Changing the Reaction Pathway of Silyl-Prins Cyclization by Switching the Lewis Acid: Application to the Synthesis of an Antinociceptive Compound

Abstract

Developing new procedures for the synthesis of tetrahydropyrans in a very stereoselective manner is of great importance for the synthesis of THP-containing natural products. Here, we report an interesting protocol for the synthesis of polysubstituted halogenated tetrahydropyrans by silyl-Prins cyclization of vinylsilyl alcohols, in which the nature of the Lewis acid determines the outcome of the process. The methodology has been applied to the synthesis of a known antinociceptive.

Introduction

Natural products containing heterocyclic systems have shown to be a remarkable source of bioactive compounds. They show a wide array of activities, such as antitumor, antiviral, antifungal, antifouling, antiproliferative, or anti-inflammatory properties.¹ Within them, halogenated secondary metabolites play an important role in the development of new therapeutic agents for various pathologies.² In particular, it has been shown that the presence of bromine or chlorine in many of these molecules profoundly influences their bioactivity profile.³ Most of these halogenated structures have been isolated from marine organisms such as sponges, fungi, or algae and comprise a large variety of compounds from which tetrahydropyrans have attracted special attention. Examples of compounds of this type include 4-bromo or 4-chloro tetrahydropyrans such as plocamiopyranoid⁴ or anverene E,⁵ monoterpenes isolated from Antarctica red algae of the genus Plocamium cartilagineum which show promising pharmaceutical properties (Figure 1).

Figure 1.

Halogenated marine drugs.

Due to the limited availability of natural sources of these useful products, the efforts of numerous researchers have been devoted to the development of new synthetic methodologies for the preparation of these types of targets. Among the different strategies for the production of tetrahydropyrans,⁶ the Prins cyclization has emerged as a powerful tool for the construction of cyclic ethers in a very efficient and selective manner.^7,8 The use of electron-rich alkenes, such as alkenylsilanes, in these cyclizations has shown several advantages, including higher reaction rates, higher selectivities, and lower occurrence of secondary reactions.^9,10 In this type of process, known as silyl-Prins cyclizations, allylsilanes have been frequently used as versatile organosilanes which, depending on their substitution pattern, provide tetrahydropyrans, methylentetrahydropyrans, or dihydropyrans.¹¹ In contrast, vinylsilanes have been less commonly employed in such cyclizations. Moreover, reported examples of the utilization of vinylsilanes in silyl-Prins cyclizations are mainly limited to the specific use of Z-1-silyl-1-alkenyl derivatives for the synthesis of dihydropyrans.¹² The mechanism of this process implies the formation of an oxocarbenium ion, by the acid-catalyzed reaction of the silyl-alkenol with the aldehyde, which readily undergoes cyclization to provide the corresponding stabilized β-silyl carbocation. The final loss of the silyl group, with the consequent formation of an endocyclic double bond, affords the final heterocycle (Scheme 1).

Scheme 1. Synthesis of Dihydropyrans by Silyl-Prins Cyclization of Z-Vinylsilyl Alcohols.

However, only a few examples of silyl-Prins cyclizations using vinylsilyl alcohols in which the silyl group and the chain bearing the alcohol are attached to the same sp² carbon have been reported to date. Within them, we have recently described an interesting process that implies two new features: the cyclization of the vinylsilyl oxocarbenium ion with the formation of an α-silyl carbocation and an unexpected aryl migration from silicon to carbon. The overall reaction affords 2,4,4,6-tetrasubstituted tetrahydropyrans in a very stereoselective manner (Scheme 2).¹³

Scheme 2. Synthesis of 2,4,4,6-Tetrasubstituted Tetrahydropyrans by Silyl-Prins Cyclization of Vinylsilyl Alcohols.

Results and Discussion

As shown, this unexpected 1,2-silyl to carbon migration was observed when TMSOTf was used as an activator. We then wondered if the same process would occur when using a metal halide activator such as BiCl₃. To study that process, we chose the reaction of vinylsilyl alcohol 1a with cinnamaldehyde, at room temperature, mediated by BiCl₃ (1 equiv). In contrast to the previous results, the reaction in the presence of BiCl₃ cleanly provided 4-chloro-tetrahydropyranyl derivative 2h, in which the silyl group remains in the cycle but not phenyl migration has taken place (Table 1, entry 4). The reaction proceeded with good yield and excellent stereocontrol since a single diastereoisomer is observed.

Table 1. Scope of the BiCl₃-Mediated Silyl-Prins-Cyclization of 1a.

entry	R	time (min)	ratio 2/3a	productb (yield, %)
1	4-MeC6H4	30	75:25	2a + 3a (44)c
2	4-MeOC6H4	30		CMd
3	4-NO2C6H4	40	66:33	2f + 3f (38)c
4	(E)-PhCH=CH	60	>95:5	2h (77)
5	(E)-nPrCH=CH	60		CMd

^aThe ratio of products was determined by ¹H NMR (400 MHz).

^bConditions: 1a (1.0 mmol), aldehyde (1.2 mmol), BiCl₃ (1.0 mmol).

^cOther minor unidentified compounds are found in the reaction mixture.

^dCM stands for the complex mixture.

We then decided to check the scope and generality of this reaction. For that purpose, we used various aryl and vinyl aldehydes. The results are shown in Table 1.

Although the formation of these 4-chlorotetrahydropyran derivatives was very promising, it was clear that the reaction mediated by BiCl₃ failed to provide the products with synthetically useful yields. Inspired by Martín and co-workers’ work,¹⁴ we decided to use TMSCl as a silicon Lewis acid additive which could serve as a chloride source, being now able to employ substoichiometric amounts of BiCl₃. Fortunately, the reaction under BiCl₃ (0.05 equiv) catalysis and in the presence of 1 equiv of TMSCl was shown to be a general and efficient process that provided the desired 4-chloro tetrahydropyrans in high yields and with excellent stereoselectivity. This implies that a catalytic amount of BiCl₃ is able to catalyze the formation of the oxocarbenium ion, while 1 equiv of TMSCl is required to trap the intermediate tetrahydropyranyl carbocation. In Table 2, the scope of the process is shown.

Table 2. Scope of BiCl₃/TMSCl-Mediated Silyl-Prins-Cyclization of 1a^a.

^aDiastereoisomer ratios were determined by integration of separated signals in the ¹H NMR spectra of crude reaction mixtures.

As shown, the reaction with both aromatic (either electron-rich or electron-deficient) and vinylic aldehydes is general and high yielding, providing a single diastereoisomer (2a–2i and 2o–2p). Good yields are also obtained for aliphatic aldehydes (2j–2m), although in some cases slightly diminished stereoselectivity is observed. Under the same conditions, the reaction with cyclohexanone provided in moderate yield, but with excellent stereoselectivity, tetrahydropyran 2n. The relative configuration of stereocenters in tetrahydropyrans 2 was determined on the basis of the NOESY experiment and the measure of coupling constants (Scheme 3).

Scheme 3. Stereochemistry Assignment.

NOESY correlations of Me-Si and both hydrogens at C2 and C6 positions in 2a indicate that the three of them are in an axial conformation. Moreover, the axial position of hydrogens at C2 and C6 was readily confirmed by NOESY correlation between them and by the corresponding coupling constants (J_H2ax-H3ax = 12.0 Hz, and J_H5ax-H6ax = 12.0 Hz).

The mechanism for this process would imply the preferent formation of an E-oxocarbenium anion, which will then undergo 6-endo cyclization to provide an α to silicon tertiary carbocation (more stable than the corresponding primary β carbocation).¹⁵ The final trapping of the tertiary tetrahydropyranyl cation by the chloride would afford the shown product (Scheme 4).

Scheme 4. Mechanism of the BiCl₃-Mediated Silyl-Prins Cyclization of Vinylsilyl Alcohols.

To explain the different outcome of the reaction in the presence of either TMSOTf or BiCl₃, we hypothesized that the approach of the bulky trimethylsiloxide to the tertiary carbocation may be precluded on the steric ground, while a small nucleophile, such as chloride, would have a relatively clear path to attack the tetrahydropyranyl carbocation. However, other stereoelectronic factors (such as the strength of the bond formed) probably also have an important role and further theoretical calculation would be needed to obtain a rationale for the different behavior of both Lewis acids.

Moreover, the high stereoselectivity observed in the process can be rationalized, according to the theoretical studies by Alder on Prins cyclization,¹⁶ by a preferred chair-like transition state in which the substituents in C2 and C6 adopt the most stable equatorial position. The subsequent nucleophilic attack (by the chloride provided by the trimethylsilylchloride) over the intermediate tetrahydropyranyl cation thus obtained will then occur through the less hindered equatorial side (Scheme 4).¹⁷

Although aware of the frequent occurrence of the competitive oxonia-Cope rearrangement in Prins cyclization when the alkenol has an adjacent group to the alcohol able to stabilize the positive charge,^18,19 we tested the reaction of alcohols 1c (R¹ = (E)-PhCH=CH) and 1d (R¹ = 4-ClPh) with phenylacetaldehyde (R² = Ph-CH₂). The reaction gave either a lower yield of the corresponding tetrahydropyran (2o, 37%) or a complex mixture from which it was difficult to isolate 2p.²⁰ Fortunately, the same tetrahydropyranyl derivatives (2o and 2p) could be obtained in high yield and selectivity by exchanging the substituents (R¹ = Ph-CH₂; R² = (E)-PhCH=CH or 4-ClPh) in the alcohol and aldehyde (as shown in Table 1). Thus, the synthetic flexibility of this methodology, as two complementary vinylsilyl alcohol/aldehyde combinations can be explored to produce a specific substituted tetrahydroyranyl derivative, increases the chances of a successful outcome.

In order to show the potential applicability of this procedure, we decided to test a gram-scale experiment, under the standard conditions, as shown in Scheme 5. To our delight, the corresponding polysusbstituted tetrahydropyranyl derivative 2b was obtained in good yield and excellent stereoselectivity.

Scheme 5. Gram-Scale silyl-Prins Cyclization.

To generate further value from this methodology, we needed to be able to control the interconversion of functional groups at the quaternary C4 in a stereoselective manner. For this purpose, we chose a desilylation process. Fortunately, treatment of compound 2n with TBAF provided the corresponding 4-clorotetrahydropyran 4 in high yield and with total retention of the configuration (Scheme 6).²¹ It has to be noticed that a desilylation process at quaternary carbon may be a challenging process, which has been reported to occur with either retention,²² inversion,²³ or loss of stereocontrol.²⁴

Scheme 6. Stereoselective Desilylation Process.

With these promising results in hand, we next decided to apply this methodology to the synthesis of biologically and pharmaceutically active compounds. For that purpose, we chose a known synthetic bioactive molecule 5, related to the structure of naproxen, which exhibits antinociceptive activity.²⁵ The key intermediate to be obtained would be tetrahydropyran 2q, which would be accessed using the described methodology (Scheme 7).

Scheme 7. Retrosynthetic Route for Bioactive Compound 5.

From the two possibilities of accessing 2q, the reaction of alcohol 1e (R¹ = α-naphthyl) with ethyl glyoxylate leads to a complex mixture, from which we could not isolate any cyclic product. However, when the alcohol bears a group R¹ = CO₂Et (1f) and the α-naphthyl moiety is introduced in the aldehyde, the desired heterocycle 2q could be isolated in a satisfying 60% (Scheme 8). Interestingly, a single 2,6-cis-tetrahydropyran 2q was obtained, despite Loh’s report on the formation of 2,6-trans-tetrahydropyranyl derivatives in Prins cyclization when the starting alcohol bears an α-alkoxycarbonyl group.²⁶

Scheme 8. Synthesis of 2,4,4,6-Tetrasubstituted Tetrahydropyrans by Silyl-Prins Cyclization of Vinylsilyl Alcohols.

Once the desired precursor (2q) of bioactive compound 5 was obtained, two further steps (desilylation and reduction of the ester) were needed to synthesize the final target. Since trying to remove the silyl moiety, by the reaction of 2q with TBAF, led to the degradation of the starting material, we decided to apply the reduction step first (Scheme 8). Thus, treatment of 2q with LiAlH₄ produced the hydroxyl derivative 6 in 80% yield. After purification, 6 was subjected to desilylation with excess TBAF to provide the desired bioactive compound 5 in 53% yield and with excellent stereoselectivity.

In conclusion, we have developed a general procedure for the synthesis of polysubstituted halogenated tetrahydropyrans in a one-pot reaction in which tertiary and quaternary stereogenic centers are created with high stereoselectivity. Interestingly, a change in the catalyst employed (from TMSOTf to BiCl₃) has proceeded with a modification of the reaction pathway (from cyclization with tandem silicon to carbon aryl-migration, to cyclization to give an α-silyl carbocation with subsequent stereoselective capture by the Lewis acid counteranion). An interesting methodology has been applied to the synthesis of a known bioactive compound with antinociceptive activity.

Experimental Section

General Information

Unless otherwise noted, experiments were carried out with dry solvents under nitrogen atmosphere. Dichloromethane was dried with preactivated molecular sieves. Flash column chromatography was performed using Silica Gel 60 (230–400 mesh ASTM). Thin layer chromatography (TLC) was performed using an aluminum backed plate, precoated with silica gel (0.20 mm, silica gel 60) with a fluorescent indicator (254 nm) from Macherey. NMR spectra were recorded at nuclear magnetic resonance service of the Laboratory of Instrumental Techniques (L.T.I., www.laboratoriotecnicasinstrumentales.es), University of Valladolid at Varian 400 MHz (1 H, 399.85 MHz; 13C, 100.61 MHz), Varian 500 MHz (¹H, 500.12 MHz; ¹³C, 100.61 MHz) spectrometers at room temperature (25 °C). Chemical shifts (δ) were reported in parts per million (ppm) relative to the residual solvent peaks recorded, rounded to the nearest 0.01 for 1 H-NMR and 0.1 for ¹³C-NMR (reference: CDCl₃ [¹H: 7.26, ¹³C: 77.2]). Spin–spin coupling constants (J) in ¹H-NMR were given in Hz to the nearest 0.1 Hz, and peak multiplicity was indicated as follows s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). ¹³C {H} NMR was recorded with complete proton decoupling. Carbon types, structure assignments, and attribution of peaks were determined from two-dimensional correlation experiments (HSQC, COSY, and HMBC). Relative stereochemistry was assigned based on the 2D-NOE experiments. High-resolution mass spectra (HRMS) were measured at the mass spectrometry service of the Laboratory of Instrumental Techniques, University of Valladolid, using a quadrupole spectrometer equipped with a TOF analyzer, on a UPLC-MS system (UPLC: Waters ACQUITY H-class UPLC; MS: Bruker Maxis Impact) by electrospray ionization (ESI positive and negative).

General Procedure for the BiCl₃/TMSCl-Promoted Cyclization

TMSCl (0.076 mL, 0.6 mmol, 1.2 equiv) was slowly introduced into a suspension of BiCl₃ (7.9 mg, 0.025 mmol, 0.05 equiv) in 4.8 mL of dichloromethane, containing the corresponding aldehyde (0.6 mmol, 1.2 equiv) and cooled to 0 °C. The mixture is stirred for 5 min and a solution of alcohol 1a or 1b (0.5 mmol, 1 equiv) in 0.2 mL of dichloromethane is added dropwise and the reaction is followed by TLC. When starting materials are consumed (typically 30 min–1 h), it is partly evaporated and filtered through a small plug of silica. Volatiles are evaporated under reduced pressure. The crude mixture is purified by column chromatography (mixtures of hexane/ethyl acetate) yielding compounds 2a–p.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-(p-tolyl)tetrahydro-2H-pyran (2a)

Faint yellow oil. According to the general procedure, the title compound 2a was obtained from alcohol 1a (110 mg, 0.500 mmol) and 4-tolualdehyde to give, after column chromatography (hexane/EtOAc: 40:1), a yellow oil (149 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 7.68–7.62 (m, 2H), 7.45–7.40 (m, 3H), 7.11 (s, 4H), 4.14 (dd, J = 12.0, 2.0 Hz, 1H), 3.55–3.44 (m, 1H), 2.47 (dt, J = 13.5, 1.9 Hz, 1H), 2.40 (dt, J = 13.4, 1.9 Hz, 1H), 2.31 (s, 3H), 2.07 (dd, J = 13.5, 12.0 Hz, 1H), 1.90 (dd, J = 13.4, 11.6 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.59 (s, 6H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 138.9, 137.3, 136.9, 134.7, 129.9, 129.0, 128.1, 125.8, 76.9, 71.4, 60.9, 46.9, 46.8, 22.1, 21.1, −3.2 (CH₃Si), −3.6. HRMS (ESI⁺) m/z calcd for C₂₁ClH₂₇NaOSi ([M + Na]⁺): 381.1412, found 381.1420.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran (2b)

Yellowish solid (mp: 72.3–73.7 °C). According to the general procedure, the title compound 2b was obtained from alcohol 1a (110 mg, 0.500 mmol) and anisaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellowish solid (152 mg, 81%). ¹H NMR (400 MHz, CDCl₃) δ 7.66–7.59 (m, 2H), 7.45–7.36 (m, 3H), 7.17–7.09 (m, 2H), 6.88–6.78 (m, 2H), 4.10 (dd, J = 11.9, 2.0 Hz, 1H), 3.76 (s, 3H), 3.53–3.41 (m, 1H), 2.44 (d, J = 13.5 Hz, 1H), 2.38 (d, J = 13.4 Hz, 1H), 2.06 (dd, J = 13.5, 11.9 Hz, 1H), 1.88 (dd, J = 13.4, 11.6 Hz, 1H), 1.14 (d, J = 6.1 Hz, 3H), 0.57 (s, 6H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 159.1 (C, p-OMe), 137.0, 134.7, 134.1, 129.9, 128.1, 127.1, 113.8, 76.6, 71.4, 60.9, 55.3, 46.9, 46.8, 22.1, −3.2, −3.6. HRMS (ESI⁺) m/z calcd for C₂₁ClH₂₇NaO₂Si ([M + Na]⁺): 397.1361, found 397.1371.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-6-(4-hydroxy-3-methoxyphenyl)-2-methyltetrahydro-2H-pyran (2c)

Off-white solid (mp: 78.8–80.8 °C). According to the general procedure, the title compound 2c was obtained from alcohol 1a (110 mg, 0.500 mmol) and vanillin to give, after column chromatography (hexane/EtOAc: 10:1), an off-white solid (137 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 7.67–7.60 (m, 2H), 7.46–7.39 (m, 3H), 6.86–6.80 (m, 1H), 6.78–6.73 (m, 1H), 6.68–6.62 (m, 1H), 5.54 (s, 1H, OH), 4.08 (d, J = 11.6 Hz, 1H), 3.89 (s, 3H), 3.54–3.44 (m, 1H), 2.45 (d, J = 13.8 Hz, 1H) 2.40 (d, J = 13.4 Hz, 1H), 2.07 (dd, J = 13.8, 11.6 Hz, 1H), 1.90 (dd, J = 13.4, 12.0 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.59 (s, 6H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 146.5, 145.2, 136.9, 134.7, 133.9, 130.0, 128.1, 119.1, 114.0, 108.4, 77.0, 71.5, 60.9, 55.9, 46.9, 46.8, 22.1, −3.1, −3.6. HRMS (ESI⁺) m/z calcd for C₂₁ClH₂₇NaO₃Si ([M + Na]⁺): 413.1310, found 413.1313.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-(4-chlorophenyl)-6-methyltetrahydro-2H-pyran (2d)

Faint yellow liquid. According to the general procedure, the title compound 2d was obtained from alcohol 1a (110 mg, 0.500 mmol) and 4-chlorobenzaldehyde to give, after column chromatography (hexane/EtOAc: 25:1), a yellow oil (138 mg, 73%). ¹H NMR (500 MHz, CDCl₃) δ 7.66–7.61 (m, 2H, Ph), 7.45–7.39 (m, 3H, Ph), 7.27 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 4.12 (dd, J = 12.0, 2.0 Hz, 1H), 3.53–3.45 (m, 1H), 2.48–2.37 (m, 2H), 1.99 (dd, J = 13.5, 12.0 Hz, 1H), 1.89 (dd, J = 13.3, 11.7 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H, CH₃), 0.59 (s, 3H, CH₃-Si), 0.59 (s, 3H, CH₃-Si). ¹³C {H} NMR (101 MHz, CDCl₃) δ 140.6, 137.0, 134.8, 133.4, 130.2, 128.7, 127.3, 76.4, 71.7, 60.6, 47.1, 46.9, 22.2, −3.1, −3.5. HRMS (ESI⁺) m/z calc. For C₂₀H₂₄Cl₂NaOSi ([M + Na]⁺): 401.0866, found 401.0872.

(2S*,4R*,6S*)-2-(6-Bromobenzo[d][1,3]dioxol-5-yl)-4-chloro-4-(dimethyl(phenyl)silyl)-6-methyltetrahydro-2H-pyran (2e)

Yellowish solid (mp: 105.6–107.7 °C). According to the general procedure, the title compound 2e was obtained from alcohol 1a (110 mg, 0.500 mmol) and 6-bromopiperonal to give, after column chromatography (hexane/EtOAc: 30:1), a colorless oil (147 mg, 63%). ¹H NMR (500 MHz, CDCl₃) δ 7.72–7.68 (m, 2H), 7.43–7.35 (m, 3H), 7.04 (s, 1H), 6.93 (s, 1H), 5.95–5.93 (m, 2H), 4.63 (dd, J = 11.9, 2.0 Hz, 1H), 3.60–3.51 (m, 1H), 2.62 (dt, J = 13.5, 2.0 Hz, 1H), 2.36 (dt, J = 13.4, 1.9 Hz, 1H), 1.84 (dd, J = 13.4, 11.6 Hz, 1H), 1.79 (dd, J = 13.5, 11.9 Hz, 1H), 1.18 (d, J = 6.1 Hz, 3H), 0.66 (s, 3H), 0.62 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 147.8, 147.6, 136.1, 135.0, 134.9, 129.8, 127.8, 112.1, 111.5, 107.6, 101.7, 76.0, 71.3, 60.5, 46.5, 45.6, 22.0, −2.6, −2.8. HRMS (ESI⁺) m/z calcd for C₂₁BrClH₂₄NaO₃Si ([M + Na]⁺): 489.0259, found 489.0266.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-(4-nitrophenyl)tetrahydro-2H-pyran (2f)

Faint yellow oil. According to the general procedure, the title compound 2f was obtained from alcohol 1a (110 mg, 0.500 mmol) and 4-nitrobenzaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (78 mg, 40%). ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.10 (m, 2H), 7.68–7.59 (m, 2H), 7.46–7.40 (m, 3H), 7.38–7.32 (m, 2H), 4.20 (dd, J = 12.2, 2.0 Hz, 1H), 3.56–3.45 (m, 1H), 2.51–2.38 (m, 2H), 1.98–1.84 (m, 2H), 1.18 (d, J = 6.1 Hz, 3H), 0.60 (s, 3H), 0.59 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 149.2, 147.2, 136.7, 134.6, 130.2, 128.3, 126.3, 123.6, 75.9, 71.6, 59.9, 46.8, 46.6, 21.9, −3.3, −3.7. HRMS (ESI⁺) m/z calcd for C₂₀ClH₂₄NNaO₃Si ([M + Na]⁺): 412.1106, found 412.1112.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-phenyltetrahydro-2H-pyran (2g)

Faint yellow oil. According to the general procedure, the title compound 2g was obtained from alcohol 1a (110 mg, 0.500 mmol) and benzaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (103 mg, 60%). ¹H NMR (500 MHz, CDCl₃) δ 7.67–7.62 (m, 2H), 7.45–7.41 (m, 3H), 7.32–7.28 (m, 2H), 7.25–7.20 (m, 3H), 4.17 (dd, J = 12.0, 2.0 Hz, 1H), 3.54–3.46 (m, 1H), 2.49 (dt, J = 13.6, 2.0 Hz, 1H), 2.41 (dt, J = 13.4, 1.9 Hz, 1H), 2.06 (dd, J = 13.6, 12.0 Hz, 1H), 1.91 (dd, J = 13.4, 11.7 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.60 (s, 3H), 0.59 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 142.0, 137.0, 134.8, 130.0, 128.4, 128.2, 127.7, 125.8, 77.0, 71.5, 60.9, 47.0, 46.9, 22.1, −3.2, −3.5. HRMS (ESI⁺) m/z calcd for C₂₀ClH₂₅NaOSi ([M + Na]⁺): 367.1255, found 367.1260.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-((E)-styryl)tetrahydro-2H-pyran (2h)

Yellowish viscous oil. According to the general procedure, the title compound 2h was obtained from alcohol 1a (110 mg, 0.500 mmol) and trans-cinnamaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellowish solid (143 mg, 77%). ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.58 (m, 2H), 7.44–7.38 (m, 3H), 7.37–7.32 (m, 2H), 7.32–7.26 (m, 2H), 7.26–7.19 (m, 1H), 6.45 (d, J = 16.0 Hz, 1H), 6.08 (dd, J = 16.0, 6.4 Hz, 1H), 3.84 (dd, J = 11.8, 6.4 Hz, 1H), 3.55–3.44 (m, 1H), 2.43 (d, J = 13.4 Hz, 1H), 2.35 (d, J = 13.5 Hz, 1H), 1.98 (dd, J = 13.4, 11.8 Hz, 1H), 1.84 (dd, J = 13.5, 11.6 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H), 0.59 (s, 3H), 0.58 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.8, 136.5, 134.7, 131.0, 130.0, 129.3, 128.5, 128.1, 127.7, 126.5, 75.6, 71.0, 60.4, 46.7, 44.8, 22.0, −3.2, −3.5. HRMS (ESI⁺) m/z calcd for C₂₂ClH₂₇NaOSi ([M + Na]⁺): 393.1412, found 393.1406.

(2S*,4R*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-((E)-pent-1-en-1-yl)tetrahydro-2H-pyran (2i)

Faint yellow oil. According to the general procedure, the title compound 2i was obtained from alcohol 1a (110 mg, 0.500 mmol) and trans-2-hexen-1-al to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (140 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 7.58–7.54 (m, 2H), 7.40–7.34 (m, 3H), 5.53 (dtd, J = 15.5, 6.6, 1.0 Hz, 1H), 5.33 (ddt, J = 15.5, 6.7, 1.5 Hz, 1H), 3.62 (dd, J = 11.8, 6.7 Hz, 1H), 3.41–3.30 (m, 1H), 2.32–2.26 (m, 2H), 1.99–1.92 (m, 2H), 1.86 (dd, J = 13.7, 11.8 Hz, 1H), 1.76 (dd, J = 13.6, 11.6 Hz, 1H), 1.41–1.32 (m, 2H), 1.10 (d, J = 6.1 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.54 (s, 3H) 0.53 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.8, 134.7, 132.9, 130.1, 129.8, 128.0, 75.8, 70.8, 60.7, 46.7, 45.1, 34.3, 22.1, 22.0, 13.7, −3.1, −3.5. HRMS (ESI⁺) m/z calcd for C₁₉ClH₂₉NaOSi ([M + Na]⁺): 359.1568, found 359.1573.

(2R*,4r*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2,6-dimethyltetrahydro-2H-pyran (2j)

Faint yellow oil. According to the general procedure, the title compound 2j was obtained from alcohol 1a (110 mg, 0.500 mmol) and acetaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (76 mg, 54%) as a mixture of stereoisomers. ¹H NMR (400 MHz, CDCl₃) δ 7.61–7.52 (m, 2H), 7.44–7.33 (m, 3H), 3.39–3.31 (m, 2H), 2.29 (d, J = 13.8 Hz, 2H), 1.75 (dd, J = 13.8, 11.7 Hz, 1H), 1.10 (d, J = 6.2, 6H), 0.53 (s, 6H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.6, 134.7, 129.8, 127.9, 70.9, 60.7, 46.6, 22.0, −3.1. HRMS (ESI⁺) m/z calcd for C₁₅ClH₂₃NaOSi ([M + Na]⁺): 305.1099, found 305.1100.

(2R*,4s*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2,6-dimethyltetrahydro-2H-pyran (3j) (Minor) (Distinguishable Signals)

¹H NMR (400 MHz, CDCl₃) δ 7.61–7.52 (m, 2H), 7.44–7.33 (m, 3H), 4.05–3.97 (m, 2H), 1.78–1.72 (m, 2H), 1.53–1.46 (m, 2H), 1.13–1.11 (m, 6H), 0.44 (s, 6H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 134.8, 129.7, 127.7, 67.5, 62.8, 40.5, 21.5, −6.5.

(2R*,4R*,6S*)-2-Benzyl-4-chloro-4-(dimethyl(phenyl)silyl)-6-methyltetrahydro-2H-pyran (2k)

Colorless oil. According to the general procedure, the title compound 2k was obtained from alcohol 1a (110 mg, 0.500 mmol) and phenylacetaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a colorless oil (99 mg, 55%) as a mixture of stereoisomers. ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.22 (m, 7H), 7.15–7.07 (m, 3H), 3.44–3.32 (m, 2H), 2.90 (dd, J = 13.2, 5.2 Hz, 1H), 2.50 (dd, J = 13.2, 8.4 Hz, 1H), 2.32 (d, J = 13.4 Hz, 1H), 2.24 (d, J = 13.3 Hz, 1H), 1.80 (dd, J = 13.4, 11.7 Hz, 1H), 1.71 (dd, J = 13.3, 11.6 Hz, 1H), 1.12 (d, J = 6.1 Hz, 3H), 0.45 (s, 3H), 0.38 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 137.7, 136.5, 134.7, 129.6, 129.4, 128.3, 127.9, 126.4, 76.1, 71.2, 60.9, 46.9, 43.8, 42.8, 22.0, −3.0, −3.8. HRMS (ESI⁺) m/z calcd for C₂₁ClH₂₇NaOSi ([M + Na]⁺): 381.1412, found 381.1418.

(2R*,4r*,6S*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2,6-dimethyltetrahydro-2H-pyran (3k) (Minor) (Distinguishable Signals)

¹H NMR (400 MHz, CDCl₃) δ 4.13–3.94 (m, 2H), 2.83 (dd, J = 13.6, 6.4 Hz, 1H), 2.57 (dd, J = 13.6, 5.0 Hz, 1H), 1.58–1.48 (m, 2H), 1.12–1.09 (m, 3H), 0.42 (s, 3H), 0.41 (s, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 138.6, 134.8, 129.7, 129.3, 128.1, 127.8, 126.1, 72.4, 67.6, 62.5, 42.2, 40.6, 38.6, 21.3, −6.5.

(2S*,4R*,6R*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methyl-6-propyltetrahydro-2H-pyran (2l)

Faint yellow liquid. According to the general procedure, the title compound 2l was obtained from alcohol 1a (110 mg, 0.500 mmol) and butyraldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (86 mg, 55%). ¹H NMR (500 MHz, CDCl₃) δ 7.58–7.55 (m, 2H, Ph), 7.43–7.36 (m, 3H, Ph), 3.35–3.28 (m, 1H), 3.19–3.14 (m, 1H), 2.31 (d, J = 13.4 Hz, 2H), 1.77 (dd, J = 13.4, 11.9 Hz, 1H), 1.73 (dd, J = 13.4, 11.7 Hz, 1H), 1.46–1.40 (m, 1H), 1.35–1.23 (m, 3H), 1.10 (d, J = 6.1 Hz, 3H, CH₃), 0.83 (t, J = 7.1 Hz, 3H, CH₃), 0.53 (s, 6H, Si-CH₃). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.9, 134.9, 129.9, 128.1, 74.8, 71.1, 61.3, 47.2, 45.1, 38.6, 22.2, 18.8, 14.1, −2.9, −3.0. HRMS (ESI⁺) m/z calcd for C₁₇H₂₇ClNaOSi ([M + Na]⁺): 333.1412, found 333.1420.

(2S*,4R*,6S*)-4-Chloro-2-cyclohexyl-4-(dimethyl(phenyl)silyl)-6-methyltetrahydro-2H-pyran (2m)

Faint yellow oil. According to the general procedure, the title compound 2m was obtained from alcohol 1a (110 mg, 0.500 mmol) and cyclohexane carboxaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (105 mg, 60%). ¹H NMR (500 MHz, CDCl₃) δ 7.58–7.53 (m, 2H, Ph), 7.42–7.34 (m, 3H, Ph), 3.33–3.25 (m, 1H), 2.92 (ddd, J = 11.9, 6.6, 1.6 Hz, 1H), 2.36–2.26 (m, 2H), 1.83–1.77 (m, 1H, Cy) 1.76–1.71 (m, 2H), 1.70–1.59 (m, 4H, Cy), 1.32–1.23 (m, 1H, Cy), 1.23–1.11 (m, 3H, Cy), 1.09 (d, J = 6.2 Hz, 3H, CH₃), 0.96–0.87 (m, 1H, Cy), 0.87–0.78 (m, 1H, Cy), 0.53 (s, 6H, Si-CH₃). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.9, 134.9, 129.9, 128.0, 79.3, 71.2, 62.0, 47.4, 43.1, 42.0, 29.3, 28.5, 26.7, 26.2, 26.1, 22.1, −2.8, −3.0. HRMS (ESI⁺) m/z calcd for C₂₀H₃₁ClNaOSi ([M + Na]⁺): 373.1725, found 373.1729.

(2S*,4R*)-4-Chloro-4-(dimethyl(phenyl)silyl)-2-methy-1-oxaspiro[5.5]undecane (2n)

Faint yellow oil. According to the general procedure, the title compound 2n was obtained from alcohol 1a (110 mg, 0.500 mmol) and cyclohexanone to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (67 mg, 40%). ¹H NMR (500 MHz, CDCl₃) δ 7.60–7.55 (m, 2H, Ph), 7.43–7.34 (m, 3H, Ph), 3.47–3.37 (m, 1H), 2.19 (dd, J = 14.7, 4.7 Hz, 1H), 1.98 (d, J = 15.1 Hz, 1H), 1.93–1.89 (m, 1H), 1.91 (dd. J = 14.7, 9.4 Hz, 1H), 1.78 (d, J = 15.1 Hz, 1H), 1.71–1.63 (m, 1H), 1.62–1.57 (m, 1H), 1.53–1.47 (m, 2H, Cy), 1.45–1.36 (m, 2H, Cy), 1.31–1.26 (m, 2H, Cy), 1.22–1.19 (m, 1H, Cy), 1.15 (d, J = 6.2 Hz, 3H, CH₃), 0.46 (s, 6H, Si-CH₃). ¹³C {H} NMR (101 MHz, CDCl₃) δ 135.6, 134.9, 129.8, 127.9, 73.1, 63.4, 59.0, 42.1, 42.0, 40.3, 36.8, 25.9, 23.1, 22.4, 22.3, −5.1, −5.5. HRMS (ESI⁺) m/z calcd for C₁₉H₂₉ClNaOSi ([M + Na]⁺): 359.1568, found 359.1578.

(2R*,4S*,6R*)-2-Benzyl-4-chloro-4-(dimethyl(phenyl)silyl)-6-((E)-styryl)tetrahydro-2H-pyran (2o)

Faint yellow oil. According to the general procedure, the title compound 2o was obtained from alcohol 1b (148 mg, 0.500 mmol) and trans-cinnamaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (179 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.12 (m, 15H, Ph), 6.48 (d, J = 16.0 Hz, 1H, Ph-CH=), 6.10 (dd, J = 16.0, 6.1 Hz, 1H), 3.89 (dd, J = 12.0, 6.1 Hz, 1H), 3.53–3.45 (m, 1H), 2.98 (dd, J = 13.2, 5.1 Hz, 1H), 2.57 (dd, J = 13.2, 8.4 Hz, 1H), 2.45 (d, J = 13.5 Hz, 1H), 2.31 (d, J = 13.6 Hz, 1H), 2.02 (dd, J = 13.5, 12.0 Hz, 1H), 1.80 (dd, J = 13.6, 11.7 Hz, 1H), 0.52 (s, 3H, SiCH₃), 0.40 (s, 3H, SiCH₃). ¹³C {H} NMR (101 MHz, CDCl₃) δ 137.6, 136.7, 136.5, 134.7, 130.9, 129.9, 129.5, 129.2, 128.5, 128.4, 128.1, 127.7, 126.5, 126.4, 76.1, 75.7, 60.6, 45.1, 43.9, 42.8, −3.2, −4.1. HRMS (ESI⁺) m/z calcd for C₂₈H₃₁ClNaOSi ([M + Na]⁺): 469.1725, found 469.1733.

(2S*,4R*,6S*)-2-Benzyl-4-chloro-4-(dimethyl(phenyl)silyl)-6-(4-chlorophenyl)tetrahydro-2H-pyran (2p)

Faint yellow oil. According to the general procedure, the title compound 2p was obtained from alcohol 1b (148 mg, 0.500 mmol) and 4-chlorobenzaldehyde to give, after column chromatography (hexane/EtOAc: 30:1), a yellow oil (189 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.25 (m, 10H), 7.17–7.13 (m, 4H), 4.15 (dd, J = 12.0, 2.0 Hz, 1H), 3.58–3.51 (m, 1H), 2.94 (dd, J = 13.3, 5.2 Hz, 1H), 2.62 (dd, J = 13.3, 8.0 Hz, 1H), 2.48 (dt, J = 13.5, 2.0 Hz, 1H), 2.35 (dt, J = 13.4, 2.0 Hz, 1H), 2.01 (dd, J = 13.5, 12.0 Hz, 1H), 1.85 (dd, J = 13.4, 11.7 Hz, 1H), 0.53 (s, 3H, CH₃), 0.42 (s, 3H, CH₃). ¹³C {H} NMR (101 MHz, CDCl₃) δ 140.4, 137.5, 136.8, 134.7, 133.2, 130.0, 129.5, 128.5, 128.3, 128.2, 127.0, 126.5, 76.4, 76.3, 60.6, 47.2, 43.9, 42.7, −3.3, −4.1. HRMS (ESI⁺) m/z calcd for C₂₆H₂₈Cl₂NaOSi ([M + Na]⁺): 477.1179, found 477.1175.

Synthesis of Compound 4 by the Stereoselective Desilylation Process

Over a suspension of 1.734 g TBAF (15% in alumina, 0.996 mmol, 3 equiv) in 6 mL THF, at room temperature and open to air, a solution of 123 mg (0.332 mmol, 1 equiv) of 2h in 0.4 mL THF is added dropwise, the system is closed, and the mixture is stirred overnight. The reaction is quenched with 20 mL of water, layers are separated and the aqueous layer is extracted 3 times with diethyl ether. The combined organic extracts are washed with brine, dried over MgSO₄, filtered, and evaporated under reduced pressure. After purification by flash column chromatography (hexane-acetate 20:1) 68 mg (0.287 mmol, 87%) of compound 4 are obtained as a yellowish oil.

(2R*,4S*,6R*)-4-Chloro-2-methyl-6-((E)-styryl)tetrahydro-2H-pyran

The spectroscopic data are in accordance with those reported in the literature.²⁷¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 2H), 7.32–7.26 (m, 2H), 7.25–7.19 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.18 (dd, J = 16.0, 6.2 Hz, 1H), 4.07 (tt, J = 11.8, 4.5 Hz, 1H), 4.04–3.97 (m, 1H, overlapped), 3.62–3.51 (m, 1H), 2.31–2.21 (m, 1H), 2.20–2.10 (m, 1H), 1.71 (dd, J = 13.6, 11.8 Hz, 1H), 1.56 (dd, J = 13.5, 11.8 Hz, 1H), 1.28 (d, J = 6.2 Hz, 3H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.5, 131.1, 128.7, 128.5, 127.7, 126.5, 77.1, 72.8, 55.3, 43.8, 42.2, 21.5. HRMS (ESI⁺) m/z calcd for C₁₄H₁₇ClKO ([M + K]⁺): 275.0605, found 275.0817.

Synthesis of Antinociceptive Compound 5

Synthesis of Tetrahydropyran 2q

To a suspension of BiCl₃ (59 mg, 0.187 mmol, 0.05 equiv) in 30 mL of dichloromethane, 1-naphthaldehyde (4.52 mmol, 1.2 equiv) is added. Then the suspension is cooled to 0 °C and TMSCl (0.95 mL, 7.54 mmol, 1.2 equiv) is added dropwise. The mixture is stirred for 5 min and a solution of 1.049 g of alcohol 1f (3.77 mmol, 1 equiv) in 4 mL of dichloromethane is added dropwise and the reaction is followed by TLC. When starting materials are consumed, the reaction is quenched with NaOH (aq) 2 M solution. The aqueous layer is extracted three times with dichloromethane. Combined organic extracts are washed with brine, dried over MgSO₄, and filtered and volatiles are evaporated under reduced pressure. The crude mixture is purified by column chromatography (hexane/ethyl acetate 10:1) yielding 1.02 g (2.25 mmol, 60%) of compound 2q as a yellow oil.

Ethyl (2S*,4R*,6R*)-4-Chloro-4-(dimethyl(phenyl)silyl)-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-carboxylate (2q)

¹H NMR (400 MHz, CDCl₃) δ 7.86–7.60 (m, 6H), 7.51–7.42 (m, 6H), 4.94 (d, J = 11.8 Hz, 1H), 4.28–4.17 (m, 3H), 2.86 (d, J = 13.5 Hz, 1H), 2.73 (d, J = 13.9 Hz, 1H), 2.38–2.28 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H, CH₃), 0.71 (s, 3H, CH₃Si) 0.68 (s, 3H, CH₃Si). ¹³C {H} NMR (101 MHz, CDCl₃) δ 169.9, 136.5, 134.8, 133.6, 130.4, 130.1, 128.9, 128.5, 128.3, 128.1, 125.8, 125.6, 125.4, 123.7, 122.9, 74.6, 73.9, 61.3, 59.7, 45.6, 41.3, 14.2, −3.4, −3.7. HRMS (ESI⁺) m/z calcd for C₂₆H₃₀ClO₃Si ([M + H]⁺): 453.1647, found 453.1655.

Synthesis of Tetrahydropyran 6

Over a suspension of 105 mg of LiAlH₄ (2.775 mmol, 3.0 equiv) in 8.8 mL of dry ethyl ether at 0 °C, a solution of 2q (419 mg, 0.925 mmol, 1.0 equiv) in 0.5 mL dry ethyl ether is added dropwise. When starting material is consumed (typically 1 h) the reaction is quenched with HCl 1 M. Layers are separated, and the aqueous layer is extracted 3 times with diethyl ether. The combined organic extracts are washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. After purification by flash column chromatography (hexane-acetate 4:1) compound 6 was isolated as a colorless oil (304 mg, 0.74 mmol, 80%).

((2S*,4R*,6R*)-4-Chloro-4-(dimethylphenylsilyl)-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-yl)methanol (6)

Colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.87–7.67 (m, 5H), 7.58–7.55 (m, 1H), 7.50–7.42 (m, 6H), 4.99 (dd, J = 12.0, 1.9 Hz, 1H), 3.77–3.72 (m, 1H), 3.66–3.54 (m, 2H), 2.74 (dt, J = 13.7, 1.9 Hz, 1H), 2.46–2.36 (m, 2H), 2.08 (dd, J = 13.5, 12.1 Hz, 1H), 1.92 (dd, J = 8.5, 4.6 Hz, 1H, OH), 0.68 (s, 3H, CH₃-Si), 0.66 (s, 3H, CH₃-Si). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.7, 136.5, 134.9, 133.7, 130.5, 130.1, 128.9, 128.5, 128.3, 126.0, 125.5, 125.4, 123.3, 123.0, 76.2, 73.5, 66.1, 60.7, 45.4, 40.7, −3.2, −3.3. HRMS (ESI⁺) m/z calcd for C₂₄H₂₇ClNaO₂Si ([M + Na]⁺): 433.1361, found 433.1366.

Synthesis of Antinociceptive Compound 5

Over a suspension of 3.05 g TBAF (15% in alumina, 1.75 mmol, 4 equiv) in 1.5 mL THF, at room temperature and open to air, a solution of 180 mg (0.438 mmol, 1 equiv) of 6 in 0.3 mL THF is added dropwise, the system is closed, and the mixture is stirred overnight. The reaction is quenched with 20 mL of water, layers are separated and the aqueous layer is extracted 3 times with diethyl ether. The combined organic extracts are washed with brine, dried over MgSO₄, filtered, and evaporated under reduced pressure. After purification by flash column chromatography (hexane-acetate 2:1), 64 mg (0.232 mmol, 53%) of compound 5 are obtained as a yellowish solid (mp: 80.1–82.6 °C).

((2S*,4R*,6R*)-4-Chloro-6-(naphthalen-1-yl)tetrahydro-2H-pyran-2-yl)methanol (5)

The spectroscopic data are in accordance with the literature.^26,281H NMR (400 MHz, CDCl₃) δ 8.02–7.98 (m, 1H), 7.90–7.80 (m, 2H), 7.64–7.60 (m, 1H), 7.57–7.46 (m, 3H), 5.15 (dd, J = 11.3, 1.9 Hz, 1H), 4.35 (tt, J = 11.8, 4.5 Hz, 1H, CH-Cl), 3.91–3.82 (m, 1H), 3.79–3.67 (m, 2H), 2.65–2.57 (m, 1H), 2.29–2.22 (m, 1H), 2.11 (dt, J = 13.1, 11.6 Hz, 1H), 2.06–2.03 (m, 1H, OH), 1.84 (dt, J = 12.8, 11.6 Hz, 1H). ¹³C {H} NMR (101 MHz, CDCl₃) δ 136.1, 133.8, 130.4, 129.0, 128.6, 126.3, 125.7, 125.4, 123.3, 122.9, 78.0, 75.7, 65.7, 55.4, 42.9, 38.1. HRMS (ESI⁺) m/z calcd for C₁₆H₁₇ClNaO₂ ([M + Na]⁺): 299.0809, found 299.0818.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00050.

• The synthetic procedure to prepare starting vinylsilyl alcohols and copies of NMR spectra (1D and 2D) for new compounds (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.