Asymmetric Construction of Ethenyl-Substituted Acyclic Quaternary Stereocenters at the α-Position of Carbonyl Surrogates via Stereoselective Sulfonylvinylation-Reductive Desulfonylation.

N-Sulfinyl metalloenamines, derived from geometry-defined ß,ß-disubstituted enesulfinamides, undergo conjugate addition-elimination reaction with ß-tosyl nitroolefin to afford α-sulfonylvinylated ketimines with high stereocontrol. Further desulfonylation using sodium naphthalenide gives carbonyl surrogates bearing a less-accessible acyclic quaternary α-stereocenters substituted with an ethenyl group and two sterically and electronically similar groups (e.g., methyl and ethyl). Synthetic application of the described protocol was demonstrated by enantioselective synthesis of (S)-bakuchiol.

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.

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.

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.

Diastereoselective α-Amination of N- tert-Butanesulfinyl Imidates Using N-Aryl- N-diphenylphosphinyldiazenes.

Diastereoselective α-amination of N- tert-butanesulfinyl imidates has been developed using N-aryl (or N- tert-butyl) N-diphenylphosphinyldiazenes as nitrogen sources. The chiral 1-azaenolates derived from imidates undergo nucleophilic addition with diazenes to give α-hydrazino imidates in good yields.

Diastereoselective α-Fluorination of N- tert-Butanesulfinyl Imidates.

A diastereoselective α-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).

Diastereoselective α-Sulfenylation of N- tert-Butanesulfinyl Imidates.

A diastereoselective α-sulfenylation of chiral α-aryl/alkyl N- tert-butanesulfinyl imidates has been developed. Suitable sulfur electrophiles can be used as sulfenylating reagents to intercept aza-enolates generated from imidate deprotonation, giving α-thiofunctionalized imidates in good yields with high diastereocontrol. This protocol for C-S bond formation can efficiently synthesize enantioenriched 1,2-sulfanyl amine derivatives such as sulconazole.

Diastereoselective Aza-Mislow-Evans Rearrangement of N-Acyl tert-Butanesulfinamides into α-Sulfenyloxy Carboxamides.

A diastereoselective [2,3] rearrangement of O-silyl N-sulfinyl N,O-ketene acetals derived from chiral N-acyl tert-butanesulfinamides was developed, giving α-sulfenyloxy carboxamides with excellent enantioselectivity. Enolization and subsequent silylation of N-acyl tert-butanesulfinamides initiate this aza variant of the Mislow-Evans rearrangement, in which the chirality at the sulfur atom in the rearrangement precursors is faithfully transferred to the α-carbon stereocenter of the products. The Ellman sulfinamide, often used as a chiral ammonia equivalent, can serve in this rearrangement as a chiral precursor for the asymmetric synthesis of α-oxygen-functionalized carboxamides.

Dialkyl Phosphite-Initiated Cyclopropanation of α,ß-Unsaturated Ketones Using α-Ketoesters or Isatin Derivatives.

Efficient cyclopropanation of α,ß-unsaturated ketones using α-ketoesters or isatin derivatives is reported. The cyclopropanation reaction occurs via a cascade transformation that starts with addition of deprotonated dialkyl phosphite to the keto groups of α-ketoesters or isatin derivatives, followed by [1,2]-phosphonate/phosphate rearrangement to generate α-phosphonyloxyenolate intermediates, which are trapped by α,ß-unsaturated ketones via Michael addition/ring closure. This protocol was used to synthesize tetra-substituted cyclopropanes with a 1,2-cis-1,3-trans configuration in high yield with excellent diastereoselectivity.

Aldol Reaction of N-tert-Butanesulfinyl Imidates under Basic Conditions for Diastereoselective Synthesis of anti-Aldols.

Diastereoselective aldol reaction of N-tert-butanesulfinyl imidates under typical hard enolization conditions is reported. Potassium bis(trimethylsilyl)amide (KHMDS) effectively promotes the aldol reaction of α-aryl- and α-alkyl-substituted imidates, providing anti-aldol adducts in high yields with good to excellent diastereoselectivities. In the case of α-aryl imidates, high conversion depends on adding trimethylsilyl chloride (TMSCl) to the reaction mixture. In the presence of a suitable Lewis acid, cyclohexanone is a good electrophile in the aldol reaction of imidates.

P(NMe2)3-Mediated Aziridination of Imines with α-Ketoesters for Synthesis of Aziridine-2-carboxylates.

Aziridination of N-sulfonyl imines with α-ketoesters in the presence of P(NMe2)3 is reported. Adducts derived from trivalent phosphorus reagents and α-ketoesters are effectively intercepted by imines, affording a range of aziridine-2-carboxylates. The diastereoselectivity of the reaction depends on steric hindrance from substituents on the substrates.

Reaction of Silyllithium, α-Keto N-tert-Butanesulfinyl Imidates and Aldehydes for Asymmetric Synthesis of α-Substituted ß-(Silyloxy)-α-hydroxy Acid Derivatives.

A single-flask reaction of silyllithium, α-keto N-tert-butanesulfinyl imidates and aldehydes has been developed for the diastereoselective synthesis of α,ß-dihydroxy acid derivatives. In this reaction, the nucleophilic addition of silyllithium to chiral α-keto imidates followed by silyl migration forms chiral aza-enolates, which react diastereoselectively with aldehydes. Subsequent [1,4]-O → O silyl migration affords α-substituted ß-(silyoxy)-α-hydroxy imidates.

Synthesis of aryl anti-vicinal diamines via aza-Brook rearrangement-initiated nucleophilic addition of α-silylamines to imines.

An efficient protocol is described for the synthesis of vicinal diamines via aza-Brook rearrangement-initiated nucleophilic addition of α-silylamines to imines. Various symmetrical and unsymmetrical aryl diamine derivatives were prepared in moderate to high yields with high anti/syn diastereoselectivity.

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.

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.

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 Electrophilic Sulfenylation of ß,ß-Disubstituted Enesulfinamides: Asymmetric Construction of Less Accessible Acyclic α,α-Disubstituted α-Sulfenylated Ketimines.

Current methods for the asymmetric α-sulfenylation of carbonyls cannot be applied to acyclic carbonyls that have two similar substituents at the α-position. This research demonstrated that the electrophilic sulfenylation of geometry-defined acyclic ß,ß-disubstituted enesulfinamides using S-aryl or S-alkyl benzenethiosulfonates can be highly stereoselective. This process results in enantioenriched α,α-disubstituted α-sulfenylated ketone surrogates with sulfur-containing acyclic tetrasubstituted carbon stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl). Furthermore, by employing the corresponding stereoisomers of enensulfinamides, any of the four stereoisomers of α-sulfenylated ketimines can be selectively accessed.

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.