Absolute configurations of griseorhodins A and C

The known antibiotic and cytotoxic compounds griseorhodin A (1) and griseorhodin C (2) were produced in solid culture by Streptomyces puniceus AB10, which was isolated from the leaf-cutter ant Acromyrmex rugosus rugosus. Their absolute configurations were unambiguously established as 6S,6aR,7S,8S and 6R,6aR,7S,8R, respectively, using vibrational circular dichroism (VCD) and density functional theory (DFT) calculations.     

2-Cyano-2-indolylpropanoic acid as a chiral derivatizing agent for the absolute configuration assignment of secondary alcohols and primary amines by 1H NMR and VCD

A convenient approach for the absolute configuration assignment of secondary alcohols in the (8R,1′R,2′S,5′R)-15,25, (8S,1′R,2′S,5′R)-15,25, (8R,1′R)-21–24, and (8S,1′R)-21–24 ester series, and of primary amines in the (8R,1′R)-32–37 and (8S,1′R)-32–37 amide series, by means of ¹H NMR and VCD spectroscopy, using 2-cyano-2-indolylpropanoic acid as a chiral derivatizing agent is presented. DFT calculations were carried out to demonstrate the anisotropic effect of the indole skeleton on the chiral alcohol or the amine fragment. Vibrational circular dichroism (VCD) measurements of the above series indicated a VCD bisignated couplet resulting from the interaction of the ester carbonyl group and the CN group. The absolute configuration assignments were further tested by X-ray diffraction analysis.     

Corrigendum to “Absolute configurations of griseorhodins A and C” [Tetrahedron Lett. 58 (50) (2017) 4721–4723]

The known antibiotic and cytotoxic compounds griseorhodin A (1) and griseorhodin C (2) were produced in solid culture by Streptomyces puniceus AB10, which was isolated from the leaf-cutter ant Acromyrmex rugosus rugosus. Their absolute configurations were unambiguously established as 6S,6aS,7S,8S and 6R,6aS,7S,8R, respectively, using vibrational circular dichroism (VCD) and density functional theory (DFT) calculations.     

Absolute configuration of diterpenoids from Jatropha dioica by vibrational circular dichroism

The absolute configuration of jatropholone A 1 and B 2, including the possibility to observe the vibrational circular dichroism (VCD) capacity to differentiate between two epimeric compounds in the presence of an inherently dissymmetric chromophore, which normally dominates VCD and electronic circular dichroism (ECD) spectra, followed after comparison of their experimental and DFT calculated VCD spectra, allowed us to conclude that although non-local (M/P) chirality generated by atropisomerism dominates over local chirality generated by an (R/S) change, the stereogenic center can confidently be assigned by VCD after DFT calculations. In addition, the absolute configurations of jatrophatrione 3 and citlalitrione 4, a compound proposed as a taxonomic marker for the genus Jatropha, were assigned by contrasting their respective calculated and experimental IR and VCD spectra. The evaluation of Flack and Hooft parameters obtained from the single-crystal X-ray diffraction data of jatropholone B acetate 6, and of 4 independently confirmed the absolute configurations of these molecules.     

Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the CO stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the CO stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)/(S)-(−). Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)/(S)-(−) for both 1 and 2. The absolute configurations of (−)-1 and (−)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the ‘conformational rigidification via chemical derivatisation’ methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

HPLC separation and VCD spectroscopy of chiral pyrazoles derived from (5R)-dihydrocarvone

(4S,7R)-(−) and (4S,7S)-(+)-4-isopropylidene-7-methyl-4,5,6,7-tetrahydro-2(1)H-indazoles 2a and 2b have been successfully separated by using HPLC over a Chiralpak AS column as the stationary phase, yielding up to 700 mg of each diastereomer. Their absolute configurations were determined by using vibrational circular dichroism (VCD) studies. This latter method proved not only very useful for determination of the conformers’ distribution, but also for analysis of the 1H,2H tautomers.     

A structure and an absolute configuration of (+)-alternamin, a new coumarin from Murraya alternans having antidote activity against snake venom

(+)-Alternamin (1), a new dihydrofuranocoumarin, was isolated from the aerial parts of Murraya alternans (Kurz) Swingle. The analysis 2-D NMR correlation of (+)-1 led to either of linear dihydrofuranocoumarin (2A, 2C) or angular one (2B). An IR and a vibrational circular dichroism (VCD) studies were conducted to distinguish the structure and to assign the absolute configuration. By comparison of the observed spectra with the calculated spectra for (S)-2A, (S)-2B, and (R)-2C, the molecular structure of (+)-1 was determined to be (S)-(+)-5,8-dimethoxymarmesin. The compound exhibited antidote activity against snake venom from Trimeresurus flavoviridis, affording experimental support for the pharmacological use of M. alternans.     

Absolute configurations of endoperoxides determined by vibrational circular dichroism (VCD)

Diastereomeric mixture on the peroxide portion of an endoperoxide acetylmajapolene A (1) was efficiently separated by HPLC on a chiral column, submitting to vibrational circular dichroism (VCD) investigation. The ab initio theoretical VCD and IR calculations of 1a and 1b were performed by density functional theory (DFT) using the B3PW91/6-31G(d,p) level of theory. Focusing on an isolated characteristic peroxide vibrational band, absolute configurations of 1a and 1b were unambiguously determined as (1R,4R,7S,10S) and (1S,4S,7S,10S), respectively. This is the first VCD application to endoperoxides which exist abundantly in nature.     

Analysis of the major chiral compounds of Artemisia herba-alba essential oils (EOs) using reconstructed vibrational circular dichroism (VCD) spectra: En route to a VCD chiral signature of EOs

An unprecedented methodology was developed to simultaneously assign the relative percentages of the major chiral compounds and their prevailing enantiomeric form in crude essential oils (EOs). In a first step the infrared (IR) and vibrational circular dichroism (VCD) spectra of the crude essential oils were recorded and in a second step they were modelized as a linear weighted combination of the IR and VCD spectra of the individual spectra of pure enantiomer of the major chiral compounds present in the EOs. The VCD spectra of enantiomer of known enantiomeric excess shall be recorded if they are not yet available in a library of VCD spectra. For IR, the spectra of pure enantiomer or racemic mixture can be used. The full spectra modelizations were performed using a well known and powerful mathematical model (least square estimation: LSE) which resulted in a weighting of each contributing compound. For VCD modelization, the absolute value of each weighting represented the percentage of the associate compound while the attached sign addressed the correctness of the enantiomeric form used to build the model. As an example, a model built with the non-prevailing enantiomer will show a negative sign of the weighting value. For IR spectra modelization, the absolute value of each weighting represented the percentage of the compounds without of course accounting for the chirality of the prevailing enantiomers. Comparison of the weighting values issuing from IR and VCD spectra modelizations is a valuable source of information: if they are identical, the EOs are composed of nearly pure enantiomers, if they are different the chiral compounds of the EOs are not in an optically pure form. The method was applied on four samples of essential oil of Artemisia herba-alba in which the three major compounds namely (−)-α-thujone, (+)-β-thujone and (−)-camphor were found in different proportions as determined by GC–MS and chiral HPLC using polarimetric detector. In order to validate the methodology, the modelization of the VCD spectra was performed on purpose using the individual VCD spectra of (−)-α-thujone, (+)-β-thujone and (+)-camphor instead of (−)-camphor. During this work, the absolute configurations of (−)-α-thujone and (+)-β-thujone were confirmed by comparison of experimental and calculated VCD spectra as being (1S,4R,5R) and (1S,4S,5R) respectively.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: phenyl glycidic acid derivatives obtained via asymmetric epoxidation using oxone and a keto bile acid

The (+)-enantiomers of the o-Br, m-F and p-CH₃ derivatives of trans phenyl glycidic acid have been obtained from the corresponding trans cinnamic acid derivatives using Oxone and the tri-keto bile acid dehydrocholic acid. Vibrational circular dichroism (VCD) spectroscopy of their methyl esters has been used to determine their absolute configurations. In each case, the absolute configurations of both methyl ester and parent acid were shown to be (2S,3R)-(+)/(2R,3S)-(−).     

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.     

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.     

Determination of the Absolute Configuration of (−)‐Mirtazapine by Vibrational Circular Dichroism

The absolute configuration of the (−)‐enantiomer of mirtazapine was determined by means of vibrational circular dichroism (VCD). The observed VCD of (−)‐mirtazapine showed excellent correlation with the calculated VCD of the (R)‐enantiomer. This is in agreement with the absolute configuration as determined by independent synthesis starting from (R)‐phenylglycine.     

Structure reassignment and absolute configuration of 9-epi-presilphiperfolan-1-ol

Reevaluation of ¹³C NMR data in combination with X-ray diffraction and VCD studies led us to reassign the structure of (−)-epi-presilphiperfolan-1-ol (1), isolated from Anemia tomentosavar.anthriscifolia, to (−)-9-epi-presilphiperfolan-1-ol (2) and to establish its absolute configuration as 1S,4S,7R,8R,9S.     

Polyhydroxylated macrolide isolated from the endophytic fungus Pestalotiopsis mangiferae

A new polyhydroxylated macrolide, named mangiferaelactone (1) was isolated from a solid culture of the endophytic fungus Pestalotiopsis manguiferae, together with ten known compounds [(6S,1′S)-LL-P880α; (6S,1′S,2′R)-LL-P880β; (1′S,2′R)-LL-880γ; (1′R)-dehydropestalotin; (−)-5-carboxylmellein; (−)-5-methylmellein; (−)-5-hydroxylmethylmellein; arabenoic acid; 5,6-dihydro-4-methoxy-2H-pyran-2-one; and the (−)-2-hexylidene-3-methylsuccinic acid]. P. manguiferae was isolated from Hyptis dilatata, a small shrub common in the central region of Panama. The structure of compound 1 was elucidated by a combination of spectroscopic methods (IR, MS, optical rotation, 1D and 2D NMR spectroscopy). The absolute configuration of 1 was established as 4R,7R,8R,9S by application of vibrational circular dichroism (VCD). Compound 1 showed a minimum inhibitory concentration (MIC) of 1.6863 mg/mL against Listeria monocytogenes, and 0.5529 mg/mL against Bacillus cereus. No activity was observed for compound 1 against Plasmodium falciparum or Trypanosoma cruzi; likewise, no cytotoxic activity was observed against A2058 and H522-T1 cells.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl-1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1?R,2?R,4?S + 2R,1?R,2?R,4?S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.     

Direct determination of the absolute configuration of a cyclic thiolsulfinate by VCD spectroscopy

Experimental and calculated vibrational circular dichroism (VCD) spectra of the enantiomers of the conformationally rigid thiolsulfinate, naphtho[1,8-cd]-1,2-dithiole 1-oxide 1, obtained by chromatographic resolution of the racemate, were in excellent agreement, showing a (+)-(S)-1/(−)-(R)-1 relationship.