Synthesis of dipeptide derivatives of 3,4-substituted 7-hydroxycoumarins

Abstract

We have previously reported the preparation of several coumarins and furocoumarins modified with amino acids. In continuation of this work, we investigated the synthesis of substances in which a dipeptide would be added to the benzopyran core.Starting 3,4-disubstituted 7-hydroxycoumarins were synthesized by Pechmann condensation of the corresponding resorcinols and esters of substituted β-ketoacids in the presence of H 2 SO 4 as condensing agent [3,4]. PMR spectra of the starting coumarins contained resonances typical of the coumarin system and its substituents.Williamson reaction of the 7-hydroxycoumarins with methylchloroacetate using potash as the base produced the corresponding esters of substituted 2-oxo-2H-7-chromenyloxyacetic acids. The esters were hydrolyzed by heating with sodium bicarbonate solution (5%). The structures of the resulting acids were confirmed by PMR spectroscopy. The spectra of the products (11-20) lacked a resonance for the hydroxyl proton of the starting 7-hydroxycoumarins and contained resonances for the acetic acid as a very broad singlet for the carboxyl at 12.0-12.5 ppm and a resonance for the α-CH 2 protons at 4.5-5.0 ppm.Dipeptide derivatives of 11-20 could be prepared by two routes, addition of the dipeptide or successive elongation of the peptide chain. We used activated esters to synthesize the amino-acid derivatives. These are used widely in peptide synthesis [5] to activate the carboxyl using the N-hydroxysuccinimide (NHS) ester, which is highly reactive and does not racemize the products.Reaction of 11-20 with NHS in absolute dioxane using diisopropylcarbodiimide as the condensing agent produced the corresponding NHS esters. Compounds 21-36 were synthesized by reaction of the NHS esters with sodium salts of glycylglycine (21-30), norleucine (31), leucine (32), and β-alanine (33) in dioxane:water (1:1) with subsequent acidolysis of the resulting salts. The isolated amino-acid derivatives had a free carboxylic acid that could be activated analogously for addition of the next amino acid. Compounds 34-36 were prepared this way. PMR spectra of the isolated compounds contained resonances for the coumarin ring, the dipeptide, amide bonds at 8.02-8.46 ppm, and the carboxylic acid at 12.11-12.69 ppm.

Epigenetic Manipulation Induces the Production of Coumarin‐Type Secondary Metabolite from Arthrobotrys foliicola

“…Compound 1, 4-ethyl-7-hydroxy-8-methyl-2H-1-benzopyran-2-one, turns out to be a new naturally occurring compound, which was previously identified as the precursor for advanced complex coumarin syntheses. [15] Additionally, we proposed a plausible biosynthetic pathway of 1. The biosynthetic route starts from glucose via phenylalanine to yield umbeliferone [24] which undergoes alkylation [25,26] to obtain 1 (Scheme 1).…”

“…This crude extract was subjected to a series of column chromatography procedures, traced by the HPLC examination, and yielded the coumarin type of compound, 4‐ethyl‐7‐hydroxy‐8‐methyl‐2 H ‐chromen‐2‐one ( 1 ), along with one benzaldehyde derivative, 6‐ethyl‐2,4‐dihydroxy‐3‐methylbenzaldehyde ( 2 ) and ten 2,5‐diketopiperazines, cyclo( l ‐Pro‐Gly) ( 3 ), cyclo( l ‐Pro‐ l ‐Val) ( 4 ), cyclo( l ‐Pro‐ l ‐Leu) ( 5 ), cyclo( d ‐Pro‐ l ‐Ile) ( 6 ), cyclo( l ‐Pro‐ l ‐Phe) ( 7 ), cyclo(4 R ‐hydroxy‐ l ‐Pro‐ l ‐Leu) ( 8 ), cyclo(4 S ‐hydroxy‐ d ‐Pro‐ d ‐Ile) ( 9 ), cyclo(4 R ‐hydroxy‐ l ‐Pro‐ l ‐Phe) ( 10 ), cyclo( l ‐Pro‐ l ‐Tyr) ( 11 ) and cyclo( l ‐Pro‐ l ‐Trp) ( 12 ) …”

“…And according to the number of degrees of unsaturation, spectroscopic data and physical data, the structure of 1 was deduced as the coumarin and illustrated in Figure . Compound 1 , 4‐ethyl‐7‐hydroxy‐8‐methyl‐2 H ‐1‐benzopyran‐2‐one, turns out to be a new naturally occurring compound, which was previously identified as the precursor for advanced complex coumarin syntheses . Additionally, we proposed a plausible biosynthetic pathway of 1 .…”

“…This crude extract was subjected to a series of column chromatography procedures, traced by the HPLC examination, and yielded the coumarin type of compound, 4-ethyl-7hydroxy-8-methyl-2H-chromen-2-one (1), [15] along with one benzaldehyde derivative, 6-ethyl-2,4-dihydroxy-3-methylbenzaldehyde (2) [16] and ten 2,5-diketopiperazines, cyclo(l-Pro-Gly) (3), [17] cyclo(l-Pro-l-Val) (4), [18] cyclo(l-Pro-l-Leu) (5), [19] cyclo(d-Pro-l-Ile) (6), [20] cyclo(l-Pro-l-Phe) (7), [18] cyclo(4R-hydroxy-l-Pro-l-Leu) (8), [21] cyclo(4S-hydroxy-d-Pro-d-Ile) (9), [22] cyclo(4R-hydroxy-l-Pro-l-Phe) (10), [21] cyclo(l-Pro-l-Tyr) (11) [23] and cyclo(l-Pro-l-Trp) (12). [21] All isolates were deduced according to their spectroscopic data and compared with the corresponding authentic samples or literature values ( Figure 2).…”

Synthesis and Anticancer Evaluation of Some New 3-Benzyl-4,8-Dimethylbenzopyrone Derivatives

“…The starting compound 1 was prepared as reported in literature [ 13 ]. Benzylidene acetohydrazides derivatives were prepared by refluxing acid hydrazide with appropriate aromatic aldehyde or acetophenone in ethanol/ glacial acetic acid, and this method was adopted for the synthesis of compounds 4a-d.…”