NHC-catalyzed asymmetric α-regioselective [4 + 2] annulation to construct α-alkylidene-δ-lactones

Article abstract of DOI:10.1021/acs.orglett.0c02573

The unprecedented NHC-catalyzed [4 + 2] annulation of α-bromoenals with dioxopyrrolidines is described. This protocol features broad substrate scope and allows rapid assembly of α-alkylidene-δ-lactones in good to high yields with excellent enantioselectivities. Notably, this process includes α-regioselective activation of azolium dienolate intermediates, which has not yet been reported.

Full text of DOI:10.1021/acs.orglett.0c02573

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Letter
NHC-Catalyzed Asymmetric α‑Regioselective [4 + 2] Annulation to
Construct α‑Alkylidene-δ-lactones
Lala Liu,§ Donghui Guo,§ and Jian Wang*
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ABSTRACT: The unprecedented NHC-catalyzed [4 + 2]
annulation of α-bromoenals with dioxopyrrolidines is described.
This protocol features broad substrate scope and allows rapid
assembly of α-alkylidene-δ-lactones in good to high yields with
excellent enantioselectivities. Notably, this process includes α-
regioselective activation of azolium dienolate intermediates, which
has not yet been reported.
s a structural subunit, α-alkylidene-δ-lactones are found in
various pharmacological properties of these compounds.4 In
addition, the unsaturated structure of α-alkylidene-δ-lactones
can be used as a highly reactive Michael receptor to bind to a
diverse set of nucleophilic molecules, generating strong
cytotoxicity in synthesized molecules.5 Owing to their
structural importance, various approaches have been developed
in recent years to prepare molecules with such α-alkylidene-δ-
lactone cores.6 It is surprising that the enantioselective
synthesis of α-alkylidene-δ-lactones has rarely been reported
thus far.6b,7
A
a variety of natural and synthetic products which possess
potent biological activities, such as vernolepin,1 teucriumlac-
tone,2 and artemisitene3 (Scheme 1a). It is believed that the α-
alkylidene-δ-lactone scaffold plays a crucial role in showing
Scheme 1. Strategies for the Construction of α-Alkylidene-
δ-lactones
Over the past decade, N-heterocyclic carbene (NHC)-
catalyzed organic reactions have attracted considerable
attention from the synthetic community,8 especially in the
asymmetric synthesis of δ-lactones. For instance, Ye and co-
workers disclosed the enantioselective [4 + 2] cycloadditions
of the o-quinone methide and enolates generated from ketenes
to give δ-lactones in good yields with high enantioselectivities.9
Later, elegant works for asymmetric synthesis of δ-lactones
using azolium enolates were reported by the groups of Rovis,
Scheidt, and Chi et al.10 Meanwhile, with the development of
NHC catalysis, the azolium dienolate intermediate was
demonstrated as an efficient tool for diverse chiral δ-lactone
synthesis. For example, Chi et al. reported a method for the
synthesis of trifluoromethyl-substituted δ-lactones by [4 + 2]
cycloaddition; soon after, the same group developed a strategy
for spirocyclic oxindole synthesis.11 However, the asymmetric
Received: August 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02573
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
synthesis of α-alkylidene-δ-lactones is still an undeveloped
project in NHC catalysis (Scheme 1b).
When the widely explored indanol-derived triazolium A−C
were used as the catalysts, only <5% of 3a was formed (entries
1−3). To further understand the importance of the catalyst
scaffold, a morpholinone-derived triazolium catalyst D was
tested but it showed almost no catalytic (entry 4). In contrast,
the L-phenylalanine-derived catalyst E afforded the desired 3a
in 62% yield with 7% ee (entry 5). To improve the
enantioselectivity, the oxazolidinone-derived catalyst F was
examined and provided 80% yield with 99% ee (entry 6).
Moreover, the catalyst G bearing an isopropyl substituent
afforded 3a in 90% yield and 99% ee (entry 7). Further
investigation of bases and solvents showed that triethylamine
and MTBE are the ideal base and medium, respectively
(entries 7−16). In addition, when the loading of catalyst G was
reduced, the reaction time had to be prolonged to complete
the reaction, which gave a slight loss of yield with 99% ee
(entries 17).
With the optimized reaction conditions in hand, we
examined the scope of dioxopyrrolidines 1. As shown in
Scheme 2, while the aryl groups have different substituents
(3a−g) at the para-, meta-, or ortho-positions, electronic effects
or substituted patterns have limited influence on yields (72−
95%) and enantioselectivities (all 99% ee). Meanwhile, the
substrates bearing multisubstituents (3h−j) could also be
carried out smoothly to afford the desired products in good to
high yield (79−92%) with excellent enantioselectivities (99%).
It is noteworthy that a number of heteroaromatic rings (e.g.,
thiophene, benzothiophene, naphthalene, and benzo-1,4-
dioxane) were tolerated and offered the desired products
3k−o in moderate to high yields (65−88%) with excellent
enantioselectivities (99%). To further investigate the scope of
the substrates, different R2 substituents (3p−r) were tested,
and the corresponding products could be obtained in moderate
to good yield (64−76%) and excellent enantioselectivities
(99%). The relative configuration of 3d was determined by X-
ray crystallography, and other products were assigned by
analogy (see the Supporting Information).
Based on our former experiences in carbene-catalyzed
enantioselective synthesis of δ-lactones,12 we predict that the
asymmetric synthesis of α-alkylidene-δ-lactones may also be
completed through NHC catalysis. In this design, the key to
constructing α-alkylidene-δ-lactones is to establish a CC
bond at the α position of δ-lactones. However, neither azolium
enolates nor azolium dienolate intermediates, which are
normal synthons in NHC catalysis, are suitable for direct
synthesis. To achieve the target structure, alternative routes are
highly demanded. Therefore, we herein report the unprece-
dented α-regioselective [4 + 2] annulation of azolium
dienolate intermediates, furnishing the desired α-alkylidene-δ-
lactones via a subsequent isomerization (Scheme 1c).
To test our hypothesis, (E)-1-benzyl-4-benzylidenepyrroli-
dine-2,3-dione (1a) and 2-bromo-3-methylbut-2-enal (2a)
were selected as the model substrates to optimize the reaction
conditions, and the key results are summarized in Table 1.
Initially, we employed triethylamine as base, tert-butyl methyl
ether (MTBE) as solvent, and 4 Å M.S. as additive, and a
number of chiral triazolium catalysts (A−G) were screened.
a
Table 1. Optimization of the Reaction Conditions
Next, we turn our focus to aldehydes (Scheme 3). The
electronic effect on the aromatic ring of aldehydes was
evaluated by systematically varying the substituent patterns.
Good yields (71−84%) and excellent ee values (99%) were
regularly observed (4a−e) when substrates with electron-
withdrawing or electron-donating groups on the benzene rings
were used. The naphthalene ring was compatible in the system
and provided the corresponding 4f in 90% yield with 99%
enantioselectivity. The aldehydes having heterocyclic motifs
(e.g., furan, benzofuran, thiophene, and benzothiophene) gave
the corresponding products (4g−j) in moderate to high yields
(67−89%) with excellent enantioselectivities (99%), as well.
Gratifyingly, when the β-phenyl group of enal became a methyl
group, the reaction proceeded smoothly to deliver the desired
product in high yield (90%) and with excellent enantiose-
lectivity (99%), exhibiting an outstanding adaptability (4k).
A postulated reaction pathway is illustrated in Scheme 4.
The addition of NHC to α-bromoenals 2a forms Breslow
intermediate I, which then undergoes a debromination to
afford acylazolium intermediate II. Intermediate II can quickly
convert to azolium dienolate III after proton transfer. After the
asymmetric [4 + 2] annulation of intermediate III and
dioxopyrrolidine 1a,10c−f intermediate IV is formed. With the
collapse of IV, lactone V is released and the active catalyst is
regenerated. Eventually, 3a is obtained from V via a
subsequent isomerization.
b
c
entry
Cat.
solvent
base
Et3N
yield (%)
ee (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
CHCl3
PhMe
<5
<5
<5
trace
62
80
90
58
21
16
<5
37
79
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
Cs2CO3
K2CO3
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
7
F
99
99
99
99
99
G
G
G
G
G
G
G
G
G
G
G
9
10
11
12
13
14
15
16
99
99
99
99
99
99
THF
CH3CN
DCM
76
41
19
81
d
17
MTBE
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), NHC (0.02
mmol), base (0.25 mmol), 4 Å M.S. (50 mg), solvent (2 mL), room
temperature, 24 h, under N2. Isolated yields. The enantiomeric
b
c
excesses (ee) were determined by HPLC with a chiral AD-H column.
d
Z/E (determined by H1 NMR) > 20:1 in all cases. 15 mol % loading
of G, 32 h.
B
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a
a
Scheme 2. Scope of Dioxopyrrolidines 1
Scheme 3. Scope of α-Bromoenals 2
a
Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), cat. G (0.02
mmol), Et3N (0.25 mmol), 4 Å M.S. (50 mg), MTBE (2 mL), room
temperature, 24 h, under N2. Z/E (determined by H1 NMR) > 20:1
in all cases.
Scheme 4. Postulated Mechanism
a
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), cat. G (0.02
mmol), Et3N (0.25 mmol), 4 Å M.S. (50 mg), MTBE (2 mL), room
1
temperature, 24 h, under N2. Z/E (determined by H NMR) > 20:1
in all cases.
To further understand the mechanism, we performed the
reaction by using a simple aldehyde 2m as the substrate, which
led to 4l in 81% yield with 99% ee (Scheme 5a). The result
indicated good reactivity and excellent enantiocontrol through
the enolate moiety using a simple aldehyde having a leaving
group at the α-position. Otherwise, we synthesized methyl
cyclopentyl disubstituted aldehyde 2n to explore the influence
of substituent effects on selective isomerization (Scheme 5b).
The reaction led to a mixture of the stereoisomers (E/Z =
10:4, identified by NOESY spectrum, see details in the
Supporting Information). We proposed that steric hindrance
and potential π−π stacking of the aryl group may play a
significant effect on the selectivity. As for regioselectivity of the
reaction, high electron density at the α-C (vs γ-C) of the
dienolate would lead to an α-regioselectivity reaction with
appropriate partners according to Sun’s work.13 Considering
the difference between their work and ours, a detailed DFT
calculation is being carried out in our laboratory to evaluate the
regioselectivity and selective isomerization of the reaction, and
the results will be reported in due course.
To demonstrate the practical utility of this work, a gram-
scale synthesis (3.6 mmol) was conducted under the standard
reaction conditions (Scheme 6), and 3a was obtained with a
slight loss of yield (83%) but with excellent enantioselectivity
(99%).
C
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Letter
orcid.org/0000-0002-3298-6367; Email: wangjian2012@
tsinghua.edu.cn
Scheme 5. Mechanistic Study
Authors
Lala Liu − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, P.R. China
Donghui Guo − School of Pharmaceutical Sciences, Key
Laboratory of Bioorganic Phosphorous Chemistry & Chemical
Biology (Ministry of Education), Tsinghua University, Beijing
100084, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02573
Author Contributions
§L.L. and D/G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 6. Gram-Scale Synthesis
We thank the National Natural Science Foundation of China
(Nos. 21871160, 21672121), the “Thousand Plan” Youth
Program of China, Tsinghua University, the Bayer Investigator
Fellow award, and the Fellowship of Tsinghua-Peking Centre
for Life Sciences (CLS) for their generous financial support.
We thank Mr. Qi Li at Tsinghua University for assistance with
the analysis of the X-ray crystallographic data.
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In conclusion, we have developed a novel carbene-catalyzed
[4 + 2] annulation of α-bromoenals with dioxopyrrolidines to
yield α-alkylidene-δ-lactones with excellent regio-, stereo-, and
enantio-control. This new protocol provides a rapid assembly
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Accession Codes
CCDC 2011879 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Jian Wang − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, P.R. China; School of
Pharmaceutical Sciences, Key Laboratory of Bioorganic
Phosphorous Chemistry & Chemical Biology (Ministry of
Education), Tsinghua University, Beijing 100084, China;
D
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