I. Application of Chiral α,β-Unsaturated Acylammonium Salts for Efficient Catalytic Transformations II. Studies toward the Total Synthesis of Rameswaralide

Abstract

The developments of novel catalytic transformations are just as important as the discoveries of new reactions. In the most common way, catalysts provide more efficient and economical alternatives to known reactions. Arguably, sometimes, catalysts enable new and amazing transformations. Described herein are methodologies that expand the field of chiral tertiary amine catalysis. In the past few decades, chiral tertiary amine-catalyzed reactions have become one of the most versatile and useful methodologies in organic transformations. Among several modes of activation by chiral tertiary amines, the α,β-unsaturated acylammonium salts is the most underexplored despite its potential to reveal three reactive sites. Two projects focusing on novel transformations of α,β-unsaturated acylammonium salts are described. The first development showed the potential of a conjugated acylammonium species in a multicomponent process, namely a Michael Michael aldol β-lactonization cascade. Three achiral (52-72% yield) and ten enantioselective (19-61% yield) examples have been demonstrated with this methodology, with excellent dr (>19:1) in the optically active examples. In parallel, an expansion of a nucleophile-catalyzed Michael proton-transfer lactamization is described with a focus on the syntheses of chiral piperidi-2-ones and a dihydropiperidinone. The NMR study of the intermediate α,β-unsaturated acylammonium salts gave us an insight into decreased 1,2-reactivity which promoted addition at the β-carbon of these reactive intermediates.

Natural products continue to be an inspiration for drug discovery and development. Due to its potent biological activity in a variety of inflammatory assays, the synthesis of rameswaralide is highly desirable, as it would enable sufficient quantities of the natural product that could be used to elucidate its mechanism of action along with a full structure activity relationship investigation.

In the second part, an approach to access the core structure of rameswralide is proposed, where the complexity is increased with each synthesized fragment. The bicyclic AD core of rameswaralide was obtained via a 6-step process from inexpensive commercially available starting materials. The tricyclic ABD and the tetracyclic core are being constructed involving either ring closing metathesis or organometallic coupling as a key step.