Stereoselective Syntheses Of ?-carboline Alkaloids And Biologically Active Compounds

?-Carboline alkaloids are widespread in nature,particularly in plants,animal,bacteria,fungi,and foodstuffs.These compounds are of great interest to medicinal and organic chemists due to diverse biological activities such as anticancer,antioxidant,antiinflammatory,antimicrobial,antiparasitic,antiviral and antihypertensive properties.This dissertation has discussed the total syntheses of ?-carboline alkaloids such as 6-hydroxymetatacarboline D,metatacarboline D,demethoxyfumitremorgin C and hyrtioerectines B.This dissertation has also discussed stereoselective syntheses of biologically active compounds such as PDE5 inhibitor tadalafil and Eg5 inhibitor HR22C16.In addition,we have developed a copper-catalyzed aerobic oxidative aromatization method for synthesis of ?-carboline compounds and a highly stereoselective method for synthesis of cis or trans-1,3-disubstituted-tetrahydro-?-carbolines.This dissertation contains three parts as described below:(1)First total syntheses of ?-carboline alkaloids 6-hydroxymetatacarboline D and metatacarboline D have been performed.6-Hydroxymetatacarboline D was synthesized by 12 steps in 21%overall yield starting from L-5-hydroxytryptophan.Metatacarboline D was synthesized by 9 steps in 22%overall yield starting from L-tryptophan.The key steps are Bischler-Napieralski reaction and the subsequent copper-catalyzed aerobic oxidation of 3,4-dihydro-?-carbolines.We have developed a general practical method for synthesis of ?-carboline compounds.The reaction was carried out under mild conditions using copper salts as catalyst and oxygen as oxidant.The method has some advandages such as practicality,operational security,low cost and high yields.We have prepared 23 ?-carboline compounds using this method.(2)New methods for preparation of tadalafil,HR22C16 and hyrtioerectines B were developed,which are suitable for industrialization.Tadalafil was obtained by 5 steps in 72%overall yield starting from D-tryptophan.HR22C16 was obtained by 5 steps in 78%overall yield starting from L-tryptophan.Hyrtioerectines B was obtained by 4 steps in 55%overall yield starting from L-5-hydroxytryptophan.A highly stereoselective method for synthesis of cis or trans-1,3-disubstituted-tetrahydro-?-carbolines has been developed.The mixture of cis and trans-1,3-disubstituted-tetrahydro-?-carbolines hydrochloride can be converted to single cis or trans isomer via a crystallization-induced asymmetric transformation process in water.The solubility of substrate could be reduced by adding sodium chloride in water.This method has advantages such as environment friendiness,high stereoselectivity,simpleness,being suitable for industrialization,non-toxicity and high availability of raw materials.We have prepared 16 eis-1,3-disubstituted-tetrahydro-?-carbolines and 12 trans isomers by using this method.The relative configuration of products were assigned by 1H-1H NOESY.(3)Starting from L-tryptophan,demethoxyfumitremorgin C was obtained by 5 steps in 42%overall yield.The key step is a Bischler-Napieralski reaction followed by a asymmetric reduction.In comparision with the known routes,this route avoided using Pictet-Spengler reaction to get tetrahydro-?-carboline intermediate,which have poor stereoselectivity and low yield.