Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis.

Abstract

ConspectusFinding efficient synthetic methods for the asymmetric synthesis of complex molecules has always been of interest to organic chemists. Creating and controlling the stereochemistry of stereogenic centers bearing branched allylic moieties in organic molecules using a catalytic process is an attractive and successful method for the synthesis of several natural products and medicinally important compounds. Remarkable progress toward their synthesis has been achieved via transition-metal catalysis, especially in the case of allylic substitution and allylic C-H oxidation chemistry. However, for allylic substitution the preinstallation of a leaving group is essential, and for allylic C-H oxidation, stoichiometric amounts of oxidant are required. Besides that, the control of regioselectivity with these methods is often problematic because the linear product can be produced as a major isomer. Our research group has developed a regioselective, enantioselective, and atom economic route toward the more valuable branched product via a Rh-catalyzed coupling of easily accessible alkynes or the double-bond isomeric allenes with pronucleophiles. It was demonstrated that, using this new approach, it is possible to add different pronucleophiles to alkynes or allenes to form branched allylic moieties through C-C and C-heteroatom bond formation. Since new organic reactions offer new opportunities in chemical synthesis and the benchmark for new synthetic methods is their application in target-oriented synthesis, we have demonstrated several successful syntheses of natural products and medicinally relevant targets. For example, in the total syntheses of Quercuslactones, Helicascolides A-C, Epothilone D, Homolargazole, and Thailandepsin B, the Rh-catalyzed hydro-oxycarbonylation of allenes was used as key step via C-O bond formation. Remarkably, the Rh-catalyzed C2-symmetric dimerization strategy was used to synthesize the complex molecules Clavosolide A and Vermiculine, leading to an extreme increase in structural complexity within a single step. For the total syntheses of Centrolobine, Pitavastatin, and Rosuvastatin, C-O bond formation was achieved through the addition of a hydroxy function to the allene moiety. The potential of the addition of nitrogen pronucleophiles to allenes was demonstrated in the total syntheses of Cusparein, Angusterein, Cermicin C, Senepodin G, Homoproline, Pipecolinol, Coniceine, Coniine, Ruxolitinib, Sitagliptin, Abacavir, Glucokinase activators, and Chaetominine. All of these examples testify to the wide applicability of the Rh-catalyzed addition of pronucleophiles to allenes or alkynes in target-oriented synthesis, and in this Account we summarize our contribution.