Synthesis of conformationally restricted cyclic pentadepsipeptides via direct amide cyclization

Article abstract of DOI:10.1016/S0040-4020(01)00091-6

The 2,2-disubstituted 2H-azirin-3-amines 6 (3-amino-2H-azirines) were used as building blocks for α,α-disubstituted α-amino acids in the preparation of 16-membered cyclic depsipeptides 14. The linear precursors containing four α,α-disubstituted α-amino acids, the pentapeptides 13, were synthesized starting with β-hydroxy acids 5 via the 'azirine/oxazolone method'. The cyclic depsipeptides 14 were formed via 'direct amide cyclization' and the influence of several factors on this cyclization was investigated in the following way: (a) using the same composition of α,α-disubstituted α-amino acids, but changing their respective positions in the peptide chain; (b) using different C-terminal α,α-disubstituted α-amino acids in the peptide chain; (c) using different β-hydroxy acids; and (d) using different diastereoisomers of the peptides.

Full text of DOI:10.1016/S0040-4020(01)00091-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2311±2326
Synthesis of conformationally restricted cyclic pentadepsipeptides
via direct amide cyclization
²
Kristian N. Koch, Anthony Linden and Heinz Heimgartnerp
È È È
Organisch-chemisches Institut der Universitat Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Received 4 December 2000; accepted 19 January 2001
AbstractÐThe 2,2-disubstituted 2H-azirin-3-amines 6 (3-amino-2H-azirines) were used as building blocks for a,a-disubstituted a-amino
acids in the preparation of 16-membered cyclic depsipeptides 14. The linear precursors containing four a,a-disubstituted a-amino acids, the
pentapeptides 13, were synthesized starting with b-hydroxy acids 5 via the `azirine/oxazolone method'. The cyclic depsipeptides 14 were
formed via `direct amide cyclization' and the in¯uence of several factors on this cyclization was investigated in the following way: (a) using
the same composition of a,a-disubstituted a-amino acids, but changing their respective positions in the peptide chain; (b) using different
C-terminal a,a-disubstituted a-amino acids in the peptide chain; (c) using different b-hydroxy acids; and (d) using different diastereoisomers
of the peptides. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
type 1 with dry HCl gas leads to the corresponding 1,3-
oxazol-5(4H)-one derivative 2 via ring closure and elimina-
tion of dimethylamine hydrochloride. In the absence of
external nucleophiles, 2 undergoes a ring enlargement to
yield the cyclic product 3 via an intramolecular attack of
the OH group at the lactone group of 2.
Cyclic depsipeptides are well known for their biological
activity. They contain, in addition to the amide bonds, one
or more ester bonds. A large number of them have been
isolated from different natural sources.1±5 The majority of natu-
rally occurring cyclic depsipeptides are produced on surface
or marine cultures of an appropriate micro-organism. Two
of the most well-known examples are the antibiotics valino-
mycin6±8 and enniatins,9 which act as ionophores.10
Several cyclic depsipeptides containing one a- or b-hydroxy
acid and two to four a,a-disubstituted a-amino acids
(2,2-disubstituted glycines) have been prepared via this
cyclization method.19±25 The a,a-disubstituted a-amino
acids have been incorporated into the peptide chains of
the linear precursors by using the so-called `azirine/oxazo-
lone method'.26 This particularly useful method has been
successfully used in the synthesis of peptaibols,27±29 endothio-
peptides30 and conformationally restricted cyclic peptides.31,32
The crucial step in the synthesis of cyclic depsipeptides is
the cyclization. Traditionally, it has been carried out via
amide bond formation,11±13 although, several examples are
known where the cyclization has been performed via ester
bond formation.14±18 A useful method for the cyclization via
ester bond formation, the so-called `direct amide cycli-
zation', has been developed in our laboratory.19±25 The
concept is shown in Scheme 1: treatment of an amide of
The tetrasubstitution of the a-carbon in these a-amino
acids results in severe steric hindrance. Peptides containing
Scheme 1.
Keywords: a,a-disubstituted a-amino acids; 3-amino-2H-azirines; azirine/oxazolone method; cyclic pentadepsipeptides; direct amide cyclization.
Corresponding author. Tel.: 141-1-635-42-82; fax: 141-1-635-68-12; e-mail: heimgart@oci.unizh.ch
È
È
Part of the PhD Thesis of K. N. K., Universitat Zurich, 2000.
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00091-6

2312
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
a,a-disubstituted a-amino acids therefore possess signi®-
cant constraints on their conformational freedom and
secondary structures such as b-turns and a- and 310-helices
are promoted in the solid state and in solution.33±37
Recently, we reported on the synthesis of four cyclic penta-
depsipeptides 4a±d containing one b-hydroxy acid and four
a,a-disubstituted a-amino acids25 via `direct amide cycliza-
tion', and the yield of monomer 4 varied considerably (24±
60%).
On the basis of these results, it was of interest to investigate
the in¯uence of speci®c changes in the pentapeptide
chain on the cyclization, especially the yield of cyclic
monomer. The following factors were examined: (a) same
composition of a,a-disubstituted a-amino acids but different
respective position in the peptide chain; (b) different C-terminal
a,a-disubstituted a-amino acids; (c) different b-hydroxy
acids; and (d) different diastereoisomers of the linear
pentapeptides.
using the `azirine/oxazolone method' according to Scheme
2 (cf. Tables 1 and 2). The amides 7, 9, 11 and 13 were
prepared via coupling of 3-amino-2H-azirines 6 with the
b-hydroxy acids or the free peptide acids in good to
excellent yields (Table 1). Hydrolysis of the C-terminal
amide was performed under standard conditions in 3N
HCl/THF at rt yielding the acids 8, 10 and 12 (Table
2). In three examples, the selective hydrolysis of the C-
terminal amide was less satisfying: treatment of the
tripeptide 9a and the two tetrapeptides 11b and d under
standard conditions resulted in hydrolysis not only of the
C-terminal amide, but also of other amide bonds of the
peptide chain. Therefore, the yields of the desired
carboxylic acids were low and, for practical reasons,
the crude products were used for the following coupling
reaction.
2. Results and discussion
The desired linear pentapeptides containing one b-hy-
droxy acid and four a,a-disubstituted a-amino acids
were synthesized according to the same strategy as
previously reported.25 With 3-amino-2H-azirines as
building blocks for a,a-disubstituted a-amino acids,
the pentapeptides could be prepared without the use of
coupling reagents,38 thereby eliminating the formation of
side products and simplifying the puri®cation procedures
considerably.
Three b-hydroxy acids were selected, namely 3-hydroxy-
2,2-dimethylpropanoic acid (5a; Dhp), 3-hydroxy-2-
phenylpropanoic acid (5b, tropic acid (Tro)) and trans-2-
hydroxycyclohexanecarboxylic acid (5c; Hcc). The 3-
amino-2H-azirines 6a±e were used as building blocks
for 2-aminoisobutyric acid (Aib), 1-aminocyclopentane-
carboxylic acid (Ac5c), and a-methylphenylalanine
(Phe(2Me)), respectively.
Generally, the coupling step is faster when 3-(N,N-
dimethylamino)-2H-azirines 6a and d are used instead
of the corresponding 3-(N-methyl-N-phenylamino)-2H-
azirines 6b and e. On the other hand, N-methylaniline is a
better leaving group than dimethylamine, thereby making
the selective hydrolysis of the N-methyl-N-phenylamide
faster than that of the N,N-dimethylamide.
In two examples, the diastereoisomeric peptides were
separated. In the ®rst case, the diastereoisomers 9b/9c
were separated by means of MPLC, and the two
2.1. Preparation of the linear pentapeptides
Seven linear pentapeptides of type 13 were synthesized

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2313
Scheme 2. For X1±X3 and R1±R3 see Schemes 3±5 and Tables 1 and 2.
diastereoisomeric pentapeptides 13f and g were then
prepared independently of each other from 9b (!10b!
11c!12d!13f) and 9c (!10c!11d!12e!13g), respec-
tively. In the second case, RP-HPLC was used for
the separation of the diastereoisomeric pentapeptides
13d and e.
Aib residues along with protein amino acids are folded
either in the 310- or a-helical structure, depending upon
the main-chain length, Aib content, sequence and environ-
mental conditions;34,35 (c) Aib is the strongest known
b-turn-forming residue, particularly of types I (I0) and III
(III0);33 (d) Phe(2Me)- and Ac5c-containing peptides
show the same strong tendency to form b-turns and helical
structures.33
The structural preferences of Aib-containing peptides have
been studied extensively by X-ray crystallography, and the
following conclusions have been drawn: (a) Aib homopep-
tides, beginning at the trimer level, adopt the 310-helical
structure stabilized by b-turns of type III (III0), irrespective
of the chain length;33 the a-helical structure has never been
observed;34 (b) tripeptides and longer peptides containing
The pentapeptide 13f (Scheme 2, Table 1) and the
previously prepared pentapeptide 13h25 have the same
combination of a,a-disubstituted a-amino acids and
differ only in the b-hydroxy acid. It was of interest to
determine whether and how the different b-hydroxy acids

2314
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
Table 1. Coupling of b-hydroxy acids 5 and peptide acids 8, 10, and 12 with 3-amino-2H-azirines 6
Starting material
Azirine
Product
Yield (%)
5a (Dhp)
5c (Hcc)
8a (Dhp±Aib)
8b/c (Hcc±Phe(2Me))
10a (Dhp±Aib±Aib)
10a (Dhp±Aib±Aib)
10b (Hcc±Phe(2Me)±Aib)
(RS,RS,SR)-Isomer
6b
6e
6b
6b
6d
6b
6a
7a (Dhp±Aib±N(Me)Ph)
7b/c (Hcc±Phe(2Me)±N(Me)Ph)
9a (Dhp±Aib±Aib±N(Me)Ph)
9b/c (Hcc±Phe(2Me)±Aib±N(Me)Ph)
11a (Dhp±Aib±Aib±Phe(2Me)±NMe2)
11b (Dhp±Aib±Aib±Aib±N(Me)Ph)
11c (Hcc±Phe(2Me)±Aib±Aib±NMe2)
(RS,RS,SR)-Isomer
93
73
90
88
35a
48b
85
10c (Hcc±Phe(2Me)±Aib)
(RS,RS,RS)-Isomer
6b
11d (Hcc±Phe(2Me)±Aib±Aib±N(Me)Ph)
(RS,RS,RS)-Isomer
92
12a (Dhp±Aib±Aib±Phe(2Me))
12b (Dhp±Aib±Aib±Aib)
12c ((R)-Tro±Aib±Aib±Aib)
12c ((R)-Tro±Aib±Aib±Aib)
12d (Hcc±Phe(2Me)±Aib±Aib)
(RS,RS,SR)-Isomer
6a
6d
6c
6d
6a
13a (Dhp±Aib±Aib±Phe(2Me)±Aib±NMe2)
13b (Dhp±Aib±Aib±Aib±Phe(2Me)±NMe2)
13c ((R)-Tro±(Aib)3±Ac5c±NMe2)
13d/e ((R)-Tro±(Aib)3±Phe(2Me)±NMe2)
13f (Hcc±Phe(2Me)±Aib±Aib±Aib±NMe2)
(RS,RS,SR)-Isomer
77
46c
87
82
71
12e (Hcc±Phe(2Me)±Aib±Aib)
(RS,RS,RS)-Isomer
6a
13g (Hcc±Phe(2Me)±Aib±Aib±Aib±NMe2)
(RS,RS,RS)-Isomer
42d
a
Overall yield of the hydrolysis of 9a followed by coupling of crude 10a with 6d.
Overall yield of the hydrolysis of 9a followed by coupling of crude 10a with 6b.
Overall yield of the hydrolysis of 11b followed by coupling of crude 12b with 6d.
Overall yield of the hydrolysis of 11d followed by coupling of crude 12e with 6a.
b
c
d
Table 2. Hydrolysis of the C-terminal amide group of the peptide amides
Peptide amides
Product
Yield (%)
7a (Dhp±Aib±N(Me)Ph)
8a (Dhp±Aib)
8b/c (Hcc±Phe(2Me))
10a (Dhp±Aib±Aib)
10b (Hcc±Phe(2Me)±Aib)
(RS,RS,SR)-Isomer
10c (Hcc±Phe(2Me)±Aib)
(RS,RS,RS)-Isomer
12a (Dhp±Aib±Aib±Phe(2Me))
12b (Dhp±Aib±Aib±Aib)
12d (Hcc±Phe(2Me)±Aib±Aib)
(RS,RS,SR)-Isomer
36
90
±
7b/c (Hcc±Phe(2Me)±N(Me)Ph)
9a (Dhp±Aib±Aib±N(Me)Ph)
9b (Hcc±Phe(2Me)±Aib±N(Me)Ph)
(RS,RS,SR)-Isomer
9c (Hcc±Phe(2Me)±Aib±N(Me)Ph)
(RS,RS,RS)-Isomer
11a (Dhp±Aib±Aib±Phe(2Me)±NMe2)
11b (Dhp±Aib±Aib±Aib±N(Me)Ph)
11c (Hcc±Phe(2Me)±Aib±Aib±NMe2)
(RS,RS,SR)-Isomer
11d (Hcc±Phe(2Me)±Aib±Aib±N(Me)Ph)
(RS,RS,RS)-Isomer
a
88
91
83
a
±
93
a
12e (Hcc±Phe(2Me)±Aib±Aib)
(RS,RS,RS)-Isomer
±
a
Yield not determined, cf. Table 1.
in¯uence the conformation.
H-bonds between N(7)±H´´´O(14) and N(4)±H´´´O(11). In
13f, the N´´´O distances (Table 4) are slightly longer than
the average value determined for a large number of intra-
molecular H-bonds in peptides,40 whereas in 13h, they are in
good agreement with the expected values. All the peptide
bonds (torsion angles v) show the s-trans-con®guration
with two (in the case of 13f) and one (in the case of 13h),
respectively, deviating markedly from planarity.41
The molecules of 13f also form two intermolecular
H-bonds, N(10)±H´´´O(200) and N(13)±H´´´O(500), linking
neighboring molecules into in®nite one-dimensional chains.
Furthermore, there is an intermolecular H-bond between the
hydroxy group O(16)±H and O(140) at the cyclohexane end
of a different neighboring molecule. This interaction links
adjacent cyclohexane ends of neighboring molecules into
centrosymmetric dimeric loops. These loops crosslink the
H-bonded chains described above. Thus, the combination
of all intermolecular H-bond interactions results in the
formation of in®nite two-dimensional networks.
The two pentapeptides were crystallized from H2O/MeOH/
CHCl3 and H2O/MeOH, respectively, and their structures
were established by X-ray crystallography (Figs. 1 and 2).
The relevant torsion angles are given in Table 3 while the
intra- and intermolecular H-bond parameters are listed in
Table 4.
The pentapeptides 13f and h adopt helical conformations
containing two distorted consecutive b-turns of type III
(III0) (f1, f2, f3 and c1, c2, c3; Table 3). The b-turns
are stabilized by two consecutive intramolecular 4 ! 1
In 13h, there is an additional intramolecular H-bond

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2315
Figure 1. ORTEP Plot39 of the molecular structure of 13f (arbitrary numbering of the atoms; 50% probability ellipsoids).
between N(10)±H and O(17) of the OH group, which
further stabilizes the helical conformation of the peptide.
The molecules of 13h are linked head-to-tail by intermol-
ecular H-bonds O(17)±H´´´O(50) and N(13)±H´´´O(20),
thus forming in®nite one-dimensional chains.
The signs of the torsion angles f4 and c4 of the Aib residue
at the C-terminal position of 13f and h are opposite to those
of the proceeding residues. This is a widely observed
phenomenon for homopeptides of a,a-disubstituted
a-amino acids.42,43
Figure 2. ORTEP Plot39 of the molecular structure of 13h (arbitrary numbering of the atoms; 50% probability ellipsoids).

2316
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
Table 3. Selected torsion angles (8) of pentapeptides 13f and h
Angle
Peptide 13f
Peptide 13h
v0
f1
c1
v1
f2
c2
v2
f3
c3
v3
f4
c4
2178.9(2)
251.8(3)
251.1(3)
2166.2(2)
264.7(3)
224.5(3)
2179.3(2)
254.7(3)
234.2(3)
167.2(2)
45.0(3)
2178.1(1)
55.2(2)
29.2(2)
178.4(1)
46.7(2)
36.9(2)
1113.9(2)
66.4(2)
12.3(2)
2179.8(2)
255.4(2)
257.4(2)
61.6(3)
Scheme 3.
In conclusion, both peptides, 13f and h, adopt the conforma-
tion of an incipient 310-helix stabilized by two distorted
consecutive b-turns of Type III0 (III). This conformation
appears to be independent of the kind of b-hydroxy acid
present.
absorption of the lactone group was observed at 1715±
1749 cm21. To determine the molecular mass of the cyclic
depsipeptides, the soft-ionization technique ESI-MS was
employed. With this technique, it was possible to differenti-
ate between the cyclic monomer 14 and the corresponding
cyclodimer. The structures of 14a±g were con®rmed by
one- and two-dimensional NMR spectroscopy. The assign-
2.2. Cyclization of the linear pentapeptides
1
ment of the different H and 13C signals was carried out
using HSQC and HMBC techniques.25
The optimum reaction conditions for the cyclization to give
16-membered cyclic pentadepsipeptides of type 14 via the
`direct amide cyclization' were elaborated in the previous
work.25 The general procedure was as follows: a stream of
dry HCl gas was slowly passed through a suspension of the
pentapeptide 13 in toluene at 1008C. When a clear solution
was formed, HCl was added for another 2±3 min. Then,
excess HCl was removed by passing a stream of N2 through
the solution for 30 min, toluene was evaporated, the residue
was suspended in THF/Et2O 1:1 at rt, and, subsequently, the
precipitated Me2NH´HCl was removed by ®ltration. The
products were then puri®ed by column chromatography.
A possible in¯uence of the amino acid sequence in the
pentapeptide chain with the same composition of a,a-disub-
stituted a-amino acids on the cyclization was examined.
Therefore, the formation of cyclic depsipeptides of type
14 containing the b-hydroxy acid 5a, three Aib residues
and one Phe(2Me) residue was studied. The ®rst example
4c with Phe(2Me) in position 2 has been prepared from 13h
earlier and was obtained in good yield (46%).25 Under the
same conditions, the analogous pentapeptides 13a and b,
with Phe(2Me) in positions 4 and 5, respectively, were
cyclized according to Scheme 3, and the cyclic monomers,
14a and b, respectively, were obtained, although in rather
All cyclic depsipeptides of type 14 were characterized by
spectroscopic methods. In the IR spectra of 14a±g, the
³
low yield (Table 5). In the case of 13a, the cyclodimer 15a
was also isolated in similar yield.
Table 4. Intra- and intermolecular H-bond parameters for the pentapeptides
13f and h
The results of these cyclizations were compared with those
previously described. The yield of 14a is less than half of
that of 4c, and the formation of the cyclodimer 15a is
favored. In the case of 14b, the difference is even more
pronounced as the yield is only a ®fth of that of 4c. This
indicates that different positions of Phe(2Me) in the
pentapeptide chain in¯uence the conformation and/or
solubility of 13 and/or the intermediates of the cyclization
b
Compound Typea
H´´´O (A) X ´´´O (A) Xb±H´´´O (8)
Ê
Ê
13f
O(16)±H´´´O(140) 1.93(3)
2.855(2)
3.350(3)
2.829(2)
3.121(2)
3.235(3)
2.908(2)
2.847(2)
2.958(2)
3.047(2)
3.302(2)
172(3)
154(2)
162(2)
167(2)
156(2)
160(2)
177(3)
167(2)
167(2)
167(2)
N(10)±H´´´O(200) 2.54(2)
N(13)±H´´´O(500) 2.03(2)
N(4)±H´´´O(11)
N(7)±H´´´O(14)
N(13)±H´´´O(20)
O(17)±H´´´O(50)
N(4)±H´´´O(11)
N(7)±H´´´O(14)
2.32(2)
2.48(2)
2.06(2)
1.99(3)
2.13(2)
2.20(2)
13h
³
Based on the similar chromatographic properties of 15a and 14a and the
ESI-MS, we propose that 15a is a cyclodimer:
N(10)±H´´´O(17) 2.45(2)
a
Primed atoms refer to molecules in the following symmetry-related posi-
0
0211x, y, z.
XˆO or N.
tions: for 13f: 12x, 22y, 2z; 002(1/2)1x, (3/2)2y, 2(1/2)1z; for 13h:
b

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2317
Table 5. Cyclization of pentapeptides 13a±g in toluene (30 ml) at 1008C
(58% yield of 14d). The difference between the lowest and
highest yield of cyclic monomer is nearly twofold. Another
interesting result is the similarity of the yields of the two
diastereoisomeric monomers 14d and e (58% and 57%,
respectively), i.e. the formation of the monomers 14d and
e is not signi®cantly in¯uenced by the chirality of the
C-terminal a,a-disubstituted a-amino acid.
Pentapeptide Cyclic monomer Yield (%) Cyclodimer Yield (%)
13a
13b
13c
13d
13e
13f
14a
14b
14c
14d
14e
14f
20
9
15a
15b
15c
15d
15e
15f
24
a
±
20
30
58
57
50
28
a
±
21
2
11
13g
14g
15g
A further point of interest was the effect of different b-hydroxy
acids on the ring closure via `direct amide cyclization'.
Pentapeptide 13b and the diastereoisomers 13d and e
contain the same sequence of a,a-disubstituted a-amino
acids and differ only in the b-hydroxy acid, with Dhp (5a)
in the former and Tro (5b) in the latter case. The cyclic
monomer 14b was obtained in 9% yield, whereas 14d and
e were formed in 58% and 57% yield, respectively. The
sixfold difference in yield shows the distinctive effect of
the b-hydroxy acid on the ring closure.
a
The proposed cyclodimers 15b and d were isolated together with other
non-identi®ed products (detected by ESI-MS).
considerably, resulting in large variations in the yields
of 14.
It was also of interest to know how different C-terminal a,a-
disubstituted a-amino acids would in¯uence the cyclization,
when the rest of the peptide chain remained identical. The
cyclic depsipeptide 4a, containing only one type of a,a-
disubstituted a-amino acid, i.e. Aib, was chosen as the refer-
ence. The new pentapeptides 13c±e were synthesized with
enantiomerically pure tropic acid ((R)-Tro), three Aib resi-
dues, and a C-terminal Ac5c and Phe(2Me) residue, respect-
ively, as described above. Ring closure of the three
pentapeptides was carried out via `direct amide cyclization'
according to Scheme 4. In each of these examples, both the
monomer 14 and the dimer 15 were formed. The yields are
summarized in Table 5.
In the above-described examples, b-hydroxy acids with a
primary hydroxy group were used. Therefore, it was of
interest to investigate whether or not a sterically more
hindered b-hydroxy acid with a secondary hydroxy group
could be used to prepare cyclic depsipeptides. Furthermore,
it was attractive to cyclize diastereoisomeric pentapeptides
13 containing the chiral Phe(2Me) within the peptide chain.
The b-hydroxy acid 5c, with the secondary hydroxy group
in a trans relationship to the carboxylic acid functionality,
was chosen. The cyclic monomer 4c with the racemic
Phe(2Me) residue in position 2 of the pentapeptide was
used as the reference. The two diastereoisomeric pentapep-
tides 13f and g were cyclized via the `direct amide cycli-
zation' according to Scheme 5. In both cases, the
corresponding monomer 14 and dimer 15 could be isolated
(Table 5).
Comparing the yields of the monomers 14 (Table 5)
with that of 4a (41%), it is evident that the C-terminal
a,a-disubstituted a-amino acid also in¯uences the yield of
cyclic monomer. The lowest yield was obtained in the case
of pentapeptide 13c containing a C-terminal Ac5c residue
(formation of 14c in only 30% yield), the highest yield
resulted with 13d containing a C-terminal Phe(2Me) residue
The diastereoisomeric cyclic monomers 14f and g were
Scheme 4.
Scheme 5.

2318
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
formed in 50% and 28% yield, respectively. This indicates
that the ease of cyclization in this case is in¯uenced remark-
ably by the con®guration of the chiral Phe(2Me) residue
next to the b-hydroxy acid. The model peptide monomer
4c has been obtained in 46% yield, thus 14f was obtained in
slightly higher yield. These results show that a sterically
more hindered b-hydroxy acid can also be used successfully
for ring closure via `direct amide cyclization'.
was added dropwise a solution of 6 in dry MeCN. The
mixture was stirred at rt under N2 (18±44 h), ®ltered,
washed with cold hexane/Et2O 1:1, and dried under h.v.
General procedure 2 (GP 2). According to GP 1, the
mixture was stirred at rt under N2 (17±92 h), evaporated,
puri®ed by column chromatography (CC), and dried under
h.v.
General procedure 3 (GP 3). Hydrolysis of amides 7, 9 and
11. The amide was dissolved in 3N HCl/THF 1:1 (v/v; ca.
5 ml/mmol) and the solution was stirred at rt (19±24 h). The
solvent was evaporated, H2O was added, and the mixture
left overnight at rt. The product was collected by ®ltration,
washed with cold H2O and Et2O, and dried under h.v.
3. Conclusions
In the present study, a number of factors which in¯uence the
formation of cyclic depsipeptides via the `direct amide
cyclization' have been investigated. The following modi®-
cations of the pentapeptide chain were found to have a
profound in¯uence on the yield of cyclic monomer 4/14:
(a) keeping the b-hydroxy acid and four a,a-disubstituted
a-amino acids in the peptide chain unchanged, but varying
the position of the different a,a-disubstituted a-amino acids
in the peptide chain; (b) using different a,a-disubstituted
a-amino acids at the C-terminal position while keeping
the b-hydroxy acid and three a,a-disubstituted a-amino
acids unchanged; (c) preserving the chain of four a,a-
disubstituted a-amino acids, but using different b-hydroxy
acids. Apart from these three factors, it was found that a
sterically hindered b-hydroxy acid containing a secondary
hydroxy group could be successfully used in the `direct
amide cyclization'. The cyclization of diastereoisomeric
pentapeptides was found to be in¯uenced by the position
of the chiral Phe(2Me) residue in the pentapeptide chain,
whereas no in¯uence was observed with the chiral
Phe(2Me) residue at the C-terminal position; the yields
of the cyclizations of the diastereoisomers with the
chiral Phe(2Me) residue next to the b-hydroxy acid differ
signi®cantly.
General procedure 4 (GP 4). According to GP 3, a solution
of the amide in 3N HCl/THF 1:1 (v/v; ca. 5 ml/mmol) was
stirred at rt (18±23 h), followed by evaporation of the
solvent. Brine was added to the oily crude product, the
mixture was extracted with AcOEt, the organic layer dried
(MgSO4), evaporated, and the residue dried under h.v.
4.2. Reaction of 2H-azirin-3-amines 6 with b-hydroxy
acids 5
4.2.1. 2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)amino]-
2,N-dimethyl-N-phenylpropanamide (7a). According to
GP 2, 5a (1.01 g, 8.50 mmol) in MeCN (10 ml), 6b
(1.54 g, 8.84 mmol) in MeCN (2 ml), stirred for 17 h, CC
(SiO2, CH2Cl2/MeOH 25:1, CH2Cl2/MeOH 10:1): 2.32 g
(93%) of 7a. White powder. Mp 103.4±104.08C. IR:
3353vs, 3257vs, 3058m, 2965s, 2867s, 1645vs, 1592vs,
1548vs, 1493vs, 1472s, 1415vs, 1384vs, 1359vs, 1309m,
1260s, 1218s, 1196s, 1172s, 1156m, 1116s, 1074m,
1058vs, 1024m, 990m, 962m, 927w, 902m, 859m, 811w,
1
778s, 709vs, 632m. H NMR: 7.39±7.19 (m, NH, 5 arom.
In summary, all ring closures of pentapeptides 13 containing
a b-hydroxy acid and four a,a-disubstituted a-amino acids
via `direct amide cyclization' gave the corresponding cyclic
monomer 4/14, but the yields vary considerably ranging
from 9 to 60%. We believe that the explanation for this
result shall be found in the difference of the conformation
and/or solubility of the linear precursors and the intermedi-
ates of the cyclization.
H); 4.96 (t, Jˆ5.1 Hz, OH); 3.26 (d, Jˆ5.0 Hz, CH2OH);
3.19 (s, MeN); 1.36, 0.96 (2s, 2Me2C). 13C NMR: 175.5,
172.4 (2s, 2CO); 145.6 (s, 1 arom. C); 128.8, 127.2, 126.5
(3d, 5 arom. C); 67.6 (t, CH2OH); 56.2, 42.9 (2s, 2Me2C);
40.0 (q, MeN); 26.1, 22.1 (2q, 2Me2C). CI-MS: 293 (36,
[M1H]1), 186 (100, [M2Me(Ph)N]1).
4.2.2. (10RS,20RS,2RS)- and (10RS,20RS,2SR)-2-Benzyl-2-
{[trans-(2-hydroxycyclohexyl)carbonyl]amino}-N-methyl-
N-phenylpropanamide (7b/7c). According to GP 2, 5c
(0.693 g, 4.81 mmol) in MeCN (10 ml), 6e (1.31 g,
5.22 mmol) in MeCN (2 ml), stirred for 40 h, CC (SiO2,
CH2Cl2/MeOH 25:1): 1.33 g (73%) of 7b/7c (ca. 1:1
mixture of diastereoisomers). White powder. Mp 143.6±
171.28C. IR: 3854w, 3545m, 3430m, 3301s, 3060m,
2931s, 2858m, 2362w, 1646vs, 1593s, 1539s, 1494vs,
1452s, 1390s, 1370s, 1310m, 1258m, 1238m, 1220m,
1105m, 1068s, 1007w, 930w, 868w, 765m, 703vs, 655m,
565w. 1H NMR: 7.98 (s, NH); 7.83 (s, NH); 7.37±7.11 (m,
2£10 arom. H); 4.76 (d, Jˆ4.4 Hz, OH); 4.60 (d, Jˆ4.5 Hz,
OH); 3.57 (m, 2CHOH); 3.23 (s, 2MeN); 3.23±3.22 (m, 2H
of 2PhCH2); 3.10±3.00 (m, 2H of 2PhCH2); 2.06±2.04 (m,
2CH); 1.83±1.11 (m, 2£4CH2); 1.28, 1.21 (2s,
2PhCH2(Me)C). 13C NMR: 173.4, 173.3, 171.9 (3s,
2£2CO); 146.2 (s, 2 arom. C); 137.1, 137.0 (2s, 2 arom.
C); 131.2, 131.0, 128.6, 127.6, 127.2, 127.0, 126.2, 126.1
4. Experimental
4.1. General
See Ref. 44. Unless otherwise stated, IR spectra in KBr and
NMR spectra in (d6)DMSO (1H: 300 MHz and 13C:
75.5 MHz). CI-MS with NH3. The following 3-amino-2H-
azirines were used: 2,2,N,N-tetramethyl-2H-azirin-3-amine
(6a), 2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine (6b), N,N-
dimethyl-1-azaspiro[2.4]hept-1-en-2-amine (6c), 2-benzyl-
2,N,N-trimethyl-2H-azirin-3-amine (6d) and 2-benzyl-2,N-
dimethyl-N-phenyl-2H-azirin-3-amine (6e) (cf. Ref. 26 and
references cited therein).
General procedure 1 (GP 1). Reaction of 6 with acids 5, 8,
10 and 12. To a stirred suspension of the acid in dry MeCN

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2319
(8d, 2£10 arom. C); 69.4 (d, 2CHOH); 58.8 (s,
2PhCH2(Me)C); 51.7, 51.5 (2d, 2CH); 41.5 (t, 2PhCH2);
39.7, 39.5 (2q, 2MeN); 35.1, 28.7, 24.7, 24.1 (4t,
2£4CH2); 22.4, 22.2 (2q, 2PhCH2(Me)C). CI-MS: 395
(28, [M1H]1), 288 (100, [M2Me(Ph)N]1).
3CO); 145.7 (s, 1 arom. C); 128.6, 127.0, 126.2 (3d, 5 arom.
C); 68.5 (t, CH2OH); 56.3, 56.0, 43.4 (3s, 3Me2C); 39.5 (q,
MeN); 25.5, 24.8, 22.1 (3q, 3Me2C). ESI-MS: 400 (100,
[M1Na]1), 271 (62, [M2Me(Ph)N]1).
4.4.2. (10 0RS,20 0RS,20RS)- and (100RS,200RS,20SR)-2-[(2-
Benzyl-2-{[trans-(2-hydroxycyclohexyl)carbonyl]amino}-
1-oxopropyl)amino]-2,N-dimethyl-N-phenylpropanamide
(9b/9c). According to GP 1, 8b/8c (0.433 g, 1.48 mmol) in
MeCN (5 ml), 6b (0.290 g, 1.66 mmol) in MeCN (1 ml),
stirred for 20 h: 0.627 g (88%) of 9b/9c (ca. 1:1 mixture
of diastereoisomers). White powder. The diastereoisomers
were separated by means of MPLC. Conditions: stationary
phase: SiO2, mobile phase: 48 ml/min, CH2Cl2/MeOH 20:1;
UV detector, 254 nm.
4.3. Hydrolysis of dipeptide amides 7
4.3.1. 2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)amino]-
2-methylpropanoic acid (8a). According to GP 4, 7a
(2.25 g, 7.68 mmol), 40 ml of 3N HCl (H2O/THF 1:1),
stirred for 23 h, 50 ml of brine, 4£50 ml of AcOEt:
0.569 g (36%) of 8a. White powder. Mp 142.8±144.08C.
IR: 3852m, 3403vs, 3339vs, 2977vs, 2626m, 1715vs,
1620vs, 1539vs, 1468s, 1457s, 1404vs, 1365s, 1279s,
1254vs, 1234s, 1179vs, 1048vs, 1019s, 980m, 942m,
1
916m, 896s, 873s, 767s, 628s. H NMR:§k 7.52 (s, NH);
Data of 9b (RS,RS,SR isomer). White powder. Mp 177.3±
175.58C. IR: 3333vs, 3028m, 2987m, 2934vs, 2859m,
1636vs, 1592s, 1523vs, 1493vs, 1454vs, 1392s, 1364s,
1276m, 1259m, 1242m, 1212s, 1132m, 1094s, 1071s,
1014m, 932m, 851w, 773m, 745w, 710vs, 614m. 1H
NMR: 7.67, 7.49 (2s, 2NH); 7.40±7.18 (m, 10 arom. H);
4.88 (d, Jˆ5.1 Hz, OH); 3.63±3.57 (m, CHOH); 3.44, 3.00
(AB, Jˆ13.4 Hz, PhCH2); 3.27 (s, MeN); 2.13±2.04 (m,
CH); 1.91±1.07 (m, 4CH2); 1.36, 1.35, 1.19 (3s, Me2C,
PhCH2(Me)C). 13C NMR: 174.1, 173.2, 172.5 (3s, 3CO);
145.8, 137.1 (2s, 2 arom. C); 130.9, 128.7, 127.5, 127.1,
126.2, 126.0 (6d, 10 arom. C); 70.2 (d, CHOH); 59.3, 56.5
(2s, Me2C, PhCH2(Me)C); 52.9 (d, CH); 39.5 (q, MeN);
39.3, 35.1, 27.9, 24.6, 24.2 (5t, 4CH2, PhCH2); 25.6, 25.5,
23.1 (3q, Me2C, PhCH2(Me)C).
3.36 (s, CH2OH); 1.35, 1.00 (2s, 2Me2C). 13C NMR:
175.7 (s, 2CO); 67.7 (t, CH2OH); 54.7, 42.7 (2s, 2Me2C);
24.7, 22.2 (2q, 2Me2C). ESI-MS: 204 (100, [M1H]1).
4.3.2. (10RS,20RS,2RS)- and (10RS,20RS,2SR)-2-Benzyl-2-
{[trans-(2-hydroxycyclohexyl)carbonyl]amino}propanoic
acid (8b/8c). According to GP 3, 7b/7c (0.700 g,
1.77 mmol), 10 ml of 3N HCl (H2O/THF 1:1), stirred for
24 h, H2O (5 ml): 0.485 g (90%) of 8b/8c (ca. 1:1 mixture of
diastereoisomers). White powder. Mp 191.3±193.08C. IR:
3459s, 3261s, 3064s, 2937vs, 2861s, 1737vs, 1643vs,
1624vs, 1552vs, 1496m, 1450s, 1396s, 1320m, 1269s,
1249s, 1223s, 1122s, 1079m, 1062m, 1006w, 950w,
1
927w, 858w, 815w, 769w, 737w, 703s, 660m. H NMR§k:
7.70 (s, NH); 7.60 (s, NH); 7.28±7.12 (m, 2£10 arom. H);
3.59±3.42 (m, 2CHOH); 3.35 (d, Jˆ13.2 Hz, 1H of PhCH2);
3.23 (d, Jˆ13.1 Hz, 1H of PhCH2); 3.08 (d, Jˆ13.1 Hz, 1H
of PhCH2); 3.04 (d, Jˆ13.2 Hz, 1H of PhCH2); 2.07±2.00
(m, 2CH); 1.86±1.62 (m, 4CH2); 1.38±1.07 (m, 4CH2);
1.28, 1.19 (2s, 2PhCH2(Me)C). 13C NMR: 175.3, 175.0,
173.7, 173.7 (4s, 2£2CO); 137.0, 136.7 (2s, 2 arom. C);
130.7, 130.4, 127.6, 127.5, 126.3, 126.1 (6d, 2£5 arom.
C); 69.8, 69.5 (2d, 2CHOH); 58.7, 58.3 (2s,
2PhCH2(Me)C); 51.7 (d, 2CH); 40.6, 39.6, 35.1, 34.7,
28.4, 28.2, 24.6, 24.2, 24.1 (9t, 2£5CH2); 22.6, 22.4 (2q,
2PhCH2(Me)C). CI-MS: 306 (100, [M1H]1), 288 (13,
[M2OH]1), 260 (36, [M2COOH]1).
Data of 9c (RS,RS,RS isomer). White powder. Mp 179.4±
181.48C. IR: 3378s, 3029m, 2986m, 2937s, 2853m, 1681vs,
1619vs, 1592s, 1494vs, 1452s, 1394s, 1365s, 1267m, 1216s,
1094s, 1070s, 1017w, 951w, 924w, 870w, 752m, 709vs,
1
618m. H NMR: 7.72 (s, NH); 7.44±7.07 (m, 1NH, 10
arom. H); 4.98 (d, Jˆ4.1 Hz, OH); 3.71, 2.97 (AB,
Jˆ13.3 Hz, PhCH2); 3.56±3.43 (m, CHOH); 3.29 (s,
MeN); 2.13±2.02 (m, CH); 2.00±1.12 (m, 4CH2); 1.38,
1.36, 1.12 (3s, Me2C, PhCH2(Me)C). 13C NMR: 174.2,
173.7, 172.4 (3s, 3CO); 146.1, 137.4 (2s, 2 arom. C);
130.7, 128.6, 127.6, 126.9, 126.1, 125.9 (6d, 10 arom. C);
71.7 (d, CHOH); 59.1, 56.4 (2s, Me2C, PhCH2(Me)C); 51.8
(d, CH); 39.3 (q, MeN); 37.5, 34.8, 27.2, 24.3, 24.0 (5t,
4CH2, PhCH2); 25.7, 25.6, 24.1 (3q, Me2C, PhCH2(Me)C).
ESI-MS: 480 (14, [M1H]1), 373 (100, [M2Me(Ph)N]1).
4.4. Reaction of 2H-azirin-3-amines 6 with dipeptides 8
4.4.1. 2-({2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)amino]-
2-methyl-1-oxo-propyl}amino)-2,N-dimethyl-N-phenyl-
propanamide (9a). According to GP 1, 8a (0.503 g,
2.48 mmol) in MeCN (5 ml), 6b (0.580 g, 3.33 mmol) in
MeCN (1 ml), stirred for 19 h: 0.840 g (90%) of 9a. White
powder. Mp 152.1±153.58C. IR: 3417vs, 3325vs, 2987s,
2960s, 2934s, 2871m, 2361w, 1668vs, 1645vs, 1595s,
1522vs, 1495vs, 1465s, 1393vs, 1362vs, 1307m, 1281m,
1250s, 1220s, 1171s, 1091vs, 1068m, 1050vs, 964w,
4.5. Hydrolysis of tripeptide amides 9
4.5.1. 2-({2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)amino]-
2-methyl-1-oxo-propyl}amino)-2-methylpropanoic acid
(10a). According to GP 4, 9a (0.765 g, 2.03 mmol), 10 ml
of 3N HCl (H2O/THF 1:1), stirred for 23 h, 25 ml of brine,
5£25 ml of AcOEt: 0.311 g of crude 10a. The material was
used for the next reaction step without further puri®cation.
1
930w, 900w, 855w, 770m, 743w, 706vs, 662m, 616m. H
4.5.2. (100RS,200RS,20SR)- and (100RS,200RS,20RS)-2-[(2-
Benzyl-2-{[trans-(2-hydroxycyclohexyl)carbonyl]amino}-
1-oxopropyl)amino]-2-methylpropanoic acid (10b and
10c, respectively). Data of 10b. According to GP 4, 9b
(0.178 g, 0.371 mmol), 2 ml of 3N HCl (H2O/THF 1:1),
stirred for 23 h, 5 ml of brine, 5£5 ml of AcOEt: 0.128 g
NMR: 7.50, 7.44 (2s, 2NH); 7.38±7.19 (m, 5 arom. H); 5.23
(m, OH); 3.43 (d, Jˆ4.4 Hz, CH2OH); 3.23 (s, MeN); 1.36,
1.34, 1.04 (3s, 3Me2C). 13C NMR: 175.3, 173.6, 172.3 (3s,
§
The signal for the COOH group could not be determined.
The signal for the OH group could not be determined.
k

2320
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
(88%) of 10b. White powder. Mp 181.2±181.48C. IR:
3416vs, 3311vs, 2984s, 2935vs, 2859s, 2551m, 1699s,
1656vs, 1522vs, 1456s, 1388s, 1302s, 1240s, 1220s,
1178s, 1129m, 1051s, 1004m, 857w, 793w, 744w, 703s,
631w. 1H NMR (CD3OD, 300 MHz): 7.25±7.19 (m, 5
arom. H); 3.68±3.65 (m, CHOH); 3.35, 3.12 (AB, Jˆ
13.6 Hz, PhCH2); 2.16±2.06 (m, CH); 2.02±1.65, 1.51±
1.14 (2m, 4CH2); 1.49, 1.46, 1.37 (3s, Me2C, PhCH2(Me)C).
13C NMR (CD3OD, 75.5 MHz): 178.0, 177.2, 175.4 (3s,
3CO); 137.6 (s, 1 arom. C); 132.1, 129.0, 127.7 (3d, 5 arom.
C); 72.3 (d, CHOH); 61.4, 57.3 (2s, Me2C, PhCH2(Me)C);
54.7 (d, CH); 42.3, 36.1, 29.6, 26.0, 25.6 (5t, 4CH2,
PhCH2(Me)C); 25.1, 25.0, 23.4 (3q, Me2C, PhCH2(Me)C).
ESI-MS: 413 (26, [M1Na]1), 391 (100, [M1H]1).
0.540 g (48% with respect to 9a). Oil. IR (Film): 3306s,
2985s, 2937s, 1652vs, 1594s, 1531vs, 1391s, 1362s,
1
1226s, 1170s, 1092s, 1027vs, 823m, 765s, 709s. H NMR:
7.79, 7.51 (2s, 2NH); 7.37±7.18 (m, 1NH, 5 arom. H); 5.33
(t, Jˆ4.5 Hz, OH); 3.51 (d, Jˆ4.2 Hz, CH2OH); 3.29 (s,
MeN); 1.44, 1.34, 1.32, 1.09 (4s, 4Me2C). 13C NMR:
177.2, 174.0, 173.3, 172.8 (4s, 4CO); 146.3 (s, 1 arom.
C); 128.6, 126.9, 125.9 (3d, 5 arom. C); 68.9 (t, CH2OH);
56.2, 56.0, 43.7 (3s, 4Me2C); 39.2 (q, MeN); 25.5, 25.2,
24.9, 22.0 (4q, 4Me2C). ESI-MS: 485 (100, [M1Na]1).
4.6.3. (100 0RS,200 0RS,200SR)-2-({2-[(2-Benzyl-2-{[trans-(2-
hydroxycyclohexyl)carbonyl]amino}-1-oxopropyl)amino]-
2-methyl-1-oxopropyl}amino)-2,N,N-trimethylpropan-
amide (11c). According to GP 1, 10b (0.124 g, 0.318 mmol)
in MeCN (2 ml), 6a (0.041 g, 0.366 mmol) in MeCN (1 ml),
stirred for 18 h: 0.136 g (85%) of 11c. White powder. Mp
235.3±237.18C. IR: 3330vs, 3283vs, 2990m, 2938s, 2861m,
2362w, 1651vs, 1538vs, 1452s, 1392s, 1381s, 1364s,
1286m, 1260m, 1207s, 1170m, 1118s, 1073m, 1017w,
Data of 10c. According to GP 3, 9c (0.272 g, 0.567 mmol),
3 ml of 3N HCl (H2O/THF 1:1), stirred for 20 h, H2O (3 ml):
0.201 g (91%) of 10c. White powder. Mp 201.3±202.38C.
IR: 3854w, 3821w, 3751w, 3736w, 3712w, 3690w, 3676w,
3635s, 3423s, 3344vs, 3289vs, 3057m, 2944s, 2857s,
1717vs, 1653vs, 1544vs, 1496m, 1458s, 1387s, 1364m,
1328m, 1314m, 1294m, 1243s, 1224s, 1162s, 1060s,
1
951w, 924w, 871w, 743m, 703m. H NMR ((d5)pyridine,
300 MHz): 8.89, 8.16, 7.63 (3s, 3NH); 7.49±7.25 (m, 5
arom. H); 6.78 (brs, OH); 4.11 (m, CHOH); 3.64, 3.41
(AB, Jˆ13.4 Hz, PhCH2); 3.16 (brs, Me2N); 2.65±2.55
(m, CH); 2.23±1.10 (m, 4CH2); 1.93, 1.91, 1.72, 1.68,
1.65 (5s, 2Me2C, PhCH2(Me)C). 13C NMR ((d5)pyridine,
75.5 MHz): 176.8, 174.5, 173.5, 172.8 (4s, 4CO); 137.1
(s, 1 arom. C); 131.6, 128.4, 127.1 (3d, 5 arom. C); 72.3
(d, CHOH); 60.8, 57.4, 57.0 (3s, 2Me2C, PhCH2(Me)C);
54.4 (d, CH); 42.8, 35.9, 28.5, 25.2, 25.0 (5t, 4CH2,
PhCH2); 38.1 (q, Me2N); 26.6, 26.4, 26.2, 25.7, 23.2 (5q,
2Me2C, PhCH2(Me)C). ESI-MS: 525 (100, [M1Na]1), 458
(35, [M2Me2N]1), 373 (15, [M2NHC(CH3)2CONMe2]1).
1
1014w, 936m, 870w, 780m, 750m, 707s, 671m, 610m. H
NMR:§k 7.70, 7.39 (2s, 2NH); 7.27±7.05 (m, 5 arom. H);
3.57, 2.94 (AB, Jˆ13.3 Hz, PhCH2); 3.52±3.45 (m,
CHOH); 2.09±2.02 (m, CH); 1.93±1.12 (m, 4CH2); 1.33,
1.28, 1.12 (3s, Me2C, PhCH2(Me)C). 13C NMR: 175.4,
174.1, 173.1 (3s, 3CO); 137.4 (s, 1 arom. C); 130.6,
127.6, 126.0 (3d, 5 arom. C); 71.4 (d, CHOH); 58.8, 54.8
(2s, Me2C, PhCH2(Me)C); 51.8 (d, CH); 37.8, 34.9, 27.3,
24.3, 24.1 (5t, 4CH2, PhCH2); 25.4, 23.8 (2q, Me2C,
PhCH2(Me)C). ESI-MS: 413 (100, [M1Na]1), 391 (56,
[M1H]1).
4.6.4. (100 0RS,200 0RS,200RS)-2-({2-[(2-Benzyl-2-{[trans-(2-
hydroxycyclohexyl)carbonyl]amino}-1-oxopropyl)amino]-
2-methyl-1-oxopropyl}amino)-2,N-dimethyl-N-phenyl-
propanamide (11d). According to GP 1, 10c (0.173 g,
0.443 mmol) in MeCN (3 ml), 6b (0.084 g, 0.482 mmol)
in MeCN (1 ml), stirred for 44 h: 0.229 g (92%) of 11d.
White powder. Mp 2118C (dec.). IR: 3635w, 3415m,
3274s, 3062w, 2985m, 2938s, 2861m, 2360w, 1716m,
1672vs, 1639vs, 1595m, 1542vs, 1495s, 1455s, 1394s,
1364m, 1265m, 1221m, 1199m, 1131w, 1093m, 1070m,
4.6. Reaction of 2H-azirin-3-amines 6 with tripeptides 10
4.6.1. 2-Benzyl-2-{[2-({2-[(3-hydroxy-2,2-dimethyl-1-oxo-
propyl)amino]-2-methyl-1-oxopropyl}amino)-2-methyl-1-
oxopropyl]amino}-N,N-dimethylpropanamide
(11a).
According to GP 2, crude 10a (0.272 g) in MeCN (5 ml),
6d (0.288 g, 1.36 mmol) in MeCN (1 ml), stirred for 23 h,
CC (SiO2, CH2Cl2/MeOH 25:1, CH2Cl2/MeOH 10:1):
0.297 g (35% with respect to 9a). Foam. IR: 3310s,
2985m, 2936m, 2362w, 1652vs, 1528vs, 1457s, 1383s,
1362m, 1229m, 1189m, 1091m, 1054m, 977w, 915w,
767w, 736w, 704m, 658m. 1H NMR ((d5)pyridine,
600 MHz): 8.25, 8.08, 7.69 (3s, 3NH); 7.44±7.23 (m, 5
arom. H); 3.88±3.80 (m, CH2OH, PhCH2); 3.39, 3.01
(2brs, Me2N); 1.88, 1.772, 1.770, 1.68, 1.65, 1.36, 1.31
(7s, 3Me2C, PhCH2(Me)C). 13C NMR ((d5)pyridine,
151 MHz): 178.7, 174.9, 174.5, 172.3 (4s, 4CO); 138.4 (s,
1 arom. C); 132.1, 128.7, 127.3 (3d, 5 arom. C); 70.5 (t,
CH2OH); 61.3, 58.0, 57.9, 44.9 (4s, 3Me2C, PhCH2(Me)C);
44.0 (t, PhCH2); 38.8 (q, Me2N); 26.8, 26.4, 26.3, 25.9, 24.4,
22.92, 22.91 (7q, 3Me2C, PhCH2(Me)C). ESI-MS: 499 (100,
[M1Na]1), 432 (45, [M2Me2N]1).
1
1013w, 933w, 871w, 753w, 707s. H NMR: 8.17 (s, NH);
7.49±7.05 (m, 2NH, 10 arom. H); 4.91 (d, Jˆ4.0 Hz, OH);
3.54±3.43 (m, CHOH, 1H of PhCH2); 2.94 (d, Jˆ13.3 Hz,
1H of PhCH2); 2.17±1.12 (m, CH, 4CH2); 1.47, 1.45, 1.43,
1.28, 1.14 (5s, 2Me2C, PhCH2(Me)C). 13C NMR: 175.5,
173.7, 173.1, 172.7 (4s, 4CO); 146.2, 137.2 (2s, 2 arom.
C); 130.7, 128.5, 127.7, 126.8, 126.2, 125.8 (6d, 10 arom.
C); 71.6 (d, CHOH); 58.8, 56.1 (2s, 2Me2C, PhCH2(Me)C);
51.7 (d, CH); 39.2 (q, MeN); 38.0, 34.8, 27.3, 24.3, 24.1 (5t,
4CH2, PhCH2); 27.2, 25.5, 23.4, 23.2 (4q, 2Me2C,
PhCH2(Me)C). ESI-MS: 587 (34, [M1Na]1), 458 (100,
[M2Me(Ph)N]1), 373 (78, [M2NHC(CH3)2CON(Me)Ph]1).
4.6.2. 2-{[2-({2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)
amino]-2-methyl-1-oxo-propyl}amino)-2-methyl-1-
oxopropyl]amino}-2,N-dimethyl-N-phenylpropanamide
(11b). According to GP 2, crude 10a (0.580 g) in MeCN
(5 ml), 6b (0.366 g, 2.10 mmol) in MeCN (1 ml), stirred for
78 h, CC (SiO2, CH2Cl2/MeOH 25:1, CH2Cl2/MeOH 10:1):
4.7. Hydrolysis of tetrapeptide amides 11
4.7.1. 2-Benzyl-2-{[2-({2-[(3-hydroxy-2,2-dimethyl-1-
oxopropyl)amino]-2-methyl-1-oxopropyl}amino)-2-methyl-
1-oxopropyl]amino}propanoic acid (12a). According to

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2321
GP 4, 11a (0.285 g, 0.598 mmol), 3 ml of 3N HCl (H2O/
THF 1:1), stirred for 18 h, 5 ml of brine, 5£15 ml of AcOEt:
0.224 g (83%) of 12a. White powder. Mp 186.0±187.78C.
IR: 3302s, 2985s, 2362w, 1741vs, 1651vs, 1526vs, 1456s,
1385s, 1364s, 1299s, 1227s, 1116m, 1053m, 912w, 744m,
703m. 1H NMR:§ 7.65, 7.34, 7.31 (3s, 3NH); 7.26±7.14 (m,
5 arom. H); 5.26 (m, OH); 3.52±3.21 (m, CH2OH); 3.26,
3.12 (AB, Jˆ13.4 Hz, PhCH2); 1.33, 1.27, 1.23, 1.01, 0.99
(5s, 3Me2C, PhCH2(Me)C). 13C NMR: 176.5, 174.7, 173.6,
173.5 (4s, 4CO); 136.6 (s, 1 arom. C); 130.4, 127.6, 126.2
(3d, 5 arom. C); 68.5 (t, CH2OH); 58.8, 56.0, 55.8, 43.4 (4s,
3Me2C, PhCH2(Me)C); 40.9 (t, PhCH2); 25.1, 24.9, 24.7,
24.6, 21.9 (5q, 3Me2C, PhCH2(Me)C). ESI-MS: 472 (100,
[M1Na]1), 450 (78, [M1H]1).
White powder. Mp 252.7±254.98C. IR: 3295vs, 2984m,
2935m, 2362w, 1646vs, 1533vs, 1456s, 1383s, 1363s,
1282m, 1243m, 1215m, 1173m, 1117m, 1052m, 985w,
1
742w, 712m, 668w, 603w. H NMR: 7.76, 7.64, 7.62 (3s,
3NH); 7.23±7.04 (m, 1NH, 5 arom. H); 5.21 (t, Jˆ4.5 Hz,
OH); 3.58, 2.94 (AB, Jˆ13.5 Hz, PhCH2); 3.47±3.42, 3.20±
3.15 (2m, CH2OH); 2.88 (brs, Me2N); 1.40, 1.39, 1.35,
1.333, 1.326, 1.23, 1.22, 0.91, 0.80 (9s, 4Me2C,
PhCH2(Me)C). 13C NMR: 177.0, 175.1, 173.5, 173.1,
172.0 (5s, 5CO); 137.3 (s, 1 arom. C); 130.6, 127.3, 125.9
(3d, 5 arom. C); 68.3 (t, CH2OH); 59.1, 56.0, 55.9, 55.6,
43.2 (5s, 4Me2C, PhCH2(Me)C); 37.9 (t, PhCH2); 37.1 (q,
Me2N); 26.5, 25.7, 25.6, 25.4, 24.1, 23.2, 23.1, 21.6, 21.5
(9q, 4Me2C, PhCH2(Me)C). ESI-MS: 584 (46, [M1Na]1),
517 (100, [M2Me2N]1).
4.7.2. 2-{[2-({2-[(3-Hydroxy-2,2-dimethyl-1-oxopropyl)
amino]-2-methyl-1-oxopropyl}amino)-2-methyl-1-oxopro-
pyl]amino}-2-methylpropanoic acid (12b). According to
GP 4, 11b (0.188 g, 0.406 mmol), 4 ml of 3N HCl (H2O/
Et2O 1:1), stirred for 19 h, 5 ml of brine, 5£15 ml of AcOEt:
0.082 g of crude 12b. The material was used for the next
reaction step without further puri®cation.
4.8.2. 2-Benzyl-2-[(2-{[2-({2-[(3-hydroxy-2,2-dimethyl-1-
oxopropyl)amino]-2-methyl-1-oxopropyl}amino)-2-methyl-
1-oxopropyl]amino}-2-methyl-1-oxopropyl)amino]-N,N-
dimethylpropanamide (13b). According to GP 2, crude
12b (0.075 g) in MeCN (3 ml), 6d (0.065 g, 0.285 mmol)
in MeCN (1 ml), stirred for 92 h, CC (SiO2, CH2Cl2/MeOH
20:1, CH2Cl2/MeOH 10:1): 0.093 g (46% with respect to
11b). White powder. Mp 205.6±209.28C. IR: 3289vs,
2983m, 2934m, 1644vs, 1533vs, 1457s, 1383s, 1362s,
1269m, 1229s, 1188m, 1166m, 1091m, 1064m, 976w,
4.7.3. (100 0RS,200 0RS,200SR)- and (100 0RS,200 0RS,200RS)-2-
({2-[(2-Benzyl-2-{[trans-(2-hydroxycyclohexyl)carbonyl]-
amino}-1-oxopropyl)amino]-2-methyl-1-oxopropyl}-
amino)-2-methylpropanoic acid (12d and e, respec-
tively). Data of 12d. According to GP 4, 11c (0.127 g,
0.253 mmol), 2 ml of 3N HCl (H2O/THF 1:1), stirred for
22 h, 1 ml of brine, 5£5 ml of AcOEt: 0.112 g (93%) of 12d.
White powder. Mp 193.98C (dec.). IR: 3332vs, 2986s,
2936s, 2858m, 1721s, 1652vs, 1533vs, 1455s, 1384s,
1363m, 1305m, 1259m, 1220s, 1168s, 1059m, 1013w,
941w, 743w, 701m, 614m. 1H NMR ((d5)pyridine,
300 MHz): 8.79, 8.25, 7.85 (3s, 3NH); 7.60±7.30 (m, 5
arom. H); 4.18 (m, CHOH); 3.75, 3.46 (AB, Jˆ13.2 Hz,
PhCH2); 2.58 (m, CH); 2.16±1.11 (m, 4CH2); 2.05, 2.04,
1.79, 1.79, 1.68 (5s, 2Me2C, PhCH2(Me)C). 13C NMR
((d5)pyridine, 75.5 MHz): 177.7, 176.7, 174.8, 173.3 (4s,
4CO); 137.3 (s, 1 arom. C); 131.7, 128.4, 127.0 (3d, 5
arom. C); 72.0 (d, CHOH); 60.8, 57.3, 56.6 (3s, 2Me2C,
PhCH2(Me)C); 54.4 (d, CH); 42.5 (t, PhCH2); 35.9, 28.6,
25.3, 25.0 (4t, 4CH2); 25.9, 25.8, 23.4 (3q, 2Me2C,
PhCH2(Me)C). ESI-MS: 498 (27, [M1Na]1), 476 (100,
[M1H]1).
1
924w, 824w, 767w, 737w, 703m, 658w. H NMR: 7.83,
7.65, 7.49, 7.34 (4s, 4NH); 7.21±7.07 (m, 5 arom. H);
5.29 (t, Jˆ4.6 Hz, OH); 3.50 (d, Jˆ4.5 Hz, CH2OH);
3.26, 3.14 (AB, Jˆ13.7 Hz, PhCH2); 3.07, 2.80 (2brs,
Me2N); 1.45, 1.40, 1.34, 1.27, 1.25, 1.23, 1.08 (7s,
4Me2C, PhCH2(Me)C). 13C NMR: 177.1, 175.0, 173.4,
173.3, 170.3 (5s, 5CO); 136.6 (s, 1 arom. C); 130.6,
127.6, 126.1 (3d, 5 arom. C); 68.6 (t, CH2OH); 59.3, 56.3,
55.9, 43.5 (4s, 4Me2C, PhCH2(Me)C); 42.2 (t, PhCH2); 37.5
(q, Me2N); 25.6, 25.3, 24.9, 24.6, 24.5, 24.3, 22.7, 21.9 (8q,
4Me2C, PhCH2(Me)C). ESI-MS: 584 (100, [M1Na]1).
4.8.3.
(R)-1-(2-{[2-({2-[(3-Hydroxy-1-oxo-2-phenyl-
propyl)amino]-2-methyl-1-oxopropyl}amino)-2-methyl-
1-oxopropyl]amino}-2-methyl-1-oxopropyl)-amino-N,N-
dimethylcyclopentanecarboxamide (13c). According to
GP 2, (R)-Tro±Aib±Aib±Aib±OH (12c)¶ (0.151 g,
0.358 mmol) in MeCN (3 ml), 6c (0.079 g, 0.572 mmol)
in MeCN (1 ml), stirred for 19 h, CC (SiO2, CH2Cl2/
MeOH 20:1, CH2Cl2/MeOH 10:1) and crystallization from
AcOEt: 0.175 g (87%) of 13c. White powder. Mp 245.68C
(dec.). [a]Dˆ125.0 (cˆ1.0, EtOH). IR: 3312vs, 2942s,
2874m, 1652vs, 1527vs, 1456s, 1384s, 1362s, 1272m,
1230s, 1169m, 1056m, 1012m, 923w, 743w, 701m, 668m.
1H NMR: 8.75, 7.48, 7.40 (3s, 3NH); 7.37±7.22 (m, 1NH, 5
arom. H); 5.11 (t, Jˆ4.3 Hz, OH); 3.98±3.90, 3.81±3.76,
3.67±3.61 (3m, CH2OH, CH); 2.98, 2.75 (2brs, Me2N);
2.07±2.06, 1.68±1.64, 1.57±1.49 (3m, (CH2)4); 1.38, 1.37,
1.36, 1.31, 1.24, 1.13 (6s, 3Me2C). 13C NMR: 174.8, 173.2,
172.9, 171.9 (4s, 5CO); 137.1 (s, 1 arom. C); 128.2, 127.9,
126.9 (3d, 5 arom. C); 65.5, 55.9, 55.8 (3s, 3Me2C,
(CH2)4C); 63.8 (t, CH2OH); 53.5 (d, CH); 37.3, 36.6 (2q,
Me2N); 35.8, 24.0 (2t, (CH2)4); 25.9, 25.13, 25.06, 24.5,
23.8, 23.6 (6q, 3Me2C). ESI-MS: 582 (100, [M1Na]1).
Data of 12e. According to GP 3, 11d (0.200 g, 0.354 mmol),
4 ml of 3N HCl (H2O/THF 1:1), stirred for 19 h, H2O (2 ml):
0.155 g of crude 12e. The material was used for the next
reaction step without further puri®cation.
4.8. Reaction of 2H-azirin-3-amines 6 with tetrapeptides
12
4.8.1. 2-[(2-Benzyl-2-{[2-({2-[(3-hydroxy-2,2-dimethyl-1-
oxopropyl)amino]-2-methyl-1-oxopropyl}amino)-2-methyl-
1-oxopropyl]amino}-1-oxopropyl)amino]-2,N,N-trimethyl-
propanamide (13a). According to GP 1, 12a (0.178 g,
0.396 mmol) in MeCN (3 ml), 6a (0.060 g, 0.535 mmol)
in MeCN (1 ml), stirred for 21 h, CC (SiO2, CH2Cl2/
MeOH 25:1, CH2Cl2/MeOH 10:1): 0.171 g (77%) of 13a.
¶
The tetrapeptide 12c was prepared as previously described25 starting with
(R)-5b.45

2322
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
4.8.4. (R,S)- and (R,R)-2-Benzyl-2-[(2-{[2-({2-[(3-hydroxy-
1-oxo-2-phenylpropyl)amino]-2-methyl-1-oxopropyl}
amino)-2-methyl-1-oxopropyl]amino}-2-methyl-1-oxopro-
pyl)amino]-N,N-dimethylpropanamide (13d/13e). Accord-
ing to GP 2, (R)-Tro±Aib±Aib±Aib±OH (12c)¶ (0.151 g,
0.358 mmol) in MeCN (3 ml), 6d (0.100 g, 0.473 mmol) in
MeCN (1 ml), stirred for 18 h, CC (SiO2, CH2Cl2/MeOH
25:1, CH2Cl2/MeOH 10:1) and crystallization from MeCN/
AcOEt: 0.178 g (82%) of 13d/13e. The diastereoisomers were
separated by means of HPLC. Conditions: stationary phase:
SPHERISORB ODS2 5.0 mm, column: 250£20 mm, mobile
phase: 5 ml/min, MeOH/H2O 2:1, 43 kg/cm2; UV detector,
254 nm.
(2brs, Me2N); 2.72±2.61 (m, CH); 2.24±1.06 (m, 4CH2);
1.91, 1.89, 1.86, 1.67, 1.653, 1.649 (6s, 3Me2C,
PhCH2(Me)C). 13C NMR ((d5)pyridine, 75.5 MHz): 177.0,
175.1, 175.1, 174.4, 173.8 (5s, 5CO); 137.0 (s, 1 arom. C);
131.7, 128.4, 127.1 (3d, 5 arom. C); 72.2 (d, CHOH); 60.4,
57.5, 57.4, 56.9 (4s, 3Me2C, PhCH2(Me)C); 54.3 (d, CH);
42.1 (t, PhCH2); 38.0 (q, Me2N); 35.8, 28.5, 25.2, 25.0 (4t,
4CH2); 26.42, 26.36, 25.9, 25.6, 23.0 (5q, 3Me2C,
PhCH2(Me)C). ESI-MS: 610 (100, [M1Na]1).
Data of 13g. According to GP 2, crude 12e (0.120 g) in
MeCN (4 ml), 6a (0.031 g, 0.276 mmol) in MeCN (1 ml),
stirred for 20 h, CC (SiO2, CH2Cl2/MeOH 15:1): 0.125 g of
crude 13g. 0.097 g of the crude 13g was puri®ed by means
of preparative HPLC. Conditions: stationary phase: SPER-
ISORB ODS2 5.0 mm, column: 250£20 mm, mobile phase:
20 ml/min, H2O/MeOH 1:2; UV detector, 254 nm: Total
yield of 13g: 0.068 g (42% with respect to 11d). White
powder. Mp 290.58C (dec.). IR: 3305vs, 2986m, 2936s,
2861m, 2362w, 1647vs, 1527vs, 1456s, 1383s, 1363m,
1284m, 1217s, 1170m, 1120m, 1072m, 1017w, 928w,
867w, 754w, 707m, 602w. 1H NMR ((d5)pyridine,
300 MHz): 9.37, 8.26, 8.09, 8.03 (4s, 4NH); 7.41±7.38
(m, 5 arom. H); 6.71 (s, OH); 4.12±4.08 (m, CHOH, 1H
of PhCH2); 3.46 (d, Jˆ13.3 Hz, 1H of PhCH2); 3.20 (brs,
Me2N); 2.49±2.43 (m, CH); 2.21±0.97 (m, 4CH2); 1.99,
1.94, 1.92, 1.89, 1.78, 1.59, 1.47 (7s, 3Me2C, PhCH2(Me)C).
13C NMR ((d5)pyridine, 75.5 MHz): 176.8, 176.1, 174.9,
174.3, 173.5 (5s, 5CO); 138.2 (s, 1 arom. C); 131.7,
128.5, 127.0 (3d, 5 arom. C); 72.8 (d, CHOH); 59.9, 57.5,
57.4, 57.0 (4s, 3Me2C, PhCH2(Me)C); 53.1 (d, CH); 40.0 (q,
Me2N); 39.0 (t, PhCH2); 35.9, 27.9, 25.0, 24.8 (4t, 4CH2);
28.7, 27.6, 26.6, 26.5, 24.0, 23.8, 23.4 (7q, 3Me2C,
PhCH2(Me)C). ESI-MS: 610 (100, [M1Na]1), 543 (16,
[M2Me2N]1). Anal. calcd for C31H49N5O6´H2O (605.75):
C 61.47, H 8.49, N 11.56; found: C 61.28, H 8.45, N 11.41.
Data of 13d. White powder. Mp 242.9±243.58C.
[a]Dˆ16.3 (cˆ1.0, EtOH). IR: 3399s, 3354s, 3308vs,
3029w, 2985m, 2938m, 1685vs, 1636vs, 1617vs, 1534vs,
1456s, 1382s, 1363m, 1278m, 1233s, 1180m, 1093m,
1
1056s, 1018m, 924w, 740w, 701s, 660m. H NMR: 8.77,
7.51 (2s, 2NH); 7.41±7.08 (m, 2NH, 10 arom. H); 5.15 (brs,
OH); 3.99±3.93, 3.82±3.77, 3.68±3.63 (m, CH2OH, CH);
3.29, 3.11 (AB, Jˆ13.6 Hz, PhCH2); 3.08, 2.82 (2brs,
Me2N); 1.47, 1.41, 1.30, 1.29, 1.26, 1.21, 1.15 (7s,
3Me2C, PhCH2(Me)C). 13C NMR: 174.6, 173.4, 173.1,
172.8, 170.3 (5s, 5CO); 137.2, 136.6 (2s, 2 arom. C);
130.6, 128.2, 127.9, 127.6, 126.9, 126.1 (6d, 10 arom. C);
63.8 (t, CH2OH); 59.4, 56.3, 55.9 (3s, 3Me2C,
PhCH2(Me)C); 53.5 (d, CH); 42.3 (t, PhCH2); 37.4 (q,
Me2N); 25.9, 25.1, 24.9, 24.0, 23.8, 22.8 (6q, 3Me2C,
PhCH2(Me)C). ESI-MS: 632 (41, [M1Na]1), 565 (100,
[M2Me2N]1).
Data of 13e. White powder. Mp 240.18C (dec.).
[a]Dˆ222.2 (cˆ0.5, EtOH). IR: 3370s, 3304vs, 3029m,
2983s, 2938m, 1691vs, 1638vs, 1532vs, 1454s, 1436s,
1382s, 1363s, 1269m, 1236s, 1178m, 1090m, 1055s,
1
1008m, 923w, 818w, 762w, 739m, 704s, 644m. H NMR:
8.73 (s, NH); 7.42±7.05 (m, 3NH, 10 arom. H); 5.13 (t,
Jˆ4.3 Hz, OH); 3.95±3.90, 3.82±3.77, 3.68±3.63 (3m,
CH2OH, CH); 3.22±3.17 (m, PhCH2); 3.07, 2.80 (2brs,
Me2N); 1.46, 1.42, 1.32, 1.25, 1.24, 1.19, 1.15 (7s,
3Me2C, PhCH2(Me)C). 13C NMR: 174.6, 173.4, 173.1,
172.7, 170.4 (5s, 5CO); 137.1, 136.6 (2s, 2 arom. C);
130.6, 128.2, 127.9, 127.6, 126.9, 126.0 (6d, 10 arom. C);
63.8 (t, CH2OH); 59.3, 56.2, 55.8 (3s, 3Me2C,
PhCH2(Me)C); 53.4 (d, CH); 42.1 (t, PhCH2); 37.4 (q,
Me2N); 26.3, 25.5, 25.3, 24.5, 23.6, 23.4, 22.7 (7q,
3Me2C, PhCH2(Me)C). ESI-MS: 632 (100, [M1Na]1).
4.9. Cyclization of pentapeptides 13 to cyclic depsi-
peptides 14
General procedure 5 (GP 5). A stirred suspension of 13 in
dry toluene (30 ml) was warmed to 1008C under N2. A
stream of dry HCl gas was slowly passed through the
suspension at 1008C for 7±15 min. The resulting solution
was then purged with N2 for 30 min to remove remaining
HCl, the toluene was evaporated, and 6 ml THF/Et2O 1:1
were added. After 30 min of stirring at rt, the suspension
was ®ltered, followed by evaporation of the solvent yielding
a solid crude product, which was puri®ed by CC.
4.8.5. (100 00RS,200 00RS,200 0SR)- and (100 00RS,200 00RS,200 0RS)-2-
{[2-({2-[(2-Benzyl-2-{[trans-(2-hydroxycyclohexyl)car-
bonyl]amino}-1-oxopropyl)amino]-2-methyl-1-oxopropyl}
amino)-2-methyl-1-oxopropyl]amino}-2,N,N-trimethyl-
propanamide (13f and 13g, respectively). Data of 13f.
According to GP 1, 12d (0.104 g, 0.219 mmol) in MeCN
(2 ml), 6a (0.030 g, 0.267 mmol) in MeCN (1 ml), stirred
for 42 h: 0.091 g (71%) of 13f. White powder. Mp 275.78C
(dec.). IR: 3308vs, 2986m, 2936s, 2858m, 1660vs, 1621vs,
1537vs, 1456s, 1383s, 1364s, 1304m, 1216s, 1170m,
1121m, 1074m, 967w, 947w, 867w, 826w, 742w, 704m,
4.9.1. 6-Benzyl-3,3,6,9,9,12,12,15,15-nonamethyl-1-oxa-
4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentone
(14a). According to GP 5, 13a (0.050 g, 0.089 mmol) in
toluene (30 ml), 10 min, CC (SiO2, CH2Cl2/MeOH 25:1)
and crystallization from Et2O: 0.009 g (20%) of 14a.pp
White powder. Mp 170.58C (dec.). IR: 3396s, 2984m,
2939m, 2362w, 1734s, 1662vs, 1522vs, 1456m, 1384m,
1365m, 1281s, 1159s, 1022w, 945w, 768w, 710m. 1H
NMR ((d5)pyridine, 600 MHz): 8.21 (s, NH, Aib(1)); 7.75
1
678m. H NMR ((d5)pyridine, 300 MHz): 9.06, 8.28, 8.12,
8.04 (4s, 4NH); 7.56±7.27 (m, 5 arom. H); 4.15 (m,
ppAs a second product, 0.011 g of a white powder was isolated, which was
identi®ed as the cyclodimer 15a (24%) by ESI-MS: 1055 (19, [M1Na]1),
539 (100, [M12Na]21).
CHOH); 3.72, 3.46 (AB, Jˆ13.4 Hz, PhCH2); 3.31, 3.01

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2323
(s, NH, Aib(3)); 7.63 (s, NH, Aib(2)); 7.52±7.51 (m, 2 arom.
H); 7.32±7.30 (m, 2 arom. H); 7.26±7.24 (m, 1 arom. H);
7.22 (s, NH, Phe(2Me)); 4.48, 4.30 (AB, Jˆ10.4 Hz,
CH2O); 4.13, 3.53 (AB, Jˆ13.5 Hz, PhCH2); 2.01 (s,
Me(a), Aib(3)); 2.01 (s, Me(b), Aib(3)); 1.84 (s,
PhCH2(Me)C); 1.59 (s, 2Me, Aib(1)); 1.56 (s, Me(a),
Aib(2)); 1.55 (s, Me(b), Aib(2)); 1.33 (s, Me(a), Dhp);
1.33 (s, Me(b), Dhp). 13C NMR ((d5)pyridine, 151 MHz):
176.1 (s, CO, Dhp); 175.8 (s, CO, Aib(1)); 174.7 (s, CO,
Aib(3)); 174.6 (s, CO, Phe(2Me)); 174.2 (s, CO, Aib(2));
138.3 (s, 1 arom. C); 131.7, 128.2, 126.8 (3d, 5 arom. C);
72.2 (t, CH2O); 61.5 (s, PheCH2(Me)C); 58.4 (s, Me2C,
Aib(3)); 57.8 (s, Me2C, Aib(2)); 56.9 (s, Me2C, Aib(1));
42.7 (s, Me2C, Dhp); 41.8 (t, PhCH2); 25.5 (q, Me(a),
Aib(2)); 25.4 (q, Me(a), Aib(1)); 25.4 (q, Me(a), Aib(3));
25.2 (q, Me(b), Aib(2)); 25.1 (q, Me(b), Aib(3)); 25.0 (q,
Me(b), Aib(1)); 23.0 (q, PhCH2(Me)C); 22.7 (q, 2Me, Dhp).
ESI-MS: 539 (100, [M1Na]1).
4.23 (m, CH); 2.90±2.87, 2.40±2.35, 1.90±1.67 (3m,
(CH2)4); 2.07 (s, Me(a), Aib(3)); 1.95 (s, Me(b), Aib(3));
1.80 (s, Me(a), Aib(2)); 1.79 (s, Me(a), Aib(1)); 1.58 (s,
Me(b), Aib(2)); 1.46 (s, Me(b), Aib(1)). 13C NMR ((d5)pyr-
idine, 151 MHz): 176.8 (s, CO, Aib(3)); 176.3 (s, CO,
Aib(1)); 174.3 (s, CO, Ac5c); 174.1 (s, CO, Aib(2)); 171.8
(s, CO, Tro); 136.4 (s, 1 arom. C); 129.2, 128.4, 128.1 (3d, 5
arom. C); 67.9 (s, (CH2)4C); 65.3 (t, CH2O); 58.8 (s, Me2C,
Aib(3)); 58.2 (s, Me2C, Aib(2)); 56.9 (s, Me2C, Aib(1));
51.4 (d, CH); 39.2, 35.0, 25.0, 24.46 (4t, (CH2)4); 28.6 (q,
Me(b), Aib(3)); 27.4 (q, Me(b), Aib(2)); 26.7 (q, Me(b),
Aib(1)); 24.48 (q, Me(a), Aib(3)); 23.3 (q, Me(a), Aib(2));
23.1 (q, Me(a), Aib(1)). ESI-MS: 537 (100, [M1Na]1).
Anal. calcd for C27H38N4O6 (514.61): C 63.02, H 7.44, N
10.89; found: C 62.98, H 7.61, N 10.88.
4.9.4. (3R,15R- and 3S,15R)-3-Benzyl-3,6,6,9,9,12,12-
heptamethyl-15-phenyl-1-oxa-4,7,10,13-tetraazacyclo-
hexadecane-2,5,8,11,14-pentone (14d/14e). Data of 14d
(isomer 1). According to GP 5, 13d (0.050 g, 0.082 mmol)
in toluene (30 ml), 15 min, CC (SiO2, CH2Cl2/MeOH 30:1)
4.9.2. 3-Benzyl-3,6,6,9,9,12,12,15,15-nonamethyl-1-oxa-
4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentone
(14b). According to GP 5, 13b (0.050 g, 0.089 mmol) in
toluene (30 ml), 11 min, CC (SiO2, CH2Cl2/MeOH 25:1):
0.004 g (9%) of 14b. Foam. IR: (CHCl3): 3454w, 3397w,
3010m, 2967w, 1738m, 1670vs, 1503s, 1457w, 1385m,
³³
and crystallization from Et2O: 0.027 g (58%) of 14d. Mp
235.28C (dec.). [a]Dˆ21.0 (cˆ0.5, EtOH). IR (KBr):
3343s, 2984m, 2938m, 1749s, 1661vs, 1521vs, 1456s,
1382m, 1364m, 1275s, 1230s, 1116m, 1043w, 741w,
1
1
1366m, 1262s, 1238m, 1199w, 1169w, 1101m, 1015m. H
702s, 600w. H NMR ((d5)pyridine, 500 MHz): 9.68 (s,
NMR ((d5)pyridine, 600 MHz): 8.33 (s, NH, Aib(1)); 7.77
(s, NH, Aib(2)); 7.48±7.42 (m, NH of Aib(3), NH of
Phe(2Me), 2 arom. H); 7.35±7.30, 7.26±7.22 (m, 3 arom.
H); 4.69, 3.80 (AB, Jˆ10 Hz, CH2O); 4.33, 3.51 (AB,
Jˆ13 Hz, PhCH2); 2.06 (s, PhCH2(Me)C); 1.91 (s, Me(a),
Aib(3)); 1.82 (s, Me(b), Aib(3)); 1.77 (s, Me(a), Aib(1));
1.66 (s, Me(a), Aib(2)); 1.54 (s, Me(b), Aib(2)); 1.42 (s,
Me(b), Aib(1)); 1.27 (s, Me(a), Dhp); 1.03 (s, Me(b),
Dhp). 13C NMR ((d5)pyridine, 151 MHz): 176.1 (s, CO,
Dhp); 175.6 (s, CO, Aib(1)); 175.2 (s, CO, Aib(3)); 174.2
(s, CO, Aib(2)); 173.3 (s, CO, Phe(2Me)); 137.9 (s, 1 arom.
C); 130.9, 128.3, 126.9 (3d, 5 arom. C); 72.1 (t, CH2O); 63.0
(s, PhCH2(Me)C); 57.9 (s, Me2C, Aib(3)); 57.4 (s, Me2C,
Aib(2)); 56.8 (s, Me2C, Aib(1)); 42.8 (t, PhCH2); 42.3 (s,
Me2C, Dhp); 27.1 (q, Me(b), Aib(3)); 26.6 (q, Me(b),
Aib(2)); 26.1 (q, Me(b), Aib(1)); 24.4 (q, Me(a), Aib(1),
Me(a), Aib(3)); 23.9 (q, Me(a), Aib(2)); 23.2 (q,
PhCH2(Me)C); 22.5 (q, Me(a), Dhp); 22.4 (q, Me(b),
Dhp). ESI-MS: 517 (100, [M1H]1).
NH, Aib(1)); 8.16 (s, NH, Aib(2)); 8.07 (s, NH,
Phe(2Me)); 7.63±7.61 (m, 2 arom. H of Phe(2Me)); 7.55±
7.54 (m, 2 arom. H of Tro); 7.49 (s, NH, Aib(3)); 7.38±7.34
(m, 2 arom. H of Phe(2Me), 2 arom. H of Tro); 7.32±7.26
(m, 1 arom. H of Phe(2Me), 1 arom. H of Tro); 4.93±4.90,
4.51±4.46 (2m, CH2O); 4.37±4.33 (m, CH); 3.91, 3.70 (AB,
Jˆ13.3 Hz, PhCH2); 2.00 (s, Me(a), Aib(3)); 1.97 (s,
PhCH2(Me)C); 1.95 (s, Me(b), Aib(3)); 1.89 (s, Me(a),
Aib(2)); 1.78 (s, Me(a), Aib(1)); 1.61 (s, Me(b), Aib(2));
1.44 (s, Me(b), Aib(1)). 13C NMR: 176.8 (s, CO, Aib(3));
176.1 (s, CO, Aib(1)); 174.3 (s, CO, Aib(2)); 173.4 (s, CO,
Phe(2Me)); 171.9 (s, CO, Tro)); 137.0 (s, 1 arom. C,
Phe(2Me)); 136.5 (s, 1 arom. C, Tro); 131.5 (d, 2 arom. C
of Phe(2Me)); 129.3, 128.5 (2d, 2 arom. C of Phe(2Me), 2
arom. C of Tro); 128.1 (d, 1 arom. C of Tro); 127.1 (d, 1
arom.
C of Phe(2Me)); 65.8 (t, CH2O); 62.2 (s,
PhCH2(Me)C); 58.8 (s, Me2C, Aib(3)); 58.2 (s, Me2C,
Aib(2)); 57.0 (s, Me2C, Aib(1)); 51.3 (d, CH); 44.4 (t,
PhCH2); 28.2 (q, Me(b), Aib(3)); 27.4 (q, Me(b), Aib(2));
26.6 (q, Me(b), Aib(1)); 24.5 (q, Me(a), Aib(3)); 23.2 (q,
Me(a), Aib(1)); 23.2 (q, Me(a), Aib(2)); 20.8 (q,
PhCH2(Me)C). ESI-MS: 587 (100, [M1Na]1). Anal. calcd
for C31H40N4O6 (564.67): C 65.94, H 7.14, N 9.92; found: C
65.43, H 7.56, N 9.42.
4.9.3.
(15R)-6,6,9,9,12,12-Hexamethyl-15-phenyl-3,3-
tetramethylen-1-oxa-4,7,10,13-tetraazacyclohexadecane-
2,5,8,11,14-pentone (14c). According to GP 5, 13c
(0.050 g, 0.089 mmol) in toluene (30 ml), 15 min, CC
(SiO2, CH2Cl2/MeOH 30:1) and crystallization from Et2O:
²²
0.014 g (30%) of 14c. White powder. Mp 279.38C (dec.).
Data of 14e (isomer 2). According to GP 5, 13e (0.051 g,
0.084 mmol) in toluene (30 ml), 14 min, CC (SiO2, CH2Cl2/
MeOH 30:1) and crystallization from Et2O: 0.027 (57%) of
14e.§§ White powder. Mp 241.68C (dec.). [a]ˆ14.4
(cˆ0.5, EtOH). IR: 3639w, 3416s, 3370s, 3325s, 3062w,
[a]Dˆ114.0 (cˆ0.4, EtOH). IR: 3361s, 2981m, 2874w,
1715s, 1669vs, 1533vs, 1473m, 1378m, 1366m, 1271s,
1233s, 1183s, 1076w, 1021w, 748m, 700m. 1H NMR
((d5)pyridine, 600 MHz): 9.55 (s, NH, Aib(1)); 8.14 (s,
NH, Aib(2)); 8.11 (s, NH, Ac5c); 7.52±7.51 (m, 2 arom.
H); 7.35±7.33 (m, NH of Aib(3), 2 arom. H); 7.30±7.28
(m, 1 arom. H); 4.94±4.93, 4.40±4.36 (2m, CH2O); 4.26±
³³
As a second fraction, 0.004 g of a material containing cyclodimer 15d
among other non-identi®ed products was obtained. 15d was identi®ed by
ESI-MS: 1151 (34, [M1Na]1), 587 (100, [M12Na]21).
§§As a second product, 0.010 g of a white powder was isolated, which was
identi®ed as the cyclodimer 15e (21%) by ESI-MS: 1151 (37, [M1Na]1),
587 (100, [M12Na]21).
²²
As a second product, 0.010 g of a white powder was isolated, which was
identi®ed as the cyclodimer 15c (20%) by ESI-MS: 1051 (32, [M1Na]1),
537 (100, [M12Na]21).

2324
K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
3029w, 2983m, 2938m, 1747vs, 1663vs, 1604w, 1542vs,
1497vs, 1455s, 1384s, 1365s, 1325m, 1280vs, 1218vs,
1170s, 1119s, 1074w, 1044w, 1027w, 974w, 933w, 770w,
743m, 704s. 1H NMR ((d5)pyridine, 600 MHz): 9.82 (s, NH,
Aib(1)); 8.38 (s, NH, Aib(3)); 8.30 (s, NH, Phe(2Me));
7.83±7.82 (m, 2 arom. H of Phe(2Me)); 7.60±7.58 (m, 2
arom. H of Tro); 7.46±7.41 (m, 2 arom. H of Phe(2Me), 2
arom. H of Tro); 7.39±7.36 (m, 1 arom. H of Tro); 7.35 (s,
NH, Aib(2)); 7.29±7.26 (m, 1 arom. H of Phe(2Me)); 4.88±
4.86, 4.71±4.67 (2m, CH2O); 4.47±4.45 (m, CH); 4.27, 3.75
(AB, Jˆ13.9 Hz, PhCH2); 2.13 (s, Me(a), Aib(3)); 2.01 (s,
Me(b), Aib(3)); 1.72 (s, Me(a), Aib(2)); 1.65 (s, Me(a),
Aib(1)); 1.65 (s, PhCH2(Me)C); 1.35 (s, Me(b), Aib(1));
1.13 (s, Me(b), Aib(2)). 13C NMR ((d5)pyridine,
151 MHz): 176.3 (s, CO, Phe(2Me)); 176.3 (s, CO,
Aib(3)); 174.6 (s, CO, Aib(1)); 173.8 (s, CO, Aib(2));
172.2 (s, CO, Tro); 138.0 (s, 1 arom. C, Phe(2Me)); 136.4
(s, 1 arom. C, Tro); 132.3 (d, 2 arom. C of Phe(2Me)); 129.6,
128.4 (2d, 2 arom. C of Phe(2Me), 2 arom. C of Tro)); 128.5
(d, 1 arom. C of Tro); 128.2 (d, 2 arom. C of Tro); 126.5 (d,
1 arom. C of Phe(2Me)); 66.6 (t, CH2O); 59.8 (s,
PhCH2(Me)C); 57.6 (s, Me2C, Aib(3)); 57.2 (s, Me2C,
Aib(1)); 57.1 (s, Me2C, Aib(2)); 51.3 (d, CH); 41.0 (t,
PhCH2); 28.5 (q, Me(b), Aib(3)); 27.3 (q, Me(b), Aib(2));
25.8 (q, Me(b), Aib(1)); 24.2 (q, Me(a), Aib(1)); 23.6 (q,
Me(a), Aib(2)); 23.3 (q, Me(a), Aib(3)); 23.2 (q,
PhCH2(Me)C). ESI-MS: 587 (100, [M1Na]1). Anal. calcd
for C31H40N4O6 (564.67): C 65.94, H 7.14, N 9.92; found: C
65.49, H 7.39, N 9.49.
(100, [M1H]1). Anal. calcd for C29H42N4O6 (542.66): C
64.19, H 7.80, N 10.32; found: C 64.04, H 8.03, N 10.15.
Data of 14g. According to GP 5, 13g (0.050 g, 0.085 mmol)
in toluene (30 ml), 11 min, CC (SiO2, CH2Cl2/MeOH 30:1)
and crystallization from Et2O: 0.013 g (28%) of 14g.¶¶
White powder. Mp 272.38C (dec.). IR: 3392s, 2984m,
2939s, 2861w, 1728s, 1664vs, 1531vs, 1455s, 1382s,
1363m, 1282s, 1231m, 1167s, 1125m, 1037w, 914w,
866w, 769w, 741w, 702m. 1H NMR ((d5)pyridine,
500 MHz): 8.64 (s, NH, Phe(2Me)); 7.81 (s, NH, Aib(1));
7.64 (s, NH, Aib(3)); 7.53 (s, NH, Aib(2)); 7.34±7.27 (m, 3
arom. H); 7.26±7.24 (m, 2 arom. H); 5.35 (dt, Jˆ11.0,
4.3 Hz, CHO); 3.45 (d, Jˆ12.6 Hz, 1H of PhCH2); 3.21
(d, Jˆ11.7 Hz, 1H of PhCH2); 2.69 (m, CH(CO)); 2.26±
2.21, 2.11±2.04, 1.86±1.78, 1.53±1.47, 1.27±1.17, 1.06±
0.99 (6m, 4CH2); 2.11 (s, Me(a), Aib(3)); 2.08 (s, Me(b),
Aib(3)); 1.92 (s, 2Me, Aib(2); 1.82 (s, PhCH2(Me)C); 1.66
(s, Me(a), Aib(1)); 1.40 (s, Me(b), Aib(1)). 13C NMR
((d5)pyridine, 126 MHz): 174.7 (s, CO, Phe(2Me)); 174.6
(s, CO, Aib(2)); 174.4 (s, CO, Aib(3)); 174.1 (s, CO, Hcc);
173.9 (s, CO, Aib(1)); 135.8 (s, 1 arom. C); 131.6, 128.5,
127.5 (3d, 5 arom. C); 75.4 (d, CHO); 60.5 (s,
PhCH2(Me)C); 58.9 (s, Me2C, Aib(3)); 58.2 (s, Me2C,
Aib(2)); 57.9 (s, Me2C, Aib(1)); 53.0 (d, CH(CO)); 44.2
(t, PhCH2); 31.5, 29.2, 25.2, 24.2 (4t, 4CH2); 26.8 (q,
Me(b), Aib(1)); 25.3 (q, Me(a), Aib(3)); 25.2 (q, Me(b),
Aib(3)); 24.5 (q, Me(a), Aib(1)); 21.4 (q, PhCH2(Me)C);
27.2 (q, Me(a), Aib(2)); 24.5 (q, Me(b), Aib(2)). ESI-MS:
565 (47, [M1Na]1), 543 (100, [M1H]1).
4.9.5. (12RS,15SR,16SR)- and (12RS,15RS,16RS)-12-
Benzyl-3,3,6,6,9,9,12-heptamethyl-15,16-tetramethylen-
1-oxa-4,7,10,14-tetraazacyclohexadecane-2,5,8,11,14-
pentone (14f and g, respectively). Data of 14f. According
to GP 5, 13f (0.050 g, 0.085 mmol) in toluene (30 ml),
7 min, CC (SiO2, CH2Cl2/MeOH 30:1) and crystallization
from Et2O: 0.023 g (50%) of 14f.kk White powder. Mp
325.78C (dec.). IR: 3400m, 3339m, 2983w, 2938m,
2863w, 2361w, 1748m, 1729m, 1664vs, 1538s, 1456m,
1382m, 1364w, 1276m, 1231m, 1163m, 1042w, 914w,
767w, 701w, 668w, 602w. 1H NMR ((d5)pyridine,
600 MHz): 8.62 (s, NH, Phe(2Me)); 7.98 (s, NH, Aib(1));
7.71 (s, NH, Aib(3)); 7.53 (s, NH, Aib(2)); 7.40±7.34 (m, 3
arom. H); 7.25±7.24 (m, 2 arom. H); 5.35 (dt, Jˆ11.0,
4.4 Hz, CHO); 4.21, 3.27 (AB, Jˆ12.1 Hz, PhCH2); 2.75
(m, CH(CO)); 2.18±2.11, 1.67±1.60, 1.47±1.42, 1.23±
1.17, 1.14±1.06, 0.91±0.85 (6m, 4CH2); 2.16 (s, Me(b),
Aib(3)); 2.03 (s, Me(a), Aib(3)); 1.95 (s, Me(b), Aib(2));
1.93 (s, Me(a), Aib(2)); 1.76 (s, Me(b), Aib(1)); 1.55 (s,
Me(a), Aib(1)); 1.20 (s, PhCH2(Me)C). 13C NMR ((d5)pyr-
idine, 151 MHz): 175.9 (s, CO, Phe(2Me)); 174.5 (s, CO,
Aib(2)); 174.4 (s, CO, Aib(3)); 174.2 (s, CO, Hcc); 173.7 (s,
CO, Aib(1)); 137.4 (s, 1 arom. C); 131.6, 128.3, 127.0 (3d, 5
arom. C); 75.1 (d, CHO); 59.6 (s, PhCH2(Me)C); 58.9 (s,
Me2C, Aib(3)); 57.9 (s, Me2C, Aib(2)); 57.6 (s, Me2C,
Aib(1)); 53.3 (d, CH(CO)); 38.9 (t, PhCH2); 31.5, 28.0,
25.0, 24.0 (4t, 4CH2); 28.2 (q, Me(a), Aib(2)); 27.3 (q,
Me(a), Aib(1)); 25.3 (q, Me(b), Aib(3)); 24.6 (q, Me(a),
Aib(3)); 23.5 (q, Me(b), Aib(2)); 23.4 (q, Me(b), Aib(1));
23.2 (q, PhCH2(Me)C). ESI-MS: 565 (18, [M1Na]1), 543
4.10. Crystal structure determination of 13f and h
See Figs. 1 and 2.46 The intensities were collected on a
Rigaku AFC5R diffractometer using graphite-monochro-
mated MoKa radiation and a 12 kW rotating anode genera-
tor. The intensities were corrected for Lorentz and
polarization effects but not for absorption. The structures
were solved by direct methods using SIR92,47 which
revealed the positions of all non-H-atoms. The non-H-
atoms were re®ned anisotropically. The amide and hydroxy
H-atoms were placed in the positions indicated by difference
electron density maps and their positions were allowed to
re®ne together with individual isotropic displacement para-
meters. All remaining H-atoms were ®xed in geometrically
calculated positions [d(C±H)ˆ0.95 ?] and each was
assigned a ®xed isotropic displacement parameter with a
value equal to 1.2Ueq of its parent atom. Re®nement of
the structure was carried out on F using full-matrix least-
squares procedures, which minimized the function
ꢀ
ꢀ
ꢀꢀ ꢀÁ
P
w Fo Fc 2: A correction for secondary extinction was
ꢀꢀ
ꢀ
applied in both cases. Neutral atom scattering factors for
non-H-atoms were taken from Ref. 48a, and scattering
factors for H-atoms were taken from Ref. 49. Anomalous
dispersion effects were included in Fc;50 the values for f0 and
f00 were those of Ref. 48b. The values of the mass attenuation
coef®cients were taken from Ref. 48c. All calculations were
performed using the teXsan crystallographic software pack-
age.51
¶¶ As a second product, 0.005 g of a white powder was isolated, which was
identi®ed as the cyclodimer 15g (11%) by ESI-MS: 1107 (100,
[M1Na]1).
kkAs a second product, 0.002 g of a white powder was isolated, which was
identi®ed as the cyclodimer 15f (2%) by ESI-MS: 1107 (100, [M1Na]1).

K. N. Koch et al. / Tetrahedron 57 (2001) 2311±2326
2325
16. Cerrini, S.; Gavuzzo, E.; Luisi, G.; Pinnen, F. Int. J. Pept.
Protein Res. 1993, 41, 282±290.
4.10.1. Crystal data for 13f. A crystal of dimension
0.40£0.45£0.48 mm3 was grown from H2O/MeOH/CHCl3.
C31H49N5O6, Mrˆ587.76, monoclinic, space group P21/n,
17. Ueda, K.; Waki, M.; Izumiya, N. Int. J. Pept. Protein Res.
1987, 30, 33±39.
Ê
aˆ14.978(4), bˆ12.363(3), cˆ18.507(3) A, bˆ108.19(1)8,
Ê 3
Vˆ3256(1) A , Zˆ4, Dxˆ1.199 g/cm3,
m
(MoKa)ˆ
18. Zanotti, G.; Pinnen, F.; Lucente, G.; Cerrini, S.; Gavuzzo, E.;
Mazza, F. Int. J. Pept. Protein Res. 1983, 22, 410±421.
19. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1984, 67,
526±533.
0.0835 mm21; Tˆ193(1) K, lˆ0.71069 A. Cell dimension
from 25 re¯ections in the range 2uˆ39±408, v/2u scans,
2u(max)ˆ508, 6259 re¯ections measured, 5724 symmetry-
independent re¯ections, 4001 re¯ections with I.2s(I)
used in the re®nement of 400 parameters. Final
Ê
20. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1987, 70,
329±338.
Rˆ0.0462,
wRˆ0.0403
(wˆ[s2(Fo)1(0.005Fo)2]21),
21. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1990, 73,
221±228.
GoFˆ2.177,
D
max/sˆ0.0002, Dr (max; min)ˆ0.27;
Ê 23
22. Villalgordo, J. M.; Heimgartner, H. Helv. Chim. Acta 1997,
80, 748±766.
20.19e A
.
4.10.2. Crystal data for 13h. A crystal of dimension
0.32£0.33£0.50 mm3 was grown from H2O/MeOH.
C29H47N5O6, Mrˆ561.72, Triclinic, space group P1;
È
23. Magirius, J. E. F. PhD Thesis, Universitat ZuÈrich, 1995.
24. Heimgartner, H.; Arnhold, F. S.; Fritschi, S.; Koch, K. N.;
Linden, A.; Magirius, J. E. F. Lectures Heterocycl. Chem.
1999, 36, 1539±1547.
Ê Ê
aˆ11.2403(9), bˆ14.127(2), cˆ10.155(2) AA, aˆ90.86(1),
Ê 3
bˆ102.374(9), gˆ89.865(8)8, Vˆ1574.8(3) A , Zˆ2,
25. Koch, K. N.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
2000, 83, 233±257.
Dxˆ1.185 g/cm3, m (MoKa)ˆ0.0832 mm21; Tˆ173(1) K,
Ê
lˆ0.71069 A. Cell dimension from 25 re¯ections in the
26. Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238±
264.
27. Wipf, P.; Heimgartner, H. Helv. Chim. Acta 1990, 73, 13±24.
range 2uˆ37±408, v/2u scans, 2u
ˆ558, 7606 re¯ec-
(max)
tions measured, 7239 symmetry-independent re¯ections,
5247 re¯ections with I.2s(I) used in the re®nement of
382 parameters. Final Rˆ0.0479, wRˆ0.0446 (wˆ
È
È
28. (a) Altherr, W. PhD Thesis, Universitat Zurich, 1994.
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[s2(Fo)1(0.005Fo)2]21), GoFˆ2.102,
D
max/sˆ0.0005,
Ê 23
Dr(max; min)ˆ0.35; 20.21e A
.
29. Luykx, R.; Bucher, C. B.; Heimgartner, H. Helv. Chim. Acta
1996, 79, 527±540.
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