Synthesis of Optically Pure (S, E)-2-Amino-5-arylpent-4-enoic Acids by Heck Reactions of Nickel Complexes

Article abstract of DOI:10.1055/s-0037-1609094

Starting from commercially available building blocks a variety of enantiomerically pure (S)-2-amino-4-enoic acids has been synthesized by the Heck reaction using Ni-(S)-BPB {Nickel- N -[(S)-benzylprolyl]aminobenzophenone} as a chiral auxiliary. The reactions proceeded in very good yields and with high E -selectivity.

Full text of DOI:10.1055/s-0037-1609094

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
S. Parpart et al.
Letter
Synlett
Synthesis of Optically Pure (S,E)-2-Amino-5-arylpent-4-enoic
Acids by Heck Reactions of Nickel Complexes
Silvio Parparta
Heck reaction
Cleavage
Zorayr Z. Mardiyana,c,d
Peter Ehlersa,b
Andranik Petrosyana,b,d
Anna F. Mkrtchyanc,d
Ashot S. Saghyanc,d
O
O
R2
O
O
O
ArBr
MeOH
HClaq
Pd(PPh3)4
HNiPr2
R1
R1
Ni
N
Ni
N
N
N
HO
N
N
R1
H2N
Δ
dioxane
100 °C, 24 h
O
O
R2
20 examples
57–97% yield
ee > 99%
Peter Langer*a,b
0
0
0
0
0-
0
0
2
7-
6
6
5
8-
9
1
2
29–92% yield
R2 = H, Me, tBu, F, CF3, CN, COOMe, OMe, Naphthyl
R1 = H, Me
a Universität Rostock, Institut für Chemie, A.-Einstein-Str. 3a,
18059 Rostock, Germany
peter.langer@uni-rostock.de
b Leibniz-Institut für Katalyse e.V. an der Universität Ros-
tock, A.-Einstein-Str. 29a, 18059 Rostock, Germany
c SPC ‘Armbiotechnology’ SNPO NAS RA, Gyurjyan Str.
14, 0056 Yerevan, Armenia
d Yerevan State University, Faculty of Pharmacy and
Chemistry, Chair of Pharmacy, Alex Manoogyan Str. 1,
0025 Yerevan,
Armenia
Received: 25.10.2017
Accepted after revision: 26.11.2017
Published online: 15.01.2018
phenone).11 Such Ni–BPB complexes were developed in re-
cent decades with optically active BPB to perform the
asymmetric induction and Ni to increase the stability and
reactivity of the coordinated amino acid.12 The complexes
are stable to air and are synthesized from readily available
building blocks (benzyl chloride, L-proline, 2-aminobenzo-
phenone). In the past, these amino acid–Ni–BPB complexes
have been applied to Michael additions,13 Mannich reac-
tions,14 aldol reactions,15 SN2 reactions,16 and Sonogashira
couplings.17
DOI: 10.1055/s-0037-1609094; Art ID: st-2017-d0787-l
Abstract Starting from commercially available building blocks a vari-
ety of enantiomerically pure (S)-2-amino-4-enoic acids has been syn-
thesized by the Heck reaction using Ni-(S)-BPB {Nickel-N-[(S)-benzyl-
prolyl]aminobenzophenone} as
proceeded in very good yields and with high E-selectivity.
a chiral auxiliary. The reactions
Key words amino acids, Heck reaction, catalysis, chiral auxiliary,
enantioselectivity
In this work, we present a new and convenient synthe-
sis of optically pure allylglycine derivatives using glycine–
Ni–BPB and alanine–Ni–BPB as starting materials. Both
compounds undergo substitution with allyl chloride in very
good yield and high enantiomeric excess. Further function-
alization via Heck18 reaction yields a great diversity of opti-
cally pure allylglycine derivatives (Scheme 1).
Naturally occurring α-allylglycine1 and its derivatives
have a high level of biological activity. The parent com-
pound is known to have antibiotic2 as well as GABA and
glutamate decarboxylase inhibiting properties;3 while its
derivatives can inhibit nitric oxidase synthase,4 viral prote-
ase,5 and cathepsin.6 Thus, synthesis of novel allyl-contain-
ing amino acids is an important topic in synthetic chemis-
try. Racemic allylglycine can be accessed easily by the malo-
nic ester synthesis.7 To obtain optically pure amino acids,
an enzymatic protocol has been used to separate racemic
allylglycineamids using a substrate selective aminopepti-
dase.8 Nevertheless, the direct synthesis of optically pure
amino acids is a topic of ongoing research. This can be
achieved by chiral catalysts, chiral substrates, or a chiral
environment.9
O
H
O
O
R
Ni
N
N
N
HO
Ar
R
H2N
O
SN2
acid
O
O
N
Heck
reaction
O
Allylglycine can be enantiomerically enriched by a
phase-transfer reaction, using different cinchonidine cata-
lysts.10 Unfortunately, the published enantiomeric excess
(ee) is limited to 75%. Higher ee values, with over 90%, are
reported for the application of amino acid–Ni–BPB com-
O
Ar
Ni
N
N
R
Ni
N
N
R
N
O
O
Scheme 1
plexes (Ni-BPB
=
nickel-N-(benzylprolyl)aminobenzo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
S. Parpart et al.
Letter
Synlett
To find the optimal conditions for the Heck reaction we
started with Pd(PPh3)4 as catalyst and examined different
bases (Table 1). It was found that K3PO4 resulted in lower
yields compared to NEt3 and HNiPr2. The best yield was ob-
tained with HNiPr2 as a 1:1 mixture with the solvent (Table
1, entry 8). Different ratios led to diminished yields of 3a.
Dioxane was the optimal solvent, while DMF gave similar
results at higher temperature (Table 1, entries 1–5). Nonpo-
lar solvents such toluene or heptane did not dissolve 2b
completely and resulted in poor yields (Table 1, entries 6
and 7). Although we examined different catalysts, the read-
ily available Pd(PPh3)4 gave the highest yield.21
With optimized reaction conditions in hand we synthe-
sized a range of derivatives to investigate the scope of this
reaction. Electron-rich as well as electron-poor aryl
bromides were tested and both achieved good to very good
yields (Table 2). ortho-Substituted aryl bromides such as
2-bromotoluene 3f led to slightly lower yields (Table 2, en-
try 6). The alkyl group of the starting material 2b did
not affect the yield. For example, 3a (Ar = Ph, R = H) and 3j
(Ar = Ph, R = Me) resulted in 88% and 91% yields, respective-
O
O
H
R
O
O
Br
Ni
N
N
Ni
N
N
R
N
N
DMF/NaOH
25 °C
O
O
1a,b
2a, R = H (85%)
2b, R = Me (87%)
Scheme 2
Initially, starting compounds glycine–Ni–(S)-BPB (1a)
and alanine–Ni–(S)-BPB (1b) were synthesized according to
a published procedure.19 Compounds 1a,b were functional-
ized with allyl bromide promoted by NaOH in DMF to ob-
tain starting materials 2a,b in 85% and 87% yields, respec-
tively (Scheme 2). These SN2 reactions proceeded stereose-
lectively due to kinetic as well as thermodynamic control
and yielded (S)-allylglycine–Ni–(S)-BPB (2a) and (S)-allyl-
alanine–Ni–(S)-BPB (2b) in high enantiomeric excess.20
Table 1 Optimization of the Heck Reactiona
PhBr (1.5 equiv)
catalyst (5 mol%)
ligand
base
solvent
(2 ml/75 mg 2)
O
O
Ph
Me
Me
O
O
Ni
N
Ni
N
N
N
N
N
100–110 °C, 24 h
O
O
2b
3a
Entry
Catalyst
Ligand (mol%)
Solvent
Base (mL)
Temp (°C)
Yield (%)b
c
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
–
DMF
K3PO4
110
110
110
110
110
100
100
100
100
100
100
100
100
100
100
36
63
77
48
36
22
0
–
DMF
Et3N (2.0)
HNiPr2 (2.0)
HNiPr2 (4.0)
HNiPr2 (0.7)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
HNiPr2 (2)
3
–
DMF
4
–
DMF
5
–
DMF
6
–
toluene
heptane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
7
–
8
–
88
38
30
41
64
20
24
27
9
–
10
11
12
13
14
15
PCy3 (10)
XPhos (10)
HPtBu3BF4 (10)
MeP(tBu)2(10)
dppe (5)
dppf (5)
a Reaction of 75 mg 2b in 2 mL solvent.
b Isolated yields.
c 5 equiv base in 2 mL DMF.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
S. Parpart et al.
Letter
Synlett
ly (Table 2, entries 1 and 10). Based on the 1H NMR spectra
it was found that the double bond was exclusively E-config-
urated.
Table 2 (continued)
Entry
R
Ar
Yield (%)
46
F
11
12
3k
3l
H
H
Table 2 Synthesis of Compounds 3a–ta
ArBr (1.5 equiv)
Pd(PPh3)4 (5 mol%)
HNiPr2
(2 ml/75 mg 1)
dioxane
85
83
F
O
O
Ar
O
O
(2 ml/75 mg 1)
Ni
N
Ni
N
N
N
R
F
R
N
N
13
3m
H
100 °C, 24 h
O
O
2a, b
3a–t
F
F
Entry
1
R
Ar
Yield (%)
14
15
16
3n
3o
3p
H
H
H
67
63
29
3a
Me
Me
Me
88
51
92
OMe
F
2
3
3b
3c
OMe
F
tBu
CN
17
3q
H
75
F
4
3d
Me
89
18
19
3r
3s
H
H
87
88
5
6
3e
3f
Me
Me
80
72
Me
NC
Me
O
OMe
20
3t
H
87
7
8
3g
3h
Me
Me
58
77
a Isolated yields.
CF3
The Ni complexes 3a–t were cleaved following a known
procedure, in order to obtain the free amino acids 4a–t (Ta-
ble 3).17,22 Afterwards the free amino acids were purified
using a cation-exchange column. The procedure worked
O
OMe
9
3i
3j
Me
H
81
91
1
well for most of the synthesized derivatives. From the H
NMR spectra of the amino acids the E/Z-selectivity was ana-
lyzed and it was found that the Heck reaction gave exclu-
sively the E-isomer of amino acids 4a–t.
10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
S. Parpart et al.
Letter
Synlett
Table 3 Synthesis of Compounds 4a–ta
O
O
CN
HO
HO
Me NH2
OMe
O
H
NH2
Ar
O
O
HCl (concd)
MeOH/H2O
4s (88%)
O
Ni
R
N
4i (83%)
N
N
HO
Ar
20 min, reflux
O
NH2
R
O
O
HO
H
3a–t
4a–t
HO
H
NH2
OMe
NH2
O
O
F
O
4j (91%)
4t (87%)
HO
HO
Me NH2
H
NH2
a Isolated yields.
4a (85%)
4k (96%)
O
O
F
In addition, compound 4l was selected to check the en-
antiomeric purity of the synthesized amino acids via HPLC
on a chiral-phase column. The enantiomeric purity from
starting material 2a (ee >99%) was maintained during the
Heck reaction and subsequent cleavage gave 4l with
ee >99% (see Supporting Information).
In conclusion, we have demonstrated a straightforward
strategy to synthesize a range of 2-amino-4-pentenoic ac-
ids. The reaction proceeds enantioselectively as well as
showing E-selectivity. Overall 20 different amino acids
were prepared in good to excellent yields with ee >99%.
F
HO
H
HO
NH2
Me NH2
4b (91%)
4l (97%)
O
O
F
HO
H
HO
NH2
Me NH2
F
F
4c (91%)
4m (83%)
O
F
O
HO
H
HO
NH2
Me NH2
F
Funding Information
4n (80%)
4d (93%)
Financial support by the State of Mecklenburg-Vorpommern, by the
DAAD (Ostpartnerschaften program), and by the Volkswagenstiftung
is gratefully acknowledged.
O
O
OMe
Me
HO
H
HO
)(
NH2
Me NH2
4o (85%)
4e (57%)
Supporting Information
O
O
Me
Supporting information for this article is available online at
HO
H
HO
https://doi.org/10.1055/s-0037-1609094.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
NH2
Me NH2
OMe
4f (93%)
4p (83%)
References and Notes
O
O
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Jpn. 1985, 26, 61. (b) Yamaura, Y.; Fukuhara, M.; Takabatake, E.;
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HO
H
HO
NH2
Me NH2
tBu
4q (91%)
4g (88%)
(2) Dittmer, K.; Goodman, I.; Stanley, J. C. J. Am. Chem. Soc. 1948, 70,
2499.
O
O
(3) (a) Alberici de Canal, M.; Rodríguez De Lores Arnaiz, G.; De
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Shekhar, A. J. Psychopharmacol. 2008, 22, 633.
CF3
HO
H
HO
NH2
Me NH2
CN
4h (90%)
4r (87%)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
S. Parpart et al.
Letter
Synlett
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(a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Weiner, B.;
Szymański, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L.
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(21) (S,E)-2-Amino-2-methyl-5-[phenyl]pent-4-enoic
(S)-BPB (3a)
acid–Ni–
Compound 2b (221 mg, 1.0 equiv), Pd(PPh3)4(23 mg, 0.05
equiv), and bromobenzene (72 μl, 1.7 equiv) were added to a
pressure tube and dissolved in 1,4-dioxane (6 ml, 15 l/mol 2b)
and HNiPr2 (6 mL, 15 l/mol 2b). The mixture was stirred at 101
°C for 24 h. After cooling to room temperature it was diluted
with ethyl acetate and washed with water. The organic layer
was dried with Na2SO4 and filtered. The solvent was removed
under reduced pressure, and the residue was purified by silica
column chromatography (ethyl acetate/heptanes, 2:1 >> 1:0) to
yield 3a as a red solid; yield 88%, mp 112–113 °C. 1H NMR (250
MHz, CDCl3): δ = 1.27 (s, 3 H, CH3), 1.35–1.74 (m, 1 H, CH2),
1.82–1.99 (m, 1 H, CH2), 2.01–2.25 (m, 2 H, CH2), 2.48–2.73 (m,
3 H, CH2), 3.27 (dd, 3J = 9.8 Hz, 3J = 7.1, 1 H, CH), 3.42–3.55 (m, 1
H, CH2), 3.61 (d, 2J = 12.7 Hz, 1 H, CH2Ph), 4.40 (d, 2J = 12.7 Hz, 1
H, CH2Ph), 6.58–6.74 (m, 3 H, CH), 6.85–7.00 (m, 1 H, CH), 7.03–
7.19 (m, 2 H, CH), 7.21–7.57 (m, 11 H, CH), 7.61–7.74 (m, 1 H,
CH), 7.96–8.10 (m, 3 H, CH). 13C NMR (63 MHz, CDCl3): δ = 23.1
(CH3), 29.7, 30.7, 43.9, 63.6 (CH2), 70.2 (CH), 78.7 (C), 120.9,
124.0, 124.2, 126.8, 127.2, 127.7, 128.0, 128.3 (CH), 128.7 (C)
128.8, 129.0, 129.1, 129.7, 130.8, 131.9 (CH), 133.5 (C), 133.7,
134.7 (CH), 136.8, 137.3, 142.0 (C), 172.8 (C=N), 180.7 (C=O),
181.9 (C=O). IR (ATR): ν = 3057 (w), 3025 (w), 2922 (br, w), 2867
(w), 1668 (m), 1634 (s), 1594 (w), 1574 (w), 1534 (w), 1495 (w),
1469 (w), 1436 (m), 1355 (s), 1331 (m), 1312 (w), 1287 (w),
1250 (s), 1163 (m), 1118 (w), 1062 (w), 1000 (w), 964 (m), 927
(w), 885 (w), 824 (w), 748 (s), 695 (s), 618 (w), 563 (w), 540 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 627 (5) [M+], 585 (15), 584 (13),
583 (32), 510, (7), 492 (4), 440 (4), 439 (4), 425 (4), 347 (1), 328
(2), 280 (2), 278 (2), 161 (9), 160 (89). ESI-HRMS: m/z calcd for
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N. Y.; Avilov, D. V.; Kuz’mina, N. A.; Raevski, N. I.; Struchkov, Y.
T.; Pysarevsky, A. P.; Belokon, Y. N. J. Chem. Soc., Perkin Trans. 1
1993, 3143.
C
37H36N3NiO3 [M + H+]: 628.21047; found: 628.20997; m/z calcd
for C37H36N360NiO3 [M + H+]: 630.20798; found: 630.20805; m/z
calcd for 37H35N3NiNaO3 [M
Na+]: 650.19241; found:
37H35N3Na60NiO3 [M Na+]:
C
+
650.19232; m/z calcd for
C
+
652.18992; found: 652.18952.
(16) Sorochinsky, A. E.; Aceña, J. L.; Moriwaki, H.; Sato, T.;
Soloshonok, V. A. Amino Acids 2013, 45, 691.
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(19) (a) Belokon, Y. N.; Bakhmutov, V. I.; Chernoglazova, N. I.;
Kochetkov, K. A.; Vitt, S. V.; Garbalinskaya, N. S.; Belikov, V. M. J.
Chem. Soc., Perkin Trans. 1 1988, 305. (b) Soloshonok, V.;
(22) (S,E)-2-Amino-2-methyl-5-[phenyl]pent-4-enoic acid (4a)
Compound 3a (190 mg, 1.0 equiv) was dissolved in MeOH/H2O
(10 ml/5 ml), and HCl (12 M, 1.5 ml) was added dropwise. The
stirred mixture was heated to reflux for 20 min (during which
time the color changed from red to green). After cooling to room
temperature the mixture was diluted with water and extracted
with DCM four times. The aqueous layer was treated with 5% aq
NH3solution to reach pH 2. The solution was further purified by
cation exchange column (Dowex 50WX8 H+, see Supporting
Information for details) to yield 4a as white solid; yield 85%, mp
1
267–268 °C. H NMR (300 MHz, CD3OD): δ = 1.64 (s, 3 H, CH3),
2.79 (dd, 3J = 7.6 Hz, 2J = 14.5 Hz, 1 H, CH2), 2.87 (dd, 3J = 7.6 Hz,
2J = 14.5 Hz, 1 H, CH2), 6.21 (dt, 3J = 7.6 Hz, 3J = 15.4 Hz, 1 H, C=C),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
S. Parpart et al.
Letter
Synlett
6.65 (d, 3J = 15.4 Hz, 1 H, C=C), 7.19–7.34 (m, 3 H, Ph), 7.40–7.45
(m, 2 H, Ph). 13C NMR (75 MHz, CD3OD): δ = 22.7 (CH3), 41.8
(CH2), 61.2 (C), 121.8 (CH), 127.7, 129.1, 129.7, 137.8 (CH),
138.1 (C), 173.5 (COOH). IR (ATR): ν = 3000 (br, m), 1656 (br, w),
1540 (w), 1573 (s), 1494 (w), 1450 (w), 1397 (s), 1366 (m),
1287 (w), 1264 (w), 1239 (w), 1130 (w), 1070 (w), 965 (s), 883
MS (EI, 70 eV): m/z (%) = 206 (4), 205 (2) [M+], 194 (5), 193 (13),
178 (4), 161 (6), 160 (64), 159 (12), 144 (12), 143 (16), 129 (13),
128 (34), 118 (31), 117 (87), 116 (50), 115 (86), 102 (12), 91
(60), 90 (6), 89 (42), 88 (100), 80 (16), 77 (15), 65 (13), 63 (11).
HRMS (EI): m/z calcd for C12H16NO2 [M + H+]: 206.11756; found:
206.11778.
(w), 788 (w), 739 (s), 690 (s), 629 (w), 587 (w), 553 (w) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F