COMMUNICATIONS TO THE EDITOR
Oct. 5 , 1964
and h l r . P. F. Stokely for the equivalent weight determination.
n-propyl group a t C-4 and confirmed the L- configuration. T h e amide of one of the two diastereomers so
(IO) Alfred P. Sloan Research Fellow.
CBz I
CBz FREDTEBBE I PHILIPM. GARRETT M. FREDERICK HAWTHORXE~~ RECEIVEDAUGVST19, 1964
DEPARTMENT O F CHEMISTRV USIVERSITYOF CALIFORSIA RIVERSIDE,CALIFORNIA
7 + OOH CH3CHaCHz
/
Chemical Studies on Lincomycin. The Structure of Lincomycin
4223
I.
Sir : T h e antibiotic linc~rnycin'-~has been found to have structure 1 as shown by the following data. Linco-
I
I
H n'S
trans
5
%
RO
SCH3 l,R=H 2,R=Ac
mycin, Cl8H34N2O6S, contains one K-methyl, two C-methyls, one basic function, pK,' = 7.5, and gives a negative iodoform test.6 T h e infrared absorption is indicative of a monosubstituted amide (13.30 and 1640 cm.-I). A tetraacetate, 2 , and isopropylidene lincomycin, 3 , could be prepared. Aqueous 2 N acid liberated methanethiol and another fragment isolated as the phenylosazone 4, C29H42N606. H--C=N-NHCeHs
I
C=N-NHCeHs HO-A-H
3
formed was found to be identical with t h a t obtained from lincomycin. Oxidation9 of 5 to (I-)(+)-propylsuccinic acid showed i t to be trans-~-4-n-propylhygric acid. Lincomycin and its acetonide (3) took up 1 arid 2 moles of periodate, respectively. Its nickel desulfuriza6 ,Oconsumed ~, 2 moles, libertion product, C ~ T H T J N ~ ating 1 mole of formic acid. Hydrazinolysis cleaved 1 into 5 as the hydrazide and compound 7, C9Hl8NO3S, methyl cu-thiolincosari~inide. The base 7, pK,' = '7.5, containing no amide, gave a negative iodoform test6 and consumed 5 moles of periodate. Acylation of 7 with the propyl carbonate mixed anhydride of 5 , both natural and synthetic. yielded crystalline 1 as the hydrochloride. Two acetyl derivatives, 8 and 9, were obtained. The n.m.r. spectrum of 7, in addition to suggesting galactose stereochemistry and an axial methylthio function,'O displayed a distinct doublet of doublets centered a t 6 3.3, J = 10.5 and 3.0 c.P.s., suggesting, in contradiction to the earlier iodoform data, that the hydrogen on the carbon bearing nitrogen was split by only two hydrogens. Therefore, the amine was not adjacent to the terminal methyl group.
CH3 4
A vigorous acid hydrolysis freed an amino acid, 5 , C9H17X00?.Preliminary comparisons with L-hygric acid and n.rn.r. studies suggested an n-propylhygric acid. Rotational shifts on acidification suggested the ~-series.' Synthesis from 4-keto-L-prolinex placed the ( I ) D . J . M a s o n , A Dietz, a n d C D e Boer, A n t i m i c r o b i a l A g e n f s Chemoi h e v n p y , 554 (1862)
(2) I
