Novel Tandem Reaction for the Synthesis of N′‐Substituted 2‐Imino‐1,3‐oxazolidines from Vicinal (sec‐ or tert‐)Amino Alcohol of Desosamine

Abstract

Dubravka Matković-Č alogović, [b] and Goran Kragol* [a][ ‡]Keywords: Macrocycles / Amino alcohols / Domino reactions / Heterocycles Two one-pot methods, sequential and tandem, for the preparation of NЈ-substituted 2-imino-1,3-oxazolidines from the vicinal (sec-or tert)-amino alcohol of desosamine via intermediary alkyl-, aryl-, heteroaryl-, and heteroalkyl-thiourea moieties are described. Particularly interesting is the novel one-pot tandem reaction of the vicinal tert-amino alcohol that involves dealkylation, thiourea formation, and a final cyclization to yield 2-imino-1,3-oxazolidine structures. The yields of

Regioselective 2‐Imino‐1,3‐thiazolidine vs. 2‐Imino‐1,3‐oxazolidine Formation from the Vicinal sec‐Amino Alcohol of Desosamine

“…The conversion of 3′‐ N ‐demethylated 9‐deoxo‐9a‐methyl‐9a‐aza‐9a‐homoerythromycin A1,2 ( 1 ) to 2′‐deoxy‐2′‐( S )‐ S ,3′‐ N ‐( N′ ‐benzylcarbonimidoyl)‐3′‐ N ‐demethyl‐9‐deoxo‐9a‐methyl‐9a‐aza‐9a‐homoerythromycin A ( 4 ) was used as a model reaction (Scheme ). In order to optimize reaction conditions for the synthesis of mainly N′ ‐substituted‐2‐imino‐1,3‐thiazolidine compounds and to avoid formation of N′ ‐substituted‐1,3‐oxazolidines, the influence of solvent, base, temperature, and reagent ratios on the course of the Mukaiyama reagent‐induced cyclization of N′ ‐thiocarbamoyl 2 was studied.…”

“…In order to optimize reaction conditions for the synthesis of mainly N′ ‐substituted‐2‐imino‐1,3‐thiazolidine compounds and to avoid formation of N′ ‐substituted‐1,3‐oxazolidines, the influence of solvent, base, temperature, and reagent ratios on the course of the Mukaiyama reagent‐induced cyclization of N′ ‐thiocarbamoyl 2 was studied. Since the Mukaiyama reagent also reacts with secondary amines, although more slowly than with alcohols,1 the synthesis had to be conducted in two steps (Scheme ): (1) the formation of 3′‐( N′ ‐benzyl)‐thiocarbamoyl intermediate 2 via reaction of 1 with benzyl isothiocyanate;1 and (2) subsequent cyclization using the polymer supported Mukaiyama reagent. The ratio of oxazolidine 3/ thiazolidine 4 compounds was determined using LC‐MS.…”

“…First, the effect of the solvent on the course of the cyclization of thiocarbamoyl intermediate 2 was assessed (Table 1, Entries 1–8). Triethylamine was used as a base in order to avoid cladinose cleavage 1. It was found that the solvent type had a striking effect on the reaction course.…”

“…In the course of our studies of diverse antibacterial macrolide transformations through the modifications of the desosamine sugar,1,2 macrolide derivatives that showed potent anti‐inflammatory properties but were devoid of antibacterial activity were discovered 3. These anti‐inflammatory macrolides were prepared by an efficient tandem reaction for the fusion of N′ ‐substituted‐2‐imino‐1,3‐oxazolidine moieties to the desosamine sugar.…”

“…The tandem reaction involved cyclization of the secondary amine at position 3′‐C and the vicinal hydroxy group at position 2′‐C of desosamine to form exclusively a 2‐imino‐1,3‐oxazolidine moiety via an intermediate 3′‐ N ‐thiocarbamoyl. Interestingly, this exclusivity was lost when a polymer‐supported Mukaiyama reagent ( N ‐methyl‐2‐chloropyridinium iodide)4 was used as a thiophilic reagent, providing a 2‐imino‐1,3‐thiazolidine side product in which the configuration at 2′‐C was supposed to be inverted (Scheme ) 1. Such desosamine modification should also diminish antibacterial activity of the parent macrolides, and consequently make them suitable for the treatment of various diseases not connected to bacterial action 6.…”