Concerning the diastereofacial selectivity of aldol reactions of chiral methyl ketone enolates: Evidence for remote chelation in the bafilomycin aldol reaction

Evidence is presented that the aldol reactions of the lithium enolates of 4 and 7 proceed preferentially by way of chelated transition structure 19.     

Oxazinanones as chiral auxiliaries: synthesis and evaluation in enolate alkylations and aldol reactions

Homochiral beta-amino esters (prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish alpha-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral alpha-methyl-beta-hydroxy-carboxylic acids.     

Proline-catalyzed aldol reactions of cyclic diketones: fluorine modifies pathways as well as transition states

Proline-catalysed aldol reactions are central to the development of organocatalysis, and have been the subjects of many studies. List’s results on the effect of fluorine substitution on proline catalysts for an intramolecular aldol condensation provide a perfect test set for computational analysis, as subtle changes in the catalyst structure lead to clear changes in the product ratios. The results show that the carbon-carbon bond forming transition states for the Hajos-Parrish-Wiechart reaction do not account for the observed selectivity in all cases. However, if an analysis of post transition-state epimerization pathways is also included, together with the effect of water, it is possible to account for all of the experimental data.     

Studies on the synthesis of tedanolide: synthesis of the C(5)-C(21) segment via a highly stereoselective fragment assembly aldol reaction of a chiral beta,gamma-unsaturated methyl ketone

[formula: see text] A highly diastereoselective synthesis of 3, corresponding to the C(5)-C(21) segment of tedanolide, has been accomplished by a route utilizing the aldol reaction of aldehyde 4 and the beta,gamma-unsaturated methyl ketone 5.     

Bicyclic proline analogues as organocatalysts for stereoselective aldol reactions: an in silico DFT study

Density functional theory has been employed in investigating the efficiency of a series of bicyclic analogues of proline as stereoselective organocatalysts for the aldol reaction. Three classes of conformationally restricted proline analogues, as part of either a [2.2.1] or [2.1.1] bicyclic framework, have been studied. Transition states for the stereoselective C-C bond formation between enamines derived from [2.2.1] and [2.1.1] bicyclic amino acids and p-nitrobenzaldehyde, leading to enantiomeric products, have been identified. Analysis of the transition state geometries revealed that the structural rigidity of catalysts, improved transition state organization as well as other weak interactions influence the relative stabilities of diastereomeric transition states and help contribute to the overall stereoselectivity in the aldol reaction. These bicyclic catalysts are predicted to be substantially more effective in improving the enantiomeric excess than the widely used organocatalyst proline. Enantiomeric excesses in the range 82-95% are predicted for these bicyclic catalysts when a sterically unbiased substrate such as p-nitrobenzaldehyde is employed for the asymmetric aldol reaction. More interestingly, introduction of substituents, as simple as a methyl group, at the ortho position of the aryl aldehyde bring about an increase in the enantiomeric excess to values greater than 98%. The reasons behind the vital energy separation between diastereomeric transition states has been rationalized with the help of a number of weak interactions such as intramolecular hydrogen bonding and Coulombic interactions operating on the transition states. These predictions could have wider implications for the rational design of improved organocatalysts for stereoselective carbon-carbon bond-forming reactions.     

High stereocontrol in aldol reaction with ketones: enantioselective synthesis of beta-hydroxy gamma-ketoesters by ester enolate aldol reactions with 2-acyl-2-alkyl-1,3-dithiane 1-oxides

The asymmetric aldol reaction of 1,2-diketones, masked as nonracemic 2-acyl dithiane oxides, with lithium enolates derived from several esters and lactones, proceeds with a high degree of stereocontrol at both carbonyl and enolate prochiral centers, the stereocontrol mainly determined by the configuration of the sulfoxide sulfur atom. The sense of induced stereochemistry observed for ester enolates is different from that seen for lactone enolates. Hydrolysis of the dithiane oxide units of the major diastereoisomerically pure aldol products affords enantiomerically pure tertiary alpha-substituted beta-hydroxy-gamma-ketoesters.     

Solvent-controlled diastereoselective synthesis of cyclopentane derivatives by a [3 + 2] cyclization reaction of alpha,beta-disubstituted (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates

Reaction of alpha,beta-unsaturated methoxycarbene complexes 1 and 11 with methyl ketone lithium enolates 2 leads to the corresponding five-membered carbocyclic compounds 4 or diast-4 and 12. The influence of the solvent and/or cosolvent (PMDTA), which turned out to be crucial to direct the reaction to 4 or diast-4, is studied, and a tentative mechanism according to these facts is proposed. In addition, the reaction of carbene complex 1a with alkynyl methyl ketone lithium enolates can be directed to the formal [3 + 2] or [4 + 1] cyclization products by a slight variation of the reaction conditions. Finally, consecutive three-component coupling reactions with carbene complex 1a, lithium enolates 2, and aldehydes 18 to give, in a diastereoselective way, hydroxy carbonyl compounds 19 and tricyclic polyethers 20 are presented.     

Boron enolates of a hydantoin chiral auxiliary derived from l-phenylalanine: a versatile tool for asymmetric aldol reactions

The aldol reactions of boron enolates derived from a hydantoin chiral auxiliary derived from l-phenylalanine occur in good yields with high syn diastereoselectivity. Aldol adduct 4a is readily cleaved by hydrolysis to afford (2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid 5a in good yield and in almost enantiomerically pure form.     

Synthesis of C13-C25 fragment of 24-demethylbafilomycin C(1) via diastereoselective aldol reactions of a ketone boron enolate as the key step

An efficient synthesis of the C13-C25 fragment is described for 24-demethylbafilomycin C1, a new member of the plecomacrolide family isolated from fermentation broth of Streptomyces sp. CS which is a commensal microbe of Maytenus hookeri. The targeted C13-C25 fragment possesses five oxygenated and three methyl-substituted stereogenic centers. It is obtained through formation of the C17-C18 syn aldol by using an ethyl ketone boron enolate with diastereomeric ratios of 95:5 and 83:17, respectively, for the chiral aldehydes substituted with acetoxy and methoxyacetoxy groups at C15. The results confirm the observation that the stereochemistry at C22 of the ketone is determinant to the diastereoselectivity of the aldol reaction. The synthesized C13-C25 fragment having a methoxyacetoxy group at C15 is considered as a useful precursor for construction of the 16-membered ring lactone of 24-demethylbafilomycin C1 through an aldol condensation of the methoxyacetate followed by formation of the C12-C13 double bond via a diene-ene RCM reaction.     

New strategic reactions for organic synthesis: catalytic asymmetric C-H activation alpha to oxygen as a surrogate to the aldol reaction

The C-H activation of silyl ethers by means of rhodium carbenoid-induced C-H insertion represents a very direct method for the stereoselective synthesis of silyl-protected beta-hydroxy esters. The reaction can proceed with very high regio-, diastereo-, and enantioselectivity and represents a surrogate to the aldol reaction. The reaction is catalyzed by the rhodium prolinate complex Rh(2)(S-DOSP)(4). A critical requirement for the high chemoselectivity is the use of donor/acceptor-substituted carbenoids such as those derived from methyl aryldiazoacetates. A range of silyl ethers may be used such as allyl silyl ethers, tetraalkoxysilanes, and even simple trimethylsilyl alkyl ethers. In general, C-H activation preferentially occurs at methylene sites, as the reactivity is controlled by a delicate balance between steric and electronic effects.     

Kinetic and stereochemical evidence for the involvement of only one proline molecule in the transition states of proline-catalyzed intra- and intermolecular aldol reactions

Contrary to the widely accepted mechanism of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, we have obtained evidence for the involvement of only one proline molecule in the transition states of both inter- and intramolecular aldol reactions. Our conclusions are based on kinetic measurements and the absence of nonlinear and dilution effects on the asymmetric catalysis, and are supported by B3LYP/6-31G* calculations. Complementary to recent theoretical studies, our results provide the foundation of a unified enamine catalysis mechanism of proline-catalyzed inter- and intramolecular aldol reactions.     

Synthetic studies on apoptolidin: synthesis of the C12-C28 fragment via a highly stereoselective aldol reaction

The stereoselective and convergent synthesis of the C12-C28 segment 2 of the apoptosis inducing macrolide antibiotic, apoptolidin (1), is described. The synthesis involves a highly stereoselective tin(II)-mediated aldol reaction between the C17-C22 ethyl ketone 3 and the C23-C28 aldehyde 4 as the key step.     

Lewis base-promoted aldol reaction of dimethylsilyl enolates in aqueous dimethylformamide: use of calcium chloride as a Lewis base catalyst.

In the presence of CaCl2, dimethylsilyl (DMS) enolates smoothly reacted with aldehydes under mild conditions to give aldol adducts in good to high yields. The catalytic activities of various metal and tetrabutylammonium salts have revealed that CaCl2 works as a Lewis base catalyst to activate DMS enolates. The CaCl2-promoted reaction proceeded even in the presence of water or in pure water. This catalytic system was applicable to the aldol reaction with aqueous aldehydes such as formalin.     

Stereoselective reactions: XIII. Total synthesis of (+)-sesbanine by a highly stereoselective cycloannelation reaction

An alkaloid sesbanine (1) was synthesized starting from 1-malic acid as a chiral four-carbon unit. The key step was a highly stereoselective cycloannelation reaction to form a chiral quaternary carbon center. By this synthesis, the absolute configuration of natural sesbanine was established to 1. Furthermore, sesbanine, in both optically active and racemic forms, was found to be marginaly cytotoxic, contrary to remarkable cytotoxicity reported.     

Electron transfer processes in reactions of lithium dialkylamides. Use of the N-propylcyclobutylaminyl radical ring opening as a probe reaction

N-Lithio-N-propylcyclobutylamine has been used as a qualitative mechanistic probe for electron transfer processes in several reactions.     

Evidence for single electron transfer in the reaction of a lithium enolate with a primary alkyl iodide

Evidence for a radical process in the reaction of the lithium enolate of propiophenone with a primary alkyl iodide was obtained by the observation of cyclization of an appropriate radical probe, by the trapping of the radical intermediate and by the comparison of the relative rates of reactions of the probe alkyl iodide with the corresponding bromide and tosylate.     

Asymmetric induction in methyl ketone aldol additions to alpha-alkoxy and alpha,beta-bisalkoxy aldehydes: a model for acyclic stereocontrol

A systematic study of methyl ketone aldol additions under nonchelating conditions with alpha-alkoxy and alpha,beta-bisalkoxy aldehydes is described. Additions to aldehydes containing a single alpha-alkoxy stereocenter generally provide the product diastereomers in accord with the Cornforth/polar Felkin-Anh models for carbonyl addition. Vicinal asymmetric induction is sensitive to the aldehyde alpha-alkyl substituent, but is relatively insensitive to the nature of the alkoxy protecting group. Aldehyde pi-facial selectivity in additions to substrates containing an additional beta-alkoxy-substituted stereocenter exhibits a striking dependence on the relative configuration of the alpha- and beta-stereocenters. Aldehydes with the alpha- and beta-alkoxy substituents in an anti relationship in most cases exhibit good diastereoselectivity, while aldehydes with the alpha- and beta-alkoxy substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on Cornforth-like transition-state arrangements is proposed.