From Gold-Catalyzed Asymmetric or Photoredox-Assisted Cyclizations to Rhodium-Catalyzed C-H alkynylations

Over the past two decades, homogenous gold(I) catalysis has become a powerful synthetic tool for the rapid construction of complex molecular structures. The unique carbophilic behavior displayed by gold catalysts has resulted in the development of new transformations that have been widely applied in the total synthesis of biologically active compounds and electronically relevant organic materials. Despite the remarkable performance as Lewis p-acid, the field of asymmetric gold catalysis has witnessed a slower growth mainly due to the linear dicoordination adopted by gold(I), which places the chiral information on the direct opposite site of the reactive center where the outer-sphere nucleophilic attack takes place. We took advantage of a rationally designed chiral gold(I) complex bearing a C2-symmetric 2,5-disubstituted pyrrolidine next to the reaction center to develop the enantioselective 6-endo-dig cyclization of aryl-tethered 1,6-enynes. The reaction was successfully applied in the first enantioselective total synthesis of carexanes I, P and O. The enynes, obtained through a Sonogashira/bromination/prenylation sequence, engaged efficiently in the asymmetric cyclization furnishing the products in good yields and excellent enantiomeric ratios. The natural products were obtained by straightforward derivatization of these bicyclic compounds. Theoretical and experimental studies point towards non-covalent interactions between the substrate and the chiral pocket in the catalyst as the source of enantio-induction during the cyclization.

Likewise, the reluctance of gold to undergo oxidative processes, which is in part related to the relativistic effects, has limited the applicability of this metal in ubiquitous cross-coupling reactions. In this context, we focused in the development of the photoredox-assisted gold(I)/gold(III)-catalyzed arylative alkoxycyclization of 1,6-enynes in the presence of aryldiazonium salts. The reaction tolerated a wide variety of functional groups including halides, remarking the orthogonality of the method with respect to traditional palladium cross-coupling. The resulting exocyclic alkenes were obtained in moderate to good yields with the complementary configuration to the one previously reported in similar gold(I)-catalyzed transformations.

Finally, we developed a method for the selective ortho-alkynylation of nitroarenes, where the nitro moiety plays the role of directing group. The approach follows the line of the recent achievements on rhodium(III)-catalyzed C–H alkynylation reported by our group. Under the optimized reaction conditions, a variety of nitro(hetero)arenes could be functionalized including the antihypertensive agent nitrenedipine. The corresponding alkynylated products could be converted in indoles via a high-yielding reduction/cyclization sequence or serve as substrates for palladium-catalyzed denitrative cross-coupling reactions. The study of the mechanism using experimental and computational means concluded that the turnover limiting C–H bond cleavage takes place in first place through an electrophilic concerted metalation deprotonation process, followed by alkyne insertion and silver-assisted bromide elimination to close the catalytic cycle.

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