Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide A and Late-Stage Modification

• Published in: Angewandte Chemie 2015-12, Vol.127 (51), p.15750-15754
• Main Authors: Haydl, Alexander M., Breit, Bernhard
• Format: Article
• Language: English
• Subjects: Allene; Allylverbindungen; Naturstoffe; Rhodium; Totalsynthesen
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201506618

Natural products of polyketide origin with a high level of symmetry, in particular C2‐symmetric diolides as a special macrolactone‐based product class, often possess a broad spectrum of biological activity. An efficient route to this important structural motif was developed as part of a concise and highly convergent synthesis of clavosolide A. This strategy features an atom‐economic “head‐to‐tail” dimerization by the stereoselective rhodium‐catalyzed addition of carboxylic acids to terminal allenes with the simultaneous construction of two new stereocenters. The excellent efficiency and selectivity with which the C2‐symmetric core structures were obtained are remarkable considering the outcome under classical dimerization conditions. Furthermore, this approach facilitates late‐stage modification and provides ready access to potential new lead structures. Lieber spät als früh: Der Naturstoff Clavosolid A weist ein C2‐symmetrisches Kernmotiv auf. Eine Rhodium‐katalysierte Dimerisierung, welche die regio‐ und diastereoselektive Addition von Carbonsäuren an Allene einschließt (siehe Schema), bietet Zugang zu dieser komplexen Struktur in nur acht Schritten ausgehend von Penta‐3,4‐dienal und einem chiralen Crotyltransferreagens. Die Methode ist breit anwendbar und für späte Diversifizierungen geeignet.