Highly Z -selective asymmetric 1,4-addition reaction of 5 H -oxazol-4-ones with alkynyl carbonyl compounds catalyzed by chiral guanidines

Article abstract of DOI:10.1021/ja200283n

An asymmetric 1,4-addition reaction of 5H-oxazol-4-ones with alkynyl carbonyl compounds was developed, and, for the first time, high enantiomeric and geometric control was achieved to afford the thermodynamically unstable Z-isomer predominantly using chir

Full text of DOI:10.1021/ja200283n

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Highly Z-Selective Asymmetric 1,4-Addition Reaction of
5H-Oxazol-4-ones with Alkynyl Carbonyl Compounds Catalyzed by
Chiral Guanidines
Tomonori Misaki,* Kei Kawano, and Takashi Sugimura*
Graduate School of Material Science, University of Hyogo, 3-2-1 Kohto, Kamigori, Hyogo 678-1297, Japan
S Supporting Information
b
Table 1. Screening of Reaction Conditions for the 1,4-
ABSTRACT: An asymmetric 1,4-addition reaction of 5H-
oxazol-4-ones with alkynyl carbonyl compounds was devel-
oped, and, for the first time, high enantiomeric and geo-
metric control was achieved to afford the thermodynam-
ically unstable Z-isomer predominantly using chiral guani-
dine catalysts bearing a hydroxy group at the appropriate
position. The method provides synthetically useful γ-bute-
nolide ester bearing a chiral quaternary stereogenic center.
Addition of 5H-Oxazol-4-one 2a (R1 = CH3, Ar1 = Ph) to
Alkynyl Carbonyl Compound 3a (R2 = OCH3) Using 1aꢀd
To Obtain Adduct 4aa
temp time yieldb
Z/E
ratioc
eed
entry catalyst 1
solvent
(°C)
(h)
(%)
(%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1c
1c
1c
1d
THF
0
1
3
50
55
47
53
47
59
52
56
54
87/13 43 (R)
92/8 53 (R)
87/13 84 (R)
THF
0
0
THF
1
toluene
CPME
CPME
tBuOMe ꢀ40
toluene
0
1
96/4
93/7
97/3
97/3
98/2
90 (R)
92 (R)
92 (R)
93 (R)
94 (R)
0
1
ꢀ40
24
16
11
28
atalytic asymmetric 1,4-addition of carbon nucleophiles to
C
R,β-unsaturated carbonyl compounds is a well-established
enantioselective carbonꢀcarbon bond-forming reaction. Various
types of 1,4-additions to conjugated alkenyl carbonyl compounds
have been developed1 and applied to the syntheses of many
biologically active natural products.2 In contrast, catalytic asym-
metric 1,4-additions to the corresponding alkynyl carbonyl
compounds are few.3 In the 1,4-additions of this type, the geo-
metric control of newly formed olefin is greatly important for
further stereoselective transformation of the obtained products
as well as the enantiomeric control. However, the high geometric
control has not been achieved yet.4 The reported catalytic asym-
metric 1,4-additions have preferably led to thermodynamically
stable E-isomers in insufficient selectivity.3 Jørgensen et al.3a and
Shibasaki et al.3c prepared only the E-isomer by the isomerization
of the Z/E mixed products after the 1,4-additions, but the iso-
merization could not produce the thermodynamically unstable
Z-isomers.5 Here, we report a highly Z-selective asymmetric 1,4-
addition of 5H-oxazol-4-ones to alkynyl carbonyl compounds
catalyzed by chiral guanidines 1 (eq 1). This 1,4-addition can also
form an oxygen-atom-substituted chiral quaternary stereogenic
center at the R-carbon atom.
ꢀ40
0
toluene
90/10 36 (S)
a Reactions were performed on a 0.3 mmol scale in 1.0 mL of anhydrous
solvent using 1.5 equiv of alkynyl carbonyl compound 3 and 5 mol % of
catalyst 1. b Combined isolated yield of Z/E-4. c Determined by 600
MHz 1H NMR analysis of the crude mixture. d Enantiomeric excess of
the Z isomer, determined by chiral HPLC analysis.
effectively induced a highly enantioselective carbonꢀcarbon
bond formation, producing R-oxygen-atom-substituted carbox-
ylates bound to a chiral quaternary R-carbon atom. Thus, instead
of using aldehydes, we selected alkynyl carbonyl compounds as
the electrophiles to prove the high stereocontrolability of the
bicyclic chiral guanidines 1 by achieving, for the first time, high
enantiomeric and geometric control during the catalytic 1,4-ad-
dition.
An initial attempt at reacting 5H-oxazol-4-one (2a: R1 = CH3,
Ar1 = Ph) with methyl propiolate (3a) using guanidine 1a
revealed that the 1,4-addition proceeded with appreciable en-
antioselectivity (Table 1, entry 1). Interestingly, the Z-isomer
was the major product. This result prompted us to enhance the
stereoselectivity by screening the reaction conditions and, more
specifically, tuning the steric and electronic properties of the
guanidines 1. As shown in Table 1, the use of electron-deficient
aromatic substituents (Ar2) on guanidine 1, such as 3,5-bis-
(trifluoromethyl)phenyl groups, remarkably improved the en-
antioselectivity without enhancing the Z/E selectivity (entry 3).
Further investigation of the reaction conditions using 1c revealed
Previously, we successfully developed a direct asymmetric
aldol reaction of 5H-oxazol-4-ones 2 as pronucleophiles with
aldehydes catalyzed by bicyclic chiral guanidines 1 bearing a
hydroxy group.6 We disclosed that the combination of 5H-
oxazol-4-one 2 and guanidine 1 as a Brønsted base catalyst7
Received: January 11, 2011
Published: March 30, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja200283n J. Am. Chem. Soc. 2011, 133, 5695–5697
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Table 2. Catalytic 1,4-Addition of Various 5H-Oxazol-4-ones 2 to Alkynyl Carbonyl Compounds 3, Catalyzed by 1ca
substrate
entry
2: R1, Ar1
3
conditions (°C, h)
product 4
yieldb(%)
Z/E ratioc
eed(%)
1
2e
2b: CH3(CH2)3, Ph
2c: (CH3)2CH, Ph
2d: PhCH2, Ph
3a
3a
3a
3a
3a
3b
3b
3c
3d
3d
3d
3d
3d
3d
3a
3a
3a
3c
3c
ꢀ40, 16
ꢀ40, 22
ꢀ40, 39
ꢀ40, 41
ꢀ40, 19
0, 47
4b
4c
4d
4e
4f
73
66
74
67
77
77
68
88
50
40
55
49
43
58
15
26
70
33
61
99/1
93
98/2
86
3
96/4
84
4
5e
2e: CH2dCHCH2, Ph
2f: BnO(CH2)4, Ph
2a: CH3, Ph
98/2
91
97/3
90
6
4g
4g
4h
4i
44/56
1/>99
76/24
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
99/1
91(91f)
91f
88(72f)
7g,h
8i
9j
2a: CH3, Ph
0, 47
2a: CH3, Ph
0, 26
2a: CH3, Ph
0, 22
97
10j
11j
12j
13j
14j
15
16k
17
18
19
2b: CH3(CH2)3, Ph
2c: (CH3)2CH, Ph
2d: PhCH2, Ph
0, 48
4j
98
0, 71
4k
4l
99
0, 40
94
2e: CH2dCHCH2, Ph
2f: BnO(CH2)4, Ph
2g: CH3, 4-CF3-C6H4
2h: CH3, 4-iPrO-C6H4
2i: CH3, 2-CH3-C6H4
2g: CH3, 4-CF3-C6H4
2h: CH3, 4-iPrO-C6H4
0, 40
4m
4n
4o
4p
4q
4r
98
0, 43
96
ꢀ40, 38
ꢀ40, 42
ꢀ40, 5
0, 7
89
93/7
83
94/6
94
83/17
70/30
91(70f)
38(20f)
0, 45
4s
aꢀd See corresponding footnote in Table 1. e CH2Cl2 was used as solvent instead of toluene. f Enantiomeric excess of the E isomer. g After completion of
the 1,4-addition, Ph2MeP (0.3 equiv) was added for the isomerization. h The absolute configuration of E-4g was determined by X-ray analysis of the
corresponding compound having a bromo substituent at the 4-position of the phenyl group.12 i The absolute configuration of Z-4h was determined by
conversion into compound 7.12 j 100 mg of 3 Å molecular sieves/0.3 mmol of 2 was added.13 k Low conversion yield (35%) caused the low isolated yield.
that toluene was the best of the investigated solvents, especially
at ꢀ40 °C (entries 3ꢀ8). It is noteworthy that the reaction with
1d, which contains a methyl ether-protected hydroxy group,
proceeded significantly more slowly and afforded the opposite
enantiomer in low selectivity (entry 9).
5H-oxazole ring of adduct 4 derived from 2g or 3d was observed
during the purification by silica gel column chromatography
(entries 9ꢀ15, 18).
Among reported 1,4-additions of carbon nucleophiles to
propiolates under simple basic conditions, 1,4-additions of 4H-
oxazol-5-ones (azlactones),8 which are structurally similar to 5H-
oxazol-4-ones 2, or glycine Schiff base derivatives9,10 show
Z-selectivity. The present 1,4-addition of 2a to 3a also proceeds
Z-selectively, even in the presence of DBU (Z/E = 85/15) or
K2CO3 (Z/E = 72/28) instead of 1c. These results indicate that
the Z/E selectivity depends on the nature of the pronucleophile
and that this dependence suggests the existence of some inter-
action. As shown in eq 2, it is likely that one face of the enolate
anion in the intermediate 5 is shielded by the 5H-oxazole ring
because the electron-enriched π orbital of the enolate interacts
with the electron-deficient carbon atom at the 2-position of the
5H-oxazole ring.10,11 Therefore, intermediate 5 most likely
undergoes protonation from the other face to afford the thermo-
dynamically unstable Z-isomer. The electron donation effect of
the R2 group on electrophile 3 and an electron-deficient aromatic
substituent at the 2-position of the 5H-oxazole ring should
enhance the shielding effect arising from this intramolecular
interaction. Accordingly, the Z/E selectivity of the present 1,4-
addition was enhanced in proportion to the electron donation
ability of the R2 group (alkynone 3b, Z/E = 44/56; thioester 3c,
Z/E = 76/24; ester 3a, Z/E = 96/4ꢀ99/1; amide 3d, Z/E > 99/1).
Next, we investigated the substrate scope of the 1,4-addition
using 1c (Table 2). The 1,4-addition to methyl propiolate (3a)
proceeded highly Z-selectively with good to excellent enantio-
selectivities (entries 1ꢀ5). Although the 1,4-additions to alky-
none 3b and thioester 3c showed low Z/E selectivities, their
enantioselectivities were high (entries 6, 8). Isomerization of Z/E
mixed adduct 4g using Ph2MeP afforded only the E-isomer, as
described by Shibasaki3c (entry 7). Uniformly high Z/E selectiv-
ities and excellent enantioselectivities were observed when amide
3d was used as an electrophile (entries 9ꢀ14). It should be noted
that the 1,4-addition of bulky pronucleophile 2c, the Z-adduct of
which was thermodynamically more disadvantageous, also re-
sulted in excellent Z/E selectivities (entries 2, 11). We also
performed the 1,4-addition with 2gꢀi, which contain a substi-
tuted aromatic ring. The 1,4-addition with 2g bearing an
electron-withdrawing group showed higher Z/E selectivity
(entries 15, 18), and 2h bearing an electron-donating group
showed lower Z/E selectivity (entries 16, 19). Ortho-substituted
2i also gave low Z/E selectivity (entry 17). In all cases, the
1
remarkable side reactions were not observed by the H NMR
analysis of the crude mixture, but relatively low chemical yields
were observed in some cases. The ring-opening reaction of the
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Journal of the American Chemical Society
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Scheme 1. Derivatization of Adducts Z-4a and Z-4i to 7a
(3) (a) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672.
(b) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007,
129, 1038. (c) Chen, Z.; Furutachi, M.; Kato, Y.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 2218. For related
work, see: (d) Poulsen, T. B.; Bernardi, L.; Bell, M; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 6551.
(4) For Z-selective racemic 1,4-addition, see: (a) Jia, C.; Lu, W.;
Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am.
Chem. Soc. 2000, 122, 7252. (b) Grossman, R. B.; Comesse, S.; Rasne,
R. M.; Hattori, K.; Delong, M. N. J. Org. Chem. 2003, 68, 871. (c) Shi, Z.;
He, C. J. Org. Chem. 2004, 69, 3669. (d) Mueller, A. J.; Jennings, M. P.
Org. Lett. 2007, 9, 5327. See also refs 8ꢀ10 for Z-selective 1,4-addition.
(5) Jørgensen also isolated the Z-isomer from the Z/E mixed
product by the selective decomposition of the E-isomer.3a
(6) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc. 2010,
132, 6286.
a Conditions: (a) for 4a, 1.0 M NaOH (aq), THF, 0 °C, 1.5 h; (b) for 4i,
CF3CO2H, THF, H2O, 0 °C, 1 h, then rt, 15 h; (c) CH3OLi, CH3OH,
0 °C, 1 h, then rt, 65 h (63% from 4a, 54% from 4i).
The Z/E selectivity order 2g > 2a > 2h was also in agreement
with the proposed mechanism.
(7) For the chiral guanidine catalysis, see: (a) Ishikawa, T. In
Superbases for Organic Synthesis; Ishikawa, T., Ed.; John Wiley & Sons:
Chippenham, 2009; pp 93ꢀ143. For a review, see: (b) Leow, D.; Tan,
C.-H. Chem. Asian J. 2009, 4, 488 and references therein.
(8) (a) Steglich, W.; Gruber, P.; H€ofle, G.; K€onig, W. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 653. (b) Wegmann, H.; Schulz, G.; Steglich, W.
Liebigs Ann. Chem. 1980, 1736.
(9) (a) Lꢀopez, A.; Moreno-Ma~nas, M.; Pleixats, R.; Roglans, A.;
Ezquerra, J.; Pedregal, C. Tetrahedron 1996, 52, 8365. (b) Guillena, G.;
Nꢀajera, C. J. Org. Chem. 2000, 65, 7310. For an exceptionally E-selective
1,4-addition of the Schiff base substrate, see: (c) Rubio, A.; Ezquerra, J.
Tetrahedron Lett. 1995, 36, 5823.
(10) An intramolecular interaction of intermediates had been pro-
posed for the explanation about Z-selectivity in a 1,4-addition of Schiff
base substrates: Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1993,
58, 6474.
(11) For a [3þ2] cycloaddition via a related intermediate, see:
Obrecht, D.; Zumbrunn, C.; M€uller, K. J. Org. Chem. 1999, 64, 6891.
(12) The absolute configurations of Z-4a, -4h, and -4i and E-4g were
assigned as (R). Except for that of E-4g, they were determined by the
conversion of 7 into the known γ-lactonecarboxylic acid: Partridge, J. J.;
Shiuey, S.-J.; Chadha, N. K.; Baggiolini, E. G.; Blount, J. F.; Uskokoviꢀc,
M. R. J. Am. Chem. Soc. 1981, 103, 1253. See the Supporting Information
for details.
Adducts Z-4 derived from 3a or 3d can be easily converted
into synthetically useful γ-butenolide without loss of enantio-
purity. As illustrated in Scheme 1, the γ-butenolide ring forma-
tion subsequent to the hydrolysis of 5H-oxazol-4-one through
treatment of Z-4a with aqueous NaOH in THF readily afforded
the corresponding imide 6, which was converted into methyl
ester 712 by the CH3OLi-mediated methanolysis. The CF3-
CO2H-mediated acidic hydrolysis also converted adduct Z-4i
into 6. The enantiopurity of 7 was confirmed by HPLC analysis.
In conclusion, we developed a highly Z-selective asymmetric
1,4-addition of 5H-oxazol-4-ones 2 to alkynyl carbonyl com-
pounds 3 and, for the first time, achieved high enantiomeric and
geometric control using chiral guanidine 1c.
’ ASSOCIATED CONTENT
S
Supporting Information. Representative experimental
b
procedures and spectral data for pronucleophiles 2gꢀi, electro-
phile 3c, adducts 4, and derivatized product 7; X-ray crystal-
lographic file in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) The ring-opening reaction via hydrolysis of the 5H-oxazole ring
of adduct 4 derived from 3d was observed during the 1,4-addition
without MS 3 Å.
’ AUTHOR INFORMATION
Corresponding Author
misaki@sci.u-hyogo.ac.jp
’ ACKNOWLEDGMENT
We gratefully acknowledge Dr. Hiroki Akutsu for the X-ray
crystallographic analysis.
’ REFERENCES
(1) For organocatalysis, see: (a) Ting, A.; Goss, J. M.; McDougal,
N. T.; Schaus, S. E. In Asymmetric Organocatalysis; List, B., Ed.; Springer:
Berlin and Heidelberg, 2010; pp 145ꢀ200. For metal catalysis, see: (b)
Christoffers, J.; Koripelly, G.; Rosiak, A.; R€ossle, M. Synthesis
2007, 1279.
(2) Examples of natural products, see the following. For
spiculisporic acid: (a) Brown, S. P.; Goodwin, N. C.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. For (þ)-tanikolide: (b)
Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006,
45, 4301. For (þ)-cylindricine C:(c) Shibuguchi, T.; Mihara, H.;
Kuramochi, A.; Sakuraba, S.; Ohshima, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2006, 45, 4635. Also see ref 1b.
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dx.doi.org/10.1021/ja200283n |J. Am. Chem. Soc. 2011, 133, 5695–5697