Solid phase synthesis of N-aminodipeptides in high optical purity

Article abstract of DOI:10.1016/j.tetlet.2007.10.152

N-Aminodipeptide derivatives can be easily prepared with high optical purity on solid phase via a Mitsunobu protocol between a solid supported α-hydroxyacid and a free phthaloylated α-Z-N-aminohydrazide.

Full text of DOI:10.1016/j.tetlet.2007.10.152

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 156–158
Solid phase synthesis of N-aminodipeptides in high optical purity
a
a
a
´
Anne-Sophie Felten, Regis Vanderesse, Nicolas Brosse,
b
a,
*
´
Claude Didierjean and Brigitte Jamart-Gregoire
aLaboratoire de Chimie Physique Macromole´culaire, UMR CNRS-INPL 7568, Nancy-Universite´, ENSIC 1,
rue Grandville BP 451, 54001 Nancy, France
bLaboratoire de Cristallographie et Mode´lisation des Mate´riaux Mine´raux et Biologiques, UMR CNRS-UHP 7036, Nancy-Universite´,
Faculte´ des sciences, BP 23, 54506 Vandoeuvre les Nancy, France
Received 3 July 2007; revised 25 October 2007; accepted 29 October 2007
Available online 4 November 2007
Abstract—N-Aminodipeptide derivatives can be easily prepared with high optical purity on solid phase via a Mitsunobu protocol
between a solid supported a-hydroxyacid and a free phthaloylated a-Z-N-aminohydrazide.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Some years ago, we demonstrated that bis-nitrogen con-
taining aminoacid analogues such as hydrazinoacid1 and
N-aminodipeptide2 derivatives could be easily synthes-
ised via an original protocol involving a Mitsunobu reac-
tion. Using this procedure, N-aminodipeptide derivatives
3 were obtained from the reaction between phthaloylated
a-aminohydrazide derivatives 1 and (S)-a-hydroxyester
2 (Scheme 1).2
and to avoid the purification steps during the synthesis,
we report in this Letter conditions which allow the syn-
thesis of these pseudodipeptides on solid support. Look-
ing at the starting materials, it was possible to consider
two possibilities depending on the nature of the reactant
linked on the resin. So the reaction can be performed
between: (i) supported acidic partner of the Mitsunobu
reaction and free alcohol (Scheme 2) or (ii) supported
alcohol and the free acidic partner (Scheme 3). Both
strategies were tested.
The success of this reaction has been attributed to the
use of an acidic partner bearing a phthalimide moiety,
which (i) confers electronwithdrawing effects able to
enhance the acidic property of the nitrogen proton and
(ii) is not too hindered and then allows the SN2 reaction.
As one of the aims of the synthesis of N-aminodipep-
tides was to insert them in longer peptidic sequences
via SPPS (solid phase peptides synthesis) protocol, we
defined good conditions which allowed to convert the
phthalimide group into the more suitable Boc group
via a multi-step one-pot protocol.3 To be more efficient
First, as it has been demonstrated for the preparation
of secondary amines derivatives on solid support,4 we
decided to synthesise the supported acidic partner
from the supported trimellitic anhydride obtained via a
Mitsunobu reaction between trimellitic anhydride and
a Wang resin. Then, the supported phthalic anhydride
5 was able to react with a-Z-N-protected aminohydr-
azide 1 R1 = Me to give the supported acidic partner 6.
The latter was then able to be involved in the Mitsunobu
R2
R2 NPht
CO2R3
R2 NHBoc
R1
H
Mitsunobu
Z
N
Z
N
Z
N
CO2R3
R1
+
N
NPht
N
N
HO CO2R3
R1
H
H
H
O
reaction
O
O
1
4
2
3
Scheme 1. Pht = phthalimide group see Ref. 2.
Keywords: Solid phase organic chemistry; N-Aminopeptide; Mitsunobu reaction.
*
Corresponding author. Tel.: +33 3 83 17 52 79; fax: +33 3 83 37 99 77; e-mail: Brigitte.Jamart@ensic.inpl-nancy.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.152

A.-S. Felten et al. / Tetrahedron Letters 49 (2008) 156–158
157
O
O
O
O
O
a)
b)
c)
O
O
HOH2C
O
O
Z-Ala N N
H
O
Wang resin
O
5
6
O
O
NHBoc
N
d)
Z
N
CO2Me
R2
Z
N
CO2Me
N
H
N
H
O
R2
O
7
8
Scheme 2. Reagents: (a) trimellitic anhydride, DIAD, PPh3, THF; (b) (1) Z-NH–CH(CH3)-CONHNH2 THF, (2) DCC, HOBt, THF; (c) 2
(R3 = Me), DIAD, PPh3, THF; (d) (1) pyrrolidine, THF, (2) Boc2O, DMAP, THF, (3) MeNH2 (2 M in MeOH, 4 equiv), THF.
Pht
N
Pht
N
R2
R2
O
O
O
THPO
R1
O
b)
a)
c)
HO
N
N
O
ZHN
OH
ZHN
O
R1
10
R1
OH
R1
O
O
9
11
Scheme 3. Reagents: (a) (1) Wang resin, DIC, DMAP, cat., THF, (2) PTSA, CH2Cl2/MeOH (97:3); (b) PhtNNHCOCH(R2)NHZ (2), DIAD, PPh3,
THF; (c) TFA/DCM (1:1).
protocol and to react with a-hydroxyester 2 to give the
supported N-aminophthalimide 7. The release from the
resin can be performed by using the transprotection pro-
tocol that we published previously, which allowed to
directly replace the phthalimide group of a hydrazine
in a Boc protection.5 While some compounds 8 have
been obtained by this way, the use of this strategy pre-
sents several drawbacks: The reaction was sometimes
not reproducible and led to the formation of several
byproducts, which complicated the purification process.
In fact, we suspected the lability of the phthalimide
group and/or of the links between the solid support
and the phthalimide moiety to be responsible for all the
problems met and decided to test the use of other sup-
ported systems. Several resins (aminomethyl resin, 2-
chlorotrityl, BHA (Benzhydrylamine), etc.) were tested
without success. Moreover, no better results were ob-
tained when changing the trimellitic anhydride by other
substituted phthalic anhydrides: 2-acid chloride or 2-iso-
cyanate. These results let us to consider a second path-
way for which the electrophilic partner is anchored
onto a resin (Scheme 3).
stitution level of the Wang resin (1.2 mmol/g of hydroxy
groups) varied from 21% to 55% depending on the nat-
ure of the lateral chain. Taking into account the four
steps of the synthesis, these results correspond to an
average yield for each step varying from 68% to 86%.
Moreover, they show that the Mitsunobu reaction is
not affected by the steric hindrance generated by the
presence of the solid support. To confirm the stereose-
lectivity of the reaction leading to inversion of the con-
figuration of 10, we converted compound 11f into the
corresponding methyl ester derivative 3f and compared
its NMR spectra with the authentic samples of 3f and
its diastereoisomer, both of which were obtained by
solution phase synthesis.2 This confirmed that the solid
support protocol resulted in inversion of the stereocen-
tre in 10, giving N-aminodipeptides 11 in diastereomer-
ically pure form (>95%).
As we started from commercially available (S)-a-
hydroxyacids or those obtained by a nitrosation reac-
tion7 of the corresponding natural aminoacids, which
proceed with total retention of configuration, the abso-
lute configuration of all compounds 11 is (S,R). This
So, the protected a-hydroxyacids 9 were linked to a
Wang resin via their carboxylic group.6 The use of
PTSA allowed to remove the THP protection and then
to recover the supported alcohol 10, which can react
via the Mitsunobu protocol with the free acidic partner
2. This protocol has been successfully used for different
values of R1 and R2 corresponding to different amino
acid side chains. The results are gathered in Table 1.
The main advantage of this procedure is that the
a-hydroxyacid derivatives are anchored on the solid
support via its carboxylic group as any first amino acids
of a peptide chain constructed by SPPS. So, classical
protocols can be used to release the final product from
the support. Starting from a Wang resin we were able
to release N-aminodipeptides 11 by using TFA in
DCM. The overall yields of 11 calculated from the sub-
Table 1. Formation of N-aminodipeptides 11
R1
R2
Overall yield in 11 (%)a
H
CH3
CH2–CH(CH3)2
CH2–Phe
H
H
H
H
H
CH3
CH3
CH3
CH3
11a (49)
11b (38)
11c (39)
11d (48)
11e (47)
11f (37)
11g (44)
11h (55)
11i (21)
11j (21)
CH3
CH2–CH(CH3)2
CH2–Phe
CH2–Phe
CH3
CH(CH3)2
CH(CH3)2
a Yields of pure products calculated from the substitution level of the
resin (1.2 mmol/g of hydroxy groups).

158
A.-S. Felten et al. / Tetrahedron Letters 49 (2008) 156–158
(1 mL/100 mg of resin) were added DIC (3 equiv), a
catalytic amount of DMAP and THPO–hydroxy acid
(3 equiv). The resulting mixture was stirred for 2 h then
filtered and washed.
Step 2: 10 mL of a solution of p-TsOH (5 mg/mL) in CH2Cl2/
MeOH (97:3) was added to the resin and the resulting
mixture was stirred for 1 h. The reaction was performed two
times and the resin was then filtered and washed.
Step 3: PPh3 (3 equiv) and Z-AA-NHNPht (3 equiv) in 5 mL
of anhydrous THF were added to the resin. DIAD (3 equiv)
was added dropwise to the reaction and the resulting mixture
was stirred for 4 h. The reaction was performed two times
and the resin was filtered and washed.
Cleavage: 10 mL of a mixture of CH2Cl2/TFA (1:1) was
added to the resin. After 30 min, the polymer was removed by
filtration and the filtrate concentrated under vacuum. Com-
pounds 11 were purified by reverse-phase HPLC using a
˚
Figure 1. Ortep drawing of 3f.
Waters DELTA PAK column (15 mm, 300 A, 7.8 · 300 mm)
with a linear gradient of A = 0.1% TFA in water and
B = 0.1% TFA and 20% water in CH3CN, from 95%A to
0%A over 25 min.
result has also been confirmed by the X-ray crystallo-
graphic analysis of 3f (Fig. 1).8 It is important to notice
that N-aminodipeptides 11 obtained by this protocol are
free on their C-terminal function and can be involved di-
rectly in a further coupling reaction. Oligomerisation of
these dimers is under active investigation.
Spectroscopic data of Z-Phew[CON(NPht)]Ala-OH 11h:
1H NMR (CDCl3, 300 MHz): d (ppm) 7.97–7.78 (m, 4H, H
arom Pht); 7.29–7.06 (m, 10H, Harom); 5.41 (d, 1H,
J = 8.6 Hz, NHCOOCH2Ph); 5.11–4.78 (m, 3H,
NHCOOCH2Ph and CHCH3); 4.60–4.53 (m, 1H,
CHCH2Ph); 3.17–2.83 (m, 2H, CHCH2Ph); 1.52; 1.39 (2d,
3H, J = 6.3 Hz, CHCH3). NMR splitting can be due to the
classical cis/trans isomerism of the urethane or ureide CO–N
amide bond.
Supplementary data
13C NMR (CDCl3):
d (ppm) 173.6 (COOH); 170.9
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.10.152.
(CON(NPht)); 166.2; 165.8 (C@O Pht); 156.2
(NHCOOCH2Ph); 136.7; 136.3 (C arom); 136.2; 136.1 (CH
arom pht); 130.3; 130.0 (CH arom Z and Phe); 129.7 (C
arom); 129.1; 128.7; 128.5; 127.8; 127.6 (CH arom Z and
Phe); 125.3 (CH arom Pht); 67.9; 67.7 (NHCOOCH2Ph);
58.4 (CHCH3); 52.9 (CHCH2Ph); 38.6 (CHCH2Ph); 14.3
(CHCH3). HRMS calcd for C28H25N3O7 [M+Na+] m/z
538.15847, found 538.15883.
References and notes
´
1. Brosse, N.; Pinto, M.-F.; Jamart-Gregoire, B. J. Org.
7. Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U.
J. Chem. Soc., Perkin Trans. 1 1993, 11–14.
Chem. 2000, 65, 4370–4374; Brosse, N.; Pinto, M.-F.;
´
Bodiguel, J.; Jamart-Gregoire, B. J. Org. Chem. 2001, 66,
8. Crystal data for 3f: C23H23O7N3, Mw = 453.44, colourless
2869–2873.
˚
prism, orthorhombic, P212121 (#19), a = 8.988(2) A,
´
2. Brosse, N.; Grandeury, A.; Jamart-Gregoire, B. Tetrahe-
dron Lett. 2002, 43, 2009–2011.
3. Brosse, N.; Jamart-Gregoire, B. Tetrahedron Lett. 2002, 43,
3
˚
˚
˚
b = 13.078(3) A, c = 19.238(3) A, V = 2261.3(8) A , Z = 4,
Dcalcd = 1.332 g/cm3, l(CuKa) = 0.837 cmÀ1, 2409 reflec-
tions measured, 2409 unique, R1 [I > 2r(I)] = 0.041, wR2
(all data) = 0.120 for 299 parameters, GooF = 1.114,
residual density (max./min.) = 0. 177/À0.175 e AÀ3. Details
of the crystal structure (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 66814.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 01223 336033 or e-mail: deposit@
ccdc.cam.ac.uk].
´
249–251.
4. Glatz, H.; Bannwarth, W. Tetrahedron Lett. 2003, 44, 149–
152.
´
5. Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Gregoire,
B. Tetrahedron Lett. 2004, 45, 3569–3572.
6. Typical procedure for the preparation of 11 using the
procedure 2:
Anchoring the alcohol derivative:
Step 1: To a suspension of 0.3 g of Wang PS resin (cross
linked with 1% DVB, 200–400 mesh, 1.2 mmol/g) in THF