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

Abstract

Eight potentially useful 15-, 17-, 20-, and 22-25-membered macrolides having an azine or hydrazide fragment were synthesized starting from L-menthol, tetrahydropyran, and 4-methyltetrahydropyran via [1 + 1]-condensation of hydrazine hydrate and some dicarboxylic dihydrazides with 7-oxooctyl 7-oxooctanoate, 3-methyl-7-oxooctyl 3-methyl-7-oxooctanoate, and (3R)-3,7-dimethyl-6-oxooctyl (3R)-3,7-dimethyl-6-oxooctanoate obtained by the Tishchenko reaction from 7-oxo-, 3-methyl-7-oxo, and (3R)-3,7-dimethyl-6-oxooctanals, respectively. * 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.[1+1]-Condensation of the latter with hydrazine hydrate or malonic, succinic, glutaric, and adipic acid dihydrazides in strongly dilute dioxane solution at room temperature, followed by treatment of the reaction mixture with methylene chloride-hexane (1 : 10), afforded 40-54% of macrolides having a ketone azine (X, XI) or bis-hydrazide fragment (XII-XVII), respectively (Schemes 1, 2).The structure of macrocyclic compounds X-XVII was determined by IR spectroscopy and 1 H and 13 C NMR; according to the HPLC data, their purity was ~95%. The NMR spectra of X-XVII were analyzed by comparing with the spectra of initial compounds, dioxo esters VII-IX and dicarboxylic acid dihydrazides. The 13 C NMR spectra of compounds XI and XVII lacked signals of carbonyl carbon atoms (δ C 214.13 and 214.42 ppm) and methylene and methine groups in the α-position to the carbonyl group (δ C 35.08, 37.53 ppm), which were typical of initial dioxo ester IX. In addition, no hydrazide NH 2 signal was observed in the 1 H NMR spectrum of macrocycle XVII (δ 4.75 ppm in the spectrum of the initial hydrazide). These findings indicate that the products have cyclic structure rather than the structure of acyclic substitution products. The 13 C NMR spectrum of XI, apart from the singlet at δ C 170.64 ppm (ester carbonyl carbon atom), contained a singlet at δ C 169.24 ppm due to C=N carbon atoms, which is consistent with the formation of macrocycle possessing an azine fragment.Compound XVII displayed in the 13 C NMR spectrum a signal ...

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).…”

“…The 13 C NMR spectra of the reaction products 6 and 7 did not show any signals of carbonyl carbon atoms of initial compounds 2 and 3 (208.86 ppm and 208.99 ppm in 6 and 208.66 ppm in 7). Furthermore, 1 H NMR spectra of the macrocycles 6 and 7 did not show resonances of the hydrazine group (NH 2 NH) (~4.63 ppm). These facts indicated that the products were not the linear substitution products.…”

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

“…We recently reported [5] on the synthesis of eight potentially useful 15-, 17-, 20-, and 22-25-membered macrocycles having an azine or hydrazide fragment starting from L-menthol (I), tetrahydropyran (II), and 4-methyltetrahydropyran (III) via consecutive Tishchenko reaction and [1 + 1]-condensation.…”

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].…”

“…Herein we report the transformations of compounds 2 and 3 in reactions with bicyclo[2.2.1]heptane-2-endo,3-endo-dicarbohydrazide (5) and its 5-endo,6-endo-and 5-endo,6-exodihydroxy derivatives 6a and 6b which were prepared DOI: 10.1134/S1070428015060020 Scheme 1. (4). Dihydrazide 5 was synthesized by treatment of 4 with excess hydrazine hydrate in ethanol at 25°C, and compounds 6a and 6b were obtained in a similar way from the corresponding dihydroxy derivatives 7a and 7b.…”