exhibit potent activity against Myco bacterium tuberculosis H 3 7 Rv and M. lepraemurium in mice. "Tuberculosis is now regarded as one of the most important specific communicable diseases," Dr. Elslager observes. There are millions of new TB cases each year. Moreover, some 11 million people are afflicted with leprosy, he adds. The ideal antitubercular and antileprotic agent should act rapidly, penetrate barriers between the microorganisms and the host, destroy both normal and drugresistant organisms, and be relatively nontoxic for the host. Dr. Elslager's discovery was some thing of an accident. It came about during a systematic study of substi tuted 4-amino-l-naphthylazo schis tosomicides. He and coworkers Dr. Myron W. Fisher, Zoe B. Gavrilis, Annette A. Phillips, and Dr. Leslie M. Werbel examined 105 compounds in the series of derivatives under study. Dr. Fisher, a microbiologist, found that the in vitro potency of 28 of them against M. tuberculosis is comparable to that of isoniazid, the most commonly used commercial anti tuberculosis drug. Of the azo compounds active in vitro, only certain ones were effective on mice. Five of them, derivatives of 1- {3- {[5,6,7,8-tetrahydro-4(phenylazo and 3-pyridylazo)-lnaphthyl] amino} propyl} -piperidines, approached isoniazid in potency against M. tuberculosis H 3 7 Rv, the strain that causes TB in man. The chemicals are made by cou pling a diazotized aniline or 3-aminopyridine derivative with the requisite l-{ 3-[(5,6,7,8-tetrahydro-l-naphthyl) amino ] propyl j piperdine percursor. An alternate route is the interaction of an N-(3-halopropyl)-5,6,7,8-tetrahydro-1-naphthylamine with an ap propriate piperidine. These five compounds were sent to Dr. Y. T. Chang at the National In stitutes of Health, Bethesda, Md., who screened them for effects against M. lepraemurium in mice. Four showed suppressive antileprotic activity when administered orally to female Swiss albino mice at dose levels from 0.00625 to 0.025% in their diet. Only 1- {3-[4-(p-chlorophenylazo)5,6,7,8 - tetrahydro -1 -naphthylamino] propyl} piperidine has been subjected to detailed toxicological studies. Dr. Elslager notes that the compound un fortunately produced undesirable pathological effects after chronic ad ministration to rats in daily doses as as low as 5 mg. per kg. of body weight during a 28-day period. Therefore, clinical trials with this compound were not initiated. The relative toxicity of other active members of the series hasn't been assessed yet.
Natural hydroazulene total synthesis achieved 1 CC ljJTH
ACS N A T , 0 N A L
MEETING Organic Chemistry
Northwestern University chemist James A. Marshall and his student, John J. Partridge, have achieved the first total synthesis of a naturally oc curring bicyclic hydroazulene. The route may offer a new general ap proach to synthesis of terpenoid carbocycles. The key to the Marshall-Partridge synthesis, and its appeal for general use, rests in a skeletal rearrangement which converts a bicyclo[4.3.1]decane derivative to the desired bicyclo[5.3.0]decane framework of the hydroazulenes. This has stereochemi cal advantages over routes based on hydroazulenes alone, Dr. Marshall points out. Asymmetric centers can be introduced stereoselectively into the relatively rigid bicyc!o [4.3.1] carbon framework; by contrast, bicyclo[5.3.0]decane (hydroazulene) precursors are flexible and stereochemistry is difficult to control. The general synthesis starts from readily available C-4-substituted cyclohexanones. These are converted to the bicyclic intermediates via ring homologation with ethyl diazoacetate,
John Partridge and Dr. James Marshall Total synthesis of bulnesol is a first followed by base-catalyzed condensa tion with methyl vinyl ketone. This gives diketo esters which are then cyclized in concentrated sulfuric acid. Lithium aluminum hydride is next used to reduce the resulting bicyclic keto esters to the corresponding diols. When the substitutent at C-4 of the starting cyclohexanone is a p-chlorophenoxymethylene group, the final hydroazulene product after a number of additional steps is bulnesol. In this case, the C-4 substituent in the origi nal cyclohexanone is converted to the isopropyl alcohol moiety found at C-7 of bulnesol. The choice of p-chlorophenoxy-
Cyclohexanone precursors are readily transformed to bicyclic intermediates via a three-step sequence Ring homologation product
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Cyclohexanone
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