Nov., 1946
2405
COMMUNICATIONS T O T H E EDITOR THE ANTITUBERCULAR ACTION OF l,l,l-TRI(p-AMINOPHENYL) -ETHANE CHLORO -2,2 -BIS-
in the form of platelets melting with decomposition from 92-95' (uncor.1 (calcd. for C14H13N2C1s: Sir: N, 8.88. Found: N, S.S0). Kepeated recrystalIn 1943 work was commenced a t the Chemical lization of an analytically pure sntnple failed to Warfare Laboratories in Ottawa on the synthesis raise the melting point or tlrcrease the iiielting range. This is probably due to decomposition, of the compound l,l,l-trichloro-2,2-bis-(fi-aminophenyl)-ethane (I) .l It appeared from studies with loss of hydrogen chloride, near the melting carried out on the Lauger hypothesis for the point. mechanism of action of DDT,2 using fluorine In vitro tests on the activity of I showed that it analog^,^^^ that this compound might possess gave complete inhibition of growth of ,lfycomarked antitubercular activity. bacterium tuberculosis a t dilutions of 1 ,/100,000 I n view of similar work recently reported by and some inhibition a t dilutions of 11 1,000,000. Burger, Graef and B a i l e ~we , ~ wish to report the Transfer experiments showed that a t dilutions of progress of these researches a t this time. 1/100,000 the compound was bactericidal while a t The synthesis of I seemed possible by the route 1/1,000,000 it was bacteristatic. 1%vivo tests on the antitubercular activity of I, using the 0 ~ N q Catal. H ~ N - ~ / short assay of FeldH-C-CCI:t HNOJ H-C-CCIa H-C-CCI, man and Hinshaw,' Redn . showed remarkable control of exDerimentI ally induced. tuberculosis in guinea pigs. The compound was fed a t a level of 0.5yo HNOa of the ration, this C?=CClz &=cat6 being the maximum 0 z N/ - a\ / well tolerated dose. The blood of guinea IV V pigs fed this level of since the work of Lange and ZufaW showed drug for a period of 56 days was found to contain that 1,l-dichloro-2,2-bis-(phenyl)-ethylene(IV) an average of 1 mgm.% of I as determined by the gave the compound 1,l-dichloro-2,2-bis-(fi-nitro-method of MarshalLs This method has proven phenyl)-ethylene (V) as the main product of entirely satisfactory for the determination of I in biological material as well as in pure solution. nitration. The nitration of l,l,l-trichloro-2,2-bis-(phenyl)- Full experimental details will be published later. ethane (11) proceeded smoothly and a crystalline (7) W. H. Feldman and H. C . Hinshaw, A m . Rev. Tuberc., 6 1 , dinitro compound melting at 166-187" uncor. 582 (1945). (8) E. K. Marshall, Proc. SOC.ExPtl. Bid. Med., 3 6 , 422 (1937). was isolated in good yield from the reaction mixOF BIOCHEMISTRY ture. This product was shown to be l,l,l-tri- THE DEPARTMENTS BACTERIOLOGY SAMUEL KIRKWOOD chloro-2,2-bis-(p-nitrophenyl)-ethane (111) by de- AND AGRICULTURAL UNIVERSITY OF WISCONSrN PAULH. PHILLIPS hydrochlorination to V. The product from the MADISON 6, WISCONSIN ELIZABETH McCoy dehydrochlorination provkd t o be identical with RECEIVED SEPTEMBER 26, I946 V prepared by the methqd of Lange and Zufall. Upon catalytic hydrogenation compound I11 took up six moles of hydroged. The resulting amine STREPTOMYCES ANTIBIOTICS. XI. THE STRUCwas unstable in the cru e form but was much TURE OF TETRAACETYLBISDESOXYSTREPTOBIOSAMlNE more stable when purifie by a procedure which Sir: will be described later. The substance crystallizes Treatment of ethyl tetraacetylthiostreptobios(1) Research Reports, Chemical Warfare Laboratories, Departaminide diethyl mercaptal' with Raney nickel ment of National Defense (army), Ottawa, Canada. catalyst gave tetraacetylbisdesoxystreptobios(2) P. LBuger, H. Martin and P. Miiller, Helw. Chim. Acta, 27, 892 (1944). amine' and tetraacetyldesoxystreptobiosamine ( 3 ) S. Kirkwood and J. R. Dacey, Can. J . Research, 24B,69 (1946). (m. p. 166-167', [ a I z 5-81' ~ (c, 1.04 in chloro(4) S. Kirkwood and P. H. Phillips, J . Pharmacal. and ExP. form). Anal. Calcd. for C13H21NOS(CH&!0)4: Thcrap., 87, 376 (1946).
a
__f
$
(5) A. Burger, E. Graef and M S. Bailey, THIS JOURNAL, 68, 1725 (1046). (6) K. Lange and A. Zufall. Ann., 271, 1 (1893).
(1) (a) Kuehl, Flynn, Brink and Folkers, THISJOURNAL, 68, 2096 (1946); (b) Hooper, Klemm, Polglase and Wolfrom, r b i d . , 68, 2120 (1946).
C, 51.32; H, 6.77; N, 2.85; CHaCO, 35.0. Found: C, 51.29; H, 6.94; N, 2.81; CH3C0, 33.6). The additional oxygen atom of the latter product is present as a glycosidic hydroxyl group, as shown by the preparation of pentaacetyldesoxystreptobiosamine (ni. p. 111-112', [(rIz5D - 132' (c, 0.62 in chloroform)) and methyl tetraacetyldesoxystreptobiosaminide (m. p. 179-1 80.5O , [ c Y ] ? ~ D- 129' (c, 0.925 in chloroform)). ilcid hydrolysis of tetraacetylbisdesoxystreptobiosamine yielded N-methyl-L-glucosamine2 and bisdesoxystreptose (m. p. 90-9lo, [cY]*~D+ 3 2 O (c, 0.975 in chloroform). Anal. Calcd. for C&&: C, 54.52; H, 9.16; 2C-CH3, 22.7; mol. wt., 132. Found: C, 54.63; H, 8.93; C-CH3, 19.4; mol. wt., 141). Bisdesoxystreptose gave a bis-p-nitrobenzoate, m. p. 141-142'. Bisdesoxystreptose was oxidized with one mole of periodic acid, and the product hydrolyzed with acid. Treatment of the solution with excess amounts of substituted hydrazines gave osazones of biacetyl. The derivatives prepared were the phenylo~azone,~ m. p. 247-249' ; 5,6-dimethyl2,3-diphenylosatetrazine,' m. p. 153-155' ; the p-bromophenylosazone, m. p. 210-21.5' ; and the p-nitrophenylo~azone,~ m. p. 312-316'. These data show that bisdesoxystreptose is a 3,4 - dihydroxy - 2,3 - dimethyltetrahydrofuran (structure I). The compound formed an acidic complex with boric acid, indicating that the hydroxyl groups have the cis configuration. Structure I1 represents tetraacetylbisdesoxystreptobiosamine. The presence of a free tertiary hydroxyl group in streptobiosamine derivatives has been indicated.las8 Periodate oxidations of N-acetylbisdesoxystrep tobiosamine' indicate a pyranose ring structure for the methylamino hexose moiety. The primary rapid reaction appeared to be with one mole of periodate, and neither formic acid nor formaldehyde could be isolated. CHt--
1
HOCH I
F
-
0 I
HOC-CHj CH - -~
I
CH-O---CH
(0
I
I
Vol. 68
COMMUNICATIONS TO THE EDITOR
?-$(N I
CHI
I
i Ac
i
H
I
HCOAc I
"TH-l I
ture I1 for tetraacetylbisdesoxystreptobiosamine, structures V, VI, VI1 and VI11 may now be written for streptobiosamine. CH-0-CH
I
H0L-R
0 [ L C HCOH HI
1
L----CH
?l i'
I HOCH I I
HOC-I
I
R'
CHzOH V, R = -CHO, R' -CHj -CHO VI, R = -CH,, R' HOCHCH-0-CH
I
0 [ Z
CHCOH IH
I
HOLH
I I
L -
I I
I I Ho?-R CH-----I
l
0
1
I
R'
CH
CHzOH VII, R = -CH,, R' -CHO VIII, R = -CHO, R' = -CHI
Other degradations, to be published shortly,' will demonstrate which of these formulas is correct. (7) Kuehl, Flynn, Brink and Folkers, i b i d , , in press.
NORMAN G. BRINK RESEARCH LABORATORIES FREDERICK A. KUEHL,JR MERCK& Co., INC. EDWINH. FLYNN RAHWAY, N. J. KARLFOLKERS RECEIVED OCTOBER 15, 1946
2,3-DICHLORO-1,4-DIOXANE
Sir : We have made two interesting and previously unrecorded observations in our study of the chlorination of dioxane.'-? Repeated contact of 2,3-dichloro-1,4-dioxane (made from technical or purifieds dioxane) with the skin, or inhalation of its vapor, quickly produces vertigo, nausea, headache, and inflamed eyes. These symptoms persist for several days: the inhalation of ammonia gives partial relief. The uncatalyzedl-s chlorination of dioxane proceeded without mishap. When the chlorination was catalyzed by stannic chloride,? the reaction proceeded satisfactorily for about sixteen hours
HorLo R'C I CH,
I ! I
~ H ~ O A C
11, R, R' = H 111, R = OH, R' = H IV, R = H, R' = OH
Tetraacetyldesoxystreptobiosaminewould have either structure I11 or IV. On the basis of struc(2) Kuehl, Flynn, Holly, hlozingo and Folkers, Trns JOURNAL, 66, 536 (1946). (3) Neubug and Reinfurth, Biochcm. Z . , 148, 563 (1923). (4) H. v. Pechmann, Be?., tl, 2751 (1888). (5) Hirsch, Biochcm. 2.. 131, 184 (1922); Neuberg and Kobel. ibid., 180, 255 (1925). (6) Brink, Kuehl. Flynn and Folkers, THIS JOURNAL, in press.
(1) B&seken, Tellegen and Henriquez, Rcc. trw. chim., 50, 909 (1931). (2) Summerbell and Christ, THIS JOURNAL, SI, 3777 (1932). (3) Baker, J . Chcm. Soc., 2666 (1932). (4) Butler and Cretcher, Tars JOURNAL, SI, 2987 (1932). (5) Wilson, Baker and Shannon, J , Cham. Soc., 1598 (1933). (6) B(kseken, Tellegen and Henriquez, TEISJOURNAL, 55, 1284
(1933).
(7) Kucera and Carpmter. ibid.. (IT, 2348 (1935). (8) Fieser, "Experiments in Organic Chemistry," D. C. Heath and Co., New York, N. Y.,1941, pp.
368-369.
