Efficient Entry to the [2.2.2]-Diazabicyclic Ring System via Diastereoselective Domino Reaction Sequence

Abstract

A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition for the synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.

Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

“…A provocative biosynthetic hypothesis involving an oxidative hetero-Diels-Alder cycloaddition, that generates the central diazabicyclo[2.2.2]octane core, was proposed by Porter and Sammes [7]. Based on that, biomimetic synthetic strategies were pursued independently by Williams [8], Liebscher [9], and more recently by Scheerer [10][11][12][13] and others [14,15].…”

Domino Transformations of Ene/Yne Tethered Salicylaldehyde Derivatives: Pluripotent Platforms for the Construction of High sp3 Content and Privileged Architectures

“…In this regard, Scheerer et al. reported an important single‐pot domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular diketopiperazine Diels–Alder cycloaddition (Scheme ) . This cascade generated a molecular complexity through the formation of three new bonds and two new rings in a single pot.…”

“…In Review Diels-Alder cycloaddition (Scheme 21). [48] This cascade generated am olecular complexity throught he formation of three new bonds and two new rings in as inglep ot. Ak ey step in this cascade is the Diels-Alder cycloaddition leading to the access of [2.2.2]-diazabicyclic structures of type 90.Adetachable diketopiperazine substituent was employed in this sequence.…”

Chemo- and Diastereoselective Synthesis of N-Propargyl Oxazolidines through a Copper-Catalyzed Domino A3 Reaction

“…Chiral oxazolidine derivatives have gained considerable attention due to their broad biological profiles in medicinal chemistry and wide utilities in chemical and material research . Among them, the study of 1,3-oxazolidine compounds as a synthetic antibiotic or κ opioid receptor agonist is of growing interest, such as quinocarcin, malbracheamide B unit, and SKY-146 (Figure ). Meanwhile, these structural motifs are diffusely explored as chiral ligands, catalysts, and chiral building blocks, exhibiting high enantioselectivity in asymmetric synthesis.…”