Radical cyclization in heterocycle synthesis. Part 10: A concise synthesis of (-)-kainic acid via sulfanyl radical addition-cyclization-elimination reaction

Article abstract of DOI:10.1016/S0040-4020(00)00579-2

Sulfanyl radical addition-cyclization-elimination of diallylamines in the presence of thiophenol and AIBN gave the 2,3,4-trisubstituted pyrrolidine in high yield. This reaction was extended to a radical cyclization using a catalytic amount of thiophenol. A successful application was demonstrated by the asymmetric synthesis of (-)-kainic acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00579-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6199±6207
Radical Cyclization in Heterocycle Synthesis. Part 10:1
A Concise Synthesis of (2)-Kainic Acid via Sulfanyl Radical
Addition±Cyclization±Elimination Reaction
*
Okiko Miyata, Yoshiki Ozawa, Ichiya Ninomiya and Takeaki Naito
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 5 June 2000; accepted 27 June 2000
AbstractÐSulfanyl radical addition±cyclization±elimination of diallylamines in the presence of thiophenol and AIBN gave the 2,3,4-
trisubstituted pyrrolidine in high yield. This reaction was extended to a radical cyclization using a catalytic amount of thiophenol. A
successful application was demonstrated by the asymmetric synthesis of (2)-kainic acid. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
1953, principally because of its potent neurotransmitting
activity in the central nervous system. Several total syn-
theses of kainic acid and related compounds have been
achieved during the last decade3 since Oppolzer7 reported
an enantioselective synthesis of a-kainic acid via an intra-
molecular ene reaction.
Radical cyclization continues to form a central methodology
for synthesis of natural products containing heterocyclic
rings.2 These radical cyclization protocols commonly have
several advantages over non-radical methods. The radical
cyclization can be carried out in neutral organic solutions,
and radical cascade reactions allow the construction of two
or more rings in one-pot reactions. Most radical cyclizations
used for the syntheses of heterocycles proceed in a 5-exo-
trig manner. Therefore, a radical cyclization reaction is
suitable for the construction of a 5-membered ring as exem-
pli®ed in several syntheses3 of (2)-a-kainic acid (1) having
a pyrrolidine ring. In this paper, we describe full details
of the sulfanyl radical-addition±cyclization±elimination4
of diallylamines and its application to total synthesis of
(2)-a-kainic acid.5
As a disconnective analysis is shown in Scheme 1, our
synthesis employs the newly developed sulfanyl radical
addition±cyclization±elimination reaction as a key step
(4!3!2). The advantage of this method is as follows: (1)
substrate for the radical cyclization is easily prepared
from (S)-methionine; (2) thiophenol used as a radical
source, is of low toxicity and is inexpensive compared
with tributyl tinhydride; (3) the key reaction involves
the sequential formation of two bonds and one bond
cleavage in one-pot construction of the trisubstituted pyrro-
lidine ring comprising kainic acid. We employed both cyclic
and acyclic diallylamines as the substrate for radical
reaction.
The marine product (2)-a-kainic acid3 has attracted con-
siderable interest since it was ®rst isolated by Takemoto6 in
Scheme 1.
Keywords: kainic acid; thiophenol; radical cyclization; pyrrolidine.
* Corresponding author. Tel.: 181-78-441-7554; fax: 181-78-441-7556; e-mail: taknaito@kobepharma-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00579-2

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O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
Scheme 2. Reagents and conditions: (a) CBr4,Ph3P, quant.; (b) (i) allyl-
amine, (ii) ZCl, 19%; (c) N-tosylallylamine, DEAD, Ph3P, 90%.
Results and Discussion
Scheme 3.
Preparation of substituted pyrrolidines having an
isopropenyl group
We next examined the reaction employing a catalytic
amount of thiophenol (entries 3, 4). Treatment of 7b having
the N-tosyl group with 0.2 equiv. of thiophenol afforded a
1:1 mixture of the cis- and trans-8b in moderate yield, while
7a gave the corresponding product 8a in only 16% yield and
the substrate 7a was mostly recovered. This reaction
mechanism is shown in Scheme 3. It involves a sequence
of transformations including intermolecular addition of a
phenylsulfanyl radical to the terminal ole®n of 7, generating
the carbon-centered radical A, ring-closure to radical B, and
subsequent b-elimination leading to the isopropenylpyrro-
lidine 8 and fanyl radical which reacts with 7 to give back
the radical A. The different reactivities between 7a and 7b
could be explained as follows (Scheme 4). The substrates 7a
and 7b would exist in conformation D preferable for intra-
molecular cyclization over the less favored conformer C due
to the steric repulsion between the substituent on nitrogen
and vinyl protons.2m,n Since the tosyl group is more bulky
than the Z-group, the radical cyclization of 7b would take
place smoothly because of large contribution of the
conformer D.
We ®rst investigated the phenylsulfanyl radical addition±
cyclization±elimination reaction of model compounds 7a,b
(Scheme 2, Table 1). The requisite dienes 7a and 7b for the
radical cyclization were prepared through either alkylation
of allylamine with the allyl bromide 6 followed by acylation
using benzyloxycarbonyl chloride (ZCl) or the Mitsunobu
reaction of the N-tosylallylamine with the hydroxy sul®de
5.8 A solution containing thiophenol (1 equiv.) and AIBN
(0.5 equiv.) in benzene was added dropwise with a syringe
pump over 2 h to a solution of the carbamate 7a in boiling
benzene while stirring under nitrogen. The solution was
then re¯uxed for further 2 h and the solvent was removed
in vacuo. The resulting residue was puri®ed by medium-
pressure column chromatography (MPCC) to give a mixture
of the cis- and trans-pyrrolidines 8a having an isopropenyl
group in 22% combined yield as an inseparable mixture
(entry 1). When 2 equiv. of thiophenol was used, the reac-
tion proceeded smoothly to give 8a in 63% yield (entry 2).
This result namely, that the pyrrolidine having an isopro-
penyl group was obtained in a one-pot procedure, suggests
that the radical cyclization is suitable for the synthesis of
kainic acid and the related kainoids.
Thus, we have developed a new and simple synthetic
method for kainoids using the phenylsulfanyl radical
addition±cyclization±elimination. Furthermore, we have
now succeeded in extending the radical cyclization to a
catalytic version which would be a potential synthetic
weapon.
Table 1. Sulfanyl radical addition±cyclization±elimination of 7a,b
Entry
Substrate
PhSH (equiv.)
AIBN (equiv.)
Yield (%)
1
2
3
4
7a
7a
7a
7b
1.0
2.0
0.2
0.2
0.5
1.0
0.2
0.2
22
63
16
50
Scheme 4.

O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
6201
Scheme 5. Reagents and conditions: (a) (i) Boc2O, (ii) LiAlH4; (b) NaIO4; (c) NaOAc, 2008C; (d) SOCl2; (e) 6, n-BuLi; (f) (i) TsCl, (ii) LiAlH4; (g) MOMCl;
(h) 10% HCl; (i) 5, DEAD, Ph3P.
Total synthesis of (2)-kainic acid
13 with allyl bromide 6 afforded 14. Attempted sulfanyl
radical addition±cyclization±elimination of 14 in the
presence of thiophenol and AIBN was unsuccessful and
the substrate 14 was mostly recovered.
According to the results shown in the previous chapter, we
undertook the synthesis of (2)-kainic acid. Based on our
previous work,3g we employed 14 having an oxazolidinone
ring as the chiral substrate for radical addition±cyclization±
elimination. The oxazolidinone 14 was prepared from
(S)-methionine methyl ester 9 as follows (Scheme 5):
ester 9 was converted into N-Boc-vinylglycinol 12 via t-
butoxycarbonylation, reduction of the ester, oxidation to
the sul®nyl group, and pyrolysis of the resulting sulfoxide
by the method reported previously.9 Treatment of 12 with
SOCl2 followed by allylation of the resulting oxazolidinone
Therefore, we next investigated synthesis of (2)-kainic acid
via the radical addition±cyclization±elimination of the
acyclic substrate (S)-19 with no oxazolidinone ring which
was prepared from 9 as follows (Scheme 5). Ester 9 was
converted into (S)-N-tosylvinylglycinol (16) by sequential
reactions involving N-tosylation, reduction of the ester,
oxidation to the sulfoxide, and pyrolysis of the resulting
sulfoxide. Alcohol 16 was treated with MOMCl to give 17
Table 2. Sulfanyl radical addition±cyclization±elimination of (S)-19
Entry
PhSH (equiv.)
AIBN (equiv.)
Additive
Solvent
Temp (8C)
Yield (%)
Ratio 20:21
1
2
3
4
5
6
7
1.0
0.2
1.8
1.0
1.5
1.5
1.5
0.5
±
±
±
±
C6H6
C6H6
C6H6
C6H6
EtOH
MeCN
C6H6
80
80
rt
94
95
27
64
10
9
1:1.3
1:1.5
1:1.4
1:1.6
1:1.6
1:1.5
1:1.4
0.2
0.6a
0.5
rt
0.75
0.75
0.75
±
80
80
80
±
Yb(OTf)3 (1.0 equiv.)
48
a Et3B was used as a radical initiator.

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O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
Table 3. Cyclizability of various diallylamines in sulfanyl radical addition±cyclization
Scheme 6. Reagents and conditions: (a) OXONEw; (b) (i) MeLi, (ii) ClCOOMe; (c) Na±Hg; (d) TFA; (e) (1)-MTPACl, py.; (f) (i) PDC, (ii) CH2N2; (g) LiOH;
(h) Li/liq. NH3.

O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
6203
and 18 in 7 and 57% yields, respectively. N,O-Diprotected
compound 17 was recycled by converting into 16 by treat-
ment with 10% HCl. The Mitsunobu reaction of 18 with the
allyl alcohol 5 afforded the desired product 19 in 75% yield.
Sulfanyl radical addition±cyclization±elimination of 19 in
the presence of thiophenol and AIBN proceeded smoothly
to give a 1:1.3 mixture of the cyclized products 20 and 21 in
combined 94% yield (Table 2, entry 1). Similarly, treatment
of 19 with a catalytic amount of thiophenol gave 20 and 21
in an almost similar ratio (Table 2, entry 2). Thus, sulfanyl
radical addition±cyclization±elimination of 19 proceeded
smoothly to give the cyclized products in excellent yield,
while 14 having an oxazolidinone ring did not give the
cyclized product as described above.
afforded (2)-kainic acid 1. The physical (mp 242±2438C
(dec.); [a]Dˆ214.0 (c 0.50, H2O)) and spectral data of the
synthetic (2)-kainic acid 1 were identical with those (mp
243±2448C (dec.); [a]Dˆ214.2 (c 0.23, H2O)) of the
authentic sample reported in the literature.11
Conclusion
We have integrated sulfanyl radical addition±cyclization of
diallylamines to sulfanyl radical addition±cyclization±
elimination by using an allyl phenyl sul®de in the substrate
which allowed us to use a catalytic amount of thiophenol.
The structure effect in sulfanyl radical addition±cyclization
was also investigated by comparison of the cyclizability of
diallylamines.
In order to improve the yield of the desired cis-product 20,
we investigated radical cyclization of 19 under other con-
ditions. However, the conditions shown in Table 2, entry 3±
7, were not so effective for improvement of the yield of the
desired product 20. The stereostructures of 20 and 21 were
deduced from comparison of the 1H NMR spectra with those
of the related compounds3g and NOE correlations.
Experimental
General
1
Melting points are uncorrected. H and 13C NMR spectra
Having obtained different results in the cyclizability of two
substrates 14 and 19, we collected all the results of sulfanyl
radical addition±cyclization of diallylamines reported
previously3g and in this paper in Table 3. Thus, all acyclic
diallylamines 22a,3g 7a, 19, and 22b3g with no oxazolidi-
none ring underwent smooth radical cyclization. On the
other hand, the cyclizability of cyclic diallylamines having
an oxazolidinone ring would depend on the substituent at
the terminal ole®n. In the case of 22c and 14 with no
alkoxycarbonyl group at the terminal ole®n, any cyclized
products could not be isolated while 22d3g afforded the
cyclized product in 85% yield. These results suggest that
the existence of an oxazolidinone ring in 22c and 14 leads to
a less favorable transition state for ring closure except for
22d having an a,b-unsaturated ester group which is a good
radical acceptor. However, we are unable at this time to
offer a detailed explanation of the in¯uence of the oxazo-
lidinone ring on the radical cyclization.
were recorded at 200, 300, or 500 and at 50 MHz, respec-
tively. IR spectra were recorded using FTIR apparatus.
Mass spectra were obtained by EI method. Flash column
chromatography was preformed using E. Merck Kieselgel
60 (230±400 mesh). MPCC was performed using Lober
È
groûe B (E. Merck 310-25, Lichroprep Si60).
Phenylmethyl
(E)-N-[(3-methyl-4-(phenylsulfanyl)-2-
butenyl)] (2-propenyl)carbamate (7a). To a stirred solu-
tion of the allyl alcohol 58 (1.94 g, 10 mmol) in benzene
(50 mL) was added CBr4 (6.8 g, 20 mmol) and Ph3P
(5.4 g, 20 mmol) at 08C under a nitrogen atmosphere.
After the solution was stirred at the same temperature for
2 h, n-pentane (200 mL) was added to the reaction mixture.
The reaction mixture was ®ltered to remove triphenyl-
phosphine oxide. The ®ltrate was concentrated under
reduced pressure to afford the crude (E)-1-bromo-3-methyl-
4-(phenylsulfanyl)-2-butene 6 (2.55 g, quant.) as a yellow
oil. After being characterized by NMR spectrum, 6 was
immediately subjected to the following reaction. To a stirred
solution of the bromide 6 (2.6 g, 10 mmol) in CH2Cl2
(50 mL) was added allylamine (1.8 mL, 24 mmol) at room
temperature under a nitrogen atmosphere. After being
stirred at room temperature for 4 h, the reaction mixture
was diluted with CH2Cl2 and washed with water. The
organic phase was dried over Na2SO4 and concentrated
under reduced pressure to give the crude (E)-N-[(3-methyl-
4-(phenylsulfanyl)-2-butenyl)] (2-propenyl)amine. To a
solution of the amine in benzene (30 mL) was added Et3N
(2 mL, 14 mmol) and Z-Cl (528 mg, 10 mmol) under a
nitrogen atmosphere at room temperature. After the solution
was stirred at the same temperature for 2 h, the reaction
mixture was ®ltered to remove triethylamine hydrochloride.
The ®ltrate was concentrated under reduced pressure, and
the residue was puri®ed by MPCC (hexane/AcOEt 1:1) to
afford the carbamate 7a (700 mg, 19%) as a yellow oil; IR
(CHCl3) 1691 (NCOO) cm21; 1H NMR (200 MHz, CDCl3)
d 1.74 (3H, br s), 3.48 (2H, br s), 3.62 (2H, m), 3.82 (2H, m),
4.92±5.26 (3H, m), 5.11 (2H, s), 5.53±5.78 (1H, m), 7.14±
Next, we examined conversion of 20 into (2)-a-kainic acid
(Scheme 6). Oxidation of the cis-product 20 with OXONEw
(potassium peroxymonosulfate) gave the sulfone 23, which
was then subjected to methoxycarbonylation (MeLi, then
ClCOOMe) to afford the sulfonyl ester 24 in high yield as
a sole product. The stereochemistry at a-position of the ester
group in 24 has not been established yet. Desulfonylation of
24 with 5% sodium-amalgam gave the ester 25, which was
identical with the authentic sample10 upon comparison of
their spectral data. The ester 25 had previously been trans-
formed into (2)-kainic acid. According to Yoo's pro-
cedure,10 the ester 25 was treated with TFA to give the
hydroxy ester 26. Optical purity of 26 was determined to
1
be nearly 100% enantiomeric excess by H NMR spectro-
scopic analysis of the corresponding (1)-MTPA ester 27,
which was derived from 26 by esteri®cation using (1)-
MTPA chloride. Finally, 26 was smoothly converted into
(2)-kainic acid. Oxidation of the alcohol 26 with PDC
followed by esteri®cation of the resulting carboxylic acid
with diazomethane gave the ester 28. Hydrolysis of 28 with
LiOH and subsequent deprotection under Birch conditions

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O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
7.42 (10H, m); HRMS (EI, m/z) calcd for C22H25NO2S (M1)
367.1605, found 367.1601.
Table 1, entry 4: According to the procedure described for
entry 1 (Table 1), treatment of 7b with 0.2 equiv. of thio-
phenol and 0.2 equiv. of AIBN afforded a 1:1 mixture of cis/
trans-4-(1-methylethenyl)-1-[(4-methylphenyl)sulfonyl]-3-
[(phenylsulfanyl)methyl]pyrrolidine 8b (50%) as an
inseparable mixture. Pale yellow oil; IR (CHCl3) 1341,
(E)-4-Methyl-N-[3-methyl-4-(phenylsulfanyl)-2-butenyl]-
N-(2-propenyl)benzenesulfonamide (7b). To a stirred
solution of allylamine (500 mg, 8.8 mmol) in CH2Cl2
(10 mL) was added triethylamine (1.6 mL, 12 mmol) and
tosyl chloride (2 g, 10.6 mmol) at 08C under a nitrogen
atmosphere. After being stirred at the same temperature
for 4 h, the reaction mixture was diluted with H2O and
extracted with CH2Cl2. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated under
reduced pressure. Puri®cation of the residue by recrystalli-
zation (hexane/Et2O) afforded 4-methyl-N-(2-propenyl)ben-
zenesulfonamide (1.5 g, 96%) as pale yellow crystals: mp
1
1158 (NSO2) cm21; H NMR (200 MHz, CDCl3) d: 1.54
(3/2H, br s), 1.60 (3/2H, br s), 1.88 (1/2H, br t, Jˆ12 Hz),
2.08±2.34 (1H, m), 2.38 (3/2H, br s), 2.43 (3/2H, br s),
2.40±2.74 (2H, m), 2.96±3.12 (3/2H, m), 3.23 (1/2H, t,
Jˆ10 Hz), 3.35±3.52 (3/2H, m), 3.63 and 3.64 (each 1/
2H, t, Jˆ8 Hz), 4.60 (1/2H, br s), 4.67 (1/2H, br s), 4.80
(1/2H, br s), 4.89 (1/2H, br s), 7.14±7.34 (7H, m), 7.71 (1H,
br d, Jˆ8 Hz), 7.74 (1H, br d, Jˆ8 Hz); HRMS (EI, m/z)
calcd for C21H25NO2S2 (M1) 387.1325, found 387.1313.
1
59±618C; IR (CHCl3) 1335, 1160 (NSO2) cm21; H NMR
(200 MHz, CDCl3) d 3.63 (2H, br d, Jˆ7 Hz), 5.12±5.25
(2H, m), 5.62±5.82 (1H, m), 7.32 (2H, br d, Jˆ8 Hz), 7.68
(2H, br d, Jˆ8 Hz).
(S)-4-Ethenyl-2-oxazolidinone (13). According to the
literature,9 l-methionine methyl ester 9 was converted into
(S)-vinylglycinol 12 via t-butoxycarbonylation, reduction,
oxidation, and pyrolysis. To a stirred solution of the (S)-
vinylglycinol 12 (4.6 g, 25 mmol) in benzene (150 mL)
was added thionyl chloride (2 mL, 25 mmol) at room
temperature under a nitrogen atmosphere. After the solution
was heated at re¯ux for 8 h, the reaction mixture was
concentrated at reduced pressure and the residue was
puri®ed by MPCC (hexane/AcOEt 3:2) to afford 13 (1.7 g,
To a solution of the sulfonamide (1.5 g, 8.5 mmol) in ben-
zene (50 mL) was added the alcohol 5 (682 mg, 3.5 mmol)
and Ph3P (2.9 g, 10.6 mmol) at 08C under a nitrogen atmos-
phere. After being stirred at the same temperature for
15 min, diethyl azodicarboxylate (DEAD) (40% in toluene)
(3.5 mL, 8.8 mmol) was added dropwise and the reaction
mixture was stirred at room temperature for 2 h. The solvent
was removed and the residue was puri®ed by MPCC
(hexane/AcOEt 3:1) to afford the sulfonamide 7b (2.48 g,
1
62%) as a yellow oil; IR (CHCl3) 1766 (NCOO) cm21; H
NMR (300 MHz, CDCl3) d 4.07 (1H, dd, Jˆ8, 6 Hz), 4.39
(1H, qt, Jˆ8, 2 Hz), 4.55 (1H, t, Jˆ8 Hz), 5.30 (2H, m),
5.84 (1H, ddd, Jˆ17, 10, 8 Hz); HRMS (EI, m/z) calcd for
C5H7NO2 (M1) 113.0477, found 113.0452. [a]2D8ˆ226.2
(c 1.03, CHCl3).
90%) as a yellow oil; IR (CHCl3) 1341, 1158 (NSO2) cm21
;
1H NMR (200 MHz, CDCl3) d 1.68 (3H, br s), 2.43 (3H, br
s), 3.43 (2H, br s), 3.50 and 3.72 (each 2H, br d, Jˆ7 Hz),
4.91±5.23 (3H, m), 5.39±5.61 (1H, m), 7.20±7.36 (7H, m),
7.64 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z) calcd for
C21H25NO2S2 (M1) 387.1325, found 387.1329.
[S-(E)]-3-[3-Methyl-4-(phenylsulfanyl)-2-butenyl]-4-(2-
propenyl)-2-oxazolidinone (14). To a stirred solution of
the oxazolidinone 13 (112 mg, 1 mmol) in THF (3 mL)
was added successively n-BuLi (1.65 M in THF) (0.6 mL,
1 mmol) and dropwise a solution of the bromide 6 (257 mg,
1 mmol) at 2788C under a nitrogen atmosphere. After being
stirred at the same temperature for 0.5 h and then at 08C for
2 h, the reaction mixture was diluted with saturated aqueous
NH4Cl and extracted with CH2Cl2. The organic phase was
washed with H2O, dried over Na2SO4, and concentrated
under reduced pressure. The residue was puri®ed by
MPCC (hexane/AcOEt 5:1) to afford 14 (49 mg, 17%) as
a pale yellow oil; IR (CHCl3) 1742 (NCOO) cm21; 1H NMR
(500 MHz, CDCl3) d 1.74 (3H, br s), 3.42 and 3.60 (2H,
ABq, Jˆ15 Hz), 3.46 (1H, dd, Jˆ15, 9 Hz), 3.54 (1H, q,
Jˆ8 Hz), 3.82 (1H, dd, Jˆ9, 7 Hz), 3.96 (1H, dd, Jˆ15,
5 Hz), 4.21 (1H, t, Jˆ9 Hz), 5.09 (1H, br d, Jˆ15 Hz),
5.17 (1H, m), 5.25 (1H, br d, Jˆ10 Hz), 5.53 (1H, ddd,
Jˆ17, 10, 9 Hz); HRMS (EI, m/z) calcd for C16H19NO2S
(M1) 289.1136, found 289.1141. [a]2D6ˆ253.7 (c 0.93,
CHCl3).
General procedure for radical cyclization
Table 1, entry 1: To a boiling solution of the carbamate 7a
(110 mg, 0.3 mmol) in benzene (3 mL) under a nitrogen
atmosphere was added a solution of thiophenol (0.03 mL,
0.3 mmol) and AIBN (24.6 mg, 0.15 mmol) in benzene
(6 mL) by a syringe pump (5 mL/h) over 2 h. After the
reaction mixture was heated at re¯ux for a further 4 h, the
solvent was evaporated under reduced pressure. Puri®cation
of the residue by MPCC (hexane/AcOEt 4:1) afforded a 1:1
mixture of phenylmethyl cis/trans-4-(1-methylethenyl)-3-
(phenylsulfanyl)methyl-1-pyrrolidinecarboxylate 8a (24 mg,
22%) as an inseparable mixture. Pale yellow oil; IR (CHCl3)
1693 (NCOO) cm21; 1H NMR (200 MHz, CDCl3) d 1.65 (3/
2H, br s), 1.70 (3/2H, br s), 2.44±3.93 (8H, m), 4.72 (1/2H,
br s), 4.80 (1/2H, br s), 4.87 (1/2H, br s), 4.94 (1/2H, br s),
5.12 (2H, br s); HRMS (EI, m/z) calcd for C22H25NO2S (M1)
367.1604, found 367.1601.
(S)-N-(1-Hydroxy-3-buten-2-yl)-4-methylbenzenesulfona-
mide (16). According to the procedure described for the
preparation of 12, l-methionine methyl ester 9 was
converted into (S)-vinylglycinol 16 via tosylation, reduc-
tion, oxidation, and pyrolysis. Yellow crystals: mp 59±
608C (Et2O); IR (CHCl3) 3589 (OH), 1336, 1160 (NSO2)
cm21; 1H NMR (300 MHz, CDCl3) d 2.41(3H, s), 3.53 (1H,
dd, Jˆ11, 6 Hz), 3.61 (1H, dd, Jˆ11, 5 Hz), 3.87 (1H, br
Table 1, entry 2: According to the procedure described for
entry 1 (Table 1), treatment of 7a with 2 equiv. of thio-
phenol and 1 equiv. of AIBN afforded 8a (63%).
Table 1, entry 3: According to the procedure described for
entry 1 (Table 1), treatment of 7a with 0.2 equiv. of thio-
phenol and 0.2 equiv. of AIBN afforded 8a (16%).

O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
6205
quint., Jˆ6 Hz), 5.05 (1H, dt, Jˆ10, 2 Hz), 5.19 (1H, dt,
Jˆ16, 2 Hz), 5.52 (1H, br d, Jˆ7 Hz), 5.61 (1H, ddd, Jˆ16,
10, 6 Hz), 7.28 (2H, br d, Jˆ8 Hz), 7.55 (2H, br d, Jˆ8 Hz);
HRMS (EI, m/z) calcd for C11H15NO3S (M1) 241.0772,
found 241.0790. [a]2D8ˆ228.0 (c 1.0, CHCl3).
Jˆ10, 7 Hz), 3.72 (1H, dd, Jˆ17, 7 Hz), 3.86 (1H, dd,
Jˆ17, 7 Hz), 4.46 and 4.49 (2H, ABq, Jˆ7 Hz), 4.54 (1H,
m), 5.10 (1H, dt, Jˆ17, 2 Hz), 5.15 (1H, dt, Jˆ10, 2 Hz),
5.26 (1H, br tq, Jˆ7, 2 Hz), 5.58 (1H, ddd, Jˆ17, 10, 7 Hz),
7.18±7.31 (7H, m), 7.68 (2H, br d, Jˆ8 Hz); HRMS (EI,
m/z) calcd for C24H31NO4S2 (M1) 461.1692, found
461.1701. [a]2D7ˆ114.3 (c 1.26, CHCl3).
Methoxymethylation of Glycinol 16. To a solution of the
glycinol 16 (723 mg, 3 mmol) in CH2Cl2 (5 mL) was added
(i-Pr)2NEt (0.76 mg, 4.5 mmol) and MOMCl (0.3 mL,
3.6 mmol) at room temperature under a nitrogen atmos-
phere. After being stirred at the same temperature for 4 h,
the reaction mixture was diluted with saturated aqueous
NH4Cl and extracted with CH2Cl2. The organic phase was
washed with H2O, dried over Na2SO4, and concentrated
under reduced pressure. The residue was puri®ed by
MPCC (hexane/AcOEt 5:1) to afford (S)-N-(methoxy-
methyl)-N-[1-(methoxy)methoxy-3-buten-2-yl]-4-methyl-
benzenesulfonamide (17) (63 mg, 7%) and (S)-N-[1-
(methoxy)methoxy-3-buten-2-yl]-4-methylbenzenesulfona-
mide (18) (487 mg, 57%).
Phenylsulfanyl radical addition±cyclization±
elimination of 19
Table 2, Entry 1: According to the procedure given for
sulfanyl radical addition±cyclization±elimination of 7a,b,
reaction of 19 (260 mg, 0.56 mmol) using thiophenol
(0.06 mL, 0.56 mmol) and AIBN (46 mg, 0.28 mmol)
gave
[2S-(2a,3b,4a)-[2-(methoxymethoxy)methyl-4-(1-
methylethenyl)-1-(4-methylphenyl)sulfonyl-3-(phenylsul-
fanyl)methyl]pyrrolidine (20) (107 mg, 41%) and [2S-
(2a,3b,4a)-[2-(methoxymethoxy)methyl-4-(1-methylethenyl)-
1-(4-methylphenyl)sulfonyl-3-(phenylsulfanyl)methyl]pyrro-
lidine (21) (138 mg, 53%).
1
17: Yellow oil; IR (CHCl3) 1341, 1160 (NSO2) cm21; H
NMR (200 MHz, CDCl3) d 2.42 (3H, s), 3.28 (3H, s), 3.32
(3H, s), 3.67 (2H, d, Jˆ7 Hz), 4.45 (1H, br q, Jˆ7 Hz), 4.50
(2H, br s), 4.71 and 4.83 (2H, ABq, Jˆ10 Hz), 5.06±5.23
(2H, m), 5.71 (1H, br ddd, Jˆ17, 10, 6 Hz), 7,27 (2H, br d,
Jˆ8 Hz), 7.74 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z) calcd
for C14H20NO4S (M12OMe) 298.1112, found 298.1123.
Table 2, Entry 2: According to the procedure given for
sulfanyl radical addition±cyclization±elimination of 7a,b,
reaction of 19 (260 mg, 0.56 mmol) using a catalytic
amount of thiophenol (0.01 mL, 0.11 mmol) and AIBN
(18 mg, 0.11 mmol) gave 20 (99 mg, 38%) and 21
(147 mg, 57%) as shown in Table 2.
1
18: Yellow oil; IR (CHCl3) 1336, 1160 (NSO2) cm21; H
1
20: Yellow oil; IR (CHCl3) 1347, 1164 (NSO2) cm21; H
NMR (300 MHz, CDCl3) d 2.43 (3H, s), 3.30 (3H, s), 3.47
(1H, dd, Jˆ10, 5 Hz), 3.52 (1H, dd, Jˆ10, 5 Hz), 3.95 (1H,
br quint., Jˆ5 Hz), 4.51 and 4.52 (2H, ABq, Jˆ6 Hz), 5.10
(1H, dt, Jˆ10, 2 Hz), 5.17 (1H, dt, Jˆ17, 2 Hz), 5.68 (1H,
ddd, Jˆ17, 10, 6 Hz), 7,28 (2H, br d, Jˆ8 Hz), 7.75 (2H, br
d, Jˆ8 Hz); HRMS (EI, m/z) calcd for C13H19NO4S (M1)
285.1033, found 285.1050. [a]2D6ˆ26.3 (c 0.96, CHCl3).
NMR (500 MHz, CDCl3) d 1.04 (1H, t, Jˆ13 Hz), 1.57 (3H,
br s), 2.27 (1H, dq, Jˆ13, 3 Hz), 2.33 (3H, s), 2.46 (1H, dd,
Jˆ13, 3 Hz), 3.04 (2H, m), 3.31 (3H, s), 3.56 (1H, m), 3.64
(1H, dd, Jˆ10, 8 Hz), 3.77 (1H, dd, Jˆ10, 4 Hz), 4.03 (1H,
br dd, Jˆ8, 4 Hz), 4.52 (1H, br s), 4.61 and 4.65 (2H, ABq,
Jˆ7 Hz), 4.86 (1H, br q, Jˆ1 Hz), 7.13±7.26 (7H, m), 7.78
(2H, br d, Jˆ8 Hz); HRMS (EI, m/z) calcd for C24H31NO4S2
(M1) 461.1692, found 461.1709. [a]2D6ˆ231.3 (c 1.02,
CHCl3). NOEs were observed between 10-H (d 3.64) and
3-H (d 2.27), 100-H (d2.46) and ole®nic-H (d 4.52), and 100 H
(d 2.46) and 2-H (d 4.03) in NOESY spectroscopy.
Hydrolysis of 17. To a solution of 17 (67 mg, 0.2 mmol) in
THF (3 mL) was added ethylene glycol (0.02 mL,
0.4 mmol) and 10% HCl (0.4 mL) at room temperature
under a nitrogen atmosphere. After being stirred at re¯ux
for 8 h, the reaction mixture was diluted with saturated
aqueous NaHCO3 and extracted with CH2Cl2. The organic
phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. The residue was puri®ed
by MPCC (hexane/AcOEt 5:1) to afford 16 (39 mg, 71%).
This compound was identical with 16 prepared from 15.
1
21: Yellow oil; IR (CHCl3) 1345, 1161 (NSO2) cm21; H
NMR (500 MHz, CDCl3) d 1.57 (3H, br s), 2.05 (1H, br td,
Jˆ10, 8 Hz), 2.45 (3H, s), 2.50 (1H, m), 2.59 (1H, dd, Jˆ13,
8 Hz), 2.93 (1H, dd, Jˆ13, 5 Hz), 3.25 (1H, dd, Jˆ12,
11 Hz), 3.26 (3H, s), 3.63 (1H, dd, Jˆ12, 8 Hz), 3.79 (3H,
m), 4 54 and 4.55 (2H, ABq, Jˆ7 Hz), 4.65 (1H, br s), 4.79
(1H, br quint., Jˆ1 Hz), 7.14±7.28 (5H, m), 7.33 (2H, br d,
Jˆ8 Hz), 7.76 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z) calcd
for C24H31NO4S2 (M1) 461.1692, found 461.1703. [a]2D6ˆ
262.9 (c 0.81, CHCl3). NOEs were observed between ole-
®nic-H (d 4.65, 4.79) and 3-H (d 2.50), and 100-H (d 2.59,
2.93) and 4-H (d 2.05) in NOESY spectroscopy.
[S-(E)]-N-[(1-Methoxy)methoxy-3-buten-2-yl]-4-methyl-
N-[3-methyl-4-(phenylsulfanyl)-2-butenyl]benzenesul-
fonamide (19). To a solution of the alcohol 5 (194 mg,
1.0 mmol) in THF (26 mL) was added 18 (570 mg,
2.0 mmol) and Ph3P (818 mg, 3.0 mmol) at 08C under a
nitrogen atmosphere. After being stirred at the same
temperature for 15 min, DEAD (40% in toluene)(1.14 mL,
2.5 mmol) was added dropwise. The reaction mixture was
stirred at room temperature for 2 h. The solvent was
removed and the residue was puri®ed by MPCC (hexane/
AcOEt 3:1) to afford the sulfonamide 19 (360 mg, 75%) as a
yellow oil; IR (CHCl3) 1336, 1152 (NSO2) cm21; 1H NMR
(500 MHz, CDCl3) d 1.74 (3H, br s), 2.41 (3H, s), 3.29 (3H,
s), 3.45 (2H, br s), 3.52 (1H, dd, Jˆ10, 7 Hz), 3,56 (1H, dd,
(S)-3-Allyl-4-ethenyl-2-oxazolidinone (22c). According to
the procedure described for the preparation of 14, allylation
of 13 (330 mg, 2.94 mmol) with allyl bromide gave 22c
(205 mg, 50%) as a colorless oil; 1H NMR (300 MHz,
CDCl3) d 3.52 (1H, ddt, Jˆ15, 7, 1 Hz), 3.97 (1H, dd,
Jˆ9, 7 Hz), 4.12 (1H, ddt, Jˆ15, 5, 2 Hz), 4.23 (1H, dt,
Jˆ9, 7 Hz), 4.44 (1H, t, Jˆ9 Hz), 5.16±5.24 (2H, m),
5.30±5.37 (2H, m), 5.63 (2H, m).

6206
O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
[2S-(2a,3b,4b)]-[2-(Methoxymethoxy)methyl-4-(1-methyl-
ethenyl)-1-(4-methylphenyl)sulfonyl-3-(phenylsulfonyl)-
methyl]pyrrolidine (23). To a solution of 20 (323 mg,
0.7 mmol) in MeOH (10 mL) was added dropwise a solution
of OXONEw (2.17 g, 3.5 mmol) in H2O (10 mL) at 08C
under a nitrogen atmosphere. After being stirred at room
temperature for 3.5 h, the reaction mixture was diluted
with H2O and extracted with CH2Cl2. The organic phase
was washed with H2O, dried over Na2SO4, and concentrated
under reduced pressure. The residue was puri®ed by MPCC
(hexane/AcOEt 1:1) to afford 23 (293 mg, 85%) as colorless
crystals: mp 120±1218C (Et2O); IR (CHCl3) 1348, 1166
Jˆ10, 6 Hz), 3.59 (3H, s), 3.52 (1H, dd, Jˆ11, 6 Hz), 3.59
(3H, s), 3.65 (1H, br dd, Jˆ7, 3 Hz), 3.67 (1H, dd, Jˆ9,
7 Hz), 3.78 (1H,dd, Jˆ9, 3 Hz), 4.52 (1H, br s), 4.64 and
4.67 (2H, ABq, Jˆ6 Hz), 4.85 (1H, br q, Jˆ6 Hz), 7.34 (2H,
br d, Jˆ8 Hz), 7.76 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z)
calcd for C20H29NO6S (M1) 411.1714, found 411.1703.
[a]2D4ˆ241.6 (c 0.77, CHCl3) [lit.10 [a]1D5ˆ231.1 (c 1.0,
CHCl3)].
Methyl [2S-(2a,3b,4b)]-[2-(Hydroxymethyl)-4-(1-methyl-
ethenyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidine-
acetate (26). To a solution of 25 (140 mg, 0.34 mmol) in
CH2Cl2 (1.2 mL) was added dropwise TFA (0.12 mL,
1.33 mmol) at room temperature under a nitrogen atmos-
phere at room temperature. After being stirred at the same
temperature for 3 h, the reaction mixture was diluted with
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
puri®ed by MPCC (hexane/AcOEt 4:1) to afford 26
(121 mg, 97%) as colorless crystals: mp 110±1118C
(Et2O) [lit.10 mp 112±1138C]; IR (CHCl3) 1732 (COO),
1
(NSO2) cm21; H NMR (300 MHz, CDCl3) d 1.42 (3H, br
s), 1.48 (1H, dd, Jˆ14, 11 Hz), 2.47 (1H, br d, Jˆ14 Hz),
2.45 (3H, s), 2.65 (1H, br dd, Jˆ11, 6 Hz), 2.89 (1H, dd,
Jˆ11, 9 Hz), 3.15 (1H, br dt, Jˆ11, 7 Hz), 3.55 (1H, dd,
Jˆ9, 7 Hz), 3.65 (1H, dd, Jˆ10, 7 Hz), 3.77 (1H, dd, Jˆ10,
4 Hz), 4.07 (1H, br dd, Jˆ7, 4 Hz), 4.48 (1H, br s), 4.67 and
4.68 (2H, ABq, Jˆ7 Hz), 4.86 (1H, br s,), 7.36±7.84 (9H,
m); HRMS (EI, m/z) calcd for C24H31NO6S2 (M1) 493.1590,
found 493.1584. Anal. calcd for C24H31NO6S2: C, 58.40; H,
6.33; N, 2.84; S, 12.99. Found: C, 58.33; H, 6.28; N, 2.83; S,
13.12. [a]2D7ˆ217.5 (c 0.97, CHCl3).
1
1345, 1163 (NSO2) cm21; H NMR (500 MHz, CDCl3) d
0.90 (1H, dd, Jˆ17, 12 Hz), 1.65 (3H, br s), 1.81 (1H, dd,
Jˆ17, 3 Hz), 2.46 (3H, s), 2.54 (1H, br ddd, Jˆ11, 6. 4 Hz),
3.00 (1H, br dt, Jˆ11, 6 Hz), 3.07 (1H, dd, Jˆ12, 9 Hz),
3.53 (1H, br t, Jˆ6 Hz), 3.58 (1H, dd, Jˆ9, 6 Hz), 3.59 (3H,
s), 3.76 (1H, dd, Jˆ11, 6 Hz), 3.80 (1H, dd, Jˆ11, 6 Hz),
4.52 (1H, br s), 4.86 (1H, br q, Jˆ2 Hz), 7.35 (2H, br d,
Jˆ8 Hz), 7.76 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z) calcd
for C18H25NO5S (M1) 367.1452, found 367.1430. Anal.
calcd for C18H25NO5S: C, 58.84; H, 6.86; N, 3.81; S, 8.73.
Found: C, 58.72; H, 6.78; N, 3.80; S, 8.62. [a]2D5ˆ221.1 (c
0.97, CHCl3) [lit.10 [a]D15ˆ213.7 (c 1.04, CHCl3)].
Methyl [2S-(2a,3b,4b)]-[2-(methoxymethoxy)methyl-4-
(1-methylethenyl)-1-[(4-methylphenyl)sulfonyl]-a-phenyl-
sulfonyl]-3-pyrrolidineacetate (24). To a solution of 23
(179 mg, 0.36 mmol) in THF (6.5 mL) was added dropwise
MeLi (1.04 M in Et2O) (2.9 mL, 2.5 mmol) at 2788C under
a nitrogen atmosphere. After being stirred at the same
temperature for 0.5 h, methyl chloroformate (0.56 mL,
7.2 mmol) was added dropwise to the reaction mixture.
After being stirred at 08C for 4 h, the reaction mixture was
diluted with saturated aqueous NH4Cl and extracted with
CH2Cl2. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated under reduced pressure.
The residue was puri®ed by MPCC (hexane/AcOEt 3:1) to
afford 24 (178 mg, 89%) as colorless amorphous; IR
Methyl [2S-[2a(Rp),3b,4b]]-2-[(3,3,3-Tri¯uoro-2-meth-
oxy-1-oxo-2-phenylpropoxy)methyl-4-(1-methylethenyl)-
1-[(4-methylphenyl)sulfonyl]-3-pyrrolidineacetate (27).
To a solution of (2)-alcohol 26 (14 mg, 0.04 mmol) in
CH2Cl2 (3 mL) was added pyridine (0.04 mL, 0.5 mmol)
and (1)-MTPACl (100 mg, 0.4 mmol) at room temperature
under a nitrogen atmosphere. After being stirred at the same
temperature for 3 h, the solvent was evaporated under
reduced pressure. Puri®cation of the residue by MPCC
(hexane/AcOEt 3:1) afford 27 (18 mg, 88%) as a colorless
1
(CHCl3) 1741 (COO), 1329, 1152 (NSO2) cm21; H NMR
(200 MHz, CDCl3) d 1.62 (3H, br s), 2.40 (3H, s), 3.17±
3.34 (4H, m), 3.30 (3H, s), 3.57 (3H, s), 3.65 (1H, dd, Jˆ11,
3 Hz), 3.78 (1H, dd, Jˆ11, 4 Hz), 3.97 (1H, d, Jˆ2 Hz),
4.50 and 4.55 (2H, ABq, Jˆ6 Hz), 4.68 (1H, br s), 4.85
(1H, br t, Jˆ4 Hz), 5.03 (1H, br s), 7.36±7.84 (9H, m);
HRMS (EI, m/z) calcd for C26H33NO8S2 (M1) 551.1646,
found 551.1668.
1
oil; H NMR (500 MHz, CDCl3) d 0.98 (1H, dd, Jˆ17,
11 Hz), 1.55 (3H, br s), 1.79 (1H, dd, Jˆ17, 3 Hz), 2.42
(1H, m), 2.44 (3H, s), 2.88 (1H, br dt, Jˆ12, 6 Hz), 2.97
(1H, dd, Jˆ12, 9 Hz), 3.39 (1H, dd, Jˆ9, 7 Hz), 3.52 (3H,
s-like), 3.76 (1H, br dd, Jˆ5, 3 Hz), 4.23 (1H, br s), 4.35
(1H, dd, Jˆ12, 3 Hz), 4.74 (1H, dd, Jˆ12, 5 Hz), 4.79 (1H,
br q, Jˆ2 Hz), 7.33 (2H, br d, Jˆ8 Hz), 7.40 (3H, m), 7.54
(2H, m), 7.74 (2H, br d, Jˆ8 Hz).
Methyl [2S-(2a,3b,4b)]-[2-(methoxymethoxy)methyl-4-
(1-methylethenyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrro-
lidineacetate (25). To a solution of 24 (56 mg, 0.10 mmol)
in MeOH (0.4 mL) was added Na2HPO4 (57 mg, 0.4 mmol)
and 5% Na±Hg (112 mg, 0.24 mmol) at 08C under a nitro-
gen atmosphere. After being stirred at the same temperature
for 4 h, the reaction mixture was diluted with H2O and
extracted with CH2Cl2. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated under
reduced pressure. The residue was puri®ed by MPCC (hex-
ane/AcOEt 3:1) to afford 25 (22 mg, 86%) as colorless crys-
tals: mp 51.5±528C (Et2O) [lit.10 mp 124±1268C (Et2O)]; IR
Methyl [2S-(2a,3b,4b)]-[2-(Methoxycarbonyl)-4-(1-methyl-
ethenyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidine-
acetate (28). To a solution of 26 (125 mg, 0.34 mmol) in
DMF (0.65 mL) was added PDC (403 mg, 1 mmol) and
Ê
molecular sieves (4 A) (260 mg) at room temperature
under a nitrogen atmosphere. After being stirred at the
1
(CHCl3) 1733 (COO), 1347, 1165 (NSO2) cm21; H NMR
(500 MHz, CDCl3) d 0.95 (1H, dd, Jˆ17, 11 Hz), 1.67 (3H,
br s), 1.80 (1H, dd, Jˆ17, 4 Hz), 2.45 (3H, s), 2.66 (1H, ddd,
Jˆ11, 6, 4 Hz), 3.03 (1H, dd, Jˆ11, 9 Hz), 3.10 (1H, br dt,
same temperature for 21 h, a solution of CH2N2
(0.41 mmol) in Et2O (10 mL) was added to the reaction
mixture. After being stirred at the same temperature for

O. Miyata et al. / Tetrahedron 56 (2000) 6199±6207
6207
2. For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon±Carbon Bonds; Baldwin, J. E., Ed.; Perga-
mon: Oxford, 1986. (b) Ramaiah, M. Tetrahedron 1987, 43, 3541±
3676. (c) Curran, D. P. Synthesis 1988, 417±439 and 489±513.
(d) Jasperse, C. P.; Curran, D. P.; Fervig, T. Chem. Rev. 1991,
1237±1286. (e) Crich, D. Organosulfur Chemistry: Synthetic
Aspects Page, P., Ed.; Academic: London, 1995; Vol. 1, pp 49±
1 h, the reaction mixture was diluted with H2O and extracted
with AcOEt. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was puri®ed by MPCC (hexane/AcOEt 2:1) to
afford 28 (117 mg, 87%) as colorless crystals: mp 115.5±
1168C (Et2O) [lit.10 mp 139±1408C]; IR (CHCl3) 1737
1
(COO), 1352, 1166 (NSO2) cm21; H NMR (500 MHz,
CDCl3) d 1.59 (3H, dd, Jˆ17, 11 Hz), 1.65 (3H, br s),
2.07 (1H, dd, Jˆ17, 4 Hz), 2.44 (3H, s), 2.81 (1H, m),
3.09 (1H, m), 3.26 (1H, dd, Jˆ9, 8 Hz), 3.56 (1H, dd,
Jˆ9, 7 Hz), 3.66 (3H, s), 3.77 (3H, s, OMe), 4.30 (1H, d,
Jˆ2 Hz), 4.59 (1H, br s), 4.89 (1H, br q, Jˆ2 Hz), 7.33 (2H,
br d Jˆ8 Hz), 7.78 (2H, br d, Jˆ8 Hz); HRMS (EI, m/z)
calcd for C19H25NO6S (M1) 395.1401, found 395.1381. Anal.
calcd for C19H25NO6S: C, 57.71; H, 6.37; N, 3.54; S, 8.11.
Found: C, 57.42; H, 6.32; N, 3.50; S, 8.22. [a]2D4ˆ246.3 (c
1.08, CHCl3) [lit.10 [a]D15ˆ248.1 (c 1.0, CHCl3)].
È
88. (f) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Org. React. (N. Y.) Paquette, L. A., Ed.;
Wiley: New York, 1996; Vol. 48, pp 301±856. (g) Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. Rev. 1996, 96, 177±194. (h) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543±17594. (i) Renaud, P.;
Gerster, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2562±2579.
(j) Chatgilialoghi, C.; Bertrand, M. P.; Ferreri, C. The Chemistry of
Free Radicals: S-Centered Radicals; Alfassi, Z. B., Ed.; Wiley:
Chichester, 1999; pp 311±348. (k) Naito, T. Heterocycles 1999,
50, 505±541. (l) Bowman, W. R.; Bridge, C. F.; Brookes, P.
J. Chem. Soc. Perkin Trans. 1 2000, 1±14. (m) Curran, D. P.;
Tamine, J. J. Org. Chem. 1991, 56, 2746±2750. (n) Musa,
O. M.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1999, 64,
1022±1025.
(2)-a-Kainic acid (1). To a solution of 28 (56 mg,
0.14 mmol) in MeOH (0.5 mL) was added a solution of
LiOH (126 mg, 3.0 mmol) in H2O (0.5 mL) at room
temperature under a nitrogen atmosphere. After being
stirred at the same temperature for 1 h, the reaction mixture
was acidi®ed to pH 2 and extracted with AcOEt. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated under reduced pressure to give the crude
dicarboxylic acid 29. To liquid ammonia (3 mL) was added
a solution of 29 in THF (0.5 mL) and then Li (8 mg,
1.1 mmol) at 2788C. After additional stirring at the same
temperature for 30 min, the reaction mixture was quenched
with isoprene. Ammonia was removed and the residue was
dissolved in H2O (1 mL) and neutralized to pH 7 with cold
2 M HCl. The resulting aqueous solution was loaded on
resin (Amberlite CG-50) in a column and washed with
water. After concentration, the residue was recrystallized
from EtOH to give 1 (26 mg, 88%) as colorless crystals:
mp 242±2438C (dec.) [lit.11 mp 243±2448C (dec.)]; IR
(nujol) 3520 (OH), 3130, 2600, 1680, 1621 (COOH,
3. For reviews for syntheses of kainoids, see: (a) Hashimoto, K.;
Shirahama, H. J. Synth. Org. Chem. Jpn 1989, 47, 212±223.
(b) Parsons, A. F. Tetrahedron 1996, 52, 4149±4174. For total
synthesis of a-kainic acid using radical cyclization, see:
(c) Baldwin, J. E.; Moloney, M. G.; Parson, A. F. Tetrahedron
1990, 46, 7263±7282. (d) Hatakeyama, S.; Sugawara, K.; Takano,
S. J. Chem. Soc., Chem. Commun. 1993, 125±127. (e) Hannessian,
S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418±5424. (f) Bachi,
M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896±1898. (g) Miyata
O.; Ozawa Y.; Ninomiya I.; Aoe K.; Hiramatsu H.; Naito T.
Heterocycles 1997, 46, 321±333. (h) Cossy, J.; Cases, M.; Pardo,
D. G. Tetrahedron 1999, 55, 6153±6166.
4. We have reported the sulfanyl radical addition±cyclization for
heterocycle synthesis. (a) Naito, T.; Honda, Y.; Miyata, O.;
Ninomiya, I. Chem. Pharm. Bull. 1993, 41, 217±219. (b) Naito,
T.; Honda, Y.; Miyata, O.; Ninomiya, I. J. Chem. Soc., Perkin
Trans. 1 1995, 19±26. (c) Miyata O.; Nishiguchi, A.; Ninomiya,
I.; Naito, T.; Aoe, K.; Okamura, K. Tetrahedron Lett. 1996, 37,
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Y.; Bhavakul, V.; Yamaguchi, S.; Fujiwara, A.; Miyata, O.;
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1
COO2) cm21; H NMR (500 MHz, CDCl3) d 1.68 (3H, br
s), 2.18 (1H, dd, Jˆ16, 8 Hz), 2.28 (1H, dd, Jˆ16, 6.5 Hz),
2.91 (1H, br dt, Jˆ11, 7 Hz), 2.97 (1H, m), 3.34 (1H, t,
Jˆ11 Hz), 3.62 (1H, Jˆ11, 7 Hz), 3.98 (1H, br s), 4.94
(1H, br s); HRMS (EI, m/z) calcd for C10H15NO4 (M1)
213.1000, found 213.1020. [a]2D4ˆ214.0 (c 0.50, H2O)
[lit.11 [a]2D4ˆ214.2 (c 0.23, H2O)].
Acknowledgements
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We are grateful to Professors S. Yoo and S. H. Lee, Korean
Research Institute of Chemical Technology, for sending us
the precious spectral data of the ester 25. This work was
supported in part by a Grant-in-Aid for Scienti®c Research
from the Ministry of Education, Science, Sports and
Culture, Japan and a research grant from the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation.
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4978±4979.
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