1798 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Cabedo et al.
ylsilylethoxy)amine (7a ; 1.3 g, 71%): [R]D -16.6° (c 0.6, EtOH);
IR (film) νmax 3385, 2954, 2929, 2856, 1690, 1471, 1256, 1089,
compound 10a (60%): LSIMS m/z 522 [MH]+, 386 [MH -
OCOCH2Ph]+; EIMS m/z (%) 521 [M]+ (5), 385 (62), 268 (20),
238 (54), 148 (100), 136 (49), 91 (79).
1
837, 777, 700 cm-1; H NMR* (300 MHz, CDCl3) δ 7.40-7.23
(m, 5H), 4.07 (dd, J ) 8.4, 3.9 Hz, 1H, CHPh), 3.72 (dd, J )
9.6, 3.9 Hz, 1H, CH2O), 3.52 (dd, J ) 9.6, 8.4 Hz, 1H, CH2O),
1.85 (br s, exchange with D2O), 0.90 (s, 9H), 0.04 (s, 6H); 13C
NMR* (75 MHz, CDCl3) δ 142.6, 128.2, 127.2, 126.9, 69.5
(CH2O), 57.6 (CHPh), 25.9, 18.2, -5.5; LSIMS m/z 252 [MH]+,
235 [M - NH2]+, 194 [M - t-BDMS]+. *The assignments were
made by COSY 45, DEPT, and HMQC.
(1S)-1-Ben zyl-(R)-N-(1-p h en yl-2-p h en yla cetyleth oxy)-
6,7-m eth ylen ed ioxy-1,2,3,4-tetr a h yd r oisoqu in olin e, 12a ,
a n d (1R,R)-Ep im er . A mixture of amide 10a (200 mg, 0.38
mmol) as inseparable cis and trans rotamers, and POCl3 (1.5
mL, 16.1 mmol) in dry CH2Cl2 (4.0 mL) was refluxed overnight
with stirring. Excess reagent and solvent were removed in
vacuo to give yellow residue of iminium 11a (LC-MSD, API-
electrospray positive: m/z 386 [M - COCH2Ph]+; LISMS m/z
504 [M]+). This compound was used for the following reaction
without purification.
A solution of this chiral isoquinolinium salt (11a ) in dry
MeOH (15 mL) was reduced by means of NaBH4 (420 mg, 11.1
mmol) at -78 °C and in stirring for 2 h. Excess NaBH4 was
decomposed with 5% aq HCl solution. The mixture was
concentrated, made basic with 5% aq NH4OH solution, ex-
tracted with CH2Cl2, washed with brine, water, dried and the
solvent was evaporated off to dryness. The crude was purified
by silica gel 60H column chromatography (hexane/AcOEt 9.2:
0.8) to attain 159 mg of (1S,R)-12a (83%) and 8 mg of (1R,R)-
epimer (4.2%).
The crude of 3,4-methylenedioxyphenylacetyl chloride (5)
obtained as described above from 0.5 g of 4 (2.78 mmol) in dry
CH2Cl2 (10 mL) was added dropwise to a solution of (R)-N-(1-
phenyl-2-tert-butyldimethylsilylethoxy)amine (7a ; 680 mg, 2.71
mmol), 4-DMAP (50 mg, 0.41 mmol) and Et3N (0.4 mL, 2.88
mmol) in dry CH2Cl2 (10 mL) under N2 atmosphere and in a
cooling ice bath. After stirring at room temperature for 1 h,
5% aq HCl (15 mL) solution was added and extracted with
CH2Cl2. The organic layer was washed with 5% aq NaHCO3
solution, brine, water, dried and the solvent was removed
under reduced pressure to give 1.03 g of compound 8a (92%):
[R]D - 8.2° (c 0.6, EtOH); IR (film) νmax 3289, 2953, 2857, 1645
(CO), 1546, 1503, 1444, 1247, 1119, 1041, 837, 779, 700 cm-1
;
1H NMR* (300 MHz, CDCl3) δ 7.30-7.13 (m, 5H), 6.79 (d, J )
7.8 Hz, 1H), 6.75 (d, J ) 1.7 Hz, 1H), 6.71 (dd, J ) 7.8, 1.7
Hz, 1H), 6.33 (d, J ) 7.5 Hz, 1H, NHCO), 5.95 (s, 2H), 4.97
(m, 1H, CHPh), 3.78 (dd, J ) 10.0, 4.0 Hz, 1H, CH2O), 3.65
(dd, J ) 10.0, 3.8 Hz, 1H, CH2O), 3.51 (s, 2H), 0.74 (s,
9H), -0.15 (s, 3H), -0.26 (s, 3H); 13C NMR* (75 MHz, CDCl3)
(1S,R)-12a : [R]D +32° (c 0.4, EtOH); IR (film) νmax 2920,
1729 (CO), 1496, 1378, 1261, 1226, 1149, 1043, 925, 850 cm-1
;
1H NMR* (300 MHz, CDCl3) δ 7.25-6.94 (m, 13H), 6.79 (d, J
) 8.4 Hz, 2H), 6.52 (s, 1H, H-5), 6.11 (s, 1H, H-8), 5.81 (s, 2H,
OCH2O), 4.39 (dd, J ) 11.2, 5.6 Hz, 1H, CH2O), 4.21 (dd, J )
11.2, 5.6 Hz, 1H, CH2O), 3.84 (t, J ) 5.6 Hz, 1H, CHPh), 3.59
(dd, J ) 8.7, 5.4 Hz, 1H, H-1), 3.44 (m, 2H, OCOCH2Ph), 3.38
(m, 1H, H-3a), 3.11 (dd, J ) 14.4, 5.4 Hz, 1H, H-3b), 2.98 (dd,
J ) 13.6, 8.7 Hz, 1H, H-R1), 2.86 (m, 1H, H-4a), 2.68 (dd, J )
13.6, 5.4 Hz, 1H, H-R2), 2.32 (dd, J ) 17.1, 3.3 Hz, 1H, H-4b);
13C NMR* (100 MHz, CDCl3) δ 171.2 (CO), 145.8 and 145.3
(C-6 and C-7), 140.3-125.8 (CH, C), 108.5 (C-5), 107.9 (C-8),
100.4 (OCH2O), 67.1 (CH2O), 62.3 (CHPh), 61.1 (C-1), 43.2
(C-R), 41.3 (OCOCH2Ph), 39.6 (C-3), 23.6 (C-4); LSIMS m/z 506
[MH]+, 414 [M - CH2Ph]+. *The assignments were made by
COSY 45, DEPT, NOESY and HMQC.
δ
170.4 (CO), 148.2, 147.0, 140.2, 128.4, 128.2, 127.2,
126.6, 122.7, 109.8, 108.8, 101.1, 66.0 (CH2O), 54.2 (CHPh),
43.5, 25.6, 17.9, -5.9; EIMS m/z (%) 413 [M]+ (1.2), 398 (14),
356 [M - tBu]+ (100), 268 (62), 236 (90), 177 (71), 135 (88),
106 (94). *The assignments were made by COSY 45, DEPT
and HMQC.
(R)-N-[2-(3,4-Met h ylen ed ioxyp h en yl)et h yl]-1-p h en yl-
eth a n ola m in e, 9a . (R)-N-(1-Phenyl-2-tert-butyldimethylsi-
lylethoxy)-2-(3,4-methylenedioxyphenyl)acetamide (8a ; 0.5 g,
1.21 mmol) in anhydrous THF (25 mL) was reduced by BF3-
etherate (ca. 47%, 0.3 mL, 1.14 mmol) and 1 M BH3-THF
solution (4.0 mL, 4.0 mmol) carefully added dropwise, at room
temperature and then, the mixture was refluxed for 2.5 h,
under N2 atmosphere. Excess reagent was destroyed with 5
N aq HCl solution. The organic solvent was evaporated off and
the aqueous solution was made basic with 15% aq NH4OH,
then extracted with AcOEt. The combined organic phases were
washed with brine, water, dried over Na2SO4 and concentrated
to dryness. Compound 9a , (310 mg, 90%) was obtained as a
white solid: [R]D -55.9° (c 0.8, EtOH); IR (film) νmax 3300,
2923, 1608, 1502, 1443, 1366, 1246, 1191, 1039, 938, 891, 809,
(1R,R)-Ep im er : [R]D -46° (c 0.3, EtOH); IR (film) νmax
2921, 1735 (CO), 1482, 1379, 1228, 1152, 1049 cm-1; 1H NMR*
(400 MHz, CDCl3) δ 7.31-7.05 (m, 15H), 6.53 (s, 1H, H-5), 6.29
(s, 1H, H-8), 5.88 and 5.86 (2d, J ) 1.4 Hz, 2H, OCH2O), 4.12-
4.02 (m, 3H, H-1 and CH2O), 3.90 (t, J ) 5.4 Hz, 1H, CHPh),
3.38 (s, 2H, OCOCH2Ph), 3.16 (m, 1H, H-3a), 3.05 (dd, J )
13.6, 8.4 Hz, 1H, H-R1), 2.86 (dd, J ) 13.6, 5.2 Hz, 1H, H-R2),
2.70 (m, 2H, H-4a and H-3b), 2.25 (m, 1H, H-4b); 13C NMR*
(75 MHz, CDCl3) δ 171.1 (CO), 146.0 and 145.4 (C-6 and
C-7), 140.1-126.0 (CH, C), 108.5 (C-5), 107.8 (C-8), 100.5
(OCH2O), 67.5 (CH2O), 62.6 (CHPh), 60.6 (C-1), 42.7 (C-R), 41.2
(OCOCH2Ph), 40.1 (C-3), 24.3 (C-4); LSIMS m/z 506 [MH]+,
414 [M-CH2Ph]+. *The assignments were made by COSY 45,
DEPT and HMQC.
(1S )-1-Be n zyl-(R )-N -(1-p h e n yl-2-h yd r oxye t h yl)-6,7-
m eth ylen edioxy-1,2,3,4-tetr ah ydr oisoqu in olin e, 13a. Com-
pound (1S,R)-12a (10 mg, 0.02 mmol) was dissolved in 5%
methanol/HCl concentrated (2 mL) and then this solution was
evaporated under reduced pressure. The residue was crystal-
lized from a mixture of CH2Cl2/MeOH affording 7 mg (91%) of
13a ‚HCl: colorless needles; mp 164-166 °C; [R]D +29° (c 0.8,
EtOH); IR (film) νmax 3435, 2918, 1481, 1379, 1227, 1038, 937
cm-1; 1H NMR* (400 MHz, CDCl3) δ 7.35-7.09 (m, 13H), 6.90
(d, J ) 7.2 Hz, 2H), 6.53 (s, 1H, H-5), 6.20 (s, 1H, H-8), 5.86
(s, 2H, OCH2O), 3.78 (m, 2H, CH2OH), 3.72 (dd, J ) 9.4, 5.3
Hz, 1H, H-1), 3.65 (dd, J ) 9.8, 3.0 Hz, 1H, CHPh), 3.55 (td,
J ) 14.0, 4.9 Hz, 1H, H-3a), 3.26 (dd, J ) 14.0, 6 Hz, 1H, H-3b),
3.05 (dd, J ) 13.7, 9.4 Hz, 1H, H-R1), 2.96 (m, 1H, H-4a), 2.80
(dd, J ) 13.7, 5.3 Hz, 1H, H-R2), 2.48 (dd, J ) 16.8, 4.9 Hz,
1H, H-4b); 13C NMR* (100 MHz, CDCl3) δ 145.8 and 145.3 (C-6
and C-7), 140.2-126.2 (CH, C), 108.4 (C-5), 107.5 (C-8), 100.4
(OCH2O), 65.4 (CHPh), 63.5 (CH2OH), 60.1 (C-1), 43.0 (C-R),
40.3 (C-3), 23.9 (C-4); LSIMS m/z 388 [MH]+; EIMS m/z (%)
386 [M - 1]+, 296 [M - CH2Ph]+, 280, 176. *The assignments
were made by COSY 45 and DEPT.
1
760, 702 cm-1; H NMR* (400 MHz, CDCl3) δ 7.35-7.20 (m,
5H), 6.71 (d, J ) 8.0 Hz, 1H), 6.62 (d, J ) 1.2 Hz, 1H), 6.59
(dd, J ) 8.0, 1.2 Hz, 1H), 5.91 (s, 2H), 3.78 (dd, J ) 8.4, 4.4
Hz, 1H, CHPh), 3.69 (dd, J ) 10.5, 4.4 Hz, 1H, CH2O), 3.53
(dd, J ) 10.5, 8.4 Hz, 1H, CH2O), 2.80-2.66 (m, 4H), 2.21 (br
s, exchange with D2O); 13C NMR* (100 MHz, CDCl3) δ 147.6,
145.8, 140.3, 133.4, 128.6, 127.6, 127.1, 121.4, 109.0, 108.1,
100.7, 66.5 (CH2O), 64.5 (CHPh), 48.5, 36.0; LSIMS m/z 286
[MH]+; EIMS m/z (%) 254 [M - CH2OH]+ (93), 150 (100), 135
(72), 121 (95). *The assignments were made by COSY 45,
DEPT and HMQC.
(R)-N-(1-P h en yl-2-p h en yla cetyleth oxy)-N-[2-(3,4-m eth -
ylen ed ioxyp h en yl)eth yl]-2-p h en yla ceta m id e, 10a . Com-
mercially available phenylacetyl chloride (0.53 mL, 4.0 mmol)
in dry CH2Cl2 (20 mL) was added dropwise to a solution of
(R)-N-[2-(3,4-methylenedioxyphenyl)ethyl]-1-phenylethanol-
amine (9a ; 560 mg, 1.96 mmol), 4-DMAP (60 mg, 0.49 mmol)
and Et3N (0.6 mL, 4.31 mmol) in dry CH2Cl2 (20 mL) under
N2 atmosphere, in an ice bath, then stirred at room temper-
ature for 2.5 h. The mixture reaction was washed with 5% aq
HCl and 5% aq NaHCO3 solutions, brine, water, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by silica gel 60H column chromatography (toluene/
CH2Cl2/AcOEt 7.2:2.2:0.6) to afford 613 mg of a colorless oily