1,4-addition reaction of 5H-oxazol-4-ones to allenic esters and ketones catalyzed by chiral guanidines

Article abstract of DOI:10.1246/cl.130295

In this paper, a chiral guanidine-catalyzed 1,4-addition reaction of 5H-oxazol-4-ones to allenic esters and ketones is described. 5H-Oxazol-4-ones substituted with a 2-chlorophenyl group were suitable pronucleophiles that gave high enantioselectivities. Subsequent hydrolysis of the obtained adduct gave the corresponding γ-butenolide ester without loss of enantiopurity and was transformed into (+)-crobarbatic acid in a few steps.

Full text of DOI:10.1246/cl.130295

doi:10.1246/cl.130295
894
Published on the web May 22, 2013
1,4-Addition Reaction of 5H-Oxazol-4-ones to Allenic Esters
and Ketones Catalyzed by Chiral Guanidines
Nari Jin, Tomonori Misaki,* and Takashi Sugimura*
Graduate School of Material Science, University of Hyogo, 3-2-1 Kohto, Kamigori, Ako-gun, Hyogo 678-1297
(Received April 4, 2013; CL-130295; E-mail: misaki@sci.u-hyogo.ac.jp)
Table 1. Optimization of the 1,4-addition of 5H-oxazol-4-ones
2 to allenic esters 3 using catalyst 1a or 1ba
In this paper, a chiral guanidine-catalyzed 1,4-addition
reaction of 5H-oxazol-4-ones to allenic esters and ketones is
described. 5H-Oxazol-4-ones substituted with a 2-chlorophenyl
group were suitable pronucleophiles that gave high enantiose-
lectivities. Subsequent hydrolysis of the obtained adduct gave
the corresponding £-butenolide ester without loss of enantio-
purity and was transformed into (+)-crobarbatic acid in a few
steps.
O
O
O
O
1a or 1b
(5 mol%)
R2
N
R2
N
+
O
0 °C, toluene
O
3a: R2 = O(CH2)7CH3
3b: R2 = OPh
Ar
Ar
4
2
Cat. Time Product Yield eeb
Substrates
Entry
1
/h
4
/% /%
2: Ar
3
1
2
3
4
5
6
7
8
2a: Ph
2a: Ph
2a: Ph
3a 1a 12
3a 1b 19
4a
4a
4b
4c
4d
4e
4f
4g
4e
4e
66
65
76
68
68
85
81
83
88
84
75
62
86
3
53
94
93
93
97
93
Recently, electron-deficient allene compounds have been
used as reactive electrophilic reactants in several organic
reactions1 including catalytic asymmetric carbon-carbon bond-
forming reactions.2 Some conjugate 1,4-addition reactions of
carbon nucleophiles to allenyl carbonyl compounds have also
been developed.3 However, Jørgensen et al. reported the only
successful example of catalytic asymmetric 1,4-addition of
carbon nucleophiles to allenyl carbonyl compounds in 2008.2c
We have successfully developed addition reactions of 5H-
oxazol-4-ones as pronucleophiles catalyzed by bicyclic chiral
guanidines4 bearing a hydroxy group,5 and disclosed that the
combination of 5H-oxazol-4-one and the guanidine is quite
effective for the highly enantioselective carbon-carbon bond
formation producing a less-accessible chiral building block,
¡-oxygen atom-substituted carboxylates bound to a chiral
quaternary ¡-carbon atom.6 Because the catalytic enantioselec-
tive carbon-carbon bond formation producing synthetically
useful ¡-hydroxy carboxylates is limited because of the
difficulty in the effective enolate generation of glycolate
derivatives,7 we here developed a method for the asymmetric
1,4-addition of 5H-oxazol-4-ones to allenic esters and ketones
catalyzed by chiral guanidines as part of our continuous study
(eq 1).
3b 1a
3.5
2b: 4-Cl-C6H4 3b 1a
2c: 3-Cl-C6H4 3b 1a
2d: 2-Cl-C6H4 3b 1a
2e: 2-F-C6H4 3b 1a
2f: 2-Br-C6H4 3b 1a
0.5
4
1
1
1
9c 2d: 2-Cl-C6H4 3b 1a
10c 2d: 2-Cl-C6H4 3b 1b
1
2
aReactions were performed on a 0.3 mmol scale in 1.0 mL of
toluene using 1.2 equiv of allenyl carbonyl compound 3 and
5 mol % of catalyst 1a or 1b. bDetermined by chiral HPLC
c
analysis. Reaction was performed at ¹20 °C.
carbon-carbon double bond on adduct 4 was not observed
during the 1,4-addition. The use of guanidine 1b did not enhance
the enantioselectivity in the 1,4-addition to 3a (Entry 2),
whereas guanidine 1b was a suitable catalyst for the 1,4-
addition to alkynones, as shown in our previous report.5c The
use of phenyl allenic ester 3b instead of 3a enhanced the
reaction rate and enantioselectivity (Entry 3). Thus, by using 3b
as an electrophile and 1a as a catalyst, we investigated the effect
of the aromatic substituent (Ar) on 5H-oxazol-4-one 2 to further
improve enantioselectivity (Entries 4-8). The 1,4-additions of
5H-oxazol-4-ones 2b and 2c showed low enantioselectivity
(Entries 4 and 5). When the 2-chlorophenyl group-substituted
5H-oxazol-4-one 2d was used as a pronucleophile, the enantio-
selectivity of the 1,4-addition was improved to 94% ee
(Entry 6). The 1,4-additions of the 2-fluoro and 2-bromo
analogues 2e and 2f, respectively, also showed high chemical
yields and enantioselectivities (Entries 7 and 8). The enantio-
selectivity was improved to 97% ee by lowering the reaction
temperature (Entry 9).
O
O
O
R1
1
O
R1
(5 mol%)
N
R2
N
∗
R2
+
ð1Þ
O
O
Ar
3
Ar
4
2
F3C
N
CF3
F3C
CF3
CF3
CF3
Me
Me
CF3
CF3
N
N
N
OH
N
H
N
OH
H
1a
Next, we applied the optimized conditions to the
1,4-addition of some 5H-oxazol-4-ones 2d, 2g, and 2h (Ar =
2-Cl-C6H4) to phenyl allenic ester 3b using catalyst 1a (Table 2,
Entries 1-3). As a result, adducts 48,9 were obtained in high
chemical yields with high enantioselectivities, even in the case
of bulky pronucleophile 2g. We also performed the 1,4-addition
with allenic ketones 3c and 3d as electrophiles, and the
1b
We selected octyl allenic ester 3a as an electrophile for the
development of the new 1,4-addition method, and the initial
attempt at reacting ¡-methyl group-substituted 5H-oxazol-4-one
(2a: Ar = Ph) to 3a using guanidine 1a revealed that the
1,4-addition proceeded with appreciable enantioselectivity, as
shown in Table 1, Entry 1. Note that, the migration of the ¢,£
Chem. Lett. 2013, 42, 894-896
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

895
O
Table 2. Catalytic 1,4-addition of 5H-oxazol-4-ones 2 (Ar =
O
O
2-Cl-C6H4) to allenic esters and ketones 3, catalyzed by 1aa
NH
PhO
N
a
b
O
O
O
O
O
O
O
1a
(5 mol%)
R1
R1
O
N
R2
N
R2
Cl
Cl
+
O
O
4e
5
3b: R2 = OPh
0 °C, toluene
97% ee
3c: R2 = CH2CH(CH3)2
Cl
Cl
3d: R2 = c-Hex
O
O
O
2d: R1 = CH3
2g: R1 = i-Pr
2h: R1 = n-Bu
4
O
c
3e:
OMe
OMe
OMe
Ph
and
O
O
O
Time
/h
Product
Yield
/%
eeb
/%
O
O
Substrates
O
6
7a
7b
Entry
59% yield from 4e
4
2
3
91% yield (7a : 7b = 82 : 18)
96% ee
1c
2c
3
4
5
2d
2g
2h
2d
2d
2d
3b
3b
3b
3c
3d
3e
1
2
0.5
1
1
24d
4e
4h
4i
4j
4k
®
88
81
77
83
81
<40e
97
96
93
98
96
®
O
O
O
O
d
OH
OH
H
OMe
O
O
O
O
O
O
N
(+)-crobarbatic acid 8
6
7a (>95% de)
crobarbatine
84% yield
a,bSee corresponding footnote in Table 1. cReaction was
performed at ¹20 °C. dReaction was performed at 0 °C for
10 h then at rt for 14 h. Conversion yield.
Scheme 1. Derivatization of adduct 4e to 6 and (+)-crobar-
batic acid (8). (a) 1.0 M NaOH (aq), THF, 0 °C, 1 h. (b) 1.0 M
CH3OLi, CH3OH, 0 °C, 2.5 h. (c) 10% Pd-C, H2, MeOH, rt,
24 h. (d) 4.0 M NaOH (aq), THF, 100 °C, 4 h, then 2 M HCl (aq),
e
20
100 °C, 1 h. Optical rotation value of 8: ½¡ꢀD = +3.76 (c 0.66,
corresponding adducts 4j and 4k were obtained in high chemical
yields with excellent enantioselectivities (Entries 4 and 5).
Unfortunately, the 1,4-addition to £-phenyl allenic ketone 3e
slowly proceeded under the optimized conditions, and a low
conversion yield (<40%) was observed after prolonged stirring
at room temperature (Entry 6).
25
H2O) [lit.10 ½¡ꢀD = +3.56 (c 1.4, H2O) (2R, 3S)].
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Adduct 4e formed by the 1,4-addition of 2d to 3b can be
easily converted into the corresponding £-butenolide 6 with-
out loss of enantiopurity.9 As illustrated in Scheme 1, the
£-butenolide ring formation, after the ring-opening hydrolysis of
5H-oxazol-4-one through the treatment of 4e with aqueous
NaOH in THF, readily afforded the corresponding imide 5,
which was converted into £-butenolide 6 by CH3OLi-mediated
methanolysis. The enantiopurity of 6 was confirmed by HPLC
analysis. To assign the absolute configuration of adduct 4e and
also to demonstrate the utility of the present 1,4-addition, we
converted £-butenolide 6 into (+)-crobarbatic acid 8,10,11 which
is a hydrolysis product of a pyrrolizidine alkaloid crobarbatine.11
The Pd-C-catalyzed hydrogenation of £-butenolide 6 afforded a
mixture of diastereoisomers 7a and 7b (7a:7b = 82:18), and the
major isomer 7a was isolable through purification by simple
column chromatography. Finally, the hydrolysis of isomer 7a
(>95% de) gave (+)-crobarbatic acid (8) in 84% yield. The
absolute configuration of obtained 8 was assigned as (2R, 3S) by
comparing its optical rotation value with the reported value;10
hence, the absolute configuration of adduct 4e was R. All
spectral data for obtained 8 were also consistent with the
reported data.10
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In conclusion, we developed a highly enantioselective
1,4-addition of 5H-oxazol-4-ones 2 (Ar = 2-Cl-C6H4) to allenic
esters and ketones 3 using chiral guanidine 1a. By examining the
effect of Ar on 2, we found that the 2-chlorophenyl group was
suitable for the 1,4-addition and gave high enantioselectivities.
An obtained adduct 4e of the 1,4-addition was derived into
(+)-crobarbatic acid in a few steps.
3
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Chem. Lett. 2013, 42, 894-896
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

896
4
5
6
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7
Chem. Lett. 2013, 42, 894-896
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/