Synthesis of diversely functionalised 2,2-disubstituted oxetanes: fragment motifs in new chemical space

Abstract

Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O–H insertion and C–C bond forming cyclisation.

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Recent years has seen considerable enthusiasm for exploring new chemical motifs in medicinal chemistry that enter unexplored chemical and intellectual property (IP) space.^1,2 Oxetanes motifs have gained significant traction as desirable modules for drug discovery.³ Carreira, Rogers-Evans, Müller and co-workers demonstrated that 3,3-disubstituted oxetanes constitute polar replacements for gem-dimethyl groups, and often afford improved solubility and physicochemical properties.⁴ Subsequently, oxetane motifs have been adopted widely in medicinal chemistry programs.^5,6 3-Substituted oxetane motifs have been examined in particular, exploiting oxetan-3-one^3,4 and 3-iodooxetane⁷ as building blocks. New spirocycles,⁸ peptidomimetics⁹ and other oxetane analogues of important compounds have been prepared (e.g.Fig. 1).^6,10

Fig. 1 Biologically active oxetane-containing compounds.

Examples of 2-substituted oxetanes remain less studied; Pfizer reported a class of 2-oxetanyl containing γ-secretase inhibitors that possessed improved properties relative to tetrahydrofuran and carbocyclic derivatives.⁶ However, oxetanes bearing functional groups on the ring are unexplored, and could provide fascinating new structural units for use by medicinal chemists. The synthesis of functionalised oxetanes continues to be a challenge. Cyclisation by intramolecular Williamson etherification is most common,³ but 2-functionality is often precluded due to unstable oxyanionic intermediates. Also, epoxide-opening and ring-closure methods using sulfoxonium ylides are not tolerant of sensitive electrophilic functionality.¹¹ On the other hand, the photochemical Paterno–Büchi reaction can introduce functionality from an alkene component, but is often restricted to very highly substituted oxetanes, with undesirable properties for medicinal chemistry.^12–14

We have targeted new oxetane derivatives due their small, polar nature and well-defined 3-D shape.¹⁵ We recently reported the preparation of 2-sulfonyl oxetanes, formed through a novel anionic C–C bond forming cyclisation (Scheme 1A).¹⁶ These fragments displayed good pH stability, and stability to liver microsomes.^16b We have also established an efficient synthesis of oxetane 2,2-dicarboxylates involving O–H insertion using diazomalonates, and C–C bond forming cyclisation (Scheme 1B).¹⁷

Scheme 1 Synthesis of oxetanes through anionic C–C bond forming cyclisation.

Here we report the synthesis of unusual oxetane motifs bearing medicinally relevant functional groups directly on the ring (Scheme 1C). Diversely functionalised oxetanes in new chemical space are prepared in a facile manner from functionalised diazo compounds by O–H insertion and C–C bond forming cyclisation. These simple but highly functionalised motifs provide interesting shape and physicochemical properties for fragments or building blocks for drug discovery that cannot be prepared by other methods.

Targeting 2,2-difunctionalised oxetanes, our investigations initially focused on a range of unsymmetrical acceptor–acceptor diazo compounds, with which to examine O–H insertion with 2-bromoethanol (Scheme 1C and Table 1).^18,19 A series of diazo compounds 1a–g bearing amide, sulfone, phosphonate, and nitrile groups were prepared from the methylene precursors using TsN₃ or TfN₃.^18,20,21 We first examined amide–ester diazo 1a (entry 1). Pleasingly, using catalytic Rh₂(OAc)₄ (0.5 mol%) in benzene at 80 °C successfully mediated O–H insertion of the carbene derived from diazo 1a into 2-bromoethanol in 75% yield.

Table 1 Scope of 2,2-disubstituted oxetanes varying diazo 1a–g

Entry	E^1	E^2		Yield 2^a (%)	Yield 3^b (%)	Oxetane 3
a O–H insertion: 1 (1.1 equiv.), 2-bromoethanol (1.0–2.0 mmol), Rh2(OAc)4 (0.5 mol%), PhH, 0.1 M, 80 °C. b Cyclisation: 2 (0.3–0.6 mmol), NaH (1.2 equiv.), DMF, 0.025 M. c 0 °C for 1 h; then 25 °C for 1 h. d 0 °C for 1 h. e 1.5 equiv. diazo 1d. f Run in CH2Cl2, 0.1 M at 25 °C for 17 h. g 10 mmol scale. h 8 mmol scale. i 1.2 equiv. diazo 1f.
1		CO2Et	a	75	93^c
2		CO2Et	b	51	96^c
3	SO2Ph	CO2Et	c	92	87^d
4	PO(OEt)2	CO2Et	d	77^e	70^d
5	CN	CO2Bn	e	85^f	88^d
6				93^f^,^g	93^d^,^h
7		CN	f	67^i	87^d
8		PO(OEt)2	g	84	72^d

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Cyclisation was then effected by treatment of 2a with NaH (1.2 equiv., 0 °C, 1 h, then 25 °C, 1 h) to afford 2-amido-2-ester-oxetane 3a in excellent yield forming the C(2)–C(3) bond. Using Weinreb amide 1b (entry 2), a slightly reduced yield was obtained for the O–H insertion (51%), but an excellent yield was obtained on cyclisation of 2b to oxetane 3b. Sulfone–ester diazo 1c smoothly underwent O–H insertion, followed by cyclisation in just 1 h at 0 °C to provide a new type of sulfonyl oxetane (entry 3).¹⁶ Phosphonate–ester diazo 1d proceeded similarly, to yield the first example of a 2-oxetanyl phosphonate, 3d.²² Interestingly, the use of nitrile–ester diazo 1e led to side reactions under the conditions for O–H insertion, with the carbenoid undergoing competitive insertion into the benzene solvent (1.2 : 1–2.4 : 1 O–H insertion : π-insertion). To prevent this unwanted side product, the reaction was performed in CH₂Cl₂ (25 °C, 17 h), and bromide 2e was isolated in 85% yield (entry 5). Cyclisation at 0 °C afforded nitrile oxetane 3e after 1 h. The sequence was also successful on a larger scale affording >1.5 g of oxetane 3e in excellent yield (entry 6). Mixed nitrile–amide and phosphonate–amide diazo compounds were also successful under the same conditions, providing oxetanes 3f and 3g respectively (entries 7 and 8). The wide variety of substituted oxetanes that can be readily accessed demonstrates the versatility of this approach.

Substituted bromohydrins were then investigated to form tri- and tetrasubstituted oxetane derivatives (Table 2). The reaction sequence successfully formed oxetanes with 4-alkyl (5a) and 4-aryl substituents (5b–e) in good yields using similar reaction conditions. The additional substituent had little influence on the O–H insertion step. However, elevated temperature and increased reaction times were required for cyclisation of all substituted examples, requiring 16 h at 25 °C for complete conversion.

Table 2 Preparation of 2,2,4-, 2,2,3-tri- and 2,2,4,4-tetrasubstituted oxetanes

Conditions: (i) O–H insertion: 1 (1.1 equiv.), β-bromohydrin (0.5–1.3 mmol), Rh₂(OAc)₄ (0.5 mol%), PhH, 0.1 M, 80 °C. (ii) Cyclisation: 4 (0.3–0.5 mmol), NaH (1.2 equiv.), DMF, 0.025 M, 25 °C, 16 h.a dr determined by ¹H NMR of crude reaction mixture.b β-Chlorohydrin used.c Oxetane isomers separated by silica chromatography.d 1.5 equiv. diazo.e Run in CH₂Cl₂, 0.1 M at 25 °C for 17 h.f 1.2 equiv. diazo.g Major diastereoisomer indicated (see ref. 23).

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For oxetanes 5a and 5b, a ∼1 : 1 mixture of diastereoisomers was obtained due to the sterically similar ester–sulfone or ester–phosphonate groups.²³ Diazo compounds with a less sterically demanding nitrile group (1e, 1h, 1i) gave increased diastereoselectivity (up to 3 : 1 dr). The incorporation of a 3-Ph group gave the 2,2,3-substituted derivative 5f (dr = 56 : 44). 2,2,4,4-Tetrasubstituted oxetane 5g was prepared from the commercially available chlorohydrin (1-chloro-2-methyl-2-propanol) in moderate yields. The synthesis of novel fused bicyclic oxetane scaffold 5h started by treating N-Boc-3-pyrroline with NBS and H₂O to provide 3-bromo-4-hydroxy-pyrrolidine, which gave ether 4h on O–H insertion. Cyclisation then afforded the bicyclic oxetane 5h as a 83 : 17 mixture of separable diastereoisomers in 95% combined yield.^21,23

Next we examined aryl–ester (donor–acceptor) diazo compounds,²⁴ to generate 2-aryl-oxetane-2-carboxylates (Table 3). Such aryl-substituted heterocycles offer attractive features for fragment screening and are little studied in medicinal chemistry.²⁵ To our delight, the O–H insertion conditions were effective for the phenyl–ester diazo 6a with an excellent 86% yield using reduced Rh₂(OAc)₄ loading (0.25 mol%, entry 1). The O–H insertion was successful across varied aryl groups (entries 3–8), including the chloropyridyl diazo 6f. However, using the NaH in DMF conditions for cyclisation gave variable yields and oxetane 8a and bromide 7a proved inseparable. Alternative bases and conditions were examined,²¹ and the use of LiHMDS (1.4 equiv.) in THF was found to give quantitative conversion to oxetane 8a with a 93% isolated yield (entry 1). This reaction sequence was similarly successful on a larger scale (entry 2). The modified cyclisation conditions worked well for substituted aryl derivatives including halogenated (entries 4 and 5), and pyridyl derivatives (entry 8). However, the electron rich p-methoxy phenyl substrate (entry 6) led to low conversion and isolated yield. Using a larger excess of LiHMDS (2 equiv.) gave an improved yield of 41% (entry 7). The cyclisation conditions were also effective for aryl–amide ether 7g (entry 9). This approach provided direct access to compounds that conform well to fragment guidelines for fragment screening.²¹

Table 3 Scope of 2-aryl-oxetane 2-carboxylates

Entry	Ar	E		Yield 7^a (%)	Yield 8^b (%)	Oxetane 8
a O–H insertion: 6 (1.1–1.5 equiv.), 2-bromoethanol (0.4–2.0 mmol), Rh2(OAc)4 (0.25 mol%), PhH, 0.1 M, 80 °C. b Cyclisation: 7 (0.3–0.5 mmol), LiHMDS (1.4 equiv.), THF, 0.025 M, 0 °C, 1 h. c Reaction on 7.5 mmol scale. d Reaction on 5.0 mmol scale. e 0.5 mol% Rh2(OAc)4. f 2.0 equiv. LiHMDS.
1	Ph	CO2Et	a	86	93
2				80^c	76^d
3	Ph	CO2iPr	b	87^e	72
4	3-ClPh	CO2Et	c	69	97
5	4-CF3Ph	CO2Et	d	64	77
6	4-MeOPh	CO2Et	e	86	22
7					41^f
8		CO2Et	f	54	76
9	3-ClPh		g	73	90

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As a more divergent approach to similar compounds, hydrolysis of ester oxetane 8a was examined (Scheme 2a). Using NaOH afforded sodium salt 9 as an attractive oxetane containing building block. Amide coupling with morpholine, directly from the salt,²⁶ gave amide 10 in a good yield over two steps. Finally, we prepared additional 2-nitrile oxetane derivatives. The nitrile group is receiving considerable attention in drug discovery,^27,28 being metabolically robust and a strong hydrogen bond acceptor. Therefore, we considered that the combination with an oxetane motif could present a fascinating structure for medicinal chemistry.^13,29 From nitrile–oxetane benzyl ester 3e, ester hydrolysis was best achieved using LiOH to afford lithium salt 11 (Scheme 2b). Amide bond formation gave nitrile amide oxetanes 12 and 13 in 30–35% yields over 2 steps. Importantly, treatment of oxetane 3f with TFA promoted Boc deprotection, 14, without other degradation, providing encouraging preliminary information on acid stability (Scheme 2c; 10 equiv. TFA, 22 h).

Scheme 2 Divergent synthesis of oxetane derivatives.

In summary, we have developed a versatile strategy to prepare diversely functionalised oxetane derivatives, involving O–H insertion and C–C bond forming cyclisation. A wide variety of functional groups have been introduced on the oxetane ring, accessing new chemical space. We believe these oxetane motifs will provide interesting new structural elements for medicinal chemistry programs as well as synthesis. Efforts towards enantioselective synthesis and studies on the stability and medicinal chemistry properties of the new oxetane derivatives will be reported in due course. We gratefully acknowledge EPSRC (CAF, EP/J001538/1; Impact Acceleration Account, EP/K503733/1), and Imperial College London. We thank EPSRC National Mass Spectrometry Facility, Swansea.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterisation data, ¹H and ¹³C NMR spectra; details of reaction optimisation and calculated molecular properties. See DOI: 10.1039/c5cc05740j

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