Angewandte
Chemie
Table 1: Catalyst screening and reaction conditions optimization for the enantioselective iodoether-
ification of oxime 1a.[a]
when dihydrocinchonidine-derived
thiourea V was employed as the
catalyst (Table 1, entry 13). Further
enhancement in enantioselectivity
was achieved when the reaction was
conducted in the presence of a cata-
lytic amount (2 mol%) of molecu-
lar iodine (Table 1, entry 15). The
reaction could be accelerated by
increasing the temperature to
Entry Catalyst Solvent
Conc. [m] I2 [mol%] T [8] t [h] Yield [%][b] e.r.[c]
1
2
3
4
5
6
7
8
none
none
I
II
II
II
II
II
II
III
IV
IV
V
V
V
V
VI
VII
toluene
toluene
toluene
toluene
CH2Cl2
toluene/CH2Cl2 (4:1)
toluene/(CH2Cl)2 (4:1) 0.1
toluene/CHCl3 (4:1)
toluene/CH2Cl2 (4:1)
toluene/CH2Cl2 (4:1)
toluene/CH2Cl2 (4:1)
CH2Cl2
toluene/CHCl3 (4:1)
toluene/CHCl3 (4:1)
toluene/CHCl3 (4:1)
toluene/CHCl3 (4:1)
toluene/CHCl3 (4:1)
toluene/CH2Cl2 (4:1)
0.25
0.25
0.25
0.25
0.25
0.1
–
–
–
–
–
–
–
–
5
–
–
–
–
5
2
2
5
–
25
2
80
–
–
–
À78 48
À78 48
À78 18
n.r.[d]
n.r.[d]
60
82:18
68:32
92:8
92:8
93.5:6.5
93:7
89:11
–
54:46
94:6
94.5:5.5
95:5
92:8
6:94
–
À608C, though with
a
slight
À78
2
92
72
79
95
decrease of enantioselectivity
À78 14
À78 46
À78 22
À78 14
À78 24
À78 48
À78 24
À78 48
À78 38
À78 68
À60 24
À78 58
À78 66
(Table 1, entry 16). The other anti-
pode of the product could be
obtained with similar enantioselec-
tivity by using the pseudoenantio-
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
9
72
10
11
12
13
14
15
16
17
18
85
n.r.[d]
90
meric
catalyst
VI
(Table 1,
entry 17). The thiocarbamate deriv-
ative VII, similar to the catalysts
developed by Yeung et al. for
a number of olefin bromocycliza-
tion reactions,[3e] surprisingly turned
out to be completely ineffective
towards this iodoetherification
reaction (Table 1, entry 18), thereby
highlighting the importance of dual
hydrogen bonding from thiourea.
Overall, almost every structural
component present in compound
V also seems functionally essential
for both catalytic activity and enan-
tioselectivity.
74
82
88
91
83
n.r.[d]
[a] Reactions were carried out using 1.0 equiv of 1a and 1.2 equiv of NIS (2). [b] Yield of isolated product
after column chromatography. [c] Enantiomeric ratio (e.r.) was determined by HPLC analysis using
a chiral stationary phase. [d] n.r.=no reaction.
With the optimal catalyst and
the reaction conditions identified
(Table 1, entry 15), the substrate
conducted with the cinchonidine-derived thiourea II
(10 mol%) in toluene, the desired D2-isoxazoline 3a was
produced in 60% yield with modest enantioselectivity (82:18
e.r.) within 18 h (Table 1, entry 4). A dramatic rate enhance-
ment was observed in the more polar solvent dichloro-
methane, but the product was obtained with significantly
inferior e.r. (Table 1, entry 5). A balance between the reaction
rate and the product enantioselectivity was reached by using
a mixture of toluene and chlorinated solvents (Table 1,
entries 6–8), with toluene/CHCl3 (4:1) emerging as the
optimum (entry 8). A small amount (5 mol%) of iodine
marginally improved the enantioselectivity (Table 1, entry 9).
The methoxy substitution on the quinoline moiety showed
a deleterious effect on the enantioselectivity as evident from
the quinine-derived thiourea III (Table 1, entry 10). Curi-
ously, the corresponding urea derivative IV, under the same
reaction conditions, completely failed to catalyze the reaction
(Table 1, entry 11). Even though IV showed sufficient cata-
lytic activity in CH2Cl2, the product could be obtained only
with very poor e.r. (Table 1, entry 12). These results are in
sharp contrast to the enantioselective iodolactonization
reported by Jacobsen and Veitch using a tertiary aminourea
catalyst[4b] and clearly point towards a different activation
principle. Product enantioselectivity was slightly improved
scope of this oxime iodoetherification reaction was explored.
A broad range of b,g-unsaturated oximes containing aromatic
substituents on olefin and oxime could be converted to the
corresponding D2-isoxazolines 3a–q in high yield with good to
excellent enantioselectivity (Table 2). Both electron-rich and
electron-deficient substituents on the aryl rings were gener-
ally tolerated. However, lower enantiomeric ratios were
obtained in the cases of ortho-tolyl-substituted olefin 3 f and
2-furyl-substituted oxime 3q. In most of these cases a single
recrystallization furnished essentially enantiopure products.
An oxime having an aliphatic substitution on the olefin was
found to be an active substrate for this reaction, and the
product 3r could be obtained with good enantioselectivity
(92:8 e.r.). In contrast, aromatic substitution on the oxime
carbon atom appears to be essential for achieving a good level
of enantioselectivity, since products from aliphatic oximes
(3s,t) were formed with very poor e.r. Therefore it is not
surprising that the product 3u with aliphatic substitution on
both sites was obtained with low e.r.
The absolute configuration of the product 3b was found to
be S by single-crystal X-ray diffraction analysis (Figure 1).[17]
The absolute configuration of the remaining examples can be
expected to be the same, when considering that a similar
catalytic mechanism is followed.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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