Sustainable Synthesis of Chiral Tetrahydrofurans through the Selective Dehydration of Pentoses

l-Arabinose is an abundant resource available as a waste product of the sugar beet industry. Through use of a hydrazone-based strategy, l-arabinose was selectively dehydrated to form a chiral tetrahydrofuran on a multi-gram scale without the need for protecting groups. This approach was extended to other biomass-derived reducing sugars and the mechanism of the key cyclization investigated. This methodology was applied to the synthesis of a range of functionalized chiral tetrahydrofurans, as well as a formal synthesis of 3R-3-hydroxymuscarine.

Abstract: l-Arabinose is an abundant resource available as aw aste product of the sugar beet industry.T hrough use of ah ydrazone-based strategy, l-arabinose was selectively dehydrated to form ac hiral tetrahydrofuran on am ulti-gram scale without the need for protecting groups. This approachw as extended to other biomass-derived reducing sugars and the mechanism of the key cyclization investigated. This methodology was applied to the synthesis of ar ange of functionalizedc hiral tetrahydrofurans, as well as af ormal synthesis of 3R-3-hydroxymuscarine.
The effective use of biomass, and in particulart hat generated as waste, [1] is essential to reduce the global dependence on petrochemical resources for the manufacture of valuablec ompounds, fuels and materials. [2] The majority of biomass is made up of carbohydrates, which are an abundant source of pentoses and hexoses. [3] For example,t he refinement of sugar beet generatesb eet pulp as am ajor waste product, and this is ar ich source of l-arabinose. [4] Avariety of techniques has been developed to convert these biomass resources into valuable small molecules, such as the dehydration of pentoses under forcing acidic conditions to give furfural (Scheme1), which can then be convertedi nto variousalcohols, alkenes,a nd heterocycles. [5] However,t he majority of compounds prepared from pentoses and hexoses in this fashion are either achiral [6] or racemic mixtures where the stereochemistry of the chiral precursors is lost. [7] Using these products as intermediates in the synthesis of more complex targets mayt herefore require the rein-troduction of stereocenters using asymmetricc atalysis [8] or resolutions. [9] The tetrahydrofuran (THF) is ap rivileged scaffold within medicinal chemistry [10] and the stereoselective synthesis of chiral THFs has been am ajor area of recentr esearch. [11] An attractive approachi st ou tilize the inherent chirality presenti ns ingle isomerb iomass-derived carbohydrates. [12] However, existing methodso ften requiret he selectivec onversion of ap rimary alcoholi nto an alkyl sulfonate or halide [13] and/ort he use of protectingg roups, [14] both of which are detrimental to the economy of as ynthetic route. [15] Herein we describe the application of N,N-dimethylhydrazine [16] for the selective dehydration of biomass-derived reducing sugars to prepare chiral THFs under mildlya cidic conditions (Scheme 1). [17] Treating l-arabinose 1a with N,N-dimethylhydrazine and Amberlyst 15 acidic resin in methanola tr oom temperature gave hydrazone 2a in 99 %y ield ( Table 1, entry 1). Stirring hydrazone 2a in methanolat408Cfor 16 hwith 20 mol %TFA resultedi n1 00 %c onversion of 2a.A nalysis of the crude 1 HNMR spectrum indicated the formation of THF 3a as a7 5:25 mixture of diastereoisomers and purification by flash column chromatography gave am ixture of the two stereoisomers in 67 % yield.T he reactionw as scaled up from a6 .7 mmol scale to a1 04 mmol scale without any significant drop in yield, giving 11.9 go fT HF 3a.T he majord iastereoisomer was isolated by recrystallization and the stereochemistry was confirmed by single-crystal X-ray diffraction ( Figure 1). Both steps were conductedi nasustainable solvent [18] (methanol) without the need for either pre-drying of the solvento rf or ad rying agenti n the reaction.
The same reactionc onditions were used to preparet he enan-tiomericT HF ent-3a from dribose (Table 1, entry 2) in a5 8% yield over two steps. It is noteworthy that the diastereoselectivity of this reactionw as comparable with that observed for the cyclization of arabinose-derived hydrazone 2a.T he methodology was also extended to dlyxose (Table 1, entry 3), with the corresponding hydrazone prepared in 98 %y ield. The TFAmediated cyclizations tep gave THF 3b in 66 %y ield as a5 5:45 mixture of diastereoisomers. THF 3b could also be prepared from d-xylose in 61 %y ield over two steps,a gain as a5 5:45 mixture of diastereoisomers (entry 4). This is ap articularly important result as d-xylose is one of the major components of biomass. [3] Xylosei sn aturallya vailable in both enantiomersa nd using lxylose it was possible to access ent-3b in ac omparable yield (entry 5). The methodology was extended to deoxy sugar lrhamnose, another constituent of sugar beet pulp, to give THF 3c in 69 %y ield as a6 0:40 mixture of diastereoisomers (entry 6). Recrystallization of hydrazone 3a yieldedt he major anti-diastereoisomer in high purity.R educing hydrazone anti-3a using hydrogen, ap alladium catalyst and Boc 2 Og ave carbamate 4 in 60 %y ield as as ingle stereoisomer (Scheme 2).
Treatment of THF 3a (d.r. = 75:25) with Amberlyst 15 acidic resin in water at room temperature resulted in rapid hydrolysis of the hydrazone to give hydrolyzed product 5 (Scheme 3). [20] Figure 1. ORTEP of the asymmetric unit in the crystal structure of hydrazone anti-3a. The thermal ellipsoids are shown at a5 0% probability level. Only hydrogen atoms belonging to the cyclic core are shown for clarity. [19] Scheme2.Reduction of hydrazone anti-3a.
Reductiono fc ompound 5 with NaBH 4 in methanol gave triol 6 as an 85:15 mixture of diastereoisomersi n9 8% yield over two steps from hydrazone 3a. Reductive amination of intermediate 5 using n-butylamine, acetic acid, and hydrogen/palladium, followed by trapping of the intermediate amine with Boc 2 O, gave carbamate 7 in 65 %y ield from hydrazone 3a as an 80:20 mixture of diastereoisomers. Compound 5 was also converted to alkene 8 using trimethyl phosphonoacetate in 73 %y ield over two steps with excellent E-selectivity.F inally,t reating compound 5 with Amberlyst 15 in methanol resulted in the formation of dimethyl acetal 9 in 74 %y ield over two steps from 3a as a6 5:35 mixture of stereoisomers. The hydrolysis/reduction sequence was also applied to the hydrazones 3b and 3c,w hich gave the corresponding triols 10 and 11 in 90 %a nd 93 %y ield respectively. l-Rhamnose-derived triol 11 is al ate-stage intermediate in Fleet'ss ynthesis of 3R-3-hydroxymuscarine 12. [21] Triol 11 wasp reviously prepared from l-rhamnose using stoichiometricb romine, trifluoromethanesulfonic anhydride, and lithiuma luminium hydride, so our route represents al ess hazardous and more sustainable alternative.
Ap lausible reactionm echanism for the cyclization of hydrazone 2a is proposedi nS cheme 4. The N,N-dialkylhydrazone group of 2a could promote the acid-mediated elimination of the adjacent hydroxyl to give vinyldiazenium intermediate 13. [22] Cyclization of this intermediate would give THF 3a as either an anti-o rsyn-diastereoisomer.R esubmission of an isomericallyp ures ample of anti-3a to the reaction conditions resulted in the same 75:25 mixture of anti-and syn-diastereoisomers that was observed in the original reaction, which suggests that the diastereoselectivity is under thermodynamic control. Conducting the reactioni n[ D 4 ]MeOH did not result in detectable incorporation of deuterium adjacent to the hydrazone, indicating that epimerization occurs through ar eversible ring closure rather than via av inylhydrazine intermediate. The proposed mechanism is also consistent with the observation that hydrazones 2a and 2b converge to THF 3a and ent-3 a with the same diastereoselectivity (Table 1, entries 1a nd 2), as the two reactions would proceed through enantiomeric vinyldiazenium intermediates.W ithoutT FA presentn oc yclization of 1a was observed.
In ap reliminary study,t he extension of this approacht o hexoses was explored (Scheme 5). Hydrazone 14,f ormed from d-galactose, was subjected to the TFA-mediated cyclization conditions. Thisg ave a6 0:40 mixture of THF 15 and tetrahydropyran 16 in 53 %i solated yield, with both heterocycles formed as single stereoisomers.
Scheme5.Extending the methodology to d-galactose. Chem. Eur.J.2015, 21,15947 -15950 www.chemeurj.org In summary,w ehave developed an efficient multi-gram approach to low-molecular weight chiral molecules from biomass feedstock sources. This route allows access to ar ange of THF products without the need for protecting groups,i ncluding af ormal synthesis of 3R-3-hydroxymuscarine. On the basis of experimentale vidence, we have proposed ar eactionm echanism for the key cyclization involving av inyldiazenium intermediate.

Experimental Section
Experimental procedures, 1 Ha nd 13 CNMR spectra, characterization data for all compounds and crystallographic data for anti-3 a are available in the Supporting Information.