The synthesis of 5-substituted ring E analogs of methyllycaconitine via the Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.bmc.2008.01.050

Novel 3,5-disubstituted ring E analogs of methyllycaconitine were prepared and evaluated in nicotinic acetylcholine receptor binding assays. The desired analogs were prepared through the Suzuki-Miyaura cross-coupling reaction of methyl 5-bromo-nicotinate.

Full text of DOI:10.1016/j.bmc.2008.01.050

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 3816–3824
The synthesis of 5-substituted ring E analogs of
methyllycaconitine via the Suzuki–Miyaura cross-coupling reaction
Junfeng Huang,a Crina M. Orac,a Susan McKay,b
Dennis B. McKayb and Stephen C. Bergmeiera,*
aDepartment of Chemistry and Biochemistry, Ohio University, Clippinger Laboratories, Athens, OH 45701, USA
bDivision of Pharmacology, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA
Received 5 November 2007; revised 17 January 2008; accepted 25 January 2008
Available online 31 January 2008
Abstract—Novel 3,5-disubstituted ring E analogs of methyllycaconitine were prepared and evaluated in nicotinic acetylcholine
receptor binding assays. The desired analogs were prepared through the Suzuki–Miyaura cross-coupling reaction of methyl 5-bro-
mo-nicotinate. The Suzuki–Miyaura cross-coupling reactions of pyridines with electron withdrawing substituents have not been
extensively described previously.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
MLA have not been identified. Most of the reported
compounds lack either potency or selectivity for the a7
nAChR.
Methyllycaconitine (MLA, 1) is a norditerpenoid alka-
loid isolated from plants of the genera Aconitum and
Delphinium.1–3 MLA is the most potent nonpeptide nic-
otinic acetylcholine receptor (nAChR) antagonist
known with selectivity for a7 nAChRs.4–7 Significant
work has been reported on the synthesis and pharmaco-
logical evaluation of analogs of MLA.8 Briefly, the ana-
logs of MLA that have been reported can be grouped
into two major groups. The first major grouping is those
that make minor (yet significant) modifications to the
MLA skeleton or related natural products. Within this
large group workers have found that the stereochemistry
and substitution of the imide ring are vitally important
to the affinity of MLA.9–11 The identity and substitution
of the hydroxyl group aree also important but variations
in binding affinity are at most 20-fold. A second major
group of MLA analogs is the synthetic ring deleted ana-
logs of MLA. These include E-ring analogs,12–17 A/E
analogs,18–23 A/E/F ring analogs,24–26 A/B/E ring ana-
logs,27–31, and A/B/E/F ring analogs.32 Of those synthe-
ses that report pharmacological data it is clear that the
necessary combination of structure and substitution to
identify simpler yet potent and selective analogs of
Our own work in this area has been focused on the syn-
thesis and evaluation of simplified analogs of MLA that
contain only the E-ring of MLA. As shown in Figure 1 a
deletion of all rings except the E-ring and the succinim-
idoanthranilate ester provides 2. This structure is further
simplified to structure 3. We have prepared a number
of analogs of this general structure with variation at
both the R group and Ar group. Our initial lead com-
pound (R = CH2CH2CH2Ph, Ar = 2-(3-methylsuccini-
mide)C6H4) shows a relatively low affinity for the a7
nAChR (IC50 value, 177 lM).14 These compounds also
act as noncompetitive antagonists at the a3* nAChR.
2. Results and discussion
In an effort to continue to define the structural determi-
nants of MLA nicotinic receptor interactions, we wished
to provide additional conformational restriction to our
previously reported ring E analogs. In addition to pro-
viding additional conformational restriction, we hoped
to address additional MLA-like non-covalent contacts.
Keywords: Methyllycaconitine analogs; Nicotinic acetylcholine
receptor.
A slightly different dissection of MLA provides the ring
deleted E-ring derivative 4 (Fig. 1). A further generaliza-
tion of this structure provides the 3,5-disubstituted
*
Corresponding author. Tel.: +1 740 517 8462; fax: +1 740 593
0148; e-mail: bergmeis@ohio.edu
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.01.050

J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
3817
OMe
OMe
OMe
OMe
H
H
OH
MeO
O
O
OH
R2
OMe
Ar
O
N
N
N
Ar
O
N
N
O
O
O
O
R1
R1
3
5
O
O
O
O
O
O
N
N
N
H3C
H3C
H3C
1
4
2
O
O
Figure 1. MLA, ring deleted compounds 2 and 4, and simple ring E analog 3 and 3,5-disubstituted ring E analog 5.
piperidine analog 5. Based on previous work, we wished
to examine a variety of groups at the Ar and R posi-
tions. Our hypothesis was that such an analog might
O
N
O
O
O
O
N
have a more MLA-like pharmacological profile than 3
for two reasons. The first is that an overlay of a typical
ring E analog of MLA with MLA requires that the ring
E analog exist in a chair conformation with the ester in
an equatorial position. Incorporation of the alkyl chain
in the 5-position (e.g. 5) should provide much more of
the conformation in which both groups were in the
equatorial conformation. A second rationale is that
the 3,5-disubstituted analogs should more readily access
non-covalent contacts similar to the B, C, and D rings of
MLA.
O
H3C
O
N
O
N
H3C
3eq
3ax
3
3
ax - 3eq = 2.2 kJ/mol
eq / 3ax = 3
O
N
O
O
O
O
O
N
CH3
H3C
CH3
O
N
O
N
H3C
5eq
5ax
5
5
ax - 5eq = 17.0 kJ/mol
eq / 5ax = 913
A conformational analysis of an E-ring MLA analog 3
was carried out using Spartan. Empirical calculations
were performed using the MMFF force field to investi-
gate the equilibrium abundance of conformational
forms for E-ring type analogs of MLA. Using the con-
formational structures generated in the Equilibrium
Conformer calculations, a second set of calculations,
Conformer Distribution, was performed using the
MM/MMFF model.33 The results of these calculations
for compounds 3eq and 3ax show that the conformation
3ax is less stable than conformation 3eq by 2.223 kJ/mol
(0.531 kcal/mol). Thus, 75% of E-ring analog molecules
3 have the ester group equatorial and 25% have the ester
group axial, 3eq/3ax = 3. For structure 5 the di-axial con-
formation is less stable than the di-equatorial conforma-
tion by 17.002 kJ/mol (4.0633 kcal/mol). This difference
in energy is translated into a higher abundance of the
di-equatorial 3,5-disubstituted analogs over the di-axial
conformer with a ratio of 913 (see Fig. 2).
Figure 2. Conformational preferences of compounds 3 and 5.
O
R
MeOOC
R
Ar
O
N
R
N
H
6
5
MeOOC
R
MeOOC
Br
N
N
7
8
Scheme 1. Retrosynthetic plan for the synthesis of compound 5.
reaction of bromopyridines is known and generally pro-
ceeds in good yields.35 Most of the pyridine substrates
for the Heck reaction make use of pyridine ring systems
that lack strongly electron withdrawing substituents.
The reaction of 8 with cyclohexene and 1-hexene under
either standard Heck conditions (Pd(OAc)2/NEt3/P(o-
tol)3 at 100 °C for 24 h)36 or the Jeffery ligand-free con-
ditions,37 provided only starting materials.
Our synthetic plan hinges on the ability to carry out a
cross-coupling reaction between methyl 5-bromo-nico-
tinate (8) and an organometallic reagent to provide 7
(Scheme 1). Catalytic hydrogenation of the resulting
3,5-disubstituted pyridine 7 should provide the cis-3,5-
disubstituted piperidine ring system 6.34 Functional
group modifications, esterification, and N-alkylation
should then provide the desired 3,5-disubstituted ring
E analogs of MLA.
We next examined the use of the Suzuki–Miyaura cross-
coupling reaction in order to generate the requisite
disubstituted pyridine 7. Like the Heck reaction, the Su-
zuki–Miyaura reaction has been reported using 2- or 4-
bromopyridine derivatives.35,38 Pyridine is a p-electron
deficient heterocycle in which the 2, 4, and 6 positions
Our initial plan was to use a Heck coupling to introduce
an alkyl group at the 5-position of the nicotinic ester.
This should be a versatile route to incorporate a wide
variety of cyclic and acyclic groups at C-5. The Heck

3818
J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
are more electron deficient thus making these position,
more prone to nucleophilic attack. Intermediates in
which the negative charge, developed during nucleo-
philic displacement, can be delocalized onto nitrogen
are more stable relative to others. The same trend hap-
pens in palladium chemistry where the 2, 4, and 6 substi-
tuted halopyridines are more accessible to the oxidative
addition to Pd (0). A large number of examples of the
Suzuki–Miyaura coupling at the 2, 4, or 6-position of
pyridine have been reported.
With an improved procedure in hand, we examined sev-
eral additional alkenes as shown in Table 2. The silyl
ether of 5-hexenol provided compound 7b in 80% yield.
Styrene and methylene cyclohexane provided poorer,
but still acceptable yields of 7c and 7d, respectively.
While the B-alkyl Suzuki reaction provides an excellent
route to alkyl-substituted pyridines, this is of course lim-
ited to mono- or 1,1-disubstituted alkenes. We next
wished to examine other boron reagents in an effort to
prepare pyridines with a 2° alkyl or aryl attachment.
Potassium trifluoroborate compounds have greater
nucleophilicity than other organoboron compounds
which facilitates the Suzuki coupling reaction.44–46 The
reaction of phenethyl potassium trifluoroborate and
phenyl potassium trifluoroborate with pyridine 8 pro-
vided 5-substituted pyridines (7c and 7e) in excellent
yield. We have also examined a boronate ester in the
Compared with the number of Suzuki coupling reac-
tions at the 2- and 4-position of a pyridine ring, the cou-
pling reaction at the 3-position of pyridine is rarely
reported. Only two examples of the Suzuki–Miyaura
coupling in which the 3-position of the pyridine ring is
substituted with an electron withdrawing substituent
have been reported.39,40 Both of these earlier examples
made use of an aryl boronic acid as the organometallic
reagent for the coupling reaction. No B-alkyl Suzuki
coupling has been reported for 5-bromo-nicotinate.
We wished to use a B-alkyl Suzuki–Miyaura reaction,41
as this should provide a wide variety of substituted alkyl
chains attached to the final piperidine molecule.
Table 2. Results of Suzuki couplings
MeOOC
Br
MeOOC
R
N
N
8
7
Coupling partner
Compound
Yield (%)
80a
We first examined the B-alkyl Suzuki reaction condi-
tions which had been reported for the synthesis of 3-
alkylpyridines.42,43 As outlined in Table 1, we have
examined a series of reaction conditions in order to opti-
mize the B-alkyl Suzuki–Miyaura cross-coupling reac-
tion for ester 8. The cross-coupling reaction of
alkylborane reagents, generated by in situ hydrobora-
tion of 1-hexene, and 8 using Pd(PPh3)4 as catalyst
and K2CO3 as the base gave no product at room temper-
ature. Changing the catalyst to PdCl2(dppf) gave a very
low yield (20%) at room temperature. Increasing the
temperature to 90 °C improved the yield slightly but also
generated significant amounts of by-products. Changing
the base to K3PO4 also improved the yield marginally.
However changing the DMF:THF ratio from 1:1 to
3:1 provided the greatest improvement yielding 7a in
82% yield. Further increases in the amount of DMF
did not lead to improved product yields. Carrying out
the reaction in 100% DMF provided little to no product.
Other solvents such as THF:H2O, Et3N, and MeOH
provided either poorer yields or no product.
7a
7b
7c
7d
7c
80a
50a
65a
60b
TBSO
Ph
BF3K
Ph
BF3K
7e
7f
85b
80b
O
B
O
a 9-BBN (2.0 equiv), 3 M K3PO4 (3.0 equiv), DMF:THF (3:1), 5 mol
PdCl2(dppf)CH2Cl2, 70 °C, 6 h.
b DMF:THF(3:1), PdCl2(dppf)CH2Cl2 (5 mol%), K3PO4 (4 equiv),
70 °C, 6 h.
Table 1. Optimization of B-alkyl Suzuki couplings
MeOOC
Br
MeOOC
1) 1-hexene, 9-BBN
2) base, catalyst
( )4
N
N
7a
8
Entry
Solvent
Catalyst (5 mol%)
Base
Time (°C)
Yield (%)
1
2
3
4
5
6
7
8
DMF:THF (1:1)
DMF:THF (1:1)
DMF:THF (1:1)
DMF:THF (1:1)
DMF:THF (3:1)
THF:H2O
Pd(Ph3P)4
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
Et3N
12 h, rt
12 h, rt
12 h, 90
12 h, 90
6 h, 70
6 h, 70
6 h, 70
6 h, 70
0
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
21
34
48
82
43
0
Et3N
MeOH
K3PO4
0

J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
MeOOC
3819
reaction with 8. Under the standard reaction conditions
compound 7f can be prepared in 80% yield.
R
N
H
9
We next turned our attention to the reduction of the pyr-
idine ring. The hydrogenation of pyridines is generally an
efficient method to produce corresponding piperidine
ring system. A key point however is the production of
the cis-disubstituted piperidine ring system. We would
expect that this would be the thermodynamically more
stable compound with both substituents in an equatorial
conformation. Usually the heterogeneous catalytic
hydrogenation of pyridines is carried out in acid media
using aqueous HCl or HOAc as the solvent, and requires
high pressure. In most cases these conditions give cis
products,47–49 although two examples did note the for-
mation of a poor cis:trans mixture.34,50 We were con-
cerned about the very acidic reaction conditions in that
we hoped to prepare additional acid sensitive groups
which would not survive such reaction conditions. We
thus decided to examine alternate reduction conditions
that did not require the use of HCl or HOAc as the sol-
vent. We first examined a neutral hydrogentation using
10 mol% of 10% Pd/C in MeOH. The starting material
was completely consumed in only 4 h but the expected
product 6 was not observed. Instead the only product
found was the enamine 9. Increasing the reaction time
to 24 h provided the same product. By increasing the
amount of catalyst to 50 mol% the reaction did go to
completion in 4 h providing 6 as a 1:1 mixture of the
cis- and trans-diastereomers.
1% AcOH, MeOH
MeOOC
MeOOC
MeOOC
R
R
N
H
N
H
10a
10b
50 mol% of 10% Pd/C
H2 (balloon)
Ph
R
CO2Me
HN
N
H
6
5-H
3-H
nOe
6e
Scheme 3. Diastereoselective hydrogenation.
compounds 6 while loading 50 mol% of 10% Pd/C and
using 1% HOAc in MeOH as the solvent (0.1 M). The
1H NMR of the crude products showed that only one
diastereomer was formed in the hydrogenation. We
would expect that this single stereoisomer should be
the cis-isomer.48,49 An examination of the spectra re-
ported in the literature provided little correlation with
these compounds, however, NOESY spectra of 6e does
provide a clear crosspeak between H-5 and H-3, corrob-
orating the cis assignment.
Compound 6 was not isolated but directly alkylated
with 1-bromo-3-phenylpropane to generate compounds
11a–11f in 60–70% overall yield. Not unexpectedly, the
methyl ester was transesterified to the ethyl ester under
these conditions. This was not a problem as compound
11 was then reduced with LiAlH4 to the alcohol 12.
Again, this compound was not isolated but directly cou-
pled to 2-(30-methyl)succinimidoanthranilic acid (13)51
to give the desired products 5 in generally good overall
yields. Compound 5 is formed as a mixture of four dia-
stereomers but we do not observe these diastereomers in
the NMR, presumably due to the distance between the
stereocenters on piperidine ring and the other stereocen-
ter on the succinimide ring (see Scheme 4).
We rationalized this mixture of diastereomers as shown
in Scheme 2. Both faces of the relatively flat enamine 9
can be readily approached by the catalyst leading to
the observed mixture of isomers. We reasoned that un-
der acidic conditions, if the enamine is formed it should
readily form the iminium 10. This iminium ion can read-
ily equilibrate between the thermodynamically favored
cis-isomer (10a) and the less favored trans-isomer (10b)
under mildly acidic conditions. The more readily re-
duced iminium should then provide cis-isomer 6 as the
sole or major product (see Scheme 3).
We found the hydrogenation of our 3,5-disubstituted
pyridines 7 can be completed in 16 h to form piperidine
The MLA analogs were subsequently examined for their
ability to displace [125I]-a-bungarotoxin (a-Bgt) binding
to a7 nicotinic receptors. Prior to pharmacological
examination, all compounds were converted to their
HCl salts by treatment with anhydrous HCl in EtOAc.
Competition binding experiments were carried out using
techniques previously described.14 As shown in Table 3,
unlike MLA, the disubstituted ring E analogs at a con-
centration of 10 lM showed little or no affinity for [125I]-
a-Bgt binding sites of a7 nicotinic receptors. While addi-
tional conformational restriction has been introduced
into the E-ring, this alone is insufficient to impart affin-
ity for the a7 nicotinic receptor.
MeOOC
R
MeOOC
R
10% Pd/C
H2 (balloon)
MeOH
N
N
H
9
7
MeOOC
R
N
H
6
Pd•H2
HN
CO2Me
R
We have shown previously that other ring E analogs of
MLA inhibit nicotine-stimulated bovine adrenal neuro-
secretion.14,16 Two of the analogs, 5a and 5e, are fairly
potent inhibitors (IC50 values of 2–3 lM), while 5b
Pd•H2
Scheme 2. Lack of diastereoselectivity under neutral hydrogenation
conditions.

3820
J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
MeOOC
R
of ring deleted analogs of MLA. In addition to the phar-
MeOOC
R
a
macological findings, we have developed a general route
to 3,5-cis-disubstituted piperidines. This general route
involves the development of Suzuki–Miyaura cross-cou-
pling conditions that allow for the synthesis of 3,5-
disubstituted pyridine derivatives. This is significant in
that no previous B-alkyl Suzuki–Miyaura reactions have
been reported with pyridines substituted with electron
withdrawing substituents. We have also found that
milder hydrogenation conditions can provide the cis-
disubstituted piperidines. This is an advance over previ-
ously reported hydrogenations of similar systems which
observed a mixture of both cis- and trans-diastereomers.
N
H
N
7
6
EtOOC
R
c
b
N
Ph
11
O
O
O
N
R
HO
R
O
N
d
N
Ph
12
Ph
O
O
O
N
4. Experimental
4.1. General
5
HO
13
All reagents used were purchased from commercial
sources or prepared according to standard literature
methods using references given in the text and purified
as necessary prior to use by standard literature proce-
dures. THF and CH2Cl2 were dried using a Solv-Tek
solvent purification system. Dry DMF was distilled from
calcium hydride and degassed for 10 min prior to use.
Column chromatography was performed using ICN
silica gel 60A. Proton (1H) and carbon (13C) magnetic
resonance spectra (NMR) were recorded on a Bruker
300 MHz Fourier transform spectrometer, and chemical
shift is expressed in parts per million (d) relative to tetra-
methylsilane (TMS, 0 ppm) as internal reference. All
High Resolution Mass Spectra (HRMS) were acquired
using positive electrospray ionization (ESI) at the Mass
Spectrometry Center of the University of Tennessee.
Scheme 4. Reagents and conditions: (a) H2, Pd/C; (b) K2CO3,
Ph(CH2)3Br, 11a, R = nC6H13, 70%, 11b, R = (CH2)5OTBS, 60%,
11c, R = CH2CH2Ph, 70%, 11d, R = CH2(cC6H11), 60%, 11e, R = Ph,
65%, 11f, R = cC6H11, 68%, all yields are for two steps; (c) LiAlH4; (d)
DCC, DMAP, 5a, R = nC6H13, 70%, 5b, R = (CH2)5OTBS, 65%, 5c,
R = CH2CH2Ph, 65%, 5d, R = CH2(cC6H11), 58%, 5e, R = Ph, 60%,
5f, R = cC6H11, 70%, all yields are for two steps.
Table 3. Effects of disubstituted E-ring analogs of MLA on a7 and
a3b4 nAChR binding
Compound
a7 nAChR
specific binding
(% of control)a
a3b4 nAChR
specific binding
(% of control)a
5a
5b
92.2% 9.5%
88.8% 4.2%
98.8% 7.5%
92.6% 4.8%
94.3% 7.3%
103.3% 5.7%
7.5% 1.7%b
105.2% 8.1%
118.5% 9.0%
103.2% 15.3%
NDc
5c
5d
4.2. General procedure for the B-alkyl-Suzuki coupling
5e
5f
MLA
86.8% 9.3%
NDc
50.1% 1.5%b
To the alkene (1 mmol) in a dry flask at 0 °C under
nitrogen was slowly added 9-BBN-H (0.5 M in THF,
4 mL, 2 mmol). The mixture was warmed to room tem-
perature and stirred for 4 h. K3PO4 (3 M in H2O, 1 mL,
3 mmol) was added slowly followed by the addition of
methyl 5-bromo-nicotinate (1.1 mmol) in dry degassed
DMF (12 mL) and finally PdCl2(dppf)CH2Cl2 (42 mg,
5 mol%) under nitrogen. The reaction mixture was stir-
red for 6 h at 70 °C, cooled to room temperature, and
then diluted with EtOAc and saturated NaHCO3 solu-
tion. The aqueous layer was re-extracted with EtOAc.
The organic layer was washed with brine, dried
(MgSO4), and evaporated to give crude products. In
most cases, the product was contaminated by 9-BBN
by-products which cannot be removed by flash column
chromatography and can effect the following reactions.
But they can be greatly reduced by dissolving crude
products in THF (15 mL), followed by the addition of
aqueous NaOH (15%, 1 mL) and H2O2 (30%, 2 mL),
and the mixture was stirred for 1 h at 0 °C. The system
was diluted with ethyl ether, washed with saturated
NaHCO3 solution, brine, dried (MgSO4), concentrated,
and purified by flash column chromatography, eluting
with hexane–EtOAc (10:1) to afford the coupling
compounds.
a Competition binding experiments using [125I]-a-Bgt (for a7 nAChR
binding) or [3H]epibatidine (for a3b4 nAChR binding) as the radi-
olabeled ligands were performed at fixed concentrations of each
analog (10 lM); values represent means SEM, n = 4–7.
b Competition binding experiments were performed at a fixed MLA
concentration of 1.0 lM.
c Not determined.
and 5c are without effects when tested up to concentra-
tions of 10 lM. These analogs have no significant effects
on a3b4 nAChR binding (Table 3) using techniques pre-
viously described.52
3. Conclusions
We have tested the hypothesis that additional conforma-
tional restriction of ring E analogs of MLA would show
affinity for a7 nAChR. These compounds failed to show
any affinity for [125I]-a-Bgt binding sites of a7 nicotinic
acetylcholine receptor subtypes. While this turned out
to be incorrect, this nonetheless provides important
information regarding structure activity relationships

J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
3821
4.2.1. Methyl 5-(hexyl)-nicotinate (7a). Following the
above general procedure, the reaction of 1-hexene
(0.15 mL, 1.2 mmol) and methyl 5-bromo-nicotinate
(286 mg, 1.33 mmol) afforded 212 mg 7a (0.96 mmol,
80%) as a colorless oil after purification by chromatog-
raphy. 1H NMR (300 MHz, CDCl3) d 8.98 (s, 1H),
8.55 (s, 1H), 8.1 (s, 1H), 3.90 (s, 3H), 2.62 (t,
J = 7.6 Hz, 2H), 1.80 (m, 2H), 1.52 (m, 2H), 1.21 (m,
4H), 0.85 (t, J = 2.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 165.9, 153.3, 148.0, 138.1, 136.9, 125.8, 52.4,
36.3, 31.5, 30.9, 28.8, 22.6, 14.1; HRMS (ESI)
C13H19NO2 m/z calculated M+H+ 222.1494, measured
M+H+ 222.1485 (4.0 ppm).
K3PO4 (3 mmol, 637 mg) and PdCl2(dppf)CH2Cl2
(42 mg, 5 mol%). The mixture was stirred for 6 h at
70 °C, cooled to room temperature, and then diluted
with EtOAc and saturated NaHCO3 solution. The aque-
ous layer was re-extracted with EtOAc. The organic
layer was washed with brine, dried (MgSO4), and evap-
orated to give crude products which were purified by
flash column chromatography, eluting with hexane–
EtOAc (10:1) to afford the coupling compounds.
4.3.1. Methyl 5-(phenethyl)-nicotinate (7c). Following
the above general procedure, the reaction of potassium
phenethyltrifluoroborate (320 mg, 1.5 mmol) and
methyl 5-bromo-nicotinate (356 mg, 1.65 mmol) affor-
ded 218 mg of 7e (0.9 mmol, 60%) as a light yellow oil
after purification by chromatography. Same analytical
data as given previously.
4.2.2. Methyl 5-(5-tert-butylmethylsilyl ether pentyl)-
nicotinate (7b). Following the above general procedure,
the reaction of tert-butyldimethyl(pent-4-enyloxy)silane
(200 mg, 1 mmol) and methyl 5-bromo-nicotinate
(238 mg, 1.1 mmol) afforded 270 mg 7b (0.8 mmol,
80%) as a colorless oil after purification by chromatog-
raphy. 1H NMR (300 MHz, CDCl3) d 9.01 (s, 1H),
8.59 (s, 1H), 8.09 (s, 1H), 3.90 (s, 3H), 3.55 (t, J = 6.4,
2H), 2.62 (t, J = 7.6 Hz, 2H), 1.62 (m, 2H), 1.55
(m, 2H), 1.35 (m, 2H), 0.85 (s, 9H), 0.08 (s, 6H);
13C NMR (75 MHz, CDCl3) d; 166.0, 153.6, 148.4,
137.7, 136.7, 125.6, 62.9, 52.3, 32.7, 32.5, 30.8, 25.9,
25.4, 18.3, ꢀ5.3; HRMS (ESI) C18H31NO3Si m/z calcu-
lated M+H+ 338.2151, measured M+H+ 338.2146
(1.5 ppm).
4.3.2. Methyl 5-(phenyl)-nicotinate (7e). Following the
above general procedure, the reaction of potassium phe-
nyltrifluoroborate (276 mg, 1.5 mmol) and methyl 5-
bromo-nicotinate (356 mg, 1.65 mmol) afforded 272 mg
of 7f (1.28 mmol, 85%) as a yellow oil after purification
by chromatography. 1H NMR (300 MHz, CDCl3) d
9.22 (s, 1H), 9.01 (s, 1H), 8.50 (s, 1H), 7.40–7.72 (m,
5H), 4.01 (s, 3H); 13C NMR (75 MHz, CDCl3) d
165.7, 136.6, 135.5, 129.3, 128.7, 127.2, 126.1, 52.6;
HRMS (ESI) C13H11NO2 m/z calculated M+H+
214.0868, measured M+H+ 218.0870 (0.9 ppm).
4.2.3. Methyl 5-(phenethyl)-nicotinate (7c). Following
the above general procedure, the reaction of styrene
(0.17 mL, 1.5 mmol) and methyl 5-bromo-nicotinate
(356 mg, 1.65 mmol) afforded 181 mg 7e (0.75 mmol,
50%) as a light yellow oil after purification by chroma-
4.3.3. Methyl 5-(cyclohexenyl)-nicotinate (7f). Following
the above general procedure, the reaction of cyclohex-
ene-1-boronic acid pinacol ester (312 mg, 1.5 mmol)
and methyl 5-bromo-nicotinate (356 mg, 1.65 mmol)
afforded 263 mg 7d (0.75 mmol, 50%) as colorless oil
after purification by chromatography. 1H NMR
(300 MHz, CDCl3) d 9.00 (s, 1H), 8.70 (s, 1H), 8.15 (s,
1H), 6.15 (s, 1H), 3.95 (s, 3H), 2.30 (m, 2H), 2.20 (m,
2H), 1.78 (m, 2H), 1.61 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 165.9, 150.1, 148.5, 137.5, 132.9, 128.5,
125.4, 52.3, 26.9, 25.8, 22,6, 21.7; HRMS (ESI)
C13H15NO2 m/z calculated M+H+ 218.1181, measured
M+H+ 218.1182 (0.5 ppm).
1
tography. H NMR (300 MHz, CDCl3) d 9.10 (s, 1H),
8.55 (s, 1H), 8.11 (s, 1H), 7.15–7.35 (m, 5H), 3.96 (s,
3H), 2.98 (m, 4H); 13C NMR (75 MHz, CDCl3) d
165.9, 153.7, 148.6, 140.4, 136.8, 136.7, 128.6, 128.4,
126.4, 125.7, 42.3, 37.2, 34.7; HRMS (ESI) C15H15NO2
m/z calculated M+H+ 242.1180, measured M+H+
242.1169 (4.5 ppm).
4.2.4. Methyl 5-(cyclohexylmethyl)-nicotinate (7d). Fol-
lowing the above general procedure, the reaction of
methylenecyclohexane (0.17 mL, 1.4 mmol) and methyl
5-bromo-nicotinate (333 mg, 1.54 mmol) afforded
212 mg 7c (0.91 mmol, 65%) as colorless oil after purifi-
cation by chromatography. 1H NMR (300 MHz,
CDCl3) d 9.08 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 3.98
(s, 3H), 2.53 (d, J = 7.0, 2H), 1.89 (m, 1H), 1.71 (m,
5H), 1.24 (m, 2H), 1.01 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 166.1, 154.2, 148.4, 137.3, 136.4, 125.6, 52.3,
40.7, 39.4, 32.9, 26.3, 26.1; HRMS (ESI) C14H19NO2
m/z calculated M+H+ 234.1494, measured M+H+
234.1486 (3.4 ppm).
4.4. General procedure for the preparation of 11
The 3,5-disubstituted pyridines 7 were dissolved in 1%
HOAc–MeOH (0.1 M) under nitrogen, then 10% Pd/C
(50 mol%) was added carefully followed by the replace-
ment of nitrogen with a balloon of hydrogen. The mix-
ture was stirred for 6 h at room temperature under a
balloon of hydrogen and then was filtered through Cel-
ite, which was subsequently washed with MeOH
(20 mL). The solvent was removed under vacuum and
gave the crude products that can be used directly in next
step. The crude piperidine compounds 6 were then dis-
solved in EtOH (0.5 M) and then K2CO3 (400 mol%)
was added followed by the addition of 1-bromo-3-phe-
nylpropane (120 mol%). The mixture was stirred for
12 h at 85 °C, cooled to room temperature, and then di-
luted with EtOAc (50 mL). The organic layer was
washed with brine, dried (MgSO4), and evaporated to
give crude products which can be purified by flash col-
4.3. General procedure for synthesis of 7c, 7e, and 7f
Methyl 5-bromo-nicotinate (1.1 mmol) was dissolved in
degassed DMF–THF (3:1) (10 mL) under nitrogen, then
trifluoroborate compound or boronic acid pinacolate
(1 mmol) was added followed by the addition of

3822
J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
umn chromatography, eluting with hexane–EtOAc (5:1)
to afford the desired compound, 11.
(m, 2H); 13C NMR (75 MHz, CDCl3) d 174.2, 142.5,
128.5, 128.2, 125.6, 63.7, 60.3, 57.8, 54.9, 41.5, 39.6,
34.7, 33.5, 33.4, 33.3, 32.2, 30.3, 29.9, 28.6, 26.7, 26.4,
14.2; HRMS (ESI) C24H37NO2 m/z calculated M+H+
372.2903, measured M+H+ 372.2903 (0.0 ppm).
4.4.1. Ethyl 5-hexyl-1-(3-phenylpropyl)piperidine-3-car-
boxylate (11a). Following the above general procedure
7a (332 mg, 1.5 mmol) was hydrogenated to provide
340 mg of crude 6a. This material was used directly in
the subsequent reaction to provide 377 mg of 11a
(1.05 mmol, 70%) as light yellow oil after purification
by chromatography. 1H NMR (300 MHz, CDCl3) d
7.10–7.30 (m, 5H), 4.10 (q, J = 7.2 Hz, 2H), 2.95 (m,
1H), 2.43–2.67 (m, 4H), 2.34 1(m, 1H), 2.24 (m, 2H),
2.1 (m, 1H), 1.70–1.97 (m, 4H), 1.10–1.30 (m, 14H),
0.87 (t, J = 4.5 Hz, 3H);13C NMR (75 MHz, CDCl3) d
174.2, 142.4, 128.5, 128.2, 125.6, 60.3, 59.9, 58.0, 54.9,
39.5, 33.6, 33.5, 32.9, 31.8, 31.7, 29.5, 28.6, 26.9, 22.7,
14.2, 14.1; HRMS (ESI) C23H37NO2 m/z calculated
M+H+ 360.2903, measured M+H+ 360.2903 (0.0 ppm).
4.4.5. Ethyl 5-phenyl-1-(3-phenylpropyl)piperidine-3-car-
boxylate (11e). Following the above general procedure
7e (271 mg, 1.27 mmol) was hydrogenated to provide
276 mg of crude 6e. This material was used directly in
the subsequent reaction to afford 290 mg of 11e
(0.82 mmol, 65%) as a light yellow oil after purification
by chromatography. 1H NMR (300 MHz, CDCl3) d
7.09–7.19 (m, 10H), 4.12 (q, J = 7.12, 2H), 3.23 (m,
1H), 3.03–3.15 (m, 1H), 2.77–2.86 (m, 1H), 2.66–2.72
(m, 1H), 2.5–2.66 (m, 2H), 2.11–2.42 (m, 4H), 1.98 (s,
1H), 1.77 (m, J = 7.4, 2H), 1.52–1.68 (m, 1H), 1.22 (t,
J = 7.12, 3H); 13C NMR (75 MHz, CDCl3) d 173.9,
144.4, 142.4, 128.5, 128.3, 128.2, 128.1, 127.4, 126.3,
125.6, 60.9, 60.4, 57.7, 54.4, 39.8, 39.2, 33.5, 32.3, 28.6,
14.3; HRMS (ESI) C23H29NO2 m/z calculated M+H+
352.2277, measured M+H+ 352.2261 (4.5 ppm).
4.4.2. Ethyl 5-(5-tert-butylmethylsilyl ether pentyl)-1-(3-
phenylpropyl)piperidine-3-carboxylate (11b). Following
the above general procedure 7b (610 mg, 1.81 mmol)
was hydrogenated to provide 620 mg of crude 6b. This
material was used directly in the subsequent reaction
to afford 512 mg of 11b (1.09 mmol, 60%) as a light yel-
4.4.6. Ethyl 5-cyclohexyl-1-(3-phenylpropyl)piperidine-3-
carboxylate (11f). Following the above general proce-
dure 7f (373 mg, 1.7 mmol) was hydrogenated to pro-
vide 380 mg of crude 6f. This material was used
directly in the subsequent reaction to afford 411 mg of
11f (1.15 mmol, 68%) as a light yellow oil after purifica-
tion by chromatography. 1H NMR (300 MHz, CDCl3) d
7.14–7.28 (m, 5H), 4.17 (q, J = 7.1, 2H), 3.04 (m, 1H),
2.53–2.73 (m, 4H), 2.32–2.43 (m, 1H), 2.14–2.30 (m,
2H), 1.93–2.08 (m, 2H), 1.52–1.86 (m, 8H), 1.10–1.33
(m, 8H), 0.84–1.05 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 173.6, 141.9, 128.5, 128.2, 125.6, 63.7, 60.3,
58.0, 54.9, 39.8, 39.7, 38.3, 33.5, 32.3, 30.4, 28.9, 28.6,
26.5, 14.3; HRMS (ESI) C23H35NO2 m/z calculated
M+H+ 358.2736, measured M+H+ 358.2719 (4.5 ppm).
1
low oil after purification by chromatography. H NMR
(300 MHz, CDCl3) d 7.71–7.72 (m, 5H), 4.12 (q,
J = 7.2 Hz, 2H), 3.55 (t, J = 6.6, 2H), 2.94 (m, 1H),
2.48–2.70 (m, 4H), 2.14–2.33 (m, 2H), 1.96 (m, 1H),
1.43–1.90 (m, 6H), 1.30–1.40 (m, 8H), 1.26 (t, J = 7.2,
3H), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 174.3, 142.5, 128.5, 128.2, 125.6, 63.3, 60.3,
57.9, 55.0, 39.5, 33.7, 33.5, 33.0, 32.8, 31.7, 28.6, 27.4,
26.9, 25.9, 22.6, 14.2, ꢀ5.3; HRMS (ESI) C28H49NO3Si
m/z calculated M+H+ 476.3560, measured M+H+
476.3568 (1.7 ppm).
4.4.3. Ethyl 5-phenethyl-1-(3-phenylpropyl)piperidine-3-
carboxylate (11c). Following the above general proce-
dure 7c (393 mg, 1.63 mmol) was hydrogenated to pro-
vide 400 mg of crude 6c. This material was used
directly in the subsequent reaction to afford 432 mg of
11c (1.14 mmol, 70%) as a light yellow oil after purifica-
tion by chromatography. 1H NMR (300 MHz, CDCl3) d
7.15–7.33 (m, 10H), 4.13 (q, J = 7.1 Hz, 2H), 2.93 (m,
1H), 2.52–2.72 (m, 6H), 2.21–2.40 (m, 2H), 1.72–2.14
(m, 4H), 1.50–1.67 (m, 5H), 1.23 (t, J = 7.1, 3H); 13C
NMR (75 MHz, CDCl3) d 174.2, 142.7, 142.4, 128.4,
128.3, 125.7, 63.7, 60.3, 57.8, 55.0, 39.5, 35.6, 33.5,
32.9, 31.7, 28.6, 14.3; HRMS (ESI) C25H33NO2 m/z cal-
culated M+H+ 380.2590, measured M+H+ 380.2580
(2.6 ppm).
4.5. General procedure for the synthesis of 5
Compounds 11a–f were dissolved in THF (0.1 M) under
nitrogen and cooled to 0 °C. LiAlH4 (200 mol%) was
added carefully. The mixture was stirred for 12 h at
room temperature, and then diluted with Et2O and
cooled to 0 °C. H2O (80 lL) was added followed by
the addition of 15% NaOH (80 lL) and H2O (0.2 mL).
The system was stirred for 2 h at room temperature
and MgSO4 was added. The mixture was filtered
through Celite, which was subsequently washed with
Et2O (20 mL). The solvent was removed under vacuum
and gave 12a–f which were used directly in the next reac-
tion. The crude reduction products, 12a–f, were dis-
solved in CH2Cl2 (0.5 M) under nitrogen. DMAP
(10 mol%) was added followed by the addition of 2-
(30-methyl)succinimidoanthranilic acid51 (120 mol%).
The mixture was cooled to 0 °C, and then DCC
(130 mol%) was added. The mixture was stirred for
12 h at room temperature, and then the solvent was re-
moved under vacuum. The residue was taken up in Et2O
ether (20 mL), and filtered through Celite. The clear
solution was concentrated and gave the crude products
which were purified by flash column chromatography,
4.4.4. Ethyl 5-(cyclohexylmethyl)-1-(3-phenylpropyl)piper-
idine-3-carboxylate (11d). Following the above general
procedure 7d (376 mg, 1.61 mmol) was hydrogenated to
provide 383 mg of crude 6d. This material was used di-
rectly in the subsequent reaction to afford 357 mg of 11d
(0.96 mmol, 60%) as a light yellow oil after purification
by chromatography. 1H NMR (300 MHz, CDCl3) d
7.10–7.22 (m, 5H), 4.11 (q, J = 7.2, 2H), 2.98 (m, 1H),
2.45–2.67 (m, 4H), 2.14–2.39 (m, 3H), 1.84–2.07 (m,
3H), 1.60–1.82 (m, 8H), 1.01–1.32 (m, 9H), 0.64–0.88

J. Huang et al. / Bioorg. Med. Chem. 16 (2008) 3816–3824
3823
eluting with hexane–EtOAc (3:1) to afford the desired
compounds.
after purification by chromatography. 1H NMR
(300 MHz, CDCl3) d 8.02 (d, J = 7.89, 1H), 7.57 (t,
J = 7.65, 1H), 7.41 (t, J = 7.71, 1H), 7.05–7.25 (m, 6H),
4.22 (d, J = 6.98, 2H), 2.98 (m, 2H), 2.32–2.80 (m, 5H),
2.05–2.29 (m, 4H), 1.45–1.89 (m, 10H), 1.25–1.40 (m,
3H), 0.96–1.24 (m, 9H); 13C NMR (75 MHz, CDCl3) d
179.8, 175.6, 164.5, 142.5, 133.2, 132.8, 131.5, 129.8,
129.2, 128.2, 125.6, 67.5, 60.2, 57.9, 55.9, 41.7, 37.0,
34.8, 33.7, 33.6, 33.1, 32.7, 29.7, 29.2, 28.7, 26.7, 26.4,
22.8, 16.6; HRMS (ESI) C34H44N2O4 m/z calculated
M+H+ 545.3379, measured M+H+ 545.3369 (1.8 ppm).
4.5.1. Succinimidoanthranilate ester 5a. Following the
above general procedure 11a (353 mg, 0.98 mmol) was re-
duced to provide crude 12a (310 mg). This material was
used directly in the subsequent coupling reaction to pro-
vide 366 mg of 5a (0.68 mmol, 70%) as a light yellow oil
after purification by chromatography. 1H NMR
(300 MHz, CDCl3) d 8.02 (d, J = 7.77, 1H), 7.56 (t,
J = 7.68, 1H), 7.39 (t, J = 7.71, 1H), 7,03–7.30 (m, 6H),
4.21 (d, J = 6.98, 2H), 2.98 (m, 2H), 2.40–2.58 (m, 5H),
2.01–2.30 (m, 4H), 1.48–1.89 (m, 6H), 1.38–1.46 (m,
3H), 1.11–1.30 (m, 10H), 0.80 (t, J = 6.81, 3H); 13C
NMR (75 MHz, CDCl3) d 179.8, 175.7, 164.4, 142.5,
133.2, 132.8, 131.5, 129.8, 129.2, 128.5, 128.2, 127.7,
125.6, 67.5, 59.8, 57.9, 56.1, 37.0, 35.3, 33.9, 33.6, 33.1,
32.5, 32.4, 31.9, 29.5, 28.7, 27.1, 24.9, 22.6, 16.4, 14.1;
HRMS (ESI) C33H44N2O4 m/z calculated M+H+
533.3379, measured M+H+ 533.3363 (3.0 ppm).
4.5.5. Succinimidoanthranilate ester 5e. Following the
above general procedure, 11e (380 mg, 1.08 mmol) was
reduced to provide crude 12e (340 mg). This material
was used directly in the subsequent coupling reaction
to provide 402 mg of 5e (0.76 mmol, 70%) as a light yel-
1
low oil after purification by chromatography. H NMR
(300 MHz, CDCl3) d 8.08 (d, J = 7.79, 1H), 7.65 (t,
J = 7.70, 1H), 7.48 (t, J = 7.71, 1H), 7.17–7.29 (m,
6H), 4.27 (d, J = 6.98, 2H), 3.06 (m, 2H), 2.40–2.70
(m, 4H), 1.89–2.39 (m, 5H), 1.55–1.86 (m, 9H), 1.30–
1.50 (m, 6H), 1.00–1.29 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 179.8, 175.8, 164.4, 142.5, 133.2, 132.8,
131.5, 129.8, 129.2, 128.5, 128.4, 128.2, 126.0, 125.6,
67.4, 61.2, 58.2, 55.9, 39.9, 37.6, 37.0, 35.3, 33.9, 32.2,
30.6, 30.5, 29.7, 28.7, 26.6, 25.6, 24.9, 16.4; HRMS
(ESI) C33H42N2O4 m/z calculated M+H+ 531.3223, mea-
sured M+H+ 531.3202 (4.0 ppm).
4.5.2. Succinimidoanthranilate ester 5b. Following the
above general procedure 11b (438 mg, 0.92 mmol) was
reduced to provide crude 12b (400 mg). This material
was used directly in the subsequent coupling reaction
to provide 386 mg of 5a (0.6 mmol, 65%) as a light yel-
1
low oil after purification by chromatography. H NMR
(300 MHz, CDCl3) d 0.00 (s, 6H), 0.849 (s, 9H), 1.12–
1.30 (m, 7H), 1.31–1.59 (m, 5H), 1.60–1.92 (m, 5H),
2.05–2.37 (m, 4H), 2.40–2.72 (m, 5H), 3.55 (m, 2H),
4.23 (t, J = 6.42, 2H), 4.23 (d, J = 7.0, 2H), 7.05–7.37
(m, 6H), 7.43 (t, J = 7.56, 1H), 7.62 (t, J = 7.56, 1H),
8.04 (d, J = 7.5, 1H); 13C NMR (75 MHz, CDCl3) d
179.0, 175.0, 163.6, 141.7, 132.4, 132.0, 130.7, 129.9,
129.4, 129.0, 128.5, 128.2, 127.7, 127.5, 124.8, 66.7,
62.5, 58.9, 57.2, 55.3, 36.2, 34.5, 33.1, 32.8, 32.3, 32.1,
31.7, 27.9, 26.2, 25.2, 25.3, 17.6, 15.6, ꢀ6.0; HRMS
(ESI) C38H56N2O5Si m/z calculated M+H+ 649.4037,
measured M+H+ 649.4009 (4.3 ppm).
4.5.6. Succinimidoanthranilate ester 5f. Following the
above general procedure, 11f (320 mg, 0.9 mmol) was re-
duced to provide crude 12f (276 mg). This material was
used directly in the subsequent coupling reaction to pro-
vide 280 mg of 5f (0.53 mmol, 60%) as a light yellow oil
after purification by chromatography. 1H NMR
(300 MHz, CDCl3) d 8.01 (d, J = 7.47, 1H), 7.56 (t,
J = 7.71, 1H), 7.38 (t, J = 7.68, 1H), 7.04–7.25 (m,
11H), 4.38 (d, J = 6.99, 2H), 2.85–3.10 (m, 3H), 2.60–
2.80 (m, 2H), 2.57 (t, J = 7.8, 2H), 1.50–1.79 (m, 4H),
1.26–1.37 (m, 3H), 1.10–1.25 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 179.8, 175.8, 164.5, 144.4, 142.4,
133.2, 132.8, 131.5, 129.8, 129.2, 128.4, 128.4, 128.3,
127.6, 127.5, 126.3, 125.7, 66.9, 60.7, 57.9, 55.3, 49.2,
38.4, 37.0, 35.3, 33.9, 33.6, 28.6, 24.9, 16.4; HRMS
(ESI) C33H36N2O4 m/z calculated M+H+ 525.2743, mea-
sured M+H+ 525.2718 (4.8 ppm).
4.5.3. Succinimidoanthranilate ester 5c. Following the
above general procedure 11c (338 mg, 0.9 mmol) was re-
duced to provide crude 12c (301 mg). This material was
used directly in the subsequent coupling reaction to pro-
vide 320 mg of 5c (0.58 mmol, 65%) as a light yellow oil
after purification by chromatography. 1H NMR
(300 MHz, CDCl3) d 8.02 (d, J = 7.4, 1H), 7.57 (t,
J = 7.65, 1H), 7.41 (t, J = 7.62, 1H), 7.08–7.38 (m,
11H), 4.19 (d, J = 6.99, 2H), 2.98 (m, 2H), 2.40–2.58
(m, 6H), 2.10–2.28 (m, 3H), 1.70–1.96 (m, 1H), 1.50–
1.59 (m, 6H), 1.38 (m, 3H), 1.18–1.27 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 178.8, 174.8, 163.4, 141.5,
132.3, 131.8, 130.5, 128.8, 128.3, 127.5, 127.3, 124.7,
66.4, 58.4, 56.9, 55.1, 36.0, 34.6, 34.3, 32.9, 32.5, 32.0,
31.2, 28.7, 27.7, 24.7, 23.9, 15.4; HRMS (ESI)
C35H40N2O4 m/z calculated M+H+ 553.3066, measured
M+H+ 553.3084 (3.3 ppm).
Acknowledgments
This work was supported by Grant DA13939 (SCB)
from the National Institutes on Drug Abuse at the Na-
tional Institutes of Health. We also acknowledge sup-
port of the NanoBioTechnology Initiative funded by
the office of the Vice President for Research at Ohio
University.
4.5.4. Succinimidoanthranilate ester 5d. Following the
above general procedure 11d (339 mg, 0.91 mmol) was re-
duced to provide crude 12d (300 mg). This material was
used directly in the subsequent coupling reaction to pro-
vide 288 mg of 5d (0.53 mmol, 58%) as a light yellow oil
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