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Cyclopeptide Macrocycles with D- and L-Proline Residues.

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amino end, could be separated from the cyclotripeptide by
~
This manuscript is
to be cited as
Angew. Chem. Suppl.
1982, 533-541
Dieses Manuskript ist
zu zitieren als
Angew. Chem. Suppl.
1982,533-541
Q Verlag Chemie GmbH.
preparative reversed phase-HPLC (Bondapak u--Cl8,Waters,
CH30H/H20). The ring sizes of the lower cyclopeptides up to
the pentadecapeptide have been identified by mass spectrometry; the size of the larger rings was determined by plot-
D-6940Weinhelm. 1982
0721-422718210303-0533$02.50/0
ting the elution volumes observed by gel chromatography vs.
the logarithm of the molecular weight of the rings.
Cyclopeptide Macrocycles with D- and L-Proline Residues
**
The properties of the oligoproline rings are presented in
Table 1. c-(D-Pro-L-Pro-L-Pro) is the first cyclotripeptide
By Manfred Rothe and Werner Mastle
This paper is dedicated to Professor Leopold Horner on the
possessing exclusively a boat conformation in solution as
well as in the crystalline state /4/. On the other hand,
occasion of his 70th birthday
cyclotripeptides containing amino acids with the same chiralPeptides with successive proline residues are considerably
ity adopt a crown-conformation whereas boat and crown forms
rastricted in their conformational flexibility due to the
relatively rigid pyrrolidine rings and strong steric inter-actions with the adjacent proline residues. Linear oligopro-
"able 1. Properties of the cyclic peptides
C - ( D - P ~ ~ - L - P ~ O - L -La!
P~~)~
lines containing both D- and L-residues therefore represent
excellent models for studying the influence of the conforma-
n
m.p.
i°Cj
*
'*
Prof. Dr. M. Rothe,Dr. W. Mastle
Lehrstuhl Organiscae Chemie 11, University of Ulm
Oberer Eselsberg, D-7900 Ulm
Cyclic peptides, 30th contribution. This work has been
supported by the Deutsche Forschungsgemeinschaft andthe
Fonds der Chemischen Industrie. 1.e thank Dr. A . Sander
for determining the mass spectri. - 29th contribution.
~4. Rothe, E. Frank, G. Schmidtberg, Peptides 193C, Proc.
16th Europ. PeptiL'e Symposium, Ed. i!. arunfrldt Copenhagen, 1981, 258.
-
533
Ve
I
bl
M+
"21 found
calc.
mll
1
181-4
+70.7
800
291.15816
291.15830
2
304
-60.9
596
582.31660
582.31737
3
230 (dec.)
-114.5
549
873.47489
873.41469
4
250 (dec.)
-72.0
492
1164.63319
1 1 64.63207
5
250 (dec.)
462
1455;(M+Na)+
-101.8 1d1
1455
[ a ] lyophilized from water. :bl c=l , H20. :cl elution volume
(GPC, Sephadex LH ZO/MeOH). :dl c=0.5, H20.
-
-
535
-
tion and a-carbon configuration of peptide chains on their
may coexist in a conformational equilibrium in solution with
ring closure.
tripeptides with at least one achiral resithe / 5 / .
We have syntbesized macrocyclic peptides with up to 24 L-
Finally, we succeeded in synthesizing the L,D-alternating
and D-proline residues, which should be of interest because
cyclohexapeptide c-(L-Pro-D-Pro)3 for which an enhanced se-
of their potentially ion-binding properties with metal and
lectivity in ion-binding and transport was assumed / 2 / .
substituted amonium ions /1,2/.
preparation of the linear syndiotactic L,D-hexapeptide BOC-
The synthesis was performed by cyclo-oligomerization of
D,L,D,L,D,L-Pro6 (m.p. =22O-l0C;
-32.4, c=l,
DMF)
The
has
active triproline esters at moderate dilution. For that pur-
been achieved by coupling Boc-D-Pro-L-Pro-D-Pro-OTcp with
pose, all diastereomeric linear tripeptides of D- and L-
L-Pro-D-Pro-L-Pro. After esterification with pentachloro-
proline have been prepared from Boc-protected amino acid p-
phenol and deprotection the cyclizing reaction was accom-
nLtropheny1 esters and unprotected dipeptides in pyridine/
plished at high dilution in pyridine at 100°C.
water at a constant pH of 9.0 in -75% yield. Boc-D-Pro-L-Pro-
of gel chromatography (Sephadex LH 20, in methanol) and pre-
L-Pro (m.p.=189'C;
= -114.3,
c=l, DMF) was obtained
by reaction of Boc-D-Pro-ONp with Di-L-Pro, and Boc-L-ProD-Pro-L-Pro (m.p.=181°C;
tali2
=
+9.9,
c=l, D W ) as well as
aoc-L-Pro-L-Pro-D-Pro (m.p. = 196Oc: [ m 1 i 2 -2.8,
c=l, DMF)
were prepared analogously. After conversion of the BOC tripeptides into the 2,4.5-trichlorophenyl (-OTcp) esters using
Extensive use
parative HPLC (Partisil-10 ODs-2, Magnum 9, Whatman) yielded
26% of the cyclo-hexaprolyl (dec.>31O0; IaiD
2
0, c=l, H20;
M+(FD)=582, calc. 582), simultaneously with small amounts of
cyclo-dodeca- and cyclo-octadecaprolyl.
The first synthesis of macrocyclic rings containing proline
residues is remarkable in different respects. Tripeptides
DCCI /3/ and subsequent cleavage of the BOC group with tr1-
with secondary CONH groups in principal react through cyclo-
fluoroacetic acid, the tripeptide active ester trifluoro-
dimerization to give the corresponding 18-membered cyclo-
acetates obtained were cyclized in pyridine or dimethylform-
hexapeptides / 6 / ,
amide/triethylamine at 100°C.
cyclotripeptides. In contrast, ring closure of all-L-tri-
In the cyclization reactions a series of the homologous cyclic oligotripeptides c-(D-Pro-L-Pro-I,-Pro)n containing up
to 24 amino acid residues (n=1-8) wes obtained in yields up
to 80% and separated by GPC on Sephadex LH 20 in methanol.
without the formation even of traces of
proline exclusively yields the 9-membered ring,
c-(Pro)3 '
Even at higher concentrations larger rings cannot be found
(,90%
yield of cyclo-triprolyl at '"..nfinite" dilution, and
even 24% at c=O. 1 M!)
.
Cyclodipeptide which may be formed by chain-cleavage from the
This may be attributed to the rather rigid helical struc-
534
- 536 -
-
-
tures (corresponding to the polyproline I or polyproline I1
helices. r e s y . , depending on the solvent) of the linear olijo-L-prolines formed by polycondensation which according to
XIIR Investigations /7/ already exist at small chain lengths
tnt3). lience, ring closure is impossible due to the sterically fixed cndgr.>ups in these helical structures.
The Incorporation of a D-proline residue results in a considerably modified steric OrientatLon of the peptide chain.
Ilue t c ; the bridgcd N-C
a L-Pro-L-Pro-1-Pro-OX
'D o-Pro-L-Pro-L-Pro-OX
linkage in every proline residue the
difierunt configuration of the a-carbon causes a very pronouncea change in the backbone conformation of the linear
peptide; this effect will be much weaker in the case of the
i i s u a l amino acids of different chirality.
Accordingly, during the cyclization of diastereomeric L,Dt.riproline derivatives
-
tiaes of a certain size
which will give identical cyclopep-
-
drastic differences in their cycll-
zation tendcncies were observed depending on the confiyurational sequence in the linear peptide precursors. Table 2
c 1-Pro-o-Pro-1-Pro-OX
shows that hiq!i lields of the cyclotripeptide were only obtained from the D,L,L-sequence under favourable cyclization
conditions (apart from small amounts of the cyclohexapeptrde) , In contrast, the L,D,L-sequence cyciodimerizes to oive
almost c:xclusi\ely cyclo-hexaprolyl under the same conditions. Finail},, only a moderate yield of cyclotripeptide was
oL>Lainril from
i
nc L,L,D-seq~ence,in addition to consider-
able amounts of diketo?iperazine.
'lode1 studies show (cf. Fig. 1 )
-
that t!ie endgroups in the
537
d L-Pro-L-Pro-0-Pro-OX
Pig. 1. Conformation as derived from Dreidinq models of
diastereomeric triproline active esters with cis-peptide
bonds to perform ring closure.
a and b: "cisoid" arrangement of the endgroups (At the same
side of the prospective ring plane, giving hlqh jlelds of
cyclotripeptides).
c and d: "transoid" arrangement of the endgroups with respect
to the peptide backbone (cyclotripeptide formation does not
occur (c) or is restricted (d)).
-
-
539
-
Cyclodimerization which occurs nearly exclusively from the
Table 2. Cyclizstion of diastereomeric triproline-2,4,5trichiorophenyl esters
L,D,L-sequence may even be obtained under conditions usually
favouring polycondensation products (c=O.1 M, DtlF as solvent)
linear
peptide
al
procedure
total
yield
DKP
.%i
!bl
c-(D-Pro-L-Pro-L-PrO)n
n=l
3
2
4
whereas the other sequences (3,L,L and L,L,D resp.) give corn5
plete series of macrocyclic rings (n=2-8) containing cyclo-
%I
yield
hexaprolyl or cyclo-nonaprolyl. resp., as the main products
78.3
2.5
3.2
51.7
L
A
81
1
L D I ,
A
57
1.6
L
L
D
A
54
20.1
D
L
L
B
60
1
5.5
L
D
L
B
78
-
-
D
L
3.5
30.8
-
-
-
at high concentration.
-
The use of diastereomeric triprolines demonstrates a very
striking example of the recently observed sequence-dependence
of the cyclization tendency of linear peptides forming iden-
4.1
22.0 11.6
5.7 Lcl
tic,il cyclopeptides /8,9/. In the present case, t h i s depend-
70.5
4.6
3.2
1
ence is based
L
L
D
5.4
74
l?
4.9
29.0
17.2
7.1
4.7
On
different conformations of the linear pep-
.Cl
tide precursors due to changes in the a-carbon ccnfiguration
A:
ii
c=O.O01
H i n
pyridine, B: c=O.1 M in DNF/triethylamine.
! configurational sequence of the linear tripeptide.
[bl dikotopiperazrne formation by N-terminal chain cleavage.
lci additional larger rings up to n=8.
/1/
V. Madison, M. Atreyi, C.M. Deber, E.R. Blout, J. Amer.
Chem. SOC. 96 (1974) 6725,
99
(1977) 4788: B. Bartman,
C.M. Deber, E.R. Blout, J. Amer. Chem. SOC. 99 (1977)
?.near
L.L,L-
as
well
as
cis-peptide bonds which are required to form a cyclotripeptrJe exist
in
1028.
the D,L,L-triproline Sequences witi,
/2/
-~
4th h e r . Peptide Symposium, Eds. R. Walter, J. Melen-
a quasi-"cisoid" arrangement with respect to
hofer, Ann Arbor Sci. Publ., Ann Arbor, 1975. p. 219.
the peptide backbone. On the contrary, in the L,D,L- and the
L,L,D-seqJences the endgroups occur in a quasi-"transoid"
/3/
M. Rothe, F.-W. Kunitz. Liebiqs Ann. Chem. GO9 (1957)
/4/
J.W. Bats, A. Friedrich, H. Fuess, H. Xessler, W.
8 6 : M. Rothe, Coll. Czech. Chem. Commun. 24 (1959) 28.
arranqement. This results in very different distances of the
chain ends of these peptides and, correspondingly, in very
F. Ascoli, P. DeSantis, A. Palleschi, R. Rizzo, ' p
different cyclrration tendencies (cyclodimerizainn or for-
Nastle, M. Rothe, Angew. Chem. 71 (1979) 573: ~ n g e w .
mation of diketopiperazines as the alternative reactions).
Chem. Int. Ed. Engl. 18 (1979) 538.
-
538
-
-
540 -
/5/
H. Kessler, in "Stereodynamics of Molecular Systems",
Ed. R.H. Sarma, Pergamon Press, N.Y., 1979, p. 187.
und 1aBt anschlieDend auf 2OoC aufwarmen, so entstehen in
50-85% Ausbeute die C-Additionsprodukte
/6/
R.
/7/
M. Rothe, H. Rott, Angew. Chem. 88 (1976) 844: Angew.
Schwyzer, P. Sieber, Helv. Chim. Acta 41 (1958) 2186.
der Umsetzung von
4
2
(Tabelle 1). Bei
mit zwei Xquivalenten R'MgX kann auf die
Base verzichtet werden
Chem. Int.
15 (1976) 77; M. Rothe, H. Rott,
~
_ Ed._Enql._
R'
I /Copt
RCONH-C
'C02Et
J. MazLnek, Proc. 14th Europ. Peptide Symposium, w&pion,
Ed. A. Loffet, Edit. de 1'Univ. de Bruxelles, 1976, p.
309.
/8/
M. Rothe, W.KreiB, Peptides
1976, Proc.
14th Europ.
Peptide Symposium, Ed. A. Loffet, Edit. de 1'Univ. de
Bruxelles, 1976, p. 71.
/9/
S . F . Brady, S.L. Varga, R.M.
Freidinger, D.A. Schwenk,
M. Mendlowski, D.F. Veber, J. Org. Chem. 44 (1979) 3101.
'f ,C02Et
RCONH-C,
C02Et
1
,CO Et
RCON=C
'C02Et
\
Br2,CC14
Br
1
RCONH-C
,cop
L
m
a
'C02Et
Received August 24, 1981
revised January 29, 1982 /Z 30
R = Ph, Me
4
S/
Durch Verwendung der g-Benzoylgruppe und Arbeiten bei
tiefer Temperatur werden Nebenreaktionen wie Addition des
Metallorganyls an den Stickstoff, Angriff auf die Estergruppen sowie radikalische Reduktion zu
/5/ und Dimeri-
sierung zu _S unterdruckt. So erqeben Acetylimino- und Ethoxycarbonyliminomalonester bei der Reaktion mit Methylmagnesiumiodid bis zu 25% der entsprechenden N_-Methyl-acylaminomalonester /6/. Mit Lithiumdimethylcuprat liefert
16% 22 neben 29%
1
und 2 1 %
2
1
( R = Ph) nur
(Fp= 177OC).
Die neue Methode gestattet auch eine einfache Darstellung
-
- 543 -
541 -
zu zitieren als
Angew. Chem. Suppl.
to be cited as
Angew. Chem. Suppl.
1982,542-548
1982,542-548
Tabelle 1. Reaktionsbedingungen und Ausbeuten bei der Umsetzung von 2 (bzw. 1) mit C-Nucleophilen zu substituierten
N_-ACylaminOmal0neste;n
zCacb)
0 Veriag Chemie GmbH. D-6940 Weinheim, 1982
0721-4227/82/03030542$02.50/0
-78
-78
1.5
1.5
-78
1.5
78
85(f)
70
66
-78
-78
-78
-78
-100
1
2
1.5
2
1.5
72
70
77
50
-100
2
54
-78
1.5
61
Reaktion von Acyliminomalonestern mit C-Nucleophilen, eine
Umpolung der Acylaminomalonester-Synthese von a-Aminosauren
Reiner Kober, Willi Hammes und Wolfgang Steglich
Bei der Synthese von a-Aminosauren nach Sorensen /1/ ist
die Alkylierung eines Acylaminomalonesters
zu
2
der ent-
scheidende Schritt. kie wir fanden, lassen sich Substitu-
66
tionsprodukte des gleichen Typs auch durch Addition von
65
3
88
Metallorqanylen und anderen C-Nucleophilen an Acylimlno-
65
2.5
65
malonester 3 / 2 /
65
4
72(l)
60
60
65
2.5
2.5
4
58")
88
70")
40
2
92
-40
1
70
herstellen.
Als Vorlaufer Yon
3
haben sich die durch Bromierung von
Acylaminomalonestern in 80-88% Ausbeute zuqanglichen Bromester 4 /3/ bewahrt. Mit Hunig-Base in Tetrahydrofuran (THF)
liefert z.B.
4
(R= Ph) quantitativ
3,
das durch IR-Banden
bei 1696 und 1686 cm-l (CHC13) charakterisiert 1st / a / .
-40
1
97
25
3
68")
Tropft man zu dieser Losung bei -78 bis -1OOOC die Squimolare Menge einer vorgekuhlten Grignard-Verbindun? in THF
Prof. Dr. W. Steglich. Dip1.-Chem. R . Itober, ar. W. Hammes
Institut fur Orqanische Chemie und Biochemie der Universitat
Gerhard-Domagk-StraDe 1. D-530J
- 542
Bonn
-
Alle Verbindungen lieferten borrekte Elenentaranalysen und nit ihrer
struktur vereinbare spktroskopische aaten. (') FP roc] : za, 47 (E~oH/P~trolether); 2,54 (EtOH/PEl; &, 83-84 (EtOAc/PE); 22, 145-146 (EmPC/
L. 51-52; 2,
PE); &, 114-115 (EtOAc/PE); Zf, 86-87 (TolUol/~-€han);
- 544
-
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