Organocatalytic stereoselective epoxidation of trisubstituted acrylonitriles

Article abstract of DOI:10.1021/jo102020a

The first diastereospecific and enantioselective epoxidation of trans-2-aroyl-3-arylacrylonitriles by means of the commercially available diaryl l-prolinol/tert-butyl hydroperoxide system has been developed. These diversely functionalized epoxides were ob

Full text of DOI:10.1021/jo102020a

pubs.acs.org/joc
limited substrate scope, essentially focused on R,β-unsaturated
Organocatalytic Stereoselective Epoxidation of
Trisubstituted Acrylonitriles
ketones as substrates.3 Indeed, only a few protocols are
suitable for the asymmetric epoxidation of R,β-unsaturated
aldehydes,4 cyclic enones,5 R,β-unsaturated esters,6 amides,
and derivatives thereof.7 The lantanoids/BINOLs/tert-butyl8
hydroperoxide (TBHP) and polyleucine/H2O2/NaOH9 sys-
tems are likely among the most versatile protocols showing
wider applicability. Surprisingly, studies have been almost
exclusively restricted on the epoxidation of trans-disubsti-
tuted electron-poor alkenes. Hence, expanding the substrate
scope of the asymmetric nucleophilic epoxidation also to
trisubstituted electron-poor alkenes would be highly desir-
able, even in consideration of the access to versatile inter-
mediates bearing quaternary stereocenters. To the best of
our knowledge, Deng and coauthors10 recently reported the
first example of highly diastereo- and enantioselective epox-
idation of trans-R-carbonyl-β-substitued acrylates mediated
by TADDOL-derived hydroperoxide11 (TADOOH) under
basic conditions (Scheme 1).
Claudia De Fusco, Consiglia Tedesco, and
Alessandra Lattanzi*
ꢀ
Dipartimento di Chimica, Universita di Salerno, Via Ponte
don Melillo, 84084, Fisciano, Italy
lattanzi@unisa.it
Received October 11, 2010
The corresponding epoxides proved to be key compounds
employed for the first asymmetric total synthesis of (-)-plicatic
acid, an agent causing inflammatory and allergic reactions.12
Over the recent years, we developed a simple and convenient
(3) For reviews, see: (a) Porter, M. J.; Skidmore, J. Chem. Commun. 2000,
1215. (b) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Synth. Org. Chem. Jpn.
2002, 60, 94. (c) Berkessel, A. In Asymmetric Synthesis-The Essentials, 2nd
€
ed.; Christmann, M., Brase, S., Eds.; WILEY-VCH: Weinheim, Germany,
2007; p 185. (d) Lattanzi, A. Curr. Org. Synth. 2008, 5, 117. (e) Dıez, D.;
The first diastereospecific and enantioselective epoxida-
tion of trans-2-aroyl-3-arylacrylonitriles by means of the
commercially available diaryl L-prolinol/tert-butyl hy-
droperoxide system has been developed. These diversely
functionalized epoxides were obtained in excellent yield
(up to 99%), complete diastereoselectivity for the trans-
isomer, and good enantioselectivity (up to 84% ee).
Highly enantioenriched epoxides can be easily obtained
after a single crystallization (ee > 90%).
ꢁ~
Nunez, M. G.; Anton, A. B.; Garcıa, P.; Moro, R. F.; Garrido, N. M.;
Marcos, I. S.; Basabe, P.; Urones, J. G. Curr. Org. Synth. 2008, 5, 186. (f)
ꢁ
ꢁ
Lattanzi, A. In Catalytic Asymmetric Conjugate Reactions; Cordova, A., Ed.;
WILEY-VCH: Weinheim, Germany, 2010; p 351.
ꢁ
(4) (a) Marigo, M.; Franzen, G.; Poulsen, T. B.; Zhuang, W.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Lee, S.; MacMillan, D. W. C.
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Tetrahedron 2006, 62, 11413. (c) Zhao, G.-L.; Ibrahem, I.; Sunden, H.;
Cordova, A. Adv. Synth. Catal. 2007, 349, 1210. (d) Wang, X.; List, B.
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Angew. Chem., Int. Ed. 2008, 47, 1119. (e) Sparr, C.; Schweizer, W. B.; Senn,
H. M.; Gilmour, R. Angew. Chem., Int. Ed. 2009, 48, 3065. (f) Lifchits, O.;
Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132, 10227.
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6070.
The asymmetric epoxidation of alkenes is a fundamental
process given the pivotal role of chiral epoxides as targets of
biological and pharmaceutical interest and most of all as
synthetic intermediates amenable to a variety of manipula-
tions of the epoxide ring.1 Several electrophilic and nucleo-
philic chiral metal-based and organocatalytic systems have
been developed to date for the epoxidation of an array of
alkenes.2 In the area of nucleophilic epoxidation of electron-
poor alkenes, numerous catalytic systems are available to
effect this transformation, although most of them have
(6) Kakei, H.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 8962.
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123, 9474. (b) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.;
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Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544.
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Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. For selected
examples, see: (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329. (b) Watanabe, S.; Arai,
T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. J. Org. Chem. 1998, 63, 8090. (c)
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Catal. A: Chem. 2003, 196, 145. (e) Wang, X.; Shi, L.; Li, M.; Ding, K. Angew.
Chem., Int. Ed. 2005, 44, 6362. (f) Wang, X.; Shi, L.; Li, M.; Ding, K. Angew.
Chem., Int. Ed. 2005, 44, 6362.
(1) For reviews, see: (a) Katsuki, T. Comprehensive Asymmetric Catal-
ysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. 2, p 621. (b) Jacobsen, E. N.; Wu, M. H. Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H, Eds.;
Springer: Berlin, Germany, 1999; p 649. (c) Katsuki, T. Curr. Org. Chem.
ꢁ
(9) For selected examples, see: (a) Julia, S.; Masana, J.; Vega, J. C.
Angew. Chem., Int. Ed. 1980, 19, 929. (b) Lasterra-Sanchez, M. E.; Roberts,
€
ꢁ
2001, 5, 663. (d) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem.
Rev. 2001, 101, 3499. (e) Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; WILEY-VCH: Weinheim, Germany, 2006; Chapters
7-9.
(2) (a) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (b) Xia, Q.-
H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603.
(c) Wong, O. A.; Shi, Y. In Chiral Ketone and Iminium Catalysts for Olefin
Epoxidation; List, B., Ed.; Topics in Current Chemistry, No. 291; Springer:
Berlin, Germany, 2009.
S. M. J. Chem. Soc., Perkin Trans. 1 1995, 1467. (c) Adger, B. M.; Barkley,
J. V.; Bergeron, S.; Cappi, M. W.; Flowerdew, B. E.; Jackson, M. P.;
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1 1997, 3501. (d) Allen, J. V.; Drauz, K.-H.; Flood, R. W.; Roberts, S. M.;
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S. M. Biopolymers 2006, 84, 74.
(10) Sun, B.-F.; Hong, R.; Kang, Y.-B.; Deng, L. J. Am. Chem. Soc. 2009,
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676 J. Org. Chem. 2011, 76, 676–679
Published on Web 12/22/2010
DOI: 10.1021/jo102020a
r
2010 American Chemical Society

De Fusco et al.
JOCNote
SCHEME 1. Trisubstituted Electron-Poor Alkenes Investigated
up to Now in the Asymmetric Epoxidation
TABLE 1. Optimization of Reaction Conditionsa
entry
1
solvent
t (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1e
1e
1e
1e
1e
1e
1e
1e
1e
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
hexane
CHCl3
toluene
ClC6H5
CF3C6H5
p-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
toluene/m-xylene 1/3
3
6
3
3
3
4
3
6
3
3
3
3
3
17
18
18
48
60
99
88
99
97
96
99
99
96
99
99
99
97
99
69
99
88
99
99
21
43
35
48
56
2
54
48
57
60
58
63
64
47
78
71
74
73
organocatalytic system for the asymmetric epoxidation of
disubstituted electron-poor alkenes, such as trans-R,β-un-
saturated ketones based on R,R-L-diaryl prolinols as promo-
ters and tert-butyl hydroperoxide (TBHP) as the oxidant.13
The trans-epoxides were obtained in good to high enantio-
selectivity. Recently, we showed that symmetrically trisubstituted
electron-poor alkenes, such as acyclic and cyclic 2-arylidene-
1,3-diketones, can be epoxidized by this system in high to
excellent yield and up to 85% ee (Scheme 1).14 These epoxides
are pharmaceutically important building blocks and inter-
mediates for the synthesis of densely functionalized epoxide
derivatives. With this background in mind and taking into
account the lack of stereoselective protocols for the epoxidation
of trisubstituted electron-poor alkenes, we became interested
in studying trans-R-carbonyl-β-substitued acrylonitriles, where
both issues of diastereo- and enantioselectivity should have
been addressed. The choice to introduce a cyano group in the
alkene was stimulated by the fact that an ever-increasing
number of important pharmaceuticals and natural products
are nitrile-containing compounds and its potential usefulness as
a synthetic group susceptible of further transformation to
amine, aldehyde, amide, and carboxylic acid moieties.15 Herein,
we describe the first asymmetric protocol for the epoxidation
of trans-2-aroyl-3-arylacrylonitriles16 by using the R,R-L-diaryl
prolinols/TBHP system that gives access to diversely func-
tionalized trans-epoxides in excellent yield, complete diaste-
reoselectivity, and up to 84% ee.
10
11
12
13
14d
15e
16e, f 1e
17g
1e
1e
18h
aUnless otherwise noted, reactions were carried with 2a (0.1 mmol),
TBHP (1.2 equiv), 1 (30 mol %), and solvent (0.5 mL). bIsolated yield after
flash chromatography. cDetermined by chiral HPLC analysis. dCumyl
hydroperoxide was used. eThe reaction was carried out with 2a (0.1 mmol),
TBHP (1.2 equiv), 1e (10 mol %), and m-xylene (2 mL) at -20 °C.
fCatalyst 1e was used at 5 mol % loading. gThe reaction was carried out
with 2a (0.1 mmol), TBHP (1.2 equiv), 1e (20 mol %), and m-xylene
(0.5 mL) at -30 °C. hThe reaction was carried out with 2a (0.1 mmol),
TBHP (1.2 equiv), 1e (10 mol %), and m-xylene (0.5 mL) at -60 °C.
available or easily accessible R,R-L-diaryl prolinols17 1 were
screened at 30 mol % loading in the epoxidation of model
compound 2a with TBHP at room temperature (Table 1).
Epoxide 3a was recovered, after a short reaction time, in
According to our previously established conditions for the
epoxidation of R,β-unsaturated ketones,13a commercially
1
excellent yield exclusively as trans-isomer as judged by H
NMR analysis on the crude reaction mixture (entries 1-6).
As expected, the asymmetric induction was significantly
influenced by the type of substitution in the organocatalysts,
with commercially available compound 1e leading to the
product with up to 56% ee (entry 5), whereas the bicyclic
derivative 1f proved to be completely unselective (entry 6).
Screening of nonpolar solvents showed that aromatic
media were the most effective and the reaction carried out
in m-xylene enabled the improvement of the ee value up to
64% (entry 13). Cumyl hydroperoxide afforded an inferior
result with respect to TBHP (entry 14). Pleasingly, working
at -20 °C with reduced catalyst loading (10 mol %) and under
more diluted conditions led to the recovery of epoxide 3a in
excellent yield and 78% ee (entry 15). The use of 5 mol % of
catalyst under similar conditions slightly affected the efficiency
of the process (entry 16). At temperatures lower than -20 °C,
the reactions proceeded with diminished enantiocontrol,
likely due to an increased heterogeneity of the reaction
mixture (entries 17 and 18).
(11) Aoki, M.; Seebach, D. Helv. Chim. Acta 2001, 84, 187.
(12) (a) Gradner, J. A. F.; Barton, G. M.; MacLean, H. Can. J. Chem.
1959, 37, 1703. (b) Chan-Yeung, M.; Giclas, P. C.; Henson, P. M. J. Allergy
Clin. Immun 1980, 65, 333. (c) Cartier, A.; Chan, H.; Malo, J.-L.; Pineau, L.;
Tse, K. S.; Chan-Yeung, M. J. Allergy Clin. Immunol. 1986, 77, 639. (d)
Weissman, D. N.; Lewis, D. M. Occup. Med. 2000, 15, 385. (e) Chan-Yeung,
M.; Chan, H.; Tse, K. S.; Salari, H.; Lam, S. J. Allergy Clin. Immunol. 1989,
85, 762.
(13) (a) Lattanzi, A. Org. Lett. 2005, 7, 2579. (b) Lattanzi, A. Adv. Synth.
Catal. 2006, 348, 339. (c) Lattanzi, A.; Russo, A. Tetrahedron 2006, 62,
12264. (d) Li, Y.; Liu, X.; Yang, Y.; Zhao, G. J. Org. Chem. 2007, 72, 288.
(14) Russo, A.; Lattanzi, A. Org. Biomol. Chem. 2010, 8, 2633.
(15) (a) Nagasawa, T.; Yamada, H. Pure Appl. Chem. 1990, 62, 1441. (b)
Fleming, F. F. Nat. Prod. Rep. 1999, 597. (c) Erdelmeier, I.; Tailhan-Lomont,
C.; Yadan, J.-C. J. Org. Chem. 2000, 65, 8152. (d) Sammis, G. M.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 4442. (e) Kukushkin, V. Y.; Pombeiro,
A. J. L. Inorg. Chim. Acta 2005, 358, 1. (f) Fleming, F. F.; Yao, L.;
Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902.
(16) For diastereoselective epoxidation of chiral electron-deficient al-
kenes, see: (a) Fraile, G. M.; Garcıa, J. I.; Marco, D.; Mayoral, J. A. Appl.
Catal., A 2001, 207, 239. (b) Nagumo, Y.; Kakeya, H.; Yamaguchi, J.; Uno,
T.; Shoji, M.; Hayashi, Y.; Osada, H. Bioorg. Med. Chem. Lett. 2004, 14,
4425.
(17) Mature, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer,
R. A.; Mohan, J. J.; Turner Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751.
With optimized conditions in hand, an array of alkenes
2 straightforwardly synthesized via Knoevenagel condensation
J. Org. Chem. Vol. 76, No. 2, 2011 677

De Fusco et al.
JOCNote
TABLE 2. Asymmetric Epoxidation of trans-2-Aroyl-3-arylacrylonitriles
with 1e/TBHPa
entry
R1
R2
3
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
99 (70)
92
77
99 (67)
99
96
99
78
99
78 (94)
73
56
76 (99)
70
77
81
84
73
4-tBuC6H4
2-CH3C6H4
4-BrC6H4
4-CNC6H4
2-naphthyl
3-furyl
FIGURE 1. Proposed ternary complex involved in the asymmetric
epoxidation.
3g
trans-cinnamyl 3h
3i
SCHEME 2. Diastereoselective Reduction of Epoxide 3a to
R,β-Epoxy Alcohol 4a
3-ClC6H4
4-CH3OC6H4 Ph
4-CH3OC6H4 4-BrC6H4
Ph
Me
Ph
3j
3k
3l
99 (60)
99
95
79 (>99)
79
48
cyclohexyl
Ph
3m
90
83
aConditions: 2 (0.2 mmol), TBHP (1.2 equiv), 1e (10 mol %), and
m-xylene (4 mL). bIsolated yield after flash chromatography; yield after
crystallization in parentheses. cDetermined by chiral HPLC analysis; ee
after crystallization in parentheses.
To demonstrate the synthetic utility of epoxides 3, reduction
of the carbonyl moiety of highly enantiomerically enriched
3a was carried out with L-Selectride in THF at -78 °C
(Scheme 2). The secondary alcohol 4a, bearing three con-
tiguous stereocenters, was obtained in 93% yield and fairly
good diastereoisomeric ratio. Reduction of compound 3a
performed with other agents such as NaBH4, DIBAL, and
K-Selectride afforded compound 4a with increasing 55/45,
63/37, 82/18 diastereoisomeric ratio, respectively.19
Although the absolute configuration of the major diaste-
reoisomer 4a was not determined, it is likely that the anti-
isomer was preferentially obtained via a chelated cyclic
transition state assuming the Cram chelation model20 as
previously reported in the reduction of differently substituted
R,β-epoxy ketones with hydrides.21,22 The stereoselective
accesss to R,β-epoxy alcohols is a challenging but important
task as these compounds are usefully exploited in the synthesis
of natural products as well as of polyhydroxylated targets.23
It is interesting to note that compounds of type 4a are difficult
to prepare via the alternative approach based on the asym-
metric Sharpless epoxidation24 of the corresponding poorly
reactive 2-cyanoallylic alcohols. Indeed, only a few examples
of primary 2-cyanoallylic alcohols have been epoxidized
were reacted to examine the scope of the epoxidation (Table 2).
In all cases, the trans-epoxide was exclusively formed in high
to excellent yield and good enantiocontrol with either electron-
rich or electron-poor phenyl-substituted derivatives 2. The
o-phenyl-substituted epoxide 3c was isolated with slightly
lower ee (entry 3). Heteroaromatic and trans-cinnamyl alkenes
2g,h selectively afforded the epoxides with 81% and 84% ee,
respectively (entries 7 and 8). The epoxidation of the β-alkyl-
substituted alkene 2l proceeded with somewhat lower en-
antioselectivity (entry 12). Interestingly, the extension of the
asymmetric epoxidation to R-acetyl derivatives appears plau-
sible as compound 2m furnished the corresponding epoxide
in high yield and fairly good ee (entry 13). Epoxides 3 are
solids and pleasingly a single crystallization, using hexane/
isopropanol mixtures, allowed a good recovery of epoxides
with ee increased to excellent values, an aspect of practical
interest (Table 2, entries 1, 4, and 10).
Absolute configuration of epoxides was assigned to be
2R,3S by analogy to that determined by single crystal X-ray
analysis performed on epoxide 3d (see the Supporting
Information). The stereochemical outcome of the reaction
is consistent with that previously observed in the epoxidation
of trans-disubstituted R,β-enones mediated by the same
system.13b Although further investigations are necessary to
address the mechanism of this epoxidation, on the basis of
previous experimental findings13a-c and the known inactivity
of sterically hindered carbonyl compounds toward iminium
ion formation with secondary amines,18 we suggest that
compound 3e serves as a bifunctional noncovalent promoter
(Figure 1).
(19) For an example of diastereoselective reduction of acyclic R,β-epoxy
ketones with Selectrides, see: Capriati, V.; Florio, S.; Luisi, R.; Nuzzo, I. J.
Org. Chem. 2004, 69, 3330.
(20) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828.
(b) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748.
(21) For selected examples, see: (a) Luche, J. L.; Rodriguez-Hahn, L.;
ꢁ
Crabbe, P. J. Chem. Soc., Chem. Commun. 1978, 601. (b) Nakata, T.;
Tanaka, T.; Oishi, T. Tetrahedron Lett. 1981, 22, 4723. (c) Oishi, T.; Nakata,
T. Acc. Chem. Res. 1984, 17, 338. (d) Taniguchi, M.; Fujii, H.; Oshima, K.;
Utimoto, K. Tetrahedron 1995, 51, 679.
(22) A significant increase of diastereocontrol was observed in the reduc-
tion of compound 3a when using chelating reducing agents such as K- and
L-Selectride which would be in agreement with the chelation of the oxygen of
both the epoxide and ketone moieties to the metal.
(23) (a) Rossiter, B. E. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 5, p 193. (b) Lauret, C. Tetrahedron:
Asymmetry 2001, 12, 2359.
The establishment of an effective network of hydrogen
bonds among the catalyst and the reagents would lead to the
formation of a ternary complex, where the alkene is suitably
positioned to undergo preferential nucleophilic attack of the
Si-face by the oxidant.
(18) For recent reviews, see: (a) Bartoli, G.; Melchiorre, P. Synlett 2008,
1759. (b) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807.
(24) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
678 J. Org. Chem. Vol. 76, No. 2, 2011

De Fusco et al.
JOCNote
column, 95:5 n-hexane:2-propanol, 1 mL/min, detection at 254
nm; minor enantiomer tR = 18.4 min, major enantiomer tR =
using stoichiometric amounts of the Ti(Oi-Pr)4/L-DET/
TBHP reagent, giving the products in good to high enantio-
selectivity, but in modest yield.25
14.0 min.
3g: 47.3 mg, (99%); yellow solid, mp 56-58 °C; [R]25D -89.8
(c 0.68, CHCl3), ee 81%; νmax (KBr)/cm-1 3139, 1701, 1598, 1268,
1166, 1024, 876, 699; 1H NMR (CDCl3, 400 MHz) δ 4.32 (s, 1H),
6.63 (m, 1H), 7.53-7.56 (m, 3H), 7.68-7.72 (m, 1H), 7.76 (s, 1H),
8.05 (dd, J=8.3, 1.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ
57.9, 58.7, 108.4, 114.5, 117.1, 129.1, 129.2, 132.7, 135.0, 143.6,
144.2, 186.8. Anal. Calcd for C14H9NO3: C, 70.29; H, 3.79; N,
5.86. Found: C, 70.60; H, 3.82; N, 5.46. HPLC analysis with
Chiralpak AS-H column, 95:5 n-hexane:2-propanol, 1 mL/min,
detection at 254 nm; minor enantiomer tR =27.6 min, major
enantiomer tR=17.9 min.
In conclusion, the first asymmetric epoxidation of trans-
2-aroyl-3-arylacrylonitriles has been developed by employ-
ing commercially available reagents, such as TBHP and R,R-
L-diaryl prolinol 1e. This simple and convenient protocol
enables the formation of a novel class of highly functionalized
epoxides with complete control of the diastereoselectivity
and good level of enantioselectivity. From a practical point
of view, epoxides can be recovered in excellent ee after a
single crystallization.
3m: 33.7 mg, (90%); pale yellow solid, mp 77.3-78.9 °C;
[R]24D -188.9 (c 0.628, CHCl3), ee 83%; νmax (KBr)/cm-1 3025,
2360, 1457,1127, 864, 813, 606; 1H NMR (CDCl3, 400 MHz) δ
2.38 (s, 3H), 4.42 (s, 1H), 7.41-7.47 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 25.0, 59.0, 64.1, 113.4, 126.6, 128.8, 129.8, 130.4,
195.5. Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48.
Found: C, 70.36; H, 4.98; N, 7.63. HPLC analysis with Chi-
ralpak AS-H column, 90:10 n-hexane:2-propanol, 1 mL/min,
detection at 254 nm; minor enantiomer tR =20.6 min, major
enantiomer tR=14.1 min.
Experimental Section
General Procedure for the Asymmetric Epoxidation. A sample
vial was charged with alkene 2 (0.2 mmol) and catalyst 1e (6.2 mg,
0.02 mmol), then m-xylene (4 mL). TBHP (5 M decane solution,
44 μL, 0.24 mmol) was added and the mixture was stirred
at -20 °C. Upon completion by TLC (petroleum ether/diethyl
ether 4:1), the solvent was removed under reduced pressure and
the crude reaction mixture was directly purified by flash chro-
matography on silica gel eluting with petroleum ether and
petroleum ether/diethyl ether mixtures (4:1) to provide the
epoxide. Crystallization with n-hexane/i-PrOH at room tempera-
ture gave prismatic crystals in enantioenriched form.
3a: 49.3 mg (99%); white solid, mp 93-95 °C; after crystal-
lization ee 94%; [R]21D -163.4 (c 0.50, CHCl3); νmax (KBr)/cm-1
3065, 1699, 1449, 1256, 1156, 760, 696; 1HNMR(CDCl3,400MHz)
δ 4.41 (s, 1H), 7.51-7.57 (m, 7H), 7.68-7.71 (m, 1H), 8.05 (dd,
J=7.9, 1.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 58.6, 64.2,
114.1, 126.7, 129.0, 129.1, 129.3, 130.0, 130.5, 132.8, 135.0, 186.8.
Anal. Calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62. Found:
C, 76.82; H, 4.47; N, 5.56. HPLC analysis with Chiralpak AS-H
Acknowledgment. MIUR and University of Salerno are
acknowledged for financial support. We thank Dr. P. Ian-
nece for elemental analyses. X-ray diffraction data were
collected at IBB-CNR (Naples, Italy); Mr. M. Amendola
and Mr. G. Sorrentino are acknowledged for technical
assistance.
Supporting Information Available: General experimental
methods, experimental procedures, characterization data, 1H
and 13C NMR spectra for new compounds, HPLC traces, and
crystallographic information file. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Aiai, M.; Robert, A.; Baudy-Floc’h, M.; Le Grel, P. Tetrahedron:
Asymmetry 1995, 6, 2249.
J. Org. Chem. Vol. 76, No. 2, 2011 679