Intramolecular Cyclization of Alkenyl Alcohols: Towards the Synthesis of Oxacycles

The presence of tetrahydropyrans and other sized oxacycles in natural products with interesting pharmacological properties has prompted researchers to try to develop new strategies for their selective synthesis. Moreover, these methodologies enable the introduction of structural modifications in the molecule for the synthesis of analogues with potential biological activity. An attractive atom economy process for the synthesis of these scaffolds is the intramolecular hydroalkoxylation of alkenes. However, this method has several drawbacks (such as the lack of generality and the presence of multiple side reactions) which have diminished its development. For many years, our research group has been devoted to developing different strategies for the regio- and stereoselective synthesis of oxygen and nitrogen heterocycles. Herein, we present our results on the effective acid catalyzed cyclization of alkenyl alcohols which bear a silyl group in their structure. As we will show, the presence of the silicon group is necessary for the cyclization to take place. Moreover, the cyclization towards tetrahydropyrans occurs with high stereoselectivity.


Introduction
Tetrahydropyrans are very important organic molecules which occur in a variety of bioactive natural products. An example of natural compound containing tetrahydropyrans is erythromycin (Figure 1), an antibiotic macrolide that decreases bacteria protein production [1]. This antibiotic was collected from bacteria Saccharopolyspora erythraea and is used to treat skin and respiratory infections produced by bacteria such as Streptococcus and Staphylococcus. The importance of these natural products is based on their interesting properties. However, due to their low availability in nature, many research groups have developed synthetic routes to access this type of heterocycle. In addition, synthesizing a molecule has the great advantage of introducing different substituents that modify the main structural core in order to create analogues with potential biological activity.   Different routes have been proposed for the stereoselective synthesis of tetrahydropyrans, some of them based on ring formation by nucleophilic substitution, annulations with epoxides, or alkene-mediated cyclizations [2].
However, despite its simplicity and atom economy efficiency, very few reported methods are based on the intramolecular cyclization of an alkenol in the presence of Brønsted [3] or Lewis [4] acids. In order to overcome the lack of generality (and frequent side reactions that result in low yields) of this type of cyclization [5], we herein propose the use of organosilanes to reduce the undesirable reactions of this process [6]. In this paper, we present a regio-and stereoselective methodology for the synthesis of tetrahydropyrans based on an intramolecular acid catalyzed cyclization of alkenyl alcohols which bear a silyl group [7].

General Procedure of Silylcupration of Alkynes and Reaction with Α,Β-Unsaturated Ketone
To a suspension of CuCN (12 mmol) in dry tetrahydrofuran (8 mL), 12 mmol of phenyldimethylsilyllithium were added and the mixture stirred at 0 °C for 30 min. The solution was then cooled to −40 °C and 12 mmol of the alkyne were added. After 1 h at this temperature, BF3.Et2O was added and the solution stirred for 10 min. The ketone (8.4 mmol) was then dropped in and the mixture stirred at −40 °C for 1 h. After warming to 0 °C, the mixture was quenched with a saturated solution of NH4Cl/NH3. The aqueous layer was extracted three times with Et2O. Organic layers, together, were washed with saturated solution of NH4Cl/NH3; dried over MgSO4, filtered, and evaporated in vacuo. Products were purified by flash chromatography (hexane/EtOAc 20:1) to give:

Synthesis of Alkenyl Ketones
Vinylmagnesiumbromide (9 mmol) was added for 10 min to a solution of CuI (3 mmol) in dry THF (40 mL) and the mixture stirred under N2 at −5 °C for 15 min. Then, the reaction mixture was cooled to −30 °C and a solution of the ketone (3 mmol) in dry THF (10 mL) was slowly added for 1 h. Thirty minutes after the addition is completed the reaction was quenched with 20 mL of a saturated solution of NH4Cl. The aqueous layer was extracted three times with Et2O. Organic layers, together, were washed with saturated solution of NH4Cl, first, and NaCl, second; dried over MgSO4, filtered, and evaporated in vacuo. Products were purified by flash chromatography (hexane/EtOAc 10:1) to give:

General Procedure for the Synthesis of Alkenyl Epoxides
To a solution of trimethylsulfonium iodide (2 mmol) in dry THF (15 mL), n-BuLi (2 mmol) was added dropwise and the mixture was stirred under N2 at 0 °C for 1 h. Then, a solution of the ketone (1.35 mmol) in dry THF (10 mL) was added. The reaction was quenched with saturated solution of NaCl (15 mL). The aqueous layer was extracted three times with Et2O. Organic layers were washed with a saturated solution of NaCl; dried over MgSO4, filtered, and evaporated in vacuo. Products were purified by flash chromatography (hexane/EtOAc 20:1) to give:

Procedure of Synthesis of Primary Alcohols
A solution of the epoxide (0.65 mmol) in dry hexane (1 mL) was added to a solution of triphenylphosphine (0.078 mmol) in dry hexane (10 mL). Then, trimethylaluminium (1.95 mmol) was added dropwise and the reaction stirred for 1 h. The reaction was then quenched with a saturated solution of NaCl (10 mL). The aqueous layer was extracted three times with Et2O. Organic layers were washed with saturated solution of NaCl; dried over MgSO4, filtered, and evaporated in vacuo. Stable products were purified by flash chromatography (hexane/EtOAc 10:1) and characterized by spectroscopy techniques to give.

Synthesis of Tetrahydropyrans
The acid was added to a stirred solution of one of the previous synthesized alcohols (0.3 mmol) in dry dichloromethane (5 mL). The reaction progress was followed by TLC (thin layer chromatography) When the reaction was over, it was quenched with a saturated solution of NaCl (5mL). The aqueous layer was extracted three times with Et2O. Organic layers were washed with saturated solution of NaCl; dried over MgSO4, filtered, and evaporated in vacuo. Products were purified by flash chromatography (hexane/EtOAc 20:1) and characterized by spectroscopy techniques to give:

Results and Discussion
The vinylsilyl alcohols needed for the synthesis of tetrahydropyrans were prepared in three steps with an initial silylcupration of alkynes followed by reaction with α,β-unsaturated ketones. The subsequent preparation of the epoxide derivative was then followed by the opening of the epoxide to obtain the primary alcohol.

Silylcupration of Alkynes and Reaction with α,β-Unsaturated Ketone
The silylcuprate needed for the silylcupration of alkynes was prepared in two steps. Thus, phenyldimethylsilylchloride reacted with an excess of metallic lithium producing quantitative phenyldimethylsilyllithium, which reacted with cyanide copper (I) to give the desired silylcuprate.

Scheme 1. Silylcupration of alkynes.
Later, the intermediate I (activated by BF3.OEt2) reacted with the corresponding α,βunsaturated ketone (Scheme 2). The activation produces a yield increment due to the formation of a new intermediate (RCu•BF3), described by Yamamoto [8,9] and Lipshutz [10], whose selectivity and reactivity are higher than the initial silylcuprate. Even though the composition and structure of this intermediate was not well established, it had an important role in conjugate additions.

Synthesis of Alkenyl Ketones
To synthesize ketone 4, a Michael addition was used. The reaction gave the desired ketone in good yield [11] (Scheme 3).

Synthesis of Alkenyl Epoxides
The ketones previously prepared were treated with trimethylsulphonium ylide (prepared in situ from trimethylsulfonium iodide and butyllithium) to yield the desired epoxides (Scheme 4).
Alcohol 12 was stable under chromatography conditions and could be purified, however, alcohols 9-11 were unstable and they were used in the next step without further purification.

Intramolecular Cyclization of Vinylalcohols
We then studied the scope of the acid-catalyzed cyclization of these vinylsilyl alcohols [19], evaluating the influence of the acid (either protonic or Lewis acid) in the process. For this process, we used vinylsilyl alcohol 11. Results are shown in Table 1. Reactions with TMSOTf (trimethylsilyl trifluoromethanesulfonate) gave a complex mixture in which no cyclization products could be identified. When the acid was changed to BF3•OEt2, the starting alcohol was obtained untransformed. The best results were obtained when p-TsOH in dichloromethane was employed. Under these conditions, the desired tetrahydropyran 13 was obtained in good yield and with very high stereocontrol (a single diastereoisomer with a 2,3-trans relative stereochemistry could be detected).
To explain the high stereoselectivity associated to this process, we proposed a chairlike reactive conformation in which destabilizing 1,3-diaxial interactions were avoided (Scheme 6). Once the optimal conditions for the cyclization were determined, we proceeded to study the influence of the vinyl alcohol substituents in the cyclization. For this purpose, two alcohols with an additional substituent in the double bound were selected. Table 2 shows the results. The cyclization of a trisubstituted alkenyl alcohol, in which an alkyl group (R = Bu) is the additional substituent (9), took place in a short time producing a unique polisubstituted tetrahydropyran 14 where the phenyldimethylsilyl group was lost. As this reaction was fast at room temperature, it confirmed that the presence of an alkyl substituent in the double bound increases its reactivity.
However, when a bulky trimethylsilyl group was bonded to the alkene (10), the reaction with p-TsOH or BF3•OEt2 gave unreacted starting alcohol either at room temperature or at reflux, while in the presence of a stronger acid, such as TfOH, a complex mixture was obtained in which no known compound could be identified. This fact seems to indicate the great influence of steric factors in this cyclization.
Finally, in order to study the role of the silyl group in this cyclization, we tried the cyclization of an analogue alcohol which lacks the silyl group substituent (12). Under the standard conditions, cyclization did not take place, which seems to confirm that an electron-rich alkene moiety is needed for the acid catalyzed hydroalkoxylation to occur (Scheme 7). Scheme 7. Influence of the silyl group in the cyclization.

Conclusions
In conclusion, a new efficient method for the synthesis of polisubstituted tetrahydropyrans by acid-catalyzed cyclization of vinylsilyl alcohols has been developed. Moreover, it has been shown that the presence of a silyl substituent in the double bound is required for the reaction to proceed. In addition, the high stereoselectivity of this cyclization can be explained by steric factors. Further transformation of the tetrahydropyrans can develop in new interesting synthetic routes.
Institutional Review Board Statement: Not applicable.