α-Aminoacid-N-Carboxy-Anhydrides and Related Heterocycles: Syntheses, Properties, Peptide Synthesis, Polymerization

219 Pages·1987·5.617 MB·English

by  Professor Dr. Hans Rytger Kricheldorf (auth.), Professor Dr. Hans Rytger Kricheldorf (eds.)

Hans Rytger Kriche1dorf
rt-Aminoacid-N -Carboxy
Anhydrides and Related
Heterocycles
Syntheses, Properties, Peptide Synthesis,
Polymerization
With 36 Figures and 33 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Professor Dr. Hans Rytger Kricheldorf
Institut fUr Technische und Makromolekulare Chemie
Universitiit Hamburg
0-2000 Hamburg 13
Library of Congress Cataloging in Publication Data
Kricheldorf, Hans Rytger, 1942. [Alpha]-aminoacid-N-carboxy-anhydrides and related heterocycles.
I. Amino acid anhydrides. 2. Peptides - Synthesis. 3. Polymers and polymerization. I. Title. [DNLM: I. Amino
Acids - chemical synthesis. 2. Oligopeptides - chemical synthesis. QU 60 K92a]
QD431.K79 1987 547.7\5 86-29763
ISBN-13: 978-3-642-71588-4 eIISBN-13: 978-3-642-71586-0
DOl: 10.1007/978-3-642-71586-0
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© Springer-Verlag Berlin Heidelberg 1987
Softcover reprint of the hardcover 1st edition 1987
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2152/3020-543210
Preface
In 1906, Hermann Leuchs, a student of Emil Fischer, discovered the class of
N-Carboxy-aminoacid-anhydrides, also known as Leuch's anhydrides, or
abbreviated NCAs. These compounds are, even 80 years after their discovery,
valuable intermediates in organic synthesis due to their reactivity: NCAs
polymerize with the elimination of carbondioxide to yield polypeptides,
model compounds for proteins. They can be used as starting material for a
variety of pharmaceutically interesting products and for synthetic polymers
(fibres and films). Ralph Hirschmann demonstrated the step by step synthesis
of ribonuclease utilizing NCAs as monomers.
The author of this monograph, Hans R. Kricheldorf, University Hamburg,
is, on account of his own research in Freiburg and Hamburg, predestined to
give the reader an insight into the organic chemistry of NCAs and related
heterocycles as well as macromolecular chemistry, that is the synthesis of
polypeptides and the structure-reactivity relationship. I predict a good accept
ance of this book about the class of cyclic aminoacid derivatives by scientists
in various areas.
Aachen, September 1986 Helmut Zahn
Acknowledgment
The author would like to express his gratitude to the american chemical
society, the royal society of chemistry, Marcel Dekker Inc., John Wiley &
Sons, Hiithig & Wepf Verlag and Kobunshi Gakkai for the permission to
reproduce figures from their journals.
The author also wisher to thank Karin Voltmer, Dipl.-chem. Ingrid
Kreiser, Dipl.-chem. Kai-Uwe Tonnes, Dr. Gert Schwarz (Institut fUr Tech
nische und Makromolekulare Chemie, Universitat Hamburg) for having
supported the preparation of the manuscript.
Table of Contents
Introduction . . . . . . . . . . . . .
1. Synthesis and Characterization of NCAs 3
1.1 Syntheses of Ct.-Amino Acid NCAs . 3
1.2 Syntheses of ~- and co-Amino Acid NCAs . 11
1.3 Thio Analogs of Ct.- and ~-Amino Acid NCAs 16
1.4 Purification and Titration of NCAs . 21
1.5 IR Spectroscopy . . 23
1.6 NMR Spectroscopy 28
1.7 Tables of NCAs 35
References . . . . . . 51
2. Oligomerization and Polymerization of NCAs.: Chemical Aspects 59
2.1 Background . . . . . . . . . . . .'. 59
2.2 Stoichiometric Reactions of NCAs . . . 60
2.2.1 Reactions with Protic Nucleophiles 60
2.2.2 Various Reactions. . . . . . 72
2.3 Stepwise Peptide Syntheses . . . . . . 78
2.3.1 With N-Unsubstituted NCAs . . . 78
2.3.2 With N-Substituted NCAs . . . . 85
2.4 Polymerization with Protic Nucleophiles 88
2.4.1 Primary Amines . . . . . 88
2.4.2 Secondary Amines . . . . 93
2.4.3 The Carbamate Mechanism 97
2.5 Tertiary Amines . . . . . . . . 103
2.5.1 Trialkylamines . . . . . . 103
2.5.2 Pyridines ........ 113
2.6 Metal Salts and Organometallic Compounds. 117
2.6.1 Various Anions. . . . . 117
2.6.2 Organometallic Initiators. . . . 126
2.7 Thermal Polymerizations . . . . . . 132
2.8 co-Amino Acid NCA and Thio NCAs . 139
2.8.1 ~- and y-Amino Acid NCAs 139
2.8.2 Thio Analogs of NCAs 143
References . . . . . . . . . . 150
VIII Table of Contents
3. Polymerization of NCAs: Physical Aspects 158
3.1 Determination of Molecular Weights . 158
3.1.1 Endgroup Analyses . . . . . . 158
3.1.2 Physical Methods . . . . . . . . 164
3.2 Molecular Weight Distributions and Polydispersity 170
3.3 Chain-Effect Polymerization. . . . . . 176
3.3.1 The Chain Effect of Polysarcosine. . 176
3.3.2 The Helical Chain Growth . . . . . 180
3.3.3 Template Polymerizations . . . . . 186
3.4 Secondary Structure of Solid Polypeptides. 188
3.4.1 Definitions and Methods. . . . . . 188
3.4.2 Secondary Structure and Crystal Growth. 191
References . . . . . . . . . . . 204
Subject Index . . . . . . . . . . . . . . . . . . 209
List of Abbreviations
cxh/Ph ratio molar cx-helix/p-sheet ratio
cx-NCA cx-amino acid N-carboxyanhydride (oxazolidine-2,
5-dione)
cx-TAD thiazolidine-2,5-dione
cx-TOO 2-thioxooxazolidone-5-one
P-NCA p-amino-acid N-carboxyanhydride (perhydro
oxazine-2,6-dione)
P-TAD perhydrothiazine-2,6-dione
Boc tert-butoxycarbonyl
BzI benzyl
CP/MAS cross-polarization/magic angle spinning
DCA dichloroacetic acid
DEAE diethylamino ethyl
DMF dimethylformamide
DMSO dimethylsulfoxide
DNP 2,4-dinitrophenyl
DP individual degree 'Of polymerization
DP (number average) degree of polymerization
DTE N-dithiocarbonyl(S-ethoxy carbonyl)
EEDQ 2-ethoxy-l-ethoxycarbonyl-dihydroquinoline
Et ethyl
FT Fourier transform
GPC gel permeation chromatography
Me methyl
M/l ratio molar monomer/initiator ratio
Mn number average molecular weight
MSA methane sulfonic acid
Mw weight average molecular weight
MWD molecular weight distribution
NEF nitrogen electric field effect
NOE nuclear Overhauser effect
Nps 2-nitrophenylsulfenyl
nuc/bas nUcleophilicity /basicity ratio
ORD optical rotatory dispersion
TFA trifluoro acetic acid
TFE trifluoroethanol
THF tetrahydrofuran
Introduction
In 1906, Herman Leuchs presented his first report [1.1] on the synthesis and
polymerization of an a.-aminoacid-N-carboxyanhydride (oxazolidine-2,5-
dione). This historic report, along with two later papers [1.2, 3] is of particular
interest because it described the synthesis of a polymer at a time when polymer
science was not in existence. At that time, many distinguished chemists agreed
that polymers built up exclusively by covalent bonds did not exist. In particu
lar, the famous Emil Fischer, who was awarded a Nobel prize in 1902 for
the stepwise synthesis of polypeptides and polysaccharides, emphasized that
biopolymers with molecular weights above' 5000 could not exist. Conse
quently, Leuchs did not dare to propose a linear polypeptide as the poly
merization product of his NCAs and suggested the formation of cyclic oligo
peptides. When in the years after 1920 the existence of macromolecules
became widely acknowledged, Wessely and his co-workers [1.4-14] resumed
systematic investigations on the synthesis, properties, and polymerization
of a.-amino acid NCAs. Since that time, the interest of organic chemists,
physicochemists, polymer chemists, biochemists, and even immunologists,
in NCAs and peptides derived from them has steadily increased.
In the past four decades, studies of the chemistry of a.-amino acid NCAs
have been stimulated by the following (among other) results. Infrared and
x-ray spectroscopic characterization of polypeptides derived from NCAs
revealed that proteinaceous amino acids may be subdivided into a.-helix
forming and a.-helix-destabilizing (exclusively ~-sheet-forming) species
[1.15]. When a.-helix-forming a.-amino acid NCAs were polymerized,
molecular weights above 100000 were obtained [1.16, 17]. High molecular
weight polypeptides, in particular polY-L-glutamates, were developed com
mercially in Japan as textile fibers [1.l8], i.e., as synthetic analogs of silk.
Poly(y-OBzl-glutamate) was also the first polymer in which a lyotropic
mesogenic phase, i.e., a liquid crystalline state, was detected [1.l9, 20]. Such
lyotropic mesogenic phases are nowadays also being discussed for naturally
occurring proteins, such as solutions of native silk in the gland of silk worms.
In many other ways also, polypeptides derived from NCAs have served as
models of proteins, because the polymerization of a.-amino acid NCAs is
still the most reliable way of preparing high molecular weight polypeptides
without racemization. However, it is noteworthy that a.-amino acid NCAs
are also useful for the stepwise synthesis of oligo- and polypeptides with
well-defined sequences of various amino acids. The preparation of the enzyme
ribonuclease-S [1.21-28] may be mentioned in this connection. Thus, a
2 Introduction
monograph summing up various aspects of the chemistry of ex-amino acid
NCAs and their analogs seems to be justified on the eightieth anniversary
of the birth of "Leuchs's Anhydrides".
1 Synthesis and Characterization of NCAs
1.1 Syntheses of ~-Amino Acid NCAs
Leuchs et al. [1.1-3] prepared N-ethoxycarbonyl and N-methoxycarbonyl
amino acid chlorides for the purpose of stepwise peptide synthesis. Upon
heating in vacuo, cyclization was observed, instead of distillation, yielding
NCAs along with alky1chlorides (Eq. 1.1). Therefore, the cyclization of N-
(1-1)
R,R' =H . Alkyl, Aryl
alkoxycarbonyl halogenides, which is a versatile and attractive route even
now for the synthesis of NCAs, is called the Leuchs method. The main short
comings of the original Leuchs method are the relatively high cyclization
temperatures, which come close to the point where several NCAs begin
to decompose. Thus, various improvements were proposed in later decades.
Leuchs originally used thiony1chloride for the chlorination of N-alkoxycar
bonyl amino acids, and this reagent has the advantage of gaseous byproducts.
Phosphorus pentachloride [1.29] is more reactive and the conversion of N
alkoxycarbonyl amino acids may be conducted at lower temperatures; yet
phosphorus oxide trichloride, formed as a byproduct, may affect the crystal
lization of NCAs. Dichloromethyl methylether was recommended for the
high purity of the resulting NCAs [1.30], whereas oxaly1chloride [1.31] does
not seem to have any particular advantage, except when the bis-NCA of
cx,cx'-diaminosuccinic acid is prepared [1.32]. The treatment of N-benzyl
oxycarbonyl amino acids with phosgene takes an unusual course, because in
the presence of triethylamine, N-benzyloxycarbonyl aziridine-2-ones are form
ed (Eq. 1.2), which upon catalytic hydrogenation yield NCAs (Eq. 1.3 [1.33]).
Y
-0-co-lH
Q-CH2-O-CO-NH-CHR-COOH +COClz.+2 NEt3, QcH2 \o (1-2)
-"EI,HCI
HN-CHR (1-3)
oc ....
o,...Co + Q-CH3
The most convenient reagent for the preparation of NCAs according to
the Leuchs method is phosphorus tribromide, because N-alkoxycarbonyl