Regioselective synthesis of trisubstituted 2,3-dihydrofurans from donor-acceptor cyclopropanes or from reaction of the corey ylide with α-sulfenyl-, α-sulfinyl-, or α-sulfonylenones

Article abstract of DOI:10.1021/ol0514606

(Chemical Equation Presented) Regioselective synthesis of 2,4,5- or 3,4,5-trisubstituted 2,3-dihydrofurans has been realized by using donor-acceptor cyclopropanes or by a Corey ylide reaction with α-sulfenyl-, α-sulfinyl-, or α-sulfonylenones. The method allowed a straightforward synthesis of the natural product calyxolane B.

Full text of DOI:10.1021/ol0514606

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4565-4568
Regioselective Synthesis of
Trisubstituted 2,3-Dihydrofurans from
Donor−Acceptor Cyclopropanes or from
Reaction of the Corey Ylide with
r
r
-Sulfenyl-,
-Sulfonylenones
r-Sulfinyl-, or
Angela M. Bernard, Angelo Frongia, Pier P. Piras,* Francesco Secci, and
Marco Spiga
Dipartimento di Scienze Chimiche, UniVersita` degli studi di Cagliari, Cittadella
UniVersitaria di Monserrato, S.S 554,BiVio per Sestu,
I-09042 Monserrato (Cagliari), Italy
pppiras@unica.it
Received June 23, 2005 (Revised Manuscript Received September 8, 2005)
ABSTRACT
Regioselective synthesis of 2,4,5- or 3,4,5-trisubstituted 2,3-dihydrofurans has been realized by using donor
−acceptor cyclopropanes or by a
Corey ylide reaction with
calyxolane B.
r-sulfenyl-, r-sulfinyl-, or r-sulfonylenones. The method allowed a straightforward synthesis of the natural product
The dihydrofuran ring system is commonly found in the
molecular skeleton of naturally occurring and biologically
active derivatives.1 Its importance has stimulated several
synthetic approaches, among which the methods that entail
ionic2 or radical3 reactions of 1,3-dicarbonyl compounds with
appropriate olefins are particularly important. Very recently,
methods have been reported on the basis of the ring
enlargement of suitably substituted cyclopropanes4,5 and by
reaction of â-ketosulfides of benzothiazole6 or â-keto poly-
fluoroalkanesulfones7 with aldehydes. Moreover, dihydro-
furans have been obtained by the reaction of ethyl (di-
methylsulfuranylidene)acetate (EDSA) with enones contain-
ing two activating groups8 and by treatment of cyclic or
(1) (a) Nakanishi, K. Natural Products Chemistry; Kodansha Ltd.,
Academic: New York, 1974. (b) Meyers, A. I. Heterocycles in Organic
Synthesis; John Wiley & Sons: New York, 1974. (c) Dean, F. M. In
AdVances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: New
York, 1982; Vol. 30, pp 167-238. (d) Dean, F. M.; Sargent, M. V. In
ComprehensiVe Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W.
H., Eds.; Pergamon: New York, 1984; Vol. 4, Part 3, pp 531-598. (e)
Vernin, G. The Chemistry of Heterocyclic FlaVoring and Aroma Com-
pounds; Ellis Horwood: Chichester, 1982. (f) Danheiser, R. L.; Stoner, E.
J.; Kojama, H.; Yamashita, D. S.; Klade, C. A. J. Am. Chem. Soc. 1989,
111, 4407. (g) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (h) Merrit, A.
T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243.
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L.; Bovicelli, P. Tetrahedron Lett. 2000, 41, 10127. (c) Antonioletti, R.;
Bovicelli, P.; Malancona, S. Tetrahedron 2002, 58, 589 (d) Lee, Y. R.;
Suk, J. Y. Tetrahedron 2002, 58, 2359.
10.1021/ol0514606 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/17/2005

acyclic R-haloenones with carbon nucleophiles involving
active methylene functions.9 Following on from our involve-
ment in the field of cyclopropanes, expecially their use in
the synthesis of new heterocycles and of naturally occurring
biologically active compounds,10 we now report the synthesis
of new 2,4,5-trisubstituted or 3,4,5-trisubstituted 2,3-dihy-
drofurans 4 and 5, the regiochemistry of which depends on
the nature of the groups R and R1 or the oxidation state of
the sulfur atom. (Schemes 1-3).
prepared selectively (cis stereochemistry based on NOE
experiments) the cyclopropylsulfides 2a-d from the stereo-
chemically defined Z alkenes 1a-d. When we treated 2a-d
with m-CPBA in dichloromethane, the expected cyclopropyl
sulfones 3a,b were obtained from 2a,b. The oxidation of
the other two cyclopropylsulfides 2c,d unexpectedly gave,
probably through the proposed mechanism, the 2-aryl-4-
phenylsulfonyl-5-methyl-2,3-dihydrofurans 4c,d instead of
the cyclopropyl sulfones 3c,d. To our knowledge, apart from
another reported case,5a derivatives 2c,d represent the first
example of donor-acceptor cyclopropanes12 where the donor
substituent is a substituted aromatic ring. It is clear that subtle
electronic effects were at work in the syntheses of the
dihydrofurans 4c,d, as it appears that only aromatic rings
(sufficiently electron-donating due to the presence of the
groups Me, OMe) can assist successfully in the acid-induced
cyclopropane ring fission.13 Even though it is known that,
during the synthesis of cyclopropanes, sometimes it is
possible to isolate dihydrofuran derivatives,5 as far as we
know, the latter compounds have never been prepared from
cyclopropanes under such mild conditions.
The present research started when we tried to prepare the
cyclopropyl sulfones 3a-d (Scheme 1) to be used as a
Scheme 1
We next planned to extend the above reaction to the
cyclopropylsulfides 2e and 2f. These, in principle would be
obtainable from the cyclopropanation of alkenes 1e and 1f.
The latter can easily be prepared as a 85:15 mixture of Z/E
isomers by Knoevenagel condensation of phenylthioaryl
ketones with aryl aldehydes. The expected cyclopropanes
2e and 2f were obtained together with the 3-substituted
dihydrofurans 5e and 5f, very likely through the intermediate
enolate, which can react either through the carbon or the
oxygen atom (Scheme 2, Table 1).
starting material for the synthesis of alkylidenecyclopropanes
according to our recently published approach.11 We first
Scheme 2
(3) (a) Ichikawa, K.; Uemura, S. J. Org. Chem. 1967, 32, 493. (b)
Nishino, I. Bull. Chem. Soc. Jpn. 1985, 58, 1922. (c) Yoshida, J.; Yano, S.;
Ozawa, T.; Kawabata, N. J. Org. Chem. 1985, 50, 3467. (d) Vinogradov,
M. G.; Kondorsky, A. E.; Nikishin, G. I. Synthesis 1988, 60. (e) Tategami,
S.; Yamada, T.; Nishino, H.; Korp, J. D.; Kurosawa, K. Tetrahedron Lett.
1990, 31, 6371. (f) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Tetrahedron 1991,
47, 6457. (g) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1991, 56, 4772.
(h) Yamada, T.; Iwahara, Y.; Nishino, H.; Korp, J. D.; Kurosawa, K. J.
Chem. Soc., Perkin Trans. 1 1993, 609. (i) McDonald, F. E.; Connolly, C.
B.; Gleason, M. M.; Towne, T. B.; Treiber, K. D. J. Org. Chem. 1993, 58,
6952. (l) Nair, V.; Mathew, J.; Radhakrishnan, K. V. J. Chem. Soc., Perkin
Trans. 1 1996, 1487. (m) Roy, S. C.; Mandal. P. K. Tetrahedron 1996, 52,
2193. (n) Nguyen, V.-H.; Nishino, H.; Kurosawa, K. Synthesis 1997, 899.
(o) Alonso, I.; Carretero, J. C.; Garrido, J. L.; Magro, V.; Pedregal, C. J.
Org. Chem. 1997, 62, 5682. (p) Garrido, J. L.; Alonso, I.; Carretero, J. C.
J. Org. Chem. 1998, 63, 9406. (q) Garzino, F.; Meou, A.; Brun, P.
Tetrahedron Lett. 2000, 41, 9803. (r) Lee, Y. R.; Kim, B. S.; Kim, D. H.
Tetrahedron 2000, 56, 8845. (s) Evans, D. A.; Sweeney, Z. K.; Rovis, T.;
Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095. (t) Zhang, Y.; Raines,
A. J.; Flowers, R. A., II. Org. Lett. 2003, 13, 2363.
(4) (a) Lee, P. H.; Kim, J. S.; Kim, S. Tetrahedron Lett. 1993, 34, 7583.
(b) Nakajima, T.; Segi, M.; Mituoka, T.; Fukute, Y.; Honda, M.; Naitou,
K. Tetrahedron Lett. 1995, 36, 1667. (c) Pohmakotr, M.; Takampon, A.;
Ratchataphusit, J. Tetrahedron. 1996, 52, 7149. (d) Yadav, V. K.;
Balamurugan, R. Org. Lett. 2001, 3, 2717.
(5) For less recent examples of synthesis of dihydrofurans using
cyclopropanes or with involvement of cyclopropanes, see: (a) Alonso, M.
E.; Morales, A. J. Org. Chem. 1980, 45, 4530. (b) Saigo, K.; Kurihara, H.;
Miura, H.; Hongu, A.; Kubota, N.; Nohira, H.; Hasegawa, M. Synth.
Commun. 1984, 14, 787. (c) Melot, J. M.; Texier-Boullet, F.; Foucaud, A.
Tetrahedron, 1988, 44, 2215.
Probably the dihydrofurans 5e and 5f arise from ring
closure through the oxygen atom, as a consequence of the
(7) Xing, C.; Zhu, S. J. Org. Chem. 2004, 69, 6486.
(8) Jiang, Y. I.; Ma, D. Tetrahedron: Asymmetry 2002, 13, 1033.
(9) Arai, S.; Nakayama, K.; Suzuki, Y.; Hatano, K.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 9739 and literature therein for dihydrofuran
formation as undesired or minor process in cyclopropanation reaction.
(10) (a) Esposito, A.; Piras, P. P.; Ramazzotti, D.; Taddei M. Org. Lett.,
2001, 3, 3273. (b) Bernard, A. M.; Floris, C.; Frongia, A.; Piras, P. P. Synlett
2002, 5, 796. (c) Bernard, A. M.; Frongia, A.; Cadoni, C.; Secci, F.; Piras,
P. P. Org. Lett. 2002, 4, 2565. (d) Bernard, A. M.; Frongia, A.; Secci, F.;
Piras, P. P. Org. Lett. 2003, 5, 2923. (e) Bernard, A. M.; Frongia, A.; Secci,
F.; Delogu, G.; Ollivier, J.; Piras, P. P.; Salau¨n, J. Tetrahedron 2003, 59,
9433. (f) Bernard, A. M.; Floris, C.; Frongia, A.; Secci, F.; Piras, P. P.
Tetrahedron 2004, 60, 449.
(6) Calo`, V.; Scordari, F.; Nacci, A.; Schingaro, E.; D’Accolti, L.;
Monopoli, A. J. Org. Chem. 2003, 68, 4406.
4566
Org. Lett., Vol. 7, No. 21, 2005

increased enolate stability arising from the presence of an
aromatic ketone. Support for this hypothesis comes from the
increased dihydrofuran/cyclopropane ratio in the case of 1f
when a chlorine atom is present in the ketone aromatic ring.15
Additional support is furnished by the results (Table 1)
1i gave only 30% of the dihydrofuran 5i (entry 5). As a
consequence of this result and the fact that the presence of
an arylketo group, like in 1e and 1f (entries 1,2), led to the
formation of moderate amounts of the dihydrofurans 5e and
5f, we expected that the contemporaneous presence of a
sulfoxide or a sulfone group and an aromatic ketone could
be ideal for obtaining high yields of dihydrofuran. This was
confirmed using the derivatives 1l and 1m which led
exclusively to 5l and 5m (entries 6 ,and7) with no detectable
traces of the corresponding cyclopropanes 2l and 2m.
Table 1. Corey Ylide Reaction with the Enones 1e-o
entry 1e-oa
R
R1
x
2 (2:5)14 yieldb(%)
1
2
3
4
5
6
7
8
9
1e
1f
1g
1h
1i
p-Me-C6H4 C6H5
p-Me-C6H4 p-Cl-C6H4
0
0
1
2
2
2
1
1
2
2e (75:25)
2f (50:50)
2g (50:50)
2hc (14:86)
2id (30:70)
2l (0:100)
2m (0:100)
2n (100:0)
2o (100:0)
85
64
95
75
90
90
71
85
63
As an application of our synthetic approach, 5m was
treated with Ni/Raney to give, in a remarkably short and
straightforward way, the natural product 6 calyxolane B
(Scheme 4) recently isolated from a marine sponge,16 whose
C6H5
C6H5
i-Pr
Me
Me
Me
1l
p-Me-C6H4 C6H5
C6H5 C6H5
p-Me-C6H4 OMe
p-Me-C6H4 OMe
1m
1n
1o
Scheme 4
a Alkenes 1g,h,n,o were obtained, as a single geometric E- isomer, by
reacting the appropriate R-phenylsulfoxide- or R-phenyl sulfone-carbonyl
compound with the corresponding aldehyde. Alkenes 1i,l,m were obtained
by oxidation of the corresponding sulfides: 1i, Z; 1l, Z/E ) 85:15; 1m,
Z/E ) 75:25. b Isolated products. c Geometric isomer of 3b. d Geometric
isomer of 3a.
chiral nonracemic synthesis has been previously reported.17
obtained from the reaction of the Corey ylide with the
derivatives 1g-m (Scheme 3) where the stability of the
intermediate enolate was increased by varying the R1 group
and the oxidation state of the sulfur atom. We found that
the sulfoxide 1g (entry 3) gave a 1:1 mixture of the
dihydrofuran 5g and the corresponding cyclopropane 2g,
present as a diastereoisomeric mixture of the two geometric
isomers.
We have also investigated the behavior of the sulfoxide
and sulfone ester derivatives 1n and 1o (Table 1, entries 8
and 9). When submitted to the action of the Corey ylide, no
detectable amounts of dihydrofuran were found, and the
sulfoxide ester 1n led stereoselectively to the cyclopropane
2n as a single geometric isomer, while the sulfone ester 1o
gave a 1:1 mixture of the two corresponding geometric
isomers 2o. While the sulfoxide and the sulfone esters 1n,o
were not suitable substituents for formation of the corre-
sponding dihydrofurans, they could be used for the prepara-
tion of 2-substituted dihydrofurans of type 9 after executing
the following reaction sequence of Scheme 5 for the
Scheme 3
Scheme 5
As expected, increased quantities of the dihydrofuran 5h
were obtained in the case of the sulfone 1h (entry 4), while
(11) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P. Synlett 2004,
1064.
(12) For reviews see: (a) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003,
103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
(13) Carrying out the oxidation with hydrogen peroxide in refluxing
methanol, in the presence of ammonium molybdate, 2c gave the expected
corresponding sulfone 3c as a mixture of the two geometric isomers.
(14) A possible conversion of 2 into 5 was ruled out by re-subjecting
the pure isolated 2c,e to the same reaction conditions. The only isolated
products were the 6-methyl-4-(4methylphenyl)-5-(phenylsulfanyl)-3,4-di-
hydro-2H-pyran and the 4-(4methylphenyl)-6-phenyl-5-(phenylsulfanyl)-
3,4-dihydro-2H-pyran, probably through the cylization of the intermediate
coming from nucleophilic ring opening of the cyclopropane ring by the
Corey ylide.
cyclopropyl sulfone ester 2o.18 These types of dihydrofuran
are particularly important as they have been previously
(16) Rodriguez, A. D.; Cobar, O. M.; Padilla, O. L. J. Nat. Prod. 1997,
60, 915.
(17) (a) Buezo, N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc.
1998, 120, 7129. (b) Buezo, N. D.; de la Rosa, J. C.; Priego, J.; Alonso, I.;
Carretero, J. C. Chem. Eur. J. 2001, 7, 3890
(18) The ester 2o used for this reaction was a single trans geometric
isomer obtained by oxidation of the corresponding sulfoxide 2n.
(15) For difference in enolate stability between analogous acetophenone
and p-chloroacetophenone, see: Dubois, J. E.; El-Alaoui, M.; Toullec, J.
J. Am. Chem. Soc. 1981, 103, 5393.
Org. Lett., Vol. 7, No. 21, 2005
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reported19 to be precursors of spiroketals by reaction with
the γ-lactone.
Acknowledgment. Financial support from the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica,
Rome, and by the University of Cagliari [National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Ap-
plicazioni” (PRIN) and “Design, synthesis and biological and
pharmacological evaluation of organic molecules as innova-
tive drugs” (FIRB)] is gratefully acknowledged.
In summary, we have found that the synthesis of 2,4,5-
trisubstituted or 3,4,5-trisubstituted 2,3-dihydrofurans can be
easily addressed and controlled by a careful choice of the
substituents and by modulation of the oxidation state of sulfur
in alkenes obtained by Knoevenagel condensation of alkyl-
or arylthio ketones with aldehydes. The method has allowed
an easy entry to the family of spiroketals and a very short
synthesis of the natural derivative calyxolane B to be
achieved. Studies on the chiral nonracemic version of these
reactions are now in progress in our laboratory that will take
advantage of the stereoselective cyclopropanation of phen-
ylthioketones 1a-f and of the sulfoxide 1n.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and characterization of
compounds 2a-i,n,o, 3a,b, 4c,d, 5e-m, and 6-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Carretero, J. C.; Rojo, J.; Diaz, N.; Hamdouchi, C.; Poveda, A.
Tetrahedron 1995, 51, 8507.
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