Synthesis of functionalized aromatic oligomers from a versatile diphenylmethane template

Article abstract of DOI:10.1021/jo970596h

An efficient synthesis of the functionalized diphenylmethane system 1 is described. Selective unmasking of the latent phenol groups on 1 allowed the introduction of various appendages onto the diphenylmethane scaffold via simple alkylation, Mitsunobu etherification, and transition-metal-mediated C- C bond formation. Conversion of 1 teiodide 18 and benzylic zinc reagent 28 followed by palladium(0)-mediated coupling of these derivatives provided homologue 29. Repetitive application of this homologation protocol was used to prepare oligomers of chain length up to 16. Several examples of functional group manipulations on these higher order oligomers are presented. Diphenylmethane 1 was also employed as a key building block in the synthesis of the elastase inhibitor 67. The potential application of extended aromatic oligomers to the field of drug discovery is discussed.

Full text of DOI:10.1021/jo970596h

5174
J . Org. Chem. 1997, 62, 5174-5190
Syn th esis of F u n ction a lized Ar om a tic Oligom er s fr om a Ver sa tile
Dip h en ylm eth a n e Tem p la te
J . G. Bruno, M. N. Chang, Y. M. Choi-Sledeski, D. M. Green, D. G. McGarry,*
J . R. Regan, and F. A. Volz
Department of Medicinal Chemistry, Rhoˆne-Poulenc Rorer, 500 Arcola Road,
Collegeville, Pennsylvania 19426-0995
Received April 2, 1997X
An efficient synthesis of the functionalized diphenylmethane system 1 is described. Selective
unmasking of the latent phenol groups on 1 allowed the introduction of various appendages onto
the diphenylmethane scaffold via simple alkylation, Mitsunobu etherification, and transition-metal-
mediated C-C bond formation. Conversion of 1 to iodide 18 and benzylic zinc reagent 28 followed
by palladium(0)-mediated coupling of these derivatives provided homologue 29. Repetitive
application of this homologation protocol was used to prepare oligomers of chain length up to 16.
Several examples of functional group manipulations on these higher order oligomers are presented.
Diphenylmethane 1 was also employed as a key building block in the synthesis of the elastase
inhibitor 67. The potential application of extended aromatic oligomers to the field of drug discovery
is discussed.
In tr od u ction
produce products most commonly associated with groove
or cleft binding. Recently, researchers at Sphinx Phar-
maceuticals described a series of versatile biphenyl,
diphenylmethane, and diphenylethane platforms,4 each
of which, by selective derivatization of an array of
protected phenols, can incorporate various functionalities
in a number of relative spatial configurations. Libraries
derived from these scaffolds have been designed to search
for agonists/antagonists of various 7-transmembrane
G-protein coupled receptor systems. The specific system
we wish to describe is shown in Figure 1. Like the
Sphinx platform, the diphenylmethane framework 1
bears a number of differentially protected phenol groups
and so can also accommodate the introduction of diverse
appendages in various permutational sets. Besides
controlling direct functionalization, the ability to unmask
individual phenol groups in 1 also allows selective
activation of the corresponding ortho carbon positions to
electrophilic attack by halogen. Introduction of bromine
or iodine in this manner greatly expands the range and
relative orientation of appendages which can be attached
to the diphenylmethane framework. The benzylic silyl
ether can also be functionalized to provide, among other
things, an attachment point for solid phase work or, as
discussed below, a chain extension point in the synthesis
of higher order aromatic oligomers such as 41.
In recent years combinatorial chemistry strategies
have emerged as widely applicable tools in drug discov-
ery.1 This has generated considerable interest in versa-
tile molecular platforms capable of supporting the diverse
arrays of functionality used to search for new pharma-
cophores. In choosing suitable platforms for this purpose,
careful consideration must be given to a number of
parameters, among them ease of preparation, amenabil-
ity to multiple derivatization, potential for incorporation
onto a solid support, and compatibility with the physi-
ological environment. In this paper, we report the
synthesis of a functionalized diphenylmethane system
which meets the criteria outlined above. We also il-
lustrate the application of this structure to the synthesis
of a family of higher order oligomeric systems of chain
length up to 16.
A number of small molecule library templates have
been reported in the literature to date. These include
both amide-based scaffolds,2 which generate product
libraries well suited to interaction with protein frame-
works, as well as simple aromatic systems,3 which
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) For some reviews of this area see (a) Balkenhohl, F.; von dem
Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2288. (b) Thompson, L. A.; Ellman, J . A. Chem. Rev.
1996, 96, 555. (c) Czarnick, A. W. Ellman, J . A., Eds. Acc. Chem. Res.
1996, 29, 112-170. (d) Terrett, N. Drug Discov. Today 1996, 1, 129.
(e) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.; Gordon,
E. M. J . Med. Chem. 1994, 37, 1233, 1386. (f) Terrett, N. K.; Gardner,
M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51,
8135.
Resu lts
P r ep a r a tion of 1. The synthesis of diphenylmethane
1 is outlined in Scheme 1. The requisite precursors (8
and 11) were both prepared from 2,5-dihydroxybenzal-
(2) For example see (a) Cheng, S.; Comer, D. D.; Williams, J . P.;
Myers, P. L.; Boger, D. L. J . Am. Chem. Soc. 1996, 118, 2567. (b) Carell,
T.; Wintner, E. A.; Sutherland, A. J .; Rebek, J .; Dunayevskiy, Y. M.;
Vouros, P. Chem. Biol. 1995, 2, 171. (c) Kocis, P.; Issakova, O.; Sepetov,
N. F.; Lebl, M. Tetrahedron Lett. 1995, 36, 6623. (d) Bray, A. M.;
Chiefari, D. S.; Valerio, R. M.; Maeji; N. J . Tetrahedron Lett. 1995,
36, 5081. (e) Kick, E. K.; Ellman, J . A. J . Med. Chem. 1995, 38, 1427.
(f) Patek, M.; Drake, B.; Lebl, M. Tetrahedon Lett. 1994, 35, 9169. (g)
Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055.
(h) Boyce, R.; Li, G.; Nestler, H. P.; Suenaga, T.; Still, W. C. J . Am.
Chem. Soc. 1994, 116, 7955. For the purposes of this discussion we
restrict ourselves to the consideration of preformed scaffolds, from
which libraries are generated by the introduction of various append-
ages. This is in contrast to systems in which a common or privileged
structure is formed during the diversification stage of library genera-
tion. For examples of this strategy, see reference 1c.
(3) For example see (a) Meyers, H. V.; Dilley, G. J .; Durgin, T. L.;
Powers, T. S.; Winssinger, N. A.; Zhu, H.; Pavia, M. R. Molecular
Diversity 1995, 1, 13. (b) Rano, T. A.; Chapman, K. T. Tetrahedron
Lett. 1995, 36, 3789. (c) Dankwardt, S. M.; Newman, S. R.; Krsten-
ansky, J . L. Tetrahedron Lett. 1995, 36, 4923. (d) Frenette, R.; Friesen,
R. W. Tetrahedron Lett. 1994, 35, 9177. See also Hermkens, P. H. H.;
Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996, 52, 4527 and
references therein (e) Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J .
W. J . Org. Chem. 1997, 62, 201.
(4) Pavia, M. R.; Cohen, M. P.; Dilley, G. J .; Dubuc, G. R.; Durgin,
T. L.; Forman, F. W.; Hediger, M. E.; Milot, G.; Powers, T. S.;
Sucholeiki, I.; Zhou, S.; Hangauer, D. G. Bioorg. Med. Chem. Lett. 1996,
4, 659. See also: Pavia, M. R.; Whitesides, G. M.; Hangauer, D. G.;
Hediger, M. E. Patent WO 95/04277, 1995.
S0022-3263(97)00596-3 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5175
F igu r e 1. Applications of diphenylmethane 1.
dehyde, in high yield, using the optimized procedures
shown. Coupling of 8 and 11 was effected by preforma-
tion of the benzylic zinc reagent 125 and cross-coupling
of this species with 8, under palladium catalysis,6 to
provide 1 in 87% yield. It should be noted that 12, like
several related reagents generated during the course of
this project, is stable in THF solution and can be stored
for several days without dramatic loss of activity. The
synthesis of 1 has been carried out routinely on a 100 g
scale with an overall yield of 60% based on dihydroxy-
benzaldehyde.
F u n ction a l Gr ou p Ma n ip u la tion of 1. A represen-
tative selection of the chemistry that has been carried
out on 1 is summarized in Schemes 2-5. As anticipated,
each of the protecting groups can be removed selectively
(Scheme 2). The benzyl-protected phenol was liberated
cleanly in the presence of the benzylic silyl ether by
hydrogenolysis7 (H2/Pd/C, 90%) to give 13. Removal of
the MEM ether was accomplished in excellent yield
(Pyridinium tosylate/2-propanol, 95%) giving 14, provided
a sterically hindered nucleophile such as 2-propanol was
used to effect transketalization. Cleavage of the benzoate
was carried out uneventfully by transesterification
(NaOMe, 94%) yielding 15, while desilylation of the
benzylic ether was effected using an acetic acid buffered
TBAF system (96%)8 to give 16.
we confined ourselves to three methods of derivatiza-
tion: Direct alkylation, Mitsunobu etherification, and
transition-metal-mediated carbon-carbon bond forma-
tion. These three synthetic methods combine to provide
access to a wide variety of appendages, but are also mild
enough to be tolerated in a multifunctionalized system
such as 1. Simple alkylation (Scheme 3) was accom-
plished using a range of alkyl halides employing one of
two experimental protocols (K2CO3, RX, CH3CN, 70-90%
or NaH, RX, THF/DMPU, 85-95%) with the choice of
reaction conditions for a particular case being dependent
on both the nature of the alkylating agent and the
particular phenolic group undergoing reaction. As il-
lustrated by the etherification of 14, standard Mitsunobu
coupling10 (DEAD/Ph3P/pyridin-2-ylethanol/THF, rt, 84%)
proved an effective alternative to alkylation in situations
where the appropriate alkyl halide was unreactive or
difficult to access. Transition-metal-mediated carbon-
carbon bond formation was effected via aryl triflates11
such as 20 (NaH/N-phenyltriflimide/THF/DMPU, 92%
based on 15) which underwent efficient cross-coupling
reaction with acetylenic-zinc reagents (((trimethylsilyl)-
ethynyl)zinc chloride/Pd(dba)2/dppf/THF, 91%),12 as well
as palladium-catalyzed methoxycarbonylation (vide in-
fra).13
As mentioned above, unmasking the latent phenolic
groups in 1 activates the corresponding ortho carbons to
electrophilic iodination.14 Optimum reaction conditions
for this conversion were found to depend on the other
functionality present in the aromatic ring. For example,
(Scheme 4) introduction of iodine meta to the benzoate
in 14 was effected successfully (79%) using a heteroge-
The phenolic hydroxyl is a versatile functional group
capable of undergoing a wide variety of useful transfor-
mations.9 However, within the context of this system,
(5) Berk, S. C.; Knochel, P.; Yeh M. C. P. J Org. Chem. 1988, 53,
5789. In all cases studied, a small amount of Wurtz type coupling
product accompanied the formation of the benzylic zinc reagent. These
products were generally isolated and characterized after the cross-
coupling reaction (see Experimental Section).
(6) Negishi, E.; King, A. O.; Okukado, N. J . Org. Chem. 1977, 42,
1823.
(7) Both the benzylic silyl ether and its corresponding benzyl alcohol
were completely resistant to hydrogenolysis with palladium catalysts
under ambient pressure.
(8) Hoffman, W. F.; Alberts, A. W.; Anderson, P. S.; Smith, R. L.;
Willard, A. K. J . Med. Chem. 1986, 29, 849.
(9) Whiting, D. A Comprehensive Organic Chemistry; Barton, D.,
Ollis, W. D., Eds.; Pergamon Press: New York, 1979; Vol. 1.
(10) Mitsunobu, O. Synthesis 1981, 1. For an application of this
reaction in the derivatization of cyclic aromatic oligomers with various
carbohydrates; see Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati,
A.; Minari, P.; Ungaro, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479.
(11) McMurry, J . E.; Scott, W. J . Acc. Chem. Res. 1988, 21, 47.
(12) Rottlander, M.; Palmer, N.; Knochel, P. Synlett 1996, 573.
(13) Dolle, R. E.; Schmidt, S. J .; Kruse, L. I. J . Chem. Soc., Chem.
Commun. 1987, 904.
(14) Merkushev, E. V. Synthesis 1988, 923.

5176 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
Sch em e 1a
a
Reagents, conditions, and yields: (i) Bz2O/Et3N then K2CO3/methanol then aqueous HCl, 92%; (ii) Br2/NaOAc; (iii) K2CO3/MeI; (iv)
NaOMe; (v) K2CO3/BnBr, 90% overall from 2; (vi) NaBH4; (vii) TBPSCl/Imid/DMAP, 94% overall from 6; (viii) NaH/MEMCl/DMPU; (ix)
NaBH4(diglyme)/THF, -35 °C, 84% overall from 2; (x) NBS/PPh3, 89%; (xi) Zn 10 equiv, -5 °C; (xii) (Ph3P)4Pd, 87%.
neous system comprised of iodine and morpholine in
dichloromethane at room temperature. However, this
system gave poor yields when installing iodine in the
presence of the MEM group, as in 15. In this situation,
optimum yields were attained by adding a dilute solution
of iodine to a mixture of phenol and morpholine at -10
°C (80%). As one might expect, in the absence of a steric
directing group, iodination of 13 resulted in a prepara-
tively useless mixture of mono- and diiodo products. In
general, o-iodophenol derivatives of these systems were
found to be only moderately stable and so were usually
further derivatized immediately, as shown for the par-
ticular case of 22, which was efficiently methylated (NaH,
MeI/THF/DMPU, 93%) to yield the stable product 18.
As illustrated in Scheme 5, stepwise oxidation of
benzylic alcohol 16 provided aldehyde 24 (Swern, 91%)
and the corresponding acid 2515 (NaClO2/isobutene, 98%).
The latter functionality underwent standard coupling
reactions, via a mixed anhydride, to provide amide
derivatives such as 26 (isopropyl chloroformate/N-meth-
ylmorpholine and then L-leucine methyl ester, 96%). In
addition to oxidative derivatization, benzylic alcohol 16
was also converted to the corresponding crystalline
bromide 27 (NBS/Ph3P, 97%) furnishing an electrophilic
carbon center. Formation of the complementary nucleo-
philic carbon center was accomplished by conversion of
bromide 27 to the benzylic zinc reagent 28, on treatment
with an excess of activated zinc dust (>80%). Such mild
nucleophilic reagents are particularly attractive in view
of their extensive application in selective carbon-carbon
bond-forming reactions.16
The foregoing chemistry by no means constitutes an
exhaustive survey of the manipulations which can be
carried out on 1. Nevertheless, this study does provide
a basis for the development of a broad range of useful
derivatives in an efficient and cost effective manner and
so, we believe, clearly demonstrates that 1 meets the
basic criteria of accessibility and versatility set forward
earlier for use as a small molecule library platform.
Although the generation of simple derivatives in the
manner outlined above is a credible and potentially
valuable application, this was not our ultimate goal in
preparing 1. Our main purpose in developing this
elaborately functionalized system was to use it as a key
building block in the construction of extended aromatic
oligomers, from which we planned to develop novel
libraries comprised of discrete compounds in the molec-
ular weight range 1000-4000 amu.
(15) (a) Kraus, G. A.; Taschner, M. J . J . Org. Chem. 1980, 45, 4825.
(b) Lidgren, B. O.; Hilsson, T. Acta Chem. Scand. 1973, 27, 888.
(16) For a review see Knochel, P.; Singer, D. Chem. Rev. 1993, 93,
2117.

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5177
Sch em e 2a
a
Reagents, conditions, and yields: (i) H2/Pd, 90%; (ii) pyridinium tosylate/2-propanol, 95%; (iii) NaOMe, 94%; (iv) Bu4NF/AcOH, 96%.
High er Or d er Oligom er s
acting partners could be relaxed,19 thereby increasing the
probability of achieving a measurable association. In
adopting this strategy it must be accepted that any
enhancement in association probability may come at the
expense of specificity. However, once a measurable
binding event has been established, the system is then
capable of providing the empirical feedback needed to
guide an optimization procedure and characterize a
minimum effective pharmacophore. With this informa-
tion, issues of selectivity and bioavailability can then be
evaluated, and if deemed appropriate, addressed in a
separate operation.
Ra tion a le. Historically, pharmaceutical research has
been focused on the discovery of small molecule drugs.
The reasons for this are far from purely economic, but
rather also reflect the very substantial advantages as-
sociated with this class of compound regarding oral
bioavailabilitysa crucial factor in defining a practical
drug candidate.17 However, small molecules are intrinsi-
cally limited in the amount of chemical information18
which can be encoded into their structures. Therefore,
effective molecular recognition processes involving such
compounds rely upon a limited number of extremely
precise interactions. Consequently, the discovery of new
drug prototypes from unbiased screening sets of small
molecules is an inherently low probability event. Indeed,
it is this situation which has provided the impetus for
the recent intense activity in the fields of combinatorial
chemistry and automated high speed synthesis.
Perhaps the simplest way of raising the information
content of a molecule is by an increase in molecular size.20
To accomplish this and realize a significant distinction
between conventional libraries, we decided to target
structures with molecular weights > 1000 amu. Specif-
For some time, we have been interested in a comple-
mentary strategy for new lead generation. In this
approach, screening libraries are designed so that the
amount of chemical information carried by each member
of the library is substantially increased relative to that
found in conventional small molecule systems. We
speculated that if the number of binding opportunities
involved in a molecular recognition process were signifi-
cantly enlarged, and then the dependence of the associ-
ated binding free energy on precise matching of inter-
(19) This approach emphasizes surface interactions which are less
geometrically and sterically constrained than the groove or cleft binding
interactions often associated with small molecule ligands. Indeed, there
is some support for the idea that substantial binding free energy can
result from the cumulative effect of a number of individually weak
interactions spread over an extended structure. For example, (a)
Cadene, M.; Morel-Desrosiers, N.; Morel, J .-P.; Bieth, J . G. J . Am.
Chem Soc. 1995, 117, 7882 and references therein. (b) van Boeckel, C.
A. A.; Petitou, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1671. (c)
Lee, Y. C. FASEB 1992, 6, 3193.
(20) While it seems obvious that increasing the number of atoms in
molecule will increase its information content, at some point,
a
intramolecular interactions will become dominant and, consequently,
as secondary structure evolves, interactions between the molecule and
its environment will decrease in number and become more precise.
We were interested in accessing structures with increased information
content over traditional small molecules, but which are not large
enough to be completely locked in secondary/tertiary structure motifs.
For an interesting discussion on the relationship between size, affinity,
and specificity, see Eaton, B. E.; Gold, L.; Zichi, D. A. Chem. Biol. 1995,
2, 633.
(17) (a) Navia, M. A.; Chaturvedi, P. R. Drug Dev. Today 1996, 1,
179. (b) Sha’afi, R. I.; Gary-Bobo, C. M.; Solomon, A. K. J . Gen. Physiol.
1971, 58, 238.
(18) In this context, we use the term chemical information to mean
that minimum set of descriptors required to characterize the interac-
tion of a molecule (in its available conformations) with its environment.

5178 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
Sch em e 3a
Sch em e 5a
a
Reagents, conditions, and yields: (i) (COCl)2/DMSO/Et3N, -78
°C to rt, 91%; (ii) NaClO2/NaH2PO4/isobutene, rt, 98%; (iii)
isopropyl chloroformate/N-methylmorpholine, 0 °C then L-leucine
methyl ester hydrochloride, 96%; (iv) NBS/Ph3P/THF, 10 °C to rt,
97%; (v) zinc (powder), 10 equiv, -5 °C, >80%.
macophore. Moreover, an oligomer format is capable of
encompassing a great deal of structural diversity by
combinatorial coupling of even a modest number of
building blocks. This traditional combinatorial chemistry
approach has, of course, proved highly successful in
oligonucleotide and peptide systems.1e,20 However, in
contrast to natural oligomers, the use of a purely syn-
thetic platform to investigate recognition events in
biological systems is not complicated or biased by the
effects of natural selection. Thus, small molecule librar-
ies, derived from sections of extended synthetic oligomers,
provide a valid benchmark from which to evaluate the
effects of increased molecular size on association prob-
ability. In considering such an undertaking from a
practical standpoint, it is important to identify advanced,
versatile intermediates capable of elaboration into a
range of extended oligomeric structures. In view of its
simple preparation, efficient functionalization, and po-
tential for chain extension, diphenylmethane 1 seemed
to us particularly well equipped to fulfill such a role.
Syn t h esis of a P r ot ot yp e Sca ffold . From the
chemistry outlined earlier, it is evident that 1 can be
selectively activated to provide the electrophilic (18,
Scheme 4) and nucleophilic (28, Scheme 5) components
of a palladium coupling reaction directly analogous to the
system used to prepare 1 itself. Coupling of these
fragments would then produce a higher order homologue
of 1 and complete an iterative cycle of chain elongation.
We anticipated that this type of cycle would provide the
basic methodology needed to assemble a prototype family
of methylene-linked aromatic oligomer scaffolds.21
In practice, as outlined in Scheme 6, repetitive ap-
plication of this activation-coupling strategy provided
the corresponding tetramer (29) and octamer (35) frame-
works with little erosion of yields (83 and 70%, respec-
tively, for the coupling step). At the outset, we were
concerned that purification of extended oligomer frame-
works of this kind could prove to be problematic. How-
a
Reagents, conditions, and yields: (i) K2CO3, BrCH2CN/CH3CN,
81 °C, 72%; (ii) 2-(2-hydroxyethyl)pyridine/DEAD/Ph3P, rt, 84%;
(iii) NaH, N-phenyltriflimide, THF/DMPU, 0 °C to rt, 92%; (iv)
TMS-acetylene/BuLi, -78 °C then ZnCl2, -78 °C to rt, then
Pd(dba)2/dppf/THF, 65 °C, 91%.
Sch em e 4a
a
Reagents, conditions, and yields: (i) I2 (solid)/morpholine/
CH2Cl2, rt, 79%; (ii) I2 (solution)/morpholine, CH2Cl2, -10 °C, 80%;
(iii) NaH, MeI/THF/DMPU, 0 °C to rt, 93%.
ically, we envisioned that a library based on a flexible
aromatic oligomer scaffold would be an attractive system
for testing the hypothesis outlined above. Such a plat-
form, we believed, would be both accessible by practical
synthetic transformations and amenable to the kind of
progressive structural variation needed to map a phar-

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5179
ever, these concerns were entirely unfounded. Indeed,
even on an octameric framework, the terminal phenol 38,
o-iodophenol 39 and o-iodomethyl ether 40 were all easily
distinguishable by simple TLC analysis. Octameric
oligomers in this series are freely soluble in aprotic
dipolar solvents such as DMF and DMSO, as well as
chlorinated hydrocarbons, particularly chloroform, but
are only sparingly soluble in ethereal solvents. In fact,
as a result of diminished solubility in THF, the final
iteration to the hexadecamer framework required the use
of DMF as a cosolvent. With this adjustment, and in
deference to the reaction scale (0.3 mmol), using 2 equiv
of benzylic zinc, the hexadecamer 41 was formed in 62%
yield (based on aryl iodide 40). With a molecular weight
of 4058 amu and, assuming an extended conformation,
an overall length of 75 Å, hexadecamer 41 is the largest
molecular framework we prepared during this program.
The synthesis of 41 underscores the tremendous utility
of palladium(0)-mediated chemistry in the construction
of large, highly functionalized, organic molecules.22 Fur-
thermore, by successfully assembling this prototype
oligomer family, we were confident that we had identified
a synthetic protocol fully capable of furnishing oligomeric
structures of any size likely to be of practical use in
pharmaceutical research.
was accomplished in an overall yield of 83%. The
efficiency of these operations highlights our general
observation, that functional groups appended to aromatic
oligomers of this kind behave in an entirely predictable
manner and are not significantly hindered or perturbed
by the extended molecular framework surrounding them.
As shown in Scheme 8, derivatized scaffolds can also
be activated for subsequent coupling using the standard
procedures already described. Thus, reductive debromi-
nation of tetramer 31 (Zn/AcOH, 86%), followed by
sequential removal of the benzyl ethers (H2/Pd), benzoate
esters (NaOMe), and sulfonylation of the resulting tet-
raphenol 52 (NaH/N-phenyltriflimide, 88% based on 50),
afforded triflate 53 in high yield. Palladium-mediated
methoxycarbonylation of 53 then provided the fully
functionalized tetrabenzoate system 54. Removal of the
MEM protecting group from 54 (H2SO4/MeOH) followed
by iodination (I2 (solid)/morpholine, 84% based on 54) and
alkylation in the usual manner (NaH/MeI/DMPU, 95%),
furnished the activated tetraester building block 57.
Coupling of 57 with 1.2 equiv of benzylic zinc 28 (from a
stock solution) afforded the hexamer scaffold 58 in 81%
yield. Combinatorial coupling of partial or fully deriva-
tized oligomers, such as 57, with units containing open
functionality such as 28, provides an obvious mechanism
for the generation of diversely functionalized systems
from a limited set of advanced intermediates.
F u n ction a liza tion of High er Or d er Oligom er s.
Derivatization of extended oligomer frameworks was
performed employing essentially the same procedures
used for the functionalization of 1. As illustrated in
Scheme 7, removal of all four benzoates from 35 (NaOMe),
followed by exhaustive alkylation of the crude product
(BrCH2CO2But/K2CO3) provided the partially substituted
framework 42 in 84% overall yield. The terminal ben-
zylic silyl ether of 42 was transformed selectively, along
the lines previously described, (Bu4NF/AcOH, 91%, and
then Swern, 92%) to yield first aldehyde 44, and then,
by further oxidation (NaClO2/isobutene, 98%), acid 45.
Alternatively, reductive debromination of 37 (Zn/AcOH)
provided the end-capped octamer 46 in 86% yield. Se-
quential removal of the benzyls (H2/Pd), and then the
benzoates (NaOMe) from 46, followed by alkylation of the
resulting octaphenol (BrCH2CO2But/K2CO3) afforded the
fully derivatized framework 49. The conversion of 46 to
49 involved a total of 16 functional group conversions and
Non -Meth ylen e-Lin k ed Oligom er s. The linkage
between aromatic units is by no means confined to the
methylene group employed above. As already demon-
strated by both Moore22a,b and Tour,22c,d extended aro-
matic oligomers, analogous to 41 but linked by acetylene
units, can be assembled with considerable efficiency. In
fact, combining common subunits using various linkers
represents a particularly economical way of altering the
spacial relationship of a given set of functional groups
along an oligomer scaffold. A specific example of the
construction of a mixed-linkage scaffold is shown in
Scheme 9. In this particular instance, the activated
diphenylmethane unit 6023 was first attached to the
salicylate derivative 68, via an acetylene linkage (CuI/
(Ph3P)4Pd/piperidine, 82%)24 to produce a trimer 61. The
free phenol of 61 was alkylated (BrCH2CO2But/K2CO3,
87%) and then the acetylene linkage selectively reduced
(H2/Pd/EtOAc, 73%) to afford 63. Conversion of the
benzylic silyl ether in 63 to the corresponding bromide
(Bu4NF/AcOH and then Ph3P/NBS, 84% overall) provided
65, which was subjected to a benzylic homocoupling
reaction (Zn/NiBr2(Ph3P)2/Bu4NI, 71%)25 to furnish the
hexamer framework 66. The assembly of 66 from diphe-
nylmethane 60 requires only six steps (30% overall) and
illustrates how alterations in the length (ethylene vs
methylene), orientation (para vs meta), and order (head
to head vs head to tail) of linkages between the aromatic
units can be achieved employing a standard set of
terminally functionalized intermediates (aryl iodide and
benzyl bromide). The ability to easily alter linkages in
this way confers an additional manifold of variability to
the aromatic oligomer system which is not readily avail-
(21) Polyanionic, methylene-linked aromatic polymers and oligomers
have been shown to exhibit a wide range of interesting biological
activities. For examples see (a) Wang, P.; Kozlowski, J .; Cushman, M.
J . Org. Chem. 1992, 57, 3861 and references therein. (b) Regan, J . R.;
Bruno, J . G.; Sabatino, R.; D’Alisa, R.; Ben-Sasson, S. A.; Eilat, D. J .
Bioact. Compat. Polym. 1993, 8, 317. (c) Benezra, M.; Vlodavsky, I.;
Yayon, A.; Bas-Shavit, R.; Regan, J .; Chang, M.; Ben-Sasson, S. A.
Cancer Res. 1992, 52, 5656. (d) Benezra, M.; Ben-Sasson, S. A.; Regan,
J .; Chang, M.; Bar-Shavit, R.; Vlodavsky, I. Arterioscler. Thromb. 1994,
14, 1992. (e) Weinstein, M.; Vosburgh, E.; Phillips, M.; Terner, N.;
Chute-Rose, L.; Moake, J . Blood 1991, 78, 2291. In addition, there are
several natural product families which are based on a methylene-linked
aromatic oligomer backbone. For examples see (a) Hufford, C. D.;
Lasswell, W. L., J r.; Hirotsu, K. Clardy, J . J . Org. Chem. 1979, 44,
4709. (b) Carte, B. K.; Troupe, N.; Chan, J . A.; Westley, J . W.; Faulkner,
D. J . Phytochemistry 1989, 28, 2917. (c) Euw, J . V.; Reichstein, T.;
Widen, C.-J . Helv. Chim. Acta 1985, 68, 1251. There is also an
extensive literature covering cyclic aromatic oligomers, known as
calixarenes. For
a review see Stoddart, J . F., Ed. Calixarenes,
monographs in supramolecular chemistry; Royal Society of Chemis-
try: Cambridge, 1989; Vol. 1.
(23) 59 was prepared by alkylation of 14 with benzyl bromide and
then removal of the benzoate using conditions described in the
Experimental Section. 68 was prepared from 5-iodosalicylic acid, in
four steps.
(24) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Int. 1995,
27, 127.
(22) (a) Zhang, J .; Moore, J . S.; Zhifu Xu; Aguirre, R. A. J . Am. Chem.
Soc. 1992, 114, 2273. (b) Nelson, J . C.; Young, J . K.; Moore, J . S. J .
Org. Chem. 1996, 61, 8160. (c) Schumm, J . S.; Pearson, D. L.; Tour, J .
M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1360. (d) Pearson, D. L.;
Tour, J . M. J . Org. Chem. 1997, 62, 1367. (e) J ones, L., II; Schumm, J .
S.; Tour, J . M. J . Org. Chem. 1997, 62, 1388 and references therein.
For a review of this field see Tour, J . M. Chem. Rev. 1996, 96, 537.
(25) Iyoda, M.; Sakaitani, M.; Hiroki, O.; Oda, M. Chem. Lett. 1985,
127.

5180 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
Sch em e 6a
a
Reagents, conditions, and yields: (i) Zn then (Ph3P)4Pd, 83%. (ii) TBAF/AcOH, 83%. (iii) NBS/Ph3P, 96%. (iv) Py Tos/IPA. (v) I2/
morpholine, 82% overall from 29. (vi) NaH/MeI/DMPU, 92%, (vii) as in (i) , 70%. (viii) as in (ii), 93%. (ix) as in (iii), 82%. (x) as in (iv). (xi)
as in (v), 79% overall from 35. (xii) as in (vi), 92%. (xiii) as in (i), 62% based on 40.
able to many other oligomeric platforms. Final depro-
tection of 66 (PPTS and then NaOH, 57%) provided the
target hexamer 67. This rather simple structure was one
of a group of extended, anionic oligomers found to be
potent inhibitors of human neutrophil elastase (67, Ki )
18 nM). Interestingly, oligomers in this series with chain
lengths less than five were at least two orders of
magnitude less active.26
Con clu sion
Diphenylmethane 1 can function as the progenitor of
a variety of low molecular weight structures by selective
derivatization of its appended functionality. In addition,
this versatile building block can be used as an advanced
intermediate in the synthesis of a wide range of extended
aromatic scaffolds, thereby greatly reducing the invest-
ment of time and effort required to prepare any indi-
vidual structure. A subset of these extended oligomers,
exemplified by hexamer 67, were found to be effective
(26) A more detailed account of the interaction of this class of
compound with HNE will appear elsewhere.

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5181
Sch em e 7a
a
Reagents, conditions, and yields: (i) NaOMe. (ii) BrCH2CO2But/K2CO3, 84% overall from 35. (iii) Bu4NF/AcOH, 91%. (iv) Swern,
92%. (v) NaClO2/isobutene, 98%. (vi) Zn/AcOH, 86%. (vii) H2/Pd. (viii) as in (i). (ix) as in (ii), 83% overall from 46.
inhibitors of human neutrophil elastase, while substan-
tially smaller oligomer fragments were almost inactive.
These observations illustrate the type of result that can
be obtained by including higher molecular weight com-
pounds in screening libraries. However, this represents
only one case and the likelihood of observing such trends
in other systems remains to be determined. Indeed,
relatively little is known about the detailed biological
interactions, metabolism, or pharmacokinetics of non-
natural oligomers in this molecular weight range.27 The
chemistry outlined in this paper, and elsewhere,22 shows
that such structures are readily accessible and provides
a basis for the development of the more extensive
libraries needed to test the ideas regarding association
probability outlined above. We believe that synthetic
oligomers of this kind have an important role to play in
the study of basic molecular recognition, as well as in
the field of drug discovery, particularly in areas where
the search for leads from small molecule libraries has
not been successful.
Exp er im en ta l Section
1H NMR spectra were recorded at a frequency of 300 MHz.
Plasma desorption mass spectra were recorded at Purdue
University. Unless otherwise specified, materials were ob-
tained from commercial suppliers and were used without
further purification. Piperidine and morpholine were distilled
from calcium hydride prior to use. NBS was recrystallized
from water and dried over P2O5. Anhydrous solvents were
obtained from Aldrich. Column chromatography was per-
formed on Merck silica gel (230-400 mesh).
Ben zoic Acid 3-F or m yl-4-h yd r oxyp h en yl Ester (2). To
a solution of 2,5-dihydroxybenzaldehyde (25.5 g, 185 mmol)
in CH2Cl2 (500 mL) was added Et3N (57 mL, 413 mmol)
followed by benzoic anhydride (87.9 g, 389 mmol) and DMAP
(2.26 g, 18.5 mmol) . The resulting solution was stirred for 5
h and then diluted with ether and washed, sequentially, with
saturated NaHCO3 solution and brine. The organic phase was
dried over MgSO4 and then concentrated under reduced
pressure. The residue was dissolved in 4:1 MeOH:THF (500
(27) Preliminary studies on the biological properties of oligocar-
bamates and peptoids suggest that these systems may possess
significant advantages over natural peptide sequences. Oligocar-
bamates: Cho, C. Y.; Moran, E. J .; Cherry, S. R.; Stephans, J . C.; Fodor,
F. P. A.; Adams, C. L.; Sundaram, A.; J acobs, J . W.; Schultz, P. G.
Science 1993, 261, 1303. Peptoids: Miller, S. M.; Simon, R. J .; Ng, S.;
Zuckermann, R. N.; Kerr, J . M.; Moos, W. H. Bioorg. Med. Chem. Lett.
1994, 2657. For other examples of extended, non-natural oligomers of
biological relevance see (a) Koert, U.; Harding, M. M.; Lehn, J .-M.
Nature 1990, 346, 339. (b) Bannwarth, W.; Bergmann, F. Tetrahedron
Lett. 1995, 36, 1839. (c) Shao, J .; Tam, J . P. J . Am. Chem. Soc. 1995,
117, 3893. (d) Richert, C.; Roughton, A. L.; Benner, S. A. J . Am. Chem.
Soc. 1996, 118, 4518 and references therein. (e) Parks, P. E.; Baird,
E. E.; Dervan, P. B. J . Am. Chem. Soc. 1996, 118, 6141, 6147, and
6153. (f) Kogan, M.; Valasinas, A.; Frydman, B. Tetrahedron. Lett.
1996, 37, 763. (g) Zanini, D.; Roy, R. J . Org. Chem. 1996, 61, 7348. (h)
Gauler, R.; Risch, N.; Tetrahedron Lett. 1997, 38, 223. (i) Hoger, S.
Synthesis 1997, 20. (j) Mulders, S. J . E.; Brouwer, A. J .; van der Meer,
P. G. J .; Liskamp, R. M. J . Tetrahedron Lett. 1997, 38, 631.

5182 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
Sch em e 8a
a
Reagents, conditions, and yields: (i) Zn/AcOH, 86%; (ii) H2/Pd/MeOH/THF, (iii) NaOMe; (iv) NaH/N-phenyltriflimide/DMPU, 88%
from 50; (v) CO/MeOH/Et3N/Pd(OAc)2/bdpp, 74%; (vi) MeOH/H2SO4; (vii) I2/morpholine, 84% overall from 54; (viii) NaH/MeI/DMPU,
95%; (ix) 28/(Ph3P)4Pd, 81%.
mL), and then anhydrous K2CO3 (25.6 g, 185 mmol) was added.
The resulting mixture was stirred for 1 h and then diluted
with ether and acidified with HCl (250 mL, 2 M). The organic
phase was washed with a saturated solution of Na2HPO4. This
wash was repeated several times until most of the benzoic acid
had been removed (TLC analysis). The ether solution was
then dried over MgSO4 and concentrated under reduced
pressure. The residual solid was recrystallized from 30%
EtOAc in hexane to give (from two crops) 41.3 g of 2 (92%),
mp 107-108 °C (lit. 107 °C).28 1H NMR (CDCl3) δ 7.05 (d, J
) 9 Hz, 1H), 7.40 (dd, J ) 9.0, 2.9 Hz, 1H), 7.46 (d, J ) 2.9
Hz, 1H), 7.53 (m, 2H), 7.66 (m, 1H), 8.20 (d, J ) 7.4 Hz, 2H),
9.88 (s, 1H), 10.9 (s, 1H). Anal. C14H10O4 requires C 69.4, H
4.2. Found C 69.2, H 4.3.
mmol) in acetic acid (35 mL). On complete addition, the
reaction mixture was stirred for a further 15 min and then
allowed to warm to room temperature over 1.5 h. The product
was isolated by pouring the reaction mixture into 1.5 L of
water and filtering the precipitated solid. The solid was
washed thoroughly with water, dried azeotropically using
toluene, and used without further purification. 1H NMR
(CDCl3) δ 7.49 (d, J ) 2.8 Hz, 1H), 7.53 (m, 2H), 7.67 (m, 1H),
7.70 (d, 2.8 Hz, 1H), 8.18 (d, J ) 7.5 Hz, 2H), 9.8 (s, 1H), 11.5
(s, 1H); MS (EI) m/z 320/322 Br pattern (M)+.
Ben zoic Acid 3-Br om o-5-for m yl-4-m eth oxyp h en yl Es-
ter (4) To a solution of 3 (64.2 g, 200 mmol) in CH3CN (450
mL) was added anhydrous K2CO3 (29.2 g, 212 mmol) and
iodomethane (62 mL, 1 mol). The resulting mixture was
stirred at 45-50 °C for 18 h and then cooled to room
temperature, and the excess iodomethane was removed by
distillation under reduced pressure. The residue was diluted
with EtOAc and then acidified with 1 M HCl. The organic
phase was separated, washed, sequentially, with water and
brine, dried over MgSO4, and then concentrated under reduced
pressure to give 64.9 g of solid. This product was dried
azeotropically with toluene and used without further purifica-
Ben zoic Acid 3-Br om o-5-for m yl-4-h yd r oxyp h en yl Es-
ter (3). To a solution of 2 (48.7 g, 201 mmol) in acetic acid
(250 mL) was added sodium acetate (18.3 g, 223 mmol), and
the resulting mixture was cooled to 15 °C. To this mixture
was added, dropwise, a solution of bromine (10.4 mL, 201
(28) Kawai, S.; Nakamura, T.; Yoshida, M. Chem. Ber. 1940, 70,
581.

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5183
Sch em e 9a
a
Reagents conditions and yields: (i) I2/morpholine, 89%; (ii) (Ph3P)4Pd/CuI/piperidine, 82%; (iii) BrCH2CO2But/K2CO3, 87%; (iv) H2/
Pd/EtOAc, 73%; (v) Bu4NF/AcOH, 93%; (vi) NBS/Ph3P, 90%; (vii) Zn/NiBr2(Ph3P)2/Bu4NI, 71%; (viii) PyTos then NaOH, 57%.
tion. 1H NMR (CDCl3) δ 4.02 (s, 3H), 7.52 (m, 2H), 7.65 (m,
1H), 7.67 (d, J ) 2.9 Hz, 1H), 7.74 (d, J ) 2.9 Hz, 1H), 8.16 (d,
J ) 7.5 Hz, 2H), 10.35 (s, 1H); MS (EI) m/z 335/337 Br pattern
(MH)+.
CH3CN (500 mL), and then K2CO3 (28.0 g 203 mmol) and
benzyl bromide (26.4 mL, 221 mmol) were added. The result-
ing mixture was stirred at 81 °C for 3 h, cooled to room
temperature, and diluted with ether. The ether solution was
washed, sequentially, with water (3×) and brine, dried over
MgSO4, and concentrated. The residue was purified by flash
chromatography (eluting with 10% ether/10% CH2Cl2 in hex-
3-Br om o-5-h yd r oxy-2-m eth oxyben za ld eh yd e (5). A so-
lution of 4 (64.9 g, 193 mmol) in anhydrous THF (550 mL)
was cooled to -45 °C. To this solution was added sodium
methoxide (46.5 mL, 25 wt % in methanol, 203 mmol). The
resulting solution was stirred for 1.25 h and then quenched
with HCl (205 mL, 1 M). The reaction mixture was then
diluted with ether and washed, sequentially, with water (3×)
and brine, dried over MgSO4, and concentrated. The crude,
solid product was triturated with hexanes and then dried
azeotropically with toluene and used without further purifica-
tion. 1H NMR (CDCl3) δ 3.94 (s, 3H), 5.6 (bs, 1H), 7.28 (d, J
) 3.0 Hz, 1H), 7.38 (d, J ) 3.0 Hz, 1H), 10.29 (s, 1H); MS (EI)
m/z 230/232 Br pattern (M)+.
1
anes) to give 58.6 g of 6 (90% based on 2), mp 61-62.5 °C. H
NMR (CDCl3) δ 3.94 (s, 3H), 5.06 (s, 2H), 7.37 (d, J ) 3.0 Hz,
1H), 7.4 (m, 5H), 7.48 (d, J ) 3 Hz, 1H), 10.3 (s, 1H); IR (KBr)
ν 3073 (w), 2868 (w), 1688 (s), 1594 (m), 1384 (m), 1227 (s),
1103 (m), 1026 (s), 986 (m) cm-1; MS (FAB nitrobenzyl alcohol)
m/z 321/323 Br pattern (MH)+. Anal. C15H13O3Br requires C
56.1, H 4.1. Found C 56.2, H 4.0.
The following compounds were prepared using essentially
the same procedure:
ter t-Bu tyl-(5-(cya n om eth oxy)-2-m eth oxy-3-(2-((2-m eth -
oxyeth oxy)m eth oxy)-5-(ben zoyloxy)ben zyl)ben zyloxy)-
d ip h en yl-sila n e (17). Purified by flash chromatography
5-(Ben zyloxy)-3-b r om o-2-m et h oxyb en za ld eh yd e (6).
The crude 5 from the previous step was dissolved in anhydrous

5184 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
(eluting with 30% Et2O/20% CH2Cl2 in hexanes): 484 mg of
13 gave 363 mg of 17 (72%). 1H NMR (CDCl3) δ 1.10 (s, 9H),
3.36 (s, 3H), 3.50 (m, 2H), 3.51 (s, 3H), 3.73 (m, 2H), 3.98 (s,
2H), 4.65 (s, 2H), 4.83 (s, 2H), 5.27 (s, 2H), 6.60 (d, J ) 3 Hz,
1H), 6.89 (d, J ) 3 Hz, 1H), 7.02 (dd, J ) 9, 3 Hz, 1H), 7.12 (d,
J ) 3 Hz, 1H), 7.20 (d, J ) 9 Hz, 1H), 7.40 (m, 6H), 7.48 (m,
2H), 7.62 (m, 1H), 7.69 (m, 4H), 8.16 (m, 2H); IR (KBr) ν 3013
(m), 2932 (m), 2859 (w), 1732 (s), 1600 (w), 1496 (s), 1265 (s),
1200 (s), 1152 (s), 1112 (s), 1077 (s), 1063 (s) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 746 (MH)+.
2-((2-Met h oxyet h oxy)m et h oxy)-5-(5-(b en zyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-(((ter t-bu tyloxyca r bon yl)m eth yl)oxy)-
p h en yl)eth yn yl)ben zoic Acid Meth yl Ester (62). Purified
by flash chromatography (eluting with 20% EtOAc/20% CH2-
Cl2 in hexanes): 750 mg of 61 gave 703 mg of 62 (87%). 1H
NMR (C6D6) δ 1.20 (s, 9H), 1.30 (s, 9H), 3.01 (s, 3H), 3.20 (m,
2H), 3.24 (s, 3H), 3.49 (s, 3H), 3.60 (m, 2H), 4.08 (s, 2H), 4.32
(s, 2H), 4.52 (s, 2H), 4.84 (s, 2H), 4.96 (s, 2H), 5.04 (s, 2H),
6.76 (s, 1H), 6.82 (d, J ) 3 Hz, 1H), 6.97 (d, J ) 9 Hz, 1H),
7.05-7.30 (m, 17H), 7.47 (d, J ) 3 Hz, 1H), 7.60 (dd, J ) 9, 2
Hz, 1H), 7.80 (m, 4H), 8.29 (d, J ) 2 Hz, 1H); IR (CHCl3) ν
3011 (w), 2932 (w), 1748 (m), 1725 (s), 1604 (w), 1506 (s), 1242
(s), 1158 (s), 1112 (s) 1078 (s) cm-1; MS (ion spray) m/z 1071
(MH)+. Anal. C65H70O12Si requires C 72.9, H 6.6. Found C
72.7, H 6.5.
(5-(Ben zyloxy)-3-br om o-2-m eth oxyph en yl)m eth an ol (7).
A solution of 6 (58.6 g 182 mmol) in THF (500 mL) was cooled
to -60 °C, and then NaBH4 (200 mL, 0.5 M in diglyme) was
added. On complete addition, the solution was warmed to -25
°C and stirred at this temperature for 1 h. The reaction was
quenched with HCl (250 mL, 2 M) and the product extracted
with EtOAc. The combined organic extracts were washed,
sequentially, with water (5 × 500 mL) and brine, dried over
MgSO4, and concentrated. The residue was further dried
azeotropically with toluene and then used for the next step
without further purification. 1H NMR (CDCl3) δ 2.04 (t, J )
6.2 Hz, 1H), 3.83 (s, 3H), 4.71 (d, J ) 6.2 Hz, 2H), 5.02 (s,
2H), 6.98 (d, J ) 3.1 Hz, 1H), 7.11 (d, J ) 3.1 Hz, 1H), 7.4 (m,
5H); MS (EI) m/z 322/324 Br pattern (M)+.
((5-(Ben zyloxy)-3-br om o-2-m eth oxyp h en yl)m eth oxy)-
ter t-bu tyld ip h en ylsila n e (8). The crude 7 from the previous
step was dissolved in CH2Cl2 (600 mL), and imidazole (18.7 g,
275 mmol) was added, followed by tert-butyldiphenylsilyl
chloride (49.4 mL, 190 mmol). The resulting mixture was
stirred for 30 min and then diluted with ether. The ether
solution was washed, sequentially, with water and brine, dried
over MgSO4, filtered, and then concentrated. The residue was
purified by flash chromatography (eluting with 5% and then
10% Et2O in hexanes) to give 96.1 g of product which solidified
on standing (94%), mp 51-53 °C. 1H NMR (CDCl3) δ 1.07 (s,
9H), 3.58 (s, 3H), 4.77 (s, 2H), 5.0 (s, 2H), 7.05 (d, J ) 3.0 Hz,
1H), 7.17 (d, J ) 3.0 Hz, 1H), 7.3-7.44 (m, 11H), 7.67 (m, 4H);
IR (KBr) ν 3066 (w), 2948 (m), 2928 (m), 2855 (m), 1597 (w),
1471 (s), 1453 (s), 1424 (s), 1208 (m), 1117 (s), 1046 (m), 699
(s) cm-1; MS (FAB nitrobenzyl alcohol) m/z 559/561 Br pattern
(MH)+. Anal. C31H33O3BrSi requires C 66.3, H 5.9. Found C
66.3, H 6.0.
previous step was dissolved in THF (250 mL) and then cooled
to -78 °C. To this solution was added NaBH4 (150 mL, 0.5 M
in diglyme). The resulting solution was warmed to -45 °C
and stirred for 20 min. The reaction was then quenched with
HCl (75 mL, 1 M) and diluted with EtOAc, washed with water
(until no diglyme shows on TLC of organic fraction) and then
brine, dried over MgSO4, and concentrated. The residue was
purified by flash chromatography (eluting with 30% EtOAc/
10% CH2Cl2 in hexanes) to yield 63.1 g of 10 (84% based on 2)
which solidified on standing, mp 43.5-45 °C. 1H NMR (CDCl3)
δ 2.38 (bt, J ) 6.4 Hz, 1H), 3.37 (s, 3H), 3.56 (m, 2H), 3.85 (m,
2H), 4.71 (d, J ) 6.4 Hz, 2H), 5.33 (s, 2H), 7.09 (dd, J ) 8.8,
2.9 Hz, 1H), 7.19 (d, J ) 8.8 Hz, 1H), 7.22 (d, J ) 2.8 Hz, 1H),
7.50 (m, 2H), 7.61 (m, 1H), 8.19 (d, J ) 7 Hz, 2H); IR (KBr) ν
3328 (bm), 3239 (bw), 3075 (w), 2930 (m), 2889 (m), 1735 (s),
1602 (w), 1496 (s), 1454 (m), 1266 (s), 1189 (s), 1106 (s), 1064
(s), 1027 (s), 996 (s) 905 (m), 850 (w) cm-1; MS (ion spray) m/z
333 (MH)+. Anal. C18H20O6 requires C 65.0, H 6.1. Found C
65.0, H 6.0.
Ben zoic Acid 3-(Br om om eth yl)-4-((2-m eth oxyeth oxy)-
m eth oxy)p h en yl Ester (11). A solution of 10 (56.0 g, 169
mmol) in THF (450 mL) was cooled to 5 °C and Ph3P (50.0 g,
191 mmol) added, followed by NBS (33.0 g, 185 mmol). The
resulting mixture was stirred for 15 min and then concentrated
under reduced pressure, and the residue was purified by flash
chromatography (eluting with 25% EtOAc in hexanes) to give
59.3 g of 11 (89%), mp 60-61 °C. 1H NMR (CDCl3) δ 3.39 (s,
3H), 3.58 (m, 2H), 3.89 (m, 2H), 4.55 (s, 2H), 5.37 (s, 2H), 7.12
(dd, J ) 8.9, 2.7 Hz, 1H), 7.20 (d, J ) 2.7 Hz, 1H), 7.23 (d, J
) 8.9 Hz, 1H), 7.51 (t, J ) 7.5 Hz, 2H), 7.64 (t, J ) 7.5 Hz,
1H), 8.18 (d, J ) 7.5 Hz, 2H); IR (KBr) ν 3074 (w), 2987 (w),
2888 (m), 1731 (s), 1603 (w), 1451 (m), 1269 (s), 1203 (s), 1156
(s), 1137 (s), 1061 (s), 988 (s), 707 (s) cm-1; MS (EI) m/z 394/
396 Br pattern (M)+. Anal. C18H19O5Br requires C 54.7, H
4.8. Found C 54.8, H 4.6.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(((ter t-bu tyld ip h en yl-
silyl)oxy)m eth yl)-2-m eth oxyben zyl)-4-((2-m eth oxyeth oxy)-
m eth oxy)p h en yl Ester (1). To a suspension of zinc powder
(100 g, 1.53 mol, 325 mesh) in THF (50 mL) was added 1,2-
dibromoethane (3.25 mL, 38 mmol). The resulting mixture
was heated to reflux, stirred vigorously for 1.5 min, and then
allowed to cool to room temperature. The activated zinc
suspension was then further cooled to -5 °C (external temp),
and then a solution 11 (57.0 g, 144 mmol) in THF (130 mL)
was added, dropwise, over 4.75 h. On complete addition, the
mixture was stirred a further 15 min, and then stirring was
stopped and the excess zinc allowed to settle. The supernatant
solution was transferred to a separate reaction flask containing
a solution of (Ph3P)4Pd (2.80 g, 2.4 mmol) and 8 (75.0 g, 134
mmol) in THF (20 mL). The zinc was washed with THF (2 ×
200 mL), and these washings also transferred to the reaction
flask. The reaction mixture was stirred at 60 °C for 17 h and
then cooled to room temperature, diluted with ether, and
washed, sequentially, with saturated NH4Cl solution, 5% NH3
solution, water, and brine. The ether solution was then dried
over MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography (eluting with 40% EtOAc
in hexanes) to give 92.7 g of 1 as an oil (87%). 1H NMR (CDCl3)
δ 1.08 (s, 9H), 3.43 (s, 3H), 3.58 (m, 2H), 3.59 (s, 3H), 3.78 (m,
2H), 4.02 (s, 2H), 4.90 (s, 2H), 5.05 (s, 2H), 5.31 (s, 2H), 6.69
(d, J ) 2.7Hz , 1H), 6.95 (d, J ) 2.7 Hz, 1H), 7.10 (dd, J ) 8.6,
2.6 Hz, 1H), 7.2 (d, J ) 2.6 Hz, 1H), 7.25 (d, J ) 8.6 Hz, 1H),
7.3-7.5 (m, 11H), 7.55 (t, J ) 7.9 Hz, 2H), 7.68 (t, J ) 7.9 Hz,
1H), 7.77 (d, J ) 7.0 Hz, 4H), 8.24 (d, J ) 7.9 Hz, 2H); IR
(KBr) ν 3055 (m), 2952 (s) 2930 (s), 2890 (s), 2857 (s), 1733
(s), 1576 (m), 1496 (m), 1262 (s), 1061 (s) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 797 (MH)+. Anal. C49H52O8Si re-
quires C 73.8, H 6.6. Found C 73.5, H 6.6. Also isolated was
5.80 g of the homocoupled product5 1,2-bis(5-(ben zoyloxy)-
2-((2-m eth oxyeth oxy)m eth oxy)p h en yl)eth a n e as a white
solid, mp 118-119 °C. 1H NMR (CDCl3) δ 2.90 (s, 4H), 3.35
(s, 6H), 3.55 (m, 4H), 3.81 (m, 4H), 5.26 (s, 4H), 6.97 (dd, J )
8.8, 2.8 Hz, 2H), 7.0 (d, J ) 2.8 Hz, 2H), 7.18 (d, J ) 8.8 Hz,
2H), 7.48 (t, J ) 7.7 Hz, 4H), 7.61 (t, J ) 7.7 Hz, 2H), 8.17 (d,
J ) 7.7 Hz, 4H); IR (KBr) ν 3055 (w), 2928 (m), 1741 (s), 1593
(m), 1465 (s), 1263 (s), 1061 (s) cm-1; MS (FAB nitrobenzyl
Ben zoic Acid 3-F or m yl-4-((2-m et h oxyet h oxy)m et h -
oxy)p h en yl Ester (9). To a chilled (-10 °C) suspension of
NaH (10.1 g, 60% dispersion in mineral oil, 252 mmol) in THF
(250 mL) was added, over 45 min, a solution comprised of 2
(54.2 g, 224 mmol), MEM chloride (30 mL, 263 mmol), and
DMPU (30 mL) in THF (300 mL). The cold bath was then
removed and stirring continued for 4 h. The reaction was
quenched with HCl (30 mL, 1 M) and then diluted with ether.
The ether solution was washed sequentially with water and
brine, dried over MgSO4, and concentrated. The residue was
further dried by toluene azeotrope and the resulting white solid
used without further purification. 1H NMR (CDCl3) δ 3.39 (s,
3H), 3.59 (m, 2H), 3.89 (m, 2H), 5.42 (s, 2H), 7.36 (d, J ) 9
Hz, 1H), 7.41 (dd, J ) 9.0, 2.6 Hz, 1H), 7.52 (m, 2H), 7.64 (m,
1H), 7.67 (d, J ) 2.6 Hz, 1H), 8.18 (m, 2H), 10.48 (s, 1H); MS
(ion spray) m/z 331 (MH)+.
Ben zoic Acid 3-(Hydr oxym eth yl)-4-((2-m eth oxyeth oxy)-
m eth oxy)p h en yl Ester (10). The crude product 9 from the

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5185
alcohol) m/z 630 (M)+. Anal. C36H38O10 requires C 68.55, H
6.1. Found C 68.3, H 6.1.
The following compounds were prepared employing es-
sentially the same procedure:
2H), 4.05 (bs, 26H), 4.81 (s, 2H), 4.83 (s, 2H), 4.86 (s, 12H),
4.96 (s, 2H), 5.22 (s, 2H), 6.54 (d, J ) 3.0 Hz, 1H), 6.57 (bs,
13H), 6.63 (d, J ) 3.1 Hz, 1H), 6.74 (d, J ) 2.8 Hz, 1H), 6.78
(bs, 13H), 6.91 (d, J ) 2.8 Hz, 1H), 7.00 (dd, J ) 8.7, 2.8 Hz,
1H), 7.13 (d, J ) 3.0 Hz, 1H), 7.16-7.5 (m, 63H), 7.5-7.62
(m, 8H), 7.65-7.75 (m, 4H), 8.04-8.16 (m, 16H); IR (KBr) ν
3053 (w), 3023 (w), 2965 (m), 2936 (m), 2863 (m), 2823 (m),
1738 (s), 1600 (m), 1468 (s), 1452 (m), 1429 (m), 1314 (w), 1263
(s), 1233 (s), 1215 (s), 1172 (m), 1137 (m), 1080 (m), 1062 (s),
1038 (m), 1025 (m), 1006 (m) cm-1; MS (plasma desorption)
average mass measured 4064. Calculated (M)+ for C259H234O43-
Si ) 4063. Anal. C259H234O43Si requires C 76.56, H 5.81.
Found C 76.1, H 6.1. Also obtained was the homocoupled
product5 1,2-bis(5-(ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-(ben -
zyloxy)-3-(5-(b en zoyloxy)-3-(5-(b en zyloxy)-3-(5-(b en zo-
yloxy)-3-(5-(ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-(ben zyloxy)-
3-(5-(ben zoyloxy)-2-((2-m eth oxyeth oxy)m eth oxy)ben zyl)-
2-m eth oxyben zyl)-2-m eth oxyben zyl)-2-m eth oxyben zyl)-
2-m eth oxyben zyl)-2-m eth oxyben zyl)-2-m eth oxyben zyl)-
2 -m e t h o x y b e n z y l )-2 -m e t h o x y b e n z y l )-2 -m e t h o x y -
p h en yl)eth a n e. 1H NMR (CDCl3) δ 2.92 (bs, 4H), 3.32 (s,
6H), 3.47 (m, 4H), 3.60 (bs, 18H), 3.67 (bs, 28H), 4.02 (s, 4H),
4.08 (bs, 24H), 4.86 (bs, 12H), 4.92 (s, 4H), 5.23 (s, 4H), 6.55
(d, J ) 2.9 Hz, 2H), 6.59 (bs, 12H), 6.74 (d, J ) 3 Hz, 2H),
6.80 (bs, 10H), 6.94 (d, J ) 2.7 Hz, 2H), 7.02 (dd, J ) 9.0, 2.7
Hz, 2H), 7.20-7.38 (m, 44H), 7.4-7.52 (m, 16H), 7.52-7.63
(m, 8H), 8.03-8.20 (m, 16H); IR (KBr) ν 3054 (w), 3020 (w),
2965 (w), 2930 (m), 2863 (m), 2823 (m), 1741 (s), 1600 (m),
1467 (s), 1452 (m), 1429 (m), 1314 (w), 1263 (s), 1233 (s), 1214
(s), 1172 (m), 1137 (m), 1080 (m), 1062 (s), 1037 (m), 1025 (m),
1004 (m) cm-1; MS (plasma desorption) average mass mea-
sured 3884. Calculated (M)+ for C246H222O44 ) 3882. Anal.
C246H222O44 requires C 76.1, H 5.8. Found C 75.7, H 5.8.
Com p ou n d 58. Purified by flash chromatography (eluting
with 40 and then 50% EtOAc/10% CH2Cl2 in hexanes): 378
mg of 57 gave 449 mg of 58 as a foam (81%). 1H NMR (CDCl3)
δ 2.35 (s, 3H), 3.36 (s, 3H), 3.51 (m, 2H), 3.59 (s, 3H), 3.65 (s,
3H), 3.66 (s, 3H), 3.67 (s, 3H), 3.68 (s, 3H), 3.73 (m, 2H), 3.77
(s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 4.03 (s, 2H),
4.08 (s, 2H), 4.09 (s, 2H), 4.10 (s, 2H), 4.12 (s, 2H), 4.84 (s,
2H), 5.28 (s, 2H), 6.44 (d, J ) 3 Hz, 1H), 6.55 (d, J ) 3 Hz,
1H), 6.92 (d, J ) 3 Hz, 1H), 7.03 (dd, J ) 8, 3 Hz, 1H), 7.20 (d,
J ) 8 Hz, 1H), 7.27 (m, 5H), 7.48 (t, J ) 9 Hz, 2H), 7.63 (m,
7H) 7.71 (d, J ) 2.2 Hz, 1H), 7.79 (d, J ) 2 Hz, 1H), 8.17 (d,
J ) 9 Hz, 2H); MS (ion spray) m/z 1255 (MH)+, 1272 (MNH4)+.
Anal. C73H74O19 requires C 69.8, H 5.9. Found C 69.6, H 6.1.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(((ter t-bu tyld ip h en yl-
silyl)oxy)m eth yl)-2-m eth oxyben zyl)-4-h ydr oxy-5-iodoph e-
n yl Ester (22). To a solution of 1 (35.18 g, 44 mmol) in
2-propanol:THF (4:1, 150 mL) was added pyridinium tosylate
(11.1 g, 44 mmol). The resulting solution was stirred at 70
°C for 32 h, cooled to room temperature, diluted with ether,
washed, sequentially, with water and brine, dried over MgSO4,
filtered, and concentrated. The residue was further dried,
azeotropically, with toluene to give ben zoic a cid 3-(5-(ben -
zyloxy)-3-(((ter t-bu tyld ip h en ylsilyl)oxy)m eth yl)-2-m eth -
oxyben zyl)-4-h yd r oxyp h en yl ester (14). 1H NMR (CDCl3)
δ 1.08 (s, 9H), 3.70 (s, 3H), 3.80 (s, 2H), 4.78 (s, 2H), 4.97 (s,
2H), 6.80 (d, J ) 3 Hz, 1H), 6.84 (d, J ) 9 Hz, 1H), 6.95 (dd,
J ) 9, 3 Hz, 1H), 7.04 (d, J ) 3 Hz, 1H), 7.09 (d, J ) 3 Hz,
1H), 7.30 (s, 1H), 7.30-7.45 (m, 11H), 7.50 (m, 2H), 7.64 (m,
1H), 7.70 (m, 4H), 8.18 (m, 2H); IR (KBr) ν 3433 (m), 3068
(w), 2955 (m), 2931 (m), 2856 (m), 1733 (s), 1599 (m), 1496 (s),
1478 (s), 1452 (s), 1429 (s), 1267 (s), 1176 (s), 1145 (s), 1109
(s), 1063 (s) 704 (s) cm-1; MS (ion spray) m/z 709 (MH)+. Anal.
C45H44O6Si requires C 76.2, H 6.3. Found C 76.2, H 6.3. This
residue was then dissolved in CH2Cl2 (150 mL) and morpholine
added (8.7 mL, 100 mmol) followed by iodine (10.1 g, 40 mmol).
The resulting mixture was stirred at room temperature for 3
h, diluted with ether, and washed, sequentially, with HCl (60
mL, 1 M), saturated sodium thiosulfate solution, and brine.
The ether solution was then dried over MgSO4, filtered, and
concentrated and the residue purified by crystallization (20%
ethyl acetate in hexanes) to give 27.6 g of 14 as a white solid
(75% based on 1), mp 133-134 °C. 1H NMR (CDCl3) δ 1.09
(s, 9H), 3.67 (s, 3H), 3.85 (s, 2H), 4.79 (s, 2H), 4.97 (s, 2H),
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-m eth oxyben zyl)-2-m eth oxyben zyl)-4-
((2-m eth oxyeth oxy)m eth oxy)p h en yl Ester (29). Purified
by flash chromatography (30% and then 40% EtOAc in
hexanes): 34.0 g of 18 gave 41.72 g of 29 as a colorless oil
(83%). 1H NMR (CDCl3) δ 1.07 (s, 9H), 3.42 (s, 3H), 3.57 (s,
3H), 3.58 (m, 2H), 3.68 (s, 3H), 3.73 (s, 3H), 3.75 (m, 2H), 4.07
(bs, 4H), 4.14 (s, 2H), 4.88 (s, 2H), 4.93 (s, 2H), 5.04 (s, 2H),
5.31 (s, 2H), 6.61 (d, J ) 2.6 Hz, 1H), 6.62 (d, J ) 2.7 Hz, 1H),
6.70 (d, J ) 2.8 Hz, 1H), 6.80 (d, J ) 2.8 Hz, 1H), 6.85 (d, J )
2.8 Hz, 1H), 6.99 (d, J ) 2.7 Hz, 1H), 7.10 (dd, J ) 9.4, 2.8 Hz,
1H), 7.20 (d, J ) 2.8 Hz, 1H), 7.25 (d, J ) 9.4 Hz, 1H), 7.26-
7.5 (m, 16H), 7.5-7.58 (m, 4H), 7.63-7.70 (m, 2H), 7.85 (d, J
) 7.9 Hz, 4H), 8.16-8.27 (m, 4H); IR (KBr) ν 3059 (w), 3026
(w), 2930 (m), 2878 (m), 2817 (w), 1737 (s), 1599 (m), 1496
(m), 1469 (s), 1451 (m), 1428 (m), 1262 (s), 1207 (s), 1174 (m),
1110 (m), 1079 (m), 1061 (s), 1005 (m) cm-1; MS (FAB,
nitrobenzyl alcohol) m/z 1262 (M)+. Anal. C79H78O13Si re-
quires, C 75.1, H 6.2. Found C 74.7, H 6.3. Also obtained
was the homocoupled product5 1,2-bis(5-(ben zyloxy)-3-(5-
(b en zoyloxy)-2-((2-m et h oxyet h oxy)m et h oxy)b en zyl)-2-
m eth oxyp h en yl)eth a n e which solidified on standing, mp
102-103 °C. 1H NMR (CDCl3) δ 2.91 (s, 4H), 3.35 (s, 6H),
3.49 (m, 4H), 3.68 (s, 6H), 3.72 (m, 4H), 4.02 (s, 4H), 4.92 (s,
4H), 5.25 (s, 4H), 6.56 (d, J ) 2.9 Hz, 2H), 6.74 (d, J ) 2.9 Hz,
2H), 6.91 (d, J ) 2.8 Hz, 2H), 7.03 (dd, J ) 8.8, 2.8 Hz, 2H),
7.18 (d, J ) 8.8 Hz, 2H), 7.26-7.37 (m, 10H), 7.46 (t, J ) 7.7
Hz, 4H), 7.60 (t, J ) 7.7 Hz, 2H), 8.16 (d, J ) 7.7 Hz, 4H); IR
(KBr) ν 3082 (w), 3054 (w), 3029 (w), 2931 (m), 2878 (m), 2817
(m), 1738 (s), 1601 (m), 1498 (s), 1479 (m), 1467 (m), 1452 (m),
1425 (m), 1315 (m), 1263 (s), 1221 (m), 1201 (s), 1156 (m), 1079
(m), 1058 (s), 1037 (m), 1027 (m), 1004 (s) cm-1; MS (FAB,
nitrobenzyl alcohol) m/z 1082 (M)+. Anal. C66H66O14 requires
C 73.2, H 6.1. Found C 73.0, H 6.3.
Com p ou n d 35. Purified by flash chromatography (30%
EtOAc/20% CH2Cl2 in hexanes): 12.0 g of 34 gave 14.0 g of 35
(70%) as a white solid, mp 153-154 °C. 1H NMR (CDCl3) δ
1.08 (s, 9H), 3.33 (s, 3H), 3.46 (m, 2H), 3.47 (s, 3H), 3.58 (bs,
9H), 3.65 (s, 6H), 3.66 (s, 3H), 3.68 (m, 2H), 4.00 (s, 2H), 4.02
(s, 2H), 4.06 (bs, 10H), 4.81 (s, 2H), 4.86 (bs, 6H), 4.96 (s, 2H),
5.23 (s, 2H), 6.53 (d, J ) 3.0 Hz, 1H), 6.57, (bs, 5H), 6.64 (d, J
) 3.0 Hz, 1H), 6.74 (d, J ) 2.8 Hz, 1H), 6.79 (bs, 5H), 6.93 (d,
J ) 2.8 Hz, 1H), 7.02 (dd, J ) 8.9, 2.8 Hz, 1H), 7.13 (d, J )
3.0 Hz, 1H), 7.2-7.5 (m, 35H), 7.55-7.6 (m, 4H), 7.67-7.71
(m, 4H), 8.09-8.17 (m, 8H); IR (KBr) ν 3082 (w), 3054 (w),
3026 (w), 2931 (m), 2820 (m), 1736 (s), 1599 (m), 1471 (s), 1452
(m), 1429 (m), 1314 (w), 1263 (s), 1215 (s), 1173 (m), 1062 (s),
1006 (m) cm-1; MS (FAB, nitrobenzyl alcohol) m/z 2196 (MH)+.
Anal. C139H130O23Si requires C 76.0, H 6.0. Found C 75.5, H
6.0. Also obtained was 2.2 g of homocoupled product 1,2-bis-
(5-(b en zyloxy)-3-(5-(b en zoyloxy)-3-(5-(b en zyloxy)-3-(5-
(b en zoyloxy)-2-((2-m et h oxyet h oxy)m et h oxy)b en zyl)-2-
m et h oxyb en zyl)-2-m et h oxyb en zyl)-2-m et h oxyp h en yl)-
eth a n e. 1H NMR (CDCl3) δ 2.91 (s, 4H), 3.33 (s, 6H), 3.47
(m, 4H), 3.60 (s, 6H), 3.67 (s, 12H), 3.69 (m, 4H), 4.01 (s, 4H),
4.07 (s, 4H), 4.08 (s, 4H), 4.86 (s, 4H), 4.91 (s, 4H), 5.23 (s,
4H), 6.54 (d, J ) 3.0 Hz, 2H), 6.57 (bs, 4H), 6.74 (d, J ) 3.0
Hz, 2H), 6.77 (d, J ) 3.0 Hz, 2H), 6.79 (d, J ) 2.8 Hz, 2H),
6.92 (d, J ) 2.8 Hz, 2H), 7.01 (dd, J ) 8.8, 2.8 Hz, 2H), 7.17
(d, J ) 8.8 Hz, 2H), 7.15-7.48 (m, 20H), 7.5-7.62 (m, 8H),
7.65-7.75 (m, 4H), 8.08-8.19 (m, 8H); IR (KBr) ν 3082 (w),
3059 (w), 3019 (w), 2932 (m), 2871 (m), 2820 (w), 1735 (s), 1600
(m), 1496 (m), 1472 (s), 1452 (m), 1429 (m), 1314 (w), 1262 (s),
1213 (s), 1174 (m), 1137 (m), 1080 (s), 1062 (s), 1006 (m) cm-1
;
MS (FAB, nitrobenzyl alcohol) m/z 2016 (MH)+. Anal.
C126H118O24 requires C 75.1, H 5.9. Found C 74.7, H 6.0.
Com p ou n d 41. Purified by flash chromatography (15%
EtOAc/30% CH2Cl2 in hexanes): 670 mg of 40 gave 731 mg of
41 (62%) as a white amorphous solid. 1H NMR (CDCl3) δ 1.08
(s, 9H), 3.33 (s, 3H), 3.45 (m, 2H), 3.47 (s, 3H), 3.58 (bs, 21H),
3.64 (bs, 18H), 3.66 (s, 3H), 3.68 (m, 2H), 4.01 (s, 2H), 4.02 (s,

5186 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
6.75 (d, J ) 2.6 Hz, 1H), 7.0 (d, J ) 2.6 Hz, 1H), 7.1 (d, J )
2.6 Hz, 1H), 7.35-7.46 (m, 12H), 7.5 (t, J ) 7.9 Hz, 2H), 7.58-
7.7 (m, 5H), 8.17 (d, J ) 7.9 Hz, 2H); IR (KBr) ν 3284 (bm),
3051 (w), 2930 (m), 2855 (m), 1731 (s), 1601 (w), 1472 (m),
1268 (m), 1216 (m), 1105 (m), 1081 (m), 1055 (m) cm-1; MS
(FAB nitrobenzyl alcohol) m/z 834 (M)+.
purified by flash chromatography (30% Et2O in hexanes) to
give 35.4 g of 18 as a colorless oil (92%): 1H NMR (CDCl3) δ
1.08 (s, 9H), 3.48 (s, 3H), 3.70 (s, 3H), 4.02 (s, 2H), 4.81 (s,
2H), 4.99 (s, 2H), 6.58 (d, J ) 3 Hz, 1H), 6.85 (d, J ) 2.8 Hz,
1H), 7.14 (d, J ) 3 Hz, 1H), 7.24-7.40 (m, 12H), 7.52 (t, J )
7.5 Hz, 2H), 7.63 (t, J ) 7.5 Hz, 1H), 7.68 (d, J ) 6 Hz, 4H),
8.14 (d, J ) 7.5 Hz, 2H); IR (KBr) ν 3055 (w), 2950 (m), 2929
(m), 2855 (m), 1735 (s), 1593 (m), 1463 (s), 1426 (s), 1259 (s),
1206 (s), 1110 (s), 1077 (m), 1059 (s), 1001 (m) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 849 (MH)+, 848 (M)+.
The following compounds were prepared using essentially
the same procedure:
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-m eth oxyben zyl)-2-m eth oxyben zyl)-4-
h yd r oxy-5-iod op h en yl E st er (33). Purified by flash
chromatography (20% EtOAc/10% CH2Cl2 in hexanes): 20.7
g of 29 gave 17.9 g of 33 as a colorless oil (82%). 1H NMR
(CDCl3) δ 1.06 (s, 9H), 3.46 (s, 3H), 3.56 (s, 3H), 3.79 (s, 3H),
3.89 (s, 2H), 3.99 (s, 2H), 4.06 (s, 2H), 4.79 (s, 2H), 4.88 (s,
2H), 4.95 (s, 2H), 6.56 (d, J ) 3 Hz, 1H), 6.61 (d, J ) 3 Hz,
1H), 6.69 (d, J ) 3 Hz, 1H), 6.73 (m, 2H), 7.02 (d, J ) 2.7 Hz,
1H), 7.11 (d, J ) 3 Hz, 1H), 7.2-7.5 (m, 22H), 7.58 (m, 2H),
7.66 (m, 4H), 8.13 (m, 4H); IR (KBr) ν 3438 (bs), 3051 (w),
2930 (m), 2856 (m), 1734 (s), 1599 (m), 1471 (s), 1428 (m), 1262
(s), 1216 (s), 1174 (m), 1062 (s) cm-1; MS (FAB nitrobenzyl
alcohol) m/z 1300 (M)+.
The following compounds were prepared using essentially
the same procedure:
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-m eth oxyben zyl)-2-m eth oxyben zyl)-4-
m et h oxy-5-iod op h en yl E st er (34). Purified by flash
chromatography (10% EtOAc/10% CH2Cl2 in hexanes): 17.9
g of 33 gave 16.6 g of 34. 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.48
(s, 3H), 3.60 (s, 3H), 3.65 (s, 3H), 3.70 (s, 3H), 4.0 (s, 2H), 4.07
(s, 2H), 4.08 (s, 2H), 4.81 (s, 2H), 4.90 (s, 2H), 4.96 (s, 2H),
6.51 (d, J ) 3.0 Hz, 1H), 6.60 (d, J ) 3.0 Hz, 1H), 6.63 (d, J )
3.0 Hz, 1H), 6.74 (d, J ) 3.0 Hz, 1H), 6.77 (d, J ) 3.0 Hz, 1H),
6.90 (d, J ) 3.0 Hz, 1H), 7.12 (d, J ) 3.0 Hz, 1H), 7.16-7.4
(m, 16H), 7.4-7.5 (m, 4H), 7.52 (d, J ) 3.0 Hz, 1H), 7.60 (m,
2H), 7.69 (m, 4H), 8.13 (m, 4H); IR (KBr) ν 3055 (w), 3021
(w), 2929 (m), 2847 (m), 2824 (w), 1740 (s), 1593 (m), 1465 (s),
1428 (m), 1261 (s), 1247 (s), 1212 (s), 1169 (m), 1060 (s), 1002
(m) cm-1; MS (FAB nitrobenzyl alcohol) m/z 1314 (M)+.
Com p ou n d 40. Purified by flash chromatography (10%
EtOAc/30% CH2Cl2 in hexanes): 1.45 g of 39 gave 1.34 g of
40. 1H NMR (CDCl3) δ 1.08 (s, 9H), 3.47 (s, 3H), 3.58 (bs, 9H),
3.64 (bs, 9H), 3.68 (s, 3H), 4.01 (s, 2H), 4.05 (s, 12H), 4.81 (s,
2H), 4.86 (bs, 4H), 4.88 (s, 2H), 4.96 (s, 2H), 6.51 (d, J ) 3.0
Hz, 1H), 6.57 (bs, 4H), 6.60 (d, J ) 2.7 Hz, 1H), 6.63 (d, J )
3.0 Hz, 1H), 6.73 (d, J ) 3.0 Hz, 1H), 6.78 (bs, 5H), 6.91 (d, J
) 2.7 Hz, 1H), 7.13 (d, J ) 3.0 Hz, 1H), 7.15-7.50 (m, 34H),
7.52 (d, J ) 3.0 Hz, 1H), 7.53-7.60 (m, 4H), 7.65-7.71 (m,
4H), 8.05-8.15 (m, 8H); IR (KBr) ν 3082 (w), 3054 (w), 3024
(w), 2930 (m), 2863 (m), 2820 (w), 1737 (s), 1599 (s), 1470 (s),
1452 (m), 1428 (m), 1314 (w), 1262 (s), 1215 (s), 1172 (m), 1138
(m), 1080 (s), 1062 (s), 1025 (m), 1007 (m) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 2284 (MH)+.
Com p ou n d 39. Purified by flash chromatography (15%
EtOAc/20% CH2Cl2 in hexanes): 2.19 g of 35 gave 1.76 g of 39
as a white solid, mp 153-156 °C dec (79%). 1H NMR (CDCl3)
δ 1.08 (s, 9H), 3.46 (s, 3H), 3.59 (bs, 9H), 3.65 (bs, 6H), 3.80
(s, 3H), 3.92 (s, 2H), 4.01 (s, 2H), 4.07 (bs, 10H), 4.82 (s, 2H),
4.87 (s, 4H), 4.90 (s, 2H), 4.96 (s, 2H), 6.57 (bs, 4H), 6.59 (d, J
) 3.0 Hz, 1H), 6.63 (d, J ) 3.0 Hz, 1H), 6.70 (d, J ) 3.0 Hz,
1H), 6.73 (d, J ) 3.0 Hz, 1H), 6.77 (bs, 3H), 6.80 (d, J ) 3.0
Hz, 1H), 7.04 (d, J ) 3.0 Hz, 1H), 7.13 (d, J ) 3.0 Hz, 1H),
7.15-7.64 (m, 40H), 7.66-7.71 (m, 4H), 8.05-8.19 (m, 8H);
IR (KBr) ν 3443 (b), 3059 (w), 3020 (w), 2929 (m), 2874 (m),
2859 (m), 2816 (m), 1742 (s), 1591 (m), 1465 (s), 1452 (s), 1428
(s), 1315 (w), 1263 (s), 1250 (s), 1233 (s), 1214 (s), 1160 (m),
1136 (m), 1079 (m), 1061 (s), 1036 (s), 1025 (s), 1002 (m) cm-1
;
MS (FAB nitrobenzyl alcohol) m/z 2235 (MH)+.
(5-(Be n zyloxy)-3-(5-h yd r oxy-4-iod o-2-((2-m e t h oxy-
et h oxy)m et h oxy)b en zyl)-2-m et h oxyb en zyloxy)-ter t-b u -
tyld ip h en ylsila n e (23). To a solution comprised of morpho-
line (0.66 mL, 7.6 mmol) and 15 (2.0 g, 2.9 mmol) in CH2Cl2
(9 mL), cooled to -10 °C, was added, dropwise, a solution of
iodine (0.75 g, 2.95 mmol) in CH2Cl2 (20 mL) over 15 min. The
resulting mixture was stirred at -10 °C for 7 h, diluted with
ether, and washed, sequentially, with HCl (4.5 mL, 1 M),
water, sodium bisulfite solution, and brine. The ether solution
was dried over MgSO4, filtered, and concentrated. The residue
was then purified by flash chromatography (eluting with 20%
EtOAc in hexanes) to give 1.90 g of 23 as a viscous oil (80%).
1H NMR (CDCl3) δ 1.08 (s, 9H), 3.35 (s, 3H), 3.48 (s, 3H), 3.49
(m, 2H), 3.68 (m, 2H), 3.84 (s, 2H), 4.81 (s, 2H), 4.95 (s, 2H),
4.97 (s, 1H), 5.11 (s, 2H), 6.52 (d, J ) 3 Hz, 1H), 6.64 (s, 1H),
7.13 (d, J ) 3 Hz, 1H), 7.35 -7.42 (m, 12H), 7.69 (m, 4H); IR
(KBr) ν 3507 (w), 3009 (m), 2931 (m), 1482 (s), 1106 (s), 1008
(s), 702 (m) cm-1; MS (ion spray) m/z 819 (MH)+.
3-Iod o-4-m eth oxy-5-(2-m eth oxy-4-(m eth oxyca r bon yl)-
3-(2-m eth oxy-4-(m eth oxyca r bon yl)-3-(3-(m eth oxyca r bo-
n yl)-5-m eth ylben zyl)ben zyl)ben zyl)ben zoic Acid Meth yl
Ester (57). Purified by flash chromatography (20% EtOAc
in hexanes): 402 mg of 56 gave 388 mg of 57 (95%). 1H NMR
(CDCl3) δ 2.34 (s, 3H), 3.65 (s, 3H), 3.66 (s, 3H), 3.67 (s, 3H),
3.76 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.84 (s, 6H), 4.09 (s,
2H), 4.13 (bs, 4H), 7.63 (bs, 4H), 7.66 (d, J ) 2 Hz, 1H), 7.72
(d, J ) 2 Hz, 1H), 7.79 (d, J ) 2 Hz, 1H), 8.36 (d, J ) 2 Hz,
1H); IR (KBr) ν 3028 (w), 3011 (w), 2952 (w), 1716 (s), 1603
(w), 1438 (m), 1310 (s), 1287 (s), 1231 (m), 1205 (s), 1165 (m),
1006 (s) cm-1; MS (FAB nitrobenzyl alcohol) m/z 841 (MH)+.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(h yd r oxym eth yl)-2-
m eth oxyben zyl)-4-((2-m eth oxyeth oxy)m eth oxy)ph en yl Es-
ter (16). To a solution of 1 (92.7 g, 116 mmol) in THF (150
mL) was added acetic acid (10.0 mL, 175 mmol) followed by
Bu4NF (162 mL, 1 M in THF). The resulting solution was
stirred for 1 h, diluted with ether, washed with water and then
brine, dried over MgSO4, and concentrated. The residue was
purified by flash chromatography (60% EtOAc in hexanes) to
give 61.98 g of product as an oil which solidified on standing
(95%), mp 57-58 °C. 1H NMR (CDCl3) δ 2.1 (bs, 1H), 3.34 (s,
3H), 3.49 (m, 2H), 3.68 (m, 2H), 3.72 (s, 3H), 4.0 (s, 2H), 4.7
(s, 2H), 4.95 (s, 2H), 5.23 (s, 2H), 6.64 (d, J ) 3 Hz, 1H), 6.87
(d, J ) 3 Hz, 1H), 6.89 (d, J ) 2.8 Hz, 1H), 7.02 (dd, J ) 8.8,
2.8 Hz, 1H), 7.16 (d, J ) 8.8 Hz, 1H), 7.2-7.4 (m, 5H), 7.5 (t,
J ) 7.6 Hz, 2H), 7.61 (m, 1H), 8.15 (m, 2H); IR (KBr) ν 3432
(bs), 3051 (m), 3019 (m), 2925 (s), 2886 (s), 2828 (s), 1730 (s),
Also prepared using essentially the same procedure:
5-(Ben zyloxy)-3-(2-(ben zyloxy)-5-h ydr oxy-4-iodoben zyl)-
2-m eth oxyben zyloxy)-ter t-bu tyld ip h en ylsila n e (60). Pu-
rified by flash chromatography (10% ethyl acetate in hex-
anes): 608 mg of 59 gave 632 mg of 60 (89%).1H NMR (CDCl3)
δ 1.11 (s, 9H), 3.39 (s, 3H), 3.89 (s, 2H), 4.80 (s, 2H), 4.89 (s,
2H), 4.93 (s, 2H), 6.55 (d, J ) 3 Hz, 1H), 6.67 (s, 1H), 7.13 (s,
1H), 7.14 (d, J ) 3 Hz, 1H), 7.2-7.45 (m, 16H), 7.67 (m, 4H);
MS (CI) m/z 820 (MH)+.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(((ter t-bu tyld ip h en yl-
silyl)oxy)m eth yl)-2-m eth oxyben zyl)-4-m eth oxy-5-iodoph e-
n yl Ester (18). To a suspension of NaH (1.89 g, 60%
dispersion in mineral oil, 47 mmol) in THF (50 mL), cooled to
-15 °C, was added a solution comprised of 22 (37.7 g, 45 mmol)
and iodomethane (7.1 mL, 114 mmol) in DMPU/THF (1:7, 100
mL). The resulting solution was allowed to warm to room
temperature and stirred for 2.5 h. The reaction was quenched
with HCl (2 mL, 2 M) and then diluted with ether. The ether
solution was washed, sequentially, with water (3×) and brine,
dried over MgSO4, filtered, and concentrated and the residue
1574 (m), 1466 (s), 1364 (m), 1302 (s), 1231 (s), 1168 (s) cm-1
;
MS (FAB nitrobenzyl alcohol), m/z 558 (M)+. Anal. C33H34O8
requires C 70.9, H 6.1. Found C 70.6, H 6.1.
The following compounds were prepared using essentially
the same procedure:

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5187
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(ben zyloxy)-3-(h ydr oxym eth yl)-2-m eth oxyben zyl)-2-m eth -
oxyb e n zyl)-2-m e t h oxyb e n zyl)-4-((2-m e t h oxye t h oxy)-
m et h oxy)p h en yl E st er (30). Purified by flash chroma-
tography (50% EtOAc in hexanes): 16.8 g of 29 gave 11.29 g
of 30 (83%). 1H NMR (CDCl3) δ 1.6 (bs, 1H), 3.33 (s, 3H), 3.48
(m, 2H), 3.61 (s, 3H), 3.66 (s, 3H), 3.67 (m, 2H), 3.70 (s, 3H),
4.01 (s, 2H), 4.05 (s, 2H), 4.07 (s, 2H), 4.70 (s, 2H), 4.86 (s,
2H), 4.96 (s, 2H), 5.22 (s, 2H), 6.54 (d, J ) 3.0 Hz, 1H), 6.56
(d, J ) 3.0 Hz, 1H), 6.68 (d, J ) 3.0 Hz, 1H), 6.75 (d, J ) 3.0
Hz, 1H), 6.79 (d, J ) 3.0 Hz, 1H), 6.92 (d, J ) 3.0 Hz, 1H),
7.03 (dd, J ) 7.9, 3.0 Hz, 1H), 7.18 (d, J ) 7.9 Hz, 1H),
7.2-7.4 (m, 10H), 7.47 (m, 4H), 7.60 (m, 2H), 8.13 (m, 4H); IR
(KBr) ν 3443 (bm), 3056 (w), 3021 (w), 2932 (m), 2876 (m),
2817 (m), 1734 (s), 1600 (m), 1496 (m), 1472 (s), 1452 (s), 1430
(m), 1314 (w), 1262 (s), 1207 (s), 1173 (m), 1080 (s), 1062 (s),
1025 (s), 1004 (s) cm-1; MS (FAB nitrobenzyl alcohol) m/z 1024
(M)+.
1264 (s), 1198 (s), 1150 (m), 1061 (s) cm-1; MS (FAB nitroben-
zyl alcohol) m/z 622, 620 (M)+.
The following compounds were prepared using essentially
the same procedure:
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(ben zyloxy)-3-(br om om eth yl)-2-m eth oxyben zyl)-2-m eth -
oxyb e n zyl)-2-m e t h oxyb e n zyl)-4-((2-m e t h oxye t h oxy)-
m et h oxy)p h en yl E st er (31). Purified by flash chroma-
tography (20% EtOAc/10% CH2Cl2 in hexanes): 11.29 g of 30
gave 11.48 g of 31 (96%). 1H NMR (CDCl3) δ 3.33 (s, 3H), 3.49
(m, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.70 (m, 2H), 3.80 (s, 3H),
4.01 (s, 2H), 4.05 (s, 2H), 4.08 (s, 2H), 4.55 (s, 2H), 4.86 (s,
2H), 4.95 (s, 2H), 5.23 (s, 2H), 6.55 (d, J ) 2.8 Hz, 1H), 6.56
(d, J ) 2.8 Hz, 1H), 6.69 (d, J ) 2.7 Hz, 1H), 6.75 (d, J ) 2.7
Hz, 1H), 6.80 (d, J ) 2.8 Hz, 1H), 6.88 (d, J ) 2.7 Hz, 1H),
6.92 (d, J ) 2.7 Hz, 1H), 7.02 (dd, J ) 8.7, 2.7 Hz, 1H), 7.19
(d, J ) 8.7 Hz, 1H), 7.2-7.38 (m, 10H), 7.42-7.51 (m, 4H),
7.57-7.64 (m, 2H), 8.1-8.2 (m, 4H); MS (FAB nitrobenzyl
alcohol) m/z 1088, 1086 (M)+.
Com p ou n d 36. Purified by flash chromatography (40%
EtOAc/30% CH2Cl2 in hexanes): 2.0 g of 35 gave 1.66 g of 36
Com p ou n d 37. Purified by flash chromatography (30%
EtOAc/30% CH2Cl2 in hexanes): 1.8 g of 36 gave 1.66 g of 37
as a white solid, mp 151-152 °C (89%). 1H NMR (CDCl3) δ
3.31 (s, 3H), 3.46 (m, 2H), 3.56 (bs, 9H), 3.64 (bs, 9H), 3.68
(m, 2H), 3.80 (s, 3H), 4.00 (s, 2H), 4.05 (s, 2H), 4.06 (bs, 10H),
4.54 (s, 2H), 4.85 (bs, 6H), 4.93 (s, 2H), 5.23 (s, 2H), 6.54 (d, J
) 2.9 Hz, 1H), 6.57 (bs, 5H), 6.68 (d, J ) 2.7 Hz, 1H), 6.74 (d,
J ) 2.7 Hz, 1H), 6.75 (bs, 5H), 6.87 (d, J ) 2.7 Hz, 1H), 6.91
(d, J ) 2.7 Hz, 1H), 7.01 (dd, J ) 8.8, 2.7 Hz, 1H), 7.16 (d, J
) 8.8 Hz, 1H), 7.18-7.38 (m, 20H), 7.38-7.5 (m, 8H), 7.5-
7.62 (m, 4H), 8.07-8.18 (m, 8H); IR (KBr) ν 3051 (w), 3024
(w), 2929 (m), 2867 (m), 2823 (m), 1742 (s), 1593 (m), 1465 (s),
1452 (m), 1425 (m), 1314 (w), 1264 (s), 1233 (s), 1213 (s), 165
as a white solid, mp 153-155 °C (93%). 1H NMR (CDCl ) δ
3
3.33 (s, 3H), 3.46 (m, 2H), 3.58 (bs, 9H), 3.63 (bs, 9H), 3.66
(m, 2H), 3.67 (s, 3H), 4.00 (s, 2H), 4.04 (s, 2H), 4.05 (s, 10H),
4.71 (s, 2H), 4.86 (bs, 6H), 4.96 (s, 2H), 5.22 (s, 2H), 6.54 (d, J
) 3.0 Hz, 1H), 6.57 (bs, 5H), 6.68 (d, J ) 3.0 Hz, 1H), 6.74 (d,
J ) 3.0 Hz, 1H), 6.80 (bs, 5H), 6.88 (d, J ) 2.8 Hz, 1H), 6.91
(d, J ) 3.0 Hz, 1H), 7.03 (dd, J ) 8.8, 3.0 Hz, 1H), 7.18 (d, J
) 8.8 Hz, 1H), 7.18-7.50 (m, 28H), 7.51-7.62 (m, 4H), 8.06-
8.18 (m, 8H); IR (KBr) ν 3436 (b), 3082 (w), 3059 (w), 3024
(w), 2936 (m), 2874 (m), 2823 (m), 1736 (s), 1590 (m), 1469 (s),
1452 (s), 1429 (m), 1315 (w), 1262 (s), 1215 (s), 1173 (s), 1137
(m), 1080 (s), 1062 (s), 1025 (m), 1006 (m) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 1959 (MH)+.
(m), 1136 (m), 1061 (s), 1036 (m), 1025 (m), 1003 (m) cm-1
;
MS (FAB nitrobenzyl alcohol) m/z 2022, 2020 (M)+.
Com p ou n d 43. Purified by flash chromatography (30%
EtOAc/30% CH2Cl2 in hexanes): 1.5 g of 42 gave 1.22 g of 43
as a white solid, mp 78-80 °C (91%). 1H NMR (CDCl 3) δ 1.40
(s, 9H), 1.41 (s, 18H), 1.45 (s, 9H), 1.7 (bs, 1H), 3.34 (s, 3H),
3.50 (m, 2H), 3.57 (bs, 9H), 3.65 (s, 9H), 3.70 (m, 2H), 3.71 (s,
3H), 3.96 (s, 2H), 4.01 (s, 2H), 4.02 (s, 10H), 4.30 (s, 2H), 4.31
(s, 4H), 4.40 (s, 2H), 4.71 (s, 2H), 4.81 (s, 6H), 4.94 (s, 2H),
5.16 (s, 2H), 6.46 (m, 2H), 6.49 (m, 10H), 6.62 (d, J ) 3 Hz,
1H), 6.69 (m, 2H), 6.85 (d, J ) 3 Hz, 1H), 7.06 (m, 1H), 7.15-
7.36 (m, 20H); IR (CHCl3) ν 3011 (w), 2935 (w), 1749 (s), 1594
(w), 1474 (s), 1370 (m), 1230 (s), 1213 (s), 1147 (s), 1082 (m),
1009 (m) cm-1; MS (ion spray) m/z 1999 (MH)+. Anal.
2-((2-Meth oxyeth oxy)m eth oxy)-5-((5-(ben zyloxy)-3-(5-
(ben zyloxy)-3-(br om om eth yl)-2-m eth oxyben zyl)-2-((((ter t-
bu tyloxycar bon yl)m eth yl)oxy)ph en yl)eth yl)ben zoic Acid
Meth yl Ester (65). Purified by flash chromatography (30%
EtOAc/20% CH2Cl2 in hexanes): 360 mg of 64 gave 343 mg of
65 (89%). 1H NMR (C6D6) δ 1.28 (s, 9H), 2.94 (m, 2H), 3.00
(m, 2H), 3.02 (s, 3H), 3.23 (m, 2H), 3.50 (s, 3H), 3.54 (s, 3H),
3.66 (m, 2H), 4.05 (s, 2H), 4.16 (s, 2H), 4.30 (s, 2H), 4.57 (s,
2H), 4.61 (s, 2H), 5.03 (s, 2H), 6.53 (s, 1H), 6.56 (s, 1H), 6.75
(d, J ) 3 Hz, 1H) 7.0-7.22 (m, 12H), 7.83 (d, J ) 2.1 Hz, 1H);
IR (CHCl3) ν 3011 (m), 2983 (w), 2948 (w), 2932 (w), 1749 (s),
1718 (s), 1600 (w), 1505 (s), 1499 (s), 1477 (m), 1465 (m), 1437
(m), 1232 (s), 1203 (s), 1154 (s), 1077 (s), 1002 (s) cm-1; MS
(ion spray) m/z 916, 918 (MNH4)+ Br pattern.
C
119H136O27 requires C 71.5, H 6.9. Found C 71.6, H 7.0.
2-((2-Meth oxyeth oxy)m eth oxy)-5-((5-(ben zyloxy)-3-(5-
(b e n zyloxy)-3-(h yd r oxym e t h yl)-2-m e t h oxyb e n zyl)-2-
((((t er t -b u t yloxyca r b on yl)m e t h yl)oxy)p h e n yl)e t h yl)-
b en zoic Acid Met h yl E st er (64). Purified by flash
chromatography (40% EtOAc/20% CH2Cl2 in hexanes): 500 mg
of 63 gave 365 mg of 64 (93%). 1H NMR (CDCl3) δ 1.44 (s,
9H), 2.23 (t, J ) 7 Hz, 1H), 2.90 (m, 4H), 3.37 (s, 3H), 3.52 (m,
2H), 3.62 (s, 3H), 3.87 (m, 2H), 3.87 (s, 3H), 3.93 (s, 2H), 4.48
(s, 2H), 4.68 (d, J ) 7 Hz, 2H), 4.90 (s, 2H), 4.91 (s, 2H), 5.30
(s, 2H), 6.51 (s, 1H), 6.57 (d, J ) 3 Hz, 1H), 6.69 (s, 1H), 6.86
(d, J ) 3 Hz, 1H), 7.15 (d, J ) 8 Hz, 1H), 7.20-7.40 (m, 11H),
7.64 (d, J ) 2 Hz, 1H); MS (ion spray) m/z 854 (MNH4)+.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(br om om eth yl)-2-m eth -
oxyben zyl)-4-((2-m eth oxyeth oxy)m eth oxy)p h en yl Ester
(27). To a solution of benzylic alcohol 16 (27.85 g, 50 mmol)
in THF (250 mL), cooled to 10 °C, was added Ph3P (14.41 g,
55 mmol) followed by NBS (9.61 g, 54 mmol). On complete
addition, the reaction mixture was allowed to warm to room
temperature, stirred for 20 min, and then concentrated under
reduced pressure. The residue was purified by flash chroma-
tography (40% EtOAc in hexanes) to give 30.12 g of 27 as a
colorless oil, which solidified on standing (97%), mp 73-74 °C.
1H NMR (CDCl3) δ 3.38 (s, 3H), 3.46 (m, 2H), 3.66 (m, 2H),
3.80 (s, 3H), 3.98 (s, 2H), 4.54 (s, 2H), 4.92 (s, 2H), 5.22 (s,
2H), 6.62 (d, J ) 3 Hz, 1H), 6.83 (d, J ) 3 Hz, 1H), 6.90 (d, J
) 3 Hz, 1H), 7.03 (dd, J ) 8.7, 3 Hz, 1H), 7.18 (d, J ) 8.7 Hz,
1H), 7.25-7.4 (m, 5H), 7.49 (t, J ) 8.5 Hz, 2H), 7.61 (t, J )
8.5 Hz, 1H), 8.17 (d, J ) 8.5 Hz, 2H); IR (KBr) ν 3041 (w),
2931 (m), 2876 (m), 2822 (w), 1733 (s), 1489 (m), 1456 (m),
Ben zoic Acid 3-(5-(Ben zyloxy)-3-(5-(ben zoyloxy)-3-(5-
(ben zyloxy)-3-m eth yl-2-m eth oxyben zyl)-2-m eth oxyben -
zyl)-2-m et h oxyb en zyl)-4-((2-m et h oxyet h oxy)m et h oxy)-
p h en yl Ester (50). To a suspension of zinc dust (3.6 g, 55
mmol, 325 mesh) in THF (10 mL) was added 1,2-dibromoet-
hane (112 µL, 1.3 mmol). The resulting mixture was heated
to reflux and then stirred vigorously for 1.5 min. Upon cooling
to room temperature, a solution comprised of 31 (3.3 g, 3 mmol)
and acetic acid (1.2 mL, 19.5 mmol) in DMF (15 mL) was
added. This mixture was stirred for 17 h, diluted with EtOAc,
and filtered to remove excess zinc. The filtrate was washed
with water and brine, dried over MgSO4, filtered, and then
concentrated. The residue was purified by flash chromatog-
raphy (30% EtOAc/20% CH2Cl2 in hexanes) to give 2.61 g of
50 (86%) as a viscous oil. 1H NMR (CDCl3) δ 2.27 (s, 3H), 3.33
(s, 3H), 3.47 (m, 2H), 3.61 (s, 3H), 3.63 (s, 3H), 3.67 (s, 3H),
3.69 (m, 2H), 4.01 (s, 2H), 4.04 (s, 2H), 4.08 (s, 2H), 4.86 (s,
2H), 4.93 (s, 2H), 5.22 (s, 2H), 6.55 (m, 3H), 6.66 (d, J ) 2.9
Hz, 1H), 6.75 (d, J ) 2.9 Hz, 1H), 6.78 (d, J ) 2.9 Hz, 1H),
6.92 (d, J ) 2.9 Hz, 1H), 7.17 (dd, J ) 8.8, 2.9 Hz, 1H), 7.25
(d, J ) 8.8 Hz, 1H), 7.25-7.40 (m, 10H), 7.40-7.51 (m, 4H),
7.54-7.63 (m, 2H), 8.05-8.18 (m, 4H); IR (KBr) ν 3063 (w),
3035 (w), 2935 (m), 2830 (w), 1731 (s), 1598 (m), 1494 (s), 1452
(s), 1250 (s), 1209 (s), 1059 (s) cm-1
; MS (FAB nitrobenzyl
alcohol) m/z 1008, (M)+. Anal. C63H60O12 requires C 75.0, H
5.6. Found C 74.7, H 5.8.
The following compounds were prepared using essentially
the same procedure:

5188 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
Com p ou n d 46. Purified by flash chromatography (15%
EtOAc/30% CH2Cl2 in hexanes): 500 mg of 37 gave 464 mg of
46 as a white solid, mp 154-155 °C (86%). 1H NMR (CDCl3)
δ 2.27 (s, 3H), 3.33 (s, 3H), 3.47 (m, 2H), 3.59 (s, 3H), 3.60 (s,
3H), 3.61 (s, 3H), 3.63 (s, 3H), 3.65 (s, 3H), 3.69 (m, 2H), 4.01
(s, 2H), 4.04 (s, 2H), 4.08 (s, 10H), 4.86 (s, 6H), 4.93 (s, 2H),
5.22 (s, 2H), 6.55 (m, 7H), 6.66 (d, J ) 2.9 Hz, 1H), 6.75 (d, J
) 2.9 Hz, 1H), 6.78 (m, 6H), 6.92 (d, J ) 2.9 Hz, 1H), 7.02 (dd,
J ) 9, 2.8 Hz, 1H), 7.12-7.38 (m, 21H), 7.38-7.5 (m, 8H), 7.58
(m, 4H), 8.05-8.18 (m, 8H); IR (KBr) ν 3054 (w), 2928 (w),
1741 (s), 1593 (m), 1466 (s), 1314 (w), 1263 (s), 1214 (s), 1061
(s) cm-1; MS (ion spray) m/z 1943 (MH)+. Anal. C123H112O22
requires C 76.1, H 5.8. Found C 75.9, H 6.0.
Com p ou n d 53. To a solution of 50 (1.91 g 1.89 mmol)
dissolved in DMF:MeOH (1:1, 10 mL) was added 10% pal-
ladium on carbon (400 mg). The resulting suspension was
stirred under a hydrogen atmosphere for 18 h. The catalyst
was then filtered and the filtrate concentrated. The residue
was dissolved in THF:MeOH (1:1, 10 mL) and cooled to -10
°C and sodium methoxide (2.1 mL, 25 wt % in methanol, 10
mmol) added. The resulting solution was stirred for 40 min
and then quenched with HCl (10 mL, 1 M). The product was
extracted with EtOAc/CH2Cl2, washed with brine (3×), dried
over MgSO4, and concentrated. The residue was further dried
by toluene azeotrope and then added to a solution comprised
of N-phenyltriflimide (3.46 g, 9.7 mmol) and DMPU (1 mL) in
THF (5 mL). This solution was then added to a slurry of NaH
(400 mg, 60% dispersion in mineral oil, 10 mmol) in THF (3
mL) which had been cooled to 0 °C. The resulting mixture
was allowed to come to room temperature and stirred for 1 h.
The reaction mixture was then concentrated and the residue
purified by flash chromatography (eluting with 30% CH2Cl2/
5% EtOAc in hexanes) to give 1.907 g of 53 as a viscous oil
(88%). 1H NMR (CDCl3) δ 2.32 (s, 3H), 3.35 (s, 3H), 3.51 (m,
2H), 3.65 (s, 3H), 3.66 (bs, 6H), 3.68 (m, 2H), 4.01 (s, 2H), 4.04
(s, 2H), 4.09 (s, 2H), 5.27 (s, 2H), 6.78 (d, J ) 3 Hz, 1H), 6.81
(d, J ) 3 Hz, 1H), 6.84 (bs, 3H), 6.99 (d, J ) 3 Hz, 1H), 7.01
(d, J ) 3 Hz, 1H), 7.12 (dd, J ) 9, 3 Hz, 1H), 7.23 (d, J ) 9 Hz,
1H); IR (KBr) ν 2946 (w), 2937 (w), 2837 (w), 1591 (w), 1471
(m), 1422 (s), 1212 (s), 1140 (s), 842 (m) cm-1; MS (ion spray)
m/z 1149 (MH)+.
(d, J ) 9 Hz, 1H), 7.60 (m, 4H), 7.61 (d, J ) 3 Hz, 1H), 7.76 (d,
J ) 2.1 Hz, 1H), 7.79 (d, J ) 2.2 Hz, 1H), 7.89 (dd, J ) 9,
2.2Hz 1H); IR (KBr) ν 2988 (w), 2949 (w), 2833 (w), 1716 (s),
1603 (w), 1434 (m), 1307 (s), 1267 (m), 1236 (m), 1203 (s), 1163
(s), 1003 (s) cm-1; MS (FAB nitrobenzyl alcohol) m/z 789 (MH)+.
Anal. C43H48O14 requires C 65.5, H 6.1. Found C 65.5, H 6.3.
3-Iod o-4-h yd r oxy-5-(2-m eth oxy-4-(m eth oxyca r bon yl)-
3-(2-m eth oxy-4-(m eth oxyca r bon yl)-3-(3-(m eth oxyca r bo-
n yl)-5-m eth ylben zyl)ben zyl)ben zyl)ben zoic Acid Meth yl
Ester (56). To a solution of 54 (470 mg, 0.596 mmol) in MeOH
(3 mL) was added 1 drop of concd sulfuric acid. The resulting
solution was heated to 60 °C and stirred at this temperature
for 2 h. The reaction mixture was diluted with EtOAc, washed
with water and then brine, dried over MgSO4, and concen-
trated. The residue was taken up in CH2Cl2 (2.0 mL) and
cooled to 10 °C. To this solution was added morpholine (120
µL, 1.4 mmol) followed by iodine (150 mg, 0.59 mmol). The
cold bath was removed and stirring continued for 3 h, HCl
(1.0 mL, 1 M) was added, and the resulting mixture was
diluted with EtOAc, washed with water and then brine, dried
over MgSO4, and concentrated. The residue was purified by
flash chromatography (eluting with 30% EtOAc/10% CH2Cl2
in hexanes to give 411 mg of 56 (84% based on 54). 1H NMR
(CDCl3) δ 2.33 (s, 3H), 3.65 (s, 3H), 3.66 (s, 3H), 3.79 (s, 3H),
3.81 (s, 6H), 3.84 (s, 3H), 3.87 (s, 3H), 4.04 (s, 2H), 4.08 (s,
2H), 4.13 (s, 2H), 7.52 (s, 1H), 7.62 (m, 3H), 7.65 (d, J ) 2 Hz,
1H), 7.78 (bs, 2H), 7.89 (d, J ) 2 Hz, 1H), 8.28 (d, J ) 2 Hz,
1H); IR (CHCl3) ν 3250 (bw), 3026 (w), 3013 (w), 2952 (w), 1716
(s), 1603 (w), 1436 (m), 1303 (bs), 1234 (m), 1206 (s), 1007 (m)
cm-1; MS (FAB nitrobenzyl alcohol) m/z 827 (MH)+.
5-(Be n zyloxy)-2-m e t h oxy-3-(2-((2-m e t h oxye t h oxy)-
m eth oxy)-5-(ben zoyloxy)ben zyl)ben za ld eh yd e (24). To
a solution of (COCl)2 in CH2Cl2 (2.7 mL, 2 M, 5.4 mmol) cooled
to -78 °C was added, dropwise, DMSO (0.5 mL, 7.05 mmol).
The resulting mixture was stirred for 5 min and then a solution
of 16 (1.49 g, 2.67 mmol) in CH2Cl2 (4.0 mL) added dropwise.
This solution was stirred for 5 min and then Et3N (2.5 mL, 18
mmol) added. The cold bath was removed and stirring
continued for 20 min. The reaction mixture was then diluted
with ether, washed with water and then brine, dried over
MgSO4, filtered, and concentrated. The residue was purified
by flash chromatography (eluting with 30% EtOAc/10% CH2-
Cl2 in hexanes) to give 1.36 g of 24 as a white solid (91%), mp
70-71.5 °C. 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.48 (m, 2H),
3.70 (m, 2H), 3.86 (s, 3H), 5.00 (s, 2H), 5.25 (s, 2H), 6.93 (d, J
) 2.9 Hz, 1H), 7.00 (d, J ) 2.9 Hz, 1H), 7.04 (dd, J ) 8.8, 2.9
Hz, 1H), 7.20 (d, J ) 8.8 Hz, 1H), 7.25 (d, J ) 2.9 Hz, 1H), 7.4
(m, 5H), 7.5 (m, 2H), 7.62 (m, 1H), 8.18 (d, J ) 7 Hz, 2H),
10.36 (s, 1H); IR (KBr) ν 3074 (w), 3035, 2925 (w), 2875 (w),
1727 (s), 1682 (s), 1599 (m), 1496 (s), 1470 (m), 1267 (s), 1206
(s), 1152 (s), 1064 (s) cm-1; MS (FAB nitrobenzyl alcohol) m/z
556 (M)+. Anal. C33H32O8 requires C 71.2, H 5.7. Found C
71.2, H 5.7.
By using essentially the same procedure for sulfonylation,
there were prepared the following compounds:
3-(5-(Ben zyloxy)-3-((ter t-bu tyld ip h en ylsiloxy)m eth yl)-
2-m et h oxyb en zyl)-4-((2-m et h oxyet h oxy)m et h oxy)p h e-
n yl Tr iflu or om et h a n e Su lfon a t e (20). Purified by flash
chromatography (eluting with 5% EtOAc/CH2Cl2 in hexanes):
825 mg of 15 gave 900 mg of 20 (92%). 1H NMR (CDCl3) δ
1.09 (s, 9H), 3.32 (s, 3H), 3.46 (m, 2H), 3.48 (s, 3H), 3.67 (m,
2H), 3.92 (s, 2H), 4.80 (s, 2H), 4.95 (s, 2H), 5.22 (s, 2H), 6.51
(d, J ) 3 Hz, 1H), 6.93 (d, J ) 3 Hz, 1H), 7.05 (dd, J ) 9, 3 Hz,
1H), 7.13 (d, J ) 3 Hz, 1H), 7.14 (d, J ) 9 Hz, 1H), 7.2-7.45
(m, 11H), 7.7 (m, 4H); IR (KBr) ν 3011 (w), 2981 (w), 2892
(w), 2859 (w), 1600 (w), 1492 (m), 1426 (m), 1221 (s), 1213 (s),
1141 (s), 1112 (m), 1002 (m), 851 (m), 701 (m) cm-1; MS (ion
spray) m/z 825 (MH)+. Anal. C43H48O9SSiF3 requires C 62.5,
H 5.9. Found C 62.4, H 5.7.
4-((2-Meth oxyeth oxy)m eth oxy)-3-(2-m eth oxy-4-(m eth -
oxyca r b on yl)-3-(2-m et h oxy-4-(m et h oxyca r b on yl)-3-(3-
(m eth oxyca r bon yl)-5-m eth ylben zyl)ben zyl)ben zyl)ben -
zoic Acid Meth yl Ester (54). To a solution of 53 (850 mg,
0.74 mmol) in DMSO (2 mL) was added MeOH (1.5 mL)
followed by 1,3-bis(diphenylphosphino)propane (80 mg, 0.193
mmol) and Pd(OAc)2 (41 mg, 0.185 mmol). The resulting
solution was flushed with carbon monoxide and then Et3N (1.0
mL, 7.25 mmol) added. The resulting solution was heated to
75 °C and stirred at this temperature for 3 h. The reaction
mixture was then cooled to room temperature, diluted with
EtOAc, and then washed with water and brine. The organic
fraction was dried over MgSO4, filtered, and then concentrated.
The residue was purified by flash chromatography (eluting
with 30% EtOAc/20% CH2Cl2 in hexanes) to give 429 mg of
54 as a viscous oil (74%). 1H NMR (CDCl3) δ 2.32 (s, 3H), 3.31
(s, 3H), 3.42 (m, 2H), 3.61 (m, 2H), 3.64 (s, 3H), 3.66 (s, 3H),
3.67 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H), 3.83 (s,
3H), 4.04 (s, 2H), 4.07 (s, 2H), 4.10 (s, 2H), 5.30 (s, 2H), 7.15
By using essentially the same procedure there were pre-
pared the following compounds:
Com p ou n d 44. 399 mg of 43 gave 372 mg of 44 (92%) used
without purification. 1H NMR (C6D6) δ 1.22 (s, 9H), 1.25 (s,
18H), 1.27 (s, 9H), 3.04 (s, 3H), 3.26 (m, 2H), 3.33 (s, 3H), 3.35
(s, 3H), 3.45 (bs, 6H), 3.50 (s, 3H), 3.51 (s, 3H), 3.52 (s, 3H),
3.58 (m, 2H), 3.94 (s, 2H), 4.11 (s, 4H), 4.15 (bs, 12H), 4.20 (s,
2H), 4.30 (s, 2H), 4.58 (s, 2H), 4.69 (bs, 6H), 4.95 (s, 2H), 6.65
(d, J ) 3 Hz, 1H), 6.69 (dd, J ) 9, 3 Hz, 1H), 6.75 (m, 12H),
6.90 (d, J ) 3 Hz, 1H), 7.0-7.2 (m, 21H), 7.47 (d, J ) 3 Hz,
1H), 10.4 (s, 1H); IR (KBr) ν 2976 (m), 2933 (m), 1750 (s), 1728
(m), 1685 (m), 1599 (m), 1473 (s), 1432 (m), 1308 (bm), 1218
(s), 1145 (s), 1080 (s) cm-1; MS (ion spray) m/z 1997 (MH)+.
5-(Be n zyloxy)-2-m e t h oxy-3-(2-((2-m e t h oxye t h oxy)-
m eth oxy)-5-(ben zoyloxy)ben zyl)ben zoic Acid (25). To a
suspension of 24 (1.22 g, 2.19 mmol) in tert-butyl alcohol (22
mL) was added 2-methylbut-2-ene (2.2 mL, 19 mmol). To this
mixture was added a solution comprised of 2.16 g of NaH2-
PO4‚H2O (2.16 g, 16 mmol) and 2.16 g of NaClO2 (2.16 g,
technical grade, 19 mmol) in water (22 mL). This solution was
stirred for 15 min and then diluted with EtOAc, washed with
water and brine, dried over MgSO4, filtered, and concentrated
to give 1.25 g of 25 as a viscous oil (99%). 1H NMR (CDCl3) δ

Synthesis of Functionalized Aromatic Oligomers
J . Org. Chem., Vol. 62, No. 15, 1997 5189
3.35 (s, 3H), 3.49 (m, 2H), 3.67 (m, 2H), 3.90 (s, 3H), 4.03 (s,
2H), 5.01 (s, 2H), 5.24 (s, 2H), 6.92 (d, J ) 2.7 Hz, 1H), 6.93
(d, J ) 2.9 Hz, 1H), 7.07 (dd, J ) 8.9, 2.7 Hz, 1H), 7.24 (d, J
) 8.9 Hz, 1H), 7.3-7.4 (m, 5H), 7.50 (m, 2H), 7.56 (d, J ) 2.9
Hz, 1H), 7.62 (m, 1H), 8.17 (d, J ) 7.2 Hz, 2H); MS (FAB
nitrobenzyl alcohol) m/z 573 (MH)+. Anal. C33H32O9 requires
C 69.2, H 5.6. Found C 69.5, H 5.9.
1203 (s), 1151 (s), 1110 (s), 1062 (s), 1005 (s) cm-1; MS (FAB
nitrobenzyl alcohol) m/z 706 (M)+.
2-((2-Meth oxyeth oxy)m eth oxy)-5-((5-(ben zyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-h yd r oxyp h en yl)eth yn yl)ben zoic Acid
Meth yl Ester (61). To a mixture of (Ph3P)4Pd (100 mg, 0.087
mmol) and CuI (12 mg, 0.06 mmol) was added a solution
comprised of iodide 60 (1.5 g, 1.83 mmol) and 68 (570 mg, 2.16
mmol) in THF (6 mL). Piperidine (450 µL, 4.5 mmol) was
added and the resulting mixture stirred for 3 h, diluted with
EtOAc, washed, sequentially, with 1 M HCl and brine, dried
over MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography (eluting with 30% EtOAc/
20% CH2Cl2 in hexanes) to give 1.44 g of 61 as a viscous oil
(82%). 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.36 (s, 3H), 3.40 (s,
3H), 3.55 (m, 2H), 3.86 (m, 2H), 3.88 (s, 3H), 3.94 (s, 2H), 4.81
(s, 2H), 4.94 (s, 2H), 4.95 (s, 2H), 5.37 (s, 2H), 5.50 (s, 1H),
6.57 (d, J ) 3 Hz, 1H), 6.68 (s, 1H), 6.94 (s, 1H), 6.93 (s, 1H),
7.14 (d, J ) 3 Hz, 1H), 7.25-7.5 (m, 17H), 7.59 (dd, J ) 8.8,
2.2 Hz, 1H), 7.71 (m, 4H), 7.96 (d, J ) 2.2 Hz, 1H); IR (CHCl3)
ν 3300 (bm), 3031 (w), 3010 (m), 2952 (m), 2932 (m), 2893 (w),
1724 (s), 1604 (w), 1505 (s), 1436 (s), 1429 (s), 1301 (s), 1242
(s), 1146 (s), 1106 (s), 1075 (s) cm-1; MS (ion spray) m/z 957
(MH)+.
2-((2-Meth oxyeth oxy)m eth oxy)-5-((5-(ben zyloxy)-3-(5-
(b en zyloxy)-3-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
m eth oxyben zyl)-2-(((ter t-bu tyloxyca r bon yl)m eth yl)oxy)-
ph en yl)eth yl)ben zoic Acid Meth yl Ester (63). To a solution
of 62 (700 mg, 0.65 mmol) in EtOAc (4.0 mL) was added 10%
palladium on carbon (150 mg). The resulting mixture was
stirred under a hydrogen atmosphere for 3 h, diluted with
EtOAc, and filtered through Celite. The filtrate was concen-
trated and the residue purified by flash chromatography
(eluting with 20% EtOAc/20% CH2Cl2 in hexanes) to give 507
mg of 63 (73%). 1H NMR (C6D6) δ 1.29 (s, 9H), 1.39 (s, 9H),
3.05 (m, 2H), 3.10 (m, 2H), 3.11 (s, 3H), 3.32 (m, 2H), 3.36 (s,
3H), 3.65 (s, 3H), 3.78 (m, 2H), 4.20 (s, 2H), 4.25 (s, 2H), 4.75
(s, 2H), 4.94 (s, 2H), 5.17 (s, 4H), 6.65 (s, 1H), 6.71 (s, 1H),
6.97 (d, J ) 3 Hz, 1H), 7.1-7.35 (m, 18H), 7.53 (d, J ) 3 Hz,
1H), 7.90 (m, 4H), 7.97 (d, J ) 2 Hz, 1H); IR (CHCl3) ν 3011
(w), 2931 (w), 1749 (s), 1733 (s), 1605 (w), 1498 (s), 1234 (s),
1202 (s), 1112 (s), 1078 (s) cm-1; MS (ion spray) m/z 1075 (M)+.
Anal. C65H74O12Si requires C 72.6, H 6.9. Found C 72.9, H
7.0.
Ben zoic Acid 3-(5-(Ben zyloxy)-3-((ter t-b u t yld ip h en -
ylsiloxy)m et h yl)-2-m et h oxyb en zyl)-4-(2-(p yr id in -2-yl)-
eth oxy)p h en yl Ester (19). To a solution of 14 (708 mg, 1.0
mmol) in THF (3 mL) were added, sequentially, 2-(2-hydroxy-
ethyl)pyridine (225 µL, 2 mmol), Ph3P (524 mg 2.0 mmol), and
DEAD (320 µL, 2.0 mmol). The resulting solution was stirred
for 3 h and then concentrated under reduced pressure. The
residue was purified by flash chromatography (eluting with
20% EtOAc in toluene) to give 684 mg of product 19 as oil
(84%). 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.19 (t, J ) 6 Hz, 2H),
3.42 (s, 3H), 3.87 (s, 2H), 4.32 (t, J ) 6 Hz, 2H), 4.81 (s, 2H),
4.93 (s, 2H), 6.52 (d, J ) 3 Hz, 1H), 6.82 (d, J ) 3 Hz, 1H),
6.87 (d, J ) 9 Hz, 1H), 7.01 (dd, J ) 9, 3 Hz, 1H), 7.04 (m,
1H), 7.08-7.5 (m, 16H), 7.57 (m, 1H), 7.70 (m, 4H), 8.15 (m,
2H), 8.49 (m, 1H); IR (CHCl3) ν 3011 (w), 2958 (w), 2932 (w),
2859 (w), 1732 (s), 1594 (w), 1498 (s), 1473 (s), 1264 (s), 1150
(m), 1081 (s), 1065 (s) cm-1; MS (FAB, nitrobenzyl alcohol) m/z
814 (MH)+. Anal. C52H51O4SiN requires C 76.7, H 6.3, N 1.7.
Found C 76.9, H 6.6, N 1.8.
1,2-Bis(5-(ben zyloxy)-3-(5-(ben zyloxy)-2-((ter t-bu tylox-
ycar bon yl)m eth oxy)-3-(2-(3-(m eth oxycar bon yl)-4-((2-m eth -
oxyeth oxy)m eth oxy)ph en yl)eth yl)ben zyl)-2-m eth oxyph e-
n yl)eth a n e (66). To a suspension of zinc powder (72 mg 1.1
mmol) in benzene (0.5 mL) was added 1,2-dibromoethane (6
µL, 0.07 mmol). The resulting slurry was heated to reflux,
stirred at this temperature for 1 min, and then allowed to cool
to room temperature. To this mixture were added Bu4NI (140
mg, 0.38 mmol) and (Ph3P)2NiCl2 (24 mg, 0.037 mmol). The
resulting red mixture was stirred for 30 min and then a
solution of 65 (335 mg, 0.37 mmol) in benzene (0.6 mL) added.
This mixture was stirred for 45 min and then diluted with
EtOAc. The EtOAc solution was washed, sequentially, with
By using essentially the same procedure there were pre-
pared the following compounds:
Com p ou n d 45. 370 mg of 44 gave 370 mg of 45 (98%). 1H
NMR (C6D6) δ 1.23 (s, 9H), 1.25 (s, 18H), 1.27 (s, 9H), 3.04 (s,
3H), 3.26 (m, 2H), 3.32 (s, 6H), 3.43 (s, 6H), 3.50 (s, 3H), 3.51
(s, 3H), 3.52 (s, 3H), 3.58 (m, 2H), 3.86 (s, 2H), 4.10 (s, 2H),
4.15 (m, 18H), 4.57 (s, 2H), 4.65 (bs, 6H), 4.93 (s, 2H), 6.60 (d,
J ) 3 Hz, 1H), 6.70 (dd, J ) 9, 3 Hz, 1H), 6.73 (m, 12H), 6.90
(d, J ) 3 Hz, 1H), 6.97 (s, J ) 3 Hz, 1H), 7.0-7.2 (m, 20H),
7.75 (d, J ) 3 Hz, 1H), MS (ion spray) m/z 2013 (MH)+. Anal.
C119H134O28 requires C 71.0, H 6.7. Found C 70.6, H, 7.1.
N-(3-(5-(Ben zoyloxy)-2-((2-m eth oxyeth oxy)m eth oxy)-
b e n zyl)-5-(b e n zyloxy)-2-m e t h oxyb e n zoyl)-(L)-le u cin e
Meth yl Ester (26). To a solution of 25 (570 mg, 1 mmol) in
CH2Cl2 (3 mL), cooled to 0 °C, was added N-methylmorpholine
(360 µL, 3.3 mmol) followed by isopropyl chloroformate (1.05
mL of a 1 M solution in CH2Cl2 1.05 mmol). This solution was
stirred for 10 min, and then L-leucine methyl ester hydrochlo-
ride (200 mg, 1.1 mmol) was added. The resulting mixture
was stirred for 20 min, diluted with ether, washed, sequen-
tially, with water and brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by flash chromatog-
raphy (eluting with 30% EtOAc/20% CH2Cl2 in hexanes to give
671 mg of 26 as a viscous oil (96%). 1H NMR (CDCl3) δ 0.89
(m, 1H), 0.97 (d, J ) 5 Hz, 3H), 0.99 (d, J ) 5 Hz, 3H), 1.72
(m, 2H), 3.34 (s, 3H), 3.48 (m, 2H), 3.68 (m, 2H), 3.76 (s, 3H),
3.79 (s, 3H), 4.02 (s, 2H), 4.86 (m, 1H), 5.0 (s, 2H), 5.24 (s,
2H), 6.82 (d, J ) 3.0 Hz, 1H), 6.92 (d, J ) 3 Hz, 1H), 7.05 (dd,
J ) 9, 3 Hz, 1H), 7.24 (d, J ) 9 Hz, 1H), 7.25 -7.4 (m, 5H),
7.49 (m, 2H), 7.52 (d, J ) 3 Hz, 1H), 7.62 (m, 1H), 8.17 (d, J
) 7.7 Hz, 2H), 8.32 (bd, J ) 8 Hz, 1H); IR (KBr) ν 3375 (bm),
3026 (w), 3013 (w), 2958 (w), 1738 (s), 1653 (m), 1600 (w), 1522
(m), 1497 (m), 1464 (m), 1265 (s), 1063 (s) cm-1; MS (FAB
nitrobenzyl alcohol), m/z 700 (MH)+. Anal. C40H45O10N re-
quires C 68.7, H 6.5, N 2.0. Found C 68.9, H 6.5, N 2.3.
(5-(Be n zyloxy)-3-(5-h yd r oxy-2-((2-m e t h oxye t h oxy)-
m eth oxy)ben zyl)-2-m eth oxyben zyloxy)-ter t-bu tyld ip h e-
n ylsila n e (15). To a solution of 1 (1.6 g, 2.0 mmol) in THF
(10 mL), cooled to -40 °C, was added NaOMe (450 µL, 25 wt
% in methanol, 2 mmol). The resulting solution was stirred
for 25 min, and then the reaction was quenched with HCl (2.5
mL, 1 M), diluted with ether, washed with water and then
brine, dried over MgSO4, filtered, and concentrated. The
residue was purified by flash chromatography (eluting with
40% EtOAc in hexanes) to give 1.304 g of 15 as a colorless oil
(94%). 1H NMR (CDCl3) δ 1.08 (s, 9H), 3.34 (s, 3H), 3.48 (m,
2H), 3.49 (s, 3H), 3.71 (m, 2H), 3.89 (s, 2H), 4.46 (s, 1H), 4.82
(s, 2H), 4.96 (s, 2H), 5.15 (s, 2H), 6.46 (d, J ) 3.0 Hz, 1H),
6.57 (d, J ) 2.9 Hz, 1H), 6.60 (dd, J ) 8.6, 2.9 Hz, 1H), 6.99
(d, J ) 8.6 Hz, 1H), 7.13 (d, J ) 3 Hz, 1H), 7.3-7.45 (m, 11H),
7.70 (m, 4H); IR (KBr) ν 3958 (w), 2962 (w), 2933 (m), 1598
(w), 1498 (s), 1478 (s), 1147 (s), 1112 (s), 1087 (s), 1010 (s) cm-1
;
MS (FAB nitrobenzyl alcohol) m/z 692 (M)+. Anal. C42H48O7-
Si requires C 72.8, H 7.0. Found C 72.4, H 7.0.
Ben zoic Acid 3-(3-((ter t-Bu tyld ip h en ylsiloxy)m eth yl)-
5-h y d r o xy-2-m e t h o x yb e n zy l)-4-((2-m e t h o xy e t h oxy )-
m eth oxy)p h en yl Ester (13). To a solution of 1 (960 mg, 1.2
mmol) in THF:MeOH (1:1, 20 mL) was added 10% palladium
on carbon (100 mg). The resulting suspension was stirred
under hydrogen until all the starting material was consumed
(TLC analysis). The catalyst was then removed by filtration
and the filtrate concentrated to give 769 mg of 13 as a foam
(90%). 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.39 (s, 3H), 3.53 (s,
3H), 3.59 (m, 2H), 3.77 (m, 2H), 3.95 (s, 2H), 4.79 (s, 2H), 5.28
(s, 2H), 5.61 (s, 1H), 6.45 (d, J ) 3 Hz, 1H), 6.97 (d, J ) 3 Hz,
2H), 7.03 (dd, J ) 9, 3 Hz, 1H), 7.14 (d, J ) 9 Hz, 1H), 7.36
(m, 6H), 7.48 (m, 2H), 7.62 (m, 1H), 7.71 (m, 4H), 8.17 (m,
2H); IR (KBr) ν 3374 (bm), 3074 (w), 2951 (m), 2931 (m), 2893
(m), 2857 (m), 1737 (s), 1599 (m), 1495 (s), 1462 (s), 1262 (s),

5190 J . Org. Chem., Vol. 62, No. 15, 1997
Bruno et al.
5% NH3 solution and brine, dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography
(eluting with 40% EtOAc/20% CH2Cl2 in hexanes) to give 215
mg of 66 as an oil (71%). 1H NMR (CDCl3) δ 1.47 (s, 18H),
2.83 (m, 8H), 2.93 (s, 4H), 3.36 (s, 6H), 3.54 (m, 4H), 3.66 (s,
6H), 3.85 (m, 4H), 3.86 (s, 6H), 4.04 (s, 4H), 4.42 (s, 4H), 4.89
(s, 4H), 4.92 (s, 4H), 5.30 (s, 4H), 6.56 (s, 2H), 6.61 (d, J ) 3
Hz, 2H), 6.64 (s, 2H), 6.75 (d, J ) 3 Hz, 2H) 7.12 (d, J ) 8 Hz,
2H), 7.19 (dd, J ) 8, 2 Hz, 2H), 7.25-7.40 (m, 20H), 7.59 (d,
J ) 2 Hz, 2H); IR (CHCl3) ν 3029 (w), 3010 (w), 2981 (w), 2948
(w), 1749 (s), 1718 (s), 1604 (w), 1505 (s), 1498 (s), 1304 (bm),
1233 (s), 1202 (s), 1155 (s), 1077 (s) cm-1; MS (ion spray), m/z
1657 (MNH4)+. Anal. C98H110O22 requires C 71.8, H 6.8.
Found C 71.7, H 6.4.
of MeOH:THF (4.0 mL). This solution was cooled to -10 °C
and then sodium methoxide (370 µL, 25 wt % in methanol,
1.82 mmol) added. The resulting solution was stirred for 1 h
and then acetic acid (105 µL, 8.0 mmol) added. The reaction
mixture was then concentrated under reduced pressure and
the residue dissolved in DMF (2.0 mL). To this solution was
added K2CO3 (396 mg, 2.9 mmol) and tert-butyl bromoacetate
(396 µL, 2.4 mmol). The resulting mixture was warmed to 78
°C and stirred at this temperature for 1 h. At this point a
further batch of both K2CO3 (396 mg) and of tert-butyl
bromoacetate (396 µL) was added. This mixture was stirred
for 2 h, cooled to room temperature, diluted with EtOAc,
washed with water and brine, dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography
(eluting with 30% CH2Cl2/20% EtOAc in hexanes) to give 328
mg of 49 as an oil (83%). 1H NMR (CDCl3) δ 1.41 (s, 54H),
1.46 (s, 9H), 1.47 (s, 9H), 2.28 (s, 3H), 3.36 (s, 3H), 3.52 (m,
2H), 3.62 (s, 3H), 3.64 (bs, 18H), 3.73 (m, 2H), 3.97 (s, 2H),
4.00 (s, 2H), 4.04 (bs, 10H), 4.31 (s, 2H), 4.32 (s, 2H), 4.33 (s,
8H), 4.40 (s, 2H), 4.42 (s, 2H), 5.20 (s, 2H), 6.41 (d, J ) 3 Hz,
1H), 6.44 (d, J ) 3 Hz, 1H), 6.49 (m, 11H), 6.59 (d, J ) 3 Hz,
1H), 6.69 (m, 2H), 7.08 (m, 1H); IR (CHCl3) ν 3024 (w), 3011
(w), 2983 (w), 2934 (w), 1748 (s), 1595 (m), 1475 (s), 1231 (s),
1147 (s), 1083 (s), 1010 (m) cm-1; MS (ion spray) m/z 2079
(MH)+. Anal. C115H152O34 requires C 66.5, H 7.4. Found C
66.9, H 7.4.
1,2-Bis(5-(ben zyloxy)-3-(5-(ben zyloxy)-2-((ca r boxym e-
th yl)oxy)-3-(2-(3-car boxy-4-h ydr oxyph en yl)eth yl)ben zyl)-
2-m eth oxyp h en yl)eth a n e (67). To a solution of 66 (192 mg,
0.117 mmol) in 2-propanol (2.0 mL) was added pyridinium
tosylate (251 mg, 1.0 mmol). The resulting mixture was
heated to 70 °C and stirred at this temperature for 24 h. The
reaction mixture was cooled and then concentrated under
reduced pressure. The residue was suspended in THF (2.0
mL) and then MeOH (1.0 mL) added, followed by NaOH
solution (2.0 mL, 2 M, 4.0 mmol). The reaction mixture was
stirred for 18 h, acidified with 2 M HCl, diluted with ethyl
acetate, washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by flash chromatog-
raphy (eluting with 2% formic acid/18% THF in CHCl3)21a to
give 89 mg of product 67 as a white solid (57%). 1H NMR
(DMSO) δ 2.80 (m, 12H), 3.58 (s, 6H), 3.84 (s, 4H), 4.55 (s,
4H), 4.85 (s, 4H), 4.90 (s, 4H), 6.33 (d, J ) 2 Hz, 2H), 6.70 (s,
2H), 6.75 (d, J ) 2 Hz, 2H), 6.84 (d, J ) 8 Hz, 2H), 6.90 (s,
2H), 7.12-7.32 (m, 20H), 7.34 (dd, J ) 8, 2 Hz, 2H), 7.63 (d,
J ) 2 Hz, 2H); IR (KBr) ν 3500-2500 (bm), 3421 (bm), 3033
(w), 2927 (w), 2866 (w), 1729 (m), 1647 (m), 1589 (m), 1506
(m), 1454 (m), 1433 (m), 1218 (s), 1209 (s), 1039 (m), 698 (m)
cm-1; MS (FAB nitrobenzyl alcohol) m/z 1323 (MH)+. Anal.
C80H74O18 requires C 72.6, H 5.6. Found C 72.6, H 5.7.
Com p ou n d 42. To a solution of 35 (3.0 g 1.366 mmol) in
THF (5.0 mL), cooled to -15 °C, was added sodium methoxide
(1.3 mL, 25 wt % in methanol, 6.4 mmol). This solution was
stirred for 3 h, and then HCl (6.0 mL, 1 M) was added. The
reaction mixture was diluted with EtOAc, washed with brine,
dried over MgSO4, filtered, and concentrated. The residue was
azeotroped with toluene, and then 1.72 g of this product was
dissolved in DMF (10 mL) and K2CO3 (1.1 g, 8 mmol) added
followed by tert-butyl bromoacetate (1.3 mL, 8.0 mmol). The
resulting mixture was heated to 80 °C and stirred at this
temperature for 24 h. The reaction mixture was diluted with
EtOAc and then washed, sequentially, with 0.1 M HCl, water
(3×), and brine. The EtOAc solution was dried over MgSO4,
filtered, and concentrated. The residue was purified by flash
chromatography (eluting with 20% EtOAc/20% CH2Cl2 in
hexanes) to give 1.88 g of 42 (84%).1H NMR (C6D6) δ 1.17 (s,
9H), 1.24 (s, 9H), 1.25 (s, 18H), 1.27 (s, 9H), 3.04 (s, 3H), 3.26
(m, 2H), 3.27 (s, 3H), 3.37 (s, 3H), 3.42 (s, 6H), 3.50 (s, 3H),
3.51 (s, 3H), 3.52 (s, 3H), 3.56 (m, 2H), 4.07 (s, 2H), 4.09 (s,
2H), 4.12 (s, 6H), 4.15 (s, 6H), 4.16 (s, 6H), 4.65 (bs, 6H), 4.82
(s, 2H), 4.93 (s, 2H), 5.04 (s, 2H), 6.69 (dd, J ) 8, 3 Hz, 1H),
6.71 (d, J ) 3 Hz, 1H), 6.72-6.8 (m, 12H), 6.84 (d, J ) 3 Hz,
1H), 6.90 (s, J ) 3 Hz, 1H), 7.0-7.25 (m, 26H), 7.46 (d, J ) 3
Hz, 1H), 7.80 (m, 4H); IR (CHCl3) ν 3012 (w), 2994 (w), 1748
(s), 1594 (m), 1474 (s), 1430 (s), 1230 (s), 1147 (s), 1088 (s),
1010 (s) cm-1; MS (ion spray) m/z 2237 (MH)+. Anal.
C135H154O27Si requires C 72.5, H 6.9. Found C 72.6, H 6.9.
Com p ou n d 49. To a solution of 46 (370 mg, 0.191 mmol)
in a 1:1:1 mixture of MeOH:DMF:THF (6.0 mL) was added
10% palladium on carbon (150 mg). The resulting suspension
was stirred under an atmosphere of hydrogen for 14 h and
then filtered through Celite and the filtrate concentrated under
reduced pressure. The residue was dissolved in a 1:1 mixture
(5-(Ben zyloxy)-3-(2-m eth oxy-5-((tr im eth ylsilyl)eth yn yl)-
b en zyl)-2-m et h oxyb en zyloxy)-ter t-b u t yld ip h en ylsila n e
(21). A solution of (trimethylsilyl)acetylene (176 µL, 1.25
mmol) in THF (2.0 mL) was cooled to -78 °C, and then n-BuLi
(0.5 mL, 2.5 M in hexanes, 1.25 mmol) was added dropwise.
The resulting solution was stirred for 15 min, and then a
solution of ZnCl2 (1.3 mL, 0.5 M in THF, 0.65 mmol) added.
The cold bath was removed and stirring continued for 10 min.
To this mixture was added a solution comprised of 20 (400
mg, 0.485 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14 mg,
0.025 mmol), and bis(dibenzylideneacetone)palladium (14 mg,
0.025 mmol) in THF (3 mL). The reaction mixture was heated
to 65 °C and stirred at this temperature for 18 h, cooled to
room temperature, diluted with EtOAc, washed, sequentially,
with saturated NH4Cl solution and brine, dried over MgSO4,
and concentrated. The residue was purified by flash chroma-
tography (eluting with 10% EtOAc in hexanes) to give 342 mg
of 21 as a viscous oil (91%). 1H NMR (CDCl3) δ 0.23 (s, 9H),
1.10 (s, 9H), 3.30 (s, 3H), 3.42 (m, 2H), 3.50 (s, 3H), 3.60 (m,
2H), 3.89 (s, 2H), 4.82 (s, 2H), 4.93 (s, 2H), 5.21 (s, 2H), 6.50
(d, J ) 3 Hz, 1H), 7.02 (d, J ) 8.5 Hz, 1H), 7.10 (s, 3 Hz, 1H),
7.19 (d, J ) 1 Hz, 1H), 7.28-7.4 (m, 12H), 7.69 (m, 4H); IR
(CHCl3) ν 3010 (w), 2960 (w), 2931 (w), 2148 (w), 1602 (w),
1495 (s), 1473 (s), 1250 (s), 1105 (s), 1081 (s), 1004 (s) cm-1
;
MS (ion spray) m/z 773 (MH)+. Anal. C47H56O6Si2 requires C
73.0, H 7.3. Found C 72.9, H, 7.7.
Ack n ow led gm en t. We thank Dr. Bih-Hsiung Hsu
and Sheng-Yuh Tang (both RPR) as well as Purdue
University for their help in obtaining mass spectra. We
also thank Dr. Edward Orton for IR spectroscopy
service. We gratefully acknowledge Dr. Christopher
Burns, Dr. Steven Condon, and Dr. Robert Groneberg
for their helpful criticism and valuable suggestions in
the preparation of this manuscript.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR of com-
pounds 1, 3-5, 7, 9, 18, 22, 23, 27, 29-31, 33-37, 39-42,
44, 49, 53, 56, 57, 60, 61, 64, and 67 (31 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of this journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O970596H