Synthesis of Chiral γ-Lactams via in Situ Elimination/Iridium-Catalyzed Asymmetric Hydrogenation of Racemic γ-Hydroxy γ-Lactams

Article abstract of DOI:10.1021/acs.orglett.7b00651

Chiral γ-lactams have been synthesized in excellent yields and enantioselectivities (up to 99% yield and 96% ee) from easily accessible racemic γ-hydroxy γ-lactams via an iridium-phosphoramidite catalyzed asymmetric hydrogenation. The reaction was designed based on insight into the reaction mechanism demonstrated in previous work and can be carried out at a reduced catalyst loading of 0.1 mol % on a gram scale. Several potential bioactive compounds can be synthesized from the reduced products. Mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from γ-hydroxy γ-lactams.

Full text of DOI:10.1021/acs.orglett.7b00651

Letter
pubs.acs.org/OrgLett
Synthesis of Chiral γ‑Lactams via in Situ Elimination/Iridium-
Catalyzed Asymmetric Hydrogenation of Racemic γ‑Hydroxy
γ‑Lactams
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: Chiral γ-lactams have been synthesized in excellent yields and
enantioselectivities (up to 99% yield and 96% ee) from easily accessible racemic
γ-hydroxy γ-lactams via an iridium-phosphoramidite catalyzed asymmetric
hydrogenation. The reaction was designed based on insight into the reaction
mechanism demonstrated in previous work and can be carried out at a reduced
catalyst loading of 0.1 mol % on a gram scale. Several potential bioactive
compounds can be synthesized from the reduced products. Mechanistic studies
indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from γ-hydroxy
γ-lactams.
Scheme 1. Synthesis of Chiral γ-Lactams
he chiral γ-lactam skeleton is an important structural
1
Tmotif, and many impressive strategies for the synthesis of
such structures have emerged,2 such as Ru-catalyzed
dehydrative intramolecular N-allylation,3a sequential allylic
amidation and atom-transfer radical cyclization,3b Rh-catalyzed
cycloisomerization4a and intramolecular C−H insertion reac-
tions,4b Pd-catalyzed allylic alkylation,5a cyclopropane functio-
nalizations,5b Au-catalyzed oxidative cyclization,6 Cu-catalyzed
C−H insertion reactions,7 organocatalytic vinylic substitution,8a
and conjugate addition.8b However, these methodologies
usually require high catalyst loadings3−8 and/or give the
products with poor enantioselectivities.7
In recent years, we have focused on the development of
transition-metal-catalyzed asymmetric hydrogenation reac-
tions.9,10 Very recently, we reported an iridium-catalyzed
asymmetric hydrogenation of β,γ-unsaturated γ-lactams for
the synthesis of chiral γ-lactams with excellent yields and
enantioselectivities (Scheme 1).10k However, the synthetic
route to β,γ-unsaturated γ-lactams is long, and β,γ-unsaturated
γ-lactams with no substituents at the 3-position undergo facile
isomerization to their corresponding α,β-unsaturated γ-
lactams.11 Mechanistic studies indicated that the reduced
products were obtained via the hydrogenation of the N-
acyliminium cations, generated from β,γ-unsaturated γ-lactams.
These results prompted us to pursue more stable and accessible
substrates for the synthesis of chiral γ-lactams. We speculated γ-
hydroxy γ-lactams can be transformed to N-acyliminium cations
via the following pathway: A carbocation is generated from the
γ-hydroxy γ-lactam in the presence of H+. Reduction of the
other resonance form of the carbocation, N-acyliminium cation,
gives the chiral γ-lactam product. An iridium-catalyzed
asymmetric hydrogenation of N-acyliminium cations, generated
from γ-hydroxy γ-lactams for the preparation of chiral γ-lactams
(especially γ-lactams lacking substituents at the 3-position), was
therefore designed (Scheme 1).
γ-Hydroxy γ-lactams 1 can be easily synthesized from
commercially available succinimide and Grignard reagents.12
Compound 1a was selected as a model substrate for the
optimization of the reaction conditions (Table 1). First, we
tested 1a with our previously developed optimized reaction
conditions for the iridium-catalyzed asymmetric hydrogenation
Received: March 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00651
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Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
b
c
entry
ligand
solvent
yield (%)
ee (%)
d
1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L1
L1
TFE/tAA
TFE/tAA
TFE
98
97
98
73
34
97
99
99
98
28
69
98
86 (R)
70 (R)
90 (R)
51 (R)
20 (R)
17 (S)
40 (R)
16 (S)
77 (R)
38 (R)
52 (R)
89 (R)
de
,
2
3
4
5
6
7
8
9
HFIP
tAA
DCM
THF
toluene
TFE
10
11
12
TFE
f
TFE
g
TFE
a
Reaction was conducted on a 0.2 mmol scale in 2.0 mL of the solvent
under 50 bar of H2 at rt for 24 h, in the presence of [Ir(cod)Cl]2 (0.5
b
mol %), ligand (2.2 mol %), and I2 (10 mol %). Isolated yield.
c
d
Determined by chiral HPLC analysis. TFE/tAA (1.8 mL + 0.3 mL).
e
f
g
TFA (1.0 equiv) was added. Under 40 bar of H2. Under 60 bar of
H2. cod = 1,5-cyclooctadiene. TFE = 2,2,2-trifluoroethanol. tAA = tert-
amyl alcohol. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol.
of β,γ-unsaturated γ-lactams.10k The reduced product 2a was
obtained with 86% ee and in 98% yield (entry 1). Notably, I2
was necessary for the success of the reaction and has been used
successfully in several iridium-catalyzed asymmetric hydro-
genation reactions.10k,13 When the reaction was carried out in
the presence of TFA, the enantioselectivity of the hydrogenated
product was reduced to 70% ee (entry 2). Next, the reaction
solvent was examined and was found to have a significant
influence on the reaction yield and enantioselectivity (entries
3−7). When using TFE as the reaction solvent, the reduced
product was obtained with 90% ee and in 98% yield. A
moderate ee was obtained when using HFIP as the reaction
solvent (entry 4); however, the desired product was obtained
with poor enantioselectivity and yield when tert-amyl alcohol
was used as the reaction solvent (entry 5). The reactions
proceeded well in aprotic solvents giving the reduced products
in excellent yields but with low enantioselectivities (entries 6−
8). Other binaphthyl phosphoramidite ligands L2−L3 were
also tested; both were inferior to L1 (entries 9 and 10 vs 3).
Finally, the effect of hydrogen pressure on the reaction was
investigated. The desired product was obtained with 52% ee
and in 69% yield when the reaction was conducted at 40 bar of
hydrogen pressure (entry 11). Increasing the pressure of
hydrogen to 60 bar gave the desired product with 89% ee and
in 98% yield (entry 12).
a
Reaction was conducted on 1 (0.2 mmol) in TFE (2.0 mL) under 50
bar of H2 at rt for 24 h, in the presence of [Ir(cod)Cl]2 (0.5 mol %),
L1 (2.2 mol %), and I2 (10 mol %). Isolated yield. Ee was determined
by chiral HPLC analysis.
Substrates with a phenyl R1 group possessing electron-
withdrawing or electron-donating substituents at the para- or
meta-position could be reduced with 82−93% ee (2c−2i). A
substrate bearing a Me group at the ortho-position of the phenyl
ring was reduced to 2j with a lower enantioselectivity of 76%
ee. Substrates bearing a 2-naphthyl and 3,4-methylenedioxy
group on the phenyl ring, and alkyl cyclohexyl groups, were
reduced to their corresponding products 2k, 2l, and 2m with
94%, 87%, and 70% ee, respectively. Additionally, we also
applied our catalytic system to the asymmetric reduction of γ-
With the optimized reaction conditions in hand (Table 1,
entry 3), a variety of γ-hydroxy γ-lactams were tested (Scheme
2). The reduction of 1 bearing a N-PMB (4-methoxybenzyl)
group gave its corresponding products with better enantiose-
lectivity than the substrate bearing a N-Me group (2b vs 2a).
B
DOI: 10.1021/acs.orglett.7b00651
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Letter
hydroxy γ-lactams bearing 3,3-dimethyl substituents because γ-
lactams bearing 3,3-dimethyl substituents are useful building
blocks for the synthesis of bioactive molecules and chiral
auxiliaries (Scheme 2).14 When the R2 group on the nitrogen
atom was Me, Et, Bn (benzyl), PMB, or DMPM (3,4-
dimethoxybenzyl), the reduced products 2n−2r were obtained
with 90−94% ee. Substrates with a phenyl R1 group bearing
various substituents at different positions on the phenyl ring
were reduced to the corresponding products 2s−2w with 90−
95% ee. A substrate possessing a 2-naphthyl group gave its
reduced product 2x with 96% ee. The absolute configuration of
2a was determined as R by comparison with our previously
published results.10k
The use of CF3CH2OD as the reaction solvent afforded β-
deuterated products 2a′, 2a″, and 2a‴, with the ratio of 2a′ to
2a″ and 2a‴ being 65:35. This result differs slightly from our
original mechanistic hypothesis (Scheme 1).
Based on the above experimental results and according to
literature data,10k,13a a catalytic cycle for the iridium-catalyzed
asymmetric reduction of γ-hydroxy γ-lactams has been
proposed (Scheme 5). The oxidative addition of I2 to Ir(I)
Scheme 5. Proposed Reaction Mechanism
The practicality of our developed catalytic system for the
asymmetric reduction of γ-hydroxy γ-lactams was evaluated.
The catalytic reaction was carried out at a low catalyst loading
(S/C = 1000) on a gram scale, and the reduced product 2b was
obtained with 93% ee in 72 h, with no loss in enantioselectivity
(Scheme 3). The product 2b was transformed to compound 3
Scheme 3. Gram-Scale Preparation of 2b and Its
Transformation
via removal of the N-protecting group. According to literature
reports, compound 3 can be transformed to various bioactive
compounds, such as cannabinoid receptor 1 inhibitor 4,15
bioavailable tankyrase inhibitor 5,16 TNF activity modulator
6,17 and plant growth regulator 718 (Figure 1).
precursor A generates the Ir(III) complex B, which could lead
to heterolytic cleavage of H2 and the generation of Ir(III)−H
species C and HI. Compound 1a then undergoes trans-
formation to the carbocation in the presence of HI. According
to the results of the deuterium-labeling experiments, it can be
seen that almost all of the carbocation is transformed to β,γ-
unsaturated γ-lactam 1a′. In the presence of HI, the N-
acyliminium cation is generated via protonation and isomer-
ization of 1a′. Hydride transfer from complex C to the N-
acyliminium cation gives the reduced product 2a and
regenerates the Ir(III) complex B. A small amount of the
carbocation may be reduced directly by Ir(III)−H species C,
giving the reduced product with lower enantioselectivity. This
is most likely responsible for the slight differences observed in
the enantioselectivities of the iridium-catalyzed asymmetric
reduction of β,γ-unsaturated γ-lactam and γ-hydroxy γ-lactam
products.
Figure 1. Potential bioactive compounds can be synthesized from 3.
In summary, an iridium-catalyzed asymmetric reduction of γ-
hydroxy γ-lactams for the preparation of chiral γ-lactams was
designed based on the reaction mechanism of our previous
work. The chiral γ-lactams can be readily obtained in excellent
yields and enantioselectivities. The reaction was also successful
at a reduced catalyst loading of 0.1 mol % on a gram scale, and
the resulting reduced product can be transformed to four
bioactive compounds. Deuterium-labeling experiments con-
firmed that the reduced products were obtained via the
hydrogenation of the N-acyliminium cationic intermediates
which are generated via the elimination, protonation, and
isomerization of γ-hydroxy γ-lactams. The reaction proceeds
through a formal asymmetric hydrogenolysis of γ-hydroxy γ-
lactams.
To gain deeper insight into the reaction pathway, a
deuterium-labeling experiment was conducted (Scheme 4).
Scheme 4. Deuterium-Labeling Experiment
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00651.
■
S
Experimental procedures and characterization data for all
reactions and products, including 1H and 13C NMR
spectra, HPLC data (PDF)
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.
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ACKNOWLEDGMENTS
■
This work was partially supported by the National Natural
Science Foundation of China (No. 21232004, 21372152,
21472123, and 21672142), Program of Shanghai Subject
Chief Scientists (No.14XD1402300), the Basic Research
Foundation of Shanghai Science and Technology Committee
(15JC1402200), and the Instrumental Analysis Center of SJTU
for characterization.
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