Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Total Synthesis of Tagetitoxin.

The intriguing structure of tagetitoxin (1), a long-standing challenge in natural product synthesis, has been the subject of multiple revisions and has been confirmed through total synthesis. The route commences from a renewable furan starting material and features a number of unusual transformations (such as rearrangements, bromocyclization, and P(V)-based phosphate installation) to arrive at the target in 15 steps. As the route was designed to enable access to both enantiomers, the absolute configuration of the natural product could be assigned using a bioassay on (+)-1 and (-)-1.

Chiral Cyclopentadienyl Ruthenium Complexes as Versatile Catalysts for Enantioselective Transformations.

Ruthenium complexes, in particular cyclopentadienyl ruthenium (ii) derivatives, catalyze a vast number of transformations in the field of homogenous catalysis. Herein we describe the first synthesis of efficient chiral cationic cyclopentadienyl ruthenium (ii) catalysts and their application in enantioselective cycloisomerizations yielding 4H-pyrans. A tremendous counterion effect on the selectivity was observed and subsequently explored, giving rise to a complementary set of neutral cyclopentadienyl ruthenium (ii) complexes able to catalyze asymmetric cyclobutene formations.

Divergent Asymmetric Synthesis of Polycyclic Compounds via Vinyl Triazenes.

Vinyl triazenes were obtained by enantioselective [2+2] cycloaddition reactions of bicyclic alkenes with 1-alkynyl triazenes in the presence of a RuII catalyst with a chiral cyclopentadienyl ligand. These triazenes serve as unique vinyl cation surrogates. Under acidic conditions, the triazene functionality can be replaced with a variety of groups, including halides, alkoxides, sulfoxides, amides, arenes, and heteroarenes, thus providing efficient access to a pool of chiral polycyclic compounds.

Asymmetric Catalysis Powered by Chiral Cyclopentadienyl Ligands.

Application of chiral derivatives of the versatile and ubiquitous cyclopentadienyl ligand has long remained an underdeveloped area in asymmetric catalysis. In this Perspective we highlight recent exciting results that demonstrate their enormous potential. In particular, we provide a comparative analysis of the available ligand families, an overview of their complexation chemistry, and an examination of their application in catalytic enantioselective reactions. We also discuss current limitations and speculate on the developments that are necessary to advance the field further.

Chiral Cationic Cp(x)Ru(II) Complexes for Enantioselective Yne-Enone Cyclizations.

The cyclopentadienyl (Cp) group is a ligand of great importance for many transition-metal complexes used in catalysis. Cationic CpRu(II) complexes with three free coordination sites are highly versatile catalysts for many atom-economic transformations. We report the synthesis of a family of Cp(x)Ru(II) complexes with chiral Cp ligands keeping the maximum number of available coordination sites. The cationic members are efficient and selective catalysts for yne-enone cyclizations via formal hetero-Diels-Alder reactions. The transformation proceeds in <1 h at -20 °C and provides pyrans in up to 99:1 er. Unsaturated ester or Weinreb-amide substrates directly yield the iridoid skeleton.

Enantioselective total synthesis and absolute configuration of apiosporic acid.

The first total synthesis of the polyketide apiosporic acid is presented. Key steps are a Julia-Kocienski olefination, a Suzuki-Miyaura cross-coupling, and an intramolecular Diels-Alder reaction. The absolute configuration of the natural product was determined.