Improved iterative synthesis of linearly disassembling dendrons

Article abstract of DOI:10.1021/jo1009849

Figure presented. We report a significant improvement in the synthesis of disassembling dendritic structures by using 4-hydroxy-3-nitrobenzoic acid as the building block. We have prepared multigram quantities of first- through third-generation linearly disassembling dendrons containing a [3-N,4-O]-benzylaryl ether disassembly pathway, capped by a vanillin-derived phenyl allyl ether trigger, and a p-nitrophenoxy (PNP) reporter group. The disassembly process of these materials was initiated by allyl deprotection and monitored by the absorbance of the PNP reporter unit in the UV-vis. Modification of the disassembly conditions for the allyl trigger resulted in decreased disassembly times, decreased incubation time for onset of disassembly from minutes to seconds, and allowed observation of indicative rate differences between generations not seen with the previously reported conditions.

Full text of DOI:10.1021/jo1009849

pubs.acs.org/joc
Improved Iterative Synthesis of Linearly Disassembling Dendrons
Adrian Ortiz, Charles S. Shanahan, David T. Sisk, Sujeewa C. Perera, Pallavi Rao, and
Dominic V. McGrath*
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721-0041
mcgrath@email.arizona.edu
Received May 19, 2010
We report a significant improvement in the synthesis of disassembling dendritic structures by using
4-hydroxy-3-nitrobenzoic acid as the building block. We have prepared multigram quantities of first-
through third-generation linearly disassembling dendrons containing a [3-N,4-O]-benzylaryl ether
disassembly pathway, capped by a vanillin-derived phenyl allyl ether trigger, and a p-nitrophenoxy
(PNP) reporter group. The disassembly process of these materials was initiated by allyl deprotection
and monitored by the absorbance of the PNP reporter unit in the UV-vis. Modification of the
disassembly conditions for the allyl trigger resulted in decreased disassembly times, decreased
incubation time for onset of disassembly from minutes to seconds, and allowed observation of
indicative rate differences between generations not seen with the previously reported conditions.
Introduction
engineered into the dendritic architecture (Figure 1a),5-7
similar in concept to so-called self-immolative dendrimers8
and polymers.9,10 Consider compound A, an example of a
linearly disassembling dendrimer that consists of a phenyl
allyl ether trigger group, benzyl ether cleavage vector, and
p-nitrophenoxy reporter subunit (Figure 1b). Removal of
the allyl group triggers an electronic cascade cleavage. A 1,6-
elimination mechanism11 (Figure 1c) results in release of a
corresponding p-quinone methide ( p-QM), which is trapped
by an endogenous nucleophile and ultimately liberates the
reporter p-nitrophenoxide (PNP) ion. Both linear5 and
geometric6,7 disassembly systems have been realized.
The use of dendrimer chemistry is an increasingly ubiqui-
tous means to alter the environment of covalently incor-
porated electro- and/or photoactive moieties.1 Dendritic
encapsulation of core moieties parallels Nature’s use of
proteins to act as insulation to create tailored microenviron-
ments, the presence of which are critical for function.2 As in
Nature, the presence of this insulation can result in dramatic
alterations of the properties of the encapsulated moieties
from their nonencapsulated forms.3 Hence, an ability to
degrade dendritic molecular architectures in a controlled
manner upon treatment with a discrete chemical or physi-
cal stimulus could be a powerful tool to regulate the
properties of a system by rapid removal of the dendritic
components.
The ability to degrade dendrimers in this fashion has the
potential to impact previously established uses of dendrimers
as well as introduce a new paradigm for their roles in chemi-
cal systems, i.e., as compact reservoirs of releasable active
Accordingly, we have developed “disassembling dendri-
mers”4 in which varying types of cleavable pathways were
(6) Szalai, M. L.; Kevwitch, R. M.; McGrath, D. V. J. Am. Chem. Soc.
2003, 125, 15688–15689.
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6154 J. Org. Chem. 2010, 75, 6154–6162
Published on Web 08/26/2010
DOI: 10.1021/jo1009849
r
2010 American Chemical Society

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FIGURE 1. (a) Schematic representation of linear disassembly in which a stimulus initiates a linear cascade cleavage through the dendritic
structure; (b) 3,4-dihydroxybenzoic acid and a second-generation linear disassembling dendron A with a [3-O,4-O]-benzyl ether cleavage
pathway (red) and p-nitrophenyl (PNP) reporter group (green) derived therefrom; (c) enabling chemistry for disassembly: upon removal of R
by a chemical or physical stimulus, the resulting vinylogous hemiacetal anion undergoes a 1,6-elimination to yield p-quinone methide ( p-QM)
and alkoxide -OR0.
species.4 We find this a powerful construct in that dendrimers
and dendritic structures can be made up of a wide variety of
subunits, made compatible with many different environ-
ments, and incorporated into countless systems, including
the biological arena.12 Indeed, the controlled and precise
degradation that is engineered into disassembling/self-
immolative systems, both dendritic and polymeric, has de-
monstrated use as well as expected impact in many fields. For
example, these systems have been applied to drug loading
and release,13 detectors,14 signal amplifiers,6,15 and degrad-
able nanoparticles.10
making these materials available in a more straightforward
fashion for further incorporation into nanoscale systems.
We report herein an improved synthesis of linearly dis-
assembling dendrons that circumvents previous synthetic
limitations and proceeds from readily available starting
materials. Our new synthetic approach introduces inherent
selectivity in the side-chain installation process and allows
for the rapid preparation of gram quantities of disassembling
dendrons.
Results and Discussion
Our original intent was to construct disassembling den-
dritic systems that mimicked the design, function, and stabi-
The design parameters of disassembling dendrimers con-
tain the following requisites: (1) a stable trigger moiety that is
chemically inert throughout the synthesis yet can be readily
deprotected on demand to initiate the disassembly process;
(2) a coherent linear disassembly pathway that, upon trigger
deprotection, results in the cascade cleavage of benzyl ether
moieties and the generation of a quinone methide; (3) an
overall convergent synthesis with complete regio- and che-
moselectivity in order to maintain the integrity of the grow-
ing dendritic scaffold; (4) the presence of a hyper-branching
molecular architecture rather than an oligomeric chain to
provide the insulative and potential energy harvesting prop-
erties of typical dendritic materials.
With these parameters in mind, we modified the synthesis
of structures such as A to adopt 4-hydroxy-3-nitrobenzoic
acid, an inexpensive commercially available starting materi-
al, as our fundamental building block (Scheme 1). Using the
3-nitro group as a latent amine, 4-O alkylation could pro-
ceed, followed by nitro reduction and subsequent amine
alkylation, to allow for complete regioselective control for
each successive generation in the synthetic sequence. The
resulting dendrimers would have a [3-N,4-O]-benzyl ether
cleavage pathway, whereby installation of a PNP reporter
group on the focal point would give us the envisioned targets
9, 15, and 20 (Scheme 1). We chose a vanillin-derived phenyl
allyl ether as our trigger moiety because of its particular
robustness toward the subsequent synthetic steps of the
dendrimer synthesis.
ꢀ
lity of typical Frechet-type benzyl(aryl ether) dendrimers,
accompanied in particular by a similar ease of large-scale
synthesis,16 a characteristic that has undoubtedly contribu-
ted to the ubiquity of benzyl(aryl ether) dendrimers in orga-
nic nanoscale systems. Our initial synthesis of linearly dis-
assembling dendrimers such as A, however, relied on the selec-
tive O-alkylation of 3,4-dihydroxybenzoate derivatives at
several points throughout the synthesis, resulting in the
[3-O,4-O] benzyl ether cleavage pathway.5 Despite our
efforts, these alkylations proceeded with only limited selec-
tivity and resulted in the undesirable consumption of
advanced dendritic intermediates at later stages of the syn-
thesis, even when applying protecting group strategies.17
There was therefore a need for a synthesis of disassembling
dendrons that circumvented this selectivity problem, thus
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(17) Kevwitch, R. M. Ph.D. Thesis, University of Arizona, 2004.
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SCHEME 1. Retrosynthetic Analysis of Disassembling Dendrons 9, 15, and 20
SCHEME 2. Synthesis of Vanillin-Derived Trigger Moiety
SCHEME 3. Synthesis of [3-N,4-O] Disassembling Dendron 8
To obtain the trigger, vanillin was O-allylated and the
resulting aldehyde reduced without purification to give 118
(Scheme 2). Subsequent chlorination provided benzyl chlor-
ide 2 as a colorless solid in a 72% yield (three steps).
Dendron Synthesis. With 2 in hand, we turned our atten-
tion to the regioselective functionalization of 4-hydroxy-
3-nitrobenzoic acid (Scheme 3). Fischer esterification of
4-hydroxy-3-nitrobenzoic acid was carried out with both
1-pentanol and EtOH to give the respective esters 3a and 3b
in 95% and 97% yield, respectively. Installation of the
trigger moiety was accomplished by alkylation of pentyl
ester 3a with benzyl chloride 2 under Williamson etherifi-
cation conditions to afford nitroester 4 in 88% yield.
Reduction of the nitro group required dissolving metal
conditions to prevent concomitant reduction of the allyl
trigger. For this reason, Fe0 and AcOH19 were employed,
resulting in aniline 5 in 84% yield.
Side chains were installed by N-alkylation of the aniline
function at each generational stage. Reductive amination
conditions using NaBH(OAc)3 and AcOH in DCE20 were
employed for all N-alkylation reactions. With these condi-
tions employed for the alkylation of 5 using 1 equiv of
benzaldehyde, a mixture of the desired N-benzyl along with
N,N-dibenzyl side product was obtained. Formation of this
side product was minimal, however, and 6 was still obtained
in 84% yield. The subsequent ethylation of 6 with acetalde-
hyde, under identical reductive amination conditions, served
to remove any protic sites from the compound to prevent any
undesirable reactions later in the synthesis. Reduction of 7
with LiAlH4 resulted in the corresponding benzyl alcohol 8,
the first-generation disassembling dendron, in 98% yield.
Homologation of 8 followed by a sequence of transforma-
tions similar to that of Scheme 3 was used in an iterative
fashion to prepare dendrons 13 and 19 (Scheme 4). Coupling
benzyl alcohol 8 with ethyl ester 3b under Mitsunobu con-
ditions gave nitroester 10 in 89% yield. Nitroester 10 was
reduced via a modified protocol using NaBH4 and SnCl221 to
yield aniline 11 in 74% yield. At this juncture, we anticipated
that sterics might play a role in the successive monoalkyla-
tion of two different substituents on the 3-position aniline.
This indeed worked to our advantage, as alkylation with
(18) Canceill, J.; Collet, A.; Gottarelli, G. J. Am. Chem. Soc. 1984, 106,
5997–6003.
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Lett. 1990, 31, 5595–5598.
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1981, 29, 1443–1445.
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SCHEME 4. Synthesis of [3-N, 4-O] Disassembling Dendrons 13 and 19
dendritic aldehydes from this point in the cycle forward gave
the mono-N-alkylated product as the predominant or ex-
clusive product obtained. Reductive amination of 11 with a
slight excess of [G-1]-CHO resulted in the N-[G-1]-mono-
alkylated product almost exclusively (ca. 4% N,N-di[G-1]
byproduct). Utilizing the knowledge that sterics largely
suppressed dialkylation of the dendritic adduct, the alkyla-
tion procedure was modified so that a two-step, “one-pot”
reaction could be conducted successively alkylating the ani-
line with both [G-1]-CHO and acetaldehyde using the same
reductant [NaBH(OAc)3] to give 12 in 94% yield and with
minimal production of the N,N-di[G-1] side product. Re-
duction of 12 with LiAlH4 gave benzyl alcohol 13, the
second-generation disassembling dendron, in 97% yield.
A second sequence around the cycle led to the third-
generation dendron 19, starting with Mitsunobu coupling
of benzyl alcohol 13 with ethyl ester 3b to provide nitroester
16 in 90% yield. Sonication during this coupling step resulted
in reaction completion in a matter of minutes rather than
hours, which has been reported to be an effective technique
for the coupling of sterically hindered or deactivated sub-
strates in the Mitsunobu reaction.22 Nitro reduction using
similar conditions for the preparation of 11 gave aniline 17 in
77% yield. The subsequent reductive aminations were again
carried out by the two-step, “one-pot” procedure to effi-
ciently yield N-[G-2]-N-ethyl tertiary aniline 18 in 97% yield.
Ester reduction using standard conditions resulted in the
production of a deallylated byproduct as seen by NMR.
Formation of the byproduct was eliminated by allowing the
reaction mixture to warm slowly from -78 °C until full
conversion was determined by TLC. Benzyl alcohol 19, the
third-generation disassembling dendron, was thus obtained
in 83% yield.
nied by the formation of a C-alkylated side product, in
addition to the O-alkylated 20. These were easily separated
by flash chromatography by eluting with 1:6:3 NEt3-
EtOAc-hexanes, which yielded the third-generation PNP
ether 20 in a moderate 57% yield. In an attempt to prepare
the PNP ethers in higher yield, we assayed the alternate
Williamson etherification for the preparation of second-
generation 15 via the corresponding chloride 14, prepared
from 13 with SOCl2. Although conversion of 13 to 14
proceeded in an excellent 97% yield, second-generation
PNP ether 15 was only obtained in 47% yield.
Disassembly Studies. The disassembly of dendrons 9, 15,
and 20 was expected to take place under standard reductive
allyl deprotection conditions since the triggers used for the
previously reported disassembling systems5,6 utilized the
same phenolic allyl group. In these prior systems, the dis-
assembly was initiated by reductive deprotection of the
phenyl allyl ether trigger with catalytic Pd(PPh3)4 and
NaBH4 in DMF. During the course of the current work,
we modified our original conditions in an attempt to elim-
inate the several-minute incubation period that we had
observed before the disassembly event initiated. We found
that by switching the palladium source to PdCl2(PPh3)2 and
adding MeOH to the reaction mixture, disassembly took
place after an initial incubation period of mere seconds
following catalyst addition. Smooth disassembly was ob-
served in the UV-vis by a rapid increase in the absorption
of PNP ion at 421 nm. This spectral evolution takes place
within 200 s under the newly modified disassembly condi-
tions (Figure 2). The final absorbance values observed at
421 nm indicated complete disassembly (i.e., disassembly
proceeding to the focal point) of 9, 15, and 20 in 88%, 93%,
and 82% yield, respectively, based on the measured absorp-
tivity of PNP under the reaction conditions.
To assay the disassembly of these [3-N,4-O] cleavage
pathway dendrons, installation of a PNP reporter moiety
was necessary, whereupon disassembly of the dendritic
system the liberated PNP anion (λmax = 421 nm) could
by tracked using time-course UV-vis experiments. Two
methods were used to install this group. Coupling dendron
8 to p-nitrophenol using a Mitsunobu protocol was used to
prepare first-generation PNP ether 9 in 48% yield. The
preparation of 20 using the same conditions was accompa-
There are two clear benefits to these modified disassembly
conditions. First, these conditions are optimal for rapid
disassembly. Disassembly experiments with the previous
conditions proceeded to completion within 15 min including
a 10-min incubation period, whereas disassembly with the
current modified conditions were completely disassembled
within 200 s requiring an incubation period of roughly 15 s.
Second, they are sensitive to the generation of dendrimer
being disassembled in that the rate of complete disassembly
(release of PNP) under these conditions is dependent on the
(22) Lepore, S. D.; Yuanjun, H. J. Org. Chem. 2003, 68, 8261–8263.
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110.8, 69.9, 65.3, 55.9; MS (FABþ) m/z 194.26 (Mþ, C11H14O3
requires 194.09).
4-Allyloxy-3-methoxybenzyl Chloride (2). To a stirred solu-
tion of 1 (21.41 g, 112.2 mmol) in CH2Cl2 (300 mL) at 25 °C were
added, in succession, DMF (1 mL) and SOCl2 (19.67 g, 165.3
mmol) dropwise (over a period of 30 min). The solution was
stirred for an additional 30 min and was quenched by the careful
addition of satd aqueous NaHCO3 (ca. 50 mL) and stirred for 1 h.
The resulting mixture was extracted with CH2Cl2 (3 ꢀ 50 mL),
dried (MgSO4), filtered through a short silica gel plug, and
concentrated in vacuo to yield 2 (22.80 g, 98%) as a colorless
1
crystalline solid: H NMR (300 MHz, CDCl3) δ 6.92 (s, 1 H),
6.90 (dd, J = 10.8, 2.4 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 6.07
(m, 1 H), 5.40 (dd, J = 17.4, 1.5 Hz, 1 H), 5.29 (dd, J = 10.5, 1.5
Hz, 1 H), 4.61 (dt, J = 5.4, 1.2 Hz, 2 H), 4.56 (s, 2 H), 3.89 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 149.5, 148.2, 133.1, 130.3,
121.0, 118.1, 113.1, 112.1, 69.8, 55.9, 46.6; MS (FABþ) m/z
212.23 (Mþ, C11H13O2Cl requires 212.06).
Pentyl 4-Hydroxy-3-nitrobenzoate (3a). A solution of 4-hy-
droxy-3-nitrobenzoic acid (100 g, 546 mmol), 1-pentanol (500
mL), and concentrated H2SO4 (1 mL) was refluxed for 72 h in a
1 L round-bottom flask fitted with a Dean-Stark trap and a
jacketed water condenser. Upon completion of the reaction
based on TLC analysis, the excess 1-pentanol was removed
from the reaction via vacuum distillation, and the resulting red
oil was dissolved in hexanes-CH2Cl2 (2:1, 80 mL) and filtered
through a short silica gel plug. The filtrate was concentrated in
vacuo to afford compound 3a (131 g, 95%) as a red oil: 1H NMR
(300 MHz, CDCl3) δ 8.81 (d, J = 2.1 Hz, 1 H), 8.24 (dd, J = 8.7,
1.8 Hz, 1 H), 7.22 (d, J = 9.0 Hz, 1 H), 4.34 (t, J = 6.9 Hz, 2 H),
1.84 - 1.74 (m, 2 H), 1.44 - 1.39 (m, 4 H), 0.94 (t, J = 6.9 Hz,
3 H); 13C NMR (125.7 MHz, CDCl3) δ 164.3, 158.0, 137.9,
133.2, 127.2, 123.1, 120.1, 65.8, 28.3, 28.1, 22.3, 13.9; MS
(FABþ) m/z 254.30 (Mþ, C12H15O5N requires 254.10). Anal.
Calcd for C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C,
56.52; H, 6.11; N, 5.51.
FIGURE 2. UV absorbance at 421 nm as a function of time during
the disassembly of 9, 15, and 20. Concentrations of 9, 15, and 20
were normalized such that quantitative disassembly would result in
the same concentrations of released PNP.
cleavage pathway length, with the initial rate approximately
proportional to 1/n where n is the number of benzyl groups in
the pathway.23 Work is currently underway in our labora-
tory on the kinetics of disassembly and will be reported in due
course.
Summary
A new class of disassembling dendrons that have a [3-N,4-O]
benzyl ether cleavage pathway were prepared by an itera-
tive pathway using 4-hydroxy-3-nitrobenzoic acid as the
building block. Disassembly proceeded smoothly under
modified disassembly conditions with a markedly reduced
incubation period relative to previous reports.5,6 The com-
plete regiochemical control afforded by the use of 4-hydroxy-
3-nitrobenzoic acid in the synthesis eliminated the undesir-
able consumption of advanced dendritic intermediates at
later stages of the synthesis. Gram quantities of disassem-
bling dendrons are now readily available using the synthe-
sis reported herein, making the incorporation of these
structures in nanoscopic systems more feasible.
Ethyl 4-Hydroxy-3-nitrobenzoate (3b).24 A solution of 4-hy-
droxy-3-nitrobenzoic acid (100 g, 546 mmol), ethanol (500 mL),
and concentrated H2SO4 (1 mL) were refluxed for 72 h in a
1 L round-bottom flask fitted with a Dean-Stark trap and a
jacketed water condenser. Upon completion of the reaction,
Et2O (500 mL) was added, and the resulting phases were sepa-
rated. The organic phase was then washed with brine (4 ꢀ 300
mL), dried (MgSO4), filtered, and concentrated in vacuo. Sub-
sequent recrystallization from 9:1 hexanes-Et2O yielded 3b
1
(112 g, 97%) as yellow crystals: H NMR (300 MHz, CDCl3)
δ 8.82 (d, J = 2.4 Hz, 1 H), 8.25 (dd, J = 9.0, 1.8 Hz, 1 H), 7.22
(d, J = 8.7 Hz, 1 H), 4.41 (q, J = 7.5 Hz, 2 H), 1.42 (t, J = 7.5
Hz, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 164.2, 158.0, 137.9,
133.2, 127.2, 123.1, 120.1, 61.6, 14.3; MS (ESIþ) m/z 212.80
(M þ Hþ, C9H10O5N requires 212.06).
Experimental Section
4-Allyloxy-3-methoxybenzyl Alcohol (1). A mixture of vanillin
(63.06 g, 414.4 mmol), allyl bromide (75.21 g, 621.6 mmol),
K2CO3 (114.5 g, 828.8 mmol), and DMF (500 mL) was stirred
and heated to 60 °C for 24 h. The mixture was poured over H2O
(500 mL) and extracted into ether (3 ꢀ 200 mL). The ethereal
layer was washed with brine (3 ꢀ 100 mL), dried (MgSO4),
filtered, and concentrated to a yellow oil. To this crude aldehyde
in THF-MeOH (2:1, 450 mL) at 25 °C was added KBH4
(33.5 g, 620 mmol). The resulting reaction mixture was then
heated to 55 °C (24 h). The reaction mixture cooled to rt,
quenched by reverse addition into 1 M HCl (500 mL), and ex-
tracted with ether (3 ꢀ 200 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo and
recrystallized from hexanes yielding 1 (58.91 g, 75%) as white
crystals: 1H NMR (300 MHz, CDCl3) δ 6.96 (s, 1 H), 6.88 (s, 2
H), 6.08 (m, 1 H), 5.42 (dd, J = 17.4, 1.5 Hz, 1 H), 5.30 (dd, J =
10.5, 1.5 Hz, 1 H), 4.62 (dt, J = 5.4, 1.2 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 149.6, 147.5, 133.9, 133.3, 119.3, 118.0, 113.3,
Pentyl4-(4-Allyloxy-3-methoxybenzyloxy)-3-nitrobenzoate(4).
To a stirred solution of 3 (79.6 g, 314.3 mmol) in DMF (500
mL) at 25 °C were added benzyl chloride 2 (79.4 g, 373.3 mmol)
and K2CO3 (86.5 g, 625.9 mmol). The reaction mixture was
then maintained at 50 °C with stirring for 72 h. After the reac-
tion mixture was allowed to cool to rt, the reaction was
quenched by reverse addition to H2O (500 mL) and the mix-
ture extracted with Et2O (4ꢀ300 mL). The combined orga-
nic extracts were then washed with 1 M HCl (200 mL), dried
(MgSO4), filtered, and concentrated in vacuo. Pure pentyl
ester 4 could be obtained by recrystallization from Et2O-
hexanes (7:1), providing 4 (119 g, 88%) as light yellow crystals:
1H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 2.4 Hz, 1 H), 8.18
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(dd, J = 8.7, 2.4 Hz, 1 H), 7.17 (d, J = 8.7 Hz, 1 H), 7.05 (d,
J = 2.1 Hz, 1 H), 6.93 (dd, J = 8.4, 2.1 Hz, 1 H), 6.87 (d, J =
7.8 Hz, 1 H), 6.14 - 6.02 (m, 1 H), 5.41 (dd, J = 17.1, 1.5 Hz, 1
H), 5.29 (dd, J = 10.5, 1.5 Hz, 1 H), 5.24 (s, 2 H), 4.62 (dt, J =
5.4, 1.3 Hz, 2 H), 4.32 (t, J = 6.6 Hz, 2 H), 3.90 (s, 3 H), 1.81 -
1.72 (m, 2 H), 1.43 - 1.38 (m, 4 H), 0.93 (t, J = 6.9 Hz, 3 H);
13C NMR (75.4 MHz, CDCl3) δ 164.5, 154.9, 149.8, 148.1,
139.8, 135.1, 133.1, 127.6, 127.1, 123.1, 119.4, 118.1, 114.6,
113.1, 110.6, 71.4, 69.9, 65.7, 56.0, 28.4, 28.1, 22.3, 14.0; MS
(FABþ) m/z 429.57 (Mþ, C23H27O7N requires 429.18). Anal.
Calcd for C23H27NO7: C, 64.32; H, 6.34; N, 3.26. Found: C,
64.30; H, 6.74; N, 3.44.
Pentyl 3-Amino-4-(4-allyloxy-3-methoxybenzyloxy)benzoate (5).
A mixture of compound 4 (59.6 g, 139 mmol), AcOH-
EtOH (1:1, 1 L), and Fe0 powder (55.9 g, 1000 mmol) was
maintained at 55 °C under Ar for 9 h with stirring. After the
reaction was allowed to cool to rt, it was poured over H2O (700
mL) and extracted with Et2O (3 ꢀ 300 mL). The combined
organics were then washed with satd NaHCO3 (500 mL), dried
(MgSO4), filtered, and concentrated in vacuo to provide the
crude product as a light brown oil. Crystallization of the oil from
hexanes/CH2Cl2 (9:1) yielded 5 (49.0 g, 88%) as a white crystal-
line solid: 1H NMR (300 MHz, CDCl3) δ 7.46 (dd, J = 8.4, 1.8
Hz, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 6.97 - 6.86 (m, 4 H), 6.16 -
6.03 (m, 1 H), 5.42 (dd, J = 17.1, 1.5 Hz, 1 H), 5.30 (dd, J =
10.5, 1.2 Hz, 1 H), 5.05 (s, 2 H), 4.63 (d, J = 3.9 Hz, 2 H), 4.26
(t, J = 6.9 Hz, 2 H), 3.90 (s, 2 H), 3.89 (s, 3 H), 1.79 - 1.70
(m, 2 H), 1.43 - 1.35 (m, 4 H), 0.93 (t, J = 6.7 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 166.7, 150.0, 149.6, 148.0, 136.1,
133.2, 129.2, 123.5, 120.8, 120.3, 118.1, 115.7, 113.2, 111.5,
110.9, 70.5, 69.9, 64.8, 56.0, 28.5, 28.2, 22.4, 14.0; MS (FABþ)
m/z 400.61 (M þ Hþ, C23H30O5N requires 400.21). Anal. Calcd
for C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C, 69.15; H,
7.33; N, 3.63.
5.29 (dd, J = 10.5, 1.5 Hz, 1 H), 5.11 (s, 2 H), 4.62 (dt, J = 5.4,
1.2 Hz, 2 H), 4.28 (s, 2 H), 4.26 (t, J = 6.9 Hz, 2 H), 3.77 (s, 3 H),
3.15(q, J = 7.5 Hz, 2 H), 1.74 (m, 2 H), 1.40 (m, 4 H), 1.00 (t, J =
6.9 Hz, 3 H), 0.92 (t, J = 6.6 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 166.7, 156.2, 149.5, 147.8, 140.0, 139.2, 133.2, 129.4,
128.4, 128.0, 126.8, 124.5, 123.1, 122.6, 120.0, 118.0, 113.1,
112.5, 111.2, 70.5, 69.9, 64.8, 56.6, 55.8, 44.9, 28.5, 28.2, 22.4,
14.0, 12.2; MS (FABþ) m/z 518.78 (M þ Hþ, C32H40O5N
requires 518.29). Anal. Calcd for C32H39O5N: C, 74.25; H,
7.59; N, 2.71. Found: C, 74.17; H, 7.86; N, 3.10.
4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethylamino)-
benzyl Alcohol (8). To a stirred slurry of LAH (0.950 g, 25.0
mmol) and freshly distilled THF (100 mL) at 25 °C was added
ester 7 (10.8 g, 20.9 mmol) as a solid in 10 equal portions. Upon
completion, the reaction was quenched by successive dropwise
addition of H2O (0.95 mL), aq NaOH (15% w/w, 0.95 mL), and
then H2O (2.85 mL). The resulting slurry was stirred for an
additional 20 min, dried (MgSO4), filtered through a short silica
gel plug, and concentrated to yield alcohol 8 (9.0 g, 99%) as a
1
light yellow oil: H NMR (300 MHz, CDCl3) δ 7.24 (m, 6 H),
6.97 (d, J = 2.1 Hz, 1 H), 6.92 (m, 3 H), 6.83 (d, J = 8.4 Hz, 1 H),
6.08 (m, 1 H), 5.40 (dd, J = 17.2, 1.5 Hz, 1 H), 5.29 (dd, J = 10.2,
0.9 Hz, 1H), 5.06 (s, 2 H), 4.61 (dt, J = 5.4, 1.2 Hz, 2 H), 4.57 (d,
J = 6.0 Hz, 2 H), 4.29 (s, 2 H), 3.77 (s, 3 H), 3.14 (q, J = 6.5 Hz,
2 H), 1.51 (t, J = 5.7 Hz, 1 H), 1.26 (t, J = 7.5 Hz, 2 H), 1.00 (t,
J = 6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 152.0, 149.4,
147.6, 140.7, 139.3, 133.7, 133.3, 130.2, 128.4, 128.0, 126.7,
121.0, 120.6, 119.9, 117.9, 114.1, 113.1, 111.2, 70.8, 69.9, 65.4,
56.6, 55.8, 44.8, 12.2; MS (FABþ) m/z 434.64 (M þ Hþ, C27H32-
O4N requires 434.23). Anal. Calcd for C27H31O4N: C, 74.80; H,
7.21; N, 3.23. Found: C, 74.95; H, 7.60; N, 3.20.
4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethylamino)-
benzyl Alcohol, 4-Nitrophenyl Ether (9). To a stirred solution of
alcohol 8 (1.06 g, 2.44 mmol) in freshly distilled THF (25 mL) at
0 °C were successively added p-nitrophenol (0.41 g, 3.0 mmol),
PPh3 (0.77 g, 2.9 mmol), and diisopropyl azodicarboxylate
(0.56 mL, 2.8 mmol) dropwise via syringe. The reaction was
then allowed to warm to ambient temperature, and upon
completion of the reaction (2 h), based on TLC analysis (SiO2,
4:1 hexanes-EtOAc), the reaction mixture was diluted with
Et2O (100 mL) and quenched with satd NaHCO3 (5 ꢀ 50 mL).
The ethereal layer was dried (MgSO4), filtered, and concen-
trated to a light yellow oil. Purification of the crude oil was
carried out by crystallization from CH3OH which provided
Pentyl 4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzylamino)-
benzoate (6). To a stirred solution of 5 (31.1 g, 77.9 mmol) in
DCE (200 mL) at 25 °C were added benzaldehyde (7.92 mL, 78.0
mmol) and AcOH (3 mL), the resulting mixture was stirred at
this temperature for 30 min before NaBH(OAc)3 (24.6 g, 116
mmol) was added, and stirring was continued for an additional
12 h. The reaction was quenched by the addition of equal
portions of CH2Cl2 (200 mL) and H2O (200 mL). The layers
were separated, and the organic phase was washed with brine
(3 ꢀ 100 mL), dried (MgSO4), filtered, and concentrated to a
light yellow oil. Purification of the oil via flash column chro-
matography (SiO2, 6:1 hexanes/EtOAc) and subsequent crystal-
lization from CH2Cl2-hexanes (1:9) afforded 6 (32.2 g, 84%) as
1
compound 9 (0.65 g, 48%) as a light yellow solid: H NMR
(300 MHz, CDCl3) δ 8.17 (d, J = 9.3 Hz, 2 H), 7.22 (m, 5 H),
6.95 (m, 6 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.09 (m, 1 H), 5.40 (dd,
J = 17.1, 1.8 Hz, 1H), 5.29 (dd, J = 10.2, 1.5 Hz, 1 H), 5.07 (s,
2 H), 5.03 (s, 2 H), 4.62 (dt, J = 5.4, 1.2 Hz, 2 H), 4.30 (s, 2 H),
3.78 (s, 3 H), 3.15 (q, J = 6.5 Hz, 2 H), 1.00 (t, J = 6.9 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 163.8, 152.5, 149.5, 147.7, 141. 5,
140.6, 139.1, 133.3, 129.9, 128.3, 128.0, 127.9, 126.7, 125.8,
121.5, 121.0, 120.0, 118.0, 114.9, 114.0, 113.1, 111.3, 70.8,
70.7, 69.9, 56.4, 55.8, 45.1, 12.3; MS (FABþ) m/z 555.77 (M þ
Hþ, C33H35O6N2 requires 555.25). Anal. Calcd for C33H34-
O6N2: C, 71.46; H, 6.18; N, 5.05. Found: C, 71.55; H, 6.50; N,
5.22.
1
a colorless, crystalline solid: H NMR (300 MHz, CDCl3) δ
7.43-6.84 (m, 11 H), 6.15-6.02 (m, 1 H), 5.41 (dd, J = 17.1, 1.5
Hz, 1 H), 5.29 (dd, J = 10.5, 1.2 Hz, 1 H), 5.06 (s, 2 H), 4.69 (t,
J = 6.0 Hz, 1 H), 4.62 (dt, J = 5.4, 1.5 Hz, 2 H), 4.39 (d, J = 5.4
Hz, 2 H), 4.24 (t, J = 6.6 Hz, 2 H), 3.83 (s, 3 H), 1.77-1.68 (m,
2 H), 1.41-1.36 (m, 4 H), 0.92 (t, J = 7.0 Hz, 3 H); 13C NMR
(125.7 MHz, CDCl3) δ 166.9, 149.5, 149.5, 148.0, 139.1, 137.9,
133.1, 129.1, 128.5, 127.5, 127.2, 123.6, 120.2, 119.2, 118.0,
113.1, 111.3, 110.7, 110.0, 70.5, 69.8, 64.7, 55.9, 47.8, 28.4,
28.2, 22.3, 14.0; MS (FABþ) m/z 490.69 (M þ Hþ, C30H36-
O5N requires 490.26). Anal. Calcd for C30H35NO5: C, 73.59; H,
7.21; N, 2.86. Found: C, 73.31; H, 7.60; N, 3.18.
Pentyl 4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzoate (7). Following the procedure for the preparation
of 6, a mixture of 6 (12.6 g, 25.7 mmol), acetaldehyde (1.70 mL,
51.4 mmol), AcOH (3 mL), DCE (60 mL), and NaBH(OAc)3
(6.53 g, 30.8 mmol) was allowed to react to yield 7 (12.9 g, 96%)
as white crystals after recrystallization from hexanes-CH2Cl2
(9:1): 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, J = 8.4, 2.4 Hz, 1
H), 7.62 (d, J = 1.8 Hz, 1 H), 7.24 (m, 6 H), 6.92 (m, 3 H), 6.83 (d,
J = 8.4 Hz, 1 H), 6.08 (m, 1 H), 5.41 (dd, J = 17.4, 1.5 Hz, 1 H),
Ethyl 4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-
ethylamino)benzyloxy)-3-nitrobenzoate (10). Following the pro-
cedure for the preparation of 9, alcohol 8 (17.5 g, 40.4 mmol) in
THF (350 mL) was reacted with compound 3b (8.56 g, 40.5
mmol), PPh3 (11.7 g, 44.6 mmol), and diisopropyl azodicarboxy-
late (8.61 mL, 43.7 mmol) to afford the crude product as a yellow
solid following precipitation from CH3OH-CH2Cl2 (9:1). Sub-
sequent purification by recrystallization from 5:1 hexanes-
1
Et2O provided 10 (22.6 g, 89%) as yellow needles: H NMR
(300 MHz, CDCl3) δ 8.49 (d, J = 2.4 Hz, 1 H), 8.12 (dd, J =
8.7, 2.4 Hz, 1H), 7.21 (m, 5 H), 7.07 (d, J = 8.7 Hz, 1 H), 6.94
J. Org. Chem. Vol. 75, No. 18, 2010 6159

Ortiz et al.
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(m, 5 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.09 (m, 1 H), 5.40 (dd, J =
17.1, 1.5 Hz, 1 H), 5.29 (dd, J = 10.8, 0.9 Hz, 1 H), 5.19 (s, 2 H),
5.06 (s, 2 H), 4.62 (dt, J = 5.4, 1.5 Hz, 2 H), 4.38 (q, J = 6.9 Hz, 2
H), 4.30 (s, 2 H), 3.77 (s, 3 H), 3.15(q, J = 6.9 Hz, 2 H), 1.40 (t,
J = 6.9 Hz, 3 H), 1.00 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 164.5, 155.0, 152.4, 149.4, 147.7, 140.6, 139.7, 139.1,
134.9, 133.3, 129.9, 128.3, 128.0, 127.2, 127.0, 126.7, 122.8,
120.9, 120.3, 120.0, 118.0, 114.6, 113.9, 113.1, 111.3, 71.5,
70.7, 69.9, 61.5, 56.3, 55.8, 45.1, 14.3, 12.2; MS (FABþ) m/z
627.83 (M þ Hþ, C36H39O8N2 requires 627.27). Anal. Calcd for
C36H38O8N2: C, 68.99; H, 6.11; N, 4.47. Found: C, 69.15; H,
6.46; N, 4.44.
113.1, 112.3, 111.3, 107.3, 100.8, 70.6, 70.5, 69.9, 69.9, 60.6,
56.8, 56.4, 55.8, 44.8, 44.6, 14.4, 12.3, 12.1; MS (MALDI) m/z
925.46 (M - H, C59H61O8N2 requires 925.44). Anal. Calcd for
C59H62O8N2: C, 76.43; H, 6.74; N, 3.02. Found: C, 76.8; H, 6.91;
N, 3.23.
4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethylamino)-
benzyl Alcohol (13). Following the procedure for the preparation
of 6, a mixture of ester 11 (1.45 g, 1.56 mmol) in freshly distilled
THF (40 mL) was allowed to react with LAH (0.12 g, 3.2
mmol) to afford alcohol 13 (1.35 g, 98%) as a colorless glass
after purification by flash column chromatography (SiO2, 2:1
1
Ethyl 3-Amino-4-(4-(4-allyloxy-3-methoxybenzyloxy)-3-(N-
benzyl-N-ethylamino)benzyloxy)benzoate (11). To a stirred solu-
tion of 10 (14.7 g, 23.5 mmol) in absolute ethanol (300 mL) and
hexanes-EtOAc): H NMR (300 MHz, CDCl3) δ 7.27 (m, 15
H), 6.92 (m, 6 H), 6.81 (d, J = 8.1 Hz, 1 H), 6.60 (d, J = 2.1 Hz,
2 H), 6.47 (t, J = 2.4 Hz, 1 H), 6.09 (m, 1 H), 5.41 (dd, J = 17.1,
1.5 Hz, 1H), 5.29 (dd, J = 10.2, 1.5 Hz, 1 H), 5.01 (s, 2 H), 4.94 (s,
2 H), 4.87 (s, 4 H), 4.61 (dt, J = 5.4, 1.5 Hz, 2 H), 4.23 (s, 2 H),
4.17 (s, 2 H), 3.74 (s, 3 H), 3.11 (q, J = 7.5 Hz, 2 H), 3.03 (q, J =
7.2 Hz, 2 H), 1.50 (t, J = 5.7 Hz, 1 H), 0.98 (t, J = 7.5 Hz, 3 H),
0.91 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 159.7,
152.1, 152.0, 149.4, 147.6, 142.1, 140.5, 140.4, 139.3, 137.0,
133.5, 133.3, 130.1, 129.7, 128.5, 128.4, 127.9, 127.8, 127.5,
126.6, 121.5, 121.1, 120.9, 120.7, 119.9, 118.0, 113.9, 113.7,
113.1, 111.3, 107.3, 100.7, 70.7, 70.6, 69.9, 69.8, 65.4, 56.9,
56.5, 55.7, 44.8, 44.6, 12.3, 12.1; MS (MALDI) m/z 885.00
(M þ Hþ, C57H61O7N2 requires 885.45). Anal. Calcd for
C57H60O7N2: C, 77.35; H, 6.83; N, 3.17. Found: C, 76.96; H,
7.11; N, 3.19.
freshly distilled THF (50 mL) at 50 °C was added SnCl2 2H2O
3
(26.4 g, 117 mmol) followed by slow addition (25 min) of a
suspension of finely ground NaBH4 (0.88 g, 23 mmol) in
absolute ethanol (50 mL). The reaction mixture was maintained
at this temperature for 20 min before being allowed to cool to
ambient temperature and quenched by the successive addi-
tion of H2O (150 mL) and aq NaOH (15% w/w, 10 mL). The
resulting mixture was then extracted with Et2O (3 ꢀ 200 mL),
and the combined organic layer was washed with aq satd
NaHCO3 (4 ꢀ 200 mL) solution, dried (MgSO4), filtered, and
concentrated in vacuo. Crystallization of the crude residue
from hexanes-CH2Cl2 (9:1) furnished compound 11 (10.4 g,
74%) as a white, crystalline solid: 1H NMR (300 MHz, CDCl3)
δ 7.44 (dd, J = 8.1, 1.8 Hz, 1 H), 7.39 (d, J = 1.8 Hz, 1 H),
7.22 (m, 5 H), 6.94 (m, 5 H), 6.84 (d, J = 6.3 Hz, 1 H), 6.81 (d,
J = 6.3 Hz, 1 H), 6.09 (m, 1 H), 5.41 (dd, J = 17.1, 1.5 Hz,
1 H), 5.30 (dd, J = 10.8, 0.9 Hz, 1 H), 5.08 (s, 2 H), 5.00 (2 H),
4.62 (dt, J = 5.4, 1.5 Hz, 2 H), 4.33 (q, J = 6.9 Hz, 2 H), 4.31
(s, 2 H), 3.82 (s, 2 H), 3.78 (s, 3 H), 3.15 (q, J = 7.2 Hz, 2 H),
1.37 (t, J = 7.5 Hz, 3 H), 1.01 (t, J = 6.9 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 166.7, 152.4, 150.1, 149.5, 147.7, 140.5,
139.1, 136.2, 133.3, 130.1, 128.9, 128.4, 128.0, 126.7, 123.3,
121.7, 121.2, 120.8, 120.0, 118.0, 115.6, 113.9, 113.1, 111.3,
110.9, 70.7, 70.6, 69.9, 60.5, 56.5, 55.8, 45.1, 14.4, 12.3; MS
(FABþ) m/z 597.76 (M þ Hþ, C36H41O6N2 requires 597.30).
Anal. Calcd for C36H40O6N2: C, 72.46; H, 6.76; N, 4.69. Found:
C, 72.85; H, 7.16; N, 4.58.
4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethylamino)-
benzyl Chloride (14). Following the procedure for the prepara-
tion of 2, a mixture of alcohol 13 (2.10 g, 2.37 mmol) in freshly
distilled CH2Cl2 (50 mL) was allowed to react with SOCl2
(0.19 mL, 2.6 mmol) and DMF (0.5 mL) to provide chloride
14 (2.10 g, 98%) as a colorless glass: 1H NMR (300 MHz,
CDCl3) δ 7.26 (m, 15 H), 6.88 (m, 9 H), 6.57 (d, J = 1.8 Hz, 2 H),
6.47 (t, J = 2.1 Hz, 1 H), 6.08 (m, 1 H), 5.40 (dd, J = 1.5, 17.1
Hz, 1H), 5.29 (dd, J = 1.5, 10.2 Hz, 1 H), 5.00 (s, 2 H), 4.94 (s,
2 H), 4.86 (s, 4 H), 4.60 (dt, J = 1.5, 5.4 Hz, 2 H), 4.51 (s, 2 H),
4.23 (s, 2 H), 4.16 (s, 2 H), 3.74 (s, 3 H), 3.09 (q, J = 6.9 Hz, 2 H),
3.02 (q, J = 6.9 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H), 0.90 (t, J =
7.5 Hz, 3 H); 13C NMR (125.7 MHz, CDCl3): δ 159.7, 152.5,
152.1, 149.4, 147.6, 141.9, 140.5, 140.4, 139.3, 137.0, 133.3,
130.1, 129.9, 129.5, 128.5, 128.4, 127.9, 127.8, 127.5, 126.6,
122.5, 121.9, 121.5, 120.9, 120.0, 118.0, 113.7, 113.6, 113.1,
111.3, 107.3, 100.8, 70.7, 70.6, 69.9, 69.9, 56.8, 56.5, 55.8, 46.8,
44.7, 44.6, 12.4, 12.1; MS (MALDI) m/z 901.43 (M - H, C57H58-
O6N2Cl requires 901.40). Anal. Calcd for C57H59ClO6N2: C,
75.77; H, 6.58; N, 3.10. Found: C, 75.72; H, 6.97; N, 3.17.
4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethylamino)-
benzyl Alcohol, 4-Nitrophenyl Ether (15). A mixture of 14
(0.79 g, 0.87 mmol), p-nitrophenol (0.15 g, 1.0 mmol),
K2CO3 (0.25 g, 1.7 mmol), and DMF (30 mL) was maintained
at 50 °C under argon for 24 h. Et2O (60 mL) was added, and
the mixture was washed with satd aqueous NaHCO3 solution
(5 ꢀ 100 mL), dried (MgSO4), filtered, and concentrated in
vacuo to afford a light yellow oil. Purification of the crude
oil was conducted by flash column chromatography (SiO2,
4:1, hexanes-EtOAc) to afford 15 (0.41 g, 47%) as a light
Ethyl 4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-
ethylamino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethyl-
amino)benzoate (12). To a stirred solution of 11 (12.1 g, 20.3
mmol) in DCE (120 mL) at 25 °C were added 3,5-dibenzyloxy-
benzaldehyde (8.36 g, 26.3 mmol) and AcOH (3 mL). The resul-
ting mixture was stirred for 30 min before NaBH(OAc)3 (5.54 g,
26.1 mmol) was added, and stirring was continued for an addi-
tional 32 h. Acetaldehyde (2.55 mL, 45.4 mmol) and an addi-
tional portion of NaBH(OAc)3 (5.54 g, 26.1 mmol) were then
added to the reaction mixture, and stirring was continued
for 1 h. The reaction solution was then diluted with Et2O
(200 mL), washed with brine (2 ꢀ 200 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Subsequent purification of
the crude product by flash column chromatography (SiO2, 4:1
hexanes-EtOAc) yielded compound 12 (17.6 g, 94%) as a
1
colorless glass: H NMR (300 MHz, CDCl3) δ 7.65 (dd, J =
9.0, 1.8 Hz, 1H), 7.63 (s, 1 H), 7.26 (m, 15 H), 6.46 (t, J = 2.4 Hz,
1 H), 6.08 (m, 1 H), 5.40 (dd, J = 17.1, 1.5 Hz, 1H), 5.29 (dd, J =
10.2, 1.5 Hz, 1 H), 5.05 (s, 2 H), 4.92 (s, 2 H), 4.86 (s, 4 H), 4.60
(dt, J = 5.4, 1.5 Hz, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 4.21 (s, 2 H),
4.15 (s, 2 H), 3.74 (s, 3 H), 3.11 (q, J = 7.2 Hz, 2 H), 3.01 (q, J =
7.2 Hz, 2 H), 1.36 (t, J = 6.9 Hz, 3 H), 0.97 (t, J = 6.9 Hz, 3 H),
0.90 (t, J = 6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 166.7,
159.7, 156.3, 152.2, 149.4, 147.6, 142.0, 140.6, 139.8, 139.2,
137.0, 133.3, 130.1, 129.0, 128.5, 128.3, 127.9, 127.8, 127.5,
126.7, 124.6, 122.9, 122.7, 121.5, 120.8, 120.0, 118.0, 113.7,
1
yellow glass: H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 9.3
Hz, 2 H), 7.27 (m, 17 H), 6.88 (m, 11 H), 6.56 (d, J = 2.7 Hz, 2
H), 6.47 (t, J = 2.4 Hz, 1 H), 6.09 (m, 1 H), 5.40 (dd, J = 17.1,
2.1 Hz, 1 H), 5.29 (dd, J = 10.8, 0.9 Hz, 1 H), 5.02 (s, 4 H), 4.95
(s, 2 H), 4.86 (s, 4 H), 4.61 (dt, J = 5.4, 1.5 Hz, 2 H), 4.24 (s,
2 H), 4.17 (s, 2 H), 3.74 (s, 3 H), 3.12 (q, J = 6.9 Hz, 2 H), 3.03
(q, J = 6.9 Hz, 2 H), 0.98 (t, J = 6.9 Hz, 3 H), 0.91 (t, J = 6.9
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.8, 159.7, 152.5,
6160 J. Org. Chem. Vol. 75, No. 18, 2010

Ortiz et al.
JOCArticle
152.1, 149.4, 147.6, 141.9, 141.4, 140.5, 140.4, 139.3, 137.00,
133.3, 129.5, 128.4, 127.94, 127.86, 127.7, 127.5, 126.6, 125.8,
121.6, 121.5, 121.0, 120.9, 120.0, 118.0, 114.8, 113.7, 113.7,
113.1, 111.3, 107.3 100.6, 70.9, 70.7, 70.6, 69.9, 69.8, 56.6, 56.5,
55.8, 45.1, 44.6, 12.4, 12.1; MS (MALDI) m/z 1007.26 (M þ
for the preparation of 12, a solution of 16 (3.15 g, 2.99 mmol)
in DCE (50 mL) was allowed to react with [G-2]-CHO (2.90 g,
3.89 mmol), NaBH(OAc)3 (1.52 g, 7.16 mmol), acetaldehyde
(0.63 mL, 15 mmol), and AcOH (2 mL) to yield 18 (5.03 g, 97%)
as a colorless oil after purification via flash column chromatog-
raphy (3:1 hexanes-EtOAc): 1H NMR (300 MHz, CDCl3)
δ 7.65 (m, 2 H), 7.25 (m, 35 H), 6.85 (m, 10 H), 6.63 (d, J =
2.7 Hz, 4 H), 6.60 (d, J = 2.1 Hz, 2 H), 6.54 (d, J = 1.8 Hz, 2 H),
6.52 (t, J = 2.4 Hz, 2 H), 6.43 (t, J = 3.3 Hz, 1 H), 6.41 (t, J = 2.4
Hz, 1 H), 6.08 (m, 1 H), 5.40 (dq, J = 17.1, 2.1 Hz, 1 H), 5.28 (dq,
J = 10.8, 0.9 Hz, 1 H), 5.04 (s, 2 H), 4.96 (s, 8 H), 4.87 (s, 2 H),
4.85 (s, 2 H), 4.78 (s, 4 H), 4.78 (s, 4 H), 4.59 (dt, J = 5.4, 1.5 Hz,
2 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.21 (s, 2 H), 4.11 (s, 2 H), 4.07
(s, 2 H), 3.10 (q, J = 7.2 Hz, 2 H), 2.98 (m, 4 H), 1.34 (t, J = 7.5
Hz, 3H), 0.96 (t, J = 7.5 Hz, 3 H), 0.86 (m, 6 H); 13C NMR (125
MHz, CDCl3) δ 166.7, 160.1, 159.7, 159.6, 156.3, 152.3, 152.0,
149.4, 147.6, 142.2, 142.0, 140.5, 140.4, 139.8, 139.5, 139.4,
137.0, 136.8, 133.3, 130.1, 129.6, 128.7, 128.5, 128.4, 128.3,
127.9, 127.8, 127.53, 127.50, 126.6, 124.6, 122.9, 122.7, 121.6,
121.5, 120.8, 119.9, 118.0, 113.5, 113.4, 113.1, 112.3, 111.3,
107.3, 107.2, 106.4, 101.5, 100.8, 100.6, 70.6, 70.5, 70.0, 69.9,
69.7, 60.6, 56.9, 56.6, 56.5, 55.7, 44.8, 44.6, 44.5, 31.6, 22.7, 14.4,
14.1, 12.3, 12.2, 12.1; MS (ESIþ) m/z 1803.20 (M þ Hþ,
2Hþ, C63H65O9N3 requires 1007.47). Anal. Calcd for C63H63
-
O9N3: C, 75.20; H, 6.31; N, 4.18. Found: C, 75.10; H, 6.69;
N, 3.97.
Ethyl 4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-
N-ethylamino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethyl-
amino)-3-nitrobenzoate (16). To a stirred solution of 13 (3.63 g,
4.08 mmol) in THF (50 mL) at 25 °C were successively added 3b
(0.79 g, 3.7 mmol), PPh3 (1.17 g, 4.45 mmol), and diisopropyl
azodicarboxylate (0.86 mL, 4.4 mmol) dropwise over 10 min.
The reaction mixture was stirred at this temperature for 10 min
before being placed in a sonication bath. After completion of
the reaction, based on TLC analysis, the reaction mixture was
diluted with Et2O (100 mL), washed with satd aqueous NaH-
CO3 solution (6 ꢀ 200 mL), dried (MgSO4), filtered, and con-
centrated in vacuo to a light yellow oil. The crude oil was puri-
fied by flash column chromatography (SiO2, 3:1 hexanes-
1
EtOAc) to afford 16 (3.49 g, 90%) as a light yellow solid: H
NMR (300 MHz, CDCl3) δ 8.47 (d, J = 1.8 Hz, 1 H), 8.11 (dd,
J = 8.7, 2.1 Hz, 1 H), 7.26 (m, 15 H), 7.06 (d, J = 9.3 Hz, 1 H),
6.90 (m, 9 H), 6.58 (d, J = 2.1 Hz, 2 H), 6.45 (t, J = 2.4 Hz, 1 H),
6.08 (m, 1 H), 5.40 (dd, J = 17.1, 2.1 Hz, 1 H), 5.28 (dd, J = 10.8,
0.9 Hz, 1 H), 5.18 (s, 2 H), 5.00 (s, 2 H), 4.93 (s, 2 H), 4.85 (s, 4 H),
4.60 (dt, J = 5.4, 1.5 Hz, 2 H), 4.36 (q, J = 7.2 Hz, 2 H), 4.24 (s, 2
H), 4.16 (s, 2 H), 3.74 (s, 3 H), 3.13 (q, J = 6.9 Hz, 2 H), 3.02 (q,
J = 6.9 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3
H), 0.90 (t, J = 7.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
164.4, 159.7, 155.0, 152.4, 152.1, 149.4, 147.6, 142.0, 140.5,
140.4, 139.7, 139.3, 137.0, 134.9, 133.3, 130.1, 129.5, 128.4,
128.3, 127.9, 127.8, 127.5, 127.1, 127.0, 126.6, 122.8, 121.5,
120.9, 120.2, 119.9, 117.9, 114.6, 113.6, 113.1, 111.3, 107.1,
100.7, 71.5, 70.7, 70.6, 69.9, 69.8, 61.4, 56.6, 56.5, 55.7, 45.1,
44.6, 14.3, 12.3, 12.1; MS (MALDI) m/z 1076.44 (M - H, C66-
H66O11N3 requires 1076.47). Anal. Calcd for C66H67O11N3: C,
73.52; H, 6.26; N, 3.90. Found: C, 73.72; H, 6.65; N, 3.79.
Ethyl 3-Amino-4-(4-(4-allyloxy-3-methoxybenzyloxy)-3-(N-
benzyl-N-ethylamino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-
N-ethylamino)benzoate (17). Following the procedure for the
preparation of 11, a solution of 16 (4.15 g, 3.96 mmol) in THF
C
117H116O15N3 requires 1803.84). Anal. Calcd for C117H115-
O15N3: C, 77.93; H, 6.43; N, 2.33. Found: C, 77.58; H, 6.60;
N, 2.41.
4-(4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethylamino)-
benzyloxy)-3-((N-3,5-bis-(3,5-dibenzyloxybenzyloxy)benzyl)-N-
ethylamino)benzyl Alcohol (19). Following a modified procedure
for the preparation of 8, a mixture of 18 (2.45 g, 1.5 mmol), LAH
(0.11 g, 2.9 mmol), and THF (10 mL) was allowed to react by
slowly warming the initial suspension from -78 °C to rt and
worked up as described previously to yield 19 (2.15 g, 83%) as a
colorless glass after purification via flash column chromatogra-
phy (3:1 hexanes-EtOAc): 1H NMR (500 MHz, CDCl3) δ 7.32
(m, 35 H), 6.87 (m, 12 H), 6.62 (d, J = 2.5 Hz, 4 H), 6.57 (d, J =
2.5 Hz, 2 H), 6.54 (d, J = 2.5 Hz, 2 H), 6.52 (t, J = 2.5 Hz, 2 H),
6.42 (t, J = 2.5 Hz, 1 H), 6.41 (t, J = 2.5 Hz, 1 H), 6.08 (m, 1 H),
5.40 (dq, J = 17.1, 2.1 Hz, 1 H), 5.28 (dq, J = 10.8, 0.9 Hz, 1 H),
5.00 (s, 2 H), 4.96 (s, 8 H), 4.87 (s, 2 H), 4.78 (s, 8 H), 4.59 (dt, J =
5.4, 1.5 Hz, 2 H), 4.51 (d, J = 6 Hz, 4 H), 4.21 (s, 2 H), 4.12 (s, 4
H), 4.09 (s, 4 H), 3.72 (s, 3 H), 3.09 (q, J = 7 Hz, 2 H), 2.99 (m, 6
H), 1.45 (t, J = 6 Hz, 1 H; 13C NMR (125 MHz, CDCl3) δ 160.1,
159.63, 159.57, 152.12, 152.07, 152.0, 149.4, 147.6, 142.22,
142.16, 140.5, 140.4, 140.3, 139.5, 139.4, 137.0, 136.8, 133.5,
133.3, 130.1, 129.7, 129.5, 128.5, 128.4, 128.3, 127.9, 127.8,
127.5, 127.5, 126.6, 121.6, 121.5, 121.1, 120.9, 120.7, 119.9,
117.9, 113.9, 113.6, 113.4, 113.1, 111.3, 107.3, 107.2, 106.4,
101.5, 100.74, 100.67, 70.8, 70.6, 70.0, 69.9, 69.8, 69.7, 65.4,
57.0, 56.7, 56.5, 55.7, 44.9, 44.7, 44.6, 12.4, 12.2, 12.1; MS (ESIþ)
m/z 1761.20 (M þ Hþ, C115H114O14N3 requires 1761.83). Anal.
Calcd for C115H113O14N3: C, 78.43; H, 6.47; N, 2.39. Found: C,
78.09; H, 6.32; N, 2.39.
4-(4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-N-ethyl-
amino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethylamino)-
benzyloxy)-3-((N-3,5-bis-(3,5-dibenzyloxybenzyloxy)benzyl)-N-
ethylamino)benzyl Alcohol, 4-Nitrophenyl Ether (20). Following
the procedure used for the preparation of 9, a mixture of 19
(1.06 g, 0.60 mmol), p-nitrophenol (0.17 g, 1.2 mmol), PPh3
(0.31 g, 1.2 mmol), THF (15 mL), and diethyl azodicarboxylate
(0.19 mL, 1.2 mmol) yielded, after recrystallization from ether-
hexanes (1:5), 20 (0.644 g, 57%) as yellow needle-like crystals:
1H NMR (500 MHz, CDCl3) δ 8.09 (m, 4 H), 7.25 (m,
35 H), 6.88 (m, 10 H), 6.61 (d, J = 2.3 Hz, 4 H), 6.55 (d, J =
2.1 Hz, 2 H), 6.52 (m, 4 H), 6.43 (t, J = 3.1 Hz, 1 H), 6.41 (t, J =
2.2 Hz, 1 H), 6.08 (m, 1 H), 5.40 (dq, J = 17.1, 2.1 Hz, 1 H), 5.28
(dq, J =10.8, 0.9 Hz, 1 H), 5.00(s, 2 H), 4.95 (s, 8 H), 4.88 (s, 2 H),
(20 mL) was allowed to react with SnCl2 2H2O (4.47 g, 19.8
3
mmol), KBH4 (0.21 g, 4.0 mmol), and absolute EtOH (75 mL)
at 70 °C. Purification of the crude residue by flash column
chromatography (SiO2, 3:1 hexanes-EtOAc) yielded 17 (3.04 g,
1
77%) as a colorless glass: H NMR (300 MHz, CDCl3) δ 7.44
(dd, J = 8.1, 1.8 Hz, 1 H), 7.26 (m, 15 H), 6.89 (m, 11 H), 6.57 (d,
J = 2.1 Hz, 2 H), 6.46 (t, J = 2.4 Hz, 1 H), 6.08 (m, 1 H), 5.40
(dd, J = 17.1, 2.1 Hz, 1 H), 5.28 (dd, J = 10.8, 0.9 Hz 1H), 5.02
(s, 2 H), 4.99 (s, 2 H), 4.89 (s, 4 H), 4.60 (dt, J = 5.4, 1.5 Hz 2 H),
4.32 (q, J = 6.9 Hz, 2 H), 4.24 (s, 2 H), 4.17 (s, 2 H), 3.79 (s, 2 H),
3.74 (s, 3 H), 3.12 (q, J = 6.9 Hz, 2 H), 3.04 (q, J = 6.9 Hz, 2 H),
1.36 (t, J = 6.6 Hz, 3 H), 0.98 (t, J = 7.5 Hz, 3 H), 0.91 (t, J = 7.5
Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 166.7, 159.7, 152.4,
152.1, 150.1, 149.4, 147.6, 142.0, 140.5, 140.2, 139.3, 137.0,
136.2, 133.3, 130.1, 129.6, 128.7, 128.5, 128.3, 127.93, 127.85,
127.5, 126.6, 123.2, 121.8, 121.5, 121.2, 120.9, 120.7, 119.9,
118.0, 115.5, 113.7, 113.6, 113.1, 111.3, 110.8, 107.3, 100.6,
70.7, 70.6, 69.9, 69.8, 60.5, 56.6, 56.5, 55.7, 45.1, 44.6, 14.4,
12.4, 12.1; MS (ESIþ) m/z 1048.30 (M þ Hþ, C66H70O9N3
requires 1048.51). Anal. Calcd for C66H69O9N3: C, 75.62; H,
6.63; N, 4.01. Found: C, 75.86; H, 7.02; N, 4.12.)
Ethyl 4-(4-(4-(4-Allyloxy-3-methoxybenzyloxy)-3-(N-benzyl-
N-ethylamino)benzyloxy)-3-(N-3,5-dibenzyloxybenzyl-N-ethyl-
amino)benzyloxy)-3-((N-3,5-bis-(3,5-dibenzyloxybenzyloxy)-
benzyl)-N-ethylamino)benzoate (18). Following the procedure
J. Org. Chem. Vol. 75, No. 18, 2010 6161

Ortiz et al.
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4.87 (s, 2 H), 4.79 (s, 4 H), 4.78 (s, 4 H), 4.59 (dt, J = 5.4, 1.5 Hz,
2 H), 4.24 (s, 2 H), 4.12 (s, 2 H), 4.10 (s, 2 H), 3.72 (s, 3 H), 3.10 (q,
J = 7.0 Hz, 2 H), 3.00 (m, 4 H), 0.96 (t, J = 7.0 Hz, 3 H), 0.87 (m,
6 H); 13C NMR (125 MHz, CDCl3) δ 163.7, 160.0, 159.6, 159.5,
152.5, 152.1, 152.0, 149.3, 147.5, 142.1, 141.8, 141.3, 140.4,
140.2, 139.4, 139.3, 137.0, 136.7, 133.3, 130.1, 129.6, 129.2,
130.1, 129.6, 129.2, 126.6, 125.7, 128.5, 128.4, 128.3, 127.90,
127.88, 127.73, 127.68, 127.5, 127.4, 121.7, 121.6, 121.5, 121.1,
120.9, 119.9, 117.9, 114.8, 113.7, 113.5, 113.3, 113.0, 111.2,
107.3, 107.1, 106.3, 101.3, 100.6, 70.8, 70.7, 70.53, 70.51, 70.0,
69.8, 69.7, 69.6, 56.64, 56.57, 56.5, 55.7, 45.1, 44.7, 44.5, 12.4,
12.2, 12.1; MS (ESIþ) m/z 1882.20 (M þ Hþ, C121H117O16N4
requires 1882.85). Anal. Calcd for C121H116O16N4: C, 77.21; H,
6.21; N, 2.98. Found: C, 77.60; H, 6.60; N, 2.85.
DMSO) were prepared. Disassembly trials were performed by
adding 30 μL of the stock substrate solution to 1.7 mL of the
stock KBH4 solution in a UV cuvette and shaking vigorously.
MeOH (100 μL) was then added to the mixture, and again the
mixture was mixed thoroughly via shaking. The UV instrument
was then autozeroed to this mixture, after which 20 μL of the
stock catalyst solution was added. A final mixing of the solution
by shaking the cuvette preceded initiation of the UV time-
course experiment. Absorbance data points were collected at
421 nm every 0.1 s.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0719437).
General Conditions for Disassembly. All disassembly experi-
ments (compounds 9, 15, 20) were performed under identical
conditions. Stock solutions of the substrate (2.17 mM in DMF),
KBH4 (1 mg/mL in DMF), and PdCl2(PPh3)2 (1 mg/mL in
Supporting Information Available: General experimental
methods and NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
6162 J. Org. Chem. Vol. 75, No. 18, 2010