Modular Bi‐Directional One‐Pot Strategies for the Diastereoselective Synthesis of Structurally Diverse Collections of Constrained β‐Carboline‐Benzoxazepines

Abstract

The development of robust and efficient strategies to access structurally diverse drug-like compound collections remains an important challenge for small molecule probe development and drug discovery. Following a build/couple/pair strategy we have established bidirectional approach to unprecedented benzoxazepines by employing a Pictet-Spengler/aza-Michael addition cascade and Schiff base/aza-Michael addition/reduction protocols, respectively. The corresponding β-carboline-fused benzoxazepines and peripherally substituted benzoxazepines are isolated in high diastereoselectivity, good to excellent yields and have, to the best of our knowledge, never been reported.

Sequencing [4 + 1]-Cycloaddition and Aza-Michael Addition Reactions: A Diastereoselective Cascade for the Rapid Access of Pyrido[2′,1′:2,3]/Thiazolo[2′,3′:2,3]imidazo[1,5-a]quinolone Scaffolds as Potential Antibacterial and Anticancer Motifs

“…The latter sets the stage for a Michael addition reaction to deliver the tetracyclic product of type VI . This initiative commonality with the many reports from our group describes the rapid synthesis of a diverse collection of privileged and nature-inspired architectures. , The ultimate goal of these initiatives is to establish a quality and diverse compound collections needed for our drug discovery campaign. In this context, we envisioned the synthesis of a pilot library of polyfunctionalized and conformationally constrained imidazo­[1,5- a ]­quinoline analogues.…”

Multidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds

“…Borrowing inspiration from our previous reports directed toward privileged substructure diversity-oriented synthesis 29 , 30 , it was envisioned that subjecting the 4-oxocyclohexa-2,5-dienyloxy)acetaldehyde 2a , and variants thereof, to reactions with various tryptamine derivatives should lead to a structurally complex and skeletally diverse octahydroindolo[2,3-a]quinolizine scaffolds (Fig. 3 ).…”

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

“…In 2017, our group reported ab i-directional build/couple/ pair strategy for the unprecedented synthesis of b-carbolinefused benzoxazepines of type 40 and peripherally substituted benzoxazepines of type 38.T he diversel ibrary of benzoxaze-pines was established by employing either aP ictet-Spengler/ aza-Michael addition cascade or Schiff base/aza-Michael addition/reductionp rotocol. [30] These divergentc ascades utilized readilya ccessible 2-allyloxy arylaldehydes( 36)a nd heteroaryl/ aryl amines (37, 39;S cheme 9). The observed trans-diastereoselectivity of b-carboline-fused benzoxazepines (40)i sa ttributed to the preferred intramolecular orientation of the reaction partners in the Pictet-Spengler reaction.…”

“…In 2017, our group reported a bi‐directional build/couple/pair strategy for the unprecedented synthesis of β‐carboline‐fused benzoxazepines of type 40 and peripherally substituted benzoxazepines of type 38 . The diverse library of benzoxazepines was established by employing either a Pictet–Spengler/aza‐Michael addition cascade or Schiff base/aza‐Michael addition/reduction protocol . These divergent cascades utilized readily accessible 2‐allyloxy arylaldehydes ( 36 ) and heteroaryl/aryl amines ( 37 , 39 ; Scheme ).…”