Highly diastereoselective and enantioselective Michael addition of 5H-oxazol-4-ones to α,β-unsaturated ketones catalyzed by a new bifunctional organocatalyst with broad substrate scope and applicability

Article abstract of DOI:10.1039/c1cc15928c

A new thiourea-tertiary amine bifunctional catalyst derived from l-tert-leucine was developed and provides excellent stereocontrol in a novel and direct Michael addition of 5H-oxazol-4-ones to α,β-unsaturated ketones with much broad substrate scope. The conjugate addition products with chiral vicinal quaternary and tertiary stereocenters can be easily transformed to structurally interesting compounds or building blocks.

Full text of DOI:10.1039/c1cc15928c

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COMMUNICATION
Highly diastereoselective and enantioselective Michael addition of
5H-oxazol-4-ones to a,b-unsaturated ketones catalyzed by a new
bifunctional organocatalyst with broad substrate scope and
applicabilitywz
Huicai Huang, Kailong Zhu, Wenbin Wu, Zhichao Jin and Jinxing Ye*
Received 23rd September 2011, Accepted 29th October 2011
DOI: 10.1039/c1cc15928c
A new thiourea–tertiary amine bifunctional catalyst derived
from L-tert-leucine was developed and provides excellent stereo-
control in a novel and direct Michael addition of 5H-oxazol-
4-ones to a,b-unsaturated ketones with much broad substrate
scope. The conjugate addition products with chiral vicinal
quaternary and tertiary stereocenters can be easily transformed
ð1Þ
On the other hand, thiourea–tertiary amine bifunctional
catalysts have been intensively studied, accelerating the develop-
ment of organocatalytic synthetic methodology.5,6 Despite the
enormous advances of this bifunctional organocatalysis,
there is a major drawback to these systems in the asymmetric
Michael addition of a,b-unsaturated ketones. All of the
reaction scope was surprisingly and totally limited primarily
to ketone substrates with bulky groups, such as chalcones and
benzalacetones.6d,7 Here, we report a new chiral thiourea–
tertiary amine bifunctional catalyst from L-tert-leucine exhibiting
excellent diastereo- and enantiocontrol in the Michael addition
of 5H-oxazol-4-ones to a,b-unsaturated ketones with broad
substrate scope. The Michael adducts with chiral vicinal
quaternary and tertiary stereocenters can be easily transformed
to structurally interesting compounds or building blocks.
We first studied the Michael addition reaction of benzal-
acetone 6a and 5H-oxazol-4-one 5a in chloroform using
various reported chiral thiourea–tertiary amine bifunctional
organocatalysts (Scheme 1).8 The reaction could proceed
smoothly at temperatures as high as 50 1C. To our surprise,
with the widely used bifunctional organocatalyst 1–2 derived
from cinchona alkaloid and diaminocyclohexane (DACH), the
diastereoselectivities were excellent, but the enantioselectivities
to structurally interesting compounds or building blocks.
Chiral hydroxycarbonyls and their derivatives with a quaternary
stereocenter have emerged as very important synthons and
building blocks in pharmaceuticals and biologically active
natural products.1 Due to their significance in organic synthesis,
considerable efforts have been devoted to the development of
their chemical synthesis through Henry reaction with a-keto-
carbonyls,2a metal-catalyzed alkylation of a-ketoesters2b,c and
allylic alkylation of enolates reactions.2d 5H-oxazol-4-one
could be considered as a simple and attractive chemical precursor
in the catalytic asymmetric construction of chiral 5,5-disub-
stituted oxazol-4-ones, which can be readily converted into
chiral hydroxycarboxylic acids and their derivatives with a
quaternary stereocenter [see eqn (1)]. Catalytic asymmetric
reactions of 5H-oxazol-4-ones have recently been studied in
different types. In a pioneering study, Trost et al. reported
the asymmetric allylic alkylation of 5H-oxazol-4-ones under
molybdenum catalysis with chiral diphosphine ligand with
excellent stereoselectivity.3 The same strategies have been
successfully studied by Misaki and Sugimura et al. in the
asymmetric Aldol reaction of 5H-oxazol-4-ones with aldehydes
and 1,4-addition with highly active terminal alkynyl carbonyl
compounds catalyzed by chiral guanidine catalysts,4 whereas
the use of less electrophilic enones has not been reported before.
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: yejx@ecust.edu.cn
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, crystal data and characterization of the Michael addition
products. CCDC 824362. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc15928c
Scheme 1 The catalysts used in the Michael addition reaction.
Chem. Commun., 2012, 48, 461–463 461
c
This journal is The Royal Society of Chemistry 2012

Table 1 Screening of reaction conditionsa
Having identified the optimized catalyst and conditions,
the scope of this asymmetric Michael addition reaction was
explored next. Various combinations of 5H-oxazol-4-ones
5 and a,b-unsaturated ketones 6 were applied in the reaction.
It is gratifying to report that the substrate generality under the
present reaction conditions was very broad, covering aryl,
aliphatic, linear and cyclic a,b-unsaturated ketones. Remarkably,
most of the diastereoselectivities were excellent, with a ratio of
>30 : 1, and the enantioselectivities were also excellent, with
over 90% ee. For the benzalacetone derivatives and analogues,
it turned out that the reaction proceeded very well in excellent
stereoselectivities, regardless of the electron-donating or electron-
withdrawing substituents on the phenyl ring and the substituent
position on the aromatic ring (Table 2, entries 1–3, 7–17,
22–28). Notably, in the case of chalcone, the reaction proceeded
very well with perfect stereoselectivity and only a single isomer
(>30 : 1 dr and >99% ee) was obtained (Table 2, entry 6). The
reactions of aliphatic a,b-unsaturated ketones showed a slightly
low reaction rate, but they could be completed in 96 h with good
to excellent stereoselectivity (Table 2, entries 5, 18, 19 and 21).
4-cyclohexylbut-3-en-2-one and 2-cyclohexenone were the only
two cases with slightly low diastereoselectivities in this Michael
Entry Catalyst T/1C Solvent
Conv (%)b drc
ee (%)d
7
1
2
3
4
5
6
7
8
1
2
3
30
30
30
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
EtOAc
THF
Dioxane
CH3CN
Toluene
Xylene
(CH2Cl)2
89
73
52
74
84
85
87
84
84
85
86
86
59
86
86
84
87
>30 : 1
>30 : 1 ꢀ10
24 : 1 ꢀ68
4a
4b
4c
4d
4e
4f
4g
4e
4e
4e
4e
4e
4e
4e
4e
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
79
91
90
91
95
92
94
93
93
97
96
90
90
97
97
9
10
11
12
13
14
15
16
17
18e
(CH2Cl)2 >95
a
Unless otherwise noted, all reactions were carried out using 1.0 equiv. of
5a (0.10 mmol), 1.5 equiv. of 6a and 0.10 equiv. of catalyst in 0.3 mL
Table 2 The scope of direct Michael reaction of various 5H-oxazol-4-
ones and a,b-unsaturated ketonesa
b
solvent. Conversion was determined by GC. Determined by
c
d
1H NMR of the crude reaction mixture. Determined by chiral HPLC.
e
With 0.2 mL CH2ClCH2Cl.
were very poor, with typically less than 10% ee (Table 1,
entries 1–2). With Wang’s bifunctional organocatalyst 3
derived from (1R, 2R)-N-sulfonyl diphenylethylenediamine
(DPEN) and (1R, 2R)-DACH with a thiourea linker,9 the
diastereoselectivity remained excellent and the enantio-
selectivity was significantly improved to 68%. We then moved
our attention to a novel bifunctional organocatalyst, which
retained the (1S, 2S)-N-sulfonyl diphenylethylenediamine
(DPEN) scaffold, but was decorated with a new chiral diamine
scaffold from easily commercially available chiral amino acids.
All of these new thiourea–tertiary amines were found to be
superior catalysts for the asymmetric Michael reaction. The
catalyst 4a derived from L-valine increased the ee value to 79%.
To our delight, all of the other catalysts 4b–4g derived from
L-tert-leucine gave excellent results, both in diastereoselectivities
(>30: 1) and enantioselectivities (>90%). Further fine-tuning
of the aza-cycle, R1 and R2 substituents in the catalysts revealed
that when R1 is a tert-butyl group, the catalysts with pyrrolidine
or piperidine, with R2 either as Ts or Ms, gave a similarly
excellent stereoselectivity of >30 : 1 dr and 90–91% ee (Table 1,
entries 5–7). The best enantioselectivity of 95% was achieved
when R2 was 4-nitrobenzenesulfonyl group (Table 1, entries
8–10). The effects of solvents were also investigated using 4e
as a catalyst. It is noteworthy that this catalytic Michael
addition was surprisingly tolerant towards solvent choices at
50 1C, including chloroform, ethyl acetate, tetrahydrofuran,
dioxane, acetonitrile, toluene, xylene and 1,2-dichloroethane
(Table 1, entries 11–18). Of the solvents studied, 1,2-dichloro-
ethane gave the best results, both in conversion (over 95%)
and stereoselectivity (>30 : 1 dr and 97% ee value, Table 1,
entry 18).
Entry R1
R2
R3
Yield (%)b drc
ee (%)d
1
Me C6H5
Me
Me
Me
Me
Me
84(7a)
97(7b)
94(7c)
94(7d)
85(7e)
>30 : 1 96
>30 : 1 >99
>30 : 1
>30 : 1
10 : 1
2
3
4
Me 3-MeC6H4
Me 4-FC6H4
Me C6H5CHQCH
Me hexyl
96
97
93
5e,f
6
Me C6H5
C6H5 87(7f)
>30 : 1 >99
7
8
9
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
C6H5
3-MeC6H4
2-MeOC6H4
Me
Me
Me
95(7g)
90(7h)
83(7i)
86(7j)
96(7k)
85(7l)
95(7m)
98(7n)
88(7o)
84(7p)
97(7q)
90(7r)
81(7s)
86(7t)
81(7u)
87(8a)
98(8b)
93(8c)
94(8d)
85(8e)
87(8f)
91(8g)
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
13 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
>30 : 1
97
97
94
92
94
90
97
97
97
97
98
96
98
99
90
97
96
95
97
98
98
98
10
11
12
13
14
15
16
17
18e
19e,f
20
21e,f
22
23
24
25
26
27
28
2,3-(MeO)2C6H3 Me
2-FC6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
4-NO2C6H4
2-furanyl
2-Naphthyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Me
C6H5
–(CH2)3–
i-Pr
n-Pr 3-MeOC6H4
n-Pr 4-BrC6H4
n-Pr 3-NO2C6H4
n-Pr 2-Thiophenyl
i-Pr C6H5
Me
Me
Me
Me
Me
Me
Me
i-Pr 3-MeOC6H4
i-Pr 4-ClC6H4
a
Unless other noted, All reactions were carried out using 1.0 equiv. of
5 (0.30 mmol, 0.5 M), 1.5 equiv. of a,b-unsaturated ketone 6, 0.10 equiv.
of catalyst 4e in CH2ClCH2Cl. Isolated yield. Determined by
b
c
1H NMR of the crude reaction mixture. Determined by chiral HPLC.
d
e
f
With 15 mol% catalyst 4e. For 96 h.
c
462 Chem. Commun., 2012, 48, 461–463
This journal is The Royal Society of Chemistry 2012

Notes and references
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2 For selected examples of the synthesis of chiral hydroxycarbonyls:
(a) H. Li, B. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128, 732;
(b) L. C. Wieland, H. Deng, M. L. Snapper and A. H. Hoveyda,
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and X. Feng, J. Org. Chem., 2007, 72, 8478; (d) B. M. Trost, J. Xu
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3 B. M. Trost, K. Dogra and M. Franzini, J. Am. Chem. Soc., 2004,
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Chem. Soc., 2011, 133, 5695.
Scheme 2 Derivatization of the conjugate addition products.
5 For reviews of thiourea-based organocatalysts, see: (a) P. R. Schreiner,
Chem. Soc. Rev., 2003, 32, 289; (b) P. M. Pihko, Angew. Chem., Int.
Ed., 2004, 43, 2062; (c) Y. Takemoto, Org. Biomol. Chem., 2005,
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2006, 45, 1520; (e) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418.
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(a) M. S. Sigman and E. N. Jacobsen, J. Am. Chem. Soc., 1998,
120, 4901; (b) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem.
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Chem., Int. Ed., 2005, 44, 6367; (d) B. Vakulya, S. Varga,
A. Csampai and T. Soos, Org. Lett., 2005, 7, 1967; (e) J. Ye,
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addition, but still had 10: 1 and 13: 1 dr, respectively (Table 2,
entries 5 and 21). The substituents in 5H-oxazol-4-ones, such as
ethyl, propyl and isopropyl groups, had no effects on the
stereoselectivity (Table 2, entries 7–28).
The utility through chemical derivatization of the Michael
product was exemplified through simple manipulation,
as demonstrated in Scheme 2. The chiral 5,5-disubstituted
oxazol-4-one was easily converted into an enlarged six-
membered ring 9a first under basic NaOH condition and then
acidic HBr condition. The Michael adduct of 7g protected
with ethane-1,2-dithiol in the presence of BF3ꢁEt2O could be
easily transformed to the corresponding a-hydroxy amide by
treatment with 2.5 N NaOH in ethanol at 60 1C,3 which can be
uneventfully converted to a-hydroxy acid 9d by reflux with
6 M HCl. The Michael adduct of cyclohexenone can be
converted into an indole compound through Fisher indole
synthesis under acetic acid conditions. Further hydrolysis
afforded the desirable a-hydroxy acid 9f.
7 (a) J. Wang, H. Li, L. Zu, W. Duan and W. Wang, J. Am. Chem.
Soc., 2006, 128, 12652; (b) Y. Zhang, Y.-L. Shao, H.-S. Xu and
W. Wang, J. Org. Chem., 2011, 76, 1472.
In conclusion, we developed a novel and highly useful
diastereoselective and enantioselective direct Michael addition
of 5H-oxazol-4-ones to a,b-unsaturated ketones with a new
chiral thiourea–tertiary amine catalyst derived from L-tert-
leucine. The reactions proceed very well with significantly
broad substrate scope and excellent stereoselectivity. In addition,
the Michael adducts can be easily transformed to structurally
interesting compounds or building blocks. Exploration of this
superior chiral catalyst system for other Michael acceptors is now
in progress in our laboratories.
8 For selected examples of organocatalyzed asymmetric Michael
addition of enones, see: (a) P. McDaid, Y. Chen and L. Deng,
Angew. Chem., Int. Ed., 2002, 41, 338; (b) N. Halland, P. S. Aburel
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2003, 42, 661; (c) M.
T. H. Fonseca and B. List, Angew. Chem., Int. Ed., 2004, 43, 3958;
(d) A. Prieto, N. Halland and K. A. Jørgensen, Org. Lett., 2005,
7, 3897; (e) F. Wu, H. Li, R. Hong and L. Deng, Angew. Chem., Int.
Ed., 2006, 45, 947; (f) J. Xie, W. Chen, R. Li, W. Du, Y. Chen,
Y. Wu, J. Zhu and J. Deng, Angew. Chem., Int. Ed., 2007, 46, 389;
(g) P. Li, Y. Wang, X. Liang and J. Ye, Chem. Commun., 2008,
3302; (h) H. Huang, F. Yu, Z. Jin, W. Li, W. Wu, X. Liang and
J. Ye, Chem. Commun., 2010, 46, 5957; (i) H. Huang, Z. Jin, K. Zhu,
X. Liang and J. Ye, Angew. Chem., Int. Ed., 2011, 50, 3232.
9 (a) C.-J. Wang, X.-Q. Dong, Z.-H. Zhang, Z.-Y. Xue and
H.-L. Teng, J. Am. Chem. Soc., 2008, 130, 8606; (b) Z.-H. Zhang,
X.-Q. Dong, D. Chen and C.-J. Wang, Chem.–Eur. J., 2008, 14, 8780.
We thank Shanghai Municipal Education Commission
(11ZZ56), Shanghai Pujiang Program (08PJ1403300), and
the 111 project (B07023) for financial support.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 461–463 463