Development And Applications Of New Synthetic Methods For The Biologically Active Compounds Containing Isoquinoline And β-Carboline Skeletons

This dissertation has discussed development and applications of some new methodologies for the syntheses of bioactive isoquinolines and β-carbolines. It contains four parts as described below:Part one:Treatment of of N-tosyl-THIQs or N-tosyl-THBCs, which are readily available from Pictet-Spengler reactions, with a base in dimethyl sulfoxide afforded dihydroisoquinolines or dihydro-β-carbolines as intermediates, which were then in situ oxidized by molecular oxygen to furnish isoquinolines or β-carbolines in good to high yields. Both one-pot conversions occurred via tandem β-elimination and aromatization under mild reaction conditions. Some advantages such as good to high yields, simple manipulation, cheapness of all reagents, using air as a clean oxidant, as well as the wide scope of reactions might allow this method to be very useful, especially for large scale preparations. The method described herein would provide a good, practical and general approach to1-substituted or1,3-disubstituted isoquinolines and β-carbolines.Part two:Treatment of N-tosyl-1-aryl-1,2,3,4-tetrahydro-isoquinolines or N-tosyl-1-aryl-1,2,3,4-tetrahydro-β-carbolines, which are readily available from Pictet-Spengler reactions, with a strong base such as NaOH or KOH at70℃in dimethylsulfoxide (DMSO) produced l-aryl-3,4-dihydroisoquinolines or l-aryl-3,4-dihydro-β-carbolines in high yields via mild and regiospecific P-eliminations. The work described herein provide an efficient and practical approach to the syntheses of1-aryl3,4-DHIQs and3,4-DHBCs.Part three:An efficient and general strategy for highly stereoselective synthesis of HR22C16-like mitotic kinesin Eg5inhibitors from both L-and D-tryptophan methyl ester hydrohalides is described. If CIAT process afforded trans-IV-3, the L-tryptophan was used as the starting material; whereas if CIAT process afforded cis-IV-3, the D-tryptophan should be used as the starting material. Both compounds (1R,3S)-trans-IV-3and (1R,3R)-cis-IV-3were efficiently converted into HR22C16-like mitotic kinesin Eg5inhibitors by the same one-pot procedure through tandem reactions.Part four: An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted THBCs to (1S,3R)-trans-1,3-disubstituted THBCs has been developed. The base-catalyzed3-epimerization of1,2.3-trisubstituted THBCs as the key point of this method was fully investigated. Moreover, as an application of this method, tadalafil (Cialis(?)) was efficiently synthesized in73.9%overall yield from less expensive1,-tryptophan methyl ester hydrochloride.