Analogs 2a Research Articles

Synthesis of two diphosphorylated lipid a derivatives containing α‐ or β‐anomeric phosphates

AbstractThe preparation of two diphosphorylated Lipid A analogues, which contain α‐ or β‐phosphates at the reducing end, is described (i.e. compounds 14d and 15d, respectively). The synthesis of these compounds was accomplished using: (i) two suitably protected glucosamine derivatives, i.e. the non‐reducing part 6 and the reducing part 3; (ii) an iridium catalyst to isomerize the anomeric allyl ethers quantitatively into 1‐propenyl ethers, which can then be removed to give simultaneously oxazoline functions (i.e. isomerization of 4b into 5 and of 7a into 7b); (iii) the levulinoyl* group for temporary protection of the 4‐hydroxyl group; (iv) 1‐hydroxybenzotriazole‐activated phosphorylating agents for the phosphorylation of the 4′‐hydroxyl group (i.e. phosphorylation of compound 8 to give 10a,b); (v) 2,2,2‐tribromoethyl phosphate for the phosphorylation of the reducing anomeric centre of Lipid A analogues (i.e. phosphorylation of 11a,b to afford 13a,b).Non‐reducing part 6 and reducing part 3 were reacted together to give the disaccharide 7a, which was converted into non‐phosphorylated Lipid A precursor 8. Phosphorylation of compound 8 at its 4′‐hydroxyl function and at its reducing anomeric centre resulted in the formation of fully protected α‐phosphorylated Lipid A analogues 14a and 14b together with the fully protected β‐phosphorylated analogues 15a and 15b. Final removal of all the protecting groups from 14a,b and 15a,b gave the α‐phosphorylated Lipid A analogue 14d and the β‐phosphorylated Lipid A analogue 15d, respectively.

The synthesis of N‐[2‐(D‐glucos‐3‐O‐yl)propionyl]‐l‐alanine and N‐[(d‐glucos‐3‐O‐yl)acetyl]‐l‐alanine

AbstractN‐[2‐(D‐Glucos‐3‐O‐yl)propionyl]‐L‐alanine (7a) was synthesized, which has a glucose residue instead of N‐acetylglucosamine residue in the muramyl peptide. N‐[(D‐Glucos‐3‐O‐yl)acetyl]‐L‐alanine (7b) was also synthesized as a glycolyl analog of 7a in order to determine the relationship between the structure of propionyl moiety in the carbohydrate analog (7a) and the adjuvant activity. These simple analogs are compounds prepared for the purpose of introduction into a synthetic polymer with the view of producing polymeric drugs.

A synthetic approach to crown ether analogs by the remote photocyclization with a pai system of phthalimide and methylthio groups

Upon irradiation a homologous series of certain phthalimides ( 2a - c ) possessing a terminal sulfide function in their N-poly-ether side chain undergo regioselective remote photocyclization affording seven to fifteen-membered crown ether analogs ( 3a - c ) in moderate yields.

Reaction of ethyl 3‐ethoxymethylene‐2,4‐dioxovalerate and ethyl ethoxymethyleneoxaloacetate with 3‐aminopyrazole analogs. Synthesis and chemistry of 3,6,7‐trisubstituted pyrazolo[1,5‐a]pyrimidine derivatives

AbstractThe chemical reactivity of a series of 3‐substituted‐6‐acetyl‐7‐carbethoxypyrazolo[l,5‐a]pyrimidines (6a,b,c) and 3‐substituted‐6,7‐dicarbethoxypyrazolo[1,5‐a]pyrimidines (7a,b,c), prepared by the condensations of the 3‐aminopyrazole analogs (3a,b,c) with ethyl 3‐ethoxymethylene‐2,4‐dioxovalerate (1) or ethyl 3‐ethoxymethyleneoxaloacetate (2), was investigated. Catalytic hydrogenation of 6 or 7 afforded 4,7‐dihydro derivatives (8 or 9). Treatment of 6a,b with acetic acid and water underwent ring transformation into 6H‐pyrazolo[1,5‐a][1,3]diazepin‐6‐ones (17a,b). By treatment with phenylhydrazine compounds of type 6 underwent cyclization to yield 2H‐dipyrazolo[1,5‐a:4′,3′‐e]pyrimidines (18a,b,c). Compounds 6 or 7 were treated with an excess of diazomethane at room temperature to give 5‐methyl‐6H‐cyclopropa[5a,6a]pyrazolo‐[1,5‐a]pyrimidines (24 and 25) in excellent yields. However, when this reaction was carried out under ice cooling, only compounds of type 23 were isolated. Reaction of 6a with ethyl diazoacetate is also described.

ChemInform Abstract: HETEROCYCLIC PROSTAGLANDINS. VI. SYNTHESIS OF 11‐DEOXY‐8,10‐DIAZAPROSTAGLANDIN E1 AND ITS 10‐METHYL DERIVATIVE

AbstractDer ausgehend von (I) oder (IV) zugängliche cyclische Harnstoff (III) wird durch Reduktion und Oxidation in den Aldehyd (V) umgewandelt.

ChemInform Abstract: SYNTHESIS OF NEW CHIRAL PHOSPHINES FOR ASYMMETRIC CATALYSIS

A new analog 6a of diop is prepared from D-mannitol. The synthesis of the 1,3-diphosphine 9a and of 1,2-aminomonophosphine 12 are described. All these phosphines behave presumably as bidentate ligands, their efficiency in asymmetric catalysis are compared in a set of reactions involving asymmetric C-H or C-C bond formations.

Heterocyclic prostaglandins. VI. Synthesis of 11-deoxy-8,10-diazaprostaglandin E1 and its 10-methyl derivative.

The synthesis of 11-deoxy-8, 10-diazaprostaglandin E1 (1a) starting from methyl 3-benzyloxycarbonyl-2-oxo-4-imidazolidinecarboxylate (3a) is reported. Alkylation of 3a with methyl 7-bromoheptanoate and NaH gave methyl 1-benzyloxycarbonyl-3-(6-methoxycarbonyl) hexyl-2-oxo-4-imidazolidinecarboxylate (9), which was converted into the 4-hydroxymethyl-imidazolidine derivative (10). The Moffatt oxidation of 10, and the Wittig reaction of the resulting aldehyde (11) with dimethyl 2-oxoheptylphosphonate provided an enone (12). Reduction of 12, and hydrolysis of a mixture of C15-epimeric alcohols (15) followed by re-esterification afforded 11-deoxy-8, 10-diazaprostaglandin E1 methyl ester (17a). Alkaline hydrolysis of 17a gave 1a as crystals in a good yield. The 10-methyl derivative (2a) was also synthesized. Methylation of 3a with methyl iodide and K2CO3 gave the 1-methylimidazolidine analog (7a), which was converted into methyl 3-(6-methoxycarbonyl) hexyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (20) after debenzyloxycarbonylation and alkylation with methyl 7-bromoheptanoate. Conversion of 20 into 2a was carried out by a synthetic sequence similar to that used for the elaboration of 1a.

Synthesis of new chiral phosphines for asymmetric catalysis

AbstractA new analog 6a of diop is prepared from D‐mannitol. The synthesis of the 1,3‐diphosphine 9a and of 1,2‐aminomonophosphine 12 are described. All these phosphines behave presumably as bidentate ligands, their efficiency in asymmetric catalysis are compared in a set of reactions involving asymmetric C‐H or C‐C bond formations.

Synthesis of yokonoside and its related compounds (author's transl)

Total synthesis of yokonoside, 2'-carboxy-4', 5-dihydroxy-2-β-D-glucopyranosyloxybenzanilide (1b), isolated from Aconitum japonicum THUNB., was carried out by two different routes. The 4'-deoxy analog (1a) was also synthesized. The Koenigs-Knorr reaction of 5-benzyloxy-2-hydroxy-2'-methoxycarbonylbenzanilide (5a) with silver carbonate gave a dimer, 2, 3'-bis (2-methoxycarbonylphenylcarbamoyl)-4, 5'-dibenzyloxy-2'-hydroxydiphenyl ether (7a), as a by-product.

Acyclic-sugar nucleoside analogs. Thymine derivatives from acyclic d-galactose and d-glucose precursors

Fusion of 2,3,4,5,6-penta- O-acetyl-1-bromo-1-deoxy-1- S-ethyl-1-thio- aldehydo- d-galactose aldehydrol ( 1) with bis(trimethylsilyl)thymine ( 2) gave a 1-epimeric pair of acyclic-sugar nucleoside derivatives ( 3a and 3b), which were saponified to their O-deacetylated analogs 4a and 4b. Similarly, the 1-methoxy ( 5) and 1-benzyloxy ( 8) analogs of the bromide 1 were converted into the corresponding protected nucleoside analogs 6 and 9, respectively; subsequent saponification gave the corresponding O-deacetylated derivatives 7 and 10. In the same way, 2,3,4,5,6-penta- O-acetyl-1-bromo-1-deoxy-1- S-ethyl-1-thio- aldehydo- d-glucose aldehydrol ( 11) was converted into the acyclic-sugar thymine nucleoside analog 13 by way of the pentaacetate 12. Exposure of 1-deoxy-1- S-ethyl-1-thio-1-(thymin-1-yl)- aldehydo- d-galactose aldehydrol ( 4) to conditions of acetolysis led to the pentaacetate 3, whereas similar treatment of the 1-(adenin-9-yl) analog ( 14) of 3 caused scission of the 1-substituents to give hepta- O-acetyl- aldehydo- d-galactose aldehydrol ( 15).

1161. The vacuum arc furnace

The synthesis of phosphonates of methylenecyclopropane nucleoside analogues 15a–18a, 15b–18b and 15c–18c by alkylation–elimination approach is described. In a foreshortened series, methanesulfonate 19 was transformed by Michaelis–Becker reaction with diethyl or diisopropyl phosphite to methylenecyclopropane phosphonates 20a or 20b. The latter were converted to vicinal dibromides 21a and 21b which were then used for alkylation–elimination of nucleic acid bases (adenine) or precursors (2-amino-6-chloropurine and N4-acetylcytosine). The intermediary Z+E-isomers 22a+23a and 22b+23b were dealkylated with bromo- of iodotrimethylsilane to free phosphonic acids 15a, 16a and phosphonate with an open cyclopropane ring 25 which were separated by ion exchange chromatography on Dowex 1. Phosphonate diesters 22c and 23c were separated by chromatography on silica gel, they were hydrolyzed to guanine derivatives 22d and 23d which were then dealkylated to give target analogues 15b, 16b and products of addition of hydrogen bromide or iodide across the double bond 26a or 26b. The E+Z-isomers 22e+23e were converted to cytosine phosphonates 15c+16c and cyclic phosphonate with an open cyclopropane ring 27a. In a homologous series of phosphonates, dibromocyclopropane 34 was converted to intermediate 31 by reaction with diisopropyl methyl phosphonate and subsequent β-elimination. Compound 31 was transformed to vicinal dibromide 36, a key component for alkylation–elimination of nucleic acid bases. The rest of the synthetic sequence followed the scheme described for the series of lower homologues to give the Z-isomeric phosphonates 17a, 17b, E-isomers 18a, 18b and E+Z-isomers 17c+18c as the final products. All methylenecyclopropane phosphonates were devoid of antiviral activity with the exception of guanine derivative 15b which inhibited the replication of varicella zoster virus (VZV) and it was non-cytotoxic.