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 stereodefinedE,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-benzoyloxysulfone8
rapidly eliminates at -78 °C using SmI2 and DMPU, alkyl-benzoyloxysulfone9
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-sulfone10
undergoes a highly chemoselective samarium-mediated
elimination, proceeding through the presumably resonance stabilized
intermediate 11, affording diene12
containing an intact benzoyloxysulfone (Scheme 5). We
envision utilizing this protocol for iterative differential alkenefunctionalizations.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.
