Synthesis of functionalised aromatic oligamide rods

Article abstract of DOI:10.1039/b712606a

A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined conformations - so called foldamers. In this manuscript we describe a modular approach for construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly restricts the conformation of the rod through intramolecular hydrogen-bonding. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b712606a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of functionalised aromatic oligamide rods†‡
Jeffrey Plante,a,b Fred Campbell,a,b Barbora Malkova,b Colin Kilner,a Stuart L. Warrinera,b and
Andrew J. Wilson*a,b
Received 14th September 2007, Accepted 22nd October 2007
First published as an Advance Article on the web 7th November 2007
DOI: 10.1039/b712606a
A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined
conformations—so called foldamers. In this manuscript we describe a modular approach for
construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific
incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly
restricts the conformation of the rod through intramolecular hydrogen-bonding.
be possible to construct short rod-like oliogoamides using a
Introduction
similar strategy. Indeed, a similar approach was used to assemble
nanometre sized rods from 4ꢀ-amino-[1,1ꢀ-biphenyl]-4-carboxylic
acid derivatives.26 Herein we describe a robust modular synthesis of
aromatic oligoamides and their structural characterisation. These
O-alkylated oligomers were recently proposed to be potential a-
helix mimetics.27
A current goal of biomolecular chemistry is to replicate the func-
tions performed by nature’s biomacromolecules with synthetic
mimics. Nature uses polymers comprising well defined monodis-
perse sequences of monomers that adopt highly defined secondary
and tertiary three dimensional architectures. Therefore, significant
effort has been devoted to identifying model systems that give
rise to well defined secondary structures termed ‘foldamers’.1,2
More recently functional properties3 have been illustrated as
evidenced by reports on foldamers that inhibit protein–protein
interactions,4 act as bacteriocidal agents5 and recognise small
molecules.6 Similarly, the knowledge derived from fundamental
studies of secondary structural motifs has recently allowed some
simple tertiary structures to be prepared.7–9 For the most well
studied class of foldamer, i.e. those derived from b-peptides,10
a key feature that has permitted these studies is the availability
of iterative syntheses that give rise to well defined sequences
incorporating many different monomers.
We have become interested in the study of aromatic oliogo-
amides11–13 because their syntheses are in principle amenable to
the methods used for conventional a-amino acid derived peptides.
Most aromatic oligoamides adopt helical conformations pre-
organised by intramolecular hydrogen-bonds, with extended or
rod-like conformations less common.14–18 Rod-like oligomers may
find use in protein,19 peptide20 and oligonucleotide recognition.21
We recently described a route to oligoamide macrocycle syn-
thesis with regiospecific incorporation of functional groups.22
The approach does not require hydrogen-bonding but instead
exploits the helical conformation23 adopted by linear N-alkylated
aromatic oligoamides which preferentially adopt the cis con-
former at the amide linkage.24 Given that phenyl-benzamides
prefer the trans conformation,25 we hypothesized that it should
Results and discussion
Synthesis
Our design of rod-like oligomers necessitates placing the carboxy-
late and amine funtionalities that form the linking amide in a para
relationship. We also required a robust method to incorporate
side-chains into each monomer unit and were attracted by O-
alkylation. This has the advantage of pre-organising the scaffold
further through 5-membered intramolecular hydrogen-bonding
between the oxygen of the alkoxy substituent and the amide
NH. Iterative synthesis via sequential coupling of masked 4-
nitro-3-alkoxybenzoic acid monomers (Scheme 1) as described for
synthesis of b-sheet binding pyrazole oligoamides20 was attractive
to us. Such an approach is fully modular, so once a monomer
has been synthesised it can be rapidly incorporated into any
desired sequence. In previously described studies,27 N to C terminal
assembly was employed, but amide bond formation with alkylated
monomers failed and a less modular amide formation then
alkylation was necessary.
aSchool of Chemistry, University of Leeds, Woodhouse Lane, Leeds,
LS29JT, United Kingdom. E-mail: A.J.Wilson@leeds.ac.uk; Fax: +44
(0)113 3431409; Tel: +44 (0)113 3436565
bAstbury Centre for Structural Molecular Biology, University of Leeds,
Woodhouse Lane, Leeds, LS29JT, United Kingdom
† Dedicated to Prof. Sir J. Fraser Stoddart on the occasion of his
knighthood and 65th birthday.
‡ Electronic supplementary information (ESI) available: CIF files, full
details of X-ray crystallographic structure determination and additional
NMR spectra. See DOI: 10.1039/b712606a
Scheme 1 Iterative synthetic strategy for construction of aromatic
oligoamide rods.
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For these solution phase studies we chose 4-nitro-3-hydroxy-
benzoic acid as the starting material due to the ease of monomer
synthesis. Scheme 2 outlines our approach which furnishes both
4-nitro-3-alkoxybenzoic acids 4a–f for chain elongation and
unmasked amines 5a–b that can be used as the starting monomer.
Alkylation of the phenolic oxygen is possible either by reaction
with commercially available alkyl halides or Mitsunobu reaction
with alcohols. The latter approach gives poorer yields and more
difficult purification; however, the compatibility of both reactions
coupled with the wide variety of commercially available alkyl
halides and alcohols, augers well for future studies.
The synthesis of trimers is shown in Scheme 3. The key steps
involve (i) amide bond formation, for which we selected dichlorot-
riphenyl phosphorane as activating agent and (ii) unmasking
of an amino group, for which we selected tin (II) chloride. For
amide bond formation, only coupling reagents that generate acid
chlorides gave decent yields and then only when heated. For
nitro group reduction, although hydrogenation over palladium on
carbon proceeded smoothly, this is not compatible with benzylic
O-alkyl substituents. We found reduction with tin (II) chloride to be
a viable alternative. Yields were consistently above 90% for each
of these steps. The final compounds 10 were fully deprotected
to expose the terminal amine and carboxylate functionalities
(hydrolysis followed hydrogenation—see below).
The synthesis of tetramers and pentamers was found to be more
challenging. Initially we conceived a 2 + 3 fragment based strategy;
however, our attempts to cleave the methyl ester of trimer 8aaa
resulted in hydrolysis of the amide group para to the terminal nitro
group. This is perhaps unsurprising given the electron withdrawing
nature of the nitro group. Thus, although we could have also
explored a 3 + 2 strategy, this result suggested that clean hydrolysis
of nitro masked dimers 6 was unlikely and we opted instead for
a simple 3 + 1 then 4 + 1 chain elongation approach (Scheme 4).
Only small reductions in yield were observed for the coupling
steps, however, the tetramers and pentamers underwent sluggish
nitro group reduction. The most likely reason for this is the poorer
solubility of these compounds in the reaction media. Indeed,
Scheme 2 Synthesis of monomers for iterative synthesis of aromatic
oligoamide rods.
Scheme 3 Synthesis of fully unmasked trimers 10 via an iterative chain elongation approach. Identity of side chains in oligomers is given from the C
terminus e.g. for 10aac R1 = a, R2 = a, and R3 = c.
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Scheme 4 Synthesis of oligoamide tetramers and pentamers (letters correspond to R groups as for Schemes 2 and 3).
we were unable to reduce tetramer 12acde whilst 12aecb gave a
poor conversion resulting in only 22% of the reduced product
although it should be noted that unreacted starting material was
also recovered.
Structural studies
Single crystals were obtained by the slow evaporation of a solution
of trimer 8abc in ethyl acetate. The X-ray structure confirms the
oligomer adopts an extended structure and the presence of an
intramolecular hydrogen-bond between the amide NH and the
alkoxy oxygen on the neighbouring phenyl ring (Fig. 1). NMR
studies indicate that this behaviour is mirrored in solution. For
example 8aaa, in both DMSO-d6 and chlorinated solvents, exhibits
strong hydrogen bonds as evidenced by the downfield shift of the
NH protons (Hf and Hl) (removed in the 1H NMR spectra) (Fig. 2a
and b). In both solvents, the NHs undergo no change upon dilution
indicating these interactions are intramolecular (Fig. S1 and S2,
ESI‡). This is further confirmed upon heating up to 100 ◦C (Fig. S3
and S4, ESI‡); in DMSO-d6, Hf and Hl experience temperature
induced shifts of 3.5 ppb K−1 and 4.3 ppb K−1 whilst in C2D2Cl4
they exhibit shifts of 0.8 ppb K−1 and 0.6 ppb K−1. The extended
Fig. 1 X-Ray crystal structure of compound 8abc shown in stick (left)
˚
and CPK (right) format. Key distances H1–O4 = 2.155 A and H2–O2 =
˚
2.132 A.
rod-like structure is confirmed in solution by correlations in the
1H–1H NOESY spectrum between NH and ArCH on adjacent
aromatic units (i.e. NHl to Hk and Hj and NHf to He and Hd)
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1
Fig. 2 1H NMR spectrum (500 MHz) of trimer 8aaa (a) 3 mM in CDCl3 and (b) 2 mM in DMSO-d6 (c) H–1H NOESY spectrum of trimer 8aaa
in CDCl3.
and the absence of cross-peaks between non-adjacent aromatic
resonances (Fig. 2c). Furthermore, this observation confirms free
rotation about the ArCO bonds, whilst the absence of cross-peaks
between H0 and NH1 or Hi and NHf suggests restricted rotation
about the ArNH bonds.
The tetramers and pentamers also exhibit downfield shifted
NH protons indicative of H-bonding, however signal overlap
prevented a thorough conformational analysis as for the trimers.
We therefore utilized molecular modelling by performing a full
Monte Carlo search in Macromodel28 using the MMFFs force
field. This revealed the lowest energy conformation of pentamer
13aaaaa in the gas phase was the extended structure (Fig. 3)
and similar results were obtained when the dielectric was set to
water. This clearly demonstrated the extended conformation is
preferred in both solution phase and gas phase. Furthermore,
we tentatively suggest that alternate alkoxy substituents prefer to
reside on opposite faces of the rod—all but two of the 20 lowest
energy conformers found in the search followed this trend.
Taken together the X-ray, NMR and modelling studies clearly
confirm an extended conformation is preferred in the solid state
and solution, and that intermolecular hydrogen-bonding fixes
rotation about the ArNH bond. However, like the nanometre
sized rods described recently by Nowick and co-workers,26 free
rotation about the ArCO bond is possible. Our rationale is that
the alkoxy substituents minimise steric hindrance by residing on
opposing faces, although this conformation would also minimise
dipole effects. The NOESY results suggest this preference is
not overwhelming as both ArCO conformations are present in
solution. Interestingly, in the solid state structure of 8abc (Fig. 1)
two of the alkoxy substituents reside on the same face suggesting
that crystal packing effects and interactions between adjacent side
chains can significantly influence the preferred conformation of
these oligomers. This is significant for the following reason: where
the molecular recognition properties of these foldamers depend on
the alkoxy substituents being presented on one face and available
for recognition (e.g. for protein19 or crystal surface29 recognition)
an entropic price would need to be paid for fixing the ArCO bond
rotation and/or breaking side-chain side-chain interactions. This
can be advantageous in that it allows for induced-fit binding. These
compounds therefore complement the fully rigidified crescent
oligomers and rods described by the groups of Gong,13 Hamilton16
and Li.17,18
Conclusion
We have described the fully modular syntheses of a series of rod
like aromatic oligoamides. These molecules can be made from
Fig. 3 Lowest energy conformer of pentamer 13aaaaa identified by a
Monte Carlo search in Macromodel using the MMFFs force field.
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easily accessible monomers and adopt well defined conformations,
whilst the building blocks and synthetic methods are compatible
with the components of other aromatic oligoamides. Our own
future studies will focus on making mixed structures containing
building blocks from this pool, elaborating solid phase approaches
for their synthesis and studying their molecular recognition
properties.
(100 mL per g of phenol). The organics were dried (Na2SO4) and
removed under reduced pressure. The crude oil was subjected to
column chromatography (SiO2, CH2Cl2) to yield a pale yellow
solid.
General procedure B for the saponification of esters
Oligoamide (1 equiv.) was dissolved in THF (25 mL per g of ester)
and MeOH (25 mL per g of ester). NaOH (10% aqueous 5 mL
per g of ester) was then added and the solution was sealed and
stirred overnight. When the reaction was complete as observed by
TLC, the organic solvent was removed under reduced pressure.
The resulting viscous solution was diluted with water (40 mL
per g of ester) and acidified to a pH of 1 using 10% aqueous
HCl. The resulting suspension was then filtered and the solid
dried overnight yielding a white solid. Alternatively the acid is
dissolved in EtOAc and separated from the spurious water and
dried (Na2SO4). Removal of the solvents under reduced pressure
yielded the acid as a white solid.
Experimental
All chemicals and solvents were purchased from Aldrich and
used without further purification. Melting points were determined
using a Griffin D5 variable temperature apparatus and are un-
corrected. 1H Nuclear magnetic resonance spectra were recorded
1
using a Bruker DRX 500 MHz or DPX 300 MHz machine. H
spectra are referenced to tetramethylsilane (TMS) and chemical
shifts are given in parts per million downfield from TMS. Coupling
constants are reported to the nearest 0.1 Hz. Microanalyses
were obtained on a Carlo Erba Elemental Analyser MOD 1106
instrument. Infrared spectra were recorded on a Perkin-Elmer
FTIR spectrometer and samples analysed in the solid phase.
Mass spectra were obtained on a Bruker microTOF using electro-
spray ionisation. Representative characterisation is given here
for all intermediates leading to a complete trimer 10abc and a
complete pentamer 13aecba. The remaining data is available in the
ESI.‡
General procedure C for the coupling reaction
Under an inert atmosphere, to a stirred solution of amine
(1.0 equiv.) and acid (1.4 equiv.) in freshly distilled CHCl3 (50 mL
per g of amine), dichlorotriphenylphosphorane (4.5 equiv.) was
added and the solution allowed to stir at reflux (80 ◦C) overnight.
The solvents were removed under a reduced pressure and the
resultant viscous oil subjected to column chromatography (SiO2,
CH2Cl2–Et2O gradient) to yield the product.
Crystal structure determination for 8abc
Single crystals were grown by the slow evaporation of a solution
of 8abc in ethyl acetate. X-Ray diffraction data were collected at
the University of Leeds. Crystal data. C35H35N3O9, M = 641.66,
crystal size 0.3 × 0.1 × 0.1 mm, triclinic, a = 8.0680(2), b =
General procedure D for reduction of a nitro group
To a solution of a nitro compound (1 equiv.) in EtOAc (5–
10 mL) was added SnCl2·2H2O (5 equiv.) and the reaction mixture
was heated to 50 ◦C under a drying tube. When TLC indicated
complete reduction (typically 24 hours), the reaction mixture was
cooled, then poured into NaOH solution (10% 100 mL) and the
flask rinsed into ethyl acetate (×2). The combined organics were
extracted twice with NaOH solution (10% 100 mL) before being
washed once with brine (50 mL). The organics were then dried
(Na2SO4) and the solvent removed under reduced pressure yielding
oils that solidify upon standing. Alternatively, the oil was subjected
to column chromatography (SiO2, CH2Cl2–Et2O gradient) to give
a cream white to yellow crystalline product.
˚
10.8740(2), c = 19.1980(5) A, a = 105.2700(10), b = 8.0820(10),
◦
3
¯
˚
c = 8.0750(10) , U = 1580.64(6) A , T = 150(2) K, P1, Z = 2, l =
−1
˚
0.098 mm , k = 0.71073 A [Mo–Ka], 13724 reflections measured,
7244 unique (Rint = 0.035), observed (I > 2r(I)). The final R1 was
0.0490 (observed reflections 0.0866) and wR(F2) was 0.1250 (all
data 0.1638) for 436 parameters.§
Molecular modelling
Structures were minimized with Macromodel (MacroModel ver-
sion 9.0, Schrodinger LLC, New York, NY, 2006) using the Monte
Carlo method (5000 structures using the automatic setup) and
minimized using the MMFF force field. The results were visualized
with Maestro (version 7) and the lowest 20 energy structures were
compared, and found to be similar.
Methyl-3-hydroxy-4-nitrobenzoate 2
A stirred solution of 3-hydroxy-4-nitro benzoic acid 1 (2.50 g,
13.66 mmol) and p-toluene sulfonic acid (0.50 g, 2.63 mmol)
in anhydrous methanol (50 mL) under an atmosphere of argon
was heated at reflux (65 ◦C) for 60 h. The reaction mixture
was concentrated to leave a bright yellow crystalline solid, which
was partitioned between EtOAc and water (4 × 50 mL). The
organic fraction was dried (MgSO4), concentrated and dried under
vacuum, isolating pure target material (2.38 g, >90%) as a bright
yellow powdered solid; mp 90–91 ◦C (90–91 ◦C Aldrich); Rf 0.63
(10% EtOAc in CH2Cl2); dH (300 MHz, CDCl3) 4.00 (s, 3H,
CO2Me), 7.65 (d, 1H, J = 8.8, ArCH), 7.87 (d, 1H, J = 1.7,
ArCH), 8.21 (d, 1H, J = 8.8, ArCH).
General procedure A for the alkylation of phenol
Under an inert atmosphere, methyl-3-hydroxy-4-nitrobenzoate
(1 equiv.) was dissolved in DMF (5 ml per g of phenol) and K2CO3
(5 equiv.) was added. The alkyl halide (1.4 equiv.) was then added
and the solution stirred at 50 ◦C overnight. The resultant solution
was poured into EtOAc (100 mL per g of phenol) and washed
twice with H2O (100 mL per g of phenol) and once with brine
§ CCDC reference number 661106. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b712606a
142 | Org. Biomol. Chem., 2008, 6, 138–146
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Methyl-3-isopropyloxy-4-nitrobenzoate 3a
reaction mixture was stirred for 200 minutes until TLC indicated
the reaction was complete. The mixture was passed through a
celite pad and concentrated before drying under vacuum to yield
the product (272 mg, 92%) as a runny pale brown oil; Rf 0.42
(5% EtOAc in CH2Cl2); dH (500 MHz, CDCl3) 1.29 (d, 6H, J =
6.1, CH3), 3.78 (s, 3H, CO2Me), 4.10 (broad singlet, 2H, NH2),
4.56 (septet, 1H, J = 6.1, CH), 6.59 (d, 1H, J = 8.1, ArCH),
7.39 (d, 1H, J = 1.5, ArCH), 7.45 (dd, 1H, J = 1.6 and 8.2,
ArCH); dC (75 MHz, CDCl3) 25.57, 52.05, 71.20, 113.80, 114.44,
119.81, 124.29, 142.62, 144.54, 167.75; mmax/cm−1 (solid state) 3500,
3373 (NH2), 2972, 2950 (CH), 1692, 1613 (CO); ESI-MS m/z 210
[M + H]+; ESI-HRMS found m/z 210.1127 [M + H]+, C11H15NO3
requires 210.1125.
To a stirred solution of methyl-3-hydroxy-4-nitrobenzoate 2
(1.00 g, 5.34 mmol), isopropanol (0.60 mL, 7.85 mmol, excess)
and triphenylphosphine (1.33 g, 5.07 mmol) in anhydrous THF
(15 mL), under an atmosphere of argon, at 0 ◦C, was added
diisopropyl azodicarboxylate (DIAD) (1.00 mL, 4.82 mmol). The
reaction mixture was allowed to warm to room temperature and
stirred for a further 72 h. The reaction mixture was concentrated
then dissolved in CH2Cl2 and washed with water (2 × 30 mL),
saturated NaHCO3 (3 × 30 mL) and brine (30 mL). The organic
fraction was concentrated and purified by column chromatogra-
phy (1 : 1; CH2Cl2–hexane) to yield the product (0.84 g, 77%) as a
bright yellow crystalline solid; mp 39–41 ◦C (found: C, 55.30; H,
5.45; N, 5.75%. C11H13NO5 requires: C, 55.23; H, 5.48; N, 5.86%);
Rf 0.55 (CH2Cl2); dH (500 MHz, CDCl3) 1.41 (6H, d, J = 6.0,
2-propyl CH3), 3.96 (3H, s, CO2Me), 4.77 (1H, hep, J = 6.0, CH),
7.65 (1H, d, J = 7.3, ArCH), 7.74 (1H, s, ArCH), 7.76 (1H, d,
J = 8.5, Ar 6-CH); dC (75 MHz, CDCl3) 21.8, 52.8, 73.0, 116.9,
121.1, 125.1, 134.4, 143.7, 150.8, 165.4; mmax/cm−1 (solid state) =
3119, 3060, 2989, 1958 (aliph CH), 1725 (CO), 1528; ESI-MS
m/z 262 [M + Na]+; ESI-HRMS found m/z 262.0694 [M + Na]+,
C11H13NNaO5 requires 262.0686.
Methyl-3-isopropoxy-4-(3-propoxy-4-nitro-benzoylamido)-
benzoate 6ab
(Procedure C) 5a (166 mg, 0.8 mmol), 4b (178 mg, 0.8 mmol),
chloroform (20 mL), Cl2PPh3 (640 mg, 1.9 mmol). Purification
by column chromatography (10% EtOAc in CH2Cl2) afforded the
target material (215.7 mg, 65%), as a pale yellow solid; mp 132–
133 ◦C (found C 60.00, H 5.80, N 6.60%. C21H24N2O7 requires: C
60.50, H 5.85, N 6.73%); dH (500 MHz, CDCl3) 1.08 (3H, t, J =
7.4, CH3), 1.44 (6H, d, J = 6.0, CH3), 1.90 (2H, tq, J = 7.1 and
6.9, CH2), 3.92 (3H, s, CO2Me), 4.17 (2H, t, J = 6.4, CH2), 4.78
(1H, hep, J = 6.1, CH), 7.37 (1H, d, J = 8.3, ArCH), 7.61 (1H, s,
ArCH), 7.67 (1H, s, ArCH), 7.74 (1H, d, J = 8.4, ArCH), 7.92
(1H, d, J = 8.3, ArCH), 8.59 (1H, d, J = 8.5, ArCH), 8.79 (1H, s,
NH); dC (75 MHz, CDCl3) 10.8, 22.6, 22.7, 52.6, 71.8, 72.3, 113.4
(Ar C, CO), 114.5, 117.6, 119.3, 123.6, 126.2, 126.3, 132.6, 140.2,
142.2, 146.3, 153.1, 163.5, 167.0; mmax/cm−1 (solid state) 3425 (NH),
Methyl-3-isopropyloxy-4-nitrobenzoate 3a
(Alternative preparation using procedure A) methyl-3-hydroxy-4-
nitrobenzoate 2 (600 mg, 3.0 mmol), K2CO3 (510 mg, 3.7 mmol),
anhydrous DMF (15 mL), 2-bromopropane (450 lL, 5.0 mmol).
Purification by column chromatography (20% EtOAc–CH2Cl2)
gave a bright yellow crystalline solid: yield: 520 mg, 71% (data as
above).
=
3092, 2977, 2951, 2884, 2621, 1932, 1683 (CO), 1598 (C C), 1516
(NO2); ESI-MS m/z = 417 [M + H]+.
3-Isopropyloxy-4-nitro benzoic acid 4a
Methyl-3-isopropoxy-4-(3-(2-naphthyloxy)-4-nitro-benzoylamido)-
benzoate 6ae
(Using minor modifications to procedure B) a stirred solution of
methyl-3-isopropoxy-4-nitrobenzoate (250 mg, 1.05 mmol) and
1 M NaOH solution (1.5 mL, 1.10 mmol) in methanol (10 mL)
was heated at reflux temperature (65 ◦C) for 12 h until TLC
indicated no remaining starting material. On cooling, the reaction
mixture was acidified to pH ∼1 (1 N HCl, ∼2 mL) precipitating a
solid which was collected by filtration and dried thoroughly under
vacuum to gi◦ve the target acid (194 mg, 82.1%) as a cream solid:
mp 173–175 C (found: C, 53.40; H, 4.90; N, 6.05%. C10H11NO5
requires: C, 53.33; H, 4.92; N, 6.22%); Rf 0.31 (15% MeOH
in CH2Cl2); dH (75 MHz, CDCl3) 1.47 (d, 6H, J = 6.1, CH3),
4.82 (q, 1H, J = 6.1, CH), 7.77 (d, 1H, J = 8.1, ArCH), 7.80
(d, 1H, J = 7.6, ArCH), 7.82 (d, 1H, J = 1.3 Hz, ArCH); dC
(75 MHz, CDCl3) 22.18, 73.52, 117.70, 122.18, 125.59, 133.70,
144.77, 151.19, 170.69; mmax/cm−1 (solid state) = 2900 (broad,
COOH), 1688 (CO), 1524, 1432; ESI-HRMS found m/z 224.0553
[M − H]−, C10H10NO5 requires 224.0553.
(Procedure C) 5a (914.3 mg, 4.4 mmol), 4e (2.0 g, 6.43 mmol),
Cl2PPh3 (6.4 g, 19.8 mmol), and chloroform (150 mL) afforded
the product (2.2 g, 100%) as a yellow solid; mp 142–143 ◦C; dH
(300 MHz, CDCl3) 1.40 (6H, d, J = 6, iPrCH3), 3.91 (3H, s,
CO2Me), 4.75 (1H, hep, J = 6, iPrCH), 5.47 (2H, s, benzylic
CH2), 7.37 (1H, d, J = 8.3, ArCH), 7.45–7.51 (2H, m, ArCH),
7.55 (1H, d, J = 8.4, ArCH), 7.59 (1H, s, ArCH), 7.72 (1H, d,
J = 8.4, ArCH), 7.79–7.96 (6H, m, ArCH), 8.56 (1H, d, J = 8.5,
ArCH), 8.76 (1H, s, NH); dC (75 MHz, CDCl3) 22.6, 52.6, 72.0,
72.3, 113.5, 115.3, 118.1, 119.3, 123.6, 125.0, 126.3, 126.5, 126.7,
126.8, 126.9, 128.2, 128.5, 129.2, 132.5, 132.8, 133.6, 133.7, 140.3,
142.5, 146.3, 152.6, 163.3, 167.0; mmax/cm−1 (solid state) 3423 (NH),
2982, 1713, 1691, 1597, 1522, 1481, 1348, 1273, 1114, 1003, 760;
ESI-HRMS found m/z 515.1809 [M + H]+, C29H27N2O7 requires
515.1813.
Methyl-4-amino-3-isopropyloxy benzoate 5a
Methyl-3-isopropoxy-4-(3-propoxy-4-amino-benzoylamido)-
benzoate 7ab
To a stirred solution of methyl-3-isopropoxy-4-nitrobenzoate 3a
(340 mg, 1.42 mmol) in anhydrous methanol (10 mL), under an
atmosphere of nitrogen, was added 10% palladium on charcoal
(30 mg). The nitrogen atmosphere was evacuated under vacuum
and hydrogen gas (1 L, excess) introduced via a balloon. The
To a stirred solution of 6ab (175 mg, 0.40 mmol) in anhydrous
methanol (7 mL), under an atmosphere of nitrogen, was added
palladium on charcoal catalyst (17.5 mg, 10% catalyst). The
nitrogen atmosphere was evacuated under vacuum and hydrogen
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gas (1 L, excess) introduced via a balloon. The reaction mixture
was stirred until TLC indicated the reaction was complete and
then passed through a celite pad, concentrated and dried under
high vacuum to yield the product (141 mg, 91%); mp 103–104 ◦C;
dH (500 MHz, CDCl3) 1.07 (3H, t, J = 7.4, CH3), 1.43 (6H,
d, J = 6.0, CH3), 1.88 (2H, tq, J = 6.9 and 6.8, CH2), 3.91
(3H, s, CO2Me), 4.06 (2H, t, J 6.4, CH2), 4.22 (2H, s, NH2),
4.75 (1H, hep, J = 6.1, CH), 6.73 (1H, d, J = 8.5, ArCH),
7.26 (1H, d, J = 8.3, ArCH), 7.44 (1H, s, ArCH), 7.58 (1H, s,
ArCH), 7.71 (1H, d, J = 8.6, ArCH), 8.51 (1H, s, NH), 8.62
(1H, d, J = 7.8, ArCH); dC (75 MHz, CDCl3) 22.3, 22.6, 30.9,
52.0, 70.0, 71.8, 91.1, 110.7, 113.2, 113.3, 118.5, 119.9, 123.5,
124.2, 124.5, 133.6, 140.5, 145.6, 146.2, 165.1, 166.9; mmax/cm−1
(solid state) 3492, 3429, 3349, 2970, 2934, 2873, 1704 (CO), 1614;
ESI-HRMS found m/z 387.1914 [M + H]+, C21H28N2O5 requires
387.1842.
Methyl-3-isopropoxy-4-(3-(2-napthyloxy)-4-(3-benzyloxy-4-nitro-
benzoylamido)-benzoylamido)-benzoate 8aec
(Procedure D) 7ae (1.1 g, 2.1 mmol), 4c (753.7 mg, 2.7 mmol),
Cl2PPh3 (3.2 g, 9.9 mmol), and chloroform (100 mL) afforded
the product (1.1 g, 70%) as a yellow solid; mp 203–204 ◦C; dH
(300 MHz, CDCl3) 1.45 (6H, d J = 6 Hz, iPrCH3), 3.92 (3H, s,
CO2Me), 4.77 (1H, hep, J = 6, CH), 5.13 (2H, s, benzylic CH2),
5.43 (2H, s, benzylic CH2), 7.28–7.53 (8H, m, ArCH), 7.60 (1H, s,
ArCH), 7.65 (1H, s, ArCH), 7.71–7.76 (3H, m, ArCH), 7.80–7.88
(5H, m, ArCH), 7.90 (1H, s, ArCH), 8.62 (1H, d J 8.5 Hz, ArCH),
8.67 (1H, d J 8.4 Hz, ArCH), 8.76 (1H, s, NH), 8.87 (1H, br,
NH); dC (75 MHz, CDCl3) 22.2, 42.5, 52.1, 71.3, 71.9, 72.1, 111.9,
113.2, 114.4, 116.9, 118.1, 118.7, 119.3, 119.5, 122.3, 123.3, 125.1,
125.2, 125.9, 126.8, 126.9, 127.2, 127.9, 128.5, 128.8, 129.0, 130.8,
131.1, 132.9, 133.0, 134.8, 139.3, 145.8, 147.9, 163.0, 164.0, 166.9;
mmax/cm−1 (solid state) 3426, 2978, 1717, 1599, 1492, 1235, 1125,
1013, 957, 849, 746; ESI-HRMS found m/z 740.2565 [M + H]+,
C43H38N3O9 requires 740.2603.
Methyl-3-isopropoxy-4-(3-(2-naphthyloxy)-4-amino-
benzoylamido)-benzoate 7ae
Methyl-3-isopropoxy-4-(3-propoxy-4-(3-benzyloxy-4-amino-
benzoylamido)-benzoylamido)-benzoate 9abc
(Procedure C) 6ae (2.2 g, 4.4 mmol), SnCl2·2H2O (5.2 g,
23.1 mmol), ethyl acetate (150 mL) afforded the product (1.4 g,
67%) as a yellow oil that solidified upon standing; mp 70–72 ◦C;
dH (300 MHz, CDCl3) 1.40 (6H, d, J = 6, iPrCH3), 3.89 (3H, s,
CO2Me), 4.33 (2H, br, NH2), 4.71 (1H, hep, J = 6, iPrCH), 5.29
(2H, s, benzylic CH2), 6.75 (1H, d, J = 8.1, ArCH), 7.29 (1H,
d, J = 8.2, ArCH), 7.47–7.52 (2H, m, ArCH), 7.56 (1H, d, J =
8.2, ArCH), 7.58 (1H, s, ArCH), 7.61 (1H, s, ArCH), 7.71 (1H, d,
J = 8.4, ArCH), 7.82–7.87 (4H, m, ArCH), 8.63 (1H, d, J = 8.5,
ArCH), 8.74 (1H, s, NH); dC (75 MHz, CDCl3) 22.6, 52.4, 71.1,
72.2, 111.8, 113.6, 113.9, 118.9, 120.7, 123.8, 124.5, 124.9, 125.9,
126.7, 126.8, 127.1, 128.2, 128.4, 128.9, 133.6, 133.7, 134.0, 134.4,
141.3, 146.1, 146.4, 165.4, 167.3; mmax/cm−1 (solid state) 3482, 3429,
3364, 2978, 1714, 1668, 1596, 1515, 1481, 1347, 1256, 1203, 1124,
1003, 956, 872, 963, 604; ESI-HRMS found m/z 485.2041 [M]+,
C29H28N2O5 requires 485.2071.
(Procedure D) 8abc (110.0 mg, 0.2 mmol), SnCl2·2H2O (200.0 mg,
1 mmol) ethyl acetate (40 mL) afforded the product (87.4 mg,
84%) as a pale yellow solid; mp 185 ◦C (found C 66.2, H 6.10, N
6.40%. C35H37N3O7·H2O requires C 66.67, H 6.24, N 6.67%); dH
(500 MHz, CDCl3) 1.12 (3H, t, J = 7.2, CH3), 1.45 (6H, d, J 6.0,
CH3), 1.94 (2H, tq, J = 7.0 and 6.9, CH2), 3.91 (3H, s, CO2Me),
4.16 (2H, t, J = 6.4, CH2), 4.77 (1H, hep, J = 5.9, CH), 4.23 (2H, s,
NH2), 5.18 (2H, s, benzylic CH2), 6.41 (1H, d, J = 8.8, ArCH),
7.63–7.31 (10H, m, Ar CH), 7.73 (1H, d, J = 8.6, ArCH), 8.62
(1H, d, J = 8.6, ArCH), 8.68 (1H, d, J = 8.7, ArCH), 8.72 (1H, s,
NH), 8.87 (1H, s, NH); dC (75 MHz, CDCl3) 9.6, 21.2, 21.5, 51.0,
69.4, 69.6, 70.9, 109.5, 110.3, 112.2, 112.5, 117.6, 118.0, 119.3,
122.4, 123.0, 123.9, 126.8, 127.3, 127.7, 128.3, 131.0, 132.2, 135.5,
139.8, 144.8, 145.0, 146.6, 163.6, 164.1, 165.82; mmax/cm−1 (solid
state) 3439, 3368 (NH), 2966, 2873, 1693 (CO), 1601, 1516, 1253;
ESI-MS m/z 612 [M + H]+, 650 [M + K]+.
Methyl-3-isopropoxy-4-(3-propoxy-4-(3-benzyloxy-4-nitro-
benzoylamido)-benzoylamido)-benzoate 8abc
Methyl-3-isopropoxy-4-(3-(2-napthyloxy)-4-(3-benzyloxy-4-
amino-benzoylamido)-benzoylamido)-benzoate 9aec
(Procedure C) 7ab (125.0 mg, 0.3 mmol), 4c (83.2 mg, 0.3 mmol),
chloroform (20 mL), Cl2PPh3 (260.0 mg, 0.8 mmol) afforded the
product (193.2 mg, 96%) as a yellow solid; mp 212–214 ◦C (found:
C, 64.55; H, 5.1; N, 6.0%. C35H35N3O9·0.5H2O requires: C, 64.61;
H, 5.58; N, 6.46%); dH (500 MHz, CDCl3) 1.11 (3H, t, J = 7.4,
CH3), 1.46 (6H, d, J = 6.0, CH3), 1.94 (2H, tq, J = 7.1 and 6.9,
CH2), 3.92 (3H, s, CO2Me), 4.18 (2H, t, J = 6.5, CH2), 4.78 (1H,
hep, J = 6.0, CH), 5.34 (2H, s, benzylic CH2), 7.43–7.34 (5H,
m, ArCH), 7.49 (2H, d, J = 7.3, ArCH), 7.62 (2H, d, J = 10.5,
ArCH), 7.73 (1H, d, J = 8.5, ArCH), 7.80 (1H, s, ArCH), 7.97 (1H,
d, J = 8.3, ArCH), 8.63 (2H, d, J = 9.1, ArCH), 8.75 (1H, s, NH),
8.87 (1H, s, NH); dC (75 MHz, CDCl3) 10.57, 22.2, 22.5, 52.1,
70.5, 71.4, 71.8, 110.7, 113.1, 114.7, 117.7, 118.6, 118.9, 119.0,
123.3, 125.1, 126.1, 127.2, 128.5, 128.8, 130.6, 130.7, 132.9, 134.9,
139.7, 142.1, 145.8, 147.8, 152.2, 163.0, 164.3, 166.8; mmax/cm−1
(solid state) 3427 (NH2), 2968, 2934, 2879, 1721 (CO), 1596, 1516
(NO2); ESI-HRMS found m/z 642.2445 [M + H]+, C35H36N3O9
requires 642.2446.
(Procedure C) 8aec (1.3 g, 1.8 mmol), SnCl2 (2.5 g, 11.1 mmol) and
ethyl acetate (150 mL) afforded the product (530.1 mg, 42%) as a
yellow solid; mp 92–93 ◦C; dH (300 MHz, CDCl3) 1.48 (6H, d, J =
6, iPrCH3), 3.95 (3H, s, CO2Me), 4.27 (2H, br, NH2), 4.77 (1H,
hep, J = 6, CH), 4.98 (2H, s, benzylic CH2), 5.42 (2H, s, benzylic
CH2), 6.65 (1H, d, J = 8.1, ArCH), 7.28 (1H, d, J = 8.2, ArCH),
7.33–7.41 (6H, m, ArCH), 7.47 (1H, s, ArCH), 7.49–7.60 (3H, m,
ArCH), 7.62 (1H, d, J = 8.2, ArCH), 7.64 (1H, s, ArCH), 7.76
(1H, d, J = 8.4, ArCH), 7.78–7.82 (2H, m, ArCH), 7.88–7.91 (2H,
m, ArCH), 7.96 (1H, s, ArCH), 8.67 (1H, d, J = 8.5, ArCH), 8.77
(1H, d, J = 8.4, ArCH), 8.80 (1H, s, NH), 8.91 (1H, br, NH); dC
(75 MHz, CDCl3) 22.6, 52.5, 70.8, 71.8, 72.3, 111.2, 111.6, 113.6,
113.9, 119.0, 119.1, 119.9, 121.2, 123.7, 123.9, 125.3, 125.5, 126.9,
127.0, 127.2, 127.3, 127.9, 128.3, 128.4, 128.6, 128.9, 129.0, 129.2,
129.6, 132.7, 133.5, 133.6, 133.7, 133.8, 136.8, 141.3, 143.2, 143.3,
147.9, 164.8, 165.4, 167.2; mmax/cm−1 (solid state) 3432, 3344, 2974,
1707, 1682, 1594, 1514, 1487, 1347, 1262, 1144, 1124, 1020, 871,
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749, 593; ESI-HRMS found m/z 710.2869 [M + H]+, C43H40N3O7
requires 710.2861.
166.8; mmax/cm−1 (solid state) 3490, 3429, 3356, 2926, 1708, 1665,
1596, 1519, 1348, 1269, 1128, 996, 871, 750; ESI-HRMS found
887.3644 m/z [M + H]+, C53H51N4O9 requires 887.3651.
3-Isopropoxy-4-(3-propoxy-4-(3-benzyloxy-4-amino-
benzoylamido)-benzoylamido)-benzoic acid 10abc
Pentamer 13aecba
(Procedure C) 12aecb (17.6 mg, 0.02 mmol), 4a (14.3 mg,
0.06 mmol), Cl2PPh3 (143.2 mg, 0.44 mmol), and chloroform
(30 mL) afforded the product (16.2 mg, 75%) as a yellow solid;
mp 255–257 C; dH (300 MHz, CDCl3) 1.09 (3H, t, J = 7.2 Hz,
(Procedure B) 9abc (70 mg, 0.1 mmol) afforded product (58 mg,
85%) isolated by precipitation; mp >246 ◦C (dec); dH NMR
(500 MHz, DMSO-d6) 1.04 (3H, t, J = 7.2, CH2CH3), 1.36 (6H, d,
J = 6.0, CH(CH3)2), 1.86 (2H, m, CH2CH2CH3), 4.15 (2H, t, J =
7.2, OCH2), 4.72 (1H, m, OCH), 5.20 (2H, s, OCH2Ar), 5.56 (2H,
brs, NH2), 6.74 (1H, d, J = 7.7, ArCH), 7.38 (4H, m, ArCH), 7.48
(3H, m, ArCH), 7.52 (4H, m, ArCH), 8.17 (1H, m, ArCH), 8.24
(1H, m, ArCH), 9.03 (1H, s, NH), 9.32 (1H, m, ArCH); mmax/cm−1
(solid state) 3429, 3364 (NH), 2971, 1681 (CO), 1594, 1488, 1259;
ESI-HRMS found m/z 596.2397 [M − H]−, C34H34N3O7 requires
596.2475.
◦
PrCH3), 1.43 (12H, apparent d, J = 6, iPrCH3), 1.89 (2H, sex, J =
6.3, –OCH2CH2CH3), 3.91 (3H, s, CO2Me), 4.05 (2H, t, J = 6.3,
PrCH2), 4.71–4.89 (2H, m overlapping hep, iPrCH), 5.08 (2H, s,
benzylic CH2), 5.44 (2H, s, benzylic CH2), 7.30–7.52 (13H, m,
ArCH), 7.56–7.61 (3H, m, ArCH), 7.69 (1H, s, ArCH), 7.73 (1H,
d J 8.4 Hz, ArCH), 7.79–7.93 (6H, m, ArCH), 8.55 (1H, d J 8.5 Hz,
ArCH), 8.61 (1H, d J 8.5 Hz, ArCH), 8.63 (1H, d J 8.4 Hz, ArCH),
8.73 (1H, s, NH), 8.74 (1H, d, J = 8.4, ArCH), 8.78 (1H, br, NH),
8.86 (1H, br, NH), 8.88 (1H, br, NH); mmax/cm−1 (solid state) 3431,
2927, 1671, 1597, 1514, 1424, 1349, 1267, 1123, 1017, 851, 745;
ESI-HRMS found 1094.4221 m/z [M + H]+, C63H60N5O13 requires
1094.4182.
Tetramer 11aecb
(Procedure C), 9aec (118.4 mg, 0.17 mmol), 4b (104.5 mg,
0.46 mmol), Cl2PPh3 (641.3 mg, 1.98 mmol), and chloroform
(50 mL) afforded the product (147.9 mg, 100%) as a yellow solid;
mp 252–253 ◦C; dH (300 MHz, CDCl3) 1.05 (3H, t, J = 7.2,
PrCH3), 1.44 (6H, d, J = 6, iPrCH3), 1.85 (2H, sex, J = 6.3,
–OCH2CH2CH3), 3.91 (3H, s, CO2Me), 4.01 (2H, t, J = 6.3,
PrCH2), 4.76 (1H, hep, J = 6, iPrCH), 5.05 (2H, s, benzylic CH2),
5.43 (2H, s, benzylic CH2), 7.23 (1H, d, J = 8.3, ArCH), 7.32–7.38
(2H, m, ArCH), 7.39–7.52 (8H, m, ArCH), 7.58–7.61 (3H, m,
ArCH), 7.71 (1H, d, J = 8.4, ArCH), 7.76–7.81 (3H, m, ArCH),
7.82–7.93 (3H, m, ArCH), 8.55 (1H, d, J = 8.5, ArCH), 8.61 (1H,
d, J = 8.5, ArCH), 8.68 (1H, s, NH), 8.72 (1H, d, J = 8.4, ArCH),
8.84 (1H, br, NH), 8.86 (1H, br, NH); dC (75 MHz, CDCl3) 10.4,
22.2, 52.1, 71.3, 71.5, 71.7, 71.9, 110.8, 111.4, 113.7, 117.3, 117.6,
118.6, 119.0, 119.2, 119.5, 120.1, 123.3, 124.1, 125.7, 126.6, 126.7,
127.1, 127.8, 127.9, 128.9, 130.0, 130.2, 131.1, 131.7, 133.0, 133.1,
133.3, 135.5, 139.3, 141.8, 145.8, 147.6, 147.7, 152.6, 163.0, 164.2,
164.3, 166.8; mmax/cm−1 (solid state) 3433, 3068, 2972, 1708, 1668,
1596, 1519, 1348, 1268, 1125, 1011, 958, 872, 745; ESI-HRMS
found 917.3410 m/z [M + H]+, C53H49N4O11 requires 917.3392.
Acknowledgements
The authors would like to acknowledge the EPSRC
(EP/D077842/1) for funding of this research and The Wellcome
Trust (080709/Z/06/Z) for a PhD studentship (BM). We would
also like to thank Franzi Schramm for early development of
monomer synthesis.
References
1 S. H. Gellman, Acc. Chem. Res., 1998, 31, 178.
2 D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes and J. S. Moore, Chem.
Rev., 2001, 101, 3893.
3 C. M. Goodman, S. Choi, S. Shandler and W. F. DeGrado, Nat. Chem.
Biol., 2007, 3, 252.
4 J. A. Kritzer, O. M. Stephens, D. A. Guarracino, S. K. Reznik and A.
Schepartz, Bioorg. Med. Chem., 2005, 13, 11.
5 E. A. Porter, X. F. Wang, H. S. Lee, B. Weisblum and S. H. Gellman,
Nature, 2000, 404, 565.
6 J.-L. Hou, X.-B. Shao, G.-J. Chen, Y.-X. Zhou, X.-K. Jiang and Z.-T.
Li, J. Am. Chem. Soc., 2004, 126, 12386.
7 D. S. Daniels, E. J. Petersson, J. X. Qiu and A. Schepartz, J. Am. Chem.
Soc., 2007, 129, 1532.
Tetramer 12aecb
(Procedure D) 11aecb (151.2 mg, 0.17 mmol), SnCl2·H20
(284.6 mg, 1.26 mmol) ethyl acetate (200 mL) and THF (50 mL)
afforded the product (33.4 mg, 22%) as a yellow solid; mp 208–
210 ◦C; dH (300 MHz, CDCl3) 1.04 (3H, t, J = 7.3, PrCH3), 1.44
(6H, d, J = 6, iPrCH3), 1.83 (2H, sex, J = 6.5, OCH2CH2CH3),
3.91 (3H, s, CO2Me), 3.92 (2H, t, J = 6.3, PrCH2), 4.22 (2H, br,
NH2), 4.76 (1H, hep, J = 6, iPrCH), 5.06 (2H, s, benzylic CH2),
5.43 (2H, s, benzylic CH2), 6.63 (1H, d, J = 8.1, ArCH), 7.18 (1H,
d, J = 8.3, ArCH), 7.29 (1H, s, ArCH), 7.37–7.51 (9H, m, ArCH),
7.57–7.60 (3H, m, ArCH), 7.72 (1H, d, J = 8.4, ArCH), 7.76–7.92
(5H, m, ArCH), 8.61 (1H, d, J = 8.5, ArCH), 8.62 (1H, d, J =
8.5, ArCH), 8.66 (1H, s, NH), 8.73 (1H, d J = 8.4, ArCH), 8.84
(1H, br, NH), 8.87 (1H, br, NH); dC (75 MHz, CDCl3) 10.6, 22.2,
30.3, 52.1, 69.8, 71.2, 71.6, 71.9, 110.3, 110.6, 111.4, 113.2, 113.3,
118.7, 119.0, 119.5, 120.1, 120.3, 123.3, 123.8, 125.0, 126.6, 126.7,
127.0, 127.9, 128.0, 128.6, 128.8, 128.9, 129.8, 131.9, 132.4, 133.1,
133.3, 135.9, 140.6, 145.8, 146.1, 147.3, 147.7, 164.4, 164.6, 165.1,
8 J. X. Qiu, E. J. Petersson, E. E. Matthews and A. Schepartz, J. Am.
Chem. Soc., 2006, 128, 11338.
9 W. S. Horne, J. L. Price, J. L. Keck and S. H. Gellman, J. Am. Chem.
Soc., 2007, 129, 4178.
10 R. P. Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101,
3219.
11 Z.-T. Li, J.-L. Hou and H.-P. Yi, Chem.–Asian J., 2006, 1, 766.
12 I. Huc, Eur. J. Org. Chem., 2004, 17.
13 B. Gong, Chem.–Eur. J., 2001, 7, 4336.
14 Y. Hamuro, S. J. Geib and A. D. Hamilton, J. Am. Chem. Soc., 1996,
118, 7529.
15 D. A. P. Delnoye, R. P. Sijbesma, J. A. J. M. Vekemans and E. W. Meijer,
J. Am. Chem. Soc., 1996, 118, 8717.
16 J. T. Ernst, J. Becerril, H. S. Park, H. Yin and A. D. Hamilton, Angew.
Chem., Int. Ed., 2003, 42, 535.
17 Z.-Q. Wu, X.-K. Jiang, S.-Z. Zhu and Z.-T. Li, Org. Lett., 2004, 6,
229.
18 J. Zhu, X.-Z. Wang, Y.-Q. Chen, X.-K. Jiang, X.-Z. Chen and Z.-T. Li,
J. Org. Chem., 2004, 69, 6221.
19 J. M. Davis, L. K. Tsou and A. D. Hamilton, Chem. Soc. Rev., 2007,
36, 326.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 138–146 | 145
©

View Article Online
20 K. Cernovska´, M. Kemter, H.-C. Gallmeier, P. Rzepecki, T. Schrader
and B. Ko¨nig, Org. Biomol. Chem., 2004, 2, 1603.
21 H. C. Gallmeier and B. Ko¨nig, Eur. J. Org. Chem., 2003, 3473.
22 F. Campbell, J. Plante, C. Carruthers, M. J. Hardie, T. J. Prior and A. J.
Wilson, Chem. Commun., 2007, 2240.
23 A. Tanatani, A. Yokoyama, I. Azumaya, Y. Takahura, C. Mitsui, M.
Shiro, M. Uchiyama, A. Muranaka, N. Kobayashi and T. Yokozawa,
J. Am. Chem. Soc., 2005, 127, 8553.
25 A. Itai, Y. Toriumi, N. Tomioka, H. Kagechika, I. Azumaya and K.
Shudo, Tetrahedron Lett., 1989, 30, 6177.
26 C. M. Gothard, N. A. Rao and J. S. Nowick, J. Am. Chem. Soc., 2007,
129, 7272.
27 J.-M. Ahn and S.-Y. Han, Tetrahedron Lett., 2007, 48, 3543.
28 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M. Lipton,
C. Caufield, G. Chang, T. Henrickson and W. C. Still, J. Comput. Chem.,
1990, 11, 440.
24 I. Azumaya, H. Kagechika, K. Yamaguchi and K. Shudo, Tetrahedron,
1995, 51, 5277.
29 L. A. Estroff, C. D. Incarvito and A. D. Hamilton, J. Am. Chem. Soc.,
2004, 123, 2.
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