1. Studies On Asymmetric Total Synthesis Of (20S)-camptothecin 2. Studies On Synthesis Of 5-(aminomethyl)-2-methylpyrimidin-4-amine

This thesis focuses on the total synthesis of (20S)-camptothecin (CPT, C-1) and the practical synthesis of 5-(aminomethyl)-2-methylpyrimidin-4-amine (GDA,2), the key intermediate of Vitamin B1. The details are summarized below:In chapter 1, the advances in total synthesis of CPT during the past 35 years have been reviewed. These approaches are organized according to synthetic strategies toward the pentacyclic skeleton of CPT.In chapter 2, according to the C ring construction strategy, an asymmetric total synthesis of CPT has been accomplished in an overall yield of 12% starting from the commercially available 2-methoxynicotinic acid. The synthetic sequence involved coupling AB ring fragment to DE ring fragment followed by a final C ring cyclization utilizing an intramolecular Heck reaction. The stereocenter of CPT was established in high stereoselectivity (94% ee) via the Sharpless asymmetric dihydroxylation.In chapter 3, according to the B ring construction strategy, an improved process for the synthesis of the chiral CDE-ring fragment of CPT has been accomplished in an overall yield of 16% starting from 2-(Methoxycarbonyl)-6-cyano-7-methy1-1,5-dioxo-A6(8)-tetrahydroindolizine. The key step in this route is an enantioselective cyanosilylation catalyzed by a bifunctional thiourea-based cinchona alkaloid.In chapter 4, two scalable processes for the synthesis of GDA, the key intermediate of Vitamin B1, were developed. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford 2-((dimethylamino)methylene)malononitrile (44), followed by the condensation with acetamidine hydrochloride to produce the 4-amino-2-methylpyrimidine-5-carbonitrile (19), subsequent hydrogenation gave GDA in 65% overall yield. In the second approach, malononitrile was treated with the ionic salt (54), in situ prepared from DMF and dimethyl sulfate, to give 44, which, without separation, was reacted with acetamidine hydrochloride to afford 19, then, following the first one's procedure, this compound was converted to GDA in 70% overall yield. We achieved 10 kg scale pilot production following these two processes.