Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

A convenient and efficient synthesis of novel achiral and chiral heterocyclic amino acid-like building blocks was developed. Regioisomeric methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC analysis, 1H, 13C, and 15N NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data.

Stereoselective Nanocarbon Imides Featuring 12-fold [5]helicenes

Despite the great progress in research on chiral molecular nanocarbons containing multiple helicenes, controlling the stereoselectivity is still a major challenge, especially when attempting to increase the number of helicene moieties. Herein, a novel molecular nanocarbon imides composed of C204 skeleton and eighteen imide groups was successfully synthesized via an inside–out ring closing strategy involving repeated Suzuki–Miyaura coupling for C–C bond formation and photocyclic aromatization. Because of the presence of quad–core twelvefold [5]helicenes, there are, in theory, more than one hundred stereoisomers. However, only one pair of stereoisomers with D3 symmetry was observed. Despite the large and rigid skeleton, the (3M,3M,3M,3M)+(3P,3P,3P,3P) enantiomers were successfully separated by chiral HPLC, and the chiroptical properties were investigated by CD spectroscopy.

Synthesis of a Möbius carbon nanobelt

New technologies for the creation of topological carbon nanostructures have significantly advanced synthetic organic chemistry and materials science. While simple molecular nanocarbons with a belt topology have been constructed recently, analogous carbon nanobelts with a twist, i.e., Möbius carbon nanobelts (MCNBs), have not yet been synthesized due to their high intrinsic strain. Herein, we report the synthesis, isolation, and characterization of a MCNB. Calculations of strain energies suggested that large MCNBs are synthetically accessible. Designing a macrocyclic precursor with an odd number of repeat units led to a successful rational synthetic route via Z-selective Wittig reactions and nickel-mediated intramolecular homocoupling reactions, which yielded (25,25)MCNB over 14 steps. NMR and theoretical calculations revealed that the twist moiety of the Möbius band moves quickly around the MCNB molecule in solution. The topological chirality originating from the Möbius structure was confirmed experimentally using chiral HPLC separation and CD spectroscopy.

Six New Antimicrobial Metabolites from the Deep-Sea Sediment-Derived Fungus Aspergillus fumigatus SD-406

Six new metabolites, including a pair of inseparable mixtures of secofumitremorgins A (1a) and B (1b), which differed in the configuration of the nitrogen atom, 29-hydroxyfumiquinazoline C (6), 10R-15-methylpseurotin A (7), 1,4,23-trihydroxy-hopane-22,30-diol (10), and sphingofungin I (11), together with six known compounds (2–5 and 8–9), were isolated and identified from the deep-sea sediment-derived fungus Aspergillus fumigatus SD-406. Their structures were determined by detailed spectroscopic analysis of NMR and MS data, chiral HPLC analysis of the acidic hydrolysate, X-ray crystallographic analysis, J-based configuration analysis, and quantum chemical calculations of ECD, OR, and NMR (with DP4+ probability analysis). Among the compounds, 1a/1b represent a pair of novel scaffolds derived from indole diketopiperazine by cleavage of the amide bond following aromatization to give a pyridine ring. Compounds 1, 4, 6, 7, 10 and 11 showed inhibitory activities against pathogenic bacteria and plant pathogenic fungus, with MIC values ranging from 4 to 64 μg/mL.

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

A genome mining survey combined with metabolome analysis of publicly available strains identified Couchioplanes sp. RD010705, a strain belonging to an underexplored genus of rare actinomycetes, as a producer of new metabolites. HPLC-DAD-guided fractionation of its fermentation extracts resulted in the isolation of five new methyl-branched unsaturated fatty acids, (2E,4E)-2,4-dimethyl-2,4-octadienoic acid (1), (2E,4E)-2,4,7-trimethyl-2,4-octadienoic acid (2), (R)-(−)-phialomustin B (3), (2E,4E)-7-hydroxy-2,4-dimethyl-2,4-octadienoic acid (4), (2E,4E)-7-hydroxy-2,4,7-trimethyl-2,4-octadienoic acid (5), and one prenylated tryptophan derivative, 6-(3,3-dimethylallyl)-N-acetyl-ʟ-tryptophan (6). The enantiomer ratio of 4 was determined to be approximately S/R = 56:44 by a recursive application of Trost’s chiral anisotropy analysis and chiral HPLC analysis of its methyl ester. Compounds 1–5 were weakly inhibitory against Kocuria rhizophila at MIC 100 μg/mL and none were cytotoxic against P388 at the same concentration.

Isolation, Structure Determination of Sesquiterpenes from Neurolaena lobata and Their Antiproliferative, Cell Cycle Arrest-Inducing and Anti-Invasive Properties against Human Cervical Tumor Cells

Seven new germacranolides (1–3, 5–8), among them a heterodimer (7), and known germacranolide (4), eudesmane (9) and isodaucane (10) sesquiterpenes were isolated from the aerial parts of Neurolaena lobata. Their structures were determined by using a combination of different spectroscopic methods, including HR-ESIMS and 1D and 2D NMR techniques supported by DFT-NMR calculations. The enantiomeric purity of the new compounds was investigated by chiral HPLC analysis, while their absolute configurations were determined by TDDFT-ECD and OR calculations. Due to the conformationally flexible macrocycles and difficulties in assigning the relative configuration, 13C and 1H NMR chemical shift and ECD and OR calculations were performed on several stereoisomers of two derivatives. The isolated compounds (1–10) were shown to have noteworthy antiproliferative activities against three human cervical tumor cell line with different HPV status (HeLa, SiHa and C33A). Additionally, lobatolide C (6) exhibited substantial antiproliferative properties, antimigratory effect, and it induced cell cycle disturbance in SiHa cells.

Regioselective and Stereoselective Epoxidation of n-3 and n-6 Fatty Acids by Fungal Peroxygenases

Epoxide metabolites from n-3 and n-6 polyunsaturated fatty acids arouse interest thanks to their physiological and pharmacological activities. Their chemical synthesis has significant drawbacks, and enzymes emerge as an alternative with potentially higher selectivity and greener nature. Conversion of eleven eicosanoid, docosanoid, and other n-3/n-6 fatty acids into mono-epoxides by fungal unspecific peroxygenases (UPOs) is investigated, with emphasis on the Agrocybe aegerita (AaeUPO) and Collariella virescens (rCviUPO) enzymes. GC-MS revealed the strict regioselectivity of the n-3 and n-6 reactions with AaeUPO and rCviUPO, respectively, yielding 91%-quantitative conversion into mono-epoxides at the last double bond. Then, six of these mono-epoxides were obtained at mg-scale, purified and further structurally characterized by 1H, 13C and HMBC NMR. Moreover, chiral HPLC showed that the n-3 epoxides were also formed (by AaeUPO) with total S/R enantioselectivity (ee > 99%) while the n-6 epoxides (from rCviUPO reactions) were formed in nearly racemic mixtures. The high regio- and enantioselectivity of several of these reactions unveils the synthetic utility of fungal peroxygenases in fatty acid epoxidation.

Enantioselective Synthesis, Tautomerism, Molecular Docking And Biological Evaluation of 4-Hydroxy-3-(3-Oxo-1-Phenylbutyl)-2H-Chromen-2-One Analogues

Keeping in view the aim of better alternatives of 4-Hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one (warfarin), eleven analogs of warfarin have been synthesized with the goal to increase enantioselectivity of (S) enantiomer by using appropriate catalyst and minimize tautomerism by replacing methyl group of the side chain with aryl group. There are many reports of the serious complications with warfarin use, which are associated with the tautomeric forms of warfarin. The key step was highly enantioselective Michael addition of variously substituted chalcone and 4-hydroxycoumarin by using cinchona based 9-amino-9-deoxyepiquinine as chiral catalyst. Synthesized compounds were characterized by IR, 1HNMR,13CNMR, EIMS and CD studies. Enantiomeric excess (%ee) was determined by chiral HPLC which was upto 98%. Synthesized analogues were screened for anticoagulant, antibacterial and antifungal activities. In-vitro anticoagulant activity was evaluated by plasma recalcification time (PRT) method and out of eleven, ten synthesized compounds showed improved IC50 values as compaired to IC50 values of standard drug warfarin. Compound 4 showed 68.25% inhibation against staphylococcus aureus and compound 7 showed 68% inhibation against bacillus subtillis, gram positive strains of bacteria, compound 6 shows 70% inhibation against fungal strain candida albicans. Furthermore, molecular docking studies were carried out with Vitamin K1 epoxide reductase VKOR1 receptor 3kp9, a potential target of warfarin for anticoagulant activity.

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

A genome mining survey combined with metabolome analysis of publicly available strains identified Couchioplanessp. RD010705, a strain belonging to an underexplored genus of rare actinomycetes, as a producer of new metabolites. HPLC-DAD-guided fractionation of its fermentation extracts resulted in the isolation of five new methyl-branched unsaturated fatty acids, (2E,4E)-2,4-dimethyl-2,4-octadienoic acid (1), (2E,4E)-2,4,7-trimethyl-2,4-octadienoic acid (2), (R)-(–)-phialomustin B (3), (2E,4E)-7-hydroxy-2,4-dimethyl-2,4-octadienoic acid (4), (2E,4E)-7-hydroxy-2,4,7-trimethyl-2,4-octadienoic acid (5), and one prenylated tryptophan derivative, 6-(3,3-dimethylallyl)-N-acetyl-L-tryptophan (6). The enantiomer ratio of 4 was determined to be approximately S/R = 56/44 by a recursive application of Trost’s chiral anisotropy analysis and chiral HPLC analysis of its methyl ester. Compounds 1–5 were weakly inhibitory against Kocuria rhizophila at MIC 100 mg/mL and none were cytotoxic against P388 at the same concentration.