A synthetic route to pyranoid epoxy-exo -glycals from D -glucose

A synthetic route to a pyranose derived epoxy-exo -glycal has been developed from D -glucose. An attempted, one-pot bromination-elimination-oxirane formation, protocol that had worked well on furanoses, resulted only in the generation of 2-bromo-C -1-methyl pyranoid glycals.


Results and Discussion
Our synthetic route to epoxy-exo-glycal 4 demanded only four steps and permitted its preparation in a respectable 33% yield from D-mannose.The preparation relied in two synthetic processes described in our laboratory: i) the reaction of mannofuranosyl chloride 7 with MeLi, 8b and ii) the one-pot three step transformation of C-1 methyl glycal 8 into 4 7,11b (Scheme 1).Scheme 1. Synthesis of furanosidic epoxy-exo-glycal 4 from furanosyl chloride 7.
By analogy, we decided to explore a synthetic route to 6a, which would include a related one-pot three step (bromination-elimination-oxirane formation) procedure.Accordingly, C-1 methyl glycal 9 8b was treated with bromine and triethylamine in CH2Cl2.However, the resulting product was 2-bromo-C-1 glycal 10, rather than the sought epoxy-exo-glycal 6a (Scheme 2).
This attempted protocol for the preparation compound 6a had relied on some insight in the electrophilic bromination of glycals, as follows.The electrophilic addition of halogens to cyclic enol ethers was first investigated by Lemieux and Fraser-Reid, 13 who proposed a general mechanism involving the initial formation of carbenium ions which, upon nucleophilic attack by halide ion, gave mainly the products of thermodynamic control.Later on, it was shown that the product formation is under kinetic control and that the stereoselectivity depends on the solvent polarity, 14 the structure of the enol ether, and the halogen.Recent studies on bromine addition to glycals in aprotic solvents 16 (a system closely related to ours) have established that the reaction is a two-step process involving an electrophilic addition (A→B, Scheme 3a) after which, an irreversibly formed bromo oxocarbenium ion (C) suffers an axial attack by the nucleophile (C→D, Scheme 3a), which is governed by the stereoelectronic -anomeric effect. 17For that reason, both cis and trans adducts D 1 and D 2 are observed.
According to these observations, two compounds (11 and 12) could arise by bromination of 9 (Scheme 3b).The former could experience Br 1 elimination either from H 2 to give compound 10, or from H 1' to generate the Δ 1,1' unsaturation in 6, a process that might be followed by nucleophilic substitution to furnish the Δ 2,3 oxirane. 18Conversely, no Br 1 elimination could take place from H 2 in dibromo derivative 12, since H 2 and Br 1 are not in an antiperiplanar disposition, nor could Δ 2,3 oxirane formation be expected either, owing to the cis-relationship between the C3-OH and Br 2 .

Conclusions
Pyranosidic epoxy-exo-glycal 6b, can be efficiently prepared from commercially available -Dglucose pentaacetate 13 in seven steps.The synthetic route from tetraol 14 22 to 6b takes place in a synthetically useful 37% yield.An alternative approach featuring a one-pot three steps transformation, which had worked well for us in related furanose systems, led to 2-bromo C-1 methyl derivative 10 instead.This route provides access to compound 6b, which is now under study in our laboratory.

Experimental Section
General.All reactions were performed in dry flasks fitted with glass stoppers or rubber septa under a positive pressure of Ar, unless otherwise noted.Air-and moisture-sensitive liquids and solutions were transferred by syringe or stainless steel cannula.Optical rotations were determined for solutions in chloroform.Flash column chromatography was performed using 230-400 mesh silica gel.Thin-layer chromatography was conducted on Kieselgel 60 F254 (Merck).Spots were observed first under UV irradiation (254 nm) then by charring with a solution of 20 % aqueous H2SO4 (200 mL) in AcOH (800 mL).Anhydrous MgSO4 or Na2SO4 were used to dry organic solutions during workup, and evaporation of the solvents was performed under vacuum using a rotary evaporator.Solvents were dried and purified using standard methods.Unless otherwise noted 1 H and 13 C NMR spectra were recorded in CDCl3 at 300 MHz and 50 MHz, respectively.Chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.25 ppm).Elemental analyses were carried out at the Centro Nacional de Química Orgánica "Manuel Lora Tamayo", Juan de la Cierva 3, 28006 Madrid, with a Heraeus CHN-Orapid elemental analyzer.