Synthesis of the bifunctional BINOL ligands and their applications in the asymmetric additions to carbonyl compounds

Efficient one-step syntheses of the bifunctional BINOL and H₈BINOL ligands (S)-6 and (S)-8 have been developed from the reaction of BINOL and H₈BINOL with morpholinomethanol, respectively. The X-ray analyses of these compounds have revealed their structural similarity and difference. The bifunctional H₈BINOL (S)-8 is found to be highly enantioselective for the reaction of diphenylzinc with many aliphatic and aromatic aldehydes and especially is the most enantioselective catalyst for linear aliphatic aldehydes. Unlike other catalysts developed for the diphenylzinc addition which often require the addition of a significant amount of diethylzinc with cooling (or heating) the reaction mixture in order to achieve high enantioselectivity, using (S)-8 needs no additive and gives excellent results at room temperature. (S)-8 in combination with diethylzinc and Ti(OⁱPr)₄ can catalyze the highly enantioselective phenylacetylene addition to aromatic aldehydes. It can also promote the phenylacetylene addition to acetophenone at room temperature though the enantioselectivity is not very high yet. Without using Ti(OⁱPr)₄ and a Lewis base additive, (S)-8 in combination with diethylzinc can catalyze the reaction of methyl propiolate with an aldehyde to form the highly functional γ-hydroxy-α,β-acetylenic esters except that the enantioselectivity is low at this stage. The bifunctional BINOL ligand (S)-6 in combination with Me₂AlCl is found to be a highly enantioselective catalyst for the addition of TMSCN to both aromatic and aliphatic aldehydes.     

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%).     

Structure influence of chiral 1,1′-biscarboline-N,N′-dioxide on the enantioselective allylation of aldehydes with allyltrichlorosilanes

A series of new axially chiral 1,1′-biscarboline-N,N′-dioxide Lewis base organocatalysts were examined in the asymmetric allylation of aldehydes with allyltrichlorosilane. The chiral catalysts (R)-1a–e bearing ester groups in 3,3′ position provided good yields of the homoallyl alcohols with excellent enantioselectivities up to 99% for a broad substrate scope that covers aliphatic, aromatic, heteroaromatic, and α,β-unsaturated aldehydes. Solvent effects on the conversion and enantioselectivity were elucidated, and CH₂Cl₂ proved to be the optimal solvent for the reactions. In addition, the allylation with crotyltrichlorosilane was explored and the result showed that anti-isomer was favored from (E)-crotyltrichlorosilane with complete diastereoselectivity.     

Enantioselective arylation of aldehydes catalyzed by a soluble optically active polybinaphthols ligand

A soluble chiral polymer ligand was synthesized by the polymerization of (R)-6,6′-dibutyl-3,3′-diformyl-2,2′-binaphthol (R-M-1) with 2,5-diaminopyridine (M-2) via a nucleophilic addition-elimination reaction. While arylboronic acids were used as the source of the transferable aryl group, the chiral polybinaphthols ligand in combination with Et₂Zn without Ti(OⁱPr)₄ exhibited higher enantioselectivity in asymmetric addition to aromatic aldehydes than alphatic aldehydes. When aromatic aldehydes with electron-withdrawing groups were chosen as substrates, the resulting diarylmethanols were produced in higher ee values than those with electron-donating groups as substrates. 2-Naphthaldehyde used as a substrate afforded product in 95% ee, which could be ascribed to the steric effect influence on this asymmetric arylation reaction. Moreover, the chiral polymer was easily recovered and reused, but exhibited a decrease of enantioselectivity in the third recycle.     

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C₂-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.     

Chiral C2-symmetric ligands containing two binaphthyl units linked by 2,2′-bipyridyl bridge in asymmetric catalysis

The catalytic activities of new chiral C₂-symmetric ligands 1–4 in the asymmetric alkylation of aromatic aldehydes with diethylzinc to give 1-arylpropanols are studied. In most cases, the yields were good and enantioselectivities up to 87% were observed. Copper-catalyzed cyclopropanation proceeded with ⩽51% enantioselectivity and ∼3:1 trans/cis-diastereoselectivity.     

Highly enantioselective vinylogous addition of 2-trimethylsilyloxyfuran to aldehydes promoted by the SiCl4/chiral Lewis base system

This paper reports the regio-, diastereo- and highly enantioselective vinylogous aldol reaction of 2-trimethylsilyloxyfuran (TMSOF) promoted by the SiCl₄/Lewis base catalytic system. Several electron-pair donors proved to be effective as SiCl₄ activators versus the TMSOF γ-selective addition to aldehydes giving rise to different diastereoisomeric ratios, while Denmark’s chiral bis-phosphoramide (R,R)-7 gave the highest enantioselectivity for both the anti- and syn-diastereoisomers. Furthermore, by using ambident electrophiles such as α,β-unsaturated aldehydes, the SiCl₄/Lewis base-promoted process leads exclusively to the 1,2-addition products.     

1,1′-Binaphthyl ligands with bulky 3,3′-tertiaryalkyl substituents for the asymmetric alkyne addition to aromatic aldehydes

The BINOL ligand (R)-2 that contains bulky 3,3′-tertiaryalkyl groups shows improved catalytic properties over the previously reported 3,3′-substituted BINOL ligands in the asymmetric alkyne addition to aromatic aldehydes. It catalyzes the phenylacetylene addition to aromatic aldehydes with high enantioselectivity (86-94% ee) and good yields without using Ti(OⁱPr)₄ and a Lewis base additive. The catalytic properties of several analogs of (R)-2 in the asymmetric alkyne addition to aldehydes have also been studied.     

Synthesis of γ-functionalized allyltrichlorosilanes and their application in the asymmetric allylation of aldehydes

Isomerically pure trans- and cis-γ-bromoallyltrichlorosilanes 4 and 5 have been synthesized and shown to react with aromatic aldehydes 1 in the presence of Lewis-basic catalysts (e.g., DMF) to produce the corresponding anti- and syn-allylbromohydrins 8 and 9, respectively, as single diastereoisomers. With BINAPO 25 as a chiral catalyst, promising enantioselectivity (?50% ee) has been attained.     

Asymmetric Mukaiyama aldol reaction of silyl enol ethers with aldehydes using a polymer-supported chiral Lewis acid catalyst

Chiral N-sulfonylated α-amino acid monomer (5) derived from (S)-tryptophan was copolymerized with styrene and divinylbenzene under radical polymerization conditions to give a polymer-supported N-sulfonyl-(S)-tryptophan (6). Treatment of the polymer-supported chiral ligand with 3,5-bis(trifluoromethyl)phenyl boron dichloride afforded a polymeric Lewis acid catalyst (16) effective for asymmetric Mukaiyama aldol reaction of silyl enol ethers and aldehydes. Various aldehydes were allowed to react with silyl enol ethers in the presence of the polymeric chiral Lewis acid to give the corresponding aldol adducts in high yield with high levels of enantioselectivity.     

Asymmetric addition of phenylacetylene to aldehydes catalyzed by soluble optically active polybinaphthols ligand

A chiral polymer ligand was synthesized by the polymerization of (S)-5,5′-dibromo-6,6′-dibutyl-2,2′-binaphthol (S-M-1) with (S)-2,2′-bishexyloxy-1,1′-binaphthyl-6,6′-boronic acid (S-M-2) via Pd-catalyzed Suzuki reaction. The application of the chiral polymer ligand to the asymmetric addition of phenylethynyl zinc to various aldehydes has been studied. The results show that the soluble chiral polybinaphthols ligand in combination with Et₂Zn and Ti(OⁱPr)₄ can exhibit excellent enantioselectivity for phenylacetylene addition to both aromatic and aliphatic aldehydes. The catalytically active center of the repeating unit S-1 used as a catalyst produced the opposite configuration of the propargylic alcohols to that of S-1, on the contrary, the chiral polymer gave the same configuration as the optically active binaphthol moiety of the polybinaphthols ligand. Moreover, the chiral polymer ligand can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

The use of bifunctional catalyst systems in the asymmetric addition of alkynylzinc to aldehydes

The bifunctional ligand 2a showed a more enhanced reactivity than that of the corresponding amino alcohol ligand in the asymmetric addition of alkynylzinc to benzaldehyde. The bifunctional ligand 2a can catalyze the addition of phenylacetylene to various types of aldehydes including aromatic aldehydes, aliphatic aldehydes, and α,β-unsaturated aldehydes with high enantioselectivity (81–98% ee). The conditions of this catalytic process are both mild and simple.     

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%).     

Indium-mediated allylation of carbonyl compounds with an allylic bromide in aqueous media: anomalous syn-diastereoselectivity regardless of allylic bromide geometry

Anomalous syn-diastereoselectivity of indium-mediated coupling of aldehydes with bromides Z-3b and E-3b is reported. The reaction afforded high syn selectivity regardless of the allylic bromide geometry. Preliminary studies on the enantioselective indium-mediated allylation were attempted and found to give the desired products in moderate yield with high syn selectivity and enantioselectivity.     

Regulation of the flexibility of planar chiral [2.2]paracyclophane ligands and its significant impact on enantioselectivity in asymmetric reactions of diethylzinc with carbonyl compounds

A series of planar chiral ligands derived from [2.2]paracyclophane were synthesized and applied as catalysts in enantioselective additions of diethylzinc to aldehydes and α,β-unsaturated ketones. When ligand 10 with a dimethyl hydroxymethyl as the substituent was used, the enantioselectivity of the reaction of diethylzinc with aldehydes was much higher than when using ligand 3c with diphenyl hydroxymethyl as the substituent. The situation was the same with the 1,4-addition of diethylzinc to α,β-unsaturated ketones with 63–83% ee being obtained when the hydroxymethyl substituted ligand 7b was used, while almost no enantioselectivity was afforded if ligand 3c was used. The role of planar chirality is also studied.     

New chiral tetraaza ligands for the efficient enantioselective addition of dialkylzinc to aromatic aldehydes

A series of chiral tetraaza ligands were studied for the enantioselective addition of dialkylzinc to aldehydes. These bis(amino amide) ligands show high enantioselectivity in the addition of organozincs to aromatic aldehydes. Different structural elements on the ligands seem to play an important role in determining the observed enantioselectivity. Ligand 4b (N,N′-bis(N-l-valinyl)-1,3-diaminopropane, with an aliphatic spacer with 3C atoms) catalyzed the addition of Et₂Zn to benzaldehyde, 1-naphtaldehyde, 4-methoxybenzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products with excellent conversions and selectivities and with enantioselectivities of 99, 97, 98, and 82%, respectively. DFT calculations provide an understanding of the mechanism of the enantioselection process.     

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.     

Synthesis of novel chiral 1,3-aminophenols and application for the enantioselective addition of diethylzinc to aldehydes

Novel chiral 1,3-aminophenols were efficiently synthesized by applying a Friedel–Crafts reaction and optical resolution. The catalytic activity of the aminophenols was studied for the addition of diethylzinc to benzaldehyde. The results showed that (S)-5a with bulky tert-butyl groups on the stereogenic carbon atom and 4,6-positions of phenol favored higher enantioselectivity (94% ee). The same ligand was also used with other aldehydes, to give optically active alcohols in good chemical yields and ee values (up to 99%).     

Enantioselective addition of diethylzinc to aldehydes catalyzed by monosubstituted [2.2]paracyclophane-based N,O-ligands: remarkable cooperative effects of planar and central chiralities

Diastereomeric monosubstituted [2.2]paracyclophane-based N,O-ligands, which unite the planar and central chiral elements, were optimized for the enantioselective diethylzinc addition to aldehydes. (S)-1-{(S_p)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanol (S_p,S)-3 catalyzed the addition to give (R)-1-phenyl-1-propanol in a high yield and with a good enantioselectivity (91% ee).     

Enantioselective addition of diethylzinc to aldehydes catalyzed by γ-amino alcohols derived from (+)- and (−)-α-pinene

Primary, secondary and tertiary γ-amino alcohols 4, 5, 7 and 9 and 1,3-diamine 6 were synthesized from (+)- and (−)-α-pinene 1 via chiral N-Boc β-amino ester 3a and carboxamide 3b. The amino alcohols and diamine obtained were applied as chiral catalysts in the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in chiral 1-aryl-1-propanols. The first evidence of the substituent-dependent enantioselectivity of 1,3-amino alcohol catalysts was observed, and the phenomenon interpreted by using molecular modelling at the ab initio level.