Enantioselective synthesis of azaflavanones using organocatalytic 6-endo aza-Michael addition

Article abstract of DOI:10.1002/adsc.201300920

A method to prepare highly enantioenriched azaflavanones using an organocatalytic 6-endo aza-Michael addition has been described. A variety of 2-aryl-, 2-vinyl- and 2-methylazaflavanones were prepared in good yields (53-84%) and excellent enantioselectivities (97.6:2.4 to 99.3:0.7 er).

Full text of DOI:10.1002/adsc.201300920

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DOI: 10.1002/adsc.201300920
Enantioselective Synthesis of Azaflavanones Using
Organocatalytic 6-endo Aza-Michael Addition
Shuanghua Cheng,a Lili Zhao,a and Shouyun Yua,*
a
State Key Laboratory of Analytical Chemistry for Life Science, Institute of Chemical Biology and Drug Innovation,
School of Chemistry and Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing 210093, Peopleꢀs Republic
of China
E-mail: yushouyun@nju.edu.cn
Received: October 16, 2013; Revised: December 24, 2013; Published online: March 12, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300920.
Abstract: A method to prepare highly enantioen-
riched azaflavanones using an organocatalytic 6-
endo aza-Michael addition has been described. A
variety of 2-aryl-, 2-vinyl- and 2-methylazaflavan-
ACHTUNGTRENNUNGones were prepared in good yields (53–84%) and
excellent enantioselectivities (97.6:2.4 to 99.3:0.7
Recently, Rueping and co-workers reported the chiral
Brønsted acid-catalyzed intramolecular aza-Michael
addition of aminochalcone derivatives for the synthe-
sis of 2-arylazaflavanones.[9] However, the enantiose-
lectivity of this reaction was not satisfactory (74.5:25.5
to 81.5:18.5 er) and no 2-alkylazaflavanones were pre-
pared using this method.
er).
The organocatalytic intramolecular aza-Michael ad-
dition has emerged as a powerful tool to prepare
enantioenriched nitrogen hetereocycles.[11] Significant
progress has been achieved in the exo-type aza-Mi-
chael addition.[12] The endo-type aza-Michael addition
turned out to be a challenging task.[8,9] As a part of
our ongoing projects on intramolecular aza-Michael
additions and their application in the total synthesis
Keywords: azaflavanones; dihydroquinolinones;
enantioselectivity; Michael addition; organocataly-
sis
Azaflavanones, which are also known as dihydroqui- of alkaloids,[13] we would like to report a highly enan-
nolinones, have been characterized as one of the tioselective 6-endo aza-Michael addition of amino-
“privileged structures” in drug development.[1] Due to chalcone derivatives using a trifunctional organocata-
their ability to provide ligands for more than one type lyst.
of receptor or enzyme targets, they exhibit important
We chose the tosyl-protected aminochalcone 1a for
biological activities, such as cytotoxic activity against the initial investigation (Table 1). Firstly, we tried
a panel of human tumor cell lines,[2] antimalarial ac- a series of organocatalysts, which have been success-
tivity[3] and potent cross-species microRNA inhibi- fully used in exo-type aza-Michael additions, including
tors.[4] They also serve as key intermediates in total phase-transfer catalysts, aminocatalysts and chiral
synthesis of biologically active natural products, in- Brønsted acids. However, none of these catalysts gave
cluding martinelline and martinellic acid.[5] Addition-
ally, it was reported that the two enantiomers of aza-
flavanones displayed distinctly different activities.[2]
Consequently, the enantioselective synthesis of these
compounds is highly desirable.
There are two major known strategies to access
enantioenriched azaflavanones (Figure 1).[6–10] One is
the asymmetric intermolecular 1,4-conjugated addi-
tion of organometalllic reagents to 4-quinolones.[7]
Only 2-arylazaflavanones could be accessed using this
approach assisted by organometallic catalysts. The
other is the 6-endo-trig cyclization of aminoalkylidene
b-keto esters.[8] The b-ester must be introduced before
cyclization and removed after cyclization, which
makes this approach not step- and atom-economical. Figure 1. Synthetic approaches to azaflavones.
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Enantioselective Synthesis of Azaflavanones
Table 1. Catalyst screening.[a]
sults (entry 5). (1S,2S)-trans-1,2-Diaminocyclohexane
proved to be mismatched with the quinine-derived
amine (entry 6). Further solvent and acid screening
could not give superior results (entries 7–11).
In order to improve the enantioselectivity further,
we next evaluated the nitrogen protecting groups
using 3d (10 mol%) as catalyst and PhCO2H
(20 mol%) as additive. As shown in Table 2, a variety
of sulfonamide-based substrates were tested (en-
tries 1–5). Disappointingly, none of them gave better
results. Carbamates turned out to be less efficient pro-
tecting groups (entries 6 and 7). The methyl group
also proved be a poor protecting group. The protect-
ing group-free substrate could not go through this
transformation at all (entry 9). Finally, we were
pleased to find that the acetyl group was a more
promising protecting group with moderate yield
(42%) and excellent enantioselectivity (97:3 er)
(entry 10). The yield could be improved to 73% with-
out any loss of enantioselectivity when 20 mol% cata-
lyst and 40 mol% acid were used at 908C (entry 11).
A higher er value (99:1) could be obtained with
slightly less yield when less acid (20 mol%) was em-
Entry
3
Acid
Solvent Yield [%][b] er[c]
Table 2. Nitrogen protecting group screening.[a]
1
2
3
4
5
6
7
8
3a TFA
THF
PhCH3
0
0
–
–
3b PhCO2H
3c PhCO2H
3d PhCO2H
3e PhCO2H
3f PhCO2H
3d PhCO2H
3d PhCO2H
3d PhCO2H
3d 4-NO2C6H4CO2H PhCH3 80
3d 4-MeOC6H4CO2H PhCH3 94
3d CH3CO2H
3d (S)-Boc-Pro
PhCH3 23
PhCH3 87
PhCH3 79
PhCH3 23
CH2Cl2 50
CH3CN 33
32:68
89:11
84:16
36:64
83:17
83:17
78:22
89:11
82:18
86:14
85:15
Entry
R
Yield [%][b]
er[c]
9
THF
25
10
11
12
13
1
2
3
4
5
6
7
8
4-MeOC6H4SO2
4-NO2C6H4SO2
PhSO2
Ms
Tf
Cbz
MeOCO
Me
46
92
69
84
28
10
14
11
0
87:17
65:35
85:15
79:21
70:30
89:11
98:2
89:11
–
PhCH3 92
PhCH3 69
[a]
Reaction conditions: a solution of 1a (0.1 mmol), 3
(0.01 mmol) and acid (0.02 mmol) in indicated solvent
(1 mL) was stirred at 608C for 48 h.
[b]
[c]
Isolated yield.
9
H
The ee value was determined by HPLC on a chiral sta-
tionary phase.
10
Ac
Ac
Ac
Ac
42
73
70
84
36
97:3
97:3
99:1
98:2
99:1
11[d,e]
12[d,f]
13[d,g]
14[d,h]
us promising results (not shown). We next turned our
attention to multifunctional organocatalysts. Quinine-
derived primary amine 3a[14] and thiourea 3b[15] could
not promote this transformation either (entries 1 and
2). trans-1,2-Diaminocyclohexane-derived thiourea
3c[16] could catalyze this reaction assisted by PhCO2H
at 608C, but only with 23% yield and 32:68 er
(entry 3). To our delight, the quinine-derived trifunc-
tional catalyst 3d[17] combined with PhCO2H was
a suitable catalyst system to give the desired product
2a with 87% yield and 89:11 er (entry 4). Cinchoni-
dine-derived catalyst 3e could not give improved re-
Ac
[a]
Reaction conditions: a solution of 1 (0.1 mmol), 3d
(0.01 mmol) and PhCO2H (0.02 mmol) in PhCH3 (1 mL)
was stirred at 608C for 48 h.
[b]
[c]
Isolated yield.
The er value was determined by HPLC on chiral station-
ary phase.
20 mol% 3d were used at 908C.
40 mol% PhCO2H were used.
20 mol% PhCO2H were used.
60 mol% PhCO2H were used.
[d]
[e]
[f]
[g]
[h]
100 mol% PhCO2H was used.
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Shuanghua Cheng et al.
Table 3. Scope of the aza-Michael additions.[a]
[a]
Reaction conditions: a solution of 4 (0.1 mmol), 3d (0.02 mmol) and PhCO2H (0.06 mmol) in PhCH3 (1 mL) was stirred at
908C for 2–4 days. The yields given are for isolated products. The er values were determined by HPLC on a chiral station-
ary phase.
ployed (entry 12) while slightly higher er value (98:2) with ketone group of the substrate to generate an imi-
and significantly higher yield (84%) were observed nium ion,[18] which is protonated by acid. The benzoic
when more acid (60 mol%) was used (entry 13). Fur- acid anion is believed to bind to the thiourea motif to
ther increasing the amount of the acid (100 mol%) provide a chiral counterion of the iminium ion.[19] The
led to significant lower yield (36%, entry 14).
tertiary amine in quinine interacts with the amide hy-
With optimal conditions established, the scope of drogen of the substrate through hydrogen bonding,[20]
the reaction was surveyed using an assay of substitut- which directs the conjugate addition from the Si face
ed acetyl-protected aminochalcones as shown in of the double bond. The absolute configuration of the
Table 3. Pleasingly, a variety of 2-arylazaflavanones desired product could be predicted as “R” by this
(5a–l, 5o) could be prepared with satisfactory yields
(67–84%) and excellent enantioselectivities (97.6:2.4
to 99.2:0.8 er) using this 6-endo aza-Michael addition.
The electronic property and position of the substitu-
tions did not affect the outcome of this reaction. Re-
markably, 2-vinylazaflavanone 5m and 2-methylaza-
flavanone 5n could also be accessed with acceptable
yields and excellent enantioselectivities using our
stategy.
In order to account for the high stereoinduction,
a well-defined transition state model is proposed as
shown in Figure 2. All of the three functional groups
of the catalyst play cooperative roles in the transition
state. The primary amine moiety of catalyst interacts Figure 2. Proposed transition state.
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Adv. Synth. Catal. 2014, 356, 982 – 986

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Enantioselective Synthesis of Azaflavanones
[6] For a review on asymmetric synthesis of azaflavanones
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model, which was confirmed by comparison of the
specific optical rotation with the literature value of
the known enantiomer.[10a]
In summary, we have described a highly enantiose-
lective 6-endo aza-Michael addition of aminochalcone
derivatives, which leads to highly enantioenriched
azaflavanones. A variety of 2-aryl-, 2-vinyl and 2-
methylazaflavanones were prepared in good yields
(53–84%) and excellent enantioselectivities (97.6:2.4
to 99.3:0.7 er). Studies on the synthetic applications of
this reaction are underway and will be reported in
due course.
[9] M. Rueping, S. A. Moreth, M. Z. Bolte, Z. Natur-
forsch. B 2012, 67, 1021.
[10] For other catalytic enantioselective syntheses of azafla-
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J. X. Liebich, Chem. Eur. J. 2009, 15, 11058; g) S. Fus-
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1211.
[12] For organocatalytic exo-type aza-Michael additions,
see: a) K. Takasu, S. Maiti, M. Ihara, Heterocycles
2003, 59, 51; b) S. Fustero, D. Jimꢅnez, J. Moscardꢄ, S.
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Carter, J. Org. Chem. 2008, 73, 5155; d) S. Fustero, J.
Moscardꢄ, D. Jimꢅnez, M. D. Pꢅrez-Carriꢄn, M.
Sꢃnchez-Rosellꢄ, C. del Pozo, Chem. Eur. J. 2008, 14,
9868; e) Q. Cai, C. Zheng, S.-L. You, Angew. Chem.
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Experimental Section
Representative Procedure for the Intramolecular
Aza-Michael Addition of Azaflavanones 5
To
a reaction vial, N-protected 2-aminochalcone 4a
(27.0 mg, 0.1 mmol), organocatalyst 3d (9.9 mg, 20 mol%),
PhCO2H (7.3 mg, 60 mol%) and toluene (1 mL) were se-
quentially added at room temperataure. The resultant solu-
tion was stirred at 908C for 2 d. After the reaction was com-
pleted (as indicated by TLC analysis), the crude reaction
mixture was subjected to flash chromatography on silica gel
with mixtures of hexanes and ethyl acetate as eluent to
afford the desired product 5a as a yellowish solid; yield:
22.6 mg (84%).
Acknowledgements
This work was supported by 863 program (2013AA092903),
National Natural Science Foundation of China (21102072
and 21272113) and Research Fund for the Doctoral Program
of Higher Education of China (20110091120008).
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