Organocatalytic enantioselective dipolar [3+2] cycloadditions of acetylenic aldehydes with nitrones for the formation of chiral 4-isoxazolines

Article abstract of DOI:10.1002/adsc.201100351

The first organocatalytic enantioselective protocol has been developed for the dipolar [3+2] cycloaddition between acetylenic aldehydes and nitrones through an iminium activation pathway. This protocol uses L-α,α- bis(3,5-ditrifluoromethylphenyl)prolinol

Full text of DOI:10.1002/adsc.201100351

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DOI: 10.1002/adsc.201100351
Organocatalytic Enantioselective Dipolar [3+2]Cycloadditions of
Acetylenic Aldehydes with Nitrones for the Formation of Chiral
4-Isoxazolines
Xianrong Cai,a,b Chao Wang,a and Jian Suna,*
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041,
Peopleꢀs Republic of China
Fax : (+86)-28-8522-2753; e-mail: sunjian@cib.ac.cn
Graduate School of Chinese Academy of Sciences, Beijing 100080, Peopleꢀs Republic of China
b
Received: May 4, 2011; Revised: October 8, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100351.
Abstract: The first organocatalytic enantioselective
protocol has been developed for the dipolar [3+
2]cycloaddition between acetylenic aldehydes and
nitrones through an iminium activation pathway.
This protocol uses l-a,a-bis(3,5-ditrifluoromethyl-
phenyl)prolinol as catalyst and 3,5-dinitrobenzoic
acid as additive and is friendly for one-pot opera-
tion for the nitrone formation and the subsequent
cycloaddition. It also exhibits a broad substrate
scope and allows for the highly efficient production
of chiral 4-isoxazolines with various substituents
under mild conditions in high yields (68–92%) with
high enantioselectivities (up to 96% ee).
as the Lewis acid catalyst, which resulted in the effi-
cient production of a set of chiral 4-isoxazolines (2,3-
dihydroisoxazoles) with different substitutents.[4] The
indispensible presence of a pyrazoyl functionality in
the acetylenic substrates for high enantioselectivity,
however, is a serious limitation to the application of
this method. Herein, we present a new method ena-
bling the highly enantioselective dipolar [3+2]cyclo-
additions of various acetylenic aldehydes with nitro-
nes using a chiral secondary amine as catalyst.
The activation of a,b-unsaturated carbonyl com-
pounds by chiral secondary amines through an imini-
um intermediate has proven to be a viable strategy
for asymmetric catalysis and has seen wide applica-
tions in methodological development in recent
years.[5] This strategy, however, is mostly limited to
the activation of olefinic aldehydes and ketones. Very
recently, MacMillan demonstrated that this strategy is
also applicable to the activation of acetylenic alde-
hydes and developed an efficient novel approach to
furnish the total synthesis of a structurally complex
Keywords: acetylenic aldehydes; dipolar [3+2]cy-
cloadditions; enantioselectivity; iminium activation;
nitrones
The catalyitc asymmetric Diels–Alder reaction repre- natural product via a highly enantioselective intramo-
sents the most important and efficient transformation lecular [4+2]cycloaddition with an acetylenic alde-
for the synthesis of chiral cyclic molecules. The devel- hyde as the dienophile.[6] Wang and Alemꢁn also used
opment of highly effective methods to implement this this strategy to activate acetylenic aldehydes for oxo-
transformation has attracted extraordinary attention Michael addition and successfully developed two cas-
in past decades.[1] So far numerous reports have ap- cade protocols that led to the highly enantioselective
peared in the literature presenting different types of production of polyfunctionalized chiral 4H-chro-
successful enantioselective Diels–Alder reactions with menes.[7]
double-bond type dienophiles such as olefins, alde-
On the basis of the acetylenic aldehyde activation
hydes, and imines.[1,2] However, there have been only strategy using a chiral secondary amine as catalyst, we
a few successful examples of catalytic enantioselective envisioned that a highly enantioselective dipolar [3+
Diels–Alder reactions with triple-bond type dieno- 2]cycloaddition of nitrones with acetylenic aldehydes
philes such as alkynes.[3]
could be implemented (Scheme 1).[8] If successful, it
Recently, Ishihara reported the first highly enantio- could provide a practical and novel approach for the
selective dipolar [3+2]cycloaddition of acetylenic de- synthesis of chiral 4-isoxazolines.
rivatives with nitrones using a chiral copper complex
Adv. Synth. Catal. 2012, 354, 359 – 363
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359

Xianrong Cai et al.
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Scheme 1. Iminium-activation of acetylenic aldehyde and asymmetric dipolar [3+2]cycloaddition with nitrone.
Thus, we set out to check the 1,3-dipolar cycloaddi- estingly, while the imidazolidine catalyst 6 gave poor
tion of phenylacetylenyl aldehyde 1a with nitrone 2a results (Table 1, entry 3,), the a,a-diarylprolinol cata-
using different types of known catalysts (4–10). As lysts 7 and 8 both exhibited a good level of enantiose-
shown in Table 1, l-proline 4 catalyzed the reaction to lectivity (81% and 83% ee, respectively, Table 1, en-
give the desired 4-isoxazoline product 3a in good tries 4 and 5), whereas their TMS ethers 9 and 10
yield but with poor enantioselectivity (Table 1, completely lost the reactivity (Table 1, entries 6 and
entry 1). When 4,5-benzo-l-proline 5 was used as cat- 7). Thus, catalyst 8 with the best overall performance
alyst, both the reactivity and the enantioselectivity was selected for further studies.
were significantly enhanced (Table 1, entry 2). Inter-
Table 1. Catalyst screen for the dipolar [3+2]cycloadditions of 1a and 2a.[a]
Entry
Catalyst
Solvent
Additive
Temperature [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
8
8
8
8
8
8
8
8
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
CHCl3
CHCl3
CHCl3
toluene
DCM
–
–
–
–
–
–
–
–
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À20
0
70
90
17
46
60
<5
<5
76
51
86
92
80
89
68
84
89
5
À63
53
81
83
–
–
88
78
92
95
93
95
82
94
85
9
TFA
benzoic acid
10
11
12
13
14
15
16
3,5-dinitrobenzoic acid
3,5-dinitrobenzoic acid
3,5-dinitrobenzoic acid
3,5-dinitrobenzoic acid
3,5-dinitrobenzoic acid
3,5-dinitrobenzoic acid
THF
CHCl3
CHCl3
[a]
Reactions were carried out with 1a (0.20 mmol), 2a (0.24 mmol), additive (0.04 mmol) and the catalyst (0.04 mmol) in the
indicated solvent (1 mL). The reaction mixture was stirred for 24 h at the temperature indicated.
Yield of the isolated product.
[b]
[c]
Determined by chiral HPLC.
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Adv. Synth. Catal. 2012, 354, 359 – 363

Organocatalytic Enantioselective Dipolar [3+2]Cycloadditions of Acetylenic Aldehydes with Nitrones
Scheme 2. Determination of the absolute stereochemistry of 3a through derivatization.
Different reaction conditions were tested to opti- lowering or raising the reaction temperature had
mize the catalytic efficacy of 8. When toluene was harmful impacts on the catalytic outcome (Table 1,
changed to CHCl3 as solvent, slightly improved yield entries 15 and 16).
and ee values were obtained (Table 1, entry 8). Benzo-
To simplify the operation, we also tried to run the
ic acid as additive was found to have beneficial effects dipolar [3+2]cycloaddition of 1a in a one-pot fashion
on both the enantioselectivity and the reactivity, af- with in situ prepared nitrone 2a. N-Benzylhydroxyl-
fording 86% yield and 92% ee (Table 1, entry 10). Its
ACHTUNGTRENaNUNG mine was mixed with benzaldehyde in chloroform at
analogue 3,5-dinitrobenzoic acid with stronger room temperature and stirred for 1 h. The resulting
Brønsted acidity further enhanced the ee value to solution was then cooled to À108C and catalyst 8, 3,5-
95% and the yield to 92% (Table 1, entry 11). Either dinitrobenzoic acid, and aldehyde 1a were added se-
Table 2. Scope of the organocatalytic three-component reaction.[a]
Entry
R1
R2
R3
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
92
90
92
82
75
80
68
70
80
81
90
90
80
76
83
81
89
85
70
95
90
94
91
95
96
87
82
87
88
90
94
88
82
96
95
95
95
77
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-naphthyl
2-furyl
1-propenyl
3-Cl-C6H4
4-CF3-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
Ph
Ph
10
11
12
13
14
15
16
17
18
19
4-Me-C6H4
4-MeO-C6H4
4-CF3-C6H4
n-C4H9
Ph
Ph
Ph
Ph
Ph
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-CF3-C6H4
n-C4H9
3s
[a]
Reactions conditions: 1 (0.20 mmol), 11 (0.40 mmol), 12 (0.32 mmol) and the catalyst 8 (0.04 mmol) in CHCl3 (1 mL) at
À108C for 24 h.
[b]
[c]
Yield of the isolated product.
Determined by using chiral HPLC.
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361

Xianrong Cai et al.
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quentially. To our delight, this reaction gave similar
In summary, we have developed a highly effective
results as the one using performed nitrone 2a catalytic enantioselective protocol for the dipolar [3+
(Table 2, entry 1). 2]cycloaddition between acetylenic aldehydes and ni-
Having established the optimal conditions, we ex- trones that are in situ formed from N-alkylhydroxyl-
plored the substrate scope of the 8-catalyzed one-pot amines and aldehydes in one-pot. Under the catalysis
AHCTUNGTRENNUNG
dipolar [3+2]cycloaddition. As shown in Table 2, this of l-a,a-bis(3,5-ditrifluoromethylphenyl)prolinol with
reaction exhibited a broad substrate tolerance. Differ- the assistance of 3,5-dinitrobenzoic acid, a variety of
ent aldehydes 11 with various substituents reacted substrates underwent the cycloaddition under mild
with N-alkylhydroxyamines 12 and subsequently with conditions to afford chiral 4-isoxazolines with various
ynals 1 to furnish the desired chiral 4-isoxazolines 3 in substituents in high yields (up to 92%) with excellent
good to high yields. Generally, a high level of enantio- enanoselectivities (up to 96% ee).
selectivity (87–96% ee) was obtained with 1, 11, and
12 – all having the variable substituents (R1, R2 and
R3, respectively) as aryl groups. Relatively electronic- Experimental Section
rich aryl R2 (Table 2, entries 1–6) and R1 (Table 2, en-
All starting materials were of the highest commercially
available grade and used without further purification. All
solvents used in the reactions were distilled from appropri-
ate drying agents prior to use.
tries 11 and 12) groups led to higher enantioselecitivi-
ties than their electronic-deficient counterparts,
whereas the electronic property of aryl R3 had little
effect on the enantioelectivity (Table 2, entries 15–
18). Non-aryl R1 (Table 2, entry 14), R2 (Table 2,
entry 8) and R3 (Table 2, entry 19) groups could also
be tolerated. The corresponding products were ob-
tained in good yields, albeit only with moderate enan-
tioselectivities.
To determine the absolute stereochemistry of prod-
ucts 3, 3a was derivatized with (S)-1-phenylethyl-
ACHTUNGTRENNUNGamine through reductive amination (Scheme 2). An
X-ray crystallographic analysis of the resulting prod-
uct 13 revealed that the chiral carbon in the 4-isoxa-
zoline ring has the S configuration.[9,10] This stereo-
chemical outcome could be easily rationalized by ste-
reoselective addition of the activated chiral iminium
dipolarophile to the Re-face of the nitrone via the
plausible transition state depicted in Scheme 3.
General Procedure for the 8-Catalyzed Asymmetric
Dipolar [3+2]Cycloaddition of Acetylenic Aldehyde
1 with Nitrone 2 in situ Formed from Hydroxylamine
12 and Aldehyde 11
To a stirred solution of aldehyde 11 (0.40 mmol) in CHCl3
(1 mL) was added N-alkylhydroxylamine 12 (0.32 mmol,
1.6 equiv.). After stirring at room temperature for 1 h, the
reaction mixture was cooled to À108C, and then catalyst 8
(0.05 mmol), 3,5-dinitrobenzoic acid (0.05 mmol), and alk-
AHCTUNGTREGyNNNU nals 1 (0.2 mmol) were added sequentially. The reaction
was stirred at À108C for 24 h. The reaction mixture was
then concentrated under vacuum. The residue was subjected
to purification by column chromatography (silica gel,
hexane/EtOAc), affording pure 4-isoxazolines 3. The ee
values were determined by HPLC with chiral stationary
phases.
Scheme 3. Proposed mechanism and catalytic cycle.
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Adv. Synth. Catal. 2012, 354, 359 – 363

Organocatalytic Enantioselective Dipolar [3+2]Cycloadditions of Acetylenic Aldehydes with Nitrones
(S)-2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazole-4-carbal-
dehyde (3a): yield: 92%; 95% ee; 1H NMR (600 MHz,
CDCl3): d=9.72 (s, 1H), 7.58 (d, J=7.02 Hz, 2H), 7.49 (t,
J=7.50 Hz, 1H), 7.41 (t, J=7.71 Hz, 2H), 7.36 (d, J=
7.02 Hz, 2H), 7.31–7.21 (m, 7H), 7.18 (t, J=7.26 Hz, 1H),
5.36 (s, 1H), 4.38 and 4.10 [d (AB-system), J=13.02 Hz,
2H]; 13C NMR (150 MHz, CDCl3): d=185.6, 168.6, 140.5,
135.1, 132.3, 129.4, 129.0, 128.6, 128.5, 128.1, 127.8, 127.1,
126.3, 116.6, 71.2, 63.4; [a]2D5: +254.4 (c 0.9, EtOH); HR-MS
(ESI): m/z=342.1493, calcd. for C23H20NO2 [M+H]+:
342.1494.
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Acknowledgements
We are grateful for financial support from the National Natu-
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20972152 and 91013006).
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