Design, Synthesis, and Utility of Defined Molecular Scaffolds

Abstract

A growing theme in chemistry is the joining of multiple organic molecular building blocks to create functional molecules. Diverse derivatizable structures—here termed “scaffolds” comprised of “hubs”—provide the foundation for systematic covalent organization of a rich variety of building blocks. This review encompasses 30 tri- or tetra-armed molecular hubs (e.g., triazine, lysine, arenes, dyes) that are used directly or in combination to give linear, cyclic, or branched scaffolds. Each scaffold is categorized by graph theory into one of 31 trees to express the molecular connectivity and overall architecture. Rational chemistry with exacting numbers of derivatizable sites is emphasized. The incorporation of water-solubilization motifs, robust or self-immolative linkers, enzymatically cleavable groups and functional appendages affords immense (and often late-stage) diversification of the scaffolds. Altogether, 107 target molecules are reviewed along with 19 syntheses to illustrate the distinctive chemistries for creating and derivatizing scaffolds. The review covers the history of the field up through 2020, briefly touching on statistically derivatized carriers employed in immunology as counterpoints to the rationally assembled and derivatized scaffolds here, although most citations are from the past two decades. The scaffolds are used widely in fields ranging from pure chemistry to artificial photosynthesis and biomedical sciences.

Synthesis of Azidoanilines by the Buchwald–Hartwig Amination

“…Organic azides are widely used in synthetic chemistry as masked amine intermediates and in various other fields such as chemical biology and materials chemistry as readily connectable compounds. − Particularly, the advent of click chemistry reactions such as copper-catalyzed azide–alkyne cycloaddition (CuAAC) and strain-promoted azide–alkyne cycloaddition (SPAAC) has greatly enhanced the utility of organic azides. In the course of our recent studies regarding azide chemistry, we found that a doubly sterically hindered aromatic azido group exhibited unique clickability, which enabled three and four sequential azido-type-selective triazole-forming reactions using triazido and tetraazido platform molecules (Figure A). ,, We also developed a radioisotope-free photoaffinity labeling method for the target identification of bioactive molecules using diazido probes having aromatic and aliphatic azido groups. In this method, the aromatic azido moiety serves as a photoreactive group to capture the target protein, whereas a detectable tag is introduced through the aliphatic azido group to analyze the photolabeled proteins (Figure B) .…”

Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution

“…Commercially available amino acid building blocks with orthogonal protecting groups, 1 which usually possess a fluorenylmethoxycarbonyl (Fmoc) protecting group on their α-amine and an orthogonal protecting group (which can be removed selectively during Fmoc-SPPS) on their side-chain functional group, are efficacious for synthesizing multi-functionalized peptides, 2,3 branched peptides, [4][5][6] and cyclic peptides. [7][8][9][10][11] Particularly, orthogonally protected amino acids with sidechain-amines, such as lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab), and 2,3-diaminopropionic acid (Dap), can be elongated/functionalized individually on their α-amine or side-chain-amine using a routine coupling protocol.…”

Modular synthesis of triazoles from 2-azidoacrylamides having a nucleophilic amino group

“…Facile methods to assemble simple modules onto platform molecules having a number of functional groups for click chemistry are of great significance for the preparation of multifunctional compounds in broad research fields such as pharmaceutical science and chemical biology. 1–4 Since click reactions have been in the construction of a vast chemical library and in the synthesis of chemical probes bearing reporter groups, various trivalent platform molecules for consecutive click reactions have been developed so far and an efficient consecutive click assembly using compact platforms is awaited (Fig. 1A).…”