Organocatalytic asymmetric conjugate addition to allenic esters and ketones

The first example of an organocatalytic enantioselective conjugate addition of cyclic beta-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral beta,gamma-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for beta-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic beta-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active alpha-vinyl-substituted alpha-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (gamma-lactames).     

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.     

A catalytic asymmetric vinylogous Mukaiyama aldol reaction

A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.     

A new method for the catalytic aldol reaction to ketones

A new method for the catalytic aldol reaction to ketones, using CuF.3PPh3.2EtOH complex as the catalyst and (EtO)3SiF as the additive, is described. The reaction can be applied to a wide range of ketones and trimethylsilyl enolates. On the basis of mechanistic studies, a working hypothesis for the catalytic cycle is proposed, in which the dynamic ligand exchange mediated by copper silicates produces the active copper enolate. Moreover, the present reaction can be extended to the catalytic enantioselective reaction using tol-BINAP as a chiral ligand.     

Intermolecular asymmetric reductive aldol reaction of ketones as acceptors promoted by chiral Rh(Phebox) catalyst

[reaction: see text] The conjugate reduction of cinnamates with hydrosilane and chiral Rh(Phebox-ip) catalyst in the presence of excess acetone is shown to provide the corresponding intermolecular reductive aldol product in extremely high enantioselectivity (up to 98%). Several cinnamates and crotonate substrates and several ketone acceptors were also examined.     

Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.     

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.     

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).     

Regiospecific organocatalytic asymmetric aldol reaction of methyl ketones and alpha,beta-unsaturated trifluoromethyl ketones

[structure: see text]. The aldol reaction of methyl ketones and alpha,beta-unsaturated trifluoromethyl ketones occurred under mild conditions with the combination of proline-derived N-sulfonylamide and trifluoroacetic acid as the catalyst to give the corresponding unsaturated alpha-trifluoromethyl tertiary alcohols in high yields with good enatioselectivities.     

Boron-mediated aldol reaction of carboxylic esters: complementary anti- and syn-selective asymmetric aldol reactions

The boron-mediated aldol reaction of carboxylic esters is described in detail. Contrary to the general belief that carboxylic esters are inert under the condition of the boron enolate formation, propionate esters are enolized with certain combinations of a boron triflate and an amine. More importantly, the stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with c-Hex2BOTf and triethylamine produces anti-aldol products, and that with Bu2BOTf and diisopropylethylamine gives syn-aldol products selectively after reaction with aldehydes. Complementary anti- and syn-selective asymmetric aldol reactions with structurally related, readily available chiral norephedrine-derived propionate esters are developed.     

Highly regioselective, catalytic asymmetric reductive coupling of 1,3-enynes and ketones

[reaction: see text] Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts of Ni(cod)(2) and a P-chiral, monodentate ferrocenyl phosphine ligand. These couplings represent the first examples of catalytic, intermolecular reductive coupling of alkynes and ketones, enantioselective or otherwise, and afford synthetically useful 1,3-dienes possessing a quaternary carbinol stereogenic center in up to 70% ee.     

Biocatalytic promiscuity: lipase-catalyzed asymmetric aldol reaction of heterocyclic ketones with aldehydes

The new promiscuous activity of lipase from porcine pancreas, type II (PPL II), has been observed to catalyze the direct asymmetric aldol reaction of heterocyclic ketones with aromatic aldehydes. PPL II showed favorable catalytic activity and had a good adaptability to different substrates in the reaction. The enantioselectivities of up to 87% ee and diastereoselectivities of up to 83:17 (anti/syn) were achieved. It is interesting that PPL II possesses the function of aldolase in organic solvents.     

Investigation of the rh-catalyzed asymmetric reductive aldol reaction. Expanded scope based on reaction analysis

[reaction: see text] A series of experiments are described that suggest that the Rh-catalyzed reductive aldol reaction proceeds by addition of a Rh(I) hydride, generated in situ, to the reacting acrylate followed by a stereochemistry-controlling aldol addition reaction. On the basis of this hypothesis, reaction conditions are engineered that allow for increased substrate scope.     

Aluminum enolates via retroaldol reaction: catalytic tandem aldol-transfer—Tischtschenko reaction of aldehydes with aldol adducts of ketones to ketones

Bidentate aluminum chelates derived from biphenol, binaphthol and catechol were found to be efficient catalysts for aldol-transfer reactions of ketone to ketone aldol adducts with aliphatic or aromatic aldehydes giving rise to the formation of aldol adducts of ketones to the aldehydes. In the presence of an excess of an aliphatic aldehyde, a catalytic tandem aldol-transfer—Tischtschenko reaction is observed. The tandem reaction produces monoesters of 1,3-diols with high anti selectivity and with modest to good chemical yield. 1,2-Unsaturated aldehydes are less reactive in the aldol-transfer reaction and require 2-4 times higher load of the catalyst to be used than aliphatic and aromatic aldehydes. Poor diastereoselectivity was observed in the formation of α-substituted aldols and 2-substituted monoesters of anti-1,3-diols indicating that the aldol-transfer reaction is not diastereoselective with the catalysts studied. The utility of the highly 1,3-anti selective formation of diolmonoesters was found to be limited by acyl migration.     

Catalytic enantioselective alkylative aldol reaction: efficient multicomponent assembly of dialkylzincs, allenic esters, and ketones toward highly functionalized delta-lactones with tetrasubstituted chiral centers

A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized delta-lactones were produced in the presence of a catalytic amount of the Cu(OAc)2-DIFLUORPHOS complex through three-component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs two C-C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkylcopper species to an allenic ester produced highly active copper enolate in situ, and the successive asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The addition of MS4A and Lewis base (Ph2S=O, DMSO, or HMPA) is important for obtaining a high yield, with suppression of the undesired alpha-addition pathway. Control/crossover experiments suggest that the addition of a Lewis base facilitated the retro-aldol reaction of the alpha-adducts (proofreading effect). The ketone and copper enolate generated through the retro-aldol reaction were converted to the desired lactone through the gamma-aldol pathway, which was trapped by irreversible lactone formation.     

Lewis base-catalyzed conjugate reduction and reductive aldol reaction of alpha,beta-unsaturated ketones using trichlorosilane

Lewis bases such as Ph3P=O and HMPA catalyze the 1,4-reduction of alpha,beta-unsaturated ketones with trichlorosilane, and because the 1,2-reduction of aldehydes scarcely proceeded under the conditions, one-pot reductive aldol reactions with aldehydes were successfully achieved; preliminary studies using a chiral Lewis base revealed a high potential for enantioselective catalysis.     

L-selectride-mediated highly diastereoselective asymmetric reductive aldol reaction: access to an important subunit for bioactive molecules

L-selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active alpha-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting alpha,alpha-dimethyl-beta-hydroxy ketones are inherent to a variety of biologically active natural products.     

Convenient and efficient decarboxylative aldol reaction of malonic acid half esters with trifluoromethyl ketones

A convenient and efficient decarboxylative ketone aldol condensation of malonic acid half esters was reported. In the presence of catalytic amount of triethylamine, a series of aromatic and alkyl trifluoromethyl ketones were transformed into the desired adducts in 61–99% yields. In a preliminary experiment, a moderate stereoselectivity was obtained. Direct reduction of the aldol product with LiAlH₄ afforded trifluoromethylated 1,3-diol.