I. R. Baxendale et al. / Tetrahedron 58 (2002) 6285–6304
6301
triethylsilane (85 mg, 0.73 mmol, 1.2 equiv.) and Nafion
SAC-13 (250 mg, 10–20% flourosulfonic acid wt.; Aldrich
Cat. No. 47,454-1) in DCM (5 mL) was heated in a sealed
tube under microwave irradiation at 1208C for 30 min. The
resin was removed by filtration washed with DCM
(3£5 mL) and the solvent evaporated to yield the title
compound 44 (95% conversion). The compound was
identical to that prepared by the previous method.
J¼10.0, 2.1 Hz, H-2), 5.01 (m, 1H, NH), 4.44 (m, 1H, H-3),
3.66 (d, 1H, J¼15.6 Hz, H-8A), 3.61 (dd, 1H, J¼12.0,
4.48 Hz, H-4a), 3.51 (d, 1H, J¼15.6 Hz, H-8B), 3.54 (br. s,
1H, H-6a), 3.04 (br. s, 1H, OH), 2.62 (s, 3H, NMe), 2.35
(ddt, 1H, J¼11.8, 4.9, 0.85 Hz, H-4b), 1.43 (dt, 1H, J¼11.8,
10.4 Hz, H-4a ); 13C NMR (100 MHz, d6-DMSO): d¼170.9
(CO), 146.3/146.0 (C-10/11), 132.5 (C-1), 131.9 (C-Ar),
131.5 (C-2), 130.4 (C-Ar), 108.6 (C-9), 105.8 (C-12), 101.0
(C-15), 64.5 (C-3), 63.4 (C-4a), 62.1 (C-6a), 44.2 (C-12b),
43.7 (C-8), 35.5 (C-4), 27.7 (C-14); HR-MS (ESI, Q-tof)
calcd for C17H19N2O4: 315.1345; found 315.1342. D-form
HR-MS (ESI, Q-tof) calcd for C17H19N2O4: 315.1345;
found 315.1337. D-form [a ]D¼þ421.3 (c¼1.3 in MeOH);
HR-MS (ESI, Q-tof) calcd for C17H19N2O4: 315.1345;
found 315.1337. Rf 2.156 (Method A), Rf 3.40 (Method B).
Crystal structure determination of compound 46 D-form.
Crystals of 46 were obtained by recystallisation from
methanol. Crystal data: C17H18N2O4, M¼314.33, ortho-
4.3.20. Preparation of 3-hydroxy-5-methyl-3,4,4a,5-tetra-
hydro-8H-7-trifluoroacetyl-[1,3]dioxolo[40,50:6,7]iso-
6,7]isoquinolin[3,4-c ]indol-6-one 45. Polymer-supported
borohydride (7.9 g, 19.8 mmol, 1.2 equiv., borohydride on
Amberlite IRA400, ,2.5 mmol/g; Aldrich Cat. No. 32,864-
2) was added to a solution of 42 (6.75 g, 16.5 mmol) in a
mixture of DCM/MeOH (3:1; 50 mL) at 108C (higher
temperature resulted in partial removal of the trifluoro
protecting group). The reaction mixture was shaken and
monitored by LC-MS until the reaction had reached
completion (1.5–2 h). The spent resin was filtered, washed
with DCM/MeOH (3:1; 3£25 mL) and the filtrate evapor-
ated under reduced pressure to give the title compound 45 as
a pale yellow oil (6.72 g, 99%): Rf 2.869 (Method A), Rf
3.42 (Method B). L-form [a]D¼þ347.3 (c¼1.64 in MeOH);
IR: 3366, 2359, 1705, 1486, 1456, 1403, 1247, 1171, 1154,
1039, 934 cm21; 1H NMR (400 MHz, d6-DMSO at 1308C):
d¼6.73 (s, 1H, H-Ar), 6.69 (s, 1H, H-Ar), 5.96 (s, 2H,
CH2O2), 5.92 (d, 1H, J¼10.05 Hz, H-1), 5.46 (dd, 1H,
J¼10.05, 2.05 Hz, H-2), 4.84 (br. s, 1H, H-6a), 4.67 (d, 1H,
J¼16.8 Hz, H-8A), 4.52 (m, 1H, H-3), 4.35 (d, 1H,
J¼16.8 Hz, H-8B), 3.83 (dd, 1H, J¼12.3, 4.65 Hz, H-4a),
2.72 (s, 3H, NMe), 2.48 (m, 1H, H-4A), 1.42 (m, 1H, H-4B);
HR-MS (ESI, Q-tof) calcd for C19H17N2O5F3Na: 433.0987;
found 433.0980. D-form [a]D¼2341.8 (c¼0.55 in MeOH);
HR-MS (ESI, Q-tof) calcd for C19H17N2O5F3Na: 433.0987;
found 433.0999.
˚
rhombic, a¼8.4037(3), b¼11.0952(4), c¼15.9005(5) A,
3
˚
a¼908, b¼908, g¼908, U¼1482.57(9) A , T¼180(2) K,
space group P212121, Z¼4, m¼0.101 mm21, 9418 reflec-
tions collected, 3245 independent reflections (Rint¼0.0379).
The final wR(F 2) was 0.0415. L-Form crystal was confirmed
as the direct reflection.
4.3.22. Preparation of 3-hydroxy-5-methyl-3,4,4a,5-
tetrahydro-8H-[1,3]dioxolo[40,50:6,7]isoquinolin[3,4-
c ]indol-6-one 46. Polymer-supported borohydride (1.22 g,
3.05 mmol, 4 equiv., borohydride on Amberlite IRA 400,
,2.5 mmol/g; Aldrich Cat. No. 32,864-2) was added to a
solution of ketone 42 (1.25 g, 3.05 mmol) in a mixture of
DCM/MeOH (1:1; 30 mL) at 508C. The reaction mixture
was shaken and monitored by LC-MS until the reaction had
reached completion (4 h). The spent resin was filtered,
washed with DCM/MeOH (1:1; 3£25 mL) and the filtrate
evaporated under reduced pressure to give the title
compound 46 as a glassy solid (0.87 g, 91%). The
compound was identical to that prepared by the previous
method (Table 5).
4.3.21. Preparation of 3-hydroxy-5-methyl-3,4,4a,5-
tetrahydro-8H-[1,3]dioxolo[40,50:6,7]isoquinolin[3,4-
c ]indol-6-one 46. A sealed tube containing compound 45
(250 mg, 0.59 mmol) and Ambersep 900 (1 g, OH-form;
Fluka Cat. No. 06476) in MeOH (4 mL) was heated at
1008C under microwave irradiation for 1 h. The resin was
removed by filtration and washed with MeOH (3£10 mL),
the combined organic fractions were evaporated under
reduced pressure to yield 46 as a yellow solid (174 mg,
94%). L-form [a]D¼þ425.7 (c¼1.2 in MeOH); IR: 3333,
4.3.23. Preparation of 3-methoxy-5-methyl-3,4,4a,5-
tetrahydro-8H-[1,3]dioxolo[40,50:6,7]isoquinolin[3,4-
c ]indol-6-one 47. A sealed tube containing compound 44
(250 mg, 0.58 mmol) and Ambersep 900 (1.0 g, OH-form;
Fluka Cat. No. 06476) in MeOH (4 mL) was heated at
1008C under microwave irradiation for 20 min. The resin
was removed by filtration and washed with MeOH
(3£10 mL) the combined organic fractions were evaporated
under reduced pressure to yield 47 as a yellow solid
(186 mg, 96%): Rf 2.380 (Method A); Rf 3.61 (Method B).
L-form [a ]D¼þ231.5 (c¼0.75 in CHCl3); IR: 2903, 2823,
1733, 1684, 1503, 1483, 1386, 1373, 1238, 1100, 1037, 931,
2925, 1678, 1503, 1485, 1242, 1038, 932, 864, 768 cm21
,
1H NMR (400 MHz, CDCl3): d¼6.50 (s, 1H, 12), 6.43 (s,
1H, 9), 5.92 (dt, 1H, J¼10.05, 1.3 Hz, H-1), 5.87 (ap. q, 2H,
J¼1.4 Hz, CH2O2), 5.77 (dd, 1H, J¼10.05, 2.0 Hz, H-2),
4.49 (ddt, 1H, J¼9.9, 4.6, 2.0 Hz, H-3), 3.91 (d, 1H,
J¼15.25 Hz, H-8A), 3.69 (br. s, 1H, H-6a), 3.66 (d, 1H,
J¼15.25 Hz, H-8B), 3.58 (dd, 1H, J¼11.9, 4.6 Hz, H-4a),
2.78 (s, 3H, NMe), 2.46 (ddt, 1H, J¼11.9, 4.7, 1.1 Hz,
H-4b), 1.43 (dt, 1H, J¼11.9, 9.9 Hz, H-4a); 13C NMR
(100 MHz, CDCl3): d¼171.9 (CO), 147.0 (C-Ar), 146.8
(C-Ar), 132.5/131.5 (C-1/2), 130.7 (C-Ar), 129.7 (C-Ar),
108.3 (C-9), 106.3 (C-12), 101.3 (C-15), 65.6 (C-3), 64.7
(C-4a), 62.6 (C-6a), 44.4 (C-8), 43.2 (C-12b), 35.5 (C-4),
1
846 cm21; H NMR (400 MHz, CDCl3): d¼6.49 (s, 1H,
Ar), 6.42 (s, 1H, Ar), 5.95 (dt, 1H, J¼10.1, 1.5 Hz, H-1),
5.88 (s, 2H, H-CH2O2), 5.82 (dd, 1H, J¼10.1, 2.1 Hz, H-2),
4.09 (ddt, 1H, J¼10.25, 4.7, 1.9 Hz, H-3), 3.95 (d, 1H,
J¼15.3 Hz, H-8A), 3.71 (s, 1H, H-6a), 3.65 (d, 1H,
J¼15.3 Hz, H-8B), 3.57 (dd, 1H J¼12.0, 4.7 Hz, H-4a),
3.43 (s, 3H, OMe), 2.77 (s, 3H, NMe), 2.52 (ddt, 1H,
J¼12.0, 4.7, 1.35 Hz, H-4A), 1.38 (dt, 1H, J¼12.0,
10.25 Hz, H-4B); 13C NMR (100 MHz, CDCl3): d¼171.7
(CO), 147.0/146.8 (C-10/11), 133.2 (C-1), 130.9 (C-Ar),
129.9 (C-Ar), 128.5 (C-2), 108.3 (C-9), 106.4 (C-12), 101.3
1
28.4 (C-14); H NMR (400 MHz, d6-DMSO): d¼6.62 (s,
1H, 12), 6.50 (s, 1H, 9), 5.90 (dd, 2H, J¼6.96, 0.76 Hz,
CH2O2), 5.75 (d, 1H, J¼10.0 Hz, H-1), 5.59 (dd, 1H,