Efficient synthesis of Nα-Me, Nβ-Boc-protected α-hydrazinoacids: access to 1:1:1 [Nα-Me α-hydrazino/α/Nα-Me α-hydrazino]trimers

Article abstract of DOI:10.1016/j.tetlet.2009.08.095

The preparation of optically pure N^α-Me, N^β-Boc-protected α-hydrazinoacids in large scale is described via a S_N2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N^α-Me α-hydr

Full text of DOI:10.1016/j.tetlet.2009.08.095

Tetrahedron Letters 50 (2009) 6377–6379
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
a
Efficient synthesis of N -Me, Nb-Boc-protected
a
-hydrazinoacids: access
a
a
to 1:1:1 [N -Me
a
-hydrazino/
a/N -Me
a
-hydrazino]trimers
*
Samir Acherar, Brigitte Jamart-Grégoire
Laboratoire de Chimie Physique Macromoléculaire, UMR CNRS-INPL 7568, Nancy-Université, 1, rue grandville BP 451, 54001 Nancy, France
a r t i c l e i n f o
a b s t r a c t
a
The preparation of optically pure N -Me, Nb-Boc-protected
a-hydrazinoacids in large scale is described
Article history:
Received 15 July 2009
Revised 31 July 2009
Accepted 26 August 2009
Available online 1 September 2009
a
via a SN2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N -Me
-hydrazino/a/N -Me a-hydrazino]trimers.
a
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pseudopeptide
a-Hydrazinoacids
SN2
Hydrazinopeptides are a class of peptide analogues for which
pounds as acidic partners. As a proof, we demonstrated that the
replacement of the alkoxycarbonyl group by an alkyl one did not
lead to any substitution. In our works dealing with the synthesis
of mixed alpha-hydrazino oligomers, we were confronted to the
one (or more) peptidic bond(s) has (have) been replaced by one
(or more) hydrazidic bond(s).1 As recently demonstrated by See-
bach and Lelais,2 the hydrazidic bond is highly resistant to prote-
ase, and hydrazinopeptides could be interesting peptidomimetic
candidates in drug design. Moreover, the few investigations con-
cerning the structural analysis of foldamers constructed starting
a
synthesis of trimers 14 and 15 bearing an alkyl group on the N
of the hydrazinoacid units (Scheme 2). This synthesis necessitated,
first, the synthesis of compound 2, analog to 1 where the Z group is
replaced by an alkyl one. As stated before, these compounds cannot
be synthesized via the Mitsunobu protocol starting from N-
alkylaminophthalimide.
In our preliminary studies, we tried to obtain compound 2 from
compound 3 (Scheme 1). Unfortunately, in spite of considerable ef-
forts, we were not able to introduce the alkyl group (Fig. 1). The
method described by Vidal et al. using oxaziridine method7 was
no more suitable for the preparation of 2 in multigram scale due
to the high cost of N-Boc-3-(4-cyanophenyl)oxaziridine (BPCO).
from
a-hydrazinoacids seem to demonstrate that the presence of
supplementary nitrogen atoms in the backbone leads to new forms
of intramolecular structuration.3 A few years ago,4–6 we demon-
a
strated that enantiomerically pure N -Z, Nb-Doc-protected
a
-
hydrazinoacids 1 (Fig. 1) can be synthesized by using a Mitsunobu
protocol as the key reaction, where N-alkoxycarbonyl aminoph-
thalimide acts as an acidic partner.
As a result, the reaction of N-tert-butyloxycarbonyl- and N-ben-
zyloxycarbonyl-aminophthalimides with commercially available
a
(S)- and (R)-
a
-hydroxyesters led to either N -protected, Nb-bispro-
In this Letter, first we describe a general method for the prepa-
tected or orthogonal N , Nb-triprotected, respectively, (R)- and (S)-
ration of N -Me, Nb-Boc-protected
a
-hydrazinoacids 2 in multi-
a
a
a
-hydrazinoesters with high optical purity. These procedures rep-
resent also an attractive alternative to the methods currently used
for the preparation of -hydrazinoacid derivatives. The use of N-
gram scale (Fig. 1) in good yields and high optical purity8 using
SN2 reaction as the key step. Second, we describe the use of com-
pound 2 as the starting material for the initial synthesis of 1:1:1
a
a
a
alkoxycarbonyl aminophthalimides as acidic partners allowed for
the first time to replace an alcohol function by a hydrazine one
via a Mitsunobu protocol. In fact, the success of this reaction is re-
lated to the presence of the phthalimide group bearing two car-
bonyl functions and to the presence of a supplementary carbonyl
belonging to the alkyloxycarbonyl one, which contributes to de-
crease the pKa of the sole hydrogen and allows to use these com-
[N -Me
a
-hydrazino/
a
/N -Me
a-hydrazino]trimers.
R'
N
O
1 : R' = Z
Boc
2 : R' = Me
OH
N
H
3 : R' = H
R
* Corresponding author. Tel.: +33 3 83 17 52 79; fax: +33 3 83 37 99 77.
E-mail address: brigitte.jamart@ensic.inpl-nancy.fr (B. Jamart-Grégoire).
Figure 1. N -Z and N -Me, Nb-Doc-protected
a-hydrazinoacids.
a
a
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.095

6378
S. Acherar, B. Jamart-Grégoire / Tetrahedron Letters 50 (2009) 6377–6379
A systematic study10 demonstrated that the yield can be consid-
O
erably increased by using 2 equiv of 2,6-lutidine. Moreover, we
demonstrated that only 1 equiv. of BocNHNHR0 was necessary to
obtain good results (Method B) (Table 1).
Boc
N
N
H
OH
NaOH 1N (2.0 equiv.)
MeOH/H2O (2:1)
95%
6b
As a result, we established the following general procedure
2b
a
(Method B) for the multigram synthesis of N -Me, Nb-Boc-pro-
O
tected a-hydrazinoesters 6a–c:
‘A solution of hydroxyester (1.0 equiv) and 2,6-lutidine
(2.3 equiv) in CH2Cl2 at 0 °C was treated with triflic anhydride
(1.1 equiv). After 15 min, a solution of BocNHNHMe in CH2Cl2
was added dropwise for 30 min and the mixture was stirred for
4 h at 0 °C. After evaporation of the solvent, Et2O was added and
2,6-lutidinium triflate was precipitated by storing the reaction
mixture overnight in the refrigerator. The 2,6-lutidinium triflate
was filtered and the filtrate was diluted with Et2O and washed
with water, dried over MgSO4, filtered, and evaporated in vacuo.
The residue was purified by flash chromatography.’
N
SOCl2 (2.1 equiv.)
HCl.H2N
O
MeOH
quantitative
7
a
a
Scheme 1. Synthesis of N -Me, Nb-Boc-protected
a-hydrazinoacid 2b and N -Me
a-
hydrazinoester 7 stabilized as hydrochloride salt.
In a preliminary study, we decided to use the protocol described
by Hoffman and Kim9 (Method A) for the synthesis of 2-(Boc-
This methodology allowed us to obtain large quantities of com-
a
pound 6 which can be involved in the preparation of 1:1:1 [N -Me
hydrazinyl) esters 5. Starting from 1 mmol of the corresponding
a
hydroxyester 4, the N -Me, Nb-Boc-protected
a-hydrazinoesters 6
a
a
-hydrazino/
a
/N -Me
a-hydrazino]trimers.
The second part of this Letter deals with the use of 6b as the start-
were obtained in good yield. Unfortunately, the yield decreased
dramatically when performing this reaction on a multigram scale
(30 mmol of hydroxyester) (Table 1).
a
ing material for the synthesis of two 1:1:1 [N -Me
a
-hydrazino/a/
a
N -Me a-hydrazino] trimers 14 and 15 (Scheme 2).
O
CH3
O
CH3
HCl.H-Ala-OMe (L or D, 1.2 equiv.)
EDC (1.2 equiv.)
Boc
N
Boc
N
O
OH
NaOH 1N (2 equiv.)
N
N
N
H
N
2b
H
H
H
HOBt (1.2 equiv.)
Et3N (2.4 equiv.)
MeOH/H2O (2:1)
O
O
CH3
CH3
CH3
CH3
(89%), 11 :
8 :
(98%), 9 :
(92%),
10 :
(93%),
7 (1.2 equiv.)
O
CH3
O
CH3
EDC (1.2 equiv.)
NaOH 1N (2 equiv.)
H
N
H
N
Boc
N
O
Boc
N
OH
HOBt (1.2 equiv.)
Et3N (2.4 equiv.)
N
N
H
N
N
N
H
N
MeOH/H2O (3:1)
H
H
O
O
O
O
CH3
CH3
CH3
CH3
12 :
(86%), 13 :
(93%),
14 :
-hydrazino]trimers 14 and 15.
(86%), 15 :
(99%),
a
a
Scheme 2. Synthesis of 1:1:1 [N -Me
a
-hydrazino/
a
/N -Me
a
Table 1
a
Synthesis of N -Me, Nb-Boc-protected
a
-hydrazinoesters 6
Method A:
R'
O
O
1.1 equiv.
1- Tf2O (
1.15 equiv.
), 2,6-lutidine ( ), 0°C, 5 min
Boc
N
HO
2.0 equiv.
2- BocNHNHR' (
), 0°C, 2 h, CH2Cl2
N
O
O
H
Method B:
R
R
1.1 equiv.
2.3 equiv.
), 2,6-lutidine (
1- Tf2O (
), 0°C, 15 min
4 (1 equiv.)
5 : R'=H
2- BocNHNHR' (1.0 equiv.), 0°C, 4 h, CH2Cl2
6 : R'=Me
Compounds
R
Method A
Method B
Yield (%) (starting from 1 mmol of 4)
Yield (%) (starting from 30 mmol of 4)
Yield (%) (starting from 30 mmol of 4)
5
See Ref. 9
CH3
CH2CH(CH3)2
CH2Ph
80–100
87
81
6a
6b
6c
48
45
45
82
80
78
80

S. Acherar, B. Jamart-Grégoire / Tetrahedron Letters 50 (2009) 6377–6379
6379
After performing the saponification of the ester group of 6b, we
References and notes
were able to obtain the corresponding free C-terminal compound
2b. The use of thionyl chloride in methanol11 led to the deprotec-
tion of hydrazine group and to the esterification of carboxylic
one giving in one pot compound 7 in quantitative yield (Scheme 1).
1. Marraud, M.; Vanderesse, R.. In Houben–Weyl; Goodman, M., Ed.; Thieme
Stuttgart: New York, NY, 2003; Vol. 86, pp 423–457.
2. Lelais, G.; Seebach, D. Helv. Chim. Acta 2003, 86, 4152–4168.
3. (a) Aubry, A.; Bayeul, D.; Mangeot, J.-P.; Vidal, J.; Stérin, S.; Collet, A.; Lecoq, A.;
Marraud, M. Biopolymers 1991, 31, 793–801; (b) Günther, R.; Hofmann, H.-J. J.
Am. Chem. Soc. 2001, 123, 247–255.
4. Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Grégoire, B. Tetrahedron Lett.
2004, 45, 3569–3572.
5. Brosse, N.; Pinto, M.-F.; Bodiguel, J.; Jamart-Grégoire, B. J. Org. Chem. 2001, 66,
2869–2873.
A first coupling reaction of the methyl ester of (D or L) alanine
and 2b under classical conditions12 led to the corresponding
pseudodipeptides 8 or 9. Saponification of 8 and 9 gave in good
yields, respectively, 10 and 11 which can be involved in a second
coupling reaction with 7, and led to the formation of the desired
trimers 14 and 15 after an ultimate step of saponification.
6. Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Grégoire, B. Tetrahedron 2007, 63,
2223–2234.
7. Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.-C.; Aubry, A.; Collet, A. Chem. Eur. J.
1997, 3, 1691–1709.
8. Ee >99% and diastereoisomers of 8 and 9 were not observed during the first
In summary, we have developed a general method for the prep-
a
aration of N -Me, Nb-Boc-protected
a-hydrazinoacids 2 using the
SN2 reaction as the key step. Starting from 2b we were able to ob-
coupling reaction of 2b with HCl.H.Ala.Ome (L or D) (Scheme 2).
a
tain for the first time the synthesis of 1:1:1 [N -Me
a
-hydrazino/
a/
9. Hoffman, R. V.; Kim, H. O. Tetrahedron Lett. 1990, 31, 2953–2956.
a
10. A paper concerning the SN2 methodology to afford N -R0, Nb-Boc-protected
a-
a
N -Me
a-hydrazino]trimers 14 and 15 in good yield. The confor-
hydrazinoacids (R,R0 = Ala, Val, Leu and Phe) is still in progress and will be
mational analysis of these oligomers is under active investigation
in order to determine their ability to fold in solution.
published as soon as possible. The high optical purity will be verified by
a
comparison of [
a
]
D
of N -CH2Ph, Nb-Boc-protected
a-hydrazinoacids already
obtained using oxaziridine method.
Acknowledgment
R'
N
O
(R,R’=Ala, Val, Leu and Phe)
The authors thank the National Research Agency (ANR) for
financial support (Synthefoldame No. NT05_4_42848).
Boc
N
OH
H
Supplementary data
R
11. Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 36, 1109–1115.
12. Bodansky, M.; Bodansky, A. In The Practice of Peptide Synthesis, 2nd ed.;
Springer: Berlin Heidelberg, 1994; pp 116–117.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.095.