Connective Stereospecific Generation of Alkenes Continued

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Paul Blakemore of Oregon State University is studying a versatile method for the preparation of an important class of molecules called alkenes. Alkenes are widespread among natural and artificial chemical substances with properties of value to medicine, engineering, agriculture, electronics, and materials science.

The method being used to generate alkenes differs from traditional approaches in that the molecule is formed directly from two so-called 'carbenoid' building blocks, which assemble in such a precise fashion that potentially any kind of alkene can be targeted with complete control of structure. Molecules to be prepared during this renewed period of support include vitamin D2, a representative member of the D vitamin family with a range of therapeutic indications (e.g., cancer, osteoporosis, and Alzheimer's disease), and pumiliotoxin 251D, a defense alkaloid from a tropical frog species, and related compounds with cardiotonic properties.

The broader impacts of the funded project extend to benefits accrued to society as the principal investigator and his research team provide summer research experiences for high school students under the auspices of the STEM academy at Oregon State University. This education and outreach program promotes interest in science and engineering from a diverse array of young learners and it includes mechanisms designed to foster participation from individuals belonging to traditionally underrepresented groups.

The award supports continued research and development of the carbenoid eliminative cross-coupling (CEXc) concept for carbon-carbon double bond synthesis. By contrast to conventional methods for connective alkene synthesis, CEXc does not rely on substituent effects to control stereochemical outcome; rather, absolute stereochemical information encoded in two stereodefined sp3-hybridized carbenoid substrates wholly determines the relative configuration of the alkene product via a three-stage stereospecific mechanism (ate-complex formation, 1,2-metalate rearrangement, and beta-elimination).

The funded research focuses on extending the concept of CEXc to classes of targets not previously investigated (cyclic styrenes, conjugated trienes, and non-conjugated alkenes) and it encompasses the use of more reactive types of carbenoids (e.g., alpha-chloroalkyl-lithiums and -boronates) and new reaction modalities (e.g., intramolecular). In the context of conjugated alkene synthesis (research thrust 1), specific goals are: assembly of conjugated trienes about the cental olefin, semi-synthesis of vitamin D2 via generation of the C7-C8 double bond (distal bond disconnection), and formation of macrocyclic styrenes by intramolecular CEXc triggered by sulfoxide-metal exchange.

The work on non-conjugated alkenes (research thrust 2) focuses on generating challenging targets with subtle stereogenicity, including: chirotopic 4-cyclohexylidenes, isotopomeric olefins, and pumiliotoxin 251D. Pursuit of the highlighted research agenda is anticipated to lead to fundamental and broadly applicable advances both to chiral carbanion chemistry and to the practice of advanced stereoablative synthetic techniques for the control of molecular configuration.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.