The oxetanes show a slight widening of the outer ring C-C-C bond angles and a small degree of wrinkling (measured by the dihedral angle θ). In the gas phase, the microwave spectroscopic data indicate that the parent oxetane has an effectively planar structure with a low wrinkling (low folding) inversion barrier. substitution at the 3-position leads to increased etiolation interactions with neighbouring methylene groups, and consequently more pronounced shrinkage (folding) of the oxetane ring is found in many structures. Nevertheless, the shrinkage (folding) angle is still very small, allowing for closer structural proximity between the oxetane and carbonyl units.
The physicochemical and pharmacokinetic properties of compounds are routinely explored early in the discovery process in modern drug discovery projects, and their optimisation is increasingly performed in parallel with target affinity and selectivity. This multidimensional optimisation strategy significantly improves the successful transition from lead compound discovery to early in vivo analysis of potential drug candidates. Nevertheless, compound property optimisation remains a considerable challenge in medicinal chemistry. Therefore small molecular moieties that can be easily grafted onto molecules and modulate compound properties in a predictable manner are of great interest. And oxetanes are one such moiety. Previously, synthesis of oxetanes was laborious and there were concerns about their metabolic stability, so they were used sparingly. Compared to other four-membered heterocycles, oxetanes have attracted particular interest in the synthetic and medicinal chemistry communities.
The best-known oxetane-containing natural product is paclitaxel, which is also the only biologically active oxetane compound approved by the FDA (Fig. 3). Often known by its brand name Taxol, the oxetane group adds three dimensionality), and the negatively charged oxygen atom confers a strong electron-withdrawing effect on the oxetane, which propagates to the 3-position through two short σ-bonding frames. Thus, it was demonstrated that with amine α-oxetanes reduce the pKa of amines from 9.9 to 7.2 by 2.7 units (i.e., about 500-fold reduction in basicity) through their electron-withdrawal effect. In addition, Hayes and colleagues (AstraZeneca) have recently shown that selected oxetane compounds are degraded by human microsomal epoxide hydrolase (mEH). This is a non-epoxide substrate being mEH, which may have the potential application of avoiding cytochrome P450 enzyme (CYP) scavenging, which can be problematic as unwanted and unpredictable drug interactions can lead to hepatotoxicity with co-administered drugs.
The high rigidity of the smaller rings coupled to negatively charged oxygen atoms also makes oxetane substrates potentially unstable to ring-opening degradation processes, especially under acidic conditions. The stability of oxetanes is usually determined by their substitution pattern, with 3,3-disubstituted examples being the most stable because the path of the external nucleophilic reagent to the C-O σ* antibonding orbital is blocked by substituent space. The instability of a particular compound may also depend on local structural features, including the presence of other basic sites. Internal nucleophilic reagents can also lead to a cyclisation process, which is one of the synthetic methods for oxetanes.