Synthesis of macrolides with N-containing (azine or hydrazide) groups

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.

Synthesis of macrocyclic azino and dihydrazido diesters by consecutive [2 + 1]- and [1 + 1]-condensations

“…Dioxo diesters XI-XX (general procedure). A solution of 0.50 mmol of the corresponding dicarboxylic acid dichloride (prepared according to the procedure reported in [10]) in 1 ml of anhydrous diethyl ether was added under stirring to a solution of 1.00 mmol of hydroxy ketone VI-X [6][7][8][9] in 1 ml of anhydrous pyridine. After 48 h (TLC), the mixture was diluted with 10 ml of diethyl ether, washed first with 5% hydrochloric acid (3 × 1.5 ml) and then with a saturated solution of sodium chloride (3 × 1.5 ml), dried over MgSO 4 , and evaporated.…”

“…All these procedures are based on initial transformation of compounds I-V into the corresponding hydroxy ketones: (6R)-8-hydroxy-2,6-dimethyloctan-3-one (VI) [6], 8-hydroxyoctan-2-one (VII) [7], 8-hydroxy-6-methyloctan-2-one (VIII) [8], 1-[(1S,2R)-2-(2-hydroxyethyl)-3,3-dimethylcyclopropyl]propan-2-one (IX) [9], and 1-[(1S,3S)-3-(2-hydroxyethyl)-2,2-dimethylcyclobutyl]ethanone (X) [9]. The subsequent [2 + 1]-condensation of compounds VI-X with glutaric and adipic acid dichlorides afforded open-chain diesters XI-XX containing two fragments of ketones VI-X as alcohol residues.…”

Reactions of bicyclo[2.2.1]heptane-2-endo,3-endo-dicarbohydrazide and its 5-endo,6-endo- and 5-endo,6-exo-dihydroxy derivatives with 7-oxooctyl 7-oxooctanoate and bis(7-oxooctyl) hexanedioate

“…Macrolides with nitrogen-containing (azine or hydrazide) fragments are commonly prepared by the Tishchenko disproportionation of ketoaldehydes to α,ω-diketo esters or [2 + 1]-condensation of hydroxy esters with α,ω-dicarboxylic acid dichlorides and subsequent macrocyclization by the action of an equimolar amount of hydrazine hydrate or α,ω-dicarboxylic acid hydrazides [1][2][3][4][5][6][7][8][9].…”

Synthesis of macrolides containing an azine or hydrazide fragment via successive tishchenko disproportionation and [1 + 1]-condensation

“…* For preliminary communications, see [1,2].It is known [3-6] that functionalized macrocyclic compounds are widely used in organic and petrochemical synthesis, detection and separation of metals by extraction, sorption and chromatographic analytical methods, ionometry, design of cardio-and psychotropic agents and studies on mechanisms of their action, development of antimicrobial, antiparasitic, and antitumor drugs, etc.In the present article we describe efficient ways of synthesis of 15-, 17-, 20-, and 22-25-membered macrolides having an azine or hydrazide fragment starting from accessible synthetic [tetrahydropyran (I) and 4-methyltetrahydropyran (II)] and natural [L-menthol (III)] compounds. The proposed approach is based on initial transformation of cyclic substrate into the corresponding oxo aldehydes, 7-oxo-, 3-methyl-7-oxo-, and (3R)-3,7-dimethyl-6-oxooctanals IV-VI, according to the procedure reported in [1,2], and their subsequent Tishchenko disproportionation to give dioxo esters VII-IX.…”

“…The proposed approach is based on initial transformation of cyclic substrate into the corresponding oxo aldehydes, 7-oxo-, 3-methyl-7-oxo-, and (3R)-3,7-dimethyl-6-oxooctanals IV-VI, according to the procedure reported in [1,2], and their subsequent Tishchenko disproportionation to give dioxo esters VII-IX.…”