Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by sequential SN2-SN2′ dialkylation of (R)-N-(benzyl)proline-derived glycine Schiff base Ni(ii) complex

Article abstract of DOI:10.1039/c4ra12658k

This work describes a new process for the asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid of high pharmaceutical importance. The sequence of the reactions includes PTC alkylation (S_N2), homogeneous S_N2′ cyclization followed by disassembly of the resultant Ni(ii) complex. All reactions are conducted under operationally convenient conditions and suitably scaled up to 6 g of the starting Ni(ii) complex. This journal is

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ARTICLE TYPE
Asymmetric synthesis of (1R,2S)-1-amino-2-
vinylcyclopropanecarboxylic acid by sequential S 2–S 2’ dialkylation of
N
N
(R)-N-(benzyl)proline-derived glycine Schiff base Ni(II) complex
a
Aki Kawashima, Chen Xie, Haibo Mei, Ryosuke Takeda, Akie Kawamura, Tatsunori Sato, Hiroki
b
b
a
a
a
a
Moriwaki, Kunisuke Izawa, Jianlin Han,* José Luis Aceña* and Vadim A. Soloshonok*
a
b
c
c,d
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
This work describes a new process for the asymmetric synthesis of (1R,2S)-1-amino-2-
vinylcyclopropanecarboxylic acid of high pharmaceutical importance. The sequence of the reactions
includes PTC alkylation (S 2), homogeneous S 2’ cyclization followed by disassembly of the resultant
1
0
N
N
Ni(II) complex. All reactions are conducted under operationally convenient conditions and suitably scaled
up to 6 g of the starting Ni(II) complex.
structural feature. Quite remarkably, at least six different drugs
Introduction
containing amino acid 6 are currently being developed for the
9
10
treatment of hepatitis C. For example, simeprevir, danoprevir,
1
Tailor-made α-amino acids are of vital importance in the
development of modern pharmaceuticals. In particular, sterically
constrained amino acids are key structural units in the design of
peptidic derivatives with limited and rationally controllable
number of conformations. In this line, so called α,β-methano-α-
amino acids or methanologs of α-amino acids represent an
extreme case of compounds containing
11
12
13
14
asunaprevir, faldaprevir, ciluprevir and grazoprevir, all
have acid 6 as a fragment, usually as its C-sulfonamide
derivative. Consequently, several approaches were developed for
preparation of amino acid 6 in enantiomerically pure form. The
majority of the literature methods includes multiple reaction
sequences and functional group transformations, but can be
applied for synthesis of various types of methanologs of α-amino
2
1
2
2
5
0
5
4
4
5
5
0
5
0
5
3
4
a
severely
5
conformationally restricted cyclopropane ring. Interestingly,
several cyclopropyl-group-containing amino acids are naturally
occurring compounds and were isolated from some higher
15
acids 1-6. More focused and straightforward protocols rely on
the sequential S 2–S 2’ dialkylation of glycine Schiff bases
N
N
using trans-1,4-dibromobut-2-ene 7 as a source of cyclopropane
6
6a
plants. For example, 1-aminocyclopropanecarboxylic acid 1
and a series of its 2-alkyl substituted derivatives, such as
16
ring and vinyl group. However, considering the current
exceptional pharmacological potential of amino acid 6 and its
derivatives, the relevant methodology is surprisingly
understudied leaving room for alternative synthetic solutions.
Taking into account our longstanding interest in the development
7
a
7b
7c
coronamic 2, norcoronamic 3, allo-coronamic 4, and allo-
7
d
norcoronamic 5 acids are found in proteins involved in various
plants’ defensive functions (Fig. 1).
1
7
of new methods for preparation of tailor-made amino acids and
COOH
COOH
(
COOH
(S)
18
S)
in particular sterically constrained structures, we turned our
(
S) Et
(S) Me
H
2
N
H
2
N
2
H N
attention to Ni(II) complexes of chiral glycine Schiff bases (S)-
19,20
H
H
and (R)-8
(Fig. 2) to explore the possibility of their
1
2
3
application for the asymmetric synthesis of amino acid 6. Here
we report rather successful results, demonstrating that the target
NH
(
2
COOH
(S)
(R)
NH
2
(R)
(S)
H
R)
60 acid (1R,2S)-6 can be conveniently prepared via sequential S 2–
N
(
S) Et
H
HOOC
H
2
N
HOOC
SN2’ dialkylation of Schiff base (R)-8 with a synthetically
H
Me
attractive stereochemical outcome.
4
5
6
3
0
Fig. 1 Some naturally occurring methanologs of α-amino acids 1-5 and
synthetic derivative 6.
The recent upsurge of interest in methanologs of α-amino acids
is related to the discovery of a novel and very potent class of
8
hepatitis C virus (HCV) NS3/4A protease inhibitors containing
3
5
(1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid 6 as a key
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Ph
Ni
Ph
Ni
agreeable with the general stereochemical trend observed in the
31
3
3
4
0
5
0
synthesis of quaternary α-amino acids as the (S)-configured
complex 8 gives preference for the α-(S) absolute configuration
of the dialkylation products.
N
N
O
N
O
N
N
O
N
O
O
O
Drawing from these data and our own experience in the
32
reactions of (S)- and (R)-8 with α,ω-dihaloalkanes, we initiated
our study trying first the direct preparation of the target product
by alkylation of (S)-8 with dibromide 7 under homogeneous
Ph
Ph
32a
(
S)-8
(R)-8
conditions.
The reaction conducted in DMF at room
Fig. 2 Structures of (S)- and (R)-proline derived Ni(II) complexes of
glycine Schiff base 8.
temperature turned out to be very messy producing numerous
products. Application of acetonitrile as solvent or lowering the
reaction temperature did not improve much the outcome
suggesting that the homogeneous conditions are too harsh for the
reagents and intermediates with multiple reaction centers.
Therefore, we decided to proceed stepwise, separating the SN2
Results and discussion
5
0
5
0
5
The chemistry of Ni(II) complexes of glycine and higher amino
acids is a well established methodology for generalized and
practical preparation of α-
enantiomerically pure form. For example, homologation of
complex 8 can be conducted under operationally convenient
2
0
21
and S 2’ alkylation procedures.
N
and β-amino acids
in
2
2
45
As presented in Scheme 1 and Table 1, phase-transfer catalysis
PTC) conditions were quite successful for preparation of
(
23
24
monoalkylated products (S)(2S)-9 and (S)(2R)-10. For the
1
1
2
2
conditions and on a relatively large-scale, usually with
practically useful results. Transformation of the glycine moiety in
25a,33
purpose of the present work, the kinetic
of diastereomers (S)(2S)-9 and (S)(2R)-10 had no importance as
50 the second S 2’ alkylation step was expected to proceed via the
ratio (about 80:20)
25
26
8
can be performed via alkyl halide alkylations, aldol,
27
28
N
Michael
and Mannich
addition reactions, affording
same intermediate enolate. Therefore, we focused on the
chemical yield and purity of the products. Application of only 1.5
equivalents of dibromide 7 (Table 1, entry 1) under liquid-liquid
PTC resulted in a moderate yield along with incomplete
conversion of the starting complex (S)-8 and, probably, formation
of binuclear Ni(II) species, complicating the purification of the
target products. Gradual increase in the excess of alkylating
reagent 7 allowed to improve the yield of (S)(2S)-9 and (S)(2R)-
10 and reduce the number of by-products (entries 2 and 3).
Scaling the reaction up under these conditions gave rather good
results as a mixture of (S)(2S)-9 and (S)(2R)-10 was prepared in
structurally varied types of α-amino acids. In particular, there are
two published examples of application of complex (S)-8 for
preparation of cyclopropyl-group-containing α-amino acids. The
first approach includes Michael addition of (S)-8 to ethyl 2-
bromoacrylate, followed by the intramolecular substitution of the
ω-bromine atom and eventually leading to (2S,3R)-2,3-methano-
5
6
6
5
0
5
29
aspartic acid. The second report deals with dialkylation of (S)-8
with chiral (S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (cyclic
30
dialkyl sulfate) to afford allo-norcoronamic acid (1S,2R)-5 (Fig.
). Obviously, these procedures cannot be used for preparation of
1
our target vinylcyclopropanecarboxylic acid 6. However, both
methods report high yields and diastereoselectivity suggesting
that the rigid structure of the Ni(II)-coordinated glycine Schiff
base presents no problem for the formation of highly sterically
congested cyclopropane rings. Furthermore, these results are
7
7.8% isolated yield (entry 4). However, slightly better results
were obtained using solid NaOH as a base (solid-liquid PTC,
entries 5-8). In this case, the yield was improved and successfully
reproduced on 5 g scale of starting complex (S)-8 (entry 8).
2
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ARTICLE TYPE
Ph
Ph
Ph
Br
N
N
O
N
O
Br
N
N
O
N
O
N
N
O
N
O
(
7)
Ni
Ni
Ni
+
O
O
Br
O
Br
n-Bu
4
NI (25 mol %)
Ph
base, (CH Cl) , rt
2
Ph
Ph
2
(
S)-8
(S)(2S)-9
(S)(2R)-10
NaOt-Bu, THF, rt
Ph
Ph
N
N
O
O
N
N
O
N
O
Ni
Ni
+
O
N
O
Ph
Ph
(
S)(2S,3R)-11
(S)(2R,3S)-12
N N
Scheme 1 Sequential S 2-S 2’ dialkylation of (S)-8 with dibromide 7.
Table 1 Monoalkylation of Ni complex (S)-8.
Entry Scale (g) PTC 7 (equiv) Base
15 Table 2 S
conditions.
N
2’ Cyclization of (S)(2S)-9 and (S)(2R)-10 under homogeneous
a
b
Yield (%) 9:10 ratio
1
2
3
4
5
6
7
8
0.1
0.1
0.1
1.0
0.1
0.1
0.1
5.0
L/L
L/L
L/L
L/L
S/L
S/L
S/L
S/L
1.5
2.5
3.5
3.5
2.5
2.5
3.5
3.5
NaOH
58.0
67.4
77.5
77.8
75.5
75.0
80.7
81.3
80:20
78:22
79:21
80:20
79:21
80:20
79:21
78:22
Entry Scale Solvent Base
Temp.
(ºC)
Time Yield 11:12
a b
NaOH
NaOH
NaOH
NaOH
KOH
NaOH
NaOH
(g)
(equiv)
(h) (%)
ratio
1
2
3
4
5
6
0.1 DMF
0.1 DMF
0.1 DMF
0.1 MeCN
0.1 THF
0.1 THF
NaOH (5) 0 to 25
KOH (5)
NaOH (5) –15 to 25 3
NaOH (5) –15 to 25 7
NaOH (5) –15 to 25 7
1
1
44.5
41.2
48.0
51.7
34.3
65.1
79:21
80:20
85:15
87:13
90:10
91:9
0 to 25
NaOt-Bu
3)
NaOt-Bu
4)
NaOt-Bu
2+2)
–15 to 25 2
(
a
b
1
Overall yield of isolated pure products. Determined by H NMR
7
8
9
0.1 THF
0.1 THF
0.05 THF
5.0 THF
0 to 25
0 to 25
0 to 25
0 to 25
1
1
1
1
70.0
75.1
73.6
75.8
90:10
91:9
5
integration.
(
With these results in hand, we proceeded next to study the
(
second S 2’ alkylation step. It should be noted that under the
PTC conditions the S 2’ alkylation products were never observed
as the synthesis of quaternary α-amino acids via Ni(II) chemistry
c
N
NaOt-Bu
(2+2)
NaOt-Bu
90:10
90:10
N
10
3
1
(2+2)
1
0
requires relatively strong bases.
experimentation we found that successful cyclization of products
S)(2S)-9 and (S)(2R)-10 could be achieved under homogeneous
After some preliminary
a
b
1
Overall yield of isolated pure products. Determined by H NMR
c
integration. The reaction was performed using pure (S)(2R)-10 as
(
starting material.
conditions using strong inorganic bases. The representative
results are collected in Table 2.
20
The reactions conducted in DMF, using NaOH (entry 1) or
KOH (entry 2) as a base, resulted in rather low yields of
complexes (S)(2S,3R)-11 and (S)(2R,3S)-12 due to a noticeable
amount of some by-products. Lowering the reaction temperature
allowed to improve the stereochemical outcome (entry 3),
however, not to a satisfactory level. Application of acetonitrile
25
(
entry 4) or THF (entry 5) did not give the desired results either.
We reasoned that NaOH or KOH are rather strong nucleophilic
bases and could react with the ω-bromide of the starting
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compounds (S)(2S)-9 and (S)(2R)-10 leading to undesired
Having thus prepared complex (R)(2R,3S)-11, our next goal
substitution and/or elimination side-reactions. Further
was its disassembly and isolation of the target
experimentation revealed that THF as a solvent and NaOt-Bu as a 40 vinylcyclopropanecarboxylic acid 6. As shown in Scheme 2,
base can provide for a synthetically suitable stereochemical
outcome. Eventually, optimal results were achieved starting the
reaction at 0 ºC (entry 6 vs. 7) and adding the base in two
portions: at the beginning and at a point of about 50% conversion
treatment of diastereomerically pure (R)(2R,3S)-11 with aq 1N
HCl in methanol at 50 ºC resulted in complete disassembly of the
Ni(II)-complex structure and the formation of chiral ligand (R)-13
along with amino acid (1R,2S)-6. Ligand (R)-13 was recovered in
5
0
5
0
5
0
of the starting (S)(2S)-9 and (S)(2R)-10 mixture (entry 8). In this 45 92.8% yield by extraction and amino acid (1S,2R)-6 was isolated
case, the target products (S)(2S,3R)-11 and (S)(2R,3S)-12 were
obtained in 75.1% yield and 91:9 ratio. Out of stereochemical
curiosity, we conducted the reaction using diastereomerically
pure complex (S)(2R)-10 as a single starting compound. Quite
expectedly, the diastereomeric ratio and yield of (S)(2S,3R)-11 50 derivatized form 15. The amino functionality was protected with
and (S)(2R,3S)-12 were virtually the same as compared with the
reactions initiated using the mixture of (S)(2S)-9 and (S)(2R)-10
by using a cation exchange resin.
1
1
2
2
3
In view of the fact that the physicochemical properties of
amino acid (1R,2S)-6 render its proper characterization rather
16a
difficult, we followed the literature suggestion and prepared its
a Boc group and the resulting compound (1R,2S)-14 was best
isolated as its dicyclohexylammonium salt. Finally, esterification
(
entry 8 vs. 9). Finally, we reproduced this procedure on 5 g
with TMSCHN afforded the fully protected derivative (1R,2S)-
2
scale; the result was rather satisfactory (entry 10) allowing
preparation and purification of the major diastereomer 55 chiroptical properties matching those of the literature data.
15. Thus prepared (1R,2S)-15 was found to possess spectral and
1
6a
(
S)(2S,3R)-11 in good yield. Considering the chiroptical
Furthermore, we confirmed its optical purity by HPLC on a chiral
stationary phase.
properties of compound 11, in particular the strong positive
2
5
optical rotation ([α]D = +866), its absolute configuration was
With these experimental data in hand, we are in position to
discuss the stereochemical aspects of these sequential S 2–S 2’
2
0,29,30
assigned as (S)(2S,3R).
N
N
Accordingly, the synthesis of the pharmacologically important 60 dialkylation reactions. First of all, we have determined that
enantiomeric compound of (2R,3S) absolute configuration would
require the use of glycine Schiff base (R)-8. With this in mind, we
decided to repeat the whole sequence of the reactions based on
application of the (S)-configured starting Ni(II) complex of
glycine Schiff base (S)-8 gives preference for the α-(S) products
11 and (R)-8 leads to α-(R) derivatives. Second, we should
emphasize the very high level of relative stereochemistry control
(
R)-8 as the starting compound (Scheme 2). Taking into account
that all reactions involved had already been optimized, we readily 65 observed in these reactions (S 2’). Thus, only pairs of (S)(2S,3R)-
reproduced the process starting with 6 g of (R)-8. The first PTC
alkylation step proceeded quite smoothly affording a mixture of
N
11 and (S)(2R,3S)-12 [starting from (S)-8] and (R)(2R,3S)-11 and
(R)(2S,3R)-12 [starting from (R)-8] were observed in the reaction
mixtures, while other theoretically possible (2S,3S) and (2R,3R)
diastereomers were never detected. The first trend, the preference
(
R)(2R)-9 and (R)(2S)-10 in about 80:20 ratio and 78.5% yield.
Without additional purification, this mixture was subjected to the
second alkylation (S 2’) step giving rise to cyclized products 70 for the α-stereochemistry on the alkylation products, is rather
N
(
R)(2R,3S)-11 and (R)(2S,3R)-12 in 90:10 ratio and 73.4% yield.
expected and well established in the numerous literature
examples. On the other hand, the excellent relative stereocontrol
is quite unexpected and deserves a particular discussion.
20
(
R)(2R)-9
NaO -Bu
t
(R)(2R,3S)-11
+
7
, NaOH
(
R)-8
+
THF, rt
First of all, we would like to note that due to the
75 conformational homogeneity of both (Z)-enolate and trans-olefin
n-Bu
4
NI (25 mol %)
(R)(2S)-10
(R)(2S,3R)-12
(
CH Cl) , rt
2
2
(
78.5%, dr: 80:20)
(73.4%, dr: 90:10)
3
4
moieties, one can build only two possible TS B and B’. As
presented in Figure 3, the S 2’ cyclization of the (R)-enolate A
might proceed by way of TS B giving rise to the product C of
N
Ph
N
HO
2
C
1) aq 1N HCl
(
2R,3S) absolute configuration. On the other hand formation of
MeOH, 50 ºC, 1 h
H
2
N
80 the other possible diastereomeric product (2R,2R)-C’ can be
anticipated via TS B’. Considering likelihood of these two
situations, one might agree that TS B’ is significantly
disadvantaged due to the apparently sterically crowded position
+
O
NH
O
2
) cation exchange
resin
Ph
(
1R,2S)-6
80.5%)
(
(
R)-13
of the whole CH=CH-CH Br group “inside” the Ni(II)-
2
(92.8%)
85 coordinated enolate, while in the TS B the only unfavorable steric
1
) Boc
Et
2
O
interactions are between the enolate oxygen and the CH Br
2
3
N
MeO
2
C
moiety. Furthermore, the formation of TS B’ requires a sterically
unfavourable “folded” conformation of the side chain in enolate
A’ generating an increase of allylic strain, as compared with the
2
O C
2
) DCHA
EtOAc
TMSCHN
2
BocHN
BocHN
2
H N
90
“extended” and much more probable conformation in enolate A,
leading to the TS B. Considering these modes of steric
interactions, and consistent with the experimental results, one
may assume that formation of TS B’ is greatly improbable
(1R,2S)-14
(1R,2S)-15
(
80.0%)
(84.0%)
35
Scheme 2 Preparation of amino acid (1R,2S)-6 and its derivative (1R,2S)-
5 from glycine Schiff base (R)-8.
rendering the second S 2’ alkylation step of very high relative
stereochemical control.
N
1
95
4
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Br
O
O
N
O
O
O
O
N
H
H
Ni
Ni
Ni
H
Br
(S)
N
N
(R)
O
N
Ph
Ph
Ph
A
B
C
Br
H
Br
O
O
N
O
O
N
O
H
O
Ni
H
R)
Ni
Ni
(
N
N
(R)
N
O
Ph
Ph
Ph
A'
B'
C'
Fig. 3 Mechanistic consideration of the reactions under study.
2
5
1
3
4
4
5
5
6
6
5
0
5
0
5
0
5
acetone, 1:1). [α]D = +1875 (c 0.033, CHCl ). H NMR (300
3
Conclusions
MHz, CDCl
.35 (m, 3H), 7.27 (t, J = 7.6 Hz, 2H), 7.20-7.03 (m, 3H), 6.87 (d,
J = 6.3 Hz, 1H), 6.67-6.49 (m, 2H), 6.06 (dt, J = 15.0, 7.4 Hz,
H), 5.60 (dt, J = 15.1, 7.5 Hz, 1H), 4.35 (d, J = 12.6 Hz, 1H),
3.98-3.76 (m, 3H), 3.59-3.32 (m, 4H), 2.67 (d, J = 6.2 Hz, 1H),
3
) δ 8.17-8.04 (m, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.56-
7
5
To conclude, we have developed a new process for asymmetric
synthesis of 1-amino-2-vinylcyclopropanecarboxylic acid 6 via
sequential S 2–S 2’ dialkylation of chiral Ni(II) complex of
1
N
N
glycine Schiff base 8. We found that application of complex (S)-8
leads predominantly to the formation of amino acid 6 with
(1S,2R) absolute configuration, while the enantiomeric and
pharmaceutically important (1R,2S)-6 can be obtained using (R)-8
as the starting glycine derivative. The sequence of the reactions
includes PTC alkylation (S 2), homogeneous S 2’ cyclization
13
2
.61-2.31 (m, 3H), 2.09-1.91 (m, 2H). C NMR (75 MHz,
CDCl ) δ 180.8, 178.9, 171.6, 142.9, 134.3, 133.8, 133.5, 132.8,
32.0, 130.8, 130.3, 129.5, 129.3, 129.3, 128.1, 127.5, 126.7,
24.1, 121.2, 70.6, 63.5, 57.4, 37.9, 32.4, 31.2, 24.3. HRMS calcd
3
1
0
1
1
+
for C H BrN NiO [M+H] 630.0902, found 630.0915.
31
31
3
3
N
N
Synthesis of Ni(II) complexes of the Schiff base of (R)-N-
followed by disassembly of the resultant Ni(II) complex. All
reactions are conducted under operationally convenient
conditions and therefore can be reasonably (6 g) scaled up
rendering the presented method practically useful for preparation
of amino acid (1R,2S)-6 of high pharmaceutical importance.
(
benzylprolyl)-2-aminobenzophenone and trans-2-amino-6-
1
5
bromohex-4-enoic acid, (R)(2R)-9 and (R)(2S)-10. The above
procedure was performed starting from (R)-8 (6.0 g, 12.04
mmol) to give a 80:20 mixture of (R)(2R)-9 and (R)(2S)-10 (5.97
g, 78.5% yield).
Synthesis of Ni(II) complexes of the Schiff base of (S)-N-
3
5
36
Experimental
(
benzylprolyl)-2-aminobenzophenone
and
1-amino-2-
and
vinylcyclopropanecarboxylic acid,
(S)(2S,3R)-11
2
2
3
0
5
0
Synthesis of Ni(II) complexes of the Schiff base of (S)-N-
(S)(2R,3S)-12). NaOt-Bu (1.52 g, 15.84 mmol) was added to a
solution of a mixture of (S)(2S)-9 and (S)(2R)-10 (5.0 g, 7.92
mmol) in THF (100 mL) at 0 ºC. The reaction was monitored by
TLC (hexane–acetone, 1:1). After stirring at room temperature
for 0.5 h, a second portion of NaOt-Bu (1.52 g, 15.84 mmol) was
added. After 1 h, the mixture was poured into H O and extracted
with CH Cl . The organic phases were then dried over Na SO
4
and concentrated at reduced pressure. Purification by column
chromatography on silica (hexane–acetone, 1:1) afforded a
diastereomeric mixture (90:10 ratio) of (S)(2S,3R)-11 and
(S)(2R,3S)-12 (3.30 g, 75.8% yield). Further purification by
(benzylprolyl)-2-aminobenzophenone and trans-2-amino-6-
bromohex-4-enoic acid, (S)(2S)-9 and (S)(2R)-10. NaOH
19b
(
1
16.06 g, 401 mmol) was added to a mixture of (S)-8 (5.0 g,
0.04 mmol), trans-1,4-dibromo-2-butene (7.51 g, 35.10 mmol)
and n-Bu NI (927 mg, 2.51 mmol) in (CH Cl) (100 mL). The
4
2
2
reaction was monitored by TLC (CH Cl –acetone, 4:1). After
2
2
2
stirring at room temperature for 30 min, the mixture was diluted
with H O and extracted with CH Cl . The organic phases were
2
2
2
2
2
2
then dried over Na SO and concentrated at reduced pressure.
2
4
Purification by column chromatography on silica (CH Cl –
2
2
acetone, 4:1) afforded a diastereomeric mixture (78:22 ratio) of
column chromatography on silica (CH Cl –acetone, 10:1) was
(
(
S)(2S)-9 and (S)(2R)-10 (5.15 g, 81.3% yield). A pure fraction of
S)(2S)-9 was isolated for characterization purposes by further
2
2
carried out to isolate the pure products. Data of (S)(2S,3R)-11:
25
1
[
α]D = +866 (c 0.021, CHCl ). H NMR (400 MHz, CDCl ) δ
3 3
purification by column chromatography on silica (hexane–
8
.03 (d, J = 7.4 Hz, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.43 (t, J = 7.2
Journal Name, [year], [vol], 00–00 |
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Hz, 2H), 7.35 (t, J = 7.0 Hz, 1H), 7.27-7.19 (m, 3H), 7.08 (t, J =
for 20 h at room temperature. After the reaction was completed,
7
2
1
.4 Hz, 1H), 7.05-6.99 (m, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.57 (s, 60 the mixture was concentrated at reduced pressure to a volume
H), 5.71-5.56 (m, 1H), 5.49 (d, J = 16.8 Hz, 1H), 5.21 (d, J =
2.3 Hz, 1H), 4.25 (d, J = 12.6 Hz, 1H), 3.78 (s, 1H), 3.41 (d, J =
under 100 mL. The solution was adjusted to pH 2-3 with solid
citric acid and extracted with EtOAc (20 mL, 3 times). The
5
0
5
0
5
0
5
0
5
0
5
12.7 Hz, 1H), 3.38-3.30 (m, 2H), 2.75 (s, 1H), 2.54-2.40 (m, 1H),
organic layers were combined, washed with H O (20 mL) and aq.
2
2
0
1
1
.04 (s, 1H), 1.91 (dd, J = 18.4, 9.6 Hz, 2H), 1.50-1.40 (m, 1H),
sat. NaCl (20 mL), dried over Na SO , filtered and concentrated
2
4
1
3
.38-0.24 (m, 1H). C NMR (75 MHz, CDCl ) δ 180.0, 174.1, 65 at reduced pressure. The crude product (1.72 g, quant) obtained
3
65.9, 142.0, 135.1, 134.9, 133.4, 132.0, 131.3, 130.0, 129.4,
29.0, 128.9, 128.8, 128.5, 127.6, 127.4, 127.0, 126.2, 123.2,
as a yellow oil was dissolved in EtOAc (10 mL, 4 v/w).
Dicyclohexylamine (1.28 g, 0.00704 mol) was slowly added to
the mixture and stirred for 20 h at room temperature and then for
1 h at 0 ºC. The resulting white crystals were filtered and washed
1
1
2
2
3
3
4
4
5
5
122.0, 120.6, 118.2, 70.8, 62.9, 60.8, 56.9, 39.3, 30.6, 25.4, 23.5.
+
HRMS calcd for C H ClN NiO [M+H] 550.1641, found
3
1
30
3
3
2
5
5
50.1640. Data of (S)(2R,3S)-12: [α]D = –669 (c 0.034, CHCl3). 70 with iced EtOAc (10 mL) to afford (1R,2S)-14 (2.3 g, 80.0%
H NMR (300 MHz, CDCl ) δ 8.35 (dd, J = 8.7, 0.9 Hz, 1H),
1
1
yield). Mp: 178 ºC (dec.). H NMR (200 MHz, CD OD): δ 5.88
3
3
8
.10 (d, J = 6.7 Hz, 2H), 7.51-7.30 (m, 7H), 7.12 (ddd, J = 8.7,
(ddd, J = 17.3, 10.3, 9.8 Hz, 1H), 5.15 (dd, J = 17.3, 2.2 Hz, 1H),
4.92 (dd, J = 10.3, 2.2 Hz, 1H), 3.22-3.06 (m, 2H), 2.16-1.61 (m,
6.8, 1.8 Hz, 2H), 6.93 (s, 1H), 6.67 (dd, J = 8.4, 1.7 Hz, 1H), 6.59
ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 5.83-5.63 (m, 1H), 5.32 (dd, J =
13
(
13H), 1.43 (s, 9H), 1.49-1.10 (m, 10H). C NMR (50.3 MHz,
1
1
3
7.1, 1.6 Hz, 1H), 5.13 (dd, J = 10.3, 1.7 Hz, 1H), 4.50 (d, J = 75 CD OD): δ 177.5, 158.1, 138.4, 115.3, 80.0, 54.4, 44.0, 33.4,
2.9 Hz, 1H), 4.19-4.05 (m, 1H), 3.47 (dd, J = 9.4, 4.3 Hz, 1H),
.18 (d, J = 12.9 Hz, 1H), 2.68-2.44 (m, 2H), 2.20-2.02 (m, 2H),
3
30.7, 29.0, 26.3, 25.7, 23.1.
Synthesis of methyl (1R,2S)-1-(tert-butoxycarbonylamino)-
2-vinylcyclopropanecarboxylate, (1R,2S)-15. 5% aq. AcOH (8
mL) was dropped to a suspension of (1R,2S)-14 (800 mg, 1.958
1.97-1.80 (m, 2H), 1.50-1.43 (m, 1H), 0.48 (dd, J = 9.9, 6.7 Hz,
13
1
H). C NMR (75 MHz, CDCl ) δ 182.1, 175.4, 167.4, 143.2,
3
1
36.0, 135.1, 134.3, 134.0, 132.8, 132.0, 130.3, 129.5, 129.0, 80 mmol) in EtOAc (8 mL) kept under 3 ºC and the mixture was
1
3
27.8, 127.3, 123.3, 120.8, 118.1, 69.0, 61.7, 60.8, 59.0, 39.2,
stirred for 30 minutes. After the reaction was completed the
organic solvent was separated and the aqueous layer was
extracted with EtOAc (25 mL, 3 times). The organic layers were
+
0.8, 26.7, 23.8. HRMS calcd for C H ClN NiO [M+H]
3
1
30
3
3
550.1641, found 550.1652.
Synthesis of Ni(II) complexes of the Schiff base of (R)-N-
combined, washed with H O (25 mL, 2 times), dried over
2
(
benzylprolyl)-2-aminobenzophenone
and
1-amino-2- 85 Na SO , filtered and concentrated at reduced pressure affording
2 4
vinylcyclopropanecarboxylic acid,
(R)(2R,3S)-11
and
472 mg, of product as a colourless oil. 400 mg of this material
was dissolved in a mixture of methanol (4 mL) and toluene (20
mL), and TMSCHN (2M in Et O, 1.144 mL, 2.288 mmol) was
(
R)(2S,3R)-12). The above procedure was performed starting
from a mixture of (R)(2R)-9 and (R)(2S)-10 (3.15 g, 5 mmol) to
give a 90:10 mixture of (R)(2R,3S)-11 and (R)(2S,3R)-12 (2.57 g,
2
2
added. The mixture was stirred for 30 minutes at room
7
3.4% yield). NMR data of both compounds matched those 90 temperature, and then it was quenched with 5% AcOH and
25
obtained for their enantiomers. For (R)(2R,3S)-11: [α] = –930
concentrated at reduced pressure. The crude was purified by
silica-gel column chromatography (hexane:EtOAc = 20:1) to give
(1R,2S)-15 as a colorless oil (360 mg, 84% yield). Its NMR data
D
2
5
(
c 0.08, CHCl ). For (R)(2S,3R)-12: [α]
= +705 (c 0.08,
3
D
CHCl3).
Synthesis
vinylcyclopropanecarboxylic acid, (1R,2S)-6. Aqueous 1N HCl 95 MeOH), lit. data: [α]D = +42.8 (c 1.00, MeOH). The optical
16a
25
of
(1R,2S)-1-amino-2-
matched those previously described. [α]D = +39.4 (c 0.45,
25
16a
(
20 mL) was added to a suspension of (R)(2R,3S)-11 (1.0 g, 1.82
purity of (1R,2S)-15 was determined as 98.6% ee by HPLC on a
ChiralCel OD-H column (5 µm, 250x4.6 mm i.d.), eluent: 1.0%
EtOH in hexane isocratic, flow rate: 0.75 mL/min, temp.: 25 ºC,
detector: UV 200 nm (t = 16.64 min for (1R,2S)-15, t = 19.17 min
mmol) in MeOH (20 mL) and the reaction mixture was stirred for
1 h at 50 ºC. After the reaction was completed, the mixture was
concentrated at reduced pressure. H O (50 mL) and EtOAc (50
2
mL) were added to the residue and then the phases were 100 for (1S,2R)-15).
separated. The aqueous layer was washed with EtOAc (50 mL)
and then concentrated at reduced pressure. The residue from the
Acknowledgments
aqueous portion was dissolved in DI H O (100 mL), placed on a
2
We thank IKERBASQUE, Basque Foundation for Science; the
Basque Government (SAIOTEK S-PE13UN098), the Spanish
Ministry of Science and Innovation (CTQ2010-19974) and
05 Hamari Chemicals (Osaka, Japan) for generous financial support.
We also thank SGIker (UPV/EHU) for HRMS analyses.
cation-exchange Dowex-50 resin column and eluted first with DI
H O, until neutral pH, followed by 8% NH OH to elute the free
2
4
amino acid. This solution was evaporated to afford the crude
1R,2S)-6 (186 mg, 80.5% yield). On the other hand, the organic
layer was washed by H O (100 mL), 4% NH OH (20 mL, 2
1
(
2
4
times) and aq. sat. NaCl (100 mL), dried over Na SO , filtered
2
4
Notes and references
and concentrated at reduced pressure to afford (R)-13 (0.65 g,
a
9
2.8% yield).
Synthesis of dicyclohexylammonium (1R,2S)-N-(tert-
Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka
533-0024, Japan
b
10 School of Chemistry and Chemical Engineering, Nanjing University,
1
1
butoxycarbonyl)-1-amino-2-vinylcyclopropanecarboxylate,
Nanjing, 210093, China. Fax: +86-25-83686133; Tel: +86-25-83686133;
E-mail: hanjl@nju.edu.cn
(
1R,2S)-14. Boc O (2.46 g, 0.01126 mol) and Et N (1.14 g,
2 3
0
0
.1126 mol) were added to a solution of (1R,2S)-6 (0,894 g,
c
Department of Organic Chemistry I, Faculty of Chemistry, University of
.00704 mol) in H O (20 mL) and acetone (20 mL) and stirred
the Basque Country UPV/EHU, 20018 San Sebastián, Spain. Fax: +34
15 943-015270; Tel: +34 943-015177; E-mail: vadym.soloshonok@ehu.es
2
6
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d
IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3,
E. Nizi, S. S. Carroll, S. W. Ludmerer, C. Burlein, J. M. DiMuzio, D.
J. Graham, C. M. McHale, M. W. Stahlhut, D. B. Olsen, E.
Monteagudo, S. Cianetti, C. Giuliano, V. Pucci, N. Trainor, C. M.
Fandozzi, M. Rowley, P. J. Coleman, J. P. Vacca, V. Summa and N.
J. Liverton, ACS Med. Chem. Lett., 2012, 3, 332–336.
4
8013 Bilbao, Spain
Electronic Supplementary Information (ESI) available: Copies of
1
†
H
1
3
and C NMR spectra and HPLC analysis of compound (1R,2S)-15. See
DOI: 10.1039/b000000x/
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DOI: 10.1039/C4RA12658K
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36 The synthesis of (R)-8 was carried out following the procedure
described in ref. 19b starting from (R)-proline.
8
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