3
02
Chemistry Letters 2002
Catalytic Asymmetric 1,3-Dipolar Cycloaddition of a Nitrone
Bearing a Bulky Amide Moiety to ꢀ-Substituted Allylic Alcohols
ꢀ
ꢀ
Xia Ding, Yutaka Ukaji, Shuhei Fujinami, and Katsuhiko Inomata
Department of Chemical Science, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received January 7, 2002; CL-020002)
A catalytic asymmetric 1,3-dipolar cycloaddition reaction of
molar amounts of 1a under the high concentration conditions,
precipitate was observed to give 3a in lower chemical yield and
enantioselectivity (Entry 6). When (Z)-2-buten-1-ol was sub-
jected to the reaction under the same conditions as Entry 1, no
a nitrone possessing diisopropyl amide moiety to ꢀ-substituted
allylic alcohols was achieved by using diisopropyl (R; R)-tartrate
as a chiral auxiliary to afford the corresponding 3,4,5-trisub-
stituted isoxazolidines with excellent enantioselectivity up to
over 99% ee.
4
cycloadduct was obtained. However, the reaction appears
general with respect to the (E)-ꢀ-alkyl-substituted allylic
alcohols. (E)-2-Hexen-1-ol (1b) afforded the corresponding
cycloadduct 3b with the enantioselectivity higher than 99% ee
(Entries 9, 10).
1
,3-Dipolar cycloaddition is one of the most important
reactions for the construction of a variety of 5-membered
heterocyclic compounds. In particular, asymmetric 1,3-dipolar
cycloaddition reaction of nitrones to alkenes has received
considerable attention in organic syntheses, since it can create
three contiguous carbon stereocenters in a single step and the
resulting isoxazolidine is a versatile chiral building block for
1
numerous attractive chemicals. In the course of our study on
asymmetric 1,3-dipolar cycloaddition reactions,2 we recently
reported an efficient enantioselective 1,3-dipolar cycloaddition of
nitrones bearing an amide moiety to a terminal olefin, 2-propen-1-
ol, in the presence of a catalytic amount of diisopropyl (R; R)-
tartrate [(R; R)-DIPT] as a chiral auxiliary to afford 3,5-cis-
Table 1. The catalytic asymmetric 1,3-dipolar cycloaddition of
the nitrone 2 to ꢀ-alkyl-substituted allylic alcohols 1
Entry
a
1
R
x
y
z
m
Yield of 3/% ee/%
b
1
a
a
a
a
a
a
a
a
Me 1.0 1.6 1.4 1.0
Me 1.4 1.6 1.4 1.0
Me 1.9 2.1 1.9 1.5
Me 1.9 2.1 1.9 1.5
Me 2.4 2.6 2.4 2.0
Me 2.4 2.6 2.4 2.0
Me 2.9 3.1 2.9 2.5
Me 3.4 3.6 3.4 3.0
24
47
51
64
53
42
57
51
99
>99
>99
>99
>99
97
2
a
disubstituted isoxazolidines with excellent enantioselectivity.
a
b
2
3
4
5
6
7
In this paper, we reveal that this catalytic strategy is also
applicable to the cycloaddition of a nitrone possessing diisopro-
pylamide moiety with a range of ꢀ-substituted allylic alcohols to
afford the corresponding 3,4,5-trisubstituted cycloadducts with
high regio-, diastereo- and enantioselectivities.
a
b
c
b,d
b
a
c
b
a
b
99
99
The catalytic asymmetric 1,3-dipolar cycloaddition of
nitrone 2 possessing diisopropylamide moiety to (E)-2-buten-1-
ol (1a) was first investigated. As shown in Table 1, the
a
b
8
9c
10
b
b
n
Pr 1.4 1.6 1.4 1.0
Pr 1.8 2.0 1.8 1.4
48
45
>99
>99
e,f
e
3
c
n
predominant formation of 3,5-cis-cycloadduct 3a and the high
2
a
aReaction was carried out on a 0.5 mmol scale in 9 ml CHCl3,
and the solid nitrone 2 was added to the reaction mixture over a
period of 2h. Enantioselectivity was determined by HPLC
enantioselectivity are comparable to the case of 2-propen-1-ol,
4
while the chemical yield was rather low (Entry 1). Formation of
regio- and diastereoisomers of 3a was not observed and no nitrone
b
c
2
was recovered due to the gradual decomposition during the
analysis (Daicel Chiralcel OD-H). Reaction was carried out
on 1.5 mmol scales in 12ml CHCl 3, and the solid nitrone 2 was
reaction. When the amount of 1a was increased together with the
proper amounts of diethylzinc, iodine and pyridine N-oxide, the
chemical yield based on the nitrone was improved (Entries
d
25
added to the reaction mixture over a period of 3 h. ½ꢁ -98
D
e
(
c 3.02, EtOH). The product was isolated as the correspond-
ing acetate and its enantioselectivity was determined by HPLC
2,3,5,7,8). In order to achieve the reproducible higher chemical
f
analysis (Daicel Chiralcel OD-H). The specific rotation of the
corresponding acetate; ½ꢁD -90 (c 2.91, EtOH).
yield and enantioselectivity, slow addition of the nitrone was
essential. By employing 2.9 molar amounts of 1a, the chemical
yield was improved to 57% with almost complete enantioselec-
tivity (Entry 7). Furthermore, the concentration of the reaction
was found to influence the reactivity. That is, while the reaction
employing 1.9 molar amounts of 1a on a 0.5 mmol scale in 9 ml of
CHCl3 afforded the corresponding cycloadduct 3a in 51% yield
25
Although the precise reaction mechanism is not yet clear, the
plausible catalytic cycle is shown in Scheme 1 to rationalize the
proper molar amounts of each reagent we found, x : y :
z : m ¼ ðm þ 0:4Þ : ðm þ 0:6Þ : ðm þ 0:4Þ : m. In order to rea-
lize the catalytic cycle, zinc-bridging chiral salt (C) must be
replaced by the zinc salt of 1 (B) being free from pyridine N-oxide
to afford (A).
(
Entry 3), the reaction performed on 1.5 mmol scales in 12ml of
CHCl3 improved the chemical yield up to 64% with complete
enantioselectivity (Entry 4). In the case of the reaction using 2.4
To broadenthe scope of the present method, thereaction of ꢀ-
Copyright Ó 2002 The Chemical Society of Japan