Synthesis of Macroheterocycles with Ester and Hydrazide Fragments on the Basis of Tetrahydropyran

Abstract

An area of application of tetrahydropyran has been expanded in the directed synthesis of macroheterocycles with ester and hydrazide fragments. The structures of the obtained macrocycles were proved by IR and NMR spectroscopy as well as mass spectrometry. We have already reported the synthesis of tetrahydropyran-based 9-oxo-2Е-decenoic acid(2) as the multifunctional pheromone [Chem. Nat. Compd. 2008, 44, 74-76] of queen honeybee Apis melliphera L., 7-oxooctyl-7-oxooctanoate (3) [Bashkir University Bulletin 2008, 3, 466-469 (in Russ.)] and bis (7-oxooctyl)adipate (4) [Butlerov Communications 2009, 17(5), 35-38 (in Russ.)] and also the application of key α,ω-diketones (3, 4) in the directed synthesis of a large variety of macroheterocycles with ester, azine and hydrazide functions, one of which [15,25-dimethyl-1,8-dioxo-16,17,23,24-tetraazacyclohentriaconta-15,24-dien-2,7,18,22-tetraone (10)] exhibited great antibacterial in vitro and in vivo activity [Butlerov Communications 2009, 16(4), 21-25 (in Russ.) [16,26-dimethyl-1,4,7-trioxa-17,18,24,25-tetraazacyclotetratriaconta-9,16,25,32-tetraen-8,19,23,34-tetraone (6), 8,22-dimethyl-1-oxa-9,10,20,21-tetraaza-8,21-cyclooctacosadien-2,11,19-trione (8), 8,23-dimethyl-1-oxa-9,10,20,22-teraaza-8,22-cyclononakosadien-2,11,20-trione (9), 4,25-dimethyl-28a,29,32,32a-tetrahydro-29,32-epoxy-11,18,2,3,26,27-benzadioxatetraazacyclotriaconta-3,25-dien-1,12,17,28- in its turn,3,4a,5,8, and separated from the reaction mixture. In our opinion, the introduction of pharmacophoric 7-oxabicyclo[2.2.1]heptane fragment [J. Med. Chem. 1985, 28, 1580-1590 Heterocycles 1978 Heterocycles , 9, 1749 Heterocycles -1757 ]. In this paper we put forward efficient methods to transform tetrahydropyran (1) as a disposable petrochemical product via intermediate α,ω-diketones [7-oxooctyl-7-oxooctanoate (3), bis(7-oxooctyl)adipate (4) and oxabis(ethan-1,2-diyl)(2'E,2'E)bis(9'-oxodec-2'-enoate) (5)] into potentially biologically and pharmacologically active macroheterocycles tetraone (11)] that contain the ester and hydrazide functions, including the olefin ones. The macrocycle (6) with conjugated ester groups was synthesized on the basis of unsaturated ketonic acid (2) by its transformation into the appropriate chloroanhydride, [2+1]-condensation with diethylene glycol and subsequent [1+1]-interaction between intermediate diketone diester (5) and glutaric dihydrazide. The synthesis of 28-(8) and 29-(9) member macrolides was performed by [1+1]-condensation of α,ω-dimethylketone (3) with azelaic and sebacic dihydrazides, respectively. The macrolide analog (10) exhibiting the antibacterial activity, i.e., macrocycle (11) with 7-oxabicyclo[2.2.1]heptane fragment in the form of a single di-exo-isomer, was obtained by [1+1]-condensation of the key precursor (4) with the linear dihydrazide of

Synthesis of Dipeptide and Carbohydrate Ivermectin B1 Derivatives

“…5-Хлорацетат ивермектина (6). Ивермектин (5.15 г, 6.0 ммоль) растворяли в 70 мл безводного хлористого мети-лена, после чего добавляли к полученному раствору пири-дин (2.3 мл, 30 ммоль).…”

“…[4] Кроме того, имеются данные о положительном влиянии дополнительных фармакофорных азотсодержащих фрагментов в молеку-лах макролидов на проявление или усиление противо-воспалительной, анальгетической, противовирусной, антимикробной и противоопухолевой, а также иммуно-модулирующей активности. [5,6] Одним из таких соединений является макролид -ивермектин В1 -полусинтетический авермектин, ко-торый представляет собой смесь 22,23-дигидроавермек-тинов В1 (1а,b), основой которого является 16-членное лактонное кольцо. [7] Ивермектин В1 отличается низкой токсичностью для теплокровных, высокой стабильностью, интенсив-ностью противопаразитарной активности и широким спектром действия, включая противовирусную актив-ность.…”

Synthesis of Macrolides with Hydrazide Fragments from Tetrahydropyran and 2,6-Pyridinedicarboxylic Acid

“…[1,2] Their [1+1]-condensation with hydrazine hydrate or dihydrazides of malonic, glutaric, adipic, [1,2] azelaic, sebacic, 7-oxabicyclo[2.2.1]heptenoic [3] and tartaric [4,5] acids led to macroheterocycles containing one or two ester groups and azine or dihydrazide fragments. One of the synthesized macrolides 4 showed a significant (at the level of erythromycin) antibacterial activity in vitro and in vivo against the museum and field strains of pathogenic microorganisms (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa).…”

“…One of the synthesized macrolides 4 showed a significant (at the level of erythromycin) antibacterial activity in vitro and in vivo against the museum and field strains of pathogenic microorganisms (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa). [6] In continuation of these studies we performed [1+1]-condensation of α,ω-diketone (2) or (3) with 2,6-pyridinedicarboxylic acid hydrazide (5) that was prepared using the standard method. [7] Introduction of 2,6-pyridinedicarboxylic acid to the macrocyclic fragment is due to the fact that its derivatives exhibit a wide range of pharmacological activity (such as, antibacterial, anti-inflammatory, anticoagulant and antitumor), [8] and derivatives of 2,6-pyridinedicarboxylic acid are widely used in chemistry of a complex formation.…”

“…Synthesis of macrocyclic compounds 6 and 7 (general procedure). The 2,6-pyridinedicarboxylic acid hydrazide (5, as described in [6] ) (0.244 g, 1.0 mmol) in 1.8 mL of H 2 O, was slowly added under vigorous stirring to 1.0 mmol of α,ω-diketones 2 or 3 in 8.5 mL of dioxane. The mixture was stirred for 48 h (monitoring TLC) and dioxane was evaporated under reduced pressure.…”