Efficient asymmetric synthesis of the functionalized pyroglutamate core unit common to oxazolomycin and neooxazolomycin using Michael reaction of nucleophilic glycine Schiff base with α,β-disubstituted acrylate

Article abstract of DOI:10.1016/j.tetasy.2008.11.036

The functionalized pyroglutamate core unit, (2R,4R)-3, which could be converted into the β-lactone/pyrrolidine or γ-lactone/pyrrolidine ring system of oxazolomycin A 1 and neooxazolomycin 2, and which possesses an exomethylene group at C3 as a scaffold for the construction of their C3 polyene segment, was synthesized by the Michael reaction of a glycine Schiff base 4 with the α,β-disubstituted acrylate 8 as the key step.

Full text of DOI:10.1016/j.tetasy.2008.11.036

Tetrahedron: Asymmetry 19 (2008) 2789–2795
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient asymmetric synthesis of the functionalized pyroglutamate core
unit common to oxazolomycin and neooxazolomycin using Michael reaction
of nucleophilic glycine Schiff base with
a,b-disubstituted acrylate
b,
Takeshi Yamada a, Kazuhiko Sakaguchi a, Tetsuro Shinada a, Yasufumi Ohfune a, , Vadim A. Soloshonok
*
*
a Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
b Department of Chemistry and Biochemistry, The University of Oklahoma, Norman, OK 73019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The functionalized pyroglutamate core unit, (2R,4R)-3, which could be converted into the b-lactone/pyr-
rolidine or -lactone/pyrrolidine ring system of oxazolomycin A 1 and neooxazolomycin 2, and which
possesses an exomethylene group at C3 as a scaffold for the construction of their C3 polyene segment,
Received 6 October 2008
Accepted 21 November 2008
Available online 20 January 2009
c
was synthesized by the Michael reaction of a glycine Schiff base 4 with the
8 as the key step.
a,b-disubstituted acrylate
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
C3 exomethylene group would play a key role in assembling the
polyene segment, can be viewed as a key synthetic intermediate
of the total synthesis of these natural products. In this paper, we de-
scribe the synthesis of (2R,4R)-tert-butyl 2-(hydroxymethyl)-1,4-
dimethyl-3-methylene-5-oxopyrrolidine-2-carboxylate 3 (Fig. 1).
Oxazolomycin A 1, isolated in 1985 by Uemura et al.,1 from the
fermentation broth of Streptomyces sp., exhibits potent antibiotic
properties against various gram positive bacteria and Agrobacte-
rium tumefaciens,2 strong anticancer activity,1,3 and various antivi-
ral activities.4 In addition, oxazolomycin A inhibits crown gall
formation in plants.5 Due to its broad biological activity profile,1,3
oxazolomycin A has received much attention as a candidate for
antibiotic and anticancer drugs. Neooxazolomycin 2, structurally
related to 1, has also been isolated from the same fermentation
broth.6 The structural features common to both 1 and 2 are charac-
terized by the highly functionalized 2,3,3,4-tetrasubstituted pyro-
glutamate core unit and the conjugate diene and triene segment
attached to C3. Their novel structures as well as their important
biological activity profiles have attracted significant attention as
important synthetic target molecules. Although a number of re-
search groups have developed and studied the polyene segment7
2. Results and discussion
Recently, we have developed an operationally convenient meth-
odology for the generalized asymmetric synthesis of various types of
b-substituted pyroglutamates 7a (Scheme 1).11,12 One of the meth-
ods involves the highly diastereoselective organic base-catalyzed
Michael addition of the achiral glycine Schiff base derivative 4 with
the chiral (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidine-2-one
5a to give the addition product 6a as individual diastereoisomers
in nearly quantitative yields in which the observed diastereoselec-
tivity (>98% dr) was induced by the chiral oxazolidinone Michael
and the b-lactone/pyrrolidine or
c-lactone/pyrrolidine ring sys-
tem8 in 1 and 2, an efficient construction of the functionalized
pyroglutamate core unit remains a challenging target. Recently,
Kende et al.9 and Hatakeyama et al.10 reported the total synthesis
of neooxazolomycin 2, although a total synthesis of oxazolomycin
1 has not yet been achieved. We considered that the pyrogluta-
mate core unit, such as 3, which possesses appropriate functional
groups at C2 and C3, that is, the C2 hydroxymethyl substituent
OMe
R
HO
OH
R
O
O
OH
O
O
O
N
N
N
O
CO2t-Bu
Me
Me
Me
O
OH
Neooxazolomycin 2
3
Oxazolomycin A 1
N
could readily cyclize to the b- or
c-lactone/pyrrolidine and the
O
OH
O
R =
N
* Corresponding authors. Tel.: +81 6 6605 2570; fax: +81 6 6605 3153 (Y.O.), tel.:
+1 405 325 8279; fax: +1 405 325 6111 (V.A.S.).
H
OH
E-mail addresses: ohfune@sci.osaka-cu.ac.jp (Y. Ohfune), vadim@ou.edu (V.A.
Soloshonok).
Figure 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.036

2790
T. Yamada et al. / Tetrahedron: Asymmetry 19 (2008) 2789–2795
Ph
(R)
O
N
R
O
O
Ph
O
R
N
N
O
N
O
N
N
O
N
O
1. 3 M HCl
O
MeOH
5a R = alkyl or aryl
5b R = CH2OBn
Ni
Ni
2
N
3
O
O
O
CO2H
N
2. 1 M NaOH
>60% from 6a
70% from 5b
O
R
DBU (15 mol %), DMF
H
Ph
Ph
5a
>95% f rom ( >98% dr)
6a
6b
R = alkyl or aryl
R = CH2OBn
7a R = alkyl or aryl
7b R = CH2OBn
4
Ph (S)
O
N
BnO
8
O
O
N
Ph
Me
N
O
O
R
O
O
Ni
O
3
O
N
N
O
N
O
CO2H
2
N
O
O
OBn
H
CO2R
Ph
Me
10a R = OBn
10b
9
11 R = protecting group
R = OCO2Me
Scheme 1.
donor.11b,12 The Michael adduct 6a can be easily hydrolyzed under
mild conditions and, upon workup, transformed into the optically
active pyroglutamate 7a. The corresponding Ni-ligand and the chiral
auxiliary were recovered and recycled.11b,12
We envisioned that the 3,4-disubstituted pyroglutamic acid 10a
is an appropriate precursor for the preparation of the pyrogluta-
authors12 (Scheme 2), that is, the carbonyl group on the chiral oxa-
zolidinone ring coordinates to Ni in which the phenyl group locates
at the opposite face of the Ni-complex. The enolate oxygen and the
amide carbonyl group are placed in close proximity to each other
by TBD-H+. The decreased diastereoselectivity in the 3,4-disubsti-
tuted adduct 9 (64% dr) in comparison to that of the 3-substituted
adduct 6b (>98% dr) may be due to steric repulsion between the
mate core unit 3 via a c-butyrolactone 11 from a carbonate 10b.
Considering the stereochemical requirements for 10a as a starting
a-methyl group of 8 and the central Ni atom of the glycine Schiff
compound for the synthesis of 3, it was considered that the reac-
tion of the glycine Schiff base 4 with the a,b-disubstituted acrylate
base B that destabilized the previously proposed rigid transition
state A.12 The use of the sterically more or less bulky amine unit
(dibutylamine or pyrrolidine) instead of the piperidine unit of 4
did not affect the product’s diastereoselectivity (dibutylamine as
an amine unit, 0.5 equiv TBD, 24 h, 71% yield, dr = 71:12:9:4:2:2;
pyrrolidine, 0.15 equiv TBD, 15 min, 66%, dr = 66:16 [a mixture of
3 diastereomers] 12:6.16 An attempt was made to obtain the
2,3,4-trisubstituted pyroglutamic acid 10c, which provides an ex-
tremely simple access to the synthesis of 3. However, the reaction
with the hydroxymethyl or benzyloxymethyl group-substituted
glycine Shiff base was disappointing, and gave a complex mixture
or the recovery of the starting material probably due to severe ste-
ric repulsion between the benzyloxymethyl group of the Michael
possessing (S)-oxazolidinone 8 would undergo stereoselective Mi-
chael addition11b,12 to give the Michael adduct, (2S,3S,4R)-9, which
can be readily converted into the corresponding pyroglutamate,
(2S,3S,4R)-10a, in a manner similar to the preparation of 7a from
6a. The use of 4 possessing the piperidine moiety as an amine unit
was the choice for the glycine Schiff base in view of its high reac-
tivity and the ease of its large-scale preparation compared to the
dibutylamine- or pyridine-containing complexes.11b In addition,
DBU as an organic catalyst was an extremely effective base for
the Michael reaction of 4 with b-substituted acrylates 5a.11b On
the other hand, the Michael addition reactions of the
a-methyl
and/or b-alkoxymethyl substituted Michael acceptors such as 5b
and 8 are unprecedented regarding their reactivity and the prod-
uct’s diastereoselectivity (Scheme 1).
Initially, we examined reaction with the b-alkoxymethyl
Michael acceptor 5b without any a-substituent. The reaction under
acceptor 8 and the
in C (Scheme 2).
a-substituent of the Michael donor as depicted
The 3,4-disubstituted pyroglutamic acid 10a with the requisite
stereochemistry was prepared from 9 by an acidic workup fol-
lowed by base treatment. Next, we turned our attention to the
introduction of a carboxyl substituent at the C2 position. Our plan
was an intramolecular trap of the carbonate from the ester enolate
according to Danishefsky’s protocol.18 In order to differentiate the
resulting ester groups at C2 for further transformation, the tert-bu-
tyl group was chosen for the carboxyl-protecting group of 10a.
Thus, the pyroglutamate 10a was converted into the N-methylated
tert-butyl ester 13 in two steps, which, upon the removal of the
benzyl group and methyl carbonate formation of the resulting
alcohol, gave the carbonate 14. The treatment of 14 with NaHMDS
standard conditions was completed within 3 min to give the
Michael adduct 6b as the exclusive diastereomer (>98% dr).13 Thus,
it was found that the reaction tolerates the b-alkoxymethyl group.
However, the
a
-methyl derivative 814 did not react at all thus
resulting in complete recovery of the starting material. After
several unsuccessful trials, 1,5,7-triazabicyclo[4,4,0]dec-5-ene
(TBD),12,15 slightly more basic than DBU, was found to catalyze
the reaction to afford a mixture of the Michael adducts. A 1H
NMR analysis of the mixture indicated that it consists of 6 diaste-
reomers (68:8:7:7:7:3). Fortunately, the major isomer was sepa-
rated by silica gel column chromatography to give 9, in 62%
isolated yield.16 The stereochemistry of 9, with the desired
(2S,3S,4R)-configuration17, was ascertained by the NOE experi-
ments of the N-methylated derivative 12, prepared from 9 in 2
steps (Scheme 2). The stereochemical course of this transformation
would be similar to the previously proposed mechanism by the
gave a mixture of the desired c-butyrolactone 15a and its hydro-
lyzed product 15b. Upon treatment of the mixture with diazo-
methane, only 15a was isolated in 89% yield. To carry out the
simultaneous nucleophilic opening of the lactone 15a and incorpo-
ration of an appropriate leaving group at the resulting C3 hydroxy-
methyl group, the lactone 15a was treated with the phenylselenide
anion prepared from diphenyldiselenide.19 The reaction proceeded

T. Yamada et al. / Tetrahedron: Asymmetry 19 (2008) 2789–2795
2791
amine unit
Ph
H
TBD
O
O
N
O
N
8
O
Ph
Me
N
N
O
N
O
N
O
N
O
H
O
TBD (15 mol %)
Ni
X
Ni
Ni
2
O
N
O
N
N
Y
OBn
O
O
N
DMF, rt
62%
O
OBn
O
Ph
Ph
Ph
N
TBD =
(2S,3S,4R)-9
4
N
N
A X = Y = H
B X = Me, Y = H
C X = Me, Y = CH2OR
H
1) 3 M HCl, MeOH
70%
2) 1 M NaOH, CH2Cl2
H
H
CO2Me
OBn
OBn
CO2H
1. SOCl2, MeOH
O
N
Me
H
H3C
O
CO2Me
2. MeI, NaH
THF
O
OBn
N
N
H
H
H
Me
12
44%, 2 steps
NOE
12
10a
OBn
5b or 8
Ph
Me
N
N
O
N
O
N
N
O
N
O
R
Ni
Ni
O
O
N
N
CO2H
R
O
O
H
optimized
conditions
R
O
O
OBn
Ph
Ph
10c
R = CH2OH or CH2OBn
Scheme 2.
smoothly to give the ring-opened product, which, upon esterifica-
tion with diazomethane, afforded the desired dicarboxyl group
differentiated ester 16 in 61% yield (2 steps). Oxidative removal
of the phenylselenyl group gave the exomethylene 17. Chemose-
lective reduction of the methyl ester 17 with Zn(BH4)2 afforded
3. No epimerization at C4 of the product 3 was ascertained by its
NOE experiments as depicted in Scheme 3.
the Michael addition of the achiral glycine Schiff base 4 with the
chiral ,b-disubstituted acrylate derivative 8. The quarternaliza-
a
tion of C2 followed by introduction of the exomethylene group at
C3 was carried out by the internal nucleophilic trap of the carbon-
ate 14 and lactone opening with the phenylselenide anion. The
total number of processes included was 12 steps, and the overall
yield was 10%. The synthesized core unit 3 possesses the appropri-
ate functional groups for the b-lactone or c-lactone formation at
C2, as well as an exomethylene group at C3 which could be a useful
scaffold for stereoselective functionalization corresponding to the
oxazolomycin’s polyene segment. Further studies to assemble the
exomethylene group directed toward the total synthesis of 1 and
2 are now in progress in our laboratories.
3. Conclusion
In conclusion, we have developed a simple and diastereoselec-
tive access to the 3,4-disubstituted pyroglutamic acid 10a using
OBn
1. t-BuOAc
70% HClO4
OCO2Me
1. H2, Pd/C
MeOH
10a
O
CO2t-Bu
N
O
CO2t-Bu
2. ClCO2Me, Py
69%, 2 steps
2. MeI, NaH
THF
73%, 2 steps
N
Me
Me
13
14
NaHMDS
THF
1. Ph2Se2
NaBH4, EtOH
2. CH2N2
SePh
OH
O
CO2Me
+
O
CO2H
O
N
N
O
N
CO2t-Bu
O
CO2t-Bu
61%, 2 steps
Me
Me CO2t-Bu
Me
16
15a
15b
CH2N2
30% H2O2
THF
89%, 2 steps
97%
CO2t-Bu
H
Zn(BH4)2
O
N
H
H
OH
CO2Me
H3C
Me
O
Et2O
90%
N
CO2t-Bu
Me
NOE
17
3
Scheme 3.

2792
T. Yamada et al. / Tetrahedron: Asymmetry 19 (2008) 2789–2795
to a mixture of 3 M HCl (40 mL) at 70 °C. Upon disappearance of
4. Experimental
4.1. General remarks
the red color of the starting complex, the reaction mixture was
evaporated in vacuo. 1 M NaOH and CH2Cl2 were added. After stir-
ring at room temperature for 1 h, the mixture was filtrated and ex-
tracted with CH2Cl2. The extracts were dried over MgSO4 and
evaporated in vacuo, to afford a mixture of ligand and chiral auxil-
iary, which could be separated by recrystallization from AcOEt and
hexane. The aqueous solution was acidified by 1 M HCl and ex-
tracted with AcOEt. The organic layers were dried over anhydrous
MgSO4, and evaporated in vacuo to afford 7b (1.74 g, 70%). 1H NMR
(300 MHz, CDCl3) d 9.12 (br s, 1H), 7.28–7.18 (m, 5H), 4.50 (d,
J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.10 (d, J = 5.3 Hz, 1H),
3.55–3.44 (m, 2H), 2.75 (m, 1H), 2.48 (dd, J = 17.4, 9.3 Hz, 1H),
All reagents and solvents were purchased from either Aldrich
Chemical Company, Inc., Merck & Co., Inc., Nacalai Tesque Co.,
Ltd, Tokyo Kasei Kogyo Co., Ltd, or Wako Pure Chemical Industries,
Ltd., Kanto Chemical Co., Ltd, and used without further purification
unless otherwise indicated. Tetrahydrofuran and ethyl alcohol
(EtOH) of anhydrous grade were used. Optical rotations were taken
on a JASCO P-1030 polarimeter with a sodium lamp (D line). FT-IR
spectra were measured on a JASCO FT/IR-420 infrared spectropho-
tometer. 1H NMR spectra were recorded on an either JEOL JNM-LA
300 (300 MHz), JEOL JNM-LA 400 (400 MHz), or Bruker AVANCE
600 (600 MHz) spectrometer. Chemical shifts of 1H NMR were
reported in parts per million (ppm, d) relative to CHCl3 (d = 7.26)
in CDCl3, or CD2HOD (d = 3.30) in CD3OD. 13C NMR spectra were
recorded on a JEOL JNM-LA 300 (75 MHz) or JEOL JNM-LA 400
(100 MHz) spectrometer. Chemical shifts of 13C NMR were re-
ported in ppm (d) relative to CHCl3 (d = 77.0) in CDCl3. Low resolu-
tion mass spectra (LRMS) and high resolution mass spectra (HRMS)
were obtained on a JEOL JMS-AX500 for fast atom bombardment
ionization (FAB) or electron ionization (EI). All reactions were
monitored by thin layer chromatography (TLC), which was per-
formed with precoated plates (Silica Gel 60 F-254, 0.25 mm layer
thickness, manufactured by Merck). TLC visualization was accom-
plished using UV lump (254 nm) or a charring solution (ethanoic
molybdophosphoric acid and butanoic ninhydrin). Daisogel IR-60
1002W (40/63 mm) was used for flash column chromatography
on silica gel.
2.27 (dd, J = 17.4, 6.3 Hz, 1H). To
a solution of 7b (4.00 g,
16.0 mmol) in methanol (80 mL) was added thionyl chloride
(2.4 mL, 32.0 mmol) dropwise at 0 °C under an argon atmosphere.
The reaction mixture was warmed to room temperature and kept
stirring for 3 h. Upon completion, the reaction mixture was evapo-
rated, and the residue was partitioned between CH2Cl2 and satu-
rated NaHCO3, brine and dried over anhydrous MgSO4. After
removal of solvent, the residue was purified by flash column chro-
matography on silica gel (AcOEt) to give the methyl ester of 7b
(4.26 g, 100%) as a colorless oil. ½a D27:0
ꢀ
¼ ꢁ27:3 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) d 7.30–7.19 (m, 5H), 6.60 (br s, 1H), 4.50
(d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.2 Hz, 1H), 4.09 (d, J = 4.6 Hz,
1H), 3.68 (s, 3H), 3.48 (d, J = 5.8 Hz, 2H), 2.79–2.69 (m, 1H), 2.44
(dd, J = 17.2, 9.4 Hz, 1H), 2.19 (dd, J = 17.2, 5.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 176.9, 172.2, 137.7, 128.4, 127.8, 127.5, 73.1,
70.5, 57.4, 52.5, 38.5, 32.6; IR (neat) 3380, 2952, 2864, 1741,
1700, 1442, 1217, 1107, 744, 701 cmꢁ1; HRMS(FAB) m/z (M+H)+
calcd for [C14H18NO4]+ 264.1236, found 264.1241.
4.2. (R)-3-((E)-4-(Benzyloxy)but-2-enoyl)-4-phenyloxazolidin-
4.4. (S)-3-((E)-4-(Benzyloxy)-2-methylbut-2-enoyl)-4-phenyl-
2-one 5b
oxazolidin-2-one 8
A solution of phosphorane14a,b (14.6 g, 30.4 mmol) and 2-ben-
zyloxymethyl acetoaldehyde14c (5.0 g, 30.5 mmol) in THF
(150 mL) was stirred at room temperature for 2 days under an
argon atmosphere. The reaction mixture was concentrated under
reduced pressure to give a crude residue. The resulting residue
was purified by column chromatography on silica gel (hexane/
AcOEt = 5:1 to 2:1), and the resulting solid residue was recrystal-
lized from AcOEt/hexane to give (R)-5b (4.11 g, 40%) as colorless
To a solution of (S)-4-phenyl oxazolidinone (16.3 g, 100 mmol)
in THF (330 mL) was added n-BuLi (1.58 M in hexane, 63.3 mL,
100 mmol) at ꢁ78 °C under an argon atmosphere. The reaction
mixture was stirred at ꢁ78 °C for 10 min, then
a-bromopropanoyl
bromide (25 g, 117 mmol) was added. After stirring at ꢁ78 °C for
10 min, the mixture was warmed to room temperature and kept
stirring for 20 min. The reaction mixture was quenched with satu-
rated NH4Cl and extracted with CH2Cl2. The combined organic lay-
ers were washed with brine, dried over anhydrous MgSO4, filtered,
and evaporated in vacuo. The residue was dissolved in MeCN
(120 mL), and triphenylphosphine (27 g, 103 mmol) was added un-
der an argon atmosphere. After stirring at 50 °C for 24 h, 2 N NaOH
(53 mL) was added at room temperature and stirred for 15 min.
The reaction mixture was extracted with CH2Cl2. The combined
organic layers were washed with brine and dried over anhydrous
MgSO4, filtered, and evaporated in vacuo. The resulting phosphor-
ane was dissolved in THF (500 mL), and 2-benzyloxymethyl aceto-
aldehyde14c (21.4 g, 150 mmol) was added. The reaction mixture
was refluxed for 6 days under an argon atmosphere. The reaction
mixture was concentrated under reduced pressure to give a crude
residue. The resulting residue was purified by flash column chro-
matography on silica gel (hexane/AcOEt = 5:1 to 2:1), and the
resulting solid residue was recrystallized from AcOEt/hexane to
give (S)-8 (21.4 g, 61%, E/Z = >30:1) as colorless needles. Mp
needles. Mp 119 °C;
½
a 2D0:9
ꢀ
¼ ꢁ69:9 (c 1.7, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.52 (dt, J = 15.5, 1.7 Hz, 1H), 7.39–7.25 (m,
10H), 7.07 (dt, J = 15.5, 4.3 Hz, 1H), 5.48 (dd, J = 8.8, 3.9 Hz, 1H),
4.69 (dd, J = 8.8, 8.8 Hz, 1H), 4.55 (s, 2H), 4.27 (dd, J = 8.8, 3.9 Hz,
1H), 4.19 (dd, J = 4.3, 1.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) d
164.2, 153.5, 146.7, 138.9, 137.6, 129.1, 128.6, 128.4, 127.7,
127.7, 125.9, 120.2, 72.7, 69.9, 68.9, 57.7; IR (neat) 1778, 1689,
1643, 1332, 1200, 1105 cmꢁ1. HRMS(FAB) m/z (M+H)+ calcd for
[C20H20NO4]+ 338.1392, found 338.1373.
4.3. (2R,3R)-Methyl 3-((benzyloxy)methyl)-5-oxopyrrolidine-2-
carboxylate, methyl ester of 7b
To a solution of Ni(II)-complex 4 (5.52 g, 11.5 mmol) in DMF
(55 mL) was added the Michael acceptor (R)-5b (3.52 g,
10.4 mmol). After stirring the mixture for 10 min at room temper-
ature, DBU (0.24 mL, 1.6 mmol) was added. The reaction was mon-
itored by TLC (sample was quenched with brine, and the products
were extracted with chloroform before being applied to the plate).
After stirring at rt for 10 min, the reaction mixture was poured into
water and stirred to initiate crystallization of the product. The
crystalline product was filtered off, thoroughly washed with water,
and dried in vacuo to afford addition products (2R,3R,40R)-6b. A
solution of 6b in MeOH (400 mL) was slowly added with stirring
128 °C; ½a 2D0:5
ꢀ
¼ þ12:9 (c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.44–7.24 (m, 10H), 6.23 (ddd, J = 5.9, 5.9, 1.5 Hz, 1H), 5.45 (dd,
J = 8.8, 7.1 Hz, 1H), 4.69 (dd, J = 8.8, 8.8 Hz, 1H), 4.55 (d,
J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.23 (dd, J = 8.8, 7.1 Hz,
1H), 4.22–4.17 (m, 2H), 1.84 (d, J = 1.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.4, 153.3, 137.8, 137.7, 135.9, 132.5,
129.2, 128.9, 128.4, 127.9, 127.8, 126.3, 72.4, 69.9, 66.2, 58.3,

T. Yamada et al. / Tetrahedron: Asymmetry 19 (2008) 2789–2795
2793
13.7; IR (neat) 1782, 1682, 1321, 1282, 1207, 1107, 1049, 764,
700 cmꢁ1; Anal. Calcd for C21H21NO4: C, 71.8; H, 6.0; N, 4.0. Found:
C, 70.9; H, 5.9; N, 4.0.
pletion, the reaction mixture was evaporated, and the residue was
partitioned between CH2Cl2 and saturated NaHCO3 solution, brine
and dried over anhydrous MgSO4. After removal of solvent, the res-
idue was purified by flash column chromatography on silica gel
(AcOEt) to give the (2S,3S,4R)-methyl pyroglutamate (78 mg,
94%) as a colorless oil. 1H NMR (400 MHz, CDCl3) d 7.35–7.25 (m,
5H), 6.50 (br s, 1H), 4.39 (d, J = 2.0 Hz, 2H), 4.29 (d, J = 7.1 Hz,
1H), 3.56 (s, 3H), 3.53–3.47 (2H), 3.01 (m, 1H), 2.65 (dq, J = 7.4,
7.4 Hz, 1H), 1.14 (d, J = 7.4 Hz, 3H). To a solution of (2S,3S,4R)-
methyl pyroglutamate (38.6 mg, 0.14 mmol) in THF (1.5 mL) was
added sodium hydride (8 mg, 0.34 mmol) at 0 °C under an argon
atmosphere. After stirring for 5 min, methyl iodide (20 mL,
0.32 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h, then quenched with saturated NH4Cl and ex-
tracted with AcOEt. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and evaporated
in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (hexane/AcOEt = 1:1) to give (2S,3S,4R)-12
(19.1 mg, 47%) as a colorless oil. 1H NMR (600 MHz, CDCl3) d
7.36–7.27 (5H), 4.44 (s, 2H), 4.17 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H),
3.53–3.47 (m, 2H), 3.00 (m, 1H), 2.63 (dq, J = 7.8, 7.8 Hz, 1H),
1.17 (d, J = 7.8 Hz, 3H).
4.5. N-(2-Benzoyl-phenyl)-2-piperidyl-acetamide Ni(II)
complex of (2S,3S,4R,40S)- 3-benzyloxymethyl-4-methyl-5-[30-
(40-phenyl-20-oxazolidinonyl)] glutamic acid Schiff base 9
To a solution of Ni-complex 4 (847 mg, 1.94 mmol) in DMF
(9 mL) was added (S)-8 (620 mg, 1.77 mmol). After stirring the
mixture for 10 min at room temperature, TBD (37 mg, 0.27 mmol)
was added. The reaction was monitored by TLC (sample was
quenched with brine, and the products were extracted with chloro-
form before being applied to the plate). After stirring at room tem-
perature for 15 min, the reaction mixture was poured into water
and stirred to initiate crystallization of the product. The crystalline
product was filtered off, thoroughly washed with water, and dried
in an oven. The crude mixture was purified by flash column chro-
matography on silica gel (CH2Cl2/acetone = 10:1 to 5:1) to give
(2S,3S,4R,40S)-9 (858 mg, 62%) as a reddish solid. Mp 144–145 °C;
½
a 2D1:2
ꢀ
¼ þ2376:3 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) d 8.63
(d, J = 8.6 Hz, 1H), 7.45 (m, 1H), 7.35–7.05 (14H), 6.81 (br d,
J = 7.6 Hz, 1H), 6.68–6.66 (2H), 5.13 (dd, J = 7.9, 2.0 Hz, 1H), 4.19
(d, J = 12.0 Hz, 1H), 4.09–4.01 (3H), 3.91 (br d, J = 16.2 Hz, 1H),
3.83 (dd, J = 8.8, 2.0 Hz, 1H), 3.61 (d, J = 16.2 Hz, 1H), 3.56 (dd,
J = 10.0, 6.8 Hz, 1H), 3.45–3.38 (m, 3H), 3.28–3.17 (m, 2H), 2.86
(m, 1H), 2.54 (m, 1H), 1.76–1.22 (m, 6H), 1.39 (d, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 177.9, 177.1, 176.5, 172.5, 153.2,
142.9, 139.5, 138.4, 134.0, 133.4, 133.0, 129.8, 129.2, 129.2,
129.1, 128.6, 128.1, 127.9, 127.8, 127.3, 127.0, 126.1, 125.4,
123.7, 121.1, 72.5, 70.1, 69.3, 68.4, 60.0, 58.1, 55.7, 54.3, 43.6,
4.8. (2S,3S,4R)-tert-Butyl-3-((benzyloxy)methyl)-1,4-dimethyl-
5-oxopyrrolidine-2-carboxylate 13
To a solution of (2S,3S,4R)-10a (493 mg, 1.78 mmol) in t-BuOAc
(2.5 mL) was added 70% HClO4 aq (3 drops) at room temperature.
The reaction mixture was stirred at room temperature for 40 h,
then quenched with saturated NaHCO3 solution, and extracted
with AcOEt. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated in vacuo.
The residue was purified by flash column chromatography on silica
gel (hexane/AcOEt = 1:4) to give the t-butyl ester (451 mg, 80%) as
38.4, 22.9, 19.8, 19.2, 10.8; IR (neat) 2361, 1778, 1637, 751 cmꢁ1
;
HRMS(FAB) m/z (M+H)+ calcd for [C43H45N4O7Ni]+ 787.2642, found
787.2657.
a colorless oil. ½a D25:4
ꢀ
¼ þ14:9 (c 1.4, CHCl3); 1H NMR (400 MHz,
4.6. (2S,3S,4R)-3-((Benzyloxy)methyl)-4-methyl-5-oxopyrrolidine-
2-carboxylic acid 10a
CDCl3) d 7.31–7.21 (m, 5H), 5.93 (br s, 1H), 4.43 (s, 2H), 4.18 (d,
J = 7.6 Hz, 1H), 3.54 (d, J = 5.4 Hz, 2H), 2.93 (m, 1H), 2.61 (dq,
J = 7.6, 7.6 Hz, 1H), 1.39 (s, 9H), 1.15 (d, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 179.9, 169.6, 137.6, 128.1, 127.4, 127.4, 82.1,
73.0, 66.3, 57.0, 41.0, 38.3, 27.7, 10.7; IR (neat) 3246, 1707, 1454,
1369, 1228, 1157, 1097, 752 cmꢁ1; HRMS(FAB) m/z (M+H)+ calcd
for [C18H26NO4]+ 320.1862, found 320.1866. To a solution of the
resulting t-butyl ester (28.4 mg, 0.09 mmol) in THF (1.0 mL) was
added sodium hydride (2.6 mg, 0.11 mmol) at 0 °C under an argon
atmosphere. After stirring for 5 min, methyl iodide (7 mL,
0.11 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h, then quenched with saturated NH4Cl, and ex-
tracted with AcOEt. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and evaporated in va-
cuo. The residue was purified by flash column chromatography on
silica gel (hexane/AcOEt = 1:1) to give (2S,3S,4R)-13 (23.7 mg, 80%)
To
a
solution of the Ni-complex (2S,3S,4R,40S)-9 (3.90 g,
4.95 mmol) in MeOH (200 mL) was slowly added aqueous 3 N
HCl (20 mL) with stirring at 70 °C. Upon disappearance of the red
color of the starting complex, the reaction mixture was evaporated
in vacuo. 1 M NaOH and CH2Cl2 were added. After stirring at room
temperature for 1 h, the mixture was filtrated and extracted with
CH2Cl2. The organic layers were combined and dried over MgSO4
and evaporated in vacuo to afford a mixture of ligand and (S)-chiral
auxiliary, which could be separated by recrystallization from AcOEt
and hexane. The aqueous solution was acidified by 1 M HCl and ex-
tracted with AcOEt. The organic layers were dried over MgSO4, and
evaporated in vacuo to afford (2S,3S,4R)-10a (958 mg, 70%) as a
colorless oil. ½a D25:7
ꢀ
¼ þ24:3 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) d 9.12 (br s, 1H), 7.57 (s, 1H), 7.32–7.18 (m, 5H), 4.38 (s,
2H), 4.29 (d, J = 7.8 Hz, 1H), 3.60–3.50 (m, 2H), 2.98 (m, 1H), 2.67
(m, 1H), 1.13 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
181.8, 174.8, 137.6, 130.0, 128.3, 127.6, 73.2, 66.3, 57.1, 41.0,
38.7, 10.5; IR (neat) 3295, 2879, 1712, 1662, 1454, 1369, 1232,
as a colorless oil. ½a D26:1
ꢀ
¼ þ25:8 (c 1.1, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.28–7.17 (m, 5H), 4.46 (d, J = 11.7 Hz, 1H), 4.37 (d,
J = 11.9 Hz, 1H), 3.94 (d, J = 9.0 Hz, 1H), 3.50 (dd, J = 9.3, 6.6 Hz,
1H), 3.37 (dd, J = 9.0, 9.0 Hz, 1H), 2.86 (dtd, J = 8.9, 8.9, 6.7 Hz, 1H),
2.72 (s, 3H), 2.53 (m, 1H), 1.35 (s, 9H), 1.09 (d, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 177.9, 169.5, 128.3, 127.7, 127.7, 82.5,
73.4, 66.7, 64.2, 37.9, 37.8, 28.7, 27.9, 11.9; IR (neat) 2360, 1732,
1697, 1457, 1369, 1226, 1156, 1100 cmꢁ1; HRMS(FAB) m/z (M+H)+
calcd for [C19H28NO4]+ 334.2018, found 334.2010.
;
1099 cmꢁ1 HRMS(FAB) m/z (M+H)+ calcd for [C14H18NO4]+
264.1236, found 264.1239.
4.7. (2S,3S,4R)-Methyl 3-((benzyloxy)methyl)-1,4-dimethyl-5-
oxopyrrolidine-2-carboxylate 12
4.9. ((2S,3S,4R)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-5-
To a stirred solution of (2S,3S,4R)-10a (78 mg, 0.30 mmol) in
MeOH (1.5 mL) was added thionyl chloride (44 mL, 0.6 mmol)
dropwise at 0 °C under an argon atmosphere. The mixture was
warmed to room temperature and kept stirring for 2 h. Upon com-
oxopyrrolidin-3-yl)methyl methyl carbonate 14
To a solution of (2S,3S,4R)-13 (851 mg, 2.55 mmol) in MeOH
(30 mL) was added Pd/C (85 mg, 10 wt %). The reaction mixture

2794
T. Yamada et al. / Tetrahedron: Asymmetry 19 (2008) 2789–2795
was stirred at room temperature for 12 h under H2. The reaction
mixture was filtered and concentrated under reduced pressure.
To a stirred solution of crude alcohol in pyridine (25 mL) was
added methyl chlorocarbonate (1.0 mL, 16.8 mmol) dropwise at
0 °C under an argon atmosphere. After stirring for 5 h at 0 °C, the
mixture was warmed to room temperature and kept stirring for
5 h. The reaction mixture was quenched with 1 M HCl and ex-
tracted with AcOEt. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and evaporated
in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (hexane/AcOEt = 1:2) to give (2S,3S,4R)-15
1H), 3.11–3.03 (m, 1H), 2.87 (s, 3H), 2.82–2.69 (m, 2H), 1.36 (s,
9H), 1.11 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 177.6,
168.5, 166.1, 133.8, 129.2, 129.0, 127.7, 84.1, 75.6, 52.7, 43.4,
38.3, 28.8, 27.7, 24.3, 11.5; IR (neat) 1736, 1706, 1251,
1155 cmꢁ1; HRMS(FAB) m/z (M+H)+ calcd for [C20H28NO5Se]+
442.1133, found 442.1128.
4.12. (2R,4R)-2-tert-Butyl 2-methyl 1,4-dimethyl-3-methylene-
5-oxopyrrolidine-2,2-dicarboxylate 17
A
solution of (2R,3S,4R)-16 (49.0 mg, 0.11 mmol) in THF
(538 mg, 70%) as a colorless oil. ½a D27:0
ꢀ
¼ þ27:5 (c 3.4, CHCl3); 1H
(2.0 mL) was treated with 30% aqueous H2O2 (0.2 mL) at room tem-
perature. After the reaction mixture was stirred at room tempera-
ture for 3 h, quenched with saturated Na2SO3 solution at 0 °C, and
extracted with AcOEt. The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The res-
idue was purified by flash column chromatography on silica gel
(hexane/AcOEt = 3:1) to give (2R,4R)-17 (30.7 mg, 97%) as a pale
NMR (400 MHz, CDCl3) d 4.26 (dd, J = 11.0, 7.4 Hz, 1H), 4.10 (dd,
J = 11.0, 8.3 Hz, 1H), 4.01 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.00–
2.91 (1H), 2.76 (s, 3H), 2.61–2.53 (dq, J = 7.6, 7.6 Hz, 1H), 1.43 (s,
9H), 1.13 (d, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 177.1,
169.2, 155.3, 83.1, 64.6, 63.7, 54.9, 37.7, 36.8, 28.8, 27.8, 11.9; IR
(neat) 3476, 2978, 1741, 1695, 1447, 1275, 1157, 963, 793 cmꢁ1
;
HRMS(FAB) m/z (M+H)+ calcd for [C14H24NO6]+ 302.1604, found
yellow oil. ½a 2D5
ꢀ
¼ ꢁ84:0 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3)
302.1613.
d 5.56 (m, 1H), 5.32 (dd, J = 2.4, 0.7 Hz, 1H), 3.81 (s, 3H), 3.09 (m,
1H), 2.97 (s, 3H), 1.47 (s, 9H), 1.31 (d, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 176.1, 167.5, 165.4, 142.7, 112.9, 83.9, 76.2,
53.1, 39.8, 28.3, 27.7, 16.2; IR (neat) 2979, 1739, 1714, 1664,
1455, 1430, 1375, 1255, 1157, 1074, 1049 cmꢁ1; HRMS(FAB) m/z
(M+H)+ calcd for [C14H22NO5]+ 284.1498, found 284.1497.
4.10. (3R,3aS,6aR)-tert-Butyl-hexahydro-1,3-dimethyl-2,6-
dioxo-1H-furo[3,4-b]pyrrole- 6a-carboxylate 15a
A solution of (2S,3S,4R)-14 (538 mg, 1.8 mmol) in THF (18.5 mL)
was treated with NaHMDS (1.9 M in THF, 2.0 mL, 3.8 mmol) at
ꢁ78 °C under an argon atmosphere. The reaction mixture was stir-
red at ꢁ78 °C for 15 min, then quenched with saturated NH4Cl, and
extracted with AcOEt. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and evaporated
in vacuo. The residue was purified by flash column chromatogra-
4.13. (2R,4R)-tert-Butyl 2-(hydroxymethyl)-1,4-dimethyl-3-
methylene-5-oxopyrrolidine-2-carboxylate 3
To a solution of (2R,4R)-17 (4.8 mg, 0.017 mmol) in ether (120
lL) was added Zn(BH4)2 (0.14 M in ether, 120 lL, 0.017 mmol) at
phy on silica gel (hexane/AcOEt = 2:1 to 1:1) to give the
c
-butyro-
room temperature under an argon atmosphere. After the reaction
mixture was stirred at room temperature for 24 h, quenched with
water, and extracted with AcOEt. The combined organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (hexane/AcOEt = 1:2) to give (2R,4R)-3 (3.9 mg, 90%) as a color-
lactone 15a (185 mg, 39%). The aqueous solution was acidified by
1 N HCl and extracted with AcOEt. The organic layers were dried
over MgSO4, and evaporated in vacuo to afford hydrolysis product
15b (281 mg). To a solution of diazomethane in ether was added a
solution of 15b in ether at 0 °C, stirred for 30 min, and concen-
trated in boiled water bath. The residue was purified by flash
column chromatography (hexane/AcOEt = 1:1) to give 15a
less powder. ½a D25:0
ꢀ
¼ ꢁ85:7 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3) d 5.35 (d, J = 2.8 Hz, 1H), 5.23 (dd, J = 2.8, 0.6 Hz, 1H), 4.05
(dd, J = 12.2, 5.4 Hz, 1H), 3.90 (dd, J = 12.2, 6.3 Hz, 1H), 3.08 (m,
1H), 2.89 (s, 3H), 2.13 (br s, 1H), 1.43 (s, 9H), 1.29 (d, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 176.3, 169.0, 145.7, 109.8, 83.0,
73.9, 64.4, 39.9, 27.8, 26.9, 15.9; IR (neat) 3309, 2981, 1725,
1681, 1656, 1459, 1436, 1398, 1369, 1257, 1164, 1139, 1076,
(240 mg, 50%) as a colorless oil. ½a D25:1
ꢀ
¼ þ88:7 (c 1.8, CHCl3); 1H
NMR (400 MHz, CDCl3) d 4.43 (dd, J = 9.5, 8.6 Hz, 1H), 4.09 (dd,
J = 9.5, 7.3 Hz, 1H), 3.37–3.31 (m, 1H), 2.93 (s, 3H), 2.73–2.65
(1H), 1.45 (s, 9H), 1.14 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 175.1, 169.8, 166.1, 84.9, 70.2, 67.2, 43.4, 37.1, 27.9,
27.4, 10.6; IR (neat) 2980, 1783, 1743, 1711, 1371, 1259, 1151,
1037, 836 cmꢁ1; HRMS(FAB) m/z (M+H)+ calcd for [C13H20NO5]+
270.1341, found 270.1340.
1014 cmꢁ1
;
HRMS(FAB) m/z (M+H)+ calcd for [C13H22NO4]+
256.1549, found 256.1551.
Acknowledgments
4.11. (2R,3S,4R)-2-tert-Butyl 2-methyl 1,4-dimethyl-5-oxo-3-
((phenylselanyl)methyl) pyrrolidine-2,2-dicarboxylate 16
This study was supported by Grants-in-Aid (16201045 and
19201045) for Scientific Research from the Japan Society for the
Promotion of Science (JSPS).
To a mixture of 15a (235 mg, 0.87 mmol) and Ph2Se2 (569 mg,
1.87 mmol) in EtOH (9.2 mL) was added NaBH4 (129 mg,
3.42 mmol) at 0 °C. After stirring at room temperature for
30 min, the mixture was heated to 60 °C and kept stirring for 1 h.
The reaction mixture was quenched with 1 M KOH and extracted
with Et2O. The aqueous layer was acidified with 1 M citric acid
and extracted with AcOEt. The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. To a solu-
tion of diazomethane in ether was added a solution of the crude
mixture in ether at 0 °C. The mixture was stirred for 30 min and
concentrated in boiled water bath. The residue was purified by
flash column chromatography on silica gel (hexane/AcOEt = 3:1)
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