61st Annual Report on Research 2016

We have investigated two major reactions of gamma-hydroxybutenolides: the Diels-Alder and aldol reactions. We finished and reported our investigations of the Diels-Alder reaction of gamma-hydroxybutenolides (Synthesis 2016), which described the scope of the reaction employing several substituted gamma-hydroxybutenolides as well as a selection of dienes that explored the stereo- and regiochemistry of the reaction. We reported one synthetic application, an approach to the tricyclic core of himbacine. We had previously reported that the chiral enolates derived from N-acyloxazolidinones and Paterson’s ethyl ketone (TL 2015) react with gamma-hydroxybutenolides diastereoselectively. A synthetic approach based on this chemistry was viable for synthesis of the all-syn C35-C39 stereopentad of etnangien, a powerful antibiotic that inhibits RNA-polymerase. As a further application of this synthetic approach, this year we investigated the synthesis of the C3-C7 fragment of tylonolide, an alglycone of the macrolide antibiotic tylosin. The synthesis of C3-C7 fragment of tylonolide relied on the diastereoselective reaction of the enolate derived from an N-propionyloxazolidinone with beta-substituted-gamma-hydroxybutenolides. After optimization of the protecting group for the synthesis, we were able to convert the functional group-rich lactone into the C3-C7 fragment in five steps and 32% overall yield. In addition to the aldol reaction, we were confronted with the stereoselective reduction of the alpha, beta-unsaturated-gamma-lactone and the reduction of the saturated gamma-lactone in the presence of the chiral auxiliary, and optimizing the regioselectivity of singlet oxygen oxidation of 3-substitued furans. This synthesis was the result of the work of three students who appear as co-authors on the paper (TL 2016) In the further exploration of the synthesis of oxygen heterocycles, we undertook the synthesis of stemofurans, a class of benzofurans with diverse biological activity. The key reaction was the addition of 2-metallated benzofurans to organomanganese arene complexes. The oxidation of the resulting organomanganese complexes and selective deprotection of the resulting products gave stemofurans C, L and T. This methodology may provide an expedient pathway to other related benzofurans. The research funded under this grant has investigated some key reactivity issues in the chemistry of gamma-hydroxybutenolides, which we feel will further aid in the continued development of this area of research. This grant supported the research presented in three publications (with a fourth one anticipated early next year) and involved students in every step of the process, with ten students working under the grant in my lab for the past four summers and numerous students during the academic year. Although my research program has formally come to an end with my retirement, the work my students have done under this grant will be noted for many years to come and they have profited from it in ways that will facilitate their callings as graduate students, industrial chemists, and pre-professional students.