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anti-Selective SMP-catalyzed direct asymmetric Mannich-type reactions: synthesis of functionalized amino acid derivatives
Abstract
The first (S)-2-methoxymethylpyrrolidine (SMP)-catalyzed direct asymmetric Mannich-type reactions of unmodified aldehydes with N-PMP-protected alpha-imino ethyl glyoxylate are described. The reaction proceeded in a highly anti-selective manner (dr up to 19:1) with enantioselectivities between 74 and 92%. (C) 2002 Published by Elsevier Science Ltd.
... 1a,b,5 Nonetheless, while amine-catalyzed asymmetric synMannich reactions via the enamine mechanism are very common, 1a,b,5 examples of organocatalytic asymmetric anti-Mannich reactions are relatively limited. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] In this regard, Barbas' group reported the first anti-selective Mannich reaction using (S)-2-methoxymethylpyrrolidine (SMP) as the catalyst in 2002. 6 The anti-selectivity was achieved through the steric interactions between the α-methoxymethyl group on the catalyst pyrrolidine ring and the imine substrates. ...
... [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] In this regard, Barbas' group reported the first anti-selective Mannich reaction using (S)-2-methoxymethylpyrrolidine (SMP) as the catalyst in 2002. 6 The anti-selectivity was achieved through the steric interactions between the α-methoxymethyl group on the catalyst pyrrolidine ring and the imine substrates. 6 Later, the same group discovered that pyrrolidine-3-carboxylic acid, which is a cyclic β-amino acid, and its derivatives are highly stereoselective catalysts for the anti-Mannich reactions. ...
... 6 The anti-selectivity was achieved through the steric interactions between the α-methoxymethyl group on the catalyst pyrrolidine ring and the imine substrates. 6 Later, the same group discovered that pyrrolidine-3-carboxylic acid, which is a cyclic β-amino acid, and its derivatives are highly stereoselective catalysts for the anti-Mannich reactions. 7 In this case, the anti-selectivity was interpreted as the result of a different preferred conformation of the enamine intermediate as compared with that in the proline catalysis. ...
A highly stereoselective method for achieving the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate was realized using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and (R)-pyrrolidien-3-carboxylic acid in the reaction media. The desired anti-Mannich products were obtained in good to excellent yields (up to 93%), excellent diastereoselectivities (up to 99:1 dr), and good to high enantioselectivities (up to 99% ee).
... It has been noted that proline or similar amine organocatalysts furnish syn Mannich products as major. But the use of (S)-2-methoxymethylpyrrolidine (SMP) (1) in the asymmetric Mannich-type reactions of unmodified aldehydes with N-PMP-protected -iminoglyoxylate afforded highly anti-selective Mannich product with enantioselectivity up to 92% (Scheme 1) [27]. The exactly opposite stereochemical outcome is due to two different mode of in-teraction in the corresponding transition states. ...
Considerable number of nitrogen containing active pharmaceutical ingredients and natural products are frequently synthesized from optically pure β-amino ketones, aldehydes, esters, and alcohols. Synthesis of 1,3-amino ketones, aldehydes, alcohols and esters engages Mannich-type reactions, the most important basic reaction-types in organic chemistry. The current trend in the development of asymmetric Mannich-type reaction is to employ unmodified ketones and aldehydes as starting materials in the presence of simple and easily accessible metal-free organocatalysts under mild and convenient reaction conditions. Although L-Proline and its derivatives are commonly and extensively studied organocatalysts in Mannich reactions, many other organocatalysts based on bifunctional thiourea, chiral Bronsted acids and some other organocatalytic systems are also equally effective. The present review comprehensively describes an overview of asymmetric Mannich reactions under different organocatalytic systems in both organic and aqueous media.
... -Methyl L-proline exhibits higher enantioselectivities and improved reaction rates when compared to Lproline. In recent years, proline, especially L-proline, has been used to catalyze essential transformations used in the fine chemical and pharmaceutical industries, such as the direct asymmetric aldol reactions [99][100][101][102][103][104][105][106][107], Diels-Alder reactions, Michael reactions [108][109][110][111][112][113][114][115], Mannich reaction [116][117][118][119][120][121][122], Multicomponent reactions [123,124], and -amination [125], -aminoxylation [126][127][128], -oxyaldehyde dimerization [100], -functionalization of carbonyl compounds [129], and -alkylation of aldehydes [130]. Organocatalytic cyclopropanation reactions were typically performed using catalyst-bound ylides. ...
This paper purports to review catalysis, particularly the organocatalysis and its origin, key trends, challenges, examples, scope, and importance. The definition of organocatalyst corresponds to a low molecular weight organic molecule which in stoichiometric amounts catalyzes a chemical reaction. In this review, the use of the term heterogenized organocatalyst will be exclusively confined to a catalytic system containing an organic molecule immobilized onto some sort of support material and is responsible for accelerating a chemical reaction. Firstly, a brief description of the field is provided putting it in a green and sustainable perspective of chemistry. Next, research findings on the use of organocatalysts on various inorganic supports including nano(porous)materials, nanoparticles, silica, and zeolite/zeolitic materials are scrutinized in brief. Then future scope, research directions, and academic and industrial applications will be outlined. A succinct account will summarize some of the research and developments in the field. This review tries to bring many outstanding researches together and shows the vitality of the organocatalysis through several aspects.
... In a conventional stirred glass, 39.4 μL of aniline, 75 μL of benzaldehide, 3 μL of POCl3 and 28 mg of the solid material were combined in 5 mL of toluene at room temperature for 30 minutes. Then 472 μL of cyclohexane was added and the mixture was stirred at room temperature for 48 hours [36]. Reaction products were identified and quantified by gas chromatography, using a GC-3900 Varian chromatograph equipped with a CP-Chirasil-Dex CB #CP7502 capillary column and flame ionization detector (FID). ...
Exciting helical mesoporous organosilicas including supplementary chirally doped moieties into their spiral walls were one-pot successfully synthesized with good structural order for first time, to the best of our knowledge. This one-step direct synthesis of helical chirally-doped Periodic Mesoporous Organosilicas (PMO) materials was carried out by combination of a tartrate-based bis-organosilicon precursor with tetraethylortosilicate (TEOS) and two surfactants, cetyltrimethylammonium bromide and perfluoroctanoic acid (CTAB and PFOA). For comparison purposes, a conventional two-step post-synthetic grafting methodology was carried out. In this method, the chiral tartrate-based moieties were grafted onto the helical silica mesoporous materials previously prepared by dual-templating approach (CTAB and PFOA). The chirally doped materials prepared by both methodologies exhibited helical structure and high BET surface area, pore size distributions and total pore volume in the range of mesopores. 13C and 29Si MAS solid-state NMR experiments confirmed the presence of the chiral organic precursor in the silica wall covalently bonded to silicon atoms. Nevertheless, one-pot direct synthesis leaded to a greater control of surface properties and presented larger incorporation of organic species, compared with the two-step post-synthetic methodology. To further prove the potential feasibility of these materials in enantiomeric applications, Mannich diastereoselective asymmetric synthesis was chosen as catalytic test. In the case of the one-pot PMO material, the rigidity of the chiral ligand backbone provided by its integration into the inorganic helical wall, in combination with the steric impediments supplied by the twisted geometry led to the reagents to adopt specific orientations. These geometrical constrictions resulted in an outstanding diastereomeric induction towards the preferred enantiomer.
Dynamic kinetic asymmetric transformations (DYKAT) are an important way of converting simple organic molecules into complex small molecules as single diastereo- and enantiomers. Herein we describe selected examples that are catalyzed by small organic molecules, which utilize activation mechanisms similar to enzymes for accomplishing the high stereoselectivity. The research area of DYKAT is growing and remarkable examples for producing important organic molecules and pharmaceuticals are demonstrated. In this context, organocatalysis will play an important role.
The Mannich reaction, one of the most fundamental C—C bond-forming reactions, is more than 100 years old and yet is still fascinating. This chapter is an update to the earlier Science of Synthesis contribution (Section 40.1.1.5.2) describing methods for the asymmetric synthesis of highly versatile β-amino carbonyl compounds and derivatives via Mannich reaction. This review predominantly focuses on recent developments in catalytic enantioselective and diastereoselective processes of direct, indirect, and vinylogous Mannich reactions using both metal-based catalysts as well as organocatalysts.
In this personal account, we describe our recent developments on the four types of amino Tf‐amide catalysts in asymmetric transformations. Firstly, axially chiral biaryl‐based secondary‐amino Tf‐amide catalyzed various stereoselective reactions via enamine intermediates. Secondly, pyrrolidine‐based secondary‐amino aliphatic Tf‐amide catalyzed asymmetric direct Mannich reaction. Thirdly, chiral primary‐amino aliphatic Tf‐amide catalyzed asymmetric direct aldol reaction and conjugate addition. Finally, modified chiral amino aromatic Tf‐amide catalyzed asymmetric transformations. These four different strategies are illustrated by using various organocatalyzed asymmetric transformations. The recent development on the four types of amino Tf‐amide catalysts in asymmetric transformations is described: (1) Axially chiral biaryl‐based secondary‐amino Tf‐amide catalysis. (2) Pyrrolidine‐based chiral secondary‐amino aliphatic Tf‐amide catalysis. (3) Chiral primary‐amino aliphatic Tf‐amide catalysis. (4) Modified chiral amino aromatic Tf‐amide catalysis.
Chiral amine catalysts are widely utilized in various asymmetric reactions. Among them, binaphthyl-based secondary amine catalysts show unique reactivity and unusual stereoselectivity in comparison with frequently used ʟ-proline and its derivatives. In spite of their utility, however, asymmetric reactions employing binaphthyl-based amines are rare because of their synthetic inefficiency. In this context, we have developed chiral secondary amine catalysts based on a phenylcyclopropane scaffold as a novel chiral motif. Newly synthesized amine catalysts function as effective catalysts for several asymmetric reactions. In addition, the phenylcyclopropane-based amino sulfonamide was found to be an effective catalyst for the syn-selective Mannich reaction and conjugate addition with alkynyl Z-ketimines.
We developed a facile and practical synthesis of various alkynyl Z-ketimines, which can be used as a synthetic equivalent of alkyl ketimines. The obtained alkynyl Z-ketimines could be successfully applied in enantioselective Mannich reaction and conjugate addition catalyzed by a chiral amine with an acid functionality.
Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.
A first stereodivergent strategy for the asymmetric synthesis of all stereoisomers of 1-hydroxymethylpyrrolizidine alkaloids is developed using an asymmetric self-Mannich reaction as a key step. An anti-selective self-Mannich reaction of methyl 4-oxobutanoate with the PMP-amine catalyzed by a chiral secondary amine is successfully optimized for the asymmetric synthesis of (+)-isoretronecanol and (-)-isoretronecanol. A syn-selective self-Mannich reaction catalyzed by proline is utilized for the asymmetric synthesis of the diastereomer, (+)-laburnine, and its enantiomer, (-)-trachelanthamidine.
The present work involved two steps: First step include some Mannich bases of substituted Isatin has been synthesized by reacting Isatin with paraformaldehyde and secondary amine. (4-Aminophenazone, Pyrazinamide,2,4-Diamino-6-phenyl-I,3,5-1fiazine, 2,6-Diamino-6-methyl-I,3,5-triazine,2,4-Diamino-6-hydroxy pyrimidin) to obtain Mannich bases (A-E). The second step include reduction ofall Mannich bases which prepared in first step by using Aluminum pure powder to obtain compounds (F-J). Some ofthe compounds were characterized by means oftheir UV, FT-IR, rH-NMR spectrosaopic data .
This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α-imino esters. A highly diastereoselective tandem N-alkylation-Mannich reaction of α-imino esters was developed. A tandem N-alkylation-addition reaction of α-imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2-amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α-quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N-addition to β,γ-alkynyl α-imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N-alkylation-vinylogous aldol reaction of β,γ-alkenyl α-imino esters was discovered. N-Alkylation of α-iminophosphonates followed by a Horner-Wadsworth-Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four-component coupling reaction with methyl vinyl ketone. α-N-Acyloxyimino esters served as highly efficient substrates for the N,N,C-trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.
Amino acid catalyzed direct Mannich-type additions to N-Tos protected α-imino ethyl glyoxylate employing unmodified carbonyl donors is described. The reaction was performed in DMSO using a catalytic amount (30 mol %) of L-proline and its derivatives providing a facile route to functionalized β-keto substituted α-amino acid derivatives with excellent diastereo- and enantioselectivities. Unmodified 3-pentanone and cyclohexanone were used as donors for the one pot generation of two quaternary stereocenter. Organocatalysis using L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate were typically syn-diastereoselective. Anti-diastereoselectivity was achieved using (S)-2-methoxymethyl-pyrrolidine and L-proline benzyl ester. Stereochemical outcomes are explained on the basis of previously proposed transition state and the reasons governing syn- and anti-selectivity are described. Poor selectivity of (S)-2-methoxy-methylpyrrolidine compared to L-proline benzyl ester in contrast to earlier reports are explained in terms of a fast cis-trans event and possible sterics.
Solvent effects in the L-tryptophan-catalyzed Mannich reaction between hydroxyacetone and glyoxylate imines have been examined. The use of a DMSO/1-butanol (4:1 v/v) mixture as solvent at rt provided the expected Mannich adducts in good yields, high anti-diastereoselectivity (up to 10.3:1 anti/syn ratio) and excellent enantioselectivities (up to >99.9% ee for the anti isomer).
Significant, recent developments in the enantioselective Mannich reaction, catalyzed by organic and organometallic compounds, are reviewed. In particular, advances that have led to the development of new asymmetric methodologies that overcome some of the traditional limitations of the Mannich reaction are highlighted.
[63126-47-6] C6H13NO (MW 115.20) InChI = 1S/C6H13NO/c1-8-5-6-3-2-4-7-6/h6-7H,2-5H2,1H3/t6-/m0/s1InChIKey = CHPRFKYDQRKRRK-LURJTMIESA-N(chiral auxiliary; asymmetric syntheses with SMP enamines2 and SMP amides;3 asymmetric Birch reductions;4 asymmetric Diels–Alder reactions5)Alternate Name: SMP.Physical Data: bp 75 °C/40 mmHg; d 0.930 g cm−3; nD20 1.4467; αD20 −3 to −4° (neat).Solubility: sol H2O, ether, dichloromethane.Form Supplied in: colorless liquid.Handling, Storage, and Precautions: store at 0–4 °C under an argon atmosphere.
Density functional study have been carried out to investigate the stereoselectivities in the Mannich-type reactions promoted by five typical amino acid catalysts with different scaffolds. The reverse diastereoselectivities in the cyclic and acyclic α- and β-amino acids-promoted Mannich reactions have been satisfactorily explained by the density functional theory (DFT) methods at the SMD/M06-2X/6-31G** computational level. The activation strain analysis has been used to account for the selectivity-switching for these selected bifunctional catalysts. © 2014 Wiley Periodicals, Inc.
An efficient route for the synthesis of all four diastereomers of PMP-protected α-amino-γ-butyrolacton to access γ-hydroxynorvaline was established. The asymmetric key steps comprise an organocatalytic Mannich reaction and an enzymatic ketone reduction. Three reaction steps could be integrated in a one-pot process, using 2-PrOH both as solvent and as reducing agent. The sequential construction of stereogenic centres gave access to each of the four stereoisomers in high yield and with excellent stereocontrol.
A polystyrene-supported, pyrrolidine-based catalyst depicting very high activity and excellent stereoselectivity in the anti-Mannich reaction of aldehydes and ketones has been developed. The very robust, immobilized catalyst has been successfully used in the implementation of a continuous flow process with short residence times (down to 6 min) for the production of highly enantioenriched anti-type Mannich adducts at the preparative scale.
Das Erbe von Gilbert Newton Lewis (1875–1946) ist im Wörterbuch der chemischen Bindung und Reaktivität allgegenwärtig. Die Bedeutung seines Konzepts der Donor-Akzeptor-Bindung kommt in den eponymen Grundbegriffen für Elektronenpaarakzeptoren (Lewis-Säuren) und -donoren (Lewis-Basen) zum Ausdruck. Lewis erkannte, dass Säuren nicht automatisch Wasserstoff enthalten müssen (Brønsted-Säuren) und trug so zum Sturz des “modernen Protonenkults” bei. Seine Entdeckung läutete zunächst die Entwicklung von Lewis-Säuren als Reagentien und Katalysatoren für organische Reaktionen ein, in den letzten Jahren wurde aber offensichtlich, dass für diese Zwecke auch Lewis-Basen eingesetzt werden können. Bezüglich der Beschleunigung chemischer Reaktionen ergänzen Lewis-Basen die entsprechenden Lewis-Säuren nicht nur elektronisch: Tatsächlich können Lewis-Basen die Elektrophilie wie auch die Nucleophilie der Verbindungen verstärken, an die sie gebunden werden. Diese unterschiedliche Reaktivität resultiert in einer bemerkenswerten Vielfalt Lewis-Base-katalysierter Reaktionen.
The diastereoselective tandem N-alkylation-Mannich reaction of α-imino esters has been achieved by using three sequential reactions: N-ethylation with diethylaluminum chloride and ethylaluminum chloride, oxidation with benzoyl peroxide (BPO), and addition of lithium enolates or ketene silyl acetals, in which “E”- and “Z”-lithium enolates or E- and Z-ketene silyl acetals give the syn and anti products, respectively. DME=1,2-dimethoxyethane; PMP=p-methoxyphenyl.
The one‐pot, three‐component Mannich reactions of thiopyran‐4‐one 1 with different aromatic aldehydes and aniline derivatives in the presence of catalytic quantities of ZrOCl2.8H2O (15 mol %) led to rapid and high yield formation of various 3‐methylamino substituted derivatives of 1 at room temperature. Spectroscopic and X‐ray analyses of the products suggested the formation of the anti stereoisomers as the major product of the reactions.
The precise mechanism of the highly anti- and enantioselective aza-Petasis-Ferrier (APF) rearrangement of hemiaminal vinyl ethers catalyzed by a chiral phosphoric acid was investigated by undertaking experimental and theoretical studies. The APF rearrangement is characterized by the following unique mechanistic features: (i) efficient optical kinetic resolution of the starting racemic hemiaminal vinyl ether; (ii) enantio-convergent process from racemic hemiaminal vinyl ethers to optically active -amino aldehyde products; and (iii) anomalous temperature effect on the enantioselectivity (enantioselectivity increases as reaction temperature increases). The following experiments were conducted to elucidate the unique mechanistic features as well as to uncover the overall scheme of the present rearrangement: (A) X-ray crystallographic analysis of the recovered hemiaminal vinyl ether to determine its absolute configuration; (B) rearrangements of enantiomerically pure hemiaminal vinyl ethers to validate the stereochemical relationship between the hemiaminal vinyl ethers and -amino aldehydes; (C) theoretical studies on the transition states of the C-O bond cleavage and C-C bond formation steps to gain an insight into the optical kinetic resolution of the hemiaminal vinyl ether and the origin of the stereoselectivity, as well as to elucidate the overall scheme of the present rearrangement; and (D) crossover experiments of two hemiaminal vinyl ethers having different vinyl ether and aliphatic substituents to comprehend the mechanism of the anomalous temperature effect and the enantio-convergent process. The results of experiments and theoretical studies fully support the proposed mechanism of the present anti- and enantioselective APF rearrangement.
An efficient diastereoselective synthesis of carbapenem Mannich bases was developed using organocatalysis. This method also provides a route to new highly functionalized diazabicyclo[4.2.1]nonanes of proposed biological significance.
In this chapter, some of the tremendous efforts and accomplishments by highly creative researchers within the developments of the metal-free aminocatalytic asymmetric Mannich reaction are covered. Examples include the prolinecatalyzed addition of unmodified ketones to in situ generated or preformed imines, the acyclic amino acid and linear chiral primary amine-catalyzed Mannich-type transformations, the use of unmodified aldehydes as nucleophiles, the cross-Mannich transformation with unmodified aldehydes, the use of these Mannichtype transformations in domino and tandem transformations, application in the synthesis of pharmaceuticals, and the ingenious design of switches in diastereoselectivity, among others. While focusing on the developments of direct Mannich-type reactions when using aminocatalysis, the chapter also presents several other important metal-free activation modes for achieving these types of transformations.
Mannich reactions of ethyl 1-aryl-2,2,2-trifluoroethylidenecarbamates and ureas with acetone in the presence of L-proline gave 1-aryl-3-oxo-1-(trifluoromethyl)butylcarbamates and ureas with an enantiomeric excess of 24–54%.
This laboratory experiment describes the preparation of a N-protected phenylalanine ethyl ester by a zinc-mediated Mannich-like multicomponent reaction between benzyl bromide, p-anisidine, and ethyl glyoxylate. The one-step reaction involves the in situ metallation of benzyl bromide into a benzylzinc reagent and its addition onto imine (Barbier conditions). The multicomponent procedure is suitable for a 4-to-5 h undergraduate organic laboratory. © 2012 The American Chemical Society and Division of Chemical Education, Inc.
The amino acid-catalyzed direct enantioselective one-step de novo synthesis of carbohydrates using dihydroxyacetone phosphate mimetics as donors and aldehydes or in situ generated imines as acceptors is presented. The addition of water significantly accelerates as well as improves the enantioselectivity of the biomimetic aldol and Mannich reactions. The C3+Cn methodology presented herein is a direct entry to orthogonally protected C-5 and C-6 ketoses (e.g., ribulose, tagatose and piscose) and deoxy- and aminosugars such as 4-amino-4-deoxy-fructose.
The first direct amino acid-catalyzed asymmetric syntheses of alpha-oxy-beta-aminoaldehydes are presented. The organocatalytic Mannich reactions between unmodified alpha-oxyaldehydes and anilines proceeded with excellent enantioselectivities. In most cases, the corresponding alpha-oxy-beta-aminoaldehyde adducts were isolated in high yield with excellent chemo- and enantioselectivity. For example, orthogonally protected 3-amino-tetroses and alpha-amino acid derivatives were isolated in up to > 99% ee. (c) 2005 Elsevier Ltd. All rights reserved.
A novel L-proline confined FAU zeolite catalyst system has been developed by confinement of L-proline in faujasite zeolite and its catalytic activity has been tested in the aqueous mediated synthesis of novel 1′,3′-di-(4-methylphenyl)-2′,3′,4′,6′-tetrahydro-1′H-spiro[indoline-3,5′-pyrimidin]-2-one (4a) and 1′,3′-di-(4-methylphenyl)-2′,3′,4′,6′-tetrahydro-1′H-spiro[indene-2,5′-pyrimidin]-1(3H)-one (4d) for the first time via the one-pot three-component condensation of lactams/cyclic ketones, amines and aqueous formaldehyde. The recyclability of the novel catalyst system was studied, which resulted in no loss of catalytic activity up to five cycles.
The amino acid catalyzed direct asymmetric Mannich reaction between aminomethyl ether 1 and cyclohexanones is presented. The unprecedented reaction proceeds via an ionic transition state and gives the corresponding Mannich bases in moderate to high yields with 75-99% ee.
The first (S)-2-methoxymethylpyrrolidine (SMP)-catalyzed direct asymmetric Mannich-type reactions of unmodified aldehydes with N-PMP-protected α-imino ethyl glyoxylate are described. The reaction proceeded in a highly anti-selective manner (dr up to 19:1) with enantioselectivities between 74 and 92%.
For Abstract see ChemInform Abstract in Full Text.
Indolizine skeletons: A highly efficient dual iminium-enolate generation/activation process is introduced as a new platform for the design of organocatalytic intermolecular domino reactions for the direct construction of 5,6-dihydroindolizine derivatives. This process provides ready access to indolizine skeletons with high optically purity from simple starting materials.
Being catalyzed by (S)-homoproline a highly enantioselective organocatalytic Michael addition reaction of ketones to beta-nitrostyrenes has been achieved.
A series of alpha,alpha-disubstituted amines such as diarylmethylamines, 1,2-diarylethylamines, and amino esters have been prepared in acetonitrile using a simple and expedient three-component Mannich-type procedure involving organic halides, aldehyde derivatives, and amines. Reactions are conducted under Barbier-like conditions using simple organic halides and zinc dust for the in situ generation of organozinc reagents.
A new homo-proline tetrazole derivative 7 has been prepared and shown to have improved properties for achieving asymmetric Michael addition of carbonyl compounds to nitro-olefins.
This report describes the unprecedented use of unmodified aldehydes as donors in catalytic three component one-pot asymmetric Mannich reactions. The Mannich-type reactions were also readily performed for the first time with both in situ generated and preformed N-PMP protected aromatic aldimines. The proline-catalyzed reactions provided an efficient and very mild entry to either enantiomer of γ-amino alcohol derivatives in high yield and stereoselectivity.
[GRAPHICS] One-pot asymmetric Mannich-hydrocyanation reactions are described. Reaction of unmodified aldehydes with MPMP-protected alpha-imino ethyl glyoxylate in the presence of catalytic amounts of L-proline followed by the addition of Et2AlCN provided highly enantiomerically pure beta-cyanohydroxymethyl alpha-amino acid derivatives possessing three contiguous stereogenic centers as single diastereomers (93-99% ee). Control of reaction temperature during the cyanation step directed whether cyclization of the products to lactones occurred.
The origins of the stereoselectivities in the axially chiral amino sulfonamide-catalyzed direct anti-Mannich and syn-aldol reactions have been studied with the aid of density functional theory method. Transition states of the stereochemistry-determining C–C bond-forming step with the enamine intermediate addition to the imine or aldehyde for the subject Mannich and aldol reactions are reported. BH and HLYP/6-31G** calculations provide a good explanation for the diastereoselectivities in the chiral amino sulfonamide-catalyzed anti-Mannich and syn-aldol reactions. Calculated and observed diastereomeric ratio and enantiomeric excess values are in good agreement.
Quantum mechanics calculations have been performed to study the stereoselectivities in the direct Mannich reactions catalyzed by different chiral secondary amine catalysts. The effects of two kinds of catalysts, (S)-1-(2-pyrrolidinylmethyl) pyrrolidine and proline on the diastereoselectivities of the direct Mannich reactions between ketimine and aldehyde have been studied with the aid of the BH and HLYP method. Transition states of the stereochemistry-determining CC bond-forming step with the enamine intermediate addition to the ketimine for the subject reactions are reported. These theoretical calculations provide a good explanation for the opposite diastereoselectivities of these two different kinds of catalysts. Calculated and observed diastereomeric ratio and enantiomeric excess values are in good agreement.
Quantum mechanics calculations have been performed to study the stereoselectivities in the direct anti- and syn-Mannich reactions catalyzed by different amino acids. The effects of two kinds of amino acid catalysts, l-proline (secondary) and l-tryptophan (primary), on the diastereoselectivity and enantioselectivity of the direct Mannich reactions between α-hydroxyacetone, p-anisidine, and p-nitrobenzaldehyde have been studied. Transition states of the stereochemistry-determining C–C bond-forming step with the enamine intermediate addition to the imine for the proline- and tryptophan-catalyzed processes are reported. These theoretical calculations provide a good explanation for the opposite syn diastereoselectivities versus anti diastereoselectivities of these two types of catalysts (syn-selectivity for the secondary cyclic amino acids such as proline and anti-selectivity for the acyclic primary amino acids such as tryptophan). Calculated and observed diastereomeric ratio and enantiomeric excess values are in good agreement.
A novel and facile method for the direct construction of C–C–N bond with unsubstituted azoles under Mannich conditions is developed for the first time. The reaction is catalyzed efficiently by l-proline to give the Mannich adducts 1a–10b in DMSO, whereas in water, insertion of two successive bonds, C–C–N and C–C–O occurred to give compounds 11a–20b. The latter are deformylated readily into the desired products 1a–10b under basic conditions. Mechanistic aspects for the formation of these products are discussed.
Enantioselective proline-catalyzed direct asymmetric cross-aldol reactions with aldehydes were performed in ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate media, which simplified product isolation and catalyst recycling, affording 3-hydroxy aldehydes in high yield with excellent stereoselectivity. In addition, the enhanced reactivity of the asymmetric cross-aldol reactions in ionic liquid allowed the catalyst loading to be lowered significantly.
The first direct organocatalytic asymmetric Mannich-type reactions in aqueous media are demonstrated herein. l-Proline-catalyzed reactions in aqueous media to provide β-formyl substituted α-amino acid derivatives with excellent diastereoselectivities (dr up to 19:1, syn/anti) and high enantioselectivities (ee between 72 and >99%). These conditions provided for the development of novel one-pot asymmetric syntheses of cyclic γ-allyl substituted α-amino acid derivatives (ee up to >99%). This was accomplished by combining the proline-catalyzed Mannich-type reactions with indium promoted allylations in aqueous media.
Directed asymmetric assembly of simple achiral building blocks into stereochemically complex molecules like triketides has been described for the first time using l-proline catalyzed asymmetric double aldol reactions. The product pyranoses contain four asymmetric centers constructed under proline catalysis in a highly diastereoselective and modestly enantioselective fashion from three aldehyde molecules. These results suggest that the construction of complex products from simple starting materials is within the realm of organocatalysis involving the simple naturally occurring amino acid l-proline. Our successful assembly of pyranoses from simple aldehydes under proline catalysis suggests that this approach may warrant consideration as a prebiotic route to sugars and polyketides.
The novel pyrrolidine-based amino sulfonamides (R,R)-2, (S)-3, and (S)-4 were designed and synthesized as organocatalysts and successfully applied for the anti-selective direct asymmetric Mannich reaction.
Enantiomerically pure 3-methyl-beta-proline was synthesized using an asymmetric phase-transfer catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-beta-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes were subsequently investigated. The catalyst was designed and found to be more soluble in non-polar organic solvents relative to the unsubstituted beta-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.
Since the pioneering times of the mid seventies (S)-2-methoxymethylpyrrolidine SMP and its enantiomer RMP belong to the most generally useful chiral auxiliaries in stoichiometric asymmetric synthesis with a very broad range of different applications. As a proline derivative, it generally shows high stereoselectivities due to the rigidity of the five-membered ring and the ability to coordinate metal fragments. The intention of this treatise is to demonstrate the synthetic utility of this important chiral auxiliary covering the literature up to 1996.
Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of a-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.
This report describes the unprecedented use of unmodified aldehydes as donors in a catalytic asymmetric Mannich-type reaction. The proline-catalyzed reaction of N-PMP-protected α-imino ethyl glyoxylate with unmodified aliphatic aldehydes provided a general and very mild entry to either enantiomer of β-amino and α-amino acids and derivatives in high yield and stereoselectivity. Six of the seven aldehydes studied yielded products with ee values of 99% or greater. The diastereoselectivity of the reaction increased with the bulkiness of the substituents of the aldehyde donor in the order R = Me < Et < i-Pr < n-Pent. In five of the cases studied, excellent syn stereoselectivities were achieved. In addition, the corresponding chiral β-amino aldehyde adducts can be readily converted to the corresponding amino acid derivatives. Most significantly, this approach provides facile access to substituted β-lactams.
The direct catalytic asymmetric Mannich reaction of unmodified ketones is described. This was achieved by the cooperative catalysis of a heterobimetallic asymmetric complex: AlLibis(binaphthoxide) (ALB) and La(OTf)3·nH2O in the presence of molecular sieves 3A. The association of ALB and La(OTf)3·nH2O was indicated by means of the Laser Desorption/Ionization Time-of-Flight Mass (LDI-TOF MS) spectrum.
By employing cis-2,6-dimethylmorpholinemethylene immonium tetrachloroaluminate (5) enamines 9 and 10, prepared from 4-tert-butylpropiophenone and propiophenone with (R)-(-)-2-(methoxymethyl)pyrrolidine (8), were converted to chiral Mannich bases 11,12 with nearly 100% ee; optical purity of these β-amino ketones drops significantly during isolation. Two-step reduction of the keto group in 11,12 afforded (S)-(-)-3-(4-tert-Butyl)phenyl-1-N-(cis-2,6-dimethyl)morpholinyl-2-methylpropane (1), (S)-enantiomer of racemic systemic fungicide, generic name fenpropimorph, and its congener 13 with 95.1% and 90.7% ee, respectively. A mechanistic model for asymmetric induction in the diastereoselective step is proposed.
High regioselectivity, good yields, and mild reaction conditions are the advantages of the reaction of iminium salts 1 with imines 2 to afford the Mannich bases 3. Since the amino group in 3 can be substituted readily, this approach enables the simple regioselective functionalization of ketones—an important goal in synthesis.
Enantioselective direct Michael additions of ketones using (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst are described. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivated ketones under mild reaction conditions.
Three chiral cyclic secondary amines are shown to be catalysts for the direct asymmetric Mannich-type reaction of acetone with a variety of preformed aldimines derived from o-anisidine. A simple one-pot three-component reaction procedure consisting of aldehyde, acetone, p-anisidine and an amine catalyst provides the corresponding β-amino ketones with 50–89% ee under very mild conditions.
The readily accessible silyl ketone (S)-1 is an intermediate in the first practical asymmetric Mannich reactions for the regio- and highly enantioselective α-aminomethylation of ketones. The synthetically and pharmaceutically valuable Mannich bases (R)-2 are obtained in excellent yields and high enantiomeric excesses rHex = 1,1,2-trimethylpropyl.
Studies on the enantioselective addition of enol silyl ethers to imines catalyzed by optically active palladium diaquo complexes 3 or binuclear palladium μ-hydroxo complex 4 are described, with particular focus on the mechanistic aspects. Asymmetric induction in the reaction using [Pd((R)-binap)(H2O)2]2+(BF4-)2 (3a) was quite sensitive to the reaction conditions, suggesting unfavorable effects of HBF4 generated from 3a in situ. Novel optically active binuclear μ-hydroxo complexes [{Pd((R)-binap)(μ-OH)}2]2+(BF4-)2 (4a), [{Pd((R)-tol-binap)(μ-OH)}2]2+(BF4-)2 (4b), [{Pd((R)-binap)(μ-OH)}2]2+(TfO-)2 (4c), and [{Pd((R)-tol-binap)(μ-OH)}2]2+(TfO-)2 (4d) were prepared and were found to be better catalysts for the asymmetric Mannich-type reaction. Benzoylalanine derivatives 5 were obtained in excellent chemical and optical yields (up to 90% ee). Mechanistic studies using 1H NMR and electrospray ionization mass spectrometry indicated that a unique binuclear palladium-sandwiched enolate 12 was involved in the reaction of enol silyl ether 1 with imine 2 catalyzed by 4.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Catalytic enantioselective Mannich-type reactions of silyl enol ethers with aldimines have been successfully performed using a novel chiral zirconium catalyst prepared from zirconium(IV) tert-butoxide (Zr(OtBu)4), 2 equiv of (R)-6,6‘-dibromo-1,1‘-bi-2-naphthol ((R)-6,6‘-Br2BINOL), and N-methylimidazole. The use of aldimines having N-substituted hydroxyphenyl moieties is essential for obtaining high selectivities, and the N-substituted groups were converted to free amines using oxidative cleavage. Aldimines derived from aromatic aldehydes as well as heterocyclic and aliphatic aldehydes reacted with silyl enol ethers smoothly to afford the corresponding β-amino acid derivatives in high yields and high enantioselectivities. Several NMR experiments have been conducted to clarify the structure of the chiral Zr catalyst and also the catalytic cycle of this asymmetric reaction. Finally, a new BINOL derivative, (R)-6,6‘-bis(trifluoromethyl)-1,1‘-bi-2-naphthol ((R)-6,6‘-(CF3)2BINOL), has been prepared. It was shown that the turnover of the catalyst using this novel ligand was improved, and high levels of yields and selectivities were obtained in the presence of a small amount of the zirconium catalyst.
A new type of chiral promoter for double asymmetric inductions of aza Diels-Alder and aldol-type reactions of imines is prepared from trialkyl berates (B(OMe)(3) or B(OPh)(3)) and optically pure binaphthol; X-ray analysis of the boron complex demonstrates that it exists as a Bronsted acid-assisted chiral Lewis acid(BLA). The aldol-type reactions of a number of N-benzhydrylimines derived from aromatic aldehydes with the ketene silyl acetal derived from tert-butyl acetate mediated by the chiral BLA afford beta-amino acid esters with high enantioselectivity. The solution conformations of the BLA.imine complexes have been studied using H-1 NMR analysis and difference NOE measurements. The absolute configurations of the adducts can be understood in terms of a rational model involving an intramolecular hydrogen binding interaction via a Bronsted acid.
Diastereoselective Synthesis of Novel Mannich (Bases ¹ ) through Titanium Reagents
Trichlorotitanium dialkylamino‐alkoxides ( 2 ; titanates of N, O‐hemiacetals) are generated either from the corresponding lithium alkoxides and titanium tetrachloride ( Scheme 1 ) or by addition of trichloro‐dialkuylamino‐titanium to aldehydes. The electrophilic (dialkylamino) alkylating reagents 2 are used to convert lithium enolates to β‐dialkylamino‐ketones and ‐esters 5 ( Mannich bases), see Scheme 2 and Table . One diastereoisomer of the products 5g–5p thus obtained with cyclohexenolate is formed preferentially (66‐84%). The configuration of the products of this first diastereoselective version of the Mannich reaction could not yet be determined. A typical procedure for carrying out the reaction is given.
The reaction of S-tert-butyl thiopropionate with a number of N-benzyl or N-allyl aldimines (4) as promoted by the chiral diazaborolidine 1 and triethylamine afforded the β-amino acid esters 5 with high diastereoselectivity and enantioselectivity, providing a simple route to chiral β-lactams 6.
Important building blocks for the synthesis of drugs or natural products are found in Mannich bases and their derivatives. Modern variants of the Mannich reaction that expand the potential of the classical intermolecular reaction significantly and enable efficient control of the regioselectivity and stereoselectivity are therefore the topic of intensive research. Intramolecular reactions, in particular as part of domino reaction sequences, often afford astoundingly simple and elegant approaches to complex target compounds.
The Li enolate of Me ketone I, obtained from (1R)-(+)-camphor and acetylene, reacted, in the presence of excess LDA, with 4-MeC6H4SO2CHRNHR1 (R = Et, Pr, BU, iso-Pr, PhCH2CH2, iso-Bu, cyclohexyl, Ph, etc.; R1 = Cbz, Boc) to give adducts having diastereoisomeric ratios of >96:4. The adducts were converted to beta-amino acids, e.g., N-Cbz beta-homovaline. [on SciFinder (R)]
A single-step enantioselective synthesis of the Wieland–Miescher ketone (5) is presented. We show that l-proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identified as catalysts of Michael and aldol addition reactions.
Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.
[reaction--see text] Direct catalytic enantio- and diastereoselective Michael addition reactions of unmodified aldehydes to nitro olefins using (S)-2-(morpholinomethyl)pyrrolidine as a catalyst are described. The reactions proceed in good yield (up to 96%) in a highly syn-selective manner (up to 98:2) with enantioselectivities approaching 80%. The resulting gamma-formyl nitro compounds are readily converted to chiral, nonracemic 3,4-disubstituted pyrrolidines.
For the first time, the L-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde is described affording (+)-(5S)-hydroxy-(2E)-hexenal 2 with ee's ranging from 57 to 90%. Further transformations of 2 into synthetically valuable building blocks are presented. A mechanism for the formation of 2 is proposed.
The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.
No AbstractSupporting information for this article is available on the WWW under http://www.angewandte.com or from the author.
- Kobayashi
Comprehensive Organic Synthesis
- E F Kleinmann
- Ward