The Knoevenagel-Doebner Reaction on 1,2-O-(2,2,2-Trichloroethylidene) Derivatives of D-Gluco- and D-Manno- furanose

The synthesis of new α,β-unsaturated furanuronic acid derivatives of α-gluco- (3), β-gluco- (6) and β-manno-chloraloses (9) via a convenient one pot procedure using the Knoevenagel-Doebner reaction approach are described. The dialdofuranose derivatives were reacted with malonic acid under Knoevenagel-Doebner reaction conditions and (E)-α,β-unsaturated furanuronic acid derivatives were obtained.


Introduction
In Organic Chemistry the well-known Knoevenagel reaction is defined by condensation of an aldehyde or ketone with compounds possessing active methylene groups such as malonic esters, or malononitrile to yield an α,β-unsaturated carboxylate products [1]. If the condensation reaction is set OPEN ACCESS up in the presence of catalytic amounts of piperidine in a basic organic solvent such as pyridine, it is called the "Doebner modification of Knoevenagel reaction" or the "Knoevenagel-Doebner reaction or condensation" [2,3]. A trans-or E-α,β-unsaturated carboxylic acid is obtained as a decarboxylation product when malonic acid is heated in pyridine [2,3]. These type of condensation reactions also have been used in carbohydrate chemistry in order to extend sugar chains [4][5][6][7]. The Knoevenagel reaction can afford different types of compounds, depending on the acidic or basic catalysis employed. The condensation of unprotected reducing sugars with 1,3-dicarbonylic compounds under acidic conditions was reported in 1956 by Gonzalez [8]. The ZnCl 2 -catalyzed Knoevenagel reaction in alcoholic solvents has been used recently as the first step of the syntheses of a cytotoxic compound, of selective inhibitors of L-fucosidases of E-and P-selectin ligands, of glycoand peptidomimetics, and of furan amino acid analogs of D-and L-serine. The so-called "Garcia Gonzalez reaction" was reinvestigated in order to improve yields using milder conditions such as CeCl 3 , InCl 3 , Sc(OTf) 3 , FeCl 3 , and scandium cation-exchanged montmorillonite [9].
The Knoevenagel condensation under basic conditions was first investigated with D-glucosamine chlorhydrate as the sugar. The reaction was extended to aldose and carbon nucleophiles such as barbituric acids and pentane-2,4-dione. When barbituric acids were used unprotected sugars gave Cglycosyl barbiturates. Reaction of pentoses or hexoses with Meldrum's acid in DMF gave the unsaturated lactone. The condensation of pentane-2,4-dione with unprotected sugars in alkaline aqueous media was explored by the group of Lubineau. The condensation product of xylose with pentane-2,4-dione using NaOH, when reduced gave an activator of glycosaminoglycans biosynthesis used in cosmetic skincare products such as L'Oreal's Pro-Xylane TM [9].
Chloraloses are furanose-type cyclic acetals of pentoses and hexoses containing a 1,2-O-trichloroethylidene ring. Although, trichloroethylidene rings are highly stable under acidic and mildly basic conditions [19], they are unstable in strong bases such as a potassium tert-butoxide. The HCl elimination from trichloroethylidene ring of a chloralose with a strong base such as alkoxides gives a cyclic ketene acetal [17,19,20]. The trichloroethylidene group can be removed by hydrogenation with Raney nickel followed by acidic hydrolysis [21].
Trichloroethylidene acetals such as α-chloralose (1) [(R)-1,2-O-(2,2,2-trichloroethylidene)-α-Dglucofuranose] are potential biologically active compounds [22]. α-Chloralose was used in humans till the early part of the twentieth century [23]. Recently, it has been widely used as a bird repellent, a rodenticide, and in neuroscience and veterinary medicine as an anesthetic and sedative [22][23][24][25]. It has been characterized as a molecule which has potent central nervous system activity and evaluated in human and animal models for its therapeutic properties [26,27]. It is an anesthetic that exerts minimal cardiovascular depression, little change in blood pressure and no change or only a small reduction in heart rate, thus it is widely used in animals [28].
In addition to the well-known effects of chloraloses, arabinochloralose has been used as an intermediate compound for the development of new antituberculosis drugs in pharmaceutical research [29]. Spiro-endoperoxide chloraloses [30,31] and aminochloraloses [32] were synthesized and investigated antimicrobial activity against some microorganisms.

Results and Discussion
α,β-Unsaturated carboxylic acid-containing sugar derivatives 3, 6, and 9 were synthesized from compounds 1, 4, and 7, respectively, as shown in Scheme 1. The structure of the Knoevenagel-Doebner condensation products 3, 6, and 9 was confirmed by using spectral methods (FTIR, 1 H-and 13 C-NMR). In the FT-IR spectrum of the new dialdofuranose compound 8, the bands corresponding to the -OH and C=O are observed at 3,493 cm -1 and 1,737 cm -1 , respectively. The aldehyde proton of this compound appeared as a singlet at 9.65 ppm in the 1 H-NMR spectrum, and the carbonyl group peak appeared at 201.8 ppm in the 13 C-NMR spectrum.
In the IR spectra of compounds 3, 6, and 9 a broad OH absorption (stretching) band at 3,218, 3,453 and 3,446 cm -1 , typical C=O absorption bands at 1,718, 1,702 and 1,693 cm -1 and characteristic C=C bands at 1,662, 1,668 and 1,658 cm -1 appeared, respectively. The -OH stretching bands of the carboxylic acid moieties were displayed at 3,481, 3,453 and 3,537 cm -1 .
The 1 H-NMR and 13 C-NMR spectral data of compounds 3, 6, and 9 are listed in Table 1. The hydroxyl and carboxylic acid group protons appeared as singlets at 5.48, 5.55, 5.76 ppm and 12.32, 12.42, 12.50 ppm, respectively. The large coupling constants (15.6 to 16.0 Hz) between 5-H and 6-H prove the formation of the E-isomer [33].
Long range couplings (1.2 to 2.0 Hz) were observed between H-4 and H-6 of the Doebner products. For compound 3, this finding was previously explained as a result of a twisted conformation of the furanose ring causing the endo-trichloromethyl group to approach the 4-H hydrogen hence shifting it downfield [20,21].   A two pot alternative synthesis of similar compounds has been reported previously [27,31,33]. Hence, now we report synthesis of α,β-unsaturated furanuronic acid derivatives via a more facile one pot procedure using the Knoevenagel-Doebner reaction approach. This study is the first report of the synthesis of (E)-α,β-unsaturated furanuronic acid derivatives of α-gluco-, β-gluco-and β-manno-chloralose.

Conclusions
In the present work, the one-pot synthesis of three new potentially biological active furanuronic acid derivatives based on the 1,2-O-(2,2,2-trichloroethylidene) unit from via a Knoevenagel-Doebner reaction of the corresponding trichloroethylidene pentadialdofuranose was achieved. The spectroscopic data of the condensation products indicate the formation of only E-isomers of the carbon-carbon double bonds.