A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).     

Asymmetric aldol reactions between cyclic ketones and benzaldehyde catalyzed by chiral Zn2+ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane: effects of solvent and additives on the stereoselectivities of the aldol products

The direct aldol reaction between cyclic ketones and 4-nitrobenzaldehyde catalyzed by chiral Zn²⁺ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane is reported. The anti-aldol products were mainly formed in cyclohexanone/N-methylpyrrolidone(NMP)/MeOH with good diastereo- and enantioselectivity, while syn-aldol adducts were obtained as major products with good enantioselectivity in cyclohexanone/H₂O and cyclohexanone/NMP/H₂O. The fact that the UV/vis spectra of 2,6-diphenyl-4-(2,4,6-triphenyl-1-pyridinio)phenolate (Reichardt’s dye) were nearly identical in these solvent systems suggests that the switch in the relative configuration of the aldol products is induced by a large excess of H₂O rather than the polarity of the solvent system. Furthermore, the addition of a small amount of TFA improved the enantioselectivity of the syn-aldol adducts produced in cyclohexanone/H₂O with up to 92% ee (anti/syn ratio = 30:70).     

Biocatalytic direct asymmetric aldol reaction using proteinase from Aspergillus melleus

The direct asymmetric aldol reaction of aromatic aldehydes with cyclic or acyclic ketones was catalyzed by proteinase from Aspergillus melleus (AMP) in acetonitrile in the presence of water. A wide range of substrates could be transformed into the corresponding aldol products in yields up to 89%, enantioselectivities up to 91% ee and diastereoselectivities up to >99:1 (anti/syn). This work provided an example of enzyme catalytic promiscuity that widens the applicability of this biocatalyst in organic synthesis without the need for additional cofactors or special equipment.     

Metal/linked-BINOL complexes: Applications in direct catalytic asymmetric Mannich-type reactions

Development of metal/linked-BINOL complexes and their applications in direct catalytic asymmetric Mannich-type reactions of hydroxyketones are reviewed. A Et₂Zn/linked-BINOL complex was effective for diastereo- and enantioselective synthesis of β-amino alcohols. By choosing the proper protective groups on the imine nitrogen, either anti- or syn-β-amino alcohol was obtained in excellent enantioselectivity (up to >99.5% ee) using the same zinc catalysis. Y{N(SiMe₃)₂}₃/linked-BINOL complex was effective for various hydroxyketones, affording syn-β-amino alcohols with high enantioselectivity (up to 98% ee). To broaden the nucleophile scope to carboxylic acid derivatives, N-acylpyrrole was utilized as an ester equivalent donor. In(O-iPr)₃/linked-BINOL complex was effective for generating an In-enolate from N-acylpyrrole in situ, giving Mannich adducts with high enantioselectivity (up to 98% 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.     

Highly stereoselective anti-aldol reactions catalyzed by simple chiral diamines and their unique application in configuration switch of aldol products

Chiral derivatives of trans-1,2-diaminocyclohexane with different N,N-dialkyl groups in well-defined orientations have been synthesized, and applied as catalysts for the asymmetric aldol reaction between a variety of aldehydes and ketones. Enantiomeric catalyst 1j catalyzed the reaction in ethanol and provided excellent diastereoselectivity and enantioselectivity. Significantly, simple replacement of organic solvents with water switched the products of the aldol reactions from anti to syn configuration. Such catalytic reactions led to the products with anti to syn diastereoselectivity up to 99:1 in ethanol, while in water gave the products with syn to anti diastereoselectivity up to 99:1.     

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 application of a structurally simple,recyclable, and large-scale l-prolinamide catalyst for asymmetric aldol reactions

A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohexanediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various ketones and aldehydes. The catalyst displayed impressive catalytic activity toward heterocyclic ketones containing oxygen, sulfur, or nitrogen, which have not been sufficiently explored. The substrate scope also covered cyclic and acyclic ketones. With heterocyclic ketones or cyclohexanone, the aldol reactions gave products in high yields and with respectable enantioselectivities (87–99% ee) and diastereoselectivities (up to >99:1 anti/syn). The catalyst could be recycled and reused up to seven times resulting in good yields and with good selectivities. This catalyst is also efficient in large-scale reactions with the enantioselectivities remaining at the same level as in the experimental scale reactions.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

The application of chiral phosphine-Schiff base type ligands in silver(I)-catalyzed asymmetric vinylogous Mannich reaction of aldimines with trimethylsiloxyfuran

Catalytic asymmetric vinylogous Mannich (AVM) reactions of readily available aldimines with trimethylsiloxyfuran in the presence of catalytic amount of AgOAc and chiral phosphine-Schiff base type ligands are described, affording the corresponding products in up to 91% yield, anti/syn >99:1 and 81% ee.     

Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions

An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing dipeptides and thiodipeptides 1a–f as organocatalysts is reported. In general, (S)-proline-containing thiodipeptides proved to be better organocatalysts relative to their analogous amides. In particular, thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may be ascribed to the increased N–H acidity of the thioamide segment that leads to stronger H-bonding interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Furthermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with isatin and isatin derivatives (ee 56–86%).     

The dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat: asymmetric synthesis of α-vinyl-β-hydroxycarboxylic acid derivatives and conversion to α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products)

The synthesis of α-vinyl-β-hydroxyesters and α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) via the dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat is described. High levels of syn-diastereoselectivity (up to >98% de) are observed for the dienolate aldol reaction with boron enolates, generated either directly with Bu₂BOTf or by transmetalation of the potassium enolate with B-bromocatecholborane. Cleavage of the resultant syn-aldol products from the auxiliary gives α-vinyl-β-hydroxyesters in >98% de and >98% ee. Subsequent isomerisation of the double bond into conjugation provides α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) in high diastereo- and enantiopurity (≥91:9 [(E):(Z)] and >98% ee).     

Enantioselective construction of quaternary asymmetric carbon centers using an aldol reaction of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate

An aldol reaction of 2,2-disubstituted trimethoxysilyl enol ethers with aldehydes catalyzed by a dilithium salt of (R)-3,3′-dichlorobinaphthol afforded the corresponding aldol adducts with quaternary carbon centers in high anti-selectivities (syn:anti = ∼1:50) and enantioselectivities (∼90% ee).     

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.     

Reductive aldol cyclizations of unsaturated thioester derivatives of 1,3-cyclopentanedione catalyzed by chiral copper hydrides

The first study on the asymmetric reductive aldol reactions of enethioate derivatives of 1,3-cyclopentanedione showed that 5 mol % of TANIAPHOS (SL-T001-1), and Cu(OAc)₂·H₂O, together with phenylsilane as the stoichiometric reductant, generated the best yields and enantioselectivities of β-hydroxythioester products. With S-benzyl keto-enethioate as substrate, the bicyclo[4.3.0] hydroxythioester product was obtained only as the all-cis diastereomer, in good yield (84%) and enantioselectivity (up to 90% ee). With the related indanedione enethioate derivatives, the reductive aldol cyclization could attain up to 96% ee. These results demonstrate that enethioates have a significantly different reactivity and selectivity profile compared to enoate derivatives in the copper-catalyzed reductive aldol cyclization.     

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.     

Highly efficient and solvent-free direct aldol reaction catalyzed by glucosamine-derived prolinamide

The catalytic activity of novel sugar-based prolinamides in the aldol reaction between ketones and aryl aldehydes has been examined. The prolinamide 1c was found to be an efficient organocatalyst for the asymmetric aldol reaction under solvent-free conditions. A variety of ketones and aldehydes were used as substrates and the corresponding aldol products were obtained in excellent chemical yields with high levels of anti diastereoselectivity (up to 99:1) and enantioselectivity (up to >99%).     

Chiral 1,1′-binaphthylazepine derived amino alcohol catalyzed asymmetric Henry reaction

The catalytic asymmetric Henry reaction of nitromethane to various aldehydes has been developed using a chiral binaphthylazepine derived amino alcohol and Cu(OAc)₂·H₂O as the catalyst. High yields and good enantioselectivities (up to 97% ee) were obtained for both aromatic and aliphatic aldehydes. Moreover, this catalytic system also works well for the diastereoselective Henry reaction to afford the corresponding adducts in up to 95:5 syn/anti selectivity and 95% enantioselectivity.     

High acceleration of the direct aldol reaction cocatalyzed by BINAM-prolinamides and benzoic acid in aqueous media

The enantioselective direct aldol reaction, organocatalyzed by recoverable BINAM-prolinamide derivatives can be highly accelerated by a catalytic amount of a carboxylic acid without a detrimental of the obtained enantioselectivities. From the study of suitable acids and reaction conditions, benzoic acid in aqueous DMF or in water was shown to give the best results with high yields and enantioselectivities. Thus, the reaction between p-nitrobenzaldehyde and acetone catalyzed by (S_a)-BINAM-l-Pro and benzoic acid can be carried out at −20 °C in only 8.5 h to give the expected product with 86% ee. In the case of butan-2-one, the iso- and the anti-isomers are obtained in a 1:1 isomer ratio up to 99% ee. Cyclohexanone gives the anti-aldol in up to 99% dr and 97% ee in only 2 h. The opposite diastereoselectivity is obtained in the case of cyclopentanone with lower ee up to 65% for the syn and 85% for the anti-isomer.