Part A: Benzyl Functionalization Through Cu(I)-catalyzed Divergent Reactivity of Styrenes Part B: Synthesis of Aminated Stereotriads Through Regio- and Stereocontrolled Allene Oxidation

Many bioactive molecules include arenes that possess benzylic functionalization. An approach to introduce benzyl functionality could involve benzyl nucleophiles or electrophiles, but these can be difficult to prepare. We developed a strategy to render either species from styrenes using Cu(I)-catalyzed hydroboration. Treatment of benzyl boronic esters with potassium-tert-butoxide generated benzyl nucleophiles suitable for reactivity with heteroallene electrophiles through combination of sterically-driven bond cleavage and formation of a strong B-O bond. The mild conditions tolerated carbanion-sensitive functional groups, and were accomplished in the same pot as hydroboration. Benzyl electrophiles were prepared through an unusual Cu(I)-catalyzed hydroboration of ortho-halostyrenes. We identified a catalyst that borylated the Ar-X bond with 1,3-migration of the halide to the benzylic position. The benzyl halide electrophile reacted with a variety of nucleophiles to form additional carbon-heteroatom bonds. The system is an example of activating group recycling, where the halide directs arene borylation, but is reincorporated into the product for further functionalization. Preliminary mechanism investigations point to an unusual 1,3-metal migration that allows intramolecular halide transposition. Part B:;Construction of densely functionalized amines is an important, yet challenging task, particularly when three or more adjacent heteroatom-containing stereocenters are present. These motifs possess diverse combinations of heteroatoms and stereochemical configurations that make efficient and flexible synthetic methods scarce. We have used allenes to assemble aminated stereotriads with excellent regio- and stereocontrol. A Rh(II)-catalyzed oxidation of allenyl carbamates and sulfamates produced bicyclic methylene aziridines, which are well-poised for elaboration to aminated stereotriads through nucleophilic ring opening and double bond functionalization. All three allene carbon atoms become heteroatom-bearing stereocenters. Flexible choice of nucleophiles and electrophiles allow multiple combinations of heteroatoms to be installed. We developed an approach to access any of the possible stereochemical configurations of 2-amino-1,3-diols from the same allene precursor. Both reagent and substrate control can be employed towards the stereodivergent oxidative amination of allenes. The methodology was demonstrated in the synthesis of all diastereomers of the amino acid detoxinine. The results highlight the potential for allene oxidation to rapidly assemble challenging, and densely functionalized amine-containing motifs in biologically relevant targets.