Synthesis of (-)-α-Kainic Acid via TMSCl-Promoted Pd-Catalyzed Zinc-ene Cyclization of an Allyl Acetate

Article abstract of DOI:10.1021/jo201341q

A highly practical synthesis of enantiopure (-)-α-kainic acid is accomplished in 37% overall yield, using 13 linear steps and a minimum of chromatographic separations via an unprecedentedTMSClpromoted palladium-catalyzed zinc-ene cyclization of an allyl acetate. (Figure presented)

Full text of DOI:10.1021/jo201341q

ARTICLE
pubs.acs.org/joc
Synthesis of (À)-α-Kainic Acid via TMSCl-Promoted Pd-Catalyzed
Zinc-ene Cyclization of an Allyl Acetate†
Guoqing Wei,*,‡ Justin M. Chalker,§ and Theodore Cohen*,‡
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
§Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S Supporting Information
b
ABSTRACT: A highly practical synthesis of enantiopure (À)-α-kainic
acid is accomplished in 37% overall yield, using 13 linear steps and a
minimum of chromatographic separations via an unprecedented TMSCl-
promoted palladium-catalyzed zinc-ene cyclization of an allyl acetate.
’ INTRODUCTION
We now report an equally expeditious synthesis, but this time
of enantiomerically pure (À)-α-kainic acid (3) by a similar
palladium-catalyzed zinc-ene cyclization of allylic acetate 1b.
The latter was generated in one step from the key doubly
protected (S)-2-vinylglycinol 8a derived from natural L-methio-
nine ($0.43/g from Sigma-Aldrich) by a process that does not
proceed through an α-amino aldehyde and thus does not involve
any loss in enantiomeric purity. It turns out that the palladium-
catalyzed zinc-ene cyclization of allylic acetate 1b occurs in as
remarkably high yield and diastereoselectivity as that of
the corresponding allyl chloride 1a but only in the presence of
trimethylsilyl chloride, a surprising discovery that may have wider
applicability.
(À)-α-Kainic acid (3) was first isolated from the Japanese
marine Digenea Simplex1 in 1953, and it exhibits an exceptional
pharmacological profile, acting as a potent agonist for ionotro-
poic glutamate receptors in the central nervous system and
inducing seizures and neurodegeneration in vivo.2 This pro-
nounced neuroexcitatory activity stems from its conformation-
ally rigid structure composed of a trans-C2,C3/cis-C3,C4
pyrrolidine core analogous to glutamic acid, a neuroexcitatory
neurotransmitter in the central nervous system. Recently, (À)-
α-kainic acid has been widely used in neuroscience research as a
neurodegenerative agent for modeling epilepsy,3 Parkinson’s
disease,4 and Alzheimer’s disease.5 However, the supply of
(À)-α-kainic acid from natural sources is very limited. The
worldwide shortage and extremely high price of (À)-α-kainic
acid have severely hampered research projects in neurodegen-
erative disorders.6 In order to address these challenges, including
diastereoselective construction of a trans-C2,C3/cis-C3,C4 pyr-
rolidine core, numerous syntheses7 have been disclosed since
the first total synthesis8 was reported by Oppolzer and co-
workers in 1982. Despite the advances achieved over the past
decades, a practical synthesis of (À)-α-kainic acid is still highly
desired in terms of atom economy9 and green chemistry10 in organic
synthesis.
’ RESULTS AND DISCUSSION
The synthesis of the precursor 8a of 1b commenced with
LiAlH4 reduction11 of L-methionine in THF at reflux to provide
β-amino alcohol 4 (Scheme 2). Introduction of the benzyl
protecting group onto nitrogen by condensation of 4 with
benzaldehyde followed by reduction with NaBH4, generated
5a,11a whose silylation with TBSCl12 after chromatography fur-
nished 6a, with a combined yield of 75% over 4 steps from
methionine. Subsequent oxidation of 6a with NaIO4 in mixed
solvents (H2O/MeOH/EtOAc 1:1:1)13 provided quantitatively
the crude sulfoxide 7a, which was subjected to thermal
elimination11b,c to give the desired allylamine 8a in 57% yield.
However, the disappointing yield was not improved in attempts
at optimization, and a scaleup experiment of this pyrolysis led to a
A short synthesis7i of kainic acid was reported in 2007 from
this laboratory, using a high-yielding and completely diastereo-
selective palladium-catalyzedzinc-enecyclization of allylicchloride
1a derived from D-serine as the key step to construct the
pyrrolidine (Scheme 1). However, the brevity was overshadowed
by the partial racemization resulting from the use of a racemiza-
tion prone α-amino aldehyde precursor of 1a.
Received: June 27, 2011
Published: August 25, 2011
r
2011 American Chemical Society
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Scheme 1. Earlier Synthesis of (À)-α-Kainic Acid (3)
Scheme 3. Intended Synthesis of (À)-Kainic Acid Precursor 1a
could be readily synthesized from methionine in 7 steps and 67%
overall yield and only one chromatographic purification for the
final product 8a was necessary.
There have been several reported asymmetric methods for
the synthesis of (S)-2-vinylglycinol and its protected analogues
by either employing a chiral substrate16 or asymmetric allylic
aminations.15,17 However, none of these provide enantiomeri-
cally pure product, and the cost associated with the recovery of
the chiral auxiliary or ligands could be prohibitive in the large
scale production of this intermediate. In fact, compound 8a
itself has been prepared in a short synthesis by an iridium-
catalyzed asymmetric allylic amination in 97% ee.15 Disadvan-
tages of this procedure, in addition of the necessity of enriching
the enantiomerism of the protected (S)-2-vinylglycinol to
100%, would be the expense of preparing the chiral ligand,
the fact that the expensive iridium catalyst bearing this ligand
would not be recoverable because of the homogeneous nature
of the reaction, and the fact that the product is formed in the
presence of 17% of an isomeric material that would have to be
removed by a tedious procedure. In contrast, our longer
synthesis is easy to perform and involves a simple baseÀacid
wash workup procedure and one chromatographic separation
for the final compound 8a.
With enantiomerically pure 8a in hand, we pursued the
preparation of allyl chloride 1a (Scheme 3) that we had pre-
viously shown7i to be an efficient precursor of (À)-α-kainic acid
after the Zn-ene cyclization. In our previous synthesis, 1a was
prepared in high yield by allylating an amine bearing a carboxylic
ester group with 9 and converting the ester group to a vinyl
group, but this procedure led to partially racemized 1a. This
racemization cannot occur in the present synthesis. However, it
was found that the sequence outlined in Scheme 3 gave poor
yields probably due to the fact that the Z-isomer of 1a, arising
from allylation of 8a with the Z-isomer contaminating 9, was
probably unstable because of cyclization by nucleophilic displa-
cement of the chloride ion by the amine.18
Since allyl acetates are versatile precursors of π-allyl palla-
dium(II) complexes,19 we replaced the chloride of 9 with an
acetoxy group (1b, Scheme 4), which would be incapable of this
unwanted nucleophilic displacement. The synthesis of allylic
bromide allylic acetate 12 began with allylic chloride allylic
alcohol 10, readily available in two steps from isoprene.20
Reaction with KOAc in the presence of a catalytic amount of
NaI gave the allylic acetate allylic alcohol 11 in moderate yield
(Scheme 4). Treatment of 11 with PBr3 at 0 °C for 1 h afforded
the desired product 12 in 73% yield.21 When alkylation22 of 8a
with 12 was performed in DMF at room temperature in the same
manner as with 9, we were surprised to observe that this reaction
was extremely sluggish. With the addition of a catalytic amount of
NaI, the reaction proceeded well and provided the zinc-ene
cyclization precursor 1b in 93% yield (Scheme 4).
Scheme 2. Two Syntheses of 8aa
a Conditions: (a) LiAlH4, THF, reflux, 24 h; (b) PhCHO, MeOH, 0 °C,
2 h; (c) NaBH4, MeOH, 0 °C, 1 h; (d) 15% NaOH, BzCl, 0 °C to rt,
24 h, 82% for 5b from methionine; (e) TBSCl, CH2Cl2, imidazole, 0 °C
to rt, 2 h, 75% for 6a from methionine and 82% for 6b from methionine;
(f) NaIO4, H2O/MeOH/EtOAc (1:1:1), rt, 3 h, quant; (g) o-dichlor-
obenzene, CaCO3, reflux, 5 h, 57% for 8a and 86% for 8b; (h) procedures
a and e, 78%; (i) procedures e, f, g, a and e, 82%. Note: no purifications
were carried out for the crude intermediates in procedures h and i.
very low yield (19%). In view of the failure of this sequence, we
replaced the benzyl protecting group with the benzoyl group,
anticipating that the more stable benzamide could survive the
harsh pyrolytic conditions better than the benzylamine
(Scheme 2). A one-pot14 sequential reduction of methionine
with LiAlH4, followed by acylation with benzoyl chloride,
provided analytically pure 5b in 82% yield after simple acidÀbase
washes.
In a fashion similar to the above procedure, silylation of 5b
followed by oxidation of the product 6b gave rise quantitatively
to analytically pure 7b. Gratifyingly, pyrolysis of 7b furnished the
desired compound 8b in 86% yield. Notably, this robust protocol
was smoothly carried out on a 20 g scale with equal efficiency.
Conversion of 8b to 8a was achieved in 78% yield after
chromatography in two steps by treatment of 8b with LiAlH4
at reflux overnight and resilylation of the resulting desilylated
product with TBSCl. In order to streamline this new reaction
sequence, crude product 8b from the pyrolysis was directly
subjected to reduction and resilylation, affording after chromato-
graphic purification the desired product 8a in 82% yield over
However, when we performed the palladium-catalyzed zinc-ene
cyclization of 1b following the reported7i procedure, we surpris-
ingly observed that this reaction completely stalled after 30À40%
5 steps from 5b. Thus, the key intermediate 8a ([α]20 +26.0
D
(c 0.92 CHCl3),15 required for the synthesis of (À)-α-kainic acid,
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Scheme 4. (À)-Kainic Acid 3 from Allylic Acetate 1b
scale-up permit an especially industrially adaptable access to
enantiomerically pure (À)-α-kainic acid to satisfy the needs of
the neuroscience research community.
’ EXPERIMENTAL SECTION
General Remarks. Reactions were performed in oven-dried glass-
ware fitted with rubber septa under an argon atmosphere. Unless
otherwise noted, all starting materials and reagents were purchased
from commercial sources and used without further purification. THF
and Et2O were distilled over sodium/benzophenone. CH2Cl2, Et3N,
pyridine, and toluene were distilled over CaH2. Glass-backed silica gel
TLC plates (0.25 mm) were used for thin layer chromatography (TLC)
analysis. Visualization of TLC plates was accomplished with aqueous
KMnO4 or ninhydrine stain. All products were purified by flash
chromatography on silica gel (32À63 μm) when necessary. NMR
spectra were recorded using CDCl3 as solvent, and chemical shifts are
reported in ppm (δ value) with solvent signals [1H NMR (300 MHz):
CDCl3 (7.27); 13C NMR (75 MHz): CDCl3 (77.0)]. Signal splitting
patterns are indicated as br, broad peak; s, singlet; d, doublet; t, triplet; q,
quartet; quin, quintet; m, multiplet.
(S)-N-[1-Hydroxy-4-(methylthio)butan-2-yl]benzamide
(5b). To a 100 mL flask charged with LiAlH4 (1.1 g, 29.0 mmol) and
anhydrous THF (40 mL) was added portionwise (S)-methionine (2.0 g,
13.4 mmol) under an argon atmosphere. After being stirred for 10 min,
the mixture was heated at reflux overnight. The mixture was then
allowed to cool to room temperature and was slowly treated with water
(1.1 mL), 15% aqueous NaOH (1.1 mL), and water (3.3 mL), succes-
sively. After addition of 15% aqueous NaOH (15.6 mL), benzoyl
chloride (1.44 mL, 12.4 mmol) was added dropwise at 0 °C, and the
resulting mixture was then stirred for 2 h. The reaction mixture was
diluted with water (200 mL) and then acidified to pH 1.5 with 6 N
aqueous HCl and extracted with CH2Cl2 (100 mL Â 3). The extracts
were combined, washed with water, saturated aqueous NaHCO3, and
brine, successively, and dried over anhydrous Na2SO4. After filtration,
concentration of the filtrate afforded 2.63 g (82%) of analytically pure 5b
as a white semisolid. IR (neat): 3284, 1636 cmÀ1; 1H NMR (300 MHz,
CDCl3): δ 2.00 (qd, J = 6.0, 3.0 Hz, 2H), 2.15 (s, 3H), 2.64 (t, J = 6.0 Hz,
2H), 2.69 (t, J = 6.0 Hz, 1H), 3.74À3.88 (m, 2H), 4.23À4.35 (m, 1H),
6.66 (d, J = 6.0 Hz, 1H), 7.41À7.57 (m, 3H), 7.76À7.85 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 15.6, 30.4, 30.8, 51.7, 64.9, 127.0, 128.6,
131.7, 134.1, 168.1; HRMSÀESI: m/z [M + Na]+ calcd for C12H17NO2-
NaS 262.0878, found 262.0877.
(S)-N-[1-(tert-Butyldimethylsilyloxy)-4-(methylthio)butan-
2- yl]benzamide (6b). To a 250 mL flask were added compound 5b
(2.4 g, 10.0 mmol), CH2Cl2 (70 mL) and imidazole (1.04 g, 15.1 mmol)
under an argon atmosphere. The resulting solution was allowed to cool
to 0 °C, and tert-butylchlorodimethylsilane (1.7 g, 10.9 mmol) was then
added portionwise. After 30 min, the reaction mixture was stirred at
room temperature overnight. The reaction was quenched with water and
extracted with CH2Cl2 (30 mL Â 2). The combined organic layer was
washed with 1 N HCl (20 mL Â 2), water and brine, successively, dried
over anhydrous Na2SO4, filtered, and concentrated to give 3.56 g
(100%) of analytically pure 6b as a clear oil. IR (neat): 3306, 3063,
1638, 1538, 838 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 0.07 (s, 3H),
0.09 (s, 3H), 0.92 (s, 9H), 1.96 (q, J = 6.0 Hz, 2H), 2.13 (s, 3H),
2.52À2.70 (m, 2H), 3.75 (d, J = 3.0 Hz, 2H), 4.26À4.38 (m, 1H), 6.53
(d, J = 9.0 Hz, 1H), 7.41À7.56 (m, 3H), 7.74À7.81 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ À5.5, 15.5, 18.2, 25.8, 30.8, 31.2, 50.2, 64.3, 126.8,
128.6, 131.5, 134.6, 166.8; HRMSÀESI: m/z [M + Na]+ calcd for
C18H31NO2NaSiS 376.1742, found 376.1746.
conversion of 1b to cyclization product and never proceeded to
completion even with a much longer reaction time. In a number
of cases, Oppolzer and co-workers had also observed low yields
of Pd-catalyzed Zn-ene cyclizations using a similar procedure
starting from allyl acetates.19b,23 In one case,23 in order to obtain
good yields, the catalyst was changed to palladium acetate in the
presence of P(Bu)3 and 20 equivalents of diethylzinc was used.
Since such conditions would be very detrimental to any effective
industrial process, we developed a novel approach to solve this
problem. It is based on the likelihood that the oxidative addition
of Pd(0) to the allyl acetate is reversible24 and that the sub-
sequent steps leading to the cyclization may be as well and/or
that a chloride ligand on Pd is far more effective25 in this process
than the acetate ligand, as evidenced by our previous very
successful cyclization of 1a. It appeared that a practical method
for addressing either or both possibilities might be to add TMSCl
along with the Pd and diethylzinc in order to silylate the acetate
ion released during the oxidative addition of the Pd to the allyl
acetate. Remarkably, when 1 equiv of TMSCl was present during
the palladium-catalyzed zinc-ene cyclization, the reaction was
complete in a much shorter period of time, and after quenching
with iodine, iodide 2 was obtained in 90% yield (Scheme 4).
To further prove that no racemization occurred in the synth-
esis of chiral allylamine 8a by the method described herein,
conversion of iodide 2 to (À)-α-kainic acid was carried out
following our previously reported procedure.7i Cyanation of
iodide 2, followed by debenzylation with methyl chloroformate,
Jones oxidation, basic hydrolysis, and purification by ion ex-
change chromatography (DOWEX 50WX8-200) furnished en-
antiomerically pure (À)-α-kainic acid (3, mp 243À246 °C
(dec), [α]20D À15.0 (c 0.61 H2O),26 whose spectroscopic data
were identical with those reported in the literature. Remarkably,
this synthesis provides rapid access to enantiopure (À)-α-kainic
acid (3) in 37% overall yield in 13 linear steps.
’ CONCLUSIONS
In summary, a practical synthesis of enantiopure (À)-α-kainic
acid (3) is accomplished in 37% overall yield in 13 linear steps
from inexpensive L-methionine, featuring an unprecedented
TMSCl-promoted palladium-catalyzed intramolecular zinc-ene
cyclization of allyl acetate 1b. The low cost of the reagents used,
the absence of any cryogenic steps, the small number of requi-
red chromatographic separations, and the ease of handling and
N-(S)-[1-(tert-Butyldimethylsilyloxy)-4-(methylsulfinyl)butan-
2-yl]benzamide (7b). A 250 mL flask was charged with compound
6b (3.53 g, 10.0 mmol), methanol (36 mL), and ethyl acetate (36 mL).
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After compound 6b was dissolved, an aqueous solution of NaIO4
(2.37 g, dissolved in 36 mL of distilled H2O) was added dropwise over
a period of 30 min. After being stirred for 3 h at room temperature, the
reaction mixture was diluted with water (150 mL), additional ethyl
acetate (50 mL) was added, and then the organic layer was separated.
The aqueous layer was extracted with ethyl acetate (50 mL Â 2). The
combined organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated to provide 3.78 g (100%) of analytically pure 7b as a
clear oil. IR (neat): 3304, 3062, 1642, 1539, 1030, 838 cmÀ1; 1H NMR
(300 MHz, CDCl3, two diastereomers): δ 0.08 (s, 3H), 0.09 (s, 3H),
0.92 (s, 9H), 2.11À2.30 (m, 2H), 2.58 (2 Â s, 3H), 2.72À2.96 (m, 2H),
3.70À3.85 (m, 2H), 4.24À4.42 (m, 1H), 6.85 and 6.94 (2 Â d, J = 9.0
Hz, 1H), 7.40À7.57 (m, 3H), 7.76À7.86 (m, 2H); 13C NMR (75 MHz,
CDCl3, two diastereomers): δ À5.6, À5.5, 18.1, 24.7, 25.5, 25.8, 38.4,
38.5, 49.7, 50.2, 50.7, 51.2, 64.5, 64.7, 126.9, 126.9, 128.5, 128.5, 131.5,
131.5, 134.0, 134.1, 167.1, 167.1; HRMSÀESI: m/z [M + H]+ calcd for
C18H32NO3SiS 370.1872, found 370.1867.
(S)-N-[1-(tert-Butyldimethylsilyloxy)but-3-en-2-yl]benzamide
(8b). To a 100 mL flask equipped with a condenser were added 7b
(3.69 g, 10 mmol), o-dichlorobenzene (50 mL), and powdered CaCO3
(2.6 g), and the resulting mixture was heated to reflux. After 5 h, the
reaction mixture was cooled to room temperature and filtered over a pad
of Celite. The solvent was removed under reduced pressure to give a
residual oil, which was purified by column chromatography (10%
EtOAc/hexanes) to afford 2.62 g (86%) of analytically pure 8b as a
clear oil. [α]20D À61.0 (c 1.15, CHCl3); IR (neat): 3310, 3065, 1639,
1538, 839 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 0.08 (2 Â s, 6H), 0.91
(s, 9H), 3.74À3.87 (m, 2H), 4.68À4.78 (m, 1H), 5.18À5.35 (m, 2H),
5.94 (ddd, J = 18.0, 12.0, 6.0 Hz, 1H), 6.60 (d, J = 6.0 Hz, 1H),
7.40À7.56 (m, 3H), 7.76À7.84 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ À5.3, 18.2, 25.8, 53.0, 65.0, 116.2, 126.8, 128.6, 131.4, 134.6, 136.0,
166.6; HRMSÀESI: m/z [M + Na]+ calcd for C17H27NO2NaSi
328.1709, found 328.1705.
resilylation, affording after chromatographic purification 2.38 g
(82%) of analytically pure compound 8a as a clear oil. All data for
8a are consistent with those reported above.
(S)-N-Benzyl-1-(tert-butyldimethylsilyloxy)-4-(methylthio)-
butan-2-amine (6a). To a 100 mL flask charged with LiAlH4 (1.1 g,
29 mmol) and anhydrous THF (40 mL) was added portionwise (S)-
methionine (2.0 g, 13.4 mmol) under an argon atmosphere. After being
stirred for 10 min, the mixture was heated at reflux overnight. The
mixture was then allowed to cool to room temperature and was slowly
treated with water (1.1 mL), 15% aqueous NaOH (1.1 mL), and water
(3.3 mL), successively. The precipitate was filtered off, and the solvent
was removed under reduced pressure. The residual oil 4 thus obtained
was dissolved in anhydrous methanol (55 mL) under an argon atmo-
sphere followed by addition of benzaldehyde (1.37 mL, 13.4 mmol), and
the resulting solution was stirred at 0 °C. After 2 h, NaBH4 (0.8 g, 21.1
mmol) was added portionwise. The reaction mixture was stirred for 1 h
and quenched with 1 N NaOH. The product was extracted with CH2Cl2.
The extracts were combined, washed with water and brine, and dried
over Na2SO4. Filtration and removal of the solvent gave 5a as a nearly
colorless oil. The crude 5a was dissolved in CH2Cl2 (90 mL) under an
argon atmosphere followed by addition of imidazole (1.36 g, 19.7 mmol)
and TBSCl (2.44 g, 15.7 mmol). After 2 h, the reaction was quenched
with water. The organic layer was separated, washed with water and
brine, and dried over anhydrous Na2SO4. The crude obtained after
filtration and removal of the solvent was purified by chromatography to
afford 3.4 g (75%) of analytically pure 6a as a clear oil. IR (neat): 3027,
1468, 1254, 1107, 838, 777 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 0.08
(s, 6H), 0.92 (s, 9H), 1.68À1.86 (m, 3H), 2.11 (s, 3H), 2.60 (t, J = 9.0
Hz, 2H), 2.78 (quin, J = 6.0 Hz, 1H), 3.54 (dd, J = 12.0, 6.0 Hz, H), 3.70
(dd, J = 12.0, 6.0 Hz, 1H), 3.82 (s, 2H), 7.21À7.40 (m, 5H); 13C NMR
(75 MHz, CDCl3): δ À5.3, À5.2, 15.4, 18.2, 25.8, 30.9, 31.2, 51.1, 57.5,
64.2, 126.8, 128.0, 128.3, 140.7; HRMSÀESI: m/z [M + H]+ calcd for
C18H34NOSiS 340.2130, found 340.2120.
(S)-N-Benzyl-1-(tert-butyldimethylsilyloxy)but-3-en-2-
amine (8a). To a 250 mL flask charged with LiAlH4 (0.87 g, 23 mmol)
and anhydrous THF (80 mL) was slowly added a 0.2 M THF solution of
8b (3.05 g, 10 mmol) via a syringe under an argon atmosphere. After
being stirred for 10 min, the mixture was heated at reflux overnight. The
mixture was then allowed to cool to room temperature and slowly
treated with water (0.87 mL), 15% aqueous NaOH (0.87 mL), and water
(2.61 mL) successively. After 1 h, the precipitate was filtered off and
washed twice with THF, and the solvent was then removed under
reduced pressure to give 1.66 g of the crude product. The crude product
was dissolved in CH2Cl2 (65 mL) under an argon atmosphere followed
by addition of imidazole (0.97 g, 14.1 mmol) and TBSCl (1.74 g, 11.2
mmol). After 2 h, the reaction was quenched with water. The organic
layer was separated and washed with water and then brine, and dried
over anhydrous Na2SO4. The crude obtained after filtration and removal
of the solvent was purified by chromatography to afford 2.27 g (78%) of
(2S)-N-Benzyl-1-(tert-butyldimethylsilyloxy)-4-(methyl-
sulfinyl)butan-2-amine (7a). A 250 mL flask was charged with
compound 6a (3.39 g, 10.0 mmol), methanol (36 mL), and ethyl acetate
(36 mL). After compound 6a was dissolved, an aqueous solution of
NaIO4 (2.37 g dissolved in 36 mL of distilled H2O) was added dropwise
over a period of 30 min. After being stirred for 3 h at room temperature,
the reaction mixture was diluted with water (150 mL), additional ethyl
acetate (50 mL) was added, and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (50 mL Â 2). The
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated to provide 3.62 g (100%) of analytically pure
7a as a clear oil. IR (neat): 3027, 1468, 1255, 1106, 838, 778 cmÀ1; 1H
NMR (300 MHz, CDCl3, two diastereomers): δ 0.06 (s, 6H), 0.90 (s,
9H), 1.78À2.01 (m, 3H), 2.53 and 2.55 (2 Â s, 3H), 2.70À2.94 (m,
3H), 3.54 and 3.57 (2 Â dd, J = 6.0, 3.0 Hz, 1H), 3.66À3.89 (m, 3H),
7.19À7.37 (m, 5H); 13C NMR (75 MHz, CDCl3, two diastereomers):
δ À5.4, 18.2, 24.6, 24.8, 25.9, 38.5, 38.5, 50.9, 51.0, 51.3, 51.4, 56.8, 57.5,
63.7, 63.8, 127.0, 128.1, 128.2, 128.4; HRMSÀESI: m/z [M + Na]+
calcd for C18H33NO2NaSiS 378.1899, found 378.1898.
(S)-N-Benzyl-1-(tert-butyldimethylsilyloxy)but-3-en-2-
amine (8a). To a 100 mL flask equipped with a condenser were added
7a (3.55 g, 10 mmol), o-dichlorobenzene (50 mL) and powdered
CaCO3 (2.6 g), and the resulting mixture was heated to reflux. After
5 h, the reaction mixture was cooled to room temperature and filtered
over a pad of Celite. The solvent was removed under reduced pressure to
give a residual oil, which was purified by column chromatography (15%
EtOAc/hexanes) to afford 1.66 g (57%) of analytically pure 8a as a clear
oil. [α]20D +26.0 (c 0.92, CHCl3); IR (neat): 3330, 3064, 1461, 1255,
1088, 838, 778 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 0.03 (s, 3H), 0.04
(s, 3H), 0.88 (s, 9H), 2.10 (br s, 1H), 3.14À3.26 (m, 1H), 3.51 (dd, J =
9.0 Hz, 1H), 3.61 (dd, J = 9.0, 6.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.87
analytically pure 8a as a clear oil. [α]20 +26.0 (c 0.92, CHCl3); IR
D
(neat): 3330, 3064, 1461, 1255, 1088, 838, 778 cmÀ1; 1H NMR (300
MHz, CDCl3): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9H), 2.10 (br s, 1H),
3.14À3.26 (m, 1H), 3.51 (dd, J = 9.0 Hz, 1H), 3.61 (dd, J = 9.0, 6.0 Hz,
1H), 3.65 (d, J = 12.0 Hz, 1H), 3.87 (d, J = 12.0 Hz, 1H), 5.13À5.28 (m,
2H), 5.57À5.72 (m, 1H), 7.17À7.34 (m, 5H); 13C NMR (75 MHz,
CDCl3): δ À5.4, À5.3, 18.2, 25.9, 51.0, 62.4, 66.2, 117.7, 126.7, 128.0,
128.3, 137.9, 140.7; HRMSÀESI: m/z [M + H]+ calcd for C17H30NOSi
292.2097, found 292.2098.
Streamlined Procedure for the Synthesis of (S)-N-Benzyl-
1-(tert-butyldimethylsilyloxy)but-3-en-2-amine (8a). The
procedures for the syntheses of 6b, 7b, 8b, and 8a, as described
above, were followed except that only final compound 8a was purified
by flash chromatography. The crude 5b (2.4 g, 10 mmol) was sub-
mitted to silylation, oxidation, thermal elimination, reduction, and
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ARTICLE
(d, J = 12.0 Hz, 1H), 5.13À5.28 (m, 2H), 5.57À5.72 (m, 1H),
7.17À7.34 (m, 5H); 13C NMR (75 MHz, CDCl3): δ À5.4, À5.3, 18.2,
25.9, 51.0, 62.4, 66.2, 117.7, 126.7, 128.0, 128.3, 137.9, 140.7; HRMSÀESI:
m/z [M + H]+ calcd for C17H30NOSi 292.2097, found 292.2098.
(E)-4-Hydroxy-2-methylbut-2-enyl Acetate (11). To a 0.25
M DMF solution of 1020 (2.41 g, 20.0 mmol) were added KOAc (4.12 g,
42.0 mmol), NaI (0.16 g, 1.06 mmol), and H2O (5.0 mL). The reaction
mixture was stirred overnight and then diluted with water and extracted
with EtOAc. The extracts were washed with brine and dried (Na2SO4).
After filtration and removal of the solvent under reduced pressure, the
crude oil was purified by column chromatography (25% EtOAc/
hexanes) to afford 1.94 g (67%) of analytically pure 11 as a clear oil.
IR (neat): 3460, 1739, 1235 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 1.35
(br s, 1H), 1.72 (s, 3H), 2.10 (s, 3H), 4.23 (dd, J = 6.0 Hz, 2H), 4.49 (s,
2H), 5.69 (tq, J = 6.0, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 13.9,
20.8, 58.8, 68.9, 127.0, 133.0, 170.8.
(E)-4-Bromo-2-methylbut-2-enyl Acetate (12). To a 0.25 M
Et2O solution of 11 (1.44 g, 10.0 mmol) was added PBr3 (0.41 mL,
4.3 mmol) at 0 °C. After 1 h, the reaction mixture was diluted with water
and extracted with Et2O. The combined organic layers were washed with
water and dried (Na2SO4). After filtration and removal of the solvent,
the crude oil was purified by column chromatography (10% Et2O/
pentane) to afford 1.51 g (73%) of analytically pure 12 as a clear oil. 1H
NMR (300 MHz, CDCl3): δ 1.77 (s, 3H), 2.10 (s, 3H), 4.15 (d, J = 9 Hz,
2H), 4.52 (s, 2H), 5.81 (tq, J = 9.0, 3.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 13.6, 20.8, 27.4, 68.3, 123.2, 136.7, 170.6.
(À)-α-Kainic Acid (3). Following our previously reported
procedure,7i cyanation of iodide 2 followed by debenzylation with
methyl chloroformate, Jones oxidation, basic hydrolysis, and purification
by ion exchange chromatography (DOWEX 50WX8-200) furnished
enantiomerically pure (À)-α-kainic acid 3 [mp 243À246 °C (dec),
[α]20D À15.0 (c 0.61 H2O)].8 1H NMR (300 MHz, D2O): δ 1.72 (s,
3H), 2.20 (dd, J = 15.0, 6.0 Hz, 1H), 2.32 (dd, J = 18.0, 6.0 Hz, 1H),
2.88À3.09 (m, 2H), 3.38 (dd, J = 12.0 Hz, 1H), 3.58 (dd, J = 12.0, 9.0
Hz, 1H), 4.03 (d, J = 3.0 Hz, 1H), 4.70 (s, 1H), 4.98 (s, 1H); 13C NMR
(75 MHz, D2O): δ 22.1, 34.6, 41.2, 45.7, 46.3, 65.7, 113.1, 140.0,
173.4, 177.9.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of
S
b
the compounds 5bÀ8b, 6aÀ8a, 11, 12, 1b, 2, and 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: guoqing_wei@yahoo.com; cohen@pitt.edu.
’ ACKNOWLEDGMENT
(S,E)-4-[Benzyl(1-tert-butyldimethylsilyloxy)but-3-en-2-yl)-
amino]-2-methylbut-2-enyl Acetate (1b). To a 0.1 M DMF
solution of 8a (1.46 g, 5.0 mmol) were added NaI (0.04 g, 0.27 mmol),
K2CO3 (0.69 g, 5.0 mmol), and 12 (1.04 g, 5.0 mmol). The reaction
mixture was stirred at room temperature. After 24 h, the reaction mixture
was diluted with water and extracted with EtOAc. The extracts were
combined, washed with water and brine, and dried (Na2SO4). The
crude, obtained after filtration and removal of the solvent under reduced
pressure, was purified by column chromatography (10% EtOAc/
hexanes) to afford 1.94 g (93%) of analytically pure 1b as a light yellow
This work was supported by funds from the University of
Pittsburgh.
’ DEDICATION
†This work is dedicated with admiration and affection to
Professor William Bailey on his 65th birthday.
’ REFERENCES
(1) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn.
1953, 73, 1026.
(2) (a) McGeer, E. G.; Olney, J. W. Kainic Acid as a Tool in
Neurobioloby; McGeer, E. G., Olney, J. W., McGeer, P. L., Eds.; Raven
Press: New York, 1978. (b) Watkins, J. C.; Krogsgaard-Larsen, P.;
Honorꢀe, T. Trends Pharmacol. Sci. 1990, 11, 25. (c) Wang, Q.; Yu, S.;
Simonyi, A.; Sun, G. Y.; Sun, A. Y. Mol. Neurobiol. 2005, 31, 3.
(3) (a) Sperk, G. Prog. Neurobiol. 1994, 42, 1. (b) Ben-Ari, Y.;
Cossart, R. Trends Neurosci. 2000, 23, 580.
1
oil. IR (neat): 1742, 1231, 1101, 838 cmÀ1; H NMR (300 MHz,
CDCl3): δ 0.03 (s, 6H), 0.89 (s, 9H), 1.63 (s, 3H), 2.07 (s, 3H),
3.06À3.31 (m, 3H), 3.54 (d, J = 15.0 Hz, 1H), 3.66À3.85 (m, 3H), 4.44
(s, 2H), 5.12À5.31 (m, 2H), 5.49À5.60 (m, 1H), 5.75À5.91 (m, 1H),
7.17À7.40 (m, 5H); 13C NMR (75 MHz, CDCl3): δ À5.5, À5.4, 14.2,
18.3, 21.0, 25.9, 47.8, 54.9, 63.4, 64.6, 69.9, 118.1, 126.6, 128.1, 128.4,
128.5, 131.8, 135.4, 140.6, 170.9; HRMSÀESI: m/z [M + H]+ calcd for
C24H40NO3Si 418.2777, found 418.2783.
(2S,3S,4S)-1-Benzyl-2-[(tert-butyldimethylsilyloxy)methyl]-
3-(iodomethyl)-4-(prop-1-en-2-yl)pyrrolidine (2). To a solu-
tion of 1b (417 mg, 1 mmol) in anhydrous Et2O (6 mL) were added
Pd(PPh3)4 (58 mg, 0.05 mmol), Et2Zn (1.0 M in hexanes, 6.0 mL, 6.0
mmol), and TMSCl (0.13 mL, 1.0 mmol). The mixture was stirred at
room temperature. After 6 h, the reaction was quenched with a solution
of I2 (3.1 g) in THF (8 mL). After 0.5 h, the reaction mixture was treated
with saturated Na2S2O3, and the resulting mixture was extracted with
EtOAc. The extracts were combined, washed with saturated Na2S2O3
and brine, and then dried (Na2SO4). The crude obtained after filtration
and concentration was purified by column chromatography (5%
EtOAc/hexanes) to afford 438 mg (90%) of analytically pure 2 as a
clear oil. 1H NMR (300 MHz, CDCl3): δ 0.08 (2 Â s, 6H), 0.92 (s, 9H),
1.74 (s, 3H), 2.43À2.61 (m, 2H), 2.67À2.85 (m, 3H), 2.90 (dd, J = 9.0,
6.0 Hz, 1H), 3.17 (dd, J = 9.0, 3.0 Hz, 1H), 3.55(d, J = 6.0 Hz, 2H), 3.63
(d, J = 15.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.61 (s, 1H), 4.86 (s, 1H),
7.19À7.41 (m, 5H); 13C NMR (75 MHz, CDCl3): δ À5.2, À5.2, 10.5,
18.4, 23.2, 26.0, 45.0, 48.4, 54.2, 60.4, 66.4, 71.2, 111.8, 126.9, 128.2,
128.8, 139.6, 141.8; HRMSÀESI: m/z [M + H]+ calcd for C22H37NOSiI
486.1689, found 486.1675.
(4) Liberman, D. M.; Corthesy, M.; Cummins, A.; Oldfield, E. H.
J. Neurosurg. 1999, 90, 928.
(5) (a) Mohmmad, A.; Sultana, R.; Keller, J.; St. Clair, D.; Markesbery,
W.; Butterfield, D. J. Neurochem. 2006, 96, 1322. (b) Goodenough, S.;
Schleusner, D.; PietrziK, C.; Skutella, T.; Behl, C. Neuroscience 2005,
132, 581.
(6) (a)Tremblay, J.-F.Chem. Eng. News2000, 78 (1), 14. (b) Tremblay,
J.-F. Chem. Eng. News 2000, 78 (10), 31. (c) Tremblay, J.-F. Chem. Eng. News
2001, 79 (5), 19.
(7) For selected examples, see: (a) Lowe, M. A.; Ostovar, M.; Ferrini,
S.; Chen, C. C.; Lawrence, P. G.; Fontana, F.; Calabrese, A. A.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2011, 50, 6370. (b) Lemiꢁere, G.; Sedehizadeh,
S.; Toueg, J.; Fleary-Roberts, N.; Clayden, J. Chem. Commun. 2011,
47, 3745. (c) Takita, S.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011,
13, 2068. (d) Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N.
Org. Lett. 2010, 12, 5756. (e) Farwick, A.; Helmchen, G. Org. Lett. 2010,
12, 1108. (f) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008,
10, 1711. (g) Tomooka, K.; Akiyama, T.; Man, P.; Suzuki, M. Tetrahedron
Lett. 2008, 49, 6327. (h) Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo,
K. S.; Jung, K. W. J. Org. Chem. 2007, 72, 10114. (i) Chalker, J. M.; Yang,
A.; Deng, K.; Cohen, T. Org. Lett. 2007, 9, 3825. (j) Sakaguchi, H.;
7916
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The Journal of Organic Chemistry
ARTICLE
Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635. (k) Thuong,
M. B. T.; Sottocornola, S.; Prestat, G.; Broggini, G.; Madec, D.; Poli, G.
Synlett 2007, 1521. (l) Pandey, S. K.; Orellana, A.; Greene, A. E.; Poisson,
J.-F. Org. Lett. 2006, 8, 5665. (m) Hodgson, D. M.; Hachisu, S.; Andrews,
M. D. Org. Lett. 2005, 7, 815. (n) Morita, Y.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2005, 7, 4337. (o) Scott, M. E.; Lautens, E. Org. Lett. 2005,
7, 3045. (p) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763.
(q) Martínez, M. M.; Hoppe, D. Eur. J. Org. Chem. 2005, 1427.
(r) Anderson, J. C.; O’Loughlin, J. M. A.; Tornos, J. A. Org. Biomol. Chem.
2005, 3, 2741. (s) Poisson, J.-F.; Orellana, A.; Greene, A. E. J. Org. Chem.
2005, 70, 10860. (t) Martinez, M. M.; Hoppe, D. Org. Lett. 2004, 6, 3743.
(u) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (v) Clayden, J.;
Menet, C. J.; Mansfield, D. J. Chem Commun. 2002, 38. (w) Clayden, J.;
Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727. (x) Xia, Qian;
Ganem, B. Org. Lett. 2001, 3, 485. (y) Hirasawa, H.; Taniguchi, T.;
Ogasawara, K. Tetrahedron Lett. 2001, 42, 7587. (z) Campbell, A. D.;
Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 3194.
(aa) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000,
56, 6199. (bb) Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000,
2, 3181. (cc) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Chem
Commun. 1999, 245. (dd) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron
1999, 55, 6153. (ee) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc.
1999, 121, 11139. (ff) Rubio, A.; Ezquerra, J.; Escribano, A. Tetrahedron
Lett. 1998, 39, 2171. (gg) Cossy, J.; Cases, M.; Pardo, D. G. Synlett
1998, 507. (hh) Bachi, M. D.; Melman, A. Pure Appl. Chem. 1998, 70, 259.
(ii)Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896. (jj)Nakada, Y.;
Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1997, 38, 857. (kk) Miyata,
O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Synlett 1997, 275. (ll)Hanessian, S.;
Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (mm) Yoo, S.-E.; Lee, S. H.
J. Org. Chem. 1994, 59, 6968. (nn) Monn, J. A.; Valli, M. J. J. Org. Chem.
1994, 59, 2773. (oo) Hatakeyama, S.; Sugawara, K.; Takano, S. J. Chem
Soc., Chem. Commun. 1993, 125. (pp) Yoo., S.-E.; Lee, S.-H.; Jeong, N.;
Cho, I. Tetrahedron Lett. 1993, 34, 3435. (qq) Takano, S.; Inomata, K.;
Ogasawara, K. J. Chem Soc., Chem. Commun. 1992, 169. (rr) Cooper, J.;
Knight, D. W.; Gallagher, P. T. J. Chem Soc., Perkin Trans.1 1992, 553. (ss)
Barco, A.; Benetti, S.; Spalluto, G. J. Org. Chem. 1992, 57, 6279. (tt) Barco,
A.; Benetti, S.; Pollini, G. P.; Spalluto, G.; Zanirato, V. J. Chem Soc., Chem.
Commun. 1991, 390. (uu) Baldwin, J. E.; Monoley, M. G.; Parsons, A. F.
Tetrahedron 1990, 46, 7263. (vv)Yoo, S.-E.; Lee, S.-H.; Yi, K.-Y.; Jeong, N.
Tetrahedron Lett. 1990, 31, 6877. (ww) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. J. Chem Soc., Chem. Commun. 1988, 1204. (xx) Takano,
S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J. Am. Chem. Soc. 1988,
110, 6467. (yy) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem Soc.,
Chem. Commun. 1987, 1220.
(18) This same problem reduced the yield of allylation product in
our earlier synthesis but in a far less severe fashion than in this one; see
footnote 21 of ref 7i. The difference from our previous report in ref 7i
most likely arises from less hindrance of 8a used in this case than in the
counterpart in ref 7i, thus causing in the present case less steric crowding
during the unwanted intramolecular SN2 displacement of the chloride
ion by the amino group.
(19) (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(b) For a precedent using an allyl acetate in a Pd-catalyzed zinc-ene
cyclization to construct a pyrrolidine ring, see: Oppolzer, W.; Schr€oder,
F. Tetrahedron Lett. 1994, 35, 7939. (c) For the palladium-catalyzed
formation of allylzincs from the corresponding allyl benzoates, see:
Yasui, K.; Goto, Y.; Yajima, T.; Taniseki, Y.; Fugami, K.; Tanaka, A.;
Tamaru, Y. Tetrahedron Lett. 1993, 34, 7619.
(20) Lambertin, F.; Wende, M.; Quirin, M. J.; Taran, M.; Delmond,
B. Eur. J. Org. Chem. 1999, 1489.
(21) The reaction conditions for preparation of 12 were not
optimized, but the 4-step synthetic route is practical in terms of the
reproducibility and the ease of purification of all intermediates by
distillation.
(22) An equimolar amount of 12 was used in this alkylation, see
Experimental Section.
(23) Oppolzer, W.; Flachsmann, F. Helv. Chim. Acta 2001, 84, 416.
(24) For reversible oxidation addition of palladium (0) to an allyl
acetate, see: Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 11770 and references therein.
(25) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(26) This specific rotation is consistent with that reported in ref 8.
(8) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.
(9) Trost, B. M. Science 1991, 254, 1471.
(10) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 13197.
(11) (a) Schneider, P. H.; Schrekker, H. S.; Silveira, C. C.; Wessjohann,
L. A.; Braga, A. L. Eur. J. Org. Chem. 2004, 2715. (b) Krebs, A.; Ludwig, V.;
Pfizer, J.; D€urner, G.; G€obel, M. W. Chem.—Eur. J. 2004, 10, 544.
(c) Helquist, P.; Shekhani, M. S. J. Am. Chem. Soc. 1979, 101, 1057.
(d) Micovic, V.; Mihailovic, M. J. Org. Chem. 1953, 18, 1190.
(12) Both 4 and 5a are highly polar, so the crudes were not purified,
and 5a was directly submitted to the silylation reaction to facilitate
isolation.
(13) This procedure is a modification of that in ref 11a. The addition
of ethyl acetate is essential for efficient stirring and high yield.
(14) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.; Ham, W.-H.
J. Org. Chem. 1999, 64, 9450.
(15) For synthesis of 8a via enantioselective iridium-catalyzed allylic
amination of the corresponding allylic carbonate (8a: [α]20 +19.0
D
(c 0.97 CHCl3, 97% ee (S)), see: Gnamm, C.; Franck, G.; Miller, N.;
Stork, T.; Br€odner, K.; Helmchen, G. Synthesis 2008, 3331.
(16) Rech, J. C.; Yato, M.; Duckett, D.; Ember, M.; LoGrasso, P. V.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490.
(17) Trost, B. M.; Horne, D. B; Wolering, M. J. Chem.—Eur. J. 2006,
12, 6607.
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