Cycloalkene Carbonitriles in Rhodium-Catalyzed 1,4-Addition and Formal Synthesis of Vabicaserin.

Cycloalkenes with exocyclic acceptor substituents still remain challenging substrates for enantioselective rhodium-catalyzed 1,4-addition. Cycloalkene carbonitriles and carboxylates have been investigated, and a highly diastereo- and enantioselective protocol for 1,4-addition to cyclopentene and cycloheptene carbonitrile has been developed. This new asymmetric transformation was subsequently applied in the asymmetric formal synthesis of the drug candidate Vabicaserin.

Heteroarylboronates in rhodium-catalyzed 1,4-addition to enones.

Rhodium(I)-catalyzed 1,4-addition of aryl and alkenylboronic acids to α,ß-unsaturated carbonyl compounds is well established, but the transfer of heteroaryl residues in this reaction remains underdeveloped. We have studied heteroaryl MIDA and pinacol boronates as alternatives to the labile boronic acid counterparts. Under racemic conditions, 12 adducts with heteroaryl residues, among them unsubstituted 3- and 4-pyridinyl, 2-furanyl, thienyl, and pyrrolyl groups, were obtained in moderate to excellent yields. The enantioselective version of the reaction proved highly sensitive to the electronic character of the heteroaryl substituents, with boronates carrying electron-rich residues giving modest to high yields but consistently high enantiomeric excesses.

Enantioselective cyclopropanation of indoles: construction of all-carbon quaternary stereocenters.

The first enantioselective copper-catalyzed cyclopropanation of N-acyl indoles is described. Using carbohydrate-based bis(oxazoline) ligands (glucoBox), the products were obtained in up to 72% ee. Cyclopropanation of N-Boc 3-methyl indole yielded a product with an all-carbon quaternary stereocenter, which is a valuable building block for the synthesis of indole alkaloids: Deprotection and rearrangement gave a tricyclic hemiaminal ester in 96% ee, which was subsequently employed as a key intermediate for the synthesis of (-)-desoxyeseroline.

Efficient pseudo-enantiomeric carbohydrate olefin ligands.

Highly efficient pseudo-enantiomeric olefin ligands were designed from D-glucose and D-galactose. These ligands yield consistently excellent levels of enantioselectivity in Rh(I)-catalyzed 1,4-additions of aryl- and alkenylboronic acids to achiral enones and high diastereoselectivity with chiral substrates. Contrary to established olefin ligands, they are obtained enantiomerically pure via short syntheses without racemic resolution steps, making them a valuable addition to the arsenal of chiral ligands with olefinic donor sites.

Bis(oxazolines) based on glycopyranosides - steric, configurational and conformational influences on stereoselectivity.

In previous studies we found that the asymmetric induction of bis(oxazolines) based on D-glucosamine strongly depended on the steric demand of the 3-O-substituents. To further probe the impact of the 3-position of the pyranose scaffold, we prepared 3-epimerised and 3-defunctionalised versions of these ligands as well as a 3-O-formyl derivative. Application of these new ligands in asymmetric cyclopropanation revealed strong steric and configurational effects of position 3 on asymmetric induction, further dramatic effects of the pyranose conformation were also observed.

Novel, efficient alkene-phosphinite hybrid ligand based on D-glucose.

A commercially available 2,3-unsaturated pyranoside, derived from d-glucose, was converted into a new type of olefin phosphorus chelate ligand in only three steps. Application in rhodium catalyzed conjugate additions of phenylboronic acid to enones led to excellent levels of stereoinduction for several cyclic substrates. The easy preparation and the high efficiency of this ligand make it an interesting and promising alternative to established systems.

Carbohydrates as synthetic tools in organic chemistry.

While amino acids, terpenes and alkaloids have found broad application as tools in stereoselective organic synthesis, carbohydrates have only lately been recognised as versatile starting materials for chiral auxiliaries, reagents, ligands and organocatalysts. The structural diversity of carbohydrates and the high density of functional groups offer a wide variety of opportunities for derivatization and tailoring of synthetic tools to a specific problem.

Synthesis of new polyether glycodendrons as oligosaccharide mimetics.

Divalent and tetravalent glycomimetics based on polyether glycodendrons have been prepared. The branched scaffolds were decorated with galactose moieties on one hand and were elaborated into new glycodendrons of a 'mixed' type on the other, carrying both galactose and mannose moieties as biologically important sugar epitopes. All synthesized glycodendrons possess a focal point that can be employed for further derivatization and functionalization.

glucoBox--a new carbohydrate-based bis(oxazoline) ligand. Synthesis and first application.

The synthesis of a new bis(oxazoline) ligand from D-glucosamine and its application in enantioselective copper(I) catalysed cyclopropanations of olefins is described.