Synthesis and NMR analysis of a conformationally controlled β-Turn Mimetic Torsion Balance

Article abstract of DOI:10.1021/acs.joc.6b02307

The molecular torsion balance concept was applied to a new conformationally controlled scaffold and synthesized to accurately evaluate pairwise amino acid interactions in an antiparallel β-sheet motif. The scaffold's core design combines (ortho-tolyl)amide and o,o,o′-trisubstituted biphenyl structural units to provide a geometry better-suited for intramolecular hydrogen bonding. Like the dibenzodiazocine hinge of the traditional torsion balance, the (ortho-tolyl)amide unit offers restricted rotation around an N-aryl bond. The resulting two-state folding model is a powerful template for measuring hydrogen bond stability between two competing sequences. The aim of this study was to improve the alignment between the amino acid sequences attached to the upper and lower aromatic rings in order to promote hydrogen bond formation at the correct distance and antiparallel orientation. Bromine substituents were introduced ortho to the upper side chains and compared to a control to test our hypothesis. Hydrogen bond formation has been identified between the NH amide proton of the upper side chain (proton donor) and glycine acetamide of the lower side chain (proton acceptor).

Full text of DOI:10.1021/acs.joc.6b02307

Article
pubs.acs.org/joc
Synthesis and NMR Analysis of a Conformationally Controlled β‑Turn
Mimetic Torsion Balance
Alyssa B. Lypson and Craig S. Wilcox*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: The molecular torsion balance concept was applied to a new conformationally controlled scaffold and synthesized
to accurately evaluate pairwise amino acid interactions in an antiparallel β-sheet motif. The scaffold’s core design combines
(ortho-tolyl)amide and o,o,o′-trisubstituted biphenyl structural units to provide a geometry better-suited for intramolecular
hydrogen bonding. Like the dibenzodiazocine hinge of the traditional torsion balance, the (ortho-tolyl)amide unit offers restricted
rotation around an N-aryl bond. The resulting two-state folding model is a powerful template for measuring hydrogen bond
stability between two competing sequences. The aim of this study was to improve the alignment between the amino acid
sequences attached to the upper and lower aromatic rings in order to promote hydrogen bond formation at the correct distance
and antiparallel orientation. Bromine substituents were introduced ortho to the upper side chains and compared to a control to
test our hypothesis. Hydrogen bond formation has been identified between the NH amide proton of the upper side chain
(proton donor) and glycine acetamide of the lower side chain (proton acceptor).
changes in amino acids on a short β-strand.7 During the design
stage we determined that the original dibenzodiazocine torsion
balance scaffold was not useful. Molecular modeling showed
INTRODUCTION
■
Thoughtful evaluations of new experimental data can enhance
our understanding of the various molecular forces that
that the scaffold did not have the correct shape (1) to match
influence biological phenomena. The “molecular torsion
the ends of an antiparallel β-sheet and (2) to establish the
balance” was first conceived as a model for biomolecule folding
distances and orientations required for intramolecular peptido-
that would serve as a tool to measure the relative free energy of
two conformationally distinct thermodynamic states.1−3
Enzyme and drug-receptor binding rely upon many inter-
and intramolecular interactions. Efforts have been made to
design secondary protein mimetic structures such as antiparallel
mimetic hydrogen bond formation. We therefore turned to an
(ortho-tolyl)amide core structure. The desired barrier between
the two competing folded states (Figure 1) would be imposed
by the restricted rotation around an aryl−nitrogen bond.7,8
β-sheet mimics that accurately model protein folding.4−6
Gellman’s β-hairpin motif5 was developed to measure the
folding and stability of β-sheets in water. That study provided
valuable NMR data to relate the thermodynamic parameters
between two conformational states. β-Sheet mimics developed
by Nowick and co-workers6 are based on a combination of
natural and synthetic amino acids to induce peptide interactions
of a protein folded state. Folding within a β-strand resulted
from the insertion of an artificial amino acid, “Orn(i-PrCO-
Hao)”, into a peptide sequence that acts to replace the β-turn
motif.
The final design also incorporated an o,o,o′-trisubstituted
biphenyl unit. Thus, both the aryl−aryl9 and N−aryl8 bonds are
sites having restricted single bond rotation.7 Although ortho-
substituents are mostly responsible for the biaryl bond
restriction, the incorporation of additional meta-substituents is
known to introduce further rotational restriction due to a
“buttressing effect”.9a,b An ortho substituent is well-known to
constrain rotation about the N−aryl bond.8,10 This was
reported by Mislow8 for acyclic and cyclic (ortho-tolyl)amides
and has been employed by the Curran group10 in their
development of o-haloanilide atropisomer selective reactivity.
A peptide torsion balance hybrid (Figure 1) was designed to
support an investigation of pairwise amino acid interactions in
an antiparallel orientation of a β-sheet and the effects of
Received: September 20, 2016
© XXXX American Chemical Society
A
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Figure 1. Example of two conformers of the β-turn mimetic torsion balance. The R groups are different, and each represents an amino acid side
chain.
Figure 2. (a) β-Turn molecular torsion balances of interest. (b) Primary targets for the biaryl core. i, ii, and iii are positions for orthogonal
protection.
a
Scheme 1. Synthesis of Asymmetrical Biaryl 13
a
Reagents and conditions: (a) H2SO4, MeOH, reflux, 99%; (b) tert-butyl bromoacetate, K2CO3, 18-crown-6, acetone, reflux, 35%; (c) benzyl
bromoacetate, K2CO3, 18-crown-6, acetone, reflux, 80%; (d) (Bpin)2, Pd(dppf)Cl2·DCM, KOAc, DMSO, 90 °C, 14 h, 70%; (e) Pd2(dba)3, SPhos,
K3PO4·H2O, toluene, 100 °C, 34%.
The design relied on the two ortho sites of the top aromatic
ring of the biaryl structure carrying different amino acid
sequences. These sequences would compete for interaction
with the lower side chain attached to the N-aryl amine. The
equilibrium established by rotation would reveal which upper
side chain formed stronger attractive interactions with the
lower side chain.
The present paper reports the synthesis and preliminary
structural analysis of this new molecular torsion balance. After
developing the synthetic pathway, we investigated the align-
ment of the o-methylene ether side chains of the top half of the
balance to promote hydrogen bonding. We hypothesized that
the ether side chains would most effectively promote intrachain
hydrogen bonding when oriented at 90° (perpendicular) to the
plane of the aromatic ring. To enforce this orientation and
further preorganize the side chains for hydrogen bonding,
bromine atoms were incorporated ortho to the aryl ether and o-
methylenes. The torsion balances prepared for this study are
shown in Figure 2a.
The structure of 1 and 2 differ by the presence or absence of
the bromines on the top ring. Derivative 2 serves as a control
for this study to evaluate conformational effects of the two
bromines. Our hypothesis was that torsion balance 1 will
support better upper-to-lower side chain hydrogen bonding
than will torsion balance 2.
RESULTS AND DISCUSSION
■
Biaryl analogue 3 (Figure 2b) was the primary target for our
synthesis of a conformationally controlled β-turn mimetic
torsion balance. The design featured the same conformational
features of the des-bromo balance shown in Figure 1 and
allowed for independent amino acid couplings at three
orthogonally protected positions (i, ii, and iii). The synthetic
route requires the installation of two different upper side chains
B
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a
Scheme 2. Synthesis of Symmetrical Biaryl 18
a
Reagents and conditions: (a) DMS, K2CO3, acetone, reflux, 99%; (b) Pd2(dba)3, SPhos, K3PO4·H2O, toluene, 100 °C, 74%; (c) BBr3, DCM, 0
°C→ rt; (d) H2SO4, MeOH, reflux, 78% over two steps; (e) Br2, CCl4, 76%; (f) benzyl bromoacetate, K2CO3, 18-crown-6, acetone, reflux, 80%.
to form an asymmetrical top rotamer (5) before aryl coupling
and bromination to give an asymmetrical biaryl (6; Scheme 1).
Synthesis of Asymmetrical Biaryl Core. The synthetic
effort began with individual preparations of the asymmetrical
top (5) and the bottom (7) halves. Bromide 5, which was
required for the Suzuki coupling, was generated according to
the protocol shown in Scheme 1.7 Fischer esterification11 of
commercially available 4-bromo-3,5-dihydroxybenzoic acid 8
afforded the methyl benzoate 9 in 99% yield. Ether 10 was
synthesized by alkylation12 on 9 with 1 equiv of commercially
available tert-butyl bromoacetate in 35% yield. Asymmetrical
product 10 was separated from the symmetrical ether 11 via
flash chromatography. The alkylation protocol12 was again
utilized to generate asymmetrical coupling fragment 5. The
product was afforded by coupling 10 with commercially
available benzyl bromoacetate in 80% yield. The bottom half
of the balance 7 was provided in 70% yield by subjecting
commercially available 2-bromo-6-nitrotoluene 12 to Miyaura
boration conditions13 with bis(pinacolato)diboron ((Bpin)2) as
the boron nucleophile. A similar procedure using additional
1,1′-bis(diphenylphosphino)ferrocene (dppf) in dioxane also
gave boronic ester 7 but with a significantly lower yield.13b
The Suzuki−Miyaura cross-coupling reaction14 of 5 and 7
furnished biaryl 13, which could then be brominated to afford
the dibromo derivative 6. We anticipated that the coupling step
should be done before bromination because of the coupling
fragments exhibiting a total of three ortho-substituents and a
meta-substituent; dibromination of 5 would not only increase
the difficulty of the coupling reaction due to the presence of
two additional meta-substituents but also decrease the yield
because of competing cross-coupling reactions. In addition,
cleavage of tert-butyl ester could be observed if longer reaction
times needed to be employed. Treatment of fragments 5 and 7
with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) in
toluene accompanied by Buchwald’s phosphine ligand14
afforded the Suzuki−Miyaura cross-coupled product 12 with
a yield of 34%.
dibromination of 13 was very slow and would not be easily
achieved without simultaneous aromatic bromination of the
benzyl ester or cleavage of the tert-butyl ester.
Preparation of Symmetrical Biaryl Core. We developed
a modified route to our goal (Scheme 2). The new pathway
featured the addition of the upper side chains after the aryl
coupling and after bromination. Bromination on the phenol
substrate before side chain attachment would be more readily
achieved because of the enhanced activation and diminished
steric hindrance of the phenol substrate in comparison with 13.
Although this synthesis does not include the attachment of
differential acetoxy side chains, our central question regarding
the effect of dibromination on conformation could be answered
more quickly using the simpler symmetrical balance 4 that
would be prepared with this new path.
The synthesis of coupling fragment 14 was straightforward
and began by using 3 equiv of dimethylsulfate (DMS) to
methylate commercially available 4-bromo-3,5-dihydroxy-
benzoic acid 8 in quantitative yield following recrystallizatio-
n.16a An alternative procedure using methyl iodide (MeI) also
gave 14 from the esterification product 9, but with a slightly
lower yield of 85%.16b Cross-coupling of bromide 14 with
boronic ester 7 using the same conditions14 for the Suzuki−
Miyaura reaction as before afforded 15 with an exceptional
yield of 74%. The increase in percent yield compared to
formation of 13 (a yield of 34% in Scheme 1) is most likely due
to the less sterically hindered nature of 14.
We were unsuccessful in our attempts to couple diphenol 9
with 7 under the same conditions.14 Protection of the phenols
was necessary, but coupling of the tert-butyldimethylsilyl ether
of 9 (not shown) with 7 was also unsuccessful. The methyl
ether was the preferred protecting group for the diphenol due
to its convenient preparation and the exceptional yield of the
cross-coupling reaction.
The next challenge was methyl ether cleavage and
functionalization of the top portion of the balance. We
envisioned a selective ether cleavage using magnesium iodide
(MgI2) in an ionic liquid following the method of Lee and co-
workers17a in order to obtain the dihydroxy-biaryl 16.
Methods attempted to achieve dibromination ortho to the
side chains to produce 6 from 13 were unsuccessful.
Employment of Br2 in AcOH15 resulted in decomposition
and cleavage of the tert-butyl ester, indicated by the formation
Treatment of biaryl 15 with 3 equiv of freshly prepared
17b
MgI2
in 1-butyl-3-methylimidazolium tetrafluoroborate
1
of tert-butyl alcohol in H NMR spectra. Addition of sodium
([bmim]BF4) at 50 °C for 7 to 24 h resulted only in isolation
of starting material.17 Consideration of the drawbacks of aryl
methyl ether cleavage procedures18 led us to conclude that
ether cleavage without ester cleavage was unlikely. A two-step
reaction sequence of nonselective demethylation of 15 by BBr3
and subsequent Fischer re-esterification11 of the acid afforded
dihydroxy-biaryl ester 16 in 78% overall yield.
In comparison to asymmetrical biaryl 13, compound 16 was
considered to be an improved substrate for dibromination due
to the more strongly electron-donating hydroxyl groups that
acetate to buffer the system prevented decomposition but failed
to provide dibromide 6. Increased reaction times resulted in a
complex mixture of products. The unsuccessful dibromination
may be due to the steric hindrance of the bulky side chains as
well as the inductively diminished activating effects of the α-
benzyloxycarbonyl ethers. Experiments using model com-
pounds revealed evidence (1H NMR and HRMS) of
undesirable aromatic bromination occurring on the benzyl
ester group. We concluded that the reaction rate for
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a
Scheme 3. Synthesis of Toluidine 20
a
Reagents and conditions: (a) Zn, HCl, EtOAc, 0 °C→ rt, 82%; (b) EtOH, THF; (c) NaBH4, THF, 53% over two steps.
a
Scheme 4. Synthesis of Primary Target 4
a
Reagents and conditions: (a) NaHCO3, CHCl3/H2O, 67%; (b) Piperidine, DMF; (b) Ac2O, pyridine, DCM, 76% over two steps.
Figure 3. Two conformers of glycine torsion balance 4 by rotation around the (aryl)-N--CO amide bond.
replaced the inductively less activating α-benzyloxycarbonyl
ether groups and due to diminished steric hindrance.
Treatment of 16 with 2.5 equiv of Br2 in carbon tetrachloride
(CCl4) afforded dibromination product 17 in 76% yield.19 The
symmetrical intermediate 18 was isolated in 80% yield after side
chain attachment12 using 17 with 2 equiv of commercially
available benzyl bromoacetate.
With the top portion in hand, we directed our efforts toward
functionalizing the bottom portion of the balance. Reduction of
biaryl 18 by Zn/HCl gave an 80% yield of 19 (Scheme 3).20 In
an initial attempt to prepare N-methyl toluidine 20, we
employed an indirect method based on alkylation of the boc
protected aniline.7 Reaction of di-tert-butyl dicarbonate
(Boc2O) with 19 generated the protected derivative, but
subsequent alkylation by treatment with MeI and NaH in DMF
resulted in a complex mixture of products. Boc group cleavage
of this mixture with TFA and purification afforded 20 in only
20% yield. Attempts to methylate 19 by treatment of its
sulphonamide derivative with diazomethane were also un-
successful.21−23
modification removed the uncertainty of the formalin reaction
and related equilibria. Treatment of 19 with 21, followed by
reduction with NaBH4,afforded the methylated biaryl 20 in
53% yield. Effects of catalysis by pyridinium p-toluenesulfonate
on the alkylation were also examined, but no significant
improvement was observed.
Only the amidation step remained en route to the torsion
balance core (Scheme 4). The approach used was based on
Carpino’s conditions.26 Commercially available 9-fluorenyl-
methyloxycarbonyl-glycine (Fmoc-gly) was converted to its
corresponding acid chloride 22 with thionyl chloride, which
was immediately coupled with biaryl 20 due to susceptibility of
22 to hydrolysis. Amide 23 was isolated in 67% yield. The final
step to synthesize torsion balance 4 involved treatment of 23
with piperidine in DMF to deprotect the amino acid, followed
by immediate acylation with acetic anhydride (Ac2O) and
pyridine (76% yield).
Analysis of E and Z Amide Conformers. We investigated
the conformational freedom of torsion balance 4. The
symmetry of the top portion of this analogue leads only to
enantiomers by rotation around the N−aryl bond when all side
chains have only achiral elements; however, rotation around the
(aryl)-N--CO amide bond does lead to two conformations
(Figure 3).
With the N-methylation proving more difficult than
anticipated, we turned to an approach based on Katritzky’s
methods for the mono-N-alkylation of anilines by Mannich
reaction.24 The Katritzky conditions were modified by
employing a separate preliminary condensation of 1-hydroxy-
methylbenzotriazole (21) with 19 (Scheme 3).25 This
The presence of (aryl)-N--CO bond rotational conformers of
torsion balance 4 is evident from the two N-methyl group
D
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a
Scheme 5. Synthesis of Torsion Balance Derivative 1
a
Reagents and conditions: (a) H2, PtO2, EtOAc, 95%; (b) CH3NH2·HCl, EDCI, HOBT, DIEA, DCM, 63%.
a
Scheme 6. Synthesis of Control Target 2
a
Reagents and conditions: (a) Piperidine, DMF; (b) Ac2O, pyridine, DCM, 90% over two steps; (c) TFA, DCM; (d) CH3NH2·HCl, EDCI, HOBT,
DIEA, DCM, 24% over two steps.
Figure 4. Three conformers of 1 and 2 (enantiomers not shown).
1
singlets in the H NMR spectra of 4 at 298 K in both CDCl3
and CD2Cl2. The two signals arise due to rotation around the
bond, and 1H NMR data reveal the ratio of E/Z rotamers to be
94:6. The 2D ROESY data confirm that (E)-4 is the major
rotamer and (Z)-4 is the minor rotamer.
subsequent employment of the same amidation protocol as
earlier mentioned provided control amide 2 in 24% yield.27
NMR Studies of Torsion Balances 1 and 2. Core target 1
was designed to demonstrate increased conformational control
of the ether side chains in comparison with amide 2. The
purpose of this increased control was to improve the
opportunities for hydrogen bonding between the upper and
lower side chains. Comparison of 1 with control amide 2 might
provide insight into the degree of control the bromines
contribute to the torsion balance structure. Furthermore, we
hoped to establish the identity of the hydrogen bond donor/
acceptor pairs (two arrangements are possible) between the
upper and lower side chains.
NMR Assignments and Initial Comparison of 1 and 2.
The three most relevant conformers of 1 and 2 to this study are
shown in Figure 4. The mixture is racemic, and only one
enantiomer each for these chiral molecules is shown.
Conformers a and b arise from two alternative arrangements
of hydrogen bonding: In a, the top side chain is the hydrogen
bond acceptor and the glycine acetamide acts as the hydrogen
bond donor. In b, the top side chain is the hydrogen bond
donor and the glycine acetamide acts an acceptor. Conformer c
Preparation of Torsion Balances with Competing
Intramolecular Hydrogen Bond Patterns. To examine
conformational effects of bromine installation on potential
hydrogen bonding between the upper and lower side chains, we
prepared target amides 1 (Scheme 5) and 2 (Scheme 6).
Debenzylation of amide 4 by H2/PtO2 reduction generated
diacid 24 in an excellent yield of 95% without any
debromination product observed.20 Amide coupling of diacid
24 using 1-hydroxybenzotriazole (HOBT) with methylamine
hydrochloride, 1-ethyl-3-(3-(dimethylamino)propyl)-
carbodiimide hydrochloride (EDCI), and N,N′-diisopropyl-
ethylamine (DIEA) afforded the desired target 1 in 63% yield.27
Synthesis of the control compound (2) is shown in Scheme
6. Amide 26 was afforded in 90% yield using the same
conditions as previously described for Fmoc deprotection and
acylation of the amino acid. Treatment of 26 with TFA and
E
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Figure 5. Summary of ROESY/EXSY data (left) and 1H NMR spectra (right) for 1 mM solutions of 1 and 2 in CD2Cl2 at 298 K for amide proton
1H NMR assignments of the major (b) and minor (c) conformers of 1 and 2. Original 2D ROESY/EXSY data are provided in Supporting
Information.
Figure 6. Selected ROESY data for 1 mM solutions of 1 (right) and 2 (left) in CD2Cl2 at 298 K for (a) aryl methyl protons and (b) upper side chain
methylene protons.
arises when rotation around the (aryl)-N--CO amide bond
affords the more extended Z amide. Note that hydrogen
bonded E amide conformers (a and b) and non-hydrogen
bonded E amide conformers (not shown) will appear as an
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1
averaged H NMR signal due to their rapid interconversion.
stronger crosspeak (V) between the upper side chain
methylene protons of 2 and the ortho aromatic protons of
the upper ring (Figure 6b). This confirms that the upper side
chains of 2 are coplanar or close to coplanar with the upper
aromatic ring. The stronger crosspeak IV in 1 points to a
perturbation in the orientation of the upper side chains caused
by introduction of bromine substituents.
NMR analysis of the dibenzyl derivative 4 reveals that c is a
minor component in solution.
In the assignment of NMR resonances observed in 1 and 2,
2D NMR spectroscopy (COSY, NOESY, ROESY, HMQC, and
HMBC) was utilized to identify the H and 13C peaks of each
1
conformer. The ROESY data were most useful in assigning the
amide proton shifts and the acetyl methyl and aryl methyl
proton chemical shifts (Figures 5and 6).
EXSY data recorded at 298 K in CD2Cl2 (0.1 mM) used to
assign the amide protons are shown in Figure 5. The major and
minor conformers of 1 and 2 are identifiable among the broad
Analysis of Torsion Balance 1 Conformers. NMR data
for 1 were collected at concentrations between 0.1 and 10 mM
in CDCl3, C7D8, and CD2Cl2 at 298 K. The presence of two
conformations is again evident from the two N-methyl group
1
singlets in the H NMR spectra in all solvents. A ratio of the
1
two N-methyl group singlets can be observed in all solvents as
was seen for torsion balance 4 (Figure 3). ROESY data confirm
that rotation around the (aryl)-N--CO amide bond is
responsible for both conformers. Results of NMR dilution
studies reveal that the broadening of N−H amide proton
signals is not due to self-aggregation.
singlets appearing between 5.4 δ and 6.5 δ. The H NMR
spectrum of the control (Figure 5) exhibits apparent overlap of
NH signals. Only five NH signals are observed, rather than the
six possible for three amide NH protons of the two observable
conformers.
The most downfield amide proton signal of control 2
belongs to that of glycine proton “ii”. This conclusion is based
on the ROESY crosspeak between the NH proton and glycine
α-protons (as shown by the red arrow in Figure 5). Major and
minor conformers, 2b and 2c respectively, appear to overlap for
this proton (as shown by the dashed blue arrow; Figure 5). In
comparison the data for the dibromo balance 1 (Figure 5)
clearly show that it is the middle NH signal that corresponds to
proton “ii” of the major glycine conformer 1b, while the most
downfield major NH peak belongs to the methylamide proton
“i” of 1b. The most upfield NH signal corresponds to
methylamide proton “i” of the minor conformer 1c. This
assignment for “i” is evident from the ROESY crosspeak
between the NH proton and N-methyl protons (as shown by
the red arrow in Figure 5).
We interpret the large change in chemical shift for proton “i”
in 1 versus 2 as evidence of a hydrogen bond that is present in
1 but not in 2. Since the glycine NH signal for “ii” barely
moves, we believe introduction of bromine substituents has
only minor effects on its environment. This insensitivity to
bromine addition supports our conclusion that the topside
chain is the hydrogen bond donor and the glycine acetamide is
the hydrogen bond acceptor.
Other observations were also useful for comparing the degree
of conformational change between the target balance and the
control. ROESY data allowed assignments of the acetyl and aryl
methyl protons (Figure 6). These two signals are very close in
chemical shift. The aryl methyl protons of both 1 and 2 show
three strong ROESY effects (Figure 6a) due to the ether
methylene protons on the upper side chains (crosspeak I), the
glycine methylene protons (crosspeak II), and aryl N-methyl
protons (crosspeak III). These ROESYs correspond to the
more upfield methyl signal for control 2. This establishes that
the upfield methyl of 2 is the aryl methyl and the downfield
methyl of 2 is the acetyl methyl. The alternative is seen for the
dibromo case. The crosspeaks correspond to the more
downfield methyl signal of 1 (Figure 6a). These data support
our 1H NMR assignment for the methyl protons. The
downfield shift observed for the aryl methyl protons between
2 and 1 indicates a conformational change upon bromine
installation.
CONCLUSIONS
■
We report herein the synthesis of a new conformationally
controlled torsion balance to use as a molecular tool for
comparing the energy of pairwise amino acid interactions in
antiparallel orientation and the effects of amino acid changes on
short β-strand stability. The design incorporates a two-state
folding model imposed by restricted rotation about an N−aryl
bond. The dibromo scaffold incorporates an additional degree
of conformational control to optimize intrachain hydrogen
bonding by the introduction of bromine substituents ortho to
the upper side chains. With this synthesis we successfully
realized our goal to promote hydrogen bond formation by
improving chain alignment between the top and bottom side
chains.
2D ROESY data clearly indicated a perturbation in the
orientation of the upper side chains for the dibromo case
compared to the control balance (2). Based on our 1H and 2D
ROESY NMR analyses, we have found that our scaffold has
improved the balance’s shape toward enforcing the correct
distance and antiparallel orientation of amino acid recognition
points of two β-strands. Hydrogen bond formation has been
identified, in which the NH amide proton of the upper side is
the hydrogen bond donor and the glycine acetamide is the
hydrogen bond acceptor.
EXPERIMENTAL SECTION
■
General Experimental Methods. Dry solvents were obtained by
distilling the solvents from the appropriate drying agent under a
nitrogen atmosphere shortly before use. References to “removal of
volatile components from the filtrate under reduced pressure” refer to
rotary evaporation of the sample at 25−65 °C at a pressure of 18−25
mmHg and then overnight under high vacuum (0.1 mmHg) at room
temperature. Reaction progress was monitored by thin-layer
chromatography (TLC) on glass silica gel plates (60 F254 0.25 mm)
and components visualized by UV radiation and KMnO4 or
phosphomolybdic acid developing reagents. Melting points were
determined using a capillary melting point apparatus and are
uncorrected. Infrared (IR) spectra were recorded with FT-IR and
are expressed in cm−1. NMR measurements (1H and 13C) were
recorded in CDCl3, CD2Cl2, or MeOD at room temperature (21−27
°C) using 300, 400, 500, 600, and 700 MHz spectrometers. Chemical
shifts are expressed in parts per million (δ) using TMS or a residual
deuterated solvent peak as the reference value. Coupling constants (J)
are valued in hertz (Hz). 1H NMR multiplicity are designated as
follows: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublet of
The ROESY data for 1 and 2 also show off-diagonal peaks
between the ether methylene protons on the upper side chains
and the aromatic proton ortho to the top aryl group (Figure
6b). This crosspeak signal (IV) is much more significant for
dibromide 1 than for control 2. ROESY data show a notably
G
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doublets); m (multiplet); ABq (AB quartet); qd (quartet of doublets).
High-resolution mass spectra (HRMS) were obtained via EI or ESI
using a QTOF, mass spectrometer.
131.1, 128.2, 127.7, 123.7, 108.7, 108.2, 69.0, 68.5, 42.0, 36.5, 30.1,
25.8, 23.1, 14.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C26H33N4O8 529.2298, found 529.2289.
Methyl 3′-(2-Acetamido-N-methylacetamido)-3,5-dibromo-2′-
methyl-2,6-bis(2-(methylamino)-2-oxoethoxy)-[1,1′-biphenyl]-4-
carboxylate (1). To a round-bottom flask equipped with a condenser
and nitrogen gas inlet were added 0.015 g (0.023 mmol) of diacid 24,
0.005 g (0.068 mmol) of methylamine hydrochloride, 0.013 g (0.068
mmol) of EDCI, 0.010 g (0.068 mmol) of HOBT, 0.015 mL (0.084
mmol) of DIEA, and 0.46 mL of DCM. The reaction mixture was
stirred at room temperature for 16 h and diluted with ethyl acetate (10
mL) and washed with 1.0 M NaOH (5 mL), water (10 mL), and then
brine (10 mL). The organic layers were combined, dried over MgSO4
and filtered, and the volatile components were removed from the
filtrate under reduced pressure to give a crude brown oil. The oil was
purified twice by flash chromatography (SiO2, (first column: hexanes/
ethyl acetate/MeOH elution gradient 1:1:0/2:3:0/0:1:0/0:9:1);
(second column: DCM/MeOH elution gradient 1:0/49:1/19:1)) to
give 0.009 g (63%) of 1 as a white foam: Rf 0.15 (100% ethyl acetate);
1H NMR (700 MHz, CD2Cl2) δ One proton of conformers: [7.43 (t, J
= 15.4 Hz), 7.39 (t, J = 15.4 Hz)], one proton of conformers: [7.30 (d,
J = 7.7 Hz), 7.17 (d, J = 7.7 Hz)], one proton of conformers: [7.30 (d,
J = 7.7 Hz), 7.26 (d, J = 7.7 Hz)], one proton of conformers: [6.80
(broad s), 6.03 (broad s)], one proton of conformers: [6.36 (broad s),
6.46 (broad s)], one proton of conformers: [6.19 (broad s), 6.26
(broad s)], two protons of conformers: [4.30, 4.27 (qd, J = 18.2, 6.3
Hz), 3.72, 3.36 (ABq, J = 6.3 Hz)], two protons of conformers: [4.18−
4.00 (ABq, J = 6.3 Hz), 4.56−3.79 (ABq, J = 14.7 Hz)], two protons of
conformers: [4.10,4.00 (ABq, J = 10.5 Hz), 4.20,4.00 (ABq, J = 10.5
Hz)], 4.00 (s, 3H), three protons of conformers: [3.36 (s), 3.21 (s)],
2.65 (d, J = 4.9 Hz, 3H), three protons of conformers: [2.59 (d, J = 4.9
Hz), 2.47 (d, J = 4.9 Hz)], three protons of conformers: [2.02 (s), 1.98
(s)], three protons of conformers: [2.00 (s), 1.88 (s)]; 13C NMR (700
MHz, CD2Cl2) δ 168.7, 167.4, 165.9, 153.5, 153.2, 143.4, 142.0, 140.0,
135.8, 135.3, 134.4, 133.6, 132.1, 132.0, 131.0, 129.3, 128.2, 127.8,
111.4, 111.1,72.2, 72.0, 42.0, 41.8, 36.5, 30.0, 26.2, 25.8, 23.2, 15.7,
15.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H31N4O8Br2
687.0488, found 687.0477.
Methyl 3′-(2-Acetamido-N-methylacetamido)-2′-methyl-2,6-bis-
(2-(methylamino)-2-oxoethoxy)-[1,1′-biphenyl]-4-carboxylate (2).
To a solution of 0.015 g (0.028 mmol) of 26 in DCM (0.045 mL)
at room temperature was added 0.009 mL (0.111 mmol) of TFA and
the reaction mixture was stirred for 2 h. The volatile components were
removed under reduced pressure to give a brown crude oil. To this
crude oil, in a vial equipped with a condenser and nitrogen gas inlet
were added 0.007 g (0.108 mmol) of methylamine hydrochloride,
0.021 g (0.108 mmol) of EDCI, 0.016 g (0.108 mmol) of HOBT,
0.023 mL (0.132 mmol) of DIEA, and 0.72 mL of DCM. The reaction
mixture was stirred at room temperature for 80 h, and the volatile
components were removed under reduced pressure to give a crude
brown oil. The oil was purified by flash chromatography (SiO2, (first
column: hexanes/ethyl acetate/MeOH elution gradient 1:1:0/2:3:0/
0:1:0/0:9:1); (second column: DCM/MeOH elution gradient 1:0/
49:1/19:1)) to give 0.004 g (24%) of 2 as a white foam: Rf 0.1 (100%
ethyl acetate); 1H NMR (700 MHz, CD2Cl2) δ one proton of
conformers: [7.44 (t, J = 7.7 Hz), 7.43 (t, J = 7.7 Hz)], 7.39 (d, J = 0.7
1H), 7.38 (d, J = 0.7 Hz, 1H), one proton of conformers: [7.29 (d, J =
7.7 Hz), 7.22 (d, J = 7.7 Hz)], one proton of conformers: [7.27 (d, J =
7.7 Hz), 7.17 (d, J = 7.7 Hz)], 6.38 (broad s, 1H), one proton of
conformers: [6.08 (broad s), 6.23 (broad s)], one proton of
conformers: [5.89 (broad s), 5.72 (broad s)], two protons of
conformers: [4.54, 4.34 (ABq, J = 14.0 Hz), 4.45, 4.44 (qAB, J =
4.9, 3.5 Hz)], two protons of conformers: [4.46, 4.42 (ABq, J = 14.7
Hz), 4.39, 4.37 (ABq, J = 7.0 Hz)], two protons of conformers: [4.25,
4.23 (qd, J = 18.2, 4.2 Hz), 3.66, 3.54 (ABq, J = 17.5, 4.2 Hz)], 3.93 (s,
3H), three protons of conformers [3.37 (s), 3.24 (s)], three protons of
conformers: [2.71 (d, J = 4.9 Hz), 2.66 (d, J = 4.9 Hz)], 2.63 (d, J =
4.9 Hz, 3H), three protons of conformers: [2.1 (s), 1.96 (s)], three
protons of conformers: [1.95 (s), 1.88 (s)]; 13C NMR (700 MHz,
CD2Cl2) δ168.7, 168.0, 166.2, 155.9, 155.5, 141.7, 136.1, 135.9, 132.5,
Dibenzyl 2, 2′-((3′-(2-Acetamido-N-methylacetamido)-3,5-dibro-
mo-4-(methoxycarbonyl)-2′-methyl-[1, 1′-biphenyl]-2,6-diyl)bis-
(oxy))diacetate (4). To 0.01 g (0.01 mmol) of 23 in a round-bottom
flask was added 0.045 mL of a 20% piperidine/DMF solution, and the
reaction mixture was stirred at room temperature for 20 min. Then
0.24 mL (mmol) of acetic anhydride and 0.71 mL (mmol) of pyridine
were added, and the solution was stirred at room temperature for 30
min. The volatile components were removed from the filtrate under
reduced pressure to give a yellow oil. The oil was purified by flash
chromatography (SiO2, hexanes/ethyl acetate/methanol elution
gradient 1:1:0/2:3:0/0:1:0/0:9:1) to give 0.007 g (76%) of 4 as a
white foam: Rf 0.34 (100% ethyl acetate); IR (thin film, cm−1) 3338,
2932, 1751, 1723, 1655, 1580, 1423, 1393, 1369, 1329, 1235, 1193,
1135, 1029, 996, 844, 806, 733; 1H NMR (700 MHz, CDCl3) δ 7.34−
7.27 (m, 8H), 7.22−7.19 (m, 4H), 7.14−7.13 (m, 1H), 6.26 (broad s,
1H), 5.07 (s, 2H), 5.02 (s, 2H), four protons of conformers: [4.25,
3.96 (qAB, J = 15 Hz), 4.20, 4.15 (qAB, J = 15 Hz)], 4.02 (s, 3H), two
protons of conformers: [3.65 (qd, J = 4.9 Hz), 3.35 (s)], 3.15 (s, 3H),
2.01 (s, 3H), 1.95 (s, 3H); 13C NMR (500 MHz, CDCl3) δ 170.0,
169.0, 167.2, 167.1, 166.1, 153.5, 141.6, 139.6, 136.4, 135.6, 135.3,
133.9, 131.4, 131.3, 127.8, 111.7, 111.3, 69.5, 67.4, 67.1, 53.7, 42.2,
36.3, 23.4, 15.3; HRMS (ESI-TOF) m/z: [M + CHO2]− calcd for
C39H37O12N2Br2 885.0700, found 885.0709.
Methyl 3-(2-(Benzyloxy)-2-oxoethoxy)-4-bromo-5-(2-tert-butoxy-
2-oxoethoxy) Benzoate (5). In a round-bottom flask, 0.49 g (1.36
mmol) of benzoate 10, 0.26 mL (1.63 mmol) of benzyl bromoacetate,
0.22 g (1.63 mmol) of K2CO3, and 0.08 g (0.33 mmol) of 18-crown-6
were dissolved in acetone (35.4 mL), and the reaction mixture was
refluxed for 24 h. The volatile components were removed under
reduced pressure, and the residue was diluted with DCM (25 mL) and
water (25 mL); the organic layer was extracted, and the aqueous layer
was washed with additional DCM (3 × 25 mL). The combined
organic layers were dried over MgSO4 and filtered, and the volatile
components were removed from the filtrate under reduced pressure to
give a crude yellow oil. The oil was purified by flash chromatography
(SiO2, hexanes/ethyl acetate, elution gradient 7:1/6:1/3:1) to yield
0.55 g (80.2%) of 5 as a white solid: Rf 0.48 (hexanes/ethyl acetate
3:2); mp 68−70 °C; IR (thin film, cm−1) 2978, 1753, 1724, 1587,
1
1423, 1369, 1337, 1241, 1194, 1133, 1029, 1000, 844, 763; H NMR
(400 MHz, CDCl3) δ 7.24 (s, 5H), 7.04 (d, J = 4 Hz, 2H), 5.14 (s,
2H), 4.70 (s, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 1.40 (s, 9H); 13C NMR
(500 MHz, CDCl3) δ 167.8, 166.9, 165.9, 155.8, 155.7, 149.9, 149.1,
143.4, 141.7, 140.0, 135.0, 130.5, 130.0, 128.7, 128.6, 128.6, 128.5,
128.5, 108.2, 107.4, 107.2, 82.9, 67.3, 67.2, 66.6, 66.3, 60.7, 52.5, 28.0;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H25O8NaBr
531.0630, found 531.0663.
4,4,5,5-Tetramethyl-2-(2-methyl-3-nitrophenyl)-1,3,2-dioxaboro-
lane (7). To a third flame-dried 200 mL round-bottom flask, 3.00 g
(13.9 mmol) of 12, 5.29 g (20.8 mmol) of (Bpin)2, 4.09 g (41.7
mmol) of KOAc, and 0.45 g of [1,1′-bis(diphenylphosphino)-
ferrocene]dichloropalladium(II), complex with DCM (Pd(dppf)Cl2·
DCM; 0.56 mmol) were added. The reaction flask was then placed on
a vacuum line for 5 min and backfilled with nitrogen and repeated.
DMSO (83.2 mL) was then added, and the solution was degassed
using the freeze−pump−thaw method three times under a nitrogen
atmosphere. The flask was sealed; the reaction mixture was stirred at
90 °C for 20 h and then cooled to room temperature. The reaction
mixture was then diluted with DCM (100 mL) and H2O (100 mL).
The organic layer was extracted and washed with H2O (3 × 100 mL).
The aqueous layer was washed with additional DCM (2 × 100 mL).
Organic extracts were combined, and the volatile components were
removed from the filtrate under reduced pressure to give a brown
crude oil. The oil was purified twice by flash column chromatography
(SiO2, hexanes/ethyl acetate, elution gradient (2 columns) 10:1/6:1;
then 30:1) to give 2.7 g (76%) of 7 as a pale yellow solid: Rf 0.89
(hexanes/ethyl acetate, 4:1); mp 52−53 °C; IR (thin film, cm−1) 3055,
2982, 2933, 1603, 1569, 1527, 1474, 1439, 1344, 1267, 1214, 1144,
H
DOI: 10.1021/acs.joc.6b02307
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1109, 1026, 1078, 963, 786, 739, 669, 579. 463; H NMR (300 MHz,
CDCl3) δ 7.94 (d, J = 7 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.27 (t, J = 8
Hz, 1H), 2.67 (s, 3H), 1.36 (s, 12H); 13C NMR (300 MHz, CDCl3) δ
151.3, 139.9, 138.2, 126.3, 126.0, 84.4, 25.0, 18.0; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C13H19BNO4 264.1407, found 264.1405.13b
Methyl 4-Bromo-3,5-dihydroxybenzoate (9). To 1.0 g (4.4 mmol)
of carboxylic acid 8 in 6.8 mL of methanol was added 0.41 mL (7.6
mmol) of H2SO4 dropwise, and the reaction mixture was refluxed for
16 h. The reaction was quenched by addition of NaHCO3 (1.2 g, 14.8
mmol), and the volatile components were removed under reduced
pressure. The residue was diluted with ethyl acetate (25 mL) and
water (25 mL); the organic layer was extracted, and the aqueous layer
was washed with additional ethyl acetate (3 × 25 mL). The organic
layers were dried over MgSO4 and filtered, and the volatile
components were removed from the filtrate under reduced pressure
to give 1.05 g (99%) of 9 as a white solid: Rf 0.34 (hexanes/ethyl
acetate 3:2); mp 225−227 °C; IR (thin film, cm−1) 3416, 3329, 1701,
1594, 1421, 1353, 1270, 1233, 1118, 1033, 990, 907, 857, 760, 705; 1H
NMR (300 MHz, MeOD) δ 7.03 (s, 2H), 4.85 (broad s, 2H), 3.85 (s,
3H); 13C NMR (600 MHz, MeOD) δ 168.1, 156.7, 131.0, 108.6,
105.1, 52.7; HRMS (EI) m/z calcd for C8H7O4Br 245.9528, found
245.9519.
106.5, 106.0, 82.9, 67.3, 66.0, 65.4, 52.6, 28.2, 16.5; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C30H31NO10Na 588.1840, found 588.1854.
Methyl 4-Bromo-3,5-dimethoxybenzoate (14). To a stirred
solution of 2.50 g (10.7 mmol) of carboxylic acid 8 and 6.2 g (45.1
mmol) of K2CO3 in acetone (67.0 mL), 3.46 mL (36.5 mmol) of
dimethyl sulfate was added. The mixture was stirred at reflux for 4.5 h
and cooled to room temperature. Volatile components were removed
under reduced pressure. The residue was then diluted with ethyl
acetate (75 mL) and H2O (75 mL); the organic layer was extracted,
and the aqueous layer was washed with additional ethyl acetate (2 ×
75 mL). The combined organic layers were washed with brine (200
mL), dried over MgSO4, and filtered, and the volatile components
were removed from the filtrate under reduced pressure to yield a white
solid. The solid was purified by recrystallization to give 2.9 g (100%)
of benzoate 14 as white crystals: Rf 0.45 (hexanes/ethyl acetate, 4:1);
mp 121−122 °C; 1H NMR (300 MHz, CDCl3) δ 7.23 (s, 2H), 3.95 (s,
6H), 3.93 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 166.7, 157.3,
130.4, 106.9, 105.8, 56.9, 52.7; HRMS (ESI-TOF) m/z calcd for
C10H11O4Br 273.9841, found 273.9829.
Methyl 2,6-Dimethoxy-2′-methyl-3′-nitro-[1,1′-biphenyl]-4-car-
boxylate (15). In a round-bottom flask, 1.45 g (5.29 mmol) of
benzoate 14, 2.08 g (7.94 mmol) of boronic ester 7, 0.19 g (0.21
mmol) of Pd2(dba)3, 0.35 g (0.85 mmol) of SPhos, and 3.66 g (15.87
mmol) of K3PO4·H2O (ground) were added and dried under reduced
pressure for 5 min and backfilled with nitrogen two times. Toluene (30
mL) was added, and the solution was degassed using the freeze−
pump−thaw method three times under a nitrogen atmosphere. The
flask was sealed; the reaction mixture was stirred at 90 °C for 18 h and
cooled to room temperature. The mixture was diluted with DCM (150
mL) and H2O (150 mL); the organic layer was extracted, and the
aqueous layer was washed with additional DCM (3 × 150 mL). The
combined organic layers were washed with brine (200 mL), dried over
MgSO4, and filtered. Volatile components were removed from the
filtrate under reduced pressure to give a reddish brown crude oil. The
oil was purified by flash chromatography (SiO2, hexanes/ethyl acetate,
elution gradient, 8:1/6:1) to give 1.19 g (74%) of 15 as a pale yellow
solid: Rf 0.28 (hexanes/ethyl acetate, 4:1); mp 119−120 °C; IR (thin
film, cm−1) 3436, 2919, 2881, 1721, 1580, 1527, 1456, 1434, 1409,
1351, 1326, 1242, 1126, 997, 770; 1H NMR (400 MHz, CDCl3) δ 7.84
(dd, J = 6, 3 Hz, 1H), 7.36−7.34 (m; 4H), 3.97 (s, 3H), 3.78 (s, 6H),
2.20 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 167.0, 157.7, 150.9,
137.0, 135.4, 132.6, 131.8, 126.1, 123.8, 121.8, 105.4, 56.3, 52.7, 16.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18NO6 332.1134,
found 332.1124.
Methyl 4-Bromo-3-(-2-tert-butoxy-2-oxoethoxy)-5-hydroxy-
benzoate (10). In a round-bottom flask, 1.0 g (4.2 mmol) of
benzoate 9, 0.62 mL (4.2 mmol) of tert-butyl bromoacetate, 1.2 g (8.8
mmol) of K2CO3, and 0.05 g (0.2 mmol) of 18-crown-6 were
dissolved in acetone (21.0 mL), and the reaction mixture was refluxed
for 24 h. The volatile components were removed under reduced
pressure, and the residue was diluted with ethyl acetate (50 mL) and
water (50 mL); the organic layer was extracted, and the aqueous layer
was washed with additional ethyl acetate (2 × 50 mL). The organic
layers were dried over MgSO4 and filtered, and the volatile
components were removed from the filtrate under reduced pressure
to give a crude yellow oil. The oil was purified by flash
chromatography (SiO2, hexanes/ethyl acetate, elution gradient 5:1/
3:2/0:1) to give 0.49 g (32.4%) of 10 as a white solid: Rf 0.44
(hexanes/ethyl acetate 3:2); mp 117−118 °C; IR (thin film, cm−1)
3393, 2923, 2852, 1724, 1590, 1497, 1438, 1354, 1247, 1158, 1117,
1011, 904, 870, 843, 767; 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H),
6.92 (s, 1H), 6.41 (s, 1H), 4.57 (s, 2H), 3.81 (s, 3H), 1.18 (s, 9H); 13C
NMR (500 MHz, CDCl3) δ 166.9, 166.0, 154.9, 153.7, 130.6, 110.4,
105.8, 105.2, 82.9, 66.4, 52.5, 28.0; HRMS (EI) m/z calculated for
C14H17BrO6 360.0209, found 360.0205. Benzoate 11 was generated as
the major product (48%) en route to benzoate 10. HRMS (EI) m/z
calcd for C14H17O6Br 360.0209, found 360.0205.
Methyl 2,6-Dihydroxy-2′-methyl-3′-nitro-[1,1′-biphenyl]-4-car-
boxylate (16). In a third-flame-dried round-bottom flask, 5.35 g
(21.36 mmol) of a 1.0 M solution of BBr3 in DCM was added
dropwise over 30 min to a stirred solution of 1.18 g (3.56 mmol) of 15
in DCM (8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
3 h and gradually warmed to room temperature and stirred for an
additional 21 h. The volatile components were removed under
reduced pressure. The residue was charged with nitrogen and slowly
diluted with MeOH (7 mL). 0.33 mL (6.14 mmol) of H2SO4 was
added dropwise at 0 °C. The reaction mixture was then heated to
reflux for 20 h. After cooling to room temperature, the reaction was
quenched by addition of NaHCO3 (1.03 g, 12.3 mmol), and the
volatile components were removed under reduced pressure. The
residue was diluted with ethyl acetate (75 mL) and H2O (75 mL); the
organic layer was extracted, and the aqueous layer was washed with
additional ethyl acetate (2 × 75 mL). The combined organic layers
were washed with brine (200 mL), dried over MgSO4, and filtered.
Volatile components were removed from the filtrate under reduced
pressure to yield a brown oil. The oil was purified by flash column
chromatography (SiO2, hexanes/ethyl acetate, elution gradient, 2:1) to
give 0.84 g (78%) of 16 as a white solid: Rf 0.22 (hexanes/ethyl
acetate, 2:1); mp 160−161 °C; IR (thin film, cm−1) 3310, 2524, 2219,
2043, 1653, 1451, 1113, 1034; 1H NMR (300 MHz, CDCl3) δ 7.92 (d,
J = 6 Hz, 1H), 7.49−7.47 (m, 2H), 7.31 (s, 2H), 5.71 (broad s, 2H),
3.92 (s, 3H), 2.31 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 154.4,
151.7, 135.53, 134.6, 133.7, 131.9, 127.5, 125.2, 118.6, 109.5, 53.0,
Methyl 2,6-Dimethoxy-2′-methyl-3′-nitro-[1,1′-biphenyl]-4-car-
boxylate (13). In a round-bottom flask, 0.17 g (0.34 mmol) of
benzoate 5, 0.14 g (0.55 mmol) of boronic ester 7, 0.013 g (0.014
mmol) of Pd2(dba)3, 0.022 g (0.055 mmol) of 2-dicyclohexyl-
phosphino-2′,6′-dimethoxybiphenyl (SPhos), and 0.24 g (1.03 mmol)
of (ground) PO4·H2O were added and dried under reduced pressure
for 5 min and backfilled with nitrogen two times. Toluene (3 mL) was
added, and the solution was degassed using the freeze−pump−thaw
method three times under a nitrogen atmosphere. The flask was
sealed; the reaction mixture was stirred at 90 °C for 18 h, and cooled
to room temperature. The mixture was diluted with DCM (30 mL)
and H2O (30 mL); the organic layer was extracted, and the aqueous
layer was washed with additional DCM (3 × 30 mL). The combined
organic layers were dried over MgSO4 and filtered, and volatile
components were removed from the filtrate under reduced pressure to
give a brown crude oil. The oil was purified by flash chromatography
(SiO2, hexanes/ethyl acetate, 5:1) to afford 0.13 g (67.6%) of 13 as a
white foam: Rf 0.36 (hexanes/ethyl acetate, 4:1); IR (thin film, cm−1)
3442, 2979, 1751, 1725, 1581, 1528, 1437, 1422, 1354, 1330, 1236,
1
1194, 1136; 1082, 1029, 999, 867, 844, 810, 771, 741, 698; H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 8 Hz, 1H), 7.42 (d, J = 7 Hz, 1H),
7.33 (broad s, 4H), 7.27 (broad s, 2H), 7.19 (s, 2H), 5.16 (s, 2H), 4.67
(s, 2H), 4.49 (s, 2H), 3.91 (s, 3H), 2.27 (s, 3H), 1.44 (s, 9H); 13C
NMR (400 MHz, CDCl3) δ 168.2, 167.4, 166.2, 156.2, 155.9, 150.8,
136.2, 135.3, 135.1, 132.8, 131.5, 128.8, 128.6, 126.0, 123.9, 122.5,
I
DOI: 10.1021/acs.joc.6b02307
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
16.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H14NO6
304.0821, found 304.0837.
temperature for 12 h. Volatile components were removed under
reduced pressure, and the reaction vial was cooled to 0 °C for 10 min.
The residue was rinsed with chilled, dry DCM followed by hexanes to
produce an off-white solid. The precipitate was isolated and taken up
into DCM, dried over K2CO3, and filtered, and volatile components
were removed under reduced pressure to give an off-white solid. The
dry intermediate was dissolved in THF (0.3 mL), and 0.01 g (0.18
mmol) of NaBH4 was added and stirred for 14 h. The reaction mixture
was concentrated under reduced pressure, and the residue was diluted
with ice, cold H2O, and DCM; the organic layer was extracted, and the
aqueous layer washed with additional DCM (2 × 4 mL). The
combined organic layers were washed with additional H2O (5 mL)
and then brine (5 mL); the organic layer was dried over MgSO4 and
filtered, and volatile components were removed from the filtrate under
reduced pressure to give a yellow foam. The foam was purified by flash
chromatography (SiO2, hexanes/ethyl acetate, elution gradient 7:1/
6:1) to yield 0.040 g (41%) of 20 as a white foam: Rf 0.38 (hexanes/
ethyl acetate 2:1; IR (thin film, cm−1) 3432, 3059, 2978, 2303, 2053,
1648, 1420, 1375, 1241, 1122, 892, 743; 1H NMR (400 MHz, CDCl3)
δ 7.33 (broad s, 5H), 7.26 (broad s, 5H), 7.12 (t, J = 8 Hz, 1H), 6.59
(d, J = 8 Hz, 1H), 6.53 (d, J = 8 Hz, 1H), 5.04 (s, 4H), 4.12, 4.00
(ABq, J = 15 Hz, 4H) 4.01 (s, 3H), 3.66 (broad s, 2H), 2.87 (s, 3H),
1.86 (s, 3H); 13C NMR (500 MHz, CDCl3) δ 167.7, 166.4, 153.7,
147.9, 138.7, 135.5, 132.3, 131.1, 128.9, 128.8, 128.6, 127.2, 121.4,
119.2, 111.0, 109.9, 69.4, 67.0, 53.6, 31.2, 30.1, 28.7, 14.6, 14.5; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C34H32Br2NO8 742.0495, found
742.0496.
(9H-Fluoren-9-yl)methyl (2-chloro-2-oxoethyl)carbamate (22).
To a solution of 0.030 g (0.1 mmol) of commercially available
Fmoc-gly in DCM (0.5 mL) was added 0.07 mL (1.0 mmol) of thionyl
chloride (SOCl2), and the reaction mixture was refluxed for 30−45
min. The solution was cooled to room temperature, and the volatile
components were removed under reduced pressure. The residue was
dissolved in minimal DCM followed by hexanes to produce an off-
white precipitate. The solid was filtered and dried in vacuo to afford
0.025 g (81%) of 22 as an off-white solid. Only IR spectra were
obtained to confirm this highly reactive intermediate: (thin film, cm−1)
3315, 3066, 2967, 2947, 1811, 1702, 1540, 1477, 1448, 1395, 1349,
1271, 1182, 1104, 1087, 1051, 991, 955, 919, 780, 758, 742.
Methyl 3,5-Dibromo-2,6-dihydroxy-2′-methyl-3′-nitro-[1,1′-bi-
phenyl]-4-carboxylate (17). In an oven-dried round-bottom flask,
0.26 mL (4.12 mmol) of Br2 in CCl4 (2.9 mL) was added dropwise
over 30 min to a stirred solution of 0.52 g (1.72 mmol) of 16 in CCl4
(7 mL) in the dark. The reaction mixture was stirred for 1 h. Saturated
NaHSO3 was then added until the red color dissipated. The mixture
was diluted with ether (30 mL), and the organic layer was extracted.
The aqueous layer was washed with additional ether (2 × 30 mL). The
combined organic layers were washed with brine (75 mL), dried over
MgSO4, and filtered, and the volatile components were removed from
the filtrate under reduced pressure to yield a brown oil. The oil was
purified by flash column chromatography to give 0.60 g (76%) of 17 as
an off-white foam: Rf 0.36 (hexanes/ethyl acetate, 4:1); mp 158−159
1
°C; IR (thin film, cm−1) 3431, 2101, 1642, 1264, 790; H NMR (400
MHz, CDCl3) δ 7.90 (dd, J = 7, 2 Hz, 1H), 7.44−7.39 (m, 2H), 5.91
(broad s, 2H), 4.02 (s, 3H), 2.28 (s, 3H); 13C NMR (600 MHz,
CDCl3) δ 166.0, 151.1, 150.5, 137.0, 135.0, 134.6, 132.9, 126.8, 124.9,
115.7, 99.3, 53.7, 16.4; HRMS (ESI-TOF) m/z: calcd for
C15H11NO6Br2 461.8900, found 461.8882.
Dibenzyl 2,2′-((3,5-Dibromo-4-(methoxycarbonyl)-2′-methyl-3′-
nitro-[1,1′-biphenyl]-2,6-diyl)bis(oxy))diacetate (18). In an oven-
dried round-bottom flask, 0.46 g (1.0 mmol) of 17, 0.38 mL (2.4
mmol) of benzyl bromoacetate, 0.42 g (3.0 mmol) of K2CO3, and 0.10
g (0.40 mmol) of 18-crown-6 were dissolved in acetone (11.1 mL),
and the reaction mixture was refluxed for 24 h. The volatile
components were removed from the filtrate under reduced pressure,
and the residue was diluted with DCM (30 mL) and water (30 mL);
the organic layer was extracted, and the aqueous layer was washed with
additional DCM (3 × 30 mL). The combined organic layers were
washed with brine (90 mL), dried over MgSO4, and filtered, and the
volatile components were removed from the filtrate under reduced
pressure to give a crude yellow oil. The oil was purified by flash
chromatography (SiO2, hexanes/ethyl acetate, elution gradient 6:1) to
yield 0.60 g (80%) of 18 as a light yellow foam: Rf 0.48 (hexanes/ethyl
acetate 2:1); 1H NMR (400 MHz, CD2Cl2) δ 7.82 (d, J = 8 Hz, 1H),
7.43 (d, J = 8 Hz, 1H), 7.36−7.34 (m, 6H), 7.30−7.24 (m, 5H), 5.02
(q, J = 4 Hz, 4H), 4.22, 4.10 (ABq, JAB = 15 Hz, 4H), 2.30 (s, 3H); 13
C
NMR (400 MHz, CD2Cl2) δ 167.2, 166.1, 154.0, 151.3, 140.4, 135.8,
135.5, 134.5, 133.1, 131.0, 129.1, 129.0, 128.9, 127.1, 125.5, 111.7,
70.0, 67.4, 17.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C33H28NO10Br2 758.01052, found 758.0080.
Dibenzyl 2, 2′-((3′-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)-
amino)-N-methylacetamido)-3,5-dibromo-4-(methoxycarbonyl)-2;-
methyl-[1,1′-biphenyl]-2,6-diyl)bis(oxy))diacetate (23). To 0.050 g
(0.07 mmol) of 20 in 0.62 mL of CHCl3 was added 0.03 g (0.09
mmol) of Fmoc-gly acid chloride 22 (generated according to above
procedure and used immediately thereafter) in 0.37 mL of CHCl3
followed by 0.62 mL of saturated NaHCO3 solution, and the reaction
mixture was stirred at room temperature for 20 min. The solution was
diluted with DCM (10 mL) and saturated NaHCO3 solution (10 mL),
the organic layer was extracted, and the aqueous layer was washed with
DCM (3 × 10 mL). The organics were dried over MgSO4 and filtered,
and the volatile components were removed from the filtrate under
reduced pressure to give a light brown crude oil. The oil was purified
by flash chromatography (SiO2, hexanes/ethyl acetate, elution gradient
5:1/3:1/2:1) to give 0.046 g (67%) of 23 as a white foam: Rf 0.31
(hexanes/ethyl acetate, 1:1); IR (thin film, cm−1) 3392, 2926, 2855,
1751, 1722, 1660, 1581, 1421, 1369, 1329, 1299, 1234, 1193, 1134,
1028, 998, 864, 845, 806, 735; 1H NMR (400 MHz, CDCl3) δ 7.66 (d,
J = 7 Hz, 2H), 7.48 (d, J = 7 Hz, 2H), 7.32−7.25 (m, 5H), 7.22−7.18
(m, 5H), 7.14−7.06 (m, 7H), 5.49 (broad s, 1H), 4.94 (s, 4H), 4.23−
4.14 (m, 4H), 4.10−4.01 (m, 4H), 3.94 (s, 3H), 3.88 (d, J = 15 Hz,
2H), 3.65, 3.32 (qd, J = 4, 17 Hz, 2H), 3.08 (s, 3H), 1.95 (s, 3H); 13C
NMR (400 MHz, CDCl3) δ 168.6, 166.8, 165.8, 156.1, 153.1, 144.0,
143.9, 141.3, 141.3, 139.3, 136.2, 135.1, 135.0, 133.6, 131.0, 128.7,
128.6, 128.5, 128.4, 128.3, 127.7, 127.4, 127.1, 125.2, 120.0, 111.3,
111.0, 69.2, 69.1, 67.0, 66.8, 53.4, 47.1, 43.2, 36.3, 15.3; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C51H45N2O11Br2 1019.13846, found
1019.13665.
Dibenzyl 2,2′-((3′-Amino-3,5-dibromo-4-(methoxycarbonyl)-2′-
methyl-[1, 1′-biphenyl]-2,6-diyl)bis(oxy))diacetate (19). 0.5 g (0.67
mmol) of 18 was dissolved in ethyl acetate (11 mL) and concentrated
HCl (0.33 mL). The solution was cooled to 0 °C, and Zn powder
(0.21 g, 3.3 mmol) was added in portions over 20 min with stirring.
The mixture was gradually warmed to room temperature and stirred
for 15 h. The reaction mixture was passed through a Celite plug and
washed with ethyl acetate (5 mL). The filtrate was washed with
saturated NaHCO3 solution (1 × 5 mL), water (1 × 5 mL), and brine
(1 × 10 mL). The organic layer was dried over anhydrous MgSO4 and
filtered, and volatile components were removed from the filtrate under
reduced pressure to give a crude yellow oil. The oil was purified by
flash chromatography (SiO2, hexanes/ethyl acetate, elution gradient
3:1/2:1) to yield 0.41 g (82%) of 19 as a light yellow foam: Rf 0.21
1
(hexanes/ethyl acetate 2:1); mp 58−59 °C; H NMR (400 MHz,
CDCl3) δ 7.34−7.30 (m, 5H), 7.28−7.25 (m, 5H), 6.99 (t, J = 8 Hz,
1H), 6.64 (d, J = 8 Hz, 1H), 6.58 (d, J = 7 Hz, 1H), 5.05 (s, 4H), 4.17,
4.00 (ABq, JAB = 15 Hz, 4H), 4.01 (s, 3H), 3.61 (broad s, 2H), 1.90 (s,
3H); 13C NMR (400 MHz, CDCl3) δ 167.6, 166.4, 153.6, 145.6,
138.7, 135.4, 132.1, 131.6, 128.9, 128.8, 128.7, 126.9, 121.9, 120.9,
115.9, 111.0, 69.4, 67.0, 53.6, 30.0, 14.8; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C33H30NO8Br2 728.02395, found 728.02593.
Dibenzyl 2,2′-((3,5-Dibromo-4-(methoxycarbonyl)-2′-methyl-3′-
(methylamino)-[1,1′-biphenyl]-2,6-diyl)bis(oxy))diacetate (20). 0.1
g (0.14 mmol) of 19 and 0.025 g (0.17 mmol) of 21 in THF (0.1 mL)
were sonicated for 5 min to give a homogeneous solution. The mixture
was then diluted with EtOH (0.16 mL) and stirred at room
2,2′-((3′-(2-Acetamido-N-methylacetamido)-3,5-dibromo-4-
(methoxycarbonyl)-2′-methyl-[1,1′-biphenyl]-2,6-diyl)bis(oxy))-
diacetic Acid (24). To a nitrogen charged flask, 0.007 g (0.008 mmol)
J
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The Journal of Organic Chemistry
Article
of 4 and 0.001 g (0.003 mmol) of PtO2 were added and dried under
reduced pressure for 5 min and backfilled with nitrogen twice. Under a
hydrogen atmosphere, ethyl acetate (0.2 mL) was added and stirred
for 13 h. The reaction mixture was passed through a Celite plug and
washed with ethyl acetate (2 mL). Volatile components were removed
from the filtrate under reduced pressure to obtain 0.005 g (91%) of 24
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1
as a glass-like foam. Rf 0.1 (9:1 ethyl acetate/MeOH); H NMR (400
MHz, CDCl3) δ 7.31 (t, J = 8 Hz, 1H) 7.22 (d, J = 8 Hz, 1H), 7.11 (d,
J = 8 Hz, 1H), 6.89 (broad s, 2H), 4.33, 4.03 (ABq, J = 16, 15 Hz, 2H),
4.17−3.97 (m, 2H), 3.68, 3.58 (ABq, J = 18, 4 Hz, 2H), 3.74 (s, 3H),
3.16 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H); 13C NMR (400 MHz, CDCl3)
δ 172.2, 169.8, 169.4, 168.7, 168.0, 166.0, 154.3, 153.4, 141.0, 139.7
135.9, 134.2, 132.3, 131.8, 129.2, 128.3, 112.1, 111.4, 70.5, 69.3, 53.8,
47.9, 43.1, 43.0, 36.6, 32.3, 30.0, 29.7, 26.7, 25.8, 24.7, 23.2, 23.0, 21.5,
15.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23Br2N2O10
656.97140, found 656.97329.
Di-tert-butyl 2,2′-((3′-(2-Acetamido-N-methylacetamido)-4-
methyoxycarbonyl)-2′-methyl-[1,1′-biphenyl]-2,6-dilyl)bis(oxy))-
diacetate (26). To 0.020 g (0.028 mmol) of carboxylate 25 in a vial
was added a 0.11 mL of a 20% piperidine/DMF solution, and the
reaction mixture was stirred at room temperature for 30 min. Then
0.35 mL (4.06 mmol) of acetic anhydride and 1.16 mL (15.4 mmol) of
pyridine were added, and the solution was stirred at room temperature
for 30 min. The volatile components were removed from the filtrate
under reduced pressure to give a crude brown oil. The oil was purified
by flash chromatography (SiO2, hexanes/ethyl acetate/methanol
elution gradient 1:5/1:20) to give 0.015 g (90%) of 26 as a white
Bergquist, K.-E.; Lund, M.; Butkus, E.; Warnmark, K. Angew. Chem.,
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Int. Ed. 2011, 50, 2071−2074. (g) Runarsson, O. V.; Artacho, J.;
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1
foam: Rf 0.22 (100% ethyl acetate); H NMR (400 MHz, CDCl3) δ
7.31−7.27 (m, 2H), 7.19−7.12 (m, 3H), 6.47 (broad s, 1H), four
protons of conformers [4.64, 4.53 (ABq, JAB = 16 Hz), 4.55, 4.50 (ABq
JAB = 15 Hz)], 3.91 (s, 3H)], 3.70 (qd, J = 18, 4 Hz, 2H), 3.29 (s, 3H),
2.03, (s, 3H), 1.98 (s, 3H), 1.45 (s, 18H); 13C NMR (500 MHz,
CDCl3) δ 169.7, 168.9, 167.7. 166.3, 155.9, 155.7, 140.1, 135.8, 135.7,
131.3, 130.7, 127.0, 126.8, 123.1, 106.1, 105.98, 82.5, 82.2 65.9. 65.6,
52.3, 42.2, 36.3, 28.0, 23.1, 14.6; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C32H42N2O10Na 637.2737, found 637.2761.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02307.
1
Copies of H, 13C, and 2D ROESY/EXSY NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: daylite@pitt.edu.
■
(8) Shvo, Y.; Taylor, E. C.; Mislow, K.; Raban, M. J. Am. Chem. Soc.
ORCID
1967, 89, 4910−4917.
Alyssa B. Lypson: 0000-0003-3687-1839
Notes
The authors declare no competing financial interest.
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6, 251. (b) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Anderson, J. E. J.
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Asymmetry 1995, 6, 2161−2164.
ACKNOWLEDGMENTS
■
Financial support from the National Institute of General
Medical Sciences (11224) and from the University of
Pittsburgh is gratefully acknowledged. We would like to
thank Prof. Peter Wipf and Prof. Matt LaPorte as well as
Prof. Damodaran Krishnan Achary and Dr. Viswanathan
Elumalai.
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7552.
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1645−1648.
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