Reports: UNI149499-UNI1: Metathesis Reactions of Acyloxysulfones for Polyene Synthesis

Gregory W. O'Neil, PhD , Western Washington University

The introduction of well-defined catalysts such as 1 and 2 for olefin metathesis has had a tremendous impact on both organic and polymer synthesis (Figure 1). Despite the success of these catalysts in preparing a wide range of structurally diverse compounds, applications to polyene synthesis remain limited. This is largely the result of problems associated with chemoselectivity, or the nonselective engagement by the metathesis catalyst of one alkene in the presence of another.

We have introduced β-acyloxysulfones (3) as a novel alkene protecting group strategy that has allowed for a metathesis approach to a variety of polyene subunits unobtainable by standard metathesis technology (Scheme 1).

Current efforts are focused on extending this strategy toward increasingly challenging targets encompassing all general types of olefin metathesis reactivity. Examples include ring-closing acyloxysulfone metathesis/elimination reactions to produce stereodefined E,Z-dienoic acids (4) and medium-ring dienyl-macrolactones (5) (Scheme 2).

This approach has provided convenient access to several important natural products including the antimicrobial alarm pheromones isopulo'upone (6)2b and haminol A (7) (Scheme 3).2c The 5,6-fused isopulo'upone core was rapidly assembled using an acyloxysulfone metathesis/elimination sequence and subsequent intramolecular Diels-Alder (IMDA) (Scheme 5). Our revised synthesis of haminol A featured a bis-samarium-mediated acyloxysulfone elimination to construct the 1,3,8-triene fragment while the first-generation approach yielded important insights into vinylpyridine metathesis reactivity. Collaborative investigations (Heather Van Epps, WWU Biology; Jacqueline Rose, WWU Psychology) are ongoing to better understand the receptor and signaling pathways responsible for the alarm-response activity of these compounds.

During the course of our investigations we have observed a significant substrate dependence on the rate of samarium-mediated benzoyloxysulfone eliminations. For example, while phenyl-benzoyloxysulfone 8 rapidly eliminates at -78 °C using SmI2 and DMPU, alkyl-benzoyloxysulfone 9 proved inert to these conditions (Scheme 4). Even after prolonged reaction times at higher temperatures, only the starting benzoyloxysulfone was recovered. Instead, the corresponding alkene product was obtained using sodium/mercury amalgam.

This trend has proven to be general as evidenced by extensive competition experiments and can be exploited as a selective deprotection strategy.3 For instance bis-benzoyloxy-sulfone 10 undergoes a highly chemoselective samarium-mediated elimination, proceeding through the presumably resonance stabilized intermediate 11, affording diene 12 containing an intact benzoyloxysulfone (Scheme 5). We envision utilizing this protocol for iterative differential alkene functionalizations.

This work has provided the basis for an ongoing research program aimed at the synthesis of biologically relevant and environmentally compelling small molecules and materials utilizing acyloxysulfones as masked alkenes. Results were presented by the PI and student participants at both regional and national meetings. Student researchers supported this grant have gone on to pursue graduate degrees in chemistry at Penn State University and the University of Colorado.

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Dr. O'Neil
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