Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. ¹H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.     

A Facile Synthesis of Secondary α-Alkoxy or α-Acetoxy Aromatic Ketones

Abstract: The treatment of HNIB with aromatic ketones and subsequent solvolysis using alcohol or acetic acid in one-pot system makes it possible to give corresponding secondary α-alkoxy or α-acetoxy ketones in high yields.     

Organocatalytic Enantioselective Diels–Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,β-Unsaturated Ketones

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels–Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,β-unsaturated carbonyl compounds 2 . Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1 , 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.     

Microwave-Assisted One-Carbon Chain Extension in the Preparation of Terminal α-Hydroxy Ketones

The microwave-assisted synthesis of terminal α-hydroxy ketones from acid chlorides and tris(trimethylsiloxy)ethylene in the presence of triethylamine is reported. The use of triethylamine had several advantages in the reaction: it increased the reactivity of the acid chloride, acted as a scavenger of the HCl that was produced in the reaction, protected the silylated enol from decomposition, and made the excess use of the silyl reagent unnecessary. Mechanistic effects of triethylamine are discussed. Effects of various base additives, reaction temperatures, reaction times, and solvents in the reaction are compared.     

Hypervalent Iodine(III)-Catalysed Enantioselective α-Acetoxylation of Ketones

An enantioselective catalytic synthesis of α-acetoxylated ketones through I(I)/I(III) catalysis using a resorcinol/lactamide-based chiral iodoarene is reported. Catalyst turnover by in situ generation of the active iodine(III) derivative is achieved by oxidation with mCPBA in the presence of acetic acid. The prior transformation of ketones to easily accessible acetyl enol ethers is beneficial and yields up to 97 % with enantioselectivities up to 88 % ee are obtained using only low catalyst loadings of only 5 mol % under mild reaction conditions.     

A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals

Reported herein is a visible-light-mediated radical approach to the α-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon S_N2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α-alkylation of ketones.     

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.     

Transformation of Aryl Acyloin O‐Alkyl and O‐Phenyl Derivatives to Ketones

The treatment of aryl acyloin (α‐hydroxyketone) O‐alkyl and O‐phenyl derivatives with 2–3 equiv of Zn and 1–2 equiv of NH₄Cl in ethanol, refluxing for 20–120 min, gave the corresponding ketones with excellent yields. Further, α,β‐epoxy ketones can be efficiently transformed to β‐hydroxy ketones, and 2,2‐dialkoxy‐1‐phenyl ketone also can be dealkoxylated to 1‐phenyl ketone.     

Asymmetric Hydrogenation of α-Hydroxy Ketones: A Reaction Sensitive toward Electronic Effect of Substrates

以[RuCl2(benzene)]2 和 SunPhos为原料现场制备的催化剂,催化不对称氢化α-羟基酮类化合物可获得手性1, 2-二醇类化合物,ee值最高达99%。     

Asymmetric 1,2-Carbamoyl Rearrangement of Lithiated Chiral Oxazolidine Carbamates and Diastereoselective Synthesis of α-Hydroxy Amides

Asymmetric 1,2-carbamoyl rearrangement of lithiated 2-alkenyl carbamates has been investigated. Deprotonation of chiral 2-alkenyl oxazolidine carbamates with sec-butyllithium in ether at −78 °C followed by warming of the resulting 1-lithio-2-alkenyl derivatives to room temperature resulted in 1,2-carbamoyl rearrangement to provide α-hydroxy amides. The rearrangement proceeded with excellent diastereoselectivity and in good to excellent isolated yield of the α-hydroxy amide derivatives. The substrate scope of the reaction was investigated with a variety of 2-alkenyl and benzyl oxazolidine carbamates. A stereochemical model is provided to explain the stereochemical outcome associated with the rearrangement. Acid-catalyzed removal of the chiral oxazolidine afforded α-hydroxy acid in high optical purity.     

Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and diastereoselectivities. The products were converted to chiral γ-lactams conveniently without a loss in the enantioselectivity.     

Enantioselective Construction of 3-Hydroxy Oxindoles via Decarboxylative Addition of β-Ketoacids to Isatins

The first highly enantioselective decarboxylative addition of β-ketoacids to isatins mediated by a bifunctional tertiary amine-thiourea catalyst has been developed, allowing facile synthesis of biologically important 3-hydroxy oxindoles in good yields and excellent enantioselectivities. The method reported represents a valuable approach of utilizing β-ketoacids as synthetic equivalents of aryl/alkyl methyl ketone enolates.     

Nickel-Catalyzed Enantioselective Decarboxylative Acylation: Rapid,Modular Access to α-Amino Ketones**

A new approach to the enantiocontrolled synthesis of α-amino ketone derivatives is disclosed by employing a decarboxylative acylation strategy. Thus, when an acyl chloride and an α-amido-containing redox-active ester are exposed to a nickel catalyst, chiral ligand, and metal reductant, α-amido ketones are produced in good yield and high ee. The reaction exhibits broad substrate scope, can be easily scaled up, and is applied to dramatically simplify the synthesis of several known structures.     

Enantioselective electrophilic bond construction to the α-carbon of α-aminoacids

In this report, we describe three possibilities for aminoacid synthesis using an enantioselective electrophilic process. Thus, enantioselective carboxylation, alkylation and protonation of Schiff bases yield optically active aminoacids with e.e. up to 76%.     

Organocatalytic synthesis of α-hydroxy and α-aminophosphonates

A new and highly flexible procedure is described for the synthesis of α-amino- and α-hydroxy phosphonates. In the presence of a catalytic amount of oxalic acid (10 mol %), trimethyl phosphite reacts with aldehydes or imines (generated in situ from an aldehyde and an amine) to yield the corresponding coupled products in good yield.     

A Catalytic Method for the Enantioselective Synthesis of α-Quaternary Ketones, α-Ketoesters and Aldehydes

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25–94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.     

Photo-isomerization of Aromatic α-Hydroxy Hydrazone

Photo-isomerization of aromatic α-hydroxy hydrazone was reported. We investigated the structures of salicylaldehyde phenylhydrozone(SP) in the ground state using density functional theory(DFT) with the B3LYP functional and the 6-311+G(d) basis set. All nine possible isomers of SP in the ground state consist of seven phenol forms and two ketone forms. Intrisic reaction coordinate(IRC) analysis discloses the existence of a cycle driven by the two proton transfer processes in the ground and excited states of SP, which suggests that no ketonic form could exist in the ground state. Further theoretical studies of the potential energy surfaces support a trans-cis conversion followed by a relaxation to the stable form of SP in the excited states.     

Organocatalytic Enantioselective Pictet–Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A

We report herein an asymmetric Pictet–Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]_D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.     

Silica Gel Catalysed Rearrangement of α-Epoxyketones to 1,2-Diketones

A convenient and simple method for the preparation of diphenylpropane-1,2-diones is described. The process involves rearrangement of α-epoxyketones on silica gel; an unusual migration of a proton instead of the more common benzoyl migration.     

Controlling the α/γ-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

The first regio-, diastereo-, and enantioselective direct Michael reaction of β,γ-unsaturated ketones with nitroolefins is enabled by Brønsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–98 % ee range.