Stereo‐ and Regioselective [3+3] Annulation Reaction Catalyzed by Ytterbium: Synthesis of Bicyclic 1,4‐Dihydropyridines

Abstract

An ytterbium catalyzed formal [3+3] cycloaddition of cyclic enamines and α,β‐unsaturated ketones catalyzed is reported. The reaction proceeds with a ‘head to tail’ regioselectivity through a conjugate addition of the enamine moiety followed by an amine‐carbonyl condensation. In addition the use of chiral enamines provided a high degree of stereoselectivity, driven by a possible balance between steric and π‐stacking effects. The resulting bicyclic 1,4‐dihydropyridines were evaluated as antiproliferative agents against A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma) human tumor cell lines. Good toxicities were found for some of the compounds against A549 and SKOV3 cell lines, with best IC50 values of 0.89 μM for A549 and 6.69 μM for SKOV3, and a very good selectivity was observed towards MRC5 (non‐malignant) cell lines.

Enantioselective Friedel–Crafts Alkylation of Indoles with β,γ-Unsaturated α-Ketoesters Catalyzed by New Copper(I) Catalysts

“…The crude product was extracted with CH 2 Cl 2 (50 mL × 3) and the combined organic layer was washed with saturated aqueous NaHCO 3 (100 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The product was purified by flash chromatography (petroleum ether: ethyl acetate = 20: 1) …”

“…The product was purified by flash chromatography (petroleum ether: ethyl acetate = 20: 1). 16 General Procedures of Enantioselective Friedel−Crafts Alkylation Reactions. A mixture of chiral ligand (L7, 5 mol %) and CuOTf (5 mol %) in CH 2 Cl 2 (2.0 mL) was stirred for 1 h under an argon atmosphere.…”

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

“…In addition, similar cyclic enamines have proved to be excellent substrates in [3+3] annulation reactions [ 12 ]. For this reason, enamine-derived chiral lactam 5b was treated with β,γ-unsaturated α-ketoester 22 in the presence of a catalytic amount of ytterbium triflate, leading to the formation of a single diastereoisomer of bicyclic dihydropyridine 23 in excellent yield ( Scheme 8 ).…”

“…Thus, tremendous efforts have been devoted during the last decades towards the efficient synthesis of functionalized γ-lactam derivatives [ 3 , 4 , 5 , 6 , 7 ]. In particular, 3-pyrrolin-2-ones (also named as 1,5-dihydropyrrol-2-ones), closely related to γ-lactams, are not only useful building blocks in chemical synthesis [ 8 , 9 ], but also core structures of bioactive natural products and pharmaceuticals [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…Key features of the structure of those substrates are the very reactive cyclic enamine moiety and the presence of a chiral stereocenter at the 5-membered ring. Taking the advantage of those two characteristics, we have used 3-amino 3-pyrrolin-2-ones as substrates in Lewis-acid-catalyzed formal [3+3] annulation reactions, for the preparation of bicyclic 1,4-dihidropyridines with a remarkably high degree of stereoselectivity [ 12 ]. Considering the easiness of the multicomponent preparation of 3-amino 3-pyrrolin-2-ones and their synthetic potential in organic synthesis, we thought that a study on the synthetic applications of such lactam substrates would be of great interest in the field.…”