H. H. WARREN,NASUEL FINKELSTEIN ASD L). A. SCOLA
1926
[CONTRIBUTION FROM
THE
1701. 84
THOMPSON CHEMICAL LABORATORY, LVILLIAMS COLLEGE, WILLIAMSTOIVX, MASS.]
The Synthesis and Antibacterial Activity of Analogs of Citrinin and Dihydrocitrinin BY HAROLD H. WARREN,MANUEL FIKKELSTEIX AND DANIELA. SCOLA RECEIVEDDECEMBER 4, 1961 A general method for the synthesis of 1-alk5-lcitrinins (1) by the condensation of orthoesters with the carboxylic acid derivative of compound A (11) has been developed. Series of l-alkylcitrinins and of l-alkpldihydrocitrinins (111) ranging from 1-propyl t o 1-nonyl have been prepared arid their antibacterial activity measured. Progressive lengthening of the chain causes a marked increase in activity which exceeds that of citrinin in the CGand higher derivatives.
A general method for the synthesis of l-substituted derivatives of citrinin (I) and of dihydrocitrinin (111) and the application of the method to the preparation of simple aryl and alkyl derivatives have been previously reported.'I2 It was found t h a t the introduction of a methyl group into citrinin causes nearly complete loss of antibiotic activity while slight activity was noted in the ethyl derivative and appreciable activity in the phenyl derivative, though considerably less than that of the parent compound. In the case of dihydrocitrinin the parent compound is inactive as are the 1-methyl, I-ethyl and 1-phenyl derivatives, while the 1-benzyl derivative shows moderate activity compared to citrinin. The present work was undertaken to determine whether the appearance of activity in l-benzyldihydrocitrinin and its reappearance in 1-ethyl- and 1-phenylcitrinin is a function of the specific nature of the substituent or merely of the size or chain length. A homologous series of 1-n-alkyl derivatives of dihydrocitrinin ranging from the 1-propyl to I-nonyl has been successfully prepared by the condensation of the appropriate normal aliphatic aldehydes with the carboxylic acid derivative of coinpound A (11)'j (hereinafter referred t o as compound F). A11 of these compounds are soluble in dilute aqueous sodium bicarbonate with evolution o f carbon dioxide and give the characteristic deep blue color with ferric chloride in dilute alcohol. The properties of the compounds are summarized in Table I . The conversion of the dihydrocitrinin derivatives to the corresponding citrinin derivatives by oxidation was less successful. Only the I-hexyl derivative was obtained in satisfactory yield by use of bromine; other oxidizing agents or catalytic dehydrogenation were equally ineffectual. .\ possible route t o the 1-alkylcitrinins was suggested by the work of Gore4 who accomplished a partial synthesis of citrinin by the condensation of coinpound F with ethyl orthoformate. \Ye have round that aliphatic orthoesters in general will undergo a cyclization reaction with compound F forming 1-alkylcitrinins. The reaction occurs readily and completely a t room temperature when cornpound F is dissolved in an excess of the orthoester. Rapid development of the lemon-yellow color characteristic of citrinin is followed in some ( 1 ) H H W a r r e n , C',
IIoiiKhertv nnd E . S. W r t l l i y , .7. A l i i f h P m
( 2 ) II If \ V . t r r e i i , (: I ~ o i i p , t i e r niid ~ ~ f< S K s l l i s , i 6 i J , 79, :1812 1'3.57). ( 3 ) 4-(2-Hyilroxq - 1 -methylpropyl)-3-methyl-y-resorcylicacid ( 4 ) 'r 9 . Gore. R . V. Talavdekar, a n d K. Venkataraman, Ci.ri.r?iil S L ~( .I d i a ) , 19, 20 (19.50); C A , , 44, 7313 (l'J50). [
cases by the spontaneous crystallization of the product. Use of ethyl acetate as a solvent permits a decrease in the amount of orthoester required and insures a homogeneous reaction mixture. No reaction occurs in ethanol. CH,
HOOC
Ay/J
OH
Ho& HOOC
OH H R
I
I11
T h a t the product of this reaction is indeed the predicted substituted citrinin was demonstrated by comparing the condensation product of ethyl orthopropionate with authentic 1-ethylcitrinin produced by the oxidation of 1-ethyldihydrocitrinin. The compounds were identical in all properties, and the melting point of a mixture showed no depression. By means of this reaction a series of 1-n-alkylcitrinins ranging from 1-propyl to 1-nonyl has been prepared. The compounds and their properties are summarized in Table 11. Each of the compounds gives the characteristic red-brown color with ferric chloride in dilute alcohol. Because of their low water solubility the higher homologs do not dissolve readily in aqueous sodium bicarbonate but do dissolve in sodium bicarbonate in dilute ethanol and are not reprecipitated by dilution with water. Immediate precipitation occurs upon acidification. -1senii-quantitative determination of the antibacterial activity of the compounds toward four representative organisms was made using the agar streak technique of U-aksman and Kei1ly.j -1s in the case of citrinin itself none of the compounds inhibits the growth of the gram-negative organism, E . coli a t a maximum concentration of 3000 dilution units (ml. of nutrient agar,/'g. of test compound). All of the compounds are active in varying tlegrce to\v:u-d S . ~ ~ ~ R.mrnycoid(.s ~ ~ ~and s R, . sirbfilis. T I W rcsiilts :ire sunim:irizetl in Table 111. I t is apparerit that ill the citrinin derivatives while introduction of a methyl group \-irtually 1.5) S . .4. \Vah,man a n d I f . C. Keilly,
Aiiai.
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