Total Synthesis of Leupyrrins A 1 and B 1 , Highly Potent Antifungal Agents from the Myxobacterium Sorangium cellulosum

• Published in: Chemistry : a European journal 2017-03, Vol.23 (14), p.3300-3320
• Main Authors: Thiede, Sebastian, Wosniok, Paul R, Herkommer, Daniel, Debnar, Thomas, Tian, Maoqun, Wang, Tongtong, Schrempp, Michael, Menche, Dirk
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; 4-Butyrolactone - chemistry; Antifungal Agents - chemical synthesis; Cyclization; Humans; Molecular Structure; Myxococcales - chemistry; Organometallic Compounds - chemistry; Zirconium - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201604445

Full details on the design, elaboration, and application of efficient strategies for the high-yielding total syntheses of leupyrrins A and B , unique antifungal agents from the myxobacterium Sorangium cellulosum, are reported. A sequential zirconocene-mediated diyne-cyclization, and regioselective opening of the zirconacyclopentadiene intermediate enabled a concise entry into the unique dihydrofuran fragment, whereas another domino reaction was developed for the butyrolactone involving a one-pot lactol opening, stereoselective aldehyde addition and in situ lactonization. Furthermore, an innovative sp -sp -cross-coupling for pyrrole functionalization and an optimized HATU-mediated amide coupling protocol of two elaborate fragments were established. In addition, an unusual protective group strategy, involving a Teoc-acetonide protected amine in combination with tert-butyl and acetate esters, was successfully elaborated. These tactics and strategies are generally useful and may be also applied in the synthesis of other functionalized compounds. It is expected that the material which was obtained by these total syntheses will enable the further exploration of the biological profile of these potent antifungal agents.