Stereoselective Synthesis of β-Substituted β-Amino Sulfones and Sulfonamides via Addition of Sulfonyl Anions to Chiral N-Sulfinyl Imines

Abstract

[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

“…Synthesis of iminothiadiazinane dioxide 9 (Scheme ) began with treatment of ( R )- tert- butylsulfinyl ketimine 36 , readily available from ketone 35 , with the conjugate base of sulfonamide 38 made from commercial 1-(4-methoxyphenyl)- N -methylmethanamine 37 . This process generated the protected β-amino sulfonamide 39 in 75% yield and high diastereomeric ratio (dr 98:2). , The tert- butylsulfinamide group was cleaved upon treatment of adduct 39 with hydrogen chloride, and the p -methoxy benzyl (PMB) group was subsequently removed using TFA to afford β-amino sulfonamide 40 . The iminothiadiazinane dioxide core was then formed in high yield using a three step protocol .…”

Applications of Menthol in Synthetic Chemistry

“…A further example demonstrating the synthetic utility of chiral sulfinimines was recently presented by researchers of Schering-Plough (see Scheme ) . Access to optically active β-amino sulfones 181 , a biologically interesting structural motif, is achieved via addition of α-lithiated sulfones 179 (R = t Bu or adamantyl; R‘ = Me) to imine 180 .…”

Catalytic Asymmetric Formation of β-Sultams

“…Similar results were obtained if both the cycloaddition step and the nucleophilic ring-opening experiments with alcohols or amines were performed in the same pot without isolation of 2a . Enantiomerically pure β-aminosulfonyl derivatives are valuable synthetic targets, since they have been identified, for example, as MMP-13 inhibitors for the treatment of rheumatoid arthritis,4f MMP-2 and -9 (gelatinase A and B) inhibitors for cancer treatment,4e or as DNA alkylating anticancer compounds 4d 4 Ring Opening of β-Sultam 2 a …”