Synthesis and conformational analysis of pentapeptides containing enantiomerically pure 2,2-disubstituted glycines

Article abstract of DOI:10.1002/hlca.200890057

The synthesis and conformational analysis of model pentapeptides with the sequence Z-Leu-Aib-Xaa-Gln-Valol is described. These peptides contain two 2,2-disubstituted glycines (α,α-disubstituted α-amino acids), i.e., Aib (aminoisobutyric acid), and a serie

Full text of DOI:10.1002/hlca.200890057

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Helvetica Chimica Acta – Vol. 91 (2008)
Synthesis and Conformational Analysis of Pentapeptides Containing
Enantiomerically Pure 2,2-Disubstituted Glycines
by Kathrin A. Brun1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
(phone þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
The synthesis and conformational analysis of model pentapeptides with the sequence Z-Leu-Aib-
Xaa-Gln-Valol is described. These peptides contain two 2,2-disubstituted glycines (a,a-disubstituted a-
amino acids), i.e., Aib (aminoisobutyric acid), and a series of unsymmetrically substituted, enantiomeri-
cally pure amino acids Xaa. These disubstituted amino acids were incorporated into the model peptides
via the ꢀazirine/oxazolone methodꢁ. Conformational analysis was performed in solution by means of
NMR techniques and, in the solid state, by X-ray crystallography. Both methods show that the backbones
of these model peptides adopt helical conformations, as expected for 2,2-disubstitued glycine-containing
peptides.
1. Introduction. – Within the last 30 years, 2,2-disubstituted glycines (i.e., a,a-
disubstituted a-amino acids) attracted increasing interest as structural units in
biologically active heterocycles (see, e.g., [1]) and in conformationally restricted peptides
(see, e.g., [2]). Of special significance are the so-called peptaibols, i.e., peptide
antibiotics, which contain a high proportion of 2,2-dimethylglycine (a-aminoisobutyric
acid (Aib)) and are produced by some filamentous fungi [3]. Due to the presence of Aib,
these peptides exhibit helical conformations [4][5]. This structure is essential for their
biological activity [6], i.e., their ability to form ion channels through membranes [7].
For this reason, several new syntheses of achiral and optically active 2,2-
disubstituted glycines have been reported in recent years [2c][8], as well as new
protocols for the introduction of these sterically congested amino acids into peptides
[9 – 11]. In our laboratory, we have developed the so-called ꢀazirine/oxazolone methodꢁ
for this purpose [12][13]. It has been shown that this protocol can be used successfully
in the synthesis of peptaibols and segments thereof [3i][5f][5g][13]. Therefore, a large
series of 2H-azirin-3-amines were prepared as synthons for symmetrical 2,2-disub-
stituted [14] and heterocyclic a-amino acids [15], as well as dipeptide synthons
[15c][16]. Furthermore, building blocks for enantiomerically pure 2-methylphenyla-
lanine [17] and 2-ethylalanine (isovaline (Iva)) [18] were obtained after chromato-
graphic separation of the corresponding diastereoisomeric 2H-azirin-3-amines bearing
a chiral residue at the exocyclic N-atom. Recently, we reported the synthesis of some
new optically active 2H-azirin-3-amines 1 as synthons for enantiomerically pure 2,2-
disubstituted glycines by using (R)-[1-(naphthalen-1-yl)ethyl]amine (NaphthEtNH2)
as the chiral auxiliary [19].
1
)
Part of the Ph.D. thesis and the Diploma thesis of K. B., Universität Zürich.
ꢂ 2008Verlag Helvetica Chimica Acta AG, Zürich

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527
It has been shown that these 2H-azirin-3-amines are suitable for the successful
incorporation of the corresponding enantiomerically pure 2,2-disubstituted glycines
into peptides by the ꢀazirine/oxazolone methodꢁ [17 – 19]. In the present paper, we
describe the synthesis and the results of the conformational analysis of model
pentapeptides 2a – 2g with the sequence Z-Leu-Aib-Xaa-Gln-Valol. With Xaa ¼ Aib or
d-Iva, this is the C-terminal segment of the naturally occurring peptaibol family of
trichotoxin A-50 (see [3i]). As the first examples, we have already described the
preparation of the pentapeptides 2c containing d- and l-Iva [18].
2. Results and Discussion. – 2.1. Synthesis of the Pentapeptides 2. The model
pentapeptides 2 were synthesized according to Schemes 1 and 3. The N-terminal
tripeptides Z-Leu-Aib-Xaa-NR3R4 3a – 3g were prepared by the ꢀazirine/oxazolone
methodꢁ. First, Z-Leu-OH was coupled with 1a, the synthon for Aib, in Et2O or CH2Cl2
at room temperature, to yield the dipeptide amide 4, which was hydrolyzed at room
temperature with 3n HCl (H2O/THF 1:1) to give Z-Leu-Aib-OH (5) [19]. The latter
was coupled with the respective azirines 1a – 1g to yield the tripeptide amides 3a – 3g
(Scheme 1 and Table 1; for the coupling with 1c – 1g, see [19]).
Subsequent hydrolysis gave the tripeptide acids 6a – 6g. The structure of (R)-6c was
established by X-ray crystallography (Fig. 1). For (R)-6c, the OH group forms an
intramolecular H-bond with the central amide O-atom, thereby creating a ten-
membered loop and a helical turn within the molecule. This interaction can be
described by the graph set motif [21] of S(10). N(1)ꢀH forms an intermolecular H-
bond with the carboxylic acid C¼O O-atom of a neighboring molecule, thereby linking

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Scheme 1
Table 1. Synthesis of the Tripeptide Amides 3 from Dipeptide 5
Xaa
Azirine 1
R1, R2
R3, R4
Tripeptide amide
3
Yield [%]
Aib
Ac5c
(S)-Iva
1a
1b
Me, Me
ꢀ(CH2)4ꢀ
Me, Et
Ph, Me
Ph, Me
NaphthEt, Me
PhEt, Me
NaphthEt, Me
PhEt, Me
NaphthEt, Me
NaphthEt, Me
NaphthEt, Me
NaphthEt, Me
NaphthEt, Me
NaphthEt, Me
ꢀProlinolꢁ
NaphthEt, Me
ꢀProlinolꢁ
NaphthEt, Me
3a
3b
95
97
(2S)-1c
(2S)-1i
(2R)-1c
(2R)-1i
(2S)-1d
(2R)-1d
(2S)-1e
(2R)-1e
(2S)-1f
(2R)-1f
(2S)-1h
(2S)-1g
(2R)-1h
(2R)-1g
(S)-3c
(S)-3i
(R)-3c
(R)-3i
(S)-3d
(R)-3d
(S)-3e
(R)-3e
(S)-3f
(R)-3f
(S)-3h
(S)-3g
(R)-3h
(R)-3g
77 [19]
93 [18]
83 [19]
91 [18]
67 [19]
69 [19]
39 [19]
38[19]
64 [19]
60 [19]
70
Me, Et
(R)-Iva
Et, Me
Et, Me
iPr, Me
(S)-Val(2Me)
(R)-Val(2Me)
(S)-Ala(2cPent)
(R)-Ala(2cPent)
(S)-Leu(2Me)
(R)-Leu(2Me)
(S)-Phe(2Me)
i
Me, Pr
cPent, Me
Me, cPent
iBu, Me
i
Me, Bu
Bn, Me
Bn, Me
Me, Bn
Me, Bn
59 [19]
79
62 [19]
(R)-Phe(2Me)
the molecules into extended chains, which run parallel to the [0 1 0] direction, and
which can be described by the graph set motif of C(11). N(4)ꢀH forms an
intermolecular H-bond with the amide O-atom of a neighboring molecule, thereby
linking the molecules into extended chains, which run parallel to the [1 0 0] direction,
and which can be described by the graph set motif of C(5). The combination of the
intermolecular interactions generates a three-dimensional framework of H-bonded
molecules. N(7)ꢀH is not involved in any H-bonding interactions. The closest acceptor
atom is O(12) within the same molecule, but the H ··· O and N ··· O distances of 2.65(3)
and 3.330(2) Š are just outside the maximum value (2.6 and 3.2 Š, resp.) considered to
be the outer limit of a significiant NꢀH ··· O H-bonding interaction.

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Fig. 1. ORTEP Plots [20] of the molecular structures of a) (R)-6c (Z-Leu-Aib-(R)-Iva-OH), b) (R)-7c
(Z-Leu-Aib-(R)-Iva-NHMe), and c) (R)-7d (Z-Leu-Aib-(R)-Val(2Me)-NHMe) (50% probability
ellipsoids, arbitrary numbering of atoms)
The standard conditions for the hydrolysis of peptide amides with a N-methyl-
anilide group are 3n HCl (H2O/THF 1:1) at room temperature. However, for the
tripeptide amides of type 3 with NaphthEt(Me)N as the chiral auxiliary group, these
conditions have proven to be too mild. Therefore, the temperature was increased, and
the solvent system was changed to H2O/MeCN 1:1. The optimized new standard
conditions were 3 h at 608.
Interestingly, the coupling of amino acids with a junction at C(3) (i.e., b-branched
amino acids, such as Val(2Me) and Ala(2cPent)) by the reaction of the corresponding
azirine with Z-Leu-Aib-OH proceeded with lower yields than that of amino acids with
a CH2(3) group (linear or g-branched amino acids; see Table 1). On the other hand, the
hydrolysis gave better yields in the case of b-branched amino acids (see Table 2).

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During this hydrolysis, a side product 7 with a N-methylamide group, which is
similar to the side products described in [22], was formed in addition to 6 (Scheme 2
and Table 2). For example, the hydrolysis of the (S)-Iva- and (R)-Iva-containing
tripeptides (S)-3c and (R)-3c gave the side products (S)-7c and (R)-7c in 30 and 29%
yield, respectively. The structures of the (R)-Iva- and (R)-Val(2Me)-containing (R)-7c
and (R)-7d were determined by X-ray crystallography (Fig. 1).
Scheme 2
The solid-state structures of (R)-7c and (R)-7d also exhibit the same H-bonding
motifs and three-dimensional framework as described above for (R)-6c with the
carboxylic acid group now replaced by the amide group involving N(10)ꢀH. N(7)ꢀH
is positioned in approximately the correct position to interact intramolecularly with
O(12), but, again, the H ··· O and N ··· O distances of 2.63(2) and 2.78(4) Š, and
3.297(2) and 3.451(3) Š, respectively, are too long to be considered as a significiant
NꢀH ··· O H-bonding interaction, particularly in the case of (R)-7d.
In the crystals of the product (R)-6c and the side product (R)-7c of the hydrolysis of
(R)-3c, as well as the side product (R)-7d of the hydrolysis of (R)-3d, the molecules
form a b-turn of type I’ or III’, which is in good agreement with the structures of the
investigated pentapeptides (Fig. 1). However, as noted earlier, the interatomic
distances for the intramolecular NꢀH ··· O interactions normally associated with such
turns (N(10)ꢀH ··· O(12) in these structures) are such that the interactions are at best
extremely weak H-bonds.
The coupling of Z-Leu-Aib-OH (5) with (2’R)-1h and (2’S)-1h, i.e., the synthons for
(R)- and (S)-Phe(2Me) [17], and with (2R)-1i and (2S)-1i, the synthons for (R)- and
(S)-Iva [18], to give tripeptide amides of type 3, as well as their hydrolysis to the
corresponding tripeptide acids 6, gave better yields than in the case of 1g and 1c
(Table 2), but their chiral auxiliary groups cannot be as widely used as the NaphthEt-
(Me)N group.

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The C-terminal dipeptide H-Gln-Valol (11) was synthesized via coupling of the
4-nitrophenyl ester Z-Gln-ONp (8) with l-valinol (Valol, 9) in CH2Cl2 and DMF
(active-ester method; Scheme 3). The obtained Z-Gln-Valol (10) was deprotected by
hydrogenolytic cleavage of the Z group (H2, Pd/C) in MeOH at room temperature to
give 11. The coupling of the tripeptide acids 6 with 11 was carried out by using classical
peptide coupling methods with O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluro-
nium hexafluorophosphate (HATU) as the coupling reagent (Table 2).
Scheme 3
The conformations of the model peptides 2 were investigated in the crystalline state.
For these studies, however, some of the peptides had to be modified by changing the N-
terminal protecting group, because the Z-protected peptides did not crystallize very
well. The 4-bromobenzoyl group proved to be very suitable for this purpose
(Scheme 4). In a first step, the N-terminus of the pentapeptide 2 was deprotected by
treating a solution of 2 in MeOH at room temperature with H2 and Pd/C. After
filtration over Celite, the deprotected pentapeptide 12 was reacted with 4-bromoben-
zoyl chloride in the presence of Et3N in CH2Cl2 to give the new pentapeptide 13
(Table 2).
Scheme 4
2.2. Conformational Analysis of the Pentapeptides. The conformations of some
model peptides 2 and 13, respectively, were investigated in the solid state as well as in
solution. X-Ray crystal-structure determinations were performed in the cases of 13a
(pBrBz-Leu-Aib-Aib-Gln-Valol), 13b (pBrBz-Leu-Aib-Ac5c-Gln-Valol), (S)-2d (Z-
Leu-Aib-(S)-Val(2Me)-Gln-Valol), (S)-2e (Z-Leu-Aib-(S)-Ala(2cPent)-Gln-Valol),
(S)-13f (pBrBz-Leu-Aib-(S)-Leu(2Me)-Gln-Valol), and (S)-13g (pBrBz-Leu-Aib-
(S)-Phe(2Me)-Gln-Valol) (Fig. 2). All pentapeptides adopt a helical conformation
stabilized by intramolecular H-bonds, which form two b-turns: N(10)ꢀH and
N(13)ꢀH interact with the C¼O O-atom that is seven atoms back along the peptide
backbone. Each of these interactions has a graph set motif [21] of S(10).
Intermolecular H-bonds also link the molecules in each structure into infinite two-
dimensional networks. In 13a, N(1)ꢀH and N(4)ꢀH form intermolecular H-bonds
with the carbonyl O-atom, O(12), and the hydroxy O-atom, O(15), respectively, at the

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Fig. 2. ORTEP Plots [20] of the molecular structures of a) 13a (pBrBz-Leu-Aib-Aib-Gln-Valol), b) 13b
(pBrBz-Leu-Aib-Ac5c-Gln-Valol), c) (S)-2d (Z-Leu-Aib-(S)-Val(2Me)-Gln-Valol), d) (S)-2e (Z-Leu-
Aib-(S)-Ala(2cPent)-Gln-Valol), e) one of the two symmetry-independent molecules of (S)-13f (pBrBz-
Leu-Aib-(S)-Leu(2Me)-Gln-Valol), and f) (S)-13g (pBrBz-Leu-Aib-(S)-Phe(2Me)-Gln-Valol) (50%
probability ellipsoids, arbitrary numbering of atoms; any solvent molecules and minor disorder
components have been omitted for clarity)

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opposite end of a neighboring molecule. These interactions link the peptide molecules
into extended chains which run parallel to the [1 0 1] direction, and which can be
described by graph set motifs of C(14). The OH group also forms an intermolecular H-
bond with the amide O-atom, O(33), of the side chain at C(11) of a different
neighboring peptide molecule, thereby linking the molecules into extended chains
which run parallel to the [1 0 0] direction, and which can be described by the C(11)
motif. The partial-occupancy H2O molecule accepts a H-bond from N(7)ꢀH and also
donates a H-bond to O(33) in a different peptide molecule, thereby linking the peptide
and H2O molecules into extended chains which run parallel to the [0 0 1] direction, and
which have a C22(12) motif. The NH2 group, N(33), of the amide side chain forms an
intramolecular H-bond with the C¼O O-atom, O(16) (S(18) motif), and an
intermolecular H-bond with O(9) from a neighboring molecule. This latter interaction
links the molecules into extended chains which run parallel to the [1 0 0] direction, and
which can be described by the C(9) motif. The combination of all intermolecular
interactions links the molecules into infinite two-dimensional networks, which lie
parallel to the (0 1 0) plane.
The structure of 13b exhibits the same pattern of H-bonding motifs and two-
dimensional network to that described above for 13a; except that with the absence of a
H2O molecule, N(7)ꢀH is not involved in a H-bond.
For (S)-2d, the H-atoms of N(37) on the terminal amide side chain are involved in
the same intra- and intermolecular interactions that were described for 13a to give the
S(18) and C(9) motifs. The remaining interactions, however, generate a different
pattern: N(1)ꢀH and N(4)ꢀH form intermolecular H-bonds with the amide O-atom,
O(37), of the terminal amide side chain of the same neighboring molecule. Each of
these interactions links the molecules into extended chains which run parallel to the
[0 1 0] direction, and which can be described by graph set motifs of C(16) and C(13),
respectively. The OH group also forms an intermolecular H-bond with the amide O-
atom of the terminal amide side chain, but on a different neighboring molecule. This
interaction links the molecules into extended chains which run parallel to the [1 0 0]
direction and have the C(11) motif. N(7)ꢀH forms an intermolecular H-bond with the
OH O-atom of yet another neighboring molecule, but also links the molecules into
extended chains which run parallel to the [0 1 0] direction and have the C(11) motif.
The combination of all intermolecular interactions links the molecules into infinite two-
dimensional networks, which lie parallel to the (0 0 1) plane.
The structure of (S)-2e exhibits the same pattern of H-bonding motifs and two-
dimensional network to that described above for (S)-2d.
The structure of (S)-13f has two molecules in the asymmetric unit, A and B. For the
H-bonding, the molecules of type A interact amongst themselves, as do those of type B,
and the patterns are identical with those described for 13b, except for differences in the
directionality of some chains. The chains involving N(1)ꢀH and N(4)ꢀH of molecule
A, and those involving the corresponding atoms of molecule B, run parallel to the [1 1 0]
direction. The chains involving the OH group, as well as those involving the NꢀH
group of the terminal amide side chain, run parallel to the [0 1 0] and [1 0 0] directions
for molecules A and B, respectively. Considered overall, the intermolecular H-bonds
link the molecules of (S)-13f into infinite two-dimensional layer networks, where each
layer consists entirely of only one type of symmetry-independent molecule. Thus, layers

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of H-bonded molecules A and layers of molecules B are stacked in an alternating
fashion along the [0 0 1] direction.
For (S)-13g, the NH2 group, N(39), on the terminal amide side chain is involved in
the same intra- and intermolecular interactions that were described for 13a to give the
usual S(18) and C(9) motifs. N(1)ꢀH and N(7)ꢀH form intermolecular H-bonds with,
the amide O-atom of the side chain, O(39), and a C¼O O-atom, O(12), respectively, in
two different neighboring peptide molecules. These interactions link the molecules into
extended chains which run parallel to the [0 1 0] direction, and which can be described
by graph set motifs of C(16) and C(8), respectively. N(4)ꢀH interacts with O(43) of
one of the two independent MeOH molecules, while O(43) is close enough to O(9) in a
different peptide molecule to be donating a H-bond to the latter atom (the H-atoms of
the solvent molecules could not be located). These interactions link the peptide and
MeOH molecules into extended chains, which run parallel to the [0 1 0] direction, and
which can be described by a graph set motif of C22(10). The OH group, O(15)ꢀH, forms
an intermolecular H-bond with O(44) of the second MeOH molecule, but this solvent
molecule does not appear to act as a H-bond donor. Considered overall, the
intermolecular interactions combine to link the molecules into infinite two-dimensional
networks, which lie parallel to the (0 0 1) plane.
In Tables 3 and 4, the torsion angles fiþ1, yiþ1, fiþ2, and yiþ2 of the b-turns are listed.
The values show that two consecutive b-turns of type III/I are formed for 13a, 13b, (S)-
2d, (S)-2e, and (S)-13f, whereas, in the case of (S)-13g, two b-turns of type III/III are
observed. The III/III combination can be considered as an incipient 310-helix.
The results described above are in good agreement with previously reported results
obtained for oligopeptides that contain Aib [23 – 29], Ac5c [14][30][31], Val(2Me)
[32], Leu(2Me) [33], and Phe(2Me) [34 – 36].
Table 3. Torsion Angles of the First b-Turn (amino acids i, i þ 1, i þ 2, and i þ 3)
fiþ1 [8]
yiþ1 [8]
fiþ2 [8]
yiþ2 [8]
Type of b-turn
13a
13b
(S)-2d
(S)-2e
(S)-13f, mol. A
(S)-13f, mol. B
(S)-13g
ꢀ 56.7(6)
ꢀ 54.9(7)
ꢀ 49.6(2)
ꢀ 51.3(2)
ꢀ 54.8(4)
ꢀ 54.3(4)
ꢀ 53.2(6)
ꢀ 42.7(6)
ꢀ 40.2(7)
ꢀ 44.6(1)
ꢀ 43.3(2)
ꢀ 43.1(3)
ꢀ 42.9(4)
ꢀ 44.2(6)
ꢀ 57.0(6)
ꢀ 58.2(7)
ꢀ 58.9(1)
ꢀ 60.1(2)
ꢀ 62.7(3)
ꢀ 59.7(4)
ꢀ 54.6(7)
ꢀ 31.5(5)
ꢀ 32.3(6)
ꢀ 24.9(1)
ꢀ 23.1(2)
ꢀ 26.5(3)
ꢀ 28.6(4)
ꢀ 37.1(7)
III
III
III
III
III
III
III
Table 4. Torsion Angles of the Second b-Turn (amino acids i þ 1, i þ 2, i þ 3, and i þ 4)
fiþ2 [8]
yiþ2 [8]
f
iþ3 [8]
yiþ3 [8]
Type of b-turn
13a
13b
(S)-2d
(S)-2e
(S)-13f, mol. A
(S)-13f, mol. B
(S)-13g
ꢀ 57.0(6)
ꢀ 58.2(7)
ꢀ 58.9(1)
ꢀ 60.1(2)
ꢀ 62.7(3)
ꢀ 59.7(4)
ꢀ 54.6(7)
ꢀ 31.5(5)
ꢀ 32.3(6)
ꢀ 24.9(1)
ꢀ 23.1(2)
ꢀ 26.5(3)
ꢀ 28.6(4)
ꢀ 37.1(7)
ꢀ 78.7(5)
ꢀ 78.3(6)
ꢀ 77.1(1)
ꢀ 76.8(2)
ꢀ 75.6(3)
ꢀ 76.8(4)
ꢀ 71.7(7)
ꢀ 4.0(5)
ꢀ 5.0(7)
ꢀ 1.0(2)
ꢀ 2.0(2)
ꢀ 9.3(4)
ꢀ 8.3(4)
ꢀ 28.1(8)
I
I
I
I
I
I
III

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Helvetica Chimica Acta – Vol. 91 (2008)
The conformation of the model peptide (S)-2g was also investigated in solution by
means of NMR techniques. An easy way is the observation of the signals of the amide
H-atoms under different conditions. Their chemical shifts show a significantly different
behavior when they are involved in an intramolecular H-bond, than when exposed to
the solvent or forming intermolecular H-bonds. Intramolecularly bound NH atoms are
much less influenced by temperature changes [14] or by addition of polar solvents or
radicals [37].
For (S)-2g, the 1H-NMR spectra were measured at different temperatures.
Although it was not possible to assign every signal in the NMR spectrum, two strongly
temperature-dependent NH signals were detected, i.e., the signals for the amide H-
atoms of Leu and Aib, which are not involved in the H-bonding pattern of the incipient
310-helix. One other signal was also temperature-dependent, but to a much lesser
extent, i.e., one of the amide H-atoms of the Gln side chain. This result is in agreement
with the X-ray crystal structure of (S)-13g, i.e., the corresponding pBrBz-protected
derivative of (S)-2g, where one amide H-atom of the Gln side chain is intramolecularly
involved in a H-bond with the C¼O group of the N-terminal-protecting pBrBz-group,
and the other amide H-atom of the Gln side chain is exposed to the environment and
should show a significant temperature dependence. All other amide H-atoms of (S)-2g
did not show a significant temperature dependence (Fig. 3). The amide H-atom of
Phe(2Me) could not be observed and is assumed to lie in the region of the aromatic H-
atoms.
Fig. 3. Temperature dependence of the signals of the amide H-atoms of (S)-2g
As can be seen in Fig. 3, the temperature dependence of the amide H-atoms is
linear. To compare the effects, the temperature coefficients were calculated and are
listed in Table 5.

Helvetica Chimica Acta – Vol. 91 (2008)
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Table 5. Temperature Coefficients of the Signals of the Amide H-Atoms of (S)-2g
Amide Protons
[Hz/K]
[10ꢀ3 ppm/K]
NH of Leu
NH of Aib
NH of Phe(2Me)
NH of Gln
NH of Valol
ꢀ 6.77
ꢀ 2.26
ꢀ 5.54
ꢀ 1.85
not observed
ꢀ 0.96
not observed
ꢀ 0.32
ꢀ 1.53
ꢀ 0.51
NH(1) of Gln Side Chain
NH(2) of Gln Side Chain
ꢀ 3.25
ꢀ 1.08
ꢀ 1.27
ꢀ 0.42
As only the amide H-atoms of Leu and Aib, but not of Phe(2Me), Gln(2Me), and
Valol are temperature-dependent, it is likely that the incipient 310-helix, which was
observed for (S)-13g in the solid state, is also the dominant conformation in solution.
In conclusion, it has been shown that the model pentapeptides of the type Z-Leu-
Aib-Xaa-Gln-Valol, with Xaa ¼ 2,2-disubstituted glycine, can be prepared conveniently
by the ꢀazirine/oxazolone methodꢁ. They adopt a helical conformation in the solid state
and in solution; the results from crystallographic and NMR investigations are in good
agreement with each other.
We thank the analytical services of our institute for NMR and mass spectra, and for elemental
analyses. Financial support by the Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel,
the Stiftung für wissenschaftliche Forschung an der Universität Zürich, and the Prof. Dr. Hans E. Schmid-
Stiftung is gratefully acknowledged. K. A. B. thanks the Stipendienfonds der Basler Chemischen Industrie
for a scholarship.
Experimental Part
1. General. See [19]. 1H- (600 MHz) and 13C-NMR (150.9 MHz) Spectra: Bruker AMX-600
instrument.
2. Preparation of H-Gln-Valol (11). 2.1. N-[(Benzyloxy)carbonyl]-glutaminyl-valinol (Z-Gln-Valol;
10). To a soln. of l-valinol (9; 0.66 g, 6.40 mmol) in abs. CH2Cl2 (50 ml), a soln. of Z-Gln-ONp (8; 2.83 g,
7.10 mmol) in abs. DMF (25 ml) was added slowly at 08. After 6 h, the gel-like precipitate was diluted
with CHCl3 (25 ml) and stirred for 18h at r.t.; then, additional CHCl 3 (50 ml) was added. After 2 h, the
precipitate was filtered, and washed with AcOEt/CHCl3 1:1 and Et2O. Recrystallization from EtOH
yielded 1.717 g (73%) of 10. Colorless crystals. M.p. 186.6 – 187.08. Rf (CH2Cl2/MeOH 10 :1) 0.20. IR:
3430s, 3300s, 3200m, 3080w, 3060w, 2960m, 2930m, 2870m, 1680s, 1660s, 1645s, 1555s, 1535s, 1505m,
1470m, 1465m, 1445m, 1415m, 1390m, 1370m, 1350m, 1330m, 1260s, 1245s, 1190w, 1140w, 1060m, 1040m,
1020m, 995w, 940w, 910w, 8 8 0w, 8 55w, 770w, 745m. 1H-NMR (CD3OD): 7.35 – 7.3 (m, 5 arom. H); 5.08(br.
s, PhCH2O); 4.14 (dd, J ¼ 8.5, 5.8, CH(2) of Gln); 3.7 – 3.55 (m, CH(2) and CH2(1) of Valol); 2.31 (t, J ¼
7.5, CH2(4) of Gln); 2.15 – 1.8( m, CH(3) of Valol, CH2(3) of Gln); 0.93, 0.89 (2d, J ¼ 6.8, 2 Me(4) of
Valol). 13C-NMR (CD3OD): 177.8( s, CONH2); 174.3 (s, CONH); 158.3 (s, OCONH); 138.1 (s, 1 arom.
C); 129.4, 128.9, 128.8 (3d, 5 arom. CH); 67.6 (t, PhCH2O); 63.0 (t, C(1) of Valol); 58.0, 56.0 (2d, C(2) of
Gln, C(2) of Valol); 32.5 (t, C(4) of Gln); 30.0 (d, C(3) of Valol); 29.1 (t, C(3) of Gln); 19.9, 18.8 (2q, 2
Me(4) of Valol). ESI-MS (MeOH): 404 (31, [M þ K]þ), 388 (100, [M þ Na]þ). Anal. calc. for
C18H27N3O5 (365.43): C 59.16, H 7.45, N 11.50; found: C 59.27, H 7.71, N 11.54.
2.2. Glutaminyl-valinol (H-Gln-Valol; 11). A soln. of 10 (14.970 g, 40.97 mmol) and Pd/C (10% on
activated charcoal, 0.550 g) in MeOH (950 ml) was treated with H2 for 18h at r.t. The mixture was
filtered over Celite, and the filtrate was evaporated: 9.419 g (99%) of 11. Colorless solid. M.p. 134.5 –
135.28. IR: 3350s, 3280s, 3200s, 3110s, 2950s, 2930s, 2870m, 1690s, 1680s, 1670s, 1645s, 1630s, 1615s,
1565s, 1550s, 1515m, 1505m, 1465m, 1450m, 1415s, 1385m, 1370m, 1350m, 1335m, 1310m, 1280m, 1245m,

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Helvetica Chimica Acta – Vol. 91 (2008)
1200w, 1150m, 1080m, 1070m, 1025m, 975m, 950m, 8 75w, 8 45w, 8 15w, 78 0w, 770w, 715m. 1H-NMR: 3.7 –
3.5 (m, CH2(1) of Valol, CH(2) of Gln); 3.4 – 3.3 (m, CH(2) of Valol); 2.35 – 2.3 (m, CH2(4) of Gln); 2.0 –
1.75 (m, CH2(3) of Gln, CH(3) of Valol); 0.96, 0.93 (2d, J ¼ 6.9, 6.8, 2 Me of Valol). 13C-NMR: 178.3,
177.1 (2s, CONH2, CONH); 63.0 (t, C(1) of Valol); 57.9, 55.7 (2d, C(2) of Gln, C(2) of Valol); 32.7, 32.5
(2t, C(3), C(4) of Gln); 30.0 (d, C(3) of Valol); 19.8, 18.8 (2q, 2 Me of Valol). CI-MS (NH3): 233 (11), 232
(100, [M þ 1]þ), 229 (10), 215 (20), 214 (12), 129 (5), 104 (7), 101 (6).
3. Peptides with Xaa ¼ Aib. 3.1. Benzyl [(S)-1-({[1,1-Dimethyl-2-({1,1-dimethyl-2-[methyl(phenyl)-
amino]-2-oxoethyl}amino)-2-oxoethyl]amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-Aib-
N(Me)Ph; 3a). To a soln. of N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyric acid (Z-Leu-Aib-OH
[19]; 5, 1.152 g, 3.29 mmol) in abs. CH2Cl2 (25 ml), 2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine (1a [38];
0.610 g, 3.50 mmol) was added at 08. The soln. was stirred for 23 h at r.t. The mixture was washed with 2n
HCl, 1n NaOH soln., and sat. aq. NaCl soln., dried (MgSO4), and evaporated: 1.645 g (95%) of 3a.
Colorless solid. M.p. 57.1 – 57.88. Rf (CH2Cl2/MeOH 10 :1) 0.51; Rf (CH2Cl2/MeOH 20 :1) 0.18. IR: 3310s,
3060m, 3030m, 2955s, 2870m, 2140w, 1950w, 1880w, 1820w, 1705vs, 1690vs, 1680vs, 1660vs, 1640vs, 1595s,
1540 – 1520vs, 1495vs, 1470s, 1455s, 1390s, 1365s, 1315m, 1265 – 1240s, 1220s, 1170m, 1120m, 1090s, 1070m,
1045m, 1030m, 1005w, 965w, 920w, 910w, 8 75w, 8 40w, 8 25w, 770m, 740m, 705s. 1H-NMR (CD3OD): 7.4 –
7.2 ( m, 10 arom. H); 5.15, 5.09 (AB, J ¼ 12.8, PhCH2O); 4.00 (t, J ¼ 7.5, CH(2) of Leu); 3.25 (br. s, MeN);
1.7 – 1.65 (m, CH(4) of Leu); 1.55 – 1.5 (m, CH2(3) of Leu); 1.47, 1.44, 1.41, 1.38(4 s, 4 Me of 2 Aib); 0.96,
0.93 (2d, J ¼ 6.7, 6.5, 2 Me of Leu). 13C-NMR (CD3OD): 176.2, 175.6, 175.2 (3s, 3 CONH); 158.8 (s,
OCONH); 146.9 (s, 1 arom. CN); 138.5 (s, 1 arom. C); 130.4, 129.7, 129.1, 128.5 (4d, 10 arom. CH); 67.6 (t,
PhCH2O); 58.7, 58.2 (2s, 2 C(2) of 2 Aib); 55.7 (d, C(2) of Leu); 41.6 (t, C(3) of Leu); 41.3 (q, MeN);
26.6, 26.4, 26.0, 24.7 (d, 3q, C(4) of Leu, 4 Me of 2 Aib); 23.4, 22.4 (2q, 2 Me of Leu). ESI-MS (NaI): 547
(100, [M þ Na]þ). Anal. calc. for C29H40N4O5 · H2O (530.67): C 65.64, H 7.72, N 10.56; found: C 65.90, H
7.56, N 10.73.
3.2. N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyryl-a-aminoisobutyric Acid (Z-Leu-Aib-Aib-
OH; 6a). A soln. of 3a (1.373 g, 2.62 mmol) in 3n HCl (THF/H2O 1:1, 40 ml) was stirred for 2 h at r.t.
Thereby, a colorless precipitate was formed. Then, 2n HCl (40 ml) was added, and the mixture was
extracted with CH2Cl2. During this operation, the precipitate dissolved. The org. soln. was dried
(MgSO4) and evaporated. Washing of the residue with AcOEt yielded 1.005 g (88%) of 6a. Colorless
solid. M.p. 192 – 1938. Rf (CH2Cl2/MeOH 10 :1) 0.18– 0.07. IR: 3385 m, 3330s, 3290s, 3060w, 3030w, 2980w,
2950m, 2865w, 1740s, 1705vs, 1660s, 1550m, 1525s, 1500m, 1470w, 1455w, 1440w, 1385m, 1365w, 1315s,
1295m, 1270s, 1245s, 1220m, 1175w, 1130w, 1120w, 1080w, 1045m, 1030w, 990w, 970w, 945w, 910w, 8 50w,
1
785w, 765w, 755w, 740w, 730w. H-NMR (CD3OD): 7.35 – 7.25 (m, 5 arom. H); 5.13, 5.08( AB, J ¼12.6,
PhCH2O); 4.02 (t, J ¼ 7.5, CH(2) of Leu); 1.7 – 1.65 (m, CH(4) of Leu); 1.52 (dd, J ¼ 7.8, 7.2, CH2(3) of
Leu); 1.44, 1.43, 1.42, 1.40 (4s, 4 Me of 2 Aib); 0.96, 0.93 (2d, J ¼ 6.5, 2 Me of Leu). 13C-NMR (CD3OD):
178.0, 175.9, 175.1 (3s, COOH, 2 CONH); 158.7 (s, OCONH); 138.3 (s, 1 arom. C); 129.5, 129.0, 128.6
(3d, 5 arom. CH); 67.6 (t, PhCH2O); 57.9, 57.1 (2s, 2 C(2) of 2 Aib); 55.5 (d, C(2) of Leu); 41.5 (t, C(3) of
Leu); 25.9 (d, C(4) of Leu); 26.1, 25.5, 24.7, 24.6, 23.3, 22.2 (6q, 4 Me of 2 Aib, 2 Me of Leu). ESI-MS
(NaI): 458(100, [ M þ Na]þ). Anal. calc. for C22H33N3O6 (435.51): C 60.67, H 7.64, N 9.65; found: C 60.55,
H 7.63, N 9.59.
3.3. N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyryl-a-aminoisobutyryl-glutaminyl-valinol (Z-
Leu-Aib-Aib-Gln-Valol; 2a). To a soln. of 6a (100 mg, 0.230 mmol) and Et3N (70 mg, 0.690 mmol) in
abs. DMF (2.5 ml) at r.t., HATU (87 mg, 0.230 mmol) was added. After 5 min, HOBt (35 mg,
0.23 mmol), and after a further 5 min, 11 (53 mg, 0.230 mmol) was added, and the mixture was stirred for
19 h at r.t. and evaporated. The residue was dissolved in AcOEt, washed with 1n HCl and 1n NaOH soln.,
dried (MgSO4), and evaporated. Recrystallization from AcOEt/hexane yielded 114 mg (77%) 2a.
Colorless crystals. M.p. 170 – 1728. Rf (CH2Cl2/MeOH 10 :1) 0.16. IR: 3310s, 3030w, 2960m, 2870w, 1655vs,
1535s, 1470w, 1455w, 1385w, 1365w, 1335w, 1310w, 1265m, 1230w, 1170w, 1120w, 1040w, 1030w, 925w,
850w, 790w, 740w. 1H-NMR (CD3OD): 7.92 (d, J ¼ 6.9, NH); 7.46 (s, NH); 7.35 – 7.25 (m, 5 arom. H); 5.13,
5.10 (AB, J ¼ 12.7, PhCH2O); 4.15 – 4.05 (m, CH(2) of Gln, CH(2) of Leu); 3.7 – 3.65 (m, CH(2) and
CH2(1) of Valol); 2.4 – 2.35 (m, CH2(4) of Gln); 2.25 – 2.2 (m, CH2(3) of Gln); 1.9 – 1.85 (m, CH(3) of
Valol); 1.75 – 1.7 (m, CH(4) of Leu); 1.6 – 1.55 (m, CH2(3) of Leu); 1.4 – 1.35 (m, 4 Me of 2 Aib); 1.0 – 0.9
(m, 2 Me of Leu, 2 Me of Valol). 13C-NMR (CD3OD): 177.9, 177.8, 176.8, 176.1, 174.4 (5s, CONH2,

Helvetica Chimica Acta – Vol. 91 (2008)
539
4 CONH); 158.9 (s, OCONH); 138.4 (s, 1 arom. C); 129.6, 129.0, 128.6 (3d, 5 arom. CH); 67.8( t,
PhCH2O); 63.6 (t, C(1) of Valol); 58.6 (d, C(2) of Gln); 58.0, 57.8 (2s, 2 C(2) of 2 Aib); 56.2, 55.9 (2d,
C(2) of Valol, C(2) of Leu); 41.4 (t, C(3) of Leu); 33.5 (t, C(4) of Gln); 30.1 (d, C(3) of Valol); 28.5 (t,
C(3) of Gln); 25.9 (d, C(4) of Leu); 26.9, 25.8, 24.6, 24.2, 23.3, 22.2 (6q, 4 Me of 2 Aib, 2 Me of Leu); 20.1,
19.4 (2q, 2 Me of Valol). ESI-MS (MeOH): 687 (25, [M þ K]þ), 672 (94, [M þ Na]þ), 650 (100, [M þ
1]þ). Anal. calc. for C32H52N6O8 · H2O (666.82): C 57.64, H 8.01, H 12.60; found: C 57.38, H 7.97, N 12.24.
3.4. N-{(S)-1-[({2-[(2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}carbon-
yl)-4-oxobutyl]amino}-1,1-dimethyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}amino)carbonyl]-3-
methylbutyl}-4-bromobenzamide (pBrBz-Leu-Aib-Aib-Gln-Valol; 13a). A soln. of 2a (71 mg,
0.109 mmol) and Pd/C (10% on activated charcoal, 7 mg) in MeOH (5 ml) was treated with H2 for
1.5 h at r.t. The mixture was filtered over cotton wool, and the filtrate was evaporated. The residue
(58mg) was dissolved in CH 2Cl2 (5 ml), and Et3N (30 mg, 0.297 mmol) and 4-bromobenzoyl chloride
(35 mg, 0.159 mmol) were added. A precipitate formed while stirring for 30 min at r.t. The mixture was
washed with 2n HCl and 1n NaOH. The precipitate dissolved after addition of a small amount of MeOH.
The org. soln. was dried (MgSO4) and evaporated. The residue (59 mg, 78%, 13a) was recrystallized from
MeOH, CH2Cl2, Et2O, and petroleum ether. Colorless crystals. M.p. 232.9 – 233.88. Rf (CH2Cl2/MeOH
10 :1) 0.15. IR: 3650w, 3420s, 3340vs, 3280vs, 3060w, 2980m, 2980s, 2960s, 2870m, 2540w, 2490w, 2440w,
2400w, 1675vs, 1660vs, 1650vs, 1595s, 1540vs, 1485s, 1465s, 1455s, 1440s, 1415m, 1390s, 1365s, 1340m, 1300s,
1235m, 1200m, 1175m, 1140m, 1070m, 1010m, 98 0w, 940w, 925w, 900w, 8 70w, 8 60w, 8 25w, 790w, 765w.
1H-NMR (CD3OD): 7.81, 7.62 (AA’BB’, J ¼ 8.5, 4 arom. H); 4.55 – 4.5 (m, CH(2) of Gln); 4.15 – 4.1 (m,
CH(2) of Leu); 3.62 (br. s, CH2(1) and CH(2) of Valol); 2.35 – 2.3 (m, CH2(4) of Gln); 2.25 – 2.0 (m,
CH2(3) of Gln); 1.85 – 1.65 (m, CH(3) of Valol, CH(4) and CH2(3) of Leu); 1.45 – 1.4 (m, 4 Me of 2 Aib);
1.01, 0.99, 0.87, 0.79 (4d, J ¼ 5.9, 6.0, 6.7, 6.8, 2 Me of Leu, 2 Me of Valol). 13C-NMR (CD3OD): 178.0,
177.8, 176.9, 175.6, 174.3 (5s, CONH2, 4 CONH); 169.6 (s, 1 CO (amide, pBrBz)); 134.0 (s, 1 arom. C);
132.8, 130.6 (2d, 4 arom. CH); 127.4 (s, 1 arom. CBr); 63.5 (t, C(1) of Valol); 58.6 (d, C(2) of Gln); 58.1,
57.9 (2s, 2 C(2) of 2 Aib); 56.1, 54.5 (2d, C(2) of Valol, C(2) of Leu); 41.2 (t, C(3) of Leu); 33.6 (t, C(4) of
Gln); 30.0 (d, C(3) of Valol); 26.6 (t, C(3) of Gln); 26.1 (d, C(4) of Leu); 28.5, 25.3, 25.1, 24.6, 23.4, 22.1
(6q, 4 Me of 2 Aib, 2 Me of Leu); 20.1, 19.3 (2q, 2 Me of Valol). ESI-MS (TFA): 737 (6, [M þ K]þ, 81Br),
721 (39, [M þ Na]þ, 81Br), 699 (100, [M þ 1]þ, 81Br), 681 (13, [M ꢀ OH]þ, 81Br), 596 (18, [M ꢀ Valol]þ,
81Br), 468(15, [ M ꢀ Gln-Valol]þ, 81Br). Anal. calc. for C31H49BrN6O7 (697.67): C 53.37, H 7.08, N 12.05;
found: C 53.26, H 7.12, N 11.99.
Crystals suitable for an X-ray crystal-structure determination were obtained from a mixture of
MeOH, CH2Cl2, Et2O, and petroleum ether by slow evaporation of the solvent.
4. Peptides with Xaa ¼ Ac5c. 4.1. Benzyl {(S)-1-[({1,1-Dimethyl-2-[(1-{[methyl(phenyl)amino]car-
bonyl}cyclopentyl)amino]-2-oxoethyl}amino)carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-Ac5c-
N(Me)Ph; 3b). As described for 3a, with 5 [19] (0.705 g, 2.01 mmol) in abs. CH2Cl2 (20 ml) and N-
methyl-N-phenyl-1-azaspiro[2.4]hept-1-en-2-amine (1b [39]; 0.439 g (containing 12.5% amide),
1.92 mmol): 1.030 g (97%) of 3b. Colorless solid. M.p. 67.7 – 69.18. Rf (CH2Cl2/MeOH 10 :1) 0.52; Rf
(CH2Cl2/MeOH 20 :1) 0.16. IR: 3310s, 3060m, 3030m, 2955s, 2870m, 1950w, 1810w, 1705vs, 1660vs, 1595s,
1520vs, 1495vs, 1470s, 1455s, 1380s, 1310m, 1260vs, 1220s, 1170m, 1120m, 1045s, 1030m, 1005w, 98 5w,
1
955w, 910w, 8 40w, 765m, 735m, 700s. H-NMR (CD3OD): 7.4 – 7.2 (m, 10 arom. H); 5.13, 5.11 (AB, J ¼
12.8, PhCH2O); 4.00 (t, J ¼ 7.5, CH2(2) of Leu); 3.22 (br. s, MeN); 2.4 – 2.35, 2.3 – 2.2, 2.2 – 1.95 (3m,
4 H of Ac5c); 1.75 – 1.65 (m, CH(4) of Leu, 4 H of Ac5c); 1.6 – 1.5 (m, CH2(3) of Leu); 1.47, 1.40 (2s, 2 Me
of Aib); 0.96, 0.93 (2d, J ¼ 6.6, 2 Me of Leu). 13C-NMR (CD3OD): 176.3, 175.6, 175.3 (3s, 3 CONH);
159.0 (s, OCONH); 147.0 (s, 1 arom. CN); 138.6 (s, 1 arom. C); 130.5, 129.8, 129.3, 128.7, 128.5, 128.3 (6d,
10 arom. CH); 68.8 (s, C(2) of Ac5c); 67.8( t, PhCH2O); 58.4 (s, C(2) of Aib); 55.8( d, C(2) of Leu); 41.7 (t,
C(3) of Leu); 41.1 (q, MeN); 38.7, 38.2 (2t, 2 C(3) of Ac5c); 26.1 (d, C(4) of Leu); 25.7, 25.6 (2t, 2 C(4) of
Ac5c); 26.8, 24.9, 23.5, 22.5 (4q, 2 Me of Aib, 2 Me of Leu). ESI-MS (NaI): 573 (100, [M þ Na]þ). Anal.
calc. for C31H42N4O5 · 0.33 H2O (556.71): C 66.88, H 7.72, N 10.06; found: C 67.12, H 7.64, N 10.02.
4.2. 1-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]-2-methyl-1-oxopro-
pyl}amino)cyclopentane-1-carboxylic Acid (Z-Leu-Aib-Ac5c-OH; 6b). As described for 6a, with 3b
(750 mg, 1.36 mmol), 3n HCl (THF/H2O 1:1, 30 ml), 2.5 h at r.t., 2n HCl (15 ml), recrystallization from
AcOEt/hexane: 566 mg (90%) of 6b. Colorless crystals. M.p. 175.0 – 176.58. Rf (CH2Cl2/MeOH 10 :1)

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Helvetica Chimica Acta – Vol. 91 (2008)
0.13. IR: 3300s, 3060m, 3030m, 2955s, 2870m, 1740s, 1720vs, 1695vs, 1660vs, 1590w, 1530vs, 1470m, 1455s,
1410m, 1390m, 1365m, 1345m, 1330m, 1315m, 1250s, 1175m, 1120m, 1050m, 1030m, 1005w, 950w, 910w,
1
770w, 735m. H-NMR (CD3OD): 7.49 (br. s, NH); 7.35 – 7.3 (m, 5 arom. H); 5.15 – 5.05 (m, PhCH2O);
4.02 (t, J ¼ 7.5, CH(2) of Leu); 2.25 – 2.0 (m, 4 H of Ac5c); 1.7 – 1.65 (m, CH(4) of Leu, 4 H of Ac5c); 1.52
(dd, J ¼ 7.5, 6.2, CH2(3) of Leu); 1.43 (br. s, 2 Me of Aib); 0.96, 0.93 (2d, J ¼ 6.7, 2 Me of Leu). 13C-NMR
(CD3OD): 177.8, 176.4, 175.0 (3s, COOH, 2 CONH); 158.7 (s, OCONH); 138.2 (s, 1 arom. C); 129.5,
129.1, 128.7 (3d, 5 arom. CH); 67.7 (t, PhCH2O); 67.3 (s, C(2) of Ac5c); 57.8( s, C(2) of Aib); 55.5 (d, C(2)
of Leu); 41.5 (t, C(3) of Leu); 38.1, 37.7 (2t, 2 C(3) of Ac5c); 25.9 (d, C(4) of Leu); 25.6 (t, 2 C(4) of Ac5c);
26.0, 24.7, 23.3, 22.2 (4q, 2 Me of Aib, 2 Me of Leu). ESI-MS (NaI): 506 (4, [M þ 2 Na ꢀ 1]þ), 484 (100,
[M þ Na]þ). Anal. calc. for C24H35N3O6 · 0.33 H2O (467.57): C 61.65, H 7.69, N 8.99; found: C 61.95, H
7.52, N 9.03.
4.3. Benzyl ((S)-1-{[(2-{[1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-4-oxobutyl]amino}carbonyl)cyclopentyl]amino}-1,1-dimethyl-2-oxoethyl)amino]carbonyl}-3-
methylbutyl)carbamate (Z-Leu-Aib-Ac5c-Gln-Valol; 2b). A soln. of 6b (239 mg, 0.518mmol) and Et 3N
(108mg, 1.069 mmol) in abs. DMF (3.5 ml) was stirred for 10 min at 0 8, then, HATU (217 mg,
0.571 mmol) was added. After stirring at 08 for 8min, 11 (132 mg, 0.57 mmol) was added, and the mixture
was stirred for 90 min at 08 and 40 h at r.t. The solvent was evaporated, the residue dissolved in AcOEt
and a small amount of MeOH, washed with 2n HCl and 1n NaOH soln., dried (MgSO4), and evaporated.
CC (CH2Cl2/MeOH 10 :1) yielded 304 mg (87%) of 2b. Colorless solid. M.p. 97.6 – 98.18. Rf (CH2Cl2/
MeOH 10 :1) 0.17. IR: 3300s, 3035w, 2960m, 2870w, 1665vs, 1535s, 1470m, 1455m, 1405w, 1390m, 1365w,
1315m, 1270m, 1220m, 1170w, 1130w, 1120w, 1045w, 1030w, 960w, 925w, 910w, 8 90w, 8 50w, 8 20w, 790w,
740w. 1H-NMR (CD3OD): 7.35 – 7.25 (m, 5 arom. H); 5.16, 5.11 (AB, J ¼ 12.7, PhCH2O); 4.16 (t, J ¼ 7.3,
CH(2) of Gln); 4.02 (t, J ¼ 7.5, CH(2) of Leu); 3.7 – 3.6 (m, CH(2) and CH2(1) of Valol); 2.4 – 2.3 (m,
CH2(4) of Gln, CH(3) of Valol); 2.25 – 2.15 (m, CH2(3) of Gln); 2.0 – 1.85 (m, 4 H of Ac5c); 1.75 – 1.55
(m, 4 H of Ac5c, CH(4) and CH2(3) of Leu); 1.40, 1.38(2 s, 2 Me of Aib); 1.0 – 0.9 (m, 2 Me of Leu, 2 Me
of Valol). 13C-NMR (CD3OD): 177.8, 177.4, 177.2, 176.1, 174.4 (5s, CONH2, 4 CONH); 159.1 (s,
OCONH); 138.4 (s, 1 arom. C); 129.6, 129.0, 128.4 (3d, 5 arom. CH); 68.1 (s, C(2) of Ac5c); 67.8( t,
PhCH2O); 63.6 (t, C(1) of Valol); 58.5 (d, C(2) of Gln); 57.8( s, C(2) of Aib); 56.2, 56.1 (2d, C(2) of Leu,
C(2) of Valol); 41.3, 38.8, 37.4 (3t, C(3) of Leu, 2 C(3) of Ac5c); 33.4 (t, C(4) of Gln); 30.1 (d, C(3) of
Valol); 28.5 (t, C(3) of Gln); 25.9 (d, C(4) of Leu); 25.7, 25.6 (2t, 2 C(4) of Ac5c); 24.7, 23.2, 22.4 (3q, 2 Me
of Aib, 2 Me of Leu); 20.1, 19.4 (2q, 2 Me of Valol). ESI-MS (TFA): 698(20, [ M þ Na]þ), 675 (100, [M þ
1]þ), 657 (15, [M ꢀ OH]þ), 572 (19, [M ꢀ Valol]þ), 444 (22, [M ꢀ Gln-Valol]þ). Anal. calc. for
C34H54N6O8 · 0.5 H2O (683.85): C 59.72, H 8.11, N 12.29; found: C 59.48, H 8.20, N 12.28.
4.4. N-((S)-1-{[(2-{[1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}carbon-
yl)-4-oxobutyl]amino}carbonyl)cyclopentyl]amino}-1,1-dimethyl-2-oxoethyl)amino]carbonyl}-3-methyl-
butyl)-4-bromobenzamide (pBrBz-Leu-Aib-Ac5c-Gln-Valol; 13b). As described for 13a, with 2b (83 mg,
0.123 mmol), Pd/C (10% on activated charcoal, 9 mg), MeOH (5 ml), and H2, 2 h at r.t., filtration over
Celite, with CH2Cl2 (5 ml), Et3N (18mg, 0.178mmol), 4-bromobenzoyl chloride (27 mg, 0.123 mmol),
1.5 h at r.t.; purification with CC (CH2Cl2/MeOH 10 :1): 76 mg (85%) of 13b. Colorless solid. M.p.
242.8– 243.6 8. Rf (CH2Cl2/MeOH 10 :1) 0.18. IR: 3405s, 3340vs, 3250s, 3060w, 2960s, 2875m, 1675vs,
1655vs, 1590s, 1540vs, 1485s, 1470m, 1455s, 1440m, 1410m, 1390m, 1360m, 1340m, 1315m, 1295m, 1255m,
1220m, 1180m, 1170m, 1150w, 1140w, 1130w, 1110w, 1095w, 1070w, 1020w, 1010m, 98 0w, 940w, 920w, 8 70w,
1
850w, 8 20w, 790w, 760w. H-NMR (CD3OD): 7.82, 7.63 (AA’BB’, J ¼ 8.4, 8.5, 4 arom. H); 4.5 – 4.45 (m,
CH(2) of Gln); 4.15 – 4.1 (m, CH(2) of Leu); 3.65 – 3.55 (m, CH(2) and CH2(1) of Valol); 2.35 – 2.3 (m,
CH2(4) of Gln); 2.3 – 2.0 (m, CH2(3) of Gln, CH(3) of Valol, 2 H of Ac5c); 1.9 – 1.85 (m, CH(4) of Leu);
1.85 – 1.65 (m, CH2(3) of Leu, 6 H of Ac5c); 1.43 (s, 2 Me of Aib); 1.02, 0.99, 0.86, 0.78 (4d, J ¼ 6.0, 6.2, 6.8,
6.8, 2 Me of Leu, 2 Me of Valol). 13C-NMR (CD3OD): 177.8, 177.4, 177.2, 175.7, 174.2 (5s, CONH2,
4 CONH); 169.8( s, 1 CO (amide, pBrBz)); 133.9 (s, 1 arom. C); 132.8, 130.6 (2d, 4 arom. CH); 127.5 (s, 1
arom. CBr); 68.2 (s, C(2) of Ac5c); 63.5 (t, C(1) of Valol); 58.4 (d, C(2) of Gln); 57.9 (s, C(2) of Aib); 55.9,
55.0 (2d, C(2) of Leu, C(2) of Valol); 41.0, 38.5, 37.8 (3t, C(3) of Leu, 2 C(3) of Ac5c); 33.4 (t, C(4) of
Gln); 30.0 (d, C(3) of Valol); 28.3 (t, C(3) of Gln); 26.1 (d, C(4) of Leu); 25.7 (t, 2 C(4) of Ac5c); 25.7,
25.3, 23.3, 22.3 (4q, 2 Me of Aib, 2 Me of Leu); 20.0, 19.3 (2q, 2 Me of Valol). ESI-MS (TFA): 763 (6,
[M þ K]þ, 81Br), 745 (35, [M þ Na]þ, 81Br), 725 (100, [M þ 1]þ, 81Br), 707 (22, [M ꢀ OH]þ, 81Br), 622

Helvetica Chimica Acta – Vol. 91 (2008)
541
(31, [M ꢀ Valol]þ, 81Br), 494 (33, [M ꢀ Gln-Valol]þ, 81Br). Anal. calc. for C33H51N6O7: C 54.77, H 7.10, N
11.61; found: C 54.49, H 7.20, N 11.76.
Recrystallization from AcOEt, MeOH, and petroleum ether gave crystals suitable for an X-ray
crystal-structure determination.
5. Tripeptide with (S)-Iva. N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyryl-(S)-isovaline (Z-Leu-
Aib-(S)-Iva-OH; (S)-6c). A soln. of (S)-3c [19] (438mg, 0.710 mmol) in 3 n HCl (MeCN/H2O 1:1,
10 ml) was stirred for 3 h at 608. The mixture was extracted with CH2Cl2, dried (MgSO4), and
evaporated. Prep. TLC (CH2Cl2/MeOH 10 :1) yielded 118mg (37%) of ( S)-6c and 98mg (30%) of
benzyl [(S)-1-({[1,1-dimethyl-2-({(S)-1-methyl-1-[(methylamino)carbonyl]propyl}amino)-2-oxoethyl]-
amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-(S)-Iva-NHMe; (S)-7c).
Data of (S)-6c. Colorless solid. M.p. 78– 80 8. Rf (CH2Cl2/MeOH 10 :1) 0.06. IR: 3320m, 2960m,
1710s, 1660s, 1525s, 1455m, 1385m, 1365w, 1315w, 1245m, 1165m, 1130w, 1050m, 945w, 8 00w, 78 0w, 740w,
700w. 1H-NMR: 7.35 – 7.3 (m, 5 arom. H); 7.18(br. s, NH); 7.08(br. s, NH); 5.75 (d, J ¼ 5.7, NH of Leu);
5.10 (br., PhCH2O); 4.15 – 4.1 (m, CH(2) of Leu); 2.05 – 1.9 (m, CH2(3) of Iva or Leu); 1.7 – 1.5 (m,
CH2(3) of Leu or Iva, Me(3) of Iva, 2 Me of Aib, CH(4) of Leu); 0.95 – 0.9 (m, 2 Me of Leu); 0.82 (t, J ¼
7.4, MeCH2 of Iva). 13C-NMR: 173.8, 172.9 (2s, 2 CONH, COOH); 156.7 (s, OCONH); 136.0 (s, 1 arom.
C); 128.5, 128.2, 127.8 (3d, 5 arom. CH); 67.1 (t, PhCH2O); 60.3, 57.2 (2s, C(2) of Iva, C(2) of Aib); 54.3
(d, C(2) of Leu); 40.7, 29.1 (2t, C(3) of Leu, C(3) of Iva); 24.6 (d, C(4) of Leu); 25.1, 22.8, 22.0, 21.7, 8.0
(5q, 2 Me of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me of Leu). ESI-MS (MeOH): 504 (15, [M þ Na þ
MeOH]þ), 488 (50, [M þ K]þ), 472 (62, [M þ Na]þ), 450 (100, [M þ 1]þ), 432 (14, [M ꢀ OH]þ), 333
(10, [M ꢀ Iva]þ). Anal. calc. for C23H35N3O6 (449.55): C 61.45, H 7.85, N 9.35; found: C 61.58, H 7.65, N
9.34.
Data of (S)-7c. Colorless solid. M.p. 204 – 2058. Rf (CH2Cl2/MeOH 10 :1) 0.43. IR: 3385m, 3314s,
3017w, 2969m, 2871w, 1703vs, 1648vs, 1523vs, 1462m, 1442w, 1410w, 1385w, 1372w, 1362w, 1341w, 1312w,
1291w, 1271w, 1243s, 1216m, 1175w, 1134w, 1118w, 1083w, 1047m, 1030w, 969w, 944w, 916w, 8 46w, 8 04w,
1
790w, 749w, 737w, 699w, 670w, 630w. H-NMR (CD3OD): 7.35 – 7.3 (m, 5 arom. H); 5.07 (s, PhCH2O);
4.04 (dd, J ¼ 8.9, 6.1, CH(2) of Leu); 2.69 (s, MeN); 2.2 – 2.05, 1.85 – 1.65, 1.65 – 1.45 (3m, CH2(3) of Iva,
CH2(3) of Leu, CH(4) of Leu); 1.42, 1.39, 1.33 (3s, Me(3) of Iva, 2 Me of Aib); 0.97, 0.95 (2d, J ¼ 6.8, 6.7,
2 Me of Leu); 0.78( t, J ¼ 7.5, Me(4) of Iva). 13C-NMR (CD3OD): ca. 177.5, 176, 175.5 (3s, 3 CONH); ca.
159 (s, OCONH); ca. 138( s, 1 arom. C); 129.4, 128.9, 128.5 (3d, 5 arom. CH); 67.5 (t, PhCH2O); 61.4, 58.0
(2s, C(2) of Iva, C(2) of Aib); 55.2 (d, C(2) of Leu); 41.2, 29.4 (2t, C(3) of Leu, C(3) of Iva); 25.7 (d, C(4)
of Leu); 26.4, 26.1, 24.4, 23.2, 23.0, 22.0, 8.0 (7q, MeN, 2 Me of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me of
Leu). CI-MS (NH3): 464 (16), 463 (56, [M þ 1]þ), 432 (14, [M ꢀ HNMe]þ), 356 (20), 355 (10, [M ꢀ
OBn]þ). Anal. calc. for C24H38N4O5 · 0.2 H2O (466.19): C 61.83, H 8.30, N 12.02; found: C 61.85, H
8.24, N 11.94.
6. Tripeptide with (R)-Iva. N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyryl-(R)-isovaline (Z-
Leu-Aib-(R)-Iva-OH; (R)-6c). 6.1. Hydrolysis of (R)-3c. As described for (S)-6c, with (R)-3c [19]
(437 mg, 0.710 mmol) and 3n HCl (MeCN/H2O 1:1, 8ml), 3 h at 60 8; CC (CH2Cl2/MeOH 100 :2, then
100 :3, 20 :1, 10 :1) and prep. TLC (CH2Cl2/MeOH 10 :1): 123 mg (39%) of (R)-6c (colorless solid) and
95 mg (29%) of benzyl [(S)-1-({[1,1-dimethyl-2-({(R)-1-methyl-1-[(methylamino)carbonyl]propyl}-
amino)-2-oxoethyl]amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-(R)-Iva-NHMe; (R)-7c).
6.2. Hydrolysis of (R)-3i. As described for (S)-6c, with (R)-3i [18] (56 mg, 0.099 mmol) and 3n HCl
(MeCN/H2O 1:1, 0.5 ml), 3 h at 608; prep. TLC (CH2Cl2/MeOH 10 :1): 37 mg (84%) of (R)-6c.
Data of (R)-6c. Colorless solid. M.p. 69 – 718. Rf (CH2Cl2/MeOH 10 :1) 0.06. IR: 3393s, 3344s, 3280s
3065m, 2955s, 1738vs, 1706vs, 1664vs, 1522vs, 1456m, 1388m, 1376m, 1329m, 1272vs, 1244s, 1216s, 1172w,
1
1135w, 1046s, 975w, 914w, 8 48w, 78 8w, 733w, 697m. H-NMR: 7.4 – 7.3 (m, 5 arom. H); 7.16 (br. s, NH);
6.95 (br., NH); 5.60 (br., NH); 5.11 (br., PhCH2O); 4.11 (br., CH(2) of Leu); 2.05 – 1.9 (m, CH2(3) of Iva
or Leu); 1.7 – 1.5 (m, CH2(3) of Leu or Iva, Me(3) of Iva, 2 Me of Aib, CH(4) of Leu); 0.95 – 0.9 (m, 2 Me
of Leu); 0.83 (t, J ¼ 7.3, MeCH2 of Iva). 13C-NMR: ca. 177, 173 (2s, 2 CONH, COOH); ca. 157 (s,
OCONH); ca. 136 (s, 1 arom. C); 128.5, 128.2, 127.9 (3d, 5 arom. CH); 67.2 (t, PhCH2O); 60.4, ca. 58 (2s,
C(2) of Iva, C(2) of Aib); 54.2 (d, C(2) of Leu); 40.8, 29.6 (2t, C(3) of Leu, C(3) of Iva); 24.6 (d, C(4) of
Leu); 25.3, 22.8, 21.9, 7.9 (4q, 2 Me of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me of Leu). ESI-MS (MeOH,
NaI): 953 (10, [2M þ Na þ MeOH]þ), 921 (14, [2M þ Na]þ), 473 (16), 472 (59, [M þ Na]þ), 451 (26), 450

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Helvetica Chimica Acta – Vol. 91 (2008)
(100, [M þ 1]þ), 432 (10, [M ꢀ OH]þ). Anal. calc. for C23H35N3O6 · 0.33 H2O (455.56): C 60.64, H 7.89, N
9.22; found: C 60.59, H 7.61, N 9.02.
Crystals suitable for an X-ray crystal-stucture determination were grown from MeOH.
Data of (R)-7c. Colorless solid. M.p. 212.8– 213.6 8. Rf (CH2Cl2/MeOH 10 :1) 0.40. IR: 3385m, 3314s,
3017w, 2969s, 2954m, 2871w, 2513w, 2483w, 1703s, 1648vs, 1523s, 1462m, 1406w, 1385w, 1372w, 1361w,
1349w, 1312w, 1291m, 1272m, 1244m, 1216m, 1175w, 1134w, 1118w, 1047m, 1030w, 968w, 944w, 917w,
1
848w, 78 9w, 748w, 699w, 629w. H-NMR (CD3OD): 7.5 (br., NH); 7.35 – 7.3 (m, 5 arom. H); 7.13 (br. s,
NH); 5.10, 5.06 (AB, J ¼ 12.6, PhCH2O); 4.05 (dd, J ¼ 8.7, 6.4, CH(2) of Leu); 2.70 (s, MeN); 1.9 – 1.85
(m, 1 H of CH2(3) of Iva, CH2(3) of Leu, or CH(4) of Leu); 1.75 – 1.65 (m, 2 H of CH2(3) of Iva, CH2(3)
of Leu, or CH(4) of Leu); 1.55 – 1.5 (m, 2 H of CH2(3) of Iva, CH2(3) of Leu, or CH(4) of Leu); 1.41, 1.40,
1.39 (3s, Me(3) of Iva, 2 Me of Aib); 0.96 (2d, J ¼ 6.4, 6.6, 2 Me of Leu); 0.79 (t, J ¼ 7.5, Me(4) of Iva).
13C-NMR (CD3OD): 177.1, 175.9, 175.3 (3s, 3 CONH); 158.3 (s, OCONH); 137.9 (s, 1 arom. C); 129.3,
128.8, 128.3 (3d, 5 arom. CH); 67.4 (t, PhCH2O); 61.1, 57.8(2 s, C(2) of Iva, C(2) of Aib); 55.1 (d, C(2) of
Leu); 41.1, 31.6 (2t, C(3) of Leu, C(3) of Iva); 25.6 (d, C(4) of Leu); 26.4, 25.9, 24.5, 23.1, 22.1, 21.7, 8.1
(7q, MeN, 2 Me of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me of Leu). CI-MS (NH3): 465 (10), 464 (45), 463
(100, [M þ 1]þ), 433 (19), 432 (56, [M ꢀ NHMe]þ), 355 (5, [M ꢀ OBn]þ), 329 (8, [M ꢀ
(benzyloxy)carbonyl þ 2]þ). Anal. calc. for C24H38N4O5 · 0.25 H2O (466.64): C 61.71, H 8.31, N 11.99;
found: C 61.74, H 8.05, N 11.91.
Crystals of (R)-7c suitable for an X-ray crystal-structure determination were grown from MeOH/
CH2Cl2.
7. Peptides with Xaa ¼ (S)-Val(2Me). 7.1. (S)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-meth-
yl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2,3-dimethylbutanoic Acid (Z-Leu-Aib-(S)-
Val(2Me)-OH; (S)-6d). As described for (S)-6c, with (S)-3d [19] (1.480 g, 2.35 mmol) and 3n HCl
(MeCN/H2O 1:1, 20 ml), 90 min at 608; CC (CH2Cl2/MeOH 100 :2, then 100 :3) and prep. TLC (CH2Cl2/
MeOH 10 :1): 711 mg (65%) of (S)-6d and 239 mg (21%) of benzyl [(S)-1-({[1,1-dimethyl-2-({(S)-1,2-
dimethyl-1-[(methylamino)carbonyl]propyl}amino)-2-oxoethyl]amino}carbonyl)-3-methylbutyl]carba-
mate (Z-Leu-Aib-(S)-Val(2Me)-NHMe; (S)-7d).
Data of (S)-6d. Colorless solid. M.p. 69 – 708. Rf (CH2Cl2/MeOH 10 :1) 0.15. IR: 3320s, 2970s, 1715s,
1670s, 1535s, 1460m, 1390m, 1370m, 1250s, 1180m, 1165m, 1130w, 1050m, 955w, 78 5w, 745w, 705m.
1H-NMR: 7.35 – 7.3 (m, 5 arom. H, NH); 6.90 (br. s, NH); 5.62 (d, J ¼ 6.5, NH); 5.10 (br., PhCH2O);
4.15 – 4.1 (m, CH(2) of Leu); 2.35 – 2.3 (m, CH(3) of Val(2Me)); 1.7 – 1.4 (m, CH2(3) and CH(4) of Leu,
2 Me of Aib, Me(3) of Val(2Me)); 0.95 – 0.85 (m, 2 Me of Leu, 2 Me(4) of Val(2Me)). 13C-NMR: 175.4,
174.5, 173.0 (3s, 2 CONH, COOH); 156.5 (s, OCONH); 136.0 (s, 1 arom. C); 128.5, 128.2, 127.9 (3d, 5
arom. CH); 67.1 (t, PhCH2O); 63.5, 57.5 (2s, C(2) of Val(2Me), C(2) of Aib); 54.3 (d, C(2) of Leu); 40.7
(t, C(3) of Leu); 33.5, 24.7 (2d, C(3) of Val(2Me), C(4) of Leu); 25.1, 24.9, 22.8, 21.7, 18.0, 17.3, 16.9 (7q,
2 Me of Aib, Me(3) and 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS (MeOH): 502 (11, [M þ K]þ), 486
(94, [M þ Na]þ), 464 (100, [M þ 1]þ), 446 (28, [M ꢀ OH]þ), 333 (13, [M ꢀ Val(2Me)]þ). Anal. calc. for
C24H37N3O6 · 0.33 H2O (469.58): C 61.39, H 7.94, N 8.95; found: C 61.34, H 8.17, N 8.79.
Data of (S)-7d. Colorless solid. M.p. 67 – 698. Rf (CH2Cl2/MeOH 10 :1) 0.41. IR: 3304s, 3035w, 2964s,
2873w, 1708s, 1664vs, 1540s, 1455m, 1411w, 1370w, 1311w, 1267s, 1222m, 1173w, 1120w, 1054m, 915w,
788w, 742w, 696w, 620w. 1H-NMR (CD3OD): 7.35 – 7.25 (m, 5 arom. H); 5.13, 5.09 (AB, J ¼ 12.6,
PhCH2O); 4.05 (dd, J ¼ 8.7, 6.2, CH(2) of Leu); 2.71 (s, MeN); 2.1 – 1.95, 1.8– 1.65, 1.65 – 1.45 (3 m, CH(3)
of Val(2Me), CH2(3) of Leu, CH(4) of Leu); 1.39 (s, Me(3) of Val(2Me), 2 Me of Aib); 0.96, 0.94, 0.89
(3d, J ¼ 7.5, 7.0, 6.8, 2 Me of Leu, 2 Me(4) of Val(2Me)). 13C-NMR (CD3OD): ca. 176.5, ca. 176, ca. 175.5
(3s, 3 CONH); ca. 159 (s, OCONH); 138.2 (s, 1 arom. C); 129.4, 129.0, 128.5 (3d, 5 arom. CH); 67.6 (t,
PhCH2O); 61.4, 58.0 (2s, C(2) of Val(2Me), C(2) of Aib); 55.6 (d, C(2) of Leu); 41.6 (t, C(3) of Leu); 36.5
(d, C(3) of Val(2Me)); 25.8( d, C(4) of Leu); 26.4, 25.9, 24.6, 23.2, 21.9, 18.5, 17.8, 17.7 (8q, MeN, 2 Me of
Aib, Me(3) of Val(2Me), 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS (MeOH, NaI): 499 (100, [M þ
Na]þ). Anal. calc. for C25H40N4O5 · 0.25 H2O (481.12): C 62.41, H 8.48, N 11.65; found: C 62.50, H 8.47, N
11.47.
7.2. Benzyl ((S)-1-{[(2-{[(S)-1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]ami-
no}carbonyl)-4-oxobutyl]amino}carbonyl)-1,2-dimethylpropyl]amino}-1,1-dimethyl-2-oxoethyl)amino]-
carbonyl}-3-methylbutyl)carbamate (Z-Leu-Aib-(S)-Val(2Me)-Gln-Valol; (S)-2d). To a soln. of (S)-6d

Helvetica Chimica Acta – Vol. 91 (2008)
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(176 mg, 0.380 mmol) and Et3N (115 mg, 1.14 mmol) in abs. DMF (2.5 ml) at r.t., HATU (144 mg,
0.380 mmol) was added. After 2 min, HOBt (57 mg, 0.380 mmol), and after further 4 min, 11 (88 mg,
0.38mmol) were added, and the mixure was stirred for 91 h at r.t. and evaporated. The residue was
dissolved in AcOEt, washed with 1n HCl and 1n NaOH solns., dried (MgSO4), and evaporated. From the
residue, crystals formed overnight. They were separated and dried. The filtrate was purified by prep. TLC
(CH2Cl2/MeOH 10 :1). Total yield of (S)-2d: 94 mg (37%). Colorless solid. M.p. 202 – 2038. Rf (CH2Cl2/
MeOH 10 :1) 0.17. IR: 3455m, 3335s, 3213m, 2957m, 2870m, 2369w, 2352w, 1706s, 1659s, 1615m, 1540s,
1
1456m, 1389m, 1274m, 1262m, 1171m, 1129w, 1043w, 698m. H-NMR: 7.93 (br. s, NH); 7.8 0 (br., NH);
7.35 – 7.25 (m, 5 arom. H); 7.05 (br., NH); 6.93 (br. s, NH); 6.73 (br., NH); 5.58(br., NH); 5.15, 5.12 ( AB,
J ¼ 12.7, PhCH2O); 4.15 – 4.0, 3.85 – 3.8, 3.7 – 3.55 (3m, CH(2) of Gln, CH(2) of Leu, CH(2) and CH2(1)
of Valol); 3.19 (br., OH); 2.45 – 2.2 (m, CH2(4) and CH2(3) of Gln); 1.95 – 1.9, 1.8– 1.6 (2 m, CH2(3) of
Leu, CH(3) of Valol, CH(3) of Val(2Me)); 1.4 – 1.35 (m, CH(4) of Leu, 2 Me of Aib, Me(3) of
Val(2Me)); 1.0 – 0.85 (m, 2 Me of Valol, 2 Me(4) of Val(2Me), 2 Me of Leu). 13C-NMR: 175.1, 174.9,
172.8(3 s, CONH2, 4 CONH); 157.1 (s, OCONH); 136.5 (s, 1 arom. C); 128.5, 128.0, 127.4 (3d, 5 arom.
CH); 66.8, 63.5 (2t, PhCH2O, C(1) of Valol); 63.0, 57.0 (2s, C(2) of Aib, C(2) of Val(2Me)); 57.5, 55.8(2 d,
C(2) of Gln, C(2) of Valol, C(2) of Leu); 39.9, 32.7, 27.7 (3t, C(4) and C(3) of Gln, C(3) of Leu); 35.6,
28.9, 24.6 (3d, C(3) of Valol, C(3) of Val(2Me), C(4) of Leu); 26.6, 22.9, 22.7, 21.5, 19.5, 19.2, 17.3, 17.2,
17.1 (9q, 2 Me of Aib, Me(3) of Val(2Me), 2 Me of Valol, 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS
(MeOH, AcOH): 699 (9, [M þ Na]þ), 680 (9), 679 (36), 678 (100, [M þ 1]þ). Anal. calc. for C34H56N6O8 ·
0.33 H2O (682.86): C 59.80, H 8.30, N 12.31; found: C 59.67, H 8.53, N 12.13.
8. Peptides with Xaa ¼ (R)-Val(2Me). 8.1. (R)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-
methyl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2,3-dimethylbutanoic Acid (Z-Leu-Aib-(R)-
Val(2Me)-OH; (R)-6d). As described for (S)-6c, with (R)-3d [19] (1.394 mg, 2.21 mmol) and 3n HCl
(MeCN/H2O 1:1, 20 ml), 2 h at 608; CC (CH2Cl2/MeOH 100 :2) and prep. TLC (CH2Cl2/MeOH 10 :1):
817 mg (80%) of (R)-6d and 92 mg (9%) of benzyl [(S)-1-({[1,1-dimethyl-2-({(R)-1,2-dimethyl-1-
[(methylamino)carbonyl]propyl}amino)-2-oxoethyl]amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-
Aib-(R)-Val(2Me)-NHMe; (R)-7d).
Data of (R)-6d. Colorless solid. M.p. 163 – 1648. Rf (CH2Cl2/MeOH 10 :1) 0.20. IR: 3320s, 2970m,
1720s, 1670s, 1540s, 1460m, 1390m, 1370m, 1250m, 1180m, 1165m, 1130w, 1050m, 745w, 707w. 1H-NMR:
7.4 – 7.3 ( m, 5 arom. H); 7.03 (br., NH); 5.57 (d, J ¼ 6.6, NH); 5.10 (br., PhCH2O); 4.15 – 4.05 (m, CH(2)
of Leu); 2.3 – 2.25 (m, CH(3) of Val(2Me)); 1.7 – 1.4 (m, CH2(3) and CH(4) of Leu, 2 Me of Aib, Me(3)
of Val(2Me)); 0.95 – 0.9 (m, 2 Me of Leu, 2 Me(4) of Val(2Me)). 13C-NMR: ca. 175, 174, 173 (3s,
2 CONH, COOH); ca. 157 (s, OCONH); 135.8( s, 1 arom. C); 128.5, 128.3, 127.9 (3d, 5 arom. CH); 67.2
(t, PhCH2O); 63.7, 57.6 (2s, C(2) of Val(2Me), C(2) of Aib); 54.0 (d, C(2) of Leu); 41.0 (t, C(3) of Leu);
33.3, 24.6 (2d, C(3) of Val(2Me), C(4) of Leu); 25.6, 24.5, 22.8, 21.8, 17.9, 17.2, 16.7 (7q, 2 Me of Aib,
Me(3) and 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS (MeOH): 502 (12, [M þ K]þ), 486 (90, [M þ
Na]þ), 464 (100, [M þ 1]þ), 446 (15, [M ꢀ OH]þ), 333 (16, [M ꢀ Val(2Me)]þ). Anal. calc. for
C24H37N3O6 · 0.33 H2O (469.58): C 61.37, H 8.09, N 8.95; found: C 61.38, H 8.01, N 8.53.
Data of (R)-7d. Colorless solid. M.p. 195.8– 196.9 8. Rf (CH2Cl2/MeOH 10 :1) 0.41. IR: 3287s, 2966m,
2875w, 1703s, 1673vs, 1518s, 1463w, 1412w, 1362w, 1315w, 1271s, 1234m, 1216m, 1175w, 1117w, 1047m,
1029w, 971w, 943w, 914w, 78 9w, 747w, 699w, 625w. 1H-NMR (CD3OD): 7.4 – 7.25 (m, 5 arom. H); 5.09, 5.05
(AB, J ¼ 12.5, PhCH2O); 4.09 (dd, J ¼ 8.9, 6.1, CH(2) of Leu); 2.69 (s, MeN); 2.05 – 1.9, 1.75 – 1.45 (2m,
CH(3) of Val(2Me), CH2(3) of Leu, CH(4) of Leu); 1.40 (s, Me(3) of Val(2Me), 2 Me of Aib); 0.97, 0.95,
0.91, 0.79 (4d, J ¼ 7.7, 7.0, 6.8, 6.8, 2 Me of Leu, 2 Me(4) of Val(2Me)). 13C-NMR (CD3OD): ca. 176.5,
176.2, ca. 175.5 (3s, 3 CONH); ca. 159 (s, OCONH); 138.1 (s, 1 arom. C); 129.4, 128.9, 128.4 (3d, 5 arom.
CH); 67.3 (t, PhCH2O); 64.1, 58.1 (2s, C(2) of Val(2Me), C(2) of Aib); 54.9 (d, C(2) of Leu); 41.4 (t, C(3)
of Leu); 36.7 (d, C(3) of Val(2Me)); 25.7 (d, C(4) of Leu); 26.9, 26.4, 23.5, 23.1, 22.1, 17.6, 17.5, 17.2 (8q,
MeN, 2 Me of Aib, Me(3) of Val(2Me), 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS (MeOH, NaI): 499
(100, [M þ Na]þ). Anal. calc. for C25H40N4O5 · 0.33 H2O (482.63): C 62.22, H 8.49, N 11.61; found: C 62.12,
H 8.47, N 12.06.
Crystals suitable for an X-ray analysis were grown from CD3OD.
8.2. Benzyl ((S)-1-{[(2-{[(R)-1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]ami-
no}carbonyl)-4-oxobutyl]amino}carbonyl)-1,2-dimethylpropyl]amino}-1,1-dimethyl-2-oxoethyl)amino]-

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carbonyl}-3-methylbutyl)carbamate (Z-Leu-Aib-(R)-Val(2Me)-Gln-Valol; (R)-2d). As described for 2a,
with (R)-6d (599 mg, 1.29 mmol), Et3N (0.54 ml, 392 mg, 3.90 mmol), abs. DMF (13 ml), and HATU
(491 mg, 1.29 mmol), 3 min at r.t., HOBt (196 mg, 1.30 mmol), 4 min at r.t., 11 (301 mg, 1.30 mmol), 65 h
at r.t.; CC (CH2Cl2/MeOH 20 :1): 357 mg (41%) of (R)-2d and 202 mg of starting material (R)-6d (34%).
Data of (R)-2d. Colorless solid. M.p. 110 – 1118. Rf (CH2Cl2/MeOH 10 :1) 0.15. IR: 3416s, 2962s,
1664s, 1534s, 1456m, 1388m, 1375m, 1264m, 1179w, 1122w, 1049w, 8 49s, 740m, 698m. 1H-NMR: 7.70 (br., 2
NH); 7.35 – 7.3 (m, 5 arom. H); 6.94 (br., NH); 6.84 (br. s, NH); 6.79 (br., NH); 6.22 (br., NH); 5.15 – 5.05
(m, PhCH2O); 4.25 – 4.15, 4.15 – 4.05, 3.75 – 3.55 (3m, CH(2) of Gln, CH(2) of Leu, CH(2) and CH2(1) of
Valol); 2.45 – 2.15 (m, CH2(4) and CH2(3) of Gln); 1.8– 1.55 ( m, CH2(3) of Leu, CH(3) of Valol, CH(3)
of Val(2Me)); 1.45 – 1.25 (m, CH(4) of Leu, 2 Me of Aib, Me(3) of Val(2Me)); 1.0 – 0.75 (m, 2 Me of
Valol, 2 Me(4) of Val(2Me), 2 Me of Leu). 13C-NMR: ca. 176, 174.3, 174.1, 172.7 (4s, CONH2, 4 CONH);
ca. 157 (s, OCONH); 136.4 (s, 1 arom. C); 128.5, 128.1, 127.5 (3d, 5 arom. CH); 66.8, 63.2 (2t, PhCH2O,
C(1) of Valol); 62.2, 57.2 (2s, C(2) of Aib, C(2) of Val(2Me)); 57.1, 54.9, 54.4 (3d, C(2) of Gln, C(2) of
Valol, C(2) of Leu); 40.1, 32.3, 27.3 (3t, C(4) and C(3) of Gln, C(3) of Leu); 33.4, 28.9, 24.6 (3d, C(3) of
Valol, C(3) of Val(2Me), C(4) of Leu); 22.7, 21.8, 19.5, 19.1, 17.8, 17.7 (6q, 2 Me of Aib, Me(3) of
Val(2Me), 2 Me of Valol, 2 Me(4) of Val(2Me), 2 Me of Leu). ESI-MS (MeOH, AcOH): 701 (11), 700
(46), 699 (100, [M þ Na]þ), 586 (10, [M ꢀ C7H7 þ 1]þ). Anal. calc. for C34H56N6O8 · 0.5 H2O (685.86): C
59.54, H 8.38, N 12.25; found: C 59.25, H 8.52, N 12.16.
9. Peptides with Xaa ¼ (S)-Ala(2cPent). 9.1. (S)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-
methyl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2-cyclopentylpropanoic Acid (Z-Leu-Aib-
(S)-Ala(2cPent)-OH; (S)-6e). As described for (S)-6c, with (S)-3e [19] (98mg, 0.149 mmol) and 3 n
HCl (MeCN/H2O 1:1, 1.5 ml), 3 h at 608; prep. TLC (CH2Cl2/MeOH 10 :1): 54 mg (74%) of (S)-6e.
Colorless solid. M.p. 79 – 818. Rf (CH2Cl2/MeOH 10 :1) 0.26. IR: 3321m, 2956s, 2871m, 1706vs, 1668vs,
1526vs, 1455m, 1386w, 1249m, 1047w, 738w. 1H-NMR: 7.35 – 7.25 (m, 5 arom. H); 7.21 (br. s, NH); 7.06 (br.
s, NH); 5.80 (br., NH); 5.10 (br. s, PhCH2O); 4.15 – 4.1 (m, CH(2) of Leu); 2.45 – 2.35 (m, CH(3) of
Ala(2cPent)); 1.75 – 1.35 (m, CH2(3) and CH(4) of Leu, 2 Me of Aib, Me of Ala(2cPent), 4 CH2 of
Ala(2cPent)); 0.95 – 0.9 (m, 2 Me of Leu). 13C-NMR: 175.7, 174.0, 173.2 (3s, 2 CONH, COOH); 156.5 (s,
OCONH); 136.1 (s, 1 arom. C); 128.4, 128.1, 127.7 (3d, 5 arom. CH); 67.0 (t, PhCH2O); 61.8, 57.4 (2s, C(2)
of Ala(2cPent), C(2) of Aib); 54.3 (d, C(2) of Leu); 46.1 (d, C(3) of Ala(2cPent)); 40.7 (t, C(3) of Leu);
27.0, 26.8, 25.3 (3t, 4 CH2 of cPent); 25.0 (q, MeN); 24.6 (d, C(4) of Leu); 22.8, 21.7, 19.5, 14.0 (4q, 2 Me of
Aib, Me of Ala(2cPent), 2 Me of Leu). ESI-MS (MeOH): 512 (100, [M þ Na]þ), 490 (52, [M þ 1]þ), 307
(13). Anal. calc. for C26H39N3O6 (489.61): C 63.78, H 8.03, N 8.58; found: C 63.80, H 8.12, N 8.24.
9.2. Benzyl {(S)-1-[({2-[((S)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}-
carbonyl)-4-oxobutyl]amino}-1-cyclopentyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}ami-
no)carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Ala(2cPent)-Gln-Valol; (S)-2e). As described
for 2a, with (S)-6e (149 mg, 0.304 mmol), Et3N (0.1 ml, 72.6 mg, 0.720 mmol), abs. DMF (2 ml), and
HATU (117 mg, 0.308mmol), 2 min at 0 8, HOAt (0.5m soln. in DMF, 0.6 ml, 0.3 mmol), 3 min at 08, 11
(70.5 mg, 0.305 mmol), 20 min at 08 and 70 h at r.t.; after the washing procedure described for 2a, crystals
suitable for X-ray crystal-structure determination were obtained. Prep. TLC (CH2Cl2/MeOH 10 :1) of
the rest; total yield: 93 mg (43%) of (S)-2e. Colorless solid. M.p. 208.0 – 209.18. Rf (CH2Cl2/MeOH 10 :1)
1
0.37. H-NMR (CD3OD): 7.35 – 7.3 (m, 5 arom. H); 5.25 – 5.05 (m, PhCH2O); 4.1 – 4.05, 3.7 – 3.65 (2m,
CH(2) of Gln, CH(2) of Leu, CH(2) and CH2(1) of Valol); 2.45 – 2.3, 2.25 – 2.15, 1.95 – 1.85, 1.8 – 1.5 (4m,
CH2(4) and CH2(3) of Gln, CH2(3) of Leu, 4 CH2 of Ala(2cPent), CH(4) of Leu, CH(3) of Valol, CH(3)
of Ala(2cPent)); 1.44 (s, Me of Ala(2cPent)); 1.39 (s, 2 Me of Aib); 0.95 – 0.9 (m, 2 Me of Valol, 2 Me of
Leu). 13C-NMR (CD3OD): 177.4, ca. 176.5, 176.2, 174.5 (4s, CONH2, 4 CONH); 158.7 (s, OCONH); ca.
143 (s, 1 arom. C); 129.4, 128.9, 128.4 (3d, 5 arom. CH); 67.5, 63.6 (2t, PhCH2O, C(1) of Valol); 63.0, 58.0
(2s, C(2) of Aib, C(2) of Ala(2cPent)); 58.6, 56.6, 55.7 (3d, C(2) of Gln, C(2) of Valol, C(2) of Leu); 49.1
(d, C(3) of Ala(2cPent)); 41.8, 33.6, 28.4, 28.1, 27.8, 26.1, 26.1 (7t, 4 CH2 of Ala(2cPent), C(4) and C(3) of
Gln, C(3) of Leu); 29.9, 25.8(2 d, C(3) of Valol, C(4) of Leu); 26.4, 23.9, 23.2, 21.9, 20.0, 19.7, 19.3 (7q,
2 Me of Aib, Me of Ala(2cPent), 2 Me of Valol, 2 Me of Leu). ESI-MS (MeOH, NaI): 725 (100, [M þ
Na]þ), 703 (100, [M þ 1]þ). Anal. calc. for C36H58N6O8 (702.89): C 61.52, H 8.32, N 11.96; found: C 61.33,
H 8.44, N 12.04.

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10. Peptides with Xaa ¼ (R)-Ala(2cPent). 10.1. (R)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-
methyl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2-cyclopentylpropanoic Acid (Z-Leu-Aib-
(R)-Ala(2cPent)-OH; (S)-6e). As described for (S)-6c, with (R)-3e [19] (200 mg, 0.304 mmol) and 3n
HCl (MeCN/H2O 1:1, 3 ml), 3 h at 608; prep. TLC (CH2Cl2/MeOH 10 :1): 113 mg (76%) of (R)-6e.
Colorless solid. M.p. 144 – 1458. Rf (CH2Cl2/MeOH 10 :1) 0.37. IR: 3309m, 2957s, 2871w, 1724s, 1662vs,
1
1526s, 1455w, 1387w, 1246w, 1049w, 737w. H-NMR: 7.33 (br., 5 arom. H); 7.23 (br. s, NH); 7.03 (br. s,
NH); 5.52 (br., NH of Leu); 5.10 (br. s, PhCH2O); 4.2 – 4.1 (m, CH(2) of Leu); 2.5 – 2.35 (m, CH(3) of
Ala(2cPent)); 1.8– 1.3 ( m, CH2(3) and CH(4) of Leu, 2 Me of Aib, Me of Ala(2cPent), 4 CH2 of
Ala(2cPent)); 0.95 – 0.9 (m, 2 Me of Leu). 13C-NMR: 173.9, 172.8(2 s, 2 CONH, COOH); 156.7 (s,
OCONH); 136.0 (s, 1 arom. C); 128.5, 128.2, 127.9 (3d, 5 arom. CH); 67.2 (t, PhCH2O); 61.9, 57.4 (2s, C(2)
of Ala(2cPent), C(2) of Aib); 53.9 (d, C(2) of Leu); 46.2 (d, C(3) of Ala(2cPent)); 41.1 (t, C(3) of Leu);
27.0, 26.7, 25.3 (3t, 4 CH2 of cPent); 24.6 (d, C(4) of Leu); 22.8, 21.8, 19.5 (3q, 2 Me of Aib, Me of
Ala(2cPent), 2 Me of Leu). ESI-MS (MeOH, NaI): 525 (10), 513 (32), 512 (100, [M þ Na]þ), 503 (6),
491 (29), 490 (99, [M þ 1]þ), 472 (47, [M ꢀ OH]þ), 333 (8, [M ꢀ Ala(2cPent)]þ). Anal. calc. for
C26H39N3O6 (489.61): C 63.78, H 8.03, N 8.58; found: C 63.50, H 8.08, N 8.53.
10.2. Benzyl {(S)-1-[({2-[((R)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]ami-
no}carbonyl)-4-oxobutyl]amino}-1-cyclopentyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}-
amino)carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Ala(2cPent)-Gln-Valol; (R)-2e). As descri-
bed for 2a, with (R)-6e (220 mg, 0.449 mmol), Et3N (136 mg, 1.35 mmol), abs. DMF (3.5 ml), HATU
(171 mg, 0.450 mmol), 4 min at 08, HOAt (62 mg, 0.456 mmol), 4 min at 08, 11 (106 mg, 0.458mmol), 3 h
at 08 and 47 h at r.t.; CC (CH2Cl2/MeOH 10 :1) and prep. TLC (CH2Cl2/MeOH 10 :1): 88 mg (28%) of
(R)-2e and 78mg of starting material ( R)-6e (35%).
Data of (R)-2e. Colorless solid. M.p. 209.5 – 210.88. Rf (CH2Cl2/MeOH 10 :1) 0.23. IR: 3426vs, 2959s,
1
2871m, 1661vs, 1532s, 1455w, 1386w, 1261w, 1175w, 1121w, 1048w, 741w. H-NMR: 8.09 (br., NH); 7.70
(br., 2 NH); 7.35 – 7.3 (m, 5 arom. H); 7.09 (br., 2 NH); 5.37 (br., 2 NH); 5.14, 5.07 (AB, J ¼ 13.1,
PhCH2O); 4.35 – 4.0, 3.75 – 3.6 (2m, CH(2) of Gln, CH(2) of Leu, CH(2) and CH2(1) of Valol); 2.65 –
2.45, 2.35 – 2.25 (2m, CH2(4) and CH2(3) of Gln); 1.85 – 1.25 (m, CH2(3) of Leu, 4 CH2 of Ala(2cPent),
CH(4) of Leu, CH(3) of Valol, CH(3) of Ala(2cPent)); 1.45, 1.42 (2s, 2 Me of Aib); 1.28( s, Me of
Ala(2cPent)); 0.95 – 0.85 (m, 2 Me of Valol, 2 Me of Leu). 1H-NMR (CD3OD): 8.51 (br. s, NH); 7.74 (d,
J ¼ 7.2, NH); 7.56 (d, J ¼ 8.9, NH); 7.4 – 7.25 (m, 5 arom. H); 7.11 (br. s, NH); 5.15 – 5.05 (m, PhCH2O);
4.25 – 4.1 (m, CH(2) of Gln, CH(2) of Leu); 3.7 – 3.6 (m, CH(2) and CH2(1) of Valol); 2.5 – 2.35, 2.2 –
2.15, 1.9 – 1.85, 1.7 – 1.4 (4m, CH(3) of Valol, CH(3) of Ala(2cPent), CH2(3) of Leu, CH2(4) and
CH2(3) of Gln, 4 CH2 of Ala(2cPent), CH(4) of Leu, Me of Ala(2cPent), 2 Me of Aib); 1.0 – 0.9 (m,
2 Me of Valol, 2 Me of Leu). 13C-NMR: 177.5, 176.0, 174.9, 174.6, 173.5 (5s, CONH2, 4 CONH); 157.1 (s,
OCONH); ca. 137 (s, 1 arom. C); 128.5, 127.9, 127.2 (3d, 5 arom. CH); 67.0, 61.6 (2t, PhCH2O, C(1) of
Valol); 58.0, 55.3, 54.0 (3d, C(2) of Gln, C(2) of Valol, C(2) of Leu); 57.0 (s, C(2) of Aib, C(2) of
Ala(2cPent)); 44.4 (d, C(3) of Ala(2cPent)); ca. 39.5, ca. 31, ca. 27, 25.0 (4t, 4 CH2 of Ala(2cPent), C(4)
and C(3) of Gln, C(3) of Leu); 28.8, 24.7 (2d, C(3) of Valol, C(4) of Leu); 22.6, 21.8, 20.3, 19.4, 19.0 (5q,
2 Me of Aib, Me of Ala(2cPent), 2 Me of Valol, 2 Me of Leu). 13C-NMR (CD3OD): 178.1, 176.6, 176.0,
175.8, 174.2 (5s, CONH2, 4 CONH); 158.7 (s, OCONH); 138.2 (s, 1 arom. C); 129.4, 128.9, 128.5 (3d, 5
arom. CH); 67.6, 63.3 (2t, PhCH2O, C(1) of Valol); 62.9, 57.9 (2s, C(2) of Aib, C(2) of Ala(2cPent)); 58.3,
55.3, 55.2 (3d, C(2) of Gln, C(2) of Valol, C(2) of Leu); 47.6 (d, C(3) of Ala(2cPent)); 41.6, 33.2, 28.7,
28.4, 28.2, 26.6, 26.2 (7t, 4 CH2 of Ala(2cPent), C(4) and C(3) of Gln, C(3) of Leu); 30.0, 25.8(2 d, C(3) of
Valol, C(4) of Leu); 24.6, 23.2, 22.2, 20.0, 19.7, 19.1 (6q, 2 Me of Aib, Me of Ala(2cPent), 2 Me of Valol,
2 Me of Leu). ESI-MS (CH2Cl2, MeOH): 725 (29, [M þ Na]þ), 703 (100, [M þ 1]þ), 685 (7, [M ꢀ OH]þ),
600 (28, [M ꢀ Valol]þ), 472 (30, [M ꢀ Gln-Valol]þ). Anal. calc. for C36H58N6O8 (702.89): C 61.52, H 8.32,
N 11.96; found: C 61.36, H 8.31, N 11.70.
Crystals suitable for an X-ray crystal-structure determination were obtained from AcOEt/MeOH by
slow evaporation of the solvent.
11. Peptides with Xaa ¼ (S)-Leu(2Me). 11.1. (S)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-
methyl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2,4-dimethylpentanoic Acid (Z-Leu-Aib-(S)-
Leu(2Me)-OH; (S)-6f). As described for (S)-6c, with (S)-3f [19] (249 mg, 0.390 mmol) and 3n HCl

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Helvetica Chimica Acta – Vol. 91 (2008)
(MeCN/H2O 1:1, 2 ml), 4 h at 608; prep. TLC (CH2Cl2/MeOH 10 :1): 87 mg (47%) of (S)-6f and 28%2)
of benzyl [(S)-1-({[1,1-dimethyl-2-({(S)-1,3-dimethyl-1-[(methylamino)carbonyl]butyl}amino)-2-oxo-
ethyl]amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-(S)-Leu(2Me)-NHMe; (S)-7f).
Data of (S)-6f. Colorless solid. M.p. 107 – 1088. Rf (CH2Cl2/MeOH 10 :1) 0.19. IR: 3306m, 2958s,
1717s, 1659s, 1523s, 1454m, 1388m, 1367m, 1237m, 1159m, 1045m, 954w, 908w, 8 55w, 78 9w, 757w, 736w,
697m. 1H-NMR: 7.3 – 7.25 (m, 5 arom. H, NH); 7.19 (s, NH); 5.8 5 d(, J ¼ 6.9, NH); 5.1 – 5.05 (m,
PhCH2O); 4.2 – 4.15 (m, CH(2) of Leu); 2.15 – 2.1 (m, CH(4) of Leu(2Me)); 1.8– 1.5 ( m, CH2(3) and
CH(4) of Leu, 2 Me of Aib, CH2(3) and Me(3) of Leu(2Me)); 0.95 – 0.85 (m, 2 Me of Leu, 2 Me(5) of
Leu(2Me)). 13C-NMR: 177.5 (s, COOH); 173.4, 172.8(2 s, 2 CONH); 156.5 (s, OCONH); 136.0 (s, 1
arom. C); 128.4, 128.1, 127.8 (3d, 5 arom. CH); 67.0 (t, PhCH2O); 59.8, 57.3 (2s, C(2) of Aib, C(2) of
Leu(2Me)); 54.0 (d, C(2) of Leu); 44.5, 40.9 (2t, C(3) of Leu, C(3) of Leu(2Me)); 24.6, 24.4 (2d, C(4) of
Leu(2Me), C(4) of Leu); 25.0, 23.9, 23.5, 23.1, 22.9, 21.8(6 q, 2 Me of Aib, Me(3) and 2 Me(5) of
Leu(2Me), 2 Me of Leu). ESI-MS (MeOH): 522 (27), 500 (100, [M þ Na]þ). Anal. calc. for C25H39N3O6
(477.60): C 62.87, H 8.23, N 8.80; found: C 62.77, H 8.14, N 8.68.
Data of (S)-7f. Colorless solid. M.p. 78.5 – 79.58. Rf (CH2Cl2/MeOH 10 :1) 0.44. IR: 3321s, 3038w,
2957s, 2871w, 1704vs, 1652vs, 1537s, 1455m, 1411w, 1382m, 1365w, 1331w, 1261s, 1223w, 1173w, 1115w,
1051w, 1031w, 907w, 78 9w, 726w, 693w. 1H-NMR (CD3OD): 7.35 – 7.3 (m, 5 arom. H); 5.08(br. s,
PhCH2O); 4.06 (dd, J ¼ 8.4, 6.5, CH(2) of Leu); 2.69 (s, MeN); 2.0 – 1.5 (m, CH2(3) of Leu(2Me), CH2(3)
of Leu, CH(4) of Leu(2Me), CH(4) of Leu); 1.40 (s, 2 Me of Aib); 1.38( s, Me(3) of Leu(2Me)); 0.97,
0.95, 0.92, 0.86 (4d, J ¼ 7.3, 7.5, 6.9, 6.6, 2 Me of Leu, 2 Me(5) of Leu(2Me)). 13C-NMR (CD3OD): ca.
177.5, 175.9, 175.5 (3s, 3 CONH); ca. 158.5 (s, OCONH); ca. 138( s, 1 arom. C); 129.4, 128.9, 128.5 (3d, 5
arom. CH); 67.5 (t, PhCH2O); 61.1, 58.0 (2s, C(2) of Leu(2Me), C(2) of Aib); 55.1 (d, C(2) of Leu); 45.2,
41.4 (2t, C(3) of Leu(2Me), C(3) of Leu); 25.8, 24.9 (2d, C(4) of Leu(2Me), C(4) of Leu); 26.5, 24.6, 24.4,
24.2, 23.2, 22.0 (6q, MeN, 2 Me of Aib, Me(3) of Leu(2Me), 2 Me(5) of Leu(2Me), 2 Me of Leu). CI-MS
(NH3): 492 (10), 491 (32, [M þ 1]þ), 460 (32, [M ꢀ HNMe]þ), 384 (22), 383 (32, [M ꢀ OBn]þ), 357 (9),
231 (12), 214 (7). Anal. calc. for C26H42N4O5 · 0.2 H2O (494.24): C 63.18, H 8.65, N 11.34; found: C 63.24,
H 8.60, N 11.28.
11.2. Benzyl {(S)-1-[({2-[((S)-1-{[((S)-4-Amino-1-{[((S)-1-{hydroxymethyl}-2-methylpropyl)ami-
no]carbonyl}-4-oxobutyl)amino]carbonyl}-1,3-dimethylbutyl)amino]-1,1-dimethyl-2-oxoethyl}amino)-
carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Leu(2Me)-Gln-Valol; (S)-2f). As described for 2a,
with (S)-6f (161 mg, 0.337 mmol), Et3N (102 mg, 1.011 mmol), abs. DMF (2.5 ml), HATU (128mg,
0.337 mmol), 4 min at r.t., HOBt (51 mg, 0.337 mmol), 5 min at r.t., 11 (78mg, 0.337 mmol), 42 h at r.t.;
CC (CH2Cl2/MeOH 10 :1): 139 mg (60%) of (S)-2f. Colorless solid. M.p. 154 – 1558. Rf (CH2Cl2/MeOH
10 :1) 0.17. IR: 3312m, 2956m, 1653s, 1534s, 1466m, 1386w, 1360m, 1260m, 1046w, 8 47w, 8 14w, 738w.
1H-NMR: 7.96 (br., NH); 7.81 (br., NH); 7.35 – 7.2 (m, 5 arom. H, NH); 7.04 (br., NH); 6.88 (br. s, NH);
6.71 (br., NH); 5.68(br., NH); 5.15, 5.12 ( AB, J ¼ 12.7, PhCH2O); 4.0 – 3.8, 3.7 – 3.55 (2m, CH(2) of Gln,
CH(2) of Leu, CH(2) and CH2(1) of Valol); 2.35 – 2.15 (m, CH2(4) and CH2(3) of Gln); 1.8– 1.6 ( m,
CH2(3) of Leu(2Me), CH2(3) of Leu, CH(3) of Valol, CH(4) of Leu, CH(4) of Leu(2Me)); 1.5 – 1.25 (m,
2 Me of Aib, Me(3) of Leu(2Me)); 0.95 – 0.8( m, 2 Me of Valol, 2 Me(5) of Leu(2Me), 2 Me of Leu).
13C-NMR: 175.6, 175.2, 175.1, 174.8, 172.8 (5s, CONH2, 4 CONH); 157.1 (s, OCONH); 136.7 (s, 1 arom.
C); 128.5, 127.9, 127.2 (3d, 5 arom. CH); 66.7, 63.5 (2t, PhCH2O, C(1) of Valol); 59.7, 56.8(2 s, C(2) of
Leu(2Me), C(2) of Aib); 57.5, 55.8(2 d, C(2) of Gln, C(2) of Valol, C(2) of Leu); 48.3, 39.8, 32.6, 27.6 (4t,
C(3) of Leu, C(3) of Leu(2Me), C(4) and C(3) of Gln); 28.9, 24.6, 23.4 (3d, C(3) of Valol, C(4) of
Leu(2Me), C(4) of Leu); 26.3, 24.3, 24.2, 23.0, 22.7, 21.6, 20.9, 19.5, 19.2 (9q, 2 Me of Aib, Me(3) of
Leu(2Me), 2 Me of Valol, 2 Me(5) of Leu(2Me), 2 Me of Leu). ESI-MS (MeOH): 714 (15, [M þ Na]þ),
691 (100, [M þ 1]þ). Anal. calc. for C35H58N6O8 · H2O (708.90): C 59.30, H 8.53, N 11.85; found: C 59.31, H
8.56, N 11.49.
11.3. N-((S)-1-{[(2-{[(S)-1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-4-oxobutyl]amino}carbonyl)-1,3-dimethylbutyl]amino}-1,1-dimethyl-2-oxoethyl)amino]carbon-
2
)
The side product (S)-7f was not isolated in the described reaction. In another experiment, it was
isolated in 28% yield; starting material (S)-3f: 249 mg (0.386 mmol); side product (S)-7f: 105 mg
(0.214 mmol).

Helvetica Chimica Acta – Vol. 91 (2008)
547
yl}-3-methylbutyl)-4-bromobenzamide (pBrBz-Leu-Aib-(S)-Leu(2Me)-Gln-Valol; (S)-13f). As descri-
bed for 13a, with (S)-2f (80 mg, 0.116 mmol), Pd/C (10% on activated charcoal, 8 mg), MeOH (5 ml),
and H2, 75 min at r.t., filtration over Celite, abs. CH2Cl2 (5 ml), Et3N (25 mg, 0.248mmol), 4-
bromobenzoyl chloride (31 mg, 0.139 mmol), 3 h at r.t., filtration and washing with CH2Cl2: 60 mg (70%)
of (S)-13f. Colorless solid. M.p. 246 – 2478. Rf (CH2Cl2/MeOH 10 :1) 0.18. IR: 3336m, 2959m, 2477m,
1648vs, 1542s, 1364m, 1278w, 1176w, 1072w, 1011w, 8 50w, 761w. 1H-NMR (CD3OD): 7.83, 7.62 (AA’BB’,
J ¼ 8.5, 4 arom. H); 4.55 – 4.5, 4.1 – 4.05 (2m, CH(2) of Gln and CH(2) of Leu); 3.65 – 3.6 (m, CH2(1) and
CH(2) of Valol); 2.4 – 2.05, 1.85 – 1.65 (2m, CH2(4) of Gln and CH2(3) of Gln, CH(3) of Valol, CH(4) and
CH2(3) of Leu, CH(4) and CH2(3) of Leu(2Me)); 1.45, 1.44, 1.41 (3s, 2 Me of Aib, Me(3) of Leu(2Me));
1.01, 0.99 (2d, J ¼ 5.6, 5.7, 2 Me); 0.95 – 0.9 (m, 3 Me); 0.81 (d, J ¼ 6.8, 1 Me). 13C-NMR (CD3OD): 177.7,
177.0, 176.7, 175.8, 174.4 (5s, CONH2, 4 CONH); 169.6 (s, 1 CO (amide, pBrBz)); 134.0 (s, 1 arom. C);
132.8, 130.7 (2d, 4 arom. CH); 127.4 (s, 1 arom. CBr); 63.6 (t, C(1) of Valol); 61.2, 58.1 (2s, C(2) of
Leu(2Me), C(2) of Aib); 58.6, 56.5, 54.5 (3d, C(2) of Gln, C(2) of Valol, C(2) of Leu); 48.5, 41.6, 33.8,
28.5 (4t, C(3) of Leu, C(3) of Leu(2Me), C(4) of Gln, C(3) of Gln); 30.1, 26.1, 24.9 (3d, C(3) of Valol,
C(4) of Leu, C(4) of Leu(2Me)); 25.5, 25.0, 23.4, 22.7, 22.2, 20.1, 19.4 (7q, 2 Me of Aib, Me(3) of
Leu(2Me), 2 Me of Valol, 2 Me of Leu, 2 Me(5) of Leu(2Me)). ESI-MS (NaI): 763 (24, [M þ Na]þ,
81Br), 741 (100, [M þ 1]þ, 81Br), 638(6, [ M ꢀ Valol]þ, 81Br), 510 (10, [M ꢀ Gln-Valol]þ, 81Br). Anal. calc.
for C34H55BrN6O7 (739.75): C 55.20, H 7.49, N 11.36; found: C 55.10, H 7.53, N 11.11.
Crystals suitable for an X-ray crystal-structure determination were obtained from CD3OD by slow
evaporation of the solvent.
12. Peptides with Xaa ¼ (R)-Leu(2Me). 12.1. (R)-2-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-4-
methyl-1-oxopentyl)amino]-2-methyl-1-oxopropyl}amino)-2,4-dimethylpentanoic Acid (Z-Leu-Aib-(R)-
Leu(2Me)-OH; (R)-6f). As described for (S)-6c, with (R)-3f [19] (200 mg, 0.31 mmol) and 3n HCl
(MeCN/H2O 1:1, 2 ml), 3 h at 608; prep. TLC (CH2Cl2/MeOH 10 :1) gave 78mg (53%) of ( R)-6f and
35%3) of benzyl [(S)-1-({[1,1-dimethyl-2-({(R)-1,3-dimethyl-1-[(methylamino)carbonyl]butyl}amino)-
2-oxoethyl]amino}carbonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-(R)-Leu(2Me)-NHMe; (R)-7f).
Data of (R)-6f. Colorless solid. M.p. 152 – 1538. Rf (CH2Cl2/MeOH 10 :1) 0.17. IR: 3301s, 2956s,
1
1727s, 1661s, 1542s, 1456m, 1366m, 1235m, 1162m, 1046m, 754w, 697m. H-NMR: 7.35 – 7.3 (m, 5 arom.
H); 7.2 – 7.05 (m, 2 NH); 5.75 (d, J ¼ 6.4, NH); 5.11 (br., PhCH2O); 4.15 – 4.1 (m, CH(2) of Leu); 2.15 –
2.1 (m, CH(4) of Leu(2Me)); 1.8– 1.45 ( m, CH2(3) and CH(4) of Leu, CH2(3) and Me(3) of Leu(2Me),
2 Me of Aib); 0.95 – 0.85 (m, 2 Me of Leu, 2 Me(5) of Leu(2Me)). 13C-NMR: 177.0 (s, COOH); 173.4,
172.6 (2s, 2 CONH); 156.6 (s, OCONH); 136.0 (s, 1 arom. C); 128.5, 128.1, 127.8 (3d, 5 arom. CH); 67.1 (t,
PhCH2O); 59.7, 57.2 (2s, C(2) of Leu(2Me), C(2) of Aib); 54.1 (d, C(2) of Leu); 44.7, 40.9 (2t, C(3) of
Leu, C(3) of Leu(2Me)); 24.6, 24.3 (2d, C(4) of Leu(2Me), C(4) of Leu); 25.3, 24.9, 24.5, 23.8, 23.2, 22.8,
21.8(7 q, 2 Me of Aib, Me(3) and 2 Me(5) of Leu(2Me), 2 Me of Leu). ESI-MS (MeOH): 495 (14), 479
(30), 478(100, [ M þ 1]þ), 460 (15, [M ꢀ OH]þ), 333 (12, [M ꢀ Leu(2Me)]þ). Anal. calc. for C25H39N3O6 ·
0.5 H2O (486.61): C 61.71, H 8.29, N 8.64; found: C 61.77, H 8.08, N 8.30.
Data of (R)-7f. Colorless solid. M.p. 110 – 1118. Rf (CH2Cl2/MeOH 10 :1) 0.45. IR: 3293s, 2958m,
2873w, 1706s, 1654vs, 1518vs, 1464m, 1411w, 1386w, 1369w, 1270s, 1242m, 1175w, 1119w, 1049m, 1029w,
970w, 78 9w, 745w, 698w, 658w. 1H-NMR (CD3OD): 7.35 – 7.25 (m, 5 arom. H); 5.09 (br. s, PhCH2O); 4.06
(dd, J ¼ 8.9, 6.1, CH(2) of Leu); 2.69 (s, MeN); 1.8– 1.65, 1.65 – 1.45 (2 m, CH2(3) of Leu(2Me), CH2(3) of
Leu, CH(4) of Leu(2Me), CH(4) of Leu); 1.47 (s, Me(3) of Leu(2Me)); 1.41, 1.39 (2s, 2 Me of Aib); 0.97,
0.95, 0.91, 0.89 (4d, J ¼ 7.6, 6.9, 6.9, 6.5, 2 Me of Leu, 2 Me(5) of Leu(2Me)). 13C-NMR (CD3OD): ca.
177.5, ca. 176, ca. 175 (3s, 3 CONH); ca. 158( s, OCONH); ca. 138( s, 1 arom. C); 129.4, 128.9, 128.5 (3d, 5
arom. CH); 67.5 (t, PhCH2O); 61.2, 58.0 (2s, C(2) of Leu(2Me), C(2) of Aib); 55.2 (d, C(2) of Leu); 47.3,
41.4 (2t, C(3) of Leu(2Me), C(3) of Leu); 25.7, 25.0 (2d, C(4) of Leu(2Me), C(4) of Leu); 26.5, 26.0, 24.3,
24.1, 23.2, 22.5, 22.0 (7q, MeN, 2 Me of Aib, Me(3) of Leu(2Me), 2 Me(5) of Leu(2Me), 2 Me of Leu).
CI-MS (NH3): 491 (4, [M þ 1]þ), 384 (21), 383 (32, [M ꢀ OBn]þ), 231 (7). Anal. calc. for C26H42N4O5
(490.64): C 63.65, H 8.83, N 11.42; found: C 63.67, H 8.62, N 11.26.
3
)
The side product (R)-7f was not isolated in the described reaction. In another experiment, it was
isolated in 35% yield; starting material (R)-3f: 909 mg (1.410 mmol); side product (R)-7f: 242 mg
(0.493 mmol).

548
Helvetica Chimica Acta – Vol. 91 (2008)
12.2. Benzyl {(S)-1-[({2-[((R)-1-{[((S)-4-Amino-1-{[((S)-1-{hydroxymethyl}-2-methylpropyl)ami-
no]carbonyl}-4-oxobutyl)amino]carbonyl}-1,3-dimethylbutyl)amino]-1,1-dimethyl-2-oxoethyl}amino)-
carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Leu(2Me)-Gln-Valol; (R)-2f). As described for 2a,
with (R)-6f (240 mg, 0.503 mmol), Et3N (153 mg, 1.515 mmol), abs. DMF (5 ml), HATU (191 mg,
0.502 mmol), 4 min at r.t., HOBt (76 mg, 0.502 mmol), 5 min at r.t., 11 (117 mg, 0.506 mmol), 94 h at r.t.;
prep. TLC (CH2Cl2/MeOH 10 :1): 177 mg (53%) of (R)-2f. Colorless foam. M.p. 105 – 1078. Rf (CH2Cl2/
MeOH 10 :1) 0.14. IR: 3302s, 2958m, 2871m, 1659s, 1533s, 1455m, 1386m, 1356m, 1264m, 1171m, 1122w,
1055w, 8 52w, 78 6w, 740m, 697m. 1H-NMR: 7.93 (br., NH); 7.84 (d, J ¼ 5.1, NH); 7.4 – 7.25 (m, 5 arom. H);
7.2 – 7.15 (m, NH); 7.11 (br. s, NH); 7.02 (br., NH); 6.70 (br., NH); 5.70 (br., NH); 5.25 – 5.05 (m,
PhCH2O); 4.1 – 3.55 (m, CH(2) of Gln, CH(2) of Leu, CH(2) and CH2(1) of Valol); 2.45 – 2.0 (m, CH2(4)
and CH2(3) of Gln, CH(3) of Valol); 1.8– 1.65 ( m, CH2(3) of Leu(2Me), CH2(3) of Leu); 1.55 – 1.25 (m,
2 Me of Aib, Me(3) of Leu(2Me)); 0.95 – 0.8( m, 2 Me of Valol, CH(4) of Leu, CH(4) of Leu(2Me), 2
Me(5) of Leu(2Me), 2 Me of Leu). 13C-NMR: 176.9, 175.1, 175.1, 174.6, 173.0 (5s, CONH2, 4 CONH);
157.4 (s, OCONH); 136.6 (s, 1 arom. C); 128.5, 128.0, 126.9 (3d, 5 arom. CH); 66.6, 63.5 (2t, PhCH2O,
C(1) of Valol); 59.8, 56.9 (2s, C(2) of Leu(2Me), C(2) of 2 Aib); 57.5, 56.1, 55.5 (3d, C(2) of Gln, C(2) of
Valol, C(2) of Leu); 40.6, 39.7, 32.6, 27.6 (4t, C(3) of Leu, C(3) of Leu(2Me), C(4) and C(3) of Gln); 28.9
(d, C(3) of Valol); 24.6, 23.4 (2d, C(4) of Leu(2Me), C(4) of Leu); 26.4, 25.0, 24.5, 24.2, 23.0, 22.7, 21.6,
19.5, 19.2 (9q, 2 Me of Aib, Me(3) of Leu(2Me), 2 Me of Valol, 2 Me(5) of Leu(2Me), 2 Me of Leu).
ESI-MS (MeOH): 729 (10, [M þ K]þ), 714 (22, [M þ Na]þ), 691 (100, [M þ 1]þ), 674 (7, [M ꢀ OH]þ),
588 (17, [M ꢀ Valol]þ), 460 (18, [M ꢀ Gln-Valol]þ). Anal. calc. for C35H58N6O8 · H2O (708.90): C 59.30, H
8.53, N 11.86; found: C 59.08, H 8.30, N 11.42.
12.3. N-((S)-1-{[(2-{[(R)-1-({[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}-
carbonyl)-4-oxobutyl]amino}carbonyl)-1,3-dimethylbutyl]amino}-1,1-dimethyl-2-oxoethyl)amino]car-
bonyl}-3-methylbutyl)-4-bromobenzamide (pBrBz-Leu-Aib-(R)-Leu(2Me)-Gln-Valol; (R)-13f). As
described for 13a, with (R)-2f (50 mg, 0.072 mmol), Pd/C (10% on activated charcoal, 7 mg), MeOH
(4 ml), and H2, 70 min at r.t., filtration over Celite, abs. CH2Cl2 (4 ml), Et3N (16 mg, 0.158mmol), 4-
bromobenzoyl chloride (18.5 mg, 0.084 mmol), 2 h at r.t., evaporation and prep. TLC (CH2Cl2/MeOH
10 :1): 16 mg (30%) of (R)-13f. M.p. 124 – 1258. Rf (CH2Cl2/MeOH 10 :1) 0.14. IR: 3317s, 3064w, 2959m,
1651vs, 1592m, 1483m, 1448m, 1428m, 1382m, 1335m, 1276m, 1234m, 1160w, 1140m, 1073w, 1012w, 974w,
961w, 8 46w, 8 06w, 78 4w, 722w, 696m. 1H-NMR (CD3OD): 7.95 – 7.9 (m, NH); 7.84, 7.62 (AA’BB’, J ¼ 8.5,
8.6, 4 arom. H); 7.45 (br. s, NH); 7.4 – 7.35 (m, NH); 4.6 – 4.5, 4.2 – 4.1 (2m, CH(2) of Gln, CH(2) of Leu);
3.65 – 3.6 (m, CH2(1) and CH(2) of Valol); 2.4 – 1.6, 1.3 – 1.25 (2m, CH2(4) and CH2(3) of Gln, CH(3) of
Valol, CH(4) and CH2(3) of Leu, CH(4) and CH2(3) of Leu(2Me)); 1.45 (s, 2 Me of Aib); 1.43 (s, Me(3)
of Leu(2Me)); 1.01, 0.99 (2d, J ¼ 5.8, 5.7, 2 Me of Valol); 0.88, 0.86, 0.83, 0.81 (4d, J ¼ 6.9, 6.6, 5.7, 6.0, 2
Me(5) of Leu(2Me), 2 Me of Leu). 13C-NMR (CD3OD): ca. 178, 177.5, 176.3, 175.5, 174.2, ca. 171 (6s,
CONH2, 5 CONH); ca. 134 (s, 1 arom. C); 132.7, 130.6 (2d, 4 arom. CH); ca. 127 (s, 1 arom. CBr); 63.4 (t,
C(1) of Valol); 61.3, 58.0 (2s, C(2) of Leu(2Me), C(2) of Aib); 58.4, 55.7, 54.3 (3d, C(2) of Gln, C(2) of
Valol, C(2) of Leu); 45.0, 41.2, 33.4, 28.8 (4t, C(3) of Leu, C(3) of Leu(2Me), C(4) of Gln, C(3) of Gln);
29.9, 26.0, 24.7 (3d, C(3) of Valol, C(4) of Leu, C(4) of Leu(2Me)); 25.2, 25.2, 25.1, 24.9, 23.8, 23.3, 22.1,
19.9, 19.2 (9q, 2 Me of Aib, Me(3) of Leu(2Me), 2 Me of Valol, 2 Me of Leu, 2 Me(5) of Leu(2Me)). ESI-
MS (NaI): 765 (12), 764 (45), 763 (100, [M þ Na]þ, 81Br), 762 (41), 741 (74, [M þ Na]þ, 79Br). Anal. calc.
for C34H55BrN6O7 · 0.5 H2O (748.76): C 54.54, H 7.54, N 11.22; found: C 54.29, H 7.55, N 10.21.
13. Peptides with Xaa ¼ (S)-Phe(2Me). 13.1. Benzyl [(S)-1-({[2-({(S)-1-Benzyl-2-[(S)-2-(1-meth-
oxy-1-methylethyl)pyrrolidin-1-yl]-1-methyl-2-oxoethyl}amino)-1,1-dimethyl-2-oxoethyl]amino}carbon-
yl)-3-methylbutyl]carbamate (Z-Leu-Aib-(S)-Phe(2Me)-NCp{2-[(1-Me)(1-MeO)Et]}; (S)-3h). As de-
scribed for 3a, with 5 [19] (109 mg, 0.311 mmol), 1-[(S)-2-benzyl-2-methyl-2H-azirin-3-yl]-2-[(S)-1-
methoxy-1-methylethyl]pyrrolidine ((2’S)-1h [17], 95 mg, 0.332 mmol), abs. CH2Cl2 (3 ml), 17 h at r.t., 2n
HCl, 1n NaOH, sat. NaCl solns.; CC (CH2Cl2/MeOH 100 :4): 140 mg (70%) of (S)-3h. M.p. 79 – 808. Rf
(CH2Cl2/MeOH 20 :1) 0.30. IR: 3330s, 2957s, 1666vs, 1623vs, 1498s, 1454s, 1413m, 1384m, 1317m, 1243m,
1086m, 1061m, 922w, 739w, 701m. 1H-NMR (CD3OD): 7.3 – 7.1 (m, 10 arom. H); 5.12, 5.04 (AB, J ¼ 12.7,
PhCH2O); 4.46 (dd, J ¼ 8.5, 3.3, CHN of Cp); 4.04 (t, J ¼ 7.5, CH(2) of Leu); 3.89 (td, J ¼ 8.4, 2.5, CHN of
Cp); 3.65 – 3.3 (m, CHN of Cp); 3.19, 3.07 (AB, J ¼ 13.9, CH2(3) of Phe(2Me)); 3.15 (s, MeO); 2.0 – 1.9
(m, CH(4) of Leu); 1.8– 1.6 ( m, 4 CH of Cp); 1.55 – 1.5 (m, CH2(3) of Leu); 1.49 (s, Me(3) of Phe(2Me));

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1.44, 1.43 (2s, 2 Me of Aib); 1.16, 1.08(2 s, Me2(MeO)C); 0.97, 0.94 (2d, J ¼ 7.3, 7.1, 2 Me of Leu).
13C-NMR (CD3OD): 175.3, 172.6 (2s, CON, 2 CONH); ca. 158( s, OCONH); 138.2, 137.4 (2s, 2 arom. C);
131.7, 129.4, 129.1, 128.9, 128.3, 127.9 (6d, 10 arom. CH); 80.0 (s, Me2(MeO)C); 67.3 (t, PhCH2O); 65.8,
55.3 (2d, C(2) of Leu, CHN of Cp); 62.2 (s, C(2) of Phe(2Me)); 58.4 (s, C(2) of Aib); 49.5 (q, MeO); 48.9,
44.1, 41.5, 26.0, 24.5 (5t, 3 CH2 of Cp, C(3) of Leu, C(3) of Phe(2Me)); 26.9, 24.6, 24.0, 23.5, 23.2, 22.2 (6q,
Me2C, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Leu); 25.8( d, C(4) of Leu). ESI-MS (MeOH, CH2Cl2,
NaI): 659 (100, [M þ Na]þ). Anal. calc. for C36H52N4O6 · 0.25 H2O (641.34): C 67.42, H 8.25, N 8.74;
found: C 67.41, H 8.08, N 8.38.
13.2. (S)-2-Benzyl-2-({2-[((S)-2-{[(benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]-2-
methyl-1-oxopropyl}amino)propanoic Acid (Z-Leu-Aib-(S)-Phe(2Me)-OH; (S)-6g). 13.2.1. Hydrolysis
of (S)-3h. As described for (S)-6c, with (S)-3h (140 mg, 0.219 mmol) and 3n HCl (THF/H2O 1:1, 8 ml),
23 h at 408; CC (CH2Cl2/MeOH 100 :9): 90 mg (80%) of (S)-6g.
13.2.2. Hydrolysis of (S)-3g. As described for (S)-6c, with (S)-3g [19] (200 mg, 0.295 mmol) and 3n
HCl (MeCN/H2O 1:1, 6 ml), 3 h at 608; CC (CH2Cl2/MeOH 100 :2) and prep. TLC (CH2Cl2/MeOH
10 :1): 37 mg (25%) of (S)-6g. Colorless solid. M.p. 130.2 – 130.68. Rf (CH2Cl2/MeOH 20 :1) 0.30. IR:
3330s, 3060m, 3030m, 2960m, 2870w, 1660vs, 1605s, 1515s, 1500s, 1455s, 1405m, 1365m, 1265m, 1245m,
1210m, 1170w, 1120w, 1045w, 1030w, 1000w, 960w, 910w, 78 0w, 740w, 700m. 1H-NMR (CD3OD): 7.45 (br.
s, NH); 7.3 – 7.25, 7.2 – 7.1 (2m, 10 arom. H); 5.1 – 5.05 (m, PhCH2O); 4.15 (t, J ¼ 7.4, CH(2) of Leu); 3.37,
3.31 (AB, J ¼ 13.3, CH2(3) of Phe(2Me)); 1.7 – 1.6 (m, CH(4) of Leu); 1.6 – 1.55 (m, CH2(3) of Leu); 1.51
(s, Me(3) of Phe(2Me)); 1.38, 1.33 (2s, 2 Me of Aib); 0.93, 0.91 (2d, J ¼ 6.8, 2 Me of Leu). 13C-NMR
(CD3OD): 180.5 (s, COOH); 175.2, 174.8(2 s, 2 CONH); 158.5 (s, OCONH); 139.2, 138.0 (2s, 2 arom. C);
131.4, 129.5, 129.0, 128.8, 127.3 (5d, 10 arom. CH); 67.9 (t, PhCH2O); 62.8( s, C(2) of Phe(2Me)); 58.2 (s,
C(2) of Aib); 55.1 (d, C(2) of Leu); 42.3, 41.8(2 t, C(3) of Phe(2Me), C(3) of Leu); 25.9 (d, C(4) of Leu);
25.8, 25.1, 24.2, 23.5, 22.0 (5q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Leu). ESI-MS (NaI): 556 (12),
550 (33, [M þ K]þ), 534 (100, [M þ Na]þ), 473 (8), 466 (6, [M ꢀ COOH]þ). Anal. calc. for C28H37N3O6 ·
0.25 H2O (516.12): C 65.16, H 7.32, N 8.14; found: C 65.28, H 7.35, N 7.81.
13.3. Benzyl {(S)-1-[({2-[((S)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]ami-
no}carbonyl)-4-oxobutyl]amino}-1-benzyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}amino)-
carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Phe(2Me)-Gln-Valol; (S)-2g). As described for 2b,
with (S)-6g (83 mg, 0.162 mmol), Et3N (33 mg, 0.327 mmol), abs. DMF (1 ml), 5 min at 08, HATU
(64 mg, 0.168mmol), 6 min at 0 8, 11 (38mg, 0.164 mmol), 30 min at 0 8, 44 h at r.t.; CC (CH2Cl2/MeOH
10 :1): 57 mg (49%) of (S)-2g. Colorless solid. M.p. 102 – 1038. Rf (CH2Cl2/MeOH 10 :1) 0.27. IR: 3300s,
3060w, 3030w, 2960m, 2870w, 1660vs, 1530s, 1455m, 1405w, 1385w, 1370w, 1340w, 1315w, 1260m, 1170w,
1120w, 1045w, 1030w, 960w, 920w, 8 45w, 740w, 700m. 1H-NMR (CD3OD): 7.42 (d, J ¼ 8.8, NH); 7.35 – 7.2,
7.15 – 7.1 (2m, 10 arom. H); 5.08, 5.05 (AB, J ¼ 12.7, PhCH2O); 4.15 – 4.05 (m, CH(2) of Gln, CH(2) of
Leu); 3.7 – 3.65 (m, CH2(1) of Valol); 3.65 – 3.6 (m, CH(2) of Valol); 3.22, 3.06 (AB, J ¼ 13.6, CH2(3) of
Phe(2Me)); 2.3 – 2.25 (m, CH2(4) of Gln); 2.25 – 2.2 (m, CH2(3) of Gln); 2.2 – 2.05 (m, CH(3) of Valol);
1.9 – 1.6 (m, CH(4) of Leu); 1.6 – 1.5 (m, CH2(3) of Leu); 1.43 (s, Me(3) of Phe(2Me)); 1.37 (s, 2 Me of
Aib); 0.95 – 0.9 (m, 2 Me of Leu, 2 Me of Valol). 13C-NMR (CD3OD): 178.0, 176.6, 176.3, 175.9, 174.3 (5s,
CONH2, 4 CONH); the signal for OCONH could not be detected; 138.2, 137.3 (2s, 2 arom. C); 131.7,
129.5, 129.4, 129.1, 128.7, 128.2 (6d, 10 arom. CH); 67.8( t, PhCH2O); 63.4 (t, C(1) of Valol); 60.7 (s, C(2)
of Phe(2Me)); 58.4 (d, C(2) of Gln); 58.0 (s, C(2) of Aib); 55.9, 55.3 (2d, C(2) of Leu, C(2) of Valol); 43.4,
41.5 (2t, C(3) of Phe(2Me), C(3) of Leu); 33.5 (t, C(4) of Gln); 30.0 (d, C(3) of Valol); 28.4 (t, C(3) of
Gln); 25.9 (d, C(4) of Leu); 25.6, 25.1, 23.5, 23.4, 22.2 (5q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of
1
Leu); 20.1, 19.2 (2q, 2 Me of Valol). H-NMR (600 MHz): 7.68( d, J ¼ 4.9, NH of Gln); 7.48( s, NH of
Aib); 7.35 – 7.3, 7.25 – 7.2, 7.1 – 7.05 (3m, 10 arom. H, 1 NH); 6.92 (s, NH); 6.60 (s, 1 H, NH2 of Gln); 6.51
(d, J ¼ 4.0, NH of Leu); 5.53 (s, 1 H, NH2 of Gln); 5.11, 5.08( AB, J ¼ 12.6, PhCH2O); 4.1 – 4.05 (m, CH(2)
of Gln); 4.0 – 3.95 (m, CH(2) of Leu); 3.75 – 3.7 (m, CH(2) of Valol); 3.65 – 3.6 (m, CH2(1) of Valol); 2.97,
2.94 (AB, J ¼ 13.6, CH2(3) of Phe(2Me)); 2.3 – 2.25 (m, CH2(4) of Gln); 2.2 – 2.05 (m, CH2(3) of Gln);
1.8– 1.75 ( m, CH(3) of Valol); 1.7 – 1.65 (m, CH(4) of Leu); 1.65 – 1.6 (m, 1 H of CH2(3) of Leu); 1.5 –
1.45 (m, 1 H of CH2(3) of Leu); 1.4 – 1.35 (m, 2 Me of Aib, Me(3) of Phe(2Me)); 0.93, 0.92 (2d, J ¼ 6.8,
8.3, 2 Me of Leu); 0.87, 0.86 (2d, J ¼ 6.9, 2 Me of Valol). 13C-NMR (150.9 MHz): 175.1, 174.7, 174.4, 172.6
(4s, CONH2, 4 CONH); 157.1 (s, OCONH); 136.4 (s, 1 arom. C of PhCH2O); 135.1 (s, 1 arom. C of

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Phe(2Me)); 130.2, 128.6, 128.3, 128.2, 127.6, 127.3 (6d, 10 arom. CH); 67.1 (t, PhCH2O); 63.4 (t, C(1) of
Valol); 60.5 (s, C(2) of Phe(2Me)); 57.1 (s, C(2) of Aib); 57.6 (d, C(2) of Valol); 55.2, 55.1 (2d, C(2) of
Leu, C(2) of Gln); 44.6 (t, C(3) of Phe(2Me)); 39.8( t, C(3) of Leu); 32.5 (t, C(4) of Gln); 29.0 (d, C(3) of
Valol); 27.3 (t, C(3) of Gln); 26.0, 23.7 (2q, 2 Me of Aib); 24.7 (d, C(4) of Leu); 22.9, 21.7 (2q, 2 Me of
Leu); 21.5 (q, Me(3) of Phe(2Me)); 19.6, 19.2 (2q, 2 Me of Valol). ESI-MS (TFA): 748(22, [ M þ Na]þ),
726 (100, [M þ 1]þ), 706 (15, [M ꢀ OH]þ), 624 (68, [M ꢀ Valol]þ), 494 (30, [M ꢀ Gln-Valol]þ). Anal.
calc. for C38H56N6O8 · 1.5 H2O (751.92): C 60.69, H 7.91, N 11.18; found: C 60.93, H 8.12, N 9.85.
13.4. N-{(S)-1-[({2-[((S)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-4-oxobutyl]amino}-1-benzyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}amino)car-
bonyl]-3-methylbutyl}-4-bromobenzamide (pBrBz-Leu-Aib-(S)-Phe(2Me)-Gln-Valol; (S)-13g). As de-
scribed for 13a, with (S)-2g (32 mg, 0.044 mmol), Pd/C (10% on activated charcoal, 7 mg), MeOH
(2 ml), and H2, 30 min at r.t., filtration over Celite, CH2Cl2 (3 ml), Et3N (10 mg, 0.099 mmol), 4-
bromobenzoyl chloride (10 mg, 0.046 mmol), 20 h at r.t., the precipitate was filtered and dried: 25 mg
(73%) of (S)-13g. Colorless solid. M.p. 236.7 – 237.68. Rf (CH2Cl2/MeOH 10 :1) 0.31. IR: 3417s, 2959m,
1
1682vs, 1654vs, 1608m, 1540m, 1399w, 1364w, 1230m, 1184w, 1068w, 1021w, 8 10w. H-NMR (CD3OD):
7.77, 7.60 (AA’BB’, J ¼ 8.6, 4 arom. H); 7.3 – 7.25, 7.15 – 7.1 (2m, 5 arom. H); 4.5 – 4.45, 4.15 – 4.1 (2m,
CH(2) of Gln and CH(2) of Leu); 3.65 – 3.55 (m, CH2(1) and CH(2) of Valol); 3.35, 3.05 (AB, J ¼ 13.6,
CH2(3) of Phe(2Me)); 2.3 – 1.95, 1.85 – 1.65 (2m, CH2(4) of Gln and CH2(3) of Gln, CH(3) of Valol,
CH2(3) of Leu); 1.6 – 1.5 (m, CH(4) of Leu); 1.46, 1.40, 1.30 (3s, 2 Me of Aib, Me(3) of Phe(2Me)); 1.01,
0.98(2 d, J ¼ 6.2, 6.3, 2 Me of Valol); 0.85,0.78 (2d, J ¼ 6.8, 2 Me of Leu). 13C-NMR (CD3OD): 177.9,
176.5, 175.5, 174.0 (4s, CONH2, 4 CONH); 169.5 (s, 1 CO (amide, pBrBz)); 137.3, 133.9 (2s, 2 arom. C);
132.7, 131.7, 130.6, 129.2, 128.0 (5d, 9 arom. CH); 127.3 (s, 1 arom. CBr); 63.2 (t, C(1) of Valol); 61.5, 58.0
(2s, C(2) of Phe(2Me), C(2) of Aib); 58.0, 55.4, 54.2 (3d, C(2) of Gln, C(2) of Valol, C(2) of Leu); ca. 48 ,
41.1, 33.3, 28.1 (4t, C(3) of Leu, C(3) of Phe(2Me), C(4) of Gln, C(3) of Gln); 29.9, 26.0 (2d, C(3) of
Valol, C(4) of Leu); 24.7, 23.9, 23.3, 22.1, 19.9, 19.0 (6q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Valol,
2 Me of Leu). ESI-MS (TFA): 813 (8, [M þ K]þ, 81Br), 798(100, [ M þ Na]þ, 81Br), 775 (86, [M þ 1]þ,
81Br), 757 (16, [M ꢀ OH]þ, 81Br), 672 (25, [M ꢀ Valol]þ, 81Br), 656 (12), 544 (53, [M ꢀ Gln-Valol]þ,
81Br). Anal. calc. for C37H53BrN6O7 · 2 MeOH (837.85): C 55.91, H 7.33, N 10.03; found: C 56.23, H 7.01, N
10.57.
Recrystallization from AcOEt/MeOH/petroleum ether gave crystals suitable for an X-ray crystal
structure determination.
14. Peptides with Xaa ¼ (R)-Phe(2Me). 14.1. Benzyl [(S)-1-({[2-({(R)-1-Benzyl-2-[(S)-2-(1-me-
thoxy-1-methylethyl)pyrrolidin-1-yl]-1-methyl-2-oxoethyl}amino)-1,1-dimethyl-2-oxoethyl]amino}car-
bonyl)-3-methylbutyl]carbamate (Z-Leu-Aib-(R)-Phe(2Me)-NCp{2-[(1-Me)(1-MeO)Et]}; (R)-3h). As
described for 3a, with 5 [19] (159 mg, 0.45 mmol), abs. CH2Cl2 (4 ml), and (R)-1h [17] (130 mg,
0.45 mmol), abs. CH2Cl2 (5 ml), 18h at r.t.; CC (CH 2Cl2/MeOH 20 :1, 25 :1, 50 :1); prep. TLC (CH2Cl2/
MeOH 20 :1): 229 mg (79%) of (R)-3h. Colorless foam. M.p. 79 – 808. Rf (CH2Cl2/MeOH 10 :1) 0.57. Rf
(CH2Cl2/MeOH 20 :1) 0.36. IR: 3323s, 3032m, 2958s, 1665vs, 1624vs, 1527vs, 1455s, 1411s, 1384s, 1316m,
1243s, 1120m, 1086s, 1061m, 921w, 737m, 700s. 1H-NMR: 7.48(br. s, NH); 7.4 – 7.3, 7.2 – 7.0 (2m, 10 arom.
H); 6.63 (br. s, NH); 5.14 (d, NH of Leu); 5.15 – 5.1 (m, NH); 5.05, 4.99 (AB, J ¼ 12.3, PhCH2O); 4.55 –
4.5 (m, CHN of Cp); 4.1 – 3.95 (m, CH(2) of Leu, CHN of Cp); 3.6 – 3.4 (m, CHN of Cp, CH2(3) of
Phe(2Me)); 3.16 (s, MeO); 2.05 – 1.95 (m, CH2(3) of Leu); 1.8– 1.4 ( m, 2 CH2 of Cp, 2 Me of Aib, Me(3)
of Phe(2Me), CH(4) of Leu); 1.17, 1.13 (2s, Me2C); 0.92 (d, J ¼ 6.3, 2 Me of Leu). 13C-NMR: 172.2, 171.5
(2s, CON, 2 CONH); the signal for OCONH could not be detected; 136.7, 136.0 (2s, 2 arom. C); 130.9,
128.4, 128.1, 127.9, 127.9, 126.6 (6d, 10 arom. CH); 67.1 (t, PhCH2O); 64.8( d, C(2) of Leu); 60.8, 57.7 (2s,
C(2) of Phe(2Me), C(2) of Aib); 54.2 (d, CHN of Cp); 49.1 (q, MeO); 48.1 (t, CH2N of Cp); 41.2, 40.3,
23.6 (3t, C(3) of Leu, C(3) of Phe(2Me), 2 CH2 of Cp); 25.3 (q, Me2C); 24.6 (d, C(4) of Leu); 22.9, 22.9,
22.2, 21.7 (4q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Leu). ESI-MS (MeOH, AcOH): 659 (7, [M þ
Na]þ), 639 (10), 638(39), 637 (100, [ M þ 1]þ). Anal. calc. for C36H52N4O6 (636.84): C 67.90, H 8.23, N
8.80; found: C 67.73, H 8.20, N 8.61.
14.2. (S)-2-Benzyl-2-({2-[((S)-2-{[(benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]-2-
methyl-1-oxopropyl}amino)propanoic Acid (Z-Leu-Aib-(R)-Phe(2Me)-OH; (R)-6g). 14.2.1. Hydrolysis

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of (R)-3h. As described for (S)-6c, with (R)-3h (120 mg, 0.188 mmol), 3n HCl (THF/H2O 1:1, 8 ml),
26 h at 408; CC (CH2Cl2/MeOH 10 :1): 57 mg (59%) of (R)-6g.
14.2.2. Hydrolysis of (R)-3g. As described for (S)-6c, with (R)-3g [19] (204 mg, 0.300 mmol) and 3n
HCl (MeCN/H2O 1:1, 6 ml), 3 h at 608; CC (CH2Cl2/MeOH 100 :2) and prep. TLC (CH2Cl2/MeOH
10 :1): 55 mg (36%) of (R)-6g. Colorless solid. M.p. 126.8– 127.3 8. Rf (CH2Cl2/MeOH 20 :1) 0.28. IR:
3330m, 3060w, 3030w, 2960m, 2860w, 1660vs, 1530 – 1510s, 1450s, 1410m, 1390m, 1365m, 1255m, 1215m,
1170w, 1120w, 1045w, 1030w, 1000w, 960w, 910w, 78 0w, 740w, 700m. 1H-NMR (CD3OD): 7.3 – 7.25, 7.15 –
7.1 (2m, 10 arom. H); 5.02, 4.97 (AB, J ¼ 12.5, PhCH2O); 4.13 (t, J ¼ 6.4, CH(2) of Leu); 3.37, 3.31 (AB,
J ¼ 13.3, CH2(3) of Phe(2Me)); 1.7 – 1.55 (m, CH(4) of Leu); 1.55 – 1.45 (m, Me(3) of Phe(2Me), CH2(3)
of Leu); 1.41, 1.38(2 s, 2 Me of Aib); 0.92, 0.90 (2d, J ¼ 6.8, 2 Me of Leu). 13C-NMR (CD3OD): 180.5 (s,
COOH); 175.3, 174.9 (2s, 2 CONH); 158.6 (s, OCONH); 139.2, 138.0 (2s, 2 arom. C); 131.5, 129.5, 129.1,
128.9, 127.3 (5d, 10 arom. CH); 66.4 (t, PhCH2O); 62.8( s, C(2) of Phe(2Me)); 58.3 (s, C(2) of Aib); 55.3
(d, C(2) of Leu); 42.3, 41.8(2 t, C(3) of Phe(2Me), C(3) of Leu); 25.9 (d, C(4) of Leu); 26.1, 24.9, 24.2,
23.5, 22.0 (5q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Leu). ESI-MS (NaI): 624 (18), 550 (20, [M þ
K]þ), 534 (100, [M þ Na]þ). Anal. calc. for C28H37N3O6 · 0.25 H2O (516.12): C 65.16, H 7.32, N 8.14;
found: C 65.01, H 7.51, N 7.84.
14.3. Benzyl {(S)-1-[({2-[((R)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]ami-
no}carbonyl)-4-oxobutyl]amino}-1-benzyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}amino)-
carbonyl]-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Phe(2Me)-Gln-Valol; (R)-2g). As described for 2b,
with (R)-6g (53 mg, 0.104 mmol), Et3N (22 mg, 0.218mmol), abs. DMF (1 ml), 5 min at 0 8, HATU
(40 mg, 0.105 mmol), 6 min at 08, 11 (24 mg, 0.104 mmol), 40 min at 08 and 25 h at r.t. Reaction control
with TLC showed still a considerable amount of (R)-6g. At 08, additional HATU (8mg, 0.021 mmol) was
added, the mixture was stirred for 4 min, and 11 (6 mg, 0.026 mmol) was added. After a further 7 min of
stirring, the mixture was warmed to r.t. and stirred for 68h. The solvent was evaporated, the residue was
dissolved in AcOEt and a small amount of MeOH, washed twice with 2n HCl, once with 1n NaOH soln.
and sat. NaCl soln., dried (MgSO4), and evaporated. A residue, which was not soluble in 50 ml of MeOH
(HATU), was filtered off. CC (CH2Cl2/MeOH 10 :1): 42 mg (56%) of (R)-2g. M.p. 94.3 – 95.08. Rf
(CH2Cl2/MeOH 10 :1) 0.35. 1H-NMR (CD3OD): 8.10 (d, J ¼ 6.8, NH); 7.40 (d, J ¼ 8.2, NH); 7.3 – 7.1 (m,
10 arom. H); 5.03, 4.96 (AB, J ¼ 12.5, PhCH2O); 4.2 – 4.15 (m, CH(2) of Gln); 4.01 (t, J ¼ 7.5, CH(2) of
Leu); 3.7 – 3.65 (m, CH2(1) and CH(2) of Valol); 3.53, 3.09 (2d, J ¼ 13.7, CH2(3) of Phe(2Me)); 2.4 – 2.35
(m, CH2(4) of Gln); 2.25 – 2.1 (m, CH2(3) of Gln); 2.0 – 1.9 (m, CH(3) of Valol); 1.7 – 1.65 (m, CH(4) of
Leu); 1.52 (t, J ¼ 7.2, CH2(3) of Leu); 1.42 (s, Me(3) of Phe(2Me)); 1.34, 1.32 (2s, 2 Me of Aib); 1.0 – 0.9
(m, 2 Me of Leu, 2 Me of Valol). 13C-NMR (CD3OD): 177.6, 176.9, 176.2, 174.7 (4s, CONH2, 4 CONH);
the signal for OCONH could not be detected; 138.2, 137.8 (2s, 2 arom. C); 132.3, 129.5, 129.1, 128.6, 127.9
(5d, 10 arom. CH); 67.7 (t, PhCH2O); 63.7 (t, C(1) of Valol); 61.3 (s, C(2) of Phe(2Me)); 58.8 (d, C(2) of
Gln); 58.0 (s, C(2) of Aib); 56.5, 56.1 (2d, C(2) of Leu, C(2) of Valol); 41.3, 40.4 (2t, C(3) of Phe(2Me),
C(3) of Leu); 33.6 (t, C(4) of Gln); 30.1 (d, C(3) of Valol); 28.6 (t, C(3) of Gln); 25.8( d, C(4) of Leu);
26.8, 24.7, 24.3, 23.2, 22.2 (5q, 2 Me of Aib, Me(3) of Phe(2Me), 2 Me of Leu); 20.1, 19.5 (2q, 2 Me of
Valol). ESI-MS (TFA): 748(18, [ M þ Na]þ), 726 (77, [M þ 1]þ), 708(12, [ M ꢀ OH]þ), 624 (100, [M ꢀ
Valol]þ), 494 (22, [M ꢀ Gln-Valol]þ).
14.4. N-{(S)-1-[({2-[((R)-2-{[(S)-4-Amino-1-({[(S)-1-(hydroxymethyl)-2-methylpropyl]amino}car-
bonyl)-4-oxobutyl]amino}-1-benzyl-1-methyl-2-oxoethyl)amino]-1,1-dimethyl-2-oxoethyl}amino)car-
bonyl]-3-methylbutyl}-4-bromobenzamide (pBrBz-Leu-Aib-(R)-Phe(2Me)-Gln-Valol; (R)-13g). As
described for 13a, with (R)-2g (25 mg, 0.035 mmol), Pd/C (10% on activated charcoal, 5 mg), MeOH
(1.5 ml), and H2, 16 h at r.t., filtration over Celite, CH2Cl2 (2 ml), Et3N (10 mg, 0.099 mmol), 4-
bromobenzoyl chloride (10 mg, 0.046 mmol), 3 h at r.t., filtration and washing with CH2Cl2: 20 mg (75%)
of (R)-13g. Colorless solid. M.p. 127.4 – 128.58. Rf (CH2Cl2/MeOH 10 :1) 0.37. IR: 3422vs, 2929m, 1648s,
1534m, 1458w, 1388w, 1284w, 1070w, 1011w, 760w, 711w. ESI-MS (NaI): 806 (12), 798 (87, [M þ Na]þ,
81Br), 757 (8, [M ꢀ OH]þ, 81Br), 729 (16), 655 (9), 613 (13), 589 (32), 573 (8), 514 (15), 485 (17), 441
(12).
After recrystallization from MeOH and acetone, crystals were obtained. The attempted X-ray
crystal-structure determination failed, as the reflexes were not strong enough to solve the structure
properly.

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Helvetica Chimica Acta – Vol. 91 (2008)
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Helvetica Chimica Acta – Vol. 91 (2008)
15. X-Ray Crystal-Structure Determination of 13a, 13b, (S)-2d, (S)-2e, (S)-13f, (S)-13g, (R)-6c, (R)-
7c, and (R)-7d (see Tables 6 and 7, and Figs. 1 and 2)4). All measurements were conducted at low temp.
using graphite-monochromated MoKa radiation (l 0.71073 Š). The data collection and refinement
parameters are given in Tables 6 and 7, and views of the molecules are shown in Figs. 1 and 2. The
intensities were corrected for Lorentz and polarization effects, and for 13a, 13b, and (S)-13g, an empirical
absorption correction, based on azimuthal scans of several reflections, was also applied [40]. For (S)-13f,
a numerical absorption correction [41] was applied. Equivalent reflections, including Friedel pairs for
(S)-2e, (R)-6c, and (R)-7d, were merged. Structures 13a, 13b, and (S)-13g were solved by Patterson
methods using DIRDIF 92 [42], which revealed the positions of the Br-atom. All remaining non-H-atoms
were located in Fourier expansions of the Patterson solution. Structures of (S)-2d, (S)-2e, (S)-13f, (R)-6c,
and (R)-7c were solved by direct methods, which revealed the positions of all non-H-atoms.
In 13a, the asymmetric unit contains one peptide molecule plus a site partially occupied by a H2O
molecule. The O-atom of the H2O molecule has a site occupation factor of ca. 0.33. The H-atom positions
were not defined for the H2O molecule. The i-Bu group is disordered. Two sets of positions were defined
for each of the atoms of this group, and the site occupation factor of the major conformation of this group
refined to 0.519(4). Similarity restraints were applied to the chemically equivalent bond lengths and
angles involving all disordered C-atoms, while neighboring atoms within and between each conformation
of the disordered group were restrained to have similar atomic displacement parameters. In 13b, the i-Bu
group is also disordered and was modelled analogously to 13a; the site occupation factor of the major
conformation refined to 0.629(6). In (S)-2e, the five-membered ring is disordered over two
conformations. Two positions were defined for the atom C(33) of this ring, and the site occupation
factor of the major conformation refined to 0.55(1). Similarity restraints were applied to the CꢀC bond
lengths involving the disordered atom. In (S)-13f, there are two symmetry-independent molecules in the
asymmetric unit. The atomic coordinates of the two molecules were tested carefully for a relationship
from a higher symmetry space group using the program PLATON [45], but none could be found.
Disorder is present in the i-Bu substituents at C(2) of molecule A, and C(42) and C(48) of molecule B.
Two positions were defined for the two terminal Me groups and the methine C-atom of each disordered
group, but in some cases, particularly at C(2) and C(48), the behavior of the refinement suggested that
the atoms of these groups adopt several orientations which results in the electron density in these regions
being smeared out. Restraints were applied to the bond lengths and the anisotropic displacement
parameters of the disordered atoms. The site occupation factors of the major conformations refined to
values ranging from 0.505(9) (group at C(2)) to 0.66(1) (group at C(42)). In (S)-13g, the asymmetric unit
contains one molecule of the peptide and two molecules of MeOH.
The non-H-atoms were refined anisotropically, except for atom C(6) in (S)-13g, which was refined
isotropcially. The OH H-atoms, where present, and the amide H-atoms, except for those in 13a and (S)-
13f, were placed in the positions indicated by difference electron-density maps, and their positions were
allowed to refine together with individual isotropic displacement parameters. All remaining H-atoms in
the structures were placed in geometrically calculated positions and refined using a riding model where
each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its
parent C-atom (1.5 Ueq for the Me groups). The refinement of each structure was carried out on F2 using
full-matrix least-squares procedures, which minimized the function Sw(F2o ꢀ F2)2. Corrections for
secondary extinction were applied, except for 13a and (S)-13g. The crystals of each compound were
enantiomerically pure, and the absolute configuration was determined experimentally for 13a, 13b, (S)-
13f, and (S)-13g (absolute structure parameters [46] of ꢀ 0.005(8), ꢀ 0.012(10), 0.004(5), and ꢀ
0.003(11), resp.). The absolute configurations of the other compounds could not be determined, as no
atoms exhibiting significant anomalous scattering are present. In these latter cases, the enantiomer used
in each refinement was based on the known configuration derived from the synthetic precursors of the
molecule.
4
)
CCDC-670070 – 670078contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 91 (2008)
555
Table 7. Crystallographic Data of Compounds (R)-6c, (R)-7c, and (R)-7d
(R)-6c
(R)-7c
(R)-7d
Crystallized from
MeOH
C23H35N3O6
449.54
colorless, prism
0.15 ꢁ 0.25 ꢁ 0.25
160(1)
MeOH/CH2Cl2
C24H38N4O5
462.59
colorless, prism
0.15 ꢁ 0.20 ꢁ 0.25
160(1)
CD3OD
C25H40N4O5
476.61
Empirical formula
Formula weight [g molꢀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
]
colorless, prism
0.22 ꢁ 0.28 ꢁ 0.30
160(1)
Crystal system
Space group
orthorhombic
P212121
orthorhombic
P212121
orthorhombic
P212121
Z
4
4
4
Reflections for cell determination
3143
4170
3446
2q Range for cell determination [8] 4 – 55
4 – 60
4 – 55
Unit cell parameters a [Š]
11.2008(2)
11.0674(1)
13.3562(2)
17.2406(3)
2548.48(6)
1.206
10.7082(2)
14.3736(3)
17.3511(4)
2670.60(10)
1.185
b [Š]
c [Š]
12.6246(2)
17.0682(3)
2413.54(7)
1.237
V [Š3]
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Diffractometer
Scan type
]
0.0894
0.0848
0.0828
Nonius KappaCCD Nonius KappaCCD Nonius KappaCCD
f and w
55
f and w
60
f and w
55
2q(max) [8]
Total reflections measured
Symmetry independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
3402851767
3126
26185722 79
3121
37349
7453
3430
28
7449
322
3426
332
312
R(F) [I > 2s(I) reflections]
0.0394
01002
0.0516; 0.3241
1.052
0.0419
0.1012
0.0503; 0.2152
1.025
0.0451
0.1216
0.0643; 0.5627
1.036
wR(F2) (all data)
Weighting parameters (a; b)a)
Goodness-of-fit
Secondary extinction coefficient
0.015(2)
0.001
0.011(2)
0.001
0.023(3)
0.001
Final Dmax/s
D1 (max; min) [e Š
ꢀ3
]
0.17; ꢀ 0.17
0.17; ꢀ 0.180.36;
ꢀ 0.17
Structure solution program
SIR92
SIR92
SIR92
a) w ¼ [s2(F2o ) þ (aP)2 þ bP]ꢀ1 where P ¼ (Fo2 þ 2F2c )/3.
Neutral-atom scattering factors for non-H-atoms were taken from [47], and the scattering factors for
H-atoms were taken from [48]. Anomalous dispersion effects were included in Fcalc [49]; the values for f’
and f’’ were those of [50]. The values of the mass attenuation coefficients are those of [51]. All
calculations were performed using the SHELXL97 program [52].
REFERENCES
[1] J.-P. Obrecht, P. Schçnholzer, C. Jenny, R. Prewo, H. Heimgartner, Helv. Chim. Acta 1988, 71, 1319.
[2] a) R. S. Rathore, Biopolymers 2005, 80, 651; b) M. Hanyu, T. Murashima, T. Miyazawa, T. Yamada,
Tetrahedron Lett. 2004, 45, 8871; c) J.-P. Mazaleyrat, K. Wright, A. Gaucher, N. Toulemonde, M.
Wakselman, S. Oancea, C. Peggion, F. Formaggio, V. Setnicka, T. A. Keiderling, C. Toniolo, J. Am.
Chem. Soc. 2004, 126, 12874.