Catalytic Aerobic Cross-Dehydrogenative Coupling of Azlactones en Route to α,α-Disubstituted α-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.0c01248

We developed a catalytic aerobic method to synthesize α,α-disubstituted α-amino acids through cross-dehydrogenative coupling of azlactones. Combining an iron catalyst with a bisoxazolidine ligand resulted in high catalytic performance, and cross-coupling with an indole proceeded smoothly under aerobic conditions. A wide variety of α-aryl and aliphatic amino acid derived azlactones were applied to the present catalysis. In addition, a quaternary carbon could be constructed using oxindole and benzofuranone under aerobic conditions.

Full text of DOI:10.1021/acs.orglett.0c01248

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Letter
Catalytic Aerobic Cross-Dehydrogenative Coupling of Azlactones en
Route to α,α-Disubstituted α‑Amino Acids
Taro Tsuji, Takafumi Tanaka, Tsukushi Tanaka, Ryo Yazaki,* and Takashi Ohshima*
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ABSTRACT: We developed a catalytic aerobic method to
synthesize α,α-disubstituted α-amino acids through cross-dehydro-
genative coupling of azlactones. Combining an iron catalyst with a
bisoxazolidine ligand resulted in high catalytic performance, and
cross-coupling with an indole proceeded smoothly under aerobic
conditions. A wide variety of α-aryl and aliphatic amino acid
derived azlactones were applied to the present catalysis. In
addition, a quaternary carbon could be constructed using oxindole
and benzofuranone under aerobic conditions.
Scheme 1. α,α-Disubstituted Amino Acid Synthesis
nnatural α-amino acids are widely distributed in
Upharmaceuticals and functional materials, and are useful
building blocks in synthetic organic chemistry and functional
materials.1 α,α-Disubstituted α-amino acids, which could
increase chemical stability and fix peptide conformation, are
attractive structural motifs for drug discovery.2 Although many
synthetic methods for unnatural α-amino acids are reported,
the number of corresponding α,α-disubstituted α-amino acids
reported is relatively small due to the steric bulkiness of the α-
carbon. In addition, environmentally friendly and efficient
methods are in high demand.
Cross-dehydrogenative coupling is a highly straightforward
and environmentally friendly method for constructing a new
carbon−carbon bond.3 Cross-dehydrogenative coupling reac-
tions toward unnatural α-amino acids, however, has been
restricted to the glycine-derived imine formation followed by a
nucleophilic addition reaction (Scheme 1A, R = H).4 Among
these reactions, a synthetic method for sterically congested
α,α-disubstituted α-amino acids has remained unexplored and
peroxide is usually required as a terminal oxidant for efficient
reaction progress (Scheme 1A, R ≠ H).5 Furthermore, the
reaction must be carried out under high temperature
conditions, which limits functional group compatibility.
Oxygen is abundant and regarded as an ideal terminal oxidant.
The difficulty in using oxygen is that the triplet state oxygen
rapidly couples with α-amino acid precursors, especially α,α-
disubstituted carbonyls, and generates undesired α-oxidation
products. Therefore, no catalytic cross-dehydrogenative
coupling reactions for α,α-disubstituted α-amino acids under
aerobic conditions have yet been reported.
Received: April 8, 2020
α-Amino acid derived azlactone has been widely utilized as a
nucleophile for the synthesis of α,α-disubstituted α-amino acid
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© XXXX American Chemical Society
A

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(Scheme 1B).6 We recently developed a tetrasubstituted
carbon constructive oxidative cross-enolate coupling reaction
using azlactone with peroxide as a terminal oxidant.7 The
reaction proceeded through a transient azlactone-derived
homocoupling dimer, enabling a chemoselective cross-coupling
reaction. In the course of this research, we observed that the
azlactone rapidly underwent dimerization8 when using an iron
catalyst under aerobic conditions without forming an
undesired α-oxidation product. Thus, we hypothesized that
heterolysis of the formed homocoupling dimer would deliver
highly electrophilic azaallyl cationic species (umpolung),9
thereby overcoming the steric constraints (Scheme 1C).
Herein we report iron-catalyzed cross-dehydrogenative cou-
pling for the synthesis of α,α-disubstituted α-amino acids
under aerobic conditions via the umpolung of azlactones
(Scheme 1D). To the best of our knowledge, this is the first
example of the synthesis α,α-disubstituted α-amino acids
through cross-dehydrogenative coupling under aerobic con-
ditions.
a
Scheme 2. Oxidative Cross-Enolate Coupling
We began our study using azlactone 1a, indole (2a), and
FeCl3 under an oxygen atmosphere as a terminal oxidant
(Scheme 2).10,11 Without any ligand, cross-coupling product
3aa was produced in 22% yield. The addition of L1 or L2
decreased the chemical yield. The structure of the
bisoxazolidine ligand highly affected the chemical yield.
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), PhCl (0.4 mL), MS4A
(100 mg). NMR yields are shown.
a
Scheme 3. Substrate Generalities
a
Conditions: 1 (0.2 mmol), R1 = Ar: 2 (0.3 mmol), R1 = alkyl: 2 (0.4 mmol), PhCl (0.4 mL), MS4A (100 mg). Isolated yields are shown.
b
c
d
Regioisomer ratio (rr) of C4/C2 of azlactone is shown. Reaction was performed at 0 °C. Air was used instead of oxygen. Reaction was
e
f
performed in 4.0 mmol scale. Reaction was performed at 0 °C in 1,2-dichloroethane. DTBP was used instead of oxygen in 1,2-dichloroethane at
g
h
70 °C. Air was used instead of oxygen in 1,2-dichloroethane at 70 °C. p-Me-C6H4 substituted azlactone 1m was used instead of PMP substituted
i
1a. p-Br-C6H4 substituted azlactone 1n was used instead of PMP substituted 1a.
B
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a
a
Scheme 4. Further Substrate Scope
Scheme 5. Transformation of the Products Conditions
a
Conditions: 1 (0.2 mmol), 2 (0.3 mmol), PhCl (0.4 mL), MS4A
(100 mg). Isolated yields are shown. Regioisomer ratio (rr) of C4/C2
of 5 is shown.
Although L3 and L4 exhibited poor catalytic performance,
ligand L5 had higher catalytic activity and provided the
product in 40% yield. The ring size of the bisoxazolidine ligand
was important to produce a high chemical yield (L7, L8).12
The bisoxazolidine ligand bearing a six-membered ring L8
exhibited higher catalytic performance than the corresponding
five-membered ring L7. A survey of substituents at the 4-
position revealed that a dibenzyl-substituted bisoxazolidine
ligand was optimal and the product was observed in 87% yield
(L11).13,14
Under the identical conditions, we determined the substrate
scope, as shown in Scheme 3. The reaction could be performed
under an air atmosphere, and product 3aa was isolated in 81%
yield. Large-scale reactions had no detrimental effects on the
yield. A variety of phenyl glycine derivatives were applicable
under optimized or slightly modified reaction conditions
(3ab−3ga). Neither electron-donating nor electron-deficient
substituents had a detrimental effect (3ab−3ea). A sterically
hindered 2-methyl substituent exhibited moderate reactivity
and provided product 3fa in 54% yield. The 2-napththyl
substrate also afforded product 3ga in high yield. Aliphatic
amino acid derived azlactones, alanine, valine, and leucine were
also applicable under slightly modified reaction conditions,
although the yields were moderate (3ha−3ja). The use of di-
tert-butylperoxide instead of oxygen as an oxidant provided the
products in higher yield (3ha−3la). The substituent at the C2
position of azlactone could be changed to p-Me-C6H4 or p-Br-
C6H4 respectively, although the chemical yields were slightly
decreased (3ma, 3na).
a
(a) (+)-CSA (10 mol %), CH2Cl2, rt, 24 h, 88%. (b) DMAP (20 mol
%), Boc2O, 1.4-dioxane, 80 °C, 48 h, 83%. (c) NH2NH2·H2O, THF/
MeOH, 70 °C, 24 h, 71%. (d) Cs2CO3, MeOH, rt, 24 h, 94%. (e)
LiOH, H2O2, THF/H2O, rt, 10 h. (f)TMSCHN2, toluene/MeOH, rt,
1 h, 62% (2 steps). (g) NMP, 70 °C, 24 h, 32% + 37%.
under the optimized conditions (3af−3ak). Although an
indole bearing a protecting-group-free hydroxy group exhibited
low reactivity, a TBS-protected hydroxy group provided the
product in high yield (3al, 3am). When 3-methyl substituted
indole was used, the reaction proceeded at the 2-position,
providing product 3an in high yield. An N-methyl indole was
also applicable (3ao).
The efficiency of the present aerobic catalysis was
demonstrated by further screening the substrate scope using
various coupling partners instead of azlactone (Scheme 4). 2-
Benzyloxythiazol-5(4H)-ones, which could be easily trans-
formed into Cbz-protected amino acid derivatives (vide
infra),15 provided the product in 27% yield (Scheme 4a).
Oxindole and benzofuranone were also applicable to the
present catalysis, allowing for the construction of a quaternary
carbon center (Scheme 4b, c).16,17 When 2-naphthol was used
instead of indole, product 11 was isolated in high yield through
cross-dehydrogenative coupling followed by intramolecular
ring opening of azlactone (Scheme 4d).
The synthetic utility of the product through catalytic aerobic
cross-dehydrogenative coupling was demonstrated by further
transformation (Scheme 5). Ring opening of azlactone by
methanol proceeded under acidic conditions followed by Boc
protection of two amino groups, delivering product 13 in high
yield. Chemoselective hydrazinolysis of imide over methyl
ester was achieved to afford the Boc-protected α,α
We next performed the reaction using various indoles 2. A
bromo substituent at the 5- or 6-positions did not affect the
chemical yields (3ab, 3ac). The 2-substituted indoles provided
highly congested α,α-diaryl α-amino acid products in high
yield (3ad, 3ae). Various substituents, an alkyl group, methoxy,
nitro, formyl, ester, and protected amino group, were tolerated
C
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-disubstituted amino acid derivative 14. Treatment of cesium
carbonate in methanol underwent α-substitution, providing
α,α-disubstituted hydroxy acid derivative 15 in high yield. 2-
Benzyloxythiazol-5(4H)-one-derived product 5 was easily
converted into readily removable Cbz-protected α,α-disub-
stituted amino ester 17, demonstrating that the present
catalysis is highly useful for synthesizing α,α-disubstituted
amino or hydroxy acid derivatives. The synthesized racemic
3aa was easily separated into an enantiopure form after an
amidation reaction with chiral phenylalanine amide by
conventional column chromatography.18,19
Scheme 6. Series of Control Experiments
We next performed several control experiments (Scheme 6).
Homocoupling dimer 21 was observed in high yield in the
absence of indole (2a) (Scheme 6a). This dimerization process
would have a sufficient reaction rate to avoid an undesired α-
oxidation reaction induced by oxygen. In contrast, no
homocoupling dimer derived from indole 22 was observed
(Scheme 6b). When homocoupling dimer 21 was subjected to
the standard reaction conditions instead of azlactone 1a,
product 3aa was observed in high yield, indicating that
homocoupling dimer 21 would be an active intermediate
(Scheme 6c). The ligand was found to facilitate the cross-
coupling of homocoupling dimer 21 with indole (2a),
presumably through the generation of ion paired catalyst
[FeLnCl2]+[FeCl4]− (Scheme 6d).20 Only low chemical yields
were observed under a nitrogen atmosphere using 1a or
homocoupling dimer 21 as the starting material (Scheme 6e
and 6f). We also confirmed the generation of azlactone-derived
azaallyl cationic species (ionic pathway) using silyl enol ethers
(Scheme 6g).21 The cross-couplings with silyl enol ethers
proceeded under optimized reaction conditions to afford the
products 23 and 24, supporting the generation of azaallyl
cationic species. These results also verified that the present
catalytic aerobic cross-dehydrogenative coupling could use a
variety of nucleophilic coupling partners instead of indoles.
The postulated catalytic cycle based on mechanistic studies
is depicted in Figure 1. First, actual catalytic species I would be
generated by L11. The enolization of azlactone would be
achieved by catalytic species I to afford enolate II.
Dimerization would proceed via the resonance radical species
III, delivering the homocoupling dimer 21 with the generation
of iron(II) species. The iron(II) species would be oxidized by
oxygen to regenerate catalytic species I. Heterolytic cleavage of
the formed homocoupling dimer 21 by catalytic species I
Figure 1. Postulated catalytic cycle.
D
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would provide highly reactive cationic species IV with the
concomitant formation of iron(II) species. A nucleophilic
attack of indole would proceed to afford the product with the
concomitant formation of FeCl3 and hydrogen chloride.
Finally, the regeneration of catalytic species I would be
achieved by oxygen.
In conclusion, we developed a catalytic aerobic cross-
dehydrogenative coupling reaction of azlactones leading to
α,α-disubstituted α-amino acids. The reaction proceeded
under very mild conditions, 30 °C without bases, and with
wide functional group compatibility. To the best of our
knowledge, this is the first example of the synthesis of α,α-
disubstituted α-amino acids through cross-dehydrogenative
coupling under aerobic conditions. Further studies to expand
the application of the present aerobic cross-dehydrogenative
coupling are in progress in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Experimental procedures and spectroscopic data for all
new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Ryo Yazaki − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan; orcid.org/
0000-0001-9405-1383; Email: yazaki@phar.kyushu-u.ac.jp
Takashi Ohshima − Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka 812-8582, Japan;
orcid.org/0000-0001-9817-6984; Email: ohshima@
phar.kyushu-u.ac.jp
Authors
Taro Tsuji − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan
Takafumi Tanaka − Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka 812-8582, Japan
Tsukushi Tanaka − Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka 812-8582, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01248
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. JP15H05846 in Middle Molecular Strategy, No.
JP18H04263 in Precisely Designed Catalysts with Customized
Scaffolding, Grant-in-Aid for Scientific Research (B) (No.
JP17H03972), Grant-in-Aid for Challenging Research (Ex-
ploratory) (No. JP19K22501), and Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS)) from AMED under Grant No.
JP19am0101091. T.T. thanks JSPS for a predoctoral fellow-
ship. R.Y. thanks Takeda Science Foundation for financial
support.
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G
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