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

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Abstract
The 2-alkylaminobenzodioxans reverse the pressor response to epinephrine and are used clinically as antihypertensive agents. 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. 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 2-fold in 2 and 18-19 fold in 3 and 4. The meso-4 was as effective as the SS isomer of 4. The results were interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.