Stereoselective Construction of Less-Accessible Acyclic α,α-Disubstituted ß-Ketiminonitriles via Electrophilic Cyanation of ß,ß-Disubstituted Enesulfinamides.

The metalloenamines, formed by NH-deprotonation of ß,ß-disubstituted enesulfinamides, can undergo reactions with commercially available electrophilic cyanating reagents such as tosyl cyanide (TsCN) or 3-oxo-1,2-benziodoxole-1(3H)-carbonitrile (CBX). Through the utilization of appropriate stereoisomers of enesulfinamides, this method enables the selective synthesis of any of the four stereoisomers of α,α-disubstituted ß-sulfinylimino nitriles, which feature acyclic quaternary stereocenters and are typically more challenging to synthesize. These compounds can then undergo stereoselective nucleophilic addition, leading to the creation of valuable enantioenriched multisubstituted ß-amino carbonyl surrogates with a high degree of structural diversity.

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

A stereocontrolled protocol was developed to construct less accessible fluorine-containing acyclic tetrasubstituted stereocenters bearing two sterically and electronically similar alkyl groups at the α-position of carbonyls. In this process, tBuOK-promoted stereospecific α-deprotonation of α,α-disubstituted N-tert-butanesulfinyl ketimines or NH deprotonation of ß,ß-disubstituted enesulfinamides generates geometry-defined multisubstituted metalloenamines, followed by stereoselective electrophilic fluorination with the N-fluoro ammonium salt of quinine, affording the acyclic α-fluorinated ketimines with excellent diastereoselectivities.

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

A method was developed for the enantioselective formal 1,2-diamination of disubstituted ketenes using iminosulfinamides as nitrogen sources. The protocol involves the addition of lithium iminosulfinamides to ketenes to form N-iminosulfinyl amide metalloenolates. These metalloenolates then undergo a [2,3]-sigmatropic rearrangement to yield unnatural α,α-disubstituted α-amino acid derivatives with high enantiopurity. The chirality present at the sulfur atom in the iminosulfinamides is effectively transferred to α carbon of the resulting products, facilitating the highly enantioselective amination of ketenes.

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

Enesulfinamides with α,ß,ß-trisubstitution undergo a Simmons-Smith reaction to yield multisubstituted cyclopropylamine derivatives with high stereocontrol. The resulting α-tertiary cyclopropylamine derivatives, which feature ß-quaternary stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl), are seldom achieved by using conventional methods. By adjusting the stereochemistry of the carbon-carbon double bond and/or sulfinyl group within the enesulfinamides, it is feasible to selectively produce four stereoisomers of the cyclopropylamines, each with different absolute configurations at the α- and ß-carbons.

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

Enamine and iminium ion-mediated asymmetric organocatalysis was not successful in achieving highly stereoselective α-chlorination of acyclic α,α-disubstituted carbonyls. To address this limitation, an alternative method was developed, which involved the use of geometry-defined persubstituted enesulfinamides to intercept the electrophilic chlorinating reagent. This approach enables the asymmetric construction of challenging acyclic α,α-disubstituted α-chlorinated ketimines with a high degree of stereoselectivity. The use of chloramine-T, a cost-effective and stable chlorine source rarely utilized in asymmetric electrophilic chlorination, plays a crucial role in achieving superior stereocontrol.

Stereoselective Construction of Acyclic ß,ß-Disubstituted Enesulfinamides via Conjugate Addition of Organocuprates to α-Substituted α,ß-Unsaturated N-Sulfinyl Ketimines.

In the presence of boron trifluoride, conjugate addition of organocuprates to α-substituted α,ß-unsaturated N-tert-butanesulfinyl ketimines provides facile access to acyclic ß,ß-disubstituted enesulfinamides with high ratios of geometric isomers. Diverse and challenging to synthesize, multisubstituted aza-enolates bearing two electronically and sterically similar ß-substituents, which are important precursors for asymmetric construction of the less accessible acyclic quaternary or tetrasubstituted stereocenters at the α-position of ketimines, can be efficiently prepared in good yields with high stereocontrol.

Stereoselective Synthesis of Less Accessible α-Tertiary Amino Ketimines via Electrophilic Amination of α-Branched N-tert-Butanesulfinyl Ketimines.

A stereocontrolled electrophilic amination of α-branched N-tert-butanesulfinyl ketimines was developed to construct α-aminoketone derivatives containing less accessible α-tetrasubstituted stereocenters. Stereospecific α-deprotonation of ketimines with potassium tert-butoxide gave stereodefined metalloenamine intermediates that could act as nucleophiles to attack azodicarboxylic derivatives, affording α-aminated products in high yields with excellent stereoselectivities.

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

An aza-variation on [2,3]-sigmatropic rearrangement of allylic sulfimides was developed. In this process, enolization of N-acyl iminosulfinamides was followed by O-silylation to generate O-silyl N-iminosulfinyl N,O-ketene aminal intermediates, which undergo a [2,3]-shift to afford α-sulfenylamino imidates that were converted to the corresponding carboxamides after desilylation triggered by acidic aqueous workup. Chirality is transferred from the sulfur stereocenter to the α-carbon, thereby enabling the enantioselective installation of an amino group at the α-position of amides.

Stereoselective Electrophilic α-Alkynylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines for Construction of Less Accessible Acyclic Quaternary Stereocenters.

In order to construct less accessible acyclic quaternary stereocenters, a protocol was developed to α-alkynylate α,α-disubstituted N-tert-butanesulfinyl ketimines stereoselectively using 1-(2-trimethylsilylethynyl)-1,2-benziodoxol-3(1H)-one in the presence of fluoride. Despite the steric and electrical similarity between the two α-substituents, the entire reaction proceeded in a strongly stereoselective manner: tBuOK promoted α-deprotonation of the acyclic ketimine to generate stereodefined fully substituted aza-enolates, which stereoselectively formed C-C bonds with electrophilic alkynylation reagents, affording α-alkynylation products with excellent stereocontrol.

Stereocontrolled α-Allylation of α-Branched N-tert-Butanesulfinyl Ketimines via a Michael-Wittig Cascade for the Construction of Acyclic Quaternary Stereocenters.

A single-flask cascade of Michael addition and Wittig olefination was developed to allow the stereoselective α-allylic alkylation of α-branched N-tert-butanesulfinyl ketimines for the construction of acyclic quaternary stereocenters bearing two sterically and electronically similar substituents. In this process, tBuOK-promoted stereoselective α-deprotonation gives fully substituted aza-enolates with a stereodefined geometry, Michael addition with α,ß-unsaturated phosphonates generates C-C bonds with exceptional stereocontrol, and finally paraformaldehyde trapping of the conjugate addition intermediate generates functionalized α-allylated imines.

Stereocontrolled Construction of Acyclic Quaternary Carbon Centers via α-Hydroxymethylation of α-Branched N-tert-Butanesulfinyl Ketimines.

Hydroxymethylation of α-branched N-tert-butanesulfinyl ketimines with formaldehyde equivalents was developed to stereoselectively construct acyclic quaternary stereocenters bearing two sterically and electronically similar substituents. The stereoselective tBuOK-promoted α-deprotonation of acyclic ketimines allowed for the stereodefined formation of fully substituted aza-enolates, followed by facially selective C-C bond formation involving formaldehyde formed in situ, yielding α-hydroxymethylated products with precise stereocontrol.

Construction of Acyclic Quaternary Stereocenters via Mannich-Type Addition of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines to Isatin-Derived Ketimines.

A Mannich reaction of deprotonated, highly enantioenriched α,α-disubstituted N-tert-butanesulfinyl ketimines with isatin-derived ketimines was developed to prepare 3-amino-3-substituted oxindoles bearing an acyclic quaternary stereogenic carbon substituted with two sterically similar groups. The excellent stereocontrol of the deprotonation enabled the formation of metalloenamine intermediates with stereodefined geometry, while the precise facial selectivity of the C-C bond formation allowed the construction of contiguous quaternary and tetrasubstituted stereocenters with excellent stereoselectivity.

Synthesis of Enantioenriched Primary tert-Butanesulfonimidamides via Imination-Hydrazinolysis of N'-tert-Butanesulfinyl Amidines.

The first synthesis of primary tert-butanesulfonimidamides with high enantiopurity was realized by imination (or imination/N-functionalization) of enantioenriched N'-tert-butanesulfinyl amidines, followed by hydrazinolysis. N'-Sulfinyl amidines served as imination precursors during copper-catalyzed sulfonyl nitrene transfer or iodonitrene-based NH transfer. Further transformations allowed access to primary tert-butanesulfonimidamides with diverse substitutions on the nitrogen of S═N.

α-Hydroxylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines with Molecular Oxygen: Stereoselective Synthesis of α-Tertiary Hydroxyimines.

α-Tertiary hydroxyimines were stereoselectively synthesized from enantioenriched N-tert-butanesulfinyl ketimines using potassium tert-butoxide, molecular oxygen, and trimethyl phosphite. The stereoselective hydroxylation of acyclic ketimines bearing two sterically similar α-substituents was achieved by controlling the geometry of the metalloenamine intermediates and the facial selectivity of hydroxylation. The synthetic utility of the resulting α-tertiary hydroxyimines was demonstrated through the successful diastereoselective synthesis of highly substituted ß-amino alcohols.

Chiral spiro phosphoric acid-catalysed enantioselective reaction of ketenes with N-H pyrroles.

In the presence of a chiral spiro phosphoric acid catalyst, the asymmetric reaction of disubstituted ketenes with N-H pyrroles occurred to afford enantioenriched C-acylated pyrroles bearing α-stereogenic carbon centres. The described reaction constitutes a rare example of a catalytic asymmetric reaction of ketenes with carbon-based nucleophiles.

Stereodivergent Construction of Vicinal Acyclic Quaternary-Tertiary Carbon Stereocenters by Michael-Type Alkylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines.

Vicinal quaternary-tertiary carbon stereocenters were constructed with excellent stereoselectivity via aza-enolization of enantioenriched acyclic N-tert-butanesulfinyl ketimines bearing two sterically similar α-linear alkyl substituents followed by conjugate addition to nitroalkenes. Further changes of the absolute configuration of the sulfinyl group and/or the α-stereocenter in the ketimine allowed the facile stereodivergent synthesis of all four diastereomers of the Michael-type alkylation adducts. This reaction is a successful example of acyclic stereocontrol based on stereoselective α-deprotonation for the formation of fully substituted aza-enolates from ketone derivatives.

Mannich-Type Reaction of α-Sulfanyl N-tert-Butanesulfinylimidates: Diastereoselective Access to α-Mercapto-ß-amino Acid Derivatives.

A series of α-mercapto-ß-amino acid derivatives were synthesized diastereoselectively in good yields through the aza-enolization of α-sulfanyl N-tert-butanesulfinylimidates, followed by their nucleophilic addition to N-tosyl imines via a Mannich-type reaction. The resulting derivatives bearing a ß-sulfonylamino sulfide moiety participated in further inter- and intramolecular transformations involving episulfonium ion intermediates generated through neighboring-group participation.

Rearrangement of N-tert-Butanesulfinyl Enamines for Synthesis of Enantioenriched α-Hydroxy Ketone Derivatives.

Treating chiral N-tert-butanesulfinyl ketimines with potassium hexamethyldisilazide (or potassium tert-butoxide) and methyl triflate gives N-methylated N-tert-butanesulfinyl enamine intermediates that undergo stereoselective [2,3]-rearrangement to afford α-sulfenyloxy ketones with excellent enantiopurities. This cascade of enamination-N-methylation-rearrangement was even used to generate acyclic tertiary α-hydroxy ketones bearing two α-substituents showing negligible differences in bulkiness, such as methyl and ethyl groups.

Addition-Rearrangement of Ketenes with Lithium N- tert-Butanesulfinamides: Enantioselective Synthesis of α,α-Disubstituted α-Hydroxycarboxylic Acid Derivatives.

Addition of the lithium salts of chiral N-substituted tert-butanesulfinamides to ketenes and subsequent silylation initiates stereoselective [2,3]-rearrangement, which affords enantioenriched α,α-disubstituted α-sulfenyloxy carboxamides through a reaction that faithfully transfers the absolute stereochemistry of the lithiated sulfinylamides to the α-carbon of the amide products. This addition-rearrangement can be performed together with ketene formation from acyl chloride in a single flask, providing a new and practical synthetic route to α-hydroxycarboxylic acid derivatives.