Regioselective ring opening and isomerization reactions of 3,4-epoxyesters catalyzed by boron trifluoride

Article abstract of DOI:10.1021/ol201378w

Efficient ring opening of 3,4-epoxyesters with alcohols to produce 4-alkoxy-3-hydroxyesters and their isomerization into 4-ketoesters using boron trifluoride as the catalyst are presented. Both transformations are simple and efficient methods for the synthesis of the above named synthetically useful compounds.

Full text of DOI:10.1021/ol201378w

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3856–3859
Regioselective Ring Opening
and Isomerization Reactions of 3,
4-Epoxyesters Catalyzed by
Boron Trifluoride
ꢀ
Javier Izquierdo, Santiago Rodrıguez, and Florenci V. Gonzalez*
´
´
ꢁ
Departament de Quımica Inorganica i Organica, Universitat Jaume I, Castello, Spain
ꢁ
ꢀ
fgonzale@qio.uji.es
Received May 22, 2011
ABSTRACT
Efficient ring opening of 3,4-epoxyesters with alcohols to produce 4-alkoxy-3-hydroxyesters and their isomerization into 4-ketoesters using boron
trifluoride as the catalyst are presented. Both transformations are simple and efficient methods for the synthesis of the above named synthetically
useful compounds.
Epoxides are valuable synthetic compounds since they
can undergo diverse transformations that give rise to other
functionalities. Among these reactions, the ring opening of
epoxides with alcohols to give β-alkoxyalcohols1 and the
Meinwald rearrangement reactions2 to give carbonyl com-
pounds are challenging transformations.
asymmetric epoxidation.4 Then, the synthesis of mono-
protected diols as depicted in Scheme 1 represents an easy
access to chiral 3,4-dihydroxyesters which are moieties
present in the structure of some natural products.5
We wanted to study these transformations as applied to
3,4-epoxyesters. The opening of 3,4-epoxyesters with an
alcohol would afford monoprotected diols, and the iso-
merization reaction would give rise to dicarbonyl com-
pounds (Scheme 1). The regioselectivity in both processes
would be controlled by the neighboring carboxylate
group.3 The starting epoxyesters can be accessed through
Scheme 1. Derivatizations of 3,4-Epoxyesters
ꢀ
(1) (a) Smith, J. G. Synthesis 1984, 629. (b) Barluenga, J.; Vazquez-Villa,
ꢀ
H.; Ballesteros, A.; Gonzalez, J. M. Org. Lett. 2002, 4, 2817. (c) Torborg,
C.; Hughes, D. D.; Buckle, R.; Robinson, M. W. C.; Bagley, M. C.;
Graham, A. E. Synth. Commun. 2008, 38, 205.
(2) (a) House, H. O. J. Am. Chem. Soc. 1955, 77, 3070. (b) Naqvi, S. M.;
Horwitz, J. P.; Filler, R. J. Am. Chem. Soc. 1957, 79, 6283. (c) Meinwald,
J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85, 582. (d)
Kulasegaram, S.; Kulawiec, R. J. J. Org. Chem. 1997, 62, 6547.
(3) For carboxylate group as a neighboring group, see: (a) Tomioka,
H.; Hirai, K.; Tabayashi, K.; Murata, S.; Izawa, Y.; Inagaki, S.;
Okajima, T. J. Am. Chem. Soc. 1990, 112, 1692. (b) Crich, D.; Hu, T.;
Cai, F. J. Org. Chem. 2008, 73, 8942. (c) Crich, D.; Sharma, I. J. Org.
Chem. 2010, 75, 8383. (d) Wang, H.; Fan, R. J. Org. Chem. 2010, 75,
6994.
We began our studies of the isomerization of 3,4-epoxyesters
by combining epoxide 1a with a chelating Lewis acid as
(5) (a) Mori, K.; Takigawa, T.; Matsui, M. Tetrahedron 1979, 35, 833.
(b) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,
T. Org. Lett. 2008, 10, 225. (c) Garbe, L.; Morgenthal, K.; Kuscher, K.;
Tressl, R. Helv. Chim. Acta 2008, 91, 993. (d) Ookura, R.; Kito, K.;
Saito, Y.; Kusumi, T.; Ooi, T. Chem. Lett. 2009, 38, 384.
(4) Wang, Z.; Tu, Y.; Frohn, M.; Zhang, J.; Shi, Y. J. Am. Chem. Soc.
1997, 119, 11224.
r
10.1021/ol201378w
Published on Web 07/06/2011
2011 American Chemical Society

magnesium bromide etherate. The reaction afforded a
mixture of bromohydrins (Table 1, entry 1). We then
submitted compound 1a to reaction with magnesium
bromide etherate in the presence of ethanol so as to
accomplish an opening of the epoxide by the alcohol, but
we again obtained a bromohydrin mixture (entry 2).
The use of several Lewis acids in the presence of alcohols
in this reaction provided halohydrins or led to the decom-
position of the starting material. After extensive investiga-
tion, we discovered that the use of boron trifluoride
etherate afforded compound 2a in high regioselectivity
and excellent yield (Table 1, entry 5).
amount of alcohol was used (5 equiv) the result was the
same (Table 2, entry 5 vs 6). The optimal amount of Lewis
acid for obtaining the best yield was also found to be 30 mol %.
Lactones 3aÀe were obtained as the minor product of the
reactions resulting from cyclization of the minor regiomeric
3-alkoxy-4-hydroxyesters.
Table 2. 3,4-Epoxyesters into 4-Alkoxy-3-hydroxyesters
We next evaluated the scope of the substrate with a
variety of differentially substituted 3-enoates using BF3 Et2O
and different alcohols (Table 2).
3
Table 1. Optimization of Conditions
a Reactions performed on a 0.5 mmol scale. b Starting material was
recovered. c A 1:1 mixture of regioisomeric lactones was obtained and
the yield was 55%. d The stereochemistry for depicted lactone is pre-
liminary, and it was obtained as a minor product (20%) as analyzed by
NMR spectroscopy (1H, 500 MHz).
a R2 = Et for all substrates except for 1a (R2 = Me). b The ratio was
measured from 1H NMR spectroscopy (500 MHz) of the unpurified
mixture. c The reaction was peformed at À5 °C for 3.5 h. d 5 equiv of the
alcohol were used. e Lactone 5 was also isolated (20%).
3,4-Epoxyesters 1aÀe were treated with a series of
alcohols in the presence of boron trifluoride as a catalyst.
The regioisomer 2 was obtained as the major product in
all cases as a result of the attack of the alcohol to the
4-position.6 The reaction was quite sensitive to steric
hindrance. For example, compound 1a having a methyl
substituent in the 4-position afforded higher regioselectiv-
ity than 1b having an ethyl substituent using the same
alcohol (Table 2, entry 1 vs 4). The regioselectivity of
the reaction was also dependent on the type of alcohol:
primary alcohols gave higher regioselectivity than second-
ary or tertiary ones. The reaction of 1a with methanol took
place at 0 °C for 3.5 h, while for the rest of assays the best
conditions were 18 h at room temperature. The amount of
catalyst that afforded the best yield for all cases was 30 mol
%. Initially the alcohol was used as a cosolvent in an equal
mixture with dichloromethane, but when a stoichiometric
When 3,4-epoxyesters 1aÀc were treated with boron
trifluoride without any alcohol at room temperature for 18
h of reaction time, 4-ketoesters 4aÀc were obtained as the
only products of the reaction in excellent yields (Scheme 2).
The isomerization of 3,4-epoxyesters into 4-ketoesters
implies that a 1,2-shift of a hydrogen from the 4-position
(7) (a) Cardellach, J.; Font, J.; Ortuno, R. M. J. Heterocycl. Chem.
1984, 21, 327. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron
Lett. 1990, 31, 5509. (c) Frenette, R.; Monette, M.; Bernstein, M. A.;
Young, R. N.; Verhoeven, I. R. J. Org. Chem. 1991, 56, 3083. (d) Short,
K. M.; Mjalli, M. M. A. Tetrahedron Lett. 1997, 38, 359. (e) Vaishali,
M. S.; Mark, R. H.; Leah, M. S.; Alexander, J. S. J. Org. Chem. 2001, 66,
7283. (f) Cristina, F.; Raffaella, G.; Francesco, M.; Patrizia, N.;
Giuliana, P.; Ennio, V. Tetrahedron: Asymmetry 2001, 12, 1039.
(8) (a) Seto, H.; Sato, T.; Urano, S.; Uzawa, J.; Yonehara, H.
Tetrahedron Lett. 1976, 4367. (b) Kosuge, T.; Tsuji, K.; Hirai, K.;
Yamaguchi, K.; Okamoto, T.; Iitaka, Y. Tetrahedron Lett. 1981, 22,
3417. (c) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.;
Sun, H.- D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org.
Lett. 2004, 6, 4327.
(6) The structure of the major regioisomer 2 was confirmed by NMR
techniques.
Org. Lett., Vol. 13, No. 15, 2011
3857

to the 3-position took place. The resulting 4-ketoesters are
intermediates for preparation of a large number of five-
membered cyclic compounds,7 and the 4-ketoester moiety
is ubiquitous within complex natural products.8 Although
several reactions have been reported for the preparation of
4-ketoesters9 and other 1,4-dicarbonyl compounds,10 new
approaches are welcomed.
Scheme 3. One-Pot Procedure
In contrast, compound 1d having a benzyl group furn-
ished lactone 511 as a mixture of syn and anti isomers, with
the anti form predominating. Compound 1e having a
phenyl group gave a complex mixture of reaction products
(Scheme 2).
the only isolated products (Scheme 4). Even in the presence
of an alcohol or using other catalysts (tris(perfluorophenyl)-
borane, or PPTS), the epoxyketones gave the furan
We also wanted to apply the same reactions to a 4,
5-epoxyester and to compare the outcome with the 3,
4-epoxyesters. We readily prepared a 4,5-epoxyester (1f
being n = 2, R1 = Et in Scheme 2) (see Supporting
Information), treated it with boron trifluoride, and obtained
γ-butyrolactone 6. This product was obtained even in the
presence of an alcohol. Compound 6 is an intermediate for
the synthesis of the communiol natural products.12
Scheme 4. Conversion of 3,4-Epoxyketones into Furans
Scheme 2. Isomerization of 3,4-Epoxyesters into 4-Ketoesters
Scheme 5. Proposed Reaction Pathways
A one-pot procedure for the conversion of 3-enoates
into 4-ketoesters was also evaluated. Ethyl 3-hexenoate
was directly converted into dicarbonyl compound 4b
through treatment with peracid followed by addition of
boron trifluoride (Scheme 3).
We also wanted to extend our study to 3,4-epoxyketones.
However, when compounds 7, 8, and 9 were treated with
boron trifluoride, furans 10, 11, and 12, respectively, were
(9) (a) Parker, K. A.; Kallmerten, J. K. J. Org. Chem. 1980, 45, 2614.
(b) Kunz, T.; Janowitz, A.; Reissig, H. U. Synthesis 1990, 43.
(c) Fujimura, T.; Aoki, S.; Nakamura, E. J. Org. Chem. 1991, 56,
2809. (d) Reissig, H. U.; Reichelt, I.; Kunz, T. Org. Synth. 1992, 71, 189.
(e) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444. (f) Ballini,
R.; Barboni, L.; Bosica, G.; Fiorini, D. Synthesis 2002, 2725. (g) Huang,
D.; Yan, M.; Zhao, W.; Shen, Q. Synth. Commun. 2005, 35, 745.
(10) (a) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2004, 126, 2314. (b) Avetta, C. T.; Konkol, L. C., Jr.; Taylor,
C. N.; Dugan, K. C.; Stern, C. L.; Thomson, R. J. Org. Lett. 2008, 10,
5621. (c) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 11546. (d) Shen, Z.; Goh, K. K. K.; Cheong, H.; Wong,
C. H. A.; Lai, Y.; Yang, Y.; Loh, T. J. Am. Chem. Soc. 2010, 132, 15852.
(11) Stereochemistry of lactone 5 was confirmed by comparison with
€
spectra from: Harcken, C.; Bruckner, R. Synlett 2001, 5, 718.
(12) Enomoto, M.; Kuwahara, S. J. Org. Chem. 2006, 71, 6287.
3858
Org. Lett., Vol. 13, No. 15, 2011

compounds asthe only productsof the reaction inexcellent
yield.
Scheme 5) that would furnish the lactone 5, with the anti
configuration as the major product.
According to Baldwin’s rules, a 4-exotet cyclization is
favored, but a 5-endotet is not. We postulate that the
carbonyl oxygen stabilizes the positive charge at the 3-position
of the oxirane ring in a 4-exotet mode, inducing the hydro-
gen to migrate from C-4 to C-3. On the other hand, if an
alcohol is present, then an intermolecular attack of the
alcohol at the less hindered 4-position occurs (Scheme 5).
In the case of compound 1f, a 5-exotet cyclization occurred
to give lactone 6 (reaction 1 in Scheme 5). Finally, the forma-
tion of compound 5can be explained through two consecutive
cyclizations: first, a 3-exotet cyclization occurs, where the
phenyl ring opens the oxirane ring to afford a phenonium
intermediate13 which then undergoes a cyclopropaneÀ
homobenzylic cation rearrangement14 (reaction 2 in
Insummary, 3,4-epoxyestersare opened withalcohols in
the presence of boron trifluoride to give 4-alkoxy-3-hydro-
xyesters in a highly regioselective fashion. 3,4-Epoxyesters
having an alkyl group furnish 1,4-dicarbonyl compounds
as a single product when treated with boron trifluoride in a
nonhydroxylic solvent. We believe both transformations
are simple and efficient methods for the synthesis of
monoprotected diols and 1,4-dicarbonyl compounds and
will find synthetic applications. The application of these
results to the synthesis of new proteases inhibitors is
ongoing, and further results will be reported in due course.
Acknowledgment. This work was financed by the Ban-
caixa-UJI Foundation (P1 1B2008-31 and P1 1A2008-09).
ꢀ
We also thank Serveis Centrals d’Instrumentacio Cientı
ca from Universitat Jaume I for technical support.
´
fi-
(13) (a) Cram, D. J. J. Am. Chem. Soc. 1949, 71, 3863. (b) Cram, D. J.
J. Am. Chem. Soc. 1952, 74, 2129. (c) Sieber, S.; Schleyer, P. V. J. Am.
Chem. Soc. 1993, 115, 6987.
(14) For similar reactions (cyclopropaneÀhomoallylic cation
rearrangement), see: (a) Marshall, J. A.; Ellison, R. H. J. Org. Chem.
1975, 40, 2070. (b) Marshall, J. A.; Ellison, R. H. J. Am. Chem. Soc. 1976,
98, 4312.
Supporting Information Available. Experimental proce-
dures and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3859