Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki–Miyaura Cross Coupling Reaction

Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki–Miyaura (S–M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S–M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model S–M coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment. This screen identified reaction conditions that gave good yields of S–M coupling product while minimally perturbing the diazirine reporter fragment. These conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of 24 pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic efficiency

Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki–Miyaura Cross Coupling Reaction

Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki–Miyaura (S–M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S–M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model S–M coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment. This screen identified reaction conditions that gave good yields of S–M coupling product while minimally perturbing the diazirine reporter fragment. These conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of 24 pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic efficiency

Convenient Preparations of 2,4-Methanopyrrolidine and 5-Carboxy-2,4-methanopyrrolidines

An efficient four-step synthesis of N-BOC-5-syn- and 5-anti-carboxymethanopyrrolidines (12 and 13) and the conversion of 12 to N-BOC-methanopyrrolidine (2) are described

Convenient Preparations of 2,4-Methanopyrrolidine and 5-Carboxy-2,4-methanopyrrolidines

An efficient four-step synthesis of N-BOC-5-syn- and 5-anti-carboxymethanopyrrolidines (12 and 13) and the conversion of 12 to N-BOC-methanopyrrolidine (2) are described

Novel Selectfluor and Deoxo-Fluor-Mediated Rearrangements. New 5(6)-Methyl and Phenyl Methanopyrrolidine Alcohols and Fluorides

Stereoselective syntheses of novel 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing 5-anti-fluoro or hydroxyl in one methano bridge and a variety of syn- or anti-chloro, fluoro, hydroxy, methyl, or phenyl substituents in the other methano bridge have been effected. Rearrangements of iodides to alcohols were initiated using Selectfluor. Rearrangement of alcohols to fluorides was initiated using Deoxo-Fluor. Ring opening of 2-azabicyclo[2.2.0]hex-5-ene exo-epoxide with organocopper reagents is regioselective at C5