Resolution of enantiomers of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid via diastereomeric salt formation with enantiopure 1-phenylethylamines

The resolution of racemic α-hydroxy-H-phosphinic acid with enantiopure 1-phenylethylamines via diastereomeric salt formation was investigated. X-Ray crystallographic analysis of the salt revealed that (R)-1-phenylethylamine to be efficient resolving agent for obtaining a single enantiomer of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid. Resolving racemic α-hydroxy-H-phosphinic acid with (S)-2-phenylethylamine also gave access to (S)-α-hydroxyalkylphosphinic acid in good yield.     

Highly efficient resolutions of 1,4-benzodioxane-2-carboxylic acid with para substituted 1-phenylethylamines

The salts of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid with eight (S)-1-arylethylamines were prepared. The determination of their melting points and of their solubilities in alcohol solvents revealed large differences between the diastereomeric benzodioxanecarboxylates of (S)-1-(p-nitrophenyl)ethylamine and of (S)-1-(p-methylphenyl)ethylamine. Therefore, these latter amines were selected to resolve (±)-1,4-benzodioxane-2-carboxylic acid by diastereoselective crystallization finding that both of them display a very high resolution ability for such a substrate, which contrasts with the null efficiency of unsubstituted 1-phenylethylamine. These results are consistent with DSC evidences, which indicated that the two successfully resolved diastereomeric systems are binary mixtures exhibiting a eutectic with a high content of the more soluble diastereomeric salt. The new procedures can advantageously replace the two resolutions we had previously reported, that of the same acid with dehydroabietylamine and that of glycerol acetonide, a precursor of 1,4-benzodioxane-2-carboxylic acid, with 1-phenylethylamine.     

Solvent-induced dual chirality switching in the optical resolution of tropic acid via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol

Solvent-induced chirality switching in the optical resolution of racemic tropic acid (TA) with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. Recrystallization of the diastereomeric salt mixture from i-PrOH or EtOH afforded the (S)-TA salt, while the (R)-TA salt was deposited from 1,4-dioxane and water-enriched alcohol solutions. Dual chirality switching was achieved by using two different types of solvents. The X-ray crystal structures of both diastereomeric salts showed that incorporation of the crystallization solvent played a crucial role in stabilizing each diastereomeric salt crystal. The mechanism of chirality switching has been discussed on the basis of the relative stability of the salt, as deduced from their structures.     

Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2‐Methoxy‐2‐naphthylpropanoic Acids

The crystal structures of salt 8 , which was prepared from (R)‐2‐methoxy‐2‐(2‐naphthyl)propanoic acid ((R)‐MβNP acid, (R)‐ 2 ) and (R)‐1‐phenylethylamine ((R)‐PEA, (R)‐ 6 ), and salt 9 , which was prepared from (R)‐2‐methoxy‐2‐(1‐naphthyl)propanoic acid ((R)‐MαNP acid, (R)‐ 1 ) and (R)‐1‐(p‐tolyl)ethylamine ((R)‐TEA, (R)‐ 7 ), were determined by X‐ray crystallography. The MβNP and MαNP anions formed ion‐pairs with the PEA and TEA cations, respectively, through a methoxy‐group‐assisted salt bridge and aromatic CH???π interactions. The networks of salt bridges formed 2₁ columns in both salts. Finally, (S)‐(2E,6E)‐(1‐²H₁)farnesol ((S)‐ 13 ) was prepared from the reaction of (2E,6E)‐farnesal ( 11 ) with deuterated (R)‐BINAL‐H (i.e., (R)‐BINAL‐D). The enantiomeric excess of compound (S)‐ 13 was determined by NMR analysis of (S)‐MαNP ester 14 . The solution‐state structures of MαNP esters that were prepared from primary alcohols were also elucidated.     

Solvent-induced chirality switching in the enantioseparation of regioisomeric hydroxyphenylpropionic acids via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol

The enantioseparation of three hydroxyphenylpropionic acid isomers via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. The racemates of all three acid isomers were successfully separated with high efficiency (0.56–0.84) after single crystallization. For 2-hydroxy-3-phenylpropionic acid 4, the configuration of the less-soluble salt was controlled by the crystallization solvent: the (R)-4 salt was crystallized from water, while 2-propanol afforded the (S)-4 salt. The chiral recognition mechanism of the three acids was discussed based on the crystal structures of the diastereomeric salts.     

Preparation of single-enantiomer semiochemicals using 2-methoxy-2-(1-naphthyl)propionic acid and 2-methoxy-2-(9-phenanthryl)propionic acid

Enantioresolution of 3-octanol, 6-methyl-5-hepten-2-ol (sulcatol), and 1-octen-3-ol was conducted using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) and (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid (M9PP acid). In each case, the diastereomeric esters obtained were readily separated by HPLC. The stereochemistry of the esters could be assigned from their respective ¹H NMR analyses. Solvolyses of the esters gave enantiopure alcohols and acids. MαNP and M9PP acids displayed almost equivalent properties in ¹H NMR anisotropy. The chiral resolving ability of M9PP acid was slightly superior to that of MαNP acid in HPLC.     

Resolution of 1-cyclohexylethylamine via diastereomeric salt formation with enantiopure 2-phenylacetic acids

The resolution of 1-cyclohexylethylamine 1 with enantiopure 2-phenylacetic acids via diastereomeric salt formation was investigated. (R)-2-Methoxy-2-phenylacetic acid 3 and the (S)-2-phenylpropionic acid 5 were found to be efficient resolving agents for obtaining the single enantiomer (S)-1 as the correspondingly less-soluble diastereomeric salt (resolution efficiency = 48% and 52%, respectively).     

A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations. Part 1. Application of the MαNP acid method to acetylene alcohols

A method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid 1 (MαNP acid) has been applied to acetylene alcohols 4–14 to determine their absolute configurations by ¹H NMR anisotropy and/or X-ray crystallography. Diastereomeric MαNP esters prepared from racemic acetylene alcohols and (S)-(+)-MαNP acid 1 were easily separable by HPLC on silica gel. From the ¹H NMR anisotropy Δδ data of separated diastereomeric MαNP esters {Δδ = δ (R,X) − δ(S,X) = δ(2nd fr.) − δ(1st fr.)}, the absolute configurations of the first eluted esters were determined. This MαNP acid method has been successfully applied to various acetylene alcohols 4–12 and 14. In the case of MαNP esters 21b, 24a, and 26a, their absolute configurations were unambiguously determined by X-ray crystallography, which confirmed the absolute configuration assignments performed by ¹H NMR anisotropy. These acetylene alcohol MαNP esters can serve as key intermediates for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations as described in Part 2 of this series.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Solvent dependency though not solvate formation in the derivative–derivative resolution of N-formylphenylalanine

The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate formation did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications.The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzylaminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-equivalent achiral basic reagent in a Pope–Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Stereodivergent synthesis of novel chiral C2-symmetric bis-trifluoromethyl-2-oxazolidinones

A simplified effective synthetic process is described for the diastereoselective synthesis of the chiral C₂-symmetric CF₃-ureas (R,R)-15 and (S,S)-15 from (S)-α-phenylethylamine, glyoxal and CF₃I.     

Prostaglandin chemistry—V : Synthesis of new prostaglandin synthons; 4(R)-(+)- and 4(S)-(−)-t-butyldimethylsiloxycyclopent-2-en-1-one

Optically active prostaglandin intermediates, 4(R)-(+)- and 4(S)-(?)-hydroxycyclopent-2-en-1-one derivatives, were synthesized from 3(R),5(R)-diacetoxycyclopent-1-ene, 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene and 3(S),5(S)-dihydroxycyclopent-1-ene obtained by microbiological hydrolysis of 3,5-diacetoxycyclopent-1-ene. The absolute configurations of all these compounds were determined by the exciton chirality method and the induced CD method. The optical purities were determined by NMR measurements of the diastereomeric esters of a versatile optically pure acid, (+)-α-methoxy-α-trifluoromethylphenylacetic acid.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

Optimization of 2-alkoxyacetates as acylating agent for enzymatic kinetic resolution of chiral amines

In this study, the activity of acetic acid esters modified with electron withdrawing 2-alkoxy-groups was investigated as acylating agent in kinetic resolution (KR) of racemic amines. A homologous series of the isopropyl esters of four 2-alkoxyacetic acids (2-methoxy-, 2-ethoxy-, 2-propoxy- and 2-butoxyacetic acids) were prepared and investigated for enantiomer selective N-acylation, catalyzed by lipase B from Candida antarctica, under batch and continuous-flow conditions. In the first set of experiments, isopropyl 2-propoxyacetate showed the highest effectivity with all of the four racemic amines [(±)-1-phenylethylamine, (±)-4-phenylbutan-2-amine, (±)-heptan-2-amine and (±)-1-methoxypropane-2-amine] in the set enabling excellent conversions (≥46%) and enantiomeric excess values (ee?≥?99%) with each amines in continuous-flow mode KRs under the optimized reaction conditions. In a second set of experiments, KRs of five additional amines – being substituted derivatives of (±)-1-phenylethylamine – further demonstrated the usefulness of isopropyl 2-propoxyacetate – being the best acylating agent in the first set of KRs – in KRs leading to (R)-N-propoxyacetamides with high ee values (≥99.8%).     

Asymmetric Strecker synthesis of enantiopure 2,4-ethanothreonines

The second generation asymmetric synthesis reported herein proceeds via a Strecker reaction of chiral ketimines, obtained from the condensation of racemic 2-methoxycyclopentanone and (S)- and (R)-1-phenylethylamine. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric nitriles, the composition of which dramatically changes under the influence of protic and aprotic solvents. Hydrolysis of the nitriles to carboxamides with concd H₂SO₄ yielded diastereomeric mixtures of carboxamides each of which was hydrogenolysed and hydrolysed after separation to the four stereoisomers of the 1-amino-2-methoxy- and 1-amino-2-hydroxy-cyclopentanecarboxylic acid. Their stereochemistry was established by NMR methods and by X-ray analyses of the trans as well as the cis configured compounds.     

Resolution of racemic cis-1-amino-2-indanol by diastereomeric salt formation with (S)-2-phenylpropionic acid

Resolution of racemic cis-1-amino-2-indanol 1, a key intermediate for the synthesis of indinavir, is reported. The conditions were optimized for an industrial-scale resolution of racemic cis-1 using (S)-2-phenylpropionic acid 6 as the resolving agent and ethanol as the solvent. The less-soluble diastereomeric salt, (1R,2S)-1·(S)-6, was obtained in 35% yield with 99% de (E >69%) by crystallization. Resolving agent 6 was efficiently recovered from the salt and the mother liquor.     

Asymmetrical nonbridgehead nitrogen-XXVI: Synthesis,configurational stability,and resolution of N,N-dialkoxyamines into antipodes

Alkoxyamines with tertiary N-alkyl substituents were chlorinated to N-chloro-N-alkoxyamines whose reaction with alcohols enabled synthesis of N,N-dialkoxyamines. The DNMR method was used to determine the barriers of inversion of these compounds. Alkaline hydrolysis (13) followed by subsequent reactions with R-(+)- and S-(?)-α-phenylethylamine yielded diastereomeric salts (+29 and ?29) whose crystallization and subsequent esterification resulted in optically active acyclic amines (?13 and +13) with the asymmetric center only at the N atom in the open chain.     

Single-crystal-to-single-crystal photocyclization of 4-(2,4,6-triisopropylbenzoyl)benzoic acid in the salt crystal with (S)-phenylethylamine

Ultraviolet irradiation of a salt crystal of 4-(2,4,6-triisopropylbenzoyl)benzoic acid with (S)-phenylethylamine promoted single-crystal-to-single-crystal photocyclization to give an enantiopure (R,R)-cyclopentenol and almost racemic cyclobutenol. The reaction paths were elucidated by X-ray crystallographic analysis of the crystal before and after irradiation.     

Efficient synthesis of optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative

An efficient synthesis and resolution of (±)-1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid has been developed for the preparation of novel optically active atropisomers. The ee values were measured by a ¹H NMR spectroscopic method using quinidine as the chiral complexing agent. Absolute configurations of the separated enantiomers were determined using single crystal X-ray diffraction measurements of both the disodium salt and the (R)-1-phenylethylamine salt of the enantiomerically pure dicarboxylic acid, separately. The analysis of the CD spectra with the aid of TD-DFT quantum chemical calculations confirmed the assignment of configurations.