Xing-Wen Sun

An advance on exploring N-tert-butanesulfinyl imines in asymmetric synthesis of chiral amines.

Although catalytic asymmetric synthesis has undergone tremendous growth in the last 30 years, chiral auxiliary-aided asymmetric synthesis continues to attract considerable attention. Chiral N- tert-butanesulfinamide, as pioneered by Ellman and co-workers, is undoubtedly one of the most efficient auxiliaries developed to date; it allows the preparation, through simple conversion, of a diverse range of enantiopure amines, which are ubiquitous in natural products and biologically active molecules. Following on from our studies of the SmI(2)-mediated asymmetric syntheses of alpha,gamma-substituted gamma-butyrolactones, we found that simple homocoupling of chiral N- tert-butanesulfinyl imines in the presence of SmI(2) produced enantiopure vicinal C2-symmetric diamines in high yield. In addition, C2-unsymmetric chiral diamines are readily prepared through SmI(2)-mediated cross-couplings of N- tert-butanesulfinyl imines and nitrones; these transformations represented the first successful examples of asymmetric cross-coupling between two different imine species. Subsequently, we discovered another useful reaction induced by SmI(2), the efficient cross-coupling of N- tert-butanesulfinyl imines and aldehydes, which provides ready access to enantiopure anti-1,2-amino alcohols. The synthetic applicability of this reaction was demonstrated through its use in the facile total syntheses of (3R,4S)-statine, d- erythro-sphinganine, (+)-CP-99,994, and (+)-L-733,060. The Zn/In-mediated allylation of chiral N- tert-butanesulfinyl imines yields homoallylic amines. After pondering the reaction mechanism, we developed optimal reaction conditions for reversing the stereogenic outcome, thereby allowing the preparation of enantiopure homoallylic amines of either handedness from single enantiomers of the (R)- or (S)-sulfinyl imine. When a benzoyl-substituted allyl bromide is used for allylation, the reaction proceeds smoothly to give 2-vinyl-substituted anti-1,2-amino alcohols in high yields and diastereoselectivities, another simple method for preparing enantiopure amino alcohols. We employed these reactions in the syntheses of enantiopure allylglycine, 3-allyl-isoindolinones, and (-)-cytoxazone. Further studies led to the discovery that the allylations of N- tert-butanesulfinyl aldimines can be performed in water. The reactions described in this Account are among the simplest and most efficient synthetic methods available for preparing enantio-enriched diamines, amino alcohols, homoallylic amines, and other amine derivatives. These reactions are additionally attractive because of the ready availability of the starting materials, the simplicity of the reaction conditions, and the high degree of stereochemical control. Their applications in the total syntheses of several biologically interesting molecules illustrate the versatility of these transformations; we hope that they will stimulate the development of new synthetic methods.

Remarkable salt effect on In-mediated allylation of N-tert-butanesulfinyl imines in aqueous media: highly practical asymmetric synthesis of chiral homoallylic amines and isoindolinones.

A highly practical and efficient asymmetric synthesis of chiral homoallylic amines by In-mediated allylation of chiral N-tert-butanesulfinyl imines in aqueous media at room temperature was developed. With 2-formylbenzoate imine substrates, the method allows the highly enantioselective achievement of a variety of pharmacologically important 3-allyl isoindolinone compounds.

Highly efficient asymmetric construction of quaternary carbon-containing homoallylic and homopropargylic amines

A highly efficient method for the asymmetric synthesis of chiral quaternary carbon-containing homoallylic and homopropargylic amines under mild conditions was achieved with good yields and high diastereoselectivities.

Highly efficient asymmetric synthesis of enantiopure dihydro-1,2-oxazines: dual-organocatalyst-promoted asymmetric cascade reaction.

A one-pot dual-organocatalyst-promoted asymmetric α-aminoxylation/aza-Michael/aldol consendation cascade reaction is presented. The targeted optically active 1,2-oxazine derivatives are synthesized in moderate yields (up to 70%), excellent enantioselectivities (ee >99% in all cases), and excellent diastereoselectivities (dr up to >99:1) under mild conditions. To further elucidate the synthetic utility of the cascade products, cleavage of the N-O bond is demonstrated and an enantiopure syn-1,4-amino alcohol derivative is achieved in excellent yield.

An eco-benign and highly efficient access to 3-heterocyclic-substituted isoindolinones in ammonia water

A highly efficient three-component reaction of 2-formyl benzoic acid, ammonia and 4-hydroxycoumarin or indole in water was developed. With this highly environmentally benign protocol, a series of isoindolinone derivatives were efficiently produced in good to excellent yields.

Recent applications of chiral N-tert-butanesulfinyl imines, chiral diene ligands and chiral sulfur–olefin ligands in asymmetric synthesis

This review highlights the recent applications of chiral N-tert-butanesulfinyl imines and chiral diene ligands, with bicyclo[3.3.0]octadiene and dicyclopentadiene skeletons, in asymmetric chemical transformations. The chiral sulfinamide–olefin products from allylation of N-tert-butanesulfinyl imines can be used as hybrid ligands for transition metal-catalyzed asymmetric reactions. The efforts in the further exploration of chiral sulfur–olefin ligands are also discussed.

Squaramide‐Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites

A new method for the construction of five-membered spirocyclic oxindoles is based on a Michael-Mannich cascade reaction of a ketimine intermediated catalyzed by a bifunctional quinine-derived squaramide. The desired products were obtained in excellent yields (up to 94%) and stereoselectivities (up to >20:1 d.r., >99% ee). A scaled-up variant also proceeded smoothly showing that the one-pot reaction might find application in the synthesis of bioactive-compound libraries.

Dual-organocatalyst-promoted asymmetric cascade reaction: highly efficient construction of enantiopure fully substituted tetrahydro-1,2-oxazines.

A four-component asymmetric α-aminoxylation/aza-Michael/Mannich cascade reaction for the construction of fully substituted chiral tetrahydro-1,2-oxazine derivatives was accomplished in high yields with excellent enantio- and diastereoselectivities under mild conditions. The 1,2-oxazine derivative could be transformed to the corresponding multifunctional chiral amino alcohol by N-O cleavage and fused-tricyclic 4-amino-substituted tetrahydroquinolines in good yields with excellent stereoselectivities followed by a Friedel-Crafts reaction. Also a 4-alkoxy-substituted tetrahydroquinoline was achieved by C-4 inversion of a 4-amino-substituted tetrahydroquinoline.

Asymmetric synthesis of poly-substituted spirocyclohexane oxindole via a squaramide catalyzed cascade Michael–Michael–aldol sequence

A squaramide-catalyzed Michael–Michael–aldol cascade sequence of three readily accessible substrates (1,3-dicarbonyl compound, nitroalkene and methyleneindolinone) was developed. The reactions led to a series of enantioenriched spirocyclohexane oxindoles bearing six contiguous stereocenters in good yields (up to 85%) and with excellent stereoselectivities (>20:1 dr, >99% ee).

Practical Asymmetric Synthesis of Amathaspiramides B, D, and F.

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8R-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared.