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WALTER ABRAHAM JACOBS December24, 1883-luly 12, 1967 BY ROBERT C. ELDERFIELD WALTER ABRAHAM JACOBS died in Los Angeles after a long ant! impressive career. He left behind some-273 publications which record important contributions in the field of the chemistry of natural products of biological im- portance, as well as the development of chemotherapeutic agentsthe significance of which was not recognized until some years had passed. Jacobs was born in New York City on December 24, 1883 and attended local elementary schools. He received an A.B. degree in 1904 and an A.M. in 1905 from Columbia Univer- sity, after which he enrollee! at the University of Berlin for study under Emil Fischer, earning a Ph.D. degree in 1907. On his return to New York, Jacobs received an appoint- ment as a fellow in chemistry in the laboratory of Phoebus A. Levene at the newly established Rockefeller Institute for Medical Research. In 1908 he became an assistant, and in 1910 an associate in Levene's laboratory. During these years with Levene, he was closely associates! with the latter's work on the chemistry of the nucleic acids. The studies, first with the nucleotide inosinic acid from beef extract, clisclosed its essential chemistry by hydrolysis to the nucleosicle, inosine, and by subsequent cleavage from the latter of its crystalline sugar component which was iclentified 247

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248 BIOGRAPHICAL MEMOIRS as D-ribose. This became the pattern for similar studies with the nucleotide guanylic acid, ant] with yeast nucleic acid (ribonucleic acid), from which the various nucleosicies were then isolated and interpreted. The attempted extension of this procedure to similar studies with thymus nucleic acid (subsequently shown to be cIesoxyribosenucleic acid) was in- terrupted by Jacobs' promotion in 1912 to associate member of the Institute with inclependent status. Dr. Simon FIexner, Director of the Institute, felt that the cleveloping fierce of chemotherapy warranted a division of its own, and Jacobs was placed in charge of it. In collaboration with Michael Heidelberger, he began an investigation of the possible chemotherapy of polio. It was known that hexameth- ylenetetramine apparently exerted a slight therapeutic effect, and an extended series of quaternary salts was prepared by reaction with aromatic and alipathic halogen compounds. Some of the salts clisplayec3 bactericidal properties, ant! a few appeared to prolong the life of polio-infected monkeys. Un- fortunately, this was clue to a loss of virulence of the virus strain. After the disappointing outcome of the chemotherapeutic studies concerning polio, the Jacobs-Heiclelberger team turned its attention to African sleeping sickness, for which no effective and non-toxic drugs were available. Ehrlich had procluced a powerful synthetic agent against trypanosomiasis in para-arsenopheny~glycine, in which the arsenic was tri- valent. The analogous pentavalent substance, para-phenyI- glycine arsonic acid, was considerably less toxic, but devoid of activity against the disease. Jacobs reasoned that the lack of activity could be due to the free carboxy] group which con- ceivably could react with many centers of the tissue proteins before reaching the parasites. He therefore proposed mask- ing the carboxy! group by conversion to the amide. The resulting substance, sodium para-pheny~glycine amicle ar-

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WALTER ABRAHAM JACOBS 249 senate, was the first, simplest, and best arsenical of a series subsequently synthesized. The new arsenical, named Tryparsamide by Simon FIexner, was found to be extremely effective in trypanosome infected! animals by Drs. Wade H. Brown and Louise Pearce, who now formed part of the chemotherapeutic team. Several patents were awarded for control of the drug and several of its analogsalthough none of the latter proved to be supe- rior to Tryparsamide. At the conclusion of World War I, Louise Pearce made an extensive study of the drug in the Belgian Congo; which showed Tryparsamicle- to be more ef- fective than previously used drugs. Further tests in the United States demonstrated some utility in the treatment of tertiary syphilis. Some years later (1953), Belgium recognizes! the successes of Tryparsami~le by making Drs. Jacobs, Heiclelberger, Brown and Pearce officers of the Order of LeopoIc} Il. During WorIc! War I, a portion of the Institute was desig- nated as U.S. Laboratory # I, and served as a training facility in laboratory techniques for army physicians. Jacobs ant] Hei- delberger investigated possible synthetic substitutes for Sal- varsan, a drug in scant supply and of unclesirable toxicity. One analog (arsenophenyI-glycine-bis-m-hydroxyanilide), which appeared to be less toxic and at least as active against syphilis when studied by Brown and Pearce in animals, shower! promising results in some one hundred human syphilitics. Unfortunately, a seconc! batch, for no apparent reason, caused severe, dangerous dermatitis and was aban- cloned. At the conclusion of the work on arsenicals, Jacobs and Heidelberger desirer! to turn to fields other than synthetic organic chemistry, but FIexner's faith in this approach pre- vailed and attention was turned to pneumococcal ant! strep- tococcal infections. The drug, Optochin, had been used with

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250 BIOGRAPHICAL MEMOIRS partial success in the treatment of pneumococcal infections, so further modification of the cinchona alkaloids was investi- gated, and a long series of papers resulted. Unfortunately, most of these substances killer! infected mice faster than drug or infection alone. The state of this area of chemistry in the United States at the time is reflected in the refusal of the Journal of the American Chemical Society to publish the work on the cinchona alkaloidson the grounds that no one in Amer- ica was interested! in alkaloids. Only after long arguments were the manuscripts accepted. One of the intermediates used in modification of the alkaloids and in other syntheses was p-aminobenzene- sulfonamide, or sulfanilamide; which had been prepared in 1908 by Gelmo in Germany. This was shown by Trefouel, rrefouel, Nitti, and Bovet to be one of the metabolic pro(l- ucts of the azo dye Prontosil, the antibiotic action of which was demonstrated in the same year (1935) by Gerhardt Domagk for which he was awarded the Nobel Prize. Actually, it cleveloped that the antibiotic action of Prontosi! was due to the sufanilamicle liberated on metabolism of Prontosil. It ap- parently never occurred to Jacobs and Heidelberger in ~ 920 that such a simple substance could control bacterial infections by other than direct antibacterial action. If the antibiotic ac- tion had been recognized, many thousands of lives could have been saved in the intervening years. After some nine and one-half years, the team of Jacobs and Heicielberger separated. FIexner agrees! that chemo- therapeutic research through synthetic methods could be abandoned, and Heidelberger was transferred to the new laboratory of Donald D. Van Slyke to become familiar with biochemistry. Jacobs became a full member of the Rocke- feller institute in 1923, and turned his attention to the eluci- dation of the structures of substances of natural origin which (displayer! powerful physiological actions in order to correlate

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WALTER ABRAHAM JACOBS 251 structure with such activity. The name of the laboratory was changer! to that of chemical pharmacology. The first group explored was that known as the cardiac glycosides, noted for their specific and powerful action on the myocarclium, and which are unrivaled in value for the treat- ment of congestive heart failure. Of the group, the glycosides from digitalis species are probably the best known. Extracts of other plants containing members of the group such as strophanthus species were used as arrow poisons by African tribes. The ancient Egyptians were familiar with the proper- ties of squill, and the Romans used it as an emetic, heart tonic, diuretic ant! rat poison. Strophanthus was introcluced into modern medicine in IS90, and the modern use of digitalis dates from 1785, when William Withering published his famous book entitled, An Account of the Foxglove and Some of Its Medicinal Uses: With Practical Remarks on Dropsy and Other D?s- eases. At the time Jacobs began his investigations on the struc- tures of these important compounds, little was known of them or their chemistry. It was known that they were glyco- sides consisting of a rather complicated aglycone moiety, which was responsible for their major pharmacological prop- erties, joiner! with one or more sugar molecules. The digitalis glycosides are present in the plant in extremely small amounts, whereas the semis of Strophanthus kombe are rela- tively rich in the glycosides of strophanthicl~n. Jacobs' plan of attack on the structures of the aglycones was to place major emphasis on the structure determination of the more acces- sible strophanthidin ant! to attempt a correlation of this struc- ture with the (ligitalis aglycones and others by chemical inter- conversions of appropriate (lerivatives. This plan proved to be completely successful and the structures of a half dozen or so of the aglycones were clemonstrate(l. It should be notes! that when the study of the cardiac

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252 BIOGRAPHICAL MEMOIRS' aglycones was begun (1923), similar studies on cholesterol and the bile acids by Windaus (1903), Diels (1903) and Wie- land (1912) in Germany were also under way. There was no reason to believe that the three groups of substances would ultimately be found to be closely related. Also, with the pos- sible exception of ultraviolet spectroscopy, none of the instru- mental methocls, such as infrared spectroscopy, X-ray spec- troscopy and nuclear magnetic resonance, were available. Chemical transformations ant! degradation with subsequent interpretation formed the basis for structural elucidation a long and tedious process at best. Conversion of a strophanthidin derivative to a periplo- genin derivative, and correlation of the latter with derivatives of digitoxigenin and gitoxigenin from digitalis followecI. Al- though many structural features of the four aglycones were known, the problem of the carbon skeleton remained un- solved. In 1927, Diels and his co-workers heate(1 cholesterol with selenium, thereby dehydrogenating it to its basic carbon ring system, cyclopentanophenanthrene. Similar clehydro- genatior~ of strophanthiclin also yielder! Diets' hydrocarbon, thus providing conclusive evidence that the basic ring system of the cardiac aglycones was, indeed, identical with that of cholesterol and the bile acids. With the aid of X-ray data, the latter basic ring system was shown to be that of the Diels' hydrocarbon, a perhydrocyclopentanophenanthrene, by British workers. The problem of the location of the unsaturated lactone side chain on the nucleus of the aglycones was resolved by application of the Barbier-Wieland degradation, used suc- cessfully in degradation of the sicle chain of cholanic acid, to a derivative of (ligitoxigenin with the formation of etiocho- lanic acid as the final product. Almost simultaneously, R. Tschesche in Germany accomplished a similar clegraclation

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WALTER ABRAHAM JACOBS 253 of another aglycone, uzarigenin, to allo-etiocholanic, the dif- ference being in the stereo configuration of the lactone side chain at the 17-position of the nucleus. Although all available evidence up to the actual Barbier- W~elanc! degradation appeared to involve the 17-position as the point of attachment of the side chain, Jacobs, a most meticulous planner of experiments, was loath to attempt the degradation of the side chain. A suitable derivative of the available strophanthiclin was not available, and only a few hundred milligrams of an appropriate digitoxigenin deriva- tive were available for the three-step degradation and charac- terization of the product. Jacobs was hesitant to commit this hard to obtain substance to a degradation the outcome of which, despite its logical prediction, was not certain. It so happenec! that the necessity for this decision arose early in the fall of 1934. Jacobs and his wife habitually took long Columbus Day weekends to admire the fall foliage of the Adirondack Mountains and this author took the opportu- nity to commit the entire supply of digitoxigenin derivative to the degradation, with considerable trepiciation. After three days and nights, pure samples of etiocholanic acid ant! its methyl and ethyl esters awaited Jacobs' return. Although the physical constants of all these agreed with the published data, Jacobs, after some hesitation, agreed to request authentic samples from Wieland in Munich for comparison. All com- pounds were identical with the samples, and this author heaver! a sigh of relief. With one minor revision, involving the position of the double bond in the unsaturated lactone side chain, the struc- ture of the cardiac aglycones was established. During his investigations of the cardiac aglycones, Jacobs began structural studies of the saponin group. These are plant glycosides that possess the distinctive property of form-

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254 . BIOGRAPHICAL MEMOIRS 1ng a soapy lather in water. The plant heart drugs also display this property, but are classified separately because of their distinctive physiological heart action. Early emphasis was placed on the readily available sarsasa- pogenin from Smiler ornata Hooker. The aglycone occurs as a glycoside with two rhamnose and one glucose units. The empirical formula of the aglycone was revised to the now accepted C27H44O3. Reinvestigation of the selenium dehydro- genation of sarsasapogenin resulted in the isolation of Diels' hydrocarbon, thus establishing that the sapogenins possess the steroid ring system. The presence of a Cal side chain was indicated by the isolation of a ketone COO, which was not identical with methyl isohexyl ketone from cholesterol. A partial structure for sarsasapogenin was suggested in 1935. By this time, great emphasis had been placed on the cor- tical steroid hormones and their possible therapeutic applica- tions. This resulted in a hectic search for accessible plant steroids which could be converted to cortical hormones. Several investigators, amply financed by the pharmaceutical industry, entered the field. Jacobs j with his small staff; was literally snowed under. However, one further correlation was accomplished that of sarsasapogenin with the representative steroid alka- loid, solanidine. By this correlation, the structure of solani- dine was established and another member of the steroid group was recognized. Beginning in 1932, an intensive study of the structures of the ergot alkaloids was undertaken in cooperation with the late Dr. Lyman C. Craig. Ergot is the product of a fungus which grows on grain, particularly on rye. Its effect on pregnancy has been known for 2,000 years and it was first used by physicians as an oxytocic agent some 400 years ago. Consumption of edible grain contaminated by the fungus has resulted in death and destruction for centuries, but it was not

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WALTER ABRAHAM JACOBS 255 recognizes! as the agent responsible for destructive epidemics until 1670. It was first employed by a physician about ISIS, although it had been user! by midwives long before. At the time this investigation was undertaken, the chem- istry of the ergot group was almost completely unknown. By ~ 934, on hydrolysis of the alkaloids, a substance namer! {yser- gic acid, which proved to be the characteristic building block of the ergot alkaloids, was isolated. The other products of hyclrolysis of the alkaloids were amino acid (derivatives joined by pepticle linkages to themselves and to lysergic acid. The structure of lysergic acid was then shown by degrada- tion ant! substantiates! by subsequent synthesis of the dihydro derivative and of lysergic acid itself. In this work an un- natural amino acid was encounterer! for the first time. Subse- quently, the now famous L.S.D., the diethy! amide of lysergic acid, was synthesized by A. Hoffmann and Arthur Stoll in Switzerland. The suspicion that such substances might be of more widespread occurrence formed the basis for a plan to extend such studies to other poisonous fungi such as ~4manita mus- carta. Although begun, this was interrupted by other work ant! has since been carried on in other laboratories. The ergot alkaloids may be regarded as the first group of a general pattern of such distorter! polypeptides encountered in the gramiciclins, penicillins ant! other antibiotics. Another field! of investigation entered by Dr. Jacobs was the chemistry of the aconite alkaloids, which embraced a large group of substances of uncletermined structure when he began his inquiry in 1936. Some of these had long been used in medicine, and in some cases are among the most poisonous substances known. These studies included the known aconitine from Aconitum napellus, commonly known as monkshooc! or wolfsbane, and the isolation of three new alkaloicIs heteratisine, hetisine and benzoy~heteratisinc- as

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256 BIOGRAPHICAL MEMOIRS well as the known atisine from Aconitum heterophyllum Wall. Closely related were delphinine ant! staphisine from Del- phinium staph~sagrza, similar in action to aconitine. Degrada- tion procedures supplementecl by syntheses were reported in some thirty-five communications, until the time of Jacobs' retirement in 1957. The final group of natural products to which Jacobs turned his attention embraces a complex family now known as the steroid bases, or veratrum alkaloids, found in various Veratrum species. These fall into two classes, as suggested by Fieser and Fieser*: the jerveratrum alkamines and the ceve- ratrum alkamines which comprise cevine and its precursors. Of the first group, Jacobs and co-workers established that rubijervine is a hydroxy! derivative of the known solanidine by conversion to the latter substance. Assignment of the hy- droxy! group to the 12-position was establishecl by infrared and rotatory dispersion data. A structure for veratramine was also proposecl, which was essentially correct except for one minor cletail. As with the saponins, interest in jervine increased with recognition of the possibility that it could serve as a starting material for the synthesis of cortisone, and it attracted exten- sive attention from industrial laboratories. In 1949, Jacobs hac! tentatively suggested a structure for jervine based on available data for this complex molecule at that time. This was shown to be in error in some respects, although in general it refIectec3 the data then available. The accepted structure was eventually proposed by a group at the Squibb Laboratories. The ceveratrum alkamines generally occur as esters of various acids. Four of the alkamine bases commonly found as such esters are veracevine, "ermine, protoverine and zyga- clenine. On alkaline hydrolysis, cevine, now recognized as an *Louis F. Fieser and Mary Fieser, Steroids (New York: Reinhold Publishing Corp., 1959), 1 1 18 pp.

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WALTER ABRAHAM JACOBS 269 phanthidin and periplogenin with digitoxigenin and gitoxi- genin. J. Biol. Chem., 92:313-21. With E. L. Gustus. Strophanthin. XXIII. Ring II of strophanthidin and of related aglucones. I. Biol. Chem., 92:323~4. With E. E. Fleck. The partial dehydrogenation of ursolic acid. I. Biol. Chem., 92:487-94. With R. C. Elderfield, A. Hoffmann, and T. B. Grave. Strophan- thin. XXIV. Isomeric hexahydrodianhydrostrophanthidins and their derivatives. I. Biol. Chem., 93:127-38. With A. B. Scott. The hydrogenation of unsaturated lactones to desoxy acids. II. l. Biol. Chem., 93:13~52. Phoebus A. LeveneThe man. Chem. Bull., 18: 121. With E. E. Fleck. Strophanthin. XIX. The dehydrogenation of stro- phanthidin and gitoxigenin. Science, 73: 133-34. 1932 With E. E. Fleck. The partial dehydrogenation of oleanolic acid. I. Biol. Chem., 96:341-54. With N. M. Bigelow. The sugar of sarmentocymarin. I. Biol. Chem., 96:355. With R. C. Elderfield. Strophanthin. XXV. The allocation of the lactone group of strophanthidin and related aglucones. I. Biol. Chem., 96:357~6. With N. M. Bigelow. Ouabain or g-strophanthin. J. Biol. Chem., 96:647-58. With E. E. Fleck. Strophanthin. XXVI. A further study of the dehydrogenation of strophanthidin. J. Biol. Chem., 97:57~1. With R. C. Elderfield. Strophanthin. XXVII. Ring III of strophan- thidin and related aglucones. I. Biol. Chem., 97:727-37. The ergot alkaloids. I. The oxidation of ergotinine. I. Biol. Chem., 97:739 43. 1933 With N. M. Bigelow. The strophanthins of Strophanthin eminii. J. Biol. Chem., 99:521-29. With R. C. Elderfield. The digitalis glucosides. VI. The oxidation of anhydrodihydrodigitoxigenin. The problem of gitoxigenin. J. Biol. Chem., 99:693-99. With R. C. Elderf~eld. The digitalis glucosides. VII. The isomeric dihydrogitoxigenins. J. Biol. Chem., 100:671-83.

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270 BIOGRAPHICAL MEMOIRS With N. M. Bigelow. Ouabain. II. The degradation of isoouabain. I. Biol. Chem., 101: 15-20. With N. M. Bigelow. Trianhydroperiplogenin. J. Biol. Chem., 101 :697-700. With R. C. Elderfield. Strophanthin. XXVIII. Further degradation of strophanthidin and periplogenin derivatives. l. Biol. Chem., 102:237-48. The chemistry of the cardiac glucosides. Physiol. Rev., 13:222-45. 1934 With L. C. Craig. The ergot alkaloids. II. The degradation of ergot- inine with alkali. Lysergic acid. I. Biol. Chem., 104:547-51. With R. C. Elderfield. The digitalis glucosides. VIII. The degrada- tion of the lactone side chain of digitoxigenin. Science, 80:434. With J. C. E. Simpson. On sarsasapogenin and gitogenin. J. Biol. Chem., 105:501-10. With L. C. Craig. The ergot alkaloids. III. On lysergic acid. J. Biol. Chem., 106:393-99. With R. C. Elderfield. Strophanthin. XXIX. The dehydrogenation of strophanthidin. Science, 79:27~80. With R. C. Elderfield. Strophanthin. XXXI. Further studies on the dehydrogenation of strophanthidin. I. Biol. Chem., 107: 143-54. With R. C. Elderfield. The structure of the cardiac glucosides. Science, 80:533-34. 1935 With R. C. Elderfield. The structure of the cardiac aglucones. I. Biol. Chem., 108:497-513. With L. C. Craig. The ergot alkaloids. IV. The cleavage of ergot- inine with sodium and butyl alcohol. I. Biol. Chem., 108:595-606. With R. C. Elderfield. Strophanthin. XXXII. The anhydrostro- phanthidins. J. Biol. Chem., 108:693-702. With I. C. E. Simpson. Sarsasapogenin. II. I. Biol. Chem., 109:573-84. With J. C. E. Simpson. The digitalis sapogenins. J. Biol. Chem., 110:42~38.

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WALTER ABRAHAM JACOBS 271 With L. C. Craig. The ergot alkaloids. V. The hydrolysis of ergot- inine. I. Biol. Chem., 110:521-30. With I. C. E. Simpson. Sarsasapogenin. III. Desoxysarsasapogenin. Further degradations of sarsasapogenin. I. Biol. Chem., 110:565-73. With L. C. Craig. The ergot alkaloids. VI. Lysergic acid. J. Biol. Chem., 111 :455~5. With L. C. Craig. The structure of the ergot alkaloids. I. Am. Chem. Soc., 57:383~4. With L. C. Craig. The hydrolysis of ergotinine and ergoclavine. J. Am. Chem. Soc., 57:96~61. With L. C. Craig. The ergot alkaloids. Science, 81:256-57. With L. C. Craig. On an alkaloid from ergot. Science, 82:16-17. ~ ~ , . ~ ,. . . ~ ~ ~ - ~' . 1 l 1 1 ~ ~ _ _ _ r A _ _ __C _ 1_ ~ _ With L. t;. (Craig. the ergot alkalolus. Synthesis ot ~-caroollne carbonic acids. Science, 82:421-22. 1936 With R. C. Elderfield. Strophanthin. XXXIII. The oxidation of anhydroaglucone derivatives. I. Biol. Chem., 113:611-24. With R. C. Elderf~eld. Strophanthin. XXXIV. Cyanhydrin syn- theses with dihydrostrophanthidin and derivatives. l. Biol. Chem., 113:62~30. With L. C. Craig. The ergot alkaloids. VIII. The synthesis of 4-carboline carbonic acids. l. Biol. Chem., 113 :759 65. With L. C. Craig. The ergot alkaloids. IX. The structure of lysergic acid. I. Biol. Chem., 113:767-78. With R. C. Elderfield. The lactone group of the cardiac aglycones and Grignard reagent. I. Biol. Chem., 114:597-99. With L. C. Craig. The ergot alkaloids. XI. Isomeric dihydrolysergic acids and the structure of lysergic acid. J. Biol. Chem., 115:227-38. With R. C. Elderfield. The N-alkyl group of aconine (aconitine). J. Am. Chem. Soc., 58:1059. With L. C. Craig. The ergot alkaloids. X. On ergotamine and ergo- clavine. I. Org. Chem., 1:245-53. With L. C. Craig. The ergot alkaloids. The structure of lysergic acid. Science, 83:3~39. With L. C. Craig and A. Rothen. The ergot alkaloids. The ultravio- let absorption spectra of lysergic acid and related substances. Science, 83:16~67.

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272 BIOGRAPHICAL MEMOIRS 1937 With L. C. Craig. The veratrine alkaloids. I. The degradation of cevine. l. Biol. Chem., 119:141-53. With O. Isler. The sapogenins of Polygala senega. ]. Biol. Chem., 119:15~70. With R. G. Gould. The ergot alkaloids. XII. The synthesis of sub- stances related to lysergic acid. l. Biol. Chem., 120:141-50. With L. C. Craig. The veratrine alkaloids. II. Further study of the basic degradation products of cevine. l. Biol. Chem., 120:447-56. With R. G. Gould. The synthesis of substances related to lysergic acid. Science, 85:24~49. 1938 With L. C. Craig. The ergot alkaloids. XIII. The precursors of pyruvic and isobutyrylformic acids. J. Biol. Chem., 122:41 ~23. With L. C. Craig. The veratrine alkaloids. III. Further studies on the degradation of cevine. The question of confine. I. Biol. Chem., 124:65~66. With L. C. Craig, T. Shedlovsky, and R. G. Gould. The ergot alka- loids. XIV. The positions of the double bond and the carboxyl group in lysergic acid and its isomer. The structure of the alka- loids. J. Biol. Chem., 125:28~98. With L. C. Craig. The veratrine alkaloids. IV. The degradation of cevine methiodide. I. Biol. Chem., 125:62~34. . _ 4t, ~ With R. G. Gould. The ergot alkaloids. XVI. Further studies of the synthesis of substances related to lysergic acid. I. Biol. Chem., 126:67-76. With L. C. Craig. The position of the carboxyl group in lysergic acid. I. Am. Chem. Soc., 60:1701-2. With R. C. Elderfield. The terpenes, saponins and closely related compounds. Annul Rev. Biochem., 7:44~72. 1939 With L. C. Craig. Delphinine. J. Biol. Chem., 127:361-66. With L. C. Craig. Delphinine. II. On oxodelphinine. J. Biol. Chem., 128:431-37. With R. C. Elderfield and L. C. Craig. The aconite alkaloids. II. The formula of oxonitine. l. Biol. Chem., 128:43~46.

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WALTER ABRAHAM JACOBS 273 With L. C. Craig. The ergot alkaloids. XVII. The dimethylindole from dihydrolysergic acid. J. Biol. Chem., 128:715-19. With L. C. Craig. The veratrine alkaloids. V. The selenium dehy- drogenation of cevine. I. Biol. Chem., 129:79 87. With R. G. Gould. The ergot alkaloids. XVIII. The production of a base from lysergic acid and its comparison with synthetic 6,8-dimethylergoline. l. Biol. Chem., 130:39~405. With R. G. Gould. The preparation of certain trimethyleneindole derivatives. I. Biol. Chem., 130:407-14. With L. C. Craig. The veratrine alkaloids. VI. The oxidation of cevine. I. Am. Chem. Sock 61:2252-53. With R. G. Gould. The synthesis of certain substituted quinolines and 5,6-benzoquinolines. I. Am. Chem. Soc., 61:289~95. 1940 With L. C. Craig. The veratrine alkaloids. VII. On decevinic acid. I. Biol. Chem., 134:123-35. With L. C. Craig. Delphinine. III. The action of hydrochloric, nitric and nitrous acids on delphinine and its derivatives. l. Biol. Chem., 136:303-21. With L. C. Craig. The aconite alkaloids. III. The oxidation of aconi- tine and derivatives with nitric acid and chromic acid. l. Biol. Chem., 136:323-34. 1941 With L. C. Craig. The veratrine alkaloids. VIII. Further studies on the selenium dehydrogenation of cevine. I. Biol. Chem., 139:263-75. With L. C. Craig and G. I. Lavin. The veratrine alkaloids. IX. The nature of the hydrocarbons from the dehydrogenation of cevine. J. Biol. Chem., 139:277-91. With L. C. Craig. The veratrine alkaloids. X. The structure of ceventhridine. J. Biol. Chem., 139:293-99. With D. D. Van Slyke. Phoebus Aaron Theodor Levene. l. Biol. Chem., 141:1-2. With L. C. Craig and G. I. Lavin. The veratrine alkaloids. XI. The dehydrogenation of jervine. I. Biol. Chem., 141:51~6. With L. C. Craig. The aconite alkaloicls. VII. On staphisine, a new alkaloid from Delphinium staphisag~a. I. Biol. Chem., 141:67~4.

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274 BIOGRAPHICAL MEMOIRS With L. C. Craig. The veratrine alkaloids. XII. Further studies on the oxidation of cevine. I. Biol. Chem., 141:253~7. The chemistry of the ergot alkaloids. In: Bicentennial Conference. Chemical Kinetics and Natural Products, pp. 27~1. Philadelphia: Univ. of Pennsylvania Press. 1942 With L. C. Craig. The veratrine alkaloids. XIII. The dehydrogena- tion of protoveratrine. I. Biol. Chem., 143:427-32. With L. C. Craig. The aconite alkaloids. VIII. On atisine. I. Biol. Chem., 143:598~03. With L. C. Craig. The aconite alkaloids. IX. The isolation of two new alkaloids from Aconitum heterophyllum, heteratisine and het- isine. I. Biol. Chem., 143:60~9. With L. C. Craig. The aconite alkaloids. X. On napelline. I. Biol. Chem., 143:611-16. With R. G. Gould and L. C. Craig. The ergot alkaloids. XIX. The transformation of dl-lysergic acid and d-lysergic acid to 6,8-dimethylergolines. }. Biol. Chem., 145:487-94. 1943 With L. C. Craig. The aconite alkaloids. XI. The action of methyl alcoholic sodium hydroxide on atisine. Isoatisine and dihydro- atisine. I. Biol. Chem., 147:567~9. With L. C. Craig. The aconite alkaloids. XII. Benzoylheteratisine, a new alkaloid from Aconitum heterophyllum. ]. Biol. Chem., 147:571-72. With L. C. Craig. The veratrine alkaloids. XV. On rubijervine and isorubijervine. I. Biol. Chem., 148:41-50. With L. C. Craig. The veratrine alkaloids. XVI. The formulation of jervine. I. Biol. Chem., 148:51-55. With L. C. Craig. The veratrine alkaloids. XVII. On "ermine. Its formulation and degradation. J. Biol. Chem., 148 :57~6. With L. C. Craig. The veratrine alkaloids. XIX. On protoveratrine and its alkamine, protoverine. J. Biol. Chem., 149:271-79. With L. C. Craig. The veratrine alkaloids. XX. Further correlations in the veratrine group. The relationship between the veratrine bases and solanidine. I. Biol. Chem., 149:451~4. With L. C. Craig. The veratrine alkaloids. XIV. The correlation of the veratrine alkaloids with the solanum alkaloids. Science, 97:122.

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WALTER ABRAHAM JACOBS 1944 275 With L. C. Craig. The veratrine alkaloids. XXI. The conversion of rubijervine to allorubijervine. The sterol ring system of rubijer- vine. I. Biol. Chem., 152:641~3. With L. C. Craig. The aconite alkaloids. XIII. The isolation of pimanthrene from the dehydrogenation products of staphisine. I. Biol. Chem., 152:64~50. With L. C. Craig. The aconite alkaloids. XIV. Oxidation of the hydrocarbon from the dehydrogenation of atisine. I. Biol. Chem., 152:651-57. With L. C. Craig, L. Michaelis, and S. Granick. The aconite alka- loids. XV. The nature of the ring system and character of the nitrogen atom. I. Biol. Chem., 154:293-304. With L. C. Craig. The veratrine alkaloids. XXII. On pseudojervine and veratrosine, a companion glycoside in Veratrum viride. I. Biol. Chem., ~ 55:565. With D. D. Van Slyke. Phoebus Aaron Theodor Levene. In: Bio- graphical Memoirs, 23:7~126. N.Y.: Columbia Univ. Press for the National Academy of Sciences. 1945 With L. C. Craig. The veratrine alkaloids. XXIII. The ring system of rubijervine and isorubijervine. I. Biol. Chem., 159:617-24. With F. C. Uhle. The veratrine alkaloids. XXIV. The octahydro- pyrrocoline ring system of the tertiary bases. Conversion of sarsasapogenin to a solanidine derivative. I. Biol. Chem., 160:243~8. With L. C. Craig. The veratrine alkaloids. XXV. The alkaloids of Veratrum virade. ],. Biol. Chem., 160:55~65. With F. C. Uhle. The ergot alkaloids. XX. The synthesis of dl- lysergic acid. A new synthesis of 3-substituted quinolines. J. Org. Chem., 10:76~6. 1947 With C. F. Huebner. The aconite alkaloids. XVI. On staphisine and the hydrocarbon obtained from its dehydrogenation. J. Biol. Chem., 169:211-20. With C. F. Huebner. The veratrine alkaloids. XXVI. On the hex- anetetracarboxylic acid from cevine and "ermine. l. Biol. Chem., 170:18 1~7.

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276 BIOGRAPHICAL MEMOIRS With C. F. Huebner. The aconite alkaloids. XVII. Further studies with hetisine. I. Biol. Chem., 170: 189-201. With C. F. Huebner. The aconite alkaloids. XVIII. The synthesis of the hydrocarbon obtained on,dehydrogenation of atisine. I. Biol. Chem., 170:203-7. With C. F. Huebner. The aconite alkaloids. XIX. Further studies with delphinine derivatives. }. Biol. Chem., 170:20~20. With C. F. Huebner. The aconite alkaloids. XX. Further studies with atisine and isoatisine. l. Biol. Chem., 170:515-25. With C. F. Huebner. The veratrine alkaloids. XXVII. Further stud- ies with jervine. I. Biol. Chem., 170:63~52. 1948 With C. F. Huebner. The aconite alkaloids. XXI. Further oxidation studies with atisine and isoatisine. I. Biol. Chem., 174: 1001-12. With Y. Sato. The veratrine alkaloids. XXVIII. The structure of jervine. I. Biol. Chem., 175:57-65. 1949 With Y. Sato. The veratrine alkaloids. XXIX. The structure of rubijervine. I. Biol. Chem., 179:623-32. With Y. Sato. The aconite alkaloids. XXII. The demethylation of delphinine derivatives. I. Biol. Chem., 180: 133~4. With Y. Sato. The aconite alkaloids. XXIII. Oxidation of iso- pyroxodelphonine, dihydroisopyroxodelphonine and their desmethylanhydro derivatives. l. Biol. Chem., 180:479-94. With Y. Sato. The veratrine alkaloids. XXX. A further study of the structure of veratramine and jervine. I. Biol. Chem., 181 :5~65. 1951 With Y. Sato. The veratrine alkaloids. XXXI. The structure of isorubijervine. l. Biol. Chem., 191:63-69. With Y. Sato. The veratrine alkaloids. XXXII. The structure of veratramine. J. Biol. Chem., 191 :71~6. With H. Jaffe. The veratrine alkaloids. XXXIII. The isomeric forms of cevine, "ermine and protoverine. l. Biol. Chem., 193:32~37. The aconite alkaloids. XXIV. The degradation of atisine and isoat- isine. l. Org. Chem., 16:1593-602.

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WALTER ABRAHAM JACOBS 1952 277 With S. W. Pelletier. The veratrine alkaloicls. XXXIV. The trans- formation of isorubijervine to solanidine. I. Am. Chem. Soc., 74:421~19. 1953 With S. W. Pelletier. The veratrine alkaloids. XXXV. Veracevine, the alkanolamine of cervadine and veratridine. I. Am. Chem. Soc., 75:324~52. With S. W. Pelletier. The veratrine alkaloids. XXXVI. A possible skeletal structure for veracevine, cevine and protoverine J. Org. Chem., 18:76~73. With S. W. Pelletier. The veratrine alkaloids. XXXVII. The struc- ture of isorubijervine. Conversion to solanidine. I. Am. Chem. Soc., 75:4442~6. 1954 With S. W. Pelletier. The aconite alkaloids. XXV. The oxygen- containing groups of delphinine. I. Am. Chem. Soc., 76: 161~9. With S. W. Pelletier. The veratrine alkaloids. XXXVIII. The ring system of the tertiary polyhydroxy veratrine bases. Oxidative studies with cevanthridine and veranthridine. l. Am. Chem. Soc., 76:2028-29. With S. W. Pelletier. The aconite alkaloids. XXVI. Oxonitine and oxoaconitine. I. Am. Chem. Soc., 76:4048 49. With S. W. Pelletier. The aconite alkaloids. XXVII. The structure of atisine. l. Am. Chem. Soc., 76:449~97. 1955 With S. W. Pelletier. The nature of a-oxodelphinine and ,8-oxodel- phinine. Chem. Ind., 30:948~9. With S. W. Pelletier. The quaternary chlorides and acetates of atisine. Chem. Ind., 43:1385~7. 1956 With S. W. Pelletier. The veratrine alkaloids. XXXIX. A study of certain selenium dehydrogenation products of cevine. I. Am. Chem. Soc., 78:191~18.

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s- 278 BIOGRAPHICAL MEMOIRS With S. W. Pelletier. The aconite alkaloids. XXXII. The structure of delphinine. I. Am. Chem. Soc., 78:3542~3. With S. W. Pelletier. The aconite alkaloids. XXX. Products from the mild permanganate oxidation of atisine. I. Am. Chem. Soc., 78:4139 43. With S. W. Pelletier. The aconite alkaloids. XXXI. A partial syn- thesis of atisine, isoatisine and dihydroatisine. I. Am. Chem. Soc., 78:4141 45. With S. W. Pelletier. The aconite alkaloids. XXXIII. The identity of a-oxodelphinine. J. Org. Chem., 2 1: 1 5 14-1 5. 1957 With S. W. Pelletier. The aconite alkaloids. XXXV. Structural stud- ies with delphinine derivatives. I. Org. Chem., 22:1423-32. 1960 With S. W. Pelletier. The nature of oxonitine. Chem. Ind. 21:591-92.

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