Facile synthesis of (+)-α-allokainic acid via Pd-catalyzed hydrogenolysis of allyl acetate derived from trans-4-hydroxy-L-proline

Article abstract of DOI:10.1016/S0040-4039(01)01440-X

Pd(PPh₃)₄/PPh₃-catalyzed hydrogenolysis of 3a derived from trans-4-hydroxy-L-proline using ammonium formate as a hydride reagent, provides olefin 4 as a major product, which is hydrolyzed to give (+)-α-allokainic acid.

Full text of DOI:10.1016/S0040-4039(01)01440-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6929–6931
Facile synthesis of (+)-a-allokainic acid via Pd-catalyzed
hydrogenolysis of allyl acetate derived from
trans-4-hydroxy- -proline
L
Dawei Ma,* Wengen Wu and Ping Deng
State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 30 May 2001; revised 23 July 2001; accepted 3 August 2001
Abstract—Pd(PPh3)4/PPh3-catalyzed hydrogenolysis of 3a derived from trans-4-hydroxy-L-proline using ammonium formate as a
hydride reagent, provides olefin 4 as a major product, which is hydrolyzed to give (+)-a-allokainic acid. © 2001 Elsevier Science
Ltd. All rights reserved.
Due to their marked biological activity in particular
neuroexcitatory activity in the mammalian central ner-
vous system, caused by acting at the kainate subtype of
ionotropic glutamate receptors, kainic acid and a-allok-
inaic acid have become attractive synthetic targets in
the past two decades.1,2 Over 20 different synthetic
routes to these compounds have been reported, how-
ever, most of the reported protocols suffer from taking
long steps, using expensive reagents, or handling of the
reactions under sensitive conditions.1,2 Herein, we wish
to describe a convenient route to (+)-a-allokainic acid
using a known compound 13 as a key intermediate
(Scheme 1).
be cleaved in a regioselective and stereoselective man-
ner, we would obtain protected (−)-kainic acid or (+)-a-
allokainic acid efficiently. Thus, a study toward the
Pd-catalyzed hydrogenolysis4 of 3 was undertaken and
the results are summarized in Table 1.
As shown in Table 1, in most cases, this hydrogenolysis
reaction gave olefin 4 as the major product. Its 4-
epimer 5, and regioisomer 6 were also isolated as minor
products. In some cases, diene 7 was isolated. The ratio
for these products was dependent on the catalytic sys-
tems, hydride reagent, or reaction temperature. The
best selectivity was observed when Pd(PPh3)4/PPh3 was
used as a catalytic system, HCO2NH4 was used as a
hydride reagent, and the reaction was carried out in
refluxing THF. In this case the olefin 4 was isolated in
69% yield (entry 1). Changing the palladium source or
the hydride reagent slightly reduced the selectivity
(compare entries 1–4). When dppp was used as the
ligand, the major product was the diene 7, which indi-
cated that this ligand promoted b-hydrogen elimination
in this case (entry 5). It was reported that tri-n-
As outlined in Scheme 2, we synthesized the ketone 1
from trans-4-hydroxy-L-proline in six steps according
to a known procedure.3 Reaction of 1 with 2-propenyl-
magnesium bromide afforded allyl alcohol 2 in 62%
yield as a mixture of two diastereomers in a ratio of
2/1. Acylation of 2 with acetyl chloride, methyl chloro-
formate, or benzoyl chloride provided 3a, 3b or 3c,
respectively. Obviously, if the O-acyl groups of 3 could
O
CO2Bu-t
CO2H
CO2H
CO2H
CO2Me
N
CO2H
N
H
N
H
COPh
kainic acid
allokainic acid
1
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01440-X

6930
D. Ma et al. / Tetrahedron Letters 42 (2001) 6929–6931
MgBr
OH
OCOR
O
Ac2O/DMAP/Et3N for 3a
NaHMDS then
CO2Bu-t
CO2Bu-t
CO2Bu-t
CO2Me
CO2Me
THF, -78 oC
62%
CO2Me
ClCO2Me for 3b
PhCOCl/DMAP/NEt3 for 3c
N
N
N
COPh
COPh
COPh
3a: R = Me, 98%
3b: R = OMe, 46%
3c: R = Ph, 94%
1
2
see
Table 1
CO2Bu-t
CO2Bu-t
CO2Bu-t
CO2Bu-t
CO2Me
+
+
+
CO2Me
CO2Me
CO2Me
N
N
N
N
COPh
COPh
COPh
COPh
4
6
5
7
Scheme 2.
Table 1. Pd-catalyzed hydrogenolysis of 3a
Entry
Substrate
Catalyst
Ligand
Hydride reagentb
Solvent
Yield (%)c
4
5
6
7
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
Ph(Ph3P)4
Pd(OAc)2
Ph(Ph3P)4
Pd(OAc)2
Pd(OAc)2
Ph(Ph3P)4
Pd(OAc)2
Ph(Ph3P)4
Pd(OAc)2
Ph(Ph3P)4
Ph(Ph3P)4
PPh3
PPh3
PPh3
PPh3
A
A
B
THF
THF
THF
THF
THF
THF
THF
1,4-dioxane
1,4-dioxane
THF
69
62
57
53
–
15
17
28
27
–
–
–
20
19
20
16
8
8
8
10
–
–
–
7
6
–
–
–
–
B
dppp
A
A
B
A
A
A
A
46d
–
P(Bu-n)3
P(Bu-n)3
PPh3
PPh3
PPh3
34d
31d
50
50
57
37
–
13
9
8
–
9
10
11
8
10
PPh3
THF
a Reaction conditions: 3 (0.5 mmol), catalyst (0.025 mmol), ligand (0.1 mmol), hydride reagent (1.0 mmol), refluxed in indicated solvent for 2 h
(in 1,4-dioxane) or 6–12 h (in THF).
b A: HCO2NH4; B: HCO2H/NEt3.
c Isolated yield.
d Some unidentified products were isolated.
and B might form, which are attacked by hydride from
the rear of the Pd species to produce either olefin 4 or
5. There is a stronger steric interaction between the Pd
species and the 3-substituent in the intermediate B, and
so the intermediate A should be more stable than B,
thereby giving the olefin 4 as the major product.
butylphosphine was a better ligand for terminal olefin
formation,4b however, in the present reaction it led to
formation of other side products (entries 6 and 7). In
addition, either raising the reaction temperature or
using other esters also reduced the selectivity (compare
entries 1 and 8, 1 and 10, 11).
Refluxing olefin 4 in aqueous sodium hydroxide fol-
lowed by a purification with Dowex-50W provided
(+)-a-allokainic acid5 in 75% yield. Thus, we have
The stereochemical outcome of this hydrogenolysis
reaction is illustrated in Fig. 1. After reaction of allyl
esters 3 with Pd(0), two (p-allyl)palladium complexes A
L
L
L'
L'
OCOR
Pd
Pd
CO2Bu-t
CO2Bu-t
[Pd]
CO2Bu-t
+
H-
CO2Me
H-
N
CO2Me
CO2Me
N
N
COPh
COPh
COPh
3
A
B
5
4
Figure 1.

D. Ma et al. / Tetrahedron Letters 42 (2001) 6929–6931
6931
CO2Bu-t
CO2Bu-t
CO2H
CO2H
CO2H
CO2H
4 N NaOH
4 N NaOH
CO2Me
CO2Me
reflux
75%
reflux
50%
N
N
N
H
N
H
COPh
COPh
4
(+)-α-allokainic acid
5
(-)-kainic acid
Scheme 3.
developed a 10-step route to (+)-a-allokainic acid in
12% overall yield. Similarly, the olefin 5 was converted
into (−)-kainic acid in 50% yield (Scheme 3). Attempts
to improve the selectivity for 5 by changing the sub-
strates in order to develop an efficient synthesis for
(−)-kainic acid is being pursued in our laboratory.
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Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 29725205), and Qiu Shi Science & Tech-
nologies Foundation for their financial support.
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