Oligomerization of N-aminodipeptides: to the synthesis of heterogeneous backbone with 1:1 α:α-N-amino aminoacid residue patterns

Article abstract of DOI:10.1016/j.tet.2008.08.087

A large number of N-aminodipeptides compounds have been obtained via a Mitsunobu protocol performed in solution or by solid-phase synthesis. The oligomerization of some of them has been studied in solution or on solid support leading to the formation of 1:1[α:α-N-amino]mers.

Full text of DOI:10.1016/j.tet.2008.08.087

Tetrahedron 64 (2008) 10741–10753
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oligomerization of N-aminodipeptides: to the synthesis of heterogeneous
backbone with 1:1 a:a-N-amino aminoacid residue patterns
a
a
a
a
b
´
´
Anne-Sophie Felten , Sebastien Dautrey , Jacques Bodiguel , Regis Vanderesse , Claude Didierjean ,
a
a,
*
´
Axelle Arrault , Brigitte Jamart-Gregoire
a
´
´
Laboratoire de Chimie-Physique Macromoleculaire, UMR CNRS-INPL 7568, Nancy-Universite, ENSIC, 1 rue Grandville, BP 20451, 54001 Nancy Cedex, France
b Laboratoire de Cristallographie et Mode´lisation des Mate´riaux Mine´raux et Biologiques, UMR CNRS-UHP 7036, Nancy-Universite´, Facult´e des Sciences et Techniques,
BP 239, 54506 Vandoeuvre-le`s-Nancy Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2008
Received in revised form 19 August 2008
Accepted 27 August 2008
Available online 4 September 2008
A large number of N-aminodipeptides compounds have been obtained via a Mitsunobu protocol per-
formed in solution or by solid-phase synthesis. The oligomerization of some of them has been studied in
solution or on solid support leading to the formation of 1:1[
a:
a-N-amino]mers.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
N-Aminodipeptide
Mitsunobu reaction
Transprotection
Oligomerization
Solid-phase organic chemistry
Solid-phase peptide synthesis
1. Introduction
the synthesis of heterogeneous oligomers alternating a- and a-N-
amino aminoacids could be of interest. In this paper, we wish to
demonstrate that the method described before for the synthesis of
N-aminodipeptides can be extended to form a large number of
compounds with different types of protecting groups. Moreover,
we will also compare methods of oligomerization of N-amino-
dipeptides in solution and on solid phase.
Specific folding of protein backbones creates specific side-chain
arrangements that lead to complex molecular activities. The re-
lationship between function and conformation has inspired many
chemists to create new oligomers, which provide a new basis for
creating useful molecules.1 In this spirit, it has been shown that
many classes of oligomers of pseudopeptides as aliphatic b-, g- or d-
peptides can fold in solution and belongs to the so-called foldamers
family.2 More recently, it was shown that heterogeneous backbones
2. Results and discussion
with a 1:1 alternation of
a- and b-aminoacid residues can also
adopt helical conformation.3 Some years ago Marraud et al.4
demonstrated that N-aminodipeptides, where the amidic proton is
replaced by an amino group, can present a folding conformation in
the solid state by the formation of an intramolecular hydrogen
bond. More interestingly, they demonstrated that NH2 protons
were not involved in the folding. A few years ago, we developed an
easy and convenient method to synthesize bis-nitrogen containing
N-Aminodipeptides 3 are obtained via a Mitsunobu protocol,
which involved
a-hydroxyesters 2 and an N-aminophthalimide
derivatives 1 as acidic partners (Scheme 1).5a The success of this
reaction has been attributed to the structure of the acidic partner
bearing a phthalimide moiety, which first confers electron with-
drawing properties able to enhance the acidity of the NH proton
and second because of its small steric hindrance. First, we will
demonstrate that conditions of reaction performed in solution can
be extended to the synthesis of a large number of dipeptides.
The Mitsunobu reaction leads in solution to the formation of
compounds 3, the results are gathered in Table 1. Whatever be the
protecting groups present on the acidic partners or on the alcohol,
compounds 3 are obtained with very good yields. So, this protocol
allowed the preparation of N-aminodipeptides bearing different
analogues such as
a-hydrazinoacid and N-aminodipeptide de-
rivatives.5 They could be easily obtained via an original protocol
involving a Mitsunobu reaction. All these results let us to think that
* Corresponding author. Tel.: þ33 3 83175279; fax: þ33 3 83379977.
´
E-mail address: Brigitte.Jamart@ensic.inpl-nancy.fr (B. Jamart-Gregoire).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.087

10742
A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
Scheme 1. Synthesis of N-aminodipeptides from
a
-Z or
a-Boc-N-protected aminohydrazides 1 and
a-hydroxyesters 2. Pht¼phthaloyl group.
protecting groups onto the C-terminal, the N-terminal or the lateral
amino group.
group. Moreover, the formation of 3k and 3r with good yields in-
dicated that the steric hindrance due to the presence of aminoacid
side chain did not affect drastically the yield of the reaction. More
interestingly, compounds 3p and 3q issued from the reaction of an
alcohol bearing a ramified lateral chain with an acidic partner can
still be obtained with acceptable yield. X-ray data have been
As a result, N-aminodipeptides 3 can be obtained starting from a-
hydroxymethyl, ethyl, tert-butyl or benzyl esters as alcohol partners
2. This protocol is also compatible with a Z or a Boc protection of the
N-terminal position and a phthalimide group on the lateral amino
Table 1
Synthesis in solution and on solid support of protected N-aminodipeptides
R1
R2
P1
Z
P2
3 (%)a
4 (%)
5 (%)b
6 (%)e
7 (%)c
8 (%)c
9 (%)d
CH3
CH3
CH3
Wang
CH3
CH2CH3
C(CH3)3
CH3
Wang
CH3
C(CH3)3
Wang
CH3
CH3
CH2Ph
CH3
CH2Ph
CH3
CH3
Wang
CH3
Wang
CH2Ph
CH2Ph
CH3
Wang
Wang
Wang
Wang
Wang
3a (85)
d
d
4a (37)f
d
d
6a (87)
d
7a (98)
d
8a (86)
d
d
d
d
d
d
d
d
9f (85)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
CH3
CH3
CH3
CH3
(L,
D
) CH3
Z
Z
Z
Z
3b (87)
3c (85)
3d (75)
3e (77)
d
d
6b (68)
6c (73)
6d (87)
6e (86)
d
d
d
CH3
CH3
H
d
d
d
d
d
d
d
d
d
4e (38)f
d
4g (100)b
4g (55)f
d
d
7e (99)
d
8e (72)
d
d
CH2Ph
CH2Ph
CH3
CH3
Z
Z
3f (100)
3g (70)
d
d
6f (95)
d
d
8f (70)
d
5g (57)
d
d
d
d
d
CH2Ph
CH2Ph
CH2Ph
CH2CH(CH3)2
CH2CH(CH3)2
CH(CH3)2
H
H
Boc
Boc
Boc
Boc
Boc
Boc
Z
3h (97)
3i (98)
3j (79)
3k (91)
3l (92)
3m (47)
3n (90)
d
d
d
d
d
CH3
CH3
H
H
CH3
H
d
4j (100)b
d
4l (87)b
d
d
6i (93)
d
7i (75)
d
d
5j (100)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
4n (49)f
d
4o (47)f
d
d
d
d
d
d
d
d
d
H
CH3
Z
3o (84)
d
d
d
d
d
d
d
d
d
H
CH3
CH(CH3)2
CH(CH3)2
H
H
H
CH3
CH(CH3)2
CH(CH3)2
Z
Z
Z
Z
Z
Z
Z
Z
3p (79)
3q (77)
3r (79)
d
d
d
d
d
d
d
d
d
d
CH(CH3)2
CH2CH(CH3)2
CH2Ph
CH2CH(CH3)2
CH2Ph
d
d
d
d
d
4s (39)f
4t (48)f
4u (44)f
4w (21)f
4x (21)f
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
CH3
d
d
d
d
d
a
Yields calculated from 1.
b
c
d
e
f
Yields calculated from 3.
Yields calculated from 6.
Yields calculated from 8.
Yields calculated from 3.
Yields calculated from the substitution level of the resin (1.2 mmol/g of hydroxy groups).

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10743
corresponding supported (S)-
a
-hydroxyacids and (S)-aminoacid
phthaloyl hydrazide derivatives.5a The optical purity of the formed
compounds was checked by 1H NMR (diastereoisomeric excess
>95% for 3a).5a,e
As it is shown in Scheme 1, new protecting groups also can be
introduced after the Mitsunobu reaction. First of all, we develop
a very elegant three-step one-pot protocol allowing the trans-
formation of the phthalimide group present on the lateral primary
amino group into a mono-tert-butyloxycarbonyl group leading to
the formation of compound 6.5b The first interest of this trans-
protection is to introduce a Boc protection, which is among the most
used protecting groups and plays a critical role in aminoacids and
peptides chemistry since it is compatible with solid-phase synthe-
sis7–9 and easily removed. Moreover, starting from compounds 6 we
were able to obtain with good yields the corresponding free
N-aminodipeptides 8 by using classical acidic conditions HCl (3 M)/
EtOAc. Atthis stage, it is interestingtonotethat, if the presence of the
phthaloyl group was essential for the success of the Mitsunobu re-
action by contributing to increase the acidity of the sole proton and
concomitantly to reduce steric hindrance, unfortunately, as other
authors reported,10 we were confronted to the difficulty to find
general and mild conditions to remove the phthaloyl group. On the
other hand, we showed that conversion of the Z protection of the
N-terminal of 6f into an Fmoc group can be done easily by using
a one-pot hydrogenolysis performed in the presence of Fmoc-OSu
and led to the formation of 6y in good yield.
With the idea in mind to undergo oligomerization of N-ami-
nodipeptides, we demonstrated that deprotected N- or C-terminal
N-aminodipeptides can be easily obtained. The choice of orthogo-
nal protections for the different functions of the molecule allowed
us to find selective conditions of deprotection. So, the deprotection
conditions we used depend on the nature of the protecting groups
that have to be removed but also of the nature of the other pro-
tecting groups present on the molecule. As a result, hydrogenolysis
conditions have been applied to remove the benzyl ester of N-
aminodipeptides 3 bearing a Boc protection on the N-terminal and
a phthalimide group on the lateral amino group. On the other hand,
acidic conditions can be used to remove the tert-butyl ester of
compound 3g bearing a Z protecting group on the N-terminal chain
and a phthalimide on the lateral amino group. These conditions
allowed the formation of the corresponding compound 4g. Finally,
when a Boc is present on the molecule (compounds 6) or when the
lateral amino group is free (compounds 8), LiOH in a mixture of THF
and water or NaOH with CaCl2 salt in a mixture of isopropanol and
water is used in order to remove the methyl ester and to lead to the
corresponding carboxylic acids 7 and 9. It is interesting to notice
that the use of NaOH with CaCl2 salt11 allowed the removal of ester
group of compound 6y without affecting the Fmoc protection. One
advantage of the use of solid-phase synthesis of N-aminodipeptides
is to obtain directly free C-terminal compounds 4 after release of
the resin by TFA. Free N-terminal aminodipeptides 5 can be
obtained by hydrogenolysis (P1¼Z) or HCl (3 M) in EtOAc (P1¼Boc).
When P2¼CH2Ph, the latter conditions lead to the formation of
a stable chlorhydrate salt. On the contrary, the use of TFA leads to
the formation of N-aminodiketopiperazine 11 (Fig. 2) due to the
cyclization of the instable corresponding trifluoroacetate salt.
The oligomerization of N-aminodipeptides was performed in
solution (Scheme 3) and on solid support (Scheme 4).
Figure 1. Ortep drawing of 3g.
collected for N-aminodipeptide 3g.6 This crystal structure showed
that phthalimide moiety is located in a perpendicular plane relative
to the peptide backbone (Fig. 1), which contributes to decreased
steric hindrance. In order to be more efficient and to avoid the pu-
rification steps during the synthesis, we found conditions, which
allow the synthesis of these pseudodipeptides on solid support.
The best way consisted in anchoring the alcohol partners of the
Mitsunobu reaction on the resin (Scheme 2). So, the protected a-
hydroxyacids 10 were linked to a Wang resin via their carboxylic
group.5e The use of PTSA allowed the removal of the THP protection
and then to recover the supported alcohol, which can react via the
Mitsunobu protocol with the free acidic partners 1 P1¼Z. This
protocol has been successfully used for different values of R1 and R2
corresponding to different aminoacid side chains. The results are
gathered in Table 1. So, starting from a Wang resin we were able to
release the N-aminodipetides 4 P1¼Z by using classical protocol
(TFA in CH2Cl2). The overall yields in 4 P1¼Z (calculated from the
substitution level of the solid support) varied from 21 to 55%
depending on the nature of the lateral chain. These results corre-
sponding to an average yield for each step (varying from 67 to 86%)
show that the Mitsunobu reaction is not affected by the steric
hindrance generated by the presence of the solid support. Fur-
thermore and as expected, whatever be the method of synthesis
used (solution or solid phase), we checked that this Mitsunobu
reaction occurred with a total inversion of configuration of the
carbon bearing the hydroxyl group.5a,f
This stereospecificity enabled the formation of a series of (L,D)-
diastereoisomers 3 or 4 in high optical purity starting from the
Scheme 2. (a) (1) Wang resin, DIC, DMAP cat., THF; (2) PTSA, CH2Cl2/MeOH (97/3); (b)
1, DIAD, PPh3, THF; (c) TFA/CH2Cl2 (1/1).
Figure 2. N-Aminodiketopiperazine 11.

10744
A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
the deprotection of the Fmoc group. The release from the resin by
the action of TFA led to the formation of pentamer 17, heptamer 18
and nonamer 19 possessing a free lateral amine, respectively, with
the overall yield of 20%, 8% and 10%. The conformational analysis of
these oligomers is under active investigation in order to determine
their ability to fold in solution.
3. Experimental section
3.1. General
Tetrahydrofuran was dried by distillation over sodium benzo-
phenone ketyl. Unless otherwise stated, reagents were purchased
from chemical companies and used without prior purification.
Reactions were monitored by thin-layer chromatography (TLC)
using aluminium-baked silica gel plates (Macherey–Nagel ALU-
GRAMÒ SIL G/UV254). TLC spots were viewed under ultraviolet
light and by heating the plate after treatment with a staining so-
lution of phosphomolybdic acid. Product purifications were per-
formed using Geduran 60 H Silica Gel (63–200 mesh). Reagent
grade solvents were used as-received. Diisopropyl azodicarboxy-
late (DIAD), N,N0-diisopropylcarbodiimide (DIC) and N,N0-di-
cyclohexylcarbodiimide (DCC) were purchased from Aldrich.
9-Fluorenylmethyl succinimidyl carbonate (Fmoc-OSu), 1-hydroxy-
benzotriazole (HOBt), O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-
uronium tetrafluoroborate (TBTU) and diisopropylethylamine (DIEA)
were purchased from Senn Chemicals or Novabiochem. Amino-
Scheme 3.
Oligomers were synthesized in solution using a convergent Boc
strategy. Different standard peptides coupling methods have been
tested in solution in order to find the best conditions, which
allowed the coupling reaction between 4 P1¼Boc and 5 P2¼CH2Ph
in the series (R1¼CH2Ph and R2¼CH3).
hydrazides
1 were obtained from phthalic anhydride and
hydrazine derivatives.12 Diethyl azodicarboxylate (DEAD) and di-
tert-butyl azodicarboxylate (DBAD) were purchased from Alfa
Aesar. Solid-phase N-aminodipeptides’ 4 syntheses were per-
Surprisingly, coupling reactions were not easy to perform.
Whatever be the conditions used like HOBt, DCC or HOBt, DIC in
THF or CH2Cl2, the reaction led to the formation of diketopiperazine
11 as major product. The best results were obtained when using the
acid fluoride method, which led to the formation of the tetramer 12
with a yield of 55%. In order to avoid the formation of diketopi-
perazine, we decided to synthesize the hexamer 15 by condensing
the free N-terminal tetramer 13 on the free C-terminal dimer 4j,
hexamer is obtained in 55% yield. Finally, the corresponding
octamer 16 is the result of the coupling reaction between the free
N-terminal tetramer 13 on the free C-terminal tetramer 14. Con-
cerning the solid-phase synthesis, we used an Fmoc/Boc strategy on
a Wang resin. As described above (Scheme 1), it was possible to
undergo the saponification of the ester of compound 6y without
deprotection of the Fmoc group. This behaviour allowed the for-
mation of 7y that can be involved in an oligomerization process
(Scheme 4). In order to be able to count the number of units fixed
on the resin, we decided to perform the reaction on an Fmoc-Leu-
Wang resin, the presence of the leucine served as a standard in
NMR. Oligomers were obtained by an iterative sequence consisting
in using TBTU/HOBt as coupling reagent and piperidine in DMF for
formed on
a Heidolph SYNTHESIS 1 apparatus. They were
purified by reverse-phase HPLC using a preparative HPLC sys-
tem (Waters Corp., Milford, MA, USA) on a Waters DELTA PAK
column (15 mm, 300 Å, 7.8ꢀ300 mm). N-Aminodipeptides were
eluted with a linear gradient of solution A (water containing
0.1% of TFA) and solution B (20% of water in CH3CN with 0.1%
of TFA) from 95 to 0% of solution A over 25 min at a flow rate
of 2 mL/min with UV detection at 254 nm. Solid-phase oligomer
syntheses were performed on a multichannel peptide synthe-
sizer PSP 400013 according to a classical Fmoc/tBu methodology.
They were purified by reverse-phase HPLC on an Interchim
column (250ꢀ21,2 mm). Oligomers were eluted with a linear
gradient of solution A (water containing 0.1% of TFA) and so-
lution B (20% of water in acetonitrile with 0.1% of TFA) from
100 to 0% of solution A over 35 min at a flow rate of 15 mL/min
with UV detection at 254 nm. 1H and 13C NMR spectra were
recorded on a Bruker Avance 300 spectrometer. Multiplicities
are reported as follow: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad, arom¼aromatic. The obser-
vation of two sets of resonances for some groups in 1H and 13C
NMR spectra suggested that 1:1[a/a-N-amino]mers were present
as two isomers. We and others have observed this phenomenon
before in the preparation of hydrazide derivatives12 or amide
containing compounds.14 IR spectra were recorded on a Bruker
Tensor 27. Melting points were obtained on a hot-stage appa-
ratus and were uncorrected. Electron spray ionization mass
spectra (ESI-MS) were recorded on a BRUKER MicroTof-Q HR
´
spectrometer in the ‘Service commun de Spectrometrie de
´
`
Masse’, Faculte des Sciences et Techniques, Vandoeuvre-les-
Nancy, France.
3.2. Typical experimental procedure for the preparation of 3
Under nitrogen atmosphere and to a stirred solution of amino-
Scheme 4. Reagents: (a) piperidine/DMF; (b) TBTU, HOBt, DIEA/DMF; (c) TFA.
hydrazide 1 (3 mmol), PPh3 (4.5 mmol) and
a-hydroxyester 2

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10745
(4.5 mmol) in anhydrous THF (50 mL), dialkyl azodicarboxylate
(4.5 mmol) was added portionwise at 0–5 ꢁC. The resulting solution
was stirred at room temperature until completion (monitored by
TLC) and concentrated in vacuo. The residue was purified by col-
umn chromatography using a mixture of EtOAc/petroleum ether as
eluent for column chromatography.
(CDCl3) d
(ppm) 174.4 (CON(NPht)), 169.3 (COOtBu), 165.7, 165.3
(C]O Pht), 155.8 (NHCOOCH2Ph), 136.9 (ArC), 135.9, 135.4 (PhtCH),
130.7, 129.8 (PhtC), 129.1, 128.6 (ArCH), 125.2, 124.8 (PhtCH), 82.7
(OC(CH3)3), 67.5 (COOCH2Ph), 58.0, 57.2 (CHCH3), 48.3, 47.8
(CHCH3), 28.5, 28.4 (OC(CH3)3), 20.7, 20.1 (CHCH3), 14.3 (CHCH3);
HRMS (ESI) calculated for C26H29N3NaO7 [MþNa]þ m/z 518.1898,
found 518.1875.
3.2.1. Z-Alaj[CON(NPht)]Ala-OMe 3a
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85 then 40/60); yield 85%,
white solid, mp¼109 ꢁC; IR (KBr) nmax/cmꢂ1 3271 (NH), 1797, 1747,
3.2.5. Z-Alaj[CON(NPht)]Gly-OMe 3e
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85 then 40/60); yield 77%,
oil; IR (KBr) nmax/cmꢂ1 3281 (NH), 1795, 1751, 1695, 1675 (C]O); 1H
1693, 1674 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.95–7.80 (m,
4H, Hpht), 7.37–7.32 (m, 5H, H arom), 5.40 (d, 1H, J¼8.5 Hz, NH),
5.15–5.11 (m, 1H, CHCH3), 5.01–4.88 (m, 2H, COOCH2Ph), 4.41–4.29
(m, 1H, CHCH3), 3.76 (s, 3H, OCH3), 1.35 (d, 3H, J¼8.3 Hz, CHCH3),
NMR (CDCl3, 300 MHz) d (ppm) 7.93–7.62 (m, 4H, Hpht), 7.37–7.17
(m, 5H, H arom), 5.83–5.71 (m, 1H, NH), 5.24–5.10 (m, 3H,
COOCH2Ph and CHCH3), 3.81 (d, 2H, J¼14.4 Hz, CH2COOMe), 3.72 (s,
1H, OCH3), 3.69 (s, 2H, OCH3), 1.42 (d, 1H, J¼6.7 Hz, CHCH3), 1.31 (d,
1.28 (d, 3H, J¼8.5 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 174.5
(CON(NPht)), 170.9 (COOMe), 165.8, 163.1 (C]O Pht), 155.6
(NHCOOCH2Ph), 136.9 (ArC), 136.0, 135.5 (Pht CH), 129.8 (PhtC),
129.2, 128.7 (ArCH), 125.3, 124.8 (Pht CH), 67.9, 67.5 (COOCH2Ph),
56.1, 55.4 (CHCH3), 53.6, 53.3 (OCH3), 48.3, 47.8 (CHCH3), 20.0, 19.7
(CHCH3), 14.5, 14.3 (CHCH3); HRMS (ESI) calculated for
C23H23N3NaO7 [MþNa]þ m/z 476.1428, found 476.1374.
2H, J¼6.7 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 170.4 (CON(NPht)),
169.7 (COOMe), 165.3, 164.6 (C]O Pht), 156.3 (NHCOOCH2Ph),
136.6, 135.9 (PhtCH), 135.3 (ArC), 129.5, 129.4, 128.5 (ArCH), 124.9,
124.6 (PhtCH), 67.4 (COOCH2Ph), 56.5, 55.1 (CHCH3), 53.5, 53.1
(OCH3), 43.1, 42.7 (CH2COOMe), 14.6, 14.3 (CHCH3); HRMS (ESI)
calculated for C22H21N3NaO7 [MþNa]þ m/z 462.1272, found
462.1246.
3.2.2. Z-Alaj[CON(NPht)](L,D)Ala-OMe 3b
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85 then 40/60); yield 87%,
white solid, mp¼109 ꢁC; IR (KBr) nmax/cmꢂ1 3271 (NH), 1797, 1747,
3.2.6. Z-Phej[CON(NPht)]Ala-OMe 3f
Dialkyl azodicarboxylate: DEAD; eluent for column chroma-
tography: EtOAc/petroleum ether (20/80); yield 100%, oil; IR (ATR)
nmax/cmꢂ1 3320 (NH), 1733, 1701, 1681 (C]O); 1H NMR (CDCl3,
1693, 1674 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.93–7.80 (m,
4H, Hpht), 7.36–7.26 (m, 5H, H arom), 5.49 (d, 0.5H, J¼8.0 Hz, NH),
5.38 (d, 0.5H, J¼8.0 Hz, NH), 5.27–4.94 (m, 3H, COOCH2Ph and
CHCH3), 4.39 (qd, 1H, J¼7.3, 6.8 Hz, CHCH3), 3.83, 3.81 (2s, 0.6H,
OCH3), 3.77, 3.75 (2s, 2.4H, OCH3), 1.52–1.25 (m, 6H, 2CHCH3); 13C
300 MHz) d (ppm) 7.86–7.75 (m, 4H, Hpht), 7.31–7.08 (m, 10H, H
arom), 5.55 (d, 0.35H, J¼9.4 Hz, NH), 5.42 (d, 0.65H, J¼9.4 Hz, NH),
5.41–4.62 (m, 4H, COOCH2Ph, CHCH2Ph and CHCH3), 4.12 (s, 1H,
OCH3), 4.10 (s, 2H, OCH3), 3.41–2.83 (m, 2H, CHCH2Ph), 1.49 (d, 1H,
J¼9.3 Hz, CHCH3), 1.42 (d, 2H, J¼9.3 Hz, CHCH3); 13C NMR (CDCl3)
NMR (CDCl3)
d (ppm) 174.5 (CON(NPht)), 170.9 (COOMe), 165.8,
163.1 (C]O Pht), 155.6 (NHCOOCH2Ph), 136.9 (ArC), 136.0, 135.5
(PhtCH), 129.8 (PhtC), 129.2, 128.7 (ArCH), 125.3, 124.8 (PhtCH),
67.9, 67.5 (COOCH2Ph), 56.1, 55.4 (CHCH3), 53.6, 53.3 (OCH3), 48.3,
47.8 (CHCH3), 20.0, 19.7 (CHCH3), 14.5, 14.3 (CHCH3); HRMS (ESI)
calculated for C23H23N3NaO7 [MþNa]þ m/z 476.1428, found
476.1401.
d (ppm) 172.7 (CON(NPht)), 170.5, 170.4 (COOMe), 166.0, 164.9
(C]O Pht), 156.4, 155.9 (NHCOOCH2Ph), 136.8, 136.4 (ArC), 135.8,
135.6, 135.4 (PhtCH), 130.6, 130.2, 130.0, 129.9, 128.9, 128.7, 128.5,
128.3, 127.5, 127.3 (ArCH), 124.8, 124.6 (PhtCH), 67.7, 67.3
(COOCH2Ph), 57.3, 56.1 (CHCH2Ph), 53.4, 53.1 (CHCH3), 52.6 (OCH3),
38.7 (CHCH2Ph), 15.0, 14.9, 14.8 (CHCH3); HRMS (ESI) calculated for
C29H27N3NaO7 [MþNa]þ m/z 552.1741, found 552.1758.
3.2.3. Z-Alaj[CON(NPht)]Ala-OEt 3c
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85 then 30/70); yield 85%,
white solid, mp¼158 ꢁC; IR (KBr) nmax/cmꢂ1 3284 (NH), 1796, 1746,
3.2.7. Z-Phej
[CON(NPht)]Ala-OtBu 3g
Dialkyl azodicarboxylate: DEAD; eluent for column chroma-
tography: EtOAc/petroleum ether (20/80); yield 71%, white solid,
mp<50 ꢁC; IR (KBr) nmax/cmꢂ1 3295 (NH), 1798, 1753, 1679 (C]O);
1674 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.87–7.75 (m, 4H,
Hpht), 7.30–7.18 (m, 5H, H arom), 5.35 (d, 1H, J¼8.0 Hz, NH), 5.20–
5.05 (m, 1H, CHCH3), 5.05–4.88 (m, 2H, COOCH2Ph), 4.32 (qd, 1H,
J¼7.3, 6.8 Hz, CHCH3), 4.16–4.09 (m, 2H, OCH2CH3), 1.62–1.13 (m,
1H NMR (CDCl3, 300 MHz)
d (ppm) 7.95–7.80 (m, 4H, Hpht), 7.31–
7.09 (m, 10H, H arom), 5.24–4.80 (m, 5H, COOCH2Ph, CHCH3,
CHCH2Ph and NH), 3.13–2.82 (m, 2H, CHCH2Ph), 1.50–1.44 (m, 12H,
9H, OCH2CH3 and 2CHCH3); 13C NMR (CDCl3)
d
(ppm) 174.1
CHCH3 and NHCOOC(CH3)3); 13C NMR (CDCl3)
d (ppm) 172.6
(CON(NPht)), 170.2 (COOEt), 165.9, 165.0 (C]O Pht), 155.8
(NHCOOCH2Ph), 136.9 (ArC), 135.9, 135.8, 135.5, 134.7 (PhtCH),
130.1, 129.9 (PhtC), 129.1, 128.9, 128.7, 128.6 (ArCH), 125.1, 125.0,
124.8, 124.6 (PhtCH), 67.9, 67.5 (COOCH2Ph), 62.9, 62.4 (OCH2CH3),
57.5, 56.7 (CHCH3), 47.6 (CHCH3), 19.7, 19.4 (CHCH3), 15.3
(OCH2CH3), 15.0, 14.6 (CHCH3); HRMS (ESI) calculated for
C24H25N3NaO7 [MþNa]þ m/z 490.1585, found 490.1557.
(CON(NPht)), 170.5 (COOtBu), 166.1, 165.1, 165.0 (C]O Pht), 156.0
(NHCOOCH2Ph), 137.0, 136.5, 136.2 (ArC), 135.8, 135.6, 135.4, 134.7,
134.6, 135.4 (PhtCH), 130.4, 130.1, 129.9, 128.7, 128.6, 128.4, 127.6,
127.4 (ArCH), 124.9, 124.7 (PhtCH), 82.7 (COOC(CH3)3), 67.6
(NHCOOCH2Ph), 58.7 (CHCH3), 58.1, 52.6 (CHCH2Ph), 38.9
(CHCH2Ph), 28.5 (COOC(CH3)3), 14.8 (CHCH3); HRMS (ESI) calcu-
lated for C32H33N3NaO7 [MþNa]þ m/z 594.2211, found 594.2195.
3.2.4. Z-Ala
j
[CON(NPht)]Ala-OtBu 3d
3.2.8. Boc-Phej[CON(NPht)]Gly-OMe 3h
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85 then 40/60); yield 75%,
white solid, mp¼150 ꢁC; IR (KBr) nmax/cmꢂ1 3281 (NH), 1795, 1751,
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (30/70); yield 97%, oil; IR (ATR)
nmax/cmꢂ1 3341 (NH), 1798, 1741, 1698 (C]O); 1H NMR (CDCl3,
1695,1675 (C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 7.95–7.78 (m,
300 MHz) d (ppm) 7.85–7.80 (m, 4H, Hpht), 7.24–7.05 (m, 5H, H
4H, Hpht), 7.73–7.28 (m, 5H, H arom), 5.73 (d, 0.2H, J¼8.0 Hz, NH),
5.50 (d, 0.8H, J¼8.0 Hz, NH), 5.15–4.92 (m, 3H, COOCH2Ph and
CHCH3), 4.60 (qd, 0.2H, J¼7.3, 6.8 Hz, CHCH3), 4.38 (qd, 0.8H, J¼7.3,
6.8 Hz, CHCH3), 1.52–1.37 (m, 15H, OC(CH3)3 and 2CHCH3); 13C NMR
arom), 5.05 (d, 0.25H, J¼9.5 Hz, NH), 4.88 (d, 0.75H, J¼9.5 Hz, NH),
4.62–4.57 (m, 2H, CHCH2Ph and CH2COOMe), 4.19 (d, 1H, J¼16.9 Hz,
CH2COOMe), 3.67 (s, 0.75H, OCH3), 3.63 (s, 2.25H, OCH3), 3.10–2.73
(m, 2H, CHCH2Ph), 1.35 (s, 2.25H, NHCOOC(CH3)3), 1.06 (s, 6.75H,

10746
A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
NHCOOC(CH3)3); 13C NMR (CDCl3)
d
(ppm) 173.4, 171.1
arom), 5.13 (s, 2H, COOCH2Ph), 4.94 (d, 1H, J¼9.8 Hz, NH), 4.74 (d,
(CON(NPht)), 168.1 (COOMe), 164.9, 164.5 (C]O Pht), 155.2
(NHCOOtBu), 136.7 (ArC), 135.6, 135.5, 135.2 (PhtCH), 130.2 (ArC),
129.3, 129.2, 128.9, 127.7, 127.6, 127.2 (ArCH), 125.0, 124.8, 124.7,
124.6 (PhtCH), 80.4 (NHCOOC(CH3)3), 53.3, 53.0 (OCH3), 51.6
(CHCH2Ph), 49.9 (CH2COOMe), 39.8, 38.9 (CHCH2Ph), 28.9, 28.7
(NHCOOC(CH3)3); HRMS (ESI) calculated for C25H27N3NaO7
[MþNa]þ m/z 504.1741, found 504.1739.
1H, J¼17.0 Hz, CH2COOCH2Ph), 4.44–4.32 (m, 1H, CHCH2CH(CH3)2),
4.24 (d, 1H, J¼17.0 Hz, CH2COOCH2Ph), 1.61–1.52 (m, 2H,
CHCH2CH(CH3)2), 1.44–1.31 (m, 10H, NHCOOC(CH3)3 and
CHCH2CH(CH3)2), 0.85 (d, 3H, J¼5.8 Hz, CHCH2CH(CH3)2), 0.73 (d,
3H, J¼5.8 Hz, CHCH2CH(CH3)2); 13C NMR (CDCl3)
d (ppm) 174.5
(CON(NPht)), 167.5 (COOCH2Ph), 164.8, 164.5 (C]O Pht), 155.4
(NHCOOtBu), 135.6 (ArC), 135.4, 135.3 (PhtCH), 130.3 (ArC), 129.3,
129.2, 129.1, 129.0, 128.9 (ArCH), 124.7, 124.6, 124.5 (PhtCH), 80.2
(NHCOOC(CH3)3), 67.8 (COOCH2Ph), 49.9 (CH2COOCH2Ph), 48.6
(CHCH2CH(CH3)2), 42.5 (CHCH2CH(CH3)2), 28.7 (NHCOOC(CH3)3),
24.9 (CHCH2CH(CH3)2), 23.6, 22.4 (CHCH2CH(CH3)2); HRMS (ESI)
calculated for C28H33N3NaO7 [MþNa]þ m/z 546.2367, found
546.2345.
3.2.9. Boc-Phe
Dialkyl azodicarboxylate: DBAD; eluent for column chromato-
graphy: EtOAc/petroleum ether (25/75); yield 98%, oil; IR (ATR) nmax
cmꢂ1 3351 (NH),1799,1744,1693 (C]O); 1H NMR (CDCl3, 300 MHz)
(ppm) 7.93–7.79 (m, 4H, Hpht), 7.29–7.14 (m, 5H, H arom), 5.49–
j[CON(NPht)]Ala-OMe 3i
/
d
5.11 (m, 1H, CHCH3), 5.00 (d, 0.3H, J¼7.8 Hz, NH), 4.89 (d, 0.7H,
J¼7.8 Hz, NH), 4.86–4.72 (m,1H, CHCH2Ph), 3.79 (s, 0.9H, OCH3), 3.75
(s, 2.1H, OCH3), 3.21–2.81 (m, 2H, CHCH2Ph), 1.49–1.22 (m, 12H,
3.2.13. Boc-Leuj[CON(NPht)]Ala-OMe 3m
Dialkyl azodicarboxylate: DBAD; eluent for column chroma-
tography: EtOAc/petroleum ether (15/85); yield 47%, oil; IR (ATR)
nmax/cmꢂ1 3359 (NH), 1754, 1691 (C]O); 1H NMR (CDCl3, 300 MHz)
NHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
d (ppm) 172.9
(CON(NPht)), 170.8, 170.4 (COOMe), 166.1, 165.1 (C]O Pht), 155.8,
155.2 (NHCOOtBu), 136.9 (ArC), 135.6, 135.5 (PhtCH), 130.7 (ArC),
130.3 (ArCH), 130.2 (ArC), 130.1, 129.1, 128.9, 127.5, 127.3 (ArCH),
125.0, 124.9, 124.8 (PhtCH), 81.1, 80.4 (NHCOOC(CH3)3), 57.2, 56.0
(CHCH3), 53.4, 53.2 (CHCH2Ph), 52.1 (OCH3), 39.1, 38.9 (CHCH2Ph),
28.9, 28.7 (NHCOOC(CH3)3),14.9 (CHCH3); HRMS (ESI) calculated for
C26H29N3NaO7 [MþNa]þ m/z 518.1898, found 518.1883.
d
(ppm) 7.92–7.77 (m, 4H, Hpht), 5.50–4.94 (m, 2H, NH and CHCH3),
4.7 (dd, 0.3H, J¼9.9, 9.3 Hz, CHCH(CH3)2), 3.93 (dd, 0.7H, J¼9.9,
9.3 Hz, CHCH(CH3)2), 3.79 (s, 0.9H, OCH3), 3.73 (s, 2.1H, OCH3),
2.01–1.99 (m, 1H, CHCH(CH3)2), 1.46–1.38 (m, 12H, NHCOOC(CH3)3
and CHCH3), 0.87–0.81 (m, 6H, CHCH(CH3)2); 13C NMR (CDCl3)
d
(ppm) 173.5 (CON(NPht)) 171.2, 170.7 (COOMe), 165.9, 164.7 (C]O
Pht), 156.4, 155.8 (NHCOOtBu), 135.7, 135.5, 135.3, 135.2 (ArCH),
130.7, 130.5, 129.9 (ArC), 125.0, 124.9, 124.6, 124.4 (PhtCH), 80.9,
80.3 (NHCOOC(CH3)3), 60.9, 57.2 (CHCH(CH3)2), 56.2, 55.9 (CHCH3),
53.0 (OCH3), 31.5, 31.2 (CHCH(CH3)2), 28.7, 28.6 (NHCOOC(CH3)3),
20.0, 18.0 (CHCH(CH3)2), 15.2, 14.9 (CHCH3); HRMS (ESI) calculated
for C22H29N3NaO7 [MþNa]þ m/z 470.1898, found 470.1887.
3.2.10. Boc-Phej[CON(NPht)]Ala-OCH2Ph 3j
Dialkyl azodicarboxylate: DEAD; eluent for column chroma-
tography: EtOAc/petroleum ether (20/80); yield 80%, gum; IR (KBr)
nmax/cmꢂ1 3430 (NH), 1799, 1750, 1702 (C]O); 1H NMR (CDCl3,
300 MHz)
d (ppm) 7.98–7.62 (m, 4H, Hpht), 7.30–6.90 (m, 10H, H
arom), 5.40 (q, 0.3H, J¼6.9 Hz, CHCH3), 5.12–5.00 (m, 3H, OCH2Ph,
CHCH2Ph and CHCH3), 4.85 (d, 0.3H, J¼9.4 Hz, NH), 4.76 (d, 0.7H,
J¼9.8 Hz, NH), 4.53 (q, 0.7H, J¼5.9 Hz, CHCH2Ph), 3.06–2.77 (m, 2H,
CHCH2Ph),1.26–1.03 (m,12H, NHCOOC(CH3)3 and CHCH3); 13C NMR
3.2.14. Z-Glyj[CON(NPht)]Gly-OMe 3n
Dialkyl azodicarboxylate: DBAD; yield 90%, white solid,
mp¼128 ꢁC; IR (KBr) nmax/cmꢂ1 3364 (NH), 1793, 1760, 1736, 1718,
(CDCl3)
d
(ppm) 172.7 (CON(NPht)), 170.0 (COOCH2Ph), 166.0, 164.8
1697 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 8.01–7.82 (m, 4H,
(C]O Pht), 155.0 (NHCOOtBu), 136.9 (ArC), 136.1, 135.3 (PhtCH),
130.2, 129.8, 129.7, 129.5, 129.0, 128.7, 127.0 (ArCH), 124.8, 124.6,
124.5 (PhtCH), 80.0 (NHCOOC(CH3)3), 68.6, 67.8 (OCH2Ph), 57.0,
56.0 (CHCH3), 51.8 (CHCH2Ph), 38.8, 38.2 (CHCH2Ph), 28.5
(NHCOOC(CH3)3), 14.6, 14.4 (CHCH3); HRMS (ESI) calculated for
C32H33N3NaO7 [MþNa]þ m/z 594.2211, found 594.2219.
Hpht), 7.42–7.21 (m, 5H, H arom), 5.63–5.52 (m,1H, NH), 5.09 (s, 2H,
COOCH2Ph), 4.55 (s, 2H, CH2COOCH3), 4.01 (d, 2H, J¼4.4 Hz,
NHCH2CO), 3.75 (s, 3H, OCH3); 13C NMR (CDCl3)
d (ppm) 170.3
(CONNPht), 167.8 (COOCH3), 164.3 (C]O Pht), 156.3
(NHCOOCH2Ph), 136.6 (ArC), 135.8 (PhtCH), 129.7 (ArC), 128.8, 128.5
(ArCH), 124.9 (PhtCH), 67.4 (NHCOOCH2Ph), 52.9 (COOCH3), 49.1
(CH2COOCH3), 42.4 (NHCH2CO).
3.2.11. Boc-Leuj[CON(NPht)]Gly-OMe 3k
Dialkyl azodicarboxylate: DIAD; eluent for column chromato-
graphy: EtOAc/petroleum ether (30/70); yield 91%, oil; IR (ATR)
nmax/cmꢂ1 3251 (NH), 1802, 1742, 1695 (C]O); 1H NMR (CDCl3,
3.2.15. Z-Glyj[CON(NPht)]Ala-OMe 3o
Dialkyl azodicarboxylate: DBAD; yield 84%, white solid,
mp¼55 ꢁC; IR (KBr) nmax/cmꢂ1 3408 (NH), 1797, 1746, 1736, 1710
300 MHz)
d
(ppm) 7.98–7.85 (m, 4H, Hpht), 5.08 (d, 0.25H, J¼9.9 Hz,
(C]O); 1H NMR (CDCl3, 300 MHz):
d (ppm) 7.93–7.62 (m, 4H, Hpht),
NH), 4.92 (d, 0.75H, J¼9.9 Hz, NH), 4.73 (d, 1H, J¼17.0 Hz,
CH2COOMe), 4.60–4.47 (m, 1H, CHCH2CH(CH3)2), 4.40 (d, 1H,
J¼17.0 Hz, CH2COOMe), 3.74 (s, 0.75H, OCH3), 3.67 (s, 2.25H, OCH3),
1.64–1.23 (m, 12H, NHCOOC(CH3)3, and CHCH2CH(CH3)2), 1.02–0.95
7.37–7.17 (m, 5H, H arom), 5.83–5.71 (m, 1H, NH), 5.24–5.10 (m, 3H,
CHCH3 and COOCH2Ph), 3.81 (d, 2H, J¼4.4 Hz, NHCH2CO), 3.72 (s,
0.45H, OCH3), 3.69 (s, 2.55H, OCH3),1.42 (d, 0.45H, J¼6.7 Hz, CHCH3),
1.31 (d, 2.55H, J¼6.7 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 170.4
(m, 6H, CHCH2CH(CH3)2); 13C NMR (CDCl3)
d
(ppm) 174.6
(CONNPht), 169.7 (COOCH3), 165.3, 165.6 (C]O Pht), 156.3
(NHCOOCH2Ph),136.6 (ArC),135.9,135.3 (PhtCH),129.5 (ArC),129.4,
128.5 (ArCH), 124.9, 124.6 (PhtCH), 67.4 (NHCOOCH2Ph), 56.5, 55.1
(CHCH3), 53.5, 53.1 (COOCH3), 43.1, 42.7 (NHCH2CO), 14.6, 14.3
(CHCH3).
(CON(NPht)), 168.2 (COOMe), 164.9, 164.5 (C]O Pht), 155.4
(NHCOOtBu), 135.5, 135.3 (PhtCH), 130.4 (ArC), 124.8, 124.6 (PhtCH),
80.3 (NHCOOC(CH3)3), 53.3 (OCH3), 49.6 (CH2COOMe), 48.7
(CHCH2CH(CH3)2),
42.6
(CHCH2CH(CH3)2),
28.9,
28.8
(NHCOOC(CH3)3), 25.2, 25.0 (CHCH2CH(CH3)2), 23.8, 23.6, 22.7, 22.4
(CHCH2CH(CH3)2); HRMS (ESI) calculated for C22H29N3NaO7
[MþNa]þ m/z 470.1898, found 470.1850.
3.2.16. Z-Glyj[CON(NPht)]Val-OCH2Ph 3p
Dialkyl azodicarboxylate: DBAD; yield 79%, white solid; IR (KBr)
nmax/cmꢂ1 3291 (NH), 1794, 1733, 1678 (C]O); 1H NMR (CDCl3,
3.2.12. Boc-Leu
j[CON(NPht)]Gly-OCH2Ph 3l
300 MHz) d (ppm) 8.01–7.65 (m, 4H, Hpht), 7.45–7.22 (m, 10H, H
Dialkyl azodicarboxylate: DIAD; eluent for column chromato-
graphy: EtOAc/petroleum ether (30/70); yield 92%, oil; IR (ATR)
nmax/cmꢂ1 3370 (NH), 1798, 1741, 1618 (C]O); 1H NMR (CDCl3,
arom), 5.64 (d, 1H, J¼4.6 Hz, NH), 5.23–5.01 (m, 4H, NHCH2CO and
NHCOOCH2Ph), 4.42–4.38 (m, 1H, CHCH(CH3)2), 3.92 (dq, 2H,
J¼17.5, 4.6 Hz, NHCH2CO), 2.23–2.05 (m, 1H, CHCH(CH3)2), 1.43 (d,
0.5H, J¼6.5 Hz, CHCH(CH3)2), 1.22 (d, 2.5H, J¼6.5 Hz, CHCH(CH3)2),
300 MHz)
d (ppm) 7.92–7.77 (m, 4H, Hpht), 7.37–7.27 (m, 5H, H

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10747
0.94 (d, 0.5H, J¼6.6 Hz, CHCH(CH3)2), 0.86 (d, 2.5H, J¼6.5 Hz,
CHCH(CH3)2); 13C NMR (CDCl3)
(ppm) 170.3 (CONNPht), 168.8
(CHCH2Ph), 38.7 (CHCH2Ph), 28.8 (NHCOOC(CH3)3), 15.0, 14.2
(CHCH3).
d
(COOCH2Ph), 165.5, 165.3 (C]O Pht), 156.3 (NHCOOCH2Ph), 136.6
(ArC), 135.8, 135.7 (PhtCH), 129.7 (ArC), 129.2, 128.9, 12.8, 128.5
(ArCH), 124.9, 124.7 (PhtCH), 67.9, 67.8, 67.4 (NHCOOCH2Ph and
COOCH2Ph), 42.8 (NHCH2CO) 64.9 (CHCH(CH3)2), 29.8
(CHCH(CH3)2), 19.7, 19.3 (CHCH(CH3)2).
3.3.2. Boc-Leu
Yield 87%, gum; IR (ATR) nmax/cmꢂ1 2968 (NH), 1798, 1741, 1692
(C]O); 1H NMR (CDCl3, 300 MHz)
(ppm) 9.87 (s, 1H, COOH), 7.98–
7.85 (m, 4H, Hpht), 5.08 (d, 0.25H, J¼9.9 Hz, NHCOOC(CH3)3), 4.92
(d, 0.75H, J¼9.9 Hz, NHCOOC(CH3)3), 4.73 (d, 1H, J¼17.0 Hz,
CH2COOH), 4.60–4.47 (m, 1H, CHCH2CH(CH3)2), 4.40 (d, 1H,
J¼17.0 Hz, CH2COOH), 1.64–1.23 (m, 12H, NHCOOC(CH3)3 and
CHCH2CH(CH3)2), 1.02–0.95 (m, 6H, CHCH2CH(CH3)2); 13C NMR
j[CON(NPht)]Gly-OH 4l
d
3.2.17. Z-Alaj[CON(NPht)]Val-OCH2Ph 3q
Dialkyl azodicarboxylate: DBAD; yield 77%, white solid,
mp¼163 ꢁC; IR (KBr) nmax/cmꢂ1 3299 (NH), 1798, 1752,1672 (C]O);
1H NMR (CDCl3, 300 MHz)
d
(ppm) 8.01–7.70 (m, 4H, Hpht), 7.51–
(CDCl3) d (ppm) 174.6 (COOH), 168.2 (CON(NPht)), 164.9, 164.5
7.12 (m, 10H, H arom), 5.62–5.51 (m, 1H, NH), 5.33–4.91 (m, 5H,
CHCH3, NHCOOCH2Ph and COOCH2Ph), 4.53–4.31 (m, 1H,
CHCH(CH3)2), 2.30–2.13 (m,1H, CHCH(CH3)2),1.51 (d, 0.6H, J¼6.8 Hz,
CHCH3), 1.35 (d, 2.4H, J¼6.8 Hz, CHCH3), 1.29 (d, 0.6H, J¼6.5 Hz,
CHCH(CH3)2), 1.20 (d, 2.4H, J¼6.5 Hz, CHCH(CH3)2), 0.96 (d, 0.6H,
J¼6.7 Hz, CHCH(CH3)2), 0.85 (d, 2.4H, J¼6.7 Hz, CHCH(CH3)2); 13C
(C]O Pht), 155.4 (NHCOOtBu), 135.5, 135.3 (PhtCH), 130.4 (ArC),
124.8, 124.6 (PhtCH), 80.3 (NHCOOC(CH3)3), 49.6 (CH2COOH), 48.7
(CHCH2CH(CH3)2),
42.6
(CHCH2CH(CH3)2),
28.9,
28.8
(NHCOOC(CH3)3), 25.2, 25.0 (CHCH2CH(CH3)2), 23.8, 23.6, 22.7, 22.4
(CHCH2CH(CH3)2); HRMS (ESI) calculated for C22H33N3NaO7
[MþNa]þ m/z 456.1741, found 456.1723.
NMR (CDCl3)
d (ppm) 175.0 (CONNPht), 169.2 (COOCH2Ph), 166.0,
165.5 (C]O Pht), 155.5 (NHCOOCH2Ph), 136.6 (ArC), 135.9 (PhtCH),
135.6, 129.7 (ArC), 129.6, 129.5, 129.2, 128.9, 128.8, 128.5 (ArCH),
124.9, 124.7 (PhtCH), 68.7, 67.9, 67.4, 67.2 (NHCOOCH2Ph and
COOCH2Ph), 60.3, 57.6 (CH(CH3)2 and CHCH(CH3)2), 25.2, 24.9, 23.3,
23.1, 22.6, 22.4 (CH(CH3)2, CHCH3 and CHCH(CH3)2).
3.3.3. Boc-[Phej[CON(NPht)]Ala]2-OH 14
Yield 100%, white solid, mp¼130 ꢁC; IR (KBr) nmax/cmꢂ1 3325
(NH and COOH), 1799, 1741, 1695 (CO); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 8.35 (d, 0.7H, J¼8.1 Hz, NHCH(CH3)), 8.25 (d, 0.3H, J¼8.0 Hz,
NHCH(CH3)), 8.10–7.80 (m, 8H, Hpht), 7.33–7.00 (m, 10H, H arom),
5.00–4.26 (m, 5H, CHCH3, CHCH2Ph and NHCOOC(CH3)3), 3.40–2.50
(m, 4H, CHCH2Ph), 1.40–1.09 (m, 15H, COOC(CH3)3 and CHCH3).
3.2.18. Z-Valj[CON(NPht)]Gly-OMe 3r
Dialkyl azodicarboxylate: DBAD; yield 79%, white solid,
mp¼135 ꢁC; IR (KBr) nmax/cmꢂ1 3290 (NH), 1796, 1743, 1699 (C]O);
3.4. Experimental procedure for the preparation of 4g
in solution
1H NMR (CDCl3, 300 MHz)
d (ppm) 8.02–7.63 (m, 4H, Hpht), 7.41–
7.22 (m, 5H, H arom), 5.54 (d, 0.25H, J¼9.9 Hz, NH), 5.39 (d, 0.75H,
J¼9.9 Hz, NH), 5.26–4.91 (m, 2H, NHCOOCH2Ph), 4.85 (d, 0.25H,
J¼17.0 Hz, NHCOOCH2Ph), 4.72 (d, 0.75H, J¼17.0 Hz, CH2COOCH3),
4.63(dd, 0.25H, J¼9.9, 7.7 Hz, CHCH(CH3)2), 4.51 (d, 0.25H, J¼17.0 Hz,
CH2COOCH3), 4.21 (dd, 0.75H, J¼9.9, 7.7 Hz, CHCH(CH3)2), 4.13 (d,
0.75H, J¼17.0 Hz, CH2COOCH3), 3.77 (s, 0.75H, COOCH3), 3.71 (s,
2.25H, COOCH3), 2.25–2.00 (m, 1H, CHCH(CH3)2), 1.09 (d, 0.75H,
J¼6.7 Hz, CHCH(CH3)2), 0.99 (d, 0.75H, J¼6.7 Hz, CHCH(CH3)2), 0.93
(d, 2.25H, J¼6.7 Hz, CHCH(CH3)2), 0.87 (d, 2.25H, J¼6.5 Hz,
To a stirred solution of 3g (0.51 g, 0.9 mmol) in anhydrous
CH2Cl2 (12 mL), trifluoroacetic acid (3 mL, 40 mmol) was added
with stirring. The resulting solution was stirred at room tempera-
ture until completion (monitored by TLC) and concentrated in
vacuo. The residue was used directly in oligomerization.
3.4.1. Z-Phej[CON(NPht)]Ala-OH 4g
Yield 100%, white solid, mp¼80 ꢁC; IR (KBr) nmax/cmꢂ1 3356
CHCH(CH3)2); 13C NMR (CDCl3)
d (ppm) 173.7, 171.1 (CONNPht),
(NH, COOH), 1798, 1745, 1692 (C]O); 1H NMR (CDCl3, 300 MHz)
167.8, 165.1 (COOCH3), 165.5, 164.6 (C]O Pht), 156.7, 156.4
(NHCOOCH2Ph),136.7 (ArC),135.5,135.4 (PhtCH),129.9,129.0 (ArC),
128.8, 128.7, 128.4, 128.3 (ArCH), 124.7, 124.5 (PhtCH), 67.6, 67.4
(NHCOOCH2Ph), 56.4, 55.9 (CHCH(CH3)2), 53.1, 52.8 (COOCH3), 49.7
(CH2COOCH3), 31.2 (CHCH(CH3)2), 19.8, 19.7, 17.7, 17.6 (CH(CH3)2).
d
(ppm) 7.95–7.80 (m, 4H, Hpht), 7.31–7.06 (m, 5H, H arom), 5.60
(d, 1H, J¼9.3 Hz, NH), 5.40 (q, 0.1H, J¼8.8 Hz, CHCH3), 5.10–5.00
(m, 1.1H, COOCH2Ph and CHCH2Ph), 5.00–4.80 (m, 1.9H,
COOCH2Ph and CHCH3), 4.65 (dd, 0.9H, J¼5.8, 8.5 Hz, CHCH2Ph),
3.20–2.82 (m, 2H, CHCH2Ph), 1.49–1.43 (d, 3H, J¼7.9 Hz, CHCH3);
13C NMR (CDCl3)
d (ppm) 173.5 (COOH), 172.6 (CON(NPht)), 165.9
3.3. Typical experimental procedure for the preparation of 4
(C]O Pht), 156.4 (NHCOOCH2Ph), 136.6, 136.3 (ArC), 136.2, 136.0,
135.7 (PhtCH), 130.3, 130.0 (ArCH), 129.7 (ArC), 129.0, 128.7, 128.6,
128.4, 127.5 (ArCH), 125.2, 125.0 (PhtCH), 67.8 (NHCOOCH2Ph),
58.0 (CHCH3), 52.8 (CHCH2Ph), 38.6 (CHCH2Ph), 14.3 (CHCH3);
HRMS (ESI) calculated for C28H25N3NaO7 [MþNa]þ m/z 538.1585,
found 538.1572.
(P2[OCH2Ph) and 14 in solution
To a stirred solution of 3 (0.9 mmol) in ethanol (20 mL), a cata-
lytic amount of 10% Pd/C was added. The resulting mixture was
flushed with H2 and vigorously stirred until completion (monitored
by TLC). The reaction mixture was filtered on Celite and evaporated
to dryness. The product was used without further purification.
3.5. Typical experimental procedure for the preparation of 4
on solid support
3.3.1. Boc-Phej[CON(NPht)]Ala-OH 4j
Yield 100%, white solid, mp¼95 ꢁC; IR (KBr) nmax/cmꢂ1 3340
(NH and COOH), 1798, 1745 (C]O); 1H NMR (CDCl3, 300 MHz)
Step a: to a suspension of 0.30 g of Wang PS resin (cross-linked
with 1% DVB, 200–400 mesh, 1.2 mequiv/g) in THF (1 mL/
100 mg of resin) were added DIC (3 equiv), a catalytic
amount of DMAP and THPO-hydroxy acid 10 (3 equiv). The
resulting mixture was stirred for 2 h and then filtered and
washed with CH2Cl2 (3ꢀ1 min), MeOH (3ꢀ1 min) and then
THF (3ꢀ1 min).
d
(ppm) 8.8 (br s, 1H, COOH), 8.00–7.82 (m, 4H, Hpht), 7.26–7.11
(m, 5H, H arom), 5.10 (d, 1H, J¼9.9 Hz, NH), 4.90 (q, 1H, J¼7.1 Hz,
CHCH3), 4.54–4.52 (dd, 1H, J¼8.9, 6.1 Hz, CHCH2Ph), 3.17–3.11 (dd,
1H, J¼8.5, 5.6 Hz, CHCH2Ph), 2.91–2.83 (dd, 1H, J¼8.3, 5.6 Hz,
CHCH2Ph), 1.50–1.18 (m, 12H, NHCOOC(CH3)3 and CHCH3); 13C
NMR (CDCl3)
d ppm 173.7 (COOH), 172.2 (CON(NPht)), 166.0, 165.9
(C]O Pht), 155.5 (NHCOOtBu), 136.7 (ArC), 135.9, 135.6 (PhtCH),
130.3, 130.2 (ArCH), 129.8 (ArC), 129.0, 127.5, 127.3 (ArCH), 125.3,
125.2, 124.9 (PhtCH), 80.7 (NHCOOC(CH3)3), 58.0 (CHCH3), 52.2
Step b: 10 mL of a solution of PTSA (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

10748
A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
the resin was then filtered and washed with CH2Cl2
3.5.5. Z-Leuj[CON(NPht)]Gly-OH 4s
Yield 39%, white solid, mp¼69 ꢁC; IR (ATR) nmax/cmꢂ1 3335
(3ꢀ1 min), MeOH (3ꢀ1 min) and then with THF (3ꢀ1 min).
(NH), 1799, 1741, 1698 (C]O); 1H NMR (DMSO-d6, 300 MHz)
Step c: PPh3 (3 equiv) and
a-Z-N-protected aminohydrazide 1
(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.
d
(ppm) 7.99–7.91 (m, 4H, Hpht), 7.65 (d, 1H, J¼9.2 Hz,
NHCOOCH2Ph), 7.38–7.26 (m, 5H, H arom), 5.08–5.01 (m, 2H,
NHCOOCH2Ph), 4.40 (d, 1H, J¼17.0 Hz, NCH2COOH), 4.31–4.18 (m,
3H, NCH2COOH and CHCH2CH(CH3)2), 1.88–1.44 (m, 3H,
CHCH2CH(CH3)2), 0.80 (d, 3H, J¼5.3 Hz, CHCH2CH(CH3)2), 0.61 (d,
3H, J¼5.3 Hz, CHCH2CH(CH3)2); 13C NMR (DMSO-d6)
d (ppm) 173.1
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.
(COOH), 168.1 (CON(NPht)), 164.3, 164.1 (C]O Pht), 155.6
(NHCOOCH2Ph), 136.7 (ArC), 135.0 (PhtCH), 129.8, 129.6 (ArC),
128.2, 127.7, 127.6 (ArCH), 123.5, 123.5 (PhtCH), 65.6, 65.4
(NHCOOCH2Ph), 49.7 (CH2COOH), 48.6 (CHCH2CH(CH3)2), 40.2
3.5.1. Z-Ala
Yield 37%, gum; IR (ATR) nmax/cmꢂ1 3293 (NH), 1794, 1745, 1676
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 12.60 (s, 1H, COOH),
j[CON(NPht)]Ala-OH 4a
(CHCH2CH(CH3)2),
23.8
(CHCH2CH(CH3)2),
22.8,
21.1
(CHCH2CH(CH3)2); HRMS (ESI) calculated for C23H25N3NaO7
[MþNa]þ m/z 490.1584, found 490.1584.
d
7.98–7.91 (m, 4H, Hpht), 7.71 (d, 1H, J¼8.9 Hz, NHCOOCH2Ph), 7.36–
7.26 (m, 5H, H arom), 4.80–4.62 (m, 3H, CHCH3 and NHCOOCH2Ph),
4.25–4.23 (m, 1H, CHCH3), 1.34 (d, 3H, J¼10.0 Hz, CHCH3), 1.12 (d,
3.5.6. Z-Phe
Yield 48%, gum; IR (ATR) nmax/cmꢂ1 3363 (NH), 1798, 1739, 1693
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 7.97–7.86 (m, 5H,
j[CON(NPht)]Gly-OH 4t
3H, J¼10.0 Hz, CHCH3); 13C NMR (DMSO-d6)
d (ppm) 172.4 (COOH),
d
170.5 (CON(NPht)), 164.9, 164.5 (C]O Pht), 155.2 (NHCOOCH2Ph),
136.6 (ArC), 135.5, 135.1 (PhtCH), 129.5, 129.3 (ArC), 129.4, 129.2,
128.3, 127.7 (ArCH), 123.8, 123.5 (PhtCH), 65.5 (NHCOOCH2Ph), 57.6
(CHCH3), 46.3 (CHCH3), 17.5 (CHCH3), 14.7 (CHCH3); HRMS (ESI)
calculated for C22H21N3NaO7 [MþNa]þ m/z 462.1271, found
462.1261.
Hpht and NHCOOCH2Ph), 7.30–7.06 (m,10H, H arom), 4.64–4.60 (m,
2H, NHCOOCH2Ph), 4.48 (d, 1H, J¼17.1 Hz, CH2COOH), 4.43–4.35 (m,
1H, CHCH2Ph), 4.27 (d, 1H, J¼17.1 Hz, CH2COOH), 3.02–2.78 (m, 2H,
CHCH2Ph); 13C NMR (DMSO-d6)
d (ppm) 172.9 (COOH), 168.1
(CON(NPht)), 164.4, 163.9 (C]O Pht), 155.4 (NHCOOCH2Ph), 137.8,
136.7 (ArC), 135.2, 134.9 (PhtCH), 129.8, 129.6 (ArC), 129.2, 128.9,
128.1, 128.0, 127.5, 127.2, 127.1, 126.2 (ArCH), 123.6, 123.4 (PhtCH),
65.4, 65.1 (NHCOOCH2Ph), 51.8 (CHCH2Ph), 49.9 (CH2COOH), 36.6
(CHCH2Ph); HRMS (ESI) calculated for C27H23N3NaO7 [MþNa]þ m/z
524.1428, found 524.1427.
3.5.2. Z-Gly
Yield 38%, gum; IR (ATR) nmax/cmꢂ1 3316 (NH), 1798, 1741, 1693
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 7.97–7.86 (m, 4H,
j[CON(NPht)]Ala-OH 4e
d
Hpht), 7.66–7.56 (m, 1H, NHCOOCH2Ph), 7.41–7.33 (m, 5H, H arom),
5.04–4.72 (m, 3H, CHCH3 and NHCOOCH2Ph), 4.35–3.92 (m, 2H,
NHCH2CO), 1.39 (d, 1H, J¼6.7 Hz, CHCH3), 1.31 (d, 2H, J¼6.7 Hz,
3.5.7. Z-Leu
Yield 44%, gum; IR (ATR) nmax/cmꢂ1 3376 (NH), 1798, 1742, 1688
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 7.95–7.89 (m, 4H,
j[CON(NPht)]Ala-OH 4u
CHCH3); 13C NMR (DMSO-d6)
d (ppm) 170.4 (COOH), 169.7, 168.8
d
(CON(NPht)), 164.7 (C]O Pht), 156.4, 156.3 (NHCOOCH2Ph), 137.1,
136.9 (ArC), 135.5, 135.3 (PhtCH), 130.1 (ArC), 129.4, 129.2, 128.2,
127.7, 127.6 (ArCH), 123.9, 123.7 (PhtCH), 65.4, 65.2 (NHCOOCH2Ph),
56.7, 55.7 (CHCH3), 41.7 (NHCH2CO), 14.6, 14.2 (CHCH3); HRMS (ESI)
calculated for C21H19N3NaO7 [MþNa]þ m/z 448.1115, found
448.1114.
Hpht), 7.58 (d, 1H, J¼9.2 Hz, NHCOOCH2Ph), 7.32–7.06 (m, 5H, H
arom), 4.82–4.73 (m, 2H, NHCOOCH2Ph), 4.61–4.56 (m, 1H, CHCH3),
4.18–4.14 (m, 1H, CHCH2CH(CH3)2), 1.56–1.19 (m, 6H, CHCH3 and
CHCH2CH(CH3)2), 0.74–0.36 (m, 6H, CHCH2CH(CH3)2); 13C NMR
(DMSO-d6)
d (ppm) 172.3 (COOH), 169.9 (CON(NPht)), 165.0, 164.5
(C]O Pht), 155.6 (NHCOOCH2Ph), 136.7 (ArC), 135.4, 135.1 (PhtCH),
129.5, 129.4 (ArC), 128.2, 127.7, 127.6 (ArCH), 123.6 (PhtCH), 65.4
(NHCOOCH2Ph), 57.5 (CHCH3), 48.9 (CHCH2CH(CH3)2), 40.2
(CHCH2CH(CH3)2), 24.0, 23.8 (CHCH2CH(CH3)2), 22.7, 21.1
(CHCH2CH(CH3)2), 15.0 (CHCH3); HRMS (ESI) calculated for
C25H27N3NaO7 [MþNa]þ m/z 504.1741, found 504.1740.
3.5.3. Z-Glyj[CON(NPht)]Gly-OH 4n
Yield 49%, white solid, mp¼107 ꢁC; IR (ATR) nmax/cmꢂ1 3355
(NH), 1798, 1732, 1698 (C]O); 1H NMR (DMSO-d6, 300 MHz)
d
(ppm) 7.98–7.87 (m, 4H, Hpht), 7.63–7.54 (m, 1H, NHCOOCH2Ph),
7.50–7.33 (m, 5H, H arom), 5.04–4.95 (m, 2H, NHCOOCH2Ph), 4.32–
3.79 (m, 4H, NHCH2CO and CH2COOH); 13C NMR (DMSO-d6)
3.5.8. Z-Phe
Yield 21%, gum; IR (ATR) nmax/cmꢂ1 3451 (NH), 1798, 1742, 1693
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 13.0 (s, 1H, COOH),
j[CON(NPht)]Val-OH 4w
d
(ppm) 170.8, 170.5(COOH), 168.1 (CON(NPht)), 164.2, 164.1 (C]O
Pht), 156.4, 156.3 (NHCOOCH2Ph), 136.9 (ArC), 135.1, 135.0 (PhtCH),
129.7, 129.3 (ArC), 128.2, 128.0, 127.7, 127.6 (ArCH), 123.7 (PhtCH),
65.4 (NHCOOCH2Ph), 49.5 (CH2COOH), 41.5 (NHCH2CO); HRMS
(ESI) calculated for C20H17N3NaO7 [MþNa]þ m/z 434.09587, found
434.0958.
d
8.03–7.84 (m, 5H, Hpht and NHCOOCH2Ph), 7.38–7.04 (m, 10H, H
arom), 4.97–4.67 (m, 3H, NHCOOCH2Ph and CHCH2CH(CH3)2), 4.41–
4.38 (CHCH2Ph), 2.98–2.76 (m, 2H, CHCH2Ph), 1.91–1.89 (m, 1H,
CHCH(CH3)2), 0.92 (d, 3H, J¼3.4 Hz, CHCH(CH3)2), 0.81 (d, 3H,
J¼3.4 Hz, CHCH(CH3)2); 13C NMR (DMSO-d6)
d (ppm) 172.5 (COOH),
3.5.4. Z-Ala
Yield 47%, gum; IR (ATR) nmax/cmꢂ1 3339 (NH), 1798, 1693
(C]O); 1H NMR (DMSO-d6, 300 MHz)
(ppm) 7.97–7.90 (m, 4H,
j[CON(NPht)]Gly-OH 4o
169.6 (CON(NPht)), 165.8, 164.5 (C]O Pht), 155.3 (NHCOOCH2Ph),
137.0, 136.7 (ArC), 135.5, 135.3 (PhtCH), 129.2 (ArC), 129.1, 128.9,
128.2, 128.0, 127.6, 127.4, 127.2, 126.5, 126.3 (ArCH), 123.9, 123.6
(PhtCH), 65.4, 65.2 (NHCOOCH2Ph), 64.3 (CHCH(CH3)2), 52.4
(CHCH2Ph), 37.6 (CHCH2Ph), 29.4 (CHCH(CH3)2), 19.1, 18.9, 18.8
(CHCH(CH3)2); HRMS (ESI) calculated for C30H29N3NaO7 [MþNa]þ
m/z 566.1897, found 566.1895.
d
Hpht), 7.72 (d, 1H, J¼8.9 Hz, NHCOOCH2Ph), 7.36–7.24 (m, 5H, H
arom), 4.76–4.72 (m, 2H, NHCOOCH2Ph), 4.41 (d, 1H, J¼17.0 Hz,
CH2COOH), 4.35 (m, 1H, CHCH3), 4.21 (d, 1H, J¼17.0 Hz, CH2COOH),
1.24, 1.15 (2d, 3H, J¼6.9 Hz, CHCH3); 13C NMR (DMSO-d6)
d (ppm)
173.4 (COOH), 168.1 (CON(NPht)), 164.4, 164.0 (C]O Pht), 155.2
(NHCOOCH2Ph), 136.0, 135.5 (ArC), 134.9 (PhtCH), 129.7 (ArC),
128.2, 127.6 (ArCH), 123.6, 123.5 (PhtCH), 65.5 (NHCOOCH2Ph), 49.9
(CH2COOH), 46.1 (CHCH3), 17.5 (CHCH3); HRMS (ESI) calculated for
C21H19N3NaO7 [MþNa]þ m/z 448.1115, found 448.1113.
3.5.9. Z-Alaj[CON(NPht)]Val-OH 4x
Yield 21%, white solid, mp¼81 ꢁC; IR (ATR) nmax/cmꢂ1 3451 (NH),
1798, 1737, 1693 (C]O); 1H NMR (DMSO-d6, 300 MHz)
d (ppm) 7.97
(m, 4H, Hpht), 7.75–7.67 (m,1H, NHCOOCH2Ph), 7.34–7.27 (m, 5H, H

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10749
arom), 5.05–4.80 (m, 3H, NHCOOCH2Ph and CHCH(CH3)2), 4.35–
4.29 (m, 1H, CHCH3), 2.05–1.90 (m, 1H, CHCH(CH3)2), 1.49–0.81 (m,
9H, CHCH3 and CHCH(CH3)2); 13C NMR (DMSO-d6)
(ppm) 173.9
3.8. Typical experimental procedure for the preparation
of 6a–6i
d
(COOH), 169.6 (CON(NPht)), 165.7, 164.6 (C]O Pht), 155.1
(NHCOOCH2Ph), 136.5 (ArC), 135.4 (PhtCH), 129.1, 128.2, 127.2
(ArCH), 123.6 (PhtCH), 65.4 (NHCOOCH2Ph), 64.3 (CHCH(CH3)2),
47.3, 46.8 (CHCH3), 29.5, 28.4 (CHCH(CH3)2), 18.9, 18.2
(CHCH(CH3)2), 17.1 (CHCH3); HRMS (ESI) calculated for
C23H25N3NaO7 [MþNa]þ m/z 490.1584, found 490.1584.
To a stirred solution of 3 (3 mmol) in anhydrous THF was added
pyrrolidine (9 mmol) in one portion. The resulting solution was
stirred at room temperature until completion (monitored by TLC).
Solvent and excess of pyrrolidine were evaporated under vacuum.
The residue thus obtained was dissolved in anhydrous THF (20 mL).
Boc2O (4.5 mmol) and a catalytic amount of DMAP were added in
one portion and the resulting solution was stirred at room tem-
perature until completion (monitored by TLC). Solvent was evap-
orated under vacuum and the mixture obtained was dissolved in
anhydrous THF (20 mL). A solution of 2 M methylamine in metha-
nol (4.5 mmol) was then added and the resulting solution was
stirred at room temperature until completion (monitored by TLC)
and evaporated under vacuum. A yellowish oil was obtained and
purified by column chromatography using a mixture EtOAc/petro-
leum ether as eluent.
3.6. Experimental procedure for the preparation of 5g (P1[Z)
To a stirred solution of 3g (0.91 g, 1.6 mmol) in glacial acetic acid
(50 mL), 10% Pd/C (0.09 g) was added. The resulting mixture was
flushed with H2 and vigorously stirred until completion (monitored
by TLC). The reaction mixture was filtered on Celite and evaporated
to dryness. The residue was dissolved in EtOAc, washed with sodium
bicarbonate solution (4%) and dried over MgSO4. After evaporation
of EtOAc, the product was purified by column chromatography.
3.8.1. Z-Alaj[CON(NHBoc)]Ala-OMe 6a
3.6.1. H-Phej
[CON(NPht)]Ala-OtBu 5g
Eluent for column chromatography: EtOAc/petroleum ether (15/
85 then 40/60); yield 87%, oil; IR (NaCl) nmax/cmꢂ1 3324 (NH), 1731,
Eluent for column chromatography: EtOAc/petroleum ether (20/
1681 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.34–7.27 (m, 5H, H
80); yield 55%, white solid, mp¼55 ꢁC; IR (2 mM in CH2Cl2) nmax
/
cmꢂ1 3360 (NH2),1777,1717,1673 (C]O); 1H NMR (CDCl3, 300 MHz)
arom), 7.19 (s, 1H, NNHCOOC(CH3)3), 5.43 (s, 1H, NHCOOCH2Ph),
5.23 (d, 1H, J¼6.0 Hz, CHCH3), 5.14–5.05 (m, 2H, NHCOOCH2Ph),
4.92–4.70 (m, 1H, CHCH3), 3.70 (s, 3H, OCH3), 1.49–1.42 (m, 12H,
CHCH3 and NNHCOOC(CH3)3), 1.36 (d, 3H, J¼6.0 Hz, CHCH3); 13C
d
(ppm) 7.76–7.73 (m, 4H, Hpht), 7.28–7.14 (m, 5H, H arom), 5.92 (dd,
1H, J¼5.6, 5.2 Hz, CHCH2Ph), 5.20 (q,1H, J¼7.3 Hz, CHCH3), 3.78–3.70
(s, 2H, NH2), 3.61–3.55 (dd, 2H, J¼8.7, 5.2 Hz, CHCH2Ph), 1.45–1.43
(m,12H, NHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
d (ppm) 172.2
NMR (CDCl3)
d (ppm) 172.9 (CON(NHBoc)), 165.7 (COOMe), 156.0
(CON(NPht)), 171.4 (COOtBu), 168.7 (C]O Pht), 138.4 (ArC), 134.4
(PhtCH), 132.5 (ArC), 129.6, 129.0, 127.2 (ArCH), 123.8 (PhtCH), 82.9
(NHCOOC(CH3)3), 54.4 (CHCH2Ph), 54.3 (CHCH3), 34.9 (CHCH2Ph),
28.6 (COOC(CH3)3), 14.5 (CHCH3); HRMS (ESI) calculated for
C24H27N3NaO5 [MþNaþ] m/z 460.1843, found 460.1812.
(NHCOOCH2Ph), 137.0 (ArC), 129.2, 128.8, 128.6 (ArCH), 82.8
(NNHCOOC(CH3)3), 67.5 (NHCOOCH2Ph), 55.2 (CHCH3), 53.2
(OCH3), 47.4 (CHCH3), 28.7 (NNHCOOC(CH3)3), 19.2 (CHCH3), 14.5
(CHCH3); HRMS (ESI) calculated for C20H29N3NaO7 [MþNa]þ m/z
446.1898, found 446.1885.
3.8.2. Z-Alaj[CON(NHBoc)](L,D)Ala-OMe 6b
3.7. Typical experimental procedure for the preparation
of 5j and 13
Eluent for column chromatography: EtOAc/petroleum ether (15/
85 then 40/60); yield 68%, oil; IR (NaCl) nmax/cmꢂ1 3313 (NH), 1742,
1678 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.33–7.27 (m, 5H, H
A solution of 3 M dry hydrogen chloride in EtOAc (10 mL) was
added to the carbamate 3j or 12 (1 mmol). The resulting solution
was stirred 1 h and co-evaporated several times with CH2Cl2 until
dryness without residual HCl.
arom), 7.04 (s, 0.5H, NNHCOOC(CH3)3), 6.94 (s, 0.5H,
NNHCOOC(CH3)3), 5.49 (s, 0.5H, NHCOOCH2Ph), 5.38 (s, 0.5H,
NHCOOCH2Ph), 5.34–5.03 (m, 3H, NHCOOCH2Ph and CHCH3), 4.39
(qd, 1H, J¼7.3, 6.8 Hz, CHCH3), 3.71 (s, 1.5H, OCH3), 3.69 (s, 1.5H,
OCH3), 1.47–1.30 (m, 15H, 2CHCH3 and NHCOOC(CH3)3); 13C NMR
3.7.1. HCl, H-Phej[CON(NPht)]Ala-OCH2Ph 5j
Yield 55%, white solid, mp¼62 ꢁC; IR (KBR) nmax/cmꢂ1 2928
(CDCl3)
d (ppm) 177.3, 176.1 (CON(NHBoc)), 173.4, 172.6 (COOMe),
156.2 (NNHCOOtBu), 155.7, 155.1 (NHCOOCH2Ph), 137.1, 136.9 (ArC),
129.0, 128.6 (ArCH), 83.8, 82.9, 82.6 (NNHCOOC(CH3)3), 67.5
(NHCOOCH2Ph), 55.2, 54.3 (CHCH3), 53.2, 53.0 (OCH3), 48.0, 47.3
(CHCH3), 28.6, 28.4 (NNHCOOC(CH3)3), 19.4, 19.0 (CHCH3), 14.4, 14.2
(CHCH3); HRMS (ESI) calculated for C20H29N3NaO7 [MþNa]þ m/z
446.1898, found 446.1885.
(NH), 1798, 1738, 1694 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm)
8.60 (s, 1.5H, NHþ3 ), 8.38 (s, 1.5H, NHþ3 ), 7.80–7.60 (m, 4H, Hpht),
7.25–7.10 (m, 5H, H arom), 5.23–4.90 (m, 4H, CHCH3, CHCH2Ph and
OCH2Ph), 4.12–3.14 (m, 2H, CHCH2Ph), 1.53–1.43 (m, 3H, CHCH3);
13C NMR (CDCl3)
d (ppm) 170.4, 169.5, 169.1, 167.9 (C]O), 165.8,
165.6, 165.4 (C]O Pht), 136.1, 135.4 (PhtCH), 133.4, 133.0 (ArC),
131.3, 130.7, 130.3 (ArCH), 129.9, 129.4, 129.3 (ArC), 129.2, 128.8,
128.1, 128.0 (ArCH), 126.0, 124.8, 124.5 (PhtCH), 68.1, 67.7 (OCH2Ph),
58.6, 57.9 (CHCH2Ph), 52.6, 52.3 (CHCH3), 36.0 (CHCH2Ph), 16.2, 15.4
(CHCH3); HRMS (ESI) calculated for C27H26N3O5 [MþH]þ m/z
472.1867, found 472.1847.
3.8.3. Z-Alaj[CON(NHBoc)]Ala-OEt 6c
Eluent for column chromatography: EtOAc/petroleum ether (15/
85 then 30/70); yield 73%, oil; IR (NaCl) nmax/cmꢂ1 3313 (NH), 1742,
1678 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.33–7.20 (m, 6H, H
arom and NNHCOOC(CH3)3), 5.48–5.31 (m, 1H, CHCH3), 5.20 (d, 1H,
J¼6.4 Hz, NHCOOCH2Ph), 5.14 (d, 1H, J¼12.2 Hz, NHCOOCH2Ph),
5.03 (d, 1H, J¼12.2 Hz, NHCOOCH2Ph), 4.90–4.68 (m, 1H, CHCH3),
4.16 (q, 2H, J¼7.1 Hz, OCH2CH3), 1.49 (s, 9H, NNHCOOC(CH3)3), 1.36
(d, 3H, J¼6.8 Hz, CHCH3), 1.32–1.29 (m, 3H, CHCH3), 1.25 (t, 3H,
3.7.2. H-[Phej[CON(NPht)]Ala]2-OCH2Ph 13
Yield 100%, white solid, mp¼94 ꢁC; IR (1 mM in CH2Cl2) nmax
/
cmꢂ1 3429, 3400, 3353(NH) 1798, 1745, 1708, 1677(C]O); 1H NMR
(CDCl3, 300 MHz)
d (ppm) 8.00–7.50 (m, 8H, Hpht), 7.30–7.10 (m,
J¼7.1 Hz, OCH2CH3); 13C NMR (CDCl3)
d (ppm) 177.4 (CON(NHBoc)),
15H, H arom), 6.80 (d, 0.7H, J¼9.8 Hz, NHCH(CH3)), 6.65 (d, 0.3H,
J¼9.8 Hz, NHCH(CH3)), 5.60–4.60 (6H, CHCH3, CHCH2Ph and
COOCH2Ph), 3.65–3.05 (m, 6H, CHCH2Ph and NH2), 1.34–1.05 (m,
6H, 2CHCH3); HRMS (ESI) calculated for C47H42N6NaO9 [MþNa]þ
m/z 857.3430, found 857.2918.
172.6 (COOEt), 156.2 (NNHCOOtBu), 155.6 (NHCOOCH2Ph), 137.0
(ArC), 129.1, 128.6 (ArCH), 82.6 (NHCOOC(CH3)3), 67.4
(NHCOOCH2Ph), 66.2 (OCH2CH3), 55.3 (CHCH3), 47.4 (CHCH3), 28.7
(NNHCOOC(CH3)3), 19.2 (CHCH3), 14.7 (OCH2CH3), 14.5 (CHCH3);

10750
A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
HRMS (ESI) calculated for C21H31N3NaO7 [MþNa]þ m/z 460.2054,
3.9. Preparation of 6y
found 460.2042.
To a stirred solution of 2,20-dipyridyl (0.5 mmol) in methanol
(12 mL) were added successively a catalytic amount of 10% Pd/C,
3.8.4. Z-Alaj
[CON(NHBoc)]Ala-OtBu 6d
Eluent for column chromatography: EtOAc/petroleum ether (15/
a solution of Z-Phej[CON(NHBoc)]Ala-OMe 6f (0.50 g, 1 mmol) in
85 then 30/70); yield 87%, white solid, mp¼146 ꢁC; IR (KBr) nmax
/
methanol (12 mL) and Fmoc-OSu (1 mmol). The resulting mixture
was flushed with H2 and vigorously stirred until completion
(monitored by TLC). The reaction mixture was filtered on Celite and
evaporated to dryness. The resulting oily solid was dissolved in
EtOAc (125 mL) and washed with 10% aqueous HCl (3ꢀ125 mL),
water (3ꢀ125 mL) and dried over MgSO4. Solvent was evaporated
under vacuum and the crude product was purified by column
chromatography.
cmꢂ1 3282 (NH), 1795, 1751, 1695, 1677 (C]O); 1H NMR (CDCl3,
300 MHz)
d (ppm) 7.34 (s, 5H, H arom), 6.90 (s, 0.5H,
NNHCOOC(CH3)3), 6.55 (s, 0.5H, NNHCOOC(CH3)3), 5.71 (d, 0.5H,
J¼6.0 Hz, NHCOOCH2Ph), 5.56 (d, 0.5H, J¼6.0 Hz, NHCOOCH2Ph),
5.29–5.03 (m, 3H, NHCOOCH2Ph and CHCH3), 4.74–4.64 (m, 1H,
CHCH3), 1.66–1.37 (m, 24H, NNHCOOC(CH3)3, COOC(CH3)3, and
2CHCH3); 13C NMR (CDCl3)
d (ppm) 176.1 (CON(NHBoc)), 172.3
(COOtBu), 155.8 (NNHCOOtBu), 155.2 (NHCOOCH2Ph), 137.2 (ArC),
129.1, 128.6 (ArCH), 83.8, 83.0 (NNHCOOC(CH3)3 and COOC(CH3)3),
67.2 (NHCOOCH2Ph), 55.0 (CHCH3), 48.1 (CHCH3), 28.7, 28.6
(NNHCOOC(CH3)3 and COOC(CH3)3), 19.7 (CHCH3), 14.4 (CHCH3);
HRMS (ESI) calculated for C23H35N3NaO7 [MþNa]þ m/z 488.2373,
found 488.2337.
3.9.1. Fmoc-Phej[CON(NHBoc)]Ala-OMe 6y
Eluent for column chromatography: EtOAc/petroleum ether (15/
85); yield 89%, oil; IR (ATR) nmax/cmꢂ1 3310 (NH),1736, 1676 (C]O);
1H NMR (CDCl3, 300 MHz)
d (ppm) 7.82–7.70 (m, 2H, H arom), 7.44–
7.24 (m, 12H, H arom and NHBoc), 5.86–5.59 (m, 1H, NHFmoc),
5.28–5.02 (m, 3H, CHFmoc and CH2Fmoc), 4.37–4.35 (m, 1H CHCH3),
4.19–4.11 (m, 1H, CHCH2Ph), 3.66 (s, 3H, OCH3), 3.28–3.24 (m, 1H,
CHCH2Ph), 2.99–2.95 (m, 1H, CHCH2Ph), 1.55–1.50 (m, 12H,
3.8.5. Z-Alaj[CON(NHBoc)]Gly-OMe 6e
Eluent for column chromatography: EtOAc/petroleum ether (15/
85 then 40/60); yield 86%, oil; IR (NaCl) nmax/cmꢂ1 3324 (NH), 1731,
NNHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
d (ppm) 176.1
1681 (C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 7.35–6.80 (m, 6H,
(CON(NHBoc)), 172.7 (COOMe), 156.3 (NNHCOOtBu), 155.8 (COFmoc),
144.7, 144.3, 137.1, 136.9 (ArC), 130.3, 128.8, 128.4, 128.1, 127.5, 127.3,
125.7, 125.6, 120.3 (ArCH), 82.5 (NNHCOOC(CH3)3), 67.5, 67.1
(FmocCH2), 55.3 (FmocCH), 52.9 (CHCH2Ph), 52.5 (OCH3), 47.5
(CHCH3), 38.2 (CHCH2Ph), 28.6 (NNHCOOC(CH3)3), 14.7, 14.4
(CHCH3); HRMS (ESI) calculated for C33H37N3NaO7 [MþNa]þ m/z
610.2524, found 610.2518.
H arom and NNHCOOC(CH3)3), 5.55 (d,1H, J¼7.1 Hz, NHCOOCH2Ph),
5.14 (d, 1H, J¼12.0 Hz, NHCOOCH2Ph), 5.05 (d, 1H, J¼12.0 Hz,
NHCOOCH2Ph), 5.00–4.50 (m, 1H, CHCH3), 4.91–4.51 (m, 2H,
CH2COOMe), 3.75 (s, 3H, OCH3), 1.48 (s, 9H, NNHCOOC(CH3)3), 1.33
(d, 3H, J¼6.8 Hz, CHCH3); 13C NMR (CDCl3)
d
(ppm) 176.2 (CON(-
NHBoc)),
170.1
(COOMe),
156.1
(NNHCOOtBu),
154.4
(NHCOOCH2Ph), 137.1 (ArC), 129.2, 128.7 (ArCH), 83.5
(NNHCOOC(CH3)3), 67.5 (NHCOOCH2Ph), 53.1 (OCH3), 48.9
(CH2COOMe), 47.3 (CHCH3), 28.7 (NNHCOOC(CH3)3), 19.4 (CHCH3);
HRMS (ESI) calculated for C19H27N3NaO7 [MþNa]þ m/z 432.1741,
found 432.1724.
3.10. Typical experimental procedure for the preparation of 7
Compound 6 (1 mmol) was dissolved in THF (10 mL). A solution
of 2.5 M LiOH (10 mL, 25 mmol) was added in one portion and the
resulting solution was stirred for 1 h. The reaction was quenched by
addition of ice and extracted with chloroform (3ꢀ20 mL). The
aqueous layer was acidified until pH¼2 by 1 M HCl and extracted
with EtOAc (8ꢀ20 mL). The organic layers were combined, dried
over MgSO4 and evaporated to dryness to give the pure product.
3.8.6. Z-Phej[CON(NHBoc)]Ala-OMe 6f
Eluent for column chromatography: EtOAc/petroleum ether (20/
80); yield 95%, oil; IR (ATR) nmax/cmꢂ1 3331, 3251 (NH), 1720, 1702,
1681 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.32–7.19 (m, 11H,
H
arom and NNHCOOC(CH3)3), 5.70 (d, 1H, J¼6.9 Hz,
NHCOOCH2Ph), 5.21–4.94 (m, 4H, NHCOOCH2Ph, CHCH2Ph and
CHCH3), 3.66 (s, 3H, OCH3), 3.19–3.12 (m, 1H, CHCH2Ph), 2.86–2.77
(m,1H, CHCH2Ph),1.55–1.40 (m,12H, NNHCOOC(CH3)3 and CHCH3);
3.10.1. Z-Ala
j
[CON(NHBoc)]Ala-OH 7a
Yield 98%, gum; IR (NaCl) nmax/cmꢂ1 3291 (OH), 1727, 1684
(C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 10.00 (s, 1H, COOH), 7.83
13C NMR (CDCl3)
d
(ppm) 176.1 (CON(NHBoc)),172.7 (COOMe),157.9
(s, 1H, NNHCOOtBu), 7.32–7.27 (m, 5H, H arom), 5.9 (d, 1H, J¼6.0 Hz,
NHCOOCH2Ph), 5.2–4.7 (m, 4H, COOCH2Ph and 2CHCH3), 1.48 (s,
9H, NNHCOOC(CH3)3), 1.41 (d, 3H, J¼6.8 Hz, CHCH3), 1.33 (d, 3H,
(NNHCOOtBu), 156.4 (NHCOOCH2Ph), 137.0, 136.8 (ArC), 130.2,
129.9, 128.8, 128.2, 127.2, 126.6 (ArCH), 82.4 (NNHCOOC(CH3)3), 67.1
(NHCOOCH2Ph), 55.3 (CHCH2Ph), 52.8 (OCH3), 52.5 (CHCH3), 28.5
(NNHCOOC(CH3)3), 14.3 (CHCH3); HRMS (ESI) calculated for
C26H33N3NaO7 [MþNa]þ m/z 522.2211, found 522.2185.
J¼6.8 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 177.5 (COOH), 176.5
(CON(NHBoc)), 156.8 (NHCOOCH2Ph), 156.1 (NNHCOOtBu), 136.6
(ArC), 129.1, 128.6, 128.6 (ArCH), 82.7 (NNHCOOC(CH3)3), 67.6
(NHCOOCH2Ph), 56.4, 47.5 (CHCH3), 28.6 (NNHCOOC(CH3)3), 18.6,
14.1 (CHCH3); HRMS (ESI) calculated for C19H27N3NaO7 [MþNa]þ
m/z 432.1741, found 432.1760.
3.8.7. Boc-Phej[CON(NHBoc)]Ala-OMe 6i
Eluent for column chromatography: EtOAc/petroleum ether (30/
70); yield 93%, oil; IR (ATR) nmax/cmꢂ1 3320 (NH) 1733, 1720, 1681
(C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 7.39–7.18 (m, 6H, H
3.10.2. Z-Ala
j
[CON(NHBoc)]Gly-OH 7e
arom and NNHCOOC(CH3)3), 5.29–4.90 (m, 3H, NHCOOCH2Ph,
CHCH2Ph and CHCH3), 3.71 (s, 3H, OCH3), 3.18–3.15 (m, 1H,
CHCH2Ph), 2.83–2.72 (m, 1H, CHCH2Ph), 1.56–1.21 (m, 21H,
NHCOOC(CH3)3, NNHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
Yield 99%, gum; IR (KBr) nmax/cmꢂ1 3304 (OH), 1730, 1680
(C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 7.86 (s, 1H, COOH), 7.35–
7.20 (m, 5H, H arom), 7.03 (s, 1H, NNHCOOtBu), 5.55 (s, 1H,
NHCOOCH2Ph), 5.13–4.90 (m, 4H, COOCH2Ph, CHCH3 and
CH2COOH), 3.80 (s, 1H, CH2COOH), 1.48 (s, 9H, NNHCOOC(CH3)3),
d
(ppm) 176.5 (CON(NHBoc)), 171.8 (COOMe), 171.7 (CON-
(NHCOOtBu)), 155.8 (NHCOOtBu), 137.3 (ArC), 130.2, 128.9, 127.3
(ArCH), 82.7 (NNHCOOC(CH3)3), 80.3 (NHCOOC(CH3)3), 55.4
(CHCH2Ph), 54.1 (CHCH2Ph), 53.1 (OCH3), 52.0 (CHCH3), 29.0, 28.9,
28.7 (NNHCOOC(CH3)3 and NHCOOC(CH3)3), 14.6 (CHCH3); HRMS
(ESI) calculated for C23H35N3NaO7 [MþNa]þ m/z 488.2367, found
488.2337.
1.32 (d, 3H, J¼5.8 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 176.4
(COOH), 172.3 (CON(NHBoc)), 156.8 (NHCOOCH2Ph), 155.1
(NNHCOOtBu), 136.7 (ArC), 129.1, 128.8, 128.7 (ArCH), 83.7
(NNHCOOC(CH3)3), 67.8 (NHCOOCH2Ph), 49.8 (CH2COOH), 47.4
(CHCH3), 28.7 (NNHCOOC(CH3)3), 18.8 (CHCH3); HRMS (ESI) cal-
culated for C18H25N3NaO7 [MþNa]þ m/z 418.1585, found 418.1567.

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10751
3.10.3. Boc-Phe
j
[CON(NHBoc)]Ala-OH 7i
3.11.3. Z-Phej[CON(NH2)]Ala-OMe 8f
Yield 75%, white solid, mp¼172 ꢁC; IR (ATR) nmax/cmꢂ1 3343,
Eluent for column chromatography: EtOAc/petroleum ether (30/
3238 (NH), 1748, 1733 (C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm)
70 then 50/50); yield 70%, oil; IR (ATR) nmax/cmꢂ1 3356, 3256 (NH),
7.39–7.18 (m, 6H, H arom and NNHCOOC(CH3)3), 5.29–4.90 (m, 3H,
NHCOOC(CH3)3, CHCH3 and CHCH2Ph), 3.18–3.15 (m, 1H, CHCH2Ph),
2.83–2.72 (m, 1H, CHCH2Ph), 1.56–1.21 (m, 21H, NHCOOC(CH3)3,
1718, 1658 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.38–7.19 (m,
10H, H arom), 5.96–5.55 (m, 2H, NHCOOCH2Ph and CHCH2Ph), 5.25
(q,1H, J¼6.6 Hz, CHCH3), 5.10 (d,1H, J¼12.4 Hz, NHCOOCH2Ph), 5.04
(d, 1H, J¼12.4 Hz, NHCOOCH2Ph), 3.66 (s, 3H, OCH3), 3.55 (s, 2H,
NNH2), 3.08 (dd, 1H, J¼5.7, 7.6 Hz, CHCH2Ph), 2.95 (dd, 1H, J¼5.7,
7.6 Hz, CHCH2Ph), 1.23 (d, 3H, J¼6.6 Hz, CHCH3); 13C NMR (CDCl3)
NNHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
d (ppm) 176.5
(COOH), 171.8 (CON(NHBoc)), 155.8 (NHCOOtBu and NNHCOOtBu),
137.3 (ArC), 130.2, 128.9, 127.3 (ArCH), 82.7 (NNHCOOC(CH3)3), 80.3
(NHCOOC(CH3)3), 55.4 (CHCH2Ph), 54.1 (CHCH3), 52.0 (CHCH2Ph),
29.0, 28.9 (NHCOOC(CH3)3 and NNHCOOC(CH3)3), 14.6 (CHCH3);
HRMS (ESI) calculated for C22H33N3NaO7 [MþNa]þ m/z 474.2211,
found 474.2214.
d
(ppm) 174.5 (CON(NH2)), 172.4 (COOMe), 156.1 (NHCOOCH2Ph),
137.2, 137.1 (ArC), 130.1, 129.3, 128.9, 128.7, 128.5, 128.4, 127.3
(ArCH), 67.1 (NHCOOCH2Ph), 53.2 (CHCH3), 52.9 (OCH3), 52.2
(CHCH2Ph), 40.6 (CHCH2Ph), 14.1 (CHCH3); HRMS (ESI) calculated
for C21H25N3NaO5 [MþNa]þ m/z 422.1686, found 422.1683.
3.10.4. Fmoc-Phej[CON(NHBoc)]Ala-OH 7y
Yield 83%, white solid, mp¼65 ꢁC; IR (ATR) nmax/cmꢂ1 3310 (NH),
3.12. Preparation of 9f
1736, 1676 (C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.44–7.24 (m,
14H, H arom and NHBoc), 5.61–5.59 (m, 1H, NHCOOFm), 5.27–4.80
(m, 3H, CHFmoc and CH2Fmoc), 4.27–4.08 (m, 2H, CHCH2Ph and
CHCH3), 3.22–3.18 (m, 1H, CHCH2Ph), 2.89–2.86 (m, 1H, CHCH2Ph),
1.49–1.44 (m, 12H, NNHCOOC(CH3)3 and CHCH3); 13C NMR (CDCl3)
Compound 8f (0.40 g, 1 mmol) was dissolved in THF (10 mL). A
solution of 2.5 M LiOH (10 mL, 25 mmol) was added in one portion
and the resulting solution was stirred for 1 h. The reaction was
quenched by addition of ice and extracted with chloroform
(3ꢀ20 mL). The aqueous layer was acidified until pH¼2 by 1 M HCl
and extracted with EtOAc (8ꢀ20 mL). The organic layers were
combined, dried over MgSO4 and evaporated to dryness to give the
pure product.
d
(ppm) 175.7 (COOH), 174.3 (CON(NHBoc)), 157.0 (NNHCOOtBu),
156.3 (COFmoc), 144.4, 141.9, 136.8 (ArC), 130.3, 129.2, 128.3, 127.7,
125.7, 120.6 (ArCH), 83.3 (NNHCOOC(CH3)3), 68.0 (FmocCH2), 57.1
(FmocCH), 52.6 (CHCH2Ph), 47.6 (CHCH3), 38.3 (CHCH2Ph), 28.2
(NNHCOOC(CH3)3), 14.8, 14.4 (CHCH3); HRMS (ESI) calculated for
C32H35N3NaO7 [MþNa]þ m/z 596.2367, found 596.2359.
3.12.1. Z-Phe
Yield 85%, oil; IR (ATR) nmax/cmꢂ1 3650 (OH), 3425 (NH), 1721,
1661, 1606 (C]O); 1H NMR (CDCl3, 300 MHz)
(ppm) 7.32–7.21 (m,
j[CON(NH2)]Ala-OH 9f
d
3.11. Typical experimental procedure for the preparation of 8
10H, H arom), 6.03 (d, 1H, J¼8.7 Hz, NHCOOCH2Ph), 5.69–5.66 (m,
1H, CHCH3), 5.28–5.24 (m, 1H, CHCH2Ph), 5.09 (d, 1H, J¼12.5 Hz,
NHCOOCH2Ph), 5.01 (d, 1H, J¼12.5 Hz, NHCOOCH2Ph), 3.05–2.97
(m, 2H, CHCH2Ph), 2.07 (s, 2H, NNH2), 1.24 (d, 3H, J¼9.0 Hz, CHCH3);
Compound 6 (1 mmol) was dissolved in a solution of HCl (3 M)
in EtOAc (10 mL). The resulting solution was stirred until comple-
tion (monitored by TLC), cooled with an ice-water bath, adjusted to
pH¼7 by addition of NaHCO3 (saturated solution) and extracted
with EtOAc (3ꢀ10 mL). The organic extracts were combined,
washed with a saturated solution of NaCl (3ꢀ10 mL) and dried over
MgSO4. Solvent was evaporated under vacuum to give the crude
product. Purification by column chromatography was performed
using EtOAc/petroleum ether as eluent if necessary.
13C NMR (CDCl3)
d (ppm) 177.1 (COOH), 175.2 (CON(NH2)), 156.6
(NHCOOCH2Ph), 137.0, 136.9 (ArC), 130.1, 129.9, 129.0, 128.9, 128.6,
128.4, 127.4 (ArCH), 67.4 (NHCOOCH2Ph), 53.5 (CHCH3), 52.3
(CHCH2Ph), 40.2 (CHCH2Ph), 13.9 (CHCH3); HRMS (ESI) calculated
for C20H23N3NaO7 [MþNa]þ m/z 408.1530, found 408.1554.
3.13. Typical experimental procedure for the oligomerization
reaction in solution
3.11.1. Z-Alaj[CON(NH2)]Ala-OMe 8a
Eluent for column chromatography: EtOAc/petroleum ether (60/
To a stirred solution of the 1:1[a:a-N-amino]mer acid form 4j or
40); yield 86%, oil; IR (KBr) nmax/cmꢂ1 3342, 3246 (NH), 1654
14 (2 mmol) and pyridine (2 mmol) in dry CH2Cl2 (10 mL) kept
under nitrogen atmosphere was added cyanuric fluoride (0.4 mL,
5 mmol) at ꢂ20 ꢁC. After stirring at room temperature for 3 h,
crushed ice and 10 mL of CH2Cl2 were added. The organic layer was
separated and the aqueous layer extracted once with 5 mL of
CH2Cl2. The combined organic layers were extracted with 10 mL of
ice-cold water and dried (MgSO4) and then the solvent was re-
moved under vacuum at room temperature to give the pure acid
fluoride. A solution of acid fluoride in 2.5 mL of CH2Cl2 was added
(C]O); 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.34–7.27 (m, 5H, H
arom), 5.73 (d, 1H, J¼7.4 Hz, NHCOOCH2Ph), 5.33–5.24 (m, 1H,
CHCH3), 5.19–5.09 (m, 3H, NHCOOCH2Ph and CHCH3), 4.08 (s, 2H,
NNH2), 3.72 (s, 3H, OCH3), 1.44 (d, 3H, J¼7.4 Hz, CHCH3), 1.35 (d, 3H,
J¼6.8 Hz, CHCH3); 13C NMR (CDCl3)
d (ppm) 176.3 (CON(NH2)),
172.5 (COOCH3), 156.1 (NHCOOCH2Ph), 137.2 (ArC), 129.1, 128.8,
128.6 (ArCH), 67.5, 67.2 (NHCOOCH2Ph), 53.3 (CHCH3), 53.9 (OCH3),
48.1 (CHCH3), 19.9 (CHCH3), 14.4 (CHCH3); HRMS (ESI) calculated
for C15H21N3NaO5 [MþNa]þ m/z 346.1373, found 346.1367.
dropwise to
a
cold stirred solution (ꢂ10 ꢁC) of amine 13
(1.77 mmol) and NaHCO3 (3.76 mmol) in 6.3 mL of dry CH2Cl2. The
mixture was allowed to warm to room temperature and stirred for
10 h. NaF salt was filtered and the solvent was evaporated. The
residue was chromatographied on silica gel.
3.11.2. Z-Alaj[CON(NH2)]Gly-OMe 8e
Eluent for column chromatography: EtOAc/petroleum ether (60/
40); yield 72%, oil; IR (ATR) nmax/cmꢂ1 3339 (NH), 1721, 1659 (C]O);
1H NMR (CDCl3, 300 MHz)
d
(ppm) 7.34–7.26 (m, 5H, H arom), 5.70
To obtain oligomer 12, amine 5j was added to a mixture of acid
fluoride of 4j and NaHCO3 in CH2Cl2 in order to minimize the for-
mation of diketopiperazine 11.
(d, 1H, J¼7.6 Hz, NHCOOCH2Ph), 5.29–5.24 (m, 1H, CHCH3), 5.11 (d,
2H, J¼10.1 Hz, NHCOOCH2Ph), 5.09 (d, 1H, J¼12.8 Hz, CH2COOMe),
4.60 (d, 1H, J¼12.8 Hz, CH2COOMe), 3.76 (s, 3H, OCH3), 2.07 (s, 2H,
NNH2), 1.38 (d, 3H, J¼6.8 Hz, CHCH3); 13C NMR (CDCl3)
d
(ppm)
3.13.1. Boc-[Phej[CON(NPht)]Ala]2OCH2Ph 12
176.7 (CON(NH2)), 170.0 (COOMe), 156.4 (NHCOOCH2Ph), 137.2
(ArC), 129.1, 128.7 (ArCH), 67.3 (NHCOOCH2Ph), 53.1 (CHCH3), 51.6
(CH2COOMe), 47.7 (OCH3), 19.4 (CHCH3); HRMS (ESI) calculated for
C14H19N3NaO5 [MþNa]þ m/z 332.1217, found 332.1182.
Eluent for column chromatography: EtOAc/petroleum ether (20/
80 then 30/70); Yield 55%, white solid, mp¼95 ꢁC; IR (1 mM in
CH2Cl2) nmax/cmꢂ1 3430, 3396, 3310 (NH), 1790, 1745, 1701, 1682
(C]O); 1H NMR (CDCl3, 300 MHz)
d
(ppm) 8.15 (d, 0.3H, J¼8.8 Hz,

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A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
NHCH(CH3)), 8.10 (d, 0.7H, J¼8.6 Hz, NHCH(CH3)), 7.95–7.60 (m, 8H,
Hpht), 7.50–6.90 (m, 15H, H arom), 5.85 (q, 0.3H, J¼6.8 Hz, CHCH3),
5.40–4.90 (m, 4H, CHCH3, CHCH2Ph and COOCH2Ph), 4.65 (q, 0.7H,
J¼7.3 Hz, CHCH3), 4.50 (q, 0.3H, J¼7.3 Hz, CHCH3), 4.30–4.20 (m,
1.7H, NHCOOtBu and CHCH2Ph), 4.00 (d, 3H, J¼10.6 Hz, NH), 3.30–
2.50 (m, 4H, CHCH2Ph), 1.54 (d, 2H, J¼6.9 Hz, CHCH3), 1.45 (d, 1H,
J¼6.8 Hz, CHCH3), 1.26–1.08 (m, 12H, CHCH3 and COOC(CH3)3);
HRMS (ESI) calculated for C52H50N6NaO11 [MþNa]þ m/z 957.3430,
found 957.3422.
3.14.1. H-[Phe
j[CON(NH2)]Ala]2Leu-OH 17
Yield 20%, gum; 1H NMR (DMSO-d6, 300 MHz)
d
(ppm) 8.34–
8.30 (m, 2H, 2NH), 8.30 (s, 2H, NNH2), 7.34–7.19 (m, 10H, H arom),
5.61–5.58 (m, 1H, CHCH2Ph), 5.06–5.00 (m, 2H, 2CHCH3), 4.20–4.16
(m, 1H, CHCH2CH(CH3)2), 4.47 (s, 5H, CHCH2Ph and NNH2), 3.33–
3.09 (m, 4H, 2CHCH2Ph),1.70–1.45 (m, 3H, CHCH2CH(CH3)2),1.33 (d,
3H, J¼7.2 Hz, CHCH3), 1.08 (d, 3H, J¼7.2 Hz, CHCH3), 0.89 (d, 3H,
J¼6.2 Hz, CHCH2CH(CH3)2), 0.83 (d, 3H, J¼6.2 Hz, CHCH2CH(CH3)2);
HRMS (ESI) calculated for C30H43N7NaO6 [MþNa]þ m/z 620.3169,
found 620.3169.
3.13.2. Boc-[Phej[CON(NPht)]Ala]3OCH2Ph 15
Eluent for column chromatography: EtOAc/petroleum ether (40/
60 then 50/50); yield 55%, white solid, mp¼116 ꢁC; IR (0.7 mM in
CH2Cl2) nmax/cmꢂ1 3396, 3313 (NH), 1797, 1743, 1702, 1677 (C]O);
3.14.2. H-[Phe
j[CON(NH2)]Ala]3Leu-OH 18
Yield 8%, gum; 1H NMR (DMSO-d6, 300 MHz)
d
(ppm) 8.25–7.98
(m, 5H, 5NH), 7.32–7.18 (m, 15H, H arom), 5.70–5.58 (m, 2H,
2CHCH2Ph), 5.02–4.99 (m, 3H, 3CHCH3), 4.74–4.64 (s, 7H, CHCH2Ph
and 3NNH2), 4.30–4.05 (m, 1H, CHCH2CH(CH3)2), 3.31–2.66 (m, 6H,
3CHCH2Ph), 1.70–1.45 (m, 3H, CHCH2CH(CH3)2), 1.29–1.06 (m, 9H,
3CHCH3), 0.89 (d, 3H, J¼6.2 Hz, CHCH2CH(CH3)2), 0.83 (d, 3H,
J¼6.2 Hz, CHCH2CH(CH3)2); HRMS (ESI) calculated for
C42H58N10NaO8 [MþNa]þ m/z 853.4336, found 853.4337.
1H NMR (CDCl3, 300 MHz)
d (ppm) 8.40–8.20 (m, 2H, 2NHCH(CH3)),
8.00–7.70 (m, 12H, Hpht), 7.50–6.90 (m, 20H, H arom), 5.50–4.00
(m, 9H, COOCH2Ph, 3CHCH3, 3CHCH2Ph and NH), 3.30–2.50 (m, 6H,
3CHCH2Ph), 1.40–1.00 (m, 18H, COOC(CH3)3 and 3CHCH3); HRMS
(ESI) calculated for C72H67N9Na2O15 [Mþ2Na]2þ m/z 671.7271,
found 671.7258.
3.13.3. Boc-[Phe
j
[CON(NPht)]Ala]4OCH2Ph 16
3.14.3. H-[Phe
j[CON(NH2)]Ala]4Leu-OH 19
Eluent for column chromatography: EtOAc/petroleum ether (50/
50 then 70/30); yield 35%, white solid, mp¼118 ꢁC; IR (0.5 mM in
CH2Cl2) nmax/cmꢂ1 3396, 3313 (NH), 1795, 1741, 1704, 1677 (C]O);
Yield 10%, gum; NMR 1H (DMSO-d6, 300 MHz)
d (ppm) 8.26–
7.98 (m, 6H, 6NH), 7.32–7.18 (m, 20H, H arom), 5.69–5.29 (m, 2H,
2CHCH2Ph), 5.02–4.99 (m, 4H, 4CHCH3), 4.74–4.64 (s, 10H,
2CHCH2Ph and 4NNH2), 4.36–4.04 (m, 1H, CHCH2CH(CH3)2), 3.30–
2.61 (m, 8H, 4CHCH2Ph), 1.70–1.40 (m, 3H, CHCH2CH(CH3)2), 1.28–
1.06 (m, 12H, 4CHCH3), 0.89 (d, 3H, J¼6.2 Hz, CHCH2CH(CH3)2), 0.84
(d, 3H, J¼6.2 Hz, CHCH2CH(CH3)2); HRMS (ESI) calculated for
C54H73N13NaO10 [MþNa]þ m/z 1086.5495, found 1086.5487.
1H NMR (CDCl3, 300 MHz)
d (ppm) 8.30–8.00 (m, 3H, 3NHCH(CH3)),
7.90–7.50 (m, 16H, Hpht), 7.40–6.70 (m, 25H, H arom), 5.40–4.20
(m, 10H, COOCH2Ph, 4CHCH3 and 4CHCH2Ph), 3.90 (m, 1H,
NHCOOC(CH3)3), 3.20–2.30 (m, 8H, 4CHCH2Ph), 1.40–0.90 (m, 21H,
COOC(CH3)3 and 4CHCH3); HRMS (ESI) calculated for
C92H84N12Na2O19 [Mþ2Na]2þ m/z 853.2880, found 852.2853.
Acknowledgements
3.14. Typical experimental procedure for the oligomerization
reaction on solid phase
The authors thank the National Research Agency (ANR) for fi-
nancial support (No. NT05_4_42848).
Step 1: Fmoc-Leu-WANG (cross linked with 1% DVB, 200–400
mesh, 0.85 mequiv/g) was placed in a dry flask and suffi-
cient DMF was added to cover the resin, which was
allowed to swell at room temperature for 30 min and
filtered.
References and notes
1. Huck, B. R.; Fisk, J. D.; Gellman, S. H. Org. Lett. 2000, 2, 2607–2610.
2. For reviews, see: Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodivers. 2004,
1, 1111–1239; Guichard, G. In Pseudo-peptides in Drug Discovery; Nielsen, P. E.,
Ed.; Wiley-VCH: Weinheim, 2004; pp 33–120; Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232; Licini, G.; Prins, L. J.; Scrimin, P.
Eur. J. Org. Chem. 2005, 969–977; Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. Rev. 2001, 101, 3893–4011.
3. (a) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew. Chem., Int. Ed.
2004, 43, 511–514; (b) Hayen, A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.;
Gellman, S. H. Angew. Chem., Int. Ed. 2004, 43, 505–510; (c) Schmitt, M. A.;
Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848–6849; (d)
Schmitt, M. A.; Choi, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127,
13130–13131; (e) Sharma, G. V. M.; Nagendar, P.; Jayaprakash, P.; Krishna, P. R.;
Ramakrishna, K. V. S.; Kunwar, A. C. Angew. Chem., Int. Ed. 2005, 44, 5878–5882;
(f) For computational work on heterogeneous peptide backbones, see: Baldauf,
C.; Gunther, R.; Hofmann, H.-J. J. Org. Chem. 2006, 71, 1200–1208; (g) For
Step 2: Fmoc group was removed by three treatments with a so-
lution of piperidine (25% in DMF) for 2, 5 and 8 min. The
resin was filtered and washed successively with CH2Cl2
(3ꢀ1 min), MeOH (3ꢀ1 min) and then with DMF
(3ꢀ1 min).
Step 3: a solution of dipeptide 7y, TBTU and HOBt (3 equiv relative
to the resin loading) was added to the resin. DIEA (9 equiv)
was added and the resulting mixture was stirred for 2 h.
The reaction was performed a second time for 4 h. The resin
was then filtered and washed with CH2Cl2 (3ꢀ1 min),
MeOH (3ꢀ1 min) and DMF (3ꢀ1 min).
a
-peptides containing a few b-residues, see: Ananda, K.; Vasudev, P. G.; Sen-
Steps 2 and 3 were repeated until the desired number of dipeptides
had been attached.
gupta, A.; Poopathi Raja, K. M.; Shamala, P. J. Am. Chem. Soc. 2005, 127, 16668–
16674 and references therein.
4. Lecoq, A.; Marraud, M.; Aubry, A. Tetrahedron Lett. 1991, 2765–2768.
5. (a) Brosse, N.; Grandeury, A.; Jamart-Gre´goire, B. Tetrahedron Lett. 2002, 43,
2009–2011; (b) Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Gregoire, B.
Tetrahedron Lett. 2004, 45, 3569–3572; (c) Bouillon, I.; Brosse, N.; Vanderesse,
Step 4: the dried peptide–resin was placed in a round-bottom flask
that contained a magnetic stir bar and cooled in an ice-
water bath. The cleavage mixture was cooled (0.5 mL H2O/
9.5 mL TFA) and added to the cooled peptide–resin. After all
the cleavage mixture had been added, the flask was re-
moved from the ice bath and allowed to warm to room
temperature. The reaction mixture was stirred at room
temperature for 1.5 h. Cold Et2O (50 mL or more) was added
into the flask after the reaction time had elapsed to pre-
cipitate the peptide. If the peptide did not precipitate, the
resin was washed several times with TFA and the solution
obtained was concentrated under vacuum and lyophylised.
´
´
R.; Jamart-Gregoire, B. Tetrahedron 2007, 63, 2223–2234; (d) Bouillon, I.; Van-
deresse, R.; Brosse, N.; Fabre, O.; Jamart-Gre´goire, B. Tetrahedron 2007, 63,
9635–9641; (e) Felten, A.-S.; Vanderesse, R.; Brosse, N.; Didierjean, C.; Jamart-
Gre´goire, B. Tetrahedron Lett. 2008, 49, 156–158.
6. Crystal data for 3g: C32H33O7N3, Mw¼571.61, colourless prism, monoclinic, P21
(#4), a¼12.7193(19) Å, b¼9.3861(12) Å, c¼12.7193(19) Å,
b
¼99.097(5)ꢁ,
V¼1499.4(4) Å3, Z¼2, Dcalcd¼1.266 g/cm3,
m
(Cu
K
a
)¼0.09 cmꢂ1
, 12 814 re-
flections measured, 3113 unique, R1[I>2
s
(I)]¼0.036, wR2 (all data)¼0.083 for
379 parameters, GooF¼0.835, residual density (max/min)¼0.199/ꢂ0.126 e Aꢂ3
.
Details of the crystal structure (excluding structure factors) have been de-
posited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 695147. Copies of the data can be obtained, free of

A.-S. Felten et al. / Tetrahedron 64 (2008) 10741–10753
10753
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
7. Green, T. W.; Walsh, P. G. M. Protecting Groups in Organic Synthesis, 2nd ed.; John
Wiley & Sons: New York, NY, 1991; pp 309–359.
10. (a) Osby, J. O.; Michael, M. G.; Ganem, B. Tetrahedron Lett. 1894, 25, 2093–2096;
(b) Merricks, D.; Sammes, P. G.; Walker, E. R.; Henrick, K.; McPartlin, M. M.
J. Chem. Soc., Perkin Trans. 11991, 2169–2176; (c) Stocksdale, M. G.; Ramurthy, S.;
Miller, M. J. J. Org. Chem. 1998, 63, 1221–1225.
8. For recent reviews about nitrogen protecting groups, see: Theodoris, G. Tetra-
hedron 2000, 56, 2339–2358; Jarow-icki, K.; Kocienski, P. J. J. Chem. Soc., Perkin
Trans. 1 1999, 1589–1615.
11. Pascal, R.; Sola, R. Tetrahedron Lett. 1998, 39, 5031–5034.
12. Brosse, N.; Pinto, M.-F.; Jamart-Gre´goire, B. J. Org. Chem. 2000, 65, 4370–
4374.
9. Kotsuki, H.; Ohishi, T.; Araki, T.; Arimura, K. Tetrahedron Lett. 1998, 39, 4869–
4870 and references cited therein.
13. Neimark, J.; Briand, J. P. Pept. Res. 1993, 6, 219–228.
14. Lewin, A. H.; Frucht, M. Org. Magn. Reson. 1975, 7, 202–225.