Enantioselective Construction of Quinoxaline-Based Heterobiaryls and P,N-Ligands via Chirality Transfer Strategy

Article abstract of DOI:10.1021/acs.orglett.0c03827

Central-to-axial chirality transfer via C-N single bond oxidation was first achieved as a versatile and conceptually distinct strategy to prepare a new family of axially chiral heteroaromatic biaryl backbones and P,N-ligands (named as Quinoxalinaps) in gram scale. Two atropisomers of Quinoxalinaps (ee >99%) were readily accessed from the same precursor enantiomer by a simple dehydrogenative oxidation with MnO2 and t-BuOOH under mild conditions. Phosphine could be introduced into the ligands before or after the chirality control process. Moreover, these Quinoxalinap P,N-ligands performed well for both asymmetric reactions of the CuBr-catalyzed alkyne conjugate addition with up to -94% ee and AgOAc-catalyzed glycinate imine [3 + 2] annulation with 90% ee, respectively.

Full text of DOI:10.1021/acs.orglett.0c03827

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Letter
Enantioselective Construction of Quinoxaline-Based Heterobiaryls
and P,N-Ligands via Chirality Transfer Strategy
Zeng Gao, Fang Wang, Jinlong Qian, Huameng Yang, Chungu Xia,* Jinlong Zhang,* and Gaoxi Jiang*
Cite This: Org. Lett. 2021, 23, 1181−1187
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ABSTRACT: Central-to-axial chirality transfer via C−N single
bond oxidation was first achieved as a versatile and conceptually
distinct strategy to prepare a new family of axially chiral
heteroaromatic biaryl backbones and P,N-ligands (named as
Quinoxalinaps) in gram scale. Two atropisomers of Quinoxalinaps
(ee >99%) were readily accessed from the same precursor
enantiomer by a simple dehydrogenative oxidation with MnO2
and t-BuOOH under mild conditions. Phosphine could be
introduced into the ligands before or after the chirality control process. Moreover, these Quinoxalinap P,N-ligands performed
well for both asymmetric reactions of the CuBr-catalyzed alkyne conjugate addition with up to −94% ee and AgOAc-catalyzed
glycinate imine [3 + 2] annulation with 90% ee, respectively.
ince the first axially chiral P,N-ligand Quinap was reported
by Brown in 1991, such hybrid ligands have emerged as
rapid racemization in the direct installation of P,N-ligands from
chiral heterobiaryl triflate or bromide via the C−P bond
coupling method. Thus, further exploration of new P,N-ligand
skeletons, practical synthesis, and structural modification of
P,N-ligands is still in great demand although it is very
challenging.1c
S
privileged and powerful chiral ligands for a broad range of
catalytic enantioselective transformations (Scheme 1a).1−6
Therefore, the innovation of new axially chiral P,N-ligand
skeletons and practical synthesis approaches continues to
attract the attention of chemists. Traditional protocols
generally focused on the chirality resolution of the racemic
axial heterobiaryl backbones to access its corresponding
atropisomeric P,N-ligands (Scheme 1b, right). Pioneeringly,
Brown and co-workers established an asymmetric resolution to
achieve the original Quinap ligand by using a stoichiometric
amount of a chiral palladium complex2 that makes it expensive
commercially (Sigma-Aldrich: $732/250 mg). Even so, the
pioneering and venerable method was extensively employed to
acquire other privileged P,N-ligand scaffolds including
Quinazolinap,3,3 PyPhos,3c and StackPhos3d by the Guiry,
Chan, and Aponick groups, respectively. Afterward, (S)-
sulfoxides instead of the expensive palladium complex as an
alternative resolution reagent for the Quinap synthesis was
then reported by the Knochel group.4 In 2004, Carreira and
co-workers demonstrated the direct chromatographic separa-
tion of two diastereomers derived from a chiral alcohol for the
synthesis of Pinap.5a In contrast with chirality resolution and
the auxiliary procedure, asymmetric catalysis is particularly
attractive although successful reports are very rare. Impres-
sively, Stoltz, Lassaletta, and Virgil have successfully developed
several elegant dynamic kinetic resolution protocols for the
synthesis of Pinap, Quinap, and their analogues via Pd-
catalyzed atropselective C−P bond coupling reactions from
preformed heterobiaryl compounds, independently.6 Mean-
while, the configurational lability of generated cationic five-
membered palladacycle intermediates is a disadvantage for
Different from these conventional approaches via later-stage
chirality manipulation of racemic axially chiral heterobiaryls,
we assumed that a central-to-axial chirality transfer process
should be a conceptually distinct strategy for building an axially
chiral hetereobiaryl through oxidative aromatization of the
CH−NH bond (Scheme 1b, left). Although central-to-axial
chirality transfer through CH−CH bond oxidation has been
realized by Thomson, Rodriguez, Bonne and others, the
following conversion from synthesized heterobiaryls without a
nitrogen atom at the 2-position was restricted to the
preparation of monodentate ligands.7,8 To acquire bidentate
ligands containing a basic coordination nitrogen through this
chirality transfer strategy, oxidative precursors with nitrogen at
the 2-position capable of oxidizing into configurational stable
axially chiral heterobiaryls have to be generated at first with
high enantiopurities. In this respect, we finally chose cascade
reactions between 2-pyrrolylanilines with aldehydes catalyzed
by a chiral Brønsted acid catalyst (0.2−2.0 mol %) to prepare
the chiral oxidative precursors.9,10 By the following chirality
Received: December 1, 2020
Published: February 4, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03827
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1181−1187
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Scheme 1. Typical Axially Chiral P,N-Ligands and the
Synthesis Pathways
Scheme 2. Investigation of the Rotational Stability and
a
Configurationally Stable P,N-Ligand Precursors
a
Reaction conditions: 3b (0.10 mmol) and oxidant (1.0 mmol, 10
equiv) were stirred in toluene (1.0 mL, 0.1 M) at room temperature
for 12 h; isolated yield was given, and ee value was determined by
b
chiral HPLC analysis. Conversion percentage (cp) = eeprd
/
c
eesm*100%. t-BuOOH (1.0 mmol, 10 equiv) was used as the oxidant
and reacted at 0 °C for 3 days.
Because of the necessity for the bulkier group at the 3-
position in pyrrole ring for the configurational stability of the
desired axially chiral ligand, a series of suitable centrally chiral
precursors were prepared from aldehyde 1 and pyrrole- or
indole-aniline 2 under CPA-catalysis of A3 in CCl4 at −10 °C
for 8 h (for details, see Supporting Information (SI)). 4,5-
Dihydropyrrolo[1,2-a]quinoxalines 3c−k with different steric
effects were prepared with high yields and ee values (91−98%
yields, 90−92% ee), except 3j in 31% yield at 80 °C. However,
unprotected substrate 2l used in the traditional Pictet−
Spengler reaction was inactive even at 80 °C. To evaluate
the practicability of this protocol for preparation of suitable
oxidative precursors, the scale of the reaction was increased to
gram-scale with a decreased CPA-loading. Gratifyingly,
compounds 3f and 3i were readily isolated in 1.34 and 1.61
g, respectively (87−93% yields), even with lowering of A3 to
0.2 mol % without obvious loss of enantioselectivities (96%
and 90% ee). During the oxidative synthesis of quinoxaline-
based heterobiaryls 4 via chirality transfer strategy (Scheme
3b), the chirality control was susceptible to the steric effect of
dihydropyrroloquinoxaline precursors, oxidants, and oxidative
reaction conditions so that a large difference in steric
interaction between the OR and naphthyl moieties with the
oxidant might enable the efficient discrimination of two
interconvert conformers ap-(S)-3 and sp-(S)-3. For the Me-
protected 3c, (R)-4c was predominantly produced with
satisfactory results under both MnO2 (68% ee, 74% cp) and
tBuOOH oxidation (82% ee, 89% cp). By changing Me (3c) to
MOM (3d), Tf (3e), TBS (3f), and TBDPS (3g), the chirality
cp were decreased for 4d (30% ee, 33% cp) and 4e (30% ee,
31% cp), but increased for 4f (84% ee, 91% cp) and 4g (80%
ee, 89% cp) with the same (R)-configuration (for details of
configuration determination, see SI). However, the larger
oxidant tBuOOH increased the steric interactions with Tf/TBS
as the main detemine factor, leading to enantiomers (S)-4e
(−77% ee, 81% cp) and (S)-4f (−4% ee, 4% cp) obtained
from another conformer sp-(S)-3. Axially chiral 4h (90% ee,
transfer via CH−NH oxidation, quinoxaline-based hetero-
biaryls were readily accessed with high to excellent yields,
enantioselectivities, and chirality exchange percentages (up to
99%). Remarkably, P,N-ligands containing quinoxaline (named
as Quinoxalinaps) were also successfully synthesized by this
strategy. Chiral heterobiaryl triflates synthesized by this
strategy have been demonstrated to be configurationally stable
in the following C−P coupling and could be transformed
diversely into P,N-ligands with diarylphosphines without
racemization.6a It is also worth mentioning that two
atropisomers of axially chiral heteroaromatic biaryl backbones
were readily accessed from the same precursor by simple
dehydrogenative oxidation.
At the outset, dynamic HPLC at various temperatures was
performed and these elution profiles were analyzed by the
DCXplorer software.11 The calculated half-life of enantiome-
rization (t1/2 = 7.4 min) and activation free energy (ΔG‡ ≈
21.68 kcal/mol at 25 °C) implied the configurational
instability of 4a due to rapid rotation around the biaryl C−C
axis (Scheme 2b).3d,12 To improve the rotational stabilities of
the designed ligand, a methyl group was installed on the
pyrrole start material to prepare more suitable oxidative
presursor 3b with 92% ee. Delightedly, as a configurationally
stable atropisomeric ligand, 4b exhibited a significant enantio-
conversion barrier and no interconversion of the two
enantiomers was detected via racemization experiment by
HPLC at 120 °C in C2H2Cl4 (Scheme 2c). The absolute
configuration of 4b was assigned as R by analogy with 5a.
Careful examination of oxidants revealed that MnO2, KMnO4,
and t-BuOOH are reactive oxidants for the oxidative
transformation of 3b into the configurationally stable chiral
4b with a moderate conversion percentage (cp); other oxidants
such as DDQ, dibenzoyl peroxide (BPO), m-CPBA, PhI-
(OAc)2, and PhI(CF3CO2)2 were not suitable.
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Scheme 3. Asymmetric Synthesis of 4,5-
Dihydropyrrolo[1,2-a]quinoxalines 4
Scheme 4. Quinoxalinap Synthesis through Later-Stage
a
a
Phosphine Introduction
a
Reagents and conditions: (C) TBAF (1.5 equiv), THF, rt. (D) Tf2O
(1.2 equiv), DMAP (2.0 equiv), DCM, rt. (E) Pd(OAc)2 (10 mol %),
dppp (10 mol %), DIPEA (4.0 equiv), Ar2P(O)H (2.0 equiv),
DMSO, 100 °C. (F) HSiCl3 (3.0 equiv), Et3N (9.0 equiv), toluene,
100 °C. (G) Ni(dppe)Cl2 (5.0 mol %), DABCO (2.0 equiv), (2-
MePh)2PH (2.0 equiv), DMF, 100 °C. (H) HCl (1.5 equiv), dioxane,
60 °C. (I) HSi(OEt)3 (3.0 equiv), Ti(Oi-Pr)4 (0.3 equiv), toluene,
100 °C.
5a and 5f were obtained in good yields. The desired
quinoxaline-based ligands LNa‑1 and LNa‑2 were gained with
>99% ee by trichlorosilane reduction from 5a and 5f,
respectively. Ligand LNa‑3 with the sterically hindered di-o-
tolylphosphine was also synthesized in 82% yield by a Ni(II)-
catalyzed C−P coupling reaction between 4fa and diary-
lphosphine. The absolute configuration of 5a was confirmed as
R through the crystal structure analysis on the copper-source
X-ray diffractometer. Of practical value, the Quinoxalinap LNa‑1
was readily prepared in 1.2 g for further catalysis research. Its
enantiomer (S)-LNa‑1 was constructed as well in >99% ee from
(S)-4e (ent-4e) (Scheme 4b). Incorporation of the strong
electron-withdrawing CF3 group into chiral ligands currently
attracted much attention.13 From CF3-substituted quinoxaline
4i, biarylphosphine oxides 5s and 5t were assembled without
obvious racemization and >99% ee was given through a
recrystallization in acetonitrile with 67% and 61% yields,
respectively. Accordingly, CF3-substituted Quinoxalinaps LF‑1
and LF‑2 were produced smoothly with >99% ee values by
simple reduction in the presence of Ti(OiPr)4 and triethox-
ysilane (Scheme 4c).
a
Reaction conditions: 1 (0.24 mmol, 1.2 equiv), 2 (0.20 mmol) and
A3 (1.0 mol %) were stirred in CCl4 (1.0 mL, 0.1 M) at −10 °C for 8
h; isolated yield was given, and ee value was determined by chiral
HPLC analysis. Toluene as the solvent instead of CCl4. Using p-
b
c
d
xylene/toluene = 2:1 (v/v) as the solvent at 0 °C. The reaction
e
f
conducted at 80 °C. The reaction scale was upon to 3.0 mmol. The
reaction scale was upon to 4.0 mmol.
94% cp) and 4i (96% ee, 98% cp) were readily constructed
from 3h and 3i, respectively. BuOOH and KMnO4 were the
optimal oxidants to promote the chirality exchange of 3k,
giving rise to the axially chiral 4k in 76% and 71% cp,
respectively.
The electronic and steric interaction of ligands generally play
a key role in asymmetric induction in transition-metal-
catalyzed transformations. Thus, diversity-oriented synthesis
of ligands with varying electronic nature is of great importance.
As shown in Scheme 4a, via deprotection of the axially chiral
compound 4f with TBAF, 4fa was obtained in 94% yield and
its enantiomeric excess can be increased up to >99% through a
recrystallization in acetonitrile. After trifluoromethane-
sulfonation and C−P bond coupling, biarylphosphine oxides
t
With the validity of this strategy for preparing quinoxaline-
based N,O-ligands 4, we expected to develop an alternative
synthetic route and further increase the chirality cp via an early
stage phosphine introduction. A large diarylphosphine oxide
group instead of an ether should cause greater steric distinction
between the two vicinal substituents, benefiting chiral control.
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As expected, a quantitative cp of >99% was detected for (R)-5a
by using both MnO2 and BuOOH from the stable conformer
MnO2, in good agreement with the experimental results in
terms of both (R)-configuration and excellent chirality
exchange percentage (for details, see SI). This protocol of
using phosphine oxide substituted aldehydes was highly
efficient for the Quinoxalinap synthesis together with simple
recrystallization and reduction. Different groups such as Me,
MeO, F, and Br atom in the aniline ring and phosphine oxide
motif were all tolerated under the reaction conditions to
acquire 5b−m in good yields (62−91%) and enantioselectiv-
ities (76−94%). Additionally, substituted pyrroles at the 1,2,3-
or 2,3-position were also applicable to provide the correspond-
ing ligands 5n and 5o in 74% and 76% ee, respectively. As
expected, a lower ee value of 24% was detected for 5p from
nonsubstituted pyrrole substrate. Excitedly, Me- and MOM-
group-protected hydroxybenzaldehyde could also be utilized to
deliver axially chiral 5q and 5r with 67% and 54% ee,
respectively. Followed by reduction with HSiCl3, naphthyl
quinoxalinap ligands LNa‑1, LNa‑4, and LNa‑5 were smoothly
synthesized with >99% ee and high yields, respectively.
t
ap-(S)-3m (Scheme 5a). Further insight into the origin of the
high chirality conversion of 3m was gained by DFT studies
employing the Gaussian 16 program. The potential energy of
the reaction transition TS-1 that resulted from ap-(S)- 3m was
found to be lower by 168.3 kJ·mol−1 40.2 kcal/mol than TS-2
from sp-(S)-3m in the oxidative cleavage of C−H bond by
Scheme 5. Eantioselective Synthesis of Quinoxaline-Based
Phosphine Oxides via Early-Stage Phosphine Introduction
a
and Synthesis of P,N-Ligands LNa‑1, LNa‑4, and LNa‑5
Preliminary investigation of these ligands in asymmetric
transition-metal catalysis was performed (Scheme 6). Enantio-
Scheme 6. Preliminary Application of Quinoxalinaps in
CuBr-catalyzed Alkyne Conjugate Addition and AgOAc-
Catalyzed Glycinate Imine [3 + 2] Annulation
a
Reaction conditions: 1 (0.60 mmol, 1.2 equiv), 2 (0. 50 mmol) and
selective addition of quinoline 5 and ethynylbenzene 6
catalyzed by CuBr/P,N-ligand proceeded efficiently, and a
−88% ee was obtained with LF‑1 (Scheme 6a).14g Besides
Cu(I)-catalysis, AgOAc-mediated [3 + 2] asymmetric
annulation14p of glycinate imine 8 and tert-butyl acrylate 9
was also selected to evaluate the chirality induction ability of
Quinoxalinaps (Scheme 6b). By using naphthyl Quinoxalinap
A3 (2.0 mol %) were stirred in a mixed solvent of p-xylene/toluene
(2:1 v/v, 5.0 mL, 0.1 M) at 0 °C for 12 h; the isolated product was
oxidized by MnO2 directly. Isolated yields were given, and ee values
were determined by chiral HPLC analysis. For the details of
b
t
recrystallization conditions, see the SI. Oxidized by BuOOH at 0
c
d
°C. Reacted for 36 h for first step. Reacted for 24 h for first step.
e
f
Reacted for 24 h at room temperature for first step. Reacted at room
g
L
Na‑5, the bicyclic amine 10 could be furnished with 90% ee
temperature in DCM solvent for 24 h. HSiCl3 (3.0 equiv), Et3N (9.0
equiv), toluene, 100 °C.
and a 95% yield. The results revealed that Quinoxalinaps could
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be regarded as the same excellent ligand as Quinap for this
reaction.
Sciences, Lanzhou 730000, China; University of Chinese
Academy of Sciences, Beijing 100049, P. R. China
Fang Wang − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China
Jinlong Qian − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; orcid.org/0000-0003-
0390-848X
Huameng Yang − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China
In summary, we developed a novel strategy for the efficient
and scalable assembly of atropisomeric quinoxaline-based P,N-
ligands (Quinoxalinaps) via CH−NH oxidative chirality
transfer. Remarkably, two atropisomers of Quinoxalinaps
could be easily obtained by different oxidation conditions
from the same precursor enantiomer. Early- and later-stage
introduction of phosphine atom, gram-scale synthesis of
naphthyl and CF3-substituted Quinoxalinaps distinguished
this strategy as a powerful and practical approach for new
P,N-ligand synthesis. Furthermore, these Quinoxalinaps
performed well in both CuBr-catalyzed alkyne conjugate
addition and AgOAc-catalyzed glycinate imine [3 + 2]
cyclization reactions, highlighting the potential application
for asymmetric catalysis. It is anticipated that this concept
would provide an opportunity for the exploitation of new
axially chiral heterobiaryl backbones and for constructing a
huge library of new X,N-ligands (X = P, O, N). Development
of other axially chiral architectures by the central-to-axial
transfer strategy is ongoing in our laboratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03827
Notes
ASSOCIATED CONTENT
* Supporting Information
■
The authors declare no competing financial interest.
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03827.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21602231), the Natural Science
Foundation of Jiangsu Province (BK20191197) is gratefully
acknowledged
Experimental details, characterization data, and NMR
spectra (PDF)
Accession Codes
CCDC 2017670 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.
REFERENCES
■
(1) For selected reviews on P,N-ligand synthesis, see: (a) Cheng, D.-
J.; Shao, Y.-D. Advances in the Catalytic Asymmetric Synthesis of
Atropisomeric Hexatomic N-Heterobiaryls. Adv. Synth. Catal. 2020,
362, 3081−3099. (b) Zilate, B.; Castrogiovanni, A.; Sparr, C.
Catalyst-Controlled Stereoselective Synthesis of Atropisomers. ACS
Catal. 2018, 8, 2981−2988. (c) Rokade, B. V.; Guiry, P. J. Axially
Chiral P,N-Ligands: Some Recent Twists and Turns. ACS Catal.
2018, 8, 624−643. (d) Carroll, M. P.; Guiry, P. J. P,N Ligands in
Asymmetric Catalysis. Chem. Soc. Rev. 2014, 43, 819−833. (e)
Privileged Chiral Ligands and Catalysts, Zhou, Q.-L., Ed., Wiley-VCH:
Weinheim, Germany, 2011. For reviews on synthesis of axially chiral
biaryl compounds, see: (f) Li, T.-Z.; Liu, S.-J.; Tan, W.; Shi, F.
Catalytic Asymmetric Construction of Axially Chiral Indole-Based
Frameworks: An Emerging Area, Chem. - Eur. J. 2020, DOI: 2615779.
(g) Zhang, Y.-C.; Jiang, F.; Shi, F. Organocatalytic Asymmetric
Synthesis of Indole-Based Chiral Heterocycles: Strategies, Reactions,
and Outreach. Acc. Chem. Res. 2020, 53, 425−446. (h) Wang, Y.-B.;
Tan, B. Construction of Axially Chiral Compounds via Asymmetric
Organocatalysis. Acc. Chem. Res. 2018, 51, 534−547. (i) Fu, W.; Tang,
W. Chiral Monophosphorus Ligands for Asymmetric Catalytic
Reactions. ACS Catal. 2016, 6, 4814−4858. (j) Akiyama, T.; Mori,
K. Stronger Brønsted Acids: Recent Progress. Chem. Rev. 2015, 115,
9277−9306. (k) 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.
(l) 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. (m) 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. (n) Bringmann, G.; Mortimer, A. J. P.; 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.
AUTHOR INFORMATION
Corresponding Authors
■
Chungu Xia − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; Email: cgxia@lzb.ac.cn
Jinlong Zhang − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; orcid.org/0000-0002-
0086-9318; Email: zhangjl@licp.cas.cn
Gaoxi Jiang − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; orcid.org/0000-0003-
1555-1107; Email: gxjiang@licp.cas.cn
Authors
Zeng Gao − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
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(2) Fernandez, E.; Guiry, P. J.; Connole, K P. T.; Brown, J. M.
Quinap and Congeners: Atropos PN ligands for Asymmetric
Catalysis. J. Org. Chem. 2014, 79, 5391−5400.
1955, 77, 450−453. (b) Meyers, A. I.; Wettlaufer, D. G. The
Complete Intramolecular Transfer of a Central Chiral Element to an
Axial Chiral Element. Oxidation of (S)-4-naphthyldihydroquinolines
to (S)-4-naphthylquinolines. J. Am. Chem. Soc. 1984, 106, 1135−
1136. (c) Nguyen, T. T. Traceless Point-to-Axial Chirality Exchange
in the Atropselective Synthesis of Biaryls/heterobiaryls. Org. Biomol.
Chem. 2019, 17, 6952−6963. For oxidation with vicinal auxiliary
stereogenic center: (d) 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. (e) Link, A.; Sparr, C. Remote Central-to-
AxialChirality Conversion: Direct Atroposelective Ester to Biaryl
Transformation. Angew. Chem., Int. Ed. 2018, 57, 7136−7139. (f) Hu,
Y.-L.; Wang, Z.; Yang, H.; Chen, J.; Wu, Z.-B.; Lei, Y.; Zhou, L.
Conversion of Two Stereocenters to One or Two Chiral Axes:
Atroposelective Synthesis of 2,3-Diarylbenzoindoles. Chem. Sci. 2019,
10, 6777−6784. (g) Hayashi, Y.; Takikawa, A.; Koshino, S.; Ishida, K.
Asymmetric Synthesis of Biaryl Atropisomers Usingan Organo-
catalyst-Mediated Domino Reaction as the Key Step. Chem. - Eur. J.
2019, 25, 10319−10322. (h) Bisag, G. D.; Pecorari, D.; Mazzanti, A.;
Bernardi, L.; Fochi, M.; Bencivenni, G.; Bertuzzi, G.; Corti, V.
Central-to-Axial Chirality Conversion Approach Designed on
Organocatalytic Enantioselective Povarov Cycloadditions: First
Access to Configurationally Stable Indole-Quinoline Atropisomers.
Chem. - Eur. J. 2019, 25, 15694−5701. (i) Bao, X.; Rodriguez, J.;
Bonne, D. Bidirectional Enantioselective Synthesis of Bisbenzofuran
Atropisomeric Oligoarenes Featuring Two Distal C−C Stereogenic
Axes. Chem. Sci. 2020, 11, 403−408. For oxidation with large steric
vicinal group: (j) Straub, A.; Goehrt, A. Inve rsion of Optically Active
Dihydropyridines by Oxidation and Electroreduction. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2662−2664. (k) Quinonero, O.; Jean, M.;
Vanthuyne, N.; Roussel, C.; Bonne, D.; Constantieux, T.; Bressy, C.;
Bugaut, X.; Rodriguez, J. Combining Organocatalysis with Central-to-
Axial Chirality Conversion: Atroposelective Hantzsch-Type Synthesis
of 4-Arylpyridines. Angew. Chem., Int. Ed. 2016, 55, 1401−1405.
(9) (a) Gholamzadeh, P. In Advances in Heterocyclic Chemistry;
Scriven, E. F. V.; Ramsden, C. A. Ed.; Elsevier: 2019; Vol. 127, pp
(3) (a) McCarthy, M.; Goddard, R.; Guiry, P. J. The Preparation
and Resolution of 2-phenyl-Quinazolinap, a New Atropisomeric
Phosphinamine Ligand for Asymmetric Catalysis. Tetrahedron:
Asymmetry 1999, 10, 2797−2807. (b) Connolly, D. J.; Lacey, P.
M.; McCarthy, M.; Saunders, C. P.; Carroll, A.-M.; Goddard, R.;
Guiry, P. J. Preparation and Resolution of a Modular Class of Axially
Chiral Quinazoline-Containing Ligands and Their Application in
Asymmetric Rhodium-Catalyzed Olefin Hydroboration. J. Org. Chem.
2004, 69, 6572−6589. (c) Kwong, F. Y.; Yang, Q.; Mak, T. C. W.;
Chan, A. S. C.; Chan, K. S. A New Atropisomeric P,N Ligand for
Rhodium-Catalyzed Asymmetric Hydroboration. J. Org. Chem. 2002,
67, 2769−2777. (d) Cardoso, F. S. P.; Abboud, K. A.; Aponick, A.
Design, Preparation, and Implementation of an Imidazole-Based
Chiral Biaryl P,N-Ligand for Asymmetric Catalysis. J. Am. Chem. Soc.
2013, 135, 14548−14551.
(4) (a) Thaler, T.; Geittner, F.; Knochel, P. A Novel Synthetic
Approach towards Chiral QUINAP via Diastereomeric Sulfoxide
Intermediates. Synlett 2007, 2007, 2655−2658. (b) Clayden, J.;
Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S. J. M. Controlling
Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines:
Application to the Asymmetric Synthesis of QUINAP by Dynamic
Thermodynamic Resolution. J. Am. Chem. Soc. 2009, 131, 5331−
5343.
(5) (a) Knoepfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Readily Available Biaryl P,N Ligands for Asymmetric
Catalysis. Angew. Chem. 2004, 116, 6097−6099; Angew. Chem., Int.
Ed. 2004, 43, 5971−5973. (b) Fekner, T.; Muller-Bunz, H.; Guiry, P.
̈
J. Synthesis and Application of Quinazoline−Oxazoline-Containing
(Quinazox) Ligands. Org. Lett. 2006, 8, 5109−5112. (c) Rokade, B.
V.; Guiry, P. J. Diastereofacial π-Stacking as an Approach To Access
an Axially Chiral P,N-Ligand for Asymmetric Catalysis. ACS Catal.
2017, 7, 2334−2338.
(6) (a) Ramírez-Lopez, P.; Ros, A.; Estepa, B.; Fernandez, R.; Fiser,
B.; Gomez-Bengoa, E.; Lassaletta, J. M. A Dynamic Kinetic C−P
Cross−Coupling for the Asymmetric Synthesis of Axially Chiral P,N
Ligands. ACS Catal. 2016, 6, 3955−3964. (b) Bhat, V.; Wang, S.;
Stoltz, B. M.; Virgil, S. C. Asymmetric Synthesis of QUINAP via
Dynamic Kinetic Resolution. J. Am. Chem. Soc. 2013, 135, 16829−
16832. (c) Han, S.; Bhat, V.; Stoltz, B. M.; Virgil, S. C.
Atroposelective Synthesis of PINAP via Dynamic Kinetic Asymmetric
Transformation. Adv. Synth. Catal. 2019, 361, 441−444.
̈
153−226. (b) Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H.
The Pictet−Spengler Reaction in Nature and in Organic Chemistry.
Angew. Chem., Int. Ed. 2011, 50, 8538−8564. (c) Kampen, D.;
Reisinger, C. M.; List, B. Chiral Bronsted acids for asymmetric
organocatalysis. Top. Curr. Chem. 2009, 291, 395−456.
(10) (a) Gao, Z.; Qian, J.; Yang, H.; Hang, X.-C.; Zhang, J.; Jiang, G.
Chiral Brønsted Acid-Catalyzed Dynamic Kinetic Resolution of
Atropisomeric ortho-Formyl Naphthamides. Chem. Commun. 2020,
56, 7265−7268. (b) Gao, Z.; Zhang, J.; Yang, H.; Jiang, G. Brønsted
Acid-Promoted Friedel-Crafts Alkylation/Cyclization of (7-Hydroxy-
naphthalenyl)pyrrole or (2-Hydroxyphenyl)pyrroles with Isatins for
the Construction of Pyrrolospirooxindole Derivatives. J. Org. Chem.
2018, 83, 11407−11414. (c) Wei, Z.; Zhang, J.; Yang, H.; Jiang, G.
Catalytic Asymmetric Cascade Cyclization for Constructing Three
Contiguous Stereocenters in Pyrrolobenzodiazepine-Based Cyclo-
pentanones. Org. Lett. 2019, 21, 2790−2794.
(11) (a) Trapp, O. A Novel Software Tool for High Throughput
Measurements of Interconversion Barriers: DCXplorer. J. Chromatogr.
B: Anal. Technol. Biomed. Life Sci. 2008, 875, 42−47. (b) Trapp, O.;
Schoetz, G.; Schurig, V. Determination of Enantiomerization Barriers
by Dynamic and Stopped-flow Chromatographic Methods. Chirality
2001, 13, 403−414. (c) D’Acquarica, I.; Gasparrini, F.; Pierini, M.;
Villani, C.; Zappia, G. Dynamic HPLC on Chiral Stationary Phases: A
Powerful Tool for the Investigation of Stereomutation Processes. J.
Sep. Sci. 2006, 29, 1508−1516. (d) Wolf, C. Dynamic Stereochemistry
of Chiral Compounds-Principles and Applications; RSC Publishing:
Cambridge, 2008.
(7) For nonoxidative chirality exchange methodologies, see:
(a) Hattori, T.; Date, M.; Sakurai, K.; Morohashi, N.; Kosugi, H.;
Miyano, S. Highly Stereospecific Conversion of C-centrochirality of a
3,4-Dihydro-2H-1,1′-binaphthalen-1-ol into Axial Chirality of a 3,4-
Dihydro-1,1′-binaphthalene. Tetrahedron Lett. 2001, 42, 8035−8038.
(b) Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. Chirality Exchange
from sp3 Central Chirality to Axial Chirality: Benzannulation of
Optically Active Diaryl-2,2-dichlorocyclopropylmethanols to Axially
Chiral α-Arylnaphthalenes. J. Am. Chem. Soc. 2004, 126, 5358−5359.
(c) Liu, Y.; Lu, K.; Dai, M.; Wang, K.; Wu, W.; Chen, J.; Quan, J.;
Yang, Z. An Efficient One-Pot Asymmetric Synthesis of Biaryl
Compounds via Diels−Alder/Retro-Diels−Alder Cascade Reactions.
Org. Lett. 2007, 9, 805−808. (d) 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. (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.
(12) (a) Goldman, I. M. Observation of a Large Isotope Effect in the
Manganese Dioxide Oxidation of Benzyl Alcohol. J. Org. Chem. 1969,
34, 3289−3295. (b) Lee, D. G. Structures and Reaction Mechanisms
of Manganese Oxidants. PATAI’S Chemistry of Functional Groups,
(8) (a) Berson, J. A.; Brown, E. Studies on Dihydropyridines. III. An
Absolute Asymmetric Synthesis and an Attempted Conversion of
Carbon Atom Asymmetry to Biphenyl Asymmetry. J. Am. Chem. Soc.
1186
https://dx.doi.org/10.1021/acs.orglett.0c03827
Org. Lett. 2021, 23, 1181−1187

Organic Letters
pubs.acs.org/OrgLett
Letter
2011. (c) Brown, M. K.; Blewett, M. M.; Colombe, J. R.; Corey, E. J.
Mechanism of the Enantioselective Oxidation of Racemic Secondary
Alcohols Catalyzed by Chiral Mn(III)-Salen Complexes. J. Am. Chem.
Soc. 2010, 132, 11165−11170.
hydroboration/oxidation, see: (q) Doucet, H.; Fernandez, E.; Layzell,
T. P.; Brown, J. M. The Scope of Catalytic Asymmetric Hydro-
boration/Oxidation with Rhodium Complexes of 1,1′-(2-Diary-
lphosphino-1-naphthyl)isoquinolines. Chem. - Eur. J. 1999, 5,
1320−1330. (r) Maeda, K.; Brown, J. M. Efficient kinetic resolution
in hydroboration of 1,2-dihydronaphthalenes. Chem. Commun. 2002,
310−311. (s) Black, A.; Brown, J. M.; Pichon, C. Regiochemical
control of the catalytic asymmetric hydroboration of 1,2-diarylalkenes.
Chem. Commun. 2005, 5284−5286. For hydroboration/amination,
see: (t) Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M.
Catalytic Asymmetric Hydroboration/Amination and Alkylamination
with Rhodium Complexes of 1,1′-(2-Diarylphosphino-1-naphthyl)-
isoquinoline. Chem. - Eur. J. 2000, 6, 1840−1846.
(13) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective
Michael Reaction of Malonates to Nitroolefins Catalyzed by
Bifunctional Organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672−
12673. (b) Chen, Z.-M.; Hilton, M. J.; Sigman, M. S. Palladium-
Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-
Disubstituted Homoallylic Alcohols. J. Am. Chem. Soc. 2016, 138,
11461−11464. (c) 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. (d) Yasumoto, K.; Kano, T.; Maruoka, K.
Synthesis of Electron-Deficient Chiral Biphenols and Their
Applications in Catalytic Asymmetric Reactions. J. Org. Chem. 2020,
85, 10232−10239.
(14) For 1,2-additions, see: (a) Koradin, C.; Polborn, K.; Knochel,
P. Enantioselective Synthesis of Propargylamines by Copper-
Catalyzed Addition of Alkynes to Enamines. Angew. Chem., Int. Ed.
2002, 41, 2535−2538. (b) Koradin, C.; Gommermann, N.; Polborn,
K.; Knochel, P. Synthesis of Enantiomerically Enriched Propargyl-
amines by Copper-Catalyzed Addition of Alkynes to Enamines. Chem.
- Eur. J. 2003, 9, 2797−2811. (c) Taylor, A. M.; Schreiber, S. L.
Enantioselective Addition of Terminal Alkynes to Isolated Isoquino-
line Iminiums. Org. Lett. 2006, 8, 143−146. (d) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Enantioselective, Copper(I)-
Catalyzed Three-Component Reaction for the Preparation of
Propargylamines. Angew. Chem., Int. Ed. 2003, 42, 5763−5766.
(e) Gommermann, N.; Knochel, P. Practical Highly Enantioselective
Synthesis of Propargylamines through a Copper-Catalyzed One-Pot
Three-Component Condensation Reaction. Chem. - Eur. J. 2006, 12,
4380−4392. (f) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M.
Highly Enantioselective Access to Primary Propargylamines: 4-
Piperidinone as a Convenient Protecting Group. Org. Lett. 2006, 8,
2437−2440. (g) Black, D.; Beveridge, A. R. E.; Arndtsen, B. A.
Copper-Catalyzed Coupling of Pyridines and Quinolines with
Alkynes: A One-Step, Asymmetric Route to Functionalized Hetero-
cycles. J. Org. Chem. 2008, 73, 1906−1910. (h) Ye, J.; Li, S.; Chen, B.;
Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao, B.; Wan, B.; Wang, Y.; Xie,
X.; Yu, Q.; Yuan, W.; Ma, S. Catalytic Asymmetric Synthesis of
Optically Active Allenes from Terminal Alkynes. Org. Lett. 2012, 14,
1346−1349. (i) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo,
H.; Miao, B.; Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S.
Enantioselective Double Manipulation of Tetrahydroisoquinolines
with Terminal Alkynes and Aldehydes under Copper(I) Catalysis.
Angew. Chem., Int. Ed. 2014, 53, 277−281. (j) Pappoppula, M.;
Cardoso, F. S. P.; Garrett, B. O.; Aponick, A. EnantioselectiveCopper-
Catalyzed Quinoline Alkynylation. Angew. Chem., Int. Ed. 2015, 54,
15202−15206; Angew. Chem. 2015, 127, 15417−15421. For
conjugate addition, see: (k) Rokade, B. V.; Guiry, P. J.
Enantioselective Catalytic Asymmetric A3 Coupling with Phosphi-
no-Imidazoline Ligands. J. Org. Chem. 2019, 84, 5763−5772.
(l) Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. Catalytic,
Enantioselective, Conjugate Alkyne Addition. J. Am. Chem. Soc. 2005,
127, 9682−9683. (m) Zarotti, P.; Knoepfel, T. F.; Aschwanden, P.;
Carreira, E. M. Nonlinear Effects with Diastereomeric Ligand
Mixtures in Enantioselective, Catalytic Additions of Terminal Alkynes
Involving Copper−PINAP Complexes. ACS Catal. 2012, 2, 1232−
1234. For cyclization reactions, see: (n) Chen, C.; Li, X.; Schreiber,
S. L. Catalytic Asymmetric [3 + 2] Cycloaddition of Azomethine
Ylides. Development of a Versatile Stepwise, Three-Component
Reaction for Diversity-Oriented Synthesis. J. Am. Chem. Soc. 2003,
125, 10174−10175. (o) Miura, T.; Yamauchi, M.; Kosaka, A.;
Murakami, M. Nickel-Catalyzed Regio- and Enantioselective
Annulation Reactions of 1,2,3,4-Benzothiatriazine-1,1(2H)-dioxides
with Allenes. Angew. Chem., Int. Ed. 2010, 49, 4955−4957. (p) Lim, A.
D.; Codelli, J. A.; Reisman, S. E. Catalytic asymmetric synthesis of
highly substituted pyrrolizidines. Chem. Sci. 2013, 4, 650−654. For
1187
https://dx.doi.org/10.1021/acs.orglett.0c03827
Org. Lett. 2021, 23, 1181−1187