Highly enantioselective transfer hydrogenation of α,β- unsaturated ketones

Article abstract of DOI:10.1021/ja065708d

We describe an efficient and highly enantioselective conjugate transfer hydrogenation of α,β-unsaturated ketones that is catalyzed by a salt made from tert-butyl valinate and a recently introduced powerful chiral phosphoric acid catalyst (TRIP). Copyright

Full text of DOI:10.1021/ja065708d

Published on Web 09/21/2006
Highly Enantioselective Transfer Hydrogenation of r,â-Unsaturated Ketones
Nolwenn J. A. Martin and Benjamin List*
Max-Planck-Institut f u¨ r Kohlenforschung, D-45470 M u¨ lheim an der Ruhr, Germany
Received August 7, 2006; E-mail: list@mpi-muelheim.mpg.de
Table 1. Selected Catalyst Screening Resultsa
Recently, asymmetric counteranion directed catalysis (ACDC)
has been introduced as a useful strategy for organic synthesis.1
According to this concept, catalytic reactions that proceed via
cationic intermediates can be conduced asymmetrically via the use
of a chiral enantiomerically enriched anion incorporated into the
catalyst. As an illustration of the concept and proof of principle,
we have shown that salts made from an achiral secondary amine
and a chiral phosphoric acid can function as highly enantioselective
iminium catalysts in the conjugate reduction of R,â-unsaturated
2
aldehydes with Hantzsch esters. Our new catalysts significantly
widened the substrate scope of this reaction by allowing us to reduce
simple aliphatic substrates, such as citral, with high enantioselec-
tivity. However, neither these ACDC catalysts nor the previously
developed chiral imidazolidinone catalysts gave satisfying yields
or enantioselectivities in the conjugate reduction of R,â-unsaturated
3
ketones. We have now developed a new class of catalytic salts, in
which both the cation and the anion are chiral. In particular, valine
ester phosphate salt 3f proved to be an active catalyst for the transfer
hydrogenation of a variety of R,â-unsaturated ketones 1 with
commercially available Hantzsch ester 4 to give saturated ketones
2
in excellent enantioselectivities.
As expected, MacMillan imidazolidinium catalysts, which are
4
highly effective for the iminium catalytic transfer hydrogenation
of R,â-unsaturated aldehydes with Hantzsch esters, proved to be
5,6
much less efficient with ketone substrates. Hypothesizing that
primary amine catalysts, due to their reduced steric requirements,
might be suitable for the activation of ketones, we studied various
7
salts of R-amino acid esters (3, Table 1). Initially we investigated
salts with achiral counteranions, and of those, the trifluoroacetates
generally gave the highest conversion in the reduction of 3-methyl-
cyclohex-2-enone (1a) to (S)-3-methylcyclohexanone (2a). While
the effect of the amino acid ester R-substituent on the enantio-
selectivity was not very pronounced, the highest enantiomeric ratio
was obtained with the valine derivative (entry 2). In addition,
catalysts incorporating the tert-butyl ester group gave the best yields
and enantiomeric ratios (i.e., compare entries 3 and 4). Encouraged
by our previous studies on asymmetric, counteranion directed
catalysis, we also investigated chiral binaphthol derived phosphate
8
counteranions. With phenyl-substituted derivative 3e, the enan-
tiomeric ratio improved from 77:23 to 87:13. Remarkably, of the
a
For additional studied catalysts, see the Supporting Information.
9
b
Determined by GC. c Reaction in Bu2O.
many phosphate salts we have studied, the TRIP counteranion once
again gave the highest enantioselectivity (entry 6).1
,8e,g,h
Moreover,
the yield could be significantly increased by running the reaction
in ether (entry 7). The chirality present in the amino acid seems to
be required as glycine derived catalyst 3g gave significantly reduced
enantioselectivity (entry 8). The phosphoric acid derivative alone
in comparison with other amino acid esters, such as tert-leucine,
with regard to catalytic efficiency, enantioselectivity, and cost. After
further optimization of solvent, temperature, substrate concentration,
Hantzsch ester structure, and catalyst loading, we identified the
following protocol as optimal: Treating the enone (0.33 M) with
commercially available Hantzsch ester 4 (1.2 equiv) in the presence
of catalytic salt 3f (5 mol%) at 60 °C in dibutyl ether for 48 h
gave the saturated ketones in high yields and enantioselectivities
(Table 2).
(3h, (R)-TRIP) was much less active than the amino acid ester salts
and gave the product in only 40:60 er (entry 9). Interestingly, when
we used the opposite enantiomeric counteranion in catalyst 3i, the
same enantiomeric product was formed but with much lower
enantioselectivity, illustrating a dramatic case of a matched/
mismatched catalyst-ion pair combination (entry 10). Valine
derivative 3f was chosen for further studies as it proved superior
Because most products are volatile, yields have been determined
by using GC or HPLC. However, if the product was isolated (entry
13368
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J. AM. CHEM. SOC. 2006, 128, 13368-13369
10.1021/ja065708d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preliminary Scope of the Transfer Hydrogenation
state structure of this new reaction will be investigated in future
studies.
Acknowledgment. We thank the DFG (Priority Program
Organocatalysis SPP1179) for funding this work. Generous support
by the Max-Planck-Society and by Novartis (Young Investigator
Award to B.L.) is gratefully acknowledged. We also thank Degussa,
Lanxess, Merck, and BASF for general support and donating
chemicals, Jutta Rosentreter and Heike Hinrichs for several GC
and HPLC measurements, and Jian Zhou, Simone Marcus, and
Marianne Hannappel for technical assistance.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC and GC traces
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
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(
(
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4
-oxoimidazolidinium trifluoroacetate (3j) and (S)-2-(tert-butyl)-3-methyl-
-oxoimidazolidinium trifluoroacetate (3k), respectively, under the reaction
4
conditions described in Table 1, (R)-3-methylcyclohexanone was formed
with low conversions (<30%) and enantioselectivities (<57:43 er). Higher
conversion (40%) and enantioselectivity (75:25 er) was obtained with
(
2S,5S)-5-benzyl-3-methyl-2-(5-methyl-2-furyl)-4-oxoimidazolidinium tri-
fluoroacetate (3l), which has previously been used with enone substrates
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(6) After the acceptance of this manuscript a related report in which catalyst
l (20 mol%) has been successfully used for the transfer hydrogenation
(
a
Determined by GC. b Absolute configuration of 2g was determined by
3
comparison with a commercial sample, all others were assigned by analogy.
Isolated yield. Determined by HPLC. With 10 mol% of catalyst 3f.
of cyclic ketones appeared. See: Tuttle, J. B.; Ouellet, S. G.; MacMillan,
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c
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(
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5
), chromatographically determined and isolated yields were
identical. The method is particularly well suited for cyclohexenones
entries 1-6), in which case the products are generally formed in
(
very high yields and good to excellent enantioselectivities. Cyclo-
pentenones are slightly less reactive but provide the products in
equally high enantioselectivities (entries 7-9). Cycloheptenones
are also suitable substrates, and 3-methylcyclohept-2-enone (1j)
gave the desired product 2j with excellent yield and enantioselec-
tivity (entry 10). Acyclic ketones may be used but gave the products
in slightly lower enantioselectivities (entries 11 and 12). Mecha-
nistically, we assume the reaction proceeds via an iminium-
phosphate ion pair that may be stabilized by hydrogen bonding
interactions. In addition to binding the iminium ion, the phosphate
counteranion may also interact with the Hantzsch ester via an
additional hydrogen bond. The detailed mechanism and transition
(
1
5
010. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-
357. Also see: (c) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005,
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T.; Bolte, M. Org. Lett. 2005, 7, 3781-3783. (e) Hoffmann, S.; Seayad,
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H.; Fuchibe, K. Synlett 2006, 141-143.
(9) TRIP: 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen
phosphate.
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