Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

l-Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with unmodified ketones smoothly occurred at ambient temperature to produce β-hydroxy-β-trifluoromethylated ketones with good to excellent diastereo (up to 96% de) and enantioselectivities (up to 91% ee).     

Proline-catalyzed asymmetric aldol reactions between ketones and alpha-unsubstituted aldehydes

[reaction: see text] With this communication we extend the methodology of proline-catalyzed direct asymmetric aldol reactions to include alpha-unsubstituted aldehydes as acceptors. This important aldehyde class gives the corresponding aldols in 22-77% yield and up to 95% ee when the reactions are performed in pure acetone or in ketone/chloroform mixtures. On the basis of these results we have developed a concise new synthesis of (S)-ipsenol.     

Lewis acid-promoted intermolecular carbonyl-ene reaction of enantiopure 4-oxoazetidine-2-carbaldehydes. Rapid entry to novel fused polycyclic beta-lactams

Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes with various activated alkenes gives 4-[(1'-hydroxy)homoallyl]-beta-lactams with a very high level of syn diastereofacial selectivity. The above homoallylic alcohols are used for the diastereoselective preparation of fused bicyclic, tricyclic, and tetracyclic beta-lactams of nonconventional structure using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences. In addition, a novel domino process was discovered, the C4-N1 beta-lactam bond breakage/intramolecular Diels-Alder reaction.     

Camphor-10-sulfonamide-based prolinamide organocatalyst for the direct intermolecular aldol reaction between ketones and aromatic aldehydes

Prolinamides derived from l-proline and N,N-dialkyl 2-aminocamphor-10-sufonamides have been synthesized and used as organocatalysts in the direct intermolecular aldol reaction. Reactions of several aromatic aldehydes with cyclohexanone, cyclopentanone, 4-oxa and 4-sulfa-cyclohexanones and acetone are investigated employing 1a as an organocatalyst. Very high to excellent selectivities are obtained in these direct aldol reactions.     

Catalytic enantioselective aldol reaction to ketones

An enantioselective aldol reaction between ketones and ketene silyl acetals is described using CuF-chiral phosphine as a catalyst. The key for high enantioselectivity was the development of a novel ligand derived from Taniaphos combined with the unique accelerative effect of PhBF3K. These conditions are applicable to various substrates such as aromatic, aliphatic, and heteroaromatic ketones. In the case of substituted nucleophiles, the reaction proceeds well. The diastereoselectivity is independent of ketene silyl acetal geometry. This is the first example of a catalytic enantio- and diastereoselective aldol reaction to ketones using ketene silyl acetals.     

Asymmetric direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives

The direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives yields the corresponding 2-hydroxy 1,4-diketones in high regioselectivity, diastereoselectivity and good enantioselectivity. This reaction provides an easy access to optically active tertiary alcohols, which are flanked by two carbonyl groups for further elaborations.     

Direct catalytic enantio- and diastereoselective aldol reaction of thioamides

A direct catalytic asymmetric aldol reaction of thioamides using a soft Lewis acid/hard Br?nsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH(3)CN)(4)]PF(6)/LiOAr is described. Exclusive enolate generation from thioacetamides through a soft-soft interaction with the soft Lewis acid allowed for a direct aldol reaction to α-nonbranched aliphatic aldehydes, which are usually susceptible to self-condensation under conventional basic conditions. A hard Lewis basic phosphine oxide has emerged as an effective additive to constitute a highly active ternary soft Lewis acid/hard Br?nsted base/hard Lewis base cooperative catalyst, enabling a direct enantio- and diastereoselective aldol reaction of thiopropionamides. Strict control of the amount of the hard Lewis base was essential to drive the catalytic cycle efficiently with a minimized retro-aldol pathway, affording syn-aldol products with high stereoselectivity. Divergent transformation of the thioamide functionality is an obvious merit of the present aldol methodology, allowing for a facile transformation of the aldol product into the corresponding aldehyde, ketone, amide, amine, and ketoester. An aldehyde derived from the direct aldol reaction was subjected to a second direct aldol reaction, which proceeded in a catalyst-controlled manner to provide 1,3-diols with high stereoselectivity.     

Facile and diastereoselective synthesis of β-acetamido ketones and keto esters via direct Mannich-type reaction

A Mannich-type three-component reaction involving aldehydes, acetamide, and enolizable ketones or β-keto esters for the preparation of β-acetamido carbonyl compounds in the presence of TMSCl is described. This newly developed protocol is operationally convenient, widely applicable, and highly diastereoselective.     

Stereoselective allylation of 4-oxoazetidine-2-carbaldehydes. Application To the stereocontrolled synthesis of fused tricyclic beta-lactams via intramolecular diels-alder reaction of 2-azetidinone-tethered trienes

Allylation reactions of racemic and optically pure 4-oxoazetidine-2-carbaldehydes were investigated both under anhydrous conditions and in aqueous media. Different Lewis acid or metal mediators showed varied diastereoselectivities on product formation during allylation reactions of the above aldehydes with allyltrimethylsilane, allyltributylstannane, or allyl bromide. Under standard reaction conditions, tin(IV) chloride-promoted addition of allyltrimethylsilane to 4-oxoazetidine-2-carbaldehydes provided the highest diastereoselectivity and the best yield. Boron trifluoride-diethyl ether-promoted reaction of allyltributylstannane provided slightly lower diastereoselectivity with the same facial preference. Indium-promoted allylation showed a reverse diastereofacial preference, although the observed selectivity is not synthetically useful. The mesylates of these homoallylic alcohols were used for the stereoselective preparation of cis-4-butadienyl-2-azetidinones. Interestingly, mesylates having an extra alkene or alkyne tether at position 1 or 3 of the beta-lactam ring, on heating in a sealed tube with equimolecular amounts of DBU in toluene, yielded fused tricyclic 2-azetidinones through a tandem one-pot elimination-intramolecular Diels-Alder reaction.     

Solvent- or temperature-controlled diastereoselective aldol reaction of methyl phenylacetate

Unlike the enolboration-aldolization of methyl propanoate, the choice of either the solvent or temperature determines the diastereoselectivity during the enolboration-aldolization of methyl phenylacetate. In CH(2)Cl(2), the reaction favors the anti-pathway at -78 °C and the syn-pathway at rt. Conversely, the reaction produces the anti-isomer up to rt and the syn-isomer at refluxing temperatures in nonpolar solvents.     

Proline-catalyzed asymmetric addition reaction of 9-tosyl-3,4-dihydro-beta-carboline with ketones

[reaction: see text] 9-Tosyl-3,4-dihydro-beta-carboline (1) reacted with a ketone in the presence of (S)-proline as a catalyst to give the corresponding addition product in good yield and high enantioselectivity. In the process, a small amount of water was found to affect the stereoselectivity of the products. The system was applied to reaction of compound 1 and 3-buten-2-one to give 3,4,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-2-one, which is a versatile precursor for the synthesis of some indole alkaloids.     

Asymmetric direct aldol reaction of functionalized ketones catalyzed by amine organocatalysts based on bispidine

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including alpha-keto phosphonates, alpha-keto esters, as well as alpha,alpha-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction.     

Proline-catalyzed direct inverse electron demand diels-alder reactions of ketones with 1,2,4,5-tetrazines

An organocatalytic direct inverse electron demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines has been developed. The process is efficiently catalyzed by proline to give Diels-Alder adducts pyridazines in high yields.     

Organocatalytic direct aldol and nitroaldol reactions between azetidine-2,3-diones and ketones or nitromethane

The reactions of enantiopure azetidine-2,3-diones with unmodified ketones or nitromethane were catalyzed by proline and N-methylephedrine, respectively, to give the corresponding 3-functionalized 3-hydroxy-β-lactams with good yields and total diastereoselectivities. It was observed that the use of both enantiomers of proline or of N-methylephedrine does result in identical levels of stereocontrol in the aldol and nitroaldol reactions.     

Catalytic enantioselective intermolecular reductive aldol reaction to ketones

We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reactions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and β-substituted α,β-unsaturated esters; and (3) reactions between acetophenone derivatives and an allenic ester. Although only moderate enantioselectivity was obtained in the first reaction type, high to excellent enantioselectivity was realized in the enantio-induction at the α-position in the second reaction type and at the δ-position in the third reaction type. Specifically, the third reaction type afforded the corresponding tertiary alcohols with up to 99% ee. Pre-activation of the nucleophile by silyl enolate formation is not necessary in these one-pot catalytic enantioselective reductive aldol reactions.     

N-(heteroarenesulfonyl)prolinamides-catalyzed aldol reaction between acetone and aryl trihalomethyl ketones

Enantiomerically enriched trihalomethyl-substituted alcohols having a quaternary chiral carbon center can be prepared by the catalytic enantioselective cross-aldol reaction of acetone with trihalomethyl ketones by using N-(8-quinolinesulfonyl)prolinamide as an organocatalyst. The MO calculations elucidate that the hydrogen bonding between the sulfonimide proton and the 8-quinolyl nitrogen atom plays an important role in exerting the enantioselectivity of the reaction.     

Proline-catalyzed asymmetric aldol reactions of tetrahydro-4H-thiopyran-4-one with aldehydes

Proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various aldehydes give anti adducts with high diastereo- and enantioselectivities in moderate to excellent yields. With the aromatic aldehydes best results were obtained in wet DMF whereas dry DMSO generally was superior with the aliphatic aldehydes. Desulfurization of the adducts with Raney Ni provides products equivalent to aldols from 3-pentanone with potential applications in polypropionate synthesis.     

Pyrrolidine as an efficient organocatalyst for direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal (1) with ketones or aldehydes was described. In the presence of 20 mol % of pyrrolidine, the reaction proceeded smoothly at room temperature to afford the aldol products in good to excellent yields (up to 95%). Pyrrolidine showed a much higher catalytic activity than piperidine in the reaction with less reactive ketones. GC analysis clearly indicated that the catalyst and the enamine intermediates were kept at extremely low concentration during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction. In addition, the asymmetric aldol reaction of 1 with cyclohexanone catalyzed by l-proline derivatives was also discussed.     

Catalytic asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and ketones

A copper(I)-catalyzed asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and simple ketones (including aromatic ketones and an aliphatic ketone) was disclosed, which afforded a series of chiral diols after an oxidative work-up in moderate yields with moderate to high diastereoselectivity and excellent enantioselectivity. The lactone moiety was easily opened with methanol to generate a chiral triol in moderate yield.