Regio- and Stereoselective Cascade of β,γ-Unsaturated Ketones by Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of Dihydrofuro-Fused [2,3-b] Skeletons

Article abstract of DOI:10.1002/anie.202106046

Chiral (dihydro)furo-fused heterocycles are significant structural motifs in numerous natural products, functional materials and pharmaceuticals. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a dipeptide-phosphonium salt-catalyzed regio- and stereoselective cascade reaction of readily available linear β,γ-unsaturated ketones with aromatic alkenes, affording a wide variety of structurally fused heterocyclic molecules in high yields with excellent stereoselectivities. Moreover, mechanistic investigations revealed that the bifunctional phosphonium salt controlled the regio- and stereoselectivities of this cascade reaction, particularly proceeding through the initial ketone α-addition followed by O-participated substitution; and the multiple hydrogen-bonding interactions between Br?nsted acid moieties of catalyst and nitro group of aromatic alkene were crucial in asymmetric induction. Given the generality, versatility, and high efficiency of this method, we anticipate that it will have broad synthetic utilities.

Full text of DOI:10.1002/anie.202106046

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How to cite:
International Edition: doi.org/10.1002/anie.202106046
German Edition: doi.org/10.1002/ange.202106046
Asymmetric Catalysis
Regio- and Stereoselective Cascade of b,g-Unsaturated Ketones by
Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of
Dihydrofuro-Fused [2,3-b] Skeletons
Hongkui Zhang+, Jiajia He+, Yayun Chen+, Cheng Zhuang, Chunhui Jiang,* Kai Xiao,
Zhishan Su,* Xiaoyu Ren, and Tianli Wang*
Abstract: Chiral (dihydro)furo-fused heterocycles are signifi-
cant structural motifs in numerous natural products, functional
materials and pharmaceuticals. Therefore, developing efficient
methods for preparing compounds with these privileged
scaffolds is an important endeavor in synthetic chemistry.
Herein, we develop an effective, modular method by a dipep-
tide-phosphonium salt-catalyzed regio- and stereoselective
cascade reaction of readily available linear b,g-unsaturated
ketones with aromatic alkenes, affording a wide variety of
structurally fused heterocyclic molecules in high yields with
excellent stereoselectivities. Moreover, mechanistic investiga-
tions revealed that the bifunctional phosphonium salt con-
trolled the regio- and stereoselectivities of this cascade reaction,
particularly proceeding through the initial ketone a-addition
followed by O-participated substitution; and the multiple
hydrogen-bonding interactions between Brønsted acid moiet-
ies of catalyst and nitro group of aromatic alkene were crucial
in asymmetric induction. Given the generality, versatility, and
high efficiency of this method, we anticipate that it will have
broad synthetic utilities.
products and pharmaceuticals.[1,2] More importantly, these
molecules provide an attractive platform for structure–
activity relationship studies and lead compound discovery in
drug development due to their broad range of anticancer,
antibacterial, and antifungal properties (Figure 1A).[3] Such
broad spectra of biological activities make the chiral indoline-
fused scaffolds attractive synthetic targets, and thus many
efforts have been devoted to access these important archi-
tectures.[4] However, they have great synthetic challenges
because of their multiple stereogenic centers, fused hetero-
cyclic structures with diversity, and intrinsically rigid ring
system bearing a tricyclic kernel.[5] Therefore, developing
general and straightforward catalytic asymmetric protocols to
access these chiral scaffolds and their related variants is highly
desirable.
On the other hand, b,g-unsaturated ketones as a class of
important reaction partners have received extensive attention
from synthetic chemists due to their broad spectrum of
chemical reactivities (Figure 1B).[6] In particular, because of
their potential enolization, these compounds have been
widely employed as highly active nucleophiles in a number
of catalytic asymmetric reactions for preparing diverse chiral
molecules.[7–12] Currently, the g-addition involving vinylogous
enolate intermediates which proceeds from their g-carbon
atom of the unsaturated carbonyl substrates has been well
studied by either metal catalysis or organocatalysis (Fig-
ure 1B, a).[8,9] In contrast, the alternative a-addition pathway
seems to be elusive, and only sporadic examples have been
documented so far (Figure 1B, b).[10] Occasionally, they
served as electrophiles upon isomerization to conjugated
a,b-unsaturated carbonyl compounds (Figure 1B, c).[10c,11]
Also, they could be utilized as C2-sythons upon their
Introduction
Optically pure (dihydro)furo-fused heterocycles, particu-
larly exemplified by furoindolines and their analogs are
structural motifs widely present in biologically active natural
[*] H. Zhang,[+] J. He,[+] Y. Chen,[+] Prof. Dr. Z. Su, Dr. X. Ren,
Prof. Dr. T. Wang
Key Laboratory of Green Chemistry & Technology of Ministry of
Education, College of Chemistry, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P. R. China)
E-mail: suzhishan@scu.edu.cn
=
deconjugated C C bonds, proceeding enantioselective cycli-
zation reactions (Figure 1B, d).[12] However, despite these
impressive advances, an efficient and general cascade ap-
proach toward the transformation of b,g-unsaturated carbon-
yl compounds is unprecedented, and further exploration in
this direction is thus highly desired. Moreover, in contrast to
the reported majority of one-step approaches, the develop-
ment of a multistep-proceeded new cascade will lead to
a practical and promising reaction mode, particularly that is,
a chiral catalyst-controlled both reactivity and regio- and
stereoselectivities as opposed to a substrate-controlled or
-influenced the catalytic reaction.
wangtl@scu.edu.cn
Y. Chen,[+] Prof. Dr. C. Jiang
School of Environmental and Chemical Engineering, Jiangsu Uni-
versity of Science and Technology
Zhenjiang 212003 (P. R. China)
E-mail: chemjiang@just.edu.cn
C. Zhuang, Prof. Dr. K. Xiao
National Chengdu Center for Safety Evaluation of Drugs and National
Clinical Research Center for Geriatrics, West China Hospital, Sichuan
University
Chengdu 610064 (P. R. China)
[+] These authors contributed equally to this work.
In connection to our recent disclosure of dipeptide-based
phosphonium salts and their applications in a number of
catalytic asymmetric reactions,[13,14] we envision that such
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106046.
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Figure 1. Asymmetric approaches for the transformation of b,g-unsaturated carbonyl compounds and a new strategy for their novel cascade
reaction towards preparing chiral fused heterocycles by bifunctional dipeptide-phosphonium salt catalysis.
highly tunable bifunctional phosphonium halide catalysts,
particularly which possess semi-enclosed cavities and also
have fascinating electrostatic potentials (ESPs) with an
electropositive region (Figure 1C), may be able to address
the reactivity and selectivity issues especially towards con-
Moreover, both chemical experiments and DFT calculations
were performed to gain insights into the origins of the
observed regio- and stereoselectivities.
trolling the chemo- and/or regioselectivities of the novel Results and Discussion
cascade approaches involving b,g-unsaturated ketone sub-
strates, leading to the intriguing but not readily available
cascade reaction proceeded by the a-addition and subsequent
O-participated substitution, both of which are extremely
challenging. In respond to this assumption, herein, we docu-
ment the first example of regio- and stereoselective cascade
reaction of linear b,g-unsaturated ketones with nitro-substi-
tuted aromatic alkenes, leading to highly diastereo- and
enantioselective construction of three types of dihydrofuro-
fused heterocyclic scaffolds, respectively (Figure 1B, e).
Asymmetric Cascade Reaction of b,g-Unsaturated Ketones with
Nitro-Substituted Aromatic Alkenes
Initially, we began our investigations by choosing cascade
between b,g-unsaturated ketone 1a and 2-nitroindole 2a as
a model reaction to evaluate the catalytic effects of various
amino acid-derived bifunctional phosphonium salts bearing
sulfonamide, amide, thiourea and dipeptide scaffolds, respec-
tively (Table 1). Fortunately, all the phosphonium salts
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Table 1: Reaction optimization.[a]
smoothly promoted but gave the corresponding products in
very low enantioselectivities (entries 1–5). Compared in L-
Val-L-Val-dipeptided phosphonium salt P5, L-Val-D-Val-
based dipeptide-phosphonium salt P6 afforded the desired
product 3a in high yield (91%) with slightly increased ee
value of 24% (entry 6). Inspired by these initial results,
further optimization was mainly focused on adjusting the
electronic and steric effects of (L, D)-dipeptided phosphoni-
um salt catalysts (P7–P15) by modifying the hydroxyl moiety
with bulky functional group of tert-butyldiphenylsilyl, or
tuning different substituents of the second -NH unit, or
changing methyl group into sterically hindered benzyl groups
of the active P-center (entries 6–16). Particularly, the D-Thr
as the second amino acid residue was also modified by
introducing a big steric hindrance substituent such as tert-
butyldiphenylsilyl group, and moreover the dipeptide-phos-
phonium salt catalyst P16 turned out to be the best, affording
the expected product in 82% yield with 93% ee (entry 16). In
order to further improve the enantioselectivity, quick screen-
ing of bases and solvents were performed (see SI for more
details),[15] and 4.0 equivalents of K3PO4·3H2O were found to
be the best base conditions and hexane was identified to be
the best solvent for the reaction, due to their affording higher
ee values with excellent yields (entries 17–20). Of note, when
the loading of catalyst P16 was reduced to only 5 mol%, the
corresponding product 3a was also isolated without loss of
reactivity and stereoselectivites after 12 hours (93% yield,
> 20:1 dr and 99% ee (entry 21).
Entry
Cat.
Sol.
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
P1
P2
P3
P4
P5
P6
P7
P8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
hexane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
78
90
45
77
89
91
90
87
63
74
84
78
79
84
80
82
84
89
88
93
93
0
À11
À4
À20
À4
24
20
36
44
70
66
64
12
35
81
93
79
73
P9
10
11
12
13
14
15
16
17
18
19[d]
20[d]
21[d,e]
P10
P11
P12
P13
P14
P15
P16
P16
P16
P16
P16
P16
K2CO3
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
94
99
99
Encouraged by above exciting results, we proceeded to
establish the substrate scope for this novel asymmetric
cascade reaction. Firstly, the scope of P16-mediated cascade
of a variety of b,g-unsaturated ketones 1/1’ with different 2-
nitroindoles 2 was evaluated, and the results are summarized
in Table 2. In general, excellent yields and stereoselectivities
were attainable for all the performed examples. The reaction
tolerated either electron-neutral, -donating or -withdrawing
groups at the ortho-, meta-, or para-position of the first
aromatic rings (Ar1) that directly bond to the carbonyl moiety
of b,g-unsaturated ketones, affording the desired cascade
products 3a–q in high yields (90–99%) with excellent both
enantio- (90–99% ee) and diastereoselectivities (> 20:1 dr).
Also, the reaction worked well for the 3,4-dimethoxyl phenyl,
1-naphthyl, 2-naphthyl, 1,3-benzodioxole, 2-furyl, 2-thienyl,
and 4-pyridyl-containing b,g-unsaturated substrates, deliver-
ing the corresponding products 3r–x in high yields with
excellent ee values, respectively. Similarly, while another
phenyl ring (Ar2) thatꢀs directly attached to the alkene moiety
of allylic ketones was modified with electron-donating or
electron-withdrawing substituents no matter their positions,
these ketone substrates were perfectly compatible with the
reaction conditions, providing the desired products 4a–q in
excellent yields (91–99%) with high diastereo- and enantio-
selectivities (> 20:1 dr, 90– > 99% ee). Moreover, we inves-
tigated the generality for the scope of 2-nitroindoles under the
optimized experimental conditions by reacting with 1a.
Delightedly, a series of 2-nitroindoles 2 particularly bearing
electron-withdrawing groups including fluoro, chloro, or
bromo at the 4- or 5-position of the phenyl ring were found
to be suitable reaction partners, affording the expected
[a] Reaction conditions: 1a (0.12 mmol), 2a (0.10 mmol), base
(0.20 mmol) and catalyst (0.01 mmol) in solvent (2 mL) at room
temperature for 12 h. All dr values were determined by 1H NMR of crude
product. [b] Yields of isolated products. [c] Determined by HPLC analysis
on a chiral stationary phase. [d] The K3PO4·3H2O (0.40 mmol) was used.
[e] The catalyst loading was 5 mol%. Boc=tert-butoxycarbonyl.
TBDPS=tert-butyldiphenylsilyl. Ts=4-toluenesulfonyl.
examined were effective in promoting this cascade by
following our expected reaction pathway, thus providing the
desired dihydrofuro-fused [2,3-b] heterocyclic products in
moderate to good isolated yields with excellent diastereose-
lectivities (all > 20:1). When the phosphonium salts (P1–P5)
bearing a sulfonamide, amide, thiourea or (L, L)-dipeptide
scaffold were employed, the cascade reaction could be
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Table 2: Asymmetric cascade reaction between b,g-unsaturated ketones
products 5a--d in high yields (90–93%) and high steroselec-
1 and 2-nitroindoles 2.[a]
tivities (> 20:1 dr, 92–94% ee). The absolute configurations of
the reaction products were assigned based on the X-ray
crystal structural analysis of compound 4i.[16]
Subsequently, we shifted our attention to explore the
substrate scopes and/or limitations of 2-nitrobenzofurans and
2-nitrobenzothiophenes for this cascade process (Table 3).
When 2-nitrobenzofuran 6a was employed as C2-synthon,
a broad range of b,g-unsaturated ketones (1/1’) that have both
electron-donating and halogenated electron-withdrawing
groups on the aromatic rings were perfectly compatible with
the reaction conditions, leading to the corresponding products
7a–g in high yields with exciting stereoselectivities. Accord-
ingly, the reaction was well applicable to various 2-nitro-
benzofurans bearing different aromatic rings, regardless of
the positions and electronic properties of their substituents on
the aromatic moiety, producing the target compounds in high
yields (up to 96%) with excellent stereoselectivities (all
> 20:1 dr and up to > 99% ee). In addition, the 2-nitro-
benzothiophene was also suitable reaction partner for this
cascade, affording product 8v in 90% yield with 94% ee and
> 20:1 dr value.
Table 3: Cascade reaction of b,g-unsaturated ketones 1 with 2-nitro-
benzofurans and 2-nitrobenzothiophenes, respectively.[a]
[a] Reaction conditions: 1/1’ (0.12 mmol), 2 (0.10 mmol), K3PO4·3H2O
(0.40 mmol) and P16 (0.005 mmol) in hexane (2 mL) at room temper-
ature for 12 h. The dr values were determined by 1H NMR of crude
product. [b] The solvent was PE/xylene (2.0 mL, v/v=1/1). [c] The
solvent was PE/xylen (2.0 mL, v/v=7/3). [d] The reaction was stirred at
08C. [e] The reaction was stirred at 108C. [f] The catalyst loading was
10 mol%.
[a] Reaction conditions: 1/1’ (0.10 mmol), 6 (0.12 mmol), NaHCO3
(0.10 mmol) and P16 (0.005 mmol) in hexane (2 mL) at room temper-
ature for 48 h. The dr values were determined by 1H NMR of crude
product. [b] The NaHCO3 (0.40 mmol) was used.
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Substrate Limitations and Synthetic Manipulations
We explored the scope frontier of both substrates (Fig-
ure 2A). Particularly, we changed the styryl moieties of b,g-
unsaturated ketones into electron-withdrawing groups such as
CN, Ac and CO2Et; and thus prepared the compounds 11a–c.
When these substrates were subjected to the cascade reaction
with 2-nitroindole 2a, the corresponding products 12a–c were
generated but with low enantioselectivities, probably because
of that the above optimized conditions were not matching to
these ketone compounds. Instead, when the compounds 11d–
l that bear weak activities of the a-carbon were employed as
substrates, these reactions could not occur, which was
generally due to that the substrates 11d–l may not be
sufficiently acidic to form the enolate. On the other hand,
when the Boc-group of 2-nitroindole were changed into H, Ts,
Me or Bn (13a–d), these structurally similar compounds were
not favorable substrates for this cascade reaction, which might
be that these compounds were not active enough for this
transformation. Notably, when the 3-nitro-substituted aro-
matic alkenes (13e–h) or indene 13i were used as the
corresponding C2-synthon, no reactions were observed. On
the other hand, we also explored other alkene substrates
(13g–l); and only a-addition products (14g–l) were obtained
in all these cases, possibly owing to the less reactivity of these
alkenes.
To demonstrate the practicality and the scalability of this
cascade transformation, large-scale reactions of 2-nitroindole
2a with b,g-unsaturated ketone 1i, 2-nitrofuran 6o with
ketone 1a, were performed, and the corresponding products
(4i and 8o) were isolated in high yields with maintained high
stereoselectivities, respectively (Figure 2B, a). Synthetically,
treatment of the optically enriched product 3a with LiAlH4
gave the alkenyl-reduced product 9 in 95% isolated yield
without loss of enantioselectivity and diastereoselectivity;
and the product 3a could be easily transformed into chiral
compound 10 in 92% yield with maintained stereoselectivi-
ties under the trifluoroacetic acid conditions (Figure 2B, b).
In addition, we tested the newly synthesized dihydrofuro-
fused heterocyclic products for their bioactivity as antitumor
agents, and particularly the cytotoxic effects of these com-
pounds were evaluated against a panel of cancer cells; and the
bioactive results suggest that such cascade products may have
potential for leading compound discovery in chiral drug
development (see Table S6 in Supporting Information for
details).[17]
Mechanistic Investigations
Above exciting results aroused our interest in the study of
the reaction mechanism. Thus, the isotope labeling experi-
ment was performed to gain insight into the reaction
mechanism (Figure 3A). When the reaction between 1a and
2a was conducted in the solvent of deuterated methanol,
deuterium incorporation into the 8a-position of the product
was observed. Subsequently, the high resolution mass spec-
troscopy (HRMS-ESI) analysis of the model reaction under
optimal conditions was further carried out (Figure 3B); and
Figure 2. Substrate limitations (A) and synthetic applications (B).
two signal peaks were detected at m/z 460.1852 and 523.2641,
which corresponded to the a-addition intermediate In-D and
the desired cascade product 3a, respectively. To gain a better
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According to these mechanistic results and our previous
findings in dipeptide-phosphonium salt catalysis,[14] the plau-
sible reaction mechanism of our cascade reaction as well as
other possible reaction pathways were proposed in Figure 4,
which illuminated that a cascade process containing a-
addition and O-participated substitution could be involved
in the catalytic cycle (Path IV). Generally, the reaction is
initiated by the base-triggered deprotonation of b,g-unsatu-
rated ketone 1a to give the anionic intermediate A (including
resonant A1, A2 and A3), which may be stabilized by
phosphonium cation. Then, the nucleophilic a-addition of
this deprotonated intermediate (A) to 2-nitroindole 2a
occurred via the transition state P16-TS1-re, generating the
intermediate B’ which was protonated for giving a-addition
intermediate In-D; and the In-D was further deprotonated by
base (or intramolecular H-transfer of B’ occured to afford
anionic E, see Figure S8 in Supporting Infromation for
details) for providing anionic intermediate E (including
resonant E1, E2 and E3). Then, the intramolecular substitution
of nitro group by O-atom of enolate proceeded via the
transition state P16-TS2-re, thus providing the desired
cascade product with simultaneously releasing the catalyst
that would enter the next reaction cycle. Of note, other types
of reaction products including 3a-1, 3a-2 or 3a-3 (Figure 4),
which would be generated from possibly workable reaction
pathways, particularly including direct g-addition (Path I),
[2+2] cyclization (Path II) or a-addition/g-carbon-selective
substitution cascade (Path III), were not observed in this
catalytic system.
To further understand the mechanism of this cascade
reaction, we performed DFT calculations using Gaussian09
program[19] at the M062X[20]-D3[21,22]/6–311 + G(d,p)(SMD, n-
hexane)//M062X-D3/6-31G(d,p)(SMD, n-hexane) theoretical
level. On the basis of catalytic cycles listed in Figure 4, the
complete energy profiles for the possible four reaction
pathways for the reaction between b,g-unsaturated ketone
1a and 2-nitroindole 2a by phosphonium salt catalyst P6 are
given in the Figure 5. Firstly, the positively charged catalyst
P6 activated 2a by dual hydrogen-bonding, resulting in the
formation of IM1. When the anionic intermediate A inter-
acted with IM1, the corresponding intermediates (I/II-IM2–
V-IM2) were stabilized well by ion-pair interactions. These
steps were exergonic by À31.9–À37.5 kcalmolÀ1. Then, the
Figure 3. Mechanistic investigations.
understanding the origin of the asymmetric induction for this
cascade, we then prepared the methylated catalysts P16-1 and
P16-2. When methylated phosphonium salts were used as the
catalyst, the reactions became slightly slower and the
enantioselectivities decreased dramatically. Besides, when
the reaction was performed in methanol, practically racemic
product was obtained (Figure 3C). Additionally, the 1H NMR
titration experiments were performed for getting more
mechanistic insights.[18] Particularly, titration of ketone sub-
strate 1a to the optimal catalyst P16 led to less pronounced
changes in the position of the amide-NH signal of catalyst,
while titration of 2-nitroindole 2a to catalyst P16 led to an
obvious change in the position of the -NH signal of P16 (see
Figure S3 in Supporting Information for details). These
results offered clear clues that the interaction of ion-pair
and H-bonding effects are essential for enhancing the
reactivity and stereoselectivities of this cascade reaction.
À
C C bonds were constructed via transition states I/II-TS1,
III-TS1 and IV-TS1 by nucleophilic addition of A resonant
(A1, A2 or A3) toward 2a. The calculations indicated that the
activation barrier along path IV was lower than those along
path I–III, indicating that the A1 exhibited higher reactivity
toward 2a. Starting from I/II-IM3, 3a-1 was obtained by
protonating I-IM3 along path I. In addition, the nucleophilic
2a could also attack the Cb-atom of A via transition state II-
TS2, constructing a four-membered ring in II-IM4 that would
be protonated for giving 3a-2. However, these protonation
processes seem difficult to occur in the view point of
2À
thermodynamics either using HPO4 or H2O as proton
reagent. In path III and path IV, the negatively charged Cg-
atom in III-IM4 or O-atom in IV-IM4 attacked the C2-atom of
À
À
indole moiety to form the C C bond or C O bond. In these
SN2-like processes, a NO2 anion was released simultaneously,
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Figure 4. Proposed reaction cycles between b,g-unsaturated ketone 1a and 2-nitroindole 2a by phosphonium salt.
affording III-IM5 or IV-IM5. The DG° in this step along path
IV was lower than that along path III by 16.8 kcalmolÀ1. That
is, the major 3a observed in the experiment was predom-
inantly produced along path IV. Moreover, the regioselectiv-
ities of this cascade were mainly determined by the relatively
low reaction energy that resulted from the initial a-addition
but not g-addition between the conjugated enolate inter-
mediates and the aromatic alkenes.
On the basis of above results, we then investigated the
origins of enantioselectivity in the presence of catalyst P16.
The competing transition states (P16-TS1-re–P16-TS1-si,
Figure 6) associated with the construction of two stereocen-
ters in 3a were located at the same theoretical level. Suffering
steric repulsion between the bulky OTBDPS group of P16
and the N-Boc group of 2a, P16-TS1-si was less stable than
that of P16-TS1-re by 1.3 kcalmolÀ1 in the first C C bond
À
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Figure 5. Energy profiles for asymmetric reactions between b,g-unsaturated ketone (1a) and 2-nitroindole (2a) catalyzed by phosphonium salt
catalyst P6 along four pathways (I–IV). The relative free energies are given in kcalmolÀ1
.
formation step (i.e., chiral-controlling step) at the M062X- Conclusion
D3/6-31G(d,p)(SMD, n-hexane) theoretical level. Mean-
À
while, the DG of P16-TS2-re and P16-TS2-si in the C O
bond formation step were comparable (À50.0 vs. À50.2 kcal
molÀ1) along re-/si-pathways, respectively. These results
indicated that re-face-selective attack was more favorable
than that of si-face.
In summary, we disclosed the first regio- and stereoselec-
tive a-addition/O-atom-selective substitution cascade of lin-
ear b,g-unsaturated carbonyl compounds with 2-nitroindoles,
2-nitrobenzofurans and 2-nitrobenzothiophenes, respectively,
by employing a dipeptide-phosphonium salt as chiral catalyst.
With this novel protocol, three types of dihydrofuro-fused
[2,3-b] architectures that bear great synthetic challenges were
conveniently and efficiently constructed in high chemical
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Figure 6. DFT-optimized key transition states and their relative Gibbs free energies (in kcalmolÀ1) in this cascade reaction catalyzed by P16,
obtained at the M062X-D3/6-31G(d,p)(SMD, n-hexane) thereotical level. Distances are given in angstroms.
yields with excellent diastereo- and enantioselectivities. The
synthetic values of our methodology and the cascade products
were demonstrated by the gram-scale preparations, facile
elaborations and their potential bioactivities. Moreover,
presented herein is the first practical approach for controlling
the a-carbon-selective nucleophilic additions but not that of
the g-carbon, together with differentiating the subsequent O-
atom-participated substitution from g-carbon-selected sub-
stitution for the cascade process of b,g-unsaturated ketones
with nitro-substituted aromatic alkenes. Our theoretical
investigations revealed that the regioselectivities of this
cascade were mainly determined by the relatively low
reaction energy that resulted from the initial a-addition but
not g-addition between the conjugated enolate intermediates
and the aromatic alkenes; and the mechanistic insights gained
may open up new avenues for the design of novel cascade
approaches involving b,g-unsaturated carbonyl compounds
and other related substrates. Such efforts are currently
ongoing in our laboratory and will be reported in due course.
Chemistry at Sichuan University and the Analytical & Testing
Center of Sichuan University for compound testing.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: (dihydro)furo-fused heterocycles ·
asymmetric cascade reaction · bifunctional phosphonium salts ·
reaction mechanism · b,g-unsaturated ketones
[1] a) S. P. Roche, J. A. Porco, Jr., Angew. Chem. Int. Ed. 2011, 50,
4068 – 4093; Angew. Chem. 2011, 123, 4154 – 4179; b) D. Zhang,
H. Song, Y. Qin, Acc. Chem. Res. 2011, 44, 447 – 457; c) W. A.
Donaldson, Tetrahedron 2001, 57, 8589 – 8627; d) S. P. Roche, J.-
J. Y. Tendoung, B. Treguier, Tetrahedron 2015, 71, 3549 – 3591;
e) Y. Ito, M. Ueda, O. Miyata, Heterocycles 2014, 89, 2029 – 2052.
[2] a) T. B. K. Lee, G. S. K. Wong, J. Org. Chem. 1991, 56, 872 – 875;
b) G. Subramaniam, O. Hiraku, M. Hayashi, T. Koyano, K.
Komiyama, T.-S. Kam, J. Nat. Prod. 2007, 70, 1783 – 1789;
c) A. M. Socha, K. L. LaPlanteb, D. C. Rowleya, Bioorg. Med.
Chem. 2006, 14, 8446 – 8454; d) Q. Zhou, L. Zhang, M. A.
Zuniga, R. M. Tombes, J. K. Stewart, Chem. Res. Toxicol. 2008,
21, 732 – 738; e) A. Shafferman, D. Barak, D. Stein, C. Kronman,
B. Velan, N. H. Greig, A. Ordentlich, Chem.-Biol. Interact. 2008,
175, 166 – 172; f) E. Iwasa, Y. Hamashima, S. Fujishiro, E.
Higuchi, A. Ito, M. Yoshida, M. Sodeoka, J. Am. Chem. Soc.
2010, 132, 4078 – 4079; g) F.-P. Miao, X.-D. Li, X.-H. Liu, R. H.
Cichewicz, N.-Y. Ji, Mar. Drugs 2012, 10, 131 – 139; h) M.
de Candia, G. Zaetta, N. Denora, D. Tricarico, M. Majellaro, S.
Cellamare, C. D. Altomare, Eur. J. Med. Chem. 2017, 125, 288 –
298.
Acknowledgements
Financial support was provided by the National Natural
Science Foundation of China (21971165, 21921002), the
National Key R&D Program of China (2018YFA0903500),
the “1000-Youth Talents Program” (YJ201702), Fundamental
Research Funds from Sichuan University (2020SCUNL108),
and the Fundamental Research Funds for the Central
Universities. We also acknowledge the comprehensive train-
ing platform of the Specialized Laboratory in the College of
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[3] a) G.-G. Cheng, D. Li, B. Hou, X.-N. Li, L. Liu, Y.-Y. Chen, P.-K.
[9] For selected examples on g-addition by organocatalysis, see:
Lunga, A. Khan, Y.-P. Liu, Z.-L. Zuo, X.-D. Luo, J. Nat. Prod.
2016, 79, 2158 – 2166; b) Y.-Y. Low, F.-J. Hong, K.-H. Lim, N. F.
Thomas, T.-S. Kam, J. Nat. Prod. 2014, 77, 327 – 338; c) L. Zu,
B. W. Boal, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 8877 – 8879;
d) A. S. ElAzab, T. Taniguchi, K. Ogasawara, Org. Lett. 2000, 2,
2757 – 2759; e) A. W. Schammel, B. W. Boal, L. Zu, T. Mesga-
naw, N. K. Garg, Tetrahedron 2010, 66, 4687 – 4695; f) C. Li, C.
Chan, A. C. Heimann, S. J. Danishefsky, Angew. Chem. Int. Ed.
2007, 46, 1444 – 1447; Angew. Chem. 2007, 119, 1466 – 1469.
[4] For selected examples, see: a) M. Tao, Y. Tu, Y. Liu, H. Wu, L.
Liu, J. Zhang, Chem. Sci. 2020, 11, 6283 – 6288; b) L. Li, K. Yuan,
Q. Jia, Y. Jia, Angew. Chem. Int. Ed. 2019, 58, 6074 – 6078;
Angew. Chem. 2019, 131, 6135 – 6139; c) D. Lachkar, N. Denizot,
G. Bernadat, K. Ahamada, M. A. Beniddir, V. Dumontet, J.-F.
Gallard, R. K. Leblanc, E. O. Nꢀnang, V. Turpin, C. Kouklovsky,
E. Poupon, L. Evanno, G. Vincent, Nat. Chem. 2017, 9, 793 – 798;
d) K. Liu, S. Tang, P. Huang, A. Lei, Nat. Commun. 2017, 8, 775 –
783; e) L. Liao, C. Shu, M. Zhang, Y. Liao, X. Hu, Y. Zhang, Z.
Wu, W. Yuan, X. Zhang, Angew. Chem. Int. Ed. 2014, 53, 10471 –
10475; Angew. Chem. 2014, 126, 10639 – 10643; f) Y.-Z. Cheng,
Q.-R. Zhao, X. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2019,
58, 18069 – 18074; Angew. Chem. 2019, 131, 18237 – 18242; g) Q.-
J. Liu, J. Zhu, X.-Y. Song, L. Wang, S. R. Wang, Y. Tang, Angew.
Chem. Int. Ed. 2018, 57, 3810 – 3814; Angew. Chem. 2018, 130,
3872 – 3876.
[5] a) M. Lachia, C. J. Moody, Nat. Prod. Rep. 2008, 25, 227 – 253;
b) N. Denizot, T. Tomakinian, R. Beaud, C. Kouklovsky, G.
Vincent, Tetrahedron Lett. 2015, 56, 4413 – 4429; c) A. Palmieri,
M. Petrini, Nat. Prod. Rep. 2019, 36, 490 – 530; d) R. Cao, W.
Peng, Z. Wang, A. Xu, Curr. Med. Chem. 2007, 14, 479 – 500.
[6] a) S. E. Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew.
Chem. Int. Ed. 2005, 44, 4682 – 4698; Angew. Chem. 2005, 117,
4760 – 4777; b) G. Casiraghi, L. Battistini, C. Curti, G. Rassu, F.
Zanardi, Chem. Rev. 2011, 111, 3076 – 3154; c) C. Curti, L.
Battistini, A. Sartori, F. Zanardi, Chem. Rev. 2020, 120, 2448 –
2612; d) B. Mao, M. FaÇanas-Mastral, B. L. Feringa, Chem. Rev.
2017, 117, 10502 – 10566; e) S. Hosokawa, Acc. Chem. Res. 2018,
51, 1301 – 1314; f) C. Schneider, F. Abels, Org. Biomol. Chem.
2014, 12, 3531 – 3543.
a) M. Meazza, R. Rios, Adv. Synth. Catal. 2021, 363, 1341 – 1345;
b) Z. Jing, X. Bai, W. Chen, G. Zhang, B. Zhu, Z. Jiang, Org.
Lett. 2016, 18, 260 – 263; c) G. Zhan, Q. He, X. Yuan, Y.-C. Chen,
Org. Lett. 2014, 16, 6000 – 6003; d) Y. Gu, Y. Wang, T.-Y. Yu, Y.-
M. Liang, P.-F. Xu, Angew. Chem. Int. Ed. 2014, 53, 14128 –
14131; Angew. Chem. 2014, 126, 14352 – 14355; e) B. Zhu, W.
Zhang, R. Lee, Z. Han, W. Yang, D. Tan, K. Huang, Z. Jiang,
Angew. Chem. Int. Ed. 2013, 52, 6666 – 6670; Angew. Chem.
2013, 125, 6798 – 6802.
[10] For selected examples on a-addition, see: a) Y.-H. Geng, Y.-Z.
Hua, S.-K. Jia, M.-C. Wang, Chem. Eur. J. 2021, 27, 5130 – 5135;
b) I. Iriarte, O. Olaizola, S. Vera, I. Gamboa, M. Oiarbide, C.
Palomo, Angew. Chem. Int. Ed. 2017, 56, 8860 – 8864; Angew.
Chem. 2017, 129, 8986 – 8990; c) T. Kang, L. Hou, S. Ruan, W.
Cao, X. Liu, X. Feng, Nat. Commun. 2020, 11, 3869 – 3878; d) I.
Urruzuno, O. Mugica, G. Zanella, S. Vera, E. Gjmez-Bengoa, M.
Oiarbide, C. Palomo, Chem. Eur. J. 2019, 25, 9701 – 9709; e) E.
Marquꢁs-Lꢂpez, R. P. Herrera, T. Marks, W. C. Jacobs, D.
Kçnning, R. M. de Figueiredo, M. Christmann, Org. Lett. 2009,
11, 4116 – 4119; f) B. Han, Z.-Q. He, J.-L. Li, R. Li, K. Jiang, T.-Y.
Liu, Y.-C. Chen, Angew. Chem. Int. Ed. 2009, 48, 5474 – 5477;
Angew. Chem. 2009, 121, 5582 – 5585.
[11] a) A. Yamaguchi, N. Aoyama, S. Matsunaga, M. Shibasaki, Org.
Lett. 2007, 9, 3387 – 3390; b) R. Yazaki, T. Nitabaru, N. Kumagai,
M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 14477 – 14479; c) A.
Yamaguchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009,
131, 10842 – 10843; d) T. Mitsudo, N. Suzuki, T. Kondo, Y.
Watanabe, J. Org. Chem. 1994, 59, 7759 – 7765; e) O. Olaizola, I.
Iriarte, G. Zanella, E. Glmez-Bengoa, I. Ganboa, M. Oiarbide,
C. Palomo, Angew. Chem. Int. Ed. 2019, 58, 14250 – 14254;
Angew. Chem. 2019, 131, 14388 – 14392.
[12] a) Y. Chen, Y. Wang, S. Wang, Y.-Y. Ma, D.-G. Zhao, R. Zhan, H.
Huang, Org. Lett. 2020, 22, 7135 – 7140; b) X. Li, X. Kong, S.
Yang, M. Meng, X. Zhan, M. Zeng, X. Fang, Org. Lett. 2019, 21,
1979 – 1983; c) Y. Lin, X.-Q. Hou, B.-Y. Li, D.-M. Du, Adv.
Synth. Catal. 2020, 362, 5728 – 5735; d) P. S. Akula, B.-C. Hong,
G.-H. Lee, Org. Lett. 2018, 20, 7835 – 7839; e) M.-L. Shi, G.
Zhan, S.-L. Zhou, W. Du, Y.-C. Chen, Org. Lett. 2016, 18, 6480 –
6483.
[7] a) Q. Zhang, X. Liu, X. Feng, Curr. Org. Synth. 2013, 10, 764 –
785; b) A. Yamaguchi, S. Matsunaga, M. Shibasaki, Org. Lett.
2008, 10, 2319 – 2322; c) J. Xu, Z. Jin, Y. R. Chi, Org. Lett. 2013,
15, 5028 – 5031; d) T.-Y. Liu, H.-L. Cui, J. Long, B.-J. Li, Y. Wu,
L.-S. Ding, Y.-C. Chen, J. Am. Chem. Soc. 2007, 129, 1878 – 1879;
e) M. Sickert, C. Schneider, Angew. Chem. Int. Ed. 2008, 47,
3631 – 3634; Angew. Chem. 2008, 120, 3687 – 3690; f) S. P. Brown,
N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 1192 – 1194.
[8] For selected examples on g-addition by metal catalysis, see: a) X.
Fu, Y. Hao, H.-Y. Bai, A. Duan, S.-Y. Zhang, Org. Lett. 2021, 23,
25 – 30; b) B. M. Trost, J. Hitce, J. Am. Chem. Soc. 2009, 131,
4572 – 4573; c) N. E. Shepherd, H. Tanabe, Y. Xu, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 3666 – 3667; d) L.
Yin, H. Takada, N. Kumagai, M. Shibasaki, Angew. Chem. Int.
Ed. 2013, 52, 7310 – 7313; Angew. Chem. 2013, 125, 7451 – 7454;
e) D. Yang, L. Wang, F. Han, D. Zhao, B. Zhang, R. Wang,
Angew. Chem. Int. Ed. 2013, 52, 6739 – 6742; Angew. Chem.
2013, 125, 6871 – 6874; f) H.-J. Zhang, C.-Y. Shi, F. Zhong, L. Yin,
J. Am. Chem. Soc. 2017, 139, 2196 – 2199; g) B. M. Trost, E.
Gnanamani, J. S. Tracy, C. A. Kalnmals, J. Am. Chem. Soc. 2017,
139, 18198 – 18201; h) H.-J. Zhang, L. Yin, J. Am. Chem. Soc.
2018, 140, 12270 – 12279; i) F. Zhong, W.-J. Yue, H.-J. Zhang, C.-
Y. Zhang, L. Yin, J. Am. Chem. Soc. 2018, 140, 15170 – 15175;
j) B. M. Trost, E. Gnanamani, C. A. Kalnmals, C.-I. Hung, J. S.
Tracy, J. Am. Chem. Soc. 2019, 141, 1489 – 1493.
[13] For selected reviews, see: a) S. Liu, Y. Kumatabara, S. Shiraka-
wa, Green Chem. 2016, 18, 331 – 341; b) T. Werner, Adv. Synth.
Catal. 2009, 351, 1469 – 1481; c) S. Wen, X. Li, Y. Lu, Asian J.
Org. Chem. 2016, 5, 1457 – 1460; d) A. Golandaj, A. Ahmad, D.
Ramjugernath, Adv. Synth. Catal. 2017, 359, 3676 – 3706; e) H.
Wang, C. Zheng, G. Zhao, Chin. J. Chem. 2019, 37, 1111 – 1119;
f) H. Li, H. Liu, H. Guo, Adv. Synth. Catal. 2021, 363, 2023 –
2036.
[14] For selected examples by our group, see: a) J. Pan, J.-H. Wu, H.
Zhang, X. Ren, J.-P. Tan, L. Zhu, H.-S. Zhang, C. Jiang, T. Wang,
Angew. Chem. Int. Ed. 2019, 58, 7425 – 7430; Angew. Chem.
2019, 131, 7503 – 7508; b) H. Zhang, C. Jiang, J.-P. Tan, H.-L. Hu,
Y. Chen, X. Ren, H.-S. Zhang, T. Wang, ACS Catal. 2020, 10,
5698 – 5706; c) L. Zhu, X. Ren, J. Du, J.-H. Wu, J.-P. Tan, J. Che,
J. Pan, T. Wang, Green Chem. 2020, 22, 7506 – 7512; d) J.-P. Tan,
X. Li, Y. Chen, X. Rong, L. Zhu, C. Jiang, K. Xiao, T. Wang, Sci.
China Chem. 2020, 63, 1091 – 1099; e) S. Fang, J.-P. Tan, J. Pan, H.
Zhang, Y. Chen, X. Ren, T. Wang, Angew. Chem. Int. Ed. 2021,
60, 14921 – 14930; Angew. Chem. 2021, 133, 15048 – 15057.
[15] See Table S1–S3 in Supporting Information for more details.
[16] Deposition Numbers 202753 (for catalyst P16), and 1966942 (for
4i) contain the supplementary crystallographic data for this
paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service www.ccdc.
cam.ac.uk/structures.
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[17] See Table S6,S7 in Supporting Information for details of
bioactivity study.
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P.
Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian, Inc. Wallingford, CT, 2013.
[18] See Figure S1–S3 in Supporting Information for more details.
[19] Gaussian09, RevisionD.01, M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakat-
suji, M. Li, X. Caricato, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, J. J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Taroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. N. C. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
[20] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215 – 241.
[21] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010,
132, 154104 – 154119.
[22] S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32,
1456 – 1465.
Manuscript received: May 5, 2021
Revised manuscript received: June 23, 2021
Accepted manuscript online: July 2, 2021
Version of record online: && &&
,
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Research Articles
Asymmetric Catalysis
H. Zhang, J. He, Y. Chen, C. Zhuang,
C. Jiang,* K. Xiao, Z. Su,* X. Ren,
T. Wang*
&&&& — &&&&
Regio- and Stereoselective Cascade of
b,g-Unsaturated Ketones by Dipeptided
Phosphonium Salt Catalysis:
Stereospecific Construction of
Dihydrofuro-Fused [2,3-b] Skeletons
A highly regio-, diastereo- and enantio-
selective cascade reaction of b,g-unsatu-
rated carbonyl compounds with 2-nitro-
indoles, 2-nitrobenzofurans and 2-nitro-
benzothiophenes was achieved through
dipeptide-phoaphonium salt catalysis.
Three types of structurally fused hetero-
cycles were obtained in excellent stereo-
selectivities. Regioselectivities were
determined by the low reaction energy
resulting from the initial a-addition but
not g-addition.
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These are not the final page numbers!