Depsipeptide dendrimers

Article abstract of DOI:10.1002/(SICI)1521-3765(20000117)6:2<247::AID-CHEM247>3.0.CO;2-M

The convergent synthesis of a new class of chiral dendrimers is described. Owing to their structural resemblance to depsipeptides they are called depsipeptide dendrimers. The ex-chiral pool synthesis starts from (R,R)-, (S,S)-, and meso-tartaric acid as b

Full text of DOI:10.1002/(SICI)1521-3765(20000117)6:2<247::AID-CHEM247>3.0.CO;2-M

FULL PAPER
Depsipeptide Dendrimers
Jürgen Kress, Alexander Rosner, and Andreas Hirsch*[a]
Abstract: The convergent synthesis of a
new class of chiral dendrimers is descri-
bed. Owing to their structural resem-
blance to depsipeptides they are called
depsipeptide dendrimers. The ex-chiral
pool synthesis starts from (R,R)-, (S,S)-,
and meso-tartaric acid as branching
units and dipeptides or tripeptides con-
sisting of glycine, (l)-alanine, and (l)-
leucine as chiral-spacer building blocks.
The key intermediates for the conver-
gent assembly of such depsipeptide
dendrimers are the peptide-tartaric acid
conjugates 13a,b, 19a,b, 25, and 27,
which contain either an unprotected C
terminus of the peptide chain (13a,b, 25)
or two unprotected hydroxy groups
within the tartaric acid termini. Dendra
up to the third-generation, by using
different combinations of stereoisomer-
ic building blocks, were synthesized and
completely characterized. Since this
construction principle of chiral depsi-
peptide dendrimers allows for a wide
variation of the length, the primary
structure of the peptide spacer, and the
configuration of both the amino acid and
the tartaric acid moieties, access to new
combinatorial libraries is conceptually
provided.
Keywords: amino acids ´ chiral pool
´ chirality ´ combinatorial chemistry
´ dendrimers
Introduction
Results and Discussion
Since Vögtleꢀs first report in 1978[1] dendrimers have become
a vast growing field in chemistry and material science. The
subject has been extensively reviewed.[2] More recently chiral
dendrimers became an attractive synthetic goal.[3] Their
chiroptical properties with respect to folding phenomena,
their ability to stereoselectively bind guest molecules, and
their potential as catalysts for stereoselective syntheses have
been investigated. The chirality of the dendritic structures
reported so far stems from i) four different branches attached
to a tetrasubstituted carbon atom,[4] ii) a chiral core,[5] iii)
chiral branching units,[5±8] iv) chiral end groups,[5, 9±12] and v) a
chiral core and chiral branching units.[13, 14] We now introduce
a new concept of chiral dendrimers that are named depsipep-
tide dendrimers owing to their structural resemblance to
depsipeptides. The expression depsipeptides was introduced
by Schemjakin[15] to describe a class of natural products that
consist of a-hydroxy and a-amino acids which are connected
by ester and amide linkages, respectively. The most prominent
Our general concept of the synthesis and the structure of
depsipeptide dendra is depicted in Scheme 1. A C-protected
amino acid or peptide is coupled to a tartaric acid derivative 1
with one unprotected carboxylic group. The configuration at
the corresponding stereogenic centers of both the amino acid
and tartaric acid derivatives can be freely chosen. The
orthogonal protecting groups PG and PG'' are alternatively
removed to yield the carboxylic acid 3 or the diol 4. The
coupling of these two units leads to the dendron 5a, which
after deprotection to the acid 5b and coupling with 4 is
transferred to the dendron 6. The latter two steps are
successively repeated for the synthesis of higher generation
dendra. The construction of the higher generation dendra can
in principle also be accomplished by using a divergent
approach, which involves the repetitive deprotection of PG''
and subsequent coupling with 3. However, no matter which
approach is followed, two prerequisites have to be provided:
1) efficient and mild esterification reactions for the synthesis
of 5, 6, and their higher analogues are required in order to
prevent epimerization at the amino acid or tartaric acid units
and 2) a set of two orthogonal protecting groups PG' and PG''
must be found.
example is probably valinomycin, which makes mitochondria
‡ [16]
membranes permeable for K .
The chiral dendrimers
presented here contain both chiral branching units and chiral
spacer units, represented by tartaric acid and peptide building
blocks, respectively.
As a first example commercially available (l)-alanineben-
zylester-p-tosylate 7 was used as the amino acid unit. The
mono-deprotected tartaric acid derivative 8 was prepared
according to a literature procedure.[17] Formation of the
coupling product 9 was accomplished by reaction of 7 with 8 in
the presence of N,N'-dicyclohexylcarbodiimide (DCC) at 08C
[a] Prof. Dr. A. Hirsch, Dipl.-Chem. J. Kress, Dipl.-Chem. A. Rosner
Institut für Organische Chemie, der Universität Erlangen-Nürnberg
Henkestr. 42, 91054 Erlangen (Germany)
Fax : (‡ 49)9131-8526864
E-mail: hirsch@organik.uni-erlangen.de
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A. Hirsch et al.
FULL PAPER
To avoid the problem of
epimerization at a1 within the
peptide chain (a1 in Scheme 1)
we decided to use achiral gly-
cine as the C terminus in order
to ªprotectº neighboring ster-
eogenic centers of chiral amino
acids from stereoepimerization.
At the same time we switched
to milder coupling procedures
namely the Steglich reaction.[18]
As a first example we used the
dipeptide 11 obtained from the
PG'O2C
PG-O2C-(a1-...-an)-NH
OPG''
OPG''
PG'O2C
HO2C
OPG''
OPG''
PG-O2C-(a1-...-an)-NH2
+
O
2
1
PG'O2C
OPG''
PG'O2C
OPG''
OPG''
(a1-...-an)-NH
O
O
OPG''
HO2C-(a1-...-an)-NH
O
PG'O2C
R-O2C-(a1-a2-...-an)-NH
O
O
3
O
2
PG'O2C
OPG''
OPG''
O
PG'O2C
PG-O2C-(a1-...-an)-NH
OH
OH
(a1-...-an)-NH
corresponding
Z-protected
O
mother compound[19] according
to a literature procedure[20] and
allowed it to react with mono-
R = PG, 5a
R = H, 5b
4
O
deprotected
tartaric
acids
(Scheme 3). In addition to the
building block 8a, which was
made from natural tartaric acid
with (R,R)-configuration, the
corresponding unnatural (S,S)-
enantiomer 8b was used for the
subsequent coupling step. The
deprotection leading to 13a,b
was carried out in analogy to
that of 9.
PG'O2C
OPG''
(a1-...-an)-NH
O
OPG''
OPG''
O
PG'O2C
(a1-...-an)-NH
O
O
O
PG'O2C
(a1-...-an)-NH
O
PG'O2C
O
O
O
O
OPG''
OPG''
4 + 5b
Carboxylic acid 13a was then
successfully coupled with the
three stereoisomeric deriva-
O
PG'O2C
(a1-...-an)-NH
tives
(R,R)-14a,
of
dimethyltartrate
(S,S)-14b, and
OPG''
PG-O2C-(a1-a2-...-an)-NH
O
PG'O2C
O
O
meso-14c by means of the Steg-
lich reaction in the presence of
O
O
(a1-...-an)-NH
6
PG'O2C
OPG''
OPG''
a
catalytic amount of 4-di-
O
(a1-...-an)-NH
O
methylaminopyridine (DMAP)
(Scheme 4). Compounds 14a
and 14b are commercially
available, the meso-isomer 14c
was prepared according to a
literature procedure.[21] Other
a = amino acid
PG = protecting group
O
Scheme 1. General concept for the convergent syntheses of depsipeptide dendra consisting of tartaric acid
moieties as branching units and peptides as spacer units.
procedures like the Steglich reaction without DMAP or
coupling via the acyl chloride gave lower yields or no product
at all. The products 15a, 15b, and 15c are first-generation
dendrimers with a chiral core (15a,b), chiral spacers (dipep-
tide unit), and chiral branching units (tartaric acid moieties).
Purification was achieved by flash chromatography (FC) on
silica gel. As eluent a mixture of toluene/EtOAc ˆ 3:5 was
successfully used. The products 15a,b,c were fully character-
in CH2Cl2 (Scheme 2). The removal of the benzylic protecting
groups by catalytic hydrogenation afforded the acid 10.
Coupling reactions of 10 with simple alcohols such as ethanol
via the corresponding acyl chloride of 10 showed that
epimerization occurred at the stereogenic center of the
alanine moiety.
H3CO2C
OBz
1
ized by H NMR, 13C NMR, IR, MS, and elemental analysis.
H3CO2C
HO2C
OBz
OBz
RO2C
NH3Ts
H
N
i)
Considering that the problem of epimerization could be
solved, the yields of 54 ± 56% are satisfactory. However, the
yields are not good enough to envisage a divergent approach
for the synthesis of higher generation dendrimers.
For the synthesis of higher generation dendra it was
necessary to create a building block like 4 with two free
alcohol groups. Since the acid-protecting benzyl group (Bn)
and the alcohol-protecting benzoyl group (Bz) of 12 are not
+
RO2C
OBz
O
R = Bn, 7
8
R = Bn, 9
R = H, 10
ii)
Scheme 2. Synthesis of the acid 10: i) NEt3, DCC, CH2Cl2, 08C, 52%; ii):
dioxane, H2, Pd-C, 100%. Bn ˆ benzyl, Bz ˆ benzoyl.
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Depsipeptide Dendrimers
247±257
The acetal deprotection was
accomplished by the action of
trifluoroacetic acid (TFA) upon
18a,b in the presence of some
water at 08C. The diols 19a,b
were released in yields of about
85% after recrystallization
from EtOAc (Scheme 5). The
Bn groups were not attacked
under these conditions. Now
the scene was set for the syn-
thesis of the unsymmetrical sec-
ond-generation dendra 20a,b
(Scheme 6). The diols 19a,b
were coupled with the carbox-
ylic acids 13a,b at room tem-
perature, with DCC as a cou-
pling reagent and DMAP as
H3CO2C
HO2C
OBz
OBz
H3CO2C
OBz
OBz
i)
R = Bn, 12a
R = H, 13a
ii)
RO2C-G-A
H
8a
8b
RO2C
N
+
NH3Br
O
H3CO2C
HO2C
OBz
OBz
H3CO2C
OBz
OBz
i)
R = Bn, 11
R = Bn, 12b
R = H, 13b
ii)
RO2C-G-A
H3CO2C
OBz
OBz
H3CO2C
OBz
OBz
O
H
=
N
- -O2C
N
- -O2C-G-A
H
O
Scheme 3. Syntheses of the carboxylic acids 13a,b: i) NEt3, DCC, CH2Cl2, 08C, 53 ± 58%; ii) dioxane, H2, Pd-C,
100%.
H3CO2C
O2C-G-A
O2C-G-A
H3CO2C
OBz
OBz
OBz
OBz
H3CO2C
HO2C
H3CO2C
O
O
O
O
H3CO2C
OH
OH
i)
ii)
H3CO2C
H3CO2C
OH
OH
H3CO2C
H3CO2C
Ph
Ph
i)
13a
+
BnO2C-G-A
BnO2C-G-A
16a
18a
19a
15a
15b
15c
14a
H3CO2C
HO2C
H3CO2C
O
O
O
O
H3CO2C
OH
OH
i)
ii)
BnO2C-G-A
19b
H3CO2C
O2C-G-A
O2C-G-A
H3CO2C
OBz
OBz
OBz
OBz
Ph
Ph
BnO2C-G-A
H3CO2C
H3CO2C
OH
OH
H3CO2C
H3CO2C
i)
16b
18b
13a
+
Scheme 5. Syntheses of the diols 19a,b: i) NEt3, DCC, CH2Cl2, 08C, 51%;
ii) TFA, H2O, 08C, 83%.
14b
H3CO2C
O2C-G-A
OBz
OBz
H3CO2C
H3CO2C
O2C-G-A
O2C-G-A
H3CO2C
OBz
OBz
OBz
OBz
i)
13a + 19a
RO2C-G-A
H3CO2C
H3CO2C
OH
OH
OBz
OBz
O2C-G-A
H3CO2C
H3CO2C
H3CO2C
i)
13a
+
14c
R = Bn, 20a
R = H, 21a
ii)
Scheme 4. Synthesis of the first-generation dendrimers 15a,b,c: i) dioxane,
DCC, DMAP, RT, 51 ± 56%.
H3CO2C
OBz
OBz
orthogonal a new building block had to be developed. The
benzylidene acetals 18a,b seemed to be an appropriate choice
(Scheme 5). They were prepared from the known benzylidene
acetals 16a,b[22] and hydrobromide 11 by using the same
reaction conditions as described previously. Purification of
18a,b was accomplished by flash chromatography. In fact,
18a,b were isolated as a mixture of diastereomers, since the
starting materials 16a,b are each a mixture of two diaster-
eomers, which differ only in the configuration of the stereo-
genic centers at the acetal moiety. However, this was not a
serious drawback, since cleavage of the acetal is the next step.
O2C-G-A
H3CO2C
i)
RO2C-G-A
13b + 19b
O2C-G-A
H3CO2C
OBz
OBz
R = Bn, 20b
R = H, 21b
ii)
Scheme 6. Syntheses of the second-generation dendra 21a,b: i) dioxane,
DCC, DMAP, 60 ± 65%; ii) dioxane, H2, Pd-C, 100%.
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A. Hirsch et al.
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H3CO2C
O2C-G-A
OBz
OBz
H3CO2C
O2C-G-A
OBz
OBz
H3CO2C
O2C-G-A
H3CO2C
O2C-G-A
O2C-G-A
OBz
H3CO2C
H3CO2C
O2C-G-A
OBz
H3CO2C
H3CO2C
OBz
OBz
i)
i)
H3CO2C
H3CO2C
OBz
OBz
19b + 21b
19a +21a
OBz
O2C-G-A
BnO2C-G-A
O2C-G-A
OBz
O2C-G-A
BnO2C-G-A
O2C-G-A
H3CO2C
H3CO2C
OBz
OBz
O2C-G-A
H3CO2C
OBz
OBz
O2C-G-A
H3CO2C
22a
22b
catalyst. After flash chromatog-
raphy the pure benzylic esters
20a,b were obtained in yields of
60 ± 65% as white solids.
19a + 21b
i)
H3CO2C
O
O
Catalytic hydrogenation of
the Bn-protected 20a,b afford-
ed the carboxylic acids 21a,b in
quantitative yields (Scheme 6).
Not surprisingly, the NMR
spectra are very similar to those
of the precursors. The absence
of the signals at d ˆ 5.1 in the
1H NMR and d ˆ 67 in the
13C NMR confirmed the suc-
cessful removal of the benzyl
group. The mass spectra (FAB)
revealed the principal peak at
H
N
O
O
O
N
H
H3CO2C
O
O
O
O
O
H
O
O
N
O
O
N
H
O
H
N
H
N
O
O
O
N
H
O
N
H
O
O
O
O
H3CO2C
O
O
O
‡
m/z 1279 [M‡Na] , the
‡
[M‡Cs] peak at m/z 1389,
H3CO2C
O
‡
O
and the [M] signal at m/z
H
N
O
O
O
1257. The third-generation den-
dra 22a,b,c were prepared as
sketched in Scheme 7. The
yields were in the range be-
tween 7 and 15% depending on
the precise reaction conditions,
especially the amount of
DMAP used as a catalyst. The
lower yield, relative to those
achieved in the synthesis of the
second-generation dendra, is
probably due to steric hin-
drance. Because of the consid-
erable polarity of the third-
H3CO2C
O
O
N
N
H
H
N
O
O
O
O
O
H
O
H3CO2C
H
N
O
O
N
H
O
O
O
H3CO2C
22c
Scheme 7. Syntheses of the third-generation dendra 22a,b,c: i) dioxane, DCC, DMAP, 7 ± 15%.
generation dendra 22, their purification by chromatography
turned out to be quite difficult. In fact, preparative HPLC was
necessary to get the pure samples. Significantly, the retention
times of the three diastereomers 22a,b,c, which differ only at
the stereochemistry of the tartaric acid units, can be very
different. For example, retention times for 22a,b,c on
analytical HPLC (silica gel; CHCl3/MeOH ˆ 96.5:3.5 flow
The first example of the synthesis of a second-generation
dendron with the tripeptide (l)-leucine-glycine-glycine as the
spacer unit is outlined in Scheme 8. In the investigation of this
synthesis we intended to find out whether there is any
influence of the sterical demand of the C-terminal amino acid
on the yield of the coupling reaction, and whether epimeriza-
tion at the stereogenic center of the C terminus takes place
under the Steglich esterification. For this purpose the hydro-
bromide 23 was prepared from the known Z-protected
1
rate: 1 mLmin ) were 8.1, 5.0, and 4.6 minutes, respecti-
vely.
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Depsipeptide Dendrimers
247±257
troscopy, mass spectrometry, elemental analysis, and by their
specific and molar optical rotations [a]D and [F]D, respec-
tively. FAB mass spectrometry turned out to be the method of
choice for these systems. As a representative example the
FAB spectrum of 22c is shown in Figure 1. The base peak m/z
O
H
N
H3CO2C
OBz
OBz
i)
RO2C
N
NH Br
+
8a
3
H
O
RO2C-L-G-G
‡
2860 corresponds to [M‡H] . Important fragments are m/z
R = Bn, 24
R = H, 25
R = Bn, 23
ii)
‡
‡
‡
2435 [M 426‡H] , 1678 [M 1182] , and 729 [728‡H] .
The smaller peaks on the right side of the base peaks at m/z
‡
‡
2882 and m/z 2992 are due to [M‡Na] and [M‡Cs] ,
respectively.
OH
OH
H3CO2C
H3CO2C
O
O
iii)
iv)
A characteristic feature of these chiral dendritic systems is
that, with the exception of the C2 symmetric compounds 15a
and 15b, all C and H atoms are topologically different even if
they originate from identical locations within a set of free
constituting precursors. This is reflected by the splitting of the
signals of the various sets of groups in the NMR spectra. As an
example three characteristic regions within the 13C NMR
spectrum of 22a, namely, the carbonyl C-atoms (d ˆ 165 ±
174), the methylene C-atoms of the glycine units (d ˆ 40.9 ±
41.7), and the methine C-atoms of the alanine moieties (d ˆ
48.4 ± 49.2) are depicted in Figure 2. All the corresponding
sets of seven topologically different C-atoms of both the
glycine and alanine units give rise to seven resolved signals,
and 32 signals for the 36 topologically different carbonyl C
atoms are resolved.
16a + 23
Ph
RO2C-L-G-G
RO2C-L-G-G
R = Bn, 26
R = Bn, 27
OBz
H3CO2C
H3CO2C
O2C-L-G-G
O2C-L-G-G
OBz
OBz
v)
25 + 27
BnO2C-L-G-G
H3CO2C
OBz
28
Scheme 8. Synthesis of the second-generation dendron 28: i) NEt3, DCC,
CH2Cl2, 08C, 44%; ii) THF, H2, Pd-C, 100%; iii) NEt3, DCC, CH2Cl2, 08C,
46%; iv) TFA, H2O, 08C, 45%; v) THF, DCC, DMAP, 9%.
The region between d ˆ 5.5 ± 6.2 in the 1H NMR spectra of
22a,b,c is an example of characteristic fingerprints caused
only by the different stereochemistry of such chiral dendra
precursor[23] by deprotection
with HBr/HOAc.[20] The subse-
quent steps were carried out in
analogy to those of the second-
generation dendra 20 and 21.
Whereas the yields for the syn-
theses of the key building
blocks 25 and 27 are satisfacto-
ry, the final coupling to the
depsipeptide dendron 28 were
less efficient. This is obviously
due to the bulky isobutyl group
in the proximity of the reaction
center. All couplings proceeded
without epimerization at the
stereogenic center of the leu-
cine moiety. This leads to the
conclusion that this concept for
the synthesis of depsipeptide
dendrimers tolerates the use of
chiral amino acids as C termini
but requires as little sterical
hindrance as possible, for ex-
ample, small C termini and
peptides of a sufficient length
in order to efficiently synthe-
size higher generation dendra.
All depsipeptide dendrimers
and their precursor building
blocks were completely charac-
Figure 1. FAB mass spectrum of 22c.
terized by NMR and IR spec-
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251

A. Hirsch et al.
FULL PAPER
outer shell resonate in the down-
field part, whereas the high-field
resonances are caused by the inner
two sets of methine protons. For the
whole region 14 doublets are ex-
pected; these are not completely
resolved. The patterns for these
signals are very different for each
diastereomer. The comparison of
22b with 22c is particularly instruc-
tive. These two compounds differ
only at the configuration of the inner
tartaric acid moiety (S,S for 22b,
R,R for 22c). In compound 22c one
proton (marked with a *) of the outer
tartaric acid units, along with the Bz
groups, undergoes a significant down-
field shift, even though it is in a
position very remote from the loca-
tion of stereochemistry differences.
Specific optical rotations [a]D and
the molar optical rotations [F]D are
shown in Table 1. To check whether
there was a concentration depend-
ence the measurements were carried
13
ˆ
Figure 2. C NMR spectrum (125.7 MHz, CDCl3) of 22a for the ranges from d ˆ 164 ± 174 (C O), d ˆ 46 ±
50 (CH alanine), and d ˆ 40 ± 42 (CH2 glycine).
out at two different concentrations.
(Figure 3). In this range the CH resonances of the tartaric acid
units are localized. Two main sections show up: a down-field
part, whose integration accounts for eight protons, and a high-
field part, which is due to six protons. The H atoms of the
With the exception of building block 12a, whose chiroptical
data show a pronounced concentration dependence of
unknown nature, the optical rotations of the other building
blocks and dendritic systems are basically independent of the
concentration. Further inspection of Table 1 shows that no
folding phenomena owing to the formation of chiral secon-
dary structures can be detected, since in a first approximation
the molar optical rotation of a larger dendritic system like 22
represents the sum of those of the constituting building blocks
like 20. The contributions to the optical rotations are mainly
due to the tartaric acid building blocks, whereas the alanine
units exhibit only a minor influence. For example, the two
diastereomers 22a and 22b, whose tartaric acid skeletons
behave like a pair of enantiomers, have almost the same molar
rotations but with opposite sign.
Table 1. Optical rotational values [a]D and molar optical rotations [F]D for
the dendrons 12, 13, 20, 21, 22 and the dendrimers 15a,b,c.
[a]
[b]
[c]
[a]
[b]
[c]
c1
[a]D
[F]D
c2
[a]D
[F]D
solvent
12a
0.414
45.65
270 0.590
94.92
561 CHCl3
‡ 390 CHCl3
840 CHCl3
‡ 943 CHCl3
1920 CHCl3
‡ 1963 CHCl3
‡ 1770 CHCl3
670 CHCl3
548 CHCl3
634 CHCl3
458 MeOH
‡ 280 MeOH
965 MeOH
‡ 391 MeOH
12b 0.414 ‡ 64.98
20a 0.785 59.87
20b 0.314 ‡ 66.88
22a 0.260 65.77
‡ 384 0.590 ‡ 66.10
807 1.047 62.37
‡ 901 0.523 ‡ 69.98
1881 0.520 67.12
22b 0.715 ‡ 68.53
‡ 1960 0.953 ‡ 68.63
22c
15a
0.715 ‡ 68.53
‡ 1960 0.953 ‡ 61.89
1.000
62.00
46.30
54.00
79.25
709 1.331
529 1.333
617 1.333
468 0.583
58.60
47.93
55.50
91.42
15b 1.000
15c
13a
1.000
0.318
13b 0.350 ‡ 59.14
‡ 296 0.600 ‡ 56.00
971 0.586 76.79
‡ 405 0.977 ‡ 31.12
21a 0.294 77.21
21b 0.735 ‡ 32.25
1
[a] Concentration in 10 mg mL 1. [b] Specific rotation in 10 1 degcm2 g
.
Figure 3. 1H NMR (500 MHz, CDCl3) of 22a, 22b, and 22c for the range
from d ˆ 5.4 ± 6.2 (CH tartaric acid).
1
[c] Molar rotation in 10 degcm2 mol
.
252
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Chem. Eur. J. 2000, 6, No. 2

Depsipeptide Dendrimers
247±257
more (TLC control, 5 min). Then the reaction was quenched by the
addition of water (50 mL). Solid NaHCO3 was added in small portions to
neutralize the solution. The crude product was extracted with EtOAc, the
solvent was removed, and the residue recrystallized twice from EtOAc.
Conclusion
We have disclosed a new concept of chiral dendrimers, which
consist of tartaric acid moieties as branching units and
peptides as spacers. We synthesized a first series of such
depsipeptide dendrimers including third-generation dendra
using a convergent approach. The corresponding dendritic
systems contain up to 21 stereogenic centers within the chiral
peptide or the building blocks derived from tartaric acid. This
impressively demonstrates the scope of this concept, since just
the variation of the chiral-pool building blocks, tartaric acid
and amino acid, whose different stereoisomers are readily
available, in principle allows for the formation of over two
million stereoisomers of those third-generation dendra. The
variation of just one stereogenic center can lead to a dramatic
change of properties. The fact that also the length and the
primary structure of the peptide can be varied demonstrates
that ideal requirements for the development of libraries are
met. First examples of depsipeptide mini libraries are
introduced. We are now in the process of synthesizing higher
generation dendra by using longer peptide spacers with small
C termini. We intend to look systematically into the biological
and catalytical properties of depsipeptide dendrimers by
developing and screening combinatorial libraries of this new
type of peptoids.
(2S,5R,6R)-1-Benzyl-7-methyl-5,6-bis(benzoyloxy)-2-methyl-4-oxo-3-aza-
heptanedicarboxylate (9): Compound 9 was synthesised according to
general procedure I with the tosylate 7 (3.51 g) and the carboxylic acid 8
(3.72 g). FC with toluene/EtOAc ˆ 4:1 (Rf ˆ 0.58). Yield 2.8 g (52%) sticky
solid; [a]2D0
ˆ
68.7 (c ˆ 2.095, CHCl3); 1H NMR (400 MHz, CDCl3, 248C,
TMS): d ˆ 1.41 (d, 3J ˆ 7.3 Hz, 3H; CH3), 3.73 (s, 3H; OCH3), 4.67 (dq,
3J1 ˆ 3J2 ˆ 7.1 Hz, 1H; CH alanine), 5.08 (d, 2J ˆ 12.3 Hz, 1H; CHH Bn),
2
3
5.14 (d, J ˆ 12.3 Hz, 1H; CHH Bn), 5.94 (d, J ˆ 2.2 Hz, 1H; CH tartaric
acid), 6.13 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid), 7.05 (d, 3J ˆ 7.1 Hz; NH),
7.26 ± 7.36 (m, 5H; Bn), 7.40 ± 7.64 (m, 6H; Bz), 8.08 ± 8.14 (m, 4H; o-H of
the Bz); 13C NMR (100.5 MHz, CDCl3, 248C, TMS): d ˆ 18.5 (CH3), 48.1
(CH alanine), 52.9 (OCH3), 67.3 (CH2), 71.9, 73.6 (CH tartaric acid), 128.0,
128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 130.1, 130.1 (phenyl C), 133.6, 134.2,
ˆ
135.0 (quaternary phenyl C), 164.7, 165.1, 165.3, 167.1, 172.2 (C O); IR
(KBr): nÄ ˆ 3358, 2954, 1762, 1730, 1665, 1524, 1600, 1584, 1524, 756,
‡
713 cm 1; MS (70 eV, EI): m/z (%): 533 (58) [M] , 398 (42), 355 (94), 105
‡
‡
(100) [C7H5O] , 77 (61) [C6H5] ; C29H27NO9 (533.57): calcd C 65.29, H 5.10,
N 2.63; found: C 65.00, H 5.04, N 2.87.
(2S,5R,6R)-7-Methyl-5,6-bis(benzoyloxy)-2-methyl-4-oxo-3-azaheptanedi-
carboxylate (10): Compound 10 was synthesized according to general
procedure III. Yield white solid (100%); [a]D20
ˆ
79.2 (c ˆ 1.540, CHCl3);
1H NMR (400 MHz, CDCl3, 238C, TMS): d ˆ 1.41 (d, 3J ˆ 7.3 Hz, 3H;
CH3), 3.72 (s, 3H; OCH3), 4.62 (dq, 3J1 ˆ 3J2 ˆ 7.1 Hz, 1H; CH alanine), 5.96
(d, 3J ˆ 2.3 Hz, 1H; CH tartaric acid), 6.12 (d, 3J ˆ 2.3 Hz, 1H; CH tartaric
acid), 7.01 (d, 3J ˆ 7.3 Hz, 1H; NH), 7.36 ± 7.65 (m, 10H; Bz), 8.04 ± 8.12 (m,
4H; o-H of the Bz group), 9.87 (br, 1H; CO2H); 13C NMR (100.5 MHz,
CDCl3, 238C, TMS): d ˆ 18.1 (CH3), 48.0 (CH alanine), 53.0 (OCH3), 71.8,
72.6 (CH tartaric acid), 128.2, 128.5, 128.6, 128.9, 130.0, 130.1 (phenyl C),
ˆ
133.7, 134.2 (quaternary phenyl C), 164.8, 165.2, 165.7, 167.2 (C O), 176.5
(CO2H); IR (KBr): nÄ ˆ 3400, 2954, 1738, 1652, 1585, 1493, 710 cm 1; MS
Experimental Section
‡
‡
‡
(70 eV, EI): m/z (%): 443 (7) [M] , 412 (11) [M
CH3O], 398 (41) [M
‡
‡
‡
CO2], 355 (70), 122 (23) [Ph CO2] , 105 (100) [Ph CO] , 77 (100) [Ph] ;
C22H21NO9 (443.44): calcd C 59.59, H 4.77, N 3.16; found: C 59.41, H 4.88, N
3.01.
1H NMR and 13C NMR spectra were recorded on JEOL GX400, JEOL
EX400, and JEOL A500 spectrometers. Mass spectra were measured with
Micromass Zab Spec (FAB) or Varian MAT (EI, 70 eV). IR spectra were
recorded on Bruker Vector 22. HPLC (preparative) were measured with
Shimadzu SIL 10A, SPD 10A, CBM 10A, LC 8A, FRC 10A (Nucleosil 100-
5, Machery-Nagel). HPLC (analytical) were measured with Shimadzu
CBM-10A, SPD-M10A, SIL-10A, LC-10AT (Nucleosil 100 Si, 5 m). TLC
(5S,8R,9R)-1-Benzyl-10-methyl-8,9-bis(benzoyloxy)-4,7-dioxo-5-methyl-
3,6-diazadecanedicarboxylate (12a): Compound 12a was synthesized
according to general procedure I with the bromide 11 (3.17 g) and the
carboxylic acid 8 (3.72 g). FC with toluene/EtOAc ˆ 3:1 (Rf ˆ 0.23). Yield
3.4 g (58%) white solid; [a]D20
ˆ
45.65 (c ˆ 0.414, CHCl3); 1H NMR
È
(Riedel-de Haen, silica gel 60 F254). Materials and solvents were obtained
3
(400 MHz, CDCl3, 328C, TMS): d ˆ 1.36 (d, J(H,H) ˆ 6.8 Hz, 3H; CH3),
3.71 (s, 3H; OCH3), 3.71 (dd, 3J1 ˆ 5.1, 2J2 ˆ 15 Hz, 1H; CHH glycine), 3.88
(dd, 3J1 ˆ 5.6 Hz, 2J2 ˆ 14.2, 1H; CHH glycine), 4.64 (dq, 3J1 ˆ 3J2 ˆ 7 Hz,
1H; CH alanine), 5.06 (s, 2H; CH2 Bn), 5.96 (d, 3J ˆ 2.5 Hz, 1H; CH
tartaric acid), 6.1 (d, 3J ˆ 2.5 Hz, 1H; CH tartaric acid), 6.89 (dd, 3J1 ˆ 3J1 ˆ
from commercial suppliers and were used without further purification.
Products were isolated by flash column chromatography (FC) (silica gel 60,
particle size 0.04 ± 0.063 nm, Merck) or recrystallization.
General procedure I for the amide formation: NEt3 (1.4 mL, 10 mmol) was
added to a suspension of 10 mmol of the hydrobromide or the tosylate in
CH2Cl2 (150 mL) to release the amine. The solution was cooled to 58C.
The equivalent amount of the carboxylic acid and (2.06 g, 10 mmol) of
DCC were added all at once. The mixture was stirred for two hours at 08C
and then overnight at room temperature. The white precipitate of
dicyclohexylurea (DCU) was filtered, the CH2Cl2 layer was washed three
times with a saturated solution of NaHCO3 (500 mL) in water and dried
over MgSO4. After removal of the solvent the crude product was purified
by FC.
3
5.4 Hz, 1H; NH glycine), 7.29 (d, J ˆ 1.7 Hz, 1H; NH alanine), 7.30 ± 7.64
(m, 11H; Bn, Bz), 8.01 ± 8.11 (m, 4H; o-H of the Bz group); 13C NMR
(100.5 MHz, CDCl3, 328C, TMS): d ˆ 18.4 (CH3), 41.1 (CH2 glycine), 48.5
(CH alanine), 52.9 (OCH3), 67.1 (CH2 Bn), 71.9, 72.6 (CH tartaric acid),
128.2, 128.2, 128.3, 128.5, 128.6, 128.9 (phenyl C), 133.6, 134.2, 135.1
ˆ
(quaternary phenyl C), 164.8, 165.1, 165.7, 167.0, 169.2, 171.7 (C O); IR
1
(KBr): nÄ ˆ 3389, 2949, 1758, 1662, 1644, 1550, 1455, 1199, 1126, 912 cm
;
‡
‡
MS (70 eV, EI): m/z (%): 590 (68) [M] , 559 (57) [M CH3O] , 483 (26)
[M C7H7O] , 426 (100); C31H30N2O10 (590.63): calcd C 63.04, H 5.13, N
‡
General procedure II for the ester formation: The carboxylic acid
(2.2 mmol) and then DCC (2.27 g, 1.1 mmol)and DMAP (10 mg) were
added at room temperature to a solution of the diol (1 mmol) in dry
dioxane or THF (150 mL). After 10 min the first DCU was formed. The
solution was stirred for five hours. The precipitate (DCU) was filtered, the
solvent removed, and the crude product purified by FC or HPLC.
4.74; found: C 63.66, H 5.19, N 4.77.
(5S,8S,9S)-1-Benzyl-10-methyl-8,9-bis(benzoyloxy)-4,7-dioxo-5-methyl-
3,6-diazadecanedicarboxylate (12b): Compound 12b was synthesized
according to the procedure used for 12a. FC with toluene/EtOAc ˆ 3:1
(Rf ˆ 0.23). Yield 3.1 g (53%) white solid; [a]2D0 ˆ 64.98 (c ˆ 0.414, CHCl3);
1H NMR (400 MHz, CDCl3, 328C): d ˆ 1.30 (d, 3J ˆ 7.2 Hz, 3H; CH3), 3.72
(s, 3H; OCH3), 3.99 (d, 5.0 Hz, 2H; CH2 glycine), 4.61 (dq, 3J1 ˆ 3J2 ˆ
7.2 Hz, 1H; CH alanine unit), 5.13 (s, 2H; CH2 Bn group), 5.98 (d, 3J ˆ
General procedure III for the removal of the Bn ester: The Bn ester was
dissolved in dioxane and 10 mass percent of Pd C (10% Pd) were added.
This suspension was subjected to hydrogenation until no more hydrogen
was consumed. The Pd C was filtered over aluminium oxide. The dioxane
was evaporated and the product dried in vacuo.
3
2.8 Hz, 1H; CH tartaric acid), 6.05 (d, J ˆ 2.8 Hz, 1H; CH tartaric acid),
6.86 (dd, 3J1 ˆ 3J1 ˆ 5.5 Hz, 1H; NH), 7.26 (m, 1H; NH), 7.30 ± 7.63 (m, 11H;
Bn, Bz), 8.06 ± 8.10 (m, 4H; o-H of the Bz group); 13C NMR (100.5 MHz,
CDCl3, 328C): d ˆ 18.5 (CH3), 41.3 (CH2 glycine), 48.7 (CH alanine), 52.9
(OCH3), 67.2 (CH2 Bn), 71.9, 72.8 (CH tartaric acid), 128.2, 128.3, 128.5,
128.6, 128.6, 128.8, 129.0, 129.9, 130.0 (phenyl C), 133.7, 134.1, 135.0
General procedure IV for the removal of the benzylidene acetal: A
suspension of the benzylidene acetal (10 mmol) in TFA (4 mL) and water
(5 drops) was stirred at 08C until no starting material could be detected any
Chem. Eur. J. 2000, 6, No. 2
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0947-6539/00/0602-0253 $ 17.50+.50/0
253

A. Hirsch et al.
FULL PAPER
ˆ
(quaternary phenyl C), 164.9, 165.0, 165.6, 167.0, 169.3, 171.7 (C O); IR
(KBr): nÄ ˆ 3385, 3067, 2955, 1734, 1660, 1601, 1524, 1453, 1359, 1317, 1246,
NH), 7.42 ± 7.64 (m, 12H; phenyl rings), 8.07 (m, 8H; o-H of the Bz group);
13C NMR (100.5 MHz, CDCl3, 258C): d ˆ 18.4 (CH3), 41.1 (CH2 glycine),
48.6 (CH alanine), 53.0, 53.3 (OCH3), 71.7, 71.9, 72.5 (CH tartaric acid),
128.2, 128.6, 128.8, 130.1 (phenyl C), 133.7, 134.1 (quaternary phenyl C),
‡
1093, 1069, 1025, 712 cm 1; MS (70 eV, EI): m/z (%): 590 (2) [M] , 559 (2)
‡
‡
[M CH3O] , 355 (65), 105 (100) [PhCO] ; C31H30NO10 (590.63): calcd C
ˆ
63.04, H 5.13, N 4.74; found: C 63.10, H 5.19, N 4.72.
158.5, 165.0, 165.2, 165.6, 167.1, 167.8, 172.0 (C O); IR (KBr) ˆ 3406, 2957,
1763, 1733, 1670, 1602, 1529, 1452, 1317, 1248, 1177, 1095, 1071, 1025,
(5S,8R,9R)-10-Methyl-8,9-bis(benzoyloxy)-4,7-dioxo-5-methyl-3,6-diaza-
decanedicarboxylate (13a): Compound 13a was synthesized according to
714 cm 1; MS (FAB): m/z (%): 1275 (7) [M‡Cs] , 1143 (36) [M] , 718
(100), 355 (65); C54H54N4O24 (1143.12): calcd C 56.74, H 4.76, N 4.90; found:
C 56.81, H 4.65, N 4.67.
‡
‡
general procedure III. Yield white solid (100%); [a]D20
ˆ
79.25 (c ˆ 0.318,
MeOH); 1H NMR (400 MHz, CD3OD, 228C): d ˆ 1.32 (d, 3J ˆ 7.1 Hz, 3H;
CH3), 3.73 (s, 3H; OCH3), 3.74 (d, 2J ˆ 17.8 Hz, 1H; CHH glycine), 3.84 (d,
2J ˆ 17.8 Hz, 1H; CHH glycine), 4.50 (m, 1H; CH alanine), 5.97 (d, 3J ˆ
3.2 Hz, 1H; CH tartaric acid), 7.48 ± 7.54, 7.62 ± 7.67 (m, 6H; Bz), 8.06 ± 8.11
(m, 4H, o-H of the Bz group); 13C NMR (100.5 MHz, CD3OD, 228C): d ˆ
18.3 (CH3), 41.7 (CH2 glycine), 50.1 (CH alanine), 53.5 (OCH3), 73.2, 73.9
(CH tartaric acid), 129.3, 129.5, 129.8, 130.0, 130.9, 131.0 (phenyl C), 135.0,
Tetramethyl(3R,4R,7S,13R,14S,20S,23R,24R)-4,23-bis(benzoyloxy)-7,20-
dimethyl-1,5,8,11,16,19,22,26-octaoxo-1,26-diphenyl-2,12,15,25-tetraoxa-
6,9,18,21-tetraazahexacosane-3,13,14,24-tetracarboxylate (15c): Com-
pound 15c was synthesized according to the procedure used for 15a, but
with (meso)-dimethyl tartrate 14c as diol. FC with toluene/EtOAc ˆ 3:5
(Rf ˆ 0.30). Yield 0.64 g (56%) white solid; [a]D20
ˆ
54.00 (c ˆ 1.000,
CHCl3); 1H NMR (400 MHz, CDCl3, 328C): d ˆ 1.34 (m, 6H; CH3), 3.71 (s,
3H; OCH3), 3.72 (s, 3H; OCH3), 3.74 (s, 3H; OCH3) 3.75 (s, 3H; OCH3),
3.85 (m, 3H; CH2 glycine), 3.94 (dd, 3J1 ˆ 6.1 Hz, 3J2 ˆ 18.2 Hz, 1H; CH2
ˆ
135.1 (quaternary phenyl C), 166.59, 166.6, 167.4, 168.5, 172.5, 174.3 (C O);
IR (KBr): nÄ ˆ 3386, 3068, 2956, 1732, 1656, 1533, 1453, 1317, 1248, 1095,
‡
1025, 712 cm 1; MS (FAB): m/z (%): 501 (100) [M] , 426 (33), 379 (21)
‡
‡
glycine), 4.62 (dq, J1 ˆ 3J2 ˆ 7.2 Hz, 1H; CH alanine), 4.69 (dq, J1 ˆ 3J2 ˆ
7.2 Hz, 1H; CH alanine), 5.51 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid), 5.59 (d,
3J ˆ 2.8 Hz, 1H; CH tartaric acid), 5.97 (d, 3J ˆ 2.8 Hz, 1H; CH tartaric
3
3
[M PhCO2H] , 355 (46), 322 (28) [M PhCO2H CO2CH3] ;
C24H24N2O10 (500.50): calcd C 57.59, H 4.84, N 5.60; found: C 57.75, H
5.10, N 5.44.
3
3
acid), 5.99 (d, J ˆ 3.3 Hz, 1H; CH tartaric acid), 6.01 (d, J ˆ 3.3 Hz, 1H;
CH tartaric acid), 6.02 (d, 3J ˆ 2.8 Hz, 1H; CH tartaric acid), 7.33 (m, 2H, 2
NH), 7.40 ± 7.63 (m, 14H; phenyl rings, 2 NH), 8.06 (m, 8H; o-H of the Bz
group); 13C NMR (100.5 MHz, CDCl3, 328C): d ˆ 17.7, 18.4 (CH3), 40.9
(2 Â CH2 glycine), 48.4, 48.5 (CH alanine), 52.8, 52.9, 52.9, 53.0 (OCH3),
70.8, 71.1 (CH tartaric acid), 71.7, 72.7 (4 Â CH tartaric acid), 128.2, 128.4,
128.5, 128.6, 128.7, 129.9, 130.0 (phenyl C), 133.6, 133.7, 134.0 (quaternary
phenyl C), 164.9, 164.94, 165.4, 165.5, 165.7, 165.8, 166.9, 167.0, 167.76,
(5S,8S,9S)-10-Methyl-8,9-bis(benzoyloxy)-4,7-dioxo-5-methyl-3,6-diazade-
canedicarboxylate (13b): Compound 13b was synthesized according to the
procedure used for 13a. Yield white solid (100%); [a]2D0 ˆ ‡59.14 (c ˆ
0.350, MeOH); 1H NMR (400 MHz, CD3OD, 328C): d ˆ 1.21 (d, 3J ˆ
6.6 Hz, 3H; CH3), 3.67 (s, 3H; OCH3), 3.81 (m, 2H; CH2 glycine), 4.60
3
(m, 1H; CH alanine), 5.94 (d, J ˆ 2.8 Hz, 1H; CH tartaric acid), 5.97 (d,
3J ˆ 2.2 Hz, 1H; tartaric acid), 7.11 (m, 1H; NH), 7.39 ± 7.58 (m, 6H; Bz),
7.63 (d, 3J ˆ 7.7 Hz, 1H; NH), 8.02 ± 8.03 (d, 3J ˆ 7.7 Hz, 4H; o-H of the Bz
group), 10.60 (br, 1H; acid proton); 13C NMR (100.5 MHz, CD3OD, 328C):
d ˆ 18.3 (CH3), 41.1 (CH2 glycine), 48.7 (CH alanine unit), 53.0 (OCH3),
71.7, 72.7 (CH tartaric acid ), 128.2, 128.2, 128.5, 128.7, 129.0, 129.9, 130.0
(phenyl C), 133.8, 134.1, 135.0 (quaternary phenyl C), 165.0, 165.1, 166.0,
ˆ
ˆ
167.80, 172.2, 172.3 (C O), 165.2 (2  C O); IR (KBr): nÄ ˆ 3406, 2958,
1765, 1734, 1674, 1602, 1585, 1452, 1317, 1249, 1178, 1095, 1070, 1025, 803,
713 cm 1; MS (FAB): m/z (%): 1275 (25) [M‡Cs] , 1143 (39) [M] , 718
‡
‡
‡
(100) [M 426] (see Figure 1), 355 (58); C54H54N4O24 (1143.12): calcd C
56.74, H 4.76, N 4.90; found: C 56.31, H 4.94, N 4.84.
ˆ
167.0, 171.3, 172.1, 172.4 (C O); IR (KBr): nÄ ˆ 3405, 2956, 1734, 1658, 1602,
1530, 1453, 1318, 1246, 1178, 1093, 1069, 1025, 711 cm 1; MS (70 eV, EI):
(5S,8R,9R)-1-Benzyl-10-methyl-8,9-(phenylmethylenedioxy)-4,7-dioxo-5-
methyl-3,6-diazadecanedicarboxylate (18a): Compound 18a was synthe-
sized according to general procedure I with the hydrobromide 11 (3.17 g)
and the acid 16a (2.52 g). FC with toluene/EtOAc ˆ 1:1 (Rf ˆ 0.46). Yield
2.40 g (51%) white solid; mixture of two diastereomers; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d ˆ 1.34 (d, 3J ˆ 6.8 Hz, 3H; CH3), 1.44
(d, 3J ˆ 7.1 Hz, 3H; CH3), 3.77 (s, 3H; OCH3), 3.82 (s, 3H; OCH3), 4.09 (m,
4H; CH2 of the two glycine), 4.62 (dq, 3J1 ˆ 3J2 ˆ 7.1 Hz, 1H; CH alanine),
‡
‡
‡
m/z (%): 501 (2) [M] , 355 (100), 327 (27) [355 CO] , 105 (100) [PhCO] ;
C24H24N2O10 (500.46) calcd C 57.60, H 4.83, N 5.60; found: C 57.70, H 4.96,
N 5.57.
Tetramethyl(3R,4R,7S,13R,14R,20S,23R,24R)-4,23-bis(benzoyloxy)-7,20-
dimethyl-1,5,8,11,16,19,22,26-octaoxo-1,26-diphenyl-2,12,15,25-tetraoxa-
6,9,18,21-tetraaza hexacosane-3,13,14,24-tetracarboxylate (15a): Com-
pound 15a was synthesized according to general procedure II with the
carboxylic acid 13a (1.10 g)and (l)-tartaric acid dimethylester 14a (0.18 g).
FC with toluene/EtOAc ˆ 3:5 (Rf ˆ 0.33). Yield 0.62 g (54%) white solid;
3
3
4.73 (dq, J1 ˆ 3J2 ˆ 7.3 Hz, 1H; CH alanine), 4.77 (d, J ˆ 3.9 Hz, 1H; CH
tartaric acid), 4.89 (d, 3J ˆ 4.6 Hz, 1H; CH tartaric acid), 4.94 (d, 3J ˆ
3
[a]2D0
ˆ
62.00 (c ˆ 1.000, CHCl3); 1H NMR (400 MHz, CDCl3, 238C,
3.6 Hz, 1H; CH tartaric acid), 5.00 (d, J ˆ 3.7 Hz, 1H; CH tartaric acid),
TMS): d ˆ 1.34 (d, 3J ˆ 7.1 Hz, 3H; CH3), 3.65 (s, 3H; OCH3), 3.70 (s, 3H;
OCH3), 3.75 (dd, 3J1 ˆ 5.4 Hz, 3J2 ˆ 18.1 Hz, 2H; CHH), 3.92 (dd, 3J1 ˆ
5.9 Hz, 3J2 ˆ 18.1 Hz, 2H; CHH), 4.59 (dq, 3J1 ˆ 3J2 ˆ 7.3 Hz, 2H; CH
alanine), 5.58 (s, 2H; CH central tartaric acid), 5.95 (d, 3J1 ˆ 2.9 Hz, 2H;
CH tartaric acid), 6.04 (d, 3J1 ˆ 2.7 Hz, 2H; CH tartaric acid), 6.89 (dq,
3J1 ˆ 3J2 ˆ 5.7 Hz, 2H; NH), 7.14 (d, 3J ˆ 7.6 Hz, 2H; NH), 7.39 ± 7.62 (m,
12H; phenyl rings), 8.02 (d, 3J ˆ 7.3 Hz, 4H; o-H of the Bz group), 8.05 (d,
3J ˆ 7.3 Hz, 4H; o-H of the Bz group); 13C NMR (100.5 MHz, CDCl3, 238C,
TMS): d ˆ 18.1 (CH3), 40.9 (CH2 glycine), 48.5 (CH alanine), 53.0, 53.2
(OCH3), 71.0, 71.8, 72.7 (CH tartaric acid), 128.1, 128.6, 128.8, 130.0 (phenyl
C), 133.7, 134.1 (quaternary phenyl C), 164.9, 165.2, 165.5, 165.9, 167.0,
5.16 (m, 4H; CH2 Bn), 6.01, 6.14 (s, 2H; CH acetal), 7.06 ± 7.57 (m, 26H;
phenyl rings and four NH); 13C NMR (100.5 MHz, CDCl3, 258C, TMS): d
ˆ18.0, 18.2 (CH3), 41.3 (CH2 glycine), 48.4, 48.5 (CH alanine), 52.8
(OCH3), 67.1, 67.2 (CH2 Bn group), 77.2, 77.9, 77.98, 78.14 (CH tartaric acid),
106.1, 106.4 (CH acetal), 127.0, 127.2, 128.4, 128.5, 128.6, 128.7, 130.1, 130.2
(phenyl C), 135.0, 135.16, 135.2 (quaternary phenyl C), 169.2, 169.5, 169.56,
ˆ
169.60, 170.4, 171.7, 172.2 (C O); IR (KBr): nÄ ˆ 3424, 2929, 1764, 1736,
1644, 1541, 1451, 1240, 1218, 1111, 1028, 752, 697 cm 1; MS (FAB): m/z (%):
‡
471 (100) [M] , 225 (36); C24H26N2O8 (470.478): calcd C 61.27, H 5.57, N
5.95; found: C 62.16, H 5.90, N 6.04.
(5S,8S,9S)-1-Benzyl-10-methyl-8,9-(phenylmethylenedioxy)-4,7-dioxo-5-
methyl-3,6-diazadecanedicarboxylate (18b): Compound 18b was synthe-
sized according to general procedure I with the hydrobromide 11 (3.17 g)
and the acid 16b (2.52 g). FC with toluene/EtOAc ˆ 1:1 (Rf ˆ 0.30). Yield
2.22 g (47%) white solid; mixture of two diastereomers; 1H NMR
ˆ
167.9, 171.8 (C O); IR (KBr): nÄ ˆ 3388, 2957, 1734, 1675, 1602, 1521, 1453,
1247, 1174, 1094, 1070, 1025, 713, 687 cm 1; MS (FAB) m/z (%): 1143 (39)
‡
‡
[M] , 718 (35) [M 426] (see Figure 1), 355 (34); C54H54N4O24 (1143.12):
calcd C 56.74, H 4.76, N 4.90; found: C 56.83, H 5.01, N 5.14.
3
3
Tetramethyl(3R,4R,7S,13S,14S,20S,23R,24R)-4,23-bis(benzoyloxy)-7,20-
dimethyl 1,5,8,11,16,19,22,26-octaoxo-1,26-diphenyl-2,12,15,25-tetraoxa-
6,9,18,21-tetraazahexacosane-3,13,14,24-tetracarboxylate (15b): Com-
pound 15b was synthesized according to the procedure used for 15a, but
with (d)-dimethyl tartrate 14b as diol. FC with toluene/EtOAc ˆ 3:5 (Rf ˆ
(400 MHz, CDCl3, 238C): d ˆ 1.13 (d, J ˆ 6.1 Hz, 3H; CH3), 1.16 (d, J ˆ
7.1 Hz, 3H; CH3), 3.71 (s, 3H; OCH3), 3.79 (s, 3H; OCH3), 3.98 (m, 4H;
CH2 glycine), 4.42 (m, 1H; CH alanine), 4.56 (m, 1H; CH alanine), 4.69 (d,
3J ˆ 3.2 Hz, 1H; CH tartaric acid), 4.80 (d, 3J ˆ 4.6 Hz, 1H; CH tartaric
3
3
acid), 4.88 (d, J ˆ 4.4 Hz, 1H; CH tartaric acid), 5.00 (d, J ˆ 3.2 Hz, 1H;
CH tartaric acid), 5.08 (s, 2H; CH2 Bn), 5.09 (s, 2H; CH2 Bn), 6.71 ± 6.85
(m, 4H; NH), 7.19 ± 7.48 (m, 20H, phenyl rings); 13C NMR (100.5 MHz,
CDCl3, 238C): d ˆ 17.3, 18.2 (CH3), 41.3 (CH2 glycine), 48.4, 48.6 (CH
alanine), 52.8 (OCH3), 67.2, 67.3 (CH2 Bn group), 77.1, 77.9, 78.0, 78.1 (CH
tartaric acid), 106.1, 106.2 (CH acetal), 126.5, 127.0, 128.4, 128.5, 128.6,
130.1 (phenyl C), 135.2, 135.6 (quaternary phenyl C), 169.1, 169.4, 169.43,
0.33). Yield 0.58 g (51%) white solid; [a]D20
ˆ
46.30 (c ˆ 1.000, CHCl3);
1H NMR (400 MHz, CDCl3, 238C): d ˆ 1.33 (d, 3J ˆ 6.3 Hz, 3H; CH3), 3.71
(s, 3H; OCH3), 3.74 (s, 3H; OCH3), 3.85 (m, 4H; CH2 glycine), 4.62 (dq,
3J1 ˆ 2J2 ˆ 7.3 Hz, 2H; CH alanine), 5.66 (s, 2H; CH central tartaric acid),
5.99 (d, 3J ˆ 3.2 Hz, 2H; CH tartaric acid), 6.07 (d, 3J ˆ 3.2 Hz, 2H; CH
tartaric acid), 7.00 (dq, 3J1 ˆ 2J2 ˆ 5.6 Hz, 2H; NH), 7.23 (d, 3J ˆ 7.6 Hz, 2H;
254
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0602-0254 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 2

Depsipeptide Dendrimers
247±257
ˆ
170.1 (C O); IR (KBr): nÄ ˆ 3306, 3276, 2927, 1733, 1641, 1552, 1443, 1242,
CHCl3); 1H NMR (400 MHz, CDCl3, 328C): d ˆ 1.24 (d, 3J ˆ 7.2 Hz, 3H;
CH3), 1.28 (d, 3J ˆ 7.1 Hz, 3H; CH3), 1.31 (d, 3J ˆ 7.1 Hz, 3H; CH3), 3.42 (s,
3H; OCH3), 3.65 (s, 3H; OCH3), 3.72 (s, 3H; OCH3), 3.80 ± 3.87 (m, 3H;
CHH, CHH glycine), 4.05 ± 4.20 (m, 2H; CH2 glycine), 4.27 ± 4.36 (m, 2H;
CHH glycine and CH alanine), 4.58 (dq, 3J1 ˆ 3J2 ˆ 7.1 Hz, 1H; CH
alanine), 4.66 (dq, 3J1 ˆ 3J2 ˆ 7.7 Hz, 1H; CH alanine), 5.09 (s, 2H; CH2
‡
1228, 1154, 1016, 757, 698 cm 1; MS (70 eV, EI): m/z (%): 470 (2) [M] , 411
‡
‡
‡
(4) [M CO2CH3] , 278 (48) [M PhCO2] , 91 (100) [PhCH2] ;
C24H26N2O8 (470.478): calcd C 61.27, H 5.57, N 5.95; found: C 60.69, H
5.62, N 5.96.
(5S,8R,9R)-1-Benzyl-10-methyl-8,9-dihydroxy-4,7-dioxo-5-methyl-3,6-di-
azadecanedicarboxylate (19a): Compound 19a was synthesized according
to general procedure IV. Yield 82% white solid; [a]2D0 ˆ ‡27.5 (c ˆ 1.020,
MeOH); 1H NMR (400 MHz, CD3OD, 218C): d ˆ 1.39 (d, 3J ˆ 7.3 Hz, 3H;
CH3), 3.77 (s, 3H, OCH3), 3.94 (d, 2J ˆ 17.6 Hz, 1H; CHH glycine), 3.99 (d,
2J ˆ 17.6 Hz, 1H; CHH glycine), 4.45 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid),
4.49 (m, 1H; CH alanine), 4.56 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid), 4.85
(br; OH), 5.15 (s, 2H; CH2 Bn), 7.34 (m, 7H; phenyl ring and NH);
13C NMR (100.5 MHz, CD3OD, 218C): d ˆ 18.1 (CH3), 42.0 (CH2 glycine),
48.4 (CH alanine), 52.8 (OCH3), 67.9 (CH2 Bn), 73.9, 74.3 (CH tartaric
acid), 129.3, 129.5 (phenyl C), 137.1 (quaternary phenyl C), 170.9, 173.7,
3
3
Bn), 5.59 (d, J1 ˆ 2.8 Hz, 1H; CH tartaric acid), 5.63 (d, J1 ˆ 2.8 Hz, 1H;
CH tartaric acid), 5.88 (d, 3J1 ˆ 2.8 Hz, 1H; CH tartaric acid), 6.00 (d, 3J1 ˆ
2.2 Hz, 1H; CH tartaric acid), 6.02 (d, 3J1 ˆ 2.8 Hz, 1H; CH tartaric acid),
3
6.20 (d, J1 ˆ 2.2 Hz, 1H; CH tartaric acid), 6.66 (br, 1H; NH), 7.13 ± 7.61
(m, 17H; phenyl rings and 5 NH), 7.99 ± 8.04 (m, 8H; o-H of the Bz group);
13C NMR (100.5 MHz, CDCl3, 328C): d ˆ 17.7, 18.2, 18.6 (CH3), 40.8, 41.3,
41.7 (CH2 glycine), 48.1, 48.7, 48.9 (CH alanine), 52.9 (2 Â ), 53.0 (OCH3),
67.2 (CH2), 71.1, 71.7, 71.8, 72.5, 72.7, 73.0 (CH tartaric acid), 128.2, 128.3,
128.4, 128.44, 128.5, 128.6, 128.64, 128.8, 128.81, 129.0, 129.9, 129.96 (phenyl
C), 133.8, 134.0, 134.1, 135.0 (quaternary phenyl C), 164.6, 164.8, 164.9,
165.1 (2 Â ), 165.8, 166.5, 166.7, 167.1, 167.8, 168.0, 169.9, 171.7, 171.8, 173.0
173.8, 175.0 (C O); IR (KBr): nÄ (cm 1) ˆ 3350, 3291, 3118, 2950, 1758, 1645,
ˆ
ˆ
(C O); IR (KBr): nÄ ˆ 3387, 2931, 1736, 1671, 1601, 1522, 1453, 1246, 1178,
1575, 1550, 1412, 1388, 1276, 1199, 1126, 1078, 912, 736, 697; MS (70 eV, EI):
‡
‡
1093, 1069, 1025, 713 cm 1; MS (FAB): m/z (%): 1347 (45) [M] , 922 (24),
m/z (%): 382 (4) [M] , 190 (100); C17H22N2O8 (382.41): calcd C 53.39, H
5.81, N 7.33; found: C 53.86, H 6.12, N 7.22.
729 (20), 355 (52), 307 (100); C65H66N6O26 (1347.37): calcd C 57.95, H 4.94, N
6.24; found: C 58.11, H 5.02, N 6.20.
(5S,8S,9S)-1-Benzyl-10-methyl-8,9-dihydroxy-4,7-dioxo-5-methyl-3,6-di-
azadecanedicarboxylate (19b): Compound 19b was synthesized according
(4R,5R,8S,14R,15R,18S)-4,5-Bis(benzoyloxy)-15-({2-[((2S)-2-{[(2R,3R)-
2-(benzoyloxy)-3,4-dimethoxy-4-oxobutanoyl]amino} propanoyl)amino]-
acetyl}oxy)-14-(methoxycarbonyl)-8,18-dimethyl-3,6,9,12,16,19-hexaoxo-
2,13-dioxa-7,10,17,20-tetraazadocosan-22-oic acid (21a): Compound 21a
was synthesized according to general procedure III. Yield white solid
to the procedure used for 19a, but with 18b as the starting material. Yield
79% white solid; [a]D20
ˆ
65.30 (c ˆ 0.268, MeOH); H NMR (400 MHz,
1
CD3OD, 328C): d ˆ 1.38 (d, 3J ˆ 7.2 Hz, 3H, CH3), 3.76 (s, 3H; OCH3), 3.95
(d, 2J ˆ 17.6 Hz, 1H; CHH glycine), 4.03 (d, 2J ˆ 17.6 Hz, 1H; CHH
glycine), 4.43 (d, 3J ˆ 2.2 Hz, 1 H, CH tartaric acid), 4.48 (dq, 3J1 ˆ 3J2 ˆ
7.1 Hz, 1H; CH alanine), 4.58 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid), 4.85 (s;
OH from the product and the solvent), 5.15 (s, 2H; CH2 Bn), 7.30 ± 7.35 (m,
7H; phenyl ring and NH); 13C NMR (100.5 MHz, CD3OD, 328C): d ˆ 18.6
(CH3), 42.1 (CH2 glycine), 48.4 (CH alanine), 52.7 (OCH3), 67.9 (CH2 Bn),
73.5, 74.3 (CH tartaric acid), 129.30, 129.31, 129.5 (phenyl C), 137.1
(100%); [a]2D0
ˆ
77.21 (c ˆ 0.294, MeOH); 1H NMR (400 MHz, CDCl3,
3
198C): d ˆ 1.30 (m, 6H; CH3), 1.37 (d, J ˆ 7.3 Hz, 3H; CH3), 3.69 (s, 3H;
OCH3), 3.73 (s, 6H; OCH3), 3.77 ± 3.94 (m, 7H; CH2 glycine, CH alanine),
4.45 (m, 2H; CH alanine), 5.66 (d, 3J ˆ 2.9 Hz, 1H; CH tartaric acid), 5.67
(d, 3J ˆ 2.9 Hz, 1H; CH tartaric acid), 5.98 (m, 4H; CH tartaric acid), 7.46 ±
7.66 (m, 12H; phenyl rings), 8.04 ± 8.09 (m, 8H; o-H of the Bz group);
13C NMR (100.5 MHz, CDCl3, 208C): d ˆ 17.4, 17.9, 18.5 (CH3 alanine),
40.9, 41.2, 41.7 (CH2 glycine), 48.6, 48.7, 49.0 (CH alanine), 53.0, 53.1
(OCH3), 71.2, 71.7, 71.8, 72.3, 72.5, 72.7 (CH tartaric acid), 128.2, 128.3,
128.5, 128.6, 128.61, 128.7, 128.8, 129.9, 130.0 (phenyl C), 133.8, 134.0
(quaternary phenyl C), 165.1, 165.3, 165.7, 165.9, 166.6, 166.9, 167.5, 168.6,
ˆ
(quaternary phenyl C), 170.9, 173.4, 174.0, 175.1 (C O); IR (KBr): nÄ ˆ
3369, 3265, 3085, 2929, 1736, 1659, 1554, 1532, 1456, 1440, 1374, 1337, 1290,
1225, 1117, 1065, 1025, 968, 870, 758, 700 cm 1; MS (70 eV, EI): m/z (%): 382
‡
‡
(4) [M] , 190 (100), 91 (100) [C7H7] ; C17H22N2O8 (382.41): calcd C 53.39, H
5.81, N 7.33; found: C 53.62, H 5.85, N 7.35.
ˆ
172.4, 173.1, 173.6 (C O); IR (KBr): nÄ ˆ 3377, 3070, 2956, 1734, 1671, 1602,
Trimethyl(3R,4R,7S,13R,14R,20S,23R,24R)-4,23-bis(benzoyloxy)-14-
{[((1S)-2-{[2-(benzyloxy)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)amino]-
carbonyl}-7,20-dimethyl-1,5,8,11,16,19,22-heptaoxo-1-phenyl-2,12,15,25-
tetraoxa-6,9,18,21-tetraazahexacosane-3,13,24-tricarboxylate (20a): Com-
pound 20a was synthesized according to general procedure II with the diol
19a (0.38 g) and the carboxylic acid 13a (1.10 g). FC with toluene/EtOAc ˆ
1528, 1453, 1248, 1178, 1095, 1070, 1025, 713, 687 cm 1; MS (FAB): m/z
‡
‡
‡
(%): 1389 (100) [M‡Cs] , 1279 (80) [M‡Na] , 1257 (84) [M] , 832 (57)
‡
[M‡H 426] , 729 (24) [see Figure 1], 426 (29) [see Figure 1], 355 (79);
C58H60N6O26 (1257.24): calcd C 55.41, H 4.81, N 6.69; found: C 55.26, H 4.90,
N 6.61.
1:2 (Rf ˆ 0.20). Yield 0.88 g (65%) white solid; [a]D20
ˆ
59.87 (c ˆ 0.785,
(4S,5S,8S,14S,15S,18S)-4,5-Bis(benzoyloxy)-15-({2-[((2S)-2-{[(2R,3R)-2-
(benzoyloxy)-3,4-dimethoxy-4-oxobutanoyl]amino} propanoyl)amino]ace-
tyl}oxy)-14-(methoxycarbonyl)-8,18-dimethyl-3,6,9,12,16,19-hexaoxo-2,13-
dioxa-7,10,17,20-tetraazadocosan-22-oic acid (21b): Compound 21b was
synthesized according to general procedure III. Yield white solid (100%);
[a]2D0 ˆ ‡32.25 (c ˆ 0.735, MeOH); 1H NMR (400 MHz, CDCl3, 328C): d ˆ
CHCl3); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 1.26 (m, 6H; CH3),
1.37 (d, 3J ˆ 7.1 Hz, 3H; CH3), 3.60 (s, 3H; OCH3), 3.65 (s, 3H; OCH3), 3.72
(s, 3H; OCH3), 3.52 ± 3.85, 4.01 ± 4.15 (m, 6H; CH2 glycine), 4.49 (dq, 3J1 ˆ
3J2 ˆ 7.3 Hz, 1H; CH alanine), 4.70 (dq, 3J1 ˆ 3J2 ˆ 7.6 Hz, 1H; CH alanine),
4.75 (dq, 3J1 ˆ 3J2 ˆ 7.1 Hz, 1H; CH alanine), 5.07 (s, 2H; CH2 Bn), 5.70 (d,
3J1 ˆ 2.7 Hz, 1H; CH tartaric acid), 5.73 (d, 3J1 ˆ 2.7 Hz, 1H; CH tartaric
acid), 6.00 (d, 3J1 ˆ 3.4 Hz, 1H; CH tartaric acid), 6.02 (d, 3J1 ˆ 3.2 Hz, 1H;
CH tartaric acid), 6.09 (d, 3J1 ˆ 3.4 Hz, 1H; CH tartaric acid), 6.15 (d, 3J1 ˆ
3.4 Hz, 1H; CH tartaric acid), 7.21 ± 7.84 (m, 23H; phenyl rings and NH),
8.02 ± 8.09 (m, 8H; o-H of the Bz group); 13C NMR (100.5 MHz, CDCl3,
258C, TMS): d ˆ 17.5, 18.1, 18.8 (CH3), 41.2, 41.3, 41.7 (CH2 glycine), 48.5,
48.6, 49.2 (CH alanine), 52.9, 52.96, 53,0 (OCH3), 67.2 (CH2 Bn), 71.4, 71.8,
71.9, 72.2, 72.7 (CH tartaric acid), 128.2, 128.3, 128.40, 128.44, 128.5, 128.6,
128.7, 128.8, 130.0, 130.1, (phenyl C), 133.75, 133.8, 134.0, 134.1, 135.0
(quaternary phenyl C), 165.2, 165.3, 165.36, 165.4, 165.6, 165.7, 165.8, 166.5,
3
3
3
1.13 (d, J ˆ 7.2 Hz, 3H; CH3), 1.20 (d, J ˆ 7.2 Hz, 3H; CH3), 1.24 (d, J ˆ
7.2 Hz, 3H; CH3), 3.66 (s, 3H; OCH3), 3.67 (s, 3H; OCH3), 3.68 (s, 3H;
OCH3), 3.71 ± 4.61 (a series of broad signals, 9H; CH2 glycine, CH alanine),
5.61 (br, 2H; CH tartaric acid), 5.89 (d, 3J ˆ 2.2 Hz, 1H; CH tartaric acid),
6.00 (br, 2H; CH tartaric acid), 6.11 (br, 1H; CH tartaric acid), 7.07 (br,
1H; NH), 7.24 ± 7.57 (m, 12H; phenyl rings), 7.69 (br, 1H; NH), 8.01 (m,
8H; o-H of the Bz group); 13C NMR (100.5 MHz, CDCl3, 328C): d ˆ 17.6,
18.3, 18.4 (CH3), 40.8, 41.2, 41.3 (CH2 glycine), 48.3, 48.7, 48.9 (CH alanine),
53.0 (OCH3), 71.2, 71.8, 72.2, 72.6 (CH tartaric acid), 128.4, 128.5, 128.6,
128.7, 128.8, 129.9 (phenyl C), 133.8, 133.9, 134.0 (quaternary phenyl C),
164.9, 165.0, 165.1, 165.2, 165.9, 166.3, 166.6, 167.1, 167.2, 168.0, 171.2, 172.4,
ˆ
166.9, 167.0, 167.5, 168.3, 169.6, 172.5, 172.9, 173.7 (C O); IR (KBr): nÄ ˆ
ˆ
172.5, 173.0 (C O); IR (KBr): nÄ ˆ 3389, 3072, 2956, 1735, 1667, 1602, 1529,
3388, 3069, 2956, 1734, 1669, 1602, 1525, 1453, 1248, 1178, 1095, 1070, 1025,
1453, 1246, 1178, 1097, 1094, 1025, 713 cm 1; MS (FAB): m/z (%): 1257 (43)
713 cm 1; MS (FAB): m/z (%): 1479 (100) [M‡Cs] , 1347 (9) [M] ;
C65H66N6O26 (1347.37): calcd C 57.95, H 4.94, N 6.24; found: C 57.60, H 4.87,
N 5.68.
‡
‡
‡
‡
[M] , 832 (16) [M 426‡H] , 729 (26), 426 (34), 355 (100); C58H60N6O26
(1257.24): calcd C 55.41, H 4.81, N 6.69; found: C 55.15, H 5.10, N 6.13.
Trimethyl(3S,4S,7S,13S,14S,20S,23S,24S)-4,23-bis(benzoyloxy)-14-{[((1S)-
2-{[2-(benzyloxy)-2-oxoethyl]amino} -1-methyl-2-oxoethyl)amino]carbon-
yl}-7,20-dimethyl-1,5,8,11,16,19,22-heptaoxo-1-phenyl-2,12,15,25-tetraoxa-
6,9,18,21-tetraazahexacosane-3,13,24-tricarboxylate (20b): Compound 20b
was synthesized according to general procedure II with the diol 19b (0.38 g)
and the carboxylic acid 13b (1.10 g). FC with toluene/EtOAc ˆ 1:2
(Rf ˆ 0.15). Yield 0.70 g (52%) white solid; [a]2D0 ˆ ‡66.88 (c ˆ 0.314,
Third-generation dendron 22a: DCC (0.167 g, 8 mmol) and DMAP (0.01 g,
0.08 mmol) were added all at once to a solution of 21a (1.018 g, 0.8 mmol)
and 19a (0.132 g, 0.3 mmol) in dioxane (20 mL). After 15 minutes a white
precipitate of DCU was formed. After stirring for an additional five
hours at room temperature the precipitate was filtered, the solvent was
removed in vacuo, and the crude product was prepurified by FC (CHCl3/
MeOH ˆ 30:1). A second purification was carried out by means of HPLC
Chem. Eur. J. 2000, 6, No. 2
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0602-0255 $ 17.50+.50/0
255

A. Hirsch et al.
FULL PAPER
(Nucleosil, 14 mLmin 1, retention time 8.72 min, CHCl3/MeOH ˆ 97:3).
133.7, 133.9, 134.0, 135.0 (quaternary phenyl C), 164.6, 164.7, 164.9, 165.10
165.1, 165.6, 165.7, 165.8, 166.2, 166.3, 166.5, 166.6, 167.1, 167.1, 167.2, 167.7,
Yield 0.08 g (8%) white solid; [a]D20
ˆ
65.77 (c ˆ 0.260, CHCl3); 1H NMR
ˆ
(500 MHz, CDCl3, 458C, TMS): d ˆ 1.21 ± 1.28 (m, 21H; CH3), 3.46, 3.53,
3.57, 3.62, 3.63, 3.64, 3.65 (7 s, 21H; OCH3), 3.66 ± 4.65 (m, 21H; CH2
glycine, CH alanine), 4.99 (d, 2J ˆ 13 Hz, 1H; CHH Bn), 5.01 (d, 2J ˆ 13 Hz,
1H; CHH Bn), 5.56 ± 5.68 (m, 6H; CH tartaric acid), 5.90 ± 5.97 (m, 6H;
167.8, 167.9, 168.1, 169.6, 172.3, 172.4, 172.6, 172.9, 173.3 (C O); IR (KBr):
nÄ ˆ 3406, 2956, 1736, 1671, 1602, 1524, 1453, 1247, 1178, 1094, 1069, 1025,
‡
‡
714 cm 1; MS (FAB): m/z (%): 2992 (3) [M‡Cs] , 2882 (16) [M‡Na] ,
‡
2860 (100) [M‡H] , 2435 (14), 1678 (38), 729 (100); C133H138N14O58 ´ 4
3
3
CH tartaric acid), 6.00 (d, J ˆ 3.5 Hz, 1H; CH tartaric acid), 6.05 (d, J ˆ
3.0 Hz, 1H; CH tartaric acid), 7.10 ± 7.81 (m, 43H; phenyl rings, NH), 7.96 ±
8.14 (m, 16H; o-H of the Bz group); 13C NMR (125.65 MHz, CDCl3, 458C,
TMS): d ˆ 16.4, 16.5, 16.6, 16.7, 17.1, 17.7, 17.9 (CH3 alanine), 39.9, 40.0, 40.1,
40.5, 40.6, 40.7, 40.8 (CH2 glycine), 47.6, 47.7, 47.7, 47.8, 48.2, 48.3 (2 Â ) (CH
alanine), 51.9, 52.0, 52.0 (OCH3), 66.1 (CH2 Bn), 70.3, 70.4, 70.5, 70.9 (2 Â ),
71.0, 71.0, 71.4, 71.5, 71.7, 71.8, 71.8, 71.9, 72.0 (CH tartaric acid), 127.2, 127.5,
127.5, 127.5, 127.6, 127.6, 127.8, 127.8, 129.0, 129.0, 129.1 (phenyl C), 132.7,
132.7, 132.8, 133.0 (br), 134.3 (quaternary phenyl C), 164.2, 164.2, 164.4,
164.4 (2 Â ), 164.4, 164.5, 164.5, 164.6, 164.7 (2 Â ), 164.8, 164.8, 164.9, 165.1,
165.3, 165.4, 165.6, 166.0, 166.0, 166.1, 166.1, 166.6, 167.0, 167.2, 167.4, 167.4,
MeOH (2988.775): calcd C 55.06, H 5.19, N 6.56; found: C 54.68, H 5.01, N
6.45.
(7S)-7-[(Benzyloxy)carbonyl]-2,5-dioxo-9-methyl-3,6-diazadecaneammo-
niumhydro bromide (23): N-Benzyloxycarbonyl-glycyl-glycyl-l-leucinben-
zylester was deprotected as described.[20] Yield (66%), yellow powder;
1H NMR (400 MHz, CDCl3, 328C, TMS): d ˆ 0.81 ± 0.85 (m, 6H; CH3),
1.52 ± 1.84 (m, 3H; CH2, CH), 4.11 ± 4.32 (m, 4H; CH2 glycine), 4.43 ± 4.56
(m, 1H; CH leucine), 4.98 ± 5.21 (m, 2H; CH2 Bn), 7.28 ± 7.41 (m, 5H;
‡
phenyl rings), 7.72 (br, 3H; NH3 ), 8.26 (br, 1H; NH); 13C NMR
(100.6 MHz, CDCl3, 328C, TMS): d ˆ 21.6, 22.7 (CH3), 24.7 (CH), 39.8
(CH2), 39.9, 42.8 (CH2 glycine), 51.7 (CH leucine), 67.3 (CH2 Bn), 128.4,
128.5, 128.8, 129.0 (phenyl C), 135.3 (quaternary phenyl C), 167.3, 170.6,
ˆ
167.7, 168.6, 171.4, 171.6, 171.7, 172.0, 172.2, 172.3, 172.6 (C O); IR (KBr):
nÄ ˆ 3420, 2957, 1736, 1671, 1524, 1453, 1247, 1178, 1094, 1070, 1025,
‡
ˆ
172.8 (C O); MS (FAB): m/z (%): 671 (15) [M2‡H HBr Br] , 336
‡
‡
713 cm 1; MS (FAB): m/z (%): 2993 (48) [M‡Cs‡H] , 2861 (83) [M] ,
2436 (100), 1679 (39), 729 (76); C133H138N14O58 ´ 2MeOH (2924.691): calcd C
55.44, H 5.03, N 6.70; found: C 55.07, H 5.03, N 6.70.
‡
(100) [M‡H Br] .
13-Benzyl-3-methyl (3R,4R,13S)-4-(benzoyloxy)-15-methyl-1,5,8,11-tet-
raoxo-1-phenyl-2-oxa-6,9,12-triazahexadecane-3,13-dicarboxylate
(24):
Third-generation dendron 22b: DCC (0.167 g, 8 mmol) and DMAP (0.02 g,
Compound 24 was synthesized according to general procedure I with 23
(6.7 g, 10 mmol) and 8a (3.72 g). FC with CHCl3/MeOH ˆ 40:1 (Rf ˆ 0.36).
Yield 3.0 g (44%) white powder; 1H NMR (400 MHz, CDCl3, 22.38C,
TMS): d ˆ 0.83 ± 0.85 (m, 6H; CH3), 1.49 ± 1.60 (m, 3H; CH2, CH leucine),
3.70 (s, 3H; OCH3), 3.78 (dd, 2J ˆ 16.6 Hz, 3J ˆ 5.4 Hz, 1H; CHH glycine),
0.16 mmol) were added all at once to
a solution of 21b (1.018 g,
0.8 mmol)and 19b (0.132 g, 0.3 mmol) in dioxane (20 mL). After 15 mi-
nutes a white precipitate of DCU was formed. After stirring for five hours
at room temperature the precipitate was filtered, the solvent was removed
in vacuo, and the crude was product prepurified by FC (CHCl3/MeOH ˆ
30:1). A second purification was carried out by means of HPLC (Nucleosil,
16 mLmin 1, retention time 15.86 min, CHCl3/MeOH ˆ 97.7:2.3). Yield
0.13 g (13%) white solid; [a]2D0 ˆ ‡68.53 (c ˆ 0.715, CHCl3); 1H NMR
(500 MHz, CDCl3, 248C): d ˆ 1.10 ± -1.29 (m, 21H; CH3), 3.32, 3.46, 3.63,
3.69 (4 s, 21H; OCH3), 3.89 ± 4.67 (m, 21H; CH2 glycine, CH alanine), 5.07
(s, 2H; CH2 Bn), 5.61 ± 5.65 (m, 6H; CH tartaric acid), 5.90 (d, 3J ˆ 2.5 Hz,
2
3
3
3.85 (dd, J ˆ 16.7 Hz, J ˆ 5.4 Hz, 1H; CHH glycine), 3.94 (d, J ˆ 5.1 Hz,
2H; CH2 glycine), 4.53 ± 4.56 (m, 1H; CH leucine), 5.08 (d, 2J ˆ 12.2 Hz,
1H; CHH Bn), 5.13 (d, 2J ˆ 12.5 Hz, 1H, CHH Bn), 5.98 (d, 3J ˆ 2.9 Hz,
3
1H; CH tartaric acid), 6.06 (d, J ˆ 2.9 Hz, 1H; CH tartaric acid), 6.86 (d,
3J ˆ 8.1 Hz, 1H; NH), 7.17 (t, 3J ˆ 5.3 Hz, 1H; NH), 7.26 ± 7.59 (m, 12H;
phenyl rings, NH), 8.03 ± 8.09 (m, 4H; o-H of the Bz group); 13C NMR
(100.6 MHz, CDCl3, 23.88C, TMS): d ˆ 21.8, 22.7 (CH3), 24.8 (CH), 41.0
(CH2), 42.8, 43.0 (CH2 glycine), 51.0 (CH leucine unit), 53.0 (OCH3), 67.1
(CH2 Bn group), 71.8, 72.7 (CH tartaric acid), 128.2, 128.3, 128.4, 128.6,
128.7, 128.8, 128.9, 130.0, 130.1, 130.3 (phenyl C), 133.7, 134.1, 135.3
3
1H; CH tartaric acid), 5.93 (d, J ˆ 2.5 Hz, 1H; CH tartaric acid), 5.95 (d,
3J ˆ 2.0 Hz, 1H; CH tartaric acid), 5.98 (d, 3J ˆ 2.0 Hz, 1H; CH tartaric
acid), 6.05 (m, 4H; CH tartaric acid), 7.14 ± 7.72 (m, 43H; phenyl rings,
NH), 8.03 (m, 16H; o-H of the Bz group); 13C NMR (125.65 MHz, CDCl3,
248C): d ˆ 16.7, 17.3, 17.4, 18.5, 18.8, 19.0 (CH3), 40.9, 41.3, 41.4, 42.0 (CH2
glycine), 48.3, 48.4, 48.5, 48.7, 49.0 (CH alanine), 52.9, 52.9, 53.1, 53.8
(OCH3), 67.1 (CH2 Bn), 71.0, 71.1, 71.3, 71.8, 71.8, 71.9, 72.1, 72.3, 72.6, 72.7,
72.8 (CH tartaric acid), 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 128.8,
129.9 (phenyl C), 133.5, 133.7, 133.9, 133.9, 134.0, 135.0 (quaternary phenyl
C), 164.4, 164.6, 164.7, 164.8, 164.9, 165.0, 165.1, 165.2, 165.3, 165.7, 166.0,
166.2, 166.3, 166.6, 167.1, 167.2, 167.8, 167.9, 168.0, 168.4, 168.6, 169.7, 172.1,
ˆ
(quaternary phenyl C), 165.2, 165.3, 166.7, 167.2, 168.5, 168.6, 172.7 (C O);
‡
‡
MS (FAB): m/z (%): 1379 (4) [M2‡H] , 822 (10) [M‡Cs] , 690 (100)
‡
[M‡H] ; C36H39N3O11 (689.72): calcd C 62.69, H 5.70, N 6.09; found: C
62.21, H 5.86, N 6.19.
(4R,5R,14S)-4,5-Bis(benzoyloxy)-14-isobutyl-3,6,9,12-tetraoxo-2-oxa-
7,10,13-triazapentadecan-15-oic acid (25): Compound 25 was synthesized
according to general procedure III. Yield 100% white solid; 1H NMR
(400 MHz, [D6]acetone, 22.48C): d ˆ 0.87 ± 0.92 (m, 6H; CH3), 1.59 ± 1.75
(m, 3H; CH2, CH), 3.72 (s, 3H; OCH3), 3.76 ± 3.98 (m, 4H; CH2 glycine),
4.43 ± 4.48 (m, 1H; CH leucine), 5.95 (d, 3J ˆ 2.4 Hz, 1H; CH tartaric acid),
ˆ
172.6, 172.6, 172.9 (C O); IR (KBr): nÄ ˆ 3392, 3069, 2956, 1737, 1673, 1602,
1525, 1453, 1247, 1178, 1094, 1070, 1025, 714 cm 1; MS (FAB): m/z (%):
‡
‡
2992 (1) [M‡Cs] , 2860 (46) [M‡H] , 2435 (9), 1678 (28), 729 (100);
3
3
6.12 (d, J ˆ 2.7 Hz, 1H; CH tartaric acid), 7.40 (d, J ˆ 8.1 Hz, 1H; NH),
7.52 ± 7.72 (m, 7H; phenyl rings, NH), 8.09 ± 8.15 (m, 4H; o-H of the Bz
group, NH), 8.37 (br, 1H; NH); 13C NMR (100.6 MHz, [D6]acetone,
24.18C): d ˆ 21.8, 23.2 (CH3), 26.1 (CH), 41.4 (CH2), 43.0, 43.6 (CH2
glycine), 51.3 (CH leucine), 53.1 (OCH3), 72.9, 73.5 (CH tartaric acid),
129.4, 129.5, 129.6, 129.7, 129.9, 130.6, 130.7, 130.8 (phenyl C), 134.6, 134.7
C
133H138N14O58 ´ 4 MeOH (2988.775): calcd C 55.06, H 5.19, N 6.56; found: C
54.72, H 5.06, N 6.37.
Third-generation dendron 22c: DCC (0.167 g, 8 mmol) and DMAP (0.03 g,
0.25 mmol) were added all at once to a solution of 21b (1.018 g, 0.8 mmol)
and 19a (0.132 g, 0.3 mmol) in dioxane (20 mL). After 15 minutes a white
precipitate of DCU was formed. After stirring for five hours at room
temperature the precipitate was filtered, the solvent was removed in vacuo,
and the crude product was prepurified by FC (CHCl3/MeOH ˆ 30:1). A
second purification was carried out by means of HPLC (Nucleosil,
17 mLmin 1, retention time 7.37 min, CHCl3/MeOH ˆ 97:3). Yield 0.13 g
(13%) white solid; [a]2D0 ˆ ‡68.53 (c ˆ 0.715, CHCl3); 1H NMR (500 MHz,
CDCl3, 258C): d ˆ 1.14 ± 1.30 (m, 21H; CH3), 3.38, 3.64, 3.68, 3.69, 3.691 (5
s, 21H; OCH3), 3.75 ± 4.67 (m, 21H; CH2 glycine, CH alanine), 5.61 ± 5.68
(m, 6H; CH tartaric acid), 5.90 (d, 3J ˆ 2.5 Hz, 1H; CH tartaric acid), 5.91
(d, 3J ˆ 2.5 Hz, 1H; CH tartaric acid), 5.94 (d, 3J ˆ 2.5 Hz, 1H; CH tartaric
acid), 5.99 (d, 3J ˆ 2.0 Hz, 1H; CH tartaric acid), 6.01 (m, 2H; CH tartaric
ˆ
(quaternary phenyl C), 165.7, 165.9, 167.2, 167.9, 169.3, 169.6, 174.1 (C O);
‡
‡
MS (FAB): m/z (%): 638 (1) [M‡K] , 622 (14) [M‡Na] , 600 (100)
‡
[M‡H] ; C29H33N3O11 (599.59): calcd C 58.09, H 5.55, N 7.01; found: C
57.83, H 5.80, N 6.53.
(4R,5R,14S)-4,5-(phenylmethylenedioxy)-14-isobutyl-3,6,9,12-tetraoxo-2-
oxa-7,10,13-triazapentadecan-15-oic acid (25) 26: Compound 26 was
synthesized according to general procedure I with 23 (10.41 g, 25 mmol)
and 16a (6.31 g, 25 mmol). FC with CHCl3/EtOAc ˆ 1:8 (Rf ˆ 0.22). Yield
6.5 g (46%) white solid; mixture of two diastereomers; 1H NMR
(400 MHz, [D6]acetone, 22.68C): d ˆ 0.87 ± 0.91 (m, 12H; CH3), 1.59 ± 1.71
(m, 6H; CH2, CH leucine), 3.76 (s, 3H; OCH3), 3.80 (s, 3H; OCH3), 3.88 ±
4.03 (m, 8H; CH2 glycine), 4.54 ± 4.57 (m, 2H; CH leucine), 4.84 (d, 3J ˆ
3
acid), 6.03 (d, J ˆ 2.0 Hz, 1H; CH tartaric acid), 6.13 (s, 1H; CH tartaric
3
acid), 7.25 ± 7.70 (m, 43H; phenyl rings, NH), 8.02 (m, 16H; o-H of the Bz
group); 13C NMR (125.65 MHz, CDCl3, 258C): d ˆ 17.0, 17.5, 18.5, 18.6,
18.7, 18.8 (CH3), 40.8, 40.9, 41.1, 41.3, 41.9 (CH2 glycine), 48.2, 48.3, 48.3,
48.5, 48.6, 48.8 (CH alanine), 52.9, 52.9 (OCH3), 67.1 (CH2 Bn), 71.1, 71.1,
71.3, 71.5, 71.8, 71.9, 72.0, 72.2, 72.6, 72.7, 72.7 (CH tartaric acid), 128.1,
128.3, 128.4, 128.4, 128.4, 128.5, 128.5, 128.6, 128.6, 128.7, 129.8 (phenyl C),
3.9 Hz, 1H; CH tartaric acid), 4.96 (d, J ˆ 3.9 Hz, CH tartaric acid), 4.97
(d, 3J ˆ 3.4 Hz, 1H; CH tartaric acid), 4.99 (d, 3J ˆ 3.4 Hz, 1H; CH tartaric
acid), 5.15 (s, 4H; CH2 Bn), 6.10 (s, 1H; CH acetal), 6.12 (s, 1H; CH acetal),
7.30 ± 7.45 (m, 16H; phenyl rings), 7.54 (br, 2H; NH), 7.60 ± 7.64 (m, 5H;
phenyl rings, NH), 7.81 (br, 1H; NH), 8.23 (br, 1H; NH); 13C NMR
(100.6 MHz, [D6]acetone, 24.48C): d ˆ 21.8, 23.1 (CH3), 25.3 (CH), 41.2
256
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0602-0256 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 2

Depsipeptide Dendrimers
247±257
(CH2), 42.9, 43.0, 43.4, 43.5 (CH2 glycine), 51.5, 51.6 (CH leucine), 52.7, 52.8
(OCH3), 67.0 (CH2 Bn), 77.8, 78.5, 79.0, 79.5 (CH tartaric acid), 106.6, 106.9
(CH acetal), 128.2, 128.3, 128.6, 128.7, 128.8, 129.0, 129.3, 130.6, 130.8
(phenyl C), 136.6, 137.0, 137.1 (quaternary phenyl C), 169.4, 169.5, 169.6,
119; b) N. Ardoin, D. Astruc, Bull. Soc. Chim. Fr. 1995, 132, 875;
c) G. R. Newkome, C. N. Moorefield, F. Vögtle, Dendritic Molecules,
1st ed., VCH, Weinheim, 1996; d) N. Feuerbacher, F. Vögtle, Top.
Curr. Chem. 1998, 197, 8; e) D. K. Smith, F. Diederich, Chem. Eur. J.
1998, 8, 1353; f) V. V. Narayanan, G. R. Newkome, Top. Curr. Chem.
1998, 197, 19; g) J. P. Majoral, A.-M. Caminade, Top. Curr. Chem. 1998,
197, 79; h) A.-D. Schlüter, Top. Curr. Chem. 1998, 197, 165; i) M.
Venturi, S. Serroni, A. Juris, S. Campagna, V. Balzani, Top. Curr.
Chem. 1998, 197, 193; j) M. Fischer, F. Vögtle, Angew. Chem. 1999, 111,
934; Angew. Chem. Int. Ed. 1999, 38, 884.
ˆ
169.7, 170.2, 170.3, 170.6, 170.8, 171.2, 173.0 (C O); MS (FAB): m/z (%):
1140 (12) [M2‡H] , 570 (100) [M‡H] ; C29H35N3O9 ´ 0.5H2O (578.92):
‡
‡
calcd C 60.20, H 6.27, N 7.26; found: C 60.24, H 6.18, N 7.32.
15-Methyl-(4S,13R,14R)-13,14-dihydroxy-4-isobutyl-3,6,9,12-tetraoxo-1-
phenyl-2-oxa-5,8,11-triazapentadecane-15-carboxylate (27): Compound 27
was synthesized according to general procedure IV. Yield white solid,
1
3
[3] a) H. W. I. Peerlings, E. W. Meijer, Chem. Eur. J. 1997, 3, 1563; b) D.
Seebach, P. B. Rheiner, G. Greiveldinger, T. Butz, H. Sellner, Top.
Curr. Chem. 1998, 197, 125.
[4] a) J. A. Kremers, E. W. Meijer, J. Org. Chem. 1994, 59, 4262; b) J. A.
Kremers, E. W. Meijer, React. Funct. Polym. 1995, 26, 137.
[5] a) D. Seebach, J.-M. Lappiere, K. Skobridis, G. Greiveldinger, Angew.
Chem. 1994, 106, 457; Angew. Chem. Int. Ed. Engl. 1994, 33, 440; b) D.
Seebach, J.-M. Lapierre, G. Greiveldinger, K. Skobridis, Helv. Chim.
Acta 1994, 77, 1673.
(45%); H NMR (400 MHz, [D6]DMSO, 23.48C): d ˆ 0.81 (d, J ˆ 6.4 Hz,
3H; CH3), 0.87 (d, 3J ˆ 6.4 Hz, 3H; CH3), 1.46 ± 1.56 (m, 3H; CH2, CH
leucine), 3.76 (d, 3J ˆ 5.4 Hz, 2H; CH2 glycine), 4.07 (d, 3J ˆ 5.1 Hz, 1H;
CH glycine), 4.10 (d, 3J ˆ 5.1 Hz, 1H; CHH glycine), 4.30 ± 4.38 (m, 3H;
CH leucine, tartaric acid), 5.11 (s, 2H; CH2 Bn), 7.30 ± 7.39 (m, 5H; phenyl
rings), 8.28 (d, 3J ˆ 7.8 Hz, 1H; NH), 8.43 (t, 3J ˆ 5.6 Hz, 1H; NH);
13C NMR (100.6 MHz, [D6]DMSO, 24.88C): d ˆ 21.3, 22.7 (CH3), 24.1
(CH), 40.1, 41.6 (CH2 glycine), 48.6 (OCH3), 50.4 (CH leucine), 65.9 (CH2
Bn), 74.4 (CH tartaric acid), 127.8, 128.0, 128.4 (phenyl C), 135.9
[6] a) J. R. Mc Elhanon, M.-J. Wu, M. Escobar, D. V. McGrath, Macro-
molecules 1996, 29, 8879; b) J. R. Mc Elhanon, D. V. Mc Grath, J. Am.
Chem. Soc. 1998, 1647.
[7] a) H.-F. Chow, C. C. Mak, Tetrahedron Lett. 1996, 37, 5935; b) C. C.
Mak, H.-F. Chow, Chem. Commun. 1996, 1185; c) H.-F. Chow, C. C.
Mak, J. Chem. Soc. Perkin Trans. 1 1997, 91; d) H.-F. Chow, C. C. Mak,
Pure Appl. Chem. 1997, 69, 483.
[8] H.-T. Chang, C.-T. Chen, T. Kondo, G. Siuzdak, K. B. Sharpless,
Angew. Chem. 1996, 108, 202; Angew. Chem. Int. Ed. Engl. 1996, 35,
182.
[9] a) P. R. Ashton, S. E. Boyd, C. L. Brown, S. A. Nepogodiev, E. W.
Meijer, H. W. I. Peerlings, J. F. Stoddart, Chem. Eur. J. 1997, 3, 975;
b) N. Jayaraman, S. A. Nepogodiev, J. F. Stoddart, Chem. Eur. J. 1997,
3, 1193.
ˆ
(quaternary phenyl C), 165.7, 168.6, 169.5, 172.2, 174.2 (C O); MS
‡
‡
‡
(FAB): m/z (%): 963 (4) [M2‡H] , 614 (8) [M‡Cs] , 504 (9) [M‡Na] ,
‡
482 (100) [M‡H] ; C22H31N3O9 (481.50): calcd C 54.88, H 6.49, N 8.73;
found: C 55.23, H 6.64, N 8.71.
3,16,30-Trimethyl-(3R,4R,13S,16R,17R,20S,29R,30R)-4,29-bis(benzoyl-
oxy)-13,20-diisobutyl-17-[(9S)-9-isobutyl-4,7,10-trioxo-12-phenyl-11-oxa-
2,5,8-triazadodec-1-anoyl]-1,5,8,11,14,19,22,25,28,32-decaoxo-1,32-diphen-
yl-2,15,18,31-tetraoxa-6,9,12,21,24,27-hexaazadotriacontane-3,16,30-tricar-
boxylate (28): DCC (0.65 g, 3.15 mmol) and DMAP (0.018 g, 0.15 mmol)
were added to a solution of 27 (0.72 g, 1.5 mmol) and the acid 25 (1.89 g,
3.15 mmol) in dry THF (75 mL). After stirring overnight the precipitate
was filtered, the solvent was removed, and the residue was dissolved in
CH2Cl2. This solution was washed with HCl (1n) and dried over MgSO4.
After removal of the solvent the crude product was purified by FC (CHCl3/
MeOH ˆ 30:1) and afterwards by means of HPLC (CHCl3/MeOH ˆ 96:4,
flow ˆ 20 mLmin 1, retention time ˆ 6.7 min). Yield 0.23 g (9.4%) white
solid; 1H NMR (400 MHz, [D6]acetone, 22.78C): d ˆ 0.83 ± 0.91 (m, 18H;
CH3), 1.56 ± 1.69 (m, 9H; CH2, CH leucine), 3.71 (s, 3H; OCH3), 3.72 (s,
3H; OCH3), 3.73 (s, 3H; OCH3), 3.84 ± 4.06 (m, 12H; CH2 glycine), 5.11 (d,
[10] G. R. Newkome, X. Lin, C. D. Weis, Tetrahedron: Asymmetry 1991, 2,
957.
[11] a) J. F. G. A. Jansen, H. W. I. Peerlings, E. M. M. de Brabander-van
den Berg, E. W. Meijer, Angew. Chem. 1995, 107, 1321; Angew. Chem.
Int. Ed. Engl. 1995, 34, 1206; b) J. F. G. A. Jansen, H. W. I. Peerlings,
E. M. M. de Brabander-van den Berg, E. W. Meijer, Science 1994, 266,
1226.
[12] T. K. Lindhorst, C. Kieburg, Angew. Chem. 1996, 108, 2083; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1953; T. K. Lindhorst, Nachr. Chem.
Tech. Lab. 1996, 44, 1073.
[13] a) D. Seebach, G. F. Herrmann, U. D. Lengweiler, W. Amreis, Helv.
Chim. Acta 1997, 80, 989; b) P. K. Murer, J.-M. Lapierre, G.
Greiveldinger, D. Seebach, Helv. Chim. Acta 1997, 80, 1648.
[14] a) R. G. Denkewalter, J. F. Kolc, W. J. Lukasavage, U. S. Pat.
4,410,688, 1979; b) R. G. Denkewalter, J. F. Kolc, W. J. Lukasavage,
U.S. 4360646 1982; Chem. Abs. 1984, 100, 103907p; c) R. G. Denke-
walter, J. F. Kolc, W. J. Lukasavage, U.S. 4289872 1981; Chem. Abs.
1985, 102, 79324q.
2J ˆ 12.5 Hz, 1H; CHH Bn), 5.15 (d, J ˆ 11.0 Hz, 1H; CHH Bn), 5.64 (d,
2
3J ˆ 2.0 Hz, 1H; CH tartaric acid), 5.72 (d, J ˆ 2.2 Hz, CH tartaric acid),
3
5.96 (d, 3J ˆ 2.4 Hz, 1H; CH tartaric acid), 5.97 (d, 3J ˆ 2.7 Hz, 1H; CH
tartaric acid), 6.11 (s, 1H; CH tartaric acid), 6.12 (s, 1H; CH tartaric acid),
7.23 (d, 3J ˆ 7.3 Hz, 1H; NH), 7.30 ± 7.74 (m, 23H; phenyl rings and 5 NH),
7.84 (d, 3J ˆ 6.3 Hz, 1H; NH), 8.01 (t, 3J ˆ 3.7 Hz, 1H; NH), 8.03 ± 8.14 (m,
8H; o-H of the Bz group), 8.39 (t, 3J ˆ 5.6 Hz, 1H; NH), 8.48 (t, 3J ˆ 5.5 Hz,
1H; NH); 13C NMR (100.6 MHz, [D6]acetone, 24.48C): d ˆ 21.4, 21.9, 22.0,
22.4, 22.7, 23.0 (CH3), 23.1, 25.1, 25.3 (CH), 40.2, 41.0, 41.3 (CH2), 42.9, 43.0,
43.2, 43.6, 43.7, 43.9 (CH2 glycine), 51.6, 51.7, 52.3 (CH leucine), 53.1, 53.2,
53.3 (OCH3), 67.1 (CH2 Bn), 72.1, 72.8, 72.9, 73.4, 73.5, 73.6 (CH tartaric
acid), 128.8, 129.0, 129.3, 129.6, 129.7, 129.8, 129.9, 130.7, 130.8 (phenyl C),
134.5, 134.6, 134.7, 134.8, 137.1 (quaternary phenyl C), 157.6, 165.7, 165.9,
[15] M. Schemjakin, Angew. Chem., 1960, 10, 342.
[16] L. Stryer, Biochemistry, 3rd ed., W. H. Freeman, New York, 1988, 965.
166.8, 166.9, 167.2, 167.3, 167.4, 167.7, 167.9, 169.7, 169.8, 169.9, 171.1, 171.3,
‡
ˆ
172.2, 173.0 (C O); MS (FAB): m/z (%): 1645 (100) [M‡H] , 1290 (4),
Â
Â
[17] J. Gawronski, K. Gawronska, U. Rychlewska, B. WarzÇajtis, J.
Rychlewski, M. Hoffmann, A. Szasecka, Tetrahedron 1997, 53, 6113.
[18] B. Neises, W. Steglich, Angew. Chem. 1978, 90, 556; Angew. Chem. Int.
Ed. Engl. 1978, 17, 522.
1233 (30), 1176 (40), 1063 (12), 582 (10), 469 (82), 412 (68), 355 (42);
C80H93N9O29 ´ H2O (1662.68) calcd C 57.79, H 5.76, N 7.58; found: C 57.86, H
5.82, N 7.44.
[19] K. Ogata, S. Ishii, Chem. Pharm. Bull. 1967, 15, 707.
[20] M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, 2nd
ed., Springer, Berlin, 1994, 138.
[21] T. K. M. Shing, E. K. W. Tam, V. W.-F. Tai, I. H. F. Chung, Q. Jiang,
Chem. Eur. J., 1996, 2, 48.
Acknowledgments
This research project was supported by the Deutsche Forschungsgemein-
schaft. We thank Dr. R. Waibel from the Institut für Pharmazie der
Universität Erlangen-Nürnberg for measuring the optical rotations.
[22] W. R. Roush, L. Banfi, J. Am. Chem. Soc. 1988, 110, 3979.
[23] P. C. Crofts, J. H. H. Markes, H. N. Rydon, J. Chem. Soc. 1959, 3610.
[1] E. Buhleier, W. Wehner, F. Vögtle, Synthesis 1978, 155.
[2] For example: a) D. A. Tomalia, A. M. Naylor, W. A. Goddart III,
Angew. Chem. 1990, 119, 119; Angew. Chem. Int. Ed. Engl. 1990, 29,
Received: April 14, 1999 [F1724]
Chem. Eur. J. 2000, 6, No. 2
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