Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of Chiral Primary β-Amino Lactams

Article abstract of DOI:10.1002/anie.201809719

A highly efficient ruthenium-catalyzed asymmetric reductive amination (ARA) of racemic β-keto lactams with molecular hydrogen and ammonium salts is disclosed for the synthesis of enantiomerically pure primary amino lactams through dynamic kinetic resolution (DKR). By this approach, a range of syn primary β-amino lactams were obtained in high yields with high chemo-, enantio-, and diastereoselectivity (up to 98 % yield, 99 % ee, >20:1 d.r., syn products). The utility of the products has been demonstrated by rapid access to a key synthetic intermediate towards biologically active drug molecules. Meanwhile, mechanistic studies and control experiments indicate that the reaction may proceed through the hydrogenation of an iminium intermediate.

Full text of DOI:10.1002/anie.201809719

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Accepted Article
Title: Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of
Chiral Primary β-amino Lactams
Authors: Yazhou Lou, Yutao Hu, Jiaxiang Lu, Fanfu Guan, Gelin Gong,
Qin Yin, and Xumu Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809719
Angew. Chem. 10.1002/ange.201809719
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10.1002/anie.201809719
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Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of
Chiral Primary β-amino Lactams
Yazhou Loua, Yutao Hua, Jiaxiang Lua, Fanfu Guana, Gelin Gonga, Qin Yin*a,b, Xumu Zhang*a
stereocenters containing a primary amino fragment via DKR has
not been systematically explored and remains a great challenge.
To our knowledge, only two catalytic examples of cyclic ketones
were recorded, yielding mainly anti amino acid derivatives with
moderate to good enantio- and diastereoselectivity.10 Herein, we
report a highly efficient asymmetric synthesis of syn primary β-
amino lactams via ARA of racemic β-keto lactams with up to 98%
yield, 99% ee and >20:1 d.r. (syn-products as major products).
Abstract: A highly efficient Ru-catalyzed asymmetric reductive
amination (ARA) of racemic β-keto lactams with molecular hydrogen
and ammonium salts has been disclosed for the synthesis of
enantiomerically pure primary amino lactams via dynamic kinetic
resolution (DKR). Using this approach, a range of syn-primary β-
amino lactams are obtained in high yields and high chemo-, enantio-
and diastereo-selectivities (up to 98% yield, 99% ee, >20:1 d.r., syn-
products). The utility of the products has been demonstrated by a
quick access to a key synthetic intermediate towards biologically
active drug molecules. Meanwhile, mechanistic studies and control
experiments indicate that the recation may proceed through a
process of hydrogenation of an iminium intermediate.
Chiral amines are very common structural units in natural
products, pharmaceuticals and agrochemicals.1 Transition
metal-catalyzed ARA of carbonyl compounds with transition
metal hydrides has emerged as a powerful and useful tool for
the construction of chiral C-N bonds.2 Due to competitive
reduction between ketone and imine intermediates in the
presence of transition metal hydrides and product inhibition of
amines to transition-metal catalysts, up to now, this field remains
underdeveloped.3 Arylamines4 or benzyl amines5 are generally
considered as the amine sources in reductive amination and
chiral secondary amines are thus obtained. An additional
deprotection step is necessary to achieve more valuable primary
amines. Compared to well-established methodologies toward
chiral secondary amines, limited reports are available regarding
the direct construction of chiral primary amines by ARA.
Considering the step efficiency and atom economy, the direct
preparation of unprotected amines in one step by ARA would be
highly desirable. In 2003, Kadyrov and co-workers reported a
Rh-catalyzed hydrogen-transfer ARA of ketones with ammonium
formate to construct primary amines.6 Subsequently, more
efficient hydrogenation processes capable of constructing chiral
primary β-amino ester with ammonium salts were developed by
the scientists in Lanxess and Takasago, respectively.7 And
shortly after, this approach was applied to prepare top-selling
drugs sitagliptin and ezetimibe.8 Very recently, Schaub and our
group independently reported Ru-catalyzed ARA of simple aryl
ketones employing ammonia or ammonium salts, respectively.9
Despite these promising results, ARA of racemic ketones with
ammonium salts or ammonia to access continuous chiral
Figure 1. Selected biologically active compounds containing
aminopyrrolidine moiety
a chiral γ-
Chiral unprotected β-amino lactams are pivotal precursors to
access primary γ-aminopyrrolidine and γ-aminopiperidine,9b
which are very common fragments in biologically active
compounds including antibacterial agents,11,12 anti-infective
agents,13 antitumor agents14 and fluoroquinolone prodrugs15
(Figure 1). However, multi-steps synthetic routes are generally
required to access these versatile chiral amine building
blocks12,16 and catalytic asymmetric approaches remain
unknown. Transition-metal-catalyzed ARA of racemic β-ketone
lactams with ammonia or its equivalents by DKR would be a
facile and ideal way to achieve this goal.
Continuing our interest in ARA,9b we started our research with
racemic α-acetyl γ-lactam 1a as the model substrate, hydrogen
as the reducing reagent and ammonium benzoate as the amine
source (Table 1). We evaluated the performance of various
diphosphine ligands in combination with a Ru precursor.
Gratifyingly, all reactions proceeded smoothly to give the desired
product, though under some conditions trace amounts of
secondary alcohols resulting from competitive ketone reduction
were detected (entries 1-9). The simple (S)-SegPhos gave the
best results in terms of enantio- and diastereoselectivities (93%
ee, >20:1 d.r., entry 2) while our previous reported C3-TunePhos
yielded comparable enantiocontrol (90% ee, entry 5). Besides,
the reaction could also work well with a Rh precursor albeit with
a decreased ee (entry 9).
[a]
[b]
Department of Chemistry and Shenzhen Grubbs Institute, Southern
University of Science and Technology, Shenzhen, Guangdong
518055, people’s Republic of China
E-mail: zhangxm@sustc.edu.cn
Academy for Advanced Interdisciplinary Studies, Southern
University of Science and Technology, Shenzhen, Guangdong
518000, People’s Republic of China.
Table 1. Ligand screening of Ru-catalyzed ARA of β-keto lactams[a]
E-mail: yinq@sustc.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201809719
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COMMUNICATION
source, 1.0 equiv AcOH as additive, 30 atm of H2 at 80 oC in 2.0
mL MeOH is the optimal choice.
Table 2. Further optimization of reaction conditions[a]
Entry
1
Ligand
Conv. (%)[b] d.r.[c]
ee (%)[d]
82
(S)-BINAP
>99
>99
>99
>99
>99
>99
>99
>99
>99
>20:1
>20:1
>20:1
>20:1
>20:1
19:1
Amine
2
(S)-SegPhos
93
Entry
Additive[b]
Solvent[b]
Conv.(%)[c]
d.r.[c]
ee(%)[d]
source[b]
3e
(R,S)-Cy-JosiPhos
(S)-DM-SegPhos
(R,R,Ra)-C3-TunePhos
(Sc,Rp)-DuanPhos
(2S,4S)-BDPP
(S,S)-f-Binaphane
(S)-SegPhos
-57
92
1
NH4F
TFA
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
>99
>99
>99
n.r.
>20:1
>20:1
n.d.
95
4
2
NH4OAc
NH4Cl
TFA
96
5
-90
44
3
TFA
n.d.
n.d.
96
6[e]
7[e]
8[e]
9[f]
4[e]
5
NH3
TFA
n.d.
>20:1
54:46
>20:1
race
-30
89
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
TsOH
AcOH
PhCOOH
-
>99
>99
>99
95(76)
78
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
n.d.
6
97
7
95
[a] The reactions were performed with 1a (0.2 mmol), PhCOONH4 (5.0 equiv),
Ru(OAc)2Ligand (2.0 mol%) and TFA (0.2 mmol) in 2.0 mL MeOH at 80 oC for 20
h. [b] determined by crude 1H NMR. [c] determined with chiral HPLC or 1H NMR.
[d] determined with chiral HPLC after acylation. [e] Prepared in situ by mixing
Ru(COD)(methylallyl)2 (2 mol%) , Ligand (2 mol%) and MeCOOH (4 mol%) in
MeOH for 30 min before using. [f] [Rh(COD)Cl]2, instead of Ru(OAc)2, was used.
TFA = trifluoroacetic acid.
8[f]
9
96
AcOH
AcOH
AcOH
AcOH
AcOH
97
10
11
12
13[g]
i-PrOH
Toluene
THF
72
97
44
97
trace
>99(85)
n.d.
97
MeOH
>20:1
[a] Unless otherwise mention, the reaction was performed with 1a (0.2 mmol),
NH4X (5.0 equiv), Ru(OAc)2(S)-SegPhos(L2) (2.0 mol%) and additive (0.2 mmol)
in 2.0 mL solvent at 80 oC for 20 h. [b] See SI for detail. [c] Determined by crude
1H NMR, isolated yield of 2a in parentheses. [d] determined with chiral HPLC
after acylation. [e] 7 atm NH3 and 30 atm H2 were used. [f] no additive was
used and 8% of alcohol was obseverd. [g] 2.5 equiv NH4OAc was used. DCE =
1,2-dichloroetnane. THF = tetrahydrofuran
Table 3. Substrate scope.[a,b,c]
Then we systematically screened the reaction conditions,
including the evaluations of ammonium salts, additives, solvents,
temperature and hydrogen pressure (Table 2, also see
Supporting Information for details). Ammonium salts such as
NH4F and NH4OAc could be used as nitrogen donors to
smoothly give the chiral primary amine product with great stereo
control, but NH4Cl, NH4Br and NH4HSO4 failed.17 An attempt
using ammonia (NH3) as the amino source did not provide any
conversion (entry 4). Investigation of acid additives revealed that
all tested acid had a positive effect on the outcome and acetic
acid proved to be the best choice, yielding syn product 2a as
the major product with 97% ee and >20:1 d.r. without formation
of any alcohol byproduct (<1%) (entry 6). Acid additives are
necessary to improve the reaction activities and suppress the
inhibitory effect of the free amines toward the catalysts.8a
Without any acid additive, the reaction proceeded with
decreased reactivity (95% conv.) and alcohol byproduct was
thereby found (8% selectivity) (entry 8). Screening of solvents
disclosed that the desired products could be obtained in various
solvents except THF, and methanol was found to be the best
solvent. Additionally, reaction temperature, H2 pressure and
catalyst loading were also evaluated (see Supporting
Information for details). To be noted, secondary amine product
formed by double reductive aminations was not observed
throughout the study. Considering both the yield and
stereoselectivity of 2a, the combination of 1.0 mol%
Ru(OAc)2(S)-SegPhos as catalyst, 2.5 equiv NH4OAc as amine
[a]The reaction was performed with
Ru(OAc)2(S)-Segphos (1.0 mol%) and AcOH (0.2 mmol) in 2.0 mL MeOH at
1 (0.2 mmol), NH4OAc (2.5 equiv),
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after acylation; d.r. values were determined by HPLC or 1H NMR analysis.
[d] The two diastereoisomers could be separated by chromatographic
purification of their corresponding acylation products (see Supporting
Information).
o
undefined.19 To gain some insights into the reaction pathway, we
conducted several isotopic labelling experiments and control
experiments (Scheme 1). From 1H NMR analysis, for either 1a or
independently prepared unprotected enamine 6a, deuterium
incorporation at the C1, C2 and C3 position was observed with
different ratios when using D2 gas,20 indicating the complexity of
this reaction and the difficulty of getting a conclusion of the
reaction pathway with only isotopic labeling experiments (Eqs 1-
2). In the presence of AcOH, 6a was smoothly transformed to
the desired syn 2a with remarkable stereocontrol, whilst only
trace amounts of conversion was observed without the acid
additive (Eq 3), implying the importance of acid to promote the
transformation from an enamine to iminium. Moreover,
decreased stereocontrol was observed in the case of Ac-
protected enamine 7a while Ms-protected enamine 8a did not
work in the present reaction at all. Based on these experimental
results and literature precedences,21 we tentatively speculate
that the final products are likely accessed through hydrogenation
of an iminium intermediate rather than an enamine intermediate.
80 C for 20 h. [b] Isolated yields. [c] ee values were determined by HPLC
A
range of racemic α-acyl-substituted γ-lactams were
synthesized and tested under the optimal conditions, and the
results are summarized in Table 3. Overall, all tested substrates
proceeded smoothly to give the corresponding primary β-amino
lactams in moderate to excellent yields with generally excellent
enantioselectivity (2a-2p, 90-99% ee ) and diastereoselectivity
(>20:1 d.r., syn-products as major products). When
nonprotected lactam 1b was used, the reaction worked smoothly
to yield the NH free primary amine 2b with 96% ee and >20:1
d.r.. Replacing the N-protecting group of lactam substrates with
a methyl-, phenyl- or p-MeO-benzyl group has little effect on the
enantio- and diastereocontrol (2c, 2d, 2e). Various alkyl
substituted β-keto lactams were well tolerated, providing the
corresponding primary amines in good yields and excellent
stereocontrol (2f-2m, 98-99% ee). Substrate 1n with
a
heteroaryl group was tolerant in this reaction with modest yield
albeit high stereoselectivity (2n). Unfortunately, substrates 1o or
1p with a benzoyl group provided the desired products 2o or 2p
in only low yields due to lower reactivity. The β-keto δ-lactams
can also be hydrogenated to the corresponding β-amino δ-
lactams in good yields (96%) with excellent enantioselectivities
(90-99% ee) (2q). However, the diastereoselectivity-control is
problematic, which may be due to the configuration effect of the
six-membered ring. Nevertheless, the two diastereoisomers
could be separated by chromatographic purification of their
corresponding Ac-protected derivatives. The extension of this
DKR process to acyclic β-keto amides proved to be inefficient at
this stage. The stereo configuration of generated β-amino γ-
lactams was assigned to be syn-(S,R) by X-ray crystallographic
analysis of 4-NO2Ts-2g (see SI). 18
To demonstrate the utility of this efficient approach, a scale-up
(0.52 g) preparation of β-amino lactams were performed, giving
2a in 94% yield with 95% ee and 97:3 d.r.. 2a was subsequently
applied to synthesize chiral pyrrolidine 5a, which is the key
intermediate to many antibacterial agents, anti-infective agents
and fluoroquinolone prodrug (see Figure 1). After the reduction
of 2a with LiAlH4, the resulting primary amine was protected with
(Boc)2O and subsequent removal of the benzyl group with Pd/C
under hydrogenation condition yielded the desired chiral
intermediate 5a in 58% overall yield, without loss of the optical
purity.
Scheme 2. Gram-scale synthesis and synthetic utility of the product 2a.
In summary, we have developed an atom- and step
economical methodology for the construction of enantiomerically
enriched primary β-amino lactams via DKR. A series of racemic
β-ketone γ- and δ-lactams could be hydrogenated to the
corresponding primary β-amino γ- and δ-lactams in good yield
with generally high stereoselectivity. The reaction pathway of
this reaction was also studied and likely involved hydrogenation
of the iminium intermediates instead of the enamine
intermediates. In addition, with this method, synthetically useful
enantioenriched β-aminopyrrolidines could be facilely obtained
in an efficient manner.
Acknowledgements
Scheme 1. Isotopic labelling experiments with D2 and control experiments.
We are grateful to a start-up fund from Southern University
of Science and Technology, Shenzhen Science and
In this reaction, the stereo-induction can be achieved through
the process of hydrogenation of the iminium or enamine
intermediate and both of them could be hydrogenated to yield
the final products. However, related research on this topic is still
Technology
Innovation
Committee
(No.
KQTD20150717103157174), Shenzhen Nobel Prize
Scientists Laboratory Project (C17213101) and National
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10.1002/anie.201809719
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Y. Kim, E. Lucien, G. Pais, M. Pucci, Q. Wang, J. A. Wiles, A. Phadke,
PCT Patent Appl. EP2414368 B1, 2013.
Natural Science Foundation of China (No. 21432007 and
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Keywords: asymmetric catalysis • asymmetric hydrogenation •
chiral lactams • primary amines • reductive amination
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10.1002/anie.201809719
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Yazhou Loua, Yutao Hua, Jiaxiang Lua,
Fanfu Guana, Gelin Gonga, Qin Yin*a,b
Xumu Zhang*a
,
Page No. – Page No.
Dynamic
Kinetic
Asymmetric
Reductive Amination: Synthesis of
Chiral Primary β-amino Lactams
A dynamic kinetic Ru-catalyzed ARA of racemic β-keto lactams with molecular
hydrogen and ammonium salts for the synthesis of enantioenriched primary
amino lactams in high yields and high chemo-, stereoselectivities (up to 98%
yield, 99% ee, >20:1 d.r.) has been achieved.
This article is protected by copyright. All rights reserved.