First synthesis of cyclotrihydrazino peptides

Article abstract of DOI:10.1039/a701932g

Synthesis of novel cyclotrihydrazino peptides using an original cyclisation method at high dilution.

Full text of DOI:10.1039/a701932g

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First synthesis of cyclotrihydrazino peptides
Sophie Carret, Miche`le Baudy-Floc’h, Albert Robert and Philippe Le Grel*
Groupe de Recherches Synthe`se et Electrosynthe`se Organiques Universite´ de Rennes I, UMR CNRS 6510 Avenue du Ge´ne´ral
Leclerc, F-35042 Rennes Ce´dex, France
Synthesis of novel cyclotrihydrazino peptides using an
original cyclisation method at high dilution.
favourable conformation bringing nearer the two reactive ends
(Fig. 1).
It is worth noting that despite the high solubility of 7 and the
insolubility of 8 in water, this solvent failed to allow cyclisation,
possibly because competitive hydrogen bonding with water
A growing number of peptides are regularly isolated from
animal and human tissues. Most exhibit interesting biological
effects as hormones or neuromediators. From this point of view
they appear to possess high potential as therapeutic agents.
However, among other reasons, their low bioavailability
represents a strong limitation on their use in this field. To solve
this problem peptide analogues have been synthesised and
screened to produce active peptidomimetic compounds with
enhanced enzyme resistance.1 Among them, pseudo-peptides,
in which the peptidic linkage is modified, are the object of great
interest and have already lead to some concrete applications.
For example ‘Zoladex’ is a powerful anticancer drug in the
azapeptide class.2
Peptidase action is also generally lower on cyclic peptides
and some, like Bottromycin, have found good use as antibiot-
ics.3 However, obtaining cyclic derivatives remains a problem-
atic aspect of peptidic synthesis; yields are generally low and
various factors influence the success or failure of cyclisation,
including the nature and the connections of amino acid residues,
solvent effects, concentration and also the type of reaction
involved to induce ring closure.4,5
Here we report preliminary results of the synthesis of, to the
best of our knowledge, the first cyclohydrazino peptides. The
linear precursors were prepared using improvements to a
methodology that we have already described in a previous
paper.6 To achieve the ring closure we perfected an original
strategy which supplements classical methods of peptide
cyclisation such as azide activation,7 activated esters8 or
coupling reagents.9 Scheme 1 summarizes the synthesis.
Reacting gem-dicyano epoxides10 1 with ButCO2NHNH2·HBr
leads to a-halo hydrazides 2.11 Substitution of the halogen by
methylhydrazine gives 3 which is then acylated by chloroacetyl
chloride to afford 4. Reiteration of these two steps gives 6 which
includes a terminal azaglycine ester linked to an aryl hydrazino-
sarcosine, itself connected to an N-chloroacylated hydrazino-
sarcosine.
R
H
N
R
CN
CN
i
CO2But
Br
N
H
H
O
O
O
1
2
ii
H
R
H
H
N
R
H
N
N
N
CO2But
CO2But
Cl
H
N
N
H
H
N
N
H
iii
O
Me
O
Me
4
3
ii
H
N
H
R
H
N
N
CO2But
N
N
N
H
Me
O
Me
O
5
iii
H
H
N
R
H
N
N
CO2But
Cl
N
N
N
H
O
Me
O
Me
O
R
6
iv
H
N
H
N
R
H
N
O
Cl
N
N
NH2•HCl
Me
H
O
Me
O
Me
O
N
H
O
7
N
N
v
H
N
O
N
N
H
Me
We took advantage of the high lability of the halogen atom in
a-halo hydrazides. Indeed, we have shown that such halogens
are easily displaced by nucleophiles when the reaction takes
place in the presence of an additional base.12 After elimination
of the Boc function we get the polyhalo compound 7 (with
undetermined HCl stoichiometry); this was then treated in high
dilution in MeCN with pyridine (5 equiv.). Cyclotrihydrazino
peptide 8 precipitated slowly as an amorphous powder (20%
yield after purification). Compound 8 was characterized by 1H
and 13C NMR spectroscopy, and its monomeric structure was
established by FAB mass spectroscopy (formation of the
cyclodimer had to be ruled out). Microanalysis confirmed the
high purity of the compound.† At the time we undertook this
work, Gani used a similar method to synthesise 1,2,5-triaze-
pine-3,6-diones.13
8a,b
a R = p-ClC6H4
b R = p-MeC6H4
Scheme
1
Reagents and conditions (for
R
=
p-ClC6H4): i, But-
CO2NHNH2·HBr, MeCN, room temp., 8 h, 99%; ii, NH2NHMe, MeCN,
0 °C, 2 h, 93%; iii, ClCH2COCl, pyridine, CH2Cl2, 0 °C, 84%; iv, HCl (g),
CH2Cl2, 5 min., room temp., 99%; v, pyridine, MeCN, room temp. 2 d,
20%
R
Me
H
O
N
N
N
H
O
H
NH2
N
Me
N
It has been shown by X-ray and model studies that hydrazino
acid residues can stabilize the folded conformation of small
pseudo-peptidic patterns by hydrogen bonding.14 The success
of our synthesis of pseudo-peptide 8 may arise from such a
Cl
Fig. 1
O
Chem. Commun., 1997
1441

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2 J. Gante, Synthesis, 1989, 405.
destroys the favourable conformation for closure. This result
emphasizes the crucial role played by the solvent in determining
the precursor’s geometry.
This preliminary work opens the way to the preparation of
other original cyclopseudo-peptides of smaller or larger size,
with different arrangements and various side chains. We also
plan to investigate solvent effects in more detail; in particular
we will examine the influence of adding ions to the reactions
carried out in water.
3 Y. A. Ovchinnikov and V. T. Ivanov, Tetrahedron, 1989, 31, 2177.
4 M. Bodanszky, Principles of Peptide Synthesis, Springer Verlag,
1984.
5 K. D. Kopple, J. Pharm. Sci., 1972, 61, 1345.
6 C. Barre´, P. Le Grel, A. Robert and M. Baudy-Floc’h, J. Chem. Soc.,
Chem. Commun., 1994, 607.
7 Y. S. Klausner and M. Bodansky, Synthesis, 1974, 549.
8 M. Waki and N. Izumiyia, J. Am. Chem. Soc., 1967, 89, 1278.
9 R. Paul and G. W. Anderson, J. Am. Chem. Soc., 1960, 82, 4596;
B. Neises and W. Steglich, Angew. Chem., Int. Ed. Engl., 1978, 17, 522;
B. Castro, J. R. Dormoy, G. Evin and C. Selve, Tetrahedron Lett., 1975,
1219; R. Knorr, A. Trzeciak, W. Bannwarth and D. Gillessen,
Tetrahedron Lett., 1989, 30, 1927.
Footnotes
* E-mail: michele.baudy-floch@univ-rennes1.fr
† Selected data for 8a: 20%; mp > 260 °C; 1H NMR (200 MHz, D2O–
CF3CO2H) 2.24 (s, 3 H), 2.58 (s, 3 H), 3.27 (m, 2 H), 3.36 (m, 2 H), 4.24
(s, 1 H), 7.37 (m, 4 H); 13C NMR (200 MHz, D2O–[2H6]DMSO) 43 (q, J
142 Hz), 44 (q, J 142 Hz), 53 (t, J 147 Hz), 59 (t, J 150 Hz), 70 (d, J 142
Hz), 128.5 (d, J 168 Hz), 129 (d, J 168 Hz), 132, 135, 166, 168, 172; nmax
(Nujol)/cm21 3290, 3240 br (NH), 1700, 1650, 1620 br (CO); HRMS
(FAB) (MH+) Calc. for C14H20N6O3Cl: 355.1284. Found: 355.1263. Calc.:
C, 47.39; H, 5.40; N, 23.69; Cl, 9.90. Found: C, 47.45; H, 5.36; N, 23.66;
Cl, 10.00%.
10 Epoxides 1 were prepared in a two step procedure. For the first one, a
Knoevenagel–Cope condensation, see P. D. Gardner and R. L. Brandon,
J. Org. Chem., 1957, 22, 1704. For the second step, a stereospecific
epoxidation of the alkene by sodium hypochlorite, see M. Baudy,
A. Robert and A. Foucaud, J. Org. Chem., 1978, 43, 3732.
11 P. Le Grel, M. Baudy-Floc’h and A. Robert, Synthesis, 1987, 306.
12 P. LeGrel, M. Baudy-Floc’h and A. Robert, Tetrahedron, 1988, 44,
4805.
13 M. M. Lenman, S. L. Ingham and D. Gani, Chem. Commun., 1996,
85.
14 M. Marraud, V. Dupont, V. Grand, S. Zerkout, A. Lecoq, G. Boussard,
J. Vidal, A. Collet and A. Aubry, Biopolymers, 1993, 33, 1135.
References
1 A. Giannis and T. Kolter, Angew. Chem., Int. Ed. Engl., 1993, 32,
1244.
Received in Glasgow, UK, 6th February 1997; 7/01932G
1442
Chem. Commun., 1997