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N-Terminal Cyclization of Peptides with N N-Carbonyldiimidazole or N N-Thiocarbonyldiimidazole.

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CAS Registry numbers:
(1 ), 66674-76-8;(Cod),Ni, 1295-35-8; Ph3P, 603-35-0; Ph3P=CH-CO--Ph,
859-65-4
[l]
[2]
[3]
141
[S]
[6]
W Keim, R. S. Bauer, H . C. Chung, P. Glockner, US-Pat. 3635937
(1969); W Keim, R. f. Mason, P . Glockner, US-Pat. 3647914 (1972);
DOS 2054009 (1972); Eur. Chem. News, Sept. 16, 60 (1977).
Cell data: a= 14.4341(6), b = 16.2935, c=9.6575(6) m-”, CI=103.897(2),
!3=97.636(2),~=80.177(3)”,V=2162.4m-30, space group Pi, Z = 2 , with
.
reflections (k=1.5418
a toluene molecule at 7, d , = l . 2 5 7 g ~ m - ~9123
m-I”), 1646 unobserved (20); R=0.067, R,=0.099.
B. L. Barnett, C. Kriiger, J. Cryst. Mol. Struct. 2, 271 (1972); D. 3 .
Brauer, C . Kriiger, P . 3 . Roberts, I!-H, R a y , Chem. Ber. 107, 3706
(1974).
C . Kriiger, Y - H . Euy, Angew. Chem. 85, 1051 (1973); Angew. Chem.
Int. Ed. Engl. 12, 998 (1973); D. J . Brauer, C. Kriiger, P . 3 . Roberts,
Z - H . Tyay, ibid. 88, 52 (1976) and 15, 48 (1976), respectively; K . Jonas,
D. J. Brairer, C. Kriiger, P . 3 . Roberts, Y - H . Tsay, J. Am. Chem. SOC.
98. 74 ( I 976).
F. Heydenreich, A . Mollbach, G . Wilke, H . Dreeskamp, E. G. Hoffmann,
G . Schroth, K . Seeuogel, W. Stempfle, Isr. J. Chem. 10, 293 (1972).
F . Rumirez, S. Dershowitz, J. Org. Chem. 22,43 (1957).
N-Terminal Cyclization of Peptides with N,”-Carbonyldiimidazole or N ,N’-Thiocarbonyldiimidazole
The significance of the procedure lies in the fact that it
provides a convenient entry to such modified peptides which
are of interest for the study of structure activity-relations
of peptide hormones. Previous methods13’ required relatively
drastic conditions and their scope is therefore very limited.
By analogy with the hydantoins (3), thiohydantoins ( 5 )
are obtained by reaction with N,N’-thiocarbonyldiimidazole
( 4 ).
(5)
R1 = ( S ) - 3 - I n d o l y l m e t h y l , R 2 = (S)-CH2-CH(CH3)2
R3 = A s p ( C H 2 P h ) - P h e - N H z
Peptides (6) containing an N-terminal p-amino acid cyclize
with (2) to form 2,4-pyrimidinediones (7).
By Franz Esser and Otto Roes[*]
We have found that N,N’-carbonyldiimidazole (2)“’ reacts
smoothly and without racemization under very mild conditions with C-terminally protected peptides to give hydantoin
peptides of type ( 3 ) [ ( 3 c ) and ( 3 d ) after removal of the
benzyl protecting group]. This cyclization can also be carried
out on a solid phase[”.
(3a)
(3h)
(3c)
(3d)
R’
R2
R3
(S)-CH2COZCH,Ph
H
(S)-3-Indolylmethyl
(R)-3-Indolylmethyl
(S)-CHzPh
(S)-3-Indolylmethyl
(S)-CH2--CH(CH3),
(S)-CH2-CH(CH3)2
NH2
Met-Gly-NH2
Asp-Phe-NH2
Asp-Phe-NH2
R’ = (S)-CH2Ph, R 2 = NH2
Characteristic data for six selected products are compiled
in Table 1. Ring formation is readily seen in the I3C-NMR
spectra. The expected signals (Table
are accompanied
by a typical shift of the C, signals of the second amino acid
unit relative to the corresponding signals of the open-chain
compounds. Diastereomers such as ( 3 c ) and (3d) can be
unequivocallydistinguished. The expected molecular ions were
observed in the mass spectra of ( 3 a ) and (7), and the species
(8) containing the hydantoin ring could be detected as key
fragment in the case of ( 3 b)[51.
That the compounds synthesized were indeed N-terminally
cyclized structures and not ureas of type ( 9 ) was proved
as follows: For example amino acid analysis of ( 3 c) revealed
a Trp :Leu :Asp :Phe ratio of 0.27 :0.46 : 1.01 : 1.O on acidic
Table 1. Selected data of compounds produced.
____
Reactant
~-
(1 a)
(I b )
(1c)
(1 c ‘ )
(1 d )
(1c)
(6)
ProdUCt
Method
(30)
(3b i
(3c )
(3c)
(3d)
(5)
(7)
A
.__
H-Asp(CH,Ph)-Phe-NH
H-Gly-Trp-Met-Gly-Pol [f]
H-Trp-Leu-Asp(CH2Ph)-Phe-NH2
H-Trp-Leu-Asp(CH2Ph)-Phe-BzPol [g]
H-D-Trp-Leu-Asp(CH2Ph)-Phe-BzPol [g]
H-Trp-Leu-Asp(CH2Ph)-Phe-NH2
H-P-Ala-Phe-NH2
____
B
A
B
B
A
A
Yield
M.P. [“C]
(dec.)
Rr [d]
[”/.I
88
40 [a]
60 [b]
94 [c]
74 [c]
91
77
166-1 69
136
161-162
158--160
152-154
103-1 I5
133-1 35
0.96
0.24
0.2
0.2
0.23
0.83
0.6
I3C-NMR [el
( c = l , DMF)
-131.8
- 18.61
~
44.7
18.60
- 27.34
- 6.54
-
_155.6
157.7
155.8
-
158.9
184.3
148.4
[a] Based on amino acid linked to the Merrifield resin: after ammonolytic cleavage. [b] After hydrogenolytic debenzylation. [c] Based on amino acid linked to
benzhydrylamine resin; after acidolytic cleavage. [dl Eluent: CHC13: MeOH:H,O=65:25:4. [el Signal of the C-atom of the newly introduced CO or CS group
(TMS=O, in [DeIDMSO); Dr. K . H.Pook, Ingelheim. [fl Pol=Merrifield resin. [g] BzPol= benzhydrylamine resin.
[*] Dr. F. Esser, Dr. 0 . Roos
C. H. Boehringer Sohn, Abteilung Pharmachemie
Postfach 200, D-6507 Ingelheim (Germany)
Angew. Chem. Int. Ed. Engl. 17 (1978) N o . 6
degradatiod6] and a ratio of 0.99 :0.95 :0.97 : 1.0 on alkaline
hydrolysis[71.The incomplete regeneration of the first two
amino acids on acid hydrolysis can only be rationalized by
467
3d-Orbital Participation in Sulfur Diimidesp*]
HNY
0
0
assuming their participation in a hydantoin ring which is
completely degraded only in an alkaline medium. Conversely,
this method is suitable for identification of the first two amino
acids of a peptide of unknown sequence,resemblingthe method
tried by We~sely'~~'.
By Richard Bartetzko and Rolf Gleiter"]
Whenever sulfur compounds exhibit unexpected physical
or chemical properties, an expansion of the electron octet
to a decet (participation of 3d orbitals in bonding) is invoked''].
The relatively high stability of sulfur diimides ( I ) and their
frequent occurrence as structural components of organic and
inorganic compounds[2]have led to their formulation with
tetravalent sulfur (I a)[31although the ground state can just
as well be described in terms of resonance between the charged
forms (1 b ) H ( l c ) .
Experimental
I
( 3 c ) by classical method (A): A solution of H-Trp-LeuAsp(CHzPh)-Phe-NHz.HCI (2 g, 2.9 mmol) in anhydrous
dimethylformamide(DMF) (50ml) was neutralized with triethylamine and added dropwise over 30 min at room temperature
to a solution of (2) (0.55g, 3.6mmol) in DMF (50ml) with
exclusion of moisture. The mixture was left to stand overnight,
stirred into an approximately tenfold volume of water, and
the white precipitate was isolated. After dissolution in methanol, precipitation by dropwise addition to water, and drying,
the hydantoin peptide benzyl ester was obtained (1.9g, 94 %).
A solution of this ester in glacial acetic acid was treated
with Hz in the presence of Pd/C as catalyst; yield 1.05g
(64 %) of ( 3 c ) .
( 3 c ) by the solid phase method (B): Boc-Phe-OH, BocAsp(CHzPhkOH,Boc-Leu-OH, and Boc-Trp-OH were successively linked by standard procedures''] to 15g of a
2 % divinylbenzene-crosslinked benzhydrylamine-polystyrene
resin (Pierce, USA). The resin was then treated for 2 h with
a solution of ( 2 ) (13 g, 80mmol 16 equiv. based on Boc-Phe
loaded resin) in DMF (150ml) at room temperature. The
hydantoin peptide was subsequently cleaved from the dried
resin by liquid H F in the presence of 10% of anisole (1 h
at O"C)'zl.After removal of H F and anisole the product was
extracted with glacial acetic acid, the solvent removed, the
residue taken up in methanol, decolorized with activated charcoal, and precipitated by addition of ether; yield 2.9 g (94 %
based on Boc-Phe loaded resin) of ( 3 c ) . HPLC: content of
( 3 d ) <0.4%.
I
I
I.
-
*k&Nk
I
(ibl
I
etc.
(ic)
Comparison of electronic spectra in stretched films as well
as photoelectron (PE) spectra of the naphtho[l,8-~d)thiadia-
1
000
a1
f
21
bi
II
1
I
CAS Registry numbers:
( l a ) , 5609-55-2; (I b), 66610-83-1; ( I c ) , 66653-18-7; ( l e ) HCI, 65864-23-5;
( I d ) , 66653-19-8; ( 2 ) , 530-62-1; ( 3 a ) , 66610-82-0; ( 3 b ) . 66610-81-9; ( 3 c ) ,
66674-35-9; ( 3 d ) , 66610-80-8; ( 4 ) , 6160-65-2; ( 5 ) . 66653-20-1 ; ( 6 ) , 3867868-1; (7), 66610-19-5
8
[l] H. A. Staab, Justus Liebigs Ann. Chem. 609, 75 (1957).
[2] J. M . Stewart, J. D. Young: Solid Phase Peptide Synthesis. W. H. Freeman,
San Francisco 1969.
[3] a) F. Wessely, K . Schlogl, G. Korger, Monatsh. Chem. 83, 1156 (1952);
b) R. Tomatis, S. Saluadori, Farmaco, Ed. Sci. 32, 592 (1977); c) J .
Pless, J. Org. Chem. 39, 2644 (1974); d) F. Wessely, K . Schlogl, E. Wawersich, Monatsh. Chem. 83, 1439 (1952); e) S. Goldschmidt, M. Wick, Justus
Liebigs Ann. Chem. 575, 217 (1952).
[4] J. H. Poupaert, M . Claesen, J. Degelaen, P . Dumont, S . Toppet, Bull.
SOC.Chim. Belg. 86, 465 (1977).
[S] Mass spectra: Dr. H. J . Fiirster, Ingelheim.
[6] Degradation: 3 N p-toluenesulfonic acid, 0.2% tryptamine, 11O"C, 20h;
cf. T Y. Liu, Y. H . Ckang, J. Biol. Chern. 246, 2842 (1971).
[7] Degradation: 4.2N NaOH, 3.3% thiodiglycol, llO"C, 72h; cf. 7: E.
Hugli,S . Moore, J. Biol. Chern. 247, 2828 (1972).
..0
0
&N<S,N**
(la)
Received: March 23, 1978 [Z 971 IE]
German version: Angew. Chem. 90,495 (1978)
468
-
*h2\\N*-
7
8
9
10
11
12
13
U
15
18
Fig. 1. PE spectra of (a)the thiadiazine ( 2 ) and (b) the triazine ( 4 ) . Band assignment was based on comparison with calculated (EH and MIND0/3 [6])
orbital energies; the I,, values lev] for ( 2 ) are 0 7.46, a2(n); 2 9.02,
b2(n-); @ 9.90, bl(n):
10.14, a l ( n + ) ; and those for ( 4 ) are
6.79,
a*, a2(n);@ 8.65, b2(n-):@9.55, bl(n): Q9.82, a l ( n + )[7].
0
8
['I
Prof. Dr. R. Gleiter, Dip].-Ing. R. Bartetzko
Institut fur Organische Chemie der Technischen Hochschule
Petersenstrasse 22, D-6100 Darmstadt (Germany)
[**I Electronic Structure of Sulfur Compounds, Part 29. This work was
supported by the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen 1ndustrie.-Part 28: R. Gleiter, R. Bartetzko, G. Briihler, H .
Bock, J. Org. Chem., in press.
Angew. Chem. Int. Ed. Engl. I7 (1978) N o . 6
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carbonyldiimidazole, thiocarbonyldiimidazole, cyclization, terminal, peptide
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