General Access to Modified α-Amino Acids by Bioinspired Stereoselective γ-C?H Bond Lactonization

Article abstract of DOI:10.1002/anie.202007899

α-Amino acids represent a valuable class of natural products employed as building blocks in biological and chemical synthesis. Because of the limited number of natural amino acids available, and of their widespread application in proteomics, diagnosis, drug delivery and catalysis, there is an increasing demand for the development of procedures for the preparation of modified analogues. Herein, we show that the use of bioinspired manganese catalysts and H₂O₂ under mild conditions, provides access to modified α-amino acids via γ-C?H bond lactonization. The system can efficiently target 1°, 2° and 3° γ-C?H bonds of α-substituted and achiral α,α-disubstituted α-amino acids with outstanding site-selectivity, good to excellent diastereoselectivity and (where applicable) enantioselectivity. This methodology may be considered alternative to well-established organometallic procedures.

Full text of DOI:10.1002/anie.202007899

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: General Access to Modified α-Amino Acids by Bioinspired
Stereoselective γ-C-H Bond Lactonization
Authors: Miquel Costas, Laia Vicens, and Massimo Bietti
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
General Access to Modified -Amino Acids by Bioinspired
Stereoselective -C-H Bond Lactonization
Laia Vicens,[a] Massimo Bietti*[b] and Miquel Costas*[a]
[a]
[b]
L. Vicens, Dr. M. Costas
Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química
Universitat de Girona, Campus Montilivi, Girona E-17071, Catalonia, Spain
E-mail: miquel.costas@udg.edu
Prof. M. Bietti
Dipartimento di Scienze e Tecnologie Chimiche
Università “Tor Vergata”, Via della Ricerca Scientifica, 1 I-00133 Rome, Italy
E-mail: bietti@uniroma2.it
Supporting information for this article is given via a link at the end of the document.
Abstract: -Amino acids represent a valuable class of natural
products employed as building blocks in biological and chemical
synthesis. Because of the limited number of natural amino acids
The main strategy for the preparation of unnatural -amino acid
derivatives relies on de novo synthesis, where the major
challenge is typically represented by the enantioselective
available, and of their widespread application in proteomics, diagnosis, construction of the chiral -carbon.[5] An alternative and more
drug delivery and catalysis, there is an increasing demand for the
development of procedures for the preparation of modified analogues.
Herein, we show that the use of bioinspired manganese catalysts and
H2O2 under mild conditions, provides access to modified -amino
acids via -C-H bond lactonization. The system can efficiently target
1º, 2º and 3º -C-H bonds of -substituted and achiral ,-
disubstituted -amino acids with outstanding site-selectivity, good to
straightforward approach is represented by chemical modification
of pre-existing natural or synthetic -amino acid structures via
side-chain CH bond functionalization.[6] Pd-catalyzed directing
group controlled reactions entailing CH activation via
organometallic intermediates stand as the most extensively
pursued methods.[7, 8] In these reactions, primary CH bonds are
preferentially functionalized driven by the kinetic advantage
arising from the formation of a five-membered ring metallacycle
(Figure 1B).[9-15] Procedures that can selectively target secondary
CH bonds, although less represented, have been also
developed.[7, 16]
excellent
diastereoselectivity
and
(where
applicable)
enantioselectivity. This methodology may be considered alternative to
well-established organometallic procedures.
For what concerns instead the issue of stereoselectivity, control
over diastereoselectivity (when applicable) remains a standing
problem in aliphatic CH bond functionalization of α-amino acid
and oligopeptide scaffolds, with the available information being
Introduction
Proteinogenic and non-proteinogenic -amino acids are among
the most important classes of natural products and constitute
highly versatile building blocks for both biological and chemical
synthesis.[1] In addition to being the fundamental subunit of
peptides and proteins and the components of peptide-based
secondary metabolites, natural -amino acid derivatives are
customarily employed as chiral building blocks, ligands or
catalysts in synthetically useful transformations.[2] However,
because of the limited number of accessible natural -amino
acids and the widespread applications of this class of molecules,
considerable efforts have been devoted toward the development
of synthetic methodologies for the preparation of unnatural amino
acids. These compounds are increasingly employed in the
synthesis of modified peptides that can often exhibit enhanced
activity and resistance toward biodegradation as well as improved
stability and pharmacokinetic properties compared to their natural
counterparts, making them essential for proteomics, diagnosis,
extremely
limited.
Within
these
reactions,
excellent
diastereocontrol has been observed in the secondary -CH
functionalization of phenylalanine residues,[13a, 15e] and in some
10e, 15b, 17]
cases, in -CH bond functionalization of valine.[10d,
Moreover, and to the best of our knowledge, with achiral ,-
disubstituted -amino acids, important structural motifs that when
incorporated into peptides have been shown to exhibit unique
stability and conformational properties,[18] information on
enantioselective CH bond functionalization is limited to the
functionalization of 2-aminoisobutyric acid (Aib).[15d]
A different approach entails CH bond cleavage by radical and
radical-like species.[19] The latter class of reactions executed by
high-valent metal-oxo species are common in aerobic
metabolisms.[20] These differ fundamentally from organometallic
CH activation processes because they entail an initial hydrogen
atom transfer (HAT), forming a short-lived carbon centered radical
that is then intercepted by a metal bound ligand to make a CX
(X = OH or halide) bond. Despite the fact that carbon centered
radicals are reactive intermediates, oxidations can proceed in a
highly stereoselective manner, a valuable aspect that is finding
increasing application in synthetically useful procedures.[21]
drug delivery and the development of peptide and protein-based
drugs (Figure 1A).[3,
expand moreover their use as intermediates in total synthesis and
their application as ligands or catalysts in enantioselective
synthetic transformations.
4]
Access to unnatural amino acids can
1
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
Small molecule coordination complexes based on iron and
manganese can reproduce the basic aspects of these reactions,
inter alia, highly site-selective and enantioselective aliphatic CH
bond oxidation.[22] This outcome is virtually inaccessible by any
other non-enzymatic method and accordingly these bioinspired
catalysts are potentially very powerful tools for the development
of highly selective CH bond functionalization reactions.
A. Unnatural and g-functionalized amino acids in drugs and natural products
O
OH
H2N
N
O
F
H
O
N
O
HN
NH
RO
OH
O
Saponins family isolated from
Alternanthera philoxeroides.
Reference 4b
O
O
O
N
N
O
H
N
S
NH
HO
HN
O
O
HN
O
O
O
Herein we uncover this potential by describing a general method
for the carboxylic acid directed -lactonization of proteinogenic
and non-proteinogenic -amino acids. The reactions occur with
low loadings of a manganese catalyst and aqueous hydrogen
peroxide as oxidant, in short reaction times and under extremely
mild conditions, leading to the exclusive formation of the lactone
product deriving from functionalization at primary, secondary or
tertiary aliphatic -CH bonds in high isolated yield. Good levels
of diastereoselectivity are observed in the reactions of -amino
acids. Most remarkably, -lactonization of achiral ,-
disubstituted -amino acids proceeds site-selectively with
NH
NTRC-739
OH
Neurotensin receptor that regulates the
action of dopamine and mediates
nonopioid analgesia and hypothermia
Reference 4a
g-amanitin
HN
H
N
Toxic component of Amanita
mushrooms that inhibits the DNA-
dependent RNA polymerase II in
eukaryotic cell nuclei.
O
O
Reference 4c
B. General organometallic approach for the directed C-H bond functionalization of amino acids
- Ag+ and PhI(OAc)2 usually used as oxidants
- Reaction time > 12 hours
- High temperatures (> 100 ºC)
- Competitive difunctionalization
- Installation and removal of
- directing groups is often needed
Free amine
Ar
O
g
b
H2
N
R
R
See reference 9 for
representative examples
a
OEt
OEt
OEt
a
H2N
unprecedented
good
to
outstanding
diastereo-
and
H2N
[Pd]
b R
O
O
g
enantioselectivity (Figure 1C). The present method offers a
valuable entry into the streamlined synthesis of modified α-amino
acids providing an alternative and complementary approach to
well-established organometallic CH activation processes.
Installation of exogeneous directing groups
Ar
O
g
O
O
b
O
N
N
OMe
OMe
OMe
a
a
N
N
[Pd]
H
H
b
N
O
N
O
g
See references10 and11 for
representative examples
Example of DG
Results and Discussion
R
Amine directed
C-H functionalization
OH
Carboxylate directed
C-H functionalization
H2N
O
The oxidation of N-protected amino acids was initially studied by
using phthalimido- protected L-norleucine (Phth-Nle-OH) as
model substrate. Optimization studies were performed using 1
mol% of (S,S)-[Mn(OTf)2(TIPSpdp)] as catalyst and 3 equiv. of H2O2,
delivered over 30 min by syringe pump at 0 oC using 2,2,2-
trifluoroethanol (TFE) as solvent (0.01 M substrate concentration)
under air. The reaction mixture was further stirred at rt for
additional 30 minutes and then subjected to 1H NMR analysis.
Under these conditions, the corresponding -lactone was formed
as the only detectable product in 68% yield, with excellent mass-
balance (Scheme 1). Use of other N-protecting groups did not
improve products yields and provided in all cases lower
diastereoselectivities (Table S8).
Free carboxylate
Ar
b
O
R
O
O
R
O
See reference14 for
representative examples
OH
OH
[Pd]
a
a
N
N
NPhth
b
O
O
O
O
Installation of exogeneous directing gruops
Ar
b
N
O
N
O
H
H
N
N
O
N
a
N
N
N
[Pd]
O
O
a
O
O
NPhth
b
Example of DG
See reference15 for
representative examples
C. This work
- Biologically inspired Mn catalyst
- H2O2 as oxidant
- Reaction time: 30 minutes
- Broad substrate scope (1º, 2º and 3º
- C-H bonds)2
- Site-selective g-C-H functionalization
- Good to excellent stereoselectivity
- Mild conditions (0-25 ºC, under air)
R2
R2
R1
R1
N
*
O
O
H2O2
Highly site-selective
1º, 2º and 3º g-C-H
bond lactonization
O
OH
N
O
O
O
O
Si
R1, R2 = H, alkyl
Up to 85% isolated yield
Up to >20:1 d.r.
N
OTf
OTf
a-amino acids
N
Mn
N
N
Si
Scheme 1. Oxidation of Phth-Nle-OH.
R
O
R
N
R
R'
*
O
O
*
Enantioselective g-C-H
bond lactonization
OH
N
O
H2O2
O
O
O
The exquisite site-selectivity for the -C-H bonds finds precedent
in recent iron and manganese catalyzed oxidation of alkanoic
acids,[23] and can be explained by a directing role of the carboxylic
acid moiety, which binds to the catalyst (Figure 2B), precisely
orienting the -C-H bonds towards the reactive high valent metal-
oxo species, facilitating a 1,7-HAT process. Fast ligand rebound
and lactonization delivers the lactone product along with the
Mn(III) resting state catalyst. The use of catalytic amounts of triflic
acid (0.1 equiv.) parallels our recent report on the chiral
lactonization of adamantaneacetic acid derivatives,[23b] and
R = alkyl
up to 77% isolated yield
up to >20:1 d.r.
a,a-disubstituted
a-amino acids
up to 97% ee
Figure 1. (A) Examples of drugs and natural products bearing unnatural or -
functionalized -amino acids. (B) General approaches for the Pd-catalyzed
directed C-H bond functionalization of -amino acids based on literature reports.
(C) Summary and main features of the current work.
2
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
results from an activation of the peroxide toward OO cleavage.
The diastereomeric ratio of the reaction was reasonably good (d.r.
= 3.5 : 1), but unfortunately it could not be further improved by
modification of the catalyst chirality or structure (for full
optimization of the reaction, see Supporting Information, Section
5). Evaluation of other N-protecting groups under the same
conditions (see Table S8, Supporting Information) revealed that
Phth- provides the bests results both in terms of product yield and
diastereoselectivity and was taken as the protecting group of
choice. From now on, and for the sake of simplicity, the Phth- and
–OH abbreviations will be omitted from the substrate name.
acid was preserved both in the starting material and in the
oxidized products (See Supporting Information).
Figure 3. Comparison between the directed and non-directed oxidation of N-
phthalimido norleucine derivatives (For details, see Supporting information,
Section 7) a Reaction conditions: (S,S)-[Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3
equiv.), HOTf (0.1 equiv.), TFE (0.01M), 0ºC, 30 min + 30 min stirring at 25ºC.
b NMR yield. Substrate conversion was 70%. cGC yield dReaction conditions: 2x
[(S,S)-[Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3 equiv.), AcOH (15 equiv.), 15 min],
CH3CN (0.1M), -40ºC. Isolated yields. Substrate conversion was 99%.
Comparison between the results obtained in the oxidation of L-
isoleucine (Ile) and D-allo-isoleucine (D-allo-Ile) deserves
consideration. With Ile, a 3:1 mixture of lactones deriving from
oxidation at the 2o and 1o -CH bonds, respectively, was
observed, with a 4.5:1 d.r. for the major product. With the D-allo-
Ile diastereoisomer, a single product was observed deriving from
2o -CH bond lactonization. The different pattern observed in the
oxidation of these two substrates was independent on the chirality
of the catalyst, which overall indicates that, upon coordination of
the carboxylic acid to the catalyst, -CH bond orientation is
crucial in determining site selectivity, balancing sizable
differences in BDE (98-99 kcal·mol-1 for 2o and 100-101 kcal·mol-
1 for 1o CH bonds).[24] A notable aspect is that interconversion
between Ile and D-allo-isoleucine does not take place under the
reaction conditions, confirming that the initial chirality of the
unreacted amino acids is also preserved.
On the other hand, complete recovery of the starting material was
observed with cyclopropylglycine (Cpg), reasonably due to the
high BDE of the cyclopropane CH bonds that prevents HAT.
Furthermore, when a remote amide moiety was introduced in the
alkyl chain, as in the lysine derivatives Lys(Ac) and Lys(Phth), -
lactonization proceeded with modest yield (26-23%), reasonably
because of the previously described side-chain CH bond
deactivation by a polarity reversal effect determined by solvent
hydrogen bonding, commensurate to the strong electron-
withdrawing character of the Phth group.[25] A low yield (17%) was
also observed in the benzylic -CH bond lactonization of
homophenylalanine (HPhe), despite of the relatively low BDE of
these bonds (85 kcal·mol-1).[24] In keeping with previous reports,
this behavior can be rationalized on the basis of competitive
aromatic oxidation that, by producing phenolate bound species,
promotes catalyst deactivation.[26] Most interestingly, under these
conditions lactonization of 1o CH bonds can be accomplished in
high yield. Selective 1o C-H bond functionalization is not
uncommon for organometallic reagents, where formation of
metallacycles via CH activation facilitates the reaction.[7]
However, it is exceedingly rare for systems that operate via HAT,
due to the high BDE of these bonds (> 100 kcal·mol-1). For
example, lactonization of Val occurs selectively at the 1o -CH
bonds in 85% isolated yield and 6.2:1 d.r., leaving the weaker and
a priori more reactive 3o CH bond untouched. An analogous
Figure 2. Literature based proposed reaction mechanism,[23] exemplified in the
lactonization of N-protected L-norleucine.
Comparison between the outcome of the oxidation of norleucine
with that observed in the oxidation of the corresponding methyl
ester, confirms the key directing role of the carboxylic acid moiety
in ensuring site-selective -CH bond oxidation (Figure 3).[23]
Oxidation of the ester under analogous conditions results in
preferential ketonization at the most remote - position in a poor
2% yield. Under optimized conditions (see foot caption of figure
3), the -ketonized product was obtained in 66% isolated yield.
The observed site-selectivity in the oxidation of the ester can be
explained in terms of the electronic deactivation exerted by the
strong electron-withdrawing Phth- group. Ketonization at the -
CH bonds is also observed as a minor pathway (6% isolated
yield).
The study was then extended to other proteinogenic and non-
proteinogenic -amino acids (Figure 4). In all cases, outstanding
site-selectivity for -lactonization was observed with no additional
product being detected in the reaction mixture. Good isolated
yields (62-77%) were obtained in the oxidation of 2o and 3o -CH
bonds of -amino acids bearing aliphatic side-chains. In the
former case, good diastereoselectivities were observed with
substrates bearing an acyclic side-chain (d.r. between 3.2 and
4.5:1). Formation of a single diastereoisomer was observed in the
oxidation of cyclohexylglycine (Chg). On the other hand, leucine
(Leu) was oxidized exclusively at the 3o -CH bond. This
contrasts with the selectivity of organometallic reagents, which
functionalize preferentially the 1º and to a lesser extent the 2º CH
bonds of this substrate.[7] In all cases, the chirality of the amino
3
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
R3
R3
O
R2
R2
R1
*
R1
N
(S,S)-[Mn(TIPSpdp)]
O
O
H2O2, TfOH
OH
N
TFE
O
O
O
O
R1, R2 = H, alkyl
R3 = H, alkyl, aryl
Conversion (Isolated Yield), %
Oxidation of 2º and 3º C-H bondsa
X-ray
X-ray
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
O
O
O
Chg
Leu
Nle
Nva
67 (62%)
d.r. > 20:1
69 (64%)
70 (63%)
d.r. = 3.2:1
73 (68%)
d.r. = 3.5:1
O
O
O
HN
N
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
+
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Lys(Phth)
30 (23%)
d.r. = 3.5 : 1
D-allo-Ile
90 (77%)
d.r. = 4:1
Cpg
r.s.m. > 95%
Lys(Ac)
32 (26%)
d.r. = 2.2 : 1
HPhe
47 (17%)
d.r. = 3.2 : 1
Ile
69 (64%) (2º:1º = 3:1)
d.r. = 4.5 : 1
Oxidation of a dipeptidea
Oxidation of 1º C-H bondsb
O
O
O
O
N
O
H
X-ray
X-ray
O
O
N
OH
N
N
N
O
O
O
O
O
O
O
O
O
Tle
77 (76%)
Val
96 (85%)
d.r. = 6.2:1
HAla
r.s.m. > 95%
Leu-Leu
55 (42%)
Figure 4. Substrate scope for the -lactonization of -amino acids. L-amino acids were used unless indicated. The configuration of the major diastereoisomer (when
indicated) was determined by X-ray diffraction (see Supporting Information, Section 9). a Reaction conditions: [(S,S)-Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3 equiv.),
b
TfOH (0.1 equiv.), TFE (0.01M), 0ºC, 30 min + 30 min stirring at 25ºC. Reaction conditions: 2x [(S,S)-Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3 equiv.), TfOH (0.1
equiv.), 30 min], TFE (0.01M), 25ºC, 30 min + 30 min stirring at 25ºC.
outcome is observed in the reaction of tert-leucine (Tle), where
exclusive formation of the product deriving from lactonization at
Information), further indicating that racemization does not occur.
In sharp contrast, homoalanine (HAla) is not reactive under these
conditions, with the starting material being completely recovered.
Comparison between Tle, Val and HAla highlights once again the
key role played by -CH bond orientation in the carboxylate
bound substrate.[27] Interestingly, oxidation of the Phth- protected
Leu-Leu provides the product lactone resulting from selective
oxidation at the C-terminal amino acid in moderate isolated yield
(42% yield, 55% substrate conversion), highlighting the potential
utility of this system in the selective oxidation of peptides.
the 1o -CH bonds in 76% isolated yield is observed. Of notice,
the chirality of unreacted Tle remains intact (see Supporting
Information, Section 6) proceeds with high isolated yields (64-
77%), good (from 6.6:1 to outstanding (a single diastereoisomer
is detected)) d.r.’s and good to excellent enantioselectivities (70-
97% ee).
A relevant aspect of these reactions is that
difunctionalized products (customarily observed in organometallic
based procedures) are never detected. Lactonization of a -
methylenic site in dipropylglycine (Dpg) proceeds in 64% isolated
yield with good stereoselectivity (6.6:1) and outstanding
enantioselectivity (94% ee) in the major diastereomer,
representing a very rare example of site and enantioselective CH
oxidation of an aliphatic chain. Equally if not more relevant is the
oxidation of diethylglycine (Deg), which delivers the
corresponding -lactone in 77% isolated yield and good
enantioselectively (75% ee), representing, to the best of our
knowledge, the first example of enantioselective primary -CH
bond functionalization.
Finally, the oxidation of achiral ,-disubstituted -amino acids
was explored (Figure 5). For this class of substrates, -CH bond
functionalization forms a stereogenic center at the -position, and
thus, enantioselective lactonization will result in
a chiral
desymmetrization. However, to the best of our knowledge,
desymmetrization of ,-disubstituted -amino acids via
enantioselective -CH functionalization is unprecedented.[15d]
Most remarkably, lactonization of bis-alkyl ,-disubstituted -
amino acids (for optimization of the reaction, see Supporting
4
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
R
O
R
N
R
N
(S,S)-[Mn(TIPSpdp)]
R'
*
O
O
*
H2O2, TfOH
OH
O
TFE
O
O
O
R = alkyl
Conversion (Isolated Yield), %
O
O
N
O
N
O
O
O
O
O
Deg
Dpg
89 (77%)a,b
X-ray
X-ray
82 (64%)c
75% ee
d.r. = 6.6:1
ee (major) = 94%
ee (minor) = 50%
OH
O
O
O
O
N
O
O
OH
OH
O
O
N
N
O
O
O
N
N
N
O
+
O
O
O
O
O
O
O
O
O
O
cBut
r.s.m. > 95%
HcLeu
cHept
cLeu
Conv. = 65%
cOct
74 (65%)e
90% ee
28%d,e
79% ee
30%d,e
70% ee
93 (67%)e
75(64%)e
91% ee
97% ee
X-ray
X-ray
X-ray
X-ray
Figure 5. Substrate scope for the -lactonization of achiral ,-disubstituted--amino acids. Unless stated, reaction conditions are the followings: (S,S)-
a
Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3 equiv.), TfOH (0.1 equiv.), TFE (0.01M), 0ºC, 30 min + 30 min stirring at 25ºC. Reaction conditions: 2x [(S,S)-
Mn(OTf)2(TIPSpdp)] (1 mol%), H2O2 (3 equiv.), TfOH (0.1 equiv.), 30 min], TFE (0.01M), 25ºC, 30 min + 30 min stirring at 25ºC. b The absolute configuration of the
lactone was determined by X-ray diffraction (see Supporting Information, Section 9). c Relative configuration, determined by X-ray diffraction. Absolute configuration
could not be determined by this analysis. e A single diastereoisomer was observed.
Particularly interesting is also the oxidation of ,-disubstituted
cyclic amino acids. The cyclobutyl derivative is recovered intact,
presumably because of conformational reasons. However, as the
cycle is enlarged, -CH bonds become accessible to the active
oxidant. In the case of cycloleucine (cLeu), two different oxidation
products were detected in a roughly 1:1 ratio and a combined 58%
yield: the -lactone and the corresponding -hydroxyacid resulting
from oxidation at the same CH bond. Thus, the reaction
proceeds site selectively and with notable enantioselectivity (69-
79 % ee). However, the most interesting results occur in the
oxidation of cyclic -amino acids bearing larger rings (C6-C8),
where the reactions proceed with outstanding selectivity
parameters. In all cases, a single diastereoisomer is observed
with excellent enantioselectivity (90-97% ee).
with reactions that proceed via HAT executed by an hypervalent
carboxylate bound manganese-oxo species. Thus, they constitute
a mechanistic alternative to organometallic CH activation
processes, enabling diverse selectivity patterns. Furthermore,
unlike contemporary CH activation processes, oxidations
proceed under very mild conditions and short reaction times and
exhibit a broad substrate scope, covering 1o, 2o and 3o CH bonds.
Overall, the reaction provides an unprecedented entry into
modified α-amino acids via site selective CH oxidation, and the
method may be considered complementary to well-established
organometallic based procedures. Good to outstanding
diastereoselectivities are observed in the oxidation of -
methylenic sites of -amino acids and of ,-disubstituted α-
amino acids. Moreover, and to the best of our knowledge, the
work describes the first enantioselective method for the
preparation of chiral ,-disubstituted--amino acids via a -CH
bond lactonization reaction. A notable aspect of this work is that
Conclusion
it represents
a
pioneering example of
a site-selective,
diastereoselective and enantioselective oxidation of 1o CH
bonds via HAT in substrates containing other functional groups
and a priori weaker and intrinsically more reactive CH bonds. We
envision that this work will serve as a starting point for the
In conclusion, herein we describe a general method for the site-
selective -CH bond lactonization of natural and unnatural -
amino acids. The reaction is based on the activation of aqueous
hydrogen peroxide with a bioinspired chiral manganese catalyst,
5
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
M. Martínez, I. Alonso, N. Rodríguez, R. Gómez Arrayás, J. C. Carretero,
ACS Catal. 2016, 6, 6868-6882.
development of novel methods for the enantioselective
functionalization of strong CH bonds and for the use of amino
acid -CH bond lactonization as a valuable tool to increase
structural and stereochemical complexity in the synthesis of
bioactive building blocks.
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Acknowledgements
We acknowledge STR of UdG for experimental support. This work
was supported by the Spanish Ministry of Science, Innovation and
Universities (PGC2018-101737-B-I00 to M.C. and PhD grant
FPU16/04231 to L.V.) and Generalitat de Catalunya (2017 SGR
00264 and ICREA Academia Award to M.C.). The authors thank
Prof. A. Riera (UB) for kindly providing access to a polarimeter.
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Keywords: amino acids • C-H oxidation • HAT • stereoselectivity
manganese • hydrogen peroxide
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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10.1002/anie.202007899
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Bioinspired stereoselective -aliphatic C-H bond lactonization of -amino acids using a manganese catalyst and H2O2 is reported.
This method allows the oxidation of 1º, 2º and 3º C-H bonds and the enantioselective preparation of chiral ,-disubstituted--amino
acid derivatives.
Institute and/or researcher Twitter usernames: @Qbiscat_UdG @IQCCUdG @MiquelCostas @MassimoBietti @lvicensserra
8
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