A Flexible Approach to Nuphar Alkaloids
1
solution of 1.06 M lithium hexamethyldisilazane in THF
(LiHMDS, 8.7 mL, 8.7 mmol) precooled to -78 °C under a
nitrogen atmosphere. After 2 h, iodomethane (0.3 mL, 4.8
mmol) was added slowly to the reaction mixture, which was
warmed to rt, and stirring was continued for a further 15 h.
The mixture was quenched by the addition of 3 N HCl to pH
≈ 3, and then extracted with EtOAc. The combined organic
layers were dried over MgSO4 and evaporated under reduced
pressure to give an oily residue. Purification by column
chromatography (2:1 petroleum ether/EtOAc) gave 12 as a
colorless solid (1.17 g, 89%). Mp 73.5-75.5 °C. [R]25D -24 (c )
Cl2). H NMR (250 MHz, CDCl3): δ 1.00 (3H, d, J ) 7.0 Hz),
1.41-1.55 (1H, m), 2.14 (1H, d, J ) 4.5 Hz), 2.46 (3H, s), 2.61
(1H, d, J ) 7.0 Hz), 2.65-2.74 (1H, m), 3.50-3.58 (2H, m),
7.34 (2H, d, J ) 8.0 Hz), 7.84 (2H, d, J ) 8.0 Hz). 13C NMR
(62.9 MHz, CDCl3): δ 13.8, 21.6, 32.9, 37.6, 42.1, 65.9, 128.0,
129.7, 134.5, 144.8. FTIR (CH2Cl2): 3417 (br), 2964 (m), 2935
(m), 1736 (s), 1495 (s), 1220 (s), 1161 (s), 1061 (s) cm-1
.
HRMS: m/z calcd for C12H18NSO3 256.1007, found 256.0995.
2(S)-[2-(tert-Butyldimethylsilanyloxy)-1(S)-methyleth-
yl]-N-(p-toluenesulfonyl)aziridine (17). tert-Butyldimeth-
ylsilyl chloride (0.33 g, 2.2 mmol) and imidazole (0.16 g, 2.3
mmol) were added to a solution of impure aziridine 16 (0.46
g) in dry THF (10 mL) at 0 °C, and the reaction mixture was
stirred for 5 h. The solvent was removed in vacuo and the
residue purified by flash chromatography (silica gel, 8:1
petroleum ether/EtOAc) to give aziridine 17 (0.61 g, 90% over
two steps) as a colorless solid, which was recrystallized from
1
1.0, CH2Cl2). H NMR (250 MHz, CDCl3): δ 1.23 (3H, d, J )
7.5 Hz), 2.38 (3H, s), 3.11 (1H, dq, J ) 4.0, 7.5 Hz), 3.45 (3H,
s), 3.62 (3H, s), 4.05 (1H, dd, J ) 4.0, J ) 9.5 Hz), 5.60 (1H, d,
J ) 9.5 Hz), 7.26 (2H, d, J ) 8.0 Hz), 7.70 (2H, d, J ) 8.0 Hz).
13C NMR (62.9 MHz, CDCl3): δ 13.6, 21.5, 42.3, 52.2, 52.6,
57.8, 127.3, 129.5, 137.0, 143.6, 170.4, 173.5. FTIR (CH2Cl2):
3357 (br), 3062 (w), 2956 (m), 1742 (s), 1344 (m), 1166 (s) cm-1
.
petroleum ether. Mp 81.0-82.0 °C. [R]25 -4 (c ) 1.0, CH2-
D
1
Anal. Calcd for C14H19NSO6: C, 51.05; H, 5.81; N, 4.25; S, 9.74.
Found: C, 50.92; H, 5.76; N, 4.20; S, 9.82.
Cl2). H NMR (250 MHz, CDCl3): δ -0.05 (6H, s), 0.84 (9H,
s), 0.89 (3H, d, J ) 6.5 Hz), 1.32-1.42 (1H, m), 2.15 (1H, d, J
) 3.0 Hz), 2.43 (3H, s), 2.55-2.70 (2H, m), 3.21 (1H, dd, J )
6.0 Hz, 9.5 Hz), 3.30 (1H, dd, J ) 4.5 Hz, 9.5 Hz), 7.32 (2H, d,
J ) 8.0 Hz), 7.81 (2H, d, J ) 8.0 Hz). 13C NMR (62.9 MHz,
CDCl3): δ -5.7, 13.5, 18.2, 21.6, 25.8, 32.0, 37.7, 42.3, 65.3,
128.1, 129.6, 135.0, 144.5. FTIR (CH2Cl2): 2957 (m), 2950 (m),
2858 (m), 1472 (m), 1323 (m), 1162 (s) cm-1. HRMS: m/z calcd
for C18H32NSO3Si 370.1872, found 370.1859. Anal. Calcd for
C18H31NSSiO3: C, 58.49; H, 8.45; N, 3.79; S, 8.68. Found: C,
58.52; H, 8.77; N, 3.78; S, 8.76.
(1R,2S)-N-(3-Hydroxy-1-hydroxymethyl-2-methyl-
propyl)-4-methylbenzenesulfonamide (13). A solution of
the diester 12 (710 mg, 2.2 mmol) in THF (10 mL) was added
dropwise via cannula to a solution of lithium aluminum
hydride (164 mg, 4.3 mmol) in THF (15 mL) at 0 °C under a
nitrogen atmosphere, and the resulting solution was stirred
for 16 h at rt. Aqueous HCl solution was added to quench the
reaction and the resulting mixture extracted with ethyl
acetate. The organic layer was dried over MgSO4 and evapo-
rated under reduced pressure to give 13 as a colorless solid
Pd-Catalyzed Cycloaddition Approach to 2(S)-[2-(tert-
butyldimethylsilanyloxy)-1(S)-methylethyl]-5-methylene-
1-(toluene-4-sulfonyl)piperidine (18). Formation of the 0.07
M palladium catalyst batch: A flask was charged with
palladium acetate (20 mg, 0.089 mmol, 1 equiv), 1,3-bis-
(diphenylphosphino)propane (92 mg, 0.22 mmol, 2.5 equiv),
and THF (1.28 mL) to give a yellow solution that was used
directly in the cycloaddition processes. To a solution of aziri-
dine 17 (300 mg, 0.81 mmol, 1 equiv) in THF (8 mL) were
added 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate (227 mg,
1.2 mmol, 1.5 equiv) and an aliquot of 0.07 M palladium
catalyst solution (1.14 mL, 0.08 mmol, 0.1 equiv), and the
reaction mixture was heated at reflux for 16 h. The solvent
was removed in vacuo and the residue purified by flash
chromatography (10:1 petroleum ether/EtOAc).
(575 mg, 98%). Mp 76.0-78.0 °C. [R]25 +7 (c ) 1.0, (CH3)2-
D
1
CO). H NMR (250 MHz, CDCl3): δ 0.86 (3H, d, J ) 7.0 Hz),
1.76-1.93 (1H, m), 2.42 (3H, s), 3.18-3.25 (1H, m), 3.31 (1H,
dd, J ) 4.0, 11.5 Hz), 3.45 (1H, dd, J ) 6.5, 11.0 Hz), 3.56
(1H, dd, J ) 3.0, 11.5 Hz), 3.75 (1H, dd, J ) 3.0, 11.0 Hz),
7.30 (2H, d, J ) 8.0 Hz), 7.77 (2H, d, J ) 8.0 Hz). 13C NMR
(62.9 MHz, CDCl3): δ 14.8, 21.5, 37.3, 58.0, 63.0, 64.0, 127.1,
129.8, 137.5, 143.6. FTIR (CH2Cl2): 3359 (br), 2968 (m), 2935
(m), 1599 (m), 1413 (s), 1332 (s), 1161 (s), 1093 (s) cm-1. HRMS
Calcd for C12H20NSO4: 274.1113. Found: 274.1115.
Toluene-4-sulfonic Acid 2-(1-Benzenesulfonylaziridin-
2-yl)propyl Ester (14). A solution of the diol 13 (220 mg, 0.8
mmol) in THF (2 mL) was cooled to 0 °C and treated with
p-toluenesulfonyl chloride (490 mg, 4.8 mmol) and a catalytic
amount of DMAP. The reaction mixture was stirred for 16 h
at rt and quenched with water and the product extracted with
ethyl acetate. Removal of solvent in vacuo and purification by
Data for 18. [R]25 +24 (c ) 1.4, CH2Cl2). 1H NMR (250
D
MHz, CDCl3): δ 0.06 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 0.95
(3H, d, J ) 6.5 Hz), 1.11-1.30 (1H, m), 1.56-1.70 (1H, m),
1.81-1.93 (1H, m), 2.09-2.26 (2H, m), 2.41 (3H, s), 3.33 (1H,
dd, J ) 8.5, 10.0 Hz), 3.58-3.82 (3H, m), 4.33 (1H, d, J ) 16.0
Hz), 4.64 (1H, br), 4.76 (1H, br), 7.24 (2H, d, J ) 8.0 Hz), 7.69
(2H, d, J ) 8.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ -5.4, 14.1,
18.3, 21.5, 24.8, 26.0, 27.3, 34.8, 47.2, 50.0, 65.6, 110.2, 127.5,
129.4, 138.0, 141.0, 142.8. FTIR (CH2Cl2): 3075 (m), 2957 (s),
2857 (s), 1806 (w), 1734 (s), 1655 (m), 1598 (s), 1472 (s), 1338
(s), 1251 (s), 1160 (s), 1092 (s), 910 (s) cm-1. HRMS: m/z calcd
for C22H38NSO3Si: 424.2341, found 424.2377.
flash chromatography (5:1 petroleum ether/EtOAc) gave 14 as
1
a colorless oil (200 mg, 64%). [R]25 +10 (c ) 1.0, CHCl3). H
D
NMR (250 MHz, CDCl3): δ 0.92 (3H, d, J ) 7.0 Hz), 1.58-
1.71 (1H, m), 2.12 (1H, d, J ) 3.5 Hz), 2.47 (6H, s), 2.53-2.63
(1H, m), 2.58 (1H, d, J ) 4.5 Hz), 3.68 (1H, dd, J ) 6.5, 9.5
Hz), 3.83 (1H, dd, J ) 5.0, 9.5 Hz), 7.35 (4H, d, J ) 8.0 Hz),
7.75 (2H, d, J ) 8.0 Hz), 7.79 (2H, d, J ) 8.0 Hz). 13C NMR
(62.9 MHz, CDCl3): δ 13.6, 21.7 (x2), 32.4, 35.0, 41.9, 71.7,
127.9, 128.0, 129.8, 129.9, 132.8 (×2), 144.9 (×2). FTIR (CH2-
Cl2): 2976 (m), 1598 (m), 1362 (s), 1327 (s), 1178 (s), 1094 (m)
cm-1. HRMS: m/z calcd for C19H24NS2O5 410.1096, found
410.1106.
Data for 19. [R]25 +22 (c ) 0.5, CH2Cl2). 1H NMR (250
D
MHz, CDCl3): δ 0.04 (6H, s), 0.78 (3H, d, J ) 7.0 Hz), 0.90
(9H, s), 1.73-1.87 (1H, m), 1.91 (3H, s), 2.40 (3H, s), 3.41 (1H,
dd, J ) 4.5, 10.5 Hz), 3.49 (1H, app q, J ) 6.0 Hz), 3.72 (1H,
dd, J ) 3.0, 10.5 Hz), 4.07 (2H, d, J ) 6.0 Hz), 5.84 (1H, d, J
) 7.0 Hz), 7.26 (2H, d, J ) 8.0 Hz), 7.72 (2H, d, J ) 8.0 Hz).
13C NMR (62.9 MHz, CDCl3): δ -5.7, -5.6, 14.4, 18.1, 20.7,
21.5, 25.8, 34.9, 56.1, 64.8, 64.9, 118.8, 127.0, 129.5, 138.4,
143.1, 170.8. FTIR (CH2Cl2): 2957 (m), 2931 (m), 1740 (s), 1600
(w), 1472 (m), 1333 (m), 1269 (s), 1094 (s) cm-1. HRMS: m/z
calcd for C20H35NSO5Si 430.2083, found 430.2072.
2(S)-[N-(p-Toluenesulfonyl)aziridin-2(S)-yl]propan-1-
ol (16). Tributylphosphine (0.56 g, 2.7 mmol, 1.5 equiv) was
added to a solution of diol 13 (0.5 g, 1.8 mmol, 1 equiv) in
toluene (12 mL) at rt under a nitrogen atmosphere. The
temperature was lowered to 0 °C and ADDP (0.69 g, 2.7 mmol,
1.5 equiv) added portionwise. The reaction mixture was stirred
for 16 h at rt, and then the solvent was removed in vacuo.
Careful chromatography provided a small sample of analyti-
cally pure 16; generally, however, the crude alcohol was used
Data for 20. [R]25 +10 (c ) 1.8, CH2Cl2). 1H NMR (250
D
directly in the subsequent reaction. [R]25 -30 (c ) 1.7, CH2-
D
MHz, CDCl3): δ 0.00 (3H, s), 0.01 (3H, s), 0.88 (9H, s), 0.95
(3H, d, J ) 6.5 Hz), 1.67 (3H, s), 1.88 (3H, s), 1.95-2.07 (1H,
m), 2.41 (3H, s), 3.26 (1H, dd, J ) 7.5, 10.0 Hz), 3.47 (1H, dd,
J ) 4.0 Hz, 10.0 Hz), 3.77 (2H, s), 3.88 (1H, dt, J ) 4.0, 9.0
(24) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapaport, H.
J. Org. Chem. 1990, 55, 3068.
J. Org. Chem, Vol. 70, No. 1, 2005 211