Iminium salt catalysts for asymmetric epoxidation: The first high enantioselectivities

Article abstract of DOI:10.1021/ol049782h

A highly enantioselective iminium salt catalyst has been prepared and tested in the catalytic asymmetric epoxidation of unfunctionalized alkenes, giving up to 95% ee, the highest ee yet reported for iminium salt-catalyzed epoxidation. Catalyst loadings as

Full text of DOI:10.1021/ol049782h

ORGANIC
LETTERS
2
004
Vol. 6, No. 10
543-1546
Iminium Salt Catalysts for Asymmetric
Epoxidation: The First High
Enantioselectivities
1
Philip C. Bulman Page,* Benjamin R. Buckley, and A. John Blacker1
Department of Chemistry, Loughborough UniVersity,
Loughborough, Leicestershire LE11 3TU, England
p.c.b.page@lboro.ac.uk
Received February 6, 2004 (Revised Manuscript Received April 1, 2004 )
ABSTRACT
A highly enantioselective iminium salt catalyst has been prepared and tested in the catalytic asymmetric epoxidation of unfunctionalized
alkenes, giving up to 95% ee, the highest ee yet reported for iminium salt-catalyzed epoxidation. Catalyst loadings as low as 0.1 mol % may
be used.
Chiral epoxides are extremely useful building blocks for
asymmetric synthesis, and the development of effective
example by oxidation of iminium salts, are useful electro-
philic oxidants for olefin epoxidation. Since the first ox-
aziridinium salts were described by Lusinchi in 1976 and
2
4
systems for asymmetric epoxidation has received consider-
3
able attention. Oxaziridinium salts, e.g., 1, generated for
the corresponding iminium salts subsequently shown to
5
catalyze epoxidation in the presence of oxone, several other
(
1) Avecia Life Science Molecules, P.O. Box 521, Leeds Road, Hud-
dersfield, HD2 1GA, England.
2) See for example: Sharpless, K. B. Aldrichimica Acta 1983, 16, 67.
groups have sought to design selective asymmetric catalysts
in this area. Enantiomeric excesses have, however, been
limited to ca. 70% at best, and few substrate types invoke
even this level of enantioselectivity. Recent reports by Yang
and Armstrong utilize acyclic chiral iminium salts generated
6
(
Gorzynski Smith, J. Synthesis 1984, 629. Behrens C. H.; Katsuki, T. Coord.
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Chinda, N. Tetrahedron 1999, 55, 2205.
(
3) See for example: Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. Katsuki, T.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 621. Jacobsen, E.
N.; Wu, M. H. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
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Wang, X. C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem.
Soc. 1998, 120, 5943. Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc.
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H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 67, 2435.
Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435.
Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. Cao, G. A.;
Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. Frohn, M.;
Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999, 121,
7718. Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721. Shu, L.; Shi, Y.
J. Org. Chem. 2000, 65, 8807. Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem.
Soc. 2002, 124, 8792. Armstrong, A.; Ahmed, G.; Dominguez-Fernandez,
B.; Hayter, B. R.; Wales, J. S. J. Org. Chem. 2002, 67, 8618.
(4) Picot, A.; Millet, P.; Lusinchi, X. Tetrahedron Lett. 1976, 17, 1573.
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3941. Boh e´ , L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett.
1993, 34, 7271. Boh e´ , L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999,
55, 141. Boh e´ , L.; Kammoun, M. Tetrahedron Lett. 2002, 43, 803.
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S.; Takemiya, A.; Nakamura, K.; Ryu, I.; Komatsu, M. Synlett 2000, 12,
1810.
9
3
1
1
1
Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622. Wang, Z.-X.; Shi, Y. J. Org.
Chem. 1998, 63, 3099. Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett.
1
0.1021/ol049782h CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/17/2004

in situ from chiral amines and aldehydes, but enantiomeric
7
excesses are again moderate and catalyst loadings high.
Scheme 1. Preparation of Catalysts
Our own approach to chiral iminium salt catalysts differs
from previous investigations, where the exocyclic group
attached to the nitrogen atom of the iminium unit has
invariably been methyl or ethyl.
moieties, and fused to (R)- or (S)-binaphthalene units. These
catalysts are directly prepared, in good yields, from the
bromomethyl carbaldehyde intermediate 6, which we prepare
in turn from commercial (R)- or (S)-(1,1′)-binaphthalenyl-
2
,2′-diol (Binol) (Scheme 1, Table 1).
We reasoned that positioning of asymmetric centers in an
exocyclic substituent on the iminium nitrogen atom, as in 2,
would bring these controlling asymmetric elements of the
catalyst nearer to the site of oxygen transfer and should
Table 1. Cyclocondensation of Primary Amines 4 and 5 with
the Bromoaldehyde 6
bromoaldehyde
amine
product
yield (%)
8
therefore increase the ee induced in an epoxidation reaction.
(R)
(S)
(S)
(R)
(S)
4
7a
ent-7a
7b
7c
7d
66
64
63
71
73
ent-4
4
5
5
With the new catalysts in hand, we were able to test their
effectiveness in several epoxidation reactions. Initially, we
screened the catalysts with our usual test substrates, 1-phen-
ylcyclohexene, R-methylstilbene, and triphenylethylene (Table
We have recently reported a new family of much more
reactive catalysts, in which the dihydroisoquinolinium moiety
has been replaced by a biphenyl structure fused to a seven-
membered ring azepinium salt. The catalyst 3, derived, as
is 2, from 5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane 4,
2
).
8
Catalyst 7a showed the best reaction profile, being not
only the most reactive but also the most enantioselective
induces complete conversion of alkenes to epoxides in only
10 min at 0 °C. A binaphthalene-fused azepinium salt
catalyst, achiral at the nitrogen substituent, has also been
described, and gave 71% ee for phenylcyclohexene oxide
6
and 45% ee for R-methylstilbene oxide. Lacour has reported
catalysis of epoxidation by oxone with the iminium salt of
3
but using an enantiomerically pure TRISPHAT counterion
9
and dichloromethane/water as the solvent system.
We describe herein several new azepinium salt catalysts,
derived from (+)- and (-)-5-amino-2,2-dimethyl-4-phen-
1
0
11,12
yl-1,3-dioxane 4 and (-)-isopinocampheylamine 5
(7) Wong, M.-K.; Ho, L.-M.; Zheng, Y.-S.; Ho, C.-Y.; Yang, D. Org.
Lett. 2001, 16, 2587. Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou,
K. Synlett 1997, 1075. Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou,
K.; Wailes, J. S. Tetrahedron 1999, 55, 2341.
(
8) Page, P. C. B.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Chem.
iminium salt epoxidation catalyst yet discovered. For ex-
ample, in the presence of 7a, 1-phenycyclohexene oxide was
produced in 69% yield with an unprecedented 91% ee in
Soc., Perkin Trans. 1 2000, 3325. Page, P. C. B.; Rassias, G. A.; Barros,
D.; Ardakani, A.; Buckley, B. R.; Bethell, D.; Smith, T. A. D.; Slawin, A.
M. Z. J. Org. Chem. 2001, 66, 6926. Page, P. C. B.; Rassias, G. A.; Barros,
D.; Ardakani, A.; Bethell, D.; Merifield, E. Synlett 2002, 4, 580.
(
9) Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002, 43,
257.
10) Nordin, I. C.; Thomas, J. A. Tetrahedron Lett. 1984, 25, 5723.
8
(12) The HPLC conditions used for analysis of 1-phenyldihydronaph-
thalene were: Chiracel OD column, flow rate 1.0, hexane/IPA 90:10,
retention times (1S,2R) 9.78 min (major isomer), (1R,2S) 11.81 min (minor
isomer).
(
(
11) IUPAC name for (-)-isopinocampheylamine is (-)-6-(1R,2R,3R,5S)-
2
,2,6-trimethylbicyclo[3.1.1]hept-3-ylamine.
1544
Org. Lett., Vol. 6, No. 10, 2004

Table 2. Asymmetric Epoxidation of Unfunctionalized Alkenes
Mediated by Catalysts 7a-da
Table 3. Asymmetric Epoxidation of Various Alkenes
Mediated by Catalyst 7aa
a
Conditions: iminium salt (5 mol %), oxone (2 equiv), Na2CO3 (4 equiv),
MeCN/H2O (1:1), 0 °C. Isolated yields. c Enantiomeric excesses were
b
1
determined by H NMR spectroscopy in the presence of (+)-Eu(hfc)3 or
by chiral HPLC using a Chiracel OD column.12 d Absolute configurations
of the major enantiomers were determined by comparison of optical rotation
with those reported in the literature.
a
Conditions: iminium salt (5 mol %), oxone (2 equiv), Na2CO3 (4 equiv),
With a number of successful epoxidation substrates
established for catalyst 7a, several cycloalkenes, of varying
ring sizes, were submitted to the asymmetric epoxidation
reaction (Table 4). Reactions were carried out using just 1
b
c
MeCN/H2O (1:1), 0 °C. Isolated yields. Enantiomeric excesses were
determined by H NMR spectroscopy in the presence of (+)-Eu(hfc)3.
Absolute configurations of the major enantiomers were determined by
1
d
comparison of optical rotation with those reported in the literature.
under 20 min, while the other catalysts (apart from ent-7a,
the enantiomer of 7a) were less selective and gave more
sluggish reactions. The isopinocamphenyl moiety offers little
enantiocontrol, leading to epoxides with only moderate ees.
The poor reactivity of catalysts 7b-d is highlighted by the
attempted epoxidations of R-methyl stilbene and triphenyl
ethylene, where poor conversions were observed after 4 h.
Catalyst 7a, however, afforded complete conversion to the
corresponding epoxides in a much shorter time and an
isolated yield of ca. 60%, although the ees were low to
moderate. In a control reaction of 1-phenylcyclohexene in
the absence of catalyst, epoxide was generated in less than
Table 4. Effect of Ring Size on the Epoxidation of Several
Cycloalkenes with Catalyst 7aa
1% yield after 8 h.
Catalyst 7a was subsequently used to epoxidize several
other olefins. Again the reactivity of the catalyst at (5 mol
) was good, but a wide range of ees was observed (Table
). 1-Phenyl-3,4-dihydronaphthalene was epoxidized with
very high enantioselectivity (95% ee and 66% yield after
5 min). para-Phenylstyrene oxide was produced with 29%
%
3
a
Conditions: iminium salt (1 mol %), oxone (2 equiv), Na2CO3 (4 equiv),
MeCN/H O (1:1), 0 °C. b Isolated yields. c Enantiomeric excesses were
determined by H NMR spectroscopy in the presence of (+)-Eu(hfc)3.
Absolute configurations of the major enantiomers were determined by
2
1
3
d
ee, the highest reported ee for epoxidation of a terminal
alkene using iminium salt catalysis.
comparison of optical rotation with those reported in the literature.
Org. Lett., Vol. 6, No. 10, 2004
1545

mol % catalyst 7a. Again, good conversions to epoxides were
achieved, and, interestingly, the five- and seven-membered
ring cycloalkenes were less reactive than was 1-phenyl-
cyclohexene. The reactions were much more sluggish, and
enantioselectivities were poorer than those observed for
previously reported that it is possible to use just 0.5 mol %
catalyst, but a loss in enantioselectivity is commonly
observed. In this case, however, catalyst loadings can be so
low that effective epoxidation of 1.0 g of 1-phenylcyclo-
hexene, with 68% yield and 88% ee, can be achieved using
just 5 mg of catalyst (0.1 mol %).
1-phenylcyclohexene: 1-phenylcyclopentene oxide was formed
in 55% ee and 1-phenylcycloheptene in 76% ee.
Catalyst 7a gives the highest ees ever reported for iminium
salt-catalyzed epoxidation and for several substrates is the
most enantioselective iminium salt catalyst known. It is also
the most active iminium salt catalyst that we have discovered
and is effective at remarkably low catalyst loading. Generally,
organic catalysts require high catalyst loadings, and decom-
position of the catalyst is often observed. In the case of
catalyst 7a, the enantioselectivity appears to be independent
of catalyst loading down to 0.5 mol %; decreasing the amount
of catalyst merely increases the reaction time.
Using 1-phenylcyclohexene as a test substrate, we also
conducted a catalyst loading study of 7a, with catalyst
loadings ranging from 0.1 to 5 mol % (Table 5). We were
delighted and extremely surprised to observe high levels of
asymmetric induction with low catalyst loadings. We have
Table 5. Catalyst Loading Study on the Epoxidation of
1
-Phenylcyclohexene with Catalyst 7aa
[
7a ] (mol %) time (h) yield (%)b
ee (%)c configurationd
Acknowledgment. This investigation has enjoyed the
support of the EPSRC and Avecia Life Science Molecules.
We are also indebted to the EPSRC Mass Spectrometry Unit,
Swansea.
5
1
0
0
.0
.0
.5
.1
0.2
1.1
2.0
6.0
69
64
65
68
91
91
91
88
(-)-(1S,2S)
(-)-(1S,2S)
(-)-(1S,2S)
(-)-(1S,2S)
a
Conditions: Oxone (2 equiv), Na2CO3 (4 equiv), MeCN/H2O (1:1), 0
Supporting Information Available: Full experimental
detail. This material is available free of charge via the Internet
at http://pubs.acs.org.
c
1
°
C. b Isolated yields. Enantiomeric excesses were determined by H NMR
spectroscopy in the presence of (+)-Eu(hfc)3. Absolute configurations of
the major enantiomers were determined by comparison of optical rotation
with those reported in the literature.
d
OL049782H
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Org. Lett., Vol. 6, No. 10, 2004