A concise and efficient reverse-phase high-performance liquid chromatography (RPLC) method has been established for absolute optical purity assay of 2-amino-1-butanol, which is an important synthetic intermediate of various drugs. Its enantiomers were derivatized with methyl (5-fluoro-2,4-dinitro-phenyl)-(S)-prolinate, which could be regarded as a structural variant of Marfey's reagent. The resultant diastereomers were further cyclized using bis(trichloromethyl)carbonate to form oxazolidin-2-one ring, leading to a distinct difference in their electronic circular dichroism (ECD) spectra. Time-dependent density functional theory (TDDFT) was then applied to simulate theoretical ECD spectra for unambiguous absolute configuration assignment of cyclized products without putative samples. Both pairs of diastereomers could be separated on a reverse-phase C18 column using a mobile phase of methanol or acetonitrile and water with UV detection at 336 nm. The tandem reactions could be integrated into one-pot synthesis with high yield. Thus, exact absolute optical purity of 2-amino-1-butanol could be directly determined by monitoring the peak ratios of these diastereomers. This method is well worth extending to the absolute optical purity assessment of other chiral amino alcohols.

A concise and efficient reverse-phase high-performance liquid chromatography (RPLC) method has been established for absolute optical purity assay of 2-amino-1-butanol, which is an important synthetic intermediate of various drugs. Its enantiomers were derivatized with methyl (5-fluoro-2,4-dinitro-phenyl)-(S)-prolinate, which could be regarded as a structural variant of Marfey's reagent. The resultant diastereomers were further cyclized using bis(trichloromethyl)carbonate to form oxazolidin-2-one ring, leading to a distinct difference in their electronic circular dichroism (ECD) spectra. Time-dependent density functional theory (TDDFT) was then applied to simulate theoretical ECD spectra for unambiguous absolute configuration assignment of cyclized products without putative samples. Both pairs of diastereomers could be separated on a reverse-phase C18 column using a mobile phase of methanol or acetonitrile and water with UV detection at 336 nm. The tandem reactions could be integrated into one-pot synthesis with high yield. Thus, exact absolute optical purity of 2-amino-1-butanol could be directly determined by monitoring the peak ratios of these diastereomers. This method is well worth extending to the absolute optical purity assessment of other chiral amino alcohols.

•Six pairs of enantiomeric alkaloids were isolated from Chelidonium majus.•Scalemic mixtures were characterized via chiral HPLC analysis and ECD data.•Absolute configurations were assigned via resolution and ECD data.•Active compound inhibited the growth of human MDA-MB-231 cell line.•Relevant biochemical reactions in C. majus are very nonselective.Six pairs of previously undescribed 6-monosubstituted dihydrobenzophenanthridine alkaloids were separated as corresponding six scalemic mixtures from the aerial part of Chelidonium majus. The elucidation for the 2D structures of these alkaloids was achieved using regular spectroscopic and chemical methods. The assignment of scalemic-mixture nature was achieved using combined examinations of their NMR data, CD spectra, calculation of specific rotations, and chiral HPLC profiles. The identification for the relative configurations of alkaloids possessing two asymmetric carbons directly connected up by a rotatable sp3-sp3 carbon-carbon single bond was significantly facilitated by discussing the erythro and threo relative configurations defined by the mutuality of the orders of decreasing steric hindrances between the two sets of ligands linked to the two chiral centers. Two scalemic mixtures were assigned as (1′R,6R/1′S,6S)- and (1′S,6R/1′R,6S)-1-(dihydrochelerythrine-6-yl)ethanols, two as (1′R,6R)/(1′S,6S)- and (1′S,6R)/(1′R,6S)-1-(dihydrosanguinarine-6-yl)ethanols, one as (±)-ethyl 2-(dihydrosanguinarine-6-yl)acetate, and one as (±)-ethyl dihydrosanguinarine-6-carboxylate, respectively. The resolution of three scalemic mixtures was achieved and the absolute configurations of the three pairs of enantiomers were assigned via time-dependent Density Functional Theory calculations of electronic circular dichroism (ECD) data. The assignment for the absolute configurations of the other three scalemic mixtures was achieved via a chiral HPLC-UV/CD method plus analyzing their ECD data. The findings of this paper demonstrated that the relevant biochemical reactions concerning the construction of these 6-monosubstituted dihydrobenzophenanthridine alkaloids in the test plant are very nonselective. Scalemic mixture of (1′R,6R)/(1′S,6S)-1-(dihydrosanguinarine-6-yl)ethanol exhibited biological activity. It inhibited the growth of human MDA-MB-231 cell line at a moderate level with IC50 value of 5.12 μM.Six previously undescribed 6-monosubstituted dihydrobenzophenanthridine alkaloids were identified from C. majus, all characterizec as scalemic mixtures of enantiomers. Resolution and identification of absolute configurations were achieved.Download high-res image (209KB)Download full-size image

•Efficient synthesis of the unnatural amino acids for stapled peptide was developed.•Synthesis strategy by chiral Ni(II) complex was modified and optimized.•α-Bisalkenyl amino acid was synthesized by achiral Ni(II) complex strategy.•Reaction condition, yield, atom economy, and optical purity were optimized.The procedures for the synthesis of various α-alkenyl and alkyne amino acids were systematically optimized in light of enhancing atom economy, reducing hazardous reagent usage, and simplifying workup. By starting with Boc-Pro-OH and coupling with EDCI/DMAP followed by alkylation, chiral auxiliary was synthesized with high yield and enantioselectivity. For alkylation of the chiral complex, tBuONa was found and proved by quantitative calculation to be superior to tBuOK in generating more nucleophilic enolate salt, thereby can significantly enhance yield under room temperature. Final Fmoc protection was also dramatically facilitated in one-pot sequential manner by adding EDTA-2Na as the nickel chelator. Synthesis of α-bisalkenyl amino acid was also accomplished by achiral complex approach with high yield and efficacy. Accordingly, five most commonly used N-Fmoc protected α-alkenyl and alkynyl amino acids were synthesized and characterized.Download high-res image (92KB)Download full-size image

•A novel isoquinoline alkaloid hendersine A was isolated from Corydalis hendersonii.•It was elucidated on the analysis of spectroscopic data, including calculated ECD.•A possible biosynthetic pathway to hendersines A and B (1 and 2) was proposed.•All isolates were assayed for neuroprotective and anti-inflammatory activities.A pair of enantiomeric alkaloids, (±) hendersine A (1a and 1b), featuring an unprecedented couple pattern of an isoquinoline and a succinic acid derivative, a new isoquinoline hendersine B (2), and a known (+)-magnoflorine (3) were isolated from the EtOH extract of Corydalis hendersonii. Their structures were elucidated on the basis of spectroscopic data including HRESIMS, NMR, and experimental and calculated electronic circular dichroism (ECD). Compound 3 exhibited strong inhibitory effects against Ca2+ overload in glutamate-induced PC12 cells. Compounds 1–3 exhibited a protective effect against H9c2 myocyte injuries induced by LPS-stimulation conditioned medium.

•Four new PPAPs were isolated from air-dried aerial parts of Hypericum scabrum.•All structures were determined by NMR spectroscopic methods and experimental and calculated ECD spectra.•Parts of compounds showed significant neuroprotective effects and moderate hepatoprotective activities at 10 μM.Hyperibrins A−D (1–4), polycyclic polyprenylated acylphloroglucinol derivatives, were identified from air-dried aerial parts of Hypericum scabrum. All structures were determined by NMR spectroscopic methods and experimental and calculated ECD spectra. Compounds 1, 3, and 4 showed significant neuroprotective effects on glutamate-induced toxicity in SK-N-SH cells. Additionally, compounds 3 and 4 showed moderate hepatoprotective activities against paracetamol-induced HepG2 cell damage.

Chiroptical properties including electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) of artemisinin and artemether have been fully studied using quantum-chemical calculation based on time-dependent density functional theory. Both theoretical ECD and ORD of these two compounds were in good match with the experimental data. ECD spectrum of artemether could be totally attributed to the peroxide group, and that of artemisinin was an overlay of contribution from δ-lactone and peroxide moieties, which leading to a positive maximum at 260 nm. Our results showed that peroxide group could produce a broad ECD band in the far-UV region originated from electron transitions of HOMO → LUMO, HOMO−1 → LUMO and HOMO−2 → LUMO in the case of artemether. This work provided a theoretical interpretation of the ECD behavior of peroxide bond.Chiroptical properties of antimalaria drugs artemisinin and artemether have been calculated theoretically using quantum-chemical method and showed high coincidence with the experimental data. The n → σ* transitions with lone pair electrons of all oxygen atoms in a carbon–oxygen chain contributed to the ECD profile of the peroxide bridge.

Buagafuran is a novel drug candidate derived from natural product. Its absolute configuration has been confirmed by electronic circular dichroism combined with modern quantum-chemical calculation using time-dependent density functional theory. The predicted UV absorbance peak is underestimated by several nanometers compared with the experimental data. The applicability of empirical rule for the CCCO system in Buagafuran has also been discussed. Our results show that electronic circular dichroism could be a useful tool for the absolute configuration assignment of chiral drugs, especially for the oily or semisolid substances, whose crystal structures are impossible to obtain.The absolute configuration of Buagafuran has been confirmed as (1R,6S,9R) by a combination of experimental and theoretical electronic circular dichroism studies.

(−)-(3R, 4S)-3-Acetoxy-4-phenylazetidin-2-one ((−)-1) was the key intermediate for preparing optical C-13 side-chain moiety in partial synthesis of docetaxel and paclitaxel. It can be successfully prepared via enantioselective hydrolysis of racemic esters ((±)-1) catalyzed by bacterial lipases, but the current reaction evaluation method is tedious and inconvenient. Electronic circular dichroism (ECD) has been widely applied in the stereochemical study of chiral compounds. In this paper, a rapid ECD spectroscopic method has been proposed and established to detect the transformation directly. The absolute configurations of lipase-catalyzed hydrolysis products have also been confirmed by quantum-chemical calculation using time-dependent density functional theory (TDDFT) methodology.

Phthiobuzone is a bis(thiosemicarbazone) derivative with a single chiral center which has been used as a racemate in the clinical treatment of herpes and trachoma diseases. In this study, its two enantiomers were prepared from chiral amino acids and their absolute configurations were investigated by electronic circular dichroism (ECD) combined with modern quantum-chemical calculations using time-dependent density functional theory. It was found that solvation changed both the conformational distribution and the ECD spectrum of each conformer. The theoretical ECD spectra of the two enantiomers were in good agreement with the experimentally determined spectra of the corresponding isomers in dimethyl sulfoxide. The ECD behavior of the bis(thiosemicarbazone) chromophore in a chiral environment is also discussed. Our results indicate that ECD spectroscopy may be a useful tool for the stereochemical evaluation of chiral drugs.The absolute configurations of chiral Phthiobuzones have been assigned by a combination of experimental and theoretical electronic circular dichroism study.Download full-size image