Enantioselective [3 + 2] Annulation of Enals with 2-Aminoacrylates Catalyzed by N-Heterocyclic Carbene

Article abstract of DOI:10.1021/acs.orglett.7b01860

A novel and convenient strategy for the enantioselective synthesis of γ-lactam derivatives via N-heterocyclic carbene catalyzed formal [3 + 2] annulation of enals with 2-aminoacrylates is disclosed. This activation mode provides a complementary approach to the synthesis of various γ-lactam derivatives in good yields with excellent diastereo- and enantioselectivities. In this process, two consecutive stereocenters are constructed, and a quaternary carbon center is also established.

Full text of DOI:10.1021/acs.orglett.7b01860

Letter
pubs.acs.org/OrgLett
Enantioselective [3 + 2] Annulation of Enals with 2‑Aminoacrylates
Catalyzed by N‑Heterocyclic Carbene
†
†,‡
†
†
†
†
†
Xing-Shuo Li, Liang-Liang Zhao, Xiao-Ke Wang, Li−Li Cao, Xiao-Qian Shi, Rui Zhang,
,
and Jing Qi*
†
‡
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, and Key Laboratory of
Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People’s Republic of
China
*
S Supporting Information
ABSTRACT: A novel and convenient strategy for the
enantioselective synthesis of γ-lactam derivatives via N-
heterocyclic carbene catalyzed formal [3 + 2] annulation of
enals with 2-aminoacrylates is disclosed. This activation mode
provides a complementary approach to the synthesis of various
γ-lactam derivatives in good yields with excellent diastereo-
and enantioselectivities. In this process, two consecutive
stereocenters are constructed, and a quaternary carbon center
is also established.
n the past decade, N-heterocyclic carbene (NHC) catalysis
Scheme 1. Stetter Reaction and Cross-Coupling Reaction
between Aldehydes and 2-Aminoacrylates or Enamides and
NHC-Catalyzed formal [3 + 2] Annulation of Enals with 2-
Aminoacrylates
I
has been applied to many organic reactions due to its unique
1
polarity reversal strategy. Acyl anion equivalents and
homoenolate equivalents generated from the reaction of
aldehydes and enals with NHC have offered unconventional
2
access to various organic transformations. In 2011, Glorius and
co-workers reported an elegant NHC-mediated asymmetric
Stetter reaction starting from aldehydes and 2-aminoacrylates
for the synthesis of α-amino acid derivatives, in which 2-
3
aminoacrylates served as Michael acceptors. Impressively,
Wang’s group recently designed enamides as a coupling partner
in the NHC-catalyzed intermolecular cross-coupling with
aldehydes, resulting in the formation of N-acyl protected
4
amine derivatives. Although the reactions of acyl anion
equivalents with 2-aminoacrylates and enamides have already
represented versatile synthetic routes, the direct application of
homoenolate equivalents with 2-aminoacrylates remains unex-
plored in NHC-catalyzed cycloaddition reactions. Motivated by
Glorius’ work with 2-aminoacrylates as a reactant, we surmised
that combining homoenolate equivalents with 2-aminoacrylates
in the presence of a NHC catalyst might lead to a Michael-type
addition occurring at the β-carbon atom of the 2-aminoacrylate
and that this might be accompanied by intramolecular N-
acylation to afford a pyridinone product. Intriguingly, instead of
the proposed formal [3 + 3] annulation, the reaction
underwent a formal [3 + 2] annulation to generate a γ-lactam
as the product (Scheme 1).
γ-Lactams are found in important naturally occurring
7
5
imine. However, the NHC-catalyzed addition of enals to imine
compounds show biological activity. Consequently, there is a
6
electrophiles has been limited to aromatic aldehyde derived N-
great deal of interest in an efficient synthesis of this core motif.
Among these synthetic methods, a versatile and challenging
strategy is the generation of homoenolate equivalents from
enals with NHCs followed by annulation with an appropriate
Received: June 22, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sulfonyl imines, enal-derived imines, cyclic ketimines, and
isatin-derived ketimines. Herein, we report a simple and
convenient strategy for the synthesis of γ-lactam derivatives
via an NHC-catalyzed formal [3 + 2] annulation that uses enals
and 2-aminoacrylates as reactants. This strategy provides a
complementary approach for the construction of various γ-
lactam derivatives in good yield with excellent diastereo- and
enantioselectivities. Notably, two consecutive stereocenters
were constructed, and a quaternary carbon center was also
established.
We began by investigating the reaction between different N-
protected 2-aminoacrylates 1 and cinnamaldehyde 2a in the
presence of the NHC precatalyst A, where THF was initially
employed as the solvent and DBU was chosen as the base.
Gratifyingly, the N-Ts-protected 2-aminoacrylates 1d exhibited
unique reactivity in the reaction and gave the desired
cycloaddition product 3a in 70% yield (Table 1, entry 2).
attention to the challenges of asymmetric synthesis of γ-lactams
using chiral triazolium salt E as the precatalyst. To our great
delight, the cycloaddition product 3a was obtained in 60% yield
and 94:6 er (Table 1, entry 9). Further optimization showed
that the use of THF as the solvent led to a significant increase
in both the reaction yield and er value (70% yield, 96:4 er)
(Table 1, entry 11). Notably, only trans-isomers were generated
as the products in all of the reactions, and we did not detect the
other isomer during our research.
With the optimized reaction conditions in hand, we next
investigated substrate scope using chiral triazolium salt E as the
precatalyst, as shown in Scheme 2. Changing the ester group
a
Scheme 2. Substrate Scope
Table 1. Screening of Reaction Conditions for the Reaction
a
of 1 with 2a
a
1
(0.1 mmol), 2a (0.12 mmol), catalyst (10 mol %), base (20 mol %).
Yields given are for the isolated products following column
chromatography. dr of product 3aa was determined via H NMR
analysis.
a
b
1
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.24 mmol, 1.2
b
equiv), NHC (20 mol %), base (20 mol %), solvent (2.0 mL). Yield
c
d
of isolated product. Determined by chiral-phase HPLC analysis. 10
mol % of NHC precatalyst was used. DBU = 1,8-diazabicyclo[5.4.0]-
undec-7-ene, DIPEA = N,N-diisopropylethylamine, Mes = mesityl, NR
from ethyl to methyl did not encumber the reaction, and the
corresponding product was obtained in good yield and with
excellent er (3b). We next focused on examining the scope of
the reaction using compound 1d with various substituted enals.
In general, a broad range of differently substituted enals,
bearing electron-donating or electron-withdrawing substituents
on the aromatic ring, reacted with N-Ts 2-aminoacrylates 1d to
form a series of γ-lactams with excellent enantioselectivity (up
to 99:1 er) (3c−p). Moreover, disubstituted β-aryl enals were
also suitable for the reaction, and the high enantioselectivities
were maintained (3q−s). Replacing the β-phenyl substituent of
=
no reaction.
Other commonly used NHCs derived from triazolium salts B,
C, and the thiazolium salt D were far less effective (Table 1,
entry 3). In comparison to DBU, other bases, such as DIPEA,
Cs CO , and K CO , furnished the desired products in reduced
yield (Table 1, entries 4−6). Changing the solvent to 1,4-
dioxane significantly increased the yield to 84% (Table 1, entry
2
3
2
3
5
). With these encouraging results in hand, we turned our
B
DOI: 10.1021/acs.orglett.7b01860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the enal moiety with a naphthyl (3t,u) or a heteroaryl (3v, 3w,
and 3x) unit did not have a significant impact on the yields and
enantioselectivities. This method was also compatible with β-
vinyl or ynal enals, giving the desired products in good yields
Scheme 4. Deuterium-Labeling Experiments
8
and excellent enantioselectivities (3z, 3aa, and 3ab). Notably,
we did not detect the cis-isomer in any of the examples except
3aa (dr >20:1). To determine the stereochemistry of the γ-
lactams formed from this unique strategy, the absolute
configuration of the product 3a was unambiguously confirmed
9
by X-ray crystallographic analysis (Figure 1).
Figure 1. X-ray crystal structure of 3a. Thermal ellipsoids were shown
at 30% probability.
Our proposed mechanism is illustrated in Scheme 3. The
catalytic cycle begins with addition of NHC E to
Scheme 3. Proposed Reaction Pathways
under the reaction conditions, but the 2-aminoacrylate is the
major form (Scheme 4, eq 1). Notably, the combination of N-
methyl-protected 2-aminoacrylates 6 with enal 2a failed to
afford any products under the reaction conditions (Scheme 4,
eq 2). These two results support the tautomerization−enal−[3
+
2] cycloaddition mechanism. Several deuterium-labeling
experiments were carried out to further explore the reaction
mechanism. When deuterated cinnamaldehyde 2a′ was used as
the starting material, the deuterium was incorporated
exclusively into the methyl group to give the product 3a-1,
and 62% deuterium was detected in the methyl group (Scheme
4
, eq 3). This result could be explained by rapid proton
exchange in a bimolecular fashion. To further determine the
reaction pathway, the standard reaction was carried out in the
presence of 3 equiv of D O; the deuterium on the α-carbon
2
atom increased to 34%, while 50% deuterium was incorporated
into the methyl group (Scheme 4, eq 4). Furthermore, when
the reaction was carried out using chloroform-d as the solvent,
the deuterium could also be detected in the methyl group
(
11%, Scheme 4, eq 5). These phenomena further confirmed
cinnamaldehyde 2a to afford enal catalyst adduct I and
the equilibrium between 2-aminoacrylates 1d and its imine
form 4 and also indicated that multiple proton exchange
reactions occur during this process. Based on current
experimental evidence, we believe that the tautomerization−
followed by a deprotonation process to form Breslow
10
intermediate II, which acts as a homoenolate equivalent.
Upon the tautomerization of 2-aminoacrylate 1d to its imine
form 4, the homoenolate intermediate undergoes a nucleophilic
addition to the imine substrate 4 to create a new carbon−
carbon bond and a quaternary stereocenter (intermediate III).
Then the resulting acyl azolium species IV undergoes an
intramolecular N-acylation to release the NHC catalyst and
form the γ-lactam 3a as the product.
To investigate the mechanism, several additional experiments
were carried out, as shown in Scheme 4. The labeling
experiment of 1d demonstrated that the tautomerization
between 2-aminoacrylate 1d and its imine form 4 is possible
11
enal−[3 + 2] cycloaddition mechanism is reasonable.
In summary, we have successfully developed an NHC-
catalyzed formal [3 + 2] annulation of enals with 2-
aminoacrylates to generate a diverse set of γ-lactams in good
yields with excellent diastereo- and enantioselectivities. In this
novel strategy, two consecutive stereocenters are constructed in
one step, and a quaternary carbon center is also established.
Further exploration of the reaction mechanism and inves-
tigation of the generality of this catalytic process are currently
ongoing in our laboratory.
C
DOI: 10.1021/acs.orglett.7b01860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Mu
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01860.
(
4
(
Details on experimental procedure, characterization data
of all compounds, HPLC data (PDF)
Single-crystal X-ray data of 3a (CIF)
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AUTHOR INFORMATION
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*
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D.; Nepomuceno, G. M.; St. Peter, M. A.; Gitre, H. H.; Martin, K. S.;
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Jing Qi: 0000-0003-1612-0229
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Natural Science Foundation of Hebei Province
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