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

An iterative protocol is a highly efficient strategy for the generation of large, complex molecules that has been applied in many different subfields of organic synthesis. The use of a tandem or cascade reaction is also an effective approach for the rapid introduction of molecular complexity into a system since the number of steps requiring independent optimization is greatly reduced. With the aim of creating new synthetic strategies to efficiently gain access to stereochemically complex small molecules, we envisioned the use of short iterative protocols to prepare reactive oligomers to which a diverse range of cascade cyclization processes could be applied. In an attempt to minimize reaction optimization and chromatographic purification steps during the development of our small molecule precursors, we first developed an iterative synthesis based on a conjugate addition/reduction sequence that has allowed us to access a diverse series of oligo-vinyl ether intermediates. Significantly, both the addition and reduction steps proceed in near-quantitative yield, and reaction co-products can be removed without column chromatography. At the same time, most of our vinyl ether intermediates are stable to silica gel, and so analytically pure samples can be prepared when desired. Except for when very sterically demanding substrates are employed as electrophiles, the intermediates are isolated as single geometrical isomers. We also developed an improved synthesis of a previously intractable class of alkynoate starting materials (4-aryl-2-butynoates) to ensure a diverse range of easily accessible monomeric building blocks were available for our use. With this effective iterative route in hand, we have several interesting small molecule targets at our disposal. We first applied our iterative route to synthesize oxygen-containing analogues of juvenile hormone III. These mono- and bis-vinyl ethers are currently undergoing biological testing (in collaboration with Dr. Steve Perlman and Dr. Michael Horst), and early results show promise as ecologically degradable insect control agents. We also developed an unprecedented 6-endo/5-exo radical cascade reaction across bis-vinyl ethers which proceeds in good yield, high diastereoselectivity, and excellent regiochemical control. This reaction represents the first cascading radical cyclization ever reported for a bis-vinyl ether system and validates our iterative approach to molecular complexity. / Graduate