Dynamic thermodynamic resolution of N-methylpseudoephedrine α-bromo esters for asymmetric syntheses of α-hydroxy carboxylic acid derivatives

An example of dynamic thermodynamic resolution in the nucleophilic substitution reactions of α-bromo esters with an oxygen nucleophile is described. Temperature controlled epimerization-substitution sequence provides a practical protocol for the preparation of highly enantioenriched α-hydroxy carboxylic acid derivatives up to 72% yield with 99:1 er.     

Dynamic resolution of α-halo carboxylic acid derivatives in asymmetric nucleophilic substitution using chiral auxiliaries

Recent results on the chiral auxiliary-mediated dynamic resolution of α-halo acid derivatives in nucleophilic substitution have been outlined and classified into two major mechanistic categories, dynamic thermodynamic resolution (DTR) and dynamic kinetic resolution (DKR). Asymmetric nucleophilic substitution of α-halo acid derivatives with various nitrogen, oxygen, sulfur, and carbon nucleophiles is widely used for the stereoselective preparation of α-substituted carboxylic acids.     

α-fluorination of ketones by xenon and iodobenzene difluorides: A stereochemical evidence demonstrating their mechanistic differences

Xenon difluoride reacts smootlhy with various steroid silyl enol ethers in the absence of any acid catalyst to afford stereoselectively α-oriented α-fluoroketones in good yields while iodotoluene difluoride reacts rather sluggishly with these silyl enol ethers to competitively produce β-oriented α-fluoro ketones, elimination and other nucleophilic substitution products. The observed stereochemical contrast clearly suggests an electrophilic and nucleophilic mechanism for these reactions, respectively.     

Water-promoted highly regio- and stereoselective synthesis of α-dehydro-β-amino esters and nitriles from Baylis-Hillman acetates

The nucleophilic addition of amines to Baylis-Hillman acetates has been efficiently carried out in water at room temperature in the absence of any base, acid, or metal catalyst to produce α-dehydro-β-amino esters and nitriles. This procedure addresses a variety of aliphatic open-chain and cyclic amines and anilines. All the reactions are highly regio- and stereoselective, fast and high yielding.     

Cu‐Catalyzed Alkylative Carboxylation of Ynamides with Dialkylzinc Reagents and Carbon Dioxide

Alkylative carboxylation of ynamides with CO₂ and dialkylzinc reagents using a N‐heterocyclic carbene (NHC)–copper catalyst has been developed. A variety of ynamides, both cyclic and acyclic, undergo this transformation under mild conditions to afford the corresponding α,β‐unsaturated carboxylic acids, which contain the α,β‐dehydroamino acid skeleton. The present alkylative carboxylation formally consists of Cu‐catalyzed carbozincation of ynamides with dialkylzinc reagents with the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO₂. Dialkylzinc reagents bearing a β‐hydrogen atom such as Et₂Zn and Bu₂Zn still afford the alkylated products despite the potential for β‐hydride elimination. This protocol would be a desirable method for the synthesis of highly substituted α,β‐ dehydroamino acid derivatives due to its high regio‐ and stereoselectivity, simple one‐pot procedure, and its use of CO₂ as a starting material.     

Facile synthesis of enantioenriched Cγ-tetrasubstituted α-amino acid derivatives via an asymmetric nucleophilic addition/protonation cascade

An asymmetric nucleophilic addition/protonation reaction of 3-substituted oxindoles and ethyl 2-phthalimidoacrylate has been described. This strategy can give direct access to C(γ)-tetrasubstituted α-amino acid derivatives bearing 1,3-nonadjacent stereocenters with up to 98% yield, 94:6 dr, and >99% ee. Dual activation is proposed in the transition state, and the opposite enantiomers can be obtained simply by changing cinchonidine-derived catalyst to the cinchonine analogue.     

Unexpected catalysis: aprotic pyridinium ions as active and recyclable Brønsted acid catalysts in protic media

Simple pyridinium salt derivatives have been (rather unexpectedly) shown to promote highly efficient acetalization reactions of both aldehydes and ketones at ambient temperature. The optimum catalyst is aprotic, yet it can promote the formation of benzaldehyde dimethyl acetal at 0.1 mol % loading more efficiently than a protic Br?nsted acid catalyst with a pKa of 2.2. The process is of wide scope with respect to both the nucleophilic and electrophilic components, and the ionic catalyst can be readily recovered by precipitation and reused without loss of activity.     

Direct Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated Butyrolactones to α,β‐Unsaturated Thioamides

Soft Lewis acid/Brønsted base cooperative catalysts have enabled direct catalytic asymmetric vinylogous conjugate addition of α,β‐ and β,γ‐unsaturated butyrolactones to α,β‐unsaturated thioamides with perfect atom economy. When using α‐angelica lactone and its derivatives as pronucleophiles, as little as 0.5 mol % catalyst loading was sufficient to complete the reaction necessary to construct consecutive tri‐ and tetrasubstituted stereogenic centers in a highly diastereo‐ and enantioselective fashion.     

New chiral phase-transfer catalysts possessing a 6,6′-bridged ring on the biphenyl unit: application to the synthesis of α,α-dialkyl-α-amino acids

A new chiral phase-transfer catalyst possessing a 6,6′-bridged ring on the biphenyl unit has been developed for the practical synthesis of α,α-dialkyl-α-amino acids. This catalyst shows very high activity for the asymmetric alkylation of an alanine derivative to give α,α-dialkyl-α-amino acid derivatives with high enantioselectivities.     

Iron-catalyzed C(sp)–H functionalization of methyl azaarenes with α-oxoesters: a facile approach to lactic acid derivatives

A highly efficient method for the C(sp³)–H functionalization of methyl azaarenes to α-oxoesters in the presence of iron(II) acetate as an inexpensive, nontoxic catalyst with moderate-to-excellent yields has been developed. This transformation represents a facile approach to medicinally important lactic acid derivatives.     

High regioselectivity in electrochemical α-methoxylation of N-protected cyclic amines

N-Protecting groups of α-substituted cyclic amines strongly affected the regioselectivity in electrochemical methoxylation of these compounds. Namely, N-acyl derivatives were transformed into α′-methoxylated compounds, while N-cyano derivatives changed into α-methoxylated derivatives. Furthermore, Lewis acid catalyzed nucleophilic substitution of the α-methoxylated compounds protected with cyano group afforded α,α-disubstituted cyclic amines.     

Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β‐unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β‐unsaturated 7‐azaindoline amides act as reactive electrophiles to participate in catalytic diastereo‐ and enantioselective vinylogous conjugate addition of γ‐butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.     

Synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives by intramolecular nucleophilic addition of tertiary enamides to in-situ generated imines

The reactivity of stable tertiary enamides in nucleophilic addition reaction with various in-situ generated imines was explored. Under very mild conditions, formyl-bearing tertiary enamides reacted with both aromatic and aliphatic amines to form imine intermediates. In the absence or presence of p-toluenesulfonic acid as a catalyst, intramolecular nucleophilic addition of enamide to imine functionality proceeded effectively to produce diverse 4-amino-1,2,3,4-tetrahydropyridine derivatives in good to excellent yields.     

Asymmetric Synthesis of a Quaternary Carbon Stereogenic Center by Organocatalysis Using a Primary Amino Acid and Its Salt

In this personal account, our recent developments on the asymmetric synthesis of a quaternary carbon stereogenic center by organocatalysis using a primary amino acid and its salt as a catalyst are described in three chapters: (1) conjugate addition to nitroalkenes and vinyl ketones, (2) nucleophilic addition to π-allyl palladium complexes, and (3) nucleophilic substitution reactions with allyl and propargyl halides. By these methods, asymmetric α-allylation of α-branched aldehydes and ketones smoothly proceeded to give γ-nitroaldehydes, ketoaldehydes, α-allylated aldehydes, and α-allylated β-ketoesters possessing a quaternary carbon stereogenic center in good yields with high enantioselectivities.     

Alkylative Carboxylation of Ynamides and Allenamides with Functionalized Alkylzinc Halides and Carbon Dioxide by a Copper Catalyst

The alkylative carboxylation of ynamides and allenamides with CO₂ and alkylzinc halides catalyzed by a copper catalyst was developed. A variety of alkylzinc halides bearing functional groups were used for this transformation to afford α,β-unsaturated carboxylic acids, which contain the α,β-dehydroamino acid skeleton, introducing the corresponding alkyl group and CO₂ across the carbon–carbon triple or double bond. This alkylative carboxylation formally consists of Cu-catalyzed carbozincation of ynamides or allenamides with alkylzinc halides and the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO₂. This protocol would be a useful method for the synthesis of α,β-dehydroamino acid derivatives possessing a functionalized alkyl group due to the high regio- and stereoselectivity, simple one-pot procedure as well as the use of CO₂ as a starting material.     

Asymmetric Michael addition of malonic diesters to acrylates by phase-transfer catalysis toward the construction of quaternary stereogenic α-carbons

A highly enantioselective construction of an all-carbon quaternary stereogenic center at the α-position of malonic diesters has been achieved by Michael addition using phase-transfer catalysis. The reaction of α-monosubstituted malonates with acrylates in the presence of N-(9-anthracenylmethyl)quininium chloride as a phase-transfer catalyst afforded the corresponding α,α-disubstituted malonic diesters in high chemical yields (up to >95% yield) with high enantioselectivities (up to 95% ee). Furthermore, the product was amenable to chemoselective transformation and could be successfully converted to the corresponding α,α-disubstituted amino acid derivatives through Curtius rearrangement.     

Catalyst free sequential one‐pot reaction for the synthesis of 3‐indole propanoates/propanoic acid/propanamides as antituberculosis agents

A highly efficient catalyst free one pot four component synthesis of highly functionalized three‐substituted indole derivatives has been reported. Thus, sequential catalyst free condensation of readily available aldehydes with Meldrum's acid followed by Michael addition of indole resulting three carbon component condensed product and concurrent decarboxylation by the nucleophilic attack of ethanol/water/amines affords three‐indole propanoates/propanoic acid/propanamides in affordable yields. Further, synthesized compounds and standard drugs were evaluated against Mycobacterium tuberculosis H37Rv strain by Alamar blue assay method. Majority of the compounds exhibited the superior activity and specifically compound 4d has MIC 1.6 μg/ml, which is better than the reference drugs used.     

Stereocontrolled ring-opening of a hindered sulfamidate with nitrogen-containing aromatic heterocycles: synthesis of chiral quaternary imidazole derivatives

This paper explores the role of a hindered cyclic sulfamidate derived from α-methylisoserine as an electrophile in a nucleophilic displacement reaction with nitrogen-containing aromatic heterocycles. Several imidazoles and pyrazole were tested as nucleophiles in the absence of an additional base to give the corresponding ring-opening compounds. We show that the process takes place by inversion of the configuration of the quaternary electrophilic center, retaining the enantiomeric excess of the starting sulfamidate. This reaction opens the way to obtain important quaternary imidazole derivatives such as an innovative type of bis-amino acid related to histidinoalanine and a novel α,α-disubstituted β-amino acid (β(2,2)-amino acid).     

Enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a CF3 moiety

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary α-amino acids in excellent yields (up to 99%) and high enantioselectivities (up to 98:2 er).     

A catalyst that plays multiple roles: asymmetric synthesis of beta-substituted aspartic acid derivatives through a four-stage, one-pot procedure

We report a new method for the catalytic, asymmetric synthesis of beta-substituted aspartic acid derivatives in which the nucleophilic catalyst serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic dehydrohalogenation of alpha-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl beta-lactams; and finally, nucleophilic ring opening to afford optically enriched beta-substituted aspartic acids in high enantioselectivity and diastereoselectivity.