Organocatalyzed Enantio- and Diastereoselective Domino [3+2]-Dipolar Cycloaddition: Synthesis of Chiral Pyrrorlo-thiazine-2-carbaldehydes and Dihydropyrrole-3-carbaldehydes

1,3-Dipolar cycloaddition of azomethine ylide and dipolarophile is an efficient method to construct N, S heterocycles such as thiazoles, 1,4-thiazines, and their chiral polyhydro derivatives. Herein, we report a proline-derived organocatalytic enantioselective synthesis of pyrrolo[1,2-d][1,4]thiazine-2-carbaldehydes using domino 1,3-dipolar cycloaddition/rearrangement sequence. This domino process yields fluorescent emissive, highly enantioenriched chiral molecules with three contiguous stereogenic centers, having one chiral quaternary center in a single step, with excellent yield, enantio- and diastereoselectivity. This strategy was extended to the stereoselective one-pot synthesis of novel chiral tetrasubstituted dihydropyrrole-3-carbaldehydes via domino 1,3-dipolar cycloaddition/rearrangement, followed by S-alkylation/base promoted ring-opening. A DFT study showed that the formation of hydropyrrolo-thiazole intermediate is the rate-determining step (TS7 E‡ = -28.49 kcal/mol) which is responsible for the formation of pyrrolo[1,2-d][1,4]thiazine-2-carbaldehydes. Due to high energy, the intermediate hydropyrrolo-thiazole’s ring opens to yield thiolate anion, followed by C-N-bond rotation, intramolecular 1,2-addition of ketone and spontaneous protonation provides pyrrolo[1,2-d][1,4]thiazine-2-carbaldehydes. An in-silico study showed that the pyrrolo-thiazine-2-carbaldehyde scaffolds have substantial anticancer activity with respect to B-Raf kinase, a non-small cell line lung cancer.