14,16
3-Ketocardiogenin (3-Keto-∆
-dianhydrogitoxigenin, 22). Oxidant was prepared by mixing absolute pyridine
(36 mL) with CHCl (220 mL) that was washed with water to remove alcohol impurities, dehydrated over anhydrous Na SO ,
3
2
4
and distilled azeotropically. The solution was cooled with ice, stirred, and cooled as CrO (25 g) was added. The cold mixture
3
was stirred for 10 min and shaken in a shuttle apparatus for 30 min at room temperature.
14,16
The oxidation was carried out by dissolving cardiogenin (∆
-dianhydrogitoxigenin, 22.4 g) in purified CHCl
3
(70 mL) and pyridine (25 mL). The solution was poured into a reaction flask containing the prepared oxidant. The mixture
was stirred in a shuttle apparatus for 5 h. Additional oxidant was added (CrO , 8 g; CHCl , 30 mL; pyridine, 8 mL). After
3
3
3 h the same amount of oxidant was added. The reaction was continued for 2 h. The oxidation took 10 h.
The solution was separated from the solid by filtration through filter paper. The solid was washed with CHCl . The
3
combined CHCl solution was washed once with water. The water layer was extracted twice with CHCl , which was combined
3
3
with the main solution. The solution was washed four times with H SO (10%) and once with Na CO solution (2%) (until
2
4
2
3
weakly basic), dried over anhydrous Na SO , and concentrated to about 200 mL, removing traces of water.
2
4
The CHCl solution was purified with Al O (30 g) by shaking the suspension for 7 min, filtering, and evaporating
3
2 3
to dryness. The solid (22 g) was dissolved in CH Cl (70 mL), treated with CH OH (200 mL), and concentrated to about
2
2
3
150 mL. The resulting crystals were separated and washd with CH OH (50 mL) to give grayish crystals (17 g).
3
The crude product (17 g) was recrystallized by dissolving in CH OH (600 mL) with heating in a flask with a reflux
3
condenser, adding Al O (level III Brockmann activity), stirring, and vacuum filtering the hot solution through a packed layer
2
3
of kieselguhr. The filtrate was concentrated (without vacuum) to ~50 mL and left overnight.
The crystals were separated, washed with CH OH (30 mL), and dried in air to give 22 (14 g) as white crystals with
3
20
a yellow tint, C H O , mp 198-199°C, [α]
+630.0±5° (c 1.3, CH OH).
3
23 28
3
D
Digitoxigenone. Digitoxigenin (25 g) was oxidized as described above for cardiogenin to give the final product
20
(15 g) as white crystals, C H O , mp 160-162/191-194°C, [α]
+27.6±2° (c 1.0, CH OH).
3
23 32
4
D
Digitoxigenone Benzylimine (6). Digitoxigenone (1.1 g) was dissolved in benzene:2-propanol (15 mL, 9:1) with
heating and placed in a long-necked flask. The solution was treated with benzylamine (C H CH NH , 0.38 g, 1.2-fold of the
6
5
2
2
calculated amount). The mixture was boiled for 2.5 h, slowlyreducing its volume toabout 2 mL and adding benzene three times
(2 mL each), and evaporated in vacuum to dryness. The solid was a glassymass. It was dissolved in CH OH (3 mL) and treated
3
with ice. The resulting solid was ground into a powder, separated on a Buchner funnel, washed with icewater (50 mL), and
dried in vacuum to give the amorphous product (1.36 g).
The amorphous powder (1.36 g) was crystallized by dissolving in CH Cl (3 mL), adding CH OH (15 mL),
2
2
3
concentrating to about 5 mL to remove completely the CH Cl , and crystallizing at room temperature (17 h). The resulting
2
2
20
crystals were separated and washed with CH OH to give the final product (6), C H NO , mp 94-97°C, [α]
D
+38.4±2°
3
30 39
3
(c 1.1, C H OH).
2
5
Cardiogenone Butylimine (9). Cardiogenone (22, 1.1 g) was placed in a long-necked flask, dissolved in benzene
(15 mL), and treated with n-butylamine [CH (CH ) NH , 0.287 g, 1.2-fold of the calculated amount]. The solution was boiled
3
2 3
2
for 30 min until vapor was no longer given off and dried in vacuum. The solid was dissolved with heating in 2-propanol
(3.5 mL). Crystals formed from the solution at room temperature. These were separated after 17 h, washed with 2-propanol,
and dried.
20
The final product is yellow and crystalline, C H NO , mp 102-105°C, [α]
+568.7±5° (c 1.0, C H OH).
2 5
27 37
2
D
The other digitoxigenone and cardiogenone imines were prepared similarly. The differences were mainly in the
reaction times which, as already noted, were monitored using TLC.
REFERENCES
1.
2.
3.
4.
L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York (1967).
J. C. Collins, Tetrahedron Lett., 30, 3363 (1968).
K.-H. Meger, S. Schutz, and K. Stoepel, Austrian Pat. No. 258486; Fr. Pat. No. 1559563.
L. T. Malaya, I. F. Makarevich, N. V. Kovganko, and Yu. G. Gorb, Cardiac Glycosides [in Russian], Osnova,
Khar′kov (1996).
5.
R. N. Yadan, Phytochemistry, 35, 1375 (1994).
55