Graduation Year
2004
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Chemistry
Major Professor
Kyung Woon Jung, Ph.D.
Committee Member
Edward Turos, Ph.D.
Committee Member
Kirpal S. Bisht, Ph.D.
Committee Member
Julie P. Harmon, Ph.D.
Keywords
γ-lactam, natural product, C-H activation, aldol, proteasome inhibitor
Abstract
Lactacystin is a microbial metabolite isolated by Omura that exhibits neurotrophic activity in neuroblastoma cell lines. Lactacystin and especially its β-lactone analog are the first examples of non-polypeptide small molecules capable of specifically inhibiting the 20S proteasome. Various asymmetric total syntheses of lactacystin and its analogs have been reported. The total synthesis of clasto -lactacystin β-lactone is achieved using L-serine methyl ester as the starting material and the sole source of stereochemical induction. The success of this synthesis hinges on two featured transformations. The first key step involves formation of the γ -lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the α-diazo-α-(phenylsulfonyl)acetamide intermediate. The methodology for this transformation has been developed and applied to the synthesis of highly functionalized stereogenic γ-lactams from natural α-amino acids. Three control elements that govern γ-lactam formation are described. This step is highlighted by the xvi simultaneous creation of two stereogenic centers of the γ-lactam core. The second key step involves the late stage aldol coupling for quaternary carbon formation and installation of the hydroxyisobutyl group. In all previously reported syntheses, this is the very first aspect which is addressed. The stereochemical outcome of this step is directed by the chiral environment of the enolate itself. Various attempts to achieve selectivity are explored and reported. Completion of the synthesis of clasto-lactacystin β-lactone requires 17 steps with an overall yield of 10%. Some general attempts for optimizing the synthetic scheme are discussed as well as the future direction of this research.
Scholar Commons Citation
Flanigan, David L. Jr., "Studies in Rhodium Catalyzed Intramolecular C-H Insertion of Amino Acid Derived α-Diazo-α-(substituted)acetamides and its Application to the Total Synthesis of clasto-Lactacystin β-Lactone" (2004). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/1037
