The C-F bond as a conformational tool in organic and biological chemistry

Abstract

Organofluorine compounds are widely used in many different applications, ranging from pharmaceuticals and agrochemicals to advanced materials and polymers. It has been recognised for many years that fluorine substitution can confer useful molecular properties such as enhanced stability and hydrophobicity. Another impact of fluorine substitution is to influence the conformations of organic molecules. The stereoselective introduction of fluorine atoms can therefore be exploited as a conformational tool for the synthesis of shape-controlled functional molecules. This review will begin by describing some general aspects of the C-F bond and the various conformational effects associated with C-F bonds (i.e. dipole-dipole interactions, charge-dipole interactions and hyperconjugation). Examples of functional molecules that exploit these conformational effects will then be presented, drawing from a diverse range of molecules including pharmaceuticals, organocatalysts, liquid crystals and peptides.

Keywords: conformation; functional molecules; organofluorine chemistry; stereochemistry; stereoelectronic effects.

Figure 1

Conformational effects associated with C–F bonds.

Figure 2

HIV protease inhibitor Indinavir (17) and fluorinated analogues 18 and 19. In analogue 18 the gauche effect reinforces the active zigzag conformation, whereas in analogue 19 the gauche effect competes against the zigzag conformation resulting in conformational disorder.

Figure 3

Cholesteryl ester transfer protein inhibitors 20 and 21. In the fluorinated analogue 21, n_O→σ*_CF hyperconjugation leads to an out-of-plane orientation of the fluoroalkyl sidechain, resulting in improved binding affinity.

Figure 4

HIV reverse transcriptase inhibitor 22 and acid-stable fluorinated analogues 23–25. The F–C–C–O gauche effect influences the ring conformations of 23–25.

Figure 5

Dihydroquinidine (26) and fluorinated analogues 27 and 28. Newman projections along the C9–C8 bonds of 27 and 28 show the proposed bioactive conformation.

Figure 6

The neurotransmitter GABA (29) and fluorinated analogues (R)-30 and (S)-30. Newman projections of (R)-30 and (S)-30 along the C3–C4 bond show the three possible staggered conformations (“a”, “b” and “c”).

Figure 7

The insect pheromone 31 and fluorinated analogues (S)-32 and (R)-32. The proposed bioactive conformation is shown in Newman projections.

Figure 8

Capsaicin (33) and fluorinated analogues (R)-34 and (S)-34.

Figure 9

Asymmetric epoxidation reaction catalysed by pyrrolidine 35. Inset: the geometry of the activated iminium ion intermediate 37 is stabilised by a gauche F–C–C–N⁺ alignment.

Figure 10

The asymmetric transannular aldol reaction catalysed by trans-4-fluoroproline (41), and its application to the total synthesis of (+)-hirsutene (46).

Figure 11

The asymmetric Stetter reaction catalysed by chiral NHC catalysts 49–52. The ring conformations of 50–52 are influenced by σ_CH→σ*_CF hyperconjugation. Cy = cyclohexyl.

Figure 12

A multi-vicinal fluoroalkane.

Figure 13

X-ray crystal structures of diastereoisomeric multi-vicinal fluoroalkanes 55 and 56. The different conformations can be explained by (i) the avoidance of 1,3-difluoro repulsion and (ii) a preference for 1,2-difluoro gauche alignments.

Figure 14

Examples of fluorinated liquid crystal molecules. Arrows indicate the orientation of the molecular dipole moments, which are quantified in the negative dielectric anisotropy values, Δε.

Figure 15

Di-, tri- and tetra-fluoro liquid crystal molecules 60–62.

Figure 16

Collagen mimics of general formula (Pro-Yaa-Gly)₁₀ where Yaa is either 4(R)-hydroxyproline (63) or 4(R)-fluoroproline (41). The fluorinated isomer is more stable, due to an increased preference for the trans amide bond and the Cγ-exo pyrrolidine ring pucker. The illustrated collagen triple helix structure is from PDB code 1CAG [45].

Figure 17

Enkephalin-related peptide 64 and the fluorinated analogue 65. The electron-withdrawing trifluoromethyl group of 65 disrupts a key hydrogen bond, leading to a different conformation as determined by NOESY experiments.

Figure 18

The C–F bond influences the conformation of β-peptides. β-Heptapeptide 66 adopts a helical conformation, reinforced by the α-fluoroamide effect and a fluorine-amide gauche alignment. In isomeric β-heptapeptide 67, the helical conformation is disrupted by the fluorine atom. The disruptive effect of fluorine is overridden in the longer helix-forming β-tridecapeptide 68.

Figure 19

The conformations of pseudopeptides 69 and 70 are influenced by the α-fluoroamide effect and the fluorine gauche effect.