Conformational analysis of 9-deoxo-9a-aza-9a- and 9-deoxo-8a-aza-8a-homoerythromycin A 6,9-cyclic iminoethers

Lazarevski, Gorjana; Vinković, Mladen; Kobrehel, Gabrijela; Ðokić, Slobodan; Metelko, Biserka

doi:10.1016/s0040-4020(01)89570-3

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…10 was in equilibrium with its 10-methyl epimer (Scheme 3). Conformational analysis and application of molecular modeling techniques to 4 and 9 were used to establish the predominant solution-state conformation [20,23] and to explain chemical reactivity. 9 and 10 were further reduced with hydrogen in the presence of Pt or with NaBH 4 to the corresponding 9-dihydro-9-deoxo-8a-aza-8a-homoerythromycin (12).…”

Section: A-azalidesmentioning

confidence: 99%

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Azalides from Azithromycin to New Azalide Derivatives

Mutak

2007

J Antibiot

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Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

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Section: A-azalidesmentioning

confidence: 99%

“…9 and 10 were further reduced with hydrogen in the presence of Pt or with NaBH 4 to the corresponding 9-dihydro-9-deoxo-8a-aza-8a-homoerythromycin (12). The reduction rate of 9a-aza-and 8a-aza-6,9-imino-ethers 4 and 9, as well as 9a-aza-9,11-imino-ether 5, have been studied using molecular modeling techniques [23].…”

Section: A-azalidesmentioning

confidence: 99%

Azalides from Azithromycin to New Azalide Derivatives

Mutak

2007

J Antibiot

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“…These types of metal-catalysed reactions have been studied from a mechanistic viewpoint and the imino-ether and amidine products have proved extremely useful in the syntheses of pharmaceutical materials and interesting organic intermediates. 10 The coordination geometry at the metal centre catalysing the nucleophilic attack on the C᎐ ᎐ ᎐ N, generally Co III , Rh III , Ir III , Ru III , Pt II or Pd II , 11 and the stabilisation of the product by complexation to the metal ion are important factors in deciding the course of these reactions. To our knowledge, only one example of Cu IIpromoted nucleophilic attack on nitrile groups has been reported.…”

Section: Introductionmentioning

confidence: 99%