Diastereospecific oxidation of ferrocenyl aminoalcohols: synthesis of new chiral ligands

Oxidation of 1-[2-(N,N-dimethylaminomethyl)ferrocenyl]ethanol by manganese dioxide proceeds with complete diastereospecificity without any catalyst. New diastereopure and enantiopure ferrocenyl compounds were produced.     

Asymmetric alkylation of carbonyl compounds with lithium or sodium tetraalkylaluminates modified by chiral aminoalcohols

Asymmetric alkylation of benzaldehyde and acetophenone by modified aluminium “ate” complexes are reported. LiAlMe₄, NaAlEt₄, LiAln-Bu₄, NaAln-Bu₄ modified by either (?)-N-methylphedrin or (+)cinchonine or (?)quinine were used.Using hydrocarbon solvents and sometimes under nickel catalysis the treatment of carbonyl compounds by modified “ate· complexes produced chiral alcohols with both chemical and optical good yields. NaAlEt₄ modified by (?)-N-methylephedrin reacted with benzaldehyde to give S(?)1-phenyl-1 propanol in 20% enantiomeric excess. The same reagent reacted with acetophenone to give S(?)2-phenyl-2 butanol in 33% e.e. NaAln-Bu₄ modified by (?)-N-methylephedrin reacted with benzaldehyde to give S(?)1-phenyl-1-pentanol in 27% e.e. or with acetophenone to give (?)2-phenyl-2-hexanol in 44% e.e.Since a wide range of new asymmetric alkylating reagents has been obtained from aluminium “ate” complexes and chiral compounds, it can be assumed that the method described could be useful to synthetise chiral alcohols with high optical yield.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

Chiral aminoalcohols with a menthane skeleton as catalysts for the enantioselective addition of diethylzinc to benzaldehyde

Novel chiral aminoalcohols were synthesized by highly diastereoselective addition of Me₃SiCN and LiCH₂CN to (−)-menthone followed by LiAlH₄ reduction. The addition of CH₂CH-MgBr and PhCHCH-MgBr to menthone and the following epoxidation, provided useful hydroxy epoxides, one of which could be aminolyzed to afford an aminodiol. In one case, the configuration of the newly formed epoxidic stereogenic center was determined by X-ray crystallography. When applied as catalysts in the enantioselective addition of Et₂Zn to benzaldehyde, the aminoalcohols induced enantiomeric excesses (e.e.s) of up to 77%.     

Chiral ligands derived from abrine. Part 5: Substituent effects on asymmetric induction in enantioselective addition of diethylzinc to benzaldehyde catalyzed by chiral oxazolidines possessing an indole moiety

A number of the indole-containing chiral oxazolidines possessing the gem-di-p-tolyl and gem-di-o-tolyl groups at C₅ were synthesized from abrine and the effects of the C₅ and C₂ substituents on the asymmetric induction in catalytic enantioselective addition of diethylzinc to benzaldehyde were examined. A working model is proposed to rationalize the asymmetric catalysis by these chiral oxazolidines.     

Sterically encumbered chiral amino alcohols for the titanium catalyzed asymmetric alkylation of benzaldehyde

Sterically encumbered chiral l-amino alcohols with secondary amines and tertiary alcohols catalyze the enantioselective alkylation of benzaldehyde with diethyl zinc. Using 2 mol % of amino alcohol catalyst predominantly gave (R)-1-phenylpropanol with enantiomeric excesses of up to 61%. Using the in situ prepared titanium complex at 2 mol % as catalyst also favored the (R)-enantiomer with enantiomeric excesses of up to 73%. In almost all cases, the addition catalyzed by the titanium complex exhibited higher enantioselectivity than that of the amino alcohol ligand alone.     

Modular amino alcohol ligands containing bulky alkyl groups as chiral controllers for Et2Zn addition to aldehydes: illustration of a design principle

A new family of enantiomerically pure (1S,2R)-1-alkyl-2-(dialkylamino)-3-(R-oxy)-1-propanols containing a very bulky alkyl substituent (tert-butyl or 1-adamantyl) on their hydrocarbon chains has been synthesized from the corresponding enantiopure epoxy alcohols, arising from the catalytic Sharpless epoxidation, by protection of the primary hydroxy group and subsequent regioselective ring opening of the epoxide by a secondary cyclic amine (C-2 attack). The performance of these amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 92-96% being recorded. The best performing ligands, those with a bulky R-oxy group, also depict a convenient activity and selectivity profile in the addition of Et(2)Zn to a representative family of aldehydes. An anomalous structure/enantioselectivity relationship of some ligands in the tert-butyl series has been studied using PM3 calculations, and conclusions have been drawn on the possible effects of including in modular designs structural fragments giving rise to a variety of rotameric transition states.     

Development of biisoquinoline-based chiral diaminocarbene ligands: enantioselective SN2' allylic alkylation catalyzed by copper-carbene complexes

Chiral biisoquinoline-based diaminocarbene ligands (BIQ) were designed to create a chiral environment extended toward the metal center, which was confirmed by an X-ray structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl-BIQ-copper complex is an efficient catalyst for enantioselective SN2' allylic alkylation with Grignard reagents showing SN2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee.     

Chiral induction by seeding surface assemblies of chiral switches

It is demonstrated by scanning tunneling microscopy that coadsorption of a molecular chiral switch with a complementary, intrinsically chiral induction seed on the Au(111) surface leads to the formation of globally homochiral molecular assemblies.     

Pd-catalyzed asymmetric allylic alkylation of indoles and pyrroles by chiral alkene-phosphine ligands

A variety of chiral binaphthyl-based terminal-alkene-phosphine hybrid ligands were synthesized in four steps with (S)-BINOL as a starting material and utilized for the Pd-catalyzed enantioselective allylic alkylations of indoles and pyrroles to afford the desired products in high yields with good to excellent ee's.     

Synthesis and application of chiral cyclopropane-based ligands in palladium-catalyzed allylic alkylation

A series of chiral, cyclopropane-based phosphorus/sulfur ligands have been synthesized and evaluated in the palladium-catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate with dimethyl malonate. Variation of the ligand substituents at phosphorus, sulfur, and the carbon backbone revealed 24d to have the optimal configuration for this reaction, giving the product in high yield and with good enantioselectivity (93%). A model for the observed enantioselectivity is discussed within the context of existing models, using X-ray crystallographic data, solution-phase NMR studies, and the absolute stereochemistry of the products. Selected ligands were also evaluated in the palladium-catalyzed intermolecular Heck reaction and the rhodium-catalyzed hydrogenation of a dehydroamino acid.     

Application of chiral dipyridylmethane ligands in the enantioselective palladium-catalyzed allylic alkylation

New chiral C₁-symmetric dipyridylmethane ligands have been prepared from naturally occurring monoterpenes according to a method based on two consecutive constructions of the pyridine rings. These ligands have been assessed in the enantioselective palladium catalyzed allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethylmalonate. Enantioselectivity up to 68% ee has been obtained.     

Quinolinophane-derived alkyldiphenylphosphines: two homologous P,N-planar chiral ligands for palladium-catalysed allylic alkylation

Two novel homologous [2]paracyclo[2](5,8)quinolinophane-derived P,N-bidentate planar chiral ligands have been synthesised and their effectiveness in asymmetric catalysis tested in palladium-catalysed allylic malonylation of 1,3-diphenylpropenyl acetate. The extent of asymmetric induction depends linearly on the ligand/metal molar ratio, indicating the involvement of P,P-type and chelate P,N-type π-allylpalladium complexes in equilibrium. The length of the chain that binds the diphenylphosphine group to the quinolinophane moiety, while appreciably affecting the P,N-complex stability, has little effect on the extent of asymmetric induction, which is due to the greater reactivity of the [PN]-exo–syn–syn– ([PN]_xss) with respect to the [PN]-endo–syn–syn– ([PN]_nss) π-allylpalladium complex.     

Synthesis of chiral 2-alkyl-8-quinolinyl-oxazoline ligands: reversal of enantioselectivity in the asymmetric palladium-catalyzed allylic alkylation

New chiral 2-alkyl-8-quinolinyl-oxazolines were synthesized from 2-alkyl-8-quinolinecarboxylic acids and enantiomerically pure amino alcohols using a convenient procedure. Enantioselective palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of 2-alkyl-8-quinolinyl-oxazolines provided an alkylation product with an opposite configuration compared to those obtained from unsubstituted quinolinyl-oxazoline ligands.     

Synthesis of new tridentate chiral aminoalcohols by a multicomponent reaction and their evaluation as ligands for catalytic asymmetric Strecker reaction

A one-step, multicomponent Mannich-type reaction between phenols, paraformaldehyde, and β-aminoalcohols in the presence of LiCl afforded N-2-hydroxybenzyloxazolidines with high ortho-selectivity. Hydrolytic or reductive ring opening of the oxazolidines provided a series of N-salicyl-β-aminoalcohols in 84-92% overall yield. The synthesized compounds were evaluated as ligands for a titanium-catalyzed catalytic asymmetric Strecker reaction. The reaction employing 10 mol % of catalyst provided the Strecker products in excellent yields and up to 98% ee.     

Synthesis of novel chiral oligopyridine derivative ligands for the enantioselective addition of diethylzinc to benzaldehyde

Several chiral dipyridine and dithiophene derived ligands have been prepared from readily available homochiral materials such as ethyl L-lactate and naproxene methyl ester, based on the dialkylation strategy using heterocyclic organometallic reagents. Each of these chiral ligands was used for the catalytic enantioselective addition of diethylzinc to benzaldehyde. The best result was obtained for 3: 70% ee was achieved. A plausible mechanism for this asymmetric induction is offered, based on X-ray crystallographic data.     

3,3'-dipyridyl BINOL ligands. Synthesis and application in enantioselective addition of Et2Zn to aldehydes

3,3'-di(2-pyridyl) BINOLs (4), prepared in three steps from commercial substances by a combined directed ortho metalation-Negishi cross-coupling protocol, constitute new members of the BINOL ligand family. They are among the most selective, general ligands, providing equal or greater stereoselectivities in the Et2Zn addition to benzaldehydes and cinnamaldehydes (Table 3) than any single BINOL ligand reported to date.     

C2-symmetrical bis(camphorsulfonamides) as chiral ligands for enantioselective addition of diethylzinc to benzaldehyde

Purpose of the research was to determine the activity of chiral bis(sulfonamide) ligands derived from camphor in the addition of diethylzinc to benzaldehyde. Chiral bis(ketosulfonamides) and bis(hydroxysulfonamides), have been synthesized in a reaction of diamines with camphorsulfonic acid chloride. Their activity in a reaction of asymmetric addition of dialkylzinc to benzaldehyde in a presence of titanium(IV) tetraisopropoxide was determined. The bis(ketosulfonamide) ligands reveal low enantioselectivity, with the ee% not exceeding 12%. The bis(hydroxysulfonamides) reveal much higher asymmetric induction in the investigated ZnEt₂ addition. The best enantiomeric excess (62%) has been observed for bis(hydroxysulfonamide) obtained from 1,3-diaminepropane. The yields of the reaction obtained after 18 h are 92–96%. Crystal structures have been solved for bis(ketosulfonamide) ligands obtained from diamines based on C₂ to C₄ chain. The (2R) configuration in the rings systems of bis(hydroxysulfonamide) containing the C₃ bridge was also determined by the crystal structure analysis. The sulfonamides have been characterized by IR, ¹H and ¹³C NMR.