Mechanism of Autoxidation of 5,7-Dihydroxytryptamine : Effect of Fluorine Substitution at Positions 4 and /or 6

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概要

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• Analogs of 5,7-dihydroxytryptamine (5,7-DHT), namely, 4-fluoro-, 6-fluoro-, and 4,6-difluoro-5,7-DHT's (30a-c) were synthesized starting from 4-fluorophenol (7a), 4-fluorobenzyl alcohol (12) and 2,4-difluorophenol (7b), erspectively.Regiospecific hydroxylation and formylation ortho to fluoro groups, both via aryllithium intermediates, were made possible by the blocking effect of tert-butyldimethylsilyloxy functions and allowed the conversion of the starting materials to the key intermediates, namely, 3,5-bis(tert-butyldimethylsilyloxy)-2-fluoro-, 4-fluoro- and 2,4-difluorobenzaldehydes (11a, b and 19,respectively). The latter were converted in one step to the corresponding benzyloxybenzaldehydes, from which indole-2-carboxylates 22a-c were synthesized via azidostyrenes 21a-c, respectively. Decarbonylation of the indole-2-carboxaldehydes(24a-c) produced from 22a-c in two steps gave 2,3-unsubstituted indoles 25a-c, respectively.Introduction of the aminoethyl side chains on C-3 of 25a-c via the corresponding indole-3-acetonitriles, and subsequent debenzylation generated the hydroxytryptamines, which were isolated as their creatinine sulfate salts 30a-c, respectively.Cyclic voltammetric studies indicated that like 5,7-DHT, 30a-c undergo electrochemical oxidation in 1M H_2SO_4 via the corresponding P-quinoneimine derivatives 31a-c by an electrochemical-chemical-electrochemical (ECE) process. The voltammetrically detectable products of the ECE process appear to be the corresponding 5-hydroxytryptamine-4,7-dione (6) derivatives 33a-c. The nature of the interaction of dissolved O_2 with 30a-c at pH 7.4 appears to be strikingly different from that of 5,7-DHT, which undergoes autoxidation at pH 7.4 via the 4-hydroperoxy derivative 4 to the quinone 6. Thus, contrary to expectation and as judged by ultraviolet-visible spectroscopy, 30a undergoes autoxidation via the p-quinoneimine 31a to give the quinone 6 with loss of fluorine ion while 30b gives an unidentified colorless product(s) and 30c does not react with oxygen at pH 7.4.

• 公益社団法人日本薬学会の論文
• 1990-11-25

著者

• 河瀬 雅美

  Department Of Medicinal Chemistry And Pharmaceutical Chemistry School Of Pharmacy The University Of

• SINHABABU Achintya

  Department of Medicinal Chemistry and Pharmaceutical Chemistry, School of Pharmacy, The University o

• BORCHARDT Ronald

  Department of Medicinal Chemistry and Pharmaceutical Chemistry, School of Pharmacy, The University o

• Sinhababu Achintya

  Department Of Medicinal Chemistry And Pharmaceutical Chemistry School Of Pharmacy The University Of

• Borchardt Ronald

  Department Of Medicinal Chemistry And Pharmaceutical Chemistry School Of Pharmacy The University Of

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