Chiral guanidine-catalyzed 1,4-addition reaction of 5H-oxazol-4-ones to alkynones

Article abstract of DOI:10.1246/cl.2012.1675

An asymmetric 1,4-addition reaction of 5H-oxazol-4-ones to alkynones using chiral guanidine catalysts bearing a hydroxy group at the appropriate position was developed, and applied to several substrates. The method provides a synthetically useful enone-su

Full text of DOI:10.1246/cl.2012.1675

doi:10.1246/cl.2012.1675
Published on the web December 8, 2012
1675
Chiral Guanidine-catalyzed 1,4-Addition Reaction of 5H-Oxazol-4-ones to Alkynones
Tomonori Misaki,* Nari Jin, Kei Kawano, and Takashi Sugimura*
Graduate School of Material Science, University of Hyogo,
3-2-1 Koto, Kamigori, Ako-gun, Hyogo 678-1297
(Received September 1, 2012; CL-120908; E-mail: misaki@sci.u-hyogo.ac.jp)
An asymmetric 1,4-addition reaction of 5H-oxazol-4-ones to
alkynones using chiral guanidine catalysts bearing a hydroxy
group at the appropriate position was developed, and applied to
several substrates. The method provides a synthetically useful
enone-substituted ¡-hydroxy acid derivatives with a chiral
quaternary ¡-carbon atom.
Table 1. Screening of the aromatic substituent (Ar) on 5H-
oxazol-4-one 2 for the 1,4-addition using catalysts 1a or 1ba
O
O
O
O
1a or 1b
(5 mol%)
R1
R2
Ph2MeP
rt.
N
R2
N
+
3a: R2 = n-Hept
3b: R2 = c-Hex
3c: R2 = Ph
0 °C, toluene
O
O
Ar
Ar
4
2
Cat. Timeb Product Yield eec
Substrates
Entry
1
/h
4
/% /%
2: Ar
3
Since the report on 1,4-additions of 1,3-diketones to
alkynones by Jørgensen et al.1 in 2004, a few successful
catalytic asymmetric 1,4-additions of carbon nucleophiles to
alkynyl carbonyl compounds have been reported.2 Later on, we
also developed a 1,4-addition of 5H-oxazol-4-ones to propiolic
acid derivatives and, for the first time, achieved high enantio-
meric and geometric control of a newly formed olefin using
chiral guanidines3 as Brønsted base catalysts.4 The method
provides a synthetically useful £-butenolide ester bearing a
chiral quaternary stereogenic center. From the viewpoint of
synthetic chemistry, the development of a highly general 1,4-
addition of 5H-oxazol-4-ones to alkynones,5 which provides
various chiral ¡-hydroxy acid derivatives bearing an enone, is as
important as the 1,4-addition to propiolates. Here, we report an
asymmetric 1,4-addition of 5H-oxazol-4-ones to alkynones,
catalyzed by chiral guanidines 1 (eq 1). The chiral guanidines 1,
originally developed as Brønsted base catalysts by our research
group, have high stereocontrollability in several addition
reactions of 5H-oxazol-4-ones to electrophiles.4,6 Since catalytic
enantioselective carbon-carbon bond formation producing ¡-
oxygen-atom-substituted carboxylates bound to a chiral quater-
nary ¡-carbon atom7 is limited by the difficulty of effective
enolate generation of glycolate derivatives, we developed the
present 1,4-addition as following research of our continuing
work.
1
2
3
4
5
6
7
8
2a: Ph
2a: Ph
2a: Ph
2a: Ph
2a: Ph
3a 1a
3b 1a
3c 1a
3a 1b
3c 1b
47
4
4a
4b
4c
4a
4c
4d
4e
4f
4g
4g
4h
4g
4i
68 91
66 89
76 74
66 90
71 88
60 90
74 64
67 87
72 93
70 86
74 92
68 90
63 85
64 90
24
20
12
48
2.5
4
2b: 4-CH3O-C6H4 3a 1b
2c: 4-Cl-C6H4
2d: 3-Cl-C6H4
3a 1b
3a 1b
3a 1b
3a 1a
3c 1b
3a 1b
9d 2e: 2-Cl-C6H4
10 2e: 2-Cl-C6H4
11d 2e: 2-Cl-C6H4
12e 2e: 2-Cl-C6H4
13 2f: 2,3-Cl2-C6H3 3a 1b
14 2g: 2-CH3-C6H4 3a 1b
aReactions were performed on a 0.3 mmol scale in 1.0 mL of
toluene using 1.5 equiv of alkynone 3 and 5 mol % of catalyst
1a or 1b. bReaction time for the 1,4-addition. After completion
of the 1,4-addition, Ph2MeP (0.3 equiv) was added for the
isomerization. Determined by chiral HPLC analysis. Reac-
tions were also attempted without Ph2MeP-mediated isomer-
ization. The results were as follows: for adduct 4g: E/Z = 61/
39, E: 95% ee, Z: 93% ee, for adduct 4h: E/Z = 57/43, E:
2
22
0.5
48
21
38
4j
c
d
e
92% ee, Z: 92% ee. Reaction was carried out at ¹20 °C.
O
O
O
R1
R1
ee) of the newly formed olefin was observed, isomerization of
the E/Z mixed adduct using Ph2MeP2c only afforded the E-
isomer in 91% ee.4 However, insufficient enantioselectivities
were observed in the 1,4-addition with other alkynones 3b
(R2 = c-Hex) and 3c (R2 = Ph) in the following research
(Entries 2 and 3). Thus, we attempted to improve the generality
of the alkynone in the 1,4-addition by examining the effect
of the aromatic substituent (Ar) on 5H-oxazol-4-one 2 with
catalysts 1a or 1b, which have previously been developed as
Brønsted base catalysts for the asymmetric aldol reaction of 5H-
oxazol-4-ones.6 As shown in Entry 4, the use of bulky catalyst
1b was not effective for the enhancement of the enantioselec-
tivity in the 1,4-addition to alkynone 3a. However, in the 1,4-
addition to alkynone 3c, the enantioselectivity was improved
with catalyst 1b (Entry 5). The use of 5H-oxazol-4-ones 2b-2d,
which contain a substituted aromatic ring, was not effective
(Entries 6-8). However, some improvement in the enantio-
N
R2
N
1
O
Ph2MeP
∗
(5 mol%)
E, Z mixture of
adduct 4
Ar
O
2
one-pot
isomerization
4
Ph
+
O
trans only
O
O
R1
R2
R2
X
ð1Þ
3
∗
OH
chiral α-hydroxy acid derivatives
F3C
CF3
F3C
CF3
R3
R3
CF3
CF3
CF3
N
N
N
N
OH
N
N
OH
H
H
CF3
1a
1b
In the previous research, the 1,4-addition to an alkynone
3a (R2 = n-Hept) instead of propiolates, using catalyst 1a, also
showed high enantioselectivity, as shown in Table 1, Entry 1.
Although low E/Z selectivity (E/Z = 56/44, E: 91% ee, Z: 91%
Chem. Lett. 2012, 41, 1675-1677
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1676
O
O
O
O
Table 2. Catalytic 1,4-addition of 5H-oxazol-4-ones 2 to
various alkynones 3, catalyzed by 1ba
a
N
NH2
O
O
O
O
O
O
R1
R1
Cl
4g Cl
93% ee
N
O
R2
N
1b
O
5
(5 mol%)
Ph2MeP
rt.
R2
+
O
0 °C, toluene
O
Cl
O
O
3
O
Cl
b
2e: R1 = CH3
2h: R1 = n-Bu
OMe
NH2
4
and
OH
OH
2i: R1 = BnO(CH2)4
2j: R1 = i-Pr
7
6
59% yield
92% ee
27% yield
90% ee
Substrates
2
Timeb Product Yield eec
Entry
3: R2
3a: n-Hept
3b: c-Hex
3c: Ph
3b: c-Hex
3b: c-Hex
3a: n-Hept
/h
2
4
/%
75
73
74
64
63
45
74
/%
93
93
92
92
91
79
94
Scheme 1. Derivatization of adduct 4g to 6 and 7. (a) 1.0 M
NaOH(aq), THF, 0 °C, 10 min; (b) cat. CH3ONa, mixture of
CH3OH and THF (1:1), 0 °C, 3 h, then rt, 10 h (6: 59%, 7: 27%
from 4g).
1
2
3
2e
2e
2e
2h
2i
2j
2e
4g
4k
4h
4l
4m
4n
4o
2.5
0.5
40
6
96
0.5
4
5
6d
7
between the optical rotation value of the obtained 7 and our
previously reported value.4
3d: Cl(CH2)3
8
2e
0.5
4p
53
84
3e:
In conclusion, we developed a highly enantioselective 1,4-
addition of 5H-oxazol-4-ones 2 to alkynones 3 using chiral
guanidine 1b. By examining the effect of the aromatic
substituent (Ar) on 2 using catalyst 1a or 1b, we disclosed that
2-chlorophenyl-substituted 5H-oxazol-4-ones as pronucleo-
philes are suitable for 1,4-additions to various alkynones 3 with
catalyst 1b.
MeO
9
2e
2.5
4q
62
91
3f:
MeO
OMe
10
2e
0.5
4r
55
94
3g:
NH
References and Notes
a-cSee corresponding footnote in Table 1. dLow conversion
yield (62%) caused the low isolated yield.
1
M. Bella, K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126,
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2
a) X. Wang, M. Kitamura, K. Maruoka, J. Am. Chem. Soc.
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selectivity was found when 2e bearing a 2-chlorophenyl group
and catalyst 1b were employed (Entry 9). In particular, in the
1,4-additions to alkynone 3c, the enantioselectivity was remark-
ably improved, from 74% ee to 92% ee, by using 2e and 1b
instead of 2a and 1a, as shown in Entries 3 and 11. The
significant effects of the aromatic substituent (Ar) on 2f, 2g were
not observed in further investigations (Entries 13 and 14).
We next investigated the substrate scope of the 1,4-addition
of the 2-chlorophenyl-substituted 5H-oxazol-4-ones to several
types of alkynones, using catalyst 1b (Table 2). As a result,
adducts 48,9 were obtained with high enantioselectivity, except
for the 1,4-addition of 5H-oxazol-4-one 2j. Several function-
alities in 2 or 3 had almost no influence on the high
enantioselectivity (Entries 5 and 7-10). A chlorine-substituted
alkynone 3d, with the possibility of 5-membered ring forma-
tion,10 and indole-substituted alkynone 3g, without a protective
group on the nitrogen atom, were also applicable to the 1,4-
addition (Entries 7 and 10). In the case of bulky 2j, the 1,4-
addition proceeded remarkably slowly and with somewhat low
enantioselectivity (Entry 6).
Adducts 4 can be easily converted into the corresponding
chiral ¡-hydroxy methyl esters and ¡-hydroxy amides without
loss of the enantiopurities.9 As illustrated in Scheme 1, the ring-
opening reaction of 5H-oxazol-4-one through treatment of
adduct 4g with aqueous NaOH in THF readily afforded the
corresponding amide 5, which was converted to methyl ester 6
in 59% yield by CH3ONa-mediated methanolysis, along with
amide 74 in 27% yield as the minor product. The enantiopurities
of 6 and 7 were confirmed by HPLC analysis, and the absolute
configuration of amide 7 was assigned as (R) after comparison
3
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4
5
Chem. Lett. 2012, 41, 1675-1677
© 2012 The Chemical Society of Japan
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phine (18 mg, 0.09 mmol) was added to the reaction mixture,
followed by being stirred at room temperature until the Z-
isomer became undetectable by silica gel TLC analysis (for
3-27 h). The resulting reaction mixture was concentrated to
give a crude mixture, which was purified by SiO2-column
chromatography to give the adduct 4.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
6
7
Examples of catalytic chiral quaternary ¡-carbon atom
constructions, see: a) B. M. Trost, K. Dogra, M. Franzini,
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General procedure: To a stirred solution of 5H-oxazol-4-one
2 (0.30 mmol) and alkynone 3 (0.45 mmol) in toluene
(1.0 mL) was added chiral guanidine 1 (15 ¯mol) at 0 °C.
After stirring at same temperature for indicated time in
Table 1 or 2 under a N2 atmosphere, methyldiphenylphos-
9
10 Examples of 5-membered ring (tetrahydrofuran ring) for-
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8
Chem. Lett. 2012, 41, 1675-1677
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/