J . Org. Chem. 1997, 62, 9339-9341
9339
(1) with various nucleophiles in the presence of a Lewis
Ster eoselective Syn th esis of
2,2,5-Tr isu bstitu ted Tetr a h yd r ofu r a n s via
th e Lew is Acid -Assisted Rea ction of Cyclic
Hem ik eta ls w ith Nu cleop h iles
acid (eq 2).9
Yutaka Nishiyama,* Takeshi Katoh, Katsuya Deguchi,
Yorikazu Morimoto, and Kazuyoshi Itoh
Department of Applied Chemistry, Faculty of Engineering
and High Technology Research Center, Kansai University,
Suita, Osaka 564, J apan
Received May 28, 1997
As the development of efficient and stereoselective
construction methods of tetrahydrofurans are desirable
in connection with the synthesis of polyether antibiotics
and natural products containing oxacyclic units,1 various
tetrahydrofuran synthetic methods have been developed.2
However, there are only a limited number of stereose-
lective synthetic methods for trisubstituted tetrahydro-
furans (e.g., the intramolecular cyclization methods such
as intramolecular cyclization of homoallylic alcohols in
the presence of iodine,3 or a palladium catalyst,4 the
acetic acid promoted intramolecular cyclization of epoxy
alcohols,5 and the Lewis acid assisted reaction of various
nucleophiles with γ-hydroxy ketones followed by cycliza-
tion6).
The reaction was carried out as follows: To a CH2Cl2
(2 mL) solution of cyclic hemiketal (1) (0.2 mmol) and 2
equiv of trimethylsilyl cyanide (4) was added 2 equiv of
trimethylsilyl triflate (TMSOTf) as a Lewis acid at -78
°C. The color of the reaction solution immediately
changed to a wine red color, the spot of 1 disappeared,
and the spots of 2,2,5-trisubstituted tetrahydrofurans (2
and 3) appeared on TLC. After the neutralization with
aqueous NaHCO3 and extraction with diethyl ether, the
product was isolated by column chromatography on silica
gel.
Dihydro-2,5-diphenyl-3,3-(trimethylenedithio)furan-
2-ol (1a ) was chosen as a model substrate and allowed
to react with trimethylsilyl cyanide (4) under various
reaction conditions (Table 1). In contrast, the use of TiCl4
shows a high yield and excellent stereoselectivity for the
synthesis of 2,5-disubstituted tetrahydrofurans by the
reduction of 1a with triphenylhydrosilane, the reaction
of 1a with 4 was not induced at all by TiCl4 (run 4).
However, when TMSOTf instead of TiCl4 was used as a
Lewis acid, the reaction of 1a with 4 smoothly proceeded
to give 2-cyano-2,5-diphenyl-3,3-(trimethylenedithio)-
furans in almost quantitative yield with high stereose-
lectivity (2a :3a ) 38.5:1.0) (run 2).10 Lowering the
amount of 4 from 2 equiv to 1 equiv led to the decrease
of the yields of 2 and 3 (run 1). At a higher reaction
temperature (0 °C), stereoselectivity is lower than that
at -78 °C, and the ratio of 2 to 3 is approximately 7.8:
1.0 (run 3). In the cases of BF3‚OEt2 and Et2AlCl, the
cyanated products were obtained in 93% and 91% yields,
respectively, but the stereoselection of 2 is lower than
that of TMSOTf (runs 5 and 8). The use of aluminum
trichloride (AlCl3) and ethyl aluminum dichloride (EtAlCl2)
Recently, we reported a convenient and highly stereo-
selective synthetic method of 2,5-disubstituted tetrahy-
drofurans by the Lewis acid-assisted reduction of cyclic
hemiketals (1), 2,5-disubstituted 3,3-(trimethylenedithio)-
furan-2-ol, with triphenylhydrosilane (eq 1).7 In the
course of our study on the development of the high
stereoselective synthesis of tetrahydrofuran derivatives,8
we found a new stereoselective synthetic method of 2,2,5-
trisubstituted tetrahydrofurans (2 and 3) based on the
reaction of dithioacetal functionalized cyclic hemiketals
(1) For example, see: (a) Westley, J . W. Polyether Antibiotics;
Naturally occurring acid ionophores; Marcel Dekker: New York, 1982,
Vols I and II. (b) Cave, A.; Cortes, D.; Figadere, B.; Hocquemiller, R.;
Laprevote, O.; Laurens, A.; Leboeuf, M. Phytochemical Potential of
Tropical Plants: Recent Advances in Phytochemical 27; Downum, K.
R., Romen, J ., Stafford, H. H. A., Eds.; Plenum Press: New York, 1993.
(c) Boivin, M. H. D. Tetrahedron 1992, 48, 8545.
(2) For reviews, see Harmange, J .-C.; Figadere, B. Tetrahedron:
Asymmetry 1993, 4, 1711. (b) Boivin, T. L. B. Tetrahedron 1987, 43,
2209 and references cited therein.
(3) Rychnovsky, S. D.; Bartlett, P. A. J . Am. Chem. Soc. 1981, 103,
3963.
(4) Hosokawa, T.; Hirata, M.; Murahashi, S.-I.; Sonoda, A. Tetra-
hedron Lett. 1978, 21, 1821.
(9) Suzuki, K. et al. have already reported that the stereoselective
synthesis of disubstituted cyclic ethers, tetrahydrofurans and tetrahy-
dropyrans, by the reaction of lactols with organometallic reagents in
the presence of Lewis acid: see Tomooka, K.; Matsuzawa, K.; Suzuki,
K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6339.
(10) The configaration of each isomer was assigned by the NOE
analysis of the ring protons of compounds 7, which were the reduction
products of 2 and 3 with LiAlH4. In the case of the minor products,
when irradiated at the frequency of the C-5 proton signal, NOE was
observed for the C-4 proton signal. On the other hand, irradiation of
the C-5 proton of a major proton did not show an NOE difference.
(5) Fukuyama, T.; Uranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron
Lett. 1987, 31, 2741.
(6) Ressig, H. U.; Holzinger, H.; Glomsda, G. Tetrahedron 1989, 45,
3139.
(7) Nishiyama, Y.; Tujino, T.; Yamano, T.; Hayashishita, M.; Itoh,
K. Chem. Lett. 1997, 165.
(8) (a) Chikashita, H.; Ishihara, M.; Takigawa, K.; Itoh, K. Chem.
Lett. 1992, 195. (b) Chikashita, H.; Fukushima, H.; Uemura, H.; Itoh,
K. Chem. Lett. 1992, 599. (c) Chikashita, H.; Nakamura, Y.; Uemura,
H.; Itoh, K. Chem. Lett. 1993, 477. (d) Chikashita, H.; Hirao, K.; Itoh,
K. Bull. Chem. Soc. J pn. 1992, 66, 195. (e) Chikashita, H.; Nikaya, T.;
Takigawa, K.; Itoh, K. Natur. Prod. Lett. 1992, 2, 183.
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