Azetidines

Introduction

Azetidine is a representative heterocyclic organic compound with C3H7N stoichiometry (Fig.1). Azetidine and related derivatives seldom appears in nature molecules due to the high rigidity and ring tension. The almost unexplored four-membered heterocycles azetidines, represent a particularly interesting class of molecules, among the family of saturated nitrogen heterocycles. Although often challenging to synthesize, substituted azetidines strongly attract chemists because of their importance in catalysis, stereoselective synthesis and medicinal chemistry. In recent years, interest in the effective access to substituted heterocycle derivatives has become even more relevant due to the increasing demand for enhanced degree of saturation and three-dimensionality in drug candidates.

Azetidines Fig.1 Azetidine Series

Applications

Pharmaceutical Chemistry:

Fragment-base drug design has become a novel paradigm for drug discovery in the last decade. The lack of molecular rigidity intrinsic to a majority of small organic molecules appears to be a serious obstacle for this promising approach (Fig.2). Conformationally restricted rigid molecules show higher reproducibility of results when used in projects utilizing in silico screening methods. One of the most popular approaches to limit molecular conformational flexibility relies on introduction of rings or ring systems. Small monocyclic scaffolds are preferable to other conformationally restricted scaffolds since their contribution to total molecular weight and lipophilicity of the molecule is less. Azetidine is the smallest nitrogen-containing saturated heterocycle possessing reasonable chemical stability. Azetidine-containing building blocks have been widely used for drug design for some time; one of the most successful examples includes calcium channel blocker azelnidipine used as antihypertensive.

Azetidines Fig.2 Noteworthy examples of biologically active drug leads and natural products incorporating the azedidine nucleus.

Organic Synthesis:

Compared to other nitrogen heterocycles such as aziridines, pyrrolidines, or piperidines, the chemistry of azetidines is much less developed, probably because of their limited availability. Recent synthetic routes to these strained heterocycles starting from readily available enantiomerically pure starting compounds have been developed. The ring strain in these heterocycles makes them excellent candidates for nucleophilic ring-opening or ring-expansion reactions yielding higher ring systems or highly substituted acyclic amines.

Biologic Chemistry:

The synthesis of novel amino acids in which the constraint is brought by a heterocyclic ring which holds the nitrogen atom of the amino acid moiety, has received considerable attention, as illustrated by numerous synthetic approaches towards proline, pipecolic acid, and glutamate analogues. In contrast, synthesis of the four-membered heterocyclic amino acid is seldom reported, which may be attributed to the lack of efficient synthetic methodologies for the preparation of functionalized azetidines, especially in enantiomerically pure forms. In 2005, Rabassoa group reported a new synthetic route towards azetidinic amino acids of general structure depicted in Fig. 3, in which the nature of the R group located at C-4 comes from enantiomerically pure β-amino alcohols (Fig.3).

Azetidines Fig.3 The examples of azetidinic amino acids

References

  1. Recent advances in the Chemistry of Metallated Azetidines, J. Name., 2013, 00, 1-3
  2. Azetidinic amino acids: stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters, Org. Biomol. Chem. , 2005, 3 , 3926–3936
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