No abstract
Potentially useful 17-, and 22÷25-membered macrolides containing azine or hydrazide groups were synthesized from tetrahydropyran via [1+1]-condensation at room temperature of 7-oxooctyl-7-oxooctanoate, which was obtained via Tishchenko reaction from 7-oxooctanal, with hydrazine hydrate and hydrazides of several dicarboxylic acids.Polyfunctional macroheterocycles with interesting complexing properties and biological activity are widely used as interphase-transfer catalysts, extractants, analytical reagents, and materials for creating ion-selective electrodes [1-3].Herein we report the synthesis of 17-(9), 22-(10), 23- (11), 24- (12), and 25-membered (13) macrolides that may exhibit complexing properties and biological activity and contain azine or hydrazide functional groups. The synthetic scheme is based on chemo-and regioselective transformations of a ketoalcohol (2) that is accessible in three steps from tetrahydropyran (1) [4]. Corey oxidation of 2 produced ketoaldehyde 3, which has been used to synthesize 9-oxo-2E-decenoic acid (multifunctional pheromone of honeybee Apis mellifera L.) [5], and small quantities (up to 15%) of 7-oxooctyl-7-oxooctanoate (4) by disproportionation of 3 via a Tishchenko reaction. The yield of 4 could be increased (up to 70%) by using the classical method [6] with catalytic quantities of aluminium triisopropoxide.[1+1]-Condensation of 4 in dioxane at high dilution and room temperature with hydrazine hydrate or dihydrazides of malonic (5), succinic (6), glutaric (7), and adipic (8) acids and subsequent successive work up of the reaction mixture with CH 2 Cl 2 and hexane (1:10 ratio) produced in good yields (40-50%) macrolides with azine (9) or hydrazide (10-13) groups, respectively.
The 1‐alkenes (I) are treated with triethylaluminum (II) in the presence of zirconocene dichloride to generate the aluminacyclopentanes (III).
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
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