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

• Main Author: Nguyen, Henry
• Other Authors: Romo, Daniel
• Format: Others
• Published: 2013
• Subjects: A1,3 strain
• Online Access: http://hdl.handle.net/1969.1/ETD-TAMU-2010-12-9035; http://hdl.handle.net/1969.1/148462

The potential of human 20S proteasome inhibitors continues to be of interest for anticancer chemotherapy and the recent FDA approval of bortezomib (Velcade) validates the proteasome as a target for cancer chemotherapy. Salinosporamide A, a marine unique bicycle [3.2.0] Beta-lactone-containing natural product, is not only a potent nanomolar inhibitor of the human proteasome but also active against bortezomibresistant multiple myeloma cells. The racemic and asymmetric syntheses of salinosporamide A and derivatives were targeted. In this dissertation, we successfully accomplished the shortest route to date with only a 9-step total synthesis of (–)-salinosporamide A. The conciseness of this strategy arises 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 high enantiopurity, which was enabled by A^1,3-strain. Several derivatives were synthesized and their inhibition activity toward chymotripsin-like, caspase-like, and trypsin-like of the human 20S proteasome was evaluated. This dissertation also included a successfully optimized Organic Syntheses procedure 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.