Synthetic Studies towards Kainic Acid Using Tandem Wittig ...shodhganga.inflibnet.ac.in/bitstream/10603/12620/7/07_chapter 2.pdf · Tandem Wittig-Intramolecular Ene Reaction

Chapter 2

Synthetic Studies towards Kainic Acid Using

Tandem Wittig-Intramolecular Ene Reaction

COOH

H (-)-Kainic acid (2)

CH2

---COOH H C ,----COOH H3C

COOH

HOOC

N _ COON

H (+)-Allokainic acid (3)

COON

H N COON

Glutamic acid (4)

CH3

/ :--COOH

&N)."'"COOH

H

(-)-Domoic acid (5)

N

----COOH

N COOH

H Acromelic acid (6)

H 3C

Chapter 2: Synthetic Studies towards Kainic Acid using Tandem Wittig-Intramolecular Ene reaction

Synthetic Studies towards Kainic Acid using Tandem Wittig- Intramolecular Ene Reaction

Introduction to Kainoids:

The kainoid amino acids 1 are unique group of non-proteinogenic pyrrolidine

dicarboxylic acids, consisting of trans-2,3-dicarboxylic acid groups on the pyrrolidine

core structure. The kainoids have attracted the scientific community due to its

neuroexcitatory properties! (-)-a-Kainic acid 2 is the parent member of the kainoids,

displaying potent anthelmintic properties and neurotransmitting activity in the central

nervous system, was first isolated from the marine algae Digenea simplex2 in 1953.

Since then number of naturally occurring kainoids 3 have been discovered including

allokainic acid 3, domoic acid 5 and acromelic acid 6. The mode of kainoid biological

action is thought to arise from their structural similarity to neurotransmitter 4 glutamic

acid 4 (Figure 1).

----COOH

N)-""'COOH

H Kainoids (1)

Figure 1. Structural comparison of kainoids with glutamic acid 4

Since the first enantioselective synthesis 5 of (-)-kainic acid 2 reported by Oppolzer W.

and Thirring K. in 1982, numerous synthetic studies have been employed, which have

Ph. D. Thesis Goa University 49


culminated, as both total synthesis and the formal synthesis of kainic acid. The

common features of all these syntheses are the construction of pyrrolidine ring.

Review of Literature:

Several syntheses of kainic acid have been disclosed because of its biological

importance as well as its synthetic interest. Oppolzer's synthesis of (-)-kainic acid

relying on an intramolecular ene reaction stands as the first, as yet remains the most

efficient approach. 5 Parsons A. F. has published a comprehensive review entitled

"Recent Development in Kainoid Amino acid Chemistry" covering the synthetic

efforts in this area prior to 1996. 3b The different approaches uses intramolecular

Pauson-Khand reaction, 6 tandem Michael reaction, 7 thiazolium8 or azomethine9 ylide

cycloaddition, Diels-Alder reaction, 1° retro Diels-Alder reaction of

ketodicyclopentandiene, 11 palladium induced cyclization, 12 aldol condensation, 13

enolate Claisen rearrangement,14 and free radical cyclization 15 reaction. Few of the

selected synthetic methods are discussed below.

CH3 COOMe

• COOMe

9 COCF3

Oppolzer W. and Andres H. described an intramolecular ene reaction approach to a-

kainic acid 2 starting from methyl-N-trifluoroacetylglycinate, which on N-alkylation

(NaH/ prenyl bromide/ HMPT/ 25 °C, 16 h) gave amido ester 7. Amido ester 7 was

treated with 2-methylthio acrylate (as Michael acceptor) and lithium-N-isopropyl

Oppolzer W. and Andres H. (1979, Scheme 1) 16 CH3

H3C CH3 COOMe

COOMe H3C \

SMe H3C

) LICA/ CH,=C(SMe)COOMe 1) mCPBA, -78 °C

N THF, -78 °C N COOMe 2) 130 °C

1 7 COCF3 8 COCF3

CH2 CH2

H3C ;..---COOMe -- H3C4 ;-----COOH

180 °C, 36h 0.•

\ 2N NaOH, reflux 4, ..ur

N COOMe N

)

COON

in I H — COCF3 (+/-)-2


CH2

H3C COOEt 1) TBAF (3eq), THF

2) Jones reagent

15 Boc OS I (CH3 )2C (CH3)3

H2

..3.,

L ts1 C001-I 16

Boc


cyclohexylamine (LICA) to give thioester 8 as a mixture of stereoisomers. Oxidation

of thioester 8 with mCPBA followed by distillation gave 1,5-diene 9. Diene 9 was

heated at 180 °C for 36 h to give cyclised pyrrolidine 10 via intramolecular ene

reaction. Saponification of diester 10 followed by purification with ion exchange resin

gave the amino-diacid which on crystallization furnished pure (±)-kainic acid 2.

Oppolzer W. and Thirring K. (1982, Scheme 2)5

The first enantioselective synthesis of (-)-a-kainic acid was described by Oppolzer W.

via intramolecular ene reaction using natural (S)-glutamic acid as starting material and

furthermore established its absolute configuration.

'COOEt 1) BH3 (3eq), THE

NaH,

HN COOH

2) tBu(Me)2SiCI , Et3N HN prenyl bromide

Boc 11

Boc OSi(CH 3)2C(CH3)3 12

CH3

H3C

COOEt

CH3

piperidine, THF H3C" 1) Lithium-2,2,6,6-tetramethy

2) PhSeCI, -78 °C, 3)30% H202

14 I

BOC OSi(CH3)2C(CH3)3 Boc 13

COOEt

) 50% soln. in toluene

130 °C, 40 h

OSi(CH 3)2C(CH3)3

CH2

1) LiOH (10 eq), 40 h )°' ,‘,.......

2) pH 2; 3) TFA, OrC H 3C "- -" COON

4) ion exchange resin N COOH

2 H

(+)-5-Ethyl glutamate was reduced selectively with diborane, followed by subsequent

silylation of resulting alcohol furnished the tert-butyldimethylsilyl ether 12. N-

alkylation of 12 with prenyl bromide/ NaH in HMPA gave mono olefin 13.

Conversion of olefin ester 13 to conjugate ester 14 involved the deprotonation of ester



13 using 2 equiv base, selenation of the resulting enolate, oxidation and selenoxide

elimination. The crucial step of closure of 5-membered ring (pyrrolidine 15) was

achieved by heating 50% solution of 1,6-diene 14 in toluene at 130 °C for 40 h using

sealed pyrex tube. Desilylation of pyrrolidine 15, subsequent oxidation of the resulting

alcohol with Jones reagent furnished corresponding acid 16, which on saponification

followed by Boc deprotection and purification using ion exchange resin gave (-)-a-

kainic acid 2.

Xia Q. and Ganem B. (2001, Scheme 3) 17

H3C CH3 EtOOC

I 1) maleic anhyd. r 2) SOCl2/EtOH 0N

NH2 3) PhCOCI, 4A° MS

3i R = H 18

R - COPh 19

H2C H2C

EtOOC CH3 EtOOC

4N HCI, EtOH

2) TMSCN (2 eq) NC

22 R 24 H H 25

H2C

2) 1N KOH HOOa N

1) 4N HCI, Me0H

H 2

The key feature of this approach is enantioselective metal-promoted ene cyclization to

give pyrrolidone, an advanced intermediate towards the synthesis of (-)-a-kainic acid.

N-prenylamine treated with maleic anhydride followed by esterification gave amide

diene 18, which was further converted to N-benzoyl derivative 19. The thermal and

metal-catalyzed intramolecular ene reaction of diene 18 or 19 can form either cis

substituted (20, 22) or trans substituted pyrrolidine (21, 23). Bis-oxazoline promoted

Mg (ID-catalytic cyclization of diene 19 provided desired cis diastereomer 22 in ratio

20:1 (for compound 22:23), which on mild hydrolysis provided pyrrolidone 24.

H3C

CH3 EtOOC

Mg(CI04)2 (2 eq) 11.

bis-oxazoline (2 eq)

R = COPh 22 R = COPh 23 (20:1)

R = H 21

H2C

CH3 EtOOC

CH3

1) Cp2ZrHCI (1.5 eq)

HOOC CH3


H3C CuCI (5 mol%)

PhSO2CI H2C Et3NHCI (5 mol%)

26

H3C

PhO2S Me0C6H4CH2 NH2 (3 eq)

CI 27

SO2 Ph

H2C H2C

(Me0)2(0)P, CH3 EtO0C CH3 EtOOC

NaH (1.2 eq) ethyl glyoxalare

N N

,.. PMB I

30 PMB PMB

1Pr-CuCI (2 mol%)

`11.10Na (10 molcA))) PMHS (4 eq)

CH3

CH3


Pyrrolidone 24 was treated with Schwartz's reagent (Cp2ZrHCI, 1.5 equiv in THF) to

give imine, which was treated with cyanotrimethyl silane (TMSCN) to afford the all-

cis nitrile 25. Nitrile 25 was reacted with 4N HCI-methanol, and then basified with

KOH to afford a-kainic acid, which was converted to (+)-ephedrine salt and

recrystallized to afford optically pure (-)-a-kainic acid 2.

Thuong M. et al. (2007, Scheme 4) 18

Giovanni P. & coworkers have described the formal synthesis of kainic acid via

intramolecular palladium-catalyzed allylic alkylation of sulfone.

PhO2S

CH3

NPMB (MeO)2 P(0)CH2

COOH (Me0)2 (0)P

28 H

I DCC, DMAP, THF, 16ri 0

29

z CH3

[Pd(C3 F15)C1j2 (5 mole%), dppe

"Bu4NBr (10 mol%), KOH

PMB

Copper catalyzed condensation between prenylsulfonyl chloride and isoprene afforded

allylic sulfone 27, which on treatment with p-methoxy benzylamine afforded allylic

amine 28, and subsequent acylation with dimethylphosphonoacetic acid gave

phosphonoacetamide 29. Intramolecular Pd-catalyzed allylic alkylation of

phosphonoacetamide 29 gave pyrrolidone phosphonate 30, followed by subsequent

Horner-Wadsworth-Emmons olefination with ethyl glyoxalate afforded diene

pyrrolidone 31. Treatment of 31 with 1,3-bis(2,6-diisopropylphenyl) imidazole-2-


Me00C

—COOMe

COOMe

Boc 40

15 kbar, 72 h N. COOMe

I 37 Boc

1) Me2CuCNLi2 H C 2) TMSCI

3) Oa, -116 °C, DMS

N COOMe 4) CH2N2

39 Boc

CH2

H3C-1/ COON

1) Li0H; 2) pyridine H

3) CH2N2; 4) DBU COOMe

38 Boc


ylidene,13u0Na and excess of poly(methylhydrosiloxane) as hydride source gave cis-

pyrrolidone 32. Finally, PMB deprotection of 32 gave Ganem's intermediate 33,

which constitute the formal synthesis of kainic acid.

Pandey, S. K. et al. (2006, Scheme 5) 19

HO TfO 1) SOCl2,MeOH

2) Bc)c-20' Et3N N COON 3) PCC N COOMe2) CH2N2

H 34 4) NaHMDS, PhNTf2 Boc 35

OSi(Me)3 OSi(Me) 3

Me0--J \ CH3 M KHSO4 Me00 H ---111' Me00

CHO

1) KHMDS, Comins Triflimide 2) Et3SiH, Pd(PPh3)

3) LiOH; 4) TFA

INN COON

H 2

4-Hydroxy-L-proline 34 was converted into N-Boc methyl ester derivative, and then

oxidized to corresponding ketone, which subsequently on treatment with NaHMDS/

PhNTf2 gave triflate 35. Pd-catalyzed methoxycabonylation afforded the desired

acrylate derivative 36. High pressure Diels-Alder reaction of acrylate 36 with 4-

methoxy-2-trimethyl-silyloxybutadiene (Danishefsky's diene) provided cyclo adduct

37 (OMe epimer), which on treatment with aq. KHSO4 was converted into enone 38.

Saponification of enone 38 gave enantiopure diacid, followed by

monodecarboxylation in hot pyridine and then esterification with diazomethane


CH3 COOMe

OTBS BnHN

41 K,CO3

CI

ICH2

H3C c -----CN

31.

N

1) NaCN, DMSO

2) CICOOMe

46 COOMe OTBS

1. Jones oxidation 2. Li0H, nPrOH (aq)

3. DOWEX (H+)


afforded the deconjugated enone, which was transformed into conjugated enone 39

using DBU. Conjugate addition of methyl group using cyanocuprate in presence of

trimethylsilyl chloride afforded the trimethylsilyl enol ether derivative which was

subjected to ozonolysis, followed by treatment with dimethyl sulfide and

diazomethane to give aldehyde 40. Conversion of the aldehyde 40 to (-)-a-kainic acid

2 was achieved through Pd-catalyzed triethylsilane reduction of enol triflate formed

with KHMDS and Comins triflimide followed by saponification, and then removal of

Boc group with TFA.

Chalker J. M. et al. (2007, Scheme 6) 20 —Cl

OH COOMe H3C

/"\

LiBH4 0 °C

43 42 I

Bn OTBS Bn OTBS

CH2

CH2 H3C-7/ 1) 5% Pd(PPh3), ZnEt2 (6 eq)

CH2

H3C

&N).'"*COOH

H 2

1) (C0C1)2, DMSO, Et3N H3C

2) Ph3P=CH2, THE 3) 1.5 eq 12 in THE

44 Bn OTBS

N-Monobenzyl and O-TBS protected methyl ester of D-serine 41 was subjected to

allylation with 4-chloro-3-methyl-l-bromo-2-butene to provide ally! chloride 42,

which on reduction gave alcohol 43. Swern oxidation and Wittig olefination of 43

provided diene 44, which was subjected to Pd(PPh3)4 and Zn(Et)2, and then quenched

with iodine to give pyrrolidine 45 as a single diastereomer. Treatment of pyrrolidine

45 with NaCN provided the corresponding nitrile, which was converted to carbamate

46 using methyl chloroformate. One-pot deprotection and Jones oxidation of TBS


HN O

Bn' 47

CH2

Boc/N

COOMe

CH2

H3C-4

1. aq KOH, Me0H

COOMe 2 . TFA , recrystallization COOH

H 2


ether provided corresponding carboxylic acid which on basic hydrolysis and

purification using ion-exchange resin provided (-)-a-kainic acid 2.

Sakaguchi H. et al. (2007, Scheme 7)21

Sakaguchi H. et al. demonstrated the construction of the fully functionalized

trisubstituted pyrrolidine ring via RCM of an acrylate derivative followed by an

intramolecular Michael addition of the resultant a,(3-unsaturated lactone.

H H H3C 0, H3C 0

RCM H., LiHMDS

Boc/N) 49

COOMe

OH 0

H3C____( H3C H

,,--COOMe „_,.. H3C Me0H H

cat. Et.,N & COOMe N

cat. TPAP, NMO D.

&N

N COOMe

Bloc

Bloc

50 Boc 51

COOMe

52

H3C

CH2 1 2 , Zn, TiCI4 31.

cat. PbCl2

The substrate 48 of RCM was prepared from oxazolidinone 47 via several steps that

includes acylation, Evans aldol condensation, introduction of glycine moiety through

Mitsunobu reaction, desilylation, and acylation with acryloyl chloride. Diene 48 was

treated with Hoveyda-Grubbs 2nd generation catalyst to give lactone 49, which was

reacted with LiHMDS base to provide pyrrolidine lactone 50 via intramolecular

Michael addition of the glycine moiety to the a,13-unsaturated lactone ring.

Methanolysis on the functionalized pyrrolidine derivative 50 provided corresponding

diester 51, which on oxidation followed by olefination under non-basic condition


Chapter 2: Synthetic Studies towards Kainic Acid using Tandem Wittig-lntramolecular Ene reaction

provided diester 53. Finally, hydrolysis of methyl ester, nitrogen deprotection and

recrystallization furnished pure (-)-a-kainic acid 2.

Sakaguchi H. et al. (2008, Scheme 8)22

Sakaguchi et al. presented the second generation route to (-)-kainic acid via

intramolecular Michael addition wherein the key S-lactone intermediate was prepared

from commercially available azetidone through the Reformatsky-type reaction.

OTBS OTBS

H3C

H

Ac COOtBu

1) BrZnCH2C00tBu H3C

1) NaBH4, EtOH

NHCbz

H

Ns TFA, 0 °C

N

s‘ss.

COOMe NHCbz 57

H3C OTBS COO tBu

NH 2) CbzCI, LiHMDS

54

N\ 2) NsNHCH2COOMe, 0 55 Cbz DEAD, ......- 3, rrn toluene 56

H =

BHoc3C 00

PhSH, K2CO3 I 1) LiHMDS, CbzCI, -60 °C

Boc.20, DMAP (cat) 2) LiHMDS COOMe NHCbz

58

NsN

COOMe

H3C Scheme 7

2-Azetidinone 54 was treated with bromozinc acetate and then with benzyl

chloroformate to provide carbamate 55, which on reduction gave amino alcohol,

followed by Mitsunobu reaction with Ns-activated glycine ester provided 56.

Treatment of 56 with TFA underwent cyclization to give lactone 57, which on

denosylation followed by Boc-deprotection gave 13-amino-ö-lactone 58. The sequential

elimination-Michael addition cascade by way of di-Cbz imide intermediate proceeded

nicely to give pyrrolidine derivative 50, which was previously transformed to (-)-a-

kainic acid (Scheme 7) by same research group.


Separation (S)-60 and (R)-60

semiprep. HPLC

Ts/

rac-60


Tomooka K. et al. (2008, Scheme 9) 23

Tomooka K. et al. reported asymmetric total synthesis for both the enantiomers of

kainic acid using the optically active amide as a chiral building block.

59 cH3

H 3C , CH2 H3C CH2 OH

cat. PdCl2(PhCN)2 (S)-60

(Sia) 2BH, THE A...- then H202 , NaOH

I 62 Ts

Ts

H2 /0TBS CH2 /0TBS H3C H3C 1,1

2) Li naphthalemide 10-

s-BuLi, O'Brien's

chiral amine then

1) TBSCI, imidazole

3) Boc2O, CICOOMe COOMe

63 Boc Bocl 64

CH2

H3C-4 ;,---COOMe H3C-4

1.- & 1) Jones reagent aq KOH, then TFA

2) TMSCHN2 , benzene-Me0H N N COOMe COOH

I H

Seven member lactam 59 was converted to required amide 60 as a racemic mixture.

Semipreperative HPLC with chiral stationary column, gave enantiomer (S)-60 in pure

form, which undergoes Cope rearrangement in the presence of Pd(II) catalyst to

provide pyrrolidine 61 with (3S,4S) configuration. Selective hydroboration of the

monosubstituted alkene 61 using disiamylborane followed by protection of hydroxyl

group with TBS, detosylation and N-Boc protection furnished pyrrolidine 63. The

lithiation of 63 with s-BuLi and O'Brien's chiral amine, followed by reaction of

methyl chloroformate provided C-2 carboxylation product 64. The treatment of

pyrrolidine ester 64 with Jones reagent, and sequential deprotection of TBSCI,

oxidation of the resulting alcohol and esterification gave corresponding diester 65.

Finally, alkaline hydrolysis of the ester moieties followed by removal of Boc group

CH2

—COON

Boc 2


EtOOC CH3

CH3

H2C H2C

CH3 HOOC EtOOC CH3

Literature deprotection 2:- --

HOOC"' .. N N esterification

2 H 24 H

R = Ph 67b

R = H 66a

R = Ph 66b

CH3 Tandem

Wittig-ene 0 N Br cH 3

H 67a I 68

Ft .-- R


using TFA yielded (-)-kainic acid 2. Similarly (+)-a-kainic acid has been prepared

using (-)-sparteine in lithiation step in above strategy.

Objective:

Amongst more than 60 publications reported towards the syntheses of (-)-a-

kainic acid, one of the efficient methods involves the preparation of pyrrolidone

(Ganem's intermediate) as an important advanced intermediate. Hence, we focused on

the Ganem's intermediate as our synthetic goal, which has two of the three

asymmetric centers of kainic acid, especially the thermodynamically less favorable C-

3, C-4 cis substituent. The objective of the present study is to devise a new, concise,

and high yielding route towards kainic acid in formal sense, by the synthesis of the

key intermediate, and further to demonstrate the feasibility and the synthetic utility of

tandem Wittig-intramolecular ene reaction approach for the construction of the cis

fused 3,4-disubstituted pyrrolidone skeleton.

Present Study:

Our proposed retrosynthetic strategy is outlined in Scheme 10.

Scheme 10. Retrosynthetic analysis of Ganem's intermediate

Our synthetic strategy involves preparation of Ganem's intermediate 24 from 3,4-

disubstituted-2-pyrrolidone 66, which in turn could be obtained from phosphorane 67

via tandem Wittig-intramolecular ene reaction. We identified two phosphoranes (67a


CH3 CH3

b C CH3

a H2N

69 70

CH3


and 67b) for our synthetic sequence. These phosphoranes could be obtained from

prenyl bromide via three steps.

Results and Discussion:

2-Pyrrolidone using N-monoalkyl substituted acetamide phosphorane (67a):

Initially, we thought of attempting a very short route utilizing N-

monosubstituted acetamide phosphorane 67a for our proposed tandem Wittig-ene

sequence. This route would have added advantage of minimizing one step of

deprotection of N-substituted amide to give Ganem's intermediate.

H3C

Scheme 11. Reagents and conditions: a) Potassium phthalimide, DMF, reflux; then

NH2NH2 H20; b) K2CO3, BrCH2COBr; c) PPh3; d) 2N NaOH

Thus, commercially available prenyl alcohol was converted to prenyl bromide

using PBr3 and then to prenylamine using Gabriel synthesis 24 utilizing potassium

phthalimide and hydrazine hydrate in 57% overall yield. The IR spectrum of

compound 69 showed two bands at 3400 cm -1 and 3290 cm -1 indicating the presence

of the NH2 functionality.

Further, prenylamine 69 was treated with bromoacetyl bromide in the presence

of K2CO3 to give N-prenyl bromoacetamide 70. The IR spectrum of 70 showed bands

at 3279, 1643 cm-1 which indicated the presence of NH and carbonyl functionalities.

Its 1 11 NMR spectrum (Figure 2) showed peak at S 1.71 (s, 31-1) and 1.76 (s, 3H) which

indicated the presence of two methyl group. The multiplets at 8 3.86-3.89 integrating


N I

H 67a

expected product


for four protons were attributed to CH2Br and NCH2 groups. The triplet at 8 5.21 (1

proton), and a broad singlet at 8 6.40 (1 proton) was attributed to vinylic and NH

protons respectively. Further, the formation of product 70 was confirmed by 13C NMR

spectrum and DEPT experiment wherein peaks at 8 29.2 and 8 165.0 indicated the

presence of CH 2Br and amide carbonyl group respectively. The peaks at 8 17.9, 25.6,

45.5, 119.5 and 128.9 were attributed to prenyl moiety. Finally, the assigned structure

70 was confirmed by HRMS showing [M+Naf peak at m/z 228.0009 for

C7H 1 2NO79BrNa.

N-prenyl bromoacetamide 70 was reacted with PPh3 in benzene at room

temperature to give triphenyl-(N-prenylacetamide)phosphonium bromide salt 71. The

'H NMR spectrum (Figure 3) showed peak corresponding to CH 2 attached to

phosphorus atom at 8 5.05 (d, J = 14.4 Hz, 2H) and the vinylic proton appeared as

triplet at 8 4.96 (1 H), whereas NH proton appeared at 8 9.24 as a broad singlet. The

peaks at 8 1.55 (s, 3H), 1.60 (s, 3H) and 3.66 (m, 2H) were attributed to two methyl

and one methylene (NCH2) respectively. Aromatic protons (PPh 3) were displayed as

multiplet at 8 7.63-7.86 (15 H). The 13C NMR spectrum showed peak at 8 31.9 [32.6]

for CH2 attached to phosphorus atom and 8 162.1 [161.9] for carbonyl group. The

multiplicities of carbon signals were determined by DEPT experiment.

H3C

Br Ph3P CH3 Ph3P

Base

solvent

Scheme 12. Preparation of Phosphorane

With the sufficient amount of this Wittig salt 71 in hand, our next plan was to

prepare the corresponding phosphorane 67a (Scheme 12). Hence, phosphonium salt 71

was subjected to deprotonation using 2N NaOH, but we could not get the

corresponding phosphorane (67a), instead we obtained N-prenyl acetamide 72, a

decomposed product of phosphorane. The 'H NMR spectrum of 72 (Figure 4) showed

N

H 71

H3C /- CH3

CH3

O N

72 H

product obtained

H3C

CH3

I

VI 13



two singlets at 8 1.69 and 8 1.64 integrating for 3 protons each indicating the presence

of two methyl group of prenyl moiety, whereas a doublet at 8 3.79 [3.81] (J = 5.7 Hz,

214) and a triplet at 8 5.17 (J= 5.7 Hz, 1H) were attributed to methylene and CH of

prenyl group respectively. A singlet at 8 1.95 integrating for 3 protons was attributed

to methyl attached to carbonyl, whereas a broad singlet at 8 5.92 integrating for one

proton was assigned to NH moiety. So, we thought that the initially formed

phosphorane may be getting decomposed to Ph3PO and N-prenyl acetamide in

aqueous reaction condition. Hence, we attempted the reaction of deprotonation using

various bases in anhydrous conditions without any success. Results obtained are

summarized in Table 1.

Table 1. Preparation of Phosphorane 67a

Entry Base/ reaction condition Products

1. 2N NaOH solution/ rt N-prenyl acetamide 72

2. 2N NaOH solution/ 0 °C N-prenyl acetamide 72

3. Et3N (2 equiv) No reaction (Wittig salt 67a)

4. DBU, CHC13, rt No reaction (Wittig salt 67a)

5. DBU, CHC13, reflux, 12h No reaction (Wittig salt 67a)

6. 1 equiv KOH (pallet) and Me0H, 5 min N-prenyl acetamide 72a

'Initially formed phosphorane decomposed within 5 min on addition of 50% aqueous glyoxalic acid

Thus, under all these reaction conditions, we could not succeed in getting the

target compound. The reason for this could perhaps be attributed to the instability of

phosphorane.

2-Pyrrolidone using N,N-disubstituted acetamide phosphorane (67b):

As we could not succeed in preparing the N-prenyl substituted acetamide

phosphorane, next we undertook the preparation of N,N-disubstituted acetamide

phosphorane and checked its feasibility towards the Wittig-ene reaction in tandem

fashion in formation of pyrrolidone skeleton (Scheme 13).


a, b c, d

Br

0 N

R = H 74

R = OMe 76

NH 2

R= H 73

R = OMe 75

R= H 69

R = OMe 77

R R = H 67a

R = OMe 78a

R R = H 67b

R = OMe 78b

HOOC


Scheme 13. Reagents and conditions: a) K2CO3, prenyl bromide; b) K2CO3,

BrCOCH2Br; c) PPh 3, benzene; d) 2N NaOH; e) 50% glyoxalic acid, solvent, reflux

Accordingly, benzylamine 73 (3 equiv) was subjected to monoalkylation using

K2CO3 and prenyl bromide to furnish N-prenyl benzylamine. Its IR spectrum showed

a band at 3400 cm' indicating the presence of the NH functionality. Treatment of

monoalkylated benzylamine with K2CO3 and bromoacetyl bromide yielded 74 whose

IR spectrum showed a band at 1647 cm -1 indicating the presence of carbonyl

functionality. In its 1 H NMR spectrum (Figure 5), peaks at 6 1.60 [1.53] (s, 3H) and

1.73 [1.71] (s, 3H) indicated the presence of two methyls of the prenyl moiety. The

peak at 6 3.91 [3.84] (s, 2H) was attributed to the methylene protons attached to the

bromine atom, whereas the benzylic protons appeared as singlet at 6 4.58 [4.55]

integrating for two protons. The peaks at 6 3.87 [4.01] (d, J = 6.6 Hz, 2H), 5.11-5.16

(m, 1 H) and 7.16-7.39 (m, 5H) were attributed to allylic, vinylic and aromatic protons

respectively. In the 13C NMR spectrum, the peaks at 6 26.3 [26.5] and 6 166.8 were

attributed to CH2Br and carbonyl group respectively. The peaks at 6 17.8, 25.6 were

attributed to two methyls, whereas peaks appearing at 6 45.7 [43.5], 119.3 [118.5],

137.2 were attributed to allylic, vinylic, and quaternary carbons of prenyl moiety



respectively. The benzylic carbon appeared at 5 48.3 [50.8], whereas peaks at S 126.3-

128.9 and 136.8 [136.2] were attributed to carbons of aromatic ring. The multiplicities

of carbons were recorded by DEPT experiment. Finally the assigned structure 74 was

confirmed by HRMS showing [M+Na] + peak at m/z 318.0474 for C141-118N079BrNa.

Reaction of N-benzyl-N-prenyl bromoacetamide 74 with PPh 3 afforded the

corresponding Wittig salt, which on deprotonation using NaOH provided the required

phosphorane 69. Its IR spectrum showed a band at 1640 cm -1 corresponding to the

amide carbonyl functionality. The formation of the product was inferred from the

disappearance of peak at S 3.91 [3.84] (s, 2H) in 'H NMR and S 26.3 [26.5] in 13C

NMR corresponding to CH2Br and the appearance of new peak at 5 2.09 (d, J = 12.6

Hz, 1H) in the 'H NMR spectrum and 5 29.6 in the 13C NMR spectrum for the CH

attached to phosphorus atom in phosphorane 69. Additionally, the 'H NMR showed

peaks in aromatic region at 5 7.10-7.51 (m, 15H, PPh 3). Further, the assigned structure

69 was confirmed by 13C NMR spectrum and DEPT experiment. Its HRMS spectrum

showed [M+H] + peak at m/z 478.2313 for C32H3 3NOP.

With the sufficient amount of phosphorane 69 in hands, our next plan was to

prepare the pyrrolidone skeleton. Towards this end, phosphorane 69 was refluxed with

glyoxalic acid with the intension of getting cyclized product via tandem Wittig-

intramolecular ene reaction. Initially, the experiment was carried out in refluxing

diphenyl ether (250 °C) for 4 h. The product obtained showed bands at 3485-3289,

1739, and 1639 cm' in its IR spectrum, indicating the presence of hydroxyl and

carbonyl functionalities. Its NMR spectrum (Figure 6) showed peak at 5 1.70 (s,

3H) indicated the presence of methyl group. Two vinylic protons appeared at S 4.85 (s,

1H) and 4.87 (s, 1H) whereas methylene attached to carboxylic group appeared at S

2.64 (dd, J = 4.8, 16.2 Hz, 2H). The peaks at 5 2.74-2.83 (m, 11-1) were attributed to

CH attached to methylene and a multiplet at 5 2.89-2.93 (1 H) was attributed to the

CH attached to carbonyl group. The methylene attached to the nitrogen appeared at S

3.10-3.16 (m, 1H) and 5 3.30-3.36 (m, 1H). The benzylic protons appeared at 5 4.42

(d, J= 14.7 Hz, 1H) and 5 4.57 (d, J= 14.7 Hz, 1H). The aromatic protons appeared as

multiplet at S 7.24-7.36 (m, 5H). In 13C NMR spectrum (Figure 7) the peaks at S 19.2,



114.0 and 142.4 were attributed to the methyl, vinylic and quaternary carbons of

isopropyl side chain respectively. The peaks at 6 34.7 and 175.7 were attributed to

CH2COOH fragment. The carbon peaks at 6 41.7, 46.4 and 47.0 were attributed to C-

3, C-4, and C-5 (NCH2) carbons respectively of the 2-pyrrolidone ring. The benzylic

carbon appeared at 6 49.5, whereas the peaks due to aromatic carbons were observed

at 6 128.1-128.9 and 135.5. The amide carbonyl carbon appeared at 6 174. The

multiplicities of carbons were determined by DEPT experiment. Finally, the formation

of compound 67 was confirmed by HRMS showing [M+Nar peak at m/z 296.1260 for

Ci6Hi9NO3Na.

Scheme 14. One-pot Wittig-ene reaction

The one step formation of pyrrolidone was taking place as expected via tandem

Wittig-ene reaction, but it was necessary to know the geometry at C-3 and C-4

substitution. In the literature, 25 the stereochemistry has been assigned, based on 6

values of methylene protons at 6 2.47 of the side chain for the cis isomer of 3,4-

disubstituted-2-pyrrolidone. However, in our product the methylene protons appeared

at 6 2.64 (dd, J= 4.8, 16.2 Hz, 2H) indicating the formation of trans product in major

amount. Further, we observed that the methyl peak of isopropenyl group appeared at 6

1.70 (s, 3H) and 6 1.46 (s, minor peak) in 7:1 ratio (Figure 6). This implied that, in cis

isomer, methyl is shielded compared to trans isomer. We have used these values of

methyl protons to assign the geometries hereafter.

We had expected that, first Wittig reaction to take place followed by ene

reaction as depicted in Scheme 14. The ene reaction is a pericyclic reaction and the

mechanism demands cis stereocenters at C-3 and C-4 position. However, we obtained

trans-isomer 67b as the major product. This could have been due to high temperature



used for the reaction, in which the cis product formed might have converted to

thermodynamically more stable trans product. As to overcome this problem, we

planned for carrying out the reaction at a slightly lower temperature. Hence,

cyclization was attempted at 120 °C in refluxing toluene for 24 h. To our delight, a

high C-3, C-4 cis selectivity (67a) was achieved over trans product (67b) in 20:1 ratio

as evident from 'H NMR spectrum (Figure 8) showing major peak at 8 1.46 (s, 3H)

and minor peak at 8 1.70 (s) corresponding to isopropenyl methyl side chain of 2-

pyrrolidone. Finally, the assigned structure 67a was confirmed by 13C NMR spectrum,

DEPT experiment and HRMS showing [M+Nar peak at m/z 296.1253 for

C161419NO3Na.

Further with intension to minimize the time required for completion of Wittig-

ene reaction, we attempted reaction at slightly higher temperature i.e. 140 °C in

xylene. Hence, phosphorane 69 was refluxed in glyoxalic acid in xylene at 140 °C.

Similar results were obtained for cyclization step in xylene and required same time (24

h) as that of the reaction in toluene. The pyrrolidone (67a:67b) is formed in 20:1 ratio

and 58% yield. The results of cyclization step in different solvents and temperature are

mentioned in tabular form (Table 2).

Table 2. Tandem Wittig-intramolecular ene reaction of phosphorane 69

Entry Substrate (R) Condition Product Ratioa (% Yield)

1. H 250 °C, PhOPh, 4h 67a:67b 1:7 (40)

2. H 110 °C, toluene, 24h 67a:67b 20:1 (60)

3. H 140 °C, xylene, 24h 67a:67b 20:1 (58)

aThe ratio of diastereomers was calculated on the basis of I H NMR.

To complete the formal synthesis of kainic acid 2, removal of the benzyl group in 67a

was necessary. With the above objective in our mind, we treated pyrrolidone 67a with

ceric ammonium nitrate (4 equiv) in Me0H for 14 h at room temperature. Usual

workup furnished oily compound, whose peaks in NMR spectra were matching with

pyrrolidone 67a (starting material) except the appearance of a new peak at 8 3.67 (s,

3H) in the 'H NMR (Figure 9), 8 51.7 in both 13C NMR spectrum and DEPT

experiment. These peaks were attributed to the carbomethoxy group. Hence, we


HOOC

0

CH3 Me00C

4 equiv CAN 3.

Me0H

CH3 Me00C

1 67a CH2Ph 79 C

I H2Ph

Scheme 15. Deprotection of pyrrolidone 67a


obtained corresponding methyl ester 79 without debenzylation. The assigned structure

79 was further confirmed by HRMS which showed [M+Nar peak at m/z 310.1412 for

C 1 7H21NO3Na. CAN is also known as mild reagent for esterification reaction. 26 Hence,

CAN/Me0H-promoted esterification of pyrrolidone 67a took place rather than N-

debenzylation reaction (Scheme 15). Further, pyrrolidone 79 was treated with 2 equiv

of CAN without any successful debenzylation. Next, the same reaction mass was

refluxed for 20 h, but starting material 79 was found to be intact. Debenzylation was

attempted in different condition such as refluxing in pTsOH, 27 Pd/C; ammonium

formate28 but all attempts were unsuccessful (Table 3).

H2c H2c H2C

CH3

Table 3. Debenzylation of pyrrolidone 67a

Entry Reaction condition Product obtained

1. CAN (4 equiv) Pyrrolidone methyl ester 79

2. pTsOH, toluene, reflux, 18 h No reaction (starting recovered)

3. Pd/C, ammonium formate, reflux, 8 h No reaction (starting recovered)

The above unsuccessful attempted debenzylation led us to slightly modify our

synthetic strategy wherein we thought of introducing the p-methoxy benzyl (PMB)

rather than benzyl group as N-protective group in early stage of the synthesis. The

PMB group is known to be more reactive towards CAN oxidation compared to benzyl

group itself. 29 Hence, modified phosphorane 77 was prepared in a similar manner as

phosphorane 69 (Scheme 13). Thus, p-methoxybenzylamine 75 (3 equiv) was treated

with prenyl bromide (1 equiv) to give N-prenyl(p-methoxy)benzylamine. Its IR

spectrum showed a band at 3300 cm"' indicating the presence of NH functionality. The



'H NMR spectrum showed singlets at 5 1.63 (s, 3H), and 5 1.73 (s, 3H) corresponding

to two methyl groups of the prenyl moiety. Allylic protons appeared at 5 3.22 (d, J

6.6 Hz, 2H), whereas benzylic protons appeared at 5 3.72 (s, 2H). The vinylic proton

appeared as triplet at S 5.26 (t, 1 H), whereas broad singlet at 5 5.91 integrating for one

proton indicated the presence of NH. Methoxy group on aromatic ring was displayed

at 5 3.80 (s, 3H) and aromatic protons appeared at 5 6.86 (d, J = 8.4 Hz, 2H) and

7.23 (d, J = 8.4 Hz, 2H).

N-prenyl(p-methoxy)benzylamine was treated with K 2CO3 and bromoacetyl

bromide to give N-(p-methoxy)benzyl-N-prenyl-2-bromoacetamide 76. Its IR

spectrum showed a band at 1647 cm 1 corresponding to amide carbonyl functionality.

The success of N-acetylation was inferred from the appearance of additional peak in

the 'H NMR spectrum (Figure 10) at 5 3.91 [3.88] (s, 2H) corresponding to the methyl

attached to the bromine atom. Further, the carbon peak in 13C NMR spectrum at 5 26.5

and 166.8 were attributed to CH2Br and amide carbonyl group respectively. Finally,

the assigned structure 76 was confirmed by HRMS, which showed [M+Na] + peak at

m/z 348.0566 for Ci5H20NO2 79BrNa.

N-(p-methoxy)benzyl-N-prenyl-2-bromoacetamide 76 was treated with PPh 3 to

give corresponding Wittig salt, which on deprotonation furnished the required

aetamide phosphorane 77. Its IR spectrum showed a band at 1647 cm 1 corresponding

to the amide carbonyl functionality. The formation of phosphorane 77 was inferred

from the disappearance of peaks at 5 3.91 [3.84] (s, 2H) in the 'H NMR and 5 26.5 in 13C NMR spectrum (corresponding to CH 2Br) and the appearance of new peaks at 5

2.01 as broad singlet integrating for one proton in the 1 H NMR (Figure 11) and 5 32.6

in the 13C NMR spectrum (Figure 12) for the CH attached to the phosphorus atom.

Further, the assigned structure 77 was confirmed by HRMS which showed [M+H] +

peak at m/z 508.2401 for C33H35NO2P.

Phosphorane 77 was treated with glyoxalic acid in refluxing toluene to give

3,4-disubstituted-2-pyrrolidone via tandem Wittig-intramolecular ene reaction. Its IR

spectrum showed bands at 3600-2245, 1722 and 1645 cm' corresponding to hydroxyl

and carbonyl functionalities. In the 1 H NMR spectrum (Figure 13), isopropenyl methyl



peaks appeared at 8 1.46 (s, 3H) and 8 1.70 (s) in 5:1 ratio respectively, indicating the

formation of the product 78a (cis) and 78b (trans) in 5:1 ratio. The peaks at 8 2.39 (dd,

J = 6.6 Hz, 17.1 Hz, 1H) and 8 2.79 (dd, J = 5.4, 17.4 Hz, 1H) were attributed to the

methylene attached to carboxylic acid group. The multiplet at 8 3.09-3.14 (m, 3H) was

attributed to CH attached to carbonyl of the amide and NCH 2, whereas the CH

attached to isopropenyl group appeared at S 3.45-3.48 (m, 1 H). The benzylic protons

were displayed as doublets at 8 4.37 (J = 14.4 Hz, 1H) and 8 4.45 (J = 14.1 Hz, 1H),

whereas two vinylic protons showed as singlets at 8 4.72 (111) and 8 4.81 (1H). The

singlet at 8 3.80 (3H) was attributed to methoxy group present on the aromatic ring.

The peaks at 8 6.87 (d, J = 8.4 Hz, 2H) and 8 7.19 (d, J = 8.4 Hz, 2H) were attributed

to the aromatic protons. In the 13C NMR spectrum, the carbon peaks at 8 41.2 and 8

42.2 were attributed to C-3 and C-4 of 2-pyrrolidone skeleton whereas carbonyl

carbon of amide and acid functionalities appeared at 8 175.1 and 8 175.5 respectively.

Further, the assigned structure 78a was confirmed by HRMS which showed [M+Nal +

peak at m/z 326.1365 for C17H2INO4Na.

Finally, the stage was set up to carry out deprotection of PMB group. Initially,

the deprotection reaction was tested using CAN in Me0H. Hence, N-(p-

methoxy)benzyl-2-pyrrolidone 78a was treated with CAN and Me0H for 12 h at room

temperature (Scheme 16). The success of the reaction was inferred from formation of

p-methoxybenzaldehyde (positive 2,4-DNP test on tic). The IR spectrum of

pyrrolidone 80 showed bands at 3203, 1732 and 1693 cm-1 indicating the presence of

NH, ester and amide functionalities respectively. Further, the success of the reaction

was inferred from the disappearance of peaks corresponding to p-methoxybenzyl

group in its NMR spectrum and the appearance of new peak at 8 6.01 (br s, 1H) in 1 11

NMR spectrum (Figure 14), which was attributed to NH of the amide group. Further,

the singlet at 8 1.67 (3 protons) was attributed to isopropenyl methyl group, whereas

two double doublets at 8 2.31 (J = 9.9, 17.4 Hz, 1H) and 8 2.80 (J = 4.5, 17.4 Hz, 1H)

were attributed to methylene attached to carbonyl group. The peak at 8 3.09 (ddd, J =

4.2, 4.5, 9.6 Hz, 1 H) was attributed to CH flanked by methylene and carbonyl of the

amide group. The multiplet at 8 3.26-3.32 (m, 2H) was attributed to the CH attached to



isopropenyl group and one proton of NCH2 group, whereas the other NCH2 proton

appeared at 6 3.59 (dd, J = 6.6, 9.9 Hz, 1H). The peaks at 6 3.70 (s, 3H), 4.78 (s, 1H)

and 4.87 (s, 1H) were attributed to the methoxy and two vinylic protons respectively.

Its 13C NMR spectrum showed peaks at 6 20.1 and 30.3 corresponding to methyl of

the isopropenyl moiety and the methylene attached to the carbonyl group. The C-3 and

C-4 carbons appeared at 6 40.4 and 44.5 respectively, whereas C-5 (CH2N) appeared

at 8 44.7. The carbon peak at 6 51.7 was attributed to methoxy of ester group. The

olefinic carbons of isopropenyl moiety appeared at 6 114.9 and 6 142.9 whereas peak

at 6 172.8 and 178.2 indicated the presence of amide and ester carbonyl respectively.

Finally, the assigned structure 80 was confirmed by HRMS which showed [M+Na]+

peak at m/z 220.0947. Hence, CAN oxidation of pyrrolidone 78a resulted in

deprotonation of PMB group as well as esterification of carboxylic acid giving the

methyl ester of the Ganem's intermediate 80.

N 4 steps( 73%) HOOC''' Nt—

ROOC HOOC CAN, ROH lit.

H H 80 : R = CH3 (95%) Kainic acid (2) 24 : R = C2H5 (68%)

Scheme 16. Synthesis of Ganem's intermediate

To complete the formal synthesis of kainic acid by preparing real Ganem's

intermediate required the ethyl ester of pyrrolidone. Hence, CAN oxidation of

pyrrolidone 78a was carried out using EtOH as solvent to furnish Ganem's

intermediate 24, after stirring the reaction for 12 h at room temperature. Its IR

spectrum showed bands at 3205, 1730, and 1696 cm -1 indicating the presence of NH

and carbonyl functionalities. The NMR spectra of pyrrolidone 24 (ethyl ester) matches

with the spectra of pyrrolidone 80 (methyl ester) except to the peaks corresponding to

ester part i.e. the peak at 6 3.70 (s, 3H) and 6 51.7 corresponding to methoxy of the

ester moiety of compound 80 in its NMR and 13C NMR respectively, disappeared

in compound 24. The appearance of new peaks at 6 1.26 (t, J = 7.2 Hz, 31-1) and 4.15



(q, J = 7.2 Hz, 21-1) in its 'H NMR (Figure 15) and i 14.1 and 60.6 in its 13C NMR

spectrum (Figure 16) was attributed to OCH 2CH3 moiety in compound 24. The

multiplicities of carbon were determined using DEPT experiment. Finally, the

assigned structure 24 was confirmed by HRMS which showed [M+Nar at m/z

234.1101 for C 11 14 171■103Na. The spectral data of Ganem's intermediate 24 were

identical to those reported in literature. 17 Further, pyrrolidone 24 could be converted to

kainic acid using literature procedure (Scheme 3). Thus, the synthesis of Ganem's

intermediate constitutes a formal synthesis of kainic acid.

Conclusions:

1. We have demonstrated the feasibility and synthetic utility of a newly

developed tandem Wittig-intramolecular ene reaction sequence for the

assembly of cis fused 3,4-disubstituted pyrrolidone.

2. The synthesis of the Ganem's intermediate has been achieved via concurrent

one-pot Wittig-ene reaction and constitutes the synthesis of (f)-kainic acid in

formal sense.



Experimental Section

2.01 Preparation of prenylamine (69):

CH3

H2N CH3

A mixture of prenyl bromide 68 (2.995 g, 0.02 mol) and potassium phthalimide (4.096

g, 0.022 mol) in DMF (15 mL) was heated to 120 °C for 30 min, and then to 160 °C

for additional 40 min. The hot mixture was poured over ice (15 g), and extracted with

CHC13 (4 x 50 mL). The combined extract was washed successively with IN KOH (2

x 20 mL), 0.5N HCl (2 x 20 mL) and with H2O (2 x 30 mL). The CHC13 solution was

dried over anhyd Na2SO4, and then concentrated to give the residual crude solid N-

prenylphthalimide (3.296 g, 76.3%). A mixture of N-prenyl phthalimide (1.200 g, 5.58

mmol) in THF (10 mL) and 0.5 mL hydrazine hydrate was refluxed for 15 h. THF was

removed under vacuum pump and added lON HCl (5 mL). Solid obtained was filtered,

washed with H2O (2 x 5 mL) and then aqueous layer was basified with 85% KOH (10

mL, basic pH). Extracted with Et20 (3 x 40 mL), dried and concentrated using

vacuum pump to provide prenylamine 69 as yellow liquid (0.356 g, 75%).

IR (neat): v.3400, 3290 cm -1 (NH2).

2.02 Preparation of N-prenyl-2-bromoacetamide (70):

5'

1' CH3

1 N 3 1 CH3

H 2 4'

To a stirred solution of prenylamine 69 (0.350 g, 4.11 mmol) and K2CO3 (0.695 g, 5.02

mmol) in CHC13 (20 mL) was added a solution of bromoacetyl bromide (1.014 g, 5.02

mmol) in CHC1 3 (1 mL) at 0 °C over a period of 10 min. The reaction mixture was

stirred for 2 h at room temp. Added H 2O (20 mL), and then extracted with CHC13 (3 x

20 mL). The organic phase was washed with H2O (2 x 20 mL), 2N HCI (3 x 30 mL),

followed by NaHCO3 (2 x 20 mL), dried over anhyd Na2SO4, filtered and concentrated

in vacuum. Purification of the residue by column chromatography (SiO2, hexanes/

Br



EtOAc, 8:2) afforded N-prenyl-2-bromoacetamide 70 as a white crystalline solid (0.554

g, 64.4%).

Mp: 59-60 °C.

IR (neat): vmax 3279 (NH), 1643 cm-1 (C=0).

111 NMR (CDC13, 300 MHz): 8 1.71 (s, 3H, CH3), 1.76 (s, 3H, CH3), 3.86- 3.89 (m,

41-1, H-2 and H-1'), 5.21 (t, J= 6.9 Hz, 1H, H-2'), 6.40 (br s, 1H, NH).

13C NMR (CDC13, 75 MHz): 8 17.9 (CH3), 25.6 (CH3), 29.2 (CH2Br), 38.2 (C-1'),

119.1 (C-2'), 137.9 (C-3'), 165.0 (C=0).

HRMS: m/z [M + Na]+ calcd for C71-1 1 2N079BrNa: 228.0000; found: 228.0009.

2.03 Preparation of N-preny1-24tripbenylphosphoniumlacetamide bromide (71)

Ph3P+

Br

1 '

5' CH3

31 CH3 4'

To a stirred solution of PPh3 (0.683 g, 2.60 mmol) in dry benzene (20 mL) was added

N-prenyl-2-bromoacetamide 70 (0.488 g, 2.37 mmol), and the solution was stirred at

room temp for 8 h. Benzene was decanted from sticky compound and then washed with

Et20 (2 x 20 mL), followed by n-hexanes to give Wittig salt 71 as a thick liquid (0.932

g, 84%).

IR (neat): vmax 3279 (NH), 1640 cm-I (C=0).

111 NMR (CDC13, 300 MHz): S 1.55 (s, 3H, CH3), 1.60 (s, 3H, CH3), 3.86 (m, 2H, H-

1'), 4.96 (t, J = 6.9 Hz, H-2'), 5.05 (d, J = 14.4 Hz, 2H, H-2), 7.63-7.86 (m, 15H, Ar-

14), 9.24 (s, 1 H, NH).

13C NMR (CDC13, 75 MHz): S 17.9 (CH3), 25.4 (CH3), 31.9 [32.6] (C-2), 38.0 (C-1'),

119.0 [119.6] (C-2'), 130.0-135.2 (Ar-C and C-3'), 162.1 [161.9] (C=0).



2.04 N-Prenyl acetamide (72):

0

H3C 1 'N 2

Hi

IR (neat): vmax 3320 (NH), 1647cm -I (C=0).

111 NMR (CDC13, 300 MHz): ö 1.64 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.95 (s, 3H, H-

2), 3.79 [3.81} (d, J = 5.7 Hz, 2H, H-1'), 5.17 (t, J = 5.7 Hz, H-2'), 5.92 (br s, 1H, NH).

13C NMR (CDC13, 75 MHz): S 17.8 (CH3), 23.1 (CH3), 25.6 (C-2), 37.6 (C-1'), 120.2

(C-2'), 133.1 (C-3'), 170.0 (C=0).

2.05 General procedure for preparation of N, N-disubstituted bromoacetamide

(74 & 76):

To a stirred solution of benzylamine 73 or p-methoxybenzylamine 75 (3 equiv) and

K2CO3 (1 equiv) in anhyd CH3CN (10 mL) was added a solution of prenyl bromide (1

equiv) in CH3CN (2 mL) over a period of 10 min in an ice cold water bath. The

reaction mixture was stirred for 1 h at room temp, and then concentrated under

reduced pressure. Purification of residue by column chromatography on silica gel

(hexanes: EtOAc = 7:3) afforded N-prenylbenzylamine (the yield of product was

calculated based on the recovery of starting benzylamine). To a stirred solution of N-

prenyl benzylamine (1 equiv) and K2CO3 (2 equiv) in CHC13 (20 mL) was added a

solution of bromoacetyl bromide (1.2 equiv) in CHCI3 (1 mL) at 0 °C over a period of

10 min. The reaction mixture was then stirred for 1 h at room temp, diluted with water

(20 mL) and product was extracted with CHC1 3 (3x 20 mL). The organic phase was

washed with H2O (2x 20 mL), followed by NaHCO 3 (2x 30 mL), dried over anhyd

Na2SO4, filtered and concentrated in vacuum. Purification of residue by column

chromatography on silica gel (hexanes: EtOAc = 7:3) afforded the desired product.



2.05a N-Benzyl-N-preny1-2-bromoacetamide (74):

41 0 H3C

31 Br,,...,„<NN 1 nu

1 2 1,1 3 1

51 CH 2Ph

Yield: 65 % (2 steps); light yellow thick oily compound.

IR (vmax): 1647 cm-1 .

1H NMR (CDC13, 300 MHz): 8 1.60 [1.53] (s, 3H, H-4'), 1.73 [1.71] (s, 3H, H-5'),

3.87 [4.01] (d, J = 6.6 Hz, 2H, H-1'), 3.91 [3.84] (s, 2H, H-2), 4.58 [4.55] (s,

2H,C1I2Ph), 5.11-5.16 (m, 1H, H-2'), 7.16-7.39 (m, 5H, Ar-H).

13C NMR (CDC13, 75 MHz): 8 17.8 (C-4'), 25.6 (C-5'), 26.3 [26.5] (C-2), 45.7 [43.5]

(C-1'), 48.3 [50.8] (CH2Ph), 119.3 [118.5] (C-2'), 126.3 [127.3] (C-3'), 127.7 [127.9],

128.5 [128.9], 136.8 [136.2] (Ar-H), 137.2 (Ar-C), 166.8 (C-1).

HRMS: m/z [M+Nar calcd for C1 4H1 8N079BrNa: 318.0469; found: 318.0474.

2.05b N-(p-methoxy)benzyl-N-prenyl-2-bromoacetamide (76):

5'

OCH 3

Yield: 66% (2 steps); light yellow thick oily compound.

IR (vmax): 1647 cm-1 .

1H NMR (CDC13, 300 MHz): 8 1.62 [1.56] (s, 3H, H-4'), 1.75 [1.73] (s, 3H, H-5'),

3.80 [3.82] (s, 31-I, OCH3), 3.91 [3.88] (s, 2H, H-2), 3.87 [3.99] (d, J = 6.9 Hz, 2H, H-

1'), 4.52 [4.49] (s, 2H, C132Ph), 5.05-5.20 (m, 1H, H-2'), 6.86 [6.89] (d, J = 8.4 Hz,

2H, Ar-H), 7.18 [7.13] (d, J= 8.4 Hz, 2H, Ar-H).

13C NMR (CDC13, 75 MHz): 8 17.9 (C-4'), 25.7(C-5'), 26.5(C-2), 45.5 [43.3] (C-1'),

47.8 [50.3] (CH2Ph), 55.2 (OCH3), 114.0 [114.3] (Ar-H), 119.5 [118.6(C-2')], 127.7


Ph ,P

22 1 CH2 Ph

1 N CH3 5'


[129.4] (Ar-H), 128.9 [128.0] (C-3'), 136.7 [137.1] (Ar-C), 159.0 [159.2] (Ar-C),

166.8 (C-1).

HRMS: m/z [M+Na]+ calcd for C15H2oNO279BrNa: 348.0575; found: 348.0566.

2.06 General procedure for preparation of Phosphorane (69 & 77):

To a stirred solution of PPh3 (1.1 equiv) in dry benzene (20 mL), N,N-disubstituted

bromoacetamide (74 or 76) (1 equiv) was added and the solution was stirred at room

temp for 8 h. Water (40 mL) was added to the reaction mixture, and washed with

benzene (3x 30 mL). Benzene (50 mL) was added to aqueous layer followed by 2N

NaOH with constant shaking to phenolphthelein end point. Benzene layer was dried

over anhyd Na2SO4 and concentrated to give a thick liquid (69 or 77).

2.06a N-Prenyl-N-benzy1-24triphenylphosphoranylidene] acetamide (69):

4' H3C

Yield: 85%; yellow thick liquid.

IR (vmax): 1640 cm I.

'H NMR (CDCI3, 300 MHz): ö 1.52 [1.48] (s, 3H, H-4'), 1.66 [1.65] (s, 3H, H-5'),

2.09 (d, J = 12.6 Hz, 1H, H-2), 3.77 [3.99] (d, J = 6.6 Hz, 2H, H-1), 4.50 [4.41] (s,

2H, CH2Ph), 5.05-5.09 [5.10-5.15] (m, 1H, H-2'), 7.10-7.51 (m, 20H, Ar-H).

13C NMR (CDCI3, 75 MHz): S 17.8 (C-4'), 25.6 (C-5'), 29.6 (C-2), 45.6 [42.6] (C-1'),

50.8 [47.7] (CH2Ph), 119.6(C-2'), 126.2, 128.3, 128.5, 131.8, 132.0, 132.8, 137.5 (Ar-

H & Ar-C), 170.5 (C-1).

HRMS: m/z [M+H]+ calcd for C32H33NOP: 478.2300; found: 478.2313.



2.06b N-Prenyl-N-(p-methoxy)benzyl-2-1triphenylphosphoranyliderre] acetamide

(77):

OCH3

Yield: 86%; yellow thick liquid.

IR (vmax): 1647 cm 1 .

1H NMR (CDC13, 300 MHz): Z. 1.59 [1.48] (s, 3H, H-4'), 1.67 [1.65] (s, 3H, H-5'),

2.01 (br s, 1H, H-2), 3.78 [3.77] (s, 3H, OCH3); 3.91 [4.16] (d, J= 6.9 Hz, 2H, H-1'),

4.38 [4.81] (s, 2H, CH2Ph), 4.97 [5.05] (t, J= 6.6 Hz, 1H, H-2'), 6.76 [6.82] (d, J= 8.4

Hz, 2H, Ar-H), 6.94 [7.11] (d, J= 8.4 Hz, 2H, Ar-H), 7.60-7.85 (m, 15H, PPh3).

13C NMR (CDC13, 75 MHz): 5 18.0 [17.8] (C-4'), 25.7 [25.6] (C-5'), 32.6 (C-2), 44.1

[46.6] (C-1'), 48.2 [50.4] (CH2Ph), 55.3 (OCH3), 113.9 [114.2] (Ar-H), 118.5 [119.0]

(C-2'), 119.1, 119.3, 120.2 [120.3] 127.9 [129.2] (Ar-H), 128.6 [128.5] (C-3'), 129.8,

129.9, 130.0, 133.6, 133.7, 133.8, 134.4, 137.3 [137.4], 158.9 (Ar-C & Ar-H), 164.0

[164.2] (C-1).

HRMS: m/z [M+H]+ calcd for C33H35NO2P: 508.2405; found: 508.2401.

2.07 Preparation of [1-benzy1-2-oxo-4-(prop-1-en-2-yl)pyrrolidin-3-yllacetic acid

(trans-67b):

To a solution of phosphorane 69 (0.332 g, 0.87 mmol) in dry diphenyl ether (20 mL),

glyoxalic acid (0.128 g, 0.87 mmol, 50% aq soin.) was added, and stirred at room



temp for 30 min. The reaction mixture was refluxed for 4 h. After the reaction was

over, it was cooled to room temp, NaHCO3 (20 mL) was added, and then mixture was

washed with Et20 (3x 20 mL). The aqueous layer was neutralized with 2N HCl (30

mL), extracted with Et 20 (3x 20 mL). The combined organic phase was dried over

anhyd Na2SO4, concentrated under reduced pressure to give light yellow thick liquid

67b (0.095 g, 40%).

IR (vmax): 3485-2289, 1739, 1639 cm 1 .

1H NMR (CD03, 300 MHz): 8 1.70 (s, 314, H-4'), 2.64 (dd, J= 4.8 Hz, 16.2 Hz, 2H,

H-1'), 2.74-2.83 (m, 1H, H-5), 2.89-2.93 (m, 1H, H-5), 3.10-3.16 (m, 1H, H-3), 3.30-

3.36 (m, 1H, H-4), 4.42 (d, J = 14.7 Hz, 111, CH2Ph), 4.57 (d, J = 14.7 Hz, 1H,

CH2Ph), 4.85 (s, 1H, H-2'), 4.87 (s, 1H, H-2'), 7.24-7.36 (m, 5H, Ar-H).

13C NMR (CD03, 75 MHz): 8 19.2 (H-4'), 34.7 (C-1'), 41.7(C-3), 46.4 (C-4), 47.0

(C-5), 49.5 (CH2Ph), 114.0 (C-2'), 127.9, 128.1, 128.7, 128.8, 128.9 (Ar-H), 135.5 (C-

3'), 142.4 (Ar-C), 174.3 (C-2), 175.7 (COO).

HRMS: m/z [M+Nar calcd for C16H20NO3Na: 296.1263; found: 296.1260.

2.08 General procedure for preparation of N-protected-2-pyrrolidone (67a &

78a):

To a solution of 1.2 equiv of phosphorane 69 or 77 in dry toluene (30 mL), 1 equiv of

glyoxalic acid (50% aq soln.) was added, and stirred at room temp for 30 min. The

reaction mixture was refluxed in Dean-stark equipped flask for 24 h. After the reaction

was over, it was cooled to room temp, NaHCO3 (20 mL) was added and then mixture

was washed with Et20 (3x 20 mL). Aqueous layer was neutralized with 2N HCl (30

mL), extracted with Et20 (3x 20 mL). The combined organic phase was dried over

anhyd Na2SO4, concentrated under reduced pressure and recrystallization using

hexanes/EtOAc (7: 3) afforded the desired product (67a or 78a).



2.08a [1-benzyl-2-oxo-4-(prop-1-en-2-yl)pyrrolidin-3-yllacetic acid (cis-67a):

2'

Yield: Recrystallised from hexanes/EtOAc (7: 3) to give white crystalline solid (60%);

mp 113-114 °C.

IR (vmax): 3485-2289, 1739, 1639 cm -I .

1H NMR (CDCI3, 300 MHz): 8 1.48 (s, 3H, 11-4'), 2.47 (dd, J = 4.5 Hz, 16.2 Hz, 1H,

1-1-1 1), 2.71 (dd, J = 8.7 Hz, 16.2 Hz, 1H, H-1'), 3.10-3.22 (m, 3H, H-5 & H-3), 3.51-

3.56 (m, 1H, H-4), 4.50 (s, 2H, C1r_bPh), 4.75 (s, 1H, H-2'), 4.85 (s, 1H, H-2'), 7.29-

7.38 (m, 5H, Ar-H).

13C NMR (CDCI3, 75 MHz): 8 19.7 (C-4'), 31.8 (C-1'), 41.1 (C-3), 42.3 (C-4), 47.2

(C-5), 49.6 (CH2Ph), 115.6 (C-2'), 128.0, 128.7, 128.8 (Ar-H), 135.3(C-3'), 142.2 (Ar-

C), 175.0 (C-2), 175.4 (COO).

HRMS: m/z [M+Na]+ calcd for C16H19NO3Na: 296.1263; found: 296.1253.

2.08b 11-(p-metboxybenzy1)-2-oxo-4-(prop-1-en-2-yDpyrrolidin-3-yllacetic acid

(cis-78a):

OCH 3

Yield: Recrystallised from hexanes/EtOAc (7: 3) to give white crystalline solid (65%);

mp 103-104 °C.

IR (vmax): 3600-2245, 1722, 1645 cm I.



1H NMR (CDC13, 300 MHz): 8 1.46 (s, 311, H-4'), 2.39 (dd, J = 6.6 Hz, 17.1 Hz, 1H,

H-1'), 2.79 (dd, J= 5.4 Hz, 17.4 Hz, 1H, H-1'), 3.09-3.14 (m, 311, H-5 & H-3), 3.45-

3.48 (m, 1H, H-4), 3.80 (s, 3H, OCH3), 4.37 (d, J = 14.4 Hz, 1H, CLI2Ph), 4.45 (d, J

14.1 Hz, 1H, CEI2Ph), 4.72 (s, 1H, H-2'), 4.81 (s, 1H, 11-2'), 6.87 (d, J= 8.4 Hz, 2H,

Ar-H), 7.19 (d, J = 8.4 Hz, 2H, Ar-H).


(C-5), 49.4 (CH2Ph), 55.2 (OCH 3), 114.2 (Ar-C), 115.5 (C-2'), 127.4 (Ar-H), 130.0

(C-3'), 142.3 (Ar-C), 159.3 (Ar-C), 175.1 (C-2), 175.5 (COO).

HRMS: m/z [M+Nar calcd for C17H2INO4Na: 326.1368; found: 326.1365.

2.09 Preparation of methyl I1-benzy1-2-oxo-4-(prop-1-en-2-yl)pyrrolidin-3-

yllacetate (79):

3' 6' 1' 21

H 3COOC

0m 1"

CH 2Ph

To an ice cooled solution of N-benzyl-2-pyrrolidone 67a (0.097 g, 0.35 mmol) in

Me0H (5 mL), was added ceric ammonium nitrate (0.779 g, 1.41 mmol) and stirred

for 1 h at 0 °C. Further, stirred for 12 h at room temp. The reaction mixture was

neutralized with aq NaHCO3 (40 mL), extracted with EtOAc (3x 20 mL), dried over

anhyd Na2SO4, and the solvent was removed in vacuum to afford a crude oil. The

purification was done on silica gel (hexanes: EtOAc = 6: 4) to afford corresponding

product 79 as a thick liquid (0.092 g, 91%).

IR (vmax): 3203, 1735, 1693 cm-I .

1 H NMR (CDC13, 300 MHz): 8 1.53 (s, 3H, H-5'), 2.06-2.35 (m, 1H, 1-1-2'), 2.80-2.88

(m, 1H, H-2'), 3.05-3.15 (m, 3H, H-5 & H-3), 3.39-3.45 (m, I IA, H-4), 3.67 (s, 311, H-

6'), 4.44 (br d, 2H, CII2Ph) 4.77 (s, 1H, H-3'), 4.80 (s, 1H, H-3'), 7.24-7.33 (m, 5H,

Ar-H).

5'




(C-5), 49.1 (CH2Ph) 51.7 (OCH3), 114.8 (C-3'), 127.7-128.7 (Ar-H), 135.9 (C-4'),

142.2 (Ar-C), 172.8 (C-2), 174.2 (COO).

HRMS: m/z [M+Na]+ calcd for C17H2INO3Na: 310.1419; found: 310.1412.

2.10 General procedure for preparation of 2-pyrrolidone (80 & 24):

To an ice cooled solution of N-protected-2-pyrrolidone 78a (1 equiv) in alcohol (5

mL), was added ceric ammonium nitrate (4 equiv) and stirred for 1 h at 0 °C. Further,

stirred for 12 h at room temp. The reaction mixture was neutralized with aq NaHCO3,

extracted with EtOAc (3x 20 mL), dried over anhyd Na2SO4, and solvent was

removed in vacuum to afford a crude oil. The purification was done on silica gel

(hexanes: EtOAc = 6: 4) to afford the desired product 80 or 24 as a white crystalline

solid.

2.10a methyl [2-oxo-4-(prop-1-en-2-yl)pyrrolidin-3-yl]acetate (80):

Yield: Recrystallized from ethyl acetate: hexanes (1:3) to give white crystalline solid

(95%); mp 89-90 °C

IR (vmax): 3203, 1732, 1693 cm'

111 NMR (CDC13, 300 MHz): 6 1.67 (s, 3H, H-5'), 2.31 (dd, J = 9.9 Hz, 17.4 Hz, 1H,

H-2'), 2.80 (dd, J = 4.5 Hz, 17.4 Hz, 1H, H-2'), 3.09 (ddd, J = 4.2 Hz, 4.5 Hz, 9.6 Hz,

1H, H-5), 3.26-3.32 (m, 2H, H-5 & H-3), 3.59 (dd, J = 6.6 Hz, 9.9 Hz, 1H, H-4), 3.70

(s, 3H, OCH3), 4.78 (s, 1H, H-3'), 4.87 (s, 1H, H-3'), 6.01 (br s, 1H, NH).


(C-5), 51.7 (OCH3), 114.9 (C-3'), 142.9 (C-4'), 172.8 (C-2), 178.2 (COO).

HRMS: m/z [M+Na] + calcd for C10Hi5NO3Na: 220.0950; found: 220.0947.



2.10b Ganem's intermediate (24) 17 :

3 1 7' 6' 1' 21 H3CH2COOC 51

Yield: Recrystallized from ethyl acetate: hexanes (1:3) to give white crystalline solid

(68%); mp 104-105 °C (lit. 17 mp 104-107 °C).

IR (vmax): 3205; 1730; 1696 cm -1 .

11I NMR (CDCI3, 300 MHz): 6 1.26 (t, J = 7.2 Hz, 3H, H-7'), 1.67 (s, 3H, H-5'), 2.28

(dd, J = 9.9 Hz, 17.4 Hz, 11-1, H-2'), 2.78 (dd, J = 4.5 Hz, 17.4 Hz, 1H, 1-1-2'), 3.07 (m,

1H, H-5), 3.55-3.60 (m, 2H, H-5 & H-3), 3.57 (dd, J = 6.6 Hz, 9.9 Hz, 1H, H-4), 4.15

(q, J= 7.2 Hz, 2H, H-6'), 4.78 (s, 11-1, 11-3'), 4.86 (s, 1H, H-3'), 6.37 (br s, 1H, NH).

13C NMR (CDCI3, 75 MHz): 6 14.1 (C-7'), 20.2 (C-5'), 30.6 (C-2'), 40.4 (C-3), 44.6

(C-4), 44.7 (C-5), 60.6 (C-6'), 114.8 (C-3'), 143.0 (C-4'), 172.3 (C-2), 178.0 (COO).

HRMS: m/z [M+Na]+ calcd for C 1 1Hr7NO3Na: 234.1106; found: 234.1101.



Spectra:

43. I I

■

7F 7

7.0 615 6.0 5.5 5.0 4.6 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Ind

Figure 2. 1 H NMR spectrum of 70

/

PPP,

Figure 3. 'H NMR spectrum of 71


\l/ \V2

5 . 5 5 . 0 4 . 5 4.7 3 . 5 3 . 0 2 . 5 2.0 1 . 5 1 . 0 0 . 5 7 . 0 7 . 5 6.5 6.0

Br

74


CH 3

I 72 H

_ -., .w _ --' ,k

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm



Goa University 84 Ph. D. Thesis

9 8

7

Figure 6. 1 H NMR spectrum of 67b


I T 1 1 7

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

Figure 7. 13C NMR and DEPT spectrum of 67b


0.5 PPM 2.0 1.5 1.0 7.5 6.5 6.0 6.6 5.0 4.5 4.0 3.5 3.0 2.5

I I I V \I I I

HOOC

0 N

67a

, i, lasr- sr) lei

Me 00C

79

H2C

N

CH2Ph

Li

7.5 7.0 6.5 6.0 5.5

'15> 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm


Figure 8. 1 H NMR spectrum of 67a

\\l\ cNf/!1/ ri 1 7 I.


CH 3


7.5 7.0 6.5

a ppm

it) VL

2.6 2.0 1.5 1.0 0.5

1 II 1 N1 11 V/////////,

2.5 4.5 to 8.0 7.5 7.0 6.6 6.0 5.5 5.0 3.5 3.0 2.0 ppm

OCH3

lei iii


%II


Figure 11. 1 11 NMR spectrum of 77


77 OCH,

•-! 170 160 150 140 130 120 110 100 90 80 70 60 30 20 ppm


Figure 12. 13C NMR and DEPT spectrum of 77

111/ V 111K

8.5 8.0

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

lf r:41 1g!

ppm

Figure 13. 1 H NMR spectrum of 78a


5.0 4.5 4.0 3.5

12.1 ci

I

li I

2.5 2.0 ppm

I

6.0 5.5 3.0


CH3

H2C

Me00C

80 H

CH3


!!!,

II V /L\/ I/

H2C

H3cH2cooca

. N

24 H

„ J nu/ LAJ)

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Figure 15. NMR spectrum of 24

Goa University 89 Ph. D. Thesis

50 40 30 20 ppm

H 2C

H3cH2cooca

0 N

24 H

180 170 160 150 140 130 120 110 100 90 80 70 60

CH 3


Figure 16. 13C NMR and DEPT spectrum of 24



References:

(1) (a) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid as a Tool in

Neurobiology; Raven: New york, 1978. (b) Simon, R. P. Excitatory amino acids;

Thieme Medical: New York, 1992. (c) Wheal, H. V.; Thomson, A. M. Excitatory

amino acids and synaptic transmission; Academic: London, 1991. (b) Moloney,

M. G. Nat. Prod Rep. 2002, 19, 597.

(2) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953, 73, 1026.

(3) For review on total synthesis of kainoids see: (a) Williams, R. M. Synthesis of

Optically Active Amino Acid; Pergamon Press, 1989. (b) Parsons, A. F.

Tetrahedron 1996, 52, 4149.

(4) (a) Lodge, D. Excitatory Amino Acid in Health and Disease; John Wiley & Sons:

New York, 1988. (b) Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005,

61,5713.

(5) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.

(6) (a) Yoo, S. E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968. (b) Yoo, S. E.; Lee, S.

H.; Jeong, N. Cho, I. Tetrahedron Lett. 1993, 34, 3435. (c) Takano, S.; Inomata,

K.; Ogasawara, K. J. Chem. Soc. Chem. Commun. 1992, 169.

(7) Barco, A.; Benetti, S.; Spalluto, G. J. Org. Chem. 1992, 57, 6279.

(8) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 2773.

(9) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc. Chem. Commun. 1988,

1204.

(10) Takano, S.; Sugihara, T.; Satosh, S.; Ogasawara, K. J. Am. Chem. Soc. 1988,

110, 6467.

(11) Nakada, Y.; Sugihara, T.; Ogasawara, K. Tetrahedron Lett. 1997, 38, 857.

(12) Yoo, S. E.; Lee, S. H.; Yi, K. Y.; Jeong, N. Tetrahedron Lett. 1990, 31, 6877.

(13) Rubio, A.; Ezquerra, J.; Escribano, A.; Remuifian, J.; Vaquero, J. Tetrahedron

Lett. 1998, 39, 2171.

(14) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc. Perkin Trans 1, 1992,

553.



(15) (a) Baldwin, J. E.; Li, C. S. J. Chem. Soc. Chem. Commun. 1987, 166. (b)

Baldwin, J. E.; Moloney, M. G.; Parson, A. F. Tetrahedron 1990, 46, 7263. (c)

Hanessian, S.; Ninkovics, S. J. Org. Chem. 1996, 61, 5418. (d) Bachi, M. D.;

Melman, A. Synlett 1996, 60. (e) Bachi, M. D.; Melman, A../. Org. Chem. 1997,

62, 1896. (t) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Synlett 1997, 275.

(16) Oppolzer, W.; Andres, H. Hely. Chim. Acta 1979, 62, 2282.

(17) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485.

(18) Thuong, M.; Sottocornola, S.; Prestat, G.; Broggini, G.; Madec, D.; Poli, G.

Synlett 2007, 1521.

(19) Pandey, S. K.; Orellana, A.; Greene, A. E.; Poisson, J-F. Org. Lett. 2006, 8,

5665.

(20) Chalker, J. M.; Yang, A.; Deng, K.; Cohen, T. Org. Lett. 2007, 9, 3825.

(21) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635.

(22) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711.

(23) Tomooka, K.; Akiyama, T.; Man, P.; Suzuki, M. Tetrahedron Lett. 2008, 49,

6327.

(24) Bottini, A. T.; Dev, V.; Klinck, J. Org. Synth. 1973, 5, 121.

(25) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J. J. Org. Chem. 2001, 66, 2597.

(26) Kuttan, A.; Nowshudin, S.; Rao, M. N. A. Tetrahedron Lett. 2004, 45, 2663.

(27) Chern, C-Y.; Huang, Y-P.; Kan, W. M. Tetrahedron Lett. 2003, 44, 1039.

(28) Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17, 415.

(29) (a) Overman, L. E.; Osawa, T ..I Am. Chem. Soc. 1985, 107, 1698. (b) Mori, S.;

Iwakura, H.; Takechi, S. Tetrahedron Lett. 1988, 29, 5391. (c) Bull, S. D.;

Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. Chem.

Commun. 2000, 337.


Documents

Synthetic Studies towards Kainic Acid Using Tandem Wittig ...shodhganga.inflibnet.ac.in/bitstream/10603/12620/7/07_chapter 2.pdf · Tandem Wittig-Intramolecular Ene Reaction