Felix Kopp

a diversity-oriented synthesis approach to macrocycles via oxidative ring expansion

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only 4–5 synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco-acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently-targeted synthetic drugs.

Halogen–magnesium exchange on unprotected aromatic and heteroaromatic carboxylic acids

The magnesiation of halogenated aromatic and heteroaromatic carboxylic acids is accomplished by their treatment with MeMgCl in the presence of LiCl and subsequent reaction with i-PrMgCl.LiCl; the resulting double-magnesiated species react with a variety of electrophiles in up to 97% yield.

Functionalized main-group organometallics for organic synthesis*

Highly functionalized Grignard-reagents can be easily obtained by an iodinemagnesim exchange reaction and further reacted with various electrophiles. Via a BZn exchange reaction, a formal Michael addition with umpolung of the reactivity can be achieved. Chiral phosphine ligands can be easily synthesized by a 2.3 sigmatropic rearrangement and used successfully in asymmetric synthesis.

Principal Component Analysis as a Tool for Library Design: A Case Study Investigating Natural Products, Brand-Name Drugs, Natural Product-Like Libraries, and Drug-Like Libraries

Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design.