- Preparation of (R)-11-hydroxyaporphine directly from (R)-10,11- dihydroxyaporphine ((R)-apomorphine)
-
A Regioselective synthesis of (R)-11-hydroxyaporphine 2 directly from (R)-10,11-dihydroxyaporphine ((R)-apomorphine, 1) is described for the first time. The isopropylidene ketal ring of 10,11-(isopropyl-idenyldioxy)aporphine 5 obtained by the isopropylidenation of apomorphine was regioselectively opened by ten equivalents of trimethylaluminum to give (R)-10-hydroxy-11- tert-butyloxyaporphine 6. The free 10-hydroxyl position of 6 was triflated with N-phenyltrifluoromethanesulfonimide and potassium carbonate under reflux to give (R)-10-[(trifluoromethyl)sulfonyloxy]-11-tert-butyloxyaporphine 7. The reduced product, 11-tert-butyloxyaporphine 8 was prepared from 7 by a palladium-catalyzed hydrogenolysis. The ether cleavage of (R)-11-tert- butyloxyaporphine with 48% hydrobromic acid afforded the desired (R)-11- hydroxyaporphine 2 in good yield.
- Kim,Bae,Kim,Choi
-
p. 531 - 533
(2007/10/03)
-
- Aporphines as Antagonists of Dopamine D-1 Receptors
-
The aporphine alkaloids are a class of compounds known to possess activity at both D-1 and-D-2 dopamine receptors. (R)-Apomorphine and (S)-bulbocapnine are examples of compounds which have agonist and antagonist activity, respectively, at D-1 receptors.A series of optically pure aporphines was synthesized and their activiy at D-1 and D-2 dopamine receptors was studied.The (R)-aporphines uniformly had greater affinity for both D-1 and D-2 receptors than their S antipodes.Dihydroxy compound (R)-apomorphine, in accord with previous studies, was found to be a D-1 agonist.Aporhines possesing a single hydroxy group at C-11 are antagonists at the D-1 receptor.The corresponding methoxy compounds are virtually inactive at dopamine receptors.The most potent compounds, (R)-11-hydroxyaporhine (R-14) and (R)-10-bromo-11-hydroxyaporphine (R-26), are more potent than bulbocapnine as D-1 antagonists but are not as selective.A model for binding of aporphines to the D-1 receptor was formulated in which binding interactions between the receptor and the basic nitrogen and the C-11 hydroxy group of the aporphine are required for high-affinity binding to the receptor.The absolute configuration at C-6a determines the orientation of the N-6 lone pair and binding is optimal for the 6aR series.The agonist or antagonist activity of an aporphine is determined by the presence or absence, respectively, of a hydroxy group at C-10.A hydrophobic binding site may be present and may account for the high antagonist activity of (S)-bulbocapnine.
- Schaus, John M.,Titus, Robert D.,Foreman, Mark M.,Mason, Norman R.,Truex, Lewis L.
-
p. 600 - 607
(2007/10/02)
-