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

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 plocamiopyranoid 4 or anverene E, 5 monoterpenes isolated from Antarctica red algae of the genus Plocamium cartilagineum which show promising pharmaceutical properties (Figure 1).
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 acidcatalyzed 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).
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 sp 2 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

■ 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 BiCl 3 . To study that process, we chose the reaction of vinylsilyl alcohol 1a with cinnamaldehyde, at room temperature, mediated by BiCl 3 (1 equiv). In contrast to the previous results, the reaction in the presence of BiCl 3 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.
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 BiCl 3 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 BiCl 3 . Fortunately, the reaction under BiCl 3 (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 BiCl 3 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.
As shown, the reaction with both aromatic (either electronrich 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).
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).
To explain the different outcome of the reaction in the presence of either TMSOTf or BiCl 3 , 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  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 (R 1 = (E)-PhCH�CH) and 1d (R 1 = 4-ClPh) with phenylacetaldehyde (R 2 = Ph-CH 2 ). 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 (R 1 = Ph-CH 2 ; R 2 = (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.
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

Scheme 3. Stereochemistry Assignment
process, which has been reported to occur with either retention, 22 inversion, 23 or loss of stereocontrol. 24 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).
From the two possibilities of accessing 2q, the reaction of alcohol 1e (R 1 = 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 R 1 = CO 2 Et (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 2,6trans-tetrahydropyranyl derivatives in Prins cyclization when the starting alcohol bears an α-alkoxycarbonyl group. 26 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 LiAlH 4 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 BiCl 3 ) 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 ( 1 H, 500.12 MHz; 13 C, 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 13 C-NMR (reference: CDCl 3 [ 1 H: 7.26, 13 C: 77.2]). Spin−spin coupling constants (J) in 1 H-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). 13 C {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 BiCl 3 /TMSCl-Promoted Cyclization. TMSCl (0.076 mL, 0.6 mmol, 1.2 equiv) was slowly introduced into a suspension of BiCl 3 (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.
The synthetic procedure to prepare starting vinylsilyl alcohols and copies of NMR spectra (1D and 2D)  The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.