Synthesis of poly(aryl propargyl ether) (PAPE) stars and evaluation of their cytotoxic properties

Article abstract of DOI:10.1055/s-2008-1032119

The synthesis of a series of low generation poly(aryl propargyl ether) (PAPE) stars 1 and 2 from the corresponding linear branches is described. The first generation branches 3 were readily constructed in a three-step sequence based on Grignard addition, Williamson propargylation, and then Sonogashira-Linstrumelle (S-L) coupling reaction. The use of iodinated compound 4 in an S-L key step allows rapid synthesis of higher linear branches. Their subsequent attachment to benzenoid core 6 via an alkylation step efficiently afforded PAPE stars up to two generations 2 containing methoxycarbonyl ester groups at their peripheries. Transesterification of methyl esters under titanium catalysis proved to be effective and gave several functionalized PAPE stars 2. These amino esters and polyhydroxy amide terminated PAPE stars 2 were evaluated for their cytocompatibility. No significant toxicity was detected in a concentration range of 0.1 to 1000 μg/mL. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032119

PAPER
1049
Synthesis of Poly(aryl propargyl ether) (PAPE) Stars and Evaluation of Their
Cytotoxic Properties
P
oly(aryl propargy
a
l
ether)
S
ta
t
rs halie L’Hermite,a Jean-François Peyrat,a Patrice Hildgen,b Jean-Daniel Brion,a Mouâd Alami*a
a
Faculté de Pharmacie, BioCIS, UMR-CNRS 8076, Université Paris Sud XI, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry,
France
Fax +33(1)46835828; E-mail: mouad.alami@u-psud.fr
Faculty of Pharmacy, University of Montreal, Montreal, Québec, H3C 3J7, Canada
b
Received 14 November 2007; revised 18 December 2007
family of dendrimers for drug-delivery is the polyami-
doamine (PAMAM) dendrimers due to their commercial
availability.6 Results from these studies proved to be dis-
appointing because of lack of biocompatibility, toxicity,
Abstract: The synthesis of a series of low generation poly(aryl pro-
pargyl ether) (PAPE) stars 1 and 2 from the corresponding linear
branches is described. The first generation branches 3 were readily
constructed in a three-step sequence based on Grignard addition,
Williamson propargylation, and then Sonogashira–Linstrumelle and/or analytical difficulties.7 Another well-known den-
(S–L) coupling reaction. The use of iodinated compound 4 in an
S–L key step allows rapid synthesis of higher linear branches. Their
subsequent attachment to benzenoid core 6 via an alkylation step ef-
ficiently afforded PAPE stars up to two generations 2 containing
methoxycarbonyl ester groups at their peripheries. Transesterifica-
tion of methyl esters under titanium catalysis proved to be effective
and gave several functionalized PAPE stars 2. These amino esters
and polyhydroxy amide terminated PAPE stars 2 were evaluated for
their cytocompatibility. No significant toxicity was detected in a
concentration range of 0.1 to 1000 mg/mL.
dritic system is based on polyether dendrimers, including
poly(ether ketone or sulfone),8 poly(aryl ether phenylqui-
noxaline),9 fluorinated poly(benzyl ether),10 and poly(hy-
droxy ether).11 Although poly(aryl ether) dendrimers were
demonstrated to be suitable candidates for drug delivery,12
it is of interest to develop and evaluate novel, biocompat-
ible, dendritic systems.
As part of our research13 towards novel dendrimers for
drug-delivery we have initiated a program on the synthe-
sis of low generation poly(aryl propargyl ether) stars 1
and 214 from linear poly(aryl propargyl ether) branches 3
possessing a phenolic anchor (Figure 1). As this function-
ality showed increased reactivity compared to aliphatic
hydroxyl group, we expect to link 3 to various cores, such
as 1,3,5-benzenetricarbonyl chloride (5) or 1,3,5-tris(bro-
momethyl)benzene (6) by an acylation or an alkylation
step, respectively. We chose to introduce as repeating
group an aryl propargyl ether moiety in which the triple
bond of the nonconjugated heteroatom-containing flexi-
ble linkage provides a focal point for further structural
manipulation (e.g., partial15 or total16 reduction, hydro-
metalation,17 followed by a coupling reaction). Further-
more, ramification materialized by the introduction of a 4-
substituted phenyl group, may potentiate the interaction
with an active drug depending on the nature of the func-
tionalities. A further particularity of star macromolecules
1 and 2 is the ease of 1H NMR analysis due to the absence
of complicated multiplicity. Herein we describe the syn-
thesis and characterization of a series of low generation
poly(aryl propargyl ether) (PAPE) stars 1 and 2 as well as
comment on their preliminary cytotoxic activities for fur-
ther applications in biological studies.
Key words: poly(aryl propargyl ether), PAPE stars, transesterifica-
tion, palladium, alkynes, Sonogashira coupling
Dendrimers are unique synthetic macromolecules, which
have attracted much interest due to their unique properties
since their introduction in the mid-1980s.1 In contrast to
linear polymers, these macromolecules prepared by an it-
erative synthetic methodology are characterized by highly
branched and well-defined structures, globular shape, nu-
merous surface functionalities, and internal cavities.
These characteristics, along with water solubility, are
some of the features that make them attractive for drug-
delivery applications.2 Dendrimers can function as drug
carriers either by encapsulating drugs within the dendritic
structure3 or by attaching it to terminal functional groups
via electrostatic or covalent bonds (prodrug).4 The cova-
lent linkage of a drug to a dendrimer provides a stable sys-
tem.
An ideal drug carrier must be biochemically inert and
nontoxic while protecting the drug until it reaches the de-
sired site of action, where the drug could be released. Over
the past years, many drug-delivery systems (e.g., lipo-
somes, synthetic and natural polymers) have been ex-
plored for this purpose.5 By contrast, the use of
dendrimers, which possess many of the above-mentioned
properties for an ideal drug carrier system, has not been
highlighted. At present, probably the most investigated
In order to avoid the formation of structural defects during
macromolecule construction, a convergent approach was
chosen. Thus, the synthesis of functionalized PAPE stars
1 and 2 required a rapid and flexible method to prepare
low generation linear branches 3 bearing a phenol substit-
uent, which will be used as the focal point functionality
(Figure 1). To this end, the synthesis of the first genera-
tion branches 3 (n = 1) will involve an iterative three-step
sequence based on Grignard addition, Williamson alkyla-
SYNTHESIS 2008, No. 7, pp 1049–1060
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032119; Art ID: Z25907SS
© Georg Thieme Verlag Stuttgart · New York

1050
N. L’Hermite et al.
PAPER
R1OOC
R1OOC
R
n
n
R
O
O
O
O
O
R
O
COOR1
R
O
O
COOR1
O
O
O
O
O
n
O
O
n
2
n
1
n
R
R
COOR1
COOR1
COOMe
COOR1
O
Cl
Br
n
O
O
I
O
O
HO
Br
Br
Cl
Cl
4
5
6
3
OMe
R
n = 1, 2 R = OMe, NMe2 R1 = Me, (CH2)2NR2
Figure 1 Compounds 1–6
tion, and then Sonogashira–Linstrumelle (S–L) coupling lytic amount of PdCl2(PPh3)2 (5 mol%) and CuI (10
reaction (Scheme 1). Repetition of this iterative three-step mol%) in Et3N. Under these conditions, the O-allyl pro-
reaction sequence would generate the higher generation tected compounds 10a–c were obtained in good yields
linear branches. For the accelerated preparation of the sec- (10a: 98%, 10b: 67%, 10c: 96%). The final step to form 3
ond generation linear branches 3 (n = 2), it was planned to was the deprotection of the phenolic group. As well
use iodinated compound 4 in an S–L coupling reaction. In known, the O-allyl group can be selectively deprotected in
order to achieve the synthesis of phenol-substituted the presence of NaBH4 and a catalytic amount of
branches 3, it was necessary to differentiate the two hy- Pd(PPh3)4.19 Under these conditions, attempts to remove
droxy groups of 8 as the alkylation step could induce se- the O-allyl group of 10a in THF or DMF at 0 °C afforded
lectivity issues. Among various protective groups low yields of 3a (<15%) contaminated with small
examined18 (MOM, MEM, TBDMS, TBDPS, or TIPS), amounts of unidentified compounds. Running the reac-
the allylic group appeared as the protecting group of tions for longer times (4 h) and at higher temperatures
choice because of its stability under basic medium and its (50 °C) had no significant improvement on the yield.
facility to be removed under mild conditions.
However, we found that the use of a combination of THF–
MeOH (2:8) as solvent at 0 °C gave the best results of 3a–
c bearing a free phenol substituent (3a: 84%, 3b: 77%, 3c:
82%). It should be noted that this four-step sequence was
scaled up to the degree that 3a–c are now available in mul-
tigram quantities in similar yields.
According to the synthetic Scheme 1, the commercially
available compound 7a was first transformed to the allylic
ether 7b and then reacted with 4-substituted aryl Grignard
reagents to afford in excellent yields the corresponding
dibenzylic alcohols 8a,b. Williamson propargylation of
8a,b yielded the propargyl ethers 9a,b on treatment with The synthesis of the second generation linear branch 3d
propargyl bromide and NaH in a mixture of DMF–THF was initially attempted by coupling of alkyne 9a with the
(1:1). To achieve the synthesis of 10, the terminal alkyne previously described iodinated dibenzylic alcohol inter-
function was reacted with 4-iodobenzoic acid methyl or mediate 11.13 Thus, the coupling product 12 was obtained
N,N-2-dimethylaminoethyl ester in the presence of a cata- in good yield (77%) in the presence of a catalytic amount
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

PAPER
Poly(aryl propargyl ether) Stars
1051
O
HO
R1O
a: R1 = H
(e)
(a)
O
O
COOR1
10a–c
COOR1
b: R1 = CH2CH=CH2
CHO
(b)
7
3a–c
R
R
a: R = OMe R1 = Me
b: R = NMe2 R1 = Me
c: R = OMe
a: R = OMe R1 = Me
b: R = NMe2 R1 = Me
c: R = OMe
(d)
R
1 = (CH2)2NMe2
R
1 = (CH2)2NMe2
O
O
COOMe
(c)
OH
O
HO
8
9
R
R
a: R = OMe
b: R = NMe2
a: R = OMe
b: R = NMe2
OH
O
O
I
OMe
11
3d
MeO
from 9a
from 9a
(i)
OMe
COOMe
(f)
(j)
O
OMe
O
(g), (h)
O
O
O
OH
12
MeO
14
MeO
OMe
Scheme 1 Reagents and conditions: (a) H2C=CHCH2Br, K2CO3 (2 equiv), KI (10 mol%), acetone, reflux (7b: 98%); (b) 4-MeOC6H4MgBr
or 4-Me2NC6H4MgBr (2 equiv), THF, 40 °C (8a: 92%, 8b: 85%); (c) NaH 60% (2 equiv), BrCH2C≡CH (2 equiv), THF–DMF (1:1), 20 °C (9a:
91%, 9b: 84%); (d) 4-IC6H4CO2R [R = Me, (CH2)2NMe2] (1 equiv), PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N, 60 °C (10a: 98%, 10b: 67%,
10c: 96%); (e) NaBH4 (6 equiv), Pd(PPh3)4 (5 mol%), THF–MeOH (2:8), 0 °C (3a: 84%, 3b: 77%, 3c: 82%); (f) 11 (1.5 equiv), PdCl2(PPh3)2
(5 mol%), CuI (10 mol%), Et3N, 60 °C (12: 77%); (g) NaH 60% (2 equiv), BrCH2C≡CH (2 equiv), THF–DMF (1:1), 20 °C (13: 99%); (h) 4-
IC6H4CO2Me (2 equiv), PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N, 60 °C (14: 58%); (i) 4 (1.5 equiv), PdCl2(PPh3)2 (5 mol%), CuI (10
mol%), Et3N, 60 °C (14: 74%); (j) NaBH4 (6 equiv), Pd(PPh3)4 (5 mol%), THF–MeOH (2:8), 30 to 10 °C (3d: 80%).
of PdCl2(PPh3)2 (5 mol%) and CuI (10 mol%) in triethyl- After the synthesis of derivatives 3a–d, their attachment
amine. Further propargylation of the hydroxyl group of 12 to different cores was carried out (Scheme 2). First, the
(13: 99%, not shown in Scheme 1) followed by an S–L acylation of 3 with the 1,3,5-benzenetricarbonyl chloride
coupling reaction afforded the O-allylic protected com- (5) core was investigated under various conditions20 in-
pound 14 (58%). To speed up the synthesis of 14, an alter- cluding Et3N, pyridine, or DMAP in CH2Cl2, THF, or tol-
nate approach based on the use of iodinated compound 413 uene. Best results were obtained when the acylation
was explored. Accordingly, we were pleased to find that reaction was conducted from 3a in the presence of trieth-
the S–L coupling reaction of 4 with alkyne 9a efficiently ylamine and DMAP in dichloromethane at 0 °C. Under
afforded the second generation branch 14 in a 74% isolat- these conditions, 40% of first generation acylated PAPE
ed yield in one-step. Finally, the deprotection step of the stars 1a were isolated. As shown in Scheme 2, performing
O-allyl ether of 14 occurred under the same conditions as the acylation reaction with 3c and 3d afforded the corre-
for the conversion of 10 to 3. It was noticed that the tem- sponding PAPE stars 1c and 1d, but in moderate yields
perature should be maintained in that case under –10 °C to (20 and 24%, respectively). Surprisingly, starting from 3b
avoid degradation. Thus, we have developed a synthetic the above mentioned reaction conditions did not yield the
scheme to the first and second generation linear branches desired PAPE stars 1b and a complex mixture of insepa-
3a–d in five steps and in good overall yields (overall rable products was obtained. It seems that the presence of
yields of 3 from 7b, 3a: 68%, 3b: 32%, 3c: 65%, 3d: the 4-dimethylaminoaryl group within the structure of 3b
49%).
interferes with the outcome of the acylation reaction with
1,3,5-benzenetricarbonyl chloride (5) core.
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

1052
N. L’Hermite et al.
PAPER
COOR1
n
5
6
O
(a) or (b) or (c)
(d) or (e)
HO
R
R1OOC
R1OOC
3a–d
n
n
R1OOC
R1OOC
O
O
R
R
n
n
O
O
O
O
O
O
O
O
O
O
R
R
O
1
2
O
O
COOR1
COOR1
n
n
R
R
a: n = 1 R = OMe R1 = Me
b: n = 1 R = NMe2 R1 = Me
d: n = 2 R = OMe
a: n = 1 R = OMe R1 = Me
c: n = 1 R = OMe
1 = (CH2)2NMe2
d: n = 2 R = OMe R1 = Me
R
R
1 = Me
Scheme 2 Reagents and conditions: (a) 3a (3.3 equiv), Et3N (30 equiv), DMAP (6 equiv), CH2Cl2, 0–20 °C (1a: 40%); (b) 3c (3.3 equiv),
pyridine (30 equiv), DMAP (6 equiv), THF, 0 °C (1c: 20%); (c) (3d: 3.3 equiv), TEA (10 equiv), DMAP (10 mol%), CH2Cl2, 0 to 20 °C (1d:
24%); (d) 3a or 3d (3.6 equiv), K2CO3 (6 equiv), KI (2.7 equiv), Aliquat 336 (cat.), acetone, reflux (2a: 80%, 2d: 90%); (e) 3b (3 equiv), NaH
60% (3.3 equiv), THF–DMF (1:1), 20 °C (2b: 22%).
Next, we explored the preparation of PAPE stars 2 using cases, all starting material were consumed and a complex
an alkylation step with 1,3,5-tris(bromomethyl)benzene mixture of inseparable products was obtained.
(6) as anchoring linkage (Scheme 2). Various experimen-
Difficulties encountered in the linkage of 3c to the core 6
tal conditions were studied using several combinations of
led us to examine an alternative route to form the PAPE
base/solvent/additive mixtures (e.g., NaH, Cs2CO3,
star 2c having on the surface functionalized polar groups
(e.g., N,N-2-dimethylaminoethoxy carbonyl group). The
presence of these latter on 2c would improve its water sol-
ubility for further biological studies. As the synthesis of
PAPE stars 2a and 2d was efficiently accomplished in
multigrams quantities, this prompted us to examine a con-
K2CO3/THF, DMF, acetone /KI, crown-ether, and
Bu4NI). It was found that the reaction of the first 3a and
second 3d generation branches with 6 in refluxing acetone
in the presence of potassium carbonate, potassium iodide,
and Aliquat 336 afforded the stars PAPE 2a and 2d in ex-
cellent isolated yields (80 and 90%, respectively). Under
vergent approach to introduce polar groups by transester-
the same conditions, the reaction of 6 with 3b having a 4-
ification of methyl esters on the surface of PAPE stars 2
dimethylaminoaryl group within the structure of linear
leading to the corresponding analogues with higher alco-
branch afforded, however, the corresponding star 2b in
hol moieties. If this transformation proves to be effective,
it should represent a straightforward route to a variety of
PAPE stars 2 carrying different functional groups on the
surface.
very low yield (<5%). This yield was enhanced to 22% by
changing the nature of the base (NaH) and solvent (THF–
DMF, 1:1). Extended reaction times and higher tempera-
ture led to decomposition and decreased the yield. It
Initial attempts to introduce the N,N-2-dimethylaminoeth-
should be noted that all our attempts to prepare 2c from 3c
yl esters by transesterification of first-generation star 2a
having an N,N-2-dimethylaminoethoxy carbonyl group
with N,N-2-dimethylaminoethanol (15) under various ba-
resulted unfortunately in unsatisfactory yields. In most
sic conditions21 (K2CO3/Aliquat 336/toluene, DBU/LiBr,
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

PAPER
Poly(aryl propargyl ether) Stars
1053
NaOH, or DABCO) afforded low yields of 2c contaminat- ously described how the TRIS [tris(hydroxymethyl)ami-
ed by inseparable starting material, the methyl ester 2a. nomethane] (18) group can be used to convert terminal
Extended reaction times led to decomposition and de- esters into terminal hydroxyls. This method could poten-
creased yields. It should be noted that similar results were tially increase in a final and single step the number of po-
obtained when using strong nonionic bases such as triami- lar terminal groups. This TRIS group has the advantage of
nophosphane,22 while under neutral iodine catalysis23 the being neutral but polar, increasing solubility without be-
transesterification was effective and afforded 2c in mod- ing charged, which can cause sometimes toxicology is-
erate yield (40%). Finally, we turned our attention to- sues. When the methyl ester terminated first generation
wards Seebach’s24 transesterification conditions based on star 2a was reacted in DMSO with an excess of TRIS (18)
titanium catalysis. When the first 2a and second 2d gener- in the presence of potassium carbonate, the star 2h having
ation stars were heated with the amino alcohol 15 at nine terminal hydroxyl groups was obtained in a 71% iso-
130 °C in the presence of a catalytic amount of titani- lated yield.
um(IV) isopropoxide (15 mol%), an almost quantitative
All these macromolecules were completely characterized
yield of PAPE stars 2c and 2e was obtained (89 and 95%,
respectively) (Scheme 3). To the best of our knowledge,
this is the first report on the use of Seebach’s conditions
to perform functionalization of dendrimer surface. On the
basis of these promising results, the transesterification re-
action of 2a was tested with diamino alcohol 16 and af-
forded the corresponding functionalized PAPE star 2f in
54% yield. The scope of this reaction was also expanded
to introduce polyallylic ethers. Thus under similar condi-
tions, reaction of 2a with alcohol 1725 gave the desired
PAPE star 2g in 84% isolated yield. Newkome had previ-
by routine physical methods including 1H, 13C NMR, IR,
elemental analysis, and MS. However, one of the reasons
why we particularly chose to develop PAPE stars is the
ease of 1H NMR analysis because of the absence of com-
plicated multiplicity induced. Careful analysis of 1H NMR
spectra allowed to characterize easily our stars. As shown
for the first and second generation stars 2a and 2d
(Figure 2), the resonance signals in 1H NMR are all sharp
and distinct so as they can be easily assigned according to
1
the chemical shifts and integrations. Analyzing the H
NMR spectrum of the first generation star 2a, the appear-
MeOOC
n
R1OOC
n
NMe2
OMe
OMe
15
HO
O
O
Me
N
16
N
HO
O
O
O
O
17
MeO
O
MeO
O
O
COOMe
n
COOR1
HO
O
O
n
O
O
O
O
(a or b or c or d)
HO
HN
OH
OH
2a: n = 1
2d: n = 2
OMe
OMe
n
n
COOMe
COOR1
O
2c:
2e:
2f:
n = 1
n = 2
n = 1
n = 1
R1 = (CH2)2NMe2
R1 = (CH2)2NMe2
OMe
O
R
1 = (CH2)2N[(CH2)2]2NMe
HO
OH
R1 = CH2C(CH2OCH2CH=CH2)3
2g:
18
H2N
OH
O
OH
(e)
O
MeO
O
OH
OH
N
O
H
O
O
2h
OMe
HO
HO
N
O
H
HO
Scheme 3 Reagents and conditions: (a) 2a or 2d (1 equiv), Ti(O-iPr)4 (15 mol%), 15, 16 or 17 (0.15 M), 130 °C, (2c: 89%, 2e: 95%, 2f: 54%,
2g: 84%); (b) 2a (1 equiv), 18 (3.3 equiv), K2CO3 (3.3 equiv), DMSO, 60 °C (2h: 71%).
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

1054
N. L’Hermite et al.
PAPER
Figure 2 1H NMR spectra of 2a and 2d
ance of core signals around 5.0 and 7.42 ppm, correspond-
ing respectively to CH2 linkage to branches and aromatic
CH signals from the core, proved the formation of the star.
1
The H NMR spectrum of the second generation star 2d
showed distinct resonance signals for each generation
even using a 200 MHz apparatus. Different signals can in-
deed be observed for the two different OMe and the two
different CH2 of the PAPE iterative unit. In most cases
simple electrospray ionization techniques were sufficient
to characterize the stars, but some needed MALDI-TOF
analysis to detect the molecular mass ions.
Cytocompatibility has been evaluated by in vitro MTT
cell proliferation assays.26 This test is a colorimetric assay
based on the enzymatic reduction of a tetrazolium salt into
purple colored formazan in metabolically active cells. The
enzymatic activity is quantified in cells surviving after
treatment with antineoplastic agents and is directly pro-
portional to the cellular proliferation response and the cy-
totoxicity of the product. No significant toxicity was
detected associated with the products tested 2c, 2e, 2f, and
2h (Figure 3) in a concentration range of 0.1 to 1000 mg/
mL.
Figure 3 MTT Cell proliferation assay results (RAW 264.7 cells)
In conclusion, we have succeeded in developing a conve-
nient route to low generation PAPE stars 1 and 2. First
generation branches 3a–c were obtained according a
three-step sequence developed previously. The second
generation branch 3d was readily obtained using iodinat-
ed compound 4. Acylated PAPE 1 stars have been isolated
in moderate yields in comparison with alkylated PAPE
stars 2, which were obtained in good to excellent yields.
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PAPER
Poly(aryl propargyl ether) Stars
1055
quenched with H2O (20 mL). The aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic layers were washed with
brine (15 mL), dried (Na2SO4), and concentrated under vacuum.
Surprisingly the presence of amino chains within com-
pound 3b interfered with star synthesis. These results led
us to explore another way of introduction of polar groups,
essential for biological studies. Transesterification proved
to be an effective way of access to stars bearing polar moi-
eties. Reaction of TRIS group with the methyl esters of 2a
and 2d afforded another polar, but neutral kind of star.
Preliminary evaluation of the cytotoxicity of some of the
synthesized PAPE stars showed that these macromole-
cules are biocompatible making them suitable for further
in vitro biological studies. Additional developments con-
cerning functionalization of the C≡C bonds on these star
macromolecules are currently in progress and will be re-
ported in due course.
Compound 8a
Purification by flash chromatography (cyclohexane–EtOAc, 7:3)
afforded 8a as a colorless oil; yield: 2.5 g (92%); Rf = 0.27 (cyclo-
hexane–EtOAc, 8:2).
IR (neat): 3421, 2933, 2836, 1608, 1584, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.26 (d, J = 8.8 Hz, 2 H), 7.25 (d,
J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H),
6.04 (m, 1 H), 5.74 (s, 1 H), 5.39 (dq, J = 17.2, 1.5 Hz, 1 H), 5.25
(dq, J = 9.0, 1.5 Hz, 1 H), 4.51 (dt, J = 5.2, 1.5 Hz, 2 H), 3.77 (s, 3
H), 2.20 (br s, 1 H, OH).
13C NMR (50 MHz, CDCl3): d = 159.0, 158.0, 136.6, 136.4, 133.3,
127.7, 117.6, 114.6, 113.8, 75.3, 68.8, 55.2.
MS (ESI): m/z = 563 (2 M + Na)+, 293 (M + Na)+.
All glassware were oven-dried at 140 °C and all reactions were con-
ducted under argon. THF was distilled from sodium/benzophenone
ketyl. Et3N was distilled from KOH under argon prior to use. The
compounds were all identified by usual physical methods: 1H NMR,
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.32; H,
6.52.
1
13C NMR, IR, and elemental analysis. H and 13C NMR spectra
Compound 8b
were recorded in CDCl3 on a Bruker AC 200 or Bruker ARX 400
spectrometer. 1H chemical shifts are reported in ppm from an inter-
nal standard TMS or of residual CHCl3 (7.27 ppm). 13C chemical
shifts are reported in ppm from the central peak of CDCl3 (77.14
ppm). IR spectra were recorded on a Bruker Vector 22 spectropho-
tometer (neat, cm–1). Elemental analyses were performed with a
PerkinElmer 240 analyzer. Mass spectra were obtained with a LCT
Micromass spectrometer. Analytical TLC analyses were performed
on Merck precoated silica gel 60F plates. Merck silica gel 60 (230–
400 mesh) was used for column chromatography. Melting points
were recorded on a Büchi B-450 apparatus and are uncorrected.
Recrystallization from cyclohexane–EtOAc (95:5) afforded 8b as a
blue solid; yield: 10.83 g (85%); mp 81 °C; Rf = 0.31 (cyclohexane–
EtOAc, 7:3).
IR (neat): 3273, 3000, 2800, 1612, 1522, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28 (d, J = 8.6 Hz, 2 H), 7.18 (d,
J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.67 (d, J = 8.6 Hz, 2 H),
6.04 (m, 1 H), 5.66 (s, 1 H), 5.39 (dq, J = 17.2, 1.6 Hz, 1 H), 5.22
(dq, J = 10.4, 1.6, Hz, 1 H), 4.53 (dt, J = 5.2, 1.6 Hz, 2 H), 4.35 (br
s, 1 H, OH), 2.88 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 158.4, 150.8, 139.4, 134.9, 134.6,
128.4, 117.2, 115.0, 113.1, 75.5, 69.3, 40.8.
4-Allyloxybenzaldehyde (7b)
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47. Found: C, 76.02; H,
7.34.
4-Hydroxybenzaldehyde (7a; 1.22 g, 10 mmol), K2CO3 (2.76 g, 20
mmol), and KI (166 mg, 1 mmol) were dispersed in anhyd acetone
(100 mL) under an inert atmosphere. 3-Bromoprop-1-ene (1.73 mL,
20 mmol) was added and the resulting mixture was refluxed and the
reaction progress was monitored by TLC analysis until complete
consumption of 7a (3 h). The solvent was concentrated under vacu-
um and the resulting residue was partitioned between EtOAc (40
mL) and brine (20 mL). The organic layer was dried (MgSO4), fil-
tered, and concentrated under vacuum to afford aldehyde 7b as a
yellow oil; yield: 1.60 g (98%); Rf = 0.51 (cyclohexane–EtOAc,
8:2).
Propargylation of Alcohols 8a,b; General Procedure
NaH (60%, 2 equiv) was suspended in anhyd THF (0.4 M) and a so-
lution of alcohol 8a,b (1 equiv) in anhyd DMF (40 mL) was added
under an inert atmosphere. The mixture was left to stir for 30 min
and 3-bromoprop-1-yne (2 equiv) was added. The mixture was
stirred at r.t. and the progress of the reaction was monitored by TLC
analysis until complete consumption of the starting material (1–3 h)
before quenching with H2O (30 mL). The aqueous layer was ex-
tracted with EtOAc (3 × 30 mL). The organic layer was washed with
brine (20 mL), dried (Na2SO4), filtered, and concentrated under vac-
uum.
IR (neat): 3076, 2925, 2837, 1686, 1596, 1575, 1507 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.98 (s, 1 H), 7.82 (d, J = 8.8 Hz,
2 H), 7.01 (d, J = 8.8 Hz, 2 H), 6.06 (m, 1 H), 5.43 (dq, J = 17.2, 1.5
Hz, 1 H), 5.31 (dq, J = 12.0, 1.5 Hz, 1 H), 4.61 (dt, J = 5.2, 1.4 Hz,
2 H).
13C NMR (50 MHz, CDCl3, 298 K): d = 190.6, 163.6, 132.3, 131.9,
130.1, 118.2, 115.0, 69.0.
Compound 9a
Purification by flash chromatography (cyclohexane–EtOAc, 9:1,
Rf = 0.39) afforded 9a as a yellow oil; yield: 4.60 g (91%); Rf = 0.39
(cyclohexane–EtOAc, 9:1).
IR (neat): 3288, 3000, 2800, 1609, 1584, 1508, 1240, 1171, 1067,
1027 cm–1.
MS (ESI): m/z = 185 (M + Na)+.
Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 73.95; H,
6.32.
1H NMR (200 MHz, CDCl3): d = 7.24 (d, J = 8.8 Hz, 2 H), 7.23 (d,
J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H),
6.01 (m, 1 H), 5.57 (s, 1 H), 5.38 (dq, J = 18.8, 1.5 Hz, 1 H), 5,25
(dq, J = 10.4, 1.5 Hz, 1 H), 4.50 (dt, J = 5.2, 1.5 Hz, 2 H), 4.10 (d,
J = 2.4 Hz, 2 H), 3.77 (s, 3 H), 2.42 (t, J = 2.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 158.1, 159.1, 133.7, 133.5, 133.3,
128.5, 117.6, 114.6, 113.8, 80.8, 79.9, 74.3, 68.8, 55.5, 55.2.
Grignard Addition to 7b; General Procedure
Under an inert atmosphere, 7b (1 equiv, 10 mmol) was dissolved in
anhyd THF (30 mL) to give a 0.3 M solution. This solution was
cooled to –40 °C, and a solution of Grignard reagent in THF (2.2
equiv) was added dropwise. The resulting mixture was stirred at this
temperature and the progress of the reaction was monitored by TLC
analysis until complete consumption of 7b (2–3 h). The mixture was
MS (ESI): m/z = 639 (2 M + Na)+, 331 (M + Na)+.
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

1056
N. L’Hermite et al.
PAPER
Compound 9b
Compound 10b
Purification by flash chromatography (cyclohexane–EtOAc, 8:2,
Rf = 0.48) afforded 9b as a yellow oil; yield: 10.4 g (91%); Rf = 0.39
(cyclohexane–EtOAc, 8:1).
IR (neat): 3288, 3000, 2800, 1610, 1520, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.25 (d, J = 8.6 Hz, 2 H), 7.18 (d,
J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 6.68 (d, J = 8.6 Hz, 2 H),
5.53 (s, 1 H), 6.02 (m, 1 H), 5.38 (dq, J = 17.2, 1.5 Hz, 1 H), 5.25
(dq, J = 10.4, 1.5 Hz, 1 H), 4.51 (dt, J = 5.0, 1.5 Hz, 2 H), 4.10 (d,
J = 2.4 Hz, 2 H), 2.92 (s, 6 H), 2.41 (t, J = 2.4 Hz, 1 H).
Obtained from 9b (1.2 equiv) and 4-iodobenzoic acid methyl ester
(1 equiv). Purification by flash chromatography (cyclohexane–
EtOAc, 9:1) afforded pure 10b as a yellow oil; yield: 910 mg (67%);
Rf = 0.30 (cyclohexane–EtOAc, 8:2).
IR (neat): 3000, 2800, 1719, 1607, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.04 (d, J = 8.2 Hz, 2 H), 7.55 (d,
J = 8.2 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.29 (d, J = 8.6 Hz, 2 H),
6.93 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6 Hz, 2 H), 6.08 (m, 1 H),
5.65 (s, 1 H), 5.44 (dq, J = 17.2, 1.5 Hz, 1 H), 5.32 (dq, J = 10.4, 1.5
Hz, 1 H), 4.57 (dt, J = 5.2, 1.5 Hz, 2 H), 4.42 (s, 2 H), 3.97 (s, 3 H),
2.99 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 166.5, 157.9, 150.2, 134.3, 133.3,
131.6, 129.4, 128.4, 128.9, 127.6, 117.5, 114.5, 112.4, 88.9, 85.3,
81.5, 68.8, 56.2, 52.1, 40.5.
13C NMR (50 MHz, CDCl3): d = 157.7, 150.0, 134.2, 133.2, 128.8,
128.2, 117.3, 114.3, 112.2, 80.9, 80.1, 74.1, 68.6, 55.2, 40.4.
Anal. Calcd for C21H23NO2: C, 78.47; H, 7.21. Found: C, 78.25; H,
7.32.
Compound 13
MS (ESI): m/z = 478 (M + Na)+, 456 (M + H)+.
Purification by flash chromatography (cyclohexane–EtOAc, 7:3)
afforded 13 as a yellow oil; yield: 3.42 g (99%); Rf = 0.54 (cyclo-
hexane–EtOAc, 7:3).
IR (neat): 3288, 2928, 2850, 1609, 1584, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.40 (d, J = 8.2 Hz, 2 H), 7.24 (m,
8 H), 6.85 (d, J = 8.8 Hz, 6 H), 6.01 (m, 1 H), 5.62 (s, 1 H), 5.60 (s,
1 H), 5.36 (q, J = 17.2, 1.5, 1.6 Hz, 1 H),.5.28 (q, J = 10.6, 1.5, 1.6
Hz, 1 H), 4.51 (dt, J = 5.2, 1.5 Hz, 2 H), 4.32 (s, 2 H), 4.11 (d,
J = 2.4 Hz, 2 H), 3.77 (s, 6 H), 2.40 (t, J = 2.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 159.3, 159.1, 158.1, 141.9, 134.0,
133.7, 133.3, 132.7, 131.8, 128.7, 128.5, 127.0, 121.9, 117.6, 114.6,
113.9, 113.8, 88.1, 85.5, 79.6, 80.9, 74.6, 68.8, 56.4, 55.6, 55.2.
Compound 10c
Obtained from 9a (1.05 equiv) and 4-iodobenzoic acid methyl ester
(1.0 equiv). Purification by flash chromatography (EtOAc–Et3N,
98:2) afforded pure 10c as a brown oil; yield: 1.91 g (96%);
Rf = 0.51 (EtOAc–Et3N, 98:2).
IR (neat): 3000, 2800, 1716, 1607, 1585, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.98 (d, J = 8.2 Hz, 2 H), 7.47 (d,
J = 8.2 Hz, 2 H), 7.28 (d, J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H),
6.88 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.02 (m, 1 H),
5.61 (s, 1 H), 5.39 (dq, J = 17.2, 1.5 Hz, 1 H), 5.26 (dq, J = 10.4, 1.5
Hz, 1 H), 4.51 (dt, J = 5.2, 1.5 Hz, 2 H), 4.42 (t, J = 5.8 Hz, 2 H),
4.35 (s, 2 H), 3.77 (s, 3 H), 2.70 (t, J = 5.8 Hz, 2 H), 2.32 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 165.9, 159.1, 158.1, 138.8, 133.5,
133.2, 131.6, 129.7, 129.5, 128.5, 127.4, 117.5, 114.6, 113.8, 88.5,
85.5, 81.3, 68.8, 63.1, 57.8, 56.3, 55.2, 45.8.
MS (ESI): m/z = 581 (M + Na)+.
Sonogashira–Linstrumelle Coupling Reaction of 9; General
Procedure
To a solution of the iodinated compound, 4-iodobenzoic acid meth-
yl or N,N-2-dimethylaminoethyl ester in freshly distilled Et3N (20
mL) were added PdCl2(PPh3)2 (5 mol%) and CuI (10 mol%). The
resulting mixture was allowed to reach 60 °C and a solution of
alkyne 9 in Et3N (20 mL) was slowly added dropwise. The mixture
was further stirred at 60 °C and the progress of the reaction was
monitored by TLC analysis until complete consumption of starting
material (2–4 h). The mixture was concentrated under vacuum. The
residue was dissolved in EtOAc (100 mL) and the EtOAc layer
washed successively with aq HCl (0.5 M, 10 mL), H2O (2 × 20 mL),
dried (Na2SO4), and concentrated under vacuum.
Anal. Calcd for C31H33NO5: C, 74.53; H, 6.66. Found: C, 74.15; H,
6.82.
Compound 12
Obtained from 9a (1 equiv) and 11 (1.5 equiv). Purification by flash
chromatography (cyclohexane–EtOAc, 7:3) afforded pure 12 as a
brown oil; yield: 3.21 g (77%); Rf = 0.27 (EtOAc–cyclohexane,
7:3).
IR (neat): 3456, 2999, 2836, 1608, 1584, 1507 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.41 (d, J = 8.6 Hz, 2 H), 7.31 (d,
J = 8.6 Hz, 2 H), 7.25 (m, 6 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.85 (d,
J = 8.8 Hz, 4 H), 6.02 (m, 1 H), 5.78 (s, 1 H), 5.63 (s, 1 H), 5.38 (dq,
J = 17.2, 1.6 Hz, 1 H), 5.26 (dq, J = 10.6, 1.6 Hz, 1 H), 4.50 (dt,
J = 5.2, 1.6 Hz, 2 H), 4.32 (s, 2 H), 3.78 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 159.1, 159.,0, 158.0, 144.4, 135.8,
133.9, 133.7, 133.3, 131.7, 128.5, 127.9, 126.2, 121.6, 117.5, 114.6,
113.9, 113.7, 86.1, 85.3, 80.9, 75.3, 68.8, 56.4, 55.2.
Compound 10a
Obtained from 9a (1 equiv) and 4-iodobenzoic acid methyl ester
(1.2 equiv). Purification by flash chromatography (cyclohexane–
EtOAc, 9:1) afforded pure 10a as a brown oil; yield: 1.7 g (98%);
Rf = 0.24 (cyclohexane–EtOAc, 9:1).
IR (neat): 2998, 2838, 1719, 1606, 1584, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.98 (d, J = 8.6 Hz, 2 H), 7.48 (d,
J = 8.6 Hz, 2 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2 H),
6.87 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.02 (m, 1 H),
5.61 (s, 1 H), 5.38 (dq, J = 17.4, 1.5 Hz, 1 H), 5.25 (dq, J = 8.4, 1.5
Hz, 1 H), 4.51 (dt, J = 5.2, 1.5 Hz, 2 H), 4.36 (s, 2 H), 3.91 (s, 3 H),
3.78 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 166.5, 159.1, 158.1, 133.8, 133.6,
133.3, 131.6, 129.7, 129.4, 128.5, 127.5, 117.6, 114.6, 113.8, 88.6,
85.5, 81.3, 68.8, 56.4, 55.2, 52.2.
Anal. Calcd for C34H32O5: C, 78.44; H, 6.20. Found: C, 78.15; H,
6.39.
Compound 14
Obtained from 9a (1 equiv) and 4 (2 equiv). Purification by flash
chromatography (cyclohexane–EtOAc, 9:1) afforded pure 14 as a
brown oil; yield: 230 mg (74%); Rf = 0.3 (EtOAc–cyclohexane,
2:8).
IR (neat): 2951, 2837, 1719, 1607, 1584, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 2 H), 7.45 (d,
J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H),
7.24 (d, J = 8.8 Hz, 6 H), 6.84 (d, J = 8.8 Hz, 4 H), 6.83 (d, J = 8.8
Hz, 2 H), 5.99 (m, 1 H), 5.62 (s, 1 H), 5.60 (s, 1 H), 5.35 (dq,
MS (ESI): m/z = 465 (M + Na)+.
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

PAPER
Poly(aryl propargyl ether) Stars
1057
J = 17.2, 1.5 Hz, 1 H), 5.23 (dq, J = 10.4, 1.5 Hz, 1 H), 4.48 (dt,
J = 5.4, 1.5 Hz, 2 H), 4.34 (s, 2 H), 4.30 (s, 2 H), 3.88 (s, 3 H), 3.76
(s, 3 H), 3.75 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 166.4, 159.3, 159.1, 158.1, 142.0,
133.9, 133.7, 132.8, 133.3, 131.8, 131.6, 129.7, 129.4, 128.7, 128.5,
127.3, 127.0, 122.0, 117.5, 114.6, 113.9, 113.7, 88.2, 86.1, 85.7,
85.5, 81.3, 80.9, 68.8, 56.5, 55.2, 52.1.
4.37 (t, J = 5.6 Hz, 2 H), 4.23 (s, 2 H), 3.68 (s, 3 H), 2.70 (t, J = 5.6
Hz, 2 H), 2.29 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 166.0, 159.0, 156.2, 133.7, 132.5,
131.5, 129.5, 128.7, 128.5, 127.5, 115.4, 113.7, 88.7, 85.4, 81.4,
62.3, 57.6, 56.3, 55.2, 45.4.
MS (ESI): m/z = 482 (M + Na)+, 460 (M + H)+.
Anal. Calcd for C28H29NO5: C, 73.18; H, 6.36. Found: C, 72.96; H,
6.52.
MS (ESI): m/z = 715 (M + Na)+.
Deprotection of Phenolic Group in 10a–c and 14; General Pro-
cedure
Compound 3d
Purification by flash chromatography (cyclohexane–EtOAc, 7:3)
afforded pure 3d as a yellow oil; yield: 260 mg (80%); Rf = 0.42
(EtOAc–cyclohexane, 4:6).
IR (neat): 3400, 2953, 2838, 1719, 1607 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.97 (d, J = 8,0 Hz, 2 H), 7.47 (d,
J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H),
7.27 (d, J = 8.4 Hz, 4 H), 7.20 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4
Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2 H), 6.08
(br s, 1 H, OH), 5.65 (s, 1 H), 5.62 (s, 1 H), 4.37 (s, 2 H), 4.33 (s, 2
H), 3.89 (s, 3 H), 3.75 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 166.6, 159.2, 158.9, 155.4, 141.9,
133.6, 133.3, 132.7, 131.7, 131.6, 129.6, 129.4, 128.7, 128.5, 127.3,
126.9, 121.9, 115.2, 113.9, 113.7, 88.2, 86.1, 85.7, 85.5, 81.3, 81.0,
56.4, 56.3, 55.2, 52.2.
To a suspension of the allylic protected branch 10a–c, 14 (1 equiv)
and Pd(PPh3)4 (5 mol%) in a mixture of anhyd MeOH (0.06 M/
branch) and anhyd THF (0.25 M/branch) was added NaBH4 (6
equiv) at 0 °C (at –10 °C for 3d). The mixture was further stirred at
0 °C (or –10 °C) and the progress of the reaction was monitored by
TLC analysis until complete consumption of the starting material
(45 min to 4 h) before workup. The mixture was dissolved in EtOAc
(100 mL) and the EtOAc layer was washed with brine (30 mL),
dried (Na2SO4), and concentrated under vacuum.
Compound 3a
Purification by flash chromatography (cyclohexane–EtOAc, 7:3)
afforded pure 3a as a yellow oil; yield: 4.27 g (84%); Rf = 0.46
(EtOAc–cyclohexane, 4:6).
IR (neat): 3382, 2975, 2851, 1720, 1607, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.97 (d, J = 8.6 Hz, 2 H), 7.47 (d,
J = 8.6 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H),
6.86 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 5.60 (s, 1 H),
5.56 (s, 1 H, OH), 4.35 (s, 2 H), 3.91 (s, 3 H), 3.78 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 166.6, 159.0, 155.3, 133.5, 133.3,
131.6, 129.5, 129.3, 128.7, 128.5, 127.4, 115.1, 113.7, 88.5, 85.4,
81.3, 56.3, 55.1, 52.2.
MS (ESI): m/z = 1322 (2 M + NH4)+, 670 (M + NH4)+.
Anal. Calcd for C42H36O7: C, 77.28; H, 5.56. Found: C, 77.02; H,
5.83.
Star 1a
A solution of 3a (170 mg, 0.42 mmol), DMAP (94 mg, 0.76 mmol),
distilled Et3N (0.53 mL, 3.84 mmol), and 5 (34 mg, 0.12 mmol) in
anhyd CH2Cl2 (1.2 mL) was stirred at 0 °C under an inert atmo-
sphere for 1 h. The mixture was then stirred at r.t. and the progress
of the reaction was monitored by TLC analysis until complete con-
sumption of 5 (3 h) before quenching with aq NaHCO3 (1 mL). The
organic layer was washed with brine (0.5 mL), dried (Na2SO4), fil-
tered, and concentrated under vacuum. Purification by flash chro-
matography (CH2Cl2–cyclohexane–EtOAc, 60:35:5) afforded pure
1a as a colorless oil; yield: 70 mg (40%); Rf = 0.69 (CH2Cl2–
EtOAc–cyclohexane, 6:1:3).
MS (ESI): m/z = 425 (M + Na)+.
Anal. Calcd for C25H22O5: C, 74.61; H, 5.51. Found: C, 74.28; H,
5.92.
Compound 3b
Purification by flash chromatography (cyclohexane–EtOAc, 7:3)
afforded pure 3b as a yellow oil; yield: 650 mg (77%); Rf = 0.27
(EtOAc–cyclohexane, 3:7).
IR (neat): 3381, 3000, 2800, 1719, 1608, 1514 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.85 (d, J = 8.2 Hz, 2 H), 7.36 (d,
J = 8.2 Hz, 2 H), 7.12 (d, J = 8.2 Hz, 2 H), 7.10 (d, J = 8.2 Hz, 2 H),
6.64 (d, J = 8.2 Hz, 2 H), 6.60 (d, J = 8.2 Hz, 2 H), 5.47 (s, 1 H),
4.24 (s, 2 H), 3.79 (s, 3 H), 2.78 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 166.7, 155.4, 150.1, 133.4, 131.6,
129.3, 128.5, 128.3, 127.6, 115.1, 112.7, 88.9, 85.3, 81.7, 56.1,
52.2, 40.6.
IR (neat): 2951, 2849, 1719, 1607, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.12 (s, 3 H), 7.91 (d, J = 8.2 Hz,
6 H), 7.42 (d, J = 8.2 Hz, 6 H), 7.39 (d, J = 8.4 Hz, 6 H), 7.23 (d,
J = 8.6 Hz, 6 H), 7.16 (d, J = 8.4 Hz, 6 H), 6.82 (d, J = 8.6 Hz, 6 H),
5.63 (s, 3 H), 4.32 (s, 6 H), 3.83 (s, 9 H), 3.72 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 163.2, 159.4, 149.9, 139.8, 136.0,
132.8, 131.7, 131.2, 129.8, 129.4, 128.8, 128.4, 127.3, 121.4, 114.0,
88.2, 85.7, 81.1, 56.5, 55.3, 52.2.
MS (MALDI-TOF-MS): m/z = 1385 (M + Na)+.
MS (ESI): m/z = 438 (M + Na)+, 416 (M + H)+.
Anal. Calcd for C84H66O18: C, 74.00; H, 4.88. Found: C, 73.25; H,
5.18.
Anal. Calcd for C26H25NO4: C, 75.16; H, 6.06. Found: C, 74.78; H,
6.18.
Star 1c
Compound 3c
To a solution of DMAP (78 mg, 0.64 mmol), distilled pyridine (0.25
mL, 3.2 mmol), and 5 (29 mg, 0.108 mmol) in anhyd THF (1.1 mL)
was added a solution of 3c (150 mg, 0.32 mmol) in anhyd THF (1
mL) at 0 °C under an inert atmosphere. The mixture was then stirred
at 0 °C and monitored by TLC analysis until complete consumption
of 5 (6 h) before quenching with aq NaHCO3 (1 mL). The organic
layer was washed with brine (0.5 mL), dried (Na2SO4), filtered, and
concentrated under vacuum. Purification by flash chromatography
Purification by flash chromatography (CH2Cl2–cyclohexane–
EtOAc, 6:3:1) afforded pure 3c as a brown solid; yield: 920 mg
(82%); mp 110–112 °C; Rf = 0.22 (CH2Cl2–EtOAc–cyclohexane,
6:1:3).
IR (neat): 2959-2835, 1720, 1609, 1510 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.85 (d, J = 8.2 Hz, 2 H), 7.32 (d,
J = 8.2 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 2 H),
6.77 (d, J = 8.4 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2 H), 5.48 (s, 1 H),
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over alumina (eluent: EtOAc) afforded pure 1c as a colorless oil;
yield: 40 mg (24%); Rf = 0.41 (EtOAc–Et3N–MeOH, 8:1:1).
IR (neat): 2951–2771, 1743, 1716, 1607, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.12 (s, 3 H), 7.92 (d, J = 8.2 Hz,
6 H), 7.42 (d, J = 8.2 Hz, 6 H), 7.39 (d, J = 7.8 Hz, 6 H), 7.23 (d,
J = 8.6 Hz, 6 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 6 H),
5.63 (s, 3 H), 4.35 (t, J = 5.8 Hz, 6 H), 4.32 (s, 6 H), 3.73 (s, 9 H),
2.64 (t, J = 5.8 Hz, 6 H), 2.26 (s, 18 H).
13C NMR (50 MHz, CDCl3): d = 166.4, 159.0, 158.1, 137.8, 134.0,
133.4, 131.6, 129.6, 129.3, 128.5, 127.4, 125.8, 114.7, 113.7, 88.5,
85.4, 81.2, 69.6, 56.3, 55.1, 52.1.
MS (MALDI-TOF-MS): m/z = 1343 [(M + Na)+, 50].
Anal. Calcd for C84H72O15: C, 76.35; H, 5.49. Found: C, 76.12; H,
5.62.
Star 2d
Purification by flash chromatography (CH2Cl2–cyclohexane–
EtOAc, 4:5:1) afforded pure 2d as a colorless solid; yield: 335 mg
(90%); mp 59–60 °C; Rf = 0.43 (CH2Cl2–cyclohexane–EtOAc,
80:16:4).
13C NMR (50 MHz, CDCl3): d = 165.9, 163.3, 159.4, 149.9, 139.9,
136.0, 132.9, 131.7, 131.2, 129.8, 129.5, 128.8, 128.4, 127.4, 121.4,
114.0, 88.2, 85.7, 81.1, 63.1, 57.8, 56.5, 55.3, 45.8 ppm.
MS (MALDI-TOF-MS): m/z = 1556.6 [(M + Na)+, 30], 1534.7
IR (neat): 2951, 2837, 1720, 1607, 1584, 1509 cm–1.
[(M + H)+, 40].
1H NMR (200 MHz, acetone-d6): d = 8.01 (d, J = 8.5 Hz, 6 H), 7.59
(d, J = 8.5 Hz, 6 H), 7.53 (s, 3 H), 7.45 (m, 12 H), 7.36 (d, J = 8.8
Hz, 6 H), 7.33 (d, J = 8.8 Hz, 12 H), 7.00 (d, J = 8.8 Hz, 6 H), 6.94
(d, J = 8.8 Hz, 6 H), 6.91 (d, J = 8.8 Hz, 6 H), 5.78 (s, 3 H), 5.70 (s,
3 H), 5.13 (s, 6 H), 4.47 (s, 6 H), 4.36 (s, 6 H), 3.91 (s, 9 H), 3.79 (s,
9 H), 3.78 (s, 9 H).
13C NMR (50 MHz, acetone-d6): d = 166.4, 160.2, 159.9, 158.9,
143.6, 138.8, 135.3, 134.8, 133.9, 132.4, 132.3, 130.7, 130.0, 129.3,
127.9, 129.05, 129.02, 127.7, 126.7, 122.5, 115.3, 114.5, 55.35,
114.3, 89.3, 86.4, 86.3, 85.8, 81.9, 81.6, 70.1, 56.8, 56.6, 55.31,
52.3.
Star 1d
To a solution of 3d (130 mg, 0.19 mmol), DMAP (1 mg, 0.006
mmol), and distilled Et3N (0.084 mL, 0.60 mmol) in anhyd CH2Cl2
(1 mL) was added a solution of 5 (16 mg, 0.06 mmol) in anhyd
CH2Cl2 (2 mL) at 0 °C under an inert atmosphere. The mixture was
stirred at r.t. and the progress of the reaction was monitored by TLC
analysis until complete consumption of 5 (6 h) before quenching
with aq NaHCO3 (1 mL). The organic layer was washed with brine
(0.5 mL), dried (Na2SO4), filtered, and concentrated under vacuum.
Purification by flash chromatography (CH2Cl2–cyclohexane–
EtOAc, 60:35:5) afforded pure 1d as a colorless solid; yield: 30 mg
(24%); mp 71 °C; Rf = 0.46 (CH2Cl2–cyclohexane–EtOAc,
80:16:4).
MS (ESI): m/z = 2091 (M + NH4)+, 1054 (M/2 + NH4)+.
Anal. Calcd for C135H114O21: C, 78.24; H, 5.54. Found: C, 77.84; H,
5.61.
IR (neat): 2952, 2837, 1721, 1607, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.18 (s, 3 H), 7.98 (d, J = 8.6 Hz,
6 H), 7.48 (d, J = 8.6 Hz, 6 H), 7.45 (d, J = 8.6 Hz, 6 H), 7.20–7.35
(m, 30 H), 6.88 (d, J = 8.6 Hz, 6 H), 6.87 (d, J = 8.6 Hz, 6 H), 5.72
(s, 3 H), 5.67 (s, 3 H), 4.37 (s, 12 H), 3.90 (s, 9 H), 3.79 (s, 9 H),
3.78 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 166.4, 163.2, 159.3, 149.8, 142.1,
140.0, 136.0, 133.0, 132.8, 131.8, 131.6, 131.2, 129.8, 129.4, 128.8,
128.4, 127.0, 127.3, 121.8, 121.3, 114.0, 88.2, 86.4, 85.7, 85.2,
81.3, 80.7, 56.5, 55.2, 52.2.
Star 2b
To a suspension of NaH (60%, 22 mg, 0.55 mmol) in anhyd THF
(1.6 mL) was added a solution of 3b (210 mg, 0.5 mmol) in anhyd
DMF (1.6 mL) under an inert atmosphere. After 30 min, a solution
of 6 (60 mg, 0.16 mmol) was added. The mixture was stirred at r.t.
and the progress of the reaction was monitored by TLC analysis un-
til complete consumption of 6 (16 h) before quenching with H2O
(0.5 mL). The aqueous layer was extracted with EtOAc (3 × 1 mL).
The combined organic layers were washed with brine (1 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. Purification by
flash chromatography (CH2Cl2–cyclohexane–EtOAc, 5:4:1) afford-
ed pure 2b as a colorless oil; yield: 50 mg (22%); Rf = 0.45
(CH2Cl2–cyclohexane–EtOAc, 5:4:1).
MS (MALDI-TOF-MS): m/z = 2152.7 [(M + K)+, 50], 2136.8 (M +
Na)+.
Anal. Calcd for C135H108O24: C, 76.69; H, 5.15. Found: C, 75.94; H,
5.22.
IR (neat): 3000, 2800, 1721, 1608, 1522, 1509 cm–1.
Stars 2a and 2d; General Procedure
1H NMR (200 MHz, CDCl3): d = 7.96 (d, J = 8.2 Hz, 6 H), 7.47 (d,
J = 8.2 Hz, 6 H), 7.42 (s, 3 H), 7.29 (d, J = 8.6 Hz, 6 H), 7.21 (d,
J = 8.8 Hz, 6 H), 6.92 (d, J = 8.6 Hz, 6 H), 6.69 (d, J = 8.8 Hz, 6 H),
5.58 (s, 3 H), 5.04 (s, 6 H), 4.35 (s, 6 H), 3.89 (s, 9 H), 2.91 (s, 18 H).
13C NMR (50 MHz, CDCl3): d = 166.4, 158.0, 150.1, 137.9, 134.6,
131.6, 129.4, 128.9, 129.6, 128.4, 127.6, 125.8, 114.6, 112.4, 88.9,
85.2, 81.5, 69.7, 56.2, 52.1, 40.5.
A suspension of 6 (1 equiv), 3a, or 3d (3.6 equiv), K2CO3 (6 equiv),
KI (2.7 equiv), and Aliquat 336 (cat.) in anhyd acetone (0.05 M, 11
mL) was stirred at 60 °C and the progress of the reaction was mon-
itored by TLC analysis until complete consumption of 6 (36 to 48
h). The mixture was then concentrated under vacuum. The resulting
residue was dissolved in EtOAc (10 mL), the organic layer was
washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), filtered,
and concentrated under vacuum.
MS (MALDI-TOF): m/z = 1382.3 (M + Na)+, 1359.4 (M + H)+.
Anal. Calcd for C87H81N3O12: C, 76.80; H, 6.00; N, 3.09. Found: C,
75.56; H, 6.13; N, 2.76.
Star 2a
Purification by flash chromatography afforded pure 2a as a color-
less solid; yield: 584 mg (80%); mp 40–42 °C; Rf = 0.46 (CH2Cl2–
cyclohexane–EtOAc, 6:3:1).
IR (neat): 2950, 2837, 1719, 1607, 1585, 1508 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.97 (d, J = 8.2 Hz, 6 H), 7.48 (d,
J = 8.2 Hz, 6 H), 7.42 (s, 3 H), 7.27 (d, J = 8.8 Hz, 12 H), 6.92 (d,
J = 8.8 Hz, 6 H), 6.87 (d, J = 8.8 Hz, 6 H), 5.61 (s, 3 H), 5.03 (s, 6
H), 4.35 (s, 6 H), 3.89 (s, 9 H), 3.76 (s, 9 H).
Compound 16
To a solution of 2-piperazin-1-ylethanol (9.25 g, 71 mmol) were
added at 0 °C formic acid (8.03 mL, 213 mmol), and then slowly
formaldehyde (16.85 mL, 213 mmol). After 20 min at 0 °C, the
mixture was heated at 80 °C for 2 days before quenching with H2O
(5 mL) and concentration under vacuum. The resulting residue was
dissolved in CH2Cl2 (6 mL), dried (Na2SO4), filtered, and concen-
trated under vacuum. Purification by flash chromatography
(CH2Cl2–MeOH–Et3N, 8:1:1) afforded the pure alcohol 16 as a col-
Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York

PAPER
Poly(aryl propargyl ether) Stars
1059
orless oil; yield: 5.4 g (53%); bp 55 °C/1.5 mm Hg; Rf = 0.51
(CH2Cl2–MeOH–Et3N, 8:1:1).
IR (neat): 3222, 2937, 2692 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.59 (t, J = 5.4 Hz, 2 H), 2.53 (t,
J = 5.4 Hz, 2 H), 2.45 (m, 8 H), 2.27 (s, 3 H).
(d, J = 8.6 Hz, 6 H), 6.89 (d, J = 8.6 Hz, 6 H), 5.68 (s, 3 H), 5.13 (s,
6 H), 4.41 (t, J = 5.8 Hz, 6 H), 4.38 (s, 6 H), 3.76 (s, 9 H), 2.74 (t,
J = 5.8 Hz, 6 H), 2.58 (m, 12 H), 2.44 (m, 12 H), 2.22 (s, 9 H).
13C NMR (50 MHz, acetone-d6): d = 166.1, 160.2, 159.2, 139.1,
135.5, 135.0, 132.6, 131.1, 130.3, 129.30, 129.27, 128.3, 126.9,
115.6, 114.6, 89.8, 85.9, 82.2, 70.4, 63.4, 57.3, 56.9, 55.7, 55.6,
53.7, 45.9.
13C NMR (50 MHz, CDCl3): d = 61.6, 59.4, 54.9, 52.8, 45.8.
MS (MALDI-TOF-MS): m/z = 1695.7 (M + K)+, 1680.7 (M + Na)+,
Anal. Calcd for C7H16N2O: C, 58.30; H, 11.18. Found: C, 58.19; H,
11.31.
1657.7 (M + H)+.
Anal. Calcd for C102H108N6O15: C, 73.89; H, 6.57. Found: C, 73.08;
H, 6.81.
Transesterification Reaction of 2a and 2d; General Procedure
A solution of 2a or 2d and Ti(Oi-Pr)4 (15 mol%) in 15, 16, or 17
(0.15 M) was heated at 130 °C and the progress of the reaction was
monitored by TLC analysis until complete consumption of the start-
ing material (15–30 min to 2 h) before quenching with H2O (0.2
mL). The aqueous layer was extracted with CH2Cl2 (2 × 0.5 mL).
The combined organic layers were washed with brine (3 × 0.2 mL),
dried (Na2SO4), filtered, concentrated under vacuum, and purified
by flash chromatography.
Star 2g
Colorless oil; yield: 30 mg (84%); Rf = 0.21 (CH2Cl2–cyclohexane–
EtOAc, 3:6:1).
IR (neat): 3000, 2853, 1719, 1607, 1509 cm–1.
1H NMR (400 MHz, acetone-d6): d = 8.02 (d, J = 8.2 Hz, 6 H), 7.57
(d, J = 8.2 Hz, 6 H), 7.53 (s, 3 H), 7.32 (d, J = 8.6 Hz, 12 H), 6.99
(d, J = 8.6 Hz, 6 H), 6.90 (d, J = 8.6 Hz, 6 H), 5.80 (m, 9 H), 5.68
(s, 3 H), 5.25 (dd, J = 17.3, 1.6 Hz, 9 H), 5.13 (s, 6 H), 5.09 (dd,
J = 10.5, 1.6 Hz, 9 H), 4.38 (s, 12 H), 3.96 (d, J = 5.2 Hz, 18 H),
3.76 (s, 9 H), 3.57 (s, 18 H).
13C NMR (100 MHz, acetone-d6): d = 166.0, 160.1, 159.2, 139.0,
136.1, 135.4, 134.9, 132.5, 131.1, 130.3, 129.2, 128.1, 126.9, 116.4,
115.5, 114.5, 89.7, 85.8, 82.1, 72.8, 70.3, 70.0, 65.3, 56.8, 55.5,
45.5.
Star 2c
Colorless oil; yield: 60 mg (89%); Rf = 0.32 (EtOAc–Et3N–MeOH,
8:1:1).
IR (neat): 2947, 2772, 1715, 1607, 1585, 1509 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.90 (d, J = 8.4 Hz, 6 H), 7.39 (d,
J = 8.4 Hz, 6 H), 7.35 (s, 3 H), 7.20 (d, J = 8.8 Hz, 12 H), 6.85 (d,
J = 8.8 Hz, 6 H), 6.79 (d, J = 8.8 Hz, 6 H), 5.54 (s, 3 H), 4.97 (s, 6
H), 4.34 (t, J = 5.8 Hz, 6 H), 4.27 (s, 6 H), 3.70 (s, 9 H), 2.63 (t,
J = 5.8 Hz, 6 H), 2.25 (s, 18 H).
13C NMR (50 MHz, CDCl3): d = 165.9, 159.1, 158.2, 137.9, 134.1,
133.5, 131.6, 129.8, 129.5, 128.5, 127.4, 125.9, 114.7, 113.8, 88.5,
85.5, 81.2, 69.7, 63.1, 57.8, 56.4, 55.2, 45.8.
MS (MALDI-TOF-MS): m/z = 2032 (M + K)+, 2016 (M + Na)+.
Anal. Calcd for C123H132O24: C, 74.08; H, 6.67. Found: C, 73.58; H,
6.89.
Star 2h
MS (ESI): m/z = 1491.4 (M + H)+.
A suspension of 2a (28 mg, 0.021 mmol), K2CO3 (10 mg, 0.0069
mmol), and 18 (8 mg, 0.07 mmol) in anhyd DMSO (0.2 mL) was
stirred at 60 °C and the progress of the reaction was monitored by
TLC analysis until complete consumption of 2a (16 h). The mixture
was filtered and the filtrate concentrated under vacuum. The result-
ing residue was suspended in MeOH (1 mL) and filtered. The result-
ing solid was suspended in acetone (1 mL), filtered, and the filtrate
was concentrated under vacuum to afford 2h as a colorless oil;
yield: 25 mg (71%).
Anal. Calcd for C93H93N3O15: C, 74.83; H, 6.28. Found: C, 73.78;
H, 5.61.
Star 2e
Colorless oil; 49 mg (95%); Rf = 0.37 (EtOAc–Et3N–MeOH, 8:1:1).
IR (neat): 2960, 2771, 1717, 1608, 1585, 1510 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.90 (d, J = 8.3 Hz, 6 H), 7.39 (d,
J = 8.3 Hz, 6 H), 7.34 (m, 12 H), 7.26 (s, 3 H), 7.18 (d, J = 8.7 Hz,
18 H), 6.84 (d, J = 8.7 Hz, 6 H), 6.79 (d, J = 8.7 Hz, 6 H), 6.77 (d,
J = 8.7 Hz, 6 H), 5.55 (s, 6 H), 4.96 (s, 6 H), 4.34 (t, J = 5.8 Hz, 6
H), 4.28 (s, 6 H), 4.24 (s, 6 H), 3.69 (s, 9 H), 3.68 (s, 9 H), 2.63 (t,
J = 5.8 Hz, 6 H), 2.25 (s, 18 H).
13C NMR (50 MHz, CDCl3): d = 165.9, 159.4, 159.1, 158.2, 142.0,
137.9, 134.2, 133.7, 132.8, 131.8, 131.6, 129.8, 129.5, 128.7, 128.6,
127.3, 127.0, 125.9, 122.0, 114.7, 114.0, 113.8, 88.2, 86.1, 85.7,
85.5, 81.3, 80.9, 69.7, 63.1, 57.8, 56.5, 55.2, 45.8.
IR (neat): 3385, 3000, 2800, 1642, 1607, 1585, 1529, 1508 cm–1.
1H NMR (400 MHz, acetone-d6): d = 7.84 (d, J = 8.4 Hz, 6 H), 7.53
(d, J = 8.4 Hz, 6 H), 7.51 (s, 3 H), 7.40 (br s, 1 H, NH), 7.31 (d,
J = 8.6 Hz, 12 H), 6.98 (d, J = 8.6 Hz, 6 H), 6.89 (d, J = 8.6 Hz, 6
H), 5.67 (s, 3 H), 5.12 (s, 6 H), 4.50 (br s, 1 H, OH), 4.37 (s, 6 H),
3.81 (s, 18 H), 3.76 (s, 9 H).
13C NMR (100 MHz, acetone-d6): d = 168.2, 166.0, 160.1, 160.1,
159.1, 139.0, 135.6, 135.4, 134.9, 132.4, 129.2, 128.2, 126.9, 126.7,
115.5, 114.5, 88.9, 85.8, 82.1, 70.3, 63.5, 63.2, 56.8, 55.5.
MS (MALDI-TOF-MS): m/z = 2280.9 (M + K)+, 2264.9 (M + Na)+.
MS (MALDI-TOF-MS): m/z = 1625.8 (M + K)+, 1609.9 (M + Na)+.
Anal. Calcd for C144H135N3O21: C, 77.09; H, 6.06. Found: C, 76.28;
H, 6.61.
Anal. Calcd for C93H93N3O21: C, 70.31; H, 5.90. Found: C, 69.88;
H, 6.21.
Star 2f
Purification by flash chromatography afforded 2f as a colorless oil;
yield: 20 mg (54%); Rf = 0.25 (EtOAc–Et3N–MeOH, 8:1:2).
Acknowledgment
The CNRS is gratefully acknowledged for support of this research
and the Ministère de la Recherche for a doctoral fellowship to N.L.
IR (neat): 2935, 2798, 2359, 1717, 1608, 1585, 1509 cm–1.
1H NMR (200 MHz, acetone-d6): d = 7.99 (d, J = 8.2 Hz, 6 H), 7.55
(d, J = 8.2 Hz, 6 H), 7.52 (s, 3 H), 7.31 (d, J = 8.6 Hz, 12 H), 7.00
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to be more appropriate than the term ‘dendrimer’ to
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Synthesis 2008, No. 7, 1049–1060 © Thieme Stuttgart · New York