Asymmetric synthesis of β-amino cyclohexyl sulfonates, β-sultams and γ-sultones

An efficient asymmetric synthesis of beta-aminocyclohexyl sulfonates, beta-sultams and gamma-sultones has been developed. The key step of the synthesis is the Lewis acid catalyzed aza-Michael addition of the enantiopure hydrazines SAMP [(S)-1] or RAMBO [(R,R,R)-2] to alkenylcyclohexyl sulfonates 3. This leads to P-hydrazino sulfonates 4a-k in moderate to good yields (41-85%) and diastereomeric excesses (de = 44-90%). The epimers were separated by preparative HPLC. Subsequent reductive N-N bond cleavage with (BH3THF)-T-. and protection of the resulting amines with CbzCl gave N-Cbz-protected beta-aminocyclohexyl sulfonates 6a-k in moderate to good yields (38-68% over 2 steps) and high enantiomeric excesses (ee greater than or equal to 96%). alpha-Alkylation of 6 with various electrophiles afforded a-alkyl-p-aminocyclohexyl sulfonates 10a-g in good to excellent yields (67-92%) and moderate to high diastereomeric excesses (de = 71-93%). After alkylation with allyl iodide, the first asymmetric iodosultonization was achieved with high selectivities. Compounds 6g-k were also cyclized in a four-step synthesis to highly enantio-enriched 3-substituted-1,2-thiazetidine 1,1-dioxides (beta-sultams) 9a-e.