Direct organocatalytic enantioselective α-aminomethylation of ketones

The scope and limitations of the direct organocatalytic asymmetric α-aminomethylation of ketones are disclosed. The proline-catalyzed classical Mannich reactions between unmodified ketones, aqueous formaldehyde and aromatic amines furnished the desired Mannich bases in high yield with up to >99% ee. Moreover, methyl alkyl ketones were regioselectively α-aminomethylated at the methylene carbon affording the corresponding Mannich products with up to >99% ee. In addition, the proline-catalyzed one-pot three-component reaction between p-anisidine, aqueous formaldehyde and 4,4-dimethyl-2-cycloxehen-1-one furnished the corresponding bicyclic aza-Diels–Alder adduct with >99% ee.     

Application of chiral mixed phosphorus/sulfur ligands to enantioselective rhodium-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation processes

Chiral mixed phosphorus/sulfur ligands 1-3 have been shown to be effective in enantioselective Rh-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation reactions (eqs 1, 2). After assaying the influence of the substituents at sulfur, the substituents on the ligand backbone, the relative stereochemistry within the ligand backbone, and the substituents at phosphorus, ligands 2c (R = 3,5-dimethylphenyl) and 3 were found to be optimal in the Rh-catalyzed hydrogenation of a variety of alpha-acylaminoacrylates in high enantioselectivity (89-97% ee). A similar optimization of the catalyst for the Rh-catalyzed hydrosilylation of ketones showed that ligand 3 afforded the highest enantioselectivities for a wide variety of aryl alkyl and dialkyl ketones (up to 99% ee). A model for asymmetric induction in the hydrogenation reaction is discussed in the context of existing models, based on the absolute stereochemistry of the products and the X-ray crystal structures of catalyst precursors and intermediates.     

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.     

General stereoretentive preparation of chiral secondary mixed alkylmagnesium reagents and their use for enantioselective electrophilic aminations

A general preparation of enantiomerically and diastereomerically enriched secondary alkylmagnesium reagents was reported as well as their use for performing highly stereoselective transition-metal free electrophilic aminations leading to α-chiral amines in up to 97% ee. Thus, the reaction of t-BuLi (2.2 equiv.) with a mixture of chiral secondary alkyl iodides and the commercially available magnesium reagent Me₃SiCH₂MgCl in a 2 : 1 mixture of pentane and diethyl ether at up to −50 °C provided optically enriched secondary mixed alkylmagnesium species of the type alkyl(Me)CHMgCH₂SiMe₃ with high retention of configuration (up to 99% ee). The resulting enantiomerically enriched dialkylmagnesium reagents were trapped with electrophiles such as non-enolizable ketones, aldehydes, acid chlorides, isocyanates, chlorophosphines and O-benzoyl hydroxylamines providing α-chiral tertiary alcohols, ketones, amides, phosphines and tertiary amines in up to 89% yield (over three reaction steps) and up to 99% ee.

We report a general method for the preparation of enantiomerically enriched secondary alkylmagnesium reagents, which undergo highly stereoselective transition-metal free electrophilic aminations, leading to α-chiral amines in up to 97% 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).     

Asymmetric hydrogenation of aromatic ketones catalyzed by the TolBINAP/DMAPEN-ruthenium(II) complex: a significant effect of N-substituents of chiral 1,2-diamine ligands on enantioselectivity

Asymmetric hydrogenation of acetophenone in the presence of Ru(II) catalysts coordinated by TolBINAP and a series of chiral 1,2-diamines was studied. The sense and degree of enantioselectivity were highly dependent on the N-substituents of the diamine ligands. The N-substituent effect was discussed in detail. Among these catalysts, the (S)-TolBINAP/(R)-DMAPEN-Ru(II) complex showed the highest enantioselectivity. The mode of enantioface selection was interpreted by using transition state models based on the X-ray structure of the catalyst precursor. The chiral catalyst effected the hydrogenation of alkyl aryl ketones and arylglyoxal dialkyl acetals to afford the chiral alcohol in >99% ee in the best cases. Hydrogenation of racemic benzoin methyl ether with the chiral catalyst through dynamic kinetic resolution gave the anti-alcohol (syn:anti = 3:97) in 98% ee, while the reaction of alpha-amidopropiophenones resulted in the syn-alcohols (syn:anti = 96:4 to >99:1) in >98% ee.     

Designing the "search pathway" in the development of a new class of highly efficient stereoselective hydrosilylation catalysts

The direct coupling of oxazolines and N-heterocyclic carbenes leads to chelating C,N ancillary ligands for asymmetric catalysis that combine both an "anchor" unit and a stereodirecting element. Reacting various N-substituted imidazoles with 2-bromo-4(S)-tert-butyl- and 2-bromo-4(S)-isopropyloxazoline gave the imidazolium precursors of the stereodirecting ancillary ligands. A library of ten different ligand precursors was obtained by using this simple procedure (65-97 % yield). These protioligands were metalated in a subsequent step by reaction with [{Rh(mu-OtBu)(nbd)}2] (nbd=norbornadiene), generated in situ from KOtBu and [{RhCl(nbd)}2] giving the corresponding N-heterocyclic carbene complexes [RhBr(nbd)(oxazolinyl-carbene)] 4 a-j in good yields. X-ray diffraction studies of two of the rhodium complexes, 4 d and 4 j, established a distorted square-pyramidal coordination geometry with the bromo ligand occupying the apical position. The rhodium-carbene bond length was found to be 2.070(4) A (4 d) and 2.012(3) A (4 j). Complexes 4 a-j were treated with AgBF4 in dichloromethane, giving the active cationic square-planar catalysts for the hydrosilylation of ketones. As a reference reaction for the catalyst optimisation, the hydrosilylation of acetophenone with diphenylsilane was studied and the system optimised with respect to the counterion (BF(4) (-)), solvent (THF) and the silane reducing agent (diphenylsilane). The reaction product (1-phenylethanol) was obtained with the highest enantiomeric excess (ee) by carrying out the reaction at -60 degrees C, whilst the enantioselectivity drops upon going both to lower and higher temperatures. The observation that the temperature dependence of the ee values goes through a maximum indicated a change in the rate-determining step as the temperature is varied. The determination of the initial reaction rate in the hydrosilylation of acetophenone upon varying the catalyst (4 d) and substrate concentrations at -55 degrees C established a rate law for the initial conversion which is first-order in both substrates as well as the catalyst (Vi = k[4][PhCOMe][Ph2SiH2]). The catalytic system derived from complex 4 d was found to afford high yields and good enantioselectivities in the reduction of various aryl alkyl ketones (acetophenone: 92 % isolated yield and 90 % ee, 2-naphtyl methyl ketone: 99 % yield, 91 % ee). The selectivity for the reduction of prochiral dialkyl ketones is comparable or even superior to the best previously reported for prochiral nonaromatic ketones; whereas cyclopropyl methyl ketone is hydrosilylated with an enantioselectivity of 81 % ee, the increase of the steric demand of one of the alkyl groups leads to improved ee's, reaching 95 % ee in the case of tert-butyl methyl ketone. Linear chain n-alkyl methyl ketones, which are particularly challenging substrates, are reduced in good asymmetric induction, such as 2-octanone (79 % ee) and even 2-butanone (65 % ee).     

A practical catalytic asymmetric addition of alkyl groups to ketones

Many catalysts will promote the asymmetric addition of alkylzinc reagents to aldehydes. In contrast, there are no reports of additions to ketones that are both general and highly enantioselective. We describe herein a practical catalytic asymmetric addition of ethyl groups to ketones. The catalyst is derived from reaction of camphor sulfonyl chloride and trans-1,2-diaminocyclohexane. The resulting diketone is reduced with NaBH4 to give the C2-symmetric exo diastereomer. Use of this ligand with titanium tetraisopropoxide and dialkylzinc at room temperature results in enantioselective addition of the alkyl group to the ketone. The resulting tertiary alcohols are isolated with high enantiomeric excess (all cases give greater than 87% ee, except one). The reaction has been run with 37 mmol (5 g) 3-methylacetophenone and 2 mol % catalyst to afford 73% yield of the resulting tertiary alcohol with 99% ee.     

Enantioselective Michael addition of alpha-substituted cyanoacetates to vinyl ketones catalyzed by bifunctional organocatalysts

A highly enantioselective Michael addition of alpha-substituted cyanoacetates to vinyl ketones was accomplished in the presence of simple bifunctional thiourea/tertiary amine organocatalysts. A number of alpha-aryl or alkyl cyanoacetates have been successfully applied to give multifunctional compounds with an all-carbon-substituted quaternary stereocenter in excellent enantioselectivities (82-97 % ee) and yields (61-99 %). The optical pure adducts could be smoothly converted to variously structured beta(2,2)-amino acid esters. Moreover, an interesting reaction model involving multiple hydrogen-bonding interactions amongst the thiourea/tertiary amine catalyst and the reactants has been proposed based on the absolute configuration of the adduct and computational studies.     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

Enantioselective synthesis of optically pure β-amino ketones and γ-aryl amines by Rh-catalyzed asymmetric hydrogenation

A series of optically pure β-amino ketones have been synthesized in high enantioselectivities (ee > 99%) by Rh-DuanPhos-catalyzed asymmetric hydrogenation of readily prepared β-keto enamides. Further reduction of these β-amino ketones with hydrogen and Pd/C leads to the formation of a variety of protected enantiomerically pure γ-aryl amines (ee > 99%), which are key building blocks in many bioactive molecules.     

Palladium‐Catalyzed Chemo‐ and Enantioselective C−O Bond Cleavage of α‐Acyloxy Ketones by Hydrogenolysis

A chemoselective C−O bond cleavage of the ester alkyl side‐chain of α‐acyloxy ketones was realized for the first time by a highly efficient palladium‐catalyzed hydrogenolysis (S/C=6000, the highest catalytic efficiency by far). Furthermore, a kinetic resolution of α‐acyloxy ketones was first developed by enantioselective hydrogenolysis with good yields and up to 99 % ee.     

SmI2-promoted Reformatsky-type reaction and acylation of alkyl 1-chlorocyclopropanecarboxylates

In the presence of HMPA in THF, highly stereoselective SmI(2)-promoted substitutions of alkyl 1-chlorocyclopropanecarboxylates 1 using various ketones, aldehydes (Reformatsky-type reaction), and acyl chlorides (acylation) proceeded to give trans-adducts (2 or 5) in good to high yield with excellent trans-stereoselectivity (trans-add/cis-add = > 99/1). The Reformatsky-type reaction of 1 with aldehydes and unsymmetrical ketones proceeded with moderate diastereoselectivity (re-face-adduct/si-face-adduct = 60/40-75/25).     

Evolution of pyrrolidine-type asymmetric organocatalysts by "click" chemistry

Click chemistry has been employed to construct a library of the pyrrolidine-type asymmetric organocatalysts. The clicked organocatalysts were evaluated in asymmetric Michael addition of ketones to nitroolefins, showing good catalytic activity and stereoselectivity (up to 100% yield, syn:anti = 99:1, 96% ee).     

Enantioselective reductions of [m] ferrocenophanones

Enantioselective reductions of prochiral ferrocenophane ketones were investigated. Oxazaborolidine mediated reduction led to corresponding chiral alcohols generally in good yields and enantioselectivities up to 97% ee. Ruthenium-catalyzed transfer hydrogenation was rather unsuccessful in reducing cyclic ferrocene ketones. Proline-derived activator together with trichlorosilane also proved to be an effective method for some substrates (up to 99% ee). Pronounced tendency of α-ferrocenyl ketones toward reductive deoxygenation was studied by DFT computational methods.     

Highly enantioselective direct aldol reaction catalyzed by cinchona derived primary amines

Highly enantioselective aldol reactions of aldehydes with cyclic ketones catalyzed by a primary amine derived from cinchonine are reported. Aromatic aldehydes reacted with various cyclic ketones cleanly to afford the anti-aldol adducts in up to 99% yield, with good diastereoselectivities (up to 9 : 1) and excellent enantioselectivities (up to 99% ee).     

Asymmetric Michael Addition of Ketones to Alkylidene Malonates and Allylidene Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.     

Enantioselective synthesis of 2,2-disubstituted terminal epoxides via catalytic asymmetric Corey-Chaykovsky epoxidation of ketones

Catalytic asymmetric Corey-Chaykovsky epoxidation of various ketones with dimethyloxosulfonium methylide using a heterobimetallic La-Li(3)-BINOL complex (LLB) is described. The reaction proceeded smoothly at room temperature in the presence of achiral phosphine oxide additives, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (97%-91% ee) and yield ( > 99%-88%) from a broad range of methyl ketones with 1-5 mol% catalyst loading. Enantioselectivity was strongly dependent on the steric hindrance, and other ketones, such as ethyl ketones and propyl ketones resulted in slightly lower enantioselectivity (88%-67% ee).     

Investigation into the enantioselection mechanism of ruthenium-arene-diamine transfer hydrogenation catalysts using fluorinated substrates

The effects of both steric and electronic properties of ketones on the selectivity in asymmetric transfer hydrogenation have been studied with aryl alkyl/fluoroalkyl ketones using four ruthenium based catalysts and two different media. The 1-arylethanones, 1-aryl-2-fluoroethanones and 2,2-difluoroacetophenones could be reduced with medium to high ee (86-99%), while the 1-aryl-2,2,2-trifluoroethanones were reduced with low selectivity in most systems. The change in enantioselectivity upon structural variation has been rationalised aided by regression analysis with substituent constants and the partial charge of the carbonyl carbon as predictors. The steric bulk of the alkyl/fluoroalkyl chain was found to be the major factor in determining selectivity in formic acid/triethylamine, while for reduction of a series of substituted 1-arylethanones and 1-aryl-2-fluoroethanones, the selectivity was found to depend on the electronic properties of the aromatic ring, supporting previous evidence that π-π interaction between the substrate and catalyst is important in determining the selectivity. For reductions in water using sodium formate as the hydrogen donor, altered and more complex selectivity mechanisms were observed. Experiments and regression focused on the variation of the alkyl/fluoroalkyl group of phenyl and 1-naphthyl ketones, showed that the selectivity correlated with the size of the substituent, but also the partial charge of the carbonyl carbon.     

Rapid identification of enantioselective ketone reductions using targeted microbial libraries

A collection of about 300 microbes was surveyed for the ability to generate chiral secondary alcohols by enantioselective reduction of a series of alkyl aryl ketones. Microbial cultures demonstrating utility in reducing model ketones were arrayed in multi-well plates and used to rapidly identify specific organisms capable of producing chiral alcohols used as intermediates in the synthesis of several drug candidates. Approximately 60 cultures were shown to selectively reduce various ketones providing both the R and S enantiomers of the corresponding alcohols in 92-99% ee with yields up to 95% at 1-4 g/L. An alternative approach to chiral alcohols based on selective microbial oxidation of racemic alcohols is also reported. This study provides a useful reference for generating chiral alcohols by selective microbial bioconversion.