Efficient synthesis of (R)- and (S)-α-(hydroxymethyl)pyroglutamic acid esters from L-proline

Article abstract of DOI:10.1055/S-0029-1217024

An efficient synthesis of (R)- and (S)-α-(hydroxymethyl)pyroglutamic acid esters from L-proline has been achieved. Each step was carried out on a decagram scale to access the N-protected (R)-ester in a highly efficient manner (44% overall yield from a pro

Full text of DOI:10.1055/S-0029-1217024

PAPER
3751
Efficient Synthesis of (R)- and (S)-a-(Hydroxymethyl)pyroglutamic Acid
Esters from L-Proline
(
R
)- and
(
S
)-
a
-(
e
H
ydroxym
t
ethyl)py
s
roglutam
u
ic
A
cid Ester
r
s
o Shinada,* Hiroki Yoshida, Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Fax +81(6)66053153; E-mail: shinada@sci.osaka-cu.ac.jp; E-mail: ohfune@sci.osaka-cu.ac.jp
Received 2 June 2009; revised 30 June 2009
containing N,O-acetal, was chosen as the self chirality
transferring substrate for the large-scale alkylation reac-
tion. The ruthenium(VIII) oxide (RuO4) oxidation of N-
(tert-butoxycarbonyl)-substituted (N-Boc) pyrrolidine 5
would produce HMPGs.11 Although enantiomer 2 could
be accessed from D-proline along these lines too, this sub-
strate is five times more expensive than L-proline. In this
study, an alternative route involving inversion of the R-
chiral center of 5 to give S-product 6 was attempted to ac-
cess enantiomer 2.
Abstract: An efficient synthesis of (R)- and (S)-a-(hydroxymeth-
yl)pyroglutamic acid esters from L-proline has been achieved. Each
step was carried out on a decagram scale to access the N-protected
(R)-ester in a highly efficient manner (44% overall yield from a pro-
line-derived bicyclic substrate).
Key words: amino acids, a-substituted proline, pyroglutamic acid
esters, stereoselective synthesis, alkylations
Several natural products possessing a,,a-disubstituted
pyrrolidine (or a-substituted pyroglutamic acid) as their
core unit have attracted much attention because of their
synthetically challenging structures and potent biological
activities.1 Much synthetic effort has been dedicated to the
enantio- and diastereoselective total syntheses of such
compounds and structure–activity relationship studies to
explore their bioactivities and modes of action.2–5 The ste-
reoselective construction of the highly substituted pyrroli-
dine core is key to their synthesis. We envisaged that
optically active a-(hydroxymethyl)pyroglutamic acid es-
ters (HMPGs)6 1 and 2 could be useful synthetic interme-
diates to achieve the above goals (Scheme 1); HMPGs are
a-(hydroxymethyl) derivatives of pyroglutamic acid es-
ters, which are widely employed in the synthesis of pyrro-
lidine-containing natural products and biologically active
compounds.7 The potent utilities of compounds 1 and 2
have been demonstrated in the synthesis of kaitocepha-
lin,4c dysibetaine,5c and omuralide.8 However, there re-
main improvements to be made to the existing syntheses
of such substrates; for example, 3 grams of a derivative of
(S)-HMPG 2, used as the key intermediate for the total
synthesis of kaitocephalin, were synthesized in 12 steps
using the asymmetric Strecker synthesis starting from le-
vulinic acid (50 g) resulting in 4% overall yield.4c In this
report, we describe a practical method for the synthesis of
both enantiomers of the HMPGs from L-proline (3).
H
O
HO
NH
OH
NMe3
O
O
O
CO2
N
H
Cl
dysibetaine
salinosporamide A
Cl
HO
H
CO2H
N
NH2
Cl
H
CO2H
N
O
H
CO2H
HO
kaitocephalin
OH
O
MeO
HO
O
O
N
N
Me
H
OH
O
O
oxazolomycin
N
OH
OH
CO2R
O
O
CO2H
N
CO2R
N
N
H
Boc
(R)-HMPG ester 1
Boc
L-proline (3)
(S)-HMPG ester 2
CH2OH
RuO4
Seebach et al.’s self asymmetric center regeneration meth-
od using L-proline (3)9 was adopted to generate the amino
group attached chiral center (Scheme 1). Chiral trichlo-
romethyl-containing N,O-acetal 4,10 which can be isolated
as a white powder, stored under ambient conditions, and
exhibits almost the same reactivity and stereoselectivity
compared to those of the moisture-sensitive tert-butyl-
CO2R
OPG
OPG
chirality
inversion
O
N
CO2Me
N
N
Boc
Boc
O
Cl3C
6
4
5
Scheme 1
The treatment of bicyclic compound 4 with lithium diiso-
propylamide followed by the addition of benzyl chloro-
methyl ether gave 7a in 67% yield (Scheme 2). The use of
chloromethyl methyl ether and [2-(trimethylsilyl)eth-
SYNTHESIS 2009, No. 22, pp 3751–3756
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217024; Art ID: F11009SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3752
T. Shinada et al.
PAPER
oxy]methyl chloride afforded the corresponding alkylated
products 7b and 7c, respectively, in moderate yields. The
direct hydroxymethylation reaction with formaldehyde
(solid paraformaldehyde or gaseous HCHO generated by
the thermolysis of paraformaldehyde) was not satisfacto-
ry, resulting in almost full recovery of starting material 4.
Based on the above results, as well as the consideration of
the protecting group manipulation required in later steps,
the scaling up of the synthesis was implemented with ben-
zyl derivative 7a. The synthesis was found to be reproduc-
ible and could be extended on a decagram scale to give
18.5 grams of product 7a in 70% yield. Benzyl ether 7a
was then converted into N-Boc derivative (R)-9 in a man-
ner similar to the reported method.10 Thus, benzyl ether 7a
was subjected to initial methanolysis using sodium meth-
oxide in methanol to give a mixture of the corresponding
amino methyl ester and its formamide. The mixture was
successively exposed to AcCl/MeOH to remove the N-
formamide furnishing the ammonium salt 8. The installa-
tion of the N-Boc group gave N-protected product (R)-9 in
78% yield from substrate 7a in three steps.
RuO2⋅2H2O
OBz
OBn
NaIO4
X
CO2Me
N
CO2Me
N
CCl4–MeCN–H2O
Boc
Boc
rac-9
solvent ratio 2:1:1, 3 h: rac-10 X = O (65%)
solvent ratio 1:1:1, 30 h: rac-11 X = H2 (30%)
K2CO3
MeOH
rac-HMPG
O
NHBoc
OH
+
BocHN
MeO2C
rac-13 38%
O
MeO2C
CO2Me
46%
rac-12
Scheme 3
gave a mixture of lactam-opening products rac-12 and
rac-13 in 46 and 38% yield, respectively.
We reported the synthesis of (R)-HMPG 16 by the mild
desilylation reaction (TBAF, AcOH) of lactam 15 during
the total synthesis of (–)-kaitocephalin.4c Moreover, the
compatibility of a tert-butyldimethylsilyl (TBS) ether
with RuO4 oxidation conditions was confirmed during the
first total synthesis of trideoxytetrodotoxin.11 Based on
these results, we turned our attention to the synthesis of si-
lyl ether 15 from benzyl ether (R)-9 (Scheme 4). The ben-
zyl group of (R)-9 was initially exchanged for a TBS
group under the conventional reaction conditions: (i) hy-
drogenation with hydrogen and palladium on carbon, and
(ii) silylation with TBSCl in the presence of 1H-imida-
zole. The RuO4 oxidation of 2-(siloxymethyl)pyrrolidine
14 in CCl4–MeCN–H2O (2:1:1) gave (R)-lactam 15 in ex-
cellent yield. The mild desilylation reaction of silyl ether
15 produced (R)-HMPG 16 without any undesired ring-
opening reaction. Each step could be practically carried
out on a decagram scale (44% overall yield starting from
4).
OR
LDA
electrophile
O
O
N
N
dr > 95:5
O
O
Cl3C
Cl3C
electrophile:
BOMCl
4
7a R = Bn 67% (1 g scale)
70% (10 g scale)
7b R = Me 59%
7c R = CH2CH2SiMe3 55%
7d R = H trace
MOMCl
SEMCl
HCHO
Boc2O
NaHCO3
1) NaOMe
MeOH
OBn
OBn
7a
CO2Me
N
CO2Me
N
2) AcCl,
MeOH
3 steps 78%
Boc
(R)-9
H
H
8
Cl
Scheme 2
OTBS
CO2Me
OBn
1) H2, Pd/C
We postulated that the dual oxidation reaction of the pyr-
rolidine ring and the benzyl group of (R)-9 with RuO4
(generated in situ from RuO2 and NaIO4) to produce a
benzoyl lactam, followed by the chemoselective removal
of the benzoyl group should provide the corresponding
(R)-HMPG. The feasibility of this synthesis was tested
with rac-9. The desired rac-(benzoyloxy)methyl-substi-
tuted lactam rac-10 was obtained in 65% yield when pro-
tected pyrrolidine rac-9 was subjected to RuO4 oxidation
in tetrachloromethane–methyl cyanide–water (CCl4–
MeCN–H2O, 2:1:1) (Scheme 3). The chosen solvent ratio
was essential for this oxidation reaction. On decreasing
the quantity of CCl4, i.e. using a solvent ratio of 1:1:1, the
reaction was found to be sluggish and provided 2-(ben-
zoyloxy)methylpyrrolidine rac-11 in 30% yield along
with a trace amount of 10 and recovery of starting material
rac-9, probably because of the poor solubility of rac-9 un-
der this condition. We next attempted the selective remov-
al of the benzoyl group of rac-10; however, a lactam-
opening reaction predominantly occurred. Thus, the treat-
ment of rac-10 with potassium carbonate in methanol
N
CO2Me
N
2) TBSCl
1H-imidazole
98% (2 steps)
Boc
14
Boc
9
RuO2, NaIO4
CCl4–MeCN–H2O
(2:1:1)
89%
TBAF
AcOH
OTBS
OH
O
O
CO2Me
N
CO2Me
N
93%
Boc
15
Boc
(R)-HMPG
methyl ester 16
Scheme 4
The synthesis of the related S-isomer 20 from (R)-9 via the
chirality switching of the quaternary amino carbon center
was attempted. The chirality switching was achieved us-
ing the following sequence of reactions: (i) reduction of
the ester moiety, (ii) protection of the resulting alcohol
with the TBS group, (iii) removal of the benzyl group, and
(iv) conversion of hydroxymethyl derivative 17 into ben-
zyl ester 18a (Scheme 5). The optical purity of 18a was
confirmed by the comparison of the optical rotation of the
corresponding methyl ester 18b with that of R-enantiomer
Synthesis 2009, No. 22, 3751–3756 © Thieme Stuttgart · New York

PAPER
(R)- and (S)-a-(Hydroxymethyl)pyroglutamic Acid Esters
3753
was added BOMCl (18.0 mL, 130 mmol), and the solution was al-
lowed to warm to –40 °C over 4 h. The mixture was then quenched
with H2O (300 mL) and extracted with EtOAc (3 × 300 mL). The
combined organic layers were dried (anhyd MgSO4) and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (Et2O–hexane, 1:7) to give 7a as a yellow
oil. Yield: 18.5 g (70%); [a]D24 +7.86 (c 1.08, CHCl3).
14. These results indicated that the TBS group did not mi-
grate during the hydrogenation reaction. Benzyl ester 18a
was converted into (S)-HMPG 20 (1.8 g) in two steps ac-
cording to the procedure for the formation of (R)-HMPG
16. The synthesis of benzyl ester 20 turned out to be ben-
eficial, allowing the option of further protecting groups at
the carboxylate moiety in HMPGs.
FTIR (neat): 3581, 3064, 3029, 2954, 2897, 2868, 1799, 1454,
1191, 1090, 1024, 837, 746 cm–1.
1) LiBH4
i-PrOH
1H NMR (400 MHz, CDCl3): d = 7.35–7.23 (m, 5 H), 4.97 (s, 1 H),
4.62 (d, J = 12.2 Hz, 1 H), 4.59 (d, J = 12.2 Hz, 1 H), 3.73 (d, J =
10.0 Hz, 1 H), 3.71 (d, J = 10.0 Hz, 1 H), 3.35–3.20 (m, 2 H), 2.33–
2.26 (m, 1 H), 2.14–2.07 (m, 1 H), 1.99–1.94 (m, 1 H), 1.74–1.62
(m, 1 H).
OBn
OH
2) TBSCl
CO2Me
N
OTBS
N
Boc
1H-imidazole
Boc
3) H2, Pd/C
(R)-9
17
81% (3 steps)
1) Swern
oxidation
2) Pinnick
oxidation
3) BnBr, K2CO3
13C NMR (100 MHz, CDCl3): d = 174.3, 137.9, 128.4, 127.6, 127.5,
102.0, 100.4, 73.5, 72.6, 72.5, 58.2, 33.7, 25.1.
71%
(3 steps)
HRMS (FAB): m/z [M + H]+ calcd for C15H16Cl3NO3: 364.0271;
found: 364.0278.
(3R,7aR)-7a-(Methoxymethyl)-3-(trichloromethyl)tetrahydro-
pyrrolo[1,2-c]oxazol-1(3H)-one (7b)
According to the procedure for the synthesis of 7a, bicyclic com-
pound 4 (147 mg, 0.60 mmol) was alkylated with MOMCl (0.08
mL, 1.07 mmol) to give 7b as a white solid. Yield: 101 mg (59%);
mp 62–63 °C; [a]D28 –0.13 (c 1.30, CHCl3).
CO2R
OTBS
CO2Bn
OR
RuO2, NaIO4
18a
O
N
N
CCl4–MeCN–H2O
(2:1:1)
TBAF 76%
AcOH
87%
Boc
Boc
19
18a R = Bn
18b R = Me
R = TBS
R = H
MeOH, K2CO3
94%
(S)-HMPG 20
benzyl ester
FTIR (neat): 2900, 1801, 1273, 1188, 1092, 1030, 945, 835, 806,
744, 667, 638 cm–1.
Scheme 5
1H NMR (400 MHz, CDCl3): d = 4.99 (s, 1 H), 3.67 (d, J = 10.2 Hz,
1 H), 3.63 (d, J = 10.2 Hz, 1 H), 3.30 (ddd, J = 12.2, 10.0, 5.8 Hz, 1
H), 3.42 (s, 3 H), 3.24 (ddd, J = 12.2, 9.8, 3.4 Hz, 1 H), 2.27 (ddd,
J = 13.2, 9.8, 7.1 Hz, 1 H), 2.12 (dddd, J = 13.2, 8.3, 3.9, 1.0 Hz, 1
H), 2.03–1.94 (m, 1 H), 1.76–1.66 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 174.4, 102.0, 100.3, 75.2, 72.4,
59.8, 58.1, 33.5, 25.1.
In summary, we have established an efficient synthesis of
(R)- and (S)-HMPGs from L-proline. Further synthetic ap-
plications starting from HMPGs on the synthesis of
glutamate analogues and pyrrolidine ring containing nat-
ural products are now in progress.
HRMS (CI): m/z [M + H]+ calcd for C9H12Cl3NO3: 287.9978;
found: 287.9960.
All reagents and solvents were purchased from Sigma-Aldrich, Na-
calai Tesque, or the Tokyo Chemical Industry and were used with-
out further purification unless otherwise indicated. Solvents of
anhydrous grade were used. Optical rotations were recorded on a
Jasco Polarimeter P-1030. Fourier transform infrared spectra were
(3R,7aR)-3-(Trichloromethyl)-7a-{[2-(trimethylsilyl)eth-
oxy]methyl}tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (7c)
According to the procedure for the synthesis of 7a, bicyclic com-
pound 4 (137 mg, 563 mmol) was alkylated with [2-(trimethylsi-
lyl)ethoxy]methyl chloride (184 mL, 1.01 mmol) to give 7c as a
colorless oil. Yield: 115 mg (55%); [a]D29 –1.18 (c 0.97, CHCl3).
1
measured on a Jasco FT/IR-6200 infrared spectrophotometer. H
NMR spectra were recorded on either a Jeol JNM-LA400 (400
MHz) or Bruker Avance 300M (300 MHz) spectrometer; chemical
shifts are reported in ppm relative to the residual peak of CHCl3 (d =
7.26) in CDCl3. 13C NMR spectra were recorded on either a Jeol
JNM-LA400 (100 MHz) or Bruker Avance 300 (75 MHz) spec-
trometer; chemical shifts are reported in ppm relative to CDCl3 (d =
77.0). HRMS was performed on a Jeol JMS-AX-500 instrument us-
ing FAB and CI techniques. All reactions were monitored by TLC,
which was performed with precoated plates (silica gel 60 F-254,
0.25-mm layer thickness, manufactured by Merck); TLC visualiza-
tion was accomplished using a UV lamp (254 nm) or a charring so-
lution (ethanoic phosphomolybdic acid). Daisogel IR-60 1002W
(40/63 mm) was used for flash column chromatography on silica
gel.
FTIR (neat): 3589, 2954, 2896, 1803, 1250, 1192, 1090, 867, 752
cm–1.
1H NMR (400 MHz, CDCl3): d = 4.99 (s, 1 H), 3.70–3.55 (m, 2 H),
3.67 (s, 2 H), 3.29 (ddd, J = 15.4, 9.8, 5.9 Hz, 1 H), 3.23 (ddd, J =
15.4, 6.3, 3.4 Hz, 1 H), 2.28 (ddd, J = 13.2, 9.8, 7.1 Hz, 1 H), 2.11
(ddd, J = 13.2, 8.3, 4.2 Hz, 1 H), 2.02–1.94 (m, 1 H), 1.74–1.63 (m,
1 H), 0.92 (t, J = 8.2 Hz, 2 H), 0.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 174.4, 101.9, 100.4, 72.7, 72.6,
72.5, 69.2, 58.1, 33.5, 25.1, 18.3, 18.1, 17.8, –1.2, –1.5, –1.7.
HRMS (FAB): m/z [M + H]+ calcd for C13H22Cl3NO3Si: 374.0530;
found: 374.0493.
(3R,7aR)-7a-[(Benzyloxy)methyl]-3-(trichloromethyl)tetrahy-
dropyrrolo[1,2-c]oxazol-1(3H)-one (7a); Typical Procedure
To a solution of i-Pr2NH (14.1 mL, 101 mmol) and THF (200 mL)
in a flame-dried, 500-mL round-bottomed flask was added 1.63 M
n-BuLi in hexane (62.0 mL, 101 mmol) at –78 °C under argon. The
mixture was stirred for 30 min at –78 °C. To the resulting LDA so-
lution was added a cooled solution (0 °C) of bicyclic compound 410
(17.7 g, 72.5 mmol) in THF (80 mL) via cannula at –78 °C under
argon. The mixture was stirred for 15 min at –78 °C. To the mixture
(R)-1-tert-Butyl 2-Methyl 2-[(Benzyloxy)methyl]pyrrolidine-
1,2-dicarboxylate (9)
A 500-mL, three-necked round-bottomed flask, equipped with a
100-mL pressure-equalizing addition funnel capped by a rubber
septum, a reflux condenser fitted with an argon balloon, and a rub-
ber septum, was filled with benzyl ether 7a (18.0 g, 49.5 mmol) and
MeOH (165 mL). To this solution was added NaOMe (1.60 g, 29.6
mmol) over 30 min. The mixture was stirred for an additional 30
Synthesis 2009, No. 22, 3751–3756 © Thieme Stuttgart · New York

3754
T. Shinada et al.
PAPER
min and then was cooled in an ice bath. The pressure-equalizing ad-
dition funnel was charged with commercially available AcCl (68.4
mL, 0.96 mol), which was added dropwise to the mixture over 1 h.
The funnel was removed and replaced with a rubber septum, and the
milky brown solution was refluxed for 20 h. The volatile organics
were removed under reduced pressure. The residue was diluted with
CH2Cl2 (90 mL), and precipitated NaCl was removed by filtration.
The filtrate was then poured into sat. Na2CO3 (200 mL), and the
mixture was extracted with EtOAc (3 × 200 mL). The combined or-
ganic extracts were dried (anhyd MgSO4) and concentrated under
reduced pressure to give methyl pyrrolidinecarboxylate 8 as a pale
red oil. To a solution of this residue in dioxane (114 mL) were suc-
cessively added sat. NaHCO3 (114 mL) and (Boc)2O (16.2 g, 74.3
mmol). The mixture was stirred for 24 h and then was concentrated
under reduced pressure. The residue was partitioned with EtOAc
(200 mL) and H2O (200 mL), and extracted. The aqueous layer was
then extracted with EtOAc (2 × 200 mL). The combined organic
layers were dried (anhyd MgSO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(hexane–EtOAc, 50:1 then 20:1) to give 9 as a colorless oil. Yield:
13.5 g (78%); a 2:3 mixture of rotamers in CDCl3; [a]D24 +37.2 (c
1.00, CHCl3).
bined organic layers were washed with brine, dried (anhyd MgSO4),
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography (hex-
ane–EtOAc, 25:1 then 15:1) to give 14 as a colorless oil. Yield: 14.2
g (99%); a 2:3 mixture of rotamers in CDCl3; [a]D25 +34.6 (c 1.05,
CHCl3).
FTIR (neat): 2954, 2933, 2885, 2858, 1743, 1699, 1471, 1396,
1099, 839, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.31 (d, J = 10.2 Hz, 2/5 H), 4.11
(d, J = 10.2 Hz, 3/5 H), 3.87 (d, J = 10.2 Hz, 2/5 H), 3.84 (d, J = 10.2
Hz, 3/5 H), 3.67 (s, 9/5 H), 3.67–3.63 (m, 9/5 H), 3.60–3.53 (m, 2/
5 H), 3.48–3.30 (m, 1 H), 2.40–2.27 (m, 1 H), 2.05–1.78 (m, 3 H),
1.41 (s, 27/5 H), 1.38 (s, 18/5 H), 0.86 (s, 9 H), 0.03 (s, 6/5 H), 0.02
(s, 9/5 H), –0.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.9, 173.8, 153.6, 153.2, 79.8,
79.3, 68.7, 68.2, 64.2, 63.0, 51.8, 51.7, 48.5, 35.9, 34.4, 28.3, 28.2,
25.7, 23.6, 23.0, 18.1, –5.49, –5.56, –5.60, –5.67.
HRMS (FAB): m/z [M + H]+ calcd for C18H35NO5Si: 374.2359;
found: 374.2362.
(R)-1-tert-Butyl 2-Methyl 2-[(tert-Butyldimethylsiloxy)methyl]-
5-oxopyrrolidine-1,2-dicarboxylate (15)
FTIR (neat): 3625, 3469, 3380, 2976, 2877, 1741, 1693, 1390,
1238, 1159, 1097, 750 cm–1.
To a solution of 2-(siloxymethyl)pyrrolidine 14 (13.2 g, 35.4 mmol)
in CCl4–MeCN–H2O (2:1:1, 230 mL) were added RuO2 (920 mg,
6.90 mmol) and NaIO4 (37.0 g, 173 mmol) with stirring. The mix-
ture was heated to 40 °C, stirred for 2 h, quenched with i-PrOH, and
filtered. To the filtrate was added sat. Na2SO3 (120 mL), and the or-
ganic layer was separated. The aqueous layer was extracted with
EtOAc (3 × 150 mL). The combined organic layers were washed
with brine, dried (anhyd MgSO4), and filtered. The filtrate was con-
centrated under reduced pressure. The residue was purified by flash
column chromatography (hexane–EtOAc, 50:1 then 10:1) to give
1H NMR (400 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 4.58 (d, J =
12.4 Hz, 2/5 H), 4.57 (d, J = 12.4 Hz, 3/5 H), 4.55 (d, J = 12.4 Hz,
3/5 H), 4.53 (d, J = 12.4 Hz, 2/5 H), 4.17 (d, J = 10.0 Hz, 2/5 H),
3.95 (d, J = 9.8 Hz, 3/5 H), 3.88 (d, J = 10.0 Hz, 2/5 H), 3.84 (d, J =
9.8 Hz, 3/5 H), 3.74–3.43 (m, 2 H), 3.69 (s, 3 H), 2.45–2.32 (m, 1
H), 2.12–1.82 (m, 3 H), 1.45 (s, 18/5 H), 1.36 (s, 27/5 H).
13C NMR (100 MHz, CDCl3): d = 173.7, 173.6, 153.9, 153.2, 138.6,
138.3, 128.3, 128.2, 127.5, 127.4, 127.3, 172.2, 79.9, 79.5, 73.5,
73.4, 71.2, 70.3, 67.9, 67.4, 51.9, 51.8, 48.5, 48.4, 36.2, 34.8, 28.4,
28.2, 23.6, 23.0.
26
15 as a colorless oil. Yield: 12.9 g (89%); [a]D +42.6 (c 1.00,
CHCl3).
HRMS (FAB): m/z [M + H]+ calcd for C19H27NO5: 350.1964;
found: 350.1959.
The analytical data of 15 were identical with those of authentic data
reported in the literature {[a]D25 +44.6 (c 1.10, CHCl3)}.4c
(R)-1-tert-Butyl 2-Methyl 2-[(tert-Butyldimethylsiloxy)meth-
yl]pyrrolidine-1,2-dicarboxylate (14)
(R)-1-tert-Butyl 2-Methyl 2-(Hydroxymethyl)-5-oxopyrroli-
dine-1,2-dicarboxylate (16)
To a solution of benzyl ether 9 (13.5 g, 38.7 mmol) in MeOH (192
mL) was added 10% Pd/C (1.30 g). The suspension was stirred for
18 h under hydrogen (balloon), diluted with EtOAc (300 mL), and
filtered using a thin Celite pad. The filtrate was concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (hexane–EtOAc, 12:1 then 6:1) to give the correspond-
ing alcohol as a colorless oil. Yield: 9.92 g (99%); a 4:5 mixture of
rotamers in CDCl3; [a]D25 –11.2 (c 0.90, CHCl3).
According to the procedure in the literature,4c silyl ether 15 (13.7 g,
35.3 mmol) was desilylated using TBAF (1 M in THF, 88.3 mL,
88.3 mmol) in the presence of AcOH (15.2 mL, 264.8 mmol) in
25
THF (150 mL) to give (R)-HMPG 16. Yield: 9.0 g (93%); [a]D
+29.9 (c 1.00, CHCl3).
The analytical data of 16 were identical with those of authentic data
reported in the literature {[a]D25 +26.2 (c 0.65, CHCl3)}.4c
FTIR (neat): 3456, 2978, 2887, 1739, 1691, 1396, 1165, 760 cm–1.
(R)-tert-Butyl 2-[(tert-Butyldimethylsiloxy)methyl]-2-(hy-
droxymethyl)pyrrolidine-1-carboxylate (17)
1H NMR (400 MHz, CDCl3): d = 4.09 (d, J = 11.7 Hz, 5/9 H), 3.88
(d, J = 11.5 Hz, 4/9 H), 3.83 (d, J = 11.5 Hz, 4/9 H), 3.88–3.83 (m,
5/9 H), 3.74 (s, 15/9 H), 3.72 (s, 12/9 H), 3.63–3.38 (m, 2 H), 2.49
(dt, J = 12.2, 6.8 Hz, 1 H), 2.20–2.05 (m, 2 H), 2.20–1.75 (m, 2 H),
1.44 (s, 45/9 H), 1.38 (s, 36/9 H).
13C NMR (100 MHz, CDCl3): d = 175.1, 173.4, 155.6, 153.2, 80.4,
70.4, 67.7, 65.8, 64.1, 52.2, 51.9, 48.5, 48.1, 34.5, 34.3, 28.2, 28.1,
22.5, 22.4.
To a solution of benzyl ether 9 (10.3 g, 29.5 mmol) in anhyd THF
(147 mL) was added LiBH4 (1.29 g, 59.0 mmol) and i-PrOH (18.0
mL, 236 mmol) in several portions at 0 °C. The mixture was stirred
for 24 h at r.t., quenched with sat. NH4Cl (130 mL), and extracted
with EtOAc (3 × 130 mL). The combined organic layers were
washed with brine, dried (anhyd MgSO4), and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography (hexane–EtOAc, 30:1 then 20:1)
to give (S)-tert-butyl 2-[(benzyloxy)methyl]-2-(hydroxymeth-
yl)pyrrolidine-1-carboxylate as a colorless oil. Yield: 8.77 g (92%);
[a]D25 +37.3 (c 0.89, CHCl3).
HRMS (FAB): m/z [M + H]+ calcd for C12H21NO5: 260.1495;
found: 260.1496.
To a solution of the resulting alcohol described above (9.92 g, 38.3
mmol) in DMF (173 mL) was added 1H-imidazole (3.53 g, 51.9
mmol), and then TBSCl (7.82 g, 51.9 mmol) was added at 0 °C with
stirring. The mixture was stirred for 18 h at r.t., partitioned with
EtOAc (50 mL) and sat. NH4Cl (200 mL), and extracted. The aque-
ous layer was then extracted with EtOAc (2 × 150 mL). The com-
FTIR (neat): 3396, 2974, 2873, 1954, 1666, 1392, 1122, 740 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 H), 5.27 (dd, J =
8.8, 2.7 Hz, 1 H), 4.61 (d, J = 12.2 Hz, 1 H), 4.51 (d, J = 12.2 Hz, 1
H), 3.77 (s, 2 H), 3.72–3.67 (m, 2 H), 3.48–3.42 (m, 1 H), 3.36–3.30
Synthesis 2009, No. 22, 3751–3756 © Thieme Stuttgart · New York

PAPER
(R)- and (S)-a-(Hydroxymethyl)pyroglutamic Acid Esters
3755
(m, 1 H), 2.15 (ddd, J = 12.4, 7.1, 2.7 Hz, 1 H), 1.89–1.78 (m, 1 H),
1.73–1.65 (m, 1 H), 1.53–1.48 (m, 1 H), 1.43 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 156.3, 138.7, 128.2, 127.4,
127.33, 127.28, 80.1, 73.4, 69.7, 68.1, 67.3, 49.2, 33.3, 28.4, 21.9.
(150 mL) and extracted with CH2Cl2 (3 × 150 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. The crude aldehyde was subjected to Pinnick oxidation
without further purification.
To a solution of the resulting aldehyde in t-BuOH (169 mL), H2O
(28.0 mL), and 2-methylbut-2-ene (22.0 mL, 200 mmol) was added
NaH2PO4 (7.09 g, 59.1 mmol) and NaClO2 (5.32 g, 59.1 mmol) at
r.t. The mixture was vigorously stirred at r.t. for 40 min, diluted with
H2O (100 mL), and extracted with EtOAc (3 × 150 mL). The com-
bined organic layers were dried (anhyd MgSO4), filtered, and con-
centrated under reduced pressure to give the crude acid.
HRMS (FAB): m/z [M + H]+ calcd for C18H27NO4: 322.2015;
found: 322.2017.
To a solution of the resulting alcohol described above (8.77 g, 27.3
mmol) in DMF (136 mL) was added 1H-imidazole (2.79 g, 41.0
mmol), and then TBSCl (6.17 g, 41.0 mmol) was added at 0 °C. The
mixture was stirred for 20 h at r.t., concentrated under reduced pres-
sure, and diluted with EtOAc (50 mL) and sat. NH4Cl (130 mL).
The mixture was extracted with EtOAc (3 × 130 mL). The com-
bined organic layers were washed with brine, dried (anhyd MgSO4),
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography (hex-
ane–EtOAc, 70:1 then 30:1) to give (R)-tert-butyl 2-[(benzyl-
oxy)methyl]-2-[(tert-butyldimethylsiloxy)methyl]pyrrolidine-1-
carboxylate as a colorless oil. Yield: 12.0 g (100%); a 4:5 mixture
of rotamers in CDCl3; [a]D30 –1.92 (c 0.83, CHCl3).
To a solution of the residue in DMF (200 mL) was added K2CO3
(3.26 g, 23.7 mmol) and BnBr (2.80 mL, 23.7 mmol) at r.t. The mix-
ture was stirred for 25 min and then was concentrated under reduced
pressure. The residue was diluted with EtOAc (150 mL) and H2O
(150 mL), and extracted. The aqueous layer was then extracted with
EtOAc (2 × 150 mL). The combined organic layers were washed
with brine, dried (anhyd MgSO4), and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(hexane–EtOAc, 70:1 then 8:1) to give 18a as a colorless oil. Yield:
6.29 g (71%); a 5:4 mixture of rotamers in CDCl3; [a]D26 –14.6 (c
1.25, CHCl3).
FTIR (neat): 2956, 2931, 2858, 1693, 1389, 1255, 1178, 1097, 829,
775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.21 (m, 5 H), 4.52 (d, J =
12.0 Hz, 4/9 H), 4.50 (br s, 10/9 H), 4.44 (d, J = 12.0 Hz, 4/9 H),
4.01 (d, J = 9.5 Hz, 5/9 H), 3.80 (d, J = 9.5 Hz, 5/9 H), 3.71 (d, J =
9.5 Hz, 4/9 H), 3.64–3.57 (m, 2 H), 3.51 (d, J = 9.5 Hz, 4/9 H), 3.45–
3.20 (m, 2 H), 2.11–2.02 (m, 2 H), 1.77–1.67 (m, 2 H), 1.41 (s, 45/
9 H), 1.39 (s, 36/9 H), 0.84 (s, 9 H), –0.02 (br s, 24/9 H), –0.03 (s,
30/9 H).
13C NMR (100 MHz, CDCl3): d = 153.8, 138.9, 138.4, 128.3, 128.2,
127.42, 127.37, 127.3, 79.2, 78.5, 73.4, 73.3, 72.0, 71.3, 66.9, 66.0,
64.7, 63.6, 49.3, 33.3, 32.0, 28.5, 25.8, 22.3, 21.7, 18.1, –5.45,
–5.53, –5.6.
FTIR (neat): 3379, 3066, 2954, 2885, 2858, 1738, 1695, 1460,
1392, 1095, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.23 (m, 5 H), 5.21 (d, J =
12.4 Hz, 1 H), 5.06 (d, J = 12.4 Hz, 5/9 H), 5.03 (d, J = 12.4 Hz, 4/
9 H), 4.38 (d, J = 10.2 Hz, 4/9 H), 4.17 (d, J = 10.2 Hz, 5/9 H), 3.92
(d, J = 10.2 Hz, 1 H), 3.72–3.65 (m, 5/9 H), 3.60–3.54 (m, 4/9 H),
3.50–3.32 (m, 1 H), 2.40–2.30 (m, 1 H), 2.10–1.78 (m, 3 H), 1.50
(s, 36/9 H), 1.41 (s, 45/9 H), 0.88 (s, 36/9 H), 0.87 (s, 45/9 H), 0.05
(s, 12/9 H), 0.04 (s, 15/9 H), 0.03 (s, 15/9 H), 0.02 (s, 12/9 H).
13C NMR (100 MHz, CDCl3): d = 173.3, 173.2, 153.6, 153.2, 136.0,
135.5, 128.6, 128.4, 128.2, 128.0, 127.9, 80.0, 79.3, 68.7, 68.3,
66.5, 66.4, 64.1, 63.0, 48.7, 48.6, 35.9, 34.4, 28.4, 28.3, 25.8, 23.7,
23.1, 18.1, –5.4, –5.5, –5.6, –5.7.
HRMS (FAB): m/z [M + H]+ calcd for C24H41NO4Si: 436.2880;
found: 436.2885.
HRMS (FAB): m/z [M + H]+ calcd for C24H39NO5Si: 450.2672;
found: 450.2688.
To a solution of the resulting silyl ether described above (12.0 g,
27.3 mmol) in MeOH (136 mL) was added 10% Pd/C (1.20 g). The
suspension was stirred for 8 h under hydrogen (balloon), diluted
with EtOAc (300 mL), and filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (hexane–EtOAc, 30:1 then 20:1) to give 17 as a
colorless oil. Yield: 8.34 g (88%); [a]D26 –24.4 (c 1.20, CHCl3).
(S)-1-tert-Butyl 2-Methyl 2-[(tert-Butyldimethylsiloxy)meth-
yl]pyrrolidine-1,2-dicarboxylate (18b)
To a solution of benzyl ester 18a (59.5 mg, 0.13 mmol) in MeOH
(1.3 mL) was added K2CO3 (101 mg, 0.73 mmol) at r.t. The mixture
was refluxed for 24 h, cooled to r.t., diluted with EtOAc (10 mL),
and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography (hex-
ane–EtOAc, 25:1 then 15:1) to give 18b as a colorless oil. Yield:
42.0 mg (94%); [a]D26 –34.1 (c 0.80, CHCl3).
FTIR (neat): 3394, 2954, 2931, 2881, 2858, 1920, 1691, 1668,
1392, 1253, 1101, 837, 773 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.25 (dd, J = 8.8, 2.4 Hz, 1 H),
4.09 (d, J = 10.2 Hz, 1 H), 3.73 (d, J = 10.2 Hz, 1 H), 3.72–3.65 (m,
2 H), 3.50–3.35 (m, 2 H), 2.11 (ddd, J = 12.7, 7.6, 5.1 Hz, 1 H),
1.95–1.82 (m, 1 H), 1.72–1.66 (m, 1 H), 1.54–1.47 (m, 1 H), 1.45
(s, 9 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 156.1, 79.9, 68.3, 62.9, 49.5, 33.3,
28.4, 25.8, 22.0, 18.1, –5.6.
The analytical data of 18b were identical with those of R-enantio-
24
mer 14, except for the optical rotation {[a]D –34.5 (c 1.05,
CHCl3)}.
(S)-2-Benzyl 1-tert-Butyl 2-[(tert-Butyldimethylsiloxy)methyl]-
5-oxopyrrolidine-1,2-dicarboxylate (19)
HRMS (FAB): m/z [M + H]+ calcd for C17H35NO4Si: 346.2410;
found: 346.2417.
To a solution of benzyl ester 18a (2.44 g, 5.43 mmol) in CCl4–
MeCN–H2O (27 mL, 2:1:1) were added RuO2 (143 mg, 1.08 mmol)
and NaIO4 (5.81 g, 27.1 mmol). The mixture was stirred for 3.5 h,
quenched with i-PrOH, and filtered. To the filtrate was added sat.
Na2SO3 (15 mL) to quench the excess amount of oxidants, and the
organic layer was separated. The aqueous layer was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed with
brine, dried (anhyd MgSO4), and filtered. The filtrate was concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (hexane–EtOAc, 30:1 then 20:1) to give
19 as an amorphous solid. Yield: 1.92 g (76%); [a]D28 –21.3 (c 1.07,
CHCl3).
(S)-2-Benzyl 1-tert-Butyl 2-[(tert-Butyldimethylsiloxy)meth-
yl]pyrrolidine-1,2-dicarboxylate (18a)
To a solution of oxalyl chloride (1.87 mL, 21.6 mmol) in CH2Cl2
(110 mL) was added DMSO (3.20 mL, 43.3 mmol) slowly at –78
°C, and the mixture was stirred for 10 min at the same temperature.
To the mixture was added a solution of hydroxymethyl derivative
17 (6.80 g, 19.7 mmol) in CH2Cl2 (90.0 mL) at –78 °C. Maintaining
this temperature, the mixture was stirred for 45 min and then Et3N
(13.7 mL, 99.0 mmol) was added. After 10 min, the mixture was al-
lowed to warm to r.t. The mixture was quenched with sat. NaHCO3
Synthesis 2009, No. 22, 3751–3756 © Thieme Stuttgart · New York

3756
T. Shinada et al.
PAPER
FTIR (neat): 2956, 2937, 2887, 2857, 2359, 2341, 1793, 1743,
1715, 1558, 1472, 1456, 1369, 1313 cm–1.
(3) For the total synthesis and synthetic studies of oxazolomycin
and neooxazolomycin, see: (a) Yamada, T.; Sakaguchi, K.;
Shinada, T.; Ohfune, Y.; Soloshonok, V. A. Tetrahedron:
Asymmetry 2008, 19, 2789. (b) Onyango, E. O.; Tsurumoto,
J.; Imai, N.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Angew. Chem. Int. Ed. 2007, 46, 6703. (c) Bennett, N. J.;
Prodger, J. C.; Pattenden, G. Tetrahedron 2007, 63, 6216.
(d) Donohoe, T. J.; Chiu, J. Y. K.; Thomas, R. E. Org. Lett.
2007, 9, 421. (e) Mohapatra, D. K.; Mondal, D.; Gonnade,
R. G.; Chorghade, M. S.; Gurjar, M. K. Tetrahedron Lett.
2006, 47, 6031. (f) Papillon, J. P. N.; Taylor, R. J. K. Org.
Lett. 2000, 2, 1987. (g) Andrews, M. D.; Brewster, A. G.;
Moloney, M. G. Synlett 1996, 612. (h) Kende, A. S.;
Kawamura, K.; Orwat, M. J. Tetrahedron Lett. 1989, 30,
5821.
1H NMR (300 MHz, CDCl3): d = 7.26–7.39 (m, 5 H), 5.19 (d, J =
12.2 Hz, 1 H), 5.13 (d, J = 12.2 Hz, 1 H), 4.31 (d, J = 10.5 Hz, 1 H),
4.00 (d, J = 10.5 Hz, 1 H), 2.69 (ddd, J = 17.4, 10.3, 8.7 Hz, 1 H),
2.47 (ddd, J = 17.4, 10.6, 4.2 Hz, 1 H), 2.26 (ddd, J = 12.8, 10.3, 4.2
Hz, 1 H), 2.05 (ddd, J = 12.8, 10.6, 8.7 Hz, 1 H), 1.44 (s, 9 H), 0.86
(s, 9 H), 0.06 (s, 3 H), 0.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.2. 171.2, 149.4, 135.0, 128.7,
128.6, 128.4, 83.6, 68.9, 67.2, 64.9, 31.6, 27.9, 26.8, 25.8, 18.1,
–5.58, –5.60.
HRMS (FAB): m/z [M + H]+ calcd for C24H38NO6Si]: 464.2468;
found: 464.2473.
(4) For the total synthesis and synthetic studies of kaitocephalin,
see: (a) Takahashi, K.; Haraguchi, N.; Ishihara, J.;
Hatakeyama, S. Synlett 2008, 671. (b) Vaswani, R. G.;
Chamberlin, A. R. J. Org. Chem. 2008, 73, 1661.
(c) Kawasaki, M.; Shinada, T.; Hamada, M.; Ohfune, Y.
Org. Lett. 2005, 7, 4165. (d) Okue, M.; Kobayashi, H.;
Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.;
Watanabe, H.; Kitahara, T. Tetrahedron Lett. 2002, 43, 857.
(e) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001, 123, 9706.
(5) For the total synthesis and synthetic studies of dysibetaine
and its analogues, see: (a) Isaacson, J.; Kobayashi, Y.
Angew. Chem. Int. Ed. 2009, 48, 1845. (b) Katoh, M.; Hisa,
C.; Honda, T. Tetrahedron Lett. 2007, 48, 4691.
(S)-2-Benzyl 1-tert-Butyl 2-(Hydroxymethyl)-5-oxopyrrolidine-
1,2-dicarboxylate (20)
In a similar manner to that reported in the literature,4c silyl ether 19
(2.74 g, 5.91 mmol) was desilylated using TBAF (1 M in THF, 14.8
mL, 14.8 mmol) in the presence of AcOH (2.5 mL, 44.3 mmol) in
THF (15 mL) to give (S)-HMPG 20 as a white solid. Yield: 1.80 g
(87%); mp 97–98 °C; [a]D23 –4.50 (c 1.10, CHCl3).
FTIR (neat): 3490, 2979, 1784, 1740, 1456, 1370, 1308, 1258 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.35 (m, 5 H), 5.22 (d, J =
12.1 Hz, 1 H), 5.15 (d, J = 12.1 Hz, 1 H), 4.17 (d, J = 11.5 Hz, 1 H),
3.94 (d, J = 11.5 Hz, 1 H), 2.33–2.79 (m, 3 H), 2.01–2.11 (m, 1 H),
1.43 (s, 9 H).
(c) Langlois, N.; Nguyen, B. K. L. J. Org. Chem. 2004, 69,
7558. (d) Wardrop, D. J.; Burge, M. S. Chem. Commun.
2004, 1230. (e) Snider, B. B.; Gu, Y. Org. Lett. 2001, 3,
1761.
13C NMR (75 MHz, CDCl3): d = 173.8, 172.0, 149.7, 134.7, 128.7,
128.6, 128.4, 84.3, 68.6, 67.5, 64.5, 30.7, 27.8, 25.2.
HRMS (FAB): m/z [M + H]+ calcd for C18H23NO6: 350.1604;
found: 350.1597.
(6) For synthetic studies of optically active(hydroxy-
methyl)pyroglutamic acid derivatives, see: (a) Moriyama,
K.; Sakai, H.; Kawabata, T. Org. Lett. 2008, 10, 3883.
(b) Miyaoka, H.; Yamanishi, M.; Hoshino, A.; Kinbara, A.
Tetrahedron 2006, 62, 4103. (c) Battistini, L.; Curti, C.;
Zanardi, F.; Rassu, G.; Auzzas, L.; Casiraghi, G. J. Org.
Chem. 2004, 69, 2611. (d) Zhang, J.; Flippen-Anderson,
J. L.; Kozikowski, A. P. J. Org. Chem. 2001, 66, 7555.
(e) Andrews, M. D.; Brewster, A. G.; Moloney, M. G.;
Owen, K. L. J. Chem. Soc., Perkin Trans. 1 1996, 227.
(7) For reviews, see: (a) Soloshonok, V. A. Curr. Org. Chem.
2002, 6, 341. (b) Nájera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 10, 2245.
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N: 4.01. Found: C,
61.84; H, 6.63; N: 4.00.
Acknowledgment
This study was supported by Grants-in-Aid (No. 16201045,
16073214, and 18510191) for Scientific Research from the Japan
Society for the Promotion of Science (JSPS).
References
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Synthesis 2009, No. 22, 3751–3756 © Thieme Stuttgart · New York