Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process

A novel and convergent approach to tetrasubstituted benzofurans was developed from <i>ortho</i>-bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu­(I) catalyzed C–O coupling on the <i>ortho</i>-bromide. The scope of this methodology was demonstrated on several similar substrates

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired <i>trans</i> alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C–O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece

Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam <b>2</b> was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 <i>syn</i>/<i>anti</i>. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate <b>3</b>, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant