Synthesis of 2,5-disubstituted tetrahydrofurans catalyzed by palladium(0)

Article abstract of DOI:10.3987/COM-00-S(I)11

A stereoselective cyclization of an allylic ester to 2,5-disubstituted tetrahydrofurans catalyzed by palladium(0) is demonstrated. In this cyclization, acetoxy heptenol (6a) having a free hydroxy group prefered trans isomer to cis isomer. By the use of the protected acetoxy heptenol (6b), the cis selectivity was observed. The stereoselectivity was enhanced by the use of DPPIO ligand.

Full text of DOI:10.3987/COM-00-S(I)11

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 419 - 424, Received, 9th March, 2000
SYNTHESIS OF 2,5-DISUBSTITUTED TETRAHYDROFURANS
CATALYZED BY PALLADIUM(0)
Osamu Hara,*a Kazushige Fujii,b Yasumasa Hamada,a and Youji Sakagamib
a Faculty of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba 263-8522, Japan
b School of Agricultural Sciences, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan
Abstract - A stereoselective cyclization of an allylic ester to 2,5-disubstituted
tetrahydrofurans catalyzed by palladium(0) is demonstrated.
In this
cyclization, acetoxy heptenol (6a) having a free hydroxy group prefered trans
isomer to cis isomer. By the use of the protected acetoxy heptenol (6b), the
cis selectivity was observed. The stereoselectivity was enhanced by the use of
DPPIO ligand.
Substituted oxygen heterocycles including substituted tetrahydrofuran (THF) and tetrahydropyran (THP)
rings have been found in polyether antibiotics and other natural products, and methods for the
construction of their structural units in a stereocontrolled fashion have attracted current attention.1
Electrophilic cyclization to the olefins and nucleophilic cleavage of epoxides with hydroxy group have
been used for the construction of these structural units, while transition metal-catalyzed cyclization is also
recognized as an effective approach to preparation of these compounds.2 Actually, Pd(II)-catalyzed
intramolecular alkoxypalladation has been known to be a well-established method.3 However, there
have been very few published methods for the stereoselective cyclization to 2,5-disubstituted
tetrahydrofurans catalyzed by Pd(0).4 Trost and Tenaglia have reported that cyclic stannylene diether (1)
including an allylic ester unit is easily converted into 2,5-disubstituted tetrahydrofuran (2) in the presence
of Pd(0) in good yield, but with less satisfactory diastereoselectivity (Figure).4a Here, we report

stereoselective construction of the 2,5- disubstituted THF ring by the allylic substitution reaction.
Allylic esters (6a and 6b) were easily prepared from the hydroxy lactone (3) obtained from L-glutamic
acid5 as shown in Scheme. After protection of the hydroxy group with THP , the protected lactone (4)
was transformed in a one-pot reaction into α,β-unsaturated ester (5) in 77% yield by the use of the
Takacs’ method.6 The reduction of the ester was carried out with DIBALH at -78 °C to give the
corresponding allyl alcohol, which was treated with Ac2O in pyridine followed by deprotection of the
THP groups with TsOH in MeOH at room temperature to give the desired diol (6a). The selective
protection of the primary hydroxy group was achieved by the treatment of tert-butyldiphenylsilyl chloride
(TBDPSCl) and imidazole in DMF at room temperature to provide another allyl ester (6b).
The results of the intramolecular allylic substitution reaction are listed in Table. Treatment of diol (6a)
with 4 mol% bis(dibenzylideneacetone)palladium (Pd(dba)2) and 20 mol% Ph3P gave a volatile THF
derivative (2), which was converted into 7 with TBDPSCl and imidazole without purification. The cis-
and trans- isomers were isolated by SiO2 column chromatography and its stereochemistry was determined
by the NOE experiment. The stereoselectivity of this reaction was very similar to the previous results
reported by Trost (Entry 1). 4a Also, no cyclization products derived from the primary alcohol to give a
THP ring were detected.4a The use of (o-tolyl)3P having a large corn angle favored inducing a cis
derivative rather than a trans derivative.4b Unfortunately, this reaction was incomplete after stirring for
60 h at room temperature and then heating for 12 h at 60 ˚C. (Entry 2). The use of n-Bu3P and addition
of metal salts or a base (silver salts and pyridine) were not effective to improve the stereoselection.
Since it is well-known that the use of chiral ligands causes the asymmetric induction in the allylic
substitution reaction, we examined the reagent-control condition for improvement of the
diastereoselectivity. 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl (BINAP), known to be one of the

most effective ligands in asymmetric synthesis, however, did not work as a catalyst in our systems
(Entries 3, 4). N,N-Dimethyl-1-[2-(diphenylphosphino)ferrocenyl]ethylamine (PPFA),7 2,6-dimethyl-9-
phenyl-9-phospabicyclo[3,3,1]nonane (9-PBN)8 and 2-(2-diphenylphosphinophenyl)-4-isopropyl-1,3-
oxazoline (DPPIO)9 gave the desired THF derivative (7) with acceptable yields, and (-)-DPPIO was an
effective ligand for the enforcement of trans stereoselection while less improvement of cis stereoselection
was observed in any ligands. Surprisingly, remarkable reversal of diastereoselectivity was observed by
the use of 6b, which afforded 7 in 85% yield in a ratio of 63:37(cis:trans) even though Ph3P was used
(Entry 11). Furthermore, this cis stereoselection was enhanced by a (+)-DPPIO ligand resulting in the
ratio of 81:19 (Entry 12). The reason for this reverse diastereoselectivity is unclear, but the presence of
a hydroxy group might influence the transition state and the stereoselectivity might be strongly dependent
upon the structure of substrate.
In conclusion we reported here a stereoselective synthesis of 2,5-disubstituted tetrahydrofurans catalyzed
by Pd(0). Further synthetic studies using this cyclization are under way.

EXPERIMENTAL
General Procedure. Optical rotations were taken with a JASCO DIP-140 polarimeter. IR spectra were
taken with a JASCO FT/IR 230 spectrophotometer. MS were taken with a JEOL JMA 2000 mass
1
spectrometer. H NMR spectra were taken with a JEOL JNM-A 400 spectrometer in CDCl3, and
13
tetramethylsilane was used as internal standard. C NMR spectra were taken with a JEOL JNM-A 400
spectrometer in CDCl3, and CDCl3 was used as internal standard.
(2S,5E)-7-Acetoxy-5-heptene-1,2-diol (6a). Under N2, to a solution of 5 (15.7 g, 44 mmol) in toluene
(150 mL) at -78 °C was added dropwise 1.5 M DIBALH in toluene (73 mL, 110 mmol) over a period of
30 mim. The solution was stirred an additional 30 min at -78 °C, and Na2SO4•10H2O was added. After
warmed to rt and stirred for 1 h, the suspension was filtered through a celite pad. Removal of the solvent
gave the crude allyl alcohol. To a solution of the above allyl alcohol in pyridine (150 mL) at 0 °C was
added Ac2O (16.6 mL, 176 mmol). The solution was warmed to rt and stirred for 9.5 h. After removal of
pyridine in vacuo, water was added and the mixture was extracted with EtOAc. The combined organic
layers were washed 1 M HCl, saturated NaHCO3 and saturated brine, and dried (Na2SO4). Removal of the
solvent gave the crude allyl acetate. To a solution of the above allyl acetate in MeOH (200 mL) at rt was
added TsOH•H2O (840 mg, 4.4 mmol). After 4 h at rt, MeOH was removed in vacuo. Saturated NaHCO3
was added, the mixture was extracted with EtOAc, and the combined organic layers were washed
saturated brine and dried (Na2SO4). Removal of the solvent and flash chromatography of the residue on
SiO2 (200 g, EtOAc - hexane (4 : 1)) gave 6a (3.19 g, 38% from 5) as an oil. [α]22D -2.0 ˚ (c 1.13, CHCl3);
1
IR neat (cm-1) 3390, 2939, 2858, 1732, 1446, 1385, 1365, 1242, 1028, 972, 868; H NMR δ (ppm) 5.79
(dt, 1H, J = 15.4, 6.6 Hz), 5.62 (dt, 1H, J = 15.4, 6.4 Hz), 4.52 (d, 2H, J = 6.4 Hz), 3.73 (m, 1H), 3.67 (dd,
1H, J = 11.0, 3.2 Hz), 3.46 (dt, 1H, J = 11.0, 7.6 Hz), 2.3 - 2.1 (m, 2H), 2.06 (s, 3H), 2.0 - 1.4 (br s, 2H),
1.56 (m, 2H); 13C NMR δ (ppm) 170.6, 135.4, 124.6, 71.6, 66.7, 65.1, 32.2, 28.3, 24.9, 21.0; Anal. Calcd
for C9H16O4: C, 57.43; H, 8.57. Found: C, 57.44; H, 8.77.
(2S,5E)-7-Acetoxy-1-tert-butyldiphenylsiloxy-5-hepten-1-ol (6b). To a solution of 6a (470.5 mg, 2.5
mmol) in DMF (15 mL) at rt were added imidazole (357.5 mg, 5.25 mmol) and TBDPSCl (0.68 mL, 2.63
mmol). After 2 h at rt, water was added and the mixture was extracted with EtOAc - hexane (1 : 1). The
combined organic layers were washed with water and saturated brine, dried (Na2SO4), and concentrated.
Flash chromatography of the residue on SiO (120 g, EtOAc - hexane (1 : 6)) gave 6b (770.1 mg, 72%) as

an oil. [α]22D +6.2 ˚ (c 0.51, CHCl3); IR neat (cm-1) 3477, 3070, 2931, 2858, 1739, 1589, 1471, 1427, 1362,
1
1232, 1113, 970, 877 823, 741, 702; H NMR δ (ppm) 7.66 (m, 4H), 7.5 - 7.3 (m, 6H), 5.74 (dt, 1H, J =
15.3, 6.6 Hz), 5.55 (dtt, 1H, J = 15.3, 6.5, 1.1 Hz), 4.49 (dd, 2H, J = 6.6, 1.1 Hz), 3.71 (m, 1H), 3.65 (dd,
1H, J = 10.0, 3.4 Hz), 3.49 (dd, 1H, J = 10.0, 7.3 Hz), 3.41 (br d, 1H, J = 3.4), 2.3 - 2.0 (m, 2H), 2.04 (s,
13
3H), 1.6 - 1.4 (m, 2H), 1.07 (s, 9H); C NMR δ (ppm) 171.3, 135.5, 135.5, 133.1, 129.8, 127.8, 124.3,
71.2, 67.9, 65.1, 31.9, 28.2, 26.8, 21.0, 19.3; Anal. Calcd for C25H34O4Si: C, 70.38; H, 8.03. Found: C,
70.18; H, 8.27.
General procedure for Pd(0)-catalyzed cyclization. Under nitrogen, to a solution of Pd(dba)2 (11.5 mg,
0.02 mmol) and monodentate ligand (10 or 20 mol%) or bidentate ligand (5 mol%) in THF (1 mL) was
added a solution of diol 6a (94.1 mg, 0.5 mmol) or monoalcohol 6b (213.3 mg 0.5 mmol) in THF (1 mL).
After stirring at room temperature for 12-24 h, the mixture was filtered through a celite pad. After
removal of the solvent, to the crude mixture of 2 were added DMF (3 mL), imidazole (204 mg, 3 mmol)
and TBDPSCl (0.39 mL, 1.5 mmol). After stirring for 6 h at rt, water was added and the mixture was
extracted 3 times with EtOAc - hexane (1 : 1). The combined organic layers were washed with water and
saturated brine, dried (Na2SO4), and concentrated. Purification of crude 7 was performed by flash
chromatography on SiO2 (25 g, Et2O-hexane (1:24)) to afford cis-7 and trans-7.
(2S,5R)-2-(tert-Butyldiphenylsiloxy)methyl-5-vinyltetrahydrofuran (cis-7). Rf 0.64 (Et2O - hexane (1 :
6); [α]22 +1.9 ˚ (c 1.12, CHCl3); IR neat (cm-1) 3070, 2958, 2931, 2858, 1589, 1471, 1427, 1113, 989,
D
1
922, 823, 740, 702; MS (EI) m/z 309 (M+-tert -Bu); H NMR δ (ppm) 7.68 (m, 4H), 7.39 (m, 6H), 5.84
(ddd, 1H, J = 17.1, 10.5, 6.6 Hz), 5.24 (dt, 1H, J = 17.1, 1.2 Hz), 5.06 (dt, 1H, J = 10.5, 1.2 Hz), 4.31 (m,
1H), 4.09 (m, 1H), 3.70 (dd, 1H, J = 10.2, 4.4 Hz), 3.63 (dd, 1H, J = 10.2, 5.5 Hz), 2.1 - 1.85 (m, 3H),
13
1.75 - 1.6 (m, 1H), 1.06 (s, 9H); C NMR δ (ppm) 139.4, 135.6, 133.6, 129.6, 127.6, 115.3, 80.8, 79.7,
66.4, 31.8, 28.0, 26.8, 19.3; Anal. Calcd for C23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.37; H, 8.41.
(2S,5S)-2-(tert-Butyldiphenylsiloxy)methyl-5-vinyltetrahydrofuran (trans-7). Rf 0.69 (Et2O - hexane
(1 : 6)); [α]22D +5.1 ˚ (c 1.12, CHCl3); IR neat (cm-1) 3072, 2958, 2931, 2858, 1589, 1471, 1427, 1113, 997,
1
922, 823, 741, 702 ; MS (EI) m/z 309 (M+-tert-Bu); H NMR δ (ppm) 7.68 (m, 4H), 7.38 (m, 6H), 5.84
(ddd, 1H, J = 17.1, 10.2, 6.3 Hz), 5.22 (dt, 1H, J = 17.1, 1.3 Hz), 5.08 (dt, 1H, J = 10.2, 1.3 Hz), 4.41 (dd,
1H, J = 13.6, 6.3 Hz), 4.18 (m, 1H), 3.69 (dd, 1H, J = 10.5, 4.6 Hz), 3.65 (dd, 1H, J = 10.5, 5.1 Hz), 2.15
- 1.95 (m, 2H), 1.95 - 1.80 (m, 1H), 1.7 - 1.6 (m, 1H) 1.06 (s, 9H); 13C NMR δ (ppm) 139.3, 135.6, 133.7,

129.6, 127.6, 115.1, 80.3, 79.3, 66.5, 32.3, 28.0, 26.8, 19.3; Anal. Calcd for C23H30O2Si: C, 75.36; H, 8.25.
Found: C, 75.21; H, 8.43.
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