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New Naturally Occurring Amino Acids.

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New Naturally Occurring Amino Acids""
By Ingrid Wagner and Hans MUSSO*
Dedicated to Professor Hans Brockman on the occasion of his 80th birthday
The majority of the 500 or so naturally occurring amino acids known today were discovered
during the last 30 years, for example during the search for new antibiotics in the culture media of microorganisms, or as components of the antibiotics in fungi, seeds, in numerous
plants and fruits, and in the body fluids of animals. Some 240 of these amino acids occur
free in nature, some only as intermediates in metabolism. This article provides an overview
of the developments that have taken place in this area since 1956 when the last review appeared. Summary accounts are presented, dealing with new unsaturated amino acids, cyclopropane- and cyclobutane-amino acids, heterocyclic amino acids, halogen-containing amino acids, sulfur-, selenium- and phosphorus-containing amino acids as well as aliphatic
amino acids. In a few cases, e.g. betalamic acid and muscaflavin, the biosynthesis is described in detail.
1. Historical Introduction
In 1820 glycine was isolated from gelatin hydrolyzates.
In the following 100 years the remaining twenty amino
acids, which are normally found in proteins, were identified. Only four more were found between 1920 and 1940.
With the development of chromatographic methods the
number of known naturally occurring amino acids increased rapidly. In 1956 alone over 60 new ones were reported[']. At the moment 500 are known, of which ca. 240
occur free in nature. Still further naturally occurring amino
acids are being found each
The methods of detection and determination of structure
have improved so much in recent years that traces of a new
fluorescent spot can be discerned in the two dimensional
chromatogram of the dansyl derivatives (dansyl = 5-dimethylamino-l-naphthyl~ulfonyl)[~-~~.
Combined GC-MS of
the N-trifluoroacetyl-methyl ester derivative^'^' confirms
that the sample is homogeneous and provides an empirical
formula and often a hint as to the structure, which can be
corroborated by 'H- and I3C-NMR on a few mg of the
amino acid. In particularly difficult cases, such as for example streptolidinis"], an X-ray structure analysis is also
necessaryisb1.Nowadays one can determine the enantiomeric purity, usually to better than 0.1%, by gas chromatography of volatile amino acid derivatives on a peptide-ester stationary phase. Equally good results are obtained by
chromatography of the free amino acids as diastereoisomeric copper complexes with L-proline on octadecylated silica-gel with aqueous eluents[']. The absolute configuration
can be easily determined from CD spectra if a characteristic longwave transition can be produced by making a complextIoal or a dinitrophenyl derivative"ob1. If there are a
number of chiral centers the unambiguous assignment of
all the isomers is possible through stereospecific synthesis,
[*I Prof.
I**]
816
Dr. H. Musso, I. Wagner
Institut fiir Organische Chemie der Universitat
Richard-Willstatter-Allee2, D-7500Karlsruhe (Germany)
For many of the new amino acids a collective reference, or one to the
most recent synthetic work, is given when possible.
0 Veriag Chemie GrnbH, 6940 Weinheim, 1983
as for example in the case of 3-hydro~yprolines["~
(cf. 39
in Section 4.1) or (-)-S-(2-carboxypropyl)-~-cysteine['~~
(cf. 151 in Section 6).
2. Unsaturated Amino Acids
Thermocymocidin 1 from a thermophilic Eumyces spec i e ~ ~ and
~ ~ myriocin
, ~ ' , ~from
~ ~the thermophilic fungus Myriococcum albomyce~['~~
are identical, both in their constitution, with a trans double-bond, and in their activity towards molds.
OH
COzH
CHzOH
OH N H 2
2
1
3
From the seeds of the bush Staphylea pinnata are obtained pinnatanine 2 and oxypinnatanine 3 ; the absolute
configuration of the dihydrofuran moiety of the latter has
been established by X-ray analysid3'].
a-Methylene-b-alanine is toxic and is found as its N-acetyl derivative in Hawaian sponges'I5J; 0-methylene-L-norvaline is found in the fungus Lactarius h e l ~ u s [ ~p-methy~I,
lene-L-norleucine in Amanita vaginata[2a1and (2S,3S)-3-hydroxy-4-methyleneglutamicacid in Gleditsia ca~pica[~gl.
yPropylidene-L-glutamic acid was isolated from Mycena
pura together with y-methylene- and y-ethylideneglutamic
acid[3i].Amino acids with methylenecyclopropyl units like
13-15 will be mentioned in Section 3. Further unsaturated
naturally occurring amino acids, mostly not bound to proteins, are presented in Table 1.
Together with the amino acids containing one or more
double bonds there are also some with triple bonds. The
0570-0833/83/1111-0816 $02.50/0
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
Table 1. New unsaturated amino acids.
Unsaturated Amino Acid
Isolated from
~-2-Amino-4-(2-aminoethoxy)-trans3-butenoicacid
2-Amino-4-(2-amino-3-hydroxypropoxy)-trans-3-butenoic
acid
4-Acetamido-2-butenoic acid
~-2-Amino-3-formyl-3-pentenoic
acid
~-2-Amino-3-hydroxymethyl-3-pentenoic
acid
~-2-Amino-4-chlor-4-pentenoicacid
trans-2-Amino-S-chlor-4-hexenoic
acid
2-Amino-4-methyl-5-hexenoic
acid
2-Amino-5-methyl-4-hexenoic
acid
2-Amino-4-methyl-4-hexenoic
acid
2-Amino-6-hydroxy-4-methyl-4-hexenoic
acid
~-2-Amino-6-hydroxy-5-methyl-4-hexenoic
acid
2-Amino-4,5-hexadienoic acid [a]
2-Amino-4-methyl-5-hexynoic
acid
2-Amino-4-hydroxy-6-heptynoic
acid
2-Amino-4-hydroxymethyl-S-hexynoic
acid
2-Amino-3-hydroxy-4-hexynoic
acid
2-Amino-4-hexynoic acid
Unidentified streptomyces
Rhizobium japonicum
Fusarium graminearum
Bankera fulgineoalba
Bankera fulgineoalba
Amanita pseudoporphyria
Amanita solitaria
Tricholomopsis rutilans
Leucocortinarius bulbiger
Aesculus californicus
Aesnrlus californicus
Blighia unijugata
Amanita solitaria
Ref.
Euphoria longan
Tricholomopsis rutilans
a New-Guinea fungus
[a] This hexadienoic acid can be regarded as a precursor in the biosynthesis of hypoglycine A 14.
poly-yne amino acids 4 and 5, which are produced by the
fungus Fayodia bisphaerigera in its advanced stage of
growth[l7],and which are isolated as the methyl esters, are
rather special. It is assumed that they are formed in nature
by acylation of the amino acids with the hydroxyenetriynoic acid since this acid is found together with 4 and 5 in
the same fungi. The synthesis was accomplished by coupling of the propiolylated amino acid with the hydroxyenediyne bromide.
as sole source of nitrogen for the bacterium Pseudomonas
sp. ACP and for the yeast Hansenula saturnus, which
deaminate it enzymatically to a-oxobutyric acid 8["l. On
hydrogenation with F't in glacial acetic acid, a-aminoisobutyric acid 9 is formed predominantly owing to the substituent effect'"', whereas in alcoholic ammonia, a-aminobutyric acid 10 is the main product[221.Similarly, in the hydrogenation of coprin 11the CH2-CH2 bond in the cyclopropane is opened to give 12. This amino acid was isolated from Coprinus atrarnentariu~'~~'
and is responsible for
the antabuse effect of this fungus"'.
3. Cyclopropane and Cyclobutane Derivatives
1-Aminocyclopropanecarboxylicacid 7 was first discovered in the late 1950s, bound to cranberry protein, and
later in apples and pears"''. This amino acid is an intermediate in the biosynthesis of
which acts as a
plant growth reguIator. In this process methionine is converted enzymatically via an adenosine complex 6 into 7
and methylthioadenosine; 7 is not, however, released but is
immediately split into ethylene and glycine-most probably while complexed with an enzyme. In addition, 7 serves
Adenosi
[*I The antabuse effect is the sensitization and intolerance of an organism towards alcohol caused by a drug.
J?
6
-t
8
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
1-Amino-2-ethyl-1-cyclopropanecarboxylicacid, also
known as coronamic acid, is a component of the toxin coronatin found in Pseudomonas coronafacience var. atropurpurea["'.
a-(Methylenecyc1opropyl)glycine13, the corresponding
alanine derivative hypoglycine A 14, and hypoglycine B
NH3
9
10
817
(the dipeptide from 14 and Glu["I) have been isolated
from the unripe fruit of Blighia sapida and from litchi
seeds[2b1.Compounds 13 and 14 reduce the blood-sugar
concentration so drastically that eating the unripe fruit can
lead to lethal hypoglycemia. Catalytic hydrogenation of 13
gave norleucine, leucine, and isoleucine (a, b, and c).
mugineic acid 25 from oat rootsf291,and clavulanic acid 26
from Streptomyces c l a v u l i g e r u ~ Nicotianarnine
~~~~.
has also
been shown to be the normalization-factor in tomato mutants['*', while 26 acts as a 0-lactamase inhibitor13".
4. Heterocyclic Amino Acids
4.1. Proline Derivatives
Besides 4-hydroxy-~-proline27 and the 4-allohydroxyL-proline 28 with cis-L-configuration, aIready discovered
by H. Wieland and B. Witkop in 1940[311,
the D-form ent-28
has also been noted as a structural unit in the antibiotic
etamy~in~~'].
4-Hydroxymethylproline 29 has been isolated
B-(Methylenecyclopropy1)-fbmethylalanine15 has been
found in the seeds of Aesculus ~alifornia'~"~,
while cis- and
trans-a-(carboxycyclopropyl)glycine, 16 and 17, can be
isolated from the seeds of Aesculus pamiflora and Blighia
sapida re~pectively~~"].
Blighia unijugata contains the homologous carboxymethyl derivative 18 as well as Lexo(cis)-3,4-methanoproline 19. The broad-spectrum antibiotic azirinomycin 20L3d1
from Streptomyces aureus is, as
expected, unstable in concentrated solutions; catalytic hydrogenation of 20 gives L-a-aminobutyric acid.
17, R
18, R
16
19
= CO2H
=
CHz-COzH
COzH
I Y
20
2,4-Methanoproline 21 and 2,4-methanoglutarnic acid
22 from the seeds o f the legume Ateleia Herbert Smithii126,271
both have the base peak corresponding to 23 together with other common fragment peaks in their mass
spectra.
21
22
2 4 , R = H, R ' = N H z
2 5 , =~R' = OH
23
26
Other new azetidine derivatives have been reported such
as nicotianamine 24 from the leaves of Nicotiana tabacum,
818
R'
?
P
QH
31,R= H
32,R
=
33
OH
= CHz
from
and from Eriobotryajaponica12b1,as has also
4-methylene-D,~-proline30/ent-30. Both 5-methyl-4-0x0prolines 31 and 32 and 3-hydroxy-5-methylproline 33
were found in the peptide lactone ring of the antibiotic actinomycin Z1[11,2fl,
while 5-methylproline has been found
in actinornycin Z513q.N-Methyl-4-hydroxyproline 27, with
NCH3 replacing NH and also known as betonicin, occurs
in many plants, one of which is y a r r o ~ [ ~ ~ ~ ~ ~ I .
To illustrate how configuration can be established by
stereoselective synthesis we shall outline the case of trans3-hydroxyproline 39, isolated by ion-exchange chromatography from collagen hydrolyzate. 39 was later also found
in Mediterranean sponges as well as in the antibiotic telomycin; the cis-isomer 41 is found only in the antibiotic136,371
In the hydroboration of N-benzoyloxycarbonyl-3,4-dehydro-D,L-proline methyl ester 34/ent-34 the molecule is
attacked preferentially from the back side; oxidation with
alkaline hydrogen peroxide gives a mixture of 68% trans-3hydroxyproline 36/ent-36, 10% trans-4-hydroxyproline
37/ent-37 and a trace of cis-4-hydroxyproline 38/ent-38,
in each case as the N-protected derivative. Oxidation of 36
with chromic acid gives the keto ester 40 which is also attacked from the rear by NaBH,. Alkaline ester hydrolysis
and catalytic hydrogenolysis of the protecting group on the
nitrogen gives the pure amino acids 39 and 41 (from 36
and 40 respectively).
The N-methyl derivatives of trans- and cis-3-hydroxyprolines 39 and 41, with NCH3 replacing NH, have been
~~~;
isolated from the ripe fruits of Courbonia ~ i r g a t a [the
trans-trans-3,4-dihydroxyproline42 is one of the seven
amino acids in virotoxin from the Destroying Angel toadstool"91 and the cis-trans-isomer is a component of a protein obtained from
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
H4
1
I
C bz
34
Cbz
36
35
0
PH
-
G
NaBH4
p H 0 z H
H
p ;I z C H 3
H
Cbz
40
39
41
(2S,3S,4S)-3-Hydroxy-4-methylproline
44 is found in
the antibiotic enchinocandin B13". The kainic acid 4SL401,
its
C-4 epimer allokainic acid 5314*'and the domoic acid 461421
have been isolated from the alga Digenea simplex. Because
of interest in the neuron-stimulating activity of these compounds enantioselective syntheses have been developed.
I
R"'R
R"!.,I,n'
42
""'4344
(Hb C 0 Z H
R
R'
OH
H
OH
H
H
OH
""H
z
H
z' 'z
bond has been esterified with an optically active menthol
derivative. Initiated by diethylaluminum chloride, 50 gives
mainly the compound with the desired configuration 51
(95%) together with 5% of the unwanted stereoisomer 52.
When the starting material 50 contains a trans double
bond the product ratio changes to 15 :S5r4'1.
OH H
CH3 H
(-)-a-Kainic acid 45 with the natural configuration was
obtained from a glutamic acid derivative 47 by a thermal
ene-reaction 48-49 with the induction of the (S,S)-configuration on the new chiral centers in 49 followed by removal of the silyl protecting group, oxidation, and ester
hydrolysis[401.The epimeric (+)-a-allokainic acid 53 is obtained by an analogous ene-reaction of the malonic ester
50, in which the carboxy group attached to the cis double
57
58
Other proline derivatives are a new amino acid 54 from
Pentaclethra ma~rophylla[~~'
and acromelic acids A 55 and
B 56 which were isolated from the poisonous toadstool
Clitocybe a~rornelalga[~~'.
cis-3-Amino-~-prolinefrom Morchella e s c u l e r ~ t aand
[ ~ ~ 4-carboxy-~-proline
~
from Chondria
coerule~ceus~~j~
should also be mentioned here. Cucurbitin
57IW1obtained from the cucurbitaceae is no more a proline
derivative than the pyrrolidineglycolic acid 58, which was
found to be a component of the depsipeptide detoxinDl-"'.
I
I
C0Z-t
47
I
cozi
COZ+
48
4.2. Piperidine, Pyridine, Quinoline, and Azepine
49
Derivatives
0
0
51
95 : 5
'COzH
53
Angew. Chem. Inf. Ed. Engl. 22 (1983) 816-828
52
Many new amino acids are derived from the long known
pipecolic acid. The N-y-L-glutamyl derivative 59 occurs in
the seeds of Gleditsia caspica12b1.
The 3-hydroxy acid was
found in halophytesfza1,the L-4-hydroxy acid in Peganum
harmala and the 4,s-dihydroxypipecolic acid 60 in Gymnocladus dioi~us'~".
(2S,SS,6S)-5-Hydroxy-6-methylpipecolic acid 61 and its 5R-epimer are found free in Fagus sil~atica'~'].
Trichoponamic acid 62 was isolated from Trichoderma poly~porurn~~'~.
5-Aminomethyl-5-hydroxypipe~oIic
acid 63 could be
identified in the hydrolyzate of Pseudomanas
(2R,4S)-2-acetylamino-4-piperidinecarboxylicacid 64 is
found in the leaves of Calliandra haernat~cephala[~'~.
819
ceps sp. is possibly an intermediate in the biosynthesis of
lysergic acidPbJ.
The L-configuration of piperidazinecarboxylic acid 77
from monamycin has been correlated with that of L-ornithine; the configuration of the two D-amino-acids 78 and
79 from the same antibiotic was similarly established[3b1.
H
62
H
H H H
63
64
H
o
e
HO O H
The pyridine derivative 65 is present as the N-terminal
amino acid in the antibiotic n i k k o r n y ~ i n [ ~ .while
~ ' ~ , the
triamino acid 66 occurs in the bone collagen of
80
HN
OH
COzH
wo2H
COzH
H O h ( C H z),T(
HO
KHZ
,
KH2
NH2
N
n + m = 3
65
66
OH
The tetrahydroisoquinolines 67 and 68 were isolated
from the seeds of Mucuna mutisiana and M. deeringianaIZbl. Tris-0-methylpeyoxylic acid 69 and its methyl
derivative 70 were found in extracts of the peyote cactudZb1,in which the possible precursor dihydro compounds
mescaloxylic acid 71 and mescaloruvic acid 72 are also
detected[2b1. The 6-hydroxy-1-methylcarboxylicacid 73
was isolated from Euphorbia rnyr~inites'~"]
and 3,4-dihydroxy-2-quinolinecarboxylic acid 74 from the sponge Aplysina aerophoba""'.
82
83
Transfer-RNA from E. coli contains the modified uridine 8013g1.
Lupinic acid 81 from the seeds of Lupinus ang u s t i f o l i ~ s and
[ ~ ~ discadenin
~,
82 from Dictyostelium discoideum as well as sinefungin from streptomyces griseol~s"~'~
are purine derivatives with amino acid residues.
84, R, R
85, R , R
=
=
H, H
;C=O
86
HO
R
COzH
67, R = H , R ' = COzH
68, R = CH3, R' = H
69, R = H
70, R = CH3
. o q H c o z H
71, R = H
72, R = CH3
OH
87
'
N'
COzH
CH3
73
74
5-Hydroxy-~-tryptophanappears in several plants['"',
Na-methyl-4-(3-methyl-2-butenyl)-~-tryptophan
75 in Lotus subglaucaE2a1;
the cyclic clavipitic acid 76 from Clavi-
75
820
76
77, R = OH, L78, R = H, D79, R = C1, D-
Compounds such as the pigment of 83 from the blossom
of Lachanthus tin~toria[~'],
the alkaloids like 84[481from
pseudobactin as well as compound 85l3"lfrom the hydrolyzate of a fluorescent peptide produced by Azotobacter vinelandii, and antibiotics such as malonomycin 86[491
or the
ionophoric antibiotic X-14547A 87[501
are formally amino
acids or related compounds but have little in common with
the amino acids dealt with here. The tetrahydropyridine
and dihydroazepine derivatives which follow, however, are
produced in ordinary amino acid metabolism.
The elucidation of the structures of the betalaine pigm e n t ~ [ ~ from
" ~ ~ ]higher plants, such as the betanins and
vulgaxanthins from red beetroot (Beta vulgaris) or rnuscaaurins I and I1 from fly agaric (Amanita muscaria), has
revealed a number of new amino acids. Mild hydrolysis of
Angew. Chem. Inr. Ed. Engl. 22 (1983) 816-828
ley[561
has recently established the biosynthesis of the more
or less unsaturated pyrrolidine moieties of the antibiotics
anthramycin, tomaymycin, sibiromycin and lincomycin
from tyrosine. To explain these results a cyclization of the
same intermediate B 99 to compounds like 98 is required.
betanidin 88 gives cyclodopa 89 and betalamic acid 90;
similar treatment of rnuscaaurin I 91 gives ibotenic acid 92
and 90, while muscaaurin I1 93 gives, together with 90,
stizolobic acid 97, which had been isolated shortly before
from Stizolobium hassio. The origin of cyclodopa 89 from
tyrosine 94 and dopa 95 is quite clear. For the formation
of betalamic acid one must imagine an oxidative opening
of the benzene ring adjacent to the hydroxy group in 95 at
point 'a' and a recyclization of the intermediate A 96 by
condensation between the amino group and the enolized
a-keto acid. This biosynthetic route has been confirmed in
uiuu with I4C- and 3H-labeled t y r ~ s i n e ' ~ ~If, the
~ ~ 'interme.
diate A 96 undergoes hemiacetal formation followed by
oxidation to a lactone, stizolobic acid 97 is obtained. This
pathway has also been confirmed with labeled precursors
in the legume Stizolobium hassio.
4.3. Oxygen Heterocycles
Related to the a-pyrones 97 and 101 are three epoxides
and three furan derivatives. Anticapsin 102 is produced by
Streptomyces grise~planus[~~],
the chloramphenicol antagonist 103 by Streptococcusfuluoviolaceous~3k1,
and (2S,9S)-2amino-9,1O-epoxy-8-oxodecanoic
acid from chlamomycin
a cyclic peptide with extreme cytostatic activity"061.~-p-(4Carboxy-3-fury1)alanine 104 occurs free in Phyllotopsis ni-
HO
HZi-4
'
92
H z V
Hs no m CN O z H
H
89
~o',cJ-.,J-co
HOzC QCOzH
H
HO~C
J+c
H
z~
88
\
H
HOz C
93
6
JHzO
-
Ho2&
HO
HO
O~H
HO~C
91
a
HH?
al
O~H
+
90
COzH
--j
94
-
HOt(cozH
98
B99
100
A further yellow amino acid, muscaflavin, was isolated
from fly agaric and identified as the dihydroazepine derivative 100. This biosynthesis could be explained in terms of
a cleavage of the benzene ring in dopa 95 at point 'b', followed by a cyclization of the intermediate B 99 analogous
to that of A 96. Oxidation of the hemiacetal of 99 yields
stizolobinic acid 101 isomeric with 97, which, together
with 97, occurs free in small amounts in beans and fungi.
The unstable betalamic acid 90 has already been detected
as the free amino acid.
In the synthesis of muscaflavin 100 the formation of the
intermediate B 99 by opening of a protected pyridine derivative was proposed. In fact the seven-membered ring in
100 is formed in this way, but first the preferred cyclization to a five-membered ring, a derivative of 98, takes
place['*'. This observation is of great interest, since HurAngew. Chem. Inf. Ed. Engl. 22 (1983) 816-828
101
dulans and the fruiting bodies of Tricholomopsis rutil ~ n s [ ~N-Methyl-fL(3-furyl)alanine
~'.
105 is found in the
cyclopeptide rhizonin A, a mycotoxin from Rhizopus mic r o s p o r u ~ ~Lycoperdic
~~'.
acid 106 was isolated from the
fungus Lycoperdon p e r l a t ~ r n [ ~ ' ~ .
102
103
104, R
105, R
=
=
H, R'= COzH
CH3, R'= H
821
4.4. Isoxazoline Derivatives
4.5. Cyclic Guanidine Derivatives
Ibotenic acid 92 from Amanita muscaria has already
been mentioned; it occurs in this toadstool in quite large
amounts and decarboxylates readily to muscimol 109 and
rearranges photochemically to muscazone l10[581.
Because
of its alleged psychotropic activity improved syntheses of
muscimol are repeatedly being developed[591.In the most
recent method[59c1N-hydroxyurea was added to dimethyl
acetylenedicarboxylate to give 107. The corresponding
amide 108 was then reduced with borane-dimethyl sulfide,
thus providing 109 in three steps in ca. 30% yield.
These compounds all occur as building units in the peptide antibiotics from microorganisms and are structurally
and stereochemically related to arginine[3c1.The structure
of the strongly basic amino acid streptolidin 119, obtained
from antibiotics such as streptolin, streptothricin and geo-
,NHR
120, R
H~COZC-C-C-CO~CH~ HO
-z
= CH3
0
124 CH3 H
H
\
125
109
111
126
NHz
110
112, R
113
= Glucosyl
114
X
R
OH
Cl
C1
Br
H
H
OH
H
The two oxazolidines 111 and 112 were isolated from
young pea seedlings and identified by spectroscopy and
degradation. Treatment with weak base and subsequent
acid hydrolysis gave a$-diaminopropionic acid from 111
and D-glucose and glutamic acid from 112. It was suggested that these highly UV-sensitive compounds take part
in a photobiological process[3c1.They were also detected in
other leguminosae, e. g . Lathyrus odoratus, in which 2-amino-4-(5-oxo-2-isoxazolyl)butyric acid 113 also occurspg1.
The constitution of quisqualic acid 114 with the L-configuration from Quisqualisfructus could be proven by synthesisph! Tricholomic acid 115 has been isolated from Tricholorna[601and the chloroisoxazolidine derivatives 116 and
117[3h1,
with antibacterial and antitumor activity, from cultures of Streptomyces sviceus. Here again synthetic routes
were investigated[611,of which the 1,3-dipolar addition of
bromonitrile oxide to vinylglycine to give 118 proved to be
successfuI[6'b1.
822
CH3
mycin by hydrolysis, which has been a subject of controversy was established by X-ray analysis and by synthesis
from chiral sugar units[8bz621.
In the case of the N-methyl
derivative 120, similarly obtained from a streptothricintype antibiotic, the configuration of the OH group is still
The two a-epimers enduracididine and alloenduracididine 121 have been isolated from e n d ~ r a c i d i d ~ ~ ] .
The two six-membered ring guanidine derivatives tuberactidine 122 and viomycidine 125'3c1
were obtained from the
hydrolyzate of the highly antitubercular tuberactinomycin,
and the capreomycidine 123 from the equally active cap r e ~ m y c i n ' ~The
~ ] . relative and absolute configurations of
stendomycidine 124 from the peptide antibiotic stendomycin have been established as L-erythro, mainly by ORD[3c1.
Tetrahydrolathyrine 126 has been isolated from Lanchocarpus costari~encis[~'1.
5. Halogen-Containing and Other Aromatic Amino
Acids
The chloro- and bromo-derivatives 127-131 of tyrosine
were isolated from the hydrolyzates of the scleroproteins
of molluscs. Halogenated tryptophane also occur in nature; the betaine 6-bromo-~-hypaphorine132 in legumes
cop
3R*cR
H
R
127
128
129
130
131
R
O
NH2
h COzH
R'
C1 H
C1 Br
Br H
c1 c1
Br Br
R
132
133
134
135
R
H
R' R" R3
Br H H
H C1 H
H H C1
H H C1
(CH3)3
H3
2H,COCHZCOzCZH5
2H, COCH2COzCH3
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
Before turning to sulfur-containing heterocycles, a few
more phenylalanine derivatives from higher plants should
be cited : the hydroxymethyl compounds 139 and 140 from
Caesalpinaia tinctoria and the p-aminophenylalanine 141
from Vigna vexiIIata'2b1.
The dimeric tyrosine 142 was identified as a component
of alkali-soluble connective tissue protein'2b1and may have
been formed by phenol oxidation'661. Whether the antibiotic ristocetin, which is reminiscent of 136 and 137, or
ristomycin A 14313'] is formed analogously is an open
question. Pretyrosine 144, derived from prephenic acid in
the blue-green alga Pseudomonas aeruginosa, is of biosynthetic interest, being enzymatically converted into phenylalanine or tyrosine 94f671.
Acid degradation of 144 gave
phenylalanine. Further dihydroarenes are: ~-$-(1,4-cyclohexadieny1)alanine 145 from rats, Leuconostoc destranicum
and streptomycetedZa1;the amino acid antibiotic L-2-amino-4-(4-amino-2,5-cyclohexadienyl)butyric acid 146L3*1;
and sponges[641and 5-chloro-~-tryptophan133 as a component of the antibiotic longi~atenamycin[~'~.
The positive
Cotton effect indicates, as in the case of D-tryptophan, a
D-configuration, which was confirmed by the ozonolysis of
133 to D-aSpartiC acid. The 4-chlorotryptophan derivatives
134 and 135 isolated from Pisum sativum also belong to
the D-seriesl2"!
Antibiotics from the vancomycin group contain as a
structural unit the unusual vancomycinic acid 136, which
itself contains 3-chloro-$-hydroxytyrosine units; the
monochlorotricarboxylic acid 137 occurs in the glycopeptide antibiotic actinoidin and 3-chloro-4-hydroxyphenylglycine 138 is a component of the antibiotic LL-AV290'3g1.
Two other chlorine-containing amino acids have already
been mentioned with the unsaturated amino acids in Table
l[3g,3e1
and the chloroisoxazolines 116 and 117 in Section
4.4.
H02CAiXH2
Hfi
A
138
CO2H HzNhCO2H
136, R = R ' = C1
137, R = H, R ' = C1
( +)-trans-2,3-dihydro-3-hydroxyanthranilicacid from Str.
R "
HO
HZN
''
-
aureofaciens S-652f681. ~-8-(2,5-Dihydroxyphenyl)alanine
from streptomycetes[2a1and N-carbamoyl-2-(4-hydroxypheny1)glycine from the leaves of Vicia fabdZa1,3-carboxy-~~],
tyrosine from the seeds of Reseda ~ d o r a t a ' ~3-formylaminosalicylic acid from antimycin A3['01, alternamic acid
14717*'from the toxin alternariolide in Alternaria mali,
blespharismone 148 from Blespharisma japonicum and finally the oxime of the p-hydroxyphenylpyruvic acid[3h1
from the sponge Hymeniacidon sanguinea are all new
derivatives of aromatic amino acids.
COzH
H zN
142
HO
COzH
-
H-02,
NHz
144
143
~
6. Sulfur-, Selenium- and Phosphorus-Containing
Amino Acids
C
O
Z
H
r\: Hz
145
Many new sulfur-containing amino acids from the plant
and animal kingdoms are derivatives or homologues of
cysteine and methionine (Table 2).
Table 2. New sufur-containing amino acids.
Sulfur-containing amino acid
isolated from
N-Formylmethionine
Clostridium pusteurianum.
rubredoxin, the thorax of the honey bee
thorax of bees
cabbage
red algae
human urine
N- Acetylrnethionine
L-Homomethionine
N-Methylmethionine sulfoxide
S-(2-Carboxy-2-hydroxyethylfcysteine
S-(Carboxymethy1)homocysteine
S-(3-Carboxy-3-hydroxypropyl)cysteine
S-(3-Carboxy-3-hydroxypropylthio)homocysteine
S-(2-Carboxy-2-hydroxyethylthio)homocysteine
S-(3-Carboxy-3-hydroxypropyl)homocysteine
S-(Carboxymethy1thio)homocysteine
S-(Z-Carboxy-2-hydroxyethylthiomethyl)-L-cysteine
Cystathionine sulfoxide
Perhydro-l,4-thiazepin-3,5-dicarboxylicacid
a-S-Cysteinylthymine
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
Ref.
urine of cystathionuric and homocystinuric patients
)Acnciu georginue
urine of cystathionuric patients
collagen from cattle hones
823
(-)-S-(2-Carboxypropyl)-~-cysteine151'121
is found in
the glutathione-like tripeptide from onions and garlic and
is converted into trans-S- 1-propenyl-L-cysteine S-oxide
152, the precursor of the lachrymatory principle of the onion"]. Asparagusic acid 153[731
found in asparagus, is also
formed from 151. The absolute configuration of 151 was
established by the synthesis of both stereoisomers. Both
enantiomers of 3-mercapto-2-methylpropionic acid ester
149 were reacted with the aziridinecarboxylic acid ester
150, which is readily available from L-serine, in the presence of BF, to give 151. After removal of the protecting
group only 151 derived from (S)-149 showed a negative
optical rotation corresponding to the natural acid["].
Further examples are the cysteine derivative isovalthine
1%'741,
which was first isolated some time ago from the
urine of people with an excessive cholesterol level, dichrostachinic acid 155[751
from the seeds of Dichrostachys glomerata, ~-1,4-thiazinane-3-carboxylic
acid 156[3k1from the
alga Heterochordaria abietina and dopa with two cysteine
residues 157'3h1from the eyes of the alligator gar Lepisosteus spatula.
.H
C02Et
150
( S )- 149
(S)-151
S
?>C02H
152
153
157
156
160
163, R = H
164, R = CH( CHJ2
165
fi&
166
167
168
169
ponents of a cyclic peptide from the sea hare Dolabella auricularia'sol, 164'8'a1 from ascidiacyclamide, the sec-butyl
isomer of 164 from bacitracin['Ib1and related compounds,
the absolute configuration of which can be derived from
degradation products obtained with singlet 02182c1,
the bithiazolylcarboxylic acid 165 as the N-terminal amino acid
of the anticancer antibiotic bleomycin AJs2I, aeruginic acid
166'831from Pseudomonas aeruginosa, 167'841from Streptomyces antibioticus, berninamycinic acid 168 from the antibiotic berninamycin A[s51and the penicillin-like antibiotic
thienamycin 169r861conclude the list of new sulfur-containing amino acids.
Several examples of selenium- and phosphorus-containing amino acids have been confirmed. Selenocysteine was
identified as amino acid No. 35 in the peptide chain of the
enzyme glutathione peroxidase from cattle erythrocyte^'^^],
Se-methylselen~cysteine[~~~
was found in Astragalus bisculatus, ~elenomethionine'~~
in lima beans and selenocystathionine 170r2a1 in Morinda reticulata. The N-Phosphonosulfonimidoxyl derivative 171'3'1 was isolated from an unclassified Streptomyces as a metabolite.
158, R = H
159, R = S-dimer
161
5-Mercapto-l-methyl-~-histidine158 can be separated
from the hydrolyzate of the Fe"'-binding adenochrome of
Octopus vulgaris. Recently 158 has been found in the eggs
of sea urchins which also contain the corresponding disulfide 159[761.
The mercaptohistidine derivatives clithioneine
160"71 and S-(2-amino-2-carboxyethyl)ergothionine161[781
were isolated from the toadstool Clitocybe acromelalga and
Neurospora crassa, respectively.
fb(2-Thia~olyl)-~-alanine'~~~
162 from bottromycin and
the other thiazole derivatives such as 163 which are com-
824
162
HNR'
H
OH
-r
175
CH3 H
I76
CH3 P O 3 2
~-2-Amino-5-phospho-3-pentenoic
acid 172I3']occurs in
a tripeptide from Streptomyces plumbeus. The phosphate
ester of 4-hydroxypipecolic acid[3kJwas isolated from PelAngew. Chem. Int. Ed. Engl. 22 (1983) 816-828
tophorum. Phosphinothricin 173[3g1is the N-terminal amino acid in a tripeptide, with two alanine residues, which is
a component of an antibiotic. L-Lombricine 174 from
Lumbricus terrestris is also found in smaller quantities in
the marine worm 77zalassema neptuni, from whose muscles
the N",Na-dimethyl derivative, L-thalassamin 175, and Nphosphothalassamin 176 were i s ~ l a t e d ~ ~ " ~ ~ ~ ~ .
I. Aliphatic Amino Acids
New amino acids whose constitutions differ only
slightly from the regular protein amino acids have also
been found in large numbers. Because of the rarity of the
nitrile group in nature[891,fi-cyanalanine from the embryos
of Vicia sativa and Acacia georginae'"' and ~-2-amino-4cyanobutyric acid from Chromobacterium violaceum cultures, which contain cyanide ion in the nutrient solution[3cJ,
are mentioned first.
butyl-~-homoserine[~~l
from Corynebacterium ethanolaminophilurn, D-allothreonine from pse~dobactin[~*],
threo-L2-amino-3,4-dihydroxybutyric
acid[2a1and L-fi-hydroxynorvalinec2"'from microorganisms, (2S,4S)-( i)-y-hydroxynorvaline and the (4R)-( -)-epimerIZbJfrom Boletus satanus, 0hydroxyvaline[2h]from an antibiotic, (2S,3R,4R)-y-hydroxyisoleucinef2h1from the seeds of Trigonella foenurn-graecum, y,6-dihydroxyisoleucine[za1from Amanita phalloides,
as well as alanosine 177c931
from Streptomyces alunosinicus.
Finally, we have the following four N-hydroxyamino
acids: ~-2-amino-5-(l-hydroxyguanidino)valericacid (Nshydro~yarginine)[~~
from Nanniizzia gypsea, the D-enantiomer from the Fe(Ir1) complex pse~dobactin[~*],
N"-hydroxylysine from aerobactincg41and compound 178 from
the fly agaric[951which forms, in situ, the pale blue complex
amavadin with vanadium.
177
7.1. Neutral a-Amino Acids
a-Amino acids with the "unnatural" D-configuration
have been repeatedly found: D-alaninelzb'in the cell walls
of bacteria and also in higher plants, D-valine in valinomycin, and D-iSOkxICine'3b1in monamycin as well as D-Na, DPhe, D - A s ~and D-GIu in a toxic peptide lophyrotonin
from larvae of a fly (Laphyrotoma interrupta), which in
Australia can be fatal for
With the cyclic peptide
or peptidolactono-antibiotics the interesting question arises as to whether the D-amino acids are incorporated as
such or whether they are first built in as the L-amino acids
and then epimerized. In the latter case D-isoleucine must
be derived from L-alloisoleucine, which has not yet been
found in nature, although N-methyl-y-methyl-L-alloisoleucine is found in etamycin and triostin Crzal.Furthermore,
N-methylallois~leucine~~~~
was found in cycloheptamycin,
2-amino-4-oxopentanoic acid[2a1in Clostridium stricklandii,
and isoleucine, acylated on the nitrogen by jasmonic and
dihydrojasmonic acids, in the fungus Giberella fujikuroi[*"'.
Glutathione derivatives of leucotrienes play an important
role in the human body["].
178
7.4. Acidic Amino Acids and Diaminodicarboxyiic Acids
New amino acids in this group are: threo-$-hydroxy-Laspartic acidc3'] from streptomyces and the compound with
a D-configuration from the Fe(r1r) complex pseudobactinL4'],erythro-fi-hydroxy-L-asparticacidrza1from Astralagus
sinicus, fi-carboxyaspartic acid from the ribosomal protein
of E . ~ o l i [ ~threo-fi-methyl-L-aspartic
~',
acid[2a1from the antibiotic amphomycin, threo-$-hydroxy-L-glutamicacid1*"]
from streptomyces, (2S,4R)-4-methylglutamicacidczb1
from
Gleditsia caspica, (2S,3S,4R)-3-hydroxy-4-methylglutamic
acid[2b]from Gleditsia caspicu and from Gymnocladus dioicus, as well as fi-hydroxy-y-methylglutamic
from
the seeds of the Kentucky coffee tree.
179
7.2. a-Branched Amino Acids
These compounds are of interest as antimetabolites and
enzyme inhibitors, as for example a-methyldopa. They also
occur naturally; like a-aminoisobutyric acid (a-methylalanine) and ( -)-isovaline (2-aminovaleric acid, "fi-ethylalanine") in peptide antibiotics. According to the X-ray crystallographic analysis of the N-chloroacetyl derivative, (-)isovaline has the ~-configuration[~'],
and is readily available through Schollkopf's lactim-ether synthesis["] with 93%
enantioselectivity.
(2S,4R)-4-(fi-~-Galactopyranosyloxy)-4-isobutylg~utamic
179 from Resedu odorata is the first example, in the
higher plants, of a glycoside in which the sugar is attached
to the hydroxyl group of an aliphatic aminohydroxy acid.
Further acidic amino acids are: 2-amino-4,5-hydroxyadipic acid from human urine[3k1,2-amino-4-methylpimelic
from the fruiting body of Luctarius quietus, 2,6-
180
181
7.3. Hydroxy-a- Amino Acids
New hydroxy-a-amino acids are : N-(2-hydroxyethyl)glycine and -alanineLZa1
from the seaweed Petalonia jascia
and from Rumen protozoa, 0-ethyl-, 0-n-propyl- and O-nAngew. Chem. In;. Ed. Engl. 22 (1983)816-828
NH
zH
'COzH
182
825
diamino-3-hydroxypimelic acidrza1from the cell walls of
microorganisms, 2,6-diamino-7-hydroxyazelaic acid[3c1
from oat roots
from edeine A and B, avenic acid 180[971
(chelates with iron), arcamin 181[981
from Acra zebra and
strombin 182f981
from Strombus gigas.
7.5. Basic Amino Acids
New basic amino acids to be mentioned are: fl-acetamido-~-alanine~~"'
from Acacia armata, fl-(3-hydroxyureido)~-aIanine[~Ofrom streptomyces, ~-2-amino-3-(oxaIamino)propionic acid""' from Lathyrus sativus, 2-amino-3-(1hydroxyureido)propionic acid[3q from Quisqualis fwctus,
4-guanidinobutyric acid together with 2,3-diaminopropionic acid from the seeds of Trichosanthes cucumeroideP", 2,3-diaminobutyric acid from asparatocin (the Lthreo- and D-erythro forms occur in amphomycin)['"], 4amino-2-(6-methyloctanoylamino)butyric acid[*"]from Bacillus colistinus as well as ~-2-amino-4-(lactoylamino)butyric acid[2b1from Beta vulgaris. 0-(2-amin0-3-hydroxypropyl)homoserine, dihydrorhizobitoxin and the corresponding B,y-unsaturated 2-amino-4-(2-amino-3-hydroxypropoxy)-trans-3-butenoic acid 183[zb1,known as rhizobitoxin,
were isolated from Rhizobium japonicum. 183 deactivates
f3-cystathionase in bacteria and plants and prevents the formation of ethylene from methionine (see 6 and 7 in Section 3). 6-hidinooxy-L-norvaline was isolated from a
bacterial
Other new basic amino acids are: 2,4diaminovaleric acidIZa1 from Clostridium stricklandii,
(2S,4R,SR)-4,5-dihydro~yornithine[~~~
from the antibiotic
7.6. Non-a-Amino Acids
Most amino acids in which the amino group does not
occur in the a-position were formerly isolated from peptide antibiotics and are themselves antibiotics such as 86
and 87 or have complex structures such as the pigment 83
or the alkaloids 84 and 85. In addition the following
and y-amino acids belong to this group: isoserine and o-tyrosineI2"]from edeine A and B, 4-amino-2,3-dihydroxy-3methylbutyric acidcza1from carcinophilin, 5-amino-4-hydroxyvaleric acid[za1from Rhodospirillum rubrum, puretanin (3-(4-aminobutylamino)propionic acid)""' from, inter
alia, human brain and urine, 3-amino-3-phenylpropionic
acidL3"]from Rocella canariensis, 4-amino-2-hydroxy-30x0-butyric acidf3k1from human urine, p-methyl-L-fl-arg i r ~ i n e ' from
~ ~ ' the antibiotic LL-BM 547 B, y-hydroxy- and
6-hydroxy-fl-lysine[2a,b1
from tuberactinomycin A as well as
4-amino-3,6-dihydroxymethylhexanoicacid[2b1from pepstatin A and 4-amino-3-hydroxy-2-methylhexanoic
acidfzb1,
also from pepstatin A. fl-2-(Thiazolyl)-s-alanine 162[791
has
already been mentioned in Section 6.
s-
The heterocyclic-substituted alanine 186[2b1
was found
in bleomycin. Anthopleurine 187['021,the alarm substance
in sea anemones, has the trimethylammonium group in the
y-position.
8. Outlook
185
echinocandin B, Nb-(1-iminoethyl)-L-ornithine[2b1 from
streptomyces (acts like an arginine metabolite), 2-amino-5(1-methy1guanidino)valeric acidF2"]from rat-liver proteins,
2-amino-5-(3,3-dimethylguanidino)valericacid and 2-amino-5-(2,3-dimethylguanidino)valeric acid["] from human
urine, y-hydroxyarginine""' from sea cucumbers, y-hydroxycitrullin[2a1from Vicia fulgens and related species,
Nc,N"-dimethyllysine[zal from amoebae, N",N",N"-trimethyl- and N"-methyllysine[zal from myosine, fl-hydroxyN",N",N"-trimethyllysine13'J
from Neurospora crassa, 6-hydro~y-N",N~,N~-trimethyl-~-lysine~~~~
and the corresponding 0-phosphoric acid ester from the cell walls of diatoms,
threo-y-hydroxy-~-lysine[~~]
from the antibiotics cerexin A
and B, N"-acetyl-allo 6-hydroxy-~-lysine[~'~
from Beta vulgaris, Na,Nc-(2,3-dihydroxybenzoyl)-~-lysine'3"
from Azotobacter vinelandii, y-oxa-L-Iysine['"' 184 from E. coli and
streptomycetes, indospicine['"' 185 from plants (should
have heptatoxic and teratogenic activity), NS-(4-amino-2hydroxybutyl)lysine'2a1from cattle brain, and N"-acetyl-N"hydroxylysine as the a-amide of citric acid in the Fe(Ir1)
complex from Aerobacter a e r o g e n e ~'I[. ~ ~ ?
826
It is to be expected that the number of new amino acids
will continue to increase, although not at the same rate as
in the last 30 years. Already the number is overwhelming
and one can ask whether it is still justifiable to group them
roughly according to their structural features. However, so
long as so little is known about their biosynthetic relationships and their function in metabolism, the form of classification chosen here may be accepted on the grounds that it
at least helps to identify new naturally occurring amino
acids.
Many modem developments in the chemistry of natural
amino acids deserve more attention, for example the recognition of new metabolic pathways for tyrosine as a precursor of pigments and antibiotics which can be used as
supporting evidence for the evolutionary tree, or the psychotropic activity of isooxazole derivatives such as ibotenic acid. Nature makes use of the N-hydroxyamino acids
as the building units of chelating agents for the accumulation of heavy metals from the en~ironment[~'',or for the
transportation of i r ~ n [ ~ ~ .Last,
' ~ ' ] .but not least, the determination of the age of bones from classical antiquity['031,
or the checking of the age of the Dead Sea Scrolls by
means of measurements of the racemization of amino
acids such as aspartic acid from the collagen which the
Angew. Chem. Int. Ed. Engl. 22 (1983) 816-828
samples contain['04' may be of general interest and useful
for non-chemists"081.
Received: June 29, 1983 [A 472 IE]
German version: Angew. Chem. 95 (1983) 827
Translated by Dr. D.Maass, Kronberg/Ts. (Germany)
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Secologanin, a Biogenetic Key CompoundSynthesis and Biogenesis of the Iridoid and Secoiridoid Glycosides
By Lutz-F. Tietze*
Dedicated to Professor Hans Brockmann on the occasion of his 80th birthday
The monoterpene glycoside secologanin is a key intermediate in the biosynthesis of most indole, cinchana, ipecacuanha, and pyrroloquinoline alkaloids, as well as of simple monoterpene alkaloids. More than a thousand alkaloids are formed from secologanin in vivo; this
represents almost a quarter of this large group of natural products. It is also the parent compound of the secoiridoids. Many of the compounds derived from secologanin display a
high degree of biological activity and are employed as pharmaceuticals, e. 9.. the dimeric indole alkaloid leurocristine (vincristine) which is used very successfully in the treatment of
acute leukemia. A knowledge of the biosynthesis and biological reactions of secologanin
provides a sound basis for the biosynthesis-orientated classification of numerous natural
products and the taxonomy of many plants. Secologanin and structurally related substances
can be synthesized in a few steps by stereocontrolled photochemical and thermal cycloadditions. Its biomimetic reaction with amines and amino acids yields other natural products
and compounds of pharmacological interest.
1. Introduction
The biosynthesis of natural products proceeds according
to simple general principles and only involves a few building blocks. The so-called biogenetic key compounds are
especially important; they are generally polyfunctional
molecules which occupy a central position in biosynthetic
pathways and act as starting compounds for a multitude of
other natural products.
An example of one such biogenetic key compound is
chorismic acid 1, which reacts in vivo to produce 0-and phydroxybenzoic acids and 0-and p-aminobenzoic acids. p -
Hydroxybenzoic acid as well as 0- and p-aminobenzoic
acids undergo further biosynthetic reactions, p-hydroxybenzoic acid yielding the ubiquinones, o-aminobenzoic
acid the amino acid tryptophan, and p-aminobenzoic acid,
folic acid. Chorismic acid is also the precursor of prephenic acid, which can be converted into the amino acids tyrosine and phenylalanine. Other key compounds worthy of
mention are squalene 2 , from which the triterpenes and
[*I Prof. Dr. L.-F. Tietze
lnstitut fur Organische Chemie der Universitlt
Tammannstrasse 2, D-3400 Goctingen (Germany)
828
0 Verlag Chemie GmbH. 6940 Weinheim, 1983
1
0570-0833/83/1111-0828 $02.50/0
2
3
Angew. Chem. Int. Ed. Engl. 22 (1983) 828-841
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