Spirocyclic Oxetanes: Synthesis and Properties

Wormholes through chemical space: Spirocyclic oxetanes are described as analogues of morpholine and also as topological siblings of their carbonyl counterparts. They are particularly promising in terms of both their physicochemical properties and the ease with which they can be grafted onto molecular structures. The data collected highlight oxetanes as both the hydrophilic sister of a gem-dimethyl unit and the carbonyl group's lipophilic brother. We were intrigued by the apparent analogy between oxetanes and the van 't Hoff description of R2CO,1 with the close correspondence of these two structural types in the “bent-bond” model proposed by Pauling.2 This abstraction sets oxetanes in a context that is broader than merely as surrogates of gem-dimethyl groups in drug discovery, as we have previously suggested.3 Herein we disclose the implementation of this correlation in a study of spirocyclic oxetanes that resemble saturated heterocycles common to medicinal chemistry (Figure 1). Left: Formal analogy between the CO and oxetanyl groups. Middle left: Calculated van der Waals surfaces15 for acetone and 3,3-dimethyloxetane. Bottom left: 3-Alkoxy and 2-amino oxetanes as “van 't Hoff analogues” of esters and amides. Right: Spirocyclic oxetane amines and a methano-bridged morpholine derivative considered in this study. In druglike structures, there are liabilities associated with carbonyl groups that stem from their susceptibility to enzymatic modification and to the epimerization of adjacent stereogenic centers, as well as their inherent electrophilic reactivity and their potential for covalent binding. Studies suggest that oxetane and aliphatic carbonyl groups have a similarly high H-bonding avidity.4, 5 Consequently, the nominal analogy of an oxetane to CO may be of interest in molecular design, particularly when a larger volume occupancy and deeper oxygen placement might be advantageous at a receptor pocket.6 To establish a point of reference for the oxetane/CO analogy, we examined the properties of spirooxetane analogues of piperidones, pyrrolidones, and azetidinones. The series is also of practical interest in view of its structural relationship to morpholine (1; R=H), an oft encountered heterocycle in medicinal chemistry. We examined a subset of spirooxetanes which position the oxygen atom in the molecular-symmetry plane at an extended distance from the nitrogen atom (2, 3) with similar or decreased lateral bulk (2). Others (4–8) place the oxygen at a reclined angle from the symmetry plane of the parent morpholine, resulting in a reduction of symmetry without introducing chirality. Furthermore, amines 2–5 may also be considered to be stable analogues of the corresponding cyclic ketoamines 10–13 (Table 1), some of which are chemically or metabolically labile. The aminooxetane derivatives 6–8 can be perceived as nonhydrolyzable analogues of the corresponding β-, γ-, and δ-lactams 14–16 (Table 1). With a comparable molecular volume, an oxetane moiety may replace a gem-dimethyl group;3 consequently, the gem-dimethyl-substituted amines 17–23 (Table 1) were included in the study for calibration. The bicyclic oxetane 9 serves as another achiral morpholine analogue. All compounds to be studied were tagged with a piperonyl residue (R in Figure 1) to facilitate analytical measurements.7 Spirooxetanes 3, 4, and 6–8 were prepared by conjugate addition to acceptors 24 or 25,3 followed by a short sequence of steps (Scheme 1). For the preparation of 2, 5, and 9, new approaches were developed (Scheme 2). Tribromopentaerythritol (26) provides ready access to 2-oxa-6-azaspiro[3.3]heptane, which can be stored conveniently as its stable oxalate salt 27. Reductive alkylation of 27 provides N-substituted variants of 2. Dibromopentaerythritol can be transformed in one step into 2,6-dioxaspiro[3.3]heptane (28).10 We observed that one of the oxetane rings in 28 undergoes opening by an ester enolate with ease to furnish the hydroxymethyl derivative 29. Compound 9 was synthesized from alcohol 30 through a short three-step sequence. Collectively, these access routes offer convenient pathways to diverse compound libraries.11 R=piperonyl. Reagents and conditions: a) H2C(CO2Me)2, NaH; b) NaCl, DMSO, 160 °C, 82 % (2 steps); c) LiAlH4; d) MsCl, NEt3; e) RNH2, 38 % (3 steps); f) MeNO2, cat. DBU, 92 %; g) DIBAL-H, 73 %; h) H2, Pd/C, then piperonal, NaBH(OAc)3, 53 %; i) PPh3, CBr4, 71 %; j) RNH2, then CH2PPh3, 29 %; k) Hg(O2CCF3)2, then NaBH4, 38 %; l) RN(H)allyl, then CH2PPh3, 53 %; m) p-TsOH, Grubbs II (2.5 mol %), 88 %; n) H2, Rh/C, 79 %. DBU=1,8-diazabicyclo[5.4.0]-7-undecene, DIBAL-H=diisobutylaluminum hydride, DMSO=dimethyl sulfoxide, Ms=methanesulfonyl, Ts=p-toluenesulfonyl. a) TsNH2, KOH, 58 %; b) Mg, MeOH, ultrasound, then H2C2O4, 81 %; c) NaBH(OAc)3, piperonal, 73 %; d) LiO(tBuO)CCH2, BF3OEt2, 75 %; e) LiAlH4, 0 °C; f) MsCl, NEt3; g) RNH2, 80 °C, 49 % (3 steps); h) H2, Pd(OH)2/C; i) MsCl, pyridine; j) RNH2, 20 % (3 steps). Bn=benzyl. All oxetanes were found to be chemically stable at pH 1–10 (37 °C/2 h). This stability is noteworthy for the strained azetidines 2 and 6. The introduction of the oxetane moiety into cyclic amines markedly reduces their basicity (Table 1). The shifts in the pKa values of 3, 5, and 8 relative to the value for the parent piperidine 31 are ΔpKa=−1.3, −1.7, and −2.6, respectively, for γ, β, and α substitution. Similar effects are observed for the pyrrolidine 4 and the azetidine 2. In contrast to piperidine 8, α-oxetanes 6 and 7 are considerably less basic (ΔpKa=−3.3). X-ray crystal data and NMR spectroscopic data suggest that the attenuated basicity reduction in 8 can be attributed to its conformational preferences.12, 13 Compound log D[b] (log P)[c] Sol.[d] Clint (h/m)[e] pKa[f] gem-Me2 17 0.8 (3.1) 290 0/16 9.6 oxetane 2 0.5 (1.2) 24 000 3/7 8.0 carbonyl 10 n.d.[g] n.d.[g] n.d.[g] n.d.[g] gem-Me2 18 2.3 (4.4) 220 23/31 9.5 oxetane 3 1.0 (2.0) 1400 6/22 8.3 carbonyl 11 1.2 (1.6) 4000 120/88 7.5 gem-Me2 19 1.4 (3.7) 40 10/39 9.7 oxetane 4 0.7 (1.5) 730 2/27 8.1 carbonyl 12 −0.1 (−0.1) 4100 100/580 6.1 gem-Me2 20 2.3 (4.3) 13 31/89 9.4 oxetane 5 1.7 (2.3) 2000 16/55 7.9 carbonyl 13 0.1 (0.5) 2100 120/120 7.6 gem-Me2 21 0.1 (2.8) 380 7/14 10.1 oxetane 6 1.3 (1.3) 1400 21/26 6.2 carbonyl 14 1.1 (1.1) 2100 5/190 – gem-Me2 22 0.9 (3.5) 41 0/13 10.0 oxetane 7 1.9 (1.9) 2100 31/74 6.3 carbonyl 15 1.2 (1.2) 1500 5/16 – gem-Me2 23 1.1 (3.9) 30 0/18 10.2 oxetane 8 2.2 (2.4) 750 19/230 7.0 carbonyl 16 1.6 (1.6) 6200 8/39 – 9 1.6 (1.8) >2600 15/41 7.1 x=3 31 0.9 (3.1) 450 8/18 9.6 x=2 32 0.2 (2.5) 580 6/18 9.7 x=1 33 −0.1 (2.1) 2500 0/11 9.5 1 1.5 (1.6) 8000 9/8 7.0 The lipophilicity (log D, Table 1) of spirocycles 2–8 increases markedly as the oxetane unit is positioned closer to the nitrogen atom. This trend follows from the reduction in basicity, which leads to a higher proportion of the neutral species at pH 7.4. However, the intrinsic lipophilicities (log P) of the oxetanes are all significantly below those of the corresponding gem-dimethyl derivatives and those of the parent amines 31–33. The pronounced polarity of the oxetane unit is a feature that is also manifested in a generally higher intrinsic solubility. Oxetanes 2–8 have a higher intrinsic lipophilicity (Δlog P: 0.2–1.8) than the carbonyl derivatives 10–16 and, accordingly, in most cases a lower intrinsic solubility (difference in intrinsic solubility: 100–5000 μg mL−1; Table 1). In general, the polarity of an oxetane unit falls between that of a gem-dimethyl unit and that of a carbonyl group. Although this trend also applies to amine basicity in these compounds, it does not apply to oxidative metabolic degradation, as measured by intrinsic clearance rates in human or mouse microsomal preparations (Table 1). Except for the unstrained γ- and δ-lactams 15 and 16, which exhibit reasonably good resistance to degradation, all ketoamines (10–13) are degraded rapidly. By contrast, the oxetane derivatives display better stability, except in those cases (6–8) in which the oxetane is at the α position to the basic amine functionality, as noted previously.3 Of particular interest are the azetidines, in which both the gem-dimethyl and oxetane derivatives in either position are remarkably resistant to oxidative degradation.14 The comparison of spirooxetane 2, morpholine 1, and 4-piperidone 11 reveals another interesting feature. Spirooxetane 2 is more slender than morpholine, and it displays its polar ether approximately 1.3 Å further out. Consequently, it may be regarded as a prolate morpholine, and 4–8 as oblate counterparts. Whereas the lone pairs of electrons on the oxygen atom in oxetane 2 and ketone 11 have the same spatial orientation, in 1 and 2 they are orthogonal (Figure 2). Furthermore, in 4-piperidone and 2 the O and N atoms are colocated. Although the two compounds exhibit comparable basicity, 2 is considerably less lipophilic, more soluble, and less sensitive to oxidative metabolic degradation than 4-piperidone. Owing to these features and its ready synthetic availability, 2, or “homospiromorpholine”, is particularly promising for further applications. Superposition of three structures: the X-ray crystal structures of the N-benzhydryl derivative of 2 (blue; the benzhydryl group is omitted)13 and N-methylmorpholine15 (green), and a model of N-methyl-4-piperidone (ochre).16 The positions of the N and O atoms in matched 4-piperidone and 2 (R=N-benzhydryl) differ by 0.12 and 0.16 Å, respectively. One conclusion from this study is that the oxetane unit can be employed to access novel analogues of and expand the chemical space around morpholine. As this heterocycle is common in medicinal chemistry, we anticipate that its oxetanyl analogues will find wide use. These analogues are particularly promising in terms of both their physicochemical properties and the ease with which the oxetane functionality can be grafted onto structures. More broadly, we also suggest a novel interpretation of the oxetane functionality that draws on the structural resemblance of this unit to a carbonyl group. The data indeed highlight the position of an oxetane ring between a gem-dimethyl unit and a carbonyl group in terms of lipophilicity, solubility, and influence on basicity. These useful features provide new prospects for the implementation of oxetanes in molecular design, drug discovery, materials, and beyond. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z800450_s.pdf or from the author. 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