Enantioselective (3+2) cycloaddition: Via N-heterocyclic carbene-catalyzed addition of homoenolates to cyclic N -sulfonyl trifluoromethylated ketimines: Synthesis of fused N-heterocycle γ-lactams

Article abstract of DOI:10.1039/c9cc09269b

An enantioselective (3+2) cycloaddition of enals and cyclic N-sulfonyl trifluoromethyl ketimines via N-heterocyclic carbene-catalyzed homoenolate addition is described. This reaction can efficiently construct fused N-heterocycle γ-lactams bearing two adjacent chiral centers with >20?:?1 dr and 94-99% ee, with one chiral center as a trifluoromethylated α-tetrasubstituted carbon stereocenter.

Full text of DOI:10.1039/c9cc09269b

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DOI: 10.1039/C9CC09269B
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Enantioselective (3+2) Cycloaddition via N-Heterocyclic Carbene-
Catalyzed Addition of Homoenolate to Cyclic N-Sulfonyl
Trifluoromethylated Ketimines: Synthesis of Fused N-Heterocycle
γ‑Lactams
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Zhen-Zhen Zhang, Yongna Zhang,* Hui-Xin Duan, Zhuo-Fei Deng and You-Qing Wang*
An enantioselective (3+2) cycloaddition of enals and cyclic N- heterocycle γ‑lactams with up to 73% ee and 6/1 dr after
sulfonyl trifluoromethyl ketimines via N-heterocyclic carbene- screening many chiral NHC catalysts.5 The (3+2) cycloaddition
catalyzed homoenolate addition is described. This reaction can reaction of cyclic imines via the NHC-catalyzed addition of
efficiently construct fused N-heterocycle γ‑lactams bearing two homoenolate has not been investigated in detail, especially
adjacent chiral centers with >20:1 dr and 94–99% ee, with one focusing on high enantioselectivities. Herein, we report highly
chiral center as trifluoromethylated α-tetrasubstituted carbon enantioselective (3+2) cycloaddition of enals with cyclic N-
stereocenter.
sulfonyl trifluoromethylated ketimines via the NHC-catalyzed
homoenolate addition, affording the fused N-heterocycle
γ‑lactams (Scheme 1b).
In the past few decades, N-heterocyclic carbenes (NHCs) have
been used as
a powerful organocatalyst for various
enantioselective reactions to construct cyclic molecules.1 The
NHC catalysis with aldehydes can generate several types of
reactive intermediates. A typical example is based on the a3-d3
umpolung of aldehydes to form the homoenolate intermediate
by the nucleophilic addition of NHC catalysts to enals.1b-c,1j The
homoenolates can be considered as d3-nucleophiles for
addition to 1,2-unsaturated activated double bond, followed
by cyclization to regenerate NHC catalyst, resulting in formal
catalytic (3+2) cycloaddition reaction. Obviously, the addition
of homoenolate to electrophilic C=N is an efficient strategy to
construct N-heterocycle γ‑lactams.2 In 2005, Bode and
coworkers reported NHC-catalyzed racemic (3+2) cycloaddition
of enals with N-sulfonylimines to produce γ-lactams.3
Subsequently, several asymmetric (3+2) cycloadditions were
reported via the NHC-catalyzed key enantioselective addition
of homoenolate to the C=N of acyclic imines,4 affording γ-
lactams with high enantioselectivities4a-f (Scheme 1a).
However, very little attention has been paid to using cyclic
imines containing an endocyclic carbon–nitrogen double bond
as electrophiles in the NHC-catalyzed (3+2) cycloaddition to
obtain the fused N-heterocycle γ‑lactams (Scheme 1b).5 Only
one five-membered cyclic N-sulfonyl ketimine was used for the
enantioselective (3+2) cycloaddition, affording fused N-
a) Acyclic imines
O
OH
X
N
(3+2)
X
N
N
R
+
N


R1
R2
N
R2
R1
R
Acyclic Imines
Homoenolate
Equivalent
b) Cyclic imines
O
OH
X
X
N
N
(3+2)
N
R
+
N
R1
R2
N
R2
R1
R
Cyclic Imines
Homoenolate
Equivalent
Fused N-Heterocycles
O
O
O
O
S
S
O
N
N
CF3
Ph
X
up to 73% ee
Previous work: Ref. [5]
up to 99% ee
This work
Scheme
1 Enantioselective (3+2) cycloadditions via NHC-catalyzed addition of
homoenolate intermediate to imines.
Benzo[e][1,2,3]oxathiazine 2,2-dioxide, a class of cyclic
sulfamidates heterocycles,6 can be considered as a N-sulfonyl
cyclic imine. In our previous research, this type of cyclic
aldimines was used for the phosphane-catalyzed (3+2)
cycloaddition7 and highly enantioselective Mannich reactions
catalyzed by primary amine organocatalysts8. The
trifluoromethyl (CF3) group-containing organic molecules are
widely used in medicinal chemistry, attributing to the
characteristic molecular properties such as improved polarity,
a. Henan Provincial Key Laboratory of Polyoxometalate Chemistry, Provincial Key
Laboratory of Natural Medicine and Immuno-Engineering, and College of
Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004,
P. R. China. E-mail: zhangyongna@henu.edu.cn, wyouqing@hotmail.com
†Electronic Supplementary Information (ESI) available: CCDC 1919445. For ESI and
crystallographic
data
in
CIF
or
other
electronic
format
see
DOI: 10.1039/x0xx00000x
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metabolic stability, lipophilicity, and bioavailability imparted 15). To the best of our surprise, the reaction proceeds
View Article Online
by fluorine.9 We envisaged incorporation of a CF3 group at the smoothly at room temperature, affording single diastereo-
DOI: 10.1039/C9CC09269B
C=N double bond10 of the benzo[e][1,2,3]oxathiazine 2,2- isomer product in the nearly enantiopure form (entry 19).15
dioxides to get cyclic N-sulfonyl trifluoromethylated ketimines
Table 1 Condition optimizationa
1,[7,11] which were viewed as more challenging imine
substrates for catalytic asymmetric transformations.12 Inspired
O
O
O
O
O
20 mol% PreNHC
20 mol% base
O
S
S
by the powerful NHC organocatalysis for diverse reactions to
build complex chiral scaffolds,1 we became interested in
exploring NHC-catalyzed enantioselective reactions of the
cyclic ketimines 1. Although NHC-catalyzed enantioselective
annulation of cyclic trifluoromethylated ketimines is one of the
most powerful tools to generate polycyclic trifluoromethylated
N-heterocycles bearing a tetrasubstituted chiral stereocenter,
it is still a challenging task (Scheme 2). In this pioneering field,
Enders and coworkers realized the enantioselective (4+2)
annulations of trifluoromethyl 2(1H)-quinazolinones.13 In this
study, enantioselective (3+2) annulations of trifluoromethyl
benzo[e][1,2,3]oxathiazine 2,2-dioxide were developed,
affording γ‑lactam products bearing two adjacent chiral
centers with excellent stereoselectivties.
O
N
O
N
H
+
solvent, 40oC
CF3
O
Ph
CF3
Ph
1a
2a
3aa
O
(S)
(S)
N
N
N
N
N
(R)
(R)
N
Ar
Ar
X
X
C-1: Ar = Mes, X = Cl
NO2
C-5: Ar = Mes, X = BF4
C-6: Ar = 2,4,6-(iPr)3C6H2, X = Cl
C-2: Ar = 2,4,6-(iPr)3C6H2, X = Cl
C-3: Ar = Mes, X = BF4
C-4: Ar = 2,4,6-(iPr)3C6H2, X = BF4
Entry
1
2
3
4
5
6
7
8
PreNHC
C-1
C-1
C-1
C-1
C-1
C-1
C-1
C-1
C-1
C-1
C-2
C-3
C-4
C-5
C-6
C-6
C-6
C-6
C-6
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
Base
TEA
Yieldb (%)
78
drc
4:1
4:1
4:1
4:1
4:1
4:1
6:1
5:1
5:1
4:1
4:1
6:1
eed (%)
85
83
85
82
83
85
85
85
85
86
91
85
92
97
98
96
97
--
K3PO4
KOAc
91
63
O
O
O
Cs2CO3
TMG
90
93
PMB
PMB
N
N
N
N

Quinine
Quinidine
DMAP
HMTA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
89
80
85
89
91
91
84
64
90
90
87
93
trace
91
CF3
R
(2+4) annulations
CF3
Enders's work
74-97% ee
X
X
NHC Catalysis
with Enals
One chiral center
9
O
O
O
10
11
12
13
14
15
16
17
18
19e
O
O
S
S
(2+3) annulations
O
N

O
N
This work

CF3
4:1
CF3
R
20:1
20:1
20:1
20:1
--
X
17:1->20:1 dr
X
1
94-99% ee
Two adjacent chiral centers
toluene
MeCN
DCM
Scheme 2 NHC-Catalyzed enantioselective annulations of cyclic trifluoromethylated
ketimines.
>20:1
99
a
Reaction conditions: imine 1a (0.05 mmol), enal 2a (0.15 mmol), PreNHC (20
Cyclic N-sulfonyl CF3 ketimine 1a was chosen as a substrate
of the model reaction with cinnamaldehyde 2a under NHC
catalysis (Table 1). Triazolium salt C-1 was chosen as the NHC
precatalyst (preNHC) and TEA as the base in DCM at 40C,
affording the desired product 3a in 78% yield with 4:1 dr and
85% ee (entry 1). Encouraged by this promising result, reaction
conditions were optimized. First, some bases were screened,
resulting in comparatively less enantioselectivities in the range
82–86% ee (entries 1–10). By taking the yields and ee value
into account, N,N-diisopropylethylamine (DIPEA) was chosen
as the optimized base for the reaction (entry 10). Next,
different chiral catalysts were examined. Catalysts with
different scaffolds greatly affected this (3+2) cycloaddition,
and indanol-derived triazolium catalysts were selected for
further screening (entries 10–15). The results showed that
nitro-substituted indanol-derived triazolium C-6 was the most
efficient catalyst,14 affording excellent stereoselectivities with
20/1 dr and 98% ee (entry 15). Further, various solvents were
screened for this reaction, and the best reactivity and
stereoselectivity was obtained using DCM as the solvent (entry
mol%), base (20 mol%), solvent (0.5 ml), 40oC. b Isolated yield. c Determined by 1H
NMR. d Determined by HPLC using a chiral column. e 1 mL of DCM and 25oC.
With the optimized reaction conditions in hand, different
substituted imine substrates were evaluated for the
enantioselective (3+2) cycloadditions, and the results are
summarized in Scheme 2. Various cyclic N-sulfonyl
trifluoromethylated ketimines 1, bearing both electron-
donating and electron-withdrawing substituents, such as
fluoride, chloride, bromide, trifluoromethyl, methyl, tert-butyl,
phenyl and methoxyl, in the fused phenyl ring all were well
tolerated under the reaction conditions, affording the fused N-
heterocycle γ‑lactams 3a–k as the trans-diastereoisomer
products with excellent stereoselectivities of 17:1–>20:1 dr
and 97–99% ee. However, only 37% yield was obtained for
imine 2g. Unfortunately, very low conversion was observed for
1,2-naphthylene-ring-containing imine 1l, probably because of
steric hindrance caused by the ortho-substitution of
sulfamidate heterocycle.
2 | J. Name., 2012, 00, 1-3
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O
O
O
O
O
Entry
1
R
4
4b
4c
4d
4e
4f
4g
4h
-
4j
4k
4l
4m
4n
4o
Yield (%)
dVriew ArticleeeO(n%lin)e
S
20 mol% C-6
O
S
DOI: 10.1039/C9CC09269B
O
N
O
N
4-F-C6H4 (1b)
4-Cl-C6H4 (1c)
4-Br-C6H4 (1d)
4-Me-C6H4 (1e)
4-MeO-C6H4 (1f)
4-NO2-C6H4 (1g)
3-Cl-C6H4 (1h)
2-Cl-C6H4 (1i)
2-naphthyl (1j)
2-furanyl (1k)
Et (1l)
97
96
97
97
90
83
43
trace
98
93
17:1
17:1
17:1
20:1
20:1
>20:1
>20:1
-
99
98
99
99
99
99
99
-
H
20 mol% DIPEA
+
2
3
4
5
6
7
8
9
10
11
12
13
14
DCM, 25oC
CF3
CF3
Ph
O
Ph
O
1
2a
3
X
X
O
O O
O
S
S
O
O
O
O
O
O
N
O
N
O
S
S
O
N
O
N
CF3
CF3
Ph
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99
95
95
94
96
95
CF3
Ph
CF3
Ph
F
F
Cl
3d, 93% yield
>20:1 dr, 98% ee
82
99
99
84
3a, 89% yield
3b, 80% yield
3c, 94% yield
n-Pr (1m)
i-Pr (1n)
n-Heptyl (1o)
>20:1 dr, 99% ee >20:1 dr, 94% ee 17:1 dr, 98% ee
O
O
O
O
O
O
O
O
O
S
S
S
O
O
O
O
N
O
N
O
N
S
O
N
CF3
CF3
CF3
Ph
Ph
Ph
CF3
Ph
The absolute and relative configurations of product 3e were
determined to be trans-(1S, 10bS)-isomer in the γ‑lactam
group by single crystal X-ray diffraction (see ESI†). The
configurations of all other products 3 (Scheme 3) and 4 (Table
2) were assigned by chemical analogy.
Me
3h, 98% yield
>20:1 dr, 98% ee >20:1 dr, 98% ee >20:1 dr, 97% ee >20:1 dr, 99% ee
CF3
3g, 37% yield
Cl
Br
3f, 80% yield
3e, 89% yield
O
O
O
O
O O
O
O
O
O
O
O
S
S
S
S
O
N
O
N
O
N
O
N
The reductive transformations of product 3a were
performed, and the corresponding results are shown in
Scheme 4. The treatment of 3a with LiAlH4 allowed reductive
cleavage of sulfamidate heterocycle and reduction of γ‑lactam
yielding ortho-hydroxylphenyl pyrrolidine 5 without loss of
enantioselectivity. γ‑Lactam 3a was treated with borane in THF
to generate cyclic hemiaminal 6 bearing three chiral centers.
The stereochemistry of new generated hydroxyl substituted
chiral carbon center was established by NOE experiments (see
CF3
CF3
CF3
Ph
CF3
Ph
Ph
Ph
tBu
3i, 97% yield
>20:1 dr, 99% ee 17:1 dr, 99% ee >20:1 dr, 99% ee
Ph
OMe
3j, 92% yield
3k, 98% yield
3l trace
Scheme 3 Scope of cyclic trifluoromethylated ketimines. (0.1 mmol reaction scale)
Subsequently, the scope of enals 2 was investigated using
the conditions similar to those used for the imine substrates.
As listed in Table 2, substantial generality of the (3+2)
cycloadditions for enals 2 displayed a broad substrate scope,
and both aromatic and aliphatic β-substituted enals were well
tolerated, affording the corresponding γ‑lactams 4 with
excellent diastereoselectivities and enantioselectivities. Both
electron-withdrawing and electron-donating substituents were
tolerated on the para position of the phenyl ring in enals 2b–g
(entries 1–6). The substrate with substituent at the meta
position of the phenyl ring in enal 2h afforded low yield of the
product, but still retained excellent enantio- and
diastereoselectivity (entry 7), and very low reactivity was
observed for enal 2i bearing ortho substituent (entry 8). The
enals with β-substituted naphthyl (2j) and heterocyclic furan
group (2k) were also suited for this reaction (entries 9–10).
Instead of aromatic enals, four aliphatic enals such as 2l–o
were also applied to the (3+2) cycloadditions, and slightly
lower enantioselectivity (94–96% ee) were obtained in fairly
good yields (entries 11–14).
ESI,† Scheme S2). Subsequently,
6 was treated with
triethylsilane and BF3-Et2O for dehydroxylation to afford
compound 7. The enantioselectivity of both compounds 6 and
7 was determined by chiral HPLC, indicating that the optical
purity was maintained in the reaction processes.
O
O
O
OH HN
S
O
N
LiAlH4
THF, 0oC to r.t.
CF3
Ph
CF3
Ph
5
3a, 99% ee
55% yield, 98% ee
BH3, THF, 60oC
O
O
O O
OH
S
S
O
N
O
N
Et3SiH, BF3-Et2O
-10oC to 0oC
CF3
CF3
Ph
Ph
6
7
68% yield, 98% ee
84% yield, 98% ee
Scheme 4 Reductive transformations of product 3a.
Table 2 Scope of enals.
Based on reported NHC-catalyzed cycloaddition reactions,[4-
a plausible catalytic cycle for this enantioselective (3+2)
cycloaddition, involving a key step of the homoenolate
addition to the C=N double bond, is proposed, as shown in
Scheme 5. The first step of the addition of NHC with enals 2
generated the Breslow intermediate I, which serves as
homoenolate equivalents. The nucleophilic addition of the
5]
O
O
O
O
O
R
20 mol% C-6
O
S
S
O
N
O
N
20 mol% DIPEA
H
+
DCM, 25oC
CF3
CF3
R
2
1a
4
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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intermediates II, the resulting acyl azoliums III undergo
intramolecular cyclization to afford the final products 3 or 4
and regenerate the NHC catalyst.
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O
O
O
S
O
N
H
N
N
N
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CF3
R
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NHC
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HO
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S
O
N
O
N
R
CF3
I
R
X
III
Homoenolate
Addition
O
O
N
N
O
O
HO
S
S
O
N
O
N
N
CF
3
CF3
R
5
6
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X
II
X
1
Scheme 5 Plausible catalytic cycle.
In conclusion, the enantioselective (3+2) cycloadditions of
enals and cyclic N-sulfonyl trifluoromethylated ketimines were
developed via the NHC-catalyzed addition of homoenolate to
the ketimines. A series of novel fused N-heterocycle γ‑Lactams
bearing two adjacent chiral centers were produced with
excellent enantio- and diastereoselectivity (94–99% ee and up
to >20:1 dr). This study extended the scope of chiral NHC
organocatalysis via the homoenolate addition using cyclic N-
sulfonyl trifluoromethylated ketimines as the substrates.
7
8
9
10 (a) X.-H. He, Y.-L. Ji, C. Peng and B. Han, Adv. Synth. Catal.,
2019, 361, 1923; (b) Y.-Y. Huang, X. Yang, Z. Chen, F.
Verpoort and N. Shibata, Chem. Eur. J., 2015, 21, 8664; (c) J.
Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011,
111, 455; (d) S. Kobayashi, Y. Mori, J. S. Fossey and M. M.
Salter, Chem. Rev., 2011, 111, 2626.
Conflicts of interest
There are no conflicts to declare.
Notes and references
11 B. H. Brodsky and J. Du Bois, J. Am. Chem. Soc., 2005, 127,
15391.
1
For selected recent reviews on NHC catalysis, see: (a) N-
Heterocyclic Carbenes in Organocatalysis, ed. A. T. Biju and
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P.-C. Chiang and J. W. Bode, TCIMAIL, 2012, 149, 2; (g) X.
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Douglas, G. Churchill and A. D. Smith, Synthesis, 2012, 44,
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Glorius, Nature, 2014, 510, 485; (j) R. S. Menon, A. T. Biju
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12 (a) H. Wang, T. Jiang and M.-H. Xu, J. Am. Chem. Soc., 2013,
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13 Q. Liu, X.-Y. Chen, S. Li, E. Jafari, G. Raabe and D. Enders,
Chem. Commun., 2017, 53, 11342.
14 (a) X.-Y. Chen, Q. Liu, P. Chauhan, S. Li, A. Peuronen, K.
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15 For more results on the reaction condition optimization,
please see ESI,† Table S1 and Scheme S1).
4 | J. Name., 2012, 00, 1-3
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