Synthesis of Nature-Inspired Medium-Sized Fused Heterocycles from Amino Acids

Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Me...

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Bibliographic Details
Published in:Chemistry : a European journal 2015-09, Vol.21 (37), p.13112-13119
Main Authors: Ventosa-Andrés, Pilar, La-Venia, Agustina, Ripoll, Carlos Alfonso Barea, Hradilová, Ludmila, Krchňák, Viktor
Format: Article
Language:English
Subjects:
Amino acids
Amino Acids - chemical synthesis
Amino Acids - chemistry
Chemistry
Chemists
Cyclization
drug discovery
fused-ring systems
Heterocyclic Compounds - chemical synthesis
Heterocyclic Compounds - chemistry
Molecular Structure
Nucleophiles
Peptides
Pharmacology
regioselectivity
Scaffolds
solid-phase synthesis
Stereoisomerism
Synthesis (chemistry)
Three dimensional
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Summary:Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid‐phase peptide synthesis, and cyclization was carried out through acid‐mediated tandem endocyclic N‐acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven‐, eight‐, and nine‐membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases. 3D scaffolds: Molecular scaffolds consisting of diverse medium‐sized fused heterocycles were synthesized by tandem iminium ion cyclization–nucleophilic addition using amino acids as the key building blocks. The molecular scaffolds covered a variety of ring sizes including [7+5], [7+6], [8+5], and [9+5] fused rings (see scheme). The molecular scaffolds can serve as pharmacologically relevant molecules, as well as conformational constraints of peptide backbone.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201501746