6 M.-C.Scherrmann ilicate layer 9 (Scheme 4).Such a mechanism was proposed for the Se-mont catalyzed Michael reaction[9]. The reaction was applied to D-xylose (7),D-arabinose (8).and Larabinose (23 affording 24,25.and 26 respectively in 76.79,and 78%yields whereas D-glucose (10)gave 27 in only 43%(Fig.1).Very interestingly,the author demonstrated that the catalyst could be re-used at least five times without any loss of activity [97]. 3 Condensation Under Basic Conditions The Knovenagel condensation under basic conditions was first investigated with ig minn n ne aqueous acetone in the presence of on w philes [100-104]
(Scheme 4). Such a mechanism was proposed for the Sc3+-mont catalyzed Michael reaction [98]. The reaction was applied to D-xylose (7), D-arabinose (8), and L-arabinose (23) affording 24, 25, and 26 respectively in 76, 79, and 78% yields whereas D-glucose (10) gave 27 in only 43% (Fig. 1). Very interestingly, the author demonstrated that the catalyst could be re-used at least five times without any loss of activity [97]. 3 Condensation Under Basic Conditions The Knovenagel condensation under basic conditions was first investigated with D-glucosamine chlorhydrate (28.HCl) as the sugar. The condensation of this reducing amino sugar with pentane-2,4-dione 1 in aqueous acetone in the presence of sodium carbonate afforded the pyrrole derivative 29 in 85% yield [99] (Scheme 5). The reaction was extended to other 2-amino-2-deoxy-aldose and carbon nucleophiles [100–104]. O O HO CHO OH OH OH OH2 Sc OH2 H2O H2O OH2 OH2 3+ silicate layer silicate layer Sc OH2 O H2O OH2 OH2 2+ O O HO OH OH OH H Sc OH2 O H2O OH2 OH2 2+ O O HO OH HO OH H Sc OH2 O H2O OH2 OH2 3+ O O HO OH OH OH H O O O O HO HO HO HO O O O 9 14 18 14 19 20 21 22 Scheme 4 Possible mechanism involved in the formation of 18 from D-ribose (9) and dimedone (14) 6 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugars HO OH OH -arabinose(23) HO HC 27 and o+ oH。 OH HN- 85% Scheme 5 Reaction of p-glucosamine chlorhydrate (28.HCl)with pentane-2.4-dione (1)in basi aqueous medium When barbituric acids 30 or 31 were used as 1.3 dicarbonylic compounds unprotected sugars gave C-glycosyl barbiturates 36 or 37 in good yields [105 106](Scheme 6).The reaction starts with the Knoevenagel condensation of the carbanion of the barbituric acid with the hemiacetalic sugar affording 32 or 33. Then the B-elimination of water followed by cyclization through a Michael-type addition afforded the B-D-C-pyranoside (equatorial)36 or 37 probably through a thermodynamic control. haw ose (10).D-galactose(12),D-mar nose(11),2-amino-2-deo (Fig.2). Using the same experimental conditions,the pentoses D-xylose(7).D-ribose(9). and D-arabinose (8)afforded the pyranoses derivatives 36f-h or 37f-h,respectively (Fig.3). Although the acidity of Meldrum's acid is quite similar to that of barbituric acids,the same reaction conducted with this dicarbonylic compound in aqueous medium instead of the expectedadduct The reaction
When barbituric acids 30 or 31 were used as 1,3 dicarbonylic compounds, unprotected sugars gave C-glycosyl barbiturates 36 or 37 in good yields [105, 106] (Scheme 6). The reaction starts with the Knoevenagel condensation of the carbanion of the barbituric acid with the hemiacetalic sugar affording 32 or 33. Then the b-elimination of water followed by cyclization through a Michael-type addition afforded the b-D-C-pyranoside (equatorial) 36 or 37 probably through a thermodynamic control. D-Glucose (10), D-galactose (12), D-mannose (11), 2-amino-2-deoxy-D-glucose (28), as well as D-glucuronic acid (38) were allowed to react with barbituric acids 30 or 31 to give b-D-glycopyranosyl barbiturates 36a–e or 37a–e in good yields (Fig. 2). Using the same experimental conditions, the pentoses D-xylose (7), D-ribose (9), and D-arabinose (8) afforded the pyranoses derivatives 36f–h or 37f–h, respectively (Fig. 3). Although the acidity of Meldrum’s acid is quite similar to that of barbituric acids, the same reaction conducted with this dicarbonylic compound in aqueous medium gave a complex mixture instead of the expected adduct [107]. The reaction HO HO HO HO O O O HO HO HO HO O O O HO HO HO HO O O O HO HO HO HO O O HO O 24 25 26 27 L-arabinose (23) O HO HO OH OH Fig. 1 Structure of L-arabinose and compounds obtained from various carbohydrates and dimedone (14) in the Sc3+-mont catalyzed reaction O HO HO NH2 OH OH O O Na2CO3 HN OH OH OH O HO 29 + H2O/acetone 85% HCl D-glucosamine chlorhydrate (28.HCl) 1 Scheme 5 Reaction of D-glucosamine chlorhydrate (28.HCl) with pentane-2,4-dione (1) in basic aqueous medium Knoevenagel Reaction of Unprotected Sugars 7
8 M.-C.Scherrmann Scheme 6 Mechanism of the O。N、C 3子R:M -0 NR Mo 39-Me 。0R0 o-glucuronic acid 38 8R: 驰R地 3R9 R产 368R: c acid(3)and B-D-glycopyranosyl barbiturates obtained from 37h Me Bo Fig.Structure of B--glycopyranosyl barbiturates obtained from pentoses was thus studied in DMF as the solvent and 3.6-anhydro-1,4-lactones 39 were
was thus studied in DMF as the solvent and 3,6-anhydro-1,4-lactones 39 were obtained as main products [107–109] (Scheme 7). The formation of 39 has been interpreted by assuming a Knoevenagel-Doebner reaction. The C-glycoside 40, obtained via the Knoevenagel condensation of the NR R O N O O Na O OH R O R OH CHO R NR R O N O O Na OH CH R O NR R O N O O Na O CH R NR R O N O Na O – H2O 30 R = Me 31 R = H 32 R = Me 33 R = H 34 R = Me 35 R = H 36 R = Me 37 R = H Scheme 6 Mechanism of the reaction of carbohydrates with barbituric acids 30 or 31 O HO HO OH OH NR R O N O O Na 36d R = Me 85% 37d R = H 70% O HO HO OH OH NR R O N O O Na O HO HO HO OH NR R O N O O Na O HO HO NH2 OH NR R O N O O Na 36a R = Me 78% 37a R = H 80% 36b R = Me 78% 37b R = H 73% 36c R = Me 80% 37c R = H 74% O HO HO OH CO2Na NR R O N O O Na 36e R = Me 77% 37e R = H 73% O HO HO OH CO2H OH D-glucuronic acid 38 Fig. 2 Structure of D-glucuronic acid (38) and b-D-glycopyranosyl barbiturates obtained from hexoses or D-glucuronic acid O HO HO OH NR R O N O O Na 36f 37f O HO HO OH NR R O N O O Na 36h 37h HO O HO OH NR NR O O O Na 36g 37g R = Me 70% R = H 80% R = Me 77% R = H 80% R = Me 80% R = H 73% Fig. 3 Structure of b-D-glycopyranosyl barbiturates obtained from pentoses 8 M.-C. Scherrmann
Knoevenagel Reaction of Unprotected Sugars Scheme 7 Reaction of Meldrum's acid in DMF as HO、 00/ EtN HOHC the solvent HO H OH。 DMF R=Hor CH2OH Meldrum's acid HO. HO R=H or CH2OH 40 Scheme 8 Mechanism of the formation of 39 through the intermediate 40 carbanion of the Meldrum's acid followed by B-elimination of ioroMichael-typaonuwetofe to give the unsaturated lactone 41.A Michael reaction afforded in most cases the furanoid lactone 39 [109](Scheme 8). As this reaction is quite slow,epimerization at C-2 occurred so that the same products 39a,b were obtained from D-ribose(9)and D-arabinose(8)together with the corresponding unsaturated lactones 41a or 41b.In the case of D-xylose (7).no Cgy25 bdand血furnoid actone39 was obtai如d with the one 41c.Co solated from 39d,the unsaturated compound Koll et al.also carefully explored the conversion of hexoses and obtained similar results:products were mainly the furanoid lactones 39(Scheme 7),partial epimer- ization occurred in most reactions,and D-mannose(11)also gave a pyranoid lactone as D-lyxose (7)[109]. The condensation of pentane-2.4-dione(1)with unprotected sugars in alkaline of sod ium hyd es 45.Also rogen carb give he B-C-glycosi e quanti. n started evenagel con densation of th tone v etalic sugar Then,the B-elimi ion of water was followed by cyclization to the intermediate C-glycoside 44.which underwent a retro-Claisen aldolization with sodium acetate elimination to give 45(Scheme 9). The selectivity for the formation of the B-D-pyranoside(equatorial)stereoiso- mer in the reaction originated from a thermodynamic control.Indeed,starting x.B-fur
carbanion of the Meldrum’s acid followed by b-elimination of water and cyclization through a Michael-type addition, underwent loss of carbon dioxide and acetone to give the unsaturated lactone 41. A Michael reaction afforded in most cases the furanoid lactone 39 [109] (Scheme 8). As this reaction is quite slow, epimerization at C-2 occurred so that the same products 39a, b were obtained from D-ribose (9) and D-arabinose (8) together with the corresponding unsaturated lactones 41a or 41b. In the case of D-xylose (7), no epimerization was observed and the furanoid lactone 39c was obtained with the unsaturated lactone 41c. Compound 39c was also isolated from the reaction involving D-lyxose (42), as well as the non-epimerized lactone 39d, the unsaturated compound 41d, and the pyranoid lactone 43 (Fig. 4, Table 2). Ko¨ll et al. also carefully explored the conversion of hexoses and obtained similar results: products were mainly the furanoid lactones 39 (Scheme 7), partial epimerization occurred in most reactions, and D-mannose (11) also gave a pyranoid lactone as D-lyxose (7) [109]. The condensation of pentane-2,4-dione (1) with unprotected sugars in alkaline aqueous media was explored by the group of Lubineau [110]. Pentane-2,4-dione reacted with aldoses in the presence of sodium hydrogen carbonate, to give quantitatively the b-C-glycosidic ketones 45. Also in this process, the reaction started with the Knoevenagel condensation of the b-diketone with the hemiacetalic sugar. Then, the b-elimination of water was followed by cyclization to the intermediate C-glycoside 44, which underwent a retro-Claisen aldolization with sodium acetate elimination to give 45 (Scheme 9). The selectivity for the formation of the b-D-pyranoside (equatorial) stereoisomer in the reaction originated from a thermodynamic control. Indeed, starting from D-glucose, after 24 h at room temperature, a mixture of the four possible a,b-furanosides 46 and 47, and a,b-pyranosides stereoisomers 48 and 45a, in which O R HO OH OH O O O O O O HO HOHC O R + Et3N DMF HO R = H or CH2OH Meldrum's acid 39 Scheme 7 Reaction of pentoses or hexoses with Meldrum’s acid in DMF as the solvent O R HO OH O O O O O O HO HOHC O R HO R=H or CH2OH OH R HO HO O O –CO2 O – 40 41 39 Scheme 8 Mechanism of the formation of 39 through the intermediate 40 Knoevenagel Reaction of Unprotected Sugars 9
M.-C.Scherrmann 66 41c 41d 66 o-lyxose(4) 43 送ofoo Table 2 Products of the condensation of pentoses with Meldrum's acid Pentose Unsaturated anoid lactone C-2 epimerized Pyranoid lactone lactone(yields)(yields) furanoid lactone D-Ribose (9) 45%r5%39阳1彩20 (yields) D-Lyx0sc4241d5%°(6%39d5%6%39c(41%(51%)43(10%(22% Pentose.Meldrum's acid.tBuNH.(1:2:1).5 days.40C [091 Pentose.Meldrum's acid.EtN (1:1:1).10 days 489C[107,108] Scheme9 Reaction of aldoses with pentane-2.4-dione(1)in alkaline aqucous media the a-furanosides 47 predominated.was obtained (Fig.5).Under further equilibra tion in basic medium,an almost exclusive formation of the B-glucopyranoside observed .D-galactose(12).D-maltose(49).and o-cellobi e(50)(Fig.6 gave compounds 45b.c.d,and e respectively [110-112](Fig.7.Table 3)
the a-furanosides 47 predominated, was obtained (Fig. 5). Under further equilibration in basic medium, an almost exclusive formation of the b-glucopyranoside isomer 45a was observed. D-Mannose (11), D-galactose (12), D-maltose (49), and D-cellobiose (50) (Fig. 6) gave compounds 45b, c, d, and e respectively [110–112] (Fig. 7, Table 3). O HO O O HO O HO HO O O O OH O O HO O OH HO O O O OH O O HO 39a 39b 39c 39d 39e O HO HO HO O O HO HO HO O O HO HO HO O O HO HO HO O 41a 41b 41c 41d D-lyxose (42) HO O HO O O 43 O OH HO OH OH Fig. 4 Structure of D-lyxose and compounds obtained from the condensation of pentoses with Meldrum’s acid Table 2 Products of the condensation of pentoses with Meldrum’s acid Pentose Unsaturated lactone (yields) Furanoid lactone (yields) C-2 epimerized furanoid lactone (yields) Pyranoid lactone D-Ribose (9) 41a (5%)a (5%)b 39a (41%)a (20%)b 39b (21%)a (61%)b – D-Arabinose (8) 41b (6%)a (6%)b 39b (51%)a (61%)b 39a (20%)a (15%)b – D-Xylose (7) 41c (5%)a (6%)b 39c (67%)a (63%)b – – D-Lyxose (42) 41d (5%)a (6%)b 39d (5%)a (3%)b 39c (41%)a (51%)b 43 (10%)a (22%)b a Pentose, Meldrum’s acid, tBuNH2 (1:2:1), 5 days, 40C [109] b Pentose, Meldrum’s acid, Et3N (1:1:1), 10 days 48–49C [107, 108] O HO OH O O HO 44 OH OH O HO OH O HO OH 45 + CH3CO2 O HO OH HO OH OH + O O NaHCO3 H2O 1 Scheme 9 Reaction of aldoses with pentane-2,4-dione (1) in alkaline aqueous media 10 M.-C. Scherrmann