Liquid and solid phase syntheses of orthogonally protected α-hydrazinoacid derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.03.063

The first solid phase synthesis of chiral α-hydrazinoacids has been developed. This synthesis was achieved by the preparation of solid supported-N-alkyloxycarbonyl-aminophthalimides used as acidic partners in the Mitsunobu protocol involving α-hydroxyesters. Two different final trans-protection steps of the phthaloyl group, developed first in liquid phase, result in efficient releases of orthogonally bis-protected or fully tris-protected hydrazine derivatives. A comparison between liquid and solid phase syntheses is outlined: even if the overall yields are sometimes rather higher by the liquid phase synthesis, the on-resin protocol is much more rapid and convenient than the liquid protocol.

Full text of DOI:10.1016/j.tetlet.2004.03.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3569–3572
Liquid and solid phase syntheses of orthogonally protected
a-hydrazinoacid derivatives
*
ꢀ
Isabelle Bouillon, Nicolas Brosse, Regis Vanderesse and Brigitte Jamart-Gregoire
ꢀ
Laboratoire de Chimie Physique Macromolꢀeculaire, UMR 7568, ENSIC-INPL, BP 451, 54001 Nancy, France
Received 13 February 2004; accepted 10 March 2004
Abstract—The first solid phase synthesis of chiral a-hydrazinoacids has been developed. This synthesis was achieved by the
preparation of solid supported-N-alkyloxycarbonyl-aminophthalimides used as acidic partners in the Mitsunobu protocol involving
a-hydroxyesters. Two different final trans-protection steps of the phthaloyl group, developed first in liquid phase, result in efficient
releases of orthogonally bis-protected or fully tris-protected hydrazine derivatives. A comparison between liquid and solid phase
syntheses is outlined: even if the overall yields are sometimes rather higher by the liquid phase synthesis, the on-resin protocol is
much more rapid and convenient than the liquid protocol.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
peptide synthesis) has not been widely explored
because of the difficulties of their preparation.2 In the
literature, four main methods are described: the cat-
alytic hydrogenation of hydrazones,3;4 the Schestakov
rearrangement,5 the electrophilic N-amination of a-
aminoacids,6 and the nucleophilic substitution of
nosyloxy esters.7
With the availability of automated techniques, the solid
phase synthesis of small organic molecules is becoming a
fundamental method for the rapid and easy preparation
of libraries of organic compounds in order to accelerate
drug discovery process.1 This approach facilitates the
rapid synthesis of a large number of compounds in a
short time frame and facilitates their use in high
throughput screening.
We have recently shown that N-tert-butyloxycarbonyl-
aminophthalimide 2a and N-benzyloxycarbonylamino-
phthalimide 2b (easily obtained by the condensation of
the phthalic anhydride 1 onto the corresponding car-
bazates8a) were good acidic partners in the Mitsunobu
protocol;8 optically pure Na and/or Nb protected a-
hydrazinoesters 3 have been prepared using this method
involving chiral a-hydroxyesters as alcoholic partners
(Scheme 1).
Chiral a-hydrazinoacids are a particularly attractive
class of amino acid analogues since they can be incor-
porated in peptide syntheses by either Na or Nb atom
leading to the preparation of two families of pseudo-
peptides: the hydrazino-and N-amino-peptides.
Nevertheless, the chemistry of chiral a-hydrazinoacid
derivatives bearing an orthogonally protected hydraz-
ino moiety (permitting selective incorporations in a
In this context, the transfer of this new liquid phase
synthesis of chiral Na, Nb orthogonally bis-protected
R
NH2
N
O
β
H2N
R
H
α
OH
N
N
N
H
H
O
O
R
O
O
α-hydrazino acid
hydrazinopeptide
N-amino peptide
Keywords: Solid phase organic synthesis; a-Hydrazinoacid; Mitsunobu reaction; Protecting group.
* Corresponding author. Tel.: +33-(0)3-83-17-53-28; fax: +33-(0)3-83-37-99-77; e-mail: nicolas.brosse@ensic.inpl-nancy.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.063

3570
I. Bouillon et al. / Tetrahedron Letters 45 (2004) 3569–3572
O
O
O
P
N N
P
H
a
b
O
N N
CH COOR''
O
O
O
R'
1
3
2a P = Boc; 2b P = Z
Scheme 1. Reagents and conditions: (a) carbazate (H2NNHBoc for preparation of 2a or H2NNHZ for preparation of 2b), toluene, reflux; (b)
RCH(OH)COOR0, Mitsunobu conditions.
Table 1. Liquid phase preparation of protected a-hydrazinoesters 5
a-hydrazinoacids onto solid phase seems to be of great
interest. In this paper, we report the first solid phase
synthesis of chiral a-hydrazinoacid derivatives involving
solid supported-N-alkyloxycarbonylaminophthalimides
as acid partners in the Mitsunobu protocol. We also
describe a trans-protection reaction, developed first in
liquid phase, which can efficiently be used as a release
step of orthogonally bis-protected a-hydrazinoacid
derivatives (BocNH–NP–CHRCOOR0) from the resin.
Moreover, and taking into account recent results9
demonstrating the great interest of fully protected
hydrazine moiety of hydrazinoacid derivatives, we
defined a second efficient cleavage method leading to the
formation of tri- protected a-hydrazinoacid derivatives.
R
P
Timea (h)
Yieldb (%)
Boc
Boc
COCF3
Z
Z
4
4
5a 71
5b 75
5c 71
5d 64
Boc
Z
12
12
Z
a For step b.
b Yield of isolated compound calculated from 3.
and 7 and to introduce different protecting groups R
onto the Nb nitrogen atom. So, the conversion of 3 to 5
can be performed in good yields by a ‘one-pot’ reaction
involving first pyrrolidine, followed by R2O and, in the
last step methylamine as reactants (Scheme 3 and Table
1).
2. trans-Protection reactions of phthalimide group:
liquid phase reactions
3. Supported synthesis of a-hydrazinoesters
We have recently described10 a very mild and efficient
conversion of N-aminophthalimide derivatives into the
corresponding N-amino-di-tert-butylimidodicarbonates
4 (Scheme 2). We have shown that the selective removal
of one of the two Boc groups was possible by using a
catalytic amount of Mg(ClO4)2 and led to the formation
of compounds 5.
Two recent papers describe the preparation and the use
of phthalimide-containing resins: in the first one, Gelb
and co-workers11 described the Gabriel reaction starting
from an aminomethyl resin and in the second one
Rademann and co-workers12 (in parallel to our work)
related the solid phase synthesis of labelled carbohy-
drates starting from a N-methyl-aminomethyl resin. In
our study, we decided to start from a Wang resin and to
synthesise the supported Mitsunobu acidic partners in
three steps: (i) the formation of the trimellitic anhydride
linker (TAL) resin 8 by coupling trimellitic anhydride to
We were able to improve our method and avoid the use
of the Mg(ClO4)2 by replacing in the first step the methyl
amine by a secondary amine, the pyrrolidine. This new
protocol allowed us to isolate the stable intermediates 6
H
P
N N
b
Boc
Boc
P
N N
a
3
CH COOR'
Boc
CH COOR'
R
R
4
5
Scheme 2. Reagents and conditions: (a) i. MeNH2 1.5 equiv, THF; ii. Boc2O 3 equiv, DMAP cat.; (b) Mg(ClO4)2 cat., CH3CN.
N
N
O
C
H
O
C
N N
Σ
Η
Σ
P
O
O
c
b
a
N N
3
P
P
CH COOMe
N N
Me
CH
COOMe
CH COOMe
5
6
7
Me
Me
Scheme 3. Reagents and conditions: (a) Pyrrolidine 3 equiv, 4 h at rt, THF; (b) R2O 3 equiv, DMAP cat.; (c) MeNH2 1.5 equiv, 3 h, rt, THF.

I. Bouillon et al. / Tetrahedron Letters 45 (2004) 3569–3572
3571
O
O
O
O
O
a
b
CH2OH
CH2O
CH2O
OH
NH
O
P
N
H
8
O
9
c
e(Cleavage A)
f (Cleavage B)
O
O
O
4
5
O
d
P
P
H
CH2O
CH2O
N N
N N
CH COOR'
R
O
10
O
11
Scheme 4. Reagents and conditions: (a) trimellitic anhydride (3 equiv), PPh3 (3 equiv), DIAD (3 equiv), THF; (b) H2NNHBoc or H2NNHZ (3 equiv),
THF; (c) DCC (4 equiv), HOBt (4 equiv), THF; (d) RCH(OH)COOR0 (3 equiv), PPh3 (3 equiv), DIAD (3 equiv), THF; (e) Cleavage A. i. MeNH2
(4 equiv), THF; ii. Boc2O (4 equiv), DMAP cat.; (f) Cleavage B. i. pyrrolidine (4 equiv), THF; ii. Boc2O (4 equiv), DMAP cat.; (iii) MeNH2 (4 equiv),
THF.
Table 2. Solid phase preparation of a-hydrazinoesters 4 and 5
the Wang resin via the Mitsunobu reaction (ii) the
transformation of the TAL resin into 9 by action of
3 equiv of the corresponding carbazate (iii) the forma-
tion of compound 10 by a cyclisation step of 9 by DCC–
HOBt. The supported a-hydrazinoesters 11 were
obtained using a second Mitsunobu reaction between 10
and various commercially available a-hydroxyesters
(Scheme 4).
P
R
R0
Cleavage
Yielda (%)
Z
CH3
H
CH3
CH3
A
A
A
A
B
B
B
B
B
B
4a 62
4b 56
4c 55
4d 35
5b 40
5e 80
5f 63
5g 65
5h 55
5i 58
Z
Z
H
CH2Ph
CH3
CH3
Boc
Boc
Z
CH3
CH3
CH3
H
CH2CH3
CH3
Z
Z
H
Ph
CH2Ph
CH3
CH3
Taking into account the results described above for
liquid phase trans-protection of the phthalimido group
(pathway A Scheme 2 and pathway B Scheme 3), we have
developed two solid phase cleavage protocols (Cleavage
A and B) permitting, respectively, the preparation of
compounds 4 and 5. The fully protected hydrazinoesters
4 (Cleavage A) were released by treatment with MeNH2
in THF (3 h) followed by action of Boc2O/DMAP cat.
After evaporation of the solvent, the excess of reagents
was removed by column chromatography. For the
preparation of the NbHBoc hydrazinoesters 5 (Cleavage
B), the solid suspension of resin-bond hydrazinoester
was treated successively by pyrrolidine, Boc2O and
methylamine. The released protected hydrazinoesters 5
were isolated after removal of the solvent and the excess
of amine by evaporation under vacuum.
Z
Z
CH2Ph
a Yield of isolated compound calculated from the resin substitution.
are quite similar to the overall yield obtained in liquid
phase.8;10 When applied to the more hindered Boc group
(compounds 4d, 5b), the solid phase protocol leads to
about 20% lower yields compared to the liquid one,
suggesting that the Mitsunobu alkylation reactions
using supported acidic partners could be more sensitive
to steric hindrance. Nevertheless, the solid phase
approach is much more rapid and convenient than the
liquid phase protocol.
In summary, we have developed the first solid phase
synthesis of orthogonally protected chiral a-hydrazino-
acid derivatives bearing three points of diversity: the
lateral chain, the ester group and the protecting group of
the Na. An original trans-protection reaction of the
phthaloyl group results in efficient releases of orthogo-
nally bis-protected NHBoc or fully tris-protected NBoc2
derivatives useful for the preparation of hydrazino- and
N-amino-pseudopeptides.
4. Results
To demonstrate the significance of the use of our resin
for the preparation of protected hydrazine derivatives,
we have prepared a small collection of protected a-
hydrazinoesters (Table 2). The syntheses involve three
points of diversity: (i) the lateral chain of the hydrazi-
noester (R) (ii) the ester group (R0) (iii) the protecting
group (P ¼ Boc or Z) of the Na nitrogen atom. The
purity of the isolated compounds was checked by NMR
and ccm; the overall yields (six steps for cleavage A,
seven steps for cleavage B) are calculated from the resin
substitution (Table 2).
5. Experimental
Liquid phase: General procedure for trans-protection
reactions of phthalimide group. To a solution of com-
pound 3 (3 mM) in THF (20 mL) was added at room
temperature 3 equiv of pyrrolidine (9 mM). The mixture
was stirred at room temperature until completion
For P ¼ Z, the yields obtained are very good for multi-
step preparations regardless the nature of R and R0 and

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I. Bouillon et al. / Tetrahedron Letters 45 (2004) 3569–3572
(about 4 h, monitored by TLC). The solvent and the
excess of amine were removed in vacuo. To the white
solid those obtained dissolved in THF (20 mL) was
References and notes
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added R2O (1.5 equiv, 4.5 mmol) and
a catalytic
amount of DMAP. The mixture was stirred at room
temperature until completion (monitored by TLC). The
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solved in THF and a solution of methylamine (4.5 mM,
2 M in MeOH) was added at room temperature. After
3 h, the solvent and the excess of amine were removed
in vacuo and 5 was purified by column chromatogra-
phy.
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Solid phase: General procedure for supported synthesis
of a-hydrazinoesters. All the reactions were performed
at room temperature; the resin suspension was gently
shaken by N2 bubbling; after each step, the resin was
filtrated, washed (twice with CH2Cl2, and twice with
THF) and resuspended in THF. Step 1: to a suspension
of 0.5 g of Wang PS resin (cross linked with 1% DVB,
200–400 mesh, 1.08 mM/g) in THF, was added PPh3
(3 equiv, 1.6 mM), trimellitic anhydride (3 equiv,
1.6 mM) and then, in one portion, DIAD (3 equiv,
1.6 mM); reaction time: 4 h. Step 2: carbazate was
added (3 equiv, 0.54 mM) to the mixture; reaction time:
4 h. Step 3: DCC (4 equiv, 2.2 mM) and HOBt (4 equiv,
2.2 mM) were added; reaction time: 3 h. Step 4: to the
suspension was added PPh3 (3 equiv, 1.6 mM), a-
hydroxyester (RCH(OH)COOR0, 3 equiv, 1.6 mM) and
then, in one portion, DIAD (3 equiv, 1.6 mM); reaction
time: 4 h. Cleavage A. Step 5: methylamine (4 equiv,
2.2 mM, 2 M in MeOH) was added in one portion;
reaction time: 3 h (without N2 bubbling). Step 6: Boc2O
(4 equiv, 2.2 mM) and a catalytic amount of DMAP
were added. After 2 h, the polymer was removed by
filtration; the filtrate was evaporated and the com-
pound 4 was chromatographed on silica gel. Cleavage
B. Step 5: pyrrolidine (4 equiv, 2.2 mM) was added in
one portion; reaction time: 3 h. Step 6: Boc2O (4 equiv,
2.2 mM) and a catalytic amount of DMAP were added;
reaction time: 3 h. Step 7: methylamine (4 equiv,
2.2 mM, 2 M in MeOH) was added in one portion; after
2 h (without N2 bubbling), the polymer was removed by
filtration; the filtrate was evaporated to yield pure
compound 5.
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