Asymmetric epoxidation of a geminally-disubstituted and some trisubstituted enones catalysed by poly-L-leucine

Article abstract of DOI:10.1016/S0040-4039(01)00535-4

Epoxidation of a range of enones derived from tetralone or related cyclic ketones, employing poly-L-leucine, urea-H₂O₂ and DBU in iso-propyl acetate is reported. The corresponding epoxides were isolated in 63-85% yield and 59-96% ee.

Full text of DOI:10.1016/S0040-4039(01)00535-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3741–3743
Asymmetric epoxidation of a geminally-disubstituted and some
trisubstituted enones catalysed by poly- -leucine
L
Paul A. Bentley, Jamie F. Bickley, Stanley M. Roberts* and Alexander Steiner
Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
Received 3 November 2000; accepted 29 March 2001
Abstract—Epoxidation of a range of enones derived from tetralone or related cyclic ketones, employing poly-L-leucine, urea–H2O2
and DBU in iso-propyl acetate is reported. The corresponding epoxides were isolated in 63–85% yield and 59–96% ee. © 2001
Elsevier Science Ltd. All rights reserved.
There is widespread interest in the use of synthetic
peptides as catalysts and ligands in stereoselective syn-
thesis.1 The seminal work of Julia´ and Colonna showed
that E-chalcone [PhCOCHꢀCHPh] can be oxidised in a
Recently, we introduced a new, non-aqueous, biphasic
reaction protocol for the Julia´–Colonna oxidation6
comprising urea–H2O2, DBU and poly-L-leucine immo-
bilised on a polystyrene support (i-PLL).7 Even under
these more powerful oxidation conditions, trisubsti-
tuted enones proved to be unreactive.8 The effect of
placing a simple alkyl unit in the a-position of the
enone on the reactivity under the biphasic conditions is
clearly illustrated in Scheme 1. Oxidation of the diene 1
produced epoxide 2 (70% yield, 92% ee) as the only
isolated product, thus leaving the unreacted olefin
available for further functionalisation.9
stereoselective manner using
a triphasic reaction
medium, comprising aqueous H2O2, a water-immiscible
organic solvent and an insoluble polyamino acid, typi-
cally poly-L-alanine, to give the corresponding epoxide
in high enantiomeric excess.2,3 These and other workers
subsequently showed that a range of E-disubstituted
enones including alkyl, aryl and extended conjugated
systems could be converted into optically active oxi-
ranes using this strategy.4,5 More recently we have
demonstrated that, using the triphasic conditions and
Aliquat® 336 as an additive, even the less reactive
phenyl-E-styrylsulphone is oxidised to the correspond-
ing epoxide (61% yield over 4 days) albeit with modest
stereoselectivity (21% ee). However electrophilic olefins
possessing other substitution patterns have been tried
without success; for example, acyclic trisubstituted
enones proved inert under the triphasic reaction
conditions.
In this paper we show that conformationally-restricted
tetralones 3a–f10 and related compounds 3g,h undergo
O
O
O
Ph
Ph
Ph
Ph
O
O
1
2
Scheme 1. Reagents and conditions: Urea–H2O2, DBU, i-
PLL, THF, 10 h, 70%.
Table 1. Oxidation of enone 3a (0.24 mmol) to the epoxide 4a
Entry
i-PLL (mg)
Oxidant (mmol)
Base (mmol)
Solvent (cm3)
Time (h)
Conversion (%) [ee (%)]
i
ii
iii
iv
100
100
100
200
30% aq. H2O2 (1.76)
Urea–H2O2 (0.3)a
Urea–H2O2 (0.3)a
Urea–H2O2 (0.12)a
4 M NaOH (0.8)
DBU (0.6)a
Toluene (0.8)
THF (0.8)
EtOAc (0.8)
i-PrOAc (1.6)
168
55
80
100 [74]
100 [62]
72 [70]
DBU (0.6)a
DBU (0.2)a
90
100 [84]
a Amount indicated added every 12 h.
Keywords: epoxides; peptides and polypeptides; asymmetric reactions; asymmetric synthesis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00535-4

3742
P. A. Bentley et al. / Tetrahedron Letters 42 (2001) 3741–3743
O
O
O
R
R
n
n
3a
3b
3c
3d
3e
3f
R=Ph; n=1
4a
R=p-Br-C6H4; n=1
R=p-NO2-C6H4; n=1
R=Me; n=1
R=tBu; n=1
R=H; n=1
4b
4c
4d
4e
4f
3g
3h
R=Ph; n=0
R=Ph; n=2
4g
4h
Figure 1. Structure of compound 4b.
Scheme 2. Reagents and conditions: Enone (0.24 mmol), i-
PLL (200 mg), urea–H2O2 (0.12 mmol every 12 h), DBU
(0.20 mmol every 12 h), iso-propyl acetate (1.6 cm3).11
epoxide 4d (Table 2, entry iv). In contrast, the tert-
butyl compound 3e was oxidised slowly (8 days) to
give the epoxide 4e of somewhat lower ee (Table 2,
entry v). The a-methylene compound 3f was oxidised
rapidly (7 h) to give the corresponding epoxide 4f in
good enantiomeric excess (Table 2, entry vi). This is
one of the rare examples where a geminally disubsti-
tuted enone is oxidised using the Julia´–Colonna
methodology.5
asymmetric epoxidation using i-PLL as the catalyst.
Thus, under the Julia´–Colonna triphasic conditions,
tetralone 3a was slowly transformed into the epoxide
4a (Table 1, entry i). The analogous biphasic reaction
was faster but slightly less stereoselective (Table 1,
entry ii). Changing the solvent to ethyl acetate (Table
1, entry iii) or iso-propyl acetate gave improved
stereoselectivity and the reaction was optimised for
the latter solvent, resulting in a slower addition of
oxidant to a more dilute solution containing an
increased amount of catalyst (Table 1, entry iv).
The effect of changing the size of the ring annealed
to the phenyl group was also investigated. For exam-
ple, the indanone derivative 3g was oxidised, furnish-
ing the epoxide 4g with good stereoselectivity (Table
2, entry vii). However, oxidation of the benzo-
suberone derivative 3h was much less satisfactory tak-
ing one week to produce epoxide 4h of modest
enantiomeric excess (Table 2, entry viii). Seemingly
the more flexible seven-membered ring renders this
substrate less amenable to polyleucine-catalysed epoxi-
dation.
The optimised conditions were utilised to investigate
the oxidation of a family of related compounds
(Scheme 2 and Table 2). Placing a substituent such as
bromine on the benzylidene group had little effect,
the epoxide 4b being obtained in good yield (Table 2,
entry ii) while the product 4c having an excellent
enantiomeric excess was obtained from the p-
nitrobenzylidene derivative 3c (Table 2, entry iii).
After recrystallisation from dichloromethane/hexane
the enantiomer of 4b could not be detected by HPLC
analysis and the absolute configuration of this pure
sample of 4b was confirmed by X-ray crystallography
(Fig. 1).12
In summary, the newly developed biphasic conditions
for the Julia´–Colonna oxidation serve to convert tet-
ralones and analogous compounds to the correspond-
ing epoxides with good to excellent enantio-
selectivity.14
However, the new protocol is still not effective for
stereoselective oxidation of endocyclic enones; for
example, the ‘tethered’ chalcone 3-phenylinden-1-one
forms epoxide under the biphasic conditions but the
product is racemic.
Replacement of the aryl moiety by a methyl group
was well tolerated with the enone 3d being trans-
formed with good stereoselectivity (92% ee) into the
Table 2. Epoxidation of enones 3a–h to give the epoxides 4a–h
Entry
Substrate
Time (h)
Product
Yield (%)
ee (%)
i
ii
3a
3b
3c
3d
3e
3f
90
72
78
60
192
7
4a
4b
4c
4d
4e
4f
76
81
85
66
63
64
72
74
84a
82a
96a
92a
83a
94b
88a
59a
iii
iv
v
vi
vii
viii
3g
3h
48
168
4g
4h
a Determined by HPLC using a Chiralpak® AD column (eluent: 10% i-PrOH in hexane, UV detection at 254 nm) using racemic epoxides13 as
standards.
b Determined by 1H NMR in the presence of the chiral shift reagent Eu(hfc)3.

P. A. Bentley et al. / Tetrahedron Letters 42 (2001) 3741–3743
3743
Acknowledgements
conditions. Cappi, M. W.; Porter, M. J.; Roberts, S. M.,
unpublished results.
9. Allen, J. V.; Bergeron, S.; Griffiths, M. J.; Mukherjee, S.;
Roberts, S. M.; Williamson, N. M.; Wu, L. E. J. Chem.
Soc., Perkin Trans. 1 1998, 3171.
The authors would like to thank the BBSRC for a
studentship to P.A.B.
10. (a) Batt, D. G.; Maynard, G. D.; Petratis, J. J.; Shaw, J.
E.; Galbraith, W.; Harris, R. R. J. Med. Chem. 1990, 33,
360; (b) Enders, D.; Zhu, J.; Kramps, L. Leibigs Ann.
Recueil 1997, 1101; (c) Fukuzawa, S. I.; Tsuchimoto, T.;
Karai, T. Bull. Chem. Soc. Jpn. 1994, 67, 2227.
11. For the oxidation of 3f, oxidant and base were added
after 0.5, 1, 3 and 6 h.
References
1. Bentley, P. A. In Biotransformations; Kelly, D. R., Ed.;
Wiley-VCH: Weinheim, 2000; Vol. 8b, Chap. 12, pp.
491–517.
2. Julia´, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed.
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4. Pu, L. Tetrahedron: Asymmetry 1998, 9, 1457.
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Chirality 2000, 12, 313 and references cited therein.
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6047.
12. Crystal data of 4b: C17H13BrO2, M=329.21, T=213(2)
,
K, u=0.71073 A, orthorhombic P212121, a=8.0308(9),
3
,
,
b=8.9960(11), c=19.876(3) A, V=1435.9(3) A , Z=4,
zcalcd=1.523 mg m−3, v(Mo Ka)=2.777 mm−1, R1 (F>
4|F)=0.051, wR2 (all data)=0.120. Data were collected
on a Stoe IPDS diffractometer and the structure was
refined on F2 using all data (SHELX-97). The absolute
structure was determined unambiguously (absolute struc-
ture parameter −0.04(2)).
13. Adam, W.; Hala´sz, J.; Ja´mbor, Z.; Le´vai, A.; Nemes, C.;
Patoray, T.; To¨th, G. J. Chem. Soc., Perkin Trans 1 1996,
395.
14. For a complementary method, using a Darzens reaction
to produce optically active epoxides of this type, see:
Arai, S.; Shirai, Y.; Ishida, T.; Shiori, T. Chem. Commun.
1999, 49.
8. For example, (E)-a-methylchalcone and (Z)-a-fluorochal-
cone were inert under the standard biphasic reaction
.