Enantio- and diastereoselective synthesis of γ-amino alcohols

The γ-amino alcohol structural motif is often encountered in drugs and natural products. We developed two complementary catalytic diastereoselective methods for the synthesis of N-PMP-protected γ-amino alcohols from the corresponding ketones. The anti-products were obtained through Ir-catalyzed asymmetric transfer hydrogenation, the syn-products via Rh-catalyzed asymmetric hydrogenation

Ruthenacycles and Iridacycles as Catalysts for Asymmetric Transfer Hydrogenation and Racemisation

Ruthenacycles, which are easily prepared in a single step by reaction between enantiopure aromatic amines and [Ru(arene)Cl2]2 in the presence of NaOH and KPF6, are very good asymmetric transfer hydrogenation catalysts. A range of aromatic ketones were reduced using isopropanol in good yields with ee’s up to 98%. Iridacycles, which are prepared in similar fashion from [IrCp*Cl2]2 are excellent catalysts for the racemisation of secondary alcohols and chlorohydrins at room temperature. This allowed the development of a new dynamic kinetic resolution of chlorohydrins to the enantiopure epoxides in up to 90% yield and 98% enantiomeric excess (ee) using a mutant of the enzyme Haloalcohol dehalogenase C and an iridacycle as racemisation catalyst.

Removal of the acyl donor residue allows the use of simple alkyl esters as acyl donors for the dynamic kinetic resolution of secondary alcohols

The dynamic kinetic resolution of secondary alcohols using a lipase and a ruthenium catalyst required some improvements to make it suitable for its use in an industrial process. The use of p-chlorophenyl acetate as acyl donor is not desirable in view of the toxicity of the side product. We herein report that simple alkyl esters can be used as acyl donors if the alcohol or ketone residue formed during the enzymatic acylation is continuously removed during the reaction. The addition of a ketone speeds up the racemisation process and allowed us to reduce the amounts of enzyme and ruthenium catalyst. The scope of this method was explored and a suitable range of acyl donors found. Various benzylic and aliphatic alcohols were reacted using isopropyl butyrate or methyl phenylacetate as acyl donor and in most cases the ester was isolated in >95% yield and 99% ee. Furthermore, it was demonstrated that the alcohol by-products of the enzymatic resolution could be used as the hydrogen source in the asymmetric reductive transesterification of ketones.

Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?

Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.

Cycloruthenated Primary and Secondary Amines as Efficient Catalyst Precursors for Asymmetric Transfer Hydrogenation

Ruthenacycles obtained by cyclometalation of enantiopure aromatic primary or secondary amines with [(η6-benzene)RuCl2]2 or with [(η6-p-cymene) RuCl2]2 are efficient catalysts for asymmetric transfer hydrogenation (TOF up to 190 h-1 at room temperature). Enantioselectivities in the transfer hydrogenation of acetophenone ranged from 38% to 89%. It is possible to prepare the catalysts in situ, which allows the use of high throughput experimentation.