Phase-transfer-catalyzed asymmetric SNAr reaction of ?±-amino acid derivatives with arene chromium complexes

Article abstract of DOI:10.1002/anie.201409065

Although phase-transfer-catalyzed asymmetric S_NAr reactions provide unique contribution to the catalytic asymmetric ?±-arylations of carbonyl compounds to produce biologically active ?±-aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron-withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S_NAr reactions of aamino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron-donating substituents. The arylation was efficiently promoted by binaphthyl-modified chiral phase-transfer catalysts to give the corresponding ?±,?±-disubstituted ?±-amino acids containing various aromatic substituents with high enantioselectivities.

Full text of DOI:10.1002/anie.201409065

Angewandte
Chemie
DOI: 10.1002/anie.201409065
Organocatalysis
Phase-Transfer-Catalyzed Asymmetric SNAr Reaction of a-Amino
Acid Derivatives with Arene Chromium Complexes**
Seiji Shirakawa, Kenichiro Yamamoto, and Keiji Maruoka*
Abstract: Although phase-transfer-catalyzed asymmetric SNAr
reactions provide unique contribution to the catalytic asym-
metric a-arylations of carbonyl compounds to produce
biologically active a-aryl carbonyl compounds, the electro-
philes were limited to arenes bearing strong electron-with-
drawing groups, such as a nitro group. To overcome this
limitation, we examined the asymmetric SNAr reactions of a-
amino acid derivatives with arene chromium complexes
derived from fluoroarenes, including those containing elec-
tron-donating substituents. The arylation was efficiently pro-
moted by binaphthyl-modified chiral phase-transfer catalysts
to give the corresponding a,a-disubstituted a-amino acids
containing various aromatic substituents with high enantiose-
lectivities.
Catalytic asymmetric a-arylation of carbonyl compounds
has been extensively studied over the last decade to prepare
biologically interesting a-aryl carbonyl compounds.[1,2] Sev-
eral catalytic asymmetric methods for a-arylation have been
developed using chiral metal complexes.[3] As another method
for asymmetric a-arylation, the phase-transfer-catalyzed
nucleophilic aromatic substitution (SNAr) reaction provides
an efficient means to realize enantioselective a-arylations
(Scheme 1).[4,5] Jørgensenꢀs and our groups have reported
highly enantioselective phase-transfer-catalyzed SNAr reac-
tions of carbonyl compounds with nitro group-bearing
fluoroarenes as electrophiles (Scheme 1a).[6] The drawback
of this method is the limited scope of fluoroarenes that can be
used, as only electron-deficient arenes are effective sub-
strates. The SNAr reactions using fluoroarenes with electron-
donating groups (EDG), did not work under the phase-
transfer conditions (Scheme 1b). As a solution to this
problem, we are interested in SNAr reaction of the chromium
complexes of fluoroarenes, which activate the arenes through
h6-coordination to Cr(CO)3.[7,8] Here we report a valuable
example of a phase-transfer-catalyzed asymmetric SNAr
reaction of a-amino acid derivatives with arene chromium
Scheme 1. Phase-transfer-catalyzed asymmetric SNAr reactions.
PTC=phase-transfer catalyst.
complexes, which produces enantioenriched a,a-disubstituted
a-amino acids[9] including those containing an electron-rich
aromatic substituents (Scheme 1c).
We first examined the asymmetric SNAr reaction of
alanine derivative 1a with chromium complex 2a derived
from fluorobenzene, promoted by biaryl-modified chiral
quaternary ammonium salts 4–6 as promising chiral phase-
transfer catalysts (Table 1).[5] Attempted reaction of 1a and
fluorobenzene derivative 2a with solid KOH in toluene under
the influence of chiral phase-transfer catalyst (R,R)-4[10] at
08C for 24 h, followed by treatment with aqueous HCl for
hydrolysis of the imine moiety and removal of chromium,
afforded the corresponding a,a-disubstituted a-amino ester
3a with moderate yield and enantioselectivity (77% ee,
entry 1). The use of simplified catalyst (R)-5,[11] which is one
of the most effective catalysts for asymmetric alkylation
reactions of 1a,[11,12] improved the enantioselectivity to give
product 3a in moderate yield with high enantioselectivity
(97% ee, entry 2). The use of biphenyl-modified catalyst (R)-
6[13] caused the decrease of enantioselectivity for the SNAr
reaction (39% ee, entry 3). Changing the base to CsOH
improved the yield (entry 4), and the highest yield and
enantioselectivity was attained by the use of saturated
aqueous CsOH[14] as base with catalyst (R)-5 (entry 5).[15]
The absolute configuration of product 3a was determined
by comparison of the optical rotation of the N-acetylated
derivative of 3a with the literature value.[6c,16]
[*] Prof. Dr. S. Shirakawa, K. Yamamoto, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Prof. Dr. S. Shirakawa
Graduate School of Fisheries Science and Environmental Studies
Nagasaki University
1-14, Bunkyo-machi, Nagasaki 852-8521 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
from JSPS and MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409065.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Asymmetric arylation of alanine derivative 1a.[a]
Entry
EDG (2)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
H (2a)
70 (3a)
71 (3b)
69 (3c)
62 (3d)
70 (3e)
68 (3 f)
61 (3g)
65 (3h)
63 (3i)
97
98
98
94
98
99
98
99
98
p-Me (2b)
m-Me (2c)
o-Me (2d)
p-OMe (2e)
m-OMe (2 f)
p-OEt (2g)
p-SMe (2h)
p-NMe2 (2i)
[a] Reaction conditions: 1a (0.30 mmol), 2 (0.10 mmol), and saturated
aqueous CsOH (1.5 mmol) in the presence of (R)-5 (10 mol%,
0.010 mmol) in toluene (2.0 mL) at 08C for 24 h. [b] Yields of isolated
products 3, which were determined on the basis of the amount of 2.
[c] Determined by HPLC analysis on a chiral stationary phase.
Entry
Catalyst
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
(R,R)-4
(R)-5
(R)-6
(R)-5
(R)-5
KOH
KOH
KOH
CsOH·H2O
sat. aq. CsOH
42
39
41
70
70
77
97
39
91
97
Table 3: Asymmetric phenylation of a-amino acid derivatives 1.[a]
[a] Reaction conditions: 1a (0.30 mmol), 2a (0.10 mmol), and base
(1.5 mmol) in the presence of phase-transfer catalyst (10 mol%,
0.010 mmol) in toluene (2.0 mL) at 08C for 24 h. [b] Yields of isolated
product 3a, which were determined on the basis of the amount of 2a.
[c] Determined by HPLC analysis on a chiral stationary phase.
Entry
R (1)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Me (1a)
Et (1b)
iBu (1c)
CH2Ph (1d)
70 (3a)
78 (3j)
60 (3k)
68 (3l)
74 (3m)
76 (3n)
73 (3o)
51 (3p)
97
99
88
95
96
90
96
92
With the optimal reaction conditions identified, we next
examined the substrate generality of the asymmetric SNAr
reaction of alanine derivative 1a with arene chromium
complexes 2 under the influence of chiral phase-transfer
catalyst (R)-5 (Table 2). The SNAr reactions with p-, m-, and
o-fluorotoluene derivatives (2b–2d) proceeded efficiently,
and gave the products (3b–3d) in good yields with high
enantioselectivities (94–98% ee, entries 2–4). Other electron-
donating group (EDG)-substituted fluoroarene derivatives
(2e–2i) could also be used in this reaction, thereby providing
the products (3e–3i) with excellent enantioselectivities (98–
99% ee, entries 5–9).[17]
=
CH2CH CH2 (1e)
CH2CH2SMe (1 f)
CH2OtBu (1g)
CH2CH2CO2tBu (1h)
[a] Reaction conditions: 1 (0.30 mmol), 2a (0.10 mmol), and saturated
aqueous CsOH (1.5 mmol) in the presence of (R)-5 (10 mol%,
0.010 mmol) in toluene (2.0 mL) at 08C for 24 h. [b] Yields of isolated
products 3, which were determined on the basis of amount of 2a.
[c] Determined by HPLC analysis on a chiral stationary phase.
Other a-amino acid derivatives 1 could be employed in
the SNAr reaction with arene chromium complex 2a
(Table 3). Not only simple alkyl-substituted a-amino acid
derivatives (1a–1c) but also phenylalanine (1d) and allylgly-
cine (1e) derivatives were tolerated in the reaction to give the
corresponding phenylation products 3j–3m in high enantio-
selectivities (88–99% ee, entries 1–5). Furthermore, hetero-
atom-containing a-amino acids, such as methionine (1 f), ser-
ine (1g), and glutamic acid derivatives (1h), were also
suitable for the reaction to give the corresponding products
3n–3p in high enantioselectivities (90–96% ee, entries 6–8).
In summary, we have successfully overcome a major
limitation of phase-transfer-catalyzed asymmetric SNAr reac-
tions by the use of arene chromium complexes. The SNAr
reaction of a-amino acid derivatives with chromium com-
plexes derived from electron-rich fluoroarenes, was efficiently
promoted by binaphthyl-modified chiral phase-transfer cata-
lysts to give the corresponding a,a-disubstituted a-amino
acids containing various aromatic substituents, in a highly
enantioselective manner. This report offers a new option for
2
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[15] The reaction on larger scale (10 times) gave a similar result
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[16] For details of the determination of the absolute configuration of
3a, see the Supporting Information.
[17] Racemic arene chromium complexes 2c, 2d, and 2 f were used
for the reaction.
Received: September 13, 2014
Published online: && &&, &&&&
Keywords: amino acids · arylation · asymmetric synthesis ·
.
organocatalysis · phase-transfer catalysis
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Communications
Organocatalysis
S. Shirakawa, K. Yamamoto,
K. Maruoka*
&&&& — &&&&
Phase-Transfer-Catalyzed Asymmetric
SNAr Reaction of a-Amino Acid
Derivatives with Arene Chromium
Complexes
Increased substrate scope in phase-
transfer-catalyzed asymmetric SNAr reac-
tions was achieved by the use of arene
chromium complexes as electrophiles. An
efficient asymmetric synthesis of a,a-
disubstituted a-amino acids containing
various aromatic substituents is shown.
PTC=phase-transfer catalyst.
4
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