MalphaNP acid, a powerful chiral molecular tool for preparation of enantiopure alcohols by resolution and determination of their absolute configurations by the (1)H NMR anisotropy method

A novel methodology using a chiral molecular tool of MalphaNP acid (1), 2-methoxy-2-(1-naphthyl)propionic acid, useful for preparation of enantiopure secondary alcohols and determination of their absolute configurations by the (1)H NMR anisotropy method was developed; racemic MalphaNP acid (1) was enantioresolved with (-)-menthol, and the enantiopure MalphaNP acid (S)-(+)-(1) obtained was allowed to react with racemic alcohol, yielding a mixture of diastereomeric esters, which was clearly separated by HPLC on silica gel. By applying the sector rule of (1)H NMR anisotropy effect, the absolute configuration of the first-eluted MalphaNP ester was unambiguously determined. Solvolysis or reduction of the first-eluted MalphaNP esters yielded enantiopure alcohols.     

New route to enantiopure MalphaNP acid, a powerful resolution and chiral 1H NMR anisotropy reagent

MalphaNP acid (+/-)-1, 2-methoxy-2-(1-naphthyl)propionic acid, was enantioresolved by the use of phenylalaninol (S)-(-)-4; a diastereomeric mixture of amides formed from acid (+/-)-1 and amine (S)-(-)-4 was easily separated by fractional recrystallization and/or HPLC on silica gel, yielding amides (R;S)-(-)-5a and (S;S)-(+)-5b. Their absolute configurations were determined by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-(-)-5a was converted to oxazoline (R;S)-(+)-8a, from which enantiopure MalphaNP acid (R)-(-)-1 was recovered. In a similar way, enantiopure MalphaNP acid (S)-(+)-1 was obtained from amide (S;S)-(+)-5b. These reactions provide a new route for the large-scale preparation of enantiopure MalphaNP acid, a powerful chiral reagent for the enantioresolution of alcohols and simultaneous determination of their absolute configurations by (1)H NMR anisotropy.     

Practical enantioresolution of alcohols with 2-methoxy-2-(1-naphthyl)propionic acid and determination of their absolute configurations by the (1)H NMR anisotropy method.

The enantioresolution of racemic alcohols as esters of 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1) and the determination of their absolute configurations on the basis of (1)H NMR anisotropy effect are described. The enantiopure MalphaNP acid (S)-(+)-1 was allowed to react with racemic 2-alkanols and 1-octyn-3-ol, yielding diastereomeric mixtures of esters, which were easily separated by HPLC on silica gel. To determine the absolute configurations of the first-eluted diastereomeric esters by the (1)H NMR anisotropy method, the general scheme was proposed. Separated esters were reduced with LiAlH(4) or hydrolyzed with KOH/EtOH to recover enantiopure alcohols.     

Preparation of single-enantiomer biofunctional molecules with (S)-2-methoxy-2-(1-naphthyl)propanoic acid

(RS)-beta-Ionol and (RS)-2-methyl-4-octanol were resolved by using (S)-2-methoxy-2-(1-naphthyl)propanoic acid [(S)-MalphaNP acid]. The specific stereochemistry of each MalphaNP ester was elucidated by 2D NMR analyses, and shielding by the 1-naphthyl group was observed in both the 1H- and 13C-NMR spectra. Solvolysis of the individual (S)-MalphaNP esters gave four single-enantiomer alcohols. The normal-phase HPLC elution order of each MalphaNP ester is also discussed.     

Preparation of enantiopure Wieland-Miescher ketone and derivatives by the MalphaNP acid method: substituent effect on the HPLC separation

Enantiopure Wieland-Miescher ketone (4, W-M ketone) and derivatives were prepared by the enantioresolution with 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1). Various racemic derivatives of 4 were esterified with acid (S)-(+)-1 yielding diastereomeric MalphaNP esters, which were separated by HPLC on silica gel. It was clarified that the HPLC separation of diastereomers depended on the substituent of the derivatives, leading to the working hypothesis that MalphaNP acid esters of alcohols with less polar and more bulky aliphatic substituents are more effectively separated. The best separation was obtained in the case of tert-butyldimethylsilyl (TBDMS) ether derivative (12a/12b): separation factor alpha=1.80, and resolution factor, Rs=1.30. The (1)H NMR spectra of separated MalphaNP esters showed anomalously large magnetic anisotropy effects, from which their absolute configurations were determined. Solvolysis or reduction of the separated MalphaNP esters yielded alcohols, which were converted to enantiopure W-M ketones 4. The results thus provided another route for preparation of enantiopure ketones (8aR)-(-)-4 and (8aS)-(+)-4.     

Synthesis of enantiopure phthalides including 3-butylphthalide, a fragrance component of celery oil, and determination of their absolute configurations

Enantiopure phthalides 2 and 5-8 were synthesized via enantioresolution of the corresponding alcohols with a chiral auxiliary of camphorsultam dichlorophthalic acid, (1S,2R,4R)-(-)-CSDP acid 3, followed by solvolysis with KOH in MeOH and the catalytic oxidation of chiral glycols with iridium complex 28. The absolute configurations of phthalides 2 and 5-8 were determined by applying the (1)H-NMR anisotropy method of MalphaNP acid (4), 2-methoxy-2-(1-naphthyl)propionic acid, to the chiral synthetic precursory alcohols. In the case of 3-phenylphthalide (R)-(-)-7, the absolute configuration determined by the (1)H-NMR anisotropy method using MalphaNP acid 4 agreed with that by the X-ray crystallographic method. By applying these methods, 3-butylphthalide (S)-(-)-2, a fragrance component of essential oil of celery, has been synthesized in an enantiopure form, and its absolute configuration was unambiguously determined.     

Enantioresolution of fluorinated diphenylmethanols and determination of their absolute configurations by X-Ray crystallographic and 1H NMR anisotropy methods

Various fluorinated diphenylmethanols were enantioresolved by the methods of chiral camphorsultam-dichlorophthalic acid (CSDP acid) and/or 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of CSDP esters and/or by the (1)H NMR anisotropy method of MalphaNP esters for the first time.     

Absolute configuration of the thyroid hormone analog KAT-2003 as determined by the 1H NMR anisotropy method with a novel chiral auxiliary, MalphaNP acid

The absolute configuration of the chiral thyroid hormone analog KAT-2003 (+)-2, showing hypocholesterolemic activities, decreases of hepatic triglyceride contents with lowering cardiac side effects, and significant inhibitory effect for the second primary hepatocellular carcinoma, was determined as S by the (1)H NMR anisotropy method using a novel chiral auxiliary, 2-methoxy-2-(1-naphtyl)propionic acid (MalphaNP acid).     

Investigations of molecular recognition aspects related to the enantiomer separation of 2-methoxy-2-(1-naphthyl)propionic acid using quinine carbamate as chiral selector: An NMR and FT-IR spectroscopic as well as X-ray crystallographic study

The chiral recognition mechanism of a cinchona alkaloid-based chiral stationary phase (CSP) showing high enantiomer discrimination potential for 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) was investigated. Conformational and structural analyses of the 1:1 complexes of 9-O-(tert-butylcarbamoyl) quinine selector (SO) and MalphaNP acid (selectand, SA) were carried out employing NMR spectroscopy in solution, Fourier-transform infrared (FT-IR) spectroscopy, and solid-state X-ray diffraction analysis. Intramolecular NOEs of a soluble analogue of the CSP afforded the conformational states of the free and complexed form of the selector. The (1)H-NMR spectra revealed that the free form of the SO constitutes anti-open as well as anti-closed and/or syn-closed conformers. Upon complexation with the (S)-MalphaNP acid enantiomer to form the more stable diastereomeric associate, a conformational transition of the selector takes place, resulting in the synthesis of the anti-open conformer nearly exclusively. FT-IR spectra reveal that, besides the primary ion-pairing interaction, stereoselective hydrogen bonding stabilizes the more stable complex via the amide hydrogen of the SO. X-ray diffraction analysis of 9-O-(tert-butylcarbamoyl)quinine and (S)-MalphaNP acid complex further revealed the occurrence of a bidentate H-bond-mediated ionic interaction between SO and SA as well as the lack of pi-pi interaction in the 1:1 complex, and corroborated the conclusions derived from spectroscopic and chromatographic studies.     

Synthesis of enantiopure 2-aryl-2-methoxypropionic acids and determination of their absolute configurations by X-ray crystallography

Racemic 2-aryl-2-methoxypropionic acids were enantioresolved by the use of (S)-(-)-phenylalaninol 4. For instance, racemic 2-methoxy-2-phenylpropionic acid (+/-)-7 was condensed with phenylalaninol (S)-(-)-4 yielding a diastereomeric mixture of amides, which was easily separated by HPLC on silica gel affording the first-eluted amide (-)-13a and the second-eluted amide (+)-13b: alpha = 3.19, Rs = 3.49. The absolute configuration of amide (-)-13a was determined to be (R;S) by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-(-)-13a was converted to oxazoline (R;S)-(-)-14a, from which enantiopure 2-methoxy-2-phenylpropionic acid (R)-(-)-7 was recovered. Other 2-aryl-2-methoxypropionic acids, (R)-(-)-8, (R)-(-)-9, (R)-(+)-10, (R)-(-)-11, and (R)-(-)-12, were similarly prepared in enantiopure forms with the use of phenylalaninol (S)-(-)-4, and their absolute configurations were clearly determined by X-ray crystallography or by chemical correlation.     

Facile synthetic route to enantiopure unsymmetric cis-2,5-disubstituted pyrrolidines

The (+/-)-cis-5-arylcarbamoyl-2-ethoxycarbonylpyrrolidines 6a-g were firstly synthesized in 53-64% yields by using meso-diethyl-2,5-dibromoadipate 3 and (S)-(-)-1-phenylethylamine in three steps. The diastereomeric mixture (S;2S,5R)-(-)-7 and (S;2R,5S)-(+)-8 were prepared by the Grignard reaction and separated by a flash column chromatography in 29 and 52% yields. The absolute configurations of (+)-8 was confirmed by X-ray crystallographic analysis and the enantiopure pyrrolidines (2S,5R)-(-)-9/(2R,5S)-(+)-9 and (2S,5R)-(-)-10/(2R,5S)-(+)-10 were obtained in good yields.     

Stereochemical studies of chiral resolving agents, M9PP and H9PP acids

The stereoselective Grignard reaction of (1R,2S,5R)-(-)-2-isopropyl-5-methylcyclohexyl pyruvate (menthyl pyruvate) with 9-phenanthrylmagnesium bromide yielded diastereomeric hydroxy-esters, where intramolecular OH em leader O=C hydrogen bond was observed in IR and (1)H NMR spectra. The alkaline hydrolysis of the major product gave (+)-2-hydroxy-2-(9-phenanthryl)propionic acid (H9PP acid (3)), whose absolute configuration was assigned as S based on the chemical correlation with (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl ester of (S)-2-methoxy-2-(9-phenanthryl)propionic acid (M9PP acid (2)); the absolute configuration of 2 had been previously established by X-ray crystallography. The enantioresolution of (+/-)-6-methyl-5-hepten-2-ol, sulcatol, an insect pheromone, was carried out using (S)-(+)-M9PP acid 2.     

Determination of absolute configurations by X-ray crystallography and 1H NMR anisotropy

To determine the absolute configurations of chiral compounds, many spectroscopic and diffraction methods have been developed. Among them, X-ray crystallographic Bijvoet method, CD exciton chirality method, and the combination of vibrational circular dichroism and quantum mechanical calculations are of nonempirical nature. On the other hand, X-ray crystallography using a chiral internal reference, and 1H NMR spectroscopy using chiral anisotropy reagents are relative and/or empirical methods. In addition to absolute configurational determinations, preparations of enantiopure compounds are strongly desired. As chiral reagents useful for both the preparation of enantiopure compounds by HPLC separation and the simultaneous determination of their absolute configurations, we have developed camphorsultam dichlorophthalic acid (CSDP acid) for X-ray crystallography and 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) for 1H NMR spectroscopy. In this review, the principles and applications of these X-ray and NMR methods are explained using mostly our own data.     

The first preparation of enantiopure 1-methyl-7-oxabicyclo[2.2.1]heptan-2-one, a versatile chiral building block for terpenoids

Methods for the resolution of (+/-)-1-methyl-7-oxabicyclo[2.2.1]heptan-2-one 1, a versatile chiral building block for terpenoids, have been investigated. While no efficient result was obtained with kinetic resolution methods, both enantiomers of 1 were prepared optically pure for the first time via esterification of the reductive products of 1 with (+)-mandelic acid and oxidation of the saponified products of diastereomer esters, in an overall yield of 70%. The absolute configurations of (-)-1 and (+)-1 were determined as (1S,4R)-(-)-1 and (1R,4S)-(+)-1 by the CD exciton chirality method and confirmed by Moshers (1)H-NMR method.     

Chiral cruciferous phytoalexins: preparation, absolute configuration, and biological activity

Synthesized by an efficient one-pot spirocyclization method, two chiral cruciferous phytoalexins, 1-methoxyspirobrassinin (2) and 1-methoxyspirobrassinol methyl ether (4a), were prepared through optical resolution using the chiral HPLC method of corresponding racemates. The absolute configuration of natural (+)-2 was elucidated as R by using the direct comparison of ECD and VCD spectra with those of known (S)-(-)-spirobrassinin (1). Another chiral phytoalexin, (-)-4a, had its absolute configuration 2R,3R elucidated through the comparison of observed and calculated VCD. Interestingly, the absolute configurations of natural (S)-(-)-spirobrassinin (1) and (R)-(+)-1-methoxyspirobrassinin (2) were opposite of each other, even though their structures are almost similar, with the exception of an N-methoxy group. A significant difference in the antiproliferative activity between (2R,3R)-(-) and (2S,3S)-(+)-4a was observed.     

Enantioresolution and absolute configurations of chiral meta-substituted diphenylmethanols as determined by X-ray crystallographic and 1H NMR anisotropy methods

meta-Substituted diphenylmethanols were enantioresolved by the method of chiral phthalic acid yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of chiral phthalate esters and/or by the (1)H NMR anisotropy method using 2-methoxy-2-(1-naphthyl)propionic acid.     

Absolute configuration of labdanes and ent-clerodanes from Chromolaena pulchella by vibrational circular dichroism

The aerial parts of Chromolaena pulchella biosynthesize two groups of diterpenes belonging to opposite enantiomeric series, specifically, the furanoid ent-clerodanes (5R,8R,9S,10R)-(-)-hardwikiic acid (1), methyl (5R,8R,9S,10R)-(-)-hardwikiate (2), (5S,8R,9S,10R)-(-)-hautriwaic acid lactone (3), methyl (5R,8R,9S,10R)-(-)-nidoresedate (4) and methyl (8R,9R)-(-)-strictate (5), as well as the labdanes (5S,8R,9R,10S)-(+)-(13E)-labd-13-ene-8,15-diol (6) and (5S,8R,9R,10S)-(+)-isoabienol (7). The absolute configuration of the two groups of diterpenes was unambiguously assigned by comparison of the vibrational circular dichroism spectra of 3 for ent-clerodanes, and of 7 for labdanes with their theoretical spectra obtained by density functional theory calculations. The results support a biogenetic proposal to diterpenes found in the studied botanical species.     

Absolute configuration of the alpha-methylbutyryl residue in longipinene derivatives from Stevia pilosa

The absolute configuration of the alpha-methylbutyryl residue in (4R,5S,7S,8S,9S,10R,11R,2'S)-7-angeloyloxy-9-hydroxy-8-(alpha-methylbutyryloxy)-longipin-2-en-L-one and (4R,5S,7S,8R,10R,11R,2'S)-7-angeloyloxy-8-(alpha-methylbutyryloxy)- longipin-2-en-L-one was determined by chemical correlation with (S)-(+)-benzyl alpha-methylbutyrate prepared from authentic (S)-(+)-alpha-methylbutyric acid. Both compounds were isolated from the hexane extracts of roots of Stevia pilosa Lag. together with four other longipinene derivatives. The developed correlation method is useful to ascertain the chirality of natural alpha-methylbutyryl esters found in nature and to reinforce the hypotheses on the biogenetic origin of these residues.     

Expeditious synthesis and chromatographic resolution of (+)- and (-)-trans-1-benzylcyclohexan-1,2-diamine hydrochlorides

The hitherto unknown (-)- and (+)-1-benzylcyclohexan-1,2-diamine hydrochlorides 4a. HCl and 4b. HCl were synthesized by means of diastereoselective alpha-iminoamine rearrangement with subsequent imine reduction and hydrogenolysis. The relative trans-configuration as well as the absolute (1S,2R) and (1R,2S) configurations of 4a and 4b, respectively, were elucidated on the basis of an X-ray analysis of 3b. HCl. The enantiomeric excess (ee) values of the title compounds (>99%) were determined by chiral HPLC on a Chirex (D) Penicillamine column.     

Stereochemical assignment of naturally occurring 2,3-epoxy-2-methylbutanoate esters

A method to determine the absolute configuration of 2,3-epoxy-2-methylbutanoate ester residues in natural products is presented, based on (i) the reduction of the ester function to yield a 2-methyl-1,2-butanediol, (ii) esterification of the obtained primary alcohol with either (R)-(+)- or (S)-(-)-Mosher's acid to afford the corresponding Mosher's ester, and (iii) 1H-NMR spectral comparison of the final product with that of the Mosher's esters prepared from 2-methyl-1,2-butanediols of known stereochemistry.