No description available.

A major goal of the Leighton group is the synthesis of biologically relevant polyketide natural products. Among the most potent and chemically intriguing member of this class is spongistatin 1. This molecule has interested biologists and chemists for more than two decades. In this thesis, we report a highly practical and efficient synthesis of the EF fragment of spongistatin 1. This relied on the rapid introduction of a complex stereochemical array using double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to quickly build the F-ring of spongistatin. The six contiguous stereocenters of the F-ring were established in just five steps. A new one-pot asymmetric strained-silane mediated allylation was developed that was greatly improved over previous methods in regards to practicality and substrate scope. This methodology was used to introduce the sensitive chlorodiene side chain. Finally, completion of the EF fragment led to the synthesis of a spongistatin 1 analog, using our previously developed redesigned ABCD fragment.

The title compound was synthesized and its chemistry studied for the first time. It reacts with carbon electrophiles initially at its $ epsilon$-position. The condensation with aliphatic imidazolides or similar acylating agents furnished methyl 6-alkyl-2,4-dihydroxy benzoates in a 5C + 1C fashion. Reaction with aromatic imidazolides, also in a 5C + 1C manner, gave unsymmetrical biphenyls with the 2-carbomethoxy-3,5-dihydroxyphenyl moiety. A regiocontrolled synthesis of naphthalene derivatives was developed by reaction with the appropriate 1,3,5-tris-electrophiles in a 5C + 5C fashion.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2007. / Title from title screen (site viewed Feb. 20, 2008). PDF text: VI, iii, 335 p. : ill. ; 15 Mb. UMI publication number: AAT 3274813. Includes bibliographical references. Also available in microfilm and microfiche formats.

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Includes bibliographical references. Also available online.

Thesis (M. S.)--University of North Carolina at Greensboro, 2006. / Title from PDF title page screen. Advisor: Jason J. Reddick ; submitted to the Dept. of Chemistry. Includes bibliographical references ( p. 71-77)

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 229-247).

Thesis (M.S.)--University of North Carolina at Greensboro, 2007. / Title from PDF title page screen. Advisor: Jason J. Reddick; submitted to the Dept. of Chemistry. Includes bibliographical references (p. 87-91).

No description available.

Phoslactomycins (PLMs) are a group of natural products belonging to a polyketides class. These polyketides are synthesized by sequential reaction catalyzed by a collection of enzymes activities called polyketide synthases. A polyketide is a large class of diverse compounds that are characterized by more than two carbonyl groups connected by single intervening carbon atoms. In other words, a polyketide is a polymer whose monomer is a ketide. The PLMs are also known as phosphazomycins or phospholines. These compounds were isolated based on antifungal and antitumor activities. This array of promising biological activities has stimulated research into the field of PLMs for treatment of various diseases such as aspergillosis. A significant success has been reported in understanding and manipulating PLM biosynthesis. However, its post-polyketide biosynthetic mechanism remains to be elucidated. In this study, we established steps needed to pave the way for the elucidation of the post-polyketide synthase tailoring steps in the phoslactomycin biosynthetic pathway. Various, biological activities of polyketide natural products are often linked with specific structural motifs, biosynthetically introduced after construction of the polyketide core. Therefore, investigation of such "post-polyketide synthase (PKS)" modifications is important, and the accumulated knowledge on these processes can be applied for combinatorial biosynthesis to generate new polyketide derivatives with enhanced biological activity. In this study, the enzymes and genes responsible for the modification of the phoslactomycin moiety have been investigated to verify their functions and to study how they are coordinated to achieve the desired phoslactomycin. The proposed modification steps in the PLM biosynthesis pathway involves, PlmT4 a cytochrome P450 monooxygenase, PlmT5, a kinase, and PlmT8 an oxidoreductase. These enzymes were successfully cloned, overexpressed, and purified from an overexpression vector. Mutant strains for two genes plmT4 and plmT8 were either constructed or studied. The function of PlmT4 tailoring enzyme was characterized, by gene disruption and an in vitro enzyme activity assay. The isolation of PLM 1 an intermediate analog from plmT4 mutant strain and the observation of a malonylated PLMs, suggests that the malonyl side chain is introduced during polyketide chain formation These results, will pave the way to delineate the intermediary steps between the PLM PKS product(s) that is released from the PLM PKS and the formation of the final phoslactomycin.