Asymmetric allylic oxidation of bridged-bicyclic alkenes using a copper-catalysed symmetrising-desymmetrising Kharasch-Sosnovsky reaction

Article abstract of DOI:10.1016/j.tetlet.2004.10.093

Enantioselective symmetrising-desymmetrising allylic oxidation of racemic bridged bicyclic alkenes using an asymmetric copper-catalysed Kharasch-Sosnovsky reaction has been explored. Good yields and reasonable levels of induction (up to 70% ee) have been

Full text of DOI:10.1016/j.tetlet.2004.10.093

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9447–9450
Asymmetric allylic oxidation of bridged-bicyclic alkenes using
a copper-catalysed symmetrising–desymmetrising
Kharasch–Sosnovsky reaction
J. Stephen Clark,a,* Melanie-Rose Clarke,a John Clough,b Alexander J. Blakea and
Claire Wilsona
aSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
bResearch Chemistry, Syngenta, JealottÕs Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
Received 29 September 2004; accepted 14 October 2004
Available online 5 November 2004
Abstract—Enantioselective symmetrising–desymmetrising allylic oxidation of racemic bridged bicyclic alkenes using an asymmetric
copper-catalysed Kharasch–Sosnovsky reaction has been explored. Good yields and reasonable levels of induction (up to 70% ee)
have been obtained using carbocyclic systems as substrates.
Ó 2004 Elsevier Ltd. All rights reserved.
The discovery of new catalytic asymmetric allylic oxida-
tion reactions has been the objective of much research
over the past decade.1,2 In 1995, independent reports
from the groups of Pfaltz and Andrus showed that it
is possible to perform enantioselective allylic oxidation
of cyclic alkenes using an asymmetric copper-catalysed
version of the Kharasch–Sosnovsky reaction in which
a perester acts as the stoichiometric oxidant.3,4 Several
other groups have since reported similar asymmetric
reactions, employing various chiral copper complexes
as catalysts.5,6 However, these reactions have largely
been restricted to the enantioselective oxidation of sim-
ple substrates and the levels of asymmetric induction
have been modest in most cases.
Kharasch–Sosnovsky reaction can be used to prepare
bridged bicyclic allylic alcohol derivatives from the cor-
responding racemic alkenes in good yield and with rea-
sonable levels of asymmetric induction.
The application of the asymmetric symmetrising–desym-
metrising allylic oxidation reaction to more complex
substrates is highly attractive. Bicyclo[3.2.1]oct-2-enes
and the O-bridged analogues are particularly attractive
substrates because of the obvious synthetic potential of
the oxidised products. At the outset, our plan was to
perform copper-catalysed asymmetric allylic oxidation
of a variety of racemic substrates 1 to give the products
3 in non-racemic form (Scheme 1). The success of the
reaction would depend on symmetrisation of the racemic
The asymmetric Kharasch–Sosnovsky reaction has sel-
dom been applied to systems other than simple cyclic
alkenes, but in a recent landmark study, Kohmura and
Katsuki showed that it was possible to use the reaction
to oxidise racemic dicyclopentadiene and derivatives to
give the corresponding allylic oxidation products in
non-racemic form.6 Subsequent applications of the
asymmetric symmetrisation–desymmetrisation concept
to the oxidation of other substrates have not appeared.
We now report that the asymmetric copper-catalysed
X
X
X
Cu(I/II)Ln, L*,
Y
Y
Y
Y
O2CAr
Y
Y
t-BuO2COAr
1. NaIO4
2. NaBH4
H
( )-1
2
3
X = CH2, CR2, O, NR
Y = H, OR
meso
1. O3
2. NaBH4
Y = OH
H
Y
Y
ArCO2
OH
X
5
X
4
H
H
O2CAr
H
H
HO
Keywords: Alkene; Catalytic; Enantioselective; Oxidation.
*
HO
OH
Corresponding author. Tel.: +44 (0)115 9513542; fax: +44 (0)115
9513564; e-mail: j.s.clark@nottingham.ac.uk
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.093

9448
J. S. Clark et al. / Tetrahedron Letters 45 (2004) 9447–9450
substrate 1 by generation of the putative meso allylic
radical 2 followed by highly enantioselective desymmet-
risation of this transient intermediate to give the allylic
alcohol derivative 3. In principle, the reaction should
accommodate diverse functionality Y and a variety of
carbon or heteroatom bridging groups X. The non-race-
mic bicyclic products 3 could be subjected to ring scis-
sion by simple oxidative cleavage of the alkene or diol,
giving the highly functionalised five- and six-membered
carbocycles/heterocycles 4 and 5 (Scheme 1).
1. LiAlH4, THF, rt
80%
CHCl3, NaOH aq.,
PhCH2NEt3+Cl–, rt
52%
2. Na, NH3, C5H12
–78 °C 52%
,
Cl
Cl
13
11a
Scheme 4.
dienes 7a–d directly.7,8 The dienes 7b–d underwent par-
tial catalytic hydrogenation to give the alkenes 8b–d,
and the dienes 7a–c were subjected to sequential dihydr-
oxylation and acetonide formation to give the acetals
9a–c in excellent yield.
The bridged bicyclic alkenes required for our study were
prepared by the routes shown in Schemes 2–4. The bicy-
clo[3.2.1]oct-2-ene framework was constructed by the
Diels–Alder cycloaddition of tetrachlorocyclopropene
with a simple cyclopentadiene or furan, following a pro-
cedure reported by Law and Tobey in 1968 (Scheme 2).7
Heating tetrachlorocyclopropene with the cyclopenta-
dienes 6a,d and the furans 6b,c resulted in Diels–Alder
cycloaddition followed by presumed ionisation and elec-
trocyclic ring opening to afford the chlorinated bicyclic
The chlorinated alkenes 8b–d and 9a–c were then
dechlorinated to give the alkene oxidation precursors.
Methods for direct and complete dechlorination were
explored, but they proved to be unreliable and delivered
mixtures of partially dechlorinated products or de-
stroyed the bridged bicyclic compounds. After extensive
experimentation, we discovered a reliable two-stage pro-
cedure for the complete dechlorination of the com-
pounds 7a, 8b, 8d and 9a–c in which removal of
chlorine at the 2- and 4-positions was achieved using
an excess of lithium aluminium hydride and the remain-
ing 3-chloro substituent was removed by treatment with
sodium in ethanol (Scheme 3).9,10 Reasonable yields of
the dechlorinated alkenes 10, 11b, 11d and 12a–c were
obtained by this simple two-step route.8
X
R
H2, Pd-C,
Cl
EtOAc, rt
Cl
Cl
Cl
Cl
R
8 Cl
R
X
Cl
Cl
R
b 91%
c 79%
d 57%
C6H6, 80 °C
Cl
Cl
Cl
X
R
6
7 Cl
The simplest substrate of those prepared, bicy-
clo[3.2.1]oct-2-ene (11a), was synthesised using
R
Me
X
R
a 86%
b 47%
c 99%
d 54%
a
O
Cl
Cl
Cl
straightforward route developed by Kraus et al.
(Scheme 4).11 Addition of dichlorocarbene to norborn-
ene afforded the dichloride 13 in 52% yield, and com-
plete dechlorination was then performed by successive
reaction of this intermediate with lithium aluminium hy-
dride and sodium in liquid ammonia to give bicy-
clo[3.2.1]oct-2-ene (11a).11
Me
O
1. OsO4, NMO, THF,
t-BuOH, H2O, rt
2. Me2C(OMe)2,
Ac2O, PTSA, rt
R
9 Cl
a 80%, 93%
b 67%, 92%
c 87%, 94%
a X = CH2, R = H b X = O, R = H
c X = O, R = Me d X = C(CH2)2, R = H
The successful synthesis of the bridged bicyclic alkenes
10, 11a, 11b, 11d and 12a–c permitted exploration of
the asymmetric copper-catalysed symmetrising–desym-
metrising Kharasch–Sosnovsky allylic oxidation of these
substrates. We had already explored the enantioselective
allylic oxidation of simple alkenes such as cyclopentene
and cyclohexene, and had identified a subset of the bis-
oxazoline (box) and pyridyl-bisoxazoline (pybox) sys-
tems as potential ligands for the copper-catalysed
reaction (Fig. 1).5e The box ligands 14a,b and the pybox
ligands 15a–d were selected for the study; the sterics and
electronics of the pybox ligands were varied by placing
appropriate substituents at the 4-position of the
pyridine.
Scheme 2.
1. LiAlH4, THF, reflux
80%
Cl
Cl
Cl
2. Na, EtOH, reflux
38%
Cl
R
7a
10
1. LiAlH4, THF, reflux
X
X
R
R
b 32%
Cl
Cl
Cl
2. Na, EtOH, reflux
b 52% d 47% (2 steps)
R
R
R
8 Cl
11
Me
Me
1. LiAlH4, THF, reflux
X
R
X
The enantioselective copper-catalysed allylic oxidation
reactions of bicyclo[3.2.1]oct-2-ene (11a) and the cyclo-
propyl homologue 11d were explored first (Eq. 1, Table
1). Asymmetric Kharasch–Sosnovsky oxidation of bicy-
clo[3.2.1]oct-2-ene (11a) proceeded to give the endo-bicy-
clo[3.2.1]oct-3-en-2-ol benzoate (16) in yields of up to
70% and with ee levels of up to 66% using copper com-
plexes of the pybox ligands 15 as catalysts.12 The substit-
O
O
O
a 62% b 54% c 61%
Cl
Cl
Cl
Me
Me
O
2. Na, EtOH, reflux
a 83% b 76% c 86%
R
9 Cl
12
a X = CH2, R = H b X = O, R = H
c X = O, R = Me d X = C(CH2)2, R = H
Scheme 3.

J. S. Clark et al. / Tetrahedron Letters 45 (2004) 9447–9450
9449
Y
N
Cu(MeCN)4PF6 (5 mol%),
15a (6 mol%), t-BuO2COPh,
O2CPh
Me Me
( )
11a
MeCN, 60 °C
O
O
O
O
16 H
NaOH,
microwave 10 h 84%, 70% ee
sealed tube 2 d 80%, 66% ee
N
N
N
N
MeOH, rt
R
R
t-Bu
t-Bu
15a Y = H
15b Y = Cl
15c Y = OMe
15d Y = 2,6-Me2C6H3
OH
16 (70% ee) [α]18D −193 (c = 1.00, CHCl3)
18 (70% ee) [α]20D −133 (c = 1.00, CHCl3) 18 H
14a R = Ph
14b R = t-Bu
Scheme 5.
Figure 1.
with an ee of 70% when the copper complex of the pybox
ligand 15a was employed as the catalyst.
Table 1. Asymmetric copper-catalysed symmetrising–desymmetrising
allylic oxidation of racemic bicyclo[3.2.1]oct-2-enes 11a and 11d
Entry Substrate Ligand
Time Product Yielda Eeb
Attempted allylic oxidation of the bicyclic diene 10 re-
sulted in complete decomposition of the starting mate-
rial, and none of the expected oxidation product was
obtained. Surprisingly, the oxygen-containing substrates
11b, 11c and 12a–c did not deliver the expected products
under the usual Kharasch–Sosnovsky conditions using
either copper box or pybox complexes as catalysts, and
a significant amount of unreacted starting material was
recovered in each case. The lack of reactivity of the oxy-
gen-containing alkenes 11b, 11c, and 12a–c is difficult to
explain and further studies will be required to reveal
why these substrates do not react under conditions that
result in efficient allylic oxidation of the carbocyclic sub-
strates 11a and 11d.
(d)
(%)
(%)
1
2
3
4
5
6
11a
11a
11a
11a
11d
11d
15a
15b
10
16
16
70
70
36
63
48
38
58 (À)
50 (À)
66 (À)
62( À)
60 (À)
54 (+)
10
10
8
15c
15d
16
16
14a
(R,R)-14a
6
17
ent-17
5
a Yield of purified product.
b The ee was determined using chiral HPLC.
uent at the 4-position of the pyridine unit in the pybox
ligand was found to have a marginal influence on the
level of asymmetric induction. Interestingly, the copper
complex of the ligand 15c delivered the lowest yield of
the product 16 but with the highest ee (entry 3). The
cyclopropyl substrate 11d also underwent asymmetric
copper-catalysed Kharasch–Sosnovsky allylic oxidation
(entries 5 and 6), but in this case the conventional box
ligand 14a proved to be superior to the pybox ligands
15. The ester 17 was obtained with ee levels of up to
60% but the yields were modest.
In summary, we have shown that it is possible to per-
form enantioselective symmetrising–desymmetrising
allylic oxidation of racemic bridged bicyclic alkenes
using an asymmetric Kharasch–Sosnovsky reaction cat-
alysed by a chiral copper box or pybox complex. Yields
of up to 84% and levels of induction up to 70% ee have
been obtained upon oxidation of the alkenes 11a and
11d. The reaction should be applicable to a variety of
other simple racemic bridged bicyclic compounds.
X
X
Cu(MeCN)4PF6 (5 mol%),
Ligand (6 mol%),
O2CPh
Acknowledgements
ð1Þ
t-BuO2COPh, MeCN, 40 °C
( )
H
We thank the Overseas Research Students Awards
Scheme (UK), University of Nottingham and Syngenta
for financial support.
11aX = CH2
16 X = CH2
11dX = C(CH2)2
17 X = C(CH2)2
Copper complexes of the S,S configured box and pybox
ligands delivered the allylic benzoate (À)-16, which was
found to have the absolute configuration 1R,2S,5S by
comparison of optical rotation data for the alcohol
(À)-18 with literature data (Scheme 5).13 Tentative ste-
reochemical assignments for the benzoate 17 were made
by analogy with those of the benzoate (À)-16.
References and notes
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oxidation product (À)-16 was obtained in 84% yield
´
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9450
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