An expedient and short synthesis of chiral α-hydrazinoesters: Synthesis and conformational analysis of 1:1 [α/α-N α-hydrazino]mers

Article abstract of DOI:10.1016/j.tet.2012.04.018

Different α-hydrazinoesters with high optical purity have been obtained in large scale via an S_N2 protocol. A coupling reaction with a natural amino acid leads to the corresponding dimers, which have been oligomerized in order to obtain the 1:1 [α/α-N^α- hydrazino]mer series. Conformational studies show that these mixed oligomers are self-organized in solution via a succession of γ-turn and hydrazinoturn whatever the absolute configuration of the chiral carbons.

Full text of DOI:10.1016/j.tet.2012.04.018

Tetrahedron 68 (2012) 4682e4692
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An expedient and short synthesis of chiral
a
-hydrazinoesters: synthesis
and conformational analysis of 1:1 [
a
/
a
-Na-hydrazino]mers
*
ꢀ
ꢀ
Ralph-Olivier Moussodia, Samir Acherar, Andrea Bordessa, Regis Vanderesse, Brigitte Jamart-Gregoire
ꢀ
ꢀ
Laboratoire de Chimie Physique Macromoleculaire, UMR CNRS-INPL 7568, ENSIC, Universite de Lorraine, 1 rue Grandville BP 451, 54001 Nancy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Different
tocol. A coupling reaction with a natural amino acid leads to the corresponding dimers, which have been
oligomerized in order to obtain the 1:1 [
-Na-hydrazino]mer series. Conformational studies show that
a-hydrazinoesters with high optical purity have been obtained in large scale via an SN2 pro-
Received 4 December 2011
Received in revised form 29 March 2012
Accepted 4 April 2012
a/a
these mixed oligomers are self-organized in solution via a succession of
g-turn and hydrazinoturn
Available online 14 April 2012
whatever the absolute configuration of the chiral carbons.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pseudopeptide
a
-Hydrazinoester
Hydrazinopeptide
1:1 [
SN2
a/a
-Na-Hydrazino]mers
Hydrazinoturn
1. Introduction
also able to fold in solution leading to the formation of a new kind
of foldamers.6 In this paper, we describe the synthesis and the
For several years now, important efforts have been devoted to
improve the pharmacological properties of natural peptides by
a structure modification of the peptide bond CONH group.1 Among
the numerous possibilities, the replacement of one (or more) pep-
tidic bond(s) by one (or more) hydrazidic bond(s) leads to hydrazi-
nopeptides.2 Hydrazinopeptides represent a valuable class of
mimetic replacements for the natural peptides backbone often
leading to analogous of bioactive peptides, which preserve biological
activity3 and enhanced proteolytic stability.4 Furthermore, this ad-
ditional backbone nitrogen might behave as a hydrogen bond ac-
ceptor able to stabilize secondary structure in oligomers.4,5 In 2003,
Lelais and Seebach succeeded in building oligomers of optically pure
conformational analysis of two series of 1:1 [
a
/
a
-Na-hydrazino]
mers alternating natural
ones.
a
-amino acid units and
a
-hydrazino acid
In our preliminary work,7 we demonstrated that bis-nitrogen
containing amino acid analogs such as Na-Me, Nb-Boc-protected
a-hydrazinoesters derivatives 3a could be easily synthesized in
large scale with high optical purity via an SN2 reaction between
tert-butyl-2-methylhydrazinecarboxylate 1a and the triflate de-
rivative of (S)-
a-hydroxyesters 2 (Scheme 1). In this paper, we de-
cided to extend this protocol in order to obtain new
a
-
hydrazinoesters 3 bearing an alkyl or a benzyl group (Bn, i-Bu, and
i-Pr) on the Na-atom, and to study the impact of their presence on
the yield of the SN2 reaction (Scheme 1). In a second part, we will
describe the oligomerization of these new building blocks leading
a
-hydrazino acids4 units. Unfortunately, due to poor resonance dis-
persion and fast exchange between the NH signals, the NMR struc-
tural analyses performed on these kinds of oligomers didn’t yield
definitive conclusion on the conformation. However, X-ray diffrac-
to a series of 1:1 [a/a
-Na-hydrazino]mers. The conformational
analysis of homo (R,R) and hetero (S,R) series was investigated in
tion of the starting
a
-hydrazinoacid (compound 4a) showed that
order to assess the impact of the chirality on the conformation.
the Na-atom adopts a pyramidal conformation with an (S)-configu-
ration and participates in the stabilization of a hydrazinoturn.
More recent works have shown that mixed oligomers alter-
nating a natural amino acid and an amino acid analogous were
2. Results and discussion
2.1. Synthesis of
hydrazino]mers
a-hydrazinoesters 3 and 1:1 [a/a
-Na-
a
-Hydrazinoesters 3 were prepared by using the same protocol
* Corresponding author. Tel.: þ33 (0)3 83 17 52 79; fax: þ33 (0)3 83 37 99 77;
as described in a previous work.7 The results summarized in Table 1,
ꢀ
e-mail address: Brigitte.jamart@ensic.inpl-nancy.fr (B. Jamart-Gregoire).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.018

R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
4683
R'
N
R'
N
O
O
SN2
Boc
Boc
+
(R)
HO (S)
N
H
N
H
H
OMe
reaction
OMe
R
R
3
1
2
a : R = Me
b : R = Bn
c : R = i-Bu
d : R = i-Pr
a : R' = Me
b : R' = Bn
c : R' = i-Bu
d : R' = i-Pr
3aa to 3dd
(16 compounds)
Scheme 1. Synthesis of
a
-hydrazinoesters 3.
Table 1
Synthesis of
a
-hydrazinoesters 3 performed on a 30 mmol scale
R'
O
O
1- Tf2O (1.1 equiv.), 2,6-lutidine (2.3 equiv.), 0°C, 15 min
Boc
N
HO
(R)
(S)
N
H
OMe
OMe
2- BocNHNHR' 1 (1.0 equiv.), 0°C, 4 hr, CH2Cl2
R
R
2 (1 equiv.)
3
25
3
1 (R0)
2 (R)
Yield (%)
[a
]
25 (c 1, MeOH)
3
1 (R0)
2 (R)
Yield (%)
[
a
]
(c 1, MeOH)
D
D
3aa
3ba
3ca
3da
3ab
3bb
3cb
3db
1a (Me)
1b (Bn)
1c (i-Bu)
1d (i-Pr)
1a (Me)
1b (Bn)
1c (i-Bu)
1d (i-Pr)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2b (Bn)
2b (Bn)
2b (Bn)
2b (Bn)
87a
83a
80a
62a
84a
82a
78a
60a
ꢀ9.1
ꢀ9.2
3ac
3bc
3cc
3dc
3ad
3bd
3cd
3dd
1a (Me)
1b (Bn)
1c (i-Bu)
1d (i-Pr)
1a (Me)
1b (Bn)
1c (i-Bu)
1d (i-Pr)
2c (i-Bu)
2c (i-Bu)
2c (i-Bu)
2c (i-Bu)
2d (i-Pr)
2d (i-Pr)
2d (i-Pr)
2d (i-Pr)
80a
78a
62a
58a
15b
10b
22a
0c
ꢀ20.2
ꢀ29.0
ꢀ19.7
ꢀ21.7
d
ꢀ20.9
ꢀ28.2
ꢀ37.0
ꢀ5.2
d
ꢀ25.6
ꢀ40.9
ꢀ0.6
d
a
Yields calculated after purification by flash chromatography.
Yields determined by 1H NMR after purification by flash chromatography.
No reaction after 3 days.
b
c
indicate that the SN2 reaction also gives good yields (58e87%)
when R is Me, Bn, and i-Bu groups. -Hydrazinoesters 3aae3dc can
esterification of carboxylic to give compounds 5a and 5b in quan-
titative yields directly.
a
be obtained on a multigram scale in only one reaction. Conversely,
we showed that this reaction was very sensitive to the steric hin-
drance of 2. As a result, compounds 3ade3bd (R¼i-Pr) were
obtained with very poor yields and no reaction occurs between 1d
and 2d. As a consequence, compounds 3ad and 3bd cannot be
isolated in a pure form but are mixed with 2d even after purifica-
tion by flash chromatography.
Various conditions (EDC, HOBt, HATU, HBTU.) were used in
order to perform the coupling reaction between 5a and Boce
L-
LeueOH and between 5b and Boce -AlaeOH. The best results were
L
obtained when using HATU and NMM, which generate dimers 6a
and 6b with excellent yields. The same protocol was also used for
the synthesis of tetramers 9a,b, hexamers 11a,b, and octamers
13a,b.
On the contrary the comparison of the yields obtained for the
synthesis of compounds 3aa to 3da, 3bb to 3db, and 3ac to 3dc
shows that the steric hindrance of R0 has little influence on the yield
of the reaction.
When applied to 5a and BoceD-LeueOH, these conditions led
to the corresponding homochiral compounds 60a and 90a. Com-
pounds 6a, 9a, 60a, and 90a can easily be transformed into corre-
sponding C-terminal amide compounds 14a, 15a, 140a, 150a,
which will be used for the conformational analysis.
Compounds 3ba and 3bc were then involved in an oligomeri-
zation process in order to obtain the hetero (S,R) and homo (R,R) 1:1
It is interesting to notice that both 13C NMR spectra of 9a and 90a
present a unique set of signals. Moreover, the signals of the
hydrazidic carbonyl groups were assigned at different chemical
[a/a
-Na-hydrazino]mer series (Scheme 2).
Heterochiral compounds 6a,b, 9a,b, 11a,b, and 13a-b were
obtained in very good yields ranging from 77 to 96% by an iterative
sequence of deprotection and coupling reactions as described in
Scheme 2. The saponification of the ester group of 3ba and 3bc led
to corresponding free C-terminal compounds 4a and 4b, re-
spectively. The use of thionyl chloride in methanol8 led simulta-
neously to the deprotection of hydrazine group and to the
shifts,
d
¼171.8 ppm and
d
¼172.1 ppm for 9a and 90a, respectively.
This result confirms the absence of epimerization (ee>95%) during
the coupling reaction and during the formation of corresponding a-
hydrazinoesters 3aa.
IR and NMR experiments were carried out in order to
determine the ability of these oligomers to fold in solution. Then

4684
R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
Scheme 2. Synthesis of hetero (S,R) and homo (R,R) 1:1 [a/a
-Na-hydrazino]mers.
we compared the conformation of homo (R,R) and hetero (S,R) di-
mers 14a and 140a and of tetramers 15a and 150a.
this parameter to obtain information on the conformation of 14a
and 140a.
First of all, the 1H NMR signals of dimers 14a and 140a were fully
assigned using a combination of 2D-COSY and 2D-NOESY experi-
ments (see Figs. S1eS4 in Supplementary data).
2.2. Conformational analysis of homo and hetero oligomer
series
- The signals of the two amidic NH protons, respectively, at
d
¼7.98 ppm and
Dd¼2.74 ppm for hetero dimer 14a.
- Similarly, we assigned the two amidic NH protons of homo
dimer 140a, at
¼7.99 ppm and ¼5.40 ppm, respectively,
which accounts for a Dd¼2.59 ppm. Theses values were in the
d
¼5.24 ppm allowed us to calculate
2.2.1. Conformational analysis of homo and hetero dimers 14a and
140a. Le Grel et al.9 demonstrated that chemical shifts difference
Dd, calculated from the 1H NMR signals of the two C-terminal
amidic protons, can give information on the structuration of
aza-b3 and amidoxy derivatives (Fig. 1).9,10 We decided to use
a
d
d

R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
4685
Hydrazic link
Bn
Amidoxy link
N
O
O
H
H
O
H
O
H
N
N
N
N
Δδ = 2.60 ppm
Δδ = 2.70 ppm
O
H
H
Hydrazinoturn
N-O turn
Fig. 1. Comparison of Dd values between hydrazidic and amidoxy links by 1H NMR (300 MHz, CDCl3/10 mM).
same order as those obtained by P. Le Grel in the aza-
b
3 series,
shifted downfield when the volume of DMSO-d6 increased
which is known to fold via an eight-membered H-bonded ring
(hydrazinoturn).
ð ꢀ
dDMSOꢀd dCDCl ¼ þ1:82 ppm and þ2:26 ppm; respectivelyÞ
6
confirming that3 the NH protons were not involved in an
intramolecular H-bond (free) (Fig. 2a).
To confirm this result, we decided to study the effect of varying
ratios of solvent in the mixture of CDCl3 and DMSO-d6 on the
chemical shifts of the NH protons of compounds 14a and 140a
(Fig. 2a). Solvents with hydrogen bond acceptor atoms, such as
DMSO-d6, are able to form intermolecular H-bonds producing
a downfield displacement for free acidic protons, which is less
significant when protons are involved in an intramolecular H-bond.
- A downfield shift was also observed for NHb. However,
the difference between dDMSOꢀd and dCDCl was lower
6
3
dDMSOꢀd
ꢀ
dCDCl ¼ þ1:58 ppm and suggested that the
6
3
hydrazidic proton was free or was involved in a weak intra-
molecular H-bond. If we take into account the results obtained
by Le Grel et al. for the aza-
bond may well be the result of the presence of a
b
3-oligomers (Fig. 3), this weak H-
g
-turn.5b,11
- Finally, and more interestingly, a very low variation of the-
- We observed that the chemical shifts of both NHc
and NHd (amidic and NHBoc) of hetero dimer 14a
chemical shift was observed for the NHa amidic proton
when switching from CDCl3 to DMSO-d6
ð
dDMSOꢀd
ꢀ
dCDCl
¼
6
3
Fig. 2. Effects of varying ratios of solvent in the mixture of CDCl3 and DMSO-d6 on the chemical shifts of the NH protons of (a) hetero dimer 14a and (homo dimer 140a) and of (b)
hetero tetramer 15a (and homo tetramer 150a) in 1H NMR (300 MHz, 10 mM).

4686
R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
hydrazidic NHs bonded
(γ-turn)
Me
Bn
(or b')
tBuO
O Hb
N
O
(R)
N
(R/S)
N
N
Δδ = 2.74 ppm
(or Δδ = 2.59 ppm)
Hc
Hd
O
Ha
(or d')
(or a') (or c')
Free NHBoc
Free NH
amidic NHs bonded
(Hydrazinoturn)
Fig. 3. Postulated structuration of 14a (and 140a) in CDCl3 solution.
þ0:15 ppmÞ confirming the presence of a strong H-bond. This
All these results are in agreement with a structuration of 1:1 [
-Na-hydrazino]mer series via a succession of
-turns and hydra-
zinoturns. Moreover, the self-structuration does not seem to be
a/
result is in agreement with the proposed hydrazinoturn
structuration (bifurcated H-bond, Fig. 3).
a
g
affected by the nature of the absolute configuration of the a-carbon
It is important to note that same results were obtained for both
(Fig. 4).
hetero and homo dimers 14a and 140a. This showed that the
structuration was not dependent on the chirality of the
a
-carbon
3. Conclusion
and that both series fold via a succession of seven- (
eight-membered H-bonded rings (hydrazinoturns).
g-turns) and
Various
a-hydrazinoesters 3aae3dc building blocks can be
obtained with high optical purity using a general protocol. Starting
2.2.2. Conformational analysis of homo and hetero tetramers 15a
from 3ba and 3bc, we were able to obtain the synthesis of two 1:1
1
[a/a
-Na-hydrazino]mer series. Conformational studies by 1H NMR
and 150a. H NMR signals of tetramers 15a and 150a were fully
show that 1:1 [
tion via a succession of
a/a
-Na-hydrazino]mers are self-organized in solu-
-turn and hydrazinoturn whatever the
assigned using a combination of 2D-COSY and 2D-ROESY experi-
ments (see Figs. S5eS8 in Supplementary data). As observed in the
dimer series, the variation of the chemical shifts of all NH protons
(Fig. 2b) was quite similar for homo tetramer 150a and hetero tet-
ramer 15a, which suggested an identical self-structuration for both
series.
g
absolute configuration of the chiral carbons.
4. Experimental
4.1. General
- The chemical shifts of the two amidic NH protons of hetero
tetramer 15a, were, respectively, at
¼5.37 ppm, given a Dd¼2.75 ppm.
- Similarly, a Dd¼2.58 ppm was calculated for the homo tetramer
150a (
¼7.84 ppm and ¼5.26 ppm for the two amidic NH
protons).
- The chemical shifts of amidic protons NHa and NHe of tetra-
mers 15a and 150a were very poorly affected by the addition of
DMSO-d6 (see Fig. 2b), which confirmed the presence of
a hydrazinoturn.
- In contrast, the evolution of the chemical shifts of
hydrazidic protons NHb of tetramers 15a and 150a was similar
to those of hydrazidic protons NHb and NH0b in dimers 14a
and 140a confirming their involvement in a weak intra-
d
¼8.12 ppm and
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. Reactions were monitored by thin-layer chro-
matography (TLC) using aluminum-backed silica gel plates
(Macherey-Nagel ALUGRAMÒ SIL G/UV254). TLC spots were viewed
under ultraviolet light and by heating the plate after treatment
with a staining solution of phosphomolybdic acid. Product purifi-
cations were performed using Geduran 60 H Silica Gel (63e200
mesh). Dichloromethane was distilled from phosphorous pentox-
ide under argon atmosphere and others reagent grade solvents
were used as received. 1H and 13C NMR spectra were recorded on
a Bruker Advance 300 spectrometer. Multiplicities are reported as
follow: s¼singlet, d¼doublet, q¼quartet, sept¼septuplet,
m¼multiplet, br¼broad, Ar.¼aromatic and coupling constants (J)
are given in hertz (Hz). IR spectra were recorded on a Brucker
Tensor 27. Melting points (mp) were recorded on a Kofler hot-stage
apparatus and were uncorrected. Electron spray ionization mass
spectra (ESI-MS) were recorded on a Brucker MicroTof-Q HR
d
d
d
molecular H-bond
(g-turns). Finally, as observed in the
dimer, NHc,NHd and NH0c,NH0d (amidic and NHBoc
protons) are free and shifted downfield when the volume of
DMSO-d6 increases ðdDMSOꢀd
ꢀ
dCDCl ¼ þ1:72 ppm and þ
6
3
1:24 ppm; respectivelyÞ.
ꢀ
spectrometer in the ‘Service commun de Spectrometrie de Masse’,
The presence of free and bonded NH protons in dimer and tet-
ramers was also confirmed by IR analysis (see Figs. S9eS12 in
Supplementary data).
ꢀ
ꢁ
Faculte des Sciences et Techniques, Vandoeuvre-les-Nancy, France.
Optical rotations were determined on an Anton Paar MCP 300
polarimeter in 5 cm cells. tert-Butyl-hydrazinecarboxylate

R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
4687
hydrazidic NHs bonded
(γ-turns)
Me
Me
Bn
(or b') Bn
Hb N
(or b')
O Hb
tBuO
N
O
O
(R)
(R)
N
N
(R/S)
(R/S)
N
N
N
Hc
Hd
O
O
Ha
Δ
δ
= 2.75 ppm
= 2.58 ppm)
He
(or d')
(or e')
(or a') (or c')
(or
Δ
δ
Free NHBoc
Free NH
amidic NHs bonded
(Hydrazinoturns)
Fig. 4. Postulated structuration of 15a (and 150a) in CDCl3 solution.
derivatives 1aed and (S)-
according to Refs. 12 and 13, respectively.
a
-hydroxyesters 2aed were prepared
(75 MHz, CDCl3)
d 16.9 (bCH3 Ala), 28.9 (3CH3, Boc), 52.2 (OeCH3),
60.8 (
a
CH Ala), 61.3 (CH2, Na-Bn), 80.3 (C, Boc), 128.1 (CH, Ar.), 128.9
(2CH, Ar.), 130.0 (2CH, Ar.), 137.6 (C, Ar.), 156.1 (C]O, Boc), 175.2
(C]O, ester); HRMS (ESI) calculated for C16H24N2O4 [MþNa]þ m/z
331.1634, found 331.1628.
4.2. Representative procedure for the preparation of
hydrazinoesters 3
a-
4.2.3. (R)-(ꢀ)-Na-iso-Butyl-Nb-Boc-(
D)-hydrazinoalanine methyl es-
A solution of (S)-a-hydroxyester 2 (1.0 equiv, 30 mmol) and 2,6-
lutidine (2.3 equiv, 69 mmol) in CH2Cl2 (40 mL) at 0 ꢁC, under an
ter or Bocea-h(i-Bu)D-AlaeOMe, 3ca. Purified by flash chromatog-
25
raphy (petroleum ether/AcOEt¼70:30), yield: 80%, yellow oil, [
a]
atmosphere of nitrogen, was treated with triflic anhydride
D
ꢀ20.9 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3362, 2982, 2857, 2908,
2873, 2843, 1740, 1734, 1710, 1690, 1678, 1659, 1562, 1510, 1483,
1469, 1462, 1452, 1412, 1389, 1380, 1368, 1238, 1200, 1160, 1124; 1H
(1.1 equiv, 33 mmol). After 15 min, a solution of BocNHNHR0
1
(1.0 equiv, 30 mmol) in CH2Cl2 (30 mL) was added dropwise for
30 min and the mixture was stirred for 4e6 h at 0 ꢁC until com-
pletion (monitored by TLC). After evaporation of the solvent, Et2O
(50 mL) was added and 2,6-lutidinium triflate was precipitated by
storing the reaction mixture overnight in the refrigerator. The 2,6-
lutidinium triflate was filtered and the filtrate was diluted in Et2O
(100 mL) and washed with water (20 mL), dried over MgSO4, fil-
tered, and evaporated in vacuo. The resulting crude material was
purified and characterized as reported below.
NMR (300 MHz, CDCl3)
d
0.9 (d, 3H, J¼6.5 Hz, CH3, Na-i-Bu), 0.97 (d,
3H, J¼6.5 Hz, CH3, Na-i-Bu), 1.37 (d, 3H, J¼7.2 Hz,
bCH3 Ala), 1.44 (s,
9H, Boc), 1.62e1.81 (m, 1H, CH, Na-i-Bu), 2.20e2.45 (m, 1H, CH2, Na-
i-Bu), 2.55e2.77 (m, 1H, CH2, Na-i-Bu), 3.48e3.65 (m, 1H,
3.71 (s, 3H, OeCH3), 6.33 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)
16.7 (
CH3 Ala), 21.7 (2CH3, Na-i-Bu), 27.2 (CH, Na-i-Bu), 28.9
(3CH3, Boc), 52.0 (OeCH3), 63.4 (
CH Ala); 65.3 (CH2, Na-i-Bu), 80.0
aCH Ala),
d
b
a
(C, Boc), 156.3 (C]O, Boc), 175.2 (C]O, ester); HRMS (ESI) calcu-
lated for C13H26N2O4 [MþNa]þ m/z 297.1791, found 297.1785.
4.2.1. (R)-(ꢀ)-Na-Methyl-Nb-Boc-(
D)-hydrazinoalanine methyl ester
or Bocea-h(Me)D-AlaeOMe, 3aa. Purified by flash chromatography
4.2.4. (R)-(ꢀ)-Na-iso-Propyl-Nb-Boc-(
D)-hydrazinolalanine methyl
ester or Bocea-h(i-Pr)D-AlaeOMe, 3da. Purified by flash chroma-
(petroleum ether/AcOEt¼50:50), yield: 87%, yellow oil, [
a
]
25 ꢀ9.1 (c
D
1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3362, 3005, 2982, 2955, 2890,
2843, 2799, 1746, 1728, 1689, 1658, 1641, 1630, 1564, 1553, 1513,
1483, 1462, 1450, 1414, 1393, 1368, 1242, 1210, 1163, 1130, 1111; 1H
tography (petroleum ether/AcOEt¼70:30), yield: 62%, yellow oil,
25
[
a
]
ꢀ28.2 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3371, 2982, 2944,
D
2908, 2881, 2843, 1745, 1728, 1711, 1692, 1683, 1498, 1490, 1486,
1471, 1460, 1452, 1391, 1383, 1366, 1332, 1275, 1246, 1198, 1161,
NMR (300 MHz, CDCl3)
d
1.37 (d, 3H, J¼7.2 Hz,
bCH3 Ala),1.45 (s, 9H,
Boc), 2.67 (s, 3H, Na-Me), 3.57e3.64 (q, 1H, J¼7.2 Hz,
a
CH Ala), 3.72
16.6
CH3 Ala), 28.8 (3CH3, Boc), 44.0 (Na-Me), 52.0 (OeCH3), 63.1 (
(b aCH
1128; 1H NMR (300 MHz, CDCl3)
d
1.08 (d, 6H, J¼6.2 Hz, CH3, Na-i-
(s, 3H, OeCH3), 6.52 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)
d
Pr), 1.37 (d, 3H, J¼7.1 Hz,
bCH3 Ala), 1.44 (s, 9H, Boc), 3.03 (sept., 1H,
J¼6.2 Hz, CH, Na-i-Pr), 3.70 (s, 3H, OeCH3), 3.82 (q, 1H, J¼7.1 Hz,
Ala), 80.2 (C, Boc), 155.9 (C]O, Boc), 174.6 (C]O, ester); HRMS (ESI)
CH Ala), 6.47 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)
d 17.1 (bCH3
calculated for C10H20N2O4 [MþNa]þ m/z 255.1321, found 255.1315.
a
Ala), 20.9 (CH3, Na-i-Pr), 21.1 (CH3, Na-i-Pr), 28.9 (3CH3, Boc), 52.1
(OeCH3), 56.0 (CH, Na-i-Pr), 58.7 (
aCH Ala), 79.9 (C, Boc), 157.0 (C]
4.2.2. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D)-hydrazinoalanine methyl ester
or Bocea-h(Bn)D-AlaeOMe, 3ba. Purified by flash chromatography
O, Boc), 175.9 (C]O, ester); HRMS (ESI) calculated for C12H24N2O4
[MþNa]þ m/z 283.1634, found 283.1628.
(petroleum ether/AcOEt¼80:20), yield: 83%, yellow oil, [
a
]
25 ꢀ9.2 (c
D
1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3370, 3091, 3064, 3032, 2984,
2955, 2907, 2846, 1737, 1728, 1709, 1659, 1641, 1630, 1564, 1494,
1486, 1462, 1456, 1435, 1424, 1393, 1367, 1237, 1213, 1159; 1H NMR
4.2.5. (R)-(ꢀ)-Na-Methyl-Nb-Boc-(
D)-hydrazinophenylalanine
methyl ester or Bocea-h(Me)D-PheeOMe, 3ab. Purified by flash
chromatography (petroleum ether/AcOEt¼70:30), yield: 84%, yel-
(300 MHz, CDCl3)
3.56 (q, 1H, J¼7.2 Hz,
2H, CH2, Na-Bn), 6.48 (br s, 1H, NH), 7.13e7.36 (m, 5H, Ar.); 13C NMR
d
1.28 (s, 9H, Boc), 1.31 (d, 3H, J¼7.2 Hz,
bCH3 Ala),
low oil, [
a
]
25 ꢀ37.0 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3357, 3089,
a
CH Ala), 3.66 (s, 3H, OeCH3), 3.82e4.01 (m,
D
3064, 3028, 3006, 2982, 2957, 2939, 2893, 1737, 1727, 1710, 1659,

4688
R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
1642, 1630, 1603, 1583, 1498, 1482, 1456, 1446, 1415, 1393, 1367,
(c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3368, 2979, 2956, 2937, 2907,
2871, 2843, 2803, 1744, 1728, 1710, 1690, 1677, 1659, 1641, 1564,
1513, 1483, 1467, 1453, 1444, 1413, 1390, 1367, 1261, 1235, 1200,
1241, 1211, 1165; 1H NMR (300 MHz, CDCl3)
d
1.47 (s, 9H, Boc), 2.64
CH Phe), 3.14 (dd,
(s, 3H, Na-Me), 2.96 (dd, 1H, J¼13.6 and 8.3 Hz,
b
1H, J¼13.6 and 6.5 Hz,
b
CH Phe), 3.59 (s, 3H, OeCH3), 3.67 (dd, 1H,
1160, 1125; 1H NMR (300 MHz, CDCl3)
d
0.91 (d, 6H, J¼6.6 Hz,
Leu), 1.45 (s, 9H, Boc), 1.36e1.53 (m, 1H, CH2 Leu), 1.59e1.73 (m,
1H, CH2 Leu), 1.85e1.99 (m, 1H,
CH Leu), 2.63 (s, 3H, Na-Me), 3.45
(dd, 1H, J¼9.0 and 6.0 Hz, CH Leu), 3.72 (s, 3H, OeCH3), 6.53 (br s,
1H, NH); 13C NMR (75 MHz, CDCl3)
22.5 ( CH Leu), 23.6 ( CH3
Leu), 25.0 ( CH3 Leu), 29.0 (3CH3, Boc), 39.9 (
CH2 Leu), 44.7 (Na-
Me), 52.0 (OeCH3), 66.2 (
dCH3
J¼8.3 and 6.5 Hz,
13C NMR (75 MHz, CDCl3)
(Na-Me), 52.0 (OeCH3), 70.1 (
a
CH Phe), 6.55 (br s,1H, NH), 7.1e7.35 (m, 5H, Ar.);
29.0 (3CH3, Boc), 37.3 ( CH2 Phe); 45.0
CH Phe), 80.6 (C, Boc), 127.2 (CH, Ar.),
b
d
b
b
g
a
a
129.0 (2CH, Ar.), 129.8 (2CH, Ar.), 138.2 (C, Ar.); 156.1 (C]O, Boc),
173.9 (C]O, ester); HRMS (ESI) calculated for C16H24N2O4 [MþNa]þ
m/z 331.1634, found 331.1628.
d
g
b
d
d
a
CH Leu), 80.3 (C, Boc), 156.4 (C]O, Boc),
175.1 (C]O, ester); HRMS (ESI) calculated for C13H26N2O4 [MþNa]þ
m/z 297.179, found 297.177.
4.2.6. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D)-hydrazinophenylalanine methyl
ester or Bocea-h(Bn)D-PheeOMe, 3bb. Purified by flash chroma-
tography (petroleum ether/AcOEt¼80:20), yield: 82%, yellow oil,
4.2.10. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D)-hydrazinoleucine methyl ester
25
[
a]
ꢀ5.2 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3362, 3091, 3065,
or Bocea-h(Bn)D-LeueOMe, 3bc. Purified by flash chromatography
D
3031, 2980, 2958, 2907, 2842, 1741, 1726, 1707, 1661, 1626, 1605,
(petroleum ether/AcOEt¼70:30), yield: 78%, yellow oil, [
(c 1.00, MeOH); 1H NMR (300 MHz, CDCl3)
Leu), 0.86.0.90 (m, 3H,
CH2 Leu), 2.04e2.13 (m, 1H,
3.73 (s, 3H, OeCH3), 3.88e4.05 (m, 2H, CH2, Na-Bn), 6.74 (br s, 1H,
NH), 7.23e7.40 (m, 5H, Ar.); 13C NMR (75 MHz, CDCl3)
22.7 ( CH
Leu), 24.2 ( CH3 Leu), 24.8 ( CH3 Leu), 28.8 (3CH3, Boc), 39.8 ( CH2
Leu), 52.0 (OeCH3), 61.8 (CH2, Na-Bn), 62.8 (
CH Leu), 80.1 (C, Boc),
128.1 (CH, Ar.), 128.8 (2CH, Ar.), 130.1 (2CH, Ar.), 137.6 (C, Ar.), 155.1
a
]
25 ꢀ29.0
D
1587, 1496, 1482, 1454, 1389, 1367, 1241, 1217, 1157; 1H NMR
d
0.72e0.74 (m, 3H, dCH3
(300 MHz, CDCl3)
6.8 Hz,
CH2 Phe), 3.07e3.17 (dd, 1H, J¼13.9 and 7.6 Hz,
3.64 (s, 3H, OeCH3), 3.62e3.83 (m, 1H, CH Phe), 3.86e4.03 (m, 2H,
CH2, Na-Bn), 6.60 (br s, 1H, NH), 7.20e7.36 (m, 10H, Ar.); 13C NMR
(75 MHz, CDCl3) 29.0 (3CH3, Boc), 37.1 ( CH2 Phe), 52.1 (OeCH3),
61.0 (CH2, Na-Bn), 67.3 (
CH Phe), 80.5 (C, Boc), 127.1 (CH, Ar.), 128.0
d
1.36 (s, 9H, Boc), 2.93e3.05 (dd, 1H, J¼13.9 and
dCH3 Leu),1.38 (s, 9H, Boc),1.49e1.82 (m, 2H,
b
b
CH2 Phe),
b
gCH Leu), 3.44e3.48 (m, 1H, CH Leu),
a
a
d
g
d
b
d
d
b
a
a
(CH, Ar.), 128.1 (CH, Ar.), 128.2 (CH, Ar.), 128.8 (CH, Ar.), 129.3 (CH,
Ar.), 129.4 (CH, Ar.), 129.5 (CH, Ar.), 129.9 (CH, Ar.), 130.1 (CH, Ar.),
137.2 (C, Ar.), 138.5 (C, Ar.), 155.8 (C]O, Boc), 174.0 (C]O, ester);
HRMS (ESI) calculated for C22H28N2O4 [MþNa]þ m/z 407.1947,
found 407.1941.
25
(C]O, Boc), 175.3 (C]O, ester). The physical data (NMR and [
are in agreement with the values reported in Ref. 4. Measured: [
a
]
)
D
25
a
]
D
25
ꢀ24.6 (c 0.99, CHCl3), literature: [
a
]
þ25.4 (c 0.99, CHCl3) (S)-
D
isomer.
4.2.7. (R)-(ꢀ)-Na-iso-Butyl-Nb-Boc-(
D
)-hydrazinophenylalanine
4.2.11. (R)-(ꢀ)-Na-iso-Butyl-Nb-Boc-(
D)-hydrazinoleucine methyl es-
methyl ester or Boce
a
-h(i-Bu)
D
-PheeOMe, 3cb. Purified by flash
ter or Bocea-h(i-Bu)D-LeueOMe, 3cc. Purified by flash chromatog-
25
chromatography (petroleum ether/AcOEt¼80:20), yield: 78%, yel-
raphy (petroleum ether/AcOEt¼90:10), yield: 62%, yellow oil, [
a]
D
low oil, [
a
]
25 ꢀ25.6 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3362, 3064,
ꢀ19.7 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3368, 2959, 2935, 2907,
2872, 2852, 1745, 1729, 1711, 1678, 1658, 1642, 1564, 1512, 1494,
1483, 1470, 1451, 1440, 1396, 1366, 1273,1241, 1195, 1174,1158, 1130;
D
3030, 3006, 2980, 2955, 2909, 2870, 2844, 1743, 1728, 1705, 1678,
1658, 1498, 1484, 1470, 1456, 1440, 1391, 1383, 1367, 1237, 1201,
1167; 1H NMR (300 MHz, CDCl3)
d
0.84 (d, 3H, J¼6.6 Hz, CH3, Na-i-
1H NMR (300 MHz, CDCl3)
d
0.83e1.05 (m, 12H, 4CH3, Na-i-Bu and
CH2 Leu and CH, Na-
CH Leu), 2.20e2.37 (m, 1H, CH2, Na-i-Bu),
CH Leu), 3.70
(s, 3H, OeCH3), 6.43 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)
20.8
(2CH3, Na-i-Bu), 23.2 ( CH3 Leu), 27.1 (CH, Na-i-
CH Leu), 25.2 (2
Bu), 28.5 (3CH3, Boc), 39.9 ( CH2 Leu), 51.8 (OeCH3), 66.2 ( CH Leu),
Bu), 0.96 (d, 3H, J¼6.6 Hz, CH3, Na-i-Bu), 1.44 (s, 9H, Boc), 1.62e1.80
dCH3 Leu), 1.44 (s, 9H, Boc), 1.68e1.82 (m, 3H, b
(m, 1H, CH, Na-i-Bu), 2.29e2.42 (m, 1H, CH2, Na-i-Bu), 2.53e2.64
i-Bu), 2.05e2.17 (m, 1H,
g
(m, 1H, CH2, Na-i-Bu), 2.90e3.02 (m, 1H,
b
CH2 Phe), 3.07e3.19 (m,
CH2 Phe), 3.61 (s, 3H, OeCH3), 3.65e3.81 (m, 1H, CH Phe),
6.42 (br s, 1H, NH), 7.15e7.32 (m, 5H, Ar.); 13C NMR (75 MHz, CDCl3)
21.2 (2CH3, Na-i-Bu), 27.1 (CH, Na-i-Bu), 29.2 (3CH3, Boc), 37.1
CH2 Phe), 52.3 (OeCH3), 66.3 (CH2, Na-i-Bu), 70.2 (
CH Phe), 80.2
2.64e2.72 (m, 1H, CH2, Na-i-Bu), 3.35e3.55 (m, 1H,
a
1H,
b
a
d
g
d
d
b
a
(b
a
68.0 (CH2, Na-i-Bu), 80.5 (C, Boc), 155.8 (C]O, Boc), 175.2 (C]O,
ester); HRMS (ESI) calculated for C16H32N2O4 [MþNa]þ m/z
339.2260, found 339.2254.
(C, Boc), 127.7 (CH, Ar.), 128.8 (2CH, Ar.), 130.4 (2CH, Ar.), 138.7 (C,
Ar.),155.6 (C]O, Boc),174.0 (C]O, ester); HRMS (ESI) calculated for
C19H30N2O4 [MþNa]þ m/z 373.2104, found 373.2098.
4.2.12. (R)-(ꢀ)-Na-iso-Propyl-Nb-Boc-(
D)-hydrazinoleucine methyl
4.2.8. (R)-(ꢀ)-Na-iso-Propyl-Nb-Boc-(
D
)-hydrazinophenylalanine
ester or Bocea-h(i-Pr)D-LeueOMe, 3dc. Purified by flash chroma-
methyl ester or Boce
a-h(i-Pr)D-PheeOMe, 3db. Purified by flash
tography (petroleum ether/AcOEt¼90:10), yield: 58%, yellow oil,
25
chromatography (petroleum ether/AcOEt¼80:20), yield: 60%, yel-
[
a
]
ꢀ21.7 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3374, 2978, 2961,
D
low oil, [
a
]
25 ꢀ40.9 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3366, 3089,
2937, 2911, 2872, 1745, 1728, 1705, 1689, 1484, 1472, 1456, 1438,
D
3064, 3030, 2980, 2955, 2937, 1743, 1728, 1710, 1680, 1644, 1603,
1391, 1366, 1268, 1252, 1233, 1195, 1163, 1130; 1H NMR (300 MHz,
1496, 1486, 1453, 1393, 1385, 1369, 1274, 1243, 1201, 1163; 1H NMR
CDCl3)
d
0.89 (d, 6H, J¼6.5 Hz,
d
CH3 Leu), 1.05e1.09 (m, 6H, CH3, Na-
(300 MHz, CDCl3)
2.90e3.01 (m, 2H,
(s, 3H, OeCH3), 3.75e3.86 (m, 1H,
7.13e7.36 (m, 5H, Ar.); 13C NMR (75 MHz, CDCl3)
Pr), 28.6 (3CH3, Boc), 38.0 (
CH2 Phe), 52.3 (OeCH3), 56.7 (CH, Na-i-
Pr), 66.2 ( CH Phe), 80.1 (C, Boc), 127.2 (CH, Ar.), 129.0 (2CH, Ar.),
d
1.05e1.09 (m, 6H, CH3, Na-i-Pr), 1.47 (s, 9H, Boc),
i-Pr), 1.44 (s, 9H, Boc), 1.63e1.77 (m, 2H, bCH2 Leu), 1.91e2.03 (m,
b
CH2 Phe), 3.08e3.20 (m, 1H, CH, Na-i-Pr), 3.54
CH Phe), 6.62 (br s, 1H, NH),
21.1 (2CH3, Na-i-
1H,
g
CH Leu), 2.98 (sept, 1H, J¼6.2 Hz, CH, Na-i-Pr), 3.69 (s, 3H,
a
OeCH3), 3.72e3.82 (m, 1H, a
CH Leu), 6.61 (br s, 1H, NH); 13C NMR
d
(75 MHz, CDCl3)
Leu), 23.3 ( CH3 Leu), 24.6 (
Leu), 51.7 (OeCH3), 56.1 (CH, Na-i-Pr), 61.3 (
d
20.5 (CH3, Na-i-Pr), 21.1 (CH3, Na-i-Pr), 22.2 (
CH3 Leu), 28.7 (3CH3, Boc), 40.1 (
CH Leu), 79.4 (C, Boc),
gCH
b
d
d
bCH2
a
a
130.0 (2CH, Ar.), 138.4 (C, Ar.), 156.8 (C]O, Boc), 175.0 (C]O, ester);
HRMS (ESI) calculated for C18H28N2O4 [MþNa]þ m/z 359.1947,
found 359.1941.
156.4 (C]O, Boc), 175.9 (C]O, ester); HRMS (ESI) calculated for
C15H30N2O4 [MþH]þ m/z 303.2284, found 303.2278.
4.2.13. (R)-(ꢀ)-Na-Methyl-Nb-Boc-(
D)-hydrazinovaline methyl ester
or Bocea-h(Me)D-ValeOMe, 3ad. Purified by flash chromatography
4.2.9. (R)-(ꢀ)-Na-Methyl-Nb-Boc-(
D
)-hydrazinoleucine methyl ester
or Boce
a
-h(Me)
D
-LeueOMe, 3ac. Purified by flash chromatography
(petroleum ether/AcOEt¼85:15), yield: 15% determined by 1H NMR
integration relative peaks (inseparable mixture of 2d and 3ad). For
(petroleum ether/AcOEt¼85:15), yield: 80%, yellow oil, [
a
]
D
25 ꢀ20.2

R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
4689
3ad: yellow oil; 1H NMR (300 MHz, CDCl3)
d
(d, 3H, J¼6.7 Hz,
g
CH3
Ar.), 156.3 (C]O, Boc), 178.2 (C]O, acid); HRMS (ESI) calculated for
C
tral data were in agreement with those reported in Ref. 4.
Val), 1.10 (d, 3H, J¼6.7 Hz,
g
CH3 Val), 1.45 (s, 9H, Boc), 1.98e2.13 (m,
18H28N2O4 [MþH]þ m/z 337.2127, found 337.2122. 1H NMR spec-
1H,
b
CH Val), 2.57 (s, 3H, Na-Me), 3.02 (d, 1H, J¼9.5 Hz,
aCH Val),
3.73 (s, 3H, OeCH3), 6.53 (br s, 1H, NH).
4.3.3. Boce
phous solid; 1H NMR (300 MHz, CDCl3)
CH3 Leu), 1.38e1.44 (m, 6H, CH3 Ala, bbCH2 Leu,
(s, 9H, Boc), 3.71e3.80 (q, 1H, J¼7.2 Hz, CH Ala), 4.01e4.17 (m, 2H,
CH2, Na-Bn), 4.19e4.30 (m, 1H,
L
-Leu-
a
-h(Bn)
D
-AlaeOH, 7a. Yield: 96%, white amor-
0.83 (d, 6H, J¼6.0 Hz,
CH Leu), 1.42
4.2.14. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D
)-hydrazinovaline methyl ester
d
or Boce
a-h(Bn)
D
-ValeOMe, 3bd. Purified by flash chromatography
2d
b
g
(petroleum ether/AcOEt¼80:20), yield: 10% determined by 1H NMR
a
integration relative peaks (inseparable mixture of 2d and 3bd). For
a
CH Leu), 5.07 (br d, 1H, J¼8.2 Hz,
3bd: yellow oil; 1H NMR (300 MHz, CDCl3)
d
0.87 (d, 3H, J¼6.9 Hz,
CH3 Val), 1.36 (s, 9H, Boc),
CH Val), 3.79 (s, 3H, OeCH3), 3.70e3.83 (m, 1H,
CH Val), 3.97e4.07 (m, 2H, CH2, Na-Bn), 6.03 (br s, 1H, NH),
NHBoc), 7.25e7.43 (m, 5H, Ar.), 8.37 (br s, 1H, NH hydrazidic). The
crude product was used in a next step without further purification.
g
CH3 Val), 1.02 (d, 3H, J¼6.9 Hz,
g
2.03e2.15 (m, 1H,
a
b
4.3.4. Boce
phous solid; 1H NMR (300 MHz, CDCl3)
Leu), 0.85 (d, 3H, J¼6.0 Hz, CH3 Leu), 1.25 (d, 3H, J¼7.2 Hz,
Ala),1.40 (s, 9H, Boc),1.40e1.52 (m,1H,
CH2 Leu), 1.96e2.06 (m, 1H, CH Leu), 3.48e3.57 (m, 1H,
3.97e4.16 (m, 2H, CH2, Na-Bn), 4.31e4.47 (m, 1H,
CH Ala), 5.69 (d,
L-Ala-a-h(Bn)D-LeueOH, 7b. Yield: 95%, white amor-
7.20e7.42 (m, 5H, Ar.).
d
0.73 (d, 3H, J¼6.0 Hz,
d
CH3
d
b
CH3
4.2.15. (R)-(ꢀ)-Na-iso-Butyl-Nb-Boc-(
D)-hydrazinovaline methyl es-
b
CH2 Leu),1.60e1.71 (m,1H,
CH Leu),
ter or Boce
a
-h(i-Bu)D-ValeOMe, 3cd. Purified by flash chromatog-
b
g
a
25
raphy (petroleum ether/AcOEt¼85:15), yield: 22%, yellow oil, [
a
]
a
D
ꢀ0.6 (c 1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3351, 2980, 2963, 2937,
1H, J¼7.2 Hz, NHBoc), 7.22e7.43 (m, 5H, Ar.), 8.39 (br s, 1H, NH
hydrazidic), 8.62 (s, 1H, OH). The crude product was used in a next
step without further purification.
2915, 2874, 1740, 1724, 1711, 1694, 1680, 1482, 1470, 1454, 1446,
1389, 1371, 1284, 1252, 1171, 1146; 1H NMR (300 MHz, CDCl3)
d 0.87
(d, 3H, J¼6.9 Hz,
g
g
CH3 Val), 0.92 (d, 6H, J¼6.7 Hz, CH3, Na-i-Bu), 1.02
(d, 3H, J¼6.9 Hz,
CH3 Val), 1.46 (s, 9H, Boc), 1.65e1.80 (m, 1H, CH,
4.3.5. Boce(
L
-Leu-
a
-h(Bn)
D
-Ala)2eOH, 10a. Yield: 94%, white
0.79 (d, 3H, J¼6.3 Hz,
CH3 Leu), 0.87 (d, 3H, J¼6.3 Hz,
CH3 Ala), 1.37 (d, 3H, J¼6.9 Hz,
CH3 Ala), 1.45 (s, 9H, Boc),1.49e1.68 (m, 6H, 2 CH2 Leu, 2 CH Leu),
3.47 (q, 1H, J¼6.9 Hz, CH Ala), 3.62e3.72 (m, 1H, CH Ala),
3.82e4.06 (m, 5H, 2CH2, Na-Bn,
CH Leu), 4.08e4.21 (m, 1H, CH
Na-i-Bu), 2.01e2.13 (m, 1H,
b
CH Val), 2.65 (d, 2H, J¼6.8 Hz, CH2, Na-
amorphous solid; 1H NMR (300 MHz, CDCl3)
d
i-Bu), 3.79 (s, 3H, OeCH3), 4.05 (d, 1H, J¼3.6 Hz,
aCH Val), 6.04 (br s,
d
CH3 Leu), 0.83 (d, 6H, J¼6.3 Hz, 2
CH3 Leu), 1.27 (d, 3H, J¼6.9 Hz,
d
b
1H, NH); 13C NMR (75 MHz, CDCl3)
Val), 21.1 (2CH3, Na-i-Bu), 27.5 (CH, Na-i-Bu), 29.0 (3CH3, Boc), 52.9
(OeCH3), 60.6 (CH2, Na-i-Bu), 75.8 (
CH Val), 81.0 (C, Boc), 157.4
d
16.7 (2
g
CH3 Val), 19.4 (
b
CH
d
b
b
g
a
a
a
(C]O, Boc), 176.0 (C]O, ester); HRMS (ESI) calculated for
a
a
C15H30N2O4 [MþNa]þ m/z 325.2104, found 325.2101.
Leu), 5.31 (br s, 1H, NHBoc), 7.22e7.42 (m, 10H, Ar.), 7.82 (s, 1H, NH),
8.23 (s, 1H, NH), 8.52 (br s, 1H, NH). The crude product was used in
a next step without further purification.
4.3. Representative procedure for the C-terminal
deprotection with NaOH 1 N
4.3.6. Boce(
L-Ala-a-h(Bn)D-Leu)2eOH, 10b. Yield: 96%, white
To a solution of ester (1.0 equiv, 22 mmol) in MeOH (80 mL) was
added at 0 ꢁC a solution of NaOH 1 N (2.0 equiv, 44 mmol) and the
mixture was vigorously stirred for 3e6 h at room temperature until
completion (monitored by TLC). After evaporation of MeOH, the
aqueous layer was washed with cyclohexane (2ꢂ10 mL). The
aqueous phase was cooled to 0 ꢁC and acidified with HCl 1 N until
pH¼1 and extracted with EtOAc (3ꢂ20 mL). The residue was dried
over MgSO4, filtered, and evaporated in vacuo to give the corre-
sponding carboxylic acid.
amorphous solid; 1H NMR of the major form (300 MHz, CDCl3)
d
0.72e1.15 (m, 18H, 4
CH2 Leu, 2 CH Leu), 1.39 (s, 9H, Boc), 3.42e3.63 (m, 2H, 2
CH Ala),
d
CH3 Leu, 2
d
CH3 Leu,), 1.24e1.99 (m, 6H,
2
b
g
aCH
Leu), 3.67e3.81 (m, 4H, 2CH2, Na-Bn), 3.88e4.23 (m, 2H, 2
a
4.94 (br s, J¼5.7 Hz, NHBoc), 7.15e7.51 (m, 10H, Ar.), 8.02 (br s, 1H,
NH), 8.12 (s, 1H, NH), 8.56 (s, 1H, NH), 9.17 (br s, 1H, OH). The crude
product was used in a next step without further purification.
4.3.7. Boce
phous solid; 1H NMR (300 MHz, CDCl3)
Leu), 0.86 (d, 3H, J¼6.0 Hz, CH3 Leu), 1.20e1.50 (m, 6H,
CH2 Leu, CH Leu), 1.43 (s, 9H, Boc), 3.65e3.80 (m, 1H,
4.06 (s, 2H, CH2, Na-Bn), 4.10e4.25 (m, 1H,
CH Leu), 4.93 (m, 1H,
D
-Leu-a
-h(Bn)
D
-AlaeOH, 70a. Yield: 82%, white amor-
0.84 (d, 3H, J¼6.0 Hz, CH3
CH3 Ala,
CH Ala),
d
d
4.3.1. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D
)-hydrazinoalanine
acid
ꢀ14.9 (c
or
d
b
a
25
Bocea-h(Bn)
D
-AlaeOH, 4a. Yield: 98%, yellow oil, [
a
]
b
g
D
1.00, MeOH); 1H NMR (300 MHz, CDCl3)
3H, J¼7.2 Hz, CH3 Ala), 3.66 (q, 1H, J¼7.2 Hz,
CH2, Na-Bn), 5.82 (br s, 1H, NH), 7.27e7.42 (m, 5H, Ar.), 9.65 (br s,
d
1.34 (s, 9H, Boc), 1.39 (d,
CH Ala), 3.97 (s, 2H,
a
b
a
NHBoc), 7.20e7.50 (m, 5H, Ar.), 8.14 (br s, 1H, NH hydrazidic). The
crude product was used in a next step without further purification.
1H, OH). The physical data (NMR and [
the values reported in Ref. 14. Measured: [
a]
D
25) are in agreement with
a
]
25 ꢀ21.7 (c 1.14, MeOH),
4.4. Representative procedure for the preparation
of compounds 5a and 5b
D
25
literature : [
a]
þ22.8 (c 1.14, MeOH) ((S)-isomer).
D
4.3.2. (R)-(ꢀ)-Na-Benzyl-Nb-Boc-(
D
)-hydrazinoleucine
acid
ꢀ16.9 (c
or
To a solution of Boc-acid 4a or 4b (1.0 equiv, 22 mmol) in MeOH
(50 mL) was added SOCl2 (2.1 equiv, 46.2 mmol) dropwise at 0 ꢁC
and the mixture was stirred for 48 h at room temperature until
completion (monitored by TLC). Evaporation of MeOH in vacuo
gives the corresponding chlorhydrate ester 5a or 5b as a white
amorphous solid in 99% yield. Compounds 5a and 5b were engaged
immediately in the next step.
25
Bocea-h(Bn)D-LeueOH, 4b. Yield: 96%, yellow oil, [a]
D
1.00, MeOH); IR (ATR) nmax/cmꢀ1: 3358, 3089, 3066, 3032, 2959,
2936, 2902, 2872, 1767, 1750, 1740, 1723, 1711, 1681, 1496, 1483,
1471, 1452, 1441, 1410, 1395, 1368, 1273, 1252, 1162; 1H NMR
(300 MHz, CDCl3)
CH3 Leu), 1.36 (s, 9H, Boc), 1.36e1.52 (m, 1H,
(m, 1H, CH2 Leu), 2.08 (br s, 1H, CH Leu), 3.45e3.55 (m, 1H,
Leu), 3.95e4.16 (m, 2H, CH2, Na-Bn), 6.54 (br s, 1H, NH), 7.26e7.41
(m, 5H, Ar.), 9.62 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3)
22.1
CH3 Leu), 28.8 (3CH3, Boc), 39.5
CH2 Leu), 61.8 (CH2, Na-Bn), 63.4 (
CH Leu), 81.0 (C, Boc), 128.2
d
0.78 (br s, 3H,
d
CH3 Leu), 0.92 (d, 3H, J¼6.0 Hz,
CH2 Leu), 1.68e1.77
CH
d
b
b
g
a
4.5. Representative procedure for the N-terminal
deprotection with TFA
d
(gCH Leu), 24.1 (dCH3 Leu), 25.0 (d
(b
a
Boc-ester compound (1.0 equiv, 9 mmol) was treated with
a mixture of CH2Cl2/TFA (9 mL/6 mL) and stirred for 3 h at room
(CH, Ar.), 128.9 (2CH, Ar.), 130.1 (CH, Ar.), 130.4 (CH, Ar.), 137.9 (C,

4690
R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
temperature. Excess of TFA was co-evaporated with MeOH and Et2O
until to obtain the corresponding trifluoroacetate salt compound as
a white amorphous solid in quantitative yield. Compounds 8a, 8b,
12a, 12b, and 80a were engaged immediately in the next step.
Boc), 1.50e1.73 (m, 6H, 2
b
CH2 Leu, 2
g
CH Leu), 3.51 (q, 1H, J¼7.2 Hz,
CH Ala), 3.71 (s, 3H, OCH3),
CH Leu), 3.91e4.28 (m, 5H, 2CH2, Na-Bn,
CH
a
CH Ala), 3.68 (q, 1H, J¼7.2 Hz,
a
3.69e3.88 (m, 1H,
a
a
Leu), 5.54 (br d, 1H, J¼7.5 Hz, NHBoc), 7.22e7.48 (m, 10H, Ar.), 7.83
(s, 1H, NH), 7.91 (br s, 1H, NH), 8.34 (br d, 1H, J¼7.5 Hz, NH); 13C
4.6. Representative procedure for the coupling reaction with
HATU/NMM
NMR (75 MHz, CDCl3)
Leu), 23.3 (
Leu), 29.0 (3CH3, Boc), 40.6 (
Ala), 52.5 ( CH Ala), 52.9 (OeCH3), 60.7 (
Bn), 62.3 (CH2, Na-Bn), 62.9 (
CH Leu), 80.9 (C, Boc), 128.3 (CH, Ar.),
d
17.0 (2
CH3 Leu), 23.6 ( CH3 Leu), 25.1 (
CH2 Leu), 41.2 (
CH Leu), 60.8 (CH2, Na-
b
CH3 Ala), 22.2 (
g
CH Leu), 23.0 (
CH3 Leu), 25.6 (
CH2 Leu), 52.3 (
g
d
a
CH
CH3
CH
d
d
b
d
b
The appropriate trifluoroacetate or hydrochloride salt (1.0 equiv,
9 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0 ꢁC. This
solution was treated successively with NMM (4.0 equiv, 36 mmol),
a solution of the Boc-protected fragment (1.0 equiv, 9 mmol) in
CH2Cl2 (5 mL), and a solution of HATU (1.0 equiv, 9 mmol) in
a minimum amount of DMF. The mixture was allowed to warm to
room temperature and then stirred until TLC indicated complete
reaction. Subsequent addition of CH2Cl2 was followed by washing
with HCl 1 N (1ꢂ25 mL), saturated aqueous NaHCO3 solution
(1ꢂ25 mL), and saturated aqueous NaCl solution (2ꢂ25 mL). The
organic layer was dried over MgSO4 and concentrated under re-
duced pressure. The resulting crude material was purified and
characterized as reported below.
a
a
a
128.5 (CH, Ar.), 128.9 (2CH, Ar.), 129.1 (2CH, Ar.), 129.8 (2CH, Ar.),
130.1 (2CH, Ar.), 136.2 (C, Ar.), 137.2 (C, Ar.), 156.9 (C]O, Boc), 172.6
(C(NH)]O), 172.7 (C(NH)]O), 172.9 (C(NH)]O), 176.0 (C]O, es-
ter); HRMS (ESI) calculated for C38H58N6O7 [MþH]þ m/z 711.4445,
found 711.4440.
4.6.4. Boce(L-Ala-a-h(Bn)D-Leu)2eOMe tetramer, 9b. Purified by
flash chromatography (petroleum ether/AcOEt¼50:50), yield: 90%,
white powder: mp¼88 ꢁC; IR (ATR) nmax/cmꢀ1: 3354, 3265, 3061,
3033, 2960, 2932, 2869, 2850, 1732, 1726, 1717, 1696, 1685, 1671,
1655, 1554, 1537, 1519, 1507, 1498, 1470, 1458, 1382, 1369, 1324,
1270, 1249, 1205, 1167, 1118; 1H NMR of the major form (300 MHz,
4.6.1. Boce
L
-Leu-
a
-h(Bn)
D
-AlaeOMe dimer, 6a. Purified by flash
CDCl3)
d
0.73 (d, 3H, J¼6.6 Hz,
d
CH3 Leu), 0.84 (d, 3H, J¼6.6 Hz,
d
d
b
CH3
CH3
CH3
chromatography (petroleum ether/AcOEt¼70:30), yield: 96%,
white powder: mp¼112 ꢁC; IR (ATR) nmax/cmꢀ1: 3322, 3217, 3072,
3037, 2983, 2958, 2938, 2873, 2853, 1754, 1738, 1707, 1681, 1671,
1612, 1558, 1523, 1501, 1457, 1439, 1392, 1368,1319,1297,1271, 1247,
Leu), 0.88 (d, 3H, J¼6.6 Hz,
Leu), 1.14 (d, 3H, J¼7.2 Hz,
d
CH3 Leu), 0.92 (d, 3H, J¼6.6 Hz,
b
CH3 Ala), 1.34 (d, 3H, J¼7.2 Hz,
Ala), 1.42 (s, 9H, Boc), 1.51e2.03 (m, 6H, 2bCH2 Leu, 2gCH Leu),
3.35e3.64 (m, 2H, 2
(s, 3H, OCH3), 4.09 (q, 1H, J¼7.2 Hz,
CH Ala), 5.09 (br d, 1H, J¼6.6 Hz, NHBoc), 7.15e7.48 (m, 10H, Ar.),
7.68 (br s, 1H, NH), 8.01 (s, 1H, NH), 8.49 (br s (1H, NH); 13C NMR of
the major form (75 MHz, CDCl3) 19.0 ( CH3 Ala), 19.5 ( CH3 Ala),
CH Leu), 23.4 ( CH3 Leu), 23.6 ( CH3 Leu),
CH3 Leu), 28.9 (3CH3, Boc), 38.0 ( CH2 Leu),
CH Ala), 50.1 ( CH Ala), 52.3 (OeCH3), 61.1
(CH2, Na-Bn), 61.4 (CH2, Na-Bn), 62.5 (
CH Leu), 65.4 ( CH Leu), 80.7
a
CH Leu), 3.64e4.06 (m, 4H, 2CH2, Na-Bn), 3.71
CH Ala), 4.32 (q, 1H, J¼7.2 Hz,
1198, 1172, 1125; 1H NMR (300 MHz, CDCl3)
CH3 Leu), 1.38 (d, 3H, J¼7.2 Hz,
1.46e1.79 (m, 3H, CH2 Leu, CH Leu), 3.63e3.78 (m, 1H,
3.73 (s, 3H, OCH3), 3.88e4.09 (m, 3H, CH2, Na-Bn,
CH Leu), 4.77 (br
d, J¼6.0 Hz, NHBoc), 7.23e7.43 (m, 5H, Ar.), 7.98 (s, 1H, NH hydra-
zidic); 13C NMR (75 MHz, CDCl3)
17.0 ( CH3 Ala), 22.3 ( CH Leu),
23.4 ( CH3 Leu), 25.4 ( CH3 Leu), 29.0 (3CH3, Boc), 41.9 ( CH2 Leu),
48.2 ( CH Ala), 52.3 (OeCH3), 60.7 (
CH Leu), 60.8 (CH2, Na-Bn),
d
0.86 (d, 6H, J¼6.6 Hz,
CH3 Ala), 1.43 (s, 9H, Boc),
CH Ala),
a
2
d
b
a
b
g
a
a
d
b
b
22.1 (
24.8 (
40.0 (
g
d
b
CH Leu), 22.9 (
CH3 Leu), 25.7 (
CH2 Leu), 48.9 (
g
d
a
d
d
d
b
g
b
d
a
d
b
a
a
a
a
80.6 (C, Boc), 128.3 (CH, Ar.), 129.0 (2CH, Ar.), 130.0 (2CH, Ar.), 137.0
(C, Ar.), 156.0 (C]O, Boc), 171.8 (C]O, ), 175.3 (C]O, ester); HRMS
(ESI) calculated for C22H35N3O5 [MþH]þ m/z 422.2655, found
422.2649.
(C, Boc), 127.8 (CH, Ar.), 128.4 (CH, Ar.), 128.8 (2CH, Ar.), 129.0 (2CH,
Ar.), 129.3 (2CH, Ar.), 130.1 (2CH, Ar.), 136.8 (C, Ar.), 137.9 (C, Ar.),
156.6 (C]O, Boc), 171.8 (C(NH)]O), 172.2 (C(NH)]O), 172.8
(C(NH)]O), 176.0 (C]O, ester); HRMS (ESI) calculated for
C38H58N6O7 [MþH]þ m/z 711.4445, found 711.4140.
4.6.2. BoceL-Ala-a-h(Bn)D-LeueOMe dimer, 6b. Purified by flash
chromatography (petroleum ether/AcOEt¼80:20), yield: 94%, white
powder: mp¼68 ꢁC; IR (ATR) nmax/cmꢀ1: 3338, 3280, 3068, 3031,
2977, 2963, 2939, 2909, 2869, 1704, 1688, 1509, 1500, 1456, 1394,
4.6.5. Boce(L-Leu-a-h(Bn)D-Ala)3eOMe hexamer, 11a. Purified by
flash chromatography (petroleum ether/AcOEt¼30:70), yield: 83%,
white powder: mp¼184 ꢁC; IR (ATR) nmax/cmꢀ1: 3332, 3286, 3065,
3033, 2958, 2936, 2876, 2853, 1740, 1722, 1704, 1684, 1665, 1534,
1513, 1495, 1470, 1459, 1382, 1370, 1299, 1275, 1254, 1236, 1216,
1170, 1129; 1H NMR of the major form (300 MHz, CDCl3)
1371,1289,1249,1205,1165; 1H NMR (300 MHz, CDCl3)
d
0.72 (d, 3H,
CH3 Leu), 1.24 (d, 3H,
CH3 Ala), 1.44 (s, 9H, Boc), 1.60e1.73 (m, 2H, CH2 Leu),
CH Leu), 3.45e3.54 (m,1H, CH Leu), 3.72 (s, 3H,
CH Ala), 4.98 (br s, NHBoc),
7.23e7.45 (m, 5H, Ar.), 8.08 (br s, 1H, NH hydrazidic); 13C NMR
(75 MHz, CDCl3) 19.5 ( CH3 Ala), 21.9 ( CH Leu), 23.7 ( CH3 Leu),
24.7 ( CH3 Leu), 29.0 (3CH3, Boc), 39.9 ( CH2 Leu), 49.9 ( CH Ala),
52.2 (OeCH3), 61.2 (CH2, Na-Bn), 62.5 (
CH Leu), 80.4 (C, Boc), 128.3
J¼6.0 Hz,
d
b
CH3 Leu), 0.86 (d, 3H, J¼6.0 Hz,
d
J¼7.2 Hz,
b
1.88e2.03 (m,1H,
g
a
d
0.61e0.99 (m, 18H, 6
(s, 9H, Boc), 1.37e1.74 (m, 9H, 3
3H, 3
CH Leu), 3.71 (s, 3H, OCH3), 3.82e4.47 (m, 9H, 3CH2, Na-Bn,
CH Ala), 5.27 (br d, 1H, J¼6.3 Hz, NHBoc), 7.18e7.48 (m, 15H, Ar.),
7.72e8.39 (m, 4H, 4NH), 8.75 (br s, 1H, NH); 13C NMR of the major
d
CH3 Leu), 1.25e1.38 (3, 9H, 3
bCH3 Ala), 1.40
OCH3), 3.85e4.12 (m, 3H, CH2, Na-Bn,
a
b
CH2 Leu, 3 CH Leu), 3.45e3.79 (m,
g
a
d
b
g
d
3a
d
b
a
a
form (75 MHz, CDCl3)
d
17.0 (3
CH3 Leu), 24.9 (2
CH3 Leu), 29.0 (3CH3, Boc), 40.3 (
CH2 Leu), 52.4 (OeCH3), 52.6 ( CH Ala), 52.8 (
CH Leu), 62.3 (a
b
CH3 Ala), 23.1 (3
CH3 Leu), 25.5 (
CH2 Leu), 40.4 (
CH Ala), 53.3 (
CH Leu), 62.5 (CH2,
g
CH Leu), 23.4
(CH, Ar.),128.9 (2CH, Ar.), 130.0 (2CH, Ar.),137.0 (C, Ar.), 155.8 (C]O,
Boc), 171.5 (C]O, hydrazidic), 175.5 (C]O, ester); HRMS (ESI) cal-
culated for C22H35N3O5 [MþNa]þ m/z 444.2475, found 444.2469.
(
(
(
d
d
b
CH3 Leu), 23.7 (
d
d
b
dCH3 Leu), 25.6
b
CH2 Leu), 41.2
CH
a
a
a
Ala), 60.0 (CH2, Na-Bn), 60.7 (2
a
4.6.3. Boce(
L
-Leu-
a
-h(Bn)
D
-Ala)2eOMe tetramer, 9a. Purified by
Na-Bn), 63.5 (CH2, Na-Bn), 80.7 (C, Boc), 127.8 (CH, Ar.), 128.1 (CH,
Ar.), 128.8 (2CH, Ar.), 129.0 (3CH, Ar.), 129.6 (6CH, Ar.), 129.8 (2CH,
Ar.), 136.3 (C, Ar.), 137.4 (C, Ar.), 138.1 (C, Ar.), 157.1 (C]O, Boc), 172.0
(C(NH)]O), 172.1 (C(NH)]O), 172.4 (C(NH)]O), 172.5 (C(NH)]O),
172.8 (C(NH)]O), 175.5 (C]O, ester); HRMS (ESI) calculated for
C54H81N9O9 [MþH]þ m/z 1000.6235, found 1000.6230.
flash chromatography (petroleum ether/AcOEt¼20:80), yield: 87%,
white powder: mp¼125 ꢁC; IR (ATR) nmax/cmꢀ1: 3352, 3247, 3066,
3033, 2958, 2940, 2871, 1740, 1729, 1723, 1711, 1691, 1680, 1674,
1657,1561, 1513,1499, 1467, 1457, 1388, 1368, 1321, 1293, 1253, 1214,
1168, 1125; 1H NMR of the major form (300 MHz, CDCl3)
d
0.81 (d,
CH3 Leu), 0.85 (d,
CH3 Leu), 1.29 (d,
bCH3 Ala), 1.41 (s, 9H,
3H, J¼6.6 Hz,
3H, J¼6.6 Hz,
3H, J¼7.2 Hz,
d
CH3 Leu), 0.83 (d, 3H, J¼6.6 Hz,
CH3 Leu), 0.90 (d, 3H, J¼6.6 Hz,
CH3 Ala), 1.34 (d, 3H, J¼7.2 Hz,
d
d
d
b
4.6.6. Boce(L-Ala-a-h(Bn)D-Leu)3eOMe hexamer, 11b. Purified by
flash chromatography (petroleum ether/AcOEt¼30:70), yield: 82%,

R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
4691
white powder: mp¼102 ꢁC; IR (ATR) nmax/cmꢀ1: 3333, 3244, 3061,
3031, 2953, 2930, 2920, 2869, 2848, 1734, 1717, 1697, 1685, 1671,
1655, 1554, 1528, 1495, 1465, 1456, 1385, 1364, 1320, 1268, 1247,
1209, 1167; 1H NMR of the major form (300 MHz, CDCl3)
(2CH, Ar.), 128.6 (9CH,Ar.), 129.0 (2CH, Ar.), 129.1 (2CH, Ar.), 129.4
(2CH, Ar.), 130.2 (2CH, Ar.), 136.8 (C, Ar.), 138.5 (2C, Ar.), 138.9 (C,
Ar.), 156.8 (C]O, Boc), 171.4 (C(NH)]O), 171.8 (2C(NH)]O), 171.9
(2C(NH)]O), 173.6 (C(NH)]O), 173.9 (C(NH)]O), 175.9 (C]O,
ester); HRMS (ESI) calculated for C70H104N12O11 [MþNa]þ m/z
1311.7846, found 1311.7840.
d
0.70e1.48 (m, 27H, 6
1.51e2.08 (m, 9H, 3 CH2 Leu, 3
Leu), 3.62e4.42 (m, 9H, 3CH2, Na-Bn, 3
d
CH3 Leu, 3
CH Leu), 3.23e3.61 (m, 3H, 3
CH Ala), 3.72 (s, 3H, OCH3),
b
CH3 Ala), 1.39 (s, 9H, Boc),
b
g
a
CH
a
4.84 (br d, 1H, J¼5.7 Hz, NHBoc), 7.11e7.41 (m, 15H, Ar.), 8.02 (br s,
4.6.9. BoceD-Leu-a-h(Bn)D
-AlaeOMe dimer, 60a. Purified by flash
1H, NH), 8.09 (br s, 1H, NH), 8.14 (s, 1H, NH), 8.45 (s, 1H, NH), 9.10
chromatography (petroleum ether/AcOEt¼70:30), yield: 80%,
white powder: mp¼83 ꢁC; IR (ATR) nmax/cmꢀ1: 3438, 3348, 3312,
3089, 3065, 2983, 2958, 2938, 2873, 2853, 1732, 1702, 1657, 1507,
1497, 1457, 1439, 1392, 1369, 1318, 1291, 1261, 1251, 1165; 1H NMR
(br s, 1H, NH); 13C NMR of the major form (75 MHz, CDCl3)
d
17.1
(
(
(
(
(
(
b
g
CH3 Ala), 17.8 (
b
CH3 Ala), 18.0 (
CH Leu), 23.7 (2
CH3 Leu), 29.0 (3CH3, Boc), 37.7 (
CH2 Leu), 50.5 ( CH Ala), 50.6 (
CH Ala), 52.4 (OeCH3), 60.8 (CH2, Na-Bn), 61.5 (2CH2, Na-Bn), 62.2
CH Leu), 66.2 ( CH Leu), 66.6 ( CH Leu), 80.9 (C, Boc), 127.4 (CH,
b
CH3 Ala), 22.1 (
gCH Leu), 23.1
CH3 Leu), 26.0
CH2 Leu), 39.5
CH Leu), 23.4 (
g
dCH3 Leu), 24.9 (2
d
b
dCH3 Leu), 26.2 (
d
(300 MHz, CDCl3)
J¼6.0 Hz, CH3 Leu), 1.16e1.50 (m, 5H,
9H, Boc), 1.54e1.63 (m, 1H, CH Leu), 3.64e3.80 (m, 1H,
d
0.78 (d, 3H, J¼6.0 Hz,
d
CH3 Leu), 0.79 (d, 3H,
CH2 Leu), 1.40 (s,
CH Ala),
b
a
a
CH2 Leu), 40.1 (
b
a
a
CH Ala), 51.1
d
b
CH3 Ala,
b
g
a
a
a
3.74 (s, 3H, OCH3), 3.81e3.92 (m, 1H, aCH Leu), 3.93e4.07 (m, 2H,
Ar.), 127.5 (CH, Ar.), 128.8 (4CH, Ar.), 129.1 (4CH, Ar.), 129.3 (2CH,
Ar.), 130.0 (CH, Ar.), 130.2 (2CH, Ar.), 136.8 (C, Ar.), 138.4 (C, Ar.),
138.7 (C, Ar.),156.8 (C]O, Boc),171.9 (C(NH)]O),172.0 (C(NH)]O),
172.8 (C(NH)]O), 173.4 (C(NH)]O), 174.4 (C(NH)]O), 175.9 (C]O,
ester); HRMS (ESI) calculated for C54H81N9O9 [MþNa]þ m/z
1022.6055, found 1022.6049.
CH2, Na-Bn), 4.82 (br d, J¼7.2 Hz, NHBoc), 7.19e7.43 (m, 5H, Ar.),
7.77 (br s, 1H, NH hydrazidic); 13C NMR (75 MHz, CDCl3)
d
16.8
CH3 Leu), 28.9
CH Ala), 52.3 (OeCH3), 61.0
CH Leu), 80.4 (C, Boc), 128.3 (CH, Ar.), 128.9
(
b
CH3 Ala), 22.9 (
(3CH3, Boc), 41.8 (
(CH2, Na-Bn), 61.3 (
g
CH Leu), 23.3 (dCH3 Leu), 25.1 (d
b
CH2 Leu), 48.3 (
a
a
(2CH, Ar.), 129.9 (2CH, Ar.), 137.1 (C, Ar.), 156.2 (C]O, Boc), 172 (C]
O, hydrazidic), 175.1 (C]O, ester); HRMS (ESI) calculated for
C22H35N3O5 [MþH]þ m/z 422.2655, found 422.2649.
4.6.7. Boce(L-Leu-a-h(Bn)D-Ala)4eOMe octamer, 13a. Purified by
flash chromatography (petroleum ether/AcOEt¼50:50), yield: 77%,
white powder: mp¼190 ꢁC; IR (ATR) nmax/cmꢀ1: 3334, 3278, 3233,
3088, 3068, 3031, 2958, 2940, 2871, 1735, 1722, 1702, 1683, 1665,
1651, 1534, 1515, 1495, 1457, 1384, 1366, 1297, 1279, 1255, 1243,
1216, 1170, 1125; 1H NMR of the major form (300 MHz, CDCl3)
4.6.10. Boce(D-Leu-a-h(Bn)D
-Ala)2eOMe tetramer, 90a. Purified by
flash chromatography (petroleum ether/AcOEt¼20:80), yield: 75%,
white powder: mp¼143 ꢁC; IR (ATR) nmax/cmꢀ1: 3440, 3348, 3311,
3234, 3089, 3065, 2961, 2937, 2872, 2855, 1740, 1728, 1697, 1660,
1655, 1548, 1551, 1520, 1498, 1470, 1457, 1438, 1391, 1369, 1318,
1293, 1259, 1162; 1H NMR of the major form (300 MHz, CDCl3)
d
0.66e1.01 (m, 24H, 8
1.40 (s, 9H, Boc), 1.45e1.82 (m, 12H, 4
3.42e3.79 (m, 4H, 4 CH Leu), 3.71 (s, 3H, OCH3), 3.81e4.35 (m, 12H,
4CH2, Na-Bn, 4
CH Ala), 5.29 (m, 1H, NHBoc), 7.08e7.49 (m, 20H,
Ar.), 7.50e9.27 (m, 7H, 7NH); 13C NMR of the major form (75 MHz,
CDCl3) 17.1 (4 CH3 Ala), 23.1 (2 CH Leu), 23.2 (2 CH Leu), 23.7
CH3 Leu), 24.9 (3 CH3 Leu), 25.5 (2 CH3 Leu), 29.0 (3CH3, Boc),
40.2 ( CH2 Leu), 40.4 ( CH2 Leu), 41.0 ( CH2 Leu), 41.7 ( CH2 Leu),
51.7 (OeCH3), 52.5 ( CH Ala), 52.8 ( CH Ala), 53.3 ( CH Ala), 53.5
CH Leu), 60.6 (CH2, Na-Bn), 60.8 (CH2, Na-Bn), 61.0
CH Leu), 62.3 (CH2, Na-Bn), 62.4 (CH2, Na-Bn), 62.6 (
CH Leu), 63.5
CH Leu), 80.7 (C, Boc), 128.3 (CH, Ar.), 128.5 (CH, Ar.), 128.6 (CH
d
CH3 Leu), 1.18e1.38 (m, 12H, 4
b
CH3 Ala),
b
CH2 Leu, 4
gCH Leu),
a
d
0.67e0.91 (m, 12H, 4
CH2 Leu, 2 CH Leu), 1.40 (s, 9H, Boc), 3.43e3.62 (m, 1H,
CH Ala, CH2, Na-Bn), 3.74 (s, 3H, OCH3),
CH Leu), 4.12e4.27 (m, 1H, CH
d
CH3 Leu), 1.13e1.49 (m, 12H, 2
b
CH3 Ala,
a
2
b
g
aCH Ala),
3.65e3.90 (m, 3H,
a
d
b
g
g
3.90e4.11 (m, 3H, CH2, Na-Bn,
a
a
(d
d
d
Leu), 4.82 (m, 1H, NHBoc), 7.08e7.47 (m, 10H, Ar.), 7.57 (br s, 1H,
b
b
b
b
NH), 7.75 (br s, 1H, NH), 8.30 (br s, 1H, NH); 13C NMR (75 MHz,
a
a
a
CDCl3)
Leu), 23.3 (
Leu), 29.0 (3CH3, Boc), 40.6 (
Ala), 52.4 (
CH Ala), 52.8 (OeCH3), 60.9 (CH2, Na-Bn), 61.1 (
Leu), 61.1 (CH2, Na-Bn), 64.7 (
d
17.2 (
b
CH3 Ala), 17.6 (
CH3 Leu), 24.8 (
CH2 Leu), 40.7 (
b
CH3 Ala), 22.4 (
CH3 Leu), 25.4 (
CH2 Leu), 52.3 (
g
CH Leu), 23.0 (
g
CH3
CH
(a
(a
(a
CH Ala), 59.8 (
a
dCH3 Leu), 23.4 (
d
b
d
d
a
b
aCH
a
a
CH
,Ar.), 128.8 (3CH, Ar.), 128.9 (4CH, Ar.), 129.4 (3CH, Ar.), 129.6 (3CH,
Ar.), 130.0 (2CH, Ar.), 130.1 (2CH, Ar.), 136.3 (C, Ar.), 137.3 (C, Ar.),
138.1 (C, Ar.), 138.7 (C, Ar.), 157.1 (C]O, Boc), 172.1 (4C(NH)]O),
172.5 (3C(NH)]O), 175.3 (C]O, ester); HRMS (ESI) calculated for
C70H104N12O11 [MþNa]þ m/z 1311.7846, found 1311.7840.
a
CH Leu), 80.6 (C, Boc), 128.2 (CH, Ar.),
128.3 (CH, Ar.), 128.8 (2CH, Ar.), 128.9 (2CH, Ar.), 129.8 (2CH, Ar.),
130.1 (2CH, Ar.), 137.1 (C, Ar.), 137.3 (C, Ar.), 156.6 (C]O, Boc), 172.4
(3C(NH)]O), 175.4 (C]O, ester); HRMS (ESI) calculated for
C38H58N6O7 [MþH]þ m/z 711.4445, found 711.4440.
4.6.8. Boce(
L
-Ala-
a
-h(Bn)
D
-Leu)4eOMe octamer, 13b. Purified by
4.7. Representative procedure for the amidation reaction
with NH4OH/MeOH
flash chromatography (petroleum ether/AcOEt¼50:50), yield: 79%,
white powder: mp¼116 ꢁC; IR (ATR) nmax/cmꢀ1: 3346, 3264, 3064,
3035, 2957, 2932, 2873, 1736, 1729, 1717, 1696, 1686, 1649, 1557,
1528, 1504, 1496, 1456, 1387, 1370, 1322, 1271, 1250, 1219, 1164,
Ammonium hydroxide (10 mL, 25% aq) was added to a stirred
solution of the appropriate oligomer ester (0.6 mmol) in MeOH
(10 mL). The reaction flask was capped with a rubber septum and
stirred vigorously at room temperature for 2 days. The reaction
mixture was then concentrated, neutralized with HCl 1 N until
pH¼7, extracted with AcOEt (3ꢂ20 mL), and evaporated in vacuo.
The resulting crude material was purified and characterized as
reported below.
1107; 1H NMR of the major form (300 MHz, CDCl3)
d
0.71e1.48 (m,
CH3 Ala), 1.39 (s, 9H, Boc), 1.52e2.02 (m, 12H,
CH Leu), 3.41e3.62 (m, 4H, 4 CH Leu), 3.66e4.44 (m,
12H, 4CH2, Na-Bn, 4
CH Ala), 3.72 (s, 3H, OCH3), 4.81 (br d, 1H,
36H, 8
dCH3 Leu, 4b
4
bCH2 Leu, 4
g
a
a
J¼6.0 Hz, NHBoc), 7.12e7.51 (m, 20H, Ar.), 8.10 (br s, 2H, 2NH), 8.42
(br s, 2H, 2NH), 8.68 (br s, 1H, NH), 8.82 (s, 1H, NH), 9.23 (s, 1H, NH);
13C NMR of the major form (75 MHz, CDCl3)
d
16.8 (
CH3 Ala), 22.2 (
CH3 Leu), 23.7 (
CH3 Leu), 26.5 (
CH2 Leu), 50.6 (2
CH Ala), 52.4 (OeCH3), 54.0 (CH2, Na-Bn), 54.2
(CH2, Na-Bn), 61.2 (CH2, Na-Bn), 61.5 (CH2, Na-Bn), 62.2 (
CH Leu),
66.3 ( CH Leu), 66.6 (3 CH Leu), 81.0 (C, Boc), 127.3 (CH, Ar.), 127.5
bCH3 Ala), 17.2
(
(
(
b
g
CH3 Ala), 17.7 (
CH Leu), 23.4 (2
b
g
d
CH3 Ala), 17.8 (
CH Leu), 23.6 (3
CH3 Leu), 26.3 (
CH2 Leu), 40.2 (
b
g
CH Leu), 23.2
4.7.1. BoceL-Leu-a-h(Bn)D-AlaeNH2, 14a. The residue was purified
d
dCH3 Leu), 24.9
by flash chromatography (petroleum ether/AcOEt¼30:70) to afford
dCH3 Leu), 26.0 (
d
dCH3 Leu), 28.9
14a (0.23 g, 95%) as a white powder: mp¼150 ꢁC; IR (ATR) nmax
/
(3CH3, Boc), 37.6 (3
CH Ala), 51.6 (
b
b
a
CH Ala), 51.4
cmꢀ1: 3481, 3438, 3346, 3312, 3034, 3009, 2960, 2932, 2902, 2871,
2841, 1730, 1725, 1704, 1687, 1662, 1656, 1602, 1505, 1498, 1457,
1436, 1391, 1370, 1291, 1262, 1166, 1123; 1H NMR (300 MHz, CDCl3/
(a
a
a
a
a
10 mM)
d
0.77 (d, 3H, J¼6.5 Hz, CH3 Leu), 0.80 (d, 3H, J¼6.5 Hz,
d

4692
R.-O. Moussodia et al. / Tetrahedron 68 (2012) 4682e4692
d
CH3 Leu), 1.35 (d, 3H, J¼7.1 Hz,
b
CH3 Ala), 1.45 (s, 9H, Boc),
CH Leu), 3.51 (q, 1H, J¼7.1 Hz, CH
CH Leu), 4.69 (br d, 1H,
J¼7.5 Hz, NHBoc), 5.32 (s, 1H, NH2), 7.26e7.38 (m, 6H, Ar., NH
hydrazidic), 8.06 (br s, 1H, NH2); 13C NMR (75 MHz, CDCl3)
22.9
CH3 Leu), 29.0 (3CH3, Boc), 40.5
CH Ala), 61.7 (CH2, Na-Bn), 62.9 (
CH Leu), 81.3
7.14e7.45 (m, 10H, Ar.), 7.58 (br s, 1H, NH hydrazidic), 7.73 (br s, 1H,
NH hydrazidic), 7.91 (br s, 1H, NH2), 8.14 (br s, 1H, NH amidic); 13
NMR (75 MHz, CDCl3) 22.9 ( CH Leu), 23.0 ( CH Leu), 23.1 (2 CH3
Ala), 25.0 (2 CH3 Leu), 25.4 (2 CH3 Leu), 29.0 (3CH3, Boc), 39.8
CH2 Leu), 40.6 ( CH2 Leu), 51.8 ( CH Ala), 52.5 ( CH Ala), 60.9
(CH2, Na-Bn), 61.0 (CH2, Na-Bn), 62.1 (
CH Leu), 63.4 ( CH Leu), 81.1
(C, Boc), 128.5 (2CH, Ar.), 129.1 (4CH, Ar.), 129.8 (2CH, Ar.), 129.9
(2CH, Ar.), 136.5 (C, Ar.), 136.6 (C, Ar.), 156.6 (C]O, Boc), 172.7
(2C(NH)]O), 173.3 (C(NH)]O), 176.2 (C]O, amide); HRMS (ESI)
calculated for C37H57N7O6 [MþNa]þ m/z 718.4268, found 718.4263.
1.40e1.62 (m, 3H,
b
CH2 Leu,
g
a
C
Ala), 3.79e4.03 (m, 3H, CH2, Na-Bn,
a
d
g
g
b
d
d
d
(b
b
a
a
a
(g
CH Leu), 23.2 (
b
CH3 Ala), 25.1 (2
d
a
(b
CH2 Leu), 52.2 (
a
a
(C, Boc), 128.7 (CH, Ar.), 129.9 (2CH, Ar.), 130.8 (2CH, Ar.), 136.4 (C,
Ar.), 156.5 (C]O, Boc), 172.6 (C]O, hydrazidic), 176.2 (C]O, am-
ide); HRMS (ESI) calculated for C21H34N4O4 [MþNa]þ m/z 429.2478,
found 429.2472.
Acknowledgements
4.7.2. Boce(L-Leu-a-h(Bn)D-Ala)2eNH2, 15a. The residue was puri-
fied by flash chromatography (AcOEt/MeOH¼95:5) to afford 15a
ꢁ
(0.26 g, 63%) as a white powder: mp¼162 ꢁC; IR (ATR) nmax/cmꢀ1
:
This work was supported by the ‘Ministere de l’Enseignement
ꢀ
Superieur et de la Recherche’ with a Doctoral fellowship for R.-O.M.,
the ‘Conseil Regional de Lorraine’ and the ‘Institut National Poly-
technique de Lorraine’ with a Postdoctoral fellowship for Dr. A.B.
3482, 3446, 3435, 3400, 3350, 3339, 3308, 3290, 3090, 3064, 2965,
2939, 2871, 2851, 1734, 1717, 1697, 1685, 1672, 1655, 1607, 1540,
1496, 1470, 1455, 1391, 1321, 1292, 1260, 1166, 1107; 1H NMR
ꢀ
(300 MHz, CDCl3/10 mM)
1.29e1.80 (m, 12H, 2 CH3 Ala, 2
Boc), 3.40e3.60 (m, 2H, 2
CH Ala), 3.80e4.05 (m, 5H, 2CH2, Na-Bn,
CH Leu), 4.06e4.20 (m, 1H, CH Leu), 5.39 (br s, 1H, NH2), 5.78 (br
d
0.69e0.91 (m, 12H,
4dCH3 Leu),
b
b
CH2 Leu, 2 CH Leu), 1.44 (s, 9H,
g
Supplementary data
a
a
a
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.04.018.
d, 1H, J¼7.2 Hz, NHBoc), 7.20e7.47 (m, 10H, Ar.), 7.95 (br s, 2H, 2 NH
hydrazidic), 8.12 (br s, 1H, NH2), 8.57 (br d, 1H, J¼5.1 Hz, 1H, NH
amidic); 13C NMR (75 MHz, CDCl3)
d
22.4 (
CH3 Ala), 25.0 (2 CH3 Leu), 25.3 (2
29.0 (3CH3, Boc), 39.8 (2 CH2 Leu), 51.5 ( CH Ala), 51.8 (
61.3 (2CH2, Na-Bn), 62.3 (2
CH Leu), 80.9 (C, Boc), 128.5 (CH, Ar.),
g
CH Leu), 22.7 (
g
CH Leu),
CH3 Leu),
aCH Ala),
References and notes
23.4 (
bCH3 Ala), 23.6 (
b
d
d
b
a
1. Gentilucci, L.; De Marco, R.; Cerisoli, L. Curr. Pharm. Des. 2010, 16, 3185e3203
and references cited herein.
a
128.6 (CH, Ar.), 129.1 (2CH, Ar.), 129.2 (2CH, Ar.), 129.7 (2CH, Ar.),
130.0 (2CH, Ar.), 136.8 (2C, Ar.), 157.4 (C]O, Boc), 172.8 (C(NH)]O),
173.0 (C(NH)]O), 174.0 (C(NH)]O), 176.6 (C]O, amide); HRMS
(ESI) calculated for C37H57N7O6 [MþNa]þ m/z 718.4268, found
718.4263.
2. Marraud, M.; Vanderesse, R. In HoubeneWeyl; Goodman, M., Ed.; Thieme:
Stuttgart, New York, NY, 2003; Vol. 86, pp 423e457.
3. Guy, L.; Vidal, J.; Collet, A. J. Med. Chem. 1998, 41, 4833e4843.
4. Lelais, G.; Seebach, D. Helv. Chim. Acta 2003, 86, 4152e4168.
€
5. (a) Mocquet, C.; Salaun, A.; Claudon, P.; Le Grel, B.; Potel, M.; Guichard, G.;
ꢀ
Jamart-Gregoire, B.; Le Grel, P. J. Am. Chem. Soc. 2009, 131, 14521e14525; (b)
€
Salaun, A.; Potel, M.; Roisnel, T.; Gall, P.; Le Grel, P. J. Org. Chem. 2005, 70,
6499e6502; (c) Busnel, O.; Bi, L.; Dali, H.; Cheguillaume, A.; Chevance, S.;
4.7.3. BoceD-Leu-a-h(Bn)D
-AlaeNH2, 140a. The residue was puri-
Bondon, A.; Muller, S.; Baudy-Floc’h, M. J. Org. Chem. 2005, 70, 10701e10708;
fied by trituration in Et2O to afford 140a (0.16 g, 65%) as a white
powder: mp¼177 ꢁC; IR (ATR) nmax/cmꢀ1: 3484, 3439, 3340, 3305,
3151, 3020, 2985, 2963, 2939, 2872, 2852, 1734, 1717, 1696, 1685,
1639, 1603, 1575, 1558, 1496, 1472, 1456, 1392, 1369, 1340, 1321,
€
(d) Gunther, R.; Hofmann, H.-J. J. Am. Chem. Soc. 2001, 123, 247e255; (e) Che-
€
guillaume, A.; Salaun, A.; Sinbandhit, S.; Potel, M.; Gall, P.; Baudy-Floc’h, M.; Le
Grel, P. J. Org. Chem. 2001, 66, 4923e4929.
€ €
6. (a) Martinek, T. A.; Fulop, F. Chem. Soc. Rev. 2012, 41, 687e702 and references
therein; (b) Guichard, G.; Huc, I. Chem. Commun. 2011, 5933e5941; (c) Claudon,
1291, 1261, 1243, 1165; 1H NMR (300 MHz, CDCl3/10 mM)
d
0.85 (d,
CH3 Ala), 1.44 (s,
CH Leu), 3.53e3.69 (m, 1H,
CH Ala), 3.79e4.15 (m, 3H, CH2, Na-Bn,
CH Leu), 4.70 (br d, 1H,
P.; Violette, A.; Lamour, K.; Decossas, M.; Fournel, S.; Heurtault, B.; Godet, J.;
ꢀ
Mely, Y.; Jamart-Gregoire, B.; Briand, J. P.; Duportail, G.; Monteil, H.; Guichard,
6H, J¼6.0 Hz, 2
d
CH3 Leu), 1.37 (d, 3H, J¼6.9 Hz,
b
G. Angew. Chem., Int. Ed. 2010, 49, 333e336; (d) Fernandes, C.; Faure, S.; Pereira,
E.; Thery, V.; Declerck, V.; Guillot, R.; Aitken, D. J. Org. Lett. 2010, 12,
9H, Boc), 1.39e1.54 (m, 3H,
b
CH2 Leu,
g
ꢀ
ꢀ
3606e3609; (e) Hetenyi, A.; Toth, G. K.; Somlai, C.; Vass, E.; Martinek, T. A.;
a
a
€ €
Fulop, F. Chem.dEur. J. 2009, 15, 10736e10741; (f) Horne, W. S.; Gellman, S. H.
J¼5.8 Hz, NHBoc), 5.39 (s, 1H, NH2), 7.22e7.44 (m, 5H, Ar.), 7.62 (br
Acc. Chem. Res. 2008, 41, 1399e1408 and references therein; (g) Hecht, S.; Huc, I.
Foldamers: Structure, Properties and Applications; Wiley-VCH: Weihneim, 2007;
(h) Violette, A.; Averlant-Petit, M.-C.; Semetey, V.; Hemmerlin, C.; Casimir, R.;
Graff, R.; Marraud, M.; Briand, J. P.; Rognan, D.; Guichard, G. J. Am. Chem. Soc.
2005, 127, 2156e2164.
s, 1H, NH hydrazidic), 7.99 (br s, 1H, NH2); 13C NMR (75 MHz, CDCl3)
d
22.9 (
g
CH Leu), 23.2 (
b
CH3 Ala), 25.1 (2
a
d
CH3 Leu), 29.0 (3CH3,
Boc), 40.7 (
b
CH2 Leu), 52.4 (
CH Ala), 61.0 (CH2, Na-Bn), 62.2 (
a
CH
Leu), 81.2 (C, Boc), 128.7 (CH, Ar.), 129.2 (2CH, Ar.), 129.9 (2CH, Ar.),
136.3 (C, Ar.), 156.5 (C]O, Boc), 172.7 (C]O, hydrazidic), 176.0 (C]
O, amide); HRMS (ESI) calculated for C21H34N4O4 [MþNa]þ m/z
429.2478, found 429.2472.
ꢀ
7. Acherar, S.; Jamart-Gregoire, B. Tetrahedron Lett. 2009, 50, 6377e6379.
8. Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 36, 1109e1115.
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9. Salaun, A.; Favre, A.; Le Grel, B.; Potel, M.; Le Grel, P. J. Org. Chem. 2006, 71,
150e158.
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10. (a) Le Grel, P.; Salaun, A.; Mocquet, C.; Le Grel, B.; Roisnel, T.; Potel, M. J. Org.
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ꢀ
Chem. 2011, 76, 8756e8767; (b) Salaun, A. Synthese et etude conformationnelle
des aza-b3-peptides et de leurs derives macrocycliques. Thesis (PhD). Univer-
sity of Rennes 1 (France), 2005.
4.7.4. Boce(D-Leu-a-h(Bn)D
-Ala)2eNH2, 150a. The residue was pu-
ꢀ
ꢀ
rified by trituration in Et2O to afford 150a (0.39 g, 93%) as a white
powder: mp¼185 ꢁC; IR (ATR) nmax/cmꢀ1: 3483, 3446, 3438, 3400,
3351, 3338, 3308, 3260, 3067, 3029, 3006, 2965, 2939, 2877, 2854,
1733, 1718, 1698, 1685, 1672, 1653, 1607, 1564, 1508, 1499, 1470,
1455, 1394, 1371, 1318, 1289, 1263, 1164; 1H NMR (300 MHz, CDCl3/
11. (a) Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428e1438; (b) Li, X.;
Yang, D. Chem. Commun. 2006, 3367e3379 and references therein; (c) Yang, D.;
Li, W.; Qu, J.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 13018e13019.
12. (a) Melendez, R. E.; Lubell, W. D. J. Am. Chem. Soc. 2004, 126, 6759e6764; (b)
Andre, F.; Marraud, M.; Tsouloufis, T.; Tzartos, S. J.; Boussard, G. J. Pept. Sci. 1997,
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5,030,724, 1991.
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1997, 3, 1691e1709.
10 mM)
Ala, 2 CH2 Leu, 2
Ala), 3.69e4.08 (m, 5H, 2CH2, Na-Bn,
CH Leu), 4.79 (br d, 1H, J¼7.5 Hz, NHBoc), 5.33 (s, 1H, NH2),
d
0.68e0.95 (m, 12H, 4
CH Leu),1.42 (s, 9H, Boc), 3.34e3.58 (m, 2H, 2
CH Leu), 4.08e4.23 (m, 1H,
d
CH3 Leu), 1.19e1.90 (m, 12H, 2
b
a
CH3
CH
b
g
a
a