Synthesis of chiral seven-membered β-substituted lactams: Via Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1039/c8ob02231c

Rh/bisphosphine-thiourea ligand (ZhaoPhos)-catalyzed asymmetric hydrogenation of seven-membered β-substituted α,β-unsaturated lactams was successfully developed to prepare various chiral seven-membered β-substituted lactams with good to excellent results (up to >99% conversion, 99% yield, and >99% ee).

Full text of DOI:10.1039/c8ob02231c

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Biomolecular Chemistry
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Synthesis of chiral seven-membered β-substituted
lactams via Rh-catalyzed asymmetric
hydrogenation†
Cite this: Org. Biomol. Chem., 2018,
16, 8819
a,b
Yi Huang,a Pan Li,a Xiu-Qin Dong *a and Xumu Zhang
*
Received 10th September 2018,
Accepted 24th October 2018
Rh/bisphosphine-thiourea ligand (ZhaoPhos)-catalyzed asymmetric hydrogenation of seven-membered
β-substituted α,β-unsaturated lactams was successfully developed to prepare various chiral seven-membered
β-substituted lactams with good to excellent results (up to >99% conversion, 99% yield, and >99% ee).
DOI: 10.1039/c8ob02231c
rsc.li/obc
However, there has been limited systematic research on the devel-
opment of efficient synthetic methodologies. It is well-known
Introduction
Optically active seven-membered β-substituted lactams and that asymmetric hydrogenation of prochiral unsaturated com-
their derivative motifs have received great attention owing to pounds is an efficient and straightforward method to construct
their wide range of applications in natural products, pharma- chiral compounds.6 Asymmetric hydrogenation of β-substituted
ceuticals, biologically active molecules and building blocks in α,β-unsaturated amides mainly focuses on acyclic, five-membered
asymmetric catalysis (Fig. 1).1–4 For example, the natural cyclic substrates.7 It is very challenging to develop an efficient
product (+)-hinckdentine A was isolated from the marine catalytic system to realize asymmetric hydrogenation of prochiral
bryozoan Hincksinoflustra denticulata in 1987.2 Thiazesim dis- seven-membered β-substituted α,β-unsaturated lactams. In 2013,
played antidepressant activity.3 BMS-911278 was identified as our group successfully developed a bifunctional bisphosphine-
a potent triple reuptake inhibitor with potential for the treat- thiourea ligand (ZhaoPhos), which exhibited excellent catalytic
ment of depression.4
performance in some asymmetric hydrogenations through
Owing to the great importance of chiral seven-membered important interactions between the thiourea group of the ligand
β-substituted lactams and their derivatives, enormous efforts and the functional group of substrates.7b,c,8 Inspired by these
were devoted to the development of synthetic methods.1c,5 results, herein, we successfully realized Rh/ZhaoPhos-catalyzed
asymmetric hydrogenation of
a series of seven-membered
β-substituted α,β-unsaturated lactams, providing chiral seven-
membered β-substituted lactams with good to excellent results
(Scheme 1, up to >99% conversion, 99% yield, and >99% ee).
Results and discussion
The seven-membered β-substituted α,β-unsaturated lactams
were prepared with cyclohexane-1,3-dione as the starting
Fig. 1 Examples of natural products and biologically active molecules
containing chiral seven-membered β-substituted lactams and their material with four steps (Scheme 2).9 First, 3-ethoxycyclohex-2-
derivative motifs.
aKey Laboratory of Biomedical Polymers, Engineering Research Centre of
Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry
and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R. China.
E-mail: zhangxm@sustc.edu.cn, xiuqindong@whu.edu.cn
bDepartment of Chemistry and Shenzhen Grubbs Institute, Southern University of
Science and Technology, Shenzhen, Guangdong, 518055, P. R. China
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, NMR spectra of compounds. CCDC 1855329. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c8ob02231c
Scheme 1 Rh-Catalyzed asymmetric hydrogenation of prochiral
seven-membered β-substituted α,β-unsaturated lactams.
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Table 1 Screening ligands for Rh-catalyzed asymmetric hydrogenation
of 4-phenyl-1,5,6,7-tetrahydro-2H-azepin-2-one 1a a
Entry
Ligand
Conv.b (%)
eec (%)
Scheme 2 Synthetic route of seven-membered β-substituted
α,β-unsaturated lactams.
1
2
3
4
5
6
7
(Rc, Sp)-Duanphos
(S)-Segphos
(S, S)-f-Binaphane
tBu-Josiphos
ZhaoPhos L1
L2
>99
>99
>99
>99
70
65
40
27
73
−56
−3
87
84
86
en-1-one was easily synthesized through a simple treatment of
ethanol in the presence of p-TsOH·H2O.9a Then, 3-ethoxycyclo-
hex-2-en-1-one was reacted with a Grignard reagent to form
3-substituted cyclohex-2-en-1-one,9a,b which went through a
condensation reaction with hydroxylamine to give oxime.9c
Finally, β-substituted α,β-unsaturated lactams were prepared
through a Beckmann rearrangement reaction.9d,e
L3
a Unless otherwise mentioned, all reactions were carried out with the
Rh(NBD)2BF4/ligand/substrate 1a (0.1 mmol) ratio of 6.0/6.6/100 under
50 atm H2 at room temperature in 1.0 mL MeOH for 24 h. b Conversion
was determined by 1H NMR analysis. c ee was determined by chiral
HPLC analysis.
We began the initial research for Rh-catalyzed asymmetric
hydrogenation of seven-membered β-phenyl substituted
α,β-unsaturated lactams using 4-phenyl-1,5,6,7-tetrahydro-2H-
azepin-2-one 1a as the model substrate to investigate the effect
of bisphosphine ligands at room temperature under 50 atm
H2. Some important bisphosphine ligands and a series of
bifunctional bisphosphine-thiourea ligands (Fig. 2) were exam-
ined in this asymmetric hydrogenation with the catalyst gener-
ated in situ by mixing Rh(NBD)2BF4 with bisphosphine ligands
in MeOH. As shown in Table 1, full conversions were obtained
with (Rc, Sp)-Duanphos, (S)-Segphos, (S, S)-f-Binaphane and
tBu-Josiphos as the ligand, but poor to moderate enantio-
selectivities were observed (Table 1, entries 1–4). The bifunc-
tional bisphosphine-thiourea ligand ZhaoPhos L1 exhibited
better enantioselectivity (70% conversion, 87% ee, Table 1,
entry 5). N-Methylation of the ZhaoPhos ligand L2 and ligand
L3 without the CF3 group on the phenyl ring provided lower
reactivities and enantioselectivities (40%–65% conversions,
84%–86% ee, Table 1, entries 6 and 7). Therefore, ZhaoPhos
L1 was selected as the optimal ligand.
this Rh/ZhaoPhos L1-catalyzed asymmetric hydrogenation of
4-phenyl-1,5,6,7-tetrahydro-2H-azepin-2-one 1a. Except CH2Cl2
with full conversion, other solvents afforded poor to good con-
versions (Table 2, entries 1–8). Among these solvents, MeOH
provided moderate conversion and the best enantioselectivity
(70% conversion, 87% ee, Table 2, entry 7). To obtain full con-
version and excellent enantioselectivity, the mixture ratio of
Table 2 Screening solvents for Rh-catalyzed asymmetric hydrogen-
ation of 4-phenyl-1,5,6,7-tetrahydro-2H-azepin-2-one 1a a
Entry
Solvent
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
DCM
DCE
>99
89
69
78
44
58
70
86
91
97
99
95
>99
40
62
65
79
70
80
82
87
−5
92
88
85
93
93
90
The solvent always has great impact on reactivity and
enantioselectivity, and various solvents were investigated in
1,4-Dioxane
THF
iPrOH
EtOH
MeOH
CF3CH2OH
DCM : MeOH = 1 : 10
DCM : MeOH = 1 : 5
DCM : MeOH = 1 : 2
DCM : MeOH = 1 : 1
DCM : MeOH = 1 : 1
DCM : MeOH = 1 : 1
9d
10d
11d
12d
13e
14e, f
a Unless otherwise mentioned, all reactions were carried out with the
ratio of Rh(NBD)2BF4/ZhaoPhos L1/substrate 1a (0.1 mmol) of 6.0/6.6/
100 under 50 atm H2 in 1.0 mL solvent at room temperature for 24 h.
b Conversion was determined by 1H NMR analysis. c ee was determined
by chiral HPLC analysis. d The reaction was conducted with 0.1 mmol
1a in the total volume of 1.0 mL solvent for 48 h; MeOH : DCM is v/v.
e The reaction was conducted with 0.2 mmol 1a in the total volume of
0.5 mL solvent for 48 h. f 1.0 mol% Rh/ZhaoPhos L1 catalyst. DCM is
dichloromethane. DCE is 1,2-dichloroethane. THF is tetrahydrofuran.
Fig. 2 The structure of bisphosphine ligands in this asymmetric
hydrogenation.
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CH2Cl2 and MeOH was inspected, high conversions and good
to excellent enantioselectivities were obtained (91%–99% con-
versions, 85%–93% ee, Table 2, entries 9–12). When the ratio
of CH2Cl2 and MeOH was 1 : 1 (v/v), 95% conversion and 93%
ee were afforded (Table 2, entry 12). Full conversion was
achieved when the reaction concentration was increased from
0.1 M to 0.4 M for 48 h (>99% conversion, 93% ee, Table 2,
entry 13). In addition, this asymmetric hydrogenation was not
finished when the catalyst loading was decreased to 1.0 mol%,
poor conversion and excellent enantioselectivity were obtained
(40% conversion, 90% ee, Table 2, entry 14).
Scheme 3 Gram-scale Rh-catalyzed asymmetric hydrogenation of
4-phenyl-1,5,6,7-tetrahydro-2H-azepin-2-one 1a.
neutral (1a) and electron-deficient (1b–1c) substituted groups
on the phenyl ring can be hydrogenated smoothly in this trans-
formation with >99% conversion, 98% yield and 91%–93% ee.
The reaction of substrates with electron-rich substituted
groups (1d–1f, 1h) on the phenyl rings proceeded well with
slightly more catalyst loading, affording the desired hydrogen-
ation products (2d–2f, 2h) with high yields and good to excel-
lent enantioselectivities (>99% conversions, 97%–99% yields,
86%–96% ee). The substrate (1g) with a 2-naphthyl group also
worked efficiently with excellent results (>99% conversion,
99% yield, 93% ee). In addition, the alkyl-substituted substrate
(1i) performed smoothly to give the hydrogenation product (2i)
with good results (86% conversion, 83% yield, 84% ee).
Moreover, the substrates with a protecting group on the nitro-
gen atom of the α,β-unsaturated lactam were also investigated
in this catalytic system. The N-p-toluenesulfonyl (p-Ts-)-pro-
tected α,β-unsaturated lactam (1j) worked efficiently, affording
the desired product (2j) with full conversion, 99% yield and
With the optimized reaction conditions in hand, we turned
our attention to explore the substrate scope for the Rh-cata-
lyzed asymmetric hydrogenation of seven-membered
β-substituted α,β-unsaturated lactams. The reaction results are
summarized in Table 3.
A variety of seven-membered
β-substituted α,β-unsaturated lactams were hydrogenated well
to provide the desired chiral seven-membered β-substituted
lactams with good to excellent results (86%–>99% conversions,
30%–99% yields, 84%–>99% ee). The substrates with electron-
Table 3 Substrate scope study for Rh-catalyzed asymmetric hydrogen-
ation of α,β-unsaturated seven-membered lactamsa
>99%
ee.
The
N-t-butyloxycarbonyl
(Boc-)-protected
α,β-unsaturated lactam (1k) was also applied in this hydrogen-
ation; the desired product (2k) was obtained with only 30%
yield, and the byproduct with N-Boc-deprotection was observed
in the reaction system. In addition, we found that the challen-
ging tetrasubstituted substrate 3-methyl-4-phenyl-1,5,6,7-tetra-
hydro-2H-azepin-2-one (1l) was very difficult to hydrogenate,
and no reaction was detected.
As shown in Scheme 3, the Rh/ZhaoPhos L1-catalyzed asym-
metric hydrogenation of the model substrate 4-phenyl-1,5,6,7-
tetrahydro-2H-azepin-2-one 1a with gram scale proceeded
smoothly, providing the hydrogenation product 2a with 97%
conversion, 95% yield and 92% ee.
Conclusions
In conclusion, we have successfully developed Rh/ZhaoPhos
L1-catalyzed asymmetric hydrogenation of a series of seven-
membered β-substituted α,β-unsaturated lactams. An efficient
synthetic methodology was developed to access various chiral
seven-membered β-substituted lactams with good to excellent
results (up to >99% conversion, 99% yield, >99% ee); they are
important motifs in natural products, pharmaceuticals, and
biologically active molecules. Furthermore, the gram-scale
asymmetric hydrogenation proceeded well with excellent
results (97% conversion, 95% yield and 92% ee).
a Unless otherwise noted, all reactions were carried out with a Rh
(NBD)2BF4/ZhaoPhos L1/substrate 1 (0.2 mmol) ratio of 6.0 : 6.6 : 100 at
room temperature in 0.25 mL CH2Cl2 and 0.25 mL MeOH under 50
atm H2 for 48 h. Conversion was determined by 1H NMR analysis.
Yield was isolated yield. The ee value was determined by HPLC on a
chiral stationary phase. b 10 mol% catalyst. c 12 mol% catalyst. The
configuration of 2f was determined by X-ray analysis of its N-p-chloro-
benzoyl derivative 3.10
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Experimental
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hydrogenation
In an argon-filled glove-box, a solution of ZhaoPhos L1
(6.6 mol%) and Rh(NBD)2BF4 (6.0 mol%) in a total volume of
0.5 mL of anhydrous CH2Cl2 and MeOH (v/v = 1 : 1) was stirred
at room temperature for 2.0 h. Then, 0.2 mmol substrate 1 was
transferred into the resulting catalytic complex to make the
concentration of the substrate 0.4 M and then stirred for
another 5 min. The vials were transferred into an autoclave,
which was then charged with 50 atm H2 and stirred at room
temperature for 48 h. The hydrogen gas was released carefully
and the solution was concentrated and purified through a
short silica gel column on silica gel to remove the metal
complex. The product was analyzed by 1H NMR spectra for
conversion-determination and purified by flash column
chromatography using petroleum ether/ethyl acetate (v : v =
1 : 5) to provide the desired hydrogenation product, which was
further analyzed by chiral HPLC for ee value determination.
Conflicts of interest
The authors declare no competing financial interest.
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21432007, 21502145),
Wuhan Morning Light Plan of Youth Science and Technology
(Grant No. 2017050304010307), Shenzhen Nobel Prize
Scientists Laboratory Project (Grant No. C17213101) and the
Fundamental Research Funds for Central Universities (Grant
No. 2042018kf0202). The Program of Introducing Talents of
Discipline to Universities of China (111 Project) is also
appreciated.
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no. CCDC 1855329.†
This journal is © The Royal Society of Chemistry 2018
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