COMMUNICATION
DOI: 10.1002/chem.201103800
Synthesis of Optically Active Oxa
ACHTUNGTRNEzNUNG oline Derivatives via Catalytic
Asymmetric Desymmetrization of 1,3-Diols
Yutaro Tsuda, Masami Kuriyama, and Osamu Onomura*[a]
Optically active oxazoline derivatives are known as signif-
yield of 3a remained at 58%
(Table 1, entry 1). The screen-
ing of different solvents re-
vealed that tert-butyl alcohol
was superior and led to excel-
lent yield and high enantiose-
lectivity (Table 1, entries 2–7).
The examination of bases
icant heterocycles.[1] They have been found in a variety of
biologically active agents,[2] agrochemicals,[3] and natural
products,[4] and they are readily transformed into diverse
scaffolds.[5] In addition, chiral oxazoline derivatives have
been firmly established as one of the most popular and suc-
cessful ligands for asymmetric synthesis.[6] Therefore, various
methods have been developed for the synthesis of chiral ox-
azolines. In general, stoichiometric quantities of
Figure 1. Structure of (R,R)-
2,2’-isopropylidenebis(4-
phenyl-2-oxazoline).
chiral amino alcohols or amino acids are employed
Table 1. Optimization of reaction conditions.[a]
in the preparation of optically active oxazoline de-
rivatives.[7] However, more efficient and flexible
synthetic methods of chiral oxazoline derivatives
have been desired due to the limitation of diversity
in natural chiral sources and many efforts for the
development of catalytic enantioselective prepara-
tion for oxazolines have been made.[8] Recently, a
catalytic method for the asymmetric synthesis of ox-
azolines bearing quaternary stereocenters has been
investigated.[9,10,11] To the best of our knowledge,
the catalytic synthesis of chiral oxazoline deriva-
tives via asymmetric desymmetrization has not
been reported. On the other hand, we have previ-
ously developed the catalytic asymmetric desym-
metrization of diols[12] and expected that our
method would work effectively for the tandem type
synthetic methods. Herein, we describe the synthe-
sis of optically active oxazolines with a quaternary
stereocenter through a catalytic asymmetric desym-
metrization of 1,3-diols.
Entry
Solvent
Base
Product 3a
Byproduct 4a
yield [%][b]
ee [%][c]
yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
MeCN
THF
1,4-dioxane
CH2Cl2
EtOH
iPrOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
Et3N
58
40
91
24
46
61
90
51
57
68
65
85
58
73
19
24
77
83
65
59
72
76
12
3
3
5
11
2
4
2
5
35
54
51
32
19
21
52
–
9
10
11
trace
3
4
33
28
iPr2NEt
[a] Reaction conditions: 1a (0.5 mmol), Cu (10 mol%), ligand (10 mol%), p-TsCl
(1.2 equiv), base (3.0 equiv), RT, 12 h. [b] Yield of isolated product. [c] Determined by
HPLC.
First, we began with the optimization of the reac-
tion conditions in the catalytic synthesis of oxazo-
lines through the asymmetric tosylation of 2-(N-benzoyl-
amino)-2-methyl-1,3-propanediol (1a) with p-toluenesulfon-
showed that potassium carbonate was a reagent of choice
(Table 1, entries 7–11).
ACHTUNGTRENNUNG
yl chloride in the presence of copper(II) triflate and (R,R)-
Ph-Box[13] (Figure 1) as a chiral catalyst.[14] The results are
summarized in Table 1. The reaction with potassium carbon-
ate in acetonitrile afforded high enantioselectivity but the
Subsequently, our attention was focused on the influence
of sulfonyl chlorides. The results of investigation for arylsul-
fonyl chlorides are shown in Table 2. Benzenesulfonyl chlo-
ride increased the ee value but gave a lower yield compared
to p-toluenesulfonyl chloride (Table 2, entries 1 and 2). An
electron-withdrawing group at the para position significantly
diminished both yield and enantioselectivity (Table 2,
entry 3). The reaction using a sulfonyl chloride bearing an
electron-donating group at the para position led to a slightly
lower yield (Table 2, entries 1 and 4). The o-toluenesulfonyl
chloride gave a good yield with moderate enantioselectivity
(Table 2, entry 5). Then, the equivalent of p-TsCl was exam-
[a] Y. Tsuda, Dr. M. Kuriyama, Prof. Dr. O. Onomura
Graduate School of Biomedical Sciences
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
Fax : (+81)95-819-2476
Supporting information for this article is available on the WWW
Chem. Eur. J. 2012, 18, 2481 – 2483
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2481