Catalytic Asymmetric Approach to 1,3,4,5-Tetrahydro-1,4-benzodiazepin-2-ones in One-Pot

Tetrahydro-1,4-benzodiazepin-2-ones are significant scaffolds in medicinal chemistry, endowed with a variety of bioactivities, including applications in CNS treatment. Generally, they contain one or more stereocenters and the classical asymmetric approach relies on the use of enantiopure starting materials derived from the chiral pool. So far, the methods reported suffer from several limitations: in many cases, they are non-catalytic processes and often the possibility of introducing functional groups at the chiral center is limited. Given this background, the development of catalytic stereoselective methodologies for the synthesis of functionalized enantioenriched tetrahydro-1,4-benzodiazepin-2-ones is highly desirable. Recently, our research group demonstrated the utility of enantioenriched 1-cyano-1-phenylsulfonyl epoxides as key intermediates in developing organocatalytic one-pot asymmetric processes aimed at synthesizing medicinally relevant compounds such as dihydroquinoxalinones, piperazin-2-ones, morpholin-2-ones, α-aryl glycine and aliphatic α-amino acid methyl esters. The synthetic protocols consist in Knoevenagel reaction/asymmetric epoxidation/domino ring-opening cyclization (DROC) sequence, where the first two steps are promoted by a recyclable organocatalyst derived from Cinchona alkaloids. A similar strategy has been devised to accomplish the asymmetric synthesis of 1,4-dihydro- 4,1-benzoxazepin-3(2H)-ones starting from readily available commercial reagents. This route gives access to a novel class of seven-membered N- and O-heterocycles, differently functionalized at the chiral center.