Iterative Synthesis of Polycyclic Ethers
J . Org. Chem., Vol. 67, No. 10, 2002 3497
Sch em e 8a
Hyd r obor a tion of 11a . To a mixture of 11a (101 mg, 0.33
mmol) in THF (3 mL) at 0 °C was added BH3‚SMe2 (130 µL,
1.33 mmol), and the mixture was allowed to warm to room
temperature with stirring. After 2 h, 1 N NaOH (2 mL) and
30% H2O2 (1 mL) were added at 0 °C, and the resulting
mixture was vigorously stirred for 0.5 h at room temperature.
The mixture was diluted with EtAOc, then washed with
saturated Na2SO3 and brine. Concentration and chromatog-
raphy gave 12a (60 mg, 61%) and 13a (25 mg, 26%).
12a : colorless needle; mp 173 °C (EtOAc); Rf ) 0.35 (EtOAc);
1
[R]20 -28.8° (c 1.00, MeOH); IR (KBr) 3600-3200 cm-1; H
D
NMR (300 MHz, CDCl3) δ 7.51-7.35 (m, 5 H), 5.52 (s, 1 H),
4.31 (dd, J ) 10.5, 4.8 Hz, 1 H), 3.71-3.64 (m, 3 H), 3.59-
3.49 (m, 2 H), 3.41-3.33 (m, 1 H), 3.24 (ddd, J ) 8.8, 8.8, 2.6
Hz, 1 H), 2.48 (ddd, J ) 11.4, 4.4, 4.4 Hz, 1 H), 2.05-1.98 (m,
2 H), 1.79-1.53 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 137.3,
129.1, 128.3, 126.2, 101.7, 82.4, 76.6, 73.1, 69.5, 69.2, 62.8, 38.3,
28.4, 28.2. Anal. Calcd for C16H22O5: C, 65.29; H, 7.53.
Found: C, 65.09; H, 7.71.
13a : colorless needle; mp 157-158 °C (EtOAc); Rf ) 0.21
(EtOAc); [R]21 +20.6° (c 1.00, MeOH); IR (KBr) 3500-3000
D
a
cm-1; H NMR (300 MHz, CDCl3) δ 7.50-7.35 (m, 5 H), 5.59
1
Reagents and conditions: (a) (i) PhNTf2, KHMDS, DMPU,
THF, -78 °C; (ii) 28, Pd(PPh3)4, benzene, rt, 78% (2 steps); (b) (i)
thexylborane, THF, 0 °C to rt, then H2O2, 3 N NaOH, 0 °C; (ii)
LiOH, THF-H2O, 40 °C; (iii) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, 0 °C to rt, the DMAP, benzene, rt, 71% (3 steps); (c) same
as a, 71%; (d) same as b, 48%.
(s, 1 H), 4.22 (dd, J ) 10.1, 4.6 Hz, 1 H), 4.07-3.98 (m, 2 H),
3.87 (dd, J ) 10.5, 4.6 Hz, 1 H), 3.80-3.60 (m, 4 H), 2.19 (ddd,
J ) 13.2, 3.8, 3.8 Hz, 1 H), 2.02-1.93 (m, 3 H), 1.77-1.54 (m,
4 H); 13C NMR (75 MHz, CDCl3) δ 129.1, 128.3, 126.1, 102.1,
79.2, 74.5, 69.9, 69.6, 66.1, 62.3, 46.8, 32.2, 28.8, 25.3. Anal.
Calcd for C16H22O5: C, 65.29; H, 7.53. Found: C, 65.10; H, 7.71.
TEMP O Oxid a tion of 12a . To a solution of 12a (30 mg,
0.1 mmol) in 3 mL of CH2Cl2 at 0 °C were added aqueous KBr
(1.0 M, 10 µL) and a catalytic amount of TEMPO. While
vigorously stirring, a freshly prepared NaClO solution (ca. 0.3
M, 1:1 mixture of comercial bleach solution and saturated
NaHCO3, 1.2 mL, 0.37 mmol) was added dropwise. After 1 h,
the mixture was quenched with Na2SO3 and extracted with
EtOAc. The organic layer was washed with brine and concen-
trated. The residue was purified by chromatography (hexane/
EtOAc, 1:1) to give 14a (26 mg, 89%): colorless needle; mp
Con clu sion
We have developed a novel method for the concise
synthesis of trans-fused cyclic ethers via the palladium-
catalyzed coupling of ketene acetal triflates and orga-
nozinc reagents. We are now in a position to synthesize
the DE and GH ring segments of gambierol efficiently
with a shorter number of steps (11 and 10 steps from
2-deoxy-D-ribose, respectively) in comparison with the
previous methods.4c,l Furthermore, the present methodol-
ogy was successfully applied to the iterative synthesis of
polycyclic ethers.
317 °C (hexane/CH2Cl2); Rf ) 0.38 (hexane/EtOAc, 1:1); [R]21
D
+63.1° (c 0.75, CHCl3); IR (KBr) 1742 cm-1
;
1H NMR (300
MHz, CDCl3) δ 7.49-7.36 (m, 5 H), 5.55 (s, 1 H), 4.33 (dd, J )
10.5, 4.8 Hz, 1 H), 4.16-4.08 (m, 1 H), 3.75-3.46 (m, 4 H),
2.83 (ddd, J ) 18.1, 9.1, 4.7 Hz, 1 H), 2.72-2.60 (m, 2 H), 2.27-
2.16 (m, 1 H), 1.96-1.81 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 169.8, 136.9, 129.2, 128.4, 126.1, 101.9, 76.1, 75.8, 74.9, 73.6,
68.9, 34.8, 27.8, 24.3. Anal. Calcd for C16H18O5: C, 66.19; H,
6.25. Found: C, 65.89; H, 6.12.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving air- and/or
moisture-sensitive materials were carried out under argon
with dry solvents. On workup, extracts were dried over MgSO4.
Reactions were monitored by thin-layer chromatography car-
ried out on 0.25 mm silica gel plates (60F-254). Column
chromatography was performed with silicagel (60N, spherical,
neutral, particle size 0.100-0.210 mm). Yields refer to chro-
matographically and spectroscopically homogeneous materials.
Syn th esis of 8. To a solution of 2,3-dimethyl-2-butene (29
µL, 0.24 mmol) in THF (1 mL) at 0 °C was added BH3‚SMe2
(23 µL, 0.24 mmol). The mixture was stirred at 0 °C for 1 h.
To the resulting thexylborane solution at 0 °C was added a
solution of 11e (65 mg, 0.20 mmol) in THF (1 mL), and the
mixture was stirred at room temperature. After 2 h, 1 N NaOH
(0.4 mL) and 30% H2O2 (0.2 mL) were added at 0 °C, and the
mixture was vigorously stirred at room temperature for 0.5
h. The mixture was quenched with saturated Na2SO3 at 0 °C
and extracted with EtOAc. The organic layer was washed with
brine, concentrated, and dissolved in ether (2 mL). To the
mixture at 0 °C was added LiAlH4 (16 mg, 0.41 mmol). After
1 h, the reaction was quenched with brine, and the resulting
white precipitate was removed by filteration through a Celite
pad. The filtrate was concentrated to give the cr ude diol 18,
which was subjected directly to TEMPO oxidation to give 8
(42 mg, 68%): colorless prism; mp 189 °C (hexane/CH2Cl2); Rf
Typ ica l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cou -
p lin g of Keten e Aceta l Tr ifla tes 9 a n d Zin c Hom oen ola te
10. Syn th esis of 11a . To a suspension of Zn-Cu couple (367
mg, 5.5 mmol) in benzene (4 mL) and DMA (0.5 mL) was added
methyl 3-iodopropionate (330 µL, 2.8 mmol). The mixture was
refluxed for 2 h and then cooled to room temperature. A
solution of 9a (510 mg, 1.4 mmol) in benzene (5 mL) and a
solution of Pd(PPh3)4 (80 mg, 0.07 mmol) in benzene (5 mL)
were added to the resulting mixture, successively. After
stirring for 3 h, the mixture was quenched with Et3N, filtered
through a silica gel pad, and concentrated. The residue was
purified by silica gel chromatography (hexane/EtOAc, 4:1
containing 0.5% Et3N) to give 11a (313 mg, 73%): colorless
needle; mp 122 °C (hexane/CH2Cl2); Rf ) 0.31 (hexane/EtOAc,
) 0.18 (hexane/EtOAc, 1:1); [R]23 +62.2° (c 1.00, CHCl3); IR
D
(KBr) 1740 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.46-7.33 (m,
5 H), 5.42 (s, 1 H), 4.32-4.23 (m, 1 H), 4.16-4.09 (m, 1 H),
3.70-3.55 (m, 4 H), 2.70 (ddd, J ) 16.3, 8.2, 8.2 Hz, 1 H), 2.55
(ddd, J ) 17.2, 7.0, 7.0 Hz, 1 H), 2.21-1.97 (m, 5 H), 1.94-
1.81 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 171.3, 137.3, 129.0,
128.3, 126.0, 101.1, 81.0, 80.8, 77.4, 75.2, 69.3, 28.5, 28.2, 27.6,
26.0. Anal. Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C,
66.90; H, 6.60.
4:1); [R]23 +58.2° (c 1.00, CHCl3); IR (KBr) 1726, 1674 cm-1
;
D
1H NMR (300 MHz, CDCl3) δ 7.52-7.36 (m, 5H), 5.61 (s, 1 H),
4.56 (dd, J ) 5.0, 2.3 Hz, 1 H), 4.39 (dd, J ) 8.4, 2.9 Hz, 1 H),
3.88-3.82 (m, 1 H), 3.79-3.75 (m, 2 H), 3.69 (s, 3 H), 2.51-
2.46 (m, 2 H), 2.38-2.24 (m, 4 H); 13C NMR (75 MHz, CDCl3)
δ 173.2, 152.2, 137.4, 129.0, 128.2, 126.1, 101.5, 94.0, 74.9, 69.8,
68.9, 51.5, 31.7, 28.8, 26.6. Anal. Calcd for C17H20O5: C, 67.09;
H, 6.62. Found: C, 66.84; H, 6.59.
Syn th esis of 30. Hydroboration of 29 (53 mg, 0.15 mmol)
with thexylborane followed by the usual oxidative workup gave