Absolute configuration of glycerol derivatives. 4. Synthesis and pharmacological activity of chiral 2-alkylaminomethylbenzodioxans, competitive .alpha.-adrenergic antagonists

Abstract

The optical isomers of alpha-adrenergic receptor antagonists prosympal (2), piperoxan (3), and dibozane (4) were prepared by methods establishing the absolute configuration of each. (2S)-3(2'-Hydroxyphenoxy)-1,2-propanediol ditosylate (10) was prepared from (2R)-3-tosyloxy-1,2-propanediol acetonide (6). Intramolecular displacement afforded (2S)-tosyloxymethylbenzodioxan [(2R)-11]. Reaction of (2R)-11 with the appropriate amine (diethylamine, piperidine, or piperazine) afforded the 2S isomers of 2, 3, and 12, respectively. Reaction of (2S)-12 with (2R)-11 afforded the SS isomer of 4. Reaction of (2S)-3-benzyloxy-1,2-propanediol ditosylate (14) with catechol (NaOMe) afforded (2R)-benzyloxymethylbenzodioxan (15). Subjecting 15 to hydrogenolysis, tosylation, and displacement with the appropriate amine afforded 2R isomers of 2, 3, and 12. Reaction of (2R)-12 with (2S)-11 afforded (RR)-4. Reaction of (2R)-12 with (2R)-11 afforded meso-4. The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4. meso-4 was as effective as the SS isomer of 4. The results are interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen, and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.

Selectivity of Benzodioxane α-Adrenoceptor Antagonists for α₁-and α₂-Adrenoceptors Determined by Binding Affinity

“…The optical isomers of the a-adreno ceptor antagonist, piperoxan. have been pre pared by Nelson et al [1977], The S isomer was a more effective antagonist of the aadrenergic response of methoxamine-induccd contraction of rabbit aortic strips by 18-fold over the R enantiomer. These results have been explained in terms of a similar conformational distribution of aminoalkyl.…”

Resolution of 2-substituted 1,4-benzodioxanes by entrainment

“…These methods are based on resolution of the respective racemates, catalyzed by enzymes 1,2 or accomplished after conversion into diastereomeric mixtures, 3,4 or on syntheses, which utilize asymmetric catalysts or start from non-racemic precursors belonging to the 'chiral pool', such as glycerol or glycidol derivatives. [5][6][7][8] The most recent examples, reported after 2000, are the palladium-catalyzed asymmetric cyclization of benzene-1,2-diol with allylic biscarbonates, 9 the palladium-catalyzed intramolecular cyclization of non-racemic 1-(2-bromophenyl)glycerol 10 and the enzymatic resolutions of 1,4-benzodioxane-2-carboxylic acid, 11 its ethyl ester 12 and 2-hydroxymethyl-1,4-benzodioxane. 13 In 2003, we developed some efficient resolution methods for 1,4-benzodioxane-2-carboxylic acid with (+)-dehydroabietylamine, giving access to both enantiopure (R)-and (S)-acids.…”

Ab initio and semiempirical conformational and configurational analysis of N-2-(1,4-dioxane)-N’-(4-methylbenzenesulfonyl)-O-(4-methylphenoxy)isourea

“…In recent years, the anomeric effect and the conformational analysis of 1,4-dioxane and its substituted analogs has attracted much attention . The major area of interest has been the pharmaceutical activities of 1,4-dioxane [27][28][29][30][31]. The anomeric effect is well recognized as an important factor in defining the predominant conformational state of many cyclic heteroatom-containing compounds.…”