Catalytic enantioselective Reformatsky reaction with ketones

Chiral tertiary alcohols were obtained with good yields and enantioselectivities via a catalytic Reformatsky reaction with ketones, including the challenging diaryl ketones, using chiral BINOL derivatives.     

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).     

Synthesis of α-fluoro-β-hydroxy esters by an enantioselective Reformatsky-type reaction

The first enantioselective Reformatsky-type reaction of ethyl iodofluoroacetate has been accomplished with alkyl aryl ketones. High diastereoselectivities and excellent enantioselectivities for the major diastereomer (93-95% ee) were achieved with large alkyl groups. For smaller alkyl groups the diastereoselectivities were moderate, but excellent enantioselectivities were obtained for both diastereomers (79-94% ee).     

Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

l-Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with unmodified ketones smoothly occurred at ambient temperature to produce β-hydroxy-β-trifluoromethylated ketones with good to excellent diastereo (up to 96% de) and enantioselectivities (up to 91% ee).     

Catalytic Enantioselective Aza‐Reformatsky Reaction with Cyclic Imines

A catalytic highly enantioselective aza‐Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral β‐amino esters with good yields and excellent enantioselectivities is reported. A readily available diaryl prolinol is used as a chiral ligand, ZnMe₂ as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five‐membered N‐sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral β‐amino esters.     

Ruthenium-Lewis acid catalyzed asymmetric Diels-Alder reactions between dienes and alpha,beta-unsaturated ketones

The complex [Ru(Cp)(R,R-BIPHOP-F)(acetone)][SbF(6)], (R,R)-1 a, was used as catalyst for asymmetric Diels-Alder reactions between dienes (cyclopentadiene, methylcyclopentadiene, isoprene, 2,3-dimethylbutadiene) and alpha,beta-unsaturated ketones (methyl vinyl ketone (MVK), ethyl vinyl ketone, divinyl ketone, alpha-bromovinyl methyl ketone and alpha-chlorovinyl methyl ketone). The cycloaddition products were obtained in yields of 50-90 % and with enantioselectivities up to 96 % ee. Ethyl vinyl ketone, divinyl ketone and the halogenated vinyl ketones worked best and their reactions with acyclic dienes consistently provided products with >90 % ee. alpha-Chlorovinyl methyl ketone performed better than alpha-bromovinyl methyl ketone. The reaction also provided a [4.3.1]bicyclic ring system in 95 % ee through an intramolecular cycloaddition reaction. Crystal structure determinations of [Ru(Cp)((S,S)-BIPHOP-F)(mvk)][SbF(6)], (S,S)-1 b, and [Ru(Cp)((R,R)-Me(4)BIPHOP-F)(acrolein)][SbF(6)], (R,R)-2 b, provided the basis for a rationalization of the asymmetric induction.     

Chiral Brønsted acid-catalyzed regio- and enantioselective arylation of α,β-unsaturated trifluoromethyl ketones

The interesting examples of chiral phosphoric acid-catalyzed regio- and enantioselective arylation of α,β-unsaturated trifluoromethyl ketones were reported. The reaction proceeded well and the desired products were obtained in good yields (up to 99%) with moderate to good enantioselectivities (up to 88% ee). Several desired products were obtained with excellent optical purities after a single recrystallization. Subsequent reduction of enantiopure products with NaBH₄ afforded two diastereomers of chiral trifluoromethyl-substituted secondary alcohols with high enantioselectivities (98% ee).     

Catalytic enantioselective allylation of ketones via a chiral indium(III) complex

[reaction: see text] A chiral indium complex has been discovered to effect high enantioselectivities in the addition of allyltributylstannanes to ketones. The allylation of a variety of aromatic, alpha,beta-unsaturated and aliphatic ketones resulted in good yields and high enantioselectivities (up to 92% ee).     

Direct aldol condensation reaction of ethyl diazoacetate with trifluoromethyl ketones

An efficient and direct aldol-type condensation of ethyl diazoacetate with trifluoromethyl ketones was developed in the presence of dialkyl zinc. A series of trifluoromethylated products were obtained in good to excellent yields (60-95%). A preliminary extension to a catalytic enantioselective aldol reaction of ethyl diazoacetate to trifluoromethyl ketones (up to 72% ee) is also described.     

Enantioselective conjugate addition of both aromatic ketones and acetone to nitroolefins catalyzed by chiral primary amines bearing multiple hydrogen-bonding donors

A new class of chiral primary amine catalysts bearing multiple hydrogen-bonding donors have been designed and synthesized. The newly developed bifunctional organocatalysts efficiently catalyzed not only enantioselective conjugate addition of aromatic ketones to nitroolefins in good yields (up to 87%) with excellent enantioselectivities (97→99% ee) but also enantioselective conjugate addition of acetone to nitroolefins in excellent yields (90-96%) with high enantioselectivities (up to 97% ee).     

Highly enantioselective direct aldol reaction catalyzed by organic molecules

We have demonstrated that a new class of l-proline-based organic compounds catalyzed the direct aldol reaction between aldehydes and acetone to provide beta-hydroxy ketones in good yields. The reaction is efficient, and 5-10 mol % of the catalyst and excellent enantioselectivities (97-99% ee) were obtained in both aromatic and aliphatic aldehydes. The presence of a gem-diphenyl group at the beta-carbon is necessary for high enantioselectivity.     

Highly enantioselective conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Asymmetric conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones was studied using chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient catalyst for the transformation. 4-Bromo-4-nitroketones were obtained with excellent enantioselectivities (97-99% ee) and good yields (61-99%) for a variety of alkyl vinyl ketones. The product could be further debrominated with Bu₃SnH/AIBN to provide chiral 4-nitroketones in good yield and without loss of the optical purity.     

Highly enantioselective Friedel-Crafts reaction of aromatic amines with ethyl glyoxylate catalyzed by chiral titanium(IV) complexes: practical synthesis of aminomandelic acid derivatives

The asymmetric Friedel-Crafts reaction of a variety of N,N-dialkylanilines with ethyl glyoxylate has been achieved by the catalysis of titanium complexes of BINOL derivatives to give corresponding ethyl esters of p-N,N-dialkylaminomandelic acids in high yields (85-99%) and good to excellent enantioselectivities (80-96.6% ee) under the optimized reaction conditions, which has added a new catalyst for this class of reactions. The reaction could also be carried out at a reduced catalyst loading (1 mol %) in gram scale, which provided a practical synthesis of enantiopure aminomandelic acid derivatives.     

Asymmetric Reformatsky Reaction of Aldehydes Catalyzed by Novel β-Amino Alcohols and Zinc Complexes

A series of β-amino alcohols derived from (1R, 2S)-2-amino-1,2-diphenylethanol and substituted salicylaldehydes as novel chiral tridentate ligands has been applied to an asymmetric Reformatsky reaction of aldehydes with ethyl iodoacetate in the presence of ZnMe₂. This novel catalytic system produced the desired β-hydroxyl esters with moderate to good enantioselectivities (up to 81% ee) and yields for many aldehydes, including aromatic, heteroaromatic, conjugated, and aliphatic aldehydes.     

Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to α,β- and α,β,γ,δ-unsaturated ketones

An enantioselective Cu(II)-catalyzed conjugate addition of dialkylzinc reagents to α,β- or α,β,γ,δ-unsaturated ketones with chiral cyclohexane-based amidophosphine ligands was developed. With 2 mol% of Cu(OAc)₂·H₂O/L5, the conjugate addition of diethylzinc to α,β-unsaturated ketones was achieved in good-to-excellent yields (up to 98%) and high enantioselectivities (up to 92% ee). This catalytic system was shown to be efficient for the 1,4-conjugate addition of Et₂Zn to (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one with 85% yield and 90% ee. Moreover, with 1 mol% of Cu(OTf)₂/L11, the conjugate addition of α,β,γ,δ-unsaturated ketones was accomplished with 1,4-regioselectivity, good yields (79–86%) and excellent enantioselectivities (up to 97% ee).     

Highly active chiral phosphoramide-Zn(II) complexes as conjugate acid-base catalysts for enantioselective organozinc addition to ketones

A highly efficient enantioselective organozinc (R2Zn) addition to ketones catalyzed by chiral phosphoramide-Zn(II) complexes (1-10 mol %) has been developed. These complexes serve as conjugate Lewis acid-Lewis base catalysts. Chiral phosphoramides are derived from an inexpensive natural amino acid (i.e., L-valine). From a variety of nonactivated aromatic and aliphatic ketones, the corresponding optically active tertiary alcohols were obtained in high yields with high enantioselectivities (up to 98% ee) under the mild reaction conditions.     

Practical asymmetric synthesis of beta-hydroxy-beta-trifluoromethylated ketones via the first example of the in situ generation of trifluoro-acetaldehyde and its successive asymmetric carbon-carbon bond formation reaction with chiral imines

Not only trifluoroactaldehyde ethyl hemiacetal or hydrate but also other polyfluoroalkylaldehydes acetals or hydrates react with an equimolar amount of various chiral imines, followed by hydrolysis to produce the corresponding (S)-beta-hydroxy-beta-polyfluoroalkyl ketones in good yields with good enantioselectivities; furthermore, the ee of the products can be improved by simple recrystallization.     

手性氨基醇催化的苯乙炔与酮的对映选择性加成

(S)-(1-Benzylpyrrolidin-2-yl)diphenylmethanol and cinchonine were evaluated as promotors in the asymmetricadditions of phenylacetylene to ketones,in order to prepare chiral propargylic alcohols.Good yields(up to 89%)and moderate enantioselectivities(up to 77.9% ee)were achieved.Addition of Ti(OPr-i)_4 can significantly improvethe enantioselectivity of the reaction.     

3-Pyrrolidinecarboxylic acid for direct catalytic asymmetric anti-Mannich-type reactions of unmodified ketones

We report the development of direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and alpha-imino esters under mild conditions. The reactions were performed using 5-10 mol % of (R)-3-pyrrolidinecarboxylic or (R)-beta-proline as catalyst in an environmentally benign solvent, 2-PrOH, at room temperature. The anti-Mannich products were obtained in good yields with high diastereo- and enantioselectivities (up to anti/syn >99:1, 99% ee). While (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid is an excellent catalyst for the anti-Mannich-type reactions of aldehydes, it did not efficiently catalyze the corresponding Mannich-type reactions of ketones; (R)-3-pyrrolidinecarboxylic acid did efficiently catalyze the Mannich-type reactions of ketones. (S)-Proline or (S)-2-pyrrolidinecarboxylic acid has been reported to catalyze the Mannich-type reactions of ketones to afford the syn-products. Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction, providing either syn- or anti-Mannich products.     

Enantioselective addition of vinylzinc reagents to aldehydes catalyzed by modular ligands derived from amino acids

[reaction: see text] A series of N-acylethylenediamine-based ligands were synthesized from Boc-protected amino acids. The ligands were screened for the ability to catalyze the asymmetric addition of vinylzinc reagents to aldehydes. Three sites of diversity on the ligands were optimized for this reaction using a positional scanning approach. The optimized ligand 3d was found to catalyze the formation of 15 different (E)-allylic alcohols with enantioselectivities that ranged from 52 to 91% ee and yields that ranged from 40 to 90%. This ligand was especially effective for the reaction of aromatic aldehydes with vinylzinc reagents derived from bulky terminal alkynes. Ligand 3d catalyzed the addition of (E)-(3,3-dimethylbut-1-enyl)(ethyl)zinc to 2-naphthaldehyde to give (R,E)-4,4-dimethyl-1-(naphthalene-1-yl)pent-2-en-1-ol in 89% ee. The ee of this product could be increased to 97% through a single recrystallization.