Degree Granting Department
Jung, Kyung Woon
Î³-lactam, Natural product, C-H activation, Aldol, Proteasome inhibitor
Lactacystin is a microbial metabolite isolated by Omura that exhibits neurotrophic activity in neuroblastoma cell lines. Lactacystin and especially its Î²-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 Î²-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 Î³-lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the Î±-diazo-Î±-(phenylsulfonyl)acetamide intermediate. The methodology for this transformation has been developed and applied to the synthesis of highly functionalized stereogenic Î³-lactams from natural Î±-amino acids. Three control elements that govern Î³-lactam formation are described. This step is highlighted by the simultaneous creation of two stereogenic centers of the Î³-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 Î²-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., "Studies in rhodium catalyzed intramolecular C-H insertion of amino acid derived Î±-diazo-Î²-(substituted)acetamides and its application to the total synthesis of clasto-lactacystin Î²-lactone" (2004). Graduate Theses and Dissertations.