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Molecular Structure of Phe2-TRH an Analogue of Thyrotropin-Releasing Hormone.

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a ) 4 . R. Rj,e, D. Wege, Aust. J . Chem. 27, 1943 (1974); b) W G. Dauben,
G. T Rioers, R. 7: TMieg, W T Zimmerman, J. Org. Chem. 41, 887
(1976);c) W Grimme, E. Schneider, Angew. Chem. 89, 754 (1977); Angew.
Chem. Int. Ed. Engl. 16, 717 (1977).
a ) J. F . Monthong, W. H. Okumnra, Tetrahedron 28, 4273 (1972); b)
J . C . Berridge, D. Bryce-Smith, A. Gilbert, 1. Chem. SOC.Chem. Commun.
197.5, 611; c) H. Rottele, W Martin, J . F. M . Oth, G. Schroder, Chem.
Ber. 102, 3985 (1965).
G K u u p p , R. Dyllick-Breniinger, Angew. Chem. 86, 523 (1974); Angew.
Chem. Int. Ed. Eugl. 13, 478 (1974).
W G. Dauben, D. L. Whalen, J. Am. Chem. SOC.93, 7244 (1971).
R. E. lrelund, D. C . Muchmore, U . Hmgartner, J . Am. Chem. Soc. 94,
5098 (1972).
P. E. Eaton, D. R. Patterson. J. Am. Chem. SOC. 100, 2573 (1978), and
rererences cited therein.
F. 4. Cotton, G. Degunello, J . Am. Chem. SOC. 95. 396 (1973), and
references cited therein.
W. Mauer, W Grimme, Tetrahedron Lett. 1976, 1835.
Figure 2 shows the molecular structure of Phez-TRH. The
proline ring is present in two conformations in the crystal.
05
3
Molecular Structure of Phe2-TRH, an Analogue of
Thyrotropin-ReleasingHormone
By Johri J . Stezowski, Claus Burvenich,and Wolfgang Voelter"]
X-ray analysis of thyrotropin-releasing hormone (TRH)
and analogous compounds has hitherto been impossible
owing to the lack of suitable crystals. We have found that
Phe2-TRH forms crystals suitable for X-ray analysis. Phe2TRH is an analogue having a relatively high biological activity"] and antidepressive action''].
Figure 1 illustrates the methodological strategy for the synthesis of PheZ-TRH.Crystals of Phe2-TRH were obtained by
19
Fig. 2. Molecular structure of Phe'-TRH. The two conformations of the
proline ring differ in the disposition of C(9). The rest of the molecule is
presented stereoscopically. Dihedral angles: N(I)C(4)C(S)N(5)=143.8".
N(5)C(6)C(7)N(7)=132.1", N(S)C(6)C(I3)C(14)= 178.8". C(6)C(13)C(14)C(
15)
=62.5", N(7)C(Il)C(l2)N(12)= - 24.3".
The two peptide bonds are trans-oriented. The water molecule
is bonded via one of its protons to O(1) of one Phe2-TRH
molecule and via its second proton to O(5) of another peptide
molecule: its oxygen atom, however, has no acceptor function.
H(1N) and H(5N) are bound via hydrogen bridges to O(12)
of the next molecule. O(7) is coupled via a hydrogen bond
with H(12N,1); H(12N,2) forms no hydrogen bonds in the
crystal.
Boc -- OH 111
2--
Boc
HCllHOAc
ONSuci31 H
H-
OCCI lHOEt
NH,
Experimental
NH, 121
NH, 1 0
NH, 151
2
HBriHOAc
The following amino acids and peptides were synthesized
according to methods given in the literature: ( I ) (see Fig.
B o c - ~ - P r o [BOC-L-P~O-NH~['~,
~~,
L-Pro-NH2.HClrsl,Z-LGl~['"~,Z-~-gIutamicanhydride[~~~,Z-~-Pyr.
DCHA['"], (3 )(7d!
L-Phe-L-Pro-NH, (4): A mixture of (2) (30g) and 1 . 2 ~
HCI/HOAc (250 ml) is stirred for 30 min at room temperature.
The solvent is then removed in a rotary evaporator and the
residue extracted several times with methanol. After removal
of the methanol by evaporation (4) is crystallized from the
remaining oil with methanol/ether; yield 22.08g (89 %), m. p.
60°C (decomp.),
- 10.95" (c= 1.13/HOAc).
Z-L-Pyr-L-Phe-L-Pro-NH, (5): A mixture of ( 3 ) ( 5 g),
(4).HCI (4.36g) and N-ethylmorpholine (1.75ml) is stirred
for 24 h at room temperature. The reaction mixture is evaporated to dryness, taken up in ethyl acetate, washed several
times with NaHC03 and water, dried with Na2S04 and crystallized from anhydrous ether; yield 3.41 g (48 %) ( 5 ) , m. p.
70°C (decomp.),
= - 68.88" (c= 1, MeOH).
Phe2-TRH[*]:A mixture of (5) (3 g ) and HBr/glacial acetic
acid is stirred for 5min at room temperature; the solvent
is then removed and the residue washed several times with
methanol. The residue recovered after subsequent evaporation
to dryness is taken up in water and treated with ion-exchanger.
After filtration the filtrate is concentrated by evaporation
and passed through a Sephadex-GI0 column and freeze dried.
[%Il,=
slow evaporation of aqueous or 2-propanol solutions; space
groupP212121,with 4 PheZ-TRH.HzOmolecules per unit cell,
cell constant^'^"] at 120K: a=14.831(4), b=11.440(2),
was
c = 11.448(2)!~ The original crystal-structure
refined with high-resolutiondata (Tz120K) to R=0.044 (3162
observed reflections).
[*] Dr. J . J. Stezowski
lnstitut fiir Organische Chemie, Biochemie und lsotopenforschung der
Universitat
Pfaffenwaldrmg 55, D-7000 Stuttgart 80 (Germany)
Prof. Dr. W. Voelter, Dip1.-Chem. C. Biirvenich
Institut fur Organische Chemie der Universitat
Auf der Morgenstelle 18, D-7400 Tiibingen (Germany)
Ailyew. Chrw
/iff
[.I,
225
Ed. Enyl. 18 (1979) N o . 3
0 Verlag Chemie, GmbH, D-6940 CVemhcim, 1979
0S70-0S33~79/0303-0225
s 02.S0I0
Yield 1.78g (81 %) Phe2-TRH, m.p. 180--183"C,
-43.2" (c= 1, MeOH).
[.ID=
Received: December 15, 1978 [Z 160 IE]
German version: Angew. Chem. 91. 243 (1979)
CAS Registry numbers:
( I ) , 13734-34-4; ( 2 ) , 69470-09-3; ( 3 ) , 40291-26-7; (41, 64774-32-9; 15),
69461-91-2; L-prolinamide, 753 1-52-4, Phe2-TRH, 34783-35-2
D. Gupta, W Voelter: Hypothalamic Hormones-Structure, Synthesis
and Biological Activity. Verlag Chemie, Weinheim 1975.
W Voelter. K . Zech, K . Klernm, G . Ludwig, H . 4 . Menge, unpublished
results.
a) J. M . Sreuart, P. A. Machin, C . Dickinson, H . Ammon, H . Heck,
H . Flack: The XRAY System, Version of 1976. Tech. Rep. TR-446,
Computer Science Center, Univ. of Maryland, College Park, M D ; h)
P . Main, L. Lessinger, M . M . Woolfson, G. Germain, J . P. Declercq:
Multan 77, A Program for the Automatic Solution of Crystal Structures
from X-ray Diffraction Data. University of York 1977.
E. Schnabel, Justus Liebigs Ann. Chem. 702, 188 (1967).
K. Zech, Dissertation, Universitat Tubingen 1973; S. Furhs, Dissertation,
Universitat Tiihingen 1975.
R. H . Chambers, F. H. Carpenter. J. Am. Chem. SOC.7 7 , 1522 (1955);
D. Hammer, J. P. Greenstein, J. Biol. Chem. 193, 81 (1951).
a)S. Goldschmidt, C . J u t z , Chem. Ber. 86, 1 116 (1953); h) W J. LeQuesne,
G . Z Young, J. Chem. Soc. 1950, 1954, 1959; c) H. Gibian, E . Klieger,
Justus Liehigs Ann. Chem. 640, 145 (1961); d) P. Kurath, A . M . Thomas,
Helv. Chim. Acta 56, 1656 (1972).
E. Piefrzik, Dissertation, Universitat Tiihingen 1977.
than one turn and thus shielded from the anion. The possibility
(ii) is actually found in the complex formed from 1,20-bis(8quinolyloxy)-3,6,9,12,15,18-hexaoxaeicosane( I ) and RbI.
Compound (1) was obtained by condensation of8-hydroxyquinoline and heptaethylene glycol in alkaline medium, and
the complex with Rbl in boiling ethyl acetatelmethanol. Synthesis of crystalline complexes with NaSCN, NH4SCN, KSCN,
Ca(SCN)2,and Ba(SCN), has so far proved unsuccessful. The
'H-NMR spectrum of (l).RbI does not exhibit any
pronounced upfield shift of the cc,P-quinoline protons (cf. "9.
Hence it may be deduced that the quinoline rings of (I).RbI
are located outside the region of mutual anisotropism.
Slow cooling of (I).RbI in methanol/ethyl acetate yields
single crystals (ca. 3 x 1 x 0.5 mm3), space group C2/c, cell
constants a=42.1?, b=10.80, c= 15.95& p=100.4". The
intensities of 4672 independent reflections were measured with
a four-circle diffractometer (CUK~).
After solving the structure
by a combination of direct and Fourier methods, the structural
data were refined to R, = 9.6 % by least-squares methods with
anisotropic temperature factors for the heavy atoms and isotropic factors for C, N, 0.
Spherical Wrapping of a Linear Polyether around a
Cation-1,20-Bis(8-quinolyloxy)-3,6,9,12,15,1&hexaoxaeicosane RbI[**]
.
By Gabriela Weber, Wolfram Saenger, Fritz Mgtle, and Heinz
Siegerpl
In addition to crown ethers and three-dimensional cryptands, linear polyethers are being increasingly used for complexing cations"! It is remarkable in this context that even
1,2-ethanediol forms crystalline complexes with alkaline earth
metal ions['] and that this property is enhanced by rigid
aromatic end groups[']. Depending upon the chain length
of the polyether, various complex structures are obtained
in the series of arene-(OCHzCH2),0-arene ligands: ligands
with n=2 wrap in a circular fashion around a cation[31,and
extension of the ether chain by one or two OCHzCH2 units
leads to helical structuresr4.'I. Two possible arrangements
are conceivable for very long ligands: (i) helical polynuclear
complexes could turn out as S-shaped arrangements, with
a cation coordinated in each S loop, each cation being bound
to an anion for geometrical reasons (see c61), or (ii) a cation
could be spherically wrapped in a long ligand with more
Fig. 1. a) Arrangement of heteroatoms of ligand ( I ) on the coordination
sphere of R h + ; h) structure of complex ( I ) . Rbl. Since 1- is not coordinated
it has been omitted.
R h + ..heteroatom distances [A] for the polar region: N(i), 3.201; N(28).
3.371; 0(25), 3.086; for equatorial region: 0(4), 2.993; 0(7), 3.025; 0(10),
3.038; 0(13), 2.954; 0(16), 2.974; 0(19), 3.009; 0(22), 3.147 (mean standard
deviation kO.008 A).
[*] Prof. Dr. W. Saenger, Dr. G. Weber
Max-Planck-Institut fur experimentelle Medizin, Ahteilung Chemie
Herman-Rein-Strasse 3, D-3400 Gottingen (Germany)
Prof. Dr. F. Vogtle, Dip1.-Chem. H. Sieger
lnstitut f i r Organische Chemie und Biochemie der Universitat
Gerhard-Domagk-Strasse I , D-5300 Bonn (Germany)
[**I Structures of Polyether Complexes, Part 7.-Part 6: G. Weber, W Sarnger,
Actd Crystallogr.. in press.
226
In the complex (l).RbI (Fig. l), all the heteroatoms lie
approximately on the surface of a sphere of radius ~ 3 . k
Its poles are occupied by N(1) and N(28), in accord with
the results of 'H-NMR studies on the complex in solution.
Starting from N(1) the ligand chain runs to the equator of
Anguw. Chem. I n t . Ed. Engl. 18 ( 1 9 7 9 ) Wo. 3
0 Verlag Chemie, GmbH, D-6940 Wrinheim, 1979
0570-0833/79/0303-0226 $ 02.50@
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releasing, structure, molecular, thyrotropin, phe2, hormone, trh, analogues
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