Macrocyclizations for medicinal chemistry: Synthesis of druglike macrocycles by high-concentration ullmann coupling

Article abstract of DOI:10.1021/jo302089f

Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5-10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles.

Full text of DOI:10.1021/jo302089f

Article
pubs.acs.org/joc
Macrocyclizations for Medicinal Chemistry: Synthesis of Druglike
Macrocycles by High-Concentration Ullmann Coupling
James C. Collins,† Kathleen A. Farley,§ Chris Limberakis,§ Spiros Liras,§ David Price,§ and Keith James*,†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Conditions have been identified for the efficient
Ullmann macrocyclization of phenol and imidazole nucleo-
philes with aryl iodides at high reaction concentrations of up to
100 mM and using 5−10 mol % loading of an inexpensive
copper catalyst. A range of substitution patterns and ring sizes
are tolerated, and the method has been exemplified by the
synthesis of a set of druglike macrocycles.
for general, practical macrocyclization conditions, coupling
unactivated aryl halides with a range of nucleophiles without
resorting to high dilutions, that are suitable for both rapid,
diverse analogue synthesis and efficient scale-up, to facilitate the
rapidly growing pharmaceutical interest in the special properties
of druglike macrocycles.
In this study, phenols and imidazoles were chosen to
represent two distinct types of heteroatom nucleophile, for
which optimized coupling conditions might be more widely
applicable. Furthermore, these functionalities also comprise the
side chains of tyrosine and histidine, potentially allowing
application of Ullmann macrocyclization methodology to the
side chain to side chain bridging strategy for peptide
stabilization.11
INTRODUCTION
■
Despite increasing interest in the use of macrocycles as an
important, yet relatively unexploited, class of potential new
drugs,1 the corresponding synthetic methodology is lacking in
two key respects. First, only a small number of reactions are
generally considered to be readily applicable to macro-
cyclization, limiting both the range of potential targets and
the flexibility of the synthesis.2 Furthermore, these reactions are
typically run at low concentration, which is both inefficient and
impractical in an industrial setting.3 We recently proposed a
macrocyclization efficiency index, Emac, which allows a
quantitative assessment of the practicality of macrocyclizations
by consideration of both reaction concentration and yield,2
revealing a wide range of efficiencies (over six orders of
magnitude) for reactions published in the recent literature. We
plan to use this metric to judge the success of our own efforts
toward development of further macrocyclization method-
ologies, because the key assumption underlying our work in
this area has been that these issues are largely the consequence
of a lack of optimization, and that it may be possible to find
practical and efficient macrocyclization conditions for a wide
range of reactions.4
The Ullmann reaction has been one of the main beneficiaries
of the significant recent progress in the field of metal-catalyzed
cross-coupling, with highly optimized catalytic systems allowing
efficient and mild coupling of a wide range of nucleophiles and
(hetero)aryl halides.5 Development of an Ullmann macro-
cyclization was pioneered by Boger toward the synthesis of
complex biaryl ether natural products,6 albeit requiring sensitive
reagents and high dilutions. Milder and more practical variants
were established by Nicolaou,7 and more recently Ma,8 which
require activating groups ortho to the aryl halide. This trend
continued further, with Ullmann coupling in complex natural
product synthesis largely being superseded by efficient metal-
free SNAr cyclizations using highly activated aryl fluorides.9
Although isolated examples of Ullmann macrocyclizations in
total synthesis continue to be reported,10 there remains a need
RESULTS AND DISCUSSION
■
The initial design of macrocyclization substrates emphasized
flexible, rapid synthesis of relatively conformationally mobile
linear precursors, containing the phenol and imidazole
nucleophiles and a meta aryl iodide. We anticipated that
meta-substitution would provide the optimal balance between
product ring strain and steric hindrance in the macrocyclization.
Ring-opening of dihydrocoumarin (1) with mono-Boc
propylenediamine and alkylation of the resulting phenol
resulting in the bifunctional intermediate 2 in excellent yield.
Sequential deprotection and amide coupling of the ester and
amine termini of this linker led rapidly to the desired precursors
3a and 3b, again in high overall yield (Scheme 1).
An iterative, small-scale array optimization of the Ullmann
macrocyclization was performed (selected results shown in
Table 1 and Supporting Information), varying ligand, base,
solvent and temperature, initially with conditions reported to
be effective for intermolecular couplings.5 Interestingly, while
yields for the phenol arylation were largely independent of the
Received: October 2, 2012
Published: November 20, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of Macrocyclization Precursors 3a and 3b
results being obtained in DMF (entries 5−7). While initial
screening found K3PO4 and Cs2CO3 to be almost equally
effective, it was subsequently found that the latter gave more
reproducible results. Microwave heating also proved beneficial
for the imidazole arylation, increasing the yield and purity of
the target macrocycles (entries 8 and 9) and ultimately allowing
lower catalyst loading. In accordance with the aims of this
study, the final round of optimization looked at increasing
reaction concentration, and we were pleased to discover that
both coupling reactions gave high conversion to the macrocycle
products at 100 mM. The optimized conditions (entries 10 and
11) result in excellent isolated yields of macrocycles 4a and 4b
at high concentration, short reaction times, and low loading of
inexpensive catalyst, with best results obtained using a lower
microwave reaction temperature for the phenol arylation.
Overall, these conditions are the only ones tested that gave
reliable, batch-independent reactivity.
Table 1. Optimization of Conditions for Ullmann
Macrocyclization of 3a and 3b
a
Two regioisomeric products were obtained from macro-
cyclization of imidazole 3b. The major regioisomer in
intermolecular imidazole N-arylation reactions has been
exclusively reported (although usually assumed) to be the
tele-isomer, via attack from the less sterically hindered distal
nitrogen atom.13 However, in intramolecular reactions, this
product likely exhibits additional ring strain imposed by the
meta-cyclophanic imidazole ring, and therefore we sought to
confirm the identity of the major product. The few imidazole
N-arylation macrocyclization examples reported provide no
comment.14 Separation of the isomers and HMBC analysis
concluded that tele-4b was indeed the major product (Figure
1), which can be rationalized by observations that Ullmann
couplings are highly sensitive to steric hindrance.15
Before undertaking further analysis of the scope of the
successful macrocyclization conditions, the structure of the
linker was altered to that as shown in compounds 7a−g
(Scheme 2), using DMEDA in place of propylenediamine and
iodophenylacetic instead of iodobenzoic acid. These changes
were expected to improve the solubility of the compound series
and provide a more stringent test of the general applicability of
the optimized conditions, by employing a less electron-deficient
aryl halide electrophile. Synthesis of the macrocyclization
precursors proceeded in fashion very similar to those in Scheme
1, with some divergence of the sequence of amide couplings to
achieve the most efficient overall route.
b
entry product
ligand
base
solvent LC yield (%)
1
4a
4a
4a
4a
4b
4b
4b
4b
4b
4a
4b
8-HQ
8-HQ
Cs2CO3
K3PO4
DMSO
DMSO
DMSO
DMF
80
82
78
−
2
3
Me2NCH2CO2H
8-HQ
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
5
8-HQ
DMSO
DMSO
DMF
25
6
Me2NCH2CO2H
8-HQ
−
7
26
50
84
c
8
8-HQ
DMSO
DMSO
DMSO
DMSO
d
e
9
8-HQ
10
11
8-HQ
95 (90)
e
f
8-HQ
97 (82 )
a
b
Ring size is denoted by number within the macrocyclic ring. Yield
calculated as percentage of total UV absorption (210 nm). Isolated
yield in parentheses. Microwave heating, 190 °C, 15 min. 200 °C, 20
min. Optimized conditions: 5 mol % CuI, 10 mol % 8-HQ, 3 equiv of
Cs2CO3, 100 mM in DMSO, 150 °C, 30 min (for 4a) or 190 °C, 15
c
d
e
Figure 2 shows the results of applying the optimized
macrocyclization conditions to precursors 7a−g, as a test of
the tolerance to various substitution patterns, with the
macrocycles identified by the same letter as the corresponding
precursors in Scheme 2. For the phenol nucleophile, reaction
with a hindered ortho-iodide was unsuccessful (9a), but the
potentially strained para-meta biaryl ether 9b and the meta-meta
biaryl ether product 9e were formed in moderate and excellent
f
min (for 4b). Isolated as a 5:1 mixture of imidazole regioisomers tele-
4b and pros-4b.
ligand or base, solvent choice (DMSO) proved critical (entries
1−4). However, the analogous imidazole arylation was instead
highly dependent upon the choice of ligand, with only 8-
hydroxyquinoline (8-HQ)12 proving effective, and similar
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Figure 1. HMBC correlation observed between C6 and N10 (isomer tele-4b) and between C6 and N8 (isomer pros-4b).
Scheme 2. Synthesis of Macrocyclization Precursors 7a−g
yields respectively, demonstrating that the aryl iodide does not
require an electron-withdrawing substituent. The imidazole
nucleophile proved much more tolerant of structural variation,
with the 4-imidazole cyclizing in good to excellent yields with
ortho-, para-, and meta-iodides (9c, 9d, and 9f). Furthermore,
reaction with the sterically hindered 2-imidazolyl analogue was
also successful, resulting in N-arylimidazole 9g, an isostere of
the heterobiaryl linkage observed in 4-imidazolyl macrocycle
pros-4b. Increasing the reaction concentration to 100 mM in
the synthesis of 9e and 9f resulted in moderate yields of the
desired products (Figure 2, yields in parentheses). In contrast
to the results obtained for macrocycle 4b, only one N-
arylimidazole isomer was obtained for 9c, 9d, and 9f.
The inclusion of two tertiary amides proved to greatly
impede the purification and characterization of this set of
compounds, as each was isolated as a mixture of at least three
rotamers. This was confirmed by VT-NMR analysis of 9f (see
Supporting Information), which showed the expected peak
coalescence at elevated temperature.
available chiral pool amino alcohols as shown in Scheme 3.
Selective O-alkylation of ephedrine (10) was achieved using
KHMDS, and the amine product 11 was coupled with Boc-
protected amino acids m-tyrosine and histidine to give
precursors 12a and 12b. A protecting-group strategy was
used for the synthesis of 15a and 15b from tetrahydroisoquino-
line 13 by a similar route. The selective O-alkylation of this
amino alcohol was subsequently achieved, thereby avoiding the
need for protection, to give 16 en-route to linker-extended
precursors 18a and 18b.
Using the optimized conditions, these precursors were
cyclized in good to excellent yields, and at relatively high
concentration (20 mM), to give the six corresponding
macrocycles (Figure 3). These results exemplify the synthesis
of smaller ring sizes than in the original optimization, with the
macrocyclic products likely now exhibiting a higher degree of
conformational restriction. These compounds represent ex-
cellent examples of small, druglike macrocycles, with calculated
properties in the desired ranges: Mr 338−442; ClogP 1.82−
4.74; tPSA 50.8−71.2.16 Another feature is the potential for
additional elaboration from the primary amine groups in 19a,b
and 20a,b; these amines were Boc-protected in the linear
To demonstrate the applicability of this methodology to the
synthesis of more druglike and conformationally constrained
macrocycles, a range of precursors was prepared from readily
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druglike macrocycles. These macrocyclizations are among the
most efficient reported over the last three years and open the
way to construction of a variety of novel macrocycles with
potentially unique 3D pharmacophores.
EXPERIMENTAL SECTION
■
General Considerations. All reagents and solvents were used as
received. Anhydrous CH2Cl2 was obtained by passing through
activated alumina columns. NMR spectra were recorded on 500 or
600 MHz instruments using residual solvent peak as a reference. Data
are reported as s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. Flash column chromatography was performed
using silica columns and CH2Cl2−MeOH gradients.
Methyl 2-(2-(3-((3-((tert-Butoxycarbonyl)amino)propyl)amino)-3-
oxopropyl)phenoxy)acetate, 2. To a solution of dihydrocoumarin
(3.13 mL, 24.7 mmol) in MeCN (200 mL) was added tert-butyl (3-
aminopropyl)carbamate (4.30 g, 24.7 mmol), and the resulting
solution stirred at rt for 16 h. The solvent was removed in vacuo
and the resulting residue taken up in DMF (100 mL). Following
addition of K2CO3 (10.2 g, 74.0 mmol) and methyl 2-bromoacetate
(3.04 mL, 32.1 mmol), the resulting suspension was heated to 50 °C
for 2 h. After cooling, the solvent was removed in vacuo and the
resulting residue taken up in EtOAc (100 mL) and extracted with H2O
(3 × 50 mL). The organic layer was dried (Na2SO4) and the solvent
removed in vacuo. The resulting residue was purified by column
chromatography to give the title compound as a white semisolid (9.29
g, 96%), δH (500 MHz, CDCl3) 7.16−7.08 (m, 3H), 6.86 (t, J 7.4,
1H), 6.66 (d, J 8.4, 1H), 6.55 (br s, 1H), 5.08 (br s, 1H), 4.69 (s, 2H),
3.78 (s, 3H), 3.16 (q, J 6.0, 2H), 2.95 (t, J 6.4, 2H), 2.89−2.81 (m,
2H), 2.54 (t, J 6.5, 2H), 1.45−1.41 (m, 2H), 1.39 (s, 9H); δC (126
MHz, CDCl3) 173.4, 170.1, 156.3, 155.4, 131.0, 129.3, 127.7, 121.7,
110.5, 78.9, 64.5, 52.4, 36.9, 36.5, 35.9, 29.8, 28.5, 28.3; HRMS (ESI)
for C20H30N2O6, MH+ 395.2177; found 395.2182 (Δ 1.3 ppm).
N-(3-(3-(2-(2-((3-Hydroxyphenethyl)amino)-2-oxoethoxy)-
phenyl)propanamido)propyl)-3-iodobenzamide, 3a. To a stirred
solution of 2 (9.27 g, 23.5 mmol) in MeOH (40 mL) at rt was added
slowly a solution of LiOH·H2O (2.59 g, 61.7 mmol) in H2O (20 mL),
and the reaction mixture was stirred for 3 h, before being washed with
CH2Cl2 (20 mL) and acidified to ca. pH 2 with 0.5 M HCl. The
solution was extracted with CH2Cl2 (3 × 50 mL), the combined
organic layers were dried (Na2SO4), and the solvent removed in vacuo
to give the carboxylic acid as a thick white semisolid (8.92 g), used in
this crude form in subsequent reactions. To a solution of this
carboxylic acid (2.00 g, 5.26 mmol) in CH2Cl2 (50 mL) and DMF (2.5
mL) were added PyBOP (3.01 g, 5.78 mmol) and DIPEA (1.84 mL,
10.5 mmol), and the resulting solution was stirred at rt for 15 min
before addition of m-tyramine (870 mg, 6.31 mmol). The reaction
mixture was stirred at rt for 18 h before being washed with 1 M HCl
(100 mL) and sat. aq NaHCO3 (100 mL) and dried (Na2SO4). The
solvent was removed in vacuo and the resulting residue partially
purified by column chromatography to give the intermediate phenol as
a white semisolid (1.93 g), δH (400 MHz, CDCl3) 8.50 (br s, 1H,
NH), 7.11 (dt, J 11.8, 7.4, 3H, ArH), 7.05 (br s, 1H, NH), 6.87 (t, J
7.4, 1H, ArH), 6.75 (s, 2H, ArH), 6.71−6.62 (m, 3H, ArH), 6.54 (s,
1H, NH), 4.90 (br s, 1H, OH), 4.38 (s, 2H, OCH2), 3.59 (q, J 6.1, 2H,
CH2), 3.20 (q, J 6.0, 2H, CH2), 3.02 (q, J 6.0, 2H, CH2), 2.90−2.86
(m, 2H, CH2), 2.78 (t, J 6.5, 2H, CH2), 2.40 (t, J 7.6, 2H, CH2), 1.52
Figure 2. Scope of Ullmann macrocyclization−substitution pattern.
Ring size is denoted by number within the macrocyclic ring.
Macrocyclizations were conducted using 10 mol % CuI, 20 mol %
8-HQ, 3 equiv of Cs2CO3 in DMSO (20 mM) at 150 °C for 30 min.
b
c
aTrace product detected. 40 mM reaction concentration. 100 mM.
precursors and were cleanly unmasked under the high-
temperature reaction conditions. While this does illustrate
one potential functional group incompatibility, the amine
product clearly does not interfere with the macrocyclization,
despite its high nucleophilicity.
Calculation of the Emac values for these reactions provides
quantitative support for our assessment that the Ullmann
macrocyclization methodology presented here is highly
effective. The most efficient example in this study, biaryl
ether 4a, has an Emac value of 7.86, placing it in the top 2%
most efficient macrocyclizations of any type (and this study in
the top five reports) published over the last 3 years. All the
druglike macrocycles in Figure 3 also score highly (Emac 6.89−
7.15), illustrating the practicality of this methodology for
potential use in a drug discovery setting.
t
(p, J 6.3, 2H, CH2), 1.38 (s, 9H, Bu).
A solution of this phenol (320 mg, 0.642 mmol) in 4 M HCl/
dioxane (1.60 mL, 6.41 mmol) was stirred at rt for 2 h. The solvent
was removed in vacuo, and a premixed solution of 3-iodobenzoic acid
(159 mg, 0.642 mmol), PyBOP (333 mg, 0.642 mmol), and DIPEA
(450 μL, 2.56 mmol) in CH2Cl2 (5 mL) was added. The reaction
mixture was stirred at rt for 6 h before being poured into brine (20
mL), and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a white semisolid (346
mg, 64% over three steps), as a mixture of rotamers, δH (400 MHz,
CONCLUSION
■
In summary, we have developed conditions for a highly efficient
Ullmann macrocyclization of phenols and imidazoles with
unactivated aryl iodides at practical concentrations. A range of
substitution patterns are tolerated, and the utility for medicinal
chemistry has been exemplified by the synthesis of a set of
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Scheme 3. Synthesis of Macrocyclization Precursors 12a,b, 15a,b, and 18a,b
136.2, 130.3, 130.2, 129.4, 129.2, 127.7, 126.3, 121.5, 119.9, 115.5,
113.2, 111.5, 93.7, 67.0, 40.5, 40.4, 37.1, 36.6, 36.4, 35.2, 28.9, 26.7;
HRMS (ESI) for C29H32IN3O5, MH+ 630.1459; found 630.1460 (Δ
0.2 ppm)
N-(3-(3-(2-(2-((2-(1H-Imidazol-4-yl)ethyl)amino)-2-oxoethoxy)-
phenyl)propanamido)propyl)-3-iodobenzamide, 3b. To a solution
of the intermediate carboxylic acid from the synthesis of 3a (2.00 g,
5.26 mmol) in CH2Cl2 (50 mL) and DMF (2.5 mL) were added
PyBOP (3.01 g, 5.78 mmol) and DIPEA (3.67 mL, 21.0 mmol), and
the resulting solution was stirred at rt for 15 min before addition of
histamine·2HCl (1.16 g, 6.31 mmol). The reaction mixture was stirred
at rt for 18 h before being washed with 1 M HCl (100 mL) and sat. aq
NaHCO3 (100 mL) and dried (Na2SO4). The solvent was removed in
vacuo and the resulting residue partially purified by column
chromatography to give the intermediate imidazole as a white
semisolid (2.46 g), which was used in this crude form in the
subsequent reactions, δH (400 MHz, CDCl3) 7.74 (br s, 1H), 7.59 (s,
1H), 7.42 (br s, 2H), 7.12 (t, J 7.0, 2H), 6.88 (t, J 7.3, 2H), 6.79 (s,
1H), 6.69 (d, J 8.2, 1H), 4.41 (s, 2H), 3.61 (q, J 6.2, 2H), 3.18−3.09
(m, 2H), 3.01−2.84 (m, 6H), 2.45 (t, J 7.3, 2H), 1.50−1.43 (m, 2H),
1.38 (s, 9H).
A solution of this imidazole (284 mg, 0.600 mmol) in 4 M HCl/
dioxane (1.50 mL, 6.00 mmol) was stirred at rt for 2 h. The solvent
was removed in vacuo, and a premixed solution of 3-iodobenzoic acid
(149 mg, 0.600 mmol), PyBOP (312 mg, 0.600 mmol), and DIPEA
(420 μL, 2.40 mmol) in CH2Cl2 (5 mL) was added. The reaction
mixture was stirred at rt for 6 h before being poured into brine (20
mL), and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried (Na2SO4), the solvent
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a white semisolid (344
mg, 94% over three steps), δH (400 MHz, CDCl3) 10.74 (br s, 1H),
8.16 (s, 1H), 8.01 (t, J 5.8, 1H), 7.84 (t, J 4.8, 1H), 7.76 (t, J 9.0, 2H),
7.55−7.49 (m, 2H), 7.16−7.05 (m, 3H), 6.88 (t, J 7.4, 1H), 6.79 (s,
1H), 6.69 (d, J 8.5, 1H), 4.42 (s, 2H), 3.58 (q, J 5.6, 2H), 3.25 (q, J
5.7, 2H), 3.19 (q, J 5.6, 2H), 2.98 (t, J 7.2, 2H), 2.86 (t, J 5.9, 2H),
2.51 (t, J 7.2, 2H), 1.62−1.51 (m, 2H); δC (101 MHz, CDCl3) 173.9,
168.7, 166.6, 155.1, 140.4, 136.4, 136.4, 134.8, 134.7, 130.6, 130.3,
129.1, 128.0, 126.3, 121.9, 117.5, 111.4, 94.4, 67.2, 39.2, 37.3, 36.6,
Figure 3. Scope of Ullmann macrocyclization: small, druglike
macrocycles. Ring size is denoted by number within the macrocyclic
ring. Macrocyclizations were conducted using 10 mol % CuI, 20 mol %
8-HQ, and 3 equiv of Cs2CO3 in DMSO (20 mM) at 150 °C for 30
min.
CD3OD) 8.11 (s, 1H), 8.07 (t, J 5.5, 1H), 7.79 (d, J 7.8, 1H), 7.74 (d, J
7.8, 1H), 7.17−7.08 (m, 3H), 7.02 (t, J 7.8, 1H), 6.85 (t, J 7.4, 1H),
6.75 (d, J 8.4, 1H), 6.65−6.57 (m, 3H), 4.45 (s, 2H), 3.47 (t, J 7.0,
2H), 3.19 (t, J 6.7, 2H), 3.13 (t, J 6.7, 2H), 2.91 (t, J 7.2, 2H), 2.73 (t, J
7.2, 2H), 2.43 (t, J 7.3, 2H), 1.61 (p, J 6.6, 2H); δC (101 MHz,
CD3OD) 174.6, 169.8, 169.8, 167.2, 157.4, 155.6, 140.6, 140.4, 136.4,
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36.2, 29.5, 27.0, 26.3; HRMS (ESI) for C26H30IN5O4, MH+ 604.1415;
found 604.1416 (Δ 0.2 ppm).
residue was purified by column chromatography to give the title
compound as a thick yellow oil (10.7 g, 99%) as a mixture of rotamers,
δH (400 MHz, CDCl3) 7.16−7.11 (m, 1H), 7.10−7.04 (m. 1H), 6.87−
6.80 (m, 1H), 6.65−6.61 (m, 1H), 4.61−4.57 (m, 2H), 3.70 (s, 3H),
3.48−3.19 (m, 4H), 2.97−2.86 (m, 5H), 2.81−2.72 (m, 3H), 2.62−
2.54 (m, 2H), 1.41−1.30 (m, 9H); δC (101 MHz, CDCl3) 172.7,
169.2, 155.6, 130.6, 130.0, 127.3, 121.5, 110.8, 79.8, 79.6, 79.2, 65.0,
52.0, 47.7, 47.2, 46.4, 46.1, 45.6, 45.1, 36.2, 35.7, 34.7, 33.6, 32.8, 28.3,
26.8, 26.6; HRMS (ESI) for C21H32N2O6, MH+ 408.2333; found
408.2335 (Δ 0.5 ppm).
General Procedure for Ullmann Macrocyclization. A
suspension of macrocycle precursor (20.0 μmol), CuI (0.38 mg,
2.00 μmol), 8-hydroxyquinoline (0.58 mg, 4.00 μmol), and Cs2CO3
(19.6 mg, 60.0 μmol) in degassed DMSO (1 mL, 20 mM reaction
concentration) was heated to 150 °C in a Biotage Initiator microwave
with air-cooling and an external temperature sensor. After 30 min at
this temperature, the reaction mixture was cooled, poured into sat. aq
NaHCO3 (10 mL), and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the macrocycle product.
tert-Butyl (2-(3-(2-(2-((3-Hydroxyphenethyl)amino)-2-
oxoethoxy)phenyl)-N-methylpropanamido)ethyl)(methyl)-
carbamate, 6a. To a stirred solution of 5 (2.00 g, 4.90 mmol) in
MeOH (8 mL) at rt was added slowly a solution of LiOH·H2O (510
mg, 12.2 mmol) in H2O (4 mL), and the reaction mixture was stirred
for 3 h. The reaction mixture was acidified to approximately pH 2 with
0.5 M HCl and extracted with EtOAc (3 × 20 mL), the combined
organic layers were dried (Na2SO4), and the solvent was removed in
vacuo to give the carboxylic acid as a colorless oil (1.75 g), which was
used crude in the following reactions. To a solution of this carboxylic
acid (830 mg, 2.09 mmol) in CH2Cl2 (25 mL) were added PyBOP
(1.20 g, 2.30 mmol) and DIPEA (730 μL, 4.18 mmol), and the
resulting solution was stirred at rt for 15 min before addition of m-
tyramine (340 mg, 2.51 mmol). The reaction mixture was stirred at rt
for 18 h before being washed with sat. aq citric acid (100 mL) and sat.
aq NaHCO3 (100 mL) and dried (Na2SO4). The solvent was removed
in vacuo and the resulting residue purified by column chromatography
to give the title compound as a thick colorless oil (710 mg, 59% over
two steps) as a mixture of rotamers, δH (600 MHz, CD3OD) 7.16−
7.12 (m, 2H), 7.04−7.00 (m, 1H), 6.90−6.86 (m, 1H), 6.78 (d, J 8.2,
1H), 6.64−6.60 (m, 2H), 6.58 (d, J 8.1, 1H), 4.46 (s, 2H), 3.51−3.46
(m, 2H), 3.46−3.41 (m, 1H), 3.37−3.33 (m, 1H), 3.28−3.23 (m, 2H),
2.94−2.85 (m, 5H), 2.81−2.72 (m, 5H), 2.62−2.53 (m, 2H), 1.39
(dapp, J 9.1, 5H), 1.34 (s, 4H); δC (151 MHz, CD3OD) 170.0, 157.6,
155.9, 140.8, 130.4, 130.3, 129.8, 129.8, 129.5, 129.5, 127.9, 127.9,
121.9, 121.8, 120.0, 120.0, 115.7, 115.7, 113.4, 111.9, 111.8, 67.4, 40.6,
40.6, 35.4, 33.2, 27.8, 27.7, 26.2; HRMS (ESI) for C28H39N3O6, MH+
514.2911; found 514.2915 (Δ 0.8 ppm).
tert-Butyl (2-(3-(2-(2-((2-(1H-Imidazol-4-yl)ethyl)amino)-2-
oxoethoxy)phenyl)-N-methylpropanamido)ethyl)(methyl)-
carbamate, 6b. To a solution of the intermediate carboxylic acid from
the synthesis of 6a (830 mg, 2.09 mmol) in CH2Cl2 (25 mL) were
added PyBOP (1.20 g, 2.30 mmol) and DIPEA (1.46 mL, 8.37 mmol),
and the resulting solution was stirred at rt for 15 min before addition
of histamine·2HCl (280 mg, 2.51 mmol). The reaction mixture was
stirred at rt for 18 h before being washed with sat. aq citric acid (100
mL) and sat. aq NaHCO3 (100 mL) and dried (Na2SO4). The solvent
was removed in vacuo and the resulting residue purified by column
chromatography to give the title compound as a thick colorless oil
(600 mg, 54% over two steps), δH (600 MHz, CD3OD) 7.54 (s, 1H),
7.17−7.10 (m, 2H), 6.91−6.86 (m, 1H), 6.80−6.74 (m, 2H), 4.48 (s,
2H), 3.53−3.49 (m, 2H), 3.46−3.42 (m, 1H), 3.37−3.33 (m, 1H),
3.27−3.24 (m, 2H), 2.95−2.86 (m, 5H), 2.82−2.74 (m, 5H), 2.65−
2.55 (m, 2H), 1.39 (dapp, J 8.6 5H), 1.33 (s, 4H); δC (151 MHz,
CD3OD) 174.9, 170.5, 156.9, 156.3, 135.6, 135.2, 130.8, 130.3, 128.3,
122.3, 117.5, 112.2, 81.0, 80.7, 80.3, 67.8, 46.7, 46.3, 46.1, 45.8, 39.4,
36.2, 36.0, 35.5, 34.6, 34.3, 34.0, 33.7, 28.1, 27.1, 26.6; HRMS (ESI)
for C25H37N5O5, MH+ 488.2867; found 488.2866 (Δ 0.2 ppm).
3-(2-(2-((3-Hydroxyphenethyl)amino)-2-oxoethoxy)phenyl)-N-(2-
(2-(2-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropana-
mide, 7a. A 4 M HCl/dioxane (2.30 mL, 9.20 mmol) solution was
added to 6a (591 mg, 1.15 mmol) and the resulting solution stirred at
rt for 1.5 h. The solvent was removed in vacuo and the crude product
amine used in subsequent reactions. To a premixed solution of 2-(2-
iodophenyl)acetic acid (157 mg, 0.600 mmol), HATU (274 mg, 0.720
mmol), and DIPEA (314 μL, 1.80 mmol) in CH2Cl2 (5 mL) was
added this amine (238 mg, 0.58 mmol). The reaction mixture was
stirred at rt for 3 h, before being poured into sat. aq NaHCO3 (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (Na2SO4), the solvent was removed in vacuo, and the
Macrocycle 4a. Macrocyclization carried out as per the general
procedure using 3a. Carried out on 100 μmol scale with 5 mol % CuI
and 10 mol % 8-HQ in 1 mL of DMSO (100 mM reaction
concentration). Obtained as a white solid (45 mg, 90%), δH (500
MHz, DMSO-d6) 8.46 (t, J 6.0, 1H), 8.23 (t, J 5.9, 1H), 7.91 (t, J 6.0,
1H), 7.64 (d, J 7.7, 1H), 7.57−7.55 (m, 1H), 7.53 (t, J 8.0, 1H), 7.37
(t, J 7.9, 1H), 7.35−7.32 (m, 1H), 7.18−7.12 (m, 2H), 7.05 (dd, J 8.1,
2.0, 1H), 7.01 (d, J 7.6, 1H), 6.91−6.86 (m, 1H), 6.79 (s, 1H), 4.47 (s,
1H), 3.38−3.32 (m, 2H), 3.25−3.20 (m, 2H), 3.06−3.00 (m, 2H),
2.84−2.79 (m, 2H), 2.79−2.75 (m, 2H), 2.31−2.26 (m, 2H), 1.61−
1.54 (m, 2H); δC (126 MHz, DMSO-d6) 172.0, 167.6, 165.3, 156.5,
155.7, 155.0, 141.2, 136.1, 130.4, 130.3, 129.7, 129.6, 127.5, 123.6,
122.7, 122.5, 121.0, 116.8, 116.7, 116.4, 111.8, 66.7, 40.2, 36.4, 36.4,
36.2, 35.1, 29.2, 26.7; HRMS (ESI) for C29H31N3O5, MH+ 502.2336;
found 502.2342 (Δ 1.2 ppm).
Macrocycle 4b. Macrocyclization carried out as per the general
procedure using 3b on 100 μmol scale with 5 mol % CuI and 10 mol
% 8-HQ in 1 mL of DMSO (100 mM reaction concentration) and
heated to 190 °C in a microwave for 15 min. Obtained as a white solid
as a mixture of regioisomers (39 mg, 82%); HRMS (ESI) for
C26H29N5O4, MH+ 476.2292; found 476.2300 (Δ 1.7 ppm). The
regioisomers were separated by supercritical fluid chromatography
using normal-phase conditions on a 150 mm × 21.2 mm 5 μm column
with a gradient of 5−50% A over 5.6 min with a flow rate of 60 mL/
min. Mobile phase A was MeOH, and mobile phase B was CO2, with
monitoring at UV 260 nm. QC was orthogonally analyzed by LC using
a 50 × 4.6 mm 3.5 μm column with 10 mM NH4OAC in H2O and
MeCN.
tele-4b: δH (600 MHz, DMSO-d6); 8.40 (s, 1H), 8.37 (t, J 5.1, 1H),
8.13 (t, J 5.5, 1H), 8.06 (s, 1H), 7.93 (t, J 5.3, 1H), 7.80 (d, J 7.9, 1H),
7.70 (s, 1H), 7.67 (d, J 7.6, 1H), 7.57 (t, J 7.8, 1H), 7.11 (t, J 7.6, 1H),
7.06 (d, J 7.3, 1H), 6.88 (d, J 8.2, 1H), 6.84 (t, J 7.4, 1H), 4.46 (s, 2H),
3.53 (q, J 5.3, 2H), 3.33−3.30 (m, 2H), 3.27 (q, J 5.8, 2H), 2.86 (t, J
7.6, 2H), 2.79−2.75 (m, 2H), 2.40 (t, J 7.7, 1H), 1.74−1.68 (m, 2H);
δC (151 MHz, DMSO-d6) 172.5, 167.6, 165.8, 155.0, 141.0, 136.9,
136.7, 135.4, 130.0, 129.1, 128.8, 127.2, 125.3, 121.5, 121.0, 118.5,
114.1, 111.6, 67.1, 37.7, 36.5, 35.7, 34.8, 27.7, 27.3, 25.2.
pros-4b: δH (500 MHz, DMSO-d6) 8.33 (t, J 5.5, 1H), 8.15 (t, J 5.9,
1H), 8.09−8.03 (m, 1H), 7.89−7.84 (m, 3H), 7.68−7.60 (m, 2H),
7.18−7.13 (m, 2H), 6.97 (s, 1H), 6.93−6.87 (m, 2H), 4.45 (s, 2H),
3.45−3.39 (m, 2H), 3.28−3.21 (m, 4H), 2.91 (t, J 8.0, 2H), 2.84 (t, J
7.3, 2H), 2.33 (t, J 7.6, 2H), 1.65−1.57 (m, 2H); δC (126 MHz,
DMSO-d6) 172.9, 167.6, 165.4, 154.8, 137.7, 136.4, 135.9, 130.2,
129.9, 129.5, 129.3, 127.9, 127.6, 127.5, 127.0, 123.3, 121.1, 111.8,
66.6, 37.3, 36.8, 35.3, 34.9, 28.4, 27.0, 24.1.
Methyl 2-(2-(3-((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)-
(methyl)amino)-3-oxopropyl)phenoxy)acetate, 5. To a solution of
dihydrocoumarin (3.37 mL, 26.6 mmol) in MeCN (150 mL) was
added tert-butyl methyl(2-methylamino)ethyl)carbamate (5.00 g, 26.6
mmol), and the resulting solution was stirred at rt for 16 h. The
solvent was removed in vacuo and the resulting residue taken up in
DMF (100 mL). Following addition of K2CO3 (11.0 g, 80.0 mmol)
and methyl 2-bromoacetate (3.27 mL, 34.5 mmol), the resulting
suspension was heated to 50 °C for 2 h. After cooling, the solvent was
removed in vacuo and the resulting residue taken up in EtOAc (100
mL) and extracted with H2O (5 × 50 mL). The organic layer was
dried (Na2SO4) and the solvent removed in vacuo. The resulting
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resulting residue was purified by column chromatography to give the
title compound as a thick colorless oil (322 mg, 85% over two steps)
as a mixture of rotamers, δH (600 MHz, CDCl3) 8.12−8.08 (m, 0.4H),
7.85−7.79 (m, 1H), 7.31−7.26 (m, 1H), 7.24−7.11 (m, 4H), 7.01−
6.90 (m, 3H), 6.81−6.71 (m, 2H), 6.71−6.66 (m, 2H), 4.69 (s, 0.3H),
4.45 (s, 1.7H), 3.86−3.74 (m, 2H), 3.64 (s, 3H), 3.62−3.57 (m, 1.8H),
3.56−3.40 (m, 1.2H), 3.15 (s, 2H), 3.11−2.91 (m, 6H), 2.85−2.73 (m,
2H), 2.70−2.56 (m, 2H); δC (151 MHz, CDCl3) 174.2, 174.0, 173.8,
171.2, 171.0, 170.7, 168.8, 168.5, 168.5, 165.4, 157.6, 157.4, 157.3,
154.9, 154.7, 140.2, 140.1, 140.0, 139.5, 139.5, 138.6, 138.4, 138.2,
133.9, 130.5, 130.4, 130.4, 130.2, 130.2, 130.2, 130.1, 130.0, 129.9,
129.2, 129.1, 129.0, 129.0, 128.8, 128.8, 128.6, 128.1, 128.0, 128.0,
122.1, 120.1, 119.9, 119.8, 115.8, 115.7, 115.6, 114.1, 114.1, 113.9,
111.6, 111.5, 101.5, 101.3, 101.3, 67.2, 67.0, 62.9, 47.8, 47.4, 47.3, 47.2,
45.8, 45.8, 45.5, 45.4, 40.4, 40.3, 40.2, 37.3, 37.1, 36.3, 36.2, 35.0, 35.0,
34.4, 34.3, 34.2, 34.0, 33.0, 25.7, 25.3, 25.2; HRMS (ESI) for
C31H36IN3O5, MH+ 658.1772; found 658.1772 (Δ 0.0 ppm).
3-(2-(2-((3-Hydroxyphenethyl)amino)-2-oxoethoxy)phenyl)-N-(2-
(2-(4-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropana-
mide, 7b. To a premixed solution of 2-(4-iodophenyl)acetic acid (157
mg, 0.600 mmol), HATU (274 mg, 0.720 mmol), and DIPEA (314
μL, 1.80 mmol) in CH2Cl2 (5 mL) was added the intermediate amine
from the synthesis of 7a (238 mg, 0.580 mmol). The reaction mixture
was stirred at rt for 3 h, before being poured into sat. aq NaHCO3 (50
mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were dried (Na2SO4), the solvent was removed in vacuo, and the
resulting residue was purified by column chromatography to give the
title compound as a thick colorless oil (295 mg, 78% over two steps)
as a mixture of rotamers, δH (600 MHz, CDCl3) 8.85 (s, 0.7H), 8.61
(s, 0.1H), 8.48 (s, 0.1H), 7.64−7.53 (m, 2H), 7.21−7.08 (m, 4H),
6.99−6.89 (m, 3H), 6.80−6.72 (m, 2H), 6.71−6.65 (m, 2H), 4.44 (s,
0.5H), 4.43 (s, 1.5H), 3.65−3.53 (m, 7H), 3.44−3.33 (m, 1H), 3.04 (s,
2H), 2.97−2.89 (m, 6H), 2.83−2.75 (m, 2H), 2.60−2.48 (m, 2H); δC
(151 MHz, CDCl3) 173.8, 173.7, 173.4, 171.3, 171.1, 171.0, 168.4,
168.2, 157.5, 157.4, 157.3, 154.9, 154.8, 154.7, 140.3, 140.2, 140.1,
137.8, 137.7, 137.7, 134.6, 134.4, 133.8, 131.2, 131.0, 130.9, 130.1,
130.1, 130.0, 129.9, 129.3, 129.1, 128.9, 128.0, 127.9, 121.9, 121.9,
120.0, 119.9, 119.8, 115.7, 115.6, 113.9, 113.9, 113.7, 111.5, 111.5,
111.4, 92.5, 92.4, 92.3, 67.3, 67.1, 67.1, 47.4, 47.2, 47.2, 47.1, 45.2,
45.1, 40.3, 40.3, 40.2, 40.2, 39.7, 37.2, 36.9, 36.2, 35.9, 35.2, 35.2, 34.1,
33.8, 33.8, 33.1, 25.9, 25.5, 25.4; HRMS (ESI) for C31H36IN3O5, MH+
658.1772; found 658.1771 (Δ 0.2 ppm).
3-(2-(2-((2-(1H-Imidazol-4-yl)ethyl)amino)-2-oxoethoxy)phenyl)-
N-(2-(2-(2-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropa-
namide, 7c. A 4 M HCl/dioxane (2.30 mL, 9.20 mmol) solution was
added to 6b (561 mg, 1.15 mmol) and the resulting solution stirred at
rt for 1.5 h. The solvent was removed in vacuo and the crude product
amine used in subsequent reactions. To a premixed solution of 2-(2-
iodophenyl)acetic acid (157 mg, 0.600 mmol), HATU (274 mg, 0.720
mmol), and DIPEA (314 μL, 1.80 mmol) in CH2Cl2 (5 mL) was
added this amine (223 mg, 0.580 mmol). The reaction mixture was
stirred at rt for 3 h, before being poured into sat. aq NaHCO3 (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (Na2SO4), the solvent was removed in vacuo, and the
resulting residue was purified by column chromatography to give the
title compound as a thick colorless oil (247 mg, 68% over two steps)
as a mixture of rotamers, δH (600 MHz, CDCl3) 10.30 (br s, 1H),
7.74−7.71 (m, 1H), 7.69−7.31 (m, 1H), 7.28−7.16 (m, 2H), 7.14−
7.07 (m, 3H), 6.89−6.83 (m, 2H), 6.71−6.59 (m, 2H), 4.41 (s, 0.3H),
4.40 (s, 1.2H), 4.38 (s, 0.5H), 3.73−3.62 (m, 2H), 3.56−3.50 (m, 2H),
3.50−3.25 (m, 4H), 3.06−2.82 (m, 8H), 2.80−2.72 (m, 2H), 2.62−
2.46 (m, 2H); δC (151 MHz, CDCl3) 173.3, 173.2, 170.7, 170.3, 168.4,
168.2, 155.1, 155.0, 139.4, 138.7, 138.3, 135.0, 134.9, 133.8, 130.5,
130.5, 130.3, 130.2, 130.2, 129.4, 129.2, 128.9, 128.9, 128.6, 128.5,
128.0, 127.9, 127.9, 121.8, 118.2, 111.3, 101.4, 101.3, 67.3, 67.2, 47.6,
47.3, 47.2, 46.8, 45.7, 45.7, 45.5, 45.3, 45.0, 38.9, 38.7, 37.0, 36.8, 36.2,
36.0, 34.3, 34.2, 33.9, 33.2, 26.5, 26.3, 26.1, 25.9, 25.9; HRMS (ESI)
for C28H34IN5O4, MH+ 632.1728; found 632.1730 (Δ 0.3 ppm).
3-(2-(2-((2-(1H-Imidazol-4-yl)ethyl)amino)-2-oxoethoxy)phenyl)-
N-(2-(2-(4-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropa-
namide, 7d. To a premixed solution of 2-(4-iodophenyl)acetic acid
(157 mg, 0.600 mmol), HATU (274 mg, 0.720 mmol), and DIPEA
(314 μL, 1.80 mmol) in CH2Cl2 (5 mL) was added the intermediate
amine from the synthesis of 7c (223 mg, 0.580 mmol). The reaction
mixture was stirred at rt for 3 h, before being poured into sat. aq
NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a thick colorless oil
(320 mg, 88%) as a mixture of rotamers, δH (600 MHz, CDCl3) 10.80
(br s, 1H), 7.87 (t, J 5.7, 0.25H), 7.81 (t, J 5.7, 0.15H), 7.73 (t, J 5.7,
0.6H), 7.59−7.39 (m, 3H), 7.19−7.12 (m, 2H), 6.97−6.84 (m, 3H),
6.77−6.68 (m, 2H), 4.46 (s, 0.35H), 4.45 (s, 1.15H), 4.44 (s, 0.5H),
3.63−3.53 (m, 4H), 3.48 (s, 2.5H), 3.40−3.29 (m, 1.5H), 3.01−2.82
(m, 10H), 2.60 (t, J 7.2, 0.3H), 2.56 (t, J 7.3, 0.4H), 2.49 (t, J 7.3,
1.3H); δC (151 MHz, CDCl3) 173.4, 173.3, 171.2, 171.0, 170.9, 168.4,
168.3, 155.1, 155.1, 155.0, 137.9, 137.8, 137.7, 134.9, 134.8, 134.5,
133.9, 131.2, 131.0, 131.0, 130.8, 130.3, 130.2, 129.4, 129.4, 129.2,
128.0, 127.9, 121.8, 121.8, 118.0, 111.4, 111.3, 92.5, 92.4, 92.3, 67.3,
67.2, 67.2, 47.4, 47.2, 47.1, 47.0, 45.3, 44.9, 40.3, 40.2, 39.6, 38.8, 38.8,
37.1, 36.9, 36.3, 35.9, 34.2, 34.1, 33.8, 33.3, 26.6, 26.5, 26.3, 26.2, 25.9;
HRMS (ESI) for C28H34IN5O4, MH+ 632.1728; found 632.1733 (Δ
0.8 ppm).
Methyl 2-(2-(3-((2-(2-(3-Iodophenyl)-N-methylacetamido)ethyl)-
(methyl)amino)-3-oxopropyl)phenoxy)acetate, 8. A solution of 5
(1.00 g, 2.45 mmol) in 4 M HCl/dioxane (4.90 mL, 19.6 mmol) was
stirred at rt for 1.5 h. The solvent was removed in vacuo, and a
premixed solution of 3-iodophenylacetic acid (770 mg, 2.94 mmol),
PyBOP (1.53 g, 2.94 mmol), and DIPEA (2.14 mL, 12.2 mmol) in
CH2Cl2 (20 mL) was added. The reaction mixture was stirred at rt for
2 h before being washed with sat. aq citric acid (100 mL) and sat. aq
NaHCO3 (50 mL) and dried (Na2SO4). The solvent was removed in
vacuo and the resulting residue purified by column chromatography to
give the title compound as a thick colorless oil (1.30 g, 96%) as a
mixture of rotamers, δH (600 MHz, CDCl3) 7.61 (s, 0.2H), 7.53−7.46
(m, 1.8H), 7.23−7.05 (m, 3H), 7.01−6.89 (m, 1H), 6.88−6.82 (m,
1H), 6.64 (d, J 8.1, 1H), 4.61 (s, 0.5H), 4.59 (s, 1.4H), 4.58 (s, 0.1H),
3.71 (s, 0.7H), 3.69 (s, 2.3H), 3.64 (s, 0.4H), 3.51 (s, 1.6H), 3.47−
3.30 (m, 4H), 3.01−2.83 (m, 8H), 2.67−2.62 (m, 0.4H), 2.60−2.55
(m, 1.6H); δC (151 MHz, CDCl3) 174.3, 174.2, 173.6, 171.9, 171.5,
171.3, 170.3, 170.2, 156.5, 138.8, 138.7, 138.6, 138.1, 137.8, 136.7,
136.6, 131.6, 131.6, 131.4, 131.1, 130.8, 130.5, 130.5, 129.5, 129.2,
128.5, 128.4, 122.6, 122.5, 111.9, 111.8, 111.7, 95.4, 95.3, 95.3, 65.9,
65.8, 53.0, 48.2, 48.0, 47.8, 46.1, 45.8, 40.9, 40.7, 40.4, 37.8, 37.7, 37.4,
36.9, 34.8, 34.7, 34.4, 34.3, 33.8, 27.8, 27.6, 27.2; HRMS (ESI) for
C24H29IN2O5, MH+ 553.1194; found 553.1197 (Δ 0.5 ppm).
3-(2-(2-((3-Hydroxyphenethyl)amino)-2-oxoethoxy)phenyl)-N-(2-
(2-(3-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropana-
mide, 7e. To a stirred solution of 8 (1.30 g, 2.45 mmol) in MeOH (8
mL) at rt was added slowly a solution of LiOH·H2O (260 mg, 6.12
mmol) in H2O (4 mL), and the reaction mixture was stirred for 2 h.
The reaction mixture was acidified to approximately pH 2 with 0.5 M
HCl and extracted with EtOAc (3 × 20 mL), the combined organic
layers were dried (Na2SO4), and the solvent was removed in vacuo to
give a quantitative recovery of the title compound as a colorless oil that
was used crude in the following reactions. To a stirred solution of this
carboxylic acid (323 mg, 0.600 mmol), HATU (274 mg, 0.720 mmol),
and DIPEA (419 μL, 2.40 mmol) in CH2Cl2 (5 mL) was added m-
tyramine hydrochloride (146 mg, 0.840 mmol), and the reaction was
stirred at rt for 2 h. The reaction mixture was poured into sat. aq
NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a thick colorless oil
(380 mg, 96% over two steps) as a mixture of rotamers, δH (600 MHz,
CDCl3) 8.81 (d, J 1.2, 0.7H), 8.49 (d, J 1.4, 0.1H), 8.41 (d, J 1.4,
0.1H), 7.63−7.51 (m, 1.9H), 7.37−7.31 (m, 0.1H), 7.23−7.05 (m,
5H), 7.05−6.97 (m, 1H), 6.97−6.90 (m, 1H), 6.82−6.63 (m, 4H),
4.46−4.42 (m, 2H), 3.66−3.58 (m, 3.8H), 3.58−3.55 (m, 3H), 3.44−
3.33 (m, 1.2H), 3.07−3.04 (s, 2H), 3.01−2.87 (m, 6H), 2.83−2.77 (m,
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2H), 2.61−2.56 (m, 0.6H), 2.55−2.50 (m, 1.4H); δC (151 MHz,
CDCl3) 173.9, 173.8, 173.5, 171.2, 171.0, 170.8, 168.4, 168.2, 157.5,
157.4, 157.3, 154.9, 154.8, 154.8, 140.4, 140.2, 140.1, 138.0, 137.9,
137.6, 137.4, 137.1, 136.5, 136.2, 136.1, 136.1, 130.5, 130.5, 130.4,
130.2, 130.2, 130.1, 130.1, 130.0, 129.3, 129.1, 129.0, 128.5, 128.3,
128.3, 128.1, 127.9, 122.0, 121.9, 120.00, 119.9, 119.8, 115.8, 115.8,
115.6, 114.0, 113.9, 113.8, 111.5, 111.4, 94.7, 94.6, 94.6, 67.3, 67.1,
67.1, 47.4, 47.3, 47.2, 45.3, 45.2, 40.3, 40.3, 40.2, 40.2, 39.8, 37.3, 37.0,
36.3, 36.0, 35.3, 35.2, 34.2, 34.1, 33.9, 33.8, 33.1, 25.8, 25.5, 25.4;
HRMS (ESI) for C31H36IN3O5, MH+ 658.1772; found 658.1774 (Δ
0.3 ppm).
(m, 2H), 2.84 (d, J 7.8, 1H), 2.82−2.74 (m, 2H), 2.74−2.60 (m,
3.5H), 2.58−2.51 (m, 2H), 2.43−2.38 (d, J 7.5, 0.5H); δC (151 MHz,
DMSO-d6) 172.2, 171.9, 171.7, 170.8, 170.7, 170.2, 168.0, 167.7,
157.6, 157.1, 156.8, 156.7, 156.0, 155.8, 155.3, 155.2, 155.1, 154.7,
141.5, 141.4, 141.4, 141.3, 131.0, 130.8, 130.7, 130.5, 130.4, 130.3,
130.2, 130.2, 130.1, 130.1, 130.0, 129.8, 129.5, 127.3, 127.3, 127.2,
123.9, 123.8, 123.4, 121.0, 120.9, 120.8, 119.7, 119.3, 118.8, 118.5,
118.1, 117.9, 117.3, 117.2, 116.9, 116.6, 111.8, 111.6, 111.2, 110.8,
67.0, 67.0, 66.3, 47.8, 47.0, 46.7, 46.4, 45.9, 44.6, 44.1, 36.7, 36.0, 35.6,
35.1, 35.0, 34.9, 34.5, 33.8, 33.4, 33.1, 32.8, 32.7, 32.4, 32.2, 26.0, 25.8,
25.4, 25.0; HRMS (ESI) for C31H35N3O5, MH+ 530.2649; found
530.2650 (Δ 0.2 ppm).
3-(2-(2-((2-(1H-Imidazol-4-yl)ethyl)amino)-2-oxoethoxy)phenyl)-
N-(2-(2-(3-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropa-
namide, 7f. To a stirred solution of the intermediate carboxylic acid
from the synthesis of 7e (1.29 g, 2.40 mmol), HATU (1.00 g, 2.64
mmol), and DIPEA (2.10 mL, 12.0 mmol) in CH2Cl2 (15 mL) was
added histamine dihydrochloride (530 mg, 2.88 mmol), and the
reaction was stirred at rt for 2 h. The reaction mixture was poured into
sat. aq NaHCO3 (100 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a thick colorless oil
(1.12 g, 74% over two steps) as a mixture of rotamers, δH (600 MHz,
CDCl3) 7.96−7.90 (m, 0.2H), 7.85 (t, J 5.6, 0.2H), 7.80 (t, J 5.4,
0.5H), 7.52−7.44 (m, 2H), 7.43−7.36 (m, 1H), 7.14−7.04 (m, 3H),
6.93 (t, J 7.8, 1H), 6.90−6.82 (m, 1H), 6.72−6.66 (m, 2H), 4.42 (s,
0.5H), 4.41 (s, 1.1H), 4.39 (s, 0.4H), 3.59−3.52 (m, 2.5H), 3.52−3.42
(m, 4H), 3.34−3.23 (m, 1.5H), 2.96 (s, 2H), 2.94−2.86 (m, 3H), 2.84
(s, 2H), 2.82−2.75 (m, 3H), 2.57 (t, J 7.2, 0.4H), 2.53 (t, J 7.3, 0.4H),
2.47 (t, J 7.2, 1.2H); δC (151 MHz, CDCl3) 173.2, 173.0, 170.8, 170.7,
170.5, 168.2, 168.1, 154.9, 154.9, 154.8, 137.9, 137.7, 137.5, 137.3,
137.0, 136.5, 135.9, 135.8, 134.8, 134.7, 130.2, 130.2, 130.1, 130.1,
129.3, 129.2, 129.1, 128.4, 128.2, 128.1, 127.8, 127.7, 127.7, 121.6,
121.6, 121.5, 111.2, 111.2, 111.1, 94.4, 94.4, 94.4, 67.1, 67.1, 67.0, 47.2,
47.0, 46.9, 46.8, 45.1, 44.7, 39.9, 39.9, 39.3, 38.8, 38.8, 36.9, 36.7, 36.1,
35.8, 33.9, 33.9, 33.6, 33.5, 33.1, 26.6, 26.5, 26.3, 26.1, 25.7; HRMS
(ESI) for C28H34IN5O4, MH+ 632.1728; found 632.1728 (Δ 0.0 ppm).
3-(2-(2-((2-(1H-Imidazol-2-yl)ethyl)amino)-2-oxoethoxy)phenyl)-
N-(2-(2-(3-iodophenyl)-N-methylacetamido)ethyl)-N-methylpropa-
namide, 7g. To a stirred solution of the intermediate carboxylic acid
from the synthesis of 7e (323 mg, 0.600 mmol), HATU (274 mg,
0.720 mmol), and DIPEA (419 μL, 2.40 mmol) in CH2Cl2 (5 mL) was
added 2-(1H-imidazol-2-yl)ethanamine dihydrochloride (155 mg,
0.840 mmol), and the reaction was stirred at rt for 2 h. The reaction
mixture was poured into sat. aq NaHCO3 (50 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), the solvent was removed in vacuo, and the resulting residue
was purified by column chromatography to give the title compound as
a thick colorless oil (318 mg, 84% over two steps) as a mixture of
rotamers, δH (600 MHz, CDCl3) 8.32−7.98 (m, 2H), 7.59−7.48 (m,
2H), 7.22−7.09 (m, 3H), 7.02−6.95 (m, 1H), 6.95−6.84 (m, 3H),
6.77−6.67 (m, 1H), 4.46 (s, 0.5H), 4.44 (s, 1.1H), 4.43 (s, 0.4H),
3.78−3.67 (m, 2H), 3.61−3.37 (m, 5H), 3.37−3.27 (m, 1H), 3.08−
2.85 (m, 10H), 2.66−2.52 (m, 2H); δC (151 MHz, CDCl3) 173.7,
173.6, 173.6, 171.0, 170.9, 170.7, 169.0, 168.9, 168.8, 155.1, 155.0,
154.9, 146.1, 145.9, 145.8, 138.1, 137.9, 137.7, 137.5, 137.1, 136.6,
136.2, 136.0, 136.0, 130.6, 130.4, 130.4, 130.3, 130.3, 129.4, 129.3,
129.3, 128.6, 128.4, 128.2, 128.0, 128.0, 121.9, 121.8, 121.8, 121.5,
111.4, 111.4, 111.3, 94.6, 94.6, 94.5, 67.2, 67.1, 67.0, 47.5, 47.3, 47.2,
47.1, 45.2, 44.9, 40.2, 40.1, 39.6, 37.6, 37.5, 37.4, 37.2, 37.1, 36.3, 36.1,
34.2, 34.1, 34.1, 33.9, 33.4, 28.5, 28.4, 28.3, 26.5, 26.1, 26.1; HRMS
(ESI) for C28H34IN5O4, MH+ 632.1728; found 632.1726 (Δ 0.3 ppm).
Macrocycle 9b. Macrocyclization carried out as per the general
procedure using 7b. Obtained as a colorless oil (4.4 mg, 42%) as a
mixture of at least four rotamers, δH (600 MHz, DMSO-d6) 8.16 (t, J
6.0, 0.3H), 7.99 (t, J 5.8, 0.2H), 7.94 (t, J 5.8, 0.2H), 7.86 (t, J 5.9,
0.3H), 7.37−7.27 (m, 1H), 7.26−7.04 (m, 4H), 7.03−6.77 (m, 5H),
6.76−6.63 (m, 1H), 6.62−6.32 (m, 1H), 4.40 (s, 0.6H), 4.38 (s,
0.65H), 4.37 (s, 0.45H), 4.25 (s, 0.3H), 3.67−3.63 (m, 1H), 3.63−
3.56 (m, 1H), 3.56−3.34 (m, 4.5H), 3.33−3.20 (m, 2.5H), 3.01−2.88
Macrocycle 9c. Macrocyclization carried out as per the general
procedure using 7c. Obtained as a colorless oil (6.7 mg, 67%) as a
mixture of at least four rotamers, δH (600 MHz, DMSO-d6) 9.32−9.18
(m, 0.6H), 8.77 (s, 0.4H), 8.66 (t, J 5.9, 0.4H), 8.34−8.24 (m, 0.6H),
7.61−7.39 (m, 4H), 7.32−7.10 (m, 2H), 6.98 (td, J 7.8, 2.1, 0.3H),
6.93−6.75 (m, 2H), 6.60 (td, J 7.5, 2.9, 0.2H), 6.36 (td, J 7.4, 2.5,
0.5H), 4.58 (s, 0.8H), 4.57 (s, 0.5H), 4.52 (s, 0.4H), 4.50 (s, 0.3H),
3.71−3.50 (m, 3H), 3.49−3.36 (m, 3H), 3.35 (t, J 6.3, 0.5H), 3.29 (t, J
5.9, 0.5H), 3.22 (t, J 6.3, 0.5H), 3.01−2.76 (m, 9H), 2.68−2.60 (m,
2.5H), 2.53 (t, J 7.5, 1H); δC (151 MHz, DMSO-d6) 173.0, 172.8,
172.2, 172.1, 170.0, 169.1, 169.1, 168.5, 168.4, 168.3, 158.4, 158.2,
158.1, 155.4, 155.0, 155.0, 154.8, 136.0, 135.8, 135.7, 135.2, 135.1,
135.1, 135.0, 134.4, 132.8, 132.3, 132.3, 132.2, 132.1, 132.0, 132.0,
130.8, 130.5, 130.3, 130.3, 130.2, 130.1, 129.9, 129.8, 129.7, 129.4,
129.2, 128.2, 128.2, 128.2, 128.1, 127.5, 127.4, 127.3, 127.0, 127.0,
126.9, 126.8, 126.6, 121.0, 120.8, 120.6, 120.5, 120.5, 120.2, 120.1,
119.3, 117.4, 115.4, 113.5, 111.7, 111.4, 111.0, 110.4, 66.8, 66.8, 66.3,
65.8, 48.8, 47.0, 46.7, 46.4, 45.9, 45.3, 44.7, 44.2, 40.1, 38.3, 38.1, 37.3,
36.3, 35.8, 35.4, 35.1, 34.8, 34.3, 33.9, 33.8, 33.5, 33.2, 33.1, 32.9, 32.6,
32.4, 26.5, 25.6, 25.3, 24.7, 24.5, 24.5, 24.3, 24.2; HRMS (ESI) for
C28H33N5O4, MH+ 504.2605; found 504.2605 (Δ 0.0 ppm).
Macrocycle 9d. Macrocyclization carried out as per the general
procedure using 7d. Obtained as a colorless oil (9.0 mg, 89%) as a
mixture of at least three rotamers, δH (500 MHz, CDCl3) 7.99−7.79
(m, 1H), 7.56−7.47 (m, 2H), 7.39−7.35 (m, 1H), 7.29−7.12 (m, 2H),
7.10−7.01 (m, 1H), 7.00−6.65 (m, 3H), 6.54−6.40 (m, 1H), 4.53−
4.46 (m, 2H), 3.88−3.56 (m, 5.7H), 3.43−3.38 (m, 0.3H), 3.21−3.17
(m, 2.6H), 3.06 (s, 0.4H), 3.01 (s, 1H), 2.91 (s, 2H), 2.83 (br s, 1H),
2.74−2.64 (m, 2H), 2.59−2.38 (m, 3H), 1.84−1.74 (m, 1H); δC (151
MHz, CDCl3) 172.2, 171.8, 171.4, 171.3, 170.8, 168.2, 168.1, 167.8,
155.3, 154.6, 154.5, 135.9, 135.8, 134.5, 134.5, 133.6, 130.5, 130.1,
129.9, 129.3, 129.1, 128.8, 128.6, 127.7, 127.6, 127.4, 127.4, 121.8,
121.7, 121.3, 120.8, 120.7, 111.3, 111.1, 111.0, 67.9, 67.4, 67.4, 49.8,
47.5, 45.8, 45.5, 43.3, 43.0, 41.0, 40.8, 40.6, 40.3, 37.4, 37.4, 37.3, 37.1,
36.4, 35.6, 34.2, 32.7, 32.5, 32.4, 31.4, 29.7, 29.5, 28.6, 28.3, 23.4, 23.0,
22.8; HRMS (ESI) for C28H33N5O4, MH+ 504.2605; found 504.2601
(Δ 0.8 ppm).
Macrocycle 9e. Macrocyclization carried out as per the general
procedure using 7e. Carried out on 80 μmol scale in 2 mL of DMSO
(40 mM reaction concentration). Obtained as a thick colorless oil (37
mg, 87%) as a mixture of at least four rotamers, δH (600 MHz, DMSO-
d6) 8.12 (t, J 5.6, 0.4H), 7.99 (t, J 5.7, 0.1H), 7.93 (t, J 5.4, 0.35H),
7.80 (t, J 5.6, 0.15H), 7.38−6.79 (m, 10H), 6.79−6.43 (m, 2H), 4.47
(br s, 0.1H), 4.42 (s, 1H), 4.39 (s, 0.7H), 4.36 (s, 0.2H), 3.63−3.54
(m, 2H), 3.47−3.37 (m, 5H), 3.34−3.19 (m, 3H), 2.93−2.90 (s, 2H),
2.86−2.80 (m, 2H), 2.78−2.66 (m, 5H), 2.38 (t, J 7.2, 0.5H), 2.18 (t, J
7.5, 0.5H);δC (151 MHz, CDCl3) 173.5, 173.1, 173.0, 171.5, 171.3,
171.2, 168.4, 168.1, 158.1, 157.6, 157.4, 157.4, 156.9, 156.2, 155.3,
155.0, 155.0, 141.4, 141.1, 136.9, 136.8, 135.4, 130.6, 130.5, 130.3,
130.3, 130.3, 130.2, 130.1, 130.0, 129.6, 129.4, 129.3, 128.1, 128.1,
127.8, 124.7, 124.5, 124.1, 123.8, 123.5, 123.2, 121.8, 121.7, 121.6,
121.2, 119.3, 119.3, 118.7, 118.4, 118.3, 118.2, 117.2, 116.9, 116.6,
111.3, 111.2, 111.1, 67.1, 67.0, 66.9, 48.5, 47.9, 47.8, 47.7, 44.7, 43.9,
41.3, 41.0, 40.9, 40.3, 40.1, 40.1, 38.1, 37.4, 36.0, 35.7, 35.4, 35.1, 33.9,
33.7, 33.7, 33.5, 33.0, 29.8, 27.6, 25.7, 25.6; HRMS (ESI) for
C31H35N3O5, MH+ 530.2649; found 530.2645 (Δ 0.8 ppm).
Macrocycle 9f. Macrocyclization carried out as per the general
procedure using 7f. Obtained as a colorless oil (7.2 mg, 71%) as a
11086
dx.doi.org/10.1021/jo302089f | J. Org. Chem. 2012, 77, 11079−11090

The Journal of Organic Chemistry
Article
mixture of at least three rotamers, δH (500 MHz, CDCl3) 8.65−8.58
(m, 1H), 8.24 (t, J 6.4, 0.15H), 7.97 (t, J 6.1, 0.3H), 7.89 (t, J 6.1,
0.55H), 7.68 (d, J 7.8, 0.3H), 7.59−7.40 (m, 2.7H), 7.34−7.28 (m,
0.5H), 7.25−7.18 (m, 2.1H), 7.16−7.10 (m, 1.4H), 6.97 (t, J 7.4,
0.55H), 6.90 (t, J 7.4, 0.3H), 6.86 (t, J 7.3, 0.15H), 6.72 (d, J 8.3,
0.5H), 6.69 (d, J 8.3, 0.3H), 6.52 (d, J 8.1, 0.2H), 4.54 (s, 0.6H), 4.52
(s, 0.4H), 4.37 (s, 1H), 3.78 (s, 1.6H), 3.65 (s, 0.4H), 3.61−3.55 (m,
1H), 3.54−3.39 (m, 4H), 3.36 (q, J 6.2, 1H), 3.19 (s, 0.5H), 3.10 (s,
0.9H), 3.06 (s, 1.6H), 2.96 (s, 0.7H), 2.94−2.87 (m, 2.8H), 2.83−2.76
(m, 2.1H), 2.76 (s, 1.4H), 2.65 (t, J 7.6, 0.6H), 2.59 (t, J 7.3, 0.4H),
2.45 (t, J 6.8, 1H); δC (151 MHz, CDCl3) 174.8,174.3, 172.8, 170.8,
170.5, 169.1, 168.5, 162.0, 155.2, 154.8, 138.5, 138.0, 137.2, 135.9,
135.7, 135.4, 133.9, 133.5, 133.3, 133.0, 132.5, 132.1, 131.5, 131.1,
130.9, 130.5, 130.4, 129.8, 129.1, 128.9, 128.3, 128.1, 127.6, 127.4,
127.2, 124.4, 124.3, 124.1, 122.3, 121.9, 121.8, 119.2, 119.0, 118.5,
117.3, 115.3, 111.3, 111.2, 111.0, 67.3, 67.1, 66.5, 47.7, 47.5, 47.4, 46.5,
46.1, 45.9, 40.0, 39.8, 39.7, 37.7, 37.5, 36.7, 36.5, 36.3, 35.9, 35.5, 34.6,
34.4, 34.3, 34.2, 33.6, 26.9, 26.6, 26.0, 24.5, 24.1, 23.8; HRMS (ESI)
for C28H33N5O4, MH+ 504.2605; found 504.2605 (Δ 0.0 ppm).
Macrocycle 9g. Macrocyclization carried out as per the general
procedure using 7g. Obtained as a colorless oil (5.4 mg, 54%) as a
mixture of at least three rotamers, δH (600 MHz, DMSO-d6) 8.35−
8.03 (m, 1H), 7.92−7.78 (m, 2H), 7.59−7.50 (m, 1H), 7.47−7.30 (m,
2.5H), 7.27−7.12 (m, 2.5H), 6.90−6.78 (m, 2H), 4.43 (s, 1H), 4.41 (s,
0.3H), 4.38 (s, 0.7H), 3.57−3.37 (m, 5H), 3.19 (t, J 6.0, 0.5H), 3.11−
3.02 (m, 3H), 3.00 (s, 0.5H), 2.94−2.75 (m, 4H), 2.72−2.51 (m, 4H),
2.25−2.17 (m, 1H); δC (151 MHz, DMSO-d6) 173.0, 173.0, 172.2,
172.1, 170.1, 169.9, 169.6, 169.6, 168.4, 168.3, 168.2, 167.8, 158.5,
158.2, 158.0, 157.8, 155.4, 155.2, 155.1, 154.9, 145.7, 145.6, 145.0,
138.2, 138.0, 137.7, 137.6, 134.4, 134.4, 134.3, 134.2, 131.7, 131.1,
130.8, 130.3, 130.2, 130.0, 130.0, 130.0, 129.7, 129.7, 129.6, 129.6,
129.4, 129.4, 129.0, 127.7, 127.6, 127.5, 127.4, 127.1, 126.9, 126.7,
126.3, 124.3, 124.1, 124.0, 123.8, 123.7, 123.5, 123.3, 123.3, 121.2,
121.1, 121.0, 120.9, 119.3, 119.2, 119.2, 117.4, 115.5, 113.5, 111.7,
111.6, 111.3, 111.1, 66.7, 66.5, 66.4, 66.3, 48.0, 47.1, 46.7, 46.1, 45.7,
44.3, 43.7, 38.5, 38.2, 36.5, 36.4, 36.4, 36.2, 36.2, 35.9, 35.1, 34.2, 33.8,
33.5, 33.3, 32.3, 32.1, 26.8, 26.7, 26.0, 25.6, 25.3, 25.2, 25.1; HRMS
(ESI) for C28H 33N5O4, MH+ 504.2605; found 504.2607 (Δ 0.4 ppm).
(1S,2R)-1-((3-Iodobenzyl)oxy)-N-methyl-1-phenylpropan-2-
amine, 11. To a solution of ephedrine (826 mg, 5.00 mmol) in THF
(20 mL) at 0 °C was slowly added KHMDS (0.5 M in PhMe, 11.0 mL,
5.50 mmol). After 15 min, 1-(bromomethyl)-3-iodobenzene (1.63 g,
5.50 mmol) was added and the reaction stirred at rt for 2 h before
being poured into sat. aq NaHCO3 (50 mL). This was extracted with
CH2Cl2 (3 × 50 mL) and the organic layers dried (Na2SO4). The
solvent was removed in vacuo and the resulting residue purified by
column chromatography to give the title compound as a pale brown oil
(1.19 g, 63%), δH (600 MHz, CDCl3) 7.67 (s, 1H), 7.60 (d, J 7.8, 1H),
7.40−7.36 (m, 2H), 7.35−7.29 (m, 3H), 7.26 (d, J 7.4, 1H), 7.06 (t, J
7.7, 1H), 4.44 (d, J 12.1, 1H), 4.32 (d, J 5.4, 1H), 4.24−4.20 (d, J 12.1,
1H), 2.81−2.76 (m, 1H), 2.34 (s, 3H), 1.28 (br s, 1H), 1.09 (d, J 6.4,
3H); δC (151 MHz, CDCl3) 141.8, 140.4, 137.4, 137.4, 130.9, 129.4,
128.7, 128.3, 127.7, 95.2, 84.9, 70.7, 60.9, 34.8, 16.0; HRMS (ESI) for
C17H20INO, MH+ 382.0662; found 382.0670 (Δ 2.1 ppm).
1H), 7.04 (t, J 7.8, 1H), 6.74−6.70 (m, 2H), 6.69−6.65 (m, 1H), 5.37
(d, J 9.0, 0.7H), 5.22 (d, J 8.3, 0.3H), 4.78−4.62 (m, 1H), 4.40−4.32
(m, 1H), 4.32−4.28 (m, 0.7H), 4.25 (d, J 6.6, 0.3H), 4.12−4.07 (m,
1H), 3.86−3.78 (m, 0.3H), 2.96−2.91 (m, 0.3H), 2.83−2.73 (m, 2H),
2.73−2.69 (m, 1H), 2.57−2.52 (m, 0.7H), 2.51−2.44 (m, 0.7H), 1.45
(s, 3H), 1.36 (s, 6H), 1.20 (d, J 6.8, 2.1H), 0.73 (d, J 6.5, 0.9H); δC
(151 MHz, CDCl3) 172.3, 172.1, 157.1, 156.8, 155.4, 154.8, 143.5,
140.7, 140.4, 139.0, 138.1, 138.0, 137.7, 136.7, 136.7, 136.6, 136.5,
130.2, 130.2, 129.9, 129.7, 129.1, 128.9, 128.5, 128.4, 128.2, 128.0,
127.1, 126.9, 126.9, 125.5, 121.0, 120.9, 120.3, 116.6, 116.5, 114.3,
114.2, 109.4, 105.0, 94.4, 94.4, 84.2, 83.8, 80.0, 79.7, 70.1, 70.0, 57.9,
51.5, 41.1, 39.3, 29.0, 28.5, 28.4, 13.6, 12.1; HRMS (ESI) for
C31H37IN2O5, MH+ 645.1820; found 645.1809 (Δ 1.7 ppm).
tert-Butyl ((S)-3-(1H-Imidazol-4-yl)-1-(((1S,2R)-1-((3-iodobenzyl)-
oxy)-1-phenylpropan-2-yl)(methyl)amino)-1-oxopropan-2-yl)-
carbamate, 12b. To 11 (381 mg, 1.00 mmol) was added a premixed
solution of N-Boc-His-OH (511 mg, 2.00 mmol), HATU (760 mg,
2.00 mmol), and DIPEA (699 μL, 4.00 mmol) in CH2Cl2 (5 mL), and
the resulting solution was stirred at rt for 16 h. The reaction mixture
was washed with sat. aq citric acid (50 mL) and sat. aq NaHCO3 (50
mL) and dried (Na2SO4). The solvent was removed in vacuo and the
resulting residue purified by column chromatography to give the title
compound as a thick colorless oil (371 mg, 60%) as a mixture of
rotamers, δH (500 MHz, CDCl3) 8.44 (br s, 1H), 7.64−7.56 (m, 2H),
7.51 (s, 1H), 7.37−7.27 (m, 5H), 7.21 (d, J 7.5, 1H), 7.05 (t, J 7.7,
1H), 6.77 (s, 0.3H), 6.67 (s, 0.7H), 5.47 (d, J 8.2, 0.7H), 5.47 (d, J 8.2,
0.3H), 4.90−4.74 (m, 0.7H), 4.74−4.68 (m, 0.3H), 4.61−4.49 (m,
0.7H), 4.38−4.32 (m, 2H), 4.19−4.11 (m, 1H), 4.01−3.94 (m, 0.3H),
2.94−2.85 (m, 0.6H), 2.80 (s, 2.1H), 2.77 (s, 0.9H), 2.43−2.31 (m,
1.4H), 1.42 (s, 2H), 1.36 (s, 7H), 1.29 (d, J 6.8, 2.4H), 1.10 (d, J 6.3,
0.6H); δC (151 MHz, CDCl3) 172.6, 156.3, 155.9, 141.3, 141.1, 139.6,
138.9, 137.6, 137.5, 137.4, 137.4, 135.9, 135.7, 131.0, 131.0, 129.7,
129.3, 129.3, 129.2, 128.2, 127.7, 127.7, 95.2, 95.2, 84.6, 84.6, 80.8,
80.5, 70.9, 70.7, 58.2, 51.1, 32.5, 31.9, 30.6, 29.9, 29.2, 29.1, 15.0, 14.2;
HRMS (ESI) for C28H35IN4O4, MH+ 619.1776; found 619.1777 (Δ
0.2 ppm).
(S)-tert-Butyl 3-(((3-Iodobenzyl)oxy)methyl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate, 14. To a solution of (S)-(1,2,3,4-tetrahy-
droisoquinolin-3-yl)methanol (750 mg, 4.60 mmol) in CH2Cl2 (10
mL) was added Boc2O (2.39 g, 4.60 mmol), and the reaction mixture
was stirred at rt for 3 h before being washed with 0.5 M HCl (100 mL)
and brine (50 mL), dried (Na2SO4) and the solvent removed in vacuo.
To a solution of this crude Boc-protected amine in DMF (20 mL) at 0
°C was added NaH (95%, 165 mg, 6.90 mmol). The reaction mixture
was stirred for 15 min before addition of 1-(bromomethyl)-3-
iodobenzene (2.05 g, 6.90 mmol). The solution was allowed to
warm to rt and stirred for 3 h before being partitioned between EtOAc
(50 mL) and sat. aq NaHCO3 (50 mL). The organic layer was washed
with H2O/brine (1:1, 5 × 30 mL), the combined aqueous layers were
extracted with CH2Cl2 (30 mL), the combined organic layers were
dried (Na2SO4), and the solvent removed in vacuo. The resulting
residue was purified by column chromatography to give the title
compound as a colorless oil (1.10 g, 50% over two steps) as a mixture
of rotamers, δH (600 MHz, CDCl3) 7.67−7.55 (m, 2H), 7.24−7.17
(m, 3H), 7.17−7.06 (m, 2H), 7.04 (s, 3H), 4.79 (s, 0.5H), 4.71 (d, J
16.8, 1H), 4.54 (s, 0.5H), 4.47−4.37 (m, 2H), 4.28 (d, J 16.8, 1H),
3.45 (s, 1H), 3.22 (m, 1H), 3.12−3.00 (m, 1H), 2.97−2.84 (m, 1H),
1.55−1.47 (m, 9H); δC (151 MHz, CDCl3) 155.3, 140.9, 140.8, 136.7,
136.6, 136.3, 133.4, 133.1, 133.0, 130.1, 129.2, 128.9, 126.9, 126.6,
126.4, 126.1, 94.4, 80.1, 72.1, 71.9, 69.9, 69.6, 49.8, 48.1, 43.8, 43.4,
30.4, 30.1, 28.6; HRMS (ESI) for C22H26INO3, MH+ 480.1030; found
480.1030 (Δ 0.0 ppm).
tert-Butyl ((S)-3-(3-Hydroxyphenyl)-1-(((1S,2R)-1-((3-iodobenzyl)-
oxy)-1-phenylpropan-2-yl)(methyl)amino)-1-oxopropan-2-yl)-
carbamate, 12a. To 11 (189 mg, 0.490 mmol) were added a
premixed solution of N-Boc-m-Tyr-OH (138 mg, 0.490 mmol),
PyBOP (255 mg, 0.490 mmol), and DIPEA (171 μL, 0.981 mmol) in
CH2Cl2 (4 mL) and the resulting solution stirred at rt for 16 h.
Further N-Boc-m-Tyr-OH (69 mg, 0.245 mmol), PyBOP (127 mg,
0.245 mmol), and DIPEA (85 μL, 0.490 mmol) were added in DMF
(2 mL), and the solution was heated to 80 °C for 1 h before being
cooled to rt and washed with sat. aq citric acid (50 mL) and sat. aq
NaHCO3 (50 mL) and dried (Na2SO4). The solvent was removed in
vacuo and the resulting residue purified by column chromatography to
give the title compound as a thick colorless oil (271 mg, 86%) as a
mixture of rotamers, δH (600 MHz, CDCl3) 8.07 (d, J 8.3, 0.5H), 7.88
(d, J 8.4, 0.5H), 7.61−7.54 (m, 3H), 7.48−7.43 (m, 0.5H), 7.35−7.29
(m, 3.5H), 7.26−7.24 (m, 1H), 7.21−7.17 (m, 1H), 7.13−7.07 (m,
tert-Butyl ((S)-3-(3-Hydroxyphenyl)-1-((S)-3-(((3-iodobenzyl)oxy)-
methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-1-oxopropan-2-yl)-
carbamate, 15a. To 14 (192 mg, 0.400 mmol) was added 4 M HCl/
dioxane (5 mL), and the solution was stirred for 1 h. The solvent was
removed in vacuo to give the crude amine. To this amine was added a
premixed solution of N-Boc-m-Tyr-OH (225 mg, 0.800 mmol),
HATU (304 mg, 0.800 mmol), and DIPEA (279 μL, 1.60 mmol) in
CH2Cl2 (5 mL), and the resulting solution was stirred at rt for 16 h.
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The reaction mixture was washed with sat. aq citric acid (20 mL) and
sat. aq NaHCO3 (50 mL). Each aqueous layer was extracted with
CH2Cl2 (30 mL), the combined organic layers were dried (Na2SO4),
the solvent was removed in vacuo, and the resulting residue was
purified by column chromatography to give the title compound as a
very pale brown oil (182 mg, 71% over two steps) as a mixture of
rotamers, δH (600 MHz, CDCl3) 7.60 (s, 0.5H), 7.57 (dd, J 13.6, 7.9,
1H), 7.49 (s, 0.5H), 7.21−7.06 (m, 5H), 7.05−6.94 (m, 2.5H), 6.83
(dd, J 15.5, 7.5, 1H), 6.78 (s, 1H), 6.75−6.69 (m, 1.5H), 5.59 (d, J 8.5,
0.6H), 5.51 (d, J 8.7, 0.4H), 5.12−5.06 (m, 0.6H), 4.97−4.92 (m,
0.4H), 4.74 (d, J 17.6, 0.6H), 4.62 (d, J 15.7, 0.4H), 4.42 (s, 0.8H),
4.30−4.25 (m, 1.2H), 4.08−4.00 (m, 0.6H), 3.72 (d, J 15.6, 0.4H),
3.39 (dd, J 9.5, 6.5, 0.4H), 3.20 (t, J 8.6, 0.6H), 3.08−2.83 (m, 4H),
2.82 (s, 1H), 2.51 (d, J 15.9, 0.5H), 2.15 (dd, J 6.0, 4.9, 1H), 1.42−
1.35 (m, 9H); δC (151 MHz, CDCl3) 173.2, 172.6, 157.5, 157.3, 156.0,
155.9, 141.2, 141.2, 138.7, 138.7, 137.6, 137.4, 137.4, 137.1, 133.5,
132.5, 132.4, 132.3, 131.0, 131.0, 130.7, 130.6, 129.6, 129.3, 128.1,
127.8, 127.7, 127.4, 127.4, 127.3, 127.2, 126.8, 122.2, 122.1, 117.6,
117.2, 115.2, 115.1, 95.2, 95.1, 80.9, 80.7, 72.9, 72.6, 70.1, 69.7, 52.8,
52.8, 52.4, 48.4, 45.7, 43.8, 41.8, 41.1, 39.6, 30.6, 30.5, 29.2; HRMS
(ESI) for C31H35IN2O5, MH+ 643.1663; found 643.1660 (Δ 0.5 ppm).
tert-Butyl ((S)-3-(1H-Imidazol-4-yl)-1-((S)-3-(((3-iodobenzyl)oxy)-
methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-1-oxopropan-2-yl)-
carbamate, 15b. To 14 (192 mg, 0.400 mmol) was added 4 M HCl/
dioxane (5 mL), and the solution was stirred for 1 h. The solvent was
removed in vacuo to give the crude amine. To this amine was added a
premixed solution of N-Boc-His-OH (204 mg, 0.800 mmol), HATU
(304 mg, 0.800 mmol), and DIPEA (279 μL, 1.60 mmol) in CH2Cl2
(5 mL), and the resulting solution was stirred at rt for 16 h. The
reaction mixture was washed with sat. aq citric acid (20 mL) and sat.
aq NaHCO3 (50 mL). Each aqueous layer was extracted with CH2Cl2
(30 mL). The combined organic layers were dried (Na2SO4), the
solvent was removed in vacuo, and the resulting residue was purified
by column chromatography to give the title compound as a very pale
brown oil (146 mg, 59% over two steps) as a mixture of rotamers, δH
(600 MHz, CDCl3) 9.18 (br s, 0.5H), 7.60−7.47 (m, 2.5H), 7.37 (s,
0.5H), 7.20−6.95 (m, 6H), 6.83 (s, 0.5H), 6.78 (s, 0.5H), 5.77 (d, J
7.9, 0.5H), 5.62 (d, J 8.0, 0.5H), 5.23−5.15 (m, 0.5H), 5.14−5.04 (m,
0.5H), 5.01−4.93 (m, 0.5H), 4.89 (d, J 17.7, 0.5H), 4.80 (d, J 15.9,
0.5H), 4.43−4.27 (m, 3H), 4.19 (d, J 17.8, 0.5H), 3.75−3.57 (m,
0.5H), 3.48−3.41 (m, 0.5H), 3.37−3.27 (m, 1H), 3.27−3.18 (m,
0.5H), 3.14−2.94 (m, 2.5H), 2.81−2.64 (m, 1H), 1.41−1.35 (m, 9H);
δC (151 MHz, CDCl3) 172.3, 171.3, 155.3, 140.4, 139.9, 137.0, 136.7,
136.6, 136.2, 135.2, 135.1, 132.5, 131.7, 131.5, 131.4, 130.3, 130.2,
129.1, 128.8, 127.4, 127.0, 126.7, 126.6, 126.4, 126.1, 94.5, 94.3, 80.0,
79.8, 72.2, 72.1, 71.2, 69.3, 53.7, 53.7, 52.3, 51.2, 50.9, 47.5, 44.4, 42.7,
42.0, 38.7, 31.9, 30.2, 30.0, 29.7, 29.7, 29.5, 28.4, 28.4, 18.1, 12.3;
HRMS (ESI) for C28H33IN4O4, MH+ 617.1619; found 617.1615 (Δ
0.6 ppm).
(S)-3-(((3-Iodobenzyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline,
16. To a solution of (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol
(920 mg, 5.64 mmol) in THF (20 mL) at 0 °C was slowly added
KHMDS (0.5 M in PhMe, 12.4 mL, 6.20 mmol). After 45 min, 1-
(bromomethyl)-3-iodobenzene (2.18 g, 7.33 mmol) was added and
the reaction stirred at rt for 2 h before being poured into 1 M HCl (50
mL). This was washed with CH2Cl2 (50 mL), and the aqueous layer
basified with NaHCO3 and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a colorless oil (1.45 g,
68%), δH (500 MHz, CDCl3) 7.82 (s, 1H), 7.72 (d, J 7.9, 1H), 7.41 (d,
J 7.6, 1H), 7.25−7.20 (m, 2H), 7.20−7.15 (m, 2H), 7.15−7.10 (m,
1H), 4.59 (s, 2H), 4.19 (d, J 15.6, 1H), 4.13 (d, J 15.7, 1H), 3.70 (dd, J
9.2, 3.8, 1H), 3.58 (dd, J 8.9, 7.7, 1H), 3.27 (ddd, J 14.4, 7.6, 3.8, 1H),
2.78 (dd, J 16.0, 4.2, 1H), 2.73 (dd, J 16.0, 10.6, 1H), 2.27, (br s, 1H);
δC (126 MHz, CDCl3) 141.1, 137.2, 137.0, 136.0, 134.5, 130.7, 129.7,
127.3, 126.7, 126.6, 126.2, 95.0, 74.9, 72.9, 53.7, 48.6, 32.0; HRMS
(ESI) for C17H18INO, MH+ 380.0506; found 380.0510 (Δ 1.1 ppm).
(S)-tert-Butyl (3-(3-(((3-Iodobenzyl)oxy)methyl)-3,4-dihydroiso-
quinolin-2(1H)-yl)propyl)carbamate, 17. A solution of 16 (379 mg,
1.00 mmol), 3-((N-Boc)amino)propyl methanesulfonate (507 mg,
2.00 mmol), NaI (300 mg, 2.00 mmol), and DIPEA (697 μL, 4.00
mmol) in DMF (10 mL) was stirred at 65 °C for 14 h. After cooling,
the reaction mixture was partitioned between EtOAc (50 mL) and sat.
aq NaHCO3 (50 mL). The organic layer was washed with H2O/brine
(1:1, 2 × 30 mL), the combined aqueous layers were extracted with
EtOAc (3 × 30 mL), the combined organic layers were dried
(Na2SO4), and the solvent was removed in vacuo. The resulting
residue was purified by column chromatography to give the title
compound as a pale yellow oil (412 mg, 77%), δH (500 MHz, CDCl3)
7.75 (s, 1H), 7.69 (d, J 7.9, 1H), 7.38−7.34 (m, 1H), 7.27−7.20 (m,
2H), 7.20−7.09 (m, 3H), 5.41 (br s, 1H), 4.55, 4.54 (ABq, JAB 12.4,
1H), 3.98−3.84 (m, 2H), 3.71 (dd, J 9.4, 6.0, 1H), 3.57−3.49 (m, 1H),
3.39−3.33 (m, 1H), 3.33−3.23 (m, 2H), 3.04 (dd, J 16.5, 5.0, 1H),
2.90−2.80 (m, 3H), 1.89−1.78 (m, 2H), 1.49 (s, 9H); δC (151 MHz,
CDCl3) 156.3, 140.7, 136.8, 136.6, 133.5, 130.3, 129.0, 126.8, 126.7,
126.1, 94.5, 79.0, 72.5, 70.1, 57.0, 51.5, 39.4, 29.8, 29.6, 28.6, 27.0;
HRMS (ESI) for C25H33IN2O3, MH+ 537.1609; found 537.1607 (Δ
0.4 ppm).
(S)-2-(3-Hydroxyphenyl)-N-(3-(3-(((3-iodobenzyl)oxy)methyl)-3,4-
dihydroisoquinolin-2(1H)-yl)propyl)acetamide, 18a. A 4 M HCl/
dioxane (1.60 mL, 6.40 mmol) solution was added to 17 (429 mg,
0.800 mmol), and the resulting solution was stirred at rt for 1.5 h. The
solvent was removed in vacuo to give the crude amine. To a portion of
this amine (175 mg, 0.400 mmol) was added a premixed solution of 2-
(3-hydroxyphenyl)acetic acid (122 mg, 0.800 mmol), HATU (304 mg,
0.800 mmol), and DIPEA (279 μL, 1.60 mmol) in CH2Cl2/DMF (1:1,
4 mL), and the resulting solution was stirred at rt for 16 h. The
reaction mixture was added to excess LiOH·H2O in MeOH/H2O (10
mL) and stirred at rt for 1 h. The reaction mixture was partitioned
between EtOAc (30 mL) and 2 M HCl (20 mL), and the organic layer
was washed with sat. aq NaHCO3 (50 mL). Each aqueous layer was
extracted with EtOAc (30 mL), the combined organic layers were
dried (Na2SO4), the solvent was removed in vacuo, and the resulting
residue was purified by column chromatography to give the title
compound as a pale yellow oil (199 mg, 87% over two steps), δH (600
MHz, CDCl3) 7.64 (s, 1H), 7.60 (d, J 7.9, 1H), 7.23 (d, J 7.5, 2H),
7.20−7.14 (m, 2H), 7.09 (d, J 6.6, 1H), 7.07−7.00 (m, 3H), 6.73 (s,
1H), 6.69 (dd, J 8.1, 2.0, 1H), 6.56 (d, J 7.4, 1H), 4.40 (s, 2H), 3.80 (d,
J 15.9, 1H), 3.64 (d, J 15.9, 1H), 3.53 (dd, J 10.0, 6.5, 1H), 3.42 (dd, J
10.0, 5.6, 1H), 3.37−3.29 (m, 3H), 3.30−3.23 (m, 2H), 2.90 (dd, J
16.8, 5.4, 1H), 2.77−2.67 (m, 3H), 1.70 (p, J 6.0, 2H); δC (151 MHz,
CDCl3) 172.4, 157.1, 140.3, 137.0, 136.6, 136.5, 132.9, 132.3, 130.4,
130.1, 129.1, 127.2, 127.0, 126.5, 120.9, 116.3, 114.8, 94.6, 72.5, 69.9,
57.3, 51.4, 50.8, 43.7, 39.0, 28.6, 25.4; HRMS (ESI) for C28H31IN2O3,
MH+ 571.1452; found 571.1454 (Δ 0.4 ppm).
(S)-2-(3-Hydroxyphenyl)-N-(3-(3-(((3-iodobenzyl)oxy)methyl)-3,4-
dihydroisoquinolin-2(1H)-yl)propyl)acetamide, 18b. A 4 M HCl/
dioxane (1.60 mL, 6.40 mmol) was added to 17 (429 mg, 0.800
mmol), and the resulting solution was stirred at rt for 1 h. The solvent
was removed in vacuo to give the crude amine. To a portion of this
amine (175 mg, 0.400 mmol) was added a premixed solution of 2-
(1H-imidazol-4-yl)acetic acid (101 mg, 0.800 mmol), HATU (304 mg,
0.800 mmol), and DIPEA (279 μL, 1.60 mmol) in CH2Cl2/DMF (1:1,
4 mL), and the resulting solution was stirred at rt for 16 h. The
reaction mixture was partitioned between EtOAc (30 mL) and 1 M
HCl (20 mL), and the organic layer was washed with sat. aq NaHCO3
(50 mL). Each aqueous layer was extracted with EtOAc (30 mL), the
combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the resulting residue was purified by column
chromatography to give the title compound as a pale yellow oil (330
mg, 76% over two steps), δH (500 MHz, CDCl3); 7.63 (s, 1H), 7.60−
7.53 (m, 2H), 7.43 (s, 1H), 7.22 (d, J 7.6, 1H), 7.17−7.10 (m, 3H),
7.10−7.06 (m, 1H), 7.04 (t, J 7.7, 1H), 7.02−6.98 (m, 1H), 6.70 (s,
1H), 4.42, 4.39 (ABq, JAB 12.4, 1H), 3.76 (d, J 15.8, 1H), 3.68 (d, J
15.8, 1H), 3.58 (dd, J 9.6, 6.0, 1H), 3.40 (s, 2H), 3.38 (d, J 6.3, 1H),
3.32 (p, J 6.4, 2H), 3.18 (p, J 5.8, 1H), 2.88 (dd, J 16.4, 5.2, 1H),
2.75−2.65 (m, 3H), 1.70 (p, J 6.4, 2H); δC (126 MHz, CDCl3) 170.6,
140.6, 136.8, 136.5, 135.3, 134.0, 133.7, 131.9, 130.3, 129.1, 126.8,
126.7, 126.6, 126.0, 117.5, 94.5, 72.4, 70.3, 57.0, 51.7, 51.3, 39.0, 35.0,
11088
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29.7, 26.4; HRMS (ESI) for C25H29IN4O2, MH+ 545.1408; found
545.1403 (Δ 0.9 ppm).
1.61 (m, 1H); δC (151 MHz, DMSO-d6) 169.8, 141.5, 139.1, 137.0,
134.9, 134.8, 133.3, 130.0, 128.9, 126.3, 126.2, 125.5, 124.0, 117.7,
117.0, 114.7, 70.1, 68.4, 57.5, 53.9, 49.4, 40.1, 37.4, 37.2, 30.9, 27.9;
HRMS (ESI) for C25H28N4O2, MH+ 417.2285; found 417.2286 (Δ 0.2
ppm).
Macrocycle 19a. Macrocyclization carried out as per the general
procedure using 12a. Obtained as a pale brown oil (6.2 mg, 74%), δH
(600 MHz, CDCl3) 7.38 (t, J 7.8, 1H), 7.36−7.32 (m, 2H), 7.29−7.24
(m, 3H), 7.17 (t, J 7.8, 1H), 7.15 (d, J 7.7, 1H), 7.09−7.05 (m, 2H),
6.72 (m, 1H), 6.68 (m, 1H), 6.45 (d, J 7.4, 1H), 4.67 (d, J 13.6, 1H),
4.48 (s, 1H), 4.45−4.39 (m, 1H), 4.19 (d, J 13.5, 1H), 3.08−2.90 (m,
2H), 2.62−2.60 (m, 4H), 2.08 (br s, 2H),1.06 (d, J 7.0, 3H); δC (151
MHz, CDCl3) 158.9, 157.5, 140.4, 139.4, 138.3, 130.6, 129.9, 128.4,
127.7, 127.5, 125.0, 123.0, 119.4, 119.2, 118.9, 115.9, 81.2, 68.5, 55.3,
41.1, 30.9, 9.5; HRMS (ESI) for C26H28N2O3, MH+ 417.2173; found
417.2173 (Δ 0.0 ppm).
ASSOCIATED CONTENT
* Supporting Information
■
S
Selected iterative array screening results, HPLC traces, and
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kjames@scripps.edu.
Macrocycle 19b. Macrocyclization carried out as per the general
procedure using 12b. Obtained as a pale brown oil (5.8 mg, 73%) as a
mixture of rotamers, δH (600 MHz, CDCl3) 7.67 (s, 1H), 7.40−7.32
(m, 6H), 7.28 (s, 1H), 6.97−6.91 (m, 2H), 6.90 (s, 1H), 5.00 (s, 1H),
4.85 (d, J 16.6, 1H), 4.76−4.69 (m, 1H), 4.35 (d, J 16.7, 0.9H), 4.28
(d, J 16.1, 0.1H), 4.07 (br s, 0.9H), 3.95 (br s, 0.1H), 3.25−3.16 (m,
1H), 3.04−2.95 (m, 1H), 2.90 (s, 0.3H), 2.80 (s, 2.7H), 1.85 (brs,
1H), 1.06 (d, J 7.7, 2.7H), 1.01 (d, J 7.5, 0.3H); δC (151 MHz, CDCl3)
177.9, 140.8, 140.2, 139.9, 138.9, 138.3, 129.8, 128.6, 127.8, 127.0,
126.7, 126.3, 124.7, 124.3, 120.1, 83.2, 66.3, 55.8, 54.3, 35.7, 32.1, 9.6;
HRMS (ESI) for C23H26N4O2, MH+ 391.2128; found 391.2131 (Δ 0.8
ppm).
Macrocycle 20a. Macrocyclization carried out as per the general
procedure using 15a. Obtained as a pale brown oil (8.4 mg, 82%), δH
(500 MHz, CDCl3) 7.43−7.36 (m, 1H), 7.32−7.27 (m, 1H), 7.23−
7.13 (m, 4H), 7.08−7.01 (m, 3H), 6.85 (d, J 7.0, 1H), 6.80 (s, 2H),
4.79 (br s, 1H), 4.64−4.53 (m, 2H), 4.43−4.06 (m, 3H), 3.66−3.57
(m, 1H), 3.26−3.19 (m, 1H), 3.15 (br s, 1H), 3.11−3.02 (m, 1H),
3.02−2.81 (m, 2H), 1.75 (br s, 2H); δC (151 MHz, CDCl3) 173.9,
158.1, 156.3, 139.7, 139.3, 134.7, 133.6, 130.3, 130.0, 128.7, 127.6,
126.4, 125.4, 125.2, 121.7, 120.4, 119.1, 118.1, 115.2, 71.7, 70.0, 53.0,
48.9, 45.6, 42.2, 30.0; HRMS (ESI) for C26H26N2O3, MH+ 415.2016;
found 415.2013 (Δ 0.7 ppm).
Macrocycle 20b. Macrocyclization carried out as per the general
procedure using 15b. Obtained as a pale brown oil (6.9 mg, 89%) as a
mixture of rotamers, δH (600 MHz, CDCl3) 7.65 (s, 1H), 7.43−7.38
(m, 1H), 7.38−7.34 (m, 1H), 7.20−7.15 (m, 1H), 7.15−7.10 (m, 2H),
7.08−7.01 (m, 2H), 6.93 (s, 2H), 4.93−4.82 (m, 1H), 4.73 (d, J 16.8,
0.1H), 4.67 (d, J 15.2, 0.9H), 4.57 (d, J 16.2, 1H), 4.45 (d, J 16.3,
0.9H), 4.40 (d, J 16.0, 0.1H), 4.20 (br s, 1H), 4.13−4.06 (m, 1H), 3.88
(d, J 10.2, 1H), 3.54 (d, J 10.1, 1H), 3.26−3.14 (m, 2H), 3.09−2.93
(m, 2H), 2.16 (s, 1H); δC (151 MHz, CDCl3) 176.2, 141.0, 140.2,
139.8, 138.5, 135.1, 129.9, 128.5, 127.6, 126.5, 125.6, 124.7, 124.5,
124.2, 119.6, 72.3, 68.7, 53.9, 51.3, 46.6, 34.4, 30.8, 29.8; HRMS (ESI)
for C23H24N4O2, MH+ 389.1972; found 389.1974 (Δ 0.5 ppm).
Macrocycle 21a. Macrocyclization carried out as per the general
procedure using 18a. Obtained as a pale brown oil (7.5 mg, 84%), δH
(600 MHz, CDCl3) 7.37 (t, J 7.8, 1H), 7.31 (t, J 7.8, 1H), 7.17−7.12
(m, 2H), 7.10 (dd, J = 8.2, 2.4, 1H), 7.08−7.02 (m, 2H), 7.01−6.94
(m, 3H), 6.81 (s, 1H), 6.57 (br s, 1H), 6.51 (s, 1H), 4.46 (s, 2H), 3.77
(d, J 15.1, 1H), 3.57−3.48 (m, 2H), 3.47 (s, 1H), 3.44 (m, 2H), 3.24
(dd, J 9.4, 6.6, 1H), 3.16−3.06 (m, 2H), 3.01−2.94 (m, 1H), 2.84 (dd,
J 16.2, 5.6, 1H), 2.74−2.55 (m, 3H), 1.78−1.67 (m, 1H), 1.67−1.56
(m, 1H); δC (151 MHz, DMSO-d6) 169.8, 157.4, 156.5, 140.8, 138.8,
134.8, 133.7, 130.1, 128.6, 126.2, 126.1, 125.5, 125.1, 122.4, 118.4,
118.3, 118.1, 115.9, 71.6, 68.9, 56.8, 51.6, 50.8, 42.8, 36.7, 30.8, 27.4;
HRMS (ESI) for C28H30N2O3, MH+ 443.2329; found 443.2349 (Δ 4.5
ppm).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Bill Farrell and Loanne Chung (Pfizer) for SFC
purification and Pfizer Worldwide R&D for funding.
■
REFERENCES
■
(1) Reviews: (a) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011,
54, 1961−2004. (b) Driggers, E. M.; Hale, S. P.; Jinbo Lee, J.; Terrett,
N. K. Nat. Rev. Drug Discovery 2008, 7, 608−624.
(2) In a recent literature survey of over 900 macrocyclization
reactions carried out from 2009 to 2011, we found that the four most
popular reactions (CuAAC, RCM, lactamization, and lactonization)
comprised 72% of all macrocyclizations; see Collins, J. C.; James, K.
Med. Chem. Commun. 2012, 3, 1489−1495.
(3) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95−
102. (b) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301−312.
(c) Curzons, A. D.; Constable, D. J. C.; Mortimer, D. N.;
Cunningham, V. L. Green Chem. 2001, 3, 1−6. (d) Constable, D. J.
C.; Curzons, A. D.; Cunningham, V. L. Green Chem. 2002, 4, 521−
527.
(4) (a) Bogdan, A. R.; James, K. Chem.Eur. J. 2010, 16, 14506−
14512. (b) Chouhan, G.; James, K. Org. Lett. 2011, 13, 2754−2757.
(5) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400−5449. (b) Beletskya, I.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337−2364. (c) Monnier, F.; Taillefer, F. Angew. Chem.,
Int. Ed. 2008, 47, 3096−3099. (d) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727−7729. (e) Ma, D.;
Cai, Q. Org. Lett. 2003, 5, 3799−3802. (f) Liu, L.; Frohn, M.; Xi, N.;
Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem. 2005, 70,
10135−10138. (g) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 284−286. (h) Maiti, D.;
Buchwald, S. L. J. Org. Chem. 2010, 75, 1791−1794.
(6) (a) Boger, D. L.; Yohannes, D. J. Org. Chem. 1991, 56, 1763−
1767. (b) Boger, D. L.; Nomoto, Y.; Teegarden, B. R. J. Org. Chem.
1993, 58, 1425−1433.
(7) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T.-Y.; Natarajan, S.; Chu, X.-J.; Brase, S.; Rubsam, F. Chem.Eur. J.
1999, 5, 2584.
(8) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276−
1279.
(9) Examples from the synthesis of glycopeptide antibiotics:
(a) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.;
Zhu, J. J. Org. Chem. 1994, 59, 5535−5542. (b) Zhu, J.; Beugelmans,
R.; Bourdet, S.; Chastanet, J.; Roussi, G. J. Org. Chem. 1995, 60, 6389−
6396. (c) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700−2704.
(d) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.;
Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 10004−10011.
Example of high-concentration macrocyclization: (e) Gonzalez, G. I.;
Zhu, J. J. Org. Chem. 1999, 64, 914−924. Reviews: (f) Zhu, J. Synlett
Macrocycle 21b. Macrocyclization carried out as per the general
procedure using 18b. Obtained as a colorless oil (6.7 mg, 80%), δH
(600 MHz, DMSO-d6) 8.22 (s, 1H), 8.11 (t, J 5.3, 1H), 7.59 (dd, J 7.8,
2.2, 1H), 7.48−7.43 (m, 2H), 7.37 (s, 1H), 7.17−7.13 (m, 2H), 7.12−
7.09 (m, 2H), 7.04 (d, J 7.3, 1H), 4.79 (d, J 15.3, 1H), 4.45 (d, J 15.3,
1H), 3.76 (d, J 15.7, 1H), 3.71 (dd, J 9.0, 4.4, 1H), 3.56 (d, J 15.7,
1H), 3.44−3.39 (m, 1H), 3.32−3.24 (m, 3H), 3.24−3.17 (m, 1H),
3.17−3.10 (m, 1H), 3.03 (dd, J 16.1, 5.8, 1H), 2.86−2.78 (m, 1H),
2.73 (d, J 16.2, 1H), 2.72−2.66 (m, 1H), 1.82−1.73 (m, 1H), 1.69−
11089
dx.doi.org/10.1021/jo302089f | J. Org. Chem. 2012, 77, 11079−11090

The Journal of Organic Chemistry
Article
1997, 2, 133−144. (g) Pitsinos, E. N.; Vidali, V. P.; Couladouros, E. A.
Eur. J. Org. Chem. 2011, 1207−1222.
(10) (a) Toumi, M.; Couty, F.; Gwilherm, E. J. Org. Chem. 2007, 72,
9003−9009. (b) Uchiro, H.; Kato, R.; Arai, Y.; Hasegawa, M.;
Kobayakawa, Y. Org. Lett. 2011, 13, 6268−6271.
(11) Selected examples: (a) Schafmeister, C. E.; Po, J.; Verdine, G.
L. J. Am. Chem. Soc. 2000, 122, 589. (b) Shepherd, N. E.; Hoang, H.
N.; Abbenante, G.; Fairlie, D. J. J. Am. Chem. Soc. 2005, 127, 2974.
(c) Meyer, F.; Collins, J. C.; Borin, B.; Bradow, J.; Liras, S.; Limberakis,
C.; Mathiowetz, A.; Philippe, L.; Price, D.; Song, K.; James, K. J. Org.
Chem. 2012, 77, 3099−3114.
(12) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043−5051.
(13) For a recent example, see Ueda, S.; Su, M.; Buchwald, S. L. J.
Am. Chem. Soc. 2012, 134, 700−706.
(14) (a) West, C. W; Rich, D. H. Org. Lett. 1999, 1, 1819−1922.
(b) Londregan, A. T.; Farley, K. A.; Limberakis, C.; Mullins, P. B.;
Piotrowski, D. W. Org. Lett. 2012, 14, 2890−2893.
(15) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007,
72, 6190−6199.
(16) Calculated using ChemBioDraw 12, CambridgeSoft.
11090
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