Application of tethered ruthenium catalysts to asymmetric hydrogenation of ketones, and the selective Hydrogenation of aldehydes

An improved method for the synthesis of tethered ruthenium(II) complexes of monosulfonylated diamines is described, together with their application to the hydrogenation of ketones and aldehydes. The complexes were applied directly, in their chloride form, to asymmetric ketone hydrogenation, to give products in excess of 99% ee in the best cases, using 30 bar of hydrogen at 60 °C, and to the selective reduction of aldehydes over other functional groups

Kinetic Resolution of Diols and Pyridyl Alcohols by Cu(II)(borabox)-Catalyzed Acylation

Boron-bridged bisoxazoline (borabox) ligands have been used in the copper(II)-catalyzed benzoylation of pyridyl alcohols and 1,2-diols. Efficient kinetic resolution of 1,2-diols was achieved using both borabox and bisoxazoline (box) ligands. Borabox ligands induced high selectivities in the benzoylation of suitable pyridyl alcohols, where they outperformed bisoxazolines. In addition, highly enantioselective Cu(II)(borabox)-catalyzed benzoylation has been used for the synthesis of both enantiomers of a pyridyl alcohol

Synthesis of Chiral Boron-bridged Anionic C2-symmetric Bisoxazolines and their Applications in Asymmetric Catalysis

Anionic boron-based chiral bisoxazoline ligands, the borabox ligands, are readily prepared from amino alcohols and haloboranes. The highly modular nature of these ligands allows both for electronic and steric tuning of the structure. The high enantioselectivities obtained in various Cu-catalyzed asymmetric reactions and especially in the kinetic resolution of pyridyl alcohols where bisoxazoline ligands exhibit almost no selectivity, point to a considerable potential of borabox ligands in asymmetric catalysis

1,3-Bis(N,N-dialkylamino)imidazolin-2-ylidenes: Synthesis and reactivity of a new family of stable N-heterocyclic carbenes

The synthesis of stable 1,3-bis(N,N-dialkylamino)imidazolin-2-ylidenes was accomplished from readily available chiral bis-hydrazones after reduction or addition of PhMgCl, cyclization to imidazolinium salts, and treatment with KN(SiMe3)2. This strategy allows the obtention of free imidazolin-2-ylidenes and their Rh(COD)Cl complexes in enantiomerically pure form. The σ-donor ability of dialkylamino-substituted diaminocarbenes was found to be slightly higher than that of alkyl(aryl) analogues.We thank the Ministerio de Educación y Ciencia (grant BQU2001-2376 and predoctoral fellowship to M.A.) and the European Commission (HPRN-CT-2001-00172 and HPMT-CT-2001-00248) for financial support.Peer reviewe

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO2H–NH2Equivalence

A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the CS carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale

An Efficient Catalytic Asymmetric Synthesis of a β²‑Amino Acid on Multikilogram Scale

We describe herein a scalable catalytic asymmetric hydrogenation process for the multikilogram-scale production of a β²-amino acid. A short and efficient synthesis of the starting unsaturated <i>N</i>-Boc-protected β²-enamide was developed followed by extensive catalysis screening and optimization studies that identified a simple Ru-BINAP catalyst system to directly afford the (<i>S</i>) product in high enantiomeric excess and yield. The final process enabled the multikilogram production in >99% ee, to be used as a key component for one of our clinical candidates

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO₂H–NH₂ Equivalence

A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale

Enantioselective CuH-Catalyzed Anti-Markovnikov Hydroamination of 1,1-Disubstituted Alkenes

Enantioselective synthesis of β-chiral amines has been achieved via copper-catalyzed hydro­amination of 1,1-disubstituted alkenes with hydroxylamine esters in the presence of a hydrosilane. This mild process affords a range of structurally diverse β-chiral amines, including β-deuterated amines, in excellent yields with high enantio­selectivities. Furthermore, catalyst loading as low as 0.4 mol% could be employed to deliver product in undiminished yield and selectivity, demonstrating the practicality of this method for large-scale synthesis