A practical synthesis of (-)-kainic acid

Article abstract of DOI:10.1055/s-0031-1289570

A highly practical total synthesis of (-)-kainic acid has been accomplished. The synthesis features the stereoselective alkylation of an iodolactone intermediate efficiently prepared from (+)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerization. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289570

3848
PAPER
A Practical Synthesis of (–)-Kainic Acid
Synthesisof (–
a
)-Kainic
A
t
cid oshi Takita,1 Satoshi Yokoshima, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 25 August 2011; revised 20 September 2011
boxylic acid, installation of the nitrogen atom, and
formation of the pyrrolidine ring.
Abstract: A highly practical total synthesis of (–)-kainic acid has
been accomplished. The synthesis features the stereoselective alky-
lation of an iodolactone intermediate efficiently prepared from (+)-
carvone and introduction of carboxylic acid by hydrolysis of a ni-
trile accompanied by epimerization.
• stereoselective introduction of the C2 unit
Key words: kainoids, iodolactone, Curtius rearrangement, stereo-
selective alkylation, total synthesis
CO2H
ref. 14
H
H
H
O
CO2H
CO2H
N
CHO
3
H
(+)-carvone (2)
(–)-kainic acid (1)
(–)-Kainic acid (1) was isolated in 1953 from the Japanese
marine alga Digenea simplex2and has been found in the
related algae.3 A variety of related compounds have also
been isolated and they constitute the kainoid family.4
Kainoids show potent anthelmintic properties5 and neu-
rotransmitting activities6 in the mammalian central ner-
vous system, and kainic acid, in particular, has been
widely used as a tool in neuropharmacology7 to stimulate
nerve cells and mimic disease states, such as epilepsy,8
Alzheimer’s disease, and Huntington’s chorea.9
• installation of N
• formation of the pyrrolidine ring
Scheme 1 Synthetic strategy for preparing (–)-kainic acid
Our synthesis started with epoxidation of (+)-carvone (2)
using basic hydrogen peroxide to furnish epoxide 4 in
89% yield (Scheme 2). Treatment of epoxide 4 with con-
centrated sulfuric acid in tetrahydrofuran gave a diaste-
reomeric mixture of diols 5, which, without further
purification, was subjected to oxidative cleavage with so-
dium periodate to afford carboxylic acid 3.14 After remov-
al of the nonacidic impurities by back extraction,
iodolactonization of 3 was conducted to fix the conforma-
tion for the stereoselective introduction of the C2 unit.
Compound 3 was thus treated with iodine and potassium
iodide under basic conditions. After completion of the re-
action, simple extraction afforded the desired iodolactone
6 in 65% yield from epoxide 4 as a 1:0.6 mixture of dia-
stereomers.
The structure of kainic acid, which includes a highly func-
tionalized trisubstituted pyrrolidine ring with three con-
tiguous stereogenic centers, has attracted considerable
attention as a synthetic target. Although several total syn-
theses and synthetic approaches have been reported to
date,10,11 few of the synthetic routes are amenable to large-
scale preparation with an efficiency comparable to that of
the conventional isolation from algae, and therefore this
compound remains quite expensive due to limited avail-
ability despite its importance in neuroscience.12 We have
recently reported a highly practical synthesis of (–)-kainic
acid,13 which features the stereoselective alkylation of an
iodolactone intermediate efficiently prepared from (+)-
carvone and introduction of carboxylic acid by hydrolysis
of a nitrile accompanied by epimerization. Herein, we
provide a detailed account of our synthetic study of (–)-
kainic acid.
Having established an efficient route to iodolactone 6, we
next concentrated on the introduction of the nitrogen atom
and the subsequent stereoselective alkylation (Scheme 3).
Oxidation of the aldehyde in 6 with sodium chlorite15 pro-
duced carboxylic acid 7 in 87% yield. Curtius rearrange-
ment of carboxylic acid 7 using diphenylphosphoryl azide
(DPPA) and triethylamine, followed by treatment with
methanol, afforded methyl carbamate 8 in 78% yield.16
Deprotonation of 8 with 2.5 equivalents of LHMDS, fol-
lowed by addition of tert-butyl bromoacetate17 at –78 °C,
gave ester 9 in 82% yield. As expected, alkylation oc-
curred from the opposite face of the substituent at the b-
position of the carbonyl group.18 Obviously, the stereo-
chemistry at the g-position of the lactone did not affect the
selectivity of the alkylation. Upon treatment with zinc in
the presence of acetic acid, the reductive ring-opening of
the iodolactone moiety in 9 proceeded to furnish carbox-
ylic acid 10.
Our synthetic strategy was based on taking advantage of
the prop-2-enyl group of a naturally abundant terpene
(Scheme 1). (+)-Carvone (2), a representative of such ter-
penes, undergoes oxidative degradation to give a versatile
synthetic intermediate 3.14 For the purpose of an efficient
synthesis of (–)-kainic acid (1), it occurred to us that 3
seems to have suitable functionalities for the stereoselec-
tive introduction of a C2 unit at the a-position of the car-
SYNTHESIS 2011, No. 23, pp 3848–3858
x
x.
x
x
.
2
0
1
1
Advanced online publication: 20.10.2011
DOI: 10.1055/s-0031-1289570; Art ID: H84011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (–)-Kainic Acid
3849
30% aq H2O2
aq NaOH
concd
H2SO4
H
H
H
O
O
O
MeOH, 0 °C
89%
THF–H2O
reflux
O
HO
OH
(+)-carvone (2)
4
5
I
I2, KI
NaHCO3
O
O
NaIO4
i-PrOH–H2O
0 °C to r.t.
CH2Cl2/H2O
0 °C
65% (3 steps)
(dr = 1:0.6)
CO2H
CHO
CHO
6
3
Scheme 2 Synthesis of iodolactone 6
I
I
I
NaClO2
NaH2PO4•2H2O
2-methylbut-2-ene
DPPA, Et3N
toluene, r.t.;
110 °C;
O
O
O
O
O
O
t-BuOH–THF–H2O
0 °C
MeOH, 75 °C
78%
(dr = 1:0.6)
87%
CO2H
7
NHCO2Me
8
CHO
6
(dr = 1:0.6)
I
LHMDS
O
CO2H
CO2t-Bu
O
THF, –78 °C;
Zn, AcOH
BrCH2CO2t-Bu
–78 °C
82%
(dr = 1:0.6)
EtOH
0 °C to r.t.
CO2t-Bu
NHCO2Me
NHCO2Me
9
10
Scheme 3 Introduction of the nitrogen atom and the C2 unit
Table 1 Optimization of the Reaction Conditions for the Formation
of the Lactam Ring
The next task was to perform cyclization of carboxylic
acid 10, which required screening of the reaction condi-
tions. The results are summarized in Table 1. Treatment
of 10 with acetic anhydride in the presence of sodium ace-
tate at ambient temperature did not induce cyclization, but
rather produced the corresponding mixed anhydride
(Table 1, entry 1). The mixed anhydride underwent cy-
clization upon heating at 100 °C to afford lactam 11, but
epimerization at the a-position of the lactam concomitant-
ly occurred (entry 2). The use of EDCI as a condensing
agent at ambient temperature produced lactam 11 in only
10% yield without epimerization (entry 3). Addition of
HOBt did not affect the progress of the reaction, and ele-
vating the reaction temperature led to epimerization (entry
4). These results suggested that the cyclization reaction
should be conducted at low temperatures to avoid epimer-
ization. After screening several condensing agents (en-
tries 6–8), we found that diethylphosphoryl cyanide
(DEPC)19 gave ideal results. Thus, upon treatment with
DEPC and triethylamine at ambient temperature, carbox-
ylic acid 10 underwent cyclization to afford the desired
cis-substituted lactam 11 in 60% overall yield from 9 on a
multigram scale (entry 8).
CO2t-Bu
CO2H
CO2t-Bu
conditions
H
H
O
N
NHCO2Me
CO2Me
10
11
Entry Conditions
Resulta
1
2
3
4
NaOAc, Ac2O, r.t.
NaOAc, Ac2O, 100 °C
not obtained
72% (1:1 mixture)b
10%
EDCI, i-Pr2NEt, CH2Cl2, r.t.
EDCI, HOBt, i-Pr2NEt, CH2Cl2,
54% (1:1 mixture)b
0 to 80 °C
5
6
7
8
BOPCl, i-Pr2NEt, CH2Cl2, r.t.
DPPA, i-Pr2NEt, CH2Cl2, 40 °C
TCT,c Et3N, CH2Cl2, r.t.
25%
40%
43%
60%
DEPC, Et3N, CH2Cl2, r.t.
a Isolated yield in 2 steps from 9.
With the lactam 11 in hand, we next attempted to intro-
duce a C1 unit at the a-position of the nitrogen atom
(Scheme 4). Lactam 11 was selectively reduced with
LiAlH(Ot-Bu)3 at 0 °C, and the resulting hemiaminal 12
b A mixture of two epimers at the a-position of the lactam was ob-
tained.
c TCT: 2,4,6-trichloro-1,3,5-triazine.
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

3850
S. Takita et al.
PAPER
H
CO2t-Bu
CO2t-Bu
TMSOTf
TMSCN
O
LiAlH(Ot-Bu)3
H
H
H
H
H
O
O
OH
THF
0 °C
CH2Cl2
0 °C to r.t.
N
N
N
CO2Me
CO2Me
CO2Me
11
12
13
CO2H
H
CO2H
NaOH
H
H
H
CN
n-PrOH–H2O
reflux
26–75%
(3 steps)
N
CO2H
N
H
CO2Me
14
(–)-kainic acid (1)
Scheme 4 Conversion of 11 into (–)-kainic acid
CO2t-Bu
CO2t-Bu
CO2t-Bu
LiAlH(Ot-Bu)3
THF, 0 °C
PPTS
H
H
H
H
H
H
O
OH
OMe
MeOH
0 °C
N
N
N
CO2Me
CO2Me
CO2Me
79%
(2 steps)
11
12
15a
Scheme 5 Synthesis of 15a
was treated with TMSOTf and TMSCN to give nitrile 14 convert 12 into the corresponding methyl ether. Thus, 12
as a mixture of diastereomers (3–4:1). Under these condi- was treated with PPTS in methanol to give 15a in 79%
tions, the tert-butyl ester was converted into the carboxy- yield from 11 as a single isomer (Scheme 5).
lic acid, possibly due to the formation of lactone
intermediate 13. Since purification of 14 was difficult be-
cause of its high polarity, the nitrile 14, without purifica-
tion, was subjected to hydrolysis with sodium hydroxide
in aqueous n-propanol at refluxing temperature to produce
(–)-kainic acid. Unfortunately, separation of the product
from impurities was very difficult at the last stage, and,
The attempted cyanation of 15a with TMSCN and boron
trifluoride–diethyl ether complex at –78 °C gave aminoni-
triles 16a and 17a in nearly quantitative yield. As expect-
ed, the tert-butyl ester remained intact, but the
stereoselectivity of the cyanation remained low (3:1,
Table 2, entry 1). The aminonitriles 16a and 17a were eas-
ily separated by column chromatography. The stereo-
moreover, cyanation of hemiaminal 12 was found to be ir-
chemistry of 16a was determined by X-ray crystal-
reproducible. Since these problematic results arose from
lography,20 which showed that 16a has the same configu-
the unwanted formation of lactone 13, we attempted to
Table 2 Attempted Cyanation of 15a with TMSCN
CO2t-Bu
CO2t-Bu
CO2t-Bu
TMSCN
H
H
H
H
H
H
OMe
conditions
CN
CN
N
N
N
CO2Me
CO2Me
CO2Me
15a
16a
17a
Entry
Conditions
BF3·OEt2, CH2Cl2, –78 °C
Ratio of 16a/17aa
Yield of 16a, 17ab
73%, 26%
50%, 10%c
63%, 31%
49%, 21%c
ND
1
2
3
4
5
6
~3:1
~3:1
~2:1
~3:1
~2:1
~1:1
TMSOTf, CH2Cl2,–78 °C to –30 °C
TiCl4, CH2Cl2, –78 °C to –30 °C
TfOH, CH2Cl2, –78 °C to –30 °C
BF3·OEt2, MeNO2, –30 °C
BF3·OEt2, toluene, –30 °C
ND
a The ratio was determined by 1H NMR spectroscopy.
b Isolated yields. ND: not determined.
c The apparent inaccuracy of the isolated yields is mainly due to the small-scale experiments (15a: 0.04 mmol).
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Kainic Acid
3851
Table 3 Effects of Substituents on the Cyanation Reaction
CO2R1
CO2R1
CO2R1
TMSCN, BF3•OEt2
H
H
H
H
H
H
OMe
CO2R2
CN
CO2R2
CN
CO2R2
CH2Cl2, –60 °C
N
N
N
15a (R1 = t-Bu, R2 = Me)
16a (R1 = t-Bu, R2 = Me)
17a (R1 = t-Bu, R2 = Me)
15b (R1 = R2 = Me)
16b (R1 = R2 = Me)
17b (R1 = R2 = Me)
15c (R1 = t-Bu, R2 = allyl)
15d (R1 = R2 = t-Bu)
16c (R1 = t-Bu, R2 = allyl)
16d (R1 = R2 = t-Bu)
17c (R1 = t-Bu, R2 = allyl)
17d (R1 = R2 = t-Bu)
Entry
R1
R2
Ratio of 16/17a
Yield of 16, 17b
1
2
3
4
t-Bu
Me
Me
~3:1
~3:1
~3:1
~3:1
73%, 26%
72%, 23%
72%, 22%
74%, 10%c
Me
t-Bu
t-Bu
Allyl
t-Bu
a The ratio was determined by 1H NMR spectroscopy.
b Isolated yields.
c The apparent inaccuracy of the isolated yield is mainly due to the small-scale experiment (15d: 0.02 mmol).
ration as (–)-kainic acid. Although we attempted to im- work of 19 might be formed via attack of the isopropenyl
prove the selectivity by introducing a variety of acid group on a nitrilium ion in 21. Obviously, the formation
catalysts (entries 2–4) or solvents (entries 5, 6), these ef- of 19 requires attack of the isocyanide from the a-face,
forts were unsuccessful.
indicating the poor stereoselectivity of the reaction.
Next, the effects of the substituents at the ester and car- Since furan is well known as an equivalent of carboxylic
bamate moieties in 15a was evaluated (Table 3). Replace- acid, the introduction of a furan ring was next attempted
ment of the tert-butyl ester with a methyl ester did not (Scheme 7). Thus, 15a was treated with 2-methylfuran in
change the selectivity ratio (Table 3, entry 2). Employing the presence of boron trifluoride–diethyl ether complex at
a more bulky protecting group of the nitrogen atom, such –60 °C in dichloromethane. The reaction successfully
as Alloc or Boc, did not change the selectivity either (en- proceeded to furnish the desired adduct 23 in 99% yield as
tries 3, 4).
a single isomer. Further transformation, however, was
problematic. Conversion of 23 into the corresponding car-
boxylic acid 24 under oxidative conditions (RuCl3 and
NaIO4, or MCPBA) did not succeed due to the concomi-
tant oxidation of the isopropenyl group.
An isocyanide21 was tried next as a more bulky nucleo-
phile to improve the selectivity (Scheme 6). Thus, treat-
ment of 15b with 1,3-dichloro-2-isocyanobenzene22 and
titanium(IV) chloride afforded adduct 18 in 53% yield as
a single isomer. In this reaction, however, 19 was obtained Epimerization of the undesired nitrile 17a was attempted
as a by-product in 14% yield. The bicyclo [3.2.1] frame- next (Scheme 8). The base-promoted epimerization of the
Cl
CN
CO2Me
Cl
CO2Me
CO2Me
NAr
TiCl4
H
H
H
H
OMe
CH2Cl2
–78 to 0 °C
N
N
N
MeO2C
Cl
CO2Me
CO2Me
NAr
15b
18 (Ar = 2,6-Cl2C6H3)
53% (single isomer)
19 (Ar = 2,6-Cl2C6H3)
14%
CO2Me
CO2Me
CO2Me
α-isomer
H
H
N
N
NAr
Cl
N
MeO2C
C
NAr
NAr
CO2Me
CO2Me
20
21
22
Scheme 6 Reaction of 15b with an isocyanide
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

3852
S. Takita et al.
PAPER
O
CO2t-Bu
O
CO2t-Bu
CO2t-Bu
BF3•OEt2
H
H
oxidation
H
H
H
H
OMe
CO2H
CH2Cl2
–60 °C
99%
N
N
N
CO2Me
CO2Me
CO2Me
15a
23
24
single isomer
Scheme 7 Reaction of 15a with 2-methylfuran
CO2t-Bu
CO2t-Bu
CO2t-Bu
t-BuOK
H
H
H
H
H
H
+
CN
CN
CN
t-BuOH–THF
0 °C
N
N
N
CO2Me
CO2Me
CO2Me
17a
16a
63%
17a
9%
Scheme 8 Epimerization of aminonitrile
CO2t-Bu
CO2t-Bu
CO2H
NaOH
NaOH
H
H
H
H
H
H
CN
n-PrOH–H2O
reflux
CN
n-PrOH–H2O
N
N
CO2H
N
H
reflux
85%
CO2Me
76%
CO2Me
(dr = >20:1)
(dr = >20:1)
(–)-kainic acid (1)
16a
17a
Scheme 9 Hydrolysis of nitriles 16a and 17a
TMSCN
BF3•OEt2
NaOH, H2O
reflux;
CO2t-Bu
CO2t-Bu
CO2H
H
H
H
H
H
H
OMe
CN
recrystallization
69% (2 steps)
CH2Cl2
–60 °C
dr = 3:1
N
N
CO2H
N
H
CO2Me
CO2Me
(–)-kainic acid (1)
15a
16a + 17a
Scheme 10 Completion of the synthesis of (–)-kainic acid
corresponding diester under a variety of conditions has In conclusion, we have achieved a highly practical synthe-
been reported.11c,p,r,v On the other hand, Ganem reported sis of (–)-kainic acid (1), featuring the efficient prepara-
that the hydrolysis of a nitrile derivative of the undesired tion of the iodolactone, Curtius rearrangement to
a-epimer under acidic conditions proceeded without introduce a nitrogen atom, stereoselective alkylation of
epimerization.11v Treatment of the undesired a-isomer the lactone to install the C2 unit, and alkaline hydrolysis
17a with potassium tert-butoxide in a mixed solvent of of the nitrile accompanied by epimerization. This synthet-
tert-butyl alcohol and tetrahydrofuran at 0 °C resulted in ic route enabled us to prepare 14.6 grams of crystalline
isomerization to afford the b-isomer 16a in 63% yield, (–)-kainic acid (1) from 100 grams of (+)-carvone (2) in
along with recovery of the a-isomer 17a in 9% yield.
13 steps and 10.3% overall yield. In view of the ease of the
entire operation and the use of the readily available and in-
expensive reagents, this synthetic route alone could satis-
fy the global demand for (–)-kainic acid.
In view of the fact that hydrolysis of 16a required quite
harsh conditions, such as refluxing with sodium hydrox-
ide in aqueous propanol, we reasoned that epimerization
of the a-isomer might take place concomitantly during the
hydrolysis. As expected, alkaline hydrolysis of the undes-
ired a-isomer 17a was accompanied by epimerization,
providing (–)-kainic acid (1) in a yield comparable to that
of the a-isomer 16a (Scheme 9). Finally, treatment of the
crude diastereomeric mixture of nitriles 16a and 17a with
sodium hydroxide in water under reflux afforded, after re-
crystallization, pure (–)-kainic acid (1) in 69% yield for
two steps (Scheme 10).
All melting points were determined with a Stanford Research Sys-
tems OptiMelt melting point apparatus and are uncorrected. Optical
rotations were measured on a JASCO P-1020 polarimeter at r.t., us-
ing the Na D line. IR spectra were recorded with a Perkin-Elmer
1
Spectrum 100 spectrometer. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a JEOL JNM-ECA-400 or
JNM-ECX-400P spectrometer. Chemical shifts for 1H NMR are re-
ported in parts per million (d value) downfield relative to TMS, us-
ing TMS and/or residual solvents as internal standards. Standard
abbreviations were used to describe the signal multiplicity. Chemi-
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Kainic Acid
3853
cal shifts for 13C NMR are reported in parts per million relative to
the center line of a triplet at 77.0 ppm or ppm from TMS as the in-
ternal standard. Chemical shifts in D2O are reported in parts per mil-
lion relative to the singlet at 30.9 ppm for acetone. Mass spectral
measurements were performed using a JEOL JMS-SX-102X or
JMS-T100GCV mass spectrometer. Elemental analysis data are
within 0.3% of the theoretical values and were determined using
a Yanaco CHN Corder MT-6. Unless otherwise noted, all experi-
ments were carried out using anhydrous solvents under an atmo-
sphere of argon. Throughout this study, Merck precoated TLC
plates (silica gel 60 F254, 0.25 mm) were used for TLC analysis,
and all spots were visualized using UV light followed by coloring
with phosphomolybdic acid or ninhydrin. Silica gel 60N (40–100
mm; Kanto Chemical Co., Inc., Tokyo, Japan) was used for flash
column chromatography.
oil. To a solution of the crude acid in CH2Cl2 (390 mL) and H2O
(390 mL) was added NaHCO3 (99.5 g, 1.18 mol) at 0 °C. A solution
of I2 (150 g, 0.592 mol) and KI (295 g, 1.78 mol) in H2O (592 mL)
was then added to this mixture. After stirring for 30 min, the reac-
tion was quenched with aq Na2S2O3 (200 mL) and extracted with
CH2Cl2 (3 × 500 mL). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated under reduced pressure to give 6
(109 g, 65%) as a yellow oil. This material was obtained as a 1:0.6
mixture of the diastereomers, which were separated by preparative
TLC for characterization. The diastereomeric ratio was determined
by 1H NMR spectroscopy.
Major Isomer
[a]D26 +24.5 (c 0.65, CHCl3).
IR (ATR): 1765, 1718, 1382, 1257, 1125, 1043, 955, 911 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.82 (1 H, s), 3.30 (2 H, s), 2.89–
(1S,4S,6S)-1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]hep-
tan-2-one (4)
2.98 (3 H, m), 2.75–2.82 (1 H, m), 2.45–2.52 (1 H, m), 1.64 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 198.5, 174.1, 84.1, 43.4, 38.0,
35.4, 27.1, 8.6.
HRMS (CI): m/z calcd for C8H12IO3 [M + H]+: 282.9831; found:
282.9876.
To a solution of (+)-carvone (2; 100 g, 0.666 mol) in MeOH (666
mL) was added 4.0 M aq NaOH (57.9 mL) at 0 °C. To this was add-
ed 30% H2O2 (82.7 mL, 0.799 mol) dropwise over a period of 1 h at
0 °C. After stirring for 1 h, the reaction was quenched with sat. aq
Na2SO3 (200 mL). The resulting mixture was filtered through a
Celite pad, and the organic solvent of the filtrate was removed under
reduced pressure. The aqueous mixture was extracted with EtOAc
(3 × 500 mL). The combined organic extracts were washed with
brine (300 mL), dried (Na2SO4), filtered, and evaporated under re-
duced pressure. The crude product was purified by distillation (95–
Minor Isomer
[a]D26 +17.5 (c 0.55, CHCl3).
IR (ATR): 1769, 1719, 1383, 1267, 1165, 1037, 926 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.80 (1 H, s), 3.49 (1 H, d, J = 11.0
Hz), 3.45 (1 H, d, J = 11.0 Hz), 3.03–3.11 (1 H, m), 2.98 (1 H, dd,
J = 17.7, 8.6 Hz), 2.89 (1 H, dd, J = 18.3, 4.3 Hz), 2.64 (1 H, dd,
J = 18.3, 9.8 Hz), 2.29 (1 H, dd, J = 17.7, 9.2 Hz), 1.48 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 198.5, 173.4, 84.3, 45.2, 36.8,
35.3, 21.2, 13.7.
24
96 °C/2.0 Torr) to give 4 (98.5 g, 89%) as a colorless oil; [a]D
–79.4 (c 1.33, CHCl3).
IR (ATR): 1705, 1439, 1118, 889, 814 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.79 (1 H, s), 4.72 (1 H, s), 3.45
(1 H, d, J = 3.0 Hz), 2.68–2.76 (1 H, m), 2.59 (1 H, ddd, J = 17.6,
4.8, 1.2 Hz), 2.38 (1 H, dt, J = 14.7, 3.0 Hz), 2.03 (1 H, dd, J = 17.6,
11.5 Hz), 1.90 (1 H, dd, J = 14.7, 11.5 Hz), 1.72 (3 H, s), 1.42 (3 H,
s).
HRMS (CI): m/z calcd for C8H12IO3 [M + H]+: 282.9831; found:
282.9851.
2-[(3S)-2-(Iodomethyl)-2-methyl-5-oxotetrahydrofuran-3-
yl]acetic Acid (7)
13C NMR (100 MHz, CDCl3): d = 205.3, 146.2, 110.4, 61.2, 58.7,
41.7, 34.9, 28.6, 20.5, 15.2.
To a solution of 6 (109 g, 0.385 mol) in t-BuOH (385 mL) and THF
(193 mL) was added 2-methylbut-2-ene (419 mL, 3.08 mol) at 0 °C.
To this mixture was added dropwise a solution of NaClO2 (69.6 g,
0.770 mol) and NaH2PO4·2H2O (300 g, 1.93 mol) in H2O (635 mL)
over a period of 1 h at 0 °C. After stirring for 1 h, the mixture was
warmed to r.t. and extracted with EtOAc (3 × 700 mL). The com-
bined organic extracts were washed with brine (300 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was diluted with EtOAc (1000 mL) and extracted with sat.
aq NaHCO3 (3 × 500 mL). The aqueous phase was acidified with
concd HCl to pH 2 and then extracted with EtOAc (3 × 700 mL).
The combined organic extracts were washed with brine (300 mL),
dried (Na2SO4), filtered, and evaporated under reduced pressure to
give 7 (99.7 g, 87%, 1:0.6 diastereomeric mixture) as a pale yellow
solid.
HRMS (CI): m/z calcd for C10H15O2 [M + H]+: 167.1072; found:
167.1063.
2-[(3S)-2-(Iodomethyl)-2-methyl-5-oxotetrahydrofuran-3-
yl]acetaldehyde (6)
To a solution of 4 (98.4 g, 0.592 mol) in THF (500 mL) and H2O
(100 mL) was added concd H2SO4 (9.47 mL, 0.178 mol). After stir-
ring for 10 h at reflux, the reaction mixture was neutralized with sat.
aq NaHCO3. After removal of the organic solvent of the mixture un-
der reduced pressure, the aqueous layer was extracted with EtOAc
(3 × 500 mL). The combined organic extracts were washed with
brine (300 mL), dried (Na2SO4), filtered, and evaporated under re-
duced pressure to give a crude diol as a yellow oil, which was used
for the next reaction without purification. To a solution of the crude
diol in propan-2-ol (1000 mL) and H2O (1000 mL) was added
NaIO4 (291 g, 1.36 mol) at 0 °C. After stirring for 4 h at 0 °C, the
reaction mixture was warmed to r.t. and stirring was continued for
16 h. The mixture was filtered through a Celite pad, and the organic
solvent of the filtrate was removed under reduced pressure. The
aqueous phase was saturated with NaCl, and extracted with EtOAc
(3 × 300 mL). The combined organic layers were extracted with sat.
aq Na2CO3 (3 × 300 mL). The combined aqueous extracts were sat-
urated with NaCl, acidified with concd HCl to pH 2, and then ex-
tracted with EtOAc (3 × 500 mL). The combined organic extracts
were washed with brine (300 mL), dried (Na2SO4), filtered, and
evaporated under reduced pressure to give a crude acid as a yellow
IR (ATR): 2971, 1764, 1700, 1410, 1221, 1152, 960, 912 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.50 (0.6 H, d, J = 11.0 Hz), 3.44
(0.6 H, d, J = 11.0 Hz), 3.33 (1 H, d, J = 11.0 Hz), 3.30 (1 H, d,
J = 11.0 Hz), 2.87–3.04 (2 + 1.2 H, m), 2.78 (1 H, dd, J = 16.5, 4.9
Hz), 2.73 (0.6 H, dd, J = 16.5, 4.9 Hz), 2.38–2.66 (2 + 1.2 H, m),
1.65 (3 H, s), 1.50 (1.8 H, s).
13C NMR (100 MHz, CDCl3): d = 176.1, 176.1, 174.1, 173.5, 84.4,
84.2, 40.3, 38.8, 35.4, 35.3, 35.1, 33.5, 27.1, 21.0, 13.6, 8.3.
HRMS (CI): m/z calcd for C8H12IO4 [M + H]+: 298.9780; found:
298.9811.
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

3854
S. Takita et al.
PAPER
Methyl {[(3R)-2-(Iodomethyl)-2-methyl-5-oxotetrahydrofuran-
3-yl]methyl}carbamate (8)
HRMS (CI): m/z calcd for C15H25IO6 [M + H]+: 442.0727; found:
442.0720.
To a suspension of 7 (99.7 g, 0.334 mmol) in toluene (1100 mL) was
added Et3N (60.5 mL, 0.434 mol) and DPPA (89.9 mL, 0.401
mmol). After stirring for 2 h at r.t., the mixture was heated at 110 °C
for 30 min. After cooling to 75 °C, MeOH (301 mL, 6.68 mol) was
added to the mixture. After stirring for 7 h at 75 °C, the reaction was
diluted with H2O (1000 mL) and extracted with EtOAc (3 × 700
mL). The combined organic extracts were washed with brine (300
mL), dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The crude product was purified by silica gel column chroma-
tography (EtOAc–hexane, 3:1 to 1:1) to give 8 (85.5 g, 78%, 1:0.6
diastereomeric mixture) as a yellow oil.
(3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-oxo-4-(prop-1-
en-2-yl)pyrrolidine-1-carboxylate (11)
To a solution of 9 (93.6 g, 0.212 mol) in EtOH (630 mL) was added
Zn (69.3 g, 1.06 mol) and AcOH (61.0 mL, 1.06 mol) at 0 °C. After
stirring for 3 h, the reaction mixture was filtered through a Celite
pad and evaporated under reduced pressure. The mixture was dilut-
ed with H2O (1000 mL) and extracted with EtOAc (3 × 500 mL).
The combined organic extracts were washed with brine (300 mL),
dried (Na2SO4), filtered, and evaporated under reduced pressure to
give a crude acid 10 as a yellow oil. To a solution of the crude acid
10 in CH2Cl2 (1000 mL) was added DEPC (48.3 g, 0.318 mol) and
Et3N (136 mL, 0.848 mol) at r.t. After stirring for 15 h, the mixture
was quenched with sat. aq NaHCO3, and extracted with CH2Cl2 (3
× 500 mL). The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (EtOAc–
hexane, 6:1) to give 11 (37.6 g, 60%) as a white solid; mp 94–95 °C
(hexane); [a]D25 +17.2 (c 0.50, CHCl3).
IR (ATR): 2950, 1766, 1698, 1529, 1248, 955 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.84 (1 H, br s), 4.77 (0.6 H, br s),
3.69 (3 + 1.8 H, s), 3.56–3.60 (1 H, m), 3.49 (0.6 H, d, J = 11.0 Hz),
3.25–3.41 (3 + 1.8 H, m), 2.62–2.85 (3 + 1.2 H, m), 2.47–2.49 (0.6
H, m), 1.64 (3 H, s), 1.52 (1.8 H, s).
13C NMR (100 MHz, CDCl3): d = 173.9, 173.4, 157.1, 157.0, 84.1,
84.0, 52.5, 44.5, 43.1, 41.3, 40.2, 33.8, 33.7, 27.7, 20.7, 14.2, 8.2.
IR (ATR): 1749, 1442, 1361, 1317, 1244, 1149, 894 cm–1.
HRMS (CI): m/z calcd for C9H15INO4 [M + H]+: 328.0046; found:
1H NMR (400 MHz, CDCl3): d = 4.88 (1 H, t, J = 1.5 Hz), 4.78 (1
H, s), 3.88 (3 H, s), 3.79–3.84 (2 H, m), 3.19–3.20 (2 H, m), 2.77 (1
H, dd, J = 17.7, 3.7 Hz), 2.23 (1 H, dd, J = 17.7, 9.8 Hz), 1.61 (3 H,
s), 1.44 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 173.9, 171.0, 152.1, 142.2, 115.5,
81.0, 53.7, 48.9, 43.2, 41.0, 31.8, 28.0, 19.9.
328.0058.
tert-Butyl 2-((3S,4R)-5-(Iodomethyl)-4-{[(methoxycarbon-
yl)amino]methyl}-5-methyl-2-oxotetrahydrofuran-3-yl)acetate
(9)
To a solution of lithium hexamethyldisilazide (ca.1.6 mol/L in THF,
406 mL, 0.650 mol) in THF (550 mL) was added dropwise a solu-
tion of 8 (85.5 g, 0.260 mol) in THF (350 mL) over a period of 45
min at –78 °C. After stirring for 15 min, tert-butyl bromoacetate
(76.8 mL, 0.520 mol) was added to the mixture. After stirring for 1
h, the mixture was quenched with a solution of AcOH (44.9 mL,
0.780 mol) in THF (100 mL), warmed to r.t., diluted with H2O
(1000 mL), and extracted with EtOAc (3 × 700 mL). The combined
organic extracts were washed with brine (300 mL), dried (Na2SO4),
filtered, and evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (EtOAc–
hexane, 4:1 to 1:1) to give 9 (93.6 g, 82%) as a yellow oil. This ma-
terial was obtained as a 1:0.6 mixture of two diastereomers due to
the stereogenic center at the g-position of the lactone. The diaste-
HRMS (CI): m/z calcd for C15H24NO5 [M + H]+: 298.1654; found:
298.1688.
Anal.: Calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C,
60.42; H, 7.65; N, 4.50.
(3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-methoxy-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (15a)
To a solution of 11 (37.6 g, 0.126 mol) in THF (630 mL) was added
LiAlH(Ot-Bu)3 (41.7 g, 0.164 mol) at 0 °C. After stirring for 1 h, the
mixture was quenched with sat. aq NH4Cl (100 mL), filtered
through a Celite pad, and evaporated under reduced pressure. The
mixture was diluted with sat. aq potassium sodium tartrate (300 mL)
and extracted with EtOAc (3 × 300 mL). The combined organic ex-
tracts were washed with brine (100 mL), dried (Na2SO4), filtered,
and evaporated under reduced pressure to give the hemiaminal 12
as a yellow oil. To a solution of the hemiaminal 12 in MeOH (420
mL) was added pyridinium p-toluenesulfonate (1.58 g, 6.30 mmol)
at 0 °C. After stirring for 15 h, the reaction mixture was quenched
with sat. aq NaHCO3 (200 mL), and extracted with EtOAc (3 × 500
mL). The combined organic extracts were washed with brine (200
mL), dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The crude product was purified by silica gel column chroma-
tography (EtOAc–hexane, 10:1) to give 15a (31.0 g, 79%) as a
colorless oil. This material was obtained as a mixture of rotamers;
[a]D25 –38.9 (c 1.15, CHCl3).
1
reomeric ratio was determined by H NMR spectroscopy, and the
diastereomers were separated by preparative TLC for characteriza-
tion.
Major Isomer
[a]D26 –29.7 (c 0.65, CHCl3).
IR (ATR): 2980, 1769, 1709, 1525, 1367, 1250, 1149 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.29 (1 H, s), 3.69 (3 H, s), 3.41–
3.50 (4 H, m), 3.10–3.16 (1 H, m), 2.93 (1 H, dd, J = 17.7, 2.4 Hz),
2.45–2.54 (2 H, m), 1.65 (3 H, s), 1.47 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 175.2, 171.3, 157.1, 82.6, 82.1,
52.4, 51.0, 40.5, 39.1, 35.8, 28.0, 27.9, 9.1.
HRMS (CI): m/z calcd for C15H25IO6: 442.0727; found: 442.0743.
IR (ATR): 1709, 1445, 1367, 1147, 1077 cm–1.
Minor Isomer
[a]D25 +34.1 (c 0.50, CHCl3).
1H NMR (400 MHz, DMSO-d6, 100 °C): d = 4.93 (1 H, d, J = 1.2
Hz), 4.90 (1 H, s), 4.71 (1 H, s), 3.65 (3 H, s), 3.30 (3 H, s), 3.27–
3.43 (2 H, m), 3.05–3.12 (1 H, m), 2.53–2.55 (1 H, m), 2.02 (1 H,
dd, J = 16.3, 4.8 Hz), 1.83 (1 H, dd, J = 16.3, 10.3 Hz), 1.71 (3 H,
s), 1.42 (9 H, s).
13C NMR (100 MHz, DMSO-d6, 100 °C): d = 170.4, 140.7, 111.5,
92.4, 79.7, 54.7, 51.6, 45.8, 43.4, 41.8, 31.3, 27.3, 27.1, 21.8.
IR (ATR): 2978, 1772, 1727, 1700, 1538, 1295, 1250, 1156, 1016
cm–1.
1H NMR (400 MHz, CDCl3): d = 5.22 (1 H, s), 3.69 (3 H, s), 3.57
(1 H, d, J = 11.0 Hz), 3.45 (1 H, d, J = 11.0 Hz), 3.37–3.42 (2 H, m),
2.90–2.99 (2 H, m), 2.48–2.58 (2 H, m), 1.51 (3 H, s), 1.48 (9 H, s).
HRMS (FAB): m/z calcd for C20H39N2O7 [M + diethanolamine +
13C NMR (100 MHz, CDCl3): d = 174.7, 171.4, 157.0, 82.5, 82.1,
52.4, 49.4, 40.9, 40.3, 35.6, 28.0, 20.8, 14.4.
H]+: 419.2757; found: 419.2716.
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Kainic Acid
3855
(2S,3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (16a) and
(2R,3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (17a)
To a solution of 15a (134 mg, 0.428 mmol) and Me3SiCN (0.268
mL, 2.14 mmol) in CH2Cl2 (4.0 mL) was added BF3·OEt2 (0.0792
mL, 0.642 mmol) at –60 °C. After stirring for 1 h, the mixture was
quenched with sat. aq NaHCO3 (5.0 mL) and extracted with CH2Cl2
(3 × 5.0 mL). The combined organic extracts were dried (Na2SO4),
filtered, and evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (EtOAc–
hexane, 4:1) to give 16a (96.6 mg, 73%) as a white solid and 17a
(34.5 mg, 26%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 5.02 (1 H, s), 4.74 (0.5 H, s), 4.71
(0.5 H, s), 4.56 (0.5 H, s), 4.52 (0.5 H, s), 3.80 (1.5 H, s), 3.78 (1.5
H, s), 3.61–3.72 (4 H, m), 3.39–3.49 (1 H, m), 3.16–3.25 (1 H, m),
3.01–3.06 (1 H, m), 2.29–2.35 (1 H, m), 2.10 (1 H, dd, J = 17.3,
11.2 Hz), 1.78 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 171.9, 171.6, 155.0, 154.4, 139.7,
139.4, 118.2, 118.1, 113.9, 113.6, 53.3, 53.2, 52.3, 52.2, 51.8, 46.8,
46.6, 46.5, 45.7, 42.7, 41.7, 31.3, 31.2, 22.6.
HRMS (CI): m/z calcd for C13H19N2O4 [M + H]+: 267.1345; found:
267.1360.
17b
This material was obtained as a mixture of rotamers; [a]D29 +47.8 (c
0.20, CHCl3).
16a
This material was obtained as a mixture of rotamers; [a]D23 –63.4 (c
IR (ATR): 2243, 1705, 1447, 1373, 1199, 1124 cm–1.
0.53, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.40 (1 H, s), 4.81–4.88 (2 H, m),
3.76–3.81 (3 H, m), 3.72 (3 H, s), 3.53–3.68 (2 H, m), 3.11–3.19 (1
H, m), 2.92 (1 H, br s), 2.62 (2 H, d, J = 7.9 Hz), 1.80 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 171.9, 171.8, 154.9, 154.5, 141.3,
116.4, 116.1, 115.6, 115.4, 53.3, 52.2, 51.5, 50.9, 50.1, 49.5, 46.9,
45.9, 40.1, 39.0, 32.1, 32.0, 29.7, 22.6.
IR (ATR): 2242, 1715, 1452, 1375, 1160 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.00 (1 H, s), 4.73 (0.5 H, s), 4.70
(0.5 H, s), 4.52 (0.5 H, s), 4.50 (0.5 H, s), 3.80 (1.5 H, s), 3.78 (1.5
H, s), 3.60–3.70 (1 H, m), 3.37–3.48 (1 H, m), 3.13–3.23 (1 H, m),
2.96–3.02 (1 H, m), 2.17–2.25 (1 H, m), 1.97–2.05 (1 H, m), 1.78 (3
H, s), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 170.6, 170.3, 154.9, 154.4, 139.9,
139.6, 118.3, 118.1, 113.7, 113.5, 81.8, 53.3, 53.2, 52.3, 51.8, 46.9,
46.7, 46.5, 45.7, 42.9, 41.9, 32.6, 32.5, 28.1, 28.0, 22.7, 22.6.
HRMS (CI): m/z calcd for C13H19N2O4 [M + H]+: 267.1345; found:
267.1318.
(2S,3S,4S)-Allyl 3-[2-(tert-Butoxy)-2-oxoethyl)]2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (16c) and
(2R,3S,4S)-Allyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (17c)
To a solution of 15c (52.8 mg, 0.156 mmol) and Me3SiCN (0.0464
mL, 0.468 mmol) in CH2Cl2 (1.0 mL) was added BF3·OEt2 (0.0288
mL, 0.233 mmol) at –60 °C. After stirring for 1 h, the mixture was
quenched with sat. aq NaHCO3 (2.0 mL), and extracted with
CH2Cl2 (3 × 5.0 mL). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
(EtOAc–hexane, 4:1) to give 16c (37.7 mg, 72%) and 17c (11.5 mg,
22%) as colorless oils.
HRMS (CI): m/z calcd for C16H25N2O4 [M + H]+: 309.1814; found:
309.1791.
Anal. Calcd for C16H24N2O4: C, 62.26; H, 7.85; N, 9.01. Found: C,
62.32; H, 7.84; N, 9.08.
17a
This material was obtained as a mixture of rotamers; [a]D23 +45.7 (c
0.65, CHCl3).
IR (ATR): 2243, 1715, 1433, 1373, 1155 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.03 (1 H, s), 4.88 (1 H, br s), 4.81
(0.5 H, s), 4.79 (0.5 H, s), 3.81 (1.5 H, s), 3.78 (1.5 H, s), 3.51–3.67
(2 H, m), 3.05–3.13 (1 H, m), 2.87–2.94 (1 H, m), 2.53–2.56 (2 H,
m), 1.81 (3 H, s), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 170.7, 170.5, 154.9, 154.5, 141.6,
116.6, 116.2, 115.4, 115.3, 81.6, 53.3, 53.2, 51.5, 50.9, 50.3, 49.8,
46.8, 45.8, 40.2, 39.1, 33.5, 33.4, 28.0, 22.7.
16c
This material was obtained as a mixture of rotamers; [a]D27 –49.5 (c
0.63, CHCl3).
IR (ATR): 2256, 1713, 1402, 1149 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.91–6.00 (1 H, m), 5.35 (1 H, dd,
J = 17.0, 10.3 Hz), 5.26 (1 H, d, J = 10.3 Hz), 5.00 (1 H, s), 4.62–
4.75 (3 H, m), 4.53 (1 H, s), 3.64–3.71 (1 H, m), 3.40–3.49 (1 H, m),
3.14–3.23 (1 H, m), 2.97–3.03 (1 H, m), 2.22 (1 H, ddd, J = 17.0,
6.7, 3.0 Hz), 2.02 (1 H, ddd, J = 17.0, 10.3, 2.4 Hz), 1.77 (3 H, s),
1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 170.6, 170.3, 154.2, 153.7, 139.8,
139.6, 132.2, 132.1, 118.4, 118.2, 118.1, 113.8, 113.5, 81.8, 66.8,
66.7, 52.3, 51.8, 46.9, 46.7, 46.5, 45.7, 42.9, 41.9, 32.6, 32.5, 28.1,
22.7, 22.6.
HRMS (CI): m/z calcd for C16H25N2O4 [M + H]+: 309.1814; found:
309.1820.
(2S,3S,4S)-Methyl 2-Cyano-3-(2-methoxy-2-oxoethyl)-4-(prop-
1-en-2-yl)pyrrolidine-1-carboxylate (16b) and
(2R,3S,4S)-Methyl 2-Cyano-3-(2-methoxy-2-oxoethyl)-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (17b)
To a solution of 15b (91.0 mg, 0.335 mmol) and Me3SiCN (0.126
mL, 1.01 mmol) in CH2Cl2 (2.0 mL) was added BF3·OEt2 (0.0620
mL, 0.148 mmol) at –60 °C. After stirring for 1 h, the mixture was
quenched with sat. aq NaHCO3 (2.0 mL), and extracted with
CH2Cl2 (3 × 5.0 mL). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
(EtOAc–hexane, 4:1) to give 16b (64.2 mg, 72%) and 17b (20.3
mg, 23%) as colorless oils.
HRMS (CI): m/z calcd for C18H27N2O4 [M + H]+: 335.1971; found:
335.1955.
17c
This material was obtained as a mixture of rotamers; [a]D28 +49.8 (c
0.37, CHCl3).
IR (ATR): 2251, 1710, 1400, 1151 cm–1.
16b
This material was obtained as a mixture of rotamers; [a]D29 –78.4 (c
1H NMR (400 MHz, CDCl3): d = 5.90–6.01 (1 H, m), 5.24–5.41 (2
H, m), 5.03 (1 H, s), 4.80–4.92 (2 H, m), 4.63–4.75 (2 H, m), 3.53–
3.69 (2 H, m), 3.07–3.14 (1 H, m), 2.86–2.95 (1 H, m), 2.55 (2 H, d,
J = 7.9 Hz), 1.81 (3 H, s), 1.46 (9 H, s).
0.44, CHCl3).
IR (ATR): 2241, 1707, 1448, 1376, 1199, 1132 cm–1.
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

3856
S. Takita et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 170.7, 170.5, 154.2, 153.7, 141.5,
132.3, 132.1, 118.3, 116.5, 116.2, 115.4, 115.3, 81.6, 66.8, 66.7,
51.4, 50.9, 50.2, 49.7, 46.8, 45.8, 40.2, 39.1, 33.5, 33.4, 28.0, 22.7.
18
This material was obtained as a mixture of rotamers; [a]D28 –10.7 (c
0.18, CHCl3).
HRMS (CI): m/z calcd for C18H27N2O4 [M + H]+: 335.1971; found:
IR (ATR): 1710, 1437, 1379, 1197, 1132 cm–1.
335.1992.
1H NMR (400 MHz CDCl3): d = 7.33 (1.2 H, d, J = 7.9 Hz), 7.32
(0.8 H, d, J = 7.9 Hz), 7.05 (0.6 H, t, J = 7.9 Hz), 7.02 (0.4 H, t,
J = 7.9 Hz), 4.98 (1 H, s), 4.74–4.76 (1.4 H, m), 4.66 (0.6 H, d,
J = 2.4 Hz), 3.72–3.81 (7 H, m), 3.62 (0.6 H, t, J = 9.2 Hz), 3.55 (0.4
H, t, J = 9.2 Hz), 3.36–3.47 (1 H, m), 3.09–3.14 (1 H, m), 2.37–2.42
(2 H, m), 1.75 (3 H, s).
(2S,3S,4S)-tert-Butyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (16d) and
(2R,3S,4S)-tert-Butyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-cyano-4-
(prop-1-en-2-yl)pyrrolidine-1-carboxylate (17d)
To a solution of 15d (7.0 mg, 0.0197 mmol) and Me3SiCN (0.0123
mL, 0.0985 mmol) in CH2Cl2 (0.20 mL) was added BF3·OEt2
(0.00365 mL, 0.0295 mmol) at –60 °C. After stirring for 1 h, the
mixture was quenched with sat. aq NaHCO3 (1.0 mL) and extracted
with CH2Cl2 (3 × 3.0 mL). The combined organic extracts were
dried (Na2SO4), filtered, and evaporated under reduced pressure.
The crude product was purified by TLC (silica gel) to give 16d (5.1
mg, 74%) and 17d (0.7 mg, 10%) as colorless oils.
13C NMR (100 MHz, CDCl3): d = 172.3, 155.0, 153.5, 142.4, 142.3,
140.9, 140.8, 128.4, 128.2, 125.7, 125.6, 125.0, 124.9, 124.8, 113.6,
113.2, 69.7, 69.2, 52.9, 52.0, 48.0, 45.0, 44.2, 42.1, 41.0, 32.6, 22.6,
22.5.
HRMS (FI): m/z calcd for C19H21Cl3N2O4 [M]+: 446.05669; found:
446.05580.
19
[a]D27 +55.2 (c 0.38, CHCl3).
16d
This material was obtained as a mixture of rotamers; [a]D27 –54.0 (c
IR (ATR): 1735, 1698, 1631, 1431, 1381, 1194, 1121 cm–1.
0.54, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.29 (2 H, d, J = 7.9 Hz), 6.95 (1
H, t, J = 7.9 Hz), 5.45 (1 H, s), 4.65 (1 H, d, J = 4.9 Hz), 3.68–3.75
(9 H, m), 3.46 (1 H, d, J = 10.4 Hz), 2.81–2.85 (2 H, m), 2.64 (1 H,
dd, J = 16.5, 6.7 Hz), 2.48 (1 H, dd, J = 16.5, 8.6 Hz), 1.90 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 172.1, 165.5, 155.7, 154.5, 144.3,
128.3, 128.0, 125.1, 125.0, 124.4, 116.6, 63.2, 52.7, 51.9, 51.3,
43.9, 43.8, 31.0, 23.6.
IR (ATR): 2237, 1730, 1708, 1382, 1367, 1145, 1134 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.99 (1 H, d, J = 1.2 Hz), 4.71 (1
H, s), 4.43 (0.4 H, s), 4.39 (0.6 H, d, J = 1.2 Hz), 3.54–3.66 (1 H,
m), 3.33–3.43 (1 H, m), 3.10–3.22 (1 H, m), 2.95–3.00 (1 H, m),
2.22 (1 H, dd, J = 17.0, 4.2 Hz), 2.05 (1 H, dd, J = 17.0, 10.3 Hz),
1.76 (3 H, s), 1.51 (9 H, s), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 170.7, 170.4, 153.7, 153.2, 140.2,
139.9, 118.5, 118.4, 113.7, 113.4, 81.8, 81.7, 81.6, 81.4, 52.0, 51.9,
47.0, 46.5, 45.7, 42.9, 42.0, 32.9, 32.8, 28.4, 28.3, 28.1, 22.7, 22.6.
HRMS (FI): m/z calcd for C19H20Cl2N2O4 [M]+: 410.08001; found:
410.08062.
HRMS (CI): m/z calcd for C19H31N2O4 [M + H]+: 351.2284; found:
351.2286.
(3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-(5-methylfu-
ran-2-yl)-4-(prop-1-en-2-yl)pyrrolidine-1-carboxylate (23)
To a solution of 15a (62.6 mg, 0.200 mmol) and 2-methylfuran
(0.0428 mL, 0.600 mmol) in CH2Cl2 (2.0 mL) was added BF3·OEt2
(0.0370 mL, 0.300 mmol) at –60 °C. After stirring for 1 h, the mix-
ture was quenched with sat. aq NaHCO3 (2.0 mL), and extracted
with CH2Cl2 (3 × 5.0 mL). The combined organic extracts were
dried (Na2SO4), filtered, and evaporated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy (EtOAc–hexane, 3:1) to give 23 (72.4 mg, ~100%) as a color-
less oil. This material was obtained as a mixture of rotamers;
[a]D29 –42.6 (c 0.75, CHCl3).
17d
This material was obtained as a mixture of rotamers; [a]D28 +39.8 (c
0.27, CHCl3).
IR (ATR): 2359, 1711, 1686, 1386, 1366, 1148 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.02 (1 H, s), 4.85 (1 H, s), 4.69–
4.77 (1 H, m), 3.48–3.62 (2 H, m), 3.06–3.13 (1 H, m), 2.83–2.89 (1
H, m), 2.46–2.58 (2 H, m), 1.80 (3 H, s), 1.52 (9 H, s), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 170.8, 170.6, 153.7, 153.1, 141.7,
141.6, 116.9, 115.1, 81.9, 81.5, 51.3, 51.1, 49.8, 49.3, 46.8, 46.0,
40.0, 39.1, 33.4, 28.3, 28.0, 22.7.
IR (ATR): 1705, 1448, 1368, 1146 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.05 (0.5 H, d, J = 1.8 Hz), 5.96
(0.5 H, d, J = 1.8 Hz), 5.87 (1 H, d, J = 1.8 Hz), 4.93 (1 H, s), 4.69–
4.75 (2 H, m), 3.46–3.71 (5 H, m), 3.07–3.17 (1 H, m), 2.75–2.83 (1
H, m), 2.26 (3 H, s), 2.18–2.24 (1 H, m), 2.00–2.11 (1 H, m), 1.72
(3 H, s), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): d = 171.7, 171.5, 155.9, 155.4, 152.7,
152.2, 151.3, 151.2, 141.9, 141.4, 112.6, 112.5, 107.2, 106.6, 106.1,
106.0, 80.9, 60.6, 60.3, 52.5, 52.4, 47.4, 47.3, 45.5, 44.5, 43.1, 42.2,
34.0, 28.1, 28.0, 22.8, 13.7.
HRMS (CI): m/z calcd for C19H31N2O4 [M + H]+: 351.2284; found:
351.2264.
(3S,4S)-Methyl 2-{Chloro[(2,6-dichlorophenyl)imino]methyl}-
3-(2-methoxy-2-oxoethyl)-4-(prop-1-en-2-yl)pyrrolidine-1-car-
boxylate (18) and (1S,5R,8S)-Methyl 4-[(2,6-Dichlorophe-
nyl)imino]-8-(2-methoxy-2-oxoethyl)-2-methyl-6-
azabicyclo[3.2.1]oct-2-ene-6-carboxylate (19)
To a solution of 15b (3.3 mg, 0.0122 mmol) and 1,3-dichloro-2-iso-
cyanobenzene (4.21 mg, 0.0243 mmol) in CH2Cl2 (0.10 mL) was
added TiCl4 (1.0 mol/L in CH2Cl2, 0.0183 mL, 0.0183 mmol) at
–78 °C. After stirring for 20 min at 0 °C, the mixture was quenched
with sat. aq NaHCO3 (2.0 mL) and extracted with CH2Cl2 (3 × 3.0
mL). The combined organic extracts were dried (Na2SO4), filtered,
and evaporated under reduced pressure. The crude product was pu-
rified by TLC (silica gel; EtOAc–hexane, 2:1) to give 18 (2.9 mg,
53%) and 19 (0.7 mg, 14%) as colorless oils.
HRMS (ESI): m/z calcd for C20H30NO5 [M + H]+: 364.21240;
found: 364.21283.
Epimerization of Aminonitrile 17a
To a solution of 17a (3.5 mg, 0.0114 mmol) in THF (0.10 mL) and
t-BuOH (0.050 mL) was added t-BuOK (1.28 mg, 0.0114 mmol) at
0 °C. After stirring for 1 h, the mixture was quenched with sat. aq
NH4Cl (2.0 mL) and extracted with EtOAc (3 × 5.0 mL). The com-
bined organic extracts were dried (Na2SO4), filtered, and evaporated
under reduced pressure. The crude product was purified by TLC
Synthesis 2011, No. 23, 3848–3858 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Kainic Acid
3857
(silica gel; EtOAc–hexane, 2:1) to give 16a (2.2 mg, 63%) as a
white solid and 17a (0.3 mg, 9%) as a colorless oil.
(5) Nitta, I.; Watase, H.; Tomiie, Y. Nature (London) 1958, 181,
761.
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Kamboj, R. K.; Hoo, K. H.; Tizzano, J. P.; Pullar, I. A.;
Farrell, L. N.; Bleakman, D. J. J. Med. Chem. 1996, 39,
3617.
(7) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid
as a Tool in Neurobiology; Raven: New York, 1978.
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(9) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
(10) For recent reviews, see: ref. 4.
(11) For selected examples, see: (a) Ueno, Y.; Tanaka, K.;
Ueyanagi, J.; Nawa, H.; Sanno, Y.; Honjo, M.; Nakamori,
R.; Sugawa, T.; Uchibayashi, M.; Osugi, K.; Tatsuoka, S.
Proc. Jpn. Acad. 1957, 33, 53. (b) Oppolzer, W.; Thirring,
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Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1988, 1204. (d) Takano, S.; Sugihara, T.; Satoh,
S.; Ogasawara, K. J. Am. Chem. Soc. 1988, 110, 6467.
(e) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F.
Tetrahedron 1990, 46, 7263. (f) Jeong, N.; Yoo, S.-E.; Lee,
S. J.; Lee, S. H.; Chung, Y. K. Tetrahedron Lett. 1991, 32,
2137. (g) Barco, A.; Benetti, S.; Pollimi, G. P.; Spalluto, G.;
Zanirato, V. J. Chem. Soc., Chem. Commun. 1991, 390.
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(–)-Kainic Acid (1)
To a solution of 15a (31.0 g, 98.9 mmol) and Me3SiCN (37.1 mL,
0.297 mol) in CH2Cl2 (495 mL) was added BF3·OEt2 (18.3 mL,
0.148 mol) at –60 °C. After stirring for 1 h, the mixture was
quenched with sat. aq NaHCO3 (100 mL) and extracted with
CH2Cl2 (3 × 200 mL). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated under reduced pressure to give
the crude nitrile. To a suspension of the crude nitrile in H2O (198
mL) was added NaOH (79.1 g, 1.98 mol). After stirring for 18 h at
reflux, the alcohols generated in situ (MeOH and t-BuOH) were re-
moved under atmospheric pressure. After stirring for 24 h at reflux,
the mixture was diluted with H2O (1000 mL), neutralized with Am-
berlite-CG-50 (H+ form), filtered, and evaporated under reduced
pressure. The residue was diluted with H2O (500 mL), filtered
through a Celite pad, and evaporated under reduced pressure. The
crude product was purified by ion exchange column chromatogra-
phy (DOWEX 1X8 200–400 mesh, OH– form, H2O to 5% aq
AcOH), and recrystallization from H2O to give (–)-kainic acid (1;
14.6 g, 69%) as colorless needles; mp 245 °C (H2O); [a]D27 –14.6 (c
0.63, H2O).
IR (ATR): 3545, 2973, 2541, 1689, 1614, 1382, 1314, 1275, 1242,
888 cm–1.
1H NMR (400 MHz; D2O): d = 5.05 (1 H, s), 4.77 (1 H, s), 4.11 (1
H, d, J = 3.6 Hz), 3.64 (1 H, dd, J = 11.5, 6.7 Hz), 3.44 (1 H, t,
J = 11.5 Hz), 2.99–3.13 (2 H, m), 2.49 (1 H, dd, J = 17.0, 6.7 Hz),
2.39 (1 H, dd, J = 17.0, 8.5 Hz), 1.76 (3 H, s).
13C NMR (100 MHz, D2O): d = 176.6, 173.8, 140.5, 114.1, 66.2,
47.0, 46.3, 41.3, 33.8, 22.7.
Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1997, 38,
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Lett. 1999, 55, 6153. (r) Campbell, A. D.; Raynham, T. M.;
Taylor, R. J. K. Chem. Commun. 1999, 245.
(s) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc.
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HRMS (CI): m/z calcd for C10H16NO4 [M + H]+: 214.1079; found:
214.1080.
Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C,
56.45; H, 7.04; N, 6.47.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This work was financially supported in part by Grant-in-Aids
(20002004) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
(w) Hirasawa, H.; Taniguchi, T.; Ogasawara, K.
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