Search

Lewis acid mediated substrate-controlled reactions of the titanium(IV) enolates of chiral α-benzyloxy ketones with conjugated nitroalkenes give 2,4-anti-4,5-syn Michael adducts in good yields and diastereomeric ratios. The supplementary Lewis acid plays a key role in the outcome of these transformations, probably as a consequence of the formation of dimetallic enolates that increase the reactivity of the enolate and direct the approach of the nitroalkene. Importantly, the most appropriate Lewis acid depends on the electrophilic partner: TiCl4 is the most suitable Lewis acid for β-aryl-nitroalkenes, whereas the best results for β-alkyl-nitroalkenes are obtained with SnCl4. Finally, the nitro group of the resultant compounds can be converted into the corresponding amine, oxime, and nitrile groups under mild conditions, which permits the synthesis of a variety of enantiomerically pure derivatives in excellent yields.

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C-C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Simple treatment of chiral titanium(IV) enolates with diacyl peroxides produces highly diastereoselective decarboxylative alkylations to efficiently deliver the corresponding adducts, most of which are not accessible through any of the current alkylating procedures. Such an unprecedented alkylation proceeds through an SET process that triggers the decomposition of the peroxide into a carbon-centered radical that finally combines with the resulting Cα radical. The procedure has been applied to the enantioselective synthesis of arundic acid.

A concise synthesis of the C9-C19 fragment of peloruside A that is both highly stereoselective and efficient is described. Achieving an overall yield of 23% over 14 steps, this synthesis not only is high yielding but also involves four chromatography steps. This approach is based on the addition of metal enolates of chiral auxiliary scaffolds generated by either catalytic or stoichiometric amounts of nickel(II) or titanium(IV) Lewis acids.

A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.

We described in a recent work the rational improvement of an esterase from Bacillus sp. BP7 aimed at investigating the efficiency of several esterase variants for enantiomeric resolution of acetate esters of tertiary alcohols. Variant EstBP7-AGA, bearing two aminoacidic changes in the oxyanion hole, showed an excellent E > 100 enantioselectivity value towards a complex tertiary alcohol acetate (2-(4-pyridyl)-3-butyn-2-yl acetate) at low reaction temperature (4 °C). We here go further in the investigation of such esterase variant by analyzing the kinetic resolution of benzylic propargylic esters to prove that this enzyme is a powerful tool to obtain enantiomerically pure tertiary as well as secondary alcohols, provided that the structural integrity of the parent benzylic propargylic ester is maintained. Understanding the mode of action and interaction of such esterase variant with the assayed substrates will allow production of interesting pharmaceutical building blocks.

The structurally simple (Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a variety of functional groups and heteroatoms at the α-position. The resultant adducts are isolated as single diastereomers in high yields and can be converted into enantiomerically pure derivatives in a straightforward manner.

Direct nickel-catalyzed alkylation of chiral N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones using a commercially available nickel(II) complex, (Me3P)2NiCl2, has been developed for tropylium and trityl tetrafluoroborate salts. The reaction provides a single diastereomer of the corresponding adducts in good to high yields, which, in turn, can be easily converted into a wide array of enantiomerically pure compounds that are difficult to obtain by other asymmetric procedures.

Lipases and esterases are important biocatalysts for synthetic organic fine chemistry. An esterase from Bacillus sp. BP-7 (EstBP7) bears in its amino acid sequence a rare GGG(A)X oxyanion hole motif, where an uncommon threonine (T) is found at the third position. Detection of this pattern motivated evaluation of the ability of EstBP7 for conversion of tertiary alcohols. The enzyme was engineered in order to optimize its performance to provide important chiral building blocks: five variants with mutations in the oxyanion hole motif were created to investigate the influence on activity and enantioselectivity in the kinetic resolution of eight acetates of tertiary alcohols. Wild-type enzyme converted all esters of tertiary alcohols assayed with low enantioselectivity, whereas some of the mutants displayed significantly increased E-values. One of the mutants (EstBP7-AGA; Mut 5) showed an E >100 towards a complex tertiary alcohol acetate (2-(4-pyridyl)but-3-yn-2-yl acetate) at low reaction temperature (4 °C). Therefore, the catalytic toolbox was expanded for biocatalysis of optically pure tertiary alcohols valuable for the pharmaceutical industry.

Aldol reactions of titanium enolates of lactate-derived ethyl ketone 1 with other ketones proceed in a very efficient and stereocontrolled manner provided that a further equivalent of TiCl4 is added to the reacting mixture. The scope of these reactions encompasses simple ketones such as acetone or cyclohexanone as well as other ketones that contain potential chelating groups such as pyruvate esters or α- and β-hydroxy ketones.

Both α- and β-C-glycosides can be prepared by SnCl 4 -mediated addition of titanium enolates from N-acetylthiazolidinethiones to glycals. Subsequent removal of the chiral auxiliary provides enantiomerically pure fragments that are useful for the synthesis of natural products.

The structurally simple (Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a variety of functional groups and heteroatoms at the α-position. The resultant adducts are isolated as single diastereomers in high yields and can be converted into enantiomerically pure derivatives in a straightforward manner.

Titanium-mediated aldol reactions based on (S)-2-tert-butyldimethylsilyloxy-3-pentanone, a lactate-derived chiral ketone, provide the corresponding 2,4-syn-4,5-syn adducts in high yields and diastereomeric ratios with a wide array of achiral and chiral aldehydes. Furthermore, spectroscopic studies of intermediates involved in the process have permitted to propose a mechanism that accounts for the experimental results.

[structure: see text]. A convergent and module-based strategy for the asymmetric synthesis of the western hemisphere (C1-C17 fragment) of salinomycin has been devised. This new synthetic approach relies on highly stereoselective C-glycosidation and aldol processes.

Highly stereoselective titanium-mediated aldol additions of ethyl ketones derived from lactic acid to α-methyl-β-OTBDPS chiral aldehydes are documented. One of these double stereodifferentiating processes represents the key step of a straightforward and efficient synthetic approach to the C1-C6 fragment of erythronolides.

Addition of the chiral titanium enolate arising from 1 to dibenzyl acetals gives access to anti-b-benzyloxy-a-methyl carbox- ylic adducts in good yields and with diastereomeric ratios up to 99:1. These adducts can be easily converted into a plethora of enan- tiopure protected derivatives. Aldol reaction nowadays constitutes one of the most pow- erful tools for the carbon-carbon bond formation, 1 giving easy access to a-alkyl-b-hydroxy oxygenated moieties present in the molecular architecture of a vast array of nat- ural products. 2 Taking into account that (i) in spite of re- cent advances, the stereoselective construction of anti aldol units is still one of the remaining challenges, 3 and that (ii) the protection of the hydroxyl group of the result- ing aldol adducts is usually required, any methodology able to provide stereoselectively protected anti aldol ad- ducts in a single step would be highly desirable. In this context, we have recently reported that the Lewis acid me- diated cross-coupling reaction of a wide range of dimethyl acetals with the titanium enolate arising from (S)-4-iso- propyl-N-propanoyl-1,3-thiazolidine-2-thione (1) fur- nishes efficiently enantiopure anti-b-methoxy-a-methyl adducts. 4 On the basis of these results, we envisaged that the use of appropriate acetals might lead to a broader va- riety of b-alkoxy-a-methyl carboxylic derivatives, which, in turn, could be considered as protected aldol synthons. Herein, we wish to report that the reaction of the titanium enolate of 1 and dibenzyl acetals affords stereoselectively anti-b-benzyloxy-a-methyl adducts that can be trans- formed into a large number of enantiopure derivatives. Initially, we examined the reaction of 1 with diallyl and dibenzyl acetals derived from benzaldehyde and isobu- tyraldehyde, 5,6 which could afford aldol adducts with eas

[reaction: see text] Lewis acid mediated addition of chiral titanium enolates to glycals provides either alpha- or beta-1'-methyl-substituted C-glycosides. This highly stereoselective methodology permits the modular preparation of three of the four possible diastereomers.

4-Pyridinecarboxaldehyde Dichloromethane 3-tert-Butyl-2-hydroxybenzaldehyde Sodium borohydride Methanol 2-(1,1-Dimethylethyl)-6-[[[(1R,2R)-2-[(4-pyridinylmethyl)amino]-cyclohexyl]amino]methyl]-phenol (1R,2R)-1,2-Diaminocyclohexane (1S)-1-(4-Nitrophenyl)-2-nitroethane-1-ol Copper acetate Ethanol p-Nitrobenzaldehyde Nitromethane Keywords: Nitroaldol; Henry reaction; p-Nitrobenzaldehyde; Nitromethane; Copper (II) complex; (R,R)-1,2-diaminocyclohexane; (1S)-1-(4-nitrophenyl)-2-nitroethane-1-ol; Aromatic aldehyde; Aliphatic aldehyde

N -Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from α-amino acids. Nucleophilic ring-opening of N -nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N -nosyl β 3 -amino acids, which can be readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple, efficient, and amenable to large-scale preparations.

Aldol reactions between the putative Z-enolate derived from 2-methyl-3-pentanone and several chiral α-tert-butyldiphenylsilyloxy aldehydes have been studied. The stereochemical outcome suggests that stereoelectronic effects play a dominant role in these reactions and the results can be accommodated by the Felkin model, with gauche pentane interactions being less important.

Stereoselectivity of TiCl4-mediated aldol reactions from (S)-2-benzyloxy-3-pentanone is dramatically improved when the reaction is carried out in the presence of 1.1 equiv of tetrahydrofuran (THF) or 1,2-dimethoxyethane (DME). The resultant 2,4-syn-4,5-syn adducts are then obtained in diastereomeric ratios up to 97:3, which proves that the appropriate choice of the Lewis acid (TiCl4-THF or DME vs Ti(i-PrO)Cl3) engaged in the process permits access to both syn-aldol adducts.

A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)-N-acyl-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or a-cyclopropyl, as well as a-trifluoromethyl groups, are well tolerated. This transformation can therefore produce the a-aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the a,b-unsaturated N-acyl counterparts give the corresponding g-adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure a-hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed.

Amides derived from pyrrolidine and methyl ( S )-lactate, methyl ( S )-2-hydroxy-3-phenylpropanoate, or methyl ( S )-2-hydroxy-3-methylbutanoate, after O -benzylation and O -silylation have been treated with EtLi or EtMgCl under suitable conditions, to give excellent overall yields of enantiopure ethyl ketones. The chelating ability of α-OBn amides (and even of α-O-TBS amides, which has been demonstrated by NMR to be better than that of N -OMe amides) accounts for the performance of the approach.

New syntheses of densely functionalized protected derivatives of 3-amino-3,6-dideoxyaminosugars have been accomplished in an efficient and straightforward manner. The key step of such approaches involves a highly stereoselective titanium-mediated aldol addition of a chiral α-bromo ketone, easily available from lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective Staudinger–aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions.

A substrate-controlled synthesis of (+)-herboxidiene from two lactate-derived chiral ketones is described. Remarkably, most of the carbon backbone was constructed through highly stereoselective titanium-mediated aldol reactions and an Ireland–Claisen rearrangement. Furthermore, an oxa-Michael cyclization and a high-yield Suzuki coupling were used to assemble the pyran ring and the diene moiety respectively.

This review deals with stereoselective acetate aldol reactions mediated by metal enolates. It summarizes recent advances in aldol additions of unsubstituted metal enolates that either incorporate chiral auxiliaries, stoichiometric Lewis acids, or catalytic Lewis acids or bases, or act in substrate-controlled reactions. These approaches provide stereocontrolled aldol transformations that allow the efficient synthesis of structurally complex natural products.

ω-Azido acids, after activation of the carboxyl groups as mixed anhydrides, N3(CH2)nCOOCOAr (Ar = 3,5-dinitrophenyl or 2,4,6-trichlorophenyl), can be converted to macrolactams in good yields by treatment with Bu3P under high-dilution conditions; the presence of 4-dimethylaminopyridine improves slightly the yields. Amides and peptides can be readily obtained by this procedure.

Amides derived from pyrrolidine and methyl ( S )-lactate, methyl ( S )-2-hydroxy-3-phenylpropanoate, or methyl ( S )-2-hydroxy-3-methylbutanoate, after O -benzylation and O -silylation have been treated with EtLi or EtMgCl under suitable conditions, to give excellent overall yields of enantiopure ethyl ketones. The chelating ability of α-OBn amides (and even of α-O-TBS amides, which has been demonstrated by NMR to be better than that of N -OMe amides) accounts for the performance of the approach.

Morpholine-derived amides react with RMgX to give the corresponding ketones in good yield. The mild conditions required and low cost of starting materials make this method very appealing for large scale preparations.

Aldol reactions between the putative Z-enolate derived from 2-methyl-3-pentanone and several chiral α-tert-butyldiphenylsilyloxy aldehydes have been studied. The stereochemical outcome suggests that stereoelectronic effects play a dominant role in these reactions and the results can be accommodated by the Felkin model, with gauche pentane interactions being less important.

N -Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from α-amino acids. Nucleophilic ring-opening of N -nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N -nosyl β 3 -amino acids, which can be readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple, efficient, and amenable to large-scale preparations.

(S)-Valinol Carbon disulfide (S)-4-Isopropyl-1,3-thiazolidine-2-thione n-Butyllithium Propanoyl chloride (S)-4-Isopropyl-N-propanoyl-1,3-thiazolidine-2-thione Keywords: 1,3-thiazolidine-2-thiones; chiral auxiliaries; tert-leucinol; acylation; carbodiimides; aldol addition; magnesium catalyst; metal enolates; iminium intermediates; waste disposal; safety

(E)-2-Methyl-3-phenylpropenal Trimethyl orthoformate (E)-3,3-Dimethoxy-2-methyl-1-propenylbenzene (S)-4-(1-Methylethyl)-3-(1-oxopropyl)2-thiazolidinethione Diisopropylethylamine Titanium tetrachloride (4S)-3-[(2R,3S,4E)-3-Methoxy-2,4-dimethyl-1-oxo-5-phenyl-4-pentenyl]-4-(1-methylethyl)-2-thiazolidinethione N,O-Dimethylaminopyridine Triethylamine Keywords: methylmethoxy carboxylic compounds; stereoselctive synthesis; titanium enolate; dibenzyl acetals; debromoaplysiatoxin; waste disposal; safety

The Lewis acid-mediated addition of titanium enolates from 1 to dimethyl ketals of aliphatic methyl ketones followed by removal of the chiral auxiliary furnishes enantiomerically pure derivatives containing a tertiary methyl ether and a contiguous stereocenter in a straightforward manner.

The Lewis acid-mediated addition of titanium enolates from 1 to dimethyl ketals of aliphatic methyl ketones followed by removal of the chiral auxiliary furnishes enantiomerically pure derivatives containing a tertiary methyl ether and a contiguous stereocenter in a straightforward manner.

Stereoselectivity of TiCl4-mediated aldol reactions from (S)-2-benzyloxy-3-pentanone is dramatically improved when the reaction is carried out in the presence of 1.1 equiv of tetrahydrofuran (THF) or 1,2-dimethoxyethane (DME). The resultant 2,4-syn-4,5-syn adducts are then obtained in diastereomeric ratios up to 97:3, which proves that the appropriate choice of the Lewis acid (TiCl4-THF or DME vs Ti(i-PrO)Cl3) engaged in the process permits access to both syn-aldol adducts.

Tin(II) complexes prepared by treatment of SnCl2or Sn(SR)2 with appropriate amounts of RSH and Et3N appear to be the best reducing agents for azides (to amines) reported so far. These tin(II) complexes also reduce primary and secondary aliphatic nitro compounds to oximes, usually within minutes at r.t. or hours in cold, and tertiary aliphatic as well as aromatic nitro compounds to afford the corresponding hydroxylamines. In general, azides react more rapidly than nitro substituents, whereas carbonyl groups, sulphoxides, sulphones, nitriles, and esters are practically unreactive under the same conditions. Some mechanistic details of the reaction of Sn(SPh)3- with azides and nitro compounds have also been elucidated.

Alternative titanium-mediated aldol procedures based on several protected beta-hydroxy ethyl ketones have been surveyed. Eventually, enolization of (S)-1-benzyloxy-2-methyl-3-pentanone (1) with (i-PrO)TiCl3/i-Pr2NEt provided a very reactive enolate that afforded the corresponding 2,4-syn-4,5-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes.

Addition of the chiral titanium enolate arising from 1 to dibenzyl acetals gives access to anti-b-benzyloxy-a-methyl carbox- ylic adducts in good yields and with diastereomeric ratios up to 99:1. These adducts can be easily converted into a plethora of enan- tiopure protected derivatives. Aldol reaction nowadays constitutes one of the most pow- erful tools for the carbon-carbon bond formation, 1 giving easy access to a-alkyl-b-hydroxy oxygenated moieties present in the molecular architecture of a vast array of nat- ural products. 2 Taking into account that (i) in spite of re- cent advances, the stereoselective construction of anti aldol units is still one of the remaining challenges, 3 and that (ii) the protection of the hydroxyl group of the result- ing aldol adducts is usually required, any methodology able to provide stereoselectively protected anti aldol ad- ducts in a single step would be highly desirable. In this context, we have recently reported that the Lewis acid me- diated cross-coupling reaction of a wide range of dimethyl acetals with the titanium enolate arising from (S)-4-iso- propyl-N-propanoyl-1,3-thiazolidine-2-thione (1) fur- nishes efficiently enantiopure anti-b-methoxy-a-methyl adducts. 4 On the basis of these results, we envisaged that the use of appropriate acetals might lead to a broader va- riety of b-alkoxy-a-methyl carboxylic derivatives, which, in turn, could be considered as protected aldol synthons. Herein, we wish to report that the reaction of the titanium enolate of 1 and dibenzyl acetals affords stereoselectively anti-b-benzyloxy-a-methyl adducts that can be trans- formed into a large number of enantiopure derivatives. Initially, we examined the reaction of 1 with diallyl and dibenzyl acetals derived from benzaldehyde and isobu- tyraldehyde, 5,6 which could afford aldol adducts with eas

4 pages, 2 figures, 2 tables.-- PMID: 12889880 [PubMed].-- Printed version published Aug 7, 2003.-- Supporting information available at: http://pubs.acs.org/doi/suppl/10.1021/ol0347848, Two intramolecular C−H···X (X = O, S) interactions in (S)-N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones are documented through crystallographic and spectroscopic evidence and high-level theoretical calculations. The key role played by the sulfur atoms has been made clear by comparison with structurally related (S)-N-acyl-4-isopropyl-1,3-oxazolidin-2-ones., Financial support from the Ministerio de Ciencia y Tecnología (Grants BQU2002-00293, BQU2002-0485-C02-01, and BQU2002-01514) and from the Generalitat de Catalunya (Grants 2001SGR00048 and 2001SGR00051).

La nitrosation de carboxamides et de dipeptides est effectuee dans l'acetonitrile en presence d'une base par NOBF 4 /sulfure de methyle ou NO 2 BF 4

A novel approach to synthesize enantiomerically pure α-hydroxy carboxylic derivatives is reported. A highly stereoselective oxidation of titanium(IV) enolates from chiral N-acyloxazolidinones is performed with oxygen under simple experimental conditions that do not require any reducing steps. The success of this approach depends on the biradical character of titanium(IV) enolates.

Morpholine-derived amides react with RMgX to give the corresponding ketones in good yield. The mild conditions required and low cost of starting materials make this method very appealing for large scale preparations.

Asymmetric syntheses of the C-1 alkyl side chains of Zaragozic acids A and C from a common chiral precursor 4 are reported. The stereoselective reduction of unsaturated ketones 8 and 10 is the key step of both syntheses.