Asymmetric Reduction Using Lithium Aluminum Hydride Modified with Chiral Ligand Prepared from (1R)-(-)-Myrtenol

The reduction of prochiral ketones with a chiral reducing reagent, prepared from lithium aluminum hydride and (1R,2S,3S,5R)-(-)-10-methoxypinanediol (2), produced secondary chiral alcohols in good chemical yields (57–98%) and moderate enantiomeric excess (8–72%).     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

Synthesis of orthogonally protected (R)- and (S)-2-methylcysteine via an enzymatic desymmeterization and Curtius rearrangement

A synthesis of differentially protected (R)- and (S)-2-methylcysteines is described. Monomethylation of dimethylmalonate followed by alkylation with tert-butylchloromethyl sulfide gave an achiral diester. Desymmeterization by selective hydrolysis of one ester with pig-liver esterase gave the acid in 97% chemical yield and 91% enantiomeric excess. Heating this acid with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol gave protected (R)-2-methylcysteine. Alternately, the acid and ester groups were interchanged and heated with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol, giving protected (S)-2-methylcysteine.     

Enzyme-catalysed improved resolution of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol

Resolutions of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity (E=13) and reacted faster with the (S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the (R)-enantiomer was 99, 99 and 98% at 52–60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol (R)-1 was up to 99% at 70% conversion without additives.     

Catalytic asymmetric synthesis of Secondary (E)-allyl alcohols from acetylenes and aldehydes via (1-alkenyl)zinc intermediates. Preliminary Communication

Hydroboration of aliphatic 1-alkynes with freshly prepared dicyclohexylborane (1 mol-equiv., hexane), treatment of the resulting [(E)-1-alkenyl]boranes 5 with Et₂Zn or Me₂Zn (1.05 mol-equiv.) followed by addition of (?)-3-exo-(dimethylamino)isoborneol (DAIB, 8 ; 0.01 mol-equiv.), subsequent addition of a solution of an aromatic or aliphatic aldehyde (1 mol-equiv., hexane), and quenching with aq. NH₄Cl provided (E)-allyl alcohols 6 usually in 70–95% yield with 79–98% enantiomeric excess (Scheme 3 and Table).     

First enantioselective synthesis of a 1-(trimethylsilyl)alkylamine

Reduction of n-propanoyltrimethylsilane NH-imine with the complex hydride LiBH₄/diethyltartrate in THF yielding enantiomerically enriched 1-(trimethylsilyl)butylamine with a 60% enantiomeric excess is the first example of the enantioselective synthesis of such an amine. Other combinations of solvent (ether or THF), hydride (NaBH₄ or LiAlH₄) and chiral inductor (mono- or diol) failed.     

Asymmetric synthesis and retroracemisation of amino acids via copper(II) complexes with schiff bases between chiral 1-(N,N-dimethylaminomethyl)-2-formylcymantrene and dipeptides

1-(N,N-Dimethylaminomethyl)-2-formylcymantrene (AFCMT) has been resolved into enantiomers through an intermediate formation of diastereomeric complexes with (S)-Ala-(S)-Ala, (S)-Ala-Gly and Gly-(S)-Ala. By the X-ray anomalous dispersion method the absolute configuration of its enantiomers has been determined: (-)₄₃₆ AFCMT-(S), (+)₄₃₆ AFCMT-(R).Alkylation of enantiomeric complexes (R)-and (S)-AFCMT-(GlyGly) Cu(II) with acetaldehyde gives, respectively, (R)-and (S)-Thr with an asymmetric yield of 92–98% and (R)- and (S)-allo-Thr with an asymmetric yield of 95–100%, only the N-terminal glycine being alkylated.The AFCMT enantiomers were also employed for retroracemisation of (R,S)-Ala-(R,S)-Nva; in this case an excess of (S)-Ala and (R)-Nva is obtained for (S)-AFCMT. (R)- and (S)-AFCMT are not liable to racemisation in the course of the threonine synthesis and retroracemisation of depeptides and can be repeatedly employed for these transformations.     

Resolution of (RS)-2-phenylpropanoic acid by enantioselective esterification with dry microbial cells in organic solvent

The microbial direct esterification of racemic 2-phenyl-1-propanoic acid with ethanol by lyophilized mycelium of Aspergillus oryzae MIM and Rhizopus oryzae CBS 112.07 in organic solvents has been investigated. Dry cells of Rhizopus oryzae CBS 112.07 gave the (R)-ethyl ester with high enantiomeric excess (>97%) when the biotransformation was carried out in heptane or pentadecane. Dry mycelium of Aspergillus oryzae MIM furnished the ethyl ester of (S)-(+)-2-phenylpropanoic acid with 90% enantiomeric excess when used in toluene in a temperature range of 20–40°C.     

Highly enantioselective Henry reaction catalyzed by a new chiral C2-symmetric N,N′-bis(isobornyl)ethylenediamine–copper complex

A new chiral C₂-symmetric N,N′-bis(isobornyl)ethylenediamine–copper complex is found to be an efficient catalyst in the enantioselective Henry reaction between nitromethane and various aldehydes to provide β-hydroxy nitroalkanes with high chemical yield (up to 95%) and high enantiomeric excess (up to 90%).     

The role of the planar chirality of iron tricarbonyl substituted homochiral amino alcohols in the asymmetric alkylation of aldehydes with diethylzinc

Homochiral amino alcohols bearing an iron tricarbonyl moiety were prepared from 2-amino-1,1-diphenylethanol derivatives 4a–d and [(3S,4S)-η^4,7-octa-4,6-dien-3-ol]Fe(CO)₃ complex 2. The addition of diethylzinc to aldehydes bearing electron donating substituents in the presence of these chiral ligands gave the alkylated products in good enantiomeric excess (up to 93% e.e.), whereas the addition to aldehydes bearing electron withdrawing substituents resulted in low yields and poor enantiomeric excesses.     

Synthesis of novel chiral Schiff-base ligands and their application in asymmetric nitro aldol (Henry) reaction

Chiral Schiff-bases prepared from chiral amino alcohols catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and p-nitrobenzaldehyde in the presence of Cu(OTf)₂ and Zn(OTf)₂. Zn(OTf)₂ promoted the reaction yield, while Cu(OTf)₂ promoted the enantiomeric excess. The highest enantioselectivities were observed with ligand 3 (44% ee) and ligand 5 (47% ee).     

A new titanate/(+)-(1R,2S)-cis-1-amino-2-indanol system for the asymmetric synthesis of (S)-tenatoprazole

Tenatoprazole, a substituted imidazopyridinyl derivative, is an irreversible proton pump inhibitor (PPI), which is used for the prevention and treatment of gastric acid-related diseases. A new highly efficient asymmetric oxidation using cumene hydroperoxide (CHP) as the oxidant in the presence of titanium tetraisopropoxide (Ti(OiPr)₄) and (+)-(1R,2S)-cis-1-amino-2-indanol, in a polar aprotic solvent at 0-20 °C, has been developed to prepare tenatoprazole with an enantiomeric excess of >99%, a chemoselectivity of >90% and a chemical yield of >90% from the corresponding sulfide. This procedure was successfully implemented on scales ranging from 100 mg to multiple kilograms. Detailed studies of the parameters controlling purity and yield for this reaction are presented.     

Intramolecular hydroamination/cyclization of aminoalkenes catalyzed by diamidobinaphthyl magnesium- and zinc-complexes

Reaction of 2 equiv of n-Bu₂Mg and Et₂Zn with the chiral l-proline-derived axial chiral tetraamines (S,S,S)-1 and (R,S,S)-1 gave the chiral bimetallic complexes [M₂{(S,S,S)-DABN(MeProline)₂}{R}₂] (M=Mg, R=n-Bu ((S,S,S)-2); M=Zn, R=Et ((S,S,S)-3)) and [M₂{(R,S,S)-DABN(MeProline)₂}{R}₂] (M=Mg, R=n-Bu ((R,S,S)-2)); M=Zn, R=Et ((R,S,S)-3)). The magnesium complexes showed moderate to high catalytic activity in the intramolecular hydroamination/cyclization of aminoalkenes, though enantiomeric excess was limited to 14% ee due to protolytic ligand exchange processes. The zinc complexes were less reactive and generally required higher reaction temperatures of 60-100 °C, but achieved slightly higher enantiomeric excess of up to 29% ee.     

Transformation of l-phenylalanine to (S)-indoline-2-carboxylic acid without group-protection

(S)-Indoline-2-carboxylic acid was synthesized by use of a nitro amination approach with l-phenylalanine as chiral pool. The first step of the synthesis was nitration of l-phenylalanine, with urea nitrate (UN)/H₂SO₄ as nitrating reagent, to give 2,4-dinitro-l-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 % yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-l-phenylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than 99.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations and gave the title compound in 42 % yield and more than 99.5 % ee.     

Lipase catalyzed acylation of primary alcohols with remotely located stereogenic centres: the resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol

Enantioselective acylation of some (±)-3-alkyl-3-phenyl-1-propanols was performed with enzymes as catalysts. Moderate enantiomeric ratios (E), ranging up to E = 11.6, were obtained. In the resolution, some of the lipases selectively acylated the (+)-enantiomer while others acylated the (−)-enantiomer of the γ-substituted primary alcohols 1–4. Thus, it is possible to obtain both enantiomers of the alcohols as remaining substrate with high enantiomeric purity. The resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol 4 was extensively studied and screening experiments were conducted to select suitable lipase(s), reaction medium, acyl donor and appropriate temperature combinations to increase the enantiomeric ratio. Chirazyme^® L-6/chloroform/vinyl propionate/38 °C and Chirazyme^® L-7/di-iso-propyl ether/vinyl propionate/0 °C were chosen to obtain both enantiomers, (R)-(+)-4 and (S)-(−)-4, respectively, via sequential resolutions in excellent enantiomeric excess (>98%) and in 25% and 22% yield, respectively.     

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: a key intermediate for the preparation of SIB-1508Y

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular hydroboration–cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the commercially available 5-bromo-3-pyridinecarboxylic acid.     

The thermodynamic parameters of sorption and enantioselectivity of the chiral smectic liquid crystal 2-methylbutyl ester of 4-(4-decyloxybenzylideneamino)-cinnamic acid

The thermodynamic characteristics of sorption of n-alkanes, arenes, aldehydes, monoatomic alcohols, and optical isomers of camphene and butanediol-2,3 by a chiral smectic liquid crystal, 2-methylbutyl ester of 4-(4-decyloxybenzylideneamino)-cinnamic acid, from the gas phase were studied over the temperature range including the S*_C and S*_A mesophases and isotropic phase. The standard and excess thermodynamic functions of sorption were determined for 26 sorbates of the classes of substances specified. The S*_C and S*_A mesophases exhibited selectivity with respect to the separation of para and meta xylenes (α _p/m = 1.06–1.07, 90–108°C) and pronounced enantioselectivity (α_R/S = 1.05–1.09, 87–108°C). The helically twisted structure of the smectic liquid crystal was shown to play an important role in the mechanism of the chiral recognition of optical isomers of polar and low-polarity compounds under gas-liquid chromatography conditions.     

Enantio- and diastereoselective construction of vicinal quaternary and tertiary carbon centers by catalytic Michael reaction of α-substituted β-keto esters to cyclic enones

A catalytic enantio- and diastereoselective Michael reaction was achieved to construct vicinal quaternary and tertiary carbon centers in one step. Using 5 mol % of La(O-i-Pr)₃ and 10 mol % of a new N-linked-BINOL type ligand, the reaction of α-substituted β-keto esters to cyclic enones provided the corresponding Michael adducts in up to quantitative yield with a diastereomeric ratio up to 86/14 and enantiomeric excess up to 86% for the major isomer. An alternative catalyst preparation method using La(OTf)₃ instead of La(O-i-Pr)₃ was also examined.     

Enantioselective Reduction of Prochiral Ketones Using a Reagent Prepared from Lithium Aluminium Hydride, (+)Threo-1,16-Dibenzyloxy, 7(R),8(R)-Dihydroxy Hexadecane and Alcohol

Asymmetric reduction of prochiral ketones to optically active chiral secondary alcohols was achieved using a reagent prepared by modifying lithium aluminium hydride with a chiral auxiliary, (+)threo-1,16-dibenzyloxy,7,8-dihydroxy hexadecane and various additive alcohols. (+)threo-1,16-dibenzyloxy,7(R),8(R)-dihydroxy hexadecane was prepared from (+)threo-9(R),10(R),16-trihydroxy hexadecanoic acid. Alcohols such as CH₃(CH₂)_n-OH of different chain length (n = 0–11) and (R)-hydnocarpic alcohol were used. Complex prepared from (+)threo-1,16-dibenzyloxy,7(R),8(R)-dihydroxy hexadecane, LAH and (R)-hydnocarpic alcohol reduced acetophenone in moderate enantioselectivity (maximum of 70% ee). Various arylalkylketones were reduced with the same complex.     

Transformation of organic compounds in the presence of metal complexes: II. Reduction of alkyl-substituted cyclohexanones via hydrogen-transfer reactions catalysed by rhodium(I) complexes

Catalyst systems prepared in situ from bidentate phosphines (Ph₂P(CH₂)_nPPh₂, where n = 1–4) and from [Rh(COD)Cl]₂ proved to be active in the transfer hydrogenation of alkylcyclohexanones (alkyl = 2-Me, 4-Me, 4-t-Bu, cis-2,6-Me₂). With the exception of 4-methylcyclohexanone, which gave a cis/trans-cyclohexanol ratio of ～ 1, mainly cis alcohols were formed, their amounts increasing in proportion to the value of n. No reduction occurred in the case of 2-t-butyl- and 2,6-di-t-butyl-cyclohexanones.