Asymmetric diethylzinc addition and phenyl transfer to aldehydes using chiral cis-cyclopropane-based amino alcohols

A new series of amino alcohols with a chiral cyclopropane backbone have been developed and used in the catalytic asymmetric diethylzinc addition and phenyl transfer to various types of aldehydes. These cyclopropane-based chiral amino alcohols show high enantioselectivity in the addition of organozincs to aromatic and aliphatic aldehydes. For diethylzinc addition to aromatic and aliphatic aldehydes, up to 97% ee and 93% ee are obtained, respectively. For the phenyl transfer to aromatic aldehydes, the best enantioselectivity was 89% ee.     

Iron(II) and zinc(II) complexes with designed pybox ligand for asymmetric aqueous Mukaiyama-aldol reactions

An iron(II) complex with a hindered hydroxyethyl-pybox (he-pybox) ligand shows improved catalytic activity and enantioselectivity for asymmetric Mukaiyama-aldol reactions in aqueous media. This water-stable chiral Lewis acid promotes condensation of aromatic silyl enol ethers with a range of aldehydes with good yields, excellent syn-diastereoselectivity and up to 92% ee. The combination of the same ligand with ZnII salt is also demonstrated as a remarkably efficient and water-compatible chiral Lewis acid.     

Biheteroaromatic diphosphine oxides-catalyzed stereoselective direct aldol reactions

A highly stereoselective direct aldol condensation of ketones to aromatic aldehydes was realized; the trichlorosilyl enolether generated in situ in the presence of tetrachlorosilane is activated by catalytic amounts of an enantiomerically pure biheteroaromatic phosphine oxide to react with aldehydes, coordinated as well as activated by the chiral cationic hypervalent silicon species. This Lewis acid-mediated Lewis base-catalyzed transformation allowed, starting from two carbonyl compounds, to directly synthesize β-hydroxy ketones generally with high anti stereoselectivity and up to 93% ee for the anti isomer.     

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.     

Multifunctional asymmetric catalysis

Two types of general and practical enantioselective catalysts, namely, bimetallic complexes and Lewis acid-Lewis base bifunctional catalysts were developed based on the concept of multifunctional catalysis. In the first part of this review, the first example of a catalytic enatioselective nitro-Mannich reaction as well as a direct catalytic enantioselective aldol reaction of 2-hydroxyacetophenone using bimetallic complexes is discussed. The new complex, composed of ytterbium, potassium, and BINOL in a ratio of 1:1:3, promoted the nitro-Mannich reaction of nitromethane with up to 91% ee. On the other hand, second generation ALB catalyzed an enantioselective and diastereoselective nitro-Mannich reaction of nitroalkanes in up to 83% ee with a diastereomeric ratio up to 7:1. Moreover, the reaction of aldehydes with 2-hydroxyacetophenone in the presence of LLB, KHMDS, and H2O selectively gave the corresponding anti-alpha,beta-dihydroxy ketones in up to 95% ee and, in the presence of the catalyst prepared from linked-BINOL and 2 eq of Et2Zn, selectively afforded the syn-alpha,beta-dihydroxy ketones in up to 86% ee. In the second part, the development of new catalysts displaying a Lewis acidity and a Lewis basicity is described. The Lewis acid of the catalyst activates aldehydes, imines, acyl quinoliniums, and ketones. At the same time, the Lewis base activates the nucleophile (TMSCN). Catalysts of this type produced a highly enantioselective cyanation of these electrophiles. Application of the catalytic enantioselective cyanosilylation of aldehydes to a total synthesis of epothilones is also described.     

Chemoenzymatic synthesis of a mixed phosphine-phosphine oxide catalyst and its application to asymmetric allylation of aldehydes and hydrogenation of alkenes

The chemoenzymatic synthesis of a Lewis basic phosphine-phosphine oxide organocatalyst from a cis-dihydrodiol metabolite of bromobenzene proceeds via a palladium-catalysed carbon-phosphorus bond coupling and a novel room temperature Arbuzov [2,3]-sigmatropic rearrangement of an allylic diphenylphosphinite. Allylation of aromatic aldehydes were catalysed by the Lewis basic organocatalyst giving homoallylic alcohols in up to 57% ee. This compound also functioned as a ligand for rhodium-catalysed asymmetric hydrogenation of acetamidoacrylate giving reduction products with ee values of up to 84%.     

The first series of chiral 2,2':6',2''-terpyridine tri-N-oxide ligands for Lewis base-catalyzed asymmetric allylation of aldehydes

The first series of chiral 2,2':6',2'-terpyridine tri-N-oxide ligands have been developed; They were showed to be active Lewis base-catalysts for asymmetric allylation of aldehydes using allyltrichlorosilane with optimal results at 0 degrees C for electron-deficient aromatic aldehydes (yields up to 97% and enantioselectivities up to 86% ee).     

手性氨基酸酰胺催化二乙基锌与芳香醛不对称加成反应

将由磺酰化氨基酸和长链的含甲氧基官能团的胺制备的(S)-N-(4-甲氧基苯乙基)-3-苯基-2-(对甲基苯磺酰胺)丙酰胺(1d)手性配体用于催化二乙基锌与系列芳香醛对映选择性加成反应.15 mol%该催化剂能够对含有吸电子基团、供电子基团及不同位阻的芳香醛均有较好的效果,能够在比较温和的条件下获得高达87%ee和中等程度的产率.     

Straightforward access to chiral diol bidentate ligands: their efficient enantioselective induction in the addition of diethylzinc to aromatic aldehydes

Enantiopure C₂‐symmetric diol bidentate ligands have been synthesized in a straightforward manner through a three‐step reaction with good yields. The synthesized C₂‐symmetric diol bidentate ligands were used in the addition of diethylzinc to various aromatic aldehydes, a general catalytic benchmark reaction, in order to assess their enantioselective induction properties. The enantioselective addition of diethylzinc to 1‐naphthaldehyde and 3‐chlorobenzaldehyde was achieved with an enantiomeric excess (ee) of up to 98%. All synthesized ligands were also evaluated in the addition of diethyzinc to aromatic aldehydes including an extra metal such as Ti(IV) (up to 99% ee). Copyright © 2014 John Wiley & Sons, Ltd.     

Polystyrene-supported amino alcohol ligands for the heterogeneous asymmetric addition of phenyl zinc reagents to aldehydes

A family of polystyrene-supported amino alcohols, characterized by a high catalytic activity in alkyl transfer from zinc to formyl groups has been successfully tested in the enantioselective addition of phenyl zinc reagents to aldehydes to afford chiral diarylmethanols. Enantioselectivities higher than 90% (mean ee 90.5%; eight examples) are recorded with aromatic aldehydes in what represents the first successful use of heterogeneous, polymeric reagents for enantiocontrol in the phenylation of aldehydes.     

Highly enantioselective addition of dimethylzinc to arylaldehydes catalyzed by (2S)-1-ferrocenyl-methylaziridin-2-yl(diphenyl)methanol

Asymmetric addition of dimethylzinc to a wide variety of aromatic aldehydes is described in the presence of a catalytic amount of chiral β-amino alcohol [(2S)-1-ferrocenyl- methylaziridin-2-yl(diphenyl)methanol], and a reaction enantioselectivity of up to 97.5% ee was achieved in this transformation in the absence of additional metals such as Ti or Ni. The results showed that this particular addition reaction, characterized by the lower reactivity of dimethylzinc with aldehydes, was more sensitive to structural variations in substrate aldehydes than the corresponding diethylzinc addition. A possible transition state for the catalytic asymmetric addition has been proposed on the basis of previous studies.     

Facile, mild, and highly enantioselective alkynylzinc addition to aromatic aldehydes by BINOL/N-methylimidazole dual catalysis

The dual Lewis acid/base catalytic system, generated from N-methylimidazole (NMI), (R)-1,1'-bi-2-naphthol [(R)-BINOL], and Ti(OiPr)4, effectively catalyzes the enantioselective alkynylation of aldehydes in the presence of Et2Zn in good yields and excellent enantioselectivities of up to 94% ee at room temperature. The mild reaction conditions make it possible to use functional alkynes in this asymmetric addition.     

Catalytic addition methods for the synthesis of functionalized diazoacetoacetates and application to the construction of highly substituted cyclobutanones

[reaction: see text] Methyl 3-(trialkylsilanyloxy)-2-diazo-3-butenoate undergoes Lewis acid-catalyzed Mukaiyama aldol addition with aromatic and aliphatic aldehydes in the presence of low catalytic amounts of Lewis acids in nearly quantitative yields. Scandium(III) triflate is the preferred catalyst and, notably, addition proceeds without decomposition of the diazo moiety. Diazoacetoacetate products from reactions with aromatic aldehydes undergo rhodium(II)-catalyzed ring closure to cyclobutanones with high diastereocontrol. Examples of complimentary Mannich-type addition reactions with imines are reported.     

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.     

The Direct catalytic asymmetric cross-Mannich reaction: a highly enantioselective route to 3-amino alcohols and alpha-amino acid derivatives

The first proline-catalyzed direct catalytic asymmetric one-pot, three-component cross-Mannich reaction has been developed. The highly chemoselective reactions between two different unmodified aldehydes and one aromatic amine are new routes to 3-amino aldehydes with dr>19:1 and up to >99 % ee. The asymmetric cross-Mannich reactions are highly syn-selective and in several cases the two new carbon centers are formed with absolute stereocontrol. The reaction does not display nonlinear effects and therefore only one proline molecule is involved in the transition state. The reaction was also catalyzed with good selectivity by other proline derivatives. The Mannich products were converted into 3-amino alcohols and 2-aminobutane-1,4-diols with up to >99 % ee. The first one-pot, three-component, direct catalytic asymmetric cross-Mannich reactions between unmodified aldehydes, p-anisidine, and ethyl glyoxylate have been developed. The novel cross-Mannich reaction furnishes either enantiomer of unnatural alpha-amino acid derivatives in high yield and up to >99 % ee. The one-pot, three-component, direct catalytic asymmetric reactions were readily scaled up, operationally simple, and conductible in environmentally benign and wet solvents. The mechanism and stereochemistry of the proline-catalyzed, one-pot, three-component, asymmetric cross-Mannich reaction are also discussed.     

联萘酚衍生C_3对称的手性配体的合成及其在诱导二乙基锌与芳基醛的不对称加成反应中的应用

合成了一种新型可重复使用的含手性联萘酚的C3对称树状小分子配体(L1),并将L1用于诱导二乙基锌和芳基醛的不对称加成反应.获得的二级醇最高的对映选择性为91%ee,产物最高收率达99%.反应完成后,只需经过简单的萃取和洗涤过程就可实现对配体L1高回收率的回收.配体L1重复使用5次其催化活性和对映选择性没有明显变化.     

Highly enantioselective addition of in situ prepared arylzinc to aldehydes catalyzed by a series of atropisomeric binaphthyl-derived amino alcohols

The direct addition of in situ prepared arylzinc to aldehydes with chiral binaphthyl-derived amino alcohols as catalysts can afford optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99 % ee, ee = enantiomeric excess). By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes; this catalytic system also works well for the phenylation of aliphatic aldehydes to give up to 96 % ee.     

Enantioselective cyanosilylation of ketones by a catalytic double-activation method with an aluminium complex and an N-oxide

Double-activation catalysis promises high catalytic efficiency in the enantioselective cyanosilylation of ketones through the combined use of a Lewis acid and a Lewis base. Catalyst systems composed of a chiral salen-Al complex and an N-oxide have high catalytic turnovers (200 for aromatic ketones, 1000 for aliphatic ones). With these catalysts, a wide range of aliphatic and aromatic ketones were converted under mild conditions into tertiary cyanohydrin O-TMS ethers in excellent yields and with high enantioselectivities (94% ee for aromatic ketones, 90% ee for aliphatic ones). Preliminary mechanistic studies revealed that the salen-Al complex played the role of a Lewis acid to activate the ketone and the N-oxide that of a Lewis base to activate TMSCN; that is, double activation.     

Synthesis of chiral sulfoximines derived from 3-aminoquinazolinones and their catalysis of enantioselective diethylzinc addition to aldehydes

A series of sulfoxides were sulfoximinated using oxidative addition of 3-aminoquinazolinones by lead tetraacetate in the presence of hexamethyldisilazane. They were applied for the first time in catalytic enantioselective addition to aromatic aldehydes with a product enantiopurity (ee) of 92% in the case of 2-methoxybenzaldehyde.     

Highly enantioselective phenyl transfer to aryl aldehydes catalyzed by easily accessible chiral tertiary aminonaphthol

A new chiral tertiary aminonaphthol ligand 3b served as a highly efficient ligand for the asymmetric catalytic phenyl transfer to aromatic aldehydes and a variety of chiral diarylmethanols was prepared in high ee values (ee up to 99%) and chemical yields. The straightforward syntheses of both 3b and its enantiomer provide an excellent opportunity for large-scale applications.