Stereoselectively fluorinated N-heterocycles: a brief survey

Abstract

The stereoselective incorporation of fluorine atoms into N-heterocycles can lead to dramatic changes in the molecules' physical and chemical properties. These changes can be rationally exploited for the benefit of diverse fields such as medicinal chemistry and organocatalysis. This brief review will examine some of the effects that fluorine substitution can have in N-heterocycles, including changes to the molecules' stability, their conformational behaviour, their hydrogen bonding ability, and their basicity. Finally, some methods for the synthesis of stereoselectively fluorinated N-heterocycles will also be reviewed.

Keywords: N-heterocycles; conformation; fluorine; iminosugars; medicinal chemistry; organo-fluorine.

Figure 1

Fluorination alters the reactivity of aziridines.

Scheme 1

Fluorination makes β-lactam derivatives more reactive towards lipase-catalysed methanolysis.

Figure 2

The ring pucker in azetidine derivatives can be influenced by a C–F^…N⁺ charge–dipole interaction.

Figure 3

Fluorination ridifies the pyrrolidine rings of ligand 10, with several consequences for its G-quadruplex DNA binding properties.

Figure 4

Proline 11 readily undergoes a ring-flip process, but (4R)-fluoroproline 12 is more rigid because of hyperconjugation (σ_CH → σ*_CF).

Scheme 2

Hyperconjugation rigidifies the ring pucker of a fluorinated organocatalyst 14, leading to higher enantioselectivity.

Figure 5

Fluorinated piperidines prefer the axial conformation, due to stabilising C–F^…N⁺ interactions.

Figure 6

Fluorination can rigidify a substituted azepane, but only if it acts in synergy with the other substituents: azepanes 21 and 22 are disordered, while azepane 23 has one dominant geometry in solution.

Figure 7

The eight-membered N-heterocycle 24 prefers an axial orientation of the fluorine substituent, giving two C–F^…N⁺ interactions.

Figure 8

Some iminosugars are “privileged structures” that serve as valuable drug leads.

Figure 9

Fluorinated iminosugar analogues 32–34 illuminate the binding interactions of the α-glycosidase inhibitor 28.

Figure 10

Fluorinated miglitol analogues, and their inhibitory activity towards yeast α-glycosidase.

Figure 11

Analogues of isofagomine (31) have different pK_aH values, and therefore exhibit maximal β-glucosidase inhibition at different pH values.

Scheme 3

General strategy for the synthesis of fluorinated N-heterocycles via deoxyfluorination.

Figure 12

Late stage deoxyfluorination in the synthesis of multifunctional N-heterocycles.

Scheme 4

During the deoxyfluorination of N-heterocycles, neighbouring group participation can sometimes lead to rearrangement (48→49) or substitution with retention (50→51).

Scheme 5

A building block approach for the synthesis of fluorinated aziridines 2 and 3.

Scheme 6

Building block approach for the synthesis of a difluorinated analogue of calystegine B (63).

Scheme 7

Synthesis of fluorinated analogues of brevianamide E (65) and gypsetin (68) via electrophilic fluorocyclisation.

Scheme 8

Organocatalysed enantioselective fluorocyclisation.

Scheme 9

Synthesis of 3-fluoroazetidine 73 via radical fluorination.

Scheme 10

Synthesis of 3,3-difluoropyrrolidine 78 via a radical cyclisation.

Scheme 11

Chemoenzymatic synthesis of fluorinated β-lactam 4b.