682 Journal of Natural Products, 2009, Vol. 72, No. 4
Baird et al.
(11Z)-1′,2′-Dihydroxystemofoline (6). To a flask containing AD-
mix-R (0.182 g) and methanesulfonamide (24.7 mg, 0.260 mmol) in
1:1 tert-butanol/water (1 mL) at 0 °C was added a solution of (11Z)-
1′,2′-didehydrostemofoline (4) (50.0 mg, 0.130 mmol) in 1:1 ratio of
tert-butanol/water (1 mL). The reaction mixture was allowed to warm
to rt and left to stir for 3 days. Sodium sulfite (0.2 g) was then added
to the reaction and left at rt for 1 h. The mixture was extracted with
chloroform (3 × 20 mL), and the combined organic extracts were
washed with 2 M KOH, dried over MgSO4, and evaporated in Vacuo.
Product 6 was obtained as a white solid (41.0 mg, 0.0979 mmol, 75%
yield) of sufficient purity (>95%) to continue to the next step. A small
amount was purified by column chromatography for characterization.
Diol 6 can also be recrystallized from CH2Cl2 to yield pure compound.
Rf ) 0.28 in MeOH/EtOAc (1:4); mp 188-190 °C (color changed to
brown); [R]2D2 +252.9 (c 0.89, CHCl3); IR νmax 3201, 2340, 1735, 1613,
14), 83.2 (C-3), 80.0 (C-2), 61.0 (C-9a), 58.9 (O-CH3), 52.4 (C-7),
48.2 (C-5), 47.6 (C-9), 34.5 (C-10), 32.7 (C-1), 27.7 (C-4′), 26.8 (C-
6), 18.3 (C-17), 9.2 (C-16); EIMS m/z 399 (23%) [M]+; HREIMS m/z
399.1687 [M]+, calcd for C22H25NO6 399.1682.
(3′R)-Stemofolenol (1). To a solution of (S)-(-)-2-methyl-CBS-
oxazaborolidine (4.46 mg, 0.0161 mmol) and 1 M borane-methyl sulfide
complex in CH2Cl2 (0.01 mL) at 0 °C was added ketone 8 (32.1 mg,
0.0805 mmol) in CH2Cl2 (1 mL). The mixture was allowed to stir at 0
°C for 1.5 h, after which time ethanolamine (1 mL) was added and the
mixture was allowed to stir at rt for 18 h. The reaction mixture was
quenched with methanol (2 mL), diluted with saturated sodium
bicarbonate solution (20 mL), and extracted with chloroform (3 × 20
mL). The combined organic extracts were washed with brine (40 mL),
dried over MgSO4, and evaporated in Vacuo. Purification by column
chromatography using EtOAc to MeOH/EtOAc (1:9) as eluent gave 1
as a white solid in 66% yield (21.4 mg, 0.0534 mmol, dr ) >95:<5).
Rf ) 0.15 in MeOH/EtOAc (1:4); mp 180 °C (color changed to brown),
194-198 °C; [R]2D2 +227.0 (c 0.72, CHCl3); IR νmax 3649, 2950, 1737,
1
1144, 1001 cm-1; H NMR (CDCl3) δ 4.24 (s, 1H, H-2), 4.14 (s, 3H,
OCH3), 3.74 (s, 1H, H-1′ꢀ), 3.56 (t, J ) J 6.5 Hz, 1H, H-2′ꢀ), 3.53 (bs,
1H, H-9a), 3.24 (m, 1H, H-5a), 3.09 (m, 1H, H-10), 3.02 (m, 1H, H-5b),
2.98 (d, J ) 6.0 Hz, 1H, H-7), 2.32 (m, 1H, H-6a), 2.08 (s, 3H, H-16),
2.02 (d, J ) 12.5 Hz, 1H, H-1a), 1.84 (m, 2H, H-6b, H-9), 1.78 (m,
1H, H-1b), 1.64 (sextet, J ) 7.0 Hz, 1H, H-3′a), 1.54 (quintet, J ) 7.0
Hz, 1H, 3′b), 1.38 (d, J ) 6.5 Hz, 3H, H-17), 0.97 (t, J ) 7.0 Hz, 3H,
H-4′); 13C NMR (CDCl3) δ 169.6 (C-15), 162.7 (C-13), 147.9 (C-11),
128.0 (C-12), 112.5 (C-8), 98.7 (C-14), 86.3 (C-3), 77.5 (C-2), 73.6
(C-2′), 73.0 (C-1′), 61.7 (C-9a), 58.8 (O-CH3), 50.6 (C-7), 50.5 (C-5),
47.6 (C-9), 34.4 (C-10), 32.8 (C-1), 28.5 (C-6), 26.1 (C-3′), 18.2 (C-
17), 10.0 (C-4′), 9.1 (C-16); EIMS m/z 419 (28%) [M]+; HREIMS m/z
419.1949 [M]+, calcd for C22H29NO7 419.1940.
(5Z)-5-[(2S,2aR,6S,7aS,7bS,8R,9S)-7b-(1E)-1-Formylhexahydro-
9-methyl-4H-2,2,6-(epoxy[1]propanyl[3]ylidene)furo[2,3,4-gh]pyr-
rolizin-10-ylidene]-4-methoxy-3-methyl-2(5H)-furanone (7). To a
vigorously stirred suspension of silica gel (1.83 g) and diethyl ether
(9.2 mL) was added a warm (ca. 40 °C) solution of NaIO4 (177 mg,
0.826 mmol) in water (1.5 mL). Diol 6 (266.0 mg, 0.635 mmol) was
dissolved in chloroform (1 mL) and added to the silica gel/NaIO4
mixture, which was left to stir at rt for 1 h. The mixture was filtered
and the silica gel was washed with chloroform. Impure product 7 was
obtained as a yellow oil and taken immediately through to the next
step to avoid decomposition due to the instability of the aldehyde. Rf
) 0.15 in MeOH/EtOAc (1:4); IR νmax 2919, 2848, 1726, 1619, 1071,
1020 cm-1; 1H NMR (CDCl3) δ 9.73 (s, 1H, CHO), 4.61 (s, 1H, H-2),
4.15 (s, 3H, O-CH3), 3.62 (s, 1H, H-9a), 3.26 (s, 1H, H-7), 3.15 (dd,
J ) 7.5 Hz, 6.5 Hz, 2H, 2 × H-5), 3.10 (m, 1H, H-10), 2.08 (s, 3H,
H-16), 2.05 (s, 1H, H-1a), 1.89 (m, 3H, 2 × H-6, H-9), 1.86 (m, 1H,
H-1b), 1.40 (d, J ) 6.0 Hz, 3H, H-17); 13C NMR (CDCl3) δ 197.6
(CHO), 169.6 (C-15), 162.6 (C-13), 147.5 (C-11), 128.1 (C-12), 112.6
(C-8), 98.9 (C-14), 89.4 (C-3), 76.5 (C-2), 61.2 (C-9a), 58.9 (O-CH3),
49.4 (C-7), 49.2 (C-5), 47.9 (C-9), 34.4 (C-10), 33.5 (C-1), 26.9 (C-
6), 18.2 (C-17), 9.1 (C-16); EIMS m/z 359 (27%) [M]+; HREIMS m/z
359.1363 [M]+, calcd for C19H21NO6 359.1369.
(5Z)-5-[(2S,2aR,6S,7aS,7bS,8R,9S)-7b-(1E)-1-(3′-Oxo-1′-butenyl-
)hexahydro-9-methyl-4H-2,2,6-(epoxy[1]propanyl[3]ylidene)furo[2,3,4-
gh]pyrrolizin-10-ylidene]-4-methoxy-3-methyl-2(5H)-furanone (8).
To a flask containing LiCl (29.6 mg, 0.699 mmol) in acetonitrile (7.1
mL) under a nitrogen atmosphere was added diethyl (2-oxopropy-
l)phosphonate (135.7 mg, 0.699 mmol, 0.13 mL), N,N-diisopropyl-
ethylamine (75.3 mg, 0.582 mmol, 0.10 mL), and aldehyde 7 (209.1
mg of crude from previous reaction, 0.582 mmol) dissolved in
acetonitrile (1 mL). The reaction mixture was allowed to stir at rt for
2 days. The mixture was diluted with water (20 mL) and extracted
with CHCl3 (3 × 20 mL), and the combined organic extracts were
washed with brine (20 mL), dried over MgSO4, and evaporated in
Vacuo. Purification by column chromatography using EtOAc to MeOH/
EtOAc (15:85) as eluent gave ketone 8 as a semisolid in 60% yield
from 6 (151.9 mg, 0.381 mmol). Rf ) 0.33 in MeOH/EtOAc (1:4);
[R]2D1 +327.4 (c 0.39, CHCl3); IR νmax 2955, 1742, 1675, 1619, 968
cm-1; 1H NMR (300 MHz, CDCl3) δ 6.81 (d, J ) 15.8 Hz, 1H, H-2′),
6.38 (d, J ) 15.8 Hz, 1H, H-1′), 4.32 (s, 1H, H-2), 4.15 (s, 3H, O-CH3),
3.56 (bs, 1H, H-9a), 3.13-3.02 (m, 3H, 2 × H-5, H-10), 2.97 (t, J )
3.3 Hz, 1H, H-7), 2.29 (s, 3H, H-4′), 2.08 (s, 3H, H-16), 1.99 (d, J )
12.3 Hz, 1H, H-1a), 1.88-1.82 (m, 3H, 2 × H-6, H-9), 1.77 (dt, J )
12.3, 3.3 Hz, 1H, H-1b), 1.40 (d, J ) 6.6 Hz, 3H, H-17); 13C NMR (75
MHz, CDCl3) δ 197.9 (CO), 169.6 (C-15), 162.7 (C-13), 147.9 (C-
11), 143.8 (C-2′), 130.6 (C-1′), 128.1 (C-12), 112.7 (C-8), 98.8 (C-
1
1618, 1007 cm-1; H NMR (300 MHz, CDCl3) δ 5.86 (dd, J ) 15.6
Hz, 5.1 Hz, 1H, H-2′), 5.75 (dd, J ) 15.6 Hz, 0.9 Hz, 1H, H-1′), 4.36
(dquintet, J ) 6.3 Hz, 0.9 Hz, 1H, H-3′), 4.24 (bs, 1H, C-2), 4.14 (s,
3H, O-CH3), 3.53 (bs, 1H, H-9a), 3.09 (m, 1H, H-10), 3.02 (m, 1H,
H-5a), 3.00 (m, 1H, H-5b), 2.88 (d, J ) 5.1 Hz, 1H, H-7), 2.08 (s, 3H,
H-16), 1.97 (d, J ) 12.0 Hz, 1H, H-1a), 1.88-1.81 (m, 3H, 2 × H-6,
H-9), 1.79 (m, 1H, H-1b), 1.38 (d, J ) 6.3 Hz, 3H, H-17), 1.28 (d, J
) 6.6 Hz, 3H, H-4′); 13C NMR (75 MHz, CDCl3) δ 169.7 (C-15),
162.8 (C-13), 148.2 (C-11), 135.3 (C-2′), 127.9 (C-12), 127.2 (C-1′),
112.7 (C-8), 98.6 (C-14), 82.8 (C-3), 80.4 (C-2), 68.1 (C-3′), 60.9 (C-
9a), 58.8 (O-CH3), 51.4 (C-7), 48.0 (C-5), 47.6 (C-9), 34.5 (C-10),
32.8 (C-1), 26.8 (C-6), 23.4 (C-4′), 18.3 (C-17), 9.1 (C-16); NMR data
agreed with that of the natural product, taken from a 1:1 mixture of 1
and 2;10 EIMS m/z 401 (28%) [M]+; HREIMS m/z 401.1823 [M]+,
calcd for C22H27NO6 401.1838.
(3′S)-Stemofolenol (2). The title compound was prepared via a
similiar method to the synthesis of 1, using (R)-(+)-2-methyl-CBS-
oxazaborolidine (13.8 mg, 0.04987 mmol) and ketone 8 (39.8 mg,
0.09975 mmol) to give 2 as a white solid in 61% yield (24.4 mg,
0.06085 mmol, dr ) 85:15). Rf ) 0.15 in MeOH/EtOAc (1:4); mp 180
°C (color changed to brown), 194-198 °C; [R]2D1 +212 (c 0.55, CHCl3);
IR νmax 3411, 2966, 1747, 1619, 1004 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.85 (dd, J ) 15.6 Hz, 5.7 Hz, 1H, H-2′), 5.74 (d, J ) 15.6
Hz, 1H, H-1′), 4.36 (dquintet, J ) 5.7 Hz, 0.9 Hz, 1H, H-3′), 4.24 (bs,
1H, C-2), 4.14 (s, 3H, O-CH3), 3.53 (bs, 1H, H-9a), 3.10 (m, 1H, H-10),
3.03 (m, 1H, H-5a), 3.00 (m, 1H, H-5b), 2.88 (d, J ) 4.8 Hz, 1H, H-7),
2.08 (s, 3H, H-16), 1.96 (d, J ) 12.0 Hz, 1H, H-1a), 1.88-1.81 (m,
3H, 2 × H-6, H-9), 1.80 (m, 1H, H-1b), 1.38 (d, J ) 6.3 Hz, 3H, H-17),
1.28 (d, J ) 5.7 Hz, 3H, H-4′); 13C NMR (75 MHz, CDCl3) δ 169.7
(C-15), 162.8 (C-13), 148.2 (C-11), 135.4 (C-2′), 127.9 (C-12), 127.1
(C-1′), 112.7 (C-8), 98.6 (C-14), 82.8 (C-3), 80.4 (C-2), 68.0 (C-3′),
60.9 (C-9a), 58.8 (O-CH3), 51.4 (C-7), 48.0 (C-5), 47.6 (C-9), 34.5
(C-10), 32.7 (C-1), 26.8 (C-6), 23.5 (C-4′), 18.3 (C-17), 9.2 (C-16);
NMR data agreed with that of the natural product, taken from a 1:1
mixture of 1 and 2;10 EIMS m/z 401 (42%) [M]+; HREIMS m/z
401.1828 [M]+, calcd for C22H27NO6 401.1838.
Preparation of (S)-MTPA Ester of 1 [(R,S)-(9)]. To a solution of
alcohol 1 (5.2 mg, 0.0130 mmol), 4-di(methylamino)pyridine (3.49 mg,
0.0285 mmol), and triethylamine (20.8 µL) in dry CH2Cl2 (0.5 mL)
was added (R)-Mosher’s acid chloride [(R)-R-methoxy-R-(trifluorom-
ethyl)phenylacetyl chloride (MTPACl)] (10.0 mg, 0.0396 mmol) under
a N2 atmosphere, and the mixture was allowed to stir at rt for 23 h.
The solvent was removed in Vacuo and the product was purified by
column chromatography, using EtOAc to MeOH/EtOAc (1:9) as eluent
to give (R,S)-9 as an oil in 87% yield (7.0 mg, 0.0113 mmol, dr )
1
93:7). Rf ) 0.57 in MeOH/EtOAc (1:9); H NMR (CDCl3) δ 7.51 (d,
J ) 7.0 Hz, 2H, ArH), 7.39 (m, 3H, ArH), 5.74 (m, 2H, H-2′, H-3′),
5.63 (t, J ) 6.0 Hz, 1H, C-1′), 4.15 (s, 1H, H-2), 4.14 (s, 3H, O-CH3),
3.57 (s, 3H, COC-OCH3), 3.49 (s, 1H, H-9a), 3.08 (m, 1H, H-10), 2.95
(m, 2H, 2 × H-5), 2.76 (d, J ) 5.5 Hz, 1H, H-7), 2.08 (s, 3H, H-16),
1.94 (d, J ) 12.5 Hz, 1H, H-1a), 1.81 (m, 2H, H-1b, H-9), 1.75 (m,
2H, 2 × H-6), 1.42 (d, J ) 6.5 Hz, 3H, H-4′), 1.37 (d, J ) 6.5 Hz, 3H,
H-17); 13C NMR (CDCl3) δ 169.7 (C-15), 165.6 (O-CO), 162.8 (C-
13), 148.2 (C-11), 132.3 (C-2′), 131.2 (Ar-C), 129.7 (Ar-C), 129.4
(Ar-C), 128.4 (C-1′), 127.2 (C-12), 112.7 (C-8), 98.7 (C-14), 82.8
(C-3), 80.1 (C-2), 72.8 (C-3′), 60.8 (C-9a), 58.8 (O-CH3), 55.4
(CF3COCH3), 51.8 (C-7), 48.0 (C-5), 47.6 (C-9), 34.5 (C-10), 32.6 (C-