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Open AccessShort Note


Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “A. Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
Authors to whom correspondence should be addressed.
Academic Editor: Norbert Haider
Molbank 2017, 2017(1), M930;
Received: 22 December 2016 / Revised: 24 January 2017 / Accepted: 7 February 2017 / Published: 10 February 2017
(This article belongs to the Section Organic Synthesis)


The two geometric isomers of 2-(tert-butyl)-4-phenyloxetane have, for the first time, been prepared starting from the commercially available 4,4-dimethyl-1-phenylpentane-1,3-dione. The latter was reduced with NaBH4 to give a mixture of diastereomeric syn and anti diols which were then stereospecifically cyclized into the corresponding oxetanes with an overall yield for the two steps of 69.6%. The newly synthesized stereoisomeric four-membered oxygenated heterocycles were separated by column chromatography on silica gel and fully spectroscopically characterized.
Keywords: oxetanes; diols; diastereoisomers; cyclization reactions; NMR; heterocycles oxetanes; diols; diastereoisomers; cyclization reactions; NMR; heterocycles

1. Introduction

Oxetanes are an important group of four-membered heterocyclic compounds that have recently received a great deal of attention as useful tools for both drug discovery and organic synthesis [1]. The oxetane motif is also ubiquitous in many natural products (e.g., taxol, oxetanocin, mitrophorone) [2,3,4] and is widely used in the medicinal chemistry for fine-tuning the physicochemical and hydrophilic properties of (biological active) organic compounds; it is also used as an isosteric replacement of both the carbonyl and the gem-dimethyl groups [5]. In addition, oxetanes are versatile templates for the construction of valuable heterocyclic compounds and several chiral synthons by ring expansion, ring opening, rearrangement and desymmetrization reactions [6,7,8,9].
The employment of these compounds in organic synthesis has progressively increased, particularly in the last 15 years, with the development of new and more efficient methods for their preparation. Nowadays, photochemical Paternò–Büchi [2+2] reactions of carbonyl compounds with alkenes [10], intramolecular Williamson etherification [11] and ring expansion of epoxides with sulfoxonium ylides [12] are already established general methods for their synthesis. More functionalized derivatives can be prepared by regioselective lithiation-electrophilic trapping processes starting from 2-aryloxetanes, 2-sulphonyloxetanes and hydrazones of oxetan-3-one [13,14,15,16,17]. The synthesis of stereodefined 2,4-disubstituted oxetane scaffolds still remains a challenge in contemporary organic synthesis. Inspired by a work of Nelson and co-workers [18,19], our group has recently reported on the preparation of 2,4-disubstituted aryloxetanes in an enantioenriched form [20], exploiting as a key step a stereoselective biocatalytic reduction of diketones to optically active β-aldols using wild-type whole cell biocatalysts (e.g., thermotolerant Kluyveromyces marxianus yeast and the Lactobacillus reuteri strain [21,22,23]). Building on this finding, in this short note we describe the preparation and the structural characterization of stereodefined and sterically demanding cis- and trans-2-(tert-butyl)-4-phenyloxetanes.

2. Results and Discussion

As a first step of the synthesis procedure, the commercially available 4,4-dimethyl-1-phenylpentane-1,3-dione 1 was reduced with NaBH4 in EtOH to give an almost equimolar mixture [diastereomeric ratio (dr): 57:43] of the two diastereomeric syn- and anti-2 diols in an overall yield of 94% (Scheme 1).
The latter could then be stereospecifically cyclized into the corresponding 2,4-disubstituted aryloxetanes according to a two-step procedure reported by Nelson [18,19]. In the first step, the mixture of diastereomeric diols was preliminary converted into orthoesters 3 by reaction with trimethyl orthoacetate, followed by treatment with acetyl bromide and quenching by a saturated aqueous solution of NaHCO3 to give the bromoacetate intermediates 4 (Scheme 2). In the next step, the crude mixture of acetates 4 was subjected to methanolysis and ring closure promoted by NaH/THF, thereby providing both trans- and cis-2-(tert-butyl)-4-phenyloxetanes (5). The overall transformation of diols into oxetanes was found to proceed via two stereospecific inversion reactions, and thus with the overall retention of the configuration at the two stereogenic centers: anti-diol 2 led to oxetane trans-5, whereas syn-diol 2 furnished oxetane cis-5, the final dr (55:45, determinated by 1H-NMR analysis of the crude) mirroring that of the starting diols anti- and syn-2. The two geomeric isomers were finally separated and purified by silica gel column chromatography: trans-5: 39% yield; cis-5: 35% yield.
The relative configuration of oxetanes trans-5 and cis-5 was established by phase-sensitive 2D-NOESY spectra whose cross-peaks are diagnostic of a spatially close hydrogen relationship. As for the major diastereoisomer, significant NOE interactions were detected between protons H1 and H3, H2 and H3′, and between protons of the tert-butyl group and H1, which are consistent with a trans arrangement of the phenyl and tert-butyl groups (Figure 1). In the case of the minor diastereoisomer, NOE interactions between proton H3 and both protons H1 and H2 are consistent with a cis arrangement of the phenyl and tert-butyl groups instead (Figure 2).

3. Materials and Methods

1H-NMR and 13C-NMR spectra were recorded on a Bruker 600 MHz (Bruker, Milan, Italy) or on a Varian Inova 400 MHz spectrometer (Agilent Technologies, Santa Clara, CA, USA) and chemical shifts are reported in parts per million (δ). Absolute values of the coupling constants are reported. FT-IR spectra were recorded on a Perkin-Elmer 681 spectrometer (Perkin Elmer, Waltham, MA, USA). GC analyses were performed on a HP 6890 model, Series II by using a HP1 column (methyl siloxane; 30 m × 0.32 mm × 0.25 μm film thickness). Analytical thin-layer chromatography (TLC) was carried out on pre-coated 0.25-mm-thick plates of Kieselgel 60 F254; visualisation was accomplished by UV light (254 nm) or by spraying a solution of 5 % (w/v) ammonium molybdate and 0.2 % (w/v) cerium(III) sulfate in 100 mL 17.6 % (w/v) aq. sulfuric acid and heating to 473 K until blue spots appeared. Chromatography was conducted by using silica gel 60 with a particle size distribution 40–63 μm and 230–400 ASTM. GC-MS analyses were performed on a HP 5995C model (Agilent Technologies, Santa Clara, CA, USA). The high resolution mass spectrometry (HRMS) analyses were performed using a Bruker microTOF QII mass spectrometer (Bruker, Milan, Italy) equipped with an electrospray ion source (ESI) operating in positive ion mode.

3.1. Synthesis of anti- and syn-4,4-dimethyl-1-phenylpentane-1,3-diols 2

To a solution of 4,4-dimethyl-1-phenylpentane-1,3-dione (1) (408 mg, 2 mmol) in EtOH (4 mL), stirred at 0 °C, NaBH4 (171 mg, 4.5 mmol) was added. After 16 h, water was added and the aqueous solution extracted with EtOAc. The residue was purified by silica gel column chromatography using hexane and EtOAc (80:20) as the eluents to yield 94% of anti- and syn- 4,4-dimethyl-1-phenylpentane-1,3-diols 2; dr anti/syn = 57:43.
Anti- and syn-4,4-Dimethyl-1-phenylpentane-1,3-diols (anti-2 and syn-2). Inseparable mixture of diastereoisomers, colourless oil. 1H-NMR (400 MHz, CDCl3): δ 7.39–7.27 (m, 5 H major stereoisomer + 5 H minor stereoisomer, aromatic protons), 5.10–5.04 (m, 1 H minor, CH(OH)), 4.95–4.88 (m, 1 H, major, CH(OH)), 3.64–3.56 (m, 1 H, major, CH(OH)), 3.54–3.47 (m, 1 H, minor, CH(OH)), 3.00–2.74 (bs, 1 H major + 1 H minor, OH, exchanges with D2O), 2.05–1.58 (m, 2 H major + 2 H minor, CH2 and 1 H major + 1 H minor, OH, exchange with D2O), 0.90 (s, 9 H, major), 0.87 (s, 9 H, minor); 13C-NMR (100 MHz, CDCl3): δ 144.7 (major stereoisomer), 144.6 (minor stereoisomer), 128.45 (major), 128.38 (minor), 127.5 (major), 127.1 (minor), 125.7 (major), 125.4 (minor), 80.9 (major), 76.2 (minor), 72.2 (minor), 71.9 (major), 40.0 (major), 39.3 (minor), 34.9 (minor), 34.6 (major), 25.5 (major), 25.4 (minor); FT IR (neat): 3370, 3089, 3063, 3038, 2957, 2870, 1454, 1393, 1365, 1323, 1208, 1175, 1057, 1014, 853, 759, 700 cm−1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H20NaO2: 231.1361; Found: 231.1356.

3.2. Synthesis of trans- and cis-2-(tert-Butyl)-4-phenyloxetanes 5

Trimethyl orthoacetate (553 μL, 3.6 mmol) and pyridinium toluene-p-sulfonate (8 mg) were added to a stirred solution of diols anti-2 and syn-2 (624 mg, 3 mmol) in dry CH2Cl2 (30 mL). The reaction mixture was stirred for 10 min at room temperature, cooled to −78 °C, and acetyl bromide (631 μL, 7.2 mmol) was added. The reaction was stirred for an additional 1.5 h, quenched with sat. aq. NaHCO3 solution, extracted with CH2Cl2 (3 × 20 mL), dried (Na2SO4), filtered and evaporated to give a crude product. The latter was dissolved in dry THF (30 mL), and MeOH (138 μL, 4.1 mmol) and NaH (444 mg, 60% dispersion in oil, 9.1 mmol) were sequentially added. The vessel was sealed with a glass cap and the reaction stirred for 24 h at 60 °C. After this time, the reaction was quenched with water and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to give a crude product which was purified by flash silica gel column chromatography (10% Et2O in hexane), to give trans- and cis-2-(tert-butyl)-4-phenyloxetanes 5.
trans-2-(tert-Butyl)-4-phenyloxetane (trans-5): 39% yield, waxy solid, Rf = 0.6. 1H-NMR (600 MHz, CDCl3): δ 7.47–7.44 (m, 2 H, aromatic protons), 7.40–7.37 (m, 2 H, aromatic protons), 7.31–7.27 (m, 1 H, aromatic proton), 5.49 (dd, 1 H, J = 8.6, 6.4 Hz, CH(OH)), 4.51 (dd, 1 H, J = 8.5, 6.4 Hz, CH(OH)), 2.84–2.79 (m, 1 H, CH2), 2.51–2.45 (m, 1 H, CH2), 1.00 (s, 9 H, t-Bu); 13C-NMR (150 MHz, CDCl3): δ 140.8, 128.4, 127.5, 125.5, 125.3, 85.7, 79.9, 30.7, 29.7, 23.8; GC MS (70 eV) m/z (%): 190 (13), 134 (13), 133 (7), 107 (22), 106 (10), 105 (100), 104 (78), 103 (36), 92 (28), 91 (10), 84 (86), 79 (18), 78 (35), 77 (45), 69 (69), 57 (73), 51 (14), 43 (10), 41 (35); FT-IR (neat): 2954, 2923, 2855, 1650, 1458, 1100, 1030, 980, 749, 696 cm−1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H18NaO+: 213.1250; Found: 213.1255.
cis-2-(tert-Butyl)-4-phenyloxetane (cis-5): 35% yield, waxy solid, Rf = 0.5. 1H-NMR (600 MHz, CDCl3): δ 7.41–7.33 (m, 4 H, aromatic protons), 7.29–7.26 (m, 1 H, aromatic proton), 5.65–5.62 [m, 1 H, CH(OH)], 4.54–4.52 (m, 1 H, CH(OH)), 2.72–2.66 (m, 1 H, CH2), 2.47–2.43 (m, 1 H, CH2), 0.92 (s, 9 H, t-Bu); 13C-NMR (150 MHz, CDCl3) δ 144.9, 128.3, 127.4, 125.5, 125.3, 85.0, 76.6, 31.5, 29.7, 24.2; GC MS (70 eV) m/z (%): 190 (10), 175 (5), 134 (4), 133 (4), 107 (33), 105 (75), 104 (76), 103 (36), 92 (16), 84 (97), 79 (18), 78 (34), 45 (77), 69 (100), 57 (50), 51 (14), 43 (10), 41 (37); FT-IR (neat): 2955, 2925, 2853, 1651, 1462, 1110, 1032, 982, 752, 697 cm−1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for: C13H18NaO+ 213.1250; Found: 213.1247.

4. Conclusions

In summary, both geometric isomers of trans- and cis-2-(tert-butyl)-4-phenyloxetane have, for the first time, been synthesized. The overall transformation involves the following steps: (a) reduction of the commercially available 4,4-dimethyl-1-phenylpentane-1,3-dione with NaBH4 to give an almost equimolar mixture of inseparable diastereomeric 1,3-diols, and (b) a one-pot, two-step stereospecific cyclization of syn- and anti-diols into the corresponding 2,4-disubstituted aryloxetanes, which could be finally separated by column choromatography and spectroscopically characterized. The corresponding enantiomerically enriched diastereomers could not be prepared via a chemoenzymatic route, as analogously done with other 2,4-disubstituted aryl derivatives [20]. In fact, no reduction was noticed when 1 was incubated in the presence of baker’s yeast whole cells or Lactobacillus reuteri DSM 20016 resting cells, and the starting 1,3-dione was quantitatively recovered. The stereoselective bioreduction of sterically demanding bulky-bulky aryl alkyl ketones by conventional whole cells has always been, indeed, quite challenging [24]. The low solubility of 1 in aqueous solutions may have contributed as well to the failure of the enzymatic activity. Thus, future work will be focused on the preparation of densely substituted stereodefined oxetanes by exploiting dynamic resolution strategies starting from racemic α-lithiated aryloxetanes and chiral ligands [25,26]. Results will be reported in due course.

Supplementary Materials

1H and 13C-NMR spectra of diol 2 and oxetanes trans-5 and cis-5 are available online.
Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4


This work was financially supported by the University of Bari within the framework of the Project “Sviluppo di nuove metodologie di sintesi mediante l’impiego di biocatalizzatori e solventi a basso impatto ambientale” (code: Perna01333214Ricat), and by C.I.N.M.P.I.S. consortium.

Author Contributions

F.M.P. and P.V. conceived and designed the experiments; S.S. performed the experiments; all authors analyzed the data; F.M.P., P.V. and V.C. contributed reagents/materials/analysis tools; F.M.P. and V.C. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.


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Scheme 1. Synthesis of anti- and syn-4,4-dimethyl-1-phenylpentane-1,3-diols (2).
Scheme 1. Synthesis of anti- and syn-4,4-dimethyl-1-phenylpentane-1,3-diols (2).
Molbank 2017 m930 sch001
Scheme 2. Cyclization reaction of diols anti-2 and syn-2 into oxetanes trans-5 and cis-5, respectively.
Scheme 2. Cyclization reaction of diols anti-2 and syn-2 into oxetanes trans-5 and cis-5, respectively.
Molbank 2017 m930 sch002
Figure 1. 2D-NOESY NMR spectrum, CDCl3, trans-2-(tert-butyl)-4-phenyloxetane (5): selected NOE interactions.
Figure 1. 2D-NOESY NMR spectrum, CDCl3, trans-2-(tert-butyl)-4-phenyloxetane (5): selected NOE interactions.
Molbank 2017 m930 g001
Figure 2. 2D-NOESY NMR spectrum, CDCl3, cis-2-(tert-butyl)-4-phenyloxetane (5): selected NOE interactions.
Figure 2. 2D-NOESY NMR spectrum, CDCl3, cis-2-(tert-butyl)-4-phenyloxetane (5): selected NOE interactions.
Molbank 2017 m930 g002
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