Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to N-Unprotected Ketimines: Efficient Synthesis of Cipargamin

Article abstract of DOI:10.1002/anie.201910008

Highly enantioselective rhodium-catalyzed addition of arylboroxines to N-unprotected ketimines is realized for the first time by employing chiral BIBOP-type ligands with a Rh loading as low as 1 mol %. A range of chiral α-trifluoromethyl-α,α-diaryl α-tertiary amines or 3-amino-3-aryloxindoles were formed with excellent ee values and yields by employing either WingPhos or PFBO-BIBOP as the ligand. The method has enabled an efficient enantioselective synthesis of cipargamin.

Full text of DOI:10.1002/anie.201910008

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201910008
German Edition: DOI: 10.1002/ange.201910008
Asymmetric Catalysis
Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to N-
Unprotected Ketimines: Efficient Synthesis of Cipargamin
Jinbin Zhu, Linwei Huang, Wei Dong, Naikai Li, Xingxin Yu, Wei-Ping Deng,* and
Wenjun Tang*
Abstract: Highly enantioselective rhodium-catalyzed addition
of arylboroxines to N-unprotected ketimines is realized for the
first time by employing chiral BIBOP-type ligands with a Rh
loading as low as 1 mol%. A range of chiral a-trifluoromethyl-
a,a-diaryl a-tertiary amines or 3-amino-3-aryloxindoles were
formed with excellent ee values and yields by employing either
WingPhos or PFBO-BIBOP as the ligand. The method has
enabled an efficient enantioselective synthesis of cipargamin.
E
nantioselective transition metal catalyzed addition of
arylboron compounds to N-protected ketimines has become
an effective method for the synthesis of chiral a-tertiary
amines.[1,2] In the presence of a chiral Rh,[3] Pd,[4] or Ni[5]
catalyst, a variety of chiral cyclic/noncyclic N-protected a-
tertiary amines can be prepared in excellent yields and
enantioselectivities (Figure 1). However, one significant
drawback with current known approaches is the requirement
of N-protected ketimines as the substrates. In many cases, N-
sulphonyl or N-carbonyl ketimines were employed, but they
are not ideally atom-economical and cost-effective. More-
over, deprotection of the N-sulphonyl or N-carbonyl amine
products often required harsh reaction conditions, therefore
limiting the practicality and applicability of such methods. It is
attractive to develop enantioselective addition of aryl boron
compounds to N-unprotected ketimines for the direct syn-
thesis of chiral a-tertiary amines. Such an approach is not only
protection/deprotection-free, but also more practical and
cost-effective. Herein we report for the first time a highly
enantioselective rhodium-catalyzed addition of arylboroxines
to two series of N-unprotected ketimines, directly forming a-
tertiary amines with excellent yields and ee values. The
method has enabled an efficient enanatioselective synthesis
of the antimalarial agent cipargamin.
Figure 1. Enantioselective rhodium-catalyzed arylation of N-unpro-
tected ketimines.
Only limited examples are available for the enantioselec-
tive metal-catalyzed addition to N-unprotected imines, with
a few reports on either allylation or alkynylation.[6] Enantio-
selective arylation of N-unprotected imines is yet to be
realized. The major challenge is the lack of efficient chiral
catalysts/ligands that can provide high reactivities and enan-
tioselectivities. We have recently developed a series of
BIBOP-type ligands for various asymmetric catalytic reac-
tions.[7] One salient feature of these ligands is the substitution
at the 4,4’-positions, adjacent to the phosphorus atoms,
providing tunability of their chiral pockets in shape, depth,
and electronic properties (Figure 2). For example, Wing-
Phos,[8] bearing two 9-anthryl groups at the 4,4’-positions,
possesses deep chiral pockets and is efficient for rhodium-
catalyzed enantioselective addition of arylboroxine to
ketones. Herein we report the applications of WingPhos as
well as a related ligand, PFBO-BIBOP, in the enantioselective
rhodium-catalyzed addition of arylboroxines to N-unpro-
tected ketimines, leading to the direct formation of chiral a-
trifluoromethyl-a,a-diaryl amines and 3-amino-3-aryloxin-
doles in excellent enantioselectivities and yields.
[*] J. Zhu, L. Huang, Prof. Dr. X. Yu, Prof. Dr. W.-P. Deng,
Prof. Dr. W. Tang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy,
East China University of Science and Technology
130 Mei Long Rd, Shanghai 200237 (China)
E-mail: weiping_deng@ecust.edu.cn
tangwenjun@sioc.ac.cn
W. Dong, Dr. N. Li, Prof. Dr. W.-P. Deng, Prof. Dr. W. Tang
State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201910008.
Figure 2. BIBOP-type ligands.
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Chiral a-(trifluoromethyl)amines[9] have become increas-
ingly important building blocks in medicinal chemistry and
exist in structures of several therapeutic agents such as
odanacatib[9b] and DPC-083.[9c–f] Efficient synthesis of such
structures has gained a great deal of interest. However, few
reports are available on enantioselective synthesis of chiral
tertiary a-(trifluoromethyl)amines. The groups of Xu,[3d]
Zhang,[4a] and Lu/Hayashi[4f] reported enantioselective aryla-
tion of N-sulphonyl and N-carbonyl ketimines. We proposed
that an enantioselective arylation of N-unprotected ketimines
would provide a more convenient method for accessing chiral
tertiary a-(trifluoromethyl)amines. Thus, 4-methoxyphenyl-
boroxine (2a) was chosen as the aryl boron reagent for
rhodium-catalyzed nucleophilic addition to 2,2,2-trifluoro-1-
phenylethan-1-imine (1a). The reaction was performed in
toluene under nitrogen for 10 hours with 1a (0.20 mmol), 2a
(0.10 mmol, 0.30 mmol “B”), and a base in the presence of
[Rh(C2H4)2Cl]2 (1.5 mol%) and WingPhos (L1, 3.6 mol%;
Table 1, entry 1). Encouragingly, a 22% yield and 98% ee
were observed when L1 was applied as the ligand. Screening
of various bases (entries 1–7) revealed that CsF was the best
in terms of yield and the product 3aa was formed in 66%
yield and 99% ee. Study of various solvents (entries 7–11)
showed toluene was superior. We found the reaction even
proceeded at 708C, providing 3aa in 72% yield and 99% ee
(entry 13). The less-than-perfect yield was due to the high
sensitivity of 1a to moisture which leads to formation of a less
reactive water adduct. A lower yield (48%) was observed
when the reaction was operated at 608C. Arylboronic acid
could also be employed, albeit with a diminished yield
(entry 15). WingPhos (L1) proved to be important for both
high enantioselectivity and yield, since lower yields and
ee values were observed with the related ligands L2–L4 and
other commercially available ligands including BINAP, Me-
DuPhos, and Josiphos (entries 16–21). This preference could
be due to the presence of the deep chiral pockets of WingPhos
compared to those of other chiral ligands.[8b,14]
The substrate scope of the enantioselective addition was
studied. As can be seen in Table 2, a series of chiral a-
trifluoromethyl-a,a-diaryl a-tertiary amines were formed
directly from N-H-a-trifluoromethyl-a-aryl ketimines with
excellent ee values and good yields. A 2-furyl-substituted
substrate was well tolerated to provide 3na in a moderate
yield and with an excellent ee value. Various arylboronic acids
were tolerated to form the corresponding chiral a-tertiary
amines (3db–dg). Interestingly, switching the substitution
pattern of the aryl group between the ketimine and the aryl
boroxine provided the product (S)-3aa in a good yield and
with an excellent ee value, but with the opposite stereo-
configuration, demonstrating the capability of this method for
preparing both enantiomers of chiral products using a single
configuration of the same chiral ligand. This method provides
expedited access to a series of chiral a-trifluoromethyl-a,a-
diaryl amines which are difficult to prepare otherwise.
Chiral 3-amino-3-aryloxindoles are present in many
biologically active natural products and pharmaceutical
drugs.[11] Their efficient syntheses have become a subject of
research interest.[12] While high enantioselectivities have been
achieved on the enantioselective arylation of N-protected 3-
ketimino-2-oxindoles,[4e] no study is available on enantiose-
lective arylation of N-H 3-ketimino-2-oxindoles. We applied
WingPhos as the chiral ligand in rhodium-catalyzed nucleo-
philic addition of 2a to 3-imino-1-tritylindolin-2-one (4a;
Table 3, entry 1). The product 5aa was isolated with an
excellent ee value (91%), albeit in low yield. Encouraged by
this result, a series of BIBOP-type ligands, L3, L5, and L6,
were used for this transformation. An improved yield was
obtained when MeO-BIBOP (L3) was employed as the
ligand, indicating that the reaction was better promoted by
ligands with shallow chiral pockets. When a more-electron-
deficient ligand, PFBO-BIBOP (L6), was used, the addition
product was isolated in an excellent yield (93%) and ee (97%;
entry 4). The bulky N-trityl substituent in 4a was important
for achieving both high enantioselectivity and good yield, as
substrates containing N-Me and N-Bn substituents proved to
be less enantioselective (entries 5 and 6). Screening of various
parameters including base, solvent, and temperature revealed
that K3PO4 as the base, toluene as the solvent, and 808C as the
reaction temperature were suitable in terms of both yield and
enantioselectivity.[13]
Table 1: Rh-catalyzed addition of 4-methoxyphenylboroxine (2a) to 2,2,2-
trifluoro-1-phenylethan-1-imine (1a).
Entry[a] L*
Base
T
(8C)
Solvent
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
K2CO3
K3PO4
KF
Cs2CO3 110
KOH 110
NaOtBu 110
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
110
110
110
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylenes
PhF
22
24
28
35
42
<5
66
47
19
8
98
97
98
95
99
–
99
99
99
99
99
99
99
99
99
63
26
91
41
55
110
110
110
110
110
90
70
60
70
70
9
10
11
12
13
14
15[d]
16
17
18
19
20
MTBE
CPME
54
69
75(72)
48
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
51
17
39
21
15
41
L3
L4
70
70
70
70
(S)-BINAP
(S,S)-Me-
Duphos
21
(R,S)-Josiphos CsF
70
toluene
19
7
[a] Unless otherwise specified, the reactions were performed under
nitrogen for 10 h with 2,2,2-trifluoro-1-phenylethan-1-imine (1a,
0.20 mmol), 4-methoxyphenylboroxine (2a, 0.10 mmol, 0.30 mmol “B”),
base (0.40 mmol), and solvent (1.0 mL) in the presence of [Rh(C2H4)2Cl]2
(1.5 mol%), L* (3.6 mol%). The R absolute configuration of 3aa was
assigned by analogy according to the X-ray structure of 3dc-acetamide.[10]
[b] Yield determined by HPLC assay. Yield of isolated product given
within parentheses. [c] Determined by chiral HPLC using a chiralcel OD-
H column. [d] 4-Methoxyphenylboronic acid (0.3 mmol) was employed.
CPME=cyclopentyl methyl ether, MTBE=methyl tert-butyl ether.
2
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Enantioselective Rh-catalyzed addition of arylboroxines to
Table 3: Rh-catalyzed addition of 2a to 3-imino-1-tritylindolin-2-one
ketimine.
(4a).
Entry[a] L*
R
Base
T [8C] Solvent Yield [%][b] ee [%][c]
1
2
3
4
5
6
L1 CPh3
L3 CPh3
L5 CPh3
L6 CPh3
L6 Me (4x) K3PO4 80
L6 Bn (4y) K3PO4 80
K3PO4 80
K3PO4 80
K3PO4 80
K3PO4 80
toluene 20
toluene 60
toluene 85
toluene 95(93)
toluene 79
toluene 85
91
89
83
97
86
88
[a] Unless otherwise specified, the reactions were performed under
nitrogen for 14 h with isatine imine (4a, 0.20 mmol), 4-methoxyphenyl-
boroxine (2a, 0.10 mmol, 0.30 mmol “B”), base (0.40 mmol), and
solvent (3.0 mL) in the presence of [Rh(C2H4)2Cl]2 (1.5 mol%), L*
(3.6 mol%). The R absolute configuration of 5aa was assigned by
analogy on the basis of the absolute configuration of 6ab.[12c] [b] Yield
determined by HPLC assay. Yield of isolated product given within
parentheses. [c] Determined by chiral-phase HPLC using a chiralcel AD-
H column.
substrate, which was considered as a difficult substrate with
greater steric hindrance,[4] proceeded smoothly to form 5la in
95% ee and 72% yield. To demonstrate the practicality of this
method, a gram-scale addition of phenylboroxine to 4a in the
presence of 1 mol% of the Rh-PFBO-BIBOP catalyst
provided the product 5ab (1.73 g) in 97% ee and 72% yield
(Scheme 1). Simple removal of the N-trityl provided (R)-3-
amino-3-phenylindolin-2-one (6ab) in 97% ee and 91% yield.
The protocol constitutes one of most facile and efficient
synthesis of chiral 3-amino-3-aryloxindoles.[14]
[a] Unless otherwise specified, the reactions were carried out at 708C in
toluene (1.0 mL) for 10 h with ketimine (0.20 mmol), arylboroxine
(0.10 mmol, 0.30 mmol “B”), and CsF (0.40 mmol) in the presence of
[Rh(C2H4)2Cl]2 (1.5 mol%) and L1 (3.6 mol%). The absolute configu-
ration of 3dc was determined by the X-ray structure of 3dc-acetamide,
and the others were assigned accordingly. Yields are those of the isolated
products. The ee values were determined by chiral-phase HPLC.
Scheme 1. Preparation of (R)-3-amino-3-(phenyl)indolin-2-one (6ab).
DCM=dichloromethane.
Cipargamin (11) is a PfATP4 inhibitor for the treatment
of malaria, currently under Phase II clinical trials.[15] To date,
only two enantioselective preparations are reported. Shiba-
saki and co-workers developed a highly enantioselective
alkynylation to N-(diphenylthiophosphinoyl)ketimine for the
establishment of the a-tertiary amine component. However,
a nine-step linear sequence was required to furnish the
molecule after the key addition.[16a] The group of Feng
reported an elegant synthesis of 11 by employing an
enantioselective aza-Diels–Alder reaction of 3-vinylindole,
albeit with the requirement of a long reaction time (6 days)
and a high loading of chiral Lewis acid (10 mol%).[16b] We
believed that an addition of the indolylboronic ester 7 to N-H
The substrate scope of the enantioselective arylation of N-
H 3-ketimino-2-oxindoles was studied (Table 4). Thus, a wide
array of chiral 3-amino-3-aryloxindoles were prepared with
excellent ee values and yields. Various aryl and heteroaryl-
boroxines, including substituted phenyl, naphthyl, furyl, and
thiophenyl groups, were well tolerated. Oxindoles with
different electronic properties and various substitution pat-
terns on the aryl ring were all compatible. A nitro-substituted
substrate was also compatible, providing the product 5ga in
96% ee and 68% yield. Interestingly, a 4-methoxy-substituted
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 4: Enantioselective Rh-catalyzed addition of arylboroxines to N-
trityl-protected isatin imines.[a]
Scheme 2. A concise enantioselective synthesis of cipargamin (11).
THF=tetrahydrofuran.
base and toluene as the solvent provided the chiral amine 9 in
96% ee and 65% yield. Acidic treatment followed by
reduction with Shibasakiꢀs conditions (BH3.2-picoline) led
to the ring closure product 10 in 81% yield with a diastereo-
meric ratio of 9:1. Final trityl removal with Et3SiH/TFA
provided 11 in 96% ee and 91% yield, thus completing an
efficient enantioselective synthesis of cipargamin.
In summary, we have demonstrated for the first time the
highly enantioselective rhodium-catalyzed addition of aryl-
boroxines to N-unprotected ketimines by employing chiral
BIBOP-type ligands, providing expedient and practical access
to a range of chiral a-trifluoromethyl-a,a-diaryl amines and
3-amino-3-aryloxindoles with excellent ee values and yields
when using a Rh loading as low as 1 mol%. The unique
tunability of the BIBOP-type ligands in terms of depth, shape,
and electronic effects has enabled the success of the
protection-free transformations that are advantageous over
the addition protocols to N-protected ketimines in terms of
atom economy and cost effectiveness. The Rh-PFBO-BIBOP
catalyst further enabled an efficient enantioselective synthesis
of antimalarial agent cipargamin.
Acknowledgements
[a] Unless otherwise specified, the reactions were carried out at 808C in
toluene (3 mL) for 14 h with ketimine (0.20 mmol), arylboroxine (0.10,
0.30 mmol “B”), and K3PO4 (0.40 mmol) in the presence of [Rh-
(C2H4)2Cl]2 (1.5 mol%) and L6 (3.6 mol%). The absolute configurations
of tertiary amines 5ab–la were assigned by analogy on the basis of the
absolute configuration of 6ab. Yields are those of the isolated products.
The ee values were determined by chiral-phase HPLC. [b] 2-Furanboronic
acid (0.3 mmol) was employed; [c] 3-Furanboronic acid (0.3 mmol) was
employed. [d] 3-Thiopheneboronic acid (0.3 mmol) was employed.
We are grateful to the Strategic Priority Research Program of
the Chinese Academy of Sciences XDB20000000, CAS
(QYZDY-SSW-SLH029), NSFC (21725205, 21432007,
21572246),STCSM-18520712200, and K.C. Wong Education
Foundation.
Conflict of interest
ketimine 8 would provide a more convergent and expedient
synthesis of 11 (Scheme 2). Thus, addition of 7 to 8 in the
presence of the Rh/ent-L6 catalyst (3 mol%) with CsF as the
The authors declare no conflict of interest.
4
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
2017, 23, 17022; e) H. Jang, F. Romiti, S. Torker, A. H. Hoveyda,
Nat. Chem. 2017, 9, 1269.
Keywords: asymmetric catalysis · enantioselectivity · ketimines ·
Pligands · rhodium
[7] a) W. Tang, B. Qu, A. G. Capacci, S. Rodriguez, X. Wei, N.
Haddad, B. Narayanan, S. Ma, N. Grinberg, N. K. Yee, D.
Krishnamurthy, C. H. Senanayake, Org. Lett. 2010, 12, 176;
b) D. R. Fandrick, K. R. Fandrick, J. T. Reeves, Z. Tan, W. Tang,
A. G. Capacci, S. Rodriguez, J. J. Song, H. Lee, N. K. Yee, C. H.
Senanayake, J. Am. Chem. Soc. 2010, 132, 7600; c) W. Li, S.
Rodriguez, A. Duran, X. Sun, W. Tang, A. Premasiri, J. Wang, K.
Sidhu, N. D. Patel, J. Savoie, B. Qu, H. Lee, N. Haddad, J. C.
Lorenz, L. Nummy, A. Hossain, N. Yee, B. Lu, C. H. Sena-
nayake, Org. Process Res. Dev. 2013, 17, 1061; d) R. Luo, K. Li,
Y. Hu, W. Tang, Adv. Synth. Catal. 2013, 355, 1297; e) C. Li, F.
Wan, Y. Chen, H. Peng, W. Tang, S. Yu, J. C. McWilliams, J.
Mustakis, L. Samp, R. J. Maguire, Angew. Chem. Int. Ed. 2019,
58, 13573; Angew. Chem. 2019, 131, 13707; f) G. Xu, C. H.
Senanayake, W. Tang, Acc. Chem. Res. 2019, 52, 1101.
[8] a) G. Liu, X. Liu, Z. Cai, G. Jiao, G. Xu, W. Tang, Angew. Chem.
Int. Ed. 2013, 52, 4235; Angew. Chem. 2013, 125, 4329; b) L.
Huang, J. Zhu, G. Jiao, Z. Wang, X. Yu, W.-P. Deng, W. Tang,
Angew. Chem. Int. Ed. 2016, 55, 4527; Angew. Chem. 2016, 128,
4603.
[9] a) S. Li, J.-A. Ma, Chem. Soc. Rev. 2015, 44, 7439; b) R. D.
Chapurlat, Expert Opin. Pharmacother. 2014, 15, 559; c) H.-N.
Yuan, S. Li, J. Nie, Y. Zheng, J.-A. Ma, Chem. Eur. J. 2013, 19,
15856; d) F.-G. Zhang, X.-Y. Zhu, S. Li, J. Niea, J.-A. Ma, Chem.
Commun. 2012, 48, 115552; e) J. Dai, D. Xiong, T. Yuan, J. Liu, T.
Chen, Z. Shao, Angew. Chem. Int. Ed. 2017, 56, 12697; Angew.
Chem. 2017, 129, 12871; f) H. Xie, Y. Zhang, S. Zhang, X. Chen,
W. Wang, Angew. Chem. Int. Ed. 2011, 50, 11773; Angew. Chem.
2011, 123, 11977.
[10] CCDC 1860584 (3dc-acetamide) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
[11] J. Kaur, S. S. Chimni, Org. Biomol. Chem. 2018, 16, 3328.
[12] For diastereoselective addition, see: a) H. H. Hung, A. W.
Buesking, J. A. Ellman, Org. Lett. 2011, 13, 3912; for enantio-
selective organocatalysis, see: b) M. Montesinos-Magraner, C.
Vila, R. Cantꢃn, G. Blay, I. Fernꢂndez, M. C. MuÇoz, J. R. Pedro,
Angew. Chem. Int. Ed. 2015, 54, 6320; Angew. Chem. 2015, 127,
6418; for asymmetric amination; c) F. Zhou, M. Ding, Y.-L. Liu,
C.-H. Wang, C.-B. Ji, Y.-Y. Zhang, J. Zhou, Adv. Synth. Catal.
2011, 353, 2945.
[1] For recent reviews on a-tertiary amines, see: a) I. Denissova, L.
Barriault, Tetrahedron 2003, 59, 10105; b) O. Riant, J. Hanne-
douche, Org. Biomol. Chem. 2007, 5, 873; c) P. G. Cozzi, R.
Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969; d) M.
Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853; e) S. Kobaya-
shi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111,
2626; f) T. Jia, P. Cao, J. Liao, Chem. Sci. 2018, 9, 546.
[2] For reviews on enantioselective addition of arylboron com-
pounds, see: a) C. S. Marques, A. J. Burke, ChemCatChem 2011,
3, 635; b) D. Chen, M.-H. Xu, Chin. J. Org. Chem. 2017, 37, 1589;
c) M. Quan, L. Wu, G. Yang, W. Zhang, Chem. Commun. 2018,
54, 10394.
[3] a) R. Shintani, M. Takeda, T. Tsuji, T. Hayashi, J. Am. Chem.
Soc. 2010, 132, 13168; b) R. Shintani, M. Takeda, Y.-T. Soh, T.
Ito, T. Hayashi, Org. Lett. 2011, 13, 2977; c) T. Nishimura, A.
Noishiki, G. C. Tsui, T. Hayashi, J. Am. Chem. Soc. 2012, 134,
5056; d) H. Wang, T. Jiang, M.-H. Xu, J. Am. Chem. Soc. 2013,
135, 971; e) T. Nishimura, A. Noishiki, Y. Ebe, T. Hayashi,
Angew. Chem. Int. Ed. 2013, 52, 1777; Angew. Chem. 2013, 125,
1821; f) T. Nishimura, Y. Ebe, H. Fujimoto, T. Hayashi, Chem.
Commun. 2013, 49, 5504; g) H. Wang, Y. Li, M.-H. Xu, Org. Lett.
2014, 16, 3962; h) T. Jiang, Z. Wang, M.-H. Xu, Org. Lett. 2015,
17, 528; i) Y.-J. Chen, Y.-H. Chen, C.-G. Feng, G.-Q. Lin, Org.
Lett. 2014, 16, 3400; j) R. Takechi, T. Nishimura, Org. Biomol.
Chem. 2015, 13, 4918; k) J. Kong, M. McLaughlin, K. Belyk, R.
Mondschein, Org. Lett. 2015, 17, 5520; l) N. Kato, T. Shirai, Y.
Yamamoto, Chem. Eur. J. 2016, 22, 7739; m) Y. Li, Y.-N. Yu, M.-
H. Xu, ACS Catal. 2016, 6, 661; n) Y.-F. Zhang, D. Chen, W.-W.
Chen, M.-H. Xu, Org. Lett. 2016, 18, 2726; o) M.-Q. Liu, T. Jiang,
W.-W. Chen, M.-H. Xu, Org. Chem. Front. 2017, 4, 2159; p) Z.
Wang, M.-H. Xu, Org. Biomol. Chem. 2018, 16, 4633.
[4] a) G. Yang, W. Zhang, Angew. Chem. Int. Ed. 2013, 52, 7540;
Angew. Chem. 2013, 125, 7688; b) C. Jiang, Y. Lu, T. Hayashi,
Angew. Chem. Int. Ed. 2014, 53, 9936; Angew. Chem. 2014, 126,
10094; c) C. Schrapel, R. Peters, Angew. Chem. Int. Ed. 2015, 54,
10289; Angew. Chem. 2015, 127, 10428; d) Y. ꢁlvarez-Casao, D.
Monge, E. ꢁlvarez, R. Fernꢂndez, J. M. Lassaletta, Org. Lett.
2015, 17, 5104; e) Q. He, L. Wu, X. Kou, N. Butt, G. Yang, W.
Zhang, Org. Chem. Front. 2015, 2, 398; f) Q. He, L. Wu, X. Kou,
N. Butt, G. Yang, W. Zhang, Org. Lett. 2016, 18, 288; g) B. Zhou,
C. Jiang, V. R. Gandi, Y. Lu, T. Hayashi, Chem. Eur. J. 2016, 22,
13068; h) B. Zhou, K. Li, C. Jiang, Y. Lu, T. Hayashi, Adv. Synth.
Catal. 2017, 359, 1969; i) C. Schrapel, W. Frey, D. Garnier, R.
Peters, Chem. Eur. J. 2017, 23, 2448; j) J.-Y. Wang, M.-W. Li, M.-
F. Li, W.-J. Hao, G. Li, S.-J. Tu, B. Jiang, Org. Lett. 2018, 20, 6616.
[5] a) M. Quan, L. Tang, J. Shen, G. Yang, W. Zhang, Chem.
Commun. 2017, 53, 609; b) M. Quan, X. Wang, L. Wu, I.
Gridnev, G. Yang, W. Zhang, Nat. Commun. 2018, 9, 2258.
[6] For a limited number of examples on enantioselective addition
of N-unprotected imines, see: a) D. N. Tran, N. Cramer, Angew.
Chem. Int. Ed. 2011, 50, 11098; Angew. Chem. 2011, 123, 11294;
b) D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2013, 52, 10630;
Angew. Chem. 2013, 125, 10824; c) K. Morisaki, H. Morimoto, T.
Ohshima, Chem. Commun. 2017, 53, 6319; d) M. Sawa, K.
Morisaki, Y. Kondo, H. Morimoto, T. Ohshima, Chem. Eur. J.
[13] See the Supporting Information for detailed optimization.
[14] See the Supporting Information for
stereochemical model.
a discussion on the
[15] a) A. Mullard, Nat. Rev. Drug Discovery 2018, 17, 693; b) M.
Rottmann, C. McNamara, B. K. Yeung, M. C. Lee, B. Zou, B.
Russell, P. Seitz, D. M. Plouffe, N. V. Dnaria, J. Tan, S. B. Cohen,
K. R. Spencer, G. E. Gonzꢂlez-Pꢂez, S. B. Lashminarayana, A.
Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H. P. Beck, R.
Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock,
E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175.
[16] a) H. Takada, N. Kumaga, M. Shibasaki, Org. Lett. 2015, 17,
4762; b) H. Zheng, X. Liu, C. Xu, Y. Xia, L. Lin, X. Feng, Angew.
Chem. Int. Ed. 2015, 54, 10958; Angew. Chem. 2015, 127, 11108.
Manuscript received: August 7, 2019
Revised manuscript received: August 28, 2019
Accepted manuscript online: August 29, 2019
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
J. Zhu, L. Huang, W. Dong, N. Li, X. Yu,
W.-P. Deng,* W. Tang*
&&&& — &&&&
Enantioselective Rhodium-Catalyzed
Addition of Arylboroxines to N-
Unprotected Ketimines: Efficient
Synthesis of Cipargamin
Wing it: Highly enantioselective rhodium-
catalyzed addition of arylboroxines to N-
unprotected ketimines is realized for the
first time by employing chiral BIBOP-type
ligands with a Rh loading as low as
methyl-a,a-diaryl a-tertiary amines or 3-
amino-3-aryloxindoles were formed in
excellent yields by employing either
WingPhos or PFBO-BIBOP as the ligand.
The method enabled an efficient enan-
tioselective synthesis of cipargamin.
1 mol%. A range of chiral a-trifluoro-
6
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!