60th Annual Report on Research 2015

γ-Hydroxybutenolides remain an underutilized moiety for the synthesis of biologically active natural products. Under this grant, we have investigated two broad reactions, the aldol and Diels-Alder reactions. We have made progress on both projects, with our methodology studies laying the foundation for the synthesis of more complex compounds that have served or could serve as intermediates in the synthesis of biologically active natural products.

We have demonstrated that two types of chiral enolates react diastereoselectively with γ-hydroxybutenolides: the enolates derived from N-acyloxazolidinones and Paterson’s ethyl ketone (TL, 2015). We demonstrated that this synthetic approach was viable for synthesizing the all-syn C₃₅-C₃₉ stereopentad of etnangien, a powerful antibiotic that inhibits RNA-polymerase. We are continuing to explore another possible application of this synthetic approach, the synthesis of the C₃-C₇ fragment of tylonolide, an alglycone of the macrolide antibiotic tylosin. We have made significant progress in the synthesis of C₃-C₇ fragment of tylonolide, reacting the enolate derived from a N-propionyloxazolidinone with Β-substituted-γ-hydroxybutenolides. We have been weighing the optimal protecting group for the synthesis, which has been a balance of diastereoselectivity in two of the key steps and durability in further steps. We have reached the point where we are optimizing the initial steps and converging on a tactical finish that will give a suitable intermediate for the synthesis of tylonolide.

Our investigations of the Diels-Alder reaction of γ-hydroxybutenolides are nearing completion. We have demonstrated high diastereo- and regioselectivity in many cases, enhanced in some cases by Lewis acid catalysis. We relied on the amine-catalyzed catalysis of the tautomerism between the diastereotopic ring and chain tautomers of the resulting γ-keto acids to help in the characterization process. We are reporting one synthetic application, an approach to the tricyclic core of himbacine. The Diels-Alder reaction of γ-hydroxybutenolides established the desired stereochemistry of three stereogenic centers of the B/C ring, governed by endo-selectivity and regioselectivity of the reaction. We have found that the diastereoselective reduction or alkylation of the resulting γ-keto acids gave rise to the diastereoselective formation of the γ-lactone. These model studies establish the groundwork for more ambitious synthetic challenges of synthesizing himbacine and its derivatives.

This past year, the grant has greatly aided the completion of one major project and the near completion of another major project that have been ongoing in my lab for several years. With further work on my part and my students, two other projects supported by this grant also will be brought to publication standards, too. This work demonstrates some key reactivity issues in the chemistry of γ-hydroxybutenolides, which we feel will further aid in the continued development of this area of research not only at Lafayette College but internationally. This research effort has involved students in every step of the process. With further support from the College, I have had been able to support four students in my lab for the last two summers. The success of the summer spills into the academic year, when several students have worked on research related to these projects. My students have been able to contribute to research that will find an audience well beyond the walls of this small college.