Enantioselective synthesis of chromanones via a tryptophan-derived bifunctional thiourea-catalyzed oxa-Michael-Michael cascade reaction

Article abstract of DOI:10.1002/adsc.201100419

Tryptophan-derived tertiary amine-thiourea catalysts were shown to promote a cascade oxa-Michael-Michael reaction between ethylene β-keto esters and nitroolefins, resulting in the formation of 3,3-disubstituted 4-chromanones bearing a quaternary center in high diastereoselectivity and enantioselectivity. The chromanone products can be readily converted to biologically important fused and spiro tricyclic chromans. Copyright

Full text of DOI:10.1002/adsc.201100419

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DOI: 10.1002/adsc.201100419
Enantioselective Synthesis of Chromanones via a Tryptophan-
Derived Bifunctional Thiourea-Catalyzed Oxa-Michael–Michael
Cascade Reaction
Haifei Wang,a Jie Luo,a Xiao Han,a and Yixin Lua,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
Fax : (+65)-6779-1691; phone: (+65)-6516-1569; e-mail: chmlyx@nus.edu.sg
Received: May 23, 2011; Revised: August 10, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100419.
Abstract: Tryptophan-derived tertiary amine-thiour-
ea catalysts were shown to promote a cascade oxa-
Michael–Michael reaction between ethylene b-keto
esters and nitroolefins, resulting in the formation of
3,3-disubstituted 4-chromanones bearing a quater-
nary center in high diastereoselectivity and enantio-
selectivity. The chromanone products can be readily
converted to biologically important fused and spiro
tricyclic chromans.
spite the aforementioned elegant synthetic strategies,
to the best of our knowledge, an organocatalytic cas-
cade reaction leading to chiral chromanones bearing a
quaternary stereogenic center has yet to be report-
ed.[8] It is thus desirable to devise an efficient synthet-
ic strategy to access this type of novel structural
motifs.
The creation of quaternary stereogenic centers is a
challenging task in organic synthesis.[9] As part of our
continuing efforts towards the enantioselective gener-
ation of quaternary stereocenters,[10] we became inter-
ested in the synthesis of chiral chromanones contain-
ing an all-carbon quaternary center. We envisioned
that an intramolecular oxa-Michael addition of
phenol to an activated alkene, followed by a subse-
quent intermolecular Michael addition to an nitroole-
Keywords: bifunctional catalysts; cascade reactions;
chromanones; chromans; tryptophan
Chiral chromans and chromanones are important fin might provide a facile one-pot synthesis of highly
structural motifs that are abundant in natural prod- functionalized 3,3-disubstituted 4-chromanones bear-
ucts and a wide range of biologically significant mole- ing a quaternary stereogenic center (Scheme 1). A bi-
cules.[1] Due to their favorable biological activities, functional tertiary amine-thiourea catalyst[11] appears
various catalytic synthetic strategies have been de-
vised for their efficient asymmetric synthesis. Hovey-
da and co-workers described an enantioselective syn-
thesis of chromanones via a Cu-catalyzed addition of
dialkylzinc to enones.[2] In their recent study, Scheidt
et al. utilized an intramolecular conjugate addition
strategy for the enantioselective synthesis of flava-
nones and chromanones.[3] Subsequently, Feng and co-
workers reported an enantioselective synthetic strat-
egy, based on chiral N,N’-dioxide Ni(II)-catalyzed in-
tramolecular oxa-Michael addition to a,b-unsaturated
ketones.[4] Organocatalytic cascade reactions[5] have
also been employed for the construction of chromans
and chromanones. Wang and co-workers developed a
cascade oxa-Michael–Michael for the facile construc-
tion of chiral chromans via an aminal intermeidate.[6]
A cascade Michael-aldol sequence has been employed
by Hong and Cꢀrdova for the asymmetric construc-
Scheme 1. Synthesis of chromanones and tricyclic chromans
tion of chromans and chromenes, respectively.[7] De- via an oxa-Michael–Michael cascade reaction.
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Haifei Wang et al.
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thetic targets[12] possessing significant biological activi-
ties.[13] Herein, we describe a highly efficient oxa-Mi-
chael–Michael cascade sequence, leading to an
enantioselective preparation of highly functionalized
chromanones with a quaternary stereogenic center.
To probe the feasibility of the proposed oxa-Mi-
chael–Michael cascade reaction, ethylene b-keto ester
1a[14] was mixed with nitroolefin 2a in the presence of
a
number of bifunctional organic catalysts
(Scheme 2), and the results are summarized in
Table 1. It should be noted that highly reactive ethyl-
ene b-keto esters have not been employed previously
in the tandem reactions. Quinidine-derived bifunc-
tional catalyst QD-1 provided sufficient activation,
and the double Michael addition reaction occurred
smoothly to afford the desired adduct 3a in moderate
yield, with excellent diastereoselectivity and good
enantioselectivity (entry 1). Quinidine-derived sulfon-
AHCTUNGTREGaNNNU mide QD-2 offered less satisfactory results (entry 2).
Tryptophan-based tertiary amine-thioureas were
found to be remarkable catalysts, and the desired
products were obtained in good yields, and with excel-
Scheme 2. Bifunctional organic catalysts investigated.
to be suitable for the substrate activations and stereo- lent diastereoselectivities and enantioselectivities.
chemical control. Moreover, derivatives of chiral Trp-2, the best catalyst in our previous studies,[10b,h]
chromanones are not only structural scaffolds of me- proved to be superior, affording the desired products
dicinal importance, but also useful synthetic inter- with a diastereomeric ratio of 35:1 and 91% ee
mediates; their facile elaboration can create fused tri- (entry 4). A solvent screening revealed that dichloro-
cyclic chromans, which are intensively pursued syn- methane was the solvent of choice for the reaction
Table 1. Construction of chromanone 3a via an oxa-Michael–Michael cascade reaction.[a]
Entry
Cat.
Solvent
t [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
QD-1
QD-2
Trp-1
Trp-2
Trp-3
Trp-4
Trp-2
Trp-2
Trp-2
Trp-2
Trp-2
Trp-2
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
THF
18
18
18
18
18
18
18
20
14
24
32
18
58
27
73
73
67
63
71
65
57
45
16
81
34:1
23:1
32:1
35:1
30:1
32:1
39:1
30:1
52:1
39:1
54:1
32:1
À83
À52
86
91
79
83
95
90
90
9
10
11
12[e]
Et2O
dioxane
CH2Cl2
89
90
95
[a]
The reactions were performed with 1a (0.2 mmol, 1.2M solution in toluene), 2a (0.1 mmol) and the catalyst (0.01 mmol)
in the solvent (0.4 mL) at room temperature.
[b]
[c]
[d]
[e]
Yield of the isolated product.
1
Determined by H NMR analysis of the crude product.
Determined by HPLC analysis on a chiral stationary phase.
The reaction was performed with 1a (0.1 mmol), 2a (0.4 mmol) and Trp-2 (0.01 mmol) in CH2Cl2 (0.4 mL) at room tem-
perature.
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Enantioselective Synthesis of Chromanones
Table 2. Scope of the cascade oxa-Michael–Michael reaction.[a]
Entry
R1/R2/R3 (1)
R4 (3)
t [h]
Yield [%][b]
2: ee [%][c]
1
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
OMe/H/H (1a)
H/Me/H (1b)
H/Me/H (1b)
H/H/H (1c)
p-CH3-C6H4 (3b)
p-F-C6H4 (3c)
p-Cl-C6H4 (3d)
p-Br-C6H4 (3e)
m-Br-C6H4 (3f)
2-furyl (3g)
2-naphthyl (3h)
n-butyl (3i)
Ph (3j)
p-Cl-C6H4 (3k)
Ph (3l)
16
24
24
20
20
18
20
24
20
24
18
80
67
74
70
65
63
73
41
83
78
46
94
97
99
91
97
87
92
89
95
96
94
2[d]
3[d]
4
5[d]
6
7
8
9
10
11
[a]
The reactions were performed with 1 (0.1 mmol, 1.2M solution in toluene), 2 (0.4 mmol) and Trp-2 (0.01 mmol) in
CH2Cl2 (0.4 mL) at room temperature.
Yield of the isolated product.
Determined by HPLC analysis on a chiral stationary phase.
The reaction was carried out at 08C.
[b]
[c]
[d]
(entries 7–12). Under the optimized reaction condi- synthetic intermediates. Their conversions into useful
tions, the desired double-Michael cascade product molecules are illustrated. As shown in Scheme 3, re-
could be obtained in 81% yield and with 32:1 dr and duction of the nitro group using zinc/acetic acid, fol-
95% ee (entry 12).
lowed by reductive amination afforded tricyclic chro-
The scope of this novel oxa-Michael–Michael cas- man 4 in high yield, a member of class of compounds
cade reaction was next examined (Table 2). Different known to be muscular nicotinic receptor non-compet-
nitroolefins were found to be suitable substrates, in itive antagonists.[13] Alternatively, chromanone 3a can
all the examples examined, single diastereomeric be readily derivatized into a chiral spiro chroman
products were obtained in moderate to high yields (Scheme 4). Treatment of 3a with sodium borohydride
and with excellent enantioselectivities (entries 1–5). afforded alcohol 5 as a single diastereomer. The tert-
Notably, the reaction was applicable to nitroalkenes butyl ester was then converted to a methyl ester 6,
containing hetereocyclic rings or an alkyl group (en- and the subsequent reduction of the nitro group re-
tries 6–8). Different alkylidene b-keto esters could be sulted in a spontaneous lactam formation, giving spi-
employed; while electron-rich aryl substitutents pro- rochroman 7 in excellent yield, which represents an
moted the reaction more efficiently, the electronically important substructure in many medicinally important
neutral phenol-substituted alkylidenes[15] afforded the agents.[16]
desired cascade product with excellent enantioselec-
tivity, although in moderate yield (entries 9–11).
In conclusion, we have developed a novel cascade
oxa-Michael–Michael reaction for the construction of
The 3,3-disubstituted 4-chromanone products re- optically enriched and densely functionalized 3,3-di-
sulting from the oxa-Michael–Michael cascade reac- substituted 4-chromanones bearing a quaternary ste-
AHCTUNGTRENNUNG
tions are rich in functionality, and can serve as useful reogenic center. The synthetic processes described
Scheme 3. Asymmetric preparation of fused tricyclic chroman 4.
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2973

Haifei Wang et al.
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Scheme 4. Synthesis of chiral spiro tricyclic chroman 7
p 395; d) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roeck-
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could be effectively promoted by tryptophan-derived
bifunctional thiourea catalysts, and our method pro-
vides an asymmetric entry to biologically important
fused and spiro tricyclic chromans.
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Experimental Section
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To a stirred solution of 2a (59.6 mg, 0.4 mmol) in CH2Cl2
(0.4 mL) at room temperature was added Trp-2 (5.16 mg,
0.01 mmol) under argon. After stirring for 5 min, 1a (83 mL,
1.2M in toluene) was introduced. The resulting mixture was
stirred at room temperature for 18 h, and extracted with
EtOAc several times (3ꢂ10 mL). The combined organic ex-
tracts were dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography (EtOAc/hexanes=1:5) to
afford 3a as a colorless oil; yield: 34.6 mg (81%). See Sup-
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1
porting Information for H and 13C NMR spectra; HR-MS
(ESI): m/z=450.1529, calcd. for C23H2823Na1N1O7, [M+
Na]+: 450.1523. The ee value of the major isomer was 95%,
tR =27.2 min and 47.9 min (Chiralcel IB, l=254 nm, 10% i-
PrOH/hexanes, flow rate=0.3 mLminÀ1); [a]Dr:t:: +45.6 (c
1.12, CHCl3)
Acknowledgements
We thank the National University of Singapore and the Min-
istry of Education (MOE) of Singapore (R-143-000-362-112)
for the generous financial support.
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