Angewandte
Chemie
DOI: 10.1002/anie.200704185
Asymmetric Catalysis
Asymmetric Counteranion-Directed Catalysis for the Epoxidation of
Enals**
Xingwang Wang and Benjamin List*
Catalytic enantioselective epoxidation of olefins has tradi-
tionally defined the state of the art in asymmetric catalysis.[1]
Groundbreaking achievements during the last thirty years
include the Ti-catalyzed Sharpless epoxidation,[2] the Jacob-
sen epoxidation using manganese–salen complexes,[3] the
polyamino acid-catalyzed Julia–Colonna epoxidation,[4] and
the chiral ketone-catalyzed Shi epoxidation.[5] In addition,
several other useful methods have been described.[6–9]
Recently, equally elegant and useful organocatalytic asym-
metric epoxidations of a,b-unsaturated aldehydes by iminium
catalysis have been developed. Jørgensen and co-workers
used a prolinol silyl ether catalyst in combination with
hydrogen peroxide, while Lee and MacMillan later reported
a procedure that required a hypervalent iodine reagent as the
oxidant and a chiral imidazolidinone as the catalyst.[10] The
potential exploitation of iminium catalytic epoxidation is
enormous because of the ready availability of the required
substrates[11] which lead to the synthesis of valuable chiral a,b-
epoxy aldehydes that are then open for further manipu-
lation,[1c,9a] However, the range of substrates is limited and
only 1,2-disubstituted enals give an enantiomeric ratio of
greater than 95:5, whereas trisubstitued enals give generally
lower enantioselectivities.
We have recently developed asymmetric counteranion-
directed catalysis (ACDC) as a new concept for enantiose-
lective synthesis. Accordingly, catalytic reactions that proceed
via cationic intermediates can be conducted in an asymmetric
fashion if a chiral counteranion is incorporated into the
catalyst. We originally used this approach to perform highly
enantioselective organocatalytic conjugate reductions of a,b-
unsaturated carbonyl compounds,[12] and subsequently
extended it to transition-metal catalysis.[13] Herein we report
initial results from using ACDC for the enantioselective
organocatalytic epoxidation of a,b-unsaturated carbonyl
compounds. We have identified a new catalytic salt 3m that
works well with disubstituted aromatic a,b-unsaturated
aldehydes and gives excellent enantioselectivities with trisub-
stituted a,b-unsaturated aldehydes, which have previously
been elusive substrates for any type of highly enantioselective
epoxidation.
In our previous conjugate reduction system, the best
catalyst was the morpholine salt of 3,3’-bis(2,4,6-triisopropyl-
phenyl)-1,1’-binaphthyl-2,2’-diyl hydrogen phosphate (TRIP,
3a),[12a] a phosphoric acid we have used in several different
reactions.[14–16] This catalyst together with tert-butyl hydro-
peroxide (tBuOOH) as oxidant converted cinnamaldehyde
(1a) into the desired 2,3-epoxyaldehyde 2a in moderate yield,
distereomeric ratio (d.r. 97:3), and enantiomeric ratio
(e.r. 77:23; Table 1, entry 1). Other oxidants such as
mCPBA, H2O2, and cumene hydroperoxide were also tested
but gave inferior results. To further optimize the enantiose-
lectivity of the reaction, a number of different amines were
investigated. Of the amine salts studied (Table 1, entries 2–4),
the dibenzylammonium salt of TRIP (3d) gave the best result
(Table 1, entry 4, 95% yield, d.r. 98:2, e.r. 83:17). Dibenzyl-
ammonium salts with other phosphate counteranions gave
significantly lower enantioselectivities (Table 1, entries 5 and
6). For further steric and electronic fine tuning, diverse
dibenzyl amine derivatives were synthesized[17] and their
TRIP salts (3g–m) tested (Table 1, entries 7–13). The epox-
idation of cinnamaldehyde with catalyst 3m (10 mol%) and
tBuOOH (1.5 equiv) in dioxane gave 2a in 71% yield, d.r. >
99:1, and e.r. 95:5 (Table 1, entry 13). Optimization of solvent
and temperature resulted in slight improvement of both the
yield and the e.r. value (Table 2, entry 1).
Having succeeded in developing an efficient and enantio-
selective catalyst (3m), we next examined the scope and
limitation of our system for the epoxidation of various 1,2-
disubstituted enals (Table 2). With aromatic substrates the
epoxidation proceeds smoothly to furnish the desired prod-
ucts (2a–n) in good yields and excellent enantioselectivities
(up to e.r. 98:2; Table 2, entries 1–13). In contrast to the
iminium catalytic epoxidation reported by Jørgensen et al.
[10a]
which gave d.r. values between 90:10 and 98:2,
by using
our ACDC catalyst with aromatic substrates the diastereose-
lectivities are improved (d.r. values from 97:3 up to > 99:1).
While simple alkyl-substituted enals are readily converted
into the corresponding epoxide, the resulting stereoselectivity
is slightly lower. For example, trans-2-nonenal (1n) gave the
corresponding epoxide with a relatively high d.r. value (94:6)
but moderate enantioselectivity (e.r. 85:15) as the major
diastereoisomer. The minor cis-isomeric product was formed
with an e.r. value of 96:4 (Table 2, entry 14).
b,b-Disubstituted a,b-unsaturated aldehydes such as 3-
methylbut-2-enal (1o), gave the corresponding epoxide in
only moderate enantioselectivity when using the system
described by Jørgensen and co-workers.[10a] Pleasingly, we
[*] Dr. X. Wang, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
[**] We thank Simone Marcus, Esther Böß, and Jutta Rosentreter for
technical assistance. Generous support by the Max Planck Society,
the DFG (SPP 1179, Organokatalyse), and Novartis (Young
Investigator Award to B.L.) is gratefully acknowledged. We also
thank BASF, Degussa, Merck, Saltigo, and Wacker for general
supportand for donating chemicals.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 1119 –1122
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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