Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis.

Raju Cheerlavancha,Xiang-Guo Hu,Qing-Quan Liu,Ahmed Ahmed,Hee-Chan Jang,Yun Cheuk Leung,Marina Cagnes,Luke Hunter,Aggie Lawer

doi:10.3762/bjoc.13.228

Raju Cheerlavancha, Xiang-Guo Hu + Show 7 more

Open Access

https://doi.org/10.3762/bjoc.13.228

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Abstract

Backbone-extended amino acids have a variety of potential applications in peptide and protein science, particularly if the geometry of the amino acid is controllable. Here we describe the synthesis of δ-amino acids that contain three vicinal C–F bonds positioned along the backbone. The ultimately successful synthetic approach emerged through the investigation of several methods based on both electrophilic and nucleophilic fluorination chemistry. We show that different diastereoisomers of this fluorinated δ-amino acid adopt distinct conformations in solution, suggesting that these molecules might have value as shape-controlled building blocks for future applications in peptide science.

Highlights

The incorporation of unnatural amino acids into a peptide structure can potentially reduce conformational disorder and improve the binding affinity of the peptide for its biological target
A more subtle example of this concept is provided by the amino acid β-methylphenylalanine (2), which exerts conformational bias through acyclic means; steric interactions associated with the β-methyl group can affect the topography of peptides which once again affects the biological affinity and selectivity [2]
We reasoned that an aldehyde such as 7 could undergo electrophilic fluorination, mediated by a chiral organocatalyst [18,19,20], to generate the fluorinated aldehyde 8 as a single stereoisomer

Summary

Introduction

The incorporation of unnatural amino acids into a peptide structure can potentially reduce conformational disorder and improve the binding affinity of the peptide for its biological target. This hypothetical approach had several attractions, including (i) the flexibility of being able to generate amino acids of different backbone lengths (e.g., 5, 6, Figure 1) via a unified strategy; (ii) an ability to access any stereoisomer of the target molecules (provided that the stereoselectivity in each fluorination step was catalyst-controlled); (iii) the lower toxicity of the electrophilic fluorination reagent NFSI (compared with nucleophilic fluorination reagents such as DeoxoFluor). Initial studies with substrate 7a (containing the phthalimide protecting group) suggested that the undesired difluorinated compound 12 was formed as the major product.

Results

Conclusion