SYNTHESIS OF ANALOGS OF PENICILLIN
April 20, 1953
Schrecker of this Laboratory and L. V. Heisey of Bridgewater College for helpful discussions
[CONTRIBUTION FROM
THE
1895
during the preparation of this manuscript. BETHESDA 14, MD.
DEPARTMENT OF CHEMISTRY, AMHERST COLLEGE]
The Synthesis of Analogs of Penicillin.'" I BY DAVIDT O D DAND ' ~ SYLVIATEICH RECEIVED SEPTEMBER 18, 1952 The condensation of L-cysteine and of DL-penicillamine with methyl y-formylbutyrate gives the bicyclic thiazolidine lactams Va and Vb, whose structure is proved via nickel desulfurization. An attempt to prepare the vinylog IV of penicillin is described.
The chemical mechanism of the antibiotic action of penicillin (I) remains obscure in spite of the fact that much biological investigation2 tends to show that penicillin may compete with glutathione in processes. involving hydrogen transfer from S H groups on molecules involved in the respiratory systems of many organisms. Because of the wellknown instability of the p-lactam ring3 in penicillin, i t is not unreasonable to suppose that a t some point in the metabolism of penicillin the p-lactam ring is opened. It is, therefore, of interest to modify this particular structural feature of penicillin in order to see if an easily-opened p-lactam ring is a sine qua non for its antibiotic action. Two modifications of the p-lactam ring have already been reported, and in each case the resulting compound was found to be devoid of antibiotic action. du Vigneaud and Carpenter4 have prepared the y-lactam 11, and Neher and co-workers5 have prepared acylated thiazolidines of the type I11 in which the p-lactam ring has been formally hydrogenated open between the two asymmetric carbon atoms. 0 S CH?
I
O
It seemed to us of interest to prepare compounds in which the p-lactam ring of penicillin is enlarged to a six-membered ring, and in particular the vinylog (IV) of penicillin. I n this paper we report the synthesis of two 8-lactams, Va and Vb, and an attempt to prepare IV.
CH I CTC,X&---CHCOOH !I l i
IV H
cyc, 11 0
I1 0
N-CHCOOH I 1 T'a, R = H Vb,R CHa
Methyl y-formylbutyrate (VI) was condensed with L-cysteine hydrochloride (VIIIa) in an aqueous alcoholic solution containing sodium acetate or sodium hydroxide to give the bicyclic thiazolidine (Va) in 2 5 3 5 % yield.
II
VIIa, R = H b, R = CHB
0 VI
1 A--~!ooH
I
i
C-Ti-CHCOOH
/I
0
--
I11
(1) (a) This work was supported by the Office of Naval Research and by the Research Corporation. (b) Worcester Foundation for Experimental Biology, Shrewsbury, Mass. (2) R. Pratt and J. Dufrenoy, Bocf. Rev., 12, 79 (1948). (3) R. Holley and A. Holley, THISJOURNAL, 71, 2771 (1950). (4) V. du Vigneaud and F. Carpenter, "The Chemistry of Penicillin," Princeton University Press, Princeton, N. J., 1949, Ch. 27. ( 5 ) R. Neher, et or., Helw. Chim. A d o , 19, 1815 1874 (1946).
Y
+ 1 HN-J-COOH 'COOH
0
Va, R = H b,R CHI
VI11
The presumed intermediate amine-ester was never isolated, the cyclization to V occurring readily under mild conditions. However, under certain conditions, a second compound was isolated whose analysis corresponded to that of VIII. Since it could not be readily cyclized to Va i t was not further characterized. Although attempts to convert Va
to the methyl ester gave no solid product, a crystalline sulfone was obtained. Condensation of the acetone derivative of cysteine, 2,2-dimetiiyl-4-thiazolidinecarboxylic acid, with VI likewise led to the formation of Va. Reductive desulfurization of the sodium salt of Va in aqueous solution by means of Kancy nickel afforded optically active a-I-(2--piperidone)-pr\)pionic acid (IXa) in 30‘;; yield.6 The DL-form of this compound was synthesized by condensation of the sodium salt of %-piperidone with methyl a-bromopropionate, followed by hydrolysis of the ester to the acid, which though optically inactive melted only four degrees below the compound obtained by degradation. Coinparison of the infrared spectra of these coinpounds shows them to be structurally identical.
v
---yEl Si(H)
A
R
K
/2
I I
l
l
\N-CH-COOH
t- f-
\&-
8 IXa, R = H b, R = CHI
I
0 S‘t
R
+
ploying the appropriately substituted cY,P-unsaturated aldehyde in the condensation with cysteine (or penicillamine Although the synthesis of thiazolidines froiii saturated aldehydes or ketones has received considerable attention,’” relatively little work has been done on the reaction with a,@-unsaturatedcarbonyl compounds. The failure of various a,p-unsaturated ketosteroids to yield thiazolidines has been reported” though crystalline products were obtained with some simpler compounds. In addition, the fact that the diethyl mercaptal of crotonaldehyde can be prepared in good yield under conditions which differ considerably from those required for the addition of ethyl mercaptan across the double bond of crotonaldehydel’ made it seem possible that preparation of the vinylog IV in the usual manner by the condensation of y-formyl- y-phenylacetylaminocrotonic ester, X , with penicillamine could be carried out, it being borne tn mind that the glutaconic half aldehyde system of X might be capable of isomerism to the structure Xa. ).
-
R
0
H
KH-C-CH~CBH~ //
SH-C-CHzCsHb
’
‘\
\C
