Intramolecular displacement of phenylselenone by a hydroxy group: Stereoselective synthesis of 2-substituted tetrahydrofurans

Article abstract of DOI:10.1021/ol401653w

An efficient and stereocontrolled synthesis of 2-substituted tetrahydrofurans has been achieved. The approach employs the asymmetric reduction of γ-phenylseleno ketones obtained by three different procedures that are peculiarly applied to the synthesis of such compounds. Finally, the intramolecular substitution of the phenylselenone residue by the oxygen atom of a hydroxy group gives the tetrahydrofuran ring.

Full text of DOI:10.1021/ol401653w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Intramolecular Displacement of
Phenylselenone by a Hydroxy Group:
Stereoselective Synthesis of
2‑Substituted Tetrahydrofurans
Lucio Minuti,† Anna Barattucci,# Paola Maria Bonaccorsi,# Maria Luisa Di Gioia,§
Antonella Leggio,§ Carlo Siciliano,§ and Andrea Temperini*,‡
Department of Chemistry, University of Perugia, via Elce di Sotto 8, 06123 Perugia,
Italy, Department of Chemical Sciences, University of Messina, Viale F. Stagno
d’Alcontres 31, 98166 Messina, Italy, Department of Pharmacy and Health Sciences and
Nutrition, Multifunctional Building, University of Calabria, 87030 Arcavacata di Rende,
Cosenza, Italy, and Department of Chemistry and Technology of Drugs, University of
Perugia, via del Liceo 1, 06123 Perugia, Italy
tempa@unipg.it
Received June 12, 2013
ABSTRACT
An efficient and stereocontrolled synthesis of 2-substituted tetrahydrofurans has been achieved. The approach employs the asymmetric
reduction of γ-phenylseleno ketones obtained by three different procedures that are peculiarly applied to the synthesis of such compounds.
Finally, the intramolecular substitution of the phenylselenone residue by the oxygen atom of a hydroxy group gives the tetrahydrofuran ring.
Oxygenated heterocycles, especially tetrahydrofurans
(THFs), represent a key structural motif of natural and
unnatural products with significant and various biological
activities. The substituted THF nucleus is the common
structural core of annonaceous acetogenins,1 lignans,2
polyether ionophores,3 and macrolides.4 Owing to their
different bioactivities such as immunosuppressive, anti-
tumor, pesticidal, antiprotozoal, antifeedant, anthelmintic,
and antimicrobial agents, considerable effort has been
devoted toward the stereoselective synthesis of substituted
THFs.5 Among the number of different approaches that
have been devised in order to construct 2-substituted
THFs, the cycloetherification reaction plays an impor-
tant role. Classical approaches have primarily focused
on the intramolecular SN2 reactions between a hydroxy
group and a tethered leaving group (e.g., halide, sulfonate,
or sulfoxonium),6 intramolecular oxy-Michael addi-
tion reaction mediated by an organocatalyst,7 hydro-
alkoxylation/cyclization of alkenols,8 alkene halo- and
selenoetherification,9 alkene carboetherification,10 olefin
metathesis,11and direct CÀH arylation/alkylation at
R-position of THF.12
(6) (a) Deziel, R.; Malenfant, E.; Thibault, C.; Frechette, S.; Gravel,
M. Tetrahedron Lett. 1997, 38, 4753. (b) Kang, B.; Chang, S.; Decker, S.;
Britton, R. Org. Lett. 2010, 12, 1716. (c) Butova, E. D.; Barabash, A. V.;
Petrova, A. A.; Kleiner, C. M.; Schreiner, P. R.; Fokin, A. A. J. Org.
Chem. 2010, 75, 6229.
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Opalka, S. M.; Steinbacher, J. L.; Lambiris, B. A.; McQuade, D. T.
J. Org. Chem. 2011, 76, 6503. (c) Asano, K.; Matsubara, S. J. Am. Chem.
Soc. 2011, 133, 16711.
† Department of Chemistry, University of Perugia.
# University of Messina.
§ University of Calabria.
‡ Department of Chemistry and Technology of Drugs, University of
Perugia.
(1) Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
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22, 696.
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T.; Hosomi, A. J. Am. Chem. Soc. 2000, 122, 11348. (b) Dzudza, A.;
Marks, T. J. Org. Lett. 2009, 11, 1523.
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D. L. J.; Chittattu, G.; Wong, C. K. Can. J. Chem. 1977, 55, 3894. (c)
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Z.; Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 3784.
r
10.1021/ol401653w
XXXX American Chemical Society

As part of our general interest in the chemistry of
organoselenium compounds,13a we have recently reported
that the phenylselenyl group can be easily and intramolec-
ularly displaced by nitrogen nucleophiles, thus affording
substituted 1,3-oxazolin-2-ones13b and N-azetidines.13c
Herein, we report a versatile and stereoselective syn-
thetic route to 2-substituted THFs 4 (Scheme 1).
Scheme 2. Preparation of γ-Phenylseleno Ketones 1aÀc by
FriedelÀCrafts Acylation, Fries Rearrangement, and Acylation
of 2-Thienyl Lithium, Respectively
Scheme 1. General Strategy for the Stereospecific Synthesis of
2-Substituted Tetrahydrofurans
Our approach involves the direct intramolecular nucleo-
philic substitution of the phenylselenone group by the
oxygen atom of an alcohol 3, that is a formal 5-exo-
tet process. There are only two reports, to date, on the
intramolecular nucleophilic deselenenylation reaction for
the synthesis of 2-substituted THFs, both of them proceed-
ing via a selenonium salt intermediate.14
The phenylseleno alcohols 2 are uncommon organose-
lenium intermediates.15 We envisaged that they could
be easily and enantioselectively prepared by asymmetric
CBS-reduction of the corresponding γ-phenylseleno ke-
tones. In our hands, the oxazaborolidine-borane reduc-
tion16 of prochiral ketones 1 gave high level of enantioselec-
tivity in almost all the studied cases. Despite the extensive
research effort directed toward the synthesis of R- and
β-phenylseleno ketones,17 the synthesis of γ-phenylseleno
ketones 1 remains an unexplored area of research.18 In
this context, we have developed three different strategies
for the synthesis of compounds 1, starting all from
4-(phenylseleno)butanoic acid (5) (Scheme 2). Thus,
the acid 5 was reacted with oxalyl chloride to lead to
the corresponding acyl chloride 6 that was subjected to
the FriedelÀCrafts acylation reaction with anisole to give
ketone 1a in 71% overall yield. Ketone 1b was prepared by
an unprecedented approach based on the Fries rearrange-
ment of the ester intermediate of 5 to ketone 7 and
successive methylation of the free hydroxy group. We
explored, also, the quick and direct reaction of an organo-
metallic reagent such as thienyl lithium, with acyl chloride
6 (Scheme 2).19 As expected, ketone 1c was obtained in
low yield together with the alcohol 8. Due to the known
limitations of the above reaction, we directed our attention
to the reactions of 6 withoctyl magnesium bromide20 in the
presence of Fe(acac)3 or with lithium dibutylcuprate.21
Both of these reactions did not give appreciable results.
Furthermore, when we reacted (3-fluorophenyl)-(methyl)-
copper(I) magnesium bromide, a mixed magnesium
cuprate,22 with compound 6, the corresponding ketone 1d
was obtained in low yield (30%). Replacement of the
methyl group with the thienyl group as a dummy ligand
allowed the preparation of the new mixed magnesium
cuprate 9d (R = 3-fluorophenyl) that, reacting with 6,
led to ketone 1d in 83% yield (Table 1, entry 1). Therefore,
various mixed magnesium cuprates 9eÀh, capable of selec-
tively transferring the R group to the skeleton of acyl
chloride 6, were employed for the synthesis of ketones
1eÀh (Table 1, entries 2À5).
(10) (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Zhang, G.; Cui,
L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474.
(11) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003, 1, 2512.
(12) (a) Inoue, A.; Shinokubo, H.; Oshima, K. Synlett 1999, 1582. (b)
Singh, P. P.; Gudup, S.; Aruri, H.; Singh, U.; Ambala, S.; Yadav, M.;
Sawant, S. D.; Vishwakarma, R. A. Org. Biomol. Chem. 2012, 10, 1587.
(13) (a) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Temperini, A.
Eur. J. Org. Chem. 2011, 5668. (b) Tiecco, M.; Testaferri, L.; Temperini,
A.; Bagnoli, L.; Marini, F.; Santi, C. Chem.;Eur. J. 2004, 10, 1752. (c)
Tiecco, M.; Testaferri, L.; Temperini, A.; Terlizzi, R.; Bagnoli, L.;
Marini, F.; Santi, C. Org. Biomol. Chem. 2007, 5, 3510.
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Tingoli, M.; Testaferri, L.; Temperini, A.; Tiecco, M. J. Org. Chem.
1996, 61, 7085.
The results reported in Table 1 show that functional
group tolerance, good yields, simplicity, and mildness of
(15) Clive, D. L. J.; Cheng, H. Chem. Commun. 2001, 605.
(16) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551.
(17) Paulmier, C. Selenium Reagents and Intermediates in Organic
Synthesis; Pergamon: Oxford, 1986; Chapter 11.
(19) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(20) Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L. Tetra-
hedron Lett. 1984, 25, 485.
(21) Posner, G. H.; Whitten, C. E.; McFarland, P. E. J. Am. Chem.
Soc. 1972, 94, 5160.
(22) Bergbreiter, D. E.; Killough, J. M. J. Org. Chem. 1976, 41, 2750.
(18) (a) Mastalerz, H.; Menard, M.; Vinet, V.; Desiderio, J.; Fung-Tomc,
J.; Kessler, R.; Tsai, Y. J. Med. Chem. 1988, 31, 1190. (b) Temperini, A.;
Terlizzi, R.; Testaferri, L.; Tiecco, M. Chem.;Eur. J. 2009, 15, 7883.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Preparation of Ketones 1dÀh by Acylation of Mixed
Magnesium Cuprates 9dÀh with Acyl Chloride 6
Table 2. Borane (S) Me-CBS-Catalyzed Asymmetric Reduction
of Ketones 1aÀh into Alcohols 2aÀh
a Isolated yield.
the experimental conditions are valuable characteristics of
this novel and alternative organo-copper mediated synthe-
sis of γ-phenylseleno ketones.
On the basis of the above findings we developed the new
strategy for accessing a range of 2-substituted THFs 4,
shown in Scheme 1. The enantioselective reduction of
ketones 1aÀh was achieved via the chiral oxazaborolidine-
catalyzed Corey procedure to give the enantioenriched
γ-phenylseleno alcohols 2aÀh in excellent yields
(77À90%, Table 2, entries 1À8); in the case of alcohols
2g and 2h a poor enantioselectivity was observed (entries 7
and 8). The configuration of the major enantiomer of
compounds 2aÀf was tentatively assumed according to
the mechanism proposed by Corey16and others.23,24 Oxi-
dation of γ-phenylseleno alcohols 2aÀh into the corre-
sponding selenones 3aÀh was carried out in THF at room
temperature with an excess of m-chloroperoxybenzoic acid
and in the presence of dipotassium hydrogenphosphate,
according to our previous report.13c The selenone inter-
mediates 3 were not isolated, although their formation
could be inferred by thin-layer chromatography (TLC)
or clearly established by 13C NMR spectroscopy of the
crude reaction mixture.13b
a Isolated yield. b (R) Me-CBS was used.
Table 3, the 2-substituted THFs 4aÀh were obtained
in good to excellent yields (76À95%) and good enan-
tiomeric ratio (Table 3, entries 1À6), as shown by
HPLC analysis on chiral stationary phase. The enan-
tiomeric composition of compounds 4aÀh reflected
that of the corresponding alcohols 2aÀh. It is worth
noting that the partial racemization during the cycliza-
tion step may be considered to be unlikely in view of the
bimolecular nucleophilic substitution character of the
reaction involved.
The low levels of enantiomeric ratio observed for pro-
ducts 4g and 4h (Table 3, entries 7 and 8) were probably
due to the poor enantioselectivity of the reduction step of
ketone 1g and 1h (Table 2, entries 7 and 8) to alcohols 2g
and 2h.24
Selenones3aÀh underwent cyclization toTHFs4aÀh by
addition of powdered potassium hydroxide. This cycliza-
tion reaction, which represents the key step of the entire
process, is a stereospecific intramolecular nucleophilic
substitution and occurs easily because of the great leaving
ability of the phenylselenonyl group. As shown in
Comparison across the data reported in Table 3 indi-
cates that oxidative cyclization of alcohols 2 occurs
in good/excellent yields under mild reaction conditions.
Along with the different functional groups tolerated in
(23) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68, 10146.
(24) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785.
(25) Okada, M.; Kitagawa, O.; Fujita, M.; Taguchi, T. Tetrahedron
1996, 52, 8135.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Oxidative Cyclization of Alcohols 2aÀh into Tetrahy-
drofurans 4aÀh
Scheme 3. Synthesis of 2,2-Disubstituted Tetrahydrofurans
acid 5with an excess of p-chlorophenyl magnesium bromide.
Oxidation of these alcohols with m-chloroperoxybenzoic
acid occurred smoothly at rt in the presence of
dipotassium hydrogenphosphate to give the corre-
sponding selenones, which cyclized after the addition
of potassium hydroxide to allow the 2,2-disubstituted
THFs 11a and 11b in 79% and 96% yields, respectively.
Compounds 11a29 and 11b30 were already prepared by
different procedures, but in lower yiels (70% and 45%,
respectively). It is worth noting, that the phenylseleno moiety
introduced at the beginning of our procedure was eliminated
as benzeneseleninic acid in the oxidation/cyclization step;
the water-soluble potassium benzeneseleninate produced
in this step can be separated and the selenium recovered as
diphenyl diselenide, thus making the process consistent
with atom economy.
In summary, we have formulated a novel, mild stereo-
selective approach to 2-substituted THFs, starting from
phenylseleno ketones 1. Different and new synthetic strate-
gies for the preparation of the γ-phenylseleno ketones 1
have been also developed. The key step of our procedure is
the ring-closure reaction, in which stereospecific intramo-
lecular nucleophilic substitution of the good leaving phe-
nylselenonyl group by the oxygen atom of the alcohol
is effected. The present procedure favorably compares
with other previously described methods for the prepara-
tion of 2-substituted THFs in enantiomeric enriched
forms. Our current efforts are directed toward the
construction of di- and trisubstituted tetrahydrofurans
and substituted tetrahydropyrans.
a Isolated yield. b Determined by chiral HPLC analysis.
the alcohol 2, this makes our method a general valuable
synthetic procedure for obtaining chiral 2-substituted
THFs. For example, compounds 4a,25 4c,26 4d,27 4e,12b
and 4g28 have been previously synthesized by different
methodologies, but they were obtained in comparable or
lower yields and as racemic mixtures.
To further explore the applicability of our methodology,
wepreparedsome2,2-disubstituted THFsby cyclization of
the corresponding tertiary alcohols 8 and 10 (Scheme 3).
Althoughcompound8 wasobtainedasabyproductduring
the preparation of 1c, the alcohol 10 was easily synthesized
in 67% overall yield from the methyl ester derivative of
Acknowledgment. The authors thank the Fondazione
Cassa Risparmio Perugia and MIUR, PRIN
20109Z2XRJ_010, for the financial support. Helpful dis-
cussions with Professor Maria Chiara Aversa (University
of Messina) and Professor Angelo Liguori (University of
Calabria) are also acknowledged.
(26) Sharma, G. V. M; Raman Kumar, K.; Sreenivas, P.; Radha
Krishna, P.; Chorghade, M. S. Tetrahedron: Asymmetry 2002, 13,
687.
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F. R.; Da Silva, A. A. Quim. Nova 2005, 28, 444.
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149, 97.
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(30) Maeda, Y.; Nishimura, T.; Uemura, S. Chem. Lett. 2005, 34,
790.
Supporting Information Available. Synthetic proce-
dures together with characterization and spectral data
for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX