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Macrocyclic Peptides in Anionic Polymers of Amino Acid N-Carboxylic Anhydrides.

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meric chlorodicarboxylic acids were converted into the dimethylamino derivatives in order to obtain a specific fragmentation.
For example, the methyl esters of the isomeric dimethylaminodecanedioic acids cleave into the characteristic fragments:
m/e 158, 172 (6), 186, 144 (y), 200, 130 (p). The CHCl proton
of the dimethyl ester of the predominantly occurring chlorodecanedioic acid shows the same shift as the 6-CH2 proton
of unsubstituted dimethyl decanoate at various Eu(fod)3 concentrations.
A solution of N-chlorodiisopropylamine (50mmol) and
decanedioic acid (50mmol) in 85 % sulfuric acid (80ml) under
nitrogen is irradiated (Hg high-pressure lamp TQ 150, Hanau)
at room temperature for 2.5 h ; thereafter no more active chlorine was detectable with potassium iodide/ammonium acetate/starch. The reaction solution is finally poured into 150ml
ice-water; the precipitated product (11.2 g after drying in a
vacuum) is filtered off and washed twice with cold dilute
hydrochloric acid. Extraction of the combined aqueous phases
for one day with ether affords (after drying in a vacuum)
a further 0.6 g of the crude mixture of isomers.
Received: February 16, 1976 [Z 408 I€]
German version: Angew. Chem. 88,334 (1976)
CAS Registry numbers:
Hexanedioic acid, 124-04-9; heptanedioic acid, 11 1 - 1 6-0; octanedioic acid,
505-48-6; nonanedioic acid, 123-99-9; decanedioic acid, 1 1 1-20-6; dodecanedioic acid, 693-23-2; N-chlorodiisopropylarnine,24948-81-0
N. C. Deno, M! E. Billups, R. Fishbein, C. Pierson, R. Whalen, and
J. C. Wyckog, J. Am. Chem. SOC.93,438 (1971).
[2] N. B. Lorette and J . H.B r o w , J. Org. Chem. 24, 261 (1951).
[3] F.
Synthesis 1973. 1.
[4] E. M. Arnett, Prog. Phys. Org. Chem. I, 223 (1963).
Macrocyclic Peptides in Anionic Polymers of Amino
Acid N-Carboxylic Anhydrides[**]
By Manfred Rothe and Dietger Miihlhausen[*]
Dedicated to Professor Werner Kern on the occasion of his
70th birthday
Amino acid N-carboxylic anhydrides (NCA) ( 1 ) can be
polymerized anionically with tertiary bases or inorganic
halides (LiC1, NaI)“]. Reaction of NCA and the NCA anion
according to a mechanism resembling that of the anionic
lactam polymerization[’, 3 l should give rise to initial formation
of an N-aminoacyl-NCA (2), which then undergoes reaction
with further NCA molecules with loss of COz to give poly-aamino acids having a C-terminal NCA moiety (3).
The isomerization of ( 2 a ) to I-hydantoin acetic acid and
the cyclization of (3 a ) , n = 5, to cyclohexaglycyl ( 4 a ) , M = 6,
are known chain termination reactions.
We have found that glycine-NCA ( I a ) can also give rise
to other macrocyclic peptides which could not be indentified
previously because of their similarity to polyglycine (sparing
solubility, high decomposition points, in part amorphous character). Extraction of anionic polymers with hot water and
removal of linear peptides and inorganic salts with ion[*] Prof. Dr. M. Rothe and Dr. D. Miihlhausen
Organisch-Chemisches Institut der Universitat Mainz
Neue Adresse: Lehrstuhl Organische Chemie 11 der Universitat
Oberer Eselsberg, 7900 Ulm (Germany)
[**I Cyclic Peptides, Part 22. This work was supported by the Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and BASF
(Ludwigshafen).-Part 21: M. Rothe and M! Kreiss, Angew. Chem. 85, 1103
(1973); Angew. Chem. Int. Ed. Engl. 12, 1012 (1973).
Anyrw. Cheni. I n t . Ed. Engl. / H I / . 15 (1976) No. 5
H N d
(a), R = H
r[ NH-C
HR-C O I n 7 ( 4 )
exchangers afforded a ninhydrin-negative mixture of cyclopeptides which could be separated by gel-permeation chromatography on Merckogel PGM 2000 in water; the peaks were
detected by differential refractometry.
Evaluation of the gel chromatograms presented difficulties
in the case of cyclic glycine peptides, since the first members
of the series up to cyclopentaglycyl deviate from normal chromatographic behavior-evidently
owing to their conformations. Only from cyclohexaglycyl onwards is the dependence
of the elution volume on log MW approximately linear.
This could be demonstrated with ring peptide mixtures
obtained by cyclization of linear oligoglycines at moderate
concentrations using the phosphite
In each case
the “monomeric” rings are accompanied by cyclic dimers,
trimers, and tetramers, i. e. diglycine gives cyclotetra-, cyclohexa-, and cyclooctaglycyl along with glycine anhydride and
triglycine gives cyclononaglycyl along with cyclohexaglycyl,
while cycloocta- and cyclododecaglycyl or cyclodecaglycyl,
respectively, are formed as higher ring oligomers from tetraand pentaglycine.
Combination of the results so obtained together with molecular weight determinations enabled definite assignment of
the peaks of all the cyclooligoglycyls mentioned.
Identification of the ring peptides obtained in the anionic
polymerization of (1 a ) was accomplished by gel- and thinlayer chromatography and in particular by mass spectrometry
( i i ~ L r d i i - ~ ~ ad
- ~ i S~+.gmm+&im
of the isolated crystalline products with authentic cyclopeptides synthesized from the linear oligoglycines and 2-chloro1,3,2-benzodioxaphosphole (0-phenylene chlorophosphite)
using the dilution techniquef4](cyclotetra-, cyclopenta-[’I, cyclohexaglycyl: in each case colorless needles, m. p. (dec)
> 330°C, > 330°C, and > 350”C, respectively; yields 35, 18
and 46 %, respectively]. In this way small amounts of cyclotetraglycyl (m/e= 328) and the new compounds cycloheptaglycyl
(m/e= 399), cyclonona-, and cyclododecaglycyl could be
detected in the NCA polymerization. The molecular peaks
of the higher, unusually difficultly volatile cyclopeptides had
hitherto not been detected; here the ring size is deduced
from gel chromatograms. Cyclodi-, cyclotri-, and cyclopentaglycyl were not detected. The type and number of rings formed
afford information about the previously largely unknown tendency to form many-membered cyclic peptides and about
ring-chain equilibria in polypeptides.
Received: February 27, 1976 [Z 412 IE]
German version: Angew. Chem. 88, 338 (1976)
CAS Registry numbers:
( 1 a), 2185-00-4; (2a). 58673-1 1-3; ( 3 a ) , 58692-71-0; (4a), 3785-17-9
D. G. H. Ballard, C. H. Barnford, and F. J. Weyrnouth, Nature 174.
173 (1954); Proc. Roy. SOC.A227, 155 (1955).
[2] C. H. Barnfordand H.Block in M. A. Stahmuri: Polyamino Acids, Polypeptides, and Proteins. Wisconsin University Press, Madison 1962, p. 65;
M. Swarc, Adv. Polym. Sci. 4, 1 (1965).
131 H. Sekiguchi and G. Froyer, C. R. Acad. Sci. C279.623 (1974).
[4] M. Rothe, I. Rothe, H. Briinig, and K.-D. Schwenke, Angew. Chem.
71, 700 (1959).
[ S ] G. Liidke, Diplomarbeit, Universitit Mainz 1964.
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acid, polymer, anhydride, anionic, amin, carboxylic, macrocyclic, peptide
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