No description available.

No description available.

Two different research projects are described in this dissertation. The first one focuses on microwave-promoted iminyl radical cyclization for the formation of azaheterocycles which are embedded within numerous pharmaceuticals and biologically active natural products (such as clindamycin, eletriptan, moxiflaxin, etc.). We are quite interested in this project because of the significance of nitrogen-containing heterocycles as pharmaceuticals and organocatalysts combined with the need for safe, simple, and economical means of constructing them. We have successfully developed an efficient one-step synthesis of 2-acylpyrroles and diastereoselective dihydropyrroles from readily available oxime ether substrates. This remarkably efficient and environmentally friendly methodology should be useful for rapid and easy preparation of potent drugs containing pyrrolidine ring systems. The second project focuses on the total synthesis of yaku'amide A. The natural compound, isolated from a marine sponge in 2010, is a medium-sized peptide that contains bulky dehydroamino acids. It has an excellent IC50 value (14 ng/mL) against leukemia cells, making it a promising anticancer agent. Because of the unique anticancer profile, potent bioactivity, and limited supply, the natural product was attractive to us for an efficient synthesis and mechanistic investigation. We have devised more efficient strategies compared to Inoue's methods for the synthesis of bulky ∆AAs and their incorporation into peptides, which are innovative and will allow us to synthesize yaku'amide A rapidly and conveniently. A one-pot sequence consisting Martin sulfurane mediated anti dehydration, azide reduction, and O→N acyl transfer was developed for the construction of E- and Z-dehydroisoleucine-containing peptides. We also developed a three-step synthesis of N-terminal acyl group involving a one-pot indium-catalyzed cross-Claisen condensation/reduction from a known compound. The most hindered coupling reaction of pentapeptide acid and nanapeptide amine in the late stage is accomplished. Our total synthesis of yaku'amide A can be completed in 19 longest linear steps and 66 total steps. Further identification of yaku'amide A for elucidation of its biological target and mode of action will be explored, which will open up new avenues in the fight against cancer.

<p>Five-membered rings are readily prepared by <i>5-exo-trig</i> radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of <i>5-exo-dig</i> cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly <i>cis</i>-selective manner. When cyclizations were performed at 17 ^oC, <i>cis</i>/<i>trans</i>-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the <i>trans</i>-diastereomer as the major product (<i>cis</i>/<i>trans </i>= 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 ^oC produced 2,4-disubstituted pyrrolidines substantially enriched in the <i>trans</i>-isomer (<i>cis</i>/<i>trans</i> = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried.</p><p>The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.</p>

Five-membered rings are readily prepared by 5-exo-trig radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of 5-exo-dig cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly cis-selective manner. When cyclizations were performed at 17 oC, cis/trans-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the trans-diastereomer as the major product (cis/trans = 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 oC produced 2,4-disubstituted pyrrolidines substantially enriched in the trans-isomer (cis/trans = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried. The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.

Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements. Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system. From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1. A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity. / Graduate

No description available.

Lyconadin A (1) is a structurally unique Lycopodium alkaloid with antitumor properties, isolated from the club moss Lycopodium complanatum. We are developing a synthetic route to 1 based on a novel 7-exo-trig/6-exo-trig acyl radical cascade cyclization. The synthesis of model acyl radical cascade precursor 23 will be presented. Key features of this synthesis include the suppression of competing elimination during the alkylation of a hindered phenethyl bromide and the use of a lactone as a precursor to a compound bearing two differentially protected primary alcohols. An account of our studies on the model acyl radical cascade cyclization (23 to 24 above) will also be given, including a stereochemical analysis of the product. Our findings have been applied to develop a more detailed stereoselective synthetic plan for Lyconadin A (1).

Lyconadin A is a pentacyclic Lycopodium alkaloid isolated from the club moss Lycopodium companatum with anticancer activity. Our approach sought to incorporate a 7-exo–6-exo acyl radical cyclization cascade to access the bicyclo[5.4.0]undecane framework of lyconadin A. Our studies created methodology for the synthesis of 5-alkyl and 3,5-dialkyl-6-carbomethoxy-2-pyridones and sterically demanding epoxide substrates. These epoxide substrates underwent an unanticipated Payne rearrangement.Cranomycin is a potent antibiotic with antiprotozoal activity. Structurally it is a cyclopentane ring system with substitution at each carbon in the ring. Another interesting structural aspect is the existence of three contiguous quaternary stereocenters including two tertiary alcohols and a tert-alkylamine. Our strategy led to the development of a highly diastereoselective synthesis of vicinal tertiary diol systems. We have successfully synthesized the cyclopentenone system shown above, from which we hope to assemble cranomycin.

No description available.