Synthesis of Linear and Tripoidal Oligo(phenylene ethynylene)-Based Building Blocks for Application in Modular DNA-Programmed Assembly

Article abstract of DOI:10.1021/jo035764m

Rigid linear and tripoidal organic modules based on the oligo(phenylene ethynylene) backbone having salicylaldehyde-derived termini are synthesized. A highly functionalized 5-iodosalicyl aldehyde was prepared and coupled to each ethynyl group of 1,4-diethynylbenzene or 1,3,5-triethynylbenzene in Sonogashira couplings. The two or three termini of the compounds are functionalized for incorporation in linear and branched oligonucleotide strands. For the linear module (LM), the two termini are equipped with amide spacers, and one of these was functionalized with a DMTr (dimethoxytrityl)-protected hydroxy group and the other with a phosphoramidite. One of the tripoidal modules is prepared with DMTr groups in two of its three termini. A tripoidal module is also synthesized with three different groups on its hydroxy termini: a phosphoramidite, a DMTr group, and an Fmoc group. Extended studies have shown that these rigid linear and tripoidal organic modules can be incorporated into short oligonucleotides. Several of these modules can be applied for DNA-directed assembly and covalent coupling into structures of predetermined connectivity. Such structures have potential application for molecular electronics and nanotechnology.

Full text of DOI:10.1021/jo035764m

Syn th esis of Lin ea r a n d Tr ip oid a l Oligo(p h en ylen e
eth yn ylen e)-Ba sed Bu ild in g Block s for Ap p lica tion in Mod u la r
DNA-P r ogr a m m ed Assem bly
Morten Nielsen,† Anne H. Thomsen,† Emiliano Clo´,† Finn Kirpekar,‡ and Kurt V. Gothelf*,†
Center for Catalysis and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry,
Langelandsgade 140, Aarhus University, 8000 Aarhus C, Denmark, and Department of Biochemistry and
Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
kvg@chem.au.dk
Received December 2, 2003
Rigid linear and tripoidal organic modules based on the oligo(phenylene ethynylene) backbone
having salicylaldehyde-derived termini are synthesized. A highly functionalized 5-iodosalicyl
aldehyde was prepared and coupled to each ethynyl group of 1,4-diethynylbenzene or 1,3,5-
triethynylbenzene in Sonogashira couplings. The two or three termini of the compounds are
functionalized for incorporation in linear and branched oligonucleotide strands. For the linear
module (LM), the two termini are equipped with amide spacers, and one of these was functionalized
with a DMTr (dimethoxytrityl)-protected hydroxy group and the other with a phosphoramidite.
One of the tripoidal modules is prepared with DMTr groups in two of its three termini. A tripoidal
module is also synthesized with three different groups on its hydroxy termini: a phosphoramidite,
a DMTr group, and an Fmoc group. Extended studies have shown that these rigid linear and
tripoidal organic modules can be incorporated into short oligonucleotides. Several of these modules
can be applied for DNA-directed assembly and covalent coupling into structures of predetermined
connectivity. Such structures have potential application for molecular electronics and nanotech-
nology.
In tr od u ction
backbone and have salicylaldehyde-derived termini. The
modules are programmed by short oligonucleotides at-
tached to each of the two and three termini of the linear
and tripoidal modules, respectively. Complementary oli-
gonucleotides at different LOMs and/or TOMs can as-
semble multiple modules in a specific predetermined
manner. Subsequent addition of ethylenediamine and a
metal salt such as Mn(OAc)2 will form metal-salen
complexes between salicylaldehyde groups, which are
held in close proximity by the attached DNA chains.
Metal-salen formation is restricted to take place at
positions between two salicylaldehyde groups attached
to hybridized oligonucleotide strands.
Molecular electronics have been subject to growing
interest during the past few years due to the increased
search for alternatives to silicon-based electronics.1 The
synthesis and testing of individual molecular electronic
components have been reported;2 however, the major
obstacle to the economical production of single molecule-
based electronics is our inability to connect molecular
electronic components to form circuits.
In a separate paper, we reported on a new bottom-up
method for the programmed assembly and formation of
covalent bonds between multiple organic modules.3 The
basic building blocks are a rigid linear oligonucleotide-
functionalized module (LOM) and a tripoidal oligonucle-
otide-functionalized module (TOM) (Scheme 1). These
modules are based on an oligo(phenylene ethynylene)
We report here on the synthesis of the linear and
tripoidal modules, which are functionalized as phos-
phoramidites for being incorporating into oligonucleotide
chains.
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Phone: +45
89423907. Fax: +45 8619619
The aim of the following work is to make molecular
building blocks, which can assemble and couple co-
valently into predetermined and geometrically well-
defined macromolecular matrix, locked in a planar
structure. Further demands on the system are that the
individual building blocks and the covalent interconnec-
tion between them must be conducting or semiconducting
because of their potential use in molecular electronics.
The modules should be linear or planar tripoidal and the
functionality, which connects them, should be linear.
Finally, the cross-linking reaction should be compatible
with the conditions under which DNA can hybridize.4
† Aarhus University.
‡ University of Southern Denmark.
(1) J oachim, C.; Gimzewski, J . K.; Aviram, A. Nature 2000, 408, 541.
(2) See, e.g.: (a) Tour, J . M. Acc. Chem. Res. 2002, 33, 791. (b) Reed,
M. A.; Chen, J .; Rawlett, A. M.; Price, D. W.; Tour, J . M. Appl. Phys.
Lett. 2001, 78, 3735. (c) Collier, C. P.; Mattersteig, G.; Wong, E. W.;
Luo, Y.; Beverly, K.; Sampaio, J .; Raymo, F. M.; Stoddart, J . F.; Heath,
J . R. Science 2000, 289, 1172. (d) Park, J .; Pasupathy, A. N.; Goldsmith,
J . I.; Chang, C.; Yaish, Y.; Petta, J . R.; Rinkoski, M.; Sethna, J . P.;
Abruna, H. D.; McEuen, P. L.; Ralph, D. C. Nature 2002, 417, 722. (e)
Liang, W.; Shores, M. P.; Bockrath, M.; Long, J . R.; Park, H. Nature
2002, 417, 725. (f) Mitchell, R. H.; Ward, T. R.; Wang, Y.; Dibble, P.
W. J . Am. Chem. Soc. 1999, 121, 2601.
(3) Gothelf, K. V.; Thomsen, A. H.; Nielsen, M.; Clo´, E.; Brown, R.
S. J . Am. Chem. Soc. 2004, 126, 1044.
10.1021/jo035764m CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
2240
J . Org. Chem. 2004, 69, 2240-2250

Synthesis of Linear and Tripoidal Organic Modules
SCHEME 1. Ba sic Str u ctu r e of LOM a n d TOM
Mod u les a n d Th eir Molecu la r Recogn ition a n d
DNA-Dir ected Cou p lin g Rea ction In d u ced by
An n ea lin g a n d Ad d ition of Eth ylen ed ia m in e a n d
The oligonucleotide-functionalized linear module contains
a salicylaldehyde-derived terminus, obtained from the
corresponding DMTr- and phoshoramidite-functionalized
organic module (Scheme 2). In this precursor, the alde-
hyde and phenol functionalities are protected since they
are not compatible with oligonucleotide synthesis.4a This
intermediate compound is obtained from the central 1,4-
diethynylbenzene and two identical 5-iodosalicylaldehyde
derivatives. We have previously reported on the synthesis
of oligo(phenylene ethynylene)-derivatized salicylalde-
hydes and salen complexes.6
a
Mn (OAc)2
In our first approach, the spacer between the oligo-
nucleotide chains and the organic modules was based on
an ester functionality. This synthesis was initiated with
the synthetic sequence illustrated in Scheme 3. The
5-iodosalicylic acid 1 was formylated in a Duff reaction7
by treatment with hexamethylenetetramine in TFA at
90 °C in a closed vessel. Hydrolysis of the iminium
intermediate was facilitated by stirring the adduct in 1
N HCl for 5 h to give 2 in 60% conversion, along with an
impurity of 3,5-diiodosalicylic acid. As previously reported
by Ruel et al., the outcome of this reaction was highly
dependent on the temperature.8 When the reaction was
carried out at a lower temperature decreased conversion
was observed, while raising the temperature above 90
°C lead to increased amounts of the byproduct. Due to
the high polarity of 2, flash chromatography proved
difficult and the crude product was treated directly with
1,3-propanediol to provide after recrystallization the
acetal 3 in 44% yield from 1. Bromopropanol was
protected with dimethoxytrityl chloride in a DMAP-
catalyzed reaction to give 4 in 83% yield. Compound 4
was subsequently reacted with 3 and triethylamine to
facilitate the ester 5 in 63% yield, which in the next step
was protected at the phenol position with a benzoyl
group. A study by Czlapinski and Sheppard revealed that
the benzoyl group was suitable for this purpose.4a After
benzoyl protection, the fully protected salicylaldehyde 6
was isolated in 81% yield.
The coupling between the central diethynylbenzene9
fragment and 2 equiv of the protected 5-iodosalicylalde-
hydes 6 was facilitated via a Sonogashira coupling with
bis(triphenylphosphine)palladium(II) chloride and copper
(4) For DNA-directed organic reactions, see: (a) Czlapinski, J . L.;
Sheppard, T. L. J . Am. Chem. Soc. 2001, 123, 8618. (b) Gartner, Z. J .;
Liu, D. R. J . Am. Chem. Soc. 2001, 123, 6961. (c) Gartner, Z. J .; Kanan,
M. W.; Liu, D. R. Angew. Chem., Int Ed. 2002, 41, 1796. (d) Gartner,
Z. J .; Kanan, M. W.; Liu, D. R. J . Am. Chem. Soc. 2002, 124, 10304.
(e) Calderone, C. T.; Puckett, J . W.; Gartner, Z. J .; Liu, D. R. Angew.
Chem., Int Ed. 2002, 41, 4104. (f) Gartner, Z.; Grubina, R.; Calderone,
C. T.; Liu, D. R. Angew. Chem., Int. Ed. 2003, 42, 1370. (g) Li, X.; Liu,
D. R. J . Am. Chem. Soc. 2003, 125, 10188. (h) Summerer, D.; Max, A.
Angew. Chem., Int. Ed. 2002, 41, 89. (i) Eckardt, L. H.; Naumann, K.;
Pankau, W. M.; Rein, M.; Schweitzer, M.; Windhab, N.; von Kiedrowski,
G. Nature 2002, 420, 286.
(5) Shortell, D. B.; Palmer, L. C.; Tour, J . M. Tetrahedron, 2001,
57, 9055. (b) Bunz, U. H. F. Acc. Chem. Res. 2001, 34, 998. (c) Huang,
S.; Tour, J . M. Tetrahedron Lett. 1999, 40, 3347. (d) J ones, L., II;
Schumm, J . S.; Tour, J . M. J . Org. Chem. 1997, 62, 1388.
(6) (a) Nielsen, M.; Gothelf, K. V. J . Chem. Soc., Perkin Trans. 1
2001, 2440. (b) Nielsen, M.; Larsen, N. B.; Gothelf, K. V. Langmuir
2002, 18, 2795.
a
Color code: LOMs (blue) and TOMs (red) are assembled by
hybridization of complementary oligonucleotides (black curved
lines) and coupled by ethylenediamine and Mn(OAc)2 (green cross).
(7) Duff, J . C.; Bills, E. J . J . Chem. Soc. 1932, 1987.
To form rigid and potentially conducting structures,
the backbone of the modules is based on oligo(phenylene
ethynylene)s as shown for the linear module in Scheme
2. Oligo(phenylene ethynylene)s have previously been
extensively studied and applied as molecular wires.2a,5
(8) Ruell, J . A.; De Clerq, E.; Pannecouque, C.; Witvrouw, M.; Stup,
T. L.; Turpin, J . A.; Buckheit, R. W.; Cushman, M. J . Org. Chem. 1999,
64, 5858.
(9) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627. (b) Yu, C. J .; Chong, Y.; Kayyem, J . F.; Gozin, M.
J . Org. Chem. 1999, 64, 2070.
J . Org. Chem, Vol. 69, No. 7, 2004 2241

Nielsen et al.
SCHEME 2
SCHEME 3
It was attempted to incorporate the linear module 9
in the middle of a DNA strand consisting of 30 bases.
The automated synthesis was performed using the phos-
phoramidite method12 using benzoyl protecting groups for
the amide groups in A, C, and G. The ester spacer used
in 9 was, however, not compatible with the reaction
conditions used for deprotection of the benzoyl groups.
The treatment of the crude DNA-synthesis product with
aqueous ammonia at 50 °C for 2 h led to complete
cleavage of the oligonucleotide into fragments containing
15 bases as verified by polyacrylamide gel electrophore-
sis.13
To increase the stability of the spacer between the
oligonucleotide chain and the organic module, the syn-
thesis of a module containing the more stable amide
spacer was consequently pursued. The synthesis was
initiated from intermediate 3, which was benzoyl pro-
tected and subsequently coupled with either 3-amino-
propanol or N-methyl-3-aminopropanol to provide the
amides 10a and 10b in moderate to good yields from 3
(Scheme 5).14 The terminal hydroxy group was protected
with a DMTr group to give 11a and 11b in excellent
yields.
The backbone of the new linear module was assembled
by a Sonogashira coupling of 11a or 11b with diethynyl-
benzene to give 12a and 12b (Scheme 6). Contrary to the
Sonogashira reactions of the ester analogues, no loss of
the DMTr protecting groups was observed in the syn-
thesis of 12a and 12b. Consequently, it was necessary
to selectively replace one of the DMTr groups with the
phosphoramidite group. Due to hindered rotation around
iodide as the catalysts (Scheme 4).6,10 The coupling
reaction proceeded in an overall yield of 79%, but
surprisingly two products were observed. These were the
expected product 7 and a product 8 carrying only one
DMTr group. From TLC analysis, it was evident that the
DMTr group was cleaved off during the reaction and not
in the weakly acidic extraction or chromatographic
separation. In several repetitions, the reaction still gave
the unexpected, however convenient, single deprotection
of one of the DMTr groups with identical ratios of 7 and
8. The synthesis of the desired linear module 9 was
completed by attachment of a phosphoramidite at the free
hydroxyl group.11
(11) (a) Asseline, U.; Thuong, N. T. Tetrahedron Lett. 1994, 35, 5221.
(b) Curran, D. P.; Sun, S. Tetrahedron Lett. 1993, 34, 6189. (c) Wang,
G.; Bergstrom, D. E. Tetrahedron Lett. 1993, 34, 6721. (d) Kojima, Y.;
Haruta, A.; Imai, T.; Otagiri, M.; Maeda, H. Bioconjugate Chem. 1993,
4, 499.
(12) Brown T.; Brown, D. J . S. In Oligonucleotides and Analogues:
A Practical Approach; Eckstein, F., Ed.; IRL Press: Oxford, 1991; pp
1-24.
(13) This problem could be circumvented by applying other protect-
ing groups for the bases in the DNA synthesis such as TBPA (4-tert-
butylphenoxyacetyl), which could be removed by aqueous ammonia at
room temperature. Under these conditions the desired oligonucleotide
containing 15 bases on each side of the linear module could be obtained.
(14) Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993, 34,
7685.
(10) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Sonogashira, K. In Comprehensive Organic Syn-
thesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3; pp 521-549.
2242 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of Linear and Tripoidal Organic Modules
SCHEME 4
SCHEME 5
1,3,5-triethynylbenzene to give 15a in 37% yield as shown
in Scheme 7. The similar reaction of 11b was also tested
and gave a slightly higher yield of 15b, compared to the
synthesis of 15a . Again, the N-methylamides gave rise
to complex mixtures of isomers and thereby a difficult
characterization. Further syntheses of the TMs were as
a consequence based on only the primary amides arising
from 11a . Compound 15a was subjected to mono-depro-
tection of one DMTr group by treating with 50% AcOH
in CH2Cl2 for 8 min. The yield of the monohydroxy
product 16 was rather low (28%) accompanied with 8%
of the dihydroxy adduct 17. More than 50% of unreacted
15a was recovered and applied in repeated deprotections.
To obtain the symmetric tripoidal compound, function-
alized for automated DNA synthesis, the free hydroxy
group of compound 16 was converted into a phosphora-
midite to give 18 in a high yield of 89%.
the amide bonds in 12b, the even distribution of E/ Z-
isomers gave rise to very complex 1H and 13C NMR
spectra of the N-methylamides. Thus, the final steps were
performed with 12a only. The deprotection of 12a was
achieved by treatment with acetic acid to give 13 in 60%
yield. The following treatment with the required phos-
phoramidite chloride provided the desired linear module
14 in an 85% yield.
The next target was to synthesize the tripoidal modules
(TM), which are based on a central 1,3,5-trisubstituted
benzene containing three phenylacetylene moieties.15
This type of molecule will function as planar three-way
branch points in the macromolecular networks. The
synthesis of both symmetric and asymmetric TMs was
initiated by the Sonogashira coupling between 11a and
To obtain a tripoidal module to which three different
nucleotide chains can be attached by automated DNA
synthesis, each of the three ends has to be functionalized
with different groups,16 and for this purpose we have
chosen the phosphoramidite, DMTr, and Fmoc groups.
This was obtained by protecting the free hydroxyl group
in 16 with FmocCl, and the protected product 19 was
obtained in 74% yield.17 Mono-deprotection of 19 was
performed in 50% AcOH in CH2Cl2 for 10 min. The yield
of 20 in this step was only 25%; however, more than 50%
of the starting material was recovered. Finally, the
(16) Shchepinov, M. S.; Southern, E. M. Russ. J . Bioorg. Chem. 1998,
24, 794.
(17) (a) J ohnson, T.; Quibell, M.; Owen, D.; Sheppard, R. C. J . Chem.
Soc., Chem. Commun. 1993, 369. (b) Seela, F.; Wenzel, T. Helv. Chim.
Acta 1992, 75, 1111.
(15) (a) Weber, E.; Hecker, M.; Koepp, E.; Orlia, W.; Czugler, M.;
Cso¨regh, I. J . Chem. Soc., Perkin Trans. 2 1988, 1251.
J . Org. Chem, Vol. 69, No. 7, 2004 2243

Nielsen et al.
SCHEME 6
asymmetric tripoidal module 21 was obtained in 70%
Exp er im en ta l P r oced u r es
yield by converting 20 into the phosphoramidite (Scheme
8).
3-F or m yl-2-h yd r oxy-5-iod oben zoic Acid (2). A round-
bottomed flask equipped with a tight screw-cap lid was charged
with 2-hydroxy-5-iodobenzoic acid 1 (3.0 g, 11.3 mmol) under
argon. Hexamethylenetetramine (7.0 g, 49.9 mmol) and tri-
fluoroacetic acid (30 mL) were added, and the suspension was
stirred overnight at 90 °C in the closed flask. The reaction
mixture was poured into aqueous HCl (1 M, 60 mL) and stirred
for 5 h. The precipitate was filtered off, washed thoroughly
with aqueous HCl (1 M) and water ,and dried under vacuum.
The crude material was used directly in the following reaction.
Con clu sion
The synthesis of linear, symmetric tripoidal, and
asymmetric tripoidal modules, which can be applied in
automated DNA synthesis, has been demonstrated. The
linear module is functionalized as a nucleoside phos-
phoramidite and can be incorporated in an oligonucle-
otide strand by automated synthesis as we have shown
in a previous communication.3 The two tripoidal modules
are applied as the branch points in symmetric and
asymmetric branched oligonucleotides. These oligonucle-
otide-functionalized organic compounds have been ap-
plied for the directed formation of metal-salen links
between the individual compounds. By the functional-
ization with specific oligonucleotide sequences in each
terminal, these modules are programmed for salen
formation with other modules having complementary
oligonucleotide sequences. This method is applied for the
formation of predetermined nanostructures, which are
potential conductors.3
3-(1,3-Dioxa n -2-yl)-2-h yd r oxy-5-iod oben zoic Acid (3).
The crude product described above containing 2 (3.0 g) was
suspended in toluene (30 mL) in a round-bottomed flask and
then 1,3-propanediol (5.0 mL, 69 mmol) and H2SO4 (100 µL,
1.9 mmol). The reaction mixture was refluxed for 16 h, allowed
to cool to rt, and neutralized with saturated aqueous NaHCO3.
Water (20 mL) was added, and the mixture was extracted with
CH2Cl2 (5 × 20 mL). The combined organic fractions were
washed with water (20 mL), dried over MgSO4, and concen-
trated. The crude product was recrystallized twice from
mixtures of toluene and pentane to yield 3 as white crystals
(1.75 g, 44% from 1): mp 88-89 °C; 1H NMR (CDCl3, 400 MHz)
δ 1.39 (d, J ) 12.8, 1H), 1.91-2.06 (m, 1H), 3.89 (t, J ) 12.0,
2H), 4.08 (dd, J ) 11.2 Hz, J ) 4.4 Hz, 2H), 5.65 (s, 1H), 7.84
(d, J ) 2.0 Hz, 1H), 8.02 (d, J ) 2.0 Hz, 1H); 13C NMR (CDCl3,
2244 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of Linear and Tripoidal Organic Modules
SCHEME 7
100 MHz) δ 26.0, 67.5, 80.9, 95.3, 116.0, 129.9, 139.1, 141.6,
158.6, 171.5; HRMS calcd 372.9549 ([M + Na]+), found
372.9553.
rt for 4 h and poured into water (20 mL). The organic layer
was separated, and the aqueous phase was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic fractions were washed
with water (10 mL), dried over MgSO4, and concentrated. The
crude product was purified by flash chromatography on silica
gel (pentane/Et2O, 9:1) to yield 4 as a reddish solid (1.078 g,
83%): 1H NMR (CDCl3, 400 MHz) δ 2.04 (qui, J ) 6.2 Hz, 2H),
3.13 (t, J ) 6.2 Hz, 2H), 3.50 (t, J ) 6.8 Hz, 2H), 3.72 (s, 6H),
3-Br om o-1-(d im et h oxyt r it yloxy)p r op a n e (4). To
a
Schlenk flask charged with 3-bromo-1-propanol (256 µL, 2.95
mmol), DMTrCl (1.00 g, 2.95 mmol), and DMAP (36 mg, 0.30
mmol) in CH2Cl2 (10 mL) was added NEt3 (412 µL, 2.95 mmol)
dropwise while stirring. The reaction mixture was stirred at
J . Org. Chem, Vol. 69, No. 7, 2004 2245

Nielsen et al.
SCHEME 8
6.76 (d, J ) 6.4 Hz, 4H), 7.14-7.25 (m, 7H), 7.35 (d, J ) 6.4
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 31.2, 33.7, 55.6, 61.2,
92.3, 113.3, 127.9, 129.4, 130.3, 136.5, 145.3, 158.6; HRMS
calcd 463.0885 ([M + Na]+), found 463.0894.
benzoyl chloride (25 µL, 0.21 mmol). The reaction mixture was
stirred at rt for 3 min. It was then neutralized with aqueous
NH4OH (20 mL) and extracted with Et2O (3 × 15 mL). The
combined organic phases were dried over MgSO4 and concen-
trated. The crude product was purified by flash chromatogra-
phy on silica gel (CH2Cl2/MeOH, 99:1) to yield 6 as a colorless
oil (93 mg, 81%): 1H NMR (CDCl3, 400 MHz) δ 1.34 (d, J )
14.0 Hz, 1H), 1.74 (qui, J ) 5.7 Hz, 2H), 2.08-2.21 (m, 1H),
3.05 (t, J ) 6.0 Hz, 2H), 3.73-3.83 (m, 8H), 4.15 (dd, J ) 10.
4 Hz, J ) 3.6 Hz, 2H), 4.30 (t, J ) 6.4 Hz, 2H), 5.57 (s, 1H),
6.78 (dd, J ) 6.8 Hz, J ) 2.0 Hz, 2H), 6.83 (dd, J ) 6.8 Hz, J
) 2.0 Hz, 2H), 7.17 (dd, J ) 6.8 Hz, J ) 2.4 Hz, 2H), 7.23-
7.29 (m, 5H), 7.36 (d, J ) 7.2 Hz, 1H), 7.50 (t, J ) 7.6 Hz,
2H), 7.56 (d, J ) 7.6 Hz, 1H), 7.64 (t, J ) 7.6 Hz, 1H) 8.16 (d,
J ) 8.4 Hz, 2H), 8.22 (d, J ) 2.4 Hz, 1H), 8.25 (d, J ) 2.4 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 25.6, 29.2, 55.6, 59.5, 63.3,
67.7, 86.0, 90.0, 96.6, 113.3, 128.0, 128.2, 128.4, 129.3, 129.4,
130.1, 130.2, 130.2, 130.4, 130.5, 134.7, 136.5, 141.0, 141.1,
145.2, 158.6, 163.2, 164.6; HRMS calcd 837.1537 ([M + Na]+),
found 837.1552.
1,4-Bis[(4-b en zoyloxy-5-(3-d im et h oxyt r it yloxyp r op -
1-yloxy)ca r bon yl-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]ben -
zen e (7) a n d 1-[(4-Ben zoyloxy-5-(3-d im eth oxytr ityloxy-
p r op -1-yloxy)ca r b on yl-3-(1,3-d ioxa n -2-yl)p h e n yl)e t h -
ynyl]-4-[(4-benzoyloxy-5-(3-hydroxyprop-1-yloxy)carbonyl-3-
(1,3-dioxan -2-yl)-ph en yl)eth yn yl]ben zen e (8). To a Schlenk
flask charged with 6 (93 mg, 0.11 mmol) were added 1,4-
diethynylbenzene (6.9 mg, 0.055 mmol), bis(triphenylphos-
phine)palladium(ΙΙ) chloride (4.0 mg, 0.006 mmol), and copper
3-(Dim eth oxytr ityloxy)p r op -1-yl 3-(1,3-Dioxa n -2-yl)-2-
h yd r oxy-5-iod oben zoa te (5). To a Schlenk flask charged
with 3 (450 mg, 1.29 mmol) and 4 (600 mg, 1.36 mmol) in DMF
(2 mL) was added NEt3 (190 µL, 1.36 mmol) dropwise. The
reaction mixture was warmed to 40 °C and stirred for 16 h.
The DMF-water mixture was poured into water (10 mL) and
extracted with Et2O (3 × 10 mL). The combined organic
fractions were washed with water (10 mL), dried over MgSO4,
and concentrated. The crude product was purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 98:2) to yield 5
as a colorless oil (580 mg, 63%): 1H NMR (CDCl3, 400 MHz)
δ 1.45 (d, J ) 13.6 Hz, 1H), 2.03 (qui, J ) 6.0 Hz, 2H), 2.16-
2.29 (m, 1H), 3.24 (t, J ) 5.6 Hz, 2H) 3.75 (s, 6H), 4.01 (t, J )
12.0 Hz, 2H), 4.25 (dd, J ) 11.2 Hz, J ) 4.8 Hz, 2H), 4.48 (t,
J ) 6.4 Hz, 2H), 5.84 (s, 1H), 6.79 (d, J ) 6.79, 4H), 7.18 (t, J
) 9.2 Hz, 2H), 7.24-7.32 (m, 5H), 7.41 (d, J ) 7.6 Hz, 2H),
7.94 (d, J ) 2.4 Hz, 1H), 8.06 (d, J ) 2.4 Hz, 1H), 11.21 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 25.9, 29.3, 55.3, 59.3, 63.5,
67.8, 80.4, 86.2, 95.8, 113.3, 114.7, 127.1, 128.2, 128.4, 129.0,
130.2, 136.4, 138.8, 142.0, 142.2, 145.1, 158.6, 169.2; HRMS
calcd 733.1274 ([M + Na]+), found 733.1277.
3-(Dim eth oxytr ityloxy)p r op -1-yl 2-Ben zoyloxy-3-(1,3-
d ioxa n -2-yl)-5-iod oben zoa te (6). To a Schlenk flask charged
with 5 (100 mg, 0.14 mmol) dissolved in THF was added NaOH
(1 M, 210 µL, 0.21 mmol) followed by dropwise addition of
2246 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of Linear and Tripoidal Organic Modules
iodide (1.1 mg, 0.006 mmol), and the mixture was stirred under
vacuum for 30 min. NEt3 (5 mL) was added, and the reaction
mixture was stirred under argon at 53 °C for 19 h. The reaction
mixture was poured into 10% aqueous NH4Cl (10 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic
fractions were washed with water, dried over MgSO4, and
concentrated. The crude product was purified by flash chro-
matography on silica gel (Et2O/pentane, 9:1) to yield 7 as a
yellow oil (23 mg, 28%) and 8 as a yellow oil (34 mg, 51%). 7:
1H NMR (CDCl3, 400 MHz) δ 1.29 (d, J ) 12.4 Hz, 2H), 1.72
(qui, J ) 5.8 Hz, 4H), 2.04-2.17 (m, 2H), 3.02 (t, J ) 5.8 Hz,
4H), 3.67 (s, 12H), 3.76 (t, J ) 12.2 Hz, 4H), 4.12 (dd, J ) 11.2
Hz, J ) 4.4 Hz, 4H), 4.27 (t, J ) 6.4 Hz, 4H), 5.57 (s, 2H),
6.72 (d, J ) 8.8 Hz, 8H), 7.10 (t, J ) 7.4 Hz, 2H), 7.16-7.23
(m, 12H), 7.31 (d, J ) 7.2, 4H), 7.42-7.48 (m, 8H), 7.58 (t, J
) 7.4, 2H), 8.02 (d, J ) 2.4 Hz, 2H), 8.07 (d, J ) 2.4 Hz, 2H),
8.13 (d, J ) 7.6 Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 29.2,
30.0, 55.4, 59.5, 63.2, 67.7, 86.0, 90.0, 90.3, 97.1, 113.2, 121.4,
123.2, 124.6, 126.9, 128.0, 128.4, 128.9, 129.4, 130.2, 130.5,
131.9, 133.3, 133.9, 135.1, 135.5, 136.5, 145.2, 148.4, 158.6,
163.9, 164.7; HRMS calcd 1521.5399 ([M + Na]+), found
1521.5505. 8: 1H NMR (CDCl3, 400 MHz) δ 1.35 (d, J ) 13.6
Hz, 2H), 1.72-1.83 (m, 4H), 2.10-2.24 (m, 2H), 3.09 (t, J )
5.8 Hz, 2H), 3.61 (q, J ) 5.6 Hz, 2H), 3.74 (s, 6H), 3.83 (t, J )
12.8 Hz, 4H), 4.18 (dd, J ) 4.2, J ) 11.8, 4H), 4.33 (t, J ) 6.2
Hz, 4H), 5.64 (s, 1H), 5.65 (s, 1H), 6.79 (d, J ) 8.8 Hz, 4H),
7.17 (t, J ) 6.8 Hz, 1H), 7.22-7.34 (m, 6H), 7.38 (d, J ) 3.6
Hz, 2H), 7.48-7.59 (m, 8H), 7.62-7.71 (m, 2H), 8.09 (d, J )
2.4 Hz, 1H), 8.10 (d, J ) 2.4 Hz, 1H), 8.13 (d, J ) 2.4 Hz, 1H),
8.20 (d, J ) 7.8 Hz, 2H), 8.22 (d, J ) 2.4 Hz, 1H), 8.25 (d, J )
7.8 Hz, 2H); 13C NMR (CDCl3, 100 Hz) δ 29.9, 30.5, 31.7, 55.4,
59.1, 59.5, 62.4, 63.2, 66.1, 67.7, 86.0, 89.9, 90.0, 90.2, 90.4,
97.1, 113.2, 121.4, 121.6, 123.1, 123.2, 124.6, 126.9, 128.0,
128.3, 128.9, 129.0, 129.4, 130.2, 130.5, 131.9, 133.3, 133.9,
134.1, 135.0, 135.2, 135.5, 136.5, 145.2, 148.2, 148.4, 158.5,
163.9, 164.5, 164.7, 164.8; HRMS calcd 1219.4092 ([M + Na]+),
found 1219.4094.
flask charged with 3 (513 mg, 1.47 mmol) dissolved in CH2Cl2
(20 mL) was added benzoyl chloride (170 µL, 1.47 mmol), and
the mixture was cooled to 0 °C. Pyridine (237 µL, 2.93 mmol)
was slowly added to the reaction mixture, which was allowed
to warm to rt and stirred for 3 h under argon. 3-Amino-1-
propanol (183 µL, 2.39 mmol) was then added before the
mixture again was cooled to 0 °C. EDC (458 mg, 2.39 mmol)
was added to the reaction mixture, which was allowed to warm
to rt and stirred for 4 h under argon. The reaction mixture
was poured into water (20 mL) and extracted with CH2Cl2 (3
× 20 mL). The combined organic fractions were washed with
water, dried over MgSO4, and concentrated. The crude product
was purified by flash chromatography on silica gel (EtOAc/
pentane, 1:1 f EtOAc/pentane, 7:3) to yield 10a as white
1
crystals (374 mg, 50%): mp 64-66 °C; H NMR (CDCl3, 400
MHz) δ 1.23 (d, J ) 13.6 Hz, 1H), 1.43 (qui, J ) 5.8 Hz, 2H),
1.95-2.10 (m, 1H), 2.62 (t, J ) 6.2 Hz, 1H), 3.35 (q, J ) 6.1
Hz, 2H), 3.43 (q, J ) 5.7 Hz, 2H), 3.66 (t, J ) 11.0 Hz, 2H),
4.02 (dd, J ) 4.8 Hz, J ) 11.2 Hz, 2H), 5.46 (s, 1H), 6.44-6.54
(m, 1H), 7.48 (t, J ) 7.6 Hz, 2H), 7.62 (t, J ) 7.4 Hz, 1H), 7.93
(d, J ) 2.4 Hz, 1H), 8.03 (d, J ) 2.4 Hz, 1H), 8.13 (d, J ) 8.2
Hz, 2H);13C NMR (CDCl3, 100 MHz) δ 25.5, 32.3, 36.9, 59.4,
67.6, 90.9, 97.0, 128.7, 129.1, 130.4, 132.4, 133.9, 134.5, 138.7,
138.9, 145.6, 165.3, 165.7; HRMS calcd 534.0390 ([M + Na]+),
found 534.0400.
1-Ben zoyloxy-6-(1,3-d ioxa n -2-yl)-2-[N-(3-h yd r oxyp r op -
1-yl)-N-m eth yla m in oca r bon yl]-4-iod oben zen e (10b). To a
Schlenk flask charged with 3 (150 mg, 0.43 mmol) dissolved
in CH2Cl2 (6 mL) was added benzoyl chloride (48 µL, 0.45
mmol) and the mixture was cooled to 0 °C. Pyridine (71 µL,
0.88 mmol) was slowly added to the reaction mixture, which
was allowed to warm to rt and stirred for 3 h under argon.
N-Methyl-3-amino-1-propanol (62 mg, 0.70 mmol) was then
added before the mixture again was cooled to 0 °C. EDC (124
mg, 0.65 mmol) was added to the reaction mixture, which was
allowed to warm to rt and stirred for 4 h under argon. The
reaction mixture was poured into water (15 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic fractions were
washed with water, dried over MgSO4, and concentrated. The
crude product was purified by flash chromatography on silica
gel (EtOAc/pentane, 1:1 f EtOAc/pentane, 7:3) to yield 10b
as white crystals (121 mg, 54%): 1H NMR (CDCl3, 400 MHz)
δ 1.25 (d, J ) 13.6 Hz), 1.58 (qui, J ) 5.8 Hz), 1.98-2.10 (m),
2.85 (s, 2. diastereomer), 2.88 (s, 1. diastereomer), 3.23 (q, J
) 5.9 Hz), 3.35 (t, J ) 6.8 Hz), 3.40-3.54 (m), 3.68 (t, J )
11.0 Hz), 3.98-4.08 (m), 5.47 (s, 2 diastereomer), 5.50 (s, 1
diastereomer), 7.45 (t, J ) 8.0 Hz), 7.56-7.62 (m), 8.02 (d, J
) 2.0 Hz), 8.09 (d, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ
25.6, 29.3, 30.5, 32.5, 37.2, 43.7, 48.1, 58.0, 59.5, 67.6, 90.3,
96.9, 125.8, 128.8, 129.0, 130.4, 133.0, 134.3, 134.4, 136.7,
137.7, 145.4, 164.6, 167.5; HRMS calcd 548.0546 ([M + Na]+),
found 548.0564.
1-[(4-Ben zoyloxy-5-(3-dim eth oxytr ityloxypr op-1-yloxy)-
ca r b on yl-3-(1,3-d ioxa n -2-yl)p h en yl)et h yn yl]-4-[(4-b en -
zoyloxy-5-(3-(2-cya n oeth oxy-N,N-d iisop r op yla m in op h os-
p h a n yloxy)p r op -1-yloxy)ca r b on yl-3-(1,3-d ioxa n -2-yl)-
p h en yl)eth yn yl]ben zen e (9). To a Schlenk flask charged
with 8 (67 mg, 0.056 mmol) dissolved in THF (5 mL) was added
diisopropylethylamine (49 µL, 0.28 mmol), and the solution
was cooled to 0 °C. 2-Cyanoethyl diisopropylchlorophosphora-
midite (44 µL, 0.20 mmol) was added dropwise while stirring.
The reaction mixture was stirred under argon at rt for 16 h.
The reaction was quenched by addition of MeOH (0.5 mL), and
the solvent was removed by vacuum distillation. The resulting
oil was dissolved in EtOAc and washed with 5.5% aqueous
NaHCO3 (2 × 10 mL), washed with water (10 mL), dried over
MgSO4, and concentrated. The crude product was purified by
flash chromatography on silica gel (EtOAc/pentane/NEt3, 4:5:1
f EtOAc/NEt3, 9:1) to yield 9 as a yellow oil (41 mg, 52%):
1H NMR (CDCl3, 400 MHz) δ 1.14-1.31 (m, 14H), 1.74 (qui, J
) 7 Hz, 4H), 2.02-2.18 (m, 2H), 2.51 (t, J ) 6.4 Hz, 2H), 2.58
(t, J ) 7.2 Hz, 2H), 3.02 (t, J ) 5.6 Hz, 2H), 3.44-3.55 (m,
4H), 3.67 (s, 6H), 3.76 (t, J ) 11.8 Hz, 4H), 4.10 (dd, J ) 4.4
Hz, J ) 11.2 Hz, 4H), 4.19-4.29 (m, 4H), 5.566 (s, 1H), 5.572
(s, 1H), 6.71 (d, J ) 8.8 Hz, 4H), 7.09 (t, J ) 7.4 Hz, 1H), 7.15-
7.22 (m, 6H), 7.31 (d, J ) 7.6 Hz, 2H), 7.40-7.52 (m, 8H),
7.54-7.62 (m, 2H), 8.02 (s, 2H), 8.06 (d, J ) 2 Hz, 1H), 8.13
(d, J ) 7.6 Hz, 2H), 8.15 (d, J ) 2.4 Hz, 1H), 8.18 (d, J ) 7.4
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.3, 23.6, 24.5, 27.9,
29.1, 42.0, 54.1, 57.4, 58.2, 58.9, 61.3, 61.9, 66.5, 84.8, 88.7,
88.8, 88.97, 89.00, 95.9, 112.0, 113.1, 120.1, 120.2, 121.9, 122.0,
123.3, 125.6, 126.7, 127.1, 127.6, 127.7, 128.2, 128.9, 129.2,
130.6, 132.0, 132.1, 132.6, 132.7, 133.8, 133.9, 134.2, 135.3,
144.0, 147.1, 147.2,157.3, 162.6, 163.4; HRMS calcd 1419.5171
([M + Na]+), found 1419.5170.
1-Ben zoyloxy-2-(N-(3-d im et h oxyt r it yloxyp r op -1-yl)-
a m in oca r bon yl)-6-(1,3-d ioxa n -2-yl)-4-iod oben zen e (11a ).
To a Schlenk flask charged with 10a (374 mg, 0.73 mmol)
dissolved in CH2Cl2 (15 mL) were added DMTrCl (452 mg, 1.33
mmol) and DMAP (16 mg, 0.13 mmol). Finally, NEt3 (210 µL,
1.51 mmol) was added, and the reaction mixture was stirred
under argon at rt for 4 h. The reaction mixture was poured
into water (15 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic fractions were washed with water (10
mL), dried over MgSO4, and concentrated. The crude product
was purified by flash chromatography on silica gel (EtOAc/
pentane/NEt3, 40:59:1) to yield 11a as yellow crystals (494 mg,
1
83%): mp 78-90 °C; H NMR (CDCl3, 400 MHz) δ 1.23 (d, J
) 13.0 Hz, 1H), 1.55 (qui, J ) 6.1 Hz, 2H), 1.96-2.10 (m, 1H),
2.99 (t, J ) 5.6 Hz, 2H), 3.29 (q, J ) 6.4 Hz, 2H), 3.66 (t, J )
11.4 Hz, 2H), 3.70 (s, 6H), 4.02 (dd, J ) 5.0, 11.0 Hz, 2H),
5.46 (s, 1H), 6.37 (t, J ) 5.4 Hz, 1H), 6.70 (d, J ) 8.8 Hz, 4H),
7.12-7.19 (m, 7H), 7.28 (d, J ) 8.4 Hz, 2H), 7.43 (t, J ) 7.8
Hz, 2H), 7.59 (t, J ) 7.4 Hz, 1H), 7.83 (d, J ) 2.0 Hz, 1H),
8.02 (d, J ) 2.4 Hz, 1H), 8.04 (d, J ) 8.2 Hz, 2H); 13C NMR
1-Ben zoyloxy-6-(1,3-d ioxa n -2-yl)-2-(N-(3-h yd r oxyp r op -
1-yl)a m in oca r bon yl-4-iod oben zen e (10a ). To a Schlenk
J . Org. Chem, Vol. 69, No. 7, 2004 2247

Nielsen et al.
(CDCl3, 100 MHz) δ 25.6, 29,5, 38.4, 55.5, 61.8, 67.6, 86.4, 90.8,
97.0, 113.3, 127.0, 128.1, 128.3, 128.9, 129.0, 130.1, 130.5,
132.9, 133.9, 134.2, 136.3, 138.5, 138.6, 144.9, 145.6, 158.6,
164.5, 164.8; HRMS calcd 836.1696 ([M + Na]+), found
836.1794.
chromatography on silica gel (EtOAc/pentane, 1:1 f EtOAc/
pentane, 7:3) to yield 12b as a yellow foam (99 mg, 64%): 1H
NMR (CDCl3, 400 MHz) δ 1.32 (d, J ) 12.4 Hz), 1.74 (q, J )
7.0 Hz, 1 diastereomer), 1.80-1.89 (m, 2 diastereomer), 2.02-
2.20 (m), 2.90 (s, 2 diastereomer), 2.93 (s, 1 diastereomer), 3.03
(t, J ) 5.2 Hz), 3.50 (t, J ) 7.8 Hz), 3.72-3.82 (m), 4.08-4.16
(m), 5.61 (s, 2 diastereomer), 5.63 (s, 1 diastereomer), 6. 82 (d,
J ) 8.8 Hz), 7.16-7.32 (m), 7.34-7.43 (m), 7.46-7.54 (m), 7.63
(t, J ) 7.2 Hz), 7.92-7.96 (m), 8.17 (d, J ) 7.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 25.7, 27.6, 29.3, 32.8, 37.8, 45.3, 49.0, 55.4,
60.9, 61.0, 67.6, 67.7, 86.1, 86.3, 90.1, 90.3, 97.4, 97.5, 113.3,
121.4, 121.5, 123.2, 126.9, 128.0, 128.3, 128.4, 128.9, 129.1,
130.1, 130.2, 130.5, 130.8, 131.0, 131.6, 131.9, 132.7, 132.8,
134.0, 136.5, 136.6, 145.2, 145.26, 145.31, 158.6, 164.5, 164.6,
166.7, 167.2.
1-Ben zoyloxy-2-(N-(3-d im eth yloxytr ityloxyp r op -1-yl)-
N-m eth yla m in oca r bon yl)-6-(1,3-d ioxa n -2-yl)-4-iod oben -
zen e (11b). To a Schlenk flask charged with 10b (120 mg,
0.23 mmol) dissolved in CH2Cl2 (5 mL) were added DMTrCl
(116 mg, 0.34 mmol) and DMAP (4 mg, 0.034 mmol). Finally,
NEt3 (51 µL, 0.36 mmol) was added, and the reaction mixture
was stirred under argon at rt for 4 h. The reaction mixture
was poured into water (10 mL) and extracted with CH2Cl2 (3
× 10 mL). The combined organic fractions were washed with
water (10 mL), dried over MgSO4, and concentrated. The crude
product was purified by flash chromatography on silica gel
(EtOAc/pentane/NEt3, 35:64:1) to yield 11b as yellow crystals
(163 mg, 87%): 1H NMR (CDCl3, 400 MHz) δ 1.22 (d, J ) 13.6
Hz), 1.60 (qui, J ) 6.9 Hz, 1 diastereomer), 1.66-1.78 (m, 2
diastereomer), 1.94-2.09 (m), 2.78 (s, 2 diastereomer), 2.80
(s, 1 diastereomer), 2.88-2.97 (m), 3.32-3.41 (m), 3.62-3.72
(m), 3.96-4.05 (m), 5.46 (s, 2 diastereomer), 5.47 (s, 1 diaste-
reomer), 6.70-6.75 (m), 7.09-7.22 (m), 7.28 (t, J ) 6.6 Hz),
7.37-7.43 (m), 7.47 (d, J ) 2.0 Hz, 1 diastereomer), 7.50-
7.56 (m, 2 diastereomer), 7.97 (d, J ) 1.6 Hz, 1 diastereomer),
7.99 (d, J ) 1.8 Hz, 2 diastereomer), 8.02-8.07 (m); 13C NMR
(CDCl3, 100 MHz) δ 25.7, 27.6, 29.3, 32.8 37.7, 45.3, 48.9, 55.5,
60.9, 61.0, 67.6, 86.0, 86.3, 90.3, 90.4, 96.9, 97.0, 113.3, 113.4,
127.0, 128.0, 128.1, 128.3, 128.4, 128.9, 129.0, 130.2, 130.5,
133.5, 133.6, 134.1, 134.3, 136.5, 136.6, 136.7, 137.3, 137.4,
145.1, 145.2, 145.3, 158.6, 164.3, 164.4, 165.8, 166.3; HRMS
calcd 850.1853 ([M + Na]+), found 850.1817.
1,4-Bis[(4-ben zoyloxy-5-(N-(3-d im eth oxytr ityloxyp r op -
1-yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]-
ben zen e (12a ). Bis(triphenylphosphine)palladium(ΙΙ) chloride
(111 mg, 0.16 mmol) and copper iodide (30 mg, 0.16 mmol)
were stirred in a Schlenk flask under vacuum for 30 min, after
which 11a (1.35 g, 1.66 mmol), 1,4-diethynylbenzene (100 mg,
0.79 mmol), and THF (18 mL) were added. Finally, NEt3 (7
mL) was added, and the reaction mixture was stirred under
argon at 53 °C for 16 h. The reaction mixture was poured into
saturated aqueous NaCl (25 mL) and extracted with Et2O (3
× 25 mL). The combined organic fractions were washed with
water (25 mL), dried over MgSO4, and concentrated. The crude
product was purified by flash chromatography on silica gel
(EtOAc/pentane, 1:1 f EtOAc/pentane, 7:3) to give 12a as a
yellow solid (753 mg, 64%): mp 118-120 °C; 1H NMR (CDCl3,
400 MHz) δ 1.24 (d, J ) 13.6 Hz, 2H), 1.59 (qui, J ) 6.0 Hz,
4H), 1.96-2.10 (m, 2H), 3.02 (t, J ) 5.4 Hz, 4H), 3.32 (q, J )
6.0 Hz, 4H), 3.67 (s, 12H), 3.69 (t, J ) 11.6 Hz, 4H), 4.04 (dd,
J ) 4.6, 11.4 Hz, 4H), 5.52 (s, 2H), 6.42 (t, J ) 5.6 Hz, 2H),
6.70 (d, J ) 8.8, 8H), 7.08-7.21 (m, 14H), 7.30 (d, J ) 7.2 Hz,
4H), 7.41 (s, 4H), 7.43 (t, J ) 8.0 Hz, 4H), 7.58 (t, J ) 7.2 Hz,
2H), 7.66 (d, J ) 2.0 Hz, 2H), 7.89 (d, J ) 2 Hz, 2H), 8.08 (d,
J ) 7.8 Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 25.7, 29.5, 38.5,
55.4, 61.9, 67.6, 86.5, 90.1, 90.3, 97.5, 113.3, 121.7, 123.2, 127.0,
128.1, 128.4, 129.0, 129.1, 130.1, 130.5, 131.4, 131.9, 132.6,
132.7, 132.8, 134.1, 136.4, 145.0, 145.7, 158.6, 164.9, 165.4;
HRMS calcd 1519.5719 ([M + Na]+), found 1519.8694.
1-[(4-Ben zoyloxy-5-(N-(3-d im et h oxyt r it yloxyp r op -1-
yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]-4-
[(4-ben zoyloxy-5-(N-(3-h ydr oxypr op-1-yl)am in ocar bon yl)-
3-(1,3-d ioxa n -2-yl)p h en yl)et h yn yl]b en zen e (13). To a
Schlenk flask charged with 12a (103 mg, 0.069 mmol) dis-
solved in CH2Cl2 (5 mL) was added AcOH (5 mL), and reaction
mixture was stirred at rt for 55 min. The reaction mixture
was poured into 5.5% aqueous NaHCO3 (132 mL) to obtain a
pH value at 7 and then extracted with CH2Cl2 (3 × 20 mL).
The combined organic fractions were washed with water, dried
over MgSO4, and concentrated. The crude product was purified
by flash chromatography on silica gel (EtOAc/pentane, 8:2) to
1
yield 13 as a yellow solid (48 mg, 60%): mp 133-135 °C; H
NMR (CDCl3, 400 MHz) δ 1.32 (d, J ) 13.2 Hz, 2H), 1.53 (qui,
J ) 6.0 Hz, 2H), 1.66 (qui, J ) 6.0 Hz, 2H), 2.04-2.18 (m,
2H), 2.83 (t, J ) 6.2 Hz, 1H), 3.10 (t, J ) 5.4 Hz, 2H), 3.39 (q,
J ) 6.0 Hz, 2H), 3.44 (q, J ) 6.3 Hz, 2H), 3.52 (q, J ) 5.6 Hz,
2H), 3.75 (s, 6H), 3.76 (t, J ) 12.4 Hz, 4H), 4.11 (dd, J ) 4.4,
11.6 Hz, 4H), 5.58 (s, 2H), 6.50 (t, J ) 5.4 Hz, 1H), 6.59 (t, J
) 6.4 Hz, 1H), 6.76 (d, J ) 8.8 Hz, 4H), 7.16-7.28 (m, 7H),
7.36 (d, J ) 7.2 Hz, 2H), 7.49 (s, 4H), 7.50 (t, J ) 8.0 Hz, 2H),
7.56 (t, J ) 7.8 Hz, 2H), 7.66 (t, J ) 7.6 Hz, 1H), 7.69 (t, J )
7.6 Hz, 1H), 7.73 (d, J ) 2.0, 1H), 7.85 (d, J ) 2.4 Hz, 1H),
7.96 (d, J ) 2.4 Hz, 2H), 8.15 (d, J ) 7.6 Hz, 2H), 8.22 (d, J )
7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 25.6, 25.7, 29.5,
32.3, 36.8, 38.5, 55.4, 59,3, 61.9, 67.6, 86.5, 89.9, 90.2, 90.3,
90.5, 97.5, 113.3, 121.7, 122.0, 123.1, 123.3, 127.0, 128.1, 128.4,
128.8, 128.99, 129.05, 129.1, 130.1, 130.5, 131.0, 131.4, 131.9,
132.6, 132.7, 132.8, 132,9, 133.1, 134.1, 134.4, 136.4, 145.0,
145.6, 145.7, 158.6, 164.9, 165.4, 166.6; HRMS calcd 1217.4412
([M + Na]+), found 1217.5266.
1-[(4-Ben zoyloxy-5-(N-(3-d im et h oxyt r it yloxyp r op -1-
y l)a m i n o c a r b o n y l)-3-(1,3-d i o x a n -2-y l)p h e n y l)e t h -
ynyl]-4-[(4-benzoyloxy-5-(N-3-(2-cyanoethoxy-N,N-diisopropyl-
a m in op h osp h a n yloxy)p r op -1-yl)a m in oca r bon yl)-3-(1,3-
d ioxa n -2-yl)p h en yl)eth yn yl]ben zen e (14). The alcohol 13
(300 mg, 0.25 mmol) was stirred under vacuum in a Schlenk
flask for 45 min. CH2Cl2 (15 mL) and diisopropylethylamine
(175 µL, 1.00 mmol) were added, and the solution was quickly
cooled to 0 °C. 2-Cyanoethyl diisopropylchlorophosphoramidite
(112 µL, 0.50 mmol) was added dropwise, and the reacting
mixture was stirred at rt for 30 min under argon. The reacting
mixture was washed with 5.5% aqueous NaHCO3 (4 × 12 mL)
and brine (4 × 12 mL). The organic layer was dried over
MgSO4 and concentrated. The crude product was purified by
precipitation in pentane to yield 14 as yellow crystals (299 mg,
1,4-Bis[(4-b e n zoyloxy-5-(N -(3-(d im e t h oxyt r it yloxy-
prop-1-yl)-N-methylaminocarbonyl)-3-((1,3)-dioxan-2-yl)phen-
yl)eth yn yl]ben zen e (12b). Bis(triphenylphosphine)palladium-
(ΙΙ) chloride (14 mg, 0.020 mmol) and copper iodide (4 mg,
0.020 mmol) were stirred in a Schlenk flask under vacuum
for 30 min, after which 12b (176 mg, 0.21 mmol), 1,4-
diethynylbenzene (13 mg, 0.10 mmol), and THF (6 mL) were
added. Finally, NEt3 (4 mL) was added, and the reaction
mixture was stirred under argon at 53 °C for 16 h. The reaction
mixture was poured into saturated aqueous NaCl (10 mL) and
extracted with Et2O (3 × 10 mL). The combined organic
fractions were washed with water (10 mL), dried over MgSO4,
and concentrated. The crude product was purified by flash
1
85%): mp 109-111 °C; H NMR (CDCl3, 400 Hz) δ 1.07 (d, J
) 7.2 Hz, 6H), 1.10 (d, J ) 7.2 Hz, 6H), 1.25 (d, J ) 13.6 Hz,
2H), 1.54-1.66 (m, 4H), 1.98-2.12 (m, 2H), 2.47 (t, J ) 6.6
Hz, 2H), 3.03 (t, J ) 5.8 Hz, 2H), 3.28-3.39 (m, 4H), 3.43-
3.55 (m, 4H), 3.56-3.75 (m, 12H), 4.01-4.08 (m, 4H), 5.52 (s,
2H), 6.41 (t, J ) 5.6 Hz, 1H), 6.51 (t, J ) 5.8 Hz, 1H), 6.71 (d,
J ) 8.8 Hz, 4H), 7.09-7.21 (m, 7H), 7.30 (d, J ) 7.2 Hz, 2H),
7.42 (s, 4H), 7.44 (t, J ) 8.0 Hz, 2H), 7.48 (t, J ) 8.4 Hz, 2H),
7.59 (t, J ) 7.6 Hz, 1H), 7.61 (t, J ) 7.6 Hz, 1H), 7.66 (d, J )
2.0 Hz, 1H), 7.76 (d, J ) 2.0 Hz, 1H), 7.89 (s, 2H), 8.08 (d, J
) 7.8 Hz, 2H), 8.16 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 100
2248 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of Linear and Tripoidal Organic Modules
MHz) δ 19.3, 23.6, 24.4, 28.2, 29.4, 36.5, 37.2, 41.9, 54.2, 57.2,
57.4, 60.6, 66.4, 85.2, 88.8, 88.9, 89.0, 89.1, 96.2, 112.1, 116.8,
120.4, 120.5, 121.9, 122.0, 125.8, 126.8, 127.1, 127.7, 127.8,
128.8, 129.2, 129.3, 130.1, 130.6, 131.3, 131.40, 131.44, 131.5,
131.6, 132.9, 133.0, 135.1, 143.7, 144.4, 144.5, 157.4, 163.6,
163.8, 164.1, 164.2; HRMS calcd 1417.5490 ([M + Na]+), found
1417.1564.
in CH2Cl2 (15 mL) was added dropwise glacial AcOH (15 mL).
The reaction mixture was stirred for 8 min, quickly diluted
with CH2Cl2 (50 mL) ,and neutralized with saturated NaHCO3.
The organic layer was washed with water (3 × 80 mL), dried
over MgSO4, and concentrated. The crude hydrolyzed mixture
was purified by flash chromatography on silica gel (CH2Cl2/
EtOAc, 85:15 f 60:40 f 0:100) to yield unhydrolyzed 15a (248
mg, 0112 mmol), 16 (118 mg, 28%), and 17 (27 mg, 7.6%). 16:
1H NMR (CDCl3, 400 MHz) δ 1.23 (d, J ) 12.8 Hz, 3H), 1.48
(qui, J ) 6.4 Hz, 2H), 1.60 (qui, J ) 6.4 Hz, 4H), 1.99-2.12
(m, 3H), 2.99 (t, J ) 6.4 Hz, 4H), 3.29-3.42 (m, 6H), 3.47 (q,
J ) 5.1 Hz, 2H), 3.67 (s, 12H), 3.70 (t, J ) 12.0 Hz, 6H), 4.04
(dd, J ) 11.2, 5.2 Hz, 6H), 5.53 (s, 3H), 6.42 (t, J ) 5.2 Hz,
2H), 6.51 (t, J ) 6.2 Hz, 1H), 6.70 (d, J ) 8.8 Hz, 8H), 7.12-
7.19 (m, 14H), 7.30 (d, J ) 8.4 Hz, 4H), 7.42-7.51(m, 6H),
7.55-7.62 (m, 6H), 7.67 (d, J ) 2.2 Hz, 2H), 7.78 (d, J ) 2.2
Hz, 1H), 7.91 (d, J ) 2.2 Hz, 3H), 8.09 (d, J ) 8.4 Hz, 4H),
8.16 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 25.3,
25.4, 29.2, 32.1, 36.5, 83.2, 55.2, 59.1, 61.6, 67.3, 86.2, 88.6,
88.8, 89.0, 89.2, 97.1, 97.2, 113.1, 121.1, 121.4, 123.6, 123.7,
126.7, 127.8, 128.1, 128.6, 128.7, 128.8, 129.8, 130.2, 130.8,
131.2, 132.3, 132.4, 132.5, 132.6, 132.7, 133.0, 133.8, 134.1,-
134.3, 136.1, 144.7, 145.5, 145.6, 158.4, 164.6, 165.1, 166.4;
MALDI-TOF MS calcd 1926.71 ([M + Na]+), found 1926.56.
17: 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, J ) 12.8 Hz, 3H),
1.48 (qui, J ) 6.4 Hz, 4H), 1.60 (qui, J ) 6.4 Hz, 2H), 1.99-
2.12 (m, 3H), 2.99 (t, J ) 6.4 Hz, 2H), 3.29-3.40 (m, 6H), 3.47
(s, br, 4H), 3.67 (s, 6H), 3.70 (t, J ) 12.0 Hz, 6H), 4.04 (dd, J
) 11.2, 5.2 Hz, 6H), 5.53 (s, 3H), 6.46 (t, J ) 5.2 Hz, 1H), 6.58
(t, J ) 6.2 Hz, 2H), 6.70 (d, J ) 8.8 Hz, 8H), 7.12-7.19 (m,
7H), 7.30 (d, J ) 8.4 Hz, 2H), 7.42-7.51 (m, 6H), 7.55-7.62
(m, 6H), 7.67 (d, J ) 2.2 Hz, 1H), 7.78 (d, J ) 2.2 Hz, 2H),
7.91 (d, J ) 2.2 Hz, 3H), 8.09 (d, J ) 8.4 Hz, 2H), 8.16 (d, J )
8.0 Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 25.4, 25.8, 28.8,
29.2, 32.0, 36.5, 38.2, 55.1, 59.0, 61.6, 67.3, 67.5, 86.1, 88.6,
88.7, 89.0, 89.2, 97.1, 113.0, 113.1, 120.9, 121.1, 121.2, 123.6,
123.7, 123.8, 123.9, 126.7, 126.9, 127.8, 127.9, 128.0, 128.4,
128.6, 128.7, 128.8, 129.5, 129.8, 130.2, 130.6, 131.0, 132.3,
132.4, 132.5, 132.5, 132.9, 133.2, 133.8, 134.0, 134.3, 135.0,
135.0, 135.9, 136.1, 144.7, 145.5, 145.6, 158.3, 158.3, 158.4,
164.6, 165.0. 165.2, 166.3; MALDI-TOF MS calcd 1624.58 ([M
+ Na]+), found 1624.30.
1,3-Bis[(4-ben zoyloxy-5-(N-(3-d im eth oxytr ityloxyp r op -
1-yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]-
5-[(4-b en zoyloxy-5-(N-(3-(2-cya n oet h oxy-N,N-d iisop r o-
p yla m in op h osp h a n yloxy)p r op -1-yl)a m in oca r b on yl)-3-
(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]ben zen e (18). The alcohol
16 (42.7 mg, 0.022 mmol) was a stirred under vacuum in a
Schlenk flask for 45 min. CH2Cl2 (3 mL) and diisopropylethy-
lamine (15.6 µL, 0.09 mmol) were added, and the solution was
quickly cooled to 0 °C. 2-Cyanoethyl diisopropylchlorophos-
phoramidite (10 µL, 0.045 mmol) was added dropwise, and the
reacting mixture was stirred at rt for 30 min under argon. The
reacting mixture was diluted with CH2Cl2 (5 mL) and washed
with saturated NaHCO3 (4 × 4 mL) and brine (4 × 4 mL).
The organic layer was dried over MgSO4 and concentrated.
The crude product was purified by precipitation in pentane to
yield 18 as yellow crystals (41.6 mg, 89%): 1H NMR (CDCl3,
400 MHz) δ 1.03-1.11 (m, 12H), 1.23 (d, J ) 12.8 Hz, 3H),
1.55-1.75 (m, 6H), 1.98-2.12 (m, 3H), 2.48 (t, J ) 7 Hz, 2H),
2.99 (t, J ) 6.4 Hz, 4H), 3.27-3.42 (m, 8H), 3.41-3.57 (m, 2H),
3.67 (s, 12H), 3.70 (t, J ) 12.0 Hz, 6H), 4.04 (dd, J ) 11.2 Hz,
J ) 5.2 Hz, 6H), 5.53 (s, 3H), 6.42 (t, J ) 5.2 Hz, 2H), 6.51 (t,
J ) 6.2 Hz, 1H), 6.70 (d, J ) 8.8 Hz, 8H), 7.12-7.19 (m, 14H),
7.30 (d, J ) 8.4 Hz, 4H), 7.42-7.51 (m, 6H), 7.55-7.62 (m,
6H), 7.67 (d, J ) 2.2 Hz, 2H), 7.78 (d, J ) 2.2 Hz, 1H), 7.91 (d,
J ) 2.2 Hz, 3H), 8.09 (d, J ) 8.4 Hz, 4H), 8.16 (d, J ) 8.0 Hz,
2H); 31P NMR δ 148.90.
1,3,5-Tr is[(4-ben zoyloxy-5-(N-3-dim eth oxytr ityloxypr op-
1-yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]-
ben zen e (15a ). Bis(triphenylphospine)palladium(II) chloride
(148 mg, 0.211 mmol) and copper iodide (40 mg, 0.211 mmol)
were stirred in a Schlenk flask under vacuum for 30 min. Then
11a (3.44 g, 4.23 mmol), triethynylbenzene (159 mg, 1.06
mmol), and THF (90 mL) were added. Finally, NEt3 (22.5 mL)
was added, and the reaction mixture was stirred under argon
at 52 °C for 16 h. The reaction mixture was diluted with CH2-
Cl2 (100 mL) and then washed with water (3 × 100 mL) and
brine (100 mL). The organic layer was dried over MgSO4 and
concentrated. The crude product was purified by flash chro-
matography on silica gel (CH2Cl2/EtOAc, 90:10) to yield
unreacted 11a (1.06 g, 1.30 mmol) and 15a as a white foam
(866 mg, 37%): 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, J ) 12.8
Hz, 3H), 1.55 (qui, J ) 6.4 Hz, 6H), 1.99-2.12 (m, 3H), 2.99
(t, J ) 6.4 Hz, 6H), 3.29 (q, J ) 6.0 Hz, 6H), 3.67 (s, 18H), 3.7
(t, J ) 12.0 Hz, 6H), 4.04 (dd, J ) 11.2, 5.2 Hz, 6H), 5.53 (s,
3H), 6.42 (t, J ) 5.2 Hz, 3H), 6.70 (d, J ) 8.8 Hz, 12H), 7.12-
7.19 (m, 21H), 7.30 (d, J ) 8.4 Hz, 6H), 7.44 (t, J ) 7.6 Hz,
6H), 7.55 (s, 3H), 7.59 (t, J ) 7.6 Hz, 3H), 7.67 (d, J ) 2.2 Hz,
3H), 7.91 (d, J ) 2.2 Hz, 3H), 8.09 (d, J ) 8.4 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) δ 25.7, 29.5, 38.5, 55.4, 61.9, 67.6,
86.5, 88.8, 89.5, 113.4, 121.4, 127.0, 128.1, 128.4, 129.0, 129.1,
130.1, 130.5, 131.5, 132.7, 132.8, 132.9, 134.1, 134.6, 136.4,
145.0, 145.9, 158.6, 164.9, 165.4; MALDI-TOF MS calcd
2228.84 ([M + Na]+), found 2228.75.
1,3,5-T r is [(4-b e n zo y lo x y -5-(N -(3-d im e t h o x y t r it y l-
oxyp r op -1-yl)-N-m eth yla m in oca r bon yl)-3-(1,3-d ioxa n -2-
yl)p h en yl)eth yn yl]ben zen e (15b). Bis(triphenylphosphine)-
palladium(II) chloride (7.7 mg, 0.011 mmol) and copper iodide
(2.1 mg, 0.011 mmol) were stirred in a Schlenk flask under
vacuum for 30 min. Compound 11b (174 mg, 0.21 mmol),
triethynylbenzene (8.0 mg, 0.053 mmol), and THF (8 mL) were
added. Finally, NEt3 (0.4 mL) was added, and the reaction
mixture was stirred under argon at 52 °C for 16 h. The reaction
mixture was diluted with CH2Cl2 (10 mL) and then washed
with water (3 × 10 mL) and brine (10 mL). The organic layer
was dried over MgSO4 and concentrated. The crude product
was purified by flash chromatography on silica gel (EtOAc/
pentane/NEt3, 60:40:1) to yield unreacted 11b (46.2 mg, 0.056
mmol) and 15b as white foam (62.3 mg, 46%): 1H NMR
(CDCl3, 400 MHz) δ 1.24 (d, J ) 12.6 Hz), 1.57 (qui, J ) 5.9
Hz), 1.99-2.12 (m), 2.82 (s, 1 diastereomer), 2.86 (s, 2
diastereomer), 2.95 (t, J ) 6.0 Hz), 3.37-3.45 (m), 3.64-3.71
(m), 4.04 (dd, J ) 11.2, 4.8 Hz), 5.54 (s, 1 diastereomer), 5.55
(s, 2 diastereomer), 6.72 (d, J ) 8.8 Hz), 7.12-7.19 (m), 7.27-
7.33 (m), 7.40-7.46 (m), 7.53-7.63 (m), 7.84-7.90 (m, 1 and
2 diastereomer), 8.06-8.12 (m, 1 and 2 diastereomer); 13C
NMR (CDCl3, 100 MHz) δ 25.4, 27.3, 29.1, 32.5, 37.4, 44.9,
48,6, 55.1, 55.7, 60.6, 60.7, 67.2, 67.3, 85.7, 85.9, 88.1, 88.4,
89.1, 89.5, 97.0, 97.1, 112.9, 113.0, 120.6, 120.8, 123.6, 123.7,
126.6, 127.7, 128.0, 128.4, 128.5, 128.6, 128.7, 128.8, 129.8,
130.2, 130.5, 130.6. 130.7, 131.5, 131.6, 131.7, 131.8, 131.9,
132.0, 132.5, 133.7, 134.3, 135.0, 136.2, 144.8, 145.0, 158.3,
164.1, 164.2, 166.3, 166.8.
1,3-Bis[(4-ben zoyloxy-5-(N-3-d im eth oxytr ityloxyp r op -
1-yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]-
5-[(4-ben zoyloxy-5-(N-(3-h yd r oxyp r op -1-yl)a m in oca r bo-
n yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]ben zen e (16) a n d
1,3-Bis[(4-ben zoyloxy-5-(N-(3-h ydr oxypr op-1-yl)am in ocar -
b on yl)-3-(1,3-d ioxa n -2-yl)p h en yl)et h yn yl]-5-[(4-b en zoy-
loxy-5-(N-3-dim eth oxytr ityloxypr op-1-yl)am in ocar bon yl)-
3-(1,3-dioxan -2-yl)ph en yl)eth yn yl]ben zen e (17). To a round-
bottomed flask charged with 15a (485 mg, 0.22 mmol) dissolved
1,3-Bis[(4-ben zoyloxy-5-(N-3-d im eth oxytr ityloxyp r op -
1-y l)a m in o c a r b o n y l)-3-(1,3-d io x a n -2-y l)p h e n y l)e t h -
yn yl]-5-[(4-ben zoyloxy-5-(N-3-(9-flu or oen ylm eth oxyca r -
bon yloxy)p r op -1-yl)a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)-
J . Org. Chem, Vol. 69, No. 7, 2004 2249

Nielsen et al.
p h en yl)eth yn yl]ben zen e (19). To a Schlenk flask charged
with 9-fluorenylmethyl chloroformate (64.2 mg, 0.25 mmol)
and N,N-dimethyl-4-aminopyridine (0.76 mg, 0.0062 mmol)
was added dropwise a solution of 16 (118 mg, 0.062 mmol) in
pyridine (4 mL). The reaction mixture was stirred at rt for 16
h under argon, diluted with CH2Cl2 (10 mL), and washed with
water (3 × 10 mL). The organic layer was dried over MgSO4
and concentrated. The crude product was purified by flash
chromatography on silica gel (CH2Cl2/EtOAc, 85:15) to yield
19 as white foam (98 mg, 74%): 1H NMR (CDCl3, 400 MHz) δ
1.23 (d, J ) 12.8 Hz, 3H), 1.60 (qui, J ) 6.4 Hz, 4H), 1.74
(qui, J ) 6.4 Hz, 2H), 2.01-2.10 (m, 3H), 2.99 (t, J ) 6.4 Hz,
4H), 3.30-3.37 (m, 6H), 3.67 (s, 12H), 3.70 (t, J ) 12.0 Hz,
6H), 4.01-4.09 (m, 8H), 4.15 (t, J ) 7.7 Hz, 1H), 4.30 (d, J )
7.7 Hz, 2H), 5.53 (s, 3H), 6.40-6.44 (m, 2H), 6.70 (d, J ) 8.8
Hz, 8H), 7.12-7.29 (m, 16H), 7.28-7.35 (m, 6H), 7.42-7.47
(m, 6H), 7.50-7.62 (m, 8H), 7.67 (d, J ) 2.2 Hz, 2H), 7.69 (d,
J ) 7.7 Hz, 2H), 7.78 (d, J ) 2.2 Hz, 1H), 7.91 (d, J ) 2.2 Hz,
3H), 8.09 (d, J ) 8.4 Hz, 4H), 8.16 (d, J ) 8.0 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 25.3, 25.4, 28.5, 29.2, 36.6, 38.2,
46.7, 55.2, 61.6, 65.5, 67.3, 69.8, 86.2, 88.6, 89.0, 89.2, 97.1,
97.2, 113.1, 120.0, 121.2, 121.4, 123.6, 123.7, 125.1, 126.7,
127.1, 127.8, 128.1, 128.6, 128.7, 128.8, 129.8, 130.9, 131.2,
132.3, 132.3, 132.5, 132.6, 133.0, 133.8, 134.0, 134.3, 136.1,
141.2, 143.3, 144.7, 145.6, 155.1, 158.3, 164.6, 164.9, 165.1,
165.4.
36.6, 38.2, 46.7, 55.1, 59.0, 61.6, 65.5, 67.3, 69.7, 86.2, 88.6,
88.7, 88.8, 88.9, 89.0, 89.2, 97.1, 97.2, 113.0, 120.0, 121.1, 121.3,
121.4, 123.6, 123.7, 125.1, 126.7, 127.1, 127.8, 128.0, 128.5,
128.6, 128.7, 128.8, 129.8, 130.2, 130.7, 130.8, 132.3, 132.4,
132.5, 132.5, 132.6, 132.9, 133.0, 133.8, 134.0, 134.1, 134.3,
136.1, 141.2, 143.2, 144.7, 145.5, 155.1, 158.3, 164.6, 165.1,
165.1, 165.4, 166.2.
1-[(4-Ben zoyloxy-5-(N-3-(d im et h oxyt r it yloxyp r op -1-
y l)a m i n o c a r b o n y l)-3-(1,3-d i o x a n -2-y l)p h e n y l)e t h -
yn yl]-3-[(4-ben zoyloxy-5-(N-(3-(9-flu or oen ylm eth oxyca r -
bonyl)prop-1-yl)aminocarbonyl)-3-(1,3-dioxan-2-yl)phenyl)-
e t h y n y l]-5-[(4-b e n z o y lo x y -5-(N -(3-(2-c y a n o e t h o x y -
N ,N -d i i s o p r o p y la m i n o p h o s p h a n y lo x y )p r o p -1-y l)-
a m in oc a r b on yl)-3-(1,3-d ioxa n -2-yl)p h e n yl)e t h yn yl]-
ben zen e (21). The alcohol 20 (25.5 mg, 0.014 mmol) was
stirred under vacuum in a Schlenk flask for 45 min. CH2Cl2
(1.5 mL) and diisopropylethylamine (9.75 µL, 0.056 mmol)
were added, and the solution was quickly cooled to 0 °C.
2-Cyanoethyl diisopropyl chlorophosphoramidite (6.25 µL,
0.028 mmol) was added dropwise, and the reacting mixture
was stirred at rt for 30 min under argon. The reacting mixture
was diluted with CH2Cl2 (3 mL), washed with saturated
NaHCO3 (2 × 4 mL) and brine (2 × 4 mL). The organic layer
was dried over MgSO4 and concentrated. The crude product
was purified by precipitation in pentane to yield 21 as yellow
crystals (19.8 mg, 70%): 1H NMR (CDCl3, 400 MHz) δ 1.12-
1.16 (m, 12H), 1.23 (d, J ) 12.8 Hz, 3H), 1.46 (qui, J ) 6.4 Hz,
2H), 1.60 (qui, J ) 6.4 Hz, 2H), 1.74 (qui, J ) 6.4, 2H), 1.99-
2.12 (m, 3H), 2.58 (t, 2H), 2.99 (t, J ) 6.4 Hz, 2H), 3.29-3.39
(m, 8H), 3.43-3.57 (m, 2H), 3.67 (s, 13H), 3.70 (t, J ) 12.0
Hz, 6H), 4.00-4.09 (m, 8H), 4.15 (t, J ) 7.7 Hz, 1H), 4.30 (d,
J ) 7.7 Hz, 2H), 5.53 (s, 3H), 6.45-6.49 (m, 2H), 6.68 (t, J )
6.2 Hz, 1H), 6.70 (d, J ) 8.8 Hz, 4H), 7.12-7.27 (m, 9H), 7.28-
7.35 (m, 4H), 7.42-7.62 (m, 14H), 7.67-7.72 (m, 3H), 7.78 (d,
J ) 2.2 Hz, 1H), 7,80 (d, J ) 2.2 Hz, 1H), 7.91 (d, J ) 2.2 Hz,
3H), 8.09 (d, J ) 8.4 Hz, 2H), 8.16 (d, J ) 8.0 Hz, 4H); 31P
NMR δ 148.89.
1-[(4-Ben zoyloxy-5-(N-3-d im eth oxytr ityloxyp r op -1-yl)-
a m in oca r b on yl)-3-(1,3-d ioxa n -2-yl)-p h en yl)et h yn yl]-3-
[(4 -b e n z o y l o x y -5 -(N -(3 -h y d r o x y p r o p -1 -y l )a m i n o -
car bon yl)-3-(1,3-dioxan -2-yl)ph en yl)eth yn yl]-5-[(4-ben zoyl-
oxy-5-(N-(3-(9-flu or oen ylm eth oxycar bon yloxy)pr op-1-yl)-
a m in oca r bon yl)-3-(1,3-d ioxa n -2-yl)p h en yl)eth yn yl]ben -
zen e (20). To a round-bottomed flask charged with 19 (114
mg, 0.054 mmol) dissolved in CH2Cl2 (5 mL) was added
dropwise glacial AcOH (5 mL). The reaction mixture was
stirred for 10 min, quickly diluted with CH2Cl2 (50 mL), and
neutralized with saturated NaHCO3. The organic layer was
washed with water (3 × 80 mL), dried over MgSO4, and
concentrated. The crude hydrolyzed mixture was purified by
flash chromatography (CH2Cl2/EtOAc, 85:15 f 60:40 f 0:100)
to yield unhydrolyzed 19 (60 mg, 0.028 mmol) and 20 (24 mg,
25%): 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, J ) 12.8 Hz, 3H),
1.46 (qui, J ) 6.4 Hz, 2H), 1.60 (qui, J ) 6.4 Hz, 2H), 1.74
(qui, J ) 6.4, 2H), 1.99-2.12 (m, 3H), 2.99 (t, J ) 6.4 Hz, 2H),
3.29-3.43 (m, 6H), 3.47 (q, J ) 5.1 Hz, 2H), 3.67 (s, 6H), 3.70
(t, J ) 12.0 Hz, 6H), 4.04 (dd, J ) 11.2, 5.2 Hz, 6H), 4.15 (t, J
) 7.7 Hz, 1H), 4.30 (d, J ) 7.7 Hz, 2H), 5.53 (s, 3H), 6.45-
6.51 (m, 2H), 6.68 (t, J ) 6.2 Hz, 1H), 6.70 (d, J ) 8.8 Hz,
4H), 7.12-7.29 (m, 9H), 7.27-7.34 (m, 4H), 7.42-7.62 (m,
14H), 7.67 (d, J ) 2.2 Hz, 1H), 7.69 (d, J ) 7.7 Hz, 2H), 7.78
(d, J ) 2.2 Hz, 1H), 7,80 (d, J ) 2.2 Hz, 1H), 7.91 (d, J ) 2.2
Ack n ow led gm en t. We thank Anette Rasmussen
and Lene Skov for assistance with the mass spectrom-
etry. Raymond S. Brown is acknowledged for helpful
advise and discussions. Finn Kirpekar was supported
by the Danish Biotechnology Instrument Center. This
study was funded in part by the Danish Technical
Research Council and the Danish National Research
Foundation.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 3-21. This material is available free of charge via
the Internet at http://pubs.acs.org.
Hz, 3H), 8.09 (d, J ) 8.4 Hz, 2H), 8.16 (d, J ) 8.0 Hz, 4H); 13
NMR (CDCl3, 100 MHz) δ 25.3, 25.4, 28.5, 29.2, 32.1, 36.5,
C
J O035764M
2250 J . Org. Chem., Vol. 69, No. 7, 2004