Acetylene as a Dicarbene Equivalent for Gold(I) Catalysis: Total Synthesis of Waitziacuminone in One Step.

The gold(I)-catalyzed reaction of acetylene gas with alkenes leads to (Z,Z)-1,4-disubstituted 1,3-butadienes and biscyclopropanes depending on the donor ligand on gold(I). Acetylene was generated in situ from calcium carbide and water in a user-friendly procedure. Reaction of acetylene with 1,5-dienes gives rise stereoselectively to tricyclo[5.1.0.02,4 ]octanes. This novel double cyclopropanation has been applied to the one step total synthesis of the natural product waitziacuminone from acetylene and geranyl acetone.

Enantioselective Folding of Enynes by Gold(I) Catalysts with a Remote C2-Chiral Element.

Chiral gold(I) catalysts have been designed based on a modified JohnPhos ligand with a distal C2-2,5-diarylpyrrolidine that creates a tight binding cavity. The C2-chiral element is close to where the C-C bond formation takes place in cyclizations of 1,6-enynes. These chiral mononuclear catalysts have been applied for the enantioselective 5-exo-dig and 6-endo-dig cyclization of different 1,6-enynes as well as in the first enantioselective total synthesis of three members of the carexane family of natural products. Opposite enantioselectivities have been achieved in seemingly analogous reactions of 1,6-enynes, which result from different chiral folding of the substrates based on attractive aryl-aryl interactions.

The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular "Inside-Out" Approach.

Bisquinolizidine alkaloids are characterized by a chiral bispidine core (3,7-diazabicyclo[3.3.1]nonane) to which combinations of an α,N-fused 2-pyridone, an endo- or exo-α,N-annulated piperidin(on)e, and an exo-allyl substituent are attached. We developed a modular "inside-out" approach that permits access to most members of this class. Its applicability was proven in the asymmetric synthesis of 21 natural bisquinolizidine alkaloids, among them more than ten first enantioselective total syntheses. Key steps are the first successful preparation of both enantiomers of C2 -symmetric 2,6-dioxobispidine by desymmetrization of a 2,4,6,8-tetraoxo precursor, the construction of the α,N-fused 2-pyridone by using an enamine-bromoacrylic acid strategy, and the installation of endo- or, optionally, exo-annulated piperidin(on)es.

The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions.

The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified ß-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3-dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate.

(2S,5R)-2-Methylaminomethyl-1-methyl-5-phenylpyrrolidine, a chiral diamine ligand for copper(II)-catalysed Henry reactions with superb enantiocontrol.

A cis-2-aminomethyl-5-phenylpyrrolidine, which is easily available from methyl Boc-L-pyroglutamate, was found to be a highly efficient chiral ligand for Cu(II)-catalysed Henry reactions. Excellent yields (>90%) and superb levels of enantiocontrol (98.5-99.6% ee) were reached with aromatic, heteroaromatic, vinylic, and aliphatic aldehydes (36 examples).