Total synthesis of penmacric acids via an intermolecular radical addition reaction

Article abstract of DOI:10.1016/j.tet.2013.06.006

The total syntheses of penmacric acid and its three stereoisomers were accomplished through the intermolecular radical addition reaction of the 4-pyrrolidyl radical derived from trans-4-hydroxy-l-proline. Furthermore, 1′,3-diepi-penmacric acid was synthesized stereoselectively via double stereoinduction in the radical reaction.

Full text of DOI:10.1016/j.tet.2013.06.006

Tetrahedron xxx (2013) 1e9
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of penmacric acids via an intermolecular radical
addition reaction
Masafumi Ueda a, Ayako Ono a, Dai Nakao a, Kenji Matsuno b, Takeaki Naito a,
,
Okiko Miyata a
*
a Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
b Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The total syntheses of penmacric acid and its three stereoisomers were accomplished through the in-
Received 11 May 2013
Received in revised form 30 May 2013
Accepted 1 June 2013
Available online xxx
termolecular radical addition reaction of the 4-pyrrolidyl radical derived from trans-4-hydroxy-L-proline.
Furthermore, 10,3-diepi-penmacric acid was synthesized stereoselectively via double stereoinduction in
the radical reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Penmacric acid
Total synthesis
Radical reaction
Amino acid
1. Introduction
completed yet.12 In 2007, we achieved the first total synthesis of
penmacric acid and its 10-epimer by using a diastereoselective in-
Various non-proteinogenic amino acids have been found in
nature in the free zwitterionic form or as constituents of peptidic
compounds. Because of their important biological activities, sci-
entists have devoted much attention to these amino acids, such as
antibiotics, neurotoxins, or enzyme inhibitors,1 and thus many of
them are interesting synthetic targets.2,3 Pyroglutamic acids, in
particular, are found to play an important role in organic chemistry.
They are widely used as building blocks in synthetic chemistry4 and
are found as core units in biologically active molecules such as
oxazolomycin A,5 salinosporamide A,6 boneratamides,7 and
amphiasterins C.8 Among the naturally occurring pyroglutamic acid
derivatives, penmacric acid 1 has an interesting and unique struc-
ture, consisting of glycine and pyroglutamic acid, which are con-
nected via a carbonecarbon bond linkage. It was isolated in 1975
independently by both Welter9 and Mbadiwe10 from the seeds of
the leguminous tree Pentaclethra macrophylla, which is traditionally
used for food, dye, and medicine for anti-inflammatory use in West
Africa. The structure was elucidated by 1H NMR, 13C NMR, CD, and
X-ray studies.11 Despite its unique structural features, biological
studies have not been reported. The first synthetic study was re-
ported by Moloney in 2003, but the total synthesis was not
termolecular radical addition reaction.13 Subsequently, in 2009,
Minassian reported the total synthesis of 1 and its 3,5-epimer via
hydrogen chloride-mediated alkylation of pyrrole.14 This was fol-
lowed by short synthesis of three protected epimers based on the
reaction of the enolate of pyroglutamate with imine reported by
Dikshit.15 Our interest is in the development of flexible synthetic
methodologies that will allow the synthesis of various stereoiso-
mers. To evaluate the biological activity of penmacric acids, the
synthesis of various stereoisomers and related compounds is im-
portant. We anticipated that the addition reaction of 4-pyrrolidinyl
radical B to the oxime ether derivative of glyoxylate A would lead to
the stereodivergent synthesis of penmacric acids (Scheme 1).
Herein, we provide a full account of the total synthesis of penmacric
acid and three stereoisomers. Furthermore, the stereoselective
synthesis of 10,3-diepi-penmacric acid by double stereoinduction
via a radical reaction is reported in this article.
2. Results and discussion
2.1. Total synthesis of penmacric acid and 10-epi-penmacric
acid
Our initial target was penmacric acid 1 and 10-epi-penmacric
acid 2. The retrosynthetic strategy is depicted in Scheme 2, which
* Corresponding author. Tel.: þ81 78 4417554; fax: þ81 78 4417556; e-mail
address: miyata@kobepharma-u.ac.jp (O. Miyata).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.006
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
Scheme 1. Synthetic strategy.
MeI, DEAD, PPh3 gave 4-iodoproline 10 in 88% yield.16 Elimination
of the iodo group with DBU afforded 3,4-dehydroproline 11 in 71%
yield. The 3,4-dehydroproline 11 was then oxidized with m-CPBA in
the presence of 4,40-thiobis(6-tert-butyl-o-cresol) as a radical
scavenger to give the epoxide 12 in 59% yield as a single stereo-
isomer.17 Regioselective ring opening of the epoxide 12 with
magnesium iodide afforded the expected 3-hydroxy-4-iodoproline
5 in 87% yield.18
With the radical precursor 5 in hand, we next investigated
a radical reaction of 5 with glyoxylic oxime ether 6, which was
found to be an excellent radical acceptor as we previously re-
ported.19 Several conditions for the radical reaction were screened
to optimize the yield and these are summarized in Table 1. When
the reaction of 3-hydroxyl-4-iodoproline 5 with 1 equiv of oxime
ether 6 was carried out in CH2Cl2 at room temperature using
5 equiv of Et3B as the radical initiator, no desired product was
isolated and 3-hydroxyproline 1320 was obtained in 46% yield
(entry 1). This result indicated the generation of 4-pyrrolidinyl
radical, which however was reduced prior to addition to oxime
ether. Even the addition of BF3$OEt2 to the reaction mixture for the
enhancement of the reactivity of oxime ether did not produce any
of the desired adduct (entry 2). We were pleased to find that the
expected radical addition reaction proceeded to afford the adduct 7
upon increasing the amount of oxime ether and Et3B. The reaction
with 20 equiv of oxime ether 6 and 12.5 equiv of Et3B in CH2Cl2 at
room temperature gave 7 in 30% yield as an inseparable 1:1 mixture
of two diastereomers at the C10 position (entry 3). This result
showed that facial selectivity of the pyrrolidine ring is completely
Scheme 2. Synthetic strategy toward penmacric acid 1.
was based on the Et3B-induced radical reaction of iodoproline 5
bearing the hydroxyl group as a stereochemical auxiliary with ox-
ime ether 6. We expected the stereoselective construction of the
C3eC10 bond in the radical addition of the pyrrolidine ring onto the
glycine equivalent.
The synthesis started with the preparation of the hydroxylated
iodoproline 5 from commercially available trans-4-hydroxy-L-pro-
line 8 (Scheme 3). After protection of the amino group with CbzCl in
THF and the carboxyl group with a catalytic amount of H2SO4 in
MeOH, the hydroxyl group was converted into the iodo group un-
der the Mitsunobu reaction condition. Thus, treatment of 9 with
Table 1
Radical addition to oxime ether 6
Entry
Radical initiator (equiv)
6 (equiv)
Solvent
T (ꢀC)
Yield (%)
1
Et3B (5)
Et3B (5)
1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Benzene
(CH2Cl)2
Benzene
rt
rt
rt
Reflux
Reflux
Reflux
Reflux
13: 46
13: 57
7b: 30
7b: 81
7b: 68
7c: 44
13: 81
2a
3
Et3B (12.5)
Et3B (15)
Et3B (15)
Et3B (15)
AIBN (0.5)
20
20
20
20
15
4
5
6
7d
a
Reaction was run in the presence of BF3$OEt2 (1.2 equiv).
1:1 mixture of diastereomers.
C4 isomers were obtained in 22% yield.
b
c
d
Scheme 3. Synthesis of 3-hydroxy-4-iodoproline 5.
Reaction was run in the presence of Bu3SnH (1.2 equiv).
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
3
controlled by the hydroxyl group that was introduced as a stereo-
chemical auxiliary. Reaction temperature and choice of solvent
were a key factor in improving the yield, and the best result was
obtained in refluxing CH2Cl2 solution (entries 4e6). Et3B was found
to be a superior radical initiator than the other initiators, such as
AIBN (entry 7).
glycine moiety and the carboxyl group at C5 position in the pyr-
rolidine ring (Scheme 6). For the anti-selective radical addition
reaction, 4-iodoproline 10 was used as a radical precursor. We
anticipated the 4-pyrrolidinyl radical would add to oxime ether,
avoiding steric repulsion by the ester moiety of proline. In contrast
to the previously mentioned reaction with hydroxyl proline 5, the
radical addition reaction of 10 induced by Et3B proceeded effi-
ciently, even at room temperature, to provide a diastereomeric
mixture (1:1) of alkylated proline 18, both of which had the desired
stereogenic center at the C3 position. Hydrogenolysis, Boc-pro-
tection, and oxidation by the same operations as those of 17 gave
the desired lactams 20a in 47% yield and 20b in 40% yield. The
stereostructures of the lactams were identified by comparison with
the reported spectroscopic data.15 Completion of syntheses of 3-
epi-penmacric acid 3 and 10,3-diepi-penmacric acid 4 was accom-
plished by deprotection under acidic conditions.24
The remaining steps began with reductive cleavage of the NeO
bond, deprotection of the Cbz group and Boc-protection of the
resulting amino groups by hydrogenolysis in the presence of
(Boc)2O (Scheme 4).21 Removal of the hydroxyl group was accom-
plished by the BartoneMcCombie radical deoxygenation.22 The
corresponding imidazolethiocarbamate 15 was prepared with N,N-
thiocarbonyldiimidazole in 93% yield, and then reduced with
Ph3SnH and AIBN to yield the deoxygenated compound 16 in 85%
yield, whereas the reduction with Bu3SnH led to decomposition.
The oxidation of proline derivative 16 with ruthenium tetraoxide
under EtOAc/H2O biphasic conditions furnished the desired lac-
tams 17a and 17b, which were separated at this stage by column
chromatography on silica gel.23 Finally, two Boc groups and two
methyl esters were deprotected with 3 M HCl to give penmacric
acid 1 and the 10-epi-penmacric acid 2 in 94% and 52% yields, re-
spectively (Scheme 5). The spectral data for our synthetic sample 1
were identical in all respects with those of the published data.10 The
stereostructure of 2 was confirmed by comparison with the re-
ported spectroscopic data.14
2.3. Asymmetric total synthesis of 10,3-diepi-penmacric acid
In the previously mentioned synthetic routes for penmacric
acid, at least one of three chiral centers was unable to be con-
structed stereoselectively, and therefore a separation step was re-
quired. We finally investigated the stereoselective synthesis of 10,3-
diepi-penmacric acid 4 by the diastereoselective radical addition
reaction to chiral oxime ether as a key step. For the stereoselective
Scheme 4. Synthesis of 17a and 17b.
construction of the C10 position, the auxiliary of choice was
Oppolzer’s camphorsultam, because it had shown a good result in
our previous work on radical reactions of oxime ether, hydrazone,
and nitrone.19c,25,26 The chiral oxime ether 21 was subjected to the
radical addition reaction with 4-iodoproline 10. As expected, the
reaction proceeded stereoselectively to give the adduct 22a in 55%
yield, in which the absolute configurations at C-10 and C-4 are both
R, along with a small amount of diastereomer 22b (Scheme 7).
With stereochemically pure adduct 22a in hand, the trans-
formation to the synthetic intermediate for 10,3-diepi-penmacric
acid 4 was investigated (Scheme 8). Hydrolysis of imide and ester
groups with LiOH, followed by methylation with TMSCHN2 gave
diester 23. Hydrogenolysis, Boc-protection, and oxidation furnished
the lactam 20b in good yields, which indicated the accomplishment
of the stereoselective total synthesis of 10,3-diepi-penmacric acid
because 20b has been converted into 4, as in Scheme 6.
Scheme 5. Completion of the total synthesis of penmacric acid 1 and 10-epi-penmacric
acid 2.
2.2. Total synthesis of 3-epi-penmacric acid and 10,3-diepi-
penmacric acid
3. Conclusion
We next investigated the synthesis of the two C3-epimers of
penmacric acid, which have an anti relationship between the
We achieved the concise total syntheses of penmacric acid and
three epimers by a radical reaction of an iodoproline derivative
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
Scheme 6. Total synthesis of 3-epi-penmacric acid 3 and 10,3-diepi-penmacric acid 4.
Scheme 7. Diastereoselective radical addition reaction of 10 with 21.
Scheme 8. Synthesis of 20b.
with an oxime ether. The hydroxyl group-induced stereoselective
construction of the C3 stereogenic center was applied to the
synthesis of penmacric acid and 10-epi-penmacric acid, whereas the
C3-epimers were synthesized by a stereoselective radical reaction
controlled by the inherent ester moiety. Furthermore, stereo-
selective synthesis of 10,3-diepi-penmacric acid by double diaster-
eoselective radical addition reaction of chiral iodoproline to
chiral oxime ether has been accomplished. The advantage of our
strategy centers on the stereoselective synthesis of various types
compounds. Therefore, our route can be applied to produce various
analogs.
4. Experimental section
4.1. General
NMR spectra were recorded at 300 MHz/75 MHz (1H NMR/13
C
NMR) or 500 MHz/125 MHz (1H NMR/13C NMR) using a Varian
Gemini-300 (300 MHz), Varian MERCURY plus 300 (300 MHz), or
of
a-substituted a-amino acids, including natural and unnatural
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
5
Varian NMR system AS 500 (500 MHz) spectrometers. Chemical
shifts ( ) are reported as follows: chemical shift, multiplicity
(8.5 g, 71%) as a colorless oil. The spectral data were identical with
those reported in the literature.28
d
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad), coupling constants, and integration. IR spectra were
obtained on a PerkineElmer SpectrumOne A spectrometer. Mass
spectra were obtained by electrospray ionization on a Hitachi M-
4100 mass spectrometer. Flash column chromatography was per-
4.5. (1R,2S,5S)-6-Oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxy
lic acid 2-methyl 3-(phenylmethyl) ester (12)
To a solution of 11 (6.6 g, 25 mmol) in 1,2-dichloroethane
(500 mL) was added m-CPBA (77%, 6.8 g, 30 mmol) and 4,40-thio-
bis(6-tert-butyl-o-cresol) (541 mg, 1.5 mmol) at room temperature
under an N2 atmosphere. After stirring under reflux for 10 h, the
reaction mixture was washed with 10% aqueous Na2S2O3 and sat-
urated aqueous NaHCO3. The organic phase was dried over MgSO4
and concentrated at reduced pressure. Purification of the residue by
flash column chromatography on silica gel (hexane/AcOEt (4:1))
formed with a 40e63
mm silica gel (Silicycle). Tetrahydrofuran
(THF) was freshly distilled from the benzophenone ketyl radical
anion prior to use.
4.2. (2S,4R)-4-Hydroxy-1,2-pyrrolidinedicarboxylic acid
2-methyl 1-(phenylmethyl) ester (9)
To a stirred solution of (2S,4R)-trans-4-hydroxy-
L-proline 8
afforded 12 (4.1 g, 59%) as a colorless oil. IR (neat): 1752, 1713 cmꢁ1
.
(10 g, 76 mmol) and NaHCO3 (8.3 g, 99 mmol) in H2O (20 mL) and
THF (65 mL) was added, dropwise, benzyl chloroformate (14 mL,
99 mmol) under an N2 atmosphere at 0 ꢀC. The reaction mixture
was allowed to reach room temperature and stirred overnight. The
reaction mixture was diluted with 20% aqueous NaOH and washed
with Et2O. The aqueous phase was acidified to pH 3 with concen-
trated HCl and extracted with AcOEt. The combined organic phase
was washed with water, dried over MgSO4, and concentrated at
reduced pressure to give N-Cbz-proline. To a solution of the Cbz-
proline (19 g, 73 mmol) in MeOH (100 mL) was added, dropwise,
concentrated H2SO4 (2 mL) at room temperature. After stirring
under reflux for 10 h, the reaction mixture was diluted with satu-
rated aqueous NaHCO3 and extracted with AcOEt. The organic
phase was dried over MgSO4 and concentrated at reduced pressure.
The residue was purified by flash column chromatography on silica
gel (AcOEt) to give 9 (18 g, 87%) as a colorless oil. Analytical data
were consistent with those reported in the literature.27
1H NMR (1:1 mixture of rotamers, 200 MHz, CDCl3)
d: 7.35e7.30
(5H, m), 5.13 (2/2H, s), 5.18, 5.04 (2/2H, ABq, J¼12.5 Hz), 4.73 (1/
2H, s), 4.65 (1/2H, s), 3.97 (1/2H, d, J¼12.5 Hz), 3.92 (1/2H, d,
J¼12.5 Hz), 3.79 (3/2H, s), 3.68 (3/2H, s), 3.80e3.67 (1Hþ1H, m),
3.55 (1/2H, d, J¼12.5 Hz), 3.49 (1/2H, d, J¼12.5 Hz). 13C NMR (1:1
mixture of rotamers, 50 MHz, CDCl3) d: 168.9, 154.8, 154.3, 135.90,
135.86, 128.11, 128.06, 127.74, 127.66, 127.5, 127.3, 66.9, 66.8,
60.3, 60.1, 56.7, 56.0, 54.3, 53.8, 52.3, 52.2, 47.0, 46.7. HRMS (EI):
calcd for C14H15NO5 (Mþ) 277.0949, found: 277.0934. [
1.28, CHCl3).
a
]
27 ꢁ8.70 (c
D
4.6. (2S,3R,4R)-3-Hydroxy-4-iodo-1,2-pyrrolidinedicarboxylic
acid 2-methyl 1-(phenyl methyl) ester (5)
To a solution of 12 (4.5 g, 16 mmol) in toluene (300 mL) was
added a solution of MgI2 (4.9 g, 18 mmol) in Et2O (10 mL) at 0 ꢀC
under an Ar atmosphere. After vigorous stirring at the same tem-
perature for 2 h, the mixture was washed with 10% aqueous
Na2S2O3 and brine. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. The residue was purified by flash
column chromatography on silica gel (hexane/AcOEt (3:1)) and
then recrystallized to give 5 (5.6 g, 87%) as colorless crystals. Mp:
93.8e94.5 ꢀC (hexane/AcOEt). IR (KBr): 3287, 1752, 1679 cmꢁ1. 1H
4.3. (2S,4S)-4-Iodo-1,2-pyrrolidinedicarboxylic acid 2-methyl
1-(phenylmethyl) ester (10)
To a stirred solution of 9 (15 g, 55 mmol) in THF (400 mL) was
added triphenylphosphine (17 g, 66 mmol) under N2 atmosphere at
room temperature. After the reaction mixture was cooled to 0 ꢀC,
diethyl azodicarboxylate (40% solution in toluene, 28.6 mL,
66 mmol) and methyl iodide (4.1 mL, 66 mmol) were added
dropwise. The reaction mixture was stirred for 17 h. The solvent
was evaporated at reduced pressure and the resulting residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt (3:1)) to afford 10 (19 g, 88%) as a yellow oil. IR (neat): 1750,
NMR (1:1 mixture of rotamers, 500 MHz, CDCl3) d: 7.36e7.29 (5H,
m), 5.19, 5.11 (2/2H, ABq, J¼12.5 Hz), 5.19, 5.04 (2/2H, ABq,
J¼12.5 Hz), 4.57e4.53 (1H, m), 4.29e4.19 (1Hþ1H, m), 4.07e4.00
(1H, m), 3.82 (3/2H, s, CO2Me), 3.81e3.74 (1H, m), 3.62 (3/2H, s,
CO2Me), 2.68 (1H, br s, OH). 13C NMR (1:1 mixture of rotamers,
125 MHz, CDCl3)
d: 170.5, 170.3, 154.0, 153.6, 136.0, 128.6,
128.5, 128.3, 128.2, 128.1, 128.0, 83.3, 82.4, 67.7, 67.6, 64.6, 64.5,
54.34, 54.25, 52.8, 52.6, 21.5, 21.0. HRMS (EI): calcd for C14H16INO5
(Mþ) 405.0072, found: 405.0079. Anal. Calcd for C14H16INO5: C,
1702 cmꢁ1. 1H NMR (1:1 mixture of rotamers, 200 MHz, CDCl3)
d:
7.35e7.32 (5H, br m), 5.25e5.00 (2H, br m), 4.56e4.47 (1/2H, br m),
4.38e4.30 (1H, br m), 4.15e3.99 (1Hþ1/2H, br m), 3.84e3.76
(1Hþ3/2H, br m), 3.60e3.56 (3/2H, br m), 2.95e2.85 (1/2H, br m),
2.62e2.56 (1/2H, br m), 2.50e2.40 (1H, br m). 13C NMR (1:1 mixture
41.50; H, 3.98; N, 3.46, found: C, 41.45; H, 3.88; N, 3.41. [
(c 0.90, CHCl3).
a]
27 þ3.89
D
of rotamers, 50 MHz, CDCl3)
d
: 172.2, 172.1, 171.6, 171.4, 154.2,
4.7. (3S,4S,5S)-3-Hydroxy-4-[2-methoxy-2-oxo-1-[(phenyl-
methoxy)amino]ethyl]-1,2-pyrrolidinedicarboxylic acid 2-
methyl 1-(phenylmethyl) ester (7)
153.8, 153.2, 136.1, 128.44, 128.36, 128.0, 127.8, 67.4, 58.9, 58.7, 58.5,
57.9, 57.4, 57.2, 56.8, 52.5, 52.3, 43.0, 42.7, 42.0, 41.7. HRMS (EI):
calcd for C14H16INO4 (Mþ) 389.0123, found 389.0121. [
1.87, CHCl3).
a
]
29 ꢁ19.7 (c
D
To a solution of oxime ether 6 (7.8 g, 40 mmol) and iodide 5
(1.1 g, 2.7 mmol) in CH2Cl2 (5 mL) was added Et3B (1.0 M in hexane,
6.7 mL, 6.7 mmol) three times every 1.5 h under an N2 atmosphere
under reflux. After stirring the reaction mixture at the same tem-
perature for 1.5 h, a solution of oxime ether 6 (2.6 g, 13 mmol) in
CH2Cl2 (2 mL) was added. Additionally, Et3B (1.0 M in hexane,
6.7 mL, 6.7 mmol) was added three times, at 1.5 h intervals. After
stirring at the same temperature for 10 h, the reaction mixture was
diluted with saturated aqueous NaHCO3 and then extracted with
CHCl3. The organic phase was dried over MgSO4 and concentrated
at reduced pressure. The residue was purified by flash column
chromatography on silica gel (hexane/AcOEt (1:1)) to afford 7
4.4. (2S)-2,5-Dihydro-1H-pyrrole-1,2-dicarboxylic acid
2-methyl 1-(phenylmethyl) ester (11)
To a solution of 10 (18 g, 46 mmol) in toluene (450 mL) was
added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 7.6 mL, 51 mmol)
at room temperature. After being stirred under an N2 atmosphere
under reflux for 6.5 h, the reaction mixture was filtered to remove
DBU$HI and the filtrate was concentrated at reduced pressure.
Purification of the residue by flash column chromatography on
silica gel (hexane/AcOEt (4:1)) afforded 3,4-dehydroproline 11
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
23
(1.02 g, 81%) as a colorless oil and a 1:1 mixture of diastereomers at
the C10. IR (neat): 3440, 1745, 1704 cmꢁ1. 1H NMR (1:1:1:1 mixture
of diastereomers and rotamers, 500 MHz, CDCl3) d: 7.37e7.28 (10H,
calcd for C23H35N4O9S (MþH)þ 543.2122, found: 543.2121. [
þ0.38 (c 3.96, CHCl3).
a]
D
m), 5.19e4.99 (2H, m), 4.71e4.63 (2H, m), 4.35e4.33 (1/4H, m),
4.17e4.09 (1/4Hþ1/4H), 4.05e3.96 (1/4Hþ1/2H, m), 3.89e3.83 (1/
4H, m), 3.81 (3/4H, s), 3.73 (3/4H, s), 3.78 (3/4H, s), 3.77 (12/4H, s),
3.81e3.72 (1/4Hþ1/2H, m), 3.71e3.60 (1/2H, m), 3.58 (3/4H, s),
3.59e3.52 (1/2Hþ1/2H, m), 3.41e3.19 (1H, m), 2.50e2.30 (1/2H, br
m), 2.18e2.00 (1/2H, br m). 13C NMR (1:1:1:1 mixture of di-
4.10. (2S,4S)-4-[1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-
methoxy-2-oxoethyl]-1,2-pyrrolidinedicarboxylic acid 1-(1,1-
dimethylethyl) 2-methyl ester (16)
To a solution of 15 (219 mg, 0.40 mmol) and AIBN (13 mg,
0.08 mmol) in benzene (5 mL) was added Ph3SnH (213 mg,
0.6 mmol) at room temperature. After stirring under reflux for 2 h
in an N2 atmosphere, the reaction mixture was concentrated at
reduced pressure. The resulting residue was purified by flash col-
umn chromatography on silica gel (hexane/AcOEt (1:1)) to afford 16
(142 mg, 85%) as a colorless oil. IR (neat) 3363, 1750, 1698 cmꢁ1. 1H
astereomers and rotamers, 125 MHz, CDCl3) d: 173.1, 172.4, 172.1,
172.0, 171.8, 171.7, 171.5, 170.6, 154.4, 154.2, 154.0, 153.9, 137.3, 136.8,
136.76, 136.4, 136.3, 136.0, 128.8, 128.75, 128.7, 128.6, 128.57, 128.5,
128.44, 128.40, 128.37, 128.28, 128.25, 128.2, 128.1, 127.98, 127.93,
127.7, 79.6, 78.5, 76.5, 76.4, 76.3, 76.2, 75.6, 74.5, 67.9, 67.6, 67.5,
67.4, 67.37, 67.1, 66.1, 66.0, 65.7, 65.6, 65.0, 64.7, 63.9, 63.8, 62.3,
52.7, 52.67, 52.42, 52.38, 52.3, 48.1, 47.7, 47.5, 47.2, 46.9, 46.6, 46.4,
NMR (mixture of diastereomers and rotamers, 200 MHz, CDCl3) d:
5.18e5.02 (1H, m), 4.44e4.14 (1Hþ1H, m), 3.74e3.72 (1H, m) 3.75
(3H, s), 3.74 (3H, s), 3.32e3.17 (1H, m), 2.70e2.23 (2H, m), 1.91e1.74
(1H, m), 1.44 (9H, br s), 1.40 (9H, br s). 13C NMR (mixture of di-
45.7, 45.3, 45.1, 44.8, 42.2, 41.4. HRMS (EI): calcd for C24H28N2O8
27
(Mþ) 472.1843, found: 472.1838. [
a
]
þ2.25 (c 1.22, CHCl3).
D
astereomers and rotamers, 50 MHz, CDCl3) d: 173.0, 171.7, 155.3,
153.3, 80.2, 58.6, 54.3, 52.4, 51.9, 48.7, 40.5, 33.3, 31.7, 28.1. HRMS
4.8. (2S,3S,4S)-3-Hydroxy-4-[1-[[(1,1-dimethylethoxy)carbonyl]
amino]-2-methoxy-2-oxoethyl]-1,2-pyrrolidinedicarboxylic
acid 1-(1,1-dimethylethyl) 2-methyl ester (14)
24
(EI): calcd for C19H32N2O8 (Mþ) 416.2156, found: 416.2162. [
a]
D
ꢁ4.21 (c 0.95, CHCl3).
4.11. Oxidation of proline derivative 16
After a suspension of palladium hydroxide (93 mg, 20 wt %) in
MeOH (5 mL) was stirred under an H2 atmosphere at room tem-
perature for 30 min, a solution of 7 (78 mg, 0.17 mmol) in MeOH
(3 mL) and (Boc)2O (0.08 mL, 0.36 mmol) were added to the sus-
pension. After stirring at room temperature under an H2 atmo-
sphere for 23 h, the reaction mixture was filtered through Celite
and the solvent was evaporated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel (hexane/AcOEt (1:1)) to afford 14 (56 mg, 79%) as a col-
To a solution of 16 (144 mg, 0.35 mmol) in AcOEt (2 mL) was
added a solution of RuO2 hydrate (6.5 mg, 0.05 mmol) and NaIO4
(84 mg, 0.39 mmol) in H2O (1 mL). After vigorous stirring overnight
at room temperature under an N2 atmosphere, the reaction mixture
was diluted with H2O and extracted with AcOEt. The organic phase
was dried over MgSO4 and concentrated at reduced pressure. The
resulting residue was dissolved in 2-propanol (3 mL) and stirred at
room temperature for 2 h to remove insoluble material in the or-
ganic solvent. The solution was washed with H2O and dried over
MgSO4. Evaporation of the solvent at reduced pressure then gave
a residue, which was purified by preparative thin layer chroma-
tography (TLC) (hexane/AcOEt (1:1)) to afford 17a (60 mg, 40%) and
17b (63 mg, 42%).
orless oil. IR (neat): 3392, 1748, 1694 cmꢁ1
.
1H NMR (mixture of
: 5.46 (1H, br),
diastereomers and rotamers, 200 MHz, CDCl3)
d
4.62e3.92 (1Hþ1Hþ1H, m), 3.78 (3Hþ3/2H, br s), 3.76 (3/2H, br s),
3.30e3.03 (1Hþ1/2H, br m), 2.89e2.83 (1/2H, br m), 2.56e2.48
(1H, br m), 1.80 (1H, br s), 1.45 (9H, br s), 1.36 (9H, br s). 13C NMR
(mixture of diastereomers and rotamers, 50 MHz, CDCl3) d: 172.3,
172.2, 171.9, 171.7, 171.3, 156.5, 155.6 (br), 154.6, 153.8, 153.2, 80.7,
80.5, 80.4, 79.9, 79.1, 77.2, 75.4 (br), 74.8, 73.8, 69.6, 67.7, 67.5, 66.0,
65.7, 64.4, 52.7, 52.3, 52.2, 52.0, 51.2, 47.7, 47.1, 46.8, 46.3 (br), 44.5,
44.0, 42.5, 41.9, 32.3, 32.0, 28.04, 27.96. HRMS (EI): calcd for
4.11.1. (
bonyl-
a
S,3R,5S)-5-(Methoxycarbonyl)-1-(1,1-dimethylethoxy)car-
a
-[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-3-
pyrrolidineacetic acid methyl ester (17a). IR (neat): 3379, 1748,
1715 cmꢁ1. 1H NMR (500 MHz, CDCl3)
d
: 5.31 (1H, d, J¼9 Hz), 4.54
C
19H33N2O9 (MþHþ) 433.2184, found: 433.2193. [
a
]
27 þ3.62 (c 1.87,
D
(1H, dd, J¼9, 3 Hz), 4.49 (1H, t, J¼8.5 Hz), 3.80 (3H, s), 3.76 (3H, s),
3.49 (1H, br m, 3-H), 2.56 (1H, ddd, J¼13, 9, 8.5 Hz), 1.96e1.90 (1H,
CHCl3).
m), 1.48 (9H, s), 1.44 (9H, s). 13C NMR (125 MHz, CDCl3)
d: 171.9,
4.9. (2S,3S,4S)-4-[1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-
methoxy-2-oxoethyl]-3-(1H-imidazol-1-ylthioxomethoxy)-1,2-
pyrrolidinedicarboxylic acid 1-(1,1-dimethylethyl) 2-methyl
ester (15)
171.2, 170.5, 156.3, 148.9, 84.2, 80.4, 57.2, 53.0, 52.5, 45.9, 28.2, 27.8,
24.5. HRMS (EI): calcd for C19H30N2O9 (Mþ) 430.1949, found:
22
430.1962. [
a]
þ5.07 (c 1.38, CHCl3).
D
4.11.2. (
bonyl-
pyrrolidineacetic acid methyl ester (17b). IR (neat): 3401, 1750, 1717,
1698 cmꢁ1 1H NMR (500 MHz, CDCl3)
: 5.67 (1H, br s, NH),
a
R,3R,5S)-5-(Methoxycarbonyl)-1-(1,1-dimethylethoxy)car-
To a solution of 14 (113 mg, 0.26 mmol) in CH2Cl2 (3 mL) was
added N,N-thiocarbonyldiimidazole (93 mg, 0.52 mmol) at 0 ꢀC
under an N2 atmosphere. After the reaction mixture was vigorously
stirred at the same temperature for 30 min, the solvent was
evaporated at reduced pressure and the resulting residue was pu-
rified by flash column chromatography on silica gel (hexane/AcOEt
(1:1)) to afford 15 (131 mg, 93%) as a yellow oil. IR (neat): 1748,
1705, 1168 cmꢁ1. 1H NMR (mixture of diastereomers and rotamers,
a-[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-3-
.
d
4.61e4.56 (1H, br m), 4.55e4.47 (1H, m), 3.80 (3H, s), 3.76 (3H, s),
3.08 (1H, td, J¼10, 4 Hz), 2.59e2.53 (1H, m), 2.16e2.06 (1H, m), 1.49
(9H, s), 1.44 (9H, s). 13C NMR (125 MHz, CDCl3)
d: 172.6, 171.4, 170.6,
155.3, 149.0, 84.2, 80.4, 57.1, 53.0, 52.8, 52.7, 45.6, 28.2, 27.9, 24.2.
HRMS (EI): calcd for C19H30N2O9 (Mþ) 430.1949, found: 430.1974.
200 MHz, CDCl3)
d: 8.32 (1H, br s), 7.60 (1H, br s), 7.07 (1H, br s),
[a
]
22 ꢁ1.49 (c 0.84, CHCl3).
D
6.13 (1H, br s), 5.35e5.31 (1H, m), 4.55e4.36 (1Hþ1H, br m),
3.96e3.86 (1H, br m), 3.80 (3H, s, CO2Me), 3.70 (3H, s, CO2Me),
3.58e3.45 (1H, br m), 3.18e3.02 (1H, br m), 1.47 (9H, s), 1.42 (9H, s).
13C NMR (mixture of diastereomers and rotamers, 50 MHz, CDCl3)
4.12. (aS,3R,5S)-a-Amino-5-carboxy-2-oxo-3-pyrrolidineacetic
acid (penmacric acid (1))
d: 182.4, 170.9, 170.3, 155.2, 153.0, 137.0, 131.2, 118.0, 84.3, 83.6, 81.2,
To a solution of 17a (18 mg, 0.042 mmol) in AcOEt (1 mL) was
80.7, 77.2, 64.1, 60.3, 52.8, 46.7, 45.8, 31.5, 28.1, 22.6,14.0. HRMS (EI):
added 3 M aqueous HCl (1 mL) at room temperature. After stirring
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M. Ueda et al. / Tetrahedron xxx (2013) 1e9
7
vigorously for 5 h, the reaction mixture was concentrated under
reduced pressure and the resulting residue was purified by ion
exchange chromatography (Dowex 50W, 10% NH3). The eluate from
10% NH3 was concentrated under reduced pressure. The resulting
residue was then washed with MeCN/water (5:1) to afford 1
(8.0 mg, 94%) as a hygroscopic white solid. IR (KBr): 3422,
an H2 atmosphere for 18 h, the reaction mixture was filtered
through Celite and the solvent was evaporated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/AcOEt (2:1)) to afford 19
(782 mg, 81%) as a colorless oil. IR (neat): 3020, 1744, 1708 cmꢁ1. 1H
NMR (mixture of diastereomers and rotamers, 200 MHz) d: 5.12
1683 cmꢁ1. 1H NMR (500 MHz, D2O)
d
: 4.34 (1H, t, J¼8.5 Hz), 4.08
(1H, br s), 4.40e4.26 (2H, m), 4.18 (1/2H, m), 3.75 (3H, s), 3.72 (3H,
s), 3.33e3.10 (1Hþ1/2H, m), 2.81e2.59 (1H, m), 2.29e2.05 (2H, m),
(1H, d, J¼7.0 Hz), 3.11 (1H, dt, J¼10.0, 6.5 Hz), 2.77 (1H, ddd, J¼13.0,
9.0, 8.5 Hz), 2.00 (1H, ddd, J¼13.0, 11.0, 8.5 Hz). 13C NMR
1.44 (9H, s), 1.40 (9H, s). 13C NMR (50 MHz)
d: 173.2, 173.0, 171.7,
(125 MHz, D2O)
d
: 179.0, 177.8, 172.0, 56.3, 55.1, 41.8, 29.5. HRMS
155.4, 154.0, 153.3, 80.2, 80.1, 58.7, 58.4, 58.0, 54.1, 52.4, 52.1, 52.0,
48.3, 47.4, 40.3, 40.1, 39.7, 39.1, 33.1, 32.1, 31.6, 28.2, 28.1. HRMS (EI):
26
(EI): calcd for C7H10N2O5 (Mþ) 202.0589, found: 202.0562. [
a]
D
þ10.1 (c 0.32, H2O).
calcd for C19H32N2O8 (Mþ) 416.2157, found: 416.2159. [
1.10, CHCl3).
a
]
27 ꢁ22.7 (c
D
4.13. (
aR,3R,5S)-a-Amino-5-carboxy-2-oxo-3-pyrrolidineacetic
acid (10-epi-penmacric acid (2))
4.16. Oxidation of proline derivative 19
According to the procedure for penmacric acid (1), the treat-
ment of 17b (63 mg, 0.15 mmol) with 3 M HCl (1.5 mL) in AcOEt
(1.5 mL) at room temperature gave 2 (15.5 mg, 52%) as a hygro-
scopic white solid. IR (KBr): 3423, 1696 cmꢁ1. 1H NMR (500 MHz,
To a solution of 19 (409 mg, 0.98 mmol) in AcOEt (4 mL) was
added a solution of RuO2 hydrate (24 mg, 0.18 mmol) and NaIO4
(385 mg, 1.8 mmol) in H2O (12 mL). After vigorous stirring over-
night at room temperature under an N2 atmosphere, the mixture
was diluted with H2O and extracted with AcOEt. The organic phase
was dried over MgSO4 and concentrated at reduced pressure. The
resulting residue was dissolved in 2-propanol (3 mL) and stirred at
room temperature for 12 h to remove insoluble material in the
organic solvent. The reaction mixture was washed with H2O, dried
over MgSO4, and concentrated at reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/AcOEt (1:1)) to afford 20a (198 mg, 47%) and 20b (170 mg,
40%) as a colorless oil.
D2O)
d
: 4.19 (1H, t, J¼8.0 Hz), 4.14 (1H, d, J¼3.0 Hz), 3.41 (1H, td,
J¼10.0, 3.5 Hz), 2.60 (1H, ddd, J¼13.5, 10.0, 8.0 Hz), 1.88 (1H, ddd,
J¼13.5, 10.0, 8.0 Hz). 13C NMR (125 MHz, D2O)
d: 182.1, 180.0, 175.2,
58.9, 55.6, 45.6, 28.8. HRMS (EI): calcd for C7H10N2O5 (Mþ)
202.0589, found: 202.0565. [
a
]
26 ꢁ3.74 (c 0.09, H2O).
D
4.14. (2S,4R)-4-[2-Methoxy-2-oxo-1-[(phenylmethoxy)amino]
ethyl]-1,2-pyrrolidinedicarboxylic acid 2-methyl 1-(phenyl-
methyl) ester (18)
To a solution of 4-iodoproline 10 (8.3 g, 21.4 mmol) and oxime
ether 6 (250 mg, 1.3 mmol) in CH2Cl2 (100 mL) was added Et3B
(1.0 M in hexane, 3.9 mL, 3.9 mmol) under an N2 atmosphere at
room temperature. After stirring at the same temperature for
1.5 h, the reaction mixture was diluted with saturated aqueous
NaHCO3 and then extracted with CH2Cl2. The organic phase was
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (hexane/AcOEt (2:1)) to afford 18 (502 mg, 85%) as a colorless
oil and a 1:1 mixture of diastereomers at the C10. IR (neat): 3260,
4.16.1. (
bonyl-
pyrrolidineacetic acid methyl ester (20a). IR (CHCl3): 3432, 1749,
1717 cmꢁ1. 1H NMR (500 MHz, CDCl3)
: 5.74 (1H, br s), 4.63 (1H, dd,
a
S,3S,5S)-5-(Methoxycarbonyl)-1-(1,1-dimethylethoxy)car-
a
-[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-3-
d
J¼10, 1.5 Hz), 4.59 (1H, dd, J¼9, 3.5 Hz), 3.78 (3H, s), 3.75 (3H, s),
3.13e3.08 (1H, m), 2.51e2.49 (1H, m), 2.23e2.19 (1H, m), 1.50 (9H,
s), 1.44 (9H, s). 13C NMR (125 MHz, CDCl3)
d: 171.5, 170.8, 155.2,
149.1, 83.9, 57.0, 52.72, 52.66, 45.1, 28.23, 28.17, 27.9, 27.8. HRMS
29
(EI): calcd for C19H31N2O9 (MþHþ) 431.2027, found: 431.2023. [
þ6.20 (c 0.90, CHCl3).
a]
D
1744, 1709 cmꢁ1
.
1H NMR (mixture of diastereomers and
: 7.39e7.28 (10H, m), 6.00e5.94 (1H,
rotamers, 500 MHz, CDCl3)
d
4.16.2. (
bonyl-
pyrrolidineacetic acid methyl ester (20b). IR (CHCl3): 3423, 1748,
1731 cmꢁ1. 1H NMR (500 MHz, CDCl3)
a
R,3S,5S)-5-(Methoxycarbonyl)-1-(1,1-dimethylethoxy)car-
m), 5.19e5.02 (2H, m), 4.642 (2/4H, s), 4.638 (2/4H, s), 4.621 (2/
4H, s), 4.618 (2/4H, s), 4.42e4.15 (1/2Hþ1H, m), 3.79e3.55 (1/
2Hþ1/2H), 3.77 (3/4H, s), 3.75(6/4H, s), 3.74 (3/4H, s), 3.722 (3/
4H, s), 3.716 (3/4H, s), 3.57 (3/4H, s), 3.56 (3/4H, s), 3.47e3.11
(1Hþ1/2H, m), 2.50e2.20 (1H, m), 2.18e1.91 (2H, m). 13C NMR
a-[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-3-
d
: 5.25 (1H, br d, J¼9 Hz), 4.59
(1H, dd, J¼9, 2 Hz), 4.49 (1H, br dd, J¼9, 2.5 Hz), 3.801 (3H, s),
3.798 (3H, s), 3.59e3.52 (1H, m), 2.31e2.21 (2H, m), 1.49 (9H, s),
(mixture of diastereomers and rotamers, 125 MHz, CDCl3)
d
:
1.45 (9H, s). 13C NMR (125 MHz, CDCl3)
d: 172.2, 171.4, 170.6, 156.4,
173.1, 173.0, 172.7, 172.6, 172.5, 154.6, 154.0, 137.4, 136.5, 136.4,
128.71, 128.66, 128.60, 128.48, 128.46, 128.4, 128.32, 128.29,
128.1, 128.04, 127.99, 127.96, 127.9, 127.8, 127.3, 76.3, 67.18, 67.16,
67.1, 66.1, 65.8, 65.54, 65.45, 58.8, 58.7, 58.5, 52.37, 52.35, 52.31,
52.27, 52.24, 52.21, 52.18, 52.1, 50.1, 49.7, 49.6, 49.2, 48.6, 37.5,
149.1, 84.1, 80.5, 56.9, 52.9, 52.7, 52.0, 45.2. HRMS (EI): calcd
for C19H31N2O9 (MþHþ) 431.2028, found: 431.2034. [
(c 1.64, CHCl3).
a]
ꢁ42.99
27
D
4.17. (aS,3S,5S)-a-Amino-5-carboxy-2-oxo-3-pyrrolidineacetic
37.4, 37.3, 36.5, 36.4, 34.3, 33.5, 33.3, 33.1, 32.5. HRMS (EI): calcd
acid (3-epi-penmacric acid (3))
25
for C24H28N2O7 (Mþ) 456.1895, found: 456.1879. [
1.67, CHCl3).
a
]
ꢁ25.98 (c
D
To a solution of 20a (24 mg, 0.056 mmol) in AcOEt (0.5 mL) was
added 3 M aqueous HCl (0.5 mL). After vigorous stirring for 26 h at
room temperature, the reaction mixture was evaporated under
reduced pressure. The resulting residue was purified by ion ex-
change chromatography (Dowex 50W, 10% NH3) to afford 3 (11 mg,
4.15. (2S,4R)-4-[1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-
methoxy-2-oxoethyl]-1,2-pyrrolidinedicarboxylic acid 1-(1,1-
dimethylethyl) 2-methyl ester (19)
99%) as a hygroscopic white solid. IR (KBr): 3211, 1688 cmꢁ1
.
1H
After a suspension of palladium hydroxide (1.2 g, 20 wt %) in
MeOH (50 mL) was stirred under an H2 atmosphere at room tem-
perature for 30 min, a solution of 18 (1.06 g, 2.32 mmol) in MeOH
(10 mL) and di-tert-butyl dicarbonate (1.17 mL, 5.11 mmol) were
added to the suspension. After stirring at room temperature under
NMR (500 MHz, D2O) d
: 4.13 (1H, dd, J¼9.5, 3 Hz), 4.07(1H, d,
J¼3.5 Hz), 3.26 (1H, td, J¼9.5, 3 Hz), 2.53 (1H, dt, J¼14, 9.5 Hz), 2.28
(1H, ddd, J¼14, 9.5, 3 Hz). 13C NMR (125 MHz, D2O)
d: 182.5, 180.6,
174.9, 58.8, 56.3, 44.1, 29.9. HRMS (EI): calcd for C7H10N2O5 (Mþ)
22
202.0589, found: 202.0574. [
a]
þ33.3 (c1.78, H2O).
D
Please cite this article in press as: Ueda, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.006

8
M. Ueda et al. / Tetrahedron xxx (2013) 1e9
4.18. (
a
R,3S,5S)-
a
-Amino-5-carboxy-2-oxo-3-pyrrolidineacetic
CDCl3) d: 172.9, 172.7, 171.6, 154.8, 154.0, 137.32, 137.27, 136.7, 136.4,
acid (10,3-diepi-penmacric acid (4))
128.6, 128.43, 128.38, 128.2, 127.92, 127.89, 127.83, 127.81, 127.76,
76.44, 76.38, 67.1, 66.9, 65.3, 65.2, 64.9, 58.9, 58.6, 53.0, 52.3, 52.1,
49.3, 48.9, 48.8, 47.8, 44.62, 44.57, 37.9, 36.5, 35.7, 33.7, 32.7, 32.6,
To a solution of 20b (223 mg, 0.52 mmol) in AcOEt (1 mL) was
added 3 M aqueous HCl (1 mL). After vigorous stirring for 26 h at
room temperature, the reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by ion ex-
change chromatography (Dowex 50W, 10% NH3) to afford 4 (62 mg,
29.7, 26.4, 20.6, 20.5, 19.9. HRMS (EI): calcd for C33H41N3O8S (Mþ)
26
639.2611, found: 639.2595. [
a]
ꢁ11.1 (c 0.15, CHCl3).
D
4.20. (2S,4R)-4-[(1R)-2-Methoxy-2-oxo-1-[(phenylmethoxy)
amino]ethyl]-1,2-pyrrolidinedicarboxylic acid 2-methyl 1-
(phenylmethyl) ester (23)
59%) as a hygroscopic white solid. IR (KBr): 3242, 1686 cmꢁ1 1H
.
NMR (500 MHz, D2O)
d
: 3.98 (1H, dd, J¼9.5, 3.5 Hz), 3.92 (1H, d,
J¼5 Hz), 2.88 (1H, td, J¼9.5, 5.5 Hz), 2.25e2.16 (2H, m). 13C NMR
(125 MHz, D2O)
d
: 180.0, 178.3, 171.7, 56.1, 55.1, 41.3, 28.4. HRMS
To a solution of 22a (26.2 mg, 0.04 mmol) in THF (8 mL) was
added a solution of LiOH (83.9 mg, 2 mmol) in H2O (2 mL) under an
N2 atmosphere at room temperature. After stirring at the same
temperature for 3 h, the reaction mixture was concentrated under
reduced pressure. The residue was diluted with CHCl3 and then
extracted with H2O. The aqueous phase was acidified to pH 4 with
3 M HCl and then extracted with CHCl3. The combined organic
phase was dried over MgSO4 and concentrated under reduced
pressure to give crude carboxylic acid. To a solution of the crude
carboxylic acid (91.3 mg, 0.21 mmol) in MeOH (2 mL) and benzene
(7 mL) was added dropwise TMSCHN2 (0.63 mL, 0.55 mmol) at room
temperature. After stirring at the same temperature for 30 min, the
reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/AcOEt (2:1)) to
give 23 (7.3 mg, 39%) as a colorless oil. IR (neat): 3252, 1742,
23
(EI): calcd for C7H11N2O5 (MþHþ) 203.0667, found: 203.0687. [
þ3.07 (c 1.75, H2O).
a]
D
4.19. Diastereoselective radical reaction of chiral oxime ether
21 with 4-iodoproline 10
To a solution of oxime ether 21 (37.7 mg, 0.1 mmol) and iodide
10 (194.5 mg, 0.5 mmol) in CH2Cl2 (3 mL) was added Et3B (1.0 M in
hexane, 0.25 mL, 0.25 mmol) under an N2 atmosphere at room
temperature. After stirring at the same temperature for 1 h, the
reaction mixture was diluted with saturated aqueous NaHCO3 and
then extracted with CHCl3. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt (2:1)) to afford 22a (34.9 mg, 55%) and 22b (8.2 mg, 7%) as
a colorless oil.
1707 cmꢁ1. 1H NMR (1:1 mixture of rotamers, 500 MHz, CDCl3)
d:
7.39e7.27 (10H, m), 5.96 (1/2H, br d, J¼10.0 Hz), 5.95 (1/2H, br d,
J¼10.0 Hz), 5.18 (1/2H, d, J¼12.0 Hz), 5.17 (1/2H, d, J¼12.0 Hz), 5.11
(1/2H, d, J¼12.0 Hz), 5.03 (1/2H, d, J¼12.0 Hz), 4.64 (1H, s), 4.62, 4.61
(1H, ABq, J¼12.0 Hz), 4.41 (1/2H, br dd, J¼8.0, 2.5 Hz), 4.36 (1/2H, br
dd, J¼8.0, 2.5 Hz), 3.77 (1/2H, dd, J¼11.0, 8.0 Hz), 3.75 (3/2H, s), 3.71
(3/2H, s), 3.69 (1/2H, dd, J¼11.0, 8.0 Hz), 3.56 (3H, s), 3.37 (1/2H, t,
J¼10.0 Hz), 3.33 (1/2H, t, J¼10.0 Hz), 3.24 (1/2H, dd, J¼11.0, 9.0 Hz),
3.13 (1/2H, dd, J¼11.0, 9.0 Hz), 2.43e2.33 (1H, m), 2.09e1.89 (2H, m).
4.19.1. (2S,4R)-4-[(1R)-2-[(3aR,6S,7aS)-Tetrahydro-8,8-dimethyl-2,2-
dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]-2-oxo-1-
(phenylmethoxy)amino]ethyl-1-(phenylmethoxy)carbonyl-2-
pyrrolidinecarboxylic acid methyl ester (22a). IR (neat): 3030, 1744,
1698 cmꢁ1. 1H NMR (1:1 mixture of rotamers, 500 MHz, CDCl3)
d:
7.38e7.26 (10H, m), 6.17 (1/2H, br d, J¼11.0 Hz), 6.14 (1/2H, br d,
J¼11.0 Hz), 5.16 (1H, d, J¼12.0 Hz), 5.09 (1/2H, d, J¼12.0 Hz), 5.02 (1/
2H, d, J¼12.0 Hz), 4.66 (1/2H, br d, J¼11.5 Hz), 4.65 (1/2H, br d,
J¼11.5 Hz), 4.61 (1/2H, br d, J¼11.5 Hz), 4.60 (1/2H, br d, J¼11.5 Hz),
4.43 (1/2H, br dd, J¼9.0, 2.0 Hz), 4.39 (1/2H, br dd, J¼9.0, 2.0 Hz),
4.24e4.16 (1H, br m), 3.97 (1H, br t, J¼6.0 Hz), 3.69 (3/2H, s), 3.67
(1/2H, dd, J¼11.0, 8.0 Hz), 3.64 (1/2H, dd, J¼11.0, 8.0 Hz), 3.54 (3/2H,
s), 3.51 (1H, s), 3.49 (1H, s), 3.26 (1/2H, dd, J¼11.0, 9.0 Hz), 3.16 (1/
2H, dd, J¼11.0, 9.0 Hz), 2.47e2.40 (1H, m), 2.32e2.19 (1H, m),
2.13e2.03 (2H, m), 1.96e1.81 (4H, m), 1.44e1.34 (2H, m), 1.11, 0.97
13C NMR (1:1 mixture of rotamers, 125 MHz, CDCl3)
d: 173.2, 173.1,
172.7, 172.6, 154.6, 153.9, 137.40, 137.36, 136.5, 136.4, 128.7, 128.5,
128.4, 128.36, 128.32, 128.1, 128.0, 127.9, 127.8, 76.3, 76.2, 67.2, 67.1,
66.1, 58.7, 58.5, 52.4, 52.29, 52.27, 52.2, 50.24, 50.2, 49.7, 37.3, 36.4,
33.5, 32.5. HRMS (EI): calcd for C24H28N2O7 (Mþ) 456.1894, found:
456.1879. [
a
]
27 ꢁ8.1 (c 0.72, CHCl3).
D
4.21. (2S,4R)-4-[(1R)-1-[[(1,1-Dimethylethoxy)carbonyl]amino]-
2-methoxy-2-oxoethyl]-1,2-pyrrolidinedicarboxylic acid 1-(1,1-
dimethylethyl) 2-methyl ester (24)
(each 3H, s). 13C NMR (1:1 mixture of rotamers, 125 MHz, CDCl3)
d:
173.0, 172.7, 172.5, 154.6, 153.9, 137.6, 137.5, 136.6, 136.5, 128.89,
128.87, 128.83, 128.79, 128.5, 128.4, 128.19, 128.15, 128.04, 127.98,
127.87, 127.84, 127.77, 76.1, 76.0, 67.1, 67.0, 65.2, 64.9, 64.8, 58.9,
58.6, 53.1, 52.4, 52.2, 49.4, 49.2, 48.6, 48.5, 47.8, 44.5, 38.4, 37.6,
After a suspension of palladium hydroxide (15 mg, 20 wt %) in
MeOH (5 mL) was stirred under an H2 atmosphere at room tem-
perature for 1 h, a solution of 23 (13.1 mg, 0.03 mmol) in MeOH
(5 mL) and di-tert-butyl dicarbonate (0.02 mL, 0.064 mmol) were
added tothe suspension. After stirring at room temperature underan
H2 atmosphere for 3.5 h, the reaction mixture was filtered through
Celite and the solvent was evaporated under reduced pressure. The
resulting residue was purified by preparative TLC (hexane/AcOEt
(2:1)) to afford 24 (8.8 mg, 73%) as a colorless oil and a 1:1 mixture of
rotamers. IR (neat): 3357, 1747, 1702 cmꢁ1. 1H NMR (1:1 mixture of
32.9, 32.8, 31.9, 26.4, 20.7, 19.9. HRMS (EI): calcd for C33H41N3O8S
26
(Mþ) 639.2611, found: 639.2633. [
a]
þ41.6 (c 0.565, CHCl3).
D
4.19.2. (2S,4R)-4-[(1S)-2-[(3aR,6S,7aS)-Tetrahydro-8,8-dimethyl-2,2-
dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]-2-oxo-1-
(phenylmethoxy)amino]ethyl-1-(phenylmethoxy)carbonyl-2-
pyrrolidinecarboxylic acid methyl ester (22b). IR (neat): 1745,
1701 cmꢁ1. 1H NMR (1:1 mixture of rotamers, 500 MHz, CDCl3)
d:
rotamers, 500 MHz, CDCl3) d: 5.09 (1H, br s), 4.41e4.34 (3/2H, m),
7.34e7.26 (10H, m), 6.29 (1/2H, br d, J¼8.0 Hz), 6.26 (1/2H, br d,
J¼8.0 Hz), 5.16 (1/2H, d, J¼12.5 Hz), 5.12 (1H, s), 5.03 (1/2H, d,
J¼12.5 Hz), 4.61 (2H, s), 4.41 (1/2H, dd, J¼8.5, 3.0 Hz), 4.36 (1/2H,
dd, J¼8.5, 3.0 Hz), 4.00 (1/2H, br t, J¼8.0 Hz), 3.97 (1/2H, br t,
J¼8.0 Hz), 3.92e3.88 (1H, m), 3.81e3.75 (1H, m), 3.73, 3.57 (each 3/
2H, s), 3.49 (1H, d, J¼13.0 Hz), 3.45 (1/2H, d, J¼13.0 Hz), 3.41 (1/2H,
d, J¼13.0 Hz), 3.31 (1/2H, dd, J¼11.0, 8.0 Hz), 3.22 (1/2H, dd, J¼11.0,
8.0 Hz), 2.88e2.74 (1H, m), 2.14e1.81 (7H, m), 1.43e1.29 (2H, m),
1.07, 0.95 (each 3H, s). 13C NMR (1:1 mixture of rotamers, 125 MHz,
4.28 (1/2H, br dd, J¼9.0, 2.0 Hz), 3.77 (3/2H, s), 3.75 (3/2H, s), 3.73 (3/
2H, s), 3.72 (3/2H, s), 3.64 (1/2H, br dd, J¼10.0, 8.0 Hz), 3.55 (1/2H, br
t, J¼10.0 Hz), 3.19 (1/2H, br t, J¼10.0 Hz), 3.15 (1/2H, br t, J¼10.0 Hz),
2.78e2.75 (1H, br m), 2.19e2.00 (2H, m),1.46 (9/2H, s),1.45 (9/2H, s),
1.44 (9/2H, s), 1.40 (9/2H, s). 13C NMR (1:1 mixture of rotamers,
125 MHz, CDCl3) d: 173.3, 173.1, 171.8, 155.5, 154.1, 153.5, 80.4, 80.3,
80.2, 58.9, 58.5, 54.1, 52.6, 52.3, 52.1, 47.7, 47.5, 40.3, 39.3, 33.1, 32.3,
29.7, 28.4, 28.3. HRMS m/z: calcd for C19H33N2O8 (Mþ) 417.2234.
Found: 417.2223. [
a
]
29 ꢁ33.6 (c 0.475, CHCl3).
D
Please cite this article in press as: Ueda, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.006

M. Ueda et al. / Tetrahedron xxx (2013) 1e9
9
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added a solution of RuO2 hydrate (0.3 mg, 0.0024 mmol) and NaIO4
(4.1 mg, 0.019 mmol) in H2O (1 mL) at room temperature. After
vigorous stirring overnight at room temperature under an N2 at-
mosphere, the reaction mixture was diluted with H2O and extrac-
ted with AcOEt. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. The resulting residue was
dissolved in 2-propanol (1 mL) and stirred at room temperature for
1 h. The reaction mixture was washed with H2O, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was purified by preparative TLC (hexane/AcOEt (1:1)) to afford 20b
(5.9 mg, 79%) as a colorless oil.
10. Mbadiwe, E. Phytochemistry 1975, 14, 1351.
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Acknowledgements
18. Bonini, C.; Righi, G. Tetrahedron 1992, 48, 1531.
This work was supported in part by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT), the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities. M.U. is grateful for
a Mitsubishi Chemical Award in Synthetic Organic Chemistry of
Japan.
19. For reviews, see (a) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140 For our
selected reports, see; (b) McNabb, S. B.; Ueda, M.; Naito, T. Org. Lett. 2004, 6,
1911; (c) Ueda, M.; Miyabe, H.; Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3,
1124; (d) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem.,
Int. Ed. 2005, 44, 6190; (e) Miyata, O.; Takahashi, S.; Tamura, A.; Ueda, M.; Naito,
T. Tetrahedron 2008, 64, 1270; (f) Ueda, M.; Miyabe, H.; Shimizu, H.; Sugino, H.;
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