Organic Chemistry - Boehringer Ingelheim Symposium
The process development of a densely functionalized, bis-spirocyclic BACE-1 inhibitor will be presented. In the course of developing a synthetic route which addressed major safety and scalability issues from the discovery route, two new reactions were developed: the addition of carbamoyl anions to N-sulfinyl imines and the electrophilic cyanation of aryl Grignard reagents via transnitrilation with dimethylmalononitrile. These methodologies enabled synthesis of the drug substance on multi-kg scale and were also explored for scope on a wide range of substrates. Several methodologies developed as extensions of the carbamoyl anion and transnitrilation reactions will be presented.
C–H activation has surfaced as a powerful platform in molecular synthesis, with transformative applications to material sciences and drug discovery, among others. In this context, we have introduced carboxylates, for position-selective C–H arylations and alkylations with versatile ruthenium(II) complexes, displaying complementary selectivities. Detailed mechanistic insights into the working mode of the key C–H ruthenation step set the stage for ruthenium(II)-catalyzed twofold C–H functionalizations as well as stepeconomical oxidative alkyne annulations. The oxidative C–H functionalization strategy enabled ruthenium(II)-catalyzed meta- and para-selective arene diversification. Also, late-stage peptide diversification and electrochemical
C–H activations will be discussed.