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OCR for page 246
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OCR for page 247
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
agents—the 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
OCR for page 248
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-
OCR for page 249
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 analogs—although 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
OCR for page 250
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 alkaloids—on 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
OCR for page 251
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
OCR for page 253
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-
OCR for page 254
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
OCR for page 255
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
OCR for page 256
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.
OCR for page 269
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. Levene—The 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.
OCR for page 272
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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Representative terms from entire chapter:
abraham jacobs
