Asymmetric transfer hydrogenation of α,β-unsaturated, α-tosyloxy and α-substituted ketones

Article abstract of DOI:10.1016/j.tet.2005.11.036

Asymmetric transfer hydrogenation of cyclic and acyclic α,β-unsaturated ketones catalysed by η⁶-p-cymene/ ruthenium(II) and η⁵-pentamethylcyclopentadienyl/rhodium(III) complexes have been investigated. Cyclic α,β-unsaturated ketones appeared to be more suitable substrates for the synthesis of enantiomerically pure allylic alcohols than do acyclic α,β-unsaturated ketones. A proposed mechanism for the formation of 4-phenyl-[1,3]-dioxolan-2-one from α-tosyloxy- and halo-substituted acetophenones is discussed. The results of further investigations into the reduction of a range of α- tosyloxyacetophenones and the dynamic kinetic resolution of α-substituted ketones is presented.

Full text of DOI:10.1016/j.tet.2005.11.036

Tetrahedron 62 (2006) 1864–1876
Asymmetric transfer hydrogenation of a,b-unsaturated,
a-tosyloxy and a-substituted ketones
Philip Peach,a David J. Cross,a Jennifer A. Kenny,a Inderjit Mann,b Ian Houson,c
Lynne Campbell,c Tim Walsgroveb and Martin Willsa,
*
aDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, UK
bGlaxoSmithKline Pharmaceuticals, Old Powder Mills, Nr. Leigh Tonbridge, Kent TN11 9AN, UK
cAvecia Huddersfield Works, PO Box A38, Leeds Road, Huddersfield, Yorkshire HD2 1FF, UK
Received 22 July 2005; revised 31 October 2005; accepted 17 November 2005
Available online 13 December 2005
Abstract—Asymmetric transfer hydrogenation of cyclic and acyclic a,b-unsaturated ketones catalysed by h6-p-cymene/ruthenium(II) and
h5-pentamethylcyclopentadienyl/rhodium(III) complexes have been investigated. Cyclic a,b-unsaturated ketones appeared to be more
suitable substrates for the synthesis of enantiomerically pure allylic alcohols than do acyclic a,b-unsaturated ketones. A proposed mechanism
for the formation of 4-phenyl-[1,3]-dioxolan-2-one from a-tosyloxy- and halo-substituted acetophenones is discussed. The results of further
investigations into the reduction of a range of a-tosyloxyacetophenones and the dynamic kinetic resolution of a-substituted ketones is
presented.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
resolution of racemic secondary allylic alcohols, reported
by Noyori et al. affords also better enantioselectivity with
cyclic substrates than acyclic substrates.9
Asymmetric transfer hydrogenation (ATH) is a valuable
synthetic tool for the catalytic asymmetric reduction of
ketones and imines.1 The extension of this methodology to
the preparation of a wide range of enantiomerically pure
secondary alcohols and amines, has resulted from the intro-
duction of highly active and enantioselective h5-pentamethyl-
cyclopentadienyl/rhodium(III) and h6-arene/ruthenium(II)
complexes of monotosylated 1,2-diamines such as 1
(in propan-2-ol or formic acid) or b-amino alcohols such
as 2 (in propan-2-ol).2,3 Most of the reductions catalysed
by these systems involve the synthesis of chiral, non
racemic benzylic alcohols;4 mainly substituted aryl/alkyl
alcohols,2a–c,3a or aryl/substituted alkyl alcohols.2h,3c,5,6
This may reflect a preference for hydride transfer to occur
via a 1,2-reduction mechanism for a cyclic enone due to
geometric restraint (i.e., enforced s-trans conformation). In
contrast, acyclic enones have a less rigid structure that may
allow a 1,4-reduction to take place and so to compete with
the 1,2-reduction pathway (Fig. 1).
X
X
H
O
M
H
M
N
N
H
H
H
H
H
O
Figure 1. Preferred reduction pathway according to the nature of the
substrate structure (MZmetal; XZO or NTs; auxiliary ligands are omitted
for clarity).
However, very few reports have appeared on the reduction
of conjugated ketonic substrates via asymmetric transfer
hydrogenation.7 With the exception of Noyori’s propargylic
ketone reductions7a and their synthetic applications,8
these studies focus mainly on the reduction of cyclic
a,b-unsaturated ketones,7b–e which give consistently better
results than acyclic substrates. The effective kinetic
We examined the reduction of cyclic and acyclic
a,b-unsaturated ketones 3–5 by ATH using well-established
catalysts A–C.10 Some of the results have been presented in
a preliminary paper.7e The catalytic systems were prepared
in situ in the reaction mixture by combination of the
dimers [RuCl2(p-cymene)]2 or [RhCl2(pentamethylcyclo-
pentadiene)]2 with the appropriate ligand (R,R)-1 or
(1R,2R)-2.2c,2f,3a
Keywords: Asymmetric; Ketone; Reduction; Hydrogenation; Transfer;
Ruthenium.
*
Corresponding author. Tel.: C44 2476523260; fax: C44 2476524112;
e-mail: m.wills@warwick.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.036

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1865
O
O
O
O
H
OH
R
R
R
R
R
Ph
(i)
3a R=Ph
3b R=OCH2Ph
3c R=NHCO2Me
8a R=Ph
8b R=OCH2Ph
8c R=NHCO2Me
5a R=Me 5b R=Et
5c R=iPr 5d R=tBu
3a R=Ph 3b R=OCH2Ph
3c R=NHCO2Me 3d R=tBu
4 R=NHCOMe
Scheme 2. Reduction of a,b-unsaturated ketones 3a–c with catalysts A–B.
Conditions: (i) 0.5 mol% (R,R)-A or (1R,2S)-B, see Table 1.
Ts
Ts
N
Ph
Ph
N
Ph
Ph
Ph
Ph
NHTs
NH2
Ru
Rh
Table 1. Reduction of cyclic a,b-unsaturated ketones 3a–d with catalysts
(R,R)-A and (1R,2R)-B
Cl
Cl
N
N
H2
H2
Entry Ketone Catalyst % Yielda % Conv. b
8
% ee Confign.c
(R,R)-1
(R,R)-A
(R,R)-C
1
2
3
4
5
3a
3a
3b
3b
3c
Ad
Bf
47
27
78
0
62
33
—
0
72e
70e
99e
—
R
S
R
—
R
Ad
Bf
O
N
OH
Ru
Ad
54
80
O
99g
—
Cl
NH2
H2
6
7
3c
3d
Bf
0
0
0
0
—
—
Ad or Bf
—
(1R,2S)-2
(1R,2S)-B
a Isolated yield.
b Determined by 1H NMR.
c Predicted using Refs. 3a and 5i.
d The reaction was carried out overnight at 28 8C using 1 mol LK1 solution
of unsaturated ketone in formic acid:triethylamine mixture (5:2).
e Determined by HPLC analysis using a Daicel chiralcel OD 4.6!250 mn
column (propan-2-ol:hexane 10:90; 0.5 mL minK1).
2. Results and discussion
Unsaturated ketone 3a was prepared by allylic oxidation of
1-phenyl-cyclohexene using a 1:1 molar combination of
tert-butyl hydroperoxide and pyridinium dichromate.11
Ether 3b was obtained by treatment of 1,2-cyclohexane-
dione with benzyloxy trimethylsilane in the presence of a
catalytic amount of trifluoromethanesulphonic acid.12
Ketone 3c was synthesised in three steps from commercially
available cyclohexanone (Scheme 1) via silyl enol ether 6.13
Oxidative azidation of 6 gave the 2-azido-cyclohexan-1-one
7.14,15 The last step of the synthesis of 3c from 7, required
heating in methyl chloroformate in the presence of a
catalytic amount of trifluoroacetic acid and sodium
perrhenate. The last cyclic enone 3d bearing a tert-butyl
f
The reaction was carried out for 3 h at rt using 0.1 mol LK1 solution of
unsaturated ketone in propon-2-ol with KOH (2.5 mol%).
g HPLC analysis using Daicel chiralcel OD (EtOH:hexane 10:90;
0.5 mL minK1).
(99%) and good yield (78%) (Table 1, entry 3). Never-
theless, no reduction of substrate 3b was obtained with
catalyst (1R,2S)-B (Table 1, entry 4).
We have observed similar failures with B in the reduction of
a-chloro- and a-methoxyacetophenone. In these cases, we
suggested an inhibition of the reduction process due to the
chelation of either the methoxy substituted derivative or the
reduction product to the catalyst.5g Since our report, a
similar mechanism has been proposed by others.3c
The chelation of ketone 3b or its 1,2-reduction product 8b
to the ruthenium, may be followed by decomposition of the
catalyst. The reduction of 2-(methoxycarbonylamino)-
cyclohex-2-en-1-one 3c with catalyst (R,R)-A gave the
allylic alcohol 8c (Scheme 2) in 80% conversion and with
excellent ee (O99%) (Table 1, entry 5). In this case, it is
interesting to note that 20% of the starting material was
reduced via a 1,4-reduction process. Catalyst (1R,2S)-B was
also an inefficient catalyst for the reduction of substrate 3c
(Table 1, entry 6). Finally, the introduction of a tert-butyl
group (3d) at the a-position gave an incompatible substrate
for ruthenium(II)-catalysed transfer hydrogenation and
no reduction occurred using either catalyst (R,R)-A or
(1R,2S)-B (Table 1, entry 7).
t
group was obtained by addition of BuLi to 7-oxabicyclo
[4.1.0]heptan-2-one, followed by water elimination.16
OTIPS
O
O
O
N3
NHCO2Me
(ii)
(iii)
(i)
95%
68%
38%
6
7
3c
Scheme 1. Synthesis of cyclic a,b-unsaturated ketone 3c. Conditions:
(i) TIPS triflate (1.1 equiv), Et3N (2.0 equiv), CH2Cl2, 0 8C, 1 h; (ii) NaN3
(4.5 equiv), (NH4)2Ce(NO3)6 (3.0 equiv), MeCN, K20 8C, 1.5 h; (iii)
NaReO4 (1 mol%), TFA (1 mol%), ClCO2Me, 55 8C, 6 h.
Enone 3a was selectively reduced at the carbonyl moiety by
either catalyst (R,R)-A or (1R,2S)-B to the corresponding
allylic alcohol 8a (Scheme 2), in modest yields and ees
(Table 1, entry 1 and 2). In neither case was 1,4-reduction
product observed in the crude reaction mixture although
some unreacted starting material was recovered. Replace-
ment of the a-aryl group of 3a by a benzyloxy group (3b)
does not influence the regioselectivity of catalyst (R,R)-A
towards the carbonyl moiety. Thus, 3b was selectively
reduced to allylic alcohol 8b (Scheme 2) with very high ee
The reduction of 3c using rhodium catalyst (R,R)-C was not
as regioselective, and the allylic alcohol 8c was obtained in
only 7% yield despite excellent enantioselectivity (92%, S).
The isolated by-products were the 1,4-reduction ketonic
product 9 (20%), found to be racemic by HPLC analysis

1866
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
and the saturated alcohol carbamate derivatives 10.
Unfortunately, the ee of cis-10 (26%) and trans-10 (13%)
could not be determined. Similar differences in
reactivity with the same catalytic systems have been
previously observed in the reduction of a-substituted
acetophenones.2h,5h
O
O
OH
(i)
NHCOMe
NHCOMe
NHCOMe
14
15
4
Scheme 4. Reduction of acyclic a,b-unsaturated ketone 4 with catalysts
(R,R)-A and (R,R)-C. Conditions: see Table 2.
O
MeO
O
OH
NHCO2tBu
NHCO2tBu
Cl
NHCl
Table 2. Reduction of acyclic a,b-unsaturated ketone 4 with catalysts
(R,R)-A and (R,R)-C
Catalysta
% Conv. 14b
% Conv. 15b
11
12
Entry
9
cis/trans-10
1
2
Ac
Ce
33
O99
67d
0
In order to gain an insight into the mechanism of formation
of the by-products, allylic alcohol 8c and ketone 9 were
independently synthesised and exposed to the reaction
conditions employed for the asymmetric transfer hydrogen-
ation of 3c. Ketone 9 was synthesised by chromous chloride
promoted radical addition of N-chloromethylcarbamate 11
to 1-methoxycyclohexene 12.17–19 Allylic alcohol 8c was
prepared by the sodium borohydride reduction of compound
3c, in the presence of catalytic amount of cerium chloride
hydrate.20
a 0.25 mol% of catalyst, 2 days with 1 mol LK1 solution of unsaturated
ketone in formic acid:triethylamine mixture (5:2).
b Determined by 1H NMR.
c 28 8C.
d Diastereomeric ratioZ1:1.
e rt.
During the work on the reduction of acyclic a,b-unsaturated
ketones, we observed that the asymmetric transfer hydro-
genation of benzylidene acetophenone (chalcone) and
benzylidene acetone 5a gave different chemoselectivity
with catalyst (R,R)-A. Indeed, chalcone was preferentially
reduced via a 1,4-reduction pathway whilst benzylidene
acetone 5a mainly gave the corresponding allylic alcohol
17a (Scheme 5, Table 3). Similar observations were
previously made by others on the same substrates, during
the hydrogen-transfer hydrogenation assisted by an iron(II)
complex.24
The carbonyl moiety of ketone 9 was partially reduced by
rhodium catalyst (R,R)-C whilst the carbon–carbon double
bond of alcohol 8c was inert to these conditions. From these
experiments, it was deduced that cis/trans-10 were formed
via the reduction of ketone 9, and not via the reduction of
the carbon–carbon double bond of 8c. No isomerisation
of alcohol 8c to ketone 9 was observed. Some examples of
isomerisation of allylic alcohols to saturated carbonyl
compounds have been reported with some ruthenium
catalyst precursors used in transfer hydrogenation.21
O
H
OH
O
(i)
We next, examined the reduction of acyclic a,b-unsaturated
ketone 4 having, as far as possible, similar functional
groups to cyclic a,b-unsaturated ketone 3c. The acyclic
a,b-unsaturated ketone 4 was synthesised in two steps from
commercially available 3-chlorobutan-2-one (Scheme 3).22,23
R
Ph
R
Ph
R
Ph
Ph
5a R=Me 5b R=Et
5c R=iPr 5d R=tBu
17a-d
18a-d
H
OH
R
O
O
O
19a-d
(i)
(ii)
NHCOMe
65%
Scheme 5. Reduction of a,b-unsaturated ketones 5a–d with catalyst (R,R)-
A. Conditions: 0.5 mol% (R,R)-A, HCO2H–Et3N (5/2), 28 8C, 7 days, for
ratios see Table 3.
35%
Cl
N3
13
4
Scheme 3. Synthesis of acyclic a,b-unsaturated ketone 4. Conditions:
(i) NaN3 (1.5 equiv), acetone, rt, 2 days; (ii) NaReO4 (1 mol%), TFMS
(1 mol%), Ac2O, 50 8C, overnight.
Table 3. Reduction of cyclic a,b-unsaturated ketones 5a–d with catalyst
(R,R)-A
Asymmetric transfer hydrogenation of 3-(acetylamino)-but-3-
en-2-one 4 with catalyst (R,R)-A affordedthe ketone 14and the
saturated alcohol 15 in 33 and 67% conversion, respectively
(Scheme 4, Table 2). No allylic alcohol was detected in the
reaction mixture. The reaction most probably proceeds via a
1,4-reduction process, even though a 1,2-reduction pathway,
followed by a rapid isomerisation of the allylic alcohol product
to a saturated ketone, is still a possibility. Unlike the ruthenium
catalyst, the reduction of compound 4 with rhodium catalyst
(R,R)-C gave only ketone 14, in O99% conversion. Catalyst B
failed to give any reduction products.
Entry Ketone % Conv.
17a
% Conv. % Conv.
18a
% ee Confign.b
17
19a
1
2
3
4
5a
5b
5c
5d
75
90
48
13
0
4
25
6
30c
6d
R
R
30
71
16
3
28d
57d
R
—
a Determined by 1H NMR.
b Assigned by the sign of optical rotation.
c Determined by HPLC analysis using a Daicel chiralcel OD 4.6!250 mn
column (eluent 10:90 EtOH:hexane; flow rate 0.5 mL minK1).
d Determined by HPLC analysis using Daicel chiralcel OD (eluent 5:95
EtOH:hexane; flow rate 0.5 mL minK1).

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1867
Bearing this in mind, we were interested in studying the
reduction of benzylidene acetone derivatives with different
alkyl substituents at the a-position. We synthesised three
acyclic benzylidene acetone derivatives in order to study the
influence of the bulkiness of the alkyl substituent on the
chemo- and enantioselectivity of their reduction. Ketone 5b
was synthesised in 55% yield through a palladium-catalysed
vinylic substitution reaction with phenyl iodide and pent-1-
en-3-one.25 Ketones 5c and 5d were synthesised by aldol
condensation of benzaldehyde with respectively 3-methyl-
butan-2-one (58% yield) and pinacolone (50% yield).
conducted a series of experiments on 2-bromo-2-phenyl-
ethanol to see, which reagents are essential for dioxolan-2-
one formation. Table 4 summarises the results of this study,
in which we measured the conversion to dioxolan-2-one. In
all cases the mass balance was completed by unreacted
alcohol starting material. Epoxide formation was not
observed.
Table 4. Cyclic carbonate formation from a-bromophenylethanol
Reaction conditions
Yield (%)
[Ru(p-cymene)Cl2]2, TsDPEN, HCO2H:Et3N, 28 8C, 24 h
[RhCp*Cl2]2, TsDPEN, HCO2H:Et3N, 21 8C, 24 h
HCO2H:Et3N, 28 8C, 24 h
CO2, Et3N, DCM, 21 8C, 6 h
CO2, DCM, 21 8C, 6 h
51
17
0
14–40
0
ATH of acyclic a,b-unsaturated ketones 5a–d with catalyst
(R,R)-A afforded mixtures different ratios of 1,2 and
1,4-reduction products (Scheme 5, Table 3). Enone 5b
with an ethyl group, afforded the allylic alcohol 17b in 90%
conversion whilst enone 5d with a tert-butyl group gave the
saturated ketone 18d in 71% conversion. Enone 5c with an
iso-propyl substituent, gave a 50% mixture of 1,2 and 1,4
reduction products. It appears that, as the bulkiness of the
alkyl group increases from ethyl to iso-propyl to tert-butyl,
the chemoselectivity towards the carbonyl functionality
decreases although the extent of the ee of the allylic alcohol
17 increases. The sense of reduction (R) is the same for
compounds 5a–c. The configuration of the reduction
product of 5d has not yet been confirmed.
As the results show, the catalyst (either ruthenium or
rhodium based) is not required to produce the dioxolan-2-
one, nor is formic acid. The only essential additives are
carbon dioxide (solid pellets added) and triethylamine. This
suggests that the mechanism involves trapping of carbon
dioxide by the alcohol, with the bromide (or tosylate) acting
as a subsequent leaving group (Scheme 7). The catalyst
system in these reactions must therefore act only as a source
of carbon dioxide by decomposing formic acid to hydrogen
and carbon dioxide. Both the ruthenium and the rhodium
transfer hydrogenation systems yield the dioxolan-2-one,
however, the ruthenium system gives it in a much greater
yield, possibly due to more rapid decomposition of the
formic acid.
In a previous paper,5h we reported that the transfer
hydrogenation of a-tosyloxy acetophenone (20a) with a
Rh(III) based catalyst gave the alcohol (21a), whilst the
Ru(II) based catalyst gave the dioxolan-2-one (22a)
(Scheme 6). We have investigated of the mechanism of
the dioxolan-2-one formation, and the extension of the
scope of this reduction to a range of a-tosyloxy ketones.
O
C O
O
OH
OTs
OTs
TRANSFER
O
Ph
Ph
20
21
O
HYDROGENATION
OH
O
i
ii
OTs
O
OTs
Ph
Ph
Ph
BASE
O
S-22a 94% ee
20
S-21a 93% ee
65%Yield
O
H
44% Yield
O
O
O
O
Scheme 6. Conditions: (i) 0.25 mol% [Rh(C5Me5)Cl2]2, 0.5 mol% (R,R)-
TsDPEN, HCO2H, Et3N, (5:2 molar ratio), rt, 200 8C; (ii) 0.25 mol%
[Ru(p-cymene)Cl2]2, 0.5 mol% (R,R)-TsDPEN, HCO2H, Et3N, (5:2 molar
ratio), rt, 30 8C.
Ph
Ph
22
OTs
Scheme 7.
We were concerned that the temperature might be
influencing the reaction, since the Rh-catalysed reactions
are generally performed at rt, ca. 20 8C, and the Ru-
catalysed reactions at slightly higher temperature, ca. 30 8C
To prove that the temperature was not the decisive factor,
the rhodium catalysed transfer hydrogenation was repeated
at 30 8C. This resulted in formation of the 21 in a lower yield
of 35% but in identical ee. Hence the only difference
between the two reaction conditions is the metal complex
employed.
We have also investigated the scope of the reaction by
testing two further a-tosyloxy acetophenone derivatives
(Scheme 8, Table 5; note that TsDPEN of S,S configuration
was used for these reductions). These were prepared in a
good yield from their respective acetophenone derivatives
and HTIB. The ketones were reduced using standard ATH
conditions. Using Rh(III) catalysts, the enantiomerically
enriched alcohols were formed in moderate to good yields
(78–41%), and dramatically variable ee (O99–15%). The
reduction using Ru(II) catalysis also gave only the alcohol
in good ee for the p-nitro derivative 24 (82%), but the
p-methoxy derivative 23 yielded the dioxolan-2-one 22a, in
a moderate yield (28%) and ee (52%). The lack of formation
of a dioxolan-2-one in the case of the p-nitro substrate may
be due to the lower nucleophilicity of the alcohol in this
case.
Preliminary studies led us to conclude that the mechanism
for the formation of 22 is likely to be via the alcohol 21,
followed by trapping out of free carbon dioxide in the
reaction mixture. However, we were also anxious to
establish whether the Ru(II) catalyst was also playing a
part in the carbon dioxide trapping process. We therefore,

1868
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
the reaction conditions. In the cases of compounds 27–29,
O
O
the DKR reactions were carried out using 0.5 mol% catalyst
in the case of 29 and 2 mol% for the other two substrates.
Product 31 was isolated in only 13% yield and 80% ee
(absolute configuration assigned by comparison with related
structures), which does not indicate a dynamic resolution.
The unreacted starting material was found to have an optical
rotation of C13.3 (cZ0.08, chloroform) and by chiral
HPLC had an ee of 5%. This ketone was redissolved in
formic acid–triethylamine (5/2) and stirred for 24 h at rt.
The substrate was found to have no optical rotation and was
racemic by chiral HPLC. This suggests that the ketone does
racemise under the reaction conditions, but is not well
matched to the catalyst. The absolute configuration of the
2-phenylcyclohexanol 33 was found to be (1S,2S) by X-ray
analysis of the tosyl ester.32 The absolute configuration of
32 could not be confirmed in a satisfactory way, therefore
the assigned configuration represents that matched to the
fused tetralone ring (see below). The reduction of 30 gave a
mixture of the alcohol (51%) and the carbamate (16%) in
ees of only 6 and 5%, respectively, indicating that no DKR
was taking place, only a diastereoselective reduction.
OH
O
O
OTs
OR
OTs
i
X
X
X
22b (X=OMe)
22c (X=NO2)
21b (X=OMe)
21c (X=NO
23 (X=OMe)
24 (X=NO2)
2
)
Scheme 8. Conditions: (i) 0.25 mol% [Ru(p-cymene)Cl2]2, 0.5 mol% (S,S)-
TsDPEN, HCO2H, Et3N, (5:2 molar ratio), 28 8C or 0.25 mol% [Rh(C5-
Me3)Cl2]2, 0.5 mol% (S,S)-TsDPEN, HCO2H, Et3N, (5:2 molar ratio), rt.
Table 5. Investigation into the role of different electronic effects on
dioxolan-2-one formation
Ketone
Metal
Product
Yield (%)
ee
23
Ru
Rh
Ru
Rh
22b
21b
21c
21c
28
59
55
78
52
15
82
51
24
2.1. Dynamic kinetic resolutions
Dynamic kinetic resolution—transfer hydrogenation (DKR-
TH) of b-tetralone derivatives has been successfully
demonstrated in our group.5k In our previous report on
this subject, the best result was obtained using substrates of
type 25, for which both high yields and ees were achieved
(Scheme 9). The scope of this work has now been extended
to ketones 27–30. This selection was made on the basis of
the diversity of the substrates. In particular, compound 27
should have a higher pKa than the 1-aryl substrates, and thus
be a more challenging substrate.
Figure 2 illustrates the possible transition states for the
formation of 26a, 32 and 33. In the first and second cases, an
established p-interaction between the h6-arene (on ruthe-
nium) and the aryl ring of the substrate serves to stabilise the
transition state with the latter ring occupying the higher
position (as illustrated).2e The enantiomer of product, which
is preferably reduced is that in which the exocyclic phenyl
ring is furthest from the catalyst, thus minimising any steric
obstacles to the approach of the ruthenium hydride to the
ketone. In the case of 33, the exocyclic arene is presumed to
engage in a stabilising interaction with the h6-arene.
However, the ketone is reduced on the face opposite this
ring, resulting in formation of a cis product.
O
O
O
O
Ph
Ph
OTs
27
28
29
30
H
H
Ts
Ts
N
NH
Ru
H
H
Ph
H
Ru
N
Ph
H
H
H
NH
OH
O
H
OH
H
H
H
Ph
OH
Ph
Ph
O
Ph
for 32
for 25a
31 13% yield
80% e.e., >97% d.e.
32 87% yield
98% e.e., >97% d.e.
33 72% yield
98% e.e., >97% d.e.
H
H
Ts
N
NH
Ru
Ph
H
H
Substrates 28 and 29 are relatively simple ketones in which
the a-aryl group is designed to increase the acidity of the
a-proton in order to make it more likely to epimerise under
H
H
O
Ph
for 33
Figure 2. Preferred reduction transition states for 26a, 32, and 33.
Ar
Ar
O
OH
i
3. Experimental
3.1. General
25a, Ar=Ph
25b, Ar=pCl(C6H4)
25c, Ar=Ph
26a 91%, 94% e.e.
26b 91%, 95% e.e.
26c 88%, 99% e.e.
All reactions were run under an atmosphere of nitrogen in
flame or oven dried glassware (round bottomed flasks or
Scheme 9. Conditions: (i) 0.25 mol% [Ru(Cymene)Cl2]2, 0.5 mol% (S,S)-
TsDPEN, HCO2H, Et3N, (5:2 molar ratio), rt, 20 8C.

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1869
Schlenk tubes) unless otherwise stated. Room temperature
refers to ambient rt (20–22 8C). 0 8C refers to an ice slush
bath, K78 8C and K10 8C refer to a dry-ice acetone bath
and ice-acetone bath, respectively. Heated experiments
were conducted using thermostatically controlled oil baths.
Reagents were used as received from commercial sources
(Aldrich, Fluka, Lancaster) unless otherwise stated. Formic
acid–triethylamine mixture (5/2) is a commercially
available azeotrope (Fluka). All anhydrous solvents were
used as supplied by Romil in HyDryTM form, except
anhydrous propan-2-ol, which was supplied by Aldrich.
Tetrahydrofuran (THF) was freshly distilled from sodium
using benzophenone. Flash column chromatography was
3.1.2. 3-Azido-butan-2-one 13. To a stirred solution of
3-chlorobutan-2-one (5 mL, 50 mmol) in acetone (50 mL)
was added sodium azide (4.9 g, 75 mmol) at rt. The reaction
mixture was stirred for 2 days and filtered off. The solvent
was removed in vacuo to give a slightly yellow oil (4.3 g,
75%). The product was sufficient pure to be used in the next
step without any further purification. nmax (film) 2989, 2941,
2098 (N3), 1726 (CO), 1360, 1256 cmK1; dH (300 MHz;
CDCl3; Me4Si) 3.95 (1H, q, JZ7.1 Hz, CHN3), 2.24
(3H, s, COCH3), 1.44 (3H, d, JZ7.0 Hz, CH3CHN3);
dC (75.5 MHz; CDCl3; Me4Si) 205.8, 64.1, 26.8 and 16.1.
3.1.3. 3-(Acetylamino)-but-3-en-2-one 4. To a stirred
solution of 3-azido-butan-2-one 13 (3.00 g, 26 mmol) in
acetic anhydride (40 mL) was added sodium perrhenate
(0.071 g, 0.26 mmol) at rt, followed by trifluoromethane-
sulphonic acid (23 mL, 0.26 mmol). The reaction mixture
was stirred overnight at 50 8C, concentrated in vacuo to give
the crude product, which was purified by flash column
chromatography (25/45% v/v ethyl acetate/hexane) to
afford a yellow oil (1.155 g, 35%). nmax (Nujol) 3330, 3180,
1714 (CO), 1660 (NHCO) cmK1; dH (300 MHz; CDCl3;
Me4Si) 8.05 (1H, br s, NH), 6.91 (1H, s, CH), 5.78 (1H, s,
CH), 2.42 (3H, s, CH3CO), 2.14 (3H, s, CH3CONH);
dC (75.5 MHz; CDCl3; Me4Si) 195.2, 169.4, 138.6, 110.4,
25.1, 24.1; m/z (CI, NH3) 144 ([MCNH3]C, 8%), 128
([MCH]C, 100), 112 ([MKMe]C, 12), 79 (23), 60 (48), 35
(80); HRMS (CI, NH3): [NH]C, found 128.0711. C6H10O2N
requires 128.0711.
˚
carried out routinely using 60 A silica gel (Merck).
Determination of ees was achieved by HPLC analysis
(Waters 501 HPLC pump, a Waters 486 tuneable
absorbance detector, a Waters 746 data module and a
Daicel chiralcel OD 4.6!250 mm column). Chiral shift
reagent Eu(hfc)3 is Europium tris [3-(heptafluoropropyl-
hydroxymethylene)-(K)-camphorate]. Optical rotations
([a]D) were measured on a Perkin-Elmer 241 polarimeter
(sodium D line) at ambient temperature with a 10 cm
rotation cell and are reported in 10K1 deg cm2 gK1 with
c (concentration) in g/100 mL. Elemental analyses were
performed using the Exeter Analytical Model CE 440.
Infrared spectra (IR) were recorded on a Nicolet Model
Avatar 320 FTIR instrument. Nuclear magnetic resonance
(NMR) spectra were recorded either on a Bruker AC-250
(250 MHz), Bruker DPX-300 (300 MHz) or DXP 400
(400 MHz) spectrometer. Chemical shifts values are reported
in d units, parts per million (ppm) downfield from the
standard tetramethylsilane (Me4Si). Coupling constants (J)
are measured in Hertz (Hz). All mass spectra and high
resolution mass spectra were recorded on a Micromass
AutoSpec instrument. Compounds 3a,11 3b,123c,14 6,13
7,14,15 11,17 12,19 20,5h 21a,5h and 22a5h have been reported
previously.
3.1.4. 1-Phenyl-pent-1-en-3-one 5b. To a mixture of phenyl
iodide (2 mL, 17 mmol) and triethylamine (3.4 mL,
24 mmol) was added vinyl ethyl ketone (0.600 g,
7.1 mmol), followed by palladium(II) diacetate (8 mg,
0.035 mmol) and acetonitrile (2 mL) at rt. The mixture was
refluxed for 7 h then ethyl acetate (5 mL) and water (5 mL)
were added. The organic layer was washed with water, dried
over anhydrous magnesium sulphate, filtered and concen-
trated in vacuo to give a yellow oil, which was purified by
flash chromatography (5/20% v/v ethyl acetate/hexane) to
afford yellow crystals (0.639 g, 56%). Mp 35–36 8C (lit.,25
38–40 8C); nmax (neat) 3057, 2974, 1689, 1664, 1607, 1447,
1121 cmK1; dH (400 MHz; CDCl3; Me4Si) 7.58–7.54 (3H,
m, aryl CH, PhCH), 7.40–7.38 (3H, m, aryl CH), 6.75 (1H, d,
JZ16.0 Hz, COCH), 2.70 (2H, q, JZ7.3 Hz, CH2), 1.17
(3H, t, JZ7.3 Hz, CH3); dC (75.5 MHz; CDCl3; Me4Si)
201.2, 142.5, 135.0, 130.7, 129.3, 128.6, 126.4, 34.4, 8.6; m/z
(EI) 161 ([MCH]C, 49%), 160 ([M]C, 52), 131
([MKC2H5]C, 100), 103 ([MKC3H5O]C, 44), 77
([C6H5]C, 30), 57 ([C2H5CO]C, 7); HRMS (EI): [M]C,
found 160.0900. C11H12O requires 160.0888.
3.1.1. (G)-2-(Methoxycarbonylamino)-cyclohexan-1-one
9. To a K78 8C cooled solution of methylcarbamate and
N-chloromethylcarbamate 11 (78/22 mol/mol, respectively)
(0.540 g, 1.3 mmol of N-chloromethylcarbamate) in chloro-
form (3 mL) and absolute methanol (1 mL) was added a
solution of 1-methoxy-cyclohex-1-ene 11 (0.409 g,
3.6 mmol) in chloroform (1 mL), pre-cooled to K78 8C. A
solution of chromous chloride (0.310 g, 2.5 mmol) in
methanol (4.5 mL) was added dropwise during 1 h at
K78 8C and the reaction mixture was stirred for another
hour at the same temperature. The cooling bath was
removed and air was allowed in the reaction vessel. A
1 M aqueous solution of sulphuric acid (1 mL) was added
and the reaction mixture was stirred for 4 h. Water was
added (20 mL) and the mixture was extracted with
dichloromethane (3!40 mL). The organic extracts were
washed with water (2!15 mL), then combined, dried over
anhydrous sodium sulphate and filtered. The solvent was
removed in vacuo to give a colourless oil, which was
purified by flash chromatography (10/30% v/v ethyl
acetate/hexane) to afford the product as white crystals
(0.123 g, 55%). For characterisation, see reduction of
2-(methoxycarbonylamino)-cyclohex-2-en-1-one 3c with
catalyst (R,R)-C (vide infra).
3.1.5. 4-Methyl-1-phenyl-pent-1-en-3-one 5c. To a stirred
solution of benzaldehyde (1.2 g, 11 mmol) in ethanol
(40 mL) was added 3-methyl-butan-2-one (0.974 g,
11 mmol), followed by the addition of a 10% aqueous
solution of sodium hydroxide (11.2 mL, 2.7 mmol) at rt.
The reaction mixture was stirred at reflux for 2 days and a
saturated aqueous solution of sodium chloride was added
(30 mL). The product was extracted with ethyl acetate (3!
20 mL) and the combined organic layers were dried over
anhydrous magnesium sulphate, filtered and concentrated in
vacuo. Purification via flash column chromatography

1870
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
(0/5% v/v ethyl acetate/hexane) affords the product as a
yellow oil (1.1 g, 58%). nmax (neat) 2967, 1686, 1661, 1610,
1448, 1053 cmK1; dH (400 MHz; CDCl3; Me4Si) 7.61 (1H,
d, JZ16.0 Hz, CHPh), 7.57–7.55 (2H, m, aryl CH), 7.40–
7.38 (3H, m, aryl CH), 6.82 (1H, d, JZ15.8 Hz, CH), 2.97–
2.90 (1H, m, CHMe2), 1.19 (6H, d, JZ7.0 Hz, 2!CH3);
dC (75.5 MHz; CDCl3; Me4Si) 204.2, 142.8, 135.1, 130.7,
129.3, 128.7, 124.8, 39.7, 18.9; m/z (EI) 174 ([M]C, 14%), 131
([MKC3H7]C, 100), 103 ([MKC4H7O]C, 30), 76 ([C6H4]C,
16); HRMS (EI): [M]C, found 174.1060. C12H14O requires
174.1045.
requires C, 82.7; H, 8.1%]; nmax (Nujol) 3172 (OH), 2341,
1160, 1052 cmK1; dH (300 MHz; CDCl3; Me4Si) 7.38–7.23
(5H, m, Ar), 6.12 (1H, br s, CH), 4.38 (1H, br s, CHOH),
2.49–2.32 (2H, m, CH2), 1.96–1.87 (2H, m, CH2), 1.74–1.65
(3H, m, CH2, OH); dC (75.5 MHz; CDCl3; Me4Si) 141.7,
140.5, 128.7, 127.8, 127.0, 125.8, 66.7, 32.08, 27.9, 19.9;
m/z (EI) 174 ([M]C, 98%), 145 (100), 131 (93), 115 (89), 91
(91), 77 (70), 51 (56).
3.2.2. (R)-(C)-2-Benzyloxy-cyclohex-2-en-1-ol 8b. 2-
Benzyloxy-cyclohex-2-en-1-one 3b (0.202 g, 1.0 mmol)
was reacted overnight with (p-cymene) ruthenium(II)
chloride dimer (1.5 mg, 2.5!10K3 mmol) and TsDPEN
(1.8 mg, 5!10K3 mmol) in a formic acid:triethylamine
mixture (0.5 mL) according to the general procedure
described above. Purification by flash chromatography
(0/5% v/v ethyl acetate/hexane) affords (R)-(C)-2-
benzyloxy-cyclohex-2-en-1-ol 8b as a colourless oil
(0.156 g, 78%). The product was determined to be of 99%
ee by chiral HPLC analysis (chiral OD column, hexane/
propan-2-olZ90:10, 0.5 mL/min), S isomer 16.7 min, R
isomer 22.7 min. [a]D21 C74.4 (c 1, EtOH); nmax (film) 3425,
3029, 2926, 1663, 1452, 1180 cmK1; dH (300 MHz; CDCl3;
Me4Si) 7.28–7.41 (5H, m, Ar), 4.85 (1H, t, JZ4.1 Hz,
CH2CH), 4.74 (2H, s, CH2Ph), 4.23 (1H, br s, CHOH), 2.37
(1H, s, OH), 2.02–1.99 (2H, m, CH2), 1.97–1.63 (3H, m,
CH2CHH), 1.62–1.49 (1H, m, CH2CHH); dC (75.5 MHz;
CDCl3; Me4Si) 155.0, 137.5, 128.9, 128.3, 128.1, 97.9,
69.3, 66.9, 31.4, 24.3, 19.2; m/z (CI) 222 ([MCNH4]C,
52%), 204 ([M]C, 39), 187 (25), 108 (67), 91 (72); HRMS
(CI, NH3): [MCNH4]C, found 222.1492. C13H20O2N
requires 222.1494.
3.1.6. 4,4-Dimethyl-1-phenyl-pent-1-en-3-one 5d. To a
stirred solution of benzaldehyde (0.300 g, 2.8 mmol) in
ethanol (10 mL) was added pinacolone (0.280 g, 2.8 mmol),
followed by the addition of a 10% aqueous solution of
sodium hydroxide (2.8 mL, 0.7 mmol). The reaction
mixture was stirred at reflux overnight and a saturated
aqueous solution of sodium chloride was added (10 mL).
The product was extracted with ethyl acetate (3!10 mL)
and the combined organic layers were dried over anhydrous
magnesium sulphate, filtered and concentrated in vacuo.
Purification via flash column chromatography (0/10% v/v
ethyl acetate/hexane) affords the product as a yellow solid
(0.263 g, 50%). Mp 38–40 8C (lit.,27 42–43 8C); nmax (neat)
2966, 2867, 1681, 1608, 1576, 1495, 1073 cmK1; dH
(250 MHz; CDCl3; Me4Si) 7.69 (1H, d, JZ15.6 Hz,
PhCH), 7.62–7.53 (2H, m, aryl CH), 7.42–7.35 (3H, m,
aryl CH), 7.13 (1H, d, JZ15.55 Hz, CH), 1.23 (9H, s,
3!CH3); dC (75.5 MHz; CDCl3; Me4Si) 204.6, 143.3,
135.3, 130.6, 129.2, 128.7, 121.1, 43.6, 26.7; m/z (EI) 189
([MCH]C, 16%), 189 ([M]C, 4), 160 (7), 131 ([MKC4H9]C,
100), 103 ([MKC5H9O]C, 19), 76 ([C6H4]C, 10), 56
([C4H8]C, 12); HRMS (EI): [M]C, found 188.1195.
C13H16O requires 188.1201.
3.2.3. (R)-(C)-2-(Methoxycarbonylamino)-cyclohex-
2-en-1-ol 8c. 2-(Methoxycarbonylamino)-cyclohex-
2-en-1-one 3c (0.170 g, 1 mmol) was reacted overnight
with (p-cymene) ruthenium(II) chloride dimer (1.5 mg,
2.5!10K3 mmol) and TsDPEN (1.8 mg, 5!10K3 mmol)
in a formic acid:triethylamine mixture (1 mL) according to
the general procedure described above. Purification by flash
chromatography (10/30% v/v ethyl acetate/hexane)
affords (R)-(C)-2-(methoxycarbonylamino)-cylohex-2-
en-1-ol 8c as a colourless oil (0.093 g, 54%). The product
was determined to be of O99% ee by chiral HPLC
analysis (chiralcel OD column, hexane:ethanolZ90:10,
0.5 mL/min), R isomer 17.3 min, S isomer 35.6 min. [a]D11
C37.5 (c 0.2, EtOH); nmax (film) 3404, 2942, 2867, 1709,
1522, 1448, 1248, 1049 cmK1; dH (300 MHz; CDCl3;
Me4Si) 6.65 (1H, br s, NH), 5.78 (1H, t, JZ4.1 Hz, CH),
4.22 (1H, br s, CHOH), 3.69 (3H, s, CH3), 3.57 (1H, br s,
OH), 2.20–1.96 (2H, m, CCHCH2), 1.94–1.64 (3H, m,
CH(OH)CH2CHH), 1.64–1.49 (1H, m, CH(OH)CH2CHH);
dC (75.5 MHz; CDCl3; Me4Si) 155.4, 134.5, 113.4, 65.9,
52.6, 31.9, 24.6, 18.7; m/z (CI) 172 ([MCH]C, 53%), 171
([M]C, 36), 157 ([MHKMe]C, 62), 154 ([MKOH]C, 100),
140 ([MKOMe]C, 85), 112 ([MKCO2Me]C, 24), 96
([MKNH2CO2Me]C, 17), 84 (9), 68 (9); HRMS (CI, NH3):
[MCH]C, found 172.0973. C8H14O3N requires 172.0974.
3.2. General procedure for the reduction of a,b-unsatu-
rated ketones 3a–c and 5a–d and with catalyst (R,R)-A
A mixture of (p-cymene) ruthenium(II) chloride dimer
(2.5.10K3 equiv) and (R,R)-(K)-N-(p-toluenesulphonyl)-
1,2-diphenylethylene-diamine (TsDPEN) (5.0!10K3 equiv)
in a formic acid–triethylamine mixture (5/2 molar) was
stirred for 20 min at 28 8C. The corresponding ketone
(1.0 equiv) was added and the reaction mixture was stirred
at 28 8C, filtered through a plug of silica gel and washed
with ethyl acetate. The organic fractions were collected,
combined and concentrated in vacuo to give the crude
product.
3.2.1. (R)-(C)-2-Phenyl-cyclohex-2-en-1-ol 8a. 2-Phenyl-
cyclohex-2-en-1-one 3a (0.860 g, 5 mmol) was reacted
overnight with (p-cymene) ruthenium(II) chloride dimer
(7.7 mg, 12!10K3 mmol)and TsDPEN (9.2 mg, 25!10K3
mmol) in a formic acid:triethylamine mixture (2.5 mL)
according to the general procedure described above.
Purification by flash chromatography (0/15% v/v ethyl
acetate/hexane) affords (R)-(C)-2-phenyl)-cyclohex-2-en-
1-ol 8a as a white solid (0.410 g, 47%). The product was
determined to be of 72% ee by chiral HPLC analysis (chiral
OD column, hexane/propan-2-olZ90:10, 0.5 mL/min),
S isomer 17.1 min, R isomer 42.0 min. Mp 59 8C; [a]D23
C9.8 (c 1.6, CHCl3). [Found: C, 82.55; H, 8.1. C12H14O
3.2.4. (R)-(C)-4-Phenyl-but-3-en-2-ol 17a. 4-Phenyl-but-3-
en-2-one 5a (0.234 g, 1.6 mmol) was reacted with (p-cymene)
ruthenium(II) chloride dimer (2 mg, 3.9!10K3 mmol)
and TsDPEN (3 mg, 8.0!10K3 mmol) in a formic

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1871
acid:triethylamine mixture (1.6 mL) for 4 days according to
the general procedure described above. Purification by flash
chromatography (0/40% v/v ethyl acetate/hexane) affords
(R)-(C)-4-phenyl-but-3-en-2-ol 17a as a white solid
(0.141 g, 60%). The product was determined to be of 30%
ee by chiral HPLC analysis (chiralcel OD column,
hexane:ethanolZ90:10, 0.5 mL/min), R isomer 13.8 min,
S isomer 18.6 min. Mp 32–33 8C (lit.,28 34–35 8C); [a]D20
C4.7 (c 0.4, EtOH) (lit.,29 [a]D23 C30.5 (c 1.0 in CHCl3),
O99% ee (R)); nmax (neat) 3338, 2971, 1493, 1448, 1265,
1140, 1056 cmK1; dH (300 MHz; CDCl3; Me4Si) 7.37–7.26
(5H, m, aryl CH), 6.57 (1H, d, JZ15.9 Hz, PhCH), 6.26
(1H, dd, JZ15.9, 6.4 Hz, CH), 4.52–4.48 (1H, m, CHOH),
1.62 (1H, br s, OH), 1.38 (3H, d, JZ6.4 Hz, CH3); dC
(75.5 MHz; CDCl3; Me4Si) 137.1, 134.0, 129.9, 129.0,
128.1, 126.9, 69.4, 23.9; m/z (CI) 148 ([M]C, 54%), 133
([MKMe]C, 27), 131 ([MKOH]C, 100), 115 ([C9H7]C,
20), 105 (23), 91 ([C7H7]C, 44); HRMS (EI): MC, found
148.0875. C10H12O requires m/z 148.0888.
CH2), 1.86–1.75 (1HmajC1Hmin, m, CHMe2, CH2),
1.71–1.67 (2Hmin, m, CHMe2, CH2), 1.56 (1Hmaj, br s,
OH), 1.32 (1Hmin, br s, OH), 0.99 (3Hmaj, d, JZ6.8 Hz,
CH3), 0.95 (3Hmaj, d, JZ6.8 Hz, CH3), 0.91 (6Hmin, d, JZ
6.8 Hz, 2!CH3).
3.2.7. (K)-4,4-Dimethyl-1-phenyl-pent-1-en-3-ol 17d.
4,4-Dimethyl-1-phenyl-pent-1-en-3-one 5d (0.200 g,
1.1 mmol) was reacted with (p-cymene) ruthenium(II)
chloride dimer (2 mg, 2.9!10K3 mmol) and TsDPEN
(2 mg, 5.7!10K3 mmol) in a formic acid:triethylamine
mixture (1 mL) according to the general procedure
described above. Purification by flash chromatography
(0/10% v/v ethyl acetate/hexane) affords (K)-4,
4-dimethyl-1-phenyl-pent-1-en-3-ol 17d as a colourless oil
(0.015 g, 7%). The product was determined to be of 57% ee
by chiral HPLC analysis (chiralcel OD column, hexane:
ethanolZ95:5, 0.5 mL/min), major isomer 15.0 min, minor
isomer 19.2 min. [a]D20 K18.0 (c 0.4, EtOH); nmax (neat)
3406, 2952, 2867, 1477, 1362 cmK1; dH (400 MHz; CDCl3;
Me4Si) 7.40–7.38 (2H, m, aryl CH), 7.33–7.30 (2H, m, aryl
CH), 7.24–7.22 (1H, m, aryl CH), 6.58 (1H, d, JZ15.8 Hz,
PhCH), 6.29 (1H, dd, JZ15.8, 7.3 Hz, CH), 3.94–3.91 (1H,
m, CHOH), 1.55 (1H, br s, OH), 0.97 (9H, s, 3!CH3); dC
(100 MHz; CDCl3; Me4Si) 136.9, 131.8, 129.6, 128.6,
127.6, 126.4, 81.0, 35.3, 25.8; m/z (EI) 190 ([M]C, 8%), 173
([MKOH]C, 90), 133 ([MKC4H9]C, 100), 115 ([C9H7]C,
15), 105 (11), 91 ([C7H7]C, 8), 56 (13); HRMS (EI): MC,
found 190.1345. C13H18O requires 190.1358.
3.2.5. (R)-(C)-1-Phenyl-pent-1-en-3-ol 17b. 1-Phenyl-pent-1-
en-3-one 5b (0.200 g, 1.2 mmol) was reacted with (p-cymene)
ruthenium(II) chloride dimer (2 mg, 3.1!10K3 mmol) and
TsDPEN (2 mg, 6.2!10K3 mmol) in a formic acid:triethy-
lamine mixture (1 mL) according to the general procedure
described above. Purification by flash chromatography
(2/20% v/v ethyl acetate/hexane) affords (R)-(C)-1-
phenyl-pent-1-en-3-ol 17b as a colourless oil (0.155 g,
80%). The product was determined to be of 6% ee by chiral
HPLC analysis (chiralcel OD column, hexane:ethanolZ
95:5, 0.5 mL/min), R isomer 17.7 min, S isomer 23.9 min.
[a]D20 C1.1 (c 0.3 in EtOH) (lit.,30 [a]2D2 K6.30 (c 2.70
CHCl3), 100% ee (S)); nmax (neat) 3333, 2962, 2929, 1493,
1450, 962 cmK1; dH (300 MHz; CDCl3; Me4Si) 7.41–7.24
(5H, m, aryl CH), 6.58 (1H, d, JZ19.2 Hz, PhCH), 6.22
(1H, dd, JZ19.2, 8.2 Hz, CH), 4.26–4.18 (1H, m, CHOH),
1.73–1.63 (2H, m, CH2), 0.98 (3H, t, JZ8.8 Hz, CH3);
dC (75.5 MHz; CDCl3; Me4Si) 137.1, 132.6, 130.8, 129.0,
128.0, 126.85, 74.8, 30.6, 10.1; m/z (EI) 162 ([M]C, 28%),
145 ([MKOH]C, 100), 133 ([MKC2H5]C, 20), 117 (19),
105 (18), 91 ([C7H7]C, 24); HRMS (EI): MC, found
162.1044. C11H14O requires 162.1045.
3.2.8. (S)-(K)-2-Phenyl-cyclohex-2-en-1-ol 8a. A mixture
of (p-cymene) ruthenium(II) chloride dimer (7.7 mg,
12!10K3 mmol) and (1R,2S)-cis-1-aminoindan-2-ol
(7.5 mg, 5!10K3 mmol) in dry and degassed propan-2-ol
(4 mL) was heated at 80 8C for 20 min. After cooling down
to rt, a solution of 2-phenyl-cyclohex-2-en-1-one 3a
(0.860 g, 5 mmol) in dry and degassed propan-2-ol
(45 mL) was added to the reaction mixture. Then a 0.1 M
solution of potassium hydroxide in dry and degassed
propan-2-ol (1.25 mL, 0.125 mmol) was added. The
reaction mixture was stirred for 3 h at rt, filtered through a
plug of silica gel and washed with ethyl acetate (2!50 mL).
The organic fractions were collected, combined and
concentrated in vacuo to give the crude product, which
was purified by flash chromatography (0/15% v/v ethyl
acetate/hexane) to afford the product as a white solid
(0.230 g, 27%) (0.400 g of starting material was recovered,
47%). The product was determined to be of 70% ee by
chiral HPLC analysis (chiral OD column, hexane:propan-
2-olZ90:10, 0.5 mL/min), S isomer 17.1 min, R isomer
41.7 min. [a]2D3 K9.1 (c 1.0 in CHCl3).1H NMR spectrum is
identical to (R)-(C)-2-phenyl-cyclohex-2-en-1-ol 8a.
3.2.6. (R)-(K)-4-Methyl-1-phenyl-pent-1-en-3-ol 17c.
4-Methyl-1-phenyl-pent-1-en-3-one 5c (0.200 g, 1.1 mmol)
was reacted with (p-cymene) ruthenium(II) chloride
dimer (2 mg, 2.8!10K3 mmol) and TsDPEN (2 mg,
5.7!10K3 mmol) in a formic acid:triethylamine mixture
(1 mL) according to the general procedure described above.
Purification by flash chromatography (0/10% v/v ethyl
acetate/hexane) affords an inseparable mixture of (R)-(K)-
4-methyl-1-phenyl-pent-1-en-3-ol 17c and 4-methyl-1-phe-
nyl-pentan-3-ol 19c in a 4:1 ratio, respectively, and in the
form of a colourless oil (0.077 g, 40%). (R)-(K)-4-methyl-
1-phenyl-pent-1-en-3-ol 17c was determined to be of
28% ee by chiral HPLC analysis (chiralcel OD column,
hexane:ethanolZ95:5, 0.5 mL/min), R isomer 16.5 min, S
isomer 21.7 min. [a]2D0 K2.5 (c 0.4, EtOH) (lit.,31 [a]D24
K8.4 (c 1.02, CHCl3); dH (400 MHz; CDCl3; Me4Si)
7.38–7.27 (5HmajC5Hmin, m, aryl CH), 6.57 (1Hmaj, d,
JZ15.8 Hz, PhCH), 6.23 (1Hmaj, dd, JZ15.8, 6.9 Hz, CH),
4.05–4.01 (1Hmaj, m, CHOH), 3.43–3.37 (1Hmin, m,
CHOH), 2.88–2.81 (1Hmin, m, CH2), 2.65–2.61 (1Hmin, m,
3.3. Reduction of a,b-unsaturated ketone 4 with catalyst
(R,R)-A
A mixture of (p-cymene) ruthenium(II) chloride dimer
(3.6 mg, 5.9!10K3 mmol) and R,R)-(K)-N-(p-toluene-
sulphonyl)-1,2-diphenylethylene-diamine (TsDPEN) (4.3 mg,
12!10K3 mmol) in a formic acid:triethylamine mixture
(5/2 molar) (2 mL) was stirred for 20 min at 28 8C. Then
3-(acetylamino)-but-3-en-2-one 4 (0.300 g, 2.4 mmol) was
added and the reaction mixture was stirred for 2 days at

1872
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
28 8C, filtered through a plug of silica gel and washed with a
20% solution of methanol in ethyl acetate (2!10 mL). The
organic fractions were collected, combined and con-
centrated in vacuo to give the crude product, which was
purified by flash chromatography (0/10% v/v methanol/
ethyl acetate) to afford a mixture of compounds described
below (overall yield 61%).
(75.5 MHz; CDCl3; Me4Si) 208.6, 157.7, 59.8, 52.5, 41.4,
36.2, 28.3, 24.4; m/z (CI) 189 ([MCNH4]C, 8%), 172
([MCH]C, 100), 157 ([MHKMe]C, 7), 140 ([MKOMe]C,
11), 127 (10), 114 (19); HRMS (CI, NH3): [MCH]C, found
172.0975. C8H14O3N requires 172.0974).
3.4.2. (R)-(C)-2-(Methoxycarbonylamino)-cyclohex-2-
en-1-ol 8c. Colourless oil (0.011 g, 7%); [a]1D1 C33.4
(c 0.2, EtOH). The product was determined to be of 92%
ee from the reduction using (S,S)-(C)-N-(p-toluenesul-
phonyl)-1,2-diphenylethylene-diamine by chiral HPLC
analysis chiralcel OD column, hexane:ethanolZ90:10,
0.5 mL/min), R isomer 16.9 min, S isomer 31.8 min. The
1H NMR spectrum is identical to the one previously
described.
3.3.1. 3-(Acetylamino)-butan-2-one 14. Yellow oil
(0.079 g, 25%); nmax (film) 3293, 1721 (CO), 1652
(NHCO), 1540, 1374, 1146 cmK1; dH (300 MHz; CDCl3;
Me4Si) 6.41 (1H, br s, NH), 4.66–4.57 (1H, m, CH), 2.23
(3H, s, COCH3), 2.03 (3H, s, NHCOCH3), 1.38 (3H, d,
JZ7.1 Hz, CH3); dC (75.5 MHz; CDCl3; Me4Si) 207.3,
170.2, 55.1, 27.0, 23.5, 18.0; m/z (CI) 147 ([MCNH4]C,
8%), 130 ([MCH]C, 100), 88 (8), 86 ([MKAc]C, 9), 44
(31), 35 (25); HRMS (CI, NH3): [MCH]C, found 130.0865.
C6H12O2N requires 130.0868.
3.4.3. (K)-cis-(2-Hydroxy-cyclohexyl)-carbamic acid
methyl ester 10. Colourless crystals (0.040 g, 26%). Mp
81–85 8C; [a]2D6 K20.1 (c 0.8, EtOH); nmax (CDCl3)
3436, 3013, 2939, 2862, 1698, 1519 cmK1; dH (300 MHz;
CDCl3; Me4Si) 5.09 (1H, br s, NH), 3.98–3.92 (1H, m,
CHOH), 3.67 (4H, br s, CHNH, CH3), 2.01 (1H, br s, OH),
1.80–1.69 (1H, m, CH(OH)CHH), 1.69–1.46 (5H, m,
CH(OH)CHHCHHCHH, CH2CHNH), 1.46–1.30 (2H, m,
CH(OH)CH2CHHCHH); dC (75.5 MHz; CDCl3; Me4Si)
157.3, 68.4, 52.9, 52.4, 32.0, 27.75, 24.1, 20.1; m/z (CI) 174
([MCH]C, 29%), 159 ([MHKMe]C, 8), 142 ([MKOMe]C,
100), 98 ([MKNH2CO2Me]C, 14), 35 (34); HRMS (CI,
NH3): [MCH]C, found 174.1130. C8H16O3N requires
174.1130. The enantiomers could not be separated by
HPLC analysis or by chiral shift reagent ([Eu(hfc)3]).
3.3.2. 3-(Acetylamino)-butan-2-ol 15. Yellow oil (0.103 g,
33%); nmax (film) 3308, 2978, 1652 (NHCO), 1557, 1455,
1374, 1301, 1142 cmK1; dH (300 MHz; CDCl3; Me4Si)
(1:1 mixture of diastereomers) 6.14 (1H, br s, NH), 6.10
(1H, br s, NH), 4.04–3.90 (1H, m, CH), 3.90–3.81 (2H, m,
2!CH), 3.78–3.68 (1H, m, CH), 2.89 (2H, br s, 2!OH),
2.01 (3H, s, CH3), 2.00 (3H, s, CH3), 1.18 (6H, d,
JZ6.2 Hz, 2!CH3), 1.17 (3H, d, JZ7.0 Hz, CH3), 1.11
(3H, d, JZ7.0 Hz, CH3); dC (75.5 MHz; CDCl3; Me4Si)
(1:1 mixture of diastereomers) 171.2, 171.1, 71.0, 70.5,
51.1, 51.0, 23.75, 23.7, 20.9, 19.1, 18.3, 14.6; m/z (CI) 132
([MCH]C, 100%), 114 ([MKH2O]C, 16), 87 (7), 44 (14),
35 (22); HRMS (CI, NH3): [MCH]C, found 132.1022.
C6H14O2N requires 132.1024).
3.4.4. trans-(2-Hydroxy-cyclohexyl)-carbamic acid methyl
ester 10. White crystals (0.020 g, 13%). Mp 111–113 8C
(lit.,26 111–112 8C); nmax (CHCl3) 3436, 2933, 2860, 1707,
1519 cmK1; dH (300 MHz; CDCl3; Me4Si) 4.78 (1H, br s,
NH), 3.69 (3H, s, CH3), 3.40–3.24 (2H, m, CHOH, CHNH),
3.00 (1H, br s, OH), 2.07–1.97 (2H, m, CH(OH)CHH,
CHHCHNH), 1.76–1.67 (2H, m, CH(OH)CH2CHHCHH),
1.41–1.09 (4H, m, CH(OH)CHHCHHCHHCHH); dC
(75.5 MHz; CDCl3; Me4Si) 164.7, 75.4, 57.4, 52.7,
34.5, 32.2, 25.0, 24.4; m/z (CI) 174 ([MCH]C, 76%),
159 ([MHKMe]C, 33), 142 ([MKOMe]C, 100), 98
([MKNH2CO2Me]C, 16), 56 (6), 35 (14); HRMS (CI,
NH3): [MCH]C, found 174.1130. C8H16O3N requires
174.1130. The enantiomers could not be separated by
HPLC analysis or by chiral shift reagent ([Eu(hfc)3]).
3.4. Reduction of a,b-unsaturated ketone 3c with
catalyst (R,R)-C
A mixture of (pentamethycyclopentadienyl) rhodium(III)
chloride dimer (1.4 mg, 2.2!10K3 mmol) and R,R)-(K)-
N-(p-toluenesulphonyl)-1,2-diphenylethylene-diamine
(TsDPEN) (1.6 mg, 4.4!10K3 mmol) in a formic acid–
triethylamine mixture (5/2 molar) (1 mL) was stirred for
20 min at rt. Then, 2-(methoxycarbonylamino)-cyclohex-2-
en-1-one 3c (0.150 g, 0.88 mmol) was added and the
reaction mixture was stirred at rt for 9 days. The reaction
mixture was filtered through a plug of silica gel and washed
with ethyl acetate (2!10 mL). The organic fractions were
collected, combined and concentrated in vacuo to give the
crude product, which was purified by flash chromatography
(0/50% v/v ethyl acetate/hexane) to afford a mixture of
products described below (overall yield 67%).
3.5. Reduction of a,b-unsaturated ketone 4 with catalyst
(R,R)-C
A mixture of (pentamethycyclopentadienyl) rhodium(III)
chloride dimer (3.6 mg, 5.9!10K3 mmol) and (R,R)-(K)-
N-(p-toluenesulphonyl)-1,2-diphenylethylene-diamine
(4.3 mg, 12!10K3 mmol) in a formic acid:triethylamine
mixture (5:2 molar) (2 mL) was stirred for 20 min at rt.
Then 3-(acetylamino)-but-3-en-2-one 4 (0.300 g, 2.4 mmol)
was added and the reaction mixture was stirred at rt for
2 days, filtered through a plug of silica gel and washed with
a 20% solution of methanol in ethyl acetate (2!10 mL).
The organic fractions were collected, combined and
concentrated in vacuo to give the crude product, which
was purified by flash chromatography (0/10% v/v
3.4.1. (G)-2-(Methoxycarbonylamino)-cyclohexan-1-
one 9. White crystals (0.030 g, 20%). Mp 54–56 8C. The
product was confirmed to be racemic by chiral HPLC
analysis (chiralcel OD column, hexane:ethanolZ90:10,
0.5 mL/min), isomer 14.2 min, isomer 19.4 min. nmax
(Nujol) 1738, 1720, 1318, 1270, 1051 cmK1; dH
(300 MHz; CDCl3; Me4Si) 5.68 (1H, br s, NH), 4.30–4.22
(1H, m, CHNH), 3.67 (3H, s, CH3), 2.65–2.46 (2H, m,
COCHH, CHHCHNH), 2.46–2.31 (1H, m, COCHH),
2.20–2.08 (1H, m, COCH2CHH), 1.95–1.56 (3H, m,
COCH2CHHCH2), 1.50–1.39 (1H, m, CHHCHNH); dC

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1873
methanol/ethyl acetate) to afford 3-(acetylamino)-butan-2-
one 14 (0.212 g, 71%). 1H NMR spectrum is identical to the
one previously described.
3.8. General procedure for asymmetric transfer
hydrogenation of tosyloxyketones using ruthenium
(p-Cymene)ruthenium chloride dimer (6.2 mg, 0.01 mmol)
and (R,R)-TsDPEN (7.3 mg, 0.02 mmol) were stirred in a
formic acid:triethylamine mixture (2 mL, 5:2 molar ratio) in
a flame dried Schlenk under a nitrogen atmosphere at 28 8C
for 20 min. Ketone (4 mmol) was added and the reaction
was stirred at 28 8C until the substrate had disappeared by
TLC (typically 48 h). The reaction mixture was then filtered
through a plug of silica and washed with ethyl acetate (2!
50 mL). The organic fractions were collected, combined and
concentrated in vacuo to give the crude product, which was
purified by flash column chromatography (5–20% ethyl
acetate in hexane) to give the product.
3.6. General procedure for the a tosylation of ketones
Hydroxytosyloxyiodobenzene (3 g) was added to a stirred
solution of ketone (0.9 g) in acetonitrile (60 mL). The
reaction mixture was stirred under reflux for 2 h, cooled to rt
and then concentrated in vacuo. Ethanol (2 mL) was added
and the mixture was left overnight in a fridge. The
suspension was then filtered and the solid washed with
cold ethanol to give white crystals. Ethanol (1 mL) was
added to the filtrate and the solution was cooled to 2 8C
overnight. The suspension was filtered, washed with cold
ethanol and the crystals combined with the first batch to
afford the product.
3.8.1. (R)-2-Tosyloxy-1-(p-methoxyphenyl)ethanol 21b.
White crystalline solid (0.38 g, 59.1%). [a]2D0 K18 (c 0.742,
CHCl3); nmax (KBr) 3490, 1700 cmK1; dH (300 MHz;
CDCl3; Me4Si) 2.4 (3H, s, Me), 3.1 (1H, br s, OH), 3.8
(3H, s, OMe), 4.1 (2H, m, CH2), 4.9 (1H, dd, JZ3.8, 4.5 Hz,
CHOH), 6.8 (2H, d, JZ6.6 Hz, ArH), 7.2 (2H, d, JZ8.6 Hz,
ArH), 7.3 (2H, d, JZ8.3 Hz, tosyl ArH), 7.7 (2H, d,
JZ8.3 Hz, tosyl ArH); dc (75.5 MHz; CDCl3; Me4Si), 22.0
(d), 55.7 (q), 71.8 (q), 74.8 (t), 114.3 (d), 127.9 (d), 128.3
(d), 130.3 (d), 130.8 (s), 133.0 (s), 145.4 (s), 160.0 (s); m/z
(CI) 322.0874 (C16H18O5S requires 322.0874), 340 (79%),
305 (83), 151 (79); (EI) 322 (13%), 305 (100); chiral HPLC;
(7.5% ethanol/hexane; 0.5 mL/min), Rt 60.5, 67.6 min, 15%
ee. A racemic standard was prepared by sodium borohydride
reduction of 23.
3.6.1. a-Tosyloxy-p-methoxyacetophenone 23. Pale red
solid (3.1 g, 74%). Mp 118–120 8C; nmax (KBr) 3414, 1686
(C]O), 1602, 1360, 1249, 1172 cmK1;dH (300 MHz;CDCl3,
Me4Si)2.4(3H, s,tosylMe),3.9(3H, s, methoxyMe),5.2(2H,
s, CH2), 6.9 (2H, d, JZ9.0 Hz, ArH), 7.3 (2H, d, JZ7.8 Hz,
Tosyl ArH), 7.8 (2H, d, JZ8.9 Hz, ArH), 7.8 (2H, d,
JZ8.3 Hz, tosyl ArH); dc (75.5 MHz; CDCl3; Me4Si)
22.0 (q), 56.0 (q), 70.2 (t), 114.5 (d), 128.6 (d), 130.3 (d),
130.8 (d); m/z (EI) 135 (100%, MCKOTs); m/z (CI)
338 (100%, MC% NH4), 151 (98%, MC% NH4KOTs);
HRMS (EI): MC, found 320.0711. C16H16O5S requires
320.0718.
3.8.2. (R)-4-(4-Methoxyphenyl)-[1,3]-dioxalan-2-one
22b. White crystalline solid, (0.11 g, 28%). Mp 60–62 8C.
[Found: C, 61.46; H, 5.21. C10H10O4 requires C, 61.85; H,
5.19]; [a]2D0 K6.25 (c 0.942, CHCl3); nmax (KBr) 3413,
1783, 1615, 1252, 1174, 1047 cmK1; dH (300 MHz; CDCl3;
Me4Si), 3.8 (3H, s, Me), 4.3 (1H, t, JZ8.3 Hz, CHHCHO),
4.7 (1H, t, JZ8.3 Hz, CHHCHO), 5.6 (1H, t, JZ8.1 Hz,
CH2CHO), 7.0 (2H, d, JZ8.7 Hz, ArH), 7.3 (2H, d,
JZ8.9 Hz, ArH); dc (75.5 MHz; CDCl3; Me4Si), 55.8 (d),
71.5 (t), 78.6 (d), 115.0 (d), 127.8 (s), 128.3 (d), 161.1 (s);
m/z (EI) 194 (63%), 121 (100), 91 (27), 77 (17); (CI) 212
(33%), 195 (25%), 135 (63), 35 (100). A racemic standard
was prepared by sodium borohydride reduction of 24.
3.6.2. a-Tosyloxy-p-nitroacetophenone 24. Pale yellow
crystalline solid (2.4 g, 59%). Mp 136–138 8C. [Found:
C, 53.61; H, 3.85; N, 4.04. C15H13O6NS requires C, 53.73;
H, 3.91; N, 4.18%); nmax (KBr) 3406, 1710, 1525, 1361,
1172 cmK1;dH (300 MHz;CDCl3;Me4Si)2.5(3H, s,Me),5.3
(2H, s, CH2), 7.3 (2H, d, JZ8.5 Hz, tosyl ArH), 7.8 (2H, d,
JZ8.6 Hz, tosyl ArH), 8.1 (2H, d, JZ8.7 Hz, ArH), 8.4
(2H, d, JZ8.6 Hz, ArH); dc (75.5 MHz; CDCl3; Me4Si);
22.1 (q), 70.4 (t), 124.5 (d), 128.5 (d), 129.7 (d), 130.4 (d);
m/z (EI) 335 (10%), 289 (11), 257 (8), 150 (100), 120 (98),
91 (72), 65 (40).
3.7. General procedure for asymmetric transfer
hydrogenation of tosyloxyketones using rhodium
3.8.3. (R)-2-Tosyloxy-1-(p-nitrophenyl)ethanol 21c.
Yellow crystalline solid. Mp 163–166 8C. [Found; C,
53.39; H, 4.43; N, 4.18. C15H15O6NS requires C, 53.26;
H, 4.47; N, 4.14%]; nmax (KBr) 3505, 1603, 1515, 1346,
1170 cmK1; dH (300 MHz; CDCl3; Me4Si), 3.3 (1H, s, Me)
4.1 (1H, d, JZ4.4 Hz, CH2), 4.9 (1H, q, JZ4.7 Hz, CHOH),
6.1 (1H, d, JZ4.7 Hz, OH), 7.4 (2H, d, JZ7.9 Hz, tosyl
ArH), 7.5 (2H, d, JZ8.7 Hz, ArH), 7.6 (2H, d, JZ8.3 Hz,
tosyl ArH), 8.1 (2H, d, JZ7.2 Hz, ArH); dc (75.5 MHz;
CDCl3; Me4Si), 21.4 (q), 69.4 (d), 74.2 (t), 123.5 (d), 127.9
(d), 128.0 (d), 130.4 (d), 145.2 (s), 147.2 (s), 148.7 (s); m/z
(CI) 355 (73%), 153 (56), 136 (100), 120 (62); (EI) 307
(19%), 106 (100), 91 (52); via rhodium catalysis: (0.53 g,
78%); [a]2D0 K32 (c 0.811, EtOAc); chiral HPLC; (7.5%
ethanol/hexane; 0.5 mL/min), Rt 77, 85 min, 51% ee via
ruthenium catalysis: (0.37 g, 55%); [a]2D0 K35.5 (c 0.42,
Pentamethylcyclopentadiene rhodium chloride dimer
(6.2 mg, 0.01 mmol) and (1R,2R)-TsDPEN (7.3 mg,
0.02 mmol) were stirred in a formic acid:triethylamine
mixture (2 mL, 5:2 molar ratio) in a flame dried Schlenk
under a nitrogen atmosphere for 20 min. Ketone
(4 mmol) was added and the reaction was stirred at rt
until the substrate had been consumed as monitored by
TLC (typically 12–48 h). The reaction mixture was then
filtered through a plug of silica and washed with ethyl
acetate (2!50 mL). The organic fractions were collected,
combined and concentrated in vacuo to give the crude
product. This was purified by flash column chromato-
graphy (5–20% v/v ethyl acetate/hexane) to give the
product.

1874
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
CHCl3); chiral HPLC; (7.5% ethanol/hexane; 0.5 mL/min),
Rt 77, 86 min, 85% ee.
product was purified by column chromatography on silica
(2% ethyl acetate/hexane) to yield a pale yellow solid
(1.25 g, 29%). Mp 50–55 8C; nmax (neat) 3027, 2891, 2831,
2362, 1948, 1595, 1494, 1450, 1337, 1211, 1155, 1110,
1076, 1030, 937, 891, 747, 719, 688 cmK1; dH (400 MHz,
CDCl3, Me4Si); 2.72 (2H, t, JZ6.4 Hz, CH2CH2CPh), 2.92
(2H, t, JZ6.4 Hz, CH2CPh), 6.83 (1H, s, CH), 7.13 (4H, m,
ArH), 7.22–7.36 (3H, m, ArH), 7.52 (1H, m, ArH); dc
(100.5 MHz, CDCl3, Me4Si); 26.8 (t), 28.7 (t), 124.9 (d),
125.6 (d), 127.1 (d), 127.5 (d), 127.7 (d), 127.8 (d), 129.0
(d), 135.3 (s), 137.2 (s), 139.1 (s), 141.6 (s); m/z 206
(100%), 191 (15), 178 912), 152 (8), 128 (36), 115 (14), 91
(36); HRMS (EI): MC, found 206.1105. C16H14 requires
206.1095).
3.9. Dioxolan-2-one hydrolysis to diol
Sodium hydroxide (10 mL, 2 M) was added to the crude
reaction mixture (approx. 4 mmol) dissolved in diethyl ether
(10 mL) at 0 8C. The reaction mixture was allowed to warm
to rt and stirred for 2 h. The reaction mixture was extracted
with ethyl acetate (3!25 mL) and the organic fractions
were collected, combined, washed with brine (10 mL), dried
(Na2SO4) and concentrated in vacuo to give diol 5.
3.9.1. (S)-1-(4-Methoxyphenyl)ethane-1,2-diol. (Enantio-
meric standard); a-AD mix (1.4 g) was dissolved in butyl
t
alcohol (5 mL) and water (5 mL) at 0 8C. p-Methoxystyrene
(0.14 g, 0.1 mmol) was added, and the reaction was stirred
for 21 h. Sodium sulphate (1.5 g) was added and the reaction
stirred for 10 min, the reaction mixture was extracted with
dichloromethane (2!10 mL), and the solution evaporated
under reduced pressure to give a white solid. This was
purified by recrystallisation from ethyl acetate to give a
white crystalline solid (0.09 g, 52%). nmax (KBr) 3402,
3232, 1609, 1513, 1244, 1025 cmK1; dH (300 MHz;
CD3CN, Me4Si); 3.5 (2H, m, CH2), 3.7 (3H, s, OMe), 4.6
(1H, m, CH), 6.9 (2H, d, JZ8.6 Hz, ArH), 7.3 (2H, d,
JZ8.6 Hz, ArH); dc (75.5 MHz, CD3OD, Me4Si), 53.0 (d),
67.5 (t), 74.4 (q), 113.4 (d), 127.4 (d), 134.0 (s), 159.5 (s);
m/z (EI) 168.0771 (C9H12O3 requires 168.0786), 151 (39%),
137 (100), 121 (15), 109 (32), 94 (25), 77 (27); chiral HPLC;
(10% IPA/hexane; 0.5 mL/min), Rt 37 min, O99% ee.
3.9.5. 1-Cyclohexyl-3,4-dihydro-1H-naphthalen-2-one
27. Magnesium shavings (0.79 g, 32.8 mmol) were stirred
in tetrahydrofuran (30 mL) and iodine (trace amount) was
added. Cyclohexyl bromide (3.8 mL, 30.7 mmol) was added
dropwise. The reaction was stirred at rt for 1.5 h.
1-Tetralone (2.8 mL, 20.5 mmol) was added slowly, stirred
at rt for 29 h, then water (10 mL) was added. The reaction
was extracted with diethyl ether (2!30 mL), and washed
with hydrochloric acid (w1 M, 20 mL). The combined
organic extracts were dried over magnesium sulphate and
evaporated under reduced pressure to yield a yellow oil
(3.40 g). The product was dissolved in toluene (80 mL), and
p-toluenesulphonic acid (1.75 g, 9.21 mmol) was added.
A Dean-Stark trap was fitted, and the reaction refluxed for
3 h. The reaction was cooled to rt and washed with water
(50 mL), backwashed with toluene (2!20 ), dried over
magnesium sulphate and evaporated under reduced pressure
to yield a black oil (2.96 g). The product was purified by
column chromatography on silica (1% ethyl acetate/hexane)
to yield 4-cyclohexyl-1,2-dihydronaphthalene as a yellow
oil (0.68 g, 16%), which was processed forward crude.
mCPBA (0.54 g, 3.15 mmol) and sodium hydrogen carbon-
ate (0.29 g, mmol) were stirred in dichloromethane:water
(1:1, 24 mL) for 30 min. 4-Cyclohexyl-1,2-dihydronaphtha-
lene (0.66 g, 3.15 mmol) was added, and the reaction stirred
at rt for 4 h, washed with water (50 mL), and back extracted
with dichloromethane (40 mL). The combined organic
extracts were dried over magnesium sulphate, and evapor-
ated to yield a black oil. (0.75 g). The oil was dissolved in
toluene (20 mL), zinc iodide (0.29 g, 0.918 mmol) was
added, and the reaction refluxed for 4 h. It was then cooled
to rt and washed with water (30 mL) and back washed with
toluene (20 mL), dried over magnesium sulphate and
evaporated under reduced pressure to yield a brown oil.
The product was purified by column chromatography on
silica (10% ethyl acetate/hexane) to yield a yellow oil
(0.098 g, 13%); nmax (neat) 3063, 3019, 2920, 2849, 2666,
1707, 1485, 1447, 1365, 125, 1150, 1008, 744 cmK1; dH
(400 MHz, CDCl3, Me4Si); 0.94 (1H, m, CyH), 1.14 (4H, m,
CyH), 1.47 (1H, m, CyH), 1.58–1.76 (4H, m, CyH),
1.81–1.90 (1H, m, CyH), 2.44 (1H, ddd, JZ7.0, 11.8,
18.3 Hz, CHHCH2CO), 2.67 (1H, ddd, JZ3.1, 6.3, 18.3 Hz,
CHHCH2CO), 2.88 (1H, ddd, JZ2.3, 7.0, 15.8 Hz,
CHHCO), 3.12 (1H, d, JZ8.3 Hz, CHCy), 3.31 (1H, ddd,
JZ6.3, 11.8, 18.3 Hz, CHHCO), 7.02–7.26 (4H, m, ArH);
dc (100.5 MHz, CDCl3, Me4Si); 26.4 (t), 26.7 (t), 27.9 (t),
31.4 (t), 32.1 (t), 37.6 (t), 40.9 (d), 62.4 (d), 126.7 (d), 127.3
(d), 128.4 (d), 130.5 (d), 136.9 (s), 137.0 (s), 217.2 (s); m/z
3.9.2. (R)-1-(4-Methoxyphenyl)ethane-1,2-diol. White
solid, (5.7 mg, 51%). dH (300 MHZ, CDCl3, Me4Si); 2.1
(1H, br s, OH), 2.5 (1H, br s, OH), 3.6 (2H, m, CH2), 3.7
(3H, s, OMe), 4.7 (1H, m, CH), 6.9 (2H, d, JZ8.6 Hz, ArH),
(2H, d, JZ8.7 Hz, ArH); chiral HPLC; (10% IPA/hexane;
0.5 mL/min), Rt 32, 34 min, O52% ee.
3.9.3. (G)-2-Tosyloxy-1-(p-nitrophenyl)ethanol 21c.
White/yellow crystalline solid (0.07 g, 52%). dH
(300 MHz, DMSO-d6, Me4Si), 3.3 (3H, s, Me), 4.1 (2H, d,
JZ5.3 Hz, CH2), 4.9 (1H, q, JZ4.7 Hz, CHOH), 6.1 (1H, d,
JZ4.7 Hz, OH), 7.3 (2H, d, JZ8.1 Hz, tosyl ArH), 7.5 (2H,
d, JZ8.7 Hz, ArH), 7.6 (2H, d, JZ8.3 Hz, tosyl ArH), 8.1
(2H, d, JZ8.9 Hz, ArH); chiral HPLC; (7.5% ethanol/
hexane; 0.5 mL/min), Rt 76, 85 min (racemic standard).
3.9.4. 3-Phenyl-1,2-dihydronaphthalene.33 Magnesium
shavings (0.68 g, 2.81!10K2 M) were stirred in tetra-
hydrofuran (20 mL) and iodine (trace amount) was added.
Bromobenzene (2.75 mL, 26.1 mmol) was added dropwise,
and the reaction stirred for 20 min. 2-Tetralone (2.71 mL,
20.1 mmol) was added, and the reaction stirred at rt for 21 h,
diluted with diethylether (100 mL) and washed with
hydrochloric acid (0.5 M, aq, 50 mL). The organic extracts
were dried over magnesium sulphate and evaporated to
yield a yellow oil (3.46 g). This was dissolved in toluene
(50 mL), p-toluenesulphonic acid (0.86 g, 4.52 mmol) was
added, and the reaction refluxed for 3.5 h. The reaction was
cooled to rt and washed with water (20 mL). The solution
was dried over magnesium sulphate, and evaporated under
reduced pressure to yield a brown oil (3.39 g). The crude

P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
1875
228 (3%), 146 (100), 128 911), 115 (18), 91 (5); HRMS
(EI): MC, found 228.1501. C16H20O requires 228.1514).
1.70!10K3 mmol) and (S,S) TsDPEN (1.2 mg, 3.40!
10K3 mmol) was stirred in formic acid:triethylamine (5:2,
0.40 mL) at 28 8C for 20 min. 2-Phenyl-3,4-dihydro-2H-
naphthalen-1-one 28 (0.0378 g, 0.170 mmol) was added
and the reaction stirred at 28 8C for 77 h. The reaction
was filtered through a plug of silica and washed through
with ethyl acetate (40 mL), evaporated under reduced
pressure to yield a brown oil (0.0423 g), then purified by
column chromatography on silica (5% ethyl acetate/
hexane) to yield a colourless solid (0.033 g, 87%). Mp
76–78 8C; [a]D24 K186.90 (cZ1.16, CHCl3); nmax (neat)
3260, 3022, 2360, 2341, 1601, 1488, 1450, 1430, 1096,
1074, 1008, 958, 758, 736, 696 cmK1; dH (400 MHz,
CDCl3, Me4Si); 1.58 (1H, d, JZ2.8 Hz, OH), 1.96 (1H,
m, CHHCH2CAr), 2.44 (1H, ddd, JZ4.1, 4.3, 5.5 Hz,
CHHCH2CAr), 2.92 (1H, m, CHHCAr), 3.02 (1H, m,
CHHCAr), 3.10 (1H, m, CHAr), 4.79 (1H, m, CHOH),
7.18–7.40 (9H, m, ArH); dc (100.5 MHz, CDCl3, Me4Si);
21.9 (t), 30.1 (t), 46.4 (d), 71.7 (d), 126.6 (d), 127.2 (d),
128.5 (d), 128.6 (d), 129.1 (d), 129.5 (d), 130.4 (d),
137.1 (s), 138.0 (s), 143.0 (s); m/z (EI) 224 (15%), 206
(49), 120 (100), 91 (40); HRMS (EI): MC, found
224.1199. C16H16O requires 224.1201. Chiral HPLC; (5%
IPA/hexane; 0.5 mL/min), Rt 13, 19 min, O98% ee. A
racemic standard was prepared by sodium borohydride
reduction of 28.
3.9.6. 2-Phenyl-3,4-dihydro-2H-naphthalen-1-one 28.
mCPBA (1.06 g, 6.18 mmol) and sodium hydrogen carbon-
ate (0.63 g, 7.41 mmol) were stirred in dichloromethane:water
(1:1, 40 mL) for 40 min. 3-Phenyl-1,2-dihydronaphthalene
(1.27 g, 6.18 mmol) in dichloromethane:water (1:1, 20 mL)
was added, and the reaction stirred at rt for 3.5 h. The
organic layer was separated and the aqueous layer back
extracted with dichloromethane (30 mL), dried over
magnesium sulphate and evaporated to yield a brown
solid (1.47 g). The solid was dissolved in toluene (40 mL),
and zinc iodide (0.63 g, 1.98 mmol) was added. The
reaction was refluxed for 2.5 h, washed with water
(30 mL) and back extracted with toluene (20 mL), dried
over magnesium sulphate, and evaporated under reduced
pressure to yield a brown oil. The oil was purified by column
chromatography on silica (4% ethyl acetate/hexane) to yield
a yellow solid. Note the ketone is in the enol form in CDCl3
solution, (0.50 g, 37%). Mp 72–74 8C. [Found: C, 86.47; H,
6.35. C16H14O requires C, 86.45; H, 6.35]; nmax (neat) 3060,
3027, 2958, 2889, 2361, 2340, 1943, 1673, 1596, 1450,
1311, 1218, 1006, 896, 757, 695 cmK1; dH (400 MHz,
CDCl3, Me4Si); 2.45 (2H, m, CH2CH2CHAr), 3.08 (2H, m,
CH2CHAr), 3.80 (1H, dd, JZ6.2, 6.3 Hz, CHAr), 7.19 (1H,
d, JZ5.8 Hz, ArH), 7.26–7.36 (6H, m, ArH), 7.50 (1H, m,
ArH), 8.10 (1H, d, JZ5.8 Hz, ArH); dc (100.5 MHz, CDCl3,
Me4Si); 29.2 (t), 31.6 (t), 127.2 (d), 127.3 (d), 128.2 (d),
128.8 (d), 128.9 (d), 130.0 (d), 133.3 (s), 133.8 (d), 140.2
(s), 144.5 (s), 146.8 (s), 198.6 (s); m/z (EIC), 222 (80%),
194 (28), 165 (7), 131 (40), 118 (100), 90 (50), 77 (14).
3.9.9. (1S,2S) 2-Phenylcyclohexanol 33. Dichloro-p-
cymene ruthenium dimer (1.8 mg, 2.87!10K3 mmol)
and (S,S) TsDPEN (2.1 mg, 5.74!10K3 mmol) were
stirred in formic acid:triethylamine (5:2, 1 mL) at 28 8C
for 1 h. 2-Phenylcyclohexane 29 (0.20 g, 1.148 mmol)
was added and the reaction stirred at 28 8C for 186 h.
The reaction was filtered through a plug of silica, and
washed through with ethyl acetate (30 mL), then
evaporated under reduced pressure to yield a red solid
(0.188 g, 72%). Mp 25–26 8C; [a]2D4 C213.37 (cZ0.95
MeOH); nmax (neat) 3558, 3439, 3024, 2927, 2858, 2365,
1941, 1600, 1496, 1445, 1227, 1182, 1114, 1049, 964,
744, 696 cmK1; dH (300 MHz, CDCl3, Me4Si); 1.20–2.01
(9H, m, 4!CH2 C OH), 2.75 (1H, dt, JZ3.0, 12.8 Hz,
CHAr), 4.02 (1H, m, CHOH), 7.20–7.37 (5H, m, ArH);
dc (75.5 MHz, CDCl3, Me4Si); 20.0 (t), 24.7 (t), 26.6 (t),
33.3 (t), 48.4 (d), 71.0 (d), 126.9 (d), 128.2 (d), 128.9
(d), 144.4 (s); m/z (EI), 176 (100%), 130 (47), 117 (35),
104 (35), 91 (63), 69 (27); HRMS (EI): MC, found
176.1199. C12H16O requires 176.1201. 98% ee deter-
mined with 25% europium tris[3(heprafluropropylhydroxy-
methylene)-(C)-camphorate]. A racemic standard was
prepared by sodium borohydride reduction of 29.
3.9.7. (1R,2S) 1-Cyclohexyl-1,2,3,4-tetrahydronaphthalen-
2-ol 31. Dichloro-p-cymene ruthenium dimer (1.6 mg,
2.61!10K3 mmol) and (S,S)-TsDPEN (1.9 mg, 5.22!
10K3 mmol) were stirred in formic acid:triethylamine
(5:2, 0.3 mL) at 28 8C for 40 min. 1-Cyclohexyl-3,
4-dihydro-1H-naphthalen-2-one 27 (0.0641 g, 0.261 mmol)
was added, and the reaction stirred at 28 8C for 140 h. The
mixture was filtered through a pad of silica and washed
through with ethyl acetate (20 mL), and evaporated under
reduced pressure to yield a brown oil (0.0609 g). The
product was purified by column chromatography on silica
(10% ethyl acetate/hexane) to yield a brown oil (0.0193 g,
30%); [a]2D4 K116.67 (cZ0.98, CHCl3); nmax (neat) 3274,
2919, 2846, 2359, 2342, 1487, 1445, 1048, 765, 735 cmK1
;
dH (300 MHz, CDCl3, Me4Si); 0.71–0.85 (1H, m, aliphatic
CH), 0.95–1.38 (5H, m, aliphatic CH), 1.55–1.93 (8H, m,
7! aliphatic CH C OH), 2.60 (1H, t, JZ4.1 Hz, aliphatic
CH), 2.76 (1H, m, aliphatic CH), 2.85–2.95 (1H, m,
aliphatic CH), 4.18 (1H, m, CHOH), 6.52–7.22 (4H, m,
ArH); dc (300 MHz, CDCl3, Me4Si); 26.9 (t), 27.3 (t), 27.3
(t), 27.7 (t), 28.9 (t), 33.2 (t), 34.1 (t), 37.6 (d), 50.3 (d),
125.7 (d), 126.4 (d), 128.5 (d), 128.8 (d), 136.8 (s), 137.8
(s); m/z (EI) 230 (0.9%), 147 (10), 130 (100), 117 (15), 91
(13), 83 (11); HRMS (EI). MC, 230.1672. C16H22O requires
230.1671). Chiral HPLC; (1% IPA/hexane; 1.0 mL/min),
Rt 17, 14 min, 80% ee. A racemic standard was prepared by
sodium borohydride reduction of 27.
Acknowledgements
We thank the EPSRC for a research studentship (J.H.) and
EPSRC/GlaxoSmithKline pharmaceuticals for a CASE
studenship (J.A.K.). Professor D. Games and Dr. B. Stein
of the EPSRC National Mass Spectroscopic service
(Swansea) are thanked for HRMS analysis of certain
compounds. We also acknowledge the generous loan of
ruthenium and rhodium salts by Johnson-Matthey limited
and the use of the EPSRC’s Chemical Database Service at
Daresbury.34
3.9.8. (1S,2S) 2-Phenyl-1,2,3,4-tetrahydronaphthalen-
1-ol 32. Dichloro-p-cymene ruthenium dimer (1.0 mg,

1876
P. Peach et al. / Tetrahedron 62 (2006) 1864–1876
7. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
References and notes
Chem. Soc. 1997, 119, 8738. (b) Katho, A.; Carmona, D.; Viguri,
F.; Remacha, C. D.; Kovacs, J.; Joo, F.; Oro, L. A. J. Organomet.
Chem. 2000, 594, 299. (c) Hennig, M.; Puntener, K.; Scalone, M.
Tetrahedron: Asymmetry 2000, 11, 1849. (d) Bianchini, C.;
Glendenning, L.; Zanobini, F.; Farnetti, E.; Graziani, M.; Nagy,
E. J. Mol. Catal. 1998, 132, 13. (e) Hannedouche, J.; Kenny,
J. A.; Walsgrove, T.; Wills, M. Synlett 2002, 263.
1. (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30,
97. (c) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev.
1992, 92, 1051.
2. (a) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-I.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 233. (b) Hashiguchi, S.;
Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 7562. (c) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(d) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 4916. (e) Haack, K. J.;
Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. 1997, 36, 285. (f) Murata, K.; Ikariya, T.;
Noyori, R. J. Org. Chem. 1999, 64, 2186. (g) Yamakawa, M.;
Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818.
(h) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T.
Org. Lett. 2002, 4, 4373. (i) Everaere, K.; Mortreux, A.;
Carpentier, J.-F. Adv. Synth. Catal. 2003, 345, 67.
8. (a) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
(b) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2001, 40, 3667. (c) Yamano, Y.; Watanabe, Y.; Watanabe, N.;
Ito, M. J. Chem. Soc., Perkin Trans. 1 2002, 2833. (d) Fujii, K.;
Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733. (e)
Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197.
9. Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288.
10. Strictly, catalysts A–C are catalyst precursors. The true
catalytic species are formed by HCl elimination.
11. Chidambaram, N.; Chandrasekaran, S. J. Org. Chem. 1987, 52,
5048.
12. Ponaras, A. A.; Younus Meah, M. Tetrahedron Lett. 1986, 27,
4953.
3. (a) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62,
5226. (b) Nordin, S. J. M.; Roth, P.; Tarnai, T.; Alonso, D. A.;
Brandt, P.; Andersson, P. G. Chem. Eur. J. 2001, 7, 1431. (c)
Everaere, K.; Mortreux, A.; Bulliard, M.; Brussee, J.; van der
Gen, A.; Nowogrocki, G.; Carpentier, J. F. Eur. J. Org. Chem.
2001, 275. (d) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M.
Organometallics 1999, 18, 2291. (e) Petra, D. G. I.; Reek,
J. N. H.; Kamer, P. C. J.; Schoemaker, H. E.; van Leeuwen,
P. W. N. M. Chem. Commun. 2000, 683. (f) Mashima, K.; Abe,
T.; Tani, K. Chem. Lett. 1998, 1199. (g) Roth, P.; Anderson,
P. G.; Somfai, P. Chem. Commun. 2002, 1752. (h) Hannedouche,
J.; Clarkson, G.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986.
4. To our knowledge, only a few examples of highly enantio-
selective reduction of alkyl/alkyl ketones have been reported
and these are using chiral bidentate phosphinooxazoline
ligands: (a) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai,
M. Organometallics 1999, 18, 2291. (b) Arikawa, Y.; Ueoka,
M.; Matoba, K.; Nishibayashi, Y.; Hidai, M.; Uemura, S.
J. Organomet. Chem. 1999, 572, 163. (c) Jiang, Y.; Jiang, Q.;
Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38, 215.
13. Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta,
B. W. Tetrahedron 1995, 51, 11087.
14. Magnus, P.; Barth, L. Tetrahedron 1995, 51, 11075.
15. Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
16. Cossy, J.; Bouzbouz, S. Tetrahedron Lett. 1996, 37, 5091.
17. (a) Procedure adapted from: Driguez, H.; Vermes, J. P.;
Lessard, J. Can. J. Chem. 1978, 56, 119. (b) Caron, G.;
Lessard, J. Tetrahedron 1993, 49, 8039.
18. Bachand, C.; Driguez, H.; Paton, J. M.; Touchard, D.; Lessard, J.
J. Org. Chem. 1974, 39, 3136.
19. Shishido, K.; Hiroya, K.; Ueno, Y.; Fukumoto, K. J. Chem.
Soc., Perkin Trans. 1 1986, 829.
20. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
¨
21. Backvall, J.-E.; Andreasson, U. Tetrahedron Lett. 1993, 34,
5459.
22. Aelterman, W.; De Kimpe, N.; Kulinkovich, O. Bull. Soc.
Chim. Belg. 1997, 106, 703.
23. Effenberger, F.; Beisswenger, T.; Rainer, A. Chem. Ber. 1985,
118, 4869.
5. (a)Watanabe,M.;Murata,K.;Ikariya,T. J.Org.Chem. 2002, 67,
1712. (b) Koike, T.; Murata, K.; Ikariya, T. Org. Lett. 2000, 2,
3833. (c) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori,
R.; Ikariya, T. Org. Lett. 1999, 1, 1119. (d) Eustache, F.; Dalko,
P. I.; Cossy, J. Org. Lett. 2002, 4, 1263. (e) Mohar, B.; Valleix,
A.; Desmurs, J. R.; Felemez, M.; Wagner, A.; Mioskowski, C.
Chem. Commun. 2001, 2572. (f) Okano, K.; Murata, K.; Ikariya,
T. Tetrahedron Lett. 2000, 41, 9277. (g) Kenny, J. A.; Palmer,
M. J.; Smith, A. R. C.; Walsgrove, T.; Wills, M. Synlett 1999,
1615. (h) Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron: Asymmetry 2001, 12,
1801. (i) Kawamoto, A.; Wills, M. Tetrahedron: Asymmetry
2000, 11, 3257. (j) Kawamoto, A. M.; Wills, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 1916. (k) Alcock, N. W.; Mann, I.; Peach,
P.; Wills, M. Tetrahedron: Asymmetry 2002, 13, 2485.
24. Bianchini,C.;Peruzzini, M.;Farnetti, E.;Kaspar, J.;Graziani, M.
J. Organomet. Chem. 1995, 488, 91.
25. Cacchi, S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236.
26. Baranov, S. V.; Mochalin, V. B. Chem. Heterocyl. Compd.
(Engl. Transl.) 1981, 8, 779.
27. House, H. O.; Giese, R. W.; Kronberger, K.; Kaplan, J. P.;
Simeone, J. F. J. Am. Chem. Soc. 1970, 92, 2800.
28. Dickinson, J. M.; Murphy, J. A.; Patterson, C. W.; Wooster,
N. F. J. Chem. Soc., Perkin Trans. 1 1990, 1179.
29. Lee, D.; Huh, E. A.; Kim, M.-J.; Jung, H. M.; Koh, J. H.; Park,
J. Org. Lett. 2000, 2, 2377.
30. Watanabe, M.; Araki, S.; Butsugan, Y. J. Org. Chem. 1991, 56,
2218.
31. Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1998, 120, 13525.
6. (a) Wills, M.; Hannedouche, J. Curr. Opin. Drug Discov. Dev.
2002, 5, 881. (b) Yamashita, H.; Ohtani, T.; Morita, S.;
Otsubo, K.; Kan, K.; Matsubara, J.; Kitano, K.; Kawano, Y.;
Uchida, M.; Tabusa, F. Heterocycles 2002, 56, 123. (c)
Tanaka, K.; Katsurada, M.; Ohno, F.; Shiga, Y.; Oda, M.;
Miyagi, M.; Takehara, J.; Okano, K. J. Org. Chem. 2000, 65,
432. (d) Miyagi, M.; Takehara, J.; Collet, S.; Okano, K. Org.
Process Res. Dev. 2000, 4, 346.
32. P. Peach, PhD Thesis, University of Warwick, 2003.
33. Lamberts, J. J. M.; Cuppen, T. J. H. M.; Laarhoven, W. H.
J. Chem. Soc., Perkin Trans. 1 1985, 1819.
34. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.