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
dc.contributor.advisor | Romo, Daniel | |
dc.creator | Nguyen, Henry | |
dc.date.accessioned | 2013-03-14T16:30:10Z | |
dc.date.available | 2013-03-14T16:30:10Z | |
dc.date.created | 2010-12 | |
dc.date.issued | 2010-11-17 | |
dc.date.submitted | December 2010 | |
dc.identifier.uri | https://hdl.handle.net/1969.1/148462 | |
dc.description.abstract | 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. | en |
dc.format.mimetype | application/pdf | |
dc.subject | A1,3 strain | en |
dc.title | 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 | en |
dc.type | Thesis | en |
thesis.degree.department | Chemistry | en |
thesis.degree.discipline | Chemistry | en |
thesis.degree.grantor | Texas A&M University | en |
thesis.degree.name | Doctor of Philosophy | en |
thesis.degree.level | Doctoral | en |
dc.contributor.committeeMember | Singleton, Daniel | |
dc.contributor.committeeMember | Connell, Brian | |
dc.contributor.committeeMember | Garcia, Luis Rene | |
dc.type.material | text | en |
dc.date.updated | 2013-03-14T16:30:10Z |
Files in this item
This item appears in the following Collection(s)
-
Electronic Theses, Dissertations, and Records of Study (2002– )
Texas A&M University Theses, Dissertations, and Records of Study (2002– )