Synthesis of Unnatural α-Amino Acid Derivatives via Light-Mediated Radical Decarboxylative Processes

Article abstract of DOI:10.1002/adsc.202000300

Unnatural amino acids (UAAs) are key building blocks with widespread application across several scientific fields. Therefore, it is highly attractive to develop straightforward and simple methodologies capable of granting quick access to these species. Herein we report a light-mediated protocol for the synthesis of UAA via radical decarboxylative processes. This methodology, which employs readily available and abundant starting materials – such as carboxylic and α-keto acids – proceeds under very mild reaction conditions and shows a high functional group tolerance. In addition, the products of the radical reaction can be readily derivatized to grant rapid access to complex UAAs. (Figure presented.).

Full text of DOI:10.1002/adsc.202000300

Title: Synthesis of Unnatural α-Amino Acid Derivatives via Light-
mediated Radical Decarboxylative Processes
Authors: Kay Merkens, Francisco Aguilar Troyano, Jonas Djossou, and
Adrián Gómez-Suárez
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000300
Link to VoR: https://doi.org/10.1002/adsc.202000300

10.1002/adsc.202000300
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Unnatural -Amino Acid Derivatives via Light-
mediated Radical Decarboxylative Processes
Kay Merkens,‡ Francisco José Aguilar Troyano,‡ Jonas Djossou and Adrián Gómez-
Suárez*
Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal (Germany). Tel.: +49 (0)202 439
2775, Fax: +49 (0)202 439 2648, email: gomezsuarez@uni-wuppertal.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
require the use of chiral catalysts to build the key -
Abstract. Unnatural amino acids (UAA) are key building
blocks with widespread application across several scientific amino stereocenter. Given the design and synthesis of
fields. Therefore, it is highly attractive to develop
straightforward and simple methodologies capable of
granting quick access to these species. Herein we report a
light-mediated protocol for the synthesis of UAA via radical
decarboxylative processes. This methodology, which
employs readily available and abundant starting materials –
such as carboxylic and -keto acids – proceeds under very
mild reaction conditions and shows a high functional group
tolerance. In addition, the products of the radical reaction
can be readily derivatized to grant rapid access to complex
UAA.
chiral ligand architectures is often a time/resource
consuming process, the development of
methodologies that do not require the use of chiral
catalysts is highly interesting (Figure 1A). Radical
chemistry offers exciting and highly attractive
approaches to access new chemical space in a rapid
fashion due, in part, to the plethora of synthetic
precursors available to generate open-shell species.[4]
In addition, with the advent of photoredox catalysis,
light-mediated protocols have become popular
strategies to initiate radical reactions, as they allow for
a controlled generation of open-shell species under
extremely mild conditions.[5] Therefore, it is not
surprising that researchers have exploited these
methodologies for the synthesis and derivatization of
amino acids and peptides.[6]
Keywords: amino acid synthesis; photoredox; radical
reactions; decarboxylation; acylation
Enantiopure unnatural a-amino acids
A
The use of peptides as potential drug candidates is
becoming ever more prominent within the
pharmaceutical industry.[1] This increased interest
evolves around the main advantages often offered by
these species – such as their high potency and target
selectivity, low accumulation in tissues, reduced
probability of observing drug-drug interactions or non-
mechanistic based toxicology – compared to small
molecule pharmaceuticals.[1] However, although
peptidic drugs offer distinctive advantages, they also
present intrinsic disadvantages that have prevented
their widespread adoption. For example, peptides are
often membrane impermeable, thus restricting their
activity to extracellular targets and preventing their
oral administration, and biologically unstable, thus
leading to poor pharmacokinetic properties.[1] An
approach to address these limitations is to introduce
unnatural amino acids (UAAs) within the peptidic
sequence to tune its properties.
Key to modify properties of peptides
O
Valuable building blocks for biologically
active molecules
OH
NH2
Widespread application across several
scientific fields
Main retrosynthetic disconection
Often requiere chiral catatalyst
formation of key a-amino stereocentre
time/resource consuming
Light-mediated diastereoselective synthesis of UAA using Beckwith-Karaday alkene –
B
State-of-the-art
Br
H
O
Jui
or
N
O
N
PC
R
N
+
O
O
R
R
N
N
Cbz
tBu
Gaunt
Cbz
tBu
1
R
This work – Synthesis of unnatural a-amino acid derivatives via radical
C
decarboxylation
O
OH
O
O
O
PC
O
O
+
O
O
or
N
O
Cbz
N
N
Cbz
Cbz
tBu
tBu
tBu
O
1
I
II
In addition to their role as key components in
peptides, unnatural amino acids are valuable building
blocks in a wide range of pharmaceuticals and
biologically active molecules. In view of their
importance and widespread application across several
scientific fields,[2] chemists have designed numerous
strategies for their synthesis.[3] However, most of them
OH
Abundant starting materials
High diastereocontrol
No need for chiral catalyst
High functional group tolerance
Readily quaternarized/derivatized products
Figure 1. a) Unnatural -amino acids; b) State-of-the-art; c)
This work
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000300
Advanced Synthesis & Catalysis
However, the application of these technologies for the
synthesis of enantiopure UAA remains highly
underexplored.[7],[8] For example, Jui[8f, 8g] and Gaunt[8h,
good to moderate yields (64-37%), products bearing
indolizine (7) and thiophene (8) motifs were obtained
in 10% and 16% yield, respectively. Gratifyingly,
aliphatic -keto acids afforded overall better yields
than their aromatic counterparts. Primary -keto acids
delivered the corresponding acylated products 9-11 in
26-93% yield, while secondary -keto acids yielded
products 12 and 13 in excellent yields (84% and 98%).
Interestingly, when conducting the reaction with
trimethyl pyruvic acid, the desired acylated species
(14) was isolated in 18% yield, while the main product
of the transformation was the alkylated species 36
(70%). This can be readily explained by the rapid
decarbonylation experienced by tertiary acyl radicals
to generate highly stabilized tertiary alkyl radical
species.[14]
8i]
have recently reported the use of photoredox
catalysis in combination with Beckwith-Karaday
alkene (1) for the synthesis of enantiopure UAA
derivatives (Figure 1B).
Herein we report a straightforward radical-based
methodology for the synthesis of a wide range of
unnatural -amino acid derivatives. This light-
mediated protocol uses readily available and abundant
starting materials, such as carboxylic or -keto
acids,[9] and chiral dehydroalanine derivative 1 (Figure
1C).[10] The latter can be readily synthesized in 3 steps
from benzyl cysteine in multigram scale. This versatile
methodology proceeds via light-mediated radical
decarboxylation processes to deliver either acylated (I)
or alkylated (II) syn oxazolidinones with excellent
diastereocontrol. These species can be readily
deprotected to afford the corresponding enantiopure
UAA or they can be readily functionalized to generate
enantiopure quaternary -amino acids,[11] thus
granting rapid access to complex UAA.
Table 1. Optimization of the reaction conditions for the
acylation reaction.
Ir-F (1 mol%)
Base (equiv.)
O
O
O
O
O
tBu
OH
+
O
N
CbzN
Solvent (M), RT, 16 h
Blue LEDs (lmax = 440 nm)
Cbz
O
tBu
1
2
Initially, the acylation of 1 was attempted using 2
equiv. of phenylglyoxylic acid, 2.5 equiv. K2HPO4, 1
mol% of [Ir(dF(CF3)(dtbbpy)][PF6] (Ir-F) and in
Ratio
Acid/1
Solvent
(M)
Base
(equiv.)
Yield 2
(%)a
Entry
1
DMF (0.2 M) and irradiating with blue LEDs (max
=
K2HPO4
(2.5)
2,6-
Lutidine
(2.0)
Cs2CO3
(2.0)
2,6-
Lutidine
(2.0)
2.0/1
DMF (0.2)
DMF (0.2)
DMF (0.2)
70
80
0
440 nm) for 16 h at room temperature. Gratifyingly,
this afforded the desired acylated product 2 in 70%
GC-yield (Table 1, entry 1).[12] Further screening of
bases and solvents (Table 1, entries 2-8) identified 2,6-
lutidine (2.0 equiv.) and 1,4-dioxane (0.2 M) as part of
the ideal reaction conditions for this transformation. It
is worth noticing that the reaction also proceeds in high
yields (83%) when an organic-based photocatalyst,
such as 4CzIPN,[13] was used (Table 1, entry 9).
Control experiments revealed that the reaction does
not proceed in the absence or light either at room
temperature or when heated at 50 °C (Table 1, entries
10 and 11, respectively). Although this set of standard
conditions worked well for the acylation reactions,
when they were applied in reactions using aliphatic or
benzylic carboxylic acids as staring materials,
diminished yields of the desired products were
obtained. Further optimization studies were carried out
to identified the ideal conditions for alkylation and
benzylation reactions, and can be found in the
Supporting Information.
1.5/1
1.5/1
1.5/1
2
3
4
DMSO
(0.2)
80
2,6-
Lutidine
(2.0)
Acetone
(0.2)
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
1.5/1
0
5
6
2,6-
Lutidine
(2.0)
2,6-
Lutidine
(2.0)
2,6-
Lutidine
(2.0)
2,6-
Lutidine
(2.0)
2,6-
Lutidine
(2.0)
2,6-
Lutidine
(2.0)
DCE (0.2)
76
1,4-
Dioxane
(0.2)
86
7
(78)b
EtOAc
(0.2)
63
83
0
8
With the optimized conditions in hand, the scope
and limitations of the methodology were explored.
First, the acylation of 1 was investigated. The use of
phenylglyoxylic acid afforded the corresponding
acylated product 2 in 78% yield. 1H NMR analysis of
the crude reaction mixture confirmed that the d.r. >
20:1, while a NOESY experiment on the isolated
product confirmed the syn configuration of 2.[12]
Addition of electron withdrawing p-substituents, such
as Cl (3) or CF3 (4), on the phenyl ring, afforded
diminished yields, 45% and 30% respectively. The use
of heteroaromatic -keto acid derivatives afforded the
corresponding products in varied yields. While indole
and dihydrofuran derivatives 5 and 6 were obtained in
1,4-
Dioxane
(0.1)
1,4-
Dioxane
(0.1)
1,4-
Dioxane
(0.1)
9c
10d
11e
0
a)
Reactions performed in 0.1 mmol scale; GC-yield
b)
calculated using methyl laurate as internal standard.
reaction performed in 0.5 mmol scale; isolated yield.
4CzIPN (5 mol%) was used instead of Ir-F. No light.
c)
e)
d)
No light, °50
2
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10.1002/adsc.202000300
Advanced Synthesis & Catalysis
CF3
PF6
F
O
O
O
O
tBu
tBu
O
PC
N
PC
O
HO
O
O
N
N
F
F
OH
N
O
Cbz
N
N
Ir
O
Cbz
Cbz
tBu
tBu
tBu
N
PC
F
Reaction conditions A
1
Reaction conditions B or C
Ir-F
CF3
Aromatic a-keto acids
Primary acids
tBu
tBu
tBu
O
tBu
O
tBu
tBu
tBu
Cbz
Cbz
O
Cbz
O
Cbz
Cbz
O
Cbz
Cbz
17 X = Br, 81%[C]
18 X = F, 66%[C]
19 X = OMe, 90%[C]
O
N
N
N
N
I
N
N
N
O
O
O
O
O
N
MeO
O
O
O
O
O
O
O
X
Cl
F3C
Ph
2 78%[A]
3 45%[A]
tBu
4 30%[A]
7 10%[A]
20 40%[C]
21 55%[C]
tBu
tBu
tBu
tBu
tBu
tBu
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
N
Cbz
O
N
N
O
N
O
N
O
N
N
O
O
O
O
O
N
X
O
Ph
Cbz
N
N
H
O
O
O
O
O
O
S
N
Cl
O
O
Br
22 78%[C]
23 X = N 0%[C]
24 X = CH 0%[C]
25 0%[C]
26 78%[C]
5 64%[A]a
6 37%[A]a
8 16%[A]
O
F
Aliphatic a-keto acids
Secondary acids
tBu
O
tBu
tBu
tBu
tBu
HO
tBu
O
OMe
O
Cbz
O
Cbz
O
Cbz
O
Cbz
O
O
O
Cbz
Cbz
Boc
BocHN
N
N
O
N
N
N
N
N
tBu
tBu
O
O
O
O
N
Cbz
N
Cbz
N
Ph
O
O
O
O
O
Boc
O
27 76% (1.5:1 d.r.)[C]
28 78% (5:1 d.r.)[C]
9 93%[A]
10 26%[A]c
11 56%[A]
tBu
12 98%[A]a
29 95%[B]
30 80% (1:1 d.r.)[B]
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Cbz
O
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
N
Cbz
Boc
O
N
O
N
O
N
O
N
N
O
N
O
N
O
N
O
O
O
O
O
O
Br
O
O
O
O
O
O
O
15 traces[A]
13 84%[A]a 14 18% (36 70%)[A]a
16 traces[A]
31 25%[B]
32 80%[B]
33 93%[B]
34 20%[B]
Tertiary acids
tBu
F
tBu
tBu
O
tBu
O
tBu
tBu
O
Cbz
Cbz
N
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
N
N
O
Cbz
N
N
N
N
N
MeO2C
N
O
O
tBu
O
tBu
tBu Ph
O
O
HO
O
O
O
O
O
N
O
O
NHBoc
Cl
O
O
O
Boc
35 73%[B]
36 48%[B]
37 65%[B]
38 45%[B]
39 87%[C]
40 72%[C]
41 40%[C]
42 73%[C]
43 traces[C]
Scheme 1. Scope & limitations of the light-mediated synthesis of UAA via decarboxylative processes. Reaction conditions:
[A] Acid (0.75 mmol, 1.5 equiv.), 1 (0.50 mmol, 1.0 equiv.), Ir-F (1.0 mol%), 2,6-lutidine (1.0 mmol, 2.0 equiv.), 1,4-
dioxane (0.2 M), RT, 16 h; [B] Acid (1.0 mmol, 2.0 equiv.), 1 (0.5 mmol, 1.0 equiv.), Ir-F (1.0 mol%), K2HPO4 (1.2 mmol,
2.4 equiv.), 1,4 dioxane (0.1 M), 42 °C, 16 h; [C] Acid (1.0 mmol, 2.0 equiv.), 1 (0.5 mmol, 1.0 equiv.), Ir-F (1.0 mol%),
K2HPO4 (1.2 mmol, 2.4 equiv.), DMSO (0.2 M), 42 °C, 16 h. a 2.5 equiv. acid, 3.3 equiv. 2,6-lutidine. b 0.2 M. c 10.0 equiv.
acid. Yields of isolated products. d.r. calculated from crude 1H NMR, unless otherwise noticed d.r. >20:1
When bromopyruvic acid or 1,3-dicarbonyl -keto
satisfactory yields (20-95%). It is worth noticing that
in the case of the reaction with Boc-protected
acids were used as radical precursors, only trace
amounts of the desired products were observed (15-16). phenylglycine (28), a remarkable 5:1 d.r. was obtained
Next, the scope of the alkylation protocol was
investigated. Primary carboxylic acids, such as
phenylacetic acid derivatives bearing p-Br, p-F and p-
OMe substituents afforded the desired benzylated
products 17-19 in good to excellent yields (66-90%).
In addition, both meta (20) and ortho substituents are
also well tolerated (21). Next, heterobenzylic
carboxylic acids were tested. Chloropyridine
derivative 22 was obtained in 78% yield. However,
reactions with pyrazine (23) and 2-pyridine (24)
heterobenzylic carboxylic acids, as well as with
unactivated primary acids, such as hydrocynnamic
acid (25), failed to afford the targeted products.
Gratifyingly, the use of Cbz-protected glycine
afforded the desired product (26) in 78% yield.
Secondary carboxylic acids bearing a wide range of
functional groups, such as benzylic ethers (27) and
amines (28), piperidines (29), prolines (30), terminal
alkenes (31), cyclobutanes (32), azetidines (33) or
cyclopropanes (34), afforded the desired products in
for the newly formed -amino stereocenter. Tertiary
carboxylic acids also perform well in this reaction (35-
42). Free hydroxy groups (35), bulky substituents (36),
amines (37), propellanes (38), piperidines (39) or
pyrans (40) were tolerated and afforded the desired
products in good to excellent yields (45-87%).
Interestingly, while benzylic cyclopentyl (41) and
cyclobutyl (42) derivatives afforded the targeted
compounds (40% and 73% yield, respectively), the
reaction with the analogous cyclopropyl derivative
(43) yielded only traces of product.
Once the scope and limitations of the methodology
were established, the deprotection and derivatization
of the oxazolidinone core was carried out (Scheme 2).
When acidic conditions were used for the deprotection
of 2,[8g-h, 10a] free -amino acid 44 was obtained in 96%
yield. The latter can be readily reacted with FmocCl or
FmocOSu to afford the corresponding Fmoc protected
-amino acid, which is a key species for the automated
solid phase synthesis of peptides.[15] In addition,
3
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10.1002/adsc.202000300
Advanced Synthesis & Catalysis
oxazolidinone species such as I and II can be readily
derivatized to access more complex UAA. For
example, when 2 was reacted with KHDMS in the
presence of MeI, -ketone methylation afforded
species 45 in 47% and 10:1 d.r.
(*IrIII) via a single electron transfer (SET) event, thus
producing an acyloxy radical that will undergo rapid
decarboxylation to afford the desired alkyl, or acyl –
in the case of -keto acids – radical species.
Subsequent radical addition to the chiral Dha
derivative 1 will generate intermediate IV. The latter
will interact with the reduced photocatalyst (IrII), thus
regenerating the key IrIII species, to afford the targeted
compound (V) (Figure 2). This is in accordance with
previously reported mechanisms for the alkylation of
Michael acceptors using photoredox catalysis.[20]
Based on the quantum yield experiments, an
alternative radical chain pathway might also be in
operation, however, further investigations would be
necessary to elucidate the exact nature of the species
involved as well as of the chain carrier. Regardless of
the pathway, the diastereoselectivity of the reaction is
Deprotection of oxazolidinone derivatives
A
tBu
Cbz
O
O
N
HCl
O
OH
Cl
1,4-dioxane
reflux, 2 h
O
NH3
O
2
44 96%
Straightforward access to complex UAA
B
tBu
tBu
Cbz
O
Cbz
O
KN(TMS)2
N
N
H
O
O
MeI
O
O
2
45 47% (d.r. 10:1)
t
determined by the bulky Bu group, which blocks the
Scheme 2. Product deprotection & derivatization.
si face of the molecule during the protonation event,
thus leading to the formation of the syn oxazolidinone
species.[8a, 8b, 8h]
Finally, preliminary mechanistic studies were
carried out to shed some light on the possible reaction
pathways.
O
Control experiments confirmed that, under the
standard conditions, the alkylation reactions do not
proceed in the absence of light or photocatalyst.
However, it was observed that for acylation reactions
with phenylglyoxylic acid and 2,6-lutidine as a base,
between 20%-30% yield of the desired product (2) was
formed when irradiated with blue LEDs (max = 440
nm) in the absence of Ir-F. Nevertheless, when the
same reaction was performed using K2HPO4 as a base,
only traces of product (1%) were observed. Moreover,
when aliphatic -keto acid derivatives, such as 2-oxo-
4-phenylbutanoic acid, were used in combination with
2,6-lutidine in the absence of Ir-F, no products were
observed. These results could be rationalized by the
potential formation of an electron donor-acceptor
(EDA)[16] complex between 2,6-lutidine and
phenylglyoxylic acid.[17] To test this hypothesis,
UV/Vis spectra of the reaction mixture, and its
components in isolation, were measured. Surprisingly,
no stark change in absorption was observed between
the spectra of phenylglyoxylic acid in isolation and
that of the reaction mixture. Based on this information,
it is possible that a reaction pathway involving the
direct excitation of phenylglyoxylic acid, similar to
that recently described by Kokotos and coworkers for
the catalyst-free photochemical hydroacylation
unactivated alkenes,[18] might be in operation when the
reaction is performed with aromatic -keto acid
derivatives in the absence of a photocatalyst.
R
O
N
Cbz
tBu
O
V
*IrIII
R
OH
III
IrIII
IrII
– H+
+ H+
SET
O
IrIII
SET
O
N
– CO2
O
PG
tBu
1
R
PG
IrII
O
R
N
tBu
IV
Figure 2. Proposed reaction mechanism
In conclusion, we have developed a general and
straightforward radical methodology for the synthesis
of a wide range of -amino acid derivatives from
readily available and abundant starting materials. This
light-mediated protocol does not require the use of
chiral catalysts, proceeds under very mild conditions
and displays a high functional group tolerance.
Moreover, the resulting acylated or alkylated
oxazolidinone species can be readily derivatized and
deprotected to grant rapid access to complex UAA.
Preliminary mechanistic investigations suggest that
the reported transformations proceed via a light-
initiated radical chain pathway. Further studies for the
synthesis of enantiopure -amino acid derivatives
using radical chemistry are currently underway in our
laboratories.
Under the standard reaction conditions, the addition
of TEMPO completely inhibited the reaction, thus
suggesting the radical nature of the process. This was
further confirmed by measuring the quantum yield of
the reaction,[12, 19] which suggests that the reported
transformations proceed via a light-initiated radical
chain mechanism.
With all this information in hand, the proposed
reaction mechanism for the reported transformations
under the standard reaction conditions is as follows
(Figure 2): First, the carboxylate derivative (III) is
oxidized by the excited state of the photocatalyst
Experimental Section
General procedure for acylation reactions (A, Scheme 1):
An 8 mL Biotage® microwave vial was charged with the
corresponding acid (0.75 mmol, 1.5 equiv.), 1 (145 mg, 0.50
mmol, 1.0 equiv.), Ir-F (5.5 mg, 5 µmol, 1 mol%), and
sealed with a septum cap. The vial was put under vacuum
for 1 min and refilled with N2 (x 3). Afterwards, 2,6-lutidine
(115 µL, 1.0 mmol, 2.0 equiv.) and degassed 1,4-dioxane
(2.5 mL, 0.2 M) were added. The reaction mixture was then
4
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10.1002/adsc.202000300
Advanced Synthesis & Catalysis
sparged with N2 for 2-5 min and irradiated with blue LEDs
(max = 440 nm) for 16 h. Afterwards, the reaction was
combined with a mixture of H2O and a saturated brine
solution (ca. 15 mL) and the organic phase extracted with
EtOAc (ca. 3 x 20 mL). The combined organic layers were
dried over Na2SO4 and the solvent evaporated. The crude
product was purified by column chromatography over silica
gel to afford the desired product.
(Ed.), Amino Acids, Peptides and Proteins in Organic
Chemistry: Building Blocks, Catalysis and Coupling
Chemistry, Wiley-VCH, 2011; c) C. T. Walsh, R. V.
O'Brien, C. Khosla, Angew. Chem. Int. Ed. 2013, 52,
7098-7124; d) K. Lang, J. W. Chin, Chem. Rev. 2014,
114, 4764-4806; e) M. A. T. Blaskovich, J. Med. Chem.
2016, 59, 10807-10836; f) E. R. Draper, D. J. Adams,
Chem 2017, 3, 390-410; g) T. K. Sawyer in Drug
Discovery Series, No. 5 (Ed.: V. Srivastava), The Royal
Society of Chemistry, Cambridge, 2017, pp. 1–34; h) I.
Maluch, J. Czarna, M. Drag, Chem. Asi. J. 2019, 14,
4103-4113; i) T. Narancic, S. A. Almahboub, K. E.
O’Connor, World Journal of Microbiology and
Biotechnology 2019, 35, 67.
General procedure for alkylation reactions (B, Scheme 1):
An 8 mL Biotage® microwave vial was charged with the
corresponding acid (1.0 mmol, 2.0 equiv.), 1 (145 mg, 0.50
mmol, 1.0 equiv.), Ir-F (5.5 mg, 5 µmol, 2 mol%), K2HPO4
(209 mg, 1.2 mmol, 2.4 equiv.), and sealed with a septum
cap. The vial was put under vacuum for 1 min and refilled
with N2 (x 3). Afterwards, degassed 1,4-dioxane (5.0 mL,
0.1 M) was added. The reaction mixture was then sparged
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with N2 for 2-5 min and irradiated with blue LEDs (max
=
440 nm) at 42 °C for 16 h. Afterwards, the reaction was
combined with a mixture of H2O and a saturated brine
solution (ca. 15 mL) and the organic phase extracted with
EtOAc (ca. 3 x 20 mL). The combined organic layers were
dried over Na2SO4 and the solvent evaporated. The crude
product was purified by column chromatography over silica
gel to afford the desired product.
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General procedure for benzylation reactions (C, Scheme 1):
An 8 mL Biotage® microwave vial was charged with the
corresponding acid (1.0 mmol, 2.0 equiv.), 1 (145 mg, 0.50
mmol, 1.0 equiv.), Ir-F (5.5 mg, 5 µmol, 2 mol%), K2HPO4
(209 mg, 1.2 mmol, 2.4 equiv.), and sealed with a septum
cap. The vial was put under vacuum for 1 min and refilled
with N2 (x 3). Afterwards, degassed DMSO (2.5 mL, 0.2 M)
was added. The reaction mixture was then sparged with N2
for 2-5 min and irradiated with blue LEDs (max = 440 nm)
at 42 °C for 16 h. Afterwards, the reaction was combined
with a mixture of H2O and a saturated brine solution (ca. 15
mL) and the organic phase extracted with EtOAc (ca. 3 x 20
mL). The combined organic layers were dried over Na2SO4
and the solvent evaporated. The crude product was purified
by column chromatography over silica gel to afford the
desired product.
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Acknowledgements
This work was supported by the Fonds der Chemischen Industrie
(Liebig scholarship to A.G.S. and Ph.D. scholarship to F.J.A.T.)
and the Bergische Universität Wuppertal. We thank Dr Lisa
Candish and Dr Karl Collins for fruitful discussions, and MSc.
Marcel Jaschinski for his assistance with HPLC purifications. Prof.
Stefan Kirsch (BUW) is greatly acknowledged for his continuous
support. Umicore A.G. is acknowledged for its generous donation
of materials.
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6
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10.1002/adsc.202000300
Advanced Synthesis & Catalysis
COMMUNICATION
Straightforward access to unnatural a-amino acids
Synthesis of Unnatural -Amino Acid
Derivatives via Light-mediated Radical
Decarboxylative Processes
O
O
PC
PC
O
HO
O
N
OH
Cbz
O
tBu
Adv. Synth. Catal. Year, Volume, Page – Page
Abundant starting materials
High functional group tolerance
No need for chiral catalyst
Kay Merkens,‡ Francisco José Aguilar Troyano,‡
Jonas Djossou and Adrián Gómez-Suárez*
O
O
23 examples 13 examples
20-95% yield 10-98% yield
O
O
N
O
Cbz
N
Cbz
tBu
tBu
7
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