Double Intramolecular Transacetalization of Polyhydroxy Acetals: Synthesis of Conformationally-Restricted 1,3-Dioxanes with Axially-Oriented Phenyl Moiety

Abstract

The synthesis of conformationally-restricted 1,3-dioxanes with a phenyl moiety fixed in an axial orientation at the acetalic center is described. Starting with diethyl 3-hydroxyglutarate (15), benzaldehyde acetal 12a and acetophenone ketal 12b bearing a protected 1,3,5-trihydroxypentyl side chain in the o-position were prepared. The first acid-catalyzed intramolecular transacetalization gave a mixture of diastereomeric 2-benzofurans 18 (ratio of diastereomers 2:2:1:1). After OH group deprotection, the second intramolecular transacetalization afforded tricyclic alcohol 14a (2-(1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepin-3-yl]ethan-1-ol). Analogous cyclizations led to the corresponding silyl ether 22a (19%) and azide 23a (13%). Whereas tricyclic alcohol 14a was obtained as a 1:1 mixture of diastereomers, the silyl ether 22a and the azide 23a afforded only one diastereomer. This observation indicates a faster cyclization of the minor diastereomers providing the thermodynamically-favored compounds with equatorially-oriented substituents in the 3-position of the tricyclic 1,5-epoxy-2-benzoxepine system. In general, acetophenone-derived ketalic compounds (b-series) required very mild reaction conditions and gave lower yields than the corresponding acetalic compounds (a-series).

1. Introduction

Heterocycles with two O-atoms in the acetalic position, such as 1,3-dioxoles, 1,3-dioxolanes, and homologous 1,3-dioxanes, are found in several important biologically-active compounds. The 1,3-dioxole ring is present in the natural product galipinine (1), found in the roots of Galipea officinalis, which is active against some chloroquine-resistant Plasmodium falciparum strains [1]. The broad-spectrum antifungal agents ketoconazole (2), terconazole (3), and itraconazole (4) [2,3,4], contain the 1,3-dioxolane ring. This five-membered heterocycle is also found in dexoxadrol (5) and etoxadrol (6), showing analgesic and anesthetic activity due to uncompetitive antagonism at the N-methyl-d-aspartate (NMDA) receptor [5,6,7] (Figure 1).

Enlargement of the 1,3-dioxolane ring of dexoxadrol (5) and etoxadrol (6) led to 1,3-dioxanes with high NMDA and σ₁ receptor antagonistic activity. The 1,3-dioxane 7 with an aminoethyl substituent at the 4-position is a potent uncompetitive antagonist at the phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) binding site of the NMDA receptor (K_i = 13 nM [6], Figure 1). The PCP affinity of the 1,3-dioxane 7 is even higher than the PCP affinity of the corresponding 1,3-dioxolane derivative [6]. Removal of the ethyl moiety at the acetalic position and the introduction of a benzyl moiety at the N-atom led to 1,3-dioxane 8 with very high σ₁ receptor affinity (K_i = 19 nM). Moreover, 1,3-dioxane 8 shows very high analgesic activity in the capsaicin assay [5]. 1,3-Dioxane 9 with substituents at the 5-position in addition to two phenyl moieties at the 2-position, reveals multi-drug resistance (MDR) modulatory properties (IC₅₀ = 11.2 μM) [8], which are even higher than the MDR modulatory activities of the analogous 1,3-dioxolane with a similar substitution pattern [6,8,9].

A common structural feature of the pharmacologically-active compounds 2–9 shown in Figure 1 is the phenyl moiety at the acetalic position. Structure-activity-relationship (SAR) studies with flexible 1,3-dioxolane- and 1,3-dioxane-based NMDA receptor antagonists led to the hypothesis that one phenyl moiety in an axially perpendicular orientation at the acetalic 2-position of the oxygen heterocycle is required for high NMDA receptor affinity [5,10,11]. 1,3-Dioxane 8 with an equatorially oriented phenyl moiety at the 2-position shows rather low PCP affinity, but rather high σ₁ receptor affinity [5].

In order to obtain insight into the preferred orientation of the phenyl moiety at the 1,3-dioxane ring, conformationally-restricted 1,3-dioxanes of type 14 (Figure 2) were envisaged bearing a phenyl moiety, which is forced to adopt an axial orientation. Herein we report on the synthesis of the tricyclic compounds 14 resulting from the 1,3-dioxanes 7–9 by connecting a phenyl moiety with the carbon atom at the 6-position of the 1,3-dioxane ring. In the tricyclic compounds 14 the phenyl ring is fixed in the axial orientation and, moreover, its rotation along the phenyl-C(acetal) bond is blocked.

2. Synthesis

The plan for the synthesis of tricyclic compounds 14 is based on two subsequent intramolecular transacetalization reactions. At first, aldehyde 11 will be prepared by acetalization of pentane-1,3,5-triol (10) with benzaldehyde and subsequent oxidation of the primary alcohol. Reaction of 11 with an arylmetal derivative bearing an acetalic substituent in the o-position will provide the secondary alcohols 12 (Scheme 1). Starting from 12, the first intramolecular transacetalization will establish the benzofuran ring, and the second intramolecular transacetalization after cleavage of the 1,3-dioxane ring (13) will afford the tricyclic system 14.

For the synthesis of pentane-1,3,5-triol (10) the diester 15 was reduced with LiAlH₄. Careful workup resulted in 97% yield of triol 10 [12]. (Scheme 1) Acetalization of benzaldehyde with triol 10 afforded stereoselectively the cis-configured 1,3-dioxane 16 in 85% yield [13,14,15]. Swern oxidation [16] of the primary alcohol 16 with DMSO and oxalyl chloride provided aldehyde 11 in 92% yield [13].

Treatment of aryl bromides 17a,b [17,18] with n-butyllithium at −78 °C led to the corresponding aryllithium intermediates, which reacted with the aldehyde 11 to give the secondary alcohols 12a,b. Both alcohols 12a and 12b were isolated as a mixture of two diastereomers in the ratio 2:1. The ratio of diastereomeric alcohols 12a and 12b was determined by integration of characteristic methyne signals (PhCH(dioxane), R₂CHOH, PhCH(OCH₃)₂) in the ¹H-NMR spectra.

The intramolecular transacetalization of 12a required careful optimization of the reaction conditions in order to avoid the cleavage of the 1,3-dioxane moiety. Various acid catalysts in different solvents (e.g., pTosOH in CH₂Cl₂, AcOH in CH₂Cl₂, and AcOH in CHCl₃) were investigated. The highest yield of the 2-benzofuran 18a (89%) was obtained using pTosOH in toluene within 2 h at room temperature. However, the concentration of pTosOH has to be carefully controlled in order to avoid complete decomposition of the compounds (Scheme 2).

Unexpectedly, treatment of the alcohol 12b with the optimized reaction conditions for the cyclization of 12a to 18a led to decomposition within 45 min. It is assumed that the higher reactivity of the ketal of 12b (forming a more stable carbenium ion) compared to the acetal 12a is responsible for this decomposition reaction. Therefore, milder reaction conditions were investigated. Low amounts of pTosOH in a 1:1-mixture of cyclohexane and toluene afforded the desired benzofuran 18b in 71% yield.

For the second intramolecular transacetalization the benzaldehyde acetal of 18 protecting the hydroxy moieties of the side chain had to be cleaved. Catalytic amounts of p-toluenesulfonic acid (pTosOH) in a mixture of methanol and water (4:1) led to cleavage of the 1,3-dioxane ring, providing the diols 13a and 13b in 87% and 55% yields, respectively. The conversion of benzofuran 18b with ketalic substructure into diol 13b was slower and gave lower yields (55%) than the preparation of diol 13a (87%) from the acetalic benzofuran 18a (Scheme 2). In general, it was observed that substrates with a ketalic substructure (12b, 18b) require milder reaction conditions than the corresponding analogues 12a and 18a with an acetalic system.

The benzofurans 18a,b, as well as the diols 13a,b, were obtained as mixtures of four diastereomers in the ratio 2:2:1:1. The ratio of diastereomers was derived from the relative intensities of the four signals for 1-H of the 2-benzofuran ring.

Although it was expected that the intramolecular transacetalization of diols 13 should easily provide six-membered acetals 14 (1,3-dioxane in the tricyclic scaffold), the synthesis of 14 was rather challenging. Several variations were investigated in order to detect the best reaction conditions. The transformation of 13a into 14a was performed in polar and nonpolar solvents (DMF, AcOH, CHCl₃, toluene), with different acids (pTosOH, AcOH and HCl in AcOH), at r.t. up to 90 °C for periods between 3 h and 7 d producing 14a in yields between 10%–46%. However, due to purification problems the yield of pure tricyclic alcohol 14a (1:1 mixture of diastereomers) did not exceed 17% (pTosOH, toluene, 85 °C, 72 h).

As shown for the reactions of ketals 12b and 18b, the final cyclization starting with the ketal 13b required very mild reaction conditions in order to avoid decomposition. Finally, the tricyclic alcohol 14b was obtained as a 1:1 mixture of diastereomers in 6% yield after stirring the diol 13b in a toluene/AcOH mixture at r.t. for 72 h.

It was hypothesized that the low yields of the tricyclic alcohols 14a and 14b could be due to competition between the secondary and primary alcohol of 13 leading to the desired compounds 14 or compounds with an eight-membered acetalic ring. Therefore, the primary alcohol of 13a was protected regioselectively with TBDMS-Cl to provide the silyl ether 19a in 58% yield. Treatment of the silyl ether 19a with HCl in AcOH led to the tricyclic silyl ether 22a in 19% yield. Although a mixture of four diastereomers (ratio 2:2:1:1) was employed in this reaction, only one diastereomer of the tricyclic silyl ether was isolated (see discussion of the stereochemistry below). The ¹H-NMR spectrum of the recovered starting material 19a indicated that the minor diastereomers of the silyl ether 19a had reacted faster than the major diastereomers.

Next, the primary alcohol of 13a should be converted into an azide. For this purpose, the diol 13a was reacted with pTosCl in the presence of catalytic amounts of Bu₂SnO [19] in refluxing CH₂Cl₂ to afford, regioselectively, the tosylate 20a as a mixture of four diastereomers (ratio 2:2:1:1) in 51% yield. Substitution of the tosylate 20a with NaN₃ led to the azide 21a in 92% yield (Scheme 2). It was assumed that the intramolecular transacetalization of azide 21a should result in higher yields than the reaction of diol 13a, since the competing primary alcohol was no longer present. The conversion of azidoalcohol 21a into tricyclic azide 23a was achieved with pTosOH in toluene (85 °C). Unexpectedly, only one isomer of 23a was isolated in 13% yield (see discussion of the stereochemistry below). The ¹H-NMR spectrum of the recovered starting material 21a showed only signals for the two major diastereomers of 21a. It was concluded that the minor diastereomers of 21a reacted faster to form the tricyclic azide 23a than the major diastereomers. The lower reactivity of the major diastereomers may explain the low yields of the tricyclic azide 23a.

In order to determine the relative configuration of the diastereomerically-pure silyl ether 22a and the azide 23a, the ¹H-NMR signals produced by the protons in the 3-, 4-, and 5-positions were analyzed. In both compounds the axially-oriented proton in the 4-position causes a ddd signal with two large coupling constants of 13 Hz and 11 Hz, and one small coupling constant of 3.7 Hz. The largest coupling constant (13 Hz) belongs to the geminal coupling of 4-H_ax with 4-H_eq. The small coupling constant reflects the interaction between 4-H_ax and the equatorially-oriented 5-H. The remaining coupling constant of 11 Hz can only be explained by an 1,2-diaxial position of adjacent protons. Therefore, the proton in the 3-position has to adopt an axial orientation resulting in equatorial position of the substituted ethyl moiety in the 3-position.

3. Experimental Section

3.1. General

Unless otherwise stated, moisture-sensitive reactions were conducted under dry nitrogen. THF was dried with sodium/benzophenone and was freshly distilled before use. Similarly, dichloromethane and methanol were distilled from calcium hydride and magnesium methanolate, respectively. For the regulation of temperature below 0 °C a cryostat (EK 90, Thermo Haake, Karlsruhe, Germany) or acetone/dry ice bath (−78 °C) was used. Solvents and liquid reagents were added to the reaction mixture with disposable syringes. Thin layer chromatography (TLC): silica gel 60 F₂₅₄ plates (Merck, Darmstadt, Germany). Flash chromatography (fc): silica gel 60, 40–64 μm (Merck); parentheses include: diameter of the column, length of column, fraction size, eluent, R_f value. IR: IR spectrophotometer IRAffinity with MIRacle 10 accessory FT-ATR-IR (Shimadzu, Duisburg, Germany). ¹H-NMR (400 MHz), ¹³C-NMR (100 MHz): Mercury plus 400 spectrometer (Varian, Willich, Germany); ¹H-NMR (600 MHz), ¹³C-NMR (151 MHz): Agilent Technologies (Waldbronn, Germany) 600/54 premium spectrometer: δ in ppm related to tetramethylsilane; coupling constants are given with 0.5 Hz resolution; ¹H- and ¹³C-NMR spectra are shown in the Supplementary Materials. MS: EI = electron impact, ESI = electro spray ionization: MicroTof (Bruker Daltronics, Bremen, Germany), calibration with sodium formate clusters (ESI) and fatty acid esters (atmospheric pressure chemical ionization (APCI)) before measurement.

3.2. HPLC Method to Determine the Purity of the Compounds

Merck Hitachi equipment; UV detector: L-7400; autosampler: L-7200; pump: L-7100; degasser: L-7614; Method A: column: LiChrospher^® 60 RP-select B (5 μm), 250–4 mm cartridge; flow rate: 1.00 mL/min; injection volume: 5.0 μL; detection λ = 210 nm; solvents: A: water with 0.05% (v/v) trifluoroacetic acid; B: acetonitrile with 0.05% (v/v) trifluoroacetic acid: gradient elution: (A%): 0–4 min: 90%, 4–29 min: gradient from 90% to 0%, 29–31 min: 0%, 31–31.5 min: gradient from 0% to 90%, 31.5–40 min: 90%.

3.3. Synthetic Procedures

Pentane-1,3,5-triol (10) [12]. Under N₂ atmosphere and ice cooling (0 °C), diethyl 3-hydroxyglutarate (15, 5.31 g, 26 mmol) in dry THF (10 mL) was added dropwise to a suspension of LiAlH₄ (2.43 g, 64 mmol) in dry THF (60 mL). The reaction mixture was heated at 66 °C for 72 h. The excess of LiAlH₄ was quenched with cold water (50 mL) under ice cooling until a completely white precipitate was observed. A solution of H₂SO₄ (1/4 conc.) was added dropwise to the mixture under ice cooling until the precipitate dissolved completely (pH 1). The reaction mixture was then heated to reflux for 12 h and the THF was removed under reduced pressure. The resulting aqueous mixture was alkalized with NH₃ solution (25%) until a gelatinous precipitate of Al(OH)₃ was observed (pH 10). The precipitate was removed by suction filtration, and the residue was washed with water (3 × 50 mL). The filtrate was concentrated in vacuo, and the residue was heated to reflux in CH₃OH (150 mL) for 4 h. The mixture was then filtered to remove the insoluble Li₂SO₄. The residue was washed with CH₃OH (3 × 50 mL). The combined filtrate was concentrated in vacuo, and the crude product was purified by fc (Ø = 6 cm, h = 15 cm, ethyl acetate:methanol = 9:1, V = 20 mL, R_f = 0.21). Colorless oil, yield 2.9 g (97%). C₅H₁₂O₃ (120.1). Exact mass (APCI): m/z = 121.0871, calcd. 121.0859 for C₅H₁₂O₃ [MH]⁺. ¹H-NMR (400 MHz, CD₃OD): δ [ppm] = 1.58–1.75 (m, 4H, CH₂CHOHCH₂), 3.69 (t, J = 6.5 Hz, 4H, CH₂OH), 3.87 (tt, J = 8.4/4.5 Hz, 1H, CHOH). Signals for the OH protons are not observed in the spectrum. ¹³C-NMR (100 MHz (CD₃)₂SO): δ [ppm] = 40.6 (2C, CH₂CHOH), 58.3 (2C, CH₂OH), 65.2 (1C, CHOH). FTIR (neat): ν (cm⁻¹) = 3298 (O-H), 2940, 2886 (C-H), 1042 (C-O).

2-[(2RS,4SR)-2-Phenyl-1,3-dioxan-4-yl]ethanol (16). p-Toluenesulfonic acid (50 mg, 0.3 mmol) was added to a solution of pentane-1,3,5-triol (10, 0.64 g, 5.3 mmol) and benzaldehyde (1.1 mL, 1.1 g, 11 mmol) in dry CH₂Cl₂ (25 mL). Then anhydrous Na₂SO₄ (3.80 g, 27 mmol) was added and the reaction mixture was stirred at r.t. for 24 h. The reaction mixture was filtered to remove Na₂SO₄, and the residue was washed with CH₂Cl₂ (3 × 10 mL). The combined filtrate was washed with saturated aqueous solution of NaHCO₃ (3 × 10 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was washed with brine (10 mL) and dried (Na₂SO₄). The solvent was removed in vacuo, and the crude product was purified by fc (Ø = 3 cm, h = 18 cm, cyclohexane:ethyl acetate = 1:1, V = 20 mL, R_f = 0.25). Colorless oil, yield 0.90 g (85%). C₁₂H₁₆O₃ (208.3). Exact mass (APCI): m/z = 209.1155, calcd. 209.1172 for C₁₂H₁₆O₃ [MH]⁺. ¹H-NMR (400 MHz, CD₂Cl₂): δ [ppm] = 1.52 (dtd, J = 13.3/2.5/1.4 Hz, 1H, 5-H_eq), 1.79 (dddd, J = 14.5/6.6/5.2/4.0 Hz, 1H, CH₂CH₂OH), 1.83–1.90 (m, 2H, CH₂CH₂OH (1H), 5-H_ax (1H), 2.07 (t, J = 4.6 Hz, 1H, CH₂OH), 3.73–3.84 (m, 2H, CH₂OH), 3.98 (ddd, J = 12.4/11.4/2.6 Hz, 1H, 6-H_ax), 4.10 (tdd, J = 11.1/4.0/2.4 Hz, 1H, 4-H_ax), 4.25 (ddd, J = 11.4/5.1/1.4 Hz, 1H, 6-H_eq), 5.53 (s, 1H, 2-H_ax), 7.32–7.40 (m, 3H, H_arom), 7.43–7.50 (m, 2H, H_arom). ¹³C-NMR (100 MHz, CD₂Cl₂): δ [ppm] = 31.8 (1C, C-5_dioxane), 38.9 (1C, CH₂CH₂OH), 60.4 (1C, CH₂OH), 67.5 (1C, C-6_dioxane), 76.7 (1C, C-4_dioxane), 101.7 (1C, C-2_dioxane), 126.6 (2C, C_arom), 128.7 (2C, C_arom), 129.2 (1C, C_arom), 139.5 (1C, Cq_arom). FTIR (neat): ν (cm⁻¹) = 3410, 3383 (O-H), 2947, 2859 (C-H), 1454, 1400, 1366 (C=C_arom), 1215, 1138, 1099 (C-O), 748, 698 (C-H_{arom monosubst}).

2-[(2RS,4RS)-2-Phenyl-1,3-dioxan-4-yl)acetaldehyde (11). Under N₂ atmosphere, a solution of oxalyl chloride in CH₂Cl₂ (3.0 mL, 6.0 mmol) was added in one portion to dry CH₂Cl₂ (10 mL) and the resulting solution was cooled down to −78 °C. Then a solution of dry (CH₃)₂SO (0.6 mL, 8.0 mmol) in dry CH₂Cl₂ (10 mL) was added dropwise (10 mL/h via a syringe pump). The reaction mixture was stirred at −78 °C for 15 min. Then a solution of alcohol 16 (0.84 g, 4.0 mmol) in dry CH₂Cl₂ (10 mL) was added dropwise (10 mL/h via a syringe pump), and the mixture was stirred at −78 °C for another 20 min. Finally, Et₃N (2.9 mL, 20 mmol) was added in one portion, and the mixture was stirred at −78 °C for additional 10 min. The mixture was allowed to warm to r.t. The reaction mixture was diluted with Et₂O (20 mL) and the precipitate was filtered off. The residue was washed with Et₂O (2 × 20 mL) and the combined filtrate was concentrated in vacuo. The crude product was purified by fc (Ø = 3 cm, h = 17 cm, cyclohexane:ethyl acetate = 8:2, V = 20 mL, R_f = 0.30). Colorless oil, yield 0.70 g (92%). C₁₂H₁₄O₃ (206.2). Exact mass (APCI): m/z = 207.1008, calcd. 207.1016 for C₁₂H₁₅O₃ [MH]⁺. ¹H-NMR (400 MHz, CD₂Cl₂): δ [ppm] = 1.61 (dtd, J = 13.3/2.5/1.4 Hz, 1H, 5-H_eq), 1.86 (dddd, J = 13.2/12.2/11.3/5.0 Hz, 1H, 5-H_ax), 2.60 (ddd, J = 16.8/4.8/1.6 Hz, 1H, CH₂CHO), 2.74 (ddd, J = 16.8/7.6/2.4 Hz, 1H, CH₂CHO), 3.95–4.04 (m, 1H, 6-H_ax), 4.25 (ddd, J = 11.5/5.0/1.4 Hz, 1H, 6-H_eq), 4.42 (dddd, J = 11.2/7.5/4.8/2.5 Hz, 1H, 4-H_ax), 5.55 (s, 1H, 2-H_ax), 7.30–7.41 (m, 3H, H_arom), 7.41–7.50 (m, 2H, H_arom), 9.81 (dd, J = 2.4/1.6 Hz, 1H, CH₂CHO). ¹³C-NMR (100 MHz, CD₂Cl₂): δ [ppm] = 31.6 (1C, C-5_dioxane), 50.0 (1C, CH₂CHO), 67.3 (1C, C-6_dioxane), 72.8 (1C, C-4_dioxane), 101.7 (1C, C-2_dioxane), 126.6 (2C, C_arom), 128.6 (2C, C_arom), 129.3 (1C, C_arom), 139.2 (1C, Cq_arom), 200.8 (1C, CH₂CHO). FTIR (neat): ν (cm⁻¹) = 2855 (C-H), 1721 (C=O), 1238, 1142, 1099 (C-O), 752, 698 (C-H_{arom monosubst}).

2-{(1RS)-2-[(2RS,4RS)- and (2SR,4SR)-4-Phenyl-1,3-dioxan-2-yl]-1-hydroxyethyl}benzaldehyde dimethyl acetal (12a). Under N₂ atmosphere, a solution of bromoacetal 17a (0.72 g, 3.1 mmol) in dry THF (10 mL) was cooled down to −78 °C. Then 1.6 M n-butyllithium in n-hexanes (2.0 mL, 3.1 mmol) was added dropwise over 15 min, and the reaction mixture was stirred at −78 °C for 10 min. Then a solution of aldehyde 11 (0.43 g, 2.1 mmol) in dry THF (5 mL) was added dropwise over 15 min. The reaction mixture was stirred at −78 °C for 2 h, and was then allowed to warm to r.t. overnight. Under ice cooling, water (15 mL) was added dropwise to the reaction mixture. THF was removed in vacuo from the mixture and the resulting aqueous layer was extracted with CHCl₃ (3 × 20 mL). The combined organic layer was washed with brine (15 mL), dried (Na₂SO₄,), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 3 cm, h = 18 cm, cyclohexane: ethyl acetate = 8:2, V = 20 mL, R_f = 0.26). Pale yellow oil, yield 0.70 g (93%), mixture of two diastereomers (2:1). C₂₁H₂₆O₅ (358.4). Exact Mass (APCI): m/z = 325.1437, calcd. 325.1434 for C₂₀H₂₁O₄ [M − HOCH₃ − H]⁺; m/z = 295.1325, calcd. 295.1329 for C₁₉H₁₉O₃ [M − HOCH₃ − OCH₃]⁺. MS (ESI): m/z = 381 [M + Na]⁺, 295 [M − HOCH₃ − OCH₃]⁺. ¹H-NMR (400 MHz, CD₃OD-d₄): δ [ppm] = 1.54 (dtd, J = 13.3/2.6/1.4 Hz, 0.33H, 5-Heq^o), 1.59 (dtd, J = 13.3/2.5/1.4 Hz, 0.67H, 5-H_eq^m), 1.68–1.97 (m, 2.34H, CH₂CHOH^m (2 × 0.67H), 5-H_ax^o+m (1H)), 2.14 (dt, J = 13.9/7.5 Hz, 2 × 0.33H, CH₂CHOH°), 3.18 (s, 3 × 0.67H, OCH₃^m), 3.22 (s, 3 × 0.33H, OCH₃^o), 3.27 (s, 3 × 0.67H, OCH₃^m), 3.27 (s, 3 × 0.33H, OCH₃^o), 3.84–4.04 (m, 2H, 6-H_eq^o (0.33H), 4-H_ax^m (0.67H), 6-H_ax^o+m (1H)), 4.12–4.28 (m, 1H, 4-H_ax^o (0.33H), 6-H_eq^m (0.67H)), 5.36 (dd, J = 7.9/5.8 Hz, 0.67H, CHOH^m), 5.42–5.47 (m, 1H, CHOH^o (0.33H), (CH(OCH₃)₂^m (0.67H)), 5.51 (s, 0.33H, 2-H_ax^o), 5.57 (s, 0.67H, 2-H_ax^m), 5.59 (s, 0.33H, CH(OCH₃)₂^o), 7.20–7.29 (m, 2 × 0.67H, H_arom), 7.30–7.40 (m, 4H, H_arom), 7.44–7.48 (m, 2H, H_arom), 7.49–7.55 (m, 0.67H, H_arom), 7.59 (ddd, J = 7.8/4.1/1.3 Hz, 1H, H_arom). Ratio of diastereomers 67:33. ^o = minor isomer; ^m = major isomer. ¹³C-NMR (151 MHz, DMSO-d₆): δ [ppm] = 30.6^m (0.67C, C-5_dioxane), 31.4^o (0.33C, C-5_dioxane), 45.3^m (0.67C, CH₂CHOH), 46.2^o (0.33C, CH₂CHOH), 53.3^m (2 × 0.67C, OCH₃), 53.5^o (2 × 0.33C, OCH₃), 63.5^o (0.33C, CHOH), 64.1^m (0.67C, CHOH), 66.3^o+m (1C, C-6_dioxane), 73.4^o (0.33C, C-4_dioxane), 74.4^m (0.67C, C-4_dioxane), 100.2^o (0.33C, CH(OCH₃)₂), 100.3^m (0.67C, CH(OCH₃)₂), 100.97^m (0.67C, C-2_dioxane), 101.0^o (0.33C, C-2_dioxane), 125.6^m (0.67C, C_arom), 125.7^o (0.33C, C_arom), 126.06^m (0.67C, C_arom), 126.08^m (2 × 0.67C, C_arom), 126.10^o (2 × 0.33C, C_arom), 126.13^o (0.33C, C_arom), 126.3^o (0.33C, C_arom), 126.5^m (0.67C, C_arom), 127.9^m (0.67C, C_arom), 128.0^m (2 × 0.67C, C_arom), 128.4^o (0.33C, C_arom), 128.5^o+m (1C, C_arom), 128.53^m (0.67C, C_arom), 133.9^o (0.33C, Cq_arom), 134.1^m (0.67C, Cq_arom), 139.0^m (0.67C, Cq_arom), 139.2^o (0.33C, Cq_arom), 144.2^m (0.67C, Cq_arom), 144.8^o (0.33C, Cq_arom). Ratio of diastereomers 67:33. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 3460 (O-H), 2947 (C-H), 1454 (C=C_aromatic), 1099 (C-O), 752, 698 (C-H_{arom mono- and 1,2-disubst}).

1-{2-[(1RS)-2-[(2RS,4RS)- and (2SR,4SR)-2-Phenyl-1,3-dioxan-4-yl]-1-hydroxyethyl]phenyl}ethanone dimethyl ketal (12b). Under N₂ atmosphere, a solution of 2′-bromoacetophenone dimethyl ketal (17b, 0.95 g, 3.7 mmol) in dry THF (12 mL) was cooled down to −78 °C. Then 2.5 M n-butyllithium in n-hexanes (1.5 mL, 3.7 mmol) was added dropwise over 15 min. The reaction mixture was stirred at −78 °C for 10 min. A solution of aldehyde 11 (0.51 g, 2.5 mmol) in dry THF (6 mL) was added dropwise over 18 min. The reaction mixture was stirred at −78 °C for 2 h, then it was allowed to warm to r.t. overnight. Under ice cooling, water (15 mL) was added dropwise to the reaction mixture. THF was removed in vacuo from the mixture and the resulting aqueous layer was extracted with chloroform (3 × 20 mL). The combined organic layer was washed with brine (15 mL), dried (Na₂SO₄), filtered, and the solvent removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 15 cm, cyclohexane:ethyl acetate = 8:2, V = 20 mL, R_f = 0.40). Pale yellow oil, yield 0.89 g (97%), mixture of two diastereomers (2:1). C₂₂H₂₈O₅ (372.5). Exact Mass (APCI): m/z = 310.1536, calcd. 310.1569 for C₂₀H₂₂O₃ [M − HOCH₃ − OCH₃ + H]⁺. MS (ESI): m/z = 395 [M + Na]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.46 (s, 3 × 0.33H, CH₃C(OCH₃)₂^o), 1.50 (s, 3 × 0.67H, CH₃C(OCH₃)₂^m), 1.53–1.79 (m, 3.34H, 5-H_eq^o+m (1H), 5-H_ax^o+m (1H), CH₂CHOH^m (2 × 0.67H)), 1.91–2.02 (m, 2 × 0.33H, CH₂CHOH^o), 3.01 (s, 3 × 0.67H, OCH₃^m), 3.07 (2s, 6 × 0.33H, OCH₃^o), 3.10 (s, 3 × 0.67H, OCH₃^m), 3.93 (qd, J = 11.4/2.7 Hz, 1H, 6-H_ax^o+m), 4.05–4.25 (m, 2H, 4-H_ax^o+m (1H), 6-H_eq^o+m (1H)), 4.97 (2d, J = 4.8 Hz, 1H, CHOH^o+m), 5.34 (ddd, J = 10.0/5.0/3.0 Hz, 0.67H, CHOH^m), 5.51 (s, 1H, 2-H_ax^m (0.67H), CHOH^o (0.33H)), 5.55 (s, 0.33H, 2-H_ax^o), 7.18 (dtd, J = 8.3/7.1/1.5 Hz, 2 × 0.67H, H_arom^m), 7.25–7.36 (m, 4H, H_arom^o+m), 7.36–7.41 (m, 2 × 0.67H, H_arom^m), 7.44 (ddd, J = 8.0/6.5/1.8 Hz, 2 × 0.67H, H_arom^m), 7.60 (td, J = 8.0/1.4 Hz, 1H, H_arom^o+m). Ratio of diastereomers 67:33. ^o = minor isomer; ^m = major isomer. ¹³C-NMR (101 MHz, DMSO-d₆): δ [ppm] = 25.7^o (0.33C, CH₃), 25.9^m (0.67C, CH₃), 30.9^m (0.67C, C-5_dioxane), 32.0^o (0.33C, C-5_dioxane), 45.9^m (0.67C, CH₂CHOH), 46.8^o (0.33C, CH₂CHOH), 48.85^m (2 × 0.67C, OCH₃), 48.88^o (2 × 0.33C, OCH₃), 63.8^o (0.33C, CHOH), 64.4^m (0.67C, CHOH), 66.77^m (0.67C, C-6_dioxane), 66.80^o (0.33C, C-6_dioxane), 74.1^o (0.33C, C-4_dioxane), 75.2^m (0.67C, C-4_dioxane), 100.6^o (0.33C, C-2_dioxane), 100.9^m (0.67C, C-2_dioxane), 102.1^o (0.33C, C(OCH₃)₂), 102.3^m (0.67C, C(OCH₃)₂), 126.5^o (2 × 0.33C, C_arom), 126.54^m (2 × 0.67C, C_arom), 126.6^o (0.33C, C_arom), 126.61^o (0.33C, C_arom), 126.7^m (0.67C, C_arom), 126.8^m (0.67C, C_arom), 128.15^o (0.33C, C_arom), 128.16^m (0.67C, C_arom), 128.2^m (0.67C, C_arom), 128.24^o (0.33C, C_arom), 128.3^o (2 × 0.33C, C_arom), 128.34^m (2 × 0.67C, C_arom), 128.8^o (0.33C, C_arom), 128.9^m (0.67C, C_arom), 138.5^o (0.33C, Cq_arom), 138.7^m (0.67C, Cq_arom), 139.5^m (0.67C, Cq_arom), 139.7^o (0.33C, Cq_arom), 144.9^m (0.67C, Cq_arom), 145.6^o (0.33C, Cq_arom). Ratio of diastereomers 67:33. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 3487 (OH), 2924, 2851 (C-H), 1450 (C=C_aromatic), 1099 (C-O), 760, 698 (C-H_{arom mono- and 1,2-disubst}).

1-Methoxy-3-[(2-phenyl-1,3-dioxan-4-yl)methyl]-1,3-dihydro-2-benzofuran (18a) (four diastereomers). A solution of p-toluenesulfonic acid in toluene (0.5 mg/mL, 18 mL) was added to alcohols 12a (0.33 g, 0.9 mmol). The reaction mixture was stirred vigorously at r.t. for 2 h. Saturated aqueous solution of NaHCO₃ (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 15 cm, cyclohexane: ethyl acetate = 9:1, V = 10 mL, R_f = 0.39). Colorless oil, yield 0.27 g (89%), mixture of four diastereomers (2:2:1:1). C₂₀H₂₂O₄ (326.4). Exact Mass (APCI): m/z = 295.1330, calcd. 295.1329 for C₁₉H₁₉O₃ [M − OCH₃]⁺; m/z = 221.0973, calcd. 221.1172 for C₁₃H₁₇O₃ [M − PhCO]⁺. MS (ESI): m/z = 349 [M + Na]⁺, 295 [M – OCH₃]⁺, 277 [M − OCH₃ − H₂O]⁺, 221 [M − PhCO]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.59–2.02 (m, 3.34H, 5-H_eq^o+m (1H), 5-H_ax^o+m (1H), CHCH₂CH^o+m+o (2 × 0.67H)), 2.04–2.27 (m, 2 × 0.33H, CHCH₂CH^m), 3.33 (s, 3 × 0.17H, OCH₃^o), 3.34 (s, 3 × 0.33H, OCH₃^m), 3.40 (s, 3 × 0.17H, OCH₃^o), 3.41 (s, 3 × 0.33H, OCH₃^m), 3.95–4.08 (m, 1.34H, 6-H_ax^o+m (1H), 4-H_ax^o (2 × 0.17H)), 4.16–4.34 (m, 1.66H, 4-H_ax^m (2 × 0.33H), 6-H_eq^o+m (1H)), 5.34 (dt, J = 10.4/4.6 Hz, 0.50H, 3-H_bf^o+m), 5.43–5.50 (m, 0.50H, 3-H_bf^o+m), 5.58 (s, 0.33H, 2-H_ax^m), 5.61 (s, 0.33H, 2-H_ax^m), 5.66 (2s, 2 × 0.17H, 2-H_ax^o), 6.12 (s, 0.33H, 1-H_bf^m), 6.14 (s, 0.17H, 1-H_bf^o), 6.20 (d, J = 2.1 Hz, 0.17H, 1-H_bf^o), 6.22 (d, J = 2.1 Hz, 0.33H, 1-H_bf^m), 7.34–7.45 (m, 16 × 0.33H + 18 × 0.17H, H_arom), 7.48–7.54 (m, 2 × 0.33H, H_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (101 MHz, DMSO-d₆): δ [ppm] = 31.0^m (0.33C, C-5_dioxane), 31.2^m (0.33C, C-5_dioxane), 32.1^o (2 × 0.17C, C-5_dioxane), 41.9^m (0.33C, CHCH₂CH), 43.0^o (0.17C, CHCH₂CH), 43.5^m (0.33C, CHCH₂CH), 44.7^o (0.17C, CHCH₂CH), 54.0^o (0.17C, OCH₃), 54.1^m (0.33C, OCH₃), 54.3^o (0.17C, OCH₃), 54.5^m (0.33C, OCH₃), 66.6^o+m (0.50C, C-6_dioxane), 66.7^m (0.33C, C-6_dioxane), 67.4^o (0.17C, C-6_dioxane), 73.8^m (0.33C, C-4_dioxane), 74.0^o (0.17C, C-4_dioxane), 74.1^m (0.33C, C-4_dioxane), 74.2^o (0.17C, C-4_dioxane), 78.8^o (0.17C, C-3), 79.0^o (0.17C, C-3), 79.03^m (0.33C, C-3), 79.3^m (0.33C, C-3), 100.5^m (0.33C, C-2_dioxane), 100.6^m (0.33C, C-2_dioxane), 100.7^o (0.17C, C-2_dioxane), 100.74^o (0.17C, C-2_dioxane), 106.2^o (0.17C, C-1), 106.3^m (0.33C, C-1), 106.6^o (0.17C, C-1), 106.7^m (0.33C, C-1), 121.6^o (0.17C, C_arom), 121.8^o (0.17C, C_arom), 121.84^m (0.33C, C_arom), 122.0^m (0.33C, C_arom), 123.4^m (2 × 0.33C, C_arom), 123.42^o (2 × 0.17C, C_arom), 126.4^m (2 × 0.33C, C_arom), 126.42^m (2 × 0.33C, C_arom), 126.5^o (2 × 0.17C, C_arom), 126.53^o (2 × 0.17C, C_arom), 128.06^m (0.33C, C_arom), 128.10^o+m (0.50C, C_arom), 128.2^o (0.17C, C_arom), 128.26^m ( 2 × 0.33C, C_arom), 128.3^m (2 × 0.33C, C_arom), 128.38^o (2 × 0.17C, C_arom), 128.39^o (2 × 0.17C, C_arom), 128.8^m (0.33C, C_arom), 128.81^o (2 × 0.17C, C_arom), 128.9^m (0.33C, C_arom), 129.6^o+m (0.50C, C_arom), 129.61^o+m (0.50C, C_arom), 137.7^o (0.17C, Cq_arom), 137.74^o (0.17C, Cq_arom), 137.8^m (2 × 0.33C, Cq_arom), 139.3^o (2 × 0.17C, Cq_arom), 139.34^m (0.33C, Cq_arom), 139.4^m (0.33C, Cq_arom), 143.3^m (0.33C, Cq_arom), 143.4^m (0.33C, Cq_arom), 143.5^o (0.17C, Cq_arom), 143.51^o (0.17C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 2947, 2858 (C-H), 1458 (C=C_aromatic), 1096 (C-O), 752, 698 (C-H_{arom mono- and 1,2-disubst}).

1-Methoxy-1-methyl-3-[(2-phenyl-1,3-dioxan-4-yl)methyl]-1,3-dihydro-2-benzofuran (18b) (four diastereomers). A solution of p-toluenesulfonic acid in toluene (25 mL, 1 mg/mL) was added to a solution of alcohols 12b (0.89 g, 2.4 mmol) in cyclohexane (25 mL). The reaction mixture was stirred vigorously at r.t. for 2 h. Saturated aqueous solution of NaHCO₃ (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 15 cm, cyclohexane:ethyl acetate = 9:1, V = 10 mL, R_f = 0.40). Pale yellow oil, yield 0.58 g (71%), mixture of four diastereomers (2:2:1:1). C₂₁H₂₄O₄ (340.4). MS (ESI): m/z = 657 [2(M − OCH3) + K]⁺, 363 [M + Na]⁺, 309 [M − OCH₃]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.55–1.65 (m, 3.66H, CH₃C(OCH₃)^o+m (3H), 5-H_eq^m (2 × 0.33H)), 1.70–1.83 (m, 1.34H, 5-H_eq^o (2 × 0.17H), 5-H_ax^o+m (1H)), 1.91–2.19 (m, 2H, CHCH₂CH^o+m), 2.82 (s, 3 × 0.17H, OCH₃^o), 2.84 (s, 1.5H, OCH₃^o+m), 2.94 (s, 3 × 0.33H, OCH₃^m), 3.94 (dd, J = 11.7/2.9 Hz, 2 × 0.33H, 6-H_ax ^m), 3.97–4.04 (m, 0.67H, 6-H_ax^o (2 × 0.17H), 6-H_eq^m (0.33H)), 4.12–4.16 (m, 2 × 0.33H, 4-H_ax^m), 4.19 (ddd, J = 8.9/5.6/3.2 Hz, 0.33H + 2 × 0.17H, 6-H_eq ^o+m+o), 4.23 (dt, J = 7.1, 2.1 Hz, 2 × 0.17H, 4-H_ax^o), 5.24 (ddd, J = 16.6/9.6/3.5 Hz, 2 × 0.17H, 3-H_bf^o), 5.39–5.47 (m, 2 × 0.33H, 3-H_bf^m), 5.52 (s, 0.33H, 2-H_ax^m), 5.60 (s, 0.33H, 2-H_ax^m), 5.63 (2s, 2 × 0.17H, 2-H_ax^o), 7.23 (qd, J = 3.8/1.6 Hz, 1H, H_arom^o+m), 7.26–7.43 (m, 7H, H_arom^o+m), 7.46 (ddd, J = 7.4/3.8/1.9 Hz, 1H, H_arom^o+m). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (101 MHz, DMSO-d₆): δ [ppm] = 26.1 ^m (0.33C, CH₃C(OCH₃)), 26.2^o (0.17C, CH₃C(OCH₃)), 26.8^m (0.33C, CH₃C(OCH₃)), 27.1 ^o (0.17C, CH₃C(OCH₃)), 30.3^m (0.33C, C-5_dioxane), 30.5^o (2 × 0.17C, C-5_dioxane), 31.5^m (0.33C, C-5_dioxane), 41.6^m (0.33C, CHCH₂CH), 41.8^m (0.33C, CHCH₂CH), 42.4^o (0.17C, CHCH₂CH), 43.2^o (0.17C, CHCH₂CH), 48.9^m (0.33C, OCH₃), 48.99^o (0.17C, OCH₃), 49.2^m (0.33C, OCH₃), 49.26^o (0.17C, OCH₃), 66.0^o+m (1C, C-6_dioxane), 73.1^m (0.33C, C-4_dioxane), 73.37^o (0.17C, C-4_dioxane), 73.4^o (0.17C, C-4_dioxane), 73.44^m (0.33C, C-4_dioxane), 76.6^m (0.33C, C-3), 76.66^o (0.17C, C-3), 78.4^o (0.17C, C-3), 78.7^m (0.33C, C-3), 99.8^m (0.33C, C-2_dioxane), 100.0^o+m (0.50C, C-2_dioxane), 100.1^o (0.17C, C-2_dioxane), 109.8^o+m (0.50C, C-1), 110.1^m (0.33C, C-1), 110.2^o (0.17C, C-1), 121.0^o (0.17C, C_arom), 121.2^o+m (0.50C, C_arom), 121.4^m (0.33C, C_arom), 121.8^o (0.17C, C_arom), 121.83^o (0.17C, C_arom), 121.9^m (2 × 0.33C, C_arom), 125.7^m (2 × 0.33C, C_arom), 125.8^m (2 × 0.33C, C_arom), 125.9^o (2 × 0.17C, C_arom), 126.0^o (2 × 0.17C, C_arom), 127.6^m (2 × 0.33C, C_arom), 127.7^m (2 × 0.33C, C_arom), 127.77^m (4 × 0.33C, C_arom), 127.8^o (0.17C, C_arom), 127.9^o (0.17C, C_arom), 128.1^m (0.33C, C_arom), 128.2^m (0.33C, C_arom), 128.3^o (0.17C, C_arom), 128.31^o (0.17C, C_arom), 128.8^o+m+m (2 × 0.33C + 0.17C, C_arom), 128.9^o (0.17C, C_arom), 138.6^m (2 × 0.33C, Cq_arom), 138.7^o (2 × 0.17C, Cq_arom), 138.72^o (0.17C, Cq_arom), 138.8^m (0.33C, Cq_arom), 139.0^o (0.17C, Cq_arom), 139.08^m (0.33C, Cq_arom), 142.3^m (0.33C, Cq_arom), 142.4^o (0.17C, Cq_arom), 142.7^m (0.33C, Cq_arom), 142.8^o (0.17C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 2932, 2855 (C-H), 1454 (C=C_arom), 1099 (C-O), 748, 698 (C-H_{arom mono- and 1,2-disubst}).

4-(3-Methoxy-1,3-dihydro-2-benzofuran-1-yl)butane-1,3-diol (13a) (four diastereomers). A solution of 2-benzofuran 18a (0.32 g, 1.3 mmol) in a mixture of methanol and water (20 mL, 4:1) was treated with p-toluenesulfonic acid (0.17 g, 1.0 mmol). The reaction mixture was stirred at r.t. for 48 h. A saturated aqueous solution of NaHCO₃ (10 mL) was added_. Methanol was evaporated in vacuo and the resulting aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 13 cm, ethyl acetate (100%), V = 10 mL, R_f = 0.44). Pale yellow oil, yield 0.27 g (87%), mixture of four diastereomers (2:2:1:1). C₁₃H₁₈O₄ (238.3). Exact Mass (APCI): m/z = 413.2047, calcd. 413.1959 for C₂₄H₃₀O₆ [2(M − HOCH3) + H]⁺; m/z = 207.1090, calcd. 207.1016 for C₁₂H₁₅O₃ [M − OCH₃]⁺. MS (ESI): m/z = 467 [M + C₁₂H₁₄O₃ + Na]⁺, 261 [M + Na]⁺, 207 [M − OCH₃]⁺, 189 [M − H₂O − OCH₃]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33–1.98 (m, 4H, CH₂CH₂OH^o+m (2H), CH₂CHOH^o+m (2H)), 3.24 (s, 3 × 0.33H, OCH₃^m), 3.28 (s, 3 × 0.17H, OCH₃^o), 3.27 (s, 3 × 0.17H, OCH₃^o), 3.31 (s, 3 × 0.33H, OCH₃^m), 3.46–3.57 (m, 2H, CH₂OH^o+m), 3.84–3.97 (m, 1H, CHOH^o+m), 4.29–4.38 (m, 1H, CH₂OH^o+m), 4.48 (d, J = 5.1 Hz, 0.33H, CHOH^m), 4.52 (d, J = 5.1 Hz, 0.33H, CHOH^m), 4.60 (d, J = 2.5 Hz, 0.17H, CHOH^o), 4.62 (d, J = 2.6 Hz, 0.17H, CHOH^o), 5.22 (dd, J = 7.4/6.2 Hz, 0.33H, 1-H_bf^m), 5.27 (dd, J = 10.4/2.5 Hz, 0.17H, 1-H_bf^o), 5.34 (ddd, J = 7.4/5.1/2.0 Hz, 0.33H, 1-H_bf^m), 5.40 (dt, J = 10.2/2.3 Hz, 0.17H, 1-H_bf^o), 6.01 (s, 0.33H, 3-H_bf^m), 6.03 (s, 0.17H, 3-H_bf^o), 6.09 (2s, Hz, 0.50H, 3-H_bf^o+m), 7.24–7.41 (m, 4H, H_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (101 MHz, DMSO-d₆): δ [ppm] = 39.8^m (2 × 0.33C, CH₂CH₂OH), 41.1^o (0.17C, CH₂CH₂OH), 41.14^o (0.17C, CH₂CH₂OH), 44.0^m (0.33C, CH₂CHOH), 44.7^o (0.17C, CH₂CHOH), 45.5^m (0.33C, CH₂CHOH), 46.3^o (0.17C, CH₂CHOH), 53.5^m (0.33C, OCH₃), 53.7^o (2 × 0.17C, OCH₃), 53.9^m (0.33C, OCH₃), 58.0^o (0.17C, CH₂OH), 58.05^o+m (0.50C, CH₂OH), 58.06^m (0.33C, CH₂OH), 64.3^o (0.17C, CHOH), 64.7^o (0.17C, CHOH), 64.72^m (0.33C, CHOH), 64.8^m (0.33C, CHOH), 79.2^o (0.17C, C-1), 79.6^o (0.17C, C-1), 79.7^m (0.33C, C-1), 80.0^m (0.33C, C-1), 105.6^m (0.33C, C-3), 105.7^o (0.17C, C-3), 106.0^o (0.17C, C-3), 106.1^m (0.33C, C-3), 121.0^o (0.17C, C_arom), 121.2^o (0.17C, C_arom), 121.3^m (0.33C, C_arom), 121.6^m (0.33C, C_arom), 122.9^m (2 × 0.33C, C_arom), 123.0^o (2 × 0.17C, C_arom), 127.5^o (0.17C, C_arom), 127.55^m (0.33C, C_arom), 127.59^o (0.17C, C_arom), 127.6^m (0.33C, C_arom), 129.1^m (0.33C, C_arom), 129.13^o (0.17C, C_arom), 129.14^m (0.33C, C_arom), 129.2^o (0.17C, C_arom), 137.3^o (0.17C, Cq_arom), 137.4^m (0.33C, Cq_arom), 137.42^m (0.33C, Cq_arom), 137.5^o (0.17C, Cq_arom), 143.46^m (0.33C, Cq_arom), 143.50^m (0.33C, Cq_arom), 143.7^o (0.17C, Cq_arom), 143.8^o (0.17C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): v (cm⁻¹) = 3375 (O-H), 2936, 2889 (C-H), 1431 (C=C_aromatic), 1080 (C-O), 752 (C-H_{arom 1,2-disubst}).

4-(3-Methoxy-3-methyl-1,3-dihydro-2-benzofuran-1-yl)butane-1,3-diol (13b) (four diastereomers). A solution of 2-benzofuran 18b (0.22 g, 0.6 mmol) in a mixture of methanol and water (12 mL, 4:1) was treated with p-toluenesulfonic acid (40.0 mg, 0.2 mmol). The reaction mixture was stirred at r.t. for 72 h. Saturated aqueous solution of NaHCO₃ (10 mL) was added_. Methanol was removed in vacuo and the resulting aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 10 cm, ethyl acetate (100%), V = 10 mL, R_f = 0.40). Yellow oil, yield 88.4 mg (55%), mixture of four diastereomers (2:2:1:1). C₁₄H₂₀O₄ (252.31). MS (ESI): m/z = 463 [2(M − HOCH3) +Na]⁺, 275 [M + Na]⁺, 203 [M − OCH₃ − H₂O]⁺, 221 [M − OCH₃]⁺, ¹H-NMR (400 MHz, CD₃OD): δ [ppm] = 1.55–2.07 (m, 7H, CH₃^o+m (3H), CH₂CHOHCH₂^o+m (4H)), 2.94 (s, 3 × 0.33H*, OCH₃^m), 2.95 (s, 3 × 0.17H*, OCH₃^o), 3.01 (s, 3 × 0.17H*, OCH₃^o), 3.04 (s, 3 × 0.33H*, OCH₃^m), 3.41–3.62 (m, 0.33H, CH₂CH₂OH^m), 3.65–3.87 (m, 3 × 0.33H + 4 × 0.17H, CH₂CH₂OH^o+m), 3.95–4.25 (m, 1H*, CH₂CHOH^o+m), 5.17–5.36 (m, 0.50H, 1-H_bf^o+m), 5.38–5.48 (m, 0.33H, 1-H_bf^m), 5.53 (dd, J = 10.2/2.3 Hz, 0.17H, 1-H_bf^o), 7.20–7.49 (m, 4H, H_arom^o+m). Ratio of diastereomers 33:33:17:17. Signals of the OH protons are not observed in the spectrum. * The integrals of these signals are slightly lower than expected. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (101 MHz, CD₃OD): δ [ppm] = 26.7^o (0.17C, CCH₃(OCH₃)), 26.73^m (0.33C, CCH₃(OCH₃)), 27.7^m (0.33C, CCH₃(OCH₃)), 27.8^o (0.17C, CCH₃(OCH₃)), 40.2^m (0.33C, CH₂CH₂OH), 40.4^m (0.33C, CH₂CH₂OH), 41.6^o (0.17C, CH₂CH₂OH), 41.63^o (0.17C, CH₂CH₂OH), 45.0^m (0.33C, CH₂CHOH), 45.6^o (0.17C, CH₂CHOH), 45.8^m (0.33C, CH₂CHOH), 46.6^o (0.17C, CH₂CHOH), 50.1^m (2 × 0.33C, OCH₃), 50.5^o (0.17C, OCH₃), 50.6^o (0.17C, OCH₃), 60.2^o+m (1C, CH₂CH₂OH), 67.0^o (2 × 0.17C, CH₂CHOH), 68.0^m (0.33C, CH₂CHOH), 68.1^m (0.33C, CH₂CHOH), 80.6^m (0.33C, C-1), 81.4^o (2 × 0.17C, C-1), 82.4^m (0.33C, C-1), 111.9^m (0.33C, C-3), 112.1^m (0.33C, C-3), 112.5^o (2 × 0.17C, C-3), 122.0^m (0.33C, C_arom), 122.3^o (0.17C, C_arom), 122.34^m (0.33C, C_arom), 122.5^o (0.17C, C_arom), 123.26^o (0.17C, C_arom), 123.3^m (0.33C, C_arom), 123.4^o (0.17C, C_arom), 123.42^m (0.33C, C_arom), 129.1^o (0.17C, C_arom), 129.2^m (0.33C, C_arom), 129.3^o (0.17C, C_arom), 129.33^m (0.33C, C_arom), 130.3^o (0.17C, C_arom), 130.36^o (0.17C, C_arom), 130.4^m (2 × 0.33C, C_arom), 140.1^o (0.17C, Cq_arom), 140.2^o (0.17C, Cq_arom), 140.4^m (0.33C, Cq_arom), 140.6^m (0.33C, Cq_arom), 144.2^o (0.17C, Cq_arom), 144.6^m (2 × 0.33C, Cq_arom), 144.9^o (0.17C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 3395 (O-H), 2935, 2881 (C-H), 1431, (C=C_aromatic), 1041 (C-O), 764 (C-H_{arom 1,2-disubst}).

[(tert-Butyldimethylsilyl)oxy]-1-(3-methoxy-1,3-dihydro-2-benzofuran-1-yl)butan-2-ol (19a) (four diastereomers). In DMF (0.50 mL), diols 13a (34.1 mg, 0.14 mmol) were treated with imidazole (29.2 mg, 0.43 mmol) and tert-butyldimethylsilyl chloride (22.2 mg, 0.14 mmol). The reaction mixture was stirred at r.t. for 24 h, diluted with EtOAc (10 mL) and washed with water (4 × 5 mL). The organic phase was separated, dried (Na₂SO₄), filtered and was concentrated under reduced pressure. The crude product was purified by fc (Ø = 2 cm, h = 10 cm, cyclohexane: ethyl acetate (8:2), V = 10 mL, R_f = 0.44). Colorless oil, yield 26.6 mg (58%). C₁₉H₃₂O₄Si (352.5). Ratio of diastereomers 33:33:17:17. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.02–0.04 (m, 6H, (CH₃)₂^tBuSi^o+m), 0.86–0.87 (m, 9H, Me₂ (C(CH₃)₃Si^o+m), 1.43–1.95 (m, 4H, CH₂CHOHCH₂^o+m), 3.28 (s, 3 × 0.33H, OCH₃^m), 3.29 (s, 3 × 0.17H*, OCH₃^o), 3.32 (s, 3 × 0.17H *, OCH₃^o), 3.34 (s, 3 × 0.33H, OCH₃^m), 3.68–3.78 (m, 2H, CH₂OH^o+m), 3.90–3.96 (m, 1H, CHOH^o+m), 4.51 (d, J = 5.3 Hz, 0.33H, CHOH^m), 4.53 (d, J = 5.3 Hz, 0.33H, CHOH^m), 4.63 (d, J = 3.3 Hz, 0.17H*, CHOH^o), 4.64 (d, J = 3.2 Hz, 0.17H *, CHOH^o), 5.26 (dd, J = 7.4/6.4 Hz, 0.33H, 1-H_bf^m), 5.31 (dd, J = 10.4/2.4 Hz, 0.17H, 1-H_bf^o), 5.34–5.39 (dd, J = 10.4/3.7 Hz, 0.33H, 1-H_bf^m), 5.43 (dd, J = 11.4/1.4 Hz, 0.17H, 1-H_bf^o), 6.04 (s, 0.33H, 3-H_bf^m), 6.06 (s, 0.17H, 3-H_bf^o), 6.12 (2s, 0.5H, 3-H_bf^o+m), 7.28–7.44 (m, 4H, H_arom). Ratio of diastereomers 33:33:17:17. * Signals were slightly lower than expected. ^o = minor isomer, ^m = major isomer, _bf = benzofuran.

[3-Hydroxy-4-(3-methoxy-1,3-dihydro-2-benzofuran-1-yl)butyl-] 4-methylbenzenesulfonate (20a) (four diastereomers). A solution of diols 13a (0.20 g, 0.84 mmol) in dry CH₂Cl₂ (4 mL) was treated with Bu₂SnO (10.7 mg, 0.04 mmol), Et₃N (176 μL, 1.3 mmol) and p-toluenesulfonyl chloride (0.18 g, 0.9 mmol). The reaction mixture was heated to reflux for 16 h. The solvent was removed under reduced pressure at 30 °C. The crude product was purified by fc (Ø = 2 cm, h = 12 cm, cyclohexane: ethyl acetate (7:3), V = 10 mL, R_f = 0.36 (1st spot); 0.19 (2nd spot)). Colorless oil, yield 0.16 g (51%), mixture of four diastereomers (2:2:1:1). C₂₀H₂₄O₆S (392.5). MS (ESI): m/z = 361 [M − OCH₃]⁺, 343 [M − H₂O − OCH₃]⁺, 171 [M − C₁₃H₁₇O₃]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.41–2.21 (m, 4H, CH₂CH₂OSO₂PhCH₃^o+m (2H), CH₂CHOH^o+m (2H)), 2.41 (2s, 3H^o+m, CH₃Ph), 3.26 (s, 3 × 0.33H, OCH₃^m), 3.28 (s, 3 × 0.17H*, OCH₃^o), 3.30 (s, 3 × 0.33H, OCH₃^o), 3.68–3.77 (m, 2 × 0.17H, CH₂CHOH^o), 3.81 (dt, J = 10.2/5.5 Hz, 2 × 0.33H, CH₂CHOH^m), 3.88–4.19 (m, 2H CH₂CH₂OSO₂PhCH₃^o+m), 4.70–4.82 (m, 2 × 0.33H, CH₂CHOH^m), 4.87–5.01 (m, 2 × 0.17H, CH₂CHOH^o), 5.18 (dd, J = 8.1/5.3 Hz, 0.33H, 1-H_bf^m), 5.22–5.27 (m, 0.17H, 1-H_bf^o), 5.29 (ddd, J = 7.3/4.6/1.9 Hz, 0.33H, 1-H_bf^m), 5.33–5.40 (m, 0.17H, 1-H_bf^o), 6.03 (s, 0.33H, 3-H_bf^m), 6.05 (s, 0.17H, 3-H_bf^o), 6.08 (d, J = 2.0 Hz, 0.33H, 3-H_bf^m), 6.10 (d, J = 2.0 Hz, 0.17H, 3-H_bf^o), 7.24–7.31 (m, 1H, H_arom^o+m), 7.31–7.42 (m, 10 × 0.33H, H_arom^o+m), 7.47 (dd, J = 8.3/3.1 Hz, 2H, H_arom^o+m), 7.78 (dt, J = 8.3/2.1 Hz, 5 × 0.33H, H_arom^o+m). Ratio of diastereomers 33:33:17:17. * A signal (3 × 0.17H) for the OCH₃ moiety of the fourth isomer cannot be observed in the spectrum, because the water peak of DMSO-d₆ is overlapping with this signal. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (151 MHz, DMSO-d₆): δ [ppm] = 28.7^o (2 × 0.17C, CH₃Ph), 29.6^m (0.33C, CH₃Ph), 30.9^m (0.33C, CH₃Ph), 35.2^m (2 × 0.33C, CH₂CH₂OSO₂PhCH₃), 35.3^o (2 × 0.17C, CH₂CH₂OSO₂PhCH₃), 43.1^m (0.33C, CH₂CHOH), 43.9^o (0.17C, CH₂CHOH), 44.7^m (0.33C, CH₂CHOH), 45.6^o (0.17C, CH₂CHOH), 53.2^m (0.33C, OCH₃), 53.7^m (0.33C, OCH₃), 54.6^o (2 × 0.17C, OCH₃), 63.2^o (2 × 0.17C, CH₂CHOH), 63.3^m (2 × 0.33C, CH₂CHOH), 68.1^o (2 × 0.17C, CH₂CH₂OSO₂PhCH₃), 68.2^m (2 × 0.33C, CH₂CH₂OSO₂PhCH₃), 79.0^o (2 × 0.17C, C-1), 79.2^m (2 × 0.33C, C-1), 105.4^m (0.33C, C-3), 105.5^o (0.17C, C-3), 105.8^o (0.17C, C-3), 105.9^m (0.33C, C-3), 120.9^o+m (0.50C, C_arom), 121.2^o+m (0.50C, C_arom), 122.7^o+m+o (0.33C + 2 × 0.17C, C_arom), 122.71^m (2 × 0.33C, C_arom), 127.3^o+m (2C, C_arom), 127.33^o+m (0.50C, C_arom), 127.4^o+m (0.50C, C_arom), 128.8^o+m (0.50C, C_arom), 128.9^o+m (0.50C, C_arom), 129.9^o+m (2C, C_arom), 132.2^m (0.33C, Cq_arom), 137.0^o+m (0.50C, Cq_arom), 137.06^o (0.17C, Cq_arom), 142.9^m (0.33C, Cq_arom), 142.92^m (0.33C, Cq_arom), 143.0^o (0.17C, Cq_arom), 143.2^o (0.17C, Cq_arom), 144.5^o+m (1C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 3506 (O-H), 2920 (C-H), 1173 (RO-SO₂R¹), 1096(C-O), 752, 737, 664 (C-H_{arom1,2- and 1,4-disubst}).

4-Azido-1-(3-methoxy-1,3-dihydro-2-benzofuran-1-yl)butan-2-ol (21a) (four diastereomers). A solution of tosylates 20a (46.6 mg, 0.12 mmol) in dry DMF (1 mL) was treated with NaN₃ (23.2 mg, 0.36 mmol). The reaction mixture was heated to 90 ^oC for 3 h. The solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 12 cm, cyclohexane: ethyl acetate (7:3), V = 10 mL, R_f = 0.48). Pale yellow oil, yield 28.7 mg (92%), mixture of four diastereomers (2:2:1:1). C₁₃H₁₇N₃O₃ (263.3). Exact Mass (APCI): m/z = 234.1121, calcd. 234.1125 for C₁₃H₁₆NO₃ [M – N₂ – H]⁺; m/z = 204.1027, calcd. 204.1019 for C₁₂H₁₄NO₂ [M – N₂ – OCH₃]⁺. ¹H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.64–2.16 (m, 4H, CH₂CHOHCH₂^o+m), 3.26–3.74 (m, 5H, OCH₃^o+m (3H), CH₂CH₂N₃^o+m (2H)), 3.87–4.06 (m, 2 × 0.17H, CH₂CHOH^o), 4.20 (dddd, J = 9.5/6.9/5.1/2.2 Hz, 2 × 0.33H, CH₂CHOH^m), 5.35–5.42 (m, 0.33H, 1-H_bf^m), 5.46 (dd, J = 7.8/3.3 Hz, 0.17H, 1-H_bf^o), 5.54 (dt, J = 10.4/2.5 Hz, 0.33H, 1-H_bf^m), 5.63 (d, J = 7.6 Hz, 0.17H, 1-H_bf^o), 6.11 (s, 0.17H, 3-H_bf^o), 6.16 (s, 0.33H, 3-H_bf^m), 6.18 (d, J = 2.0 Hz, 0.17H, 3-H_bf^o), 6.20 (d, J = 2.1 Hz, 0.33H, 3-H_bf^m), 7.17–7.22 (m, 1H, H_arom), 7.35–7.42 (m, 3H, H_arom). Ratio of diastereomers 33:33:17:17. Signals due to the OH protons are not observed in the spectrum. ^o = minor isomer; ^m = major isomer; _bf = benzofuran. ¹³C-NMR (101 MHz, CDCl₃): δ [ppm] = 36.7^o (0.17C, CH₂CH₂N₃), 36.8^o (0.17C, CH₂CH₂N₃), 36.84^m (0.33C, CH₂CH₂N₃), 36.9^m (0.33C, CH₂CH₂N₃), 42.4^o (0.17C, CH₂CHOH), 43.4^m (0.33C, CH₂CHOH), 44.1^o (0.17C, CH₂CHOH), 44.6^m (0.33C, CH₂CHOH), 48.5^m (0.33C, CH₂CH₂N₃), 48.6^m (0.33C, CH₂CH₂N₃), 48.8^o (2 × 0.17C, CH₂CH₂N₃), 55.1^o+m (0.50C, OCH₃), 55.7^m (0.33C, OCH₃), 56.1^o (0.17C, OCH₃), 66.5^o (0.17C, CH₂CHOH), 66.7^o (0.17C, CH₂CHOH), 68.8^m (0.33C, CH₂CHOH), 69.0^m (0.33C, CH₂CHOH), 81.1^o (0.17C, C-1), 81.6^o (0.17C, C-1), 83.8^m (0.33C, C-1), 84.0^m (0.33C, C-1), 107.1^o (0.17C, C-3), 107.3^m (0.33C, C-3), 108.2^o+m (0.50C, C-3), 121.27^m (0.33C, C_arom), 121.30^o (0.17C, C_arom), 121.5^m (0.33C, C_arom), 121.53^o (0.17C, C_arom), 123.6^o (0.17C, C_arom), 123.62^m (0.33C, C_arom), 123.64^m (0.33C, C_arom), 123.7^o (0.17C, C_arom), 128.6^o (0.17C, C_arom), 128.7^o+m (0.50C, C_arom), 128.8^m (0.33C, C_arom), 130.0^o+m (0.50C, C_arom), 130.04^o+m (0.50C, C_arom), 137.2^m (0.33C, Cq_arom), 137.3^m (0.33C, Cq_arom), 137.9^o (0.17C, Cq_arom), 138.0^o (0.17C, Cq_arom), 142.5^o (0.17C, Cq_arom), 142.7^o (0.17C, Cq_arom), 142.8^m (0.33C, Cq_arom), 142.9^m (0.33C, Cq_arom). Ratio of diastereomers 33:33:17:17. ^o = minor isomer; ^m = major isomer. FTIR (neat): ν (cm⁻¹) = 3464 (O-H), 2932 (C-H), 2091 (N=N=N), 1084 (C-O), 752 (C-H_{arom 1,2-disubst}).

2-[(1RS,3RS,5RS)- and (1RS,3SR, 5RS)-1,5-Epoxy-1,3,4,5-tetrahydro-2-benzoxepin-3-yl]ethan-1-ol (14a). A solution of p-toluenesulfonic acid in toluene (4 mL, 0.5mg/mL) was added to diols 13a (49.2 mg, 0.21 mmol). The reaction mixture was heated to 85 °C for 72 h. Saturated aqueous solution of NaHCO₃ (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 12 cm, CH₂Cl₂:ethyl acetate (6:4), V = 10 mL, R_f =0.46 (1st isomer), 0.35 (2nd isomer)). Colorless solid, yield 7.23 mg (17%), mixture of two diastereomers (1:1). C₁₂H₁₄O₃ (206.2). Exact mass (APCI): m/z = 207.1014, calcd. 207.1016 for C₁₂H₁₅O₃ [MH]⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.52–1.93 (m, 2.5H, 4-H_eq (1H), CH₂CH₂OH (1.5H)), 2.00 (m, 1.5H, CH₂CH₂OH (0.5H), 4-H_ax (1H)), 3.66–3.81 (m, 2H, CH₂CH₂OH), 3.82–3.93 (m, 1H, 3-H_ax (0.5H), 3-H_eq (0.5H)), 4.61 (d, J = 4.4 Hz, 0.5H, CH₂CH₂OH), 4.73 (d, J = 5.7 Hz, 0.5H, CH₂CH₂OH), 5.33 (d, J = 10.8 Hz, 0.5H, 5-H_eq), 5.41 (dd, J = 7.9/3.6 Hz, 0.5H, 5-H_eq), 6.05 (s, 0.5H, 1-H_eq), 6.09 (s, 0.5H, 1-H_eq), 7.26–7.44 (m, 4H, H_arom). Ratio of diastereomers 50:50. FTIR (neat): ν (cm⁻¹) = 3372 (O-H), 2874 (C-H), 1462 (C=C_arom), 1080 (C-O), 748 (C-H_{arom 1,2-disubst}).

2-[{(1RS,3RS,5RS)- and (1RS,3SR,5RS)-1-Methyl}-1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepin-3-yl]ethan-1-ol (14b). A solution of diols 13b (50.0 mg, 0.2 mmol) in a mixture of toluene/AcOH (4:1, 5mL) was stirred at r.t. for 72 h. Saturated aqueous Solution of NaHCO₃ (5 mL) was added. The mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layer was washed with brine (5 mL), dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 10 cm, ethyl acetate/cyclohexane (1:1)), V = 10 mL, R_f = 0.45 (1st spot) and 0.25 (2nd spot)). Yellow oil, yield 2.6 mg (6%) mixture of two diastereomers (1:1). C₁₄H₂₀O₄ (220.27). ¹H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.26 (2s, 3H, 6 × 0.5H, CH₃), 1.62–1.89 (m, 1H, 4-H_eq (0.5H) *, CH₂CH₂OH (0.5H)), 1.89–2.15 (m, 1.5H, CH₂CH₂OH), 2.17–2.33 (m, 1H, 2 × 0.5H, 4-H_ax), 3.88 (dd, J = 12.0/4.7 Hz, 1H**, 2 × 0.5H, CH₂CH₂OH), 3.94–3.98 (m, 1H **, 2 × 0.5H, CH₂CH₂OH), 4.01–4.09 (m, 0.5H, 3-H_ax), 4.08–4.14 (m, 0.5H, 3-H_ax), 5.31–5.36 (m, 0.5H, 5-H_eq), 5.67 (dd, J = 6.1/2.7 Hz, 0.5H, 5-H_eq), 7.19 (m, 1H, 2 × 0.5H, H_arom), 7.29–7.47 (m, 3H, 6 × 0.5H, H_arom). Ratio of diastreoisomers 50:50. * Signals for one isomer is overlapping with other signals including the signal for the residual water in CDCl₃. ** Signals are slightly higher than expected due to impurities. Due to the low amount of 18b the ¹³C-NMR, IR and MS spectra could not be recorded.

(1RS,3SR,5RS)-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepine (22a). In toluene (5 mL), silyl ethers 19a (26.6 mg, 0.08 mmol) were treated with 0.1 M HCl in AcOH (15 μL) and was heated to 65 °C for 60 h. The reaction mixture was diluted with EtOAc (10 mL) and was washed with saturated aqueous solution of NaHCO₃ (3 × 5 mL). The pooled organic phase was dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 10 cm, cyclohexane: ethyl acetate (9:1), V = 10 mL, R_f = 0.48). Colorless oil, yield 4.5 mg (19%). C₁₈H₂₈O₃Si (320.5). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.12 (s, 3H, (CH₃)₂^tBuSi), −0.14 (s, 3H, (CH₃)₂^tBuSi), 0.68 (s, 9H, Me₂ (C(CH₃)₃Si), 1.44 (ddd, J = 13.8/7.7/1.9 Hz, 1H, 4-H_eq), 1.50–1.62 (m, 2H, CH₂CH₂OTBDMS), 2.01 (ddd, J = 13.2/11.2/3.7 Hz, 1H, 4-H_ax), 3.20–3.28 (m, 1H, 3-H_ax), 3.44–3.53 (m, 2H, CH₂OTBDMS), 5.23 (dd, J = 3.7/1.8 Hz, 1H, 5-H_eq), 6.12 (s, 1H, 1-H_eq), 7.25–7.37 (m, 4H, H_arom).

(1RS,3SR,5RS)-3-(2-Azidoethyl)-1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepine (23a). A solution of p-toluenesulfonic acid in toluene (5 mL, 0.5 mg/mL) was added to azide 21a (69.8 mg, 0.27 mmol). The reaction mixture was heated to 85 °C for 72 h. Saturated aqueous solution of NaHCO₃ (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was dried (Na₂SO₄), filtered, and the solvent was removed in vacuo. The crude product was purified by fc (Ø = 2 cm, h = 12 cm, cyclohexane: ethyl acetate (8:2), V = 10 mL, R_f = 0.45). Yellow oil, yield 7.7 mg (13%). C₁₂H₁₃N₃O₂ (231.3). After fc purification, only one diastereomer was isolated. MS (ESI): m/z =424 [2(M – OCH3) + Na + H]⁺, 232 [MH]⁺, 204 [M –N₂ + H]⁺. ¹H-NMR (400 MHz, CD₂Cl₂): δ [ppm] = 1.54–1.66 (m, 2H, 4-H_eq (1H), CH₂CH₂N₃ (1H)), 1.76 (ddt, J = 14.5/8.7/5.8 Hz, 1H, CH₂CH₂N₃), 2.17 (ddd, J = 13.0/11.1/3.7 Hz, 1H, 4-H_ax), 3.22–3.35 (m, 3H, CH₂CH₂N₃ (2H), 3-H_ax (1H)), 5.22 (dd, J = 3.8/1.8 Hz, 1H, 5-H_eq), 6.11 (s, 1H, 1-H_eq), 7.28–7.40 (m, 4H, H_arom). ¹³C-NMR (151 MHz, CDCl₃): δ [ppm] = 35.1 (1C, CH₂CH₂N₃), 37.6 (1C, C-4), 47.2 (1C, CH₂CH₂N₃), 65.3 (1C, C-3), 77.9 (1C, C-5), 100.8 (1C, C-1), 119.6 (1C, C_arom), 121.3 (1C, C_arom), 128.0 (1C, C_arom), 128.6 (1C, C_arom), 138.7 (1C, Cq_arom), 143.0 (1C, Cq_arom). FTIR (neat): ν (cm⁻¹) = 2874 (C-H), 2095 (N=N=N), 1015 (C-O), 756 (C-H_{arom 1,2-disubst}).

4. Conclusions

Herein the synthesis of 1,3-dioxanes is reported, which are bearing a phenyl moiety in the axial orientation at the acetalic center without any freedom to rotate around the phenyl-C-bond. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic compounds 14, 22, and 23. The central hydroxyacetals 12 were prepared in a three-step sequence starting from pentane-1,3,5-triol (10). Whereas the first intramolecular transacetalization of 12 under mild reaction conditions resulted in high yields of 2-benzofurans 18, the second intramolecular transacetalization of 13 gave only low yields of tricyclic alcohols 14 even after several optimization experiments. Protection or substitution of the competing primary alcohol of 13a did not result in higher yields of tricyclic silyl ether 22a or azide 23a. Since only one isomer of 22a and 23a was isolated and the major isomer remained partly unchanged after cyclization of 19a and 21a, it was postulated that the minor isomers of 19a and 21a reacted faster than the major isomers. Due to fast decomposition, the transformations of ketalic compounds (b-series) required milder reaction conditions than the acetalic compounds (a-series).