Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the formation of the major enantiomer in this reaction.     

Highly efficient primary amine organocatalysts for the direct asymmetric aldol reaction in brine

Organocatalytic systems made up of six primary amine organocatalysts, derived from natural primary amino acids, in combination with 2,4-dinitrophenol (DNP) have proven to be efficient in the presence of brine without further addition of organic solvents. The system formed by 1f and DNP was the most efficient one; it can catalyze the direct aldol reaction with a broad range of ketones and aromatic aldehydes, giving the corresponding aldol products in high yields with up to nearly perfect diastereo- and enantioselectivities (up to 99/1 syn/anti, >99% ee).     

The cooperative effect of a hydroxyl and carboxyl group on the catalytic ability of novel β-homoproline derivatives on direct asymmetric aldol reactions

Novel β-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a-d, were synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to 69% ee, 95% yield), which was similar to the results catalyzed by l-proline (71% ee, 96% yield). Relatively low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for example, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected carboxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high diastereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reactions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.     

Efficient ball-mill procedure in the ‘green’ asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides in the presence of water

The organocatalytic activity of (S)-proline-based dipeptides 1a-c has been evaluated in the asymmetric aldol reaction between representative ketones with various aromatic aldehydes under solvent-free conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of water, and 5 mol % of benzoic acid as additive.     

Highly diastereo- and enantioselective direct aldol reactions promoted by water-compatible organocatalysts bearing a pyrrolidinyl-camphor structural scaffold

Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor containing organocatalysts (1-10). Structural modifications were made by varying the stereo- and electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts (20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the stereochemical bias of the asymmetric aldol reaction is presented.     

Aromatic l-prolinamide-catalyzed asymmetric Michael addition of aldehydes to nitroalkenes

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr).     

Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the asymmetric aldol reaction

Peptides and especially prolinamides have been identified as excellent organocatalysts for the aldol reaction. The combination of prolinamides with derivatives bearing the 2-pyrrolidinone scaffold, deriving from pyroglutamic acid, led to the identification of novel organocatalysts for the intermolecular asymmetric aldol reaction. The new hybrids were tested both in organic and aqueous media. Among the compounds tested, 22 afforded the best results in petroleum ether, while 25 afforded the products in brine in high yields and selectivities. Then, various ketones and aldehydes were utilized and the products of the aldol reaction were obtained in high yields (up to 100%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).     

Linear polystyrene anchored l-proline,new recyclable organocatalysts for the aldol reaction in the presence of water

Two l-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol reaction of various aromatic aldehydes and ketones. By using 5 mol % of the catalysts, the corresponding products of the aldol reaction were obtained in good yields (up to 94%) and with excellent anti diastereoselectivities (up to 96:4) and enantioselectivities (up to 96% ee) in DMF in the presence of water. The yields of these reactions in a ketone/water mixture were lower than those in wet DMF (up to 76%). However, the stereoselectivity was comparable (up to 93:7 anti/syn ratio and 95% ee, respectively). In addition, catalysts 1a and 1b could be recovered by a simple precipitation and filtration process. They could also be re-used for at least five times without obvious loss of catalytic efficiency.     

Resolution of 1-arylalkylamines with 6-(1,2:3,4-di-O-isopropylidene-α-d-galactopyranosyl)hydrogen phthalate

The resolving ability of a new acidic resolving agent, the hydrogen phthalate of 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose 1, against various 1-arylalkylamines 2a–k is described. Treatment of 1 with amines 2a–f to obtain diastereomeric salts 1·(S)2a–f in 2-propanol allowing the corresponding (S)-amines 2a–f to be recovered in good yield and 61–89% ee. Recrystallization in dichloromethane/hexane, and regeneration gave the amines in enhanced enantiomeric purity (>98% ee). 1 resolved 1-phenylpropylamine 2f in high enantiomeric purity (99% ee) than 1-phenylethylamine 2g (11% ee) and o- and m-methoxy 2h–i, o-chloro-2j and p-fluoro-2k substituted 1-arylamines (11–19% ee). A possible chiral recognition mechanism based on the ability of 1 to exist in two conformations is described.     

Carbohydrate-derived alcohols as organocatalysts in enantioselective aldol reactions of isatins with ketones

The catalytic activity of carbohydrate-derived amino alcohols in the enantioselective aldol reaction of ketones with isatin and its derivatives has been examined for the first time. The carbohydrate-derived amino alcohols 5 were found to be efficient organocatalysts for asymmetric aldol reactions. A variety of isatins were used as substrates and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 75%).     

BINAM-prolinamides as recoverable catalysts in the direct aldol condensation

New BINAM-prolinamides were developed and tested as organocatalysts in the direct aldol condensation between aldehydes and several aliphatic ketones. C₂-symmetrical (Sa)-BINAM-l-prolinamide gives the best enantioselectivities for this transformation, being recovered and reused after the reaction by simple extractive techniques. The reaction was performed in DMF/H₂O at 0 °C to give the aldol products in up to 95% ee for acetone. For 2-butanone, the corresponding iso-regioisomers were regioselectively obtained in up to 96% ee working in DMF at rt. In the case of cyclohexanone, dr up to 10:1 in favour of the anti products, which were obtained in 90–93% ee, was achieved.     

Thiazolidine-based organocatalysts for a highly enantioselective direct aldol reaction

A set of enantiopure thiazolidine-based organocatalysts have been synthesized from l-cysteine, in a straightforward manner allowing numerous structural variations. In particular, organocatalyst 3a exhibits the highest catalytic performance working in an aqueous medium. It catalyzed the direct catalytic asymmetric intermolecular aldol reaction between unmodified ketones and an aldehyde with excellent stereocontrol and furnished the corresponding aldol products in up to 99% ee. Compound 3a also showed excellent asymmetric catalytic activity in the asymmetric Michael reaction (up to 99% ee).     

Protonated chiral prolinamide catalyzed enantioselective direct aldol reaction in water

Protonated chiral prolinamide organocatalysts have been shown to catalyze an enantioselective direct aldol process in water to provide the aldol product in high yield and good enantioselectivity. The two diastereomeric catalysts (S,R)-4b and (S,S)-4c show different reactivity.     

Synthesis of a biphenyl-based axially chiral amino acid as a highly efficient catalyst for the direct asymmetric aldol reaction

A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the use of only 0.1 mol % of (S)-2 was sufficient to complete the reaction between acetone and 4-nitrobenzaldehyde, giving the corresponding aldol adduct in good yield with an excellent enantioselectivity.     

Enantioselective intramolecular Morita–Baylis–Hillman reaction using chiral bifunctional phosphinothiourea as an organocatalyst

Chiral cyclohexane-based phosphinothioureas were found to be efficient organocatalysts for the enantioselective intramolecular Morita–Baylis–Hillman reaction of ω-formyl-enone. Among the solvents screened, t-BuOH was the best one which provided good yield and enantioselectivity. Moreover in the presence of 3 mol % of phosphinothiourea 2b, the desired products were obtained in good-to-excellent yields with up to 98% ee under mild reaction conditions.     

Biomimetic asymmetric aldol reactions catalyzed by proline derivatives attached to β-cyclodextrin in water

Two proline derivatives, (S)-2-aminomethylpyrrolidine and (R)-2-aminomethylpyrrolidine modified β-CD (CD-1, CD-2) were synthesized in the yields of 31% and 14%. Their self-inclusion conformations were characterized by ¹H ROESY NMR studies and quantum calculation. When CD-1 was applied to asymmetric aldol reactions, up to 94% ee was obtained. Substrate selectivity was also observed in these asymmetric aldol reactions.     

The first regio- and diastereoselective synthesis of homochiral perhydroimidazoisoxazoles via the 1,3-dipolar cycloaddition of imidazoline 3-oxides with (1S)-(−)-β-pinene

The 1,3-dipolar cycloaddition of imidazoline 3-oxides 1 with (1S)-(−)-β-pinene proceeds regio- and diastereoselectively to give homochiral perhydroimidazoisoxazole derivatives 3 in high yields in the cases of imidazoline 3-oxides 1a–e but in low yields in the reactions of 1f–g. The preferred attack of (1S)-(−)-β-pinene to the cyclic nitrone was shown to be anti–endo. The reaction of racemic nitrones (±)-1f–g with the homochiral β-pinene gave the adduct from the (S)-nitrone and the corresponding imidazole. The adducts 3 undergo retro-1,3-dipolar cycloaddition when heated in the condensed phase or in diphenyl ether to give the corresponding imidazole and β-pinene.     

Enantioselective enzymatic acylation of 1-(3′-bromophenyl)ethylamine

An efficient biocatalytic process has been developed for the resolution of 1-(3′-bromophenyl)ethylamine (RS)-1 by way of enantioselective lipase-mediated (R)-selective acylation with ethyl 2-methoxyacetate to afford (S)-amine (S)-1 and (R)-2″-methoxyacetamide ((R)-2) in 91–95% and 90–92% isolated yield, respectively, and both with >99% ee.     

Enantioselective α-hydroxylation of β-keto esters catalyzed by chiral S-timolol derivatives

A screen of aryloxy aminopropanol organocatalysts derived from the β-blocker inhibitor S-timolol determined the most active catalyst of asymmetric α-hydroxylation of β-keto esters. (R)-1-(tert-butylamino)-3-(3,4,5-trimethoxyphenoxy) propan-2-ol (3k) was the most effective derivative, enantioselectively catalyzing α-hydroxylation of β-keto esters using tert-butyl hydroperoxide as the oxidant in hexane to afford the corresponding products in excellent yield and with good enantioselectivity (up to 96% yield, 88% ee).     

New stereospecific synthesis of Tesaglitazar and Navaglitazar precursors

A new synthetic route of to pharmaceutical intermediates (S)-1a–b and (S)-14 is reported. The reaction pathway is based on the baker’s yeast-mediated reduction of the α-alkoxy cinnamaldehydes 9a–c to give the corresponding (S)-alcohols in good yields and excellent ee.