Gumer Yu. Ishmuratov,@ Marina P. Yakovleva, Galina R. Mingaleeva, Rinat R. Muslukhov, Evgeny M. Viripaev, Evgeny G. Galkin, and Alexander G. Tolstikov
Institute of Organic Chemistry, Ufa Scientific Centre of RAS, 450054 Ufa, Russia
@Corresponding author E-mail: insect@anrb.ru
DOI: 10.6060/mhc2011.1.11
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.)]. 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 [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-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 7-oxabicyclo[2.2.1]hepta-5-en-2,3-dicarbonic acid. The latter, in its turn, was synthesized from dimethyl ester 7-oxabicyclo[2.2.1]hept-5-en-2,3-dicarbocylic acid mixed with the cyclic derivative [2,3,4a,5,8,8a-hexahydro-5,8-epoxyphtalazin-1,4-dione] 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, 9, 1749-1757] will serve to increase the known pharmacological activity and display its new types. It should be noted that all macrocyclization reactions were carried out at room temperature in dioxane under high-dilution conditions. The structures of the obtained macrocycles (6, 8, 9, 11) were determined by IR, NMR 1Н and 13С spectroscopy; their purity was HPLC controlled.
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