Stereoselective Synthesis of 2,2,5-Trisubstituted Tetrahydrofurans via the Lewis Acid-Assisted Reaction of Cyclic Hemiketals with Nucleophiles

Full text of DOI:10.1021/jo9709312

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.
S0022-3263(97)00931-6 CCC: $14.00 © 1997 American Chemical Society

9340 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Ta ble 1. Rea ction of 1a w ith Tr im eth ylsilyl Cya n id e in
th e P r esen ce of Va r iou s Lew is Acid s
Ta ble 2. Rea ction of Cyclic Hem ik eta ls w ith Va r iou s
Nu cleop h iles in th e P r esen ce of TMSOTfa
Me3SiCN
(equiv)
Run
Lewis acid
time, min
yield, %a (2a /3a )b
1
2
3c
4
5
6
7
8
TMSOTf
TMSOTf
TMSOTf
TiCl4
Et2AlCl
EtAlCl2
AlCl3
1
2
2
2
2
2
2
2
5
1
1
240
240
5
79 (39.3/1.0)
99 (38.5/1.0)
91 (7.8/1.0)
no reaction
91 (6.5/1.0)
96 (37.2/1.0)
98 (35.5/1.0)
93 (2.4/1.0)
1
15
BF3‚OEt2
a
b
Isolated yield based on 1a . Determined by 1H NMR. c The
reaction was carried out at 0 °C.
gave almost the same yield and stereoselectivity as that
of TMSOTf (runs 6 and 7).
In order to determine the scope and limitation of the
stereoselective synthesis of 2,2,5-trisubstituted tetrahy-
drofurans using the Lewis acid assisted reaction of cyclic
hemiketals (1) with organometallic compounds, the reac-
tion of hemiketals with various organometallic com-
pounds was examined (Table 2).11 It is interesting to note
that the stereoselectivity of the products and the reactiv-
ity of the substrates depended on their substituents at
both the C-1 and C-4 positions of the cyclic hemiketals.
When 4-alkyl-substituted cyclic hemiketals, dihydro-5-
ethyl- (1b) or dihydro-5-methyl-2-phenyl-3,3-(trimethyl-
enedithio)furan-2-ol (1c), and 2-alkyl-substituted cyclic
hemiketals, dihydro-2-methyl-5-phenyl-3,3-(trimethyl-
enedithio)furan-2-ol (1d ), instead of 1a which possesses
phenyl groups at both the C-1 and C-4 positions, were
used as the substrate, cyanation of these compounds
required a longer reaction time than that of 1a , and the
stereoselectivities of tetrahydrofurans are slightly lower
than 1a (runs 1-3). In the reaction of 1d , TiCl4 also
shows the same activity as that of TMSOTf, in contrast
with having no activity in the cases of 1a , 1b, and 1c.
The reaction of 1a with enol silyl ethers and allyl silanes,
which are often used as good carbon nucleophiles in
organic synthesis, was next examined in the presence of
TMSOTf. In the case of the enol silyl ether, 1-phenyl-
1-(trimethylsilyloxy)-2-ethene, the corresponding 2,2,5-
trisubstituted tetrahydrofuran was formed in 53% yield
with high stereoselectivity (run 5). On the other hand,
allyltrimethylsilane did not give a good result (run 6).
However, when allyltributylstannane instead of allyl-
trimethylsilane was used as an allylated reagent, an
allylated product was obtained in good yield (91% yield)
with high stereoselectivity (2f:3f ) 15.4:1.0) (run 7). In
the case of the synthesis of a 2-methyl-2,5-diphenyl-
substituted tetrahydrofuran by the reaction of 1a with
dimethylzinc, a satisfactory yield was not obtained due
to the formation of several byproducts (run 8). When
methanol was employed under the same reaction condi-
tions, the corresponding cyclic ketal was formed in poor
yield (run 9). However, the yield of the cyclic ketal was
increased by the addition of MgSO4 as a dehydrating
a
Reaction conditions: cyclic hemiketal (0.2 mmol), nucleophile
(0.4 mmol), TMSOTf (0.4 mmol) in CH2Cl2 (2 ml) at -78 °C.
Isolated yield based on cyclic hemiketal. c Determined by 1H
b
NMR. TiCl4 was used as a Lewis acid. e Reaction was carried out
d
at 25 °C. f In the coexistance of 0.5 equiv amount of MgSO4.
agent (2h :3h ) 1.9:1.0) (run 10). The monothioketal was
also obtained by the reaction of 1a with thiol in 79% yield
(run 11).
Although we have so far not been able to obtain clear
evidence for the high selectivity, we suggested that the
nucleophiles attacked an oxonium ion intermediate (5)
from the peripheral side owing to the steric hindrance of
3,3-trimethylenedithio group, in which the Lewis acid
was coordinated on one of the sulfur atoms of the 3,3-
trimethylenedithio group, to form 2 predominantly
(Scheme 1).12 However, in the case of alcohol or thiol the
coordination of the Lewis acid on the sulfur atom was
suppressed by these compounds, and the steric interac-
tion of 6 appeared to be smaller than that of 5 (Scheme
2). Therefore, the decrease of steric effect led to the
decrease of stereoselectivity.
In summary, we succeeded in the stereoselective
synthesis of 2,2,5-trisubstituted tetrahydrofurans based
(12) Reissig, H. U. et al. has already reported the stereoseletive
synthesis of 2,2,5-trisubstituted tetrahydrofurans by the Lewis acid
assisted reaction of γ-hydroxy ketones with various organosilicon
reagents.6 In this paper, he suggested that the reaction proceeded by
Lewis acid induced cyclization of γ-hydroxy ketones followed by
addition of organosilicon reagents to the similar oxocarbonium cation
intermediates. However, the stereoselectivity of products with H. U.
Reissig’s method was opposite to that observed by our method. From
these results, we suggested that the 3,3-trimethylenedithio group
played an important role on the stereoselectivity.
(11) The configuration of all products was assigned by the NOE
analysis.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9341
Syn th esis of Cyclic Hem ik eta ls. To a THF (60 mL)
solution of dithianyl alcohol (12.5 mmol) was added n-BuLi (15%
hexane solution) (75 mmol, 48 mL) dropwise at -40 °C under a
nitrogen atmosphere. The reaction mixture was stirred at -40
°C for 2 h and then at -15 °C for 3 h. After the solution was
cooled to -40 °C, HMPA (75 mmol, 13.2 mL) was added. After
the solution was stirred at -40 °C for 2 h, ethyl benzoate (75
mmol, 12 mL) was added dropwise and stirred for 5 h at -40
°C and then at -15 °C for 15 h. The reaction mixture was
quenched by the addition of aqueous NH4Cl (100 mL) and
extracted with ethyl acetate (100 mL × 3). The combined
organic layers were dried over MgSO4, concentrated under
reduced pressure, and then purified by column chromatography
on silica gel to give the corresponding cyclic hemiketals.
Lew is Acid -Assisted Rea ction of Cyclic Hem ik eta ls w ith
Or ga n om eta llic Rea gen t. To a CH2Cl2 (2 mL) solution of
cyclic hemiketal (0.2 mmol) and organometallic compound (0.4
mmol), was added TMSOTf (0.4 mmol) dropwise at -78 °C and
stirred for 1 min. After the reaction, the reaction mixture was
quenched with aqueous NaHCO3 (10 mL) and extracted with
diethyl ether (10 mL × 3). The combined organic layers were
washed with brine solution (30 mL) and dried over MgSO4. The
solution was concentrated with reduced pressure, and the
resulting solution was purified by column chromatography on
silica gel to afford the corresponding 2,2,5-trisubstituted tet-
rahydrofuran derivatives.
Sch em e 1
Sch em e 2
Mixture of 2a and 3a (2a :3a ) 0.8:0.2): 1H NMR (CDCl3) δ
1.71-1.90 (c, 3H), 2.17-2.23 (m, 0.2H), 2.45-2.51 (m, 0.8H),
2.61-2.71 (c, 0.4H), 2.73-2.79 (m, 0.8H), 2.82 (dd, J ) 11.0, 14.0
Hz, 0.8H), 2.92-3.03 (c, 1H), 3.07-3.13 (c, 1H), 5.48 (dd, J )
6.2, 9.5 Hz, 0.2H), 5.61 (dd, J ) 5.5, 11.0 Hz, 0.8H), 7.31-7.49
(c, 6H), 7.53-7.58 (c, 2H), 7.87-7.97 (c, 1.6H), 7.99-8.00 (c,
0.4H); 13C NMR (CDCl3) δ 23.7, 26.6, 27.7, 50.5, 50.6, 50.7, 60.5,
81.5, 81.5, 81.6, 90.1, 119.5, 126.2, 127.0, 128.0, 128.3, 128.7,
129.9, 134.4, 139.5: IR (KBr) 2358, 1045, 763, 748, 698 cm-1
exact mass calcd for C20H19NOS2 353.5090, found 353.5066.
;
Red u ction of 2a . To a THF (5 mL) solution of LiAlH4 (0.9
mmol, 34 mg) was added 2a (0.18 mmol, 63 mg) dropwise at 0
°C and stirred at room temperature for 18 h. After the reaction,
the reaction mixture was quenched with H2O (10 mL) and
extracted with diethyl ether (10 mL × 3). The combined organic
layers were washed with brine solution and dried over MgSO4.
The solution was concentrated with reduced pressure, and the
resulting solution was purified by column chromatography on
silica gel (benzene:EtOAc ) 1:1) to afford 7.
on the reaction of cyclic hemiketals with various nucleo-
philes in the presence of TMSOTf.
Exp er im en ta l Section
Ma ter ia ls. 1H and 13C NMR spectra were measured with
400 and 100 MHz using tetramethylsilane as the internal
standard. IR spectra were obtained on an FT-IR spectropho-
tometer. Styrene oxide, methanol, R-toluenethiol, ethyl ben-
zoate, ethyl acetate, and HMPA were purified by the usual
methods and freshly distilled before use. All Lewis acids,
trimethylsilyl cyanide, allyltrimethylsilane, allyltributylstan-
nane, dimethylzinc (in toluene solution), n-BuLi (in hexane
solution), butylene oxide, and propylene oxide were high grade
commercially available product and used without purification.
1,3-Dithiane was synthesized by a reported method.13
1
7: H NMR (CDCl3) δ 1.36 (s, 2H), 1.80-1.91 (m, 1H), 2.01-
2.07(m, 1H), 2.57 (dt, J ) 3.3, 14.0 Hz, 1H), 2.67 (dd, J ) 11.0,
13.0 Hz, 1H), 2.80-2.85 (m, 1H), 2.95-3.08 (c, 2H), 3.24 (d, J )
14.0 Hz, 1H), 3.37-3.41 (c, 2H), 5.49 (dd, J ) 5.1, 11.0 Hz, 1H),
7.31-7.47 (c, 8H), 7.70-7.72 (c, 2H); 13C NMR (CDCl3) δ 25.4,
28.7, 28.7, 49.8, 50.3, 62.7, 80.1, 92.1, 126.3, 127.0, 127.9, 128.1,
128.1, 128.9, 139.5, 141.4: IR (KBr) 1031, 756, 700 cm-1
.
Syn th esis of Dith ia n yl Alcoh ols. To a THF (30 mL)
solution of 1,3-dithiane (3.17 g, 26 mmol) was added dropwise a
15% hexane solution of n-BuLi (24.5 mL, 39 mmol) at -40 °C
under a nitrogen atmosphere. The reaction mixture was stirred
for 2 h at -40 °C and then for 2 h at 0 °C. The solution was
cooled to -40 °C and epoxide (22 mmol) was added dropwise
and stirred for 2 h at -40 °C. The reaction mixture was
quenched by the addition of aqueous NH4Cl (50 mL) and
extracted with ethyl acetate (50 mL × 3). The combined organic
layers were dried over MgSO4, concentrated under reduced
pressure, and then purified by column chromatography on silica
gel to give the corresponding dithianyl alcohols.
Ack n ow led gm en t. We thank the donors of Grant-
in-Aid (09750958) from the Ministry of Education,
Science, and Culture of J apan and The Science Research
Promotion Fund administered by the J apan Private
School Promotion Foundation for this research.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and data for compounds 2a -i, 3a -i, and 7 (33 pages).
This material is contained in libraries on microfiche, im-
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(13) Corey, E. J .; Seebach, P. Organic Syntheses; Wiley: New York,
1988; Coll. Vol. 6, p 556.
J O9709312