Synthesis, resolution, absolute stereochemistry, and enantioselectivity of 3',4'-dihydroxynomifensine

Abstract

3',4'-Dihydroxynomifensine, 8-amino-1,2,3,4-tetrahydro-4-(3,4-dihydroxyphenyl)-2-methylisoquinoli ne (1a), is an agonist of dopamine receptors in central and peripheral systems. Since this dopamine receptor agonist bears an asymmetric center at position 4, its synthesis and resolution were undertaken as part of a study directed toward determining the mode of interaction of these agents with the receptor(s). The enantiomers of 3',4'-dihydroxynomifensine are of particular interest, as they provide additional probes of present conceptual models of the dopamine receptor(s). Initial attempts to prepare 1a were inefficient or unsuccessful; instead, an isomeric compound, 1,2,4,5-tetra-hydro-2-(3,4-dihydroxyphenyl)-4- methyl-3H-1,4-benzodiazepine (9), was obtained. For this reason, a new route to 3',4'-dihydroxynomifensine was employed. The racemic dimethoxy intermediate 1d, thus obtained, was resolved. Methoxyl cleavage of the isomers of 1d afforded the enantiomers of 1a. Enantiomeric excess of these antipodes or appropriate derivatives was examined by NMR, CD, and HPLC methods. CD analysis suggests an enantiomeric excess greater than 99%. Determination of the absolute configuration of the enantiomers of 1a was determined by single-crystal X-ray diffractometric analysis. Examination of the isomers in several pharmacological test systems revealed a high degree of enantioselectivity. D-1 dopaminergic activity resides almost exclusively in the S enantiomer. The findings of the study have been employed to suggest an accessory binding site on the dopamine receptor(s) that differs from that advanced earlier. This accessory binding site may be specific for the D-1 subpopulation of dopamine receptors.

Dopamine D1 receptor ligands: Where are we now and where are we going

“…48,49 There was a hypothesis that the preferred binding of benzazepine analogues to the D 1 receptor might be the consequence of a p-p non-bonded interaction between the C1-aromatic ring and a complementary residue of Phe, Tyr, or Trp on the receptor surface. 50 To probe the validity of such a concept, conformationally constrained benzazepines 8-10 were developed (Fig. 3).…”

Zinc‐Catalyzed Alkyne Oxidation/CH Functionalization: Highly Site‐Selective Synthesis of Versatile Isoquinolones and β‐Carbolines

“…[17, 11c,d] Notably,h ydration products were obtained as the main product under gold catalysis conditions. [19] In addition, the synthesis of the Ca +2 influx and IL-2 production inhibitor 14 a [20] and the natural product bauerine A( 14 b) [21] could be achieved in 31.9 and 28.4 % overall yields (4 steps), respectively,b yazinc-catalyzed oxidative cyclization and diborane reduction in ao ne-pot process,a nd subsequent deprotection and dehydrogenative oxidation. As summarized in Scheme 3, reduction of the cyclization product 2a with B 2 H 6 ,followed by deprotection could furnish 4-phenyl 1,2,3,4tetrahydroisoquinoline (THIQ; 11)w hich displays high affinity to the PCP binding site.…”

Practical Demethylation of Podophyllotoxin and Efficient Preparation of 4-Amino-4-deoxy-4′-demethylepipodophyllotoxin

“…This method has been used only rarely up to now. [19,20] This reagent was used without success when applied to podophyllotoxin 2. The reaction medium rapidly turned dark red and gave only degradation products, aromatization of the C ring, or tars (Table 1, entry 1).…”