New synthetic routes to the kainoids: A synthesis of kainic acid and its analogues

Article abstract of DOI:10.1016/j.tet.2011.10.030

New approaches to the synthesis of kainic acid and its analogues are presented. Two distinctly different approaches are described; the former utilised an intermolecular nitrile oxide addition to a homochiral substrate to furnish epikainate models and the

Full text of DOI:10.1016/j.tet.2011.10.030

Tetrahedron 67 (2011) 10267e10273
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New synthetic routes to the kainoids: a synthesis of kainic acid and its analogues
*
Philip J. Parsons , Stephen P.G. Rushton, Raghava R. Panta, Adrian J. Murray, Martyn P. Coles, Jason Lai
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2011
Received in revised form 8 October 2011
Accepted 10 October 2011
Available online 19 October 2011
New approaches to the synthesis of kainic acid and its analogues are presented. Two distinctly different
approaches are described; the former utilised an intermolecular nitrile oxide addition to a homochiral
substrate to furnish epikainate models and the second utilised amino acid chemistry to secure kainic
acid.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Excitatory amino acids
Nitrile oxide
Kainate
Ene-reaction
Isoxazolidinone
1. Introduction
a review by Parsons.1 Despite this devotion to kainic acid 1,
which is one of the most investigated synthetic targets to date,
many of the published syntheses are limited in yield and
stereoselectivity.
Our approaches to the kainates reported herein offer alterna-
tive routes to analogues of kainic acid 1 and provide hitherto
unknown structures, which possess kainate like architecture.
These compounds will be useful for the design of novel excitatory
amino acids. The nitrile oxide approach to the epikainates dem-
onstrates further the unexpected stereocontrol of addition to the
alkene 3.
(ꢀ)-Kainic acid 1 and its analogues1 have attracted a great deal
of interest from the chemical and biological communities since the
1950’s. Their potent anthelmintic properties have been utilized for
hundreds of years2 and kainic acid has become a very powerful tool
in neurobiology3 through use in experimental models for Hun-
tington’s chorea,4,5 epilepsy6 and dementia. Although the kainates
are unlikely to be used in therapeutic areas, the information gained
from biological models could lead to treatments for neuronal
diseases.
We have shown previously that photoaddition of the ketal 2 to
the alkene 3 proceeds with regio and stereochemical control
(Scheme 1).49
The limited availability of kainic acid7,8 and its analogues mean
that new and efficient routes are still required to fulfil the demands
of the neuropharmacologists.
Kainic acid 1 has a highly functionalised pyrrolidine ring
containing three contiguous asymmetric centres and has
attracted significant synthetic interest, particularly with regard
to the crucial syn-relationship that exists between the sub-
stituents at the C-3 and C-4 positions. Many past syntheses
have solved this issue by utilising a stereoselective formation of
the C-3/C-4 bond or by using a stereoselective ring closure with
the C-2 substituent. There have been more than 30 enantiose-
lective syntheses to date,9e48 many of which are included in
Scheme 1. Reagents and conditions: (i) hn, EtOAc (38%); (ii) MeONa.
Methoxide induced ring opening of the cyclobutane 4 gave the
carboxylate 5. This initially surprising stereochemical result led
us49 and others50 to investigate the general chemistry of the al-
kene 3.
* Corresponding author. E-mail address: p.j.parsons@sussex.ac.uk (P.J. Parsons).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.030

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P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
1.1. Cyclisation studies and the new approach to kainate
synthesis
In view of the unexpected photoaddition of alkenes to the
more hindered face of 3 and the unexpected addition of elec-
trophiles to the more hindered face of the double bond in 3 we
initially investigated the intermolecular addition of a range of
nitrile oxides to 3. Our retrosynthetic analysis of the kainoids is
shown in Scheme 2
Scheme 2.
The alkene 3 was treated with a series of nitrile oxides
(Scheme 3), which were generated by known methods (Table 1).51,52
Scheme 4. Reagents and conditions: (i) Raney Ni, H2, B(OH)3, MeOHþH2O (5:1) (77%);
(ii) pTSA, toluene, reflux, (75%); (iii) NaH, DMM, THF, 0 ꢁC to rt (90% 1:1); (iv) Ph3P]
CH2, ꢀ78 ꢁC, (70%); (v) NaCl, DMSOþH2O (9:1), 170 ꢁC, 8 h, (72%).
Scheme 3.
Table 1
Nitrile oxides for cycloaddition.
R
Compound
Yield (%)
Scheme 5.
Me
Ph
6a
6b
6c
68
68
36
Isocyanates are known to react with epoxides and we envisaged
that the readily available isocyanate 15 could react with epoxide 16
to form the heterocycle 14 in one synthetic operation (Scheme 6).
6d
6e
95
24
Calculations from our laboratory have shown that the homo of
the alkene 3 reveals an unsymmetrical pi bond with a higher
electron density on its endo face.49
Scheme 6.
Cleavage of the weak NeO bond in 6a with Raney-Nickel53
gave the enone 7. Addition of sodio dimethyl malonate54 to 7
gave a mixture of adducts 8 and 9 in a 1:1 ratio, which, were
easily separated on silica (Scheme 4). Reaction of 8 and 9 with
methylidene-triphenylphosphorane22 gave the alkenes 10 and 11,
which, followed by decarboxylation55 afforded the esters 12
and 13.
The isocyanate 15 was prepared by the method reported by
Christopherson56 and the epoxides 16 were prepared by modifi-
cation of the procedure reported by Font et al.57 When the iso-
cyanate and epoxide were reacted together following the general
procedure reported by Herweh et al.58 the ester 19 was isolated
instead of the desired product 17 (Scheme 7). The unsaturated ester
moiety seems to destabilize cation formation and hence the iso-
cyanate reacted at the least hindered face.
In view of the results obtained, which allow the preparation of
the allo-kainate models, we were encouraged to design a specific
synthesis of kainic acid 1, which utilised the cyclic carbamate unit
as a template for intramolecular ene reactions.
1.2. Investigation into kainate synthesis
We have devised a ‘one-pot’ synthesis of kainic acid, which
utilises a two component coupling sequence (Scheme 5).
Scheme 7. Reagents and conditions: (i) CaCl2, DMF,
D (4%).

P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
10269
Calcium chloride was added to the DMF in order to act as a Lewis
2. Conclusion
acid and to remove any traces of dimethylamine. Chloride anion
was found to add to the initially formed acrylate 18.
The overall yield of kainic acid 1 starting from
D-serine is 20%
over eight steps and compares favourably with previous synthetic
approaches including the most recent route by Fukuyama, which,
gives a 10% yield over thirteen operations.40 We believe that this
approach offers a new and simple access to kainic acid and its an-
alogues using chemistry well suited to scale up without the need
for use of heavy metal derivatives. The unusual addition of nitrile
oxides to the double bond of the carbamate 3 offers additional
flexibility for the preparation of a wide range of hitherto unknown
amino acids.
1.3. Total synthesis of kainic acid
In view of the undesired regiochemistry of addition of epoxide
16 to the isocyanate 15 we elected to carry out the synthesis of
kainic acid using D-Serine methyl ester as the starting material. The
new route to kainic acid is shown in Scheme 8.
3. Experimental
3.1. General
Reactions were conducted at room temperature under an at-
mosphere of nitrogen unless otherwise stated. They were moni-
tored using analytical thin layer chromatography with visualization
by UV light and potassium permanganate (KMnO4) dip. Reaction
solvents were purified and dried according to the literature
methods. Tetrahydrofuran and diethyl ether were distilled from
sodium and benzophenone as indicator; dichloromethane was
distilled from calcium hydride. Petrol refers to distilled petroleum
40e60 ꢁC. All other solvents were used as supplied. Flash chro-
matography was performed using silica gel 60, 230e400 mesh. 1H
NMR spectra were recorded on a Varian 500 MHz machine oper-
ating at ambient probe temperature using an internal deuterium
lock. Chemical shifts were reported in parts per million (ppm)
using residual solvent as an internal standard. Standard abbrevia-
tions were used throughout. (s singlet; br d broad doublet; br s
broad singlet; d doublet; dd doublet of doublets; dt doublet of
triplets; dq doublet of quartets; t triplet; q quartet; m multiplet).
Coupling constants were measured in hertz (Hz). 13C NMR spectra
were recorded at 126 Hz operating at ambient probe temperature
using an internal deuterium lock. Chemical shifts were reported in
parts per million (ppm) using residual solvent as an internal
standard. DEPT and correlation experiments were used for as-
signment of spectra. ESI mass spectra were recorded on a Bruker
Daltonics Apex spectrometer with methanol as a solvent. EI mass
data were recorded on a Fisons VG Autospec spectrometer. Infra red
spectra were recorded on a PerkineElmer spectrum One FT-IR
spectrometer fitted with an ATR accessory. Crystal structures
were obtained from a Bruker/Enraf Nonius Fr590 KappaCCD.
Structures were named using the ACD labs ACD/IUPAC name v8.05.
The result of the ACD/IUPAC Name was obtained using ACD/I-Lab
service.
Scheme 8. Reagents and conditions: (i) NaH, THFþDMF (4:1), 1-bromo-3-methyl-2-
butene 0 ꢁC-rt, (78%); (ii) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, followed by NH4Cl (C6H5)3P]
CHCO2CH3, ꢀ20 ꢁC, (83%); (iii) MW, DEA, 200 ꢁC, 4 h (80% 7:1 in favour of 14); (iv)
Cs2CO3, MeOH, rt, 5 days (80%); (v) SO3, Et3N, DMSO, CH2Cl2, 0 ꢁC-rt, (89%); (vi) NaClO2,
NaHPO4, 2-methyl-2-butene, tBuOH, H2O, rt; (vii) NaOH(aq), MeOH,
D, 18 h followed by
Ion-exchange chromatography and recrystallisation from water (60% from aldehyde).
D-Serine hydrochloride was treated with triphosgene to afford
ester 20 quantitatively.59 N-alkylation of the ester 20 with 1-
bromo-3-methyl-2-butene in the presence of sodium hydride
gave the N-alkylated ester 21 in 78% isolated yield.60 DIBAL re-
duction of the aforementioned ester 21 gave an aldehyde,60 which
was converted directly to the unsaturated ester 17 using Wittig
methodology. When a solution of the unsaturated ester was heated
in diethylaniline to 200 ꢁC in a microwave oven the ene-product 14
and an allo-kainate precursor 22 were isolated in a combined yield
of 80% in a diastereomeric ratio of 7:1 in favour of the desired en-
antiomer. This product was carried through to final steps as a crude
mixture containing traces of the allo-kainate compound.
3.1.1. (Z)-6-(1-(Methoxyimino)ethyl)tetrahydropyrrolo[1,2-c]oxazol-
3(1H)-one (6a). Triethylamine (162 mg, 1.6 mmol) was added to
a stirred solution of 1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one 3
(100 mg, 0.8 mmol), nitroethane (72 mg, 0.96 mmol) and p-toluene
sulphonyl chloride (305 mg, 1.6 mmol) in benzene (20 mL) at 0 ꢁC.
The reaction mixture was allowed to warm to room temperature
and stirred for 12 h. Solvent removed under reduced pressure and
residue purified by flash chromatography (1:1 hexane/ethyl
acetated100% ethyl acetate) yielded 6a (98 mg, 68%) as a white
crystalline solid, mp 123e127 ꢁC. Spectra consistent with those
In contrast to the work of Oppolzer and Thirring the intra-
molecular ene-reaction in our system took only 4 h to complete
instead of 40 h.9 With the crude ene-product 14 in hand we sa-
ponified with methanol in the presence of caesium carbonate61 to
afford the desired alcohol 22 in 80% isolated yield. Oxidation of the
alcohol 23 using ParikheDoering conditions afforded the aldehyde
24 in high yield.62 Oxidation of the aldehyde with sodium chlorite63
gave the intermediate carboxylic acid 25, which was not isolated
but globally deprotected with aqueous sodium hydroxide in
methanol. Ion-exchange chromatography followed by recrystalli-
sation from water removed any traces of the undesirable allo-type
previously reported. ½a D25
ꢂ
ꢀ1.7 (c 1.00, CH2Cl2). IR (neat)
n )
(cmꢀ1
2922, 1737 (C]O), 1463, 1192 (CeO), 993 (NeO), 777; dH (500 MHz
CDCl3): 5.06 (m, 1H, OCH), 4.69 (dd,1H, J¼2.59, 8.98 Hz, OCH2), 4.48
(t,1H, J¼8.39, 17.16 Hz, OCH2), 4.05 (d,1H, J¼5.41 Hz NCH2), 4.08 (m,
1H, NCH), 3.84 (t,1H, J¼8.12 Hz, NCH2CH), 3.27 (ddd, 1H, J¼7.69,
12.84, 20.52 Hz, NCH2), 2.03 (s, 2H, CH3). dC (126 MHz, CDCl3): 175.3
(C]O), 155.1 (N]C), 83.6 (OCH), 64.3 (OCH2), 62.7 (NCH), 58.1 (N]
compound and afforded (ꢀ)-
a
-kainic acid 1 in 60% isolated yield.9

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P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
CCH), 48.0 (NCH2), 11.2 (CH3). HRMS (ESIþ) calcd for C8H10N2O3, m/z
205.0583, found 205.0584.
CH). dC (126 MHz, CDCl3): 22.1, 22.3, 25.3, 26.4, 50.5, 54.1, 63.2, 64.9,
85.5, 133.9. HRMS (ESIþ) calcd for C13H16N2O3, m/z 271.1058, found
271.1045.
3.1.2. (3aS,8aR,8bR)-3-Phenyl-3a,8,8a,8b-tetrahydro-4H[1,3]oxazolo
[30,40:1,5]pyrrolo[3,4-d]isoxazol-6-one
(6b). N-Hydrox-
3.1.5. (3aS,8aR,8bR)-3-tert-Butyl-3a,8,8a,8b-tetrahydro-4H-[1,3]ox-
azolo[30,40:1,5]pyrrolo[3,4-d]isoxazol-6-one (6e). To a stirred solu-
tion of 1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one 3 (100 mg,
0.80 mmol), 3,3-dimethylbutanal oxime (129 mg, 1.12 mmol),
triethylamine (0.13 mL, 0.96 mmol) in dichloromethane (10 mL),
8% aqueous sodium hypochlorite (10 mL) was added dropwise
over 15 min at 0 ꢁC. The reaction mixture was allowed to stir for
12 h, the aqueous phase was separated before extraction with
dichloromethane (3ꢃ50 mL), and the organic layer were combined
and washed with water (2ꢃ50 mL), then dried (MgSO4) and
concentrated under reduced pressure. The solid residue was fil-
tered and rinsed with diethyl ether (30 mL), and then recrystal-
lised from methanol give 6e as a white solid (45 mg, 24%), mp
ybenzenecarboximidoyl chloride (2.0 g, 10.0 mmol) and 1,7a-
dihydropyrrolo[1,2-c]oxazol-3(5H)-one 3 (1.26 g, 10.0 mmol) were
dissolved in benzene (25 mL). To this stirring solution, triethyl-
amine (1.21 g, 12.0 mmol) was added dropwise. Following 18 h the
white solid was filtered, washed with cold ether (30 mL) and
recrystallised from dichloromethane to yield 6b as colourless
crystals (1.63 g, 68%), mp 225e226 ꢁC, ½a D25
ꢀ197 (c 0.60, MeOH); IR
ꢂ
(neat) n
(cmꢀ1) 2974, 1745 (C]O carbamate), dH (500 MHz CD3OD):
7.75e7.78 (tt, 2H, J¼1.9, 5.2 Hz, Hmeta) 7.69 (d, 2H, J¼1.8 Hz, Hor-
tho), 7.56 (d,1H, J¼1.9 Hz, Hpara) 5.54 (dd, 1H, J¼4.3, 8.6 Hz, OCH2),
4.94 (dd, 1H, J¼2.5, 8.9 Hz, OCH2), 4.73 (t, 1H, J¼8.6 Hz, NCH), 4.55
(td, 1H, J¼2.1, 8.4 Hz, NOCH), 4.41 (m, 1H, NCH2CH), 4.25 (dd, 1H,
J¼1.8, 12.7 Hz, NCH2), 3.66 (dd, 1H, J¼8.2, 12.7 Hz, NCH2). dC
(126 MHz, CD3OD): 157.3 (C]O) 147.6 (N]C), 131.2 (Cpara), 131.0
(N]CC),129.4 (Cmeta), 127.5 (Cortho), 85.9 (OCH), 64.9 (OCH2), 63.1
(NCH), 55.0 (NCH2CH), 49.9 (NCH2). HRMS (ESIþ) calcd for
C13H12N2O3, m/z 267.0745, found 267.0735.
200e205 ꢁC, ½a 2D7
ꢂ
ꢀ162 (c 0.4, CHCl3); IR (neat)
n
(cmꢀ1) 1730 (C]
O) 2955; dH (500 MHz CDCl3): 1.03 (s, 9H, C(CH3)3), 1.54 (s, 2H
CCH2), 2.17 (d, 1H, J¼12.8 Hz), 2.45 (d, 1H, J¼14.8 Hz), 3.26 (dd, 1H,
J¼7.7, 12.8 Hz), 3.91 (t, 1H, J¼7.9 Hz), 4.05 (m, 2H), 4.48 (t, 1H,
J¼8.5 Hz), 4.69 (dd, 1H, J¼2.4, 8.9 Hz), 5.02 (dd, 1H, J¼4.8, 8.5 Hz).
dC (126 MHz, CDCl3): 29.8 (CH3), 31.4 (C(CH3)3), 39.1 (NCH2), 48.3
(NCH2CH), 58.6 (CCH2), 62.7 (NCH), 64.5 (OCH2), 83.0 (OCH), 125.2
(N]C), 157.0 (C]O). HRMS (ESIþ) calcd for C12H18N2O3Na, m/z
261.1215, found 261.1202.
3.1.3. (3aS,8aR,8bR)-3-(4-Ethylphenyl)-3a,8,8a,8b-tetrahydro-4H-
[1,3]oxazolo[30,40:1,5]pyrrolo[3,4-d]isoxazol-6-one (6c). To a stirred
solution of 1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one 3 (164 mg,
1.31 mmol), ethyl benzaldehyde oxime (234 mg, 1.57 mmol), trie-
thylamine (0.22 mL, 1.573 mmol) in dichloromethane (10 mL), 8%
aqueous sodium hypochlorite (10 mL) was added dropwise over
15 min at 0 ꢁC. The reaction mixture was allowed to stir for 12 h, the
aqueous layer was separated before extraction with dichloro-
methane (3ꢃ50 mL), and the organic phases were combined and
washed with water (2ꢃ50 mL), then dried (MgSO4) and concen-
trated under reduced pressure. The solid residue was filtered
and washed with diethyl ether (30 mL), and then recrystallised
from methanol to give 6c as a white solid (128 mg, 36%), mp
3.1.6. 6-Acetyl-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one
(7). Raney-Nickel (20 mg) was added to 6a (680 mg, 3.73 mmol)
and boric acid (485 mg, 7.84 mmol), in 5:1 mixture of methanol
and water (30 mL). The reaction mixture was allowed to stir for
8 h under hydrogen atmosphere. Raney-Nickel was removed by
filtration through Celite and solvent removed under reduced
pressure. The crude residue was dissolved in stirring toluene and
a catalytic amount of pTSA$H2O was added and the mixture
heated to refluxed using DeaneStark apparatus. After 2 h the
solvent was removed and the residue purified using flash chro-
matography (9:1 ethyl acetate and hexane) to give 7 (560 mg, 89%)
260e263.5 ꢁC, ½a D29
ꢂ
ꢀ318 (c 0.35, CHCl3); IR (neat)
n
(cmꢀ1) 1736,
C]O, 2968; dH (500 MHz CDCl3): 7.53 (d, 2H, J¼7.9 Hz, Hortho), 7.25
(t, 2H, J¼8.4 Hz, Hmeta), 5.22 (m, 1H, NOCH), 4.74 (d, 1H, J¼8.9 Hz,
OCH2), 4.52 (t, 1H, J¼8.6 Hz, OCH2), 4.33 (t, 1H, J¼8.3 Hz, NCH2CH),
4.19 (m, 1H, NCH), 4.05 (d, 1H, 12.6 Hz, NCH2, 12.6 Hz, NCH2), 3.45
(ddd, 1H, J¼1.5, 8.2 Hz), 2.68 (q, 2H, J¼7.5 Hz, CH2), 1.25 (t, 3H,
J¼7.5 Hz, CH3). dC (126 MHz, CDCl3): 157.5 (C]O), 147.0 (N]C),
128.3 (CHmeta), 126.9 (CHortho), 124.7 (CH3CH2C), 109.8 (CC]N),
85.1 (NOCH), 64.3 (OCH2), 62.5 (NCH), 54.5 (NCH2CH), 49.3 (NCH2),
28.6 (CH2),15.1 (CH3) HRMS (ESIþ) calcd for C15H16N2O3Na, m/z
295.1059, found 295.1043.
as a brown oil. ½a D25
ꢂ
ꢀ0.9 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1) 2922 (]
C enone), 1733 (C]O carbamate), 1671 (C]O enone), 1185 (CeO),
1006 (H3CeN), 775; dH (500 MHz CDCl3): 6.65 (s, 1H, ]CH), 4.93
(m, 1H, NCH), 4.64 (t, 1H, J¼8.9 Hz, OCH2), 4.61 (d, 1H, J¼15.7 Hz,
NCH2), 4.39 (m, 1H, OCH2), 4.01 (d, 1H, J¼15.8 Hz, NCH2), 2.38 (s,
3H, CH3). dC (126 MHz, CDCl3): 193.8 (C]O enone) 162.5 (C]O
carbamate), 145.0 (C]CH), 138.0 (]CH), 67.3 (OCH2), 65.3 (NCH),
53.6 (NCH2), 27.1 (CH3). HRMS (ESIþ) calcd for C8H9NO3, m/z
190.0475, found 190.0478.
3.1.4. (3aS,8aR,8bR)-3-Cyclohex-1-en-1-yl-3a,8,8a,8b-tetrahydro-
4H-[1,3]oxazolo[30,40:1,5]pyrrolo[3,4-d]isoxazol-6-one
(6d). Triethylamine (221 mg, 2.192 mmol) was added to a stirred
solution of 1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-one 3 (137 mg,
1.096 mmol), 1-(nitromethyl) cyclohexene (170 mg, 1.21 mmol) and
p-toluenesulfonyl chloride (418 mg, 2.19 mmol) in chloroform
(25 mL) at 0 ꢁC, the reaction mixture was allowed to warm room
temperature for 15 h before being washed with water (3ꢃ50 mL).
The organic phase was dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by flash column chro-
matography on silica gel, eluting with 7:1 diethyl ether/petrol to
3.1.7. Dimethyl
[(6S,7R,7aS)-6-acetyl-3-oxotetrahydro-1H-pyrrolo
[1,2-c][1,3]oxazol-7-yl]malonate (8) and dimethyl [(6R,7S,7aS)-6-
acetyl-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-7-yl]malonate
(9). To a suspension of sodium hydride (60% dispersion in oil,
0.51 g, 8.5 mmol) in THF (40 mL) was added a solution of dimethyl
malonate (1.12 g, 8.5 mmol) in THF (15 mL). After being stirred at
room temperature for 2 h, a solution of 7 (1.42 g, 8.5 mmol) in THF
(15 mL) was added dropwise at 0 ꢁC. The mixture was stirred
overnight at room temperature. The reaction was quenched with
a saturated ammonium chloride solution (20 mL) and extracted
with diethyl ether (5ꢃ30 mL). The combined organic phase was
washed with brine (20 mL), dried (MgSO4) and the solvent removed
under reduced pressure. The residue was purified using flash col-
umn chromatography (hexanes/ethyl acetate: 7/3) to yield a sepa-
rable mixture of two isomers 8 and 9 in 1:1 ratio, (2.33 g, 90%) as
yield 6d as colourless crystals (284 mg, 95%), mp 228e232 ꢁC. ½a D28
ꢂ
ꢀ288.4 (c 0.95, MeOH); IR (neat)
n
(cmꢀ1) 1742 (C]O), 2924; dH
(500 MHz CDCl3): 1.59 (m, 2H,]CCHCHCH), 2.20 (m, 4H,
HCHCHC]), 3.31 (dd, 1H, J¼8.3, 12.4 Hz, NCH2), 3.93 (dd, 1H, J¼2.0,
12.6 Hz, NCH2) 4.00 (td, 1H, J¼2.1, 8.4 Hz, NCH2CH), 4.09 (m, 1H,
NCH), 4.42 (t, 1H, J¼8.5 Hz, NOCH), 4.61 (dd, 1H, J¼2.5, 8.9 Hz,
OCH2), 5.01 (dd, 1H, J¼4.1, 8.3 Hz, OCH2), 5.94 (t, 1H, J¼3.9 Hz, C]
a pale yellow solid. Compound 8 ½a D25
ꢂ
ꢀ2.5 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2929 (CH3), 1732(C]O lactone),1728 (C]O of ester) 1680
(C]O ketone), 1436 (CH2), 1248 (CeN), 1154, 767. dH (500 MHz

P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
10271
CDCl3): 4.41 (m, 2H), 4.06 (m, 2H), 3.77e3.72 (s and s, 6H), 3.46 (d,
2H), 3.34 (m, 2H), 3.03 (dd, 1H, J¼19.0, 8.1 Hz), 2.22 (s, 3H); dC
(126 MHz, CDCl3): 205.5 (C]O ketone), 168.4 (C]O ester), 168.1
(C]O ester), 160.3 (C]O lactone), 64.1 (CeO lactone), 59.9 (CH
lactone), 55.1 (CH attached to esters), 53.0 (OCH3), 53.1 (OCH3), 51.2
(CH), 48.3 (CH2), 42.2 (CH), 29.8 (CH3); HRMS (ESI): calcd. For
7.8 Hz), 4.38 (dd, 1H, J¼9.3, 4.2 Hz), 3.84e3.72 (m, 1H), 3.67 (s, 3H,),
3.48e3.34 (m, 2H), 2.72, 2.56, 2.23e2.04 (dd, dd, m, 4H, first dd:
J¼19.4, 7.7 Hz, second dd: J¼15.7, 3.7 Hz), 1.69 (s, 3H); dC (126 MHz,
CDCl3): 172.2 (C]O ester), 160.8 (C]O lactone), 141.2 (C]C), 114.1
(]CH2), 67.7 (CeO lactone), 64.7 (CH of lactone), 52.9 (CH attached
to esters), 51.8 (OCH3), 48.7 (CH), 43.4 (CH2), 34.9 (CH), 18.2 (CH3);
HRMS (ESI): calcd. For C12H17NO4 [MþNa]þ 240.1050 found
240.1228.
C13H17NO7 [MþNa]þ 322.0897 found 322.0893. Compound 9 ½a 2D3
ꢂ
ꢀ0.9 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2959 (CH3), 1737 (C]O
lactone),1730 (C]O ester) 1701 (C]O ketone), 1432 (CH2), 1273
(CeN), 1020, 769. dH (500 MHz CDCl3): 4.52 (m, 1H), 4.44 (m, 1H),
4.33(m, 1H), 4.01(m, 1H), 3.87 (m, 1H), 3.74 (s and s, 6H), 3.51(s, 1H),
3.27(s, 1H), 3.04(s, 1H), 2.22(d, 3H); dC (126 MHz, CDCl3): 205.5 (C]
O ketone), 168.3 (C]O ester), 168.2 (C]O ester), 160.4 (C]O lac-
tone), 68.6 (CeO lactone), 62.5(CH lactone), 58.4(CH attached to
esters), 55.9(OCH3), 52.9(OCH3), 52.5(CH), 47.5(CH2), 44.8(CH),
29.8(CH3). HRMS (ESIþ): calcd for C13H17NO7 [MþNa]þ 322.0897
found 322.0906.
3.1.11. Methyl [(6S,7R,7aS)-6-isopropenyl-3-oxotetrahydro-1H-pyr-
rolo[1,2-c][1,3]oxazol-7-yl]acetate (13). Prepared by same method
as previous to yield (72 mg, 75%) of 13 as an orange oil ½a D24
þ3.2 (c
ꢂ
1.0, CHCl3); IR (neat) n
(cmꢀ1): 2945 (CH3), 2920 (]CH2), 1730 (C]
O lactone), 1645 (C]O ester), 1437 (CH2), 1378 (CH2), 1207 (CeN),
1169, 1013, 895. dH (500 MHz CDCl3): 4.92e4.83 (s and s, 2H), 4.45
(dd, 1H, J¼9.5, 8.7 Hz), 4.37 (dd, 1H, J¼8.4, 4.2 Hz), 4.12 (1H, dt,
J¼11.5, 5.8 Hz), 3.85 (1H, dd, J¼11.9, 7.2 Hz), 3.70 (3H, s), 3.05e2.97
(1H, m), 2.65e2.55 (1H, m), 2.47 (1H, dt, J¼13.0, 6.5 Hz), 2.40e2.30
(2H, m), 1.76 (3H, s). dC (126 MHz, CDCl3): 172.4 (C]O ester), 161.5
(C]O lactone), 141.9 (C]C), 113.3 (]CH2), 64.7 (CeO lactone), 59.6
(CH lactone), 52.7 (CH attached to esters), 51.9 (OCH3), 50.2 (CH),
40.5 (CH2), 33.3 (CH), 20.2 (CH3). HRMS (ESIþ): calcd for C12H17NO4
[MþNa]þ 240.1050 found 240.1233.
3.1.8. Dimethyl [(6R,7R,7aS)-6-isopropenyl-3-oxotetrahydro-1H-pyr-
rolo[1,2-c][1,3]oxazol-7-yl]malonate (10). nBuLi in hexane (2.5 M,
2.84 mL) was added to a suspension of Ph3PMeBr (12.03 g) in THF
(30 mL) at ꢀ78 ꢁC. The mixture was stirred at room temperature for
20 min and then brought to ꢀ60 ꢁC prior to the addition of a solu-
tion of 8 (0.85 g) in THF (20 mL). The reaction mixture was kept at
ꢀ60 ꢁC for 1 h and warmed to 25 ꢁC over a period of 0.5 h, after
which time it was filtered over Celite-silica gel. The solvent was
removed under reduced pressure and the residue subject to column
chromatography (60% ethyl acetate in hexane) to afford 10 as
3.1.12. Methyl 3-chloro-3-[3-(3-methylbut-2-en-1-yl)-2-oxo-1,3-
oxazolidin-5-yl] propanoate 19. To a stirring solution of epoxide
16 (551 mg, 4.3 mmol) in DMF (10 mL) was added CaCl2 (150 mg,
1.4 mmol) in 1 portion, at room temperature. The resulting solu-
tion was heated to 160 ꢁC and once all solid had dissolved 3,3-
dimethylallyl isocyanate 15 was added dropwise. The resulting
solution was held at reflux for 6 h, after this time the reaction was
cooled and water (50 mL) was added. The organic components
were extracted using diethyl ether (3ꢃ30 mL) washed with satu-
rated brine (1ꢃ25 mL) then dried, (MgSO4) concentrated under
reduced pressure and purified via flash chromatography (1:1
hexanes/diethyl ether) to afford the title compound 19 (45 mg, 4%)
a white solid (0.61 g, 72%): ½a D25
ꢂ
ꢀ1.28 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2956 (CH3), 2929 (]CH2), 2163 (C]C),1728 (C]O lactone),
1645 (C]O ester), 1435 (CH2), 1225 (CeN), 1157, 1005, 902. dH
(500 MHz CDCl3): 4.83e4.81(s and s, 2H); 4.51(dd, 1H, J¼9.5,
8.0 Hz); 4.42 (dd, 1H, J¼9.5, 4.3 Hz); 4.05 (m, 1H, J¼8.5,4.3 Hz);
3.76e3.68 (m, 6H); 3.54e3.45 (m,1H); 3.37 (dd,1H, J¼11.6e9.4 Hz);
3.0e2.92 (m, 1H); 2.43 (m, 1H); 1.69 (s, 3H); dC (126 MHz, CDCl3):
168.1 (C]O ester), 167.5 (C]O ester), 160.3 (C]O lactone), 141.7
(C]O ketone), 114.7 (]CH2), 68.2 (CeO lactone), 62.2(CH lactone),
53.1 (CH attached to esters), 52.7 (OCH3), 52.5 (OCH3), 52.3 (CH),
48.5 (CH2), 45.7 (CH), 17.6 (CH3); HRMS (ESIþ): calcd for C14H19NO6
[MþNa]þ 320.1105 found 320.1101.
as a brown liquid. IR (neat) n
(cmꢀ1) 2966 (CeH), 1731 (C]O), 1436
(CeH), 1241 (CeO), 1200 (CeOester), 1165 (CeN), 755 (CeCl); dH
(500 MHz CDCl3): dC (500 MHz, CDCl3): 5.14 (t, J¼7.0 Hz, 1H, CH
alkene), 4.5 (dt, J¼4.1, 8.4 Hz, 1H, CH), 4.06 (dd, J¼6.2, 15.5 Hz, 1H,
CH2), 3.96 (ddd, J¼3.9, 8.2 Hz, 1H, CH), 3.75 (d, J¼4.2 Hz, 2H, CH2),
3.71 (s, 3H, Me), 3.67 (dd, J¼7.9, 15.4 Hz, 1H, CH2), 2.82e2.76 (dd,
J¼3.7, 16.4 Hz, 1H, CH2), 2.56 (dd, J¼9.1, 16.4 Hz, 1H, CH2), 1.74 (s,
3H, Me), 1.70 (s, 3H, Me): dC (125.7 MHz, CDCl3): 170.3 (CO), 156.3
(CO), 137.9 (alkene), 117.7 (CH alkene), 76.9 (CH), 54.2 (CH), 52.0
(OMe), 45.4 (NeC), 40.1 (CH2) 37.0 (CH2), 25.6 (Me), 17.96 (Me).
HRMS (ESIþ) calcd for C12H18ClNO4Na, m/z 298.0810, found
298.0816.
3.1.9. Dimethyl [(6S,7S,7aS)-6-isopropenyl-3-oxotetrahydro-1H-pyr-
rolo[1,2-c][1,3]oxazol-7-yl]malonate (11). Compound 11 was pre-
pared by same method as previous to yield 11 (0.69 g, 81%) as
a white solid ½a 2D4
ꢂ
ꢀ2.1 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2962(CH3),
2929 (]CH2), 2030 (C]C), 1728 (C]O lactone), 1690 (C]O ester),
1440 (CH2), 1243 (CeN), 1150, 1008, 923. dH (500 MHz CDCl3):
4.88e4.82 (s and s, 2H), 4.54 (m, 1H, J¼8.8, 5.2 Hz); 4.4 (dd, 1H,
J¼9.9, 8.9 Hz); 3.9 (dd, 1H, J¼10.2, 5 Hz); 3.90e3.83 (m, 1H);
3.76e3.65 (s, 6H), 3.43 (dd, 1H, J¼19.4, 10.9 Hz); 3.08e2.90 (m, 2H);
2.59 (td, 1H, J¼9.8, 7.6 Hz); 1.72 (s, 3H); dC (126 MHz, CDCl3): 168.8
(C]O ester), 167.8 (C]O ester), 160.9 (C]O lactone), 141.0 (C]O
ketone), 114.5 (¼CH2), 68.4 (CeO lactone), 59.9 (CH lactone),
53.1(CH attached to esters), 52.2 (OCH3), 52.2 (OCH3), 51.4 (CH),
50.8 (CH2), 42.6 (CH), 18.8 (CH3). HRMS (ESIþ): calcd for C14H19NO6
[MþNa]þ 320.1105 found 320.1102.
3.1.13. (4S)-3-(3-Methylbut-2-en-1-yl)-2-oxo-1,3-oxazolidine-4-
carboxylate 21. Oxazolidinone 20 (360 mg, 2.48 mmol) was
added dropwise to
a stirring suspension of NaH (65 mg
2.73 mmol) in 4:1 THF/DMF (5 mL). Upon complete dissolution
of solids, 3,3-dimethylallyl bromide (506 mg, 3.23 mmol) was
added dropwise. Following 16 h, water (5 mL) was added and
organics extracted with diethyl ether (3ꢃ30 mL), combined,
dried (Na2SO4) and solvent removed under reduced pressure. The
residue was subject to flash chromatography (3:1 hexanes/ethyl
acetate) to afford the title compound 21 (410 mg, 78%) as a col-
3.1.10. Methyl [(6R,7S,7aS)-6-isopropenyl-3-oxotetrahydro-1H-pyr-
rolo[1,2-c][1,3]oxazol-7-yl]acetate (12). NaCl (29 mg) was added to
150 mg of 10 in 12 mL of hydrated DMSO and heated to 170 ꢁC for
8 h. After cooling down to room temperature, extraction with ethyl
acetate and removing the solvent under reduced pressure gave
ourless liquid. ½a D24
ꢂ
þ21.1 (c 1.00, CH2Cl2). IR (neat)
n
(cmꢀ1) 2919
(CeH), 1739 (C]O), 1207 (CeO), 1173; dH (500 MHz CDCl3): 5.13
(t, J¼7.4 Hz, 1H, CH alkene), 4.50e4.36 (m, 1H, OeCH2),
4.35e4.25 (m, 2H, OeCH2), 4.13 (ddd, J¼14.9, 6.2, 0.7 Hz, 1H,
CH2), 3.3 (dd, J¼8.8, 14.8 Hz, 1H, CH2), 3.78 (s, 3H, Me), 1.76 (s,
3H, Me), 1.65 (s, 3H, Me). dC (126 MHz, CDCl3): 170.3 (CO), 157.4
(CO), 139.0 (alkene), 117.3 (CH alkene), 64.3 (CH2), 56.2 (NeC)
(80 mg, 83%) of 12 as orange oil, ½a D25
ꢂ
þ5.2 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2953 (CH3), 2918 (]CH2), 1730 (C]O lactone), 1644 (C]O
ester), 1437 (CH2), 1394 (CH2), 1206 (CeN), 1166, 1002, 897. dH
(500 MHz CDCl3): 4.89e4.85 (s and s, 2H), 4.50 (dd, 1H, J¼9.4,

10272
P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
52.8 (OMe), 40.9 (NCH2), 25.7 (Me), 17.7 (Me) HRMS (ESIþ) calcd
for C10H15NO4Na, m/z 236.0893, found 236.0893.
added in one portion Cs2CO3 (32 mg, 0.1 mmol). After 5 days the
reaction was quenched with H2O (5 mL) and extracted with AcOEt
(3ꢃ15 mL). The organic extracts were combined, dried (Na2SO4)
and solvent removed under reduced pressure. The residue was
subject to column chromatography eluting with hexanes/ethyl ac-
etate (3:2) to afford the title compound (23) (426 mg, 80%) as
3.1.14. Ethyl (2E)-3-[(4R)-3-(3-methylbut-2-en-1-yl)-2-oxo-1,3-
oxazolidin-4-yl]acrylate 17. To a stirring solution of methyl ester
(21) (321 mg, 1.51 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢁC was added
dropwise DIBAL-H (1 M in diethyl ether) (2.4 mL, 2.4 mmol). Fol-
lowing 1 h the solution was warmed to ꢀ10 ꢁC and saturated am-
monium chloride solution (3.0 mL) was added followed by cannular
a brown oil. ½a 2D4
ꢂ
ꢀ42.3 (c 1.00, CH3Cl). IR (neat)
n
(cmꢀ1) 3454
(OeH), 2920 (CeH), 2850 (CeH), 1735 (C]O), 1678 (C]O), 1450,
1376; dH (500 MHz CDCl3): 4.89 (s, 1H, alkene), 4.64 (s, 1H, alkene),
3.76 (m, 1H, NCH), 3.70 (app. s, 5H, NCH2), 3.65 (s, 3H, OMe), 3.47
(m, 2H, CH2OH), 2.96 (m, 1H, NCH2CH), 2.56 (m, 1H, CH), 2.22 (m,
2H, COCH2), 1.69 (s, 3H, Me) dC (126 MHz, CDCl3): 172.7 (COMe),
157.3 (NCOMe), 141.6 (alkene), 112.9 (CH2 alkene), 65.8 (NCH2), 65.4
(NCH), 52.8 (OMe carbamate), 51.7 (OMe ester), 48.3 (CH2OH), 45.6
(NCH2CH), 39.0 (CH), 33.0 (COCH2), 22.3 (Me). HRMS (ESIþ) calcd
for C13H22NO5, m/z 272.11492, found 272.1499.
addition of ethyl (triphenylphosphoranylidene)acetate (1.57
g
4.52 mmol) in CH2Cl2 (5 mL) Following 16 h at room temperature,
the liquid was decanted and after solvent removal in vacuo, the
residue was purified by flash chromatography (4:1 hexanes/ethyl
acetate) to afford the title compound 17 (318 mg, 83%) as a colour-
less liquid. ½a 2D4
ꢂ
þ36.7 (c 1.10, CH2Cl2).IR (neat)
n
(cmꢀ1) 2979
(CeH), 2911 (CeH), 1748 (C]O), 1717 (C]O), 1263, 1175 (CeO),
1055; dH (500 MHz CDCl3): 6.76 (dd, J¼8.5, 15.7 Hz, 1H, CH alkene),
6.00 (d, J¼15.6 Hz, 1H, CH alkene), 5.13 ( t, J¼7.3 Hz, 1H, CH alkene),
4.43 (app. t, J¼8.7 Hz, 1H, OCH2), 4.34 (app. dd, J¼15.3, 8.5 Hz, 1H,
NCH), 4.23 (q, J¼7.1 Hz, 2H, CH2CH3), 4.03 (dd, J¼6.24, 15.0 Hz, 1H,
NCH2), 3.99 (dd, J¼6.7, 8.6 Hz, 1H, OCH2), 3.60 (dd, J¼15.1, 8.4 Hz,
1H, NCH2), 1.73 (s, 3H, Me), 1.63 (s, 3H, Me), 1.31 (t, J¼7.2 Hz, 3H,
CH2CH3). dC (126 MHz, CDCl3): 165.0 (COEt), 157.6 (CO carbamate),
143.0 (alkene), 138.1 ((CH3)2C), 125.7 (alkene), 117.7 (CH alkene),
66.2 (OCH2), 61.0 (CH2 ethyl), 56.3 (NCH), 40.3 (NCH2), 25.7 (Me),
18.0 (Me), 14.1 (Me ethyl). HRMS (ESIþ) calcd for C13H19NO4Na, m/z
276.1206, found 276.1215.
3.1.17. Methyl (2S,3S,4S)-2-formyl-4-isopropenyl-3-(2-methoxy-2-
oxoethyl)pyrrolidine-1-carboxylate 24. Py$SO3 (1.36 g, 8.55 mmol)
was dissolved in DMSO (3 mL) and CH2Cl2 (4 mL) and cooled to 0 ꢁC.
Triethylamine (1.49 mL, 10.7 mmol) was added dropwise. After
10 mins alcohol 23 in CH2Cl2 (4 mL) was added dropwise at 0 ꢁC.
The reaction mixture was allowed to warm to room temperature.
After 16 h saturated ammonium chloride (4 mL) was added and
extracted with CH2Cl2 (3ꢃ15 mL). The organic layers were collected
combined, dried (Na2SO4) and the solvent was removed under re-
duced pressure. The residue was purified by column chromatog-
raphy eluting with petrol/ethyl acetate (3:1) to afford the title
3.1.15. Ethyl [(6S,7S)-6-isopropenyl-3-oxotetrahydro-1H-pyrrolo[1,2-
c][1,3]oxazol-7-yl]acetate 14 and ethyl [(6R,7S)-6-isopropenyl-3-
compound 24 (471 mg, 82%) as a yellow oil ½a D23
ꢀ58.1(c 1.05,
ꢂ
CH2Cl2). IR (neat) n
(cmꢀ1) 2958 (CeH), 1693 (C]O), 1689 (C]O),
oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-7-yl]acetate
24. Ene
1449, 1380, 1131 (CeO); dH (500 MHz CDCl3): 9.58 (d, J¼28.1 Hz, 1H,
aldehyde), 4.90 (d, J¼14.8 Hz, 1H, alkene), 4.67 (d, J¼13.6 Hz, 1H,
alkene), 4.14 (d, J¼54.3 Hz, 1H, NCH), 3.72 (app. s, 1H, NCH2),
3.70e3.60 (m, 6H, OMe), 3.59e3.41 (m, 1H, NCH2), 2.87 (m, 1H, CH),
2.84e2.72 (m, 1H, NCH2CH), 2.36e2.27 (m, 1H, COCH2), 2.27e2.12
(m, 1H, COCH2), 1.68 (s, 3H, Me). dC (126 MHz, CDCl3): 198.5 (al-
dehyde), 172.3 (ester), 155.7 (carbamate), 140.9 (alkene), 113.8 (CH2
alkene), 69.8 (NCH), 51.9 (OMe carbamate), 48.4 (OMe ester), 47.9
(NCH2), 45.9 (NCH2CH), 38.5 (CH), 32.1 (COCH2), 22.3 (Me). HRMS
(ESIþ) calcd for C13H19NO5Na, m/z 292.1155, found 292.1156.
precursor 17 (1 g 3.95 mmol) was dissolved in N,N-diethylaniline
(20 mL) in a thickwalled microwave vial (35 mL). The vial was placed
in the microwave at 200 ꢁC for 4 h. The solution was subject to flash
chromatography (5:1 hexanes/ethyl acetate) to afford a 7:1 mixture
of title compounds 14 and 22 (800 mg, 80%) as a brown liquid.
Compound 14 ½a 2D3
ꢂ
ꢀ14.4 (c 1.01, CH2Cl2). IR (neat)
n
(cmꢀ1) 2980
(CeH), 2913 (CeH), 1748 (C]O), 1726 (C]O), 1263, 1175 (CeO); dH
(500 MHz CDCl3): 4.94 (s, 1H, alkene), 4.75 (s, 1H, alkene), 4.54 (dd,
J¼9.1, 8.3 Hz, 1H, NCH2), 4.25e4.19 (dd, J¼4.81, 9.26 Hz, 1H, NCH2),
4.17e4.06 (m, 2H, CH2 ethyl), 3.86e3.77 (m, 2H, OCH2 and NCH), 3.16
(dd, J¼6.5, 11.8 Hz, 1H, OCH2 carbamate), 2.99 (app. dd, J¼14.4,
7.7 Hz,1H, ]CCH), 2.48e2.34 (m, 2H,), 2.26e2.16 (m,1H),1.73 (s, 3H,
Me), 1.29e1.20 (t, J¼7.15 Hz, 3H, OMe).dC (126 MHz, CDCl3): 172.2
(COEt),161.3 (CO carbamate),142.3 (alkene),114.6 (CH2 alkene), 68.8
(NCH2), 63.6 (NCH), 60.8 (CH2 ethyl), 49.7 (OCH2 carbamate), 49.3
(NCH2CH), 43.1 (CH), 33.3 (COCH2), 22.5 (Me), 14.1 (CH3 ethyl).
HRMS (ESIþ) calcd for C13H19NO4Na, m/z 276.1206, found 276.1217.
3.1.18. (ꢀ)-a-Kainic acid 1. To a stirring solution of aldehyde 24
(1.42 g, 5.28 mmol) in tBuOH (15 mL) and 2-methyl 2-butene
(25 mL) at room temperature was added dropwise a solution of
sodium chlorite (4.30 g, 47.5 mmol) and sodium dihy-
drogenphosphate (5.76 g, 36.9 mmol) in water (150 mL) over a pe-
riod of 10 m. After 16 h the volatiles were removed under reduced
pressure and the residue was dissolved in water (25 mL) and
extracted with hexanes (3ꢃ25 mL). The aqueous phase was acidi-
fied to pH 3 with concentrated HCl(aq) and extracted with diethyl
ether (3ꢃ50 mL). The organic layers were combined, dried (Na2SO4)
and concentrated under reduced pressure. The crude acid 25 was
dissolved in stirring MeOH (70 mL) and aqueous NaOH (38%)
(70 mL) was added. The mixture was heated to reflux. Following
18 h the solvent was removed under reduced pressure and the
crude product was added to a column containing Dowex-50Hþ
(WX8-200 cross-linking, 100e200 wet mesh). Elution with NH4OH
(1 M), evaporation and treatment with Amberlite CG-50 (100e200
dry mesh) afforded after recrystallisation from water, which, re-
Compound 22 IR (neat) n
(cmꢀ1) 2974 (CeH), 2904 (CeH),1750 (C]
O),17,129 (C]O),1206,1175 (CeO); dH (500 MHz CDCl3): 4.89 (s,1H,
alkene), 4.86 (s, 1H, alkene), 4.52 (app. t, J¼8.6 Hz, 1H, OCH2 carba-
mate), 4.42 (dd, J¼9.4, 4.2 Hz,1H, OCH2 carbamate), 4.13 (t, J¼6.9 Hz,
2H, CH2 ethyl), 3.82e3.73 (m, 1H, NCH), 3.47 (app. t, J¼10.7 Hz, 1H,
NCH2), 3.40 (app. t, J¼10.2 Hz, 1H, NCH2), 2.78e2.67 (m, 1H),
2.62e2.51 (dd, J¼3.6,15.7 Hz,1H, COCH2), 2.19 (dd, J¼9.7,15.3 Hz,1H,
COCH2), 2.15e2.07 (m,1H),1.71 (s, 3H, Me),1.27 (t, J¼7.1 Hz, 3H, CH3
ethyl).dC (126 MHz, CDCl3): 172.0 (COEt),161.4 (CO carbamate),141.3
(alkene), 114.7 (alkene), 67.8 (OCH2 carbamate), 64.7 (NCH), 60.9
(CH2 ethyl), 55.0 (NCH2CH), 48.67 (NCH2), 43.3 (CH), 35.3 (COCH2),
18.1 (Me), 14.1 (CH3 ethyl). HRMS (ESIþ) calcd for C13H19NO4Na, m/z
276.1206, found 276.1218.
moved the undesired allo-kainic acid, the title compound (ꢀ)-
a-
kainic acid 1 (720 mg, 60%) as white needle crystals, mp 245 ꢁC.
Spectra consistent with those previously reported. ½a D23
ꢀ14.6 (c
ꢂ
3.1.16. Methyl (2S,3S,4S)-2-(hydroxymethyl)-4-isopropenyl-3-(2-
methoxy-2-oxoethyl)pyrrolidine-1-carboxylate 23. To a stirring so-
lution of ene-product 14 contaminated with allo-kainate product
22 (500 mg, 1.97 mmol) in MeOH (4 mL) at room temperature was
0.65, H2O). IR (neat) n
(cmꢀ1) 3534, 2976 (CeH), 2528 (CeH), 1689
(C]O), 1615 (C]O),1383, 1276, 891. dH (500 MHz, D2O): 4.98 (1H, s,
alkene), 4.69 (1H, s, alkene), 4.03 (s 1H, NCH), 3.64 (1H, dd, J¼11.5,
6.7 Hz, NCH2), 3.35 (app dd, J¼27.9, 16.9 Hz, 1H, NCH2), 2.96 (app s,

P.J. Parsons et al. / Tetrahedron 67 (2011) 10267e10273
10273
22. Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418e5424.
23. Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896e1898.
24. Ogasawara, K.; Nakada, Y.; Sugahara, T. Tetrahedron Lett. 1997, 38, 857e860.
1H, NCH2CH), 2.40 (dd, J¼15.5, 4.1 Hz, 1H, COCH2), 2.31 (dd, J¼16.2,
8.2 Hz, 1H, COCH2), 1.70 (3H, s, Me). dC (126 MHz, D2O): 176.2
(COCH2), 173.7(NCO), 139.9 (alkene), 113.4 (CH2 alkene), 65.6 (NCH),
46.4 (NCH2), 45.7 (CH), 40.7 (NCH2CH), 33.3 (COCH2), 22.1 (Me).
HRMS (ESIþ) calcd for C10H16NO4Na, m/z 214.1074, found 214.1077.
25. Ogasawara, K.; Nakagawa, H.; Sugahara, T. Org. Lett. 2000, 2, 3181e3183.
~ꢀ
26. Rubio, A.; Ezquerra, J.; Escribano, A.; Remuinan, M. J.; Vaquero, J. J. Tetrahedron
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27. Cossy, J.; Cases, M.; Gomez Pardo, D. Tetrahedron 1999, 55, 6153e6166.
28. Montgomery, J.; Chevliakov, M. V. J. Am. Chem. Soc. 1999, 121, 11139e11143.
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31. Ganem, B.; Xia, Q. Org. Lett. 2001, 3, 485e487.
Acknowledgements
We thank Drs. Iain Day and Alaa Abdul-sada for NMR and mass
spectroscopy. The award of Professor Parsons fellowship to S.R. is
noted.
32. Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727e4733.
33. Anderson, J. C.; Whiting, M. J. Org. Chem. 2003, 68, 6160e6163.
34. Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467e1470.
35. Hoppe, D.; Martinez, M. M. Org. Lett. 2004, 6, 3743e3746.
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42. Lautens, M.; Scott, M. E. Org. Lett. 2005, 7, 3045e3047.
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