A chirally stable, atropoisomeric, Cα-tetrasubstituted α-amino acid: Incorporation into model peptides and conformational preference

Article abstract of DOI:10.1002/1522-2675(20010228)84:2<481::AID-HLCA481>3.0.CO;2-C

A variety of model peptides, including four complete humologous series, to the pentamer level, characterized by the recently proposed binaphthyl-based, axially chiral. C^α-tetrasubstituted, cyclic α-amino acid Bin, in combination with Ala. Gly, or Aib residues, was synthesized by solution methods and fully characterized. The solution conformational propensity of these peptides was determined by FT-IR absorption and ¹H-NMR techniques. Moreover, the molecular structures of the free amino acid (S)-enantiomer and an N^α-acylated dipeptide alkylamide with the heterochiral sequence -(R)-Bin-Phe- were assessed in the crystal state by X-ray diffraction. Taken together, the results point to the conclusion that β-bends and 3₁₀ helices are preferentially adopted by Bin-containing peprides, although the tully extended conformation would also be adopted in solution by the short oligomers to some extent. We also confirmed the tendency of (R)-Bin to fold a peptide chain into right-handed bend and helical structures. The absolute configuration of the Bin residue(s) was correlated with the typically intense exciton-split Cotton effect of the ¹B_b binaphthyl transition near 225 nm.

Full text of DOI:10.1002/1522-2675(20010228)84:2<481::AID-HLCA481>3.0.CO;2-C

Helvetica Chimica Acta ± Vol. 84 (2001)
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A Chirally Stable, Atropoisomeric, Ca-Tetrasubstituted a-Amino Acid:
Incorporation into Model Peptides and Conformational Preference
by Fernando Formaggio, Cristina Peggion, Marco Crisma, and Claudio Toniolo*
Biopolymer Research Centre, CNR, Department of Organic Chemistry, University of Padova, via Marzolo 1,
I-35131 Padova (e-mail: biop02@chor.unipd.it)
and Luba Tchertanov and Jean Guilhem
Institut de Chimie des Substances Naturelles, UPR 2301, F-91198 Gif-sur-Yvette
and Jean-Paul Mazaleyrat, Yolaine Goubard, Anne Gaucher, and Michel Wakselman
Ã
SIRCOB, Bat. Lavoisier, University of Versailles, F-78035 Versailles
A variety of model peptides, including four complete homologous series, to the pentamer level,
characterized by the recently proposed binaphthyl-based, axially chiral, Ca-tetrasubstituted, cyclic a-amino acid
Bin, in combination with Ala, Gly, or Aib residues, was synthesized by solution methods and fully characterized.
1
The solution conformational propensity of these peptides was determined by FT-IR absorption and H-NMR
techniques. Moreover, the molecular structures of the free amino acid (S)-enantiomer and an Na-acylated
dipeptide alkylamide with the heterochiral sequence -(R)-Bin-Phe- were assessed in the crystal state by X-ray
diffraction. Taken together, the results point to the conclusion that b-bends and 310 helices are preferentially
adopted by Bin-containing peptides, although the fully extended conformation would also be adopted in
solution by the short oligomers to some extent. We also confirmed the tendency of (R)-Bin to fold a peptide
chain into right-handed bend and helical structures. The absolute configuration of the Bin residue(s) was
correlated with the typically intense exciton-split Cotton effect of the 1Bb binaphthyl transition near 225 nm.
Introduction. ± One of the major drawbacks for the exploitation of peptides as
drugs is their remarkable conformational flexibility leading to undesired interactions
with different receptors. As a consequence, in recent years, conformationally con-
strained analogues of bioactive peptides have acquired increasing popularity among
medicinal chemists, in an effort to firmly establish three-dimensional structure-
bioactivity relationships and to develop new drugs with prolonged action and/or more
selective properties [1 ± 7]. In particular, conformational restriction through Cia $ Cia
cyclization generates the family of 1-aminocycloalkane-1-carboxylic acid (Acnc)
residues [7].
Theoretical and experimental studies of the preferred conformations of peptides
characterized by the Acnc (n ˆ 4 ± 9) residues have been the subject of recent review
articles and papers [8 ± 12]. In a close parallelism to the structural behaviour of Aib (a-
aminoisobutyric acid) [8][13] (Fig. 1), the prototype of Ca-tetrasubstituted achiral a-
amino acids and Iva (isovaline), the prototype of their chiral analogues [14 ± 16], it was
shown that regular b-bend forms [17 ± 19] or 310-helical structures [20] are adopted as a
function of main-chain length.
We now describe the synthesis and conformational propensity of peptides
containing Bin (ˆ4,5-dihydro-4-amino-3H-cyclohepta[2,1-a :3,4-a']dinaphthalene-4-

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Fig. 1. Chemical structures of Aib, Ac7c and the Bin enantiomers
carboxylic acid) (Fig. 1), a Ca-tetrasubstituted a-amino acid related to the Acnc family,
in particular to Ac7c (Fig. 1), the seven-membered ring compound [9 ± 11]. More
specifically, four model peptide series based on the (S)-Bin/Ala, (S)-Bin/Gly, and (S)-
Bin/Aib sequences to the pentamer level were prepared by solution methods, fully
characterized, and their preferred conformation studied in solution by FT-IR
1
absorption and H-NMR techniques. Moreover, the crystal-structure analyses of the
free amino acid itself ((S)-enantiomer) and a terminally blocked dipeptide with the
heterochiral sequence Bz (R)-Bin Phe NHChx (Bz, benzoyl; Chx, cyclohexyl)
were also performed by X-ray diffraction. Finally, a configurational investigation by
CD spectroscopy of the Bin residues was carried out.
In addition to being a member of the Acnc family, Bin is optically active, as it is
characterized by an axial chirality (atropisomerism) related to the hindered rotation
about the C(1) C(1') (ˆC(11b) C(11c)) bond of the 1,1'-binapthalene moiety [21 ± 23].
Indeed, the chain-bridged derivative Bin preserves the C2 symmetry of 1,1'-
binaphthalene (because of the presence of two identical substituents at the 2,2'-
positions), but a twist is induced by the chiral binaphthalene moiety in the prochiral,
fused Ac7c structure [24]. Because of their highly stable configuration, 1,1'-binaptha-
lene systems have been extensively exploited as chiral auxiliaries in stereoselective
organic synthesis, in the preparation of chiral hosts for molecular-recognition studies,
and in the construction of new materials [21 ± 23][25][26]. Preliminary accounts of a
limited part of this work have been published [27 ± 30]. The results of an X-ray
diffraction investigation, photophysical experiments based on the binaphthalene
fluorophore, and molecular-mechanics conformational calculations of a hexapeptide
containing a single, N-terminal (S)-Bin residue have been reported [31]. A derivative
of an interesting binaphthalene Ca-trisubstituted a-amino acid, 1-(1-naphthyl)-2-
naphthylalanine
(ˆ b-([1,1'-binaphthalen]-2-yl)alanine ˆ a-amino-[1,1'-binaphtha-
lene]-2-propanoic acid), has been prepared via a tandem catalysis procedure [32].
Closer Bin analogues with atropoisomeric 2,2',6,6'-tetrasubstituted 1,1'-biphenyl

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483
architectures, which possess either Me [33] or OH groups (precursor of crown-ether
receptors) [34][35] in the 6,6'-positions, have also been described.
Results and Discussion. ± Amino-Acid and Peptide Synthesis. The synthesis and
characterization of racemic Bin, the Bin enantiomers, and their derivatives
H
Z
Bin OtBu (OtBu, tert-butoxy), Boc Bin OH (Boc, (tert-butoxy)carbonyl), and
Bin OH (Z, (benzyloxy)carbonyl) were already described [27 ± 30]. Briefly, Ca-
bis-alkylation of a Schiff base from H Gly OtBu by either racemic or enantiomeri-
cally pure 2,2'-bis(bromomethyl)-1,1'-binaphthalene under phase-transfer conditions
led in good yields (ca. 80%) to the corresponding a-amino esters H Bin OtBu.
Acidolysis of the amino esters with CF3COOH/CH2Cl2 1:1 gave the free amino acids.
The Na-protected derivatives were prepared by standard methods. Direct and indirect
racemate separation of the free amino acid and the Na-protected derivatives were
achieved by HPLC on a chiral stationary phase or by pre-column derivatization with a
chiral reagent [36].
In the present work, the peptides 1 ± 14 containing Bin were studied (Table 1). The
(S)-Bin/Ala and (S)-Bin/Gly peptides were synthesized by means of the step-by-step
strategy in solution starting from the C-terminus. (S)-Bin Ala, (S)-Bin Gly,
Ala Ala and Gly Gly peptide-bond formation was achieved by the DCC/HOBt
(DCC, N,N'-dicyclohexylcarbodiimide; HOBt, 1-hydroxy-1H-1,2,3-benzotriazole)
method [37], while the Ala (S)-Bin and Gly (S)-Bin couplings were performed by
the symmetrical-anhydride procedure. The Na-Boc protecting group was removed on
treatment with either HCl/AcOEt or CF3COOH/CH2Cl2 1:1. The terminally protected
(S)-Bin Aib dipeptide was prepared by means of the pivaloyl (Piv) mixed-anhydride
method [38][39]. The tert-butyl ester protecting group at the C-terminus was removed
by acidolysis (CF3COOH/CH2Cl2 1:1). Then, a coupling strategy from the N-terminus,
involving carboxy-group activation of peptides with either Aib or (S)-Bin as the C-
terminal residue through the oxazol-5(4H)-one intermediate [38][39] (prepared by
intramolecular dehydration of the peptide free acid with Ac2O at high temperature),
Table 1. Peptides Containing Bin
1
1'
2
Ac (R)-Bin Phe NHChx
Bz (R)-Bin Phe NHChx
Ac (S)-Bin Phe NHChx
3
4
5
Boc Gly (S)-Bin Gly OMe
Boc (Gly)2 (S)-Bin Gly OMe
Boc (S)-Bin (Gly)2 (S)-Bin Gly OMe
6
7
8
Boc Ala (S)-Bin Ala OMe
Boc (Ala)2 (S)-Bin Ala OMe
Boc (S)-Bin (Ala)2 (S)-Bin Ala OMe
9
10
11
Z
Z
Z
(S)-Bin (Aib)2 OtBu
(S)-Bin (Aib)2 (S)-Bin OtBu
(S)-Bin (Aib)2 (S)-Bin Aib OtBu
12
13
14
Z
Z
Z
(Aib)2 (S)-Bin OtBu
(Aib)2 (S)-Bin Aib OtBu
(Aib)2 (S)-Bin (Aib)2 OtBu
15
H
Phe NHChx

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was employed. Acylation of either H Aib OtBu or H (S)-Bin OtBu by the
peptide oxazolones required several days, but, in general, this reaction gave good yields
(ca. 80%) of the (S)-Bin/Aib peptides.
The synthesis and characterization of the terminally blocked dipeptides Bz (R)-
Bin Phe NHChx (1'), the X-ray diffraction structure of which is described below,
Ac (R)-Bin Phe NHChx (1), and Ac (S)-Bin Phe NHChx (2) were already
reported [29]. The a-amino amide H Phe NHChx (15) was used as a chiral auxiliary
for the medium-scale resolution of (RS)-Bin.
Configurational Analysis. The electronic absorption spectrum of naphthalene
consists of one main band (1Bb) at 220 nm, accompanied by two weaker bands at
286 nm (1La) and 310 nm (1Lb). In the spectra of 1,1'-binaphthalene derivatives, the
strongest UV band at ca. 220 nm and the corresponding, extremely intense CD exciton-
1
split bands at 200 ± 240 nm are associated with coupling of the two Bb transitions
located on different naphthalene rings [40 ± 42]. From a study on a large variety of
compounds, it was concluded that the (S)-enantiomer of a C2-symmetrically substituted
binaphthalene would exhibit a positive Cotton effect at longer wavelengths and a
negative Cotton effect at shorter wavelengths.
However, in open-chain binaphthalenes, the sign of the exciton-split Cotton effect is
also sensitive to the value of the dihedral angle q defined by the two naphthalene planes,
from (M)-helicity (0 <j qj< 908, s-cis conformer) to (P)-helicity (908<j qj< 1808, s-trans
conformer). Therefore, the absolute configuration of open-chain binaphthalene
compounds is not independently determinable from the CD data alone: in these cases,
information on the dihedral angle q is needed. Luckily, as in our Bin peptides
characterized by a bridged-chain binaphthalene system, the q angle is forced to be less
than 908 by the fusion to the seven-membered ring, the absolute configuration only
plays a role on the determination of the sign of the exciton-split Cotton effect at 220 nm.
Fig. 2 shows the CD spectra (200 ± 250 nm region) of the diastereoisomeric
Ac (R)-Bin Phe NHChx (1) and Ac (S)-Bin Phe NHChx (2) in MeOH
solution. From these two CD patterns and those recorded for other Bin peptides
1
(not shown) it is evident that the (S)-Bin peptides show a consistently positive Bb
Cotton effect at longer wavelengths, whereas a negative Cotton effect at longer
wavelengths is exhibited by the (R)-Bin peptides. Thus, the CD technique proved to be
very useful for a fast and unequivocal configurational assignment of Bin peptides. An
inspection of all of the CD curves strongly support the view that neither the chiral
sequence nor main-chain length (and hence, presumably, peptide conformation),
nature of the aromatic N-blocking group (Bz, Z) and amino acid side chain (Phe) have
any marked influence on their shapes and intensities. By contrast, the intensity of the
exciton-split Cotton effect is approximately doubled in the peptides with two (S)-Bin
residues compared to that of the peptides with only one (S)-Bin residue.
Solution Conformational Analysis. The preferred conformations adopted by the
four terminally protected peptide series based on (S)-Bin in combination with Gly, Ala,
or Aib residues were assessed in CDCl3, a solvent of low polarity, by FT-IR absorption
1
and H-NMR techniques as a function of concentration (over the range 10 ± 0.1 mm).
Figs. 3 and 4 show the FT-IR absorption spectra in the conformationally most
informative N H stretching region. In general, the spectra are characterized by main
1
1
bands at 3455 ± 3425 cm (free, solvated N H groups) and at 3375 ± 3330 cm

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Fig. 2. CD Spectra in the 200 ± 250-nm region of Ac (R)-Bin Phe NHChx (1) and Ac (S)-Bin
Phe NHChx (2) in MeOH solution. Peptide concentration, 1.0 mm.
(strongly H-bonded N H groups) [43 ± 45]. The intensity of the low-frequency band
relative to the high-frequency band(s) increases as the peptide main chain is elongated.
This effect is quite remarkable when a (S)-Bin residue is incorporated at the N-
terminal position of the Gly and Ala series (see 5 and 8 in Fig. 3), whereas the intensity
enhancement is more gradual in the two Aib-rich series (Fig. 4). Concomitantly, the
absorption maximum shifts significantly to lower wavenumbers. We were also able to
demonstrate that, even at 10-mm concentration, only marginal changes take place in
the spectra of the various oligomers (with the single exception of the Gly/(S)-Bin
pentamer 5 where a variation, albeit small, is seen). Therefore, the band at 3375 ±
1
3330 cm should be interpreted as arising almost exclusively from intramolecular
N
H ´´´ OˆC interactions. In addition, with the exclusion of the Aib/(S)-Bin series
12 ± 14 characterized by only one binaphthalene residue, we noted a small additional
band (shoulder) in the 3415 ± 3395 cm region. This medium-frequency absorption is
1
typical of weakly intramolecularly H-bonded N H groups of fully-extended (C5)
conformers [18][46]. In a parallel analysis, the Na-blocked (S)-Bin/Phe dipeptide
alkylamides 1, 1', and 2 turned out to be extensively intramolecularly H-bonded in
CDCl3 solution (data not shown).
The present FT-IR absorption study has provided convincing evidence that main-
chain length dependent intramolecular H-bonding is a factor of paramount importance
influencing the conformation of (S)-Bin peptides in CDCl3 solution. Our results also
support the view that the Ca-tetrasubstituted a-amino acid (S)-Bin, like Aib, is a much
stronger inducer of intramolecularly H-bonded folded conformers than the Ca-di- and
trisubstituted protein amino acids Gly and Ala. However, if the two (S)-Bin/Aib series
are compared, it turns out that it is in the series 12 ± 14 with only one binaphthalene
residue where the regularly folded species exceedingly prevail, i.e., (S)-Bin seems to be
slightly less effective than Aib in supporting bends/helices in peptides.

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1
Fig. 3. FT-IR Absorption spectra (3500 ± 3200-cm region) in CDCl3 solution of a) Boc Gly (S)-Bin Gly-
OMe (3), Boc (Gly)2 (S)-Bin Gly OMe (4), and Boc (S)-Bin (Gly)2 (S)-Bin Gly OMe (5);
b) Boc Ala (S)-Bin Ala OMe (6), Boc (Ala)2 (S)-Bin Ala OMe (7), and Boc (S)-Bin (Ala)2 (S)-
Bin Ala OMe (8). Peptide concentration, 1.0 mm.
With the aim of obtaining a more detailed information on the preferred
conformations of the terminally protected (S)-Bin peptides in CDCl3 solution, we
carried out a 400-MHz 1H-NMR investigation. Unfortunately, among the four
pentapeptides examined, only in the case of Z (Aib)2 (S)-Bin (Aib)2 OtBu (14),
all NH resonances were clearly visible, without any serious overlapping from the
aromatic protons. The upfield resonance of this pentapeptide in CDCl3 solution was
unambiguously assigned to the urethane N(1) proton [44]. All other NH resonances
were assigned by means of a 2D-ROESYexperiment. From an analysis of the spectra as
a function of concentration (over the 10 ± 1.0-mm range) in CDCl3 solution (results not
shown), it turned out that dilution induced a small shift (0.11 ppm) to higher fields of
the H N(1)1) resonance. For this reason, the conformational investigation was
performed at 1.0-mm peptide concentration where self-association is absent. The
delineation of inaccessible (or intramolecularly H-bonded) NH groups was carried out
by means of i) solvent dependence of NH chemical shifts on addition of increasing
amounts of the strong H-bonding acceptor solvent dimethylsulfoxide (DMSO) to the
CDCl3 solution [47], and ii) free-radical TEMPO (2,2,6,6-tetramethylpiperidin-1-
yloxy)-induced line broadening of NH resonances [48] (Fig. 5). In the pentapeptide,
1
)
The locants 1 ± 5 refer to the position of the amino-acid residue in the peptide chain.

Helvetica Chimica Acta ± Vol. 84 (2001)
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Fig. 4. FT-IR Absorption spectra (3500 ± 3200-cm 1 region) in CDCl3 solution of a) Z (S)-Bin (Aib)2 OtBu
(9),
Z
(S)-Bin (Aib)2 (S)-Bin OtBu (10), and
Z
(S)-Bin (Aib)2 (S)-Bin Aib-OtBu (11);
b) Z (Aib)2 (S)-Bin OtBu (12), Z (Aib)2 (S)-Bin Aib OtBu (13), and Z (Aib)2 (S)-Bin (Aib)2-
OtBu (14). Peptide concentration 1.0 mm
two classes of NH protons were observed. Class A (H N(1) and H N(2)1) includes
protons whose chemical shifts are sensitive to the addition of DMSO and whose
resonances broaden upon addition of TEMPO. Interestingly, the sensitivity of H N(1)
is higher than that of H N(2). Class B (H N(3) to H N(5)1) includes those
displaying a behaviour characteristic of shielded protons (relative insensitivity of
chemical shifts to solvent composition and of line widths to the presence of TEMPO).
1
The present H-NMR results establish that, in CDCl3 solution at 1.0 mm concen-
tration, the H N(3) to H N(5)1) protons of 14 are almost inaccessible to the
perturbing agents and are, therefore, most probably, intramolecularly H-bonded. In
view of the FT-IR absorption and 1H-NMR findings, it is reasonable to assume that the
most populated structure adopted in the structure-supporting solvent CDCl3 by this
terminally protected (S)-Bin pentapeptide 14 is the 310 helix, where only the H N(3)
to H N(5)1) protons are involved in the intramolecular H-bonding scheme.
Two views of a molecular model of the Na-acylated pentapeptide sequence (S)-
Bin (Aib)2 (S)-Bin Aib of 11 in the 310-helical structure are shown in Fig. 6. They
clearly illustrate the overlapping of the two Bin side chains, one on top of the other after
one complete turn of the ternary helix.
Crystal-State Conformational Analysis. The molecular and crystal structures of the
‡
free amino acid H ´ H (S)-Bin
O
and the terminally blocked, heterochiral

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1
Fig. 5. a) Plot of NH chemical shifts in the H-NMR spectrum of Z (Aib)2 (S)-Bin (Aib)2 OtBu (14) as a
function of increasing percentages of DMSO added to the CDCl3 solution (v/v). b) Plot of bandwidths of the NH
signals in the 1H-NMR spectrum of 14 as a function of increasing percentages of TEMPO (w/v) added to the
CDCl3 solution. Peptide concentration, 1.0 mm.
Fig. 6. Molecular model of the 310-helical structure formed by the Na-acylated pentapeptide sequence
(S)-Bin (Aib)2 (S)-Bin Aib of 11. a) Top view; b) side view.

Helvetica Chimica Acta ± Vol. 84 (2001)
489
‡
Fig. 7. X-Ray diffraction structures of a) H ´ H (S)-Bin
O and b) Bz (R)-Bin Phe NHChx (1') with
numbering of the atoms. The CˆO ´´´ H N intramolecular H-bond is indicated by a dashed line. Arbitrary
numbering.

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Table 2. Selected Side-Chain Torsion Angles ([8]) of the X-Ray Diffraction Structures of H ´ H2-Bin
Peptides. For numbering, see Fig. 7)
O and Its
‡
Torsion angle
H ´ H (S)- Bz (R)-
Boc (S)-Bin Ala Aib TOAC-
Bin
O
Bin Phe NHChx (1') (Ala)2 OtBua)
mol. A
74.7(5)
73.1(5)
1.4(6)
mol. B
72.8(5)
74.7(5)
1.5(6)
C(a) C(b) C(2) C(1)
C(a) C(b') C(2') C(1')
C(b) C(2) C(1) C(1')
C(b') C(2') C(1') C(1)
C(2) C(1) C(1') C(2')
C(2) C(b) C(a) C(b')
C(2') C(b') C(a) C(b)
71.9(3)
69.4(4)
0.8(4)
74.1(6)
73.7(6)
2.7(8)
5.4(4)
2.6(8)
0.8(6)
2.5(6)
53.8(4)
40.3(3)
44.9(3)
56.5(7)
43.9(6)
43.5(6)
54.3(6)
46.3(5)
40.6(5)
55.9(6)
40.8(5)
46.8(5)
a) Ref. [31].
dipeptide Bz (R)-Bin Phe NHChx (1') were determined by X-ray diffraction (see
Fig. 7). Selected Bin side-chain torsion angles for the two structures, in comparison
with those of Boc (S)-Bin Ala Aib-TOAC (Ala)2 OtBu (TOAC, 2,2,6,6-tetra-
methylpiperidin-1-oxyl-4-carboxylic acid), the only published X-ray diffraction struc-
ture of a Bin-containing peptide [31], are given in Table 2.
The dipeptide 1' was obtained from racemic Bz (RS)-Bin OH by reaction with
optically active H Phe NHChx (15) [29], yielding 1:1 mixture of the (R,S)- and
(S,S)-diastereoisomers, which were separated by column chromatography. The
configuration of the binaphthalene unit of the crystalline diastereoisomer subjected
to X-ray diffraction analysis was suspected to be (R) from the specific optical rotation
by comparison with previously prepared series of similar compounds. The present X-
ray diffraction data confirmed the relative configuration rel-(R,S) of dipeptide 1' which
is characterized by two stereogenic units, a chirality axis (Bin two-fold axis) and a
chirality center (C(a)-atom of Phe).
‡
The free amino acid is found in the dipolar (zwitterionic) form H ´ H (S)-
Bin
O and co-crystallizes with two MeOH molecules, while the dipeptide 1' co-
crystallizes with two AcOEt molecules. The length of the characteristic C(1) C(1')
bond joining the two naphthalene moieties of Bin (1.495(4) Š for the free amino acid
and 1.501(7) Š for 1') compare well with those already published for the same residue
[31]. In the heterochiral dipeptide 1' all amide (peptide) moieties (w torsion angles)
are trans-planar [49 ± 51]. The other backbone torsion angles [52] are: f1 ˆ 47.6(7)8,
y1 ˆ 42.7(7)8 and f2 ˆ 84.4(7)8, y2 ˆ 8.4(8)8. This folded conformation, stabi-
lized by an intramolecular H-bond C(30)ˆO(0) ´´´ H N(3), the O(0) ´´´ N(3) distance
(2.965(7) Š) being normal for such an interaction [53 ± 55], is termed type-I b-bend
[17 ± 19]. The observation that the thermal ellipsoids of the atoms of this ten-membered
pseudo-ring are significantly smaller than those of the remaining atoms of flexible parts
of the molecule indicates rigidity of this pseudo-cyclic structure. The Phe side chain and
the peptide unit are found to be in a syn-clinal disposition, the c1 torsion angle being
72.1(7)8 [56]. The definite preference of the Phe aromatic group for c2 ꢀ 908
(105.4(9)8) is confirmed, in this conformation the ring being approximately perpen-
dicular to the plane defined by the C(a), C(b), and C(g) atoms. We also observed
unusual C H ´´´ p interactions in this structure. The Phe aromatic ring is in a good

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position for accepting a Csp2 H-atom of the Bin binaphthalene system. Actually, all
H ´´´ C distances (in the range 3.570 ± 3.336 Š) are consistent with a weak intra-
molecular H-bond interaction of the C(3') H ´´´ p type [57]. An analysis of the
geometry of the Bin residues in the two structures shows that deformations may be
produced in the heptacyclic system, compared to the saturated ring of the parent Ac7c,
by unfavourable steric interactions. More specifically, in each Bin residue, the seven-
membered ring is pseudo-symmetrical with a non-crystallographic C2 axis passing
through the C(a) atom and the middle of the opposite C(1) C(1') bonds, the two
sterically encumbering binaphthalene systems being largely non-planar (the dihedral
angle between the normal to their average planes is close to 608) [31]. The exocyclic
torsion angle about the C(1) C(1') bond is 58.4(4)8 in the (S)-amino acid and
62.4(8)8 in the (R)-Bin dipeptides.
In both structures, the a-amino substituent of the Bin residue is halfway between
the axial and equatorial position with respect to the average plane of the seven-
membered ring.
The conformation of the seven-membered ring in the two compounds is close to a
twist-boat (TB) [58 ± 62], with the following puckering parameters [63]: QT ˆ
1.066(3) Š,q2 ˆ 84.7(2)8, f2 ˆ 272.5(1)8, and f3 ˆ 268.2(15)8 for the free amino acid,
and QT ˆ 1.123(6) Š, q2 ˆ 85.3(3)8, f2 ˆ 90.0(3)8, and f3 ˆ 88(3)8 for the (R)-Bin
dipeptide 1'. According to literature data, in the family of conjugated cycloheptadienes,
the seven-membered ring adopts a boat or a flat boat conformation [64]. The vicinal
CˆC bond moiety is intermediate between the cis and gauche conformations. If two
aromatic rings are vicinally fused to cycloheptane, they are rotated about the joining
C(1) C(1') bond forming a gauche conformation with a torsion angle in the range
Æ45 ± 608. All seven-membered rings of this type are classified as distorted boats, most
of them adopting a conformation with the two torsion angles about the fusion bonds
(C(b) C(2) C(1) C(1') and C(b') C(2') C(1') C(1)) close to 08. Indeed, the
absolute values observed for these two torsion angles in our two compounds are in the
range 0.9 ± 5.48.
‡
In the crystal structure of the free amino acid H ´ H (S)-Bin O , the three H-
atoms of the ammonium group participate in strong H-bonds of the N H ´´´ O type.
Two of them are bound to the carboxylate O-atoms O(1) and O(2) of ( x, y ‡ 1/2, z)
and ( x, y 1/2, z) symmetry-related molecules, respectively, the N(1) ´´´ O(1) and
N(1) ´´´ O(2) distances being 2.701(4) and 2.856(4) Š, respectively. The third H-atom is
linked to the MeOH O-atom (N ´´´ O(MeOH 2), 2.833(4) Š). Each of the two MeOH
molecules doubly interacts, as donor and acceptor centres, forming O H (MeOH 1) ´´´
O(2)(carboxylate) (2.669(4) Š) and O H(MeOH 2) ´´´ O(MeOH 1) (2.677(6) Š)
intermolecular H-bonds [65][66]. The five different H-bonds in the crystal form a
complex network of three types of ten-membered H-bonded pseudocycles.
In the b-turn-forming dipeptide 1', two types of intermolecular N H ´´´ O
interactions stabilize the crystal structure: N(2) H (peptide) ´´´ O(AcOEt 1 carbonyl
O-atom) (2.983(8) Š) and N(1) H(amide) ´´´ O(2) ˆC(13)(amide) with the (1 x,
y ‡ 1/2,
z ‡ 1/2) symmetry-related dipeptide molecule, the N ´´´ O distance being
2.873(7) Š.
In summary, as far as the backbone conformation of Bin is concerned, the present
crystal-state analysis confirms the published result [31] that this Ca-tetrasubstituted a-

492
Helvetica Chimica Acta ± Vol. 84 (2001)
amino acid has a marked tendency to fold, as already observed for Aib [8][13] and Iva
[14 ± 16], the prototypes of this family, and Acnc residues, including Ac7c [8 ± 12]. In
addition, in analogy with the hexapeptide structure [31], also in the dipeptide discussed
in this work, the relationship between amino-acid chirality and screw sense of the bend/
helix formed is opposite to that commonly observed for protein amino acids, namely
(R)-Bin forces the peptide chain to fold into right-handed bends/helices.
Conclusions. ± The conformational tendencies of coded a-amino acids, in which
chirality is exclusively associated with the presence of one (or, in few cases, two)
asymmetric C-atom(s), have been extensively investigated in the last fourty years
[67][68]. We now have reported for the first time a detailed analysis of the preferred
conformation of a chiral a-amino acid lacking any asymmetric C-atom, the chirality of
which is rather based on a different type of molecular dissymmetry, the biarene axis
(pseudo-C2 symmetry). Actually, the present study is a second step in our ongoing
conformational analysis of peptides characterized by atropisomeric biarene-containing
a-amino acids. In our first investigation, we have recently examined Bip, the biphenyl
congener of Bin [69][70]. However, Bip undergoes racemization at room temperature
which is indicative of a residual mobility in the biphenyl system. This property is
responsible for the complicated conformational assignment of Bip-rich peptides, owing
to the concomitant occurrence of diastereoisomeric species in their equilibrium
mixtures. In contrast, Bin, a rigidified axially chiral residue is configurationally stable.
We have conclusively shown that in analogy with Aib- [8][13], Iva- [14 ± 16], and
Ac7c-based [9 ± 11] peptides, Bin peptides tend to fold into b-bends and 310-helices, and
that the relationship between amino-acid chirality and screw sense of the bends/helices
formed is opposite to that of protein amino acids. However, at least in the very short
oligomers, a non-negligible population of fully extended conformers is also observed.
The fact that this last property is slightly less pronounced in Bin peptides than in the
corresponding Bip peptides [69][70] is possibly ascribed to the more marked chiral
twist of the binaphthalene/Ac7c fused molecular system.
Experimental Part
General. Abbreviations: DCU, N,N'-dicyclohexylurea; EDC, 1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide; NMM; N-methylmorpholine. Anal. TLC and prep. column chromatography (CC): silica gel F 254 and
silica gel 60 (0.040 ± 0.063 mm) plates (Merck), resp.; eluent systems: 2.5% MeOH/CH2Cl2 (A); 5% MeOH/
CH2Cl2 (B); 10% MeOH/CH2Cl2 (C); UV detection (254 nm) on TLC for all compounds, even at low
concentration. M.p.s: determination with a temp. raise of 38/min; uncorrected. [a]D: Perkin-Elmer 241
polarimeter, 1-dm thermostated cell. CD Spectra: Jasco J-715 dichrograph, 1.0- and 0.2 ± mm fused-quartz cells;
spectrograde MeOH (Fluka); [q]T (total molar ellipticity) in 8 ´ cm ´ dmol 1. FT-IR Spectra: solid-state IR by
the KBr disk technique, with a Perkin-Elmer 580-B spectrophotometer equipped with a Perkin-Elmer 3600 IR
data station; solution IR with a Perkin-Elmer 1720 X-FT-IR spectrophotometer, N2-flushed, equipped with a
1
sample-shuttle device, at 2 cm nominal resolution, averaging 100 scans; solvent (baseline) spectra were
obtained under the same conditions; 0.1-,1.0-, and 10-mm cells with CaF2 windows, spectrograde CDCl3 (99.8%
1
D) from Fluka. H- and 13C-NMR Spectra: in CDCl3 (99.96% D; Aldrich) or (D6)DMSO (99.96% D6, Acros
Organics) at 300 (400) MHz and 77 MHz, resp. Bruker AC-300 or -AM-400 spectrometer; d in ppm rel. to SiMe4
as internal standard, J in Hz; TEMPO from Sigma. MS: m/z (rel. T).
Boc (S)-Bin Ala OMe. To a suspension of Boc (S)-Bin OH [28] (0.113 g, 0.25 mmol), HCl ´
H
Ala OMe (0.070 g, 0.5 mmol)), and HOBt (0.068 g, 0.5 mmol) in THF (2 ml) and CH2Cl2 (2 ml), a soln.
of Et3N (0.051 g, 0.5 mmol) in CH2Cl2 (0.5 ml) and then a soln. of DCC (0.064 g, 0.3 mmol) in CH2Cl2 (0.5 ml)
were added. The mixture was magnetically stirred at r.t. overnight and then evaporated. The residue was stirred

Helvetica Chimica Acta ± Vol. 84 (2001)
493
for a few min in the presence of AcOEt (50 ml) and the insoluble solid (DCU) filtered off. The soln. was
extracted with 0.5n HCl (2 Â 100 ml), H2O (100 ml), 5% NaHCO3 soln. (2 Â 100 ml), and H2O (2 Â 100 ml),
dried (MgSO4) and evaporated and the crude product submitted to CC (column 1.5 Â 41 cm, silica gel, B). The
chromatographically pure sample was crystallized from CH2Cl2/hexane: 0.129 g (96%) of pure solid dipeptide.
25
25
25
25
25
M.p. 1418. [a]
ˆ
49, [a]
ˆ
52, [a]
ˆ
65, [a]
ˆ
199, [a]
ˆ
947 (c ˆ 1, MeOH). Rf 0.75 (B).
589
578
546
436
365
1H-NMR: 7.96 ± 7.19 (m, 12 arom. H); 7.11 (br. m, NH (Ala)); 4.70 (s, NH (Bin)); 4.63 (dq, J ˆ 7.3, 7.3,
H
C(a)(Ala)); 3.79 (s, MeO); 3.41 ± 2.33 (dd, J ˆ 12.9, H C(b) (Bin)); 3.31 ± 3.12 (br. dd, J ꢀ 13.4, H C(b)
(Bin)); 1.49 (s, Boc); 1.40 (d, J ˆ 7.2, H C(b) (Ala)). Anal. calc. for C33H34N2O5 ´ 0.5 H2O (547.626): C 72.37,
H 6.44, N 5.11; found: C 72.12, H 6.38, N 4.91.
H
(S)-Bin Ala OMe. To Boc (S)-Bin Ala OMe (0.118 g, 0.22 mmol) in AcOEt (4 ml), 4.8n HCl in
AcOEt (4 ml) was added. The resulting soln. was stirred at r.t. for 2 h and then evaporated. The residue was
dissolved in AcOEt and the soln. extracted as described above for the Boc-dipeptide. The crude product was
25
submitted to CC (column 1.5  41 cm, silica gel, C): 0.083 g (86%) of pure dipeptide. Solid foam. [a] ˆ ‡165,
589
25
25
25
25
[a] ˆ ‡171, [a] ˆ ‡192, [a] ˆ ‡264, [a]
ˆ
235 (c ˆ 0.5, MeOH). Rf 0.45 (B), 0.75 (C). 1H-NMR:
578
546
436
365
7.97 ± 7.91 (m, 4 arom. H); 7.82 (d, J ˆ 7.7, NH (Ala)); 7.58 ± 7.19 (m, 8 arom. H); 4.59 (dq, J ˆ 7.3, 7.3, H C(a)
(Ala)); 3.81 (s, MeO); 3.39 ± 2.33 (dd, J ˆ 13.1, 2 H C(b) (Bin)); 3.11 ± 2.48 (dd, J ˆ 13.2, 2 H C(b) (Bin));
2.08 (s, NH2(Bin)); 1.45 (d, J ˆ 7.2, Me(b) (Ala)). 13C-NMR: 175.0, 173.5 (CˆO (Ala, Bin)); 136.3 ± 124.8
(arom. C); 68.6 (C(a) (Bin)); 52.3 (MeO); 47.7 (Ca) (Ala)); 45.3 (C(b) (Bin)); 43.3 (Cb') (Bin)); 17.9 (C(b)
(Ala)). Anal. calc. for C28H26N2O3 ´ 0.3 H2O (452.917): C 74.25, H 6.14, N 6.18; found: C 74.32, H 6.06, N 5.99.
Z
Ala (S)-Bin Ala OMe. To an ice-cold soln. of Z Ala OH (0.165 g, 0.74 mmol) in MeCN (2 ml), a
soln. of DCC (0.076 g, 0.37 mmol) in MeCN (0.5 ml) was aded. The mixture was stirred at 08 for 1 h, filtered
through glass wool for elimination of the DCU precipitate, and added to an ice-cold soln. of H (S)-
Bin Ala OMe (0.081 g, 0.18 mmol) in MeCN (2 ml). The resulting soln. was stirred from 08 to r.t. overnight
and then evaporated. The residue was dissolved in AcOEt (150 ml) and the soln. extracted as described above
for Boc (S)-Bin Ala OMe. The crude product was submitted to CC (column 1.5 Â 41 cm, silica gel, C). The
resulting chromatographically pure sample was crystallized from CH2Cl2/hexane: 0.100 g (84%) of tripeptide.
25
25
25
25
25
Amorphous solid. M.p. 2168. [a]
ˆ
68, [a]
ˆ
72, [a]
ˆ
86, [a]
ˆ
222, [a]
ˆ
862 (c ˆ 0.5,
589
578
546
436
365
MeOH). Rf 0.70 (C). 1H-NMR (Z Ala1-Bin Ala2 OMe): 7.92 ± 7.86 (m, 4 arom. H); 7.55 ± 7.22 (m, 13 ar-
om. H); 7.20 (d, J ꢀ 7.2, NH (Ala2), partly masked, identified by 2D COSY); 6.10 (s, NH (Bin)); 5.28 (d, J ˆ 6.5,
NH (Ala1)); 5.09 ± 5.01 (dd, J ˆ 12.2, CH2 (Z)); 4.53 (dq, J ˆ 7.2, 7.2, H C(a) Ala2)); 4.01 (br. dq, J ꢀ 6.8, 6.8,
H
C(a) (Ala1)); 3.76 (s, MeO); 3.37 ± 2.39 (dd, J ꢀ 12.8, 2 H C(b) (Bin)); 3.43 ± 3.15 (dd, J ꢀ 13.5, 2 H C(b)
(Bin)); 1.42 (d, J ˆ 7.0, Me(b) (Ala1)); 1.36 (d, J ˆ 7.2, Me(b) (Ala2)). 13C-NMR: 173.7, 172.2, 171.0 (CˆO (Ala1,
Ala2, Bin)); 156.2 (CˆO (Z)); 135.9 ± 125.2 (arom. C); 70.7 (C(a) (Bin)); 67.2 (CH2 (Z)); 52.3 (MeO); 51.4,
48.3 (C(a) (Ala1, Ala2)); 42.6 (C(b) (Bin)); 36.1 (C(b') (Bin)); 17.5 (C(b) (Ala1, Ala2)). Anal. calc. for
C39H37N3O6 ´ 0.5 H2O (652.718): C 71.76, H 5.87, N 6.43; found: C 71.76, H 5.88, N 6.21.
Z
(S)-Bin Ala Ala OMe. To a suspension of Z (S)-Bin OH [28] (0.122 g, 0.25 mmol), HCl ´
H
Ala Ala OMe (0.105 g, 0.5 mmol) and HOBt (0.068 g, 0.5 mmol) in THF (2 ml) and CH2Cl2 (2 ml), a
soln. of Et3N (0.051 g, 0.5 mmol) in CH2Cl2 (1 ml) was added, then a soln. of DCC (0.065 g, 0.3 mmol) in CH2Cl2
(1 ml). The mixture was magnetically stirred at r.t. overnight and then evaporated. The residue was dissolved in
AcOEt (150 ml) and the soln. extracted as described above for Boc (S)-Bin Ala OMe. Repeated CC (silica
gel, C) of the crude product, followed by crystallization from CH2Cl2/hexane gave 0.130 g (81%) of pure
25
25
25
25
25
tripeptide. Solid. M.p. 1528. [a]
ˆ
66, [a]
ˆ
70, [a]
ˆ
84, [a]
ˆ
222, [a]
ˆ
880 (c ˆ 0.6,
589
578
546
436
365
MeOH). Rf 0.70 (C). 1H-NMR (Z Bin Ala1 Ala2 OMe): 7.94 ± 7.85 (m, 4 arom. H); 7.55 ± 7.22 (m,
13 arom. H); 7.07 (br. m, NH (Ala1)); 6.66 (d, J ˆ 7.4, NH (Ala2)); 5.19 ± 5.04 (dd, J ˆ 12.1, CH2 (Z)); 5.08 (s,
NH (Bin)); 4.54 (dq, J ˆ 7.2, 7.2, H C(a) (Ala2)); 4.51 (br. m, H C(a) (Ala1)); 3.75 (s, MeO); 3.45 ± 2.33
(dd, J ꢀ 12.8, 2 H C(b) (Bin)); 3.14 ± 3.07 (dd, J ꢀ 13.3, 2 H C(b) (Bin)); 1.42 (d, J ˆ 7.2, Me(b) (Ala2)); 1.34
(d, J ˆ 7.0, (Ala1) Me(b)). 13C-NMR: 173.1, 171.8 (CˆO (Ala1, Ala2, Bin)); 155.4 (CˆO (Z)); 135.9 ± 125.3
(arom. C); 70.3 (C(a) (Bin)); 67.2 (CH2 (Z)); 52.4 (MeO); 49.1, 48.2 (C(a) (Ala1, Ala2)); 42.3 (C(b) (Bin)); 37.9
(C(b') (Bin)); 17.8, 17.6 (C(b) (Ala1, Ala2)). Anal. calc. for C39H37N3O6 ´ 0.5 H2O (652.718): C 71.76, H 5.87,
N 6.43; C 71.79, H 5.94, N 6.22.
Boc Ala (S)-Bin Ala OMe (6). To a soln. of Boc (S)-Bin Ala OMe (0.168 g, 0.31 mmol) in
CH2Cl2 (5 ml), CF3COOH (5 ml) was added. The soln. was stirred at r.t. for 3 h and then evaporated. The
residue was solubilized in AcOEt (100 ml). The soln. was extracted with 5% NaHCO3 soln. (100 ml), dried
(MgSO4), and evaporated. The crude H (S)-Bin Ala OMe (0.137 g, 0.31 mmol) was dissolved in MeCN
(4 ml) and the soln. cooled to 58 and added to a cold soln. of (Boc Ala)2O, previously prepared by stirring a
soln. of Boc Ala OH (0.236 g, 1.25 mmol) and EDC (0.120 g, 0.63 mmol) in MeCN (6 ml) at 58 for 1 h. The

494
Helvetica Chimica Acta ± Vol. 84 (2001)
mixture was magnetically stirred from 58 to r.t. for 24 h and then evaporated. The residue was dissolved in
AcOEt (150 ml) and the soln. extracted as described above for Boc (S)-Bin Ala OMe. CC (cilica gel, B) of
25
25
25
the crude product gave 0.154 g (81%) of pure 6. Solid. M.p. 1428. [a]
ˆ
62, [a]
ˆ
65, [a]
ˆ
81,
589
578
546
25
25
[a]
ˆ
218, [a]
ˆ
887 (c ˆ 0.2, MeOH). Rf 0.50 (B). 1H-NMR (Boc Ala1 Bin Ala2 OMe): 7.93 ±
436
365
7.87 (m, 4 arom. H); 7.56 ± 7.18 (m, 9 arom. H, masked NH (Ala2)); 6.29 (s, NH (Bin)); 5.04 (d, J ˆ 6.4, NH
(Ala1)); 4.55 (dq, J ˆ 7.2, 7.2, H C(a) (Ala2)); 3.97 (dq, J ˆ 6.8, 6.8, H C(a) (Ala1)); 3.75 (s, MeO); 3.44 ± 3.13
(dd, J ꢀ 13.8, 2 H C(b) (Bin)); 3.38 ± 2.41 (dd, J ꢀ 12.7, 2 H C(b) (Bin)); 1.40 (d, J ˆ 7.2, Me(b) (Ala)); 1.39
(d, J ˆ 7.3, Me(b) (Ala)); 1.36 (s, Boc). 13C-NMR: 173.6, 172.5, 171.2 (CˆO (Ala1, Ala2, Bin)); 155.7 (CˆO
(Boc)); 134.7 ± 125.2 (arom. C); 80.5 (Boc); 70.6 (C(a) (Bin)); 52.2 (MeO); 50.9, 48.3 (C(a) (Ala1, Ala2)); 42.5
(C(b) (Bin)); 36.3 (C(b') (Bin)); 28.2 (Boc); 17.7, 17.6 (C(b) (Ala1, Ala2)). Anal. calc. for C36H39N3O6 ´ 0.5 H2O
(618.704): C 69.88, H 6.52, N 6.79; found: C 69.88, H 6.57, N 7.01.
Boc Ala Ala (S)-Bin Ala OMe (7). Boc Ala-(S)-Bin Ala OMe (6; 0.142 g, 0.23 mmol) was N-
deprotected in CH2Cl2 (5 ml) and CF3COOH (5 ml) as described above for Boc Ala (S)-Bin Ala OMe. A
soln. of a mixture of the crude H Ala (S)-Bin Ala OMe (0.119 g, 0.23 mmol), Boc Ala OH (0.066 g,
0.35 mmol), and HOBt (0.062 g, 0.47 mmol) in THF (5 ml) and CH2Cl2 (2.5 ml) was cooled to 58, and a soln.
of EDC (0.067 g, 0.35 mmol) in CH2Cl2 (2.5 ml) was added. The mixture was magnetically stirred from 58 to
r.t. for 24 h and then evaporated. The residue was dissolved in AcOEt (150 ml) and the soln. extracted as
described above for Boc (S)-Bin Ala OMe. CC (silica gel, C) of the crude product gave 0.148 g (93%) of
25
25
25
25
25
pure 7. Solid. M.p. 1318. [a]
ˆ
109, [a]
ˆ
118, [a]
ˆ
139, [a]
ˆ
336, [a]
ˆ
1449 (c ˆ 0.2,
589
578
546
436
365
MeOH). Rf 0.50 (C). 1H-NMR (Boc Ala1 Ala2 Bin Ala3 OMe): 7.91 ± 7.85 (m, 4 arom. H); 7.52 ± 7.16
(m, 9 arom. H, masked NH (Ala3)); 6.99 (br. d, NH (Ala2)); 6.64 (s, NH (Bin)); 5.08 (d, J ˆ 7.2, NH (Ala1)); 4.50
(dq, J ˆ 7.2, 7.2, H C(a) (Ala3)); 4.17 (dq, J ˆ 6.6, H C(a) (Ala2)); 4.08 (br. m, H C(a) (Ala1)); 3.71
(s, MeO); 3.40 ± 3.09 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 3.29 ± 2.47 (dd, J ꢀ 12.8, 2 H C(b) (Bin)); 1.42 (d, J ˆ 7.0,
Me(b) (Ala)); 1.35 (d, J ˆ 7.3, Me(b) (Ala)); 1.22 (d, J ˆ 7.0, Me(b) (Ala)); 1.32 (s, Boc). 13C-NMR: 173.8,
173.2, 172.0, 171.2 (CˆO (Ala1, Ala2, Ala3, Bin)); 155.4 (CˆO Boc)); 135.0 ± 125.2 (arom. C); 80.3 (Boc); 70.6
(C(a) (Bin)); 52.3 (MeO); 52.2, 50.9, 48.3 (C(a) (Ala1, Ala2, Ala3)); 42.4 (C(b) (Bin)); 35.7 (C(b') (Bin)); 28.2
(Boc), 17.8, 17.5, 17.4 (C(b) (Ala1, Ala2, Ala3)). ESI-MS (pos.): 681 (17, [M ‡ H] ), 703 (100, [M ‡ Na] ), 719
‡
‡
‡
(8, [M ‡ K] ). Anal. calc. for C39H44N4O7 ´ H2O (698.790): C 67.03, H 6.63, N 8.02; found: C 66.94, H 6.43, N 7.82.
Boc (S)-Bin Ala Ala (S)-Bin Ala OMe (8). Boc Ala Ala (S)-Bin Ala OMe (7; 0.135 g,
0.20 mmol) was N-deprotected in CH2Cl2 (5 ml) and CF3COOH (5 ml) as described above for the synthesis
of Boc Ala (S)-Bin Ala OMe. To
a soln. of crude H Ala Ala (S)-Bin Ala OMe (0.110 g,
0.19 mmol), Boc (S)-Bin OH (0.086 g, 0.19 mmol), and HOBt (0.038 g, 0.28 mmol) in THF (10 ml) and
CH2Cl2 (5 ml), a soln. of EDC (0.043 g, 0.23 mmol) in CH2Cl2 (5 ml) was added. The mixture was magnetically
stirred at r.t. for 48 h and evaporated. The residue was dissolved in AcOEt (150 ml) and the soln. extracted as
described above for Boc (S)-Bin Ala OMe. CC (silica gel, B) of the crude product, followed by
25
25
crystallization from MeCN, gave 0.098 g (49%) of pure 8. Crystals. M.p. 2208. [a]
ˆ
89, [a]
(C).
ˆ
94,
589
578
25
25
25
[a]
ˆ
115,
[a]
ˆ
297,
[a]
ˆ
1139
(c ˆ 0.2,
MeOH).
Rf
0.55
1H-NMR
546
436
365
(Boc Bin1 Ala2 Ala3 Bin4 Ala5 OMe): 8.00 ± 7.13 (m, 24 arom. H); 7.45 (masked d, identified by 2D
COSY, NH (Ala2, NOE with NH (Bin1)); 7.32 (masked d, identified by 2D COSY, NH (Ala5)); 6.67 (s, NH
(Bin4)); 6.51 (d, J ˆ 6.5, NH (Ala3)); 4.95 (s, NH (Bin1)); 4.57 (dq, J ꢀ 7.2, 7.2, H C(a) (Ala5)); 4.14 (dq, J ꢀ 6.6,
6.6, H C(a) (Ala2), H C(a) (Ala3)); 3.71 (s, MeO); 3.57 ± 2.29 (dd, J ꢀ 12.7, 2 H C(b) (Bin)); 3.54 ± 2.65
(dd, J ꢀ 13.0, 2 H C(b) (Bin)); 3.52 ± 2.23 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 2.97 ± 2.90 (dd, J ꢀ 13.0, 2 H C(b)
(Bin)); 1.50 (d, J ˆ 7.2, Me(b) (Ala)); 1.41 (d, J ˆ 7.3, Me(b) (Ala5)); 1.33 (d, J ˆ 7.3, Me(b)); 1.40 (s, Boc).
13C-NMR: 173.9, 172.9, 172.5, 172.1, 171.7 (CˆO (Ala2, Ala3, Ala5, Bin1, Bin4)); 155.6 (CˆO (Boc)); 135.2 ±
125.0 (arom. C); 81.4 (Boc); 70.9, 70.0 (C(a) (Bin1, Bin4)); 52.2 (MeO); 51.0, 49.8, 48.2 (C(a) (Ala2, Ala3,
Ala5)); 42.6, 41.5, 39.4, 36.4 (C(b), C(b') (Bin1, Bin4)); 28.2 (Boc); 17.5, 16.9, 16.5 (C(b) (Ala2, Ala3, Ala5). ESI-
‡
‡
MS (pos.): 1038 (100, [M ‡ Na] ), 1016 (29, [M ‡ H] ). Anal. calc. for C63H61N5O8 ´ H2O (1034.174): C 73.16,
H 6.14, N 6.77; found: C 73.23, H 6.14, N 6.72.
Boc (S)-Bin Gly OMe. To a suspension of Boc (S)-Bin OH (0.181 g, 0.40 mmol), HCl ´ H Gly-
OMe (0.100 g, 0.80 mmol) and HOBt (0.108 g, 0.80 mmol) in THF (5 ml) and CH2Cl2 (5 ml), a soln. of
CF3COOH (0.081 g, 0.80 mmol) in CH2Cl2 (5 ml) was added and then a soln. of EDC (0.095 g, 0.50 mmol) in
CH2Cl2 (5 ml). The mixture was magnetically stirred at r.t. overnight and then evaporated. The residue was
dissolved in AcOEt (150 ml) and the soln. extracted as described above for Boc (S)-Bin Ala OMe. CC
25
25
(silica gel, A) of the crude product gave 0.203 g (97%) of pure dipeptide. Solid. M.p. 1648. [a] ˆ ‡127, [a]
ˆ
589
578
‡128, [a] ˆ ‡143, [a] ˆ ‡171, [a] ˆ ‡371 (c ˆ 0.3, CHCl3). Rf 0.25 (B). 1H-NMR: 7.95 (d, J ˆ 8.3,
25
25
25
546
436
365
2 arom. H); 7.90 (d, J ˆ 8.4, 2 arom. H); 7.63 (d, J ˆ 8.3, 1 arom. H); 7.48 ± 7.18 (m, 8 H, arom. H, masked NH

Helvetica Chimica Acta ± Vol. 84 (2001)
495
(Gly)); 4.78 (br. s, NH (Bin)); 4.19 ± 3.99 (2dd, J ˆ 18.2, 5.7 ± 18.2, 5.0, 2 H C(a) (Gly)); 3.75 (s, MeO); 3.47 ±
2.34 (dd, J ꢀ 12.8, 2 H C(b) (Bin)); 3.34 ± 3.10 (br. dd, J ꢀ 13.1, 2 H C(b) (Bin)); 1.48 (s, Boc). 13C-NMR:
172.9, 170.5 (CˆO (Gly, Bin)); 154.8 (CˆO (Boc)); 134.7 ± 125.1 (arom. C); 82.3 (Boc); 70.5 (C(a) (Bin)); 52.2
(MeO); 42.4 (C(a) (Gly)); 41.4, 37.5 (C(b), C(b') (Bin)); 28.3 (Boc). Anal. calc. for C32H32N2O5 (524.592):
C 73.26, H 6.15, N 5.34; found: C 73.22, H 6.28, N 5.24.
Boc Gly (S)-Bin Gly OMe (3). To a soln. of Boc (S)-Bin Gly OMe (0.196 g, 0.37 mmol) in
CH2Cl2 (5 ml), CF3COOH (5 ml) was added. The soln. was stirred at r.t. for 3 h and evaporated. The residue
was solubilized in AcOEt (100 ml). The soln. was extracted wtih 5% NaHCO3 soln. (100 ml), dried (MgSO4),
and evaporated. The crude H (S)-Bin Gly OMe (0.157 g, 0.37 mmol) was dissolved in MeCN (5 ml) and
CH2Cl2 (5 ml). This soln. was added to a soln. of (Boc Gly)2O previously prepared by stirring a soln. of
Boc Gly OH (0.262 g, 1.50 mmol) and EDC (0.143 g, 0.74 mmol) in MeCN (10 ml) for 1 h. The mixture was
magnetically stirred at r.t. for 24 h and then evaporated. The residue was dissolved in AcOEt (150 ml) and the
soln. extracted as described above for Boc (S)-Bin Ala OMe. The crude product was purified by
25
crystallization from CH2Cl2/cyclohexane to give 0.184 g (85%) of pure 3. Crystals. M.p. 1508. [a]
ˆ
589
25
25
25
25
43, [a]
ˆ
46, [a]
ˆ
58, [a]
ˆ
174, [a]
ˆ
808 (c ˆ 0.2, MeOH). Rf 0.25 (B). 1H-NMR
578
546
436
365
(Boc Gly1 Bin Gly2 OMe): 7.95 ± 7.89 (m, 4 arom. H); 7.63 (d, J ˆ 8.4, 1 arom. H); 7.48 ± 7.19 (m,
8 arom. H, masked NH (Gly2)); 6.38 (s, NH (Bin)); 5.11 (br. t, NH (Gly1)); 4.17 ± 3.94 (2dd, J ˆ 18.2, 5.5 ±
18.2, 5.2, 2 H C(a) (Gly2)); 3.78 ± 3.68 (2dd, J ˆ 16.3, 5.7 ± 16.3, 6.1, 2 H C(a) (Gly1)); 3.76 (s, MeO); 3.54 ±
2.40 (br. dd,J ꢀ 12.8, 2 H C(b) (Bin)); 3.41 ± 3.13 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 1.37 (s, Boc). 13C-NMR:
172.2, 170.5, 169.9 (CˆO (Gly1, Gly2, Bin)); 155.0 (CˆO (Boc)); 134.7 ± 125.3 (arom. C); 81.0 (Boc); 70.9 (C(a)
(Bin)); 52.2 (MeO); 45.4, 42.3 (C(a) (Gly1, Gly2)); 41.3, 37.3 (C(b), C(b') (Bin)); 28.1 (Boc). Anal. calc. for
C34H35N3O6 ´ 0.5 H2O (590.652): C 69.13, H 6.14, N 7.11; found: C 69.14, H 6.35, N 7.05.
Boc Gly Gly (S)-Bin Gly OMe (4). Boc Gly (S)-Bin Gly OMe (3; 0.167 g, 0.29 mmol) was N-
deprotected in CH2Cl2 (5 ml) and CF3COOH (5 ml) as described above for the synthesis of Boc Gly (S)-
Bin Gly OMe. To a soln. of crude H Gly (S)-Bin Gly OMe (0.138 g, 0.29 mmol), Boc Gly OH
(0.075 g, 0.43 mmol), and HOBt (0.062 g, 0.47 mmol) in THF (5 ml) and CH2Cl2 (2.5 ml), a soln. of EDC
(0.082 g, 0.43 mmol) in CH2Cl2 (2.5 ml) was added. The mixture was magnetically stirred at r.t. for 24 h and
evaporated. The residue was dissolved in AcOEt (150 ml) and the soln. extracted as described above for
Boc (S)-Bin Ala OMe. CC (silica gel, B) of the crude product gave 0.080 g (44%) of pure 4. Solid. M.p. 1838.
25
25
25
25
25
[a]
ˆ
39, [a]
ˆ
44, [a]
ˆ
53, [a]
ˆ
163, [a]
ˆ
757 (c ˆ 0.2, MeOH). Rf 0.35 (C).1H-NMR
589
578
546
436
365
(Boc Gly1 Gly2 Bin Gly3 OMe): 7.90 ± 7.81 (m, 4 arom. H); 7.57 (d, J ˆ 8.3, 1 arom. H); 7.50 ± 7.17
(m, 10 H, arom. H, masked NH (Gly2), NH (Gly3), NH (Bin)); 5.42 (br. t, NH (Gly1)); 4.10 ± 3.84 (dd, partly
masked dd, J ˆ 17.6, 6.1 ± 17.6, 5.1, 2 H C(a) (Gly3)); 3.84 ± 3.73 (2 partly masked dd, 2 H C(a) (Gly2)); 3.64 ±
3.51 (2 masked dd, J ꢀ 16.8, 5.9, 2 H C(a) (Gly1)); 3.65 (s, MeO); 3.37 ± 2.62 (dd, J ꢀ 13.1, 2 H C(b) (Bin));
3.32 ± 3.16 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 1.08 (s, Boc). 13C-NMR: 173.0, 171.4, 170.6, 169.2 (CˆO (Gly1, Gly2,
Gly3, Bin)); 156.4 (CˆO (Boc)); 134.8 ± 125.2 (arom. C); 80.5 (Boc); 70.8 (C(a) (Bin)); 52.1 (MeO); 44.4, 43.9,
42.1 (C(a) (Gly1, Gly2, Gly3)); 41.3, 36.7 (C(b), C(b') (Bin)); 27.9 (Boc). ESI-MS (pos.): 677 (9, [M ‡ K] ), 661
‡
‡
(100, [M ‡ Na] ), 639 (13, [M ‡ H]). Anal. calc. for C36H38N4O7 ´ 0.5 H2O (647.704): C 66.75, H 6.07, N 8.65;
found: C 66.71, H 6.16, N 8.51.
Boc (S)-Bin Gly Gly (S)-Bin Gly OMe (5). Boc Gly Gly (S)-Bin Gly OMe (4; 0.067 g,
0.11 mmol) was N-deprotected in CH2Cl2 (5 ml) and CF3COOH (5 ml) as described above for
Boc Gly (S)-Bin Gly OMe. To
a soln. of the crude H Gly Gly (S)-Bin Gly OMe (0.056 g,
0.11 mmol), Boc (S)-Bin OH (0.047 g, 0.11 mmol), and HOBt (0.021 g, 0.16 mmol) in THF (10 ml) and
CH2Cl2 (7.5 ml), a soln. of EDC (0.024 g, 0.13 mmol) in CH2Cl2 (2.5 ml) was added. The mixture was
magnetically stirred at r.t. for 48 h and evaporated. The residue was dissolved in AcOEt (150 ml) and the soln.
extracted as described above for Boc (S)-Bin Ala OMe. CC (silica gel, B) of the crude product followed
25
by crystallization from CH2Cl2/hexane gave 0.076 g (74%) of pure 5. Solid. M.p. 2238. [a]
ˆ
116,
589
25
25
25
25
[a]
ˆ
125, [a]
ˆ
150, [a]
ˆ
369, [a]
ˆ
1361 (c ˆ 0.2, MeOH). Rf 0.40 (C). 1H-NMR
578
546
436
365
(Boc Bin1 Gly2 Gly3 Bin4 Gly5 OMe): 8.04 (br. t, NH (Gly2 or Gly3)); 7.97 ± 7.01 (m, 24 arom. H); 7.20
(masked d, identified by 2D COSY, NH (Gly5)); 7.17 (masked d, identified by 2D COSY, NH (Gly3 or Gly2));
6.94 (s, NH (Bin4)); 5.04 (s, NH (Bin1)); 4.08± 3.88 (dd, masked dd, J ˆ 16.1, 5.7, 2 H C(a) (Gly5)); 3.87 (masked
d, 2 H C(a) (Gly3 or Gly2)); 3.86 ± 3.70 (2 masked dd, J ꢀ 17.8, 6.2, 2 H C(a) (Gly2 or Gly3)); 3.56 (s, MeO);
3.46 ± 2.55 (dd, J ˆ 13.2, 2 H C(b) (Bin)); 3.11 ± 2.20 (dd, J ꢀ 13.2, 2 H C(b) (Bin)); 2.72 (s, 2 H C(b) (Bin));
1.35 (s, Boc). 13C-NMR: 173.7, 172.9, 170.9, 170.5, 169.1 (CˆO (Gly1, Gly2, Gly3, Bin1, Bin2)); 156.0 (CˆO
(Boc)); 134.6 ± 124.9 (arom. C); 81.4 (Boc); 70.6, 69.9 (C(a) (Bin1, Bin2)); 52.0 (MeO); 44.1, 43.7, 42.2 (C(a)
(Gly1, Gly2, Gly3)); 42.1, 41.3, 7.2, 36.9 (C(b), C(b') (Bin1, Bin2)); 28.2 (Boc). ESI-MS (pos.): 996 (100,

496
Helvetica Chimica Acta ± Vol. 84 (2001)
‡
‡
[M ‡ Na] ), 974 (31, [M ‡ H] ). Anal. calc. for C60H55N5O8 ´ H2O (992.096): C 72.63, H 5.79, N 7.06; found:
C 72.72, H 5.77, N 7.01.
Z
Aib Aib (S)-Bin OtBu (12). A soln. of the oxazol-5(4H)-one from Z Aib Aib OH [38] (0.336 g,
1.10 mmol) and H (S)-Bin OtBu [28] (0.368 g, 0.90 mmol) in MeCN (25 ml) was refluxed for 4 d and then
evaporated. The residue was solubilized in AcOEt (150 ml). The soln. was extracted with 5% citric acid (2 Â
50 ml), H2O (100 ml), 5% NaHCO3 soln. (2 Â 50 ml), H2O (2 Â 100 ml), dried (MgSO4), and evaporated. The
crude product was submitted to CC (column 2 Â 47 cm, silica gel, B) and then to prep. TLC (A): 0.500 g (78%)
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25
25
25
25
of pure 12. Powder. M.p.1298. [a] ˆ ‡89, [a] ˆ ‡92, [a] ˆ ‡103, [a] ˆ ‡136, [a]
ˆ
167 (c ˆ 0.7,
589
578
546
436
365
MeOH). Rf 0.30 (B). 1H-NMR (Z Aib1 Aib2 Bin OtBu): 7.92 ± 7.83 (m, 4 arom. H); 7.55 (d, J ˆ 8.3,
1 arom. H); 7.45 ± 7.06 (m, 13 H, arom. H, NH (Aib2 or Bin)); 6.38 (s, NH (Bin or Aib2)); 5.06 (s, NH (Aib1));
4.63 ± 4.38 (dd, J ꢀ 12.3, CH2 (Z)); 3.23 ± 3.16 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 3.11 ± 2.73 (dd, J ꢀ 12.9, 2 H C(b)
(Bin)); 1.57, 1.47 (2s, Me(b), Me(b') (Aib)); 1.49 (s, OtBu); 1.39, 1.32 (2s, Me(b), Me(b') (Aib)). 13C-NMR:
173.2, 172.4, 170.8 (CˆO (Aib1, Aib2, Bin)); 155.1 (CˆO (Z)); 136.0 ± 124.8 (arom. C); 80.9 (OtBu), 69.9 (C(a)
(Bin)); 66.7 (CH2 (Z)); 57.2, 56.7 (C(a) (Aib1, Aib2)); 41.1, 37.3 (C(b), C(b') (Bin)); 27.9 (OtBu); 25.8, 25.4,
25.2,25.0 (C(b), C(b') (Aib1, Aib2)). Anal. calc. for C44H47N3O6 ´ 0.5 H2O (722.848): C 73.11, H 6.69, N 5.81;
found: C 73.25, H 6.76, N 5.69.
Z
Aib Aib (S)-Bin OH. To a soln. of Z Aib Aib (S)-Bin OtBu (12; 0.481 g, 0.67 mmol) in
CH2Cl2 (5 ml), CF3COOH (5 ml) was added. The soln. was stirred at r.t. for 3 h and evaporated. The residue
was solubilized in AcOEt (150 ml). The soln. was extracted with H2O (2 Â 100 ml), dried (MgSO4), and
evaporated. The residue was dissolved in MeOH and the soln. filtered and evaporated: 0.443 g (100%) of crude
25
tripeptide as a solid, which was used in the next step without further purification. M.p. 2058. [a] ˆ ‡100,
589
25
25
25
25
[a] ˆ ‡103, [a] ˆ ‡116, [a] ˆ ‡160, [a]
ˆ
129 (c ˆ 0.2, MeOH). Rf 0.30 (C). 1H-NMR
578
546
436
365
(Z Aib1 Aib2 Bin OH): 7.92 ± 7.79 (m, 4 arom. H); 7.51 ± 7.06 (m, 13 arom. H); 6.80, 6.78 (2s, 2 H, NH
(Aib2, Bin)); 6.28 (s, NH (Aib1)); 4.35 (br. m, CH2 (Z)); 3.30 ± 3.14 (br. dd, J ꢀ 13.6, 2 H C(b) (Bin)); 3.02 ±
2.79 (br. dd, J ꢀ 13.2, 2 H C(b) (Bin)); 1.50, 1.41 (2s, Me(b), Me(b') (Aib)); 1.41, 1.38 (2s, Me(b), Me(b')
(Aib)). 13C-NMR: 174.3, 173.6, 171.2 (CˆO (Aib1, Aib2, Bin)); 155.9 (CˆO (Z)); 135.7 ± 125.1 (arom. C); 70.1
(C(a) (Bin)); 66.3 (CH2 (Z)); 56.9, 56.7 (C(a) (Aib1, Aib2)); 40.8, 36.8 (C(b), (C(b') (Bin)); 26.3, 25.6, 23.8, 23.3
(C(b), C(b') (Aib1, Aib2). Anal. calc. for C40H39N3O6 ´ 1.5 H2O (684.760): C 70.15, H 6.18, N 6.14; found:
C 70.01, H 6.16, N 6.02.
Oxazol-5(4H)-one from Z Aib Aib (S)-Bin OH. A soln. of Z Aib Aib (S)-Bin OH (0.433 g,
0.67 mmol) in Ac2O (20 ml) was stirred at 115 ± 1208 for 40 min and then evaporated. The residue was
repeatedly dissolved in toluene and the soln. evaporated: 0.430 g (100%) of the crude oxazolone as a solid,
25
25
which was used in the next step without further purification. M.p. 1638. [a] ˆ ‡127, [a] ˆ ‡128,
589
578
25
25
25
[a] ˆ ‡143, [a] ˆ ‡172, [a]
ˆ
313 (c ˆ 0.2, CHCl3). Rf 0.65 (B), 0.80 (C). 1H-NMR
546
436
365
(Z Aib1 Aib2 Bin ox): 7.97 ± 7.89 (m, 4 arom. H); 7.50 ± 7.17 (m, 13 arom. H); 6.96 (br. s, NH (Aib2));
5.22 (s, NH (Aib1)); 5.10 (s, CH2 (Z)); 3.05 ± 2.62 (dd, J ꢀ 13.6, 2 H C(b) (Bin)); 2.97 ± 2.65 (dd, J ꢀ 13.3,
2 H C(b) (Bin)); 1.61, 1.59 (2s, Me(b), Me(b') (Aib)); 1.54, 1.52 (2s, Me(b), Me(b') (Aib)). Anal. calc. for
C40H37N3O5 ´ 1.2 H2O (661.339): C 72.64, H 6.00, N 6.35; found: C 72.64, H 6.07, N 6.15.
Z
Aib Aib (S)-Bin Aib OtBu (13). HCl ´ H Aib OtBu [39] (0.315 g, 1.61 mmol) was stirred for a
few min in Et2O (75 ml) and 5% NaHCO3 soln. (20 ml). The separated org. phase was dried (MgSO4) and
evaporated at 258. A soln. of the resulting H Aib OtBu (0.220 g, 1.38 mmol) and the oxazol-5(4H)-one from
Z
Aib Aib (S)-Bin OH (0.412 g, 0.65 mmol) in MeCN (15 ml) was refluxed for 24 h and then treated as
described above for 12. The crude product was submitted to CC (column 2.3 Â 49 cm, silica gel, B): 0.427 g
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25
25
25
25
(83%) of pure 13. Solid. M.p. 1578. [a] ˆ ‡30, [a] ˆ ‡30, [a] ˆ ‡32, [a] ˆ ‡13, [a]
ˆ
364 (c ˆ 0.2,
589
578
546
436
365
MeOH). Rf 0.60 (C). 1H-NMR (Z Aib1 Aib2 Bin Aib3 OtBu): 7.87 ± 7.77 (m, 4 arom. H); 7.58 (d, J ˆ 8.3,
1 arom. H); 7.43 ± 7.02 (m, 12 arom. H); 6.88, 6.86, 6.31 (3s, 3 NH (Aib2, Aib3, Bin)); 5.36 (s, NH (Aib1)); 4.46 ±
4.42 (dd, J ꢀ 12.9, CH2 (Z)); 3.52 ± 3.23 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 3.17 ± 2.63 (dd, J ꢀ 13.1, 2 H C(b)
(Bin)); 1.52 (s, tBuO); 1.54, 1.51, 1.47, 1.41, 1.47, 1.41 (6s, 18 H, Me(b), Me(b) (Aib). 13C-NMR: 174.1, 173.8,
172.6, 171.2 (CˆO (Aib1, Aib2, Aib3, Bin)); 155.4 (CˆO (Z)); 136.4 ± 124.7 (arom. C); 80.2 (tBuO); 70.4 (C(a)
(Bin)); 67.0 (CH2 (Z)); 57.1, 56.8, 56.3 (C(a) (Aib1, Aib2, Aib3)); 42.7, 34.7 (C(b), C(b') (Bin)); 27.9 (tBuO); 27.5,
26.4, 25.7, 24.0, 23.7, 23.2 (C(b), C(b') (Aib1, Aib2, Aib3)). Anal. calc. for C48H54N4O7 (798.944): C 72.16, H 6.81,
N 7.01; found: C 72.24, H 6.96, N 6.92.
Z
Aib Aib (S)-Bin Aib OH. Z Aib Aib (S)-Bin Aib OtBu (13; 0.422 g, 0.52 mmol) was C-
deprotected in CF3COOH (5 ml) and CH2Cl2 (5 ml) as described above for Z Aib Aib (S)-Bin OH:
0.379 g (96%) of crude tetrapeptide as a solid, which was used in the next step without further purification. M.p.
25
25
25
25
25
2198. [a] ˆ ‡37, [a] ˆ ‡37, [a] ˆ ‡40, [a] ˆ ‡20, [a]
ˆ
363 (c ˆ 0.2, MeOH). Rf 0.10 (C).
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Helvetica Chimica Acta ± Vol. 84 (2001)
497
1H-NMR (Z Aib1 Aib2 Bin Aib3 OH): 7.89 ± 7.69 (m, 6 arom. H); 7.41 ± 7.05 (m, 11 arom. H); 7.01, 6.73,
6.70 (3s, 3 NH (Aib2, Aib3, Bin)); 6.11 (s, NH (Aib1)); 4.08 (br. m, CH2 (Z)); 3.26 ± 3.04 (dd, J ꢀ 13.8, 2 H C(b)
(Bin)); 2.87 ± 2.82 (dd, J ꢀ 13.4, 2 H C(b) (Bin)); 1.67, 1.52, 1.41, 1.30, 1.28, 1.27 (6s, 18 H, Me(b), Me(b')
(Aib)). 13C-NMR: 176.3, 175.5, 174.8, 172.8 (CˆO (Aib1, Aib2, Aib3, Bin)); 155.9 (CˆO (Z)); 135.6 ± 125.0
(arom. C); 70.0 (C(a), (Bin)); 66.3 (CH2 (Z)); 57.2, 56.9, 56.7 (C(a) (Aib1, Aib2, Aib3)); 42.2, 35.9 (C(b), C(b')
(Bin)); 27.2, 26.1, 25.9, 24.2, 23.2, 22.6 (C(b), C(b') (Aib1, Aib2, Aib3)). Anal. calc. for C44H46N4O7 ´ H2O
(760.856): C 69.45, H 6.36, N 7.36; found: C 69.41, H 6.38, N 7.21.
Oxazol-5(4H)-one from Z Aib Aib (S)-Bin Aib OH. Z Aib Aib (S)-Bin Aib OH (0.372 g,
0.50 mmol) was treated with Ac2O as described above for the oxazol-5(4H)-one from Z Aib Aib (S)-
Bin OH to give 0.359 g (99%) of crude oxazolone as a solid, which was used in the next step without further
25
25
25
25
25
purification. M.p. 1888. [a] ˆ ‡82, [a] ˆ ‡83, [a] ˆ ‡93, [a] ˆ ‡108, [a]
ˆ
239 (c ˆ 0.3, MeOH).
589
578
546
436
365
Rf 0.50 (C). 1H-NMR (Z Aib1 Aib2 Bin Aib3 ox): 7.91 ± 7.86 (m, 3 arom. H); 7.81 ± 7.66 (dd, J ˆ 8.3,
2 arom. H); 7.46 ± 7.10 (m, 12 arom. H); 7.09, 6.20 (2s, 2 NH (Aib2, Bin)); 4.92 (s, NH (Aib1)); 4.72 ± 4.45
(dd, J ꢀ 12.2, CH2 (Z)); 3.41 ± 3.27 (dd, J ꢀ 14.0, 2 H C(b) (Bin)); 3.02 ± 2.95 (dd, J ꢀ 13.1, 2 H C(b) (Bin));
1.44, 1.39, 1.37, 1.36, 1.28, 1.26 (6s, 18 H, Me(b), Me(b') (Aib)). Anal. calc. for C44H44N4O6 ´ 0.5 H2O (733.832):
C 72.01, H 6.18, N 7.63; found: C 72.34, H 6.29, N 7.49.
Z
Aib Aib (S)-Bin Aib Aib OtBu (14). A soln. of H Aib OtBu (0.166 g, 1.04 mmol), obtained as
described above for 13, and the oxazol-5(4H)-one from Z Aib Aib (S)-Bin Aib OH (0.351 g, 0.48 mmol)
in MeCN (20 ml), was refluxed for 40 h and then treated as described above for Z Aib Aib (S)-
Bin Aib OtBu. CC (column 2 Â 51 cm, silica gel, B) of the crude product gave 0.346 g (81%) of pure 14. Solid.
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25
25
25
25
M.p. 2528. [a] ˆ ‡6, [a] ˆ ‡5, [a] ˆ ‡3, [a]
ˆ
38, [a]
ˆ
400 (c ˆ 0.2, MeOH). Rf 0.65 (C).
589
578
546
436
365
1H-NMR (Z Aib1 Aib2 Bin Aib3 Aib4 OtBu): 7.87 ± 7.73 (m, 4 arom. H); 7.40 ± 7.07 (m, 13 arom. H);
7.52, 6.72, 6.69, 6.47 (4s, 4 NH (Aib2, Aib3, Aib4, Bin)); 6.21 (s, NH (Aib1)); 4.06 ± 4.02 (dd, J ꢀ 12.3, CH2 (Z));
3.28 ± 3.13 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 2.86 ± 2.80 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 1.42 (s, tBuO); 1.66, 1.53,
1.51, 1.48, 1.47, 1.42 (masked), 1.27, 1.21 (8s, 24 H, Me(b), Me(b') (Aib)). 13C-NMR: 174.3, 174.2, 174.0, 173.7,
171.0 (CˆO (Aib1, Aib2, Aib3, Aib4, Bin)); 155.8 (CˆO (Z)); 136.2 ± 124.9 (arom. C); 79.7 (tBuO); 70.2 (C(a)
(Bin)); 66.5 CH2 (Z)); 57.0, 56.6, 56.5, 55.9 (C(a) (Aib1, Aib2, Aib3, Aib4)); 42.5, 35.3 (C(b), C(b') (Bin)); 27.8
(tBuO); 27.7, 26.5, 25.9, 24.2, 23.2, 23.0, 22.74, 22.71 (C(b), C(b') (Aib1, Aib2, Aib3, Aib4)). Anal. calc. for
C52H61N5O8 ´ 0.5 H2O (893.056): C 69.93, H 7.00, N 7.84; found: C 69.92, H 7.05, N 7.82.
Z
(S)-Bin Aib OtBu. To a soln. of Z (S)-Bin OH (0.243 g, 0.5 mmol) and Et3N (0.084 ml, 0.6 mmol)
in toluene (2 ml) cooled to 58, a soln. of Piv-Cl (0.074 ml, 0.6 mmol) was added. The resulting suspension was
stirred at 58 for 1.5 h, then at r.t. for 2 h, and evaporated at 308. To the solid mixture (containing crude Z (S)-
Bin OPiv), a soln. of H Aib OtBu (0.225 g, 1.4 mmol; obtained as described above for 13) in toluene (10 ml)
was added. The mixture was stirred at 608 overnight, then evaporated and treated as described above for 13. The
crude product was submitted to CC (column 1.5 Â 41 cm, silica gel, A, then C): 0.097 g (40%) of recovered pure
25
25
25
Z
[a]
(S)-Bin OH and 0.171 g (54%) of pure dipeptide. Solid. M.p. 1198. [a]
ˆ
4, [a]
ˆ
5, [a]
ˆ
10,
589
578
546
25
25
ˆ
92, [a]
ˆ
687 (c ˆ 0.2, MeOH). Rf 0.85 (B). 1H-NMR: 7.94 ± 7.83 (m, 4 arom. H); 7.55 (d, J ˆ 8.4,
436
365
1 arom. H); 7.47 ± 7.19 (m, 13 H, arom. H, NH (Aib)); 5.24 ± 5.09 (d ´ br. d, J ꢀ 12.1, CH2 (Z)); 4.93 (s, NH
(Bin)); 3.44 ± 2.32 (dd, J ꢀ 12.9, 2H C(b) (Bin)); 3.31 ± 3.06 (br. dd, J ꢀ 13.2, 2 H C(b) (Bin)); 1.55, 1.50 (2s,
Me(b), Me(b') (Aib)); 1.43 (s, tBuO). 13C-NMR: 173.9, 170.6 (CˆO (Aib, Bin)); 155.1 (CˆO (Z)); 136.2 ±
125.1 (arom. C); 81.3 (tBuO); 70.6 (C(a) (Bin)); 66.7 CH2 (Z)); 56.8 (C(a) (Aib)); 42.2, 37.1 (C(b), C(b')
(Bin)); 27.7 (tBuO); 24.2, 24.0 (C(b), C(b') (Aib)). Anal. calc. for C40H40N2O5 (628.736): C 76.41, H 6.41, N 4.46;
found: C 76.14, H 6.53, N 4.27.
Z
(S)-Bin Aib OH. Z (S)-Bin Aib OtBu (0.162 g, 0.26 mmol) was C-deprotected in CF3COOH
(5 ml) and CH2Cl2 (5 ml) as described above for the synthesis of Z Aib Aib (S)-Bin OH to give 0.138 g
(93%) of crude dipeptide as a solid, which was used in the next step without further purification. M.p. 1938.
25
25
25
25
25
[a]
ˆ
11, [a]
ˆ
14, [a]
ˆ
21, [a]
ˆ
116, [a]
ˆ
762 (c ˆ 0.2, MeOH). Rf 0.10 (B). Anal. calc.
589
578
546
436
365
for C36H32N2O5 ´ H2O (590.648): C 73.20, H 5.80, N 4.74; found: C 73.59, H 5.94, N 4.55.
Oxazol-5(4H)-one from Z (S)-Bin Aib OH. Z (S)-Bin Aib OH (0.130 g, 0.23 mmol) was treated
with Ac2O as described above for oxazol-5(4H)-one from Z Aib Aib (S)-Bin OH to give 0.125 g (99%) of
25
the crude oxazolone as a glassy solid, which was used in the next step without further purification. [a] ˆ ‡10,
589
25
25
25
25
[a] ˆ ‡5, [a] ˆ ‡4, [a]
ˆ
53, [a]
ˆ
531 (c ˆ 0.2, CHCl3). Rf 0.80 (B). 1H-NMR: 7.96 ± 7.83
578
546
436
365
(m, 4 arom. H); 7.62 ± 7.23 (m, 13 arom. H); 5.20 ± 5.10 (d ´ br. d, J ꢀ 12.1, CH2 (Z)); 4.89 (s, NH (Bin)); 3.31 ±
3.18 (br. dd, J ꢀ 14.0, 2 H C(b) (Bin)); 3.25 ± 2.48 (dd, J ꢀ 12.9, 2 H C(b) (Bin)); 1.38, 1.26 (2s, Me(b),
Me(b'), Aib). Anal. calc. for C36H30N2O4 ´ 2 H2O (590.648): C 73.20, H 5.80, N 4.74; found: C 73.28, H 5.89, N 4.62.

498
Helvetica Chimica Acta ± Vol. 84 (2001)
Z
(S)-Bin Aib Aib OtBu (9). A soln. of H Aib OtBu (0.166 g, 1.04 mmol), obtained as described
above for the synthesis of Z Aib Aib (S)-Bin Aib OtBu, and the oxazol-5-(4H)-one from Z (S)-
Bin Aib OH (0.119 g, 0.21 mmol) in MeCN (30 ml), was refluxed for 72 h and then treated as described
above for Z Aib Aib (S)-Bin OtBu. CC (column 2 Â 51 cm, silica gel, B) of the crude product gave 0.139 g
25
25
25
25
25
(91%) of pure 9. Solid. M.p. 1308. [a]
ˆ
58, [a]
ˆ
62, [a]
ˆ
75, [a]
ˆ
200, [a]
ˆ
801 (c ˆ 0.2,
589
578
546
436
365
MeOH). Rf 0.50 (B). H-NMR (Z Bin Aib1 Aib2 OtBu): 7.93 ± 7.83 (m, 4 arom. H); 7.44 ± 7.19 (m, 14 H,
arom. H, NH (Aib)); 6.48 (s, NH (Aib)); 5.23 (s, NH (Bin)); 5.21 ± 5.10 (dd, J ꢀ 12.2, CH2 (Z)); 3.17 ± 2.31
(dd, J ꢀ 12.8, 2 H C(b) (Bin)); 3.13 ± 3.08 (dd, J ꢀ 14.0, 2 H C(b) (Bin)); 1.51,1.49, 1.47, 1.44 (4s, 12 H, Me(b),
Me(b') (Aib1, Aib2); 1.45 (s, tBuO). 13C-NMR: 173.6, 172.6, 170.3 (CˆO (Aib1, Aib2, Bin)); 155.5 (CˆO (Z));
136.0 ± 125.2 (arom. C); 80.3 (tBuO); 70.4 (C(a) (Bin)); 67.0 CH2 (Z)); 56.7, 56.2 (C(a) (Aib1, Aib2)); 42.6, 36.9
(C(b), C(b') (Bin)); 27.8 (tBuO); 25.7, 24.9, 24.7, 24.1 (C(b), C(b') (Aib1, Aib2)). Anal. calc. for C44H47N3O6
(713.840): C 74.03, H 6.63, N 5.89; found: C 74.26, H 6.68, N 5.81.
1
Z
(S)-Bin Aib Aib OH. Z (S)-Bin Aib Aib OtBu (9; 0.134 g, 0.19 mmol) was C-deprotected in
CF3COOH (5 ml) and CH2Cl2 (5 ml) as described above for Z Aib Aib (S)-Bin OH to give 0.118 g (96%)
25
of crude tripeptide as a solid, which was used in the next step without further purification. M.p. 2198. [a]
ˆ
589
25
25
25
25
46, [a]
ˆ
49, [a]
ˆ
62, [a]
ˆ
180, [a]
ˆ
790 (c ˆ 0.2, MeOH). Rf 0.05 (B). Anal. calc. for
578
546
436
365
C40H39N3O6 ´ 2.5 H2O (590.648): C 68.36, H 6.31, N 5.98; found: C 68.71, H 6.47, N 5.85.
Oxazol-5(4H)-one from Z (S)-Bin Aib Aib OH. Z (S)-Bin Aib Aib OH (0.112 g, 0.17 mmol)
was treated with Ac2O as described above for the oxazol-5(4H)-one from Z Aib Aib (S)-Bin OH to give
0.109 g (100%) of crude oxazolone as a powder, which was used in the next step without further purification.
25
25
25
25
25
M.p. 1408. [a] ˆ ‡44, [a] ˆ ‡43, [a] ˆ ‡45, [a] ˆ ‡10, [a]
ˆ
469 (c ˆ 0.2, CHCl3). Rf ˆ 0.70 (B).
589
578
546
436
365
1H-NMR (Z Bin Aib1 Aib2 ox): 7.94 ± 7.82 (m, 4 arom. H); 7.54 ± 7.19 (m, 13 arom. H); 6.83 (br. s, NH
(Aib1)); 5.22 ± 5.11 (d ´ br. d, J ꢀ 12.0, CH2 (Z)); 4.87 (s, NH (Bin)); 3.33 ± 2.35 (br. dd, J ꢀ 12.9, 2 H C(b)
(Bin)); 3.20 ± 3.10 (br. dd, J ꢀ 13.6, 2 H C(b) (Bin)); 1.54, 1.46, 1.42, 1.26 (4s, 12 H, Me(b), Me(b') (Aib1,
Aib2)). Anal. calc. for C40H37N3O5 (675.752): C 71.09, H 6.12, N 6.22; found: C 71.01, H 6.21, N 6.02.
Z
(S)-Bin Aib Aib (S)-Bin OtBu (10).
A soln. of the oxazol-5(4H)-one from Z (S)-
Bin Aib Aib OH (0.104 g, 0.16 mmol) and H (S)-Bin OtBu (0.082 g, 0.2 mmol) in MeCN (30 ml) was
refluxed for 21 d, then treated as described above for 12. The crude product was submitted to CC (column 1.5 Â
43 cm, silica gel, A, then B and C), followed by prep. TLC (B): 0.083 g (49%) of pure 10. Solid. M.p. 2288.
25
25
25
25
25
[a]
ˆ
131, [a]
ˆ
140, [a]
ˆ
169, [a]
ˆ
413, [a]
ˆ
1472 (c ˆ 0.2, MeOH). Rf 0.40 (B).
589
578
546
436
365
1H-NMR (Z Bin1 Aib2 Aib3 Bin4 OtBu): 7.93 ± 6.95 (m, 31 H, 29 arom. H, 2 NH (Aib or Bin4)); 6.12
(s, NH (Aib or Bin4)); 5.25 ± 5.06 (dd, J ꢀ 12.1, CH2 (Z)); 5.01 (s, NH (Bin1)); 3.29 ± 3.14 (dd, J ꢀ 13.9, 2 H C(b)
(Bin)); 3.13 ± 2.86 (dd, J ꢀ 13.1, 2 H C(b) (Bin)); 2.96 ± 2.08 (dd, J ꢀ 13.1, 2 H C(b) (Bin)); 2.59 (s, 2 H C(b)
(Bin)); 1.65, 1.57, 1.34, 1.14 (4s, 12 H, Me(b), Me(b') (Aib2, Aib3)); 1.51 (s, tBuO). 13C-NMR: 173.9, 171.9, 171.3
(CˆO (Aib2, Aib3, Bin1, Bin4)); 155.6 (CˆO (Z)); 136.3 ± 124.4 (arom. C); 80.6 (tBuO); 70.0, 69.9 (C(a) (Bin1,
Bin4)); 67.4 CH2 (Z)); 57.0, 56.8 (C(a) (Aib2, Aib3)); 42.1, 41.2, 37.8, 37.1 (C(b), C(b') (Bin1, Bin4)); 28.0 (tBuO);
26.6, 26.0, 24.7, 24.5 (C(b), C(b') (Aib2, Aib3)). Anal. calc. for C68H64N4O7 ´ 0.5 H2O (1058.232): C 77.17, H 6.19,
N 5.29; found: C 77.17, H 6.29, N 5.11.
Z
(S)-Bin Aib Aib (S)-Bin OH. Z (S)-Bin Aib Aib (S)-Bin OtBu (10; 0.076 g, 0.07 mmol)
was C-deprotected in CF3COOH (5 ml) and CH2Cl2 (5 ml) as described above for Z Aib Aib (S)-Bin OH
to give 0.071 g (99%) of crude tetrapeptide as a solid, which was used in the next step without further
25
25
25
25
25
purification. M.p. 2808. [a]
ˆ
130, [a]
ˆ
139, [a]
ˆ
167, [a]
ˆ
407, [a]
ˆ
1460 (c ˆ 0.2,
589
578
546
436
365
MeOH). Rf 0.25 (B), 0.40 (C). Anal. calc. for C64H56N4O7 ´ H2O (1011.136): C 76.01, H 5.78, N 5.54; found:
C 76.03, H 5.92, N 5.38.
Oxazol-5(4H)-one from Z (S)-Bin Aib Aib (S)-Bin OH. Z (S)-Bin Aib Aib (S)-Bin OH
(0.067 g, 0.07 mmol) was treated with Ac2O as described above for the oxazol-5(4H)-one from
Z
Aib Aib (S)-Bin OH to give 0.066 g (100%) of crude oxazolone as a powder, which was used in the
25
25
25
25
25
next step without further purification. M.p. 1698. [a] ˆ ‡62, [a] ˆ ‡59, [a] ˆ ‡63, [a] ˆ ‡7, [a]
ˆ
589
578
546
436
365
698 (c ˆ 0.2, CHCl3). Rf 0.85 (B), 0.90 (C). Anal. calc. for C64H54N4O6 ´ 3 H2O (1029.152): C 74.69, H 5.88,
N 5.44; found: C 75.01, H 6.29, N 5.07.
Z
(S)-Bin Aib Aib (S)-Bin Aib OtBu (11). A soln. of H Aib OtBu (0.067 g, 0.42 mmol, obtained
as described above for the synthesis of 13) and the oxazol-5(4H)-one from Z (S)-Bin Aib Aib (S)-
Bin OH (0.062 g, 0.06 mmol) in MeCN (10 ml) was refluxed for 72 h and then treated as described above for
12. The crude product was submitted to CC (column 1.5 Â 40 cm, silica gel, B), then to prep. TLC (A); 0.056 g
25
25
25
25
25
(78%) of pure 11. Solid. M.p. 2138. [a]
ˆ
183, [a]
ˆ
194, [a]
ˆ
230, [a]
ˆ
532, [a]
ˆ
1674
589
578
546
436
365
(c ˆ 0.2, MeOH). Rf 0.40 (B). 1H-NMR (Z Bin1 Aib2 Aib3 Bin4 Aib5 OtBu): 7.93 ± 6.47 (m, 32 H,

Helvetica Chimica Acta ± Vol. 84 (2001)
499
29 arom. H, 3 NH (Aib or Bin4)); 6.37 (s, NH (Aib or Bin4)); 5.10 (s, CH2 (Z)); 5.03 (s, NH (Bin1)); 3.31 ± 2.97
(dd, J ꢀ 13.5, 2 H C(b) (Bin)); 2.72 ± 2.17 (dd, J ꢀ 13.2, 2 H C(b) (Bin)); 2.66 ± 2.18 (dd, J ꢀ 13.8, 2 H C(b)
(Bin)); 2.00 ± 1.91 (dd, J ꢀ 14.0, 2 H C(b) (Bin)); 1.53 (s, tBuO); 1.53 (masked), 1.51, 1.50, 1.49, 1.41, 1.24 (6s,
18 h, Me(b), Me(b') (Aib2, Aib3, Aib5)). 13C-NMR: 174.2, 173.6, 173.4, 171.3, 171.0 (CˆO (Aib2, Aib3, Aib5,
Bin1, Bin4)); 155.6 (CˆO (Z)); 136.1 ± 124.2 (arom. C); 80.1 (tBuO); 70.0, 69.9 (Ca) (Bin1, Bin4)); 67.4 (CH2
(Z)); 56.9, 56.8, 56.1 (C(a) (Aib2, Aib3, Aib5)); 42.6, 42.3, 35.5, 34.4 (C(b), C(b') (Bin1, Bin4)); 27.9 (tBuO); 27.3,
26.7, 25.8, 23.9, 23.3 (C(b), C(b') (Aib2, Aib3, Aib5)). Anal. calc. for C72H71N5O8 ´ H2O (1152.344): C 75.04,
H 6.39, N 6.08; found: C 74.71, H 6.55, N 5.91.
‡
X-Ray Diffraction. The compounds investigated, H ´ H (S)-Bin
O and Bz (R)-Bin Phe NHChx,
are chiral and accordingly they crystallize in a non-centrosymmetric space group, P21 for the free amino acid and
P212121 for the terminally blocked dipeptide. For these two structures, data were collected on an Enraf-Nonius
CAD-4 diffractometer with graphite-monochromated CuKa (l ˆ 1.54184 Š) radiation. Lattice parameters were
obtained by accurate centring of 25 standard reflections. Both structures were solved with the program
SHELXS 86 [71]. Refinement was carried out with SHELXL 93 [72] for the free amino acid and with
SHELXL 97 [73] for the dipeptide. In the structure of the free amino acid, the NH H-atoms were located on a
difference-Fourier map, while H-atoms bound to C-atoms were placed in an ideal position. All H-atoms of the
free amino acid were refined with individual isotropic thermal parameters. In the structure of the dipeptide, all
H-atoms were calculated at idealized positions and refined as riding, with Uiso set equal to 1.2 times the Ueq of the
‡
Table 3. Crystallographic Data and Details of Structure Determinations for H ´ H (S)-Bin
Solvate and Bz (R)-Bin Phe NHChx (1') Ethyl Acetate Bis-Solvate
O Methanol Bis-
‡
H ´ H (S)-Bin
O
Bz (R)-Bin Phe NHChx (1')
Empirical formula
Mr
C26H27NO4
417.5
C54H59N3O7
862.0
Crystal system
Space group
a [Š]
b [Š]
c [Š]
monoclinic
P21
orthorhombic
P212121
11.225(4)
16.717(10)
26.156(6)
90
4908(4)
4
1.167
0.615
12.705(3)
6.411(2)
13.411(2)
95.38(1)
1130.6(5)
2
b [8]
V [Š3]
Z
3
Dx [Mg ´ m
m [mm
]
1.226
0.662
1
]
Radiation
CuKa (l ˆ 1.5418 Š)
CuKa (l ˆ 1.5418 Š)
Crystal size [mm]
Mode of scan
F (000)
0.8 Â 0.5 Â 0.3
0.5 Â 0.1 Â 0.1
w
2q
w
2q
444
1840
q Range [8]
Index ranges
3.2 ± 68.0
4.7 ± 60.0
15 ꢁ h ꢁ 15
12 ꢁ h ꢁ 12
6 ꢁ k ꢁ 7
0 ꢁ k ꢁ 17
0 ꢁ l ꢁ 16
0 ꢁ l ꢁ 29
Reflections collected
4634
7926
Independent reflections
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices (I > 2s(I))
2259 (R(int) ˆ 0.062)
6794 (R(int) ˆ 0.058)
none
none
full-matrix least squares on F2
2244/1/361
1.096
R1 ˆ 0.0562
wR2 ˆ 0.1309
R1 ˆ 0.0828
wR2 ˆ 0.1640
0.327/ 0.438
full-matrix least squares on F2
6794/43/583
1.019
R1 ˆ 0.0699
wR2 ˆ 0.1812
R1 ˆ 0.1465
wR2 ˆ 0.2223
0.197/ 0.224
R Indices (all data)
Largest difference peak and
3
hole [e ´ Š
]

500
Helvetica Chimica Acta ± Vol. 84 (2001)
parent atom. The high displacement parameters observed for the terminal phenyl and cyclohexyl groups in the
dipeptide indicated a low accuracy in the determination of the positions of their atoms. Crystallographic data
and details of the structure determinations are given in Table 3. Atomic coordinates, bond distances and angles,
and anisotropic displacement parameters have been deposited with the Cambridge Crystallographic Data Centre
(CCDC) as deposition No. CCDC 150266 and 150267. Copies of the data can be obtained, free of charge, on
application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: ‡44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk).
F. F., M. C., and C. T. gratefully acknowledge MURST, the Ministry of University and Scientific and
Technological Research, and the National Research Council (CNR) of Italy for the continuous support to this
research.
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Received October 5, 2000