Computational insights into the mechanisms and origins of switchable selectivity in gold(i)-catalyzed annulation of ynamides with isoxazoles via 6π-electrocyclizations of azaheptatrienyl cations.

Electrocyclizations of acyclic conjugated π-motifs have emerged as a versatile and effective strategy for accessing various ring systems with excellent functional group tolerability and controllable selectivity. Typically, the realization of 6π-electrocyclization of heptatrienyl cations to afford seven-membered motif has proven difficult due to the high-energy state of the cyclizing seven-membered intermediate. Instead, it undergoes the Nazarov cyclization, affording a five-membered pyrrole product. However, the incorporation of a Au(i)-catalyst, a nitrogen atom and tosylamide group in the heptatrienyl cations unexpectedly circumvented the aforementioned high energy state to afford a seven-membered azepine product via 6π-electrocyclization in the annulation of 3-en-1-ynamides with isoxazoles. Therefore, extensive computational studies were carried out to investigate the mechanism of Au(i)-catalyzed [4+3] annulation of 3-en-1-ynamides with dimethylisoxazoles to produce a seven-membered 4H-azepine via the 6π-electrocyclization of azaheptatrienyl cations. Computational results showed that after the formation of the key α-imino gold carbene intermediate, the annulation of 3-en-1-ynamides with dimethylisoxazole occurs via the unusual 6π-electrocyclization to afford a seven-membered 4H-azepine exclusively. However, the annulation of 3-cyclohexen-1-ynamides with dimethylisoxazole occurs via the commonly proposed aza-Nazarov cyclization pathway to majorly generate five-membered pyrrole derivatives. The results from the DFT predictive analysis revealed that the key factors responsible for the different chemo-, and regio-selectivities observed are the cooperating effect of the tosylamide group on C1, the uninterrupted π-conjugation pattern of the α-imino gold(i) carbene and the substitution pattern at the cyclization termini. The Au(i)-catalyst is believed to assist in the stabilization of the azaheptatrienyl cation.

Synthesis and in vitro anticancer activities of substituted N-(4'-nitrophenyl)-l-prolinamides.

Prolinamides are present in secondary metabolites and have wide-ranging biological properties as well as antimicrobial and cytotoxic activities. N-(4'-substituted phenyl)-l-prolinamides 4a-4w were synthesized in two steps, starting from the condensation of p-fluoronitrobenzene 1a-1b with l-proline 2a-2b, under aqueous-alcoholic basic conditions to afford N-aryl-l-prolines 3a-3c, which underwent amidation via a two-stage, one-pot reaction involving SOCl2 and amines, to furnish l-prolinamides in 20-80% yield. The cytotoxicities of 4a-4w against four human carcinoma cell lines (SGC7901, HCT-116, HepG2 and A549) were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; with good tumour inhibitory activities (79.50 ± 1.24%-50.04 ± 1.45%) against HepG2. 4a exhibited the best anti-tumour activity against A549 with percentage cell inhibition of 95.41 ± 0.67% at 100 µM. Likewise, 4s (70.13 ± 3.41%) and 4u (83.36 ± 1.70%) displayed stronger antineoplastic potencies against A549 than the standard, 5-fluorouracil (64.29 ± 2.09%), whereas 4a (93.33 ± 1.36%) and 4u (81.29 ± 2.32%) outperformed the reference (81.20 ± 0.08%) against HCT-116. SGC7901 showed lower percentage cell viabilities with 4u (8.02 ± 1.54%) and 4w (27.27 ± 2.38%). These results underscore the antiproliferative efficacies of l-prolinamides while exposing 4a and 4u as promising broad-spectrum anti-cancer agents. Structure-activity relationship studies are discussed.