α-Amino acids as acid components in the Passerini reaction: influence of N-protection on the yield and stereoselectivity

The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived from α-amino acids. However, racemisation of isocyanides derived from α-amino acid esters severely limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of the α-amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and >98% de.     

PADAM reactions of α-aminoaldehydes: Identity of major and minor diastereomers from the Passerini reaction

The Passerini reaction was conducted using N-Boc-L-phenylalaninal and a variety of achiral or chiral acids and isocyanides to prepare a library of 27 Passerini products. Reaction diastereoselectivity varied between 1.7:1 and 2.5:1 and in most cases isolation of the individual diastereomers was possible. Passerini products were subjected to a deprotection and acyl migration sequence to give a library of peptidomimetic α-hydroxy-β-acylaminoamides in generally excellent yield. Single crystal X-ray analysis of two of the final products enabled identification of the major diastereomer as having an (R) configuration at the newly-formed stereogenic centre, which corresponds to anti-Felkin-Anh addition of the isocyanide to the aldehyde.     

Tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture of isocyanides: One-pot synthesis of heterocycles

This paper reports the tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture of isocyanides. According to this strategy, plenty of isocyanides have been synthesized, which is immediately used for the tandem reaction of Passerini/Wittig reaction in one pot. Compared to the previous work, this strategy avoids the separation, purification, and storage of isocyanides, which prominently solves the problems of isocyanide-based multicomponent reaction such as: (a) The environmentally unfriendly (strong foul odor), (a) the labile of Isocyanides, (c) high toxicity of isocyanides. In the meantime, in order to expand the application scope of our strategy, 1H-isochromenes and 3H-2-benzoxepin-1-ones have also been synthesized, which undergoes four-step transformations in one-pot. In addition, a relatively credible reaction mechanism has also been proposed, based on a series of control experiments. Furthermore, preliminary testing was performed on biological activity of some obtained compounds; These results showed that the synthesized compounds exhibited certain activity over P. digitatum and P. italicum. ^© 2019 Elsevier Science. All rights reserved.     

Diastereoselective Passerini reactions using p-toluenesulfonylmethyl isocyanide (TosMIC) as the isonitrile component

p-Toluenesulfonylmethyl isocyanide (TosMIC) is used for the first time as the isonitrile component in a diastereoselective Passerini reaction with sugar-derived aldehydes to afford products in moderate to good yields (40-90%) and selectivities (30-90% de’s).     

New efficient synthesis of 4-aminocarbonyl substituted 4H-3,1-benzoxazines by a Passerini 3CC/Staudinger/aza-Wittig sequence

α-Acyloxy-carboxamide azides 1, obtained from Passerini reaction of easily accessible o-azidobenzaldehyde with isocyanides and carboxylic acids, reacted with triphenylphosphine to give various 4-aminocarbonyl substituted 4H-1,3-benzoxazines 3 in moderate to high yields via sequential Staudinger and intramolecular aza-Wittig reaction. However, α-hydroxy carboxamide azides 5 were obtained in moderate yields when pyruvic acid was used in the Passerini reaction. Further sequential reaction of azides 5 with triphenylphosphine and isocyanates produced 2-amino-4-aminocarbonyl substituted 4H-1,3-benzoxazines 8 via a tandem Staudinger/aza-Wittig/heterocumulene-mediated annulation.     

Synthesis of α-carboranyl-α-acyloxy-amides as potential BNCT agents

Novel α-carboranyl-α-acyloxy-amides were prepared as potential BNCT agents utilizing three-component Passerini reaction. Preliminary cytotoxicity of the representative compounds on two brain tumor cell lines (U-87 and A-172) showed no effect on cell viability; an essential requirement for utility as potential BNCT agents.     

Facile access to α-acyloxyamides via epoxide rearrangement/three-component domino reaction catalyzed by indium(III) chloride

A simple and efficient Passerini reaction of epoxides involving highly regioselective rearrangement of epoxide to aldehyde/three-component Passerini reaction catalyzed by indium(III) chloride is described. In the present protocol, epoxides served as wonderful substrates to furnish a library of α-acyloxyamides under mild reaction conditions in shorter reaction times and in good yields.     

Multicomponent reaction design: a one-pot route to substituted di-O-acylglyceric acid amides from α-diazoketones

A four-component assembly of substituted di-O-acylglyceric acid amides has been developed from α-diazoketones. The process involves copper-catalyzed reaction of the α-diazoketone with a carboxylic acid, and subsequent Passerini condensation of the in situ formed α-acyloxyketone.     

Studies on the application of the Passerini reaction and enzymatic procedures to the synthesis of tripeptide mimetics

A new, efficient method for the multicomponent synthesis of tripeptide mimetics is presented. Simple, chemoenzymatic transformations of Passerini reaction products enable the introduction of varied amino acid moieties into the tripeptide scaffold, with control of the stereochemistry. Additionally, this method allows the convenient introduction of a methyl group to the amide nitrogen, leading to derivatives of N-methylated amino acids—compounds of interest for medicinal chemistry.     

A direct link between the Passerini reaction and α-lactams

α-Lactams (aziridinones) can function to replace two of the three reactants, the oxo-compound and the isonitrile, in the Passerini reaction. Four α-lactams (5a-d) were reacted with mono- and dicarboxylic acids of positive pK_a values to give 2-acyloxycarboxamides (4) and bis-2-acyloxycarboxamide products 12 and 13, respectively. The same compounds were also prepared via the Passerini reaction. Acids with a negative pK_a decarbonylate α-lactams to give immonium salts. The main path of the reaction depends on the pK_a of the acid component, the reactivity of the α-lactam, and the reaction conditions.     

A Passerini/Tsuji-Trost access to dienamide derivatives

The Passerini reaction of α, β-unsaturated aldehydes affords allylic acetates which may be involved in Tsuji-Trost elimations towards conjugated dienamides. The interest of these 2,4-dienamides has been demonstrated in several TiCl₄ triggered Diels-Alder reactions with N-phenylmaleimide.     

The 100 facets of the Passerini reaction

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction. After being nearly neglected for many years, now this reaction has become quite popular, thanks to the achievements of the last 30 years, which have revealed several chances of exploitation in organic synthesis. Though not being comprehensive, this review means to show the various ways that have been used in order to expand the utility of the Passerini reaction. Post-MCR transformations to give heterocycles or peptidomimetics, variants through single component replacement, stereochemical issues, and applications in total syntheses will be especially covered.

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction.     

The homo‐PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α‐Oxo‐ or α‐Hydroxy‐γ‐acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α‐oxo‐γ‐acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection–acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo‐Passerini–amine deprotection–acyl migration (PADAM) strategy. Highly stereoselective reduction of the α‐oxo‐γ‐acylaminoamides afforded α‐hydroxy‐γ‐acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.     

Massive parallel catalyst screening: toward asymmetric MCRs

[reaction: see text]. Hundreds of Lewis acid/ligand combinations have been screened for stereochemical induction in the Passerini multicomponent reaction. The combination of titan tetraisopropylate and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane was found to give enantiomeric excesses between 32% and 42% in several examples. The absolute stereo induction of one example was determined chemically and by means of X-ray crystallography. This comprises the first asymmetric Passerini reaction and the first example of a stereochemical induction in an isocyanide based multicomponent reaction by a chiral Lewis acid.     

Multicomponent diversity and enzymatic enantioselectivity as a route towards both enantiomers of α-amino acids—a model study

A model study on a new, enantioconvergent method for the synthesis of chiral, nonracemic α-amino acids is presented. α-Acetoxyamides obtained in a Passerini multicomponent reaction are selectively hydrolyzed by Wheat Germ lipase. Studies on conversion of the thus obtained, enantiomerically enriched α-hydroxyamides into α-aminoamides are presented. Products of these reactions are then hydrolyzed to give α-amino acids.     

Photocaging of Carboxylic Acids: A Modular Approach

Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.     

微波辐射下离子液体介质中经由Passerini反应合成α-酰氧基酰胺及α-酰氧基酰胺-嘧啶核苷杂化体

研究了微波辐射下离子液体介质中的羧酸、醛及异腈的三组分反应,即Passerini反应.研究发现,该反应可在微波辐射条件下很快完成,并以较高的收率生成相应的α-酰氧基酰胺类衍生物.与文献方法相比,该方法具有对环境友好、效率高、操作简便、反应条件温和等优点.笔者已经成功地将这一方法应用到了具有潜在生物活性的α-酰氧基酰胺-...     

New approaches to studying the kinetics of the radical reaction of N-phenyl-1,4-benzoquinone monoimine with 2-mercaptobenzothiazole

The kinetics of the reaction of N-phenyl-1,4-benzoquinone monoimine with 2-mercaptobenzothiazole in chlorobenzene at 298 and 343 K under argon has been studied by kinetic spectrophotometry. The reaction orders have been determined. The influence of tetraphenylhydrazine and azobisisobutyronitrile initiators has been investigated. An accelerating effect of one of the reaction products, 4-hydroxydiphenylamine, has been discovered. The accelerating effect strenthens with an increasing 2-mercaptobenzothiazole concentration. Two methods are proposed for determination of the kinetic parameters of the reaction. The first method uses data on the consumption rate of quinoneimine in the noninitiated reaction in the presence of 4-hydroxydiphenylamine. In the second method, the accumulation of quinone monoimine is studied during initiator decomposition in the presence of mixtures of 4-hydroxydiphenylamine and 2-mercaptobenzothiazole and parameters are estimated from the dependences of the limiting concentration of accumulated quinone monoimine on the initiation rate and on the concentrations of the reactants Using the proposed approaches, the numerical values of a number of kinetic parameters of the radical reactions of the quinone compounds with thiols have been determined for the first time for the reaction studied.     

Aqueous medium effects on multi-component reactions

The effect of aqueous media on many organic reactions has been studied, and often those reactions exhibiting pressure acceleration are also accelerated in water. Because some specific examples of the Ugi and Passerini reactions that are inefficient under conventional conditions have been accelerated by pressure, we examined Ugi and Passerini reactions in aqueous solutions, where significant increases in efficiency were observed. These effects were correlated to the cohesive energy density of aqueous solutions.     

Keto-Enol Tautomerism in Passerini and Ugi Adducts

The use of arylglyoxal as starting material in Passerini and Ugi reactions affords β-ketoamides. This has allowed to study keto-enol tautomerism in these systems and assess the way in which the presence of acyloxy or aminoacyl groups bound to the C2 position affects such tautomerism, and to investigate the reactivity of both the enol and carbonyl forms. In this work we also prove the versatility of the Passerini reaction, since depending on the conditions to which the corresponding adducts are subjected different products of synthetic interest can be obtained.