Resolution and Absolute Configuration Assignment of a Natural Racemic Chromane from Peperomia obtusifolia (Piperaceae)

The resolution of the natural racemic chromane 3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3 ``-methyl-2 ``-butenyl)-2-(4`-methyl-1`,3`-pentadienyl)-2H-1-benzopyran-6-carboxylic acid (1) isolated from the leaves of Peperomia obtusifolia has been accomplished using stereoselective HPLC. The absolute coil figuration of the resolved enantiomers was determined by the analysis of optical rotations and CD spectra. The finding of a racemic mixture instead of an enantiomerically pure metabolite raises questions about the final steps in the biosynthesis of this class of natural products, suggesting that the intramolecular chromane ring formation step may not be enzymatically controlled at all in P. obtusifolia. Chirality 21:799-801, 2009. (C) 2008 Wiley-Liss, Inc.

Resolution and Absolute Configuration Assignment of a Natural Racemic Chromane from Peperomia obtusifolia (Piperaceae)

The resolution of the natural racemic chromane 3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3 ''-methyl-2 ''-butenyl)-2-(4'-methyl-1',3'-pentadienyl)-2H-1-benzopyran-6-carboxylic acid (1) isolated from the leaves of Peperomia obtusifolia has been accomplished using stereoselective HPLC. The absolute coil figuration of the resolved enantiomers was determined by the analysis of optical rotations and CD spectra. The finding of a racemic mixture instead of an enantiomerically pure metabolite raises questions about the final steps in the biosynthesis of this class of natural products, suggesting that the intramolecular chromane ring formation step may not be enzymatically controlled at all in P. obtusifolia. Chirality 21:799-801, 2009. (C) 2008 Wiley-Liss, Inc.

Assignment of the absolute configuration at the sulfur atom of thioridazine metabolites by the analysis of their chiroptical properties: The case of thioridazine 2-sulfoxide

Thioridazine (THD) is a commonly prescribed phenotiazine neuroleptic drug, which is extensively biotransformed in the organism producing as main metabolites sulfoxides and a sulfone by sulfur oxidation Significant differences have been observed in the activity of the THD enantiomers as well as for its main metabolites, and enantioselectivity phenomena have been proved in the metabolic pathway. Here the assignment of the absolute configuration at the sulfur atom of enantiomeric THD-2-sulfoxide (THD-2-SO) has been carried out by circular dichroism (CD) spectroscopy The stereoisomers were separated by HPLC on Chiralpak AS column, recording the CD spectra for the two collected enantiomeric fractions The theoretical electronic CD spectrum has been obtained by the TDDFT/B3LYP/6-31G*. as Boltzmann averaging of the contributions calculated for the most stable conformations of the drug The comparison of the simulated and experimental spectra allowed the absolute configuration at the sulfur atom of the four THD-2-SO stereoisomers to be assigned The developed method should be useful for a reliable correlation between stereochemistry and activity and/or toxicity

Automatic assignment of absolute configuration from 1D NMR data

Opposite enantiomers exhibit different NMR properties in the presence of an external common chiral element, and a chiral molecule exhibits different NMR properties in the presence of external enantiomeric chiral elements. Automatic prediction of such differences, and comparison with experimental values, leads to the assignment of the absolute configuration. Here two cases are reported, one using a dataset of 80 chiral secondary alcohols esterified with (R)-MTPA and the corresponding 1H NMR chemical shifts and the other with 94 13C NMR chemical shifts of chiral secondary alcohols in two enantiomeric chiral solvents. For the first application, counterpropagation neural networks were trained to predict the sign of the difference between chemical shifts of opposite stereoisomers. The neural networks were trained to process the chirality code of the alcohol as the input, and to give the NMR property as the output. In the second application, similar neural networks were employed, but the property to predict was the difference of chemical shifts in the two enantiomeric solvents. For independent test sets of 20 objects, 100% correct predictions were obtained in both applications concerning the sign of the chemical shifts differences. Additionally, with the second dataset, the difference of chemical shifts in the two enantiomeric solvents was quantitatively predicted, yielding r2 0.936 for the test set between the predicted and experimental values.

Absolute configuration reassignment of two chromanes from Peperomia obtusifolia (Piperaceae) using VCD and DFT calculations

Previous analysis of the ECD spectra of two prenylated benzopyrans isolated from Peperomia obtusifolia, by means of the helicity rule for the chromane chromophore, resulted in the incorrect assignment of their absolute configuration, (5) instead of (R) for a deduced P-helicity of the chromane ring for the (+)-enantiomers. This was discovered by the application of DFT calculations and VCD spectroscopy. Experimental and calculated (B3LYP/6-31G(d)) VCD and IR spectra were compared, and a definitive absolute configuration of (+)-1 and (+)-2 is reassigned directly in solution as (R). The assumption of equatorial positioning of bulky groups, shown here to be invalid for the title molecules, is the underlying cause of the previous incorrect assignment of absolute configuration. Moreover, TDDFT (B3LYP/6-311++G(2d,2p)//B3LYP/6-31G(d)) calculations of ECD spectra have shown that both P- and M-helicity of the heterocyclic ring, for a given absolute configuration, lead to the same sign for the (1)L(b) ECD band, thus bringing into question the validity of the empirical ECD helicity rule for chromane molecules. (C) 2010 Elsevier Ltd. All rights reserved.

Absolute configuration reassignment of two chromanes from Peperomia obtusifolia (Piperaceae) using VCD and DFT calculations

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Long-Chain Acyl-Homoserine Lactones from Methylobacterium mesophilicum: Synthesis and Absolute Configuration

The acyl-homoserine lactones (acyl-HSLs) produced by Methylobacterium mesophilicum isolated from orange trees infected with the citrus variegated chlorosis (CVC) disease have been studied, revealing the occurrence of six long-chain acyl-HSLs, i.e., the saturated homologues (S)-N-dodecanoyl (1) and (S)-N-tetradecanoyl-HSL (5), the uncommon odd-chain N-tridecanoyl-HSL (3), the new natural product (S)-N-(2E)-dodecenoyl-HSL (2), and the rare unsaturated homologues (S)-N-(7Z)-tetradecenoyl (4) and (S)-N-(2E,7Z)-tetradecadienyl-HSL (6). The absolute configurations of all HSLs were determined as 3S. Compounds 2 and 6 were synthesized for the first time. Antimicrobial assays with synthetic acyl-HSLs against Gram-positive bacterial endophytes co-isolated with M. mesophilicum from CVC-infected trees revealed low or no antibacterial activity.

Structure and absolute configuration of mycobactin J

Mycobactin J 1 is a commercially available siderophore isolated from Mycobacterium avium subsp, paratuberculosis. There are discrepancies between previous reports of its structure and none have addressed its absolute configuration. We report here the complete structure and stereochemistry of mycobactin J, along with methodology to enable the determination of the absolute configuration of other mycobactins on a small scale. (C) 2001 Elsevier Science Ltd. All rights reserved.

A fluorescente bicyclic Calix[4] Arene-Oxacyclophane with planar chirality: Resolution, chiroptical, properties, and absolute configuration.

A new inherently chiral calix[4]arene ICC 1 has been disclosed. The dissymmetry of 1 is generated from a chirality plane in the quinol moiety of a 1,3-bridged bicyclic calix[4]arene. ICC 1 has been resolved by enantioselective HPLC, and the chiroptical properties of both isolated antipodes (pS)-1 and (pR)-1 confirm their enantiomeric nature. The absolute configuration of the (pS)-1/(pR)-1 enantiomeric pair was established through time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (CD) spectra. (C) 2014 Elsevier Ltd. All rights reserved.

Total synthesis of (+/-) maculalactone A, maculalactone B and maculalactone C and the determination of the absolute configuration of natural (+) maculalactone A by asymmetric synthesis

Maculalactones A, B and C from the marine cyanobacterium Kyrtuthrix maculans are amongst the only compounds based on the tribenzylbutyrolactone skeleton known in nature and (+) maculalactone A from the natural source possesses significant biological activity against various marine herbivores and marine settlers. We now report a concise synthesis of racemic maculalactone A in five steps from inexpensive starting materials. Maculalactones B and C were synthesized by a minor modification to this procedure, and the synthetic design also permitted an asymmetric synthesis of maculalactone A to be achieved in around 85% ee. The (+) and (-) enantiomers of maculalactone A were assigned, respectively, to the S and R configurations on the basis of the chiral selectivity expected for catecholborane reduction of an unsymmetrical ketone in the presence of Corey's oxazoborolidine catalyst. Surprisingly, it appeared that natural (+) maculalactone A was biosynthesized in K. maculans in a partially racemic form, comprising ca. 90-95% of the (S) enantiomer and 5-10% of its (R) enantiomer. Coincidentally therefore, the percentage enantiomeric excess of the product obtained from asymmetric synthesis almost exactly matched that found in nature. (C) 2004 Elsevier Ltd. All rights reserved.

(+)- and (-)-Mutisianthol: First Total Synthesis, Absolute Configuration, and Antitumor Activity

The first synthesis of the natural product (+)-mutisianthol was accomplished in 11 steps and in 21% overall yield from 2-methylanisole. The synthesis of its enantiomer was also performed in a similar overall yield. The absolute configuration of the sesquiterpene (+)-mutisianthol was assigned as (1S,3R). Key steps in the route are the asymmetric hydrogenation of a nonfunctionalized olefin using chiral iridium catalysts and the ring contraction of 1,2-dihydronaphthalenes using thallium(III) or iodine(III). The target molecules show moderate activity against the human tumor cell lines SF-295, HCT-8, and MDA-MB-435.

Absolute Configuration and Selective Trypanocidal Activity of Gaudichaudianic Acid Enantiomers

Gaudichaudianic acid, a prenylated chromene isolated from Piper gaudichaudianum, has been described as a potent trypanocidal compound against the Y-strain of Trypanosoma cruzi. We herein describe its isolation as a racemic mixture followed by enantiomeric resolution using chiral HPLC and determination of the absolute configuration of the enantiomers as (+)-S and (-)-R by means of a combination of electronic and vibrational circular dichroism using density functional theory calculations. Investigation of the EtOAc extract of the roots, stems, and leaves from both adult specimens and seedlings of P. gaudichaudianum revealed that gaudichaudianic acid is biosynthesized as a racemic mixture from the seedling stage onward. Moreover, gaudichaudianic acid was found exclusively in the roots of seedlings, while it is present in all organs of the adult plant. Trypanocidal assays indicated that the (+)-enantiomer was more active than its antipode. Interestingly, mixtures of enantiomers stowed a synergistic effect, with the racemic mixture being the most active.

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

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structure and absolute configuration of a secolignan from Peperomia blanda

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)