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

Abstract

Efficient procedures for the synthesis of 21-24-and 28-31-membered macrocyclic azino diesters and dihydrazido diesters were developed starting from L-menthol, Δ 3 -carene, (+)-α-pinene, tetrahydropyran, and 4-methyltetrahydropyran. The key steps in these syntheses were consecutive [2 + 1]-and [1 + 1]-condensations. The 31-membered dihydrazido diester exhibited strong antibacterial activity.* For preliminary communications, see [1][2][3][4].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.We now propose efficient procedures for the transformation of compounds I-III, as well as of accessible monoterpenes, Δ 3 -carene (IV) and (+)-α-pinene (V), into macrocyclic azino diesters XXI-XXIX and dihydrazido diesters XXX-XXXIX. 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). 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. Dioxo diesters XI-XX were then subjected to cyclization via [1 + 1]-condensation with hydrazine hydrate and glutaric acid dihydrazide in strongly dilute dioxane solution at room temperature to obtain azino diesters XXI-XXIX and dihydrazido diesters XXX-XXXIX, respectively (Schemes 1-4). The purity of intermediate compounds XI-XX and target macroheterocycles XXI-XXXIX was checked by HPLC, and their structure was confirmed by IR, 1 H and 13 C NMR, and mass spectra.The synthesized compounds were tested for biological activity at the Noncontagious Internal Diseases, Clinical Diagnostics, and Pharmacology Department, Bashkir State Agrarian University [4]; it was found that 31-membered macrocyclic dihydrazido diester XXXIII showed in vitro and in vivo antibacterial activity comparable with the activity of Erythromycin. EXPERIMENTALThe IR spectra were recorded on a UR-20 spectrometer from thin films. The NMR spectra were measured on a Bruker AM-300 spectrometer at 300.13 MHz for 1 H and 75.47 MHz for 13 C using CDCl 3 as solvent and tetramethylsilane as internal reference. Chromatographic analysis was performed on Chrom-5 [1.2-m column, stationary phase 5% of SE-30 on Chromaton N-AW-DMCS (0.16-0.20 mm), oven temperature 50-300°C] and Chrom-41 instruments [2.4-m column, stationary phase PEG-6000, oven temperature 50-200°C]; carrier gas helium. HPLC analyses were obtained on a Shimadzu LC-20AD liquid chromatograph equipped with an SPD M20A diode matrix detector [250 × 4.6-mm Phenomenex column; sorbent Luna C18, grain size 5 μm; eluent water-acetonitrile, flow rate 1 ml/min; analytical wavelength 215 nm]. Silica gel, 70-230 μm

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

“…Yield 0.22 g (77%, a), 0.24 g (85%, b). The IR, 1 H and 13 C NMR, and mass spectra of 8 were identical to those given in [5].…”

“…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].…”

“…Compounds 8 and 9 were synthesized previously by [1 + 1]-condensation of 2 and 3 with hydrazine hydrate [2][3][4][5]. Obviously, the formation of azines 8 and 9 is the result of decomposition of dihydrazides 6a and 6b with liberation of hydrazine (cf.…”

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).…”

“…We previously proposed the synthesis from tetrahydropyran (1) of α,ω-diketones 2 and 3 containing one (2) or two (3) ester groups. [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.…”