Total Synthesis of (+)-Isoschizandrin
MeOH (10 mL), and allowed to warm to rt. The material was
filtered, concentrated and purified via chromatography (40%
EtOAc in hexanes) to give 0.513 g (70%) of material: Rf ) 0.3
(50% EtOAc in hexanes); [R]28D +21.9 (c 4.54, CHCl3); IR (film)
3500, 2938, 2847, 2751, 2250, 1685, 1588, 1482 cm-1; 1H NMR
(500 MHz, CDCl3) δ 9.52 (s, 1H), 7.35 (s 1H), 6.90 (s, 1H), 4.23-
4.21 (m, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.85 (s,
3H), 3.63 (s, 3H), 3.60 (s, 3H), 2.55 (bs, 1H); 13C NMR (125
MHz, CDCl3) δ 190.8, 153.8, 153.2, 151.5, 150.9, 147.5, 141.1,
135.8, 129.9, 127.8, 117.8, 107.7, 105.5, 63.5, 61.0, 60.9, 60.7,
60.5, 56.0, 55.8; HRMS m/z calcd for (C20H24O8 + Na)+
415.1369, found 415.1361.
6.82 (s, 1H), 6.69 (s, 1H), 5.88-5.85 (dq, J ) 11.5, 1.69 Hz,
1H), 5.49-5.48 (dq, J ) 11.7, 6.98 Hz, 1H), 4.10 (s, 2H), 3.83
(s, 9H), 3.79 (s, 3H), 3.61 (s, 3H), 3.57 (s, 3H), 2.57 (br s, 1H),
1.77-1.76 (d, J ) 7.08, 1.72 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 152.8, 151.9, 151.08, 151.03, 141.0, 140.7, 135.1,
132.2, 128.8, 125.9, 122.5, 121.5, 108.6, 106.8, 63.2, 60.6, 60.49,
60.40, 60.1, 55.7, 55.5, 14.2; HRMS m/z calcd for (C22H28O7 +
Na)+ 427.1733, found 427.1733.
(+)-(R)-4,5,6,2′,3′,4′-H exa m et h oxy-6′-[(Z)-p r op en yl]b i-
p h en yl-2-ca r ba ld eh yd e [(+)-22]. To a solution of the benzyl
alcohol (+)-21 (0.1058 g, 0.261 mmol) in CH2Cl2 (3 mL) was
added 0.166 g (0.391 mmol) of Dess-Martin reagent at 0 °C
under N2. The mixture was warmed to rt and was monitored
for completion via TLC. After 2 h, the mixture was diluted
with Et2O and poured into a 1:1 mixture of saturated aqueous
NaHCO3 and Na2S2O3 (1.5 M). The mixture was stirred until
the ether layer was clear. The organic layer was then sepa-
rated, washed with brine, dried with Na2SO4, and concentrated
to give 0.0945 g (90%) of the desired aldehyde: Rf ) 0.3 (EtOAc
(+)-(R)-4,5,6,2′,3′,4′-Hexa m eth oxy-6′-(tr iisop r op ylsila -
n yloxym eth yl)bip h en yl-2-ca r ba ld eh yd e [(+)-18]. To a
solution of hydroxy aldehyde (+)-14 (0.504 g, 1.28 mmol) in
CH2Cl2 (13 mL, 0.10 M) were added DMAP (0.023 g, 0.15
mmol), imidazole (0.130 g, 0.192 mmol), and TIPSCl (0.271 g,
1.41 mmol) at 0 °C. The mixture was allowed to warm to rt
and stirred under N2 for 2 h. The reaction was quenched with
H2O, washed with brine, dried with Na2SO4, and concentrated.
After purification via radial chromatography (20% EtOAc in
hexanes), 0.609 g (98%) of the silyl ether was obtained as an
in hexanes); mp 116-119 °C; [R]26 +66.86 (c 1.895, CHCl3);
D
IR (film) 2938, 2844, 1733, 1635, 1588, 1483 cm-1; H NMR
1
(500 MHz, CDCl3) δ 9.41 (s, 1H), 7.24 (s, 1H), 6.64 (s, 1H),
5.81-5.79 (dq, J ) 11.5, 1.7 Hz, 1H), 5.50-5.46 (dq, J ) 11.4,
6.99 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.59 (s, 3H), 3.57 (s, 3H), 1.70-1.69 (d, J ) 6.96, 1.7 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 190.9, 152.9, 152.7, 151.8,
151.2, 147.3, 140.6, 132.9, 129.6, 129.0, 128.6, 126.8, 119.0,
108.2, 104.5, 60.69, 60.66, 60.38, 60.35, 55.78, 55.76, 14.19;
HRMS m/z calcd for (C22H26O7 + Na)+ 425.1576, found
425.1583. Anal. Calcd for C22H26O7: C, 65.66; H, 6.51. Found:
C, 65.44; H, 6.43.
oil: Rf ) 0.3 (20% EtOAc in hexanes); [R]27 +16.2 (c 4.66,
D
CHCl3); IR (film) 2941, 2892, 2865, 2748, 2604, 1964, 1681,
1
1588, 1481 cm-1; H NMR (500 MHz, CDCl3) δ 9.48 (s, 1H),
7.31 (s, 1H), 7.05 (s, 1H), 4.46 (d, J ) 13.5 Hz, 1H)), 4.24 (d, J
) 13.5 Hz, 1H), 3.90 (s, 6H), 3.87 (s, 3H), 3.81 (s, 3H), 3.60 (s,
3H), 3.57 (s, 3H), 0.99 (s, 18H), 0.97 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 190.0, 153.4, 153.0, 151.2, 151.1, 147.4, 140.1,
136.3, 129.6, 127.7, 116.1, 105.1, 104.8, 62.8, 60.7, 60.6, 60.5,
60.3, 55.8, 55.5, 17.7, 12.1, 11.7; HRMS m/z calcd for (C29H44O8-
Si + Na)+ 571.2703, found 571.2687.
(+)-(R)-2-(2′-Oxop r op yl-4,5,6-tr im eth oxy-2′-[(Z)-p r op e-
n yl]-3′,4′,5′-tr im eth oxybip h en yl [(+)-3]. A suspension of
0.58 g (1.4 mmol) of (R-methoxyethyl)triphenylphosphonium
chloride in 2.5 mL of THF was cooled to -78 °C under argon,
and n-BuLi (0.90 mL of a 1.6 M solution in hexanes, 1.44
mmol) was added dropwise, giving a characteristic red color
that persisted after 30 min of stirring at -78 °C. Aldehyde
(+)-22 (0.058 g, 0.14 mmol) in THF (2.0 mL) was then added
at -78 °C to the ylide mixture, and the resulting suspension
was stirred for 3 h at -78 °C. The reaction was quenched with
H2O and extracted with Et2O. The combined organic extracts
were concentrated to give the crude enol ether. A catalytic
amount of p-TsOH (1 crystal) was added to the crude enol ether
in THF (2 mL) at 0 °C, and the mixture was stirred for 30
min. The reaction was then quenched with water and extracted
with Et2O. The organic extracts were dried with Na2SO4,
concentrated, and purified via radial chromatography (40%
EtOAc in hexanes) to give 0.033 g (54%) of ketoolefin: Rf )
0.2 (30% EtOAc in hexanes); IR (film) 2937, 2847, 1712, 1592,
1483 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.72 (s, 1H), 6.53 (s,
1H), 5.88 (dq, J ) 11.7, 1.8 Hz, 1H), 5.55 (dq, J ) 11.7, 7.1
Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H),
3.67 (s, 3H), 3.62 (s, 3H), 3.28 (AB, J ) 10.3 Hz, 2H), 1.91 (s,
3H), 1.84 (dd, J ) 7.1, 1.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 206.7, 152.7, 152.2, 151.6, 132.4, 129.4, 128.9, 128.8, 126.6,
126.1, 123.6, 122.9, 108.5, 108.3, 60.8, 60.7, 60.6, 60.4, 55.9,
55.8, 47.9, 29.5, 14.5; HRMS m/z calcd for (C24H30O7 + Na)+
453.1889, found 453.1875.
(+)-(R)-(4,5,6,2′,3′,4′-Hexa m eth oxy-6′-[(Z)-p r op en yl]bi-
p h en yl-2-ylm eth oxy)tr iisop r op ylsila n e [(+)-20]. To a sus-
pension of ethyltriphenylphosphonium bromide (1.21 g, 3.23
mmol) in 30 mL of freshly distilled THF at 0 °C under N2 was
added via syringe KHMDS (6.56 mL of a 0.5 M solution in
toluene, 3.23 mmol). The resulting orange solution was allowed
to stir at 0 °C for 30 min. The ylide solution was then cooled
to -78 °C, and a solution of the aldehyde (+)-18 (0.600 g, 1.09
mmol) in 30 mL of THF was added dropwise. The reaction was
stirred at -78 °C and then slowly warmed to rt. The reaction
was then quenched with cold MeOH, extracted with EtOAc,
dried with Na2SO4, and concentrated. The crude reaction
provided 0.520 g (85%) of a 4:1 mixture of Z/E olefins. After
column chromatography via flash MPLC, 0.327 g (54%) of a
>10:1 Z/E mixture was obtained. This sample was carried
through the rest of the synthesis: Rf ) 0.3 (20% EtOAc in
hexanes); [R]26 +39.9 (c 4.07, CHCl3); IR (film) 2940, 2892,
D
2865, 2716, 1593, 1562, 1483 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.09 (s, 1H), 6.71 (s, 1H), 5.93 (d, J ) 11.6 Hz, 1H), 5.55 (dq,
J ) 11.5, 6.9 Hz, 1H), 4.36-4.25 (AB, J ) 14.0 Hz, 2H), 3.89
(s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H),
3.62 (s, 3H), 1.83 (d, J ) 6.6 Hz, 3H), 1.00 (s, 18H), 0.99 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 152.7, 151.9, 151.3, 150.8,
140.9, 140.0, 135.9, 132.0, 128.8, 125.7, 122.2, 119.7, 108.4,
104.3, 62.5, 60.7, 60.6, 60.3, 60.2, 55.8, 55.5, 17.8, 14.4, 11.8;
HRMS m/z calcd for (C31H48O7Si + Na)+ 583.3067, found
583.3096.
(+)-(R)-(4,5,6,2′,3′,4′-Hexa m eth oxy-6′-[(Z)-p r op en yl]bi-
p h en yl-2-yl)m eth a n ol [(+)-21]. To a solution of the silyl
ether (+)-20 (0.117 g, 0.208 mmol) in THF (2 mL) at 0 °C was
added TBAF (0.260 mL of a 1 M solution in THF, 0.260 mmol).
The reaction was stirred under N2 and was warmed to rt over
1-2 h. The reaction was quenched with H2O and extracted
with Et2O. The combined organic extracts were washed with
brine, dried with Na2SO4, and concentrated. After purification
via column chromatography (30% EtOAc in hexanes), 0.076 g
(91%) of benzyl alcohol was obtained as an oil: Rf ) 0.2 (40%
EtOAc in hexanes); [R]26D +20.0 (c 3.92, CHCl3); IR (film) 3494,
(+)-Isosch iza n d r in (1). A solution of samarium(II) iodide
was generated by adding CH2I2 (0.084 g, 0.31 mmol) to a slurry
of samarium metal (0.048 g, 0.32 mmol) in THF (3 mL). After
the solution was stirred overnight, HMPA (0.500 mL) was
added followed by the dropwise addition of ketoolefin (+)-3
(0.027 g, 0.063 mmol) and t-BuOH (9 mg, 0.125 mmol) in THF
(12 mL) via syringe pump over 2 h. Two hours after the
addition was complete, the reaction was quenched with aque-
ous NaHCO3, concentrated, and extracted with EtOAc. The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified via radial chromatog-
raphy (40% EtOAc in hexanes) to give the natural product as
2937, 2838, 1540, 1483 cm-1 1H NMR (500 MHz, CDCl3) δ
;
J . Org. Chem, Vol. 68, No. 25, 2003 9539