Catalytic, asymmetric carbon-nitrogen bond formation using metal nitrenoids: from metal-ligand complexes via metalloporphyrins to enzymes

Abstract

The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this are developed. With this aim, the potential of nitrene chemistry has long been appreciated but its application has been constrained by the extreme reactivity of these labile species. This liability however can be attenuated by complexation with a transition metal and the resulting metal nitrenoids have unique and highly versatile reactivity which includes the amination of certain types of aliphatic C-H bonds as well as reactions with alkenes to afford aziridines. At least one new chiral centre is typically formed in these processes and the development of catalysts to exert control over enantioselectivity in nitrenoid-mediated amination has become a growing area of research, particularly over the past two decades. Compared with some synthetic methods, metal nitrenoid chemistry is notable in that chemists can draw from a diverse array of metals and catalysts , ranging from metal-ligand complexes, bearing a variety of ligand types, via bio-inspired metalloporphyrins, all the way through to, very recently, engineered enzymes themselves. In the latter category in particular, rapid progress is being made, the rate of which suggests that this approach may be instrumental in addressing some of the outstanding challenges in the field. This review covers key developments and strategies that have shaped the field, in addition to the latest advances, up until September 2023.

Fig. 1. A brief summary of the development of nitrene and metal nitrenoid chemistry from 1891 to the present day.

Fig. 2. Evans' enantioselective aziridination using copper-BOX catalysis.

Fig. 3. Dodd and Dauban's enantioselective intramolecular aziridination of aliphatic alkenes.

Fig. 4. Enantioselective synthesis of trans-3-amino-4-arylchromans.

Fig. 5. Site- and enantioselective intramolecular δ-C(sp³)–H amination using Cu-BOX catalysis.

Fig. 6. Applications of Ag(i)-BOX catalysis to asymmetric intramolecular aziridination and C(sp³)–H amination.

Fig. 7. Xu's enantioselective indole aminohydroxylation reaction.

Fig. 8. Application of Xu's AnBOX to asymmetric aziridination.

Fig. 9. Application of the TripTOX ligand to asymmetric aziridination.

Fig. 10. Application of a Ru-(PyBOX) complex for asymmetric intramolecular C(sp³)–H amination.

Fig. 11. Application of a cyclometallated Ru–PYBOX complex to asymmetric intramolecular C(sp³)–H amination.

Fig. 12. Enantioselective C(sp³)–H amination catalysed by a heteroleptic silver complex and directed by hydrogen bonding interactions.

Fig. 13. Jacobsen's copper-catalysed asymmetric aziridination of unactivated olefins using a chiral diimine ligand.

Fig. 14. Katsuki's first- and second-generation salen ligands for asymmetric aziridination. Py-N-oxide = pyridine-N-oxide.

Fig. 15. Progression from second- to third-generation M(Salen) catalysts.

Fig. 16. Application of M(Salen) catalysts to C(sp³)–H amination.

Fig. 17. Other copper-diimine complexes used for asymmetric aziridination.

Fig. 18. Enantioselective amination of 8-alkyl quinoline through enantiodetermining CMD.

Fig. 19. Blakey's asymmetric allylic amination of alkene feedstocks.

Fig. 20. Asymmetric intramolecular amination of dioxazolones showcasing different chiral ligand designs.

Fig. 21. Chang's asymmetric spirolactamisation of dioxazolones.

Fig. 22. Catalysts reported by Meggers for asymmetric nitrene transfer.

Fig. 23. Meggers' first asymmetric amination using chiral-at-metal catalysts.

Fig. 24. Meggers' asymmetric synthesis of enantioenriched α-amino acids.

Fig. 25. A catalytic cycle for C(sp³)–H amination catalysed by a Rh(ii,ii) dimer.

Fig. 26. Common Rh(ii,ii) dimer symmetries.

Fig. 27. Early application of chiral Rh(ii,ii) dimers to asymmetric nitrene transfer.

Fig. 28. Evolution of Rh₂(S-TCPTTL)₄ and application to various asymmetric nitrene transfer reactions.

Fig. 29. Asymmetric aziridination of terminal alkenes and trisubstituted styrenes catalysed by Rh₂(S-TFPTTL)₄.

Fig. 30. Enantioselective aza-Rubottom oxidations and allylic aminations using chiral Rh(ii,ii) paddlewheel dimers.

Fig. 31. Enantioselective intramolecular nitrene transfer using asymmetric Rh(ii,ii) catalysis.

Fig. 32. Advent of Rh₂(esp)₂ and Bach's development of an effective chiral variant.

Fig. 33. Application of chiral rhodium “Sulfonesp” dimers to the asymmetric benzylic amination of 4-arylbutan-1-ols.

Fig. 34. Application of chiral rhodium “Sulfonesp” dimers to the asymmetric aziridination of alkenyl alcohols. In all cases R = –SO₂OCH₂C₂F₅.

Fig. 35. Miller's aspartyl β-turn-based dirhodium(ii,ii) metallopeptide for benzylic C(sp³)–H amination.

Fig. 36. Che's asymmetric aziridination and amination reactions catalysed by chiral M(Porphyrin) complexes. Additive = 4-phenyl-pyridine-N-oxide.

Fig. 37. A catalytic cycle for functionalisation using Co(Porphyrin) nitrenoids (upper). Equivalent representations of nitrene radical ligands. Figure adapted from ref. (Dalton Trans., 2011, 40, 5697–5705).

Fig. 38. Zhang's development of chiral porphyrin catalysts for enantioselective intramolecular and intermolecular aziridination.

Fig. 39. Styrene aziridination using azides containing alternative hydrogen bond-acceptor groups.

Fig. 40. Enantioinduction modes in asymmetric metallonitrene amination.

Fig. 41. Catalyst design leads to enantiodivergent amination, even with the same chiral hydrogen bond-donors. For each transition state only the top half of the porphyrin is shown for clarity.

Fig. 42. Enantioconvergent C–H amination catalysed by a chiral porphyrin leading to α-tertiary amine stereocentres.

Fig. 43. Highly convergent metalloradical-catalysed allylic amination.

Fig. 44. Application of a new chiral porphyrin design to enantioselective intramolecular nitrene cyclisations. The absolute stereochemistry of the new chiral centre is denoted in brackets.

Fig. 45. Breslow and Dawson's initial application of a CYP to asymmetric intramolecular nitrene transfer.

Fig. 46. A rare example of biological nitrene transfer which was discovered after the directed evolution of enzymes to perform the same reactivity.

Fig. 47. Early CYP-catalysed nitrene transfer reactions developed in the Arnold laboratory. TTN = total turnover number.

Fig. 48. More challenging intermolecular CYP-catalysed nitrene transfer reactions developed in the Arnold laboratory. TTN = total turnover number.

Fig. 49. Initial results towards the selective functionalisation of unactivated hydrocarbons using engineered CYPs.