Effective and recyclable dendritic catalysts for the direct asymmetric Michael addition of aldehydes to nitrostyrenes

Direct catalytic enantio- and diastereoselective Michael addition reaction of aldehydes to nitrostyrenes is described using a series of recyclable chiral 2-trimethylsilanyloxy-methyl-pyrrolidine-based dendritic catalysts. Good yields (up to 82%), and high diastereoselectivities (up to syn/anti = 95/5) and enantioselectivities (up to 99% ee) have been obtained.     

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.     

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.     

l-Proline amides catalyze direct asymmetric aldol reactions of aldehydes with methylthioacetone and fluoroacetone

Direct aldol reactions of aldehydes with methylthio- and fluoroacetone catalyzed by proline amides have been investigated. l-Prolinamide 5e was found to be the best catalyst. Under the optimized reaction conditions, a series of aromatic and aliphatic aldehydes reacted smoothly with methylthioacetone, to generate 1-methylthio-4-hydroxyketones 3 in good yields and with high regio- and enantioselectivities. Excellent enantioselectivities of up to 98% ee were observed for aromatic aldehydes and even higher enantioselectivities of >99% ee were observed for aliphatic aldehydes. Asymmetric direct aldol reactions of fluoroacetone with aldehydes in the presence of 20 mol % of 5e preferentially occurred at the fluoromethyl group, yielding products with high enantioselectivities (up to 98% ee).     

A new organocatalyst derived from abietic acid and 4-hydroxy-l-proline for direct asymmetric aldol reactions in aqueous media

Enantioselective direct aldol reactions were carried out in aqueous media with a new organocatalyst that was derived from 4-hydroxy-l-proline and abietic acid via a simple and convenient synthetic protocol with a high overall yield (75%). The new organocatalyst was used for aldol reactions between substituted aromatic aldehydes and various ketones in the presence of several acid additives in aqueous media. The corresponding aldol products were obtained in high isolated yields (up to 99%) and with high anti-diastereoselectivities (up to 94%) and enantioselectivities (>99.9%). The catalyst loading can be efficiently reduced to only 1 mol %. The aldol reactions were found to be extremely fast which is very unusual in organocatalyzed reactions in water.     

Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (Sa)-binam-l-prolinamide

The combination of (S_a)-binam-l-Pro (5 mol %) and benzoic acid (10 mol %) was used as catalysts in the direct aldol reaction between different aliphatic ketones and 4-nitrobenzaldehyde under solvent-free reaction conditions. Three different procedures are assayed: magnetic stirring (method A), magnetic stirring after previous dissolution in THF and evaporation (method B), and ball mill technique (method C), methods A and B being the simplest. These reaction conditions allowed us to reduce the amount of required ketone to 2 equiv to give the aldol product in similar reaction times and regio-, diastero-, and enantioselectivities than in organic or aqueous solvents.     

Chiral quaternary alkylammonium ionic liquid [Pro-dabco][BF4]: as a recyclable and highly efficient organocatalyst for asymmetric Michael addition reactions

A novel series of chiral quaternary ammonium ionic liquids have been synthesized and shown to be very effective catalysts for the asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with excellent yields (up to 100%), diastereoselectivities (syn/anti = 99:1), and enantioselectivities (up to 97%). The catalytic system, an ionic liquid organocatalyst in [Bmim][BF₄], could be reused five times without a significant loss in catalytic activity or stereoselectivity.     

A novel C3-symmetric prolinol-squaramide catalyst for the asymmetric reduction of ketones by borane

A novel C₃-symmetric prolinol-squaramide has been developed for the asymmetric reduction of ketones by borane. By using only 5 mol % catalyst 1a for the reaction, high yields and excellent enantioselectivities (up to 95% yield, 93% ee) were obtained. Moreover, 1a can be easily recovered by simple precipitation and re-used for four cycles without losing the selectivity.     

Enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines catalyzed by β-aminoalcohols with the prolinol skeleton

Several β-aminoalcohols with the prolinol framework are shown to be very efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of the catalyst leads to the expected addition products in good yields and with ee up to 94% in a reaction time of only 4 h at room temperature. This ee is the highest value reported so far using 0.5 equiv of an aminoalcohol as a promoter. High enantioselectivities are obtained in the addition of dialkylzincs to both aromatic and aliphatic imines. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. A very interesting effect of the addition rate and temperature on the enantioselectivity was also observed.     

Asymmetric nitroaldol reaction catalyzed by copper–diamine complexes: selective construction of two contiguous stereogenic centers

Chiral copper(II) complexes of secondary bisamines derived from 1,2-diaminocyclohexane were successfully used in the diastereoselective nitroaldol reaction. The reactions were carried out in the presence of 10 mol % of the Cu(II) complex and 7.7 mol % of i-Pr₂NEt in 2-propanol at ?30 °C. Good to excellent yields, enantioselectivities of up to 99%, and moderate to excellent diastereoselectivities were obtained for both aromatic or aliphatic aldehydes and various prochiral nitrocompounds forming the corresponding β-nitroalcohols with two contiguous stereocenters.     

Recoverable Cinchona ammonium salts as organocatalysts in the enantioselective Michael addition of β-keto esters

Several dimeric Cinchona-alkaloid anthracenyldimethyl-derived ammonium salts, are used as organocatalysts in the enantioselective Michael addition reaction of cyclic β-keto esters to α,β-unsaturated carbonyl compounds, in the presence of diisopropylethylamine as a base (30 mol %), for the generation of enantiomerically enriched adducts bearing quaternary stereocenters. Quinine and quinidine-derived dimeric ammonium salts (1–10 mol %) afford the opposite and higher enantioselectivities of the corresponding adducts (up to 94% ee) in good yields (up to 98%). Substituted 2-alkoxycarbonyl-1-indanones are used as nucleophile precursors, as well as ethyl 2-oxocyclopentanecarboxylate and tert-butyl 2,5-dioxo-1-phenylpyrrolidine-3-carboxylate. These organocatalysts can be recovered at the end of the reaction by precipitation in ether and reused without any loss of activity.     

Highly diastereo- and enantioselective direct aldol reactions by 4-tert-butyldimethylsiloxy-substituted organocatalysts derived from N-prolylsulfonamides in water

A new set of 4-tert-butyldimethylsiloxy-substituted organocatalysts derived from N-prolylsulfonamide has been designed and proved to be effective in catalyzing the direct aldol reactions of cyclic ketones with a series of aromatic aldehydes. Furthermore, to the best of our knowledge, there are no reports on the aldol reaction generating the products in very good yields (>99%) and with excellent diastereoselectivities up to >99:1 and enantioselectivities up to >99% by using lower catalyst loadings (only 3 mol %), without using any additives in a large amount of water under mild conditions.     

Chemoenzymatic synthesis of piperoxan,prosympal, dibozane,and doxazosin

The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.     

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.     

Enantioselective cyanoformylation of aldehydes organocatalyzed by recyclable cinchonidine ammonium salts

Enantiomerically enriched O-methoxycarbonyl cyanohydrins were obtained using an enantioselective addition of methyl cyanoformate to aldehydes organocatalyzed by a dimeric anthracenyldimethyl-derived cinchonidine ammonium salt (1 mol % catalyst loading) in the presence of substoichiometric amounts of triethylamine (20 mol %). Aromatic and heteroaromatic aldehydes usually afford high enantioselectivities (up to 96%) and quantitative yields of the corresponding O-methoxycarbonyl cyanohydrins, whereas aliphatic and α,β-unsaturated aldehydes give lower enantioselectivities (up to 60%) in high yields. The observed sense of the enantioselection was always the same, and the organocatalyst was almost quantitatively recovered by ether-promoted precipitation without any loss of activity. The use of resin-supported cinchonidine-derived ammonium salts as an organocatalyst in this transformation was also explored.     

Resolution of N-protected amino acid esters using whole cells of Candida parapsilosis ATCC 7330

Whole cells of Candida parapsilosis ATCC 7330 were used for the resolution of N-acetyl amino acid esters. Excellent enantioselectivities (E = 40 to >500) were achieved for the resolution of N-protected protein and non-protein amino acid esters giving good yields (28–50%) and high enantiomeric excesses (up to >99%) for both enantiomers.     

Readily available (S)-proline-derived organocatalysts for the Lewis acid-mediated Lewis base-catalyzed stereoselective aldol reactions of activated thioesters

A set of enantiomerically pure Lewis bases containing different diphenyl phosphinyl oxide groups were easily synthesized in a straightforward procedure by reaction of readily available proline-based scaffolds and phosphinoyl chlorides. The newly synthesized derivatives were employed (0.1 mol equiv) as organocatalysts in the Lewis acid-mediated Lewis base-promoted direct stereoselective aldol reactions of activated thioesters with aromatic aldehydes, carried out in the presence of tetrachlorosilane and a tertiary amine. β-Hydroxy thioesters were obtained in moderate to high yields, with very high syn diastereoselectivities (dr up to >98:2), and fair enantioselectivities (ee up to 51%). Theoretical studies were performed in order to elucidate the origin of the stereoselection.     

Enantioselective 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds catalyzed by rhodium(I)-chiral phosphoramidite complexes

A chiral bidentate phosphoramidite (5a) was synthesized from Shibasaki’s linked-(R)-BINOL and P(NMe₂)₃ as a new ligand for rhodium(I)-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds. The effects of 5a and Feringa’s monodentate phosphoramidite (4, R¹, R² = Et) on the yields and enantioselectivities were fully investigated. The reaction was significantly accelerated in the presence of a base such as KOH and Et₃N, allowing the reaction to be completed at the lower temperatures than 50 °C. The addition to cyclic enones such as 2-cyclopentenone, 2-cyclohexenone and 2-cycloheptenone at 50 °C in the presence of an [Rh(coe)₂Cl]₂-4 (R¹, R² = Et) complex resulted in enantioselectivities up to 98%, though it was less effective for acyclic enones (0–70% ee). On the other hand, a complex between [Rh(nbd)₂]BF₄ and 5a completed the addition to cyclic enones within 2 h at room temperature in the presence of Et₃N with 86–99% yields and 96–99.8% ee. This catalyst was also effective for acyclic enones, resulting in 62–98% yields and 66–94% ee. The 1,4-additions of arylboronic acids to unsaturated lactones and acyclic esters with rhodium(I)-phosphoramidites complexes were also investigated.     

Enantioselective anti-Mannich reaction catalyzed by modularly designed organocatalysts

A highly stereoselective method for achieving the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate was realized using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and (R)-pyrrolidien-3-carboxylic acid in the reaction media. The desired anti-Mannich products were obtained in good to excellent yields (up to 93%), excellent diastereoselectivities (up to 99:1 dr), and good to high enantioselectivities (up to 99% ee).     

Enantioselective synthesis of chiral 1,2-diamines by the catalytic ring opening of azabenzonorbornadienes: application in the preparation of new chiral ligands

In the presence of a rhodium catalyst (5 mol %) generated in situ from [Rh(cod)Cl]₂ and (S,S′)-(R,R′)-C₂-ferriphos-tolyl, the asymmetric ring-opening reaction of N-Boc-azabenzonorbornadienes with dibenzylamine proceeded with excellent enantioselectivity (up to >99% ee) to give the corresponding 1,2-diamine scaffolds in high yields. The sequential deprotection of the ring-opened products and treatment with tartaric acid gave the enantiomerically pure 1,2-diamine tartrate salts. These salts were used for the preparation of new chiral ligands such as the salen-type ligands and Trost-type ligands.