A New Paradigm for the Asymmetric Diels-Alder Reaction

The Diels–Alder (DA) reaction is one of the most powerful carbon–carbon bond forming methods in organic chemistry. This reaction enables the simultaneous regioselective formation of two σ bonds leading to six-membered rings, thereby establishing up to four potential stereogenic centres in a single step. The asymmetric variation of the DA reaction was first investigated in 1961, where studies into the control of absolute topicity began. After which, dozens of natural products and pharmaceutical drugs have been synthesized exploiting this methodology. The common approach of using a chiral dienophile or chiral catalyst has been well investigated by Trost and Koga. The alternative approach of using a chiral diene has been somewhat explored, yet the area remains largely underdeveloped. The application of a chirally modified 2-amido-1,3-diene is lacking in the literature and current routes to synthesize the 1-amido-1,3-diene isomers suffer from low yields and lengthy syntheses. The Guiry group reported a Pd-catalysed method to synthesise achiral 2-amino-1,3-dienes from propargylic precursors in excellent yields (30 examples, up to 98% ) which shows a broad tolerance to functional group diversity. Such methodology enables the catalytic access of a new range of 2-amino-1,3-dienes. This project builds on the previous work by utilising chiral oxazolidinones as chiral auxiliaries in the DA reaction. A range of chiral oxazolidinones and pyrrolidinones were prepared in good yields and applied in the modified Pd-catalysed decarboxylative dienylation, delivering 13 examples in yields of up to 97% . The reactivity of the prepared 2-amido-1,3-dienes was assessed in a number of DA reactions. The chiral dienes demonstrated excellent levels of stereoinduction, delivering 40 examples of the corresponding DA products in yields up to 70% and diastereoselectivities up to 93:7 dr. Following which, four examples of the hydrolysed ketone products were prepared in yields up to 81% and ee’s of 92%. The reactivity of the prepared 2-amido-1-phenyl-1,3-dienes was assessed in a number of DA reactions. The chiral dienes demonstrated lower levels of stereoinduction when compared to the 2-amido-1,3-dienes, delivering 27 examples of the corresponding DA products in yields of up to 82% and diastereoselectivities up to 86:14 dr. Following which, one example of the hydrolysed ketone product was prepared in a 70% yield as a single diastereomer. A stereochemical investigation into the geometry of the ketone product was conducted using XRD analysis. Finally, efforts to derivatise and functionalise the novel diene and DA products were carried out to assess their potential value as precursors to pharmaceutical compounds and test their synthetic versatility.