Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

• Published in: Nature (London) 2017-12, Vol.552 (7685), p.347-354
• Main Authors: Nguyen, Thach T., Koh, Ming Joo, Mann, Tyler J., Schrock, Richard R., Hoveyda, Amir H.
• Format: Article
• Language: English
• Subjects: 140/131; 639/638/403/933; 639/638/403/977; 639/638/77; Alkenes; Alkenes - chemical synthesis; Alkenes - chemistry; Analysis; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Catalysis; Chemical properties; Chemical synthesis; Chemistry Techniques, Synthetic - methods; Humanities and Social Sciences; Indoles - chemical synthesis; Indoles - chemistry; Metathesis; multidisciplinary; Science; Stereoisomerism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature25002

Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity—namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products—and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E - or Z -trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E - or Z -trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z ). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D. An approach for the synthesis of E - and Z - trisubstituted alkenes in high stereoisomeric purity is developed by merging catalytic cross-metathesis and cross-coupling processes. Alkenes: as E - Z - as 1, 2, 3! Alkene metathesis is a ubiquitous transformation in organic chemistry, as well as in the manufacture of polymers. In the past few years, key advances have been made in achieving high levels of stereoselectivity in certain classes of substrate. However, no general method for the preparation of trisubstituted alkenes is yet available. Here, Amir Hoveyda, Richard Schrock and colleagues report the synthesis of both E - and Z -trisubstituted alkenes with high stereoselectivity by merging cross-coupling and cross-metathesis. Easy-to-access substrates are used to prepare more complex and challenging E - or Z -trisubstituted alkenes. In many cases, the products are vinyl halides, so have a functional handle with which to react further. This is used to good effect in the synthesis of an antifungal and an anti-inflammatory compound.