On the synthesis and selective deprotection of low-generation dendrons with orthogonally protected peripheral amine groups and a possible impact of the deprotection conditions on the stability of dendronized polymers' skeletons

Article abstract of DOI:10.1002/hlca.200690246

The synthesis of first- and second-generation dendrons with defined ratios of orthogonally protected amine groups in the periphery ((benzyloxy)carbonyl (Cbz) and (tert-butoxy)carbonyl (Boc) protection) and the degree to which they can be selectively remov

Full text of DOI:10.1002/hlca.200690246

Helvetica Chimica Acta – Vol. 89 (2006)
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On the Synthesis and Selective Deprotection of Low-Generation Dendrons
with Orthogonally Protected Peripheral Amine Groups and a Possible Impact
of the Deprotection Conditions on the Stability of Dendronized Polymersꢀ
Skeletons
by Rabie Al-Hellani and A. Dieter Schlüter*
Department of Materials, Institute of Polymers, ETH-Zürich, Wolfgang-Pauli-Strasse 10, HCI J 541,
CH-8093 Zürich (fax: +41-44-6331395)
The synthesis of first- and second-generation dendrons with defined ratios of orthogonally protected
amine groups in the periphery ((benzyloxy)carbonyl (Cbz) and (tert-butoxy)carbonyl (Boc) protection)
and the degree to which they can be selectively removed are described. The reaction conditions required
for these deprotections were applied to methacrylic acid (=2-methylprop-2-enoic acid) based dendron-
ized polymers carrying the same peripheral protecting groups to investigate whether they have any det-
rimental interference with the polymer skeleton. Specifically it was explored whether dendrons attached
to the backbone could possibly be cleaved off as a whole (de-dendronization). Finally it was investigated
how de-dendronizations can be used for quantifyingboth the dendron-structure perfection and the pol-
ymer-backbone configurations.
Introduction. – The surface functional groups of dendrimers [1][2] and dendronized
polymers [3–6] play a key role in the property engineering of these intriguing macro-
molecules. By the proper choice of these groups, fundamental issues such as solubility
in either water or organic media [1][2] and the temperature range at which the glass
transition occurs can be addressed [7][8]. More sophisticated aspects have also been
treated, including the attachment of cell-targeting units and drugs [2] or compactization
of DNA [2][9]. Recently, specifically surface-designed dendronized polymers were
used to conduct elementary steps in the so-called bottom-up approach to the nano-
sciences [10]. So far, most dendrimers and dendronized polymers carry only one
kind of peripheral functional group. Therefore, there is an obvious demand for syn-
thetic strategies leading to compounds with individually addressable surface function-
alities. This then would allow for a more flexible surface decoration and, thus, consid-
erably widen the application scope. Besides a preliminary disclosure of parts of the
present paperꢀs findings [11], there have only been a few reports on dendrons, the
key buildingblocks for dendrimers and dendronized polymers with orthogonally pro-
tected functional groups [12–14]. Related studies on desymmetrization during dendron
synthesis are also available (see, e.g., [15]).
In our laboratory, a several-gram-scale route to first(G1)- through fourth-genera-
tion (G4) dendrons with (tert-butoxy)carbonyl(Boc)-protected amine groups was
developed which proved reliable and useful and was, therefore, applied to the synthesis
of a wide variety of dendronized polymers [16–18]. We here report on an extension of
this strategy leading to G1 and G2 dendrons with two and four peripheral amines,
ꢁ 2006 VerlagHelvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
respectively, which carry the orthogonal Boc and (benzyloxy)carbonyl (Cbz) protecting
groups in all possible combinations. Thus, on the G2 level, the dendrons carry 4 Boc, 3
Boc and 1 Cbz, 2 Boc and 2 Cbz, 1 Boc and 3 Cbz, or, finally, 4 Cbz groups. High-molar-
mass dendronized polymers carry easily hundreds if not thousands of protected amine
groups per macromolecule. It was, therefore, of utmost importance to check the degree
of orthogonality of the chosen protecting groups. Any incomplete deprotection cannot
be improved anymore. This is why the present work addresses also this aspect in some
depth. At this point, it should be mentioned that another potentially promisingpair of
protectinggroups, namely Boc and (9 H-fluoren-9-ylmethoxy)carbonyl (Fmoc), could
not be reasonably applied because the solubility of polymers which carry many Fmoc
units is known to be very low [19].
Deprotection does not only lead to a hopefully complete removal of protecting
groups but may also cause defects in the denpol skeleton. In many of these macromo-
lecules, the dendrons are attached to the backbone through benzylic ester linkages
which are known to be quite sensitive to conditions also relevant for deprotection.
Such a cleavage would result in a loss of complete dendrons (de-dendronization), a
process which of course cannot be accepted normally. Another aim of the present
work was, therefore, to investigate to what extent certain deprotection conditions are
associated with de-dendronizations. This refers specifically to hydrogenolysis, a com-
monly used protocol for deprotection of Cbz, which is known to also cleave benzylic
esters. A point of concern was whether the steric crowdingaround the backbone caused
by the dendrons would be sufficient to shield the internal benzylic ester functions.
Finally, the present work addresses the issue of whether de-dendronization can actually
be done quantitatively and used for two purposes: a) to analyze the structure by NMR
spectroscopy of the cleaved-off dendrons and b) to determine the configuration of the
polymer backbone. Aspect a) would be of importance in regard to the otherwise diffi-
cult to perform quantification of structure perfection of the dendrons of a dendronized
polymer which was synthesized accordingto the attach-to route. Aspect b) is of princi-
pal interest in regard to the issue whether the dendritic substitution of macromonomers
affects the stereochemical course of the polymerization.
Results and Discussion. – The synthetic sequences to the orthogonally protected
dendrons are shown in Schemes 1–4. Scheme 1 depicts the transformations done on
the G1 level to provide all necessary startingdendrons for further growth. Some of
these transformations have already been described but were improved to provide
pure products on a larger scale. Scheme 2 shows how the orthogonally Cbz- and Boc-
protected G1 buildingblock 4 was converted into the G2 dendrons with either 3 Boc
and 1 Cbz (7a) or 1 Boc and 3 Cbz (7b). Scheme 3 describes the access to the remaining
combinations on the G2 level (9a: 4 Boc; 9b: 2 Boc, 2 Cbz; 9c: 4 Cbz). Scheme 4, finally,
compiles the deprotections done on the G2 level. All reactions use standard steps of
organic and peptide synthesis. The arms of the branching units were attached to the aro-
matic nucleus by Suzuki–Miyaura cross-coupling[20][21], and amides were synthe-
sized by the EDC/HOBt method [22][23] (EDC=N-[3-(dimethylamino)propyl]-N’-
A
ethylcarbodiimide, HOBt=1-hydroxy-1H-benzotriazole). Deprotection of Boc groups
was uniformly done with 25% aqueous HCl solution. The Cbz groups were removed by
hydrogenation by using two different methods, A (5% aqueous formic acid, Pd/C, Hz

Helvetica Chimica Acta – Vol. 89 (2006)
2747
Scheme 1
a) 1. 9-BBN (9-borabicyclo[3.3.1]nonane), CH2
08, then 12 h at r.t.; 2. 1, [Pd(PPh3)4], 1M KOH, toluene, 1008, 14 h (86%). b) 1. 9-BBN, CH2
NHCbz, dry toluene, 08, then 12 h at r.t.; 2. 1, [Pd(PPh3)4], 1M KOH, toluene, 608, 48 h, (66%). c) 1.
9-BBN, CH2CHCH2NHBoc, dry toluene, 08, then 12 h at r.t.; 2. 3, [Pd(PPh3)4], 1M KOH, toluene,
A
NHBoc or CH2CHCH2
ACHTREUNG
AHCTREUNG
ACHTREUNG
A
ACHTREUNG
1008, 14 h (86%). d) KOH, 558, 10 h (92%). e) KOH, 558, 4 h (94%). f) MeOH/H2O (3 :1), KOH,
508, 14 h (93%).
(3.5 bar)) and B (cyclohexa-1,4-diene, Pd/C, Hz (3.5 bar)), dependingon the respective
startingcompound. In the following, only a few steps will be commented. The G2 den-
drons reported carry hydroxy functions at the focal point, which give the possibility to
attach polymerizable units in future polymer applications.
The dibromo ester 1 was converted into both the symmetric G1 dendrons 2a [16]
and 2b [24] and the non-symmetric analog 4a. To achieve the important desymmetriza-
tion, startingmaterial 1 was first converted into the ꢂmono-armedꢀ compound 3 which
then was reacted further to give 4a [25][26] (Scheme 1). The scale in which these steps
were performed was significantly increased. Therefore, the key compound 4a is now
available in the 20-gscale with an overall yield of analytically pure material of 56%
referringto 1.
The subsequent reduction of 4a to 5a was performed with LiAlH4. It turned out to
be essential to strictly keep the reaction temperature below 108 to avoid an attack at
Cbz (Scheme 2). When the same reaction was carried out at 208, the yield of 5a dropped
from 81% to ca. 25%. All other reactions of Schemes 1–3 (! 5b,c, 6a–d, 7a,b, 8a,b, and
9a–c) succeeded as expected. This refers also to the deprotection reactions; the degree

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Helvetica Chimica Acta – Vol. 89 (2006)
to which they proceeded was monitored either by TLC or NMR spectroscopy. Two of
the compounds, 7b and 9c, required some attention. Dendron 7b required prolonged
hydrogenation times (Method B, 20 h instead of 10 h) to achieve complete deprotection
of Cbz and 9c failed even then to give completely deprotected material. Therefore, the
somewhat harsher Method A was applied which led to success. All deprotection reac-
tions were performed on a 200–400-mgscale and reached yields above 95% (for
Boc groups) and in the range 85–94% (for Cbz). The deprotected compounds were
used without further purification. The dendrons 9a–c were obtained on a larger
scale (9a: 8 g ;9b: 7 g ;9c: 4 g) than 7a and 7b (0.5–1 g) because of the lower number
of steps involved. Some of the amide formations, for example the ones of 6a and 7a,
were not only performed with HOBt/EDC but also with active-ester chemistry
(HOSu/DCC (=N-hydroxysuccinimide/dicyclohexylcarbodiimide)). Though the cou-
plingyields increased by ca. 10–15% in all cases with the latter reagents, the purifica-
tion of the products was more tedious, renderingthe overall efficiency of the former
protocol higher. All dendrons were purified by conventional silica gel column chroma-
tography with loadings of up to 3 g.
The deprotection reactions of the G2 dendrons 7a,b and 9b,c (Scheme 4) were
checked by high-field NMR spectroscopy, the one of 9a has already been reported
[16]. Emphasis was of course placed on the orthogonally protected dendrons 7a,b
and 9b to assess the selectivity of their deprotection, but also the deprotection of the
all-Cbz decorated 9c was investigated in some detail. Cbz had occasionally proven a
delicate protectinggroup in polymer applications. In all cases, it was not only checked
whether the signals of the respective protecting group had completely disappeared
after deprotection, but also the intensity of the NMR signal of the remaining protecting
group was compared with the dendritic fragment by integration to make sure that it had
stayed unaffected. Finally, the entire dendritic fragment was checked by integration for
1
structural integrity. Fig. 1 shows three triples of H-NMR spectra whereby each triple
contains the respective startingdendron at the bottom ( 7a, 7b, 9b) followed by the
products where Boc (in the middle) and Cbz have been removed (top), respectively.
The spectra of the startingmaterials were recorded in CDCl 3, all those of deprotected
dendrons, irrespective of the remainingprotectinggroup, were recorded in CDCl 3/CD3-
A
ingchemical shifts: Boc at d 1.44 and Cbz (CH2 group) at d 5.02. As can be seen, the
spectra of the deprotected dendrons do not show any indication of the removed pro-
tecting groups, even if the relevant shift ranges are amplified considerably. From this,
it is concluded that the deprotections are virtually quantitative, and Boc and Cbz are
virtually orthogonal. The deprotection of 9c was investigated with the same rigorosity
and also found to be quantitative (NMR spetra not shown). To determine eventual loss
of some of the protectinggroup supposed to remain intact while the other is removed,
the integrals of the remaining group were compared with the dendritic skeleton by
usingNMR spectra recorded with pulse sequences so as to allow for reliable integra-
tions. Exemplary this may be described for the transformations of 7a, 7b, and 9b into
10c, 10g, and 10e, respectively. The remainingBoc signal, which in all cases appeared
at d 1.44, was compared with the dendron signals at d 2.55 and 4.55 before and after
deprotection. Within the accuracy of this method, no reduction of Boc intensity was
observed. Also no indication for structural defects could be obtained.

Helvetica Chimica Acta – Vol. 89 (2006)
2749
Scheme 2
a) 4a, LiAlH4, THF, <108, 8.5 h (81%). b) 25% HCl soln., THF, r.t. (94%). c) AcOEt/EtOH 1.1,
Pd/C, cyclohexa-1,4-diene, H2, 4 h (92%). d) 1. 2d, HOBt, EDC, CH2Cl2, ꢀ308, 3 h; 2. 5c, Et3N,
CH2Cl2, MeOH, ꢀ208, then 14 h at r.t. (69% for both steps). e) 25% HCl soln, THF, r.t. (96%). f) 1.
2c, HOBt, EDC, CH2Cl2, ꢀ308, 3 h; 2. 5b, Et3N, CH2Cl2, MeOH, ꢀ208, then 14 h at r.t. (84% for
both steps). g) THF/AcOEt/EtOH 1:1:1, Pd/C cyclohexa-1,4-diene, H2, 5 h (99%). h) 1. 4b, HOBt,
EDC, CH2Cl2, ꢀ208, 3 h; 2. 6d, Et3N, CH2Cl2, MeOH, ꢀ208, then 15 h at r.t. (80% for both steps). i)
1. 4b, HOBt, EDC, CH2Cl2, ꢀ208, 3 h; 2. 6b, Et3N, CH2Cl2, MeOH, ꢀ208, then 14 h at r.t. (69% for
both steps).
AHCTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 3
a) 2a, LiAlH4, THF, 08, 10 h (93%). b) 25% HCl soln., THF, r.t. (96%). c) 1. 2c, HOBt, EDC,
CH2Cl2, ꢀ308, 3 h; 2. 8b, Et3N, CH2Cl2, MeOH, ꢀ208, then 14 h at r.t. (65% for both steps). d) 1. 4b,
HOBt, EDC, CH2Cl2, ꢀ208, 3 h; 2. 8b, Et3N, CH2Cl2, MeOH, ꢀ208, then 15 h at r.t. (86% for both
AHCTREUNG
AHCTREUNG
steps). e) 1. 2d, HOBt, EDC, CH2Cl2, ꢀ308, 3 h; 2. 8b, Et3N, CH2Cl2, MeOH, ꢀ208, then 14 h at r.t.
G
(72% for both steps).
The next step was to show whether dendronized polymers are sensitive to both
deprotection conditions in their main skeleton. Most internal functional groups con-
tained in the denpols in question are the relatively inert amide functions which in
the above experiments had proved robust. The focus was put, therefore, on the benzylic
ester functions which serve as linkage between the dendrons and the backbone. Very
similar to the dendrons observed above, all denpols reported from this group withstood
treatment with either trifluoroacetic acid or 25% aqueous HCl solution under the pub-
1
lished conditions. Not even slight changes in the highly resolved H- and 13C-NMR
spectra before and after the treatment with acid were observed. However, in contrast
to the above findings for the dendrons with Cbz groups, hydrogenolysis of denpols
turned out to be critical. In several attempts, G1 and G2 denpols [16] suffered cleavage
of dendrons directly at the benzylic position. Even worse, no hydrogenolysis conditions
could be found where de-dendronization would not occur at least partially. To find out
whether an increased steric crowdingat the sensitive position would help overcome this
problem, the G3 denpol 13 (Scheme 5) was investigated accordingly. It was synthesized

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 4
a) 25% HCl soln., THF, r.t. b) Pd/C, cyclohexa-1,4-diene, H2, r.t., 3.5 bar. c) Pd/C, 5% formic acid,
H2, r.t, 3.5 bar.
by the attach-to route startingfrom G1 denpol 11 [16]. Reaction of the deprotected
form 11 with the active-ester dendron 12 gave polymer 13, whose coverage was virtually
complete (see below). Somewhat against our expectation, subjecting 13 to several
hydrogenolysis conditions led again to at least partial de-dendronization. Under certain
conditions (10% formic acid for 4 d at 208), it could even be driven to completion fur-
nishingpoly(methacrylic acid) ( 14) and the correspondingdendron 15. The latter car-
ries a Me group at the focal point, which is indicative for the cleavage process to be
actually hydrogenolytic and not solvolytic in nature. The fact that de-dendronization
occurs even for a G3 denpol like 13 shows that the steric shieldingis insufficient, and
any search for conditions to deprotect at a denpolsꢀ periphery of this kind must also
take the internal functional groups into consideration even if they are located near
the backbone and the conditions are heterogeneous. A lesson to be learned from this
is that the density around the backbone imposed by the dendritic layer is lower than
perhaps expected. At a first glance this is a disappointing finding as it suggests that
Cbz is not a good protecting group for denpols based on acrylate polymerizable groups.
However, this could be easily escaped by usingdenpols based on acrylamide polymer-
izable groups [27]. In this way, the critical linkage between dendron and backbone
would be turned into a robust amide.
The initially unwanted de-dendronization opens interestingnew options which will
be briefly discussed in the following. Denpols prepared by the attach-to route have the
intrinsic disadvantage that their structure will have defects due to an incomplete cover-
age of the starting denpol with dendrons. Though this coverage can be driven to values
above 99% [28], it still has to be quantified in each case which is a rather tedious pro-
cedure. UVand Fluorescence spectroscopy were used for this purpose after appropriate
labelling[27]. Each of these methods has its intrinsic limitations and uncertainties and
involves a considerable effort. It was, therefore, of interest to have a third independent
and perhaps easier to perform method available. This is where the above de-dendroni-
zation comes into play.

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Fig. 1. 1H-NMR Spectra of a) 7a, b) 7b, and c) 9b and their respective selectively deprotected counter-
parts (see text) to show the degrees to which the deprotections can be achieved. *: Solvent signals,
#: grease signals.

Helvetica Chimica Acta – Vol. 89 (2006)
2753
The 1H-NMR chemical shifts of CH2 groups in a-position to amine or amide groups
do not differ much normally. In many cases, however, the difference is large enough to
be used for quantification. If a dendronization of a denpol (like the one shown in
Scheme 5) does not lead to a complete coverage of the terminal amines with dendrons,
a product is obtained which contains these unreacted amines next to reacted (ami-
dated) ones. Given the shift difference between the respective CH2 groups in a-posi-
tion, this could in principle be used to quantify the degree of coverage by NMR inte-
gration. As long as one deals with the entire denpol, NMR signals are too broad to
even consider such a method. If, however, the dendrons can be completely cleaved
off the backbone prior to the NMR investigation by some simple treatment, highly
resolved NMR spectra of the resultingdendrons can be obtained at a reasonable effort,
and the quantification can be done. This procedure was tried for denpol 13 whose syn-
thesis is given in the Exper. Part. For that purpose, the model compounds 17b and 19
were prepared from 16 and 18, respectively (Scheme 6). They served as reference points
for the relevant chemical shifts of the CH2 groups in a-position. The de-dendronization
of 13 was performed as described above. When driven to completion, it furnished den-
dron 15 in yields of 80 and 85% (Run 1 and 2, resp., in Fig. 2) after the crude product
had been passed once through a short silica gel column to remove impurities. During
this simple step, it was paid attention to not remove any eventually existingincomplete
dendron with free amino groups (for details, see Exper. Part). For the NMR analysis,
the spectra of compounds 19 and 17b, and of the two samples of 15 which stemmed
from independent preparations (Runs 1 and 2) were compared (Fig. 2).
The critical signal is the one of 17b at d 2.85 which represents the protons of a CH2
group in a-position to a free amino group (arrow in Fig. 2,b). This signal does, of
course, not appear for model compound 19 (Fig. 2,a). The spectrum of dendron 15
(Run 1) shows a low-intensity signal in the relevant shift range whose intensity was esti-
mated by integration to be 1.5% assuming that it represents two protons (Fig. 2,c).
Given the fact that the samples of 15 used for the study had not been carefully purified
it was not clear at this point whether this small signal actually stemmed from a CH2
group in a-position. Fig. 2,d shows the spectrum of dendron 15 (Run 2): Virtually noth-
ingwas to be seen in the shift range d 2.70–2.90, and an integration was, therefore, not
performed. It is clear from this experiment that one deals with a level of structure per-
fection which is at or even below the limit of what NMR spectroscopy can provide.
Defects amountingto a few percent would certainly be detected. This findingis in
good agreement with the other quantification experiments described earlier which
underlines that the attach-to route can be a powerful and reliable tool for the synthesis
of structurally defined, high-molar-mass and high-generation dendronized polymers.
Apart from the issue of structure perfection, the observed de-dendronization of 13
opens another interestingpossibility which is to determine the backboneꢀs tacticity. It is
still an open question whether there is a preorientation of dendronized monomers prior
to their polymerization to denpols [29]. Possibly occurringisotactic or syndiotactic
backbones may be caused by such phenomena, though a nonoccurrence of tacticity,
1
of course, does not mean that there is no preorientation. The H-NMR spectrum of
the poly(methacrylic acid) (14) obtained by de-dendronization of 13 by comparison
with literature spectra of highly iso-, syndio-, and atactic poly(methacrylic acids) (not
shown) [30] shows that polymer 14 is mainly atactic with some isotactic units.

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Scheme 5

Helvetica Chimica Acta – Vol. 89 (2006)
2755
Scheme 5 (cont.)
a) 12, Et3
ACHTREUNG
Fig. 2. 1H-NMR Spectra of a) model compound 19, b) model compound 17b, and c)d) crude dendron
15 obtained from two independent experiments (c) Run 1 and d) Run 2). All spectra were run in
CDCl3 which is marked (*). Solvent signals (DMF, CH2Cl2, grease) are marked (#).

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 6
a) 12, Et3
ACHTREUNG
AHCTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
2757
This work was supported by the German Science Foundation (DFG-Sfb 448, TP A1) which is grate-
fully acknowledged. We thank Sabine Fuchs and Stefan Müller for helpful discussions most notably
regarding an optimized procedure for compound 3.
Experimental Part
General. Dendrons 2a–d, 4b, 8a,b, 9a, 10a, and 12 were prepared accordingto literature procedures
[16][24]. Reagents were purchased from Aldrich, Acros, or Fluka. Methacryloyl chloride (=2-methyl-
prop-2-enoyl chloride; MAC) was freshly distilled before use. Tetrahydrofuran (THF) and triethylamine
(Et3N) were refluxed over Na with benzophenone as indicator, CH2Cl2 was dried by distillingover CaH 2.
G
All other reagents and solvents were used as received. All reactions were performed under N2. Column
chromatography (CC): silica gel 60 M (Macherey–Nagel; 0.04–0.063 mm, 230–400 mesh); FC=flash
1
chromatography. Tg =Glass-transition temp. H- and 13C-NMR Spectra: Bruker AM-300 (300 (1H) and
75 MHz (13C)), AV-500 (500 (1H) and 125 MHz (13C)), and AV-700 (700 MHz (1H)) spectrometers; at
r.t. (if not otherwise stated); CDCl3 or CD3OD as solvent; d in ppm, J in Hz. ESI-MS: MS-service of
G
the Laboratorium für Organische Chemie, ETH Zürich; IonSpec-Ultra instrument; in m/z (rel. %). Ele-
mental analyses were performed by the Mikrolabor of the Laboratorium für Organische Chemie, ETH
Zürich; the samples were dried rigorously under vacuum prior to analysis to remove strongly adhering
solvent molecules. Gel permeation chromatography (GPC): PL-GPC-220 instrument with 2” PL-Gel
Mix-B LS column set (2”30 cm) equipped with RI (refractive index), viscosity, and LS (light scattering
with 15 and 908 angle) detectors (DMF+1 g lꢀ1 LiBr as eluent at 808); universal calibration with PMMA
standards in a range of Mp 2680 to 3900000 (Polymer Labs. Ltd, UK).
Ethyl 3-Bromo-5-{3-{[(benzyloxy)carbonyl]amino}propyl}benzoate (3). A soln. of benzyl prop-2-
enylcarbamate (12.50 g, 65.4 mmol) in dry toluene (150 ml) in a Schlenk flask under N2 was degassed
(3”), and at 08, 9-BBN (8.65 g, 71.5 mmol) was added. The mixture was stirred for 12 h at r.t. The result-
ingmixture was then transferred to 1 M KOH (100 ml), 1 (20.00 g, 65.3 mmol), and toluene (50 ml). The
soln. was again degassed (3”), and then tetrakis(triphenylphosphine)palladium(0) (2.00 g, 1.7 mmol) was
added. The mixture was stirred at 608 for 48 h under N2. Then, the org. phase was washed with brine (100
ml) and NaHCO3 soln. (100 ml), dried (MgSO4), and evaporated and the residue subjected to CC (silica
gel, hexane/AcOEt 15 :1, then 8 :1), followed by FC (CH2Cl2): 3 (16.78 g, 66%). Slightly yellow oil. 1H-
NMR (CDCl3): 1.33 (t, MeCH2O); 1.75 (m, 1 CH2); 2.60 (t, ArCH2); 3.09 (m, NHCH2); 4.30 (q, MeCH2-
A
N
(s, 1 arom. H). 13C-NMR (CDCl3): 14.23; 31.32; 32.49; 40.03; 61.24; 66.69; 122.35; 128.09; 128.47; 130.19;
132.43; 135.53; 143.89; 156.39; 165.27. EI-MS: 419 (M+). Anal. calc. for C20H22BrNO4 (418.8): C 57.15, H
5.25, N 3.33; found: C 57.30, H 5.27, N 3.23.
Ethyl 3-{3-{[(Benzyloxy)carbonyl]amino}propyl}-5-{3-{[(tert-butoxy)carbonyl]amino}propyl}ben-
zoate (4a). As described for 3, with tert-butyl prop-2-enylcarbamate (8.20 g, 52.3 mmol), toluene (150
ml), and 9-BBN (7.00 g), (12 h at r.t), and then with 1M KOH (100 ml), 3 (16.70 g, 39.8 mmol), toluene
(50 ml), and tetrakis(triphenylphosphine)palladium(0) (1.50 g, 1.3 mmol) (14 h at 1008). CC (silica gel,
hexane/AcOEt 8 :1 then 3 :1): 4a (18.63 g, 86%). Yellow oil. 1H-NMR (CDCl3): 1.35 (t, MeCH2O);
1.44 (s, Me
A
ACHTREUNG
4.63 (br. s, 1 NH); 4.85 (br. s, 1 NH); 5.02 (s, PhCH2
AHCTREUNG
(s, 2 arom. H). 13C-NMR (CDCl3): 14.23; 28.32; 31.31; 31.47; 32.61; 32.67; 40.24; 60.89; 66.59; 79.08;
127.07; 127.13; 127.99; 128.42; 130.71; 133.09; 141.76; 141.95; 156.39; 156.79; 165.27. FAB-MS (3 kV):
521 (5.15, [M+Na]+). Anal. calc. for C28H38N2O6 (498.61): C 67.45, H 7.68, N 5.62; found: C 67.32, H
7.48, N 5.25.
Benzyl tert-Butyl {[5-(Hydroxymethyl)-1,3-phenylene]dipropane-3,1-diyl}bis[carbamate] (5a). A
soln. of 4a (2.00 g, 4.0 mmol) in abs. THF (30 ml) was added dropwise to a suspension of LiAlH4 (0.36
g, 9.6 mmol) in THF (10 ml) within 30 min under N2 at 08. The mixture was stirred for 8 h below 108,
and the reaction was quenched by addingacidified water (4 ml; pH 5). The resultingprecipitate was fil-
tered and washed with AcOEt (3”60 ml), and the solvent was evaporated. CC (silica gel, AcOEt/hexane
1
1:1) yielded 5a (1.48 g, 81%)). Colorless viscous oil. H-NMR (CDCl3): 1.43 (s, Me3
A

2758
Helvetica Chimica Acta – Vol. 89 (2006)
CH2); 2.45 (t, 4 H, ArCH2); 3.10 (q, 2 H, CH2
G
G
NH); 4.95 (s, PhCH2
AHCTREUNG
28.19; 31.08; 31.25; 32.54; 32.59; 39.66; 40.12; 64.36; 66.27; 78.85; 124.38; 126.60; 126.99; 127.25; 127.77;
128.10; 128.21; 136.41; 141.39; 141.53; 155.92; 156.38. ESI-MS: 479.3 ([M+Na]+). Anal. calc. for
C28H38N2O6 (456.26): C 68.40, H 7.95, N 6.14; found: C 68.11, H 7.92, N 6.17.
Benzyl {3-[3-(3-Aminopropyl)-5-(hydroxymethyl)phenyl]propyl}carbamate Hydrochloride (5b). A
soln. of 25% HCl soln. (1.37 ml, 4 equiv.) in THF (3 ml) was added slowly to a soln. of 5a (1.20 g, 2.6
mmol) in THF (25 ml) under N2 at 08 (TLC monitoring). After completion of the reaction (ca. 3 h),
the solvent was evaporated at r.t.: 5b (0.97 g, 94%). Viscous oil. The product was used for the next
step without further purification.
tert-Butyl {3-[3-(3-Aminopropyl)-5-(hydroxymethyl)phenyl]propyl}carbamate (5c). A mixture of 5a
(1.00 g, 2.2 mmol) in AcOEt/EtOH 1:1 (20 ml), 10% Pd/C (100 mg), and cyclohexa-1,4-diene (1.74 g,
22.0 mmol) was hydrogenated under 3 bar of H2 at r.t. for 4 h. The soln. was then filtered through Celite
and the solvent evaporated at r.t.: 5c (0.7 g, 92%). Viscous oil. The product was used for the next step
without further purification.
Dibenzyl
{{5-{{{{3-{3-{[(tert-Butoxy)carbonyl]amino}propyl}-5-(hydroxymethyl)phenyl}propyl}-
amino}carbonyl}-1,3-phenylene}dipropane-3,1-diyl}bis[carbamate] (6a). To a mixture of 5c (1.13 g, 2.2
mmol) and 1-hydroxy-1H-benzotriazol (HOBt; 0.36 g, 2.4 mmol) in CH2Cl2 (60 ml) in a Schlenk flask
was added N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl; 0.47 g, 2.5
mmol) at ꢀ308 under N2. The mixture was stirred until the hydrochloride was dissolved. Then a soln.
of 2c (0.58 g, 1.8 mmol) and Et3N (0.75 ml, 5.4 mmol) in MeOH/CH2Cl2 1:1 (15 ml) was added dropwise
A
at ꢀ208. The mixture was warmed to r.t. and stirred for 14 h, then washed with aq. NaHCO3 soln. (50 ml)
and brine (50 ml), dried (MgSO4), and concentrated. CC (silica gel, AcOEt/hexane 3 :1) yielded 6a (1.01
g, 69%). Colorless foam. 1H-NMR (CDCl3): 1.45 (s, Me3
ACHTREUNG
(m, 8 H, ArCH2); 2.97 (m, 6 H, CH2
A
ACHTREUNG
(s, 2 PhCH2O); 5.28 (br. s, 2 NH); 6.77 (s, 1 arom. H); 6.84 (s, 1 arom. H); 6.88 (s, 2 arom. H); 6.97 (s, 1
A
arom. H); 7.19 (m, 10 arom. H); 7.27 (s, 1 arom. H). 13C-NMR (CDCl3): 28.06; 30.55; 30.95; 31.18; 32.45;
32.92; 39.38; 40.18; 64.24; 65.99; 78.60; 124.21; 124.49; 126.98; 127.50; 127.55; 128.03; 131.15; 134.44;
136.37; 141.26; 141.34; 141.41; 141.47; 155.92; 156.34; 167.60. ESI-MS: 831 (M+). Anal. calc. for
C47H60N4O8 (809.01): C 69.78, H 7.48, N 6.93; found: C 69.63, H 7.68, N 6.94.
Dibenzyl {{5-{{{3-[3-(3-Aminopropyl)-5-(hydroxymethyl)phenyl]propyl}amino}carbonyl}-1,3-phe-
nylene}dipropane-3,1-diyl}bis[carbamate] Hydrochloride (6b). To a soln. of 6a (1.20 g, 2.6 mmol) in
THF (25 ml) was slowly added a soln. of 25% HCl soln. (1.37 ml, 4 equiv.) in THF (3 ml) under N2 at
08. The mixture was stirred for 3 h. The solvent was evaporated at r.t. to yield 6b (1.00 g, 96%). Viscous
oil. The product was used for the next step without further purification.
Di(tert-butyl) {{5-{{{3-{3-{3-{[(Benzyloxy)carbonyl]amino}propyl}-5-(hydroxymethyl)phenyl}pro-
pyl}amino}carbonyl}-1,3-phenylene}dipropane-3,1-diyl}bis[carbamate] (6c). To a soln. of the acid den-
dron 2c (1.10 g, 2.5 mmol) in CH2Cl2 (30 ml) was added HOBt (0.39 g, 2.7 mmol) at r.t. After 10 min
at ꢀ308, EDC·HCl (0.50 g, 2.6 mmol) was added. The mixture was stirred for 3 h. Then a soln. of 5b
(0.82 g, 2.1 mmol) and Et3N (1.45 ml, 10.4 mmol) in MeOH/CH2Cl2 1:1 (15 ml) was added dropwise at
A
ꢀ208. The resultingmixture was warmed to r.t. and stirred for 14 h. It was then washed with brine
and aq. NaHCO3 soln. The org. phase was dried (MgSO4) and the solvent evaporated. CC (silica gel,
AcOEt/hexane 2 :1, then 3 :1) yielded 6c (2.65, 84%). Colorless foam. 1H-NMR (CDCl3): 1.44 (s, 2 Me3-
A
N
A
ACHTREUNG
6.97 (s, 1 arom. H); 7.01 (s, 1 arom. H); 7.07 (s, 1 arom. H); 7.32 (m, 5 arom. H); 7.39 (s, 2 arom. H). 13C-
NMR (CDCl3): 28.10; 30.54; 30.76; 31.21; 32.12; 32.57; 32.99; 39.50; 39.80; 64.33; 66.13; 78.66; 124.24;
124.57; 127.04; 127.57; 127.66; 128.11; 131.23; 134.48; 136.30; 141.32; 141.45; 155.90; 156.44; 167.68.
ESI-MS: 797 ([M+Na]+). Anal. calc. for C44H62N4O8 (775.00): C 68.19, H 8.06, N 7.23; found: C
67.92, H 8.23, N 7.12.
Di(tert-butyl) {{5-{{{3-[3-(3-Aminopropyl)-5-(hydroxymethyl)phenyl]propyl}amino}carbonyl}-1,3-
phenylene}dipropane-3,1-diyl}bis[carbamate] (6d). Into a hydrogenation flask, 6c (2.15 g, 2.8 mmol) in
THF/AcOEt/EtOH 1:1:1 (30 ml), 10% Pd/C (0.22 g) and cyclohexa-1,4-diene (0.4 ml, 10 equiv.) were

Helvetica Chimica Acta – Vol. 89 (2006)
2759
added. The mixture was hydrogenated under 3 bar of H2 at r.t. (TLC monitoringuntil the reaction was
finished (ca. 5 h)). The product was filtered and washed with AcOEt (50 ml). Evaporation of the solvent
at r.t. yielded 6d (1.77 g, 99%). Viscous oil. The product was used for the next step without further puri-
fication.
Benzyl Tri(tert-butyl) {[5-(Hydroxymethyl)-1,3-phenylene]bis(propane-3,1-diyliminocarbonylben-
zene-5,1,3-triyldipropane-3,1-diyl)}tetrakis[carbamate] (7a). To a soln. of acid dendron 4b (1.50 g, 3.2
mmol) and HOBt (0.53 g, 3.9 mmol) in CH2Cl2 (80 ml) was added EDC·HCl (0.7 g, 3.66 mmol) at
ꢀ208 under N2. The mixture was stirred until the hydrochloride was dissolved completely (ca. 3 h). To
this soln. were added 6d (1.77 g, 2.7 mmol) and Et
The mixture was stirred for 15 h at r.t. It was then washed with aq. NaHCO3 soln. (70 ml) and brine
A
(70 ml), the org. phase dried (MgSO4), and the solvent evaporated. CC (silica gel, AcOEt/hexane 3 :1)
1
yielded 7a (2.4 g, 80%). Colorless foam. Tg 35.108. H-NMR (CDCl3, 500 MHz): 1.43 (s, 27 H, Me3
ACHTREUNG
1.71 (m, 8 H, CH2); 1.86 (m, 4 H, CH2); 2.55 (m, 12 H, ArCH2); 3.06 (q, 6 H, CH2
ACHTREUNG
A
N
ACHTREUNG
6.96 (s, 2 arom. H); 7.02 (s, 2 arom. H); 7.27 (m, 5 arom. H); 7.29 (s, 2 arom. H); 7.30 (s, 2 arom. H). 13C-
NMR (CDCl3, 500 MHz): 28.41; 30.77; 31.36; 32.50; 33.29; 39.62; 65.00; 66.59; 78.67; 124.75; 127.66;
128.04; 128.46; 131.48; 134.57; 141.34; 141.41; 141.96; 156.13; 156.35; 167.73. FAB-MS (3 kV): 1115
(100, [M+Na]+). Anal. calc. for C62H88N6O11 (1093.41): C 68.11, H 8.11, N 7.69; found: C 67.92, H
8.25, N 7.51.
Tribenzyl tert-Butyl {[5-(Hydroxymethyl)-1,3-phenylene]bis(propane-3,1-diyliminocarbonylben-
zene-5,1,3-triyldipropane-3,1-diyl)}tetrakis[carbamate] (7b). As described for 7a, with 4b (0.72 g, 1.7
mmol), HOBt (0.22 g, 1.7 mmol), CH2Cl2 (30 ml), EDC·HCl (0.33 g, 1.73 ml), 6b (0.85 g, 1.3 mmol), Et3N
G
(0.93 ml, 6.7 mmol), and MeOH/CH2Cl2 1:1 (15 ml). After 14 h at r.t., the mixture was washed with brine
(50 ml) and aq. NaHCO3 soln. (50 ml), the org. phase dried (MgSO4), and the solvent evaporated. CC
1
(silica gel, CH2Cl2/MeOH 4 :1) yielded 7b (0.91 g, 69%). Colorless foam. Tg 33.108. H-NMR (CDCl3,
500 MHz): 1.44 (s, 9 H, Me
ACHTREUNG
(t, 2 H, CH2NH); 3.10 (q, 6 H, CH2
A
G
A
ACHTREUNG
6.91 (s, 1 arom. H); 6.97 (s, 2 arom. H); 7.03 (s, 1 arom. H); 7.27 (m, 20 arom. H). 13C-NMR (CDCl3,
500 MHz): 28.39; 30.64; 31.00; 31.29; 32.44; 33.21; 39.66; 40.14; 64.88; 66.60; 78.60; 124.88; 127.60;
127.99; 128.02; 128.44; 131.53; 134.77; 136.57; 141.55; 141.71; 141.88; 155.92; 156.66; 167.90. FAB-MS
(3 kV): 1183 (65.15, [M+Na]+). Anal. calc. for C68H84N6O11 (1161.45): C 70.32, H 7.29, N 7.24; found:
C 70.52, H 7.05, N 6.96.
O,O’’-Dibenzyl O’,O’’’-Di-(tert-butyl) {[5-(Hydroxymethyl)-1,3-phenylene]bis(propane-3,1-diylimi-
nocarbonylbenzene-5,1,3-triyldipropane-3,1-diyl)}tetrakis[carbamate] (9b). As described for 7a, with 4b
(1.20 g, 2.6 mmol), HOBt (0.35 g, 2.6 mmol), CH2Cl2 (30 ml), EDC·HCl (0.53 g, 2.8 mmol), 8b (0.30 g,
1.0 mmol), Et3N (0.8 ml), and MeOH (10 ml). After 15 h at r.t., the mixture was washed with aq.
U
NaHCO3 soln. (40 ml) and brine (40 ml), the org. phase dried (MgSO4), and the solvent evaporated.
CC (silica gel, AcOEt/hexane 4 :1) yielded 9b (0.98 g, 86%). Colorless foam. Tg 43.908. 1H-NMR
(CDCl3, 500 MHz): 1.43 (s, 18 H, Me3
ArCH2); 2.69 (t, 4 H, ArCH2); 3.06 (q, 4 H, CH2
4.52 (s, HOCH2); 4.85 (br., 1 NH); 5.01 (s, 2 PhCH2
ACHTREUNG
N
A
ACHTREUNG
AHCTREUNG
arom. H); 6.98 (s, 2 arom. H); 7.04 (s, 2 arom. H); 7.27 (m, 14 arom. H). 13C-NMR (CDCl3, 500
MHz): 28.15; 30.55; 30.85; 31.00; 32.23; 32.99; 36.19; 39.44; 39.92; 64.33; 66.17; 78.76; 124.33; 124.62;
127.00; 127.62; 127.77; 128.16; 130.55; 131.27; 134.55; 136.40; 141.44; 141.58; 156.00; 156.49; 167.74.
FAB-MS (3 kV): 1149 (100, [M+Na]+). Anal. calc. for C65H86N6O11 (1127.43): C 69.25, H 7.69, N 7.45;
found: C 69.03, H 7.87, N 7.52.
Tetrabenzyl {[5-(Hydroxymethyl)-1,3-phenylene]bis(propane-3,1-diyliminocarbonylbenzene-5,1,3-
triyldipropane-3,1-diyl)}tetrakis[carbamate] (9c). To a soln. of the acid dendron 2d (1.64 g, 3.3 mmol)
in CH2Cl2 (30 ml) was added HOBt (0.45 g, 3.3 mmol) at r.t. After 10 min at ꢀ308, EDC·HCl (0.66 g,
3.4 mmol) was added. The mixture was stirred for 3 h. Then a soln. of 8b (0.4 g, 1.4 mmol) and Et3N
G
(1.5 ml, 10.8 mmol) in MeOH (10 ml) was added dropwise at ꢀ208. The resultingmixture was warmed
up to r.t. and stirred for 14 h. It was then washed with brine (50 ml) and aq. NaHCO3 soln. (50 ml), the
org. phase dried (MgSO4), and the solvent evaporated. CC (silica gel, CH2Cl2/MeOH 20 :1) yielded 9c

2760
Helvetica Chimica Acta – Vol. 89 (2006)
1
(1.17 g, 72%). White foam. Tg 32.078. H-NMR (CDCl3, 500 MHz): 1.58 (m, 8 H, CH2); 1.71 (m, 4 H,
CH2); 2.39 (m, 12 H, ArCH2); 2.90 (t, 8 H, CH2
8 H, 4 PhCH
C
NH); 4.40 (s, HOCH2); 4.95 (s,
AHCTREUNG
Deprotection of the Boc Group of the Orthogonally Protected Second-Generation Dendrons: General
Procedure 1 (G.P. 1). A soln. of the G2-dendron in THF was cooled to 08 in an ice bath. Then 25% HCl
soln. (4 equiv. per Boc group) in THF was added dropwise, and the mixture was stirred at 08 for 1 h and at
r.t. for another 2 h. Then, the mixture was evaporated and the residue dried in vacuo at r.t. affordingthe
deprotected dendrons in quantitative yield.
Benzyl
{3-{3-(3-Aminopropyl)-5-{{{3-{3-{3-{[3,5-bis(3-aminopropyl)benzoyl]amino}propyl}-5-
Trihydrochloride (10b).
(hydroxymethyl)phenyl}propyl}amino}carbonyl}phenyl}propyl}carbamate
Accordingto the G.P. 1, with 7a (0.23 g, 0.21 mmol), THF (10 ml), 25% HCl soln. (0.50 ml, 18 equiv.),
1
and THF (6 ml) at 08 for 1 h and at r.t. for another 4 h: 10b (0.18 g, 93%). Colorless viscous oil. H-
NMR (CD
ArCH2); 2.66 (m, 8 H, ArCH2); 3.08 (t, 2 H, CH2
(s, PhCH2O); 6.93 (s, 1 arom. H); 6.96 (s, 2 arom. H); 7.18 (s, 2 arom. H); 7.25 (m, 5 arom. H); 7.43 (s,
2 arom. H); 7.48 (s, 2 arom. H). 13C-NMR (CD3
OD, 500 MHz): 30.05; 32.22; 33.26; 34.33; 40.29;
40.88; 66.85; 67.33; 126.33; 126.71; 127.88; 128.64; 129.44; 139.02; 142.66; 143.05; 156.33; 170.09.
Dibenzyl {[5-(Hydroxymethyl)-1,3-phenylene]bis{propane-3,1-diyliminocarbonyl[5-(3-amino-
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
propyl)-3,1-phenylene]propane-3,1-diyl}}bis[carbamate] Dihydrochloride (10d). Accordingto the G.P.
1, with 9b (0.40 g, 0.4 mmol), THF (15 ml), 25% HCl soln. (0.5 ml, 11 equiv.), and THF (5 ml) at 08
for 1 h and at r.t. for another 3 h: 10d (0.34 g, 97%). Viscous oil. 1H-NMR (CDCl3/CD3
ACHTREUNG
A
G
A
ACHTREUNG
AHCTREUNG
124.79; 127.00; 127.35; 127.88; 128.16; 130.55; 131.27; 134.55; 136.40; 141.33; 141.76; 156.88; 168.21.
Dibenzyl {{5-{{{3-{3-{3-{{3-(Aminopropyl)-5-{3-{[(benzyloxy)carbonyl]amino}propyl}benzoyl}ami-
no}propyl}-5-(hydroxymethyl)phenyl}propyl}amino}carbonyl}-1,3-phenylene}dipropane-3,1-diyl}bis[car-
bamate] Hydrochloride (10f). Accordingto the G.P. 1, with 7b (0.18 g, 0.16 mmol), THF (10 ml), 25%
HCl soln. (0.12 ml, 6 equiv.), and THF (4 ml) at 08 for 1 h and at r.t. for 3 h: 10f (0.16 g, 98%). Colorless
solid. 1H-NMR (CDCl3/CD3
ArCH2); 2.75 (t, 2 H, CH2NH); 3.03 (q, 6 H, CH2
(s, 3 PhCH2
O); 6.86 (s, 1 arom. H); 6.90 (s, 2 arom. H); 6.99 (s, 1 arom. H); 7.27 (m, 20 arom. H). 13C-
NMR (CDCl3/CD3OD, 500 MHz): 30.64; 31.11; 31.29; 32.44; 33.21; 39.66; 40.14; 66.66; 78.60; 124.88;
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
AHCTREUNG
127.60; 127.99; 128.02; 128.44; 131.53; 134.77; 136.57; 141.55; 141.71; 141.88; 156.92; 167.90.
Deprotection of the Cbz Group of the Orthogonally Protected Second-Generation Dendrons. General
2 (G.P. 2). The G2-dendron was dissolved in THF/AcOEt/EtOH (1 :1:1). Then cyclohexa-1,4-diene
(Method B) or 5% formic acid (Method A) and Pd/C were added, and the soln. was transferred into a
hydrogenation flask. The mixture was hydrogenated under 3.5 bar of H2 at r.t. overnight. The product
was filtered through Celite, and the solvent was evaporated at r.t. to yield the deprotected dendrons.
Di(tert-butyl) {{5-{{{3-{3-{3-{{3-(3-Aminopropyl)-5-{3-{[(tert-butyl)carbonyl]amino}propyl}benzoyl}-
amino}propyl}-5-(hydroxymethyl)phenyl}propyl}amino}carbonyl}-1,3-phenylene}dipropane-3,1-diyl}bis-
[carbamate] (10c). Accordingto the G.P. 2, with 7a (0.17 g, 0.2 mmol), THF/AcOEt/EtOH 2 :1:1 (20
ml), cyclohexa-1,4-diene (0.06 ml, 0.6 mmol), and 10% Pd/C (20 mg): 10c (0.14 g, 94%). Slightly pale
1
solid. H-NMR (CDCl3, 500 MHz): 1.39 (s, 27 H, Me3
ACHTREUNG
(m, 8 H, ArCH2); 2.59 (t, 4 H, ArCH2); 2.88 (t, 2 H, CH2
A
ACHTREUNG
NH); 4.50 (s, HOCH2); 6.88 (s, 1 arom. H); 6.93 (s, 1 arom. H); 6.96 (s, 1 arom. H); 7.02 (s, 2 arom. H);
7.31 (s, 4 arom. H). 13C-NMR (CDCl3): 28.30; 30.66; 31.47; 32.44; 33.03; 39.44; 65.75; 78.67; 124.66 124.76;
127.66; 128.04; 128.44; 131.48; 134.55; 141.34; 141.44; 141.96; 156.33; 167.73.

Helvetica Chimica Acta – Vol. 89 (2006)
2761
Di(tert-butyl) {[5-(Hydroxymethyl)-1,3-phenylene]bis{propane-3,1-diyliminocarbonyl[5-(3-amino-
propyl)-3,1-phenylene]propane-3,1-diyl}}bis[carbamate] (10e). Accordingto the G.P. 2, with 9b (0.40 g,
0.3 mmol), THF/AcOEt/EtOH 1:1:1 (21 ml), cyclohexa-1,4-diene (0.68 ml, 7.01 mmol), and 10% Pd/
1
C (40 mg): 10e (0.29 g, 95%). Pale solid. H-NMR (CDCl3, 500 MHz): 1.43 (s, 18 H, Me3
ACHTREUNG
8 H, CH2); 1.88 (m, 4 H, CH2); 2.60 (m, 12 H, ArCH2); 2.69 (t, 4 H, ArCH2); 3.03 (q, 4 H, CH2
3.23 (q, 4 H, CH2
ACHTREUNG
AHCTREUNG
7.29 (s, 2 arom. H); 7.46 (s, 2 arom. H). 13C-NMR (CDCl3): 28.11; 30.44; 31.03; 32.22; 32.54; 32.99;
39.36; 40.44; 64.01; 78.86; 124.22; 124.48; 127.00; 131.14; 134.55; 141.48; 141.88; 156.02; 167.70.
tert-Butyl {3-{3-(3-Aminopropyl)-5-{{{3-{3-{3-{[3,5-bis(3-aminopropyl)benzoyl]amino}propyl}-5-
(hydroxymethyl)phenyl}propyl}amino}carbonyl}phenyl}propyl}carbamate (10g). Accordingto the G.P.
2, with 7b (0.20 g, 0.2 mmol), THF/AcOEt/EtOH 1:1:1 (15 ml), cyclohexa-1,4-diene (0.40 g, 5.2
mmol), and 10% Pd/C (50 mg). The NMR of the product showed that there were still some Cbz-protect-
ing groups present. Therefore, the product was treated for another night by the same procedure: 10g (0.10
g, 85%). Slightly yellow viscous oil. 1H-NMR (CDCl3/CD3
CH2); 1.82 (m, 6 H, CH2); 1.92 (m, 4 H, CH2); 2.68 (m, 8 H, ArCH2); 2.72 (m, 10 H, ArCH2, CH2
3.04 (t, 2 H, CH2NH); 3.34 (t, 4 H, CH2NH); 4.51 (s, HOCH2); 6.95 (s, 1 arom. H); 6.97 (s, 2 arom. H); 7.23
(s, 1 arom. H); 7.26 (s, 1 arom. H); 7.40 (s, 1 arom. H); 7.42 (s, 3 arom. H). 13C-NMR (CDCl3/CD3
OD, 500
A
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
MHz): 28.39; 31.00; 31.29; 33.99; 34.31; 39.99; 41.78; 65.22; 79.50; 125.77; 125.91; 128.55; 132.77; 132.88;
142.89; 143.22; 143.68; 156.66; 170.30.
N,N’-{[5-(Hydroxymethyl)-1,3-phenylene]dipropane-3,1-diyl}bis[3,5-bis(3-aminopropyl)benzamide]
(10h). Accordingto the G.P. 2, with 9c (0.31 g, 0.3 mmol), THF/AcOEt/EtOH 1:1:1 (15 ml), 5% formic
acid (0.5 ml), and 10% Pd/C (70 mg) for 48 h: 10h (0.12 mg, 85%). Viscous brown oil. 1H-NMR (CDCl3/
CD
NH); 3.18 (t, 4 H, CH2
H); 7.22 (m, 20 arom. H); 7.34 (s, 4 arom. H). 13C-NMR (CDCl3/CD3
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
31.71; 33.11; 33.39; 33.99; 40.44; 40.55; 78.60; 125.44; 125.76; 128.22; 132.34; 135.77; 142.20; 142.44;
142.73; 169.67.
Poly{3,5-bis{3-{{3,5-bis{3-{{3,5-bis{3-{[(tert-butoxy)carbonyl]amino}propyl}benzoyl}amino}propyl}-
benzoyl}amino}propyl}benzyl 2-Methylprop-2-enoate} (13). A soln. of 11 (0.04 g, 0.1 mmol) and Et3N
E
(0.23 ml) in MeOH (5 ml) was added dropwise to a soln. of 12 (0.23 g, 0.2 mmol, 1.75 equiv. per amine
group) in CH2Cl2/MeOH (15 ml) at ꢀ208. The mixture was stirred at r.t. for 48 h. The solvent was evapo-
rated, and then another portion of 12 (0.03 g, 0.03 mmol) and Et3N (0.20 ml) in DMF (10 ml) was added
A
and the mixture stirred for further 12 h. The polymer was then washed with brine, the solvent evaporated,
and the crude product purified 3 times by dissolvingit in CHCl 3 followed by precipitation with AcOEt/
1
hexane 1:1 until all excess of 12 had been completely removed: 13 (0.25 g, 93%). Colorless solid. H-
NMR (CDCl3, 700 MHz): 0.66 (br., 3 H, Me); 0.80 (br., 2 H, CH2); 1.35 (br., 72 H, Me); 1.65 (br., 28
H, CH2); 2.35 (br., 28 H, ArCH2); 2.89 (br., 28 H, NHCH2); 4.85 (br., 10 H, CH2O, NH); 7.11 (br., 10
arom. H); 7.28 (br., 11 arom. H). 13C-NMR (CDCl3, 500 MHz): 28.23; 31.44; 32.95; 40.55; 66.69;
79.29; 125.22; 128.03; 128.22; 128.73; 132.00; 135.05; 137.11; 142.41; 157.00; 157.50; 168.86. GPC: Mn
3.9·106; PDI 3.23.
Octa(tert-butyl) {(5-Methyl-1,3-phenylene)bis[propane-3,1-diyliminocarbonylbenzene-5,1,3-triylbis-
A
soln. of 13 (0.04 g, 0.02 mmol) THF/AcOEt/EtOH 1:1:1 (32 ml). 10% Formic acid (1 ml) and 10%
Pd/C (80 mg) were added, and the soln. was transferred into a hydrogenation flask. The mixture was
hydrogenated under 3.5 bar of H2 at r.t. for 4 d. The mixture was filtered, the solvent evaporated at
1
r.t., and the product purified by CC (silica gel, 7.5% MeOH/CH2Cl2): 15 (0.03 g, 84%). Pale solid. H-
NMR (CDCl3, 700 MHz): 1.39 (s, 72 H, Me); 1.76 (m, 18 H, CH2); 1.87 (m, 8 H, CH2); 1.95 (m, 4 H,
CH2); 2.22 (s, 3 H, Me); 2.52 (m, 24 H, ArCH2); 2.68 (t, 4 H, ArCH2); 3.08 (q, 18 H, CH2NH); 3.37 (q,
A
8 H, CH2
N
N
7.04 (s, 2 arom. H); 7.06 (s, 4 arom. H); 7.36 (s, 4 arom. H); 7.41 (s, 8 arom. H). 13C-NMR (CDCl3,
500 MHz): 23.09; 28.88; 30.10; 31.11; 31.75; 32.11; 32.32; 32.88; 34.80; 37.00; 37.53; 40.00; 79.53;
125.33; 128.90; 132.00; 133.43; 135.11; 142.20; 156.55; 168.03.

2762
Helvetica Chimica Acta – Vol. 89 (2006)
Ethyl 3-{3’-{[(Benzyloxy)carbonyl]amino}propyl}-5-{3-{{3,5-bis{3-{{3,5-bis{3-{[(tert-butoxy)carbo-
nyl]amino}propyl}benzoyl}amino}propyl}benzoyl}amino}propyl}benzoate (17a). A soln. of 16 (0.05 g,
0.1 mmol) and Et3N (0.12 ml) in CH2Cl2/MeOH 1:1 (5 ml) was added dropwise to a soln. of 12 (0.16
G
g, 0.1 mmol) in CH2Cl2 (20 ml) at ꢀ208. The mixture was stirred at r.t. overnight. It was then washed
with brine (30 ml) and aq. NaHCO3 soln. (30 ml). The org. phase was dried (MgSO4), and the solvent
evaporated. CC (silica gel, CH2Cl2/MeOH 20 :1) yielded 17a (0.14 g, 83%). White foam. 1H-NMR
(CDCl3, 700 MHz): 1.32 (t, MeCH2O); 1.38 (s, 36 H, Me); 1.72 (m, 8 H, CH2); 1.87 (m, 4 H, CH2);
1.95 (m, 2 H, CH2); 2.52 (t, 8 H, ArCH2); 2.59 (t, 6 H, ArCH2); 2.68 (t, 2 H, ArCH2); 3.01 (q, 8 H, CH2-
A
NH); 3.35 (q, 4 H, CH2
U
G
N
AHCTREUNG
(m, 5 arom. H); 7.38 (s, 4 arom. H); 7.41 (s, 2 arom. H); 7.61 (s, 1 arom. H); 7.66 (s, 1 arom. H). 13C-NMR
(CDCl3, 500 MHz): 14.58; 28.83; 31.00; 31.37; 31.77; 32.87; 33.00; 33.20; 34.00; 39.55; 39.66; 40.00; 40.88;
66.85; 79.45; 125.22; 127.48; 127.55; 128.36; 128.33; 128.84; 131.00; 131.94; 132.00; 133.68; 135.11; 135.15;
137.00; 142.15; 142.11; 142.29; 142.55; 156.58; 156.99; 167.22; 168.33; 168.45. HR-MALDI-MS: 1575
([M+Na]+).
Ethyl
benzoyl}amino}propyl}benzoyl}amino}propyl}benzoate (17b). Accordingto G.P. 2, with 17a (0.08 g,
0.055 mmol), THF/EtOH 2 :1 (15 ml). 10% Formic acid (0.5 ml), and 10% Pd/C (80 mg) for 48 h: 17b
3-(3-Aminopropyl)-5-{3-{{3,5-bis{3-{{3,5-bis{3-{[(tert-butoxy)carbonyl]amino}propyl}-
AHCTREUNG
1
(60 mg, 83%). Slightly pale solid. H-NMR (CDCl3/CD3
H, Me); 1.74 (m, 8 H, CH2); 1.91 (m, 6 H, CH2); 2.05 (m, 2 H, CH2); 2.56 (m, 8 H, ArCH2); 2.65 (m, 8
H, ArCH2); 2.88 (q, 2 H, CH2NH); 3.04 (q, 8 H, CH2NH); 3.35 (q, 6 H, CH2NH); 3.37 (q, 4 H, CH2NH);
4.29 (q, MeCH2O); 4.95 (br., 4 NH); 7.03 (s, 2 arom H); 7.07 (s, 1 arom. H); 7.25 (s, 1 arom. H); 7.43 (s, 4
arom. H); 7.51 (s, 2 arom H); 7.57 (s, 1 arom. H); 7.63 (s, 1 arom. H); 8.12 (br., 4 NH). 13C-NMR (CDCl3/
CD3OD, 500 MHz): 14.56; 28.68; 30.66; 30.81; 31.55; 32.29; 32.88; 33.18; 34.00; 39.23; 39.66; 39.91; 79.10;
A
N
N
AHCTREUNG
AHCTREUNG
125.22; 127.53; 128.00; 131.04; 132.11; 132.28; 133.55; 134.65; 134.88; 140.74; 142.22; 142.39; 142.55;
156.92; 167.22; 169.05; 169.22.
Ethyl 3,5-Bis{3-{{3,5-bis{3-{{3,5-bis{3-{[(tert-butoxy)carbonyl]amino}propyl}benzoyl}amino}pro-
pyl}benzoyl}amino}propyl}benzoate (19). A soln. of 18 (15 mg, 0.05 mmol) and Et3N (0.07 ml) in
E
CH2Cl2/MeOH 1:1 (5 ml) was added dropwise to a soln. of 12 (0.13 g, 0.1 mmol) in CH2Cl2 (15 ml) at
ꢀ208. The mixture was stirred at r.t. overnight. It was then washed with brine (25 ml) and aq.
NaHCO3 soln. (25 ml). The org. phase was dried (MgSO4), and the solvent evaporated. CC (silica gel,
CH2Cl2/MeOH 15 :1) yielded 19 (94 mg, 89%). White foam. 1H-NMR (CDCl3): 1.30 (t, MeCH2O);
1.38 (s, 72 H, Me); 1.71 (m, 18 H, CH2); 1.83 (m, 8 H, CH2); 1.96 (m, 4 H, CH2); 2.52 (m, 24 H,
ArCH2); 2.68 (t, 4 H, ArCH2); 3.08 (q, 18 H, CH2
4.30 (q, 2 H, MeCH2
C
G
A
AHCTREUNG
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Received June 14, 2006