Nβ-Fmoc- Nβ-Methyl-aza-β3- amino acids

Article abstract of DOI:10.1055/s-0030-1259510

The potential of peptides as drug candidates is limited by their poor pharmacokinetic properties. Many peptides have a short half-life, in vivo half-life, and insufficient oral availability. Inspired by the N-methylation of peptides as a promising way to

Full text of DOI:10.1055/s-0030-1259510

LETTER
327
Nb-Fmoc-Nb-Methyl-aza-b3-amino Acids
b
N
r
-
N
-Met
è
hyl-aza
-
b
-
3n
a
minoAcidse Nicolas, Ksenija Kisseljova, Patrick Bauchat, Michèle Baudy-Floc’h*
Groupe ‘Ciblage et Auto-Assemblages Fonctionnels’, UMR 6226 CNRS, Sciences Chimiques de Rennes, Université de Rennes I,
263 Av. du Général Leclerc, 35042 Rennes Cedex, France
Fax +33(2)3236738; E-mail: michele.baudy-Floch@univ-rennes1.fr
Received 29 October 2010
Unnatural aza-b3-peptides are synthetic compounds de-
signed to mimic peptides and increased their bioavailabil-
ity.14 They can have chemically diverse side chains, but
they are required to have amide bonds with increased un-
Abstract: The potential of peptides as drug candidates is limited by
their poor pharmacokinetic properties. Many peptides have a short
half-life, in vivo half-life, and insufficient oral availability. Inspired
by the N-methylation of peptides as a promising way to rationally
improve key pharmacokinetic characteristics, we report our efforts proteolytically stability, rendering these peptides resistant
toward an easy synthesis of new monomers Nb-Fmoc-Nb-Me-aza-
to enzymatic proteolysis. Yet, additional modifications
are required to generate peptides with enhanced enzymat-
ic stability and improved oral bioavailability.
b3-amino acids. These synthetic building blocks will be useful for
solid-phase synthesis of new peptidomimetics.
Key words: N-methyl, aza analogues, hydrazine, reductive amina-
tion, amino acids
The aim of the work reported here was to synthesize Nb-
Fmoc-Nb-Me-aza-b3-amino acid monomers as new build-
ing blocks.
Low bioavailability of orally administrated peptides is at-
tributed to their inactivation in the gastrointestinal tract.
R1
FmocCl
Fmoc
R1CHO
70–90%
Fmoc
This enhanced enzymatic degradation in the gut wall by a
NH2
CH2Cl2, Et3N
N
N
MeNHNH2
N
variety of peptidases expressed at the enterocytes brush
border1 and to their poor intestinal permeability.2 In addi-
tion, the instability of peptides toward peptidases in the
systemic blood circulation causes their rapid elimination
(i.e., short half-life). These factors limit the use of pep-
tides as therapeutic agents in the clinical setting. Several
strategies have been used to reduce enzymatic cleavage
and enhance uptake into the systemic blood circulation,
including prodrug approaches, use of peptidomimetics,
and various structural modifications, such as covalent at-
tachment of polyethylene glycol (PEG),3 lipidation,4 and
chemical modifications, for example, cyclization,5 D-ami-
no acid substitution, and N-methylation.6
N-Methylation is a precious tool to improve lipophilicity,7
proteolytic stability,8 and bioavailability9 and to induce
conformational rigidity to the peptide backbone.10 How-
ever, multiple N-methylation has been rarely employed,11
probably owing to the limited availability of N-methylat-
ed amino acids and their tediously synthesis.12 To our
knowledge, N-methyl-N-nosyl-b3-amino acids are the
first amino acid analogues which have been described
(Figure 1).13
–78 °C
92%
Me
1
2
3
Me
R1
R
N
O
OCHCO2H
NaBH3CN
Fmoc
NaBH3CN
Fmoc
N
NH
OH
HCl (2 M)
96 %
HCl (2 M)
94%
N
5 R = CH2R1
Me
4
Me
Nβ-Fmoc-Nβ-Me-aza-β3-aa-OH
Scheme 1 General procedure Nb-Fmoc-Nb-Me-aza-b3-aa-OH 5
We have previously reported a method to prepare Nb-
Fmoc-aza-b3-amino acids via reductive amination of gly-
oxilic acid and Fmoc-hydrazine.15 Using a similar route,
we performed the same reactions starting from methyl hy-
drazine instead of hydrazine. Thus, the corresponding N-
Fmoc-N-methylhydrazine (2) was prepared in using the
enhanced nucleophilicity of the methylated N atom of me-
thylhydrazine (1).16 Methylhydrazine was treated with
fluorenyl methyl chloroformiate at –78 °C in the presence
of one equivalent of triethylamine. The monoacylation oc-
curred on the substituted nitrogen in 92% yield. No acyla-
tion was observed on the unsubstituted nitrogen.17 Then,
the N-substituted Fmoc hydrazones were obtained by con-
densing fluorenylmethyl carbazate 2 with the appropriate
aldehyde or ketone.18 Reduction of the hydrazone 3 with
sodium cyanoborohydride afforded the N,N,N¢-trisubsti-
tuted hydrazine 4.19 Reductive amination of glyoxilic acid
and hydrazine 4 led to the Nb-Fmoc-Nb-Me-aza-b3-aa-OH
5 (R = CH2R1;20 Scheme 1 and Table 1).
R
N
R
O
Fmoc
Fmoc
OH
N
OH
N
O
Me
Me
Nβ-Fmoc-Nβ-Me-aza-β3-aa-OH
Fmoc-N-Me-aa–OH
Figure 1 Fmoc-N-Me-aa-OH and Nb-Fmoc-Nb-Me-aza-b3-aa-OH
In the case of the analogue Fmoc-Nb-Me-aza-b3-Phe-OH
(5e), no condensation was observed with the benzalde-
hyde and the carbazate 2 at room temperature or by heat-
ing with a Dean–Stark apparatus. In contrast, microwaves
SYNLETT 2011, No. 3, pp 0327–0330
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.01.2011
DOI: 10.1055/s-0030-1259510; Art ID: G29610ST
© Georg Thieme Verlag Stuttgart · New York

328
I. Nicolas et al.
LETTER
Table 1 Overall Yield of Nb-Fmoc-Nb-Me-aza-b3-aa 5
Compd 5
Nb-Fmoc-Nb-Me-aza-b3-aa
R
Yield of 5 (%)
5a
5b
5c
5d
5e
5f
Fmoc-Nb-Me-aza-b3-Gly-OH
Fmoc-Nb-Me-aza-b3-Ala-OH
Fmoc-Nb-Me-aza-b3-Val-OH
Fmoc-Nb-Me-aza-b3-Leu-OH
Fmoc-Nb-Me-aza-b3-Phe-OH
Fmoc-Nb-Me-aza-b3-Orn(Boc)-OH
Fmoc-Nb-Me-aza-b3-Arg(Boc)2-OH
Fmoc-Nb-Me-aza-b3-Asp(t-Bu)-OH
H
83
28
47
37
89
34
20
61
Me
CH(CH3)2
CH2CH(CH3)2
CH2Ph
(CH2)3NHBoc
(CH2)3NHC(NHBoc)NBoc
CH2CO2t-Bu
5g
5h
activation of the condensation led to the hydrazone 3
(R1 = Ph) with 99% yield.21 Then, reduction of the hydra-
zone 3 (R1 = Ph) and reductive amination gave the expect-
ed Nb-Fmoc-Nb-Me-aza-b3-Phe-OH (5e, Scheme 1).
FmocCl
Me
NH
CH2Cl2, Et3N
Fmoc
MeNHNHMe
N
4 (R1 = H)
–78 °C
39%
6
Me
OCHCO2H
NaBH3CN
HCl (2 M)
For the glycine analogue, a direct reductive amination of
glyoxilic acid and fluorenylmethyl carbazate 2 with
NaBH3CN and HCl 2 N gave the corresponding Nb-Fmoc-
Nb-Me-aza-b3-Gly-OH (5a, Scheme 2).
To introduce the side chain for the aspartic analogue Nb-
Fmoc-Nb-Me-aza-b3-Asp-OH (5h), a nucleophilic substi-
tution of the corresponding tert-butyl bromo acetate with
Nb-Fmoc-Nb-Me-aza-b3-Gly-OH (5a) was done with an
overall yield of 61%22 (Scheme 2).
94%
Me
O
Fmoc
N
N
OH
Me
5b
Nβ-Fmoc-Nβ-Me-aza-β3-Ala-OH
Scheme 3 Synthesis of Nb-Fmoc-Nb-Me-aza-b3-Ala (5b)
O
H
we first prepare the Nb-Fmoc-Nb-Me-aza-b3-Orn(Boc)-
OBn (7f). Condensation of 3-tert-butoxycarbonyl amino-
propanal with the N-Fmoc-N-Me hydrazine (2) followed
by a reduction of the hydrazone with sodium cyanoboro-
hydride afforded N,N,N¢-trisubstituted hydrazine 4f. Nu-
cleophilic substitution of benzyl bromoacetate with
hydrazine 4f led to Nb-Fmoc-Nb-Me-aza-b3-Orn(Boc)-
OBn (7f). Selective deprotection of 7f with trifluoroacetic
acid (TFA) gave 7 with 90% yield. The crude amine 7 was
guanidinylated with the Goodman reagent (Boc-
NH)2NTf25 to afford the arginine ester analogue 7g in 66%
yield. Finally, catalytic hydrogenation H2, Pd/C (10%) in
ethanol gave the expected Nb-Fmoc-Nb-Me-aza-b3-
Arg(Boc)2-OH (5g, Scheme 4).
OCHCO2H
NaBH3CN
Fmoc
N
2
N
OH
HCl (2 M)
94%
Me
5a
Nβ-Fmoc-Nβ-Me-aza-β3Gly-OH
BrCH2CO2t-Bu
70%
DIPEA
t-BuCO2
O
Fmoc
N
N
OH
Me
5h
Nβ-Fmoc-Nβ-Me-aza-β3-Asp-OH
Scheme 2 Synthesis of Nb-Fmoc-Nb-Me-aza-b3-Gly (5a) and Nb-
Fmoc-Nb-Me-aza-b3-Asp (5h)
Reductive amination of glyoxilic acid with hydrazine 4f
afforded the Nb-Fmoc-Nb-Me-aza-b3-Orn(Boc)-OH (5f,
Scheme 4).
The analogue alanine was prepared in four step following
the general procedure using formaldehyde in solution in Pyramidal inversion of the nitrogen atoms was observed
water (Scheme 1). A straightforward way was performed by 1H NMR, which is slow due to a steric hindrance and
in two step. Nucleophilic substitution of fluorenyl chloro- to the three different substituents on the two nitrogen at-
formiate and N,N¢-dimethylhydrazine 6 at –78 °C in the oms. Thus the 1H NMR spectrum appears for most of the
presence of one equivalent of triethylamine afforded the monomers as a mixture of two diastereomers. Such slow
monosubstitution in 39% yield after purification.23 Then, pyramidal inversion has already been observed in a 24-
the reductive amination led to 5b (Scheme 3).
membered macrocycle of aza-b3-cyclohexapeptides but
never in linear monomer.26
Similarly to the synthesis of Nb-Fmoc-aza-b3-Arg(Boc)-
OH,24 to get Nb-Fmoc-Nb-Me-aza-b3-Arg(Boc)-OH (5g),
Synlett 2011, No. 3, 327–330 © Thieme Stuttgart · New York

LETTER
Nb-Fmoc-Nb-Methyl-aza-b3-amino Acids
329
Weyl); Goodman, M.; Felix, A.; Moroder, L.; Toniolo, C.,
Eds.; Thieme: Stuttgart, 2002, 215. (b) Biron, E.;
Chatterjee, J.; Ovadia, O.; Langenegger, D.; Brueggen, J.;
Hoyer, D.; Schmid, H. A.; Jelinek, R.; Gilon, C.; Hoffman,
A.; Kessler, H. Angew. Chem. Int. Ed. 2008, 47, 2595.
(7) Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med.
Chem. 1995, 2, 654.
(8) Cody, W. L.; He, J. X.; Reily, M. D.; Haleen, S. J.; Walker,
D. M.; Reyner, E. L.; Stewart, B. H.; Doherty, A. M. J. Med.
Chem. 1997, 40, 2228.
BocHN
BocHN
Fmoc
O
3
BrCH2CO2Bn
Fmoc
N 3
N
N
DIPEA
70%
N
OBn
Me
H
Me
7f
4f
NaBH3CN
HCl (2 M)
72%
TFA, CH2Cl2
90%
OCHCO2H
BocHN
H2N
(9) Barker, P. L.; Bullens, S.; Bunting, S.; Burdick, D. J.; Chan,
K. S.; Deisher, T.; Eigenbrot, C. T.; Gadek, R.; Gantzos, R.;
Lipari, M. T.; Muir, C. D.; Napier, M. A.; Pitti, R. M.; Padua,
A.; Quan, C.; Stanley, M.; Struble, M.; Tom, J. Y. K.;
Burnier, J. P. J. Med. Chem. 1992, 35, 2040.
O
O
Fmoc
N
Fmoc
N
N
N
OBn
OH
Me
Me
7
5f
(10) Chatterjee, J.; Mierke, D.; Kessler, H. J. Am. Chem. Soc.
Nβ-Fmoc-Nβ-Me-aza-β3-Orn(Boc)-OH
(BocNH)2NTf
2006, 128, 15164.
Et3N
66%
(11) Holladay, M. W.; Kopecka, H.; Miller, T. R.; Bednarz, L.;
Nikkel, A. L.; Bianchi, B. R.; Witte, D. G.; Shiosaki, K.; Lin,
C. W.; Asin, K. E.; Nadzan, A. M. J. Med. Chem. 1994, 37,
630.
BocNH
H
NBoc
(12) (a) Rohrer, S. P.; Birzin, E. T.; Mosley, R. T.; Berk, S. C.;
Hutchins, S. M.; Shen, D. M.; Xiong, Y.; Hayes, E. C.;
Parmar, R. M.; Foor, F.; Mitra, S. W.; Degrado, S. J.; Shu,
M.; Klopp, J. M.; Cai, S. J.; Blake, A.; Chan, W. W. S.;
Pasternak, A.; Yang, L.; Patchett, A. A.; Smith, R. G.;
Chapman, K. T.; Schaeffer, J. M. Science 1998, 282, 737.
(b) Di Gioia, M. L.; Leggio, A.; Le Pera, A.; Liguori, A.;
Napoli, A.; Siciliano, C.; Sindona, G. J. Org. Chem. 2003,
68, 7416. (c) Di Gioia, M. L.; Leggio, A.; Liguori, A. J. Org.
Chem. 2005, 70, 3892. (d) Teixido, M.; Albericio, F.; Giralt,
E. J. Peptide Res. 2005, 65, 153.
(13) Belsito, E.; Di Gioia, M. L.; Greco, A.; Leggio, A.; Liguori,
A.; Perri, F.; Siciliano, C.; Viscomi, M. C. J. Org. Chem.
2007, 72, 4799.
(14) Dali, H.; Busnel, O.; Hoebeke, J.; Bi, L.; Decker, P.; Briand,
J. P.; Baudy-Floc’h, M.; Muller, S. Mol. Immunol. 2007, 44,
3024.
N
Pd/C (10%)
H2
NBoc
O
BocNH
H
56%
Fmoc
N
N
N
OBn
Me
7g
O
Fmoc
N
N
OH
Me
5g
Nβ-Fmoc-Nβ-Me-aza-β3-Arg(Boc)2-OH
..
Scheme 4 Synthesis of Nb-Fmoc-Nb-Me-aza-b3-Orn (5f) and -Arg
(5g)
In conclusion, we developed a highly efficient and simple
way to obtain new N-methyl a-amino acid analogues with
various side chains, the Nb-methyl-aza-b3-amino acids.
Our methodology allows us to easily obtain a variety of
Nb-Fmoc-Nb-methyl-aza-b3-amino acids in a few synthet-
ic steps and under very mild conditions. These new mono-
mers, compatible with standard protocols for Fmoc/t-Bu
SPPS, will enriched the arsenal of building blocks in the
synthesis of modified peptides and peptidomimetics. The
solid-phase synthesis of such hybrid peptides will be re-
ported soon.
(15) Busnel, O.; Baudy-Floc’h, M. Tetrahedron Lett. 2007, 48,
5767.
(16) Gibson, C.; Goodman, S. L.; Hahn, D.; Hölzemann, G.;
Kessler, H. J. Org. Chem. 1999, 64, 7388.
(17) To a solution of methylhydrazine (0.88 g, 19 mmol) in
CH2Cl2 (20 mL) at –78 °C and Et3N (2.1 g, 1.1 equiv) was
added dropwise a CH2Cl2 (10 mL) solution of FmocCl (3.80
g, 0.8 equiv) over 2 h. The reaction mixture was allowed to
stir for 1 h at r.t., diluted with CH2Cl2, and washed with H2O
(3×), brine, dried over anhyd Na2SO4, and concentrated
in vacuo. The crude solid was triturated in PE. The
FmocMeNNH2 (1) was obtained as a white powder (2.9 g,
73%); mp 84 °C. 1H NMR (200 MHz, CDCl3): d = 3.17 (s, 3
H), 4.13 (br s, 2 H), 4.30 (t, 1 H, J = 6.8 Hz), 4.48 (d, 2 H,
J = 6.8 Hz), 7.29–7.85 (m, 8 H) ppm. 13C NMR (75.5 MHz,
CDCl3) d = 157.4, 143.7 141.3, 127.7 127.1 125.0, 120.0,
67.4, 47.2, 38.4 ppm.
(18) To a solution of N-Fmoc-N-MeNH2 1 (1 equiv) in CH2Cl2
(or EtOH for R1 = H; 20 mL) was added the aldehyde or the
ketone (1.2 equiv). The mixture was stirred overnight at r.t.
(or refluxed for 2 h for R1 = H). After removal of the solvent
under reduced pressure, the crude hydrazone was obtained,
which was pure enough to be used in the following step.
Compound 3d [R1 = CH(CH3)2]: yield 77%; mp 80 °C. 1H
NMR (200 MHz, CDCl3): d = 1.24 (d, 6 H, J = 6.8 Hz), 2.74
(m, 1 H), 3.30 (s, 3 H), 4.35 (t, 1 H, J = 7.7 Hz), 4.49 (d, 2 H,
J = 7.7 Hz), 7.03 (d, 1 H, J = 5.2 Hz), 7.29–7.85 (m, 8 H)
ppm. 13C NMR (75.5 MHz, CDCl3): d = 154.78, 148.91,
References and Notes
(1) Woodley, J. F. Crit. Rev. Ther. Drug Carrier Syst. 1994, 11,
61.
(2) Salamat-Miller, N.; Johnston, T. P. Int. J. Pharm. 2005, 294,
201.
(3) Roberts, M. J.; Bentley, M. D.; Harris, J. M. Adv. Drug
Delivery Rev. 2002, 54, 459.
(4) Flinn, N.; Hussain, I.; Shaw, A.; Artursson, P.; Gibbons,
W. A.; Toth, I. Int. J. Pharm. 1996, 138, 167.
(5) Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512;
Angew. Chem. 1982, 94, 703.
(6) (a) Gilon, C.; Dechantsreiter, M. A.; Burkhart, F.; Friedler,
A.; Kessler, H. In Methods of Organic Chemistry (Houben-
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330
I. Nicolas et al.
LETTER
hydrazone was used in the next step without further
143.90, 141.30, 127.71, 127.09, 125.58, 119.94, 68.34,
46.98, 31.39, 30.5, 20.29 ppm.
purification.
(19) The hydrazone 3 (1 equiv) was dissolved in MeOH (40 mL).
NaBH3CN (1.2 equiv) was added, and the pH value was
brought to 3 by slowly adding a solution of 2 N HCl. The
mixture was stirred for 1 h, and then adjusted the pH value
to 1. After 10 min of stirring, the solution was neutralized
with solid NaHCO3, the mixture was filtered, concentrated
under vacuum, and the residue was taken up with EtOAc (50
mL) and washed with H2O and brine. The organic layer was
dried over Na2SO4, and the solvent was removed to give
crude oil, which was purified by chromatography on silica
gel (EtOAc–PE, 3:7 and 5:5), or precipitate, which was
recrystallized in EtOH. Due to the slow pyramidal inversion
of trisubstituted nitrogen atom some NMR spectrum appears
as a set of two conformers or are not well resolved.
Compound 3 (R1 = Ph): yield 99%; oil. 1H NMR (300 MHz,
CDCl3): d = 3.31 (s, 3 H), 4.26 (t, 1 H, J = 10.5 Hz), 4.43 (d,
2 H, J = 10.6 Hz), 7.59 (s, 1 H), 7.18–7.77 (m, 13 H) ppm.
13C NMR (75.5 MHz, CDCl3): d = 154.8, 143.9, 141.4,
139.9, 135.0, 129.7, 128.8, 127.8, 127.2, 127.1, 125.6,
120.0, 68.5, 47.1, 30.8 ppm.
(22) Nb-Fmoc-Nb-Me-aza-b3-Gly-OH (5, R = H; 500 mg, 1.53
mmol) with BrCH2CO2t-Bu (2 equiv, 597 mg, 3.06 mmol),
and DIEA (2.2 equiv, 0.44 g) were mixed at r.t. in DMF (10
mL) for 2 d. Reaction mixture was diluted with EtOAc,
extracted with H2O (3×), brine, dried over anhyd Na2SO4,
and evaporated in vacuo. Crude product was purified by
column chromatography using EtOAc–PE (1:1) as eluent;
4.78 g (91%) of Nb-Fmoc-Nb-Me-aza-b3-Asp(Ot-Bu)-OH
(5h, R = CH2CO2t-Bu) was obtained.
Compound 4d [R1 = CH(CH3)2]: yield 95%; oil. 1H NMR
(200 MHz, CDCl3): d = 0.83 (br s, 3 H), 0.90 (br s, 3 H), 3.12
(s, 3 H), 3.22 (br s, 1 H), 4.28 (t, 1 H, J = 6.1 Hz), 4.52 (br, 2
H), 4.67 (br s, 1 H), 7.30–7.90 (m, 8 H) ppm. 13C NMR (75.5
MHz, CDCl3): d = 154.8, 143.9, 141.3, 127.7, 127.1, 125.6,
119.9, 68.3, 47.0, 31.4, 39.1, 20.8, 20.7 ppm.
Nb-Fmoc-Nb-Me-aza-b3-Asp(Ot-Bu)-OH (5h,
R = CH2CO2t-Bu): 1H NMR (300 MHz, CDCl3): d = 1.48 (s,
9 H, CH3), 3.12 (s, 3 H, CH3), 3.74 (br s, 2 H, CH2), 4.25 (t,
1 H, J = 6 Hz), 4.49 (br d, 2 H), 4.55 (s, 2 H), 7.27–7.78 (m,
8 H) ppm. 13C NMR (75.5 MHz, CDCl3): d = 169.7, 166.4,
156.4, 143.8, 141.3, 127.8, 127.1, 124.9, 120.0, 82.6, 67.2,
61.3, 51.0, 47.2, 37.5, 28.0. ESI-HRMS: m/z calcd for
C24H28N2O6 [M + H]+: 440.194738; found: 440.1951 (3
ppm).
(20) N-Fmoc-N-methylhydrazine (4, 5 mmol) and glyoxilic acid
(1 g, 2 equiv) were dissolved in MeOH–CH2Cl2 (15 mL:10
mL) and NaBH3CN (0.67 g, 2 equiv) was added in portions
over 1 h. Reaction was monitored by TLC using Et2O–
toluene (1:1) as eluent. After 1.5 h of stirring reaction was
quenched with 2 M aq HCl, concentrated in vacuo, diluted
with EtOAc, and extracted with H2O (3×), brine, and dried
over anhyd Na2SO4. Crude Nb-Fmoc-Nb-Me-aza-b3-aa-OH
was obtained and was purified by column chromatography.
Due to the slow pyramidal inversion of trisubstituted
nitrogen atoms most of the NMR spectrum appears as a set
of two diastereomers or are not well resolved.
(23) MeNHNHMe·2HCl (0.50 g, 3.76 mmol) was dissolved in
MeCN (7 mL), Et3N (2.5 equiv, 2.11 mL) was added and
precipitate formed was removed by filtration. To remaining
solution of MeNHNHMe solution of FmocCl (0.5 equiv,
0.49 g) was added dropwise over 2.5 h at 0 °C. Reaction was
monitored by column chromatography using EtOAc–PE
(1:1) as eluent. Organic phase was then diluted with EtOAc,
extracted with H2O (3×), brine, dried over anhyd Na2SO4,
concentrated in vacuo, and purified by column chroma-
tography using EtOAc–PE (2:3) as eluent; 0.54 g (39%) of
MeFmocNNHMe 4b was obtained.
Nb-Fmoc-Nb-Me-aza-b3-Leu-OH (5d, R = CH2CH(CH3)2]:
yield 80%. 1H NMR (200 MHz, CDCl3): d = 0.85, 0.93 (m,
6 H), 1.39 (m, 1 H), 2.10–3.10 (AB, 2 H), 2.72 (s, 3 H), 3.17,
3.37 (AB, 2 H), 4.24 (t, 1 H, J = 5.7 Hz), 4.63 (br, 2 H), 7.29–
7.83 (m, 8 H) ppm. 13C NMR (75.5 MHz, CDCl3): d = 172.4,
158.15, 143.5, 141.7, 127.8, 127.2, 124.95, 120.0, 67.95,
62.5, 57.3, 47.3, 30.4, 26.3, 20.6, 20.3 ppm. ESI-HRMS:
m/z calcd for C22H26N2O4 [M + H]+: 383.19708; found:
383.1971 (0 ppm).
MeFmocNNHMe (4b): 1H NMR (300 MHz, CDCl3):
d = 2.55 (br s, 3 H), 3.05 (s, 3 H), 4.27 (t, 1 H, J = 6 Hz), 4.48
(s, 2 H), 7.37–7.75 (m, 9 H) ppm.
(24) Busnel, O.; Bi, L.; Dali, H.; Cheguillaume, A.; Chevance, S.;
Bondon, A.; Muller, S.; Baudy-Floc’h, M. J. Org. Chem.
2005, 70, 10701.
(21) A mixture of N-Fmoc-N-MeNH2 (0.766 g, 2.86 mmol),
benzaldehyde (0.334 g 1.1 equiv), and MgSO4 (0.1 g) was
irradiated (power 30 W) for 15 min. The reaction was carried
without solvent. The crude product was diluted in CH2Cl2,
filtered, and concentrated under reduced pressure. The crude
(25) Planas, M.; Bardaji, E.; Jensen, K. J.; Barany, G. J. Org.
Chem. 1999, 64, 7281.
(26) Le Grel, P.; Salaun, A.; Potel, M.; Le Grel, B.; Lassagne, F.
J. Org. Chem. 2006, 71, 5638.
Synlett 2011, No. 3, 327–330 © Thieme Stuttgart · New York

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