Asymmetric Three-Component Reaction of Two Diazo Compounds and Hyrdroxylamine Derivatives for the Access to Chiral α-Alkoxy-β-amino-carboxylates

Abstract

Hydroxylamine derivatives are commonly used as both nitrogen and oxygen sources in the aminohydroxylation of alkenes, which is a powerful and practical method for the rapid assembly of synthetically useful 1,2-aminoalcohols. In this work, we disclose an unprecedented asymmetric formal aminohydroxylation of two diazo compounds with O-benzyl hydroxylamines, which involves a N–O bond activation, fragment modification, and reassembly cascade process. This cascade reaction forms multiple bonds in one-pot, including CN, C–O, and C–C bonds, providing a potent complement for the aminohydroxylation using alkenes to that using two different diazo compounds, and leading to chiral α-alkoxy-β-amino-carboxylate derivatives with two adjacent tertiary chiral centers in generally good yields and high to excellent enantioselectivity.

Theoretical Analysis of a Three-Component Reaction between Two Diazo Compounds and a Hydroxylamine Derivative: Mechanism, Enantioselectivity, and Effect of Cooperative Catalysis

“…10 Inspired by these works, Hu and co-workers utilized a dual catalytic system for developing a conceptually distinct and highly attractive three-component asymmetric aminohydroxylation involving two diazo compounds and a hydroxylamine derivative. 11 The process relies on the use of Rh 2 (OAc) 4 and a chiral phosphoric acid (CPA) as two components of a cooperative catalytic system (Scheme 1), providing the chiral vicinal amino alcohol derivatives with significant structural diversity. 12 The catalytic cycle shown in Scheme 2 comprises the following steps: (i) the formation of active rhodium carbene A, (ii) the nucleophilic attack of the nitrogen center of N-hydroxyaniline, (iii) the formation of ketimine species C via "rebound hydrolysis", and (iv) the generation of oxonium ylide E (or its enolate form E′) from the second diazo compound and the leaving BnOH fragment of the first step, in the presence of the same dirhodium catalyst, through carbene intermediate D; the (v) asymmetric Mannich-type addition of the above ketimine species C and oxonium ylide E (or E′), furnishing the aminohydroxylation products.…”

“…12 The catalytic cycle shown in Scheme 2 comprises the following steps: (i) the formation of active rhodium carbene A, (ii) the nucleophilic attack of the nitrogen center of N-hydroxyaniline, (iii) the formation of ketimine species C via "rebound hydrolysis", and (iv) the generation of oxonium ylide E (or its enolate form E′) from the second diazo compound and the leaving BnOH fragment of the first step, in the presence of the same dirhodium catalyst, through carbene intermediate D; the (v) asymmetric Mannich-type addition of the above ketimine species C and oxonium ylide E (or E′), furnishing the aminohydroxylation products. 11 Based on the mechanisms proposed by Hu and co-workers, 11 we unveiled a detailed reaction pathway for the title catalytic reaction, as illustrated in Scheme 3. Aiming at better understanding the overall reaction mechanism in these intriguing transformations (Scheme 3), we report herein an exhaustive DFT calculation study that investigates the role of chiral phosphoric acid (CPA) and sheds light on the origin of unusual enantioselectivity.…”

“…Inspired by these works, Hu and co-workers utilized a dual catalytic system for developing a conceptually distinct and highly attractive three-component asymmetric aminohydroxylation involving two diazo compounds and a hydroxylamine derivative . The process relies on the use of Rh 2 (OAc) 4 and a chiral phosphoric acid (CPA) as two components of a cooperative catalytic system (Scheme ), providing the chiral vicinal amino alcohol derivatives with significant structural diversity .…”

“…The process relies on the use of Rh 2 (OAc) 4 and a chiral phosphoric acid (CPA) as two components of a cooperative catalytic system (Scheme ), providing the chiral vicinal amino alcohol derivatives with significant structural diversity . The catalytic cycle shown in Scheme comprises the following steps: (i) the formation of active rhodium carbene A , (ii) the nucleophilic attack of the nitrogen center of N -hydroxyaniline, (iii) the formation of ketimine species C via “rebound hydrolysis”, and (iv) the generation of oxonium ylide E (or its enolate form E′ ) from the second diazo compound and the leaving BnOH fragment of the first step, in the presence of the same dirhodium catalyst, through carbene intermediate D ; the (v) asymmetric Mannich-type addition of the above ketimine species C and oxonium ylide E (or E′ ), furnishing the aminohydroxylation products . Based on the mechanisms proposed by Hu and co-workers, we unveiled a detailed reaction pathway for the title catalytic reaction, as illustrated in Scheme .…”

Facile Friedel–Crafts alkylation of arenes under solvent-free conditions

“…This method can be divided into two strategies: the transition-metal-catalyzed C(sp 2 )–H insertion of α-aryl-α-diazoesters and the direct Friedel–Crafts alkylation of arenes. In the transition-metal-catalyzed C(sp 2 )–H insertion reactions of arenes, the commonly used transition metals are rhodium, 7 gold, 8 iron 9 and copper, 10 and the metal–carbene intermediate is initially formed from diazo compounds (Scheme 1a). 11 However, electron-rich arenes are needed in these reactions.…”