Investigation of NH-π (Ph) interaction in the 1:1[α:α-N- amino]mers using 1H NMR and FTIR absorption spectroscopy

Article abstract of DOI:10.1016/j.tet.2012.02.070

¹H NMR and FTIR experiments performed on the 1:1[α:α-N-amino]mers series let us to point out a rare NH-π interaction between the carbamidic NH of the i residue and the phenyl group of a phenylalanine residue located at i+2.

Full text of DOI:10.1016/j.tet.2012.02.070

Tetrahedron 68 (2012) 4362e4367
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journal homepage: www.elsevier.com/locate/tet
Investigation of NHe
p
(Ph) interaction in the 1:1[
a
:
a-N-amino]mers using
1H NMR and FTIR absorption spectroscopy
*
ꢀ
ꢀ
Dautrey Sebastien, Bodiguel Jacques, Arrault Axelle, Jamart-Gregoire Brigitte
ꢀ
ꢀ
Laboratoire de Chimie-Physique Macromoleculaire, UMR CNRS-INPL 7568, Nancy-Universite, ENSIC, 1 rue Grandville, BP 20451, 54001 Nancy Cedex, France
a r t i c l e i n f o
a b s t r a c t
1H NMR and FTIR experiments performed on the 1:1[
a:
a-N-amino]mers series let us to point out a rare
Article history:
Received 30 September 2011
Received in revised form 23 February 2012
Accepted 27 February 2012
Available online 3 March 2012
NHe
p interaction between the carbamidic NH of the i residue and the phenyl group of a phenylalanine
residue located at iþ2.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-aminodipeptide
Oligomerization
NHe
p (Ph) interaction
1H NMR experiments
FTIR experiments
1. Introduction
solution and belong to the so-called foldamers family.10 In this
context, we have recently reported a method for obtaining het-
Hydrogen bonding plays a key role in the structure and the
function of proteins. For a long time, much research has concen-
trated interest on classical hydrogen bonds XeH/A in which both
X and A are very electronegative atoms (mainly N and O).
erogeneous oligomers (Fig. 1) alternating
a- and a-N-amino
aminoacids.11
P2
R1
P3
However, it has been shown that some non-conventional hy-
N
N
O
P1
P4
drogen bonds, in particular the variant N/OeH/
p (Aryl), can also
N
H
O
be found in structural biology.1 This kind of interaction was first
pointed out in bovine pancreatic trypsin inhibitor (BPTI)2 and in
hemoglobin protein proteineligand interactions.3
n
O
R2
Fig. 1. Structure of fully protected 1:1[a:a-N-amino]mers.
Since then, a great number of XeH/p hydrogen bonds in pro-
teins have been found to be involved in a wide variety of functions
such as secondary structure stabilization,4 drug recognition,5 DNA
recognition,6 enzymatic action,7 and interactions of structural wa-
ter molecules.8
The great variety of structures and functions displayed by bi-
ological molecules is remarkable and has inspired many chemists
who have focused their interest on the synthesis of artificial back-
bones, which provides a new basis for the design of useful mole-
cules.9 For example, many classes of oligomers have been designed
rationally in order to obtain molecules able to be structured in
solution thus to mimic biological compounds. This is the case for
2. Results and discussion
FTIR and NMR experiments on the N-aminomers 2a, 3a, and 4a
previously synthesized11 (Fig. 2) allowed us to point out an original
weak polar interaction between the carbamidic hydrogen and the
aromatic rings.
1a n = 1
O
O
O
Ph
N
N
2a n = 2
3a n = 3
4a n = 4
pseudopeptides like aliphatic b-, g- or d-peptides, which can fold in
Boc
CH2Ph
N
H
O
n
O
* Corresponding author. Tel.: þ33 3 83175279; fax: þ33 3 83 379977; e-mail
Fig. 2. Fully protected 1:1[
residues.
a:a-N-amino]mers incorporating phenylalanine and alanine
address: Brigitte.Jamart@ensic.inpl-nancy.fr (J.-G. Brigitte).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.070

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D. Sebastien et al. / Tetrahedron 68 (2012) 4362e4367
4363
This interaction was first detected by comparing 1H NMR spectra
N
-aminodipeptide 1a
free carbamidic NH
1,4
1,2
1,0
0,8
0,6
0,4
0,2
of N-aminodipeptide 1a and tetramer 2a in chlorinated solvent
(CDCl3). In these spectra, NH signals of the Boc-NH group are suffi-
ciently resolved and distinct from other signals to be assigned by
using the 2D NMR COSY sequence. The two sets of resonance ob-
served for the carbamidic proton suggest that compounds 1a and 2a
are present as two isomers. In fact, these isomers are the result of
a hindered rotation around one nitrogen-carbonyl bond allowing
thusto distinguishbetween Z and E forms. We and others had already
observed this phenomenonwhenpreparing hydrazides derivatives12
or amide containing compounds.13 The same phenomenon can also
be observed on compound 1b onwhich a 2D NMR ROESYexperiment
(Fig. S5, Supplementary data) was performed in order to fully assign
resonance signals.
Tetramer 2a
Hexamer 3a
Octamer 4a
carbamidic NH-
π
interaction
bonded amidic NH
Nevertheless, we can observe that the introduction of a second
N-aminoamide bond leads to an upfield shift for both Z and E
carbamidic protons (Fig. 3).
3500
3450
3400
Wavenumber cm-1
3350
3300
3250
Fig. 4. FTIR spectra of compounds 1a, 2a, 3a, and 4a (NH concentration of 0.002 M,
CH2Cl2) in the frequency domain corresponding to the NH stretching vibration.
compared to those of compound 1a (3425 cmꢀ1) confirmed the
existence of an interaction between the Boc-NH proton and an ar-
omatic ring.15
The weak NH stretch transition at 3425 cmꢀ1 in oligomers 2a,
3a, and 4a is due to the carbamidic NH group, which is not involved
in the NHe
p interaction. So a dynamic equilibrium exists in solu-
tion between a bonded Boc-NH form and a free Boc-NH form cor-
responding to oligomers 2a, 3a, and 4a. Considering the respective
intensities of the signals, the bonded form seems to be favored. It is
interesting to notice that only an average of these two forms is
observed in NMR.
The existence of the aforementioned NHep interaction was
definitively proven when we identified the aromatic ring involved.
In fact, several aromatic rings can potentially interact with the
carbamidic proton (five, for example, in tetramer 2a).
Fig. 3. 1H NMR spectra of compounds 1a and 2a (300 MHz, CDCl3).
The same shielding effect (Dd¼ꢀ0.8 ppm) was also observed for
the carbamidic protons of hexamer 3a and octamer 4a.
A conventional hydrogen bond NH/O (O]C) cannot yield these
results as this kind of interaction is known to lead to a downfield
shift of the NH proton.
We first evaluated the participation of the two phenyl rings
borne by the two side chains of tetramer 2a in this interaction.
Consequently three new tetramers 2bed, bearing a valine residue
replacing each phenylalanine, respectively, were synthesized by
using the same protocol as previously described11 and were ana-
lyzed in solution by 1H NMR and FTIR absorption spectroscopy. The
spectra were then compared to those recorded for tetramer 2a.
Tetramers 2bed were synthezised in solution using a conver-
gent Boc strategy (Scheme 1). They resulted from the coupling re-
action between the free N-terminal N-aminodipeptides 1a00 or 1b00,
obtained from N-aminodipeptides 1a or 1b treated by using acidic
conditions, on the free C-terminal compounds 1a0 or 1b0 obtained
by hydrogenolysis of N-aminodipeptides 1a or 1b.
On the contrary, this kind of anomalous shift has already been
reported in the literature and explained by a NH/p (Ar) interaction
between an aromatic ring and a closed NH proton. The delocalized
electrons of the aromatic ring change the local magnetic field of the
NH proton, thereby causing a shift called aromatic ring shift.14
In order to confirm the presence of this kind of interactions in
our compounds, we carried out FTIR absorption spectroscopy
analyses in CH2Cl2 and had a close look at the frequency domain
corresponding to the NH (Boc-NH) stretching vibration.
The comparison of the 1H NMR spectra shows no specific aro-
matic ring shift for the carbamidic proton of tetramers 2b and 2c.
On the contrary, the carbamidic proton of tetramer 2d presents an
upfield shift comparable to that observed for oligomer 2a. Fur-
thermore, the comparison of FTIR spectra in the frequency domain
corresponding to the NH (Boc-NH) stretching vibration shows one
band at 3395 cmꢀ1 only for compound 2d (Fig. 5). These spectro-
scopic results allows us to conclude that the observed aromatic ring
shift is due to the interaction between the Boc-NH proton and the
phenyl group located in the iþ2 residue.
A free NHCO group is expected to give an NH absorption supe-
rior to 3400 cmꢀ1. When involved in a classical hydrogen bond, this
absorption is shifted to lower frequencies between 3350 and
3250 cmꢀ1. In the case of an NH/
p
(Ar) interaction, the red shift is
smaller and leads to a signal located between 3400 and 3380 cmꢀ1
.
As presented in Fig. 4, oligomers 2a, 3a, and 4a exhibit a low
stretching band at ca. 3395 cmꢀ1 corresponding to the Boc-NH
vibrator and another very well visible band with the maximum at
ca. 3310 cmꢀ1 assigned to the NH stretching vibration of hydrogen-
bonded NeH amide protons. The variation of the NH chemical
shifts of 2a as a function of the concentration of DMSO-d6 con-
firmed that only amidic protons (Z and E) are involved in a hydro-
gen bond. (Dd¼0.5 ppm). On the contrary, the Dd of about 3 ppm
observed in the case of both carbamidic protons confirms that they
are not involved in a hydrogen bond Thus, the 30 cmꢀ1 red shift
observed for the Boc-NH vibrator in N-aminomers 2a, 3a, and 4a
The correlation observed in the ROESY spectrum of tetramer 2d
proves that the NHBoc group, of the i residue and the phenyl group,
of the iþ2 residue, are located close to one another. Indeed, the tert-
butyl group shows ROE cross-peaks to phenyl protons of the phe-
nylalanine residue (Fig. S22, Supplementary data).
We also demonstrated that the same kind of interaction can
also be observed in longer oligomers 3a and 4a. We performed

ꢀ
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D. Sebastien et al. / Tetrahedron 68 (2012) 4362e4367
NPht
3. Conclusion
R1
O
Boc
N
CH2Ph
N
H
O
These spectroscopic results demonstrated the presence of an
O
interaction between the carbamidic NH donor of residue i and the
phenyl group of residue iþ2.
1a R1 = CH2Ph
1b R1 = CH(CH3)2
It is important to note that such NH(i)eAr(iþ2) interactions are
very rare. Indeed, considering the NHeAr interaction investigated
by data mining14,16 in the Protein Data Bank17 (PDB), 7.10 and 2.08%
are, respectively, attributed to NH(i)eAr(iꢀ1) and NH(i)eAr(iꢀ2)
interactions. However, less than 0.1% are due to an NH(i)eAr(iþ2)
interaction.
H2, Pd/C
NPht
HCl (3M)/AcOEt
NPht
R1
O
R1
O
H
N
CH2Ph
Boc
N
H
N
H
O
N
H
O
O
O
1a' R1 = CH2Ph (quantitative yield)
1a" R1 = CH2Ph (quantitative yield)
Furthermore, as the global organization of the N-terminal ex-
1b' R1 = CH(CH3)2 (quantitative yield)
1b" R1 = CH(CH3)2 (quantitative yield)
tremity of each oligomer seems to be equivalent, the NH/
interaction appears to be an important secondary structural element
of 1:1[ -N-amino]mers series. Complementary studies are needed
in order to confirm that this NH/ (Ph) interaction supports a hy-
p (Ph)
a:a
(CFN)3, pyridine, CH2Cl2
p
NPht
R2
O
NPht
drogen-bond secondary structure. Taking into account that amidic
protons of oligomers 2a, 3a, and 4a are involved in a hydrogen bond,
complementaryNMR and FTIRexperiments, aimingatidentifyingthe
acceptor CO group, will be performed in solution.
R1
O
Boc
N
N
CH2Ph
N
H
N
H
O
O
O
2b R1 = CH(CH3)2; R2 = CH(CH3)2 (61 %)
2c R1 = CH2Ph; R2 = CH(CH3)2 (51 %)
2d R1 = CH(CH3)2; R2 = CH2Ph (51 %)
4. Experimental section
4.1. General
Scheme 1. Synthesis of tetramers 2bed from N-aminodipeptides 1a or 1b.
Pht¼phthaloyl group.
The starting materials were purchased from Aldrich, Acros
Organics, Merck, Fluka, Senn Chemicals, Novabiochem, etc. and used
without any purification. THF was dried and distilled over sodium
and benzophenone, dichloromethane over P2O5 or LiAlH4. The re-
actions were monitored by Thin Layer Chromatography (TLC) using
Kieselgel 60 with fluorescent indicator UV254 (purchased from Merck
or MachereyeNagel). Detection was performed by UV or phospho-
molybdic acid. Chromatographic columns were made using silica gel
Tetramer 2a
Tetramer 2b
Tetramer 2c
Tetramer 2d
carbamidic NH-π interaction
1,0
0,8
0,6
0,4
0,2
0,0
free carbamidic NH
60 (70e200
mm). Flash chromatography was performed on columns
of silica gel 60 (40e63
mm). All yields have been calculated from pure
isolated products. NMR spectra were recorded on a BRUKER AVANCE
spectrometer operating at 300 MHz, in deuterated chloroform
(CDCl3) or deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts
are given using tetramethylsilane (TMS) as an internal standard
(
d
¼0 ppm for TMS). Some NMR 1H and 13C spectra show peak
splitting due to the slow rotation around N-aminoamide bond. In-
frared spectra were recorded on a BRUKER TENSOR 27 spectrometer.
Electron spray ionization mass spectra (ESI-MS) were recorded on
a BRUKER MicroTof-Q HR spectrometer in the ‘Service commun de
3460
3440
3420
3400
3380
Wavenumber cm-1
ꢀ
ꢀ
Spectrometrie de Masse’, Faculte des Sciences et Technologies, Uni-
Fig. 5. FTIR spectra of tetramer 2a and tetramers 2bed (0.001 M, CH2Cl2) in the fre-
quency domain corresponding to the carbamidic NH stretching vibration.
ꢀ
ꢀ
ꢁ
versite Henri Poincare, Vandoeuvre-les-Nancy, France.
additional IR and 1H NMR experiments on octamer 4db
incorporating only one phenylalanine residue in the iþ2
position (Fig. 6). Compound 4db resulted from the coupling
reaction between the free N-terminal tetramer 2d0 obtained from
compound 2d, on the free C-terminal tetramer 2b00 obtained from
compound 2b.
4.2. Procedure for the Mitsunobu protocol
Under nitrogen atmosphere, diethyl azodicarboxylate (4.5 mmol)
was added portionwise at 0e5 ꢁC to a stirred solution of amino-
hydrazide Boc-Phe-NH-NPht or Boc-Val-NH-NPht (3.0 mmol), PPh3
(4.5 mmol), and benzyl (S)-(ꢀ)-lactate (3.6 mmol) in anhydrous THF
(50 mL). The resulting solutionwas stirred at room temperature until
completion (monitored by TLC) and concentrated under vacuum.
The residue was purified by column chromatography using mixture
EtOAc/petroleum ether as eluent for column chromatography.
NPht Ph
O
NPht
NPht
NPht
O
O
O
Boc
N
N
N
N
CH2Ph
N
H
N
N
H
N
H
O
O
O
O
H
O
4db
4.2.1. BocPhej[CON(Pht)](R)AlaOBn 1a. Formula: C32H33N3O7, Mo-
Fig. 6. Structure of octamer 4db.
lecular weight: 571 g molꢀ1, gum, 80%. Eluent for column chro-
matography: EtOAc/petroleum ether (20/80). IR (KBr) nmax/cmꢀ1
Oligomer 4db exhibits an intense absorption near 3390 cmꢀ1
(in CH2Cl2) and a resonance (in CDCl3) at 3.95 ppm (carbamidic
proton). These two characteristics are in agreement with the
3430 (NH), 1799, 1750, 1702 (C]O). 1H NMR (CDCl3):
d (ppm)
7.98e7.62 (m, 4H, HPht), 7.30e6.90 (m, 10H, Harom), 5.40 (q, 0.3H,
J¼6.9 Hz, CHCH3), 5.12e5.00 (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), 3.06e2.77 (m, 2H, CHCH2Ph),
aforementioned NH/p (Ph) interaction observed in oligomers 2a,
3a, 4a, and 2d.

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D. Sebastien et al. / Tetrahedron 68 (2012) 4362e4367
4365
1.26e1.03 (m, 12H, NHCOOC(CH3)3, and CHCH3). 13C NMR (CDCl3):
(ppm) 172.7 (CO), 170.0 (OCH2Ph), 166.0, 164.8 (COPht), 155.0
NHCOCH), 8.10e7.80 (m, 8H, HPht), 7.33e7.00 (m, 10H, Harom),
5.00e4.26 (m, 5H, 2ꢂ CHCH3, 2ꢂ CHCH2Ph and NHCOOC(CH3)3),
3.40e2.50 (m, 4H, 2ꢂ CHCH2Ph), 1.40e1.09 (m, 15H, COOC(CH3)3,
d
(NHCOOtBu), 136.9 (Carom), 136.1, 135.3 (CHPht), 130.2 (CPht), 129.8,
129.7, 129.5, 129.0, 128.7, 127.0 (CHarom), 124.8, 124.6, 124.5 (CHPht),
80.0 (CH3), 68.6, 67.8 (OCH2Ph), 57.0, 56.0 (CH3), 51.8 (CH), 38.8,
38.2 (CH2Ph), 28.5 (CH3), 14.6, 14.4 (CH3). HRMS (ESI) calculated for
C32H33N3NaO7 [MþNa]þ m/z 594.2211 found 594.2219.
and 2ꢂ CHCH3). 13C NMR (CDCl3):
d (ppm) 174.0,173.0 (COOH),172.0,
171.5 (CO and CONH), 167.2, 166.7, 166.0 (COPht), 155.3 (NHCOOtBu),
137.4, 137.1, 137.0, 136.3, 136.1, 135.9, 135.7, 135.5, 130.2, 130.0, 129.9,
129.6, 127.4, 127.3, 125.6, 125.3, 124.7 (Carom and CHarom), 80.8, 80.3
(C), 59.4, 58.4 (CHCH3), 52.1, 51.9, 50.5, 50.2 (CH), 38.3, 37.5 (CH2Ph),
28.8 (CH3), 15.2, 14.8, 14.3, 13.9 (CH3).
4.2.2. BocValj[CON(Pht)](R)AlaOBn 1b. Formula: C28H33N3O7, Mo-
lecular weight: 523 g molꢀ1, Colorless solid, 55%. Eluent for column
chromatography: EtOAc/petroleum ether (20/80). IR (2 mM in
CHCl3) nmax/cmꢀ1 3436 (NH), 1799, 1748, 1715, 1694 (C]O). 1H NMR
4.3.4. BocValj[CON(Pht)](R)Ala Phej
[CON(Pht)](R)AlaOH 2d0.
Formula: C41H44N6O11, Molecular weight: 796 g molꢀ1, Colorless
(CDCl3):
d
(ppm) 7.94e7.77 (m, 4H, HPht), 7.40e7.30 (m, 5H, Harom),
solid, w100%. IR (ATR) nmax/cmꢀ1 3308, 2990 (NH and COOH),
5.45 (q, 0.25H, J¼6.9 Hz, CHCH3), 5.30e5.12 (m, 2.75H, OCH2Ph,
CHCH3), 5.00 (d, 0.25H, J¼10.2 Hz, NH), 4.76 (d, 0.75H, J¼10.4 Hz,
NH), 4.53 (t, 0.25H, J¼8.7 Hz, CHCH(CH3)2), 3.95 (t, 0.75H, J¼9.0 Hz,
CHCH(CH3)2), 2.20e1.89 (m, 1H, CH(CH3)2), 1.50e1.23 (m, 12H,
C(CH3)3, and CHCH3), 0.90e0.73 (m, 6H, CH(CH3)2).13C NMR (CDCl3):
1800, 1742, 1695 (C]O). 1H NMR (CDCl3):
d (ppm) 8.47e8.27 (m,
1H, NHCOCH), 8.06e7.63 (m, 8H, HPht), 7.63e6.96 (m, 5H, Harom),
5.35e4.02 (m, 4H, CHCH3, CHCH2Ph, and NHBoc), 3.84e3.77 (m,
1H, CHCH(CH3)2), 3.56e3.00 (m, 2H, CHCH2Ph), 2.09e1.72 (m,
1H, CH(CH3)2), 1.67e1.01 (m, 15H, CHCH3, and C(CH3)3),
d
(ppm) 173.2 (CO),170.2 (CO),166.0,164.8 (COPht),156.4,155.8 (CO),
1.01e0.60 (m, 6H, CH(CH3)2). 13C NMR (CDCl3):
d (ppm) 174.1,
136.2 (Carom), 135.5, 135.4 (CHPht), 130.8 (CPht), 130.7 (CHarom), 130.0
(CPht), 129.7, 129.1, 128.9, 128.8 (CHarom), 125.0, 124.7 (CHPht), 80.9,
80.4 (C), 68.7, 68.0 (OCH2), 57.5 (CH), 56.0 (2CH), 31.4, 31.2 (CH), 28.8,
28.6 (3CH3), 20.7, 18.1 (CH), 15.5, 14.7 (CH3). HRMS (ESI) calculated
for C28H33N3NaO7 [MþNa]þ m/z 546.2211 found 546.2215.
173.1, 172.8, 172.0, 171.5, 170.4, 170.2 (CO), 167.1, 166.8, 166.4,
166.0, 165.9, 164.9 (COPht), 155.8 (CO), 136.7, 136.3 (Carom), 136.2,
136.9, 135.8, 132.0, 131.5 (CHarom), 131.0 (Carom), 129.9, 129.8,
129.5, 129.2, 129.1, 128.6, 127.4, 125.4, 125.3 (CHarom), 80.9 (C),
59.1, 58.6 (CH), 56.0 (CH), 50.2 (CH), 37.6, 36.5 (CH2Ph), 30.4
(CH), 28.8 (3CH3), 20.0, 18.1 (CH), 14.8, 14.2, 14.0, 13.7 (CH3).
4.3. General Procedure for benzyl ester deprotection
4.4. General procedure for Boc deprotection
A catalytic amount of 10% PdeC was added to a stirred solution
of corresponding oligomer (0.9 mmol) in ethanol (20 mL). The
resulting mixture was flushed with H2 and vigorously stirred at
room temperature until completion (monitored by TLC). The re-
action was filtered on Celite and the filtrate was evaporated at re-
duced pressure. The product was used without further purification.
A solution of dry hydrogen chloride 3 M in EtOAc (10 mL) was
added to the corresponding carbamate (1 mmol). The resulting so-
lutionwas stirred during 1 h at room temperature and co-evaporated
several times with CH2Cl2 until dryness at reduced pressure. The
crude product was used directly in oligomerization reaction.
4.3.1. BocPhe
j
[CON(Pht)](R)AlaOH 1a0. Formula: C25H27N3O7,
4.4.1. HCl, HPhej
[CON(Pht)](R)AlaOBn1a00. Formula: C27H25N3O5.HCl,
Molecular weight: 481 g molꢀ1, Colorless solid, w100%. IR (KBr)
Molecular weight: 507.5 g molꢀ1, Colorless solid, w100%. IR (KBR)
nmax/cmꢀ1 2928 (NH), 1798, 1738, 1694 (C]O). 1H NMR (CDCl3):
nmax/cmꢀ1 3340 (NH and COOH), 1798, 1745 (C]O). 1H NMR
(CDCl3):
d
(ppm) 8.8 (br, 1H, COOH), 8.00e7.82 (m, 4H, HPht),
d
(ppm) 8.60 (br, 1.5H, NHþ3 ), 8.38 (br, 1.5H, NHþ3 ), 7.80e7.60 (m, 4H,
7.26e7.11 (m, 5H, Harom), 5.10 (d, 1H, J¼9.9 Hz, NH), 4.90 (q, 1H,
J¼7.1 Hz, CHCH3), 4.54e4.52 (dd, 1H, J¼8.9, 6.1 Hz, CHCH2Ph),
3.17e3.11 (dd, 1H, J¼8.5, 5.6 Hz, CHCH2Ph), 2.91e2.83 (dd, 1H,
J¼8.3, 5.6 Hz, CHCH2Ph), 1.50e1.18 (m, 12H, NHCOOC(CH3)3, and
HPht), 7.25e7.10 (m, 10H, Harom), 5.23e4.90 (m, 4H, CHCH3, CHCH2Ph,
and OCH2Ph), 4.12e3.14 (m, 2H, CHCH2Ph), 1.53e1.43 (m, 3H, CHCH3).
13C NMR (CDCl3):
d (ppm) 170.4, 169.5, 169.1, 167.9 (CO), 165.8, 165.6,
165.4 (COPht), 136.1, 135.4 (CHPht), 133.4, 133.0 (Carom), 131.3, 130.7,
130.3 (CHarom), 129.9, 129.4, 129.3 (Carom), 129.2, 128.8, 128.1, 128.0
(CHarom), 126.0, 124.8, 124.5 (CHPht), 68.1, 67.7 (OCH2Ph), 58.6, 57.9
(CHCH2Ph), 52.6, 52.3 (CH), 36.0 (CH2Ph), 16.2, 15.4 (CH3). HRMS (ESI)
calculated for C27H26N3O5 [MþH]þ m/z 472.1867 found 472.1847.
CHCH3). 13C NMR (CDCl3):
d ppm 173.7 (COOH), 172.2 (CO), 166.0,
165.9 (COPht), 155.5 (COOtBu), 136.7 (Carom), 135.9, 135.6 (CHPht),
130.3, 130.2 (CHarom), 129.8 (CPht), 129.0, 127.5, 127.3 (CHarom),
125.3, 125.2, 124.9 (CHPht), 80.7 (CH3), 58.0 (CH3), 52.2 (CH), 38.7
(CH2Ph), 28.8 (CH3), 15.0, 14.2 (CH3).
4.4.2. HCl, HValj
[CON(Pht)](R)AlaOBn 1b00. Formula: C23H25N3O5.HCl,
4.3.2. BocVal
Molecular weight: 433 g molꢀ1, Colorless solid, w100%. IR (KBr) nmax
cmꢀ1 3340 (NH), 1799, 1750, 1685 (C]O). 1H NMR (CDCl3):
(ppm)
j
[CON(Pht)](R)AlaOH
1b0. Formula: C21H27N3O7,
Molecular weight: 459.5 g molꢀ1, Colorless solid, w100%. IR (ATR)
nmax/cmꢀ1 2922 (NH), 1802, 1740, 1689 (C]O). 1H NMR (CDCl3):
/
d
d
(ppm) 8.65 (br, 1.5H, NHþ3 ), 8.50 (br, 1.5H, NHþ3 ), 7.94e7.68 (m, 4H,
8.00e7.86 (m, 4H, HPht), 5.10 (d, 0.25H, J¼10.2 Hz, NH), 4.85e4.80 (m,
1.5H, 0.75 NH, and 0.75CHCH3), 4.41e4.34 (m, 0.5H, 0.25CHCH(CH3)2,
and 0.25CHCH3), 3.95 (t, 0.75H, J¼10 Hz, CHCH(CH3)2), 2.25e1.98 (m,
1H, CHCH(CH3)2), 1.60e1.33 (m, 12H, C(CH3)3, and CHCH3), 1.03e085
HPht), 7.40e7.26 (m, 5H, Harom), 5.30e5.12 (m, 3H, OCH2Ph, CHCH3),
4.88e4.70 (m, 1H, CHCH(CH3)2), 2.65e2.51 (m, 0.6H, CH(CH3)2),
2.25e2.07 (m, 0.4H, CH(CH3)2), 1.58e1.07 (m, 3H, CHCH3), 1.07e0.90
(m, 6H, CH(CH3)2). 13C NMR (CDCl3):
d (ppm) 170.9,169.4,169.0,168.5
(m, 6H, CHCH(CH3)2).13C NMR (CDCl3):
d
(ppm) 174.4 (CO),171.2 (CO),
(2CO), 166.3, 165.9, 165.3 (COPht), 136.1 (Carom), 135.8, 135.5 (CHPht),
130.7 (Carom), 129.7 (CHarom), 129.3, 129.2, 129.1, 129.0 (CHarom), 126.1,
125.0, 124.8, 124.7 (CHPht), 68.9, 68.4 (OCH2), 60.6, 59.0 (CH), 58.7, 56.9
(CH), 33.8, 30.2 (CH), 20.0, 19.3 (2CH3), 16.8, 16.6, 15.5 (CH3). HRMS
(ESI) calculated for C23H26N3O5 [MþH]þ m/z 424.187 found 424.184.
166.7, 165.8 (COPht), 156.5, 156.0 (CO), 136.0 (CHPht), 134.8 (Carom),
132.9, 131.7, 131.0 (CHPht),130.3,129.7 (CPht), 125.5, 125.1 (CHPht), 80.9
(C), 60.7 (CH), 58.6 (CH), 56.2 (2CH), 31.8, 31.0 (CH), 28.9 (3CH3), 20.6,
18.2 (CH), 14.4, 14.0 (CH3). HRMS (ESI) calculated for C21H27N3NaO7
[MþNa]þ m/z 456.1741 found 456.1714.
4.4.3. HCl, H(Phej
[CON(Pht)](R)Ala)2OBn 2a00. Formula: C47H42N6O9.
4.3.3. Boc(Phe
Molecular weight: 844 g molꢀ1, Colorless solid, w100%. IR (KBr) nmax
cmꢀ1 3325 (NH and COOH), 1799, 1741, 1695 (CO). 1H NMR (CDCl3):
(ppm) 8.35 (d, 0.7H, J¼8.1 Hz, NHCOCH), 8.25 (d, 0.3H, J¼8.0 Hz,
j
[CON(Pht)](R)Ala)2OH 2a0. Formula: C45H44N6O11,
HCl, Molecular weight: 870.5 g molꢀ1, Colorless solid, w100%. IR
/
(1 mM in CH2Cl2) nmax/cmꢀ1 3429, 3400, 3353(NH), 1798, 1745, 1708,
1677(C]O). 1H NMR (CDCl3):
d
(ppm) 7.98e7.50 (m, 8H, HPht),
d
7.43e7.06 (m, 15H, Harom), 6.82 (d, 0.7H, J¼9.8 Hz, NH), 6.68 (d, 0.3H,

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D. Sebastien et al. / Tetrahedron 68 (2012) 4362e4367
4366
J¼9.8 Hz, NH), 5.59e4.58 (6H, 2ꢂ CHCH3, 2ꢂ CHCH2Ph, and
COOCH2Ph), 3.6e3.00 (m, 6H, 2ꢂ CHCH2Ph, and NH2), 1.34e1.05 (m,
column chromatography: EtOAc/petroleum ether (30/70). IR (1 mM
in CH2Cl2) nmax/cmꢀ1 3433 (NHBoc), 3318 (NH amidic), 1798, 1746,
6H, 2ꢂ CHCH3). 13C NMR (CDCl3):
d
(ppm) 172.6, 171.4, 169.9, 169.6,
1697,1677 (C]O). 1H NMR (CDCl3):
d (ppm) 8.15 (m,1H, NHCOCH2),
169.0, 168.8 (CO), 166.3,165.7 (COPht),138.2, 137.2, 136.0, 135.8,135.5,
135.3, 134.0, 132.5, 132.3, 130.8, 129.8, 129.7, 127.5, 125.0, 124.9, 123.9
(Carom and CHarom), 68.9, 67.5 (OCH2Ph), 57.2, 55.8, 54.0 (CHCH3),
53.5, 51.8, 51.0 (CHCH2Ph), 37.4, 37.0, 36.7 (CHCH2Ph), 14.8,14.8,14.3,
12.3 (CHCH3). HRMS (ESI) calculated for C47H42N6NaO9 [MþNa]þ m/z
857.3430 found 857.2918.
8.05e7.64 (m, 8H, HPht), 7.53e7.05 (m, 5H, Harom), 5.86 (q, 0.3H, J
6.8 Hz, CHCH3), 5.33e4.48 (m, 5H, NHBoc, CHCH3, CHCH(CH3)2, and
OCH2Ph), 4.40 (q, 0.7H, J¼8.1 Hz, CHCH(CH3)2), 4.00e3.80 (m, 1H,
CHCH(CH3)2), 2.56e1.91 (m, 2H, 2CH(CH3)2), 1.72e1.03 (m, 15H,
2CHCH3, and C(CH3)3), 1.03e0.70 (12H, m, 2CH(CH3)2). 13C NMR
(CDCl3):
d (ppm) 173.9, 173.8, 172.7, 171.7, 170.9, 170.5, 170.2 (CO),
167.2, 166.4, 166.0, 165.1 (COPht), 155.8 (CO), 136.0, 135.9 (CHarom),
131.0, 130.4 (Carom), 130.0, 129.7, 129.6, 125.3, 124.9, 124.6 (CHarom),
80.9, 80.6 (C), 68.6, 67.6 (OCH2Ph), 60.6, 60.3, 57.5, 56.7 (CH), 56.0,
54.8, 53.9 (CH), 33.7, 33.5 (CH), 28.8 (3CH3), 19.4, 18.6, 18.3, 17.8
(CH), 15.6, 15.3, 14.4, 14.3 (CH3). HRMS (ESI) calculated for
C44H50N6NaO11 [MþNa]þ m/z 861.3430 found 861.3408.
4.4.4. HCl, H(Valj
[CON(Pht)](R)Ala)2OBn 2b00. Formula: C39H42N6O9.
HCl, Molecular weight: 774.5 g molꢀ1, Colorless solid, w100%. IR
(ATR) nmax/cmꢀ1 3294, 2963 (NH), 1800, 1747, 1683 (C]O). 1H NMR
(CDCl3):
d
(ppm) 8.61e7.61 (m, 12H, HPht, NH, and NHþ3 ), 7.50e7.08
(m, 5H, Harom), 5.42e3.96 (m, 6H, OCH2Ph, 2ꢂ CHCH3, and 2ꢂ
CHCH(CH3)2), 2.54e1.94 (m, 2H, 2ꢂ CH (CH3)2), 1.68e1.18 (m, 6H, 2ꢂ
CHCH3), 1.18e0.63 (m, 12H, 2ꢂ CH(CH3)2). 13C NMR (CDCl3):
d
(ppm)
4.5.3. BocPhej[CON(Pht)](R)AlaValj[CON(Pht)](R)AlaOBn
175.3, 173.7, 172.0, 171.6, 170.9, 169.6, 169.0 (CO), 167.2, 166.8, 166.4,
165.4 (COPht), 136.2, 135.8, 135.6, 135.5, 135.3 (CHarom), 130.4 (Carom),
129.6, 129.2, 129.1, 128.8, 125.0, 124.5 (CHarom), 68.6, 68.1 (OCH2),
62.3, 60.5, 58.9, 57.9, 55.2, 55.0 (2CH), 33.8, 31.3, 30.9, 29.8 (CH), 21.2,
20.0, 19.3, 18.3 (CH), 17.7, 16.8, 15.4, 14.8 (CH3). HRMS (ESI) calculated
for C39H42N6NaO9 [MþNa]þ m/z 761.2905 found 761.2894.
2c. Formula: C48H50N6O11, Molecular weight: 886 g molꢀ1, Color-
less solid, 51%. Eluent for column chromatography: EtOAc/petro-
leum ether (30/70 then 35/75). IR (1 mM in CH2Cl2) nmax/cmꢀ1 3428
(NHBoc), 3325 (NH amidic), 1798, 1747, 1713, 1699, 1679 (C]O). 1H
NMR (CDCl3):
d
(ppm) 8.16 (d, 0.5H, J¼11.8 Hz, NHCOCH2), 8.07 (d,
0.5H, J¼10.6 Hz, NHCOCH2), 8.03e7.69 (m, 8H, HPht), 7.53e6.86 (m,
10H, Harom), 5.50 (q, 0.5H, J¼6.8 Hz, CHCH3), 5.35e4.86 (m, 3.5H,
0.5CHCH3, 0.5CHCH(CH3)2, 0.5 NHCOOC(CH3)3, and 2 OCH2Ph),
4.85e4.59 (m, 1.5H, CHCH3, and 0.5 NHCOOC(CH3)3), 4.59e4.27 (m,
1.5H, CHCH2Ph, and 0.5ꢂ CHCH3), 3.22e2.68 (m, 2H, CH2Ph),
2.37e2.10 (m, 1H, CHCH(CH3)2), 1.77e1.03 (m, 15H, 2ꢂ CHCH3, and
C(CH3)3), 1.03e0.68 (m, 6H, 2CHCH(CH3)2). 13C NMR (CDCl3):
4.5. General procedure for the oligomerization reaction
Under nitrogen atmosphere, cyanuric fluoride (0.4 mL, 5 mmol,
2.5 equiv) was added at ꢀ20 ꢁC to a stirred solution of the 1:1[
a/a-
N-amino]mer acid form (2 mmol) and pyridine (2 mmol) in dry
CH2Cl2 (10 mL). After stirring at ꢀ10 ꢁC for 3 h, crushed ice and
CH2Cl2 (10 mL) were added. The organic layer was separated and
the aqueous layer extracted once with CH2Cl2 (5 mL). The combined
organic layers were washed with ice-cold water (10 mL) and dried
(MgSO4). The solvent was removed under vacuum at room tem-
perature to give the pure acid fluoride. A solution of acid fluoride in
CH2Cl2 (2.5 mL) was added dropwise to a cold stirred solution
(10 ꢁC) of amine (2 mmol) and NaHCO3 (4 mmol, 2 equiv) in dry
CH2Cl2 (6.3 mL). The mixture was stirred at room temperature
during 10 h. NaF salt was filtered and the solvent was evaporated.
For tetramers 2bed: amine (2 mmol) was added to a mixture of
acid fluoride (2 mmol) and NaHCO3 (4 mmol, 2eq) in CH2Cl2
(2.5 mL) in order to minimize the formation of diketopiperazine.
d
(ppm) 173.7,173.5,172.7,171.2,170.8, 170.5,170.1 (CO),166.3,166.0
(COPht), 155.3 (CO), 137.0, 136.7 (Carom) 136.0, 135.9, 135.8, 135.7,
135.3 (CHarom), 130.9, 130.8, 130.7 (Carom), 130.1, 129.7, 129.2, 125.5,
125.4, 124.7, 124.6 (CHarom), 80.7, 80.4 (C), 68.6, 67.6 (OCH2), 60.4,
59.7, 57.5, 56.9 (CH), 54.8, 54.0 (CH), 54.7 (CH), 54.4 (CH), 38.8
(CH2), 31.2, 31.0 (CH), 28.0 (3CH3), 20.2, 20.0, 18.6, 18.3 (2CH3), 15.5,
15.3,14.8,14.2,14.0 (CH3). HRMS (ESI) calculated for C48H50N6NaO11
[MþNa]þ m/z 909.3430 found 909.3415.
4.5.4. BocValj[CON(Pht)](R)AlaPhej[CON(Pht)](R)AlaOBn
2d. Formula: C48H50N6O11, Molecular weight:886 g molꢀ1, Colorless
solid, 51%. Eluent for column chromatography: EtOAc/petroleum
ether (30/70 then 35/75). IR (1 mM in CH2Cl2) nmax/cmꢀ1 3428, 3394
(NHBoc), 3315 (NH amidic), 1797, 1744, 1700, 1680 (C]O). 1H NMR
4.5.1. Boc(Phe
j
[CON(Pht)](R)Ala)2OBn 2a. Formula: C52H50N6O11,
(CDCl3): d (ppm) 8.25 (m, 1H, NHCOCH), 8.05e7.68 (m, 8H, HPht),
Molecular weight: 934 g molꢀ1, Colorless solid, 55%. Eluent for
column chromatography: EtOAc/petroleum ether (20/80 then
30/70). IR (1 mM in CH2Cl2) nmax/cmꢀ1 3430, 3396 (NHBoc), 3310
(NH amidic), 1790, 1745, 1701, 1682 (C]O). 1H NMR (CDCl3):
7.53e6.93 (m, 10H, Harom), 5.90 (q, 0.5H, J¼6.8 Hz, CHCH3), 5.50 (m,
0.5H, CHCH2Ph), 5.30e4.90 (m, 2H, 0.5CHCH3, 0.5CHCH2Ph, and
OCH2Ph), 4.69 (q, 0.6H, J¼7.1 Hz CHCH3), 4.50 (q, 0.4H, J¼7.5 Hz,
CHCH3), 4.20 (d, 0.6H, J¼10.6 Hz, NHBoc), 4.05 (d, 0.4H, J¼10.6 Hz,
NHCOOC(CH3)3), 3.85e3.62 (m,1H, CHCH(CH3)2), 3.33e2.90 (m, 2H,
CH2Ph), 1.96e1.72 (m,1H, CHCH(CH3)2),1.72e1.01 (m, 15H, 2CHCH3,
and C(CH3)3), 1.01e0.57 (m, 6H, 2CH(CH3)2). 13C NMR (CDCl3):
d
(ppm) 8.19 (d, 0.3H, J¼8.8 Hz, NHCOCH), 8.12 (d, 0.7H, J¼8.6 Hz,
NHCOCH), 7.98e7.68 (m, 8H, HPht), 7.50e6.93 (m, 15H, Harom), 5.85
(q, 0.3H, J¼6.8 Hz, CHCH3), 5.51e4.90 (m, 3.7H, 0.7ꢂ CHCH3,
CHCH2Ph, and COOCH2Ph), 4.68 (q, 0.7H, J¼7.3 Hz, CHCH3), 4.52 (q,
0.3H, J¼7.3 Hz, CHCH3), 4.30e4.20 (m, 1.7H, 0.7ꢂ NHCOOC(CH3)3,
and CHCH2Ph), 4.02 (d, 0.3H, J¼10.6 Hz, NH), 3.36e2.42 (m, 4H, 2ꢂ
CHCH2Ph), 1.54 (d, 2H, J¼6.9 Hz, CHCH3), 1.45 (d, 1H, J¼6.8 Hz,
CHCH3), 1.26e1.08 (m, 12H, CHCH3, and COO C(CH3)3). 13C NMR
d
(ppm) 173.1,172.8,172.0,171.0,170.4,170.2 (CO),167.1,166.8,166.4,
166.0, 165.9, 164.9 (COPht), 155.8 (CO), 137.2, 137.0 (Carom), 135.8,
135.6, 135.3 (CHarom), 130.9, 130.7, 130.4 (Carom), 129.8, 129.6, 129.3,
129.0, 128.9, 128.6 (CHarom), 80.7, 80.4 (C), 68.6, 67.7 (OCH2), 59.9,
59.1, 57.3, 56.7 (CH), 56.0, 55.8 (CH), 49.7, 49.2 (CH), 37.9, 37.1 (CH2),
30.4 (CH), 28.8 (3CH), 20.0, 18.1 (2CH3), 15.0, 14.8, 14.1 (CH3). HRMS
(ESI) calculated for C48H50N6NaO11 [MþNa]þ m/z 909.3430 found
909.3420.
(CDCl3):
d (ppm) 172.9, 172.5, 171,8, 171.1, 170.5, 170.2(CO), 166.5,
166.0 (COPht), 155.3 (NHCOOtBu), 137.3, 135.8, 135.7, 135.5, 130.9,
130.8, 129.9, 129.7, 129.2, 128.7, 128.5, 125.3, 125.1, 124.9, 124.7
(Carom and CHarom), 80.6, 80.3 (C), 68.9, 67.8 (OCH2Ph), 60.0, 59.3,
57.3, 56.9 (CH), 51.9, 49.8, 49.1 (CH), 38.4, 37.8, 37.2 (CH2Ph), 28.8
(CH3), 15.0, 14.8, 14.0, 13.8 (CH3). HRMS (ESI) calculated for
C52H50N6NaO11 [MþNa]þ m/z 957.3430 found 957.3422.
4.5.5. Boc(Phej[CON(Pht)](R)Ala)3OBn 3a. Formula: C72H67N9O15,
Molecular weight: 1296 g molꢀ1, Colorless solid, 55%. Eluent for
column chromatography: EtOAc/petroleum ether (40/60 then
50/50). IR (0.7 mM in CH2Cl2) nmax/cmꢀ1 3396 (NHBoc), 3313 (NH
4.5.2. Boc(Val
j
[CON(Pht)](R)Ala)2OBn 2b. Formula: C44H50N6O11,
amidic), 1797, 1743, 1702, 1677 (C]O). 1H NMR (CDCl3):
d
(ppm)
Molecular weight: 838 g molꢀ1, Colorless solid, 61%. Eluent for
8.32e8.17 (m, 2H, NHCOCH), 8.00e7.62 (m, 12H, HPht), 7.50e6.86

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D. Sebastien et al. / Tetrahedron 68 (2012) 4362e4367
4367
(m, 20H, Harom), 5.53e4.00 (m, 9H, COOCH2Ph, 3ꢂ CHCH3, 3ꢂ
CHCH2Ph, and NHCOOC(CH3)3), 3.38e2.47 (m, 6H, 3ꢂ CHCH2Ph),
1.40e1.00 (m, 18H, COOC(CH3)3, and CHCH3). 13C NMR (CDCl3):
(C), 68.5, 67.5 (OCH2), 60.9, 59.9, 57.3, 55.8 (CH), 54.9, 54.5, 54.4
(CH), 49.2 (CH), 37.8 (CH2), 31.0, 30.2 (CH), 28.7 (3CH3), 24.5, 20.1,
20.0, 19.1, 18.8, 18.1 (CH), 15.3, 14.6, 14.3 (CH3). HRMS (ESI) calcu-
lated for C80H84N12NaO19 [MþNa]þ m/z 1539.5868 found
1539.5877.
d
(ppm) 173.3, 172.6, 171.8, 171.5, 170.8, 170.2 (CO), 165.9, 165.3
(COPht), 155.2 (NHCOOtBu), 137.3, 136.9 (Carom), 131.1, 135.5, 135.2
(CHarom), 130.7 (Carom), 128.5, 127.2, 127.1, 125.0, 124.8, 124.6, 124.4
(CHarom), 80.7, 80.6 (COOC(CH3)3), 68.4, 67.5 (OCH2Ph), 60.7, 60.1,
59.9, 57.0, 56.7 (CHCH3), 51.8, 51.0, 50.5, 49.7, 49.4 (CHCH2Ph), 39.1,
38.3, 37.8, 37.2 (CHCH2Ph), 30.0 (COOC(CH3)3), 15.1, 14.9, 14.2
(CHCH3). HRMS (ESI) calculated for C72H67N9Na2O15 [Mþ2Na]2þ
m/z 671.7271 found 671.7258.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.070.
4.5.6. Boc(Phej[CON(Pht)](R)Ala)4OBn 4a. Formula: C92H84N12O19,
References and notes
Molecular weight: 1660 g molꢀ1, Colorless solid, 35%. Eluent for
column chromatography: EtOAc/petroleum ether (50/50 then 70/
30). IR (0.5 mM in CH2Cl2) nmax/cmꢀ1 3396 (NHBoc), 3313 (NH
1. Steiner, T.; Koellner, G. J. Mol. Biol. 2001, 305, 535e557.
2. Wlodawer, A.; Walter, J.; Huber, R.; Spolin, L. J. Mol. Biol. 1984, 180, 301e329.
3. Perutz, M. F.; Fermi, G.; Abraham, D. J.; Poyart, C.; Bursaux, E. J. Am. Chem. Soc.
1986, 108, 1064e1078.
€
amidic), 1795, 1741, 1704, 1677 (C]O). 1H NMR (CDCl3):
d(ppm)
4. Armstrong, K. M.; Fairman, R.; Baldwin, R. L. J. Mol. Biol. 1993, 230, 284e291.
5. Kryger, G.; Silman, I.; Sussman, J. L. Structure 1999, 7, 297e307.
6. Parkinson, G.; Gunasekera, A.; Vijtechovsky, J.; Zhang, X.; Kunkel, T. A.; Berman,
H.; Ebright, R. H. Nat. Struct. Biol. 1996, 3, 837e841.
7. Liu, S.; Ji, X.; Gilliland, G. L.; Stevens, W. J.; Armstrong, R. N. J. Am. Chem. Soc.
1993, 115, 7910e7911.
8. (a) Engh, R. A.; Brandstetter, H.; Sucher, G.; Eichinger, A.; Baumann, I.; Bode, W.;
Huber, R.; Poll, T.; Rudolph, R.; Saal, W. V. D. Structure 1996, 4, 1353e1362; (b)
Deacon, A.; Gleichmann, T.; Kalb (Gilboa), A. J.; Price, H.; Raferty, J.; Bradbrook,
G.; Yariv, J.; Helliwell, J. R. J. Chem. Soc., Faraday Trans. 1997, 93, 4305e4312; (c)
Koellner, G.; Kryger, G.; Millard, C. B.; Silman, I.; Sussman, J. L.; Steiner, T. J. Mol.
Biol. 2000, 296, 713e735.
8.30e8.04 (m, 3H, NHCOCH), 7.90e7.26 (m, 16H, HPht), 7.26e6.70
(m, 25H, Harom), 5.42e4.00 (m, 10H, COOCH2Ph, 4ꢂ CHCH3, and 4ꢂ
CHCH2Ph), 3.95e3.84 (m, 1H, NHCOOC(CH3)3), 3.29e2.33 (m, 8H,
4ꢂ CHCH2Ph), 1.40e0.72 (m, 21H, COOC(CH3)3 and 4ꢂ CHCH3). 13
C
NMR (CDCl3):
d (ppm) 173.3, 172.6, 171.8, 171.5, 170.9, 170.2, 170.0
(CO), 167.6, 167.3, 166.2, 165.8, 165.6, 165.0 (COPht), 155.1
(NHCOOtBu), 137.3, 137.1, 136.9 (Carom), 136.2, 135.8, 135.5, 135.2,
130.7 (CHarom), 130.7 (Carom), 130.4, 130.2, 130.0, 129.9, 129.2, 128.9,
128.5,128.4,127.2,125.7,125.3,125.0,124.8,124.4 (CHarom), 80.7 (C),
67.4, 68.2 (OCH2Ph), 60.7, 60.5, 60.4, 60.1, 60.0, 56.6, 55.5 (CH), 52.3,
51.7, 50.6, 50.5, 49.4 (CH), 39.2, 38.2, 37.7, 36.7 (CH2Ph), 28.7 (CH3),
15.0, 14.8, 14.5, 14.2 (CH3). HRMS (ESI) calculated for
C92H84N12Na2O19 [Mþ2Na]2þ m/z 853.2880 found 853.2853.
9. Huck, B. R.; Fisk, J. D.; Gellman, S. H. Org. Lett. 2000, 2, 2607e2610.
€
10. (a) Le Grel, P.; Salaun, A.; Potel, M.; Le Grel, B.; Lassagne, F. J. Org. Chem. 2006,
€
71, 5638e5645; (b) Salaun, A.; Mocquet, C.; Perochon, R.; Lecorgne, A.; Le Grel,
B.; Potel, M.; Le Grel, P. J. Org. Chem. 2008, 73, 8579e8582; (c) Seebach, D.; Beck,
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4.5.7. BocValj[CON(Pht)](R)AlaPhej[CON(Pht)](R)Ala[Valj
[CON(Pht)](R)Ala]2OBn 4db. Formula: C80H84N12O19, Molecular
weight: 1513 g molꢀ1, Colorless solid, 15%. Eluent for column
chromatography: EtOAc/petroleum ether (50/50 then 70/30). IR
(0.5 mM in CH2Cl2) nmax/cmꢀ1 3432, 3391 (NHBoc), 3305 (NH),
11. Felten, A. S.; Dautrey, S.; Bodiguel, J.; Vanderesse, R.; Didierjean, C.; Arrault, A.;
ꢀ
Jamart-Gregoire, B. Tetrahedron 2008, 64, 10741e10753.
ꢀ
12. (a) Brosse, N.; Pinto, M. F.; Jamart-Gregoire, B. J. Org. Chem. 2000, 65,
1796, 1743, 1697, 1671 (C]O). 1H NMR (CDCl3):
d(ppm) 8.20 (d, 1H,
ꢀ
4370e4374; (b) Brosse, N.; Pinto, M. F.; Bodiguel, J.; Jamart-Gregoire, B. J. Org.
Chem. 2001, 66, 2869e2873.
J¼8.9 Hz, NHCOCH), 8.11e7.59 (m, 18H, HPht, and NHCOCH),
7.46e6.98 (m, 10H, Harom), 5.56e4.44 (m, 7H, OCH2Ph, 4CHCH3, and
CHCH2Ph), 4.44e4.03 (m, 2H, 2CHCH(CH3)2), 3.95 (d, 1H, J¼10.8 Hz
NHCOOC(CH3)3), 3.76e3.57 (m,1H, CHCH(CH3)2), 3.29e2.91 (m, 2H,
CH2Ph), 2.27e1.90 (m, 3H, 3CH(CH3)2), 1.56e1.02 (m, 21H, C(CH3)3,
and 4CHCH3), 0.97e0.57 (m, 18H, 4CH(CH3)2). 13C NMR (CDCl3):
13. Lewin, A. H.; Frucht, M. Org. Magn. Reson. 1975, 7, 206e225.
14. Worth, G. A.; Wade, R. C. J. Phys. Chem. 1995, 99, 17473e17482.
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15. Jimenez, A. I.; Cativiela, C.; Gomez-Catalan, J.; Perez, J. J.; Aubry, A.; Paris, M.;
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Singh, J. Nature 1993, 366, 413; (d) Toth, G.; Watts, C. R.; Murphy, R. F.; Lovas, S.
Proteins: Struct., Funct., Genet. 2001, 43, 373e381.
d
(ppm) 173.5, 173.3, 172.8, 172.1, 171.5, 170.6, 170.0 (CO), 167.5,
166.9, 166.3 (COPht), 155.8 (CO), 136.7 (Carom), 135.4, 135.2 (CHarom),
130.8(Carom), 130.0, 129.6, 127.2, 125.5, 125.3, 124.5 (CHarom), 80.8
17. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J.; Meyer, E. E.; Brice, M. D.; Rodgers,
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