Wenhao Hu

Cooperative Catalysis with Chiral Brønsted Acid-Rh2(OAc)4: Highly Enantioselective Three-Component Reactions of Diazo Compounds with Alcohols and Imines

An asymmetric three-component reaction of diazo compounds and alcohols with imines catalyzed cooperatively by a rhodium complex and a chiral Brønsted acid provides a general and efficient entry to beta-amino-alpha-hydroxyl acid derivatives in high yields with excellent stereoselectivities.

Highly enantioselective trapping of zwitterionic intermediates by imines

Reactions with the unstable and highly reactive zwitterionic intermediates generated in processes catalysed by transition metals are providing new opportunities for molecular constructions. Insertion reactions involve the collapse of zwitterionic intermediates, but trapping them would allow structural elaborations that are not currently available. To synthesize complex molecules in this manner, reactive electrophiles can be used to trap the zwitterionic intermediates. Here, we describe the use of imines, activated by chiral organocatalysts, and a highly efficient integrated rhodium and chiral Brønsted acid co-catalysed process to trap zwitterionic intermediates that have been proposed previously to undergo a formal C–H insertion reaction, allowing us to obtain polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity. Reactions with unstable and highly reactive zwitterionic intermediates generated in transition-metal-catalysed processes provide new opportunities for molecular constructions. Here imines, activated by chiral organocatalysts, have been employed to trap the zwitterionic intermediates to give polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity.

Diastereoselectively Switchable Enantioselective Trapping of Carbamate Ammonium Ylides with Imines

The diastereoselectively switchable enantioselective trapping of protic carbamate ammonium ylides with imines is reported. The intriguing Rh(2)(OAc)(4) and chiral Brønsted acid cocatalyzed three-component Mannich-type reaction of a diazo compound, a carbamate, and an imine provides rapid and efficient access to both syn- and anti-α-substituted α,β-diamino acid derivatives with a high level control of chemo-, diastereo-, and enantioselectivity.

Catalytic Asymmetric Functionalization of Aromatic CH Bonds by Electrophilic Trapping of Metal‐Carbene‐Induced Zwitterionic Intermediates

Asymmetric functionalization of aromatic C-H bonds of N,N-disubstituted anilines with diazo compounds and imines is reported for the efficient construction of α,α-diaryl benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. This Rh(II)/chiral phosphoric acid cocatalyzed transformation is proposed to proceed through a metal-carbene-induced zwitterionic intermediate which undergoes electrophilic trapping. To the best of our knowledge, this is the first asymmetric example of metal carbene-induced intermolecular functionalization of aryl C-H bonds.

Bicyclic Pyrazolidinone Derivatives from Diastereoselective Catalytic [3 + 3]-Cycloaddition Reactions of Enoldiazoacetates with Azomethine Imines

A highly regio- and diastereoselective synthesis of bicyclic pyrazolidinone derivatives by rhodium(II) acetate catalyzed [3 + 3]-annulation with enoldiazoacetates and azomethine imines has been achieved in high yield. A vinylogous reaction of the metal enol carbene with the azomethine imine initiates [3 + 3]-cycloaddition, whereas reaction at the carbene center effects N-N-cleavage of the azomethine imine.

A Strategy to Synthesize Taxol Side Chain and (−)-epi Cytoxazone via Chiral Brønsted Acid-Rh2(OAc)4 Co-catalyzed Enantioselective Three-Component Reactions†

A new approach to synthesize optically active β-amino-α-hydroxyl acid derivatives via chiral Brønsted acid-Rh(2)(OAc)(4) cocatalyzed three-component reactions of diazo acetates with alcohols and imines is reported. A matched reaction system was identified to give the products in moderate diastereoselectivity and good enantioselectivity. Application of this methodology is demonstrated in the efficient synthesis of a taxol side chain and (-)-epi-cytoxazone.

Salen-Ti(OR)4 complex catalysed trimethylsilylcyanation of aldehydes

Abstract Chiral salen-titanium complexes were found to be efficient catalysts for the enantioselective trimethylsilylcyanation of aldehydes. An enantioselectivity up to 87.1% e.e. was obtained by using 10mol% Ti(IV)-salen 2d as catalyst. The reaction mechanism was proposed and proved experimentally.

Catalytic Enantioselective Trapping of an Alcoholic Oxonium Ylide with Aldehydes: RhII/ZrIV‐Co‐Catalyzed Three‐Component Reactions of Aryl Diazoacetates, Benzyl Alcohol, and Aldehydes

Catalytic asymmetric multicomponent reactions (CAMCRs), in which three or more reactants are combined in a single chemical step to stereoselectively produce chiral molecules, have received considerable attention. In addition to lowering costs, saving time and energy, and being environmentally friendly, CAMCRs are capable of efficiently building chiral molecules such as those with stereogenic quaternary carbon atoms that would otherwise be inaccessible by traditional methods. Although significant progress has been made in the area of multicomponent reactions, there is still a high demand for new CAMCRs to meet the increasing need for the rapid construction of polyfunctional chiral molecules. Herein we disclose a novel type of CAMCR in which polyfunctional dihydroxy acid derivatives with two stereogenic centers, one of which is a tetrasubstituted carbon center, are constructed in a single step. We have previously reported three-component reactions of diazo compounds 1, alcohols 2, and aldehydes 3 to yield racemic mixtures of dihydroxy acid frameworks with quaternary stereogenic centers 4 [Eq. (1)]. The reaction was proposed to proceed through the alcoholic oxonium ylide intermediates IIa or IIb (Scheme 1), which are generated in situ from 1 and benzyl alcohol (2) in the presence of Rh2(OAc)4. Trapping intermediates II with aldehydes resulted in 4 ; the desired process was in competition with an irreversible intramolecular proton transfer within IIa/IIb leading to the O H insertion side products 5 (Scheme 1). We also observed that addition of a stoichiometric amount of the Lewis acid Ti(OtBu)4 suppressed the O H insertion. This observation supported the proposed mechanism, including the competing intramolecular process, because the Lewis acid would have increased the electrophilicity of the aldehydes, and thereby activating them. On the basis of this observation and the previous success of chiral Lewis acid catalysts in facilitating highly enantioselective aldol reactions, we envisioned that by using appropriate chiral Lewis acid cocatalysts it might be possible to achieve asymmetric catalysis of the target three-component reaction. In the presumed mechanism, an alcoholic oxonium ylide II, which is formed in situ from a diazoacetate and an alcohol, would experience a “delayed proton transfer” and instead undergo an enantioselective aldol-type addition onto an aldehyde III activated with chiral Lewis acid to generate optically active 4 (Scheme 1). To validate the hypothesis a number of chiral Lewis acids, such as combinations of Cu(OTf)2, Yb(OTf)3, Mg(ClO4)2, or Sn(OTf)2 (Tf = trifluoromethanesulfonyl) with chiral bisoxazoline ligands and combinations of Ti salts with chiral binol (binol= (1,1’-bi-2-naphthyl)) derivatives, were screened as chiral co-catalysts for the target CAMCR. None yielded satisfactory chemoand stereoselectivities. Never-

An Ylide Transformation of Rhodium(I) Carbene: Enantioselective Three‐Component Reaction through Trapping of Rhodium(I)‐Associated Ammonium Ylides by β‐Nitroacrylates

The chiral Rh(I)-diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and β-nitroacrylates was achieved to obtain γ-nitro-α-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh(I)-carbene-induced ylide transformation.

Highly Enantioselective Catalytic Synthesis of Functionalized Chiral Diazoacetoacetates

The Michael reaction is one of the most general and versatile methods for carbon-carbon bond formation,1 and its Mukaiyama-Michael variant provides an efficient strategy for the addition of silyl enol ethers to α,β-unsaturated carbonyl compounds.2 Catalytic asymmetric reactions with broad variations in α,β-unsaturated carbonyl compounds and chiral catalyst (Lewis acid and Bronsted acid) are well documented,3,4 and the enantioenriched 1,5-dicarbonyl compounds formed from these reactions have proven to be useful building blocks. However, there has been limited variation in the silyl enol ethers used in these reactions, and none of them have incorporated multiple functional groups.