Direct Synthesis of Chiral NH Lactams via Ru-Catalyzed Asymmetric Reductive Amination/Cyclization Cascade of Keto Acids/Esters

Article abstract of DOI:10.1021/acs.orglett.0c00669

Lactams with a stereogenic center adjacent to the N atom have existed in many medicinal agents and bioactive alkaloids. Herein we report a broadly applicable synthesis of enantioenriched NH lactams through a one-pot asymmetric reductive amination/cyclization sequence of easily available keto acids/esters. Such cascade processes alleviate the demand for protecting group manipulations as well as intermediate purification. This strategy is capable of constructing enantioenriched lactams and benzo-lactams of a five-, six-, or seven-membered ring in generally high yield and with excellent enantioselectivities (up to 97% ee). Scalable and concise syntheses of key drug intermediates have further displayed the importance of this methodology.

Full text of DOI:10.1021/acs.orglett.0c00669

pubs.acs.org/OrgLett
Letter
Direct Synthesis of Chiral NH Lactams via Ru-Catalyzed Asymmetric
Reductive Amination/Cyclization Cascade of Keto Acids/Esters
Yongjie Shi,# Xuefeng Tan,# Shuang Gao,# Yao Zhang, Jingxin Wang, Xumu Zhang, and Qin Yin*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00669
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Lactams with a stereogenic center adjacent to the N
atom have existed in many medicinal agents and bioactive
alkaloids. Herein we report a broadly applicable synthesis of
enantioenriched NH lactams through a one-pot asymmetric
reductive amination/cyclization sequence of easily available keto
acids/esters. Such cascade processes alleviate the demand for
protecting group manipulations as well as intermediate purification.
This strategy is capable of constructing enantioenriched lactams and benzo-lactams of a five-, six-, or seven-membered ring in
generally high yield and with excellent enantioselectivities (up to 97% ee). Scalable and concise syntheses of key drug intermediates
have further displayed the importance of this methodology.
including pyrrolidines, piperidines, and benzo-fused N-hetero-
hiral lactams widely exist in natural products and key
Cpharmacophores in numerous biologically active mole- cycles, which are among the most prevailing structural subunits
in medicinal agents and bioactive alkaloids.4 NH lactams are
cules. In particular, lactams with a stereogenic center adjacent
extremely useful and highly desirable because they could serve
as a starting point to increase the molecular complexity
through elaboration on the N atom. However, documented
asymmetric syntheses of chiral NH lactams are limited and
usually indirect, requiring chiral auxiliaries and multiple steps
(e.g., protection and deprotection manipulation on the N
atom).5 In particular, catalytic asymmetric methods that are
able to directly furnish structurally diverse NH lactams are
rare.6,7
to the N atom are privileged scaffolds in medicinal chemistry
(Figure 1).1,2 In addition, chiral isoindolinones, containing a
benzolactam system, are also ubiquitous in many natural and
unnatural products with promising therapeutic activities.3 On
the other hand, lactams can serve as versatile synthetic
intermediates to valuable chiral molecules through facile
elaborations. For example, upon reduction, enantiomerically
pure lactams can be converted to saturated N-heterocycles
Because of the high efficiency and easy availability of starting
materials, the reductive amination8,9 of keto acids/esters has
been regarded as one of the most attractive approaches to
access chiral lactams. In Scheme 1, two pathways involving
either a stepwise or cascade process are illustrated. The
stepwise processes require the prepreparation of imines via the
condensation of keto acids/esters with an amide or aniline,
followed by asymmetric hydrogenation (AH), hydrogen
transfer reactions (AHT) of imines, or a diastereoselective
reduction process with the aid of chiral auxiliaries.10 The
resulting N-protected amino acid/esters generally need a
further deprotection step before final cyclization to provide
NH lactams. These multistep processes are laborious and
costly.
Received: February 20, 2020
Figure 1. Selected examples of biologically active or naturally
occurring chiral lactams.
https://dx.doi.org/10.1021/acs.orglett.0c00669
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
desired product 2a (entry 6). In some cases, a small amount of
the potential side product lactone 2a′ was observed. With
these encouraging results, we further tested different esters
1ab−ad and acid 1ae, aiming to improve the enantiocontrol.
To our delight, along with the bulkiness of ester moiety
increasing, the enantioselectivity of 2a is enhanced as well
(entries 7−10). For tert-butyl substrate 1ad, both the yield and
ee of 2a reached an excellent level (96% yield and 94% ee,
entry 9). In comparison with L2, DTBM-SegPhos yielded
inferior enantiocontrol (entry 11 vs 9).14b For the detailed
screening of solvents, temperature, and pressure, see the
Supporting Information.
Scheme 1. Asymmetric Synthesis of Chiral Lactams via
Reductive Amination of Keto Acids/Esters
With optimal reaction conditions in hand (entry 9, Table 1),
a wide range of aryl-substituted γ-keto esters were prepared
Table 1. Optimization of Reaction Conditions
In contrast, a cascade process combining reductive
amination and subsequent cyclization is highly desirable,
whereas limited progress has been achieved (Scheme 1b).
Xiao, Sakai, and other groups had studied the catalytic
conversion of levulinic acid or its derivatives with various
amines to yield racemic N-substituted pyrrolidinones.11 To
date, the only asymmetric cascade cyclization was recently
realized by an enzymatic strategy with a limited scope (Scheme
1b).12 Despite this progress, the enantioselective and control-
lable construction of NH lactams with different ring sizes or
patterns from simple and easily accessed substrates remains
challenging and rewarding.
Herein we report a Ru-catalyzed asymmetric reductive
amination (ARA) and cyclization cascade capable of furnishing
enantioenriched lactams of a five-, six-, or seven-membered
ring in generally high yield and with high enantioselectivities
(Scheme 1c). The easy access to substrates and the utilization
of ammonium salts as amine sources as well as H2 as a
reductant offer a straightforward and practical route to obtain
NH lactams.
a
b
c
entry substrate
[Ru]
yield (%) ee (%)
1
2
3
4
5
6
7
8
1aa
1aa
1aa
1aa
1aa
1aa
1ab
1ac
1ad
1ae
1ad
RuCl2(S)BINAP(DMF)n
Ru(OAc)2(S)-BINAP
Ru(OAc)2(S)-SegPhos
Ru(OAc)2(R)-MeO-BIPHEP
Ru(OAc)2(L1)
Ru(OAc)2(L2)
Ru(OAc)2(L2)
Ru(OAc)2(L2)
Ru(OAc)2(L2)
75
90
94
90
94
95
95
96
96
91
93
10
16
5
15
14
77
83
88
94
38
89
9
10
11
Ru(OAc)2(L2)
Ru(OAc)2(R)-DTBM-SegPhps
a
Reaction conditions: 1 (0.2 mmol), NH4OAc (0.4 mmol), [Ru] (1
mol %), TFE (0.4 mL), H2 (50 bar), 90 °C, 24 h. TFE = 2,2,2-
trifluoroethanol. Isolated yield. Determined by HPLC using chiral
b
c
columns.
The direct ARA of ketones with NH3 or its surrogates in the
presence of a H2 atmosphere has recently attracted attention
because it offers a straightforward and practical route to
synthetic valuable chiral primary amines.13 Very recently,
Schaub14a and our group14b independently realized the Ru-
catalyzed ARA of simple aryl ketones with either NH3 or
ammonium salts as the amine source and H2 as the reducing
agent, providing an efficient and practical way to synthesize
chiral primary benzylamines. Inspired by these precedents and
continuing our interest in ARA,15 we envisaged that the
strategy might be applicable to γ-keto acids/esters, thus
furnishing chiral NH lactams of different ring sizes via the
ARA/cyclization cascade. To test our idea, we choose aryl-
substituted γ-keto esters and acid 1 for condition screening.
First, we evaluated the performance of various combinations of
ruthenium precatalysts and chiral diphosphine ligands in the
reaction of 1aa and NH4OAc under 50 atm of H2. The
Ru(OAc)2 complex provided slightly better enantiocontrol
compared with the RuCl2 complex (entry 2 vs 1). Whereas
SegPhos, MeO-BIPHEP, and the simplest C3*-TunePhos L1
did not provide satisfying results, the utilization of sterically
more hindered C3*-TunePhos L2 supplied 77% ee of the
and tested. In general, aryl-substituted esters 1 with either
halogen (F, Cl, Br) or electron-donating (Me, Bu, MeO)
t
groups on the benzene ring were transformed into the
corresponding optically active γ-lactams with good to excellent
enantioselectivities (2b−k, 85−95% ee, Table 2). In addition,
2-naphthyl substrate 1m was converted to the desired lactam
2m with 92% ee. According to the observed results, substrates
with a substituent on the para position of the benzene ring
show higher reactivity than ortho-substituted substrates.
Additionally, we also tested aliphatic keto esters 1n, which
provided the desired product 2n in moderate 41% yield and
with 50% ee.
After the evaluation of the scope of γ-keto esters, we
continued to extend the scope to construct more structurally
diverse chiral lactams with different ring sizes. A series of δ-
B
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
was only slightly superior to that of the corresponding δ-keto
acid (4a, 86−94% ee). Substituents such as Me, MeO, and F
on different positions of benzene ring were well tolerated,
providing the corresponding δ-lactams 4 in excellent yield and
with excellent enantioselectivities (4b−h, 90−92% ee). To our
delight, ε-keto 3i was also applicable, yielding the seven-
membered lactam 4i in 42% yield and with 90% ee in the
presence of 1 equiv of Ti(OiPr)4. In contrast, the side product
from ketone reduction was dominant in the absence of
Ti(OiPr)4.
Table 2. Scope of γ-Keto Esters
Whereas chiral isoindolinones are core subunits in many
biologically active molecules, catalytic enantioselective meth-
ods for the direct construction of NH isoindolinones remain
rare and challenging.3a,7a,d,e,g,i To our delight, benzo-fused keto
acids/esters 5 are also suitable for our catalytic system, thus
efficiently affording NH isoindolinones (Table 4). It is
Table 4. Scope of Benzo-Fused Keto Acids
keto esters/acids were then synthesized and probed (Table 3).
For these substrates, interestingly, the effect of ester moiety on
reaction enantiocontrol is not remarkable. As shown in Table
3, the enantiocontrol of methyl, iso-propyl, or tert-butyl ester
Table 3. Scope of δ- and ε-Keto Esters
noteworthy that benzo-fused keto acid offers higher
enantiocontrol than the corresponding methyl ester (6a, 97%
ee vs 84% ee). Apart from methyl (5a) and ethyl ketone (5b),
substrates with either a bromo group or an electron-donating
group (Me, MeO) on the benzene ring proceeded smoothly to
afford the corresponding chiral isoindolinones in excellent
yield and with excellent ee values (6a−f, 92−97% ee).
Delightedly, pyridine-fused substrate 5g, which is commercially
available, was also well tolerated, giving 6g in 81% yield and
with 91% ee. The expansion of the ring size of lactam was
subsequently evaluated. With substrates of a suitable chain
length, both six- and seven-membered benzo-fused lactams
were achieved with excellent ee (6h,i, 90% yield, 94% ee and
52% yield, 90% ee, respectively). Furthermore, diaryl ketone
substrate 5j reacted smoothly to yield the corresponding
product 6j in 53% yield and with 88% ee.
Because this methodology supplies quick access to chiral
NH lactams from readily available starting materials, it allows
C
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
streamlined access to key drug intermediates that would
otherwise need more steps for their synthesis. For example, the
semigram synthesis of enantiopure pyrrolidine 7 (eq a, Scheme
2), a key intermediate to the anticancer drug molecule
Scheme 3. Control Experiments and Plausible Reaction
Routes
Scheme 2. Scale-up Syntheses and Product Applications
cascade, that is pathway a, is more reasonable. At this moment,
however, the exact pathway of stereo induction, which may be
enabled by the reduction of an enamine or imine intermediate,
is unclear.
In summary, we have realized a facile and highly
enantioselective strategy toward the synthesis of chiral lactams
from easily accessed keto acids/esters. The utilization of cost-
Larotrectinib,16a was accomplished in only two steps from 1b,
which is prepared in one step from a commercially available
ketone. In comparison, patented methods to 7 require either
eight steps from aldehyde 8 via a chiral auxiliary strategy16b or
five steps from bromo-arene 9 using stoichimetric (−)-spartei-
ne.16c The gram-scale synthesis of 6c, a potential intermediate
to access quinolone antibiotic drug Garenoxacin, was also
conducted with a S/C ratio of 500 (eq b, Scheme 2).17 In
addition, the gram-scale conversion of 3a was also successful,
providing δ-phenyl-substituted chiral lactam 4a (85% yield and
91% ee),7b,10 which could be easily converted into diverse
medicinal agents such as the antagonist of CGRP receptor IV2d
and the modulator of TNFα signaling 10 (eq c, Scheme 2).18
Possible reaction routes for this cascade process are depicted
in Scheme 3, as exemplified with 1ad. Initially, 1ad reacts with
+
effective and operationally friendly NH4 as an amine source
renders a practical way for the direct synthesis of synthetically
useful NH lactams. The reaction is compatible with substrates
with diverse patterns or chain lengths and offers the rapid
assembly of five-, six-, or seven-membered ring lactams or
benzolactams, which is complementary to existing catalytic
methods.6 The structural diversity and easy availability of chiral
lactams will benefit the corresponding biological activities
evaluation. The gram-scale syntheses of intermediates of drugs
or biological molecules further showcase the practicality of this
method.
ASSOCIATED CONTENT
■
sı
* Supporting Information
+
NH4 to provide imine intermediate A or its HOAc salt (not
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00669.
shown), which can be reduced with Ru−H species to yield
chiral primary amine D, followed by spontaneous cyclization to
give chiral lactam 2a (path a).10−12 Alternatively, A can
isomerize to enamine B, which is then transformed into
General information, general procedures for the syn-
thesis of substrates, Ru-catalyzed asymmetric reductive
amination/cyclization cascade of keto acids/esters,
control experiments, plausible enantioinduction models,
references, NMR spectra, and HPLC (PDF)
t
enelactams C through the elimination of BuOH. Asymmetric
hydrogenation of C finally furnishes 2a. To get some evidence
to support reaction pathway a, some control experiments were
conducted. First, enamide C was independently synthesized
and subjected to the standard reaction conditions. Racemic 2a
in 10% yield was observed, which did not fit pathway b (eq a,
Scheme 3). In addition, the effect of the ester group on
asymmetric induction (see Table 1) also did not support this
reaction pathway. Furthermore, keto amide E, a potential
intermediate, was also prepared and investigated, and inferior
results were obtained (eq b, Scheme 3). On the basis of these
experimental results, the initially proposed ARA/cyclization
AUTHOR INFORMATION
■
Corresponding Author
Qin Yin − Shenzhen Grubbs Institute and Department of
Chemistry and Academy for Advanced Interdisciplinary Studies,
Southern University of Science and Technology, Shenzhen
518055, China; orcid.org/0000-0003-3534-3786;
Email: yinq@sustech.edu.cn
D
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
(4) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
Yongjie Shi − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; Department of Chemistry, State Key
Laboratory of Synthetic Chemistry, The University of Hong
Kong, Hong Kong, P. R. China
Xuefeng Tan − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Shuang Gao − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Yao Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Jingxin Wang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Xumu Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0001-5700-
0608
(5) For recent reviews, see: (a) Royer, J. Asymmetric Synthesis of
Nitrogen Heterocycles; Wiley-VCH: Weinheim, Germany, 2009.
(b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Recent advances in the synthesis of piperidones and piperidines.
Tetrahedron 2003, 59, 2953−2989. (c) Ye, L.-W.; Shu, C.; Gagosz, F.
Recent progress towards transition metal-catalyzed synthesis of γ-
lactams. Org. Biomol. Chem. 2014, 12, 1833−1845. (d) Caruano, J.;
Muccioli, G. G.; Robiette, R. Biologically active γ-lactams: synthesis
and natural sources. Org. Biomol. Chem. 2016, 14, 10134−10156.
(6) During the preparation of this work, elegant examples on
catalytic enantioselective syntheses of γ-substituted NH lactams were
reported, however, benzofused lactams or lactams of a 6- or 7-
membered ring were either unreported or obtained with very low ee,
see: (a) Wang, H.; Park, Y.; Bai, Z.; Chang, S.; He, G.; Chen, G.
Iridium-Catalyzed Enantioselective C(sp3)−H Amidation Controlled
by Attractive Noncovalent Interactions. J. Am. Chem. Soc. 2019, 141,
7194−7201. (b) Xing, Q.; Chan, C.-M.; Yeung, Y.-W.; Yu, W.-Y.
Ruthenium(II)-Catalyzed Enantioselective γ-Lactams Formation by
Intramolecular C−H Amidation of 1,4,2-Dioxazol-5-ones. J. Am.
Chem. Soc. 2019, 141, 3849−3853. (c) Park, Y.; Chang, S.
Asymmetric formation of γ-lactams via C−H amidation enabled by
chiral hydrogen-bond-donor catalysts. Nat. Catal. 2019, 2, 219−227.
(d) Zhou, Z.; Chen, S.; Hong, Y.; Winterling, E.; Tan, Y.; Hemming,
M.; Harms, K.; Houk, K. N.; Meggers, E. Non-C2-Symmetric Chiral-
at-Ruthenium Catalyst for Highly Efficient Enantioselective Intra-
molecular C(sp3)−H Amidation. J. Am. Chem. Soc. 2019, 141,
19048−19057.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00669
Author Contributions
#Y.S., X.T., and S.G. contributed equally.
Notes
(7) For selected recent examples on the catalytic enantioselective
synthesis of N-substituted lactams, see: (a) Ray, S. K.; Sadhu, M. M.;
Biswas, R. G.; Unhale, R. A.; Singh, V. K. A General Catalytic Route
to Enantioenriched Isoindolinones and Phthalides: Application in the
Synthesis of (S)-PD 172938. Org. Lett. 2019, 21, 417−422. (b) Yuan,
Q.; Sigman, M. S. Palladium-Catalyzed Enantioselective Relay Heck
Arylation of Enelactams: Accessing α, β-Unsaturated δ-Lactams. J.
Am. Chem. Soc. 2018, 140, 6527−6530. (c) Lang, Q.; Gu, G.; Cheng,
Y.; Yin, Q.; Zhang, X. Highly Enantioselective Synthesis of Chiral γ-
Lactams by Rh-Catalyzed Asymmetric Hydrogenation. ACS Catal.
2018, 8, 4824−4828. (d) Yuan, Q.; Liu, D.; Zhang, W. Iridium-
Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated γ-Lactams:
Scope and Mechanistic Studies. Org. Lett. 2017, 19, 1144−1147.
(e) Min, C.; Lin, Y.; Seidel, D. Catalytic Enantioselective Synthesis of
Mariline A and Related Isoindolinones through a Biomimetic
Approach. Angew. Chem., Int. Ed. 2017, 56, 15353−5357. (f) Pedroni,
J.; Cramer, N. Chiral γ-Lactams by Enantioselective Palladium(0)-
Catalyzed Cyclopropane Functionalizations. Angew. Chem., Int. Ed.
2015, 54, 11826−11829. (g) Bisai, V.; Suneja, A.; Singh, V. K.
Asymmetric Alkynylation/Lactamization Cascade: An Expeditious
Entry to Enantiomerically Enriched Isoindolinones. Angew. Chem., Int.
Ed. 2014, 53, 10737−10741. (h) Shu, C.; Liu, M.-Q.; Wang, S.-S.; Li,
L.; Ye, L.-W. Gold-Catalyzed Oxidative Cyclization of Chiral
Homopropargyl Amides: Synthesis of Enantioenriched γ-Lactams. J.
Org. Chem. 2013, 78, 3292−3299. (i) Yang, G.; Shen, C.; Zhang, W.
An Asymmetric Aerobic Aza-Wacker-Type Cyclization: Synthesis of
Isoindolinones Bearing Tetrasubstituted Carbon Stereocenters.
Angew. Chem., Int. Ed. 2012, 51, 9141−9145.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Prof Henry N. C. Wong (The Chinese University
of Hong Kong) on the occasion of his 70th birthday. We are
grateful to the National Natural Science Foundation of China
(no. 21801119), Shenzhen Nobel Prize Scientists Laboratory
Project (C17783101), and Shenzhen Science and Technology
Innovation Committee (no. KQTD20150717103157174).
REFERENCES
■
̈
(1) (a) Brase, S. Privileged Scaffolds in Medicinal Chemistry: Design,
Synthesis, Evaluation; RSC, 2015. (b) Rivas, F.; Ling, T. Advances
toward the Synthesis of Functionalized γ-Lactams. Org. Prep. Proced.
Int. 2016, 48, 254−295.
(2) (a) Liu, H.; He, X.; Phillips, D.; Zhu, X.; Yang, K.; Lau, T.; Wu,
B.; Xie, Y.; Nguyen, T. N.; Wang, X. Azacyclic compounds as
inhibitors of cannabinoid receptor 1 and their preparation,
pharmaceutical compositions and use in the treatment of CB1-
mediated diseases. WO2008076754A2, 2008. (b) Khadem, S.; Marles,
R. J. Chromone and Flavonoid Alkaloids: Occurrence and Bioactivity.
Molecules 2012, 17, 191−206. (c) Reichard, G. A.; Paliwal, S.; Shih,
N.-Y.; Xiao, D.; Tsui, H.-C.; Shah, S.; Wang, C.; Wrobleski, M. L.
Preparation of arylpyrrolidinones as neurokinin-1 (NK1) antagonists.
WO2003042173, 2003. (d) Wood, M. R.; Gallicchio, S. N.; Selnick,
H. G.; Zartman, C. B.; Bell, I. M.; Stump, C. A. Substituted
spiro[Indane-azaindolinone] derivatives as CGRP receptor antago-
nists and their preparation, pharmaceutical compositions and use in
the treatment of CGRP-associated diseases such as headaches.
US20070265225, 2007.
(8) For reviews, see: (a) Wang, C.; Xiao, J. Asymmetric Reductive
Amination. Top. Curr. Chem. 2013, 343, 261−282. (b) Nugent, T. C.;
El-Shazly, M. Chiral Amine Synthesis - Recent Developments and
Trends for Enamide Reduction, Reductive Amination, and Imine
Reduction. Adv. Synth. Catal. 2010, 352, 753−819.
(9) For representative examples on ARA, see: (a) Kadyrov, R.;
(3) (a) Speck, K.; Magauer, T. The chemistry of isoindole natural
products. Beilstein J. Org. Chem. 2013, 9, 2048−2078. (b) Li, E.; Jiang,
L.; Guo, L.; Zhang, H.; Che, Y. Pestalachlorides A−C, antifungal
metabolites from the plant endophytic fungus Pestalotiopsis adusta.
Bioorg. Med. Chem. 2008, 16, 7894−7899.
̈
Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Borner, A. The First
Highly Enantioselective Homogeneously Catalyzed Asymmetric
Reductive Amination: Synthesis of α-N-Benzylamino Acids. J. Org.
Chem. 2003, 68, 4067−4070. (b) Williams, G. D.; Pike, R. A.; Wade,
E
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
́
C. E.; Wills, M. A One-Pot Process for the Enantioselective Synthesis
of Amines via Reductive Amination under Transfer Hydrogenation
Conditions. Org. Lett. 2003, 5, 4227−4230. (c) Li, C.; Villa-Marcos,
B.; Xiao, J. Metal-Brønsted Acid Cooperative Catalysis for
Asymmetric Reductive Amination. J. Am. Chem. Soc. 2009, 131,
O.; Yus, M. Synthesis of γ-, δ-, and ε-!Lactams by Asymmetric
Transfer Hydrogenation of N-(tert-Butylsulfinyl)iminoesters. J. Org.
Chem. 2013, 78, 3647−3654. (d) Das, B. G.; Nallagonda, R.; Dey, D.;
Ghorai, P. Synthesis of Air- and Moisture-Stable, Storable Chiral
Oxorhenium Complexes and Their Application as Catalysts for the
Enantioselective Imine Reduction. Chem. - Eur. J. 2015, 21, 12601−
12605.
́
́
6967−6969. (d) Rubio-Perez, L.; Perez-Flores, F. J.; Sharma, P.;
Velasco, L.; Cabrera, A. Stable Preformed Chiral Palladium Catalysts
for the One-Pot Asymmetric Reductive Amination of Ketones. Org.
Lett. 2009, 11, 265−268. (e) Strotman, N. A.; Baxter, C. A.; Brands,
K. M. J.; Cleator, E.; Krska, S. W.; Reamer, R. A.; Wallace, D. J.;
Wright, T. J. Reaction Development and Mechanistic Study of a
Ruthenium Catalyzed Intramolecular Asymmetric Reductive Amina-
tion en Route to the Dual Orexin Inhibitor Suvorexant (MK-4305). J.
Am. Chem. Soc. 2011, 133, 8362−8371. (f) Zhou, S.; Fleischer, S.;
Jiao, H.; Junge, K.; Beller, M. Cooperative Catalysis with Iron and a
Chiral Brønsted Acid for Asymmetric Reductive Amination of
Ketones. Adv. Synth. Catal. 2014, 356, 3451−3455. (g) Gallardo-
Donaire, J.; Ernst, M.; Trapp, O.; Schaub, T. Direct Synthesis of
Primary Amines via Ruthenium-Catalysed Amination of Ketones with
Ammonia and Hydrogen. Adv. Synth. Catal. 2016, 358, 358−363.
(h) Yang, P.; Lim, L. H.; Chuanprasit, P.; Hirao, H.; Zhou, J. S.
Nickel-Catalyzed Enantioselective Reductive Amination of Ketones
with Both Arylamines and Benzhydrazide. Angew. Chem., Int. Ed.
2016, 55, 12083−12087. (i) Huang, H.; Liu, X.; Zhou, L.; Chang, M.;
Zhang, X. Direct Asymmetric Reductive Amination for the Synthesis
of Chiral β-Arylamines. Angew. Chem., Int. Ed. 2016, 55, 5309−5312.
(j) Zhou, H.; Liu, Y.; Yang, S.; Zhou, L.; Chang, M. One-Pot N-
Deprotection and Catalytic Intramolecular Asymmetric Reductive
Amination for the Synthesis of Tetrahydroisoquinolines. Angew.
Chem., Int. Ed. 2017, 56, 2725−2729. (k) Zhang, Y.; Yan, Q.; Zi, G.;
Hou, G. Enantioselective Direct Synthesis of Free Cyclic Amines via
Intramolecular Reductive Amination. Org. Lett. 2017, 19, 4215−4218.
(l) Song, B.; Chen, M.-W.; Zhou, Y.-G. Synthesis of chiral sultams
with two adjacent stereocenters via palladium-catalyzed dynamic
kinetic resolution. Org. Chem. Front. 2018, 5, 1113−1117. (m) Yang,
T.; Yin, Q.; Gu, G.; Zhang, X. A one-pot process for the
enantioselective synthesis of tetrahydroquinolines and tetrahydroiso-
quinolines via asymmetric reductive amination (ARA). Chem.
Commun. 2018, 54, 7247−7250. (n) Zhao, X.; Xu, H.; Huang, X.;
Zhou, J. S. Asymmetric Stepwise Reductive Amination of
Sulfonamides, Sulfamates, and a Phosphinamide by Nickel Catalysis.
Angew. Chem., Int. Ed. 2019, 58, 292−296. (o) Wu, Z.; Du, S.; Gao,
G.; Yang, W.; Yang, X.; Huang, H.; Chang, M. Secondary amines as
coupling partners in direct catalytic asymmetric reductive amination.
Chem. Sci. 2019, 10, 4509−4514. (p) Chen, Y.; He, Y.-M.; Zhang, S.;
Miao, T.; Fan, Q.-H. Rapid Construction of Structurally Diverse
Quinolizidines, Indolizidines, and Their Analogues via Ruthenium-
Catalyzed Asymmetric CascadeHydrogenation/ReductiveAmination.
Angew. Chem., Int. Ed. 2019, 58, 3809−3813. (q) Chen, Y.; Pan, Y.;
He, Y.-M.; Fan, Q.-H. Consecutive Intermolecular Reductive
Amination/Asymmetric Hydrogenation: Facile Access to Sterically
Tunable Chiral Vicinal Diamines and N-Heterocyclic Carbenes.
Angew. Chem., Int. Ed. 2019, 58, 16831−16834. (r) Wang, L.-R.;
Chang, D.; Feng, Y.; He, Y.-M.; Deng, G.-J.; Fan, Q.-H. Highly
Enantioselective Ruthenium-Catalyzed Cascade Double Reduction
Strategy: Construction of Structurally Diverse Julolidines and Their
Analogues. Org. Lett. 2020, DOI: 10.1021/acs.orglett.0c00444.
(s) Yuan, S.; Gao, G.; Wang, L.; Liu, C.; Wan, L.; Huang, H.;
Geng, H.; Chang, M. The combination of asymmetric hydrogenation
of olefins and direct reductive amination. Nat. Commun. 2020, 11,
No. 621. (t) Mori, K.; Miyake, A.; Akiyama, T. Enantioselective
synthesis of fused heterocycles with contiguous stereogenic centers by
chiral phosphoric acid catalyzed symmetry breaking. Chem. Commun.
2015, 51, 16107−16110.
(11) (a) Huang, Y. B.; Dai, J. J.; Deng, X. J.; Qu, Y. C.; Guo, Q. X.;
Fu, Y. Ruthenium-Catalyzed Conversion of Levulinic Acid to
Pyrrolidines by Reductive Amination. ChemSusChem 2011, 4,
1578−1581. (b) Wei, Y.; Wang, C.; Jiang, X.; Xue, D.; Li, J.; Xiao,
J. Highly efficient transformation of levulinic acid into pyrrolidinones
by iridium catalysed transfer hydrogenation. Chem. Commun. 2013,
49, 5408−5410. (c) Wei, Y.; Wang, C.; Jiang, X.; Xue, D.; Liu, Z.-T.;
Xiao, J. Catalyst-free transformation of levulinic acid into
pyrrolidinones with formic acid. Green Chem. 2014, 16, 1093−1096.
(d) Ogiwara, Y.; Uchiyama, T.; Sakai, N. Reductive Amination/
Cyclization of Keto Acids Using a Hydrosilane for Selective
Production of Lactams versus Cyclic Amines by Switching of the
Indium Catalyst. Angew. Chem., Int. Ed. 2016, 55, 1864−1867. (e) Xu,
Z.; Yan, P.; Jiang, H.; Liu, K.; Zhang, Z. C. Iridium-Catalyzed
Reductive Amination of Levulinic Acid to Pyrrolidinones under H2 in
Water. Chin. J. Chem. 2017, 35, 581−585.
́
(12) Mourelle-Insua, A.; Zampieri, L. A.; Lavandera, I.; Gotor-
́
Fernandez, V. Conversion of γ- and δ-Keto Esters into Optically
Active Lactams. Transaminases in Cascade Processes. Adv. Synth.
Catal. 2018, 360, 686−695.
(13) (a) Kadyrov, R.; Riermeier, T. H. Highly Enantioselective
Hydrogen-Transfer Reductive Amination: Catalytic Asymmetric
Synthesis of Primary Amines. Angew. Chem., Int. Ed. 2003, 42,
5472−5474. (b) Steinhuebel, D.; Sun, Y.; Matsumura, K.; Sayo, N.;
Saito, T. Direct Asymmetric Reductive Amination. J. Am. Chem. Soc.
2009, 131, 11316−11317. (c) Mattei, P.; Moine, G.; Puntener, K.;
̈
Schmid, R. Asymmetric Synthesis of (S)-3-Amino-4-methoxy-butan-
1-ol by Way of Reductive Amination. Org. Process Res. Dev. 2011, 15,
353−359. (d) Matsumura, K.; Zhang, X.; Hori, K.; Murayama, T.;
Ohmiya, T.; Shimizu, H.; Saito, T.; Sayo, N. Practical, Catalytic
Enantioselective Hydrogenation to Synthesize N-Unprotected β-
Amino Esters. Org. Process Res. Dev. 2011, 15, 1130−1137.
(14) (a) Gallardo-Donaire, J.; Hermsen, M.; Wysocki, J.; Ernst, M.;
̈
Rominger, F.; Trapp, O.; Hashmi, A. S. K.; Schafer, A.; Comba, P.;
Schaub, T. Direct Asymmetric Ruthenium-Catalyzed Reductive
Amination of Alkyl−Aryl Ketones with Ammonia and Hydrogen. J.
Am. Chem. Soc. 2018, 140, 355−361. (b) Tan, X.; Gao, S.; Zeng, W.;
Xin, S.; Yin, Q.; Zhang, X. Asymmetric Synthesis of Chiral Primary
Amines by Ruthenium-Catalyzed Direct Reductive Amination of Alkyl
Aryl Ketones with Ammonium Salts and Molecular H2. J. Am. Chem.
Soc. 2018, 140, 2024−2027.
(15) (a) Lou, Y.; Hu, Y.; Lu, J.; Guan, F.; Gong, G.; Yin, Q.; Zhang,
X. Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of
Chiral Primary β-Amino Lactams. Angew. Chem., Int. Ed. 2018, 57,
14193−14197. (b) Yang, T.; Guo, X.; Yin, Q.; Zhang, X.
Intramolecular asymmetric reductive amination: synthesis of
enantioenriched dibenz[c, e]azepines. Chem. Sci. 2019, 10, 2473−
2477.
(16) (a) Scott, L. J. Larotrectinib: First Global Approval. Drugs
2019, 79, 201−206. (b) Ning, Z.; Yang, L.; Peng, F.; Wei, G.; Huang,
X.; Faming Zhuanli Shenqing. Preparation method of (R)-2-(2-
substituted-5-fluorobenzene)pyrrolidine, CN109053525, 2018.
(c) Haas, J.; Andrews, S. W.; Jiang, Y.; Zhang, G. Substituted
pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors and
their preparation and use in the treatment of diseases,
WO2010048314A1, 2010.
(17) (a) Yamada, M.; Hamamoto, S.; Hayashi, K.; Takaoka, K.;
Matsukura, H.; Yotsuji, M.; Yonezawa, K.; Ojima, K.; Takamatsu, T.;
Taya, K.; Yamamoto, H.; Kiyoto, T.; Kotsubo, H. Processes for
producing 7-isoindolinequinolonecarboxylic derivatives as antibacte-
rial agents and intermediates therefor, salts of 7-isoindolinequinolo-
necarboxylic acids, hydrates thereof, and composition containing the
(10) (a) Cheemala, M. N.; Knochel, P. New P, N-Ferrocenyl
Ligands for the Asymmetric Ir-Catalyzed Hydrogenation of Imines.
Org. Lett. 2007, 9, 3089−3092. (b) Rajender Reddy, L.; Prasad, K.;
Prashad, M. A. A Protocol for an Asymmetric Synthesis of γ-Amino
Acids. J. Org. Chem. 2012, 77, 6296−6301. (c) Guijarro, D.; Pablo,
F
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
same as active ingredient. WO9921849, 1999. (b) Ling, F.; Ai, C.; Lv,
Y.; Zhong, W. Traceless Directing Group Assisted Cobalt-Catalyzed
C-H Carbonylation of Benzylamines. Adv. Synth. Catal. 2017, 359,
3707−3712. (c) Wu, X.; Mao, Y. The Synthesis of Garenoxacin. Chin.
J. Mod. Appl. Pharm. 2009, 26, 218−220.
(18) Breinlinger, E. C.; Cox, P. B.; Daanen, J.; Dietrich, J.; Djuric, S.;
Dombrowski, A. W.; Frank, K. E.; Friedman, M. M.; Gomtsyan, A.; Li,
H.-Q.; Longenecker, K., Osuma, A.; Rowley, A. M.; Schmidt, R.;
Vasudevan, A.; Wilson, N. Preparation of tricyclic compounds as
modulators of TNF signalling. WO2016168641, 2016.
G
https://dx.doi.org/10.1021/acs.orglett.0c00669
Org. Lett. XXXX, XXX, XXX−XXX