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Erythromycin study: 9-Amino-3-0-cladinosyl-5-0-desosaminyl-6,11,12- tryhydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide

Erythromycin study: 9-Amino-3-0-cladinosyl-5-0-desosaminyl-6,11,12- tryhydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide

Tetrahedron Letters N0.17, pp. 1645-1647, 1967. PergamoaPressLtd. Printedin GreatBritain. ERYTHROMYCIN STUDY: 9-AMINO-3-O-CLADINOSYL-5+DESOSABdINY...

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Tetrahedron Letters

N0.17, pp. 1645-1647, 1967.


Printedin GreatBritain.

ERYTHROMYCIN STUDY: 9-AMINO-3-O-CLADINOSYL-5+DESOSABdINYL-~.11,12TRYHYDROXY-2,4,6,8,10,12-HEXAMETHYLP~NTADECANE-13-OLIDE Slobodan Djokid and Zrinka Tamburagev* Research Department, "PLIVA" Pharmaceutical and Chemical Works, Zagreb Yugoslavia (Received

23 January 1967)

IN reduction of erythromycin (I) to dihydrberythromycin (VI) the keto carbonyl in position 9 of the aglycon part of the molecule was transformed into a hyaroxyl group.lp2 No other reactions involving specific changes in keto grcup of I are described. Attempts to prepare the usual carbonyl derivatives of failed until now. In reaction with hydrazine erythromycin yiel-


ded neither the expected hydrazone nor a hydrazide. Only partial structure for the product of this reaction was progosed.2 Since dihydroerythromycin is biOlOgiCally


it is supposed that the keto group is one of the deci-

sive factors for antibiotic activity of erythromycin. In order to get a better insight in the influence of the keto group of I on its antibiotic activity, the reaction of erythrcmycin with hydroxylamine was performed. The reaction was carried out with hydroxylamine hydrochloride in methanol in the presence of barium carbonate under anhydrous condi-


Taken in part from a thesis submitted by Z.T. to the Technical Faculty of the University in Zagreb in partial fulfilment of the requirement for the degree of Doctor of Chemical Sciences.

'E.H.Flynn,&.:".Sigal,Jr .,P.F.Wiley and K.Gerzon, J.Am.Chem.Ssc. E,


(1954) 'M.V.Sigal,Jr .,P.F.bviley,K.Gerzon,E.H.Flynn,V.C.Quarck and O.Weawer, J.Am. w.







From the reaction mixture erythromycin oxime (II) was isolated in a-

bout 50 % yield. After recrystalization from absolute methanol the compound had a.m.p. 184-189' (dec.),/d/i5=



1% in methanol),C37H68N2013.P

In the infra-red spectra the original carbonyl band at 5,9l disappeared but

$v”~-‘“3 p2






Rl= cladinosyl, R2= desosamiwl,


Rl= cladinosyl, R2= desosaminyl, X= NOH


Rl= cladinoayl, R2= desosaminyl, R3= NH2


Rl= H,


= H, = NH2 R2= H, Rl R3 Rl= cladinosyl, R2= desosaminyl, R3= OH


Rl= H,


Rl= H,

X= 0

R2= desosaminyl, R3= NH2

R2= desosaminyl, R3= OH R2

= H,

R3= OH

a new absorption band at 6,15 considered as being typical for -C=N-4*5 is prfsent. Ey reduction of II with sodium borohydride the 9-amino-3-O-cladinosyl-j~-desosami~l-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethylpentadecane25 13-elide (III) was obtained in 70% yield, m.p. 142-147',/d /D = -50' (c= 1%

'L.C.Cheney and J.R.Pianing, J.Am.Chem.Soc. %,731(1945) eAl1 new compounds gave satisfactory analyses 4F.W.L.Gaes and F.W.Bope, J.Am.Pharm.Assoc. @,186(1949) 5M.M.Randall,N.Fueon,R.G.Fowler and J.R.Dangl, Infrared Determination of Organic Structures p. 5, D. Van Nostrand Co., New York, Toronto, London (1952)

in methanol), C37R70N2012, Dipicratem.p. 185-187', C49H76N8026. Dihydrochloride m.p; 142-144', C37H72012C12. In order to show with certainty that III hae the structure proposed, the following reactions were carried out. Hydrolysis of III with 1% hydrochloric acid solution in methanol at room temperature yielded 9-amino-5-O-deeosami~l-3,6,11,12-tetrahydrolry-2,4,6,8,10,12-hexamethylpenta~ecane-l3-olide (IV), m.p. 157-162', / &/g5=

-35' (c= 1% in methanol), C2gH56N20gB By hydro-

lysis of IV with 2N hydrochloric acid at 60' 9-amino-3,5,6,11,12-pentahydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-elide (V) was obtained, m.p. 108115O, /0(/;5=

+35O cc= 1% in methanol), C21H41N07.Picrate, m.p. 115-118',

C27H44N4014. Reaction of V with sodium nitrite followed by hydrolysis gave the compound identical in all respects with *dehydration product A" prepared by Sigal and coworkers from VII or VIII.2 The assay for the antibiotic activity of erythromycin oxime and 9-amino-3-0-cladinosyl-5-O-desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethyl pentadecane-l3-elide on Bacillus subtilis and Eacillua mycoidea showed that the first possesses an activity of 500-550 U/m&

and second 460-500 U/mg

respectively. This indicates that oximation of the keto group and rdUCtiOn Of


oxime did not effect a loss of antibiotic activity as it wae the case

after the reduction of the keto group. The above compounds and their derivatives are under further studies in our laboratory.

Acknowledgements - We are indebted to Mx. J. Hranilovid and his staff for microanalysee and the infrared spectra and to Xrs. Poic for the microbiological essay, respectively.