Unified mild reaction conditions for C2-selective Pd-catalysed tryptophan arylation, including tryptophan-containing peptides

Article abstract of DOI:10.1039/c5ob01174d

Pd-mediated C-H bond functionalisation protocols have been designed and developed on tryptophan derivatives and tryptophan-containing peptides. The examination of different arylation reactions (three sets of different conditions A-C), all of which are notable for their low temperatures (≤40°C), allowed identification of unified and complementary synthetic approaches toward a series of functionalised tryptophan-containing products. Tryptophan-containing peptides demonstrated to be susceptible to aromatic oxidation were successfully and selectively modified through the application of diaryliodonium salts in good yields.

Full text of DOI:10.1039/c5ob01174d

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Unified mild reaction conditions for C2-selective
Pd-catalysed tryptophan arylation, including
tryptophan-containing peptides†
Cite this: DOI: 10.1039/c5ob01174d
Alan J. Reay, Thomas J. Williams and Ian J. S. Fairlamb*
Pd-mediated C–H bond functionalisation protocols have been designed and developed on tryptophan
derivatives and tryptophan-containing peptides. The examination of different arylation reactions (three
sets of different conditions A–C), all of which are notable for their low temperatures (≤40 °C), allowed
identification of unified and complementary synthetic approaches toward a series of functionalised
tryptophan-containing products. Tryptophan-containing peptides demonstrated to be susceptible to aro-
matic oxidation were successfully and selectively modified through the application of diaryliodonium salts
in good yields.
Received 10th June 2015,
Accepted 26th June 2015
DOI: 10.1039/c5ob01174d
www.rsc.org/obc
on non-natural peptidic scaffolds.11a The conditions facilitated
selective C2-arylation of the synthetic indole, in the presence
Introduction
Pd-mediated cross-couplings for the formation of C–C bonds of a tryptophan.11b
are well established and effective methods for selective functio-
Recently, we communicated a convenient method for the
nalisation and modification of simple molecular systems.1 C2-selective Pd-mediated direct arylation of a tryptophan
Metal-mediated direct C–H bond functionalisation has derivative 1a and tryptophan-containing peptides.8 The initial
emerged as a viable alternative2 to classical cross-coupling work for our Pd-mediated C–H bond functionalisation pro-
methodologies as they eliminate, either in part or in full, the cesses utilised conditions reported by Sanford et al. using
need for substrate pre-functionalisation, which potentially pre- PhB(OH)2 and PhI(OAc)2.12 This allowed access to the desired
sents improved utility in the synthesis of natural products3 C2-arylation product 2a in moderate yield (“Conditions A”,
and biomolecules.4 For example, we have reported the mild5 Scheme 1). The notable advantage of this protocol is the mild
and selective direct C–H bond functionalisation of sensitive temperature and use of readily available reagents to effect the
purine nucleosides, adenosine and 2′-deoxyadenosine.6 In this desired transformation.
paper we have focused on the development of unified synthetic
protocols facilitating the mild and efficient arylation of trypto- adding Cu(OAc)2 as a co-catalyst for re-oxidation of the Pd0
phan derivatives and tryptophan-containing peptides. (atmospheric air being the terminal oxidant) afforded 2a in an
It was found subsequently that eliminating PhI(OAc)2 and
Tryptophan is a hydrophobic, indole-containing amino acid improved yield of 93%. This methodology was then demon-
which alters the structure of proteins and is a natural fluo- strated on a series of arylboronic acids under the conditions
rescent marker.7 Extension of the π-system within tryptophans, described in Scheme 2 (“Conditions B”).
through conjugation with an aromatic group, significantly
“Conditions B” were successfully applied to the arylations
improves the intrinsic photophysical properties of the indole of two selected tryptophan-containing peptides 3 and 5
motif, which has been evidenced in 2-aryl-,8 5-aryl- and 7-aryl-
tryptophans.9c The 2-aryl-tryptophans can be accessed via clas-
sical Pd-mediated cross-couplings,9 or frontier-leading C–H
bond functionalisations.10 Ackermann et al. have reported the
selective metal-free arylation of engineered indole derivatives
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK.
E-mail: ian.fairlamb@york.ac.uk; Tel: +44 (0)1904 324091
†Electronic supplementary information (ESI) available: HPLC-ESI-MS data for
peptide arylations, UV-Vis spectra for novel compounds and NMR spectra for all
compounds. See DOI: 10.1039/c5ob01174d
Scheme 1 Direct arylation of tryptophan with PhI(OAc)2 using “Con-
ditions A”.
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of the arylating reagent formed in situ, i.e. whether the arylat-
ing reagent was derived from PhB(OH)2, PhI(OAc)2 or both.
ESI-HRMS (+ve mode) analysis of the product isotopologues
from this reaction indicated that an approximately
1 : 1 mixture of H- and D-labelled products were formed under
the reaction conditions. The outcome suggests that PhI(OAc)2
is not simply acting as an oxidant. Indeed, it has been pro-
posed previously that a mixture of an organoboronic acid and
PhI(OAc)2 can form an IIII-based arylating agent in situ under
similar reaction conditions. Our observation makes a more
convincing case for a role of an in situ generated symmetrical
Ph2I+ species, which adequately accounts for our observation.13
The non-selective aryl donation from the diaryliodonium(III)
species presented a potential synthetic problem, as it required
that the aryl group of the organoboronic acid matched that of
the IIII reagent, an issue which would become significant for
the introduction of substituted aromatic groups. The higher-
yielding “Conditions B” appeared an ideal way of circumvent-
ing this dilemma.
Scheme 2 Direct arylation of 1a with Cu(OAc)2 as a co-catalyst using
“Conditions B”.
In other work on the peptide arylation reactions mediated
by Pd and Cu, in the presence of PhB(OH)2 alone, it was found
that two specific tryptophan-containing peptides were suscep-
tible to aromatic oxidation, namely Ac-AlaTrpAla-OH and Ac-
SerGlyTrpAla-OH 9 (Scheme 5). From the reaction of AlaTr-
pAla-OH 7, arylation was noted along with complete loss of
starting material; HPLC-MS analysis also revealed the for-
Scheme 3 Direct arylation of two selected peptides using “Conditions B”.
(Scheme 3), both of which afforded high conversion to the
desired arylation products 4 and 6, respectively.
Results and discussion
With the primary goal of identifying unified synthetic proto-
cols facilitating the mild and efficient arylation of tryptophan
derivatives and tryptophan-containing peptides, a focus was
placed on understanding the role of the proposed oxidant in
the reaction described in Scheme 1, namely PhI(OAc)2.
An analogous experiment was conducted using d5-PhB-
(OH)2 (Scheme 4), which allows the delineation of the structure
Scheme 4 Direct arylation of tryptophan with d5-PhB(OH)2 using
“Conditions A”. Ratio of isotopologues 2a and 2a-d5 determined by
ESI-HRMS.
Scheme 5 Direct arylation of two peptides containing a C-terminal
alanine residue using “Conditions B”.
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mation of dihydroxylated byproducts as well as diarylated catalyst is not necessary for the reaction. Variation of the
byproducts (selectivity ratio 1 : 0.6 : 0.1). The reaction of Ac-Ser- solvent showed that MeCN, acetone or DMF were not viable
GlyTrpAla-OH 9 afforded the desired arylation product and (entries 2–4). Increasing yields, in a range of alcohols, were
i
similar dihdroxylation byproducts (selectivity ratio 1 : 1.4). The recorded, in the order MeOH < EtOH < PrOH (entries 5–7).
involvement of CuII in the oxidation process (i.e. oxidative C–H The best solvent however, was found to be EtOAc, which
bond activation)14 appears to be critical, as does the presence showed full conversion to 2a (entry 8, “Conditions C”).
of a terminal alanine neighbouring tryptophan. Free C-termi-
In addition to the desired phenylated product 2a, a small
nus alanines are known to form stable complexes with CuII,15 amount of the mesitylated product 2f was also isolated,
therefore it is proposed that such species are responsible for formed by donation of the sterically hindered mesityl group,
the observed hydroxylation of the arylated peptide products.
giving a product ratio of 2a : 2f of ca. 10 : 1 prior to purifi-
Given these limitations we chose to avoid the use of CuII as cation. In an attempt to prevent this non-selective arylation,
a co-catalyst, thus circumventing the over-oxidation issues. It the optimised conditions found in the solvent screen (Table 1,
was hypothesised that utilising a single arylating reagent entry 8) were used with another sterically-hindered 2,4,6-tri-
would be more appealing, also avoiding O2 as the terminal isopropylphenyl group on the iodonium salt (11b). This
oxidant required in the Pd/Cu chemistry. Upon recalling our however did not have the desired effect, as it appeared to lower
observations regarding the formation of Ph2I+ species in situ, the reactivity of the system and reduce product selectivity, with
we examined the reactivity of pre-synthesised highly electro- the ratio of 2a to tri-isopropylphenyl side product 2g being 5 : 1
philic diaryliodine(III) salts, which have garnered a great deal (Table 1, entry 9).
of interest for use in C–H bond functionalisations in recent
Application of “Conditions C” to small tryptophan-contain-
years.16 These species can be furnished with a sterically- ing peptides was next examined to assess the methodology
hindered aryl group which does not transfer in the catalytic against more structurally complex systems. A protection/
process to Pd (and the organic substrate), in tandem with a deprotection strategy was chosen to prepare small tryptophan-
second aryl group that can incorporate a range of chemical containing dipeptides, but the N-Ac protecting group pre-
substituents.
viously used for compound 1a proved synthetically challenging
Reaction of two equivalents of the [MesPhI]OTf salt 11a when utilised in these dipeptides. A switch to an N-Boc pro-
(readily synthesised in a high-yielding one-pot procedure)17 tecting group was therefore explored. During these efforts it
with 1a is shown under the conditions described in Table 1. was discovered that when the optimised arylation conditions
Pleasingly, in acetic acid this gave the desired arylation shown in Table 1, entry 8 (“Conditions C”) were applied to
product 2a in a yield of 65% (entry 1), indicating that a CuII co- N-Boc, O-Me protected tryptophan 1b, only a trace of the
desired arylation product was observed. Unreacted starting
material 1a was recovered along with the expected side pro-
ducts from the diaryliodonium salts used (i.e. iodobenzene/
iodomesitylene). A switch to the N-Tfa protecting group
circumvented this problem and when “Conditions C” were
applied to the N-Tfa, O-Me protected tryptophan 1c the desired
arylation product 12a was obtained in 82% isolated yield (with
17% of the undesired mesityl product 12b) (Scheme 6).
Table 1 Solvent screening in the direct arylation of 1a using
[MesPhI]OTfa
“Conditions C” were demonstrated on the dipeptides Tfa-
GlyTrp-OMe 13 and Tfa-LeuTrp-OMe 15 (Scheme 7), affording
the desired arylation products 14a and 16a in moderate to
good yields, thus highlighting the utility of this protocol when
applied to small tryptophan-containing peptides.
“Conditions C” were also applied to peptides 7 and 9,
which had proved problematic with the Cu-containing “Con-
ditions B” (Scheme 5), affording the desired arylation products
2ab, %
2fb, %
Entry
Solvent
(yield, %)c
(yield, %)c
1
2
3
4
5
6
7
8
9
AcOH (at 40 °C)
MeCN
Acetone
DMF
70 (65)
0
0
0
12
15
47
91 (85)
50
0
0
0
0
0
0
3
MeOH
EtOH
iPrOH
EtOAcd
EtOAce, f
9 (3)
10
a All reactions conducted with 1a (0.192 mmol), 11a (0.384 mmol),
Pd(OAc)2 (5 mol%) and solvent (5 mL) at 25 °C, unless otherwise stated.
b Conversion determined by 1H NMR spectroscopic analysis.
c Following flash column chromatography. d Referred to throughout as
“Conditions C”. e Using iodonium triflate salt 11b (0.384 mmol),
containing a 2,4,6-tri-isopropylphenyl group, instead of 11a. f 50% 2a,
10% 2g rather than 2f, 40% starting material (1a).
Scheme 6 Effect of N-protecting group on the direct arylation of
tryptophans using “Conditions C”.
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Our previous work demonstrated the use of both an aryl
boronic acid/iodobenzene diacetate system (“Conditions A”) as
well as conditions utilising Cu(II) as a co-catalyst (“Conditions
B”).8 These conditions allowed several C2-aryl tryptophan ana-
logues to be accessed in high yields. The use of a CuII salt was
shown to be incompatible with certain peptidic motifs; in the
examples tested a free C-terminal alanine neighbouring trypto-
phan proved problematic, leading to aromatic oxidation
(major competing side reactions) and also diarylation (minor
competing side reaction), demonstrating poor product selecti-
vity (1 : 0.6 : 0.1 and 1 : 1.4).
Our methodology was therefore extended to the use of pre-
synthesised asymmetric diaryliodonium salts (“Conditions C”),
the arylation conditions for which have been developed and
optimised to proceed effectively at 25 °C in ethyl acetate under
air (which is not necessary as an oxidant, but allows reactions
to be run conveniently without the need for inert conditions).
Other advantages of “Conditions C” include the avoidance of
strong oxidants and metal co-catalysts (e.g. CuII). These con-
ditions have been successfully applied to small tryptophan-
containing peptides and the desired arylation products
obtained with complete selectively and in synthetically useful
yields, without the undesirable aromatic oxidation previously
observed.
Scheme 7 Direct arylation of two selected peptides using a diaryliodo-
nium salt (“Conditions C”).
Our current work is involved with extending these methodo-
logies to more complex systems, as well as examining the
underlying mechanisms involved with the arylation of 1a and
derivatives under the different reaction conditions described
within this paper.
Experimental
General experimental details
Scheme 8 Direct arylation of peptides susceptible to dihydroxylation
using a diaryliodonium salt.
Commercially available reagents were purchased from Sigma
Aldrich, Fluorochem, Fisher Scientific, Alfa Aesar or Acros
Organics and used as received unless otherwise noted. Room
temperature (rt) refers to reactions where no thermostatic
control was applied and was recorded as 16–22 °C. Petrol
refers to the fraction of petroleum ether boiling in the range of
40–60 °C. Dry THF was first obtained from a Pure Solv MD-7
solvent machine and stored under nitrogen, then dried further
and any hydroperoxide species removed by refluxing over
sodium for 3 days and distilling under argon. Dry methanol
was obtained by drying over activated 3 Å molecular sieves and
storing under nitrogen. Triethylamine (Et3N) and diisopropyl-
ethylamine (DIPEA) were distilled from potassium hydroxide
and stored under nitrogen. Air sensitive procedures were per-
formed using standard Schlenk techniques and carried out in
oven- or flame-dried glassware. Nitrogen gas was oxygen free
and dried immediately prior to use by passing through a
8 and 10 (Scheme 8); for these polar molecules, isopropanol
was used in place of ethyl acetate as the reaction solvent. None
of the mesityl byproduct was detected in these reactions, poss-
ibly because of greater steric encumbrance from the peptides
as compared to a single tryptophan residue. Importantly “Con-
ditions C” provide complete selectivity for the desired arylation
products, addressing the drawbacks of “Conditions B” high-
lighted, pleasingly this is also achieved at significantly lower
catalyst loadings.
Conclusion
The global aim of this study was to develop synthetic protocols column of potassium hydroxide pellets and silica. Thin layer
that facilitate the mild and efficient arylation of tryptophan chromatography (TLC) analysis was performed using Merck
derivatives and tryptophan-containing peptides. This has been 5554 aluminium backed silica plates and visualised using UV
broadly achieved, with the different reaction conditions (A–C) light (λmax = 254 nm). All flash column chromatography was
being particularly attractive and highly complementary.
performed using Merck silica gel 60 (particle size 40–63 µm)
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and a solvent system as stated in the text. Retardation factors was collected and dried over MgSO4, filtered and the solvent
are quoted to two decimal places. Optical rotations were removed under reduced pressure to give the crude residue.
recorded using a JASCO DIP-370 digital polarimeter at 20 °C The residue was dry-loaded onto silica gel and purified by
(using the sodium D line, 259 nm) using a path length of flash column chromatography to give the title compound.
100 mm and at a concentration indicated in the text. The
General procedure 2: preparation of diaryl iodonium salts17
Bis(acetyloxy)phenyl-λ3-iodane (1 eq.) and the desired aryl sub-
ings taken for each sample and the average [α]D values in units
appropriate solvent was used as a background with ten read-
of 10−1 deg cm3 g−1 are quoted to one decimal place. Melting
strate (1.1 eq.) were added to a round-bottomed flask and dis-
points were recorded using a Stuart digital SMP3 machine and
are quoted to the nearest whole number. Where applicable,
decomposition (dec) is noted. NMR spectra were recorded on
either a Jeol ECS400 or Jeol ECX400 spectrometer and pro-
cessed using MestReNova. Spectra were typically recorded at
298 K, unless otherwise specified. Chemical shifts are reported
in parts per million (ppm). Coupling constants are reported in
Hz and quoted to 0.5 Hz. Multiplicities are described as
singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin),
sextet, (sext), heptet (hept), multiplet (m), apparent (app) and
broad (br). 1H NMR spectra were typically recorded at
400 MHz. Chemical shifts are internally referenced to residual
undeuterated solvent and given to two decimal places. 13C
NMR spectra were recorded at 101 MHz. Chemical shifts are
internally referenced to residual undeuterated solvent and
given to one decimal place. 11B NMR spectra were recorded at
128 MHz and obtained with 1H decoupling. Chemical shifts
are externally referenced to BF3·OEt2 and given to one decimal
place. 19F NMR spectra were recorded at 376 MHz and
obtained with 1H decoupling. Chemical shifts are externally
referenced to CFCl3 and given to one decimal place. 31P NMR
spectra were recorded at 162 MHz and obtained with 1H
decoupling. Chemical shifts are externally referenced to H3PO4
and given to one decimal place. Mass spectrometry was per-
solved in CH2Cl2. The mixture was cooled to 0 °C then
trifluoromethanesulfonic acid (1.1 eq.) was added dropwise
with stirring. After complete addition the reaction was stirred
for 2 h over which time it was allowed to warm to rt. After 2 h
the solvent was removed under reduced pressure to give an
orange-white residue to which Et2O was added to precipitate a
white solid. This was filtered through a glass sinter and
washed on the filter with more Et2O until the filtrate ran clear
of coloured components. The solid was then dried in vacuo at
100 °C to give the title compound.
General procedure 3: direct arylation using diaryl iodonium
salts (“Conditions C”)
To a microwave tube was added substrate (1 eq.), the desired
diaryl iodonium salt (2 eq.), Pd(OAc)2 (5 mol%) and EtOAc.
The reaction mixture was stirred at 25 °C for 16 h. The result-
ing black reaction mixture was filtered through Celite then
washed with sat. aq. NaHCO3. The organic layer was collected
and dried over MgSO4, filtered and the solvent removed under
reduced pressure to give the crude residue. This was dry-
loaded onto silica gel and purified by flash column chromato-
graphy to give the title compound.
Methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate hydrochlo-
formed using a Bruker Daltronics micrOTOF spectrometer ride.18 To a Schlenk tube under N2 was added dry MeOH
using electrospray ionization (ESI). Mass to charge ratios (m/z) (50 mL). Thionyl chloride (4.3 mL, 7.02 g, 59 mmol, 2.4 eq.)
are reported in Daltons with percentage abundance in paren- was added dropwise at −15 °C. L-Tryptophan 20 (5 g,
theses along with the corresponding fragment ion, where 24.5 mmol, 1 eq.) was then added in three portions, resulting
known. Where complex isotope patterns were observed, the in a white suspension. The reaction mixture was warmed to
most abundant ion is reported. High resolution mass spectra ambient temperature and stirred for 24 h. During this time a
are reported with <5 ppm error. IR spectrometry was per- clear orange solution was formed. Water (5 mL) was added to
formed using a Bruker Alpha FT-IR spectrometer and signals the reaction mixture and the solvent removed under reduced
are reported in wavenumbers (cm−1) to the nearest whole pressure to give product as an off-white solid (6.18 g, 99%). Mp
1
number. UV-visible spectroscopy was performed using a Jasco 205–206 °C dec (lit.19 214 °C dec); H NMR (400 MHz, CD3OD,
V-560 spectrometer. A baseline in the appropriate solvent was δ): 10.61 (br s, 1H), 7.54 (dt, J = 8.0, 1.0 Hz, 1H), 7.40 (dt, J =
obtained prior to recording spectra. Elemental (CHN) analysis 8.0, 1.0 Hz, 1H), 7.22 (s, 1H), 7.14 (ddd, J = 8.0, 7.0, 1.0 Hz,
was carried out using an Exeter Analytical CE-440 Elemental 1H), 7.07 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.33 (dd, J = 7.5, 5.5
Analyser. All values are given as percentages to two decimal Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J = 15.0, 5.5 Hz, 1H), 3.37 (dd,
places. “Conditions A” and “Conditions B” are also reported in J = 15.0, 7.5 Hz, 1H); 13C NMR (101 MHz, CD3OD, δ): 170.8,
our preliminary communication on this work.8
138.3, 128.2, 125.6, 122.9, 120.3, 118.8, 112.7, 107.4, 54.6, 53.6,
27.5; ESI-MS m/z (ion, %): 219 ([M − Cl]+, 100); ESI-HRMS m/z:
219.1130 [M − Cl]+ (calc. for C12H15N2O2 219.1128); IR (solid
state ATR, cm−1): 3259, 2856, 1747, 1501, 1436, 1351, 1210,
General procedure 1: direct arylation using arylboronic acids
(“Conditions B”)8
To a microwave tube was added substrate (1 eq.), the desired 1108, 730; anal. calc. for C12H15ClN2O2: C 56.58, H 5.94,
boronic acid (2 eq.), Cu(OAc)2 (10 mol%), Pd(OAc)2 (5 mol%) N 11.00 found: C 56.44, H 5.85, N 10.87.
and AcOH. The reaction mixture was stirred at 40 °C for 16 h.
Methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate,
The resulting brown reaction mixture was filtered through 1a .18 To a three-necked round-bottomed flask fitted with a
Celite then washed with sat. aq. NaHCO3. The organic layer reflux condenser and purged with N2 was added methyl
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(2S)-2-amino-3-(1H-indol-3-yl)propanoate hydrochloride (3 g, for 16 h, during which time a clear solution formed. After 16 h
13.7 mmol, 1 eq.), dry THF (150 mL) and dry triethylamine the solvent was removed under reduced pressure and the
(2 mL). The mixture was stirred to give a white suspension resulting residue acidified with 2 M HCl, before being
before being cooled to 0 °C, then acetic anhydride (1.4 mL, extracted into EtOAc three times. The organic layers were com-
1.5 g, 15.1 mmol, 1.1 eq.) was added in one portion. The reac- bined then washed with brine, dried over MgSO4, filtered and
tion was then stirred for 2 h at 80 °C to give a white suspen- the solvent removed under reduced pressure to give the
sion. This was added to deionised water (150 mL) and product as an off-white solid (1.35 g, 90%). Rf 0.16 (3 : 1 petrol/
extracted into EtOAc (3 × 150 mL). The organic layers were EtOAc v/v); [α]D = +50.7 (c 0.10, CHCl3); Mp 108–109 °C (lit.23
combined and washed sequentially with
1 M
aq. HCl 107–109 °C); 1H NMR (400 MHz, CDCl3, δ): 8.30–8.18 (br s,
(100 mL), sat. aq. NaHCO3 (100 mL) and brine (100 mL). The 1H), 7.54–7.47 (m, 1H), 7.36 (dt, J = 8.0, 1.0 Hz, 1H), 7.22 (ddd,
organic layer was collected and dried over MgSO4, filtered and J = 8.0, 7.0, 1.0 Hz, 1H), 7.15 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.96
the solvent removed under reduced pressure to give a colour- (d, J = 2.5 Hz, 1H), 6.95 (s, 1H), 4.94 (dt, J = 8.0, 5.0 Hz, 1H),
less oil. Trituration with Et2O resulted in the product as an off- 3.73 (s, 3H), 3.42 (dd, J = 5.0, 1.0 Hz, 2H); 13C NMR (101 MHz,
2
white solid (2.93 g, 82%). [α]D = +41.5 (c 0.10, CHCl3); Mp CDCl3, δ): 170.8, 156.9 (q, JCF = 37.5), 136.2, 127.4, 123.1,
1
1
154–155 °C (lit.19 155–156 °C); H NMR (400 MHz, CDCl3, δ): 122.6, 120.0, 118.3, 116.3 (q, JCF = 287.0), 111.6, 108.8, 53.5,
8.27 (s, 1H), 7.53 (dd, J = 8.0, 1.0 Hz, 1H), 7.39–7.33 (m, 1H), 53.0, 27.2; 19F NMR (376 MHz, CDCl3, δ): −75.8; ESI-MS m/z
7.19 (ddd, 8.0, 7.0, 1.0 Hz, 1H), 7.12 (ddd, J = 8.0, 7.0, 1.0 Hz, (ion, %): 315 ([M + H]+, 50), 332 ([M + NH4]+, 40), 337
1H), 6.97 (d, J = 2.5 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 4.96 (dt, ([M + Na]+, 100), 353 ([M + K]+, 10); ESI-HRMS m/z: 315.0950
J = 8.0, 5.0 Hz, 1H), 3.70 (s, 3H), 3.35 (dd, J = 15.0, 5.0 Hz, 1H), [M + H]+ (calc. for C14H14F3N2O3 315.0951).
3.29 (dd, J = 15.0, 5.0 Hz, 1H), 1.95 (s, 3H); 13C NMR (101 MHz,
Methyl (2S)-2-acetamido-3-(2-phenyl-1H-indol-3-yl)propano-
CDCl3, δ): 172.6, 169.4, 136.1, 127.1, 123.7, 120.1, 118.4, 118.0, ate, 2a. Method A (“Conditions A”): To a microwave tube was
111.5, 109.6, 53.2, 51.8, 27.1, 22.3; ESI-MS m/z (ion, %): 261 added phenylboronic acid (47 mg, 0.384 mmol, 2 eq.), bis(acetyl-
([M + H]+, 5), 283 ([M + Na]+, 100); ESI-HRMS m/z: 283.1053 oxy)phenyl-λ3-iodane (123 mg, 0.384 mmol, 2 eq.), Pd(OAc)2
[M + Na]+ (calc. for C14H16N2O3Na 283.1053); IR (solid state, (2 mg, 9.6 μmol, 5 mol%) and AcOH (5 mL). The reaction
ATR, cm−1): 3405, 3315, 1732, 1661, 1520, 1434, 1220, 1123, mixture was stirred at 40 °C for 10 min. To the resulting
746, 665, 613, 519, 427; anal. calc. for C14H16N2O3: C 64.60, orange-brown solution was added methyl (2S)-2-acetamido-3-
H 6.20, N 10.76 found C 64.34, H 6.23, N 10.47.
(1H-indol-3-yl)propanoate (50 mg, 0.192 mmol, 1 eq.) 1a. The
Methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(1H-indol-3- reaction was stirred at 40 °C for 16 h. The resulting black reac-
yl)propanoate, 1b.20 To a round-bottomed flask containing a tion mixture was filtered through Celite, and the solvent
solution of methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate removed under reduced pressure to give a brown solid. This
hydrochloride (100 mg, 0.39 mmol, 1 eq.) and K2CO3 (54 mg, was dissolved in EtOAc (10 mL) then washed with sat. aq.
0.39, 1 eq.) in deionised water (1 mL) was added a solution of NaHCO3. The organic layer was collected and dried over
di-tert-butyl dicarbonate (85 mg, 0.39 mmol, 1 eq.) in acetone MgSO4, filtered and the solvent removed under reduced
(1 mL) at 0 °C with stirring. The solution was stirred for 2 h pressure to give a brown solid. This was dry-loaded onto silica
during which time it was allowed to warm to rt. After 2 h the gel and purified by flash column chromatography (40% petrol/
acetone was removed under reduced pressure and deionised EtOAc, v/v) to give product as an off-white solid (36 mg, 56%).
water added. This was extracted into EtOAc three times, dried Method B: Synthesised using General Procedure 1 from
over MgSO4, filtered and the solvent removed under reduced methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate 1a (50 mg,
pressure to give the product as an off-white solid (117 mg, 0.192 mmol, 1 eq.), phenylboronic acid (47 mg, 0.384 mmol,
94%). [α]D = +43.1 (c 0.10, CHCl3); Mp 146–148 °C (lit.21 2 eq.), Cu(OAc)2 (3.5 mg, 19.2 µmol, 10 mol%) and Pd(OAc)2
145–146 °C); 1H NMR (400 MHz, CDCl3, δ): 8.20 (br s, 1H), (2 mg, 9.6 µmol, 5 mol%) in AcOH (5 mL). Flash column
7.58–7.53 (m, 1H), 7.35 (dt, J = 8.0, 1.0 Hz, 1H), 7.19 (ddd, J = chromatography (40% petrol/EtOAc, v/v) gave the product as
8.0, 7.0, 1.0 Hz, 1H), 7.12 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.99 an off-white solid (60 mg, 93%). Method C: Synthesised using
(s, 1H), 5.09 (d, J = 8.0 Hz, 1H), 4.71–4.59 (m, 1H), 3.68 (s, 3H), General Procedure 3 from methyl (2S)-2-acetamido-3-(1H-
3.29 (dd, J = 5.5, 3.0 Hz, 2H), 1.43 (s, 9H); 13C NMR (101 MHz, indol-3-yl)propanoate 1a (50 mg, 0.192 mmol, 1 eq.), phenyl
CDCl3, δ): 172.9, 155.4, 136.3, 127.6, 123.0, 122.1, 119.5, 118.6, (2,4,6-trimethylphenyl)iodonium
trifluoromethanesulfonate
111.4, 109.8, 80.0, 54.3, 52.3, 28.4, 28.0; ESI-MS m/z (ion, %): 11a (181 mg, 0.384 mmol, 2 eq.) and Pd(OAc)2 (2 mg, 9.6 μmol,
319 ([M + H]+, 14), 341 ([M + Na]+, 100); ESI-HRMS m/z: 5 mol%) in EtOAc (5 mL). Flash column chromatography (40%
341.1465 [M + Na]+ (calc. for C17H22N2NaO4 341.1472).
petrol/EtOAc, v/v) gave the product as an off-white solid
Methyl (2S)-3-(1H-indol-3-yl)-2-(trifluoroacetamido)propano- (55 mg, 85%). Rf 0.27 (40% petrol/EtOAc v/v); [α]D = +47.3
ate, 1c .22 To a round-bottomed flask containing methyl (c 0.10, CHCl3); Mp 83–84 °C (lit.24 85–86 °C); 1H NMR
(2S)-2-amino-3-(1H-indol-3-yl)propanoate hydrochloride (1.27 g, (400 MHz, CDCl3, δ): 8.20 (s, 1H), 7.60–7.54 (m, 3H), 7.51–7.45
5 mmol, 1 eq.) was added Et3N (0.75 mL, 0.54 g, 5 mmol, (m, 2H), 7.42–7.34 (m, 2H), 7.21 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H),
1 eq.) and MeOH (2.5 mL) and the resulting suspension stirred 7.14 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 5.79 (d, J = 8.0 Hz, 1H), 4.84
for 5 min. After 5 min ethyl trifluoroacetate (0.85 mL, 1.01 g, (dt, J = 8.0, 5.5 Hz, 1H), 3.55 (dd, J = 5.5, 1.0 Hz, 2H), 3.29
6.35 mmol, 1.27 eq.) was added and the mixture stirred at rt (s, 3H), 1.66 (s, 3H); 13C NMR (101 MHz, (CDCl3, δ): 172.3,
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1
169.9, 136.1, 135.9, 133.3, 129.4, 129.1, 128.4, 128.0, 122.5, dec; H NMR (400 MHz, CDCl3, δ): 8.18 (br s, 1H), 7.56 (ddt,
120.0, 118.8, 111.2, 106.5, 52.9, 52.1, 26.6, 22.9; ESI-MS m/z J = 8.0, 1.5, 1.0 Hz, 1H), 7.54–7.48 (m, 2H), 7.34 (dt, J = 8.0, 1.0
(ion, %): 337 ([M + H]+, 40), 359 ([M + Na]+, 100); ESI-HRMS Hz, 1H), 7.20 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.17–7.12 (m, 3H),
m/z: 337.1546 [M + H]+ (calc. for C20H20N2O3 337.1547); 5.84 (d, J = 8.0 Hz, 1H), 4.83 (dt, J = 8.0, 5.5 Hz, 1H), 3.56–3.40
IR (solid state ATR, cm−1): 3272, 1735, 1651, 1519, 1436, 1373, (m, 2H), 3.33 (s, 3H), 1.70 (s, 3H); 13C NMR (101 MHz, (CDCl3,
1
1215, 739, 696, 496.
Methyl
δ): 172.3, 169.7, 162.9 (d, JCF = 249.0 Hz), 135.8, 135.1, 130.3
3
4
(2S)-2-acetamido-3-[2-(4-methylphenyl)-1H-indol- (d, JCF = 8.0 Hz), 129.5, 129.4 (d, JCF = 3.5 Hz), 122.8, 120.3,
2
3-yl]propanoate, 2b. Synthesised using General Procedure 1 119.0, 116.3 (d, JCF = 21.5 Hz), 111.1, 107.0, 52.9, 52.2, 26.8,
from methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate 1a 23.1; 19F NMR (376 MHz, CDCl3, δ): −112.8–−112.9 (m);
(50 mg, 0.192 mmol, 1 eq.), 4-methylphenylboronic acid ESI-MS m/z (ion, %): 355 ([M + H]+, 60), 377 ([M + Na]+, 100);
(52 mg, 0384 mmol, 2 eq.), Cu(OAc)2 (3.5 mg, 19.2 µmol, ESI-HRMS m/z: 355.1442 [M + H]+ (calc. for C20H20FN2O3
10 mol%) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in AcOH 355.1452).
(5 mL). Flash column chromatography (1 : 1 petrol/EtOAc, v/v)
gave the product as an off-white solid (59 mg, 88%). Rf 0.32 indol-3-yl}propanoate, 2e. Synthesised using General Pro-
(1 : 1 EtOAc/petrol); [α]D = +51.9 (c 0.11, CHCl3); Mp 97–99 °C; cedure from methyl (2S)-2-acetamido-3-(1H-indol-3-yl)
Methyl (2S)-2-acetamido-3-{2-[4-(trifluoromethyl)phenyl]-1H-
1
1H NMR (400 MHz, CDCl3, δ): 8.09 (s, 1H), 7.56 (d, J = 8.0 Hz, propanoate 1a (50 mg, 0.192 mmol, 1 eq.), 4-(trifluoromethyl)-
1H), 7.48–7.44 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.30 (d, J = phenylboronic acid (36 mg, 0.384 mmol, 2 eq.), Cu(OAc)2
8.0 Hz, 2H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.13 (ddd, J = (3.5 mg, 19.2 µmol, 10 mol%) and Pd(OAc)2 (2 mg, 9.6 µmol,
8.0, 7.0, 1.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 4.82 (dt, J = 8.0, 5 mol%) in AcOH (5 mL). Flash column chromatography (1 : 1
5.5 Hz, 1H), 3.53 (d, J = 5.5 Hz, 1H), 3.52 (d, J = 5.5 Hz, 1H), petrol/EtOAc, v/v) gave the product as a brown solid (45 mg,
3.33 (s, 3H), 2.41 (s, 3H), 1.66 (s, 3H); 13C NMR (126 MHz, 58%). Rf 0.34 (1 : 1 EtOAc/petrol); [α]D = +62.0 (c 0.13, CHCl3);
CDCl3, δ): 172.3, 169.8, 138.0, 136.2, 135.7, 130.3, 128.2, 122.4, Mp 202–206 °C; 1H NMR (400 MHz, CDCl3, δ): 8.41 (s, 1H),
120.0, 118.8, 111.1, 106.4, 60.5, 53.0, 52.1, 26.7, 22.9, 21.3, 7.72–7.63 (m, 4H), 7.58 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz,
14.3; ESI-MS m/z (ion, %): 391 ([M + H]+), 100); ESI-HRMS m/z: 1H), 7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.15 (ddd, J = 8.2, 7.0,
350.1628 [M + H]+ (calc. for C21H22N2O3 350.1630); IR (solid 1.2 Hz, 1H), 5.87 (d, J = 8.0 Hz, 1H), 4.84 (dt, J = 8.0, 5.2 Hz,
state ATR, cm−1
)
3331, 2951, 1731, 1657, 1506, 1372, 1H), 3.59–3.48 (m, 2H), 3.29 (s, 3H), 1.67 (s, 3H); 13C NMR
1305, 1215, 1010, 822, 742; UV-Vis (DMSO, nm) λmax 310 (ε = (101 MHz, CDCl3, δ): 172.2, 169.9, 136.9, 136.1, 134.3, 129.9
2
3
8893 mol dm−3 cm−1).
(q, JCF = 32.0 Hz), 129.5, 128.5, 126.1 (q, JCF = 4.0 Hz), 124.1
1
Methyl (2S)-2-acetamido-3-[2-(4-methoxyphenyl)-1H-indol- (q, JCF = 247.0 Hz), 123.3, 120.4, 119.2, 111.4, 108.2, 53.0,
3-yl]propanoate, 2c. Synthesised using General Procedure 1 52.2, 27.0, 23.0; ESI-MS m/z (ion, %): 405 ([M + H]+, 30), 427
from methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate 1a ([M + Na]+, 100); ESI-HRMS m/z: 405.1410 [M + H]+ (calc. for
(50 mg, 0.192 mmol, 1 eq.), 4-methoxyphenylboronic acid C21H20F3N2O3 405.1421); IR (solid state ATR, cm−1) 3288, 2925,
(58 mg, 0384 mmol, 2 eq.), Cu(OAc)2 (3.5 mg, 19.2 µmol, 2860, 1730, 1651, 1505, 1438, 1285, 1245, 1215, 1027, 835, 743;
10 mol%) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in AcOH UV-Vis (DMSO, nm) λmax 318 (ε = 10 297 mol dm−3 cm−1).
(5 mL). Flash column chromatography (1 : 1 petrol/EtOAc, v/v)
gave the product as a brown solid (20 mg, 28%). Rf 0.15 (1 : 1 indol-3-yl]propanoate, 2f. Synthesised using General Pro-
EtOAc/petrol v/v); [α]D = +34.9 (c 0.10, CHCl3); Mp 202–205 °C; cedure from methyl (2S)-2-acetamido-3-(1H-indol-3-yl)-
Methyl
(2S)-2-acetamido-3-[2-(2,4,6-trimethylphenyl)-1H-
3
1H NMR (400 MHz, CDCl3, δ): 8.56 (br s, 1H), 7.57–7.51 propanoate 1a (50 mg, 0.192 mmol, 1 eq.), phenyl (2,4,6-
(m, 1H), 7.46–7.39 (m, 2H), 7.34–7.28 (m, 1H), 7.17 (dd, J = 7.0, trimethylphenyl)iodonium trifluoromethanesulfonate 11a
1.5 Hz, 1H), 7.12 (dd, J = 7.0, 1.5 Hz, 1H), 6.95–6.90 (m, 2H), (181 mg, 0.384 mmol, 2 eq.) and Pd(OAc)2 (2 mg, 9.6 μmol,
5.85 (d, J = 8.0 Hz, 1H), 4.81 (dt, J = 8.0, 5.5 Hz, 1H), 3.81 5 mol%) in EtOAc (5 mL). Flash column chromatography (40%
(s, 3H), 3.48 (d, J = 5.5 Hz, 2H), 3.34 (s, 3H), 1.66 (s, 3H); petrol/EtOAc, v/v) gave the product as an off-white solid (2 mg,
13C NMR (101 MHz, (CDCl3, δ): 172.4, 169.8, 159.5, 136.1, 3%). Rf 0.31 (1 : 1 EtOAc/petrol v/v); [α]D = +35.2 (c 0.10,
135.7, 129.6, 129.5, 125.6, 122.2, 119.9, 118.6, 114.6, 111.1, CHCl3); Mp 158–159 °C; 1H NMR (400 MHz, CDCl3, δ): 7.89 (br
105.9, 55.5, 53.0, 52.2, 26.7, 23.0; ESI-MS m/z (ion, %): 367 s, 1H), 7.61 (ddt, J = 7.5, 1.5, 1.0 Hz, 1H), 7.37–7.33 (m, 1H),
([M + H]+, 50), 389 ([M + Na]+, 100); ESI-HRMS m/z: 389.1458 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.99 (ddt,
[M + Na]+ (calc. for C21H22N2NaO4 389.1472).
Methyl (2S)-2-acetamido-3-[2-(4-fluorophenyl)-1H-indol-3-yl]- 7.5, 7.0, 5.0 Hz, 1H), 3.47 (s, 3H), 3.17 (dd, J = 15.0, 5.0 Hz,
propanoate, 2d. Synthesised using General Procedure 1H), 3.02 (dd, J = 15.0, 7.0 Hz, 1H), 2.35 (s, 3H), 2.11 (d, J =
J = 4.0, 1.5, 1.0 Hz, 2H), 5.64 (d, J = 7.5 Hz, 1H), 4.72 (ddd, J =
1
from methyl (2S)-2-acetamido-3-(1H-indol-3-yl)propanoate 1a 1.0 Hz, 6H), 1.75 (s, 3H); 13C NMR (101 MHz, (CDCl3, δ): 172.5,
(50 mg, 0.192 mmol, 1 eq.), 4-fluorophenylboronic acid 169.9, 138.9, 138.3, 138.2, 135.9, 134.7, 128.8, 128.7, 128.7,
(54 mg, 0384 mmol, 2 eq.), Cu(OAc)2 (3.5 mg, 19.2 µmol, 128.6, 122.1, 119.9, 118.8, 110.9, 108.0, 100.1, 53.1, 52.3, 27.2,
10 mol%) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in AcOH 23.1, 21.3, 20.4, 20.3; ESI-MS m/z (ion, %): 379 ([M + H]+, 40),
(5 mL). Flash column chromatography (1 : 1 petrol/EtOAc, v/v) 401 ([M + Na]+, 100); ESI-HRMS m/z: 379.2015 [M + H]+ (calc.
gave the product as a brown solid (52 mg, 77%). Rf 0.23 (1 : 1 for C23H27N2O3 379.2016); IR (solid state, ATR, cm−1): 3402,
EtOAc/petrol v/v); [α]D = +54.4 (c 0.10, CHCl3); Mp 213–216 °C 3289, 2953, 2919, 2852, 1741, 1646, 1515, 1458, 1435, 1373,
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1304, 1293, 1260, 1239, 1218, 1129, 1031, 1012, 987, 854, 798, 7.61–7.50 (m, 3H), 7.50–7.41 (m, 2H), 7.39–7.33 (m, 2H), 7.19
744, 591, 505, 445; UV-Vis (DMSO, nm): λmax 288 (ε = (ddd, J = 8.0, 7.0, 1.5 Hz, 1H), 7.15 (s, ddd, J = 8.0, 7.0, 1.5, 1H),
15 092 mol dm−3 cm−1).
6.18 (br d, J = 8.0 Hz, 1H), 5.95 (br t, J = 5.0 Hz, 1H), 4.80
2-Acetamidoacetic acid. To a round-bottomed flask was (dt, J = 8.0, 5.5 Hz, 1H), 3.66–3.38 (m, 4H), 3.34 (s, 3H), 1.87
added glycine (5 g, 66.6 mmol, 1 eq.) and water (150 mL). To (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.8, 170.3, 168.3,
this, acetic anhydride (18.9 mL, 20.4 g, 200 mmol, 3 eq.) was 136.2, 135.9, 133.2, 129.4, 129.3, 128.4, 128.2, 122.8, 120.2,
added dropwise and the reaction mixture was stirred at rt for 118.8, 111.3, 106.5, 77.4, 53.1, 52.3, 42.7, 26.6, 23.0; ESI-MS
1 h. The mixture was then cooled to 4 °C for 16 h, and the m/z (ion, %): 394 ([M + H]+, 10), 416 ([M + Na]+, 100); ESI-HRMS
resulting precipitate collected by filtration through a sintered m/z: 394.1763 [M + H]+ (calc. for C22H24N3O4 394.1761).
funnel to give product as a white solid (4.46 g, 57%). Mp
Arylated product of Ac-TrpLysLeuValGlyAla-OH 5, 6. To a
207–208 °C (lit.25 206–208 °C dec); 1H NMR (400 MHz, microwave tube was added peptide 5 (10 mg, 0.014 mmol, 1
(CD0)2SO) δ 12.51 (s, 1H), 8.18 (s, 1H), 3.71 (d, J = 6.0 Hz, 2H), eq.), phenylboronic acid (8.5 mg, 0.07 mmol, 5 eq.), Cu(OAc)2
1.84 (s, 3H); 13C NMR (101 MHz, (CD3)2SO) δ 171.5, 169.6, (1.5 mg, 0.0084 mmol, 60 mol%), Pd(OAc)2 (0.9 mg,
40.6, 22.3; ESI-MS m/z (ion, %): 118 ([M + H]+, 40), 140 ([M + 0.0042 mmol, 30 mol%) and AcOH (1 mL). The reaction
Na]+, 100); ESI-HRMS m/z: 118.0501 [M + H]+ (calc. for mixture was stirred at 40 °C for 16 h. The solvent was removed
C4H8NO3 118.0499); IR (solid state ATR, cm−1) 3350, 1944, under reduced pressure to give a brown residue, which was
1897, 1717, 1580, 1547, 1439, 1379, 1351, 1276, 1227, 1137, analysed by HPLC-ESI-MS. ESI-MS m/z (ion, %): 791 (M+, 86).
993, 902. 682.
Arylated product of Ac-AlaTrpAla-OH 7, 8. Method A: To a
Methyl (2S)-2-(2-acetamidoacetamido)-3-(1H-indol-3-yl)- microwave tube was added peptide 7 (10 mg, 0.026 mmol,
propanoate, 3. To a Schlenk tube was added methyl (2S)- 1 eq.), phenylboronic acid (16 mg, 0.13 mmol, 5 eq.), Cu(OAc)2
2-amino-3-(1H-indol-3-yl)propanoate hydrochloride (190 mg, (2.8 mg, 0.0156 mmol, 60 mol%), Pd(OAc)2 (1.8 mg,
0.872 mmol,
1 eq.), 2-Acetamidoacetic acid (102 mg, 0.0078 mmol, 30 mol%) and AcOH (1 mL). The reaction
0.872 mmol, 1 eq.) and N-(3-Dimethylaminopropyl)-N′-ethyl- mixture was stirred at 40 °C for 16 h. The solvent was removed
carbodiimide hydrochloride (EDC·HCl) (167 mg, 0.872 mmol, under reduced pressure to give a brown residue, which was
1 eq.). The reaction mixture was placed under vacuum and analysed by HPLC-ESI-MS. Method B: To a microwave tube was
refilled with N2, and this process repeated twice. Dry CH2Cl2 added peptide 7 (10 mg, 0.026 mmol, 1 eq.), phenyl(2,4,6-
(5 mL) was added, and the mixture stirred for 16 h at ambient trimethylphenyl)iodonium trifluoromethanesulfonate, 11a
temperature. The solvent was removed under reduced (25 mg, 0.052 mmol, 2 eq.), Pd(OAc)2 (0.6 mg, 0.0026 mmol,
i
pressure. The resulting residue was dissolved in EtOAc (15 mL) 10 mol%) and PrOH (1 mL). The reaction mixture was stirred
and washed with 1 M aq. HCl (20 mL), sat. aq. NaHCO3 at 25 °C for 16 h. The resulting brown reaction mixture was fil-
(40 mL) and brine (40 mL). The organic layer was collected tered through Celite with MeOH (5 mL) and the solvent
and dried over MgSO4, filtered and the solvent removed under removed under reduced pressure to give a brown residue,
reduced pressure to give product as a white solid (96 mg, which was analysed by HPLC-ESI-MS. ESI-MS m/z (ion, %): 465
35%). [α]D = +36.5 (c 0.10, CHCl3); Mp 98–102 °C (lit.26 178 °C); ([M + H]+, 100).
1H NMR (400 MHz, CD3OD) δ 7.48 (dt, J = 8.0, 1.0 Hz, 1H),
Arylated product of Ac-SerGlyTrpAla-OH 9, 10. Method A: To
7.31 (dt, J = 8.0, 1.0 Hz, 1H), 7.10–7.04 (m, 3H), 7.00 (ddd, J = a microwave tube was added peptide 9 (10 mg, 0.022 mmol,
8.0, 7.0, 1.0 Hz, 1H), 4.73 (dd, J = 7.0, 6.0 Hz, 1H), 3.83 (d, J = 1 eq.), phenylboronic acid (13 mg, 0.11 mmol, 5 eq.), Cu(OAc)2
16.5, 1H), 3.78 (d, J = 16.5 Hz, 1H), 3.64 (s, 3H), 3.27 (ddd, J = (2.4 mg, 0.0132 mmol, 60 mol%), Pd(OAc)2 (1.5 mg,
14.5, 7.0, 0.5 Hz, 1H), 3.19 (ddd, J = 14.5, 7.0, 0.5 Hz, 1H), 1.92 0.0066 mmol, 30 mol%) and AcOH (1 mL). The reaction
(s, 3H); 13C NMR (101 MHz, CD3OD) δ 173.9, 173.7, 171.4, mixture was stirred at 40 °C for 16 h. The solvent was removed
138.0, 128.7, 124.6, 122.5, 119.9, 119.1, 112.3, 110.3, 54.8, 52.7, under reduced pressure to give a brown residue, which was
49.0, 43.4, 28.4; ESI-MS m/z (ion, %): 318 ([M + H]+, 20), 340 analysed by HPLC-ESI-MS. Method B: To a microwave tube was
([M + Na]+, 100); ESI-HRMS m/z: 318.1433 [M + H]+ (calc. for added peptide 9 (10 mg, 0.022 mmol, 1 eq.), phenyl(2,4,6-
C16H20N3O4 318.1448); IR (solid state ATR, cm−1) 3286, 2947, trimethylphenyl)iodonium trifluoromethanesulfonate, 11a
1737, 1655, 1610, 1508, 1460, 1439, 1372, 1285, 1248, 1215, (21 mg, 0.044 mmol, 2 eq.), Pd(OAc)2 (0.5 mg, 0.0022 mmol,
i
1177, 1030.
10 mol%) and PrOH (1 mL). The reaction mixture was stirred
Methyl (2S)-2-(2-acetamidoacetamido)-3-(2-phenyl-1H-indol- at 25 °C for 16 h. The resulting brown reaction mixture was fil-
3-yl)propanoate, 4. Synthesised using General Procedure 1 tered through Celite with MeOH (5 mL) and the solvent
from methyl (2S)-2-(2-acetamidoacetamido)-3-(1H-indol-3-yl)- removed under reduced pressure to give a brown residue,
propanoate 3 (10 mg, 0.032 mmol, 1 eq.), phenylboronic acid which was analysed by HPLC-ESI-MS. ESI-MS m/z (ion, %): 538
(20 mg, 0.16 mmol, 5 eq.), Cu(OAc)2 (0.6 mg, 3.2 µmol, 10 mol ([M + H]+, 100).
%) and Pd(OAc)2 (0.36 mg, 1.6 µmol, 5 mol%) in AcOH
Phenyl(2,4,6-trimethylphenyl)iodonium trifluoromethane-
(0.5 mL). Flash column chromatography (2% MeOH/EtOAc, sulfonate, 11a. Synthesised using General Procedure 2 from
v/v) gave the product as an off-white solid (42 mg, 68%). bis(acetyloxy)phenyl-λ3-iodane (3.22 g, 10 mmol, 1 eq.), 1,3,5-
Rf 0.24 (2% MeOH/EtOAc, v/v); [α]D = +32.1 (c 0.10, CHCl3); trimethylbenzene (1.54 mL, 1.32 g, 11 mmol, 1.1 eq.) and
Mp 199 °C dec; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), trifluoromethanesulfonic acid (0.96 mL, 1.65 g, 11 mmol,
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1.1 eq.) in CH2Cl2 (20 mL) to give the product as a white solid (400 MHz, CDCl3, δ): 8.00 (br s, 1H), 7.59 (dd, J = 8.0, 1.0 Hz,
(4.49 g, 95%). Mp 149–150 °C (lit.27 147–148 °C); 1H NMR 1H), 7.39–7.34 (m, 1H), 7.22 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.17
(400 MHz, CDCl3, δ): 7.69 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.5 Hz, (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.99 (d, J = 2.5 Hz, 2H), 6.58 (d,
1H), 7.39 (t, J = 7.5 Hz, 2H), 7.09 (s, 2H), 2.61 (s, 6H), 2.34 J = 7.5 Hz, 1H), 4.76 (td, J = 7.0, 5.5 Hz, 1H), 3.50 (s, 3H), 3.26
(s, 3H); 13C NMR (101 MHz, CDCl3, δ): 144.5, 142.6, 133.1, (dd, J = 15.0, 5.5 Hz, 1H), 3.13 (dd, J = 15.0, 7.0 Hz, 1H), 2.36
132.4, 131.9, 130.5, 120.5, 111.8, 27.2, 21.2; 19F NMR (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); 13C NMR (101 MHz, CDCl3,
2
(376 MHz, CDCl3, δ): −78.2 (s, 3F); ESI-MS m/z (ion, %): 323 δ): 170.8, 157.0 (q, JCF = 38.0 Hz), 139.0, 138.1, 135.9, 135.2,
1
([M − OTf]+, 100); ESI-HRMS m/z: 323.0303 [M − OTf]+ (calc. 128.7, 128.3, 128.0, 122.2, 120.0, 118.4 (q, JCF = 288.0 Hz),
for C15H16I 323.0291); IR (solid state, ATR, cm−1): 3060, 2919, 111.1, 106.7, 53.5, 52.7, 27.0, 21.2, 20.1; 19F NMR (376 MHz,
1445, 1247, 1222, 1158, 1025, 985, 945, 857, 741, 683, 632, 574, CDCl3, δ): −75.7; ESI-MS m/z (ion, %): 433 ([M + H]+, 5), 450
515, 454; anal. calc. for C16H16F3IO3S: C 40.69, H 3.41 found: ([M + NH4]+, 40), 455 ([M + Na]+, 100), 471 ([M + K]+, 5);
C 40.43, H 3.24.
ESI-HRMS m/z: 455.1547 [M + Na]+ (calc. for C23H23F3N2NaO3
Phenyl(2,4,6-triisopropylphenyl)iodonium trifluoromethane- 455.1553); IR (solid state, ATR, cm−1): 3391, 2955, 2919,
sulfonate, 11b. Synthesised using General Procedure 2 from 2851, 1712, 1614, 1543, 1458, 1439, 1378, 1344, 1292, 1206,
bis(acetyloxy)phenyl-λ3-iodane (805 mg, 2.5 mmol,1 eq.), 1,3,5- 1163, 1011, 909, 853, 731, 510; UV-Vis (DMSO, nm): λmax 288
triisopropylbenzene (665 µl, 562 mg, 2.75 mmol, 1.1 eq.) and (ε = 9725 mol dm−3 cm−1).
trifluoromethanesulfonic acid (241 µL, 413 mg, 2.75 mmol,
2-(Trifluoroacetamido)acetic acid.22 To a round-bottomed
1.1 eq.) in CH2Cl2 (5 mL) to give the product as a white solid flask containing glycine (826 mg, 11 mmol, 1 eq.) was added
(1.19 g, 86%). Mp 177–179 °C (lit.17 169–179 °C); 1H NMR Et3N (1.5 mL, 1.11 g, 11 mmol, 1 eq.) and MeOH (5.5 mL) and
(400 MHz, CDCl3, δ): 7.70–7.65 (m, 2H), 7.58–7.52 (m, 1H), the resulting suspension stirred for 5 min. After 5 min ethyl
7.47–7.40 (m, 2H), 7.19 (s, 2H), 3.25 (quin, J = 6.5 Hz, 2H), 2.96 trifluoroacetate (1.7 mL, 1.99 g, 14 mmol, 1.27 eq.) was added
(hept, J = 7.0 Hz, 1H), 1.26 (dd, J = 15.0, 7.0 Hz, 18H); 13C NMR and the mixture stirred at rt for 16 h, during which time a
(101 MHz, CDCl3, δ): 193.8, 155.9, 152.6, 132.7, 132.1, 125.5, clear solution formed. After 16 h the solvent was removed
120.4, 113.0, 100.1, 39.7, 34.4, 24.4, 23.8; ESI-MS m/z (ion, %): under reduced pressure and the resulting residue acidified
407 ([M − OTf]+, 100); ESI-HRMS m/z: 407.1247 [M − OTf]+ with 2 M HCl, before being extracted into EtOAc three times.
(calc. for C21H28I 407.1230); anal. calc. for C22H28F3IO3S: The organic layers were combined then washed with brine,
C 47.49, H 5.07 found: C 47.26, H 4.93.
dried over MgSO4, filtered and the solvent removed under
Methyl (2S)-3-(2-phenyl-1H-indol-3-yl)-2-(trifluoroacetamido)- reduced pressure to give the product as a white solid (1.68 g,
propanoate, 12a. Synthesised using General Procedure 3 from 89%). Mp 119–121 °C (lit.28 118–119 °C dec); 1H NMR
methyl (2S)-3-(1H-indol-3-yl)-2-(trifluoroacetamido)propanoate (400 MHz, CD3OD, δ): 4.00 (s, 2H); 13C NMR (101 MHz,
2
1
1c (58 mg, 0.192 mmol, 1 eq.), phenyl (2,4,6-trimethylphenyl)- CD3OD, δ): 171.5, 159.4 (q, JCF = 37.5 Hz), 117.4 (q, JCF
=
iodonium trifluoromethanesulfonate 11a (181 mg, 0.384 mmol, 286.0 Hz), 41.7; 19F NMR (376 MHz, CD3OD, δ): −77.3; ESI-MS
2 eq.) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in EtOAc (5 mL). m/z (ion, %): 194 ([M + Na]+, 100); ESI-HRMS m/z: 194.0033 [M
Flash column chromatography (3 : 1 petrol/EtOAc, v/v) gave the + Na]+ (calc. for C4H4F3NNaO3 194.0035).
product as an off-white solid (59 mg, 82%). Rf 0.32 (3 : 1 petrol/
Methyl (2S)-3-(1H-indol-3-yl)-2-[2-(trifluoroacetamido) acet-
13. 2-(Trifluoroacetamido)acetic acid
EtOAc, v/v); [α]D = +42.4 (c 0.10, CHCl3); Mp 155–156 °C; amido]propanoate,
1H NMR (400 MHz, CDCl3, δ): 8.15 (br s, 1H), 7.58–7.52 (100 mg, 0.58 mmol, 1 eq.), methyl (2S)-2-amino-3-(1H-indol-
(m, 3H), 7.50 (dd, J = 8.0, 7.0 Hz, 2H), 7.44–7.36 (m, 2H), 7.23 3-yl)propanoate (163 mg, 0.64 mmol, 1.1 eq.) and O-(benzo-
(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.19–7.14 (m, 1H), 6.64 (d, J = triazol-1-yl)-N,N,N′,N′-tetramethyluronium
tetrafluo-roborate
8.0 Hz, 1H), 4.83 (dt, J = 8.0, 5.5 Hz, 1H), 3.61 (dd, J = 5.5, (TBTU) (225 mg, 0.70 mmol, 1.2 eq.) were added to a round-
1.0 Hz, 2H), 3.35 (s, 3H); 13C NMR (101 MHz, CDCl3, δ): 170.7, bottomed flask which was fitted with a septum and flushed
156.7 (q, J = 37.5), 136.5, 135.8, 132.6, 129.3, 129.1, 128.5, with argon from a balloon for 20 min. After 20 min dry, dis-
128.4, 122.9, 120.4, 118.7, 114.9 (q, J = 288.0 Hz), 111.2, 105.6, tilled DIPEA (0.4 mL, 300 mg, 2.32 mmol, 4 eq.) and dry
53.4, 52.6, 26.5; 19F NMR (376 MHz, CDCl3, δ): −75.9; ESI-MS CH3CN (5.8 mL) were added via syringe to give a clear solution
m/z (ion, %): 391 ([M + H]+, 10), 408 ([M + NH4]+, 35), 413 and the reaction was stirred at rt for 2 h. After 2 h CH2Cl2 was
([M + Na]+, 100), 429 ([M + K]+, 10); ESI-HRMS m/z: 413.1074 added, then the reaction mixture was washed with sat. aq.
[M + Na]+ (calc. for C20H17F3N2NaO3 413.1083).
NH4Cl and extracted three times with CH2Cl2. The organic
Methyl (2S)-3-(2-phenyl-1H-indol-3-yl)-2-(trifluoroacetamido)- layers were combined, dried over MgSO4, filtered and the
propanoate, 12b. Synthesised using General Procedure 3 from solvent removed under reduced pressure to give a crude
methyl (2S)-3-(1H-indol-3-yl)-2-(trifluoroacetamido)propanoate residue. This was dry-loaded onto silica gel and purified by
1c (58 mg, 0.192 mmol, 1 eq.), phenyl (2,4,6-trimethylphenyl)- flash column chromatography (3 : 1 EtOAc/petrol, v/v) to
iodonium trifluoromethanesulfonate 11a (181 mg, 0.384 mmol, give the product as an off-white solid (201 mg, 93%). Rf 0.52
2 eq.) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in EtOAc (5 mL). (3 : 1 EtOAc/petrol v/v); [α]D = +40.7 (c 0.10, CHCl3); Mp
1
Flash column chromatography (3 : 1 petrol/EtOAc, v/v) gave the 53–55 °C; H NMR (400 MHz, CDCl3, δ): 8.28–8.18 (br s, 1H),
product as an off-white solid (14 mg, 17%). Rf 0.42 (3 : 1 petrol/ 7.50–7.44 (m, 1H), 7.38 (t, J = 5.0 Hz, 1H), 7.30 (dt, J = 8.0,
1
EtOAc v/v); [α]D = +34.4 (c 0.10, CHCl3); Mp 58–60 °C; H NMR 1.0 Hz, 1H), 7.18 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 7.11 (ddd, J =
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8.0, 7.0, 1.0 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 8.0 Hz, 20.3, 20.2; 19F NMR (376 MHz, CDCl3, δ): −75.7; ESI-MS m/z
1H), 4.93 (dt, J = 8.0, 5.5 Hz, 1H), 3.85 3.74 (m, 2H), 3.73 (ion, %): 512 ([M + Na]+, 100); ESI-HRMS m/z: 512.1773
(s, 3H), 3.37–3.24 (m, 2H); 13C NMR (101 MHz, CDCl3, δ): [M + Na]+ (calc. for C25H26F3N3NaO4 512.1768); IR (solid state,
2
172.3, 166.8, 157.3 (q, JCF = 38.0 Hz), 136.2, 127.4, 123.2, ATR, cm−1): 3339, 2959, 2919, 2850, 1718, 1670, 1523, 1458,
1
122.5, 120.0, 118.3, 116.6 (q, JCF = 287.0 Hz), 111.6, 109.4, 1437, 1260, 1157, 1006, 853, 800, 744, 517; UV-Vis (DMSO,
53.2, 52.8, 42.5, 27.5; 19F NMR (376 MHz, CDCl3, δ): −75.6; nm): λmax 288 (ε = 12 188 mol dm−3 cm−1).
ESI-MS m/z (ion, %): 372 ([M + H]+, 10), 394 ([M + Na]+, 100);
(2R)-4-Methyl-2-(trifluoroacetamido)pentanoic acid.22 To a
ESI-HRMS m/z: 394.0988 [M + Na]+ (calc. for C16H16F3N3NaO4 round-bottomed flask containing L-leucine (1 g, 7.6 mmol, 1
394.0985); IR (solid state, ATR, cm−1): 3391, 3341, 1729, eq.) was added Et3N (1.06 mL, 769 mg, 7.6 mmol, 1 eq.) and
1704, 1654, 1560, 1532, 1445, 1351, 1215, 1184, 1150, MeOH (7.6 mL) and the resulting suspension stirred for 5 min.
1005, 968, 742, 608, 536, 428; UV-Vis (DMSO, nm): λmax 284 After 5 min ethyl trifluoroacetate (1.13 mL, 1.35 g, 9.5 mmol,
(ε = 10 138 mol dm−3 cm−1).
Methyl (2S)-3-(2-phenyl-1H-indol-3-yl)-2-[2-(trifluoroaceta- during which time a clear solution formed. After 16 h the
1.25 eq.) was added and the mixture stirred at rt for 16 h,
mido)acetamido]propanoate, 14a. Synthesised using General solvent was removed under reduced pressure and the resulting
Procedure 3 from methyl (2S)-3-(1H-indol-3-yl)-2-[2-(trifluoro- residue acidified with 2 M HCl, before being extracted into
acetamido)acetamido]propanoate 9 (71 mg, 0.192 mmol, 1 eq.), EtOAc three times. The organic layers were combined then
phenyl (2,4,6-trimethylphenyl)iodonium trifluoromethane- washed with brine, dried over MgSO4, filtered and the solvent
sulfonate 11a (181 mg, 0.384 mmol, 2 eq.) and Pd(OAc)2 (2 mg, removed under reduced pressure to give the product as a white
9.6 µmol, 5 mol%) in EtOAc (5 mL). Flash column chromato- solid (1.67 g, 97%). [α]D = +31.6 (c 0.10, CHCl3); Mp 75–77 °C
1
graphy (40% EtOAc/petrol, v/v) gave the product as an off-white (lit.29 76–77 °C dec); H NMR (400 MHz, CD3OD, δ): 4.48 (dd,
solid (41 mg, 48%). Rf 0.28 (40% EtOAc/petrol, v/v); [α]D
=
J = 10.0, 5.0 Hz, 1H), 1.81–1.60 (m, 3H), 0.97 (d, J = 6.0 Hz,
+51.0 (c 0.10, CHCl3); Mp 82–84 °C; 1H NMR (400 MHz, CDCl3, 3H), 0.94 (d, J = 6.0 Hz, 3H); 13C NMR (101 MHz, CD3OD, δ):
δ): 8.22 (br s, 1H), 7.55–7.49 (m, 3H), 7.46 (dd, J = 8.0, 7.0 Hz, 174.4, 158.9 (q, 2JCF = 38.0 Hz), 117.5 (q, JCF = 287.0 Hz), 52.4,
1
2H), 7.40–7.33 (m, 2H), 7.22 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.12 40.7, 26.1, 23.3, 21.5; 19F NMR (376 MHz, CD3OD, δ): −77.0;
(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.93 (br s, 1H), 6.00 (d, J = ESI-MS m/z (ion, %): 250 ([M + Na]+, 100); ESI-HRMS m/z:
7.5 Hz, 1H), 4.83 (dt, J = 7.5, 5.0, 1H), 3.70–3.60 (m, 2H), 3.42 250.0665 [M + Na]+ (calc. for C8H12F3NNaO3 250.0661).
(s, 3H), 3.30–3.20 (m, 2H); 13C NMR (101 MHz, CDCl3, δ):
Methyl
(2S)-3-(1H-indol-3-yl)-2-[(2R)-4-methyl-2-tri-fluoro-
2
171.6, 166.1, 156.7 (q, JCF = 37.5 Hz), 141.9, 136.3, 135.8, acetamido)pentanamido] propanoate, 15. (2R)-4-Methyl-2-
133.2, 129.4, 129.2, 128.3, 128.3, 128.1, 122.9, 120.3, 118.7, (trifluoroacetamido)pentanoic acid (500 mg, 2.2 mmol, 1 eq.),
1
114.9 (q, JCF = 287.0 Hz), 111.2, 106.2, 53.3, 52.6, 42.0, 26.3; methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate (616 mg,
19F NMR (376 MHz, CDCl3, δ): −75.7; ESI-MS m/z (ion, %): 470 2.42 mmol, 1.1 eq.) and 3-(Diethoxyphosphoryloxy)-1,2,3-
([M + Na]+, 100); ESI-HRMS m/z: 470.1292 [M + Na]+ (calc. for benzotriazin-4(3-H)-one (DEPBT) (790 mg, 2.64 mmol, 1.2 eq.)
C22H20F3N3NaO4 470.1298); IR (solid state, ATR, cm−1): 3340, were added to a round-bottomed flask which was fitted with a
3061, 2954, 2930, 1722, 1666, 1528, 1441, 1351, 1211, 1153, septum and flushed with argon from a balloon for 20 min.
1074, 1004, 908, 730, 698, 515; UV-Vis (DMSO, nm): λmax 308 After 20 min dry, distilled DIPEA (1.5 mL, 1.14 g, 8.8 mmol,
(ε = 20 684 mol dm−3 cm−1).
4 eq.) and dry CH2Cl2 (22 mL) were added via syringe to give a
Methyl (2S)-2-[2-(trifluoroacetamido)acetamido]-3-[2-(2,4,6- yellow solution and the reaction was stirred at rt for 2 h. After
trimethylphenyl)-1H-indol-3-yl]propanoate, 14b. Synthesised 2 h the reaction mixture was washed with sat. aq. NH4Cl and
using General Procedure 3 from methyl (2S)-3-(1H-indol-3-yl)- extracted three times with CH2Cl2. The organic layers were
2-[2-(trifluoroacetamido)acetamido]propanoate 13 (71 mg, combined, dried over MgSO4, filtered and the solvent removed
0.192 mmol, 1 eq.), phenyl (2,4,6-trimethylphenyl)iodonium under reduced pressure to give a crude yellow residue. This
trifluoromethanesulfonate 11a (181 mg, 0.384 mmol, 2 eq.) was dry-loaded onto silica gel and purified by flash column
and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in EtOAc (5 mL). Flash chromatography (1 : 1 EtOAc/petrol, v/v) to give the product as
column chromatography (40% EtOAc/petrol, v/v) gave the an off-white solid (568 mg, 60%). Rf 0.48 (1 : 1 EtOAc/pxetrol
product as an off-white solid (4 mg, 4%). Rf 0.38 (40% EtOAc/ v/v); [α]D = +33.9 (c 0.10, CHCl3); Mp 129–131 °C; 1H NMR
petrol, v/v); [α]D = +33.3 (c 0.10, CHCl3); Mp 90–92 °C; 1H NMR (400 MHz, CDCl3, δ): 8.19 (br s, 1H), 7.48 (d, J = 8.0 Hz, 1H),
(400 MHz, CDCl3, δ): 7.87 (br s, 1H), 7.56 (dd, J = 8.0, 1.0 Hz, 7.36–7.33 (m, 1H), 7.23–7.08 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H),
1H), 7.36 (dt, J = 8.0, 1.0 Hz, 1H), 7.22 (ddd, J = 8.0, 7.0, 1.0 Hz, 6.45 (d, J = 8.0 Hz, 1H), 4.97–4.84 (m, 1H), 4.51–4.36 (m, 1H),
1H), 7.16 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.05–7.00 (m, 2H), 6.89 3.70 (s, 3H), 3.38–3.25 (m, 2H), 1.68 (s, 1H), 1.62–1.41 (m, 3H),
(d, J = 1.0 Hz, 1H), 5.74 (d, J = 7.5 Hz, 1H), 4.76 (dt, J = 7.5, 1.29–1.18 (m, 3H), 0.89–0.75 (m, 6H); 13C NMR (101 MHz,
2
5.5 Hz, 1H), 3.74 (dd, J = 17.0, 4.5 Hz, 1H), 3.57 (dd, J = 17.0, CDCl3, δ): 172.0, 170.4, 157.1 (q, JCF = 37.5 Hz), 136.2, 127.5,
1
4.5 Hz, 1H), 3.50 (s, 3H), 3.18 (d, J = 5.5 Hz, 2H), 2.36 (s, 3H), 123.3, 122.5, 120.0, 118.4, 116.6 (q, JCF = 288.0 Hz), 111.5,
2.14 (s, 3H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3, δ): 171.7, 109.3, 53.2, 52.7, 52.2, 41.5, 27.6, 24.7, 22.7, 22.1; 19F NMR
2
166.2, 156.0 (q, JCF = 37.5 Hz), 139.3, 138.2, 138.1, 135.8, (376 MHz, CDCl3, δ): −75.6; ESI-MS m/z (ion, %): 428
134.7, 128.9, 128.8, 128.6, 128.6, 122.3, 120.0, 118.4, 115.7 ([M
+ +
H]+, 75), 450 ([M Na]+, 100); ESI-HRMS m/z:
1
(q, JCF = 287.0 Hz), 111.1, 107.4, 53.5, 52.5, 42.1, 27.0, 21.2, 450.1612 [M + Na]+ (calc. for C20H24F3N3NaO4 450.1611);
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IR (solid state, ATR, cm−1): 3277, 3084, 2959, 2933, 2873, 1714, 1353, 1210, 1155, 1008, 909, 853, 731; UV-Vis (DMSO, nm):
1652, 1551, 1439, 1341, 1209, 1184, 1156, 1094, 1010, 988, 742, λmax 290 (ε = 8712 mol dm−3 cm−1).
719, 652, 632, 521; UV-Vis (DMSO, nm): λmax 282 (ε = 5734 mol
dm−3 cm−1).
Methyl (2S)-2-[(2R)-4-methyl-2-(trifluoroacetam-ido)pentan-
amido]-3-(2-phenyl-1H-indol-3-yl)propanoate, 16a. Synthesised
Acknowledgements
using General Procedure 3 from methyl (2S)-3-(1H-indol-3-yl)- The research leading to these results has received funding
2-[(2R)-4-methyl-2-(trifluoroacetamido)pentanamido]propanoate from the Innovative Medicines Initiative Joint Undertaking
15 (82 mg, 0.192 mmol, 1 eq.), phenyl (2,4,6-trimethylphenyl)- under grant agreement no 115360 (Chem21 project), resources
iodonium trifluoromethanesulfonate 11a (181 mg, 0.384 mmol, of which are composed of financial contribution from the
2 eq.) and Pd(OAc)2 (2 mg, 9.6 µmol, 5 mol%) in EtOAc (5 mL). European Union’s Seventh Framework Programme (FP7/2007-
Flash column chromatography (3 : 1 petrol/EtOAc, v/v) gave the 2013) and EFPIA companies’ in kind contribution.
product as a yellow solid (63 mg, 65%). Rf 0.19 (3 : 1 petrol/
EtOAc, v/v); [α]D = +43.8 (c 0.10, CHCl3); Mp 83–85 °C dec;
1H NMR (400 MHz, CDCl3, δ): 8.18 (br s, 1H), 7.57–7.53 (m,
3H), 7.49 (ddt, J = 8.0, 6.5, 1.0 Hz, 2H), 7.42–7.35 (m, 2H),
Notes and references
7.25–7.19 (m, 1H), 7.15 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H),
6.91–6.84 (m, 1H), 5.93–5.83 (m, 1H), 4.79 (dq, J = 7.5, 5.5,
5.0 Hz, 1H), 3.96 (td, J = 8.0, 5.0 Hz, 1H), 3.65–3.48 (m, 2H),
3.38 (s, 3H), 1.54–1.34 (m, 3H), 0.82–0.75 (m, 6H); 13C NMR
1 (a) S. De Ornellas, T. J. Williams, C. G. Baumann and
I. J. S. Fairlamb, in Catalytic C–H/C–X Bond Activation, ed.
X. Ribas, RSC Publishing, Cambridge, 2013; (b) T. O. Ronson,
R. J. K. Taylor and I. J. S. Fairlamb, Tetrahedron, 2014, 71,
989; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew.
Chem., Int. Ed., 2005, 44, 4442. An elegant example of the
Suzuki–Miyuara reaction performed on proteins containing
genetically incorporated aryl iodides can be found in.
(d) C. D. Spicer, T. Triemer and B. G. Davis, J. Am. Chem.
Soc., 2012, 134, 800.
2 L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem.,
Int. Ed., 2009, 48, 9792.
3 (a) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew.
Chem., Int. Ed., 2012, 51, 8960. For a beautiful example,
see: (b) M. E. Kieffer, K. V. Chuang and S. E. Reisman,
J. Am. Chem. Soc., 2013, 135, 5557.
2
(101 MHz, CDCl3, δ): 171.7, 170.1, 156.6 (q, JCF = 37.5 Hz),
136.2, 135.8, 132.9, 129.3, 129.2, 129.1, 128.4, 128.3, 128.2,
122.8, 120.2, 118.6 (q, 1JCF = 287.5 Hz), 111.2, 106.2, 53.3, 52.3,
51.8, 42.0, 26.6, 24.6, 22.7, 22.1; 19F NMR (376 MHz, CDCl3, δ):
−72.4; ESI-MS m/z (ion, %): 504 ([M + H]+, 5), 521 ([M + NH4]+,
15), 526 ([M + Na]+, 100), 542 ([M + K]+, 5); ESI-HRMS m/z:
526.1925 [M + Na]+ (calc. for C26H28F3N3NaO4 526.1924);
IR (solid state, ATR, cm−1): 3337, 3061, 2958, 2930, 2873, 1715,
1658, 1530, 1448, 1209, 1155, 742, 698; UV-Vis (DMSO, nm):
λmax 308 (ε = 20 467 mol dm−3 cm−1).
Methyl (2S)-2-[(2R)-4-methyl-2-(trifluoroacetamido) pentan-
amido]-3-[2-(2,4,6-trimethylphenyl)-1H-indol-3-yl]propanoate,
16b. Synthesised using General Procedure 3 from methyl (2S)-
3-(1H-indol-3-yl)-2-[(2R)-4-methyl-2-(trifluoroacetamido)pentan-
amido]propanoate 15 (82 mg, 0.192 mmol, 1 eq.), phenyl
4 A. F. M. Noisier and M. A. Brimble, Chem. Rev., 2014, 114,
8775.
5 J. Wencel-Delord, T. Dröge, F. Liu and F. Glorius, Chem.
Soc. Rev., 2011, 40, 4740.
(2,4,6-trimethylphenyl)iodonium
trifluoromethanesulfonate
11a (181 mg, 0.384 mmol, 2 eq.) and Pd(OAc)2 (2 mg, 9.6 µmol,
5 mol%) in EtOAc (5 mL). Flash column chromatography (3 : 1
petrol/EtOAc, v/v) gave the product as a yellow solid (13 mg,
12%). Rf 0.29 (3 : 1 petrol/EtOAc, v/v); [α]D = +31.1 (c 0.10,
CHCl3); 1H NMR (400 MHz, CDCl3, δ): 7.87 (br s, 1H),
7.61–7.56 (m, 1H), 7.39–7.34 (m, 1H), 7.22 (td, J = 8.0, 7.5,
1.0 Hz, 1H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.03 (d, J = 3.5 Hz,
2H), 6.91–6.85 (m, 1H), 5.67 (d, J = 7.0 Hz, 1H), 4.69 (td, J =
7.5, 4.5 Hz, 1H), 4.19–4.08 (m, 1H), 3.54 (s, 3H), 3.23 (dd, J =
15.0, 5.0 Hz, 1H), 3.01 (dd, J = 15.0, 7.5 Hz, 1H), 2.35 (s, 3H),
6 (a) T. E. Storr, A. G. Firth, K. Wilson, K. Darley,
C. G. Baumann and I. J. S. Fairlamb, Tetrahedron, 2008, 64,
6125; (b) T. E. Storr, C. G. Baumann, R. J. Thatcher, S. De
Ornellas, A. C. Whitwood and I. J. S. Fairlamb, J. Org.
Chem., 2009, 74, 5810; (c) T. E. Storr, J. A. Strohmeier,
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8 T. J. Williams, A. J. Reay, A. C. Whitwood and I. J. S. Fairlamb,
Chem. Commun., 2014, 50, 3052.
2.12 (s, 3H), 2.08 (s, 3H), 1.54–1.41 (m, 3H), 0.96–0.64 (m, 6H);
9 For C2-arylated tryptophan using the Suzuki–Miyaura reac-
tion, see: (a) F. Kolundzic, M. N. Noshi, M. Tjandra,
M. Movassaghi and S. J. Miller, J. Am. Chem. Soc., 2011,
133, 9104. An example of the S–M reaction performed on
the tryptophan-containing natural product apicidin can be
found in: (b) S. L. Colletti, C. Li, M. H. Fisher, M. J. Wyvratt
and P. T. Meinke, Tetrahedron Lett., 2000, 7825. The S–M
reaction can also be used to access 5- and 7-arylated trypto-
phans: (c) A. D. Roy, R. J. M. Goss, G. K. Wagner and
M. Winn, Chem. Commun., 2008, 4831.
2
13C NMR (101 MHz, CDCl3, δ): 171.8, 170.3, 156.7 (q, JCF
=
37.5 Hz), 139.4, 138.3, 137.9, 135.8, 134.7, 129.00, 128.9, 128.4,
1
128.0, 122.4, 120.1, 118.4, 116.5 (q, JCF = 288.0 Hz), 111.1,
107.6, 53.5, 52.5, 51.8, 42.6, 29.6, 27.1, 24.6, 22.8, 22.3, 21.2,
20.3; 19F NMR (376 MHz, CDCl3, δ): −75.8; ESI-MS m/z (ion,
%): 546 ([M + H]+, 2), 563 ([M + NH4]+, 15), 568 ([M + Na]+,
100), 584 ([M + K]+, 2); ESI-HRMS m/z: 568.2384 [M + Na]+
(calc. for C29H34F3N3NaO4 568.2394); IR (solid state, ATR,
cm−1): 3391, 3341, 2957, 2927, 1710, 1661, 1529, 1458, 1439,
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