Application of E1cB Elimination in Asymmetric Organocatalytic Cascade Reactions to Construct Polyheterocyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.9b03138

By introducing a carbon functionality at 2-position of chromane, the formal asymmetric functionalization of the 3-position of 2-substituted chromane has been realized via a highly chemo-, regio-, and stereoselective organocatalytic cascade reaction in a sequential one-pot manner involving an E1cB mechanism governed ring-opening process. Critical to our success was the design of a chiral dipeptide-based bifunctional acid-base organocatalyst, which exhibited high catalytic activity at low catalyst loading (1-0.1 mol %), leading to biologically interesting polyheterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.9b03138

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Application of E1cB Elimination in Asymmetric Organocatalytic
Cascade Reactions To Construct Polyheterocyclic Compounds
Zhi-Hao You,† Ying-Han Chen,† Yu Tang,†,‡ and Yan-Kai Liu*,†,‡
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, China
‡Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao
266003, China
S
* Supporting Information
ABSTRACT: By introducing a carbon functionality at 2-
position of chromane, the formal asymmetric functionalization
of the 3-position of 2-substituted chromane has been realized
via a highly chemo-, regio-, and stereoselective organocatalytic
cascade reaction in a sequential one-pot manner involving an
E1cB mechanism governed ring-opening process. Critical to
our success was the design of a chiral dipeptide-based
bifunctional acid−base organocatalyst, which exhibited high
catalytic activity at low catalyst loading (1−0.1 mol %),
leading to biologically interesting polyheterocyclic com-
pounds.
he base-induced E1cB elimination being a textbook
Scheme 1. Motivation and Design
T
reaction is a two-step process, where the C−H bond
breaking precedes C-X bond breaking to form an alkene,
especially the electron deficient one, via a stabilized carbanion
(eq 1, X = leaving group).1 Undoubtedly, the combination of a
highly acidic proton and a relatively good leaving group means
that E1cB elimination would be extremely easy. It should be
further noted that the whole elimination process is potentially
reversible, which thus provides an excellent opportunity to
design novel cascade reactions for the construction of
structurally complex molecules from simple starting materials.
The compound chroman-2-ol exists as an equilibrium
mixture of the cyclic form and the linear form. In fact, the
transformation from the cyclic form to the linear form under
basic conditions is considered to proceed through E1cB
mechanism (Scheme 1a).2 The deprotonation of chroman-2-ol
provided an acetal oxyanion instead of carbanion intermediate,
followed by expelling phenoxide anion as a leaving group to
yield the parent aldehyde moiety, which can be protonated to
generate the hydroxyl aldehyde (linear form). However, the
base catalyst also favors the deprotonation of the phenolic
hydroxy group in the linear form, which makes the process
reversible.
synthetically useful 3-substituted chroman-2-ol compound,3
which can be converted into the corresponding 3-substituted
chromane after reductive dehydroxylation (Scheme 1b).
Therefore, the hydroxyl group of chroman-2-ol could be
Recently, we were interested in the application of chroman-
2-ol in enamine-triggered asymmetric cascade reactions by
reacting with electrophile (E) to prepare enantioenriched
Received: September 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
considered as an oxygen functionality to furnish 3-substituted
chromane via the formal asymmetric functionalization of the 3-
position of chromane.
We began our investigations by examining the reactivity of
different electrophiles bearing one or two electrophilic sites
(see the Supporting Information for details). However, no
designed cascade reaction occurred, and only α-addition
product chromane C was obtained in all cases, suggesting
that the development of such processes has been a challenging
task. To our surprise, in the presence of Et3N at 40 °C, the
reduction of chromane malononitrile 1a with Hantzsch ester as
the reductant afforded the ring-opened product (eq 2), which
indicated the availability of the electron deficient alkene
intermediate II as shown in Scheme 1.
Instead, given the requirement to facilitate the occurrence of
E1cB elimination, namely a highly acidic proton and a
relatively good leaving group, we questioned the possibility
of introducing a carbon functionality instead of the hydroxyl
group (oxygen functionality) of chroman-2-ol to give an ether-
type 2-substituted chromane compound. It is expected that this
ether-type chromane substrate could be directly applied in
asymmetric organocatalytic cascade reactions involving the
above-mentioned E1cB mechanism governed reversible ring-
opening process, leading to 2,3-disubstituted chromane
derivatives.
In this vein, we designed and synthesized a novel functional
synthon chromane malononitrile 1a bearing a highly acidic α-
proton and a phenolic oxygen-centered leaving group (Scheme
1c). During the designed process, the α-deprotonation of 1a
afforded the carbanion intermediate I, which could be
converted into the electron deficient alkene intermediate II
via E1cB mechanism governed ring-opening process in the
presence of chiral Lewis base. The subsequent deprotonation
of II afforded carbanion III, which could act as a direct
vinylogous nucleophile,4 followed by stereocontrolled intra-
molecular oxa-Michael addition to realize the formal
asymmetric functionalization of the 3-position of 1a, providing
the desired 2,3-disubstituted chromane A combined with one
electrophile. Further deprotonation of product A resulted in
the formation of another desired 2,3-disubstituted chromane B
combined with two electrophiles. Clearly, there is a strong
competitive reaction pathway, where the E1cB elimination is
interrupted, leading to the corresponding 2-sbustituted
chromane C from the reaction of intermediate I and
electrophile. Of course, there would be another better choice
of a substrate bearing two electrophilic reactive sites (E1−E2)
to work with the nucleophilic carbanion of III and I in
succession, leading to structurally more complex polyheter-
ocyclic chromane compounds. To the best of our knowledge,
the development of this kind of cascade process involving
E1cB elimination into a general, catalytic, and enantioselective
process has never been achieved by serving as the formal
asymmetric functionalization of the 3-position of chromane.
However, several challenging issues need to be addressed for
this unprecedented cascade reaction: (1) the proper choice of
an organocatalytic system to first provide the required α,α-
dicyanoalkene intermediate via E1cB elimination and then to
promote the subsequent asymmetric vinylogous addition; (2)
the precise control of the chemo- and regioselectivity between
the two nucleophilic carbanions of intermediate I and III when
reacting with electrophiles; and (3) the choice of a suitable
electrophile to give preferentially the vinylogous product A but
not the α-addition product C.
Encouraged by these results, we next moved toward the
application of more reactive biselectrophilic substrates (see the
SI for details). To our delight, as shown in Table 1, the desired
cascade reaction of chromane malononitrile 1a and biselec-
trophilic chromone ketoester 2a, which has never been used as
a competent electrophile in a catalytic enantioselective
approach,5 proceeded smoothly in the presence of 10 mol %
of Takemoto catalyst 3a in CH2Cl2 at 25 °C,6 providing the
desired product 4a in good yield, albeit with low
enantioselectivity (entry 1). It should be noted that only one
isomer of 4a was isolated with five continuous stereogenic
centers, one of which is a quaternary center, illustrating the
remarkable regio-, chemo-, and diastereoselectivity of the
designed cascade process, which resulted in a large increase in
complexity starting from readily available achiral substrates.
Subsequently, it was found that both the chiral scaffolds and
acid−base properties of the bifunctional catalysts did not
significantly benefit the reaction efficiency (entries 2−5).7
Considering the number of carbonyl groups in 2a, which are all
the potential hydrogen-bond acceptors, we envisioned that a
multiple H-bond donor catalyst may have higher catalytic
activity.8 As expected, catalyst 3f bearing an amide hydrogen as
additional H-bond donor site provided significant improve-
ments in enantioselectivity (entry 6).9 Consequently, a series
of L-tert-leucine derived bifunctional amine−thiourea catalysts
bearing different substituents on the amide moiety were
evaluated, and catalyst 3g proved to be slightly better than the
others according to a combination of reaction activity and
enantioselectivity (entries 7−10).10 Encouraged by these
promising results, catalyst 3k and 3l containing dipeptide
and tripeptide moieties, respectively, were designed, which
could potentially provide multiple hydrogen-bonding inter-
actions and thus allow the reaction to operate at a low catalyst
loading. Not surprisingly, in the presence of either the new
dipeptide-based catalyst 3k or the new tripeptide catalyst 3l,
the cascade reaction proceeded smoothly and afforded the
desired product 4a in high yield with good enantioselectivity
most likely through multiple hydrogen-bonding interactions
(entries 11 and 12). While considering that catalyst 3l was
prepared in more steps but gave only slightly better results, we
thus carried out further research by application of the catalyst
3k.11 Expectedly, lowering the catalyst loading to 2 mol %
resulted in an increase of the enantioselectivity, despite the
longer reaction times needed (entry 13). The use of 4 Å
molecular sieves (MS) gave an improved enantioselectivity
Herein, we illustrate for the first time that it is possible to
efficiently apply the E1cB elimination in asymmetric organo-
catalytic cascade reactions to provide highly functionalized
polyheterocyclic compounds. It should be noted that a new
dipeptide-based bifunctional tertiary amine−thiourea catalyst
derived from L-tert-leucine has been developed and exhibited
excellent catalytic activity with a low catalyst loading (as low as
0.1 mol %), providing a highly chemo-, regio-, and stereo-
selective route to the desired products under mild reaction
conditions.
B
DOI: 10.1021/acs.orglett.9b03138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope
b
c
entry
3 (mol %)
solvent (mL)
time (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
3a (10)
3b (10)
3c (10)
3d (10)
3e (10)
3f (10)
3g (10)
3h (10)
3i (10)
3j (10)
3k (10)
3l (10)
3k (2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
toluene (1.0)
MTBE (1.0)
CHCl3 (1.0)
2
4
4
4
8
10
2
4
4
2
85
77
68
68
85
90
91
90
95
91
92
94
88
88
86
79
78
76
62
81
28
32
0
36
40
64
68
66
67
63
80
81
86
87
93
91.5
89.5
89
28
91
was replaced by a naphthalene group, similar good results were
also obtained (4r−u). Moreover, substrates 2 containing
biphenyl, indolyl, and even a functionalized phenol moiety
were applicable to this reaction (4v−x).
In particular, we wondered if the complexity-generating
power of the cascade reaction could be further expanded by
accessing structurally more complex molecules. Interestingly, a
C2-symmetric substrate 5 was synthesized and applied in this
reaction sequence, resulting in C2-symmetric product 6 in 71%
yield with 90% ee (Scheme 3a). Even more interesting is the
9
10
11
12
13
14
15
16
17
18
19
4
4
32
36
10
36
68
10
12
18
d
3k (2)
3k (1)
3k (0.5)
3k (0.2)
3k (1)
de
de
de
de
de
3k (1)
3k (1)
Scheme 3. More Applicable Substrates
de
20
a
Unless otherwise noted, the reaction was conducted with 1a (0.1
b
mmol) and 2a (0.11 mmol), 3 in CH2Cl2 at 25 °C. Isolated yield.
c
d
Determined by HPLC analysis on a chiral stationary phase. With 4
e
Å MS (20 mg). At 40 °C.
(entry 14). Much to our delight, the catalyst loading could be
decreased to only 1 mol %, affording 4a in good yield with
even higher enantioselectivity under dilute conditions at 40 °C
after relatively shorter reaction times (entry 15).12 Indeed, a
further decrease in catalyst loading led to similar good results
but required a much longer reaction time (entry 16 and 17).
Furthermore, no better results were obtained when other
solvents were used (entries 18−20).
With the optimal conditions in hand (Table 1, entry 15), the
substrate scope and generality of this cascade reaction were
investigated. As shown in Scheme 2, different substituents on
the benzene ring of both 1 and 2 were well-tolerated,
regardless of their electronic properties, providing the desired
products 4a−q in good yields with good to excellent
enantioselectivities. When the phenyl ring in both 1 and 2
reaction of 7 bearing three Michael receptor moieties with 3.3
equiv 1a, leading to product 8 in moderate yield with excellent
enantioselectivity as a 4:1 diastereomeric mixture, and the
diastereomerically pure 8 could be obtained in 28% total yield
after one recrystallization (Scheme 3b).
Additionally, the model reaction could be carried out on a 1
mmol scale with a remarkably low catalyst loading (0.1 mol %)
at a higher concentration (3 mL of CH2Cl2 for a 1 mmol
C
DOI: 10.1021/acs.orglett.9b03138
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Letter
reaction), providing 4a with 97% ee in good yield (Scheme
4a). Furthermore, in the presence of catalyst 3k at 25 °C, the
asymmetric vinylogous Michael addition by reacting with
chromone ketoester 2a to form intermediate B. The following
stereocontrolled intramolecular oxa-Michael addition and
aldol-type reaction sequence afforded the desired polyheter-
ocyclic product 4a as a single isomer.
Scheme 4. One-Pot and 1 mmol Scale Synthesis
In summary, we have developed an efficient asymmetric
organocatalytic cascade reaction, which involves sequential
E1cB elimination, vinylogous Michael addition, intramolecular
oxa-Michael addition, and aldol-type reaction. Although there
are several undesired competitive reaction pathways in the
presence of a rationally designed bifunctional acid−base
organocatalyst with low catalyst loading, this novel cascade
process proceeds smoothly in a highly chemo-, regio-, and
stereoselective manner, providing biologically interesting
polyfused heterocyclic compounds bearing five continuous
stereogenic centers, one of which is a quaternary center. We
believe that the methodology described here may open the
possibility for the design of novel asymmetric cascade reactions
to construct structurally complex molecules. Further studies on
this concept are ongoing.
chromane malononitrile 1a could be synthesized in situ by the
reaction of chroman-2-ol and malononitrile, which was directly
used to work with chromone ketoester 2a to afford the desired
product 4a in 50% yield with 98% ee via a one-pot procedure.
The relative configuration of the product 4a (CCDC
1943632) was confirmed by X-ray crystallography (Figure 1,
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03138.
Detailed optimization, complete experimental proce-
dures, spectroscopic data for all new compounds, and X-
ray data (PDF)
Accession Codes
Figure 1. X-ray crystallographic structure of ( )-4a.
CCDC 1943632 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.
see the SI for details), and the absolute configuration of 4a was
assigned by means of TD-DFT calculations of the electronic
circular dichroism (ECD) spectra. The remaining config-
urations were assumed by analogy.
A plausible reaction pathway for the developed one-pot
cascade reaction was proposed as illustrated in Scheme 5. The
in situ condensation of chroman-2-ol with malononitrile could
be catalyzed by catalyst 3k to provide the key intermediate
chromane malononitrile 1a. Next, the 3k-promoted E1cB
elimination of 1a led to the activated alkylidene A, which could
be used as the precursor to take part in the subsequent
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuyankai@ouc.edu.cn.
ORCID
Yu Tang: 0000-0001-8224-4639
Yan-Kai Liu: 0000-0002-6559-2348
Notes
Scheme 5. Plausible Reaction Pathway
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC-Shandong Joint Fund
for Marine Science Research Centers (No. U1606403), the
National Science and Technology Major Project for Significant
New Drugs Development (No. 2018ZX09735004), and the
Scientific and Technological Innovation Project Financially
Supported by Qingdao National Laboratory for Marine
Science and Technology (No. 2015ASKJ02-06).
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