Iridium-Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated γ-Lactams: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/acs.orglett.7b00171

An efficient asymmetric hydrogenation of β,γ-unsaturated γ-lactams using an iridium-phosphoramidite complex is reported. The chiral γ-lactams were obtained in excellent yields and enantioselectivities (up to 99% yield and 99% ee). The mechanistic studies

Full text of DOI:10.1021/acs.orglett.7b00171

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated
γ‑Lactams: Scope and Mechanistic Studies
Qianjia Yuan,† Delong Liu,*,‡ and Wanbin Zhang*,†,‡
‡
†School of Chemistry and Chemical Engineering and School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: An efficient asymmetric hydrogenation of β,γ-
unsaturated γ-lactams using an iridium−phosphoramidite
complex is reported. The chiral γ-lactams were obtained in
excellent yields and enantioselectivities (up to 99% yield and
99% ee). The mechanistic studies indicated that the reduced
products were obtained via the hydrogenation of the N-
acyliminium cations, generated from β,γ-unsaturated γ-lactams,
1
which was verified by H NMR analysis. The reaction was
carried out at a reduced catalyst loading of 0.1 mol %, and the
reduced products can be transformed to two potential bioactive compounds. A new route is provided for the synthesis of chiral γ-
lactams.
γ-Lactams, bearing chiral 5-carbon atoms, exist as key structural
elements in many natural products and bioactive molecules and
are useful building blocks for the total synthesis of natural
products and chiral auxiliaries (Figure 1).1 For these reasons,
Scheme 1. Asymmetric Hydrogenation of Enamides
these hydrogenation reactions, the carbonyl group of the
enamide in the substrate is required in order to obtain high
enantioselectivity by forming a chelate complex with the metal
of the catalyst in the transition state.3b The asymmetric
hydrogenation of cyclic enamides, i.e., unsaturated lactams,
catalyzed by Rh and Ru complexes has not been reported,
possibly due to the inability of the carbonyl group of the
enamide in the cyclic species to coordinate with the metal
center of the catalyst. In contrast to Rh and Ru diphosphine
complexes, Ir-based catalysts do not require a coordinating
group in close proximity to the CC bond and, therefore,
enable the hydrogenation of a much wider range of alkenes.5
The Ir-catalyzed asymmetric hydrogenation of enamides has
been realized with moderate enantioselectivities (Scheme 1b);6
Figure 1. Representative structures of natural products, bioactive
molecules, and chiral auxiliaries containing a 5-substituted γ-lactam
moiety.
the development of efficient methodologies for the enantiose-
lective synthesis of γ-lactam derivatives has attracted much
attention.2 However, no reports on the asymmetric hydro-
genation of β,γ-unsaturated γ-lactams for the preparation of
chiral γ-lactams have been published.
Transition-metal-catalyzed asymmetric hydrogenation reac-
tions hold a prominent position in organic synthesis because of
their operational simplicity, high atom economy, and low
environmental impact.3,4 Asymmetric hydrogenations of
enamides catalyzed by Rh and Ru complexes bearing chiral
phosphine ligands are elegant and efficient methods for the
enantioselective synthesis of chiral amides (Scheme 1a).3b,e In
Received: January 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
however, first direct asymmetric hydrogenation of endocyclic
enamides is yet to be reported and still remains a challenge.
Our group has long been interested in developing novel
substrates and catalytic systems for the asymmetric hydro-
genations.7 In continuation of these studies, we here report the
first asymmetric hydrogenation of β,γ-unsaturated γ-lactams
catalyzed by an iridium−phosphoramidite complex for the
synthesis of chiral γ-lactam derivatives in excellent yields and
enantioselectivities (Scheme 1).
Compound 1a was selected as a model substrate because γ-
lactams bearing 3,3-dimethyl substituents are also useful
building blocks for the synthesis of bioactive molecules and
chiral auxiliaries.1b,i Additionally, it can be readily prepared and
is relatively stable. Studies to elucidate optimal reaction
conditions for the asymmetric hydrogenation of 1a using a
privileged phosphoramidite ligand L1 were undertaken (Table
1).8 The reaction solvent has a significant influence on the
reaction conversion and product enantioselectivity.9 Notably, I2
was paramount to the success of the hydrogenation reaction
and has been used successfully in several iridium-catalyzed
asymmetric hydrogenation reactions.10 Finally, the ratio of TFE
to tert-amyl alcohol was tested (entries 1−5). When the ratio of
TFE/tAA was adjusted to 6:1 (v/v), 94% ee and full conversion
were obtained (entry 4). Other binaphthyl phosphoramidite
ligands including our newly prepared ligand L2, reported
ligands L3 and L4, and chiral spiro phosphoramidite ligand L5
and L6 were also tested, and all were inferior to L1 (entries 6−
10 vs 4). Our previously developed D2-symmetric biphenyl
phosphoramidite ligand L7, which has provided excellent
behavior in asymmetric catalysis, displayed unsatisfactory
results for this reaction (entry 11).11 Axially unfixed P,N-ligand
L8, which has provided excellent results in iridium-catalyzed
asymmetric hydrogenations of exocyclic α,β-unsaturated
carbonyl compounds, was almost unreactive (entry 12).7a,b,d
Reactions with P,N-ligand (S)-tBu-PHOX and diphosphine
ligand (S)-BINAP gave poor conversions and enantioselectiv-
ities (entries 13 and 14).
With the optimized reaction conditions in hand, a variety of
β,γ-unsaturated γ-lactams were tested (Scheme 2). First, the
influence of the substituted group R2 on the nitrogen atom of
the substrate was examined. The reduction of 1 bearing N-Bn
(benzyl), N-PMB (4-methoxybenzyl), or N-DMPM (3,4-
dimethoxybenzyl) groups gave the corresponding products
with better enantioselectivities than those bearing N-Me or N-
a
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope
b
c
entry
1
ligand
solvent (v/v)
conv (%)
ee (%)
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
TFE/tAA (1:1)
TFE/tAA (2:1)
TFE/tAA (4:1)
TFE/tAA (6:1)
TFE/tAA (8:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
TFE/tAA (6:1)
69
89
72 (R)
89 (R)
91 (R)
94 (R)
86 (R)
80 (R)
16 (R)
38 (R)
62 (S)
51 (R)
9 (S)
−
d
2
3
>99
>99
>99
>99
61
e
4
f
5
e
6
e
7
e
8
28
e
9
>99
>99
45
e
10
e
e
e
e
,
,
,
,
g
g
g
g
11
12
13
14
<5
(S)-tBu-PHOX
(S)-BINAP
17
<5
26
<5
a
Reaction was conducted on a 0.2 mmol scale in 2.0 mL of the solvent
under 50 bar H2 at rt for 24 h in the presence of [Ir(cod)Cl]2 (0.5 mol
b
a
%), ligand (2.2 mol %), and I2 (10 mol %). Determined by 1H NMR
Reaction was conducted on 1 (0.2 mmol) in TFE/tAA (6:1 v/v, 2.1
mL) under 50 bar H2 at rt for 24 h, in the presence of [Ir(cod)Cl]2
c
d
analysis. Determined by chiral HPLC analysis. TFE/tAA (1.4 mL +
e
f
0.7 mL). TFE/tAA (1.8 mL + 0.3 mL). TFE/tAA (1.6 mL + 0.2
(0.5 mol %), L1 (2.2 mol %), and I2 (10 mol %). Isolated yield. ee was
g
b
mL). Ir/ligand = 1:1.1. cod = 1,5-cyclooctadiene. TFE = 2,2,2-
determined by chiral HPLC analysis. Reaction solvent is HFIP/tAA
trifluoroethanol. tAA = tert-amyl alcohol.
(2:1 v/v, 2.1 mL). HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol.
B
DOI: 10.1021/acs.orglett.7b00171
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Organic Letters
Letter
Et groups (2c−e vs 2a and 2b). The reaction of 1 bearing a free
N-H group could also afford the corresponding product 2f with
90% ee. Benzyl was selected as the nitrogen atom substituent
for the examination of substrates bearing different 5-substituted
R3 groups. When R3 was a phenyl group bearing electron-
withdrawing F, Cl, Br, or CF3 substituents or electron-donating
Me, tBu, iBu, or MeO substituents at the para-position, the
reduced products 2g−n were obtained in high enantioselectiv-
ities and excellent yields. With a F or Me substituent at the
meta-position of the phenyl ring, the related reduced products
2o and 2p were obtained in 95% and 99% ee, respectively. A
substrate with a MeO substituent at the ortho-position of the
phenyl ring, gave the reduced product 2q in 93% ee. Substrates
with two or three substituents located at different positions of
the phenyl ring were reduced in 93−99% ee (2r−w). A
substrate substituted with a fused-ring aryl, 2-naphthyl, gave the
reduced product 2x in 97% ee. A substrate with a 3,4-
methylenedioxy group on the phenyl ring was reduced in 90%
ee (2y). β,γ-Unsaturated γ-lactams with no substituents at the
3-position isomerized easily to their corresponding α,β-
unsaturated γ-lactams,12 hydrogenation of which gave racemic
products. Therefore, asymmetric hydrogenation of β,γ-unsatu-
rated γ-lactams with no substituents at the 3-position was a
more challenging problem. To our delight, using our catalytic
system the reduced products 2z and 2aa could be obtained with
91% and 92% ee, respectively. The absolute configuration of 2i
was determined as R by means of X-ray crystallography. In
addition, other types of enamides were also tested with the
optimized reaction conditions.9
Scheme 4. Proposed Reaction Mechanism
Scheme 5. Efficiency of the Catalytic System
Scheme 6. Transformations of the Product 2d
To gain insight into the reaction mechanism, a deuterium-
labeling experiment was conducted (Scheme 3). The use of
CF3CH2OD/tBuOD (6:1) as the reaction solvent afforded β-
deuterated products 2a′, 2a″, and 2a‴ in a ratio of 72:14:14.
Scheme 3. Deuterium-Labeling Experiment
On the basis of the above experimental results, a catalytic
cycle for the iridium-catalyzed asymmetric hydrogenation of
β,γ-unsaturated γ-lactams has been proposed (Scheme 4). The
oxidative addition of I2 to Ir(I) precursor A generates the
Ir(III) complex B.10a Heterolytic cleavage of H2 generates
Ir(III)−H species C and HI. In the presence of HI, the N-
acyliminium cation 1a′ is generated via protonation and
isomerization of β,γ-unsaturated γ-lactam 1a, which was verified
by 1H NMR analysis.9 Hydride transfer from complex C to the
N-acyliminium cation 1a′ may proceed via an outer sphere
mechanism to give the reduced product 2a and regenerate the
Ir(III) complex B.
To evaluate the efficiency of our developed catalytic system,
a ratio of S/C = 1000 was tested, and the reduced products 2c
and 2d were both obtained in 95% ee with quantitative yields in
48 h (Scheme 5).
To demonstrate the potential of this simple and highly
efficient catalytic asymmetric hydrogenation, further trans-
formations of the reduced products were carried out as shown
in Scheme 6. Compound 2d was transformed to compound 2f
easily via removal of the N-protecting group in 90% yield and
without a loss in enantioselectivity. Compound 3, a potential
CGRP receptor antagonist, can be synthesized from 2f.1i
Compound 2f was readily converted into 5 by reduction.
Potential selective androgen receptor modulator 4 can be
readily prepared from 5.13
In summary, an asymmetric hydrogenation of β,γ-unsatu-
rated γ-lactams for the preparation of chiral γ-lactams was
realized using an iridium−phosphoramidite complex. The chiral
γ-lactams were obtained in excellent yields and enantioselectiv-
ities (up to 99% yield and 99% ee). Deuterium-labeling
experiments indicated that the reduced products were obtained
via the hydrogenation of the N-acyliminium cations, generated
from β,γ-unsaturated γ-lactams, rather than directly obtained by
the hydrogenation of the latter. The N-acyliminium cationic
1
intermediate was verified by H NMR analysis. The reaction
was also successful at a reduced catalyst loading of 0.1 mol %.
Potential CGRP receptor antagonist 3 and potential selective
C
DOI: 10.1021/acs.orglett.7b00171
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
1
reactions and products, including H and 13C NMR spectra,
Chem., Int. Ed. 2014, 53, 1978. (d) Bernasconi, M.; Muller, M.-A.;
̈
HPLC data, crystal data, and crystallographic data. The
Supporting Information is available free of charge on the
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Experimental procedures and characterization data for all
reactions and products, including 1H and 13C NMR
spectra, HPLC data, and crystal data (PDF)
Crystallographic data for compound 2i (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dlliu@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Wanbin Zhang: 0000-0002-4788-4195
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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This work was partially supported by the National Natural
Science Foundation of China (Nos. 21232004, 21372152,
21472123, and 21672142), Program of Shanghai Subject Chief
Scientists (No.14XD1402300), and the Instrumental Analysis
Center of SJTU for characterization.
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