Chiral Ugi-type amines: Practical synthesis, ligand development, and asymmetric catalysis

Article abstract of DOI:10.1021/acscatal.0c04077

Ugi's amine has become one type of privileged chiral skeleton for chiral ligand design bearing central/planar chirality, and such ligands have exhibited tremendous success in various asymmetric catalysis. However, the current access to enantiopure Ugi's amine is quite tedious and relies heavily on optical resolution, which impedes its practical applications, to some extent. Herein, we present a facile asymmetric synthesis of enantioenriched Ugi-type amines bearing a long-carbon chain through Ir-catalyzed cascade allylation/2-aza-Cope rearrangement, followed by amino exchange and Pd/C-catalyzed one-pot hydrogenation/reductive amination. The protocol could be readily scaled up, and it has been conducted in 20-g-scale asymmetric synthesis of (S)-Ugi-type amine from commercially available reagents, in >99% ee and >70% overall yield in four steps with one short silica gel-plug purification. (S,R_p)-PPFA-type and (S,R_p)-Josiphos-type ligands, readily prepared from the achieved Ugi-type amine, exhibited higher or comparable asymmetric induction and catalytic efficacy in several Cu(I)-catalyzed asymmetric reactions, which indicated great potential of the applications of the readily accessible Ugi-type amines in ligand/catalyst design.

Full text of DOI:10.1021/acscatal.0c04077

pubs.acs.org/acscatalysis
Letter
Chiral Ugi-Type Amines: Practical Synthesis, Ligand Development,
and Asymmetric Catalysis
Wu-Wei Dong, Yi-Nan Li, Xin Chang, Chong Shen, and Chun-Jiang Wang*
Cite This: ACS Catal. 2020, 10, 12954−12959
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Ugi’s amine has become one type of privileged
chiral skeleton for chiral ligand design bearing central/planar
chirality, and such ligands have exhibited tremendous success in
various asymmetric catalysis. However, the current access to
enantiopure Ugi’s amine is quite tedious and relies heavily on
optical resolution, which impedes its practical applications, to some
extent. Herein, we present a facile asymmetric synthesis of
enantioenriched Ugi-type amines bearing a long-carbon chain
through Ir-catalyzed cascade allylation/2-aza-Cope rearrangement,
followed by amino exchange and Pd/C-catalyzed one-pot hydro-
genation/reductive amination. The protocol could be readily scaled
up, and it has been conducted in 20-g-scale asymmetric synthesis of (S)-Ugi-type amine from commercially available reagents, in
>99% ee and >70% overall yield in four steps with one short silica gel-plug purification. (S,Rp)-PPFA-type and (S,Rp)-Josiphos-type
ligands, readily prepared from the achieved Ugi-type amine, exhibited higher or comparable asymmetric induction and catalytic
efficacy in several Cu(I)-catalyzed asymmetric reactions, which indicated great potential of the applications of the readily accessible
Ugi-type amines in ligand/catalyst design.
KEYWORDS: asymmetric synthesis, ligand design, chiral amine, planar chirality, central chirality
Despite the significance of Ugi’s amine in ligand design, the
he development of efficient chiral ligands derived from
Tprivileged chiral structures incorporating central, axial, modulation of such a skeleton is extremely challenging and the
current available methods to access enantioenriched Ugi’s
amine are still rather limited. The classical method to chiral
Ugi’s amine relies heavily on the optical resolution of racemic
Ugi’s amine using a stoichiometric amount of resolving agents,
as shown in Scheme 2a,2 and only a few attempts have been
documented on this type of framework by the catalytic
asymmetric preparation of enantioenriched 1-ferrocenyl
alcohols, followed by acetylation with acetic anhydride and
amination with dimethylamine (Scheme 2b).12,13 The catalytic
asymmetric construction of Ugi-type amines remained a
formidable task and is highly desirable from the viewpoint of
synthetic practicability. Previously, We and others have
reported transition-metal-catalyzed asymmetric cascade allyla-
tions/2-aza-Cope rearrangement of aldimines to deliver chiral
homoallylic amines.14,15 We envisioned that the strategy of
chirality transfer might also work for ferrocenecarboxaldehyde-
derived imine and therefore allow for a direct and catalytic
and/or planar chirality are significantly important in transition-
metal-catalyzed asymmetric synthesis.1 As an example, N,N-
dimethyl-1-ferrocenylethylamine (Ugi’s amine)2 represents
one type of the privileged chiral skeleton, which could readily
induce additional planar chirality from its intrinsic central
chirality.3 Since the seminal pioneering contribution of Ugi and
co-workers on the C2 functionalization of enantiopure Ugi’s
amine via diastereoselective ortho-lithiation2 and further
unique stereospecific SN1-type substitution reaction of the
dimethylamino moiety with configuration retention (Scheme
1),4 a variety of chiral ligands, such as PPFA,5 TRAP,6
Josiphos,7 Walphos,8 Bophos,9 Zhaophos,10 Wudaphos,11 etc.,
have been developed and exhibited tremendous success and
efficacy in broad types of transition-metal-catalyzed asym-
metric transformations.
Scheme 1. Ugi’s Amine, Diastereoselective ortho-Lithiation,
and Selected Ugi’s Amine-Based Chiral Ligands
Received: September 17, 2020
Revised: October 21, 2020
https://dx.doi.org/10.1021/acscatal.0c04077
© XXXX American Chemical Society
ACS Catal. 2020, 10, 12954−12959
12954

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Scheme 2. Reported Approaches to Enantioenriched Ugi’s
Amine Derivatives and This Design
Scheme 3. Initial Study on the Synthesis of Chiral Long-
Chained Ugi-Type Amine Derivative
asymmetric approach toward primary Ugi-type amines
(Scheme 2c). The long-chained Ugi-type amines are expected
to induce better planar stereochemical control in diaster-
eoselective ortho-lithiation, considering that the diastereose-
lectivity in the case of Ugi’s amine arises from a strong
repulsive interaction between the methyl group at the central
stereocenter and the lower Cp ring.2 However, one
conspicuous challenge had to be met for the successful
realization of this design: would the cascade protocol also
provide the stereointegrity for both the initial allylation and the
ensuing rearrangement, with respect to the aldimine emanated
from the sterically bulky three-dimensional aldehyde? Herein,
we illustrate that a scalable catalytic asymmetric synthesis of
enantioenriched long-chained Ugi-type amines, the develop-
ment of chiral ligands with this new skeleton and preliminary
applications in enantioselective catalysis.
Scheme 4. Practical Preparation of Enantioenriched Long-
Chained Ugi-Type Amine (S)-15 and (S)-16
The aldimine substrates 8 and 11 were readily prepared in
quantitative yield by simple condensation of ferrocenecarbox-
aldehyde with methyl l-leucinate hydrochloride and 9-amino-
fluorene hydrochloride, respectively (for details, see the
Supporting Information). Since the bimetallic Cu/Ir14a and
monometallic Ir catalysts15a16 have been discovered partic-
ularly effective for chiral homoallylic amine synthesis, we
initially surveyed these two catalytic systems for the designed
cascade allylation/2-aza-Cope rearrangement of 8 and 11,
respectively (see Scheme 3). The desired rearranged products
10 and 12a were respectively obtained in high yield with
excellent enantioselectivity under each optimal reaction
conditions, which demonstrates that the sterically bulky
three-dimensional ferrocene moiety does not deteriorate the
efficacy and stereointegrity of this cascade transformation.
Although the cost-efficiency favors a bimetallic system, because
of the much less expensive starting material methyl l-leucinate
hydrochloride,17 monometallic catalytic system turned out to
be the better one given that the solid product 12a is easier to
be handled for the scale-up synthesis (vide infra) (For the
experimental results with other allylic carbonates, see the
Supporting Information for details.)
aforementioned Ir-catalyzed cascade allylation/2-aza-Cope
rearrangement of N-fluorenyl imine 11 at 100 mmol scale,
the rearranged product (S)-12 could be purified via
recrystallization and obtained in 90% yield with >99% ee.
Subsequent amino exchange with HONH2·HOAc released
primary amine (S)-15 in quantitative yield14a without erosion
of enantioselectivity through a short plug of silica gel
purification. Meanwhile, 9-fluorenone oxime, isolated in
quantitively yield, could be directly hydrogenated back to 9-
aminofluorene in 90% yield. The target long-chained Ugi-type
amine (S)-16 was readily obtained as a brown crystalline solid,
which is an unexpected bonus for further manipulation, compared
to the oil Ugi’s amine, in 85% yield from (S)-15 via Pd/C-
catalyzed one-pot hydrogenation/reductive amination. Note
that the entire four-step synthetic sequence was efficiently
accomplished on a 20-g scale with only one short silica gel plug
purification, and the key intermediate (S)-12 could be readily
achieved through simple crystallization. The absolute config-
Encouraged by these experimental results, tens-gram-scale
synthesis of enantioenriched long-chained Ugi-type amine 16
was conducted (see Scheme 4). Ferrocenecarboxaldehyde-
derived N-fluorenyl imine 11 could be easily obtained in
quantitatively yield through simple condensation of commer-
cially available ferrocenecarboxaldehyde 13 and 9-amino-
fluorene hydrochloride 14 under basic conditions. Through
12955
https://dx.doi.org/10.1021/acscatal.0c04077
ACS Catal. 2020, 10, 12954−12959

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
uration of (S)-16 was determined by X-ray diffraction (XRD)
analysis of (S)-16·BH3 complex.18
Having established the readily scalable synthetic route to
access enantioenriched long-chained Ugi-type amine (S)-16,
we next prepared some chiral ligands with this novel chiral
skeleton and examined their performance in transition-metal-
catalyzed asymmetric transformations. As shown in Scheme 5,
Scheme 6. Comparative Studies of (S,Rp)-PPFA and (S,Rp)-
17b in Cu(I)-Catalyzed 1,3-Dipolar Cycloaddition
Reactions of Azomethine Ylides
Scheme 5. Synthesis of Chiral PPFA-Type and Josiphos-
Type Ligands
treatment of (S)-16 with n-BuLi at room temperature via
direct diastereoselective ortho-lithiation followed by trapping
with PR2Cl, led to easy access to PPFA-type ligands (S,Rp)-17a
and (S,Rp)-17b in high yield with impressive diastereoselec-
tivity (>50:1 diasteromeric ratio (dr), based on the crude 31P
NMR), which is ascribed to the long carbon chain on the
stereogenic center.2 Subsequent stereospecific SN1-type
reaction of the dimethylamino moiety with PR′2H reagent,
which occurred with full retention of configuration, furnished
Josiphos-type chiral bisphosphine ligands (S,Rp)-L3−L6 in
satisfactory yields.
PPFA-type ligands (S,Rp)-17 were used for the direct
comparison of their catalytic performances with the original
PPFA ligand in transition-metal-catalyzed asymmetric reaction.
We conducted a comparative ligand evaluation in kinetic
resolution of the racemic convex ( )-endo-3-oxodicyclo-
pentadiene and ( )-endo-3-oxodicyclopentadiene via Cu(I)-
catalyzed 1,3-dipolar cycloaddition, and (S,Rp)-PPFA was
originally revealed as the superior chiral ligand in effecting
such asymmetric transformations.19 The newly developed
(S,Rp)-17b was also found equally potent in this Cu(I)-
catalyzed kinetic resolution protocol with racemic ( )-endo-3-
oxodicyclopentadiene 18 as the dipolarophile, affording the
recovered (−)-endo-18 in 46% yield with 97% enantiomeric
excess (ee), accompanied by the cycloadduct endoendo-20 in
49% yield with exclusive diastereoselectivity and 97% ee (S =
278) (Scheme 6a). Although (S,Rp)-PPFA was also identified
as the best ligand for the kinetic resolution of racemic ( )-exo-
3-oxodicyclo-pentadienes, racemic ( )-2-phenyl-substituted
exo-3-oxo-dicyclopentadiene 21 was revealed as a challenging
molecule and was only resolved with S factor of 28 (45% yield
and 82% ee for endoexo-22; 42% yield and 86% ee for exo-
(−)-21) through this protocol in previous work. Pleasingly,
employing (S,Rp)-17b as the chiral ligand under otherwise
identical reaction conditions, ( )-exo-21 could be efficiently
resolved with the significantly enhanced S factor (52),
delivering a 47% yield of recovered exo-(−)-21 with 99% ee,
accompanied by a 48% yield of cycloadduct endoexo-22 with
82% ee (Scheme 6b), which is obviously better than that
obtained with the corresponding (S,Rp)-PPFA.19
enantioselective ligands for Cu(I)-catalyzed asymmetric
Michael addition of Grignard reagents to α,β-unsaturated
esters for the synthesis of enantioenriched β-substituted
esters.21 Given these facts, we begin by evaluating Josiphos-
type ligands (S,Rp)-L3−L6 in the model addition reaction of
ethyl magnesium bromide 24a to methyl (E)-5-pheynlpent-2-
enoate 23a. After a thorough optimization (see the Supporting
Information for details), ligand (S,Rp)-L3 was revealed as the
best choice, in terms of reactivity and enantioselectivity with
Cu(CH3CN)4BF4 as the metal source and dichloromethane as
the solvent, and the reaction proceed smoothly, affording the
desired product 25a in 93% yield with 92% ee (Table 1, entry
1). Under the optimized reaction conditions, we further
investigated the generality of substrate scope of Grignard
reagents and α,β-unsaturated esters. As shown in Table 1, a
series of linear alkyl Grignard reagents were well-tolerated in
this Cu(I)/(S,Rp)-L3-catalyzed asymmetric Michael addition
to methyl (E)-5-pheynlpent-2-enoate 23a, affording the
corresponding adducts 25b−25e in high yields with excellent
enantioselectivity (Table 1, entries 2−5). With MeMgBr as the
nucleophile, consistent with previous reports,21 the corre-
sponding adduct 25f could be obtained in high enantiose-
lectivity albeit with moderate yield (Table 1, entry 6). Grignard
reagent 24g containing the CC bond was also a viable
nucleophile, providing the corresponding product 25g in 94%
yield with 97% ee (Table 1, entry 7). Next, the scope
Cu-catalyzed asymmetric Michael addition of organometallic
reagents to α,β-unsaturated compounds has been extensively
investigated over the past decades.20 (R,Sp)-Josiphos and (R)-
Tol-BINAP have been demonstrated to be the highly
12956
https://dx.doi.org/10.1021/acscatal.0c04077
ACS Catal. 2020, 10, 12954−12959

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
great potential of the newly developed Ugi-type amines in
ligand/catalyst design. Further investigation on mechanistic
origin of the high enantioselectivity control and efficacy of Ugi-
type amine-based ligands, as well as development of other kind
of ligands/catalysts, are underway in our laboratory.
Table 1. Scope of Cu(I)-Catalyzed Asymmetric Michael
Addition of Grignard Reagents to α,β-Unsaturated Esters
a
b
yield
(%)
enantiomeric
c
ASSOCIATED CONTENT
entry
R
R′
25
excess, ee (%)
■
1
2
3
4
5
PhCH2CH2 Et
PhCH2CH2 nPr
PhCH2CH2 nBu
PhCH2CH2 nPentyl
PhCH2CH2 nHeptyl
PhCH2CH2 Me
25a
25b
25c
25d
25e
25f
93
89
88
84
93
45
94
92
94
97
97
97
91
97
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04077.
Experimental procedures and characterization data for
all reactions and products, including H and 13C NMR
1
d
6
spectra, HPLC spectra, ( PDF)
7
PhCH2CH2 CH2
25g
CH(CH2)2
Crystallographic data for (S)-16·BH3 (CIF)
8
9
10
Me
n-Pr
n-Pr
Et
25h
25i
25j
25k
25l
25m
25n
25o
25p
25q
25r
97
88
81
85
77
86
87
94
96
74
84
91
94
91
95
91
98
95
91
92
97
96
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
e
AUTHOR INFORMATION
■
11
12
n-hexyl
n-hexyl
i-Pr
e
Corresponding Author
Chun-Jiang Wang − Engineering Research Center of
Organosilicon Compounds & Materials, Ministry of Education,
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China; State Key Laboratory of Elemento-
organic Chemistry, Nankai University, Tianjin 300071, China;
Email: cjwang@whu.edu.cn
13
e
14
f
Cy
Ph
15
16
17
18
PhCH2
2-furyl
2-thienyl
a
All reactions were performed with 0.30 mmol 23 and 1.5 mmol 24
Authors
b
(1.0 M in tBuOMe) in 1.5 mL of CH2Cl2 within 8−12 h. Yields refer
to the isolated products after chromatographic purification. The ee
value was determined by chiral HPLC or GC analysis. Reaction was
performed at −40 °C. Ethyl ester was used. CuBr·SMe2 was used.
c
Wu-Wei Dong − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University, Wuhan
430072, China
d
e
f
Yi-Nan Li − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University, Wuhan
430072, China
Xin Chang − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University, Wuhan
430072, China
Chong Shen − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University, Wuhan
430072, China
generality, with respect to α,β-unsaturated esters, was further
investigated, and an array of variety of α,β-unsaturated esters
bearing linear or branched alkyl group, aryl or heteroaryl
groups, all reacted smoothly with EtMgBr, affording the
corresponding adducts in 74%−97% yields with 91%−98% ee
(Table 1, entries 8−18). Those achieved comparative
experimental results of Cu(I)/(S,Rp)-L17b-catalyzed 1,3-
dipolar cycloaddition reactions and Cu(I)/(S,Rp)-L3-catalyzed
Michael addition of Grignard reagents showcased great
potential of the long-chained Ugi-type amines in asymmetric
catalysis.
In summary, a practical catalytic asymmetric synthesis of
Ugi-type amine has been successfully developed. Ir-catalyzed
asymmetric cascade allylation/2-aza-Cope rearrangement of
ferrocenecarboxaldehyde-derived N-fluorenyl imine, followed
by amino exchange and Pd/C-catalyzed one-pot hydro-
genation/reductive amination, led to chiral Ugi-type amine
bearing long-carbon chain in excellent enantioselectivity
(>99% ee). The current protocol represents the first method
to access Ugi-type amine in catalytic asymmetric manner,
featuring with readily available reagents, easy manipulation and
scale-up to tens of grams, which pave the way for the practical
utility of this privileged scaffold in asymmetric catalysis. PPFA-
type and Josiphos-type chiral ligands bearing both central
chirality and planar chirality were expediently prepared
through C2 functionalization via a highly efficient diaster-
eoselective ortho-lithiation and the ensuing stereospecific
substitution. More importantly, the long-chained Ugi-type
amine-based chiral ligands exhibited higher or comparable
asymmetric induction and catalytic efficacy in several
transition-metal-catalyzed asymmetric reactions, indicating
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04077
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21525207, 21772147, and
220711186), and Huibei Province NSF (No. 2020CFA036).
The Program of Introducing Talents of Discipline to
Universities of China (111 Project) is also appreciated. We
thank Prof. Yan Zhou at Guangxi University for Nationalities
for solving the crystal structure of (S)-16·BH3 complex.
DEDICATION
■
Dedicated to Professor Xumu Zhang on the occasion of his
60th birthday.
12957
https://dx.doi.org/10.1021/acscatal.0c04077
ACS Catal. 2020, 10, 12954−12959

ACS Catalysis
REFERENCES
pubs.acs.org/acscatalysis
Letter
6669−6673. (b) Chen, C.; Wen, S.; Dong, X.-Q.; Zhang, X. Highly
Stereoselective Synthesis and Application of P-Chiral Ferrocenyl
Bisphosphorus Ligands for Asymmetric Hydrogenation. Org. Chem.
Front. 2017, 4, 2034−2038.
(12) (a) Ohno, A.; Yamane, M.; Hayashi, T.; Oguni, N.; Hayashi, M.
Preparation and Use of Chiral Ferrocenylphosphines Containing New
Alkyl Substituents on the Ferrocenylmethyl Position. Tetrahedron:
Asymmetry 1995, 6, 2495−2502. (b) Tappe, K.; Knochel, P. New
Efficient Synthesis of Taniaphos Ligands: Application in Ruthenium-
and Rhodium-Catalyzed Enantioselective Hydrogenations. Tetrahe-
dron: Asymmetry 2004, 15, 91−102. (c) Matsumoto, Y.; Ohno, A.; Lu,
S.-J.; Hayashi, T.; Oguni, N.; Hayashi, M. Enantioselective Synthesis
of 1-Metallocenylalkanols by Catalytic Asymmetric Alkylation of
Metallocenecarboxaldehydes with Dialkylzincs. Tetrahedron: Asymme-
■
(1) (a) Ding, K. Asymmetric Catalysis and Synthesis:An Exciting
Field with Challenges. Acta Chim. Sinica 2014, 72, 755−756.
(b) Noyori, R. Asymmetric Catalysis: Science and Opportunities.
Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (c) Tang, W.; Zhang, X.
New Chiral Phosphorus Ligands for Enantioselective Hydrogenation.
Chem. Rev. 2003, 103, 3029−3069. (d) Privileged Chiral Ligands and
Catalysts; Zhou, Q.-L., Ed.; Wiley−VCH: Weinheim, Germany, 2011.
(e) Yoon, T.; Jacobsen, E. N. Privileged Chiral Catalysts. Science
2003, 299, 1691−1693. (f) Walsh, P. J.; Kozlowski, M. C.
Fundamentals of Asymmetric Catalysis; University Science Books:
Sausalito, CA, 2008.
(2) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.
Stereoselective Syntheses. VI. Correlation of Central and Planar
Chirality in Ferrocene Derivatives. J. Am. Chem. Soc. 1970, 92, 5389−
5393.
(3) (a) Hayashi, T. In Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH:
Weinheim, Germany, 1995; pp 105−142. (b) Richards, C. F.; Locke,
A. J. Recent Advances in the Generation of non-Racemic Ferrocene
Derivatives and Their Application to Asymmetric Synthesis.
Tetrahedron: Asymmetry 1998, 9, 2377−2407. (c) Colacot, T. J. A
Concise Update on the Applications of Chiral Ferrocenyl Phosphines
in Homogeneous Catalysis Leading to Organic Synthesis. Chem. Rev.
̈
try 1993, 4, 1763−1766. (d) Cotton, H. K.; Norinder, J.; Backvall, J.-
E . S c r e e n i n g o f L i g a n d s i n t h e A s y m m e t r i c
Metallocenethiolatocopper(I)-Catalyzed Allylic Substitution with
Grignard Reagents. Tetrahedron 2006, 62, 5632−5640.
(13) (a) Gao, D.-W.; Gu, Q.; Zheng, C.; You, S.-L. Synthesis of
Planar Chiral Ferrocenes via Transition-Metal-Catalyzed Direct C−H
Bond Functionalization. Acc. Chem. Res. 2017, 50, 351−365. (b) Liu,
C.-X.; Gu, Q.; You, S.-L. Asymmetric C−H Bond Functionalization of
Ferrocenes: New Opportunities and Challenges. Trends Chem. 2020,
2, 737−749. (c) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-
L. Enantioselective Synthesis of Planar Chiral Ferrocenes via
Palladium-Catalyzed Direct Coupling with Arylboronic Acids. J. Am.
Chem. Soc. 2013, 135, 86−89. (d) Pi, C.; Li, Y.; Cui, X.; Zhang, H.;
Han, Y.; Wu, Y. Redox of Ferrocene Controlled Asymmetric
Dehydrogenative Heck Reaction via Palladium-Catalyzed Dual C−
H Bond Activation. Chem. Sci. 2013, 4, 2675−2679. (e) Gao, D.-W.;
Yin, Q.; Gu, Q.; You, S.-L. Enantioselective Synthesis of Planar Chiral
Ferrocenes via Pd(0)-Catalyzed Intramolecular Direct C−H Bond
Arylation. J. Am. Chem. Soc. 2014, 136, 4841−4844. (f) Deng, R.;
Huang, Y.; Ma, X.; Li, G.; Zhu, R.; Wang, B.; Kang, Y.-B.; Gu, Z.
Palladium-Catalyzed Intramolecular Asymmetric C−H Functionaliza-
tion/Cyclization Reaction of Metallocenes: An Efficient Approach
toward the Synthesis of Planar Chiral Metallocene Compounds. J. Am.
Chem. Soc. 2014, 136, 4472−4475. (g) Gao, D.-W.; Gu, Q.; You, S.-L.
An Enantioselective Oxidative C−H/C−H Cross-Coupling Reaction:
Highly Efficient Method to Prepare Planar Chiral Ferrocenes. J. Am.
Chem. Soc. 2016, 138, 2544−2547. (h) Cai, Z.-J.; Liu, C.-X.; Wang,
Q.; Gu, Q.; You, S.-L. ThioKetone-Directed Rhodium(I) Catalyzed
Enantioselective C−H Bond Arylation of Ferrocenes. Nat. Commun.
2019, 10, 4168−4175. (I) Liu, C.-X.; Cai, Z.-J.; Wang, Q.; Wu, Z.-J.;
Gu, Q.; You, S.-L. Rhodium-Catalyzed Pyridine-Assisted C−H
Arylation for the Synthesis of Planar Chiral Ferrocenes. CCS Chem.
2020, 2, 642−651.
́
2003, 103, 3101−3118. (d) Gomez Arrayas, R.; Adrio, J.; Carretero, J.
C. Recent Applications of Chiral Ferrocene Ligands in Asymmetric
Catalysis. Angew. Chem., Int. Ed. 2006, 45, 7674−7715. (e) Chiral
Ferrocenes in Asymmetric Catalysis; Dai, L.-X., Hou, X.-L., Eds.; VCH:
Weinheim, Germany, 2010.
(4) Gokel, G.; Marquarding, D.; Ugi, I. Stereoselective Syntheses.
VIII. Retentive Nucleophilic Displacements of α-Substituted
Alkylferrocenes. J. Org. Chem. 1972, 37, 3052−3058.
(5) (a) Hayashi, T.; Yamamoto, K.; Kumada, M. Asymmetric
Catalytic Hydrosilylation of Ketones Preparation of Chiral Ferroce-
nylphosphines as Chiral Ligands. Tetrahedron Lett. 1974, 15, 4405−
4408. (b) Hayashi, T.; Mise, T.; Mitachi, S.; Yamamoto, K.; Kumada,
M. Asymmetric Hydrogenation Catalyzed by a Chiral Ferrocenyl-
phosphine-Rhodium Complex. Tetrahedron Lett. 1976, 17, 1133−
1134.
(6) (a) Sawamura, M.; Hamashima, H.; Ito, Y. A Trans-Chelating
Chiral Diphosphine Ligand: Synthesis of 2,2″-Bis[1-
(diphenylphosphino)ethyl]-1,1″-Biferrocene and its Complexes with
Platinum(II) and Palladium(II). Tetrahedron: Asymmetry 1991, 2,
593−596. (b) Sawamura, M.; Hamashima, H.; Sugawara, M.;
Kuwano, R.; Ito, Y. Synthesis and Structures of Trans-Chelating
Chiral Diphosphine Ligands Bearing Aromatic P-Substituents, (S,S)-
(R,R)- and (R,R)-(S,S)-2,2”-Bis[1-(diarylphosphino)ethyl]-1,1”-Bifer-
rocene (ArylTRAPs) and Their Transition Metal Complexes.
Organometallics 1995, 14, 4549−4558.
(7) (a) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert,
H.; Tijani, A. A Novel Easily Accessible Chiral Ferrocenyldiphosphine
for Highly Enantioselective Hydrogenation, Allylic Alkylation, and
Hydroboration Reactions. J. Am. Chem. Soc. 1994, 116, 4062−4066.
(b) Blaser, H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.;
Togni, A. Solvias Josiphos Ligands: From Discovery to Technical
Applications. Top. Catal. 2002, 19, 3−16.
(8) Sturm, T.; Weissensteiner, W.; Spindler, F. A Novel Class of
Ferrocenyl-Aryl-Based Diphosphine Ligands for Rh- and Ru-
Catalysed Enantioselective Hydrogenation. Adv. Synth. Catal. 2003,
345, 160−164.
(9) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Phosphinoferrocenylaminophosphines as Novel and Practical Ligands
for Asymmetric Catalysis. Org. Lett. 2002, 4, 2421−2424.
(10) Zhao, Q.; Li, S.; Huang, K.; Wang, R.; Zhang, X. A Novel
Chiral Bisphosphine-Thiourea Ligand for Asymmetric Hydrogenation
of β, β-Disubstituted Nitroalkenes. Org. Lett. 2013, 15, 4014−4017.
(11) (a) Chen, C.; Wang, H.; Zhang, Z.; Jin, S.; Wen, S.; Ji, J.;
Chung, L. W.; Dong, X.-Q.; Zhang, X. Ferrocenyl Chiral Bi-
sphosphorus Ligands for Highly Enantioselective Asymmetric Hydro-
genation via Noncovalent Ion Pair Interaction. Chem. Sci. 2016, 7,
(14) (a) Wei, L.; Zhu, Q.; Xiao, L.; Tao, H.-Y.; Wang, C.-J.
Synergistic Catalysis for Cascade Allylation and 2-Aza-Cope
Rearrangement of Azomethine Ylides. Nat. Commun. 2019, 10,
1594−1605. (b) Shi, L.-M.; Sun, X.-S.; Shen, C.; Wang, Z.-F.; Tao,
H.-Y.; Wang, C.-J. Catalytic Asymmetric Synthesis of α-Trifluor-
omethyl Homoallylic Amines via Umpolung Allylation/2-Aza-Cope
Rearrangement: Stereoselectivity and Mechanistic Insight. Org. Lett.
2019, 21, 4842−4848. (c) Shen, C.; Wang, R.-Q.; Wei, L.; Wang, Z.-
F.; Tao, H.-Y.; Wang, C.-J. Catalytic Asymmetric Umpolung
Allylation/2-Aza-Cope Rearrangement for the Construction of α-
Tetrasubstituted α-Trifluoromethyl Homoallylic Amines. Org. Lett.
2019, 21, 6940−6945. (d) Wei, L.; Xiao, L.; Wang, Z.-F.; Tao, H.-Y.;
Wang, C.-J. Ir/PTC Cooperatively Catalyzed Asymmetric Cascade
Allylation/2-aza-Cope Rearrangement: An Efficient Route to
Homoallylic Amines from Aldimine Esters. Chin. J. Chem. 2020, 38,
82−86. (e) Sun, X.-S.; Ou-Yang, Q.; Xu, S.-M.; Wang, X.-H.; Tao, H.-
Y.; Chung, L. H.; Wang, C.-J. Asymmetric Synthesis of Quaternary α-
Trifluoromethyl α-Amino Acids by Ir-Catalyzed Allylation Followed
by Kinetic Resolution. Chem. Commun. 2020, 56, 3333−3336.
(f) Wang, R.-Q.; Shen, C.; Cheng, X.; Wang, Z.-F.; Tao, H.-Y.;
Dong, X.-Q.; Wang, C.-J. Sequential Ir-Catalyzed Allylation/2-Aza-
Cope Rearrangement Strategy for the Construction of Chiral
12958
https://dx.doi.org/10.1021/acscatal.0c04077
ACS Catal. 2020, 10, 12954−12959

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Homoallylic Amines. Chin. J. Chem. 2020, 38, 807−811. (g) Sun, X.-
S.; Wang, W.-H.; Tao, H.-Y.; Wei, L.; Wang, C.-J. Catalytic
Asymmetric Synthesis of Quaternary Trifluoromethyl α- to ε-Amino
Acid Derivatives via Umpolung Allylation/2-aza-Cope Rearrange-
ment. Chem. Sci. 2020, 11, 10984−10990.
(15) (a) Liu, J.; Cao, C.-G.; Sun, H.-B.; Zhang, X.; Niu, D. Catalytic
Asymmetric Umpolung Allylation of Imines. J. Am. Chem. Soc. 2016,
138, 13103−13106. (b) Wang, Y.; Deng, L.-F.; Zhang, X.; Niu, D.
Catalytic Asymmetric Synthesis of α-Tetrasubstituted α-Trifluoro-
methyl Homoallylic Amines by Ir-Catalyzed Umpolung Allylation of
Imines. Org. Lett. 2019, 21, 6951−6956. (c) Cao, C.-G.; He, B.; Fu,
Z.; Niu, D. Synthesis of β3-Amino Esters by Iridium-Catalyzed
Asymmetric Allylic Alkylation Reaction. Org. Process Res. Dev. 2019,
23, 1758−1761. (d) Zhuo, C.-X.; Furstner, A. J. Catalysis-Based Total
̈
Syntheses of Pateamine A and DMDA-Pat A. J. Am. Chem. Soc. 2018,
140, 10514−10523. (e) Bai, X.-D.; Zhang, Q.-F.; He, Y.
Enantioselective Iridium Catalyzed α-Alkylation of Azlactones by a
Tandem Asymmetric Allylic Alkylation/Aza-Cope Rearrangement.
Chem. Commun. 2019, 55, 5547−5550.
(16) For a recent excellent and comprehensive review on Ir-
catalyzed asymmetric allylic substitution reactions, see: Cheng, Q.;
Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Chem. Rev.
2019, 119, 1855−1969.
(17) Methyl l-leucinate hydrochloride (CAS No. 7517-19-3):
$56.50/25 g (Sigma−Aldrich, USA); 129 CNY/100 g (Energy
Chemical, China); 9-aminofluorene hydrochloride (CAS No. 5978-
75-6): $71.00/5 g (Sigma−Aldrich, USA); 3335 CNY/100 g (Energy
Chemical, China).
(18) The supplementary X-ray crystallographic data for (S)-16·BH3
(CCDC 2017755) can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(19) Chang, X.; Sun, X.-S.; Che, C.; Hu, Y.-Z.; Tao, H.-Y.; Wang, C.-
J. Copper(I)-Catalyzed Kinetic Resolution of exo-3-Oxodicyclopenta-
dienes and endo-3-Oxodicyclopentadiene. Org. Lett. 2019, 21, 1191−
1196.
(20) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Catalytic Asymmetric Conjugate Addition and Allylic
Alkylation with Grignard Reagents. Chem. Rev. 2008, 108, 2824−
2852.
(21) (a) Lopez, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A.
J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752−2756.
(b) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. Cu(I) Tol-BINAP-Catalyzed
Enantioselective Michael Reactions of Grignard Reagents and
Unsaturated Esters. J. Am. Chem. Soc. 2007, 129, 276−277.
12959
https://dx.doi.org/10.1021/acscatal.0c04077
ACS Catal. 2020, 10, 12954−12959