Highly Enantioselective Synthesis of Chiral γ-Lactams by Rh-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acscatal.8b00827

A Rh/bisphosphine-thiourea (ZhaoPhos) catalytic system has been identified for the straightforward asymmetric synthesis of chiral γ-lactams. A variety of NH free α,β-unsaturated lactams bearing a β-aryl or β-alkyl substituent were smoothly hydrogenated to

Full text of DOI:10.1021/acscatal.8b00827

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Highly Enantioselective Synthesis of Chiral #-
Lactams by Rh-Catalyzed Asymmetric Hydrogenation
Qiwei Lang, Guoxian Gu, Yaoti Cheng, Qin Yin, and Xumu Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00827 • Publication Date (Web): 23 Apr 2018
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ACS Catalysis
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Highly Enantioselective Synthesis of Chiral γ-Lactams by Rh-
Catalyzed Asymmetric Hydrogenation
Qiwei Lang,† Guoxian Gu,† Yaoti Cheng,† Qin Yin,*,†,‡ and Xumu Zhang*,†
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†Department of Chemistry, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China
‡Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000, Peoꢀ
ple’s Republic of China
ABSTRACT: A Rh/bisphosphineꢀthiourea (ZhaoPhos) catalytic system has been identified for the straightforward asymmetric
synthesis of chiral γꢀlactams. A variety of NH free α,βꢀunsaturated lactams bearing a βꢀaryl or ꢀalkyl substituent were smoothly
hydrogenated to provide the desired γꢀlactams in up to 99% yield and 99% ee. This methodology provides a highly practical pathꢀ
way to synthesize chiral γꢀlactams or γꢀamino acids.
Key words: asymmetric hydrogenation, bisphosphineꢀthiourea, α,βꢀunsaturated lactams, chiral γꢀlactams, γꢀamino acids
lines,18 and others.19 Considering the possible hydrogenꢀ
INTRODUCTION
bonding interaction between thiourea subunit in ZhaoPhos and
Chiral γꢀlactams have attracted increasing attention due to
the amide group of the substrate, we envisioned that ZhaoPhos
their ubiquitous existence in bilogical compounds,1 especially
could also be applied in the Rhꢀcatalyzed hydrogenation of
clinic therapeutics, such as the antidepressant drug (R)ꢀ
α,βꢀunsaturated lactams.
Rolipram2 and antiepilepsy drug Brivaracetam.3 Additionally,
their ringꢀopened products, γꢀamino acids, are key intermediꢀ
ates to access a variety of natural products and drug moleꢀ
cules,4 such as Baclofen5 and Pregabalin6 (upper, Figure 1).
Tremendous efforts have thus been devoted to the preparation
of chiral γꢀlactams.7,8 Rhꢀcatalyzed asymmetric conjugate adꢀ
dition of organometallic reagents to α,βꢀunsaturated lactams
represents a straightforward and efficient strategy.8 Seminal
works from He,8a Lin8b,8c and others8d,8e have made this method
reliable to obtain chiral γꢀlactams. It is noteworthy that a proꢀ
tecting group, either electronꢀdonating or ꢀwithdrawing, on the
N atom of the substrates is critical and generally no reaction
would occur for free lactam substrates. An additional deproꢀ
tection operation is requisite to liberate more versatile NH
amide or amine products (lower left, Figure 1). Alternatively,
we envisaged βꢀsubstituted chiral γꢀlactams could be directly
synthesized via asymmetric hydrogenation of βꢀsubstituted
α,βꢀunsaturated lactams (lower right, Figure 1). In comparison
with wellꢀestablished asymmetric hydrogenation of α,βꢀ
unsaturated lactones,9 maleinimides10 and maleic anhydrides,11
hydrogenation of structurally similar but more inert α,βꢀ
unsaturated lactams remains a formidable task and no asymꢀ
metric manner has been developed so far.12,13 Herein, we reꢀ
ported an unprecedented Rhꢀcatalyzed asymmetric hydrogenaꢀ
tion of βꢀsubstituted α,βꢀunsaturated lactams, which could
successfully tolerate free NH amide group.
Figure 1. Selected biologically active molecules with a chiral
γꢀlactam or γꢀamino acid unit (upper) and methods toward
them (lower).
RESULTS AND DISCUSSION
We initiated our study by investigating the performance of
different combinations of rhodium precatalysts and various
chiral bisphosphine ligands with the standard substrate NH
lactam 1a under 60 atm of H2. While several commercially
available ligands, such as Binap, SegPhos, DuanPhos and Joꢀ
siPhos (Figure 2), exhibited very limited activities in the hyꢀ
drogenation reactions catalyzed by Rhꢀligand complexes, we
were pleased to observe that ZhaoPhos displayed encouraging
outcome in terms of conversion and enantiocontrol (entry 5 vs
entries 1ꢀ4, Table 1). Further evaluation of rhodium source
Recently we have reported a novel ligand, ZhaoPhos, comprisꢀ
ing a chiral ferrocenylbisphosphine scaffold and a tunable
thiourea moiety.14 This ligand has found broad application in
Rhꢀcatalyzed asymmetric hydrogenation of a variety of subꢀ
strates, such as substituted nitroꢀolefins,14,15 unsaturated carꢀ
boxylic acid derivatives,16 unprotected imines,17 isoquinoꢀ
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(entries 6 and 7) unveiled Rh(NBD)2BF4 as the best precataꢀ
Page 2 of 6
lectivities were generally obtained, the conversion is highly
dependent on the solvent. Overall, dichloromethane afforded
the best results in terms of conversion and enantioselectivity
(entries 1ꢀ7, Table 2). Interestingly, 99% ee of 2a could be
1
2
3
4
lyst, affording the desired product 2a in 91% yield and 96% ee
(entry 6). Attempts to use other metal precatalysts,
[Ir(COD)Cl]2 and [RuCl2(pꢀcymene)]2 in combination with
ZhaoPhos did not bring satisfactory results (entries 8 and 9).
o
achieved in THF at 25 C albeit with moderate conversion of
1a. Attempts to enhance the reaction conversion in THF by
elevating the reaction temperature proved to be fruitful (entries
7ꢀ9). The optimal conversion of 1a in THF (88%) was finally
achieved when the reaction was carried out at 60 oC, however,
with slightly decreased enantioselectivity of 2a (96% ee, entry
9). On the other hand, full conversion was fortunately obtained
in the case of CH2Cl2 when the temperature was increased to
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60
o
35 C, without sacrificing the reaction enantiocontrol (entry
10). When we reduced the hydrogenation pressure from 60 to
40 atm (entry 11), the conversion decreased to 86%. Given
both the yield and enantioselectivity of 2a, the combination of
Rh(NBD)2BF4/ZhaoPhos as catalyst, CH2Cl2 as solvent, 60
atm of H2 at 35 oC is the optimal conditions.
Figure 2. Tested chiral bisphosphine ligands for the asymmetꢀ
ric hydrogenation of 1a.
Table 2. Optimization of reaction conditions for the asymmetꢀ
ric hydrogenation of 1aa
Table 1. Screening of ligands and metal precatalysts for the
asymmetric hydrogenation of 1aa
Temp.
(ºC)
25
Conv.
(%)b
91
Ee
(%)c
96
87
84
94
93
75
99
98
96
96
96
Entry
Solvent
Conv. Ee
1
2
CH2Cl2
ClCH2CH2Cl
iPrOH
Entry
Precatalyst
Ligand
(%)b (%)c
25
21
1
2
Rh(COD)2BF4
Rh(COD)2BF4
SꢀBinap
0
-
3
25
14
SꢀSegPhos
30
2
4
MeOH
25
33
SC,RPꢀ
DuanPhos
3
Rh(COD)2BF4
44
3
5
CF3CH2OH
1,4ꢀdioxane
THF
25
35
6
25
43
4
5
6
7
8
Rh(COD)2BF4
Rh(COD)2BF4
Rh(NBD)2BF4
[Rh(COD)Cl]2
[Ir(COD)Cl]2
RꢀJosiPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
ZhaoPhos
19
74
91
56
9
1
7
25
65
87
96
76
-78
8
THF
35
84
9
THF
60
88
10
11d
CH2Cl2
CH2Cl2
35
>99
86
35
[RuCl2(pꢀ
cymene)]2
9
ZhaoPhos
0
-
aUnless otherwise noted, all reactions were carried out with a
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ratio of 1 : 1.1 : 100 in
aUnless otherwise noted, all reactions were carried out with a
b
1.0 mL of solvent under hydrogen (60 atm) for 48 h. Deterꢀ
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ratio of 1 : 1.1 : 100 in
1
c
mined by H NMR. Determined by HPLC analysis using a
chiral stationary phase. dThe reaction was carried out under 40
atm of hydrogen pressure.
b
1.0 mL of CH2Cl2 under hydrogen (60 atm) for 48 h. Deterꢀ
1
c
mined by H NMR. Determined by HPLC analysis using a
chiral stationary phase. The absolute configuration of 2a was
determined as R by comparing the optical rotation data with
literature.7j
To gain insight into this catalytic system, two other chiral ligꢀ
ands L1–L2 were tested and the results are summarized in
Table 3. Interestingly, the Nꢀmethylated ligand L1 exhibited
comparable activity and enantiocontrol (entry 2, 96% ee).
To further improve the conversion and enantiocontrol, solvent
and temperature effects were surveyed. While good enantioseꢀ
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However, the ligand L2 without the thiourea group displayed
91% ee. Substrates with a benzyl (1v) or more bulky isopropyl
(1w) group were also transformed smoothly to their correꢀ
sponding products (95 % ee for 2v, 96% ee for 2w). Substrate
1x with an alkyl group on the α position furnished the desired
product 2x in excellent yield albeit with very poor enantioseꢀ
lectivity (6% ee).
1
2
3
4
5
6
7
8
very low activity and led to nearly no asymmetric induction
(entry 3). A combination of L2 and thiourea completely shut
down the reaction (entry 4). In addition, nonꢀchiral ligand dppf
gave similar reactivity as L2 (entry 5). These results suggest
the importance of hydrogen bonds in this reaction, and the
thiourea motif not only efficiently activates the carbonyl group
through hydrogen bonding interaction but also works as a diꢀ
recting group.
Table 4. Substrate scopea,b,c
R
R
Rh(NBD)2BF4 (1 mol%)
ZhaoPhos (1.1 mol%)
*
O
O
9
H2 (60 atm), CH2Cl2, 35 C, 48 h
N
X
N
Table 3. Evaluation of structureꢀactivity relationship of
X
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ZhaoPhosa
1
2
OMe
Me
MeO
O
N
H
O
O
O
N
N
N
H
2d
H
H
2a
98%, 96% ee
2b
95%, 95% ee
2c
94%, 96% ee
86%, 95% ee
F
Cl
F3C
MeO
O
N
O
O
O
N
N
H
N
H
H
H
Entry
Ligand
ZhaoPhos
L1
Conv. (%)b
Ee (%)c
2e
2f
2g
2h
97%, 96% ee
99%, 92% ee
99%, 96% ee
98%, 96% ee
MeO
1
2
3
4
5
>99
>99
22
96
96
2
S
O
O
O
N
N
O
O
N
H
H
N
L2
Boc
2l
98%, 99% ee
H
2i
2j
97%, 97% ee
MeO
2k
98%, 96% ee
99%, 97% ee
L2 + thiouread
dppf
0
ꢀ
Me
20
0
aAll reactions were carried out with a [Rh(NBD)2BF4]/ligand/
1a (0.1 mmol) ratio of 1 : 1.1 : 100 in 1.0 mL of CH2Cl2 under
hydrogen (60 atm) for 48 h. bDetermined by 1H NMR.
cDetermined by HPLC analysis using a chiral stationary phase.
dL2/thiourea = 1:1, thiourea refers to thiocarbamide.
O
O
N
N
But
O
O
N
N
Me
Boc
Boc
2m
95%, 99% ee
2n
85%, 98% ee
2o
98%, 95% ee
2p
98%, 97% ee
O
With optimal conditions in hand, we then turned our attention
to the substrate scope. A wide range of βꢀaryl substituted α,βꢀ
unsaturated lactams were investigated, and in general, hydroꢀ
genation proceeded smoothly to afford the desired chiral γꢀ
lactams with free NH in excellent yield as well as enantioꢀ
meric excess (Table 4). Both electronꢀdonating (Me or MeO as
in 2bꢀ2e) and electronꢀwithdrawing (F, Cl or CF3 as in 2fꢀ2h)
substituents on the aryl ring at different positions were well
tolerated, and the reactivity and enantioselectivity were excelꢀ
lent throughout. Lactam 1j possessing a thienyl substitute was
also compatible, affording the desired product 2j in 97% yield
and 97% ee. It is noteworthy that substrate 1k with a disubstiꢀ
tuted aryl group on the β position proceeded smoothly to proꢀ
vide 2k, an antidepressant drug (Rolipram), in 98% yield and
96% ee. Besides, a series of aryl substituted α,βꢀunsaturated
N
O
O
O
N
N
N
PMP
Bn
Ph
PMP
2q
2r
98%, 97% ee
2s
2t
98%, 96% ee
99%, 96% ee
97%, 91% ee
n-C7H15
Me
Ph
*
O
O
N
O
N
O
N
N
PMP
Ph
PMP
PMP
2w
2u
99%, 93% ee
2x
2v
99%, 95% ee
98%, 96% ee
97%, 6% ee
aUnless otherwise noted, all reactions were carried out with a
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ratio of 1 : 1.1 : 100 in
b
1.0 mL of solvent under hydrogen (60 atm) for 48 h. Isolated
c
yield. Determined by HPLC analysis using a chiral stationary
phase. The configuration of 2a, 2g, 2k, 2l was determined as R
by comparing the optical rotation data with literatures.7j,8b
PMP = pꢀmethoxyphenyl.
t
lactams (1lꢀ1s) with various substituents (Boc, Me, Bu, Bn,
Ph or PMP) on N atom were also investigated. To our delight,
all reactions furnished the desired products (2lꢀ2s) in excellent
yields and enantiomeric excesses, regardless of the electronic
or steric property of the substituents on N atom. Gratifyingly,
unsaturated lactam 1t with an alkyl group on the β position is
also a suitable substrate, giving the desired γꢀlactam 2t, a preꢀ
cursor to the antiepilepsy drug Brivaracetam, in 97% yield and
To demonstrate the synthetic utility of this method, a gramꢀ
scale transformation of 1k was conducted under standard conꢀ
ditions. Satisfyingly, the hydrogenated product 2k was obꢀ
tained in 94% yield and 96% ee. Similarly, scalable hydrogenꢀ
ations of 1g and 1e were performed to furnish 2g and 2e reꢀ
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Page 4 of 6
We are grateful to Southern University of Science and Technoloꢀ
spectively in excellent yields and ee (Scheme 1). The former
2g was subsequently treated with 6 N HCl, affording GABA
receptor agonist (R)ꢀBaclofen hydrochloride (3),5,8b and the
latter 2e underwent hydride reduction with LiAlH4 and subseꢀ
quent reductive amination, furnishing chiral pyrrolidine 4
(76% yield for 2 steps), which is known to have high affinity
for an αꢀ2ꢀadrenoceptor subtype.20
gy, Shenzhen Science and Technology Innovation Committee
(JCYJ20170817110055425 and JCYJ20170817104350391) for
financial support. We greatly acknowledge Professor Tiezheng Jia
(Southern University of Science and Technology) for polishing
the paper.
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MeO
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standard conditions
94%, 96% ee
O
O
O
N
N
H
H
1k (1.04g, 3.8 mmol)
(R)-Rolipram (2k)
(2) Synthesis of (R)-Baclofen
Cl
Cl
Cl
6 N HCl
standard conditions
97%, 95% ee
reflux
O
HCl
NH2
O
O
N
N
H
HO
H
1g (232 mg, 1.2 mmol)
2g
(R)-Baclofen (3)
(3) Synthesis of -2-adrenoceptor antagonist
1) LiAlH4, THF
standard conditions
MeO
99%, 92% ee
MeO
MeO
2) ArCHO, MeOH
NaBH3CN
O
76% for 2 steps
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N
N
H
H
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-2-adrenoceptor
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1e (227 mg, 1.2 mmol)
2e
SUMMARY
In summary, we have identified a straightforward asymmetric
hydrogenation strategy towards synthetically useful chiral γꢀ
lactams from βꢀsubstituted α,βꢀunsaturated lactams catalyzed
by Rh(NBD)2BF4/ZhaoPhos. Of particular interest is the imꢀ
pressive performance of ZhaoPhos against other commercially
available ligands in this method, especially for unsaturated
lactams with free NH. The asymmetric hydrogenation strategy
reported herein represents a direct synthetic pathway to preꢀ
pare chiral γꢀlactams with high enantiomeric excess. In addiꢀ
tion, scalable and facile syntheses of drug molecules such as
Rolipram, Baclofen and αꢀ2ꢀadrenoceptor antagonist 4 highꢀ
lighted the practicality of this methodology.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: yinq@sustc.edu.cn; zhangxm@sustc.edu.cn
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Synthesis and characterization of detailed experimental proceꢀ
dures (PDF)
ACKNOWLEDGMENT
asymmetric
C–H
insertion
of
Nꢀarylalkyl,
Nꢀ
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