Total Synthesis of the Marine Alkaloids (-)-Lepadins
J . Org. Chem., Vol. 66, No. 10, 2001 3345
(isobutane) m/z 604 (MH+, 100). Anal. Calcd for C35H45NO6Si:
C, 69.62; H, 7.51; N, 2.32. Found: C, 69.47; H, 7.58; N, 2.41.
(2S,4a R,5S,7S,8S)-5-(Ben zyloxy)-7-{[ter t-b u t yl(d ip h e-
n yl)silyl]oxy}-2-[2-(m eth oxym eth oxy)eth yl]-8-m eth yloc-
ta h yd r op yr id o[1,2-b][1,2]oxa zin e (26). To a stirred solution
of 24 (2.94 g, 4.87 mmol) in THF (60 mL) was added
methylmagnesium bromide (0.92 M solution in THF, 10.6 mL,
9.75 mmol) at 0 °C. After 10 min, the mixture was quenched
with 10% aqueous NaOH (40 mL). The layers were separated
,and the aqueous layer was extracted with Et2O (3 × 100 mL).
The combined extracts were washed with brine, dried, and
concentrated in vacuo to afford the crude enamine (3.62 g),
which was immediately dissolved in THF (40 mL) and acidified
by a addition of AcOH. To this was added NaBH3CN (1.61 g,
24.4 mmol) in one portion at 0 °C. After being stirred for 1 h,
the mixture was neutralized with 10% aqueous NaOH (40 mL)
and extracted with CHCl3 (3 × 30 mL). The combined extracts
were washed with brine, dried, and concentrated in vacuo. The
residue was purified by chromatography (hexane/AcOEt, 20:
(3H, d, J ) 6.9 Hz), 1.50-1.73 (3H, m), 1.74-2.02 (3H, m),
2.32 (1H, br s), 3.12 (1H, br s), 3.76 (3H, br s), 4.09 (1H, br s),
4.36 (1H, br s), 4.65 (1H, br s), 5.18 (1H, br s), 7.27-7.45 (5H,
m); 13C NMR (100 MHz, CDCl3, amide rotamer) δ 14.4, 23.8,
29.5, 32.3, 49.3, 51.6, 51.8, 52.6, 66.4, 119.8, 125.8, 128.5 (2
carbons), 129.2 (2 carbons), 134.6, 136.6, 170.5, 172.8; EIMS
m/z (relative intensity) 330 (M+ + 1, 21), 311 (13), 296 (98),
270 (23), 215 (5), 182 (24), 147 (83), 104 (100); HRMS (EI) calcd
for C19H23NO4 (M+) 329.1627, found 329.1632.
The second fractions afforded 44 as a colorless oil: [R]25
D
-132.4 (c 1.24, CHCl3); IR (neat) 3300, 1730, 1604 cm-1; H
1
NMR (400 MHz, CDCl3, amide rotamer) δ 1.17 (3H, d, J ) 6.5
Hz), 1.37-1.80 (4H, m), 1.95 (1H, br s), 2.12-2.47 (2H, m),
3.36-3.42 (1H, m), 3.70 (3H, br s), 4.07 (1H, br s), 4.40 (1H,
br s), 4.72 (1H, br s), 5.47 (1H, br s), 7.24-7.41(5H, m); 13C
NMR (100 MHz, CDCl3, amide rotamer) δ 14.4, 21.8, 28.8, 32.0,
48.5, 50.2, 52.0, 52.7, 66.1, 124.7, 125.8, 128.4 (2 carbons),
129.1 (2 carbons), 133.8, 136.9, 170.3, 173.3; EIMS m/z
(relative intensity) 329 (M+, 59), 311 (8), 296 (100), 270 (49),
171 (13), 148 (47), 104 (80); HRMS (EI) calcd for C19H23NO4
(M+) 329.1627, found 329.1627.
1) to afford 26 (2.4 g, 82%) as a colorless oil: [R]22 +102.4 (c
D
1.41, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.07 (12H, s), 1.24-
1.32 (2H, m), 1.51-1.62 (1H, m), 1.67-1.77 (1H, m), 1.82-
1.95 (1H, m), 2.07-2.13 (1H, m), 2.17 (1H, dt, J ) 12.8, 3.7
Hz), 2.39-2.47 (2H, m), 2.68-2.78 (1H, m), 3.36 (3H, s), 3.54-
3.74 (3H, m), 4.01-4.08 (1H, m), 4.09-4.18 (1H, m), 4.20 and
4.27 (2H, ABq, J ) 11.3 Hz), 4.63 (2H, s), 7.19-7.33 (5H, m),
7.35-7.48 (6H, m), 7.70-7.80 (4H, m); 13C NMR (100 MHz,
CDCl3) δ 16.7, 19.8, 23.1, 27.2, 28.1, 30.8, 36.8, 55.1, 63.6, 64.9,
69.2, 71.4, 71.7, 72.8, 76.0, 96.5, 127.5 (2 carbons), 127.6 (2
carbons), 127.7 (2 carbons), 127.8, 128.4 (2 carbons), 129.7,
129.8, 134.0, 134.3, 136.1 (2 carbons), 136.2 (2 carbons), 138.5;
ter t-Bu tyl (2S,3S,4a S,5R,8a R)-3-{[ter t-Bu tyl(d im eth yl)-
silyl]oxy}-5-(h yd r oxym eth yl)-2-m eth ylocta h yd r o-1(2H)-
qu in olin eca r boxyla te (49). To a solution of 47 (69 mg, 4.66
mmol) in THF (4 mL) was added 10% palladium on activated
carbon (100 mg), and the resulting suspension was shaken
with hydrogen at 5 atm for 18 h. The catalyst was removed
by filtration, and the filtrate was concentrated in vacuo to
provide 58 mg of crude ((2S,3S,4aS,5R,8aR)-3-{[tert-butyl-
(dimethyl)silyl]oxy}-2-methyldecahydro-5-quinolinyl)metha-
nol 48 as an oil: 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s),
0.11 (3H, s), 0.97 (9H, s), 1.17 (2H, qd, J ) 12.7, 3.5 Hz), 1.36
(3H, d, J ) 5.9 Hz), 1.52-1.66 (4H, m), 1.69-1.95 (4H, m),
2.10-2.23 (2H, m), 2.32 (1H, br s), 3.12 (2H, br d, J ) 5.1 Hz),
3.32 (1H, br s), 3.67 (1H, A of ABX, J ) 10.8, 2.9 Hz), 3.72
(1H, B of ABX, J ) 10.9, 4.8 Hz); 13C NMR (100 MHz, CDCl3,)
δ -5.1, -4.2, 16.9, 17.9, 20.5, 25.9, 29.0, 29.9, 32.2, 33.1, 36.9,
56.5, 57.1, 64.6, 67.5.
This product was dissolved in CH2Cl2 (2 mL), and triethy-
lamine (28 mg, 0.276 mmol) and di-tert-butyl dicarbonate (59
mg, 0.270 mmol) were sequentially added at 0 °C. The mixture
was stirred at room temperature for 15 h, diluted with CHCl3
(100 mL), washed with brine, and dried. Evaporation of the
solvent followed by purification of the crude material by
chromatography (hexane/AcOEt, 4:1) gave 49 (60.8 mg, 85%)
as a colorless oil: [R]25D +6.45 (c 1.10, CHCl3); IR (neat) 3440,
1690 cm-1; 1H NMR (500 MHz, CDCl3, amide rotamer) δ 0.06
and 0.07 (total 6H in 2:1 ratio, each s), 0.89 and 0.88 (total
9H in 2:1 ratio, each s), 1.12 (3H, d, J ) 7.0 Hz), 1.33 (2H, br
d, J ) 11.2 Hz), 1.45 (9H, s), 147-1.72 (5H, m), 1.74-1.81
(1H, m), 1.84-1.92 (1H, m), 1.96 (1H, q, J ) 12.2 Hz), 3.65
(1H, t, J ) 7.6 Hz), 3.73 (1H, q, J ) 10.4 Hz), 3.79 (1H, ddd,
J ) 11.0, 6.3, 4.6 Hz), 4.07 and 3.98 (total 1H in 2:1 ratio,
each dt, J ) 12.5, 4.3 Hz), 4.18 and 4.30 (total 1H in 2:1 ratio,
each quint, J ) 6.7 Hz); 13C NMR (125 MHz, CDCl3, amide
rotamer) δ -4.9, -4.7, 15.3 and 14.9 (1 carbon in 2:1 ratio),
18.0, 21.3, 22.6 and 22.5 (1 carbon in 2:1 ratio), 25.8 (3
carbons), 28.0 and 28.7 (1 carbon in 2:1 ratio), 28.4 (3 carbons),
30.4 and 30.6 (1 carbon in 2:1 ratio), 34.6 and 35.0 (1 carbon
in 2:1 ratio), 42.6 and 42.8 (1 carbon in 2:1 ratio), 48.9 and
49.9 (1 carbon in 2:1 ratio), 51.4 and 50.6 (1 carbon in 2:1 ratio),
64.0 and 64.3 (1 carbon in 2:1 ratio), 70.7 and 70.4 (1 carbon
in 2:1 ratio), 79.4 and 79.3 (1 carbon in 2:1 ratio), 155.1 and
155.2 (1 carbon in 2:1 ratio); EIMS m/z (relative intensity) 413
(M+, 3), 357 (5), 341 (10), 312 (10), 299 (100), 282 (30); HRMS
(EI) calcd for C22H43NO4Si (M+) 413.2961, found 413.2934.
ter t-Bu tyl (2S,3S,4a S,5R,8a R)-3-{[ter t-Bu tyl(d im eth yl)-
silyl]oxy}-5-[(E)-2-iodoeth en yl]- 2-m eth yloctah ydr o-1(2H)-
qu in olin eca r boxyla te (51). To a stirred, cooled (-78 °C)
solution of oxalyl chloride (102 mg, 0.803 mmol) in CH2Cl2 (5
mL) was added dropwise a solution of DMSO (125 mg, 1.60
mmol) in CH2Cl2 (1 mL). The mixture was stirred at -78 °C
for 30 min followed by dropwise addition of a solution of 49
(167 mg, 0.403 mmol) in CH2Cl2 (4 mL). After the mixture was
stirred at -78 °C for 1 h, triethylamine (243 mg, 2.40 mmol)
CIMS (isobutane) m/z 604 (MH+, 100). Anal. Calcd for C36H49
-
NO5Si: C, 71.60; H, 8.18; N, 2.32. Found: C, 71.65; H, 8.02;
N, 2.40.
(2S,3S,4a R,5S,8a R)-1-Ben zoyl-3-{[ter t-bu tyl(d ip h en yl)-
silyl]oxy}-4a -h yd r oxy-2-m et h yld eca h yd r o-5-q u in olin e-
ca r ba ld eh yd e (40). A solution of 39 (437 mg, 0.786 mmol),
AcOH (9.4 mg, 0.157 mmol), and piperidine (13.4 mg, 0.157
mmol) in benzene (40 mL) was refluxed for 1 h with a Dean-
Stark apparatus. After being allowed to cool to room temper-
ature, the mixture was concentrated in vacuo. The resulting
oil was purified by chromatography (hexane/AcOEt, 1:1) to give
40 (38.1 mg, 87%) as a colorless oil: [R]24 +5.20 (c 2.23,
D
CHCl3); IR (neat) 3382, 1718, 1614 cm-1; 1H NMR (400 MHz,
CDCl3, amide rotamer) δ 0.97 and 1.10 (total 9H in 1.5:1 ratio,
each br s), 1.27 (3H, d, J ) 7.1 Hz), 1.28-1.48 (2H, m), 1.70-
1.89 (3H, m), 1.89-2.05 and 2.30-2.39 (total 2H in 1.5:1 ratio,
each m), 2.29 (1H, br s), 4.03 and 3.39 (total 1H in 1.5:1 ratio,
each br s), 4.41 (1H, quint, J ) 5.4 Hz), 4.45-4.57 and 5.10
(total 1H in 1.5:1 ratio, m and br s), 7.19-7.73 (15H, m), 9.66
and 9.45 (total 1H in 1.5:1 ratio, each br s); 13C NMR (100
MHz, CDCl3, amide rotamer) δ 16.8, 18.9, 22.5, 23.7, 26.8 (3
carbons), 30.2, 30.4, 53.5, 57.1, 60.0, 66.3, 72.9, 126.0, 127.5
(2 carbons), 127.6 (4 carbons), 128.4 (2 carbons), 129.0, 129.5,
129.7 (2 carbons), 133.4, 133.5, 135.2, 135.5 (2 carbons), 136.6,
172.8, 204.6; EIMS m/z (relative intensity) 555 (M+, 0.1), 498
(M+ - t-Bu, 12), 296 (5), 268 (42), 105 (36); HRMS (EI) calcd
for C30H32NO4Si (M+ - t-Bu) 498.2101, found 498.2086.
Meth yl (2S,3S,5R,8a R)-1-Ben zoyl-3-h yd r oxy-2-m eth yl-
1,2,3,5,6,7,8,8a-octah ydr o-5-qu in olin ecar boxylate (44) an d
Met h yl (2S,3S,5S,8a R)-1-Ben zoyl-3-h yd r oxy-2-m et h yl-
1,2,3,5,6,7,8,8a -octa h yd r o-5-qu in olin eca r boxyla te (45). To
a stirred solution of 43 (126 mg, 0.222 mmol) in THF (3 mL)
was added a 1 M tetrabutylammonium fluoride solution in
THF (1.11 mL, 1.11 mmol) at 0 °C. After being stirred at room
temperature for 5 d, the mixture was poured into saturated
aqueous NH4Cl (10 mL) and extracted with Et2O (3 × 20 mL).
The combined organic phases were washed with brine, dried,
and concentrated in vacuo. Chromatography (hexane/AcOEt,
1:1) of the residue provided a mixture of 44 and 45 (63.2 mg,
87%) in a ratio of 2:1 (based on 1H NMR) as a colorless oil.
This mixture was separated by further chromatography (hex-
ane/AcOEt, 1:1), and the first fractions afforded 45 as a
colorless oil: [R]25D -23.4 (c 0.82, CHCl3); IR (neat) 3382, 1738,
1612 cm-1; 1H NMR (400 MHz, CDCl3, amide rotamer) δ 1.19