Total Syntheses of (+)-α-Allokainic Acid and (-)-2- epi-α-Allokainic Acid Employing Ketopinic Amide as a Chiral Auxiliary

Article abstract of DOI:10.1021/acs.joc.8b01383

Asymmetric Michael reaction of iminoglycinate 4 to α,β-unsaturated esters had been developed with >98:<2 diastereoselectivity. A reverse of diastereoselectivity for Michael reaction could be achieved by the replacement of lithium enolate with magnesium en

Full text of DOI:10.1021/acs.joc.8b01383

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Note
Total Syntheses of (+)-#-Allokainic Acid and (–)-2-epi-#-
Allokainic Acid Employing Ketopinic Amide as Chiral Auxiliary
Yu-Fu Liang, Chuang-Chung Chung, De-Jhong Liao, Woo-Jer Lee, Yu-Wei Tu, and Biing-Jiun Uang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01383 • Publication Date (Web): 30 Jul 2018
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Page 1 of 11
The Journal of Organic Chemistry
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Total Syntheses of (+)-α-Allokainic Acid and (–)-2-epi-α-
Allokainic Acid Employing Ketopinic Amide as Chiral Auxiliry
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Yu-Fu Liang, Chuang-Chung Chung, De-Jhong Liao, Woo-Jer Lee, Yu-Wei Tu, Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua University, 101 Sec. 2, Kuang Fu Road, Hsinchu 30013, Taiwan
ABSTRACT: Asymmetric Michael reaction of iminoglycinate 4 to α,β-unsaturated esters had been developed with >98:<2 dia-
stereoselectivity. A reverse of diastereoselectivity for Michael reaction could be achieved by the replacement of lithium enolate
with magnesium enolate. This methodology was applied to the total syntheses of (+)-α-allokainic acid 1 and (−)-2-epi-α-allokainic
acid 6 each in 11 synthetic steps starting from 4 in 17.8 and 18.0% yields respectively.
stereogenic centers.9 Elegant catalytic enantioselective Mi-
(+)-α-Allokainic acid 1, is a neurologically active natural
product that isolated from the Japanese marine alga Digenea
simplex by Takemoto and coworkers in 1953.1a (−)-α-kainic
acid 22 is also isolated from Digenea simplex1b, and domoic
acid 3 is isolated from Vidalia obtusiloba.3 They belong to
kainoids which are an important group of naturally occurring
nonproteinogenic amino acids (Figure 1). These amino acids
contain highly functionalized pyrrolidine ring with three con-
tiguous stereocenters as core skeleton. They have been shown
to possess multiple biological activities such as anthelmintic,
insecticidal activity, and principally neuroexcitatory,4a which
can be attributed to their structural characteristics as confor-
mationally restricted analogues of glutamic acid.4b In addition,
they have been used in the studies of several neurological dis-
eases such as Huntingtoncorea,5 Epilepsy, and Alzheimer,s
disease.6 Many synthetic organic chemists have been inspired
to develop efficient synthetic methods toward their core pyr-
rolidine structures and total synthesis of kainoids due to their
characteristic structures and bioactivities. Although there are
sixteen enantioselective7 and five racemic8 syntheses of allo-
kainic acid have been reported to date, it remains some rooms
for the improvement of enantioselective synthesis of this class
of compounds.
chael reaction of iminoglycinate with α,β-unsaturated esters
by chiral catalysts had been reported.10 However, diastereose-
lectivity for longer β-alkyl substituted Michael acceptor re-
mains to be improved.10d Michael reaction of iminoglycinate
with α,β-unsaturated esters by chiral auxiliaries had also been
reported.11 It had been reported that α-functionalization of
iminoglycinate employing ketopinic acid as auxiliary via a
dianionic enolate gave poor diastereoselectivity.12 Our previ-
ous experience on α-alkylation of iminoglycinate using dian-
ionic enolate did not show good diastereoselectivity either.13
Therefore, we explored the diasteroselective Michael addition
of the enolate from iminoglycinate 4 with α,β-unsaturated
esters for the preparation of 2,3-disubstituted pyroglutamates.
The results and application toward the total syntheses of (−)-2-
epi-α-allokainic acid 6 and (+)-α-allokainic acid 1 are report-
ed herein (Scheme 1).
Scheme 1. Retrosynthesis of 1 and 6.
O
O
RO
OP
NH
NH
2
R
+
1
CO t-Bu
HO C
2
2
R
1
2
N
CO t-Bu
5
(+)-α-allokainic acid 1:
R
= H, R = COOH
2
PO
O
1
2
(−)-α-2-epi-allokainic acid 6: R = COOH, R = H
P=Protecting Group
Ni-Pr
2
4
At the outset, we investigated the diastereoselectivity of the
Michael addition with lithium enolate 4-Li to methyl crotonate
(Table 1, entry 1). Treatment of 4 with lithium diisopropyl-
amide (LDA) in tetrahydrofuran followed by the addition of
methyl crotonate at −78 °C for 3 h and it gave Michael adduct
7 after acidic workup in 87% yield as the sole product. A few
(E)-β-monosubstituted α,β-unsaturated esters were also reacted
with the lithium enolate 4-Li in tetrahydrofuran at −78 °C
Figure 1. Structures of kainoids.
Michael reaction is one of the promising carbon-carbon bond
forming reaction with concomitant generation of one or two
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(Table 1, entries 2-5) and the corresponding Michael adducts A plausible chelated transition state model was proposed for
1
2
3
4
5
6
7
8
were obtained with excellent diastereoselectivities and yields
after 3 h at −78 °C. The stereochemistry of Michael adduct 10
was confirmed by X-ray crystallographic analysis.14 The new-
ly formed stereogenic centers at C2 and C3 are R and S con-
figurations, respectively, which correspond to the stereochem-
istry at C2 and C3 of (−)-2-epi-α-allokainic acid 6.
the asymmetric Michael addition of enolate 4-Li to α,β-
unsaturated esters based on the observed stereochemistry for
Michael adduct 7 (Scheme 2). Presumably, (Z)-enolate was
selectively produced from the treatment of 4 with lithium
diisopropylamide due to lithium ion chelation according litera-
ture precedents.11c-e The approach of enolate 4-Li to methyl
crotonate should have occurred at re(Cα)-face of enolate to
si(Cβ) of ester due to the steric hinderance of [2.2.1] moiety
(shown as T1 in Scheme 2) to produce 7.
Table 1. Diastereoselective Michael Addition of 4-Li with
α,β-Unsaturated Esters.
9
Scheme 2. A Plausible Transition state of Michael addition
with Lithium Enolate.
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Entry
Acceptor
R
T (h) Product Yield
Ratio
(%) (2R,3S:2S,3S)
＞98:2a
＞98:2
1
2
methyl crotonate
Me
Pr
3
3
7
87
methyl-trans-2-
8a
90
hexenoate
3
methyl-4-methyl-2-
pentenoate
i-Pr
3
9
71b
＞98:2
It is reasonable to adopt this Michael addition strategy to pre-
pare (−)-2-epi-α-allokainic acid 6 followed by epimerization
of its C2 to synthesize (+)-α-allokainic acid 1. (Scheme 3)
4
5
methyl cinnamate
dimethyl fumarate
Ph
3
3
10
11
84
83
＞98:2
＞98:2
CO2Me
aNo second isomer was detected by 400 MHz 1H NMR spectroscopy. bWith a
recovery of 15% unreacted 4.
At the outset, iminoglycinate 4 was treated with LDA in THF
at −78 , followed by the addition of α,β-unsaturated ester 13
(available in three steps from 1,3-propandiol) to give 14a as
sole product in 84% yield. Based on previous outcome (Table
2, entry1) and X-ray analysis,14 we realized that incorrect ste-
reochemistry at C2 for (+)-α-allokainic acid and epimerization
of this chiral center is needed at a later synthetic stage. To
avoid the hydrolysis of ester groups in Michael adduct, Rol-
land’s method16 was employed to remove auxiliary moiety.
Lactam 15a was obtained in 68 % yield (2 steps) from the
hydrolysis of 14a with citric acid followed by heating in meth-
anol and recovered ketoamide 16 in 95% yield. Protection of
amide nitrogen in lactam 15a with (Boc)2O gave Boc-
protected lactam 17a. Deprotonation of 17a with LHMDS
followed by the treatment with acetone in the presence of BF3
etherate provided 18a as a single diastereomer.17 Subsequent
dehydration with the Burgess reagent18 provided alkene 19a in
87% yield. Boc-protected amide 19a was reduced with
DIBAL-H at −78 °C, and the crude product was reacted with
Et3SiH in the presence of BF3 etherate to give pyrrolidine 20a.
Hexamethylphosphoramide (HMPA) and crown ethers were
known to chelate metal cation and break metal ion chelation
between enolate and Michael acceptor. When the Michael
addition reaction of enolate 4-Li to methyl crotonate was con-
ducted in the presence of 2 equiv. or 4 equiv. of HMPA, or 12-
crown-4 (Table 2, entries 2-4), it gave poor stereoselectivity.
A decrease of product ratio from >98:<2 to 3:2 was observed
between 7 and 12 in each case. The stereochemistry of Mi-
chael adduct 12 was confirmed by X-ray crystallographic
analysis.15 Michael addition presumably proceeded through a
non-chelated transition mode in these cases. Based on these
experimental results, one may conclude that metal ion chela-
tion played an important role in this reaction.
Table 2. Additive Influence on Diastereoselective Michael
Addition of 4-Li Enolate with Methyl Crotonate.
Entry
1
Base
LDA
Additive
T (h)
3
Yield (%)
87
Ratio (7:12)
＞98:2
-
2
3
4
LDA
LDA
LDA
HMPA (2 eq.)
HMPA (6 eq.)
12-crown-4 (2 eq.)
3
3
3
70
68
76
3:2a
3:2
3:2
aDetermined by 400MHz 1HNMR spectroscopy of the crude mixture.
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Scheme 3. Total Synthesis of (−)-2-epi-α-Allokainic Acid 6
1
2
3
4
5
6
7
8
Entry
Acceptor
T(h) Product Yield(%)
Ratio
(2S,3S:2R,3S)
20b
92
＞98:2a
＞98:2
＞98:2
1
2
3
methyl crotonate
methyl crotonate
3
12
12
8b
18
18
9
methyl-trans-2-
hexenoate
13
66c
10
11
12
13
14
4
18
14b 70d
＞98:2
aNo second isomer was detected by 400 MHz 1H NMR spectroscopy. bWith a
recovery of 76% unreacted .cWith a recovery of 30% unreacted 4.d With a recov-
ery of 20% unreacted 4.
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We tried to resolve the incorrect stereochemistry at C2 by
epimerization with base. However, epimerization of 20a with
DBU, KOBut, LDA, or LHMDS gave no detectable C2-
epimer 20b after deprotonation and acidification sequence,
and only 20a was recovered (Scheme 4). Presumably, the ste-
ric hindrance of C3 substituent and Boc group which leaded to
protonation on α-face (favored) rather than β-face (disfavored),
and failed to invert configuration at C2 (Scheme 4).
Table 4. Additive Influence on Diastereoselective Michael
Addition of 4-Mg Enolate with Methyl Crotonate.
Scheme 4. Attempted Epimerization of 20a.
Entry Base
Additive
T (h)
18
Yield (%)
a65
Ratio (12:7)
1
2
3
MDA
MDA
MDA
HMPA (2 eq.)
HMPA (6 eq.)
15-crown-5 (2 eq.)
2:1
1:1
1:1
18
b60
c60
18
aWith a recovery of 76% unreacted 4. bWith a recovery of 10% unreacted 4 . cWith
a recovery of 11% unreacted 4. dWith a recovery of 5% unreacted 4.
After unsuccessful epimerization of 20a at C2, we decided to
explore synthetic strategy toward (−)-2-epi-α-allokainic acid at
this stage. Treatment of 20a with DDQ to remove PMB group
gave alcohol 21a in 90% yield. Finally, total synthesis of (−)-
2-epi-α-allokainic acid 6 can be accomplished by treatment
21a with Jones reagent and trifluoroacetic acid.7 (−)-2-epi-α-
Allokainic acid 6 could be synthesized with this synthetic pro-
tocol from 4 with 11 synthetic steps in 18% overall yield. Ac-
cording to X-ray analysis,19 the stereochemistry at C2 re-
mained as an R configuration. Although it had been reported
that epimerization of C2 stereochemistry could be achieved by
Michael addition of enolate 4-Mg to methyl trans-hexenoate
and 13 gave the corresponding Michael adducts 8b and 14b as
sole product, respectively. (Table 3, entries 3-4) Additive in-
fluence on MDA condition was also investigated (Table 4,
entries 1-3). When magnesium enolate 4-Mg reacted with
methyl crotonate at −78 °C for 18 h in the presence of 2 equiv.
HMPA, a decrease of product ratio from >98:2 to 2:1 between
12 and 7 was observed (Table 4, entry 1). Further increase
with the amount of HMPA from 2 equiv. to 6 equiv. gave no
selectivity (Table 4, entry 2). It gave no selectivity at C2 posi-
tion when the Michael reaction was conducted in the presence
of 15-crown-5 (Table 4, entry 3). The replacement of lithium
ion with magnesium ion resulted in a reverse of selectivity for
Michael reaction at C2. A plausible chelated transition state
model was proposed as shown in Scheme 5.
o
heating (−)-2-epi-α-allokainic acid 6 at 130-140 C for 5 h in
30-50% yield,8a it may not be practical.
To solve C2 stereochemistry for the synthesis of (+)-α-
allokainic acid 1, we investigated the possibility of stereose-
lective variant at C2 of Michael adduct 7 and explored the
metal ion effect on Michael addition reaction. When 4 was
treated with magnesium diisopropylamide (MDA) in tetrahy-
drofuran followed by the addition of methyl crotonate at −78
°C for 3 h, a change of stereoselectivity for Michael reaction at
C2 position was observed, and Michael adduct 12 was ob-
tained as sole product although in a lower yield (Table 3, entry
1). When the reaction time was prolonged from 3 h to 18 h, an
improvement on yield for Michael adduct 12 from 20% to
92% was observed (Table 3, entry 2).
Scheme 5 . A Plausible Transition State of Michael Addi-
tion with MDA.
Cα-si
CO Me
2
sterically favored
H
H
CO Me
2
H
Me
Ot-Bu
MDA
N
O
Me
4
H
N
O
Mg
.
−
Ot-Bu
2 Br
N
O
N
O
O
Mg
N
4-Mg
(Pri)
N
O
2
Mg
O
Cα-re
sterically disfavored
t-BuO
N(iPr)
2
H
O
N
x
Mg
4-Mg
T2
MeO
H
C
2
+
t-BuO
H
H
Me
12
Table 3. Diastereoselective Michael Addition of 4-Mg eno-
late with α,β-Unsaturated Esters .
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Based on a previous report,20 magnesium enolate could gather
Page 4 of 11
obtained and noted at 400 MHz (Bruker DPX-400 or Varian-
Unity-400). 13C NMR spectra were obtained at 100 MHz.
Chemical shifts are reported in values, in parts per million
(ppm) relative to relative to residual chloroform (7.26 ppm for
1
2
3
4
5
6
7
8
to form dimeric complex. Imagine that dimeric magnesium
enolate complex as a box, the less hinder moiety of chiral aux-
iliary was at the inner part of the box and more hindered gem-
dimethyl moiety of chiral auxiliary was at the outer part of the
box. The attack of magnesium enolate was not easy to happen
at re(Cα)-face (the inner part of the metal complex box) of
enolate to si(Cβ)-face of α,β-unsaturated ester due to metal ion
coordination with the other magnesium enolate. Therefore, the
attack of enolate occurred at the more hindered si(Cα)-face of
enolate to α,β-unsaturated ester (shown as T2 in Scheme 5).
The reactivity of magnesium enolate is lower and it required a
prolonged reaction time to achieve a reasonable yield (Table 3,
entry 2) due to the above mentioned steric hindrance. Through
this magnesium ion chelation pathway, compound 12 was
produced as the major product in the reaction of magnesium
enolate 4-Mg with methyl crotonate.
1H NMR, 77.00 ppm for 13C NMR) or H2O (4.80 ppm for H
1
NMR) as an internal standard. The multiplicities of the signals
are described using the following abbreviations: s = singlet, d
= doublet, t = triplet, q = quartet, dd = doublet of doublets, m
= multiplet, br = broad band. The melting point was recorded
on a melting point apparatus (Buchi512– melting point system)
and is uncorrected. IR spectra were performed in a spectropho-
tometer Bomen MB 100 FT-IR and only noteworthy IR ab-
sorptions (cm-1) are listed. Optical rotations were measured on
Perkin-Elmer 241 polarimeter. Mass spectrometric analyses
were performed by the Center for Advanced Instrumentation
and Department of Applied Chemistry at National Chiao Tung
University, Hsinchu, Taiwan.
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To extend this methodology further, a total synthesis of (+)-α-
allokainic acid 1 is illustrated on Scheme 6. With 14b in hand,
one could follow the same synthetic protocol as for the synthe-
sis of (−)-2-epi-α-allokainic acid to accomplish the synthesis
of (+)-α-allokainic acid 1 in 11 steps with 17.8% overall yield
(Scheme 6).
Tert-butyl
(1S)-2-(1-(N,N-diisopropylaminocarbonyl)-7,7-
dimethyl-bicyclo[2.2.1]hept-2-ylideneamino)ethanoate (4).
To a 250 mL two-necked round-bottom flask was added 1621
(9.0 g, 33.9 mmol), toluene (70 mL) and benzoic acid (12.36 g,
101.7 mmol). The mixture was heated to reflux for 2 h with
Dean-Stark apparatus to remove water. After 2 h, tert-butyl
glycinate (9 mL, 66.0 mmol) was added by means of a syringe
pump over 24 h and the resulting brown solution was stirred
for 12 h at 140 °C. After that, the reaction mixture was cooled
to room temperature, then was neutralized to pH = 6~7 by the
addition of saturated NaHCO3 solution (40 mL). The aqueous
layer was extracted with EtOAc (3 x 20 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by flash chromatography (eluent: EtOAc/hexanes, 1/10 + 1%
Et3N) to provide 4 (8.29 g, 21.9 mmol, 65 %) as white solid
Scheme 6. Total Synthesis of (+)-α-Allokainic acid 1.
and recover 16 (2.25 g, 8.5 mmol, 25 %).
22
Rf = 0.42 (EtOAc/hexanes, 1/6); mp = 98.0-98.8 °C; [α]D
–
106.0 (c 1.5, CHCl3); IR (neat) 2972, 1717, 1681, 1625, 1437,
1366, cm-1; 1H NMR (400 MHz, CDCl3) δ 4.25 (septet, J = 6.8
Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.80 (d, J = 15.6 Hz, 1H),
3.28 (septet, J = 6.8 Hz, 1H), 2.39 (ddd, J = 16.8, 4.4, 2.8 Hz,
1H), 2.14-1.87 (m, 4H), 1.77-1.69 (m, 1H), 1.43 (d, J = 6.8Hz,
3H), 1.42 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H), 1.30-1.22 (m, 1H),
1.16 (d, J = 6.8 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.05 (d, J =
6.8 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 181.2, 170.2,
169.3, 80.8, 65.2, 54.9, 50.9, 48.3, 46.1, 44.0, 35.3, 28.6, 28.0,
27.2, 21.5, 21.0, 20.6, 20.3, 20.2; HRMS (HRFI) m/z: [M]
Calcd for C22H38N2O3 378.2882; Found 378.2888.
The spectral data of (+)-α-allokainic acid are identical to those
reported ones, and specific rotation [α]D +7.8 (c 0.2, H2O) is in
agreement with the literature value (Lit.:7 [α]D +7.1(c 0.1,
H2O).
In conclusion, an asymmetric Michael reaction of imino-
glycinate bearing ketopinic amide as auxiliary has been devel-
oped with excellent diastereoselectivity. Switching of stere-
oselectivity at C2 of the Michael adducts could be achieved by
replacing lithium enolate with magnesium enolate. Utilization
of this methodology for the total syntheses of (−)-2-epi-α-
allokainic acid and (+)-α-allokainic acid from chiral imino-
glycinate 4 in 11 synthetic steps with 18 % and 17.8 % overall
yields respectively had been demonstrated.
General Procedures for Syntheses of Michael Adducts 7-11
Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethyl-icyclo[2.2.1]heptan-2-ylidene)-
amino)-3-methyl- glutamate (7). A solution of LDA in THF
was prepared under argon with diisopropylamine (0.1 mL,
0.69 mmol), THF (1 mL) ,and n-BuLi (2.3 M solution in n-
hexane, 0.28 mL, 0.64 mmol) at 0 °C. After stirring for 30 min,
the solution was cooled to –78 °C with a dry ice-acetone bath.
A solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0
mL) was added over 20 min, and the mixture was stirred for
30 min, then a solution of methyl crotonate (0.07 mL, 0.69
mmol) in THF (1 mL) was added slowly. The mixture was
stirred at –78 °C for 3 h then a 2% H2C2O4 (aq) solution (2 mL)
was added to the reaction mixture and the temperature was
■ EXPERIMENTAL SECTION
General information. Reagents were obtained from com-
mercial sources and used without further purification. Most
reactions were performed under an argon atmosphere in anhy-
drous solvents, which were dried prior to use following stand-
ard procedures. Merck Art. No. 7734 and 9385 silica gels were
1
employed for flash chromatography. H NMR spectra were
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raised to 0 °C. The mixture was neutralized to pH = 6~7 with
44.0, 43.0, 37.9, 36.6, 34.9, 32.7, 27.8, 21.9, 21.8, 20.8, 20.7,
20.6, 20.4, 20.3, 19.8, 14.3; HRMS (ESI) m/z: [M + H]+ Calcd
for C29H51N2O5 507.3792; Found 507.3799.
1
2
3
4
5
6
7
8
additional 2% H2C2O4(aq). The aqueous layer was extracted
with EtOAc (3 x 20 mL). The combined organic phases were
washed with brine (20 mL), dried over anhydrous Na2SO4, and
evaporated in vacuo. The residue was purified by flash chro-
matography (eluent: EtOAc/hexanes, 1/8 + 1% Et3N) to pro-
vide 7 (0.22 g, 0.46 mmol, 87 %) as white solid. Rf = 0.36
Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-
ylidene)amino)-3-phenyl- glutamate (10). Starting with a solu-
tion of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL),
and followed the same procedure as in the synthesis of 7 pro-
vided 10 (0.24 g, 0.45 mmol, 84 %) as white solid. Rf = 0.36
28
(EtOAc/hexanes, 1/6); mp = 142-145 °C; [α]D –9.9 (c 1.0,
CHCl3); IR (neat) 2969, 2940, 2889, 1738, 1728, 1679, 1630,
1
1474, 1436, 1335 cm-1; H NMR (400 MHz, CDCl3) δ 4.16
23
(EtOAc/hexanes, 1/6); mp = 162-163 °C; [α]D -6.3 (c 1.0,
9
(septet, J = 6.4 Hz, 1H), 3.64 (d, J =6.4 Hz, 1H), 3.60 (s, 3H),
3.24 (septet, J = 6.4 Hz, 1H), 2.53-2.45 (m, 3H), 2.15-2.02 (m,
2H), 1.95-1.81 (m, 2H), 1.74-1.64 (m, 2H), 1.37 (d, J = 6.4 Hz,
3H), 1.33 (s, 9H), 1.29 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4 Hz,
3H), 1.12 (s, 3H), 1.09-1.05 (m, 1H), 1.06 (s, 3H), 1.00 (d, J =
6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H) ; 13C NMR (100 MHz,
CDCl3) δ 180.7, 172.9, 169.8, 169.6, 81.0, 69.9, 65.4, 51.5,
51.3, 48.0, 45.9, 43.9, 37.6, 36.4, 32.9, 29.2, 27.8, 27.2, 21.7,
20.8, 20.6, 20.4, 20.3, 16.0; HRMS (ESI) m/z: [M + H]+ Calcd
for C27H47N2O5 479.3479; Found 479.3472.
CH2Cl2); IR (neat) 2994, 2971, 2932, 1742, 1728, 1686, 1436,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1425, 1365, 1334 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-
7.12 (m, 5H), 3.98 (d, J = 10.4 Hz, 1H), 3.94 (septet, J = 6.8
Hz, 1H), 3.64 (dt, J = 10.4, 4.0 Hz, 1H), 3.46 (s, 3H), 3.26
(septet, J = 6.8 Hz, 1H), 2.84 (dd, J = 15.6, 4.4 Hz, 1H), 2.70
(dd, J = 15.6, 10.8 Hz, 1H), 2.40-2.32 (m, 1H), 1.77-1.73 (m,
1H), 1.63-1.58 (m, 1H), 1.48-1.44 (m, 1H), 1.34 (s, 9H), 1.32
(d, J = 8.8 Hz, 3H), 1.30 (d, J = 8.8 Hz, 3H), 1.25 (d, J = 6.8
Hz, 3H), 1.15-1.11 (m, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.94 (d,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.7, 172.0,
170.0, 169.7, 140.7, 128.8, 127.9, 127.0, 81.5, 71.0, 65.6, 51.5,
51.2, 47.8, 46.1, 44.0, 43.6, 37.4, 36.1, 28.6, 27.9, 26.8, 22.0,
21.9, 20.7, 20.6, 20.2; HRMS (ESI) m/z: [M + H]+ Calcd for
C32H49N2O5 541.3644; Found 541.3636.
Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
aminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-
ylidene)amino)-3-propyl-glutamate (8a). Starting with a solu-
tion of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL),
and followed the same procedure as in the synthesis of 7 pro-
vided 8a (0.24 g, 0.48 mmol, 90 %) as white solid. Rf = 0.41
Tert-butyl 2,3-dimethyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diiso-
propylamino-arbonyl)-7,7-imethyl-bicyclo[2.2.1]heptan-2-yl-
23
(EtOAc/hexanes, 1/6); mp = 150-151 °C; [α]D –5.3 (c 1.0,
idene)amino)propane-1,2,3-tricarboxylate (11). Starting with
a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0
mL), and followed the same procedure as in the synthesis of 7
provided 11 (0.23 g, 0.44 mmol, 83 %). Rf = 0.24 (EtOAc/
hexanes, 1/6); mp = 160-162 °C; [α]D25 -114.3 (c 1.0, CH2Cl2);
IR (neat) 2970, 1736, 1676, 1475, 1437, 1368, 1335, 1150 cm-
1; 1H NMR (400 MHz, CDCl3) δ 4.14 (d, J = 8.0 Hz, 1H), 4.13
(septet, J =6.4 Hz, 1H), 3.64 (s,6H), 3.39-3.20 (m, 1H), 3.27
(septet, J= 6.4 Hz, 1H), 2.72 (dd, J = 6.0, 2.0 Hz, 1H), 2.52-
2.45 (m, 1H), 2.12 (dt, J = 12.0, 4.0 Hz, 1H), 1.98-1.88 (m,
1H), 1.87-1.78 (m, 1H), 1.84 (d, J =16.8 Hz, 1H), 1.75-1.70
(m, 1H), 1.36 (s, 9H), 1.35 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.8
Hz, 3H), 1.28-1.19 (m, 2H), 1.18 (s, 3H), 1.16 (d, J = 6.4 Hz,
3H), 1.11 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 182.5, 173.2, 172.1, 169.5, 168.4, 82.0, 66.3,
65.5, 51.8, 51.7, 51.6, 48.0, 46.0, 44.2, 43.9, 36.1, 32.8, 29.0,
27.8, 27.1, 21.8, 21.6, 20.7, 20.6, 20.4, 20.3; HRMS (ESI) m/z:
[M + H]+ Calcd for C28H47N2O7 523.3378; Found 523.3378.
CH2Cl2); IR (neat) 2964, 2928, 2868, 1738, 1722, 1626, 1434,
1370 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.18 (septet, J = 6.8
Hz, 1H), 3.84 (d, J =6.8 Hz, 1H), 3.60 (s, 3H), 3.27 (septet, J =
6.8 Hz, 1H), 2.58 (dd, J =15.6, 4.8 Hz, 1H), 2.54-2.46 (m, 1H),
2.43-2.35 (m, 1H), 2.25 (dd, J = 15.6, 7.6 Hz, 1H), 2.20-2.11
(m, 1H),1.97-1.85 (m, 2H), 1.77 (s, 1H), 1.70 (t, J = 4.5 Hz,
1H), 1.43-1.36 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.36 (s, 9H),
1.31 (d, J = 6.8 Hz, 3H), 1.30-1.21 (m, 2H), 1.17 (d, J = 6.4
Hz, 3H), 1.16-1.12 (m ,1H), 1.16 (s, 3H), 1.09 (s, 3H), 1.02 (d,
J=6.4 Hz, 3H), 0.84 (m, 3H) ; 13C NMR (100 MHz, CDCl3) δ
180.8, 173.5, 170.0, 169.7, 81.0, 67.8, 65.6, 51.6, 51.3, 48.0,
46.0, 44.0, 37.9, 36.6, 34.9, 32.7, 29.3, 27.8, 27.2, 21.9, 20.8,
20.7, 20.4, 20.3, 19.8, 14.3; HRMS (ESI) m/z: [M + H]+ Calcd
for C29H51N2O5 507.3792; Found 507.3796.
Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
aminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-
ylidene)amino)-3-isopropyl-glutamate (9). Starting with a
solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0
mL), and followed the same procedure as in the synthesis of 7
provided 9 (0.19 g, 0.37 mmol, 71 %) as white solid, and re-
General Procedures for the Synthesis of Michael Adduct
12 Using MDA
Tert-butyl methyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylide-
covered
4 (0.03 g, 0.08 mmol, 15 %). Rf = 0.43
27
(EtOAc/hexanes, 1/6); mp = 156-158 °C; [α]D +32.6 (c 1.0,
CH2Cl2); IR (neat) 2966, 2938, 2883, 1739, 1730, 1630, 1474,
1368, 1335 cm-1; 1H NMR (CDCl3, 400 MHz) δ 4.17 (septet, J
= 6.8 Hz, 1H), 3.87 (d, J =6.8 Hz, 1H), 3.59 (s, 3H), 3.24 (sep-
tet, J = 6.8 Hz, 1H), 2.53 (dd, J =16.0, 4.0 Hz, 1H), 2.50-2.30
(m, 2H), 2.23 (dd, J = 16.0, 6.8 Hz, 1H), 2.18-2.04 (m, 1H),
1.99-1.83 (m, 2H), 1.77 (d, J = 16.8 Hz, 1H), 1.73-1.64 (m,
1H), 1.38 (d, J = 6.8 Hz , 3H), 1.34 (s, 9H), 1.29 (d, J = 6.8
Hz , 3H), 1.26-1.24 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.14 (d,
J = 6.8 Hz, 3H), 1.13 (s, 3H), 1.06 (s, 3H), 1.00 (d, J = 6.8 Hz,
3H), 0.82 (m, 3H) ; 13C NMR (CDCl3, 100 MHz) δ 180.8,
173.5, 170.0, 169.8, 81.0, 67.8, 65.6, 51.6, 51.3, 48.0, 46.0,
ne)amino)-3-methyl-glutamate (12). A solution of MDA in
THF was prepared under argon with diisopropylamine (0.1
mL, 0.69 mmol), THF (1.3 mL), and methylmagnesium bro-
mide (3.0 M solution in THF, 0.21 mL, 0.64 mmol) at 0 °C.
After stirring for 30 min, the solution was cooled to –78 °C
with a dry ice-acetone bath. A solution of iminoglycinate 4
(0.2g, 0.53 mmol) in THF (1.0 mL) was added over 20 min,
and the mixture was stirred for 1 h, then a solution of methyl
crotonate (0.07 mL, 0.69 mmol) in THF (1 mL) was added
slowly. The mixture was stirred at –78 °C for 18 h, then a 2%
H2C2O4(aq) solution (2 mL) was added. The reaction mixture
5
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was warmed to 0 °C and neutralized with additional 2% 3412, 2937, 2864, 1613, 1513, 1464, 1442, 1365, 1302, 1248,
1174, 1090, 1084 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.22 (d,
J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H), 3.77 (s,
3H), 3.72 (t, J = 5.6 Hz, 2H), 3.60 (t, J = 5.8 Hz, 2H), 2.56 (br,
1H), 1.89-1.77 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 159.1,
130.1, 129.2, 113.7, 72.8, 68.9, 61.6, 55.2, 32.0; HRMS (ESI)
m/z: [M + Na]+ Calcd for C11H16O3Na 219.0992; Found
219.0995.
1
2
3
4
5
6
7
8
H2C2O4(aq) to pH=7~8. The aqueous layer was extracted with
EtOAc (3 x 20 mL). The combined organic phases were
washed with brine (20 mL), dried over anhydrous Na2SO4, and
evaporated in vacuo. The residue was purified by flash chro-
matography (eluent: EtOAc/hexanes, 1/10 + 1% Et3N) to pro-
vide 12 (235 mg, 0.49 mmol, 92 %). Rf = 0.38 (EtOAc/hexanes,
27
1/6); mp = 143-145 °C; [α]D
–193.5 (c 1.0, CH2Cl2); IR
(neat) 2969, 2935, 2885, 1736, 1728, 1677, 1628, 1436, 1367
Ethyl (E)-5-((4-methoxybenzyl)oxy)pent-2-enoate (13). To a
100 mL round-bottom flask containing DMSO (2.52 mL,
35.61 mmol) and DCM (30 mL) was slowly added oxalyl
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.17 (septet, J = 6.8 Hz,
9
1H), 3.62 (d, J =7.2 Hz, 1H), 3.56 (s, 3H), 3.25 (septet, J = 6.8
Hz, 1H), 2.62-2.39 (m, 3H), 2.17-2.01 (m, 2H), 1.96-1.85 (m,
2H), 1.81-1.69 (m, 2H), 1.37 (s, 9H), 1.35 (d, J = 6.8 Hz, 3H),
1.29 (d, J = 6.8 Hz, 3H), 1.23-1.15 (m, 1H), 1.12 (d, J = 6.8
Hz, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H),
0.89 (d, J = 6.8 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ
180.8, 173.4, 169.8, 169.7, 80.6, 69.0, 65.3, 51.2, 50.4, 48.0,
45.9, 43.9, 37.0, 35.6, 33.0, 28.5, 27.9, 27.3, 21.6, 21.5, 20.8,
20.3, 20.2, 16.7; HRMS (ESI) m/z: [M + H]+ Calcd for
C27H47N2O5 479.3479; Found 479.3488.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
chloride (1.52 mL, 17.80 mmol) at -78 C. After the reaction
mixture was stirred for 30 min, a solution of 22 (2.33 g, 11.87
mmol) in DCM (9 mL) was added. After stirring for 1 h, the
mixture was added triethylamine (6.7 mL, 47.48 mmol) and
o
slowly warmed to 0 C for 1 h. The reaction mixture was
quenched by the addition of saturated sodium bicarbonate
solution (10 mL), then organic layer was washed with brine
(3×20 mL). Aqueous layer was extracted with EtOAc (2×20
mL). Combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude prod-
uct was used without purification. To a 50 mL round-bottom
flask containing NaH (60% in mineral oil, 522 mg, 13.06
mmol) and THF (20 mL) was added triethylphosphonoacetate
Tert-butyl methyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylid-
ene)amino)-3-propyl-glutamate (8b). Starting with a solution
of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL), and
followed the same procedure as in the synthesis of 12 provided
8b (0.177 g, 0.35 mmol, 66 %) as white solid and 4 (42 mg,
0.16 mmol, 30 %). Rf = 0.46 (EtOAc/hexanes, 1/6); mp = 153-
o
(2.8 mL, 14.24 mmol) at 0 C. The mixture was stirred for 30
min, then a solution of crude aldehyde in THF (5.7 mL) was
added. After stirring for additional 30 min, the reaction mix-
ture was quenched by the addition of saturated aqueous am-
monium chloride solution (10 mL) and brine (10 mL). The
aqueous phase was extracted with EtOAc (3×20 mL). Com-
bined organic layers were dried over anhydrous Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by
flash chromatography (eluent: EtOAc/hexanes, 1/3) to provide
13 (2.38 g, 9.02 mmol, 76 %) as colorless liquid. Rf = 0.56
(EtOAc/hexanes, 1/2); IR (neat) 2937, 2905, 2859, 1718, 1655,
23
155 °C; [α]D –175.3 (c 1.0, CH2Cl2); IR (neat) 2960, 2935,
2878, 1735, 1720, 1629, 1435, 1375 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.23 (septet, J = 6.8 Hz, 1H), 3.86 (d, J =6.8 Hz, 1H),
3.59 (s, 3H), 3.31 (septet, J = 6.8 Hz, 1H), 2.52-2.40 (m, 2H),
2.37-2.29 (m, 1H), 2.22-2.14 (m, 1H), 2.10-2.02 (m, 1H),1.99-
1.86 (m, 3H), 1.76-1.71(m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.41
(s, 9H), 1.33 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.4 Hz, 3H),
1.30-1.21 (m, 1H), 1.18 (s ,3H), 1.17 (s, 3H), 1.16-1.12 (m, 1H)
1.10 (d, J = 6.6 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H), 0.83 (m, 3H) ;
13C NMR (100 MHz, CDCl3) δ 180.8, 173.7, 170.3, 167.9,
80.7, 68.5, 66.7, 51.2, 50.8, 48.4, 46.3, 43.7, 37.5, 35.6, 35.1,
33.4, 28.0, 27.8, 27.5, 21.5, 21.3, 21.0, 20.8, 20.7, 20.2, 14.1;
HRMS (ESI) m/z: [M + H]+ Calcd for C29H51N2O5 507.3792;
Found 507.3796.
1
1612, 1513, 1248, 1175, 1096, 1037 cm-1; H NMR (CDCl3,
400 MHz) δ 7.22 (d, J = 8.6 Hz, 2H), 6.94 (dt, J = 15.7, 7.0 Hz,
1H), 6.85 (d, J = 8.6 Hz, 2H), 5.86 (dt, J = 15.7, 1.5 Hz, 1H),
4.42 (s, 2H), 4.15 (q, J= 7.1 Hz, 2H), 3.77 (s, 3H), 3.52 (t, J =
6.5 Hz, 2H), 2.46 (qd, J = 6.6, 1.6 Hz, 2H), 1.26 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 166.4, 159.1, 145.6,
130.1, 129.2, 122.8, 113.7, 72.6, 67.9, 60.1, 55.2, 32.5, 14.2;
HRMS (ESI) m/z: [M + Na]+ Calcd for C15H20O4Na 287.1254;
Found 287.1250.
Synthesis of Michael Acceptor 13
Syntheses of (+)-α-Allokainic acid 1 and (−)-2-epi-α-
Allokainic acid 6
3-((4-Methoxybenzyl)oxy)propan-1-ol (22). To a suspension
of sodium hydride (60% in mineral oil, 1.22 g, 30.6 mmol) in
dry THF (50 mL) was added TBAI (1.028 g, 2.78 mmol) at 0
oC and stirred for 5 min. A solution of 1,3-propanol (2 mL,
Tert-butyl Ethyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-ylide-
o
27.78 mmol) in THF (6 mL) was then added at 0 C and the
ne)amino)-3-(2-((4-methoxy-benzyl)oxy)-ethyl)glutamate
(14a). A solution of LDA in THF was prepared under argon
with diisopropylamine (0.55 mL, 3.96 mmol), THF (4.2 mL),
and n-BuLi solution (2.3 M solution in hexane, 1.61 mL, 3.70
mixture was warmed to room temperature for 30 min. After 30
min, reaction mixture was again cooled to 0 oC, and p-
methoxybenzyl chloride (3.76 mL, 27.85 mmol) was added
slowly with additional stirring for 12 h. Finally, the reaction
was quenched by the addition of iced water. The aqueous
phase was separated and extracted with EtOAc (3×50 mL).
The combined organic layers were washed with water, brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by flash chromatography (eluent: EtOAc/
hexanes, 2/1) to provide 22 (4.74 g, 24.17 mmol, 87 %) as
colorless liquid. Rf = 0.36 (EtOAc/hexanes, 1/1); IR (neat)
o
mmol) at 0 C. After stirring for 30 min, the solution was
o
cooled to –78 C with a dry ice-acetone bath and a solution of
iminoglycinate 4 (1.0 g, 2.64 mmol) in THF (1.8 mL) was
added over 20 min. The mixture was stirred for 30 min, then
the solution of 13 (0.84 g, 3.17 mmol) in THF (0.8 mL) was
added slowly. The mixture was stirred for 4 h at –78 oC, then a
solution of 2% H2C2O4(aq) (10 mL) was added. The reaction
o
mixture was warmed to 0 C then was neutralized with addi-
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The Journal of Organic Chemistry
tional 2% H2C2O4 (aq) to pH=6~7. The aqueous layer was Tert-butyl (2R,3S)-3-(2-((4-methoxybenzyl)oxy)ethyl)-5-oxo-
1
2
3
4
5
6
7
8
extracted with EtOAc (3 x 20 mL). The combined organic
phases were washed with brine (20 mL), dried over anhydrous
Na2SO4, and evaporated in vacuo. The residue was purified by
flash chromatography (eluent: EtOAc/hexanes, 1/8 + 1% Et3N)
to provide 14a (1.42 g, 2.21 mmol, 84 %) as colorless liquid.
Rf = 0.22 (EtOAc/hexanes, 1/6); [α]D21 –4.8 (c 1.0, CH2Cl2); IR
(neat) 2969, 2936, 1734, 1628, 1513, 1438, 1367, 1335, 1248,
pyrrolidine-2-carboxylate (15a). To a 25 mL flask was
charged with 14a (1.0 g, 1.55 mmol) in THF ( 5.2 mL) and an
aqeous solution of 15% citric acid ( 3.4 mL, 1.63 mmol). The
mixture was stirred at room temperature for 9 day, then con-
centrated under reduced pressure to remove THF. The residue
was dissolved in H2O (5 mL). The aqueous phase was adjusted
to pH 7 using saturated Na2CO3 solution then extracted with
dichloromethane (2 x 30 mL). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The crude amino ester was dissolved in MeOH (7.8
mL) and refluxed for 6 h. Finally, MeOH was evaporated in
vacuo, and the residue was purified by flash chromatography
(eluent: EtOAC/hexanes, 1/2 to DCM/MeOH, 10/1) to provide
15a (368 mg, 1.05 mmol, 68%) as colorless liquid and auxilia-
ry 16 (393 mg, 1.48 mmol, 95 %). Rf = 0.16 (EtOAc/hexanes,
1
1160 cm-1; H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.7 Hz,
2H), 6.82 (d, J = 7.7 Hz, 2H), 4. 39-4.35 (m, 2H), 4.16 (septet,
J = 6.4 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.90 (d, J =6.4 Hz,
1H), 3.76 (s, 3H), 3.55-3.38 (m, 2H), 3.35-3.20 (m, 1H), 2.68-
2.39 (m, 3H), 2.31 (dd, J = 15.9, 4.0 Hz, 1H), 2.21-2.06 (m,
1H), 2.02-1.82 (m, 3H), 1.80-1.58 (m, 4H), 1.43 (d, J = 6.8 Hz,
2H), 1.39-1.35 (m, 2H), 1.37 (s, 9H), 1.32 (d, J = 6.4 Hz, 3H),
1.21 (d, J = 6.4 Hz, 3H), 1.25-1.15 (m, 2H), 1.16 (s, 3H), 1.09
(s, 3H), 1.01 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 181.2, 172.8, 169.9, 169.7, 159.0, 130.4, 129.1, 113.6, 81.1,
72.3, 67.8, 67.7, 65.5, 60.1, 55.1, 51.7, 48.0, 46.0, 44.0, 36.5,
35.7, 35.1, 30.2, 29.3, 27.8, 27.4, 27.1, 21.8, 20.8, 20.7, 20.4,
20.3, 14.2; HRMS (ESI) m/z: [M + H]+ Calcd for C37H59N2O7
643.4317; Found 643.4331.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23
1/1); [α]D –8.1 (c 1.0, CH2Cl2); IR (neat) 3252, 2979, 2936,
2863, 2290, 1732, 1682, 1515, 1456, 1422, 1369, 1301, 1249,
1156, 1095, 1034 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.23 (d,
J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.00 (br, 1H), 4.43
(d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.04 (d, J = 8.0
Hz, 1H), 3.80 (s, 3H), 3.56-3.41 (m, 2H), 2.92-2.79 (m, 1H),
2.33 (dd, J = 16.4, 8.2 Hz, 1H), 2.17 (dd, J = 16.4, 9.9 Hz, 1H),
1.93-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.46 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 178.3, 170.3, 159.2, 130.1, 129.2, 113.8,
82.5, 72.7, 67.4, 59.8, 55.2, 35.7, 34.9, 30.3, 28.0; HRMS (ESI)
m/z: [M + Na]+ Calcd for C19H27NO5 Na 372.1781; Found
372.1785.
Tert-butyl Ethyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropyl-
amino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene-
)amino)-3-(2-((4-methoxy-benzyl)oxy)-ethyl)-glutamate (14b).
A solution of MDA in THF was prepared under argon with
diisopropylamine (0.56 mL, 3.96 mmol), THF (6.7 mL), and
Methylmagnesium bromide solution (1.0 M solution in THF,
3.7 mL, 3.70 mmol) at 0 oC. After stirring for 30 min, the solu-
Tert-butyl (2S,3S)-3-(2-((4-methoxybenzyl)oxy)ethyl)-5-oxo-
o
pyrrolidine-2-carboxylate (15b). Starting with 14b (1.0 g, 1.55
mmol) and followed the same procedure as in the synthesis of
15 a provided 15b (381 mg, 1.09 mmol, 70 %) as colorless
liquid and recovered auxiliary 16 (379 mg, 1.43 mmol, 92 %).
tion was cooled to –78 C with a dry ice-acetone bath and a
solution of iminoglycinate 4 (1.0 g, 2.64 mmol) in THF (1.8
mL) was added over 20 min. The mixture was stirred for 1 h,
then a solution of 13 (0.7 g, 2.64 mmol) in THF (2.6 mL) was
added slowly. The mixture was warmed to – 60 oC, and stirred
for an additional 18 h, then a solution of 2% H2C2O4(aq) (10
23
Rf = 0.11 (EtOAc/hexanes, 1/1); [α]D +17.8 (c 1.0, CH2Cl2);
IR (neat) 3246, 2972, 2928, 2858, 1734, 1700, 1514, 1457,
1369, 1290, 1247,1156,1100, 1034 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
6.35 (br, 1H), 4.42 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz,
1H), 3.82 (d, J = 5.6 Hz, 1H), 3.80 (s, 3H), 3.53-3.46 (m, 2H),
2.68-2.56 (m, 1H), 2.51 (dd, J = 16.6, 9.0 Hz, 1H), 2.02 (dd, J
= 16.5, 6.6 Hz, 1H), 2.02-1.99 (m, 1H), 1.76-1.67 (m, 1H),
1.45 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 176.9, 170.7,
159.1, 130.2, 129.1, 113.7, 82.4, 72.6, 67.6, 61.4, 55.2, 36.5,
36.1, 34.6, 27.9; HRMS (ESI) m/z: [M + Na]+ Calcd for
C19H27NO5Na 372.1786; Found 372.1780.
o
mL) was added. The reaction mixture was warmed to 0 C
then neutralized with additional 2% H2C2O4(aq) to pH=7~8.
The aqueous layer was extracted with EtOAc (3 x 20 mL). The
combined organic phases were washed with brine (20 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by flash chromatography (eluent: EtOAc/
hexanes, 1/8 + 1% Et3N) to provide 14b (1.19 g, 1.85 mmol,
70 %) as pale yellow liquid and 6 (0.2 g, 0.53 mmol, 20 %). Rf
= 0.23 (EtOAc/hexanes, 1/6); [α]D 21 –39.6 (c 1.0, CH2Cl2); IR
(neat) 2969, 2935, 2885, 1732, 1627, 1513, 1367, 1365,
1
1247,1155 cm-1; H NMR (400 MHz, CDCl3) δ 7.22 (d, J =
Di-(tert-butyl) (2R,3S)-3-(2-((4-methoxybenzyl)oxy)ethyl)-5-
oxo-pyrrole- dine-1,2-dicarboxylate (17a). To a 10 mL round-
bottom flask containing a solution of 15a (0.59 g, 1.67 mmol)
in MeCN (5.5 mL) was added Boc2O (0.77 mL, 3.35 mmol)
and DMAP (0.02 g, 0.17 mmol). The reaction mixture was
8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 4.45-4.31(m, 3H), 4.23
(septet, J = 6.8 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.96 (d, J
=6.2 Hz, 1H), 3.80 (s, 3H), 3.44 (t, J = 6.5 Hz, 1H), 3.34-3.24
(m, 1H), 2.82-2.62 (m, 1H), 2.50 (dd, J = 16.0, 4.0 Hz, 1H),
2.45-2.30 (m, 2H), 2.15-2.05 (m, 1H), 2.03-1.87 (m, 1H),
1.79-1.60 (m, 3H), 1.42 (s, 9H), 1.41 (d, J = 6.8 Hz, 3H), 1.34
(d, J = 6.8 Hz, 3H), 1.29-1.20 (m, 3H), 1.18 (d, J = 6.8 Hz,
3H), 1.16 (d, J = 6.8 Hz, 3H), 1.12 (s, 3H), 1.09 (s, 3H), 1.04
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 181.2,
173.1, 170.1, 169.6, 159.0, 130.6, 129.3, 113.6, 80.7, 72.3,
68.1, 66.7, 65.4, 60.0, 55.2, 50.5, 48.1, 46.0, 44.0, 35.7, 35.7,
35.5, 35.2, 30.7, 28.6, 28.0, 27.4, 21.9, 21.6, 20.9, 20.3, 14.1;
HRMS (HRFI) m/z: [M] Calcd for C37H58N2O7 642.4244;
Found 642.4239.
o
cooled to 0 C for 10 min, then triethylamine (0.7 mL, 5.01
mmol) was added dropwise. The reaction mixture was warmed
to room temperature, and stirred for 12 h. A saturated Na-
HCO3(aq) solution was added to the reaction mixture with
stirring. The aqueous layer was extracted with EtOAc (3 x 20
mL). The combined organic phases were washed with brine
(20 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by flash chromatography (el-
uent: EtOAc/hexanes, 1/2) to provide 17a (741 mg, 1.65 mmol,
99 %) as colorless liquid. Rf = 0.44 (EtOAc/hexanes, 1/1);
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27
[α]D –5.4 (c 1.0, CHCl3); IR (neat) 3521, 2980, 2934, 2877,
1790, 1761, 1696, 1583, 1542, 1515, 1456, 1372, 1316, 1160,
1030 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.22 (d, J = 8.6 Hz,
2H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.39
(d, J = 11.5 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H),
3.56-3.42 (m, 2H), 2.73-2.60 (m, 1H), 2.48 (dd, J =16.9, 8.0
Hz, 1H), 2.36 (dd, J =16.8, 12.7 Hz, 1H), 1.93-1.81 (m, 1H),
1.73-1.63 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 173.3, 170.0, 159.2, 149.2, 130.0, 129.3,
113.8, 83.3, 82.6, 72.7, 67.2, 63.3, 55.2, 37.3, 31.6, 30.4, 28.0,
27.9; HRMS (ESI) m/z: [M + Na]+ Calcd for C24H35NO7Na
472.2306; Found 472.2313.
provided 18b (323 mg, 0.64 mmol, 77%). Rf = 0.35 (EtOAc/
26
1
2
3
4
5
6
7
8
hexanes, 1/1); [α]D
– 4.0 (c 1.0, CHCl3); IR (neat) 2976,
2930, 2861, 1784, 1734, 1700, 1515, 1457, 1369, 1307, 1249,
1
1156 cm-1; H NMR (CDCl3, 400 MHz) δ 7.20 (d, J = 8.4 Hz,
2H), 6.84 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 11.2 Hz, 1H),
4.38(d, J = 11.2 Hz, 1H), 4.14 (d, J = 4.4 Hz, 1H), 4.01 (br,
1H), 3.77 (s, 3H), 3.60 (t, J = 5.3 Hz, 2H), 2.45 (d, J = 6.1 Hz,
1H), 2.22-2.13 (m, 1H), 2.01-1.91 (m, 1H), 1.87-1.76 (m, 1H),
1.48 (s, 9H), 1.44 (s, 9H), 1.21 (s, 3H), 1.19 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 175.0, 169.9, 159.1, 148.9, 129.9, 129.0,
113.6, 83.7, 82.2, 72.6, 72.0, 66.8, 63.6, 58.3, 55.1, 36.8, 34.1,
27.7, 27.0, 26.1; HRMS (ESI) m/z: [M + Na]+ Calcd for
C27H41NO8 Na 530.2729; Found 530.2722.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Di-(tert-butyl) (2S,3S)-3-(2-((4-methoxybenzyl)oxy)ethyl)-5-
oxo-pyrrolidine-1,2-dicarboxylate (17b). Starting with 15b
(423 mg, 1.2 mmol) and followed the same procedure as in the
synthesis of 17a provided 17b (510 mg, 1.14 mmol, 95 %) as
pale yellow liquid. Rf = 0.49 (EtOAc/hexanes, 1/1); [α]D26 –2.3
(c 1.0, CHCl3); IR (neat) 2979, 2927, 2853, 1792, 1734, 1717,
1700, 1559, 1508, 1457, 1369, 1313, 1249, 1155, 1034 cm-1;
1H NMR (CDCl3, 400 MHz) δ 7.21 (d, J = 8.7 Hz, 2H), 6.84
(d, J = 8.7 Hz, 2H), 4.42 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.5
Hz, 1H), 4.19 (d, J = 3.2 Hz, 1H), 3.76 (s, 3H), 3.54-3.44 (m,
2H), 2.69 (dd, J =17.5, 8.9 Hz, 1H), 2.42-2.33 (m, 1H), 2.18
(dd, J = 17.5, 3.8 Hz, 1H), 1.93-1.83 (m, 1H), 1.72-1.61 (m,
1H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
172.9, 169.8, 159.1, 149.2, 129.9, 129.0, 113.6, 83.2, 82.0,
72.6, 66.9, 64.7, 55.1, 37.5, 34.6, 32.0, 27.8, 27.7; HRMS (ESI)
m/z: [M + Na]+ Calcd for C24H35NO7Na 472.2311; Found
472.2303.
Di-(tert-butyl)
(2R,3S,4R)-3-(2-((4-methoxybenzyl)oxy)-
ethyl)-5-oxo-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate
(19a). To a stirred solution of alcohol 18a (283 mg, 0.56 mmol)
in toluene (6 mL) was added Burgess reagent18a (405 mg, 1.70
mmol). The mixture was stirred at 110 °C for 10 min then
cooled to room temperature. After cooling, the solvent was
evaporated and the residue was purified by flash chromatog-
raphy (EtOAc/hexanes, 1/1) to give 19a (233 mg, 0.48 mmol,
85 %) as colorless liquid. Rf = 0.56 (EtOAc/hexanes, 1/1); [α]D
24
–25.0 (c 1.0, CH2Cl2); IR (neat) 2978, 2936, 1793, 1735,
1514, 1457, 1369, 1313, 1250, 1157 cm-1; H NMR (CDCl3,
1
400 MHz) δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
5.04 (s, 1H), 4.90 (s, 1H), 4.46-4.33 (m, 3H), 3.79 (s, 3H),
3.57 (t, J = 6.0 Hz, 2H), 3.12 (d, J = 12.7 Hz, 1H), 2.73-2.60
(m, 1H), 1.81-1.72 (m, 1H), 1.71 (s, 3H), 1.69-1.56 (m, 1H),
1.49 (s, 9H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
172.9, 169.0, 159.2, 149.3, 139.2, 130.2, 129.2, 117.6, 113.7,
83.3, 82.6, 72.5, 66.5, 61.4, 56.0, 55.2, 34.4, 29.4, 28.0, 18.9;
HRMS (ESI) m/z: [M + Na]+ Calcd for C27H39NO7Na 5
12.2619; Found 512.2631.
Di-(tert-butyl) (2R,3S,4R)-4-(2-hydroxypropan-2-yl)-3-(2-
((-4-methoxybenzyl)-oxy)ethyl)-5-oxopyrrolidine-1,2-
dicarboxylate (18a). To a 25 mL round-bottom flask contain-
ing 17a (624 mg, 1.39 mmol) in THF (3.6 mL) was dropwise
added LHMDS (1.06 M solution in THF, 1.7 mL, 1.81 mmol )
at –78 °C. The resulting mixture was stirred for 1 h before the
Di-(tert-butyl) (2S,3S,4R)-3-(2-((4-methoxybenzyl)oxy)ethyl)-
5-oxo-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (19b).
Starting with 18b (303 mg, 0.60 mmol), and followed the
same procedure as in the synthesis of 19a provided 19b (254
mg, 0.52 mmol, 87%) as colorless liquid. Rf = 0.51 (EtOAc/
hexanes, 1/1); [α]D
.
solution of BF3 OEt2 (0.34 mL, 2.78 mmol) and acetone (0.2
mL, 2.78 mmol) in THF (1.0 mL) was added dropwise at –78
oC. After 7 h, the reaction mixture was quenched with the ad-
dition of saturated NH4Cl solution (5 mL), and the aqueous
layer was extracted with EtOAc (3 ×15 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (eluent: DCM/EtOAc, 7:2)
to give 18a (605 mg, 1.14 mmol, 82 %) as colorless liquid. Rf
25
–9.2 (c 1.0, CH2Cl2); IR (neat) 2978,
2936, 1792, 1742, 1514, 1369, 1311, 1249, 1157 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 7.20 (d, J = 8.5 Hz, 2H), 6.83 (d, J
= 8.5 Hz, 2H), 4.96 (s, 1H), 4.87 (s, 1H), 4.40 (d, J = 11.5 Hz,
1H), 4.36 (d, J = 11.2 Hz, 1H), 4.10 (d, J = 6.4 Hz, 1H), 3.77
(s, 3H), 3.53 (t, J = 6.2 Hz, 2H), 2.98 (d, J = 8.3 Hz, 1H),
2.41-2.31 (m, 1H), 2.02-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.71
(s, 3H), 1.49 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 172.4, 169.8, 159.1, 149.3, 140.0, 130.1, 129.1, 116.3, 113.6,
83.4, 82.0, 72.4, 66.4, 63.5, 57.4, 55.0, 35.8, 34.1, 27.7, 19.4;
HRMS (ESI) m/z: [M + Na]+ Calcd for C27H39NO7Na
512.2619; Found 512.2630.
27
= 0.42 (EtOAc/hexanes, 1/1); [α]D –18.0 (c 0.9, CHCl3); IR
(neat) 3491, 2978, 2936, 2871, 1789, 1736, 1696, 1613, 1514,
1
1459, 1370, 1305, 1254, 1158 cm-1; H NMR (CDCl3, 400
MHz) δ 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.46
(d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.35 (d, J = 8.3
Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J = 7.6, 4.5 Hz, 2H), 2.59-2.42
(m, 2H), 2.19-2.07 (m, 1H), 1.64-1.54 (m, 1H), 1.50 (s, 9H),
1.45 (s, 9H), 1.26 (s, 3H), 1.25 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 175.9, 169.0, 159.2, 149.0, 130.1, 129.2, 113.8, 83.9,
82.9, 72.7, 72.2, 66.9, 61.8, 55.9, 55.2, 33.5, 30.6, 28.2, 27.9,
27.8, 25.9; HRMS (ESI) m/z: [M + Na]+ Calcd for C27H41NO8
Na 530.2724; Found 530.2722.
Di-(tert-butyl)
(2R,3S,4R)-3-(2-((4-methoxybenzyl)oxy)-
ethyl)-4-(prop-1-en-2-yl)-pyrrolidine-1,2-dicarboxylate (20a).
To a solution of 19a (0.20 g, 0.41 mmol) in THF (4.1 mL) was
added DIBAL-H (1.0 M solution in toluene, 3.28 mL, 3.28
mmol) at -78 °C under a argon atmosphere. After 90 min, the
reaction mixture was quenched with saturated potassium sodi-
um tartrate (aq) and warmed to room temperature. The reac-
tion mixture was stirred vigorously for 1 h, and two phases
were separated. The aqueous layer was extracted with EtOAc
(3 x 20 mL). The combined organic phases were dried over
Di-(tert-butyl)
(2S,3S,4R)-4-(2-hydroxypropan-2-yl)-3-(2-
((4-methoxybenzyl)oxy)-ethyl)-5-oxopyrrolidine-1,2-
dicarboxylate (18b). Starting with 17b (373 mg, 0.83 mmol),
and followed the same procedure as in the synthesis of 18a
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The Journal of Organic Chemistry
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
MHz) δ 171.1, 153.6, 141.8, 114.1, 81.6, 79.7, 62.9, 60.5, 49.3,
48.8, 41.5, 31.1, 28.1, 27.9, 18.2; HRMS (ESI) m/z: [M + Na]+
Calcd for C19H33NO5Na 378.2251; Found 378.2261.
1
2
3
4
5
6
7
8
crude product was used without purification. The above crude
product (0.20 g) was dissolved in DCM (3.1 mL) and Et3SiH
(0.13 mL, 0.82 mmol) was added at -78 °C. After 15 min, a
Di-(tert-butyl) (2S,3S,4R)-3-(2-hydroxyethyl)-4-(prop-1-en-
2-yl)pyro-lidine-1,2-dicarboxylate (21b). Starting with 20b
(74 mg, 0.15 mmol), and followed the same procedure as in
.
solution of BF3 OEt2 (0.1 mL, 0.82 mmol) in CH2Cl2 (1.0 mL)
was added dropwise under an argon atmosphere. The resulting
mixture was stirred 2 h at -78 °C, and quenched with saturated
NaHCO3(aq) solution. The aqueous layer was separated and
extracted with CH2Cl2 (3 x 10 mL). The combined organic
phases were dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash chroma-
tography (eluent: EtOAc/hexanes, 1/3) to give 20a (176 mg,
0.37 mmol, 2 steps for 90%) as colorless liquid. Rf = 0.70
(EtOAc/hexanes, 1/3); [α]D 26 –33.1 (c 1.30, CH2Cl2); IR (neat)
2976, 2933, 2857, 1738, 1730, 1614, 1515, 1456, 1394, 1367,
the synthesis of 21a provided 21b (46 mg, 0.13 mmol, 85 %)
19
as pale yellow liquid. Rf = 0.44 (EtOAc/hexanes, 1/1); [α]D
–
14.0 (c 1.0, CH2Cl2); IR (neat) 3474, 2978, 2933, 2886, 1739,
1702, 1404, 1368, 1255, 1171,1156, 1133 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 4.85 (m, 2H), 3.93 (dd, J = 14.8, 7.7 Hz,
1H), 3.82-3.57 (m, 3H), 3.23-3.13 (m, 1H), 2.54-2.41 (m, 1H),
2.22-2.12 (m, 1H), 1.88-1.76 (m, 1H), 1.73-1.53 (m, 2H), 1.69
(s, 3H), 1.46 (s, 9H), 1.41 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 173.2, 153.6, 142.0, 113.8, 81.7, 80.1, 65.0, 60.8, 52.0, 50.0,
45.1, 36.4, 28.3, 28.0, 19.3; HRMS (ESI) m/z: [M + Na]+
Calcd for C19H33NO5Na 378.2251; Found 378.2255.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1301, 1249, 1172, 1158, 1135 cm-1; H NMR (CDCl3, 400
MHz) δ 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.85
(s, 2H), 4.46-4.35 (m, 2H), 4.25 and 4.16 (d, J = 8.2 Hz, 1H),
3.78 (s, 3H), 3.75-3.48 (m, 3H), 3.26-3.06 (m, 1H), 2.86-2.70
(m, 1H), 2.55-2.39 (m, 1H), 1.83-1.71 (m, 2H), 1.67(s, 3H),
1.45 (s, 9H), 1.45 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
171.0, 159.1, 153.7, 142.2, 130.5, 129.2, 114.1, 113.8, 81.4,
79.8, 72.5, 67.8, 62.9, 55.3, 49.7, 48.9, 41.4, 28.7, 28.4, 28.1,
18.5; HRMS (ESI) m/z: [M + Na]+ Calcd for C27H41NO6 Na
498.2826; Found 498.2836.
(−)-2-epi-α-Allokainic acid (6). To a solution of 21a (52 mg,
0.15 mmol) in acetone (1.50 mL) was dropwise added a fresh-
prepared Jones reagent (2.50 M in H2O, 0.11 mL, 0.28 mmol)
at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched
with 2-propanol, and filtered through a plug of Celite. The
filtrate was added water (1 mL) and the mixture was extracted
with EtOAc (3 x 10mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to give the crude carboxylic acid which
was directly employed in the next step. To a solution of the
crude dicarboxylic acid in DCM (2.9 mL) was added TFA
(0.14 mL, 1.73 mmol) at room temperature. The mixture was
heated for 2 h at 40 oC and concentrated in vacuo to give crude
allokainic acid. The residue was purified using Dowex-50 H+
(100–200 wet mesh) column chromatography (elution with 1
N NH4OH) to give 6 (26 mg, 0.12 mmol, 80 % for 2 steps) as
Di-(tert-butyl) (2S,3S,4R)-3-(2-((4-methoxybenzyl)oxy)ethyl)-
4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (20b). Start-
ing with 19b (137 mg, 0.28 mmol), and followed the same
procedure as in the synthesis of 20a provided 20b (110 mg,
0.23 mmol, 2 steps for 82%) as colorless liquid. Rf = 0.66
25
(EtOAc/hexanes, 1/1); [α]D –27.2 (c 1.0, CH2Cl2); IR (neat)
2976, 2935, 1736, 1701, 1514, 1394, 1366, 1248, 1172, 1157,
1
1135, 1092 cm-1; H NMR (CDCl3, 400 MHz) δ 7.20 (d, J =
24
1
8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 4.37 (s,
2H), 3.86-3.78 (m, 1H), 3.76 (s, 3H), 3.75-3.68 (m, 1H), 3.62-
3.43 (m, 2H), 3.22 (td, J = 10.8, 3.6 Hz, 1H), 2.55-2.42 (m,
1H), 2.34-2.19 (m, 1H), 1.91-1.70 (m, 2H), 1.67 (s, 3H), 1.43
(s, 9H), 1.42 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 172.1,
158.9, 153.5, 142.0, 130.4, 128.9, 113.6, 113.6, 80.9, 79.8,
72.2, 67.4, 65.4, 55.1, 51.4, 50.3, 43.9, 32.8, 28.2, 27.9, 19.1;
HRMS (ESI) m/z: [M + Na]+ Calcd for C27H41NO6Na
498.2826; Found 498.2829.
white solid. [α]D –15.8 (c 0.8, D2O); H NMR (D2O, 400
MHz) δ 4.99 (s, 1H), 4.94 (s, 1H), 4.28 (d, J = 8.0 Hz, 1H),
3.66 (dd, J = 12.0, 8.4 Hz, 1H), 3.29 (t, J = 10.0 Hz, 1H), 2.87-
2.75 (m, 2H), 2.43 (dd, J = 16.0, 6.8 Hz, 1H), 2.33 (dd, J =
16.0, 7.6 Hz, 1H), 1.74 (s, 3H); 13C NMR (D2O, 100 MHz) δ
175.5, 170.1, 139.5, 114.7, 61.3, 48.4, 47.8, 39.5, 32.8, 17.3;
HRMS (ESI) m/z: [M + H]+ Calcd for C10H16NO4 214.1079;
Found 214.1076.
(+)-α-Allokainic acid (1). To a solution of 21b (65 mg, 0.18
mmol) in acetone (1.80 mL) was dropwise added a fresh-
prepared Jones reagent (2.50 M in H2O, 0.14 mL, 0.36 mmol)
at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched
with 2-propanol, and filtered through a plug of Celite. The
filtrate was added water (1 mL) and the mixture extracted with
EtOAc (3 x 10 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to give the crude carboxylic acid which
was directly employed in the next step. To a solution of the
crude dicarboxylic acid in DCM (3.60 mL) was added TFA
(0.17 mL, 2.16 mmol) at room temperature. The mixture was
Di-(tert-butyl) (2R,3S,4R)-3-(2-hydroxyethyl)-4-(prop-1-en-
2-yl)-pyrrolidine-1,2-dicarboxylate (21a). To a mixed solution
containing 20a (58 mg, 0.12 mmol), DCM (1.1 mL), and
H2O (0.06 mL) was added DDQ (40 mg, 0.18 mmol) at 0 oC.
The mixture was stirred at room temperature for 2 h, then
quenched with saturated NaHCO3 solution (5 mL), filtered and
the collected solids were washed with CH2Cl2 (20 mL). The
filtrate was dried over anhydrous Na2SO4, filtered and concen-
trated in vacuo. The residue was purified by column chroma-
tography (eluent: EtOAc/hexanes, 1/2) to give 21a (39 mg,
0.11 mmol, 90 %) as pale yellow liquid. Rf = 0.45 (EtOAc/
27
o
hexanes, 1/1); [α]D –31.9 (c 0.3, CH2Cl2); IR (neat) 3460,
heated for 2 h at 40 C and evaporated in vacuo to give crude
allokainic acid. The residue was purified using Dowex-50 H+
(100–200 wet mesh) column chromatography (elution with 1
N NH4OH) to give 1 (31 mg, 0.15 mmol, 82 % for 2 steps) as
2977, 2931, 2857, 1733, 1704, 1479, 1455, 1394, 1368, 1299,
1
1259, 1221, 1172, 1159, 1136 cm-1; H NMR (CDCl3, 400
MHz) δ 4.77 (s, 2H), 4.23 (dd, J = 17.8, 8.1 Hz, 1H), 3.70-
3.50 (m, 3H), 3.09 (t, J = 10.2 Hz, 1H), 2.96-2.74 (br, 1H),
2.73-2.59 (m, 1H), 2.49-2.29 (m, 1H), 1.59 (s, 3H), 1.65-1.53
(m, 2H), 1.39 (s, 9H), 1.33 (s, 9H); 13C NMR (CDCl3, 100
24
colorless oil. [α]D +7.8 (c 1.0, H2O) {Lit.7 [α]D +7.7 (c, 0.2,
1
H2O)} or {Lit.7 [α]D +7.1 (c, 0.1, H2O)};. H NMR (D2O, 400
MHz) δ 4.93 (s, 1H), 4.91 (s, 1H), 3.88 (d, J = 8.6 Hz, 1H),
9
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α-Kainic Acid and α-alloKainic Acid by Pd(0) Mediated Olefin Inser-
3.52-3.45 (m, 1H), 3.30 (t, J = 11.0 Hz, 1H), 2.83 (dt, J = 10.0,
8.1 Hz, 1H), 2.71-2.56 (m, 2H), 2.35 (dd, J = 14.7, 7.8 Hz,
1H), 1.70 (s, 3H); 13C NMR (125 MHz, D2O) δ 179.0, 173.7,
140.6, 114.7, 64.9, 51.5, 48.2, 42.6, 39.4, 17.7; HRMS (ESI)
m/z: [M + H]+ Calcd for C10H16NO4 214.1079; Found
214.1076.
tion-Carbonylation Reaction. Tetrahedron Lett. 1990, 31, 6877. (d)
Murakami, M.; Hasegawa, N.; Hayashi, M.; Ito, Y. Synthesis of (±)-
α-Allokainic Acid via the Zinc Acetate Catalyzed Cyclization of γ-
Isocyano Silyl Enolates. J. Org. Chem. 1991, 56, 7356. (e) Mooiweer,
H. H.; Hiemstra, H.; Specamp, W. N. Total Synthesis of (±)-α-
alloKainic Acid via Two Allylsilane N-acyliminium Ion Reactions.
Tetrahedron 1991, 47, 3451.
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ASSOCIATED CONTENT
(9). Rossiter, B. E.; Swingle, N. M. Asymmetric Conjugate Addition.
Chem. Rev. 1992, 92, 771.
Supporting Information
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1
Copies of the H and 13C NMR spectra for all new compounds,
9
and X-ray crystallographic data (CIF) for compounds 6, 10, and
12.
The Supporting Information is available free of charge on the
ACS Publications website.
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■ AUTHOR INFORMATION
Corresponding Author
* E-mail: bjuang@mx.nthu.edu.tw
(11). (a) Yang, T. K.; Chen, R. Y.; Lee, D. S.; Peng, W. S.; Jiang, Y.
Z.; Mi, A. Q.; Jong, T. T. Application of New Camphor-Derived
Mercapto Chiral Auxiliaries to the Synthesis of Optically Active Pri-
mary Amines. J. Org. Chem. 1994, 59, 914. (b) Achqar, A. E.;
Boumzebra, M.; Roumestant, M. L.; Viallefont, P. 2-Hydroxy-3-
Pinamone As Chiral Auxiliary in the Asymmetric Synthesis of α-
Amino Acids. Tetrahedron 1998, 44, 5319. (c) Yamamoto, H.;
Kanemasa, S.; Wada E. Asymmetric Michael Addition of the N-
Alkylidene Derivative of an α-Amino Ester to Methyl (E)-3-
[(3R,7aS)-2-Phenylperhydropyrro
lo[1,2-c]imidazol-3-yl]propenoate. Bull. Chem. Soc. Jpn. 1991, 64,
2739. (d) Kanemasa, S.; Tatsukawa, A.; Wada, E. Highly Diastere-
oselective Michael Addition of Lithiated Camphor Imines of Glycine
Esters to α,β-Unsaturated Esters. Synthesis of Optically Pure 5-Oxo-
2,4-pyrrolidinedicarboxylates of Unnatural Stereochemistry. J. Org.
Chem. 1991, 56, 2875. (e) Kanemasa, S.; Tatsukawa, A.; Wada, E.;
Tsuge, O. Absolutely Diastereoselective Asymmetric Michael Addi-
tion of the Camphor Imine of t-Butyl Aminoacetate with 2-
Alkylidenemalonates. Chem. Lett. 1989, 1301. (f) Liang, B.; Carroll,
P. J.; Joullie, M. M. Progress toward the Total Synthesis of Callipeltin
A (I): Asymmetric Synthesis of (3S,4R)-3,4-Dimethylglutamine. Org.
Lett. 2000, 2, 4157. (g) Chavan, S. P.; Sharma, P.; Sivappa, R.; Bhad-
bhade, M. M.; Gronnade, R. C.; Kalkote, U. R. Enantioselective Syn-
thesis of L-CCG-I. J. Org. Chem. 2003, 68, 6817.
(12). Casella, L.; Jommi, G.; Montanari, S.; Sisti, M. Metal-Directed
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(13). (a) Lu, S. S.; Uang, B. J. Asymmetric Synthesis of α-Amino
Acids from Glycine. J. Chin. Chem. Soc. 1992, 39, 245.(b) Yeh, T. L.;
Liao, C. C.; Uang, B. J. Enantioselective Synthesis of α-Amino Acids
from Glycine t-Butyl Ester. Tetrahedron. 1997, 53, 11141.
(14). For X-ray crystallographic analysis of 10, see Supporting Infor-
mation.
(15). For X-ray crystallographic analysis of 12, see Supporting Infor-
mation.
ORCID
Biing-Jiun Uang: 0000-0003-4304-0064
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENT
We thank the Ministry of Science and Technology, Taiwan for
financial support (MOST 106-2113-M-007-003).
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