New acylides: synthesis of 3-O-[γ-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives

In search of new erythromycin derivatives 3-O-[γ-(4-oxo-2-aryl-thiazolidin-3-yl)butyryl]erythromycin A derivatives have been synthesized. The 3-hydroxy group was derivatised to a primary amine and subsequently the thiazolidinone nucleus was generated at the amino functionality through DCC mediated one-pot three-component reaction in good yields.

However structural modification and generation of new prototypes has been challenging due to structural complexity of the erythromycin molecule. Therefore, development of new strategies for the synthesis of novel structures is of prime importance in the area of macrolides.
Acylides are a promising new class of macrolide antibiotics [8,9]. These derivatives are active against erythromycin resistant strains and the activity is comparable to ketolides such as telithromycin. It is important to note that 3-O-acyl derivatives with nitrogen heterocyclic moieties, namely pyridylacetyl, were mostly active [9]. This encouraged us to explore the synthesis of 3-O-acylides bearing other heterocyclic systems for example thiazolidinone in place of the pyridyl residue. The thiazolidinone functionality in the molecule may be advantageous for antibacterial activity in view of similar system having been reported as antibacterials [10,11]. The thiazolidin-4-ones can be generated under very mild conditions using the DCC mediated one-pot synthesis reported by us [12].

Results and Discussion
Decladinosyl-6-O-methylerythromycin A (1) was generated using the method available in the literature [13]. We have developed a synthesis where the 3-OH group of 1 was functionalized to an amino group using the γ-aminobutyryl spacer and subsequently a variety of thiazolidinone moieties were generated at the amino group. We have explored other spacers for generating the amino group e.g. Z-Gly, Z-Ala and Z-β-Ala etc. but due to severe steric hindrance the formation of the thiazolidinone was not successful. Therefore we have utilized the γ-aminobutyric acid (γ-Abu) as spacer for the present synthesis.
Starting from clarithromycin the novel derivatives 4a-f have been synthesized as shown in Scheme 1. Reaction of 1 with γ-[(Benzyloxycarbonyl)amino]butyric acid using diisopropylcarbodiimide mediated coupling in the presence of 4-(dimethylamino)pyridine resulted in the formation of a 2',3-disubstituted acylide intermediate which upon treatment with methanol for several hours gave the desired 3-O-acyl derivative 2 in 72% yield after silica gel column chromatography. Compound 2 was subjected to catalytic hydrogenation using 10% Pd/C in methanol. The reaction was complete within 1 h as monitored by tlc. After usual work up the desired γ-aminoacylide derivative 3 was obtained in ~96% yield. The amino group (of compound 3) thus obtained was utilized to append the desired thiazolidinone described below. The desired thiazolidinone was generated on 3 by dicyclohexylcarbodiimide-mediated three-component onepot reaction, in which the amine 3 was reacted with appropriate aldehydes and mercaptoacetic acid (1:4:6 molar equivalents) in dichloromethane followed by addition of DCC at room temper-

Conclusion
In summary, a facile synthesis of a novel series of substituted 3-O-acylides has been developed. Synthesis of the thiazolidinone moiety on the amino funtionalized erythromycin derivative has been found to be better as compared to the attachment of thiazolidinone bearing carboxylic acids at 3-OH of the erythromycin derivative. The present procedure offers a straightforward synthetic approach with minimal protection for the synthesis of a variety of derivatives in moderate yields. The mild experimental conditions are very much suitable for the highly sensitive macrolide molecule.

Experimental
Refer to Supporting Information File 1 for full experimental data.

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The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc) The definitive version of this article is the electronic one which can be found at: doi:10.3762/bjoc.4.14