Asymmetric arene hydrogenation: towards sustainability and application

Abstract

(Hetero)aromatic compounds are vastly available and easy to functionalise building blocks in the chemical industry. Asymmetric arene hydrogenation enables direct access to complex three-dimensional scaffolds with (multiple) defined stereocentres in a single catalytic process and, by this, the rapid installation of molecular complexity. The potential usage of hydrogen from renewable sources and perfect atom economy bears the potential for sustainable and broadly applicable transformations to valuable products. The aim of this review is to present the state-of-the-art in transition-metal catalysed asymmetric hydrogenation of (hetero)arenes, to highlight recent advances and important trends and to provide a broad overview for the reader.

Fig. 1. Hydrogenation as an environmentally benign method to provide direct access to diverse saturated carbo- and heterocyclic motifs.

Fig. 2. Major challenges in asymmetric arene hydrogenation: high kinetic activation barrier, stereoselectivity and chemoselectivity.

Fig. 3. Prominent ligand motifs in asymmetric arene hydrogenation.

Fig. 4. The alkaloid (–)-Galipine (left) containing a tetrahydroquinoline was accessed via enantioselective hydrogenation by Zhou and co-workers. The two ligands enabling high selectivities in asymmetric quinoline hydrogenation by Zhou and co-workers are shown on the right.

Scheme 1. Enantiodivergent hydrogenation of 2-arylated quinolines by Dong, Zhang and co-workers.

Scheme 2. Outer sphere mechanism of the enantioselective hydrogenation of 2-substituted pyridines. After protonation the quinolinium cation undergoes a 1,4-hydride addition forming an enamine intermediate. Acid catalysed tautomerisation and subsequent 1,2-hydride addition gives the chiral tetrahydroquinoline cation.

Scheme 3. Transfer hydrogenation of 2-substituted quinolines with a water-soluble chiral iridium complex by Sun and co-workers.

Scheme 4. Synthesis of chiral terpyridine N,N,N-ligands via an enantioselective hydrogenation with a chiral Ru-diamine catalyst by Fan and co-workers.

Scheme 5. Manganese catalysed enantioselective hydrogenation of 2-substituted quinolines published by Lan, Liu and co-workers.

Scheme 6. Cascade hydrogenation-condensation strategy for the synthesis of chiral indolizidines and quinolizidines involving an enantioselective hydrogenation published by Fan and co-workers.

Scheme 7. In situ formation of aromatic isochromenylium cations followed by enantioselective hydrogenation for the synthesis of chiral 1H-isochromenes by Yu, Fan and co-workers.

Scheme 8. (A) Synthesis of chiral cis-configurated 1,3-disubstituted tetrahydroisoquinolines via enantioselective hydrogenation published by Stoltz and co-workers. (B) Application as key step in the total syntheses of the natural products (−)-jorunnamycin A and (−)-jorumycin by Stoltz and co-workers.

Scheme 9. trans-Selective directed enantioselective hydrogenation of 1,3-disubstituted isoquinolines with subsequent formation of an oxazolidine-2-one by Stoltz and co-workers.

Scheme 10. Iridium catalysed enantioselective hydrogenation of 2- and 3-substituted indoles and benzofurans by Han, Ding and co-workers.

Fig. 5. Overview of the scope of diverse heterocycles for the efficient enantioselective hydrogenation with the privileged Ru-SINpEt catalyst by Glorius and co-workers.

Fig. 6. Overview of the suitable (hetero)arenes for the efficient enantioselective hydrogenation with the privileged Ru-PhTRAP catalyst established by Kuwano and co-workers.

Scheme 11. Asymmetric hydrogenation of carbocylic motifs to access axial-chiral and central-chiral products by Zhou and co-workers. (A) Desymmetrisation of 9-phenyl substituted anthracenes. (B) Kinetic resolution of phenyl-substituted naphtalenes. (C) Enantioselective hydrogenation of 9-subtituted phenanthracenes. (D) Structures of the ligands used for these reported hydrogenations.

Scheme 12. Molybdenum catalysed enantioselective full hydrogenation of quinolines and naphthalenes to the corresponding decahydroquinolines and decalines by Chirik and co-workers.

Fig. 7. Top: Overview of the susceptible pyridine motifs for enantioselective hydrogenation. Middle: Common activation strategies of pyridines for homogenous asymmetric hydrogenation. Bottom: Examples for successfully used ligands in enantioselective pyridine hydrogenation.

Fig. 8. Top: Overview of pyrimidines and pyrazines successfully employed in an enantioselective hydrogenation reaction. Middle: Corresponding product motifs after hydrogenation. Bottom: Examples for successfully used ligands in these hydrogenation reactions.

Fig. 9. Asymmetric induction in heterogeneous catalysis. (A): Homogeneous catalyst bound to the metal surface. (B): Chiral modifier on the metal surface, interacting with the substrate. (C): Electronic attractive or steric repulsive interactions of a molecule with the metal surface.

Scheme 13. Conformational alignment of Evans’ auxiliary.

Scheme 14. Chiral auxiliary assisted asymmetric hydrogenations of pyridines and pyridinium salts.

Scheme 15. Investigation of substituent effects on the diastereoselective hydrogenation of 1-substituted indanes.

Scheme 16. Substrate induced asymmetric diastereoselective hydrogenations in total syntheses of natural products and drug candidates.

Scheme 17. Asymmetric diastereoselective hydrogenations of (A) 2-oxindoles, 3,4-dihydroquinolones and (B) aromatic 2,5-diketopiperazines with a highly selective Rh-CAAC catalyst.

Scheme 18. Hydrogenations employing relay catalysis to first set a stereocentre and then perform a diastereoselective hydrogenation.

Fig. 10. Illustration of future objectives to improve the sustainability and broaden the applicability of asymmetric arene hydrogenation.

Lukas Lückemeier

Marco Pierau

Frank Glorius