kainic acid

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PAPER3848

A Practical Synthesis of ()-Kainic Acid

Synthesisof()-KainicAcidSatoshi 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: [email protected]

Received 25 August 2011; revised 20 September 2011

SYNTHESIS 2011, No. 23, pp 38483858xx.xx.2011Advanced online publication: 20.10.2011DOI: 10.1055/s-0031-1289570; Art ID: H84011SS

Georg Thieme Verlag Stuttgart New York

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.

Key words: kainoids, iodolactone, Curtius rearrangement, stereo-selective alkylation, total synthesis

()-Kainic acid (1) was isolated in 1953 from the Japanesemarine alga Digenea simplex2and has been found in the

related algae.3

A variety of related compounds have alsobeen 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 beenwidely used as a tool in neuropharmacology7 to stimulatenerve cells and mimic disease states, such as epilepsy,8

Alzheimers disease, and Huntingtons chorea.9

The structure of kainic acid, which includes a highly func-tionalized trisubstituted pyrrolidine ring with three con-tiguous stereogenic centers, has attracted considerableattention as a synthetic target. Although several total syn-

theses and synthetic approaches have been reported todate,10,11 few of the synthetic routes are amenable to large-

scale preparation with an efficiency comparable to that ofthe conventional isolation from algae, and therefore thiscompound remains quite expensive due to limited avail-ability despite its importance in neuroscience.12 We haverecently reported a highly practical synthesis of ()-kainicacid,13 which features the stereoselective alkylation of aniodolactone intermediate efficiently prepared from (+)-

carvone and introduction of carboxylic acid by hydrolysisof a nitrile accompanied by epimerization. Herein, weprovide a detailed account of our synthetic study of ()-kainic acid.

Our synthetic strategy was based on taking advantage ofthe 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 versatilesynthetic intermediate 3.14 For the purpose of an efficientsynthesis of ()-kainic acid (1), it occurred to us that 3seems to have suitable functionalities for the stereoselec-tive introduction of a C2 unit at the a-position of the car-

boxylic acid, installation of the nitrogen atom, andformation 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 in89% yield (Scheme 2). Treatment of epoxide 4 with con-centrated sulfuric acid in tetrahydrofuran gave a diaste-reomeric mixture of diols 5, which, without furtherpurification, 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 of3 was conducted to fix the conforma-

tion for the stereoselective introduction of the C2 unit.Compound 3 was thus treated with iodine and potassiumiodide 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.

Having established an efficient route to iodolactone 6, wenext concentrated on the introduction of the nitrogen atomand 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 withmethanol, afforded methyl carbamate 8 in 78% yield.16

Deprotonation of8 with 2.5 equivalents of LHMDS, fol-lowed by addition oftert-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 inthe presence of acetic acid, the reductive ring-opening ofthe iodolactone moiety in 9 proceeded to furnish carbox-ylic acid 10.

NH

CO2HH H

CO2HCHO

CO2H

installation of N formation of the pyrrolidine ring

stereoselective introduction of the C2 unit

ref. 14

(+)-carvone (2) ()-kainic acid (1)3

O

H

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PAPER Synthesis of ()-Kainic Acid 3849

Synthesis 2011, No. 23, 38483858 Thieme Stuttgart New York

The next task was to perform cyclization of carboxylicacid 10, which required screening of the reaction condi-tions. The results are summarized in Table 1. Treatmentof10 with acetic anhydride in the presence of sodium ace-tate at ambient temperature did not induce cyclization, butrather produced the corresponding mixed anhydride

(Table 1, entry 1). The mixed anhydride underwent cy-clization upon heating at 100 C to afford lactam 11, butepimerization at the a-position of the lactam concomitant-ly occurred (entry 2). The use of EDCI as a condensingagent at ambient temperature produced lactam 11 in only10% yield without epimerization (entry 3). Addition ofHOBt did not affect the progress of the reaction, and ele-

vating the reaction temperature led to epimerization (entry4). These results suggested that the cyclization reaction

should be conducted at low temperatures to avoid epimer-ization. After screening several condensing agents (en-tries 68), we found that diethylphosphoryl cyanide(DEPC)19 gave ideal results. Thus, upon treatment withDEPC and triethylamine at ambient temperature, carbox-

ylic acid 10 underwent cyclization to afford the desiredcis-substituted lactam 11 in 60% overall yield from 9 on amultigram scale (entry 8).

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

Scheme 2 Synthesis of iodolactone 6

O

(+)-carvone (2)

O

O

O

OHHO

O O

I

CHO

3

4 5

6

H H H

CHO

CO2H

30% aq H2O2aq NaOH

concdH2SO4

I2, KINaHCO3

MeOH, 0 C89%

THFH2Oreflux

NaIO4

i-PrOHH2O0 C to r.t.

CH2Cl2/H2O0 C

65% (3 steps)(dr = 1:0.6)

Scheme 3 Introduction of the nitrogen atom and the C2 unit

O O

I

CO2H

O O

I

NHCO2Me

OO

I

CHO

OO

I

NHCO2Me

CO2t-Bu

6

CO2H

NHCO2Me

CO2t-Bu

7 8

9 10

NaClO2NaH2PO42H2O

2-methylbut-2-ene

DPPA, Et3Ntoluene, r.t.;

110 C;

LHMDSTHF, 78 C; Zn, AcOH

t-BuOHTHFH2O0 C

87%(dr = 1:0.6)

MeOH, 75 C78%

(dr = 1:0.6)

BrCH2CO2t-Bu78 C82%

(dr = 1:0.6)

EtOH0 C to r.t.

Table 1 Optimization of the Reaction Conditions for the Formation

of the Lactam Ring

Entry Conditions Resulta

1 NaOAc, Ac2O, r.t. not obtained

2 NaOAc, Ac2O, 100 C 72% (1:1 mixture)b

3 EDCI, i-Pr2NEt, CH2Cl2, r.t. 10%

4 EDCI, HOBt, i-Pr2NEt, CH2Cl2,0 to 80 C 54% (1:1 mixture)b

5 BOPCl, i-Pr2NEt, CH2Cl2, r.t. 25%

6 DPPA, i-Pr2NEt, CH2Cl2, 40 C 40%

7 TCT,c Et3N, CH2Cl2, r.t. 43%

8 DEPC, Et3N, CH2Cl2, r.t. 60%

a Isolated yield in 2 steps from 9.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.

CO2H

NHCO2Me

CO2t-Bu

10

N

CO2Me

O

CO2t-Bu

H Hconditions

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cal shifts for 13C NMR are reported in parts per million relative tothe 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 spectralmeasurements were performed using a JEOL JMS-SX-102X or

JMS-T100GCV mass spectrometer. Elemental analysis data arewithin 0.3% of the theoretical values and were determined usinga 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 TLCplates (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 (40100

mm; Kanto Chemical Co., Inc., Tokyo, Japan) was used for flashcolumn chromatography.

(1S,4S,6S)-1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]hep-

tan-2-one (4)To a solution of (+)-carvone (2; 100 g, 0.666 mol) in MeOH (666mL) 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 at0 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 withbrine (300 mL), dried (Na2SO4), filtered, and evaporated under re-

duced pressure. The crude product was purified by distillation (9596 C/2.0 Torr) to give 4 (98.5 g, 89%) as a colorless oil; [a]D

24

79.4 (c 1.33, CHCl3).

IR (ATR): 1705, 1439, 1118, 889, 814 cm1.

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), 2.682.76 (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).

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.

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 of4 (98.4 g, 0.592 mol) in THF (500 mL) and H 2O(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 crudediol 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 for16 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

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 determinedby 1H NMR spectroscopy.

Major Isomer

[a]D26 +24.5 (c 0.65, CHCl3).

IR (ATR): 1765, 1718, 1382, 1257, 1125, 1043, 955, 911 cm1.

1H NMR (400 MHz, CDCl3): d = 9.82 (1 H, s), 3.30 (2 H, s), 2.892.98 (3 H, m), 2.752.82 (1 H, m), 2.452.52 (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.

Minor Isomer

[a]D26 +17.5 (c 0.55, CHCl3).

IR (ATR): 1769, 1719, 1383, 1267, 1165, 1037, 926 cm1.

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), 3.033.11 (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.


282.9851.

2-[(3S)-2-(Iodomethyl)-2-methyl-5-oxotetrahydrofuran-3-

yl]acetic Acid (7)To a solution of6 (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 NaH2PO42H2O (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 withconcd 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 togive 7 (99.7 g, 87%, 1:0.6 diastereomeric mixture) as a pale yellow

solid.

IR (ATR): 2971, 1764, 1700, 1410, 1221, 1152, 960, 912 cm1.

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), 2.873.04 (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), 2.382.66 (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.


298.9811.


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3854 S. Takita et al. PAPER


Methyl {[(3R)-2-(Iodomethyl)-2-methyl-5-oxotetrahydrofuran-

3-yl]methyl}carbamate (8)To a suspension of7 (99.7 g, 0.334 mmol) in toluene (1100 mL) was

added Et3N (60.5 mL, 0.434 mol) and DPPA (89.9 mL, 0.401mmol). 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) wasadded to the mixture. After stirring for 7 h at 75 C, the reaction wasdiluted 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 (EtOAchexane, 3:1 to 1:1) to give 8 (85.5 g, 78%, 1:0.6

diastereomeric mixture) as a yellow oil.

IR (ATR): 2950, 1766, 1698, 1529, 1248, 955 cm1.

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), 3.563.60 (1 H, m), 3.49 (0.6 H, d, J= 11.0 Hz),

3.253.41 (3 + 1.8 H, m), 2.622.85 (3 + 1.2 H, m), 2.472.49 (0.6H, 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.

HRMS (CI): m/z calcd for C9H15INO4 [M + H]+: 328.0046; found:

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 of8 (85.5 g, 0.260 mol) in THF (350 mL) over a period of 45min 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 productwas purified by silica gel column chromatography (EtOAchexane, 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 tothe stereogenic center at the g-position of the lactone. The diaste-

reomeric ratio was determined by 1H NMR spectroscopy, and thediastereomers 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 cm1.

1H NMR (400 MHz, CDCl3): d = 5.29 (1 H, s), 3.69 (3 H, s), 3.413.50 (4 H, m), 3.103.16 (1 H, m), 2.93 (1 H, dd, J= 17.7, 2.4 Hz),2.452.54 (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.

Minor Isomer

[a]D25 +34.1 (c 0.50, CHCl3).

IR (ATR): 2978, 1772, 1727, 1700, 1538, 1295, 1250, 1156, 1016cm1.

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), 3.373.42 (2 H, m),

2.902.99 (2 H, m), 2.482.58 (2 H, m), 1.51 (3 H, s), 1.48 (9 H, s).

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.


442.0720.

(3S,4S)-Methyl 3-[2-(tert-Butoxy)-2-oxoethyl]-2-oxo-4-(prop-1-

en-2-yl)pyrrolidine-1-carboxylate (11)

To a solution of9 (93.6 g, 0.212 mol) in EtOH (630 mL) was addedZn (69.3 g, 1.06 mol) and AcOH (61.0 mL, 1.06 mol) at 0 C. Afterstirring 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) andEt3N (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 productwas purified by silica gel column chromatography (EtOAchexane, 6:1) to give 11 (37.6 g, 60%) as a white solid; mp 9495 C

(hexane); [a]D25 +17.2 (c 0.50, CHCl3).

IR (ATR): 1749, 1442, 1361, 1317, 1244, 1149, 894 cm1.

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), 3.793.84 (2 H, m), 3.193.20 (2 H, m), 2.77 (1H, 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.

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 of11 (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, themixture 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 12as a yellow oil. To a solution of the hemiaminal 12 in MeOH (420

mL) was added pyridiniump-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 500mL). The combined organic extracts were washed with brine (200mL), dried (Na2SO4), filtered, and evaporated under reduced pres-

sure. The crude product was purified by silica gel column chroma-tography (EtOAchexane, 10:1) to give 15a (31.0 g, 79%) as a

colorless oil. This material was obtained as a mixture of rotamers;[a]D

25 38.9 (c 1.15, CHCl3).

IR (ATR): 1709, 1445, 1367, 1147, 1077 cm1.

1H NMR (400 MHz, DMSO-d6, 100 C): d = 4.93 (1 H, d, J= 1.2Hz), 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), 3.053.12 (1 H, m), 2.532.55 (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.

HRMS (FAB): m/z calcd for C20H39N2O7 [M + diethanolamine +

H]+: 419.2757; found: 419.2716.


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(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 of15a (134 mg, 0.428 mmol) and Me3SiCN (0.268

mL, 2.14 mmol) in CH2Cl2 (4.0 mL) was added BF3OEt2 (0.0792mL, 0.642 mmol) at 60 C. After stirring for 1 h, the mixture wasquenched 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 productwas purified by silica gel column chromatography (EtOAchexane, 4:1) to give 16a (96.6 mg, 73%) as a white solid and 17a(34.5 mg, 26%) as a colorless oil.

16a

This material was obtained as a mixture of rotamers; [a]D23 63.4 (c

0.53, CHCl3).

IR (ATR): 2242, 1715, 1452, 1375, 1160 cm1.

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), 3.603.70 (1 H, m), 3.373.48 (1 H, m), 3.133.23 (1 H, m),2.963.02 (1 H, m), 2.172.25 (1 H, m), 1.972.05 (1 H, m), 1.78 (3H, 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 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 cm1.

1

H 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), 3.513.67(2 H, m), 3.053.13 (1 H, m), 2.872.94 (1 H, m), 2.532.56 (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.


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 of15b (91.0 mg, 0.335 mmol) and Me3SiCN (0.126mL, 1.01 mmol) in CH2Cl2 (2.0 mL) was added BF3OEt2 (0.0620mL, 0.148 mmol) at 60 C. After stirring for 1 h, the mixture wasquenched 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

(EtOAchexane, 4:1) to give 16b (64.2 mg, 72%) and 17b (20.3mg, 23%) as colorless oils.

16b


0.44, CHCl3).

IR (ATR): 2241, 1707, 1448, 1376, 1199, 1132 cm1.

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), 3.613.72 (4 H, m), 3.393.49 (1 H, m), 3.163.25 (1 H, m),

3.013.06 (1 H, m), 2.292.35 (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.

17bThis material was obtained as a mixture of rotamers; [a]D

29 +47.8 (c

0.20, CHCl3).

IR (ATR): 2243, 1705, 1447, 1373, 1199, 1124 cm1.

1H NMR (400 MHz, CDCl3): d = 5.40 (1 H, s), 4.814.88 (2 H, m),

3.763.81 (3 H, m), 3.72 (3 H, s), 3.533.68 (2 H, m), 3.113.19 (1H, 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.

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 of15c (52.8 mg, 0.156 mmol) and Me3SiCN (0.0464

mL, 0.468 mmol) in CH2Cl2 (1.0 mL) was added BF3OEt2 (0.0288mL, 0.233 mmol) at 60 C. After stirring for 1 h, the mixture was

quenched with sat. aq NaHCO3 (2.0 mL), and extracted withCH2Cl2 (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

(EtOAchexane, 4:1) to give 16c (37.7 mg, 72%) and 17c (11.5 mg,

22%) as colorless oils.

16c


0.63, CHCl3).

IR (ATR): 2256, 1713, 1402, 1149 cm1.

1H NMR (400 MHz, CDCl3): d = 5.916.00 (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), 3.643.71 (1 H, m), 3.403.49 (1 H, m),

3.143.23 (1 H, m), 2.973.03 (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.


335.1955.

17cThis material was obtained as a mixture of rotamers; [a]D

28 +49.8 (c

0.37, CHCl3).

IR (ATR): 2251, 1710, 1400, 1151 cm1.

1H NMR (400 MHz, CDCl3): d = 5.906.01 (1 H, m), 5.245.41 (2

H, m), 5.03 (1 H, s), 4.804.92 (2 H, m), 4.634.75 (2 H, m), 3.533.69 (2 H, m), 3.073.14 (1 H, m), 2.862.95 (1 H, m), 2.55 (2 H, d,

J= 7.9 Hz), 1.81 (3 H, s), 1.46 (9 H, s).


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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.


335.1992.

(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 of15d (7.0 mg, 0.0197 mmol) and Me3SiCN (0.0123mL, 0.0985 mmol) in CH2Cl2 (0.20 mL) was added BF3OEt2(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 weredried (Na2SO4), filtered, and evaporated under reduced pressure.

The crude product was purified by TLC (silica gel) to give 16d (5.1mg, 74%) and 17d (0.7 mg, 10%) as colorless oils.

16dThis material was obtained as a mixture of rotamers; [a]D

27 54.0 (c

0.54, CHCl3).

IR (ATR): 2237, 1730, 1708, 1382, 1367, 1145, 1134 cm1.

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), 3.543.66 (1 H,m), 3.333.43 (1 H, m), 3.103.22 (1 H, m), 2.953.00 (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.


351.2286.

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 cm1.

1H NMR (400 MHz, CDCl3): d = 5.02 (1 H, s), 4.85 (1 H, s), 4.694.77 (1 H, m), 3.483.62 (2 H, m), 3.063.13 (1 H, m), 2.832.89 (1

H, m), 2.462.58 (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.


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 of15b (3.3 mg, 0.0122 mmol) and 1,3-dichloro-2-iso-

cyanobenzene (4.21 mg, 0.0243 mmol) in CH2Cl2 (0.10 mL) wasadded 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 3.0mL). The combined organic extracts were dried (Na2SO4), filtered,

and evaporated under reduced pressure. The crude product was pu-rified by TLC (silica gel; EtOAchexane, 2:1) to give 18 (2.9 mg,

53%) and 19 (0.7 mg, 14%) as colorless oils.

18This material was obtained as a mixture of rotamers; [a]D

28 10.7 (c0.18, CHCl3).

IR (ATR): 1710, 1437, 1379, 1197, 1132 cm1.

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), 4.744.76 (1.4 H, m), 4.66 (0.6 H, d,J= 2.4 Hz), 3.723.81 (7 H, m), 3.62 (0.6 H, t,J= 9.2 Hz), 3.55 (0.4

H, t,J= 9.2 Hz), 3.363.47 (1 H, m), 3.093.14 (1 H, m), 2.372.42(2 H, m), 1.75 (3 H, s).

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]D

27 +55.2 (c 0.38, CHCl3).

IR (ATR): 1735, 1698, 1631, 1431, 1381, 1194, 1121 cm1.

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), 3.683.75(9 H, m), 3.46 (1 H, d,J= 10.4 Hz), 2.812.85 (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.

HRMS (FI): m/z calcd for C19H20Cl2N2O4 [M]+: 410.08001; found:

410.08062.

(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 BF3OEt2(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 extractedwith 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 (EtOAchexane, 3:1) to give 23 (72.4 mg, ~100%) as a color-less oil. This material was obtained as a mixture of rotamers;[a]D

29 42.6 (c 0.75, CHCl3).

IR (ATR): 1705, 1448, 1368, 1146 cm1.

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), 3.463.71 (5 H, m), 3.073.17 (1 H, m), 2.752.83 (1

H, m), 2.26 (3 H, s), 2.182.24 (1 H, m), 2.002.11 (1 H, m), 1.72

(3 H, s), 1.46 (9 H, s).

13

C 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 (ESI): m/z calcd for C20H30NO5 [M + H]+: 364.21240;

found: 364.21283.

Epimerization of Aminonitrile 17aTo a solution of17a (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. aqNH4Cl (2.0 mL) and extracted with EtOAc (3 5.0 mL). The com-

bined organic extracts were dried (Na2SO4), filtered, and evaporatedunder reduced pressure. The crude product was purified by TLC


ResearchInstitute.



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(silica gel; EtOAchexane, 2:1) to give 16a (2.2 mg, 63%) as awhite solid and 17a (0.3 mg, 9%) as a colorless oil.

()-Kainic Acid (1)To a solution of15a (31.0 g, 98.9 mmol) and Me3SiCN (37.1 mL,

0.297 mol) in CH2Cl2 (495 mL) was added BF3OEt2 (18.3 mL,0.148 mol) at 60 C. After stirring for 1 h, the mixture wasquenched 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 givethe crude nitrile. To a suspension of the crude nitrile in H2O (198mL) 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. Thecrude product was purified by ion exchange column chromatogra-phy (DOWEX 1X8 200400 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]D

27 14.6 (c

0.63, H2O).

IR (ATR): 3545, 2973, 2541, 1689, 1614, 1382, 1314, 1275, 1242,888 cm1.

1H NMR (400 MHz; D2O): d = 5.05 (1 H, s), 4.77 (1 H, s), 4.11 (1H, 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), 2.993.13 (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.

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 athttp://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.

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