Menthyl Esters Research Articles

A Highly Enantiopure Biconcave Porphyrin with Effective D 4-Structure

A first representative of an effectively D4-symmetric biconcave porphyrin (1) was prepared from a tetramerizing condensation of a C2-symmetric pyrrole (2). The chiral pyrrole 2 was synthesized in a six-step reaction sequence starting from the C2h-symmetric 2,6-di-tert-butylanthracene. The relevant stereochemistry was introduced in a highly diastereo-discriminating Diels-Alder reaction with fumaric acid di(-)menthyl ester, catalyzed by aluminum chloride. X-ray analyses of two of the dimenthyl esters prepared unambiguously secured their tentatively assigned absolute configuration and that of the pyrrole 2 (as the S,S isomer). The enantiomeric purity of the pyrrole 2 was determined as 99% ee, using the Co11 complex of the porphyrin 1 as a chiral shift reagent. The pyrrole 2 lent itself to a stereochemically nearly uniform preparation of the chiral, biconcave porphyrin 1. Applying Horeau's principle, 1 was calculated to be present in an enantiomeric excess of about 10(9):1. The validity of the statistical considerations relevant for this estimate were verified by examination of the results from preparative tetramerization experiments in which the enantiomeric purity of the pyrrole 2 was deliberately lowered.

Addition of cyclopentadiene and 2-trimethylsilyloxyfuran to quinones bearing a menthyl ester chiral auxiliary

Addition of cyclopentadiene to 2-carbomethoxy-1,4-benzoquinone 9 afforded Diels-Alder adduct 10 using the Lewis acids ZnCl 2 and ZnBr 2 whereas the fragmenatation product 11 was the major product when using SnCl 4 and TiCl 4. Addition of cyclopentadiene to 1,4-benzoquinone 8 bearing a menthyl ester at C-2 afforded Diels-alder adduct 12 in moderate diastereomeric excess using ZnCl 2 and ZnBr 2 as Lewis acids. Use of TiCl 4 and SnCl 4 afforded the fragmentation product 13 also in moderate diastereomeric excess. Addition of 2-trimethylsilyloxyfuran to chiral naphthoquinone 4 and benzoquinone 8 afforded furofuran adducts 14 and 15 respectively as a 1:1 mixture of diastereomers.

Convenient enantioselective preparation of salsolinol-1-carboxylic acid

Pictet-Spengler condensation of dopamine with (+)-menthyl pyruvate afforded a diastereomeric mixture of menthyl salsolinol-1-carboxylate, from which pure diastereomer was isolated by repeated recrystallizations in ca. 20% yield. Acid hydrolysis of the menthyl ester furnished (−)-( R)-salsolinol-1-carboxylic acid in good yield.

Aerobic epoxidation via alkyl-2-oxocyclopentanecarboxylate co-oxidation with cobalt or manganese Jacobsen-type catalysts

In the presence of methyl, tert-butyl, or (−)-menthyl esters of 2-oxocyclopentanecarboxylic acids Jacobsen-type complexes of cobalt(II) and manganese(III) form active catalysts for alkene epoxidation using molecular oxygen. Alkyl-1-hydroxy-2-oxocyclopentanecarboxylates and 1-alkyl-2-oxo-hexanedicarboxylic acids are formed as co-oxidation products. The (−)-menthyl/cobalt system is selective for epoxide production but the products are racemic consistent with radical epoxidation in solution rather than at the cobalt complex. The manganese Jacobsen-type complex gives lower yields of epoxides (40–60%) but for 2,2-dimethylchromene and styrene these are optically active (12–60% ee).

Separation of Rosmarinic Acid Enantiomers by Three Different Chromatographic Methods (HPLC, CE, GC) and the Determination of Rosmarinic Acid inHedera helix L.

Three methods employing high performance liquid chromatography (HPLC), capillary electrophoresis (CE), and gas chromatography (GC) were developed for the separation of enantiomers of rosmarinic acid (RA). Chiral resolution of underivatized RA was achieved on a chiral AGP® HPLC column and by micellar electrokinetic capillary chromatography (MECC). Alternatively, after derivatization, the resulting diastereomeric 3,4-di-hydroxyphenyllactic acid (-)-menthyl esters were separated by non-chiral GC. These methods allow reliable and rapid determination of the enantiomeric ratio of RA samples. RA obtained from vegetative material of Hedera helix L. (Araliaceae) was determined to be (R)-(+)-RA. In contrast to published data, the optical rotation value of rosmarinic acid was found to be +106°.

Synthesis and ene reactions of di-(−)-menthyl diazenedicarboxylate

The preparation di-(−)-menthyl diazendicarboxylate 3 is described. Reaction of hydrazine with excess (−)-menthyl chloroformate 1 afforded dimenthyl diazanedicarboxylate 2 which was then oxidized to the azo-enophile 3. The azo-ene reactions of 3 with the alkenes trans-3-hexene 4, trans-4-octene 6, cyclohexene 8 and cyclopentene 10 were carried out using the Lewis acid catalyst tin tetrachloride. Trans-3-hexene 4 and trans-4-octene 6 afforded the ene adducts 5 (80%) and 7 (70%) with a diastereomeric excess of 2.5:1 and 2:1 respectively. Use of cyclohexene 8 and cyclopentene 10 afforded the ene adducts 9 and 11 in 81% and 88% yield, however, no diastereomeric excess was observed. Finally use of conjugated aromatic acyclic alkenes 12 and 14 afforded the chlorides 13 and 15 in 93% and 56% yield respectively. In these latter cases an ionic addition proceeded rather than a pericyclic ene reaction. Attempted removal of the chiral menthyl ester auxiliary from the ene adduct 5 proved difficult.

The Use of Vicinal Twofold Heck Reaction Products in Diastereoselective Sequential Michael Additions — A Convenient Access to Enantiomerically Pure Six‐Ring Anellated Cispentacin Derivatives

AbstractThe palladium‐catalyzed coupling reactions of various acrylic acid derivatives 2a–e (e.g. methyl, tert‐butyl, benzyl, menthyl esters) with 1,2‐dibromobenzene (1), 1,2,3‐tribromobenzene (4) and 1,2‐dibromocyclohexene (6) yielded the correspondingly substituted ortho‐diethenylarenes 3a–e, 1,2,3‐triethenylarenes 5a,b and (E,E)‐1,3,5‐hexatriene derivatives 7a,b. Some of these vicinal diacrylates (3a–d, 5b, 7a,b) were converted to 1,2,3‐trisubstituted indane‐ and tetrahydroindane derivatives 10a–d, 15a,b, 18, 20, 23, and 12a,b, 16b by domino conjugate addition of nitrogen, carbon, and sulfur nucleophiles. With benzyl(trimethylsilyl)amine (9) as an ammonia equivalent, the relative configuration of all three newly formed stereogenic centers was controlled (d.e. >90%). Therefore, with chiral non‐racemic ammonia equivalents like benzyl[(S)‐phenylethyl]amine (14) and TMS‐(R)‐AMP (17), protected diastereomerically pure β‐amino esters were obtained, which could easily be deprotected by standard methods to yield the enantiomerically pure β‐amino acids 27 and 28.

Lipase-catalyzed stereoselective esterification of dl-menthol in organic solvents using acid anhydrides as acylating agents

Stereoselective esterification of racemic menthol in n-hexane using acid anhydrides as acylating agents was successfully achieved with lipase AY-30 from Candida cylindracea. Molar yields of menthyl esters as high as 23–30% were observed in the control without the presence of enzyme after 48 h incubation at 30°C in n-hexane. Molar percentage yield, enantiomeric ratio (E), and percentage enantiomeric excess (ee%) of product menthyl esters were estimated using capillary gas chromatography and a chiral column. The (−) menthol was preferentially esterified by lipase AY-30 with a yield as high as 64%. The highest E (14) and ee% (86%) were achieved in n-hexane solution containing a 1:1 molar ratio (±)menthol:butyric anhydride. The addition of a weak base, NaHCO 3, did not enhance enantioselectivity of lipase AY-30; however, it did improve the overall yields in both the control and the systems containing lipase AY-30.

Molecular structure of the (−)menthyl ester of N-(2,4,6-tri-tert-butylphenyl)imidophosphinous acid

Molecular structure of the (−)menthyl ester of N-(2,4,6-tri-tert-butylphenyl)imidophosphinous acid

Studies of cardiotonic agents. 8. Synthesis and biological activities of optically active 6-(4-(benzylamino)-7-quinazolinyl)-4,5-dihydro-5-methyl-3(2H)- pyridazinone (KF15232).

We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7-quinazolinyl)-3-methyl-4-oxobutyric acid (-)-menthyl ester (6) was separated into both diastereoisomers, and each was converted to optically pure 1 (> 99% ee) in an enantioselective manner. In order to determine the absolute configuration of the isomers, an alternative synthesis of optically active 1 was employed. The precursor of (-)-1 ((+)-9) was obtained by enantioselective synthesis from (R)-D-alanine. Consequently, we concluded that the absolute configuration of (-)-1 at the 5-position of the pyridazinone ring was R. The cardiotonic effects and inhibitory activities to PDE III and V of racemic 1 and (-)-1 were more potent than those of (+)-1. These compounds also demonstrated greater vasorelaxant effects in guinea pig aorta. In contrast, (+)-1 showed only weak cardiotonic and vasodilating effects, although the compound displayed potent Ca(2+)-sensitizing activity. Racemic and (-)-1 attracted our interest for the treatment of congestive heart failure.

High-performance continuous operation for enanthioselective esterification of menthol by use of acid anhydride and free lipase in organic solvent

By using propionic anydride as a highly reactive and non-water-producing acyl donor, and free lipase OF 360 suspended in cyclohexane as a biocatalyst under the optimized conditions, efficient and stable enantioselective esterification of (+-)-menthol is possible and has been carried out very stably for 2 months in a continuous stirred-tank reactor at 30°C, retaining a 47%–35% conversion of menthol and high optical purity of the (−)-menthyl ester produced (95%–98% e.e.). However, when the corresponding propionic acid was used as an acyl donor, the conversion ratio of menthol decreased rapidly after the start of continuous operation, indicating a higher productivity with the anhydride than with the free acid. In the case of the acid anhydride, the water content of the reaction medium, which has a great effect on the reactivity and stability of lipase, was easily controlled in long-term operation by the occasional micro-adjustment of the flow rate or concentration of the feed solution of the acid anhydride, and could essentially be kept constant (2–4 mM), avoiding the inactivation of the enzyme.

L-(+)-α-Bromobenzeneacetic Acid (−)-Menthyl Ester

The crystal structure of L-(+)-α-bromobenzeneacetic acid (-)-menthyl ester (C 18 H 25 BrO 2 ) is reported. The Br atom and the O(carbonyl) atom are in trans positions. The 1-methyl-4-isopropylcyclohexane ring has a chair conformation. The dihedral angle between the least-squares plane through the phenyl ring and the least-squares plane of the C-CO 2 group is 45.0(2)°. The bond distances and angles of the molecule are in the normal ranges.

Characterization of Enantiomeric Pairs of Optically Active 10-P-5 Phosphoranes with Asymmetry Only at Phosphorus

Abstract Diastereomeric phosphoranes (o-OC(CF3)2C6H4)2P*CH2CO2-(−)-menthyl (3-RP and 3-SP) of which absolute stereochemistry was determined were treated with LiAlH4 to give (o-OC(CF3)2C6H4)2P*CH2CH2OH (4-RP and 4-SP) as the first optically active pair of enantiomeric phosphoranes of rigid stereochemistry with asymmetry only upon the pentacoordinate phosphorus atom. The high enantiomeric purities of the alcohols were confirmed by converting them to their (+)-MTPA esters. Furthermore, when diastereomeric phosphoranes (o-OC(CF3)2C6H4)2P*CH2NHC*HCH3Ph (10-RP and 10-SP) of which absolute stereochemistry was also determined were treated with MeLi the first optically active pair of enantiomeric P–H phosphoranes (o-OC(CF3)2C6H4)2P*H (2-RP and 2-SP) with asymmetry only upon the pentacoordinate phosphorus atom could be obtained. The high enantiomeric purities of the P–H phosphoranes were confirmed by converting each of them to their corresponding (−)-menthyl esters 3-RP and 3-SP.

Amplification of double stereodifferentiation in the asymmetric hydrogenation by a solvent effect

High diastereoselectivities of more than 96 % leading to ( S)-amino acid menthyl esters were found in the hydrogenation of both the newly prepared enantiomers 3 and 4 of menthyl (Z)-2-N-benzoylamidocinnamate with the rhodium(I)-chelate of (Ph-ß-glup-OH) 1 as chiral catalyst in polar solvents. The analogous chelate of (Me-α-glup) 2 forms a mismached pair with the enantiomer 4 giving the ( S)-product in a low diastereoselectivity which can be inversed in the apolar solvent benzene to 86 % of the ( R)-diastereomer. Of particular note is the possibility of obtaining high yields either of ( R)- or ( S)-amino acids with the same catalyst with a single ligand derived from D-glucose.

Asymmetric 9-(1′-naphthyl)fluorenes: enantioselective synthesis, determination of absolute configuration and retention of axial chirality in the fluorenyl carbanions

The rotamers of 1-methyl-9-[2′-(methoxymethyl)-1′-naphthyl]fluorene 10 and 11 were synthesised enantioselectively via ligand coupling reactions of 1-(alkyl or arylsulfinyl)naphthalene-2-carboxylate esters with 1-methylfluorenyllithium and the absolute configurations established by a single crystal X-ray study of the (1R)-menthyl ester 4; deprotonation of 10 and 11 affords fluorenyl carbanions, ent-12 and 12, respectively, which retain axial chirality.

MM2 conformational analysis of some diastereoisomeric ethyl and menthyl esters of 3-substituted 2,3-diphenylpropanoic acids

Abstract The conformations of ethyl and menthyl esters of 3-amino- and 3-hydroxy-2,3-diphenylpropanoic acid were studied with the MM2 force field enhanced with the addition of electrostatic corrections to the aromatic force field, as proposed by Allinger and Lii (J. Comput. Chem., 8 (1987) 1146) (dipole—dipole interactions), and the special MM2 hydrogen bonding parameters for the van der Waals function. The molecular mechanics results for the amino esters closely matched the experimental data. The populations of conformations with the carbonyl oxygen of an ester group as a proton acceptor in hydrogen bonding were exaggerated for the hydroxy compounds.

The stereoselective alkylation of cyclohexane-1,2-dicarboxylic acid mono-(−)-menthyl ester

The dianion of (1 R),(2 S)-cyclohexane-1,2-dicarboxylic acid mono-(−)-menthyl ester reacts with alkyl bromides and an iodide to give alkylation with selectivities ranging from 7:1 to 32:1, the configuration of one product has been proved by X-ray crystallography.

Elucidation of the stereochemistry of the ?-amidoalkylation products resulting from the interaction of allyltrimethylsilane with electrophilic glycine menthyl ester derivatives

α-Amidoalkylation of allyltrimethylsilane with (−)- and (+)-menthyl-2-(o–Chlorobenzoylamino)-2-halogenoethanoate (2, 4a and 4b) gave in the presence of zinc chloride, separable mixtures of the diastereomers (−)- and (+)-menthyl-2-(o–Chlorobenzoylamino)-4-pentenoate (5a, 5b and 6a, 6b). The absolute configurations of 5a, 5b and 6a, 6b were determined through conversion of 5a into S-(+)-norvaline hydrochloride.

Preparation of 2(R) and 2(S) methyl-2-methylglycerates

Optically pure samples of both enantiomers of methyl 2,3-dihydroxy-2-methylpropanoate were prepared by a chromatographic separation of their (−)-menthyl esters followed by hydrolysis and methylation. Their absolute stereochemistries were established by conversion into their 3- O-acetyl derivatives, compounds of established configuration. NMR and CG-MS methods of determining the optical purities of the diols are described.

Absolute Stereochemistry of Dimethyl 9-(1,1-Dimethyl-2-phenylethyl)-9,10-dihydro-9,10-ethenoanthracene-11,12-dicarboxylate Rotamers

Abstract Absolute stereochemistry of the title compounds is determined through X-ray analysis of the 11-(−)-menthyl ester of the corresponding 11-carboxylic acid and its CD spectra are reported. Features of the molecular structure are discussed and revival of a term “absolute conformation” is proposed.