Stereodivergent conjugate reduction of α-substituted α,β-unsaturated N-sulfinyl ketimines: flexible access to challenging acyclic β,β-disubstituted enesulfinamides

Abstract

stereoselective 1,4-reduction protocol for α-substituted α,β-unsaturated N-tert-butanesulfinyl ketimines has been developed, providing a flexible pathway to various geometry-defined acyclic β,β-disubstituted enesulfinamides featuring two electronically and sterically similar β-substituents. The reductant-controlled...

Diastereoselective Synthesis of Less Accessible Fluorine-Containing Acyclic Tetrasubstituted Stereocenters via Electrophilic Fluorination of β,β-Disubstituted Metalloenamines

“…This result indicates that using the chiral fluorinating reagent 2c solely, the enesulfonamide lacking chiral auxiliary is not effective for highly stereoselective fluorination. In contrast, either of the four stereoisomers of enesulfinamide 6a , easily prepared by our conjugate reduction protocol (Scheme B­(iii)), underwent fluorination reaction to afford the corresponding stereoisomers of α-fluoro imine 3a in high yields (>90%) with excellent stereocontrol (≥98.5:1.5 dr, Scheme b), once more confirming that stereocontrol in this process is not influenced by matched or mismatched stereochemical pairings of a substrate and a fluorinating agent. The reaction of enesulfinamide ( R S , Z )- 6a can be successfully scaled up to 1 g, producing ( R S ,2 S )- 3a with nearly identical yield and diastereoselectivity with the microscale synthesis.…”

“…Enesulfinamide 6 (1.0 equiv) or N -sulfinyl ketimine 1 (preparation and the diastereomeric ratio for the corresponding ketimines see refs − ) in freshly distilled anhydrous THF (∼1 M) was added to a flame-dried Schlenk flask equipped with a magnetic stirring bar under argon. The resulting clear solution was then cooled to −78 °C, and a solution of potassium tert -butoxide in THF (1.0 M, 1.2 equiv) was added dropwise to the mixture via a syringe.…”

“…To form geometry-defined enamines derived from these stereoselectivity-hard-to-control carbonyl substrates, we recently developed two protocols that involve stereospecific α-deprotonation ,,, of enantioenriched α-branched N - tert -butanesulfinyl ( N - t BS) ketimines (Scheme B­(i)) and conjugate addition of organocuprates or organohydride to α,β-unsaturated N - t BS ketimines (Scheme B­(ii,iii)). The β,β-disubstituted enesulfinamides (β-position relative to the nitrogen atom) contain chiral pendant ( t BS) that could raise enantiofacial selectivity in their subsequent nucleophilic transformations and enable enantioselective construction of C–C, , C–Cl, C–N, and C–O, bonds to give less accessible quaternary or tetrasubstituted stereocenters.…”

Stereoselective Cyclopropanation of Multisubstituted Enesulfinamides: Asymmetric Construction of α-Tertiary Cyclopropylamine Derivatives Containing β-Quaternary Stereocenters

“…Recently, we have successfully synthesized geometry-defined α,β,β-trisubstituted NH-enesulfinamides through sterospecific α-deprotonation of enantioenriched α-tertiary N - tert -butanesulfinyl ( N - t BS) ketmines as well as stereoselective 1,4-conjugate addition [Scheme F (i)] and 1,4-conjugate reduction [Scheme F (ii)] of α,β-unsaturated N - t BS ketimines. These NH-containing multisubstituted aza-enolates, which are β-substituted with two similar groups in electronics and size ( e.g ., methyl and ethyl), have been utilized in a series of nucleophilic reactions to establish less-accessible quaternary or tetrasubstituted stereocenters at the α-position of the imino group .…”

Stereoselective Electrophilic Chlorination of β,β-Disubstituted Enesulfinamides with Chloramine-T: Asymmetric Synthesis of Acyclic α,α-Disubstituted α-Chlorinated Carbonyl Surrogates

“…To address the difficulties associated with controlling the geometry in the formation of acyclic β,β-disubstituted enamines, we have developed three protocols for the selective formation of acyclic β,β-disubstituted enesulfinamides. These protocols involve the stereospecific α-deprotonation of α-branched N - tert -butanesulfinyl ( N - t BS) ketimines (Scheme C (i)), the 1,4-reduction α,β-unsaturated N - t BS imines (Scheme C (ii)), and the 1,4-addition of organocuprates to α,β-unsaturated N - t BS imines (Scheme C (iii)) . The chiral sulfinyl group in the enesulfinamides allows for enantiofacial control in their nucleophilic reactions, facilitating the construction of less-accessible acyclic tetrasubstituted stereocenters at the α-position of the imino group. , We hypothesized that an appropriate electrophilic chlorinating agent could intercept the geometry-defined enesulfinamides, enabling the selective construction of challenging acyclic α,α-disubstituted α-chlorinated imines.…”