3874
Vol. 86
COMMUNICATIONS T O T H E EDITOR Tetracycloxides. I. A New Class of Tetracycline Derivatives
Sir : We wish to report the synthesis and characterization of a new class of tetracycline derivatives which allows for previously unattainable modifications of the fundamental tetracycline structure.l We propose that these novel derivatives, which are characterized by a t,6-oxygen bridge, be named "tetracycloxides"2 based on the hypothetical compound I .
I I1 I11 IV V
R1
=
KI
Rt RI
= = R1 =
H, Rz H, Rz H , R* CI, Rz
H OH N(CH3)s OH C1, Rz = N(CH3)a = =
Compound 11, the first member of this class encountered, resulted (67y0 isolated yield) from an attempt to chlorinate 6-demethyltetracyclinc (VI) with a combination of concentrated hydrochloric acid and sodium chlorate in acetic acid.3 The same reaction with 6-demethyl-6-deoxytetracyclinehad given 1lachloro-6-demethyl-6-deo~ytetracycline~ (50% isolated yield). Since I1 had the spectral characteristics MeOH. 0.1 N HC! 258 and 338 mC: (log E 4.64 and ihm,, 3.67) ; :,A" 5.78 p) of an lla-chloro substituted tetracycline5 it. was surprising when the elemental analysis revealed, in addition to the loss of dimethylamine, no chlorine to account for the shortening of the B-C-D chromophore. I: nul. Calcd. for CI9Hl5NO9: C, 50.85; H . 3.77; N , 3.51. Found: C , 56.61; H , 4.02; N,3 . 4 0 ; C1, none. When I1 was treated with excess methylamine under conditions of reductive amination, the resulting product had incorporated nitrogen and now had a typical tetracycline ultraviolet spectrum with the long wave length maximum a t 355 rnp. When the aminated compound was, in turn, reductively methylated (formaldehyde, H z , Pd-C) the product was VI. Coming full circle ill this manner made it evident that the product of the reductive amination was 4-dedimethylamino-4methylamino-6-demethyltetracycline. Since reaction of I1 with methylamine gave a tetracycline-like prod(1) ( a ) I l e r i v a t i v e s of t h i s new class of c o m p o u n d s were first described tly K (.' E s e a n d G M . Sieger. S o u t h African P a t e n t Application 6314i91
(filed O c t . 22. 1983, accepted M a r c h 25, 1964) ( h ) After t h i s c o m m u n i c a tiun was s u b m i t t e d . a n article a p p e a r e d describing related work with t e t r a cycline [ K K Blackwood a n d C . K. S t e p h e n s , J . A m . C h e m . S O L . ,86, 2736 (1861)J ( c ) See also t h e a c c o m p a n y i n g c o m m u n i c a t i o n : R . C. Esse. J . A. Lowery. C K T a m o r r i a , a n d G M Sieger, tbrd., 66, 3875 (1964). (21 T h u s I 1 becomes "4-hydroxytetracycloxide" f o r which a trivial n a m e I S " 4 - d e d i m e t h y l a m i n o - 4 a x o ~ f i ~ d e m e t h y l t e t r a c y c l i n e4 . 6 - h e m i k e t a l " while t h e s y s t e m a t i c n a m e is ' ' I .?.4a,A.,5a,6,1i,Ila,l2,12a-decahydro-4~,6!,-epoxy:ila.l0.l2aa-tetrahydroxy-l, 11.12 trioxo-2-naphthacenecarhoxamide." I X P . Keveridin a n d P CrPpieux. Ber , 33, 2503 (1900). ( 4 ) C K S t e p h e n s , J J . Beerehoom. H H R e n n h a r d , P. N. G o r d o n , K h l u r a i , K K Blackwood, a n d hl S c a c h von W i t t e n a u , J . A m . C h e m . .so< 8 6 , 2643 (196.3) ( 5 1 T h e effect which s u b s t i t u t i o n a t C I l a h a s o n t h e spectral p r o p e r t i e s of t h e tetracyclines h a s been f r e q u e n t l y noted (cf A G r e e n , R G. Wilkinson. a n d J H . Briothe. i b r i i , 8 2 , 3947 CISSO),a n d H H. R e n n h a r d , K K . Blackw o o d a n d C I< S t e p h e n s , ibrd , 8 3 , 2775 (196111
uct only when reducing conditions were employed, it seemed most likely that C-4 was ketonic. This supposition was supported when I1 was treated with hydroxylamine to give an oxime,"::x:( 309 and 350 mp (log E 4.32 and 4.19). No : : :A between 5 and 6 p was observed. Anal. Found for CI9HlRN2O9. CHaOH: C, 53.62; H , 4.26; N,6.38.) Oxime formation was established as having occurred a t the C-4 position when the oxime was catalytically reduced in the presence of formaldehyde to give VI. The 4-oxime analog had further significance in that its formation resulted in the removal of the apparent C - l l a block of the B--C-D ultraviolet chromophore. It was thus established that reducing conditions were not necessary for the recovery of the long wave length ultraviolet maximum. The observed chemical transformations (reductive amination, oxime formation) could be explained on the basis of C-4 being ketonic as in structure VII. How-
CON&
OH 0
OH VI1
ever, this structure does not account for the apparent block a t C - l l a . If, however, VI1 is considered to be in the form of a 4,G-hemiketal it must assume the configuration depicted in VIII. An inspection of molecular
-
/
\
H I
OH
oH
OH 0
\
H
OH VI11
models of VI11 reveals that the 4,6-oxide linkage imposes a nonplanarity on the B-diketone system which prevents enolization of the C-12 ketone. Thus structure VIII, with its ketone (in the form of a hemiketal) a t C-4 and its "block" a t C - l l a , accounts for both the chemical and spectral properties of 11. 7-Chloro-6-demethyltetracycline also forms a 4,6hemiketal (IV) ( h ~ ~ ~ l Ni H ~C I " . 258 l and 350 mp (log t 4.40 and 3.66), hi:: 5.79 1.1. Anal. Found for C1~H1~N09.dimethylformamide: C, 51.94; H . 3.95; N,5.58; C1. 7.09) under the same conditions which lead to 11. I t has been found that in addition to sources of positive halogen a variety of reagents can promote tetracycloxide formation. Among them are air, cupric acetate, and mercuric acetate. When a solution of VI in diniethylformamide was treated with 1 mole of mercuric acetate, a new product was detected. I t
Sept. 20, 1964
COMMUNICATIONS TO THE EDITOR
had the characteristic spectral properties of I1 but an analysis ( X ~ ~ OJ~ H s 258 and 336 mp (log e 4.36 5.83. Anal. Found for C21HmN208: and 3.70); A”:, C, 58.75; H , 4.86; N , 6.46) revealed that the dimethylamino group was still present. Mild acid hydrolysis readily converted it to 11. When it was reduced with sodium borohydride under alkaline conditions it gave back V I having the natural configuration a t C-4. This product must certainly be 4-dimethylaminotetracycloxide (111) and its isolation necessarily sheds light on the sequence of events leading from V I to 11. It would appear that the net effect of attack by positive halogen, or the previously noted oxidizing agents, is the loss of hydride ion resulting in the formation of the ternary iminium compound X .
3875
OH
FNF
%%”*
OH OH 0 OH 0 I-XI1
sulting derivatives are summarized in Table I. The reductive aminations were carried out a t room temperature a t pressures of 50 lb. or less, with 10% palladium on carbon as the catalyst. Generally, 10 equiv. of amine was used. The large excess of amine served two purposes; it afforded the alkaline conditions necessary for the success of the reaction and it minimized the formation of 4-dedimethylamino-4-hydroxyHsC, ?Ha 6-dernethyltetra~ycline.~ These reactions were rapid, R OH +N being complete within 20 min. Even so, there was a considerable loss in side reactions which stems from the great alkaline instability of 4-hydroxytetracycloxide. CONHn Rapid handling of the reaction solution prior to OH 0 OH 0 commencing hydrogenation was essential to minimize X , R = H or C1 losses. The yields of crystalline product isolated ranged from 20 to 40%. Compound X would be subject to ready attack by Three factors strongly suggest that the products of water to give the 4-keto analog, which in turn would Table I have mainly the 4-epi configuration: (1) the undergo hemiketal formation with the C-6 hydroxyl to A ring ultraviolet chromophore of these products has give the 4-hydroxytetracycloxide. Alternatively, under its maximum a t ca. 255 mp which is characteristic of essentially anhydrous conditions X would simply 4-epi-tetracyclines3; ( 2 ) reductive methylation of I1 undergo nucleophilic attack by C-6 hydroxyl to give gives mainly the known 4-epi-6-demethyltetracycline4; the 4-dimethylaminotetra~ycloxide.~ and (3) column chromatography of I1 has permitted Although the stereochemistry of 7-chlorotetracycline the isolation of a minor component which has the ultrahas now been completely defined by X-ray crystalviolet spectrum, relative polarity, and increased biolography,’ 111 does provide chemical confirmation for logical activity (7-fold) which would be expected the relative configurations of four of the five asymmetric for the “natural” C-4 epimer of 11. Attempts to epicenters in 6-demethyltetracycline. The configuration merize the products of Table I in glacial acetic acid or a t carbons 4a,8 5a, 6, and 12a is rigidly defined since by formation of a calcium chelate as described by Nosethe 4,6-oxide bridge can form only when the relative worthy5failed. stereochemistry is as shown in VIII. A number of the derivatives in Table I have been (6) For a discussion of the formation and reactions of ternary iminiurn reductively alkylated catalytically. Of the new comcompounds see, for example: N . J. Leonard, A. S. Hay, R . W. Fulmer, and pounds formed, those which have been isolated in pure W. V . Gash, J . A m . C h e m . Sor.. 7 7 , 439.11955); N . J . Leonard and A. S. H a y , i b i d . , 78, 1984 (1956). form are listed in Table 11. The reductive alkylations (7) J. Donohue. J . D . Dunitz, K . N . Trueblood, and M . S. Webster. i b i d . , were run overnight a t 50 lb. pressure and were best 86, 851 (1963). accomplished a t somewhat elevated +.emperatures (8) There is same slight ambiguity concerning C-4a since epimerization a t this site could conceivably occur wia the nonprotonated (enamine) form of X. (50-60”). The crude products from the reductive PHARMACEUTICAL PRODUCT ROBERTC. ESSE alkylation were subjected to the epimerizing condiDEVELOPMENT SECTION J. A. LOWERY t i o n ~which ~ failed with the 4-amino and 4-monoalkylLEDERLE LABORATORIES C. RICHARD TAMORRIA PEARL R I V E R , NEWYORK G. M. SIEGER amino analogs. In contrast, the 4-dialkylamino analogs were epimerized completely. The compounds RECEIVEDJULY 1, 1964 reported in Table I1 have the “riatural” configuration a t C-4. Tetracycloxides. 11. Transformations a t the The antimicrobial potencies of the N-demethyl C-4 Position analogs of Table I are very low in comparison with the fermentation-derived tetracyclines. This is to be Sir : expected since they have the 4-epi configuration but, I t was noted in the accompanying report’ that 4beyond that, a small amount of the “natural” epimer hydroxytetracycloxide can be reductively aminated of I1 was isolated and it assayed6 a t only 7yoof tetracatalytically with methylamine to give 4-dedimethyl(2) The 4-hydroxy analog has not been fully characterized, but we have amino-4-methylamino-6-demethyltetracycline (11) and little doubt as t o its identity. that this product can, in turn, be reductively methyl(3) J. R . D . McCormick, S. M . Fox, L. 1.. Smith, B. A. Bitler. G Reichenthal, V . E . Origoni, W. H . Muller, R . Winterbottom, and A . P . Doerschuk. ated with formaldehyde * to yield 6-demethyltetraJ . A m . C h e m . Soc., 79, 2849 (19571. cycline (VIII). The reductive amination step has (41 J. R . D . McCormick. N . 0 . Sjolander, U. Hirsch. E R . Jensen, and been extended to include the use of ammonia and a A. P. Doerrhuk, i b i d . , 79, 4561 (1957). (5) M . M . Noseworthy, U . S. Patent 3,009,956 ( N o v . 21, 1961). number of simple aliphatic primary amines. The re(6) Activities were measured turbidimetrically against Staphylococcus
(1) R . C . Esse, J . A. Lowery, C R . Tamorria, and G. M. Sieger, J . A m . C h e m . Soc.. 88, 3874 (19641.
nureus by the method of E. Pelcak and A. Dornbush. A n n .
51, 218 (1948)
N . Y Acad. Scr..
