Enantioselective epoxidation of dihydroquinolines by using iminium salt organocatalysts

Article abstract of DOI:10.1002/ejoc.201403132

The first examples of asymmetric epoxidation of dihydroquinoline substrates using iminium salt organocatalysts are reported. The 3,4-epoxytetrahydroquinoline products are obtained in good yields and with moderate to good enantioselectivities.

Full text of DOI:10.1002/ejoc.201403132

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403132
Enantioselective Epoxidation of Dihydroquinolines by Using Iminium Salt
Organocatalysts
Philip C. Bulman Page,*[a] David P. Day,[a] and Yohan Chan[a]
Keywords: Asymmetric catalysis / Homogeneous catalysis / Alkenes / Epoxidation / Heterocycles
The first examples of asymmetric epoxidation of dihydro-
quinoline substrates using iminium salt organocatalysts are
reported. The 3,4-epoxytetrahydroquinoline products are ob-
tained in good yields and with moderate to good enantio-
selectivities.
Introduction
The tetrahydroquinoline core motif is commonly found
in a wide range of natural products; a recent review on
tetrahydroquinolines by Menéndez[1] shows a surge in inter-
est in this area of heterocyclic chemistry, with as many as
400 publications in the last 5 years. Some of the most inter-
esting tetrahydroquinoline-derived natural products have
shown potent biological activity, for example benzastatins
(C and D) and virantmycin (1).[2] The natural products
tuberosine B (2),[3] and helquinoline (3)[4] have recently been
isolated, but their biological activity has not yet been re-
ported. Drug molecules containing a tetrahydroquinoline
ring system have also been reported to have antiviral (anti-
HIV; 4),[5] antitrypanosomal (5),[6] and multidrug resistance
(6) properties (Figure 1).[7]
Synthesis of racemic or achiral tetrahydroquinolines has
been achieved by diverse methodologies.[8] The generation
of epoxides from various nitrogen-protected dihydroquinol-
ine substrates has only previously been reported by utilizing
m-CPBA,[9] or by hydrobromination with aqueous N-
bromosuccinimide (NBS) followed by base-catalysed elimi-
nation.[10]
A limited number of methodologies have been used to
achieve the asymmetric synthesis of non-racemic chiral
tetrahydroquinolines.[11] Guingant achieved the synthesis of
(R)-sumanirole, an anti-Parkinson’s drug,[12] by using a
chiral auxiliary carried on the nitrogen atom of a dihydro-
quinoline, and m-CPBA as the oxidant.[13] The catalytic
asymmetric epoxidation of dihydroquinolines has, however,
only very rarely been reported. The only examples in the
literature were reported by Wuts,[14] in which just one di-
hydroquinoline was converted into the chiral 3,4-epoxy-
Figure 1. Structures of tetrahydroquinoline-derived natural prod-
ucts and pharmaceuticals.
tetrahydroquinoline by using both the Shi[15] and
Jacobsen[16] protocols.
Oxaziridinium salts, which were first reported by
Lusinchi in 1976,[17] are usually prepared in situ by the
action of oxone on the corresponding iminium salts. They
are highly effective as catalytic oxidants.[18] We have
achieved high enantioselectivities in the epoxidation of alk-
enes by using iminium salt catalysts, such as 7,[19] 8,[20] and
9.[21] Epoxidation of cis-alkenes with tetraphenylphosphon-
ium monoperoxysulfate[22] (TPPP) as the stoichiometric
[a] School of Chemistry, University of East Anglia,
Norwich Research Park, Norwich, Norfolk NR4 7TJ, U.K.
E-mail: p.page@uea.ac.uk
www.uea.ac.uk/chemistry/people/profile/p-page
Supporting information for this article is available on the
WWW der http://dx.doi.org/10.1002/ejoc.201403132.
Eur. J. Org. Chem. 2014, 8029–8034
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. C. Bulman Page, D. P. Day, Y. Chan
SHORT COMMUNICATION
oxidant under non-aqueous conditions was particularly Table 1. N-Protection of dihydroquinolines 10 and 12.
successful;[23] for example, scuteflorin A was obtained with
99%ee by using iminium salt 7 (Figure 2).[24]
Figure 2. Iminium salt catalysts.
Herein, we describe the first examples of asymmetric
epoxidation of dihydroquinolines by using iminium salt
catalysis, to afford 3,4-epoxy-tetrahydroquinolines in good
conversions, yields and enantioselectivities.
Results and Discussion
Several approaches have been reported for the prepara-
tion of racemic or achiral dihydroquinolines.[9,25,26]
A
number of asymmetric syntheses are also known.[27] By
using Ward’s methodology,[26] we generated a number of
dihydroquinolines 10–13 in moderate yields (Scheme 1).
Scheme 1. Reagents and conditions: (i) aniline (1 equiv.), 3-chloro-
3-methyl-1-butyne (1 equiv.), copper (I) chloride (1 equiv.), copper
powder (1 equiv.), toluene, reflux, 24 h.
We have observed that dihydroquinolines unprotected at
nitrogen are generally unstable to oxidative conditions, but
it is possible to generate racemic epoxides from dihydro-
quinolines with a trifluoroacetyl protecting group and m-
CPBA as the oxidant.[9] We therefore investigated the incor-
poration of a number of nitrogen protecting groups
(Table 1).
Dihydroquinoline 11, the nitro derivative, proved unreac-
tive. Dihydroquinoline 13 decomposed under the reaction
conditions. We were unable to prepare any N-acetyl or N-
formyl derivatives, but we were able to generate N-tri-
fluoroacetyl, benzoyl, BOC, and CBz derivatives from the
other substrates. The new nitrogen-protected dihydroquin-
oline substrates were subjected to epoxidation with m-
CPBA as the oxidant, to determine their reactivity towards
oxidative species, their stability, and to provide racemic
standards (Scheme 2, Table 2).
The epoxidation of the various N-protected 6-chloro-
and 6-cyano-dihydroquinolines with m-CPBA showed that
the olefin double bond is reactive towards electrophilic oxy-
gen sources, and the products appear to be stabilized by
the electron-withdrawing nature of the protecting groups.
Scheme 2. Reagents and conditions: (i) m-CPBA (2 equiv.),
NaHCO3 (4 equiv.), dichloromethane, 0 °C, 24 h.
1
In each case, the reaction progress was monitored by H
NMR spectroscopy of the crude reaction mixture, and, at by silica gel flash column chromatography. Dihydroquinol-
full conversion, the reactions were worked up and purified ine 20 was unreactive.
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Enantioselective Epoxidation of Dihydroquinolines
Table 2. Racemic epoxidation of substrates 14–19.
improvement in ee value of about 10% was recorded. Di-
hydroquinolines 14 and 17 were unreactive.
Substrate
Conv. [%][a]
Yield [%]
When we investigated the effect of changing the catalytic
system to a non-aqueous one (Protocol B) with a different
complementary catalyst, in this case dichloromethane with
dihydroisoquinolinium iminium salt 9, we observed some of
the best enantioselectivities, at the cost of sacrificing con-
version to the product. Under these conditions, the sub-
strates tested that provided the highest enantioselectivities
were those that contained a trifluoroacetyl protecting
group; for example the non-aqueous asymmetric epoxid-
ation of 14 (6-cyano) and 18 (6-chloro) afforded higher
enantioselectivities for the epoxide products (62 and 73%ee,
respectively), but both were obtained at a low conversion
(Ͻ 50%). When the protecting group was changed from a
trifluoroacetyl group to a Cbz- or a benzoyl group, the con-
version was poor, even over five days. Use of solvents other
than dichloromethane was unsuccessful.
In an attempt to increase the enantioselectivity, we tested
a number of the dihydroquinoline substrates under the non-
aqueous solvent conditions of protocol B with biphenyl-de-
rived azepinium catalyst 7. We were surprised to find that
substrates 14, 15, 17, and 18 showed no conversion to their
corresponding epoxides after one week, as the biphenyl cat-
alysts are the more reactive under aqueous conditions. We
have previously observed that binaphthyl catalysts such as
8 provide only very slow epoxidation under non-aqueous
conditions.
14
15
16
17
18
19
100
100
100
100
100
100
60
53
71
78
52
53
[a] All starting material consumed as evaluated by 400 MHz 1H
NMR spectroscopy.
Asymmetric epoxidation was then carried out on the
nitrogen-protected dihydroquinoline substrates 14–20 with
catalysts 7, 8, and 9 by using two protocols: aqueous, with
Oxone as the oxidant (Protocol A, Table 3), and non-
aqueous, with TPPP (Protocol B, Table 3). The enantio-
selectivities ranged from low to good, depending upon the
substrate, epoxidation conditions, protecting group, and
catalyst used. Background epoxidation was not observed in
the absence of catalyst.
Table 3. Epoxidation of N-protected dihydroquinolines 14–20.
Substrate Catalyst/ Time Yield Conv.
Condi-
ee
Abs. config. of the
major enantio-
mer[28]
[h]
[%] [%][b] [%][c]
tions[a]
14
15
16
17
18
19
20
16
14
15
17
18
7 A
7 A
7 A
7 A
7 A
7 A
7 A
8 A
9 B
9 B
9 B
9 B
24
24
2
48
24
0.5
24
4
120
120
120
120
76
68
90
0
87
–
0
70
10
97
89
100
0
100
–
0
100
37
37
66
12
–
22
–
(–)-(3R,4S)
(–)-(3R,4S)
(–)-(3R,4S)
–
Figure 3 shows the preferred direction of approach of
oxygenation of chromene substrates for all three of the
catalysts described here.
(–)-(3R,4S)
decomposition
–
–
23
73
–
–
62
(–)-(3R,4S)
(–)-(3R,4S)
–
Ͻ 5 Ͻ 5
0
13
0
46
–
(–)-(3R,4S)
[a] Epoxidation conditions: Protocol A: 5 mol-% catalyst, Oxone
(2 equiv.), NaHCO3 (5 equiv.), acetonitrile/water (10:1), 0 °C. Pro-
tocol B: 10 mol-% catalyst, TPPP (2 equiv.), dichloromethane, 0 °C.
[b] Conversions were evaluated by 400 MHz 1H NMR spec-
troscopy. [c] Enantioselectivities were determined by chiral HPLC
with a Chiralcel ODH column and hexane/2-propanol mixtures as
eluent.
Figure 3. Mnemonic for stereoselectivity and expected major
enantiomer.
By utilizing biphenyl-derived iminium salt 7 under the
aqueous conditions, the enantioselectivity varied widely de-
pending on the protecting group attached to the nitrogen
atom. When the protecting group was tert-butoxycarbonyl Conclusions
(Boc), the enantioselectivities obtained were low
We have demonstrated the first examples of the asym-
(Ͻ 25%ee). When this group was replaced with a benzoyl
protecting group, we observed a dramatic increase in ee
value; for example, the epoxide derived from substrate 15
was generated in 66%ee under these conditions. Carb-
oxybenzyl (Cbz)-protected dihydroquinolines 17 and 20
were unreactive under these conditions, whereas Boc-
protected 19 decomposed quickly.
metric epoxidation of dihydroquinoline substrates by using
iminium salt catalysis, providing the products with up to
73%ee. These results show clear potential for the applica-
tion of the chemistry to the synthesis of tetrahydroquinoline
natural products such as virantmycin 1 and helquinoline 3.
We also observed that changing from the biphenyl
moiety of catalyst 7 to the binaphthyl moiety of catalyst 8
afforded one successful example of asymmetric epoxidation,
Experimental Section
3-Chloro-3-methylbut-1-yne:[29]
Calcium
dichloride
(23 g,
that of substrate 16, under aqueous conditions, where an 209 mmol), cuprous chloride (20 g, 204 mmol), copper powder
Eur. J. Org. Chem. 2014, 8029–8034
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P. C. Bulman Page, D. P. Day, Y. Chan
SHORT COMMUNICATION
(0.4 g, 6.67 mmol) and cold concentrated hydrochloric acid
(250 mL) were added to a 2 L three-neck flask equipped with a
General Procedure for the Formation of Racemic Epoxides: The re-
quired nitrogen-protected dihydroquinoline (1 equiv.) was dissolved
stirrer bar at 0 °C. The solution was left to stir for 5 min at 0 °C in dichloromethane (5 mL/20 mg of dihydroquinoline) and the
and the reaction mixture was purged with argon four times. The
corresponding tertiary alcohol (56 g, 667 mmol) was added drop-
wise over 30 min, and the reaction was left to stir for 1 h at 0–5 °C.
The upper organic layer was extracted directly from the reaction,
and washed three times with cold concentrated hydrochloric acid
(3ϫ 150 mL). The organic layer was further extracted with cold
water (2ϫ 150 mL), saturated sodium hydrogen carbonate solution
(150 mL) and dried on magnesium sulfate to afford the product as
a colourless liquid (40 g, 58.4%). 1H NMR (300 MHz, CDCl3): δH
solution was cooled to 0 °C. m-Chloroperbenzoic acid (2 equiv.)
and sodium hydrogen carbonate (4 equiv.) were added as one por-
tion. The reaction was allowed to stir at 0 °C until reaction comple-
tion was observed by TLC. A saturated solution of sodium
hydrogen carbonate (2 mL/20 mg of dihydroquinoline) was added
to quench the reaction. The organic layer was separated and the
aqueous layer was extracted with dichloromethane (2ϫ 2 mL/
20 mg of dihydroquinoline). The combined organic layers were
washed with water and brine, dried over magnesium sulfate, and
= 1.82 (s, 6 H), 2.59 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ the solvents were removed under reduced pressure. The crude prod-
= 34.6, 56.9, 71.9, 86.5 ppm. IR (neat): ν
= – 2984, 1448, 1368, uct was purified by flash column chromatography on silica gel with
mixtures of ethyl acetate/petroleum ether/triethylamine as eluents.
˜
max
1226, 1118, 786 cm–1.
General Procedure for the Formation of Chiral Epoxides[30]
General Procedure for the Formation of 1,2-Dihydroquinolines:[9,26]
The required aniline (1 equiv.) and 3-chloro-3-methyl-but-1-yne
(1 equiv.) were dissolved in toluene (15 mL/gram of aniline), to
which cuprous chloride (1 equiv.) and fine copper powder (1 equiv.)
were added to the stirring solution. The reaction was heated under
reflux for 24 h. The reaction was cooled, and water (10 mL/gram
of aniline) was added. The organic layer was separated, and the
aqueous phase was extracted with dichloromethane (10 mL/gram
of aniline). The organic layers were combined, and dried over mag-
nesium sulfate. The solvents were removed under reduced pressure.
Purification of the crude material by column chromatography on
silica gel (ethyl acetate/petroleum ether as the eluent) afforded the
dihydroquinolines as crystalline solids or oils.
Aqueous Conditions: The required nitrogen-protected dihydroquin-
oline (1 equiv.) and catalyst (5 mol-%) were dissolved in acetonitrile
(1 mL/0.05 g of nitrogen protected dihydroquinoline) and water
(0.1 mL/0.05 g of nitrogen protected dihydroquinoline) and the
mixture cooled to 0 °C. A mixture of Oxone (2 equiv.) and sodium
hydrogen carbonate (5 equiv.) was added as a solid in one portion
to the mixture with vigorous stirring. The mixture was stirred at
0 °C until complete conversion of the alkene was observed by TLC.
Diethyl ether (10 mL/0.05 g of nitrogen protected dihydroquinol-
ine) was added, and the reaction mixture was filtered through a
pad of mixed MgSO4 and sodium bisulfite. The solvent was re-
moved under reduced pressure. Pure epoxides were obtained by
column chromatography on silica gel with ethyl acetate/petroleum
ether/triethylamine as eluents.
General Procedure for the Synthesis of N-Trifluoroacetyl-1,2-di-
hydroquinolines: Trifluoroacetic anhydride (2 equiv.) was added
dropwise to a stirring solution of dihydroquinoline dissolved in
dichloromethane (10 mL/100 mg of dihydroquinoline) and pyridine
(1 equiv.) at 0 °C. The reaction was allowed to reach ambient tem-
perature, and after further stirring for one hour, the reaction was
quenched with water (5 mL/100 mg of dihydroquinoline). The or-
ganic phase was separated and the aqueous phase was extracted
with dichloromethane (5 mL/100 mg of dihydroquinoline). The
combined organic layers were washed with a copper sulfate solu-
tion, brine, and dried with magnesium sulfate. The solvents were
removed under reduced pressure. The crude organic mixture was
purified by column chromatography on silica gel (ethyl acetate/pe-
troleum ether as the eluent).
Non-aqueous Conditions:[20b] Tetraphenylphosphonium mono-
peroxysulfate (2 equiv.) was dissolved in dichloromethane (2 mL/
0.05 g of TPPP) and the solution cooled to 0 °C. A solution of
the iminium salt (10 mol-%) in dichloromethane (0.5 mL/0.05 g of
TPPP) was cooled to 0 °C and added dropwise to the solution con-
taining the TPPP over 20 min. The temperature of the reaction
vessel was monitored to minimize the increase in temperature dur-
ing the addition. A solution of the alkene in dichloromethane
(0.5 mL/0.05 g of TPPP) was added dropwise. The mixture was
stirred at 0 °C with the reaction progress monitored by TLC. Di-
ethyl ether (pre-cooled to the reaction temperature) (20 mL/0.05 g
of TPPP) was added to induce precipitation of the remaining oxi-
dant, and the mixture was filtered through Celite. The solvents were
removed under reduced pressure. If the reaction does not reach
completion the epoxide can be separated from the alkene by col-
umn chromatography on silica gel eluting with ethyl acetate/light
petroleum.
General Procedure for the Preparation of Various Nitrogen Protected
1,2-Dihydroquinolines: The desired dihydroquinoline (1 equiv.) was
dissolved in anhydrous THF (50 mL/gram of dihydroquinoline) in
a flame-dried round-bottomed flask under an atmosphere of nitro-
gen. The reaction mixture was cooled to –78 °C and nBuLi
(1.4 equiv.) was added slowly over 15 min. The reaction mixture
was allowed to stir for 2 h at this temperature. A solution of tert-
butylcarboxyl anhydride/benzoyl chloride/benzyl chloroformate
(1.5 equiv.) in THF (10 mL/gram of dihydroquinoline) was then
added dropwise over 15 min. The reaction progress was monitored
by TLC. When total disappearance of the starting material was
observed, the reaction mixture was quenched with an ammonium
chloride solution (10 mL/gram of dihydroquinoline). Ethyl acetate
(20 mL/gram of dihydroquinoline) was added, and the organic
layer was separated. The aqueous layer was then extracted with
ethyl acetate (2ϫ 20 mL/gram of dihydroquinoline). The combined
organic layers were then washed with brine (10 mL/gram of di-
hydroquinoline), dried with sodium sulfate and concentrated under
reduced pressure to afford the title compounds as viscous oils/sol-
ids.
Acknowledgments
This investigation has enjoyed the support of the University of East
Anglia and the ERDF (ISCE-Chem. & INTERREG IVa pro-
gramme 4061). We are also indebted to the EPSRC Mass Spec-
trometry Unit, Swansea.
[1] J. C. Menéndez, V. Sridharan, P. A. Suryavanshi, Chem. Rev.
2011, 111, 7157–7259.
[2] a) W.-G. Kim, J.-P. Kim, C.-J. Kim, K.-H. Lee, I.-D. Yoo, J.
Antibiot. 1996, 49, 20–25; b) W.-G. Kim, J.-P. Kim, I.-D. Yoo,
J. Antibiot. 1996, 49, 26–30; c) S. Omura, A. Nakagawa, H.
Hashimoto, R. Oiwa, Y. Iwai, A. Hirano, N. Shibukawa, Y.
Kojima, J. Antibiot. 1980, 33, 1395–1396; d) A. Nakagawa, Y.
8032
www.eurjoc.org
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Enantioselective Epoxidation of Dihydroquinolines
Iwai, H. Hashimoto, N. Miyazaki, R. Oiwa, Y. Takahashi, A.
Hirano, N. Shibukawa, Y. Kojima, S. Omura, J. Antibiot. 1981,
34, 1408–1415; e) Y. J. Morimoto, J. Heterocycl. Chem. 1998,
35, 279–284.
a) S. Sang, S. Mao, A. Lao, Z. Chen, Tianran Chanwu Yanjiu
Yu Kaifa 2000, 12, 1; b) S. Sang, S. Mao, A. Lao, Z. Chen,
Chem. Abstr. 2000, 133, 360801.
[15]
[16]
[17]
Y. Tu, Z.-X. Wang, Y. Shi, J. Am. Chem. Soc. 1996, 118, 9806–
9807.
W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am.
Chem. Soc. 1990, 112, 2801–2803.
a) P. Milliet, A. Picot, X. Lusinchi, Tetrahedron Lett. 1976, 17,
1573–1576; b) P. Milliet, A. Picot, X. Lusinchi, Tetrahedron
Lett. 1976, 17, 1577–1580.
[3]
[4]
[5]
R. N. Asolkar, D. Schröder, R. Heckmann, S. Lang, I. Wagner-
Döbler, H. Laatsch, J. Antibiot. 2004, 57, 17–23.
[18]
a) G. Hanquet, X. Lusinchi, P. Milliet, Tetrahedron Lett. 1987,
28, 6061–6064; b) L. Bohé, G. Hanquet, M. Lusinchi, X. Lus-
inchi, Tetrahedron Lett. 1993, 34, 7271–7274; c) V. K. Aggar-
wal, M. F. Wang, Chem. Commun. 1996, 191–192; d) L. Bohé,
M. Lusinchi, X. Lusinchi, Tetrahedron 1999, 55, 141–154; e) L.
Bohé, M. Kammoun, Tetrahedron Lett. 2002, 43, 803–805; f)
J. Vachon, C. Lauper, K. Ditrich, J. Lacour, Tetrahedron:
Asymmetry 2006, 17, 2334–2338; g) J. Vachon, S. Rentsch, A.
Martinez, C. Marsol, J. Lacour, Org. Biomol. Chem. 2007, 5,
501–506; h) R. E. del Río, B. Wang, S. Achab, L. Bohé, Org.
Lett. 2007, 9, 2265–2268; i) R. Novikov, J. Vachon, J. Lacour,
Chimia 2007, 61, 236–239; j) J. M. Crosthwaite, V. A. Farmer,
J. P. Hallett, T. Welton, J. Mol. Catal. A 2008, 279, 148–152;
k) R. Novikov, G. Bernardinelli, J. Lacour, Adv. Synth. Catal.
2008, 350, 1113–1124; l) R. Novikov, G. Bernardinelli, J. Lac-
our, Adv. Synth. Catal. 2009, 351, 596–606; m) R. Novikov, J.
Lacour, Tetrahedron: Asymmetry 2010, 21, 1611–1618.
P. C. B. Page, G. A. Rassias, D. Barros, A. Ardakani, D. Beth-
ell, E. Merrifield, Synlett 2002, 4, 580–582.
a) P. C. B. Page, B. R. Buckley, A. J. Blacker, Org. Lett. 2004,
6, 1543–1546; b) P. C. B. Page, B. R. Buckley, D. Barros, A. J.
Blacker, B. A. Marples, M. R. J. Elsegood, Tetrahedron 2007,
63, 5386–5393; c) P. C. B. Page, B. R. Buckley, M. M. Farah,
A. J. Blacker, Eur. J. Org. Chem. 2009, 3413–3426.
D. Su, J. J. Lim, E. Tinney, B.-L. Wan, M. B. Young, K. D.
Anderson, D. Rudd, V. Munshi, C. Bahnck, P. J. Felock, M.
Lu, M.-T. Lai, S. Touch, G. Moyer, D. J. DiStefano, J. A.
Flynn, Y. Liang, R. Sanchez, S. Prasad, Y. Yan, R. Perlow-
Poehnelt, M. Torrent, M. Miller, J. P. Vacca, T. M. Williams,
N. J. Anthony, Bioorg. Med. Chem. Lett. 2009, 19, 5119–5123.
R. J. Pagliero, S. Lusvarghi, A. B. Pierini, R. Brun, M. R. Maz-
zieri, Bioorg. Med. Chem. 2010, 18, 142–150.
R. Hiessböck, C. Wolf, E. Richter, M. Hitzler, P. Chiba, M.
Kratzel, G. Ecker, J. Med. Chem. 1999, 42, 1921–1926.
a) V. V. Kouznetsov, C. M. Meléndez Gómez, F. A. Rojas Ruíz,
E. Del Olmo, Tetrahedron Lett. 2012, 53, 3115–3118; b) S. Ya-
mazaki, M. Takebayashi, K. Miyazaki, J. Org. Chem. 2010, 75,
1188–1196; c) P. J. Stevenson, I. Graham, ARKIVOC 2003, vii,
139–144; d) P. J. Stevenson, M. Nieuwenhuyzen, D. Osborne,
ARKIVOC 2007, xi, 129–144; e) R. Lavilla, M. C. Bernabeu,
I. Carranco, J. L. Diaz, Org. Lett. 2003, 5, 717–720; f) M.
Ueda, S. Kawai, M. Hayashi, T. Naito, O. Miyata, J. Org.
Chem. 2010, 75, 914–921; g) N. T. Patil, H. Wu, Y. Yamamoto,
J. Org. Chem. 2007, 72, 6577–6579; h) M. Prakesch, U.
Sharma, M. Sharma, S. Khadem, D. M. Leek, P. Arya, J.
Comb. Chem. 2006, 8, 715–734; i) U. Sharma, S. Srivastava, M.
Prakesch, M. Sharma, D. M. Leek, P. Arya, J. Comb. Chem.
2006, 8, 735–761; j) M. Prakesch, S. Srivastava, D. M. Leek, P.
Arya, J. Comb. Chem. 2006, 8, 762–773; k) E. Rafiee, A. Azad,
Bioorg. Med. Chem. Lett. 2007, 17, 2756–2759; l) J. S. Yadav,
B. V. S. Reddy, M. Srinivas, B. Padmavani, Tetrahedron 2004,
60, 3261–3266.
[6]
[7]
[8]
[19]
[20]
[21]
[22]
P. C. B. Page, L. F. Appleby, D. Day, Y. Chan, B. R. Buckley,
S. M. Allin, M. J. McKenzie, Org. Lett. 2009, 11, 1991–1993.
a) S. Campestrini, F. Di Furia, G. Labat, F. Novello, J. Chem.
Soc. Perkin Trans. 2 1994, 2175–2180; b) P. C. B. Page, D.
Barros, B. R. Buckley, A. Ardakani, B. Marples, J. Org. Chem.
2004, 69, 3595–3597.
a) P. C. B. Page, B. R. Buckley, H. Heaney, A. J. Blacker, Org.
Lett. 2005, 7, 375–377; b) C. J. Bartlett, Y. Chan, D. Day, P.
Parker, B. R. Buckley, G. A. Rassias, A. M. Z. Slawin, S. M.
Allin, J. Lacour, A. Pinto, P. C. B. Page, J. Org. Chem. 2012,
77, 6128–6138; c) P. C. B. Page, L. F. Appleby, D. Day, Y. Chan,
B. R. Buckley, S. M. Allin, M. J. McKenzie, Org. Lett. 2009,
11, 1991–1993; d) P. C. B. Page, L. F. Appleby, Y. Chan, D. P.
Day, B. R. Buckley, A. M. Z. Slawin, S. M. Allin, M. J. Mc-
Kenzie, J. Org. Chem. 2013, 78, 8074–8082.
[9]
[10]
N. M. Williamson, A. D. Ward, Tetrahedron 2005, 61, 155–165.
[23]
R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop, M. F.
Lipton, I. J. Martin, M. A. Mauragis, M. F. Piercey, N. F.
Nichols, P. J. K. D. Schreur, M. W. Smith, M. W. Moon, J.
Med. Chem. 1997, 40, 639–646.
[11]
a) M. G. Unthank, N. Hussain, V. K. Aggarwal, Angew. Chem.
Int. Ed. 2006, 45, 7066–7069; Angew. Chem. 2006, 118, 7224;
b) A. O’Byrne, P. Evans, Tetrahedron 2008, 64, 8067–8072; c)
S.-M. Lu, C. Bolm, Adv. Synth. Catal. 2008, 350, 1101–1105;
d) N. Mrsˇic´, L. Lefort, J. A. F. Boogers, A. J. Minnaard, B. L.
Feringa, J. G. De Vries, Adv. Synth. Catal. 2008, 350, 1081–
1089; e) M. Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. Int. Ed. 2006, 45, 3683–3686; Angew. Chem. 2006, 118,
3765; f) M. Ori, N. Toda, K. Takami, K. Tago, H. Kogen,
Angew. Chem. Int. Ed. 2003, 42, 2540–2543; Angew. Chem.
2003, 115, 2644; g) O. Hara, T. Koshizawa, K. Makino, I. Kun-
imune, A. Namiki, Y. Hamada, Tetrahedron 2007, 63, 6170–
6181; h) S. A. Bentley, S. G. Davies, J. A. Lee, P. M. Roberts,
J. E. Thomson, Org. Lett. 2011, 13, 2544–2547; i) L. L. Taylor,
F. W. Goldberg, K. K. Hii, Org. Biomol. Chem. 2012, 10, 4424–
4432; j) B.-L. Chen, B. Wang, G.-Q. Lin, J. Org. Chem. 2010,
75, 941–944; k) A. R. Jagdale, R. S. Reddy, A. Sudalai, Org.
Lett. 2009, 11, 803–806.
[24]
[25]
C. J. Bartlett, D. P. Day, Y. Chan, S. M. Allin, M. J. McKenzie,
A. M. Z. Slawin, P. C. B. Page, J. Org. Chem. 2012, 77, 772–
774.
a) N. Sakai, A. Ridder, J. F. Hartwig, J. Am. Chem. Soc. 2006,
128, 8134–8135; b) K. C. Nicolaou, A. J. Roecker, R. Hughes,
R. van Summeren, J. A. Pfefferkorn, N. Wissinger, Bioorg.
Med. Chem. 2003, 11, 465–476; c) Y. Yokoyama, N. Takagi, H.
Hikawa, S. Kaneko, N. Tsubaki, H. Okuno, Adv. Synth. Catal.
2007, 349, 662–668; d) P. Kothandaraman, S. J. Foo, P. W. H.
Chan, J. Org. Chem. 2009, 74, 5947–5952; e) K. Makino, O.
Hara, Y. Takiguchi, T. Katano, Y. Asakawa, K. Hatano, Y.
Hamada, Tetrahedron Lett. 2003, 44, 8925–8929; f) J. Su, J. Ju,
R. Hua, Curr. Org. Synth. 2012, 9, 273–277.
a) C. L. Francis, N. Williamson, A. D. Ward, Synthesis 2004,
16, 2685–2691; b) N. M. Williamson, D. R. March, A. D.
Ward, Tetrahedron Lett. 1995, 36, 7721–7724.
a) M. Takamura, K. Funabashi, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2000, 122, 6327–6328; b) M. Takamura, K.
Funabashi, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2001,
123, 6801–6808; c) Y. Yamoka, H. Miyabe, Y. Takemoto, J.
Am. Chem. Soc. 2007, 129, 6686–6687; d) A. Alexakis, F.
Amiot, Tetrahedron: Asymmetry 2002, 13, 2117–2122; e) F.
Amiot, L. Cointeaux, E. J. Silve, A. Alexakis, Tetrahedron
[26]
[27]
[12]
R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop, M. F.
Lipton, I. J. Martin, M. A. Mauragis, M. F. Piercey, N. F.
Nichols, P. J. K. D. Schreur, M. W. Smith, M. W. Moon, J.
Med. Chem. 1997, 40, 639–646.
L. Jean-Gérard, F. Macé, A. N. Ngo, M. Pauvert, H. Dentel,
M. Evain, S. Collet, A. Guingant, Eur. J. Org. Chem. 2012,
4240–4248.
[13]
[14]
P. G. M. Wuts, R. L. Gu, J. M. Northuis, T. A. Kwan, D. M.
Beck, M. J. White, Pure Appl. Chem. 2002, 74, 1359–1368.
Eur. J. Org. Chem. 2014, 8029–8034
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8033

P. C. Bulman Page, D. P. Day, Y. Chan
SHORT COMMUNICATION
2004, 60, 8221–8231; f) L. Cointeaux, A. Alexakis, Tetrahe-
dron: Asymmetry 2005, 16, 925–929.
[28] The absolute stereochemistry of the epoxide products is as-
signed based upon that observed in the epoxidation of the cor-
responding 2,2-dimethyl chromene substrates by using the
same catalysts and in kinetic resolution experiments, see ref.
23.
[29] I. E. Kopka, Z. A. Fataftah, M. W. Rathke, J. Org. Chem. 1980,
45, 4616–4622.
[30] a) M.-K. Wong, L.-M. Ho, Y.-S. Zheng, C.-Y. Ho, D. Yang,
Org. Lett. 2001, 3, 2587–2590; b) P. C. B. Page, B. R. Buckley,
M. M. Farah, A. J. Blacker, J. Org. Chem. 2007, 72, 4424–4430.
Received: August 25, 2014
Published Online: November 19, 2014
8034
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 8029–8034