Fused N‐Heterocycles with Contiguous Stereogenic Centers Accessed by an Asymmetric Catalytic Cascade Reaction of Tertiary Enamides

Abstract

We report in this article a cascade reaction strategy for the synthesis of complex N‐heterocyclic compounds with contiguous and tetrasubstituted stereogenic carbons. Under the sequential catalysis of a chiral binol–Ti complex and BF3, cyclopentanone‐derived tertiary enamides undergo an enantioselective enamine addition to ketone carbonyls followed by diastereoselective trapping of the resulting acyliminiums by electron‐rich aryl moieties to furnish four‐ and five‐membered ring‐fused N‐heterocyclic products as the sole diastereomers in high yields with up to 99 % ee.

Domino Reactions of Tertiary Enamides in Organic Synthesis

“…23 It is interesting to note that both the Lewis acid and Brønsted acid catalyzed domino double cyclization reactions work perfectly for the cyclopentanone-derived tertiary enamides, enabling the one-step construction of 5-5-6-6 fused tetracyclic ring structure in excellent yield and diastereoselectivity. 25 For example, upon the treatment with a catalytic amount of InCl3 or p-toluenesulfonic acid, tertiary enamide 34 is converted almost quantitatively into 35 as the sole product. After optimizing the chiral Lewis acid and Brønsted acid catalysts, we found the complex from chiral binol (L2) and Ti(O i Pr)4 (Cat-2) is capable of delivering highest enantioselectivity to the final product albeit the chemical yield is moderate (Scheme 9b).…”

Tertiary Enamides as Versatile and Valuable Substrates to Reach Chemical Diversity

“…More recently, Wang and co-workers examined a similar strategy -as previously mentioned -for the synthesis of complex fused N-heterocycles 120 with contiguous tetrasubstituted stereogenic centers (Scheme 21B). 37 Tertiary enamides 119 underwent enantioselective intramolecular addition to ketones with subsequent trapping of the resulting acyliminium ions by electron-rich aryl moieties to provide fused N-heterocyclic products 120 with good yields and high selectivity.…”

Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates

“…Enamides are substrates of high value in organic synthesis [1,2]. Their multifacial reactivity has been explored in asymmetric alkylations [3], hydroalkynylations [4], trifluoromethylcyanations [5], heterocycle synthesis [6], asymmetric acylations [7], hydroborations [8], hydrogenations [9], etc. They are also important pharmacophores, which display a range of cytotoxic, antifungal, or antibiotic properties [10][11][12].…”