Highly enantioselective addition of aliphatic aldehydes to 2-hydroxychalcone enabled by cooperative organocatalysts

Article abstract of DOI:10.1039/d0cc04424e

Herein, we developed an enantioselective addition of aliphatic aldehydes to 2-hydroxychalcone promoted by cooperative organocatalysts, giving access to hybrid flavonoids in excellent enantioselectivities. This reaction took advantage of cycloisomerization of 2-hydroxychalcone to form a transient flavylium under the irradiation of 24 W CFL, which was trapped by the in situ generated chiral enamine intermediate. The synergistic action of chiral phosphoric acid secured the excellent outcome of this reaction by ion-pairing with the transient flavylium.

Full text of DOI:10.1039/d0cc04424e

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC04424E
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Highly Enantioselective Addition of Aliphatic Aldehydes to 2-
Hydroxychalcone Enabled by Cooperative Organocatalysts
Received 00th January 20xx,
Accepted 00th January 20xx
Jiadong Hu,ab† Yu-Qi Gao,a† Dongyang Xu,a Le Chen,a Wen Wen,b Yi Hou,a Lu Chen,a and Weiqing
Xie*ac
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, we developed an enantioselective addition of aliphatic enantioselective nucleophilic addition of aldehyde to
aldehydes to 2-hydroxychalcone promoted by cooperative flavonium salt catalyzed by chiral imidazolidinone, delivering
organocatalysts, giving access to hybrid flavonoids in excellent the hybrid flavonoids in moderate enantioselectivities and
enantioselectivities. This reaction took advantage of diastereoselectivities. More recently, Toste and colleagues5c
cycloisomerization of 2-hydroxychalcone to form a transient reported the enantioselective nucleophilic addition of phenol
flavylium under the irradiation of 24W CFL, which was trapped by or naphthol to flavylium salts by using chiral phosphoric acid as
the in situ generated chiral enamine intermediate. The synergistic anionic phase transfer catalyst. Despite of those advances, a
action of chiral phosphoric acid secured the excellent outcome of mild methodology for the enantioselective construction of the
this reaction by ion-pairing with the transient flavylium.
C4-C1’’ linker remains highly desirable.
1. structure of Fissistigmatins:
Flavonoids are important plant pigment that widely
distributed in nature,1a which display important biological
activities including anti-inflammatory, antioxidant, anti-
microbial, antiviral, as well as anticancer profiles.1b Hybrid
flavonoids are a small family of flavonoids, possessing a
flavonoids unit and another type of natural product units.2 In
this regard, Fissistigmatins are a novel type of sesquiterpene
hybrid flavonoid isolated from Fissistigma bracteolatum Chatt.
(Annonaceae) by Adam and co-workers (Figure 1).3 Structurally,
Fissistigmatins contain a flavonoid and sesquiterpene fragment,
which is connected by a C4-C1’’ bond. In this context, the
enantioselective forging of the linker between those two
fragments has posed formidable challenge.2
OMe
OMe
OMe
H
MeO
O
4
MeO
O
MeO
O
H
H
H
H
H
1''
MeO
MeO
MeO
H
H
H
HO
Fissistigmatin A
2. light-driven enatioselective addition of alehyde to 2-hydroxychalcone:
HO
Fissistigmatin B
Fissistigmatin C
R1
H
O
O
O
A4
10 mol%
H
10% mol R-TRIP
Ar
H
+
R2
R2
R1
24W CFL
Et2O, RT
OH
O
3
Ar
2
1
up to 98% ee, >20:1 dr
light-driven synthesis;
cooperative organocatalysts;
wide substrate scope;
excellent enatioselectivities.
Despite of the great advances have been made in the
synthesis of hybrid flavonoids from 2-hydroxychalcone or
flavylium salts,4 the catalytic asymmetric syntheses of this
scaffold are scarcely reported.5 In this context, Shi5a reported
palladium catalyzed enantioselective addition of 2-hydroxyaryl
boronic acid to 2-hydroxychalcone to construct bridged hybrid
flavonoids. In 2010, Cozzi and co-workers5b reported an
Figure 1. Structure of Fissistigmatins and enantioselective addition of aliphatic
aldehydes to 2-hydroxychalcone.
With the blooming evolution of organocatalysts,6
tremendous progresses have been witnessed by employing
cooperative organocatalysts to realize enantioselective
reactions that are otherwise difficulty achieved by using single
organocatalyst.7 Recently, we developed
a bio-inspired
a. Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling
712100, Shaanxi, China. Email: xiewq@nwafu.edu.cn
synthesis of hybrid flavonoids from 2-hydroxychalcone driven
by visible light.8 The reaction took advantage the
photocyclization of 2-hydroxychalcone under the irradiation of
24 W CFL via tandem E to Z isomerization/dehydrative
cyclization process to generate a flavylium intermediate.8,9 In
line with our previous work, we discovered that the highly
enantioselective addition of aliphatic aldehydes to 2-
hydroxychalcone promoted by cooperative organocatalysts
b. School of Medicinal and Chemical Engineering, Yangling Vocational & Technical
College, 10 Xinong Road, Yangling 712100, Shaanxi, China.
c. Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling 712100,
Shaanxi, China.
† Those two authors contributed equally.
Electronic Supplementary Information (ESI) available: General experimental
procedures, and spectroscopic date for the all new compounds. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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driven by visible-light, enabling enantioselective construction combining chiral imidazolidinone A4 with C2 gave excellent
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DOI: 10.1039/D0CC04424E
of the C4-C1’’ linkage of Fissistigmatins. Herein, we would like enantioselectivity (98% ee) and high diastereoselectivity (12:1)
to report our preliminary results.
(Table 1, entry 11). Furthermore, the combination of (S)-C2
with imidazolidinone A4 was also tested to investigate
whether stereodivergent synthesis of 3a could be realized
(Table 1, entry 12). However, only low enantioselectivity and
diastereoselectivity was obtained, suggesting the mismatching
of those two chiral organocatalysts.
Table 1. Optimization of the Reaction Conditionsa
O
Ph
O
H
H
O
conditions
Ph
＋
H
Ph
24W CFL
RT
OH
O
3a
Ph
1a
2a
R1
O
O
amine
additive
yield
ee (%)c
O
H
H
A4
C2
10 mol%
10 mol%
entry
dr
(%)b
59
71
ND
ND
ND
74
91
74
82
29
major, minor
79, 58
94, 83
NA
R2
R3
H
+
R2
(10 mol%)
A1
(10 mol%)
TFA
C1
Et2O, RT
24W CFL
R1
OH
O
3
1
R3
1
2
3d
4
5
6
7
8
9
1:1
2:1
NA
NA
NA
3:1
2.5:1
2 1
2:1
2:1
12:1
3:1
2
A1
A1
A1
--
A1
A1
A1
A2
R1
H
C1
--
C1
C2
C3
C4
C2
C2
O
Ph
O
H
H
H
NA
NA
2
3
O
O
R3
95, 55
79, 20
68, -10
95, 91
-38, 12
98, 53
68, 41
4
: R1 = Bn
3h
3i
3j
: R3 = 4-Me
3a
81%, 98% ee, 12:1 dr
83%, 98% ee, 10:1 dr
90%, 96% ee, 8:1 dr
75%, 97% ee, 10:1 dr
72%, 95% ee, 5:1 dr
83%, 98% ee, 11:1 dr
63%, 95% ee, 6:1 dr
67%, 96% ee, 6:1 dr
86%, 98% ee, 17:1 dr
92%, 95% ee, 11:1 dr
85%, 98% ee, 7:1 dr
91%, 96% ee, 6:1 dr
90%, 99% ee, 12:1 dr
: R3 = 4-OMe
(5 mmol scale)
3b
: R1 = Et,
: R1 = n-Bu
: R3 = 4-Cl
3c
(5 mmol scale)
: R3 = 3-Br
10
11
12
A3
A4
A4
3d: R1 = i-Pr,
3k
: R1 = Allyl
3e
3f
C2
(S)-C2
81
73
: R1 = (CH2)3N3
3g: R1 = (CH2)2CO2Me
TBSO
MeO
Ph
5
O
A1
A2
A3
: PG = TBS
: PG = TMS
: PG = H
R
Ph
Ph
OPG
H
H
MeO
O
6
H
H
C1
: R = H
N
R2
O
O
P
H
i
C2
C3
C4
: R = 2,4,6-(Pr3)C6H2
7
O
8
O
Me
O
: R = 2-PhC6H4
OH
O
OMe
3p
N
: R = 9'-phenanthrene
: R2 = 7-Me
86%, 98% ee, 13:1 dr
3l
Ph
R
t-Bu
3m: R2 = 7-OMe 88%, 95% ee, 8:1 dr
N
H
A4
90%, 98% ee, >20:1 dr
(10 mmol scale)
: R2 = 7-Br 71%, 95% ee, 4:1 dr
3n
3o
: R2 = 6-Me 83%, 92% ee, 3.5:1 dr
Scheme 1. Substrate scope.
a Reaction conditions: Reactions were performed with 2-hydroxylchalcone 1a (0.1
mmol), hydrocinnamaldehyde 2a (0.1 mmol), amine catalyst (10 mol %) and
Brϕnsted acid (10 mol %) in Et2O (1.0 mL) and irradiated by 24W CFL at RT for 24
h. b Isolated yields. c Determined by chiral HPLC on ChiralPak AD-H column. d Run
in the dark.
Upon establishing the optimal reaction conditions, the
substrate scope was then extensively examined (Scheme 1).
Aliphatic aldehydes with different type of side chains (linear
and branch) or functionalities (olefin, azide, and ester) were all
well tolerated with the reaction conditions, delivering
flavonoids 3a to 3g in excellent stereoselectivties (95%-98% ee
and 5-12:1 dr). This reaction also showed good compatibility
with substituents on both aromatic rings of 2-hydroxychalcone.
As displayed in Scheme 1, electron-donating (Me, OMe) or
electron withdrawing groups (Br, Cl) could be presented on
both aromatic rings to afford corresponding flavonoids in
excellent enantioselectivities and high diastereoselectivities
(3h to 3o). The reaction could be executed on gram scale,
which gave comparable results (3a and 3j). To our delight,
flavonoid 3p for the synthesis of Fissistigmatins could be
prepared in gram scale from a TBS-protected aliphatic
aldehyde in 90% yield with 98% ee and >20:1 dr.
Initially, the reaction of 2-hydroxylchalcone 1a with
hydrocinnamaldehyde 2a was optimized by varying the
combination of chiral amine and Brϕnsted acid under the
irradiation of 24W CFL (Table 1). To our delight, under the
action of prolinol A1 with TFA as additive the desired coupled
product 3a could be isolated in 59% yield and 79% ee with 1:1
dr (Table 1, entry 1). It is noteworthy that using chiral
phosphoric acid C1 as co-catalyst, the enantioselectivity was
greatly improved to 94% ee albeit with 2:1 dr (Table 1, entry 2).
In sharp contrast, when the reaction was performed in the
dark (Table 1, entry 3) or in the absence of C1 or A1 (Table 1,
entries 4 and 5), no product was isolated. Those results
indicated the reaction proceed via the generation of a
transient flavylium,8 not by the direct Michael
addition/dehydrated cyclization process.4 Subsequent
screening of different solvents revealed that Et2O was the
solvent of choice (see Supporting Information). To improve the
diastereoselectivity, different chiral phosphoric acids and
prolinol derivatives were thus evaluated (Table 1, entries 6-10).
Unfortunately, none of them was beneficial for the
stereoselectivity, excepting that C2 afforded a slightly higher
diastereoselectivity (3:1, Table 1, entry 6). To our delight,
To explore the synthetic potential and determine the
stereochemistry of the coupled product, derivatizations of
flavonoid 3a were thus conducted. As depicted in Scheme 2,
Wittig
reaction
of
flavonoid
3a
with
(carbethoxymethylene)triphenylphosphorane
4
afforded
unsaturated ester 5 in 95% yield with 98% ee. Reduction of the
aldehyde 3a with NaBH4 followed by treatment with TsOH to
promote ketalization produced benzo[d][1,3]dioxocine 6 in 88%
2 | J. Name., 2012, 00, 1-3
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yield for two steps. Fortunately, a crystal of 6 was obtained phosphate with the flavylium moiety made the Si-face of
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and the X-ray crystallographic analysis firmly established the flavylium available for the nucleophilicDaOtIt:a1c0k.1.03O9n/D0thCeC0o44th24eEr
absolute configuration.10 Based on this result, the coupled hand, chiral E-enamine 10 favored the Si-face incoming of the
product 3p could be utilized for the asymmetric synthesis of electrophile. Consequently, the synergistic operation of those
Fissistigmatin A. However, the C2 stereochemistry of 3p was two chiral organocatalysts secured the formation of (R,R)-
opposite to the C1’’ configuration of Fissistigmatin B.3 isomer in excellent enantioselectivities.
Therefore, epimerization of 3p was carried out. After some
O
trials (see Supporting Information for details), we found that
O
treatment of 3p with DBU in toluene at 80 oC smoothly
provided a separable 2-epi-3p in 50% yield with 95% ee and 49%
of 3p was also recovered in 98% ee.
Ph
OEt
PPh3
H
H
EtO
4
CH3CN, 60 o
95%
C
O
Ph
O
H
H
Based on our previous work and observations in this study
(Table 1), we proposed a putative reaction mechanism (Figure
2). The reaction consisted of three reaction processes: light-
driven cycloisomerization, chiral phosphoric acid catalyzed
dehydration and chiral imidazolidinone promoted nucleophilic
addition. In the photochemistry process, under the irradiation
of visible-light, E to Z isomerization of 2-hydroxychalcone 1
gave rise to Z-enone 7, which spontaneously cyclized to give
hemiketal 8.8,9 A transient chiral flavylium salt 9 was then
generated via the dehydration hemiketal 8 in the phosphoric
acid catalyzed process.6g-h,8 Meanwhile, aldehyde 2 condensed
with chiral amine A4 to afford the enamine intermediate
10.6c,11 The attack of the latter to the chiral flavylium cation 9
delivered iminium 11, which produced the coupled product 3
upon hydrolysis to regenerate A4 and R-TRIP. As depicted the
transition state TS, the ion-pairing and π-π stacking of the
5
98% ee
O
H
3a
Bn
H
98% ee
O
2. NaBH4
3. TsOH
O
88% (2 steps)
6
6
ORTEP of
2
98% ee
TBSO
MeO
TBSO
MeO
2
O
O
H
H
H
H
DBU, toluene
50% (49% sm)
MeO
O
MeO
O
OMe
3p
OMe
2-epi-3p
95% ee, >20:1 dr
98% ee, >20:1 dr
Scheme 2. Derivatization of the Coupled Products.
O
O
Me
N
H2O
Ar
H
3
Bn
Bn
R1
t-Bu
N
Ar
2
H
R2
OH
Bn
N
R2
R
A4
O
H2O
Me
H2O
Bn
O
R1
cyclization
O
8
Ar
O
O
Ar
O
OH
7
O
P
O
O
O
O
N
N
light
P
R1
O
O
CPA
em
R-TRIP
Me
E to Z
isomerization
O
t-Bu
t-Bu
N
N
H
O
R
24W CFL
O
N
R1
H
Me
R-TRIP
t-Bu
10
Ar
Ar
9
Ar
R2
R2
TS
3
OH
1
R = 2,4,6-(iPr3)C6H2
O
Ar
11
Figure 2. Proposed reaction mechanism.
We are grateful for financial supporting from the National
Natural Science Foundation of China (grants. 21722206,
21672171). J.H. thanks the Natural Science Basic Research
Program of Shaanxi (Program No.2020JQ-993). Financial
support from Shaanxi Government and the Scientific Research
Foundation of Northwest A&F University (grant no.
Z109021709, Z111021501 and Z109021600). is also
acknowledged.
In conclusion, by taking advantage of chiral phosphoric acid
and chiral imidazolidinone as co-operative organocatalysts,
direct coupling of 2-hydroxychalcone with aliphatic aldehydes
was realized under the irradiation of visible-light. Excellent
enantioselectivities were obtained by merging two different
organocatalyzed processes, confirming the synergistic action
of those two organocatalysts. The application of this protocol
in the asymmetric synthesis of Fissistigmatins is currently
pursued in our laboratory and the results will be reported in
due course.
Notes and references
1
(a) S. S. Azimova and V. I. Vinogradova, Natural Compounds:
Flavonoids; Springer: New York, 2013. (b) H. Swanson,
Flavonoids, inflammation and cancer; World Scientific
Publishing: Singapore, 2016.
Conflicts of interest
There are no conflicts to declare
2
3
K. Suzuki, Chem. Rec., 2010, 10, 291-307.
A. Porzel, T. P. Lien, J. Schmidt, S. Drosihn, C. Wagner, K.
Acknowledgement
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DOI: 10.1039/D0CC04424E
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DOI: 10.1039/D0CC04424E
R1
H
O
O
O
H
A4
R-TRIP
10 mol%
10% mol
H
Ar
+
R2
R2
R1
24W CFL
Et2O, RT
OH
O
Ar
1
2
upto 98% ee, >20:1 dr
3
light-driven synthesis;
cooperative organocatalysts;
wide substrate scope;
excellent enantioselectivities;