Total synthesis of (-)-tetrazomine and biochemical studies

2001 Summer.Includes bibliographical references.The total synthesis of (-)-tetrazomine is presented in which the relative and absolute stereochemistry of the natural product has been determined. The synthesis features a unique iminium cyclization followed by a 1,3-dipolar cylcoaddition. The stereochemistry of advance intermediates were determined by extensive 2D NMR techniques. The asymmetric synthesis of all four stereoisomers of β-hydroxy pipecolic acid has also been described. These stereoisomers were compared to the amino acid isolated from the hydrolysis of tetrazomine to determine the absolute stereochemistry of the amino acid moiety on the natural product. The route used to complete the total synthesis allowed for pipecolic acid analogs to be synthesized in order to study the effect of structure on the biochemical characteristics of these compounds. Along with oxazolidine ring containing analogs, ring opened amino nitrile analogs were also studied

Synthetic and DNA cross-linking studies of bioxalomycinα₂

1999 Fall.Includes bibliographical references.The preparation of a [3 + 2] cycloaddition precursor towards the total synthesis of bioxalomycin α2 is presented. The route contains four key steps. These include a Staudinger reaction that sets the required syn stereochemistry at C-13a and C-13b, a stereoselective Pictet-Spengler reaction, an intramolecular transamidation to open a β-lactam ring, and a regioselective reduction of a diketopiperazine. The cycloaddition product afforded by this route though not amenable to the total synthesis of bioxalomycin α2, may be an entry into analogs of bioxalomycin α2. Evidence for interstrand DNA cross-linking induced by bioxalomycin α2 is outlined. The sequence specificity for the cross-link formation and the alkylated residue of DNA is identified. The requirement of reductive activation of cyanocycline A for DNA cross-linking is presented. The synthesis of quinocarcin analogs, which contain the epi stereochemistry at C-11a, was completed. The analogs were designed to alkylate DNA without any undesired indiscriminate DNA strand scission. When evaluated the analogs demonstrated no evidence of DNA strand scission nor DNA alkylation. From these efforts a new quinocarcin analog, which may have the capacity to alkylate DNA, has been proposed

Studies towards the total synthesis of (-)-lemonomycin

2006 Spring.Includes bibliographical references.An asymmetric synthesis of the tetracyclic core of (-)-lemonomycin is presented. It features an efficient route towards a highly versatile tetrahydroisoquinoline intermediate, in which a diastereoselective Pictet-Spengler reaction has been developed. In addition, a novel oxidation was discovered in the process of an azomethine ylide cyclization for construction of C and D rings of lemonomycin. An investigation into the mechanism of this novel oxidation has been carried out and the results discussed. The tetracyclic enamide from this process represents a highly functionalized and versatile intermediate. Interestingly, the enamide double bond proved very resistant to reduction and this transformation was fully investigated. More recently, with high-pressure hydrogenation equipment, promising leads towards hydrogenation of this enamide have been uncovered