Phenols-useful templates for the synthesis of bi-functional orthogonally protected dendron building blocks via solid phase Mitsunobu reaction

Article abstract of DOI:10.1016/j.tet.2009.11.106

Bi-functional dendritic building blocks for convergent dendrimer growth were successfully synthesized from phenolic templates in the solid phase via a Mitsunobu reaction. Each arm of the dendron building block carries an orthogonally protected secondary amine along the arm, and a peripheral primary amine or phenol group (building block type 1) or a tertiary amine junction with orthogonally protected peripheral primary amine or carboxyl groups (building block type 2). The synthetic routes reported in this work are general and applicable for the preparation of diverse building blocks, controlling protection, arm length, and peripheral moieties. These novel dendron units can form unusual dendritic architectures by solid-phase chemistry, which may be incorporated into specific complex structures expanding the scope of dendrimer science.

Full text of DOI:10.1016/j.tet.2009.11.106

Tetrahedron 66 (2010) 878–886
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Phenols-useful templates for the synthesis of bi-functional orthogonally protected
dendron building blocks via solid phase Mitsunobu reaction
,
a
,
,
,
Gary Gellerman a , Sagit Shitrit b, Tzachi Shalit a b, Orit Ganot a b, Amnon Albeck b
*
a Department of Biological Chemistry, Ariel University Center of Samaria, Ariel 40700, Israel
b The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Bi-functional dendritic building blocks for convergent dendrimer growth were successfully synthesized
from phenolic templates in the solid phase via a Mitsunobu reaction. Each arm of the dendron building
block carries an orthogonally protected secondary amine along the arm, and a peripheral primary amine
or phenol group (building block type 1) or a tertiary amine junction with orthogonally protected pe-
ripheral primary amine or carboxyl groups (building block type 2). The synthetic routes reported in this
work are general and applicable for the preparation of diverse building blocks, controlling protection,
arm length, and peripheral moieties. These novel dendron units can form unusual dendritic architectures
by solid-phase chemistry, which may be incorporated into specific complex structures expanding the
scope of dendrimer science.
Received 30 June 2009
Received in revised form
10 November 2009
Accepted 26 November 2009
Available online 1 December 2009
Keywords:
Dendron building block
Mitsunobu coupling
Ó 2009 Elsevier Ltd. All rights reserved.
Orthogonal protection
Solid-Phase Organic Chemistry (SPOC)
1. Introduction
amine or hydroxyl), which are typically blocked with only one type
of protecting group.9 This feature limits the choices for ‘surface’
Dendrites are branched synthetic macromolecules with many
arms emanating from a central core. Important features of the
dendritic architecture include a high degree of structural symmetry
and a defined number of terminal groups at the surface, which may
be distinguished from the interior core. Depending on their size
(generation or order), dendrons not only have an impact on the
backbone conformation and flexibility but also allow the in-
troduction of a large number of functional groups at the periphery.
The combination of these features creates an environment within
the dendrimer molecule, which facilitates new discoveries in many
important research areas, such as material and biomedical sci-
ences.1 Current syntheses of dendrimers require exhaustive control
of the critical molecular design parameters, such as size, surface
chemistry, flexibility, and topology.1a,2–4 Effective techniques in-
clude the Starburst divergent strategy,2,3 the convergent growth
strategy,5 and the self-assembly strategy.6 These synthetic
approaches are effective in creating macromolecules with a unique
combination of properties.7,8 However, most dendronized polymers
known today carry only one kind of functional group (usually either
engineering to modify either all groups at once or a certain amount
of these randomly distributed over the entire macromolecule. The
orthogonal introduction of two different chemical modifications is
therefore not possible. Overcoming this limitation and thus
increasing the options for surface chemical derivatization can be
achieved by the development of dendronized macro-monomers
and polymers, which carry orthogonally protected peripheral
groups at each repeat unit. Selective deprotection should then
allow the introduction of predetermined numbers of molecular
components to each repeat unit.
Solution synthesis is the most common synthetic methodology
for the preparation of dendrimers.1 However it suffers major
problems when it comes to practical synthesis, in particular, the
necessity for repeated and time-consuming purifications. The
solid-phase synthesis of dendrimers on the other hand has a major
advantage: a large excess of reagents, which pushes the reaction to
completion, can be used without the problems usually associated
with purification, which becomes only a matter of extensive
washing. It should also be noted that resin-bound dendrimers can
enhance resin loading. This seems extremely important nowadays,
because of the huge demand for solid-phase synthetic resins with
increased loading capacity and reduced cost.
Abbreviations: Alloc, allyloxycarbonyl; Boc, t-butyloxycarbonyl; Cbz, benzyloxy-
carbonyl; DCM, dichloromethane; o-Nosyl, 2-nitrophenylsulfone; Fmoc, 9-Fluo-
renylmethoxycarbonyl; NMM, N-methyl morpholine; PE, petrol ether; SPOC, Solid-
Phase Organic Chemistry.
* Corresponding author.
E-mail address: garyg@ariel.ac.il (G. Gellerman).
Here we report the synthesis of bi-functional dendron building
blocks (BB) from phenolic templates via Mitsunobu reaction for
convergent dendrimer growth on solid support. These building
blocks are attributed to two types, differing from each other by the
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.106

G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
879
number and nature of the peripheral groups (Fig. 1). The protecting
groups used in this work were matched to the orthogonal or semi-
orthogonal combinations utilizing Alloc/Allyl, o-Nosyl, Fmoc, Boc,
and Cbz. The comparison between solution- and solid-phase ap-
proaches for the synthesis of our dendronic building blocks is also
discussed.
convergent dendrimer growth. The CO2H moiety on the phenol
ring has two functions: it acts as an anchor for assembly or im-
mobilization of the protected dendron building blocks on the acid-
sensitive resin (Cl–Trt resin) for fast convergent dendritic growth
on solid support, and it could be used for conjugation chemistry
after cleavage.
P1
Y
Y
P1
2.1. Solution-phase synthesis of tri-Alloc-protected 3,4,5-
trihydroxybenzoic acid and tetra-Alloc-protected type 1
dendron building block
N
Y
Y
P2
N
N
P2
P1
X
X
Y
N
P2
We started our research by the examination of a triple
condensation of N-Boc-2-bromoaminoethane16 to methyl 3,4,5-
trihydroxybenzoate (Scheme 1) via phenolic alkylation17 and
Mitsunobu reaction.15 The aim of the experiment was to examine
and tune the conditions for the key reaction step before engaging
in the assembly of our structurally more complex dendritic
building blocks. After saponification of the benzoate ester, the
acid-labile Boc group in 2b could be further replaced by Alloc
protection, leading to protected unit 3. Actually, this tri-armed
unit 3 served as a model toward the incorporation of more
complicated linkers containing orthogonally protecting groups.
Thus, the triple reaction of 1 with BocNHCH2CH2OH under
standard Mitsunobu conditions consistently yielded 2a in higher
yield (63%) than the standard alkylation with BocNHCH2CH2Br
(44%), even if a stronger base, Cs2CO3 instead of K2CO3, was used
in the alkylation reaction. Furthermore, the hydrolysis of 2a
yielded triply-Boc-protected benzoic acid 2b, which was sub-
jected to deprotection (TFA/DCM, 1:1 at rt) and subsequent
reprotection with Alloc-Cl to give 3 in 72% overall yield for the
three steps. Noteworthy, the shorter pathway to 3, applying
a direct Mitsunobu coupling of AllocNHCH2CH2OH to 1, was less
successful. Based on these results, we decided to use the more
effective Mitsunobu reaction as a key step for assembling the
multi-functional dendron building blocks.
P1
Y
P2
iso-dendron BB type-1
dendron BB type-2
X = CO2H, Y= NH, N-Alkyl, S, CO2, O
P1, P2 = Alloc/Allyl, Boc/t-Bu, Cbz/benzyl, DDZ, DDE, Fmoc, o-Nosyl, Tr, etc.
- carbohydrate, aromatic ring.
(linker)
Figure 1. Schematic structure of dendron building blocks (BB) of types 1 and 2.
2. Results and discussion
The dendron building blocks described in this paper can be di-
vided into two classes: type 1 and type 2 (Fig.1). BB type 1 possess
branch arms carrying a protected main chain secondary amine and
a terminal primary amine or phenol group. Phenolic BB of type 2,
which are more versatile and represent an extended version of
dendron BB type 1, are generated from BB type 1 by alkylation of
the deprotected secondary amine. BB type 2 present a tertiary
amine junction and a protected peripheral primary amine or
carboxyl group. Type
2 building block is more versatile in
dendrimer synthesis, creating opportunities for variable linkage
moieties (primary and secondary amides, carbamates, esters, ureas,
etc.), while type 1 is more limited due to the fixation of the
secondary amine at the junction.
NHBoc
Br
, Cs2CO3
BocHN
AllocHN
AcCN, reflux
44%
OH
1. TFA:DCM
O
O
HO
OH
(1:1) rt
O
O
O
O
BocHN
NHBoc
AllocHN
NHAlloc
CO2Me
2. Alloc- Cl,Et3N,
DCM, 0 °C to rt
NHBoc
HO
CO2R
2a, R = Me
2b, R = H
CO2H
DIAD, Ph3P, THF
1
NaOH,
MeOH,
rt; 8h,
3
(72% for 3 steps)
reflux
63%
Scheme 1. Solution-phase synthesis of tri-Alloc-protected 3,4,5-trihydroxybenzoic acid 3.
In order to synthesize the schematic structures in Fig 1, the
methodology must allow the selective incorporation of function-
Next, we moved to the synthesis of dendron building block of
type 17b (Scheme 2). The first attempt to synthesize 7b was carried
out in solution. This compound bears four Alloc protecting groups,
which is a reasonable model for further experiments.
´
alities within the dendron scaffold. Frechet showed in a series of
publications how the convergent approach can be utilized in the
control of surface10 and internal11 functionality. We aim to achieve
a better control in the construction of dendrimers incorporating
a variety of compatible building blocks of type 1 and 2 possessing
multi-linkage capabilities.
Polyhydroxybenzoic acids are useful starting materials for
generating complex macromolecules by tethering of their hy-
droxyl groups.12,13 Therefore we propose the use of phenols as
a basic unit in the synthesis of our dendron building blocks.
Phenolic scaffolds seem suitable for the synthesis of dendrons via
two key steps: phenolic alkylation14 and the Mitsunobu reaction.15
The existence of more than one hydroxyl group in combination
with the carboxylic acid on the benzene ring provides a versatile
starting point for the synthesis of branched dendritic units for
In order to improve the yield of the hydrolysis step,18 as was
observed also for 2b, we initially synthesized dihydroxyl core
structure 4 (Scheme 2), which bears a more convenient, acid-labile
t-Bu ester, instead of base-labile methyl ester as in 2a. The desired
monoalkylated 4 was prepared by the reaction of threefold excess
of 1,3,5-trihydroxybenzene with t-butyl bromoacetate (K2CO3,
DMF, rt, overnight) in 79% yield. The linker 6 was almost quanti-
tatively prepared from commercially available 2-(2-amino-
ethylamino)ethanol by standard double protection with Alloc-Cl.
Finally, 4 was submitted to the double Mitsunobu condensation
(DIAD, Ph3P in THF:DCM, rt) with 2 equiv of 6 affording tetra-Alloc
t-butyl ester intermediate 7a in a moderate yield (52%, after chro-
matography, 1:1 EtOAc/PE). t-Butyl removal in TFA/DCM (1:1) gave

880
G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
O
Br
HO
OH
O
OH
O
HO
1. DIAD, Ph3P
THF:DCM
(1:1) 0 °C to rt
NHAlloc
AllocHN
K2CO3, DMF, rt
79%
O
O
Alloc
O
Alloc
O
OH
N
N
52%
Phloroglucinol
4
2. TFA:DCM
(1:1)
Alloc-Cl, TEA,
DCM, rt,
97%
O
91%
H
N
Alloc
N
CO2R
HO
NH2
HO
NHAlloc
6
7a, R= t-Bu
7b, R= H
2
Scheme 2. Solution-phase synthesis of tetra-Alloc-protected dendron BB type 1d7b.
the final dendron BB type 17b in 91% yield after purification. At this
point of our work we decided to move to solid-phase chemistry to
improve the overall yield in the assembly process of the building
blocks.
Therefore, we decided to use the acid-sensitive di-t-butyl azo-
dicarboxylate (DBAD) instead of DIAD, which is degradable under
acid cleavage conditions. Finally, upon submitting 8 to two
repeated double Mitsunobu reactions with DBAD followed by
cleavage (3% TFA/DCM) and purification by RP-18 solid-phase
extraction, building block 10 was obtained in 87% yield.
2.2. Solid-phase synthesis of tetra-Alloc-protected dendron
BB type 1
2.3. Solid-phase synthesis of orthogonally protected
dendron BB type 1
As stated above, fast solid-phase organic chemistry (SPOC) has
two clear advantages over solution chemistry. First, solvent, excess
reagents and side products are easily removed from the reaction
mixture by suction, replacing laborious chromatography. Second,
repeated reactions can be employed for improving the yield.
In this work, the solid-phase synthesis of dendron building block
10, analogous to 7b, started by loading of 3,5-dihydroxybenzoic acid
on the chlorotrityl resin (0.64 mmol/g) in anhydrous DMF/morpho-
line followed by capping of the unreacted resin (Scheme 3). As
expected, the loading proceeded through the more nucleophilic car-
boxylate anion, leaving the hydroxy groups untouched and ready for
the following double Mitsunobu condensation. Thus, 8 was reacted
with linker 6 (5 equiv) initially using diisopropyl azodicarboxylate
(DIAD, 5 equiv) with Ph3P (5 equiv) in THF/DCM. After first conden-
sation, a test of a small sample by HPLC detected insufficient con-
densation (mixture of mono- and dicondensed products). Repeated
condensation under the same conditions and subsequent cleavage
(3% TFA in DCM) afforded dicondensed product 10 in good yield (84%)
after fast purification by solid-phase extraction pack (RP-18, first
washed with water and then extracted with acetonitrile). Note-
worthy, we identified unreacted DIAD in the 1H NMR spectrum of
crude 10 even after several washing steps of 9a before the cleavage.
In the next step we decided to expand the scope of dendron BB
synthesis by coupling orthogonally protected linkers to 8. First, we
prepared linker 5, bearing two orthogonal protecting groups Fmoc
and Alloc (Scheme 3). The synthesis of 5 started from mono Fmoc
protection of N-(2-hydroxyethyl) ethylenediamine with Fmoc-Osu
(0.5 equiv) in alkali (Na2CO3) dioxane/water mixture. Under these
conditions only the primary amine reacts.19 After work up, the in-
termediate was submitted to the subsequent Alloc protection with
Alloc-Cl in DCM in the presence of TEA, yielding the desired linker 5
in 67% overall yield. Unfortunately, our attempts to condense 5 with
8 to give 9b failed, most probably due to unfavorable interactions of
the protecting groups with the phenol.20 This phenomenon may
indicate that the length of the linker and protecting group positions
along the linker are crucial parameters for the successful Mitsu-
nobu condensation to the phenolic scaffold.
In order to overcome this problem, we prepared a series of
longer linear linkers 12, 13 (Scheme 4) and phenolic linker 11
(Scheme 5), which has a benzene spacer. These linkers, bearing
various orthogonal protecting groups applicable in Fmoc SPOC,21
were prepared by a previously reported procedure.22 Initially, the
NHAlloc
AllocHN
Alloc
N
HO
NHAlloc
Alloc
O
Alloc
O
HO
OH
Chlorotrityl resin
HO
OH
N
N
6
Morpholine,DMF
(extra dry)
DBAD, PPh3
THF:DCM
(1:1)
HO
O
O
O
8
(double coupling)
O
O
1. Fmoc-OSU, Na2CO3 in
H2O/dioxane, rt,
9a
Alloc
N
H
N
HO
NHFmoc
HO
NH2
3%TFA/ DCM
87%
5
2. Alloc-Cl, TEA in
DCM, rt,
Mitsunobu
67%
(after two steps)
NHFmoc
AllocHN
NHAlloc
FmocHN
Alloc
O
Alloc
Alloc
Alloc
O
N
N
N
N
O
O
O
HO
O
HO
9b
10
Scheme 3. Solid-phase synthesis of tetra-Alloc-protected dendron BB type 1d10.

G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
881
Alloc-Cl, Et3N
MsCl, Et3N
DCM
MsO
NHAlloc
HO
NHAlloc
18
HO
NH2
DCM
19
86%
82%
HO
NH
HO
N
NHAlloc
H
20
AcCN, reflux
80%
Fmoc-Cl, Et3N
DCM
THF
78%
HO
72%
HO
N
NHAlloc
N
NHAlloc
Fmoc
o-Nosyl
12
13
Scheme 4. Synthesis of orthogonally protected 3-(3-aminopropylamino)propan-1-ol linkers 12, 13.
HO
NH2
1.
OAllyl
Boc
AcCN, reflux
RO
HO
1. AllylBr, Cs2CO3
2. MsCl, TEA, DCM
HO
N
OAllyl
OH
2. Boc2O,
TEA, MeOH
11
83%
(for the 2 steps)
21, R=H,
22, R=Ms,
72%
(for the 2 steps)
Scheme 5. Synthesis of orthogonally protected 4-((3-hydroxypropylamino)methyl)phenol linker 11.
quantitative Alloc protection of 3-aminopropanol gave the corre-
sponding carbamate 18, which was then O-sulfonylated to give the
respective mesylate 19 in 86% yield (Scheme 4). The mesylate
(without any purification) was further displaced with 3-amino-
propanol to give the secondary amine intermediate 20, which was
N-Fmoc-protected or N-o-Nosyl-protected, leading after flash
chromatography purification (EtOAc) to hydroxyl linkers 12 and 13,
respectively, in reasonable overall yields (72% for 12, 78% for 13).
Similarly, 4-hydroxybenzyl alcohol was etherified by Allyl-Br
exclusively on the phenol ring to afford intermediate 21, which
after reacting with MsCl gave 22 as a viscous oil (Scheme 5).
Compound 22 was further reacted with 3-aminopropanol to afford,
after sequential Boc protection and purification, the desired linker
11 in overall 67% yield. Noteworthy, this synthetic approach is ap-
plicable to various orthogonally protected diamino alcohol linkers,
generating bi-functional arms varying in length and linking moiety.
Having the orthogonally protected linkers 12, 13, and 11 in hand,
we moved to the synthesis of dendritic building blocks 14,15, and 16
correspondingly, using the previously immobilized 8 (Scheme 6).
Finally, after submitting the above linkers to repeated Mitsunobu
HO
N
NAlloc
NHAlloc
P1
AllocHN
P1
P
HO
OH
12,13
HO
OH
Chlorotrityl resin
DBAD, PPh3
THF:DCM
(1:1)
1.
Morpholine,DMF
(extra dry)
N
N
O
O
HO
O
O
O
8
(double coupling)
2.
1%TFA/ DCM
HO
OAllyl
O
Boc
HO
N
1.
11
14
15
P
P
1 = o-Nosyl (74% from 8)
1 = Fmoc (77% from 8)
DBAD, PPh3
THF:DCM
(1:1)
(double coupling)
2. cold 1%TFA/ DCM
AllylO
OAllyl
N
N
Boc
Boc
O
O
HO
O
16 (68% from 8)
Scheme 6. Solid-phase synthesis of orthogonally protected dendron BB type 1d14, 15, and 16.

882
G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
condensations ([THF:DCM (1:1), DBAD, Ph3P, overnight]ꢀ2) with 8
and subsequent mild acidic cleavage, the desired orthogonally
protected units 14, 15, and 16 were obtained in reasonable yields
from resin-bound 3,5-dihydroxybenzoate 8 (74% for 14, 77% for 15
and 68% for 16) after purification by fast RP-18 solid-phase extrac-
tion. The purity of dendron BBs was determined by HPLC and ranged
between 87% and 93%.
minimal distance of the first protecting group on the linker from
the phenolic core should be at least four atoms.
The synthetic routes reported in this work are general and ap-
plicable for the preparation of diverse building blocks, controlling
protection, arm length and peripheral moieties enabling fast gen-
eration of versatile dendritic architectures by SPOC.
4. Experimental
4.1. General
2.4. Solid-phase synthesis of orthogonally protected
dendron BB type 2
Next we explored whether dendron building blocks of type 1 can
serve as precursors for more versatile dendron building units of type
2. For this purpose we employed the resin-bound Fmoc/Alloc pro-
tected unit 17 in alkylation with various functional bromoalkyl
groups. Thus, pre-made 17 (which is actually 15 before cleavage)
(Scheme 7) was submitted first to Fmoc deprotection (20% piperidine
in DMF, 10 min, twice), followed by double cycled dialkylation (NMP,
Analytical HPLC was performed on a 250ꢀ4.2 mm Lichroprep
RP-18 column from Merck, with a 1 mL/min flow and detection at
214 nm. The eluents were triply distilled water and HPLC-grade
CH3CN containing 0.1% TFA or MeOH. The concentration of all the
samples was 0.5%. Mass spectra were measured in the positive
and negative modes using a quadrupole mass spectrometer
equipped with an electro spray ionization source and cross-flow
inlet. 1H and 13C NMR spectra were recorded at 300 MHz and
75 MHz, respectively, in CDCl3. Assignments in the final products
were supported by 2D COSY, TOCSY, NOESY, ROESY, HMBC, and
HMQC spectroscopy. All chemical shifts are reported with respect
to TMS. SPE was performed on LiChrospher 60 RP-18Ò columns
purchased from Agilent Technologies. Chromatography was car-
DIEA, 50 ꢁC, 18 h, 2 cycles) with allyl
mopropylcarbamate, and N-(3-bromopropyl)-2-nitrobenzene-
a-bromoacetate, benzyl 3-bro-
sulfonamide. Finally, cleavage from the resin (3%TFA in DCM,) and
RP-18 solid-phase extraction afforded relatively pure (86–92% purity
by HPLC) orthogonally protected type 2 dendron building blocks 18a,
18b, and 18c in 62–70% yield from 17.
NHAlloc
X
AllocHN
NHAlloc
AllocHN
N
N
N
N
X
Fmoc
Fmoc
O
O
O
O
1. 20% Piperidine in DMF (twice)
BrCH2CO2Allyl (for 18a) or
2.
HO
O
O
O
BrCH2CH2CH2NHCBz (for 18b) or
BrCH2CH2CH2NHo-Nosyl (for 18c)
18a, X = -CO2Allyl (70%)
18b, X = -CH2CH2NHCbz (67%)
18c, X = -CH2CH2NHo-Nosyl (62%)
DIEA, DMF, 24h, 50°C
(2 cycles)
17
3. 1%TFA/ DCM
Scheme 7. Solid-phase synthesis of orthogonally protected dendron BB type 2d18a,b,c.
In summary, the fast solid phase synthetic methodology de-
scribed in this paper can yield orthogonally protected dendron
building blocks of type 1 and 2 for generation of more complex
dendron architectures by SPOC. Attempts to facilitate the reactions,
including the use of microwave-assisted chemistry, as well as the
implementation of our dendron building blocks for convergent
dendrimer synthesis on solid support are in progress.
ried out by standard flash chromatography and TLC on silica-gel
(Merck 7735).
4.1.1. Methyl 3,4,5-tris(2-(tert-butoxycarbonylamino)ethoxy)benzoate
(2a). Method A: To a solution of BocNHCH2CH2Br (1.28 g, 5.7 mmol)
in acetonitrile (50 mL) was added methyl trihydroxybenzoate 1
(0.35 g, 1.8 mmol) and Cs2CO3 (4.55 g, 13.3 mmol). The reaction
mixture was refluxed at 80 ꢁC under nitrogen overnight. The re-
action mixture was filtered and evaporated to give a brown oil,
which was dissolved in DCM (50 mL). The organic phase was
washed sequentially with water, saturated NaHCO3 solution, and
brine (50 mL each), dried over anhydrous Na2SO4 and evaporated.
Chromatography (EtOAc/PE 1:1) gave 2a as a brown oil (0.52 g, 44%
yield). Method B: To the dry solution of BocNHCH2CH2OH (1.12 g,
5.7 mmol) in THF (50 mL) were added DIAD (0.31 mL, 1.33 mmol)
and PPh3 (0.34 g, 1.33 mmol) under a nitrogen atmosphere. The
reaction mixture was stirred overnight, and then diluted with ether
(150 mL), and washed with saturated aqueous sodium bicarbonate
solution (2ꢀ100 mL). The organic layer was dried over sodium
sulfate. Excess solvent was removed under reduced pressure
initially on a rotary evaporator and then under high vacuum
(0.2 mm for 5 h at 40 ꢁC). The resulting oil was dissolved in ether
(40 mL) and while stirring hexane (40 mL) was added. After careful
decantation the resulting oil was dried under vacuum and chro-
matographed (EtOAc/PE 1:1) to give 2a as a brown oil (0.73 g, 63%
yield). Rf¼0.75 (EtOAc/PE, 1:1), HRMS m/z 614.3332 (MHþ, calcu-
lated 614.3243 for C29H47N3O11); nmax (KBr): 1685, 1650, 1305,
3. Conclusions
We demonstrated a simple and convenient synthesis of two
types of orthogonally protected bi-functional dendritic building
blocks from phenolic templates in solid phase via the Mitsunobu
reaction for convergent dendrimer growth. The type 1 building
block carries on each branch a protected main chain secondary
amine and a terminal primary amine or phenol groups. The type 2
building block, on the other hand, is the result of simple alkylation
of the deprotected secondary amine in dendron BB type 1
precursor, presenting a tertiary amine junction and a protected
peripheral primary amine or carboxyl groups. The key step in
preparation of these dendron units involves multiple Mitsunobu
condensation of orthogonally protected functional linkers to di-
and trihydroxybenzene core structures. The repeated Mitsunobu
cycle is necessary for achieving sufficient yields and purity. Steric
factors of the protecting groups appears to be important for the
successful preparation of the building blocks, suggesting that the

G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
883
1235 cmꢂ1; 1H NMR:
3.59–3.56 (m, 4H), 3.42 (m, 2H), 1.43 (s, 27H); 13C NMR:
d
7.26 (s, 2H), 4.14–4.08 (m, 6H), 3.88 (s, 3H),
167.0 (C),
evaporated to give Fmoc-protected intermediate as a colorless oil
(4.2 g) ready for the next step without further purification.
d
157.3 (C), 143.4 (C), 143.0 (C), 131.2 (CH), 123.7 (C), 60.3 (C), 59.6
(CH2), 41.0 (CH2), 31.3 (CH3).
The Fmoc-protected intermediate was then dissolved in DCM
(100 mL) and triethylamine (20 mL) and the mixture was cooled to
0 ꢁC. A solution of Alloc-Cl (2.14 mL, 20 mmol) in DCM (20 mL) was
added dropwise over 10 min and the mixture was stirred for 1 h at
0 ꢁC. The reaction mixture was allowed to warm up to rt, and the
solution was stirred overnight under a nitrogen atmosphere. The
organic phase was washed twice with 1 N HCl, aqueous sodium
carbonate and brine (50 mL each), dried over anhydrous Na2SO4,
evaporated and chromatography (EtOAc) to give linker 5 as a yel-
lowish oil (4.9 g, 79% yield). Rf¼0.80 (EtOAc/PE, 1:1), MS (CI): m/z
411 (MHþ, 80); nmax (KBr): 3470–3150 br s, 1655, 1610, 1500,
4.1.2. 3,4,5-Tris(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid
(2b). To 2a (0.44 g, 0.7 mmol) in MeOH (20 mL) was added a solu-
tion of 1 N NaOH (10 mL). The reaction mixture was stirred at rt for
8 h, and then DCM (100 mL) and water (50 mL) were added, fol-
lowed by 1 N HCl to adjust pH¼4. The organic phase was washed
with brine (2ꢀ50 mL), dried over anhydrous Na2SO4 and evapo-
rated to give intermediate benzoic acid 2b as a yellow oil (0.40 g,
89% yield). The acid 2b was used in the next step without any pu-
rification. Rf¼0.40 (EtOAc), HRMS m/z 600.324 (MHþ, calculated
600.310 for C28H45N3O11); nmax (KBr): 3500–3100 br s, 1690, 1650,
1430 cmꢂ1 1H NMR:
; d 7.78–7.73 (m, 2H), 7.52–7.48 (m, 2H), 7.43–
7.41 (m, 4H), 5.90 (ddt, J¼17.1, 10.5, 5.4 Hz, 1H), 5.32 (dd, J¼17.1,
1.2 Hz, 1H), 5.25 (dd, J¼10.5, 1.2 Hz, 1H), 4.60 (d, J¼4.2 Hz, 2H), 4.50
(d, J¼5.4 Hz, 2H), 4.14 (t, J¼4.2 Hz, 1H), 3.70–3.67 (m, 2H), 3.17–3.14
(m, 4H), 3.00–2.97 (m, 2H).
1340, 1180 cmꢂ1 1H NMR:
; d 7.30 (s, 2H), 4.14–4.10 (m, 6H), 3.60–
3.57 (m, 4H), 3.42 (bd, J¼6.5 Hz, 2H), 1.47 (s, 9H), 1.43 (s, 18H).
4.1.3. 3,4,5-Tris(2-(allyloxycarbonylamino)ethoxy)benzoic acid (3). To
acid 2b (0.22 g, 0.6 mmol) was added a 4 ꢁC cold solution of
TFA:DCM (1:1, 20 mL). The mixture was stirred at 0 ꢁC for 15 min
and then warmed to rt and stirred for additional 1 h. The solvents
were evaporated to give a brown oil, which was further treated
with DCM (30 mL) and triethylamine (4 mL). The reaction mixture
was stirred at 0 ꢁC for 15 min and followed by dropwise addition
over 20 min of a solution of Alloc-Cl (0.39 mL, 3.6 mmol) in DCM
(20 mL). The reaction mixture was stirred at rt overnight under
a nitrogen atmosphere. After evaporation of the solvent, the
resulting yellow semi-solid was taken in DCM (20 mL), the organic
phase was washed sequentially with HCl 1 N and brine (20 mL
each), dried over anhydrous Na2SO4 and evaporated to give
a brownish oil, which after chromatography (EtOAc) afforded 3 as
a yellow oil (0.31 g, 72% yield). Rf¼0.50 (EtOAc/PE, 1:1), HRMS m/z
552.2237 (MHþ, calculated 552.2194 for C25H33N3O11); nmax (KBr):
4.1.6. Allyl 2-(N-(2-hydroxyethyl)allylcarbamate)ethylcarbamate(6)16. A
solution of 2-aminoethylaminoethanol (1.94 mL, 19.2 mmol) and
triethylamine (26.76 mL) in DCM (120 mL) was stirred at 0 ꢁC under
a nitrogen atmosphere for 20 min. A solution of Alloc-Cl (4.49 mL,
42 mmol) in DCM (20 mL) was added dropwise over 10 min and the
mixture was stirred for 1 h at 0 ꢁC. The reaction mixture was allowed
to warm up to rt, and the solution was stirred overnight under a ni-
trogen atmosphere. The organic phase was washed twice with 1 N
HCl, aqueous sodium carbonate solution and brine (60 mL each),
dried over anhydrous Na2SO4 and evaporated to give linker 6 as
a colorless oil (2.6 g, 50% yield) ready for the next step without further
purification. Rf¼0.55 (EtOAc/PE, 1:1), MS m/z 272.1 (MHþ, 100); nmax
(KBr): 3300–2900 br s, 1650,1390, 1030 cmꢂ1; 1H NMR:
d 5.91 (ddt,
J¼17.5, 10.5, 5.4 Hz, 2H), 5.28 (dd, J¼17.4, 1.8 Hz, 2H), 5.21(dd, J¼10.5,
1.8 Hz, 2H), 4.74(d, J¼5.4 Hz, 4H), 3.78 (m, 2H), 3.45–3.41 (m, 6H).
3450–3120 br s,1695,1655,1450,1270 cmꢂ1; 1H NMR:
d 7.38 (s, 2H),
5.92 (ddt, J¼17.1, 10.5, 5.7 Hz, 3H), 5.31 (dd, J¼17.1, 1.8 Hz, 3H), 5.23
4.1.7. (3,5-Bis-{2-[allyloxycarbonyl-(2-allyloxycarbonylamino-
ethyl)-amino]-ethoxy}-phenoxy)-acetic acid (7b). To a dry solution
of linker 6 (2.72 g, 10.0 mmol) and 4 (1.08 g, 4.5 mmol) in THF
(60 mL) were added DIAD (1.35 mL, 10.0 mmol) and PPh3 (1.50 g,
10.0 mmol) under nitrogen atmosphere. The reaction mixture was
stirred overnight, and then diluted with ether (150 mL), and
washed with saturated aqueous sodium bicarbonate solution
(2ꢀ100 mL). The organic layer was dried over anhydrous Na2SO4
and the excess solvent was removed under reduced pressure ini-
tially on a rotary evaporator and then under high vacuum (0.2 mm
for 5 h at 40 ꢁC). The resulting oil was dissolved in ether (50 mL)
and, while stirring, hexane (50 mL) was added. After careful
decantation, the resulting oil was dried under vacuum and chro-
matographed (EtOAc/PE 1:1) to give 7a as yellow oil (1.70 g, 52%
yield). Compound 7a was taken into a cold mixture of TFA/DCM
(1:1, 40 mL) and after stirring for 1 h at rt, the solvent was evapo-
rated, and the residue was purified by chromatography (EtOAc) to
give 7b as yellowish oil (1.46 g, 91% yield). Rf¼0.40 (CHCl3), HRMS
m/z 693.2928 (MHþ, calculated 693.2906 for C32H44N4O13); nmax
(dd, J¼10.5, 1.8 Hz, 3H), 4.57 (d, J¼5.7 Hz, 6H), 3.62–3.58 (m, 6H),
3.33–3.27 (m, 6H); 13C NMR:
d 168.0 (C), 158.1 (C), 145.3 (C), 142.4
(C), 133.8 (CH), 122.9 (C), 116.4 (CH2), 106.6 (CH), 69.1 (CH2), 68.8
(CH2), 64.7 (CH2), 40.3 (CH2).
4.1.4. (3,5-Dihydroxy-phenoxy)-acetic acid tert-butyl ester (4). A
solution of phloroglucinol dehydrate (10 g, 61.6 mmol) in DMF
(20 mL) was added dropwise over 2 h to a solution of potassium
carbonate (12.64 g, 91.5 mmol), and t-butyl bromoacetate (2.953 g,
20.5 mmol) in DMF (20 mL). The reaction mixture was stirred
overnight. Then water (100 mL) was added and the pH was ad-
justed to 6 by careful addition of 1 N HCl. DCM (50 mL) was added,
the phases were separated, and the organic phase was washed with
brine (50 mL), dried over anhydrous Na2SO4 and evaporated to give
4 as an orange oil (3.79 g, 79% yield based on BrCH2CO2t-Bu), which
was used in the next step without further purification. Rf¼0.45
(EtOAc), MS (CI): m/z 240 (MHþ, 78%),185 (100%); nmax (KBr): 3500–
3100 br s, 1700, 1430, 1170 cmꢂ1
;
1H NMR:
d
6.02 (br s, 1H), 5.99–
166.2 (C), 155.2
5.97 (br s, 2H), 4.40 (s, 2H), 1.42 (s, 9H); 13C NMR:
d
(KBr): 3550–3150 br s, 1705, 1660, 1405, 1120 cmꢂ1
;
1H NMR
(C), 142.1 (C), 133.8 (CH), 116.4 (CH), 69.3 (C), 67.6 (CH2), 30.7 (CH3).
(600 MHz):
d
6.53(br s,3H), 5.88 (ddt, J¼16.2, 10.5, 5.6 Hz, 4H), 5.70
(br s, 1H), 5.25 (dd, J¼16.0, 2.0 Hz, 4H), 5.18 (dd, J¼10.5, 2.0 Hz, 4H),
5.02 (br s, 2H), 4.68 (d, J¼5.6 Hz, 4H), 4.52 (d, J¼5.6 Hz, 4H), 4.17–
4.15 (m, 4H), 3.73–3.71 (m, 4H), 3.54–3.53 (m, 4H), 3.44–3.42 (m,
4.1.5. Allyl 2-(N-(2-hydroxyethyl)oxycarbonyl)-(9H-fluoren-9-yl)-
methyl ethyl carbamate (5)16. 2-Aminoethylaminoethanol (2 mL,
19.8 mmol) was dissolved in a 1:1 mixture of 1 N Na2CO3/dioxane
(60 mL) and Fmoc-Osu (5.07 g, 15 mmol) was added in small por-
tions over 5 min at 0 ꢁC. The reaction mixture was stirred for an
additional 5 h at rt. The reaction volume was then reduced to
a third under vacuum and the residue was taken in DCM (100 mL).
The organic phase was washed with aqueous sodium carbonate
solution and brine (100 mL each), dried over anhydrous Na2SO4 and
4H); 13C NMR (150 MHz):
d 172.3 (C), 160.6 (C), 158.2 (C), 156.8 (C),
147.7 (C), 131.8 (CH), 120.3 (CH2), 111.4 (CH), 106.0 (CH), 73.3 (CH2),
66.4 (CH2), 64.9 (CH2), 40.6 (CH2), 48.3 (CH2), 42.5 (CH2).
4.1.8. 3,5-Bis(2-((allyloxycarbonyl)(2-(allyloxycarbonyl-
amino)ethyl)amino) ethoxy) benzoic acid (10). To 2-chlorotrityl resin
(0.2 g, 0.28 mmol loading) in a reactor was added a solution of

884
G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
dihydroxybenzoic acid (0.04 g, 0.26 mmol) in dry DMF (3.5 mL) and
after addition of diisopropylethylamine (DIEA, 185 L, 1.04 mmol)
the crude 20 was satisfactory for the next step. Rf¼0.50
(MeOH:CHCl3, 1:20), MS (CI): m/z 217 (MHþ, 100); nmax (KBr):
m
the reaction mixture was shaken for 1.5 h. After completion of the
loading, dry MeOH (1.5 mL) was poured into the reactor and
shaking was continued for additional 20 min. The solvent was
filtered out and the following washings were sequentially
performed: 2ꢀDCM:MeOH:DIEA (17:2:1), 2ꢀDCM, 2ꢀDMF, 2ꢀDCM,
2ꢀDCM:DMF (1:1) (3 mL each). To the loaded resin 8 in the
reactor was added, under a nitrogen atmosphere, linker 6 (0.361 g,
1.33 mmol) in dry THF:DCM (1:1, 5.2 mL), DBAB (0.306 mL,
1.33 mmol), and PPh3 (0.348 g, 1.33 mmol). After shaking overnight,
the solution was filtered out and the following washings were se-
quentially performed: 1ꢀTHF, 1ꢀDCM, 1ꢀ10% DIEA/DMF, 1ꢀDMF,
3ꢀMeOH, 3ꢀDMF, 3ꢀDCM (3 mL each). The coupling and the
washings were repeated to yield 9a.
3400–3100 br s, 1650, 1310 cmꢂ1; 1H NMR:
d
5.91 (ddt, J¼17.1, 10.8,
5.1 Hz, 1H), 5.30 (dd, J¼17.1, 1.2 Hz, 1H), 5.21 (dd, J¼10.8, 1.2 Hz, 1H),
4.55 (d, J¼5.1 Hz, 2H), 3.81 (t, J¼5.7 Hz, 2H), 3.24 (t, J¼6.3 Hz, 2H),
2.87 (t, J¼5.7 Hz, 2H), 2.68 (t, J¼5.7 Hz, 2H), 1.65–1.72 (m, 4H); 13C
NMR:
d 157.6 (C), 135.4 (C), 120.3 (C), 67.4 (CH2), 65.3 (CH2), 42.8
(CH2), 34.3 (CH2), 26.1 (CH2), 20.8 (CH2).
4.1.11. 4-(Allyloxy)phenyl methanol (21). To a solution of K2CO3
(22.6 g, 0.16 mmol) in DMF (200 mL) was added under vigorous
stirring over 30 min 4-hydroxybenzyl alcohol (10 g, 0.08 mol) and
allyl bromide (10 mL, 0.10 mol). The reaction mixture was stirred
overnight at rt and after completion of the reaction (TLC:MeOH/
EtOAc,1:99) 1 N HCl (400 mL) was added and the aqueous phasewas
washed with diethyl ether (4ꢀ40 mL). The combined organic phases
were dried over anhydrous Na2SO4 and evaporated to give crude 21
as a colorless oil (11.9 g, 90% yield), which was used in the next step
The resin was transferred to a vial for cleavage and a 4 ꢁC cold
solution of 1% TFA in DCM (2 mL) was added. After shaking for
30 min, the solution was collected and the resin was washed sev-
eral times with DCM (3 mL each). After combining the organic so-
lutions, the solvent was evaporated first by N2 stream and then in
vacuum to give 10 as an orange oil (0.12 g, 68% yield). Rf¼0.30
(CHCl3), HRMS m/z 663.2475 (MHþ, calculated 663.2754 for
C31H43N4O12); nmax (KBr): 3300–3080 br s, 1700, 1655, 1320,
without further purification. Rf¼0.65 (EtOAc); 1H NMR:
d 7.13 (d,
J¼8.5 Hz, 2H), 6.89(d, J¼8.5 Hz, 2H), 5.96 (ddt, J¼17.1, 10.5, 5.7 Hz,
1H), 5.40 (dd, J¼17.1,1.2 Hz,1H), 5.28 (dd, J¼10.5,1.2 Hz,1H), 4.51 (d,
J¼5.7 Hz, 2H), 4.20 (s, 2H); 13C NMR:
d 153.4 (C),133.7 (C),128.8 (CH),
126.2 (CH), 118.3 (CH2), 114.5 (CH), 69.1 (CH2), 63.2 (CH2).
1080 cmꢂ1; 1H NMR (600 MHz):
d 7.20 (br s,2H), 6.67(br s,1H), 5.91
(ddt, J¼16.8, 10.8, 5.4 Hz, 4H), 5.58 (br s, 1H), 5.30 (dd, J¼16.8,
1.8 Hz, 4H), 5.20 (dd, J¼10.8, 1.8 Hz, 4H), 4.61 (d, J¼5.4 Hz, 4H), 4.55
(d, J¼5.4 Hz, 4H), 4.16–4.13 (m, 4H), 3.70–3.67 (m, 4H), 3.58–3.55
4.1.12. 4-(Allyloxy)benzyl methanesulfonate (22). To a solution of 22
(5.95 g, 36.2 mmol), and triethylamine (10.16 mL, 0.10 mol) in DCM
(100 mL) at 0 ꢁC, methanesulfonyl chloride (14.2 mL, 0.18 mol) was
added dropwise over 30 min under a nitrogen atmosphere. The
reaction mixture was stirred at 0 ꢁC for 1 h and slowly warmed to rt
and stirred overnight under nitrogen. The reaction mixture was
then cooled to 0 ꢁC, and a 4 M NaOH solution (32 mL) was added
slowly with vigorous stirring. The organic phase was separated and
washed twice with water and brine (50 mL each), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuum to give mesylate 22 as a brown oil (7.90 g, 92% yield), which
was immediately reacted in the next step. Rf¼0.70 (EtOAc/PE, 1:2),
(m, 4H), 3.47–3.44 (m, 4H); 13C NMR (150 MHz):
d 170.1 (C), 159.5
(C), 159.19 (C), 157.8 (C), 157.1 (C), 132.3 (CH), 118.1 (CH2), 108.4 (CH),
107.0 (CH), 66.8 (CH2), 65.9 (CH2), 39.8 (CH2), 40.3 (CH2), 47.3 (CH2).
4.1.9. Allyl 3-hydroxypropylcarbamate (18)16. A solution of 3-amino-
propanol (1.69 mL, 22.1 mmol) and triethylamine (6.97 mL,15 mmol)
in DCM (120 mL) was stirred at 0 ꢁC for 15 min and a solution of
Alloc-Cl (2.59 mL, 24.3 mmol) in DCM (25 mL) was added dropwise
over 20 min. The reaction mixture was stirred at rt overnight under
a nitrogen atmosphere. The organic phase was washed three times
with 1 N HCl, aqueous sodium carbonate solution, and brine (100 mL
each), dried over anhydrous Na2SO4 and evaporated to give linker 18
as yellow oil (2.94 g, 82% yield). Rf¼0.60 (MeOH:CHCl3, 1:99), MS (CI):
m/z 160 (MHþ,100); nmax (KBr): 3350–3020 br s,1650,1220 cmꢂ1; 1H
1H NMR:
d
7.15 (d, J¼8.5 Hz, 2H), 6.93 (d, J¼8.5 Hz, 2H), 5.98 (ddt,
J¼17.1, 10.5, 5.4 Hz, 1H), 5.40 (dd, J¼17.1, 1.2 Hz, 1H), 5.28 (dd,
J¼10.5, 1.2 Hz, 1H), 4.51 (d, J¼5.4 Hz, 2H), 4.55 (s, 2H), 3.14 (s, 3H);
13C NMR:
d 156.0 (C), 135.3 (C), 130.1 (CH), 128.7 (CH), 120.6 (CH2),
117.9 (CH), 71.0 (CH2), 65.3 (CH2), 36.4 (CH3).
NMR:
d
5.89 (ddt, J¼17.1,10.8, 5.1 Hz,1H), 5.29 (dd, J¼17.1,1.2 Hz,1H),
5.18 (dd, J¼10.8, 1.2 Hz, 1H), 4.49 (d, J¼5.1 Hz, 2H), 3.78 (t, J¼6.3 Hz,
4.1.13. tert-Butyl 4-(allyloxy)benzyl(2-hydroxyethyl)carbamate (11).
Mesylate 22 (5.90 g, 24.5 mmol) and 3-aminopropanol (13.8 g,
0.18 mol) were dissolved in acetonitrile (80 mL). The mixture was
stirred at 75 ꢁC under a nitrogen atmosphere overnight. After
completion of the reaction (TLC:EtOAc, Rf¼0.6) the solution was
concentrated under reduced pressure. The residue was dissolved in
DCM (80 mL) and washed with aqueous sodium carbonate
(3ꢀ50 mL). The organic layer was separated, dried over anhydrous
Na2SO4, filtered and evaporated to give intermediate crude 3-(4-
(allyloxy)benzylamino)propan-1-ol as a yellowish oil (2.52 g, 83%
yield) with satisfactory purity for the next step. Rf¼0.50
(MeOH:CHCl3, 1:20), MS (CI): m/z 208 (MHþ, 100); nmax (KBr):
2H), 3.32 (t, J¼6.3 Hz, 2H), 1.85 (q, J¼6.3 Hz, 4H).
4.1.10. Allyl 3-(3-hydroxypropylamino)propylcarbamate (20). A so-
lution of 18 (2.94 g, 18.4 mmol) and triethylamine (25.6 mL,
184 mmol) in DCM (50 mL) was stirred at 0 ꢁC under a nitrogen
atmosphere for 20 min. MsCl (3.7 mL, 41 mmol) was added drop-
wise over 10 min. The mixture was stirred for 1 h at 0 ꢁC and then at
rt overnight. The solution was cooled to 0 ꢁC and cold 4 N NaOH
(32 mL) was added. The organic phase was washed with water
(2ꢀ50 mL), dried over anhydrous Na2SO4 and evaporated to give
intermediate methanesulfonate 19 as a yellow oil (3.7 g, 86% yield),
which was used in the next step without further purification.
3400–3000 br s, 1650, 1130 cmꢂ1; 1H NMR:
d
7.02 (d, J¼8.7 Hz, 2H),
Rf¼0.85 (EtOAc/PE, 1:1); 1H NMR:
d
5.90 (ddt, J¼17.1, 10.8, 5.1 Hz,
6.86 (d, J¼8.7 Hz, 2H), 5.89 (ddt, J¼17.1, 10.8, 5.4 Hz, 1H), 5.28 (dd,
J¼17.1, 1.2 Hz, 1H), 5.26 (dd, J¼10.8, 1.2 Hz, 1H), 4.49 (d, J¼5.4 Hz,
2H), 4.1 (s, 2H), 3.53–3.51 (m, 2H), 3.21–3.19 (m, 2H), 1.64–1.62 (m,
2H).
1H), 5.29 (dd, J¼17.1, 1.2 Hz, 1H), 5.19 (dd, J¼10.8, 1.2 Hz, 1H), 4.99
(br s, 1H), 4.55 (d, J¼5.1 Hz, 2H), 4.55 (t, J¼6.3 Hz, 2H), 3.32
(t, J¼6.3 Hz, 2H), 3.02 (s, 3H), 1.96 (quint, J¼6.3 Hz, 2H).
Next, mesylate 19 (3.7 g, 15.6 mmol) and aminopropanol
(4.77 mL, 62.4 mmol) were dissolved in acetonitrile (40 mL). The
reaction mixture was refluxed under nitrogen overnight, cooled to
rt and evaporated to give a yellow oil, which was redissolved in
DCM (30 mL). The organic phase was washed with saturated
Na2CO3 solution (30 mL), dried over anhydrous Na2SO4 and evap-
orated to afford 20 as a yellow oil (4.22 g, 80% yield). The purity of
A solution of 3-(4-(allyloxy)benzylamino)propan-1-ol (2.33 g,
10.5 mmol) in a solution of triethylamine/MeOH (1:7, 300 mL) was
stirred at 0 ꢁC for 10 min, followed by dropwise addition over
10 min of a solution of di-tertbutyl dicarbonate (3.43 g, 15.7 mmol)
in MeOH (95 mL). After stirring for 1 h at 0 ꢁC, the temperature was
allowed to warm gradually to rt, and the solution was continued
stirring overnight under a nitrogen atmosphere. After evaporation

G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
885
of the solvent under reduced pressure, the yellow oily residue was
1300 cmꢂ1; 1H NMR:
d
8.00–7.98 (m, 2H), 7.90–7.88 (m, 2H), 7.61–
taken in DCM (100 mL) and the organic phase was washed with
water and brine (50 mL each). After separation, the organic layer
was dried over anhydrous Na2SO4 and evaporated to give a yellow
residue, which after chromatography (EtOAc) yielded linker 11 as
a yellowish oil (3.18 g, 87% yield). Rf¼0.60 (EtOAc/PE, 1:1), MS (CI):
m/z 308 (MHþ, 20), 208 (MHþꢂBoc 100); nmax (KBr): 3500–3100 br
7.59 (m, 4H), 7.26–7.25 (m, 2H), 6.53 (m, 1H), 5.90 (ddt, J¼17.1, 10.5,
5.1 Hz, 2H), 5.35 (dd, J¼17.1,1.8 Hz, 2H), 5.23 (dd, J¼10.5,1.8 Hz, 2H),
4.58 (d, J¼5.1 Hz, 4H), 3.91–3.88 (m, 4H), 3.47–3.44 (m, 8H), 3.27–
3.25 (m, 4H), 2.05–2.03 (m, 5H) 1.84–1.82 (m, 4H); 13C NMR:
d 170.7
(C), 159.6 (C), 159.2 (C), 157.2 (C), 137.2 (C), 135.8 (C), 134.7 (CH),
133.8 (CH), 132.5 (CH), 128.9 (CH), 124.4 (CH), 118.1 (CH2), 108.5
(CH), 107.3 (CH), 68.1 (CH2), 66.2 (CH2), 45.1 (CH2), 44.4 (CH2), 38.8
(CH2), 29.8 (CH2), 29.0 (CH2).
s, 1660, 1650, 1280 cmꢂ1; 1H NMR:
d
7.14 (d, J¼8.7 Hz, 2H), 6.87 (d,
J¼8.7 Hz, 2H), 6.06 (ddt, J¼17.1, 10.8, 5.4 Hz, 1H), 5.41 (dd, J¼17.1,
1.2 Hz, 1H), 5.29 (dd, J¼10.8, 1.2 Hz, 1H), 4.53 (d, J¼5.4 Hz, 2H), 4.31
(s, 2H), 3.55–3.53 (m, 2H), 3.36–3.34 (m, 2H),1.69–1.67 (m, 2H),1.47
4.1.17. 3,5-Bis(3-((((9H-fluoren-9-yl)methoxy)carbonyl)(3-(allyloxy-
carbonylamino) propyl)amino)propoxy)benzoic acid (15). Compound
15 was synthesized in the same manner as for 10 from 2-chlorotrityl
resin (0.2 g, 0.28 mmol loading), dihydroxybenzoic acid (0.04 g,
0.27 mmol) and linker 12 (0.58 g, 1.33 mmol). After usual work up
(fast purification by solid-phase extraction pack RP-18, first washed
with water and then extracted with acetonitrile, 5 mL each) 15 was
obtained as a yellowish oil (0.18 g, 77% yield). Rf¼0.70 (EtOAc/PE,
2:1), HRMS m/z 996.4342 (10%), MHþ-Fmoc 773.4316 (100%) (MHþ,
calculated 996.4423 for C57H62N4O12); nmax (KBr): 3390–3050 br s,
(s, 9H); 13C NMR:
d 157.1 (C), 154.7 (C), 134.1 (C), 127.7 (CH), 122.1
(CH), 115.6 (CH2), 112.8 (CH), 77.3 (CH2), 60.6 (CH2), 57.5 (CH2), 50.7
(CH2), 42.1 (CH2), 28.7 (CH2), 27.6 (CH3).
4.1.14. Allyl 3-(N-(3-hydroxypropyl)-2-(9H-fluoren-9-yl)methoxycar-
bonyl) propyl carbamate (12). A solution of 20 (2.11 g, 9.7 mmol) and
DIEA (5 mL, 28.8 mmol) in DCM (35 mL) was stirred at 0 ꢁC for
20 min under a nitrogen atmosphere and a solution of Fmoc-Cl
(2.98 g, 11.5 mmol) in DCM (35 mL) was added dropwise over
20 min. The reaction mixture was stirred at rt overnight under
a nitrogen atmosphere. The organic phase was washed three times
with 1 N HCl, aqueous sodium carbonate solution and brine (40 mL
each), dried over anhydrous Na2SO4 and evaporated to give 12 after
chromatography (EtOAc) as a yellow oil (3.05 g, 72% yield). Rf¼0.75
(EtOAc/PE, 1:1), MS (CI): m/z 439 (MHþ, 100); nmax (KBr): 3430–
1700, 1650, 1510, 1430, 1200 cmꢂ1 1H NMR:
; d 7.73–7.70 (m, 4H),
7.55–7.52 (m, 4H), 7.32–7.28 (m, 8H), 7.01 (m, 2H), 6.52 (m,1H), 5.92
(ddt, J¼17.1, 10.5, 5.4 Hz, 2H), 5.30 (dd, J¼17.1, 1.2 Hz, 2H), 5.25 (dd,
J¼10.5,1.2 Hz, 2H), 4.61 (d, J¼4.2 Hz, 4H), 4.54 (d, J¼5.4 Hz, 4H), 4.20
(t, J¼4.2 Hz, 2H), 3.81–3.79 (m, 4H), 3.24–3.20 (m, 8H), 2.97–2.95 (m,
4H),1.94–1.90 (m, 4H),1.83–1.80 (m, 4H); 13C NMR:
d 170.6 (C),159.8
3100 br s, 1650, 1600, 1520, 1300 cmꢂ1
;
1H NMR:
d
7.76–7.75 (m,
(C), 159.7 (C), 159.6 (C), 157.3 (C), 143.7 (C), 141.4 (CH), 131.3 (CH),
127.7 (CH), 127.2 (CH), 124.5 (CH), 119.9 (CH),117.9 (CH2),108.1 (CH),
107.5 (CH), 68.3 (CH2), 66.8 (CH2), 65.5 (CH2), 47.4 (CH2), 45.1 (CH2),
43.6 (CH), 38.7 (CH2), 29.7 (CH2), 28.9 (CH2).
2H), 7.58–7.57 (m, 2H), 7.42–7.40 (m, 4H), 5.91 (ddt, J¼17.1, 10.5,
5.4 Hz, 1H), 5.3 (dd, J¼17.1, 1.2 Hz, 1H), 5.22 (dd, J¼10.5, 1.2 Hz, 1H),
4.70 (d, J¼4.2 Hz, 2H), 4.54 (d, J¼5.4 Hz, 2H), 4.20 (t, J¼4.2 Hz, 1H),
3.73–3.72 (m, 2H), 3.21–3.19 (m, 4H), 2.94–2.93 (m, 2H), 1.84–1.83
(m, 2H), 1.73–1.71 (m, 2H); 13C NMR:
d
157.6 (C), 156.1 (C), 144.0 (C),
4.1.18. 3,5-Bis(3-((4-(allyloxy)benzyl)(tert-butoxycarbonyl)-
amino)propoxy) benzoic acid (16). Compound 16 was synthesized
in the same manner as for 10 from 2-chlorotrityl resin (0.2 g,
0.28 mmol loading), dihydroxybenzoic acid (0.04 g, 0.27 mmol) and
linker 11 (0.41 g, 1.33 mmol). After the usual work up and cleavage
in 4 ꢁC cold 1% TFA/DCM for 10 min, 16 was obtained as colorless oil
(0.15 g, 68% yield). Rf¼0.65 (EtOAc/PE, 2:1), HRMS m/z 761.3825
(MHþ, 5), 661.3847 (MHþꢂBoc, 8), 561.3886 (MHþꢂBoc-Boc, 100),
(MHþ, calculated 761.3932 for C43H57N2O10); nmax (KBr): 3400–
140.3 (C), 135.4 (C), 128.2 (CH), 126.5 (CH), 123.7 (CH), 120.3 (C),
68.0 (CH2), 67.4 (CH2), 65.3 (CH2), 45.8 (CH), 42.8 (CH2), 34.3 (CH2),
26.1 (CH2), 20.8 (CH2).
4.1.15. Allyl 3-(N-(3-hydroxypropyl)-2-nitrophenylsulfonamido)propyl
carbamate (13). o-Nitrobenzenesulfonyl chloride (4 g, 18.04 mmol)
in DCM (15 mL) was added dropwise over 30 min to an ice cold
solution of triethylamine (6.2 mL, 44.8 mmol) and 20 (3.91 g,
18.04 mmol) in dry DCM (35 mL). The mixture was stirred over-
night at rt, washed with a 10% aqueous solution of NaHCO3
(3ꢀ25 mL), dried over anhydrous Na2SO4 and evaporated to
dryness. The residue was taken into diethyl ether (25 mL) and the
solvent was evaporated. The crude was triturated with CHCl3
and n-hexanes (1:9) and chromatographed (EtOAc), to give 13 as
a yellow oil (5.63 g, 78% yield). Rf¼0.55 (EtOAc/PE, 1:1), MS (CI): m/z
402 (MHþ, 100); nmax (KBr): 3500–3100 br s, 1650, 1610, 1480,
3000 br s, 1705, 1655, 1500, 1480, 1190 cmꢂ1; 1H NMR:
d 7.28–7.26
(m, 2H), 7.12 (d, J¼8.7 Hz, 4H), 6.89 (d, J¼8.7 Hz, 4H), 6.60 (m, 1H),
6.01 (ddt, J¼17.1, 10.5, 5.1 Hz, 4H), 5.38 (dd, J¼16.8, 1.8 Hz, 4H), 5.20
(dd, J¼10.8,1.8 Hz, 4H), 4.61 (d, J¼5.4 Hz, 4H), 4.55 (d, J¼5.4 Hz, 4H),
4.14–4.11 (m, 4H), 3.69–3.65 (m, 4H), 3.55–3.52 (m, 4H), 3.43–3.40
(m, 4H), 1.45 (s. 9H); 13C NMR:
d 170.1 (C), 159.5 (C), 159.1 (C), 157.8
(C), 157.11 (C), 132.3 (CH), 118.1 (CH2), 108.4 (CH), 107.0 (CH), 66.8
(CH2), 65.9 (CH2), 39.8 (CH2), 40.3 (CH2), 47.3 (CH2), 32.1 (CH3).
1290 cmꢂ1 1H NMR:
; d 8.00 (m, 1H), 7.67–7.65 (m, 3H), 5.91 (ddt,
J¼17.1, 10.5, 5.1 Hz,1H), 5.21 (dd, J¼17.1, 1.5 Hz, 1H), 5.21 (dd, J¼10.5,
1.5 Hz, 1H), 4.55 (d, J¼5.4 Hz, 2H), 3.68–3.66 (m, 2H), 3.39–3.37 (m,
4H), 3.23–3.22 (m, 2H), 2.02–2.01 (m, 2H) 1.79–1.77 (m, 2H); 13C
4.1.19. 3,5-Bis(3-((2-(allyloxy)-2-oxoethyl)(3(allyloxycarbonyl-
amino)propyl) amino) propoxy)benzoic acid (18a). To 2-chlorotrityl
resin (0.2 g, 0.28 mmol loading) in a reactor was added a solution of
dihydroxybenzoic acid (0.04 g, 0.26 mmol) in dry DMF (3.5 mL) and
NMR:
d 157.6 (C), 146.7 (C), 136.0 (CH), 135.8 (CH), 135.4 (C), 134.3
(C), 132.3 (CH), 126.9 (C), 120.3 (C), 67.0 (CH2), 65.3 (CH2), 44.8
(CH2), 42.6 (CH2), 36.6 (CH2), 27.0 (CH2), 21.7 (CH2).
after addition of diisopropylethylamine (DIEA, 185 mL, 1.04 mmol)
the reaction mixture was shaken for 1.5 h. After completion of the
loading, dry MeOH (1.5 mL) was poured into the reactor and
shaking continued for an additional 20 min. The solvent was fil-
tered out and the following washings were sequentially performed:
2ꢀDCM:MeOH:DIEA (17:2:1), 2ꢀDCM, 2ꢀDMF, 2ꢀDCM,
2ꢀDCM:DMF (1:1) (3 mL each). To the loaded resin 8 in the reactor
was added, under a nitrogen atmosphere, linker 12 (0.582 g,
1.33 mmol) in dry THF:DCM (1:1, 5.2 mL), DBAB (0.306 mL,
1.33 mmol) and PPh3 (0.348 g, 1.33 mmol). After shaking overnight,
the solution was filtered out and the following washings were se-
quentially performed: 1ꢀTHF, 1ꢀDCM, 1ꢀ10% DIEA/DMF, 1ꢀDMF,
3ꢀMeOH, 3ꢀDMF, 3ꢀDCM (3 mL each). The coupling and the
4.1.16. 3,5-Bis(3-(N-(3-(allyloxycarbonylamino)propyl)-2-nitro-
phenylsulfonamido) propoxy)benzoic acid (14). Compound 14 was
synthesized in the same manner as for 10 from 2-chlorotrityl resin
(0.2 g, 0.28 mmol loading), dihydroxybenzoic acid (0.04 g,
0.27 mmol) and linker 13 (0.53 g, 1.33 mmol). After the usual work
up (fast purification by solid-phase extraction pack RP-18, first
washed with water and then extracted with acetonitrile, 5 mL
each), 14 was obtained as orange oil (0.16 g, 74% yield). Rf¼0.60
(EtOAc/PE, 2:1), HRMS m/z 921.2415 (MHþ, calculated 921.2563 for
C39H48N6O16S2); nmax (KBr): 3430–3100 br s, 1700, 1650, 1600, 1520,

886
G. Gellerman et al. / Tetrahedron 66 (2010) 878–886
washings were repeated to yield resin bound 17. The Fmoc pro-
tecting group was removed by reaction with 20% piperidine in NMP
(2ꢀ15 min, 5 mL each) and subsequent washing (2ꢀDCM, 2ꢀDMF,
5 mL each). Then, a solution of allyl bromoacetate (0.235 g,
1.33 mmol) and DIPA (1 mL) in DMF (4.5 mL) was added to the resin
and shaken for 24 h at 40 ꢁC. Then the resin was washed with
2ꢀ10% DIPA in DMF, 3ꢀDMF, 3ꢀDCM (3 mL each) and the alkyl-
ation procedure was repeated. The resin was transferred to a vial for
cleavage and a 4 ꢁC cold solution of 1% TFA in DCM (2 mL) was
added. After shaking for 30 min, the solution was collected and the
resin was washed several times with DCM (3 mL each). After
combining the organic solutions, the solvent was evaporated first
by N2 stream and then in vacuum to give after the usual work up
(fast purification by solid-phase extraction pack RP-18, first washed
with water and then extracted with acetonitrile, 5 mL each), 18a as
a yellowish oil (0.083 g, 70% yield). Rf¼0.80 (MeOH:EtOAc, 1:99),
HRMS m/z 746.8475 (MHþ, calculated 746.8412 for C37H54N4O12);
1.8 Hz, 2H), 4.52 (d, J¼5.1 Hz, 4H), 4.01–3.98 (m, 4H), 3.83–3.77
(m, 4H), 3.28–3.24 (m, 8H), 2.10–2.06 (m, 8H) 1.82–1.78 (m, 12H);
13C NMR:
d 172.1 (C), 160.5 (C), 158.7 (C), 155.9 (C), 136.1 (C), 134.7
(C), 134.1 (CH), 132.5 (CH), 130.3 (CH), 129.0 (CH), 125.3 (CH), 117.0
(CH2), 110.5 (CH), 107.0 (CH), 69.6 (CH2), 65.0 (CH2), 47.5 (CH2), 44.8
(CH2), 38.4 (CH2), 28.9 (CH2), 27.4 (CH2).
Acknowledgements
We wish to thank Mr. Vladimir Gaisin for analytical assistance.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.11.106.
nmax (KBr): 3400–3100 br s, 1700–1660 br s, 1640, 1220, 1170 cmꢂ1
1H NMR (600 MHz):
7.20 (m,2H), 6.63(m,1H), 5.92–5.88 (m, 4H),
;
References and notes
d
5.50–5.45 (m, 8H), 4.60–4.55 (m, 8H), 4.24 (d, J¼5.4 Hz, 4H), 3.66–
1. (a) Al-Jamal, K. T.; Ramaswamy, C.; Florence, A. T. Adv. Drug Delivery Rev. 2005,
57, 2238–2270; (b) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117–132; (c) Tomalia,
D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.;
Smith, P. Macromolecules 1986, 19, 2466–2468; (d) Tomalia, D. A.; Hall, M.;
Hedstrand, D. J. Am. Chem. Soc. 1987, 109, 1601–1603; (e) Tomalia, D. A.; Berry, V.;
Hall, M.; Hedstrand, D. M. Macromolecules 1987, 20, 1164–1167.
3.62 (m, 6H), 3.55–3.50 (m, 6H), 2.74–2.70 (m, 4H), 1.90–1.80 (m,
8H); 13C NMR (150 MHz):
d 172.8 (C), 157.5 (C), 156.1 (C), 155.8 (C),
152.1 (C), 130.4 (CH), 120.2 (CH2), 105.4 (CH), 104.0 (CH), 67.3 (CH2),
65.6 (CH2), 38.3 (CH2), 37.4 (CH2), 37.1 (CH2).
4.1.20. 3,5-Bis(3-((3-(allyloxycarbonylamino)propyl)(2-(benzyloxy-
carbonylamino)ethyl)amino) propoxy)benzoic acid (18b). Compound
18b was synthesized in the same manner as for 18a from 2-chloro-
trityl resin (0.2 g, 0.28 mmol loading) bound 17 and benzyl 3-bro-
mopropylcarbamate (036 g, 1.33 mmol). After the usual work up
(fast purification by solid-phase extraction pack RP-18, first washed
with water and then extracted with acetonitrile, 5 mL each),18b was
obtained as yellow oil (0.104 g, 67% yield). Rf¼0.70 (MeOH:EtOAc,
1:99), HRMS m/z 841.3073 (MHþꢂC6H5CH3, calculated 841.4347 for
C42H61N6O12); nmax (KBr): 3400–3010 br s, 1680–1650 br s, 1570,
2. (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III. Angew. Chem., Int. Ed. Engl.
1990, 102, 119–128; (b) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III. Angew.
Chem., Int. Ed. Engl. 1990, 29, 130–141.
3. Tomalia, D. A.; Hedstrand, D. M.; Ferritto, M. S. Macromolecules 1991, 24, 1435–
1444.
4. (a) Nagasaki, T.; Ukon, M.; Arimori, S.; Shinkai, S. J. Chem. Soc., Chem. Commun.
1992, 608–610; (b) Nagasaki, T.; Kimura, O.; Ukon, M.; Arimori, S.; Hamachi, I.;
Shinkai, S. J. Chem. Soc., Perkin Trans. 1 1994, 75–81.
5. (a) Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1993,
´
´
1287–1297; (b) Frechet, J. M. J. Science 1994, 263, 1710–1712; (c) Frechet, J. M. J.
Science 1995, 269, 1080–1082.
6. Zimmerman, S. C.; Zeng, F.; Richert, D. E. C.; Kolotuchin, S. V. Science 1996, 271,
10985–10987.
7. Bell, T. W. Science 1996, 271, 1077–1081.
1480, 1180 cmꢂ1 1H NMR:
; d 7.45–7.38 (m, 6H), 7.10–7.02 (m, 4H),
8. (a) van Hest, J. C. M.; Delnoyer, D. A. P.; Baars, M. W. P. L.; van Genderen, M. H. P.;
Meije, E. W. Science 1995, 268, 1592–1595; (b) Johan, F. G. A.; Janson, J. E.;
Meijer, W.; de Brabander-van den Berg, E. M. M. J. Am. Chem. Soc. 1995, 117,
4417–4426; (c) Johan, F. G. A.; Janson, J.; de Brabander-van den Berg, E. M. M.;
Meijer, E. W. Science 1995, 266, 1266–1269; (d) Gopidas, K. R.; Leheny, A. R.;
Caminati, G.; Turro, N. J.; Tomalia, D. A. J. Am. Chem. Soc. 1991, 113, 7335–7343.
9. Al-Hellani, R.; Schluter, A. D. Macromolecules 2006, 39, 8943–8951.
7.20 (m, 2H), 6.55 (m,1H), 5.95 (ddt, J¼17.1,10.5, 5.1 Hz, 2H), 5.30 (dd,
J¼17.1, 1.8 Hz, 2H), 5.22 (dd, J¼10.5, 1.8 Hz, 2H), 5.26 (s, 4H), 5.03 (s,
4H), 4.47 (d, J¼5.1 Hz, 4H), 3.87–3.82 (m, 4H), 3.25–3.18 (m, 8H),
2.11–2.06 (m, 8H) 1.86–1.77 (m,12H); 13C NMR:
d 172.6 (C),170.3 (C),
162.5 (C), 154.9 (C), 154.3 (C), 136.0 (C), 135.3 (C), 135.1 (CH), 133.2
(CH), 131.7 (CH), 128.0 (CH), 127.3 (CH), 115.0 (CH2), 111.6 (CH), 106.0
(CH), 70.9 (CH2), 64.0 (CH2), 45.9 (CH2), 43.7 (CH2), 40.3 (CH2), 28.3
(CH2), 26.5 (CH2).
´
10. Grayson, S. M.; Frechet, J. M. J. Chem. Rev. 2001, 101, 3819–3868.
11. Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638–7647.
12. Dankwardt, S. M.; Phan, T. M.; Krstenansk, J. L. Mol. Div. 1996, 1, 113–120.
13. Hardcastle, I.; Barber, A.; Marriott, J.; Jarman, M. Tetrahedron Lett. 2001, 12,
1363–1365.
14. Basso, A.; Evans, B.; Pegg, N.; Bradley, M. Chem. Commun. 2001, 697–698.
15. Arai, T.; Sekiguti, T.; Iizuka, Y.; Sasaia, H. Tetrahedron: Asymmetry 2002, 13,
2083–2087.
16. Gelerman, G.; Kremer, M.; Elgavi, A. J. Pept. Res. 2001, 57, 277–290.
17. (a) Nithyanandhan, J.; Jayaraman, N. Tetrahedron 2005, 61, 11184–11191; (b)
Kasemi, E.; Zhuang, W.; Rabe, J. P.; Schluter, A. D. J. Am. Chem. Soc. 2006, 128,
5091–5099; (c) Chow, H. F.; Mak, C. C. Pure Appl. Chem. 1997, 69, 483–488.
18. Lagnoux, D.; Darbre, T.; Schmitz, M. L.; Reymond, J. L. Chem.d Eur. J 2005, 11,
3941–3950.
19. Atherton, E.; Sheppard, R. C. In The Fluorenylmethoxycarbonyl Amino Protecting
Group in Peptides; Udenfriend, S., Meienhofer, J., Eds.; Academic: New York, NY,
1987; Vol. 9, p 1.
20. Czerwenka, C.; La¨mmerhofer, M.; Lindner, W. J. Sep. Sci. 2003, 26, 1499–1508.
21. Gellerman, G.; Hazan, E.; Albeck, A.; Shatzmiler, S. Tetrahedron 2009, 65, 1389–
1396.
4.1.21. 3,5-Bis(3-((3-(allyloxycarbonylamino)propyl)(2-(2-nitrophenyl-
sulfonamido)ethyl)amino) propoxy)benzoic acid (18c). Compound 18c
was synthesized in the same manner as for 18a from 2-chlorotrityl
resin (0.2 g, 0.28 mmol loading) bound 17 and N-(3-bromopropyl)-
2-nitrobenzenesulfonamide (0.43 g, 1.33 mmol). After the usual
work up (fast purification by solid-phase extraction pack RP-18,
first washed with water and then extracted with acetonitrile, 5 mL
each), 18c was obtained as orange oil (0.113 g, 62% yield). Rf¼0.60
(MeOH:EtOAc, 1:99), HRMS m/z 1035.1503 (MHþ, calculated
1035.1478 for C45H62N8O16S2); nmax (KBr): 3500–3150 br s, 1700–
1650 br s, 1605, 1510, 1200 cmꢂ1 1H NMR:
; d 8.05–8.00 (m, 2H),
7.64–7.58 (m, 6H), 7.24–7.22 (m, 2H), 6.50 (m, 1H), 5.93 (ddt, J¼17.1,
22. (a) Nagarajan, M.; Xiao, X.; Cushman, M. J. Med. Chem. 2003, 46, 5712–5724;
(b) Kaur, N.; Phanstiel, O. J. Med. Chem. 2005, 48, 3832–3839.
10.5, 5.1 Hz, 2H), 5.31 (dd, J¼17.1, 1.8 Hz, 2H), 5.27 (dd, J¼10.5,