A new approach to the synthesis of aliphatic triamines and diamino alcohols that are analogs of the anti-TB drug ethambutol

Abstract

A method for the synthesis of diastereomerically pure diamino alcohols and triamines was developed. The products obtained are new asymmetric structural analogs of the anti TB drug ethambutol. The method involves reductive cleavage of the N-N bond in appropriate func tionalized pyrazolidines and 2 pyrazolines under the action of a diborane complex with THF. The cleavage occurs with retention of the configurations of the asymmetric centers of the starting compounds.Key words: reductive cleavage of the N-N bond, pyrazolidines, 2 pyrazolines, diastereo merically pure diamino alcohols, diastereomerically pure triamines, ethambutol.Being efficient ligands, polyamines have found wide application in catalysis; chiral polyamines are used in asymmetric synthesis. 1 In addition, linear polyamines and amino alcohols are not only employed in drug design 2 but also exhibit a broad spectrum of biological activity and find increasingly frequent medical use. 3 A tight tuberculo sis epidemic situation and the enhanced resistance of its pathogen to antibiotics urge a search for, and develop ment of, new efficient medicaments against this disease. 4 A number of drugs 5 are available for tuberculosis control. One of the most efficient first line drugs is the dihydroxy diamine ethambutol ((+) N,N´ bis[1 (hydroxymethyl) propyl]ethylenediamine dihydrochloride). 5 This com pound has a bacteriostatic effect on actively replicating drug sensitive Mycobacterium tuberculosis and M. bovis, some nontuberculous mycobacteria (M. kansasii, M. avium, and M. xenopi), and mycobacteria resistant to strepto mycin, kanamycin, isoniazid, and ethionamide. The mechanism of action of ethambutol is not fully under stood. This drug is believed to penetrate promptly into the actively replicating mycobacterial cells and precludes the formation of their walls by disrupting the cell metabolism. According to biochemical data, 6 when penetrating into a mycobacterial cell, ethambutol inhibits the biosynthesis of not only arabinogalactan but also lipoarabinomannan, which are the main structural components of the myco bacterial cell wall. In addition, ethambutol disrupts the lipid metabolism in the cell, inhibits the synthesis of RNA and proteins, reacts with divalent metal ions (Cu and Mg), and breaks the ribosome structure. 4b,7 Data on the nature of the increasing resistance of M. tuberculosis to ethambu tol have been published. 8 The synthesis and preclinical in vitro tests of new struc tural analogs of ethambutol can reveal its new modifica tions with anti TB activity. 9 Therefore, a search for new nitrogen containing compounds (earlier unknown diami no alcohols and triamines with anti TB activity) is a topic of current interest. 10 The natural sources providing suit able compounds for the solution of this problem are very limited, for which reason the main attention is given to synthetic and semisynthetic methods. 11 The latter involves modification of the functional groups in natural com pounds possessing carbon frameworks (typically, sugars). However, other e...

Copper-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of Propargylic Acetates with Hydrazines: Enantioselective Synthesis of Optically Active 2-Pyrazolines

“…For example, the enantioenriched 2-pyrazoline 3aa can be readily converted into the corresponding chiral 1,3-diamine 5 without the deterioration of enantiomeric purity by the treatment with BH 3 in refluxing THF. 16 In addition, a substituent could be introduced into 3-position of 3aa via a sequential addition/ oxidation process, giving chiral 1,3,5-trisubstituted 2-pyrazoline 6 without any loss in enantioselectivity.…”

“…In an attempt to exhibit the synthetic utility of our method for generating interesting and useful chiral building blocks, some transformations were carried out on the cycloadduct obtained in the course of our studies (Scheme ). For example, the enantioenriched 2-pyrazoline 3aa can be readily converted into the corresponding chiral 1,3-diamine 5 without the deterioration of enantiomeric purity by the treatment with BH 3 in refluxing THF . In addition, a substituent could be introduced into 3-position of 3aa via a sequential addition/oxidation process, giving chiral 1,3,5-trisubstituted 2-pyrazoline 6 without any loss in enantioselectivity.…”