An unexpected directing effect in the asymmetric transfer hydrogenation of α,α-disubstituted ketones

Article abstract of DOI:10.1021/ol201643v

α,α-Disubstituted ketones containing an aromatic ring or alkene are reduced in high enantiomeric excess using an asymmetric transfer hydrogenation catalyst. The sense of reduction indicates that the unsaturated region of the ketone adopts a position adjacent to the Ru-bound η⁶-arene ring in the reduction transition state.

Full text of DOI:10.1021/ol201643v

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4304–4307
An Unexpected Directing Effect
in the Asymmetric Transfer
Hydrogenation of r,r-Disubstituted
Ketones
Rina Soni, John-Michael Collinson, Guy C. Clarkson, and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, U.K.
m.wills@warwick.ac.uk
Received June 17, 2011
ABSTRACT
R,R-Disubstituted ketones containing an aromatic ring or alkene are reduced in high enantiomeric excess using an asymmetric transfer
hydrogenation catalyst. The sense of reduction indicates that the unsaturated region of the ketone adopts a position adjacent to the Ru-bound
η6-arene ring in the reduction transition state.
Asymmetric transfer hydrogenation (ATH) of ketones
represents a valuable method for the formation of enan-
tiomerically pure alcohols.1ꢀ4 The catalyst system 1 based
on Ru(II) η6-benzene complexes of the readily available
diamine ligand TsDPEN has proven to be particularly
versatile.2 The mechanism of action of these catalysts is
believed to involve the formation of an enantiomerically
pure precatalyst 1 which is then converted to hydride 2 via
unsaturated complex 3.3 Hydride 2 transfers two hydrogen
atoms to the substrate via the cyclic six-membered transi-
tion state shown in Figure 1.3
The enantioselectivity depends on an edge-face CH/π
interaction which stabilizes the electron-rich (usually
Figure 1. Complexes 1ꢀ4 and involvement of N-H and CH/π
interaction in ATH transition state using hydride derived from 1
(R = R0 = H) and 4 (RꢀR0 = (CH2)3).
aromatic) ring of a substrate in a specific orientation
relative to the Ru η6-arene. Excellent ee’s are thus observed
for acetophenone derivatives. For substrates not fitting
this model, ee’s are frequently lower and unpredictable,
although there are examples of alternative ATH catalysts
which have a broad substrate range.5
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r
10.1021/ol201643v
Published on Web 07/14/2011
2011 American Chemical Society

We are interested in extending the range of substrates to
which ATH catalysts, notably those derived from Ru(II)/
TsDPEN combinations, can be successfully applied in the
formic acid/triethylamine (FA/TEA) reduction system.6
One challenging group ofketones isthe one whichcontains
an adjacent quaternary center.2f,g,7 Some notable successes
have been reported, for example, the use of a Ru(II)/amino
alcohol catalyst in the ATH of cyclic ketones containing R,
R-dimethyl substituents,2f and Ru(II)/oxazoline catalysts
capable of ATH of both pinacolone and 2,2-dimethylcy-
clohexanone in ee’s of >99%.2g In contrast, Ru(II)/
TsDPEN complexes, and their close analogues, appear
to be less efficient in the reduction of such substrates.
Tethered catalyst 46 has proved to benefit from an increased
level of activity and, therefore, seemed appropriate for use
in tests on hindered substrates. The reduction of pinaco-
lone gave, in our hands, a product of only 10% ee (S, 56%
isolated yield) after 24 h at 30 °C using 1 mol % of catalyst
(R,R)-4.6a This is in contrast to the reduction of PhCOtBu
which with 0.5 mol % of (R,R)-4 is reduced in 77% ee
(R, 95% conversion) after 32 h.6b In the latter case, the sense
of reduction is directed by the established CH/π interaction.
Given the challenge presented by sterically hindered sub-
strates, and the potential for the generation of novel
homochiral alcohols, we undertook an investigation into
the ATH of a range of R,R-disubstituted ketones.
Scheme 1. Reduction of β-Tetralone Derivatives
We prepared ketones 5aꢀe, which represent a series in
which steric bulk adjacent to the ketone is systematically
varied. The reduction of β-tetralone is reported to proceed
in 82% ee (R) in FA/TEA using catalyst (R,R)-1,2b although
methoxy-substituted β-tetralones have been reported to be
reduced with higher enantioselectivity.2e The product is of
a configuration which indicates that a CH/π edge/face
interaction determines the enantiocontrol of the reaction
(Figure 3a).2b Similarly, β-tetralone 5awas reduced in88%
ee (R) using catalyst (R,R)-4 (Scheme 1, Figure 2). In
previous work in our group, we have demonstrated that
R-substitutedβ-tetralones are alsoreduced inhigh ee under
the control of the key CH/π edge/face interaction
(Figure 3a).8 By placing large substituents between the
aryl ring of the substrate and its ketone, we hoped that the
effect would be to disrupt this interaction and provide a
means for correlation of the steric bulk with the enantios-
electivity of reduction.
(2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
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Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–
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Figure 2. Alcohols formed by reduction of hindered β-tetralones
using catalyst (R,R)-4.
In the event, the results were surprising. All of com-
pounds 5bꢀe were reduced in high enantiomeric excess,
higher than for β-tetralone 5a and with the same absolute
configuration (Scheme 1, Figure 2). This indicates that, in
this series, despite their high steric bulk, the substituents
reinforce the enantiocontrol of the reaction by the catalyst.
Indeed, as the group gets larger, the ee increases and
remains high even for 5c possessing a saturated spiro cycle.
For substrates 5d and 5e, an additional CH/π effect may
(4) (a) Bradley, P. A.; Carroll, R. L.; Lecouturier, Y. C.; Moore, R.;
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Asymmetry 2002, 13, 2485–2490. (b) Alcock, N. J.; Hannedouche, J.;
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7035–7044. (b) Hayes, A. M.; Morris, D. J.; Clarkson, G.; Wills, M.
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also be operating between the Ru(II) η6-arene and the
alkene or second aromatic ring respectively (Figure 3b).
The reason for the increased enantioselectivity for the
reduction of 5b and 5c is less clear, however there has been
speculation that hydrophobic (dispersion) effects can con-
tribute to the control of ATH reductions.3f
Figure 4. X-ray crystallographic structures of camphorsulfonic
acid derivatives (a) (R)-79 and (b) (R)-12.11
resulted in formation of 10 in 71% ee (S configuration
assigned by analogy with pinacolone reduction), whereas 9
gave 11 in 93% ee (1 mol % catalyst, 28 °C). The absolute
configuration of 11 was determined by an X-ray crystal-
lographic study of the (1S)-(þ)-10-camphorsulfonic acid
derivative 12 (Figure 4b).11 The sense of reduction of 9
must arise through a transition state in which the quatern-
ary center is orientated in the position proximal to the
Ru(II) η6-arene (Figure 3c). In the comparison between 8
and 9, the aromatic ring of the substrate clearly results in
an improvement of the ee, over that of a similar substrate
lacking this group.
Figure 3. Proposed stabilizing interactions in transition states of
reduction of hindered ketones and tetralones with (R,R)-4. For
clarity, the CꢀH bond on the arene is omitted in bꢀf.
In the case of 6e, an X-ray crystallographic structure
of the (1S)-(þ)-10-camphorsulfonic acid derivative 7
was obtained (Figure 4a) in order to establish the
absolute configuration.9 For 6d the Mosher derivative
was prepared and the configuration was assigned by
1
reference to shifts in the H NMR spectrum (see the
Supporting Information).10 The reduction of the en-
antiomerically enriched sample of compound 6d gave
6c with identical configuration to that obtained by
direct reduction of 5c, confirming the same sense of
reduction of both the saturated and unsaturated ke-
tones 5c and 5d respectively. The configuration of 6b
was also assigned using the Mosher derivative method
(see the Supporting Information).
The speculated importance of an unsaturated function
in directing the ATH of R,R-disubstituted ketones was
further substantiated by a study of the asymmetric transfer
hydrogenation of the acyclic ketones 13aꢀc using the
tethered catalyst (R,R)-4. The enantiomeric excesses of
theproducts14aꢀcwere61%, 92%, and 90%respectively.
The configurations of the chiral centers in14a and 14c were
The “spiro” CH/π effect can alone direct enantioselec-
tive reductions, as illustrated by the contrasting results
obtained for reduction of compounds 8 and 9. Reduction
of 8 under the same conditions as shown in Scheme 1
1
assigned by H NMR analysis of the Mosher derivatives
(see the Supporting Information).10 The configuration of
14b was assigned by hydrogenation to give 14a of identical
configuration to that generated using the same enantiomer
of catalyst.
(9) X-ray data for (R)-7 (CCDC no. 817154), C28H32O4S, M =
˚
464.60, orthorhombic, space group P2(1)2(1)2(1), a = 7.43712(9) A,
(11) X-ray data for (R)-12 (CCDC no. 817152), C24H32O4S, M =
˚
416.56, monoclinic, space group P2(1), a = 9.9752(2) A, b =
˚
˚
b = 8.62914(9) A, c = 36.4793(4) A, R = 90°, β = 90°, γ = 90°, U =
3
˚
˚
˚
˚
2341.09(5) A , T = 100(2) K, λ = 1.54184 A, Z = 4, D(calc) = 1.318
Mg/m3, F(000) = 992. μ(Mo KR) = 1.491 mmꢀ1. Crystal character:
colorless block. Crystal dimensions 0.20 ꢁ 0.16 ꢁ 0.08 mm.
10.52392(16) A, c = 11.2107(2) A, R = 90°, β = 116.107(3)°, γ =
3
˚
˚
90°, U = 1056.81(3) A , T =100(2) K, λ = 0.71073 A, Z = 2, D(calc) =
1.309 Mg/m3, F(000) = 448. μ(Mo KR) = 0.181 mmꢀ1. Crystal
character: colourless block. Crystal dimensions 0.50 ꢁ 0.30 ꢁ 0.30 mm.
(10) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
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Org. Lett., Vol. 13, No. 16, 2011

These results again indicate that an element of unsatura-
tion in the cyclic part of the substrate is beneficial for high
enantioselectivity in the ATH reaction. However, the ATH
ofsubstrate13d to 14d ofjust 73% ee alsoindicates thatthe
ester has an additional directing effect;possibly a further
CH/π interaction with the Ru(II) η6-arene;and that both
are required for high ee’s to be obtained with these sub-
strates (Figure 3d).
given that the closely analogous PhCOtBu was reduced in
significantly lower ee (77%). An attempt to form the
(1S)-(þ)-10-camphorsulfonic acid derivative of 18a led to
the isolation of a racemic ether (see the Supporting
Information). However, the Mosher ester derivative
was formed and isolated, analysis of which indicated
that the configuration was R (see the Supporting
Information).10,14 This result indicates that the CH/π
directing effect of an aromatic ring directly adjacent to
the ketone with the Ru(II) η6-arene remains the domi-
nant one (Figure 3f). The same reactions, in similar ee
but at lower rates, could be also achieved for
certain substrates using catalyst 1 (see the Supporting
Information).
The effect can also be extended to the enantioselective
reduction of 1,3-diketones.12 Diketone 15c was reduced in
99% ee with an almost complete selectivity for the trans
product 16c, the configuration of which was assigned using
the Mosher ester method.10 In contrast, the saturated
derivative 15b was reduced in low diastereoselectivity, with
an unexpected preference for the cis isomer but still with a
high enantioselectivity for the chiral trans product 16b. 2,2-
Dimethylcyclohexa-1,3-dione 15a was reduced in only
55:45 dr (trans isomer of 83% ee). These results again
underline the capacity of a unsaturated functionality,
together with an additional carbonyl group to direct highly
enantioselective reductions of ketones which do not con-
tain directly adjacent aromatic rings (Figure 3e). In the
case of 15c, this CH/π interaction is sufficient to also direct
the second ketone reduction. In the case of 15b, it cannot,
and the cis product is predominantly formed, possibly via a
noncatalyst-directed diastereoselective reduction.
Finally, we wished to establish whether this directing
effect was more or less effective than the well-established
CH/π interaction (Figure 1). This required the preparation
of 17a and 17b, which was achieved in one step from R-
tetralone by alkylation with 1,2-di(bromomethyl)benzene
and methyl iodide respectively. Reduction with catalyst
(R,R)-4 proceeded in quantitative yield to give products
18a (99%ee) and 18b (98% ee) respectively. Alcohol 18b is
known13 and was shown to be the R-enantiomer by
comparison of its optical rotation to that reported (see
the Supporting Information). The additional rigidity of
17b clearly has an important influence on the selectivity,
In summary, although not as strong a directing effect as
the established CH/π interaction with an aromatic ring
directly adjacent to the ketone, the interaction of an
unsaturated carbocyclic group of the substrate with the
Ru(II) η6-arene appears to be a constructive one which can
alonedirectthe asymmetricreduction ofketonesinhighee.
This directing effect provides a means for the highly
enantioselective reduction of hindered ketones and may
prove useful in the design of future catalysts for use in
asymmetric synthesis. The enantiopure alcohols prepared
may also form the basis of novel ligands for extended
applications and new structural motifs.
Acknowledgment. We thank Warwick University for
support of R.S. through a Warwick Postgraduate Re-
search Studentship. J.-M.C. was an undergraduate student
supported by Warwick University. The X-ray diffract-
ometer was funded through the AWM Science City Ad-
vanced Materials project and ERDF support.
Supporting Information Available. Full experimental
procedures for synthesis of ketones and their reductions,
1
X-ray crystallographic data, H and 13C NMR spectra,
and ee determination. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) For assignment of configuration, in all cases we have followed
the IUPAC convention in giving a phenyl ring priority over a tBu group:
Cross, L. C.; Klyne, W. Pure Appl. Chem. 1976, 45, 11–30.
€
(12) Leijondahl, K.; Fransson, A.-B. L.; Backvall, J.-E. J. Org. Chem.
2006, 71, 8622–8625.
(13) Jaonen, G.; Meyer, A. J. Am. Chem. Soc. 1975, 97, 4667–4672.
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