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A broad class of spirocycles which has attracted significant interest in drug discovery are those containing a four‐membered ring [48]. This is mainly due to their structural novelty and historically poor exploration of the associated chemical and intellectual property space, hence presenting important opportunities for the development and patenting of new drugs without overlapping with other traditionally densely populated IP spaces [48]. Among them, substituted spiro‐cyclobutanes/oxetanes/thietanes/azetidines are among the most represented due to their chemical robustness. A recent survey of the literature by Carreira and Fessard suggested that the incidence of drug‐like spirocyclic structures containing at least one four‐membered ring in research articles and patents remained relatively low and steady from the early 1960s to c. 2000, while it has followed an exponential growth and approximately quintupled between 2000 and 2013. Unsurprisingly, this correlated with major advances in the synthesis of such motifs during the same period. Those will be discussed in the following chapters of this book. This illustrative example is another testament that the general interest for new molecular scaffolds in medicinal chemistry usually evolves hand in hand with the development of new synthetic methodologies to access them, and is fuelled by the downstream associated benefits in research and development. Such benefits include, for example, structural novelty, improved physicochemical and pharmacokinetic properties of drug candidates, and the potential for exploiting new intellectual property. Of note, epoxides, aziridines, and episulfides are generally avoided due to their intrinsic reactivity. For the same reason, functional groups bearing heteroatoms in a 1,2‐relationship (dioxolanes, pyrazolidines, disulfides, isoxazolidines, oxathiolanes, and isothiazolidines) and 1,3‐relationship (ketals, aminals, 1,2‐dithianes, oxazolidines, oxathiolanes, and thiazolidines) are generally avoided due to their chemical susceptibility to reducing agents and nucleophiles [49]. They are generally used as protecting groups in synthesis and sometimes for prodrug approaches, rather than as critical structural drug motifs.

A survey of the literature reveals several key strategies for the synthesis of oxetanes, thietanes, and azetidines, some of which are shown in Scheme 2.2. Such strategies include: (i) intramolecular displacement of a leaving group (e.g. halogen or activated alcohol nucleofuge) by the heteroatom; (ii) ring formation via the reaction of a nucleophile with doubly activated substrates bearing LGs in a 1,3 relationship; (iii) [2+2]‐cycloaddition reactions, including Paternò−Büchi or reduction of lactams obtained by Staudinger ketene cycloaddition. Controlling the regioselectivity of cycloadditions is difficult, and often limits the scope and utility of such approaches; (iv) Gold‐catalyzed cyclization of propargylic alcohols and amines toward their 3‐oxo‐substituted products. The wide range of methods available to prepare optically active propargyl alcohols and amines [9] make this fourth approach particularly attractive, greatly expanding the scope of substitution patterns that can be introduced onto the azetidine and oxetane scaffolds.

Scheme 2.2 Summary of common strategies for the synthesis of common four‐membered rings encountered in spirocyclic systems of medicinal chemistry interest.

Oxetanes have been known for 140 years [50]; however, historically they have received little attention in medicinal chemistry [51] compared with epoxides, tetrahydro‐furans, and pyrans. This is mainly due to their perceived reactivity: due to ring strain, they are generally seen as too reactive for their incorporation in drug candidates, despite the harsh conditions needed for their opening. Early reports have suggested that despite displaying similar ring strain to epoxide [52], their opening with nucleophiles is actually much slower [53]. Only in the last decade have oxetanes and their spiro analogues found applications in medicinal chemistry [48, 51, 54]. Due to its geometry and electronic properties, the oxetane ring has been used as a bioisosteric replacement for gem‐dimethyl and carbonyl units (Figure 2.5). Despite useful to increase the affinity of a ligand to a target receptor, the introduction of a bulky hydrophobic gem‐dimethyl motif generally increases the lipophilicity and decreases the solubility of a lead compound, which is often unwanted. The oxetane geometry mimics that of a gem‐dimethyl, while being more hydrophilic due to its oxygen atom.

Carreira’s lab and collaborators from Hoffman‐La Roche examined the physicochemical and biological properties of spiro‐oxetanes 22–30, along with their corresponding carbonyls and gem‐dimethyl analogues (Table 2.2) [55]. The oxetane ring generally provides higher metabolic stability, lower log P/D, and higher aqueous solubility than its gem‐dimethyl counterparts across all series scrutinized. Unsurprisingly, this trend also correlated with a lower pK _a (1.2–1.6 units) for the amine, resulting from the inductive effect of the oxygen. While being less water soluble than carbonylated analogues, spiro‐oxetanes displayed much improved metabolic stability toward oxidation in the piperidine and pyrrolidine series. Properties of the azetidin‐3‐one derivative could not be determined due to its low stability.

Figure 2.5 Comparison between carbonyl, gem‐dimethyl, and oxetane groups, highlighting similar spatial arrangement of lone pairs and hydrophobic bulk.

Four‐membered ring containing spirocycles have also been scrutinized for their potential as bioisosteres of morpholines (Y = O), piperidines (Y = CR₂), piperazines (Y = NR), and thiomorpholines (Y = S, SO, SO₂), for the development of lead molecules with improved physicochemical and pharmacokinetic properties (Figure 2.6a) [48, 56]. While both classes display a similar relative positioning of polar and apolar groups, the comparison has its limitations. For example, the N–Y distance in these six‐membered heterocycles is approximately 3 Å, while it is significantly higher and is slightly above 4 Å in their spirocyclic counterparts (Figure 2.6a). Similarly, the C–O distance in an oxetane is around 2 Å, while the C–O distance in the parent carbonyl group is approximately 1.2 Å. Another important difference is the introduction of exit vectors “out‐of‐plan” in these isosteres compared with the parent groups (Figure 2.6b). Nevertheless, such differences also contribute to the unique properties of the spiro analogues and make them interesting structural features for bioisosteric replacement (Figure 2.6c). For example, incorporation of morpholine rings into drug scaffolds is an established strategy for improving aqueous solubility. However, oxidative metabolism is a known inactivation pathway of morpholines, most often resulting from ring opening. Spiro‐oxetanes 26 and 29 (Table 2.3) were proposed as replacements for morpholine 31, due to the similar relative spatial disposition of their hydrophobic and polar features. Interestingly, 29 displays higher solubility and lower logP than the parent morpholine, while also remaining stable to oxidative metabolism. A number of other potential spirocyclic morpholine mimics based on [3.3], [3.4], and [3.5] motifs have been reported by Carreira, displaying a range of unique dipoles and exit vectors for tunable properties [55].

Another illustrative successful example is the bioisosteric replacement of the metabolically labile morpholine unit of BTK inhibitor 32 (Figure 2.7). This led to the development of 2‐oxa‐6‐azaspiro[3.3]heptane functionalized analogue 33, which displays enhanced stability and solubility while retaining similar potency to its target compared with the parent molecule [57].

Thalidomide 34 (Figure 2.8) was introduced on the market in the late 1950s–early 1960s as an antiemetic and sedative, and banned a few years later due to its shattering side‐effects. Overall, thalidomide is thought to have caused numerous and severe birth defects in more than 10 000 children during that time [25]. While thalidomide was initially administered as a racemic mixture, it has since been shown that the (R) enantiomer has sedative effects and the (S) enantiomer is teratogenic. It is also known that racemization spontaneously takes place in vivo due to the acidity of H_a (Figure 2.8), although as of today the exact mechanism underlying the teratogenicity of thalidomide is still under investigation. In 2013, Carreira and coworkers reported derivative 35 where one of the imide carbonyls is replaced by an oxetane [56], with the goal of limiting in vivo metabolism and racemization, and potentially altering teratogenicity (Figure 2.8). Not unexpectedly, 35 displayed higher pK _a, lower lipophilicity, and increased solubility. It displayed similar intrinsic clearance rates in human microsomes compared with 34; however, showed much improved plasma stability after five hours. Pleasingly, 35 was configurationally stable to racemization in human blood plasma after five hours, thereby showing that a carbonyl to oxetane switch can be a viable approach to mitigate epimerization at adjacent stereocenters.

Table 2.2 Physicochemical and biochemical properties of selected oxetanes, and their carbonylated and gem‐dimethyl counterparts.

Source: Based on Wuitschik et al. [55].

Solubility (μg ml−1)	4000	1400	220	4100	730	40	n.d.	24 000	290
Lipophilicity logD (logP)	1.2 (1.6)	1.0 (2.0)	2.3 (4.4)	−0.1 (−0.1)	0.7 (1.5)	1.4 (3.7)	n.d.	0.5 (1.2)	0.8 (3.1)
hCLint (min−1 mg−1 μl)	120	6	23	100	2	10	n.d.	3	0
mCLint (min−1 mg−1 μl)	88	22	31	580	27	39	n.d.	7	16
pK a amine	7.5	8.3	9.5	6.1	8.1	9.7	n.d.	8.0	9.6

Figure 2.6 (a) Spiro‐oxetane as a morpholine bioisostere.

Sources: Based on Carreira and Fessard [48]; Burkhard et al. [56];

(b) comparison of exit vectors in the piperidine motif and its spiro counterpart; (c) spirocyclic oxetane based on mimics of morpholine.

Table 2.3 Comparison of the properties of spirocyclic oxetanes with their morpholine parent.

Source: Adapted from Carreira Wuitschik et al. [55].

Solubility (μg ml−1)	730	8000	24 000
Lipophilicity logD (logP)	0.7 (1.5)	1.5 (1.6)	0.5 (1.2)
hCLint (min−1 mg−1 μl)	2	9	3
mCLint (min−1 mg−1 μl)	27	8	7
pK a amine	8.1	7.0	8.0

Figure 2.7 Replacement of morpholine by 2‐oxa‐6‐azaspiro[3.3]heptane in BTK inhibitors.

Figure 2.8 Top: Structure of thalidomide 34 and its oxetano analogue 35. Bottom: comparison of the physicochemical properties of thalidomide and oxetano‐thalidomide.

Source: Modified from Burkhard et al. [56].

Notes: ^aLogarithmic n‐octanol/water distribution coefficient at pH 7.4. ^bIonization constants determined at 23 °C by spectrophotometry in water. ^cIntrinsic solubility measured at pH 6.5 by a Lyophilization Solubility Assay [μg ml⁻¹]. ^dIntrinsic clearance rates [μl min⁻¹ 10⁻⁶ cells] measured in human hepatocytes. ^eStability in human plasma after five hours incubation time, expressed as a percentage of the initial concentration. The reported values represent the average of three runs (n = 3).