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(1H, ddd, J ¼ 13.5, 10.2, 3.2 Hz), 1.63–1.79 (3H, m), 1.98 (1H, t,
J ¼ 11.5 Hz), 2.46 (1H, td, J ¼ 11.4, 4.1 Hz), 2.58 (1H, ddd, J ¼ 12.4,
4.6, 2.5 Hz), 2.64 (1H, dd, J ¼ 15.7, 3.0 Hz), 3.00 (1H, ddd, J ¼ 11.3,
5.9, 1.6 Hz), 3.04 (1H, dd, J ¼ 11.8, 4.2 Hz), 3.06–3.10 (1H, m), 3.13
(1H, dd, J ¼ 11.8, 3.2 Hz), 3.34–3.44 (1H, m), 3.84 (6H, s), 6.58 (1H, s),
6.68 (1H, s); 13C NMR (CDCl3) (125 MHz) d 21.7, 24.1, 25.3, 29.1,
39.6, 40.5, 41.6, 51.9, 55.8, 55.9, 60.0, 60.9, 74.5, 107.8, 111.4, 126.3,
129.3, 147.1, 147.4; MS (ESI) (positive ion) m=z 320.2 (M þ H). Anal.
calcd. for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C, 71.33; H,
9.10; N, 4.39.
(ꢀ)-a-Dihydrotetrabenazine [(ꢀ)-2]
Compound (þ)-(4) (17.5 g, 0.025 mol) was suspended in H2O (200 mL),
and concentrated NH4OH (10 mL) was added, followed by CH2Cl2
(200 mL). The mixture was stirred for 15 min, and the layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (200 mL). The
CH2Cl2 layers were combined, dried (Na2SO4), filtered, and evaporated
under vacuum to give a yellow foamy solid (6.72 g). The solid (6.72 g)
was chromatographed on silica gel 60 (275 g) using 2% MeOH=CH2Cl2.
Fractions were collected and checked by TLC (silica gel, EtOAc), and
similar fractions were combined and evaporated under vacuum to give
a pale yellow solid (6.19 g). The solid was triturated with hexanes to give
24:6ꢄ
5.85 g (74%) of (ꢀ)-(2) as an off-white solid: mp 107–108 ꢄC; ½aꢅD ꢀ 59.1ꢄ
(c 1.248, MeOH); TLC single spot, Rf 0.74 [silica gel, CHCl3=MeOH=
concentrated NH4OH (90:9:1)]; chiral HPLC single peak (100%), tR
9.3 min, on system A [Co-injection strategy B: chiral HPLC analysis in
system A: (ꢀ)-2 single peak, tR 9.3 min; (ꢁ)-2 two peaks, tR 9.6 min and
10.5 min; and co-injection (ꢀ)-2 and (ꢁ)-2 two peaks tR 9.5 min (large
peak) and 10.5 min (small peak)]; HPLC single peak (100%), tR 7.5 min,
on a Varian Dynamax C18 column (5 m) (4.6 ꢂ 250 mm) using a gradient
(25% B ! 65% B over 30 min) at 1.0 mL=min with UV detection at
220 nm, with solvent A being 0.1% TFA=H2O and solvent B being
0.1% TFA=CH3CN; 1H NMR (CDCl3) (500 MHz) d 0.92 (3H, d,
J ¼ 6.5 Hz), 0.94 (3H, d, J ¼ 6.5 Hz), 1.06 (1H, ddd, J ¼ 13.6, 9.7,
4.2 Hz), 1.49 (1H, q, J ¼ 11.5 Hz), 1.58 (1H, ddd, J ¼ 13.4, 10.2, 3.3 Hz),
1.64–1.78 (3H, m), 1.97 (1H, t, J ¼ 11.4 Hz), 2.46 (1H, td, J ¼ 11.4,
4.1 Hz), 2.58 (1H, ddd, J ¼ 12.3, 4.5, 2.5 Hz), 2.64 (1H, dd, J ¼ 15.7,
2.8 Hz), 3.00 (1H, ddd, J ¼ 11.3, 5.9, 1.6 Hz), 3.04 (1H, dd, J ¼ 11.8,
4.2 Hz), 3.06–3.10 (1H, m), 3.12 (1H, d, J ¼ 11.6 Hz), 3.35–3.43 (1H, m),
3.84 (6H, s), 6.58 (1H, s), 6.68 (1H, s); 13C NMR (CDCl3) (125 MHz) d
21.7, 24.1, 25.3, 29.1, 39.6, 40.5, 41.6, 51.9, 55.8, 55.9, 60.0, 60.9, 74.5,