Synthesis of Enantioenriched α-Deuterated α-Amino Acids Enabled by an Organophotocatalytic Radical Approach

Article abstract of DOI:10.1021/acs.orglett.0c00154

A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled ca

Full text of DOI:10.1021/acs.orglett.0c00154

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Letter
Synthesis of Enantioenriched α‑Deuterated α‑Amino Acids Enabled
by an Organophotocatalytic Radical Approach
Peng Ji, Yueteng Zhang, Yue Dong, He Huang, Yongyi Wei, and Wei Wang*
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ABSTRACT: A mild, versatile organophotoredox protocol has been
developed for the preparation of diverse, enantioenriched α-
deuterated α-amino acids. Distinct from the well-established two-
electron transformations, this radical-based strategy offers the
unrivaled capacity of the convergent unification of readily accessible
feedstock carboxylic acids and a chiral methyleneoxazolidinone
fragment and the simultaneous highly diastereo-, chemo-, and
regioselective incorporation of deuterium. Furthermore, the
approach has addressed the long-standing challenge of the
installation of sterically demanding side chains into α-amino acids.
sotopically labeled amino acids, in particular, the α-
Ideuterated version, are broadly used in almost every
subdiscipline in the life sciences for studying biosynthetic
pathways1 and enzymatic mechanisms,2 and probing the
secondary and tertiary structures of peptides and proteins by
nuclear magnetic resonance (NMR) and mass spectrometry
(MS) techniques.3 Furthermore, the incorporation of
deuterium into the α-position of amino acids can enhance
the metabolic stability and reduce the rate of epimerization of
peptido and peptidomimetic therapeutics and thus enhance the
efficacy or decrease the potential toxicity (see representatives
in Figure 1).4 Therefore, there is a long-standing interest in the
synthesis and application of enantioenriched α-deuterated
amino acids.5−7
rely on the asymmetric alkylation of deuterated glycine-derived
imines10 or the H/D exchange of amino-acid-derived imines11
̈
using chiral auxiliary (e.g., Schollkopf’s bis-lactam ether) or
chiral promoter-catalyzed enolization (Scheme 1A1). Transi-
Scheme 1. Synthesis of Enantioenriched α-Deuterated
Amino Acids
Figure 1. Examples of α-deuterated amino acid therapeutics.
In the routes available for the synthesis of chiral α-
deuterated amino acids, enzyme-catalyzed approaches, includ-
ing the enzyme-mediated deuteration of α-amino acids8 and
the enzymatic reductive amination of pyruvates,9 are largely
limited by a narrow substrate scope. The commonly used
methods with the capacity of access to unnatural α-amino acids
Received: January 11, 2020
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© XXXX American Chemical Society
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A

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a
tional-metal-catalyzed C−H activation followed by H/D
exchange12 or 1,3-deuteride transfer13 provides an alternative
to incorporate the isotope into the α-position of amino acids
(Scheme 1A2). Although these techniques represent the state-
of-the-art strategies for the synthesis of α-deuterated amino
acids, they all rely on a polar bond connection and therefore
carry inherent limitations such as poor chemo-, regio-, and
enantioselectivity and, in many cases, a moderate level of
deuteration. Furthermore, an intrinsic limitation of these ionic
strategies is that it is difficult to synthesize highly sterically
demanding amino acids, a class of structures widely used in the
field of peptides and peptidomimetics, to constrain their
conformations and thus improve their potency and selectivity,
lipophilicity, and metabolic stability.14 To overcome these
issues, it is clear that a new design paradigm is needed.
Table 1. Exploration and Optimization
b
yield (%),
c
entry
1
derivation from standard conditions
D-content (%)
Cs2CO3 (1.5 equiv) as base, anhydrous DCE as
solvent for 24 h
59, 92
e
2
3
4
Ir[dF(CF3)ppy]2(dtbpy)PF6 as PS,
<5, nd
Cs2CO3 (1.5 equiv) as base, and D2O (40 equiv)
used in anhydrous DCE for 24 h
4CzIPN as PS, Cs2CO3 (1.5 equiv) as base,
and D2O (40 equiv) used in anhydrous DCE for
24 h
e
<5, nd
Cs2CO3 (1.5 equiv) as base, D2O (40 equiv) used,
anhydrous DCE as solvent for 24 h
52, 85
An open-shell radical process would offer a distinct and
pragmatic approach for introducing the bulky groups into
amino acids by virtue of the favorable formation of 3°
radicals.15 The radical addition to dehydroalanine (Dha)
derivatives has been demonstrated as a viable approach for the
synthesis of α-amino acids.16 In recent efforts, notably, an
efficient Giese-type reaction of tertiary amines or halogenated
pyridine with Dha derivatives was realized with photoredox
catalysis by Jui and coworkers.17 Molander and colleagues
elegantly introduced fluorine at the α-position of amino acids
by regioselective carbofluorination of Dha compounds using
alkyl trifluoroborate reagents as radical precursors.18 We
envisioned that the direct addition of a decarboxylative radical
4 to Dha derivatives such as (S)-methyleneoxazolidinone 219
as a chiral inducer could lead to enantioenriched amino acids 3
by the employment of ubiquitous, readily accessible alkyl
carboxylic acids 1 as radical progenitors (Scheme 1B).20 The
ready accessibility of feedstock alkyl carboxylic acids 1 makes
possible the synthesis of more structurally diverse amino acids.
Furthermore, drawing from the mechanistic evidence amassed
in these and our studies,17,18,21 we conceived that the Re-face-
selective deuteration of the chiral anion intermediate 6 would
potentially provide a novel approach to enantioenriched α-
deuterated amino acids 3. It is expected that the power of the
strategy is fueled by the simultaneous chemo-, regio-, and
diastereo-selective incorporation of bulky side chains and
deuterium into α-amino acids. To our knowledge, a strategy of
this type has not been previously documented.
5
6
7
8
9
10
0.6 equiv of DBU used
1.2 equiv of 1a used
none
no base
no PS
69, 96
63, 96
70 (68), 95
<5, nd
<5, nd
d
e
e
e
no light
<5, nd
a
Reaction conditions: Unless specified, a mixture of 1a (0.3 mmol), 2
(0.2 mmol), and catalyst (0.01 mmol) in anhydrous MeCN (2.0 mL)
was irradiated with 40 W Kessil blue LEDs in a N2 atmosphere at rt
b
c
d
for 36 h. Yield based on 1H NMR. Determined by 1H NMR. Yield
e
of isolated products. Not determined.
Further optimization reaction conditions including the solvent
(entry 4) and the amount of D2O (entry 4), 1a, and base
(entries 5, 6, and 3) revealed the optimized reaction conditions
(entry 7): 0.3 equiv of DBU, 80 equiv of D2O, and anhydrous
MeCN. The control experiments confirmed that base, light,
and photocatalyst were prerequisites for this transformation
(entries 8−10).
With optimized reaction conditions in hand, we first
evaluated the coupling reactions utilizing glycosyl carboxylic
acids 1 with 2 by providing an alternative for the synthesis of
β-glycosyl α-deuterated amino acids. The protocol worked well
for the tested pentose and hexose to give the desired products
3a−c in moderate yield and with a high level of deuterium
incorporation at the desired α-position (Scheme 2A). It should
be noted that the anomeric effect of the glycosyl radicals
delivers highly stereoselective anomeric products, consistent
with our previous works.22,23 Furthermore, the chiral (S)-
oxazolidinone controlled the deuteration very well with >20:1
dr by only forming one diastereomer.
Encouraged by the above studies, we extended the strategy
for the synthesis of highly valued, structurally diverse, and
unique unnatural α-deuterated amino acids, which are difficult
to be accessed by the established polar bond connection
methods (Scheme 2B−D). The results from the studies show
that the protocol serves as a general approach to various
unnatural α-deuterated amino acids. In the view of biological
importance of the bulky side chains of amino acids in peptido-
and peptidomimetic relevant drug discovery and biological
studies, the difficulty in accessing them using prior methods
made them an ideal starting point. We first paid attention to
the sterically demanding tertiary alkyl carboxylic acids (Scheme
2B). To our delight, despite their high steric hindrance, the
tested tertiary carboxylic acids including an adamantyl group
and analogue (3d−f), cyclohexyl derivatives (3g−l), or a tert-
To investigate the feasibility of this proposal, in the initial
attempt, we probed a reaction of deuterated methyl 2,3-O-(1-
methylethylidene)-β-D-ribofuranosiduronic acid (1a, 1.5
equiv) as the glycosyl radical precursor, (S)-methyleneox-
azolidinone 2 (1.0 equiv) as the amino acid surrogate, and
D2O (80 equiv) as the deuterium source in the presence of a
photosensitizer (PS) irradiated by a 40 W Kessil blue LED
(Table 1). Commonly used Cs2CO3 (1.5 equiv) as the base in
photoredox decarboxylation was tested in anhydrous dichloro-
ethane (DCE) as the solvent for 24 h. It should be noted that
the use of deuterated acid and an anhydrous solvent
(eliminating H2O) was necessary to achieve a higher
deuteration level. It was found that the reaction efficiency
was PS-dependent (entries 1−3). Among the PSs probed,
mesityl acridinium salt (Mes-Acr-Me+·ClO4 ) delivered the
−
desired product 3a in an encouraging 59% yield (entry 1),
whereas PSs with a low reduction potential, Ir[dF(CF3)-
ppy]2(dtbpy)PF6 (entry 2) and (4CzIPN (entry 3), failed to
produce the product. In addition, 85% D-incorporation with an
excellent diastereometric ratio (dr) > 20:1 was achieved.
B
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Scheme 2. Scope of the Organophotoredox-Mediated Asymmetric α-Deuterated α-Amino Acid Synthesis with Simple
a
Carboxylic Acids
a
Reaction conditions: Unless specified, a mixture of 1 (0.3 mmol), 2 (0.2 mmol), and Mes-Acr-Me+·ClO4− (0.01 mmol) in anhydrous MeCN (2.0
b
c
mL) was irradiated with 40 W Kessil blue LEDs in a N2 atmosphere at rt for the specified time. Yield of isolated products. Deuteration and dr
d
1
determined by H NMR. No desired product was obtained under the standard reaction conditions. The reaction was carried out as follows: A
mixture of 1 (0.24 mmol), 2 (0.2 mmol), Cs2CO3 (0.24 mmol), and 4CzIPN (0.01 mmol) in anhydrous DMF (2.0 mL) was irradiated with 40 W
Kessil blue LEDs in a N2 atmosphere at rt for the specified time.
C
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butyl group bearing various functional groups (3k−o) gave
good to excellent yield with uniformly high diastereoselectivity
(dr >20:1) and a high deuteration level (91−99%). Moreover,
the bridged structures (3p−q) could also be incorporated with
high efficiency. Next, cyclic secondary alkyl radicals (3r−v)
bearing five-, six-, and seven-membered rings were probed
(Scheme 2C). The less hindered structures gave rise to a
higher yield (80−91%) without sacrificing the deuteration level
(93−98%) and diastereoselectivity (>20:1 dr). The same trend
was observed for acyclic secondary carboxylic acid (3w−y),
including the natural amino acid D-leucine and aldehyde
precursor acetal. This study was further expanded to primary
carboxylic acids (3z−ae, Scheme 2D) as alkyl radical
precursors, which are generally difficult to generate. As
shown, the protocol worked smoothly for the cases of 3z−ae
in terms of the reaction yield, dr, and deuteration. It should
also be pointed out that under the mild reaction conditions,
this radical-based method exhibits broad functional group
tolerance, as demonstrated for protected amines (3m, 3u, and
3ae), free hydroxyl (3n), alkene (3l), ester (3q), ether (3a−c,
3o and 3aa), acetal (3y), carbonyl (3ac, ad), and
heteroaromatic groups (3ab). No desired products were
obtained under the standard reaction conditions for 3f, 3u,
3v, 3y, and 3ae. However, the reaction could proceed
smoothly with a mixture of 1 (0.24 mmol), 2 (0.2 mmol),
and 4CzIPN (0.01 mmol) in anhydrous DMF (2.0 mL)
irradiated with 40 W Kessil blue LEDs in a N2 atmosphere at
rt.
Scheme 3. Late-Stage Functionalization of Pharmaceutics
and Natural Products, Conversion to Amino Acids, and
Radical Clock Reaction
To further demonstrate the utility of this mild decarbox-
ylative deuteration methodology, we performed a series of late-
stage modifications on medicinal agents and natural products.
As shown in Scheme 3A, the standard protocol (for detailed
experiments, see Scheme 2 footnote [a] and the SI) was
successfully applied to natively and selectively modify the drugs
bezafibrate and gemfibrozil, clinically used lipid-lowering
agents, to give amino acid derivatives 7 and 8 in 79 and
68% yield with 96 and 97% D-incorporation, respectively, and
with >20:1 dr. Moreover, an anti-inflammatory agent,
indomethacin (3-indolacetic acid), was efficiently transformed
into the corresponding isotopically labeled amino acid (9) in
good yield (85%) and with high deuteration (97%) and
excellent dr (>20:1). Finally, enoxolone (10) containing a
secondary alcohol and an α,β-unsaturated ketone was
tolerated. Of note, a modified protocol using 0.6 equiv of
DBU with a 0.05 M concentration was used to improve the
reaction efficiency.
The synthesized products 3 could be conveniently trans-
formed into α-deuterated α-amino acids, as showcased in the
synthesis of α-deuterated Leu (11) by reacting with conc. HCl
for 30 min without the erosion of the deuteration level
(Scheme 3B). Intrigued by the apparent breadth of scope, we
conducted a preliminary mechanistic inquiry (Scheme 3C).
Radical clock experiments, cyclopropyl ring-opening (12) by
forming alkenyl-derived amino acid 13, suggest the presence of
alkyl radicals. This observation is consistent with previously
reported decarboxylative coupling studies.20,22,23
a
Reaction conditions: Unless specified, see footnote [a] in Scheme 2
b
c
and see the SI. Yield of isolated products. Deuteration and dr
determined by H NMR.
1
transformations so often prescribed in the literature. This
radical-based strategy offers the unrivaled capacity of the
convergent unification of readily accessible feedstock carbox-
ylic acids and a chiral methyleneoxazolidinone fragment and
the simultaneous highly diastereo-, chemo-, and regioselective
incorporation of deuterium, which could vastly expand the
domain of highly biologically and medicinally valued α-
deuterated amino acids. Furthermore, the approach has
addressed the long-standing challenge of the installation of
sterically bulky side chains into α-amino acids. Customizable
by design, the simplicity and efficiency of this procedure
should resonate with medicinal chemists requiring rapid access
to these highly sought building blocks.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00154.
Experiment details and spectroscopic data (PDF)
AUTHOR INFORMATION
■
In summary, a mild, versatile organophotoredox protocol has
been developed for the preparation of diverse, enantioenriched,
α-deuterated α-amino acids. The distinct radical approach
represents a significant departure from the two-electron
Corresponding Author
Wei Wang − Department of Pharmacology and Toxicology and
BIO5 Institute, University of Arizona, Tucson, Arizona 85721,
D
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(5) For reviews of synthesis deuterated building blocks, see: ref 4e
and (a) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C-H
Functionalisation for Hydrogen Isotope Exchange. Angew. Chem.,
Int. Ed. 2018, 57, 3022. (b) Sattler, A. Hydrogen/Deuterium (H/D)
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D.; Rivera, N. R.; Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C.
Photoredox-catalyzed deuteration and tritiation of pharmaceutical
compounds. Science 2017, 358, 1182. (c) Koniarczyk, J.; Hesk, D.;
Overgard, A.; Davies, I. W.; McNally, A. A General Strategy for Site-
Selective Incorporation of Deuterium and Tritium into Pyridines,
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Email: wwang@pharmacy.arizona.edu
Authors
Peng Ji − Department of Pharmacology and Toxicology and
BIO5 Institute, University of Arizona, Tucson, Arizona 85721,
United States
Yueteng Zhang − Department of Pharmacology and Toxicology
and BIO5 Institute, University of Arizona, Tucson, Arizona
85721, United States
Yue Dong − Department of Pharmacology and Toxicology and
BIO5 Institute, University of Arizona, Tucson, Arizona 85721,
United States
He Huang − Department of Pharmacology and Toxicology and
BIO5 Institute, University of Arizona, Tucson, Arizona 85721,
United States
Yongyi Wei − Department of Pharmacology and Toxicology and
BIO5 Institute, University of Arizona, Tucson, Arizona 85721,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00154
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (5R01GM125920-
03).
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