Stereoselective synthesis of (±)-α-kainic acid using free radical key reactions

Article abstract of DOI:10.1021/jo9607875

Thiol-mediated free radical isomerization of a deliberately substituted but-3-enyl isocyanide 12a, and n-Bu₃SnH/AIBN-mediated free radical cyclization of a deliberately substituted but-3-enyl isothiocyanate 22, afforded, respectively, the (ethylthio)pyrroline 13a and the thiopyroglutamates 5 and 23. Reduction, protection, and deprotection of these heterocyclic compounds afforded proline derivatives 6 and 25 which contain all the structural elements of α-kainic acid (1) except the C-2 acetic acid moiety. These intermediates were stereospecifically converted into (±)-α-kainic acid using a new method of temporary sulfur connection. Accordingly, CH₂CO₂Me is linked to the chiral isopropenyl anchor and then intramolecularly connected to the pyrrolidine ring and eventually disconnected from its anchor by a sequential reductive double elimination process in which the isopropenyl double bond is restored.

Full text of DOI:10.1021/jo9607875

7
116
J . Org. Chem. 1996, 61, 7116-7124
Ster eoselective Syn th esis of (()-r-Ka in ic Acid Usin g F r ee Ra d ica l
Key Rea ction s
Mario D. Bachi,* Nira Bar-Ner, and Artem Melman
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
Received April 29, 1996X
Thiol-mediated free radical isomerization of a deliberately substituted but-3-enyl isocyanide 12a ,
and n-Bu
isothiocyanate 22, afforded, respectively, the (ethylthio)pyrroline 13a and the thiopyroglutamates
and 23. Reduction, protection, and deprotection of these heterocyclic compounds afforded proline
3
SnH/AIBN-mediated free radical cyclization of a deliberately substituted but-3-enyl
5
derivatives 6 and 25 which contain all the structural elements of R-kainic acid (1) except the C-2
acetic acid moiety. These intermediates were stereospecifically converted into (()-R-kainic acid
using a new method of temporary sulfur connection. Accordingly, CH CO Me is linked to the chiral
2 2
isopropenyl anchor and then intramolecularly connected to the pyrrolidine ring and eventually
disconnected from its anchor by a sequential reductive double elimination process in which the
isopropenyl double bond is restored.
In tr od u ction
R-Kainic acid (1) is the prototype of a group of neu-
roexcitatory amino acids which activate a particular
subtype of glutamic acid receptors. These amino acids
are important substrates in physiological and pharma-
cological studies of the central nervous system.1 The
synthesis of R-kainic acid continues to challenge organic
chemists, providing an arena for developing and testing
new strategies and methodologies.2-11 One of the major
obstacles to be overcome in the synthesis of R-kainic acid
is the achievement of the 3,4-cis-stereochemistry. Most
of the reported syntheses are based on the construction
of the substituted pyrrolidine system by the stereocon-
trolled formation of the 3,4-carbon to carbon bond.2
Another commonly employed strategy is to delay to the
end of the synthesis the involvement of compounds
carrying an acidic C-2 hydrogen atom. Accordingly most
authors reported on hydroxy compounds of type 2 as
pretargets which are oxidized to carboxylates at an
advanced stage of the synthesis.2
the carboxylate group designed to occupy position-2 in
R-kainic acid (1). An early step in this plan entails the
generation of a carbon-centered imidoyl radical of type
1
2
3.
Such a radical possesses all the building blocks
composing the target molecule except for the C-3 acetic
acid moiety. The array of substituents and functional
groups in 3 was designed to allow, in a single stage, the
stereoselective formation of either a pyrroline 4 or a
pyrrolidinethione 5. Reduction of both pyrrolines 4 and
thiopyroglutamates 5 to the key intermediate compound
6 was based on conventional methods. The C-2 carboxy-
late and C-4 isopropenyl groups of pyrrolidine 6 have the
,4,5,7-9
,4-9,11
13
same relative stereochemistry as (-)-R-kainic acid (1).
The conversion of pyrrolidine 6 into R-kainic acid (1)
requires the formal substitution of the 3â-hydroxyl group
Syn th etic P la n
2
by 3R-CH COOH. For the introduction of the acetic acid
In contrast to the conventional strategies mentioned
above, our synthetic strategy involves the stereocon-
trolled construction of the substituted heterocyclic system
by the formation of the 4,5-carbon to carbon bond and
on the use of a starting material which already possesses
appendage in the desired stereochemistry a new method
14
based on temporary sulfur connection was developed.
It was designed with the purpose of securing the preva-
lence of substitution at position-3 rather then TsOH
elimination.
X
Abstract published in Advance ACS Abstracts, September 1, 1996.
Syn th esis of Key P yr r olid in e Der iva tives
6 a n d 25
(
1) Shinozaki, H. In Excitatory Amino Acid Receptors. Design of
Agonists and Antagonists; Krogsgaard-Larsen, P., Hansen, J . J ., Eds.;
Ellis Horwood: New York, 1992; pp 261-291.
(
(
2) Oppolzer, W.; Thirring, K. J . Am. Chem. Soc. 1982, 104, 4978.
3) Takano, S.; Iwabuhi, Y.; Ogasawara, K. J . Chem. Soc., Chem.
The ω-(ethylthio)dimethylacrylaldehyde 9, obtained
from the bromoacetal 7,15 was condensed with lithium
enolate of isocyanide 10 to give a separable mixture of
the syn and anti hydroxy esters 11a and 11b (Scheme
Commun. 1988, 1204.
4) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J . Am. Chem.
Soc. 1988, 110, 6467.
5) Baldwin, J . E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1990,
6, 7263.
6) Takano, S.; Inomata, K.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1992, 169.
7) Barco, A.; Benetti, S.; Spalluto, G.; Casolari, A.; Pollini, G. P.;
Zanirato, V. J . Org. Chem. 1992, 57, 6279.
8) Cooper, J .; Knight, D. W.; Gallagher, P. T. J . Chem. Soc., Perkin
Trans. 1 1992, 553.
9) Hatakeyama, S.; Sugawara, K.; Takano, S. J . Chem. Soc., Chem.
Commun. 1993, 125.
(
(
4
2
1). To avoid elimination of H O from hydroxy esters 11,
(
(
(12) Bachi, M. D.; Melman, A. J . Org. Chem. 1995, 60, 6242.
(13) All chiral compounds in this work are racemic; just one
enantiomer of each pair is addressed to in the text and displayed in
the structural formulas.
(14) Preliminary report: Bachi, M. D.; Melman, A. Synlett 1996,
60.
(
(
(
(
10) Monn, J . A.; Valli, M. J . J . Org. Chem. 1994, 59, 2773.
11) Yoo, S. E.; Lee, S. H. J . Org. Chem. 1994, 59, 6968.
(15) Gaonach, O.; Maddaluno, J .; Chauvin, J .; Duhamel, L. J . Org.
Chem. 1991, 56, 4045.
S0022-3263(96)00787-6 CCC: $12.00 © 1996 American Chemical Society

Stereoselective Synthesis of (()-R-Kainic Acid
J . Org. Chem., Vol. 61, No. 20, 1996 7117
Sch em e 1
isocyanide group of 12a , generating the carbon-centered
imidoyl radical 16, ring-closure to radical 17, and sub-
sequent, or probably concerted, â-elimination leading to
•
the isopropenyl(ethylthio)pyrroline 13a and EtS which
continues the chain reaction. The crowded substitution
array of 13a is instrumental in preventing migration of
the double bond to the exocyclic position as does occur
in the case of a less crowded 4-vinyl(ethylthio)pyrroline
which spontaneously isomerizes to the corresponding
ethylidene derivative.1
6,17
Isomerization of the isoprope-
nyl derivative 13a to the isopropylidene derivative 18
would induce considerable allylic-1,3 strain on both sides
of the isopropylidene group.
Reduction of the ethylthioimidate function in 13a with
NaB(CN)H
nitrogen protection afforded the pyrrolidine 14a (Scheme
). Desilylation of 14a gave the tetrasubstituted pyrro-
3
under mild acidic conditions, followed by
1
the conditions described in the Experimental Section
should be carefully followed. O-Silylation of 11a afforded
the highly functionalized alkenyl isocyanide 12a which
contains an allylic radical leaving group (EtS). Treat-
ment of 12a with catalytic amounts of EtSH and AIBN
induced a free radical transposition to the isopropenyl-
lidine 6. The assigned relative stereochemistry was
corroborated by X-ray diffraction analysis.18
Although the original synthetic plan was based on the
use of the tetrasubstituted pyrrolidine 6 as key interme-
diate we subsequently examined the suitability of its
(
ethylthio)pyrroline 13a . The mechanism of this isomer-
(
16) Bachi, M. D.; Balanov, A.; Bar-Ner, N.; Bosch, E.; Denenmark,
D.; Mizhiritskii, M. Pure Appl. Chem. 1993, 65, 595.
17) Bachi, M. D.; Balanov, A.; Bar-Ner, N. J . Org. Chem. 1994, 59,
7752.
ization is shown on the bottom right side of Scheme 1. It
involves a sequence of homolytic transformations includ-
ing intermolecular addition of ethylthiyl radical to the
(

7
118 J . Org. Chem., Vol. 61, No. 20, 1996
Bachi et al.
Sch em e 2
diastereoisomer 25 as an additional intermediate for the
synthesis of (()-R-kainic acid. For this purpose the
sequence of reactions from the condensation of com-
pounds 9 and 10 up to the formation of (ethylthio)-
pyrroline 13a ,b was repeated without separation of the
acyclic diastereoisomeric mixtures 11a ,b and 12a ,b.
Diastereomerically pure isomers 13a and 13b were
obtained by chromatography of their mixture. In con-
as an allylic radical leaving group. While isocyanide 12a
isomerizes to (ethylthio)pyrroline 13a when treated with
EtSH/AIBN, the structurally related isocyanide 21 reacts
with t-BuSH/ACN (ACN, 1,1′-azobis(cyclohexanecarbo-
nitrile)) to give the corresponding isothiocyanate 22. A
similar difference in reaction selectivity between primary
thiols and thiols which may release stabilized radical on
the cleavage of their C-S bond was observed also in
1
7
trast to the case of isomer 13a , the NaB(CN)H
3
reduction
reactions of other alkenyl isocyanides. n-Bu SnH/ACN-
3
mediated cyclization of 2220 afforded the 4-isoprope-
of the ethylthioimidate moiety in isomer 13b was ac-
companied by partial reduction of the isopropenyl group
leading to the isopropenylpyrrolidine 14b which con-
tained 15-20% of isopropylpyrrolidine 15. Pure isopro-
penylpyrrolidine 14b was eventually obtained by the
alternative method described below which proved to be
also an excellent alternative method for the preparation
of isopropenylpyrrolidine 14a .
nylpyrrolidinethiones 5 and 23 (ratio 1.4:1) in excellent
yield. This one-pot reaction consists of a sequence of
consecutive homolytic steps combining intermolecular
addition, intramolecular addition, â-elimination, and
intermolecular hydrogen atom transfer as shown at the
bottom of Scheme 2. The immediate products of the free
radical process are two diastereomeric (stanniothio)-
pyrrolines 26 which spontaneously hydrolyze on silica gel
to give after chromatography the 4-isopropenylpyrroli-
dine thiones 5 and 23. Conversion of 23 into the 2,3-
trans-hydroxy ester 25 involves N-protection. In order
to avoid migration of the double bond in 24b to the
exocyclic position the introduction of the BOC group
should be done under mild conditions (see Experimental
This alternative method required the synthesis of
pyrrolidinethiones 5 and 23 (Scheme 2). 4-Alkylpyrro-
lidinethiones are readily obtained by the n-Bu
AIBN-mediated cyclization of alk-4-enyl isothiocyan-
3
SnH/
ates.1
2,16,19
In order to obtain the desired substitution
pattern, we designed and synthesized the highly func-
tionalized alkenyl isothiocyanates 22 which carries t-BuS
Section). Crude 24b was reduced with n-Bu
the isopropenylpyrrolidine 14b, and after desilylation the
,3-trans-hydroxy ester 25. Following the same proce-
3
SnH to give
(
18) (a) We thank Dr. Felix Frolow for X-ray diffraction analyais of
compound 6. (b) The authors have deposited atomic coordinates for
this structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 IEZ,
U.K. (c) 3D structural formula, ORTEP drawing, and details of X-ray
data acquisition are given as supporting information.
2
dure 4-isopropenylpyrrolidinethiones 5 was converted
(20) For preparative purpose the isothiocyanate 22 was used in the
(19) Bachi, M. D.; Denenmark, D. J . Org. Chem. 1990, 55, 3442.
same pot without purification (see Experimental Section)

Stereoselective Synthesis of (()-R-Kainic Acid
J . Org. Chem., Vol. 61, No. 20, 1996 7119
Sch em e 3
involve the regeneration of the double bond, (c) both thio
and sulfonyl substituents on acetic esters increase the
acidity of the R-hydrogen atoms and therefore allow the
generation of the required nucleophilic center under mild
basic conditions.
For adding a methyl mercaptoacetic unit, in the desired
regiochemistry, we used the sulfenyl chloride of methyl
mercaptoacetate.22 This reaction afforded in good yield
the chloroalkyl sulfide 28 as a single diastereomer as
shown in Scheme 3. This remarkable diastereoselectivity
derives from shielding of the isopropenyl group by the
tosyloxy group, from the â-side. This shielding is re-
1
flected in the H NMR spectrum of 27, which exhibits a
marked upfield shift of the signal of the vinylic methyl
group (ca. 0.4) and of the vinylic protons (ca. 0.3 ppm).
Treatment of the chloroalkyl sulfide 28 with MeOK failed
to induce the desired intramolecular substitution of the
tosyloxy group as the reaction was reverted to give
isopropylene 27. Addition of alkylsulfenyl chlorides to
2
3
terminal double bonds is a reversible reaction. Under
neutral conditions at room temperature the equilibrium
lies in the direction: 33 f 34 f 35; however, under basic
conditions it is reverted and the isopropenyl derivative
into the 2,3-cis silyloxy ester 14a , identical to the
substance obtained from (ethylthio)pyrroline 13a .
2
7 is recovered. To overcome this setback we oxidized
the chloroalkyl sulfide 28 into the corresponding rather
stable chloro-sulfone 29. Treatment with potassium
methylate in THF/methanol afforded the desired chlo-
romethyl bicyclic sulfone 30 which carries the acetic acid
residue at the desired site and configuration. The
disconnection of the acetic acid moiety from its temporary
anchor with concomitant regeneration of the isopropenyl
double bond was initially achieved by treatment of
Com p letion of th e Syn th esis of 1 by Tem p or a r y
Su lfu r Con n ection
The conversion of key intermediate 6 into R-kainic acid
1) requires the formal substitution, with inversion of
(
configuration, of the 3-hydroxy group by an acetic acid
residue. For this purpose the hydroxy group in pyrroli-
dine 6 was converted into its tosyl derivative 27. An
chloromethyl bicyclic sulfone 30 with n-Bu
3
SnH/AIBN.
Sn extrusion of the chlorine atom with concomitant
â-cleavage generates the sulfonyl radical 36 which pre-
sumably undergoes R-elimination of SO giving the
stabilized carbon-centered radical 37, and, after hydrogen
•
intermolecular S
N
2 substitution of the tosyloxy group by
n-Bu
3
a carbon nucleophile was excluded due to the competitive
facile elimination involving the acidic hydrogen at C-2.
We reasoned that an intramolecular substitution might
be feasible, and we investigated the possibility of using
the isopropenyl group, which is in the desired R-config-
uration, as an anchor for the temporary linking of an
acetic acid residue. In order to allow a sterically favored
substitution of the tosyloxy group the acetic acid residue
should be linked to the inner end of the double bond of
the isopropenyl anchor by a one-atom linker. Further-
more, this linker should be prone to eventual extrusion
with concomitant regeneration of the double bond in its
original site. Since silicon, which proved to be an efficient
linker in temporary tethered reactions,21 was deemed
unsuitable for solving our particular problems, we were
prompted to invent a new type of temporary tethered
reactions.
2
atom abstraction from n-Bu
acid 31.
3
SnH, the protected kainic
Sulfur was selected as the temporary linking unit in
the present work because: (a) of the availability of
reactions allowing the regiocontrolled addition of sulfur-
compounds to terminal double bonds, (b) of the avail-
ability of several efficient processes for selectively cleav-
ing carbon-sulfur bonds, including by reactions which
However, we were not satisfied with the yield of this
process which did not exceed 12% protected R-kainic acid
31 along with 50% recovered starting material 30. The
(21) Bols, M.; Skrydstrup, T. Chem. Rev. 1995, 95, 1253.

7
120 J . Org. Chem., Vol. 61, No. 20, 1996
Bachi et al.
Sch em e 4
which incorporates the major structural features of the
target molecule is obtained by a free radical sequential
reaction of a highly functionalized open chain precursor.
The lacking structural element, the acetic acid residue,
is introduced in a regio- and stereocontrolled manner by
a new method based on temporary sulfur connection. The
disconnection of the acetic acid from its sulfur linker, with
concomitant regeneration of the isopropenyl group, is
based on a new reductive sequential double elimination.
Exp er im en ta l Section
Gen er a l P r oced u r e. For general procedures see reference
1
2. MPLC (medium-pressure liquid chromatography) was
performed on column l ) 40 cm, d ) 30 mm, filled with
Lichroprep 15-40 µm, flash chromatography on silica gel 60
from Merck. All chiral compounds are racemic.13
4
-(E t h ylt h io)-3-m et h yl-2-b u t en a l (9). To a solution of
1
5
1
,1-dimethoxy-3-methyl-4-bromobut-2-ene (7) (89 mmol) in
methanol (50 mL) at -30 °C was added a solution of NaOH
(
(
3.6 g, 90 mmol) and ethanethiol (5.6 g, 90 mmol) in methanol
50 mL). The temperature was raised to 20 °C, and water (100
low yield, which could not be improved by modulating
temperature, concentration, and stoichiometry, is at-
tributed to the build up of byproducts which inhibit this
complex chain reaction and arrest it at low conversion.
It was reasoned that a similar process can be induced
by employing reducing agents which do not necessarily
require a radical chain reaction. The involvement of the
C-Cl rather then the weaker C-I bond in 30 limits the
arsenal of suitable reagents. However, samarium(II)
iodide, which was reported as an efficient reagent for ring
scission of cyclic â-chloro ethers,24 was found as an
excellent reagent for the conversion of the chloromethyl
sulfone 30 into the protected kainic acid 31. The tert-
butyl and BOC groups were removed by TFA and the
methyl protecting group by dilute sodium hydroxide to
give, after ion exchange resin chromatography, (()-R-
kainic acid (1).
mL) was added. The formed suspension was extracted with
hexane (3 × 150 mL), dried, and evaporated, and the residue
(dimethylacetal 8) was dissolved in a mixture of THF (70 mL),
water (10 mL), and HCO
reaction mixture was poured into saturated NaHCO
tracted with hexane (3 × 200 mL), dried (NaHCO and Na
SO ), and evaporated to afford aldehyde 9 (12 g, 94%) as
mixture of Z and E isomers (E/Z ratio ca. 3:1). IR (neat): 1629,
2
H (5 mL). After 3 h at 20 °C, the
3
, ex-
3
2
-
4
-
1
1
1
7
675 cm
.
H NMR (δ): 1.10 (t, J ) 7.4 Hz, E), 1.11 (t, J )
.4 Hz, Z), total 3H; 2.16 (d, J ) 1.2 Hz, E), 1.98 (d, J ) 1.3
Hz, Z), total 3H; 2.31 (q, J ) 7.4 Hz, E), 2.35 (q, J ) 7.4 Hz,
Z), total 2H; 3.11 (d, J ) 0.8 Hz, 2H); 5.88 (d, J ) 8 Hz, E);
5.95 (d, J ) 8 Hz, Z), total 1H; 9.97 (d, J ) 8 Hz, Z), 9.90 (d,
J ) 8 Hz, E), total 1H.
syn -ter t-Bu tyl 2-Isocya n o-3-(ter t-bu tyld im eth ylsiloxy)-
5
-m eth yl-6-(eth ylth io)h ex-4-en eoa te (12a ). To a solution
of phenanthroline (ca. 1 mg) and BuLi (22 mL of 1.6 M solution
in hexane, 34.6 mmol) in THF at -72 °C under vigorous
stirring was added dropwise tert-butyl isocyanoacetate (10)
On the grounds of the reported easy inversion of
configuration at C-2 of some â-kainic acid (all cis-kainic
acid) derivatives,3 and of the racemic nature of the
compounds used in the present work, it was decided to
convert compound 25 into (()-R-kainic acid (1). This was
accomplished by following the sequence of reactions
described in Scheme 4. It was noted that the diastereo-
(
4.88 g, 34.6 mmol) while the temperature was kept below -65
°C. The reaction mixture was stirred for an additional 5 min,
a small quantity of butyllithium (ca. 1 mL) was added to
preserve the deep rose color of Li-phenanthrolide, and 4-(eth-
ylthio)-3-methyl-2-butenal (9) (5.23 g, 36.3 mmol) was added
in one portion. The reaction mixture was stirred for 5 min at
-
72 °C and then quenched with acetic acid (7 mL). The
resulting suspension was poured into saturated aqueous
NaHCO
(100 mL), and hexane (150 mL) was added. The
organic layer was separated, dried (Na SO and NaHCO ), and
2 2
selectivity of ClSCH CO Me addition to 2,3-trans, 3,4-
3
trans isopropenyl derivative 38 is lower than that of
addition to 2,3-trans, 3,4-trans isopropenyl derivative 27
as it gives a 5:1 mixture of chloromethyl epimers 39. This
difference may originate from a better directive effect
2
4
3
evaporated. The residue was separated by MPLC to afford
syn hydroxy ester 11a (6.00 g, 21 mmol, 61%, E/Z ratio 3:1),
R
0.28 (EtOAc-hexane, 1:1). 1H NMR (δ) 1.23 (t, J ) 7.4 Hz,
f
E), 1.27 (t, J ) 7.4 Hz), total 3H; 1.53 (s, E), 1.52 (s, Z), total
exerted by the CO
,3-cis oriented isomer 27.
Treatment of chloroalkyl sulfone 40 with potassium
2
t-Bu group on the TsO group of the
9
2
3
H; 1.86 (s, E), 1.91 (s, Z) total 3H; 2.43 (q, J ) 7.4 Hz, E),
.52 (m, Z), total 2H; 3.13, 3.15 (2d, J ) 13.6 Hz, E) ,3.24,
.26 (2d, J ) 12.4 Hz, Z), total 2H; 4.16 (d, J ) 3.7 Hz, E),
2
methoxide resulted in substitution of the tosyloxy group
accompanied by inversion of configuration at C-2. The
resulting cyclic chloromethyl sulfone 41 is identical to
4.15 (d, J ) 3.5 Hz, Z) total 1H; 4.84 (m, E), 4.83 (m, Z), total
1H; 5.44 (d, J ) 8.6 Hz, E), 5.49 (d, J ) 9.6Hz, Z), total 1H;
and anti hydroxy ester 11b (3.05 g, 11 mmol, 31%, E/Z ratio
ca. 10.1), R
isomer) 1.22 (t, J ) 7.2 Hz, 3H); 1.48 (s, 9H); 1.86 (s, 3H); 2.42
q, J ) 7.2 Hz, 2H); 3.13, 3.12 (s, 2H); 4.34 (d, J )5.0 Hz, 1H);
.82 (dd, J )5 , J )9 Hz, 1H); 5.44 (d, J ) 9 Hz, 1H). The syn
f
0.20 (EtOAc-hexane, 1:1), 1H NMR (δ, major
compound 30 obtained as shown in Scheme 3 except for
being a mixture of two isomers at position 1′.13
(
4
In summary (()-R-kainic acid (1) was obtained by two
routes: (a) from the highly substituted alkenyl isocyanide
hydroxy ester 11a was dissolved in methylene chloride (10
mL), the solution was cooled to -72 °C, 2,6-lutidine (3.36 g,
31.4 mmol) and tert-butyldimethylsilyl triflate (5.8 g, 22 mmol)
were added consequently, and the reaction mixture was stirred
for 10 min at -72 °C. Temperature was raised to 20 °C in 20
min, hexane (15 mL) was added, and the resulting mixture
was purified by flash chromatography to afford syn isocyanide
12a (6.94 g, 50% from tert-butyl isocyanide 10) as a mixture
1
(
2
1a in 14% overall yield (series a in Schemes 1 and 3);
b) from isothiocyanate 22 in 20% overall yield (Schemes
and 4). In both routes a key heterocyclic intermediate
(
(
22) Masaki, Y.; Sakuma, K.; Kaji, K. Chemistry Lett. 1980, 1061.
23) K u¨ hle, E. The chemistry of sulfenic acid; Thieme Publishers:
Stuttgart, 1973.
24) Crombie, L.; Rainbow, L. J . Tetrahedron Lett. 1988, 29, 6517.
-
1 1
(
of E/Z isomers (E/Z ratio 3:1). IR (neat): 1745, 2149 cm . H

Stereoselective Synthesis of (()-R-Kainic Acid
J . Org. Chem., Vol. 61, No. 20, 1996 7121
NMR (δ) 0.07, 0.09 (2s, 6H); 0.89 (s, E), 0.88 (s, Z), total 9H;
tracted with EtOAc-hexane mixture (1:5, 2 × 100 mL). The
organic layer was dried and evaporated, and the residue was
separated by MPLC to afford pyrrolidine 14a (4.0 g, 9.1 mmol,
1
.24 (t, J ) 7.4 Hz, E), 1.29 (t, J ) 7.4 Hz), total 3H; 1.50 (s,
E), 1.49 (s, Z), total 9H; 1.82 (s, 3H); 2.44 (q, J ) 7.4 Hz, E),
-
1
1
2
.52 (q, J ) 7.4 Hz, Z), total 2H; 3.11 (s, 2H); 4.01 (d, J ) 4.3
79%). IR (neat): 1706, 1741 cm
. H NMR (two conformers)
Hz, E), 4.15 (d, J ) 4.5 Hz, Z) total 1H; 4.86 (dd, J ) 4.2, 9
Hz, E), 4.82 (m, Z), total 1H; 5.40 (d, J ) 9 Hz, E), 5.42 (d, J
(δ): 0.06, 0.11 (2s, major), 0.06, 0.10 (2s, minor), total 6H; 0.89
(s, major), 0.88 (s, minor), total 9H; 1.46 (s, major), 1.47 (s,
minor), total 9H; 1.50 (s, major), 1.49 (s, minor), total 9H; 1.74
(s, 3H); 3.06 (m, 1H); 3.28 (t, J ) 9.8 Hz, major), 3.22 (t, J )
10.4 Hz, minor), total 1H; 3.68 (dd, J ) 8.9, 10.7 Hz, major),
3.65 (t, J ) 8.2 Hz, minor), total 1H; 4.16 (d, J ) 7.6 Hz, major),
4.27 (m, minor), total 1H; 4.27 (m, 1H; 4.92 (s, major), 4.91 (s,
)
3
9Hz, Z), total 1H. Anal. Calcd for C20H37NO SiS: C, 60.15;
H, 9.27; N, 3.51; S, 8.02. Found: C, 59.89; H, 9.56; N, 3.25; S,
7
.67.
2
â-(ter t-Bu toxycar bon yl)-3â-(ter t-bu tyldim eth ylsiloxy)-
4
r-isop r op en yl-5-(eth ylth io)-4H-2,3-d ih yd r op yr r ole (13a )
fr om Isocya n id e 12a . Syn isocyanide 12a (6.25 g, 17.4
mmol), AIBN (0.43 g, 2.6 mmol), ethanethiol (0.27 g, 4.3 mmol),
and toluene (250 mL) were stirred for 5 h at 60 °C. The solvent
was evaporated, and the residue was purified by flash chro-
matography (EtOAc-hexane 1:5) to afford the dihydropyrrole
5
minor), total 2H. Anal. Calcd for C23H43NO Si: C, 62.59; H,
9.75; N, 3.17. Found: C, 62.30; H, 9.90; N, 2.84.
1,2â-Bis(ter t-b u t oxyca r b on yl)-3â-h yd r oxy-4r-isop r o-
p en ylp yr r olid in e (6). To pyrrolidine 14a (3.0 g, 6.8 mmol)
were added AcOH (120 mg, 7 mmol) and a solution of
tetrabutylammonium fluoride in THF (15 mL of 1 M solution).
The reaction mixture was kept 48 h at 20 °C and then poured
-
1
1
1
0
(
(
3a (4.79 g, 77%). IR (film): 1570, 1735 cm
.
H NMR (δ):
.05, 0.04 (2s, 6H), 0.86 (s, 9H), 1.32 (t, J ) 7.3 Hz, 3H), 1.47
s, 9H), 1.70 (s, 3H), 2.96, 3.11 (2dq, J ) 7.3, 13 Hz, 2H), 3.56
3
into saturated NaHCO (50 mL). The formed emulsion was
t, J ) 3 Hz, 1H), 4.56 (m, 2H), 4.90, 4.99 (2s, 2H). Anal. Calcd
extracted with EtOAc-hexane mixture (1:4, 2 × 50 mL) dried,
and evaporated, and the residue was purified by flash chro-
matography to afford the alcohol 6 (2.0 g, 90%). Mp 109-111
for C20
C, 60.14; H, 9.49; N, 3.63; S, 7.88.
-(ter t-Bu toxyca r bon yl)-3-(ter t-bu tyld im eth ylsiloxy)-
-isop r op en yl-5-(eth ylth io)-4H-2,3-d ih yd r op yr r oles (13a
3
H37NO SiS: C, 60.15; H, 9.27; N, 3.51; S, 8.02. Found:
-
1
1
2
°C. IR (neat): 1679, 1704, 1739, 3437 cm
.
H NMR (two
4
conformers) (δ): 1.41 (s, major), 1.39 (s, minor), total 9H; 1.44
(s, major), 1.45 (s, minor), total 9H; 1.72 (s, 3H); 3.04 (m, 2H);
3.27 (t, J ) 9.5 Hz, major), 3.15 (t, J ) 10.3 Hz, minor), total
1H; 3.72 (dd, J ) 10.6, 8.6 Hz, major), 3.67 (dd, J ) 10.3, 8.8
Hz, minor), total 1H; 4.21 (d, J ) 7.8 Hz, major), 4.28 (d, J )
7.7 Hz, minor), total 1H; 4.34 (t, J ) 8.2 Hz, major), 4.33 (t, J
) 8.2 Hz, minor), total 1H; 4.86 (m, 2H). Anal. Calcd for
a n d 13b), Sta r tin g fr om Isocya n oa ceta te 10. To a solution
of phenanthroline (∼1 g) and BuLi (1.6 M solution in hexane,
6
6 mL, 104 mmol) in THF (360 mL) at -72 °C under vigorous
stirring was added dropwise tert-butyl isocyanoacetate (10) (15
mL, 103 mmol), while the temperature was kept below -65
°
C. The reaction mixture was stirred for additional 5 min. A
small quantity of BuLi was added to preserve the deep rose
color of Li-phenanthroline, and 4-(ethylthio)-3-methyl-2-bute-
nal (9) (14.96 g, 103.2 mmol) was added dropwise to the
solution, while the temperature was kept below -68 °C. The
reaction mixture was stirred for additional 5 min at -72 °C
and quenched with AcOH (17 mL). The resulting suspension
17 5
C H29NO : C, 62.36; H, 8.93; N, 4.28. Found: C, 62.35; H,
8.88; N, 4.26.
4-(ter t-Bu tylth io)-3-m eth yl-2-bu ten a l (19). To a cold
(-40 °C) solution of 1,1-dimethoxy-3-methyl-4-bromo-2-butene
1
5
(7) (35.9 g, 172 mmol) in methanol (150 mL) was added a
solution of NaOH (6.9 g, 172 mmol) and tert-butyl mercaptan
(19.4 mL, 172 mmol) in methanol (150 mL). The temperature
was allowed to rise to room temperature, and the reaction
mixture was stirred for 1.5 h. Water (250 mL) was added,
and the resultant suspension was extracted with hexane (3 ×
was poured into saturated NaHCO
with hexane (3 × 360 mL). The hexane layer was dried (Na
SO and NaHCO ) and evaporated to give a mixture of the
four syn/anti-cis/trans hydroxy esters 11a , 11b. The crude
mixture of 11a and 11b was dissolved in CH Cl (48 mL). The
3
(260 mL) and extracted
2
-
4
3
2
2
2 4
250 mL). The combined hexane solution was dried (Na SO )
solution was cooled to -72 °C, 2,6-lutidine (19.2 mL, 155 mmol)
and tert-butyldimethylsilyl triflate (29.2 mL, 113 mmol) were
added, and the reaction mixture was stirred for 1 h. The
temperature was allowed to rise to 20 °C, hexane (100 mL)
was added, the resulting suspension was washed with 1 N HCl
and evaporated to give (E)- and (Z)-1,1-dimethoxy-3-methyl-
-1 1
4-(tert-butylthio)but-2-enes (E/Z, 3:1). IR (neat) 1673 cm . H
NMR E isomer (δ) 1.33 (s, 9H), 1.85 (d, J ) 1.12 Hz, 3H), 3.20
(s, 2H), 3.31 (s, 6H), 5.03 (d, J ) 6.33 Hz, 1H), 5.48 (dd, J )
6.30, 0.79 Hz, 1H); Z isomer: (δ) 1.31 (s, 9H), 1.88 (m, 3H),
3.25 (s, 2H), 3.33 (s, 6H), 5.08 (d, J ) 6.35, 1H), 5.33 (dd, J )
6.42, 0.73 Hz, 1H). This compound was dissolved in a mixture
(
140 mL), saturated NaHCO
Na SO ), and evaporated. Flash chromatography (hexane-
EtOAc, 15:1) of the residue afforded a mixture of 12a and 12b
29.9 g, 74.9 mmol, 78% yield from isocyanide 10). Isonitriles
2a , 12b were dissolved in toluene (1 L), AIBN (1.8 g, 10 mmol)
3 3
(140 mL), dried (NaHCO and
2
4
of THF (120 mL), H
h at room temperature, the reaction mixture was poured into
saturated NaHCO
(300 mL) and extracted with hexane (3 ×
250 mL). The combined hexane solution was dried (NaHCO
and Na SO ) and evaporated. Flash chromatography (hex-
2 2
O (12 mL), and HCO H (6 mL). After 4.5
(
1
3
and ethyl mercaptan (1.4 mL, 27 mmol) were added, and the
reaction mixture was refluxed until the reaction was completed
3
2
4
(
TLC). The solvent was evaporated, and flash chromatography
ane-EtOAc, 8.5:1.5) gave the title compound 19 (29.6 g, 95%
(
1
hexane-EtOAc, 10:1) of the residue afforded dihydropyrrole
yield) as a mixture of two isomers (E/Z, 3:1). IR (neat) 1677,
-
1
1
3a (10.2 g, 25.3 mmol) and dihydropyrrole 13b (11 g, 27.5
1630 cm
.
H NMR E isomer: (δ) 1.34 (s, 9H), 2.29 (d, J )
mmol). Total yield of the reaction was 51% from isocyanide
1
above. Dihydropyrole 13b: IR (film): 1586, 1734 cm
NMR (δ): 0.06, 0.08 (2s, 6H), 0.89 (s, 9H), 1.34 (t, J ) 7.2 Hz,
3
2
1.28 Hz, 3H), 3.31 (d, J ) 1.04 Hz, 2H), 6.07 (ddd, J ) 8.0,
2.4, 1.2 Hz, 1H), 9.99 (d, J ) 7.6 Hz, 1H); Z isomer: (δ) 1.37
(s, 9H), 2.11 (d, J ) 1.36 Hz, 3H), 3.64 (br s, 2H), 6.05 (br d,
1
0. Dihydropyrole 13a : IR, H NMR identical to that described
-
1
1
.
H
9 16
J ) 8 Hz, 1H,), 9.98 (d, J ) 8.0 Hz, 1H). Anal. Calcd for C H -
OS: C, 62.79; H, 9.30; S, 18.60. Found: C, 62.55; H, 9.59; S,
18.33.
H) 1.49 (s, 9H), 1.67 (s, 3H), 2.96, 3.11 (2dq, J ) 7.2,13 Hz,
H), 3.56 (d, J ) 3.7 Hz, 1H), 4.41 (d, J ) 3.6 Hz,1H), 4.48 (t,
J ) 3.6 Hz,1H), 4.90, 4.95 (2s, 2H). Anal. Calcd for C20
H
37
N
3
-
ter t-Bu tyl 2-Isocya n o-3-(ter t-bu tyld im eth ylsiloxy)-5-
m eth yl-6-(ter t-bu tylth io)h ex-4-en eoa te (21). To a solution
of phenanthroline in THF (259 mL) at -40 °C was added a
solution of n-BuLi (1.6 M in hexane, 50 mL). The temperature
was reduced to -72 °C, and tert-butyl isocyanoacetate (10)
(12.2 mL, 0.082 mol) was added dropwise at a rate that kept
the temperature below -65 °C. After the addition was
completed, more n-BuLi (∼2.5 mL) was added until the
solution obtained deep rose color. The reaction mixture was
cooled to -72 °C, and thioaldehyde 19 (14.4 g, 0.082 mol) was
added in one portion. After stirring for 7 min, the reaction
mixture was quenched with acetic acid (14 mL), poured into
SiS: C, 60.14; H, 9.49; N, 3.63. Found: C, 60.24; H, 9.02; N,
.74.
,2â-Bis(ter t-bu toxyca r bon yl)-3â-(ter t-bu tyld im eth yl-
3
1
siloxy)-4r-isop r op en yl-p yr r olid in e (14a ). To a solution
of dihydropyrrole 13a (4.6 g, 11.5 mmol) and bromocresol green
(ca. 1 mg) in methanol (15 mL) and AcOH (5 mL) under
stirring was added NaBH CN. The reaction mixture was
3
stirred at room temperature while an additional amount (5
mL) of AcOH was added to preserve the yellow color of
solution. Di-tert-butyl dicarbonate (5.0 g, 23 mmol) and DMAP
(
1
10 mg) were added, and the reaction mixture was stirred for
h, neutralized with triethylamine (up to green color of
solution), evaporated, poured into water (100 mL), and ex-
saturated NaHCO
300 mL). The organic layer was dried (Na
3
(210 mL), and extracted with hexane (2 ×
2
SO and NaHCO )
4
3

7
122 J . Org. Chem., Vol. 61, No. 20, 1996
Bachi et al.
1
and evaporated to give alcohol 20 as a mixture of four isomers.
To the cold (-60 °C) solution of the alcohol 20 in CH Cl (40
the ester 14a (5.69 g, 13 mmol, 84% yield). IR; H NMR are
described above.
2
2
mL) were added in rapid succession 2,6-lutidine (16 mL, 0.123
mol) and TBDMSOTf (24.3 mL, 0.09 mol). The reaction
mixture was stirred at the same temperature for 1 h. The
temperature was allowed to rise to 0 °C, and hexane (250 mL)
was added. The emulsion was washed with 1 N HCl (125 mL),
saturated NaHCO (125 mL), dried (NaHCO and Na SO ),
3 3 2 4
and evaporated. The residue was purified by flash chroma-
tography (hexane-EtOAc, 10:1) to afford the silylated alcohol
1,2â-Bis(ter t-b u t oxyca r b on yl)-3r-h yd r oxy-4â-isop r o-
p en ylp yr r olid in e (25). To a cold (-40 °C) solution of
2
thiolactam 23 (4.73 g, 12.7 mmol) and (BOC) O (3.3 mL, 15.2
mmol) in THF (40 mL) was added a solution of DMAP (0.236
g, 1.93 mmol) in THF (4 mL). The reaction mixture was kept
at -40 °C. The reaction was monitored by TLC (hexane-
EtOAc, 8.5:1.5) and color (reddish color is indicative of double
bond migration to exocyclic position). In case reddish color
appears the reaction should be immediately quenched. After
consumption of starting material, hexane (800 mL) was added
2
2
0
9
4
1 (23.83 g, 85% yield) as a mixture of four isomers. IR (neat)
-
1
1
149 1747 cm
.
H NMR (δ) 0.05, 0.06, 0.08, 0.09 (s, 6H),
.88, 0.89 (s, 9H), 1.33, 1.35, 1.37 (s, 9H), 1.49, 1.50, 151 (s,
H), 1.82, 1,83, 1.84, 1.88 (s, 3H), 3.11-3.26 (m, 2H), 3.99,
.14, 4.20, 4.23 (four d, J ) 4.20 Hz, J ) 4.91 Hz, J ) 3.29
and the mixture was washed with saturated NaH
80 mL). The hexane layer was separated, dried (Na
2
PO
4
(2 ×
2
SO
4
), and
evaporated under reduced pressure. The residue which con-
sisted of crude thiolactam 24b was dissolved in toluene (300
mL). n-Bu SnH (7.5 mL, 27.9 mmol) and AIBN (0.32 g, 1.95
3
mmol) were added, and the reaction mixture was immersed
Hz, J ) 4.27 Hz, 1H), 4.78-4.85 (m, 1H), 5.50-5.55 (m, 1H).
Anal. Calcd for C22 SSi: C, 61.82; H, 9.60; N, 3.28; S,
.49. Found: C, 61.77; H, 9.82; N, 3.20; S, 7.15.
H
41NO
3
7
in a hot oil bath (∼200 °C). After the reaction was completed
ter t-Bu tyl 2-Isoth iocya n o-3-(ter t-bu tyld im eth ylsiloxy)-
-m eth yl-6-(ter t-bu tylth io)h ex-4-en eoa te (22). A mixture
(∼2 h), the toluene was evaporated. The residue was dissolved
5
in pentane (40 mL) and extracted with CH
The combined CH CN layers were evaporated and flash
chromatography of the residue gave the ester 14b (3.48 g,
3
CN (10 × 250 mL).
of isocyanide 21 (0.66 g, 1.50 mmol), tert-butyl mercaptan (0.28
mL, 1.98 mmol), and ACN (0.066 g, 0.27 mmol) in toluene (18
mL) was refluxed for 10 min. The solvent was evaporated,
and flash chromatography (hexane-EtOAc, 12:1) of the resi-
due gave isothiocyanate 22 (0.55 g, 80% yield) as a mixture of
3
-
1
containing ∼10% (BOC)
2
O). IR (neat) 1739, 1706, 1648 cm .
1
H NMR (δ) 0.038, 0.050 (2s, 3H), 0.09, 0.10 (2s, 3H), 0.86,
0.877, 0.882, 0.89 (4s, 9H), 1.74 (br s, 3H), 2.69-2.79 (m, 1H),
-
1
1
four isomers. IR (neat) 2060, 1741 cm
.
H NMR (δ) 0.04,
3
8
1
.29-3.37 (m, 1H), 3.65, 3.78 (2 dd, J ) 8.14, 13.1 Hz, J )
.10, 11.02 Hz, 1H), 3.92, 4.00 (2 d, J ) 4.08 Hz, J ) 4.48 Hz,
H), 4.25-4.31 (m, 1H), 4.90 (br s, 2H). A mixture of
0
9
3
2
4
.05, 0.06, 0.09 (s, 6H), 0.88, 0.89, 0.90 (s, 9H), 1.33-1.36 (m,
H), 1.50, 1.51, 1.52 (s, 9H), 1.82, 1.83 1.87 (s, 3H). 3.12-
.27 (m, 2H,), 3.83, 4.02, 4.12, 4.14 (four d, J ) 3.27 Hz, J )
.52 Hz, J ) 4.62 Hz, J ) 4.60 Hz, 1H), 4.75-5.00 (m, 1H),
compound 14b (3.10 g, 7.04 mmol), AcOH (0.4 mL, 7.15 mmol),
and TBAF (1 N solution in THF, 15 mL) was stirred at room
temperature overnight. The solution was poured into water
3 2
.80-5.52 (m, 1H). Anal. Calcd for C22H41NO S Si: C, 57.52;
H, 8.93; N, 3.05; S, 13.94. Found: C, 57.80; H, 9.20; N, 2.98;
S, 13.54.
(
30 mL) and extracted with ether (2 × 40 mL). The organic
layer was dried (Na SO ), the solvent was evaporated, and
2
4
2
-(ter t-Bu toxyca r bon yl)-3-(ter t-bu tyld im eth ylsiloxy)-
-isop r op en yl-5-th ioxop yr r olid in es 5 a n d 23. A mixture
of isocyanides 21 (12.34 g, 28.9 mmol), tert-butyl mercaptan
flash chromatography (hexane-EtOAc, 6:1) of the residue gave
the alcohol 25 (1.62 g, 40% yield from 23). IR (Nujol) 3354,
4
-1
1
1
1
744, 1663 cm
. H NMR (δ) 1.36, 1.38, 1.41, 1.42 (4s, 18H),
(
(
3.7 mL, 32.9 mmol), and ACN (1.13 g, 4.62 mmol) in toluene
800 mL) was refluxed for about 10 min to give the isothiocy-
anate 22 (see above). n-Bu SnH (8.9 mL, 32.9 mmol) was
3
added, and the reaction mixture was boiled for 15 min. The
solvent was evaporated, and flash chromatography (hexane-
EtOAc, 4:1) of the residue afforded the two isomers of the
thiolactam 5 and 23 (9.86 g, 26.6 mmol, 92%; 5/23, 1.4:1). More
.69 (br s, 3H), 2.1 (br, OH), 2.59-2.70 (m, 1H), 3.17, 3.20 (2
app t, J ) 11.02 Hz, J ) 11.20 Hz, 1H), 3.63, 3.78 (2 dd, J )
8
6
(
.26, 10.7 Hz, J ) 7.96, 10.96 Hz, 1H), 3.87, 3.91 (2 d, J )
.40 Hz and J ) 6.36 Hz, 1H), 4.01-4.10 (m, 1H), 4.84, 4.85
5
s and t, J ) 1.26 Hz, 2H). Anal. Calcd for C17H29NO : C,
6
2.36; H, 8.93; N, 4.28. Found: C, 62.54; H, 8.98; N, 4.34.
,2â-Bis(ter t-bu toxycar bon yl)-3â-(p-tolu en esu lfon yloxy)-
r-isop r op en ylp yr r olid in e (27). To a solution of alcohol 6
1
polar isomer 5: mp 91.5 °C (hexane). IR (CH
2
Cl
2
) 3398 , 1739,
4
(
-
1
1
1
(
4
4
648, 1486 cm .
s, 9H), 1.51 (s, 9H), 1.84 (s, 3H), 3.52 (d, J ) 3.04 Hz, 1H),
.39 (d, J ) 5.36 Hz, 1H), 4.61 (dd, J ) 5.24, 3.52 Hz, 1H),
H NMR (δ) 0.11 (s, 3H), 0.13 (s, 3H), 0.88
2.0 g, 6.1 mmol) and phenanthroline (ca. 1 mg) in THF (20
mL) at -72 °C was added BuLi (4 mL of 1.6 M solution, 6.1
mmol) until deep rose color of phenanthroline was obtained.
A solution of p-toluenesulfonyl chloride (2.34 g, 12.3 mmol) in
THF (2 mL) was added, the reaction mixture was stirred 15
min at -72 °C, and the temperature was slowly raised to 20
.94 (s, 1H), 5.06 (s, 1H), 7.75 (br s, 1 H). Anal. Calcd for
C
18
H
33NO
3
SSi: C, 58.22; H, 8.89; N, 3.77; S, 8.62. Found: C,
5
°
(
3
1
1
8.51; H, 9.15; N, 3.71; S, 8.34. Less polar isomer 23: mp 98
-
1
1
C dec. IR (CH
2
Cl
2
) 3395, 1739.5, 1650, 1495 cm
.
H NMR
°
C (30 min). The reaction mixture was evaporated and the
δ) 0.11 (s, 3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.50 (s, 9H), 1.75 (s,
residue was dissolved in EtOAc-hexane (1:5 mixture, 30 mL),
washed with water, dried, and evaporated. The residue was
separated by flash chromatography to afford the tosylate 27
H), 3.41 (d, J ) 3.8 Hz, 1H), 4.17 (dd, J ) 3.24, 0.64, Hz,
H), 4.60 (dd, J ) 3.76, 3.32 Hz, 1H), 4.98 (s, 1H), 5.05 (s,
H), 7.75 (br s, 1 H). Anal. Calcd for C18
H
33NO
3
SSi: C, 58.22;
-1
1
(
2.85 g, 97%). IR (neat): 1702, 1738 cm
conformers) (δ): 1.36 (s, major), 1.48 (s, minor), total 3H, 1.42
s, major), 1.43 (s, minor), total 9H, 1.52 (s, major), 1.47 (s,
.
H NMR (two
H, 8.89; N, 3.77; S, 8.62. Found: C, 58.14; H, 8.96; N, 3.85; S,
.56.
,2â-Bis(ter t-bu toxyca r bon yl)-3â-(ter t-bu tyld im eth yl-
siloxy)-4r-isop r op en ylp yr r olid in e (14a ). To a cold (-40
C) solution of thiolactam 5 (5.74 g, 15.5 mmol) and (BOC)
4 mL, 18.7 mmol) in THF (45 mL) was added a solution of
8
(
1
minor), total 9H, 2.46 (s, 3H), 3.09 (m, 1H), 3.22 (dd, J ) 8.5,
10.7 Hz, major), 3.22 (m, minor), total 1H, 3.69 (dd, J ) 8.8,
10.7 Hz, major), 3.69 (m, minor), total 1H, 4.49 (d, J ) 7.6 Hz,
1H), 4.43 (d, J ) 7.5 Hz, minor), total 1H, 4.66, 4.68 (2s, major),
4.73 (m, minor), total 2H, 4.84 (t, J ) 8 Hz, major), 4.87 (m,
minor), total 1H, 7.33 (d, J ) 8.2 Hz, 2H); 7.77 (d, J ) 8.2 Hz,
2H). Anal. Calcd for C24H35NO S: C, 59.88; H, 7.28; N, 2.91;
7
S, 6.65. Found: C, 59.60; H, 7.52; N, 2.78; S, 6.54.
1,2â-Bis(ter t-bu toxycar bon yl)-3â-(p-tolu en esu lfon yloxy)-
4r-[2′-ch lor o-1′-[[(m eth oxyca r bon yl)m eth yl]th io]-1′-m e-
°
(
2
O
DMAP (0.307 g, 2.5 mmol) in THF (5 mL). The reaction
mixture was kept at -40 °C for 10 min (the reaction was
monitored by TLC (hexane/EtOAc, 9.5:2) and color (if the
reaction starts turning red, it must be stopped) and then was
dissolved in hexane (800 mL) and washed with saturated
NaH
Na SO
due (thiolactam 24a ) was dissolved in toluene (375 mL). n-Bu
2
PO
4
(2 × 80 mL). The hexane layer was separated, dried
(
2
4
), and evaporated under reduced pressure. The resi-
t h ylet h yl]p yr r olid in e (28). To a solution of (SCH
Me)
mmol), and pyridine (0.87 g, 11 mmol) in dry CH
2
CO
(0.31 g, 1.5 mmol), methyl mercaptoacetate (1.06 g, 10
Cl (8 mL)
2
-
3
-
2
SnH (9.2 mL, 34.2 mmol) and AIBN (0.394 g, 2.4 mmol) were
added, and the reaction mixture was immersed in a hot oil
bath (∼200 °C) for 2 h, and then the toluene was evaporated.
The residue was dissolved in pentane (40 mL) and extracted
2
2
at -70 °C was added sulfuryl chloride (1.35 g, 10 mmol). The
reaction mixture was warmed to 0 °C and kept 10 min at 0
°C. The resulting solution of crude ClSCH
dropwise to precooled (-70 °C) solution of tosylate 27 (4.60 g,
9.56 mmol) in CH Cl (20 mL). The reaction mixture was
2 2
CO Me was added
with CH
3
CN (10 × 250 mL). The combined CH
3
CN layers
were evaporated and flash chromatography of the residue gave
2
2

Stereoselective Synthesis of (()-R-Kainic Acid
J . Org. Chem., Vol. 61, No. 20, 1996 7123
stirred for 10 min at -70 °C, warmed to 0 °C, neutralized to
pH 6 with several drops of pyridine, and evaporated. The
residue was triturated with EtOAc-hexane (1:9, 5 mL), and
the precipitate crude crystals were collected and extracted with
EtOAc-hexane (1:1). Pyridine hydrochloride was filtered off,
and the filtrate was evaporated to afford the crystalline
chloroalkyl sulfide 28 (4.81 g, 7.7 mmol, 81%), mp 119-120
and aqueous NaOH (1 M, 2mL) was added. After 2 h the
reaction mixture was neutralized with AcOH, washed with
ether (5 mL), and chromatographed on an anion-exchange
column (Dowex 1 × 8, charged with acetate-ion, eluent water
f 5% aqueous AcOH) to afford racemic kainic acid (1) as
-1
monohydrate (142 mg, 78%). IR (KBr): 1617, 1720, 3450 cm
.
1
H NMR (D O, δ): 1.75 (s, 3H); 2.38 (dd, J ) 16.8, 8.3 Hz,
2
-
1
1
°
C. IR (neat): 1705, 1737 cm
δ): 1.24 (s, major), 1.35 (s, minor), total 3H; 1.42 (m, 18H);
.47 (s, 3H); 3.16-3.31 (m, 4H); 3.50-3.78 (m, 6H); 4.57 (d, J
7.7 Hz, major), 4.46 (d, J ) 7.7, minor), total 1H; 5.36 (dd,
J ) 7.8, 9 Hz, major), 5.35 (m, minor), total 1H; 7.37 (d, J )
.1 Hz, 2H); 7.86 (d, J ) 8.3 Hz, 2H). Anal. Calcd for
40ClNO : C, 52.36; H, 6.41; N, 2.24; S, 10.25. Found:
C, 52.13; H, 6.69; N, 2.02; S, 9.85.
,2â-Bis(ter t-bu toxycar bon yl)-3â-(p-tolu en esu lfon yloxy)-
.
H NMR (two conformers)
1H); 2.47 (dd, J ) 6.3, 16.8 Hz, 1H); 3.05 (m, 2H); 3.42 (t, J )
11.6 Hz, 1H); 3.62 (dd, J ) 7.2, 11.9 Hz, 1H); 4.09 (d, J ) 3.3
Hz, 1H); 4.75 (s, 1H); 5.04 (s, 1H), all identical to authentic
(
2
)
sample from Sigma. Anal. Calcd for C10
H
15NO
4
2
‚H O: C,
51.95; H, 7.36; N, 6.06. Found: C, 51.73; H, 7.33; N, 5.73.
Red u ction of 1-(Ch lor om eth yl)-1-m eth yl-2,2-d ioxo-3-
(m e t h o x y c a r b o n y l)-4â,5-b is (t e r t -b u t o x y c a r b o n y l)-
8
C
27
H
9 2
S
h exa h yd r oth ien o[3r,4r-c]p yr r olid in e (30)w ith n -Bu Sn H.
3
To the solution of chloroalkyl sulfone 30 (425 mg, 0.89 mmol)
and ACN (86 mg, 0.35 mmol) in toluene (50 mL) under reflux
1
4
r-[2′-ch lor o-1′-[[(m eth oxyca r bon yl)m eth yl]su lfon yl]-1′-
m eth yleth yl]p yr r olid in e (29). To a solution of chloroalkyl
sulfide 28 (2.14 g, 3.45 mmol) in methylene chloride (5 mL) at
3
was added by syringe pump a solution of n-Bu SnH (0.52 g,
1.77 mmol). The addition was complete within 2 h, the
reaction mixture was refluxed for an additional 30 min and
evaporated. The residue was dissolved in 50 mL of MeCN and
extracted with 20 mL of pentane, and the pentane solution
was extracted with 30 mL of MeCN. The combined MeCN
solutions were evaporated, the residue was separated by flash
chromatography to afford kainate 31 contaminated with 30%
-
20 °C was added MCPBA (2.23 g of 80% reagent, 3 equiv),
and the reaction mixture was slowly warmed to 20 °C and
stirred 30 min at 60 °C. The resulting suspension was poured
into EtOAc-hexane (1:1 mixture, 50 mL), washed with
3 2 4
saturated NaHCO solution, dried (Na SO ), and evaporated.
The residue was purified by flash chromatography to afford
the chloroalkyl sulfone 29 (2.1 g, 93%). IR (neat): 1702, 1743
3
of n-Bu SnCl (64 mg, ca. 12% yield) and recovered starting
material (242 mg, contaminated with 10% of n-Bu SnCl, ca.
3
50% yield).
-
1
1
cm
major), 1.43 (s, minor), total 9H; 1.45 (s, 3H), 2.49 (s, major),
.48 (s, minor), total 3H; 3.58 (m, 2H); 3.78-4.31 (m, 8H), 4.51
d, J ) 7.7 Hz, major), 4.35 (d, J ) 7.8 Hz, minor), total 1H ;
.
H NMR (two conformers) (δ),1.39 (s, 9H); 1.44 (s,
2
(
1,2â-Bis(ter t-b u t oxyca r b on yl)-3r-(p -t olu en esu lfon yl-
oxy)-4â-isop r op en yl p yr r olid in e (38). To a solution of
alcohol 25 (2.5 g, 7.7 mmol) and phenanthroline (ca. 1 mg) in
THF (20 mL) at -72 °C was added BuLi (4.8 mL of 1.6 M
solution, 7.7 mmol) until deep rose color of phenanthroline was
reached. Solution of p-toluenesulfonyl chloride (2.9 g, 15
mmol) in THF (2 mL) was added, the reaction mixture was
stirred for 15 min at -72 °C, and the temperature was slowly
(30 min) raised to 20 °C. The reaction mixture was evapo-
rated, and the residue was dissolved in EtOAc-hexane (1:5
mixture, 100 mL) washed with water, dried, and evaporated.
The residue was separated by MPLC to afford the tosylate 38
5
2
2
.22 (m, 1H), 7.40 (d, J ) 8.3 Hz, 2H), 7.88 (d, J ) 8.3 Hz,
H). Anal. Calcd for C27 : C, 49.81; H, 6.09; N,
.13; S, 9.75. Found: C, 49.84; H, 6.33; N, 2.01; S, 9.32.
-(Ch lor om et h yl)-1-m et h yl-2,2-d ioxo-3-(m et h oxyca r -
bon yl)-4â,5-bis(ter t-bu toxyca r bon yl)-h exa h yd r oth ien o-
3r,4r-c]p yr r olid in e (30). To a solution of chloroalkyl
H
40ClNO11S
2
1
[
sulfone 29 (1.48 g, 2.28 mmol), methanol (3 mL), and methyl
formate (1.5 mL) in THF (60 mL) was added potassium
methylate (350 mg, 5 mmol). The reaction mixture was stirred
at 20 °C for 3 h, neutralized with AcOH, and evaporated. The
residue was dissolved in EtOAc-hexane (3:7 mixture, 50 mL),
washed with water, dried, and evaporated. The residue was
purified by flash chromatography to afford the title cyclic
(3.52 g, 7.3 mmol, 95%). IR (neat): 1706, 1745 cm-
1
. H NMR
1
(two conformers) (δ): 1.41 (s, major), 1.43 (s, minor), total 9H;
1.46 (s, 9H); 1.59 (s, major), 1.67 (s, minor), total 3H; 2.46 (s,
3H); 2.83 (m, major), 2.95 (m, minor), total 1H; 3.46 (dd, J )
7.0, 11.2 Hz, major), 3.22 (m, minor), total 1H; 3.69 (dd, J )
8.2, 11.2 Hz, major), 3.69 (m, minor), total 2H; 4.23 (d, J )
2.7 Hz, 1H); 4.78 (d, J ) 4.3 Hz, major), 4.78 (d, J ) 4.6 Hz,
minor), total 2H; 5.05 (dd, J ) 2.9, 4.6 Hz, 1H); 7.35 (d, J )
-
1
1
sulfone 30 (779 mg, 72%). IR (neat): 1702, 1748 cm
.
H
NMR (δ): 1.43, 1.48, 1.49 (3s, 18H), 1.60 (s, 3H), 3.06 (m, 1H),
3
4
6
6
.43 (t, J ) 8.7 Hz, 1H), 3.68 (m, 2H), 3.80-4.01 (m, 6H), 4.07,
.19 (2s, 1H). Anal. Calcd for C20 32ClNO S: C, 49.84; H,
.69; N, 2.90; S, 6.65. Found: C, 50.14; H, 6.53; N, 3.14; S,
.33.
H
8
7
8.0 Hz, 2H); 7.81 (m, 2H). Anal. Calcd for C24H35NO S: C,
1
,2â-Bis(ter t-bu toxyca r bon yl)-3r-[(m eth oxyca r bon yl)-
m eth yl]-4r-isop r op en ylp yr r olid in e (31). Cyclic sulfone 30
0.74 g, 1.5 mmol) was mixed with a solution of SmI (50 mL
59.88; H, 7.28; N, 2.91; S, 6.65. Found: C, 59.58; H, 7.50; N,
2.75; S, 7.01.
(
2
1,2â-Bis(ter t-b u t oxyca r b on yl)-3r-(p -t olu en esu lfon yl-
oxy)-4â-[2′-ch lor o-1′-[[(m eth oxyca r bon yl)m eth yl]th io]-1′-
of 0.1 M in THF, 5 mmol) and methanol (2 mL). The reaction
mixture was left for 20 min at 20 °C and quenched with
m eth yleth yl]p yr r olid in e (39). To a solution of (SCH
2 2
CO -
aqueous NaHCO
3
(10 mL). The resulting suspension was
Me) (0.31 g, 1.5 mmol), methyl mercaptoacetate (1.06 g, 10
2
extracted with EtOAc-hexane (1:1 mixture, 2 × 100 mL) and
mmol), and pyridine (0.87 g, 11 mmol) in dry methylene
chloride (8 mL) at -70 °C was added sulfuryl chloride (1.35 g,
10 mmol). The reaction mixture was warmed to 0 °C and kept
EtOAc (2 × 50 mL). The combined organic extracts were dried
2 4
(Na SO ) and evaporated, and the residue was purified by flash
chromatography to afford the title pyrrolidine 31 (413 mg,
2 2
10 min at 0 °C. The resulting solution of crude ClSCH CO -
2%). IR (neat): 1705, 1742 cm-1
δ): 1.43 (s, major), 1.47 (s, minor), total 9H, 1.49 (s, major),
.48 (s, minor), total 9H; 1.69 (s, 3H); 2.26 (dd, J ) 8.7, 16.5
.
1
H NMR (two conformers)
7
Me (7 mL, 1.02 equiv) was added dropwise to a precooled (-70
°C) solution of tosylate 38 (3.3 g, 6.9 mmol) in methylene
chloride (20 mL). The reaction mixture was stirred 10 min at
-70 °C, warmed to 0 °C, neutralized to pH 6 with pyridine,
and evaporated. The residue was dissolved with EtOAc-
hexane (1:5 mixture, 50 mL), washed with saturated aqueous
(
1
Hz, major), 2.33 (dd J ) 5.9, 16.5 Hz, major), 2.30 (m, minor),
total 2H; 2.80 (m, 1H); 2.97 (m, 1H); 3.49 (dd, J ) 8.2, 10.8
Hz, major), 3.42 (dd, J ) 7.9, 10.7 Hz, minor), total 1H; 3.67
(
dd, J ) 7.3, 10.8 Hz, major), 3.61 (dd, J ) 7.2, 10.7 Hz, minor),
NaH
2
PO
4
(2 × 10 mL), dried, and evaporated. The residue
total 1H; 3.70 (s, major), 3.68 (s, minor), total 3H; 3.93 (d, J )
was triturated with 10% EtOAc-hexane mixture (5 mL), and
the formed crystals of chloroalkyl sulfide 39 (1.50 g, 2.4 mmol)
were filtered. The filtrate was evaporated, and the residue
was separated by MPLC to afford more of the title chloroalkyl
sulfide 39 (0.87 g, 1.4 mmol) and starting material 38 (1.24 g,
2.6 mmol). Yield 2.37 g (56%, the product consists of two
diastereomers with 5:1 ratio), and 1.24 g (37%) of starting
3
1
8
.5 Hz, major), 4.01 (d, J ) 3.7 Hz, minor), total 1H; 4.69 (s,
H), 4.91 (s, 1H). Anal. Calcd for C20 : C, 62.66; H,
.62; N, 3.66. Found: C, 62.87; H, 8.90; N, 3.53.
â-Ca r boxy-4r-isop r op en yl-3r-p yr r olid in ea cetic Acid ,
H
33NO
6
2
(
()-Ka in ic Acid (1). To a solution of pyrrolidine 31 (300
mg, 0.79 mmol) in methylene chloride (2 mL) was added
trifluoroacetic acid (2 mL). The reaction mixture was left for
-1
1
material was recovered. IR (neat): 1707, 1742 cm
. H NMR,
2
h at 20 °C, toluene (10 mL) was added, the mixture was
Major product (two conformers) (δ): 1.30 (s, major), 1.29 (s,
minor), total 3H; 1.39-1.53 (m, 18H); 2.47 (s, 3H); 3.16-3.40
evaporated, the residue was dissolved in methanol (0.5 mL),

7
124 J . Org. Chem., Vol. 61, No. 20, 1996
Bachi et al.
(
m, 4H); 3.48-3.92 (m, 6H); 4.40 (s, major), 4.38 (s, minor),
cm-1. 1H NMR (δ, two diastereomers, two conformers): 1.40-
total 1H; 5.44 (d, J ) 3.7 Hz, major), 5.49 (d, J ) 3.7 Hz,
1.54 (m, 21H, 2 × t-Bu, CH
3 3
); 2.47 (s, 3H, ArCH );3.00-3.50
minor), total 1H; 7.38 (d, J ) 8.4 Hz, 2H); 7.92 (d, J ) 8.1 Hz,
(m, 2H); 3.80-4.30 (m, 6H); 5.45-5.60 (m, 1H); 7.38 (m, 2H);
7.90 (m, 2H). Anal. Calcd for C27 : C, 49.81; H,
1
2
H). H NMR of minor product shows different peaks at 4.30
H40ClNO11S
2
(
5
s, major), 4.28 (s, minor), total; 5.28 (d, J ) 3.7 Hz, major),
6.09; N, 2.13; S, 9.75; Cl, 5.41. Found: C, 49.52; H, 6.31; N,
1.97; S, 9.31; Cl, 5.79.
.31 (m, minor), total 1H. Anal. Calcd for C27 Cl:
9 2
H40NO S
C, 52.36; H, 6.41; N, 2.24; S, 10.25; Cl, 5.68. Found: C, 52.35;
H, 6.60; N, 2.21; S, 10.22; Cl, 6.00.
1-(Ch lor om et h yl)-1-m et h yl-2,2-d ioxo-3-(m et h oxyca r -
bon yl)-4â,5-Bis(ter t-bu toxyca r bon yl)-h exa h yd r oth ien o-
[3a ,4a -c]p yr r olid in e (41). To a solution of chloroalkyl
sulfone 40 (1.32 g, 2.0 mmol) in THF (250 mL) at -70 °C was
added potassium methylate (1.15 g, 10 mmol). The reaction
mixture was stirred 5 min at -70 °C, 2 h at 20 °C, neutralized
with AcOH, and evaporated. The residue was purified by flash
chromatography to afford title cyclic sulfone 41 (730 mg, 75%).
Ba ck Con ver sion of 1,2â-Bis(ter t-bu toxyca r bon yl)-3r-
p-tolu en esu lfon yloxy)-4â-[2′-ch lor o-1′-[[(m eth oxyca r bo-
(
n yl)m eth yl]th io]-1′-m eth yleth yl]pyr r olidin e (39) in to 1,2â-
Bis(ter t-bu t oxyca r bon yl)-3r-(p-t olu en esu lfon yloxy)-4â-
isop r op en ylp yr r olid in e (38). To a solution of chloroalkyl
sulfide 39 (44 mg, 0.07 mmol) in THF (1 mL) at -40 °C was
added a solution of MeOK in THF (0.1 M, 0.5 mL, 0.05 mmol).
The reaction mixture was warmed to room temperature and
evaporated, and the residue was purified by flash chromatog-
raphy to afford tosylate 38 (12 mg, 50% yield based on MeOK).
The product was TLC identical to a sample of tosylate 38.
-
1
1
IR (neat): 1702, 1748 cm
. H NMR (δ): 1.43, 1.48, 1.49 (3s,
18H), 1.60 (s, 3H), 3.06 (m, 1H), 3.43 (t, J ) 8.7 Hz, 1H), 3.68
(m, 2H), 3.80-4.01 (m, 6H), 4.07, 4.19 (2s, 1H). Calcd for
C H ClNO S: C, 49.84; H, 6.69; N, 2.90; Cl, 7.35. Found:
2
0
32
8
C, 50.14; H, 6.93; N, 2.73; Cl, 7.63.
1
,2â-Bis(ter t-b u t oxyca r b on yl)-3r-(p -t olu en esu lfon yl-
oxy)-4â-[2′-ch lor o-1′-[[(m eth oxycar bon yl)m eth yl]sylfon yl]-
′-m eth yleth yl]p yr r olid in e (40). To the solution of chloro-
Su p p or tin g In for m a tion Ava ila ble: A copy of the 1
H
1
NMR spectrum of compound 9, 3D structural formula, ORTEP
drawing, and details of X-ray data aquisition for 1,2â-bis(tert-
butoxycarbonyl)-3â-hydroxy-4R-isopropenylpyrrolidine (6) (4
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
alkyl sulfide 39 (1.4 g, 2.3 mmol) in methylene chloride (5 mL)
at -20 °C was added MCPBA (1.46 g of 80% reagent, 3 equiv),
and the reaction mixture was slowly warmed to 20 °C and
stirred 20 min at 50 °C. The resulting suspension was poured
into 50 mL of 20% EtOAc-hexane mixture, washed with
saturated NaHCO
3 2 4
solution, dried (Na SO ), and evaporated.
The residue was purified by flash chromatography to afford
the chloroalkyl sulfone 40 (1.38 g, 93%). IR (neat): 1707, 1748
J O9607875