Synthesis of Chiral Heteroaryl-Substituted Dihydropyran Derivatives via Ring Closing Enyne Metathesis Reaction

The ring closing enyne metathesis reactions have been applied to systems derived from homopropargylic alcohol backbones are described. The key intermediates 2benzofuranyl and 2-benzothiophenyl homopropargylic alcohols were synthesized from their corresponding carboxyaldehyde derivatives and resolved to give the corresponding enantiopure acetates and the alcohols with high ee values through enzymatic resolution. Then, enantiomerically enriched enyne skeletons derived from homopropargylic alcohols were subjected to the ring closing metathesis reaction via first generation Grubbs' catalysts and corresponding chiral heteroaryl-substituted dihydropyran derivatives were obtained with good yields.


Introduction
Dihydropyrans which are among the most investigated heterocyclic structural motifs in the past decade are widely occur in numerous natural and synthetic products. 1Many of these compounds show potential biological activities, such as cytotoxicity against some cancers, anti-infectivity and anti-HCV activities, and are widely used in pharmaceuticals. 2 Some of the most widely used methods for the preparation of dihydropyrans are based on hetero-Diels-Alder cycloaddition, 3 electrophile-initiated alkylation of glycals, 4 olefin metathesis, 5 dioxanone Claisen rearrangement 6 and allylation-Prins cyclization. 79] Tremendous carbocyclic and heterocyclic rings have been elegantly constructed cycles in the presence of a metathesis catalyst, for example, first and second generation of Grubbs' ruthenium-based catalyst from relatively simple precursors by the RCM reaction.
Benzothiophene and benzofuran molecules are found to be important scaffolds in synthetic medicinal chemistry.Their natural and synthetic derivatives display a wide spectrum of pharmacological activities like antioxidant, antibacterial, antimicrobial, antifungal, antiviral and anticancer activities etc [13-17].Moreover substituted benzofurans find application such as of oxidant [18], antioxidants, fluorescent sensor [19], brightening agents, a variety of drugs and in other field of chemistry and agriculture [20].
Herein, we describe the chemoenzymatic synthesis of optically active heteroaryl substituted dihydropyrans starting from benzofuran and benzothiophene-substituted homopropargyl alcohols.

Results and Discussion
The parent benzofuranyl and benzothiophenyl homopropargylic alcohols 1a-b were synthesized by the addition of propargyl nucleophile to corresponding aldehydes and enzymatically resolved in our previous study [21].Chiral heteroaryl-substituted homopropargylic alcohols are good candidates for the preparation of chiral enyne systems because of their O-anchoring site.These enyne scaffolds are very valuable precursors for the construction of dihydropyran skeletons by ring closing metathesis reaction.

Conclusion
In summary, we have described the design and synthesis of novel hybrid compounds between heteroaryl ring (benzofuran and benzothiophene) and dihydropyran scaffold.The enantiomerically enriched homopropargylic alcohols were converted to chiral enyne structures by O-allylation method.Then, ring closing metathesis reaction was applied on these enynes.In conclusion, novel chiral heteroaryl-substituted dihydropyran derivatives were prepared in this study.

General
All experiments were carried out in pre-dried glassware an inert atmosphere of argon. 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 on a Bruker Spectrospin Avance DPX-400 spectrometer. 1 H (400 MHz) and 13  Flash column chromatography was performed bu using thick-walled glass columns and silica gel (60-mesh; Merck).The reactions were monitored by thin-layer chromatography (TLC) using Merck 0.2-mm silica gel 60 F254 analytical aluminum plates, visualized by UV light.All extracts were dried over anhydrous magnesium sulfate and solutions were concentrated under reduced pressure by using a rotary evaporator.

General procedure for the synthesis of enyne derivatives (-)-2a-b.
To a solution of (-)-1a-b in dry THF (10 mL) was added NaH (96 mg, 60% dispersion in mineral oil, 2.4 mmol) under argon.The solution was stirred until H 2 gas removal was complete (approximately 30 min).Next, allyl bromide added dropwise followed by tetrabutylammonium iodide (2 mmol).The mixture was stirred for an additional 2 h and hydrolyzed by cautious addition of water (20 mL).The aqueous layer was extracted with ether (3x20 mL).The combined organic phase was dried over MgSO 4 and evaporated in vacuo.The crude product mixtures were purified by flash column chromatography using ethyl acetate/ hexane (1:7) as the eluent.
C NMR were recorded in CDCl 3 and the chemical shifts are expressed in ppm relative to CDCl 3 (δ 7.26 and 77.0 for H and 13 C NMR, as the internal standard.Optical rotations were measured in a 10 cm cell using a Rudolph Research, Autopol III polarimeter.HRMS spectra were recorded on an Waters SYNAPT G1 MS (ESI-TOF-MS) at METU Central Laboratory R&D Training and Measurement Center.