A short scalable route to (-)-α-kainic acid using Pt-catalyzed direct allylic amination

Article abstract of DOI:10.1002/chem.201406557

An increased supply of scarce or inaccessible natural products is essential for the development of more sophisticated pharmaceutical agents and biological tools, and thus the development of atom-economical, step-economical and scalable processes to access these natural products is in high demand. Herein we report the development of a short, scalable total synthesis of (-)-α-kainic acid, a useful compound in neuropharmacology that is, however, limited in supply from natural resources. The synthesis features sequential platinum-catalyzed direct allylic aminations and thermal ene-cyclization, enabling the gram-scale synthesis of (-)-α-kainic acid in six steps and 34% overall yield.

Full text of DOI:10.1002/chem.201406557

DOI: 10.1002/chem.201406557
Communication
&
Total Synthesis
A Short Scalable Route to (À)-a-Kainic Acid Using Pt-Catalyzed
Direct Allylic Amination
Ming Zhang,[a] Kenji Watanabe,[a] Masafumi Tsukamoto,[a] Ryozo Shibuya,[a]
Hiroyuki Morimoto,[a] and Takashi Ohshima*[a, b]
neural-excitability effect and is widely used in neuropharmaco-
Abstract: An increased supply of scarce or inaccessible
logical studies of the mechanisms of neuronal apoptosis,[4]
natural products is essential for the development of more
amyotrophic lateral sclerosis,[5] Alzheimer’s disease,[6] and Hun-
sophisticated pharmaceutical agents and biological tools,
tington’s disease.[7] The huge demand for (À)-a-kainic acid (1)
and thus the development of atom-economical, step-eco-
in the neuroscience field and its limited supply from natural
nomical and scalable processes to access these natural
sources has resulted in a worldwide shortage and a high price
of 1.[8] Although 1 is a potential target for total synthesis, the
construction of three contiguous stereogenic centers in the
products is in high demand. Herein we report the devel-
opment of a short, scalable total synthesis of (À)-a-kainic
acid, a useful compound in neuropharmacology that is,
pyrrolidine ring, especially the thermodynamically less favora-
ble C3–C4 cis configuration, is highly challenging.[9] Since the
however, limited in supply from natural resources. The
synthesis features sequential platinum-catalyzed direct
pioneering achievement of the enantioselective synthesis of
1 by Oppolzer and Thirring,[10] several efficient total syntheses
allylic aminations and thermal ene-cyclization, enabling
the gram-scale synthesis of (À)-a-kainic acid in six steps
of 1 have been reported.[11] Recently, Fukuyama and co-
workers accomplished a multigram-scale practical synthesis of
1 using an intramolecular olefin ring-closing metathesis, but
the process required 13 linear steps.[11ai] Lin and co-workers re-
ported the shortest synthesis of 1 (7 steps) with approximately
40% overall yield, but the process provided 1 only on a scale
of less than 50 mg.[11an] Thus, there remains much room to
and 34% overall yield.
The dramatic evolution of organic chemistry in the twentieth
century enabled the syntheses of many complex molecules, in-
cluding highly functionalized natural products.[1] An increased
supply of scarce or inaccessible natural products is essential
for the production of more sophisticated pharmaceutical
agents and biological tools. Practical syntheses of such
complex molecules, however, remain quite difficult, even with
modern organic chemistry techniques, and thus the
development of highly practical, atom-economical, and step-
economical processes is in high demand.[2]
develop
a highly practical, atom-economical, and step-
economical process of 1.
Herein we disclose a short and scalable synthesis of (À)-a-
kainic acid (1), featuring sequential platinum-catalyzed direct
allylic aminations and ene-cyclization. A gram-scale synthesis
of 1 also proceeded with the same efficiency to afford chemi-
cally and optically pure crystalline 1 in 6 steps and 34-37%
overall yield. Moreover, a one-pot process of Pt-catalyzed allylic
amination and ene-cyclization further improved the pot-
economy of the whole process to only 5 pots.
(À)-a-Kainic acid (1), a member of the kainoid family con-
taining a glutamic acid scaffold[3] (Figure 1), exhibits a potent
To satisfy the global demand for (À)-a-kainic acid (1) in an
environmentally friendly manner, we planned to develop an
atom- and step-economical scalable production of 1. We re-
cently reported the successful development of a direct catalyt-
ic substitution of allylic alcohols with aryl amines, alkyl amines,
ammonia, or carbon nucleophiles, promoted by the combina-
tion of [Pt(cod)Cl2] and a large bite-angle ligand, DPEphos or
Xantphos (Scheme 1).[12] This process proceeded in a highly
Figure 1. Structures of (À)-a-kainic acid, kainoids, and l-glutamic acid.
[a] Dr. M. Zhang, Dr. K. Watanabe, M. Tsukamoto, R. Shibuya, Dr. H. Morimoto,
Dr. T. Ohshima
Graduate School of Pharmaceutical Science, Kyushu University
3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582 (Japan)
E-mail: ohshima@phar.kyushu-u.ac.jp
Homepage: http://green.phar.kyushu-u.ac.jp
[b] Dr. T. Ohshima
CREST, JST
3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406557.
Scheme 1. Pt-catalyzed direct catalytic substitution of allylic alcohols.
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monoallylation-selective manner to afford the desired monoal-
lylation products in high yield, because a sterically congested
p-allyl–Pt intermediate created by the large bite angle ligand
allows for a preferential selective reaction with the substrate
over the monoallylated products, thereby preventing problem-
atic over-reactions.[13] This process does not require the pre-ac-
tivation of allylic alcohols, and produces the desired allylated
products together with water as the sole coproduct. In terms
of atom-economical and environmental aspects, this is a more
straightforward and desirable method than conventional
transition-metal catalyses, which require pre-activated allylic
alcohols such as allylic acetates and carbonates. We therefore
envisioned the use of this Pt catalysis for the construction of
diallylamine 3 having different allyl moieties from allylic
alcohol 5 and alkenyl epoxide 4 (Scheme 2). Subsequent ene-
cyclization would provide fully functionalized pyrrolidine 2 in
a diastereoselective manner.
and 7b in 74% and 81% yield, respectively, without undesired
over diallylation or b-hydride elimination. Excess DMB amine
6b was recovered quantitatively by column chromatography.
The product 7b was also obtained in 77% yield under conven-
tional heating conditions (48 h), and we selected this condition
for the large-scale production of 7b (see below).
The second allylation reaction to give diallyl product 3 was
key to the synthesis of 1. First, we examined ethyl 4,5-dihy-
droxy-2-butenoate and its acetonide derivative as an electro-
phile, but, despite intensive investigation of the reaction condi-
tions, only a trace amount of the desired coupling product
was obtained due to the presence of an electron-withdrawing
ester group, which greatly reduced the electron density of the
C=C double bond and diminished the reactivity towards p-allyl
complex formation.[13] Next, we examined the more reactive
alkenyl epoxide 4 as the electrophile. Because the electrophil-
icity of alkenyl epoxide 4 was higher than that of the allylic
alcohol, an epoxide-opening reaction proceeded without
any reagent or catalyst, but amine 7 attacked only the less-
hindered terminal position (d-position) to give regioisomer 3’.
We also examined various Brønsted and Lewis acids as well as
base additives, but these conditions gave only an inseparable
mixture of regioisomers (3a/3a’=1:2–4). Under transition-
metal catalyzed allylic amination conditions, the amine nucleo-
phile was expected to attack the desired allylic position (g-po-
sition) to give diallylamine 3 in a highly regioselective manner
because the reaction proceeds through a p-allyl–metal com-
plex, but Pd catalyst[14] also gave a mixture of regioisomers
(3a/3a’=1.2:1).[13] Under the optimized conditions for the Pt
catalysis, the desired coupling reaction of (Æ)-4a[13] with 7a
proceeded to give the desired diallylamine 3a, suggesting the
superiority of the Pt catalysis, although the yield of 3a was
only 34% and unexpected dienylamine byproduct 8a was ob-
tained in 16% yield (Scheme 4). Although 8a was first thought
to be formed via regioisomer 3a’, treatment of isolated 3a’
under the same Pt catalysis conditions did not give 8a. Finally
we found that 8a was produced from 3a under Pt catalysis
conditions, probably through retro-reaction (p-allyl–Pt
formation) or aziridinium cation formation and the following
b-hydride elimination.[13] This side reaction was effectively
suppressed by decreasing the reaction temperature to room
temperature, and after optimizing the reaction conditions
the desired product 3a was obtained in 95% yield without
the formation of 8a.
Scheme 2. Retrosynthetic analysis for (À)-a-kainic acid (1).
The synthesis of (À)-a-kainic acid 1 commenced with the
direct amination of a,a-disubstituted allylic alcohol 5 rather
than g,g-dimethyl allylic alcohol 5’, because platinum catalysis
is more strongly affected by steric congestion around the C=C
double bond in the allylic alcohol than that around the
hydroxy group[12] (Scheme 3). Initially, 4-methoxybenzyl (PMB)
For the synthesis of (À)-a-kainic acid 1, (S)-4 was designed
as the coupling partner of amine 7 because platinum-catalyzed
allylation via a p-allyl complex was expected to proceed with
double inversion of the chiral center. From commercially avail-
able optically pure (S)-glycidol 9, the epoxide (S)-4b was syn-
thesized in 85% yield without loss of enantiopurity (>99% ee)
by a one-pot sequential catalytic 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO) oxidation and Wittig reaction (Scheme 5).[13]
When chiral epoxide (S)-4b was used as the substrate for
the second allylation, the reaction afforded 3b in 94% yield,
but partial epimerization occurred (92% ee) (Table 1, entry 1).
To accelerate nucleophilic attack of allylamine 7b to p-allyl–Pt
intermediate in preference to undesired epimerization, we
Scheme 3. Synthesis of monoallylamine 7 using Pt-catalyzed direct
amination of allylic alcohol 5.
amine (6a) was examined as a nitrogen nucleophile, but we fi-
nally selected 2,4-dimethoxybenzyl (DMB) amine (6b), because
of the ease of removing the DMB group under acidic condi-
tions in the last stage of the synthesis. Although combining
the alkylamine and the alkyl-substituted allylic alcohol was dif-
ficult due to the low reactivity and potential risk of b-hydride
elimination, respectively, the Pt-catalyzed direct substitution of
5 with 6a and 6b proceeded smoothly under microwave heat-
ing conditions (3 h) to give the desired monoallylamines 7a
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With the desired chiral diallylamine 3b in hand, we then
performed an ene-cyclization to construct the pyrrolidine ring
with three contiguous stereogenic centers. Based on the previ-
ous synthesis of a structurally related compound,[10] a toluene
solution of 3b was heated at 1358C in a sealed tube, and the
desired cyclized compound 2b was obtained in 70% yield
with 10:1 diastereoselectivity (minor diastereoisomer 2b’ was
the allokainic acid-type C-4 epimer; Scheme 6). For large-scale
Scheme 6. Synthesis of pyrrolidine 2b using thermal ene-cyclization.
production, we changed the solvent to xylene, allowing this
thermal reaction to proceed with ordinal open reactors. The
addition of a catalytic amount of iPr2NEt effectively prevented
the partial decomposition of the substrate, and under the
optimized conditions 2b was obtained in 75% yield with
higher diastereoselectivity (14:1).
Scheme 4. Synthesis of diallylamine 3a using Pt-catalyzed amination of
(Æ)-4a.
To make our synthesis more sophisticated, we considered
“pot economy,” which allows the elimination of several purifi-
cation steps, to minimize the generation of waste chemicals
and save time.[15] We therefore tackled a one-pot sequential Pt-
catalyzed epoxide opening and ene-cyclization process. After
the first Pt-catalyzed reaction of of alkenyl epoxide 4b with
allylamine 7b at room temperature, the reaction mixture was
heated to 1358C. This one-pot procedure gave the desired
pyrrolidine 2b, but the yield of isolated 2b was only 35% and
dienylamine 8b was obtained as the major product (48%;
Scheme 7). Based on the aforementioned mechanism of the
Scheme 5. One-pot synthesis of optically pure alkenyl epoxide (S)-4b.
Table 1. Concentration effects on Pt-catalyzed allylic amination of (S)-4b.
Entry
Concentration [m]
Yield [%][a]
ee [%][b]
1
2
3
0.25
0.40
0.50
94
93
95
93
95
98
[a] Yield of isolated product; [b] ee was determined by chiral HPLC (Chiral-
pak OD3, hexane/iPrOH/DEA=98:2:0.1, 1 mLminÀ1, l=254 nm).
Scheme 7. One-pot sequential Pt-catalyzed allylic amination and ene-
cyclization process.
screened various conditions and finally found that higher
concentration conditions (0.5m) efficiently suppressed the epi-
merization, and the desired product was obtained in 95% yield
and 98% ee (Table 1, entry 3). The absolute configuration of 3b
was determined to be S, after its conversion into the final
formation of 8 through Pt-catalyzed reaction at high tempera-
ture, we anticipated that the addition of a platinum scavenger
before the ene-cyclization step might prevent such an unde-
sired side reaction. Indeed, the addition of 2-aminoethanethiol
or silica-supported dimercaptotriazine effectively suppressed
the formation of 9b and greatly improved the yield of 2b to
70% (2 steps from 4b) with 14:1 diastereoselectivity.[13,16]
product (À)-a-kainic acid
1 (see below), indicating that
the reaction proceeded with the expected double-inversion
mechanism.
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Completion of the total synthesis of (À)-a-kainic acid 1 re-
quired the oxidation of primary alcohol to carboxylic acid and
the removal of the DMB and tBu groups of 2b. We screened
several common oxidation conditions for the oxidation of
primary alcohol 2b to carboxylic acid 10b, such as TEMPO,
2-azaadamantane N-oxyl (AZADO), tetrapropylammonium
perruthenate (TPAP), pyridinium dichromate (PDC), and Jones
oxidation. Among them, only classical Jones oxidation gave
satisfactory results (full conversion of 2b; Scheme 8). Even
HPLC analysis after conversion to N-4-nitrobenzyoyl-kainic acid
11.
Finally, to demonstrate the practicality of this process, we
conducted a gram-scale synthesis of (À)-a-kainic acid 1. All re-
actions (8.6 to 95 mmol scale) proceeded with nearly identical
efficiency, and 1.11 g of pure 1 was obtained in 34% overall
yield in an only 6-step chemical transformation (Scheme 9).
Scheme 9. Gram-scale synthesis of (À)-a-kainic acid.
In conclusion, we have achieved the shortest total synthesis
of (À)-a-kainic acid reported to date from commercially avail-
able allylic alcohol 5 and (S)-glycidol 9 (6 steps, 34–37% overall
yield). The key intermediate, diallylamine 3b, was synthesized
using platinum-catalyzed allylic amination reactions with high
monoallylation selectivity and regioselectivity. This process can
be performed with ordinary equipment and readily available
reagents and does not require any special operation or cryo-
genic conditions, suggesting the potential of our synthetic
protocol to supply the global demand for (À)-a-kainic acid in
an efficient and environmentally friendly manner. Further
investigation for large-scale production using a flow system is
ongoing in our laboratory.
Scheme 8. Completion of total synthesis of (À)-a-kainic acid 1 from 2b and
determination of its optical purity.
when the amount of CrO3 was reduced to 1.5 mol% with 5.0
equivalents of terminal oxidant H5IO6, the reaction proceeded
with the same efficiency. After oxidation, crude material was
passed through a short silica-gel column to remove chromium
metal, and then subjected to the final deprotection process. In
our initial studies using N-PMB-protected analog 2a or 10a in-
stead of DMB-protected 2b or 10b, the PMB group showed
substantial resistance to acids and oxidants as follows: 1) Reac-
tions under strongly acidic conditions lead to decomposition
or formation of undesired isokainic acid- and d-lactone-type
byproducts, and 2) reactions with oxidants such as cerium(IV)
ammonium nitrate (CAN) afforded only low yields (20–30%) of
the corresponding free amine. To our delight, both DMB and
tBu groups were easily removed under mildly acidic conditions
using trifluoroacetic acid (TFA) with Et3SiH to give (À)-a-kainic
acid 1 in >80% yield (NMR yield). Further purification by
recrystallization of the crude material from ethanol afforded
Acknowledgements
This work was financially supported by Grant-in-Aid for Scien-
tific Research (B) (No. 24390004), Scientific Research on Innova-
tive Areas (No. 24106733) and Platform for Drug Discovery, In-
formatics, and Structural Life Science from MEXT, and CREST
from JST. M.Z. acknowledges financial support from Kobayashi
International Scholarship Foundation. R.S. is the grateful
recipient of a scholarship from JSPS.
Keywords: allylic amination · amino acids · homogeneous
catalysis · platinum · total synthesis
optically pure
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[16] Chemically and optically pure 2b can be obtained by recrystallization
of a diastereomixture of 2b (d.r.=14:1).
Received: December 19, 2014
Published online on && &&, 0000
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COMMUNICATION
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Total Synthesis
M. Zhang, K. Watanabe, M. Tsukamoto,
R. Shibuya, H. Morimoto, T. Ohshima*
&& – &&
A Short Scalable Route to (À)-a-Kainic
Acid Using Pt-Catalyzed Direct Allylic
Amination
Kainoid enabled: A short and scalable
synthesis of (À)-a-kainic acid, featuring
sequential platinum-catalyzed direct
allylic aminations and ene-cyclization is
reported. Gram-scale synthesis of (À)-a-
kainic acid proceeds with high efficiency
to afford the chemically and optically
pure crystalline product in six steps and
34% overall yield.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!