Amino-Acid Derivatives of Pyranocoumarins
- PDF / 172,174 Bytes
- 5 Pages / 594 x 792 pts Page_size
- 11 Downloads / 259 Views
AMINO-ACID DERIVATIVES OF PYRANOCOUMARINS
I. V. Krasylov, V. S. Moskvina,* S. V. Shilin, and V. P. Khilya
A methodology for synthesizing amino-acid derivatives of pyranocoumarins in three steps using pyranocoumarin oximes as starting compounds was developed. A series of pyranocoumarins containing the amino acids glycine, alanine, phenylalanine, methionine, leucine, and β-alanine in their structures could be prepared using the activated ester method. Keywords: amino acids, coumarins, pyranocoumarins, (spiro)pyranocoumarins, oximes. Synthetic transformations of natural biologically active compounds represent a scientific thrust comprising the development of fine organic synthetic methods and medicinal chemistry. Coumarins have been some of the most promising compounds over many decades for various structural modifications to design new drugs with broad spectra of useful activity [1, 2]. On the other hand, introduction of amino acids and peptides into the coumarin scaffold can alter the biochemical and physical characteristics of the target structures [3, 4]. Currently, the synthesis of coumarins with amino-acid and peptide moieties incorporated into them is of growing interest and was the subject of a recent review [5]. Also, synthetic methods were developed for several fluorescent coumarinyl amino acids that were used successfully as labels for studying the biophysical properties and conformational changes in peptides and proteins [6]. Amino-acid derivatives of coumarins are known to possess cytotoxic [7], antimicrobial [8], analgesic, anti-inflammatory [9], and anticancer activity [10, 11]. Previously, our research group developed various synthetic strategies for amino-acid derivatives of coumarins via C-aminomethylation of 5- and 6-hydroxycoumarins [12, 13] using symmetric anhydrides [13–15] and activated esters [13, 16, 17]. The goal of the present work was to develop a synthetic strategy for amino-acid derivatives of a synthetic analog of the natural furanocoumarin graveolone, which was isolated from dill [18, 19] and parsley [20]. H3C
O
O
O
H3C O
Graveolone
The synthetic methodology for amino-acid modification that was proposed by us included introduction of a carboxylic acid into the structure of synthetic graveolone analogs followed by its activation. The starting compounds were pyranocoumarin oximes 1 and 2 [21]. For example, oximes 1 and 2 reacted with ethyl chloroacetate in refluxing MeCN using K2CO3 as the base to give corresponding esters 3 and 4. Attempted acid hydrolysis of the obtained esters was unsuccessful. Target acids 5 and 6 were successfully obtained via alkaline hydrolysis of 3 and 4 upon heating at 50°C for 4 h in i-PrOH with added aqueous NaOH (1 M). The preparation of (spiro)pyranocoumarins 5 and 6 allowed their targeted amino-acid modification. The carboxylic acid was activated using N-hydroxysuccinimide esters as the activated esters. This method had several advantages, e.g., the intermediate N-hydroxysuccinimide esters could be used in situ, which considerably shortened the time
Data Loading...
