Structural effects in the Pd-induced enantioselective deprotection–decarboxylation of β-ketoesters

Structural effects in the chiral base and the influence of some key reaction parameters (catalyst type and solvent) in the Pd-induced enantioselective decarboxylation (cascade reaction) of three different ,-disubstituted benzyl β-ketoesters were explored. The reaction intermediate after debenzylation (β-keto-carboxylic acid) was synthesized and its decarboxylation studied independently. The highest ee (up to 60%) in the cascade reaction was achieved with those substrates that contained an aromatic ring system and with chiral amino alcohols that possessed an extended aromatic ring (quinine and quinidine). Polar solvents with weak H-bond donor and acceptor properties favor enantioselection.     

Catalysis of 3‐Carboxy‐1,2‐benzisoxazole Decarboxylation by Hydrophobic Antibody Binding Pockets

Monoclonal antibodies were generated against a 3‐phenyl‐1,2‐benzisoxazole derivative and shown to catalyze the solvent‐sensitive decarboxylation of 3‐carboxy‐1,2‐benzisoxazoles. In addition to rate accelerations up to 2300‐fold over background, the antibodies exhibit distinctive selectivities for substrates bearing 5‐ or 6‐NO₂ substituents, with preferential decarboxylation of the less reactive substrate in one case. These effects are the likely consequence of substrate destabilization, achieved by forcing the carboxylate group into a relatively apolar binding pocket and stabilization of the charge‐delocalized transition state through dispersive interactions. Comparison with a more active antibody decarboxylase previously raised against 2‐acetamido‐naphthalene‐1,5‐disulfonate suggests, however, that a judicious mix of polar and apolar interactions may ultimately be more effective for achieving high decarboxylase activity.     

Allyl‐Palladium‐Catalyzed α,β‐Dehydrogenation of Carboxylic Acids via Enediolates

A highly practical and step‐economic α,β‐dehydrogenation of carboxylic acids via enediolates is reported through the use of allyl‐palladium catalysis. Dianions underwent smooth dehydrogenation when generated using Zn(TMP)₂⋅2 LiCl as a base in the presence of excess ZnCl₂, thus avoiding the typical decarboxylation pathway of these substrates. Direct access to 2‐enoic acids allows derivatization by numerous approaches.     

Transition‐Metal‐Free Formal Decarboxylative Coupling of α‐Oxocarboxylates with α‐Bromoketones under Neutral Conditions: A Simple Access to 1,3‐Diketones

A transition‐metal‐free formal decarboxylative coupling reaction between α‐oxocarboxylates and α‐bromoketones to synthesize 1,3‐diketone derivatives is presented. In this reaction, a broad scope of substrates can be employed, and neither a metal‐based reagent nor an additional base is required. DFT calculations reveal that this reaction proceeds through a coupling followed by decarboxylation mechanism and the α‐bromoketone unprecedentedly serves as a nucleophile under neutral conditions. The rate‐determining step is an unusual hydrogen‐bond‐assisted enolate formation by thermolysis.     

Palladium-Catalyzed Decarboxylative Alkynylation of α-Acyloxyketones by C(sp3)−O Bond Cleavage

Palladium-catalyzed decarboxylative alkynylation of α-acyloxyketones triggered by C(sp³)−O bond cleavage is disclosed. The decarboxylation strategy featuring a neutral reaction condition enabled an unprecedent catalytic alkynylation of a ketone enolate. The reaction was applied to a variety of substrates, giving desired products in good yields. We successfully obtained X-ray crystallography of a new palladium–enolate intermediate that was synthesized by a reaction of [Pd(cod)(CH₂TMS)₂] with XPhos and α-acyloxyketone at room temperature, indicating facile C(sp³)−O bond disconnection.     

Temperature effects upon aqueous micellar-assisted decarboxylation of 6-nitrobenzisoxazole-3-carboxylate and its 5-methyl derivative

An investigation of temperature effects upon first-order rate constants in the micellar pseudophase for decarboxylation of 6-nitrobenzisoxazole-3-carboxylate (6-NBIC) and its 5-methyl derivative (6-NBIC-5-Me) was carried out. Surfactants used were cationic cetyltrialkylammonium bromide with alkyl = methyl (CTABr), ethyl (CTEABr), n-propyl (CTPABr), and n-butyl (CTBABr). The investigation shows that micelles speed up reactions by decreasing enthalpies of activation. Increase in head group bulk further speeds reactions still by a small decrease in the enthalpies, for both substrates. Values of DeltaH# and DeltaS# for 6-NBIC in the various surfactants give linear isokinetic plot, with CTBABr as outlier.     

Development of a catalytic aromatic decarboxylation reaction

A palladium-catalyzed aromatic decarboxylation reaction has been developed. With electron-rich aromatic acids, the reaction proceeds efficiently under fairly mild conditions in good yields. The method was useful with complex functionalized substrates containing hindered carboxylic acids.     

Stereoselective Metal‐Free Synthesis of β‐Amino Thioesters with Tertiary and Quaternary Stereogenic Centers

β‐Amino thioesters are important natural building blocks for the synthesis of numerous bioactive molecules. An organocatalyzed Mannich reaction was developed which provides direct and highly stereoselective access to acyclic β²‐ and β^2,3,3‐amino thioesters with adjacent tertiary and quaternary stereocenters. Mechanistic studies showed that the stereochemical course of the reaction can be controlled by the choice of the substrates. The β‐amino thioesters were further functionalized by, for example, stereoselective decarboxylation to access β^2,3‐frameworks. In addition, the value of the β‐amino thioesters was shown in coupling‐reagent‐free peptide synthesis.     

Enantioselective Cu-catalyzed decarboxylative propargylic amination of propargyl carbamates

A copper-catalyzed asymmetric propargylic amination with a chiral ketimine P,N,N-ligand that proceeds via decarboxylation of propargyl carbamates has been developed. The reaction can be performed under the mild condition for a broad range of substrates, providing the corresponding propargylic amines in high yields and with up to 97% ee. This reaction represents a new and facile access to optically active propargylic amines.     

Visible‐Light‐Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives

Visible‐light‐induced radical decarboxylative functionalization of carboxylic acids and their derivatives has recently received considerable attention as a novel and efficient method to create C? C and C? X bonds. Generally, this visible‐light‐promoted decarboxylation process can smoothly occur under mild reaction conditions with a broad range of substrates and an excellent functional‐group tolerance. The radical species formed from the decarboxylation step can participate in not only single photocatalytic transformations, but also dual‐catalytic cross‐coupling reactions by combining photoredox catalysis with other catalytic processes. Recent advances in this research area are discussed herein.     

Ireland-Claisen rearrangement of ynamides: stereocontrolled synthesis of 2-amidodienes

The Ireland-Claisen rearrangement of propargyl ynamido ester substrates is reported. The expected allenamide carboxylic acid products from [3,3]-sigmatropic rearrangement are not isolated, with 2-amidodienes alternatively formed in good yield with high levels of stereocontrol after decarboxylation.     

Reaction Of β,γ-Unsaturated Carboxylic Acids With Thallium Triacetate (Tta): Lactonization VS Oxidative Decarboxylation

The reaction of six β,γ-unsaturated carboxylic acids with thallium triacetate (TTA) was studied. The nature of the products is highly sensitive to the substitution pattern of the substrates. Aliphatic acids gave mainly lactones, while those bearing an aromatic ring furnished only decarboxylation products.     

Theoretical studies on the decarboxylation reaction in thiamin catalysis

The conformational behavior and the stability of thiazolium and thiamin diphosphate (ThDP) adducts formed by the C2 addition of the substrates pyruvate and glyoxylate to the corresponding thiamin systems are investigated within the force-field version PIMM 90 as well as the semiempirical AM 1 and PM 3 methods. Moreover, the reaction coordinate of the decarboxylation process of the adducts with respect to the C2α(SINGLEBOND)COO⁻ bond are calculated by PM 3 and AM 1. The calculations on the key intermediates of the Breslow mechanism are performed in order to study the steric aspects of both substrate adducts that show a different pathway in the catalytic cycle. The alternative structural findings for the decarboxylation products are compared with first 6–31C * studies on the corresponding thiazolium model systems. Especially, the PM 3 calculations show that the elimination of CO₂ is favored if the arrangement of the carboxylate group is nearly perpendicular to the plane of the thiazolium ring. These results support the least-motion maximum-overlap mechanism in the enzymatic decarboxylation reaction, proposed by Kluger. The most stable conformers of the ThDP adducts and its decarboxylation products are characterized by V-like structures and the formation of a significant intramolecular hydrogen bonding under participation of the 4′-aminopyrimidine ring. © 1996 John Wiley & Sons, Inc.     

Structure-based design,synthesis of novel probes for cytochrome P450 OleT

Cytochrome P450 OleT_SA, a new cytochrome P450 enzyme from Staphylococcus aureus, catalyzes the oxidative decarboxylation and hydroxylation of fatty acids to generate terminal alkenes and fatty alcohols. The mechanism of this bifurcative chemistry remains largely unknown. Herein, a class of derivatized fatty acids were synthesized as probes to investigate the effects of substrate structure on the product type of P450 OleT_SA. The results demonstrate that the fine-tuned structure of substrates, even in a remote distance from the carboxyl group, significantly regulates OleT catalyzed decarboxylation/hydroxylation reactions. Molecular docking analysis indicated the potential interactions between the carboxylate groups of different probes and the enzyme active center which was attributed to the bifurcative chemistry.     

Non-oxidative decarboxylation of glycine derivatives by a peroxidase

Under anaerobic, peroxide-free conditions (pH 5.5, 25 degrees C), horseradish peroxidase (HRP) catalyzes the rapid, non-oxidatve decarboxylation of N-alkyl-N-phenylglycine derivatives to the corresponding N-alkyl-N-methylanilines in 100% yield. When the reaction is conducted in D2O buffer, the product contains a single deuterium in the methyl group. The reactions are very fast compared to the oxidative decarboxylation of the same substrates under standard peroxidatic conditions (i.e., hydrogen peroxide added, air present) and in fact are inhibited by peroxide and oxygen. To account for these unprecedented observations, we propose a cyclic mechanism in which ferric HRP abstracts an electron from the substrate, giving an aminium ion intermediate that decarboxylates; protonation of the resulting alpha-aminoradical on carbon gives an aminium ion that is reduced by ferrous HRP to complete the cycle.     

TEMPO-catalyzed decarboxylation reactions for the synthesis of 1,2-unsubstituted indolizines

An efficient synthesis of 1,2-unsubstituted indolizines was developed via 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)–catalyzed decarboxylation reaction. A series of target products were successfully prepared with the tolerance of a variety of functional groups. This protocol features advantages such as easily available substrates, broad substituent scope, and eco-friendly conditions.     

High-performance liquid chromatographic procedure for the simultaneous determination of aromatic L-amino acid decarboxylase activity towards 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan

A high-performance liquid chromatographic method with electrochemical detection has been developed and applied in the simultaneous determination of aromatic L-amino acid decarboxylase activity with respect to L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as substrates. Both substrates are included in the incubation mixture, and the decarboxylated products, dopamine and serotonin, respectively, are detected. In contrast to several earlier claims, we found that the ratio of the decarboxylase activity to L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan is quite constant across several different rat tissues, supporting the notion that there is only one major single enzyme rather than two. We also observed that an erroneous ratio with respect to the L-3,4-dihydroxyphenylalanine/5-hydroxytryptophan decarboxylation activities, is obtained if these activities are assessed under non-linear kinetic conditions.     

Nájera oxime-derived palladacycles catalyze intermolecular Heck reaction with Morita-Baylis-Hillman adducts. An improved and highly efficient synthesis of α-benzyl-β-ketoesters

An improved and highly efficient synthesis of several α-benzyl-β-ketoesters from Morita-Baylis-Hillman adducts is described. These adducts were used as substrates for an intermolecular Heck reaction catalyzed by a Nájera oxime-derived palladacycles. These efficient catalytic conditions probed to be very selective providing only the corresponding functionalized β-ketoesters in high yield with no decarboxylation product. It seems that the method herein described is one of the most efficient for the synthesis of α-benzyl-β-ketoesters.     

Thermal deesterification and decarboxylation of alternating copolymers of styrene with β-substituted t-butyl α-cyanoacrylates

Alternating copolymers of styrene with β-carboalkoxy-substituted t-butyl α-cyanoacrylates undergo facile deesterification at 150–190°C, about 60°C below the deprotection temperature of poly(t-butyl methacrylate), and decarboxylation at 170–200°C. When the β-substituent is a methyl ester, the two events are clearly separated, with the deesterification occurring at a maximum rate at 165°C and decarboxylation at 193°C. Anhydride formation is negligible in this case. The copolymer with t-butyl cyanofumarate exhibits simultaneous deesterification and decarboxylation events at 180°C with concomitant minor dehydration.     

An Easy Synthesis of 3-Amino- and 3-Nitrothiophene

3-Amino- and 3-nitrothiophene are readily made by the decarboxylation of the corresponding thiophene-2-carboxylic acids which are easily prepared from the commercially available methyl 3-aminothiophene-2-carboxylate.