Alkene epoxidation catalyzed by bicyclo[3.2.1]octan-3-ones: Effects of structural modifications on catalyst efficiency and epoxidation enantioselectivity

Article abstract of DOI:10.1016/S0957-4166(00)00170-1

Several 2-substituted bicyclo[3.2.1]octan-3-ones are prepared and have been tested as catalysts for alkene epoxidation by Oxone(). Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00170-1

Tetrahedron: Asymmetry 11 (2000) 2057±2061
Alkene epoxidation catalyzed by bicyclo[3.2.1]octan-3-ones:
e€ects of structural modi®cations on catalyst eciency and
epoxidation enantioselectivity
Alan Armstrong,a,*,y Barry R. Hayter,a William O. Moss,b Jonathan R. Reevesa
and J. Steven Wailesa
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bZeneca Pharmaceuticals, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
Received 11 April 2000; accepted 4 May 2000
Abstract
Several 2-substituted bicyclo[3.2.1]octan-3-ones are prepared and have been tested as catalysts for alkene
epoxidation by Oxone1. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The use of chiral dioxiranes, generated in situ from ketones and Oxone1, is an extremely promising
approach for the asymmetric epoxidation of `unfunctionalised' alkenes.1 4 Amongst several
notable contributions, the fructose derived ketone 1 reported by Shi and co-workers2 a€ords
very high enantioselectivities for epoxidation of a range of alkenes. However, it su€ers from
decomposition by Baeyer±Villiger reaction under the reaction conditions, necessitating the use of
relatively high quantities, although loadings can be lowered if the reaction is performed at higher
pH.2 We recently described the novel ketone 2, obtained by electrophilic ¯uorination of the tri-
methylsilyl enol ether of commercially available N-carbethoxytropinone.4 This ketone was found
to be stable to the Baeyer±Villiger reaction, allowing its use in relatively low loadings (<10 mol%),
even at near neutral pH (7.5). Non-racemic 2 was prepared by chiral base desymmetrisation of
N-carbethoxytropinone 3, which proceeded in ca. 70% ee; fortunately, it was possible to increase
the enantiomeric purity of 2 by recrystallisation. Enantiomerically pure 2 prepared in this way
provided encouraging epoxidation enantioselectivities: for example, room temperature epoxidation
of E-stilbene proceeded in 76% ee, whilst phenylstilbene a€orded the corresponding epoxide in
83% ee.4 While these results are promising, clearly it would be desirable to increase epoxidation
* Corresponding author. E-mail: a.armstrong@ic.ac.uk
y
Present address: Department of Chemistry, Imperial College, London SW7 2AY, UK.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00170-1

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enantioselectivity still further. An attractive feature of the tropinone template is the possibility of
preparing a range of modi®ed derivatives by structural alteration at several sites in the catalyst.
Here we describe initial investigations into some of these modi®cations, and show that highly
promising catalysts can indeed be prepared.
2. Results and discussion
The most obvious alteration of 2 is to replace the a-¯uorine substituent. Several such derivatives
were prepared, initially in racemic form, from the common silyl enol ether 4.5 Reaction with
N-chlorosuccinimide (NCS) a€orded the chloride 5, while oxidation with dimethyldioxirane
(DMDO) provided the a-hydroxy ketone 6, acetylation of which led to 7.6 We were intrigued by
the idea of incorporating the a-acetonide motif believed to be responsible for the high enantio-
selectivities a€orded by the Shi ketone 1. The target 9 was accessed from 4 by a sequence of
cyclopropanation and regioselective ring opening to give the enone 8,7 followed by dihydroxylation
and acetonide protection (Scheme 1).
Scheme 1. (a) LDA, TMSCl, THF, ^78ꢀC; (b) NCS, NaOAc, acetone/H2O, 18 h, 73% from 3; (c) dimethyldioxirane,
acetone, CH2Cl2, 60% from 3; (d) Ac2O, Sc(OTf)3, 74%; (e) Et2Zn/CH2I2, Et2O, rt, 18 h, 42% from 3; (f) SnCl4,
.
DMSO, CH2Cl2, rt, 24 h, 80%; (g) K2OsO4 2H2O, NMO, quinuclidine, acetone/H2O, rt, 16.5 h, 82%; (h) 2,2-dimethoxy-
propane, HClO4, acetone, 0ꢀC, 3 h, 70%
In order to evaluate the e€ect of varying the bridgehead heteroatom, we also prepared the
corresponding oxabicycles 12±14 from the parent ketone 108 (Scheme 2).
These new racemic ketones were then subjected to preliminary screening for catalytic activity
under the Yang9 Oxone1/CH3CN/H2O system (pH ca. 7.5). For comparison, results using 24
are also included in Table 1. Chloride 5 (entry 2) was markedly less e€ective than 2, while,
disappointingly, use of 9 led to low conversion (entry 3), with the catalyst appearing to undergo
Baeyer±Villiger decomposition. This result underscores the dramatic structural dependency of

A. Armstrong et al. / Tetrahedron: Asymmetry 11 (2000) 2057±2061
2059
Scheme 2. (a) (i) LDA, THF, ^78ꢀC; (ii) TMSCl, Et3N, THF; (b) Select¯uorTM, CH3CN, rt, 1 h, 33% from 10; (c)
dimethyldioxirane, acetone, CH2Cl2, 40% from 10; (d) Ac2O, Sc(OTf)3, 77%
catalyst stability.2c,10 The alcohol 6 was also a poor promoter (entry 4), presumably due to sus-
ceptibility to oxidation to an unstable diketone. However, the corresponding acetate 7 a€orded
better results: although less active than 2, it appeared to be stable (entries 5±7). The oxygen
heterocycles 12 and 14 were also e€ective catalysts (entries 8±12), although again slightly less
active than 2.
Table 1
Epoxidation of E-stilbene catalysed by racemic ketones 2, 5, 6, 7, 9, 12 and 14a
Having evaluated the racemic catalysts, we now attempted their preparation in non-racemic
form using chiral base desymmetrisation.11 Unlike ketone 2, we were not able to improve catalyst
enantiomeric excess of 5, 7, 12 or 14 by recrystallisation, so the ketones tested for the epoxidation
of E-stilbene were not enantiomerically pure. Table 2 therefore includes an `eemax' value, the

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A. Armstrong et al. / Tetrahedron: Asymmetry 11 (2000) 2057±2061
expected product ee with enantiomerically pure catalyst based on the assumption that there is an
approximately linear relationship between catalyst ee and product ee. We have established that
this is indeed the case for ¯uoroketone 2.12 Again, results using 2 are included in Table 2 for
comparison. As well as being a less active catalyst, the chloride 5 a€ords lower enantioselectivity
than 2 (compare entries 1 and 2). However, acetate 7 showed higher eemax than 2 (entry 3).
Altering the bridgehead heteroatom to oxygen, with 12, also improved the eemax relative to 2
(entry 4). Pleasingly, the e€ects of the two bene®cial features appeared to be additive: the a-acetoxy-
oxabicycle 14 a€orded eemax of up to 95% (entries 5 and 6). These are highly encouraging results
given that they were obtained at room temperature and without optimisation of solvent or reaction
pH. Moreover, the potential exists for replacement of the acetate unit with a range of alternative
ester substituents.
Table 2
Epoxidation of E-stilbene catalysed by non-racemic ketones 2, 5, 7, 12 and 14a
In summary, we have prepared and tested several novel bicyclo[3.2.1]octan-3-ones as catalysts
of Oxone1 epoxidation of alkenes. The highest eemax is obtained using the a-acetoxy-oxabicycle
14. Ongoing work must address the ecient preparation of 14 in enantiomerically pure form, and
its testing in the asymmetric epoxidation of a wider range of alkenes.
Acknowledgements
We thank the following for funding: the EPSRC, the DTI and a consortium of chemical
companies through the LINK Asymmetric Synthesis Second Core Programme (studentship to
BRH); the EPSRC (Quota studentship to J.S.W.); and the EPSRC and AstraZeneca (CASE
award to J.R.R.).

A. Armstrong et al. / Tetrahedron: Asymmetry 11 (2000) 2057±2061
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