Stereoselective synthesis ofvic-halohydrins and an unusual Knoevenagel product from an organocatalyzed aldol reaction：A non-enamine mode

Stereoselective synthesis by an aldol reaction between chloroacetone and aldehyde was studied using a synthesized chiral organocatalyst and triethylamine. The reaction gave α-chloro-β-hydroxy ketones in excellent yield with highantiselectivity and enantioselectivity. The chiral organocatalyst was also used in the Knoevenagel reaction, which gave α-cyano-β-hydroxy ketones at a low tem-perature and the usual Knoevenagel product at a high temperature. Both products were obtained in good to moderate yield with goodanti selectivity in the case of α-cyano-β-hydroxy ketone deriva-tives.     

Aldolisation stereocontrolee par un groupe thermolabile. Synthese stereoselective de composes possedant trois carbones asymetriques consecutifs

The bulkiness of thermolabile norbornenyl and oxanorbonenyl groups has been used to induce good to excellent syn diastereoselective aldol condensations between Diels-Alder adducts of α,β-ethylenic ketones and various aldehydes. The aldols thus obtained give rise after thermolysis to syn α-methyl-β-siloxy-α'-ethylenic ketones of great synthetic potential. The reduction of these latters is achieved following known or original methods to give with high selectivity allylic 1,3-diols with three successive asymmetric carbons of well defined stereochemistry.     

Diastereoselective synthesis of piperidine imino sugars using aldol additions of metalated bislactim ethers to threose and erythrose acetonides

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the gamma-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, high trans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-L-altronojirimycin, 1-deoxy-D-gulonojirimycin, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin and 1-deoxy-D-talonojirimycin.     

An efficient synthesis of α,β-unsaturated aldehydes by a four-carbon unit extension of Grignard reagents

Copper-catalyzed addition of organomagnesium halides to 2-(2,2-diethoxyethyl)oxirane ( 1 ) affords aldol acetals 2 which upon acid treatment undergo hydrolysis and dehydration to give α,β-unsaturated aldehydes 7 with high yields.     

Regioselective addition of Ti enolates to conjugated enones: New insights into the mechanism based on experimental and DFT investigation

The regioselective addition mechanism of the Ti(IV) enolates derived from α-diazo-β-keto carbonyl compounds and α-diazo-β-keto phosphonates to conjugated enones has been studied on the basis of a hypothetical bridging chloride-controlled theory, by density functional theory (DFT), and experimentally. The DFT results indicate that, for the Ti(IV) enolate 3 derived from α-diazo-β-keto carbonyl compounds, the free energy of the bridging chloride-controlled 1,2-addition transition state is 2.4 kcal/mol higher than that of 1,4-addition, and the calculated enthalpies of 1,2-addition is 4.36 kcal/mol more than that of 1,4-addition. For the Ti(IV) enolate 4 derived from α-diazo-β-keto phosphonates, in contrary, the free energy of the bridging chloride-controlled 1,2-addition transition state is 1.1 kcal/mol lower than that of 1,4-addition, and the calculated enthalpy of 1,2-addition is 3.46 kcal/mol less than that of 1,4-addition. Our findings demonstrate that the nucleophilic addition of these Ti(IV) enolates to conjugated enones was carried out not only kinetically but also irreversibly for the first time.     

Synthesis of fluorinated materials catalyzed by proline or antibody 38C2 in ionic liquid

The utility of reusable ionic liquid-proline (or aldolase antibody 38C2) reaction system, proceeding the aldol reactions, is described. Further, obtained α-chloro-β-hydroxy compounds were transformed to the optically active α,β-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was able to reuse in Michael additions and the reaction of fluoromethylated imines.     

Diastereoselective auto-protonation of enolates anti-houk selectivity

1,4-Addition reaction of lithiated methyl dithioacetate with α,β-disubstituted enones affords 5-oxodithioesters. The diastereoselectivity ranges from moderate to high (> 95:5) in favour of the syn isomer. This anti-Houk selectivity arises from an ‘auto-protonation’, involving transfer of the hydrogen α to the thiocarbonyl group towards the enolate moiety. A pseudo-cyclic transition state leading to the syn product is postulated.     

The first total synthesis of (R)-convolutamydine A

The first total synthesis of (R)-convolutamydine A has been achieved by the organocatalytic addition of acetone to 4,6-dibromoisatin. The absolute configuration was determined by single crystal X-ray diffraction. DFT studies were used to model the transition states for the aldol reaction and equilibrium geometries of the post-aldol reaction intermediates. The DFT study revealed that the aldol bond forming reaction was considerably endothermic.     

Unnatural tripeptide as highly enantioselective organocatalyst for asymmetric aldol reaction of isatins

The development of unnatural tripeptides as highly enantioselective organocatalysts for the asymmetric aldol reaction of isatins was achieved. H-Pro-Gly-d-Ala-OH with the d-alanine residue as the C-terminal amino acid residue expressed the best enantioselectivity. The H-Pro-Gly-d-Ala-OH-catalyzed reaction of isatins gave various aldol adducts with up to 93% yield and up to 97% ee. Investigation of the transition state via DFT calculation revealed that high optical purity was realized by the d-alanine controlled steric environment.     

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

Synthesis of some 7-substituted 3-chloro-3,4-dihydro-1-hydroxycarbostyrils by the reduction cyclization of α-chloro-β-(4-substituted-2-nitrophenyl)propionic acids

A new method was developed for the synthesis of some 7-substituted 3-chloro-3,4-dihydro-l-hydroxycarbostyrils 3c-g in which α-chloro-β-(4-substituted-2-nitrophenyl)propionic acids 2c-g were reductively cyclized by catalytic hydrogenation over platinum-on-carbon sulfided catalyst. In particular, this method was applied to α-chloro-β-(2-nitrophenyl)propionic acids bearing 4-methyl 2c , 4-ethyl 2d , 4-ethoxy 2e , 4-(n-butyl 2f and 4-phenyl 2g substituents to afford good yields of the corresponding 7-methyl 3c , 7-ethyl 3d , 7-ethoxy 3e , 7-(n-butyl) 3f , and 7-phenyl 3g substituted 3-chloro-3,4-dihydro-l-hydroxycarbostyrils. The various 4-substituted α-chloro-β-(2-nitrophenyl)propionic acids 2c-q were synthesized by reacting the in situ diazotized salts of the appropriate 4-substituted-2-nitroanilines in aqueous acetone with acrylic acid in the presence of cuprous chloride and hydrochloric acid. All compounds prepared in this study were characterized by microanalytical and ir and nmr spectral data.     

Water influences the enantioselectivity in the proline or prolinamide-catalyzed aldol addition of acetone to isatins

The addition of small quantities of water to the proline or prolinamide-catalyzed aldol addition of acetone to isatin can result in increased enantioselectivity. DFT B3LYP calculations with a water molecule explicitly incorporated in the aldol transition states reproduce the observed enantioselectivity.     

Synthesis and properties of 3-chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils and related heterocyclic compounds

3-Chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils were synthesized by the catalytic hydrogenation of the α-chloro- and α,4-dichloro-β-(o-nitrophenyl)propionic acids in strong acidic solution over platinum-on-carbon sulfided catalyst. However, the catalytic hydrogenation of α-bromo-β-(o-nitrophenyl)propionic acid yielded 3,4-dihydro-1-hydroxycarbostyril under the same experimental conditions. The 3-chloro-3,4-dihydro-1-hydroxycarbostyril and the α-chloro-β-(o-nitrophenyl)propionic acid underwent facile dehydrochlorination in mild alkaline solution to give 1-hydroxycarbostyril and o-nitrocinnamic acid, respectively. Selective reduction of 3-chloro-3,4-dihydro-1-hydroxycarbostyril and 1-hydroxycarbostyril to the corresponding lactams, 3-chloro-3,4-dihydrocarbostyril and carbostyril, was effected by catalytic hydrogenation in hydrochloric acid over platinum black catalyst. The structures of the substituted carbostyril derivatives were correlated with their proton nmr spectra.     

Platinum/scandium-cocatalyzed cascade cyclization and ring-opening reaction of tertiary amines with substituted salicylaldehydes to synthesize 3-(aminoalkyl)coumarins

The synthesis of 3-(aminoalkyl)coumarins starting with a platinum/scandium-cocatalyzed oxidative dehydrogenation of α,β-C(sp(3))-H bonds of tertiary amines in the presence of ambient oxygen followed by reactions with substituted salicylaldehydes is revealed. The in situ formed enamines reacted with various salicylaldehydes, which resulted in the development of a one-pot synthetic protocol involving aldol reaction, cyclization, and then ring-opening.     

Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols

The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by L-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-L-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-L-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis.     

Double diastereoselection in anti aldol reactions mediated by dicyclohexylchloroborane between an l-erythrulose derivative and chiral aldehydes

Anti aldol reactions of an l-erythrulose derivative with several α-chiral aldehydes mediated by dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results are best explained when the reactions are assumed to occur via boat-like transition states with minimization of 1,3-allylic strain and avoidance of syn pentane interactions.     

Diastereoselective aldol additions of chiral beta-hydroxy ethyl ketone enolates catalyzed by Lewis bases

The trichlorosilyl enolates derived from chiral ethyl ketones bearing a beta-hydroxyl group and an alpha-stereogenic center were employed in the phosphoramide-catalyzed aldol reaction. The addition of Z-enolates to achiral aldehydes produced aldol products in good yields and high syn relative diastereoselectivities. The internal diastereoselectivity is controlled by the catalyst configuration, allowing for selective formation of either syn diastereomer. [reaction: see text]     

DFT Study on the （S）-Proline-catalyzed Direct Aldol Reaction between Acetone and 4-Nitrobenzaldehyde

1 INTRODUCTION Aldol reaction, one of the most important C–C bond-formation reactions, is widely utilized in orga- nic synthesis[1]. Extensive efforts have been donated to the development of catalytic stereo-selective va- riants of this reaction[2]. However, the direct aldol reaction between unmodified carbonyles would be the most attractive synthetic alternative. Proline-catalyzed intermolecular direct aldol reac- tion between acetone and 4-nitrobenzaldehyde was first reported by List…     

α-Al2O3阻氢微观机制研究

采用基于密度泛函理论广义梯度近似下的平面波赝势方法研究了刚玉(α-Al2O3)的阻氢微观机制, 对氢原子在α-Al2O3中的占据结构进行了计算, 发现氢原子占据空隙位置时能量最低, 寻找其过渡态得到活化能为1.59 eV, 利用动力学计算得到了氢原子在α-Al2O3中的扩散系数表达式为D(T)=(3.37×10-7)exp(-1.59/kT). 结果表明, 氢原子占据在α-Al2O3八面体空隙处的结构最稳定; 低温时扩散难以发生; 高温时扩散沿着空隙方向.     

Reexamination of CeCl3 and InCl3 as activators in the diastereoselective Mukaiyama aldol reaction in aqueous media

A search for suitable reaction conditions in Mukaiyama-type aldol condensations activated by CeCl(3) and InCl(3) revealed that the reaction proceeds best in i-PrOH/H(2)O (95:5). Contrary to literature precedent, no reaction was observed in pure water, and the encountered destruction of the starting silyl enol ether can be ascribed to initial hydrolysis of the Lewis acid. As anticipated from the dual parameter (pK(h), WERC value) characteristics of CeCl(3) and InCl(3), the former proved more efficient as Lewis acid-promoter, in terms of reaction speed and yield. Nevertheless, InCl(3) was a superior catalyst during evaluation of the diastereoselectivity of the process. In this regard, determination of diastereoselectivity as a function of time showed that the InCl(3)-catalyzed reaction is irreversible, whereas the CeCl(3)-catalyzed reaction is a reversible process. In both cases, formation of the syn product is kinetically preferred, although DeltaDeltaG(++)273K(InCl(3)) = 1.50 kcal/mol versus DeltaDeltaG(++)273K (CeCl(3)) = 0.38 kcal/mol. Molecular modeling (semiempirical PM3, ab initio HF/3-21G*, hybrid B3LYP/3-21G*, and B3LYP/LANL2DZ) of the diastereoselective aldol reaction promoted by InCl(3) supports a "closed", Zimmermann-Traxler transition state.