Laila F. Awad

Synthesis of Interglycosidically S‐Linked 1‐Thio‐Oligosaccharides Under Microwave Irradiation*

Microwave irradiation (MWI) has accelerated the synthesis of S‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl)thiouronium bromide (2a), whose reaction with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glucopyranosyl bromide (1a) in the presence of Et3N afforded stereoselectively the acetylated β,β‐1‐thiotrehalose 4a. Similarly, the respective D‐galactopyranosyl 4b and 2‐acetylamino‐2‐deoxy‐D‐glucopyranosyl 4c analog as well as 4,4′‐di‐O‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl) 4d and 4,4′‐di‐O‐(2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glucopyranosyl) 4e derivatives of 2,2′,3,3′,6,6′‐hexa‐O‐acetyl β,β‐1‐thiotrehalose were prepared. Presented at the EUROCARB12, Grenoble, France, 2003, PB 074, 286.

Novel Regioselective Hydroxyl-Alkylation of 4,5-Diphenylimidazole-2-Thione and A Competitive Intramolecular Ring Closure of the S-Hydroxyalkyl-Imidazoles to Imidazo[2,1-b]Thiazines and Thiazoles. Role of Catalyst, Microwave Irradiation, and Solid Support

Under both conventional method (CM) and microwave (MW) irradiation (MWI) conditions, alkylation of 4,5-diphenylimidazole-2-thione (1) with halogeno-alkanols 2 or 5, chloroglycerol 11 and 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (8) in presence of sodium ethoxide or sodium acetate in alcohol afforded regioselectively the corresponding S-alkylated analogues 3, 6, 9, and 12; they also were obtained using MW in absence and presence of bentonite as solid support with no change in regioselectivity. In the presence of potassium carbonate in DMF, the bisalkylated analogues 4, 7, 10, and 13 were obtained except in case of compound 13 where it was accompanied with the imidazothiazine 14. A convenient approach for imidazo-[2,1-b]thiazines and thiazoles 14–16 could be achieved by intramolecular dehydrative ring closure of the S-hydroxyalkylated imidazoles 3, 6, and 12 using potassium carbonate in DMF under both conventional and microwave methods. Isopropylidenation of 12 and 13 and deprotection of 9 and 10 also were investigated.

Microwave-Assisted Organic Synthesis of 3-(D-gluco- Pentitol-1-Yl)-1H-1,2,4-Triazole

The condensation of D-glucono- and D-galactono-1,5-lactone and thiocarbohydrazide to give 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 is accelerated by the use of microwave-assisted organic reaction (MAOS). The deamination and dethiolation of compound 4 to give 6 was also accelerated by the use of MAOS. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 8 and 9 , respectively, within 4 min under microwave irradiation (MWI), whereas with ethyl chloroacetate the thioalkylated products 14 and 15 were obtained in 8 min. The structures of the synthesized compounds were confirmed by 1 H NMR, 2D NMR, and mass spectra.

Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

Publisher Summary This chapter explores that dimedone is a versatile precursor for annulated heterocycles. Dimedone(1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methylene group and exists in a tautomeric transenolized form where intramolecular hydrogen bonding is not possible. Dimedone is an excellent precursor for partially hydrogenated fused heterocycles where two of the carbon atoms of dimedone are part of the backbone of the formed heterocycles. The chapter illustrates that dimedones structural features and its reactivity to form more functionalized derivatives have led to the construction of a wide range of fused or spiral biheterocycles. Finally, this chapter emphasizes the role of 1 in the synthesis of fused heterocycles, classified according to the size of the ring and the number of heteroatoms in the heterocycle fused to the cyclohexane ring and subdivided according to the heteroatoms and their arrangement in the ring.

Synthesis of 5‐Aryl‐3‐Glycosylthio‐4‐Phenyl‐4H‐1,2,4‐Triazoles and Their Acyclic Analogs Under Conventional and Microwave Conditions

Under microwave irradiation (MWI), 4‐phenyl‐5‐substituted‐4H‐1,2,4‐triazole‐3‐thiol derivatives 7 and 8 were synthesized in a good yield by intramolecular cyclization of the aroyl phenyl thiosemicarbazides 5 and 6. The respective triazolylglycosides (Str‐glycosides) 12–17 were obtained by reaction of triazoles 7 and 8 with glycosyl halides 9–11 in dry acetone in the presence of potassium carbonate as base under both conventional and MWI conditions. Alkylation of 7 and 8 with haloalchols 18–20 in boiling ethanolic solution containing sodium ethoxide as a base gave the corresponding alkylated analogs 21–26. MWI conditions led to higher yield in shorter reaction time than the conventional method. Treatment of 26 with tosyl chloride gave the unexpected product 29 and not 27 or 28. Oxidation of 26 with sodium metaperiodate afforded triazole 8 and not the aldehyde 30. Attempted glycosylation and alkylation of the phenolic OH group in triazole 8 were unsuccessful; this was proved by theoretical calculations using the AM1 semi‐empirical method.

NOVEL SYNTHESIS OF seco TYPE OF ACYCLO C-NUCLEOSIDES OF 1,2,4-TRIAZOLE AND 1,2,4-TRIAZOLO[3,4-b][1,3,4]THIADIAZINE

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D- galacto-pentitol-1-yl)-1H-1,2,4-triazoles (8 and 9) were obtained in a one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. Condensation of 1, 2, and 4-amino-3-(D-glycero-D-gulo-hexitol-1-yl)-5-mercapto-1,2,4-triazole (12) with phenacylbromide (11) afforded the corresponding 3-(D-gluco-, D-galacto-pentitol-1-yl) and 3-(D-glycero-D-gulo-hexitol-1-yl)-6-phenyl-7H-1,2,4- triazolo[3,4-b][1,3,4] thiadiazines (15, 16, and 17). Acetylation of 15–17 gave the penta- and hexa-O-acetyl derivatives 18–20, respectively. The structures were confirmed by using 1H, 13C, and 2D NMR spectra, DQFCOSY, HMQC, and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.

A Novel Approach for the Synthesis of seco C-Nucleoside Analogues

Abstract The synthesis of 4-amino-3-(D-gluco- or D-galacto-pentitol-1.yl)-5-mercapto-1,2,4-triazoles and their conversion to the respective 6-methyl-3-(1,2,3,4,5-penta-O-acetyl-pentitol-1-yl)1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles have been achieved. The vicinal coupling constants were used to deduce the favored conformations.

Inhibition of some hepatic lysosomal glycosidases by ethanolamines and phenyl 6-deoxy-6-(morpholin-4-yl)-β-d-glucopyranoside

The hepatic lysosomal glycosidases alpha-glucosidase and beta-glucuronidase were inhibited in vitro and in vivo by mono- and diethanolamines. The in vivo inhibition is dose dependent and occurs at a value less than LD50. Phenyl 6-deoxy-6-(morpholin-4-yl)-beta-D-glucopyranoside inhibited alpha-glucosidase both in vitro and in vivo. The treatment of the enzymes in vitro by ethanolamine exhibited a reversible inhibition of the mixed and competitive types for alpha-glucosidase and beta-glucuronidase, respectively. Diethanolamine showed a reversible inhibition of the competitive type for both enzymes. It is a potent inhibitor for beta-glucuronidase, in vitro, whose inhibition constant (Ki) is 5 x 10(-5) M. Phenyl 6-deoxy-6-(morpholin-4-yl)-beta-D-glucopyranoside is a potent inhibitor only for hepatic alpha-glucosidase with a Ki value of 1.6 x 10(-5) M. The pattern of the pH dependence of enzymic activity was not affected by ethanolamine inhibition. The magnitude of the inhibition of enzymes is dependent on the structure of the inhibitor.

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.

Synthesis of new 7-alkylated theophyllines by chemical modification of dyphylline

Chemical modification of the propyl side chain of 7-(2,3-dihydroxyprop-1-yl)theophylline led to a variety of hetero-cyclic compounds linked to the theophylline by a methylene group.