Synthesis of Diene and Dienophile Substrates for In-vitro Selection of RNA-hetero-diels-alder Catalysts

Abstract

The hetero-Diels-Alder reaction provides a general and facile entry for the synthesis of six-membered heterocyclic structures, which serve as precursors for a host of biologically active compounds. Although there are a wide variety of heterodienes and heterodienophiles available for synthetic applications, our research focuses on the cycloaddition of activated 1,3-butadienes with an activated aromatic aldehyde dienophile and an unactivated aliphatic aldehyde dienophile. Cycloadditions of this type provide access to an important class of compounds known as dihydropyrans, which are useful intermediates for the preparation of carbohydrates and many other biologically active compounds. Synthesis of pyrans by HDA cycloaddition has been limited to the reaction of either highly electron rich dienes (e.g. Danishefsky's diene) with a broad range of aldehydes or highly activated aldehydes (e.g. glyoxylates) with dienes of varying activity. Currently there are few examples of cycloadditions between unactivated aldehyde dienophiles and dienes that are less activated than Danishefsky's diene. Also, the catalysts currently available for this transformation provide access to only one of two possible regioisomers and provide a single diastereomer almost exclusively. If efficient catalysts for the uncommon HDA regio- and stereoisomers are attainable, then we believe that in vitro selection of these catalysts from a pool of 10∧14 random RNA sequences will provide invaluable clues as to structural properties necessary for such catalysts. To this end, we have prepared novel dienes and dienophiles suitable for in vitro selection of new RNA biocatalysts capable of assembling novel heterocyclic products via a hetero-Diels-Alder cycloaddition.