Total Syntheses of Lycoricidine and Narciclasine
J. Am. Chem. Soc., Vol. 121, No. 22, 1999 5189
30%, 40%, and 50% EtOAc/hexanes, collecting 8 mL fractions. The
product-containing fractions (33-53) were collected and concentrated
to give 41 (2.06 g, 88% yield) as a colorless foam and a single isomer:
Rf 0.45 (50% EtOAc/hexanes); 500 MHz 1H NMR (CDCl3) δ 7.80 (d,
J ) 8.2 Hz, 2H), 7.39-7.19 (m, 12 H), 7.04 (d, J ) 1.9 Hz,1H), 6.65
(s, 1H), 5.91 (d, J ) 1.4 Hz, 1H), 5.80 (d, J ) 1.4 Hz,1H), 5.04 (bd,
J ) 11.0 Hz, 1H), 4.75 (ABq, ∆ν ) 19.4 Hz, J ) 11.5 Hz, 2H), 4.62
(dd, J ) 6.9, 1.9 Hz, 1H), 4.35 (dd, J ) 6.9, 2.2 Hz, 1H), 3.97-3.95
(m, 2H), 3.65 (s, 3H), 2.45 (s, 3H), 1.46 (s, 3H), 1.28 (s, 3H); 125
MHz 13C NMR (CDCl3) δ 165.7, 151.5, 145.8, 141.1, 140.4, 137.0,
136.5, 132.9, 132.6, 132.5, 132.1, 129.8, 129.6, 129.2, 128.9, 128.8,
128.7, 128.5, 127.8, 122.2, 108.3, 107.9, 103.1, 79.1, 77.4, 74.3, 74.1,
68.5, 65.3, 52.9, 26.3, 24.0, 21.9; IR (CHCl3) 3650 (b), 3173 (b), 1715
cm-1. Anal. Calcd for C38H37NO11S2: C, 61.03; H, 4.99; N, 1.87; S,
8.58. Found: C, 61.17; H, 5.07; N, 1.85; S, 8.54.
152.3, 146.6, 135.8, 134.4, 134.1, 129.9, 129.4, 127.9, 127.6, 127.2,
112.3, 106.7, 102.8, 100.7, 78.6, 77.6, 74.0, 57.2, 27.3, 25.2; IR (CHCl3)
1671, 1548 cm-1; HRMS m/z (EI) calcd for C23H21NO7S 455.1039,
found 455.1046.
Preparation of Methyl 6-{(3aS,4R,7R,7aR)-7-Hydroxy-2,2-di-
methyl-4-[(phenylmethoxy)amino]-6-phenylthio(2,3,4,7,3a,7a-hexahy-
dro-1,3-dioxainden-5-yl)}-4-hydroxy-2H-benzo[d]1,3-dioxolene-5-
carboxylate (43). To a stirring solution of 41 (303 mg, 0.405 mmol)
in 8.1 mL of THF at 0 °C (ice/water bath) was added H2O (145 uL,
145 mg, 8.1 mmol) followed by a solution of SmI2 (10 mL, 1.0 mmol,
0.1 M in THF). After 10 min the reaction was quenched with 10 mL
of a 2% aqueous HCl solution and diluted with 75 mL of EtOAc. The
layers were separated, and the organic layer was washed with 25 mL
of a saturated solution of Na2S2O3, dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of this material was
accomplished by RPLC using a 4 mm plate eluting with a gradient of
100 mL each of 40, 50, and 60% EtOAc/hexanes, collecting 8 mL
fractions. The product-containing fractions (15-21) were collected and
concentrated to give the phenol 43 (212 mg, 94% yield) as a colorless
foam: Rf 0.61 (50% EtOAc/hexanes); [R]20D ) +108.5 (c 1.2, CHCl3);
500 MHz 1H NMR (CDCl3) δ 10.6 (s, 1H) (exchangeable with D2O),
7.38-7.20 (m, 10H), 6.42 (s, 1H), 6.04 (ABq, ∆ν ) 7.6 Hz, J ) 4.4
Hz, 2H), 5.93 (bs, 1H) (exchangeable with D2O), 4.83-4.80 (m, 3H),
4.64 (d, J ) 12.4 Hz, 1H), 4.55 (dd, J ) 6.9, 2.2 Hz, 1H), 4.04 (bs,
1H), 3.98 (bs, 1H), 3.48 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H); 125 MHz
13C NMR (CDCl3) δ 169.7, 152.8, 145.3, 139.5, 137.5, 136.9, 134.4,
133.0, 132.8, 131.7, 129.0, 128.9, 128.9, 128.6, 127.9, 109.5, 108.5,
102.8, 102.4, 78.4, 77.1, 73.8, 67.6, 65.9, 52.2, 26.3, 24.1; IR (CHCl3)
3371, 1676 cm-1. Anal. Calcd for C31H31NO9S: C, 62.72; H, 5.26; N,
2.36; S, 5.40. Found: C, 62.82; H, 5.33; N, 2.30; S, 5.34.
Preparation of Methyl 6-{(3aS,4R,7R,7aR)-7-Hydroxy-2,2-di-
methyl-4-[(phenylmethoxy)amino]-6-phenylthio(2,3,4,7,3a,7a-hexahy-
dro-1,3-dioxainden-5-yl)}-4-methoxy-2H-benzo[d]1,3-dioxolene-5-
carboxylate (40). To a stirring solution of phenol 43 (352 mg, 0.593
mmol) in 6 mL of DMF was added K2CO3 (164 mg, 1.18 mmol)
followed by MeI (369 µL, 842 mg, 5.93 mmol) via syringe. After 22
h the reaction was quenched with 25 mL of H2O and diluted with 100
mL of EtOAc. The layers were separated, and the organic layer was
washed with 25 mL of a saturated solution of Na2S2O3, saturated
aqueous CuSO4 solution (2 × 25 mL), H2O (25 mL), and 25 mL of
brine. The organic layer was dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification of this material was
accomplished by RPLC using a 4 mm plate eluting with a gradient of
100 mL each of 20%, 30%, and 40% EtOAc/hexanes, collecting 8 mL
fractions. The product-containing fractions (18-27) were collected and
concentrated to give 40 (347 mg, 96% yield) as a colorless foam: Rf
0.39 (35% acetone/hexanes); [R]20D ) +12.1 (c 1.2, CHCl3); 500 MHz
1H NMR (CDCl3) δ 7.37-7.30 (M, 7H), 7.24-7.18 (m, 3H), 6.90 (bs,
1H), 6.45 (s, 1H), 5.98 (d, J ) 1.4 Hz, 1H), 5.93 (d, J ) 1.4 Hz, 1H),
5.09 (bs, 1H), 4.73 (ABq, ∆ν ) 7.5 Hz, J ) 11.8 Hz, 2H), 4.65 (dd,
J ) 6.9, 1.6 Hz, 1H) 4.39 (dd, J ) 6.9, 1.9 Hz, 1H), 3.98 (s, 3H), 3.97
(s, 3H), 3.90 (s, 1H), 3.70 (s, 3H), 1.48 (s, 3H), 1.28 (s, 3H),; 125
MHz 13C NMR (CDCl3) δ 167.6, 151.2, 141.2, 141.2, 137.0, 136.5,
134.9, 132.7, 132.5, 132.3, 128.9, 128.7, 128,6, 128.4, 127.6, 120.4,
108.2, 103.3, 101.9, 78.9, 77.1, 74.0, 68.2, 65.4, 60.4, 52.6, 26.3, 23.9;
IR (CHCl3) 3532 (b), 3221, 1708 cm-1. Anal. Calcd for C32H33NO9S:
C, 63.25; H, 5.47; N, 2.30; S, 5.28. Found: C, 63.41; H, 5.55; N, 2.31;
S, 5.28.
Preparation of (2S,5aS,2aR,5bR)-2,8-Dihydroxy-4,4-dimethyl-
2,6,2a,5a,5b-pentahydro-10H-1,3-dioxolano[4,5-c]1,3-dioxoleno[4,5-
j]phenanthridin-7-one (42). To a stirring solution of the hydroxylamine
41 (70 mg, 0.094 mmol) in THF (1.9 mL) was added a premade solution
of SmI2 (1.9 mL, 0.19 mmol, 0.1 M in THF). After the indicated time
an additional amount of SmI2 (1.9 mL, 0.19 mmol) was added: 36
min, 27 h, and 42 h (8 equiv of SmI2 total). After a total of 6 days the
reaction was diluted with 15 mL of THF and quenched with 20 mL of
a 1% aqueous solution of HCl. The reaction was further diluted with
30 mL of EtOAc, and the layers were separated. The aqueous layer
was back extracted with EtOAc (3 × 10 mL), and the combined organic
layers were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of this material was accomplished by flash
chromatography on a 1 × 8 cm column, eluting with a gradient of 20
mL each of 40%, 50%, 60%, and 70% EtOAc/hexanes, collecting 4
mL fractions. The product-containing fractions (18-25) were collected
and concentrated to give the acetonide 42 (15 mg, 46% yield)36b as a
tan crystalline solid: mp 270-271 °C (dec) [lit.37 275-276 °C (dec),
lit.5a 274 °C]; [R]20 ) -24.0 (c 0.35, THF) (lit.37 [R]20 ) -33 (c
D
D
0.35, THF); Rf 0.16 (35% EtOAc/hexanes); 500 MHz 1H NMR (DMSO-
d6) δ 13.75 (s, 1H), 8.82 (s, 1H), 7.01 (s, 1H), 6.48 (bs, 1H), 6.06 (d,
3.3 Hz, 2H), 5.82 (d, J ) 5.5 Hz, 1H), 4.16-4.09 (m, 2H), 4.07 (dd,
J ) 7.7, 7.7, 1H), 3.97 (dd, J ) 7.7, 6.3 Hz, 1H), 1.46 (s, 3H), 1.32 (s,
3H); 125 MHz 13C NMR (DMSO-d6) δ 167.6, 152.6, 145.2, 133.3,
128.9, 128.3, 125.9, 109.8, 104.3, 102.1, 94.3, 79.0, 78.5, 71.0, 54.6;
IR (CHCl3) 3640, 1675 cm-1; HRMS m/z (EI) calcd for C17H17NO6
347.1005, obsd 347.0991.
Preparation of (2S,5aS,2aR,5bR)-2,8-Dihydroxy-4,4-dimethyl-
2,6,2a,5a,5b-pentahydro-10H-1,3-dioxolano[4,5-c]1,3-dioxoleno[4,5-
j]phenanthridin-7-one (42) and (5aS,2R,2aR,5bR)-2,8-Dihydroxy-
4,4-dimethyl-1-phenylthio-2,6,2a,5a,5b-pentahydro-10H-1,3-
dioxolano[4,5-c]1,3-dioxoleno[4,5-j]phenanthridin-7-one (42s). To a
stirring solution of 38 (76 mg, 0.12 mmol) in 2.5 mL of THF was
added a solution of SmI2 (2.8 mL, 0.28 mmol, 0.1 M in THF). After
2 h an additional portion of SmI2 (2.8 mL, 0.28 mmol) was added.
The reaction was allowed to stir for 42 h, then quenched with a 1%
aqueous HCl solution (20 mL) and diluted with 15 mL of THF and 30
mL of EtOAc. The layers were separated, and the aqueous layer was
back-extracted with EtOAc (3 × 15 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of this material was accomplished by flash column
chromatography on a 1 × 8 cm column, eluting with a gradient of 25
mL each of 40%, 50%, 60%, and 70% EtOAc/hexanes, collecting 4
mL fractions. The product-containing fractions [12-15 (vinyl sulfide
42s) and 16-25 (narciclasine-3,4-acetonide 42)] were collected and
concentrated to give vinyl sulfide 42s (7.5 mg, 13% yield) as a
crystalline pale yellow solid and narciclasine-3,4-acetonide 42 (16.5
mg, 38% yield) as a tan crystalline solid: Rf 0.14, 0.16 (50% EtOAc/
Preparation of (2S,5aS,2aR,5bR)-2-Hydroxy-8-methoxy-4,4-di-
methyl-6-(phenylmethoxy)-1-phenylthio-2,6,2a,5a,5b-pentahydro-
10H-1,3-dioxolano[4,5-c]1,3-dioxoleno[4,5-j]phenanthridin-7-one (44).
To a stirring solution of hydroxylamine 40 (102 mg, 0.168 mmol) in
3.4 mL of THF was added Me3Al (92.6 µL, 0.185 mmol, 2.0 M in
hexanes) dropwise. The reaction was then slowly warmed to 60-65
°C and allowed to stir for 12 h, then cooled to rt and quenched with 6
mL of a saturated solution of Na and K tartrates. After 30 min of
stirring, the reaction mixture was diluted with 20 mL of EtOAc and
the layers were separated. The organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of this
material was accomplished by flash chromatography using a 1 × 8 cm
column, eluting with a gradient of 50 mL each of 20%, 30%, and 40%
hexanes) for 42s and 42, respectively; [R]20 ) +295 (c 0.54, THF)
D
1
(vinyl sulfide 42s); 500 MHz H NMR (CDCl3) (vinyl sulfide 42s) δ
13.14 (s, 1H), 8.23 (s, 1H), 7.31-7.20 (m, 5H), 6.95 (bs, 1H), 6.04 (s,
2H), 4.37 (d, J ) 5.2, 5.2 Hz, 1H), 4.32 (d, J ) 7.9, Hz, 1H), 4.13 (dd,
J ) 7.9, 7.9 Hz, 1H), 4.07 (dd, J ) 7.9, 6.1 Hz, 1H), 3.16 (d, J ) 4.3
Hz, 1H), 1.55 (s, 3H), 1.39 (3H); 125 MHz 13C NMR (CDCl3) δ 167.6,
(37) Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445.