Enantioselective Synthesis of Medium‐Sized Lactams via Chiral α,β‐Unsaturated Acylammonium Salts

Abstract

Medium-sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium-sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral α,β-unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and δ-lactones.

Palladium‐Catalyzed [4+2] and [5+2] Annulation for the Synthesis of Tetrahydroquinolines and 1,4‐Benzoxazepines

“…The palladium‐catalyzed cyclization of propargylic compound, particularly of propargylic carbonates, via the key intermediate of π‐propargyl palladium has been well developed for the synthesis of various cyclic compounds. In this paper, we reported a palladium‐catalyzed [4+2] annulation of propargylic carbonates with malonate‐tethered anilines to give tetrahydroquinoline (Scheme , reaction a). The corresponding [5+2] annulation of propargylic carbonates with 2‐aminobenzylic alcohols to give 1,4‐benzoxazepines was also realized (Scheme , reaction b).…”

Innentitelbild: Enantioselective Organocatalytic Four‐Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones (Angew. Chem. 2/2019)

“…[5] Lately,two organocatalytic approaches were reported relying on Lewis base catalysis:Lu, Ullah, and co-workers proposed a( 4 + +4) annulation based on allenes activation with ac hiral phosphine catalyst to afford azocines, [6] and the group of Romo used the reactivity of catalytically generated a,b-unsaturated acyl ammonium salts with ac hiral tertiary amine catalyst in (5+ +3) annulations. [7] Over the last two decades,o rganocatalytic cascade reactions have established as ag eneral and sustainable strategy to rapidly access highly functionalized, structurally diverse and complex molecules free from metal residues. [8] Nevertheless, most of the established organocascades focus on the preparation of energetically favorable five-and six-membered rings.Otherwise,ring expansion strategies provide an appealing way to prepare medium-sized rings from readily available small rings.…”

“…Notably,c hiral glutarimide moieties are found in biologically active natural and synthetic products including marketed drugs, [16] but enantioselective methods for their synthesis remain scarce. [7,17] Ascreening of archetypal Brønsted and Lewis bases with substrate 3b (Table S1 in the Supporting Information) allowed identifying DBU as acompetent catalyst for the desired transformation, which after optimization afforded the glutarimide 4b in good yield without significant erosion of optical purity but some epimerization at the imide enolizable position. Similarly,t he benzazocinones 3e,3eh, 3ei and ent-3 k reacted with DBUto afford the corresponding glutarimides 4e,4h, 4i, and ent-4 k. Mechanistically,t his transformation may proceed by at hermodynamically-controlled transannular ring-rearrangement involving the Brønsted base properties of the catalyst.…”

Enantioselective Organocatalytic Four‐Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones

“…[5] Lately, two organocatalytic approaches were reported relying on Lewis base catalysis: Lu, Ullah, and co-workers proposed a (4+ +4) annulation based on allenes activation with a chiral phosphine catalyst to afford azocines, [6] and the group of Romo used the reactivity of catalytically generated a,b-unsaturated acyl ammonium salts with a chiral tertiary amine catalyst in (5+ +3) annulations. [7] Over the last two decades, organocatalytic cascade reactions have established as a general and sustainable strategy to rapidly access highly functionalized, structurally diverse and complex molecules free from metal residues. [8] Nevertheless, most of the established organocascades focus on the preparation of energetically favorable five-and six-membered rings.…”

“…Notably, chiral glutarimide moieties are found in biologically active natural and synthetic products including marketed drugs, [16] but enantioselective methods for their synthesis remain scarce. [7,17] A screening of archetypal Brønsted and Lewis bases with substrate 3 b (Table S1 in the Supporting Information) allowed identifying DBU as a competent catalyst for the desired transformation, which after optimization afforded the glutarimide 4 b in good yield without significant erosion of optical purity but some epimerization at the imide enolizable position. Similarly, the benzazocinones 3 e, 3 eh, 3 ei and ent-3 k reacted with DBU to afford the corresponding glutarimides 4 e, 4h, 4 i, and ent-4 k. Mechanistically, this transformation may proceed by a thermodynamically-controlled transannular ring-rearrangement involving the Brønsted base properties of the catalyst.…”