Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based alpha-helix mimetics

Article abstract of DOI:10.1007/s00706-015-1599-0

The modular synthesis of teraryl-based alpha-helix mimetics can be accomplished by sequential Suzuki-couplings of arylboronic acid building blocks with 4-iodophenyltriflate core-fragments. We report about new synthetic accesses to core fragments featuring

Full text of DOI:10.1007/s00706-015-1599-0

Monatsh Chem
DOI 10.1007/s00706-015-1599-0
ORIGINAL PAPER
Improved and scalable synthesis of building blocks
for the modular synthesis of teraryl-based alpha-helix mimetics
Melanie Trobe1 Rolf Breinbauer1
•
Received: 14 October 2015 / Accepted: 27 October 2015
Ó Springer-Verlag Wien 2015
Abstract The modular synthesis of teraryl-based alpha-
helix mimetics can be accomplished by sequential Suzuki-
couplings of arylboronic acid building blocks with
4-iodophenyltriflate core-fragments. We report about new
synthetic accesses to core fragments featuring the side
chains of Leu, Lys, Cys, Glu, Gln, Ser, and Thr starting
from simple phenol precursors.
Introduction
Over the last two decades, protein–protein interactions
(PPIs) have been recognized as one of the main factors in
controlling protein function in living cells. The number of
different PPIs in human cells is estimated to be *65,000
[1–3], with a-helices playing a role in *60 % of the
interaction sites [4, 5]. For the study and pharmaceutical
intervention of PPIs, tool compounds are needed, which
allow the control of the particular interaction of a specific
target protein [6]. As short peptides have limitations as
drugs due to their conformational instability, their poor
proteolytic stability, and bioavailability, strategies have
been pursued to overcome these limitations [7] by using
stapled peptides [8], b-peptides [9, 10], b-hairpins [11], or
a-helix mimetics [12–30] addressing the so called ‘‘hot
spots’’ at the protein interaction area responsible for a
significant amount of the overall binding energy. Hamilton
and co-workers have presented a quite general approach of
mimicking a-helices by suitable positioning of amino acid
side chains around a terarylic scaffold [31], which has been
successfully applied for the design of inhibitors of several
PPIs. As a-helix-based PPIs are such a frequent phe-
nomenon, which provides numerous opportunities for
controlling cellular events by small molecules, we have
started a program to produce a comprehensive library of
teraryl-based a-helix mimetics, taking advantage of a
highly modular and convergent strategy developed in our
laboratory, in which a central iodophenyltriflate-core
exhibiting leaving groups with differentiated reactivity is
decorated with pyridine boronic acids using Pd-catalyzed
cross-coupling reactions (Fig. 1) [32–34]. With a set of
2 9 18 building blocks, any representative of the 5670
permutations of a-helix mimetics featuring the proteino-
genic amino acids should be accessible within a day.
Graphical abstract
Keywords Baeyer–Villiger oxidation Á
Claisen rearrangement Á Iodination Á Peptidomimetics Á
Protein–protein interactions Á Wittig reaction
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1599-0) contains supplementary
material, which is available to authorized users.
& Rolf Breinbauer
breinbauer@tugraz.at
1
Institute of Organic Chemistry, Graz University of
Technology, Graz, Austria
123

M. Trobe, R. Breinbauer
Fig. 1 Peptidomimetic design
and synthetic strategy
While we are currently in the final steps of providing a
comprehensive set of building blocks, we have also rec-
ognized that several of our originally published synthetic
routes toward 4-iodophenyltriflates are not of sufficient
efficiency regarding steps and overall yields to provide the
desired building blocks in the gram quantities required for
library synthesis. In this manuscript, we report about sec-
ond generation syntheses of essential 4-iodophenyltriflate
core fragments, which are much shorter and higher yielding
than the previously reported routes and present routes to
building blocks featuring the amino acid side chain func-
tionality in a form more suitable for long-term storage and
subsequent teraryl assembly [32].
butyl side chain (Scheme 1, previous route) [32]. In addi-
tion to its poor atom economy, this route was also
hampered by low yields for the formation of a sensitive
destabilized ylide product B. Especially upon scale-up
hydrolysis of phosphonium-salt B was observed resulting
from adventitious water introduced by hygroscopic KOtBu.
In order to overcome these limitations, we envisioned to
use a Claisen-rearrangement of phenyl-methallyl ether 1 to
introduce the side chain in the ortho-position (Scheme 1,
new route) [43]. The use of N,N-dimethylformamide
(DMF) as a solvent resulted in only 75 % conversion due
to thermic decomposition of DMF. When the thermally
more robust N,N-dimethyl acetamide (DMAc) was used as
solvent, the reaction reached 95 % conversion. Product 2
could be isolated by a simple extractive workup, in which
through a base/acid-switch unconsumed starting material
and DMAc were removed. Although isomerization of the
double bond to the thermodynamically more stable, higher
substituted double bond C was observed to some extent,
this had no further consequences as in the next step the
double bonds of the mixture of 2 and C were hydrogenated
with an H-cube flow reactor with Raney-Ni (RaNi) as
catalyst leading to the same saturated product 3. With this
reaction sequence, the desired Leu-core unit fragment 5
Results and discussion
The synthesis of 4-iodophenyltriflates can be accomplished
by iodination of 2-substituted phenols, followed by trifla-
tion of the HO-group. For most amino acid side chains, the
corresponding 2-substituted phenols have to be prepared
from commercially available starting materials [32].
In our original publication for synthesizing, the Leu core
fragment a Wittig reaction was used to introduce the iso-
Scheme 1
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
could be isolated in 71 % overall yield (4 steps) using
inexpensive reagents, which compares well to our initial
route (32 % overall yield over 5 linear steps including
synthesis of reagent B).
The second key step was the reduction of the double
bond in 21. As catalytic hydrogenation with Pd would have
resulted in the dehalogenation of the iodide, we chose
diimide reduction instead, which is distinguished by
functional group tolerance toward halogens. Among the
possible precursors for diimide generation, we selected
potassium azadicarboxylate (PADA) 20 [39]. No degra-
dation-products of the precursor remain in the reaction and
unreacted PADA 20 can be removed simply by filtration as
this salt is insoluble in the organic solvent used for the
reaction [40]. Gln-core unit fragment 22 was isolated in
46 % overall yield (4 steps).
A common precursor for several core unit fragments
containing polar amino acid side chains in its protected
form is compound 8, which results from iodination and
triflation of salicylic aldehyde 6. Under the initial reaction
conditions full conversion could be detected only after
8 days including several additions of ICl. The central role
of 8 in our synthetic scheme made it necessary to optimize
its synthesis. By changing the solvent from AcOH to
dichloromethane (DCM), the iodination occurred faster and
91 % conversion was detected after 48 h (Table 1) [37].
Intermediate 8 could be further converted in an
improved procedure to the protected Cys-core fragment 11
(Scheme 2) [32]. Similarly, we gained access to the Ser-
core unit 12 and Thr-core unit 14, which we now have
protected as tert-butyldiphenylsilyl (TBDPS) ethers to
avoid decomposition of the triflate under storage
conditions.
The Glu-core unit fragment 18 was accessible starting
from dihydrocoumarine (15) (Scheme 3). After iodination
[41], the lactone was converted to the corresponding
methyl ester 17 via transesterification followed by triflation
under standard conditions. The Glu-core unit fragment 18
was isolated in its ester protected form in 78 % overall
yield (3 steps).
With the two routes presented in Scheme 3, we have
now described for the first time the core-fragments for Gln
22 and in its protected form for Glu 18.
In our previous publication, the Glu- and Gln-core unit
fragments were planned to be accessed from a common
nitrile-containing precursor F (Scheme 3) [32]. In the last
step, nitrile F should be converted either to the carboxylic
acid ester 18 or to the amide 22. Despite considerable
effort, we have not been able to perform these transfor-
mations with F and only observed decomposition of the
starting material. In this paper, we present a solution to this
problem by introducing the individual side chains earlier in
the synthesis (Scheme 3). Gln-core unit 22 could be
accessed by transforming the iodinated and triflated alde-
hyde 8 to amide 21 via Wittig reaction. The orchestration
of the sequence of events turned out to be crucial, as any
attempt to introduce the triflate on a substrate with already
installed primary amide side chain was accompanied by
dehydration leading to a nitrile [38].
An important amino acid side chain representing hot
spot interactions at PPI interfaces is Lys. The original route
for the synthesis of the Lys-building block 30 started from
dihydrocoumarine (15), which was reduced to the corre-
sponding lactol. Taking advantage of the equilibrium
between lactol and open chain aldehyde allowed a Henry-
reaction leading to G, whose hydroxy-function was
removed by NaBH3CN in MeOH under reflux temperature
(Scheme 4). After iodination and introduction of the triflate
group, in the final step, the nitro-group was reduced to the
corresponding amine I with Fe in 2 M aqueous HCl at RT
(quantitative conversion) [32]. This long linear reaction
sequence and a low overall yield of 9 % made an improved
reaction route necessary, in which we also planned to
present the Lys-building block in its Boc-protected form to
Table 1 Different methods for iodination of 7 [35–37]
Reagent
Solvent
T/°C
Time
Conversiona/%
ICl
AcOH
AcOH
AcOH
THF
22
3 days
8 days
8 days
48 h
45
94b
ICl
22
ICl
40
96
I2, ICl
I2, ICl
ICl
22
32 %
THF
40
24 h
39
91 (68 % yield)c
DCM
0–22
48 h
a
Conversion according to GC–MS
b
c
Additional 0.5 eq ICl were added
Isolated yield in parenthesis
123

M. Trobe, R. Breinbauer
Scheme 2
Scheme 3
facilitate teraryl assembly via Suzuki-coupling and
purification.
oxidation, followed by introduction of the iodide and
transesterification to methyl ester 26. Triflation and
reduction of the ester with DIBAL-H to the corresponding
alcohol resulted in 28, which was then converted to amine
Encouraged by the positive outcome of the successful
transesterification sequence in the synthesis of the Glu-
building block 18, a similar strategy was used for the
synthesis of the Lys-building block 30 starting from the
7-membered lactone 24 (Scheme 4). Lactone 24 was syn-
thesized from a-tetralone (23) via Baeyer–Villiger
29 via
a
Mitsunobu–Staudinger sequence using
diphenylphosphorylazide (DPPA) as an azide donor [42].
In the final step, the amine was Boc-protected to yield Lys-
core unit 30 in good 26 % overall yield (7 steps).
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
Scheme 4
In order to exemplify an application of these new set of
building blocks, we have used Lys-core unit fragment 30
for the assembly of the Leu-Lys-Leu teraryl 32 via Suzuki
coupling [33]. Both leaving groups were coupled in one
step since the pyridine building block 31 representing Leu
should be attached twice. After simple acidic cleavage of
the Boc-protecting group, the desired teraryl 32 was iso-
lated in 53 % overall yield (Scheme 5).
Conclusion
In summary, we have reported second generation syntheses
of 4-iodophenyltriflates serving as building blocks for the
modular assembly of teraryl-based alpha-helix mimetics,
which are scalable to gram quantities. Importantly, we have
presented Ser-, Thr-, Gln-, Glu-, and Lys-building blocks in
versions which are more suitable for long-term storage and
Scheme 5
123

M. Trobe, R. Breinbauer
offer advantages during teraryl assembly. At the moment,
we use these routes to establish a comprehensive collection
of building blocks allowing the synthesis of all permuta-
tions of teraryls containing all proteinogenic side chains
relevant for protein–protein interactions.
0.25 lm) at a constant helium flow. The GC was coupled
to a Waters GCT Premier Micromass. For Direct Inlet (DI-
EI) only the Waters GCT Premier Micromass unit was
used. Melting points were determined on a ‘‘Mel-Temp’’
melting-point apparatus (Electrothermal). Chemicals were
purchased from Sigma-Aldrich, Fisher Scientific, Merck,
or Alfa Aesar. All reagents were used without further
purification unless otherwise noted. Tetrahydrofuran (THF)
and Et2O were distilled, to remove the stabilizer 2,6-di-
tert-butyl-4-methyl-phenol (BHT) and stored over KOH to
avoid peroxide formation. DCM was dried over CaH2 and
distilled under an argon atmosphere before use. When
referring to ‘‘oil pump vacuum,’’ the applied pressure is
usually in the region of 10-2-10-3 mbar by using a rotary
vane pump. For reactions requiring cryogenic temperatures
over several hours, a cryostat was used.
Experimental
NMR spectra were recorded on a Bruker Avance III
300 MHz FT NMR spectrometer (300.36 MHz (1H),
75.53 MHz (13C)). Chemical shifts d [ppm] are referenced
to residual protonated solvent signals as internal standard
DMSO-d6: d = 2.50 ppm (1H), 39.52 ppm (13C) and
CDCl3: d = 7.26 ppm (1H), 77.16 ppm (13C). GC–MS
measurements were performed on an Agilent Technologies
7890A (G3440A) GC system equipped with an Agilent
Technologies J&W GC-column HP-5MS [(5 %-phenyl)-
methylpolysiloxane; length 30 m; inner diameter
0.250 mm; film 0.25 lm] at a constant helium flow rate
(He 5.0; Air Liquide; ‘‘Alphagaz’’; 1.085 cm3/min; aver-
age velocity 41.6 cm/s) in split mode 1/175 [inlet
temperature 250 °C; injection volume 2.0 mm3; sample
concentration *0.5 mg/cm3 in ethyl acetate (EtOAc),
methanol (MeOH), dichloromethane (DCM), or diethyl
ether (Et2O)]. The GC was coupled to a 5975C inert mass
sensitive detector with triple-axis detector (MSD, EI,
70 eV; transfer line 300 °C; MS source 240 °C; MS quad
180 °C), with a solvent delay of 3.50 min. One general
gradient MT_50_S (initial temperature 50 °C, 1.0 min;
linear ramp 40 °C/min; final temperature 300 °C; final time
2-(2-Methylallyl)phenol (2)
A 15 cm3 ‘‘Ace pressure tubeÒ, back seal’’ (Aldrich
Z181064) with a ‘‘Duro-Silicone O-ring’’ was charged
with 4.0 cm3 methallyl phenyl ether (1, 26.0 mmol) and
15 cm3 N,N-dimethylacetamide. The flask was sealed, and
the mixture was stirred at 190 °C for 5 days. When
conversion stopped (*95 % according to GC–MS), the
reaction was cooled to RT and 100 cm3 n-pentane were
added. The organic phase was extracted with 2 M NaOH
(4 9 100 cm3). The aqueous phase was acidified with
70 cm3 conc. HCl (pH 2–3) and extracted with Et2O
(4 9 100 cm3). The combined organic layers were washed
with saturated NaCl-solution (1 9 200 cm3), dried over
Na2SO4 and filtered. The solvent was removed in vacuo,
and 3.58 g (93 %) 2 was isolated as brown oil. The crude
product was used in the next step without further purifi-
cation. NMR data were found to agree with those described
in Ref. [43].
5.0 min;
post
run
1.0 min;
detecting
range
50.0–550.0 amu) was applied. Analytical thin layer chro-
matography (TLC) was performed on Merck silica gel
60-F254, and spots were visualized by UV-light (k = 254
and/or 366 nm), or by treatment with cerium ammonium
molybdate solution (CAM) (CAM 2.0 g Ce(IV)SO4, 50 g
(NH4)2MoO4, 50 cm3 concentrated H2SO4 in 400 cm3
water) or ninhydrin (1.5 g ninhydrin, 100 cm3 n-butanol,
3.0 cm3 acetic acid). Flash column chromatography was
2-Isobutylphenol (3)
Hydrogenation was performed utilizing an H-CubeTM at a
pressure of 60 bar at 60 °C with a Raney-Ni powder
cartridge (THS 01112). A solution of 3.50 g 2 (23.6 mmol)
in 250 cm3 MeOH (*0.1 M) was used in continuous flow
mode of 1.0 cm3/min. The hydrogenation was run in a loop
until full conversion was detected by GC–MS (24 h). After
removing the solvent under reduced pressure, 3.51 g
(99 %) 3 was isolated as colorless oil. An analytical
sample was purified by distillation. B.p. 45 °C/0.3 mbar
(Ref. [44]; 45-50 °C/1.3 mbar); NMR data were found to
agree with those described in Ref. [32].
˚
performed using silica gel 60 A (35-70 lm particle size)
from Acros Organics at an air pressure of *1.5 bar. If the
crude product was not well soluble in the eluent, the
sample was dissolved in a proper solvent (DCM or EtOAc),
and 2.5 fold amount of CeliteÒ 545 (particle size 0.02-
0.1 mm) was added, followed by removing the solvent
using a rotary evaporator and drying in vacuo. High Res-
olution Mass Spectrometry (HRMS) was performed on an
Agilent Technologies 7890A (G3440A) GC system
equipped with an Agilent Technologies J&W GC-column
DB-5MS (length 30 m; inner diameter 0.250 mm; film
4-Iodo-2-isobutylphenol (4)
The synthesis was performed in analogy to Ref. [45]. In a
one-neck round-bottom flask, 1.50 g 3 (10.0 mmol) was
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
dissolved in 14 cm3 acetic acid (*0.75 M) and 1.62 g
iodine monochloride (ICl, 10.0 mmol) was added at RT.
After 24 h, 648 mg ICl (3.99 mmol) was additionally
added and quantitative conversion was detected after
further 24 h. The reaction mixture was quenched by the
addition of 100 cm3 0.5 M NaHCO3 solution and the
aqueous phase was extracted with DCM (3 9 50 cm3). The
combined organic layers were washed with 1 M Na2S2O3
solution (3 9 100 cm3), followed by saturated NaCl solu-
tion (1 9 100 cm3). After drying over MgSO4 and
filtering, the solvent was removed under reduced pressure.
The crude product was purified via flash column chro-
matography (cyclohexane/EtOAc = 12/1, Rf = 0.20, UV
and CAM) to yield 2.35 g (85 %) 4 as pale orange powder.
M.p. 62–63 °C (Ref. [32]; 62–63 °C); NMR data were
found to agree with those described in Ref. [32].
Methyl 3-(2-hydroxy-5-iodophenyl)propanoate (17,
C10H11IO3)
In a flame dried and argon flushed Schlenk flask 2.00 g
6-iodochroman-2-one (16, 7.30 mmol, 1.00 eq) was sus-
pended in 140 cm3 MeOH. H2SO4 (1.95 cm3) was added to
this colorless suspension. The suspension dissolved and the
colorless solution was warmed to 55 °C and stirred
overnight at this temperature. After full conversion (24 h)
was detected by GC–MS, the brown solution was neutral-
ized by addition of 50 cm3 saturated NaHCO3 solution and
the solvent was removed in vacuo. The brown residue was
diluted with 100 cm3 H2O, and extracted with DCM
(3 9 100 cm3). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo. The crude
product was purified via flash column chromatography
(cyclohexane/EtOAc = 5/1, Rf = 0.18, UV and CAM) and
1.70 g (76 %) 17 were isolated as a light yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.39–7.35 (m, 3H, HAr,
OH), 6.65–6.62 (m, 1H, HAr), 3.66 (s, 3H, CH3), 2.82 (t,
J = 5.9 Hz, 2H, CH2), 2.69 (t, J = 5.9 Hz, 2H, CH2) ppm;
13C NMR (76 MHz, CDCl3, APT): d = 176.2 (Cq, CO),
154.6 (Cq, CAr), 139.2 (CAr), 137.0 (CAr), 130.4 (Cq, CAr),
119.9 (CAr), 82.9 (Cq, CAr), 52.6 (CH3), 35.0 (CH2), 24.5
(CH2) ppm; GC-MS (EI, 70 eV; MT_50_S): tR = 6.92 -
min; m/z (%) = 306 (17) [M?], 274 (100) [M?-OCH3],
246 (64) [M?-C2H3O2], 91 (0.31) [M?-C4H7O2I]; TLC:
Rf = 0.18 (cyclohexane/EtOAc = 5/1, UV and CAM);
HRMS (EI): m/z calcd for [M?] 305.9753, found 305.9766.
4-Iodo-2-isobutylphenyl trifluoromethanesulfonate (5)
The synthesis was performed in analogy to Ref. [32]. In a
one-neck round-bottom flask, 2.20 g 4 (7.97 mmol) was
dissolved in 9 cm3 pyridine (*1 M). After cooling the
solution to 0 °C 2.10 cm3 trifluoromethanesulfonic anhy-
dride (Tf2O, 8.76 mmol) was added dropwise. After stirring
5 min at 0 °C, the solution was allowed to warm to RT and
stirred until quantitative conversion was detected by TLC
(2 h). Et2O (60 cm3) was added and the organic phase was
washed with H2O (3 9 30 cm3), followed by extracting the
combined aqueous layers with Et2O (2 9 30 cm3). The
combined organic layers were washed with 1 M HCl
(2 9 60 cm3) and saturated NaCl solution (1 9 60 cm3),
dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified via flash column chromatography
(cyclohexane, Rf = 0.50, UV and CAM) and 2.97 g (91 %)
5 was isolated as pale yellow oil. NMR data were found to
agree with those described in Ref. [32].
Methyl 3-[5-iodo-2-[[(trifluoromethyl)sul-
fonyl]oxy]phenyl]propanoate (18, C11H10F3IO5S)
In a one-neck round-bottom flask 800 mg 17 (2.61 mmol)
was dissolved in 2.5 cm3 pyridine (*1 M). After cooling
the solution to 0 °C 700 mm3 Tf2O (2.90 mmol) was
carefully added. After stirring 5 min at 0 °C, the solution
was allowed to warm to RT and stirred until quantitative
conversion was detected by TLC (2 h). Et2O (100 cm3)
was added and the organic phase was washed with H2O
(3 9 50 cm3), followed by extracting the combined aque-
ous layers with Et2O (2 9 50 cm3). The combined organic
layers were washed with 1 M HCl (2 9 50 cm3) and
saturated NaCl solution (1 9 50 cm3), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified via flash column chromatography (cyclohexane/
EtOAc = 20/1, Rf = 0.26, UV and CAM) and 966 mg
(84 %) 18 was isolated as colorless oil. 1H NMR
(300 MHz, CDCl3): d = 7.69 (d, J = 2.1 Hz, 1H, HAr),
7.62 (dd, J = 8.7 Hz, 2.1 Hz, 1H, HAr), 7.01 (d,
J = 8.7 Hz, 1H, HAr), 3.69 (s, 3H, CH3), 2.99 (t,
J = 7.7 Hz, 2H, CH2), 2.65 (t, J = 7.7 Hz, 2H, CH2) ppm;
13C NMR (76 MHz, CDCl3, APT): d = 172.3 (Cq, CAr),
147.9 (Cq, CAr), 140.3 (CAr), 137.6 (CAr), 135.8 (Cq, CAr),
123.4 (CAr), 118.7 (q, J = 318 Hz, CF3), 93.4 (Cq, CN),
6-Iodochroman-2-one (16)
The synthesis was performed in analogy to Ref. [41]. In a
flame dried and argon flushed 250 cm3 two-neck round-
bottom flask equipped with dropping funnel and argon-inlet
5.00 g dihydrocoumarin (15, 33.8 mmol) was dissolved in
35 cm3 DCM. ICl (5.48 g, 33.8 mmol) dissolved in 35 cm3
DCM was added through the dropping funnel within
15 min. After full conversion (20 h), the reaction mixture
was diluted with 100 cm3 DCM and washed with 0.1 M
Na2S2O3-solution (2 9 50 cm3). The combined aqueous
layers were re-extracted with DCM (2 9 50 cm3). The
combined organic layers were washed with saturated NaCl
solution (1 9 200 cm3), dried over MgSO4, filtered, and
the solvent was removed in vacuo. Recrystallization from
DCM/cyclohexane (1/4) afforded 8.28 g (90 %) 16 as
colorless powder. M.p. 134–136 °C (Ref. [37];
133–134 °C); NMR data were found to agree with those
described in Ref. [41].
123

M. Trobe, R. Breinbauer
52.0 (CH3), 33.7 (CH2), 25.0 (CH2) ppm; GC-MS (EI,
70 eV; MT_50_S): tR = 6.65 min; m/z (%) = 438 (4)
[M?], 407 (11) [M?-OCH3], 289 (100) [M?-CF3O3S] 91
(34) [M?-C5H3F3IO4S]; TLC: Rf = 0.26 (cyclohexane/
EtOAc = 20/1, UV and CAM); HRMS (EI): m/z calcd for
[M?] 437.9246, found 437.9276.
purified via flash column chromatography (cyclohexane/
EtOAc = 40/1, Rf = 0.28 UV and CAM) and 19.2 g
(93 %) 8 were isolated as yellow oil. NMR data were
found to agree with those described in Ref. [32].
2-(3-Amino-3-oxoprop-1-en-1-yl)-4-iodophenyl
trifluo-
romethanesulfonate (21, C10H7F3INO4S)
(2-Amino-2-oxoethyl)triphenylphosphonium
In a flame dried and argon flushed Schlenk flask 983 mg
phosphonium salt 19 (2.76 mmol) was suspended in
20 cm3 absolute MeOH. After cooling the suspension to
0 °C, 310 mg KOtBu (2.76 mmol) was added. The yellow
reaction mixture was stirred at 0 °C for 10 min. 8 (1.00 g,
2.63 mmol) was added and the orange solution was stirred
at RT until full conversion of the starting material was
observed by TLC. After quantitative conversion (16 h), the
solvent was removed under reduced pressure and the
orange crude product was purified via flash column
chromatography (cyclohexane/EtOAc = 1/1, Rf = 0.21,
UV and CAM) to yield 616 mg (55 %) 21 as pale yellow
crystals. 1H NMR (300 MHz, DMSO-d6): d = 8.16 (bs,
1H, CONH2), 7.91 (d, J = 8.6 Hz, 1H, HAr), 7.59 (bs, 1H,
CONH2), 7.44–7.31 (m, 3H, HAr, CH), 6.81 (d,
J = 15.7 Hz, 1H, CH) ppm; 13C NMR (76 MHz, DMSO-
d6, APT): d = 165.3 (CONH2), 146.8 (Cq, CAr), 139.8
(CH), 136.5 (CAr), 130.4 (Cq, CAr), 128.8 (CAr), 128.4
(CAr), 124.2 (CAr), 118.0 (q, J = 321 Hz, CF3), 95.3 (Cq,
CAr) ppm; HPLC–MS (Poroshell, ESI?, MT_general):
tR = 3.67 min; m/z = 422 [M?H?], 444 [M?Na?];
chloride (19)
The synthesis was performed in analogy to Ref. [32]. In a
flame dried Schlenk flask 7.86 g PPh3 (30.0 mmol) and
2.67 g 2-chloroacetamide (28.6 mmol) were suspended in
30 cm3 nitromethane. The mixture was stirred for 19 h at
105 °C. The pale brown solution was allowed to cool to
RT, and the formed colorless precipitate was isolated by
filtration, washed with EtOAc (2 9 10 cm3), Et2O
(1 9 15 cm3) and dried in vacuo. 19 (10.1 g, 99 %) was
isolated as colorless powder. M.p. 219-221 °C (Ref. [29];
215–218 °C); NMR data were found to agree with those
described in Ref. [32].
2-Hydroxy-5-iodobenzaldehyde (7)
The synthesis was performed in analogy to Ref. [37]. In a
one-neck round-bottom flask a solution of 16.1 g ICl
(99.1 mmol) in 100 cm3 DCM (*1 M) was cooled to
0 °C. Salicylaldehyde (6, 10.0 cm3, 99.1 mmol) dissolved
in 40 cm3 DCM (*2.5 M) was added. The reaction was
warmed to RT and stirred until full conversion was
observed (24 h). The reaction mixture was diluted with
100 cm3 DCM and washed with 1 M Na2S2O3 solution
(2 9 100 cm3). The aqueous phase was extracted with
DCM (3 9 50 cm3) and the organic layer was then washed
with saturated NaCl solution (1 9 200 cm3). After drying
over Na2SO4 and filtering, the solvent was removed in
vacuo. Recrystallization from cyclohexane afforded 16.7 g
(68 %) 7 as pale yellow powder. M.p. 97-99 °C (Ref. [32];
97-99 °C); NMR data were found to agree with those
described in Ref. [32].
kmax = 239 nm;
TLC:
Rf = 0.21
(cyclohexane/
EtOAc = 1/1, UV and CAM); m.p. 115–117 °C; HRMS
(EI): m/z calcd for [M?] 420.9093, found 420.9094.
Dipotassium azodicarboxylate (PADA) (20)
The synthesis was performed in analogy to Ref. [39]. In a
100 cm3 round-bottom flask, 18.3 cm3 KOH solution
(7 M) was cooled to -10 °C by a cryostat. Azodicar-
bonamide (5.84 g, 50.3 mmol) was added in small
portions. The yellow-orange suspension was stirred at
-10 °C for 60 min. Then the yellow precipitate was
collected by filtration and washed with cold MeOH
(3 9 50 cm3). After drying in vacuo 9.34 g (96 %) 20
was collected as yellow powder. M.p 186 °C
(decomposition).
2-Formyl-4-iodophenyl trifluoromethanesulfonate (8)
The synthesis was performed in analogy to Ref. [32]. In a
flame dried and argon flushed two-neck round-bottom flask
equipped with argon-inlet 13.5 g 7 (54.4 mmol) was
dissolved in 110 cm3 DCM and 6.60 cm3 pyridine
(81.7 mmol). The pale yellow solution was cooled to
0 °C and 18.3 cm3 Tf2O (109 mmol) was added. After
5 min, the orange suspension was allowed to warm to RT.
When quantitative conversion was detected by GC–MS
(4 h), the reaction mixture was washed with 200 cm3 H2O.
The aqueous phase was extracted with DCM
(6 9 100 cm3) and the combined organic layers were
washed with saturated NaCl solution (1 9 100 cm3), dried
over Na2SO4, filtered, and the solvent was removed under
reduced pressure. The brown, oily crude product was
2-(3-Amino-3-oxopropyl)-4-iodophenyl trifluoromethane-
sulfonate (22, C10H9F3INO4S)
In a 25 cm3 round-bottom flask equipped with reflux
condenser 280 mg 21 (665 lmol) was dissolved in 4.5 cm3
1,2-DME. PADA (20, 387 mg, 1.99 mmol) was added.
AcOH (114 mm3, 1.99 mmol) was added to the yellow
suspension and the reaction-mixture was heated to 50 °C.
When full conversion (3 days) was achieved the reaction
was cooled to RT and unreacted PADA was removed by
filtration. The solution was concentrated in vacuo. The
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
brown, solid crude was purified via flash column chro-
matography (cyclohexane/EtOAc = 1/1, Rf = 0.23, CAM)
and 258 mg (92 %) 22 was isolated as colorless powder.
1H NMR (300 MHz, DMSO-d6): d = 7.84 (s, 1H, HAr),
7.75 (dd, J = 8.6 Hz, 1.9 Hz, 1H, HAr), 7.34 (bs, 1H,
CONH2), 7.18 (d, J = 8.6 Hz, 1H, HAr), 6.85 (bs, 1H,
CONH2), 2.83 (t, J = 7.5 Hz, 2H, CH2), 2.41 (t,
J = 7.5 Hz, 2H, CH2) ppm; 13C NMR (76 MHz, DMSO-
d6, APT): d = 172.4 (CONH2), 147.4 (Cq, CAr), 139.7
(CAr), 137.2 (CAr), 136.4 (Cq, CAr), 123.3 (CAr), 118.0 (q,
J = 320 Hz, CF3), 94.8 (Cq, CAr), 34.1 (CH2), 24.8
(CH2) ppm; HPLC–MS (Poroshell, ESI?, MT_general):
tR = 3.65 min; m/z = 424 [M?H?], 446 [M?Na?];
Na2SO4, filtered, and the solvent was removed under
reduced pressure. The yellow, oily crude product was
purified via flash column chromatography (cyclohexane/
EtOAc = 100/1, Rf = 0.34, UV and CAM) and 8.07 g
(79 %) 12 was isolated as colorless oil. 1H NMR
(300 MHz, CDCl3): d = 8.02 (m, 1H, HAr), 7.70–7.64
(m, 5H, HAr), 7.50–7.39 (m, 6H, HAr), 6.98 (d, J = 8.6 Hz,
1H, HAr), 4.79 (s, 2H, CH2), 1.14 (s, 9H, 3 x CH3) ppm;
13C NMR (76 MHz, CDCl3, APT): d = 146.3 (Cq, CAr),
138.3 (CAr), 137.8 (CAr), 136.0 (Cq, CAr), 135.6 (CAr),
132.7 (Cq, CAr), 130.2 (CAr), 128.0 (CAr), 122.8 (CAr),
118.6 (q, J = 320 Hz, CF3), 93.5 (Cq, CAr), 59.9 (CH2),
27.0 (CH3), 19.4 (Cq) ppm; TLC: Rf = 0.19 (cyclohexan,
UV), 0.34 (cyclohexane/EtOAc 100/1 (v/v), UV); HRMS
(EI): m/z calcd for [M?-C4H9] 562.9457, found 562.9446.
kmax = 239 nm;
TLC:
Rf = 0.23
(cyclohexane/
EtOAc = 1/1, UV and CAM); m.p. 115–118 °C; HRMS
(EI): m/z calcd for [M?] 422.9249, found 422.9258.
2-(1-Hydroxyethyl)-4-iodophenyl
trifluoromethanesul-
2-(Hydroxymethyl)-4-iodophenyl
fonate (13)
trifluoromethanesulfonate (9)
The synthesis was performed in analogy to Ref. [32]. In a
flame dried and argon flushed Schlenk flask 69.1 mg Mg
turnings (2.84 mmol) was stirred for 20 min without
solvent. Then the turnings were suspended in 5 cm3 Et2O
and 180 mm3 iodomethane (2.84 mmol) dissolved in
5 cm3 Et2O was added. The reaction mixture was heated
to reflux until the complete amount of Mg was dissolved
(30 min). The colorless suspension was added dropwise to
a solution of 900 mg 8 (2.37 mmol) in 10 cm3 Et2O. The
pale yellow suspension was stirred until quantitative
conversion was detected by TLC (5 h). The reaction was
diluted with 100 cm3 Et2O and washed with 1 M HCl
(1 9 100 cm3), saturated NaHCO3 solution (1 9 100 cm3)
and saturated NaCl solution. The organic layer was dried
over MgSO4, filtered and the solvent was removed in
vacuo. The yellow, oily crude product was purified via
flash column chromatography (cyclohexane/EtOAc = 10/
1, Rf = 0.21, CAM) and 882 mg (94 %) 13 was isolated as
pale yellow powder. M.p. 37-40 °C (Ref. [32]; 37–40 °C);
NMR data were found to agree with those described in Ref.
[32].
The synthesis was performed in analogy to Ref. [32]. In a
flame dried and argon flushed Schlenk flask, 5.00 g 8
(13.2 mmol) was dissolved in 20 cm3 absolute DCM. This
solution was cooled to -78 °C and 26.3 cm3 diiso-butyl-
aluminum hydride (DIBALH, 1.0 M in toluene,
26.3 mmol) was slowly added via a dropping funnel. After
stirring for 2 h at -78 °C the bright yellow solution was
quenched by addition of 17 cm3 MeOH and 60 cm3
saturated Rochelle salt solution. A yellow emulsion was
formed and stirred overnight until phase separation occurs.
The phases were separated and the aqueous phase was
extracted with DCM (3 9 100 cm3). The combined
organic layers were dried over Na2SO4, filtered, and the
solvent was removed under reduced pressure. The yellow,
oily crude product was purified via flash column chro-
matography (cyclohexane/EtOAc = 5/1, Rf = 0.37, UV
and CAM) and 4.19 g (83 %) 9 was isolated as pale yellow
powder. M.p. 28–30 °C (Ref. [32]; 28–30 °C); NMR data
were found to agree with those described in Ref. [32].
2-[[(tert-Butyldiphenylsilyl)oxy]methyl]-4-iodophenyl tri-
fluoromethanesulfonate (12, C24H24F3IO4SSi)
2-[1-[(tert-Butyldiphenylsilyl)oxy]ethyl]-4-iodophenyl tri-
fluoromethanesulfonate (14, C25H26F3IO4SSi)
A 500 cm3 round-bottom flask with drying-tube was
charged with 6.28 g 9 (16.4 mmol) dissolved in 75 cm3
DCM. Imidazole (2.95 g, 43.4 mmol) and 6.5 cm3 tert-
butyldiphenylchlorsilane (TBDPSCl, 25.0 mmol) were
added via syringe. When the whole amount of TBDPSCl
was added a colorless solid started to precipitate. The
reaction was stirred overnight (16 h) at RT. When quan-
titative conversion was detected by TLC, the reaction was
quenched by the addition of 120 cm3 3 M NaOH and
transferred to a separation funnel. After phase separation,
the aqueous phase was extracted with DCM
(3 9 120 cm3). The combined organic layers were washed
with saturated NaCl solution (1 9 120 cm3), dried over
In a 250 cm3 round-bottom flask 8.24 g 13 (20.7 mmol)
was dissolved in 95 cm3 DCM and 3.52 g imidazole
(51.8 mmol)
was
added.
Then
5.4 cm3
tert-
butylchlorodiphenylsilane (20.8 mmol) was added to the
yellow solution and a white precipitate was formed. After
the reaction was stirred for 16 h at RT additional 540 mm3
tert-butylchlorodiphenylsilane (2.1 mmol) was added
because of incomplete conversion detected by TLC. After
stirring the reaction for another 5 h the reaction was diluted
with 20 cm3 DCM and washed with 3 M NaOH
(1 9 150 cm3). The aqueous layer was re-extracted with
DCM (1 9 150 cm3) and the combined organic layers
123

M. Trobe, R. Breinbauer
were washed with saturated NaCl solution (1 9 200 cm3).
Then the organic layer was dried over Na2SO4, filtered and
the solvent was removed under reduced pressure to give a
yellow oil. The crude product was purified via flash column
after 60 min. Then the reaction mixture was neutralized
with 1 cm3 1 M HCl and diluted with 20 cm3 H2O. The
aqueous phase was extracted with DCM (3 9 20 cm3). The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The oily crude product was
purified via flash column chromatography (cyclohexane/
EtOAc = 50/1, Rf = 0.27, UV and CAM) and 245 mg
(82 %) 11 was isolated as colorless oil. NMR data were
found to agree with those described in Ref. [32].
chromatography
[cyclohexane
to
cyclohexane/
EtOAc = 50/1, Rf = 0.38 (cyclohexane/EtOAc = 100/1,
UV and CAM)] and 9.86 g (75 %) 14 was isolated as
1
colorless oil. H NMR (300 MHz, CDCl3): d = 8.10 (d,
J = 2.0 Hz, 1H, HAr), 7.62 (d, J = 6.3 Hz, 2H, HAr), 7.53
(dd, J = 8.6 Hz, 2.2 Hz, 1H, HAr), 7.44 (d, J = 6.6 Hz,
2H, HAr), 7.35 (m, 4H, HAr), 7.23 (m, 2H, HAr), 6.79 (d,
J = 8.6 Hz, 1H, HAr), 5.03 (m, 1H, CH), 1.32–1.30 (d,
J = 6.2 Hz, 3H, CH3), 1.04 (s, 9H, 39 CH3) ppm;
13C NMR (75 MHz, CDCl3, APT): d = 145.0 (Cq, CAr),
141.3 (Cq, CAr), 137.9 (CAr), 137.6 (CAr), 135.8 (CAr),
135.8 (CAr), 133.6 (Cq, CAr), 132.9 (Cq, CAr), 130.0 (CAr),
129.9 (CAr), 127.8 (CAr), 127.8 (CAr), 122.5 (CAr), 118.4
(q, J = 320.2 Hz, CF3), 93.4 (Cq, CAr), 65.6 (CH), 27.1
(CH3), 25.7 (CH3), 19.5 (Cq) ppm; GC–MS (EI, 70 eV;
MT_50_S): tR = 8.467 min; m/z (%) = 485 (45) [M?-
CF3O3S]; TLC: Rf = 0.38 (cyclohexane/EtOAc = 100/1,
UV and CAM); HRMS (EI): m/z calcd for [M?-C4H9]
576.9614, found 576.9585.
4,5-Dihydrobenzo[b]oxepin-2(3H)-one (24)
In a 250 cm3 round-bottom flask 10.0 cm3 1-tetralone (23,
75.3 mmol) was dissolved in 200 cm3 CHCl3. mCBPA
(23.2 g, 94.1 mmol) was added to the resulting pale yellow
solution. The yellow suspension was stirred until full
conversion was detected by TLC (48 h). The reaction
mixture was washed with 5 % NaHCO3 solution
(2 9 100 cm3) and H2O (1 9 100 cm3). Then the organic
layer was dried over Na2SO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified via flash column chromatography (cyclohexane/
EtOAc = 5/1, Rf = 0.50, UV and CAM) and 10.9 g
(89 %) 24 was isolated as yellow oil. NMR data were
found to agree with those described in Ref. [46].
2-(Chloromethyl)-4-iodophenyl trifluoromethansulfonate
(10, C8H5ClF3IO3S)
7-Iodo-4,5-dihydrobenzo[b]oxepin-2(3H)-one (25,
C10H9IO2)
A 50 cm3 round bottom flask equipped with reflux
condenser was charged with 2.12 g 9 (5.2 mmol) and
20 cm3 thionylchloride. The pale yellow solution was
heated to 95 °C for 24 h. When full conversion was
detected by GC–MS the remaining thionylchloride was
removed in vacuo. The brown, oily crude product was
purified via flash column chromatography (cyclohexane,
Rf = 0.30, UV and CAM) and 1.44 g (69 %) 10 was
isolated as colorless oil. 1H NMR (300 MHz, CDCl3):
d = 7.87 (d, J = 2.0 Hz, 1H, HAr), 7,72 (dd, J = 8.7 Hz,
3.1 Hz, 1H, HAr), 7.06 (d, J = 8.7 Hz, 1H, HAr), 4.43 (s,
2H, CH2) ppm; 13C NMR (76 MHz, CDCl3): d = 147.1
(Cq, CAr), 141.1 (CAr), 139.6 (CAr), 133.1 (Cq, CAr), 132.6
(CAr), 120.8 (CAr), 118.6 (q, J = 320 Hz, CF3), 93.3 (Cq,
CAr), 24.5 (CH2) ppm; GC-MS (EI, 70 eV; MT_50_S):
tR = 6.08; m/z (%) = 400 (75) [M?], 267 (100) [M?-
CF3O2S], 365 (6) [M?-Cl]; HRMS (EI): m/z calcd for [M?]
399.8645, found 399.8626.
In a 100 cm3 two-neck round-bottom flask equipped with
dropping funnel and argon inlet, 1.5 g 24 (9.19 mmol) was
dissolved in 10 cm3 DCM. ICl (1.5 g, 9.19 mmol) dis-
solved in 10 cm3 DCM was added dropwise. After full
conversion (20 h) the reaction was diluted with 100 cm3
DCM and washed with 1 M Na2S2O3 solution
(2 9 50 cm3). The combined aqueous layers were re-
extracted with DCM (2 9 50 cm3). The combined organic
layers were washed with saturated NaCl solution
(1 9 200 cm3), dried over Na2SO4, filtered, and the
solvent was removed in vacuo. The brown, oily crude
product was purified via flash column chromatography
(cyclohexane/EtOAc = 10/1, Rf = 0.33, UV and CAM)
and 2.20 g (83 %) 25 was isolated as yellow solid.
1H NMR (300 MHz, CDCl3): d = 7.58 (dd, J = 8.4 Hz,
2.0 Hz, 1H, HAr), 7.54 (d, J = 1.8 Hz, 1H, HAr), 6.84 (d,
J = 8.4 Hz, 1H, HAr), 2.84 (t, J = 7.2 Hz, 2H, CH2), 2.48
(t, J = 7.2 Hz, 2H, CH2), 2.23 (q, J = 7.1 Hz, 2H, CH2)
ppm; 13C NMR (76 MHz, CDCl3, APT): d = 170.9 (Cq,
CO), 151.9 (Cq, CAr), 138.5 (CAr), 137.8 (CAr), 132.8 (Cq,
CAr), 121.6 (CAr), 89.6 (Cq, CAr), 31.1 (CH2), 28.1 (CH2),
26.4 (CH2) ppm; GC-MS (EI, 70 eV; MT_50_S):
tR = 6.86 min; m/z (%) = 288 (100) [M?], 233 (64)
[M?-C2H4O], 161 (14) [M?-I]; TLC: Rf = 0.33 (cyclo-
hexane/EtOAc = 10/1, UV and CAM); m.p. 75–78 °C;
HRMS (EI): m/z calcd for [M?] 287.9647, found 287.9660.
S-5-Iodo-2-[[(trifluoromethyl)sulfonyl]oxy]benzyl
etha-
nethioate (11)
The synthesis was performed in analogy to Ref. [32]. In a
flame dried and argon flushed Schlenk flask 300 mg 10
(674 lmol) was dissolved in 2 cm3 absolute THF. K2CO3
(205 mg, 1.28 mmol) and 57.8 mm3 thioacetic acid
(809 lmol) were added. The colorless suspension was
stirred at RT until full conversion was detected by GC-MS
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
Methyl
4-(2-hydroxy-5-iodophenyl)butanoate
(26,
J = 320.2 Hz, CF3), 123.3 (CAr), 93.5 (Cq, CAr), 51.8
(CH3), 33.3 (CH2), 29.0 (CH2), 25.0 (CH2) ppm; GC-MS
(EI, 70 eV; MT_50_S): tR = 6.94 min; m/z (%) = 425
(27) [M?], 421 (26) [M?-CH3O], 378 (25) [M?-C3H5O2],
319 (31) [M?-CF3O2S]; TLC: Rf = 0.28 (cyclohexane/
EtOAc = 20/1, UV and CAM); HRMS (EI): m/z calcd for
[M?] 451.9402, found 451.9423.
C11H13IO3)
In a Schlenk flask 4.10 cm3 conc. H2SO4 was added to a
colorless suspension of 2.20 g 25 (7.64 mmol) in 30 cm3
MeOH. The solid dissolved and the pale yellow solution
was warmed to 55 °C and stirred overnight at this
temperature. After full conversion (24 h) was detected by
TLC, the brown solution was neutralized with 50 cm3
saturated NaHCO3 solution and the phases were separated.
The aqueous phase was extracted with DCM
(3 9 100 cm3). The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuum. The
crude product was purified via flash column chromatogra-
phy (cyclohexane/EtOAc = 5/1, Rf = 0.16, UV and CAM)
and 2.42 g (99 %) 26 was isolated as light brown oil.
1H NMR (300 MHz, CDCl3): d = 7.39–7.36 (m, 2H, HAr),
6.75 (bs, 0.8H, OH), 6.63 (d, J = 9.0 Hz, 1H, HAr), 3.73 (s,
3H, CH3) 2.58 (t, J = 7.7 Hz, 2H, CH2), 2.40 (t,
J = 6.6 Hz, 2H, CH2), 1.86 (q, J = 7.1 Hz, 2H, CH2)
ppm; 13C NMR (76 MHz, CDCl3, APT): d = 175.7 (Cq,
CO), 154.7 (Cq, CAr), 138.7 (CAr), 136.6 (CAr), 130.1 (Cq,
CAr), 118.5 (Cq, CAr), 82.2 (Cq, CAr), 52.2 (CH3), 32.6
(CH2), 29.2 (CH2), 24.9 (CH2) ppm; GC-MS (EI, 70 eV;
MT_50_S): tR = 7.22 min; m/z (%) = 320 (48) [M?], 288
(100) [M?-CH3O], 260 (20) [M?-C2H3O2], 233 (66) [M?-
C4H7O2]; TLC: Rf = 0.16 (cyclohexane/EtOAc = 5/1, UV
and CAM); HRMS (EI): m/z calcd for [M?] 319.9909,
found 319.9914.
2-(4-Hydroxybutyl)-4-iodophenyl trifluoromethanesulfonate
(28, C11H12F3IO4S)
In a flame dried and argon flushed Schlenk flask 2.60 g 27
(5.75 mmol, 1.0 eq) was dissolved in 8.0 cm3 absolute
DCM. This solution was cooled to -78 °C and 11.5 cm3
diiso-butyl-aluminum hydride (DIBALH, 1.0 M in DCM,
11.5 mmol) was carefully added via syringe. The colorless
solution was warmed to RT. After quantitative conversion
was detected by TLC (2 h), the solution was cooled again
to -78 °C and quenched by the addition of 8 cm3 MeOH.
Saturated Rochelle-salt solution (20 cm3) was added and
the emulsion was stirred until phase separation occurred
(24 h). The phases were separated and the aqueous phase
was extracted with DCM (3 9 50 cm3). The combined
organic layers were dried over Na2SO4 and the solvent was
removed under reduced pressure. 28 (2.26 g, 93 %) was
isolated as colorless oil and used in the next step without
further purification. 1H NMR (300 MHz, CDCl3):
d = 7.68 (d, J = 1.9 Hz, 1H, HAr), 7.59 (dd, J = 8.6 Hz,
2.1 Hz, 1H, HAr), 6.98 (d, J = 8.6 Hz, 1H, HAr), 3.69 (t,
J = 6.1 Hz, 2H, CH2), 2.69 (t, J = 7.6 Hz, 2H, CH2),
1.73-1.61 (m, 4H, 29 CH2) ppm; 13C NMR (76 MHz,
CDCl3, APT): d = 148.0 (Cq, CAr), 140.2 (CAr), 137.6
(CH2), 137.0 (CAr), 123.3 (CAr), 118.7 (d, J = 320.2 Hz,
CF3), 93.5 (Cq, CAr), 62.5 (CH2), 32.3 (CH2), 29.5
(CH2) ppm; GC-MS (EI, 70 eV; MT_50_S): tR = 6.90 -
min; m/z (%) = 424 (31) [M?], 378 (92) [M?-C2H5O];
TLC: Rf = 0.23 (cyclohexane/EtOAc = 5/1, UV and
CAM); HRMS (EI): m/z calcd for [M?] 423.9453, found
451.9423.
Methyl 4-[5-iodo-2-[[(trifluoromethyl)sulfonyl]oxy]phenyl]-
butanoate (27, C12H12F3IO5S)
In a one-neck round-bottom flask 2.40 g 26 (7.84 mmol)
was dissolved in 8 cm3 pyridine (*1 M). After cooling the
solution to 0 °C, 2.10 cm3 Tf2O (8.62 mmol) was carefully
added. After stirring 5 min at 0 °C, the solution was
allowed to warm to RT and stirred until quantitative
conversion was detected by TLC (2 h). Et2O (60 cm3) was
added and the organic phase was washed with H2O
(3 9 30 cm3), followed by extracting the combined aque-
ous layers with Et2O (2 9 30 cm3). The combined organic
layers were washed with 1 M HCl (2 9 60 cm3) and
saturated NaCl solution (1 9 60 cm3), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified via flash column chromatography (cyclohexane/
EtOAc = 20/1, Rf = 0.28, UV and CAM) and 2.68 g
(78 %) 27 were isolated as pale yellow oil. 1H NMR
(300 MHz, CDCl3): d = 7.67 (d, J = 1.9 Hz, 1H, HAr),
7.59 (dd, J = 8.6 Hz, 2.1 Hz, 1H, HAr), 6.99 (d,
J = 8.6 Hz, 1H, HAr), 3.67 (s, 3H, CH3), 2.69 (t,
J = 7.8 Hz, 2H, CH2), 2.37 (t, J = 7.3 Hz, 2H, CH2),
1.94 (q, J = 7.5 Hz, 2H, CH2) ppm; 13C NMR (76 MHz,
CDCl3, APT): d = 173.3 (Cq, CO), 147.9 (Cq,CAr), 140.2
(CAr), 137.3 (CAr), 136.7 (Cq, CAr), 118.6 (q,
2-[4-[(tert-Butoxycarbonyl)amino]butyl]-4-iodophenyl tri-
fluoromethanesulfonate (30, C16H21F3INO5S)
In a 50 cm3 round-bottom flask, 2.20 g 28 (5.20 mmol)
was dissolved in 20 cm3 THF. The colorless solution was
cooled to 0 °C and 930 mm3 DIPEA (5.20 mmol), 1.63 mg
PPh3 (6.23 mmol), 1.24 cm3 DIAD (6.23 mmol), and
1.34 cm3 DPPA (6.23 mmol) was added. The pale yellow
suspension was stirred for 4 h at RT. When quantitative
conversion of alcohol 28 was detected by TLC, 1.77 g
PPh3 (6.48 mmol) dissolved in 4.0 cm3 THF was added
and the reaction was stirred overnight at RT. After adding
2.0 cm3 H2O, the reaction was warmed to 50 °C and stirred
until full conversion of the azide intermediate was detected
by GC–MS. The solvent was removed under reduced
pressure and the oily residue (amine intermediate 29) was
123

M. Trobe, R. Breinbauer
dissolved in 50 cm3 DCM. Boc2O (1.13 g, 5.20 mmol) was
added to this pale yellow solution. The reaction was stirred
at RT overnight. When quantitative conversion of amine 29
was detected by TLC the reaction was dried over Na2SO4,
filtered, and the solvent was removed under reduced
pressure. The pale yellow, oily crude product was purified
via flash column chromatography (cyclohexane/
EtOAc = 15/1, Rf = 0.26, UV and ninhydrin) and 1.32 g
(49 %) 30 was isolated as pale yellow oil. 1H NMR
(300 MHz, CDCl3): d = 7.66 (d, J = 1.9 Hz, 1H, HAr),
7.58 (dd, J = 8.6 Hz, 2.0 Hz, 1H, HAr), 6.58 (d,
J = 8.6 Hz, 1H, HAr), 4.54 (bs, 1H, NH), 3.15 (d,
J = 5.4 Hz, 2H, CH2), 2.69–2.63 (m, 2H, CH2),
1.67–1.51 (m, 4H, 29 CH2), 1.44 (s, 9H, 39 CH3) ppm;
13C NMR (76 MHz, CDCl3, APT): d = 156.5 (Cq, CO),
147.5 (Cq, CAr), 141.1 (CAr), 137.4 (Cq, CAr), 136.9 (CAr),
125.1 (Cq, CAr), 119.0 (d, J = 320 Hz, CF3), 93.3 (Cq,
CAr), 79.2 (Cq), 40.1 (CH2), 29.5 (CH2), 29.1 (CH2), 28.1
(39 CH3), 27.0 (CH2) ppm; TLC: Rf = 0.44 (cyclohexane/
EtOAc = 5/1, UV and ninhydrin); HRMS (EI): m/z calcd
for [M?] 523.0137, found 523.0171.
(CH3) ppm; HPLC–MS (Poroshell, ESI?, MT_60 to 100):
tR = 4.06 min; m/z = 526 [M?H?], 539 [M?Na?];
kmax = 269 nm;
EtOAc = 2/1, UV and CAM); HRMS (DI-EI): m/z calcd
TLC:
Ri = 0.30
(cyclohexane/
for [M?] 515.3512, found 515.3525.
4-[2,5-Bis(5-isobutylpyridin-3-yl)phenyl]butan-1-amine
hydrochloride (33, C28H38ClN3)
Compound 32 (100 mg, 194 lmol) was dissolved in 4 cm3
DCM in a 10 cm3 round-bottom flask. The colorless
solution was cooled to 0 °C and 390 mm3 HCl (5 M in
iPrOH, 1.94 mmol) was added. The colorless solution was
stirred at RT until full conversion of the starting material
was detected by HPLC–MS (7 h). The solvent was
removed in a N2-flow and the product was dried in
vacuum. 33 (81.0 mg, quant.) was isolated as colorless
powder. 1H NMR (300 MHz, DMSO-d6): d = 9.28 (s, 1H,
HAr), 8.92–8.80 (m, 4H, HAr), 8.45 (s, 1H, HAr), 8.20 (bs,
3H, NH3), 8.09 (s, 1H, HAr), 7.93 (d, J = 7.8 Hz, 1H, HAr),
7.54 (d, J = 7.9 Hz, 1H, HAr), 3.80–3.72 (m, 1H, CH),
2.77–2.67 (m, 8H, CH2), 2.07-1.96 (m, 2H, CH2),
1.61–1.50 (m, 4H, CH2), 0.92 (d, J = 6.1 Hz, 12H, CH3)
ppm; 13C NMR (76 MHz, DMSO-d6): d = 145.3 (CAr),
143.1 (CAr), 141.1 (Cq, CAr), 140.9 (Cq, CAr), 140.5 (CAr),
140.4 (Cq, CAr), 139.6 (CAr), 138.3 (Cq, CAr), 137.8 (CAr),
137.7 (CAr), 137.5 (Cq, CAr), 136.1 (Cq, CAr), 134.6 (Cq,
CAr), 131.3 (CAr), 128.7 (CAr), 125.2 (CAr), 40.5 (CH2),
38.3 (CH2), 31.6 (CH2), 27.1 (CH2), 26.6 (CH2), 25.5
(CH), 21.8 (CH3), 21.7 (CH3) ppm; HPLC–MS (Poroshell,
ESI?, MT_general): tR = 4.55 min; m/z = 416 [M?H?];
kmax = 269 nm; HRMS (DI-EI): m/z calcd for [M?-HCl]
415.2987, found 415.2995.
tert-Butyl [4-[2,5-bis(5-isobutylpyridin-3-yl)phenyl]butyl]-
carbamate (32, C33H45N3O2)
The synthesis was performed in analogy to Ref. [30]. A
flame dried Schlenk flask was charged with 270 mg
pyridine boronic acid ester 31 (1.03 mmol), 672 mg
Cs2CO3 (2.06 mmol), and 42.1 mg PdCl2(dppf)
(10 mol %). After drying in vacuo, a solution of 270 mg
core unit fragment 30 (516 lmol) in 5 cm3 absolute,
degassed 1,2-DME (*0.2 M) was added. The reaction
mixture was stirred at 80 °C overnight. The resulting black
suspension was filtered through a pad of SiO2 (3 9 2 cm,
eluent 100 cm3 MeOH) and after concentrating to dryness,
the crude product was purified via flash column chro-
matography (15 g SiO2, 1.5 9 20 cm, eluent: cyclohexane/
EtOAc = 2/1, Rf = 0.30, UV and CAM). To obtain pure
substrate, the product was purified via semi-preparative
HPLC and 142 mg teraryl 32 (53 %) was isolated as pale
Acknowledgments We thank Michael Bumberger, Patrick
Dobrounig, Anna Schweiger, and Beate Steller for skillful assistance
in the lab and Dr. Martin Peters for fruitful discussions in the early
phase of this project. This research was funded by grants of the
Volkswagenstiftung, Hannover, the PLACEBO (Platform for Chem-
ical Biology) project as part of the Austrian Genome Project GEN-
¨
AU funded by the Forschungsforderungsgesellschaft (FFG) and
Bundesministerium fu¨r Wissenschaft und Forschung (BMWF), and
NAWI Graz.
1
yellow, highly viscous oil. H NMR (300 MHz, CDCl3):
d = 8.64 (bs, 1H, HAr), 8.36 (bs, 3H, (HAr), 7.63 (bs, 1H,
HAr), 7.41 (d, J = 11.2 Hz, 3H, HAr), 7.24–7.20 (m, 1H,
HAr), 4.43 (bs, 1H, NH), 2.96–2.94 (m, 2H, CH2),
2.61–2.55 (m, 2H, CH2), 2.52–2.48 (m, 4H, CH2),
1.95–1.79 (m, 2H, CH2), 1.50–1.40 (m, 2H, CH2), 1.34
(s, 9H, CH3), 0.91–0.88 (m, 12H, CH3) ppm;
13C NMR (76 MHz, CDCl3): d = 145.1 (Cq, CCarbonyl),
149.1 (CAr), 148.9 (CAr), 147.0 (CAr), 144.5 (CAr), 141.0
(Cq, CAr), 137.9 (Cq, CAr), 137.9 (Cq, CAr), 137.5 (CAr),
137.1 (Cq, CAr), 136.5 (Cq, CAr), 136.0 (Cq, CAr), 135.3
(CAr), 131.1 (CAr), 128.4 (CAr), 125.0 (CAr), 89.2 (Cq), 42.5
(CH2), 42.3 (CH2), 40.3 (CH2), 33.0 (CH2), 30.2 (CH),
30.1 (CH2), 28.7 (CH2), 28.5 (CH3), 22.4 (CH3), 22.3
References
1. Stumpf MPH, Thorne T, de Silva E, Stewart R, An HJ, Lappe M,
Wiuf C (2008) Proc Natl Acad Sci USA 105:6959
2. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH,
Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S,
Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde
¨
A, Toksoz E, Droege A, Krobitsch S, Korn B, Birchmeier W,
Lehrach H, Wanker EE (2005) Cell 122:957
3. http://ppi.fli-leibniz.de/. Accessed 3 Nov 2015
4. Jochim AL, Arora PS (2010) ACS Chem Biol 5:919
5. Jochim AL, Arora PS (2009) Mol BioSyst 5:924
6. Berg T (2003) Angew Chem Int Ed Engl 42:2462
123

Improved and scalable synthesis of building blocks for the modular synthesis of teraryl-based…
7. Pelay-Gimeno M, Glas A, Koch O, Grossmann TN (2015)
Angew Chem Int Ed 54:8896
27. Horwell DC, Howson W, Ratcliffe GS, Willems HMG (1996)
Bioorg Med Chem 4:33
8. Kim YW, Grossmann TN, Verdine GL (2011) Nat Protocols
6:761
9. Johnson LM, Mortenson DE, Yun HG, Horne WS, Ketas TJ, Lu
M, Moore JP, Gellman SH (2012) J Am Chem Soc 134:7317
10. Kritzer JA, Lear JD, Hodsdon ME, Schepartz A (2004) J Am
Chem Soc 126:9468
28. Moon H, Lim H (2015) Curr Opin Chem Biol 24:38
29. Jayatunga MDP, Thompson S, Hamilton AD (2014) Bioorg Med
Chem Lett 24:717
30. Azzarito V, Long K, Murphy NS, Wilson AJ (2013) Nat Chem
5:161
31. Cummings CG, Hamilton AD (2010) Curr Opin Chem Biol
14:341
11. Robinson J (2008) Acc Chem Res 41:278
12. Azzarito V, Prabhakaran P, Bartlett AI, Murphy NS, Hardie MJ,
Kilner CA, Edwards TA, Warriner SL, Wilson AJ (2012) Org
Biomol Chem 10:6469
13. Sopkova-de Oliveira Santos J, Voisin-Chiret AS, Burzicki G,
Sebaoun L, Sebban M, Lohier JF, Legay R, Oulyadi H, Bureau R,
Rault S (2012) J Chem Inf Model 52:429
32. Peters M, Trobe M, Tan H, Kleinweischede R, Breinbauer R
(2013) Chem Eur J 19:2442
33. Peters M, Trobe M, Breinbauer R (2013) Chem Eur J 19:2450
34. Trobe M, Peters M, Grimm SH, Breinbauer R (2014) Synlett
25:1202
35. Toumi M, Couty F, Evano G (2007) Angew Chem Int Ed 46:572
36. Djukic B, Poddutoori PK, Dube PA, Seda T, Jenkins HA,
Lemaire MT (2009) Inorg Chem 48:6109
¨
14. Gomes CP, Metz A, Bats JW, Gohlke H, Gobel MW (2012) Eur J
Org Chem 3270
´
´
´
15. Williams AB, Hanson RN (2012) Tetrahedron 68:5406
16. Thompson S, Vallinayagam R, Adler MJ, Scott RTW, Hamilton
AD (2012) Tetrahedron 68:4501
17. Reuter C, Huy P, Neudoerfl JM, Kuehne R, Schmalz HG (2011)
Chem Eur J 17:12037
37. Martınez RF, Avalos M, Babiano R, Cintas P, Jimenez JL, Light
ME, Palacios JC (2011) Eur J Org Chem 3137
38. Subhas Bose D, Jayalakshmi B (1999) Synthesis 64
39. Beruben D, Marek I, Normant JF, Platzer N (1995) J Org Chem
60:2488
´
¨
18. Ehlers I, Maity P, Aube J, Konig B (2011) Eur J Org Chem 2474
19. Lee TK, Ahn JM (2011) ACS Comb Sci 13:107
20. Lee JH, Zhang Q, Jo S, Chai SC, Oh M, Im W, Lu H, Lim HS
(2011) J Am Chem Soc 133:676
40. Peng W, Blagg BSJ (2006) Org Lett 8:975
41. Davies SG, Pyatt D, Thomson C (1990) J Organomet Chem
387:381
42. Scott JP, Alam M, Bremeyer N, Goodyear A, Lam T, Wilson RD,
Zhou G (2011) Org Process Res Dev 15:1116
21. Restorp P, Rebek J Jr (2008) Bioorg Med Chem Lett 18:5909
22. Moisan L, Odermatt S, Gombosuren N, Carella A, Rebek Jr J
(2008) Eur J Org Chem 1673
23. Che Y, Brooks BR, Marshall GR (2007) Biopolymers 86:288
24. Oguri H, Tanabe S, Oomura A, Umetsu M, Hirama M (2006)
Tetrahedron Lett 47:5801
´
43. Nicolai S, Erard S, Gonzalez DF, Waser J (2010) Org Lett 12:384
44. Azzena U, Dettori G, Pireddu R, Pisano L (2004) Tetrahedron
60:1617
45. Rodriguez JM, Ross NT, Katt WP, Deepali D, Lee G, Hamilton
AD (2009) ChemMedChem 4:649
25. Antuch W, Menon S, Chen QZ, Lu Y, Sakamuri S, Beck B,
¨
Schauer-Vukasinovic V, Agarwal S, Hess S, Domling A (2006)
46. Nicolaou KC, Yu R, Shi L, Cai Q, Lu M, Heretsch P (2013) Org
Lett 15:1994
Bioorg Med Chem Lett 16:1740
26. Jacoby E (2002) Bioorg Med Chem Lett 12:891
123