Reductive Asymmetric Aza‐Mislow‐Evans Rearrangement by 1,3,2‐Diazaphospholene Catalysis**

Abstract

1,3,2-diazaphospholene hydrides (DAPÀ H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent SÀ O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,Oketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAPÀ H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.

Catalytic enantioselective reductive Eschenmoser-Claisen rearrangements

“…We reasoned that appropriate covalently bound robust chiral catalyst enabling well-defined and rigid transition states at higher reaction temperatures paired with a suitable catalyst turnover strategy would be of pivotal importance for a general enantioselective Claisen rearrangement. Our recent investigation of tandem pericyclic rearrangement reactions triggered by 1,3,2-diazaphospolene (DAP)–catalyzed conjugate reduction of α,β-unsaturated carboxylic acid derivatives ( 25 , 26 ) demonstrated the considerable potential of DAP catalysis to address this gap in enantioselective catalysis. To date, chiral DAP catalysts have only been used for enantioselective reductions in which the hydride transfer was the enantio-determining step ( 27 – 29 ).…”

Enantioselective Formal 1,2-Diamination of Ketenes with Iminosulfinamides: Asymmetric Synthesis of Unnatural α,α-Disubstituted α-Amino Acid Derivatives

“…On the basis of our prior success in the formal 1,2-aminooxygenation of ketenes via the aza-Mislow–Evans rearrangement, we hypothesized that asymmetric formal 1,2-diamination of disubstituted ketenes could be realized using iminosulfinamides, also known as sulfinamidines (Scheme B). The proposed mechanism involves the nucleophilic addition of NH-deprotonated iminosulfinamides to ketenes, leading to the formation of N -iminosulfinyl amide metalloenolates.…”

Enantioselective Formation of α-Amino Acid Derivatives via [2,3]-Sigmatropic Rearrangement of N-Acyl Iminosulfinamides

“…The observed stereochemistry can be rationalized through preferential formation of the ( Z )-enolate to minimize steric clash between the bulky iminosulfinamide group and the R group, as well as enantiofacial selectivity in favor of the exo transition state TS-1 previously proposed for aza-Mislow–Evans rearrangement (Scheme ). ,, The endo transition state TS-2 is disfavored because of steric repulsion between the t Bu group on the sulfur atom and Me 3 SiO group on the CC bond. The exo rearrangement leads to a (2 R )-amino imidate intermediate that, after acidic desilylation, can be transformed into the corresponding α-amino carboxamide derivative.…”

“…One example is Mislow–Evans rearrangement, which refers to [2,3]-sigmatropic rearrangement from allylic sulfenates to allylic sulfoxides and its reverse transformation in the presence of thiophiles (Scheme a). , We developed an aza-variation on Mislow–Evans rearrangement by replacing the carbon atom at the allylic position of allylic sulfoxides with a nitrogen atom to generate α-sulfenyloxy carbonyls (Scheme b; R 3 = OSiMe 3 or Ar) . More recently, Cramer and co-workers developed a reductive aza-Mislow–Evans rearrangement, which converts N -sulfinyl acrylamides into α-hydroxy amides (Scheme b; R 3 = O­[ P ]) . In both aza-variants, chirality is transferred from the sulfur stereocenter to the α-carbon of carbonyls with high enantiospecificity.…”

“…4 More recently, Cramer and coworkers developed a reductive aza-Mislow−Evans rearrangement, which converts N-sulfinyl acrylamides into α-hydroxy amides (Scheme 1b; R 3 = O[P]). 5 In both aza-variants, chirality is transferred from the sulfur stereocenter to the αcarbon of carbonyls with high enantiospecificity.…”