Stereoselective synthesis of N-heterocycles enabled by tertiary amine catalysis and synthetic efforts towards C-ring synthons of rameswaralide.


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Extensions of the nucleophile catalyzed aldol lactonization (NCAL) of keto acids, previously developed for the synthesis of carbocycle-fused β-lactones, are described to access a series of N-heterocycle-fused β-lactones. Pyrrolidine- and piperidine-fused tricyclic β-lactones were successfully prepared in moderate to good yields and with high diastereoselectivity. A catalytic, enantioselective process was developed for the synthesis of bicyclic N-heterocycle-fused β-lactones in high enantiomeric purity. The utility of these adducts was explored briefly through deprotection of the N-tosyl group and functionalization of the β-lactones. The utility of chiral α, β unsaturated acylammonium salts, derived from carbonic anhydrides and chiral isothiourea catalysts, was extended to aza-Michael initiated organocascades, delivering pyrazolidinones and 1,5-benzodiazepinones. Finally, efforts toward the synthesis of C ring synthons useful for the total synthesis of rameswaralide were pursued. Key strategies involved a C-H oxygenation and γ-alkylation of (R)-carvone leading to serviceable intermediates for a total synthesis of this natural product.



Tertiary amine catalysis. N-heterocycles synthesis.