Natural α-amino acids represent perhaps the most versatile class of natural products,
as assembling a limited set of just about 20 of such building blocks into peptides
and proteins makes it possible to control the vast majority of biochemical processes
in every living cell.[1] Expanding the set of natural α-amino acids by preparing their analogues through
enzymatic[2] and classical chemical synthesis[3] has been recognized as an indispensable tool for studying and engineering the protein
functions and development of new pharmaceuticals.[4]
Andrey Shatskiy(left) graduated as an engineer in polymer processing technology from the D. Mendeleev
University of Chemical Technology of Russia in 2011. In 2014, he completed a master’s
program in organic chemistry at Stockholm University and subsequently joined the group
of Professor Björn Åkermark at Stockholm University as a PhD student. His graduate
studies were focused on the development and mechanistic studies of ruthenium-based
water-oxidation catalysts. He received his PhD degree in 2018 and then joined the
Kärkäs group as a postdoctoral researcher at KTH Royal Institute of Technology, Stockholm.
Currently, his research interests include photoredox catalysis, solar fuels, and organic
electrosynthesis.
Markus D. Kärkäs (right) received his undergraduate degree from Stockholm University in 2008. In the
same year he began his graduate studies under the direction of Professor Björn Åkermark
at Stockholm University. His thesis concerned the development and mechanistic insight
of artificial water oxidation catalysts. After receiving his PhD degree in 2013, he
joined Professor Corey Stephenson’s research group at the University of Michigan as
a postdoctoral fellow. His postdoctoral work focused on the development of photochemical
methods for valorization of lignin. In late 2016, he returned to the Department of
Organic Chemistry at Stockholm University. In August 2018, he joined the Department
of Chemistry at KTH Royal Institute of Technology as an assistant professor. His research
interests include photoredox catalysis, organic electrosynthesis, and transition-metal
catalysis.
Chemical synthesis of unnatural α-amino acids has been realized mostly through the
two-electron reaction manifolds, including Strecker-type reactions,[3a] phase-transfer catalysis,[3b] asymmetric hydrogenation of unsaturated α-amino acid precursors,[3c] and other stereoselective methods.[3`]
[e]
[f] In recent years, reactions proceeding through open-shell free-radical intermediates
have also drawn significant attention, allowing both de novo synthesis of unnatural α-amino acids and modification of peptides and proteins through
noncanonical retrosynthetic strategies (Scheme [1]).[5] Harnessing the full potential of free-radical intermediates was made possible by
the development of new photoredox methods[6] employing the next-generation metal-[7] and organic-based photocatalysts.[8] In classical radical chemistry, achieving the desired transformation typically requires
consecutive atom-transfer processes accompanied by a radical chain reaction, in which
each step of the cyclic process involves free-radical intermediates.[9] Conversely, in photoredox catalysis, visible light-initiated single-electron transfer
(SET) processes are prevalent and can be rationally combined with proton–electron
transfer and atom-transfer reactions, while innate radical chain reactions are observed
only in a limited number of photocatalytic systems.[10] These factors together with the availability of a large number of bench-stable photocatalysts
with finely tunable electrochemical and photophysical properties has allowed applying
photoredox catalysis to the synthesis and modification of complex chemotypes, including
natural products, inaccessible with classical radical chemistry.[6]
Scheme 1 Common radical precursors and radical acceptors used in photoredox-mediated synthesis
of unnatural α-amino acids
Photoredox-mediated synthesis of unnatural α-amino acids has been demonstrated in
both symmetric and asymmetric fashion using a variety of synthetic strategies. Among
these, addition of photochemically generated free-radical species to unsaturated radical
acceptors currently represents the most common synthetic approach. Two notable classes
of radical acceptors giving rise to unnatural α-amino acids are dehydroalanine[11] and α-imino ester derivatives,[12] which can be used for assembling complex α-amino acids branched at the γ- and β-positions,
respectively. Effective addition of alkyl radicals to chiral cyclic dehydroalanine
derivatives was demonstrated early on by Beckwith and co-workers, providing the desired
unnatural α-amino acids in moderate yields and moderate to excellent diastereoselectivity.[13] However, the key C-centered free-radical intermediates in these reactions were generated
from alkyl iodides either under thermal control or harsh UV-light irradiation with
toxic stannanes or mercuric halides as the radical initiators, severely limiting applicability
of this synthetic approach.
Realizing such free-radical-mediated reactions in a more sustainable fashion under
mild reaction conditions became possible with widespread introduction of photoredox
catalysis. In an early photoredox catalytic system demonstrated by Yoshimi, Hatanaka,
and co-workers, the radical addition to an α-imino ester derivative (glyoxylic oxime
ether) was achieved with phenanthrene (Phen) as the photoredox catalyst and 1,4-dicyanobenzene
(DCB) as an electron-transfer mediator (Scheme [2]).[14] In this reaction, readily available carboxylic acids were used in place of alkyl
halides as precursors to the free-radical species with overall reaction being redox-neutral.
Only moderate yields of the desired unnatural α-amino acid products could be obtained,
yet this approach paved the road to a number of other photocatalytic decarboxylative
strategies for modification of α-amino acids.[15]
Scheme 2 Photocatalytic approach to unnatural α-amino esters demonstrated by Yoshimi, Hatanaka,
and co-workers
More recently, photoredox-mediated decarboxylative reaction manifolds have received
renewed attention. A number of more selective decarboxylation methods has been reported,
operating via either one-electron reduction of redox-active esters or one-electron oxidation of
carboxylate salts.[16] Some examples of light-mediated decarboxylative synthesis of unnatural α-amino acids
through radical addition to achiral α-imino ester derivatives were demonstrated with
redox-active esters as radical precursors (Scheme [3]).[17] Shen and co-workers employed N-hydroxyphthalimide (NHPI) esters as the radical precursors with an N-protected α-imino
ester as the radical acceptor.[17a] In this photocatalytic system, [Ru(bpy)3]2+ and the Hantzsch ester (HE) were employed as the photocatalyst and the sacrificial
electron donor, respectively. The photocatalytic cycle was proposed to proceed through
reductive quenching of the photocatalyst by HE, furnishing the reduced form of the
photocatalyst that is responsible for one-electron reduction of the NHPI ester, onsetting
its decomposition to a C-centered radical. The thus-formed C-centered radical then
undergoes addition to the α-imino ester followed by hydrogen atom transfer (HAT) from
the HE-derived species, furnishing the desired N-protected α-amino ester product.
Interestingly, addition of an inorganic base (K2CO3) to the reaction mixture resulted in significant improvement of selectivity, presumably,
by preventing formation of umpolung products from reductive dimerization of the aldimine
radical acceptor. Based on the computational studies, the base was proposed to modulate
the reactivity of one-electron oxidized HE, improving the efficiency of the last HAT
step. This photocatalytic system was applied for synthesis of a range of unnatural
α-amino esters derived from primary, secondary, and tertiary C-radicals, including
α-heteroatom radicals derived from carbamate-protected natural α-amino acids. The
majority of the products were isolated in high yields (>80%) and the protocol tolerated
such sensitive functional groups as terminal alkene and alkyl bromide.
Scheme 3 Photoredox-mediated synthesis of unnatural α-amino esters with redox-active esters
as radical precursors
A related photochemical synthetic strategy was demonstrated by Mariano, Wang, and
co-workers (Scheme [3]).[17b] Here, N-aryl-protected α-imino esters were employed as radical acceptors with N-hydroxytetrachlorophthalimide (TCNHPI) esters of protected uronic acids as radical
precursors. Employing an electron-poor TCNHIP redox-active group (E
pc ≈ –0.81 V vs SCE, saturated calomel electrode; E
pc ≈ ca. –1.2 V vs SCE for the NHIP esters) allowed conducting the reaction in the absence
of any photocatalyst, as the excited state of HE was sufficiently reducing to trigger
generation of the C-centered radicals from the TCNHIP ester radical precursors. The
reaction was completely prohibited in the absence of iPr2NEt·HBF4 as a stoichiometric additive, implying that protonation of the N-aryl-substituted imine radical acceptor is required for effective addition of a nucleophilic
C-centered radical intermediate. As expected, the α-amino ester products were obtained
with no stereoselectivity at the α-position, yet excellent α-stereoselectivity for
the anomeric position of the carbohydrate substrates, guided by the steric and stereoelectronic
factors. High isolated yields (generally >80%) of the desired α-amino ester products
were obtained for a range of hexose and pentose substrates bearing the common for
carbohydrate chemistry O-protecting groups.
Scheme 4 Photoredox-mediated synthesis of unnatural α-amino esters/acids with unactivated
carboxylic acids as radical precursors
The above methods proved efficient for the synthesis of a wide range of unnatural
α-amino acids; however, employing the phthalimide redox-active esters renders the
overall transformation as reductive and requires superstoichiometric amounts of an
HE reducing agent, significantly decreasing the atom economy of the process. This
factor can be effectively overcome by direct oxidation of readily available unactivated
carboxylic acids as radical precursors, which renders the overall transformation redox-neutral.
Yet, activation of free carboxylic acids through oxidative SET is generally more challenging
and is associated with lower chemoselectivity of the process.
Scheme 5 Diastereoselective photoredox-mediated synthesis of unnatural α-amino esters with
unactivated carboxylic acids as radical precursors demonstrated by Kärkäs and co-workers
Photoredox-mediated synthesis of unnatural α,β-diamino acids was demonstrated by Ye
and co-workers, employing N-Boc-protected α-amino acids as radical precursors and glyoxylic oxime ether as the
radical acceptor.[18] An organic acridinium-based photocatalyst Acr-1 with a moderately oxidizing excited state (E* ≈ +1.65 V vs SCE) was observed to be efficiently quenched by the deprotonated carboxylic
acid substrates, furnishing the key C-centered radical intermediates upon extrusion
of CO2 from the carboxylate radical (Scheme [4]). Moderate to high yields of the desired α,β-diamino ester products were observed;
however, the method was less efficient (47% yield) when using pivalic acid as the
radical precursor, highlighting that radicals that are not stabilized by α-heteroatom
are more challenging to incorporate in this type of photocatalytic system.
More recently, several methods for photoredox-mediated decarboxylative radical addition
reactions featuring a more diverse set of unactivated carboxylic acids as radical
precursors were employed for the synthesis of γ-branched unnatural α-amino acids.[19] For these catalytic systems, acyclic and cyclic dehydroalanine derivatives were
used as radical acceptors. Shah and co-workers demonstrated efficient addition of
functionalized primary, secondary, and tertiary radicals to an N,N-di-Boc-protected dehydroalanine benzyl ester,[19a] using the same acridinium-based photocatalyst (Acr-1) as in the catalytic system developed by Ye.[18] Diastereoselective variants of such radical addition manifolds were demonstrated
with the use of a chiral N-Cbz-protected methyleneoxazolidinone derived from dehydroalanine by the groups of
Gómez-Suárez,[19b] Schubert,[19c] and Wang[19d] (Scheme [4]). Curiously, although these photocatalytic systems are expected to operate through
a related mechanism, the identified optimal reaction conditions included three different
photocatalysts and solvents – iridium-, carbazole-, and acridinium-based photocatalysts
with 1,4-dioxane or DMSO, DMF, and MeCN as solvents for the three photocatalytic systems,
respectively. In all cases, excellent diastereoselectivity was observed for the radical
addition reactions. For the photocatalytic system described by Wang,[19d] conducting the reaction in the presence of D2O also allowed selective deuterium labeling of the resulting amino acids at the α-position.
Notably, the photocatalytic system by Gómez-Suárez[19b] was applied to a diverse set of aromatic and aliphatic α-keto acid radical precursors,
although with generally lower yields of the desired products.
Photoredox-mediated radical addition to dehydroalanine and α-imino ester derivatives
has also been recently demonstrated with other radical precursors, including electron-deficient
alkyl bromides,[17c] heteroaryl bromides,[20a] alkyl bis(catecholato)silicates,[20b] silyl hemiaminals obtained in situ from tertiary amides,[20c] hydrosilanes,[20d] alkyl trifluoroborates,[20e]
[f] alkyl enol ethers,[20g] ketals,[20h] and in situ formed iminium ion.[20i] Furthermore, related transformations were achieved via C–H activation in amines,[20j] aldehydes,[20k] and adamantanes.[20l]
Concurrently with the recently surfaced decarboxylative strategies for photoredox-mediated
synthesis of unnatural α-amino acids, our group aimed at realizing this approach with
a chiral glyoxylate-derived N-sulfinyl imine as the radical acceptor.[21]
Previously, Baran and co-workers demonstrated a highly versatile stereoselective radical-based
approach to unnatural α-amino acids with the same radical acceptor.[22] In this catalytic system, the free-radical intermediates were generated by one-electron
reduction of TCNHPI esters with Zn as the stoichiometric reducing agent (3 equiv.)
and a Ni-based promoter (25 mol%). Aiming at improving the atom economy of this process
and excluding the use of toxic transition-metal reagents, our group attempted the
radical-addition reaction under photoredox conditions in a redox-neutral fashion,
using unactivated carboxylic acids as the radical precursors. Similar to the previous
observations by Maestro, Alemán, and co-workers,[23] high sensitivity of the N-sulfinyl imine substrate to the typical decarboxylation conditions was observed,
completely prohibiting the desired reaction. Gratifyingly, careful optimization of
the reaction conditions revealed that employing the highly oxidizing acridinium-based
photocatalyst Acr-3 (E* ≈ ca. 2.09 V vs SCE)[8f] with α,α,α-trifluorotoluene (PhCF3) as the solvent furnished the model pivalic acid derived product in high yield (91%)
and excellent diastereoselectivity (> 95:5 dr), while using near-stoichiometric amounts of the radical precursor and acceptor (Scheme
[5]). The optimized reaction conditions were then applied to a diverse set of carboxylic
acid substrates.
In general, the highest yields of the desired chiral α-amino esters were obtained
with tertiary and α-heteroatom-stabilized radicals, while secondary and primary radicals
appeared to be less efficient. Notably, the reaction tolerated a magnitude of molecular
functionalities, including aliphatic and aromatic ethers and ketones; fluoro-, chloro-,
and bromo-substituted aromatic substrates; aliphatic substrates containing CF2, CF3, and CCl2 functionalities; aryl cyanide- and alkyl aryl thioether-containing substrates. A
few pharmaceutically relevant compounds were efficiently employed as the radical precursors,
including gemfibrozil, cyhalofop, nateglinide, ciprofibrate, indomethacin, and diprogulic,
fenofibric and clofibric acids. In all cases, excellent diastereoselectivity was observed
at the α-position of the product, while several compounds also displayed slight diastereoselectivity
at the β-position. Selective removal of the N-sulfinyl amide chiral auxiliary group was demonstrated under mild acidic conditions
in near-quantitative yields for complex α-amino ester products derived from indomethacin,
cyhalofop, and nateglinide, highlighting the practicality of the devised reaction.
The mechanism of the developed transformation was proposed based on the literature
precedents and the results of electrochemical, spectroscopic, and computational mechanistic
studies. In the proposed catalytic cycle, the excited-state acridinium photocatalyst
is quenched by the carboxylate anion via an SET process, furnishing the carboxylate
radical that quickly fragments to the key C-centered radical intermediate. This intermediate
undergoes addition to the chiral glyoxylate-derived N-sulfinyl imine substrate in the stereodetermining step of the reaction, furnishing
a transient N-centered radical. The latter is transformed into the desired product
upon SET from the reduced photocatalyst and protonation, concurrently closing the
photocatalytic cycle. A detailed computational study of the stereodetermining radical-addition
step highlighted the key role exerted by the intramolecular hydrogen bonding in the
N-sulfinyl imine substrate for the stereoselective outcome of the reaction. Interestingly,
no intramolecular hydrogen bonding was observed for the one-electron-reduced form
of the substrate (α-amino radical), explaining the poor diastereoselectivity when
the reaction is conducted with a more reducing Ir-based photocatalyst, as was observed
during optimization of the reaction conditions.
The described decarboxylative strategies for synthesis of β- and γ-branched unnatural
α-amino acids cover vast chemical space, making a significant contribution to the
previously explored synthetic strategies. In particular, employing ubiquitous carboxylic
acids with electron-deficient radical acceptors allows accessing unnatural α-amino
acids in a redox-neutral fashion, eliminating the need for stoichiometric oxidation/reduction
agents and additional synthetic steps for introduction of the redox-active groups.
The photoredox-mediated radical-based reaction manifolds allows conducting the synthesis
under mild conditions and in the presence of various functional groups that would
be intolerable under typical nucleophilic addition or transition metal catalysis conditions.
Yet, a major remaining challenge is to realize such radical manifolds in a stereoselective
fashion without chiral auxiliaries – the challenge persistent to all radical chemistry
with no general solution.[24]
