The total synthesis of D,L- and meso-isochrysohermidin and DNA binding properties
Abstract
An investigation of the singlet oxygen chemistry of 5-(methoxycarbonyl)pyrrole-2-carboxylic acids as a direct method for the synthesis of the 5-(methoxycarbonyl)-5-hydroxy-3-pyrrolin-2-one, a subunit characteristic to isochrysohermidin is described. The reaction involves an initially formed endoperoxide generated by (4+2) cycloaddition of a pyrrole with singlet oxygen, followed by a mild and regioselective oxidative decarboxylation. This new methodology provided an efficient and direct route to the carbinolamide functionality present in isochrysohermidin, confirming its potential application for the total synthesis. Our study then proceeded to the total synthesis of d,l- and meso-isochrysohermidin, colorless alkaloids first isolated from Mercurialis leiocarpa, possessing a highly functionalized 3,3$\sp\prime$-pyrrolin-2-one dimeric structure. The approach is based on an extension of the scope of the inverse electron demand Diels-Alder reaction of 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine in a sym-tetrazine $\to$ 4,4$\sp\prime$-bi-1,2-diazine $\to$ 3,3$\sp\prime$-bipyrrole strategy for the construction of the carbon backbone of isochrysohermidin. This novel two-step protocol involving a double Diels-Alder reaction followed by a double reductive ring contraction reaction constitutes a new and effective synthesis of 3,3$\sp\prime$-bipyrroles. Subsequent differentiation of the C2/C2$\sp\prime$ and C5/C5$\sp\prime$ methoxycarbonyl groups, by cyclic anhydride protection of the C2/C2$\sp\prime$ esters, provided the key 3,3$\sp\prime$-bipyrrole-2,2$\sp\prime$-dicarboxylic acid. Implementation of our singlet oxygen methodology resulted in the preparation of both d,l -and meso-isochrysohermidin. With the agents in hand, the study moved to an examination of the DNA binding properties of d,l -and meso-isochrysohermidin. Although no biological data was available, the characteristic carbinolamides present in isochrysohermidin suggested the potential for interstrand DNA cross-linking. It was anticipated that the cross-linking event would most likely occur by two sequential reversible carbinolamide exchange reactions with nucleophilic sites within duplex DNA. Isochrysohermidin (d,l -and meso-isomers equivalent) was shown to generate interstrand DNA cross-links with $\Phi$X174 Pst I DNA and $\sp{32}$P singly 5$\sp\prime$-end labeled w794 DNA. Additional studies revealed that isochrysohermidin is able to relax $\Phi$X174 supercoiled DNA. The identification of the cross-linking properties of isochrysohermidin marked a significant contribution as it represented only the fourth class of naturally occurring cross-linking agents.
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry
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