Timmer et al.
dry THF (2 mL) was added dropwise. After being stirred for 1
h, the reaction mixture was allowed to warm to rt. Saturated
aq NH4Cl was added and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried (Mg-
SO4), filtered, and evaporated. Column chromatography of the
crude product (toluene f 1% acetic acid in toluene) yielded
h, water (0.5 mL) was added and shaking was continued for
0.5 h. The resin was filtered and washed (dioxane, H2O,
dioxane DCM, Et2O). After repeating the procedure the resins
were dried in vacuo.
Cou p lin g of Ca r bon yl Ch lor id es. The resins (0.11 g, 0.05
mmol) were swollen in DMF (1 mL) and either diphenylcar-
bamoyl (58 mg, 0.25 mmol, 5 equiv), benzyloxycarbonyl (36
µL, 0.25 mmol, 5 equiv), or benzoyl (29 µL, 0.25 mmol, 5 equiv)
chloride was added. After DiPEA (33 µL, 0.20 mmol, 4 equiv)
was added, the mixtures were shaken overnight, filtered,
washed (DMF, MeOH, DCM, MeOH, DCM, Et2O), and dried
in vacuo to yield resins 13.
pure 8 (0.36 g, 0.57 mmol, 84%). [R]20 +2.4 (c 0.1, MeCN); IR
D
(thin film) 2928, 2855, 2098, 1709, 1489, 1452, 1427, 1277,
1107 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.72-7.35 (m, 10H),
5.51 (m, 3H), 5.05 (m, 3H), 4.02 (m, 2H), 3.49 (m, 3H), 3.14
(dd, 1H, J ) 6.9, 12.4 Hz), 3.14 (dd, 1H, J ) 5.9, 12.4 Hz),
2.35 (t, 2H, J ) 7.3 Hz), 2.13 (m, 2H), 1.64 (m, 2H), 1.30 (m,
12H), 1.09 (s, 9H); 13C NMR (50.1 MHz, CDCl3) δ 179.5, 135.5,
134.3, 134.0, 132.9, 132.6, 129.9, 127.7, 124.6, 116.9, 85.8, 84.9,
78.2, 76.7, 70.0, 52.1, 33.8, 29.7, 29.1, 28.9, 28.8, 27.7, 26.6,
18.7; ESI-MS (m/e) 656.3 [M + Na]+; HRMS m/z calcd for
Rin g-Closin g Meta th esis Cycliza tion /Clea va ge. Resins
13 (0.11 g, 0.05 mmol) were coevaporated with dichloroethane
and dispersed in DCM (1 mL) under an argon atmosphere.
Grubbs catalyst B (2 mg, 2.5 µmol, 5 mol %) was added and
the mixtures were refluxed for 16 h. The resins were filtered
off and washed with DCM. After concentration of the mother
liquor, the residues were taken up in 15% ethyl acetate in
toluene and purified by filtration over a silica plug. Washing
with the same solution yielded homogeneous pyranofurans 14.
P yr a n ofu r a n 14-1A (24 mg, 48 µmol, 96%): IR (thin film)
C
36H51N3O5SiNa 656.3495, obsd 656.3514.
(4a S,6R,7R,7a S)-6-Azid om et h yl-7-ter t-b u t yld ip h en yl-
sila n yloxy-1,5-d ioxa bicyclo[4.3.0]n on -3-en e (9). Anhydro-
glucitol 8 (0.20 g, 0.32 mmol) was coevaporated with toluene
and dissolved in DCM (2 mL) under argon. After addition of
second generation Grubbs catalyst B (3 mg, 3.2 µmol, 0.01
equiv), the mixture was refluxed for 1 h. The solvent was
evaporated and the product purified by flash column chroma-
tography to yield homogeneous 9 (0.137 g, 0.316 mmol, 99%).
IR (thin film) 2932, 2855, 2098, 1470, 1427, 1265, 1184, 1111
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.72-7.35 (m, 10H), 6.07-
5.92 (m, 2H), 4.27 (m, 1H), 4.10-4.03 (m, 2H), 3.98-3.81 (m,
3H), 2.99 (dd, 1H, J ) 7.4, 12.7 Hz), 2.86 (dd, 1H, J ) 4.14,
12.7 Hz), 1.09 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 135.7,
133.1, 133.0, 131.1, 130.1, 130.0, 127.8, 122.1, 116.9, 85.6, 82.0,
80.2, 71.9, 64.2, 52.2, 26.9, 19.1; ESI-MS (m/e) 458.2 [M + Na]+,
893.4 [2M + Na]+; HRMS m/z calcd for C24H29N3O3SiNa
458.1876, obsd 458.1998.
3325, 2930, 2871, 1717, 1663, 1508, 1491, 1258, 1110 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.34-7.14 (m, 15H), 5.99-5.90
(m, 2H), 5.25-5.22 (m, 1H), 5.07-5.03 (m, 1H), 4.87 (d, 1H, J
) 3.7 Hz), 4.87 (d, 2H, J ) 5.8 Hz), 4.33-4.11 (m, 1H), 4.10-
4.08 (m, 1H), 4.33-3.84 (m, 3H), 3.65-3.54 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) δ 156.3, 155.2, 143.0, 137.6, 131.8, 129.2,
128.7, 128.1, 127.6, 127.5, 125.8, 121.2, 82.1, 80.8, 79.8, 71.5,
64.3, 45.2, 42.9; ESI-MS (m/e) 500.4 [M + H]+ 522.5 [M + Na]+,
999.4 [2M + H]+; HRMS m/z calcd for C29H29N3O5H 500.2185,
obsd 500.2233.
P yr a n ofu r a n 14-2A (18 mg, 41 µmol, 82%): IR (thin film)
3325, 2928, 2871, 1717, 1701, 1522, 1508, 1456, 1244, 1142,
1088 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 10H),
6.08-6.01 (m, 2H), 5.40 (m, 1H), 5.10 (s, 2H), 5.04 (m, 1H),
4.91 (d, 1H, J ) 3.3 Hz), 4.42-4.31 (m, 2H), 4.24-3.86 (m,
5H), 3.62-3.44 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ 155.6,
154.6, 140.1, 131.7, 128.8, 128.4, 128.0, 127.9, 127.7, 121.4,
82.4, 81.0, 79.7, 71.7, 66.6, 64.5, 45.2, 43.2; ESI-MS (m/e) 439.4
[M + H]+, 461.3 [M + Na]+, 899.5 [2M + Na]+; HRMS m/z
calcd for C24H26N2O6Na 461.1688, obsd 461.1723.
P yr a n ofu r a n 14-3A (18 mg, 37 µmol, 74%): IR (thin film)
3320, 2924, 2873, 1726, 1653, 1539, 1489, 1456, 1286, 1238,
1167, 1074 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.76-7.73 (m,
2H), 7.40-7.23 (m, 8H), 6.72-6.70 (m, 1H), 6.08-6.04 (m, 1H),
5.99-5.97 (m, 1H), 5.00 (AB, 2H), 4.96 (d, 1H, J ) 3.1 Hz),
4.79 (br s, 1H), 4.53 (m, 2H), 4.16-4.04 (m, 3H), 3.81-3.75
(m, 3H), 3.66-3.61 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ
156.1, 155.6, 137.2, 137.1, 131.8, 129.1, 128.7, 128.4, 128.0,
127.9, 121.3, 118.7, 82.3, 81.1, 79.7, 71.8, 64.5, 54.3, 43.2; ESI-
MS (m/e) 409.1 [M + H]+, 431.2 [M + Na]+; HRMS m/z calcd
for C23H24N2O5Na 431.1582, obsd 431.1625.
P yr a n ofu r a n 14-1B (26 mg, 50 µmol, 99%): IR (thin film)
3265, 2930, 2835, 1724, 1653, 1599, 1510, 1489, 1416, 1298,
1265, 1217, 1178, 1090, 1030 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.33-7.24 (m, 11H), 7.20-7.16 (m, 2H), 6.90 (br s, 1H), 6.84-
6.80 (m, 2H), 6.01-5.91 (m, 2H), 5.22 (br t, 1H, J ) 5.2 Hz),
4.91 (d, 1H, J ) 3.8 Hz), 4.14 (dd, 1H, J ) 4.8, 8.8 Hz), 4.08-
4.07 (br s, 1H), 4.02-3.89 (m, 3H), 3.78 (s, 3H), 3.78 (app t,
2H, J ) 5.1 Hz); 13C NMR (100.6 MHz, CDCl3) δ 156.4, 152.6,
142.9, 131.8, 130.6, 128.8, 127.5, 125.9, 121.2, 114.2, 81.9, 80.8,
79.8, 71.6, 64.4, 55.5, 42.8; ESI-MS (m/e) 516.2 [M + H]+, 538.2
[M + Na]+; HRMS m/z calcd for C29H29N3O6Na 538.1954, obsd
538.1964.
P yr a n ofu r a n 14-2B (20 mg, 45 µmol, 89%): IR (thin film)
3312, 2927, 2848, 1717, 1705, 1541, 1514, 1456, 1221, 1180,
1092, 1032 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m,
7H), 6.87-6.84 (m, 2H), 6.54 (br s, 1H), 6.10-5.99 (m, 2H),
5.37-5.35 (m, 1H), 5.07 (s, 2H), 4.26-4.02 (m, 5H), 3.79 (s,
3H), 3.64-3.47 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ 154.7,
153.6, 140.1, 132.2, 131.7, 128.9, 128.4, 128.3, 121.8, 114.7,
E/Z-11-[(2S,3R,4S,5R)-3-Allyloxy-5-a zid om et h yl-4-h y-
d r oxytetr a h yd r ofu r a n -2-yl]u n d ec-10-en oic Acid (10). An-
hydroglucitol 8 (2.0 g, 3.2 mmol) was dissolved in THF (15
mL) and cooled to 0 °C. After dropwise addition of tetra-n-
butylammonium fluoride (1.5 equiv, 4.47 mmol, 3.0 mL 1.6 M
in THF) the resulting mixture was allowed to warm to room
temperature and stirring was continued for 1 h. Evaporation
of the solvent gave the crude product, which was purified by
column chromatography (toluene f 2% acetic acid in toluene)
to give 10 (1.13 g, 2.86 mmol, 89%) as a mixture of E/Z isomers.
IR (thin film) 3230, 2962, 2932, 2874, 2091, 1717, 1462, 1381,
1
1381, 1242, 1053 cm-1; H NMR (200 MHz, CDCl3) δ 5.95-
5.53 (m, 3H), 5.33-5.15 (m, 2H), 4.86 (dd, 0.7H, J ) 4.4, 7.7
Hz), 4.48 (dd, 0.3H, J ) 4.4, 8.0 Hz), 4.17-4.11 (m, 1H), 4.05-
4.01 (m, 1H), 3.93-3.83 (m, 1H), 3.82-3.75 (m, 1H), 3.47-
3.43 (m, 2H), 2.38-2.29 (m, 2H), 2.14-2.01 (m, 2H), 1.66-
1.56 (m, 2H), 1.41-1.21 (m, 12H); 13C NMR (50.1 MHz, CDCl3),
major isomer, δ 179.3, 135.2, 134.1, 124.2, 117.0, 85.8, 83.0,
77.6, 76.4, 71.0, 52.3, 33.9, 29.4, 29.1, 29.0, 28.9, 27.8, 24.6;
HRMS m/z calcd for C20H33N3O5Na 418.2312, obsd 418.2322.
Con d en sa tion of 10 w ith Rin k Am id e Resin . After
swelling of Rink amide resin (0.55 mmol/g, 0.80 g, 0.45 mmol)
in DMF, a preactivated (1-2 min) mixture of acid 10 (0.36 g,
0.91 mmol, 2 equiv), BOP (0.60 g, 1.35 mmol, 3 equiv), and
DiPEA (0.31 mL, 1.8 mmol, 4 equiv) in DMF (2 mL) was added.
The mixture was shaken overnight, filtered, washed (DMF 2×,
MeOH, DCM, MeOH, DCM, Et2O), and dried to yield resin
11.
Isocya n a te Rea ction s. To resin 11 (0.33 g, 0.15 mmol) in
DCM (2 mL) were added DiPEA (100 µL, 0.6 mmol, 4 equiv)
and either benzyl (92.6 µL, 0.75 mmol, 5 equiv), methoxyphe-
nyl (97.2 µL, 0.75 mmol, 5 equiv), or phenyl (81.7 µL, 0.75
mmol, 5 equiv) isocyanate. The resins were shaken overnight,
filtered, washed (DCM, MeOH, DCM, MeOH, DCM, Et2O), and
dried in vacuo to gain resins 12.
Sta u d in ger Red u ction . To resins 12 (0.33 g, 0.15 mmol)
in dioxane (2 mL) was added trimethylphosphine (0.75 mmol,
0.75 mL 1 M in toluene). After the mixture was shaken for 1
9410 J . Org. Chem., Vol. 68, No. 24, 2003