Organic Synthesis - Intramolecular Diels-Alder Chemistry

Our research is concerned with the development of new reactions for the synthesis of complex polycyclic rings. Efforts have focused on cycloaddition chemistry, more specifically the development of the type 2 intramolecular Diels-Alder reaction. The constraints resulting from the connectivity in the Diels-Alder precursor creates a strong regio- and stereochemical bias in the cycloaddition step limiting the number of products to a single isomer. We have exploited the intrinsic stereo- and regiochemical bias of the cycloaddition for the synthesis of highly substituted carbocyclic and heterocyclic rings. The utility of this reaction in more complex settings has been demonstrated by its use in the total synthesis of complex natural products. These include (+)- adrenosterone, (±)-plocamine D, (±)-alloyohimbane, (±)-ledol, (±)-ledene and formal total syntheses of ( ±)-compressanolide, and (±)-resrepine as well as advanced intermediates for the total synthesis of (+)-aldosterone and (±)-taxusin. Current targets include (-)-stenine and (±)-upitol.

Hetero Diels-Alder Cycloadditions

More recently our focus has been on heteroatom variants of this reaction. An example is the type 2 intramolecular acyl nitroso Diels-Alder cycloaddition. Intramolecularity provides regiochemical and stereochemical control of the cycloaddition.

Intramolecular Acylnitroso Diels-Alder Cycloaddition
Synthsis of Bridged Oxazinolactams

Selective elaboration of the novel oxazinolactam cycloadduct affords stereoselective entry to seven and eight membered heterocyclic rings. The novel polycyclic structures that result from this research provides powerful tools for the synthesis of biologically important compounds.

Intramolecular Acyl Nitroso Cycloaddition
Stereoselective Lactam Systhesis

Asymmetric Catalysis

We have been developing asymmetric catalysts for the type 2 IMDA cycloaddition reactions. One of the more exciting findings has been our discovery of a catalyst that serves two distinct functions in the heteroatom asymmetric Diels-Alder reaction. The catalyst, a chiral ruthenium salen complex, first oxidizes hydroxamic acids and N-hydroxy formate esters to the corresponding acyl nitroso and nitroso formate intermediates. The spent oxidation catalyst then recaptures the reactive intermediate and catalyzes the subsequent diastereofacial Diels-Alder cycloaddition.

We are studying the scope and mechanism of this reaction as well as developing additional asymmetric catalysts for the type 2 IMDA.