Scalable Synthesis of Enantiomerically Pure Bicyclo[2.2.2]octadiene Ligands

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]­octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition–aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product <b>4a</b> (6-hydroxy-5-phenylbicyclo[2.2.2]­octan-2-one) is transformed into phenylbicyclo[2.2.2]­oct-5-en-2-one <b>2</b>, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi’s Ph-bod* ligand, as well as novel unsymmetrical chiral dienes

Scalable Synthesis of Enantiomerically Pure Bicyclo[2.2.2]octadiene Ligands

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]­octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition–aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product <b>4a</b> (6-hydroxy-5-phenylbicyclo[2.2.2]­octan-2-one) is transformed into phenylbicyclo[2.2.2]­oct-5-en-2-one <b>2</b>, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi’s Ph-bod* ligand, as well as novel unsymmetrical chiral dienes

Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin

A concise catalytic asymmetric synthesis of idasanutlin (<b>1</b>) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction. Further development of the [3 + 2] cycloaddition reaction resulted in an improvement in diastereoselectivity and enantioselectivity by changing the catalyst system to Cu­(I)/BINAP. While producing equivalent high quality API, the copper­(I) catalyzed process not only increased the overall yield but also demonstrated benefit with respect to cycle times, waste streams, and processability. The optimized copper­(I) catalyzed process has been used to prepare more than 1500 kg of idasanutlin (<b>1</b>)