close

Вход

Забыли?

вход по аккаунту

?

Heinrich Wieland Centennial His Lifework and His Legacy Today.

код для вставкиСкачать
Volume 16 * Number 9
September 1977
Pages 559 - 662
International Edition in English
Heinrich Wieland Centennial:
His Lifework and His Legacy Today[**]
By Bernhard Witkopc‘]
Many of Heinrich Wieland’s friends and disciples remember
all too well his sixtieth, sixty-fifth“], seventieth, and eightieth
birthdays; the last-named one was observed quietly on June
4, 1957[’]. He thanked us all with the Goethe quotation,
behind which he tried to hide his emotionr3]. Of the two
colleagues in Munich who were Wieland‘s very close friends,
Hans Fischer, in Wieland’s words, paraphrased from Goethe’s
Faust, “could not be held back by the ringing of the Easter
Bells from taking his own life, on Saturday, March 31, 1945”[41,
but Walter Gerlach is with us today as a living link to a
tradition so great and unique that the present student generation may have difficulties in grasping its true dimensions.
It seems appropriate to let physics, as the more logical and
mathematical science, lead us to an evaluation which would
d s o facilitate a re-interpretation of the history of chemistry.
In doing so, as a useful exercise in epistemology, let us look
at the famous experiment of Stern and Gerlach (1920-1923)
when the two scholars used a beam of silver atoms to prove
the quantization of space and to measure the magnetonr5- ’1.
These memorable experimentsL8J were the turning point in
the study of the mechanics of the atom, leading, eventually,
to the electron spin, the development of molecular beam technique by I. I. Rabi, magnetic resonance, maser and laser and
related work in pure
In this presentation we are
looking, as it were, at the “fine structure” of a small segment
of the spectrum of physics. Will it be possible to transfer
this kind of analysis to the historical development of modem
organic chemistry and to the contributions of Heinrich Wieland, who always considered “biochemistry an area neglected
by organic
c‘]
B. Witkop
National Institutes of Health (4-330)
Bethesda, Maryland 20014 (USA)
p*]Commemorative lecture under the auspices of the Gesellschaft Deutscher
Chemiker at the Fall Meeting in Munich, September 13, 1977.
Angew. Chem. I n t . Ed. Engl. 16, 559-572 ( 1 9 7 7 )
Heinrich Wieland [photograph by B. Witkop at Starnberg in 19531.
Munich’s tradition as the origin and nursery of great ideas
and men of sciencebegan with Liebig, who passed the ‘‘Olympic
fire” on to Adolf von Baeyer, Richard Willstatter, Heinrich
Just as our old master
Wieland, and many others (Fig.
is very much present and with us at this moment, so are
the disciples who, in the words of A . W von Hofmann “have
preceded us”[121.Liebig continued his studies on silver fulminate, begun with Kastner, in Paris with Vauquelin:
in 1832 Gay-Lussac presented the results to the Academy
in the presence of Alexander von Humboldt. Thanks to Humboldt and Gay-Lussac’s sponsorship, Liebig was appointed
559
-
Alexander v. Humboldt
(1769-1859)
- - - - JUSTUS VON LIEBIG..
-.
-.
/
- - Joseph Louis Gay-Lussac
.-.
...
(1803-1873)
(1778-1850)
I
/
I
/
!
,
1825: Ordinarius
1852: From Giessen to Munich
1
II
J. J . Berzelius
ADOLF VON BAEYER
(1835-1917)
( 1779-1848)
I
I
1875: From Strasbourg to Munich
,
,,
Isomerism
,,l , q O..,
1877: Dedication of the Chemisches
Laboratorium des Staates
I
,’
Silvercyanate
(F. Wohler)
1824: Extraordinarius
in Giessen
I
‘ Silver
fulminate
(with Gay-Lussac)
I
I
I
J.
RICHARD WILLSTATTER
( 1872-1942)
19 16 : From Berlin to Munich
Investig~tionson
1924: Resignation
fulminic acid
1903-1933
.....HEINRICH WIELAND
(1877-1957)
1926: From Freiburg to Munich
1944: Destruction of the institutes
Fig. 1. The Munich Chair of Organic Chemistry in the course of history.
/p
- H2
HSC-CHZ-OH
HO-N*
H,C-C,
-H20
C-H
02N/
t
-
- co*
Ho-N\\
H
+NzOa
/p
/c-C
02N
\OH
HO-N
H
-
0
\ \ / /
F-c\
fN20,
HO-N\\
-HNo2
H’
H
40
c-c,
OH
1-
HNO)
C=N-OH
17a)
A4-isoxazolin-5-imine (I 0), Grundmann’s prefulminuric acid
(10j1151.
Ring opening of (10) leads to fulminuric acid (11 j.
Thus, Wielund‘s essentially correct reaction mechanism of the
oligomerism of fulminic acid was not revised until very
recently. The identical composition of silver fulminate and
silver cyanate was recognized by Liebig and prompted Berzelius to coin the term isomerism in 1830. Wieiand’s extensive
investigations on nitrogenous compounds have been reviewed
by Friederich Kluges and later by Rolf Huisgenr’] who by
the use of modern methods and the entire armamentarium
of electronic theory, quantum mechanics, and NMR spectroscopy expanded and completed his mentor’s heritage in a manner hardly foreseeable.
Hg(CNO), + H 2 0
HgO
+
2 HCNO
H<’rN--+O
(7b)
Fig. 2. Formation of fulminic acid ( 7 a ) or ( 7 b ) from alcohol, nitric acid,
and mercury.
Extraordinarius for philosophy at Giessen in 1824r‘3].Liebig
performed an accurate analysis of silver fulminate. Wieiand’s
contribution to this highly traditional field came in 1903 when
he elucidated the formation and polymerization of fulminic
acid. He showed methylnitrolic acid (6) to be the key intermediate in the classical preparation of fulminic acid (7) from
alcohol (I j , nitric acid, and mercury (Fig. 2).
Liebig’s fulminic acid or 2-nitromalonamidonitrile (I I j
arises by dimerization of free fulminic acid through partial
hydrolysis of the mercury salt. Nef’s formulation of fulminic
acid as formoxime ( 7 a ) has recently been changed to that
of formonitrile oxide ( 7 b)[I4]. Dimerization leads to (hydroxyimino)acetonitrile oxide (8) which adds more fulminic acid
to yield furoxanaldoxime (9 j that then rearranges to 4-nitro560
Fig. 3. Dimerization of fulminic acid ( 7 ) t o fulminuric acid ( 1 1 )
Wieland himself enjoyed remembering his predecessor by
telling the famous story of Liebig’s “Abendvorlesung” on
February 12, 1853, when, in the presence of their majesties,
King Maximilian I1 and the Queen of Bavaria, accompanied
Angew. Chem. Int. Ed. Engl. 16, 889-572 (1977)
by Princes and Princesses, a violent explosion injured not
only Liebig but also members of the Royal Court[’61.According to Wieland, the beauteous Princess Mary saved the situation when she got up and returned, with a curtsy and a
smile, a piece of equipment that had landed on her lap to
the dumbfounded Liebig. Frederick Schonbein, a close friend
of Liebig, characterized Munich in those days[’7]: “Of all
the cities in Europe, Munich probably has the largest number
of eminent chemists. If I am not mistaken, there are no less
than seven professors who teach their discipline and head
their own laboratories”.
In our historical analysis we now come to the dichotomy
of style: classical versus romantic. Among Liebig’s scientific
progeny we have proponents of both attitudes. We would
certainly consider Warburg on the side of strict form, fact,
reason, and rigid deduction. Wieland, on the other hand, shows
in his work an artistic streak, is intuitive and guided more
by emotion and imagination. During his student days he
had trouble renting a room in Munich because he was an
undaunted piano player to the extent that he enjoyed the
reputation of a “forte-pianist’’ throughout the neighborhood.
In the selection of his topics, especially among natural products
(see Charts I and 11), he was guided by his closeness to,
and love of, nature. The details of this part of his research
have been adequately described, but the latent underlying
principles require some elaboration. Nowadays we face the
question of classification of natural products: clearly Wieland
was attracted by physiological activity rather than by taxonomy, but to some extent he had a sixth sense for the
subtle aspects of biogenesis, as we know it today. From the
tacky industrial yeast mother liquors of ergosterol production
H3cn
FH3
(I4), R = H
( 1 5 ) , R = OH
/J
H O HO
I
(161, R = CH,-CH(CH,),
( 1 7 ) . R = CH,-CH(CH,)-CO,H
( l S ) , R = COzH
HO’.
Fig. 4. Biosynthesis of cholic acid ( I 8 ) by enzymatic stereoselective cyclization
of squalene 2,3-epoxide ( J 2 ) via lanosterol ( 1 3 ) and cholesterol ( 1 4 ) with
intramolecular migration of the methyl groups at C-10 and C-15.
Steroids
(with Dane et al. 1916-1944)
Respiration and metabolism of yeasts
4
Yeast &other liquors
of industrial
ergosterol production
Bileicids
-
J
Dehydronorcholene (20)
“Activated acetic acid”
(F. Lynen)
t
I
Squalene
Quinovic acid
G
Basis of the
biosynthesis and
biochemical
transformations
of cholesterol
(Bloch, Schonheimer, Sonderhoff)
12-Ketocholanic acid (19)
Lanosterol (13)
(Wieland’s
cryptosterol)
Cholesterol (14)
c-
1
Bile acids
1
Historical beginning of the
“marriage” between
X-ray structure analysis
and organic chemistry
(Bernal, Rosenheim,
King 1932)
Frog poisons
(Witkop, Daly
from 1960)
Batrachotoxins (52)
Histrionicotoxins
(53),( 5 4 )
Gephyrotoxins
Pumiliotoxins
(over 100 alkaloids)
\
Sodium transport
in nerve and muscle
Choleic acids
(with Sorge 1916)
Complexes of bile
acids with fatty acids
make possible resorption
through intestinal membrane
Toad venoms
(19 13-1944)
Bufotoxins (51)
Bufotalins
I
Methylcholanthrene (21)
(1933)
1
Carcinogenic
hydrocarbon
Metabolic activation by
microsomal hydroxylases
from liver: general principle
of carcinogenesis by polycyclic aromatic hydrocarbons
(including benzpyrene
in tobacco smoke)
4
Hormones
1
Receptors
I
Acetylcholine receptor
Arene oxides as active
carcinogens (24) + (25)
Chart 1. Wieland’s work on natural products: juxtaposition of the static classical chemistry of natural products performed by Wieland and the dynamic biochemistry of metabolic processes that resulted therefrom. Wieland’s classical approach to natural products chemistry is apparent from the isolation and
structural elicidation of key compounds, such as squalene, cryptosterol, and cholesterol from the yeast mother liquors of industrial ergosterol production.
It was not until the 1940’s that Konrad Block, Rudo!fSchonheimrr, and (in 1937) Wieland’s student Robert Sondrrhoffintroduced isotopic labeling, which permitted
elucidation of the biosynthesis of cholesterol and the bile acids. Likewise, forty years elapsed between Wieland’s synthesis of the carcinogenic hydrocarbon methylcholanthrene and proof of the connection between formation of labile arene oxides in the liver or lung and carcinogenesis. The only compound that has not yet
served as the basis for biochemical developments is quinovic acid, a pentacyclic triterpene from the mother liquors of quinine production. Wieiand’s first foray
into biochemical dynamics was his work on metabolism and respiration of yeast. These studies led to the concept of “activated acetic a c i d and-through
F . Lynen-to its structure.
Angew. Chem. l n t . Ed. Engl. 16, 559-572 ( 1 9 7 7 )
561
he hoped to isolate intermediates in steroidal biosynthesis.
Indeed, he demonstrated the presence of squalene and “cryptosterol”, i. e. lanosterol ( 1 3 ) ; however, these precursors were
~ l 4)
not related with cholesterol ( 1 4 ) until Konrad B l o ~ h [ ’(Fig.
established a most fascinating concerted stereoselective intramolecular cyclization of squalene 2,3-oxide (12), followed by
oxidative rearrangement to cholesterol (14).
The introduction of radioactive markers or deuterium goes
back to Rudolf S~honheimer[‘~l
who established the concept
of the dynamic state of body constituents[”I, and to Wieland’s
laboratory, especially Robert Sonderhoff[’’], the promising
young biochemist who had such an early, tragic death. The
new isotopic label technique showed clearly that e. g . cholic
acid ( 1 8 ) arises from cholesterol ( 1 4 ) via intermediates (15),
( 1 6 ) , and ( 1 7 ) . These transformations form the basis of concepts on the etiology of atherosclerosis as they were developed
by Ludwig Aschoff, Rudolf Schonheimer, and others (Fig. 5).
L. Aschoff
19 10 Cholesterol esters in atheromatous plaques
A. Windaus
19 10 Morphological findings confumed by chemical
means, studies on the chemical constitution
of cholesterol and related compounds
H. Wieland
19 10
G . Anitschkow
19 13 Model of arteriomatosis in the rabbit
S. Thannhauser
1929 Cholesterol metabolic defects,
origin of bile acids
R. Schonheimer
1925- Proof of endogenous formation of cholesterol
1933 in the animal organism, arteriosclerosisresearch,
metabolism of cholesterol
Studies on bile acids
“Bay1‘-region
\
Fig. 7. Mechanism of carcinogenesis by a carcinogenic aromatic hydrocarbon.-An intermediate aliphatic epoxide is likewise postulated in the case
of aflatoxin Br which causes liver cancer. However, it reacts with guanine
BI [26a].
units of DNA to form 2-(N7-guanyl)-2,3-dihydro-3-hydroxyaflatoxin
bay region (Fig. 7). Opening of this short-lived diol-epoxide
( 2 4 ) in uitro by the 2-amino group of polyguanylic acid or
in uiuo by similar electrophilic groups (or phosphate residues)
of DNArz4]leads to adducts ( 2 5 ) which probably introduce
errors in transcription, unless the faulty nucleic acid sequence
is removed by excision with the help of special enzymes and
repair mechanisms[’ ’I. The active mutagens and probably carcinogenic metabolites of benzanthracene and of 3-methylcholanthrene are similarly formulated as ( 2 6 ) and (27) (Fig. 8)IZ6l.
R2
0
0
Fig. 5. Work on cholesterol metabolism and atherosclerosis [IS].
H
Wieland and Dane obtained methylcholanthrene ( 2 1 ) by
distillation of 12-ketocholanicacid (19) and selenium dehydrogenation of dehydronorcholene (20) (Fig. 6).This hydrocarbon was soon found to be highly carcinogenic, and represents
the starting point in a long search for a mechanism of carcinogenesis by polycyclic aromatic hydrocarbons. The mechanism
would have delighted Wieland, because it shows how strongly
reactions of an initially purely academic nature are involved in
intermediate metabolism.
(191
(20)
~A,\.QH
h...OH
(26)
3
C
F
(27)
Fig. 8. Presumably carcinogenic metabolites of benzanthracene (26) and
methylcholanthrene (27).
Through Wieland and Windaus we learned about steroids.
Subsequently steroidal hormones such as estradiol (28) (Fig.
9) were systematically modified to give new estrogens (e.g.
mestranol ( 2 9 ) ) and developed from there into antifertility,
agents (e.g. norethindrone (311).
(21)
Fig. 6. Formation of methylcholanthrene ( 2 1 ) from 12-ketocholanic acid
( I 9 ) via dehydronorcholene( 2 0 ) .
Metabolic activation starts with hepatic hydroxylase P-448
(P-450)to yield, by insertion of an oxygen atom, (autoxidizable)
phenols[221or, by addition of oxygen to a double bond, (labile)
arene o x i d e ~ [that
~ ~ l open up to trans-dihydrodiols with the
aid of epoxide-hydrase. Thus benzo[a]pyrene would initially
form the epoxide (22), easily opened to the (synthetically
accessible)optically active highly mutagenic and carcinogenic
trans-diol (23), presumably the precursor of the “ultimate
carcinogen” ( 2 4 ) by a second epoxidation at the so-called
562
0
(30)
Fig. 9. Stepwise modification of the estrogenic properties of estradiol f 3 )
via mestranol ( 2 9 ) to the contraceptive norethindrone (30).
The introduction of contraceptive steroids has slowed down
the population explosion and changed the culture and morals
of the present generation. This provides a straightforward
and impressive example for the interdependence of science
Angew. Chem. l n t . Ed. Engl. 16, 559-572 ( 1 9 7 7 )
and culture. Immunosuppression through corticoids has made
possible a new technology of organ transplantation. The intricate action of steroid hormones on their target cell nuclei
has only recently been e l u c i ~ f a t e d ~Accordingly,
~~!
cell function
is modified by hormonal action in six steps (Fig. 10).
Hormone (H)
+
receptor (R)
(cytoplasm)
Transport
of new RNA
to cytoplasm
-
Activation of
transcription:
formation of
new mRNA
+--
I
Protein synthesis
Hormonereceptor
complex (HR)
--+
Alteration
of cell function
-
-
Transport of HR
to nucleus
1
Binding of HR
to nucleic acid
in cell nucleus
-
Immunosuppression,
anti-inflammatory
action, contraception,
etc.
Fig. 10. Mechanism of action of steroidal hormones [27].
The first formulation ( 3 1 ) of the bile acids and cholesterol
(Fig. 11) rested on an overuse of the so-called Blanc rule
and led to an “intelligent error” (in ecclesiastical terms: oh
felix culpa). The transition from the old ( 3 1 ) to the new
formulation ( 3 3 ) is easier to follow by looking at the somewhat
unusual presentation ( 3 2 ) .
A highly historical event occurring in the year 1932
was the fortunate consequence of this error, namely,
the “marriage” of X-ray crystallographic analysis with “the
ocean of organic chemistry” (Fig. 13), in a manner reminiscent
of “Lo Sposalizio Di Venezia Col Mare” as the beginning
of Venice as a great Mediterranean powerrzs1.This wedding
Strychnine
Fig. 11. Comparison of the old formula of deoxycholic acid ( 3 1 ) with the
revised formula (33) via a helpful intermediate way of writing (32).
opened a new era, initially recognized and accepted by classical
organic chemists with considerable reluctance. To the crystallographer Bernal, and the interpreters Rosenlzeirn and King,
Wieland’s old structure ( 3 1 ) should be a “thick molecule”.
But the crystalline dimensions of deoxycholic acid called
for a “thin, lath-like molecule” as represented by the flat
tetracyclic structure ( 3 3 ) which Wielandand Dane by 1932 had
independently deduced from new chemical evidence. Thereafter, important natural compounds, precious by virtue of
Nitrogenous natural products
f
iversion”
of strychnine
and vomicine
(Robinson 1948)
/
1
1
(Tetrahydro-)
folic acid
Curare
42 Alkaloids from
alebash curare
(Hans Schmid et al.)
Toxins of deathcap
toadstool
(with Renz, Lynen.
Hallermayer, Witkop
1932-1944)
alkaloids (481
(with Scheuing,
Schopf, et al
1921-1939)
mann 1925-1944)
Identical with
caracurine v11
(Hans Schmid,
Karrer 1958)
Nor-xrarine
-
(with Pistor,
Bahr, Witkop
1937-1943)
Toxiferine (421
(from Strychnos
toxifera)
Morphine (34)
T-(35I
(with Kotake,
Small, Schopf)
one-carbon
fragments”
.1
Synthetic morphinanes:
Separation of analgesic
activity and addiction
(Small, Eddy, May
from 1930)
1
Amanitine, phalloidine
Amatoxins (391, (401,
phallotoxins,
antamanide (50)
(Th. Wieland from 1950)
Dihydrohiopterin
3
Hydroxylation of
phenylalanine
NIH shift
(Udenfriend, Witkop, Daly, Jerina,
et al. from 1967)
Phenylketonuria
Chart 11. Wielund‘s studies on nitrogenous natural products have had a lasting effect on developments in biochemistry. For example, work on the pigments of
butterfly wings with Schupf and Purrmann provided the basis of the chemistry of pterins, from which the entire dynamics of the folk acid components of
important enzymes can be derived, and also the mechanisms of enzymatic hydroxylation which led to the discovery of the NIH shift. The toxins of the deathcap
toadstool have been further investigated by Wieland’s son Theodor, and utilized in various ways in molecular biology. The antamanides were used by Isabella
Karle in X-ray studies on the folding and unfolding of cyclic peptides. Synthetic work on the opium alkaloids was continued in Bethesda by Wieland‘s student
L. F . Small, E. Moseftig, and E. L. M a y , and resolved into addictive and analgetic components. In Puul Karrer’s laboratory, Huns Schmid (1917-1976)
demonstrated how the Wieland-Gumlich aldehyde obtained from strychnine by oxidation could be transformed into alkaloids from calebash curare also
investigated by Wielund. (Wieland’s fields of study are underlined in Chart 11.)
564
Angew. Chem. Int. Ed. Engl. 16, 559-572 (1977)
their paucity, became fully known up to the last conformational
detail and their absolute stereochemistry. Dorothy Hodgkin’s
very personal, charming, and lucid account of her brilliant
X-ray analysis of vitamin B12[291is essential and pleasurable
reading for every chemist[301.Further examples are selected
(Fig. 12) with a strong pro domo attitude and an explicable
admiration for the pioneering work of Jsabelfu and Jerome
Karle, the inventors of the “symbolic addition
At this juncture, we should return first to Wieland‘s work
on “alkaloids” (Chart 11) that covers a wide range from basic
N-CH,
-CH,
1341
(35)
CHzOH
I
CHOH
COzH
I
CH-CH,
I
CH-CO-NLCO-NH-
I
NH
0
I
d’
I
I
I
co
I
NH
I
Hz-TH
CH
NH
CH
I
,
plant products-strychnine, vomicine, lobelines (38), morphine ( 3 4 ) , thebaine (35), calabash curare alkaloids (36)-to
non-basic butterfly wing pigments (38) and cyclic peptides
(39) and (40)[321from Arnanita phalloides, the most poisonous
mushroom known (Figs. 12 and 16).
Wieland’s intuition and “prepared mind’”331 in selecting
topics for his research, recalls Goethe’s way of linking good
fortune or serendipity to merit: “Wie sich Verdienst und Gliick
verketten, das geht den Toren niemals ein, wenn sie den Stein
der Weisen hatten, der Weise mangelte dem Stein.”[341Historians and sociologists must examine “cases of serendipity gained
and serendipity
In Wieland’s work, such gains and
losses often merge, become latent or dormant and then surface
again to produce spectacular results. The most striking example in this respect is a rather academic degradation product of
strychnine (Fig. 13), the so-called Wieland-Gumlich aldehyde
(41)[361. It was probably standing on the shelf when H.-J.
Pistor, K . Biihr, and I started postdoctoral work on calabash
curare in Wieland’s private laboratory in 19SO.Wethen isolated,
from the bark of Strychms toxifera toxiferine-I ( 4 2 ) , one of the
most toxic alkaloids known[371.It was not until 1958 that this
alkaloid was recognized in Paul Karrer’s laboratory by Hans
Schmid and his collaborators as the product of a condensation
and dimerization of the Wieland-Gumlich aldehyde or its methobaser3 *- “!The N-acetyl derivative of the Wieland-Gumlich aldehyde occurs as diabolin (43) in calabash curare as well
as its methochloride. Over 40 tertiary and quaternary alkaloids
[e.g. C-calebassin, ( 4 4 ) ] were separated and isolated from
calabash curare by H . Schmid and P. Karrer using cumbersome
column chromatography. X-Ray analysis finally confirmed
the complex structures based on chemical reactions[42!
The lobelia alkaloids (48) were introduced into pharmacology as respiratory stimulants by Wieland‘s brother Herrna12nr431,
into industrial production by an intriguingly simple
synthesis[44]at C. H. Boehringer, Ingelheim, by Georg ScheuingL4’];they helped to start postpartum respiration for Wieland’s first grandchild.
Racemic lobeline (Fig. 14) or cis-2,6-diphenacyl-N-methylpiperidine (48) is easily obtained by catalytic hydrogenation
co
I
I+H
CO
I
CHZ-NH-CO-CH-NH-CO-CH,
I
I
I
CH-CH,
C2H5
(391
Fig. 12. Some nitrogenous natural products investigated by Wieland.
Anyew. Chem. I n t .
Ed. Engl. 16, 559-572 ( 1 9 7 7 )
141)
1431
Fig 13. Wieland-Gumlich aldehyde ( 4 1 ) is not only a natural product (43)
but IS also the parent substance for most of the alkaloids from Strychnos
toxifera and calebash curare.
565
of the methosulfate of 2,6-diphenacylpyridine (45), whereas
its hydrochloride yields lobelanidine ( 4 7 ) , and its free base
the pyridine-dicarbinol ( 4 6 ) on hydrogenation.
(45) *HC1
+
Hz
“The new truths of science begin as heresy, advance to
orthodoxy, and end up as superstition”[511.This description,
by T. H . Huxley, not necessarily in the same sequence, may
OH
H , C , - & H - H Z C ~ C H ~ - C H?H
--C,N,
H”
N
H
Fig. 14. Scheuing’s synthesis of noriobelanidine (47) and lobeline ( 4 8 ) by catalytic reduction
of the hydrochloride and methosulfate of 2,6-dipbenacylpyridine ( 4 5 ) .
Lyndon F. Small, from Wieland’s laboratory, brought back
to the United States an interest in opium alkaloids and in
their replacement by nonaddictive synthetic analgesics. More
than 40 years later, thanks to the efforts of the late Nathan
B. Eddy and Everette May, the search for a better analgesic[46]
has come to a point at which separation of analgesic power
from undesirable morphine-type drug dependence holds more
than promise. On optical resolution of a 5,9-dialkylbenzomorphane a levorotatory antipode ( 4 9 ) was obtained (Fig. 15)
which was a better analgesic than morphine, was not addicting
in rhesus monkeys and, like desmethyl-N-allylmorphine
(nalorphine), was an antagonist of morphine. The reversal
of the two alkyl groups in 5-methyl-9a-propyl-6,7-benzomorphane also gave long-acting opiate a n t a g o n e ~ i s ~ ~Further
’~~~].
development of this principle of optical resolution has led
in the case of N-tetrahydrofurfurylnoroxymorphones to compounds suitable for clinical testingr4’”I.
Here we enter the new area of opiate receptors in the
brain[50]and of endogenous analgesic peptides, such as endorphin, derived from b-lip~tropin[~~!
CH2-C HZ-C H3
(equatorial)
Fig. 15. Optical resolution of a benzomorphane into a levorotatory analgetia l l y active, non-addicting antagonistic antipode ( 4 9 ) and a dextrorotatory,
weakly analgetic, strongly addicting antipode.
Effects in rhesus monkeys
EDso
Physical dependence capacity
Antagonism (nalorphine= 1)
566
Levorotatory
antipode ( 4 9 )
Dextrorotatory
antipode
0.8 mg/kg
0
0.2
12.3 mg/kg
strong
0
be applied to some of the stages in Wieland‘s work on pterins.
When Wieland, in 1925, followed a suggestion of his disciple
Clemens Schopf to resuscitate F . G . Hogkins’ work (1889-91)
on butterfly pigments, he had, as pointed out more than
once in this paper, an intuitive preconception of some metabolic significance of the pterins, especially when his student
Koschara found xanthopterin ( 3 8 ) as a regular urinary metab ~ l i t e ~ ’For
~ ] .a while, especiallyduring the war, pterin research
was salvaged by giving it the label of “studies on the antipernicious anemia factor”. From the vantage point of hindsight
we now recognize the importance of Wieland’s work on pterins,
to which his student Robert Purrmann contributed some cruciql
ideas and experiments. In a similar way research on curare
was salvaged during the war by giving it the label of “relevance to surgery”, because the toxiferines are strong muscle
relaxants. These memories have gained significance because
“the relevance of scientificresearch” has again been questioned
today. Wieland’s work is ample proof that highly qualified
research is always “rele~ant”~’
Zai.
We are fully aware of the importance of the activated onecarbon units[53’ in metabolism and of tetrahydrofolic acid
and dihydrobiopterin as prosthetic groups of essential enzymes
whose absence in genetic defects creates grave metabolic problems, such as phenylketon~ria[~~].
The search for rapid assays
of enzymes involved in the biosynthesis and metabolism of
cat echo la mine^[^ ’1 led to the discovery of the “NIH-shift”,
the existence of arene oxides as extremely labile intermediates
in the hydroxylation of aromatic s~bstrates[’~~~’i,
and an
understanding of the carcinogenic action of aromatic polycyclic hydrocarbons, such as the above-mentioned methylcholanthrene.
My entrance into Wieland’s private laboratory in 1938
required, as initiation fee, the work-up of half a ton of Amanita
phalloides (Fig. 16), the deathcap, Europe’s most poisonous
and most fatal mushroom. The constant contact with these
mushrooms, partly fresh, partly dried and powdered, led
Angew Chem. Int Ed. Engl. 16, 559-572 (1977)
Fig. 16. In the field ofnatural products, Wieland’s legacy has proved extremely
fruitful in two particular areas: Theodor Wieland has shown that constituents
of the deathcap (toadstool) are important tools in molecular biology, and
the first acetylene derivatives found in animals have been isolated from
Dendrobates histionicus.-Most of the photographs of frogs were supplied
by Dr. C. W Myers, American Museum of Natural History, New York.
(a) to (c): Deathcap toadstools (Amanita phalloides) at various stages of
growth. They contain amatoxins [cf. ( 3 9 ) ] , phallotoxins and antamanide
(50). The photographs were provided by Dr. D. M . Simons, Wilmington,
Delaware. (d): Dendrobates histrionicus. It contains the spirocyclic acetylene
derivatives (53) and ( 5 4 ) . (e): Dendrobates auratus. It occurs in Panama,
Costa Rica, Nicaragua, and Colombia and contains numerous pumiliotoxins
which are all derivatives of cis-decahydroquinoline and in some cases bear
acetylenic substituents. ( f ) Dendrobates uiridis. Newly discovered species from
western Colombia which mainly contains pumiliotoxin B. (g) Dendrobates
Lehrnanii. Newly disovered species [Ha] containing ahout eight pumiliotoxins. (h): Phyllobates aurotaenia, a variant of the classical poison dart
frog containing the extremely poisonous batrachotoxins ( 5 2 ) . (See p. 563.)
to unpleasant dermatitis and conjunctivitis, discomfitures
which, in those days, were endured with a sense of pride
to be in the vanguard of scientific battle. Wieland himself
encouraged such an attitude. When Rudorf Hallermayer,
shortly before the crystallization of amanitin, complained
in 1941: “Herr Geheimrat, this morning it took about
ten minutes until I was able to open my festering eyelids,”
the rejoinder came with ill-concealed satisfaction: “At long
last we seem to be getting very good enrichment!”[58]
The crystallizationof phalloidin by F. Lynen and U. Wieland,
preliminary results on its hydrolysis, the crystallization of
“amanitin”-these events are the beginning of a long natural
product sagac5’],an inheritance that took H . Wieland’s second
son Theodor a quarter of a century to explore completely and
bring to full
In reprospect there is seen to be
a continuity between work on phalloidin, its cleavage to secophalloidin by Theodor Wieland, and the general exploitation
of such neighboring group effects for the extremely useful,
selective nonenzymatic cleavage of peptides and proteins with
cyanogen bromide-extending up to the sequence determination of immunoglobulin (molecular weight 148000 with more
than 1200 amino
The amatoxins ( 3 9 ) and (40)L3’] are selective inhibitors of
nucleotide polymerase B in the cell nucleus, while the related
phallotoxins selectively bind to the actin of hepatocytes. The
lipophilic cyclic decapeptide, antamanide, (50) has afinity
to membranes which then are protected from the toxic effects
of phalloidin. The natural and synthetic antamanides form
complexes with lithium, sodium, and calcium ions. The alkali
n
Fig. 17. In the lithium complex of natural antamanide the pentacovalent
metal ion sits on the cyclic decapeptide folded to a saddle and bears a
molecule of solvent as a “cap” (acetonitrile). In this structure the peptide
carbonyls are directed towards the interior of the molecule, and the amide
groups towards the exterior [61].
in the pentacovalent complexes sits in a saddle (Fig. 17) and
has, as a cap, a molecule of solventr6’].Zsabella Karle extended
this beautiful X-ray analysis to the uncomplexed antamanide
in which the peptide backbone is turned inside out, more
unfolded and hcld in place by a pair of intramolecular hydro-
Fig. 18. In the uncomplexed trihydrate of synthetic [Phe4,Va16]antamanide
the unfolded decapeptide is stabilized by three molecules of structural water
(W). The amide groups are now directed to the interior of the molecule
and the peptide groups to the exterior [63].
gen bonds of the (5- 1)type[62]as well as by
strategically placed molecules of structural water (Fig. 18). The uncomplexed synthetic [Phe4, VaPlantamanide exists, with little
conformational change, also as a dodecahydrate (Fig. 19)1641.
Fig. 19. In the uncomplexed dodecahydrate of synthetic [Phe4,Va16]antamanide the arrangement of the four antamanide molecules shown leaves
channels in the crystal structure which are tilled with structural water (solid
circles) of varying degree of association. Such structures might possibly serve
as models for explaining the unusual properties of water molecules in proteins
and cell membranes [MI.
Angew. Chem. Int. Ed. Engl. 16, 559-572 (1977)
567
The crystal lattice in this case contains cavities and channels
that are filled with water molecules of various degrees of
associative binding. Here one is reminded of the lipophilic
peptide part of trans-membrane proteins, such as the surface
glycoprotein of human erythrocytes, glycophorin, and in that
respect the organization of water in the antamanide lattice
gains in significance for membrane models and for understanding its protective action against phalloidin in the membranes
of liver cells.
The digression from Wieland‘s toad venoms [bufotoxin
(51 )] to frog toxins [batrachotoxin ( 5 2 ) ] conceptually seems
to be only a small step (Fig. 20): the disciple varies a theme
given by the “mayister ludi”. When it comes to methodology
and detail, the comparison shows up the great progress made
since Wieland’s isolation of the cardiotonic bufotoxin in 1913.
Just the initial phase, the process of collection, demonstrates
this point: most of the toads (Sufo tlulyaris), about 27000,
were “milked” and set free again by schoolchildren in the
pleasant Black Forest area, and the result was 21 grams of
crystalline bufotalin and bufotoxin (51 )Ie5]. Bufotoxin ( 5 1 )
is a conjugate ofan unusual steroid with suberylarginine linked
at the 3-hydroxyl, originally formulated by Wieland as attached
to the 14-hydroxyl. In addition, there is a P-acetoxy group
at carbon 16, previously assigned to C(5). By contrast, the
tiny poison dart frogs (Phyllohates uurotaenia) of Western
Colombia, were collected in an impenetrable jungle with an
annual rainfall of 12 meters. Transportation is only possible
on the rivers by launch or balsa raft1661.The frogs weigh
only 1-2 grams and contain 50 micrograms of toxins, which
the frog inactivates under stress or on death. One of the
four components, batrachotoxinin A, the steroid moiety of
batrachotoxin, was eventually crystallized and established a
H
H
NH
COOH
Fig. 20. The principal venom of the toad Bufo culyaris is bufotoxin ( 5 1 )
which was formulated by Wirland as the conjugate with suberyl-arginine
in position 14 and with an acetoxy group in position 5 instead of 16. The
principal toxin of the frog Phyllobates aurotaenia is batrachotoxin (52) which
shares the steroidal skeleton and some stereochemical features with bufotoxin.
Fig. 21. The histrionicotoxins (53), ( 5 4 ) . ( 5 5 ) show reversible biuding to the ion conductance modulator of the
acetylcholine receptor, while the snake venom, bungarotoxtn ( 5 6 ) binds irreversibly to thc recognttron site of this
receptor. A molecule of choline is shown under the formula of molecule 1 5 3 ) for comparison.
568
Angew. Chem. I n t . Ed. Engl. 16, 559-572 ( 1 9 7 7 )
record for Isabell Karle as the smallest crystal, length 1/10mm,
which supplied all the X-ray data required for complete structure analysis[671.In the ester, batrachotoxin ( 5 2 ) , we meet
the familiar steroid skeleton with unprecedented new features,
such as a new heterocyclic ring sharing a common axis with
rings C and D in the manner of the propellanes. Ten years
later batrachotoxin ( 5 2 ) has become one of the most useful
tools in electrophysiology for the study of the properties of
the sodium channel in axons, synapses, and muscle[68]. It
opens up irreversibly and selectively the “gate” of sodium
channels while its antagonist, the less toxic tetrodotoxin, the
poisonous principle of the puffer fish, closes these sodium
channels in a reversible manner.
Another frog, Dendrobates histrionicus (Fig. 16d), which
occurs in many colorful varieties in Colombia, Ecuador, and
Peru has given us the first acetylenic alkaloids [(53) and
( 5 4 ) ] (Fig. 21) of animal origin[691.They have proven their
value in the study of receptor mechanisms: tritiated perhydrohistrionicotoxin ( 5 5 ) does not bind like bungarotoxin (56),
a powerful snake venom, to the recognition site of the acetylcholine receptor but to a special protein subunit, hopefully
identifiable with the ion translocation siter7’]. In all there
are now known to be present more than 100 different novel
alkaloids in the many Phyllobates and Dendrobates species
of South America.
The contributions of the organic chemist, John W Duly,
and of the herpetologist-taxonomist, Charles W Myers, have
added up to more than the sum of their partsf7’].The significance of the frog toxins for the study of receptors, membranes,
and ion transport may eclipse that of the toad and salamander
(Clemens Schopf) venoms, but the thematic origin clearly
goes back to the old master, Heinrich Wieland.
When one mentions Wieland’s name to present-day biochemists, they remember him for his theories on the “activation of
hydrogen” that brought him into-at times violent--opposition
to Warburg (I 883-1970), another founder of modern biochemi ~ t r y [ ~Wieland
~].
“diminished” the role of oxygen to that of
an acceptor for activated hydrogen by replacing O2 by
quinones, metals, or methylene blue[731.Warburg’s feelings
toward this hypothesis and its originator are best characterized
by his reaction to reading his own obituary in the Times
(of London) of January 12, 1938: “An error had occurred:
he had been mistaken for a distant relation, the distinguished
botanist and Zionist leader, also called Otto Warburg (18591938). The error was corrected on the following day with
appropriate apologies. Warburg was mildly amused and mildly
annoyed when, as a subscriber to the Times, he read the
news of his demise; annoyed because he thought that deliberately no reference had been made to what he considered to
be one of his most important discoveries, that of nicotinamide
in the coenzymes of dehydrogenases and the chemical nature
of its reversible reduction and oxidation. He commented:
‘it looks as if the obituary was written jointly by poor old
Heinrich Wieland and poor old Torsten Thunberg’. These
two scientists had published much work on dehydrogenations
without establishing the chemical mechanism and, quite
wrongly, Warburg considered them his adver~aries”[~*l.
Since
the departure of Wieland and Warburg, we can now see the
two scientists in the same historical perspective as Isaac Newton (1642-1727) and Christian Huygens (1629-1695): light,
in its ambivalence, is understandable both in undular and
Angew. Chem. I n t . Ed. Engl. 16, 559-572 (1977)
corpuscular terms. Likewise the unity of biochemistry[731now
reigns in the close coupling of oxido-reduction mechanisms
and of “anabolic versus catabolic, amphibolic and ‘anaplerotic’
proce~ses”1~~!
At the time of their controversy, their fascination by models, the surface of platinum[761or of charcoal[771,
served well as a formal basis for polemics, but action was
not restored until D. Keilin turned to the living wax moth
(Galleria melloneh) to establish the physiological role of
cytochrome reactionsf78!
There was then little reason to suspect that Wieland‘s favorite
two enzymes for-putatively metal-free-model dehydrogenations, viz. the “Schardinger enzyme”, xanthine oxidase,
and the “Thunberg enzyme”, succinate dehydrogenase, would
turn out to be multi-centered iron-sulfur-containing flavoprotein complexes1791.
In xanthine oxidase the iron-sulfur centers
act as an electron reservoir serving to maintain molybdenum
as Mo“’ (for efficient reduction) and flavin as FADH2 (for
efficient oxidation) as visualized by the plausible but
unproven intermediates observable under anaerobic conditionsL8’I. The reaction of xanthine oxidase with oxygen
involves both paired and unpaired electronic transition states
between xanthine, oxygen, and reduced flavin adenine dinucleotide (FADH2).A new form of active oxygen, the superoxide
anion, O f ,suspected by neither Warburg nor Wieland, enters
the enzymatic arena[81].
The most recent investigations on the mechanism of biological oxidation, Wieland’s lifelong theme and quest, make use
of the classical Schardinger enzyme, xanthine oxidase, in order
to produce superoxide anion required for the activity of indoleamine 2,3-oxygenase, a novel catabolic enzyme discovered
by Hayaishi (Fig. 22). In this system methylene blue, utilized
Substrate
Methylene
Fig. 22. The action of indoleamine 2.3-oxygenase involves a catalytically
active ferric heme-superoxide complex that is in resonance equilibrium with
the ferrous heme-dioxygen complex and, in the presence of substrate, is
converted to product and ferrous heme-enzyme. Methylene blue, a cofactor,
is required for maximum enzyme activity [82].
so often by Wieland as a substitute for oxygen in model
reactions, surprisingly enough assumes the role of a new cofactor required for maximal enzymatic activity.
We approach the end of our excursion through the garden
of Wieland’s natural products. We, the later generation, have
accumulated enough knowledge through biosynthetic studies
with labeled or radioactive precursors to recognize or predict
the gross biogenetic origin of practically all natural products
discussed so farKs3].Again, Wieland had anticipated much
of this development. It was in his laboratory that studies
on yeast, previously agitated under oxygen and, therefore,
“ ~ e r a r m t ” [(depleted)
~~]
by combustion of intracellular ingredients, led to the discovery of an “induction time” until added
acetic acid was further metabolized. This experiment furnished
569
information which did not become transformed into knowledge until Feodor Lynen provided the correct interpretation.
“When does information become knowledge?” is a pertinent
to ask especially in an age of the production
of more data than the human brain is capable of grasping.
Lynen’s postulate of an “activated acetic
rested on
a proper interpretation of the induction phenomenon and
on the fact that on addition of an easily combustible substrate,
such as a small amount of ethanol, the induction time became
shorter. The further development has become history: Lynen’s
discovery of the nature of active acetic acid as Acetyl-CoA,
the biotin carboxylase (“aktivierte Kohlensaure”), the “doubly
activated acetic acid” (“aktivierte aktivierte Essigsaure”), uiz.,
malonyl-CoA, the multienzyme complex of fatty acid synthesis,
all these discoveries led directly to breath-taking new vistas
impressively described in his Nobel lecturec8’I.
When we now compare the impact of Wieland’s example and
discoveries on the growth and expansion of organic chemistry in its widest interpretation, i. e,, encompassingbiochemistry
and molecular biology, we could construct a tree somewhat
comparable to the one based on the Gerlach-Stern experiment[’] with which we started this historical critical essay.
“In a centenary celebration, the rich heir complacently goes
over the treasure which past centuries have
if
we heed Ortega’s advice, expressed in 1932 as a reaction
to what he then considered “the breakdown of the university
in the face of men’s present needs”, we have to do more
than worship the past or more than putting Weland on
a pedestal. “There is but one way left to save a classic: to
give up revering him and use him for our own salvation.. .
bring him close to us to make him contemporary, resurrect
our classic by immersing him in life once more”[881.
There are types of excellence that involve doing something
well and types that involve being a certain kind of person.
Wieland excelled in both respects and both faculties grew
commensurate with the risks and responsibilities. It is not
everyone that finds the age he deserves. Perhaps he might
have been worthy of a better century, but then we would
not know how he met the challenges of his time.
We must not forget that at a time when, in the words
of Karl Jaspers, the German universities had lost their dignity,
students looked up for courage and help to their teachers.
Barely a hundred years earlier another man had dishonored
the constitution and broken the instruments of law, namely
the narrow-minded and opinionated Ernst August, King of
Hanover. Against his tyranny rose the “Seven Professors of
Gottingen” as one man, among them the intrepid Jacob Grimm
for whom “science meant the search for the metaphysical
ethos in the physical world. To him doctrine and science
were one, in the same way as thought and action formed
an indissoluble unity. Thus, at the age of 52 years, he courageously faced an uncertain exileL8’’.
One hundred years later this bright example was followed by
a great darkness fortunately illuminated by “professores” (confessors),such as Kurt Huber and Heinrich Wieland,who had the
courage to stand up and be counted. Wieland’s student Hans
Carl Leipelt, because of his allegianceto Kurt and Clara Huber,
was arrested by the Gestapo on October 8, 1943, and hanged
on January 29, 1945[’01. At the mock trial of Leipett, Wieland,
invited as a witness, defied the dreaded Roland Freisler, “President of the Folk Tribunal” by walking up to the helpless
570
defendant and by exchanging a handclasp of deep sympathy
and approval.
In today’s agonizing world of constant redefinitions of old
standards and values, he would not have seen a problem
in reconciling excellence with democratic principles, i. e. equality with quality. He would have quoted William Learned:
“The conception of a democratic education as one leveled
to a colorless mediocrity is as grotesque an interpretation
of democratic principles as (a conception) of health in which
abounding vitality ... is deprecated on the ground that
only average health is fair to the community. No one believes
this.”[’lI “The right of competition may only be limited in
order to preserve it. For excesses of competition lead to monopoly, as excesses of liberty lead to absolutism.”[’
We admire the scientist who uses his intellectual gifts in
the service of one of the highest values of our civilization-the
search for truth. At a time when many intellectuals place
their gifts in the service of chicanery and lend themselves
to the cause of tyranny and brutality, this requires great
fortitude.
In Germany, more so than in the United States, the period
of institutional crises, especially of the University, is not yet
over. Many students in their radicalism laid claim to ownership
of “their” university as an instrument for social change or
experimentation. Wieland, as a protagonist of a correctly
defined
if called upon to express his opinion
today, would have challenged such aclaim: “Yes, the university
is indeed owned. There are proprietors. They are not listed
in your catalog. They are not students, faculty members, or
alumni. Rather they are, especially for Munich, Fraunhder,
Liebig, Baeyer, Willstutter, Thomas Mann, Max Weber, Karl
Vossler, Kurt Huber, and you may go back further to Pluto,
Aristotle, and Confucius. They are the proprietors. The rest
of us hold the University in trust for them and for those
whose names have yet to join this timeless throng.”
Today we are happy in the knowledge that Heinrich Wieland,
a faithful trustee during his lifetime, has entered the ranks
of the scholarly proprietors.
Received: April 22, 1977 [A 175 IE]
German version: Angew. Chem. 89, 575 (1977)
Naturwissenschaften 30, 333-373 (1942).
RolfHuisgen, Proc. Chem. SOC.1958, 210-219.
H . Wieland, Starnberg, July 1957:
Meinen feyerlich Bewegten
Mache Dank und Freude kund:
Das Gefuhl das Sie erregten
Schliesst dem Dichter selbst den Mund.
(Goethes Goldener Jubeltag 1825).
Cf. R . Huisgen, Naturwissenschaften 44, 317-318 (1975); C. Schopf;
Angew. Chem. 7 1 , 1-5 (1959).
H . Wieland,Angew. Chem. 62,l-4 (1950).-The passage from Goethe’s
Faust, in the translation of Philip Wayne, is as follows:
“Of the depth of chanting, whence the blissful tone
That lames my lifting of the fatal glass?
Do bells already tell with vibrant drone
The solemn opening of the Easter Mass?”
0. Stern, W Gerlnch, 2. Physik 8 , 110 (1921).
0. Stern, W Gerfach, 2. Physik 9, 349 (1922).
0. Stern, W Gerlach, Phys. 2. 23,476 (1922).
E. Segrd, Biogr. Mem. Nat. Acad. Sci 43,215-236 (1973).
G. Holton: Thematic Origins of Scientific Thought: From Kepler to
Einstein, Harvard University Press, Cambridge, Mass. 1973, p. 418.
The author depicts a tree with extensive ramifications having its roots
in the Stern-Gerlach experiment.
“Natural organic chemistry is biochemistry, the chemistry of life processes”: F. K n o o p , Angew. Chem. 49, 558 (1936).
F. Krohnke, Liebigs Ann. 1973, 547-552; H . A. K r e b s , Nature 215,
144-1445 (1967). Viewed historically both the autonomy and the
Angew. Chem. Int. Ed. Engl. 16,559-572 ( 1 9 7 7 )
institutionalization of science began with Liebig as convincinyl\
depicted by Joseph Ben-David in his study ‘The Scientist’s Role i n
Society”. Prentice-Hall, Englewood Cliffs, New Jersey 1971 : “Touard
the end of the century the laboratories of some of the professors became
so famous that the ablest students from all over the world went there
for varying periods of time, The list of students who worked in such
places often included practically all the important scientists of the
next generation. ..,These unplanned and unexpected developments were
an even more decisive step in the organization of science than the
early nineteenth century reform. Research started to become a regular
career, and scientists in a number of fields started to develop into
much more closely knit networks than ever before. Their nuclei were
now university laboratories training large numbers of advanced students,
thus establishing between them personal relationships, highly effective
means of personal communication, and the beginning of deliberately
concentrated and coordinated research efforts in a selected problem
area.” (pp. 124-125.)
August Wilhelm uon Hofmann’s (1818-1 892) three volumes of “Erinnerungen an vorangegangene Freunde” immortalize famous scholars, such
as Justus uon Liebig, Friedrich Wohler, Thomas Graham, Jean-Baptiste
Dumas, Quintinio Sella, Peter Griess, and many others. The endearing
title probably has a Roman or Greek origin aqd is found engraved
on the tombstone at Serignan of Jean-Henry Fabre, the French entomologist: Quos perisse putamus praemissi sunt (whom we believe to have
lost, preceded us).-Cf. K . Guggenheimr Sandkorn fur Sandkorn, Die
Begegnung mit J.-H. Fabre, Artemis Verlag, Zurich 1959.
H . Dechend: Justus von Liebig. Verlag Chemie, Weinheim 1965.
W Beck, E . Schuierer, K . Feldl, Angew. Chem. 77, 722 (1965); Angew.
Chem. Int. Ed. Engl. 4, 698 (1965).
C . Grundmann, R . K . Bansal, P . S. Osmanski, Justus Liebigs Ann. Chem.
1973, 898-909.
W Prandtt. Die Geschichte des Chemischen Laboratoriums der Bayerischen Akademie der Wissenschaften in Miinchen. Verlag Chemie,
Weinheim 1952, p. 40.
F. Schonbein: Menschen und Dinge. Mittheilungen aus dem Tagebuch
eines Naturforschers. Anonym erschienen. Verlag von Rudolf Besser,
Stuttgart und Hamburg 1855.
[IS] K . Bloch, Science 150, 19-28 (1965).
[19] H.-J. Staudinger, Freiburger Universitatsblatter. Verlag Rombach, Freiburg 1974, No. 44.
[20] J. S. Fruton: Molecules and Life, Historical Essays on the Interplay
of Chemistry and Biology, Wiley-Interscience, New York 1972.
[21] R . SonderhoK H . Thomas, Justus Liebigs Ann. Chem. 530, 195 (1937).
[22] R . J . Lorentzen, W J . Caspary, S.A . Lesko, P. 0. P . Wo, Biochemistry
14, 3970-3977 (1975).
[23] W Leuin, A . W Wood, H . Yagi, D. M . Jerina, A . H . Conney, Proc.
Natl. Acad. Sci. (USA) 73, 3867-3871 (1976); Nature 266, 378 (1977).
[24] M . Koreeda, P. D. Moore, H . Yagi, H. 7: C. Yeh, D. M . Jerina, J.
Am. Chem. SOC.98, 6720-6722 (1976) and references cited therein.Concerning the stereochemistry of opening of diol epoxides: H . Yagi,
D. R. Thakker, 0. Hernandez, M . Koreeda, D. M . Jerina, J. Am. Chem.
SOC.99, 1604-1611 (1977).
[25] K . Shinohara, P . A . Cerutti, Proc. Natl. Acad. Sci. (USA) 74, 979-983
(1977).
[26] D. M . Jerma, J . W D a / y : Oxidation at carbon, drug metabolism-from
Microbe to Man. Taylor and Francis, London 1976, pp. 13-32.
[26a] J . M . Essigmann, R . G . Croy, A . M . Nadzan, W F. Busby, Jr., K
N . Reinhold, G . Biichi, G . N . Wogan, Proc. Natl. Acad. Sci. (USA)
74, 1870 (1977).
[27] B . W: O’Malley, A . R . Means, Science 183, 610-620 (1974); B. W
O’Malley, W T Schrader, Sci. Am 234, No. 2, 32-43 (1976); B. S.
McEwen, Sci. Am. 235, No. 1,48-67 (1976).
1281 This event dates hack to AD 1000 and was celebrated on August
15, La Sensa, i.e. L‘Ascensione or L‘Assunta, by the Doge sailing
out into the Adriatic on his Maesta Nave (after 1311 il Bucintoro,
probably from Nauilirrm Ducentorum Hominum) to drop a golden ring,
consecrated by the Pope, into the sea with the words: “Desponsamus
te, mare” (we wed thee sea).-On his way from his home in Starnberg
to the station, Wieland often passed a house with a big fresco of the
“Buzentaur”, a replica of the Bucintoro, used by Ludwig I1 of Bavaria
for aquatic pageants on the lake with the inscription: “Schon war
die Vergangenheit, schoner noch wird die Zukunft Starnbergs sein.”
At least for Wieland, Starnberg became his haven after the destruction
of his house, Arcisstrasse 1, and his laboratory in 1944.
[29] Dorothy Crmfoot-Hodgkin, Prog. Chem. of Nat. Prod. 15, 167-220
(1958).
1301 “The structure of vitamin BIZ,as we think of it today, is based on
a fascinating complex of evidence obtained by X-ray analysis and by
more traditional chemical means. We have reached a position in which
we can almost say we “see” the molecule-if not quite as clearly,
perhaps, as we should like. We can assign positions in space to the
atoms of this very large molecule within less than half an Angstrom
unit in t w o different crystal structures. We know its absolute configuraAngew. Chem. Int. Ed. Engl. 16, 559-572 ( 1 9 7 7 )
tion and the exact stereochemistry of all the different asymmetric centres
present. Yet most of this knowledge rests o n a way of using X-ray
diffraction effects which is very far from rigid in its application. Part,
at least, of our evidence that our method works at all is the character
of the structure it has given us for BI2-a structure that fits in an
extraordinarily reasonable way with such a variety of observations,
chemical and stereochemical and biogenetic, that it is impossible not
to believe it is essentially correct.” Ref. [29], pp. 167-168.
[31] J . Karle, 1. L. Karle, Acta Crystallogr. 21, 849 (1966).
[32] E. C . Kostansek, W N . Lipscomb, R . R . Yocum, W E . Theissen, J.
Am. Chem. SOC.99, 1273-1274 (1977).
[33] H . A . Krebs, J . H . Shelley: The creative process in science and medicine.
Excerpta Medica, Amsterdam 1975.
[34] “How luck and merit are close-hound
Fools never see and never will;
And if the wise man’s stone were found,
The stone would lack the wise man still.”
The wise man’s stone which conferred wealth, power, and long life,.
was the object of much alchemical research. Translation by Charles
E. Passage, J . IT Goethe: Faust. The Library of Liberal Arts, Bobbs-Merril Co., Indianapolis, New York, Kansas City, 1965, p. 181.
[35] B . Barber, R . C . Fox, Am. Journal of Sociol. 64, 128 (1958).
[36] H . Wieland, W Gumlich, Justus Liebigs Ann. Chem. 494, 191 (1932).
[37] H . Wieland, K . Bahr, B. Witkop, Justus Liebigs Ann. Chem. 547, 156
(1941).
[38] K . Bernauer, F . Berlage, W u. Phifipsborn, H . Schmid, P . Karrer, Helv.
Chim. Acta 41, 2293 (1958).
1391 K . Bernauer, Progr. Chem. Nat. Prod. 17, 183-247 (1959).
[40] A . R . Battersby, H . F . Hodson, Alkaloids 11, 189-204 (1968).
[41] M . Fehlmann, H. Koyama, A . Niggli, Helv. Chim. Acta 48, 303-304
(1964).
[42] N . D. Jones, W Nouackj, J. Chem. SOC.Chem. Commun. 1972, 805.
[43] Hermann Wieland, Ber. Dtsch. Chem. Ges. 54, 1784 (1921).
[44] C . Schopf, G . Lehmann, Justus Liebigs Ann. Chem. 518, 12 (1935).
[45] C. Scheuing, R. Winterhalder,Justus Liebigs Ann. Chem. 473, 126 (1929).
1461 N . B. Eddy, E. L. M a y , Science 181, 407-414 (1973).
1471 K . C . Rice, A . E. Jacobson, J. Med. Chem. 19, 430 (1976).
[48] K . C . Rice, W A . Klee, M . D. Aceto, H . H. Swain, A . E. Jacobson,
J. Pharm. Sci. 66, 193-197 (1977).
[48a] H . Merz, K . Stockhaus, H . Wick, J. Med. Chem. 20, 844 (1977).
[49] F. H . H. Loh, L. F. Tseng, E. Wei, C . H . Li, Proc. Natl. Acad. Sci.
(USA) 73, 2895-2898 (1976).
[SO] S. H . Snyder, Sci. Am. 236, Nr. 3, 44-67 (1977).
[51] Leonard Huxley: Life and Letters of Thomas Henry Huxley. London,
MacMillan 1900.
[52] W Koschara, Hoppe-Seylers Z. physiol. Chem. 240, 127 (1936).
[52a] Today’s gigantic research effort is endangered precisely because of a
too narrow interpretation of relevance; it can hardly be avoided that
an increasingly centralistic bureaucracy will insist that research be
directed towards the solution of certain national problems, or that
certain areas, such as genetic engineering, he placed under state supervision. In his study “The Logic of Liberty” (London 1951), Michael
Polansky pleads for freedom of research: “What technical inventions
were the discoveries of the Nobel Laureates Planck, Einstein, Perrin,
Millikan, Michaelson, Rutherford, Aston, Chadwick, Barkla, Heisenberg, Compton, Frank, G. Hertz, Rubens, Laue, Joliot, Fermi. Urey,
Anderson, W. H. and W. L. Bragg, Schrodinger, Dirac, etc., unconsciously intended to produce? No one can tell-so the new theory of
science must pass them over. One wonders how the great physicists in
the list above would have fared if, before embarking on their investigation, they had to get a certificate of its social usefulness from a scientific
directorate, as contemplated by Marxist scientists and their friends. To
what conflicts may not have led their “arrogant pretence” to he the sole
judges of their own preference!” (pp. 82-83).
[53] M . Obermayer, F. Lynen, Trends Biochem. Sci. 1 , 169-171 (1976).
[54] G. A. Jeruis, Proc. SOC.Exp. Biol. Med. 82, 514 (1953).
[55] C . R . Creueling, J . W Daly: Methods of Biochem. Anal. 19, 153-182
(1971).
1561 J . W Daly, D. M . Jerina, B. Witkop, Experientia 28, 1129 (1972).
[57] D. M . Jerina, J . W Daly, Science 185, 573-582 (1974).
[58] “If you want to become a chemist, so Liebig told me, when I worked
in his laboratory, you have to ruin your health. Who does not ruin
his health by his studies, nowadays will not get anywhere in Chemistry”.
A . Kekul6, Ber. Dtsch. Chem. Ges. 23, 1308 (1890).
[S9] W Litten, Sci. Am. 232, No. 3 , 90-101 (1975).
[60] Th. Wieland, Science 159, 946-952 (1968).
[60a] B. Witkop, Science 162, 318-326 (1961); Adv. Protein Chem. 16,
221 (1961).
[61] 1 . L . Karle, J . Karle, Th. Wieland, W Burgermeister, K . Faulstich,
B. Witkop, Proc. Natl. Acad. Sci. (USA) 70, 1836-1840 (1973); I. L.
Karle, J. Am. Chem. SOC.99, 4000 (1977).
[62] 1. L. Karle: 4. American Peptide Symposium. Ann Arbor Science Publishers, Ann Arbor 1975, pp. 61 -84.
571
[63] I. L. Karle, J . Karle, Th. Wieland, W Burgermeister, B. Wirkop, Proc.
Nat. Acad. Sci. (USA) 73, 1782-1785 (1976).
[64] I. L. Karle, E. Duesler, Proc. Nat. Acad. Sci. (USA) 73, 2602 (1977).
The dodecahydrate of antamanide was obtained in the presence of
calcium ions. Concerning the possible presence of calcium ions in the
crystal lattice, Isabella Karle expressed her views in a personal communication as follows: “The question arises as to the whereabouts of the
C a + + ions present in the crystallizing solution. Are they still in the
mother liquor surrounding the crystal? Or is it possible that some
of the sites in the inner core of the channel are partially occupied
by C a t + rather than by H 2 0 ? The X-ray diffraction data cannot
distinguish between the type of ion or atom occupying a site when
dealing with partial occupancies, since the occupancy and the weight
of an atom are not independent variables. The distances between the
sites in the inner core and the H 2 0 in the bound layer are compatible
with C a + + . . . Oligands.”
[64a] On booking at this frog, one is reminded of Charles Darwin’s description
in The Voyage of the Beagle (1831), Chap. 5: “Amongst the Batrachian
reptiles I found only one little toad (Phryniscus nigricans), which was
most singular from its color. If we imagine, first, that it had been
steeped in the blackest ink and then, when dry, allowed to crawl
over a board freshly painted with the brightest vermilion so as to
color the soles of its feet and parts of its stomach, a good idea of
its appearance will be gained. If it had been an unnamed species,
surely it ought to have been called Diabolicus, for it is a fit toad
to preach in the ear of Eve.” Charles Darwin and the Voyage of
the Beagle. Edited by Nora Barlow. (Rough notebooks kept during
the voyage together with many previously unpublished letters written
during the voyage.) Philosophical Library, New York 1946.
[65] H . Wieland, W Konz, H . Mittasch, Justus Liebigs Ann. Chem. 513,
1-25 (1934).
166) M. Latham, Nat. Geogr. Magazine 129, 683-693 (1966).
1671 7: Tokuyama, J . W Daly, B. Witkop, I. L. Karle, J . Karle, J. Am.
Chem. SOC.90, 1917 (1968).
[68] E. X . Albuquerque, J . W Daly, B. Witkop, Science 172, 995-1002
(1971); E. X . Albuquerque, J . Daly in P. Cuatrecases: Receptors and
Recognition. Chapman and Hall, London 1977, Series 9, Vol. 1, pp.
297-338.
[69] J . W Daly, I . L. Karle, C . W Myers, ?: Tokuyama, J . W Waters,
B. Witkop, Proc. Natl. Acad. Sci. (USA) 68, 1870-1875 (1971).
1701 A. 7: Eldefrawi, M . E. Eldepawi, E. X . Albuquerque, A . C. Oliviera,
N . Mansour, M . Adler, J . Daly, G. B. Brown, W Burgermeister, B.
Witkop, Proc. Nat. Acad. Sci. (USA) 74, 2172-2176 (1977).
1711 C . W Myers, J . 19: Daly, Bull. Am. Museum of Natl. History 157,
177-262 (1976).
[72]
[73]
[74]
1751
[76]
[77]
[78]
[79]
1801
H. A. Krebs, Biogr. Mem. Fellows R. SOC.18, 629-699 (1972).
W Franke, Naturwissenschaften 30, 342-351 (1942).
W D . McElroy, Trends Biochem. Sci. 1 , 93 (1976).
J. S. Fruton: Molecules and Life, Historical Essays on the Interplay
of Chemistry and Biology. Wiley-Interscience, New Y ork 1972.
H . Wieland: On the Mechanism of Oxidation. Yale University Press,
New Haven, Connecticut 1932; Naturwissenschaften 34, 111 (1947).
0. Warburg: Heavy Metal Prosthetic Groups and Enzyme Action.
Oxford University Press, London, and New York 1949.
D. Keilin, Proc. Roy. SOC.(London), Ser. B 98. 312 (1925); K. Okunuki
in M . Florkin, E. H . Stotr: Comprehensive Biochemistry. Elsevier,
Amsterdam 1966, pp. 232-304.
H . Beinert, B. A . C . Ackrell, E. B. Kearney, Th. P . Singer, Eur. J.
Biochem. 54, 185-194 (1975).
F. J . S. Olson, D . P. Ballou, G. Palmer, P! Massey, J. Biol. Chem.
249,4363-4382 (1974).
[XI] F. J. S. Olson, D. P. B a l h , G. P a h e r , c! Massey, J. Biol. Chem.
249,4350-4362 (1974).
[82] F. Hirata, 7: Ohnishi, 0. Hayaishi, J. Biol. Chem. 252, 4637, 4643
(1977).
[83] K. Nakanishi, Natural Products Chemistry. Academic Press, New York
1974.
[84] H . Widand, 0. Probst, M . Crawford, Justus Liebigs Ann. Chem. 536,
51 (1938).
[SS] H . K Wyatt, Nature 235, 86-89 (1972).
[86] F. Lynen, Justus Liebigs Ann. Chem. 552, 270 (1942).
1871 Feodor Lynen, Angew. Chem. 77, 929-944 (1965).
[88] Ortega y Gasset: In Search of Goethe from Within (Pidiendo un Goethe
Desde Dentro), The Dehumanization of Art (and other writings on
Art and Culture), Doubleday, Garden City, N. Y. 1956.
1891 Jacob Grimm: Uber seine Entlassung. Schweighauserische Buchhandlung, Basel t838.
[90] Clara Huber: Kurt Huber zum Gedachtnis, Bildnis eines Menschen,
Denkers und Forschers, Dargestellt von seinen Freunden. Verlag Josef
Hahbel, Regenshurg 1947, p. 39.
[91] William S. Learned: The Quality of the Educational Process in the
United States and in Europe. Bulletin No. 20. The Carnegie Foundation
for the Advancement of Teaching, New York 1927, p. 35.
[92] Richard Hofstadter: Social Darwinism in American Thought. The
Beacon Press, 1955, p. 121.
[93] Wiefand’s unconstrained elitist attitude in the area of science and
research poses no problem even in today’s more refined social philosophy
and criticism; cf. the chapters on “Meritocracy and Equality” as well as
“The Redefinition of Meritocracy” in Daniel Bell: The Coming of the
Post-Industrial Society, a venture in social forecasting. Basic Books,
Inc., New York 1973, pp. 408 and 446.
Electrocyclic Ring Opening Reactions of Ethylene Oxides II**]
By Rolf Huisgenpl
Substituents capable of stabilizing negative charge endow ethylene oxides with the ability
to undergo electrocyclic ring opening at the CC bond; heating or irradiation generates small
equilibrium concentrations of carbonyl ylides which can engage in 1,3-dipolar cycloadditions.
Apart from the normal conrotatory mode of ring opening, predicted by the Woodward-Hoffmann
rules, the disrotatory process, forbidden by orbital symmetry, also appears to occur in the
case of cL-cyano-cis-stilbene oxide. Kinetic studies on a-cyano-trans- and -cis-stilbene oxide
permit construction of the energy profile for electrocyclic ring opening to give the stereoisomeric
carbonyl ylides and for their recyclization and rotation.
1. Ring Opening of the Cyclopropyl Anion
One of the most stimulating ideas to have Permanently
influenced our concept of the reaction event during the past
[*] Prof. R. Huisgen
Institut fur Organische Chemie der Universitat
Karlstrasse 23, D-8000 Miinchen 2 (Germany)
[**I Extended version of the Roger Adams Award Address, National Organic
Symposium of the American Chemical Society, Fort Collins (Col.), June
24. 1975. and a Dlenarv lecture delivered at the GDCh General Meetine
at Cologne, Sept. 9, 1975.
.~
572
I
decade is the principle of the conservation of orbital symmetry.
The initial publication of the Woodward-Hoffmann rules in
1965 spurred an enormous number of experimental and quantum-chemical studies; the stream of relevant publications has
not receded to this day.
Any formation or cleavage ofa bond proceeds with conservation of orbital symmetry. This principle can be demonstrated
for electrocyclic reactions, cycloadditions, and sigmatropic
shifts‘ These processes involve the breaking Or forming Of
several bonds coupled in a single step.
Angew. Chem. Int. Ed. Engl. 16, 572-585 ( 1 9 7 7 )
Документ
Категория
Без категории
Просмотров
1
Размер файла
4 609 Кб
Теги
todaу, heinrich, centennial, wieland, lifework, legacy
1/--страниц
Пожаловаться на содержимое документа