Hyperforin is the component of the medicinal herb St. John's Wort (Hypericum perforatum) responsible for its antidepressant activity. It works by blocking the reuptake of a variety of neurotransmitters through a unique mechanism of action and may be a critical lead for the treatment of depression and possibly other human diseases. However, the therapeutic potential of hyperforin is severely handicapped by its poor water solubility, facile oxidative degradation, and potent activation of pregnane X receptor, leading to increased expression of many genes involved in xenobiotic metabolism. Access to a wide variety of hyperforin analogs is critical for mitigating these shortcomings while maintaining therapeutic activity. While limited semisynthetic manipulation of isolated hyperforin is feasible, total synthesis is the only possible means of obtaining diverse hyperforin analogs. / Chemistry and Chemical Biology

Gilvocarcin V (GV) and ravidomycin (RMV) exhibit excellent antitumor activities in the presence of near-UV light at low concentration maintaining a low in vivo cytotoxicity. Although, the exact molecular mechanism for in vivo actions of these antibiotics has yet to be determined, a [2+2] cycloaddition reaction of the vinyl side chain with DNA thymidine residues in addition to the inhibition of topoisomerase II and DNAhistone H3 cross-linking are reported for the GV’s mechanism of action. Such activities have made these molecules interesting candidates for the biosynthetic investigation to generate analogues with improved activity/solubility. Previous biosynthetic studies have suggested that the GV biosynthetic pathway involves a number of synchronously occurring transformations leading to the oxidative C-C bond cleavage and other intriguing biosynthetic reactions, such as the vinyl side chain formation, methylations, Cglycosylation and dehydrogenation. Although gene inactivation results identified many candidate genes whose corresponding enzymes are involved in these biochemical transformations, their exact functional roles and the identity of their natural substrates remained elusive. To provide more insights into these complex biochemical tranfrormations, three specific aims were set up. Specific aim 1 was to clone and characterize the RMV biosynthetic gene cluster. Through the comparison of GV cluster with the RMV cluster, the genes encoding the biosynthesis of sugar and tetracyclic aromatic moieties were identified. RavGT, the sole glycosyltransferase of the RMV cluster has demonstrated to have unprecedented sugar donor substrate flexibility, transferring an amino-pyranose sugar as well as a neutral furanose sugar. Specific aim 2 was to characterize all of the TDP-D-ravidosamine biosynthetic enzymes. The aim also included to a one-pot enzymatic synthetic protocol for the routine production of TDP-D-ravidosamine. Specific aim 3 focussed on a total enzymatic synthesis of defucogilvocarcin M (defucoGM), the polyketide-derived core of GV and RMV. This aim clearly identified the minimal enzymes required to biosynthesize the complex architecture of defucoGM from the simple building blocks acetate and malonate. In addition, the GV-pathway enzyme GilR was fully characterized. Through in vitro studies, GilR was shown to catalyze the dehydrogenation of hemiacetal moiety of the penultimate intermediate pregilvocarcin V to the lactone moiety of GV at the last step.

Despite over a century of advancement, tuberculosis remains a grave threat to world health. In particular, third world countries continue to struggle with the crushing weight of the disease. Furthermore, the emergence of drug resistance in TB strains poses a significant threat to the first world where incidence and mortality is low. The dwindling efficacy of current drug regimens necessitates research into new small molecules capable of arresting the growth and spread of TB. The capuramycin family of nucleoside antibiotics shows strong potential to become part of this new generation of anti-TB small molecules. Indeed, their ability to inhibit Translocase I, a key enzyme in the biosynthesis of bacterial cell walls, makes them exciting targets for medicinal chemistry efforts. The synthesis of the family focused on dividing the molecules into three congruent, synthetically separate parts: the variable amide linked tail, the hexauronic acid linker, and the uridine "head". Construction of the ubiquitous core structure comprised of the hexauronic acid and uridine would allow rapid diversification while the variable tail would allow SAR studies and development of novel new members of the family.

This is a thesis in two parts. Part A examines two potential routes towards the synthesis of the communesin family of alkaloids, as well as an overview of some of the successful synthetic routes to date. Our first proposed route involves the gold catalyzed isomerization of an o-amino aryallene to a vinyl imine and subsequent (formal) cycloaddition with an indole. This would have allowed quick access to the pentacyclic core of the communesins; however, the unexpected 5-endo-dig product was exclusively obtained in good to excellent yields. The second route involves the use of a Meerwein- Eschenmoser Claisen rearrangement. This route was successful in affording the C, D, E and F rings of the communesin alkaloids, however future work is required for completion of the synthesis. Also discussed in these sections is an alternative endgame approach involving a novel Pictet-Spangler reaction to afford the G ring, and the possibility of an asymmetric variation to the proposed route. Part B examines the use of alkyl aluminum sesquichlorides in the catalysis of Diels-Alder cycloadditions of sterically hindered systems, a current obstacle in organic chemistry. Previously developed methods are discussed and preliminary results are presented. Ethyl aluminum sesquichloride is compared to other alkyl aluminum catalyst, and the effects of temperature, catalysts loading, choice of solvent, the use of additives, and the use of chiral oxazolidinones are reported and what these result can tell us about the mechanism of catalysis are discussed.

Neovibsanin A and B are natural products which induced neurite outgrowth in PC12 cells. They belong in the neovibsane class under the rare vibsane natural product family, whose structures are characterized by polycyclic, polyoxygenated cores. Based on a proposed biosynthesis, the synthetic strategy towards neovibsanin A and B involved synthesizing a key enone intermediate. Initial investigation using this intermediate lead to the total synthesis of 2-O-methylneovibsanin H. Crucial to this concise synthesis was an acid-catalyzed, one-pot, four-step cascade reaction. Modifying the reaction condition leads to a different five-step cascade pathway, resulting in the total synthesis of 4,5-bis-epi-neovibsanin A and B. The synthetic trials and tribulations encountered on the road to these final compounds are explored. It is envisaged that other related neovibsane natural products may arise based on this synthetic sequence. 4,5-Bis-epi-neovibsanin A and B, as well as several other structural analogues collected during the synthesis, were biologically assayed using NGF-stimulated PC12 cells. All compounds induced a significant proportion of neurons to extend neurite processes compared to control cultures. The structure-activity relationship studies indicated that the tricyclic core, as well as the 3,3-dimethylacroyl enol ester side chain, may be responsible for promoting a biological response.

No description available.

Neovibsanin A and B are natural products which induced neurite outgrowth in PC12 cells. They belong in the neovibsane class under the rare vibsane natural product family, whose structures are characterized by polycyclic, polyoxygenated cores. Based on a proposed biosynthesis, the synthetic strategy towards neovibsanin A and B involved synthesizing a key enone intermediate. Initial investigation using this intermediate lead to the total synthesis of 2-O-methylneovibsanin H. Crucial to this concise synthesis was an acid-catalyzed, one-pot, four-step cascade reaction. Modifying the reaction condition leads to a different five-step cascade pathway, resulting in the total synthesis of 4,5-bis-epi-neovibsanin A and B. The synthetic trials and tribulations encountered on the road to these final compounds are explored. It is envisaged that other related neovibsane natural products may arise based on this synthetic sequence. 4,5-Bis-epi-neovibsanin A and B, as well as several other structural analogues collected during the synthesis, were biologically assayed using NGF-stimulated PC12 cells. All compounds induced a significant proportion of neurons to extend neurite processes compared to control cultures. The structure-activity relationship studies indicated that the tricyclic core, as well as the 3,3-dimethylacroyl enol ester side chain, may be responsible for promoting a biological response.

No description available.

Neovibsanin A and B are natural products which induced neurite outgrowth in PC12 cells. They belong in the neovibsane class under the rare vibsane natural product family, whose structures are characterized by polycyclic, polyoxygenated cores. Based on a proposed biosynthesis, the synthetic strategy towards neovibsanin A and B involved synthesizing a key enone intermediate. Initial investigation using this intermediate lead to the total synthesis of 2-O-methylneovibsanin H. Crucial to this concise synthesis was an acid-catalyzed, one-pot, four-step cascade reaction. Modifying the reaction condition leads to a different five-step cascade pathway, resulting in the total synthesis of 4,5-bis-epi-neovibsanin A and B. The synthetic trials and tribulations encountered on the road to these final compounds are explored. It is envisaged that other related neovibsane natural products may arise based on this synthetic sequence. 4,5-Bis-epi-neovibsanin A and B, as well as several other structural analogues collected during the synthesis, were biologically assayed using NGF-stimulated PC12 cells. All compounds induced a significant proportion of neurons to extend neurite processes compared to control cultures. The structure-activity relationship studies indicated that the tricyclic core, as well as the 3,3-dimethylacroyl enol ester side chain, may be responsible for promoting a biological response.

Neovibsanin A and B are natural products which induced neurite outgrowth in PC12 cells. They belong in the neovibsane class under the rare vibsane natural product family, whose structures are characterized by polycyclic, polyoxygenated cores. Based on a proposed biosynthesis, the synthetic strategy towards neovibsanin A and B involved synthesizing a key enone intermediate. Initial investigation using this intermediate lead to the total synthesis of 2-O-methylneovibsanin H. Crucial to this concise synthesis was an acid-catalyzed, one-pot, four-step cascade reaction. Modifying the reaction condition leads to a different five-step cascade pathway, resulting in the total synthesis of 4,5-bis-epi-neovibsanin A and B. The synthetic trials and tribulations encountered on the road to these final compounds are explored. It is envisaged that other related neovibsane natural products may arise based on this synthetic sequence. 4,5-Bis-epi-neovibsanin A and B, as well as several other structural analogues collected during the synthesis, were biologically assayed using NGF-stimulated PC12 cells. All compounds induced a significant proportion of neurons to extend neurite processes compared to control cultures. The structure-activity relationship studies indicated that the tricyclic core, as well as the 3,3-dimethylacroyl enol ester side chain, may be responsible for promoting a biological response.