Comrrriw \TTOUS
4.564
TO THE
Yol. 7 ' )
EDITOR
8.871, which was isomerized with alkali. The resulting iso-compound, without purification, was pyrolyzed giving a small yield of 4-chloro-7hydroxyphthalide, m.p. 155-15T0, which was identified by comparison with a known sample prepared by an unambiguous synthesis reported by Boothe, et al., in an accompanying communication.10
hydride in AT sodiuin hydroxide yielded 4-chloro-imethoxyphthalide-3-carboxylic acid (R = CHa, R' = H, R" = COOH) in 90y0yield; n1.p. 175176" with effervescence; 216 n i p ( 6 32,200); 240 mp ( E 8,240); 313 mp (E 5,220). ~ maX 0 .A 1J NaOH (after standing one hourj6 314 mp ( ~ 3 1 , 5 0 0 )285mp ; (€2,190). (10) J. H . Boothe, A. Green, J . P. Petisi, R G Wilkinson a n d C . \V Anal. Calcd. for C10H70QC1: C, 49.3; H, 2 . 9 ; Waller, THISJOURNAL, 79, 4664 (1957) C1, 14.6. Found: C, 49.5; H, 3.3; C1, 14.8. RESEARCH DIVISION 7 . S. \\'EBB The phthalidecarboxylic acid was then decnrORGANIC CHEMICAL R.W.~ R O S C H A R D RESEARCH SECTION D. €3. C O S G L I ~ Hboxylated by heating 5-10 minutes just above its AMERICAN cYAS.4MID COMPAXY LT. J. STEIN melting point to yield 4-chloro-7-methoxy-phthalPEARL RIVER,NEW YORK C. F.WOLF ide (R = CH3, R' = R" = HI which was sublimed RECEIVED AIJCL-ST 1, 195'7 at 175" (760 mm.); yield, 705%; m.p. 167-168" ~ 0 . S1 H C l 215 < nip (. 37,300); 236 nip ( E S,S30); mp ( E 4,560); A~:;vNaoH (after standing one DEMETHYLTETRACYCLINES. SYNTHESIS OF A DEGhour)6286 mp (E 2,190). RADATION PRODUCT Sir: Anal. Calcd. for C9H7OaC1: C, 54.4; 13, 3 . 6 : I n an accompanying communication' there is C1, 17.9. Found: C, 54.8; H, 3.7; C1, 17.7. described a new series of antibiotics closely related The methyl ether was cleaved by refluxing in to the tetracyclines, both in antibacterial activity 48y0hydrobromic acid for 2.5 hours. The product, and in structure. I n a second accompanying 4-chloro-7-hydroxyphthalide (R = K' = K" = H ) , communication* evidence has been presented that crystallized from the hydrobromic acid on coolirigthese new antibiotics differ from the parent corn- in 70:%, yield and was then sublimed at 100"(15.-20 pounds only in that they lack a methyl group at rnm.). The m.p. was 158-159" and there was no the 6-position of the tetracycline nucleus. depression upon admixture with the degradation Ilye now wish to report the synthesis of a deg- product.' The ultraviolet and infrared spectra were radation product which proves that the arrange- identical; A~:;'""' 235 mp ( E 8,400); 308 nip O . 1 S s a O H-54 3 mp ( E 5,400); 343 111p ment of substituents in the D ring and in portions ( e 4,]*50);~ "nx of the C ring of demethylchlorotetracycline is the ( E 6,180). same as in chlorotetracycline except for the C-6 Anal. Calcd. for C8H6O3C1: C, 52.1; H, 3.7; methyl group. This conipound is 4-chloro-7C1, 10.2. Found: C, 52.2; H, 3 . 2 ; C1, 19.0. hydroxyphthalide (R = R ' = R" = H) which is analogous to 4-chloro-7-hydroxy-3-rnethylphthalide (6) Upon standiug in 0.1 N sodium hydroxide f o r a n hour or less the long wave length absorption maximum undergoes a hypsochrolnic (R = R' = H , R" = CH3), obtained by the same shift which is reversible b y acidification. This is assumed t o be tlegradative route from chlorotetracycline. attributable t o t h e opening and closing of t h e lactone ring and will
37;
R'
c1
A,/"'
0:) OR
O \
be dealt with in mare detail in a subsequent publication.
RESEARCH DIVISIOX
ORGAXIC CHEMICAL
J. H. BOOTHE A . GREEX
J. P. PETISI R. G. WILKIXSON PFARI.RIVER,NEWYORK C . W.\VAI.I.ER RECEIVED AUGUST1, 1967
RESE.4RCH S E C T I O S
h E R 1 C A X CYAN.4MID COMP-4NY
The starting point for the synthesis is 4-chloro-3or,or'-DIGLYCEROPHOSPHATEI N PLANTS = R' = CH3, K" = OH) whose synthesis has already been Sir: reported from this laboratory. This compound We have observed a P3*-labeled compound in was oxidized with potassium permanganate in 0.5 hydrolysates of Scendesmus phosphatides which N sodium hydroxide a t 90" for one hour to contained more than a third of the lipid phosphorus. yield the 4-chloro-3-hydroxy-7-methoxyphthalideThe same phosphate ester also possessed as much 3-carboxylic acid (R = CHa, R' = OH, R" = as 90% of the alcohol-soluble non-lipid phosphorus COOH) in 67y0 yield. This compound has been of Scenedesmus cultured at low light intensity in isolated as a degradation product of chlorotetra- media containing P32. The cellular concentration cycline and was named there as the tautomeric of the ester, calculated from its Pa2activity and thcl acid.5 The nutrient specific activity, was as high as 10-3 -1r. keto-acid, 6-chloro-3-methoxyphthalonic reduction of this compound with sodium boro- The same compound in lower concentrations oc(11 J. R. D. McCormick, N. 0. Sjolander, U. Hirsch, E. R . Jensen curred in the only two species of higher plants 79, 4561 (1957). and A. P. Doerschuk, THISJOURNAL, (clover) tested. I t was isolated by chromatog( 2 ) J , S. Webb, R . W. Broschard, D. B. Cosulich, W. J . Stein, and raphy on Whatman KO. 1 paper with Rf = 0.36 C . F. Wolf, ibid., 79, 4563 11957). in phenol-water and Rf = 0.11 in butanol-pro(3) C . R . Stephens, L. H . Conover, R . Pasternack, F. A . Hochstein, W. T. hloreland, P. P . Regna, F. J . Pilgrim, K. J . Brunings and pionic acid-water.' These RE values correspond R . B . Woodward, { b i d . , 76, 3568 (19.54). to those recorded by Dawson2 for an unknown i i i (4) J. H. Boothe, S. Kushner, J. P. Petisi and J. H. Williams, i b i d . , rat liver extracts. 75, 3261 (1953).
hydroxy-7-methoxy-3-methylphthalide (R
( 5 ) B. L. Hutchings, C . W. Waller, S. Gordon, R. W, Broschard, C. F. Wolf. A. A. Goldman and J. H . Williams, ibid., 74, 3710 11952). For a discussion of and references to this t y p e o f t a u t ~ m e r i s msee ref. 4.
(1) A A. Benson, J. A Bassham, M. Calvin, T C G o o d d e , V A Haas and W Stepka. TRISJ O U R N A L , 73, 1710 (1950) 12) R h I C Dawson, Bwchim el B t o p k y s Acto, 14, 374 f l Y 5 4 )
