Organocatalytic asymmetric Michael addition of 5 H -oxazol-4-ones to nitroolefins

Article abstract of DOI:10.1021/ol401062z

The first organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins has been developed. In the presence of easily prepared l-tert-leucine-derived tertiary amine/thiourea catalyst, the Michael addition of 5H-oxazol-4-ones to nitroolefins proceeded in an excellent diastereo- and enantioselective manner (up to 99% ee and >19:1 dr). The Michael adducts obtained are valuable precursors for the synthesis of chiral α-alkyl-α-hydroxy carboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds.

Full text of DOI:10.1021/ol401062z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic Asymmetric Michael
Addition of 5H‑Oxazol-4-ones to
Nitroolefins
Baokun Qiao,† Yongqiang An,‡ Qian Liu,‡ Wenguo Yang,‡ Hongjun Liu,‡ Juan Shen,§
Lin Yan,† and Zhiyong Jiang*,†,‡
Institute of Chemical Biology and Key Laboratory of Natural Medicine and
Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan,
P. R. China, 475004, and Waksman Institute of Microbiology, Rutgers, the State
University of New Jersey, Piscataway, New Jersey 08854, United States
chmjzy@henu.edu.cn
Received March 15, 2013
ABSTRACT
The first organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins has been developed. In the presence of easily prepared
L-tert-leucine-derived tertiary amine/thiourea catalyst, the Michael addition of 5H-oxazol-4-ones to nitroolefins proceeded in an excellent
diastereo- and enantioselective manner (up to 99% ee and >19:1 dr). The Michael adducts obtained are valuable precursors for the synthesis of
chiral r-alkyl-r-hydroxy carboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds.
Enantiomeric pure R-alkyl-R-hydroxy carboxylic acid
derivatives, containing an R-substituted tertiary hydroxy
group of the carboxylic acid, are key chiral structural
motifs, presenting in a number of natural and non-natural
products as well as medicinally important agents, such
as columbianadin derivatives, inonotusin A, glycosides,
4-hydroxy-4-methylglutamic acids, provitamin, and 3,4-
dihydroxy-pyrrolidin-2-ones (Figure 1).1 All these com-
pounds display crucial biological and medicinal properties
including analgesic, anti-inflammatory, and calcium-
channel blocking as well as folk medicine applications for
the treatment of hyperactivity, cough, tuberculosis, and
mumps.1 The development of synthetic methodologies for
the preparation of chiral R-alkyl-R-hydroxy carboxylic
acid derivatives has thus attracted the attention of organic
chemists in the past few years.2À5
The direct addition of R-alkyl-R-hydroxy-substituted es-
ters to unsaturated bonds would be the most atom-economic
(2) For selected examples, see: (a) Kumagai, N.; Matsunaga, S.;
Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169. (b) Fringuelli, F.;
Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org. Chem. 2003, 68, 7041. (c) Wang,
M.-X.; Deng, G.; Wang, D.-X.; Zheng, Q.-Y. J. Org. Chem. 2005, 70,
2439. (d) Qian, Y.; Jing, C.; Shi, T.; Ji, J.; Tang, M.; Zhou, J.; Zhai, C.;
Hu, W. ChemCatChem 2011, 3, 653. (e) Luo, J.; Wang, H.; Han, X.; Xu,
L.-W.; Kwiatkowski, J.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2011, 50, 1861. (f) Liu, C.; Dou, X.; Lu, Y. Org. Lett. 2011, 13, 5248. For
selected examples on enantioselective Henry reactions of R-ketoesters,
see: (g) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2002, 67, 4875. (h) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org.
Chem. 2005, 70, 3712. (i) Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.;
Feng, X. J. Org. Chem. 2007, 72, 9323. (j) Takada, K.; Takemura, N.;
Cho, K.; Sohtome, Y.; Nagasawa, K. Tetrahedron Lett. 2008, 49, 1623.
(k) Uraguchi, D.; Ito, T.; Nakamura, S.; Sakaki, S.; Ooi, T. Chem. Lett.
2009, 38, 1052.
† Institute of Chemical Biology, Henan University.
‡ Key Laboratory of Natural Medicine and Immuno-Engineering of Henan
Province, Henan University.
§ Waksman Institute of Microbiology, Rutgers, the State University of
New Jersey.
(1) For selected examples, see: (a) Yamada, S.; Nakayama, K.;
Takayama, H. Tetrahedron Lett. 1981, 22, 2591. (b) Helaine, V.; Bolte,
J. Tetrahedron: Asymmetry 1998, 9, 3855. (c) Coutrot, P.; Claudel, S.;
Didierjean, C.; Grison, C. Bioorg. Med. Chem. Lett. 2006, 16, 417. (d)
Zan, L.-F.; Qin, J.-C.; Zhang, Y.-M.; Yao, Y.-H.; Bao, H.-Y.; Li, X.
Chem. Pharm. Bull. 2011, 59, 770. (e) Wu, X.; Wang, Y.; Huang, X.-J.;
Fan, C.-L.; Wang, G.-C.; Zhang, X.-Q.; Zhang, Q.-W.; Ye, W.-C.
J. Asian Nat. Prod. Res. 2011, 13, 728. (f) Zhang, Y.-B.; Li, W.; Yang,
X.-W. Phytochemistry 2012, 81, 109.
(3) Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004,
126, 1944.
r
10.1021/ol401062z
XXXX American Chemical Society

Figure 2. Catalyst structures.
Table 1. Optimization of the Reaction Conditionsa
Figure 1. Selected natural and non-natural products.
protocol;2a however, low reactivity of the nucleophiles raised
doubts on applicability. The first breakthrough was reported
by Trost and co-workers in 2004, in which they introduced
5H-oxazol-4-ones as R-alkyl-R-hydroxy ester surrogates in a
chiral diphosphinemolybdenum catalyzed highly enantio-
selective allylic alkylations.3 Since then, the research groups
of Misaki, Ye, and Wang have successively developed
asymmetric aldol, Michael, and Mannich reactions by using
5H-oxazol-4-ones as nucleophiles.4 Very recently, our group
also introduced a highly enantio- and diastereoselective
organocatalytic Mannich reaction of 5H-oxazol-4-ones
to aryl/alkyl imines, successfully affording important
R-methyl-R-hydroxy β-amino acid derivatives, such as the
R-methylated C-13 side chains of Taxol and Taxotere.4e
In 2012, Trost and co-workers presented the first asym-
metric Michael reaction of 5H-oxazol-4-ones to nitroole-
fins catalyzed by a dinuclear zinc complex, affording a
range of highly functionalized R-alkyl-R-hydroxy car-
boxylic acid derivatives with excellent results.5 Neverthe-
less, to the best of our knowledge, no report has yet been
published on the organocatalytic asymmetric variant of this
productive Michael reaction, which is still highly desirable
and represents a formidable task. As part of our ongoing
research efforts toward the organocatalytic asymmetric con-
struction of tertiary alcohols,6,4e we thus became interested in
the development of an efficient organocatalytic asymmetric
Michael additions of 5H-oxazol-4-ones to nitroolefins.
Initially, to probe the feasibility of the proposed strategy
under the organic catalyst, 5H-oxazol-4-one 1awas treated
withnitroolefin2ainthe presence of Et3N inTHF at26 °C.
Wefoundthatthereaction workedsmoothly, accessingthe
desired adduct 3aa with 85% yield in 5:1 dr after 24 h
entry catalyst solvent temp (°C) time (h) yieldb (%) eec (%) drd
1
Et3N THF
26
26
26
26
26
26
26
26
26
26
26
26
10
2
24
18
18
18
18
18
18
18
18
18
18
18
24
40
40
85
90
97
84
84
96
90
93
47
91
96
96
92
95
75
NA
24 10:1
6:1
5:1
2
I
THF
3
II
THF
4
4
III
IV
V
THF
46 10:1
64 10:1
55 10:1
78 11:1
69 11:1
5
THF
6
THF
7
IV
IV
IV
IV
IV
IV
IV
IV
IV
toluene
CH2Cl2
CH3CN
EA
CPMEe
MTBEf
MTBE
MTBE
MTBE
8
9
50
76 12:1
75 9:1
9:1
10
11
12
13
14
15
81 10:1
83 10:1
88 16:1
85 16:1
À10
a The reaction was carried out with 0.05 mmol of 1a, 0.055 mmol of
2a, and 0.005 mmol of catalyst in 0.5 mL of solvent. b Isolated yield.
c Determined by HPLC methods. d Determined by 1H NMR analysis.
e CPME = cyclopentyl methyl ether. f MTBE = tert-butyl methyl ether.
(Table 1, entry 1). Next, we endeavored to investigate the
asymmetric reaction conditions. As a kind of bifunctional
catalyst, L-amino acid-derived tertiary amine/thioureas are
very easily prepared, and their efficacy has been proven in
many asymmetric reactions.7 Most recently, we reported
direct vinylogous conjugate additions using L-tert-leucine-
derived tertiary amine/thiourea I as the catalyst (Figure 2)
which could be easily prepared and displayed a strong
stereocontrolling ability.7f In this context, we investigated
the reaction between 5H-oxazol-4-one 1a and nitroolefin
2ainthe presenceof 10mol % of I atfirst (Table1, entry 1).
The process led to the desired Michael adduct 3aa with
(4) (a) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc.
2010, 132, 6286. (b) Misaki, T.; Kawano, K.; Sugimura, T. J. Am. Chem.
Soc. 2011, 133, 5695. (c) Huang, H.; Zhu, K.; Wu, W.; Jin, Z.; Ye, J.
Chem. Commun. 2012, 48, 461. (d) Zhao, D.; Wang, L.; Yang, D.;
Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2012, 51, 7523. (e) Han, Z.;
Yang, W.; Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2013, DOI: 10.1002/
adsc.201300135, manuscript in revision.
(5) Trost, B. M.; Hirano, K. Angew. Chem., Int. Ed. 2012, 51, 6480.
(6) (a) Yang, Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C.-H.
Org. Lett. 2012, 14, 4762. (b) Zhang, W.; Tan, D.; Lee, R.; Tong, G.; Chen,
W.; Qi, B.; Huang, K.-W.; Tan, C.-H.; Jiang, Z. Angew. Chem., Int. Ed.
2012, 51, 10069. (c) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.;
Tan, D.; Huang, K.-W.; Jiang, Z. Angew. Chem., Int. Ed. 201310.1002/
anie.201302274.
(7) For selected examples on L-tert-leucine-derived amine-thiourea as
catalyst, see: (a) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem.;Eur. J.
2010, 16, 13068. (b) Du, Z.; Siau, W.-Y.; Wang, J. Tetrahedron Lett.
2011, 52, 6137. For a selected example on L-tryptophan-derived amine-
thiourea as catalyst, see: (c) Han, X.; Kwiatkowski, J.; Xue, F.; Huang,
K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2009, 48, 7604. For selected examples
ꢀ
on L-valine-derived amine-thiourea as catalyst, see: (d) Andres, J. M.;
Manzano, R.; Pedrosa, R. Chem.;Eur. J. 2008, 14, 5116. (e) Manzano, R.;
ꢀ
ꢀ
ꢀ
ꢀ
Andres, J. M.; Alvarez, R.; Muruzabal, M. D.; de Lera, A. R.; Pedrosa, R.
Chem.;Eur. J. 2011, 17, 5931. For a selected example on L-tyrosine-
derived amine-thiourea as catalyst, see: (f) Zhao, S.-L.; Zheng, C.-W.;
Wang, H.-F.; Zhao, G. Adv. Synth. Catal. 2009, 351, 2811.
B
Org. Lett., Vol. XX, No. XX, XXXX

24% ee and 10:1 dr. Subsequently, we screened catalysts
II and III derived from L-phenylalanine and L-valine
(entries 2 and 3) and found that catalyst III gave higher
enantioselectivity (46% ee, entry 3). These results indicate
that the side chain of the catalyst should be important
to influence the stereoselectivity. In an attempt to improve
the catalyst, we replaced pyrrolidinyl (the Brønsted base
functional group) in I and III with piperidinyl to afford
catalysts IV and V (Figure 2). Results from reactions with
the piperidine catalysts revealed that the ee of adduct 3aa
improved to 64% when catalyst IV was used (Table 1,
entry 5). Accordingly, catalyst IV was used for further
investigations in different solvents and temperatures
(entries 6À14). We found that the reactions performed in
less polar solvents proceeded well and with high enantio-
selectivities. MTBE proved best with respect to catalytic
reactivity and enantioselectivity (98% yield, 81% ee,
entry 11). Lower reaction temperatures slightly improved
the enantio- and diastereoselectivity and the optimal tem-
perature is at 2 °C (88% ee, entry 13).
Table 3. Asymmetric Michael Addition of 5H-Oxazol-4-ones 1
to Nitroolefins 2a
Table 2. Asymmetric Michael Addition of 5H-Oxazol-4-ones 1
to Nitroolefin 2aa
entry
1, (Ar)
3
time (h) yieldb (%) eec (%) drd
1
2
3
4
5
6
1b (4-MePh) 3ba
40
60
40
40
21
40
87
90
93
98
92
83
88
90
90
94
84
83
11:1
>19:1
>19:1
>19:1
10:1
1c (3-FPh)
1d (3-ClPh)
1e (3-MePh)
3ca
3da
3ea
1f (3-MeOPh) 3fa
1g (2-MePh) 3ga
7:1
a The reaction was carried out with 0.05 mmol of 1, 0.055 mmol of 2a
and 0.005 mmol IV in 0.5 mL of solvent. b Isolated yield. c Determined by
HPLC methods. d Determined by 1H NMR analysis.
Next, we began to investigate the influence of the aryl
group of 5H-oxazol-4-ones (1bÀg) in affecting stereo-
selectivity. The results are summarized in Table 2. 5H-
Oxazol-4-one 1b with a methyl group at the para position
of the phenyl ring gave similar enantioselectivity, but the
diastereoselectivity decreased (entry 1). When substituent
groups (F, Cl, methyl, methoxy) were introduced at the
meta position of the phenyl ring (1cÀf, entries 2À5), both
enantio- and diastereoselectivity improved with the excep-
tion of 5H-oxazol-4-one 1f (entry 5). Adduct 3ea with a
m-methylphenyl group was obtained with the best results
(94% yield, 94% ee, >19:1 dr, entry 4). The diastereo- and
enantioselectivity decreased when 5H-oxazol-4-one 1g
with an o-methylphenyl group was used (entry 6).
a The reaction was carried out with 0.10 mmol of 1, 0.11 mmol of 2,
and 0.01 mmol of IV in 1.0 mL of solvent. b Isolated yield of major
diastereomer of 3 (dr >19:1, determined by 1H NMR analysis).
c Determined by HPLC methods. d dr = 16:1. e dr = 10:1
nitroolefins 2 (Figure 3) by using 10 mol % of L-tert-
leucine-derived tertiary amine/thiourea catalyst IV (Table 3).
We first examined the viability of various aryl nitroolefins
(2aÀo) with different electronic and steric properties using
5H-oxazol-4-one 1e as the nucleophile (entries 1À15).
Adducts 3eaÀeo could be obtained with 79À99% yield,
90À96% ee and 10:1 to >19:1 dr. Our studies showed
that the introduction of various substituents onto phenyl
groups of aryl nitroolefins did not affect the enantio- and
diastereoselectivities. We are delighted to find that the
R,β,γ,δ-unsaturated nitroolefin 2p produced adduct 3ep
in 89% yield with 94% ee and >19:1 dr (entry 16).
With the optimized reaction conditions in hand, we
evaluated the performance of the organocatalytic asym-
metric Michael reactions between 5H-oxazol-4-ones 1 and
Org. Lett., Vol. XX, No. XX, XXXX
C

Moreover, we conducted the reaction of 1e with the ali-
phatic nitroolefin 2q and reasonable results were obtained
(entry 17). Other 5H-oxazol-4-ones 1hÀk with different
substituents at the C5-position, such as ethyl, isopropyl,
n-butyl and benzyl, also gave the corresponding adducts
3haÀka in good to excellent yields with excellent enantio-
and diastereoselectivites (entries 18À21). The results indi-
cate that more hindered substituent at the C5-position of
5H-oxazol-4-one should help increase the reaction enantio-
selectivity but make the reactivity lower. The absolute con-
figurations of Michael adducts could be assigned from the
analyses of 1H NMR and HPLC of the diastereomers of 3ea
with the known data reported by Trost and co-workers.8
Based on the observed stereochemistry of the Michael
adduct, a plausible transition-state model was proposed
(Figure 3). The hydrogen at the C5-position of 5H-oxazol-
4-one was deprotonated by piperidine group of the catalyst
IV, and the activated 5H-oxazol-4-one enolate should then
attack the thiourea-activated nitroolefin from the Re face.
This proposed transition state makes the results in Table 2,
on the substituent effect of the aryl ring of 5H-oxazol-4-
one, easily understood.
modified ester and nitro groups. Interestingly, the amide
6 could be achieved when treated 3ea with 10 equiv of
NaOH(2 N inH2O) at60°C for6 h without compromising
the ee value.
Scheme 1. Transformation of the Michael Adducts
In conclusion, we have developed the first organocata-
lytic asymmetric Michael addition of 5H-oxazol-4-ones to
nitroolefins with excellent diastereo- and enantioselectiv-
ities (up to 99% ee and >19:1 dr) by using easily prepared
L-tert-leucine-derived tertiary amine/thiourea catalyst.
From the Michael adducts, several R-alkyl-R-hydroxycar-
boxylic acid derivatives as significant intermediates to
access various corresponding natural and non-natural
products, as well as medicinally important agents, could
be obtained from simple modifications. Investigations into
the extension of 5H-oxazol-4-onesinotherorganocatalytic
asymmetric reactions to achieve other R-alkyl-R-hydroxy
carboxylic acid derivatives are ongoing.
Figure 3. Selected natural and non-natural products.
Acknowledgment. This work was supported by NSFC
(nos. 21072044, 21202034), the Program for New Century
Excellent Talents in University of Ministry of Education
(NCET-11-0938), and Excellent Youth Foundation of
Henan Scientific Committee (114100510003).
Subsequently, the transformations of the Michael ad-
ducts into R-alkyl-R-hydroxy carboxylic acid derivatives
were conducted as shown in Scheme 1. When the hydro-
lysis of 3ea was conducted in the presence of 5.0 equiv of
NaOH (1 N in H2O) in THF at À15 °C, an R-methyl-R-
hydroxyimide 4 was obtainedin 73% yield. Inthe presence
of Er(OTf)3, imide 4 could be conveniently converted to
the corresponding ester 5 with 94% ee, which represents a
versatile chiral building block due to bearing readily
Supporting Information Available. General informa-
tion, typical experimental procedures, characterization,
and HPLC and NMR spectra of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org
The authors declare no competing financial interest.
(8) See the Supporting Information for details.
D
Org. Lett., Vol. XX, No. XX, XXXX