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Key Building Blocks of Natural Product Biosynthesis and Their Significance in Chemistry and Medicine.

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[20] S L. Rrgeil, D. P. Lee, J . Am. Chem. Soc. 96, 294 (1974).
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!If. Tomoi. 0.Ahe, M . lkedu. K . Kihura, H . Krrkiuchi, Tetrahedron
Lclr. 1978, 3031.
[22] S L. Rrgeii. L. Duluk, J. Am. Chem. Soc. YY, 623 (1977).
[23] S. L. Rrgtw, J . Am. Chem. Soc. YY. 3838 (1977).
[24] S. I-. Regrii. J . J . Besse. J . M c L ~ c k .J. Am. Chem. Soc.. in press.
[XI S. L. Regen. A . Nigum. J . J . Brsse, Tetrahedron Lett. 1978. 2757;
M 'hmoi. 7: Takuho, M . IkPdn. H . Kokiuchi. Chem. Lett. lY76. 473.
[26] S. Colonnu. R. Foriiusier. U . rferltrr, J. Chern. Soc. Perkin Trans. 1
I Y 7 X . 8.
[27] E . Chiellini, R. Soluru, J . Chem. Soc. Chem. Commun. 1977. 231.
[28] If. J . - M . Dou, R. Gullo, P . Hu.ssuiioly, J . Merzger, J . Org. Chem. 42,
1275 (1977).
1291 4. W Hrrrioir. D. Picker. J. Am. Chem. Soc. 97. 2345 (1975).
1301 S. 1.. Regeri, J . Heh. unpublished work.
1311 K . If. Gruhb.\. L. C . Kroll, J. Am. Chem. Soc. 93, 3062 (1971); R.
H . Gruhhs, L. C. Kroll, C. M. Sweer, J. Macromol. Sci. Chem. 7, 1047
1321
1331
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[35]
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1411
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(1973): R. H . Gruhhs: Catalysis in Organic Synthesis. Academic Press,
New York 1976, p. 153.
S. L. Rcgrii. D. P. Lee, Isr. J . Chem., in press.
5. L. Rrgen. A . Nigam, J. Am. Chem. SOC., in press.
S. L. Reyen. J. Org. Chem. 42, 875 (1977).
S. L. Regen. J . McLick, J . H e k . unpublished work.
F . Hel/ferich' Ion Exchange. McGraw-Hill, New York 1962. p. 525.
For a brief description of the different types of crosslinked polystyrene,
see: J . M . J . Frechef. M . J . farrall in: Chemistry and Properties of
Cross-linked Polymers. Academic Press, New York 1977. p. 59
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Fcwdler, Adv. Phys. Org. Chem. 8. 271 (1970).
F. M . Mtwger. J . Am. Chem. SOC.92. 5965 (1970).
Key Building Blocks of Natural Product Biosynthesis and Their
Significance in Chemistry and Medicine[**]
By Burchard Franckl*l
The principal features of the biosynthesis of natural products have been elucidated during the
past thirty years by the use of isotopic methods. It was discovered that large groups of natural
products originate from the same biosynthetic precursor-the key building block. The conversion of key building blocks into biologically active natural products serves as a model for the
development of more efficient syntheses in chemistry. In medicine, information about key
building blocks permits the elucidation and therapy of metabolic diseases.
1. Introduction
Natural products are defined as carbon compounds which
are formed in plants, microorganisms, animals, and man.
Many of these natural products, e. g. vitamins and antibiotics, are indispensable for man's existence.
The number of structurally elucidated natural products
has increased greatly in recent years. This is due, on the one
hand, to the great interest shown in biologically active substances and, on the other hand, to the highly developed
methods available for their isolation and structural determination. Thus, approximately 20000 natural products are
known"'; that is less than 1% of all organic compounds.
From the point of view of man and other organisms, however, they are an elite group of compounds which have been
selected out during the course of evolution for the necessities
of life.
Nalural product biosynthesis is an important field of research in modern natural product ~hemistryl~-~'.
Work in this
field led, primarily, to an understanding of the diversity of
organic natural products, gave an insight into metabolism
and induced the development of simpler s y n t h e s e ~ [ ~ . ~ - ' ~ ] .
The biosynthesis of natural products was elucidated by
isotopic labeling[']. Surprisingly, it was discovered that entire
groups of natural products originated from the same biosyn-
thetic precursor. These precursors are the key building blocks
of natural product biosynthesis. Information about a few key
building blocks is sufficient to obtain an overall view of the
diversity of natural products.
The key building blocks of biosynthesis occupy an important position in the metabolism of living organisms. Numerous diseases are caused by a modification of the biosynthetic
steps involving the key building blocks[''. In medicine, information about a few kcy building blocks thus allows elucidation and treatment of several metabolic diseases.
A knowledge of the key building blocks led to a revolutionary development in the chemical synthesis of natural
products. Many natural products can be synthesized in the
laboratory by using key building blocks as starting materials[4.5.10. I I ] . , such syntheses, which utilize biosynthesis as a
model, are often superior to the customary natural product
syntheses.
In the following, a greatly simplified survey of natural
product biosynthesis will first be given. The application of
biogenetic findings to chemical syntheses and in medicine
will then be dealt with using topical examples. Finally, it will
be discussed why natural product biosynthesis proceeds via
certain key building blocks.
2. Biosynthesis of the Main Groups of Natural Products
['I
Prof'. Dr B. Franck
Organisch-Chemisches lnstitut der Universitat
Orleans-Ring 23. D-4400 Munster (Germany)
["I Basrd on a plenary lecture given to the 110th Meeting of the Geseilschaft
Deutscher Naturforscher und Ante on September 19, 1978 in lnnsbruck (Austria).
Aiiyew. Chum. I n t . Ed. Eiigl.
iX. 429-439 ( 1 9 7 9 )
The 20000 natural products can be divided into four large
groups according to their biosvntheses. Three typical compounds of each of these groups are given as examples in
Table 1.
0 Verlug Chrmie, GmhH, 6940 Weinheim, 1979
0570-0833!7').'0h06-f)4~9S 0?.50/1~
429
of carbon dioxide, water and nitrogen. Thus, there is a fluent
transition between biosynthesis and biological degradation.
Figures 2 and 3, respectively, show situations in which the
first step of biosynthesis and the last step of biological degradation proceed at their highest possible intensities.
Table 1. The four main groups of natural products (with examples).
1 . Carbohydrates
2. Arenes
D-Glucose
Vitamin C
Cellulose
3. Acelogenines
Flower pigments
Vitamin K ,
Lignin
4. Nitrogen-containing natural products
Nucleosides
Blood pigment
Proteins
Fatty acids
Vitamin D
Caoutchouc
The biosynthesis of all these natural products starts with
atmospheric carbon dioxide, water and nitrogen (Fig. 1).
Carbon dioxide and water are converted, with the assistance
of sunlight and chlorophyll, into u-glucose by the process of
photosynthesis elucidated by Calvin“’]. This simple sugar (Dglucose) not only acts as a key building block for the very
large group of carbohydrate natural products, but also for
the three other groups. These three other groups result from
D-glucose via the key building blocks shikimic, acetic, and
amino acids. Ammonia is formed from atmospheric nitrogen
in a reaction sequence-nitrogen fixati~n[’~]-whichis only
found in a few microorganisms. D-Glucose is thus the central
key building block of natural product biosynthesis. The
quantities of glucose produced annually in photosynthesis
far exceed those of any other technically or biologically synthesized organic compound.
INY]
D-Glucose
OH
Shikimic acid
4
2) Arenes
Acetic acid
Amino acids
4
4
3. Problems in Natural Product Synthesis
The first synthesis of a natural product was accomplished
150 years ago by Friedrich Wohler in Berlin; this was his famous urea synthesis[141.The then current dogma that natural
products could only be formed in living organisms was thus
refuted. Chemical natural product synthesis has made a great
deal of progress since then. This is apparent if urea (1) is
compared, for example, with erythronolide B (2). The complete synthesis of erythronolide was recently achieved by
Corey and co-workers[”I. Erythronolide B is an aglycon of
the erythromycin antibiotics. As it contains ten chiral carbon
atoms in a relatively flexible ring system, its total synthesis
was regarded as an almost “hopelessly complex” task twenty
years ago‘’].
.
I
Fi
Fig. 2. Rice plantation on the Philippines in a state of full photosynthesis (photograph: BASF).
I
4) N -containing-
3) Acetoaenines
natural products
171
co2
+
H,O
Fig. I . Biosynthesis of the four main groups of natural products via the key build.
ing blocks D-glucose, shikimic acid, acetic acid and amino acids.
During the course of biosynthesis, the key building blocks
shown in Figure 1 are followed by further key building
blocks which are precursors for smaller natural product
groups. All of these natural products undergo reactions
which finally end in biological degradation and reformation
430
Figure 4 shows a sample of Wohler’s first urea together
with his publication in Poggendorffs A n r ~ a l e n ~ ’the
~ ’ ; urea
was sealed and labeled by Wohler himself; he gave it to his
friend Emanuel Merck in Darmstadt. Wohler had purified
his preparation so thoroughly that, according to its modern
IR spectrum, it i s as pure as “Merck” analytical urea (Fig.
5).
[‘I
R. B Woodward (1956) 116): “Erythromycin. with all our advantages. looks
at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers.. .”.
A n g e R . Chem. Int. Ed. Engl. I S . 429-439 (1979)
Fig. 3. Degradation of residual substances of natural product hiosynthesis hy bacteria in a modern sewage plant
(photograph: BASF).
Fig. 4. Original sample of Wohler's first synthetic urea and his publication in Poggendorffs Annalen (141 (photograph: Merck)
.Irrytzrr. <'/wr?i.
fiii.
Ed. Eiigi. 18. 424-419 (19791
43 1
Despite the development of impressive total syntheses,
natural product synthesis is still in a dilemma. Syntheses
suitable for the technical production of natural products are
only available in relatively few cases. Most total syntheses of
the more complicated natural products require so many reaction steps that the total yield becomes vanishingly low. This
can best be illustrated by the example of the medically important steroid hormone, cortisone (6).
0
Average
Yield [“.I
c
W o ~ d w a r d [ was
~ ’ ~ the first to succeed in performing the
sensational, total synthesis of this natural product with its six
chiral carbon atoms in 1952. The synthesis started with methoxytoluquinone (3) and proceeded via 49 steps, the total
xon
70
1
99
90
82
74
10
20
30
40
90
70
2.8
0.08
0.0023
O.ooOo64
0.0000016
61
61
35
12
4.2
I .5
0.52
ElocH3
0
.
(31
90
Steps
SO
0
I000
Table 2. The dependence of the total yields [%j in multistep syntheses on the
average yields and number ofstepc.
2000
la0
iX(l
considered as very good-the total yield decreases drastically
as the number of reaction steps increases. As multistep syntheses with such yields are of no use in practice, either the
average yield must be increased (to 99%) or the number of
reaction steps must be greatly reduced. These requirements
can be met if natural syntheses are based on biosynthetic
models with the utilization of key building blocks. Such
biomimetic syntheses are generally characterized by a small
number of steps and a high total yield. Furthermore, it is
generally important that they are carried out under mild conditions and that the formation of by-products is avoided by
means of high selectivity.
The first definitive example of a natural product synthesis
based on a biosynthetic model was the laboratory synthesis
of the alkaloid, tropinone (8). Willstatter[201
synthesized this,
then regarded as problematic, bridged heterocycle from su-
sol1
,/I0
,//I,
- - [cm-’]
Y
i’g.5. IR spectra of Wohkr’s urea (upper spectrum) and “Merck” analytical urea (lower spectrum) in KBr (photograph
Merck).
yield was less than lo-’%. This does not detract in any way
from the great scientific significance of this achievement.
The further efforts of industrial laboratories were then directed towards improving yields by reducing the number of
steps. The 27-step synthesis developed by Roussel in France
from a tetralone (4) gave a technically interesting total yield
of 1%[”’.A synthesis performed by Syntex in the
(13
steps, 3.3% total yield) starts with the readily available steroid natural product, diosgenin (S), and is thus not a total
synthesis.
Table 2 shows the relationship between the number of
reaction steps and the total yields in multistep syntheses. If
the average yield is 70“0 per reaction step-which can be
432
beric acid (7) in a 15-step total synthesis. The yield was only
0.76%. The one-step synthesis based on biosynthetic concepts
developed by Robinson and Schopf provided a n impressive
Angew. Chem. Znt. Ed. Enyl. 18. 429-439 (19791
comparison; the yield was over 80%["]. Stimulated by this
success. intensive efforts were then initiated to work out simple, efficient syntheses for alkaloids and other natural products using the key building blocks of biosynthesis.
a
H
4. Elucidation of the Key Building Blocks
Isotopic methods are indispensable for the elucidation of
the key building blocks of natural product biosynthesis. The
four isotopes of carbon are most important; these are available as a result of highly developed enrichment and nuclear
transformation techniques (Table 3). The two most important, the stable I3C and the radioactive 14C, complement one
Table 3 Radioactive and stable isotopes of carbon.
C isotope
Abundance r X ]
Half-life
20.4 min
in
I*)
5600 years
another with respect to their possible applications[22].Biosynthetic experiments in which the reliable determination of labeled products at high dilutions is important can be performed with 14C due to its extremely low natural abundance.
I3C allows (with, however, a considerably lower detection
sensitivity) very simple determination of labeling positions in
molecules by means of I3C-NMR spectroscopy. The shortlived "C is utilized in medicine for metabolic investigations.
The main features of the biosynthesis of natural products
have been elucidated over the past 30 years by using isotopic
methods'x]. With the help of this information, it is now usually simple to recognize the key building blocks of a natural
product and the main group to which it belongs. This is illusand the
trated by the formulas for rubber (9) (i~oprene)['~1
antibiotic, penicillin (10) (cysteine and ~ a l i n e ) [ The
~ ~ ? biosynthesis of some novel natural products from marine organisms, e. g. the extremely toxic saxitoxin (11)[251,
is less evident.
The synthesis and function of more complex key building
blocks are still under intensive investigation. Although these
compounds give rise to smaller natural product groups than
do the basic key building blocks, they furnish very useful information for chemistry and medicine. This topic will be dis-
2 XQ
cussed for four groups of biologically active natural products
in the following sections. The unsaturated hydrocarbon,
squalene (12), is the key building block for the steroids and
triterpene~l~'.~'~.
Numerous, structurally related compounds
(anthraquinoids) are derived from the anthraquinone emodin (13)[281.
Many isoquinoline alkaloids, e. g. morphine, are
formed from the key building block reticulin (14)L2'1.The
structurally complex uroporphyrinogen Ill (15) is the precursor for heme13"), vitamin B,213'1and similar natural products.
C0.H
5. Key Building Blocks of Acetogenine Biosynthesis
The cyclization of squalene (12) to the tetracyclic steroid
molecule is a fascinating biosynthetic reaction. Four rings
are closed and eight centers of chirality are formed in a concerted reaction; this is triggered by hydroxy cation via a terminal epoxidation. In order to account for the stereospecific-
R
CH,
no
no
I
H
Anguw. Chem. lnr. Ed. Engl. 18. 429-439 (19791
H
433
ity of such a complicated reaction sequence, it is assumed
that the carbon chain of the squalene in solution prefers an
arrangement in which the individual rings of the steroid molecule are, as it were, preformedL3*].The cyclization of the
key building block, squalene, understandably represented a
challenge to the chemist to synthesize the medically valuable
steroids in a similar fashion. W. S. Johnson et al.L321
have
achieved remarkable results; the simple biomimetic synthesis
of 16,17-didehydroprogesterone(1 7) is shown as an example.
The elegant construction of a steroid-like ring system (16)
was accomplished under mild conditions starting with a precursor similar to the key building block, squalene. The
steroid hormone (17) was obtained from this in three further
steps. This strategy of biomimetic synthesis has already
proved to be of value in other steroid syntheses.
Our laboratory has also been very involved with work on
one of these groups of fungal toxins, the ergochromes. The
e r g o ~ h r o r n e s are
~ ~ ' produced
~
by molds mainly found in rye,
maize and rice. In rye they form the sclerotia known as ergot.
As the structure of the most important ergochrome secalonic
acid A (20) shows, these compounds are dimeric xanthone
derivative^^^^.^^^.
1) 0 5 0 4
2) Pb(0Ac)s
13 ergochromes have so far been isolated from molds and
451. It appeared likely that these ergochromes
could be prepared via a novel biosynthetic route in which
emodin (13) is the key building block. Each half of the ergochrome molecule might be formed in a few steps in which
lichen^[^^.^('
Emodin (13), a key building block which, like squalene
(121, is formed from acetic acid, is involved in the biosynthesis of a group of toxins produced by mold fungi. Many molds
found in food contain poisonous substances whose danger is
partially increased by their accumulation in the organism
and their lingering a ~ t i o n l ~Figure
~ ' . 6 shows a pure culture
of such a fungus on bread. The strongly active aflatoxin B,
(IN) from Aspergillusflauus and the weakly active roquefortin (19) from Penicillium roqueforti are examples of fungal
toxins from food molds[34.351.
t
no
on
CH3
H3CO&
0
emodin is first cleaved oxidatively to give benzophenone
(21). Subsequent cyclization, together with reductive reactions, would then furnish the xanthone derivative (20a)
OH
0
OH
Fig. 6 . A pure culture of Penicillium i.r/andicumon bread (from [361)
434
Anget%. Chem. Int. E d . Enyl. 18. 429-43') ( 1 9 7 9 )
found in the ergochromes. We have studied this hypothesis
using emodin derivatives labeled with C and H isotopes.
After feeding molds with labeled anthraquinones, these compounds were indeed converted into ergochromes in high
yields via a benzophenone intermediate [cf.
4xI. This
is the first evidence for oxidative ring opening of an anthraquinone in b i o sy n t h e s i ~ [ ~It~ was
] . later discovered that further natural products, are also derived from emodin (13),
which is thus a n especially versatile key building block, by
demonstrated that
ring cleavage at a or b. Gutenbeck et aZ.[501
the benzophenone sulochrin (23) is a ~eco-anthraquinone~~'~.
Using isotopically labeled precursors, we were further able to
show that the antibiotic geodin (24)I5'l and ravenelin (22jLS2l
can also be classed as <em-anthraquinones. Emodin (13)
could be converted into (21) and products of type (20a) in
biomimetic s y n t h e s e ~ ~ ' " ~The
~ l . formulas again show how
completely different structures can be related to one another
by means of their origin from the same key building block in
biosynthesis.
I
q+p
%
\
/
\
\
Fig. 7. Eight basic alkaloid skeletons which are derived from derivatives of the
key hiosynthetic building block. henzyl tetrahydroisoquinoline (enclosed within
the rectangle). T h e alkaloids are of the following types (upper row): crytaustoline, aporphine, morphine. erythrinane, (lower row): cularine. proaporphine. pdvine, protoberberine (from left to right in each case).
6. Key Building Blocks of Alkaloid Biosynthesis
Alkaloids, as the name suggests, are natural products with
basic properties. They are mainly produced by plants and are
distinguished by their specific pharmacological effects on
human and animal nervous systems. This fact has long been
made use of by man. Approximately 5000 alkaloids are
known. Considering their varied structures, it is surprising
that almost all of them are formed from only four amino
acids or their derivatives[5s1;these are ornithine (25), lysine
(26), tryptophan (27) and phenylalanine (28).
The economy of this biosynthetic scheme is impressive
and it is a n ideal model for the technical production of a
range of chemical products. In the past 40 years, numerous
groups of workers have thus tried to simulate this scheme in
the laboratory. The first experiments were carried out independently by Schopf [571 and Robinson[sx1.
They oxidized ben-
H
HO
o%OH
\
The biosynthesis of morphine will be taken as an example.
Two phenylalanine derivatives split off carbon dioxide and
ammonia to form benzyltetrahydroisoquinoline (29) as key
building block155.5h1
which can undergo especially diverse
reactions [cf. reticulin (14)]. The three-dimensional ring system of morphine (30) results after 180" rotation around the
bond indicated and subsequent ring linkage.
The key building block (29) enclosed within the rectangle
gives rise to additional basic skeletons from which a total of
approximately 2000 alkaloids are derived (Fig. 7).
H
HO
o%
OH
H
\
OH
OH
zyl tetrahydroisoquinoline (31) in the hope that they would
obtain an aporphine or a morphinane. Ring closure with a
70% yield was achieved but resulted in a cryptaustoline de-
I
1
(29 )
Afrqew. ( ' I i m . lfrt. Ed. Efrql. 18. 429-439 ( 1 9 7 9 )
435
rivative. We later found that the oxidative ring closure could
be steered to give the desired aporphine in 62% yield by quaternization at the nitrogen [(31)1-(32)]1"]. This was the first
biomimetic synthesis of the basic aporphine skeleton from
which numerous alkaloids with diverse pharmacological
effects are derived.
Biomimetic synthesis of the basic morphinane skeleton
was more difficult. Bartonfbo1
first demonstrated that ring closure could be achieved by oxidative condensation of the key
building block (33). The yield could be increased to 4% by
using a two-phase oxidation systeml6'I and to 40% by utilizing vanadium oxide trichloride as oxidizing agent
thus
making this reaction suitable for synthetic purposes. It
should be mentioned in this context that morphine, which is
indispensable in medicine, is still obtained from poppy
plants. Misuse cannot be ruled out. It is therefore urgent that
a method be found in which morphine can be produced industrially under supervisable conditions.
The finding that aporphine and morphine alkaloids can be
relatively easily produced from their key building blocks
raises the question as to whether this synthesis can also take
place spontaneously or undesirably in living organisms. According to recent results, this is indeed the case in chronic alcoholism. The first reports of a connection between alcohol
and opium addiction first appeared several years
It is
now certain that the similarity between the disease symptoms
in alcoholism and opium addiction is of chemical origin[64-661
(Fig. 8). The alcohol consumed is dehydrated in the liver to
has produced. Porphyrins existed on the surface of the earth
2.5 billion years agorh7],they catalyze vital metabolic processes in almost all organisms. As far as man is concerned, heme
(34) is the most important porphyrin1"I. It is a component of
the proteid hemoglobin, which is responsible for the transport of oxygen from the lungs to the cells within the body.
Minor modifications in heme biosynthesis cause lethal blood
diseases''. I'.
CH,
CO,H
CO,H
The blood pigment heme and related natural products
originate from two very simple compounds-glycine and
succinic acid. The first information concerning heme biosynthesis is to be found in the pioneering studies of Shemin1691.
This work started 30 years ago with an experiment which, on
the basis of the then current knowledge, was rather risky.
Shemin synthesized 66 g glycine labeled with I5Nand swallow-
CH,- CHO
'
OH
$HZ
y42
:HZ
CH2
CqH
CqH
Fig. 9. Biosynthesis of heme from glycine and succinic acid [69]. The encircled
atoms are derived from glycine, the others from succinic acid.
Fig. 8. Opiate formation in chronic alcoholism
acetaldehyde which, depending on its quantity, then blocks
to a lesser or greater extent the normal degradation of phenylalanine in the organism. Phenylethylamine and phenylacetaldehyde derivatives are thus produced in higher concentrations which then condense spontaneously to give the key
building block for aporphine and morphine biosynthesis [see
(29)].Formation of the key building block and the alkaloids
derived from it have been clearly demonstrated in experiments on animals. These results are extremely important for
the preventive, psychological, and medicinal therapy of
chronic alcoholism[6h1.
7. Key Building Blocks of Porphyrin Biosynthesis
Key building blocks have an especially impressive role in
the biosynthesis of the blood pigment heme and related compounds. The basic heme skeleton is a porphyrin. The porphyrins belong to the most interesting systems which nature
436
ed it. He subsequently showed that the glycine nitrogen
was directly incorporated into the heme of his blood. Further
biosynthetic experiments-with duck blood-demonstrated
that heme is produced from eight molecules of glycine and
eight of succinic acid (Fig. 9).
Succinic acid and glycine first condense with decarboxylation to give 5-aminolevulinic acid (35). Two molecules of 5aminolevulinic acid then give the pyrrole derivative, porphobilinogen (36). This reaction step is inhibited, for example, in
lead pois~ning''"~;the detectable concentration of 5-aminolevulinic acid in urine is a direct calibration of the degree of
lead poisoning. In this way, less heme is synthesized. This results in damage due to oxygen deficiency which first affects
the brain17'1. Four molecules of the very reactive porphobilinogen (36) are then assumed to condense to form the
porphyrin.
Until fairly recently, there were many possible explanations for this condensation1721.Several years ago we were able
to show for the first time by total synthesis of radioactively
labeled uroporphyrinogen I11
and its conversion to
heme by enzymes in duck blood, that uroporphyrinogen 111
is the direct biosynthetic precursor of the blood pigment
Angeu'. Chum. iixt.
Ed. Engl. 18. 429-43')
( 1979)
74H
y 2
Coenzyme A
p y r i d o x a l phosphate
*
-c 4
y 2
co
I
CHZ-NHZ
As is the case with alkaloids and steroids[7x1,there are also
biomimetic syntheses for the porphyrins which are distinguished by their simplicity and good yields. Porphobilinogen
(36) in dilute acid can be converted in high yields into porphyrins[”]. The main product is uroporphyrinogen 111 (15),
(35)
9
0
heme (34)[301.Scott et UZ.~~’]
subsequently found that the vitamin B,, ring system is also formed from uroporphyrinogen
111. Chlorophyll is probably synthesized in a similar way.
Uroporphyrinogen 111 may thus be a biogenetic key building
block which is of central importance for all organisms. Its
synthesis from the monopyrrole porphobilinogen (36) is now
CI C
0
Fig. 10. Strategies for multistep syntheses: a) branched. b) converging. c ) linear
(taken from [89f).
the key building block of heme biosynthesis“”]. The reaction
product contains, however, smaller quantities of the three
other isomers of this key building block. The high specificity
of reaction is surprising; for example, open-chained condensation products or ring systems with more than four pyrrole
units are not produced’”]. Simple syntheses for known, biologically active and also novel porphyrins have been developed with the help of these very efficient, biomimetic porphyrin s y n t h e s e ~ [ ~ ’ -Examples[x21
~~].
are the highly strained,
A=CI+-CC+H
P- C b - C%-C%H
being intensively investigated by several groups of worke r ~ [ ’’].
’ ~ A simplified scheme containing the most important
parts of heme biosynthesis starts with eight molecules of both
glycine and succinic acid (“G + S”). These condense in pairs
to give aminolevulinic acid (35), two molecules of which
then furnish the monopyrrole building block, porphobilinog-
J
4
(34)
en (36). After this, the reaction pathway leads to uroporphyrinogen I11 (15) and heme (34). This biosynthetic scheme
constitutes an ideal model for a rational natural product synthesis. This embodies perfectly the important principle of
“converging” synthesis in which a high total yield is attained
with as small a number of successive, linear synthesis steps as
possible (Fig. 10).
Angeu. Chem. l n t . Ed Engl. 18, 429-439 ( 1 9 7 9 )
I
0.5 N HCL
63%
.,-
”Yn ~ n - p l a n a r ~N,N,N,N-tetramethylporphyrinogen
~~l
(37) and
its green dehydration product called N,N,N,N-tetramethylporphyrin (38)[”l whose syntheses have been attempted for
40 years.
8. Conclusion
The question as to why natural product biosynthesis proceeds via relatively few key building blocks and in essentially
a similar fashion in all organisms deserves special attention.
One reason may be that it would be rational if a large range
of natural products were formed via as few as possible versa437
tile intermediates. Organisms whose metabolism did not develop in accordance with this principle would then be inferior and would disappear during evolution. A further possible explanation may be that most of the key building
blocks of natural product biosynthesis already existed on the
surface of the earth over three billion years ago.
In experiments on the simulation of the “primeval atmosphere”lss. 861 (water, methane, hydrogen, ammonia), it was
shown that, under the influence of radiant energy, a “primeval soup” was formed. This “primeval soup” contained prac-
+
+I..2.1
H$
1
1
H-C‘O
+
- CH3
+i
I
CH3-CZ
OH
Fig. 1 1 . Fundamental prebiotic reactions.
tically all the substances (amino acids, fatty acids, sugars, purine bases, porphyrins etc.) which, as is now known, are necessary for the metabolism of living organisms. Synthesis of
all these compounds is, according to modern mechanistic
concepts, easy to explain (see e. g. Fig. 11, 12[Xh-X81).
H-CH=O
A+
cn2= 0
0
1 ..e
CH2-0:
1
CH=O
OZCH- H
I
i +):
HO-C
I
H-CH=O
:i+
t
O=CH-H
1 + j ;
-H
+ H-C-OH
I
HO-C-H
I
H-C-OH
I
H ,- CH = 0
!(+
I
O=CH-H
Fig. 12. The synthesis of hexoses from formaldehyde in a simulation experiment.
The aim of this article has been to show what the key
building blocks of natural product biosynthesis are and their
significance in chemistry and medicine. Research on key
building blocks in natural product chemistry has led to a plethora of interesting results with many different applications.
Many-even
complex-natural
products are apparently
compounds which were selected out during evolution not
only for their biological activity but also on account of their
especially simple mode of formation. An understanding and
simulation of this mode of formation could, in the future,
lead to simple total syntheses of useful, biologically active
natural products.
438
I am especially indebted to the co-authors of our publications
cited. Their enthusiasmf o r thematically and methodically multifarious problems made possible the exploration of the relationships described. Generous support b-v the Deutsche Forschungsgemeinschaft, the Landesamt f l r Forschung in Nordrhein- Westfalen, and the Fonds der Chemischen Industrie is
gratefully acknowledged.
Received: November 23, 1978 [A 262 lE]
German version: Angew Chem. Y2. 453 (1979)
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