# An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane Compounds from Substituted Ketofurfuryl Alcohols

Claire Cuyamendous, Mathieu Yves Laurent, Christine Saluzzo

► To cite this version:

Claire Cuyamendous, Mathieu Yves Laurent, Christine Saluzzo. An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane Compounds from Substituted Ketofurfuryl Alcohols. Molecules, 2024, 29, 10.3390/molecules29225474. [https://doi.org/10.3390/molecules29225474](https://doi.org/10.3390/molecules29225474)

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Article

# An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane Compounds from Substituted Ketofurfuryl Alcohols

Claire Cuyamendous, Mathieu Yves Laurent and Christine Saluzzo

MSO, Institut des Molécules et Matériaux du Mans (IMMM), UMR CNRS 6283, Le Mans Université, Avenue O. Messiaen, 72085 Le Mans, CEDEX 9, France; claire.cuyamendous@u-paris.fr (C.C.); mathieu.laurent@univ-lemans.fr (M.Y.L.)

* Correspondence: christine.saluzzo@univ-lemans.fr

**Abstract:** Oximation of substituted ketofurfuryl alcohols in the presence of hydroxylamine hydrochloride and pyridine in ethanol as solvent led to a new class of spiro derivatives presenting a 7-methylene-1,6-dioxa-2-azaspiro [4.4] nona-2,8-diene skeleton along with, in some cases, the predictable oxime. The structures of such spiro compounds were determined by 2D NMR spectroscopy. The suggested formation of this skeleton involves an in situ oximation/dehydration/$S_N'$ cascade reaction.

**Keywords:** spiro compound; dihydroxazole; isoxazoline; furfural; oxime; cascade reaction; rearrangement; bis-heterocycle

## 1. Introduction

Oxime, a versatile functional group in organic chemistry, permits the introduction of a nitrogen atom into a chemical structure [1,2]. Derived from carbonyl groups, oximes can be transformed into amines [3,4], hydroxylamines [4,5], nitriles [6], nitrile oxides [7], amides [8], enamides [9], imines [9] and nitrones [10], but it can also be involved in the preparation of aza-heterocycles [1,2,11–18] (Scheme 1).

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Overview of oximes transformations.</figcaption></figure>

Among nitrogen-containing heterocycles, 4,5-dihydroisoxazoles derivatives (five-membered ring bearing N-O bond) have attracted increasing attention due to their biological activities [19]. Some of them are natural products such as acivicin, produced by *Streptomyces sviceus* [20], and subereamolline A and aerothionin, isolated from marine sponges [21] (Figure 1). The latter two present an interesting spiroisoxazoline backbone for which Nishiyama developed a new electrochemical synthesis involving anodic oxidation [22].

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**Citation:** Cuyamendous, C.; Laurent, M.Y.; Saluzzo, C. An Unexpected Formation of Spiro Isoxazoline-Dihydrofurane Compounds from Substituted Ketofurfuryl Alcohols. *Molecules* **2024**, *29*, 5474. https://doi.org/10.3390/molecules29225474

Academic Editor: László Somsák

Received: 7 October 2024

Revised: 15 November 2024

Accepted: 16 November 2024

Published: 20 November 2024

<figure><img src="image_5.png" /></figure>

**Copyright:** © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
<figure><img src="image_6.png" /><figcaption>**Figure 1.** Some natural dihydroisoxazole derivatives.</figcaption></figure>

The most common synthetic methods for isoxazolines typically involve 1,3-dipolar cycloaddition of nitrile oxide [23–27], nitronate [28,29] or oxime [30] with alkenes, including functionalized ones. On the other hand, the synthesis of spiroisoxazolines is more challenging. Moreover, to the best of our knowledge, isoxazolines are scarcely engaged in a spiro linked ring with a THF unit [31–34]. In 1978, Tarmakovskii et al. [31] synthesize for the first time a spiroisoxazoline with a THF unit using a thermal rearrangement of a nitro cyclic nitronate in dimethylformamide (DMF) (Scheme 2, Equation (1) (eq.1)). Twenty years later, Smietana et al. [32] have reported a spiro ketalization of an α-hydroxyiminoester (Scheme 2, Equation (2) (eq. 2)). The last methodology reported by Das et al. [33] is based on the bromination with pyridinium tribromide of aromatic isoxazoles that contain a pendant alcohol (Scheme 2, Equation (3) (eq. 3)).

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Syntheses of spiroisoxazolines presenting a THF unit.</figcaption></figure>

We report herein the formation of a new class of spiro compounds presenting an isoxazoline unit along with a dihydrofurane moiety including a methylene group as shown in Figure 2.

<figure><img src="image_8.png" /><figcaption>**Figure 2.** Structure of the new class of spiroisoxazoline.</figcaption></figure>
## 2. Results and Discussion

As indicated in Scheme 3, in our retrosynthetic analysis, ketoalcohol III would be a key intermediate to form the corresponding oxime I and/or the spiroderivative II. This ketoalcohol III could be generated by the functionalization in C-5 position of a 2-substituted furfurylalcohol IV easily obtained from furfuraldehyde, a biomass derivative.

<figure><img src="image_9.png" /><figcaption>**Scheme 3.** Retrosynthetic analysis of oxime/isoxazoline formation.</figcaption></figure>

### 2.1. Preparation of Ketoalcohol Key Intermediates

A series of *tert*-butyldimethylsilyl ketofurfuryl alcohols **4a–e** presenting alkyl, alkenyl or aromatic groups were prepared from furfuraldehyde according to the four steps reaction sequence depicted in Scheme 4.

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<table><caption>**Scheme 4.** Synthesis of protected ketofurfuryl alcohols **4**.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">R<sub>1</sub></th><th rowspan="2">R<sub>2</sub></th><th colspan="4">Yields</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td><b>a</b></td><td>Et</td><td>Me</td><td>54%</td><td>72%</td><td>91%</td><td>90%</td></tr><tr><td><b>b</b></td><td>iPr</td><td>Me</td><td>79%</td><td>84%</td><td>56%</td><td>88%</td></tr><tr><td><b>c</b></td><td>iBu</td><td>Me</td><td>71%</td><td>94%</td><td>44%</td><td>73%</td></tr><tr><td><b>d</b></td><td>3-butenyl</td><td>Me</td><td>91%</td><td>92%</td><td>60%</td><td>73%</td></tr><tr><td><b>e</b></td><td>Ph</td><td>Me</td><td>60%</td><td>86%</td><td>66%</td><td>89%</td></tr><tr><td><b>f</b></td><td>Ph</td><td>CH<sub>2</sub>OPh</td><td></td><td></td><td>50%</td><td>30%</td></tr></tbody></table>

The first step involved the nucleophilic addition of a Grignard reagent to furfural giving the expected alcohols **1a–e** in 54 to 91% yields. After protection of the alcohol as *tert*-butyldimethylsilyloxy ether (OTBS), the C-5 functionalization of the THF ring was performed by lithiation reaction. The resulting anions reacted with methyl oxirane or with methylglycidyl ether providing the corresponding 2,5-disubstituted furans **3a–f** in good to excellent yields (44–91%). As already reported in the literature, the yield depends on the nature of both furan and epoxide derivatives involved in this reaction [35,36]. Subsequent oxidation of the free alcohol function of compounds **3a–f** was carried out with Dess–Martin periodinane reagent (DMP) to form compounds **4a–f** in 30 to 90% yields.

Deprotection of *tert*-butyldimethylsilyl (OTBS) ethers **4a–f** was first performed with tetrabutylammonium fluoride (TBAF) (Scheme 5). Unfortunately, yields varied considerably from degradation to 87% (Table 1) and did not seem to be correlated with the nature of R₁ and R₂ substituents. The use of Et₃N·3HF (Scheme 5) significantly improved the yields of products **5b**, **5d** and **5f** (entries 3, 6 and 9, Table 1). These differences in yield can be explained by the presence of moisture in the TBAF reagent, which decreases its reactivity compared to Et₃N·3HF [37].
<figure><img src="image_12.png" /><figcaption>**Scheme 5.** Deprotection of *tert*-butyldimethylsilyl.</figcaption></figure>

<table><caption>**Table 1.** *Tert*-butyldimethylsilyl ether deprotection.</caption><thead><tr><th rowspan="2">Entry</th><th colspan="2">Substrate 4</th><th rowspan="2">Conditions *</th><th rowspan="2">Product 5</th><th rowspan="2">Yield %</th></tr><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th></tr></thead><tbody><tr><td>1</td><td><b>4a</b></td><td>Et</td><td>Me</td><td>A</td><td><b>5a</b></td><td>40</td></tr><tr><td>2</td><td rowspan="2"><b>4b</b></td><td rowspan="2">iPr</td><td rowspan="2">Me</td><td>A</td><td rowspan="2"><b>5b</b></td><td>14</td></tr><tr><td>3</td><td>B</td><td>64</td></tr><tr><td>4</td><td><b>4c</b></td><td>iBu</td><td>Me</td><td>A</td><td><b>5c</b></td><td>61</td></tr><tr><td>5</td><td rowspan="2"><b>4d</b></td><td rowspan="2">3-Butenyl</td><td rowspan="2">Me</td><td>A</td><td rowspan="2"><b>5d</b></td><td rowspan="2">Degradation<br>59</td></tr><tr><td>6</td><td>B</td></tr><tr><td>7</td><td><b>4e</b></td><td>Ph</td><td>Me</td><td>A</td><td><b>5e</b></td><td>87</td></tr><tr><td>8</td><td rowspan="2"><b>4f</b></td><td rowspan="2">Ph</td><td rowspan="2">CH<sub>2</sub>OPh</td><td>A</td><td rowspan="2"><b>5f</b></td><td>16</td></tr><tr><td>9</td><td>B</td><td>86</td></tr></tbody></table>

## 2.2. Oximation of Ketoalcohol 5

The oximation of ketones **5a–f** was then performed in ethanol according to the Han procedure [38]. However, in these conditions (i.e., hydroxylamine hydrochloride in the presence of pyridine), ketone **5a–f** led, in some cases, to spiroisoxazoline derivatives **6a–f** along with or without the expected oxime **7a–f** being protected as ethyl ether, the starting material having been completely consumed (Scheme 6 and Table 2).

<figure><img src="image_13.png" /><figcaption>**Scheme 6.** Oximation of ketones **5a–f**.</figcaption></figure>

<table><caption>**Table 2.** Oximation of ketone 5.</caption><thead><tr><th rowspan="2">Entry</th><th colspan="2">Substrate 5</th><th rowspan="2">Product 6 (Yield %)</th><th rowspan="2">Product 7 (Yield %)</th></tr><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th></tr></thead><tbody><tr><td>1</td><td><b>5a</b></td><td>Et</td><td>Me</td><td><b>6a</b> (4)</td><td><b>7a</b> (34)</td></tr><tr><td>2</td><td><b>5b</b></td><td>iPr</td><td>Me</td><td><b>6b</b> (1)</td><td><b>7b</b> (12)</td></tr><tr><td>3</td><td><b>5c</b></td><td>iBu</td><td>Me</td><td><b>6c</b> (14)</td><td><b>7c</b> (14)</td></tr><tr><td>4</td><td><b>5d</b></td><td>3-Butenyl</td><td>Me</td><td><b>6d</b> (16)</td><td><b>7d</b> (32)</td></tr><tr><td>5</td><td><b>5e</b></td><td>Ph</td><td>Me</td><td><b>6e</b> (61)</td><td><b>7e</b> (0)</td></tr><tr><td>6</td><td><b>5f</b></td><td>Ph</td><td>CH<sub>2</sub>OPh</td><td><b>6f</b> (72)</td><td><b>7f</b> (0)</td></tr></tbody></table>

When the substituent R<sub>1</sub> is an alkyl group, the obtained yield was very low and a mixture of expected oxime (12–34%) and spiroisoxazoline derivatives (1–16%) was observed (entries 1–4, Table 2). When the substituent R<sub>1</sub> is a phenyl group, only the spiroisoxazoline derivatives **6e** and **6f** were isolated in good yield (entries 5 and 6, Table 2). This could be due to the mesomeric stabilization effect of the phenyl group on the conjugated exocyclic alkene.

<footnote>* Condition A: 1.5 eq. TBAF, THF, rt, 2 h; Condition B: 1.5 eq. Et<sub>3</sub>N·3HF, CH<sub>3</sub>CN, rt, 16 h.</footnote>
Compared with the starting ketones **5e–f**, compounds **6e–f** were characterized from HRMS spectra by a lack of 3 units, compatible with the formation of the bicyclic structure (Scheme 6). Moreover, an AB system correlated to both R₂ and vinylic proton (HMBC spectra S61 and S67) confirmed the cyclic isoxazoline backbone (Figure 3). Quaternary carbon of the spiro junction was observed at 119.9/120.2 ppm, suggesting a ketal carbon.

<figure><img src="image_14.png" /><figcaption>**Figure 3.** NOESY (S62 for **6e**) and HMBC (S61 for **6e**, S67 for **6f**) experiments for structure determination of compounds **6e** and **6f**.</figcaption></figure>

The NOESY experiment (S62) for compound **6e** was in accordance with Z stereochemistry of the exocyclic double bond as it showed an interaction between the two vinylic hydrogens (Figure 3). We assumed the same stereochemistry for compound **6f** according to the similarity between both spectra.

Based on these results, we proposed the following mechanism to explain the formation of these spiroheterocycles **6** and oximes **7** (Scheme **7**). First of all, the free hydroxylamine formed in situ the expected oxime **X**. The hydroxyl group of the furfuryl alcohol moiety was then protonated leading to intermediate **I**₁. Dehydration led to the carbocation **I**₂ which can evolved in two routes. Route A: a nucleophilic substitution with ethanol leading to oxime **7**; route B: an S<sub>N</sub>1' involving the oxygen atom of the oxime resulting in a dearomatization of the furan ring by migration of the double bond, and then formation of the bicyclic compound **6** with no control of the stereochemistry of the chiral spiro center.

<figure><img src="image_15.png" /><figcaption>**Scheme 7.** Suggested mechanism for the formation of spiranic isoxazole **6** and oxime **7**.</figcaption></figure>

**3. Materials and Methods**

**3.1. General**

Reagents were purchased from commercial suppliers and used without additional purification. Furfuryl alcohols **1a** [39,40], **1b** [39,41], **1c** [39,42], **1d** [43–45] and **1e** [39,46] were synthesized according to the literature procedures, with Grignard reagents prepared. Dichloromethane, diethyl ether and THF were dried over activated alumina column in DRY STATION Glass Technology (Geneva, Switzerland) GTS 100 glassware. All reactions were conducted in oven-dried glassware, under inert atmosphere and were monitored by TLC. Column chromatography was performed using 60 µm silica gel. Thin-layer chromatography was performed with G/UV254 plates and revealed under UV light, then
it was performed with phosphomolybdic acid or vanillin stains. All melting points were recorded on a ThermoFisher IA9300 apparatus and were uncorrected. The NMR spectra were acquired on a Bruker AVANCE 400 spectrometer operating at 400 and 100 MHz for ¹H and ¹³C nuclei, respectively, and were recorded in CDCl₃. Chemical shifts and coupling constants were presented in parts per million relative to Me₄Si and Hertz, respectively. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad signal. Proton and carbon assignments were established using COSY, HSQC, HMBC and DEPT experiments. Infrared spectra were recorded on an FT spectrophotometer from neat compounds using an ATR (Attenuated Total Reflexion) module. The wavenumbers of maximum absorption peaks of IR spectroscopy are presented in cm⁻¹. High-resolution mass spectra were performed on a micrOTOF QIII Bruker mass spectrometer; the method used for HRMS was mentioned for each spectrum.

## 3.2. *Synthesis and Characterization*

### 3.2.1. General Protocol for Alcohol Protection

To a solution of alcohol **1** (1 equivalent) in DCM (2 mL/mmol of alcohol), TBSCI (1.55 equivalent), imidazole (1.5 equivalent) and DMAP (0.01 eq.) were added at 0 °C. The reaction mixture was stirred overnight. Saturated aqueous solution of NH₄Cl (2 mL/mmol of alcohol) was added and extracted with diethyl ether (3 × 1.5 mL/mmol of alcohol). The organic phases were dried over MgSO₄, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography to afford protected product **2**.

**tert-Butyl-(1-furan-2-yl-propoxy)-dimethyl-silane (2a).**

The crude product obtained from the alcohol **1a** (10.43 g, 82.7 mmol), TBSCI (18.87 g, 125 mmol, 1.51 equivalent), imidazole (8.25 g, 121 mmol, 1.46 equivalent) and DMAP (99 mg, 0.81 mmol, 0.01 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (14.40 g, 59.9 mmol, 72% yield). *Rf* 0.70 (cyclohexane/EtOAc 8/2); IR (neat) *v* 2959, 2933, 2858, 1465, 1257, 1231, 1156, 1108, 1082, 1063, 1007, 840 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 7.31 (1H, dd, *J* = 1.8, 0.9 Hz), 6.28 (1H, dd, *J* = 3.2, 1.8 Hz), 6.14 (1H, d, *J* = 3.2 Hz), 4.59 (1H, d, *J* = 6.5 Hz), 1.74–1.85 (2H, m), 0.87 (3H, t, *J* = 7.4 Hz), 0.86 (9H, s), 0.04 (3H, s), −0.07 (3H, s); ¹³C NMR (100 MHz, CDCl₃) *δ* 157.6 (Cq), 141.3 (CH), 110.1 (CH), 105.8 (CH), 70.1 (CH), 30.2 (CH₂), 26.0 (3CH₃), 18.5 (Cq), 10.0 (CH₃), −4.7 (CH₃), −4.9 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₃H₂₄NaO₂Si [M+Na]⁺: 263.1438, found 263.1435.

**tert-Butyl-(1-furan-2-yl-2-methyl-propoxy)-dimethyl-silane (2b).**

The crude product obtained from the alcohol **1b** (7.59 g, 54.1 mmol), TBSCI (12.73 g, 84.5 mmol, 1.56 equivalent), imidazole (5.57 g, 81.8 mmol, 1.5 equivalent) and DMAP (67 mg, 0.55 mmol, 0.01 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (11.64 g, 45.7 mmol, 84% yield). *Rf* 0.44 (cyclohexane/EtOAc 9/1); IR (neat) *v* 2959, 1473, 1067, 1011, 840, 780, 732 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 7.33 (1H, dd, *J* = 1.8, 0.8 Hz), 6.29 (1H, dd, *J* = 3.2, 1.8 Hz), 6.14 (1H, d, *J* = 3.2 Hz), 4.33 (1H, d, *J* = 6.9 Hz), 2.02 (1H, octuplet, *J* = 6.7 Hz), 0.95 (3H, d, *J* = 6.7 Hz), 0.88 (9H, s), 0.80 (3H, d, *J* = 6.8 Hz), 0.03 (3H, s), −0.14 (3H, s); ¹³C NMR (100 MHz, CDCl₃) *δ* 156.9 (Cq), 140.9 (CH), 109.8 (CH), 106.4 (CH), 74.2 (CH), 34.4 (CH), 25.8 (3CH₃), 18.7 (CH₃), 18.4 (CH₃), 18.2 (Cq), −5.0 (CH₃), −5.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₄H₂₆NaO₂Si [M+Na]⁺: 277.1600, found 277.1594.

**tert-Butyl-(1-furan-2-yl-3-methyl-butoxy)-dimethyl-silane (2c).**

The crude product obtained from the alcohol **1c** (8.89 g, 57.7 mmol), TBSCI (13.56 g, 90.0 mmol, 1.56 equivalent), imidazole (5.90 g, 86.7 mmol, 1.5 equivalent) and DMAP (71 mg, 0.58 mmol, 0.01 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (14.53 g, 54.1 mmol, 94% yield). *Rf* 0.71 (cyclohexane/EtOAc 9/1); IR (neat) *v* 2959, 2933, 2858, 1473, 1257, 1086, 1007, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 7.32 (1H, dd, *J* = 1.9, 0.8 Hz), 6.28 (1H, dd, *J* = 3.2, 1.9 Hz), 6.13 (1H, d, *J* = 3.2 Hz), 4.71 (1H, dd, *J* = 8.2, 5.8 Hz), 1.74–1.82 (1H, m), 1.69 (1H, sept., *J* = 6.7 Hz), 1.52–1.60 (1H, m), 0.87 (3H, d, *J* = 6.0 Hz), 0.86 (3H, d, *J* = 6.0 Hz), 0.85 (9H,
s), 0.03 (3H, s), -0.12 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 157.8 (Cq), 141.4 (CH), 110.2 (CH), 105.8 (CH), 66.9 (CH), 46.2 (CH₂), 26.0 (3CH₃), 24.5 (CH), 23.3 (CH₃), 22.3 (CH₃), 18.4 (Cq), -4.6 (CH₃), -4.9 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₅H₂₈NaO₂Si [M+Na]⁺: 291.1751, found 291.1753.

**tert-Butyl-(1-furan-2-yl-pent-4-enyloxy)-dimethyl-silane (2d) [44,45].**

The crude product obtained from the alcohol **1d** (14.11 g, 92.7 mmol), TBSCI (21.80 g, 144.6 mmol, 1.56 equivalent), imidazole (9.53 g, 140.0 mmol, 1.51 equivalent) and DMAP (114 mg, 93.3 mmol, 0.01 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (21.33 g, 80.1 mmol, 86% yield). *Rf* 0.69 (cyclohexane/EtOAc 9/1); IR (neat) *ν* 2933, 2858, 1644, 1477, 1351, 1257, 1098, 1011, 918, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.32 (1H, dd, *J* = 1.8, 0.8 Hz), 6.28 (1H, dd, *J* = 3.2, 1.8 Hz), 6.15 (1H, ddd, *J* = 3.2, 0.8, 0.8 Hz), 5.79 (1H, ddt, *J* = 17.1, 10.2, 6.6 Hz), 5.02 (1H, ddt, *J* = 17.1, 1.7, 1.7 Hz), 4.98 (1H, ddt, *J* = 10.2, 1.7, 1.3 Hz), 4.68 (1H, dd, *J* = 7.2, 5.6 Hz), 2.00-2.14 (2H, m), 1.78-1.97 (2H, m), 0.87 (9H, s), 0.04 (3H, s), -0.09 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 157.4 (Cq), 141.4 (CH), 138.5 (CH), 114.9 (CH₂), 110.2 (CH), 105.9 (CH), 68.1 (CH), 36.4 (CH₂), 29.8 (CH₂), 26.0 (3CH₃), 18.4 (Cq), -4.7 (CH₃), -4.9 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₅H₂₆NaO₂Si [M+Na]⁺: 289.1594, found 289.1590.

**tert-Butyl-(furan-2-yl-phenyl-methoxy)-dimethyl-silane (2e) [47].**

The crude product obtained from the alcohol **1e** (22.91 g, 132 mmol), TBSCI (30.9 g, 205 mmol, 1.55 equivalent), imidazole (13.51 g, 198 mmol, 1.5 equivalent) and DMAP (162 mg, 0.11 mmol, 0.01 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (35.03 g, 121 mmol, 92% yield). *Rf* 0.32 (cyclohexane/EtOAc 6/4); IR (neat) *ν* 2933, 1477, 1067, 1011 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.44 (2H, m), 7.30-7.37 (3H, m), 7.27-7.30 (1H, m), 6.29 (1H, dd, *J* = 3.0, 1.7 Hz), 6.07 (1H, dd, *J* = 3.1, 0.7 Hz), 5.80 (1H, s), 0.93 (9H, s), 0.07 (3H, s), 0.04 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 157.0 (Cq), 142.1 (Cq), 142.0 (CH), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 110.0 (CH), 106.7 (CH), 70.6 (CH), 25.8 (3CH₃), 18.3 (Cq), -5.0 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₇H₂₄NaO₂Si [M+Na]⁺: 311.1443, found 311.1438; *m/z* calcd for C₁₇H₂₄KO₂Si [M+K]⁺: 327.1183, found 327.1177.

### 3.2.2. General Protocol for Epoxide Opening

At -78 °C, nBuLi solution (2 M in hexane, 1 equivalent) was added dropwise to a solution of silylated alcohol **2** (1 equivalent) in THF (1.4 mL/mmol of silylated alcohol). The reaction mixture was slightly warmed to room temperature during 2h 30min, and epoxide (2 eq.) was added dropwise during 10 to 15 min. The reaction was stirred at room temperature overnight. Saturated aqueous solution of NH₄Cl (1.4 mL/mmol of silylated alcohol) was added and extracted with diethyl ether (3 × 1 mL/mmol of silylated alcohol). The organic phases were dried over MgSO₄, filtrated and concentrated under reduced pressure. The crude product **3** was purified by column chromatography.

**1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-propyl]-furan-2-yl]-propan-2-ol (3a).**

The crude product obtained from the silylated alcohol **2a** (8.8 g, 36.6 mmol), n-BuLi (20.4 mL, 1.8 M, 36.7 mmol, 1 equivalent) and methyl oxirane (5.1 mL, 73.3 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (9.99 g, 33.5 mmol, 91% yield) as an inseparable 1:1 mixture of diastereoisomers. *Rf* 0.39 (cyclohexane/EtOAc 8/2); IR (neat) *ν* 3350, 2962, 2933, 2858, 1465, 1257, 1063, 1011, 840, 776 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.06 (1H, d, *J* = 3.1 Hz), 6.01 (1H, d, *J* = 3.1 Hz), 4.54 (1H, t, *J* = 6.5 Hz), 4.00-4.08 (1H, m), 2.78 (1H, ddd, *J* = 14.9, 4.6, 1.8 Hz), 2.70 (1H, dd, *J* = 14.9, 7.6 Hz), 1.72-1.82 (3H, m), 1.23 (3H, d, *J* = 6.2 Hz), 0.89 (3H, d, *J* = 7.4 Hz), 0.87 (9H, s), 0.05 (3H, s), -0.051 and -0.055 (3H, 2s); ¹³C NMR (100 MHz, CDCl₃) δ 156.53, 156.52, 151.42, 151.39 (2Cq), 107.47, 107.46 (CH), 106.36, 106.35 (CH), 69.87, 69.86 (CH), 66.8, 66.7 (CH), 38.0 (CH₂), 29.85, 29.84 (CH₂), 25.8 (3CH₃), 22.6 (CH₃), 18.2 (Cq), 10.0 (CH₃), -4.8 (CH₃), -5.0 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₆H₃₀NaO₃Si [M+Na]⁺: 321.1859, found 321.1852.

**1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-propyl]-furan-2-yl]-propan-2-ol (3b).**
The crude product obtained from the silylated alcohol **2b** (3.04 g, 11.9 mmol), *n*-BuLi (9.0 mL, 17.9 mmol, 1.5 equivalent) and methyl oxirane (1.67 mL, 23.9 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 98/2) to give a yellow oil (2.08 g, 6.66 mmol, 56% yield) as an inseparable 1:1 mixture of diastereoisomers. *Rf* 0.40 (cyclohexane/EtOAc 8/2); IR (neat) *v* 3383, 2933, 2858, 1562, 1473, 1387, 1257, 1063, 940, 840, 776 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.05 (1H, d, *J* = 3.0 Hz), 6.01 (1H, m), 4.26 and 4.25 (1H, 2d, *J* = 6.9 Hz), 4.00-4.11 (1H, m), 2.78 (1H, dt, *J* = 14.9, 4.7 Hz), 2.70 (1H, ddd, *J* = 14.8, 7.5, 5.0 Hz), 1.99 (1H, octuplet, *J* = 6.7 Hz), 1.77 and 1.75 (1H, 2d, *J* = 4.0 Hz), 1.22 (3H, d, *J* = 6.3 Hz), 0.95 and 0.94 (3H, 2d, *J* = 6.7 Hz), 0.86 (9H, s), 0.79 and 0.78 (3H, 2d, *J* = 6.7 Hz), 0.02 (3H, s), -0.136 and -0.138 (3H, 2s); ¹³C NMR (100 MHz, CDCl₃) δ 156.02, 156.00, 151.24, 151.19 (2Cq), 107.41, 107.35 (CH), 107.18, 107.13 (CH), 74.19, 74.15 (CH), 66.9, 66.7 (CH), 37.96, 37.95 (CH₂), 34.3 (CH), 25.8 (3CH₃), 22.5 (CH₃), 18.7, 18.5, 18.4, 18.2 (CH₃+Cq), -4.9 (CH₃), -5.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₇H₃₃O₃Si [M+H]⁺: 313.2193, found 313.2198; calcd for C₁₇H₃₂NaO₃Si [M+Na]⁺: 335.2015, found 335.2013; *m/z* calcd for C₁₇H₃₂KO₃Si [M+K]⁺: 351.1748, found 351.1752.

**1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyl]-furan-2-yl]-propan-2-ol (3c).**

The crude product obtained from the silylated alcohol **2c** (8.5 g, 31.7 mmol), *n*-BuLi (17.6 mL, 1.8 M, 31.7 mmol, 1 equivalent) and methyl oxirane (4.4 mL, 63.3 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (4.56 g, 14.0 mmol, 44% yield) as an inseparable 1:1 mixture of diastereoisomers. *Rf* 0.31 (cyclohexane/EtOAc 8/2); IR (neat) *v* 3330, 2959, 2933, 2858, 1562, 1469, 1365, 1257, 1082, 1011, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.06 (1H, d, *J* = 3.0 Hz), 6.01 (1H, d, *J* = 3.0 Hz), 4.67 (1H, dd, *J* = 8.0, 5.7 Hz), 4.00-4.08 (1H, m), 2.78 (1H, ddd, *J* = 15.0, 4.3, 3.5 Hz), 2.70 (1H, ddd, *J* = 15.0, 7.6, 2.5 Hz), 1.71-1.84 (2H, m), 1.62-1.67 (1H, m), 1.45-1.54 (1H, m), 1.23 (3H, d, *J* = 6.2 Hz), 0.90 (3H, d, *J* = 6.6 Hz), 0.88 (3H, d, *J* = 6.6 Hz), 0.85 (9H, s), 0.04 (3H, s), -0.103 and -0.106 (3H, 2s); ¹³C NMR (100 MHz, CDCl₃) δ 156.71, 156.68 (Cq), 151.50, 151.45 (Cq), 107.51, 107.46 (CH), 106.38, 106.37 (CH), 66.79, 66.65 (2CH), 45.8 (CH₂), 38.0 (CH₂), 25.8 (3CH₃), 24.3 (CH), 23.1, 22.6, 22.0 (3CH₃), 18.2 (Cq), -4.8 (CH₃), -5.1 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₈H₃₄NaO₃Si [M+Na]⁺: 349.2169, found 349.2170.

**1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enyl]-furan-2-yl]-propan-2-ol (3d).**

The crude product obtained from the silylated alcohol **2d** (8.53 g, 32.0 mmol), *n*-BuLi (17.8 mL, 1.8 M, 31.9 mmol, 1 equivalent) and methyl oxirane (4.5 mL, 63.9 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a yellow oil (6.27 g, 19.3 mmol, 60% yield) as an inseparable 1:1 mixture of diastereoisomers. *Rf* 0.29 (cyclohexane/EtOAc 8/2); IR (neat) *v* 3352, 2955, 2933, 2858, 1644, 1562, 1465, 1365, 1257, 1089, 1011, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.07 (1H, d, *J* = 3.0 Hz), 6.02 (1H, d, *J* = 3.0 Hz), 5.80 (1H, ddt, *J* = 17.3, 10.3, 6.3 Hz), 5.01 (1H, dq, *J* = 17.3, 1.7 Hz), 4.95 (1H, dm, *J* = 10.4 Hz), 4.63 (1H, dd, *J* = 7.2, 5.6 Hz), 4.00-4.09 (1H, m), 2.78 (1H, ddd, *J* = 15.0, 4.8, 2.9 Hz), 2.71 (1H, ddd, *J* = 15.0, 7.6, 2.3 Hz), 1.97-2.18 (2H, m), 1.70-1.97 (3H, m), 1.23 (3H, d, *J* = 6.2 Hz), 0.87 (9H, s), 0.04 (3H, s), -0.078 and -0.083 (3H, 2s); ¹³C NMR (100 MHz, CDCl₃) δ 156.29, 156.28 (Cq), 151.57, 151.53 (Cq), 138.2 (CH), 114.7 (CH₂), 107.52, 107.48 (CH), 106.53, 106.51 (CH), 67.8 (CH), 66.8, 66.7 (CH), 38.0 (CH₂), 36.0 (CH₂), 29.7 (CH₂), 25.8 (3CH₃), 22.6 (CH₃), 18.2 (Cq), -4.8 (CH₃), -5.0 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₈H₃₂NaO₃Si [M+Na]⁺: 347.2013, found 347.2006.

**1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-propan-2-ol (3e).**

The crude product obtained from the silylated alcohol **2e** (5.0 g, 17.3 mmol), *n*-BuLi (8.66 mL, 17.33 mmol, 1 equivalent) and methyl oxirane (2.43 mL, 34.66 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (3.94 g, 11.4 mmol, 66% yield) as an inseparable 1:1 mixture of diastereoisomers. *Rf* 0.58 (cyclohexane/EtOAc 8/2); IR (neat) *v* 3406, 2858, 1722, 1689, 1454, 1067, 1015, 1086, 840 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.42 (2H, m), 7.30-7.35 (2H, m), 7.20-7.29 (1H, m), 5.99 (1H, d, *J* = 3.1 Hz), 5.91 (1H, d, *J* = 3.1 Hz), 5.74 (1H, s), 3.95-4.08 (1H, m), 2.75 (1H, dd, *J* = 14.9, 4.6 Hz), 2.68 (1H, dd, *J* = 14.9, 7.5 Hz), 1.77 (1H, bs), 1.20 (3H, dd, *J* = 6.1, 0.6 Hz),
0.91 (9H, s), 0.05 and 0.034 (3H, 2s), 0.029 and 0.00 (3H, 2s); ¹³C NMR (100 MHz, CDCl₃) δ 156.2, 156.1 (Cq), 152.3 (Cq), 141.9 (Cq), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 107.7, 107.59 (CH), 107.56 (CH), 70.53, 70.48 (CH), 66.7 (CH), 37.9 (CH₂), 25.8 (3CH₃), 22.6 (CH₃), 18.3 (Cq), -5.0 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₂₀H₃₀NaO₃Si [M+Na]⁺: 369.1862, found 369.1856; *m/z* calcd for C₂₀H₃₀KO₃Si [M+K]⁺: 385.1601, found 385.1596.

### 1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-3-phenoxy-propan-2-ol (3f).

The crude product obtained from the silylated alcohol 2f (2.0 g, 6.93 mmol), n-BuLi (6.1 mL, 1.14 M, 6.94 mmol, 1 equivalent) and 2-phenoxymethyl-oxirane (1.9 mL, 13.88 mmol, 2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (1.52 g, 3.47 mmol, 50% yield). Rf 0.35 (cyclohexane/EtOAc 8/2); IR (neat) ν 2955, 2929, 2858, 1603, 1499, 1249, 1086, 840, 754 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.41 (2H, m), 7.23-7.35 (4H, m), 6.82-6.99 (4H, m), 6.03 (1H, d, *J* = 3.1 Hz), 5.94 (1H, d, *J* = 3.1 Hz), 5.73 (1H, s), 4.19-4.25 (1H, m), 3.93 (1H, ddd, *J* = 9.4, 3.6, 3.6 Hz), 3.86 (1H, ddd, *J* = 9.4, 6.5, 3.8 Hz), 2.93 (2H, d, *J* = 6.4 Hz), 2.38 (1H, bs), 0.90 (9H, s), 0.04 (3H, s), 0.02 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 158.5 (Cq), 156.2 (Cq), 151.2 (Cq), 141.9 (Cq), 129.5 (2CH), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 121.1 (CH), 114.6 (2CH), 107.9 (CH), 107.7 (CH), 70.9 (CH₂), 70.5 (CH), 69.0 (CH), 32.4 (CH₂), 25.8 (3CH₃), 18.3 (Cq), -5.0 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₂₆H₃₄NaO₄Si [M+Na]⁺: 461.2119, found 461.2110.

### 3.2.3. General Protocol for Alcohol Oxidation to Ketone

A solution of alcohol 3 (1 eq.) in DCM (2 mL/mmol of alcohol) was degassed by bubbling a flush of argon. This solution was cooled to 0 °C and DMP (1.2 equivalent) was added. The reaction mixture was stirred at 0 °C during 1h and 2h 30min at room temperature. The reaction was quenched by adding a saturated solution of Na₂S₂O₃ (2 mL/mmol of alcohol) and a saturated aqueous solution of NaHCO₃ (1 mL/mmol of alcohol). The reaction mixture was then extracted with DCM (3 × 1 mL/mmol of alcohol). The organic phase was dried over MgSO₄, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography to afford ketone 4.

#### 1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-propyl]-furan-2-yl]-propan-2-one (4a).

The crude product obtained from the alcohol 3a (0.371 g, 1.24 mmol) and DMP (0.764 g, 1.80 mmol, 1.45 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (0.332 g, 1.12 mmol, 90% yield). Rf 0.48 (cyclohexane/EtOAc 8/2); IR (neat) ν 2959, 2933, 2858, 1723, 1465, 1361, 1127, 1104, 1063, 1019, 911, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.11 (2H, s), 4.55 (1H, dd, *J* = 6.5, 6.5 Hz), 3.66 (2H, s), 2.14 (3H, s), 1.73-1.80 (2H, m), 0.86 (3H, t, *J* = 7.3 Hz), 0.85 (9H, s), 0.03 (3H, s), -0.06 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.4 (Cq), 157.2 (Cq), 146.9 (Cq), 108.7 (CH), 106.7 (CH), 69.8 (CH), 43.4 (CH₂), 29.9 (CH₂), 29.0 (CH₃), 25.8 (3CH₃), 18.2 (Cq), 9.8 (CH₃), -4.8 (CH₃), -5.0 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₆H₂₈NaO₃Si [M+Na]⁺: 319.1700, found 319.1700.

#### 1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-propyl]-furan-2-yl]-propan-2-one (4b).

The crude product obtained from the alcohol 3b (1.16 g, 3.71 mmol) and DMP (2.36 g, 5.58 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 85/15) to give a yellow oil (1.02 g, 3.28 mmol, 88% yield). Rf 0.55 (cyclohexane/EtOAc 85/15); IR (neat) ν 3473, 2959, 2933, 2858, 1722, 1596, 1514, 1473, 1391, 1365, 1257, 1071, 1026, 1011 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.11 (1H, d, *J* = 3.2 Hz), 6.09 (1H, d, *J* = 3.2 Hz), 4.27 (1H, d, *J* = 6.9 Hz), 3.66 (2H, s), 2.14 (3H, s), 2.00 (1H, octuplet, *J* = 6.7 Hz), 0.94 (3H, d, *J* = 6.7 Hz), 0.87 (9H, s), 0.79 (3H, d, *J* = 6.7 Hz), 0.03 (3H, s), -0.12 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.4 (Cq), 156.7 (Cq), 146.8 (Cq), 108.6 (CH), 107.5 (CH), 74.1 (CH), 43.5 (CH₂), 34.3 (CH), 28.9 (CH₃), 25.8 (3CH₃), 18.7 (CH₃), 18.3 (CH₃), 18.2 (Cq), -4.9 (CH₃), -5.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₇H₃₀NaO₃Si [M+Na]⁺: 333.1856, found 333.1862.

#### 1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyl]-furan-2-yl]-propan-2-one (4c).
The crude product obtained from the alcohol **3c** (1.89 g, 5.79 mmol) and DMP (3.69 g, 8.70 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a yellow oil (1.38 g, 4.25 mmol, 73% yield). *Rf* 0.63 (cyclohexane/EtOAc 8/2); IR (neat) *v* 2959, 2933, 2858, 1722, 1689, 1469, 1365, 1253, 1086, 1007, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.11 (2H, s), 4.68 (1H, dd, *J* = 8.1, 5.9 Hz), 3.67 (2H, s), 2.15 (3H, s), 1.48–1.79 (3H, m), 0.90 (3H, d, *J* = 6.1 Hz), 0.89 (3H, d, *J* = 6.1 Hz), 0.85 (9H, s), 0.05 (3H, s), -0.09 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.3 (Cq), 157.4 (Cq), 147.0 (Cq), 108.7 (CH), 106.7 (CH), 66.7 (CH), 46.0 (CH₂), 43.4 (CH₂), 29.0 (CH₃), 25.8 (3CH₃), 24.3 (CH), 23.1 (CH₃), 22.1 (CH₃), 18.2 (Cq), -4.7 (CH₃), -5.1 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₈H₃₂NaO₃Si [M+Na]⁺: 347.2013, found 347.2014.

**1-[5-[1-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enyl]-furan-2-yl]-propan-2-one (4d).**

The crude product obtained from the alcohol **3d** (1.58 g, 4.87 mmol) and DMP (3.09 g, 7.29 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a yellow oil (1.15 g, 3.57 mmol, 73% yield). *Rf* 0.53 (cyclohexane/EtOAc 8/2); IR (neat) *v* 3078, 2955, 2933, 2858, 1722, 1477, 1361, 1257, 1093, 1011, 914, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.11 (2H, s), 5.80 (1H, ddt, *J* = 17.1, 10.3, 6.7 Hz), 5.01 (1H, dm, *J* = 17.1 Hz), 4.95 (1H, dm, *J* = 10.3 Hz), 4.64 (1H, dd, *J* = 7.3, 5.6 Hz), 3.67 (2H, s), 2.15 (3H, s), 1.97–2.13 (2H, m), 1.71–1.95 (2H, m), 0.87 (9H, s), 0.05 (3H, s), -0.07 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.3 (Cq), 157.0 (Cq), 147.1 (Cq), 138.2 (CH), 114.8 (CH₂), 108.7 (CH), 106.9 (CH), 67.8 (CH), 43.4 (CH₂), 36.1 (CH₂), 29.6 (CH₂), 29.0 (CH₃), 25.8 (3CH₃), 18.2 (Cq), -4.8 (CH₃), -5.0 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₈H₃₀NaO₃Si [M+Na]⁺: 345.1856, found 345.1861.

**1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-propan-2-one (4e).**

The crude product obtained from the alcohol **3e** (3.9 g, 11.3 mmol) and DMP (5.73 g, 13.5 mmol, 1.2 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a colorless oil (3.46 g, 10.0 mmol, 89% yield). *Rf* 0.50 (cyclohexane/EtOAc 7/3); IR (neat) *v* 2955, 2933, 2858, 1715, 1603, 1257, 1182, 840, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.25–7.41 (5H, m), 6.09 (1H, d, *J* = 3.2 Hz), 5.99 (1H, d, *J* = 3.2 Hz), 5.74 (1H, s), 3.63 (2H, s), 2.10 (3H, s), 0.91 (9H, s), 0.05 (3H, s), 0.04 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.3 (Cq), 156.8 (Cq), 147.8 (Cq), 141.9 (Cq), 128.1 (2CH), 127.4 (CH), 126.3 (2CH), 108.8 (CH), 107.9 (CH), 70.5 (CH), 43.4 (CH₂), 29.0 (3CH₃), 25.8 (CH₃), 18.3 (Cq), -5.0 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₂₀H₂₈NaO₃Si [M+Na]⁺: 367.1705, found 367.1697.

**1-[5-[(tert-Butyl-dimethyl-silanyloxy)-phenyl-methyl]-furan-2-yl]-3-phenoxy-propan-2-one (4f).**

The crude product obtained from the alcohol **3f** (0.345 g, 0.79 mmol) and DMP (0.501 g, 1.18 mmol, 1.45 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (103 mg, 0.24 mmol, 30% yield). *Rf* 0.69 (cyclohexane/EtOAc 8/2); IR (neat) *v* 2955, 2933, 2858, 1737, 1603, 1499, 1250, 1063, 1022, 840, 758 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (2H, d, *J* = 8.0 Hz), 7.23–7.35 (5H, m), 6.99 (1H, t, *J* = 8.0 Hz), 6.81 (2H, d, *J* = 8.7 Hz), 6.14 (1H, d, *J* = 3.2 Hz), 6.01 (1H, d, *J* = 3.2 Hz), 5.73 (1H, s), 4.56 (2H, s), 3.85 (1H, s), 0.90 (9H, s), 0.04 (3H, s), 0.03 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 202.0 (Cq), 157.6 (Cq), 157.0 (Cq), 146.3 (Cq), 141.9 (Cq), 129.6, 128.1, 127.4, 126.3, 121.7, 114.6 (10CH), 109.2 (CH), 107.9 (CH), 72.0 (CH₂), 70.5 (CH), 39.3 (CH₂), 25.8 (3CH₃), 18.3 (Cq), -5.0 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₂₆H₃₂NaO₄Si [M+Na]⁺: 459.1962, found 459.1957.

### 3.2.4. General Protocol for Silylated Alcohol Deprotection

**Procedure with TBAF reagent:** A solution of TBAF (1.0 M in THF, 1.5 equivalent) at room temperature was added to a solution of silylated alcohol **4** (1 equivalent) in anhydrous THF (2 mL/mmol of silylated alcohol). The reaction mixture was followed by TLC and stopped when starting material completely disappeared (1 or 2 h). A saturated solution of NH₄Cl (2 mL/mmol of silylated alcohol) was added. The reaction mixture was then extracted with EtOAc (3 × 1 mL/mmol of silylated alcohol). The organic phases were dried
over MgSO₄, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography to afford product 5.

Procedure with Et₃N.3HF reagent: A solution of Et₃N.3HF (1.5 equivalent) at room temperature was added to a solution of the silylated alcohol 4 (1 equivalent) in anhydrous acetonitrile (1.25 mL/mmol of silylated alcohol). The reaction mixture was followed by TLC and stopped when starting material completely disappeared (1 or 2 h). A saturated solution of NaHCO₃ (2 mL/mmol of silylated alcohol) was added. The reaction mixture was then extracted with CH₂Cl₂ (3 × 1 mL/mmol of silylated alcohol). The organic phases were dried over MgSO₄, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography to afford product 5.

**1-[5-(1-Hydroxy-propyl)-furan-2-yl]-propan-2-one (5a).**

The crude product obtained from the silylated alcohol 4a (0.332 g, 1.12 mmol) and TBAF (1.65 mL, 1.65 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (81 mg, 0.44 mmol, 40% yield). *Rf* 0.39 (cyclohexane/EtOAc 8/2); IR (neat) *ν* 3413, 2970, 2936, 2880, 1719, 1421, 1361, 1242, 1026, 1048, 966, 795 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 6.19 (1H, d, *J* = 3.1 Hz), 6.14 (1H, d, *J* = 3.1 Hz), 4.56 (1H, dd, *J* = 6.8, 6.8 Hz), 3.70 (2H, s), 2.17 (3H, s), 1.70–1.90 (2H, m), 0.95 (3H, t, *J* = 7.3 Hz); ¹³C NMR (100 MHz, CDCl₃) *δ* 204.2 (Cq), 156.4 (Cq), 147.6 (Cq), 108.8 (CH), 107.0 (CH), 69.1 (CH), 43.3 (CH₂), 29.2 (CH₃), 28.8 (CH₂), 9.9 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₀H₁₄NaO₃ [M+Na]⁺: 205.0835, found 205.0834.

**1-[5-(1-Hydroxy-2-methyl-propyl)-furan-2-yl]-propan-2-one (5b).**

The crude product obtained from the silylated alcohol 4b (1.28 g, 4.12 mmol) and Et₃N.3HF (1.0 mL, 6.18 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a yellow oil (521 mg, 2.65 mmol, 64% yield). *Rf* 0.38 (cyclohexane/EtOAc 6/4); IR (neat) *ν* 3435, 2962, 2929, 2877, 1715, 1562, 1473, 1387, 1361, 1298, 1242, 1212, 1067, 1022 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 6.19 (1H, d, *J* = 3.1 Hz), 6.14 (1H, d, *J* = 3.1 Hz), 4.33 (1H, d, *J* = 7.3 Hz), 3.69 (2H, s), 2.16 (3H, s), 2.08 (1H, octuplet, *J* = 6.8 Hz), 1.88–2.02 (1H, bs), 1.01 (3H, d, *J* = 6.8 Hz), 0.86 (3H, d, *J* = 6.8 Hz); ¹³C NMR (100 MHz, CDCl₃) *δ* 204.1 (Cq), 155.9 (Cq), 147.4 (Cq), 108.8 (CH), 107.6 (CH), 73.5 (CH), 43.3 (CH₂), 33.2 (CH), 29.1 (CH₃), 18.7 (CH₃), 18.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₁H₁₆NaO₃ [M+Na]⁺: 219.0988, found 219.0992.

**1-[5-(1-Hydroxy-3-methyl-butyl)-furan-2-yl]-propan-2-one (5c).**

The crude product obtained from the silylated alcohol 4c (0.695 g, 2.14 mmol) and TBAF (3.22 mL, 3.21 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a yellow oil (273 mg, 1.30 mmol, 61% yield). *Rf* 0.43 (PE/EtOAc 6/4); IR (neat) *ν* 3435, 2959, 2925, 2873, 2854, 1719, 1599, 1514, 1469, 1391, 1361, 1223, 1160, 1071, 1022 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 6.16 (1H, d, *J* = 3.1 Hz), 6.11 (1H, d, *J* = 3.1 Hz), 4.69 (1H, dd, *J* = 5.7, 5.7 Hz), 3.68 (2H, s), 2.16 (3H, s), 1.60–1.80 (4H, m), 0.93 (3H, d, *J* = 6.2 Hz), 0.91 (3H, d, *J* = 6.2 Hz); ¹³C NMR (100 MHz, CDCl₃) *δ* 204.2 (Cq), 156.9 (Cq), 147.5 (Cq), 108.8 (CH), 106.8 (CH), 65.9 (CH), 44.4 (CH₂), 43.2 (CH₂), 29.1 (CH₃), 24.6 (CH), 23.0 (CH), 22.1 (2CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₂H₁₈NaO₃ [M+Na]⁺: 233.1148, found 233.1140.

**1-[5-(1-Hydroxy-pent-4-enyl)-furan-2-yl]-propan-2-one (5d).**

The crude product obtained from the silylated alcohol 4d (1.16 g, 3.60 mmol) and Et₃N.3HF (0.89 mL, 5.39 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a yellow oil (440 mg, 2.11 mmol, 59% yield). *Rf* 0.20 (cyclohexane/EtOAc 7/3); IR (neat) *ν* 3406, 3078, 2977, 2925, 2858, 1715, 1644, 1562, 1361, 1242, 1212, 1164, 1067, 1015 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 6.20 (1H, d, *J* = 3.2 Hz), 6.14 (1H, d, *J* = 3.2 Hz), 5.83 (1H, ddt, *J* = 17.3, 10.3, 6.6 Hz), 5.05 (1H, dm, *J* = 17.2 Hz), 4.99 (1H, dm, *J* = 10.4 Hz), 4.67 (1H, t, *J* = 6.8 Hz), 3.70 (2H, s), 2.07–2.28 (2H, m), 2.18 (3H, s), 1.93 (3H, td, *J* = 7.1, 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃) *δ* 204.0 (Cq), 156.3 (Cq), 147.7 (Cq), 137.8 (CH), 115.2 (CH₂), 108.9 (CH), 107.1 (CH), 67.2 (CH), 43.3 (CH₂), 34.5 (CH₂), 29.8 (CH₂), 29.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₂H₁₆NaO₃ [M+Na]⁺: 231.0992, found 231.0990.
### 1-[5-(Hydroxy-phenyl-methyl)-furan-2-yl]-propan-2-one (5e).

The crude product obtained from the silylated alcohol **4e** (3.38 g, 9.81 mmol) and TBAF (14.7 mL, 14.7 mmol, 1.5 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 95/5) to give a colorless oil (1.97 g, 8.56 mmol, 87% yield). *Rf* 0.17 (cyclohexane/EtOAc 7/3); IR (neat) *ν* 3406, 3063, 3029, 2959, 2925, 2854, 1715, 1599, 1357, 1160, 963, 724, 702 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 7.27-7.43 (5H, m), 6.11 (1H, d, *J* = 3.2 Hz), 6.03 (1H, d, *J* = 3.2 Hz), 5.76 (1H, s), 3.66 (2H, s), 2.85 (1H, bs), 2.12 (3H, s); ¹³C NMR (100 MHz, CDCl₃) *δ* 204.2 (Cq), 155.7 (Cq), 148.2 (Cq), 140.7 (Cq), 128.3 (2CH), 127.9 (CH), 126.5 (2CH), 108.9 (CH), 108.5 (CH), 69.9 (CH), 43.1 (CH₂), 29.2 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₄H₁₄NaO₃ [M+Na]⁺: 253.0835, found 253.0829.

### 1-[5-(Hydroxy-phenyl-methyl)-furan-2-yl]-3-phenoxy-propan-2-one (5f).

The crude product obtained from the silylated alcohol **4f** (1.03 g, 2.36 mmol) and Et₃N·3HF (0.65 mL, 4.0 mmol, 1.7 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 9/1) to give a colorless oil (658 mg, 2.04 mmol, 86% yield). *Rf* 0.47 (cyclohexane/EtOAc 7/3); IR (neat) *ν* 3426, 3062, 2919, 1736, 1598, 1494, 1241, 1080, 1058, 1016 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) *δ* 7.25-7.45 (7H, m), 7.00 (1H, t, *J* = 7.3 Hz), 6.84 (2H, dd, *J* = 8.7, 1.0 Hz), 6.17 (1H, d, *J* = 3.1 Hz), 6.05 (1H, d, *J* = 3.1 Hz), 5.78 (1H, s), 4.59 (2H, s), 3.91 (2H, s), 2.43 (1H, bs); ¹³C NMR (100 MHz, CDCl₃) *δ* 202.3 (Cq), 157.6 (Cq), 155.8 (Cq), 147.0 (Cq), 140.6 (Cq), 129.7, 128.5, 128.1, 126.6, 121.8, 114.5 (10CH), 109.4 (CH), 108.7 (CH), 72.2 (CH₂), 70.1 (CH), 39.1 (CH₂); HRMS (ESI⁺) *m/z* calcd for C₂₀H₁₈KO₄ [M+K]⁺: 361.0842, found 361.1036.

### 3.2.5. General Protocol for Oxime Formation

NH₂OH.HCl (4 eq.) and pyridine (4 eq.) were added to a solution of ketone **5** (1 equivalent) in ethanol (5 mL/mmol of ketone). After heating 1h at reflux, the reaction mixture was diluted with water (5 mL/mmol of ketone) and then extracted with EtOAc (3 × 5 mL/mmol of ketone). The organic phases were dried over MgSO₄, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography to afford products 6 and 7.

#### 1-[5-(1-Ethoxy-propyl)-furan-2-yl]-propan-2-one oxime (7a).

The crude product obtained from the ketone **5a** (191 mg, 1.049 mmol), NH₂OH.HCl (292 mg, 4.20 mmol, 4 equivalent) and pyridine (0.34 mL, 4.20 mmol, 4 equivalent) give a mixture which was purified by column chromatography on silica gel (cyclohexane/EtOAc 8/2) to give a colorless oil (81.1 mg, 0.36 mmol, 34% yield) as an inseparable 9:1 mixture of E:Z oximes **7a**. *Rf* 0.34 (cyclohexane/EtOAc 6/4); IR (neat) *ν* 3292, 2971, 2931, 2876, 1666, 1556, 1368, 1149, 1096, 968 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) Major E-7a-oxime *δ* 8.82 (1H, bs), 6.16 (1H, d, *J* = 3.1 Hz), 6.05 (1H, d, *J* = 3.1 Hz), 4.12 (1H, t, *J* = 7.0 Hz), 3.51 (2H, s), 3.32-3.51 (2H, m), 1.88 (3H, s), 1.74-1.91 (2H, m), 1.16 (3H, t, *J* = 7.0 Hz), 0.89 (3H, t, *J* = 7.4 Hz); characteristic signals of minor Z-7a-oxime *δ* 3.75 (2H, s), 1.82 (3H, s); ¹³C NMR (100 MHz, CDCl₃) Major E-7a-oxime *δ* 155.3 (Cq), 154.5 (Cq), 150.0 (Cq), 108.2 (CH), 107.6 (CH), 76.4 (CH), 64.0 (CH₂), 34.8 (CH₂), 27.3 (CH₂), 15.2 (CH₃), 13.1 (CH₃), 10.1 (CH₃); characteristic signals of minor Z-7a-oxime *δ* 154.9 (Cq), 154.2 (Cq), 149.6 (Cq), 108.4 (CH), 107.7 (CH), 27.5 (CH₂), 19.3 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₂H₁₉NNaO₃ [M+Na]⁺: 248.1257, found 248.1263; calcd for C₁₂H₁₉KNO₃ [M+K]⁺: 264.0997, found 264.0981.

#### 1-[5-(1-Ethoxy-2-methyl-propyl)-furan-2-yl]-propan-2-one oxime (7b) and 7-isobutylidene-3-methyl-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6b).

The crude product obtained from the ketone **5b** (280 mg, 1.43 mmol), NH₂OH.HCl (397 mg, 5.71 mmol, 4 equivalent) and pyridine (0.46 mL, 5.71 mmol, 4 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 99/1 to 90/10) to give a yellow oil (44 mg, 0.18 mmol, 13% yield) as an inseparable 77:15:8 mixture of E-7b:Z-7b:6b. *Rf* 0.61 (cyclohexane/EtOAc 6/4); IR (neat) *ν* 3253, 2962, 2929, 2873, 1674, 1559, 1473, 1387, 1372, 1238, 1156, 1093, 1015 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) Major oxime E-7b *δ* 8.46 (1H, bs), 6.14 (1H, d, *J* = 3.1 Hz), 6.05 (1H, d, *J* = 3.0 Hz), 3.81 (1H, d, *J* = 8.0 Hz), 3.51 (2H, s), 3.32 and 3.45 (2H, 2dq, *J* = 9.2, 7.0 Hz), 2.03-2.10 (1H, m), 1.87 (3H,
s), 1.15 (3H, t, *J* = 7.0 Hz), 1.01 (3H, d, *J* = 6.6 Hz), 0.77 (3H, d, *J* = 6.6 Hz); characteristic signals of minor oxime Z-7b δ 3.75 and 3.76 (2H, 2s), 1.81 (3H, s); characteristic signals of bicyclic spiro compound 6b 6.27 (1H, d, *J* = 5.6 Hz), 5.92 (1H, d, *J* = 5.6 Hz), 4.44 (1H, d, *J* = 9.2 Hz), 3.13 (1H, dd, *J* = 18.1, 1.1 Hz), 3.02 (1H, d, *J* = 18.1 Hz), 2.75 (1H, d sept., *J* = 9.2, 6.7 Hz), 2.07 (3H, s); ¹³C NMR (100 MHz, CDCl₃) Major oxime E-7b δ 155.4 (Cq), 154.1 (Cq), 149.9 (Cq), 108.7 (CH), 107.6 (CH), 80.9 (CH), 64.4 (CH₂), 34.8 (CH₂), 32.5 (CH), 19.1 (CH₃), 18.7 (CH₃), 15.1 (CH₃), 13.0 (CH₃); characteristic signals of minor oxime Z-7b δ 155.0 (Cq), 153.9 (Cq), 149.5 (Cq), 108.9 (CH), 107.7 (CH), 27.5 (CH₂), 19.3 (CH₃); characteristic signals of bicyclic spiro compound 6b 156.6 (Cq), 130.1 (CH), 126.5 (CH), 118.4 (Cq), 111.3 (CH), 46.7 (CH₂), 25.3 (CH), 13.4 (CH₃). HRMS of oximes 7b (ESI⁺) *m/z* calcd for C₁₃H₂₁NNaO₃ [M+Na]⁺: 262.1414, found 262.1408.

### 1-[5-(1-Ethoxy-3-methyl-butyl)-furan-2-yl]-propan-2-one oxime (7c).

The crude product obtained from the ketone 5c (272.5 mg, 1.3 mmol), NH₂OH.HCl (361 mg, 5.2 mmol, 4 equivalent) and pyridine (0.42 mL, 5.2 mmol, 4 equivalent), giving a mixture of 7c and 6c, was purified by column chromatography on silica gel (PE/EtOAc 85/15) to give a yellow oil (45.7 mg, 0.18 mmol, 14% yield) as an inseparable 87:13 mixture of E and Z oximes 7c. *Rf* 0.49 (PE/EtOAc 7/3); IR (neat) *ν* 3320, 2959, 2929, 2873, 1469, 1369, 1171, 1089 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) Major oxime 7c δ 8.56 (1H, bs), 6.16 (1H, d, *J* = 3.1 Hz), 6.05 (1H, d, *J* = 3.1 Hz), 4.27 (1H, dd, *J* = 8.0, 6.1 Hz), 3.51 (2H, s), 3.45 (1H, dq, *J* = 9.2, 7.0 Hz), 3.36 (1H, dq, *J* = 9.2, 7.0 Hz), 1.88 (3H, s), 1.75-1.84 (1H, m), 1.55-1.71 (2H, m), 1.15 (3H, t, *J* = 7.0 Hz), 0.91 (3H, d, *J* = 6.5 Hz), 0.89 (3H, d, *J* = 6.5 Hz); characteristic signals of minor oxime 7c δ 3.75 and 3.76 (2H, 2s), 1.82 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 155.3 (Cq), 154.8 (Cq), 150.0 (Cq), 108.1 (CH), 107.6 (CH), 73.1 (CH), 63.9 (CH₂), 43.2 (CH₂), 34.8 (CH₂), 24.6 (CH), 22.8 (CH₃CH), 22.3 (CH₃), 15.2 (CH₃), 13.1 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₄H₂₃NNaO₃ [M+Na]⁺: 276.1576, found 276.1570.

### 3-Methyl-7-(3-methyl-butylidene)-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6c).

Compound 6c was obtained in the same experiment as 7c and purified by column chromatography on silica gel (CH/EtOAc 90/10) to give a yellow oil (37.7 mg, 0.18 mmol, 14% yield). *Rf* 0.47 (PE/EtOAc 7/3); ¹H NMR (400 MHz, CDCl₃) δ 6.31 (1H, d, *J* = 5.5 Hz), 5.94 (1H, d, *J* = 5.5 Hz), 4.60 (1H, t, *J* = 7.7 Hz), 3.14 and 3.02 (2H, 2d, *J* = 18.2 Hz), 2.08 (3H, s), 2.04-2.06 (2H, m), 1.55-1.68 (1H, m), 0.90 (3H, d, *J* = 6.7 Hz), 0.89 (3H, d, *J* = 6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 156.6 (Cq), 155.4 (Cq), 129.9 (CH), 126.5 (CH), 118.4 (Cq), 102.7 (CH), 46.7 (CH₂), 34.4 (CH₂), 28.7 (CH), 22.3 (CH₃), 22.2 (CH₃), 13.4 (CH₃); HRMS (ESI⁺) *m/z* calcd for C₁₂H₁₇NNaO₂ [M-H₂O+Na]⁺: 230.1151, found 230.1142.

### 1-[5-(1-Ethoxy-pent-4-enyl)-furan-2-yl]-propan-2-one oxime (7d) and 3-Methyl-7-pent-4-enylidene-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6d).

The crude product obtained from the ketone 5d (394 mg, 1.89 mmol), NH₂OH.HCl (526 mg, 7.58 mmol, 4 equivalent) and pyridine (0.61 mL, 7.58 mmol, 4 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 99/1) to give a yellow oil (62 mg, 0.25 mmol, 13% yield) as an inseparable 65:26:9 mixture of E-7d:Z-7d:6d. *Rf* 0.55 (cyclohexane/EtOAc 6/4); IR (neat) *ν* 3268, 3082, 2977, 2925, 2858, 1644, 1569, 1443, 1372, 1335, 1160, 1067, 1089 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) Major oxime E-7d δ 8.54 (1H, bs), 6.16 (1H, d, *J* = 3.1 Hz), 6.05 (1H, d, *J* = 3.1 Hz), 5.80 (1H, ddt, *J* = 17.3, 10.3, 6.3 Hz), 5.01 (1H, dq, *J* = 17.3, 1.7 Hz), 4.96 (1H, dq, *J* = 10.4, 1.5 Hz), 4.22 (1H, t, *J* = 7.0 Hz), 3.51 (2H, s), 3.45 (1H, dq, *J* = 9.3, 7.0 Hz), 3.36 (1H, dq, *J* = 9.3, 7.0 Hz), 2.03-2.16 (1H, m), 1.80-2.03 (1H, m), 1.88 (3H, s), 1.60 (3H, t, *J* = 7.0 Hz); characteristic signals of minor oxime Z-7d δ 3.75 (2H, d, *J* = 1.8 Hz), 1.82 (3H, s); characteristic signals of bicyclic spiro compound 6d δ 6.30 (1H, d, *J* = 5.6 Hz), 5.95 (1H, d, *J* = 5.6 Hz), 4.58 (1H, t, *J* = 7.4 Hz), 3.15 (1H, d, *J* = 18.1 Hz), 3.03 (1H, d, *J* = 18.1 Hz), ¹³C NMR (100 MHz, CDCl₃) Major oxime E-7d δ 155.3 (Cq), 154.4 (Cq), 150.2 (Cq), 138.0 (CH), 114.9 (CH₂), 108.3 (CH), 107.7 (CH), 74.1 (CH), 64.1 (CH₂), 34.8 (CH₂), 33.4 (CH₂), 29.8 (CH₂), 15.2 (CH₃), 13.1 (CH₃); characteristic signals of minor oxime Z-7d δ 154.9 (Cq), 154.1 (Cq), 149.7 (Cq), 138.0 (CH), 108.4 (CH), 107.7 (CH), 74.1 (CH), 64.0 (CH₂), 27.5 (CH₂); characteristic signals of bicyclic spiro compound 6d δ 129.8 (CH), 126.8 (CH), 102.8 (CH), 46.7 (CH₂); HRMS of oximes 7d (ESI⁺) *m/z* calcd for
$C_{14}H_{21}NNaO_3$ [M+Na]$^+$: 274.1414, found 274.1417; HRMS of bicyclic spiro compound 6d (ESI$^+$) *m/z* calcd for $C_{12}H_{16}NO_2$ [M+H]$^+$: 206.1176, found 206.1178.

**7-Benzylidene-3-methyl-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6e).**

The crude product obtained from the ketone 5e (500 mg, 2.17 mmol), $NH_2OH.HCl$ (604 mg, 8.69 mmol, 4 equivalent) and pyridine (0.7 mL, 8.7 mmol, 4 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 90/10) to give a white solid (354 mg, 1.56 mmol, 72% yield). *Rf* 0.41 (cyclohexane/EtOAc 6/4); mp 113.5–115.0 °C; IR (neat) ν 3104, 3052, 2985, 2925, 2858, 1652, 1599, 1391, 1369, 1339, 1179, 1108, 940, 844, 825 cm$^{-1}$; $^1$H NMR (400 MHz, $CDCl_3$) δ 7.60 (2H, dd, *J* = 7.2, 1.3 Hz), 7.29 (2H, t, *J* = 7.5 Hz), 7.16 (1H, tt, *J* = 7.3, 1.2 Hz), 6.45 (1H, d, *J* = 5.5 Hz), 6.08 (1H, dd, *J* = 5.5, 0.7 Hz), 5.51 (1H, s), 3.25 (1H, dq, *J* = 18.3, 1.1 Hz), 3.13 (1H, dq, *J* = 18.3, 0.6 Hz), 2.11 (3H, s); $^{13}$C NMR (100 MHz, $CDCl_3$) δ 156.9 (*Cq*), 155.3 (*Cq*), 135.2 (*Cq*), 131.2 (CH), 128.5 (2CH), 128.3 (2CH), 127.5 (CH), 126.3 (CH), 119.9 (*Cq*), 103.3 (CH), 47.0 (*CH₂*), 13.4 (*CH₃*); HRMS (ESI$^+$) *m/z* calcd for $C_{14}H_{14}NO_2$ [M+H]$^+$: 228.1025, found 228.1019; *m/z* calcd for $C_{14}H_{13}NNaO_2$ [M+Na]$^+$: 250.0844, found 250.0847.

**7-Benzylidene-3-phenoxymethyl-1,6-dioxa-2-aza-spiro [4.4]nona-2,8-diene (6f).**

The crude product obtained from the ketone 5f (191 mg, 0.59 mmol), $NH_2OH.HCl$ (164.7 mg, 2.37 mmol, 4 equivalent) and pyridine (0.2 mL, 2.4 mmol, 4 equivalent) was purified by column chromatography on silica gel (cyclohexane/EtOAc 7/3) to give a colorless oil (118 mg, 0.369 mmol, 62% yield). *Rf* 0.52 (cyclohexane/EtOAc 7/3); $^1$H NMR (400 MHz, $CDCl_3$) δ 7.55 (2H, dd, *J* = 7.9, 0.7 Hz), 7.25-7.35 (4H, m), 7.16 (1H, t, *J* = 7.4 Hz), 7.04 (1H, t, *J* = 7.4 Hz), 6.99 (2H, dd, *J* = 8.7, 0.9 Hz), 6.48 (1H, d, *J* = 5.5 Hz), 6.09 (1H, dd, *J* = 5.5, 0.7 Hz), 5.53 (1H, s), 4.97 and 4.93 (2H, 2d, *J* = 13.0 Hz), 3.349 and 3.347 (2H, 2d, *J* = 18.5 Hz); $^{13}$C NMR (100 MHz, $CDCl_3$) δ 157.7 (*Cq*), 157.5 (*Cq*), 155.1 (*Cq*), 135.0 (*Cq*), 131.6 (CH), 129.7 (2CH), 128.6 (2CH), 128.3 (2CH), 127.0 (CH), 126.5 (CH), 121.9 (CH), 120.2 (*Cq*), 114.8 (2CH), 103.9 (CH), 62.9 (*CH₂*), 43.6 (*CH₂*); HRMS (ESI$^+$) *m/z* calcd for $C_{20}H_{18}NO_3$ [M-H$^+$: 320.1281, found 320.1280; calcd for $C_{20}H_{18}NNaO_3$ [M+Na]$^+$: 342.1101, found 342.1103.

**4. Conclusions**

Oximation of ketofurfuryl alcohols in ethanol with hydroxylamine hydrochloride in the presence of pyridine led, in most cases, to an oxime along with a spiroisoxazoline. The oxime/spiroisoxazoline product ratio depended mainly on the nature of the substituent attached to the furfuryl alcohol moiety (i.e., $R_1$). If the substituent was a phenyl group, only the spiroisoxazoline presenting a dihydrofurane moiety including a phenyl methylene group was obtained (yield up to 72%), suggesting an important stabilisation by a mesomeric effect. The suggested formation of spiranic derivatives involved an in situ oximation/dehydration/$S_N'$ cascade reaction.

This original pathway, giving access to new pharmacophores, prompted us to further study rearrangement from furyloximes.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29225474/s1, Figures S1–S10: NMR spectra of silylated alcohols **2a–e**; Figures S11–S22: NMR spectra of compounds **3a–f**; Figures S23–S34: NMR spectra of compounds **4a–f**; Figures S35–S46: NMR spectra of keto alcohols **5a–f**; Figures S47–S54: NMR spectra of compounds **7a–d**; Figures S55–S67 NMR spectra of compounds **6c,e** and **f**.

**Author Contributions:** Conceptualization, C.S.; validation, M.Y.L. and C.S.; investigation, C.C.; writing—original draft preparation, C.S.; writing—review and editing, M.Y.L. and C.S.; visualization, C.S.; supervision, C.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data are contained within the article and Supplementary Materials.
**Acknowledgments:** The authors would like to thank the Ministère de l'Enseignement Supérieur et de la Recherche and the CNRS for their financial support. They also wish to extend thanks to Alexandre Benard and Patrick Daubias for his contribution to the HRMS analysis.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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