Asymmetric Synthesis of β2-Aryl Amino Acids through Pd-Catalyzed Enantiospecific and Regioselective Ring-Opening Suzuki–Miyaura Arylation of Aziridine-2-carboxylates

Article abstract of DOI:10.1002/chem.201902009

A Pd-catalyzed enantiospecific and regioselective ring-opening Suzuki–Miyaura arylation of aziridine-2-carboxylates was developed. The cross-coupling allows for the asymmetric preparation of enantioenriched β²-aryl amino acids, starting from co

Full text of DOI:10.1002/chem.201902009

A Journal of
Accepted Article
Title: Asymmetric Synthesis of β²-Aryl Amino Acids through Pd-
Catalyzed Enantiospecific and Regioselective Ring-Opening
Suzuki-Miyaura Arylation of Aziridine-2-carboxylates
Authors: Youhei Takeda, Tetsuya Matsuno, Akhilesh K. Sharma, W. M.
C. Sameera, and Satoshi Minakata
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To be cited as: Chem. Eur. J. 10.1002/chem.201902009
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COMMUNICATION
b2
Asymmetric Synthesis of -Aryl Amino Acids through Pd-
Catalyzed Enantiospecific and Regioselective Ring-Opening
Suzuki-Miyaura Arylation of Aziridine-2-carboxylates
Youhei Takeda,* Tetsuya Matsuno, Akhilesh K. Sharma, W. M. C. Sameera* and Satoshi Minakata*
Dedicated to the memory of the late Professor Keiji Morokuma
Abstract: We have developed a Pd-catalyzed enantiospecific and
regioselective ring-opening Suzuki-Miyaura arylation of aziridine-2-
carboxylates. The cross-coupling allows for the asymmetric
preparation of enantioenriched b2-aryl amino acids, starting from
commercially available enantiopure D- and L-serine esters.
Mechanism and selectivity of the reaction was rationalized by
computational methods.
cross-couplings of 2-arylaziridines with organoboron reagents.8,9
The arylative cross-coupling proceeds with the regioselective
ring opening of the aziridine at the more sterically-congested
C(sp3)–N bond, which is enabled by a highly s-donating NHC
(SIPr)-ligated Pd catalyst.7a With this finding, we embarked on
tackling a hitherto unestablished retrosynthetic route to b2-amino
acids3i using a donor synthon and an umpolung a2 synthon
(Figure 1b).10 Although regioselective nucleophilic ring opening
of aziridines is a useful synthetic method for b-functionalized
amines,11 the ring opening of aziridine-2-carboxylates with
carbonaceous nucleophiles has encountered difficulties:12–14 the
ring opening with carbanions (e.g., Wittig reagents12a and
b-Amino acids are less abundant in the nature than a-amino
acids,1 and they exhibit intriguing pharmacological properties
and serve as useful chiral building blocks for b-peptide
foldamers.2 Therefore, the asymmetric synthesis of b-amino
acids has attracted much attention over the last few decades.3
Currently, b3-amino acids (i.e., b-substituted b-amino acids) are
readily accessible through a variety of homologations (e.g.,
Arndt-Eistert homologation,4a Kowalski ester homologation,4b
Coates oxazoline carbonylation,4c and Kolbe reaction) of a-
amino acid derivatives. Thus, most of the b3-amino acids with
proteogenic substituents are commercially available. In contrast,
enantiopure b2-amino acids (i.e., a-substituted b-amino acids)
are less accessible.3i Previous studies on the asymmetric
preparation of b2-amino acids utilize chiral auxiliaries,3 while
recent progress focuses on the use of transition metal- and
organo-catalysis toward efficient and divergent access to
enantioenriched b2-amino acids under mild conditions.3j,5 Herein
we present a new catalytic synthetic method for enantioenriched
malonates12b
reagents,13a,b,e alkynyllithium reagents,13c,d and organocopper
reagents13a,b,e
leads to the concomitant production of
) and organometallic reagents (e.g., Grignard
)
regioisomeric ring-opened products. In addition, the use of
highly nucleophilic organometallic reagents deteriorates the
ester functionalities.13b,c,d,e Furthermore, Lewis acid-promoted
Friedel-Crafts ring opening is not suitable for b2-amino acid
synthesis, due to the exclusive C-3 regioselectivity and the
limited scope of arene nucleophiles.14
a) Present work
Ts
H
Ar
Pd/L cat.
H
N
ArB(OH)2
+
NHTs
MeO2C
MeO2C
✔enantiospecific (invertive)
✔regioselective (branch only)
b2-aryl amino acids through
a
highly regioselective and
NH2
H
Ar
net transformation
H
NH2
OH
enantiospecific ring-opening cross-coupling of enantiopure
aziridine-2-carboxylates with arylboronic acids enabled by a Pd
catalysis (Figure 1a). Since the aziridine substrates are readily
prepared from serine esters,6 the net transformation is regarded
as an enantiospecific synthetic route to b2-aryl amino acids from
an a-amino acid (serine) (Figure 1a).
HO2C
HO2C
serine (α-amino acid)
b) Unestablished retrosynthetic route
donor synthon
β2-amino acids
R
FG
+
• carbanions
• R–M
• indoles
R
H
N
+
NH2
#
NH2
HO2C
HO2C
RO2C
Recently, our group7 reported a novel Pd catalysis for
regioselective and stereospecific (stereo-invertive) ring-opening
*
a2 synthon
(umpolung synthon)
unestablished
Figure 1. Schematic illustrations of a) the present work and b) retrosynthesis
of b2-amino acids using a donor and a2 synthons.
[*]
Prof. Dr. Y. Takeda, T. Matsuno, Prof. Dr. S. Minakata
Department of Applied Chemistry, Graduate School of Engineering
Osaka University
Yamadaoka 2-1, Suita, Osaka 565-0871 (Japan)
E-mail: takeda@chem.eng.osaka-u.ac.jp;
minakata@chem.eng.osaka-u.ac.jp
As the results of extensive screening of reaction conditions
for the coupling of (S)-N-tosyl-aziridine-2-carboxylate (1a) with
PhB(OH)2 (2a),15 a highly s-donating NHC ligand bearing two
NMe2 groups on the 3,4-positions of the IPr core (NMe2IPr)16 was
found to allow the regioselective and enantiospecific cross-
coupling to exclusively give coupled product 3aa in an excellent
yield with high enantiospecificity (es) (Entry 1, Table1), which
was determined by chiral HPLC analysis (see the SI).15 The
validity of NMe2IPr ligand is obvious, when compared to the
results with IPr (44% yield, 74%es) (Entry 2) and SIPr (54%
Dr. A. K. Sharma
Fukui Institute for Fundamental Chemistry, Kyoto University
Takano-Nishihiraki-cho 34-3, Sakyo-ku, Kyoto, Kyoto 606-8103
(Japan)
Prof. Dr. W. M. C. Sameera
Institute of Low Temperature Science, Hokkaido University
Kita-ku, North 19 West 8, Sapporo, Hokkaido 060-0819 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201902009
Chemistry - A European Journal
COMMUNICATION
analysis. [c] Isolaion yield: 91%.
yield, 48% es) (Entry 3), which is the best ligand for coupling of
2-arylaziridines.7a Another s-donating NHC ligand MeIPr was
found to be an alternative promising ligand for the coupling
(Entry 4). Interestingly, the regioselection of ring opening was
controllable by the choice of ligand: PCy3/Pd catalyst resulted in
the ring opening of the aziridine at the opposite site (at the C-3)
to give a-amino acid derivative 4aa in 32% along with TsNH2 6
in 60% yield (Entry 5). In contrast, biarylphosphine ligand XPhos
gave b2-amino acid derivative 3aa in good yield with a high es
(Entry 6). It is noted that the presence of NaOTf, which should
be generated in situ through the abstraction of acidic C–H of
NHC salts with NaOtBu, was important to prevent the
racemization of coupled product 3aa (Entry 7 vs Entry 1). The
control experiments suggested that NHC ligands dramatically
promote the racemization of the product 3aa [Eq. (S4)–(S7)]. It
is also noted that the presence of water accelerated the reaction
efficiency (Entry 8). Alkyl groups in the ester functionality
significantly affect the reaction results. When benzyl
aziridinecarboxylate 1b was applied as the substrate instead of
1a under the “standard conditions”, the benzylic C–O bond was
cleaved to give diphenylmethane in substantial yields (Table
S14 and Eq. (S1) and (S2)).17
Absolute stereochemistry of the product 3aa was determined
by the specific rotation of b2-amino acid 7a, which was
quantitatively obtained from 3aa through the hydrolysis of the
ester group and removal of Ts group [Eq. (1)]. Nice agreement
of [a]30 of 7a (+91.0°, c 0.2, H2O) with that reported in literature
D
([a]3D0 = +94.0˚, c 0.2, H2O)18 clearly confirmed the net stereo-
inversion through the cross-coupling to give (R)-3aa, which is
fully consistent with our previous results.7 The opposite
enantiomer (S)-3aa is also accessible by applying (R)-1a under
the standard conditions [Eq. (S3)], highlighting the synthetic
value of the herein reported reaction.
CO2Me
CO2H
H
H
PhOH (4 equiv)
NHTs
NH2
(1)
33% HBr aq.
130 ˚C, 18 h
(R)-7a
95%
3aa
0.6 mmol
(92%ee)
30
[α]D = +91.0° (c 0.2, H2O)
(lit [α]3D0 = +94.0° (c 0.2, H
2
O) (ref. 18)
With the optimization conditions in hand, the generality of
this method was examined by applying varied arylboronic acids
(Table 2). Cross-coupling with arylboronic acids bearing an
electron-donating group (EDG) at the p-position proceeded
efficiently under the standard conditions to give enantioenriched
b2-aryl amino acid derivatives 3ab, 3ac, 3ad, and 3ae in good
yields with excellent es. The reaction was also applicable to the
Table 1. The effect of reaction conditions.
NHTs
Ph
CO2Me
H
H
[Pd(cinnamyl)Cl]2 (2.5 mol%)
NMe2IPr•HTOf (20 mol%)
NaOtBu (20 mol%)
NHTs
Ts
MeO2C
4aa
Ph
H
N
3aa
(β2-product)
+ PhB(OH)2
Na2CO3 (1.1 equiv)
toluene/H2O
MeO2C
(S)-1a
(>99%ee)
(α-product)
2a
45 ˚C, 6 h
“standard conditions”
(1.1 equiv)
NHTs
TsNH2
MeO2C
6
coupling with
a
heteroaromatic boronic acid to afford
5
enantioenriched product 3af in a high yield. The presence of a
sterically-demanding ortho-substituent did not significantly affect
the chemical yield and es of coupling product 3ag. The coupling
with 2-naphthylboronic acid gave the corresponding product 3ah
in a moderate yield, keeping its stereochemical information at a
high level. Notably, the chlorine functionality survived the
reaction conditions when XPhos was used as the ligand,
although the use of strongly s-donating NHC ligands (NMe2IPr
and MeIPr) did not give any desired product, probably due to the
preference in the oxidative addition at the C–Cl bond. The
highlight of the reaction is the applicability of arylboronic acids
having an electron-withdrawing (EWG) functional groups (F and
CO2Me), making a nice contrast with the Friedel-Crafts arylation
of 1a14 in terms of ring-opening regioselectivity (2- vs 3-position)
and substrate electronic nature (EWG vs EDG). Nevertheless, in
the case of 3ak, the stereochemical information has been
completely lost. Probably, this would be associated with the
presence of a more acidic a-hydrogen in product 3ak than those
of other products, which may undergo the insertion by free NHC
followed by elimination to form enolate/enol, leading to
racemization. This racemization process may compete with the
main cross-coupling mechanism. It is noted that another
racemization pathways such as via the equilibrium between C-
and O-bound Pd-enolates are not totally excluded (for the
detailed discussion, see the mechanistic section). It should be
noted that the developed Pd catalytic system was also
successfully applied to 2,3-disubstituted aziridine 8 to give the
cross-coupling product 9 in an excellent regioselective and
diastereoselective (dr > 20:1) manner [Eq. (2)].
Yield [%][a]
Recov
ery of
1a [%]
Alternations
“standard conditions”
from
Entry
3aa
4aa
5
6
(es)[b]
1
2
3
4
none
97[c]
(94)
0
0
0
0
42
25
7
IPr/NaOTf instead of
NMe2IPr•HTOf/NaOtBu
44
(74)
0
0
0
12
20
0
0
0
0
SIPr/NaOTf instead of
NMe2IPr•HTOf/NaOtBu
54
(48)
MeIPr/NaOTf instead
of
NMe2IPr•HTOf/NaOtBu
91
(90)
5
6
7
PCy3
instead
of
0
32
0
0
0
0
60
12
0
8
8
NMe2IPr•HTOf/NaOtBu
(ND)
XPhos instead of
NMe2IPr•HTOf/NaOtBu
78
(87)
NMe2IPr instead of
NMe2IPr•HTOf/NaOtBu
64
(85)
0
21
8
w/o H2O
14
(ND)
0
0
0
81
R
R
[a] Determined by 1H NMR
analysis of the crude product.
[b] enantiospecificity (es)
(eepro/eesub) × 100%. ee was
determined by chiral HPLC
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
PCy2
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
SIPr
NMe2IPr (R = NMe2
)
=
i-Pr
IPr (R = H)
MeIPr (R = Me)
ClIPr (R = Cl)
XPhos
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Table 2. Scope of ArB(OH)2.[a,b]
In order to obtain some insights about the mechanism and
selectivity,19 we have performed a computational study using the
B3LYP-D3BJ functional. For this purpose, we have used NMe2IPr-
Pd0 as the catalyst and (S)-1a as the substrate. Computed free
energy profile (in blue) is shown in Figure 2.
Starting from NMe2IPr-Pd0 catalysts, the reference energy
point, coordination of (S)-1a to the Pd center is straightforward,
and the resulting complex (I1) is –5.8 kcal/mol lower in energy.
Then, regioselective and stereo-invertive aziridine ring opening
occurs with a barrier of 6.6 kcal/mol (TS1), giving rise to I2 (–4.5
kcal/mol). In the presence of an anionic N atom, I2 can be
stabilized by H2O in solution.20 The resulting intermediate,
I2.3H2O, is 3.4 kcal/mol stable than I2. Then, the proton transfer
occurs through TS2 (–7.1 kcal/mol), which is almost barrierless.
The subsequent intermediate (I3.2H2O) is 17.3 kcal/mol stable
than the entry point of the free energy profile. Intermediate I3
(without H2O) is only 0.4 kcal/mol above I3.2H2O, indicating
water molecules may not stabilize I3. Then, coordination of the
Lewis acidic boron center of ArB(OH)2 to the hydroxyl group of
I3 is straightforward, giving rise to I4 (–36.9 kcal/mol). After the
rearrangement of I4 into I4’ through TS3 (–21.2 kcal/mol), the
transmetalation occurred through TS4 (–20.4 kcal/mol) to give I5.
Dissociation of B(OH)3 side product from the metal coordination
sphere is straightforward, as the resulting intermediate, I6, is 9.0
kcal/mol more stable than I5. Finally, the reductive elimination
takes place with a barrier of 19.2 kcal/mol (TS5), and the
coupling product (R)-3aa (P in Figure 2) is formed.
[a] The reactions were conducted with 0.50 mmol of (S)-1a and 0.55 mmol
(1.1 equiv) of 2 in a two-phase system of toluene (7.5 mL) and H2O (1.0
mL) using Na2CO3 (0.22 mmol, 1.1 equiv) in the presence of the following
catalysts and additives at the temperature and reaction time shown under
the products. Catalysts used for standard conditions: [Pd(cinnamyl)Cl]2
(12.5 µmol, 2.5 mol%) and NMe2IPr•HTOf (100 µmol, 20 mol%); Catalysts
used for Conditions A: [Pd(cinnamyl)Cl]2 (25.0 µmol, 5.0 mol%), MeIPr
(100 µmol, 20 mol%), and NaOTf (100 µmol, 20 mol%); Catalysts used
for Conditions B: [X-Phos-Pd(cinnamyl)Cl] (50.0 µmol, 10 mol%). [b]
Values shown under products indicate the isolation (1H NMR) yields and
es determined by chiral HPLC analysis.
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10.1002/chem.201902009
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COMMUNICATION
Ts
Ts
H
N
NHC = NMe2IPr
SIPr
N
H
MeO2C
O
H
H
H
NHC–Pd
H
O
MeO2C
NHC–Pd
TS1 (0.8)
TS1 (2.0)
H
O
H
Ts
N(H)Ts
N(H)Ts
1 (0.0, 0.0)
NH
OH
H
TS2 (–7.1)
TS2 (–8.1)
H
H
NHC–Pd
+
Sub
MeO2C
NHC–Pd
I2 (–4.5)
I2 (–2.6)
Ph
B
MeO2C
NHC–Pd
Ph
H
I1 (–5.8)
I1 (–6.5)
MeO2C
NHC–Pd
OH
I2.3H2O
(–7.9)
O
B
OH
+
–
N(H)Ts
Ph
O
H
N Ts
OH
PhB(OH)2
H
H
I3 (–16.9)
I3 (–20.0)
TS4 (–20.4)
TS4 (–22.2)
O
H
+
I2.3H2O
(–8.4)
MeO2C
MeO2C
NHC–Pd
3H2O
TS3 (–21.2)
TS3 (–22.8)
+
NHC–Pd
I3.2H2O (–17.3)
I3.2H2O (–19.9)
Ts
–
N
H
TS5 (–30.8)
TS5 (–29.9)
2H2O
I4' (–25.1)
I4' (–25.0)
Ts
O
H
H
H
+
N
H
B(OH)3
H
O
MeO2C
N(H)Ts
H
H
H
+
1
+
O
H
+
H
NHC–Pd
H
MeO2C
NHC–Pd
O
H
Ph
B
MeO2C
NHC–Pd
O
H
OH
I4 (–36.9)
I4 (–38.5)
N(H)Ts
H
O
MeO2C
Ph
O
H
OH
I5 (–41.0)
I5 (–40.6)
H
N(H)Ts
H
MeO2C
NHC
P (–50.7, –50.7)
N(H)Ts
I6 (–50.0)
I6 (–50.2)
H
Pd OH
Ph
MeO2C
NHC–Pd
B
HO
I7 (–66.1)
I7 (–67.0)
Ph
OH
Figure 2. Computed free energy profiles (kcal/mol) for the mechanism of the catalytic cycle.
information) suggested that the interactions between the catalyst
and the aziridine substrate is the key to stabilizeTS1A over TS1B,
where the aziridine substrate is relatively closer to Pd in TS1A
(Figure 3).
According to our experimental results, NMe2IPr-Pd0 catalyst
resulted in 97% yield of (R)-3aa, whereas SIPr-Pd0 catalyst gave
54% yield. In order to understand this discrepancy, we have
calculated the free energy profile of the mechanism using the
SIPr-Pd0 as the catalyst and (S)-1a as the substrate (red lines in
Figure 2). Overall picture of the free energy profile is qualitatively
similar to the free energy profile of NMe2IPr-Pd0 catalyst. The rate-
determining reductive elimination step has a barrier of 20.3
kcal/mol (vs 19.2 kcal/mol for the NMe2IPr-Pd0 catalyst). As the
barrier for the rate-determining step for SIPr-Pd0 catalyst is
relatively larger than NMe2IPr-Pd0 catalyst, the overall reaction
would be slow with the SIPr-Pd0 catalyst, giving a relatively
lower yield.
Figure 3. Optimized transition states for the oxidative addition at the
carboxylic position (TS1=TS1A) and the terminal position (TS1B).
Based on the computed free energy profile, we concluded
that the rate-determining step of the mechanism is the reductive
elimination, and the regioselectivity- and enantiospecificity-
determining aziridine ring opening occurs in the SN2 fashion at
the 2-position of (S)-1a. The transition states for the ring opening
at the carboxylic position (TS1A) and the terminal position (TS1B)
are shown in Figure 3. The free energy difference between TS1A
and TS1B is 3.3 kcal/mol, and therefore the calculated
regioselectivity of the ring opening is 100:0, which is in
agreement with the experimental data. An energy decomposition
analysis (EDA)7b on the TS1A and TS1B (see the SI for more
Scheme 1 illustrates a plausible catalytic cycle based on the
results obtained from experiments and computational studies.
The reduction of Pd(II) with ArB(OH)2 generates Pd(0)–L
species.7a.20 The coordination of a highly s-donating ligand
allows for the exclusively regioselective oxidative addition at the
more sterically-hindered side (C-2) in a stereo-invertive manner
(a in Scheme 1). The following transmetalation and reductive
elimination with the retention of the stereochemical information
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10.1002/chem.201902009
Chemistry - A European Journal
COMMUNICATION
produce enantioenriched coupling product 3a. The racemization
of 3a would mainly involve an NHC-catalyzed pathway (from
(R)-3a to rac-3a) as suggested from experimental data (see S4–
S7 in the SI). A possible mechanism may involve the insertion of
the carbene (NHC) into the acidic methine C–H bond of 3a
followed by the elimination to give racemic enolates (for a
possible pathway, see Scheme S1).21 The role of NaOTf would
be complexation with NHC in organic phase to capture excess
NHC and store it in water phase, where NHC is gradually
released again into organic phase as the NHC ligand is
consumed. However, even when NaOTf is added, racemization
is not perfectly suppressed (Entries 2 and 3 in Table 1). Other
possible racemization pathways might be involved in the
catalytic cycle such as the one through an equilibrium between
C- and O-bound Pd enolates.22
grant 17H066445. Supercomputing resources at the Institute of
Molecular Science in Japan and the Academic center for
computing at media studies at Kyoto University are also
acknowledged.
Keywords: amino acids • asymmetric synthesis • cross-coupling
• nitrogen heterocycles • regioselectivity
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ArB(OH)2
base, H2O
Ph
Ar
L
Pd
Ph
Ts
Cl
H
N
MeO2C
(S)-1a
CO2Me
H
Pd0–L
NHTs
Ar
(R)-3a
L = NMe2IPr, MeIPr,
or XPhos
a) oxidative addition
d) reductive elimination
CO2Me
CO2Me
[4]
[5]
H
H
—NTs
NHTs
(R)-C
Pd+
Ar
Pd+
L
L
(R)-A
b) proton transfer
& PdOH generation
CO2Me
H
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c) transmetalation
H2O
NHTs
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ArB(OH)2 + base
(R)-B (η1-C)
OH
Scheme 1. A plausible catalytic cycle of the cross-coupling.
In conclusion, we have successfully developed a new
catalytic asymmetric synthetic method for enantioenriched b2-
aryl amino acids from commercially available serine esters. The
method is based on a Pd-catalyzed highly regioselective and
enantiospecific ring-opening cross-coupling of aziridine-2-
carboxylates with arylboronic acids. The key to the success was
the use of highly s-donating NHC ligands to promote not only
the oxidative addition step but also transmetalation and
reductive elimination processes. The mechanism of the catalytic
cycle and the selectivity were rationalized by the computational
studies.
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Acknowledgements
This work was supported by KAKENHI JP16H01023 in Precisely
Designed Catalysts with Customized Scaffolding. The authors
deeply acknowledge for Prof. Dr. Vincent César (CNRS &
Université de Toulouse, France) for the fruitful advice for the
preparation of IPrNMe2 ligand. WMCS thanks to MEXT KAKENHI
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10.1002/chem.201902009
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COMMUNICATION
A Pd-catalyzed regioselective and
enantiospecific ring-opening Suzuki-
Miyaura arylation of 2-
Y. Takeda,* T. Matsuno, A. K. Sharma,
W. M. C. Sameera,* S. Minakata*
Page No. – Page No.
alkoxycarbonylaziridines was
developed. The cross-coupling
allowed for the asymmetric
preparation of enantiopure b2-amino
acids, starting from commercially
available serine esters. Computational
studies rationalized the plausible
catalytic cycle.
Asymmetric Synthesis of
b
2-Aryl
Amino Acids through Pd-Catalyzed
Enantiospecific and Regioselective
Ring-Opening Suzuki-Miyaura
Arylation of Aziridine-2-carboxylates
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