The Journal of Organic Chemistry
Article
flash column chromatography (pentane/EtOAc 2:1) to give the
ketone 22 (242.0 mg, 0.72 mmol, 84%) as colorless oil. Rf = 0.18
1.89−1.78 (m, 1H), 1.71−1.60 (m, 1H), 1.37 (s, 3H), 0.97 (d, J = 6.8
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ = 207.7, 177.4, 171.0, 74.6,
63.1, 52.9, 51.0, 46.4, 39.5, 35.6, 27.6, 24.5, 19.7, 15.1, 4.4; HRMS
(ESI) m/z calcd for C15H22IO5 [M + H]+: 409.0506, found 409.0508;
(pentane/EtOAc 2:1); [α]2D5 = −68.5 (c 0.49, MeOH); FTIR (neat) ν
̃
= 2955, 2887, 1776, 1733, 1709, 1457, 1364, 1297, 1230, 1148, 1020,
963, 823, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ = 4.85 (t, J = 4.8
Hz, 1H), 4.47 (d, J = 9.3 Hz, 1H), 3.95−3.84 (m, 3H), 3.83−3.75 (m,
2H), 3.64 (s, 3H), 2.61 (dd, J = 10.3, 6.1 Hz, 1H), 2.43−2.32 (m, 1H),
2.26−2.11 (m, 2H), 2.03−1.86 (m, 2H), 1.59−1.53 (m, 2H), 1.33 (s,
3H), 1.03 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ =
207.7, 177.5, 171.1, 103.5, 74.6, 65.0, 64.7, 63.3, 52.6, 50.9, 46.3, 36.1,
34.8, 27.7, 24.3, 19.5, 16.8; HRMS (ESI) m/z calcd for C17H25O7 [M
+ H]+: 341.1595, found 341.1591.
Samarium(II) Iodide. Following a literature procedure,47
samarium (151 mg, 1.0 mmol, 1.0 equiv) was activated by hot stirring
with a heat gun in vacuo. After cooling, 1,2-diiodoethane (prewashed
by extraction with saturated aqueous Na2S2O3 solution, 141 mg, 0.5
mmol, 1.0 equiv) was added under argon atmosphere. THF (dried
over sodium, 2 mL) was added and the mixture was stirred for 5 min
at room temperature. After that time, more THF (3 mL) was added
and the solution was stirred until it turned dark blue and SmI2 was
obtained as a 0.1 M solution in THF and was used as such.
Methyl (3aS,5R,7aR)-3a-methyl-1,4-dioxo-5-((R)-4-oxobutan-2-
yl)octahydroisobenzofuran-5-carboxylate (23). The ketone 22
(227.0 mg, 0.67 mmol, 1.0 equiv) was dissolved in acetone (10 mL)
and 1 M aq. HCl solution (5 mL) was added. The resulting mixture
was stirred at rt for 17 h. The reaction was quenched by addition of a
saturated aq. NaHCO3 solution and extracted three times with EtOAc.
The combined organic layers were dried over Na2SO4, filtered and
evaporated under reduced pressure to yield pure aldehyde 23 (195.8
mg, 0.66 mmol, 99%) as colorless oil; Rf = 0.56 (pentane/EtOAc 1:1);
Methyl (3aR,5aR,6R,8aR,8bS)-8a-hydroxy-6,8b-dimethyl-3-oxo-
decahydro-5aH-indeno[4,5-c]furan-5a-carboxylate (26). Iodide 25
(118.0 mg, 0.289 mmol, 1.0 equiv) was dissolved in hexamethylphos-
phoramide (500 μL, 2.89 mmol, 10.0 equiv) under nitrogen
atmosphere and cooled down to 0 °C. A freshly prepared SmI2
solution (0.1 M in THF, 7.22 mL, 0.722 mmol, 2.5 equiv) was added
and the resulting mixture was slowly heated up to rt and stirred for 1 h.
The reaction was quenched by addition of a saturated aqueous
Rochelle’s salt solution and stirred at that temperature for 20 min.
Extraction was performed three times with EtOAc. The combined
organic layers were dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue was purified by flash chromatography
on silica (pentane/EtOAc 4:1, CAM dip) giving the tricyclic product
26 (61.5 mg, 0.218 mmol, 76%) as a white solid; mp 97.8−98.6 °C; Rf
= 0.41 (pentane/EtOAc 4:1); [α]2D5 = −17.6 (c 0.29, MeOH); FTIR
[α]2D5 = −87.8 (c 0.42, CHCl3); FTIR (neat) ν
̃
= 2956, 2360, 2339,
1
1776, 1717, 1457, 1385, 1295, 1234, 1155, 1022, 991, 787 cm−1; H
NMR (400 MHz, CDCl3) δ = 9.72 (d, J = 1.7 Hz, 1H), 4.60 (d, J = 9.4
Hz, 1H), 3.90 (d, J = 9.4 Hz, 1H), 3.68 (s, 3H), 2.94 (dqd, J = 9.8, 6.8,
3.0 Hz, 1H), 2.69 (t, J = 7.4 Hz, 1H), 2.67−2.60 (m, 1H), 2.52−2.43
(m, 1H), 2.31−2.19 (m, 2H), 2.08−1.94 (m, 2H), 1.36 (s, 3H), 1.00
(d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ = 208.1, 200.7,
177.3, 170.8, 74.7, 62.3, 52.8, 51.2, 46.8, 46.2, 31.3, 27.2, 24.5, 18.9,
16.6; HRMS (ESI) m/z calcd for C15H21O6 [M + H]+: 297.1333
found 297.1328.
̃
(neat) ν = 3495, 2959, 2900, 2877, 1770, 1708, 1454, 1435, 1384,
1354, 1325, 1291, 1270, 1239, 1181, 1148, 1102, 1076, 1058, 1040,
1009, 988, 966, 920, 896, 845, 768, 739, 714, 681 cm−1; 1H NMR (400
MHz, CDCl3) δ = 5.17 (d, J = 2.1 Hz, 1H), 4.44 (d, J = 9.5 Hz, 1H),
3.97 (d, J = 9.5 Hz, 1H), 3.79 (s, 3H), 2.40−2.32 (m, 1H), 2.24−2.16
(m, 1H), 2.14−2.00 (m, 2H), 1.96−1.86 (m, 2H), 1.82−1.71 (m, 1H),
1.66−1.58 (m, 1H), 1.43 (td, J = 13.9, 2.6 Hz, 1H), 1.35−1.29 (m,
1H), 1.23 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ = 178.8, 178.5, 85.4, 74.6, 58.0, 52.6, 48.1, 46.8, 45.1, 36.9,
33.8, 29.4, 23.1, 22.4, 21.2; HRMS (ESI) m/z calcd for C15H22NaO5
[M + Na]+: 305.1359, found 305.1359.
Methyl (3aS,5R,7aR)-5-((R)-4-hydroxybutan-2-yl)-3a-methyl-1,4-
dioxooctahydroisobenzofuran-5-carboxylate (24). Aldehyde 23
(78.1 mg, 0.26 mmol, 1.0 equiv) was dissolved in hexafluoroisopro-
panol (1 mL). Sodium tris(hexafluoroisoproopoxy)borohydride (1 M
in THF, 791 μL, 0.79 mmol, 3.0 equiv) was added at rt under nitrogen
atmosphere and stirred for 15 h. The reaction was quenched by
addition of saturated NH4Cl solution and extracted three times with
EtOAc. The combined organic layers were dried over Na2SO4, filtered
and evaporated under reduced pressure. The residue was purified by
flash chromatography (pentane/EtOAc 2:3) giving alcohol 24 (66.9
mg, 0.224 mmol, 85%) as colorless oil; Rf = 0.26 (EtOAc/pentane
(3aR,5aR,6R,8aR,8bS)-8a-Hydroxy-6,8b-dimethyl-3-oxodecahy-
dro-5aH-indeno[4,5-c]furan-5a-carbaldehyde (27).11d In a dry
round bottomed flask under argon atmosphere, ester 26 (19.7 mg,
0.070 mmol, 1.0 equiv) was dissolved in dry THF (2 mL) and cooled
to 0 °C. Borane-methyl sulfide complex (2 M in THF, 70 μL, 0.140
mmol, 2.0 equiv) was added, the resulting mixture was stirred for 15
min at 0 °C and subsequently at 45 °C for 5.5 h. The mixture was
allowed to cool down to rt for 10 min before ethanol was added until
bubbling (exothermic) ceased. The solution was evaporated giving a
colorless oil. Purification was performed by flash chromatography
(pentane/EtOAc 3:2) giving aldehyde 27 (11.6 mg, 0.0460 mmol,
66%) as a white solid; mp 51.4−51.9 °C; Rf = 0.32 (pentane/EtOAc
3:2); [α]2D5 = −79.9 (c 0.18, MeOH); FTIR (neat) ν
̃
= 3529, 3407,
2955, 2884, 1775, 1731, 1708, 1456, 1385, 1364, 1293, 1231, 1187,
1154, 1055, 1021, 989, 916, 848, 732, 681 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 4.48 (d, J = 9.3 Hz, 1H), 3.94 (d, J = 9.3 Hz, 1H), 3.74
(ddd, J = 11.0, 8.8, 5.5 Hz, 1H), 3.69 (s, 3H), 3.67−3.58 (m, 1H), 2.64
(t, J = 8.4 Hz, 1H), 2.45−2.34 (m, 1H), 2.28 (dt, J = 9.3, 4.4 Hz, 1H),
2.25−2.17 (m, 1H), 2.07−1.92 (m, 2H), 1.69−1.52 (m, 2H), 1.39−
1.33 (m, 1H), 1.37 (d, J = 2.9 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ = 208.1, 177.5, 171.3, 74.6, 63.2, 61.0,
52.8, 51.0, 46.5, 35.3, 34.8, 27.4, 24.4, 19.8, 16.1; HRMS (ESI) m/z
calcd for C15H22NaO6 [M + Na]+: 321.1309, found 321.1308.
3:2, CAM dip); [α]2D5 = −13.7 (c 0.19, MeOH); FTIR (neat) ν
̃
= 3484,
Methyl (3aS,5R,7aR)-5-((R)-4-iodobutan-2-yl)-3a-methyl-1,4-di-
oxooctahydroisobenzofuran-5-carboxylate (25). Alcohol 24 (26.0
mg, 0.087 mmol, 1.0 equiv) was dissolved in dry benzene (5 mL)
under nitrogen atmosphere. Triphenylphosphine (45.7 mg, 0.174
mmol, 2.0 equiv), imidazole (23.7 mg, 0.349 mmol, 4.0 equiv), and
iodine (44.2 mg, 0.174 mmol, 2.0 equiv) were added at rt and the
resulting mixture was stirred overnight. The crude mixture was filtered,
washed with benzene and evaporated under reduced pressure. The
resulting oil was purified by flash chromatography (pentane/EtOAc
2:1) to give iodide 25 (33.8 mg, 0.083 mmol, 95%) as a white solid; Rf
= 0.44 (pentane/EtOAc 2:1); [α]2D5 = −9.8 (c 0.58, CHCl3); FTIR
2957, 2876, 1748, 1704, 1460, 1373, 1287, 1227, 1158, 1140, 1003,
1
973, 855, 793, 732, 690, 551 cm−1; H NMR (400 MHz, CDCl3) δ =
9.84 (s, 1H), 4.23 (d, J = 0.8 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.51
(s, 1H), 2.29−2.18 (m, 2H), 2.12 (dddd, J = 14.4, 10.4, 9.1, 2.2 Hz,
2H), 1.98−1.84 (m, 2H), 1.82−1.72 (m, 1H), 1.72−1.60 (m, 1H),
1.51−1.41 (m, 1H), 1.41−1.32 (m, 1H), 1.22 (d, J = 0.8 Hz, 3H), 1.08
(d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ = 210.1, 178.9,
86.4, 75.0, 59.8, 47.5, 46.4, 44.6, 37.8, 31.5, 30.5, 22.5, 22.3, 19.8;
HRMS (ESI) m/z calcd for C14H20O4Na [M + Na]+: 275.1254, found
275.1253.
(3aR,5aS,6R,8aR,8bS,11S)-11-Hydroxy-6,8b-dimethylhexahydro-
6H-8a,5a-(epoxyethano)indeno[4,5-c]furan-3,10(1H)-dione (28). In
a dry round bottomed flask under argon atmosphere, ester 26 (31.8
mg, 0.113 mmol, 1.0 equiv) was dissolved in dry THF (3 mL) and
cooled to 0 °C. Borane-methyl sulfide complex (2 M in THF, 113 μL,
0.225 mmol, 2.0 equiv) was added, the resulting mixture was stirred
for 15 min at 0 °C and subsequently at 45 °C for 7 h. The mixture was
̃
(neat) ν = 3245, 2971, 2927, 2860, 2171, 1762, 1728, 1700, 1591,
1532, 1489, 1439, 1385, 1368, 1287, 1230, 1207, 1173, 1119, 1069,
1012, 977, 961, 922, 905, 852, 773, 764, 722, 692 cm−1; 1H NMR (400
MHz, CDCl3) δ = 4.48 (d, J = 9.3 Hz, 1H), 3.93 (d, J = 9.3 Hz, 1H),
3.71 (s, 3H), 3.33 (ddd, J = 9.8, 7.7, 4.3 Hz, 1H), 3.07 (td, J = 9.5, 7.1
Hz, 1H), 2.68−2.60 (m, 1H), 2.37−2.14 (m, 3H), 2.05−1.91 (m, 2H),
K
J. Org. Chem. XXXX, XXX, XXX−XXX