α-Amido Sulfones as Imine Precursors in Enantioselective Nucleophilic Additions

(A) Mannich Reaction α-Amido sulfones are used as aliphatic imine precursors in the catalytic asymmetric Mannich reaction with glycine derivative 5. Linear, branched or cyclic substrates give the corresponding products in excellent diastereo- and enantioselectivities. Noteworthy are the use of formaldehyde-derived α-amido sulfone for α-aminomethylation of glycine derivatives and the selective orthogonal N-deprotection of the obtained β-alkyl-α,β-diamino acid derivatives 6.3 (B) Hydrophosphonylation Enantioenriched α-amino phosphoric acid derivatives 8 can be synthesized by the asymmetric hydrophosphonylation of aliphatic NCbz and N-Boc α-amido sulfones 3 using a phase-transfer catalyst. High yields and enantioselectivities are afforded. 4 (C) Cycloaddition Propionyl chloride 9 and α-amido sulfones as precursors of N-thioacylimines undergo catalytic asymmetric [4+2] cycloadditions with excellent enantio- and diastereoselectivities. The in situ formation of the imine is crucial to overcome its tautomerization to the enamine. The final enantioenriched thiazinone adducts 10 behave as activated ester surrogates.5 (D) Alkylation The catalytic enantioselective addition of organometallic reagents to α-amido sulfones was developed by Feringa and co-workers. Dialkyl zinc reagents are utilized for the addition of ethyl, isopropyl and n-butyl nucleophiles. However, the introduction of the methyl group is achieved with Me3Al. High enantioselectivities are obtained with para- and meta-substituted substrates, whereas ortho-substituted and aliphatic α-amido sulfones lead to a low enantiomeric excess.6 (E) Strecker Reaction Differently N-protected aromatic α-amido sulfones undergo the organocatalytic enantioselective cyanation catalyzed by quinine. KCN is used as the cyanide source. The cyanated products 12 are obtained in good yields and enantioselectivities.7a The asymmetric Strecker reaction with aliphatic α-amido sulfones has also been carried out.7b (F) Alkynylation Several N-Cbz protected propargylic amines 14 are prepared by the catalytic enantioselective addition of aromatic alkynes 13 to imines in situ generated from aromatic α-amido sulfones using Et 2Zn and a BINOL-type ligand. Further transformations of the alkynylation products were successfully achieved.8 (G) Aza-Henry Reaction The asymmetric addition of nitroalkanes to N-Boc imines, in situ formed from α-amido sulfones, is performed in the presence of a novel rosin-derived thiourea catalyst and a base. The reaction proceeds in a doubly stereocontrolled manner with high enantioselectivities and moderate diastereoselectivities.9a Catalytic phase transfer conditions have also been successfully applied to the asymmetric aza-Henry reaction of α-amido sulfones.9b (H) Aza-Morita-Baylis-Hillman Reaction N-Boc α-amido sulfones are demonstrated to be suitable imine precursors in the asymmetric addition of vinyl methyl ketone catalyzed by a BINOL-derived catalyst. Moderate to high yields and enantioselectivities are afforded. 10a The enantioselective aza-Baylis-Hillman-type reaction with α,β-unsaturated aldehydes and α-amido sulfones has also been reported.10b. © Georg Thieme Verlag Stuttgart · New York.