Two‐Step Synthesis of Complex Artificial Macrocyclic Compounds

Abstract

The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53-MDM2 antagonism.

Structure and Reactivity of Glycosyl Isocyanides

“…We successfully combined sugars with spiro indole-based compounds, [32] lactones, [33] and artificial macrocycles. [34] Thus, we performed an U-3CR on the indole-based imines yielding compounds 14ae. Then, utilizing phenyl glyoxal in a Passerini reaction, we were able to synthesize compound 15 which could be transformed to a variety of derivatives.…”

Medium‐Sized‐Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

“…The N‐H‐N distance shortened from 2.72 to 1.95 Å with larger rings, with the Ar‐CO dihedral angle approaching 0° in the 12‐membered ring, thus permitting conjugation between the amide and the aromatic ring. This behaviour suggested a transannular hydrogen bond, a characteristic of interest for the development of bioactive molecules with “hidden hydrophilicity” …”

Artificial Macrocycles by Ugi Reaction and Passerini Ring Closure

“…Several macrocyclic stapled peptides have been described with great affinity toward MDM2 and MDMX [35]. We designed a series of nonpeptidic artificial macrocyclic compounds that inhibit the p53–MDM2 interaction [27,28] These macrocycles target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 as shown by 2D NMR thus potentially increasing the affinity to the receptor(Fig. 3A).…”

“…Thus we devised the shortest ever artificial macrocycle synthesis known, a 2-step sequence from generally available starting materials (Fig. 2C) [27]. …”