*Communication*

## **Unexpected Formation of Oxetanes during the Synthesis of Dodeco-6,7-diuloses**

#### **Marius Bayer, Cäcilia Maichle-Mössmer and Thomas Ziegler \***

Institute of Organic Chemistry, University of Tuebingen, Auf der Morgenstelle 18, 72076 Tuebingen, Germany; marius.bayer@uni-tuebingen.de (M.B.); Caecilia.Maichle-Moessmer@uni-tuebingen.de (C.M.-M.)

**\*** Correspondence: thomas.ziegler@uni-tuebingen.de

Received: 11 December 2019; Accepted: 9 January 2020; Published: 14 January 2020

**Abstract:** During the synthesis of symmetrical dodeco-6,7-diuloses that are potential candidates for inhibition of glycosidases, an unanticipated epoxide-oxetane rearrangemen<sup>t</sup> was observed. A bicyclic sugar consisting of a glycal moiety and an anomeric esterified furanose was oxidized under epoxidation conditions (*m*CPBA/KF). The isolation of the pure epoxide was not possible since a rapid reversible conversion accompanied by the migration of the ester group took place and resulted in the formation of an unusual oxetane-bridged disaccharide scaffold. X-ray diffractometric structure elucidation and the suggested mechanism of the rearrangemen<sup>t</sup> are provided.

**Keywords:** oxetane; epoxide; rearrangement; carbohydrate; *C*-glycosylation; spiro-oxetane; ester group migration

## **1. Introduction**

Oxetane rings attached directly to a carbohydrate unit rarely occur in literature, due to steric reasons [1]. The most common representatives are 3,5-anhydrofuranose derivatives, which are formed by nucleophilic [2,3] or additive [4] intramolecular ring closure reactions. In addition to the furanoid 3,5-linked oxetanes, there also exists a limited number of 1,2-fused or anomeric spiro-oxetanes having a pyranoid constitution. These highly strained scaffolds are prepared photochemically [5–7] or via template-directing *C*-glycosylations [8,9]. In synthesis, sugar oxetanes are used as versatile precursors since the rigid conformation and steric repulsion of the bridge favor high stereoselectivities [10]. Furthermore, the detection of antimicrobial properties has brought these structures closer to the focus of current research [4]. In this communication, we introduce a new method for the generation of anomerically bridged oxetanes whose formation was initiated by an unexpected rearrangemen<sup>t</sup> of an epoxide assisted by an adjacent ester group.

#### **2. Results and Discussion**

Starting from the known compounds **1** [11] and **2** [12] a base-induced coupling of two anomeric centers analogous to Shiozaki's protocol [13] was performed (Scheme 1). Contrary to Shiozaki's procedure, which involved the use of toxic stannylated glycals, we could employ 1-phenylsulfinyl glycals since it is known that they are easily lithiated in a similar fashion with one equivalent of phenyllithium [14]. Sulfoxide 1 was treated with phenyllithium at –78 ◦C followed by quenching with *manno*-lactone 2 after 5 minutes. The observance of this reaction time is mandatory since a longer reaction time results in the irreversible formation of the protonated glycal species in increasing amounts leading to by-products. The coupled disaccharide 3 was isolated as an anomeric mixture (α/β ratio 1:5) in 80% yield. Next, the anomeric hydroxyl group was masked in order to avoid its coordinating effect on the envisaged stereoselective epoxidation. For this purpose, we decided to choose the ester protecting groups acetyl and benzoyl. Thus, the fully protected disaccharides **4a** and **4b** were obtained

after the acylation step in 96% and 68% yield, respectively. In both cases solely the β-anomers were obtained which was proven by H,H-NOESY NMR spectroscopy (see Supplementary Materials).

**Scheme 1.** Synthesis of the isopropylidene-protected oxetane-bridged disaccharide **8** and X-ray structures of **5a** and **7a**.

Furthermore, the configuration could be confirmed by growing crystals of **5a** suitable for X-ray diffraction by recrystallization of the latter from *n*-hexane and ethyl acetate. Compound **5a** was obtained through desilylation of **4a** with tetra-*n*-butylammonium fluoride (Scheme 1). The moderate yield of 71% can be explained by detectable partial cleavage of the acetyl group in alkaline milieu during desilylation. The benzoyl protecting group was significantly more stable under the same conditions resulting in a yield of 89% for the conversion of **4b** to **5b**. In our efforts to synthesize symmetrical dodeco-6,7-diuloses both sugar moieties need to be *manno*-configured. Therefore, the next step was to stereoselectively convert the glycal entity into a mannose derivative. Conventional methods for the implementation of stereoselective dihydroxylation on similar allyl alcohol systems use substrate-directing reagents such as molybdenum catalysts [15], vanadyl acetylacetonate (VO(acac)2) [16,17] or *meta*-chloroperbenzoic acid (*m*CPBA) [17,18] for epoxidation. Subsequent epoxide opening leads to the desired diol derivatives. When these methodologies were applied to disaccharides **5a** and **5b** the best results were achieved using the Camps reagen<sup>t</sup> (*m*CPBA/KF) [18,19]. The addition of potassium fluoride reduces the solubility of *m*CPBA and *m*CBA and thus, inhibiting nucleophilic epoxide opening by the acids. However, we could not isolate the pure epoxides **6a** and **6b** for a rapid rearrangemen<sup>t</sup> of the latter to oxetane species **7a** and **7b** occurred. Upon early quenching of the epoxidation reaction, only 8:1 mixtures of epoxide and oxetane could be isolated in yields of 94% for **6a** and 90% for **6b**, respectively. In order to enable the complete conversion of the epoxide to the oxetane derivatives the reaction times were extended and **7a** and **7b** could be obtained neatly in 70% and 63% yields, respectively. Crystals of compound **7a** suitable for X-ray crystallography could be obtained by overlaying a saturated solution of **7a** in methylene

chloride with *n*-heptane and slowly evaporating the methylene chloride. Thus, the oxetane-bridged disaccharide structure of **7a** with two anomeric α-configurations could be unambiguously verified (Scheme 1). For the formation of oxetanes **7** we propose a mechanism deduced from the X-ray data in which ester group migration from position 7 to 6 occurs simultaneously with *O*-heterocyclic ring extension of the oxirane ring to the less strained oxetane ring (Figure 1). The rearrangemen<sup>t</sup> process can also be visualized by 1H-NMR spectroscopy since the H-5 signal of oxetane **7a** (4.96 ppm, 4.6 Hz) is significantly shifted to lower field compared to the characteristic doublet of H-5 in epoxide **6a** (3.66 ppm, 2.4 Hz) (Figure 1). To some extent, this rearrangemen<sup>t</sup> resembles the Ferrier rearrangemen<sup>t</sup> of acetylated glycals. Alternatively, a stepwise mechanism via the intermediate formation of carbenium ions can also be envisaged.

**Figure 1.** Proposed mechanisms for the rearrangemen<sup>t</sup> from epoxide **6a** to oxetane **7a** and their 1H-NMR spectra in CDCl3 to illustrating the reaction progress.

It must also be mentioned that the rearrangemen<sup>t</sup> appeared to be reversible for in attempts to recrystallize **7a** from boiling *n*-hexane the precipitation of an amorphous substance which turned out to be epoxide **6a** was observed. Studies are ongoing to evaluate both the effect of the temperature and of the solvent on the equilibrium ratio between compounds **6a** and **7a**. After removal of the ester protecting groups of **7a** and **7b** with ammonia in methanol, oxetane **8** was obtained from both compounds in 99% and 80% yield respectively (Scheme 1). Oxetanes **8** did not recede to the corresponding epoxides according to TLC monitoring. Consequently, it was proven that **7b** is also present as an oxetane-fused disaccharide.

#### **3. Materials and Methods**

All reactions were performed under an atmosphere of nitrogen using solvents dried by standard procedures. Reaction progress was monitored by TLC on Polygram SIL G/UV254 silica gel plates from Macherey and Nagel, Germany. Detection of spots was affected by carbonizing with sulfuric acid (5% in EtOH), staining by spraying the plates with an alkaline aqueous solution of potassium permanganate or by inspection of the TLC plates under UV light (254 nm). Preparative flash chromatography was performed on silica gel (0.032–0.063 mm) from Macherey-Nagel, using plastic cartridges from Götec. The flowrate was regulated by a Sykam S1122 solvent delivery system. Nuclear magnetic resonance (NMR) spectra were recorded with a Bruker Avance 400 spectrometer and calibrated for the solvent signal (1H: CDCl3: δ = 7.26 ppm; acetone-*d*6: δ = 2.05 ppm; DMSO-*d*6: δ = 2.50 ppm; 13C: CDCl3: δ =77.16 ppm; acetone-d6: δ = 29.92 ppm; DMSO-*d*6: δ = 39.52 ppm). All NMR-assignments were proven by 2D-experiments to be correct. ESI-TOF-HRM spectrometry was performed on a Bruker MAXIS 4G spectrometer. Elemental analyses were obtained from a HEKA tech Euro EA 3000 apparatus. Optical rotations were determined with a Perkin-Elmer Polarimeter 341 in a 10 cm cuvette at 20 ◦C with a wavelength of 589 nm (Na-lamp). Melting points were measured with a Büchi Melting Point M-560 apparatus.

## *2,6-Anhydro-5-deoxy-4-O-(tert-butyldimethylsilyl)-1,3:8,9:11,12-tri-O-isopropylidene-*d*-arabino-*l*-gulododeco-7-ulo-6-enitol (***3***)*

To a suspension of **1** (2.62 g, 6.18 mmol) and grounded molecular sieve (3 Å, 30 mg) in THF (40 mL) was added phenyllithium (1.9 M in Bu2O, 3.57 mL, 6.79 mmol) at −78 ◦C over a period of 15 min. After 5 min a further solution containing **2** (1.75 g, 6.79 mmol) in THF (20 mL) was added dropwise over a period of 30 min. Subsequently, the reaction mixture was stirred for 2 h at the same temperature before the cooling bath was removed. The reaction was quenched by addition of sat. aq. NH4Cl-solution (60 mL) at ambient temperature and the molecular sieve was filtered <sup>o</sup>ff. The organic layer was separated, the aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the combined organic layers were dried with Na2SO4. Removing of the solvent followed by column chromatography (methylene chloride/ethyl acetate 5:1) furnished **3** (2.77 mg, 4.97 mmol, 80%, anomeric mixture <sup>α</sup>:β, 1:5) as a colorless crystalline solid. Rf = 0.22–0.46 (methylene chloride/ethyl acetate 5:1).

**3**β**\***(major anomer): 1H-NMR (400 MHz, CDCl3): δ(ppm) = 5.04 (d, *J*5,4 = 2.2 Hz, 1H, H-5), 4.82 (dd, *J*9,8 = 5.7 Hz, *J*9,10 = 3.5 Hz, 1H, H-9), 4.53 (d, *J*8,9 = 5.9 Hz, 1H, H-8), 4.38–4.44 (m, 1H, H-11), 4.33–4.35 (m, 1H, H-4), 4.15 (dd, *J*10,11 = 7.2 Hz, *J*10,9 = 3.5 Hz, 1H, H-10), 4.07–4.11 (m, 1H, H-12a), 4.03 (dd, *J* = 8.7 Hz, *J* = 4.9 Hz, 1H, H-12b), 3.86–3.95 (m, 2H, H-1a, H-1b), 3.71–3.76 (m, 2H, H-2, H-3), 2.77 (s, 1H, OH), 1.50, 1.44, 1.42, 1.40, 1.38, 1.31 (6s, 18H, C(C*H*3)2), 0.87 (s, 9H, SiC(C*H*3)3), 0.07, 0.06 (2s, 6H,SiC*H*3). 13C-NMR (101 MHz, CDCl3): δ(ppm) = 150.4 (C-6), 113.3, 109.1 (*C*(CH3)2), 104.3 (C-5), 103.4 (C-7), 99.4 (*C*(CH3)2), 86.7 (C-8), 80.0 (C-9), 79.4 (C-10), 73.2 (C-11), 72.9 (C-3), 70.2 (C-2), 68.2 (C-4), 66.7 (C-12), 61.7 (C-1), 28.9, 26.8, 25.8 (C(*C*H3)2), 25.7 (SiC(*C*H3)3), 25.4, 25.0, 19.1 (C(*C*H3)2), 18.1 (Si*C*(CH3)3), –4.4, –4.8 (Si*C*H3).

**3**α**\***(minor anomer): 1H-NMR (400 MHz, CDCl3): δ(ppm) = 5.07 (d, *J*5,4 = 2.1 Hz, 1H, H-5), 4.79 (dd, *J*9,8 = 6.0 Hz, *J*9,10 = 3.7 Hz, 1H, H-9), 4.62 (d, *J*8,9 = 6.0 Hz, 1H, H-8), 4.34–4.35 (m, 2H, H-4, H-11), 4.10–4.11 (m, 1H, H-12a), 4.01–4.02 (m, 1H, H-12b), 3.85–3.88 (m, 2H, H-1a, H-1b, 3.76–3.80 (m, 3H, H-2, H-3, H-10), 2.77 (s, 1H, OH), 1.57, 1.49, 1.42, 1.40, 1.36 (5s, 18H, C(C*H*3)2), 0.88 (s, 9H, SiC(C*H*3)3), 0.08, 0.07 (2s, 6H, SiC*H*3). 13C-NMR (101 MHz, CDCl3): δ(ppm) = 150.8 (C-6), 113.6, 109.3 (*C*(CH3)2), 103.1 (C-5), 100.6 (C-7), 99.6 (*C*(CH3)2), 80.7 (C-8), 80.0 (C-9), 78.6 (C-10), 73.2 (C-11), 72.8 (C-3), 70.3 (C-2), 67.8 (C-4), 67.2 (C-12), 61.7 (C-1), 28.9, 26.9, 25.9 (C(*C*H3)2), 25.8 (SiC(*C*H3)3), 25.2, 24.6, 19.0 (C(*C*H3)2), 18.2 (Si*C*(CH3)3), –4.4, –4.8 (Si*C*H3). HRESIMS *m*/*z* 581.27570 (calcd for C27H46O10SiNa, 581.27524); anal. C 58.37, H 8.21, calcd for C27H46O10Si, C 58.04, H 8.39. \*Anomers **3**β and **3**α could be interchanged
