Diene, Enyne, and Diyne Metathesis in Natural Product Synthesis

Abstract

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility, metathesis has firmly established itself in the toolbox of target-oriented chemists. RCM is now routinely integrated in the retrosynthetic planning of natural product syntheses. The availability of metathesis catalysts with different activity, and hence chemoselectivity, allows one increasingly to influence the regio- and stereoselectivity of metathesis events. With the advent of the highly active NHC-bearing catalysts, CM also began to emerge from the shadow of RCM as a novel and economical alternative for the formation of electron-deficient and highly substituted double bonds. This progress in olefin CM translates into an increasing number of natural product-directed fragment syntheses and has also been useful for convergent assembly of main fragments. An increasing number of uniquely short and atom-economical natural product syntheses feature sequences of several metathesis events, by combining ring-opening metathesis with RCM and/or CM with concomitant chirality transfer to transform one ring into a thermodynamically more stable one. Enyne metathesis, which can be performed by the same catalysts, produces synthetically useful 1,3-dienes that lend themselves to further structural elaboration through subsequent cycloadditions or metathesis cascades. However, although many general studies have demonstrated the preparative use of inter- and intramolecular enyne metathesis, natural product-directed applications are, if compared with diene metathesis, still relatively scarce. The remaining drawback of macrocyclic RCM is the lack of control over the stereochemistry of the newly formed double bond. A solution to this problem is provided by a sequence of ring-closing diyne metathesis and stereoselective partial hydrogenation. As diyne metathesis demands different catalyst systems, sequences of chemoselective olefin, alkene, and alkyne metathesis events have been used in the synthesis of increasingly complex natural products.