University of Vermont

Research Description

Our Research

        Research in our group focuses on the development of new organic reactions and applications of these reactions to the synthesis of complex organic molecules and natural products. The overarching objective of our research is to develop synthetic methods that facilitate the efficient preparation of complex nitrogen-containing heterocyclic compounds from trivial starting materials and to apply these methods to the synthesis of both natural products and non-natural medicinal agents. The following are descriptions of our ongoing research interests.

A Ring Fragmentation Approach to Tethered Aldehyde Ynoates and polycyclic 2,5-dihydropyrroles. 

        We have discovered that cyclic γ-silyloxy-β-hydroxy-α-diazoesters (e.g. 1, Scheme 1) undergo efficient rupture of the Cβ-Cγ bond when treated with Lewis acids to provide tethered aldehyde ynoate products in excellent yield (e.g. 2, Scheme 1). This discovery is important because there are few synthetically-useful ring fragmentation reactions known, and ring fragmentations can unmask latent functional groups under chemoselective reaction conditions to provide functionalized synthetic intermediates that are otherwise difficult to prepare.

Scheme 1

Tethered aldehyde ynoates are versatile synthetic intermediates and this functional group combination is unique to the fragmentation reaction we discovered. We are currently exploring the use of these bi-functional compounds as precursors to structurally complex heterocyclic products. For example, we have noted that the fragmentation products are excellent substrates for intramolecular azomethine ylide 1,3-dipolar cycloadditions to provide polycyclic 2,5-dihydropyrrole products. As shown in Scheme 2, this fragmentation/cycloaddition sequence provides an efficient 3-step route from simple α-silyloxy ketones to more structurally complex 2,5-dihydropyrroles. We are in the process of using this reaction sequence in the synthesis of several alkaloid natural products.  

Scheme 2

The Reaction of Sulfonium Salts with Hydrazones: New Synthetic Routes to Nitrogen-Containing Heterocycles.
        We recently discovered that the hydrazone functional group reacts with chlorodimethylsulfonium chloride to give a variety of products depending on the reaction conditions and the hydrazone substitution pattern. For example, N-unsubstituted hydrazones easily and cleanly react with chlorodimethylsulfonium chloride to provide alkyl chlorides (e.g. 7) in high yield (Scheme 2). Changing the reaction conditions to include two equivalents of Et3N inhibits alkyl chloride formation and instead provides diazo compounds (e.g. 9) in high yield. The dehydrogenation of hydrazones to provide diazo compounds is well precedented, but has most often been achieved by treatment with toxic and environmentally deleterious heavy metals (e.g. mercury(II) oxide, lead(IV) acetate). Our method represents a significantly more Green route to diazo compounds under mild conditions at low temperature (-78 °C).

Scheme 3

    This research has now evolved toward heterocycle synthesis because we identified the novel chemical reaction shown in Scheme 4 below. Under appropriate conditions, hydrazones that contain a pendent alkene (e.g. 10, Scheme 4) react with dimethylsulfide ditriflate (11) to provide a highly reactive 1-aza-2-azoniallene salt (13) as an intermediate. Intermediate 13 then undergoes a subsequent reaction with the pendent alkene via transition state 14 to form a new carbon-carbon and a new carbon-nitrogen bond at one time, ultimately yielding the bicyclic diazenium salt product 15. This reaction is important because there are limited methods available to make carbon-carbon bonds, and this method is a mild way to do so. This reaction also provides a more structurally complex product (15 is a bicyclic product that has interesting 3-dimentional structure) from a structurally simple starting material, and the structures that we make using this methodology may provide useful pharmacophores for drug discovery. This is a fairly general process that can provide a variety of different bicyclic ring systems. Perhaps more importantly, we are finding that the cationic product 15 is itself a reactive species that shows diverse reactivity and it will likely be a useful intermediate in many different synthetic applications. In terms of synthetic chemistry, this varied reactivity is ideal because it provides many options for using structures such as 15 in subsequent reactions. We are currently exploring the use of this intramolecular cycloaddition in natural product synthesis.

Scheme 4



Last modified January 04 2012 04:36 PM

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