title: Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence.
abstract: Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Rico
authors.initials: R
authors.lastname: Petersen
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: A Emil
authors.initials: AE
authors.lastname: Cohrt
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Michael Åxman
authors.initials: MÅ
authors.lastname: Petersen
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark. Electronic address: mhc@kemi.dtu.dk.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Clausen
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 207, DK-2800 Kgs. Lyngby, Denmark; Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 637551 Singapore, Singapore. Electronic address: ten@kemi.dtu.dk.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
mesh_terms: D000577:Amides / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis*; D061565:Cycloaddition Reaction; D055808:Drug Discovery; D007546:Isoquinolines / Q000138:chemical synthesis*; D008670:Metals / Q000737:chemistry*; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis*
chemical_list: D000577:Amides; D001688:Biological Products; D007546:Isoquinolines; D008670:Metals; D054852:Small Molecule Libraries
keywords: Drug discovery; Heterocycles; Molecular diversity; Molecular libraries; Pictet–Spengler