N-Arylation of Amino Acid Esters to Expand Side Chain Diversity in Ketoxime Peptide Ligations

Article abstract of DOI:10.1021/acs.joc.9b02810

Palladium-catalyzed N-arylations of amino acid tert-butyl esters using 4-bromo-N,N-dimethylaniline as a coupling partner are reported. The resulting N-aryl amino acid esters are suitable building blocks for the synthesis of electron-rich N-aryl peptides, which undergo oxidative couplings to aminooxy groups to afford ketoxime peptides under mild conditions. N-aryl amino acid tert-butyl esters possessing unnatural side chains were also accessed via glycine Schiff base alkylation, further increasing the scope of Cα-substitution in ketoxime peptides.

Full text of DOI:10.1021/acs.joc.9b02810

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Note
N-Arylation of Amino Acid Esters to Expand Side
Chain Diversity in Ketoxime Peptide Ligations
Hailey A. Young, Quibria A. E. Guthrie, and Caroline Proulx
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 03 Dec 2019
Downloaded from pubs.acs.org on December 3, 2019
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N-Arylation of Amino Acid Esters to Expand Side Chain Diversity in Ketoxime
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Peptide Ligations
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Hailey A. Young, Quibria A. E. Guthrie, and Caroline Proulx*
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Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA.
R1
N
Br
N
R1
OtBu
H2N
OtBu
tBuBrett Phos Pd G3
NaOtBu, THF, rt
N
H
O
O
N
R1
O2, pH 7
2O NH2
N
R1
R
O
Peptide
R2
Peptide
N
H
O
ArNH2
O
ABSTRACT
Palladium-catalyzed N-arylations of amino acid tert-butyl esters using 4-bromo-N,N-
dimethylaniline as a coupling partner are reported. The resulting N-aryl amino acid esters
are suitable building blocks for the synthesis of electron-rich N-aryl peptides, which
undergo oxidative couplings to aminooxy groups to afford ketoxime peptides under mild
conditions. N-aryl amino acid tert-butyl esters possessing unnatural side chains were also
accessed via glycine Schiff base alkylation, further increasing the scope of Ca-
substitution in ketoxime peptides.
Methods that allow the chemoselective functionalization of common amino acid
building blocks streamline the synthesis and structure-activity relationship (SAR) studies
of bioactive compounds, and enable site-specific bioconjugation reactions of functionally-
dense biomolecules.1 For example, N-arylation of amino acids has been used as a key
step to furnish protein kinase modulators,2,3,4 and conditions for amino acid side-chain
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arylation (e.g. of Cys, Lys, Tyr, Trp residues) have been developed for macrocyclization
and labeling of peptide and protein substrates.5 Conversely, N-aryl glycine derivatives
have emerged as valuable precursors to create libraries of unnatural amino acids via site-
selective aC–H backbone functionalization reactions, presumably proceeding through an
a-imino amide intermediate.6 Recently, N-phenylglycinyl peptides were found to undergo
oxidative couplings with alkoxyamines to afford oxime ligation products via formation of
similar aniline Schiff base intermediates7 under mild aqueous conditions.8 Beyond glycine
derivatives, this method has allowed the chemoselective oxidation of Ca-substituted N-
aryl peptides into reactive a-ketimino amide intermediates,9 allowing expansion of side
chain diversity at the site of oxime ligation.
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To proceed under oxygen atmosphere and at neutral pH, ketoxime ligations using
N-aryl peptide substrates require very electron rich aryl rings.9 Specifically, while analogs
with a dimethylamino group (s = –0.83)10 at the para position of the aryl ring readily
undergo oxidation, similar compounds with a methoxy substituent instead (s = –0.27)10
do not afford ketoxime peptides.9 Previously, the required N-aryl peptide substrates were
prepared using a two-step submonomer peptoid synthesis procedures,11 where racemic
a-substituted bromoacetic acid derivatives were coupled to resin-bound peptides,
followed by an SN2 displacement using 4-dimethylamino aniline as the nucleophile
(Scheme 1a). However, extensive exploration of functionalized ketoxime peptides has
been hampered by the limited commercial availability of bromoacetic acid derivatives.
Here, we expand the scope of side chain diversity in ketoxime peptides via access to N-
(4-Me2N-Ph) amino acid tert-butyl ester building blocks using an N-arylation of more
widely accessible amino acid esters (Scheme 1b).
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a) Previous approach:
O
■ limited commercial availability
of bromoacetic acid derivatives
1.
Br
OH
O
H
R1
N
Peptide
DIC, DMF
N
H
H2N Peptide
= Resin
R1
N
2.
N
NH2
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N-aryl peptide
1.5 M in DMF
3. TFA/H2O/TIPS
b) This approach:
O
N
Br
O
H
H2N
N
OtBu
OtBu
tBuBrett Phos Pd G3
NaOtBu, THF, rt
R1
R1
N
Scheme 1. Synthesis of N-aryl peptides via a) submonomer peptoid synthesis procedure
(previous method) and b) N-arylation of amino acid tert-butyl esters (this approach).
N-arylation of amino acids and amino acid esters has previously been
accomplished using both copper-catalyzed2,3,4,12 and palladium-catalyzed13 cross-
coupling reaction procedures. In particular, Buchwald et al. recently reported mild
conditions for the epimerization-free N-arylation of amino acid esters with aryl triflate as
coupling partners, using palladacycle precatalysts and cesium carbonate as base.13e
However, the use of electron-rich 4-bromo-N,N-dimethylaniline as a coupling partner has
not been reported under these conditions, and would be highly relevant in the context of
bioconjugation. Thus, our initial evaluations employed t-BuBrettPhos Pd G3 as the
precatalyst in 2-Me THF with Cs2CO3 as base, closely mimicking the previously optimized
procedure with aryl triflates.13e While we were initially successful using HCl × L-Phe-OtBu
as a test substrate, the use of cesium carbonate caused reproducibility issues in our
hands, which were ultimately relieved by changing the base to sodium tert-butoxide.14
NaOtBu was previously shown to lead to decreased functional group tolerance15 and
increased epimerization using amino acid esters as substrates;13e however, our
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downstream application in ketoxime ligations eliminated the need to isolate enantiopure
material. Gratifyingly, treating amino acid tert-butyl esters 1a-f with NaOtBu (3 equiv), t-
BuBrettPhos Pd G3 (5 mol%), and 4-bromo-N,N-dimethylaniline (1 equiv) at room
temperature afforded N-aryl amino acid tert-butyl esters 3a-f, possessing a variety of
hydrophobic side-chains, in 75-93% yields after 2 hours (Scheme 2). Importantly, these
analogs can be purified by column chromatography,16 and do not undergo oxidation to
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Scheme 2. Pd-catalyzed N-arylation of amino acid tert-butyl
esters using 4-bromo-N,N-dimethylaniline as the aryl halide.
the a-ketimino amide until exposed to phosphate buffer at neutral pH.9 In contrast, N-
arylation of glycine tert-butyl ester with 4-bromo-N,N-dimethylaniline provided variable
results, which may be due to the ease of oxidation of the resulting N-aryl glycine tert-butyl
ester product in organic solvent9 and exacerbated by the palladium catalyst. It should also
be mentioned that despite extensive optimization attempts, N-arylations of amino acid
methyl esters proved unsuccessful, likely due to the use of NaOtBu as the base. To
expand our scope, analogs 3g-k were pursued to include unnatural side chain diversity
(Scheme 3). The required amino ester substrates 1g-k were accessed in racemic form
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from known glycine Schiff base alkylation procedures,17 using benzyl bromide derivatives
and 1-iodo-3-methyl butane as the electrophiles. Orthogonal deprotection of the
benzophenone imine was next accomplished using hydroxylamine hydrochloride in
pyridine.18 Using two equivalents of base instead of three in the N-arylation procedure,
the desired N-aryl amino acid esters 3g-k products were obtained in 46 to 94% yields.
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Scheme 3. Synthesis and N-arylation of unnatural amino acid
tert-butyl esters 1g-k.
We next sought to optimize conditions for the activation and coupling of the N-aryl
amino acids onto a resin-bound peptide, using LYRAG as a representative example.
Initially, protection of the secondary amine with a tert-butoxycarbonyl (Boc) or
fluorenylmethyloxycarbonyl (Fmoc) group was thought to be required. However,
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difficulties in performing these protection reactions prompted us to investigate the
coupling of these substrates without protecting the amino group, with the hope that the
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Scheme 4. Synthesis of N-aryl peptides via the activation
of protecting-group free N-aryl amino acids.
poor nucleophilicity of the N-aryl amino acids19 would prevent unwanted oligomerization
upon activation of the carboxylic acid with HBTU/DIEA (Scheme 4). Conveniently, this
was found to be the case, with most analogs providing the desired N-aryl peptides as the
major product with little to no byproduct observed by LCMS analysis (Table 1). Cleavage
of the N-aryl peptides from the solid support and purification by reverse-phase HPLC
afforded 7a-k in 10-44% isolated yield (Table 1).
Table 1. Characterization data for N-aryl peptides 7a-k.
entry peptide
crude purity (%)a
yield (%)b
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6
7a
7b
7c
7d
7e
7f
97
79
77
85
92
74
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18
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7g
7h
7i
88
88
92
25
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7
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10
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7j
7k
94
84
44
26
aThe purity at 214 nm wavelength is reported in all cases. Yields
b
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after purification by RP-HPLC are based on initial resin loading.
With N-aryl peptides 7a-k in hand, we next assessed their ability to undergo
ketoxime ligation reactions in phosphate buffer (pH 7) under an O2 atmosphere, using O-
benzylhydroxylamine hydrochloride as a model a-nucleophile (Scheme 5, Table 2). Most
analogs afforded the desired E/Z ketoxime peptides as the major products after 24 h,
albeit some reacted more slowly. The majority of ketoxime peptides in our current study
were observed as ~1:1 mixtures of E and Z isomers, with the exception of those obtained
from oxidative couplings to N-aryl-Met-LYRAG 7b and N-aryl-Ala-LYRAG 7c (Table 2,
entries 2-3). While situated relatively far from the a-carbon, electron-withdrawing groups
at the para position of the benzyl side chain in N-aryl phenylalanine analogs 7g-h appear
to slow down oxidation (Table 2, entries 7 and 8). Conversely, in the case of analog 7j,
which possesses a bulky 2-naphthyl substituent, steric hindrance is likely responsible for
the observed decrease in reactivity (Table 2, entry 10). Moreover, in agreement with our
previous findings,9 b-branched substitution in amino acids (i.e. Val and Ile) was found to
be detrimental, giving ketoximes 8e-f as minor products with appearance of other side
products (Table 2, entries 5-6). Methionine side chain oxidation was not detected in
analog 7b under these mild conditions (Table 2, entry 2). Overall, in addition to the mild
procedure, fewer limitations are encountered using this approach compared to methods
starting from less reactive a-keto amide substrates. For example, while we note slower
reactivity with N-aryl amino acids possessing electron-poor benzyl side-chains, the
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desired ketoxime peptides are produced cleanly nonetheless after 24 to 72 h when
starting from N-aryl peptide substrates. As a comparison, other methods have failed to
produce similar ketoximes in high yields.20
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Scheme 5. Ketoxime ligation reactions between N-aryl
peptides 7a-k and O-benzylhydroxylamine hydrochloride.
Table 2. Characterization data for ketoxime peptides 8a-k.
entry N-aryl peptide % ketoximea
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4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
90
82
98
99
38b
24b
36(75)c
65(90)c
85
10
11
7j
7k
40(89)d
85
aUnless noted otherwise, % ketoxime is at t = 24 h and ketoxime
conversions were calculated using areas obtained from the two peaks
corresponding to the E and Z isomers on LCMS traces at 214 nm. b%
ketoxime at t = 24 h showed 50% oxidation, where ~20% of an a-keto
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c
d
amide byproduct was detected. % ketoxime after 48 hours.
ketoxime after 72 hours.
%
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In summary, a Pd-catalyzed N-arylation reaction using 4-bromo-N,N-
dimethylaniline as the aryl halide and amino acid tert-butyl ester substrates is reported in
high yield, expanding the scope of electron-rich N-(p-Me2N-Ph)-peptide substrates
available for ketoxime peptide ligation reactions. The efficiency of the N-arylation reaction
procedure described here, combined with the simplicity of existing glycine Schiff base
alkylation procedures and the breadth of commercially available electrophiles, will
contribute to expand side chain diversity even further in ketoxime peptide ligations.
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Experimental Section
General. All glycine Schiff base alkylations and deprotections were performed in round-
bottom flasks. All N-arylation reactions were performed in oven-dried microwave vials
sealed with microwave caps and stirred using teflon-coated magnetic stir bars. Tert-butyl
deprotections were performed in 20-mL scintillation vials. Tetrahydrofuran (THF) was
dried by passage over a column of activated alumina (JC Meyers Solvent System). Thin
layer chromatography (TLC) was performed using Silicycle silica gel 60 F-254 precoated
plates (0.25 mm) that were visualized by exposure to ultraviolet (UV) light and/ or
submersion in aqueous potassium permanganate or ninhydrin solutions. Samples were
purified using a Biotage® Isolera One, employing polypropylene cartridges preloaded
with silica gel (25 micron) and were eluted with UV detection (254, 280 nm). Nuclear
magnetic resonance (NMR) spectra (1H, 13C) were recorded on a 600 and 700 MHz
Bruker spectrometer at 24 oC. Chemical shifts are expressed in parts per million (ppm, δ
scale) and are referenced to residual protium in the NMR solvent (CDCl3, δ 7.26 ppm or
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CD3OD, δ 3.31). Data are represented as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant in Hertz,
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and integration. Chemical shits for C NMR spectra are recorded in parts per million
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(ppm, δ scale) and are referenced to the central peak of deuterochloroform (δ 77.16 ppm)
or methanol (δ 49.00 ppm). All spectra were obtained with complete proton decoupling.
Infrared (IR) spectra were collected on a Thermo Scientific Nicolet iS5 FTIR instrument
using attenuated total reflectance (ATR) mode and signals are reported in reciprocal
centimeters (cm-1). Only selected IR frequencies are reported. Melting points were
obtained on a Mettler Toledo MP50 One Click Melting Point System. Optical rotation data
was obtained using a Jasco P-2000 polarimeter equipped with a sodium (589 nm, D)
T
lamp. The corresponding data are presented as follows: specific rotation ([α]D ),
concentration (1 g/ 100 mL), and solvent.
Polystyrene Rink Amide resin (0.61 mmol/ g) was purchased from Protein Technology,
IncTM, and the manufacturer’s reported loading of the resin was used in the calculation of
the yields. Solid phase peptide synthesis (SPPS) was performed using an automated
Biotage Syro WaveTM peptide synthesizer in 10 mL parallel reactors with PTFE frits.
Incorporation of the N-aryl amino acids were performed manually in disposable filter
columns with 20 μM PE frit filters and caps purchased from Applied Separations (catalog
# 2413 for 3-mL filter columns) with gentle agitation on a Thermo Fisher vortex mixer
equipped with a microplate tray. Solution draining and washing of the resin was done by
connecting the filter columns to a water aspirator vacuum via a waste trap. Analytical LC-
MS analyses were performed using an Agilent Technologies 1260 Infinity II series LCMS
Single Quad instrument with ESI ion-source and positive mode ionization, equipped with
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either a 5 μM, 150 x 4.6 mm C18 Vydac column purchased from Mac-Mod Analytical, Inc.
(catalog # 218TP5415) or a 5 μM, 150 x 4.6 mm C18 Luna column purchased from
Phenomenex (catalog # 00F-4252-E0). A flow rate of 0.5 mL/ min. and 5-95% or 20-80%
gradient of CH3CN [0.1% trifluoroacetic acid (TFA)] in water (0.1% TFA) over 12 minutes
(total run time = 22 minutes) were used for all LC-MS analyses. Peptides were purified
on a preparative HPLC (Agilent 218 purification system) using a preparative column (10-
20 μM, 250 mm x 22 mm, C18 Vydac column, catalog # 218TP101522 or 10 μM, 250 mm
x 21.2 mm, C18 Luna column, catalog # 00G-4253-P0-AX) at a flow rate of 10 mL/ min.
with gradients of CH3CN (0.1% TFA) in water (0.1% TFA) over 30 minutes (total run time
= 60 minutes).
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General Procedure for the N-arylation of Amino Acid tert-Butyl Esters 1a-f with 4-
Bromo-N,N-dimethylaniline
The amino acid t-butyl ester hydrochloride (1.0 mmol, 1.0 equiv), 4-bromo-N,N-
dimethylaniline (1.0 mmol, 1.0 equiv), t-Bu BrettPhos Pd G3 (0.05 mmol, 0.05 equiv), and
sodium t-butoxide (3.0 mmol, 3.0 equiv) were added to an oven-dried 5-mL microwave
vial. The vial was capped and flushed with argon. Dry tetrahydrofuran (2.0 mL) was added
to the vial, and the reaction mixture was stirred at room temperature for two hours. The
reaction mixture was filtered through a small plug of celite and rinsed with
dichloromethane (2 x 10 mL), evaporated to dryness on a rotary evaporator, and purified
by automated flash-column chromatography.
4-(p-dimethylamino-phenyl) phenylalanine tert-butyl ester (3a). This was synthesized
according to the general procedure described above, using HCl · L-Phe-OtBu (100.0 mg,
0.39 mmol). The product was purified by silica gel column chromatography using 5-40%
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ethyl acetate in hexanes to afford a red-brown solid (120.7 mg, 91% yield). 1H NMR (600
MHz, CDCl3): δ 7.31 - 7.28 (m, 2H), 7.25 - 7.23 (m, 3H), 6.72 (s, 2H), 6.62 (s, 2H), 4.16
(s (br), 1H), 3.84 (s (br), 1H), 3.11 - 3.06 (m, 2H), 2.83 (s, 6H), 1.34 (s, 9H). 13C {1H} NMR
(150 MHz, CDCl3): δ 172.8, 144.5, 139.0, 137.0, 129.6, 128.3, 126.8, 115.7, 115.5, 81.5,
59.6, 42.2, 39.0, 28.0. IR (neat) 3407, 2976, 2928, 2791, 1710, 1519, 1475, 1255, 1146.
HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C21H29N2O2 341.2224; Found 341.2217.
[α]D23 + 0.081 (c 1.0, CHCl3). Rf = 0.18 (20% ethyl acetate in hexanes). MP = 75.3 – 77.4
ºC.
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4-(p-dimethylamino-phenyl)methionine tert-butyl ester (3b). This was synthesized
according to the general procedure described above, using HCl · L-Met-OtBu (100.0 mg,
0.41 mmol). The product was purified by silica gel column chromatography using 5-40%
ethyl acetate in hexanes to afford a dark yellow solid (117.5 mg, 88% yield). 1H NMR (600
MHz, CDCl3): δ 6.70 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 4.00 (s (br), 1H), 3.82
(s (br), 1H), 2.81 (s, 6H), 2.63 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 2.08 – 2.04 (m, 1H), 1.98
– 1.92 (m, 1H), 1.42 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 173.4, 144.7, 139.2,
115.6, 115.5, 81.5, 57.7, 42.1, 32.8, 30.4, 28.1, 15.5. IR (neat) 3350, 2973, 2779, 1727,
1520, 1443, 1327, 1254, 1145, 1116. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for
C17H29N2O2S 325.1944; Found 325.1938. [α]D23 –0.906 (c 1.0, CHCl3). Rf = 0.21 (20%
ethyl acetate in hexanes). MP = 76.5 – 78.1 ºC.
4-(p-dimethylamino-phenyl)alanine tert-butyl ester (3c). This was synthesized
according to the general procedure described above, using HCl · L-Ala-OtBu (100.0 mg,
0.55 mmol). The product was purified by silica gel column chromatography using 10-60%
1
ethyl acetate in hexanes to afford a yellow-brown solid (126.4 mg, 87% yield). H NMR
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(600 MHz, CDCl3): δ 6.71 (s (br), 2H), 6.61 (s (br), 2H), 3.94 (s (br), 1H), 3.78 (s (br), 1H),
2.82 (s, 6H), 1.43 (s, 9H), 1.41 (d, J = 6.8 Hz, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ
174.3, 144.6, 139.1, 115.5, 115.3, 81.0, 53.8, 42.0, 28.0, 19.0. IR (neat) 3385, 2973,
2932, 2788, 1705, 1518, 1445, 1288, 1259. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd
for C15H25N2O2 265.1911; Found 265.1906. [α]D23 –0.008 (c 1.0, CHCl3). Rf = 0.38 (35%
ethyl acetate in hexanes). MP = 47.5 – 50.3 ºC.
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4-(p-dimethylamino-phenyl)leucine tert-butyl ester (3d). This was synthesized
according to the general procedure described above, using HCl · L-Leu-OtBu (100.0 mg,
0.45 mmol). The product was purified by silica gel column chromatography using 2-15%
ethyl acetate in hexanes to afford a yellow-brown solid (103.2 mg, 75% yield). 1H NMR
(600 MHz, CDCl3): δ 6.71 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 6.3 Hz, 2H), 3.88 (s (br), 1H),
3.64 (s (br), 1H), 2.82 (s, 6H), 1.87 – 1.80 (m, 1H), 1.63 – 1.55 (m, 2H), 1.41 (s, 9H), 1.00
(d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ 174.5,
144.6, 139.6, 115.6, 115.4, 81.0, 57.2, 42.6, 42.2, 28.1, 25.0, 22.8, 22.5. IR (neat) 3374,
3344, 2956, 2867, 2791, 1722, 1517, 1368, 1269, 1145. HRMS (HESI/ orbitrap) m/z: [M
+ H]+ Calcd for C18H31N2O2 307.2380; Found 307.2372. [α]D23 –1.25 (c 1.0, CHCl3). Rf =
0.21 (10% ethyl acetate in hexanes). MP = 64.7 – 67.8 ºC.
4-(p-dimethylamino-phenyl)valine tert-butyl ester (3e). This was synthesized
according to the general procedure described above, using HCl · L-Val-OtBu (100.0 mg,
0.55 mmol). The product was purified by silica gel column chromatography using 10-35%
ethyl acetate in hexanes to afford an orange-brown solid (133.9 mg, 83% yield). 1H NMR
(600 MHz, CDCl3): δ 6.72 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 3.80 (s(br), 1H),
3.66 (d, J = 5.4 Hz, 1H), 2.82 (s, 6H), 2.10 – 2.05 (m, 1H), 1.43 (s, 9H), 1.04 (t, J = 6.5
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Hz, 6H). 13C {1H} NMR (150 MHz, CDCl3): δ 173.3, 144.5, 140.1, 115.7, 81.2, 64.4, 42.2,
31.6, 28.1, 19.2, 18.8. IR (neat) 3383, 2970, 2931, 2875, 2786, 1705, 1519, 1471, 1274,
1156. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C17H29N2O2 293.2224; Found
293.2217. [α]D23 –2.28 (c 1.0, CHCl3). Rf = 0.27 (20% ethyl acetate in hexanes). MP =
84.1 – 87.2 ºC.
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4-(p-dimethylamino-phenyl)isoleucine tert-butyl ester (3f). This was synthesized
according to the general procedure described above, using HCl · L-Ile-OtBu (100.0 mg,
0.47 mmol). The product was purified by silica gel column chromatography using 5-35%
ethyl acetate in hexanes gradient to afford a red-brown oil (127.2 mg, 93% yield). 1H NMR
(600 MHz, CDCl3): δ 6.71 (s (br), 2H), 6.63 (s (br), 2H), 3.74 (s (br), 1H), 2.82 (s, 6H),
1.85 – 1.78 (m, 1H), 1.68 – 1.63 (m, 1H), 1.42 (s, 9H), 1.35 – 1.29 (m, 1H), 0.99 – 0.96
(m, 6H). 13C {1H} NMR (150 MHz, CDCl3): δ 173.2, 144.5, 139.9, 115.7, 115.4, 81.2, 62.9,
42.2, 38.1, 28.1, 25.9, 15.5, 11.7. IR (neat) 3390, 2969, 2877, 2787, 1703, 1519, 1477,
1275, 1155. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C18H31N2O2 307.2380; Found
307.2375. [α]D23 –3.74 (c 1.0, CHCl3). Rf = 0.27 (20% ethyl acetate in hexanes).
General Procedure for the Glycine Schiff Base Alkylation
5g-k
were
prepared
following
literature
procedures.17
Briefly,
N-
(diphenylmethylene)glycine tert-butyl ester (1.0 mmol, 1.0 equiv) and the corresponding
electrophile (4.0 mmol, 4.0 equiv) (if solid) were transferred to a 10-mL round bottom
flask. DCM (6.67 mL) was added, followed by tetrabutylammonium hydroxide (TBAH, 1.5
M in H2O, 1.2 mmol, 1.2 equiv) and 10% aq. NaOH (2.5 mmol, 2.5 equiv). The reaction
mixture was allowed to stir at room temperature overnight. The crude solution was
transferred to a separatory funnel and the organic layer was washed with saturated brine
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(3 x 15 mL). The organic layer was dried over Na2SO4, evaporated to dryness using a
rotary evaporator, and purified by automated flash-column chromatography. Note: due to
the lack of ionization sites on these molecules, HRMS data could not be obtained for this
series of compounds.
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Tert-butyl 2-((diphenylmethylene)amino)-3-(4-(trifluoromethyl)phenyl)propanoate
(5g). This was synthesized according to the general procedure described above, using
N-(diphenylmethylene)glycine tert-butyl ester (295.4 mg, 1.0 mmol). The product was
purified by silica gel column chromatography using 5-15% diethyl ether in hexanes to
afford a white solid (362.1 mg, 80% yield). 1H NMR (600 MHz, CDCl3): δ 7.60 – 7.59 (m,
2H), 7.46 (d, J = 8.1 Hz, 2H), 7.40 – 7.28 (m, 6H), 7.19 (d, J = 8.0 Hz, 2H), 6.64 (s(br),
2H), 4.15 (q, J = 9.2, 4.1 Hz, 1H), 3.30 – 3.28 (m, 1H), 3.25 – 3.21 (m, 1H), 1.46 (s, 9H).
13C {1H} NMR (150 MHz, CDCl3): δ 170.8, 170.5, 142.8, 139.4, 136.2, 132.5, 130.4,
130.3, 130.2, 128.9, 128.8, 128.6, 128.5, 128.4 128.3, 128.2, 127.6, 125.1 (q, J = 3.6 Hz),
124.3 (q, J = 271.8 Hz), 81.6, 67.6, 39.5, 28.2. IR (neat) 2976, 2932, 1726, 1616, 1448,
1188, 1151, 1064. Rf = 0.25 (10% diethyl ether in hexanes). MP = 106.6 – 112.7 ºC.
Tert-butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate (5h). This
was synthesized according to the general procedure described above, using N-
(diphenylmethylene)glycine tert-butyl ester (886.1 mg, 3.0 mmol). The product was
purified by silica gel column chromatography using 10% diethyl ether in hexanes to afford
a white crystalline solid (1.03 g, 85% yield). 1H NMR (600 MHz, CDCl3): δ 7.56 (d, J = 7.2
Hz, 2H), 7.29 – 7.27 (m, 2H), 7.25 – 7.24 (m, 4H), 6.99 – 6.96 (m, 2H), 6.83 (t, J = 8.7
Hz, 2H), 6.65 (s (br), 2H), 4.08 (d of d, J = 9.1, 4.3 Hz, 1H), 3.19 – 3.16 (m, 1H), 3.13 –
3.10 (m, 1H), 1.40 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 170.6, 170.4, 162.3, 160.7
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139.4, 136.3, 134.1, 134.1, 131.3 (d, J = 7.8 Hz), 130.0, 129.1 (d, J = 280.2 Hz), 128.7,
128.3, 128.1, 128.0, 127.6, 114.8, 114.7, 81.1, 67.8, 38.8, 28.0. IR (neat) 2976, 2928,
1725, 1626, 1507, 1446, 1369, 1283, 1220, 1143, 1039. Rf = 0.22 (10% diethyl ether in
hexanes). MP = 69.3 – 77.5 ºC.
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Tert-butyl 2-((diphenylmethylene)amino)-3-(m-tolyl)propanoate (5i). This was
synthesized according to the general procedure described above, using N-
(diphenylmethylene)glycine tert-butyl ester (886.1 mg, 3.0 mmol). The product was
purified by silica gel column chromatography using 10% diethyl ether in hexanes to afford
1
a light yellow oil (718.3 mg, 60% yield). H NMR (600 MHz, CDCl3): δ 7.59 – 7.58 (m,
2H), 7.35 – 7.31 (m, 2H), 7.29 – 7.27 (m, 3H), 7.06 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.5
Hz, 1H), 6.88 – 6.85 (m, 2H), 6.62 (s (br), 1H), 4.13 (d of d, J = 9.4, 4.2 Hz, 1H), 3.23 –
3.20 (m, 1H), 3.16 – 3.13 (m, 1H), 2.22 (s, 3H), 1.46 (s, 9H).13C {1H} NMR (150 MHz,
CDCl3): δ 171.0, 170.3, 139.7, 138.3, 137.7, 137.6, 136.5, 132.5, 130.8, 130.2, 128.8,
128.4, 128.3, 128.1, 128.0, 127.8, 127.0, 126.9, 81.2, 68.0, 39.6, 28.2, 28.1, 21.3. IR
(neat) 2977, 2928, 1726, 1626, 1507, 1446, 1368, 1283, 1220, 1144, 1039. Rf = 0.29
(10% diethyl ether in hexanes).
Tert-butyl 2-((diphenylmethylene)amino)-3-(napthalen-2-yl)propanoate (5j). This
was synthesized according to the general procedure described above, using N-
(diphenylmethylene)glycine tert-butyl ester (295.4 mg, 1.0 mmol). The product was
purified by silica gel column chromatography using 5% ethyl acetate in hexanes to afford
a yellow solid (349.8 mg, 80% yield). 1H NMR (600 MHz, CDCl3): δ 7.76 – 7.74 (m, 1H),
7.68 – 7.65 (m, 1H), 7.62 – 7.60 (m, 1H), 7.54 (s, 1H), 7.41 – 7.36 (m, 2H), 7.34 – 7.31
(m, 1H), 7.29 – 7.27 (m, 3H), 7.23 – 7.22 (m, 1H), 7.17 (t, J = 7.7 Hz, 2H), 6.57 (s (br),
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1H), 4.30 (d of d, J = 9.3, 4.3 Hz, 1H), 3.46 (d of d, J = 13.5, 4.2 Hz, 1H), 3.38 (d of d, J
= 13.4, 9.4 Hz, 1H), 1.47 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 196.8, 170.9, 170.6,
139.6, 137.7, 136.4, 136.0, 133.5, 132.5, 132.2, 130.2, 130.2, 128.8, 128.5, 128.4, 128.3,
128.1, 128.0, 127.8, 127.6, 127.6, 125.9, 125.3, 81.3, 68.0, 39.9, 28.6, 28.2. IR (neat)
3061, 2969, 2844, 1734, 1658, 1624, 1286, 1147. Rf = 0.51 (5% ethyl acetate in hexanes).
MP = 86.4 – 93.2 ºC.
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Tert-butyl 2-((diphenylmethylene)amino)-5-methylhexanoate (5k). This was
synthesized according to the general procedure described above, using N-
(diphenylmethylene)glycine tert-butyl ester (886.1 mg, 3.0 mmol). The product was
purified by silica gel column chromatography using 10% diethyl ether in hexanes to afford
1
a yellow oil (986.0 mg, 90% yield). H NMR (600 MHz, CDCl3): δ 7.70 – 7.69 (m, 2H),
7.47 – 7.42 (m, 3H), 7.38 – 7.36 (m, 1H), 7.33 – 7.31 (m, 2H), 7.21 – 7.20 (m, 2H), 3.95
(q, J = 7.9, 5.1 Hz, 1H), 1.98 - 1.88 (m, 2H), 1.53 – 1.50 (m, 1H), 1.48 (s, 9H), 1.25 – 1.20
(m, 1H), 1.19 – 1.14 (m, 1H), 0.89 (q, J = 6.7, 3.9 Hz, 6H). 13C {1H} NMR (150 MHz,
CDCl3): δ 171.7, 169.8, 139.9, 136.9, 132.5, 130.2, 130.1, 128.9, 128.5, 128.5, 128.4,
128.1, 128.0, 80.8, 66.5, 35.3, 31.7, 28.2, 28.0, 22.7, 22.6. IR (neat) 2976, 1725, 1626,
1508, 1446, 1368, 1284, 1144, 1039. Rf = 0.36 (10% diethyl ether in hexanes).
General Procedure for Benzophenone Imine Deprotection.
Following literature procedures,21 the desired benzophenone imine protected unnatural
amino acid ester (0.34 mmol, 1.0 equiv) and hydroxylamine hydrochloride (1.38 mmol,
4.0 equiv) were transferred to an oven-dried round-bottom flask. The compounds were
dissolved in pyridine (8.01 mL) and allowed to stir at 60 ºC overnight. Pyridine was
evaporated using a rotary evaporator, followed by co-evaporation with DCM (x 3) to
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remove trace amounts of pyridine. The residue was digested with 5% MeOH in DCM for
2 hours to remove the insoluble excess hydroxylamine hydrochloride salt. The solution
was filtered through a plug of cotton and evaporated to dryness on a rotary evaporator.
The crude was re-dissolved in DCM and concentrated using a rotary evaporator (x 3),
then placed under high vacuum for several hours prior to flash column chromatography.
Note: thorough removal of pyridine and methanol from the reaction and digestion
procedures, respectively, was found to be critical for effective separation.
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Tert-butyl 2-amino-3-(4-(trifluoromethyl)phenyl)propanoate (1g). This was
synthesized according to the general procedure described above, using 5g (1.34 g, 3.0
mmol). The crude product was purified by silica gel column chromatography using a step
gradient from 5% methanol in dichloromethane to 10% methanol in dichloromethane to
afford a beige crystalline solid (567.6 mg, 66% yield). 1H NMR (600 MHz, CD3OD): δ 7.63
(d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.17 (t, J = 7.3 Hz, 1H), 3.27 – 3.24 (m, 1H),
3.21 – 3.17 (m, 1H), 1.36 (s, 9H). 13C {1H} NMR (150 MHz, CD3OD): δ 169.5, 140.8, 130.8
(q, J = 32.4 Hz), 126.7 (q, J = 3.7 Hz), 125.6 (q, J = 271.2 Hz), 85.0, 55.4, 37.8, 28.0. IR
(neat) 2983, 2864, 2630, 1731, 1621, 1565, 1502, 1372, 1325, 1245, 1128, 1108, 1019.
HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C14H19F3NO2 290.1362; Found 290.1364.
Rf = 0.28 (5% methanol in dichloromethane). MP = 168.3 – 176.1 ºC.
Tert-butyl 2-amino-3-(4-fluorophenyl)propanoate (1h). This was synthesized
according to the general procedure described above, using 5h (670.6 mg, 1.7 mmol). The
product was purified by silica gel column chromatography using a step gradient from 3%
methanol in dichloromethane to 10% methanol in dichloromethane to afford a yellow oil
(235.9 mg, 59% yield). 1H NMR (600 MHz, CDCl3): δ 7.13 (q, J = 8.3, 5.5 Hz, 2H), 6.92
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(t, J = 8.6 Hz, 2H), 3.54 (s (br), 1H), 2.94 (d of d, J = 13.4, 4.6 Hz, 1H), 2.79 (d of d, J =
13.5, 6.8 Hz, 1H), 1.83 (s (br), 2H), 1.36 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ
174.0, 161.7 (d, J = 244.6 Hz), 133.1, 130.8 (d, J = 7.8 Hz), 115.1 (d, J = 21.2 Hz), 81.3,
56.2, 40.2, 27.9. IR (neat) 3607, 3555, 2982, 2850, 2631, 1732, 1617, 1509, 1397, 1243,
1144, 1096, 1054. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C13H19FNO2 240.1394;
Found 240.1391. Rf = 0.32 (5% methanol in dichloromethane).
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Tert-butyl 2-amino-3-(m-tolyl)propanoate (1i). This was synthesized according to the
general procedure described above, using 5i (718.3 mg, 1.8 mmol). The product was
purified by silica gel column chromatography using a step gradient from 3% methanol in
dichloromethane to 10% methanol in dichloromethane to afford a yellow oil (186.9 mg,
44% yield). 1H NMR (600 MHz, CDCl3): δ 7.17 (t, J = 7.4 Hz, 1H), 7.03 – 6.99 (m, 3H),
3.60 (s (br), 1H), 3.00 (d of d, J = 13.5, 5.3 Hz, 1H), 2.81 (d of d, J = 13.5, 7.6 Hz, 1H),
13
2.31 (s, 3H), 1.76 (s (br), 1H), 1.42 (s, 9H). C {1H} NMR (150 MHz, CDCl3): δ 172.7,
138.3, 136.6, 130.5, 128.7, 127.9, 126.8, 82.2, 55.9, 40.0, 28.2, 21.6. IR (neat) 2977,
2928, 1726, 1626, 1508, 1447, 1393, 1284, 1144, 1039. HRMS (HESI/ orbitrap) m/z: [M
+ H]+ Calcd for C14H22NO2 236.1645; Found 236.1642. Rf = 0.33 (5% methanol in
dichloromethane).
Tert-butyl 2-amino-3-(naphthalen-2-yl)propanoate (1j). This was synthesized
according to the general procedure described above, using 5j (150.0 mg, 0.34 mmol).
The product was purified by silica gel column chromatography using a step gradient from
50% ethyl acetate in hexanes to 100% ethyl acetate to afford a yellow oil (57.3 mg, 61%
yield). 1H NMR (600 MHz, CD3OD): δ 7.82 – 7.77 (m, 3H), 7.70 (s, 1H), 7.46 – 7.41 (m,
2H), 7.37 (d of d, J = 8.4, 1.8 Hz, 1H), 4.07 (t, J = 7.0 Hz, 1H), 3.28 – 3.20 (m, 2H), 1.31
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(s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 170.9, 134.9, 134.1, 133.9, 129.5, 129.5,
128.7, 128.6, 128.3, 127.4, 127.0, 84.3, 55.9, 39.2, 28.1. IR (neat) 2977, 2929, 2632,
1727, 1623, 1507, 1446, 1507, 1368, 1247, 1148, 1067, 1020. HRMS (HESI/ orbitrap)
m/z: [M + H]+ Calcd for C17H22NO2 272.1645; Found 272.1638. Rf = 0.22 (100% ethyl
acetate).
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Tert-butyl 2-amino-5-methylhexanoate (1k). This was synthesized according to the
general procedure described above, using 5k (986.0 g, 2.7 mmol). The product was
purified by silica gel column chromatography using a step gradient from 1% methanol in
dichloromethane to 10% methanol in dichloromethane to afford a yellow oil (282.7 mg,
52% yield). 1H NMR (600 MHz, CDCl3): δ 5.95 (s (br), 2H), 3.78 (t, J = 5.9 Hz, 1H), 1.87
– 1.82 (m, 2H), 1.56 – 1.51 (m, 1H), 1.44 (s, 9H), 1.36 – 1.31 (m, 1H), 1.22 – 1.16 (m,
1H), 0.85 (t, J = 6.9 Hz, 6H). 13C {1H} NMR (150 MHz, CDCl3): δ 171.1, 83.1, 54.3, 33.9,
30.1, 28.1, 27.7, 22.5, 22.3. IR (neat) 2963, 2868, 1718, 1596, 1449, 1366, 1296, 1249,
1149, 1089, 1028. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C11H24NO2 202.1802;
Found 202.1802. Rf = 0.20 (5% methanol in dichloromethane).
General Procedure for N-arylations of Unnatural Amino Acid t-Butyl Esters 1g-k
with 4-Bromo-N,N-dimethylaniline
The amino acid t-butyl ester hydrochloride (1.0 mmol, 1.0 equiv), 4-Bromo-N,N-
dimethylaniline (1.0 mmol, 1.0 equiv), t-Bu BrettPhos Pd G3 (0.05 mmol, 0.05 equiv), and
sodium t-butoxide (2.0 mmol, 2.0 equiv) were added to the oven-dried 5-mL microwave
vial. The vial was immediately capped and flushed with argon. Dry tetrahydrofuran (2.0
mL) was added to the vial and the reaction mixture was stirred at room temperature for
two hours. The crude solution was filtered through a small plug of celite, rinsed with
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dichloromethane, evaporated to dryness on a rotary evaporator, and purified by flash-
column chromatography.
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Tert-butyl2-((4-dimethylamino)phenyl)amino)-3-(4-(trifluoromethyl)phenyl)
propanoate (3g). This was synthesized according to the general procedure described
above, using 1g (50.0 mg, 0.17 mmol). The product was purified by silica gel column
chromatography using 5-40% ethyl acetate in hexanes to afford a red oil (66.6 mg, 94%
yield). 1H NMR (600 MHz, CDCl3): δ 7.55 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H),
6.79 (d, J = 7.7 Hz, 2H), 6.62 (d, J = 8.3 Hz, 2H), 4.18 (s (br), 1H), 3.13 (d, J = 6.2 Hz,
2H), 2.85 (s, 6H), 1.34 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 172.4, 144.2, 141.4,
139.3, 130.0, 129.6, 129.2 (q, J = 32.3 Hz), 125.4 (q, J = 3.6 Hz), 124.2 (q, J = 271.9 Hz),
116.2, 115.6, 82.1, 59.3, 42.6, 38.8, 28.1. IR (neat) 2978, 1725, 1517, 1322, 1151, 1118,
1065. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C22H28F3N2O2 409.2097; Found
409.2103. Rf = 0.18 (20% ethyl acetate in hexanes).
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Tert-butyl 2-((4-(dimethylamino)phenyl)amino)-3-(4-fluorophenyl)propanoate (3h).
This was synthesized according to the general procedure described above, using 1h
(100.0 mg, 0.42 mmol). The desired compound was purified by silica gel column
chromatography using 5-40% ethyl acetate in hexanes to afford a yellow oil (103.0 mg,
69% yield). 1H NMR (600 MHz, CDCl3): δ 7.20 – 7.19 (m, 2H), 7.00 – 6.99 (m, 2H), 6.72
(s (br), 2H), 6.63 (s (br), 2H), 4.14 (s (br), 1H), 3.85 (s (br), 1H), 3.06 – 3.05 (m, 2H), 2.84
(s, 6H), 1.36 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 172.6, 161.8 (d, J = 244.6 Hz),
144.8, 138.7, 132.8 (d, J = 3.1 Hz), 131.1 (d, J = 7.9 Hz), 115.6, 115.5, 115.1 (d, J = 21.2
Hz), 81.6, 59.6, 42.0, 38.1, 28.0. IR (neat) 2976, 2790, 1725, 1601, 1509, 1367, 1220,
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1150. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C21H28FN2O2 359.2129; Found
359.2132. Rf = 0.16 (20% ethyl acetate in hexanes).
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Tert-butyl 2-((4-dimethylamino)phenyl)amino)-3-(m-tolyl)propanoate (3i). This was
synthesized according to the general procedure described above, using 1i (100.0 mg,
0.43 mmol). The product was purified by silica gel column chromatography using 5-40%
ethyl acetate in hexanes to afford a yellow oil (126.5 mg, 84% yield). 1H NMR (600 MHz,
CDCl3): δ 7.20 – 7.17 (m, 1H), 7.06 – 7.03 (m, 3H), 6.72 (d, J = 8.3 Hz, 2H), 6.62 (d, J =
8.4 Hz, 2H), 4.15 (s (br), 1H), 3.83 (s, (br), 1H), 3.09 – 3.05 (m, 1H), 3.03 – 3.00 (m, 1H),
2.83 (s, 6H), 2.33 (s, 3H), 1.34 (s, 9H). 13C {1H} NMR (600 MHz, CDCl3): δ 172.9, 144.7,
139.0, 137.9, 136.9, 130.4, 128.3, 127.5, 126.6, 115.6, 115.6, 81.5, 59.6, 42.2, 39.0, 28.0,
21.5. IR (neat) 2954, 1728, 1520, 1458, 1368, 1257, 1151. HRMS (HESI/ orbitrap) m/z:
[M + H]+ Calcd for C22H31N2O2 355.2380; Found 355.2385. Rf = 0.21 (20% ethyl acetate
in hexanes).
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Tert-butyl 2-((4-(dimethylamino)phenyl)amino)-3-(naphthalen-2-yl)propanoate (3j).
This was synthesized according to the general procedure described above, using 1j (25.0
mg, 0.09 mmol). The product was purified by silica gel column chromatography using 5-
40% ethyl acetate in hexanes to afford a red oil (16.7 mg, 46% yield). 1H NMR (600 MHz,
CDCl3): δ 7.84 – 7.82 (m, 1H), 7.80 – 7.79 (m, 2H), 7.96 (s, 1H), 7.49 – 7.45 (m, 2H), 7.41
– 7.39 (m, 1H), 6.74 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 4.28 (t, J = 6.4 Hz, 1H),
3.89 (s (br), 1H), 3.30 – 3.23 (m, 2H), 2.84 (s, 6H), 1.33 (s, 9H). 13C {1H} NMR (150 MHz,
CDCl3): δ 172.9, 144.8, 138.9, 134.7, 133.5, 132.5, 128.2, 128.0, 127.9, 127.7, 127.6,
126.1, 125.6, 115.6, 115.6, 81.6, 59.7, 42.1, 39.2, 28.0. IR (neat) 2975, 2788, 1723, 1601,
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1516, 1477, 1367, 1253, 1147, 1055. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for
C25H31N2O2 391.2380; Found 391.2365. Rf = 0.18 (20% ethyl acetate in hexanes).
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Tert-butyl 2-((4-(dimethylamino)phenyl)amino)-5-methylhexanoate (3k). This was
synthesized according to the general procedure described above, using 1k (100.0 mg,
0.50 mmol). The product was purified by silica gel column chromatography using 5-40%
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ethyl acetate in hexanes to afford a red oil (98.8 mg, 62% yield). H NMR (600 MHz,
CDCl3): 6.71 (s (br), 2H), 6.62 (s (br), 2H), 3.83 (s (br), 1H), 2.82 (s, 6H), 1.81 – 1.69 (m,
2H), 1.61 – 1.54 (m, 1H), 1.43 (s, 9H), 1.35 – 1.31 (m, 2H), 0.91 (d of d, J = 6.6, 4.4 Hz,
6H). 13C {1H} NMR (150 MHz, CDCl3): δ 173.0, 137.9, 136.9, 130.4, 128.3, 127.5, 126.6,
115.8, 115.6, 81.5, 59.6, 42.3, 39.0, 28.0, 21.5. IR (neat) 2976, 1727, 1610, 1519, 1478,
1367, 1257, 1154. HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C19H33N2O2 321.2537;
Found 321.2542. Rf = 0.28 (20% ethyl acetate in hexanes).
General Procedure for N-aryl Amino Acid Coupling to Resin-Bound Peptide
The amino acid tert-butyl ester (100.0 mg, 0.061 mmol, 1.0 equiv) was transferred to a
new 20-mL scintillation vial, dissolved in 1:1 TFA/ DCM (2 mL), and allowed to stir at room
temperature for two hours. The reaction mixture was evaporated to dryness using a
Biotage V10 evaporator (volatile setting), followed by co-evaporation (x 5) with
dichloromethane to remove residual TFA. The resulting oil was used in the next step
without further purification.
Dimethylformamide (DMF) was added to resin-bound LYRAG peptide (100.0 mg, 0.061
mmol, 1.0 equiv) in a 3-mL disposable filter column with a 20 μM PE frit filter and allowed
to swell on a shaker for approximately twenty-five minutes. DMF was drained from the
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cartridge. The N-aryl amino acid (0.183 mmol, 3.0 equiv) dissolved in DMF (1.0 mL) was
added to the cartridge, followed by 2-(1H-benzotriazol-1-yl)-1,2,3,3-tetramethyluronium
hexafluorophosphate (HBTU) (0.183 mmol, 3.0 equiv) and diisopropylethylamine (DIEA)
(0.366 mmol, 6 equiv). The resin was allowed to shake for two hours, after which the
reagents were drained and the resin was washed with DMF, MeOH, and DCM (x3).
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Test cleavage of resin-bound peptides
A small aliquot of resin (1-5 mg) was transferred to a 1-mL disposable filter column with
a 20 μM PE frit filter. A freshly made solution of TFA/TIPS/H2O (95:2.5:2.5, v/v/v, 0.2 mL)
was added to the cartridge and allowed to shake at room temperature for two hours. The
resin was filtered through the PE frit and the filtrate was collected in a 20-mL scintillation
vial and evaporated to dryness on a Biotage V10 evaporator (volatile setting). Addition of
cold ether (1 mL) to the crude oil caused a precipitate to form, which was redissolved in
1:1 MeCN/ H2O v/v (1 mg/ mL) prior to LCMS analysis.
Full cleavage of resin-bound peptides
The resin-bound peptide was transferred to a 20-mL scintillation vial and treated with a
freshly made solution of TFA/TIPS/H2O (95:2.5:2.5, v/v/v, 4.0 mL). The vial was capped
and allowed to shake at room temperature for two hours. The cleavage mixture was
filtered through a 3-mL disposable filter column with a 20 μM PE frit filter into a 50-mL
falcon tube containing cold ether (25-30 mL). The falcon tube was centrifuged for 5
minutes at 7000 RPM, the ether was decanted, and the precipitate was redissolved in 1:1
MeCN/ H2O v/v before freeze-drying.
Analysis and purification of peptides 7a-k
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Crude peptides 7a-k were analyzed and characterized by LCMS as described in the
General Methods. Following gradient optimization, the peptides were purified by
preparative HPLC as described in the General Methods. Peptides 7a, 7d and 7f were
purified using a 25-80% MeCN (0.1% TFA) in water (0.1% TFA) gradient. Peptide 7b was
purified using 20-70% MeCN (0.1% TFA) in water (0.1% TFA) gradient. Peptide 7c was
purified using 10-70% MeCN (0.1% TFA) in water (0.1% TFA) gradient. Peptides 7e was
purified using a 20-80% MeCN (0.1% TFA) in water (0.1% TFA) gradient. Peptides 7g-k
was purified using a 30-90% MeCN (0.1% TFA) in water (0.1% TFA) gradient. The
contents of the HPLC fractions were analyzed using LC-MS. The fractions containing the
desired peptide were collected, frozen immediately, and lyophilized. 7a: HPLC (5−95%
MeCN, 12 min) retention time = 9.12 min; HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for
C43H62N11O7 844.4828; Found 844.4832; 7b: HPLC (5−95% MeCN, 12 min) retention
time = 8.48 min; HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C39H62N11O7S 828.4549;
Found 828.4556; 7c: HPLC (5−95% MeCN, 12 min) retention time = 7.91 min; HRMS
(HESI/ orbitrap) m/z: [M + H]+ Calcd for C37H58N11O7 768.4515; Found 768.4528; 7d:
HPLC (5−95% MeCN, 12 min) retention time = 8.96, 9.10 min; HRMS (HESI/ orbitrap)
m/z: [M + H]+ Calcd for C40H64N11O7 810.4985; Found 810.4997; 7e: HPLC (5−95%
MeCN, 12 min) retention time = 8.92 min; HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for
C39H62N11O7 796.4828; Found 796.4839; 7f: HPLC (5−95% MeCN, 12 min) retention time
= 8.99 min; HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C40H64N11O7 810.4985; Found
810.4998; 7g: HPLC (5−95% MeCN, 12 min) retention time = 10.08 min; HRMS (HESI/
orbitrap) m/z: [M + H]+ Calcd for C44H61F3N11O7 912.4702; Found 912.4724; 7h: HPLC
(5−95% MeCN, 12 min) retention time = 9.53 min; HRMS (HESI/ orbitrap) m/z: [M + H]+
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Calcd for C43H61FN11O7 862.4734; Found 862.4732; 7i: HPLC (5−95% MeCN, 12 min)
retention time = 9.73 min; HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C44H64N11O7
858.4985; Found 858.4985; 7j: HPLC (5−95% MeCN, 12 min) retention time = 10.00 min;
HRMS (HESI/ orbitrap) m/z: [M + H]+ Calcd for C47H64N11O7 894.4985; Found 894.4991;
7k: HPLC (5−95% MeCN, 12 min) retention time = 9.70 min; HRMS (HESI/ orbitrap) m/z:
[M + H]+ Calcd for C41H66N11O7 824.5141; Found 824.5145.
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General procedure for ketoxime ligation reactions
All ligation reactions were performed using previously reported reaction conditions.8,9
Briefly, stock solutions of the peptide (2 mM) and O-benzylhydroxylamine hydrochloride
(10 mM) were prepared in phosphate buffer pH 7. 1 mL of each reagents were combined
in a 4 mL vial, and the solution was sparged with O2 for thirty seconds. The reaction was
allowed to stir at room temperature for twenty-four hours under O2 atmosphere, after
which a small aliquot (100 μL) of the reaction mixture was analyzed by LCMS. Oxime
conversions were calculated using peak areas at 214 nm, where % oxime conversion =
[(area of oxime 8a-k)/(area of 7a-k + 8a-k)] x 100. Ketoximes 8a-k were analyzed and
characterized by LCMS as described in the General Methods. 8a: HPLC (5−95% MeCN,
12 min) retention time = 11.22, 11.76 min; LCMS (ESI) calcd for C42H57N10O8 [M + H]+
m/z 829.4, m/z (obs) 829.7; 8b: HPLC (5−95% MeCN, 12 min) retention time = 10.86,
11.35 min; LCMS (ESI) calcd for C38H57N10O8S [M + H]+ m/z 813.4, m/z (obs) 813.6; 8c:
HPLC (20-80% MeCN, 12 min) retention time = 10.06, 10.86 min; LCMS (ESI) calcd for
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C36H53N10O8 [M + H]+ m/z 753.4, m/z (obs) 753.6; 8d: HPLC (5−95% MeCN, 12 min)
retention time = 11.21, 11.83 min; LCMS (ESI) calcd for C39H59N10O8 [M + H]+ m/z 795.4,
m/z (obs) 795.7; 8e: HPLC (5−95% MeCN, 12 min) retention time = 11.18, 11.75 min;
LCMS (ESI) calcd for C38H57N10O8 [M + H]+ m/z 781.4, m/z (obs) 781.6; 8f: HPLC (5−95%
MeCN, 12 min) retention time = 11.28, 11.89 min; LCMS (ESI) calcd for C39H59N10O8 [M
+ H]+ m/z 795.4, m/z (obs) 795.6; 8g: HPLC (5−95% MeCN, 12 min) retention time =
12.28, 12.76 min; LCMS (ESI) calcd for C43H56F3N10O8 [M + H]+ m/z 897.4, m/z (obs)
897.6; 8h: HPLC (5−95% MeCN, 12 min) retention time = 11.68, 12.18 min; LCMS (ESI)
calcd for C42H56FN10O8 [M + H]+ m/z 847.4, m/z (obs) 847.7; 8i: HPLC (5−95% MeCN, 12
min) retention time = 11.91, 12.39 min; LCMS (ESI) calcd for C43H59N10O8 [M + H]+ m/z
843.4 m/z (obs) 843.7; 8j: HPLC (5−95% MeCN, 12 min) retention time = 12.20, 12.69
min; LCMS (ESI) calcd for C46H59N10O8 [M + H]+ m/z 879.4, m/z (obs) 879.6; 8k: HPLC
(5−95% MeCN, 12 min) retention time = 11.93, 12.50 min; LCMS (ESI) calcd for
C40H61N10O8 [M + H]+ m/z (cald) 809.5, m/z (obs) 809.7.
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ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for compounds 1g-k, 3a-k, and 5g-k.
LCMS traces for peptides 7a−k and ketoxime peptides 8a-k. The Supporting Information
is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* cproulx@ncsu.edu
ACKNOWLEDGMENT
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We thank North Carolina State University for start up support. All NMR experiments were
performed in the Molecular Education, Technology, and Research Innovation Center
(METRIC) at NC State University.
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REFERENCES
1. For selected recent reviews, see: (a) deGruyter, J. N.; Malins, L. R.; Baran, P. S.
Residue-Specific Peptide Modification: A Chemist's Guide. Biochemistry 2017, 56,
3863-3873. (b) Boutureira, O.; Bernardes, G. J. L. Advances in Chemical Protein
Modification. Chem. Rev. 2015, 115, 2174-2195. (c) Noisier, A. F. M.; Brimble, M. A.
C-H Functionalization in the Synthesis of Amino Acids and Peptides. Chem. Rev.
2014, 114, 8775-8806.
2. Haynes-Smith, J.; Diaz, I.; Billingsley, K. L., Modular Total Synthesis of Protein Kinase
C Activator (-)-Indolactam V. Org. Lett. 2016, 18, 2008-2011.
3. Ma, D. W.; Zhang, Y. D.; Yao, J. C.; Wu, S. H.; Tao, F. G. Accelerating effect induced
by the structure of alpha-amino acid in the copper-catalyzed coupling reaction of aryl
halides with alpha-amino acids. Synthesis of benzolactam-V8. J. Am. Chem. Soc.
1998, 120, 12459-12467.
4. Han, C.; Kelly, S. M.; Cravillion, T.; Savage, S. J.; Nguyen, T.; Gosselin, F. Synthesis
of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of alpha-amino acids.
Tetrahedron 2019, 75, 4351-4357.
5. Zhang, C.; Vinogradova, E. V.; Spokoyny, A. M.; Buchwald, S. L.; Pentelute, B. L.
Arylation Chemistry for Bioconjugation. Angew. Chem. Int. Ed. 2019, 58, 4810-4839.
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6. For selected examples, see: (a) Zhao, L.; Li, C. J. Functionalizing glycine derivatives
by direct C-C bond formation Angew. Chem. Int. Ed. 2008, 47, 7075-7078. (b) Zhao,
L.; Basle, O.; Li, C. J. Site-specific C-functionalization of free-(NH) peptides and
glycine derivatives via direct C–H bond functionalization Proc. Natl. Acad. Sci. U. S.
A. 2009, 106, 4106-4111. (c) Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang, X.; Chen.
F.; Tang, J. Auto-Oxidative Coupling of Glycine Derivatives. Angew. Chem. Int. Ed.
2014, 53, 13544-13547. (d) Huo, C.; Wang, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y.
Copper(I) Chloride-Catalyzed Aerobic Oxidative Arylation of Glycine Ester and Amide
Derivatives. Adv. Synth. Catal. 2014, 356, 411-415. (e) Segundo, M. S.; Guerrero, I.;
Correa, A. Co-Catalyzed C(sp3)−H Oxidative Coupling of Glycine and Peptide
Derivatives. Org. Lett. 2017,19, 5288-5291. (f) Xie, J.; Huang, Z. Z. Cross-
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15
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17
18
19
20
21
22
23
24
25
26
27
28
29
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54
55
56
57
58
59
60
Dehydrogenative Coupling Reactions by Transition-Metal and Aminocatalysis for the
Synthesis of Amino Acid Derivatives. Angew. Chem. Int. Ed. 2010, 49, 10181-10185.
(g) Liu, P.; Wang, Z.; Lin, J.; Hu, X. An Efficient Route to Quinolines and Other
Compounds by Iron-Catalysed Cross-Dehydrogenative Coupling Reactions of
Glycine Derivatives. Eur. J. Org. Chem. 2012, 1583-1589. (h) Zhang, G.; Zhang,
Y.; Wang, R. Catalytic Asymmetric Activation of a Csp3H Bond Adjacent to a Nitrogen
Atom: A Versatile Approach to Optically Active a-Alkyl a-Amino Acids and C1-
Alkylated Tetrahydroisoquinoline Derivatives. Angew. Chem. Int. Ed. 2011, 50, 10429-
10432. (i) Salman, M.; Zhu, Z. Q.; Huang, Z. Z. Dehydrogenative Cross-Coupling
Reaction between N-Aryl α-Amino Acid Esters and Phenols or Phenol Derivative for
Synthesis of α-Aryl α-Amino Acid Esters. Org. Lett. 2016, 18, 1526-1529. (j) Xie, Z.; Liu,
X.; Liu, L. Copper-Catalyzed Aerobic Enantioselective Cross-Dehydrogenative
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