Taichi Kano

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric anti-Selective Mannich Reactions and syn-Selective Cross-Aldol Reactions

A direct asymmetric Mannich reaction using a novel axially chiral amino sulfonamide (S)-3 that is highly anti- and enantioselective has been developed. For instance, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and alpha-imino esters proceeded smoothly to give anti Mannich products with a significantly higher anti/syn ratio and enantioselectivity than previously possible. By utilizing N-Boc-protected aromatic imines instead of alpha-imino esters, the synthetically useful Boc protecting group and various aromatic or heteroaromatic substituents were installed into the anti Mannich products and consequently the substrate scope of the anti-selective Mannich reaction and the synthetic utility of the anti Mannich products have been expanded. The axially chiral amino sulfonamide (S)-3 has also been successfully applied to asymmetric direct cross-aldol reaction between two different aldehydes. The catalyst (S)-3 has the advantage of giving mainly syn products, whereas proline shows the opposite anti selectivity.

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric Mannich Reactions of N‐Boc‐Protected Imines

The moderate nucleophilicity of the axially chiral amino sulfonamide (S)-1 suppresses the problematic side reactions, including aldol reactions, in the asymmetric Mannich reaction of N-Boc-protected imines with aldehydes. The corresponding adducts are obtained in good yield and excellent stereoselectivity (see scheme; Boc = tert-butoxycarbonyl, Tf = trifluoromethanesulfonyl).

Direct Asymmetric Benzoyloxylation of Aldehydes Catalyzed by 2-Tritylpyrrolidine

A direct asymmetric benzoyloxylation of aldehydes with benzoyl peroxide was found to be catalyzed by (S)-2-(triarylmethyl)pyrrolidines (S)-2. This method provides a new approach for the preparation of optically active alpha-benzoyloxyaldehydes as useful chiral building blocks.

Stereocontrolled Synthesis of Vicinal Diamines by Organocatalytic Asymmetric Mannich Reaction of N-Protected Aminoacetaldehydes: Formal Synthesis of (−)-Agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.

Design of chiral organocatalysts for practical asymmetric synthesis of amino acid derivatives

A series of structurally rigid, chiral quaternary ammonium salts and several chiral sec-amine catalysts derived from commercially available (R)- or (S)-binaphthol have been designed as new C(2)-symmetric chiral phase-transfer catalysts and chiral bifunctional amino-catalysts. These chiral organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives.

Metal‐Free Direct Asymmetric Aminoxylation of Aldehydes Catalyzed by a Binaphthyl‐Based Chiral Amine

Chiral a-hydroxy carbonyl motifs are prevalent in natural products and biologically active compounds, and are versatile building blocks for the synthesis of structurally complex molecules. It is known that such chiral a-hydroxy carbonyl compounds are prepared by asymmetric oxygenations of preformed enolates and enamines, such as epoxidation, dihydroxylation, and aminoxylation. Over the past several years, a number of direct asymmetric a-oxygenations of aldehydes and ketones catalyzed by chiral secondary amines have been reported. In this area, nitroso compounds have been commonly utilized as an electrophile for asymmetric aaminoxylation, and virtually optically pure a-aminoxy carbonyl compounds have been prepared. However, the aaminoxy aldehydes and the reduced b-aminoxy alcohols produced are highly labile, probably owing to oligomerization and/or N O bond cleavage. Recently, Sibi and Hasegawa reported the asymmetric aaminoxylation of aldehydes using a stable radical, 2,2,6,6tetramethylpiperidine 1-oxyl free radical (TEMPO), which is considered to progress via a radical coupling pathway between TEMPO and the enamine radical cation generated from the enamine intermediate and a metal single electron oxidant (Scheme 1a). Whilst this metal-promoted reaction requires further improvement of the reaction conditions and the substrate scope, the resulting aminoxy aldehydes are attractive chiral building blocks as O-protected a-hydroxy aldehydes because of their stability. Accordingly, we have been interested in the possibility of utilizing oxoammonium salt 1, which could be generated in situ by oxidation from TEMPO, as a non-metal single-electron oxidant and an aminoxylating agent in the aminoxylation of aldehydes (Scheme 1b). Herein, we report a metal-free organocatalytic asymmetric aminoxylation of aldehydes using TEMPO and benzoyl peroxide (BPO) with high enantioselectivity and broad substrate scope. To oxidize TEMPO into 1, which is known as a catalyst in TEMPO oxidation, BPO was chosen as an organic oxidant. In the presence of chiral pyrrolidine catalyst (S)-2, 3-

Organocatalytic Approach to Enantioselective One-Pot Synthesis of Pyrrolidine, Hexahydropyrrolizine, and Octahydroindolizine Core Structures

An enantioselective organocatalytic, one-pot synthesis of pyrrolidine, hexahydropyrrolizine, and octahydroindolizine core structures was realized starting from readily available glycine esters by combination with several different organocatalytic reactions.

Efficient organocatalytic cross-aldol reaction between aliphatic aldehydes through their functional differentiation.

A chemo- and stereoselective asymmetric direct cross-aldol reaction between aliphatic aldehydes and α-chloroaldehydes has been developed as a method for the formation of the sole cross-aldol adduct with both enantio- and diastereocontrol, and either anti- or syn-aldol adducts were obtained in good to excellent stereoselectivities by use of proline or a novel axially chiral amino sulfonamide as catalyst.

Design of chiral bifunctional secondary amine catalysts for asymmetric enamine catalysis

A series of binaphthyl-based secondary amine catalysts containing various functional groups have been designed as new chiral bifunctional amine catalysts. These chiral organocatalysts have been successfully applied to several asymmetric reactions via enamine intermediates and exhibit unique reactivity and selectivity in comparison with proline and its derivatives.

Direct Asymmetric Iodination of Aldehydes Using an Axially Chiral Bifunctional Amino Alcohol Catalyst

A direct asymmetric iodination reaction of aldehydes with NIS was found to be catalyzed by the novel axially chiral bifunctional amino alcohol (S)-1d. This method represents the rare example of the catalytic and highly enantioselective synthesis of optically active alpha-iodoaldehydes.