Synthesis And Manipulation Of Carbasugars And Natural Product Scaffolds

My doctoral studies have focused on the construction of natural products and diversification of complex natural product scaffolds. A specific natural product with interesting bioactivity, sch202596, an antagonist for the galinin receptor, contains two moieties that formed the basis for my graduate studies: a carbasugar and a spirocoumaranone (dienone). Work, therefore, focused on two areas: (1) asymmetric regio-resolution of allylic oxides for the synthesis and incorporation of spirocyclization. carbasugars; and (2) asymmetric hypervalent iodide oxidative A system was developed in which a racemic allylic oxide underwent a Tsuji-Trost allylation to yield four different enantioenriched regioisomers which were carried onto four different carbasugar natural products: streptol, MK7607, cyathiformine B and polyporapyranone G. This method, termed allylic oxide regio resolution (AORR), allowed for the control of product distribution through prudent ligand and protecting group selection. Additionally, AORR allowed for the incorporation of carbasugars into phenolic natural product scaffolds. Rubiyunnanin B, a glycosidic macrocyclic peptide with an interesting bioactivity profile was one particular natural product scaffold which could be subjected to AORR. A short synthesis of the rubiyunnanin B aglycone was developed and 1H NMR analysis was used to determine the overall structure of the core. The second area of research resulted in the synthesis of arnottin II through hypervalent iodine mediated oxidative spirocyclization

Synthesis of ( S)-3-Amino-4-(difluoromethylenyl)-cyclopent-1-ene-1-carboxylic Acid (OV329), a Potent Inactivator of γ-Aminobutyric Acid Aminotransferase

( S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329, 1) is being developed for the treatment of epilepsy and addiction. The previous 14-step synthesis of OV329 was low yielding, involved an unselective α-elimination to form the cyclopentene, required the use of tert-butyllithium, and produced toxic selenium byproducts in the penultimate step. A new synthesis, which avoids the aforementioned issues, was carried out on large scale, reducing the step count from 14 to 9 steps and increasing the overall yield from 3.7% to 8.1%

Streamlining SuFEx Inhibitor Development: A Unified Approach Using Orthogonal Sulfinate Protecting Groups

Sulfonyl fluorides have gained significant importance due to their classification as a click reaction and therefore have seen increased use in drug discovery and biochemistry. Their use, however, is complicated by the methods by which they are synthesized and their general synthetic instability. This results in sulfonyl fluorides being introduced late in a synthetic route with minimal structural diversity. Masking the reactivity of a sulfonyl fluoride by protecting the parent sulfinate is one method to ameliorate these issues. This study outlines discovery and selection of sulfinate protecting groups (SPGs) based on their overall stability, ease of synthesis, and simple deprotection conditions. This includes the discovery of two novel, photolabile sulfinate protecting groups (SPGs), para¬-methoxybenzyl Rongalite and ortho-nitrobenzyl Rongalite that can be directly converted to the sulfonyl fluoride using light and selectfluor. Along with known SPG, 2-trimethylsilylethyl sulfone (SES), all three SPGs were found to possess broad stability when exposed to numerous common synthetic conditions and are easily coupled to aryl halides from their sulfinate salt precursor. Overall, having access to a wide range of stable, easily functionalized SPGs will aid in increasing the structural diversity of sulfonyl fluorides

Syntheses of Arnottin I and Arnottin II

Short total syntheses of arnottin I and II were accomplished in 5 and 6 steps, respectively. A sesamol-benzyne cycloaddition with a 3-furyl-benzoate followed by regiospecific lactonization provided rapid, large-scale access to the core of arnottin I. Saponification of arnottin I and hypervalent iodide mediated spirocyclization provided an efficient and direct preparation of racemic arnottin II

Regiodivergent Addition of Phenols to Allylic Oxides

The regiodivergent addition of substituted phenols to allylic oxides has been demonstrated using <i>C</i>₂-symmetric palladium complexes. Complex phenol donors tyrosine, estradiol, and griseofulvin follow the predictive model

From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

Summary: Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat’s oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite’s capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease