Diastereoselectivity in the epoxidation of γ-hydroxy α,β-unsaturated esters: Temperature and solvent effect

Article abstract of DOI:10.1016/j.tetlet.2004.05.080

The diastereoselectivity in the nucleophilic epoxidation of γ-hydroxy α,β-unsaturated compounds using lithium-tert-butylperoxide is highly dependent on the reaction solvent but not influenced by the temperature. The free hydroxyl is key for stereoselection.

Full text of DOI:10.1016/j.tetlet.2004.05.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5359–5361
Diastereoselectivity in the epoxidation of c-hydroxy
a,b-unsaturated esters: temperature and solvent effectq
*
ꢀ
Santiago Rodrıguez, Alberto Vidal, Juan J. Monroig and Florenci V. Gonzalez
ꢀ
Departament de Quꢀımica Inorgꢁanica i Orgꢁanica, Universitat Jaume I, E-12071 Castellꢀo, Spain
Received 27 April 2004; revised 17 May 2004; accepted 17 May 2004
Abstract—The diastereoselectivity in the nucleophilic epoxidation of c-hydroxy a,b-unsaturated compounds using lithium-tert-
butylperoxide is highly dependent on the reaction solvent but not influenced by the temperature. The free hydroxyl is key for
stereoselection.
Ó 2004Elsevier Ltd. All rights reserved.
Asymmetric epoxidation of c-chiral a,b-unsaturated
esters provides chiral a,b-epoxyesters that can be con-
verted into useful chiral building blocks.1 Although
some reports have been published about the asymmetric
epoxidation of c-hydroxy a,b-unsaturated sulfoxides2
and sulfones,3 there are no reports of diastereoselective
epoxidation of c-hydroxy a,b-unsaturated esters.
The most convenient method for the epoxidation of
unsaturated esters is using a hydroperoxide in the
presence of a base.4 The diastereoselectivity of this
reaction must be interpretated as a conjugate addition to
Scheme 1. General epoxidation reaction of compound 1.
an unsaturated ester modulated by a stereocentre in c-
The model compound 1 was obtained through treatment
of ethyl (E)-4-oxo-2-butenoate 5 with a grignard
(Scheme 2).
position.5
We now wish to report a study of the diastereoselectivity
in the epoxidation of c-chiral c-hydroxy-a,b-unsatu-
rated esters and particularly the influence of the tem-
perature and solvent effect on the process.
Fumaraldehydic ester 5 was obtained6 starting from 2-
furoic acid, which was converted into butenolide 3
through a photooxygenation reaction according to J. D.
White’s procedure.7 Compound 3 was then submitted to
ketalisation–esterification8 reaction followed by potas-
sium bisulfate9 treatment and the resulting compound 4
was then hydrolysed10 to afford aldehyde 5, which upon
treatment with methyl magnesium chloride gave
hydroxyester 1 (Scheme 2).
We chose ethyl trans-4-hydroxy-2-pentenoate 1 as a
model system and lithium-tert-butylperoxide (TBPLi) as
oxidative reagent. The stereoselectivity was measured as
the ratio between racemic mixtures of anti/syn diastereo-
mers 2 (Scheme 1).
Table 1 documents the influence of the solvent. The
diastereoselectivity of the epoxidation of compound 1
proved to be highly dependent on the reaction solvent.
Keywords: Diastereoselective epoxidation; Unsaturated esters; Solvent
effect; Temperature influence.
q Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tetlet.2004.05.080
* Corresponding author. Tel.: +34-964728241; fax: +34-964728214;
e-mail: fgonzale@qio.uji.es
We carried out the reactions using ethyllithium11 as base
at )20 °C for 20 h in different solvents. The results show
the more polar the media was, the better selectivity was
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.080

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S. Rodrıguez et al. / Tetrahedron Letters 45 (2004) 5359–5361
5360
The selectivity was also studied at different tempera-
tures, all the assays were done using ethyllithium as base
and THF as solvent but differing on the temperature and
time (Table 2).
Table 2 shows there is no temperature dependence since
the diastereomeric ratios at different temperatures in a
range between )80 and 50 °C are same within experi-
mental error.
Scheme 2. Synthesis of ethyl trans-4-hydroxy-2-pentenoate 1. Re-
agents and conditions: (a) hm, Rose Bengal, CH3OH; (b) (i) EtOH,
BF3ÆEt2O, (ii) KHSO4; (c) Amberlyst-15, H2O, acetone, (39%, three
steps); (d) CH3MgCl, THF, )78 °C, 72%.
On the other hand, compound 1 was protected as O-tert-
butyldiphenylsilyl ether and the protected compound 6
was epoxidised under the same conditions as 1 (in this
case room temperature was needed for reaction go to
completion). The epoxidation of compound 6 was
nonselective (dr 55:45), this result shows that the free
hydroxyl is key for stereoselection (Scheme 3).
Table 1. Diastereoselectivity in the epoxidation of 1 in different sol-
vents
The stereochemistry of epoxides was assigned by trans-
forming the mixtures of epoxides through treatment
with thiophenol, which opened the oxirane ring through
attack of the more reactive position followed by cycli-
sation of the resulting diol to afford the corresponding
diastereomeric c-butyrolactones 7, separable by silica-
gel chromatography (Scheme 4).
Entry
Solvent
T (°C)/t (h)
anti/syna
Yield (%)
1
THF/HMPA
THF/DMF
THF
)20/20
)20/20
)20/20
)20/20
)20/20
88/12
85/15
75/25
54/46
32/68
42
51
40
25
53
2
3
4Hexanes
5
Toluene
The stereochemical assignment was performed by NOE
experiments over the c-butyrolactones: major c-bu-
tyrolactone gave NOE between the methyl and H-1 and
between the methyl and H-2 whilst the minor c-bu-
tyrolactone gave NOE between the methyl and OH but
not between the methyl and H-1.13
a Ratio measured over 13C NMR in reaction crude.
reached in favour of the anti diastereomer. If DMF or
HMPA are used as co-solvents in the presence of THF
the selectivity was better than in THF itself.
In summary, we report a study of the influence of the
temperature and solvent over the stereoselectivity in the
epoxidation of c-hydroxy a,b-unsaturated esters
employing lithium tert-butyl peroxide. The results de-
scribed herein show that the reaction is dependent on
the nature of the solvent and is not influenced by the
temperature when THF is used. Studies of the influence
of protecting groups and substituents in the epoxidation
of these compounds is currently underway in our labo-
ratory.
The poorest selectivity was obtained using hexanes,
toluene gave the syn isomer as the major one, opposite
to selectivity reached using more polar solvents.
The solvent effect can be rationalised in terms of the
solvation of lithium cation by the solvent: the better the
solvent coordinates to lithium (THF, DMF and
HMPA12), the better selectivity is observed furnishing
anti isomer as the major one.
Table 2. Diastereoselectivity in the epoxidation of 1 at different tem-
peratures
Entry
Solvent
T (°C)/t (h)
anti/syna
Yield (%)
1
THF
THF
THF
)80/72
)60/46
)40/24
)20/20
/26 0/1474 55
25/3
73/27
78/22
77/23
75/25
30
55
54
60
2
3
4THF
5
6
7
THF
THF
THF
78/22
5 76/244
52
50/5
a Ratio measured over 13C NMR in reaction crude.
Scheme 4. Opening of epoxyalcohols.
Scheme 3. Epoxidation of compound 6.

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S. Rodrıguez et al. / Tetrahedron Letters 45 (2004) 5359–5361
5361
5. For stereoselective Michael reactions of c-alkoxy a,b-
unsaturated esters see: (i) Yamamoto, Y.; Chounan, Y.;
Nishii, S.; Ibuka, T.; Kitahara, H. J. Am. Chem. Soc. 1992,
114, 7652–7660; (ii) Asao, N.; Shimada, T.; Sudo, T.;
Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 6274–6282.
6. Although the reactions in Scheme 2 appear in the
literature, they have been optimised so as to provide an
efficient way of making aldehyde 5.
Acknowledgements
This work was financed by Conselleria d’Educacio,
ꢀ
ꢁ
i Ciencia de la Generalitat Valenciana
Cultura
(CTIDIA/2002/124) and Bancaixa-UJI foundation (PI-
1B2002-06). We thank Serveis Centrals d’Instrumen-
ꢀ
ꢀ
tacio Cientıfica de la Universitat Jaume I for technical
support and especially Prof. William R. Roush for
helpful discussions.
7. White, J. D.; Carter, J. P.; Kezar, H. S., III. J. Org. Chem.
1982, 47, 929–932.
8. Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T.
A.; Strickland, R. C. J. Org. Chem. 1973, 38, 1974–1982.
9. Distillation over potassium bisulfate of the crude is
necessary to convert a nondesired product resulting from
ethanol incorporation into the desired alkene 4:
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ꢂ
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ꢂ
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