Studies towards a total synthesis of kainic acid

Article abstract of DOI:10.1016/S0040-4020(03)00425-3

The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by Wittig methylenation gave the kainoid derivative 18.

Full text of DOI:10.1016/S0040-4020(03)00425-3

Tetrahedron 59 (2003) 3307–3314
Studies towards a total synthesis of kainic acid
*
E. S. Greenwood, P. B. Hitchcock and P. J. Parsons
The Chemical Laboratories, School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer,
Brighton, East Sussex BN1 9QJ, UK
Received 10 January 2003; revised 5 March 2003; accepted 13 March 2003
Abstract—The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. Base induced
fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by Wittig methylenation gave the
kainoid derivative 18. q 2003 Published by Elsevier Science Ltd.
1. Introduction
The kainoid amino acids have attracted considerable interest
in the fields of biology and neurobiology due to their
pronounced insecticidal, anthelmintic and, principally,
neuroexcitatory properties.1 Kainic acid (1) has demon-
strated extremely potent activity on both the vertebrate and
invertebrate glutaminergic systems, leading to specific
neuronal death in the brain,2 and its pronounced neuro-
excitatory properties have been well documented.3 The
pharmacological effects and the patterns of neuronal
degeneration observed after the injection of kainoids have
been shown to mimic the symptoms of neuronal conditions
such as epilepsy,4 Alzheimer’s disease and Huntington’s
chorea.5 Additionally, it has been proposed that the neuronal
death induced by kainoids is a good experimental model for
the neuronal cell loss observed in senile dementia.2
The authors have recently published initial results of a
photochemical approach to the kainoid ring system.6
The key step involves a [2þ2] photocycloaddition of the
dioxinone 2 to protected 3-pyrroline 3 to generate the
diastereomeric cyclobutanes 4,5. Subsequent methoxide
induced cyclobutane fragmentation, and methylenation
of the resultant ketone 6, generates the desired C3/C4
functionality with the requisite cis stereochemistry
(Scheme 1). Application of this approach to the elucidation
of the full kainoid skeleton is detailed below.
Scheme 1. (i) hv/EtOAc; (ii) NaOMe (0.1 equiv.)/MeOH/reflus; (iii) Cp2TiMe2/THF/reflux.
Keywords: excitatory; kainate; photocyclisation; fragmentation; stereoselection.
*
Corresponding author. Tel.: þ44-1273-678861; fax: þ44-1273-677196; e-mail: p.j.parsons@sussex.ac.uk
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00425-3

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E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
Scheme 2. (i) SOCI2/MeOH; (ii) Boc2O, iPr2EtN, DMAP/Dioxane (96% over two steps); (iii) MsCI, Et3N, DMAP/DCM (82%); (iv) Ph2Se2, NaBH4/EtOH
(86%); (v) 30% aq. H2O2soln, pyr./DCM (80%); (vi) 2, hv/EtOAc.
2. Results and discussion
would be formed with a highly hindered concave face,
generating a greater level of facial differentiation (Scheme
3). To this end the ester functionality was reduced to the
alcohol 13, with the intention of deprotecting the nitrogen
functionality and forming the oxazolidinone ring by
reaction with phosgene. Fortuitously, a recent publication
by Zhao and Thurkauf8 detailed the action of diethyl-
aminosulfur trifluoride (DAST) on a Boc-protected 1,2-
amino alcohol, where-by an oxazolidinone was unexpect-
edly generated in good yield, and none of the desired
fluorinated compound was observed. Treatment of the
alcohol 13 in dichloromethane with DAST at 08C gave
the desired bicyclic system 14 in a reasonable yield.
It was hoped that submission of alkene 10, derived from
trans-4-hydroxyproline, to the previously optimized photo-
chemical conditions would generate a cyclobutane with the
desired trans, cis stereochemistry around the pyrrolidine
ring. As steric effects have previously been shown to play a
strong role in directing photocycloadditions,7 the bulk of
the C-2 ester group was expected to induce the approach of the
dioxinone from the opposite face of the 3-pyrroline system.
Unfortunately, no facial or regiochemical bias was
observed, and the cyclobutane products 11, 12 were
recovered, after extensive column chromatography, in a
disappointingly low yield (Scheme 2). Increasing the steric
bulk of the C-2 (kainoid numbering) group to either the tert-
butyl ester or the tert-butyldimethylsilyl protected alcohol
offered no increase in yield or diastereoselectivity.
With the desired oxazolidinone 14 in hand, the photo-
cycloaddition could be attempted. Irradiation of a continu-
ously degassed solution of the oxazolidinone 14 and the
dioxinone 2 gave a 38% yield of just one photoproduct 15,
together with isolated starting materials. The structure of
15 has been confirmed by X-ray crystallographic analysis.
This reaction is noteworthy for two reasons: firstly, the
photocycloaddition has occurred with complete regio- and
stereoselectivity; Secondly, the dioxinone 2 has added onto
the sterically hindered concave face of the oxazolidinone
14, contrary to expectation. Whilst this reaction generates
an all cis arrangement of the substituents around the
pyrrolidine ring, the C2 centre (kainoid numbering) is
readily epimerized at a later stage, and thus a rapid route
into the kainoid ring system was envisaged.
It was assumed that if the ester group of the proline
derivative 10 could be tethered to the nitrogen in the form of
an oxazolidinone ring then a ‘butterfly’ shaped molecule
The multiple ring fragmentation of photoadduct 15 with
sodium methoxide in refluxing methanol was expected to
proceed with good yields; as the chemistry of the lactone
ring had been explored previously,6 and oxazolidinone rings
are known to open readily under these conditions.9 It was
therefore surprising that, when the photoadduct 15 was
submitted to the previously optimized ring opening
conditions, the oxazolidinone 16 was obtained in modest
yield, despite the use of up to one equivalent of sodium
Scheme 3. (i) LiAIH4/Et2O (76%); (ii) DAST/DCM/08C(75%); (iii) 2, hv/
EtOAc (38%).
Scheme 4.

E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
3309
Table 1.
18, followed by oxidation of the resultant alcohol and
subsequent deprotection would generate kainoid skeleton in
a rapid fashion.
Conditions
% 16
% 17
NaOMe (1.0 equiv.)/methanol/reflux/24 h
Ti(OiPr)4 (0.1 equiv.)/methanol/rt/2 h
AlMe3 (0.1 equiv.)/methanol/rt/2 h
BF3OEt2 (0.1 equiv.)/methanol/rt/2 h
49
63
65
33
0
A shorter route to the kainoid skeleton, which avoids the
problematic epimerization and subsequent methylenation
steps, can be envisaged if the O-6 ether oxygen of the
tetracycle 15 is replaced by a methylene group. Subsequent
treatment of the resultant cyclobutane with strong base
would drive the fragmentation of both the lactone and the
oxazolidinone moieties with concomitant nitrogen depro-
tection and formation of the desired exo-methylene
functionality in one step, without risk of epimerization
(Scheme 6). In order for this to be possible the pyranone
19 was required to be synthesized and to undergo the
photocycloaddition with the same regio- and stereoselec-
tivity as the dioxinone 2.
18
15
10
methoxide (Scheme 4). In an attempt to avoid the
epimerization at C-7, a variety of Lewis acid catalyzed
fragmentations were conducted, the results of which are
tabulated in Table 1.
The predominant product in each of these reactions was the
epimerized oxazolidinone 16. Ongoing studies within the
group are concentrating on performing the lactone ring
opening without the concomitant epimerization, so as to
maintain the required C6/C7 cis stereochemistry.
The pyranone 19 was formed according to the procedure
of Dugger and Heathcock;13 whereby methyl senecioate
undergoes deprotonation with LDA followed by conden-
sation with acetone, which subsequently undergoes intra-
molecular 1,2 nucleophilic substitution on the ester to yield
pyranone 19. The procedure was modified by the addition
of 0.5 equiv. of cadmium chloride to promote the initial
1,5-nucleophilic addition to acetone.14 Submission of the
pyranone 19 and the oxazolidinone 14 to the standard
photocycloaddition conditions gratifyingly gave just one
photoadduct 20. As with the previous oxazolidinone, the
photoproduct 20 was a crystalline solid enabling an X-ray
crystallographic confirmation of its structure; the desired
C-6 methylene analogue of the previously obtained tetra-
cycle 15.
To complete the synthesis of the kainoid skeleton, the
ketone functionality was required to be converted to its exo-
methylene analogue. In our previous studies this was
achieved by the dimethyltitanocene (Cp2TiMe2) procedure
of Petasis and Bzowej.10 Unfortunately, submission of
oxazolidinone 17 to the same procedure resulted in the
recovery of starting material, with prolonged reaction times
causing a small amount of decomposition. Another non-
basic method developed by Takai et al.11 in which the
ketone is added to a solution of zinc, diiodomethane and
titanium tetrachloride in tetrahydrofuran, was also attempted
without success. In order to effect the methylenation, Wittig
chemistry12 was resorted to. Thus, the ylide formed from
methyl triphenylphosphonium bromide using butyllithium
was added to the ketone 16 to generate the exo-methylene
compound 18 in a reasonable yield (Scheme 5). It should be
noted however, that the use of this basic methodology on the
real system 17 resulted in epimerization at C-7.
Base-induced fragmentation of photoadduct 20 was
attempted by treatment with sodium hydroxide in methanol
at reflux. Unfortunately, starting material was recovered
quantitatively after 24 h. A range of acidic, basic and radical
fragmentation methodologies were consequently investi-
gated, (Table 2) all of which returned only starting material
after prolonged reaction times.
It can be seen that opening of the oxazolidinone ring of
3. Conclusion
Whilst the initial photochemical route towards the kainoid
skeleton has been shown to be successful, the facile
epimerization of the C-4 center limits the synthetic viability
Scheme 5. (i) CH3PPh3Br, nBuLi/THF/2788C (46%).
Scheme 6. (i) LDA, CdCI2/Et2O, then (CH3)2CvO (37%); (ii) 14, hv/EtOAc (43%).

3310
E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
Table 2.
reaction mixture was stirred at room temperature for 2 h
then 4-dimethylaminopyridine (0.13 g, 1.1 mmol) was
added and the reaction mixture stirred overnight. The
reaction mixture was concentrated under reduced pressure
and taken up in ethyl acetate (300 ml). The solution was
washed with 1 M aqueous citric acid (100 ml), 1 M aqueous
sodium bicarbonate solution (100 ml) and water
(2£100 ml), dried over magnesium sulfate and concentrated
under reduced pressure to give the pure, protected
hydroxyproline as a yellow oil (13.0 g, 96%). TLC, (ethyl
acetate) Rf¼0.41; [a]3D0 240.5 c 0.79 in chloroform (lit.,
[a]2D0 264.9 c 0.98);15 nmax (thin film)/cm21 3443 (s, OH),
3004 and 2937 (s, CH2/CH3), 2885 (m, CH), 1751 (s,
CO2Me), 1685 (s, N–CvO), 1408 (s, OH), 1358 (C(CH3)3),
1215 (s, C–O), 1129 (s, C–OH); dH (300 MHz; CDCl3) 4.51
(1H, br s, 4-H), 4.50–4.35 (1H, m, 2-H), 3.74 (3H, s, OMe),
3.68–3.38 (2H, m, 5-H), 2.37–2.22 (1H, m, 3-H), 2.15–2.02
Conditions
Time
Result
NaOMe (2 equiv.)/MeOH/reflux
Conc. H2SO4/MeOH/reflux
Cat. HClO4/MeOH/reflux
Excess NaOH/MeOH/reflux
Bu3SnH, AIBN/THF/reflux
SmI2/THF/reflux
72 h
24 h
24 h
24 h
8 h
Starting material recovered
Starting material recovered
Starting material recovered
Starting material recovered
Starting material recovered
Starting material recovered
8 h
of such methodology. Further studies in this area are
concentrating on the development of a non-basic fragmen-
tation methodology to enable significant amounts of the
C-3/C-4 cis compound to be generated. Conversely, the
successful fragmentation of the highly inert, pyranone
derived cyclobutane 20 would bypass the troublesome
epimerization problem, and present an even more rapid
route into the kainoid amino acids.
t
(1H, m, 3-H), 1.50 and 1.45 (9H, 2£s, Bu); dC (75 MHz;
CDCl3) 174.1 (CO2Me), 154.4 (N–CvO), 80.8 (C(CH3)3),
69.8 (C-4), 58.3 (C-2), 55.1 (C-5), 52.5 (OMe), 39.5 (C-3),
28.6 (tBu); m/z (FAB) 246 (MþH, 24%), 190 (79), 146 (85),
144 (M2Boc, 77), 130 (43), 57 (tBu, 100).
4. Experimental
4.1. General
4.1.2. (4S)-N-tert-Butoxycarbonyl-4-methylsulfonyloxy-
L-proline methyl ester.16 To a stirred solution of (4S)-N-
tert-Butoxycarbonyl-4-hydroxy-L-proline methyl ester
(13.0 g, 56 mmol) in dichloromethane (300 ml) at 08C
was added triethylamine (8.5 ml, 61 mmol) followed by
methanesulfonyl chloride (5.6 ml, 72 mmol). 4-Dimethyl-
aminopyridine (2.0 g, 17 mmol) was added and the reaction
mixture stirred at 08C for 1 h then allowed to warm to room
temperature and stirred overnight. The reaction mixture was
poured into ice/water (500 ml) and the layers were
separated. The organic layer was washed with 1 M aqueous
citric acid (500 ml), 1 M aqueous sodium bicarbonate
solution (500 ml) and water (500 ml), dried over mag-
nesium sulfate and concentrated under reduced pressure to
leave a yellow oil. This was purified by column chroma-
tography (50% petroleum ether/diethyl ether eluent) to give
a colourless oil, which solidified upon prolonged standing
(14.8 g, 82%). TLC, (ethyl acetate) Rf¼0.59; mp 82–858C
(lit., 85–868)16 [a]D35 250.7, c 1.5 in chloroform (lit., [a]2D0
252.3, c 1.6);16 nmax (thin film)/cm21 2922 and 2853
(s, CH3/CH2), 1747 (s, CO2Me), 1698 (s, N–CvO), 1358
(s, C(CH3)3), 1215 (m, C–O), 1171 (m, –SO2O–); dH
(300 MHz; CDCl3) 5.26 (1H, m, 4-H), 4.50–4.37 (1H, m,
2-H), 3.88–3.75 (2H, m, 5H), 3.76 (3H, s, CO2Me), 3.06
(3H, s, SO2Me), 2.70–2.53 (1H, m, 3-H), 2.31–2.19 (1H,
m, 3-H), 1.47 and 1.32 (9H, 2£s, tBu); dC (75 MHz; CDCl3)
173.1 (CO2Me), 153.7 (N–CvO), 81.4 (C(CH3)3), 78.6 and
78.3 (C-4), 57.8 and 57.5 (C-2), 52.9 (CO2CH3), 52.7 and
52.6 (C-5), 39.2 (SO2CH3), 37.9 and 36.7 (C-3), 28.7 and
28.6 (C(CH3)3); m/z (FAB) 346 ([MþNa], 3%), 324
([MþH], 22), 268 (78), 224 (84), 128 (76), 57 (tBu, 100),
55 (55).
Photoreactions were carried out in 150 ml or 350 ml
reaction flasks with a quartz immersion well and photo-
excited using a 125 W medium pressure mercury lamp
(Model 3140) purchased from Photochemical Reactors Ltd,
Blounts Farm, Blounts Court Road, Sonning Common,
Reading, Berkshire, RG4 9PA.
Melting points were recorded on an electrothermal melting
point apparatus, and are measured in degrees centigrade and
are uncorrected. 1H NMR spectra were recorded on a Bruker
Advance AC-300 instrument measured at 300 MHz and a
Bruker 500 at 500 MHz. 13C NMR spectra were recorded on
a Bruker Advance AC-300 instrument at 75 MHz and a
Bruker 500 at 125 MHz. Chemical shifts are measured in
ppm on the d scale; coupling constants (denoted by J) are
measured in hertz. Infrared spectra were recorded on a
Perkin-Elmer 1710 Fourier transform spectrophotometer,
as a thin film between sodium chloride plates, with nmax
measured in cm21. High resolution and low resolution mass
spectra were recorded on a Fisons Instrument VG Autospec
mass spectrometer.
4.1.1. (4S)-N-tert-Butoxycarbonyl-4-hydroxy-L-proline
methyl ester.15 The title compound was prepared by a
15
´
modification of the procedure of Joullie et al. To a
stirred suspension of trans-4-hydroxy-L-proline (50.0 g,
381 mmol) in methanol (200 ml) at 08C was added thionyl
chloride (30.0 ml, 419 mmol). The reaction mixture was
stirred at 08C for 1 h then refluxed for 36 h. The reaction
mixture was allowed to cool and then precipitated with
diethyl ether. The precipitate was collected by filtration and
washed with diethyl ether to give a quantitative yield of the
desired methyl ester as a white solid.
4.1.3. (4R)-N-tert-Butoxycarbonyl-4-phenylselenyl-L-
proline ethyl ester. To a stirred solution of diphenyl
diselenide (7.50 g, 24 mmol) in ethanol (300 ml) at 08C was
added sodium borohydride (2.00 g, 52 mmol) portionwise.
The solution was stirred until the yellow colouration
had vanished. (4S)-N-tert-Butoxycarbonyl-4-methylsulfonyl-
oxy-L-proline methyl ester (13.0 g, 40 mmol) in ethanol
To a stirred solution of the above proline ester (8.0 g,
55 mmol) in dioxane (30 ml) at room temperature was
added diisopropylethylamine (17.0 ml, 94 mmol). Di-tert-
butoxy dicarbonate (15.7 g, 72 mmol) in dioxane (70 ml)
was added slowly and vigorous effervescence observed. The

E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
3311
(150 ml) was added and the solution refluxed for 3 h, then
stirred at room temperature overnight. The solvent was
removed under reduced pressure and the residue taken up in
diethyl ether (500 ml). The solution was washed with water
(250 ml) followed by a saturated brine solution (250 ml),
dried over magnesium sulfate and concentrated under
reduced pressure. The resultant vivid yellow oil was purified
by column chromatography (10% ethyl acetate/petroleum
ether eluent) to give the desired product as a yellow oil
(13.66 g, 86%). TLC, (ethyl acetate) Rf¼0.59; [a]2D6 228.0,
c 2.1 in chloroform; nmax (thin film)/cm21 3057 (w, aryl
CH), 2976 and 2933 (s, CH3/CH2), 2872 (m, CH), 1745
(s, CO2Et), 1703 (s, N–CvO), 1578 (m, C6H5), 1394
(s, C(CH3)3), 1251 (m) and 1190 (s, CvO), 741 (s,
Ar-H), 693 (m, Ar-H); dH (300 MHz; CDCl3) 7.55 (2H,
dd, J¼7.4, 1.8 Hz, 8-H), 7.30–7.25 (3H, m, 9- and 10H),
4.28–4.12 (3H, m, 2-H and OCH2CH3), 4.02–3.86
(1H, m, 4-H), 3.64–3.48 (1H, m, 5-H), 3.46–3.37 (1H, m,
5-H), 2.74–2.63 (1H, m, 3-H), 2.07–1.96 (1H, m, 3-H),
1.48 and 1.39 (9H, 2£s, tBu), 1.28–1.23 (3H, m,
OCH2CH3); dC (75 MHz; CDCl3) 172.6 (CO2Et), 153.5
(COt2Bu), 135.3 (C-8), 129.5 (C-9), 128.3 (C-10), 127.8
(C-7), 80.6 and 80.5 (C(CH3)3), 61.4 (C-5), 59.5 and 59.1 (C-
4), 53.3 (C3), 38.2 and 37.6 (OCH2CH3), 36.8 and 36.7 (C-
2), 28.6 and 28.5 (C(CH3)3), 14.5 (OCH2CH3); m/z (EI) 399
(M, 15%), 326 ([M2 CO2Et], 10), 298 ([M2Boc], 6), 157
(PhSe, 18), 77 (C6H5, 15), 57 (tBu, 100); HRMS (EI) found
395.0761, (M, C18H25NO746Se requires 395.0976).
11S) N-tert-Butoxycarbonyl-11-carboxy-5,5,7-trimethyl-
3-oxo-10-aza-4,6-dioxa-tricyclo[6.3.0.02,7] undecane
ethyl ester (12). A solution of the freshly distilled dioxinone
2 (0.47 g, 3.3 mmol) and prolinate 10 (1.20 g, 5.0 mmol) in
dry, distilled ethyl acetate, under continuous degassing with
nitrogen, was irradiated with a 125W medium pressure
mercury lamp. After 2 h no dioxinone 2 remained by TLC
and so the reaction mixture was concentrated under reduced
pressure. The resultant yellow oil was purified by column
chromatography three times (20 to 50% petroleum ether/
diethyl ether eluent) to isolate two distinct cyclobutane
products.
endo-Cyclobutane (11), a colourless oil (40 mg, 3.2%).
TLC, (50% petroleum ether/diethyl ether) Rf¼0.33; [a]D26
16.7, c 8.4 in chloroform; nmax (thin film)/cm21 2962
(s, CH3/CH2), 2874 (m, CH), 1745 (s, CO2Et), 1702 (s,
COt2Bu), 1391 (s, C(CH3)3), 1365 (s, C(CH3)3), 1168 (s,
C–O), 1087 (m, C–O); dH (500 MHz; CDCl3) 4.93 and
4.76 (1H, 2£d, J¼1.5 Hz, 11-H), 4.16 and 4.15 (2H, 2£q,
J¼7.1 Hz, OCH2CH3), 4.04 and 4.03 (1H, 2£d, J¼12.0 Hz,
9-H), 3.24 and 3.21 (1H, 2£dd, J¼5.4, 3.5 Hz, 9-H), 3.11–
3.07 (1H, m, 8-H), 2.96–2.93 (1H, m, 7-H), 2.82–2.77
(1H, m, 1-H), 1.61 (3H, s, 2-Me), 1.58, 1.56, 1.54 and 1.53
t
(6H, 4£s, 4-Me), 1.47 and 1.43 (9H, 2£s, Bu) 1.27–1.23
(3H, m, OCH2CH3); dC (125 MHz; CDCl3) 172.4 and
172.2 (CO2Et), 167.7 and 167.3 (C-6), 153.9 and 153.4
(N–CvO), 105.2 and 104.7 (C-4), 80.3 and 80.0
(C(CH3)3), 70.9 (C-2), 61.2 (OCH2CH3), 58.4 and 57.8
(C-11), 53.8 and 52.6 (C-1), 46.8 and 46.6 (C-9), 40.5 and
40.4 (C-7), 36.2 and 35.2 (C-8), 28.7, 28.6, 28.5, 28.4, 28.3
and 28.2 (4-Me, 2-Me and C(CH3)3), 14.3 and 14.1
(OCH2CH3); m/z (EI) 328 (37%), 310 ([M2CO2Et], 61),
282 ([M2Boc], 7), 210 (44), 185 (59), 143 (87), 68 (89), 57
(tBu, 100); HRMS (EI) found 310.1668, (M2CO2Et,
C16H24NO5 requires 310.1654).
4.1.4. N-tert-Butoxycarbonyl-3,4-didehydro-L-proline
ethyl ester (10). The title compound was prepared by a
modification of the procedure of Dormay.17 To a stirred
solution of (4R)-N-tert-Butoxycarbonyl-4-phenylselenyl-L-
proline ethyl ester (13.00 g, 32.6 mmol) in dichloromethane
(300 ml) at 08C was added pyridine (4.0 ml, 49.0 mmol)
followed by a 30% aqueous solution of hydrogen peroxide
(9.3 ml, 82 mmol) gradually over 5 min. The reaction
mixture was stirred at room temperature for 16 h then
washed with 1 M aqueous citric acid (2£100 ml), saturated
aqueous sodium bicarbonate solution (100 ml) and water
(100 ml), dried over magnesium sulfate and concentrated
under reduced pressure. The resultant yellow oil was
purified by column chromatography (15% ethyl acetate/
petroleum ether eluent) to give 10 as a pale yellow oil
(6.21 g, 80%). TLC, (25% ethyl acetate/petroleum ether)
Rf¼0.45; [a]3D1 2230.0, c 11.3 in chloroform (lit., [a]2D0
2234.0, c 10.2);17 nmax (thin film)/cm21 2980 and 2936 (s,
CH3/CH2), 1751 (s, CO2Et), 1708 (s, N–CvO), 1450 (m,
CH2), 1396 and 1370 (s, C(CH3)3), 1319 and 1162 (s, C–O);
dH (300 MHz; CDCl3) 6.00–5.93 (1H, m, 4-H), 5.79–5.70
(1H, m, 3-H), 5.04–4.93 (1H, m, 2-H), 4.26–4.15 (4H, m,
exo-Cyclobutane (12), a colourless oil (55 mg, 4.4%). TLC,
(50% petroleum ether/diethyl ether) Rf¼0.46; [a]2D6 232.9,
c 8.2 in chloroform; nmax (thin film)/cm21 2979 (s, CH3/
CH2), 2935 (s, CH3/CH2), 1740 (s, CO2Et), 1702 (s,
N–CvO), 1457 (m, CH3/CH2), 1391 (s, C(CH3)3), 1365
(s, C(CH3)3), 1186 and 1031 (s, C–O); dH (500 MHz;
CDCl3) 4.83 and 4.75 (1H, 2£s, 11-H), 4.17–4.09 (3H, m,
9-H and OCH2CH3), 3.36 and 3.33 (1H, 2£dd, J¼11.8,
8.5 Hz, 9-H), 3.25 and 3.20 (1H, 2£dd, J¼7.4, 9.8 Hz, 1-H),
3.04 (1H, dd, J¼9.8, 1.8 Hz, 2-H), 2.71 (1H, m, 8-H), 1.58–
1.56 (6H, m, 5-Me), 1.53–1.52 (3H, m, 7-Me), 1.45 and
1.42 (9H, 2£s, C(CH3)3), 1.25–1.23 (3H, m, OCH2CH3); dC
(75 MHz; CDCl3) 171.5 and 171.4 (CO2Et), 167.8 and
167.4 (C-3), 153.8 (N–CvO), 105.3 and 104.8 (C-5), 80.3
and 80.0 (C(CH3)3), 70.9 and 70.8 (C-7), 61.3 and 61.2
(OCH2CH3), 60.1 and 59.6 (C-11), 48.7 and 47.8 (C-8), 44.6
and 44.5 (C-9), 41.0 and 40.8 (C-2), 39.9 and 39.1 (C-1),
28.61, 28.56, 28.39 and 28.24 (7-Me, 5-Me, and C(CH3)3),
14.2 and 14.1 (OCH2CH3); m/z (EI) 383 (M, 4%), 382
([M2H], 5), 328 (23), 310 ([M2CO2Et], 60), 282 ([M2Boc],
44), 254 (88), 196 (100), 57 (tBu, 98). HRMS (EI) found
310.1656, (M2CO2Et, C16H24NO5 requires 310.1654).
t
OCH2CH3 and 5-H), 1.48 and 1.44 (9H, 2£s, Bu), 1.31–
1.24 (3H, m, OCH2CH3); dC (75 MHz; CDCl3) 173.2
(CO2Et), 155.9 (N–CvO), 131.8 and 131.7 (C-4), 127.4
and 127.3 (C-3), 82.7 and 82.6 (C(CH3)3), 69.2 and 68.9
(C-2), 63.7 (OCH2CH3), 56.0 and 55.8 (C-5), 30.9 and 30.8
(s, C(CH3)3), 16.8 and 16.6. (OCH2CH3); m/z (EI) 242
(MþH, 8%), 200 (47), 184 (M2tBu, 36), 154 (78), 68 (64),
57 (tBu, 100).
4.1.5. (1R,2S,7R,8R,11S)N-tert-Butoxycarbonyl-11-carb-
oxy-2,4,4-trimethyl-6-oxo-10-aza-3,5-dioxatricyclo-
[6.3.0.02,7]-undecane ethyl ester (11) and (1S, 2R, 7S, 8R,
4.1.6. (S)N-tert-Butoxycarbonyl-2-hydroxymethyl-3-pyr-
roline (13). To a stirred solution of prolinate 10 (10.0 g,
41 mmol) in diethyl ether (200 ml) at 08C was added lithium

3312
E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
aluminium hydride (1.6 g, 41 mmol) portionwise. The reac-
tion mixture was stirred overnight then poured into a 20%
aqueous solution of Rochelle’s salt (250 ml) and stirred for
an hour. The layers were separated and the organic layer
washed with water (2£50 ml), dried over magnesium sulfate
and concentrated under reduced pressure to yield 13 as a
colourless oil (6.26 g, 76%). TLC, (25% ethyl acetate/
petroleum ether) Rf¼0.12; [a]2D6 2107.2, c 13.9 in chloro-
form; nmax (thin film)/cm21 3417 (s, OH), 3083 (m,
H–Cv), 2975 and 2931 (s, CH3/CH2), 2868 (s, CH),
1696 and 1679 (s, N–CvO), 1625 (s, CvC), 1471 and
1455 (s, CH3/CH2), 1407 (s, OH), 1367 (s, C(CH3)3), 1255
and 1174 (s, C–O); dH (300 MHz; CDCl3) 5.83 (1H, m,
4-H), 5.63 (1H, m, 3-H), 4.73 (1H, m, 2-H), 4.20 (1H, d,
J¼15.7 Hz, 5-Hu), 4.08 (1H, dm, J¼15.7 Hz, 5-Hd), 3.79,
(1H, dd, J¼11.3, 2.2 Hz, 6-H), 3.58 (1H, dd, J¼11.3,
4.16 (1H, dd, J¼9.6, 2.6 Hz, 13-H) 3.69 (1H, d, J¼12.8 Hz,
9-Hd), 3.66 (1H, dd, J¼9.5, 8.4 Hz, 13-H), 2.75 (1H, m,
14-H), 2.41–2.34 (1H, m, 1-H), 2.302.16 (3H, m, 2-H, 8-H
and 9-Hu), 1.34 (3H, s, 5-Me), 0.97 (3H, s, 7-Me), 0.93 (3H,
s, 5-Me); dC (75 MHz; CDCl3) 168.5 (C-11), 160.9 (C-3),
105.6 (C-5), 75.3 (C-7), 63.9 (C-13), 59.5 (C-14), 50.2
(C-2), 45.1 (C-9), 43.9 (C-1), 38.1 (C-8), 29.4 (5-Me), 28.7
(7-Me), 22.3 (5-Me);m/z (EI) 268 ([MþH], 7%), 210 (45),
143 (dioxinone, 14), 125 ([M2dioxinone], 94), 85 (oxazo-
lidinone, 100); HRMS (EI) found 268.1185, (MþH,
C13H18NO5 requires 268.1185).
4.1.9. (5R,6S,7S)7-Acetyl-6-carboxymethyl-2-oxo-1-aza-
3-oxabicyclo[3.3.0]octane methyl ester (16) and (5R,6S,
7R)7-Acetyl-6-carboxymethyl-2-oxo-1-aza-3-oxabi-
cyclo[3.3.0]octane methyl ester (17). To a stirred solution
of the tetracycle 15 (0.134 g, 0.50 mmol) in dry methanol
(2 ml) was added a 2 M solution of trimethylaluminium in
hexane (0.125 ml, 0.25 mmol). The reaction mixture was
stirred for 2 h then quenched with saturated aqueous sodium
bicarbonate solution (5 ml) and extracted with ethyl acetate
(2£5 ml). The combined organics were dried over mag-
nesium sulfate and concentrated under reduced pressure.
The resultant colourless oil was purified by column
chromatography (ethyl acetate eluent) to give a small
quantity of the desired cis product 17 and a reasonable yield
of the trans product 16.
t
6.9 Hz, 6-H), 3.20 (1H, br s, OH), 1.50 (9H, s, Bu); dC
(75 MHz; CDCl3) 157.0 (N–CvO), 127.2 (C-3), 127.0
(C-4), 81.0 (C(CH3)3), 68.1 (C-2), 67.7 (C-5), 54.6 (C-6),
28.8 (C(CH3)3); m/z (FAB) 222 (MþNa, 18%), 200 (MþH,
22), 168 ([M2CH2OH], 16), 144 (69), 112 (75), 57 (tBu,
100); HRMS (EI) found 168.1041, (M2CH2OH, C9H14NO2
requires 168.1025).
4.1.7. (5R)2-Oxo-1-aza-3-oxabicyclo[3.3.0]oct-6-ene (14).
To a stirred solution of alcohol 13 (7.40 g, 37 mmol) in dry
dichloromethane (200 ml) at 08C was added N,N-diethyl-
aminosulfur trifluoride (6.45 g, 40 mmol) dropwise. The
reaction mixture was stirred for 4 h then quenched with
saturated aqueous sodium bicarbonate solution (200 ml).
The layers were separated and the aqueous extracted with
dichloromethane (2£200 ml). The combined organics were
dried over magnesium sulfate and concentrated under
reduced pressure. The resultant oil was purified by column
chromatography (diethyl ether eluent) to give 14 as a
colourless oil (3.46 g, 75%). TLC, (diethyl ether) Rf¼0.29;
[a]D31 218.0, c 25.0 in chloroform; nmax (thin film)/cm21
2983 and 2918 (m, CH2), 2880 (m, CH), 1751 (s, N–CvO),
1604 (m, CvC); dH (300 MHz; CDCl3) 6.08–6.04 (1H, m,
7-H), 5.93–5.89 (1H, m, 6-H), 4.75–4.70 (1H, m, 5-H),
4.62 (1H, dd app t, J¼8.7 Hz, 4-H), 4.40 (1H, dddd app ddt,
J¼15.6, 3.1, 2.0 Hz, 8H), 4.25 (1H, dd, J¼8.5, 5.1 Hz, 4-H),
3.87–3.79 (1H, m, 8-H); dC (75 MHz; CDCl3) 162.5 (C-2),
131.0 (C-7), 128.9 (C-6), 68.7 (C-4), 64.6 (C-5), 54.8
(C-8); m/z (EI) 125 (M, 60%), 95 ([M2CH2O], 85), 67
([M2CO2CH2], 100); HRMS (EI) found 125.0487, (M,
C6H7NO2 requires 125.0477).
trans-Oxazolidinone (16), (a colourless oil, 0.146 g, 65%).
TLC, (ethyl acetate) Rf¼0.50; [a]3D1 24.9, c 8.1 in
chloroform; nmax (thin film)/cm21 2957 (s, CH3/CH2),
1751 (br s, N–CvO and C10vO), 1711 (s, C11vO), 1363
(s, COCH3); dH (300 MHz; CDCl3) 4.39 (1H, dd, J¼8.1,
10.0 Hz, 4-H), 4.15 (1H, dd, J¼2.9, 10.0 Hz, 4-H), 4.08–
4.03 (1H, m, 5-H), 3.78 (1H, dd, J¼11.8, 8.7 Hz, 8-H), 3.65
(3H, s, OMe), 3.26 (1H, dd, J¼11.8, 5.1 Hz, 8-H), 3.10–
3.04 (1H, m, 7-H), 2.78–2.73 (1H, m, 6-H), 2.46 (1H, dd,
J¼16.7, 5.9 Hz, 9-H), 2.21 (3H, s, 12-H), 2.16 (1H, dd,
J¼16.7, 9.6 Hz, 9H); dC (75 MHz; CDCl3) 207.1 (C-11),
172.4 (C-10), 161.4 (C-2), 64.1 (C-4), 60.3 (C-5), 56.9
(C-7), 52.5 (OMe), 46.4 (C-8), 39.6 (C-6), 33.1 (C-9), 29.8
(C-12); m/z (EI) 241 (M, 22%), 210 ([M2OMe], 25), 198
([M2CH3CO], 21), 171 (100), 43 (CH3CO, 75); HRMS
(EI) found 241.0934, (M, C11H15NO5 requires 241.0950).
cis-Oxazolidinone (17), (colourless crystals, 0.146 g, 15%).
TLC, (ethyl acetate) Rf¼0.32; mp (ethyl acetate) 97–1018;
[a]D23 26.7, c 3.0 in chloroform; nmax (thin film)/cm21 2924
(br s) and 2853 (s, CH3/CH2), 1728 (br s, N–CvO and
C10vO), 1707 (s, C11vO), 1459 (s, CH3/CH2); dH
(300 MHz; CD2Cl2) 4.41–4.27 (3H, m, 4-H and 5-H),
3.76 (1H, dd, J¼11.4, 5.8 Hz, 8H), 3.65 (3H, s, OMe), 3.54–
3.41 (1H, m, 7-H), 3.25 (1H, dd, J¼11.7, 7.5 Hz, 8-H),
2.96–2.81 (1H, m, 6-H), 2.47–2.34 (2H, m, 9-H), 2.21 (3H,
s, 12-H); dC (75 MHz; CD2Cl2) 208.0 (C-11), 173.1 (C-10),
162.1 (C-2), 65.1 (C-4), 62.0 (C-5), 55.4 (OMe), 52.8 (C-7),
47.8 (C-8), 40.1 (C-6), 31.6 (C-12), 29.5 (C-9); m/z (EI) 241
(M, 9%), 210 ([M2OMe], 40), 198 ([M2CH3CO], 21), 171
(77), 55 (88), 43 (CH3CO, 100); HRMS (EI) found
241.0951, (M, C11H15NO5 requires 241.0950).
4.1.8. (1S,2R,7S,8R,14R)5,5,7-Trimethyl-3,11-dioxo-10-
aza-4,6,12-trioxa-tetracyclo[6.6.0.0.2,7010,14]tetradecane
(15). A solution of (5R) 2-Oxo-1-aza-3-oxabicyclo[3.3.0]-
oct-6-ene (14) (3.75 g, 22.0 mmol) and the dioxinone 2
(2.13 g, 11.0 mmol) in ethyl acetate (400 ml), under
continuous degassing with nitrogen, was irradiated with a
125 W medium pressure mercury lamp until no dioxinone 2
remained by TLC. The reaction mixture was concentrated
under reduced pressure and purified by column chroma-
tography (diethyl ether eluent) to give 15, which was
recrystallized from ethyl acetate (1.32 g, 33%). TLC,
(diethyl ether) Rf¼0.19; mp (ethyl acetate) 178–1808;
[a]D31 24.2, c 26.5 in chloroform; nmax (thin film)/cm21
2921 and 2853 (s, CH3/CH2), 1739 (br s, CvO), 1384 and
1376 (s, (CH3)2), 1089 (m, C–O); dH (300 MHz; CDCl3)
4.1.10. 7-Isopropenyl-6-carboxymethyl-2-oxo-1-aza-3-
oxabicyclo[3.3.0]octane methyl ester (18). To a stirred

E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
3313
solution of methyl triphenylphosphonium bromide (0.214 g,
0.5 mmol) in tetrahydrofuran (5 ml) was added a 2.5 M
solution of n-butyl lithium in hexane (0.24 ml, 0.6 mmol).
The reaction mixture was stirred at room temperature for 1 h
then cooled to 2788 and the epi-oxazolidinone (epi-16)
(0.124 g, 0.5 mmol) in tetrahydrofuran (1 ml) added drop-
wise. The reaction mixture was allowed to warm to room
temperature then quenched with saturated aqueous ammo-
nium chloride solution (10 ml) and extracted with ethyl
acetate (2£10 ml). The combined organics were dried over
magnesium sulfate and concentrated under reduced pressure.
The resultant yellow oil was purified by column chroma-
tography (diethyl ether eluent) to give the desired product.
(20). A solution of (5R) 2-oxo-1-aza-3-oxabicyclo[3.3.0]-
oct-6-ene (14) (2.25 g, 18.0 mmol) and 4,6,6-trimethyl-5,6-
dihydropyran-2-one (19) (1.26 g, 9.0 mmol) in ethyl
acetate, under continuous degassing with nitrogen, was
irradiated with a 125 W medium pressure mercury lamp
until no pyranone 19 remained by TLC. The reaction
mixture was concentrated under reduced pressure and
purified by column chromatography (diethyl ether eluent)
to give 20, which recrystallized from ethyl acetate (0.766 g,
32% (43% based on recovered starting material)). TLC,
(diethyl ether) Rf¼0.21; mp 184–1898C; [a]2D5 4.2, c 16.8 in
chloroform; nmax (thin film)/cm21 2956 and 2924 (s, CH3/
CH2), 1737 (s, N–CvO), 1722 (C3vO), 1369 (m, C–O);
dH (300 MHz; CDCl3) 4.66 (1H, dd, J¼9.6, 3.0 Hz, 13-H),
4.58 (1H, dd, J¼9.6, 8.4 Hz, 13-H), 4.05 (1H, dd, J¼13.7,
1.3 Hz, 9-Hu), 4.02–3.98 (1H, m, 14-H), 3.10 (1H, dd, J¼
13.6, 8.0 Hz, 9-Hd), 3.04–3.00 (1H, m, 1-H), 2.60 (1H, dddd
app tt, J¼7.8, 1.2 Hz, 8H), 2.44–2.42 (1H, m, 2-H), 2.07
(1H, d, J¼14.8 Hz, 6-Hd), 1.90 (1H, dd, J¼14.8, 1.0 Hz,
6-Hu), 1.48 (3H, s, 5-Med), 01.42 (3H, s, 5-Meu), 1.23 (3H,
s, 7-Me); dC (75 MHz; CDCl3) 172.8 (C-3), 167.3 (C-11),
82.5 (C-5), 63.4 (C-13), 60.1 (C-14), 50.1 (C-8), 46.0 (C-9),
45.3 (C-6), 44.0 (C-1), 39.2 (C-2), 33.7 (C-7), 31.1 (5-Med),
28.8 (5-Meu), 23.5 (7-Me); m/z (EI) 265 (M, 17%), 210 (37),
141 (pyranone, 100), 123 ([cyclobutane–pyranone], 67);
HRMS (EI) found 265.1320, (M, C14H19NO4 requires
265.1314).
epi-Oxazolidinone (18), (a colourless oil, 0.054 g, 46%.
TLC, (ethyl acetate) Rf¼0.43; nmax (thin film)/cm213078
(w, CvCH2), 2982, 2950 and 2920 (m, CH3/CH2), 1755 (br
s, CvO), 1645 (m, CvC), 899 (m, CvCH2); dH (300 MHz;
CDCl3) 4.89 (1H, s, 13-H), 4.81 (1H, s, 13-H), 4.43 (1H, ddd
app q, J¼9.0 Hz, 4-H), 4.37–4.31 (1H, m, 5-H), 4.12–4.07
(1H, m, 4-H), 3.81 (1H, dd, J¼11.8, 7.2 Hz, 8-H), 3.67 (3H,
s, OMe), 2.99 (1H, dd, J¼11.8, 8.9 Hz, 8-H), 2.60–2.53
(1H, m, 7-H), 2.46 (1H, dd J¼16.9, 5.5 Hz, 9-H), 1.73 (3H,
s, 12-H); dc (75 MHz; CDC13) 172.9 (C-10), 162.0 (C-2),
143.2 (C-11), 113.9 (C-13), 65.2 (C-4), 60.0 (C-5), 53.1
(C-6), 52.4 (OMe), 50.6 (C-8), 41.2 (C-7), 33.9 (C-9), 20.6
(C-12); m/z (EI) 239 (M, 25%), 208 ([M2OMe], 17), 154
(59), 55 (100), 41 (CH3CvCH2, 24); HRMS (EI) found
239.1171, (M, C12H17NO4 requires 239.1158).
Diffraction data were measured on a Nonius KappaCCD
diffractometer at 173 K using Mo Ka radiation and refined
on F2.
4.1.11. 4,6,6-Trimethyl-5,6-dihydropyran-2-one (19). To
a stirred solution of preformed lithium diisopropylamide
(171 mmol) in dry tetrahydrofuran (100 ml) at 2788C was
added methyl senecioate (13.0 g, 114 mmol) dropwise over
1 h. The reaction mixture was stirred for 30 min before
addition of cadmium chloride (11.6 g, 57 mmol) (ground in
a mortar and dried overnight in a vacuum oven at 1108C).
The resulting suspension was stirred for a further 30 min at
2788C before addition of acetone (8.37 ml, 114 mmol)
dropwise over 1 h. The reaction mixture was allowed to
warm to 108C then quenched with saturated aqueous
ammonium chloride solution (100 ml). The reaction mixture
was filtered through celite and the layers separated. The
aqueous was extracted with diethyl ether (2£100 ml) and
the combined organics washed with a saturated brine
solution (100 ml), dried over magnesium sulfate and
concentrated under reduced pressure. The resultant yellow
oil was purified by column chromatography (diethyl ether
eluent) and then by distillation (1108C/3 mmHg) to give the
desired product as a colourless oil (3.32 g, 21% (36% based
on recovered starting material)). TLC, (diethyl ether)
Rf¼0.55; nmax (thin film)/cm21 3060 (w, CvCH), 2978
and 2935 (s, CH3/CH2), 1704 (br s, CvO), 1651 (m, CvC),
1383 (s, C(CH3)3); dH (300 MHz; CDCl3) 5.84–5.83 (1H,
m, 3-H), 2.34 (2H, s, 5-H), 1.97 (3H, m, 4-Me), 1.44 (6H, s,
6-Me); dC (75 MHz; CDCl3) 178.0 (C-2), 155.2 (C-4), 115.8
(C-3), 79.3 (C-6), 40.8 (C-5), 27.6 (6-Me), 23.2 (4-Me); m/z
(EI) 141 ([MþH], 25%), 140 (M, 16), 125 ([M2Me], 88),
82 ([M2(CH3)2CO], 100); HRMS (EI) found 140.0848, (M,
C8H12O2 requires 140.0837).
Crystal data for 15: C13H17NO5, M 267.3, Orthorhombic,
P212121 (No. 19), a 6.1730 (6), b 9.8187 (9), c 20.7031
3
(19)A, V 154.8 (2)A , Z 4, m 0.11 mm21. 6184 Measured
reflections, 2214 unique (Rint 0.084), R1 0.058 (for 1678
reflections with I.2sI), wR2 0.141 (for all reflections).
˚
˚
4.2. X-Ray data
4.2.1. (1S,2R,7S,8R,14R)5,5,7-Trimethyl-3,11-dioxo-10-
aza-4,6,12-trioxa-tetracyclo[6.6.0.0.2,7010,14]tetradecane
(15).
4.1.12. (1S,2R,7S,8R,14R)5,5,7-Trimethyl-3,11-dioxo-10-
aza-4,12-dioxa-tetracyclo[6.6.0.0.2,7010,14] tetradecane

3314
E. S. Greenwood et al. / Tetrahedron 59 (2003) 3307–3314
(b) Ishida, M.; Shinozaki, H. Brain Res. 1988, 474, 386.
(c) Shinozaki, H.; Ishida, M.; Okamoto, T. Brain Res. 1986,
399, 395. (d) Maruyama, M.; Takeda, K. Brain Res. 1989, 504,
328. (e) Shinozaki, H.; Ishida, M.; Gotoh, Y.; Kwak, S. Brain
Res. 1989, 503, 330.
Crystal data for 20: C14H19NO4, M 265.30, Orthorhombic,
P212121 (No. 19), a 6.1728 (3), b 10.0767 (6), c 20.4092
3
(15)A, V 1274.5 (15)A , Z 4, m 0.10 mm21. 4747 Measured
reflections, 2160 unique (Rint 0.042), R1 0.042 (for 1849
reflections with I.2sI), wR2 0.098 (for all reflections).
˚
˚
3. (a) In Kainic Acid as a Tool in Neurobiology; McGeer, E. G.,
Olney, J. W., McGeer, P. L., Eds.; Raven: New York, 1978.
(b) In Excitatory Amino Acids; Simon, R. P., Ed.; Thieme
Medical: New York, 1992. (c) In Amino Acids and Synaptic
Transmissions; Wheal, H. V., Thomson, A. M., Eds.;
Academic: London, 1991. (d) Watkins, J. C.; Krogsgaard-
Larsen, P.; Honore, T. Trends Pharmacol. Sci. 1990, 11, 25.
4. Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1.
5. (a) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
(b) McGeer, E. G.; McGeer, P. L. Nature (London) 1976, 263,
517.
4.2.2. (1S,2R,7S,8R,14R)5,5,7-Trimethyl-3,11-dioxo-10-
aza-4,12-dioxa-tetracyclo[6.6.0.0.2,7010,14]tetradecane
(20).
6. Greenwood, E. S.; Parsons, P. J. Synlett 2002, 167.
7. see Bach, T. Synthesis 1998, 683, and references therein.
8. Zhao, H.; Thurkauf, A. Synlett 1999, 1280.
9. (a) Hirai, Y.; Chintani, M.; Yamazaki, T.; Momose, T. Chem.
Lett. 1989, 1449. (b) Baldwin, J. E.; Moloney, M. G.; Parsons,
A. F. Tetrahedron 1991, 47, 155. (c) Horikawa, M.;
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331. (d) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61,
5418. (e) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Aoe, K.;
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Acknowledgements
11. Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron
Lett. 1985, 26, 5579.
We wish to thank the Royal Commission for the Exhibition
of 1851 and Tocris Cookson Limited for funding this
research.
12. Wittig, G.; Schoellkopf, U. Ber 1954, 87, 1318.
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1181.
14. Lei, B.; Fallis, A. G. Can. J. Chem. 1991, 69, 1450.
´
15. Schumacher, K. K.; Jiang, J.; Joullie, M. M. Tetrahedron
Asymmetry 1998, 9, 47.
References
1. For a comprehensive review, see: Parsons, A. F. Tetrahedron
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16. Abraham, D. J.; Mokotoff, M.; Sheh, L.; Simmons, J. E.
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17. Dormoy, J.-R. Synthesis 1982, 753.