59th Annual Report on Research 2014

The reaction of chiral enolates with gamma-hydroxybutenolides and the Diels-Alder reactions of gamma-hydroxybutenolides have enormous potential in synthesis. 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 investigated two types of chiral enolates: the enolates derived from N-acyloxazolidinones, and enolates derived from Paterson’s ethyl ketone. For simple gamma-hydroxybutenolides (R=H, 3-alkyl), we obtained the corresponding lactones in good to excellent yield (60-85%) and good diastereoselectivity (75-94% de) using the titanium enolates. The use of the appropriate conjugate base of the gamma-hydroxybutenolide was pivotal in the development of optimal conditions. We have two synthetic applications we are pursuing: the synthesis of the all-syn C₃₅-C₃₉ stereopentad of etnangien, a powerful antibiotic that inhibits RNA-polymerase, and the synthesis of the C₃-C₇ fragment of tylonolide hemiacetal, another antibiotic. For the synthesis of the stereopentad of etnangien, we have achieved our goal and the project is ready for a preliminary communication. We have made some progress in the synthesis of C₃-C₇fragment of tylonolide hemiacetal, although we have encountered difficulties with the two protecting groups employed thus far.

We have investigated the Diels-Alder reaction of a variety of gamma-hydroxybutenolides (R=5-CH₃, (CH₂)₉CH₃, CH₂OAc, CH₂CH=CH_2, (CH₂)₂Ph) with a variety of dienes (cyclopentadiene; 2,3-dimethyl-1,3-butadiene; isoprene; 1,3-cyclohexadiene; 1-phenyl-3-methyl-1,3-butadiene) under thermal as well as catalytic conditions (DIPEA/SnCl₄, Sc(OTf)₃). In many cases we have achieved high diastereo- and regioselectivity. In some cases, we still need to completely characterize the products, which often are diastereomeric ring tautomers in equilibrium with the chain tautomer. The mixture of compounds has slowed our progress in determining the stereo- and regioselectivity in some cases. We are vigorously pursuing one synthetic application of the Diels-Alder reaction of gamma-hydroxybutenolides, an approach to the tricyclic core of himbacine. The Diels-Alder reaction of gamma-hydroxybutenolides established the desired stereochemistry of three stereogenic centers of the B/C ring, governed by endo-selectivity and ortho regioselectivity of the reaction.