The first catalytic, enantioselective vinylogous mannich reaction of acyclic silyl dienolates is reported. Upon protonation of the imines, chiral contact ion pairs are generated in situ. Direct enantioselective vinylogous mannich reaction of. Ytterbium triflatecatalyzed reactions of imines with a chiral nonracemic silyloxypyrrole. Mannichtype reaction of aldimines with 2silyloxydienes. The vinylogous mannich reaction of triisopropylsilyloxyfurans with aldimines in the presence of catalytic amounts of the tio i pr 4 s binol. Guijun li ab, xiaoliang xu a, hongchang tian a, xiaotong liu a, wen chen a, xiaodong yang a and hongbin zhang a a key laboratory of medicinal chemistry for natural resource, ministry of education, school of. The vinylogous aldol reaction in nature euphoperfolianes appendino, j. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amideznotf 2 catalyst and et 3 n. Because the vinylogous mannich reaction of substituted furans with iminium ions is a useful construction in alkaloid synthesis, it is important to know what effects substituents on the two reacting partners have upon the stereoselectivity of the reaction. The bronsted acid catalyzed, enantioselective vinylogous mannich. Asymmetric vinylogous mannich reaction of silyloxy furans with ntertbutanesulfinyl ketimines v. The vinylogous mannich reaction of triisopropylsilyloxyfurans with aldimines in the presence of catalytic amounts of the complex gave substituted aminoalkyl butenolides in good yield and enantioselectivities up to 54% ee. Threecomponent agcatalyzed enantioselective vinylogous.
The reaction products were generally obtained in high yields and as a single diastereoisomer having the r,r. A58365a 7 has been achieved following a strategy in which a vinylogous mannich reaction and a lactonelactam rearrangement served as the key transformations. Recent advances on organocatalysed asymmetric mannich reactions. A combined vinylogous mannichdielsalder approach for the. We have recently investigated the vinylogous mannich reaction as a key construction for the synthesis of alkaloid natural. A concise enantiospecific synthesis of the angiotensin converting enzyme inhibitor. An organocatalytic asymmetric synthesis of aminoketoester derivatives has been developed. The brominated product served as a suitable electrophile for common sn2 nucleophilic. Catalytic, asymmetric additions of triisopropylsilyloxyfurans to aldimines. In our opinion the vinylogous mannich reaction10, 10a, 10b, 10c of a synthetic equivalent of acetoacetate dianion represents a more convenient approach for the synthesis of 1. Stereoselective formal synthesis of pumiliotoxin 251d.
Abstract the first catalytic, enantioselective vinylogous mannich reaction of acyclic silyl dienolates is reported. The related reactions, such as vinylogous aldol reaction, vinylogous mannich reaction, vinylogous michael reactions, as well as allylic alkylation reaction, have been well developed in the past two decades. Asymmetric organocatalytic vinylogous mannich reaction of. Novel applications of vinylogous mannich reactions. Key steps in the formation of the bicyclic products are an organocatalytic vinylogous mukaiyamamannich and a dielsalder reaction. Trimethylsiloxyfuran underwent a vinylogous mannich. The related reactions, such as vinylogous aldol reaction, vinylogous mannich reaction, vinylogous michael reactions, as well as allylic alkylation reaction, have been well developed in the past. The methyl group at c3 of tbsof has been shown to play the. Request pdf mannich reaction threecomponent aminomethylation from amine, aldehyde.
Effective asymmetric vinylogous mannich reaction of isatin imines. A chiral bronsted acidcatalyzed direct asymmetric mannich reaction has been described. An efficient enantioselective vinylogous mannich reaction of nboc aminosulfones with noncyclic. The catalytic system was extended to a bisvinylogous mannich type reaction by changing the ligand. Regio and diastereoselective vinylogous mannich addition of.
The vinylogous mannich reaction vmr between 2tertbutyldimethylsilyloxyfuran tbsof and rstbsimine 12a and the application of the vmr adduct butenolide a as a versatile chiral. Studies on the viability of cyclopropanecontaining. Lopez department of chemistry and biochemistry, the university of texas at austin, austin, tx 78712, usa received 1 july 1999. The vinylogous aldol and related addition reactions. It is possi ble that two mechanistic pathways are operative in this reaction. A direct enantioselective vinylogous mannich reaction of ketimines with butenolide has been developed. Various phosphoric acids, prepared from binol and h8binol derivatives, have been evaluated for catalyzing the direct mannich reaction. An efficient, mild, solventfree, onepot threecomponent mannich reaction catalyzed by c 4 h 12 n 2 2 bicl 6clh 2 o h. However, mannichtype reaction of imines with 2silyloxydienes, which provides easy access to. The key to control the regioselectivity is the combination of a bulky nacylpyrazole and a bulky bisphosphine ligand. The enantioselective, bronsted acid catalyzed, vinylogous mannich reaction marcel sickert institut fur organische chemie, universitat leipzig, johannisallee 29, 04103 leipzig, germany, fax.
Asymmetric organocatalytic vinylogous mannich reaction of 3methyl5arylfuran23hones with n2pyridinesulfonyl imines. Tetrahedron leffers pergamon tetrahedron letters 40 1999 89498953 vinylogous mannich reactions. Development of efficient and practical catalytic enantioselective variants of such reactions stands as a critical goal in chemical synthesis. The selectivity was strongly influenced by the bulkiness of the csubstituent of the nitrone. In an attempted asymmetric synthesis of pandamarilactonineb 2, an unanticipated syndiastereoselective dr 95. Butenolides 7af,k were readily converted into substituted lactones 8 and 5 and 6substituted 5hydroxypiperidin2ones 11ag, which are, in turn, key. A decade of advance in the asymmetric vinylogous mannich reaction. A chiral disulfonimide dsi serves as a highly efficient precatalyst for a vinylogous mukaiyama mannich reaction of readily available dioxinone. The aldol reaction is a means of forming carboncarbon bonds in organic chemistry.
Organocatalytic and highly stereoselective direct vinylogous mannich reaction. Transition metal saltcatalyzed direct threecomponent mannich reactions of aldehydes, ketones, and carbamates. Chiral 2substituted6methyl 2, 3dihydropyidinones 9, which can be facilely obtained from an asymmetric vinylogous mannich reaction vmr with 1, 3bistrimethysily enol ether, were used as. Organocatalytic vinylogous mannich reaction of trimethylsiloxyfuran with isatinderived benzhydrylketimines giulia rainoldi,a alessandro sacchetti,b alessandra silvani,a and giordano lesmaa adipartimento di chimica, universita degli studi di milano, via golgi 19, milano, 203, italy.
The dissertation committee for andreas reichelt certifies that this is the approved version of the following dissertation. Studies on the asymmetric synthesis of pandamarilactonines. Oxidative mannich reaction of ncarbobenzyloxy amines with 1,3dicarbonyl compounds ji. A stereoselective threecomponent vinylogous mannich type reaction vmr of 1,3bistrimethylsily enol ether 7 was therefore investigated and was found to give cyclized chiral dihydropyridinone compound 9 as an adduct. Enantioselective vinylogous mannich reaction of acyclic. The trimethylsilyloxyfuran derived from 25, which was prepared from the known sulfoxide 16, served as the nucleophilic partner in a. Disubstituted butenolides zhenhua wang,a yong you,a yongzheng chen,c xiaoying xub and weicheng yuanb ainstitute for advanced study, chengdu university, chengdu 610106, china. Stereoselective vinylogous mannich reaction of 2trimethylsilyloxyfuran with lgulosederived chiral nitrones in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate was investigated. Toward this end, the additions of the methylated furans 9a. Request pdf a decade of advance in the asymmetric vinylogous mannich reaction when the principle of vinylogy is applied to imines as electrophiles, the socalled vinylogous mannich reaction. General procedure for vinylogous mannich reaction of dicyanoalkylidenes with. A concise synthesis of 3, a known precursor of pumiliotoxin 251d, has been completed using a vinylogous mannich reaction as a key construction.
A onestep, 3component vinylogous mannich reaction of trimethylsilyloxyfuran or nprotected tertbutyldimethylsilyloxypyrrole with a variety of nitrogencontaining heterocycles in the presence of diverse electrophiles is described. An organocatalytic asymmetric synthesis of daminobketoester derivatives has been developed. The asymmetric vinylogous mannich reaction of noncyclic. The product of this reaction is a betaamino carbonyl compound. Aug 10, 2016 organocatalytic vinylogous mannich reaction of trimethylsiloxyfuran with isatinderived benzhydrylketimines. Although many vinylogous mannichtype reactions have been developed 27 36, only a few examples that describe the selective preparation of. Thus, the first synthesis of 3a,b commenced with the conversion of the known indole 17 into 24 via the addition of the furan 22 to the iminium ion 21, which was generated in. A versatile approach to functionalized heterocycles. The acyclic products were formed by a vinylogous 9 mannich reaction mechanism. A concise enantiospecific synthesis of the angiotensinconverting enzyme inhibitor a58365a has been achieved. Mannich reactions rank among the most versatile class of transformations in organic chemistry. The second pathway features the intramolecular vinylogous mannich.
Asymmetric vinylogous mannich reaction vmr of 2tertbutyldimethylsilyloxyfuran tbsof, 1 with rs or sstbsimines 3 furnished 5aminoalkylbutenolides 7ak in 7587% yields with antisyn ratios ranging from 75. Spectroscopic and xray data are among the physical evidence provided that shed light on the identity of the agbased chiral catalysts and some of the mechanistic subtleties of this class of. Effective asymmetric vinylogous mannich reaction of isatin. The first direct asymmetric vinylogous mannich avm reaction of alpha,alphadicyanoolefins and nboc aldimines was described promoted by a simple chiral bifunctional thioureatertairy amine organocatalyst. A direct catalytic asymmetric vinylogous mannich type reaction has been disclosed in good yield, excellent regio, diastereo and enantioselectivity. The schiff base is an electrophile which reacts in the second step in an electrophilic addition with a compound containing an acidic proton which is, or had become an enol. Silyloxyfuran 10 added to methoxypyrrolidine 20 in the presence of tmsotf to give a mixture 4. Rainoldi g, sacchetti a, silvani a, lesma g org biomol chem, 1432. Trialkylsilyloxyfurans are interesting substrates in the vinylogous mannich reaction, which is an important process, involving an iminium or an acyl iminium salt, for the synthesis of alkaloids and other nitrogencontaining biologically active compounds. To overcome these limitations, modern variants of mannich reaction utilize preformed imines, enolates, appropriate use of catalyst and reaction con. Catalytic, asymmetric additions of triisopropylsilyloxyfurans to aldimines stephen e martin and omar d. A catalytic asymmetric vinylogous mannichtype reaction of. However, previous reports on the iminoaldol reaction of the brassard diene 2a, under lewis acid catalysis, pointed out the occurrence of the competing cyclization of the resulting openchain vinylogous. The enantioselective, bronsted acid catalyzed, vinylogous.
The first of these involves cyclization of 11, which in turn would be formed by the intermolecular vinylogous mannich reaction of the iminium ion and the silyloxy furan 14 path a. International audiencea onestep, 3component vinylogous mannich reaction of trimethylsilyloxyfuran or nprotected tertbutyldimethylsilyloxypyrrole with a variety of nitrogencontaining heterocycles in the presence of diverse electrophiles is described. Previously reported agcatalyzed enantioselective vinylogous mannich and azadielsalder reactions of arylsubstituted aldimines herein, we describe the development of a protocol for efficient threecomponent agcatalyzed enantioselective vm reactions of the more demanding alkylsubstituted aldimines, a class of substrates that cannot be. Catalytic asymmetric construction of halogenated stereogenic. Bruno dudot, jacques royer, mireille sevrin, pascal george. Chiral bronsted acidcatalyzed direct asymmetric mannich reaction. Diastereoselective threecomponent vinylogous mannich. Mannichtype reactions are widely recognized as a powerful method for constructing a variety of baminoketones 1 6. Silyloxyfuran 10 added to methoxy pyrrolidine 20 in the presence of tmsotf to give a mixture 4. Both enantiomers of the products could be obtained by using pseudoenantiomeric. There are two reaction manifolds that can lead to 10. Substituted aminoalkylbutenolides 7 examples are formed in good yield and enantioselectivities up to 54% e. The mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by dehydration to the schiff base.
Organocatalytic and highly stereoselective direct vinylogous mannich reaction t. Both chiral metal complex catalysts and organocatalysts have proven to be useful. A conceptually novel approach to the potent immunosuppressant fr901483 has been proposed. Reduction and global deprotection of 21 afforded the bicyclic lactam 23. Direct asymmetric vinylogous and bisvinylogous mannich. Studies on the viability of cyclopropanecontaining peptidomimetics and application of the vinylogous mannich reaction to the syntheses of indolizidine natural products committee. Jan 21, 2009 the new naryl unit is crucial for conversion of the asymmetric vinylogous mannich avm products to the unprotected amines in high yields. Catalytic asymmetric vinylogous mannich reaction of n2. Mannich reaction mechanism reaction details and applications. Jan 14, 2000 cheminform abstract the first example of a catalytic, asymmetric vinylogous mannich reaction involving siloxyfurans and aryl aldimines is given. A secondgeneration 2,2dihydroxy1,1binaphthyl binolbased phosphoric acid has been developed and further optimized as an enantioselective organocatalyst. Enantio and diastereoselective direct vinylogous mannich reaction of alkylimines xiaofeng xiong,a zhijun jia,a wei du a kun jiang,a tianyu liu,a yingchun chen,a,b a key laboratory of drugtargeting and drug delivery system of education ministry, department of medicinal chemistry, west china school of pharmacy, sichuan university, chengdu 610041,china. In the key step, a sequence involving a vinylogous mannich reaction followed by a baseinduced lactonelactam rearrangement was applied to establish the indolizidine core of the molecule.
Cyclization of 24 by a novel srn1 reaction followed by removal of the nbenzyl group furnished a mixture 1. In an alternative approach to these alkaloids, the biaryl 35 was reduced with dibalh to give an intermediate imine that underwent spontaneous cyclization via an intramolecular vinylogous mannich addition to provide 36a,b. The mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. Organocatalytic vinylogous mannich reaction of trimethylsiloxyfuran with isatinderived benzhydrylketimines. Agcatalyzed diastereo and enantioselective vinylogous. Concise syntheses of the ergot alkaloids rugulovasine a 3a, rugulovasine b 3b, and setoclavine 2 have been completed by strategies that feature inter and intramolecular vinylogous mannich reactions as the key steps. Department of life science and applied chemistry, graduate school of engineering, nagoya institute of technology, gokiso, showaku, nagoya 4668555, japan frontier research institute for material science, nagoya institute of technology, gokiso, showaku, nagoya 4668555, japan article views are the. A decade of advance in the asymmetric vinylogous mannich. However, the classical mannich reaction has limitations such as lack of selectivity, competitive aldol reactions, etc.