Letters in Organic Chemistry - Volume 16, Issue 12, 2019

A new synthesis of the 2,6-naphthyridine alkaloid 4-methyl-2,6-naphthyridine from Antirrhinum majus has been developed. Key steps are a regioselective oxidation of 3-bromo-4,5- dimethylpyridine to the corresponding 4-formyl derivative, and the annulation of the second pyridine ring by Suzuki-Miyaura cross-coupling using (E)-2-ethoxyvinylboronic acid pinacol ester as a masked acetaldehyde equivalent. This protocol gives the alkaloid in four steps starting from commercially available 3,4-dimethylpyridine in 15% overall yield. This annulation protocol should be useful for the synthesis of other condensed pyridines as well.

OctaGel resin is a unique, highly uniformed surface-active resin. Here, we compared the performance of OctaGel with that of known resins on the market, namely polystyrene and ChemMatrix, in Solid-Phase Peptide Synthesis. The synthesis of the ‘difficult’ Aib-ACP (65-74) decapeptide showed that OctaGel has the potential to yield molecules with satisfactory purity. Given its high swelling capacity and large bead size, OctaGel also shows efficient interaction with various solvents, including those mainly used for SPPS (DMF and DCM).

Rhazya stricta is a rich indole alkaloid medicinal plant species, that is used in traditional medicine particularly in Middle East countries to treat inflammations, diabetes, rheumatism, and skin disorders. The alkaloid plant extract of R. stricta was fractionated on aluminum oxide column and further purified by different chromatographic methods. The chemical structures of the isolated compounds were elucidated by interpretation of their 1D and 2D NMR, IR, UV and MS spectral data. The potential antitumor effect was examined against three cancer cell lines; HCT-116-colon cancer, PC-3-prostate cancer and HepG2-liver cancer as well as a control cell line (Vero) using MTT assay. Two new indole alkaloids, identified as 16-epi-stemmadenine-N-oxide (1) and stemmadenine-N-methyl (2), along with the known indole alkaloid 20-epi-antirhine (3) were isolated from the leaves of Rhazya stricta. Compound 2, stemmadenine-N-methyl exhibited a reasonable selectivity index and a broad anticancer effect against the examined cell lines with IC50 35.0±0.7, 35.0±0.6, 40.0±0.7and 79.0±1.0 μM, respectively. Furthermore, the effect of stemmadenine-N-methyl was evaluated on cell migration using woundhealing assay. It significantly hindered cell migration and delayed-wound healing. 16-epistemmadenine- N-oxide and stemmadenine-N-methyl are new indole alkaloids isolated from the leaves of Rhazya stricta, of which stemmadenine-N-methyl selectively inhibited the proliferation of three different cancer cell lines. In addition, it prevented cell migration and delayed wound-healing. Further studies are required to confirm the mechanism by which this promising alkaloid exhibits its antitumor activity.

Dimethyl 6,6’-bis(bromomethyl)-[2,2’-bipyridine]-4,4’-dicarboxylate (2) was synthesized from dimethyl 6,6’-dimethyl-2,2'-bipyridine-4,4'-dicarboxylate (1) through dibromination and debromination. Debromination of dimethyl 6,6’-bis(dibromomethyl)-[2,2’-bipyridine]-4,4’-dicarboxylate (4) with diethyl phosphite and N,N-diisopropylethylamine in THF afforded target product 2 in 58% overall yield. The biggest advantage of the presented method is to avoid so much impurities and the difficulty of purification in the direct bromination method reported previously.

A series of new N-heterocyclic carbene (NHC) precursors, containing bicyclic pyrrolo[1,2- c]imidazole framework, were prepared from N-(tert-butoxycarbonyl)-L-proline (1-Boc-L-proline). The sequential attachment of nitrogen nucleophiles and subsequent ring closure gave the desired bicyclic NHC precursors in good yields. The structures of these new NHC precursors were determined on the basis of spectroscopic techniques, including NMR and MS.

Deprotection is significant and conducted over mild reaction conditions, in order to restrict any more side reactions with sensitive functional groups as well as racemization or epimerization of stereo center because the protective groups are often cleaved at last stage in the synthesis. P - Methoxy benzyl (PMB) ether appears unique due to its easy introduction and removal than the other benzyl ether protecting groups. A facile, efficient and highly selective cleavage of P - methoxy benzyl ethers was reported by using 20 mole% Zinc (II) Trifluoromethanesulfonate at room temperature in acetonitrile solvent over 15-120 min. time period. To study the generality of this methodology, several PMB ethers were prepared from a variety of substrates having different protecting groups and subjected to deprotection of PMB ethers using Zn(OTf)2 in acetonitrile. In this methodology, zinc triflate cleaves only PMB ethers without affecting acid sensitivity, base sensitivity and also chiral epoxide groups.

Bis(indolyl)methane derivatives (BIMs) were synthesized in moderate to good yields by (thio)urea catalyzed electrophilic substitution of indole (2) with various aldehydes 1. Reactions were performed under conventional and microwave (MW) heating, either using 1,2-dichloroetane as solvent or without solvent. The procedure using microwave heating was also applied to the synthesis of the natural products vibrindole A (3n), arsindoline A (3i), arundine (3o) and tris(1H-indol-3-yl)methane (3j). Additionally, the synthesis of streptindole was carried out via intermediate 3g. This methodology is well suited for the synthesis of bis(indolyl)methanes: it offers good yields of products, low sensitivity to moisture and oxygen, high tolerance to different functional groups on the aldehydes such as alkynes and trimethylsilane, and simplicity in operation

A series of novel ethyl 6-[2-(3-aryl-1-phenyl-1H-pyrazol-4-yl)vinyl]-2-oxo-4-phenyl- 1,2,3,4-tetrahydropyrimidine-5-carboxylates (9a-9d) has been synthesized by adopting a multistep synthetic strategy. The structure of the targets was confirmed on the basis of physical and spectral techniques. The synthetically achieved targets were evaluated for their antioxidant activity by in-vitro DPPH free radical scavenging assay. Of the chemical entities screened, most of them exhibit good to better radical scavenging profile and among those, the nitro substituent bearing molecule 9c displayed the highest activity (82%) with IC50 value 621.6 μM. Further, as a representative molecule, compound 9a has been subjected to density functional theory calculations employing B3LYP method with 6311(++G) basis set to optimize its structure.

Disclosed herein is a general approach for the synthesis of chiral thiazolo triazoles 5a-e. An efficient 3-step synthetic strategy has been developed to obtain the fused heterocycles in good yields. The key step involves formation of a secondary carbocation under acidic condition and intramolecular attack of the nitrogen of the 1,2,4-triazolo part leads to the formation of fused bicyclic compound in a regioselective manner. A new chiral center was created during the reaction and Chiral HPLC analyses confirmed the presence of the same and the racemic nature of the synthesized compounds. Their antimicrobial activities were evaluated by broth micro-dilution method and expressed as the minimum inhibitory concentration. The preliminary bioassay results demonstrate that most of the target compounds exhibit a significantly wide spectrum activity against S. aureus and E. coli comparable to ampicillin. The efficacies of compounds against C. albicans are either more or similar compared to Griseofulvin.

Structural elucidation of synthesized 2,6-diphenylspiro[cyclohexane-1,3’-pyrido[1,2- a]pyrimidine]-2’,4,4’-trione has been done by UV, FT-IR, 1H, 13C NMR and mass spectroscopy. The molecule was further subjected to density functional theory (DFT) studies with B3LYP function using 6-31G(d,p) basis atomic set. The title molecule was investigated on the basis of thermodynamic properties, polarizability, hyperpolarizability, intermolecular interactions, HOMO and LUMO energy values, MESP, ESP and NBO computations to correlate experimental results with in-silico studies.

A series of new 1,2,4-triazole Schiff bases incorporating a chlorinated indole moiety were prepared from the condensation reaction of 4-amino-5-mercapto-3-[(5-chloro-2-methyl-1H-indol-3- yl)methyl]1,2,4-triazole with substituted benzaldehydes in the presence of (+)-tartaric acid as an acidic catalyst. The structures of Schiff bases were elucidated by FTIR, NMR and mass spectral data. The cytotoxic, antibacterial and free radical scavenging activities of Schiff bases were performed using MTT, 96-well microbroth dilution and DPPH assays, respectively. Schiff bases 3k and 3l with both electron donating groups at meta and para positions of the phenyl ring demonstrated higher cytotoxic activity against COLO-205 and A549 cell lines. On the other hand, Schiff base 3f comprising p-chlorophenyl substituent exhibited significant inhibition against Bacillus cereus and Staphylococcus aureus at MIC 3.91 μg/ml and 15.63 μg/ml, respectively. The results of the free radical scavenging activity revealed that Schiff bases with the presence of a Cl or OCH3 group in the para position of the phenyl ring act as a better antioxidant than BHT.

Isofebrifugine, as a kind of natural quinazolinone alkaloid with important physiological activities and good pharmacological effects, was isolated from a Chinese medicinal plant, Chang Shan (Dichroa febrifuga). In this paper, the synthesis of a series of novel isofebrifugine analogues was accomplished by employing the N-alkylation of 4(3H)-quinazolinones with benzyl (3aR,7aR)-rel-2- (bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)carboxylates and the subsequent N-deprotection. These analogues were characterized by 1H NMR, 13C NMR and HRMS spectra. The MTT assay was used to examine the inhibitory effects of these analogues on the growth of human hepatoma cells (HepG2). The results indicated that some halogenated or hemiketal analogues showed interesting inhibition activity.