Copper-catalyzed: N -(hetero)arylation of amino acids in water

Article abstract of DOI:10.1039/c6ra23364c

An environmentally benign, mild, cost-effective and gram-scalable copper-catalyzed method for the N-(hetero)arylation of zwitterionic natural and unnatural amino acids using 2-isobutyrylcyclohexanone as a β-diketone ligand and aryl bromides as coupling partners in water for 50 min at 90 °C under microwave irradiation is reported. Electronically and sterically diverse aryl coupling partners were inserted efficiently, including challenging heteroaryl electrophilic partners in high yields without affecting the enantiopurity of the product.

Full text of DOI:10.1039/c6ra23364c

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Copper-catalyzed N-(hetero)arylation of amino acids in water
Krishna K. Sharma, Meenakshi Mandloi, Neha Rai and Rahul Jain
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An environmentally benign, mild, cost-effective and gram-scalable and efficient routes to synthesize N-arylated compounds from
copper-catalyzed method for the N-(hetero)arylation of aryl halides.5-6 Higher cost of palladium catalysts and
zwitterionic natural and unnatural amino acids using 2- phosphine-based ligands, air and moisture sensitivity and toxic
isobutyrylcyclohexanone as β-diketone ligand and aryl bromides nature of palladium renders them environmentally-unfriendly
as coupling partners in water for 50 min at 90 oC under microwave catalytic systems for chemical transformations.6 The classical
irradiation is reported. The electronically and sterically diverse Ullmann reaction also suffers due to harsh conditions, high
aryl coupling partners were inserted efficiently, including temperature, sluggish rate, stoichiometric use of metal, low
challenging heteroaryl electrophilic partners in high yields without yield, and use of high boiling toxic solvents such as DMF,
affecting the enantio-purity of the product.
DMSO or toluene dampening its applicability in the benign
During the past two decades, functionalized amino acids have synthesis of enantiomerically pure products.7 Over the years,
received great attention in synthetic organic chemistry, and copper-catalyzed modified Ullmann-type reactions have
drug discovery emanating out of peptide-based structural received great attention primarily due to the advent of
design.1-2 Presence of synthetically modified natural and inexpensive and non-toxic copper salts and a wide array of
unnatural amino acids in biologically relevant structural commercially available low molecular weight bidentate
scaffolds makes them potential lynchpin for functionalization.
ligands.8 Significant progress in copper-catalyzed reactions is
Natural peptides and proteins show high activity, but have witnessed due to the application of a plethora of nitrogen- and
limited therapeutic potential because of large size, oxygen-based bidentate ligands such as phenanthrolines,
conformational flexibility and proteolysis-initiated low aliphatic 1,2-diamines, ethylene glycol, diethyl salicylamide,
metabolic stability. The introduction of functionalized amino thiophene 2-carboxylate, amino acid derivatives, β-diketones,
acids in the peptide backbone is one of the promising β-ketoesters, BINOL and oxalic diamides on aliphatic and
approaches to address these issues.3 Specifically designed N- aromatic amine substrates.9 Despite of such advances in
alkylated amino acids provide potential chiral building blocks copper-catalyzed reactions, direct application of the reaction
for incorporation in peptides, peptidomimetics and proteins in the synthesis of N-arylated amino acids under benign
leading to modulated conformational freedom, altered binding conditions is absent or rare due to toxic reaction solvent and
site interactions, and enhanced pharmacokinetic properties.4 loss of enantiomeric purity in the desired chiral products.10
Due to difficult accessibility, the application of N-arylated Few reports describe the use of water as solvent in amination
amino acids in the synthesis of bioactive peptides is an reactions on aliphatic amines11 and amino acids,12 but with
interesting but rather an unexplored area of research.
limitations such as use of designer ligands, lack of diverse
The transition metal copper-catalyzed Ullmann and palladium- substrate scope and harsh reaction conditions, making them
catalyzed Buchwald-Hartwig amination reactions are common unsuitable for the synthesis of enantiomerically pure products.
More recently, some reports on the N-arylation of amino acid
esters using designer and expensive palladium-ligand
precatalytic systems in conventional organic medium have
emerged.13 Therefore, an environmentally benign and
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
Corresponding Author * E-mail: rahuljain@niper.ac.in
Electronic Supplementary Information (ESI) available: Experimental
procedures, product characterization, copies of 1H and 13C NMR and
chiral purity studies. See DOI: 10.1039/c000000x/
generalized protocol for the N-arylation and challenging N-
heteroarylation leading to synthesis of enantiopure N-
(hetero)arylated amino acids using inexpensive coupling
partners is highly desirable. We planned N-(hetero)arylation
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J. Name., 2013, 00, 1-3 | 1
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reactions on the zwitterionic amino acids due to their cost- tetramethyl-ethylenediamine (L5) produced 2a ranged
effective and cheap access. Functionalization of fully between 17-24% yield (scheme 1). Next, we explored the
unprotected amino acid due to its zwitterionic character is one applicability of nitrogen containing aromatic ligands such as
of the most difficult reaction; some exceptions includes amide 2,2’-bipyridine (L6) and 1,10-phenanthroline (L7), herein ligand
bond formation, Kent ligation and Staudinger ligation.14 To L6 afforded only trace amount of product while no product
overcome these limitations, we set our task in developing a formation was noted with ligand L7 (scheme 1). We next
racemization-free method for the N-arylation of unprotected explored various acyclic and cyclic β-diketones ligands (L8, L9,
amino acids under aqueous conditions.
L10 and L11) under aqueous conditions and noted that L11
In continuation of our work on the synthesis of functionalized afforded 53% yield of the product, and clearly emerged as the
amino acids and heterocycles and their exploration in search most suited ligand for N-arylation reaction in water.
of potent peptide- and peptidomimetic-based chemical
Table 1
.
Optimization of reaction parameters for N-arylation
entities,15 we required a variety of N-(hetero)arylated amino
acids. Herein, we report that inexpensive electrophilic aryl
bromides undergo highly efficient cross-coupling with
unprotected amino acids under environmentally benign
conditions using a copper(I)-catalyzed protocol in the presence
of β-diketone ligand in water mediated by microwave (MW)
irradiation. The method is applicable to reactions scalable up
to multi-gram of substrates. To the best of our knowledge, this
is the first racemization-free report on the copper(I)-catalyzed
N-(hetero)arylation of natural and unnatural zwitterionic
amino acids in water using inexpensive aryl bromides as
coupling partners and β-diketone as ligand.
reactiona
Br
OH
OH
Cu(I), L11
H2N
N
H
Base, H2O, 50 min, MW
O
O
1
2a
Entry [Cu]
(5 mol%)
CuI
Base
Temp.
Additive
2a
(%yield)b
1
2
3
4
5
K2CO3
K2CO3
K2CO3
KOH
90 °C
80 °C
110 °C
90 °C
90 °C
–
–
–
–
–
50c
41
47
15
7
CuI
CuI
CuI
CuI
K3PO4
6
7
CuI
Cu2O
Cs2CO3
K2CO3
90 °C
90 °C
–
–
11
17
Br
CuI (5 mol%),
OH
8
9
10
11
CuBr
CuCl
CuOAc
CuI
K2CO3
K2CO3
K2CO3
K2CO3
90 °C
90 °C
90 °C
90 °C
–
–
–
19
46
26
10
OH
L (20 mol%)
H2N
N
H
K2CO3 (2.5 equiv.), H2O
50 min, 90 oC, MW
O
O
1
2a
Ethylene
glycol
12
13
14
15
16
17
18
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
Glycerol
PEG
Trace
45
OH
R
R
R
R
N
N
N
H
N
N
N
N
R'
R'
R'
R'
O
PEG-400
PEG-400
PEG-400
PEG-200
PEG-600
82d
L6 (5%)
L4. R = H, R' = Me; (19%)
L5. R = Me, R' = Me; (17%)
L2. R = H, R' = H; (18%)
L3. R = H, R' = Me; (24%)
L1 (33%)
87e
82f
61
56
O
O
R
O
O
R
R
N
N
L8. R = Me; (23%)
L9. R = tBu; (31%)
19
20
K2CO3
K2CO3
90 °C
90 °C
PEG-400
PEG-400
11g
L10. R = Me; (42%)
L11. R = iPr; (53%)
L7 (0%)
Traceh
Scheme 1. Screening of ligands for N-arylation reaction
aAll reactions were performed with
L-valine (1.2 equiv.), PhBr (1 equiv. 0.5
mmol), base (2.5 equiv.), H2O (1 mL), L11 (20 mol%); bisolated yield,
We began model experiments by reacting L-valine (1) and
d
e
f
creaction time (70 min); PEG-400 (1 equiv.); PEG-400 (1.5 equiv.); CuI (
10 mol%), ligand (40 mol%); gligand was not used; hconventional heating for
24 h.
coupling partner bromobenzene to identify a suitable N-
arylation protocol under aqueous conditions. First, we
investigated cross-coupling reaction of bromobenzene with
1
With the success of the most appropriate ligand identification
study, we turned our attention to the optimization of other N-
arylation reaction parameters (table 1). We attampted a
reaction by increasing the reaction time to 70 min; however no
improvement in the product yield was noted (table 1, entry 1).
The attempts towards temperature variations did not offer any
advantage by means of enhancement in product formation
(table 1, entries 2-3). The use of alternate bases such as KOH,
K3PO4, and Cs2CO3 did not show any improvement in yield of
product (table 1, entries 4-6). The use of other catalytic
sources such as Cu2O, CuBr, CuCl and CuOAc did not enhance
yield of N-arylated product (table 1, entries 7-10).
in the presence of copper(I) iodide (5 mol%), ligand (20 mol%)
and K2CO3 as a base (2.5 equiv.) under conventional heating at
90 oC for 24 h in water (1 mL), to observe no product
formation. We then switched heating mode to more safe and
faster microwave (MW) irradiation and were delighted to note
that the use of well-known amino acid ligand, L-proline (L1)
afforded the desired N-arylated product 2a in 33% yield,
providing necessary encouragement to further investigate N-
arylation reaction in water. Under the reaction conditions
described above, the use of ligands such as constrained
aliphatic amines 1,2-diaminocyclohexane (L2) and trans-N,N′-
dimethylcyclohexane-1,2-diamine (L3), and non-constrained
amines N,N′-dimethylethylenediamine (L4) and N,N,N′,N′-
2 | J. Name., 2012, 00, 1-3
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Table 2: Substrate scope of aryl bromidesa-b
We reasoned that attempts to improve yield failed possibly
because of the partial solubility of the reactive state
complexes in the solvent medium. An examination of the
literature reports revealed that the use of additives results in
enhanced product formation, possibly by increasing the
solubility of transition state intermediates without affecting
reaction sustainability.16 This prompted us to examine the
applicability of various additives such as ethylene glycol,
glycerol, PEG, PEG-200, PEG-400 and PEG-600 in the N-
arylation reaction. The use of strongly hydrophilic PEG-400 (1
equiv.) afforded 2a in 82% yield (table 1, entry 14) while
increasing its quantity to 1.5 equivalents afforded remarkably
higher 87% yield of 2a under aqueous conditions (table 1,
entry 15). The use of ethylene glycol, glycerol, PEG, PEG-200,
and PEG-600 afforded 2a ranged in trace-61% yield (table 1,
entries 11-13, and 17-18). It was noted that omitting the ligand
from the reaction under optimized conditions afforded
product in 11% yield, clearly confirming that β-diketone ligand
L11 is critical for reaction (table 1, entry 19). No product
formation was observed in an attempt to conduct reaction
under conventional heating conditions reflecting on the
desirability of MW irradiation in the N-arylation reaction in
water (table 1, entry 20).
CuI (5 mol%),
OH
Ar
OH
L11 (20 mol%)
(Het)Ar Br
H2N
N
H
K2CO3 (2.5 equiv.),
PEGꢀ400, H2O,
50 min, 90 oC, MW
O
O
1
2
OH
OH
OH
HN
HN
HN
O
O
O
CH3
(2c, 85%)
CH3
(2a, 87%)
(2b, 84%)
OH
OH
OH
HN
O
HN
HN
O
O
(2d, 80%)
(2e, 83%)
(2f, 81%)
OH
OH
OH
HN
O
HN
HN
O
O
Cl
Cl
CF3
(2i, 90%)
To demonstrate the utility of newly developed sustainable in-
water protocol, aryl substrate scope of electronically and
(2g, 88%)
(2h, 90%)
sterically diverse aryl bromides was investigated with
1 as
OH
OH
OH
HN
O
HN
HN
nucleophilic partner. Less electrophilic electron-donating aryl
partners easily cross-coupled under the developed protocol in
high yields (table 2, entries 2b-d). Electron-withdrawing group
O2N
O
O
O2N
CF3
NO2
(2k, 91%)
substituted aryl bromides also coupled very efficiently with
1
(2l, 88%)
(2j, 82%)
to afford product in up to 91% yield (table 2, entries 2e-r). The
N-arylation method was found highly robust in coupling
sterically bulky electrophilic partners such as tert-butylphenyl
bromide, biphenyl bromide and naphthyl bromide to produce
arylated amino acids in 80-83% yields (table 2, entries 2d-f).
The reaction is noted to exhibit excellent functional group
tolerance as a range of functional group containing aryl
bromide easily coupled in high yields (table 2, entries 2g-r).
Noticeable examples are ortho-substituted derivative (table 2,
entry 2m) and disubstituted derivatives (table 2, entries 2j, and
2q-r). Chemically reactive functional groups containing aryl
bromides also coupled efficiently with complete
chemoselectivity due to mild nature of the developed protocol
(table 2, entries 2g-h, and 2n-o). Heteroaryl bromides such as
3-bromopyridine, 3-bromoquinoline and 6-bromoquinoline
OH
OH
OH
HN
HN
HN
O
O2N
O
O
CN
(2n, 86%)
CHO
(2o, 87%)
(2m, 82%)
OH
OH
HN
OH
HN
HN
O
F
O
O
F
F
F
F
(2q, 83%)
(2p, 87%)
(2r, 81%)
OH
OH
OH
HN
HN
HN
O
also coupled with the zwitterionic L-valine (1) in excellent
O
O
yields to provide entry to difficult to access N-heteroarylated
amino acid derivatives (table 2, entries 2s-u).
N
N
(2s, 82%)
N
We then examined the amino acid scope of the reaction by
coupling of bromobenzene with a large number of natural and
unnatural amino acids and the results of the study are
summarized in table 3. The reaction was noted to have wide
applicability amply demonstrated by successful N-arylation of
(2t, 88%)
(2u, 78%)
aAll reactions were performed with
L-valine (1.2 equiv.), PhBr (1 equiv., 1
mmol), K2CO3 (2.5 equiv.), PEG-400 (1.5 equiv.), H2O (2 mL), CuI (5 mol%),
L11 (20 mol%); bisolated yield.
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various α-, β- and even cyclic amino acids in high yields,
irrespective of the size and the nature of the side chain.
surprisingly, N-arylation of unprotected L-histidine was not
allowed under this protocol (table 3, entry 4j). We envision
that it is due to the formation of Cu-histidine complex during
the reaction, besides its tautomeric character and H-bond
donor and acceptor properties rendering it difficult to
functionalize without protection.17
Table 3. Substrate scope of amino acids
To examine the wider application of the protocol, the N-
arylation of amino acids was scaled up to 10 mmol. As noted
Br
R
CuI (5 mol%),
R
OH
L11 (20 mol%)
H2N
OH
N
H
K2CO3 (2.5 equiv.),
PEGꢀ400, H2O,
from scheme 2, almost identical yields of 2e, 2h and 3t were
O
O
3
4
obtained under the optimized mild and benign reaction
conditions (scheme 2).
50 min, 90 oC, MW
OH
N
OH
OH
OH
N
N
H
O
H
H
O
O
CulI
(4b. 86%)
(4c. 88%)
(4a. 81%)
K2CO3
LH
L
S
L CulI
ꢀ I
LꢀCul
OH
OH
OH
N
N
N
H
O
H
H
O
OH
O
O
(4d. 80%)
(4e. 89%)
(4f. 91%)
OH
H2N
HN
O
N
O
NH
Reductive
Elimination
Nucleophile
Coordination
OH
OH
O
N
OH
N
H
O
H
O
NH
Ph
L CuIII
N
(4h. 88%)
(4i. 82%)
(4g. 90%)
L CuI
TS-1
OH
O
H
TS-4
N
NH
Base
Oxidative
Addition
Deprotonation
OH
OH
N
OH
Br
N
N
BH+
H
H
O
H
O
O
Ph
Br
(4k. 84%)
OH
O
(4l. 83%)
(4j. 0%)
L CuI
NH
O
L CuI NH
Electrophile
Coordination
OH
TS-2
N
N
OH
O
H
H
O
TS-3
OH
(4n. 78%)
(4m. 85%)
PhBr
aAll reactions were performed with amino acids (1.2 equiv.), PhBr (1 equiv.;
1 mmol), K2CO3 (2.5 equiv.), PEG-400 (1.5 equiv.), H2O (2 mL), CuI (5 mol%),
L11 (20 mol%), b isolated yield.
Scheme 3. Plausible reaction mechanism
A plausible mechanistic cycle of the copper(I)-catalyzed N-
arylation reaction of zwitterionic amino acids with electrophilic
aryl bromides proceeds through a modified Ullmann-type
mechanism via an oxidative-addition-reductive elimination
cycle involving Cu(I)/Cu(III) intermediates (scheme 3).18 It is
envisioned that N-arylation reaction proceeds via
complexation of copper(I) iodide with β-ketone ligand L11,
which is followed by nucleophile coordination by amino group,
resulting in the formation of the transition state TS-1. Next,
deprotonation by the base results in the Cu(I)-centred
intermediate stage TS-2, which subsequently via electrophilic
coordination with bromobenzene gave Cu(I)-centred complex
TS-3. The oxidative addition transformation results in the
Cu(III)-centered transition state TS-4. In the final step of the
Br
R'
R
CuI (5 mol%; 95 mg),
L11 (20 mol%; 336 mg)
R
OH
H2N
OH
R'
1.55 g ꢀ 2.33 g
N
K2CO3 (2.5 equiv.; 3.45 g),
PEGꢀ400 (1.5 equiv.; 6 g),
H2O (6 mL), 50 min,
90 oC, MW
O
H
O
1a. 1.40 g
1a. 1.40 g
3h. 2.45 g
NH
OH
N
OH
N
OH
N
N
H
H
O
H
O
O
(2e. 81%; 2.18 g)
(4h. 85%; 2.39 g)
(2t. 86%; 2.11 g)
Scheme 2. Multi-gram scale synthesis
catalytic cycle, TS-4 rearranges to form the desired N-phenyl-L-
Natural α-amino acids were N-arylated in up to 91% yield with
bromobenzene (table 3, entries 4a-b and 4d-i). The unnatural
amino acids also coupled readily with bromobenzene to
produce the N-arylated products in yields ranged between 78-
84% (table 3, entries 4k-n). We noted although not
valine via reductive elimination and regeneration of the Cu(I)-
L11 complex in the reaction medium through the expulsion of
bromide anion.
4 | J. Name., 2012, 00, 1-3
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The racemization study of the synthesized N-arylated amino
acids was performed on HPLC using a ChiralPak WH column
and a mobile phase of 0.25 mM copper(II) sulfate in water
(93%) and 2-propanol (7%) for 180 min. The column
Fairlie, S. Liras and D. Price, Chem. Biol. Drug Des., 2013, 81
,
136; (c) F. Albericio and H. G. Kruger, Future Med. Chem.,
2012,
2000,
4
, 1527; (d) D. A. Dougherty, Curr. Opin. Chem. Biol.
4, 645.
o
temperature was kept at 50 C, and the flow rate of 1 mL/min
(4) (a) S. Royo-Gracia, K. Gaus and N. Sewald, Future Med.
Chem., 2009, , 1289; (b) A. Grauer and B. Konig, Eur. J. Org.
was fixed for analysis. For the purpose of comparision, we also
undertook the synthesis of N-phenyl-DL-valine. The chiral
purity of N-phenyl-L-valine (2a), N-phenyl-D-valine (4c), and N-
1
Chem., 2009, 30, 5099.
(5) (a) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev.,
2004, 248, 2337; (b) C. Fischer and B. Koenig, Beilstein J. Org.
phenyl-DL-valine under the optimized conditions was
examined, and it was found that enantiomeric purity of N-
phenyl-L-valine and N-phenyl-D-valine remained intact during
Chem., 2011, 7, 59; (c) J. F. Hartwig, Angew. Chem. Int. Ed.,
the copper(I)-catalyzed transformation (please see, SI). It is
evident that the use of zwitterionic amino acids prevents the
1998, 37, 2046; (d) L. Jiang and S. L. Buchwald, Palladium-
Catalyzed Aromatic Carbon-Nitrogen Bond Formation, Wiley-
VCH: Weinheim, 2nd edn, 2004, p. 699; (e) E. M. Beccalli, G.
Broggini, M. Martinelli and S. Sottocornola, Chem. Rev., 2007,
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base-mediated α-proton abstraction, resulting in intact
enantiomeric integrity of the arylated amino acids.
In conclusion, we have successfully developed an efficient,
rapid, environmentally benign, gram-scalable, practical and
experimentally safe approach for the N-(hetero)arylation of
amino acids under mild conditions using inexpensive aryl
bromides as coupling partners. This protocol allow low catalyst
and ligand loading for N-arylation transformation in 50 min
under MW irradiation and uses copper(I) iodide as catalyst, 2-
isobutyrylcyclohexanone (L11) as ligand and PEG-400 as
(6) H. Zhang, Q. Cai and D. Ma, J. Org. Chem., 2005, 70, 5164.
(7) (a) F. Ullmann, Chem. Ber., 1903, 36, 2382; (b) F. Ullmann
and P. Sponagel, Chem. Ber., 1905, 38, 2211.
(8) For selected reviews on copper-catalyzed cross coupling
reactions, see: (a) I. P. Beletskaya and A. V. Cheprakov, Coord.
additive in water. This catalytic transformation readily coupled Chem. Rev., 2004, 248, 2337; (b) S. V. Ley and A. W. Thomas,
ortho-, meta-, and para-positions reactive functional group
containing aryl bromides in high yields. This protocol is equally
applicable to access challenging N-heteroarylated amino acids
under the identical reaction conditions. By using this protocol,
various α- and β- natural and unnatural amino acids were N-
arylated in high yields. The application of method on fully
unprotected zwitterionic amino acids provides scaffolds that
could be easily modified at either of the terminus rendering
them suitable for immediate assembly in a peptide-based
structure. Chiral HPLC study shows that enantiomeric purity of
the product during N-arylation of zwitterionic amino acid
Angew. Chem., Int. Ed., 2003, 42, 5400; (c) K. Kunz, U. Scholz
and D. Ganzer, Synlett, 2003, 15, 2428.
(9) (a) R. K. Gujadhur, C. G. Bates and D. Venkataraman, Org.
Lett., 2001,
and S. L. Buchwald, J. Org. Chem., 2004, 69, 5578; (c) L. Jiang,
G. E. Job, A. Klapars and S. L. Buchwald, Org. Lett., 2003,
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5
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4
new perspectives for the synthesis of N-arylated amino acids
under environmentally benign conditions in a cost-effective
manner. Further application of N-(hetero)arylated amino acids
in search of the bioactive peptides and peptidomimetics is
currently under investigation.
(h) H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer,
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Acknowledgements
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†Krishna K. Sharma thanks University Grant commission (UGC), New
Delhi, India for the award of Senior Research Fellowship.
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Copper-catalyzed N-(hetero)arylation of amino acids in water
Krishna K. Sharma, Meenakshi Mandloi, Neha Rai and Rahul Jain
Transition metal-catalyzed, environmentally benign, rapid and cost-effective
method for the N-(hetero)arylation of zwitterionic amino acids in water is
reported.
R
Br
X
X
R
OH
CuI (5 mol%), L11 (20 mol%)
K2CO3 (2.5 eq), H2O,
PEG-400, 50 min,
H2N
OH
n
O
R
N
R
n
O
H
n = 1, 2
90 oC, MW
X = C, N
35 Examples, Yield: 78-91%
∗ Environmentally benign and rapid protocol (50 min) in water
∗ Use of inexpensive aryl bromides as coupling partners
∗ Low catalyst and ligand loading
∗ Racemization-free and wide substrate scope
∗ Provide access to challenging N-heteroarylated amino acids
∗ Gram scalable and cost-effective