Knoevenagel Reaction of Unprotected Sugars 11 H0 HO- O HO- HO HO Fig.5 The four possible B-furanosides 46 and 47,and B-pyranosides stercoisomers4 and 45a obtained dunng the reaction of b-glucose with pentane-2,4-dione (1) OH OH 品 HO OH D-maltose(49) D-cellobiose(50) Fig.6Structure of p-maltose and D-cellobiose HO OH OH OH 45b 45c 45d OH OH 0 。 45e dom ()lcte(m ()and D-ccnoolos Table 3 Reaction conditions and results for the condensation of unprotected carbohydrates with pentane-2.4-dione (1)in aqucous medium Starting sugar Conditions Product References (yield D-Glucose(10)H2O.pentane-2.4-dione 1(1.2 cquiv.).NaHCOs 45a(100)[110] D-Mannose(11) 45b(100)【110 D-Galactose(12)H2O/THF(2/1),pentane-2.4-dione 1(2 equiv.).45e(90)[112] D-Maltose(49) 45d(9)【1 D-Cellobiose (50)H2O.pentane-2,4-dione 1(1.2 equiv.).NaHCOs 45e(100)[11] (1.5 equiv..12h,90C
HO O HO OH O HO OH HO OH HO O O HO OH HO HO O O HO O HO HO OH O 46 47 48 45a Fig. 5 The four possible a,b-furanosides 46 and 47, and a,b-pyranosides stereoisomers 48 and 45a obtained during the reaction of D-glucose with pentane-2,4-dione (1) HO O HO HO OH D-maltose (49) O O HO HO OH HO O HO HO OH O O HO HO OH D-cellobiose (50) OH OH Fig. 6 Structure of D-maltose and D-cellobiose HO O HO OH OH O 45b O HO HO OH OH O 45c HO O HO HO OH 45d O O HO HO OH O HO O HO HO OH O O HO HO OH O 45e Fig. 7 Compounds obtained from D-mannose (11), D-galactose (12), D-maltose (49), and D-cellobiose (50) Table 3 Reaction conditions and results for the condensation of unprotected carbohydrates with pentane-2,4-dione (1) in aqueous medium Starting sugar Conditions Product (yield %) References D-Glucose (10) H2O, pentane-2,4-dione 1 (1.2 equiv.), NaHCO3 (1.5 equiv.), 6 h, 90C 45a (100) [110] D-Mannose (11) H2O, pentane-2,4-dione 1 (1.2 equiv.), NaHCO3 (1.5 equiv.), 12 h, 90C 45b (100) [110] D-Galactose (12) H2O/THF (2/1), pentane-2,4-dione 1 (2 equiv.), NaHCO3 (4 equiv.), 24 h, 90C 45c (90) [112] D-Maltose (49) H2O, pentane-2,4-dione 1 (1.2 equiv.), NaHCO3 (1.5 equiv.), 12 h, 90C 45d (91) [111] D-Cellobiose (50) H2O, pentane-2,4-dione 1 (1.2 equiv.), NaHCO3 (1.5 equiv.), 12 h, 90C 45e (100) [111] Knoevenagel Reaction of Unprotected Sugars 11
12 M.-C.Scherrmann It is worth pointing out that the ketones derivatives 45a,45e obtained in one step from D-glucose and D-cellobiose were previously prepared in seven and eight steps respectively,and low overall yields from commercial 2.3.4.6-tetra-O-benzyl-D ]repored that,in cases, nounts of the a-linked compounds as well as furan derivatives 3 wers mall obtained. Researchers of L'Oreal confirmed the results obtained by Lubineau's group and applied the reaction to other sugars such as D-xylose (7).D-lactose(51).D-fucose (52).D-arabinose (8).and 3-deoxy-D-arabinose (53)[115](Fig.8). Using the experimental conditions described by Lubineau's group (Table 3). they obtained the corresponding B-D-linked ketones 54-59 in excellent to moderate vields (Fig.9). The effect of the base used for the condensation of xylose (7)with pentane-2.4 Th leplmen In the aim to prepare isosteric analogs of nucleotide-activated sugars,this straightforward method was applied to the preparation of C-glycosides related HO OH OH HO OH Ho OH o-lactose(51) se(52)3-deoxy-D-arabinose (53) Fig.8 Structure of p-lactose,D-fucose,and 3-deoxy-D-arabinose HO OH OH HO H HO. HO HO HO 6 5487%) 55(79% 56192% HO 58(40%) 59(59 Fig.Compoundso ned from D-xylose (7).D-lactose(51).D-fucose(52),D-arabinose (8).and 5 Ho HO Pro-XylaneTM (60)
It is worth pointing out that the ketones derivatives 45a, 45e obtained in one step from D-glucose and D-cellobiose were previously prepared in seven and eight steps, respectively, and low overall yields from commercial 2,3,4,6-tetra-O-benzyl-Dglucopyranose [113]. Riemann et al. [114] reported that, in certain cases, working a lower temperature, small amounts of the a-linked compounds as well as furan derivatives 3 were obtained. Researchers of L’Ore´al confirmed the results obtained by Lubineau’s group and applied the reaction to other sugars such as D-xylose (7), D-lactose (51), D-fucose (52), D-arabinose (8), and 3-deoxy-D-arabinose (53) [115] (Fig. 8). Using the experimental conditions described by Lubineau’s group (Table 3), they obtained the corresponding b-D-linked ketones 54–59 in excellent to moderate yields (Fig. 9). The effect of the base used for the condensation of xylose (7) with pentane-2,4- dione (1) was carefully examined. The best results were obtained using NaOH since 54 was obtained in 45 min at 50C in 97% yield. Reduction of 54 gave 60, an activator of glycosaminoglycans biosynthesis, launched on the market in cosmetic skincare products as Pro-XylaneTM by L’Ore´al in 2006 [116, 117] (Fig. 10). In the aim to prepare isosteric analogs of nucleotide-activated sugars, this straightforward method was applied to the preparation of C-glycosides related O HO HO HO OH O O HO HO OH D-lactose (51) OH O HO HO HO OH D-fucose (52) 3-deoxy-D-arabinose (53) O HO HO OH Fig. 8 Structure of D-lactose, D-fucose, and 3-deoxy-D-arabinose O HO HO HO OH O O HO HO OH 55 (79%) O HO HO HO 56 (92%) 58 (40%) O O HO O HO HO O 54 (87%) 59 (59%) O HO HO HO O O HO HO O Fig. 9 Compounds obtained from D-xylose (7), D-lactose (51), D-fucose (52), D-arabinose (8), and 3-deoxy-D-arabinose (53) HO O HO HO OH Pro-XylaneTM (60) Fig. 10 Structure of ProXylaneTM, an activator of glycosaminoglycans biosynthesis (L’Ore´al) 12 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugar 13 0 NaHCO3 HO OH 27% D-fructose(60) 61 Me HO Scheme 10 Reaction of D-fructose with pentane-2.4-dione (1)in alkaline aqueous media OH C OH (CH2)nCHa Ho] OH _(CH2)CH HO 63n8 88n85 58n885 Fig.11 Symmetrical fatty B-diketones 63 used to prepare the C-glycolipids 64 and 65 to D-and L-glycero-B-D-manno-heptoses by the group of Kosma [118,119]. Lichtenthaler and colleagues studied the application of this reaction to D-fructose ough.a bicyclic on of the int oduct 62 was obtained in 27%yield by e 10) use f other 1.- ica ompounds s specieswas swere tested in the condensation,giving rise to mixtures of C-glycosides 111,114. In order to prepare carbohydrate-based amphiphiles by this efficient methodol- ogy,symmetrical B-diketones 63a,b were used [111].The reactions of these diketones with D-glucose (10)in EtOH/H2O as the solvent and NaHCO,as the base were complete and the C-glycolipids were isolated in 75%(64a)and 52% vield (64b)usi g the less soluble diketo ne 63b.The condensation was also obtain 65a or 65b (Fig.11)[111,121]. applied n or pen and gal tosamine aqueous med a was firs investigated by Riemann et al.[114].This group reported that the condensationo pentane-2,4-dione with N-acetyl-D-glucosamine (66)gave a 1:1 mixture of a-and B-C-glycosidic ketones in poor yield (36%).This reaction was reinvestigated and it was demonstrated that actually,gluco and manno C-glycosidic ketones 69a and 70a were obtained [1121 (Fig.11). The formation of the N-acetyl-D-mannosamine ketone 70a could be rationalized considering the alkaline epimerization of N-acetyl-D-glucosamine(66)giving
to D- and L-glycero-b-D-manno-heptoses by the group of Kosma [118, 119]. Lichtenthaler and colleagues studied the application of this reaction to D-fructose (60) [120]. Surprisingly enough, a bicyclic product 62 was obtained in 27% yield by a double cycloketalization of the intermediate 61 (Scheme 10). The use of other 1,3-dicarbonyl compounds as nucleophilic species was also investigated in this reaction. In particular, unsymmetrical diketones were tested in the condensation, giving rise to mixtures of C-glycosides [111, 114]. In order to prepare carbohydrate-based amphiphiles by this efficient methodology, symmetrical b-diketones 63a, b were used [111]. The reactions of these diketones with D-glucose (10) in EtOH/H2O as the solvent and NaHCO3 as the base were complete and the C-glycolipids were isolated in 75% (64a) and 52% yield (64b) using the less soluble diketone 63b. The condensation was also applied to D-maltose (49) to obtain 65a or 65b (Fig. 11) [111, 121]. The condensation of pentane-2,4-dione with unprotected N-acetyl-D-gluco-, manno-, and galactosamine (66, 67, and 68) in alkaline aqueous media was first investigated by Riemann et al. [114]. This group reported that the condensation of pentane-2,4-dione with N-acetyl-D-glucosamine (66) gave a 1:1 mixture of a- and b-C-glycosidic ketones in poor yield (36%). This reaction was reinvestigated and it was demonstrated that actually, gluco and manno C-glycosidic ketones 69a and 70a were obtained [112] (Fig. 11). The formation of the N-acetyl-D-mannosamine ketone 70a could be rationalized considering the alkaline epimerization of N-acetyl-D-glucosamine (66) giving OH OH OH OH O HO O O OH OH OH OH HO O HO O HO O OH Me OH OH NaHCO3 H2O 61 62 + 27% D-fructose ( 60) 1 Scheme 10 Reaction of D-fructose with pentane-2,4-dione (1) in alkaline aqueous media HO O HO HO OH O O HO HO OH O (CH2)nCH3 O O (CH2)nCH3 (CH2)nCH3 63a n = 5 63b n = 8 65a n = 5 65% 65b n = 8 30% HO O HO HO OH O (CH2)nCH3 64a n = 5 75% 64b n = 8 52% Fig. 11 Symmetrical fatty b-diketones 63 used to prepare the C-glycolipids 64 and 65 Knoevenagel Reaction of Unprotected Sugars 13
14 M.-C.Scherrmann N-acetyl-D-mannosamine(67),but the intermediate 72 can undergo an epimeriza- tion to 74(Scheme 11)through the formation of 73 before the Michael addition took place,as observed by Wen and Hulting in the preparation of C-linked timized conditions(pentanedione 2 equiv..NaHCO 4 equi .H20 THF 2:1.90C.)N- 166 gave the mine(67)led to the same products in a 3:1 ratio and 40%yield.This poor yield has been explained by the instability of 70a in the reaction mixture.These compounds were easily separated by crystallization of their acetylated derivatives 69b and 70b.Applied to N-acetyl-D-galactosamine(68),the same reaction conditions gave the C-glycosidic ketone 71a,isolated as the acetylated compound 71b(Fig.12. Table 4). OH NHAC 73 Scheme 11 Possible intermediates involved in the reaction of N-acetyl-p-glucosamine (66)and acetyl-D-mannosamine (67 OH HO OH OR RO OR NHAC NHAG I S Re 70 R-Ae 7IR-Ae 达(tio Yield (% etyl-D-glucosamin N-Acetyl-p-galactosamine (68) 713 50
N-acetyl-D-mannosamine (67), but the intermediate 72 can undergo an epimerization to 74 (Scheme 11) through the formation of 73 before the Michael addition took place, as observed by Wen and Hulting in the preparation of C-linked glycophosphonates [122]. Using optimized conditions (pentanedione 2 equiv., NaHCO3 4 equiv., H2OTHF 2:1, 90C, 24 h), N-acetyl-D-glucosamine (66) gave the gluco- and manno ketones 69a and 70a in a 4:6 ratio and 83% yield, whereas N-acetyl-D-mannosamine (67) led to the same products in a 3:1 ratio and 40% yield. This poor yield has been explained by the instability of 70a in the reaction mixture. These compounds were easily separated by crystallization of their acetylated derivatives 69b and 70b. Applied to N-acetyl-D-galactosamine (68), the same reaction conditions gave the C-glycosidic ketone 71a, isolated as the acetylated compound 71b (Fig. 12, Table 4). HO O HO NHAc OH O O HO O HO NHAc OH O O HO O HO NHAc OH O O 69a 70a 72 73 74 Scheme 11 Possible intermediates involved in the reaction of N-acetyl-D-glucosamine (66) and N-acetyl-D-mannosamine (67) RO O RO NHAc OR O 70a R = H 70b R = Ac O RO RO NHAc OR O 71a R = H 71b R = Ac RO O RO NHAc OR O 69a R = H 69b R = Ac HO O HO NHAc OH N-acetyl D-mannosamine (67) O HO HO AcNH OH N-acetyl D-galactosamine (68) HO O HO AcNH OH N-acetyl D-glucosamine (66) OH OH OH Fig. 12 Structure of N-acetyl-D-gluco-, manno-, and galactosamine and the C-glycosyl ketones derivatives Table 4 Results for the aqueous condensation of N-acetylated amino sugars with 2,4-pentanedione (1) in the presence of NaHCO3 at 90C Starting sugar Products (ratio) Yield (%) N-Acetyl-D-glucosamine (66) 69a 70a (4:6) 83 N-Acetyl-D-mannosamine (67) 69a 70a (1:3) 40 N-Acetyl-D-galactosamine (68) 71a 50 14 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugar 15 4 Conclusion An important task of today's chemistry is to design new products prepared from renewable starting materials and produced using green processes.This chapter has described many reactions that follow these concepts.The development of reactions allowing the transformation of carbohydrates without the use of the tedious protect- ing and deprotecting steps is of great interest because it allows time,money,and ator eco mies.The Knoevenagel reaction is one of these reactions:it can afford omp s.depe ending on the acidic or basic cataly employed and its compatibility with the use of water as solvent make it particularly attractive in the context of green chemistry. References 2.ee vengel ction I Tro d)Comprchensive e1E(1894 Chem ber27:2345-2346 3. Venkat Narsaiah AV,Basak AK.Visali B.Nagaiah K (2004)Synth Commun 34:2893-2901 5.Balalaie S.Barrjanian M.Hekmat S.Salehi P(2006)Synth Commun 36:3703-3711 35 8.Green B.Crane RI.Khaidem IS.Leighto RS.Newaz SS.Smyser TE (1985)JOrg Chem 50:640-644 an 11.Abaee MS.Mojtahedi MM,Zahedi MM.Khanalizadeh G(2006)ARKIVOC 15:48-52 12.Bartoli G.Bosco M.Carlone A.Dalpozzo R.Gialzerano P.Melchiorre P.Sambri L(2008) Giuliani A.Marcantoni E.Massaccesi M.Paoletti M(2006) Ventur n Le ct29:2261- 35:153-158 e DJ.Clark H.Lambe t A.Mdoe JEG.Pries 18.. shi T.Suzuki T.Hagiwara H (20 5)Mo cm9317-320 20.Vanteva P 13-122-128 21.Calvino-Casilda V. Martin-Arada RM.Lope-Peinado J.Sob1Ziolek M(009) 1422 aS P 996 JCatal163392-39% 24.Corma A.Fornes V.Martin-Aranda RM.Rey F(1992)J Catal 134:58-6 .Big.Chesimi Sartor G()Org Chem 64:1033-1035
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