Synthesis and structure revision of tyroscherin, a growth inhibitor of IGF-1-dependent tumor cells

Synthesis of the proposed structure of tyroscherin, a growth inhibitor of IGF-1-dependent cancer cells, was succeeded by one-pot Julia coupling. However, spectral data of the synthetic compound were not identical with those of natural tyroscherin. The stereochemistry of tyroscherin was revised to be 2S,3R,8R,10R by syntheses of stereoisomers.     

The first total synthesis and structural determination of antibiotics K1115 B1s (alnumycins)

K1115 B₁, isolated from the broth of Streptomyces species, was found to be a mixture of stereoisomers. Authors synthesized all stereoisomers of K1115 B₁ by convergent synthesis coupling a rhamnose derivative, an isobenzofuranone, and a chiral tetraol. Comparison of ¹H NMR spectra and optical rotations made it clear that the absolute structures of K1115 B_1α (the major isomer) and K1115 B_1β (the minor isomer) were (1R, 17S)- and (1R, 17R)-configurations, respectively. The optical rotations of the stereoisomers revealed that alnumycin, reported as the identical structure with K1115 B₁, might be another mixture of stereoisomers.     

Stereoselective synthesis of 1-methoxyspiroindoline phytoalexins and their amino analogues

The stereoselective synthesis of the spiroindoline phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer were achieved by the bromine-induced spirocyclization of 1-methoxybrassinin using chiral auxiliaries (+)- and (−)-menthol, followed by oxidation of the obtained menthyl ethers. The TFA-catalyzed methanolysis of chiral 1-methoxyspirobrassinol menthyl ethers provided (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and its other three unnatural stereoisomers. The enantiomers of the 2-amino analogues of the indole phytoalexin (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether were prepared by the TFA-catalyzed replacement of the chiral alkoxy group with an amine. The synthesized compounds were tested in vitro on cancer cell lines and examined with enantiopure 2-amino analogues of the indole phytoalexin (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether, which showed in most cases, lower activity than the corresponding racemates.     

Pheromone synthesis. Part 245: Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum

All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from a mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-γ-cyclodextrin was employed as a chiral stationary phase. Complete separation of the four stereoisomers of 1 on reversed-phase HPLC at −54 °C was achieved after oxidation of 1 to the corresponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.     

Determination of the absolute configuration of marine oxylipin topsentolide A1 by the synthesis of the enantiomer of the natural product

Two possible stereoisomers of topsentolide A₁, a cytotoxic oxylipin against human solid tumor cell lines, were prepared in order to determine the stereochemistry of natural product. That is, the enantiomer of topsentolide A₁, (8S,11S,12R)-isomer, and its diastereomer was efficiently synthesized in a stereoselective manner. The stereochemistry of topsentolide A₁ was determined to be 8R,11R,12S by comparing NMR spectra and specific rotations of the synthetic isomers and the natural product.     

Determination of the absolute configuration of nodulisporacid A by the concise synthesis of four stereoisomers via three-component reaction and one-pot construction of the framework

Four stereoisomers of nodulisporacid A (1) were synthesized by the concise approach which includes three-component reaction and subsequent one-pot construction of the whole framework. The ¹H NMR comparison of the derivatives (10-12) revealed the absolute configuration of natural 1 to be 4R,4′R,6′R.     

An efficient stereoselective synthesis of six stereoisomers of 3, 4-diaminocyclohexane carboxamide as key intermediates for the synthesis of factor Xa inhibitors

An efficient stereoselective route for the preparation of six stereoisomers of tert-butyl ((1R, 2S, 5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate 1 starting from simple 3-cyclohexene-1-carboxylic acid has been described. Stereochemistry of the title compounds was controlled at C2 center by Mitsunobu reaction and at C5 via a base-catalyzed epimerization. Only a limited usage of column chromatography has provided a direct and scalable route for the six stereoisomers.     

Pheromone synthesis. Part 250: Determination of the stereostructure of CH503, a sex pheromone of male Drosophila melanogaster,as (3R,11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol by synthesis and chromatographic analysis of its eight isomers

All the eight stereoisomers of 3-acetoxy-11,19-octacosadien-1-ol (1), the male sex pheromone (CH503) of Drosophila melanogaster, were synthesized from two acetylenic starting materials and the enantiomers of 3,4-epoxy-1-butanol PMB ether. Complete separation of the eight isomers of 1 by reversed phase HPLC at ?20 °C was achieved after their esterification with (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanecarboxylic acid (27), and the natural CH503 was found to be (3R,11Z,19Z)-1.     

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

Pheromone synthesis. Part 243: Synthesis and biological evaluation of (3R,13R,1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata, and its stereoisomers

All of the four stereoisomers of (1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the female sex pheromone of Clania variegata, were synthesized by employing olefin cross metathesis as the key reaction and starting from (R)- or (S)-2-methyl-1-butanol, (R)- or (S)-citronellal, and (S)-2-methyl-3-pentanol. Their bioassay revealed the (3R,13R,1′S)-isomer as the bioactive one, whose more efficient synthesis was achieved in two different ways by employing Wittig reaction as the key step.     

Enantioselective synthesis and stereochemical revision of communiols A-C

Enantioselective synthesis of the proposed structure of communiol C, an antibacterial tetrahydrofuran derivative produced by Podospora communis, and its stereoisomers revealed that the genuine stereochemistry of communiol C should be 3R, 5R, and 6S. Two other structurally related metabolites of the same microbial origin, communiols A and B, were also synthesized based on the revised stereochemistry.     

Rapid access to cis-cyclobutane γ-amino acids in enantiomerically pure form

The (+)-(1R,2S) and (−)-(1S,2R) stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared using a short and efficient strategy, which employs the photochemical [2+2] cycloaddition reaction between ethylene and an unsaturated γ-lactam as the key step.     

Application of ionic liquids in enzymic resolution by hydrolysis of cycloalkyl acetates

A comparative study was performed in the enzymic resolution of the isomers of 2-(4-methoxybenzyl)cyclohexyl acetates 1 and 2. The investigation consisted in application of three commercially available lipases (Novozyme 435, Lipozyme IM and non-immobilized powdered lipase from Candida antarctica), two ionic liquids (1-butyl-4-methylpyridinium chloride and 1,3-dimethylimidazolinium methyl sulfate), three modifications of the reaction conditions and two respective isomers of the racemic substrate (1 and 2), and resulted in our finding the appropriate conditions to get both of the products, stereoisomers of 2-(4-methoxybenzyl)cyclohexanol (3; 1S,2S) or (5; 1S,2R), and (in some cases) also the stereoisomers of the deracemized substrate (4; 1R,2R) or (6; 1R,2S) with high or acceptable enantiomeric purity.     

Syntheses of the four stereoisomers of Phytophthora mating hormone α2 and a concise synthesis of mating hormone α1

Four stereoisomers of Phytophthora mating hormone α2 were synthesized using both enantiomers of citronellol as starting materials. The absolute configuration of the natural product was determined to be 7S,11R,15R by oospore-inducing assays of the synthetic isomers. A concise synthetic procedure of α1 was also established using a common synthetic intermediate of α2.     

Assignment of absolute configurations of permethrin and its synthon 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic circular dichroism,optical rotation,and X-ray crystallography

The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute configurations are of central importance for the detailed investigation and correct assignment of stereoselective effects. In this context, single stereoisomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), a precursor, metabolite, and environmental degradation product of PM, were isolated from a mixture of all four stereoisomers in enantiomeric excesses of >99% via a two-step chromatographic process combining a diastereoselective reversed-phase separation in the first step with a direct enantiomer separation in the second step. Esterification of DCCA stereoisomers with 3-phenoxybenzyl alcohol yielded PM. Electronic circular dichroism (ECD) spectra of DCCA and PM stereoisomers were measured in non-polar (cyclohexane containing 5% v/v 1,2-dichloroethane) and non-protic polar (acetonitrile) solvents. Cotton effects suitable to distinguish the four stereoisomers of each DCCA and PM were obtained. Absolute configurations of DCCA were determined by confrontation of calculated (time-dependent density-functional theory using B3LYP hybrid functional) and experimental ECD and optical rotation (OR) data. Fully convergent results between ECD and X-ray diffractometry (analysis of DCCA isomers co-crystallized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine), which was employed as a reference method, were obtained. The importance of considering dimer formation of DCCA in solution for the computational delineation of absolute configurations was demonstrated by (1R,3R)-cis-DCCA for which the ΔG Boltzmann averaged calculated monomeric form delivered the opposite sign of OR compared to the dimeric form and the value determined experimentally in dichloromethane. For (1S,3R)-trans-DCCA both monomer and dimer delivered the identical sign of OR and this was in agreement with the experimental measurement. In contrast to OR, the calculated ECD spectra of these two DCCA stereoisomers were less sensitive toward intermolecular association.     

Versicolactones A and B: total synthesis and structure revision

To further determine absolute configurations of versicolactones A and B, total synthesis of versicolactones A and B and their six stereoisomers were reported in this Letter. The ¹H and ¹³C NMR spectra of the synthetic erythro-stereoisomers matched perfectly with those of the natural products. Combined with the comparison of the specific rotations, the absolute configuration of versicolactones A and B were revised as (4Z,6R,7S)- and (4E,6R,7S)- from the corresponding (4Z,6R,7R)- and (4E,6R,7R)-6,7-dihydroxyocta-2,4-dien-4-lactone, respectively.     

Camphor-derived amber/woody odorants: 1,7,7-trimethyl-2′-iso-propylspiro[bicyclo[2.2.1]heptane-2,4′-(1,3-dioxanes)]

Six stereoisomers of a new camphor-derived 1,7,7-trimethyl-2′-iso-propylspiro[bicyclo[2.2.1]heptane-2,4′-(1,3-dioxane)] odorant were prepared. Their design with the help of an amber olfactophore model and structure–odour relationship are reported. The (1R,2S,4R,2′S) isomer has by far the strongest and the most characteristic amber-like odour.     

Arylacetic acid derivatization of 2,3- and internal erythro-squalene diols. Separation and absolute configuration determination

We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6S,7S)-6,7-SO, and (10R,11R)- and (10S,11S)-10,11-SO. Monoderivatization of the corresponding racemic squalene diol intermediates with pure stereoisomers of (S)-(+)-methoxyphenyl acetic acid ((S)-(+)-MPA), (S)-(+)-9-anthrylmethoxyacetic acid ((S)-(+)-9-AMA) and (S)-(+)-acetoxyphenylacetic acid ((S)-(+)-APA) afforded the diastereomeric esters which could be easily separated by column flash chromatography with silica gel. In addition, the absolute configuration for these diastereoisomers of the derivatized diols was advantageously inferred from ¹H NMR data according to the models depicted for these derivatizing chiral agents. In order to demonstrate the absolute configuration assignment of the different stereoisomers, (S)-(+)-AMA showed the larger Δδ by ¹H NMR, however, (S)-(+)-MPA esters were much more stable derivatives.     

Gymnasterol, a new antitumor steroid against IGF-dependent cells from Gymnascella dankaliensis

A new antitumor substance, gymnasterol (1), was isolated from the culture broth of Gymnascella dankaliensis. The structure of 1 was determined to be a novel ergostane steroid on the basis of NMR studies. Gymnasterol selectively inhibited IGF-1-dependent growth of MCF-7 human breast cancer cells.     

Synthesis of all the four stereoisomers of (1′S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata

All the four stereoisomers of (1′S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Clania variegata, were synthesized by starting from (R)- or (S)-2-methylbutan-1-ol, (R)- or (S)-citronellal, and (S)-2-methylpentan-3-ol. Olefin cross metathesis was employed as the key reaction.