Yan-Jun Xu

Diethyl Phosphite Initiated Coupling of α-Ketoesters with Imines for Synthesis of α-Phosphonyloxy-β-amino Acid Derivatives and Aziridine-2-carboxylates.

Coupling of α-ketoesters with imines initiated by diethyl phosphite in the presence of alkaline metal hexamethyldisilazides is reported. Base-promoted addition of diethyl phosphite to α-ketoesters, followed by [1,2]-phosphonate/phosphate rearrangement, generates α-phosphonyloxy enolates that are subsequently intercepted by imines. The use of suitable azomethine coupling partners allows selective construction of syn-α-hydroxy-β-amino acid derivatives or trans-aziridine-2-carboxylates in high yields with excellent diastereoselectivities.

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.

Diastereoselective synthesis of 2-methoxyimidoyloxiranes via dimethyl phosphite-mediated coupling of α-keto N-sulfinyl imidates with aldehydes

Dimethyl phosphite-initiated coupling of α-keto N-tert-butylsulfinyl imidates with aldehydes is reported. The epoxide formation involves a cascade transformation initiated by base-promoted addition of phosphite to α-ketoimidates, followed by [1,2]-phospha-Brook rearrangement. This generates α-phosphonyloxy enolates that are subsequently intercepted by aldehydes, leading to [1,4] O→O dialkoxyphosphinyl migration and finally to intramolecular ring closure. This protocol was used to synthesize a range of enantioenriched trans-α,β-epoxy imidates in moderate to high yields with excellent diastereoselectivities.

Stereoselective Synthesis of Enantioenriched 2-Chloro-2-aroylaziridines by Cascade Reaction between Aryl Nitriles, Silyldichloromethanes, and tert-Butanesulfinylimines

The cascade coupling of aryl nitriles, silyldichloromethanes, and tert-butanesulfinylimines is described, in which silyldichloromethyllithiums, generated from silyldichloromethanes in the presence of lithium diisopropylamide, undergo nucleophilic addition with aryl nitriles and subsequent [1,3]-aza-Brook rearrangement to give dichlorocarbanions bearing α-N-silyl imine (or their 1-azaenolate equivalents), which are then trapped by tert-butanesulfinylimines via an aza-Darzens-type transformation, affording enantioenriched 2-chloro-2-aroylaziridines after acidic hydrolysis of the N-silyl imine group. The stereochemistry of this cascade reaction can be tuned by selecting appropriate silyl groups on the silyldichloromethanes and altering the order of addition of the imines and the hexamethylphosphoramide additive.

Silyllithium-Initiated Coupling of α-Ketoamides with tert-Butanesulfinylimines for Stereoselective Synthesis of Enantioenriched α-(Silyloxy)-β-amino Amides

A silyllithium-initiated coupling of α-ketoamides with tert-butanesulfinylimines was developed for the efficient, stereoselective synthesis of enantioenriched α-(silyloxy)-β-amino amides. Nucleophilic addition of silyllithium to α-ketoamides, followed by 1,2-Brook rearrangement, generates nucleophilic enolates, which are then intercepted by chiral imines to provide three-component coupling products. Use of α-ketoamides is critical for achieving high yields and diastereoselectivities in the resulting α-hydroxy-β-amino acid derivatives.

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

Efficient cyclopropanation of α,β-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,β-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.

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.

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.

Reaction of Silyllithium, α-Keto N-tert-Butanesulfinyl Imidates and Aldehydes for Asymmetric Synthesis of α-Substituted β-(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,β-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 β-(silyoxy)-α-hydroxy imidates.

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.