Progress in the synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1080/00397911.2010.515327

Causing neuronal death, kainic acid and its derivatives are toxic to several known animal species, including rats. Kainic acid and its derivatives have been shown to cause neuroexcitatory activity observed in several neurological disorders. In this research project, a synthetic route that involves control of the stereochemistry to synthesize a pure stereoisomer of kainic acid is proposed. The pure stereoisomer possesses certain medical properties of interest to pharmacological companies. This laboratory synthesis is gaining popularity and increasing importance all over the world because extraction from seaweeds, where kainic acid is found, does not produce reasonable yields. This laboratory procedure will attempt to synthesize kainic acid using an ENE reaction in the final step of the 12 steps as shown in the graphical abstract. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515327

Synthetic Communications1, 41: 2539–2543, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515327
PROGRESS IN THE SYNTHESIS OF (ꢀ)-a-KAINIC ACID
Nandeo Choony, Lisa James, and Courtney Rabun
Department of Chemistry and Physics, University of South Carolina–Aiken,
Aiken, South Carolina, USA
GRAPHICAL ABSTRACT
Abstract Causing neuronal death, kainic acid and its derivatives are toxic to several known
animal species, including rats. Kainic acid and its derivatives have been shown to cause neu-
roexcitatory activity observed in several neurological disorders. In this research project, a
synthetic route that involves control of the stereochemistry to synthesize a pure stereoisomer
of kainic acid is proposed. The pure stereoisomer possesses certain medical properties of
interest to pharmacological companies. This laboratory synthesis is gaining popularity
and increasing importance all over the world because extraction from seaweeds, where kai-
nic acid is found, does not produce reasonable yields. This laboratory procedure will attempt
to synthesize kainic acid using an ENE reaction in the final step of the 12 steps as shown in
the graphical abstract.
Keywords ENE reaction; kainic acid; OBO protecting group
INTRODUCTION
b-Hydroxy a-amino acids are an important class of compounds because
of their inherent biological activities.[4] They are structural components of many
complex biomolecules, such as D-allo-threonine, found in antibiotics such as katano-
sins and accuminatum. They have also been used as intermediates in the synthesis of
many other compounds.[5] Kainic acid is a natural product that was first isolated
from red algae found in Japan.[7] This structure is analogous to L-glutamate, an
excitatory amino acid, which causes permanent structural adjustments to several
brain regions as shown by hippocampal malfunction in adult rats. Administration
of this toxic substance can cause seizure activity such as kindling in rats, neuronal
loss, and rearrangement of synaptic associations. It also induces heightened neuronal
stimulation, causing hyperexcitability.[1] This compound has been used in studying
several neurological disorders including, but not limited to, epilepsy, Alzheimer’s,
Received January 29, 2010.
Address correspondence to Nandeo Choony, Department of Chemistry and Physics, University of
South Carolina–Aiken, Aiken, SC 29801, USA. E-mail: nandeoc@usca.edu
2539

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N. CHOONY, L. JAMES, AND C. RABUN
and Huntington’s diseases.[7] Despite its many harmful side effects, pure stereo-
isomers of kainic acid can be used in treatment of the previously mentioned diseases
as well as other neurological disorders.[1,7]
OBJECTIVE
The goal of this project is to use L-serine, a b-hydroxy a-amino acid, to syn-
thesize a pure stereoisomer of kainic acid that has limited harmful side effects in
which pharmacological means may enable the treatment of neurological diseases.
An attempt is under way to synthesize kainic acid in the laboratory in 12 steps as
shown in Scheme 1. The key step for this scheme is the synthesis of the enantiomeri-
cally pure N-protected L-serine-4-methyl-2,6,7-trioxabicyclo[2.2.2] ortho ester
(OBO) (7) to prevent epimerization at the a-carbon in 6 during allylation at the
nitrogen atom[5] followed by the ene reaction.[6,7]
EXPERIMENTAL
Melting points were obtained on a Kofler hot-stage apparatus. 1H NMR spec-
tra were obtained on a Varian Mercury 400-MHz instrument, using CDCl3 solutions
with tetramethylsilane (TMS) as internal reference, unless otherwise indicated. d
values are given in parts per million (ppm), and coupling constants are given in hertz
(Hz). Subscript letters refer to the hydrogen assignments as noted in the numbered
structures. Thin-layer chromatography (TLC) was carried out on 0.25-mm GF60A
silica plates, and column chromatography utilized Sorbisil silica. Solvent ratios are
in volumes prior to mixing. Dichloromethane (DCM) solvent was dried over calcium
chloride and then distilled. Reaction solvents were purified and dried according to
literature methods.[8] Extraction solvents were removed under reduced pressure using
the rotary evaporator. Petroleum ether refers to the fraction of boiling range between
40 and 60 ꢁC.
Triethyl Ammonium-N-trifluoroacetyl-L-serinate (2)
Triethylamine (9.62 g, 0.1 mol) and methyl trifluoroacetate (15.24 g, 0.12 mol)
were added dropwise to a finely ground suspension of L-serine (1) (10 g, 0.1 mol)
in dry methanol (50 mL), over a period of an hour. Extra care was taken as methyl
trifluoroacetate is volatile and the fumes are poisonous upon inhalation. So, this
reaction was carried out in a well-ventilated fume hood. The resulting mixture was
stirred at room temperature under dry nitrogen for 15 h, which gave a colorless
solution. After this time, the solvent was removed in vacuo, which gave the triethyl
ammonium salt of N-trifluoroacetylserine (2) as a colorless oil, which then crystal-
lized as a yellowish white solid on standing[9] (23.5 g, 78%); mp 30 ꢁC.
1H NMR (CDCl3, 400 MHz): d 1.25 (9 H, t), 3.20 (6 H, q), 3.90 (2 H, m), 4.10
(1 H, m), 4.20 (br, s, 1 H, OH, exch. with D2O), 8.10 (1 H, d, exch. with D2O).
19F NMR (CDCl3, 400 MHz): d ꢀ73.118.

(–)-a-KAINIC ACID
2541
Scheme 1. Proposed total synthesis of kainic acid.
Cesium-N-trifluoroacetyl-L-serinate (3)
The triethyl ammonium salt of N-trifluoroacetylserine (2) (15.1 g, 0.05 mol) was
dissolved in DMF (30 mL), and cesium carbonate (19.3 g, 0.1 mol) was added and
stirred for 1 h. After that time, a white solid, which is the cesium salt of
N-trifluoroacetylserine (3), was obtained (10.5 g, 63%).
1H NMR (CD3CN, 400 MHz): d 3.80–3.94 (m, 2H, b-CHH), 4.26 (m, 1 H, a
1
ꢀCH), 7.40 (br, s, 1 H, OH), 9.02 (br, s, 1 H, NH). H NMR (H2O, 400 MHz): d
3.65–3.67 (m, 2 H, b-CHH), 3.88 (t, J ¼ 4.6 Hz 1 H, a-CH). 13C NMR (D2O,
400 MHz): d 178.69, 164.88, 162.06, 63.27, 58.90.

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N. CHOONY, L. JAMES, AND C. RABUN
3-Methyl-3-(tosylate)oxetane (4)
Freshly recrystallized toluenesulfonyl choride (28 g, 0.15 mol) was added to a
solution of 3-methyl-3-(hydroxymethyl)oxetane (10.0 g, 0.1 mol) in freshly distilled
dry pyridine (150 mL), and the resulting mixture was stirred at room temperature
under nitrogen for 2.5 h. After that time, the mixture was poured onto ice water
(400 mL) and stirred again for 1 h, which gave a white precipitate. This was col-
lected by vacuum filtration and washed copiously with cold water to give the tosyl
oxetane ester (4) as a white solid. This was dried in a vacuum desiccator over
phosphorus pentoxide (20.48 g, 80%); mp 54–55 ꢁC; 1H NMR (CDCl3,
400 MHz): d 1.25 (3 H, s), 2.5 (3 H, s), 4.10 (2 H, s), 4.4 (4 H, s), 7.4 (2 H,
d), 7.8 (2 H, d).
N-Trifluoroacetyl-3-methyl-3-oxetane-L-serinate (5)
The cesium salt of N-trifluoroacetylserine (3) (6.00 g, 0.018 mol) was suspended
in dry DMF (30 mL), and the tosyl oxetane ester (4) (4.61 g, 0.018 mol) was added,
followed by sodium iodide (15 g, 0.1 mol). The mixture was stirred at room tempera-
ture under dry nitrogen for 80 h.
After that time, the solvent was removed in vacuo to leave an orange residue
(5). This was partitioned between ethyl acetate (50 mL) and distilled water
(50 mL). The organic layer was washed with saturated aqueous sodium hydrogen
carbonate (2 ꢂ 30 mL) and brine (2 ꢂ 30 mL). The organic layer was dried with anhy-
drous sodium sulfate, and the solvent was removed in vacuo to give yellow oil (5)
25
1
(3.05 g, 63%); ½aꢃD ꢀ4.5 ꢁ, (c ¼ 1.00, EtOAc). H NMR (CDCl3, 400 MHz): d 1.30
(s, 3 H, oxetane CH3), 3.20–3.54 (dd, J ¼ 1.8, 2.0 Hz, 1 H, OH, exch. with D2O),
3.97–3.92 (m, 1 H, b-CHH), 4.25–4.10 (m, 2 H, a-CH, b-CHH), 4.78–4.48 (m, 6
H, 3 oxetane CH2O), 7.50 (br, d, J ¼ 6.75 Hz, 1 H, NH, exch. with D2O).
13C NMR (CDCl3, 400 MHz): d 171.37, 169.03, 157.26, 79.29, 69.17, 61.88, 54.98,
39.49, 20.82. 19F NMR (CDCl3, 400 MHz): d ꢀ76.227.
N-Protected L-Serine-4-methyl-2,6,7-trioxabicyclo[2.2.2]ortho Ester
(OBO) (6)
Compound 5 (0.92 g, 3.2 mmol) was dissolved in 15 mL freshly distilled dichlor-
omethane and cooled to 0 ꢁC, and a solution of BF3 ꢄ Et2O (53.2 mL) was then added.
The mixture was stirred for 8 h and allowed to reach room temperature.
After that time, triethyl amine (100 mL) was added to the solution and then
evaporated to dryness. The residue was purified by flash column using 3:1 ethyl
acetate=hexane loaded in dichloromethane.
Finally, the product was recrystallized using ethyl acetate=hexane, which gave
colorless crystals of the N-protected L-serine-4-methyl-2,6,7-trioxabicyclo[2.2.2]
25
ortho ester (OBO) (6) (0.61 g, 67%); mp 130–132 ꢁC; ½aꢃD ꢀ17.5 ꢁ (c ¼ 1.00, EtOAc);
1H NMR (CDCl3, 400 MHz): d 0.90 (s, 3 H, ortho CH3), 3.00 (br, dd, J ¼ 8.5, 4.0 Hz,
1 H, OH, exch. with D2O), 3.74–3.64 (m, 1H b-CHH), 3.95 (s, 6 H, 3 ortho CH2O),
4.00–3.90 (m, 2 H, a-CH, b-CHH), 6.50 (br, d, J ¼ 9.0 Hz 1 H, NH).

(–)-a-KAINIC ACID
2543
ACKNOWLEDGMENTS
We thank the University of South Carolina (USC) for offering us partial fund-
ing for this project through the Magellan Scholar program and the University of
South Carolina–Aiken (USCA) for startup funding. We also thank the NMR facility
staff at USC in Columbia for running almost all our NMR samples.
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