I. A1,3-Strain Enabled Retention of Chirality During Bis-Cyclization of ?-Ketoamides: Asymmetric Synthesis and Bioactivity of Salinosporamide A and Derivatives II. Optimization of an Organic Syntheses: Asymmetric Nucleophile-Catalyzed Aldol- Lactonization of Aldehyde Acids

摘要

The potential of human 20S proteasome inhibitors continues to be of interest foranticancer chemotherapy and the recent FDA approval of bortezomib (Velcade)validates the proteasome as a target for cancer chemotherapy. Salinosporamide A, amarine unique bicycle [3.2.0] Beta-lactone-containing natural product, is not only a potentnanomolar inhibitor of the human proteasome but also active against bortezomibresistantmultiple myeloma cells. The racemic and asymmetric syntheses ofsalinosporamide A and derivatives were targeted.In this dissertation, we successfully accomplished the shortest route to date withonly a 9-step total synthesis of (?)-salinosporamide A. The conciseness of this strategyarises from the key bis-cyclization of a Beta-keto tertiary amide, amenable to gram scale,constructs both the Gamma-lactam and the fused-Beta-lactone in one operation with highenantiopurity, which was enabled by A^1,3-strain. Several derivatives were synthesized and their inhibition activity toward chymotripsin-like, caspase-like, and trypsin-like ofthe human 20S proteasome was evaluated.This dissertation also included a successfully optimized Organic Synthesesprocedure for asymmetric synthesis of (1S,5R)-6-oxaspiro[bicyclo[3.2.0]heptane-3,2'-[1,3]dioxolan]-7-one via the nucleophile-catalyzed aldol-lactonization.