20 mol %), 1a (0.10 mmol), 2a (3 equiv), and base (2 equiv) in
solvent (1.0 mL) at 35 °C. Yield of isolated product. Determined by
HPLC analysis on a chiral stationary phase. Conducted with 3 Å
M.S. (10 mg). Conducted with 1b (0.10 mmol). Carried out with 2a
(0.15 mmol), catalyst (10 mol %) and 3 Å M.S. (15 mg).
b
c
d
e
f
Encouraged by above results, the generality of sulfonamides
1 was further investigated with anhydride 2a (Scheme 3).
Installing other substituents at the para position in o-tert-butyl-
NH-anilide did not show any obvious influence on the
enantioselectivity of the present transformation (3s−v).
However, switching the o-tert-butyl group to smaller
substituents, such as methyl, bromo, or iodo groups in anilide,
led to an apparent drop in chiral control (3w−y, 81−85%
yields, 73−81% ee). Next, several sulfonamide substrates were
surveyed. Similar to p-tosyl amide 1a, the reaction with
benzenesulfonamide gave the expected N-acylation products
3aa with moderate yield (48%) and good enantioselectivity
(87% ee). The yield of products 3aa increased to 67% when
the reaction was performed with 3 equiv of anhydride 2a.
Under such conditions, benzenemethanesulfonamide 1k and
cyclohexyl sulfonamide 1l were tested, and the corresponding
products 3ab and 3ac were obtained in satisfactory outcomes
(3ab, 80 yield, 95% ee; 3ac, 73 yield, 91% ee, respectively).
representative chiral isothiourea catalysts with different
skeletons were screened with KOtBu as the base in
dichloromethane (DCM) at 35 °C. It was disappointing to
find that the reaction did not occur in the presence of either
benzotetramisole C1 or tetramisole C2 (entries 1 and 2). To
our delight, chiral homobenzotetramisole (HBTM) C3, first
developed by Birman’s group,18 could promote the N-acylation
reaction smoothly, affording the desired acyl sulfonyl
substituted anilides 3a in high yield (96%) with a promising
enantioselectivity (entry 3, 67% ee).18,19 These proof-of
principle results validated that the control of axial chirality of
anilides by isothiourea-catalyzed atroposelective N-acylation
reaction was feasible. Then other reaction parameters such as
the nature of solvent, base, additive, and catalyst loading were
examined. It was observed that the solvent displayed a
significant effect on the reactivity and enantioselectivity of
the process (entries 3−6). Generally, highly polar solvents, for
example THF, led to more inferior results than those of
B
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a
Scheme 2. Substrate Scope of α,β-Unsaturated Carbonic
Anhydrides
Scheme 3. Substrate Scope of Sulfonamides
a
a
All of the reactions were performed with C3 (10 mol %), DIPEA (2
equiv), 3 Å M.S. (15 mg), 1 (0.10 mmol), and 2a (0.15 mmol) in
b
toluene (1 mL) at 35 °C. With 3 equiv of 2a.
(Scheme 5). Initially, the nucleophilic attachment of HBTM
C3 to α,β-unsaturated carbonic anhydride 2 afforded the
acylisothiouronium intermediate, wherein the carbonyl group
could be fixed in position through an no to σ*C−S interaction.22
On one hand, to avoid sterical replulsion with the phenyl
group on the catalyst C3, the sulfonamide anions preferably
approached this acylisothiouronium intermediate from the
opposite side of phenyl group. On the other hand, the
existence of bulky o-tert-butyl group on phenyl ring reduced
the π−π interaction between the substrates and the skeleton of
catalyst. In contrast, the attractive interaction between oxygen
of sulfonyl moiety and the positive electronic charge on the
face of the imidazolium salt was proposed to display an
important role in this process.23 Therefore, the sulfonamide
anions attached the acylisothiouronium plane in the fashion
illustrated in Scheme 5, and the corresponding (R)-3l was
afforded as the major product, which was consist with the
experimental results.
In summary, we have developed a new protocol for the
synthesis of axially chiral anilides through isothiourea-catalyzed
atroposelective N-acylation of sulfonamides with α,β-unsatu-
rated carbonic anhydrides. The reaction was performed under
mild conditions, delivering a number of atropoisomeric
sulfonyl-substituted anilides in good yields and high to
excellent enantioselectivities. This strategy was highlighted by
gram-scale preparation and transformation of the product.
a
All of the reactions were performed with C3 (10 mol %), DIPEA (2
equiv), 3 Å M.S. (15 mg), 1b (0.10 mmol), and 2 (0.15 mmol) in
toluene (1.0 mL) at 35 °C. Determined by H NMR.
b
1
To demonstrate the practicability of this transformation, we
carried out a gram-scale reaction. As shown in Scheme 4a, 3.5
mmol of the compound 1b reacted smoothly with 1.5 equiv of
anhydride 2l, furnishing the desired product 3m in 90% yield
(1.26 g) with 93% ee. Hydrogenation of the product 3m was
conducted in the presence of Pd/C, delivering the desired
product 5 in high yield with maintained ee value (Scheme 4b).
To get more insight into the reaction process, several control
experiments were carried out. When benzoic acid derived
anhydride 6 was examined, the side products 4a and 4b were
obtained in large quantities with excellent enantioselectivities
(4a, 69% yield, 95% ee; 4b, 76% yield, 96% ee, respectively).
The reaction of acetic anhydride 7 occurred smoothly,
providing the expected product 4c in moderate yield (44%
yield) with equally high ee value (90% ee). Inspired by Ye’s
work,21b commercially available cinnamic acid 8 was used as
the starting material, and the desired product was obtained in
lower yield (36%) with excellent enantioselectivity (93% ee).
On the basis of previous works14a and the crystal structure of
the product 3l, a possible transition state model was proposed
C
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Accession Codes
Scheme 4. Scale-up Synthesis of 3m and Further
Transformation
CCDC 1999875 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Shunxi Dong − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0002-3018-3085; Email: dongs@scu.edu.cn
Authors
Dawei Li − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
Sijing Wang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Shulin Ge − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478
Scheme 5. Proposed Working Mode
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01581
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the National Natural Science Foundation of
China (Nos. 21801175 and 21921002) and the Fundamental
Research Fund for the Central Universities for financial
support. “Thousand Talents Program” of Sichuan Province is
gratefully acknowledged.
REFERENCES
■
(1) For representative reviews, see: (a) Wang, Y.-B.; Tan, B.
Construction of Axially Chiral Compounds via Asymmetric Organo-
catalysis. Acc. Chem. Res. 2018, 51, 534. (b) Bonne, D.; Rodriguez, J.
Enantioselective Syntheses of Atropisomers Featuring a Five-
membered Ring. Chem. Commun. 2017, 53, 12385. (c) Kumarasamy,
E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J. Nonbiaryl and
Heterobiaryl Atropisomers: Molecular Templates with Promise for
Atropselective Chemical Transformations. Chem. Rev. 2015, 115,
11239. (d) Takahashi, I.; Suzuki, Y.; Kitagawa, O. Asymmetric
Synthesis of Atropisomeric Compounds with an N−C Chiral Axis.
Org. Prep. Proced. Int. 2014, 46, 1.
(2) (a) Glunz, P. W. Recent Encounters with Atropisomerism in
Drug Discovery. Bioorg. Med. Chem. Lett. 2018, 28, 53. (b) Farand, J.;
Mai, N.; Chandrasekhar, J.; Newby, Z. E.; Veldhuizen, J. V.; Loyer-
Drew, J.; Venkataramani, C.; Guerreo, J.; Kwon, A.; Li, N.; Zherebina,
Y.; Wilbert, S.; Zablocki, J.; Phillips, G.; Watkins, W. J.; Mourey, R.;
Notte, G. T. Selectivity Switch between FAK and Pyk2: Macro-
cyclization of FAK Inhibitors Improves Pyk2 Potency. Bioorg. Med.
Chem. Lett. 2016, 26, 5926. (c) Zask, A.; Murphy, J.; Ellestad, G. A.
Biological Stereoselectivity of Atropisomeric Natural Products and
Further studies on the synthesis of other axially chiral systems
are underway in our laboratory.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01581.
Experimental procedures, full spectroscopic data for all
new compounds, 1H, 13C{1H}, 19F{1H} NMR, and
HPLC spectra (PDF)
D
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Drugs. Chirality 2013, 25, 265. (d) LaPlante, S. R.; Edwards, P. J.;
Fader, L. D.; Jakalian, A.; Hucke, O. Revealing Atropisomer Axial
Chirality in Drug Discovery. ChemMedChem 2011, 6, 505. (e) LaP-
lante, 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. (f) Liu, P.; Lanza, T. J.; Chioda, M.; Jones, C.;
Chobanian, H. R.; Guo, Y.; Chang, L.; Kelly, T. M.; Kan, Y.; Palyha,
O.; et al. Discovery of Benzodiazepine Sulfonamide-Based Bombesin
Receptor Subtype 3 Agonists and Their Unusual Chirality. ACS Med.
Chem. Lett. 2011, 2, 933. (g) 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. (h) Deur, C.; Agrawal, A. K.;
Baum, H.; Booth, J.; Bove, S.; Brieland, J.; Bunker, A.; Connolly, C.;
Cornicelli, J.; Dumin, J.; Finzel, B.; Gan, X.; Guppy, S.; Kamilar, G.;
Kilgore, K.; Lee, P.; Loi, C.-M.; Lou, Z.; Morris, M.; Philippe, L.;
Przybranowski, S.; Riley, F.; Samas, B.; Sanchez, B.; Tecle, H.; Wang,
Z.; Welch, K.; Wilson, M.; Yates, K. N(6,7-dichloro-2,3-dioxo-1,2,3,4-
tetrahydroquinoxalin-5-yl)-N-Alkylsulfonamides as Peripherally Re-
stricted N-Methyl-D-Aspartate Receptor Antagonists for the Treat-
ment of Pain. Bioorg. Med. Chem. Lett. 2007, 17, 4599.
Asymmetry of Transient Atropisomers of o-Iodoanilides by Radical
Cyclizations. J. Am. Chem. Soc. 2005, 127, 14994. (j) Kitagawa, O.;
Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. Optically
Active Axially Chiral Anilide and Maleimide Derivatives as New
Chiral Reagents: Synthesis and Application to Asymmetric Diels−
Alder Reaction. J. Org. Chem. 1998, 63, 2634. (k) Kitagawa, O.; Izawa,
H.; Taguchi, T.; Shiro, M. An Efficient Synthesis of Optically Active
Axially Chiral Anilide and Its Application to Iodine-mediated
Asymmetric Diels-Alder Reaction. Tetrahedron Lett. 1997, 38, 4447.
(8) (a) Paul, B.; Butterfoss, G. L.; Boswell, M. G.; Huang, M. L.;
Bonneau, R.; Wolf, C.; Kirshenbaum, K. N-Naphthyl Peptoid
Foldamers Exhibiting Atropisomerism. Org. Lett. 2012, 14, 926.
(b) Paul, B.; Butterfoss, G. L.; Boswell, M. G.; Renfrew, P. D.; Yeung,
F. G.; Shah, N. H.; Wolf, C.; Bonneau, R.; Kirshenbaum, K. Peptoid
Atropisomers. J. Am. Chem. Soc. 2011, 133, 10910.
(9) (a) Yang, G.-H.; Zheng, H. L.; Li, X.; Cheng, J.-P. Asymmetric
Synthesis of Axially Chiral Phosphamides via Atroposelective N-allylic
Alkylation. ACS Catal. 2020, 10, 2324. (b) Kikuchi, Y.; Nakamura, C.;
Matsuoka, M.; Asami, R.; Kitagawa, O. Catalytic Enantioselective
Synthesis of N−C Axially Chiral Sulfonamides through Chiral
Palladium-Catalyzed N-Allylation. J. Org. Chem. 2019, 84, 8112.
(c) Lu, S. C.; Ng, S. V. H.; Lovato, K.; Ong, J.-L.; Poh, S. B.; Ng, X.
(3) 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.
Q.; Ku
̈
rti, L.; Zhao, Y. Practical Access to Axially Chiral Sulfonamides
and Biaryl Amino Phenols via Organocatalytic Atroposelective N-
Alkylation. Nat. Commun. 2019, 10, 3061. (d) Li, S.-L.; Yang, C.; Wu,
Q.; Zheng, H.-L.; Li, X.; Cheng, J.-P. Atroposelective Catalytic
Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides
with Achiral Morita−Baylis−Hillman Carbonates. J. Am. Chem. Soc.
2018, 140, 12836. (e) Liu, Y. L.; Feng, X. Q.; Du, H. F. Asymmetric
Synthesis of Axially Chiral Anilides by Pd-Catalyzed Allylic
Substitutions with P/olefin Ligands. Org. Biomol. Chem. 2015, 13,
125. (f) Liu, K.; Wu, X. F.; Kan, S. B. J.; Shirakawa, S.; Maruoka, K.
Phase-Transfer-Catalyzed Asymmetric Synthesis of Axially Chiral
Anilides. Chem. - Asian J. 2013, 8, 3214. (g) Shirakawa, S.; Liu, K.;
Maruoka, K. Catalytic Asymmetric Synthesis of Axially Chiral o-
Iodoanilides by Phase-Transfer Catalyzed Alkylations. J. Am. Chem.
Soc. 2012, 134, 916. (h) Terauchi, J.; Curran, D. P. N-Allylation of
Anilides with Chiral Palladium Catalysts: the First Catalytic
Asymmetric Synthesis of Axially Chiral Anilides. Tetrahedron:
Asymmetry 2003, 14, 587. (i) Kitagawa, O.; Kohriyama, M.;
Taguchi, T. Catalytic Asymmetric Synthesis of Optically Active
Atropisomeric Anilides through Enantioselective N-Allylation with
Chiral Pd-tol-BINAP Catalyst. J. Org. Chem. 2002, 67, 8682.
(4) (a) Mino, T.; Nishikawa, K.; Asano, M.; Shima, Y.; Ebisawa, T.;
Yoshida, Y.; Sakamoto, M. Chiral N-1-adamantyl-N-trans-Cinnamy-
laniline Type Ligands: Synthesis and Application to Palladium-
catalyzed Asymmetric Allylic Alkylation of Indoles. Org. Biomol. Chem.
2016, 14, 7509. (b) Brandes, S.; Bella, M.; Kjœrsgaard, A.; Jørgensen,
K. A. Chirally Aminated 2-NaphtholsOrganocatalytic Synthesis of
Non-Biaryl Atropisomers by Asymmetric Friedel−Crafts Amination.
Angew. Chem., Int. Ed. 2006, 45, 1147.
(5) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. Atroposelective
Thermal Reactions of Axially Twisted Amides and Imides. J. Am.
Chem. Soc. 1994, 116, 3131.
(6) (a) Blaser, H.-U.; Pugin, B.; Spindler, F.; Thommen, M. From a
Chiral Switch to a Ligand Portfolio for Asymmetric Catalysis. Acc.
Chem. Res. 2007, 40, 1240. (b) Blaser, H.-U. The Chiral Switch of
(S)-Metolachlor: A Personal Account of an Industrial Odyssey in
Asymmetric Catalysis. Adv. Synth. Catal. 2002, 344, 17. (c) Blaser, H.-
U.; Spindler, F. Enantioselective Catalysis for Agrochemicals. The
Case Histories of (S)-Metolachlor, (R)-Metalaxyl and Clozylacon.
Top. Catal. 1997, 4, 275.
̈
(7) (a) Bruch, A.; Frohlich, R.; Grimme, S.; Studer, A.; Curran, D. P.
(10) (a) Fan, X. Z.; Zhang, X.; Li, C. Y.; Gu, Z. H. Enantioselective
Atropisomeric Anilides Synthesis via Cu-Catalyzed Intramolecular
Adjacent C−N Coupling. ACS Catal. 2019, 9, 2286. (b) Hirata, T.;
Takahashi, I.; Suzuki, Y.; Yoshida, H.; Hasegawa, H.; Kitagawa, O.
Catalytic Enantioselective Synthesis of N-C Axially Chiral Phenan-
thridin-6-one Derivatives. J. Org. Chem. 2016, 81, 318. (c) Kitagawa,
O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi,
Y.; Taguchi, T. Highly Enantioselective Synthesis of Atropisomeric
Anilide Derivatives through Catalytic Asymmetric N-Arylation:
Conformational Analysis and Application to Asymmetric Enolate
Chemistry. J. Am. Chem. Soc. 2006, 128, 12923. (d) Kitagawa, O.;
Takahashi, M.; Yoshikawa, M.; Taguchi, T. Efficient Synthesis of
Optically Active Atropisomeric Anilides through Catalytic Asym-
metric N-Arylation Reaction. J. Am. Chem. Soc. 2005, 127, 3676.
(11) (a) 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. (b) Tanaka, K.;
Takeishi, K.; Noguchi, K. Enantioselective Synthesis of Axially Chiral
Anilides through Rhodium-Catalyzed [ 2 + 2 + 2] Cycloaddition of
1,6-Diynes with Trimethylsilylynamides. J. Am. Chem. Soc. 2006, 128,
4586.
One Product, Two Pathways: Initially Divergent Radical Reactions
Reconverge To Form a Single Product in High Yield. J. Am. Chem.
Soc. 2011, 133, 16270. (b) Guthrie, D. B.; Geib, S. J.; Curran, D. P.
Radical and Heck Cyclizations of Diastereomeric o-Haloanilide
Atropisomers. J. Am. Chem. Soc. 2011, 133, 115. (c) Ayitou, A. J.-
L.; Sivaguru, J. Reactive Spin State Dependent Enantiospecific
Photocyclization of Axially Chiral α-Substituted Acrylanilides. Chem.
̈
Commun. 2011, 47, 2568. (d) Bruch, A.; Ambrosius, A.; Frohlich, R.;
Studer, A.; Guthrie, D.; Zhang, H.; Curran, D. P. Memory of Axial
Chirality in Aryl Radical Phosphanylations. J. Am. Chem. Soc. 2010,
132, 11452. (e) Guthrie, D. B.; Geib, S. J.; Curran, D. P. Synthesis of
Highly Enantioenriched 3,4-Dihydroquinolin-2-ones by 6-Exo-trig
Radical Cyclizations of Axially Chiral α-Halo-ortho-alkenyl Anilides. J.
Am. Chem. Soc. 2009, 131, 15492. (f) Ayitou, A. J.-L.; Sivaguru, J.
Light-Induced Transfer of Molecular Chirality in Solution:
Enantiospecific Photocyclization of Molecularly Chiral Acrylanilides.
J. Am. Chem. Soc. 2009, 131, 5036. (g) Ayitou, A. J.-L.; Jesuraj, J. L.;
Barooah, N.; Ugrinov, A.; Sivaguru, J. Enantiospecific Photochemical
Norrish/Yang Type II Reaction of Nonbiaryl Atropchiral α-
Oxoamides in SolutionAxial to Point Chirality Transfer. J. Am.
Chem. Soc. 2009, 131, 11314. (h) Lapierre, A. J. B.; Geib, S. J.;
Curran, D. P. Low-Temperature Heck Reactions of Axially Chiral o-
Iodoacrylanilides Occur with Chirality Transfer: Implications for
Catalytic Asymmetric Heck Reactions. J. Am. Chem. Soc. 2007, 129,
494. (i) Petit, M.; Lapierre, A. J. B.; Curran, D. P. Relaying
(12) (a) Crawford, J. M.; Stone, E. A.; Metrano, A. J.; Miller, S. J.;
Sigman, M. S. Parameterization and Analysis of Peptide-Based
Catalysts for the Atroposelective Bromination of 3-Arylquinazolin4-
(3H)-ones. J. Am. Chem. Soc. 2018, 140, 868. (b) Diener, M. E.;
Metrano, A. J.; Kusano, S.; Miller, S. J. Enantioselective Synthesis of 3-
E
https://dx.doi.org/10.1021/acs.orglett.0c01581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective
Bromination. J. Am. Chem. Soc. 2015, 137, 12369.
Chem., Int. Ed. 2011, 50, 5553. (b) Yang, X.; Birman, V. B.
Homobenzotetramisole-Catalyzed Kinetic Resolution of a-Aryl-, a-
Aryloxy-, and a-Arylthioalkanoic Acids. Adv. Synth. Catal. 2009, 351,
2301.
(13) (a) Zhang, J.-W.; Xu, J.-H.; Cheng, D.-J.; Shi, C.; Liu, X.-Y.;
Tan, B. Discovery and Enantiocontrol of Axially Chiral Urazoles via
Organocatalytic Tyrosine Click Reaction. Nat. Commun. 2016, 7,
10677. (b) Zhang, J. L.; Zhang, Y. L.; Lin, L. L.; Yao, Q.; Liu, X. H.;
Feng, X. M. Catalytic Asymmetric Desymmetrization of N-
Arylmaleimides: Efficient Construction of Both Atom Chirality and
Axial Chirality. Chem. Commun. 2015, 51, 10554. (c) Liu, H.; Feng,
W.; Kee, C. W.; Leow, D.; Loh, W.-T.; Tan, C.-H. Brønsted Base-
Catalyzed Tandem Isomerization−Michael Reactions of Alkynes:
Synthesis of Oxacycles and Azacycles. Adv. Synth. Catal. 2010, 352,
3373. (d) Duan, W.-L.; Imazaki, Y.; Shintani, R.; Hayashi, T.
Asymmetric Construction of Chiral C−N Axes Through Rhodium-
Catalyzed 1,4-Addition. Tetrahedron 2007, 63, 8529.
(14) For representative reviews, see: (a) Merad, J.; Pons, J.-M.;
Chuzel, O.; Bressy, C. Enantioselective Catalysis by Chiral
Isothioureas. Eur. J. Org. Chem. 2016, 5589. (b) Flanigan, D. M.;
Romanov-Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic
Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015,
115, 9307. (c) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Amidines,
Isothioureas, and Guanidines as Nucleophilic Catalysts. Chem. Soc.
Rev. 2012, 41, 2109. (d) Wurz, R. P. Chiral Dialkylaminopyridine
Catalysts in Asymmetric Synthesis. Chem. Rev. 2007, 107, 5570.
(15) (a) In ref 9a, Curran and co-workers disclosed their efforts at an
asymmetric acylation strategy; however, only low ee’s (typically <
20%) were afforded (unpublished results). (b) For an example of
atropselective acylation via kinetic resolution, see: Munday, E. S.;
Grove, M. A.; Feoktistova, T.; Brueckner, A. C.; Walden, D. M.;
Young, C. M.; Slawin, A. M. Z.; Campbell, A. D.; Cheong, P. H.-Y.;
Smith, A. D. Isothiourea-Catalyzed Atropselective Acylation of Biaryl
Phenols via Sequential Desymmetrization/Kinetic Resolution. Angew.
Chem., Int. Ed. 2020, 59, 7897.
(16) For selected examples, see: (a) Liu, H. L.; Slawin, A. M. Z.;
Smith, A. D. Isothiourea-Catalyzed Enantioselective Synthesis of
Tetrahydro-α-carbolinones. Org. Lett. 2020, 22, 1301. (b) Matviitsuk,
A.; Greenhalgh, M. D.; Taylor, J. E.; Nguyen, X. B.; Cordes, D. B.;
Slawin, A. M. Z.; Lupton, D. W.; Smith, A. D. Unanticipated Silyl
Transfer in Enantioselective α,β-Unsaturated Acyl Ammonium
Catalysis Using Silyl Nitronates. Org. Lett. 2020, 22, 335. (c) Shu,
C.; Liu, H.; Slawin, A. M. Z.; Carpenter-Warren, C.; Smith, A. D.
Isothiourea-catalysed Enantioselective Michael Addition of N-
Heterocyclic Pronucleophiles to α,β-Unsaturated Aryl Esters. Chem.
Sci. 2020, 11, 241. (d) Greenhalgh, M. D.; Qu, S.; Slawin, A. M. Z.;
Smith, A. D. Multiple Roles of Aryloxide Leaving Groups in
Enantioselective Annulations Employing α,β-Unsaturated Acyl
Ammonium Catalysis. Chem. Sci. 2018, 9, 4909. (e) Kang, G.;
Yamagami, M.; Vellalath, S.; Romo, D. Enantioselective Synthesis of
Medium-Sized Lactams via Chiral α,β-Unsaturated Acylammonium
Salts. Angew. Chem., Int. Ed. 2018, 57, 6527. (f) Matviitsuk, A.;
(20) According to previous work, we envisioned that the role of the
molecular sieves was to prevent the deactivation of catalyst. For
details, see: Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y. H.;
Yang, X.; Birman, V. B. Kinetic Resolution of Secondary Alcohols
Using Amidine-Based Catalysts. J. Org. Chem. 2012, 77, 1722.
(21) (a) Dong, S. X.; Frings, M.; Cheng, H. C.; Wen, J.; Zhang, D.;
Raabe, G.; Bolm, C. Organocatalytic Kinetic Resolution of
Sulfoximines. J. Am. Chem. Soc. 2016, 138, 2166. (b) Chen, X.-Y.;
Gao, Z.-H.; Song, C.-Y.; Zhang, C.-L.; Wang, Z.-X.; Ye, S. N-
Heterocyclic Carbene Catalyzed Cyclocondensation of α,β-Unsatu-
rated Carboxylic Acids: Enantioselective Synthesis of Pyrrolidinone
and Dihydropyridinone Derivatives. Angew. Chem., Int. Ed. 2014, 53,
11611.
(22) The presence of intramolecular nonbonded S···O interaction
has been recognized; see: (a) Young, C. M.; Elmi, A.; Pascoe, D. J.;
Morris, R. K.; McLaughlin, C.; Woods, A. M.; Frost, A. B.; de la
Houpliere, A.; Ling, K. B.; Smith, T. K.; Slawin, A. M. Z.; Willoughby,
P. H.; Cockroft, S. L.; Smith, A. D. The Importance of 1,5-Oxygen···
Chalcogen Interactions in Enantioselective Isochalcogenourea Catal-
́
ysis. Angew. Chem., Int. Ed. 2020, 59, 3705. (b) Barrios Antunez, D.-J.;
Greenhalgh, M. D.; Brueckner, A. C.; Walden, D. M.; Elías-Rodríguez,
P.; Roberts, P.; Young, B. G.; West, T. H.; Slawin, A. M. Z.; Cheong,
P. H.-Y.; Smith, A. D. Catalytic Enantioselective Synthesis of
Perfluoroalkyl-substituted β-Lactones via a Concerted Asynchronous
[2 + 2] Cycloaddition: a Synthetic and Computational Study. Chem.
Sci. 2019, 10, 6162. (c) Greenhalgh, M. D.; Smith, S. M.; Walden, D.
M.; Taylor, J. E.; Brice, Z.; Robinson, E. R. T.; Fallan, C.; Cordes, D.
B.; Slawin, A. M. Z.; Richardson, H. C.; Grove, M. A.; Cheong, P. H.-
Y.; Smith, A. D. A C = O···Isothiouronium Interaction Dictates
Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary
Heterocyclic Alcohols. Angew. Chem., Int. Ed. 2018, 57, 3200.
(d) Robinson, E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. Anhydrides as α,β-unsaturated acyl ammonium
precursors: isothiourea-promoted catalytic asymmetric annulation
processes. Chem. Sci. 2013, 4, 2193. (e) Liu, P.; Yang, X.; Birman, V.
B.; Houk, K. N. Origin of Enantioselectivity in Benzotetramisole-
Catalyzed Dynamic Kinetic Resolution of Azlactones. Org. Lett. 2012,
14, 3288.
(23) (a) Nakata, K.; Gotoh, K.; Ono, K.; Futami, K.; Shiina, I.
Kinetic Resolution of Racemic 2-Hydroxy-γ-butyrolactones by
Asymmetric Esterification Using Diphenylacetic Acid with Pivalic
Anhydride and a Chiral Acyl-Transfer Catalyst. Org. Lett. 2013, 15,
1170. (b) Yang, X.; Bumbu, V. D.; Liu, P.; Li, X.; Jiang, H.; Uffman, E.
W.; Guo, L.; Zhang, W.; Jiang, X. T.; Houk, K. N.; Birman, V. B.
Catalytic, Enantioselective N-Acylation of Lactams and Thiolactams
Using Amidine-Based Catalysts. J. Am. Chem. Soc. 2012, 134, 17605.
(c) Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A.
Kinetic Resolution of the Racemic 2-Hydroxyalkanoates Using the
Enantioselective Mixed-Anhydride Method with Pivalic Anhydride
and a Chiral Acyl-Transfer Catalyst. Chem. - Eur. J. 2010, 16, 167.
́
Greenhalgh, M. D.; Antunez, D.-J. B.; Slawin, A. M. Z.; Smith, A. D.
Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,β-
Unsaturated Acyl Ammonium Catalysis. Angew. Chem., Int. Ed.
2017, 56, 12282. (g) Abbasov, M. E.; Hudson, B. M.; Tantillo, D. J.;
Romo, D. Stereodivergent, Diels−Alder-initiated Organocascades
Employing α,β-Unsaturated Acylammonium salts: Scope, Mechanism,
and Application. Chem. Sci. 2017, 8, 1511. (h) Robinson, E. R. T.;
Walden, D. M.; Fallan, C.; Greenhalgh, M. D.; Cheong, P. H.-Y.;
Smith, A. D. Non-Bonding 1,5-S···O Interactions Govern Chemo- and
Enantioselectivity in Isothiourea-Catalyzed Annulations of Benza-
zoles. Chem. Sci. 2016, 7, 6919.
(17) Fukata, Y.; Asano, K.; Matsubara, S. Facile Net Cycloaddition
Approach to Optically Active 1,5-Benzothiazepines. J. Am. Chem. Soc.
2015, 137, 5320.
(18) Birman, V. B.; Li, X. Homobenzotetramisole: An Effective
Catalyst for Kinetic Resolution of Aryl-Cycloalkanols. Org. Lett. 2008,
10, 1115.
(19) (a) Yang, X.; Birman, V. B. Nonenzymatic Dynamic Kinetic
Resolution of a-(Arylthio)- and a-(Alkylthio)alkanoic Acids. Angew.
F
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