Stereoselective synthesis of 3,4-dihydroxylated prolines and prolinols starting from L -tartaric acid

Article abstract of DOI:10.1002/jhet.1634

A straightforward and stereoselective synthesis of 3,4-dihydroxyprolines and 3,4-dihydroxyprolinols is described. The key reaction in this synthesis is a protective group-controlled diastereoselective cyanation of a chiral acyliminium intermediate derived from l-tartaric acid. Methanolysis of the obtained cyanolactam gave methyl 3,4-dihydroxypyroglutamate that was converted to 3,4-dihydroxyproline and 3,4-dihydroxyprolinol by reduction of the lactam carbonyl and ester groups in a stepwise manner.

Full text of DOI:10.1002/jhet.1634

January 2014
Stereoselective Synthesis of 3,4-Dihydroxylated Prolines and Prolinols
Starting from L-Tartaric Acid
237
a
b
a
*
M. Oba, S. Koguchi, and K. Nishiyama
aDepartment of Materials Chemistry, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
bDepartment of Chemistry, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
*
E-mail: moba@tokai-u.jp
Additional Supporting Information may be found in the online version of this article.
Received August 31, 2011
DOI 10.1002/jhet.1634
Published online 31 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
A straightforward and stereoselective synthesis of 3,4-dihydroxyprolines and 3,4-dihydroxyprolinols is
described. The key reaction in this synthesis is a protective group-controlled diastereoselective cyanation
of a chiral acyliminium intermediate derived from L-tartaric acid. Methanolysis of the obtained cyanolactam
gave methyl 3,4-dihydroxypyroglutamate that was converted to 3,4-dihydroxyproline and 3,4-dihydroxypro-
linol by reduction of the lactam carbonyl and ester groups in a stepwise manner.
J. Heterocyclic Chem., 51, 237 (2014).
INTRODUCTION
3,4-dihydroxyprolines [8] and 3,4-dihydroxyprolinols
[9–11] have appeared in the literature, most of which
were designed for specific targets. Therefore, facile and
generalized methods of accessing a broad range of 3,4-
dihydroxypyrroridine systems are needed.
3,4-Dihydroxyproline and 3,4-dihydroxyprolinol each has
three chiral centers, allowing eight stereoisomers to exist for
each pyrrolidine systems. Some such pyrrolidines have been
isolated from natural sources, such as plants and microorgan-
isms, and have been found to display a variety of biological
activities [1,2]. In particular, 3,4-dihydroxyprolinols,
also known as 1,4-dideoxy-1,4-iminosugars, have attracted
considerable attention as potent glycosidase inhibitors
because of their structural similarity with an oxocarbenium
ion-like transition state [3], which is presumed to be involved
in enzymatic hydrolysis of glycosyl linkages. For example,
naturally occurring 1,4-dideoxy-1,4-imino-D-arabinitol
(DAB-1, 1; Fig. 1) has been shown to be a potent inhibitor
of a-glucosidase [4,5], a-mannosidase [5], and glycogen
phosphorylase [6]. The 3b-epimer of 1, 1,4-dideoxy-1,4-
imino-D-lyxitol (D-Lyx, 2), was proved to be an inhibitor
of a-galactosidase and a-mannosidase [4]. Interestingly,
1,4-dideoxy-1,4-imino-L-arabinitol (LAB-1, 3), the syn-
thetic enantiomer of 1, was found to be a much more
powerful inhibitor of mammalian intestinal a-glucosidase,
including maltase, sucrase, and isomaltase, than 1 [7]. Thus,
structurally diverse libraries of 3,4-dihydroxypyrroridine
derivatives have been screened for inhibitory activity against
a variety of glycosidases [4–7].
We have already reported the synthesis of eight possible
isomers of 3,4-dihydroxyglutamic acids (DHGAs) starting
from L-, D-, and meso-tartaric acids (Scheme 1) [12]. The
chiral cyanolactams, derived from tartaric acid, may also be
precursors of 3,4-dihydroxypyrrolidine derivatives because
the required chiral centers have already been embedded
within the pyrrolidine ring. In a continuation of our work
on the utility of the chiral cyanolactams for synthesis of
non-proteinogenic amino acid derivatives, we describe
herein a facile synthesis of 3,4-dihydroxyprolines and
3,4-dihydroxyprolinols via reduction of the lactam
carbonyl group and conversion of the cyano group. Con-
struction of D-xylo- and L-arabino-configured pyrrolidine
systems could be accomplished by protective group-
controlled stereoselective cyanation of the iminium inter-
mediate derived from L-tartaric acid [12a,12b].
RESULTS AND DISCUSSION
The acetoxylactam 4, a precursor of N-acyliminium inter-
mediate 5, is a known compound [13] and was prepared from
L-tartaric acid according to the reported procedure
(Scheme 2) [12b,13a,13c,14]. In the current study, a benzyl
Increasing interest in these systems has spurred the
development of efficient synthetic methods. Despite their
relatively simple structures, many synthetic routes to
© 2013 HeteroCorporation

238
M. Oba, S. Koguchi, and K Nishiyama
Vol 51
6 and 7 into the target 3,4-dihydroxylated proline and
prolinol (vide infra). In the cyanation of the O-tert-
butyldimethylsilyl (O-TBS) derivative 4a (entries 1–7),
the nucleophilic attack occurs cis to the adjacent O-TBS
group to give 6a as a major diastereomer in all cases.
By contrast, a complete reversal in diastereoselectivity
was observed for the cyanation of the O-acetyl (O-Ac)
derivative 4b (entries 8–9). Treatment of 4b with
a Me3SiCN–BF3•OEt2 system gave a mixture of 6b and 7b
in a ratio of 20/80 (entry 8). In this case, the use of TBSCN
or Bu3SnCN as a cyanating agent gave unsatisfactory results.
It is well known that the diastereoselectivity of nucleo-
philic addition toward the chiral acyliminium cation derived
from tartaric or malic acid is largely affected by the nature of
the O-protective groups [13a,13c,14b,15]. We assume that
the counter anion of 5a is located in the face trans to the ad-
jacent O-TBS group and thus directs the nucleophilic attack
toward the face cis to the substituent [16]. On the other hand,
the opposite diastereoselectivity observed in the cyanation of
5b can be rationalized by a neighboring group participation
effect of the O-Ac group. Theoretical studies that explain
the observed reversal in diastereoselectivity are in progress.
The O-TBS cyanolactams 6a and 7a were chromato-
graphically separable and were isolated in 80% and
17% yields, respectively, under the conditions shown
in entry 3 of Table 1. Transformation of the major cya-
nolactam 6a into 3,4-dihydroxypyrrolidine derivatives is
outlined in Scheme 3. Treatment of 6a with HCl in
MeOH followed by reprotection of the liberated hy-
droxyl groups during acidic methanolysis gave methyl
pyroglutamate 8 in 60% yield. Chemoselective reduc-
tion of the lactam carbonyl group was best effected by
BH3•THF to produce protected dihydroxyproline 9 in
80% yield. Hydrolysis of 9 in refluxing 6 M HCl,
debenzylation by catalytic hydrogenolysis, and ion
exchange chromatography afforded (2S,3S,4S)-3,4-dihy-
droxyproline (10), a natural non-proteinogenic amino
acid [2a], in 66% yield. Comparison of the physical
and spectral data of 10 with literature data
[8a,8b,8e,8h,8i] completely confirmed its identity.
Figure 1. Examples of 3,4-dihydroxyprolinols as glycosidase inhibitors.
Scheme 1. Preparation of 3,4-dihydroxyglutamic acid (DHGA) starting
from tartaric acid. P = protective group, PMB = 4-methoxybenzyl.
group was used for N-protection instead of a p-methoxyben-
zyl (PMB) group for economic and synthetic reasons.
Lewis acid-promoted cyanation of 4 was then carried out
under various reaction conditions and the results are compiled
in Table 1. Although we have previously reported a similar
cyanation of the corresponding N-PMB derivatives
[12a,12b], reinvestigation was conducted in order to deter-
mine optimal conditions for stereoselective cyanation in the
present system. For example, a solution of 4a and Me3SiCN
in CH2Cl2 was treated with BF3•OEt2 at room temperature
for 1 h. The 1H NMR analysis of the reaction mixture showed
quantitative formation of cyanolactam as a mixture of diaster-
eomers (6a/7a = 75/25) (entry 1). Similar treatment at a lower
temperature (entry 2) or in toluene (entry 3) slightly improved
the diastereoselectivity; however, the cyanation did not pro-
ceed in toluene at À80ꢀC (entry 4). We tested other cyanating
agents, such as tert-butyldimethylsilyl cyanide (TBSCN) and
Bu3SnCN (entries 5–7). Although the tin reagent achieved
considerable improvement in stereoselectivity, the chemical
yields were reduced because of the formation of unidentified
by-products. The use of other Lewis acids, such as Me3SiI,
Me3SiOTf, TiCl4, and MgBr2, resulted either in no reaction
or a complex mixture.
The stereochemistry at the newly created chiral center at
3
the C-5 position was determined by comparing the J4,5
The dihydroxyproline derivative 9 could also be con-
verted to 3,4-dihydroxyprolinols. Reduction of the
methyl ester of 9 was achieved with the use of diisobu-
tylaluminum hydride (DIBAL-H) to give 11 in 84%
values (7 and 4 Hz for cis- and trans-isomers, respectively)
with those of the corresponding N-PMB derivatives [12b].
The stereochemistry was further confirmed by converting
Scheme 2. Preparation of cyanolactams.
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Stereoselective Synthesis of 3,4-Dihydroxylated Prolines and Prolinols
Starting from L-Tartaric Acid
239
Table 1
Stereoselective cyanation of acetoxylactam 4.
Entry
R
Cyanating agent
Solvent
Temperature (ꢀC)
Time (h)
Yielda (%)
6/7b
1
2
3
4
5
6
7
8
9
10
TBS (a)
TBS (a)
TBS (a)
TBS (a)
TBS (a)
TBS (a)
TBS (a)
Ac (b)
Me3SiCN
Me3SiCN
Me3SiCN
Me3SiCN
TBSCN
Bu3SnCN
Bu3SnCN
Me3SiCN
TBSCN
CH2Cl2
CH2Cl2
Toluene
Toluene
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
RT
À80
RT
À80
RT
RT
RT
RT
RT
RT
1
1
1
1
1
2
4
1
1
2
91
94
97
0
93
85
52
99
75/25
81/19
83/17
c
76/24
90/10
90/10
20/80
Ac (b)
Ac (b)
96
26/74
d
c
Bu3SnCN
aCombined isolated yield of 6 and 7.
bDetermined by 1H NMR spectroscopy.
cNot determined.
dComplex mixture.
Scheme 3. Preparation of (2S,3S,4S)-3,4-dihydroxyproline (10) and (2R,3S,4S)-3,4-dihydroxyprolinol (12). Reagents and conditions: (i) HCl, MeOH; (ii)
TBSCl, imidazole, DMF, 60% (two steps); (iii) BH3•THF, THF, 80%; (iv) 6 M HCl, reflux, 98%; (v) H2, 10% Pd/C, H2O, then DOWEX 50WX8, 66%;
(vi) DIBAL-H, 0ꢀC, CH2Cl2, 84%; (vii) c-HCl, MeOH, quant.; (viii) H2, 10% Pd/C, H2O, quant.
Scheme 4. Preparation of (2R,3S,4S)-3,4-dihydroxyproline (15) and (2S,3S,4S)-3,4-dihydroxyprolinol (LAB-1, 3). Reagents and conditions: (i) MeONa,
MeOH; (ii) TBSCl, imidazole, DMF, 61% (two steps); (iii) BH3•THF, THF, 98%; (iv) 6 M HCl, reflux, 99%; (v) H2, 10% Pd/C, H2O, then DOWEX
50WX8, 60%; (vi) DIBAL-H, 0ꢀC, CH2Cl2, 70%; (vii) c-HCl, MeOH, quant; (viii) H2, 10% Pd/C, H2O, quant.
yield, which, upon treatment with concentrated HCl in
MeOH, gave a quantitative yield of N-benzyl-3,4-dihy-
droxyprolinol. Finally, (2R,3S,4S)-3,4-dihydroxyprolinol
(1,4-dideoxy-1,4-imino-D-xylitol, 12) was obtained
quantitatively as its hydrochloride salt by catalytic
hydrogenolysis of the N-benzyl derivative, with data in
agreement with those published [13a,17].
Using a similar protocol as described previously,
L-arabino-configured pyrrolidine systems can be accessed
from the O-Ac cyanolactam 7b that can be obtained as a
major diastereomer in 78% isolated yield under the
conditions of Table 1 (entry 8). Thus, treatment of
7b with MeONa in MeOH, protection of the liberated
hydroxyl group as a TBS ether, and chromatographic
Journal of Heterocyclic Chemistry
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240
M. Oba, S. Koguchi, and K Nishiyama
Vol 51
4H), 5.22 (d, J= 15 Hz, 1H, PhCH2), 7.24–7.38 (m, 5H, Ph). 13C
NMR (CDCl3) d À4.78, À4.56 (overlapped), À4.18, 17.85, 18.28,
25.66, 25.79, 45.17, 52.91, 76.63, 76.85, 115.67, 128.46, 128.55,
129.22, 134.39, 170.82. HRMS (EI) m/z 461.2618 [(M + H)+, calcd.
for C24H41N2O3Si2 461.2618].
purification gave methyl pyroglutamates 13 in 61%
yield (Scheme 4). Reduction of the lactam carbonyl
moiety of 13 gave protected dihydroxyproline derivative
14 in 98% yield, which upon deprotection afforded
unnatural (2R,3S,4S)-3,4-dihydroxyproline (15) in 60%
yield. The ester group of 14 was further reduced to give
the dihydroxyprolinol derivative 16 in 70% yield. Desily-
lation of 16 and subsequent debenzylation furnished
(2S,3S,4S)-3,4-dihydroxyprolinol (3), also known as
1,4-dideoxy-1,4-imino-L-arabinitol (LAB-1), quantita-
tively as its hydrochloride salt. The structure was
confirmed by comparison of its physical and spectral
data with those reported in the literature [10a,17c,18].
Further elution with a mixture of hexane and ethyl acetate (90:10)
gave the corresponding (3R,4S,5R)-isomer 6a (749 mg, 1.63 mmol,
1
80%) as a colorless oil. [a]2D3 +85.26 (c 1.00, CHCl3). H NMR
(CDCl3) d 0.07 (s, 3H, Me), 0.12 (s, 3H, Me), 0.18 (s, 3H, Me),
0.24 (s, 3H, Me), 0.92 (s, 9H, tert-Bu), 0.94 (s, 9H, tert-Bu), 4.02
(d, J= 15 Hz, 1H, PhCH2), 4.11 (d, J= 7 Hz, 1H 5H,), 4.16 (dd,
J= 7 and 7 Hz, 1H, 4H), 4.32 (d, J= 7 Hz, 1H, 3H), 5.09 (d,
J= 15 Hz, 1H, PhCH2), 7.24–7.42 (m, 5H, Ph). 13C NMR (CDCl3)
d À4.76, À4.66, À4.64, À4.18, 17.97, 18.38, 25.71, 25.81, 45.70,
51.07, 73.60, 75.89, 114.65, 128.66, 129.25, 134.06, 170.76. HRMS
(EI) m/z 460.2550 [M+, calcd. for C24H40N2O3Si2 460.2550].
(3R,4S,5R)-1-Benzyl-5-cyano-3,4-diacetoxy-2-pyrrolidinone (6b)
and (3R,4S,5S)-1-benzyl-5-cyano-3,4-diacetoxy-2-pyrrolidinone
(7b). To a solution of acetoxylactam 4b (2.53 g, 7.24 mmol) and
trimethylsilyl cyanide (1.35 mL, 10.8 mmol) in CH2Cl2 (40 mL)
was added boron trifluoride etherate (1.82 mL, 14.7 mmol) at room
temperature under an argon atmosphere. After it was stirred at room
temperature for 1 h, the reaction mixture was quenched with
saturated aqueous Na2CO3 and extracted with CHCl3. The organic
layer was dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(CHCl3) to give the title compound 6b (353 mg, 1.12 mmol, 15%)
as a colorless oil. [a]D23 +156.48 (c 1.00, CHCl3). 1H NMR (CDCl3)
d 2.195 (s, 3H, Me), 2.198 (s, 3H, Me), 4.03 (d, J=15Hz, 1H,
PhCH2), 4.61 (d, J= 8 Hz, 1H, 5H), 5.18 (d, J=15Hz, 1H,
PhCH2), 5.29 (dd, J= 8 and 7 Hz, 1H, 4H), 5.55 (d, J= 7 Hz, 1H,
3H), 7.27–7.43 (m, 5H, Ph). 13C NMR (CDCl3) d 20.51, 20.57,
46.04, 48.93, 69.76, 72.45, 113.00, 128.72, 128.89, 129.32, 133.00,
165.95, 169.69, 170.24. Anal. Calcd. for C16H16N2O5: C, 60.75; H,
5.10; N, 8.86. Found: C, 60.88; H, 5.05; N, 8.69.
Further elution with CHCl3 gave a mixture of 6b and 7b
(137 mg, 433 mmol, 6%) and pure 7b (1.79 g, 5.66 mmol,
78%) as a colorless oil. [a]2D3 À16.71 (c 1.00, CHCl3). 1H
NMR (CDCl3) d 2.08 (s, 3H, Me), 2.20 (s, 3H, Me), 4.01
(d, J = 4 Hz, 1H, 5H), 4.06 (d, J = 15 Hz, 1H, PhCH2), 5.28
(d, J = 15 Hz, 1H, PhCH2), 5.34 (d, J = 4 Hz, 1H, 3H), 5.48
(dd, J = 4 and 4 Hz, 1H, 4H), 7.27–7.42 (m, 5H, Ph). 13C
NMR (CDCl3) d 20.50, 20.57, 45.74, 50.78, 73.08, 73.15,
114.19, 128.78, 128.91, 129.42, 133.42, 166.43, 169.57,
169.87. HRMS (APCI) m/z 317.1158 [(M + H)+, calcd. for
C16H17N2O5 317.1132].
(3R,4S,5S)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-5-
methoxycarbonyl-2-pyrrolidinone (8). A solution of compound
6a (503mg, 1.09 mmol) in methanol (11 mL) was cooled in an ice
bath, and a slow stream of HCl was introduced with stirring to
saturation. After being refrigerated overnight, saturated aqueous
NaHCO3 (6.5mL) was added to the solution and the resulting
mixture was stirred at room temperature for 5 h. The precipitated
insoluble materials were removed by filtration and the filtrate was
concentrated in vacuo. The residue was dissolved in DMF
(15 mL). To the solution was added imidazole (1.33 g, 13.2mmol)
and tert-butyldimethylchlorosilane (1.33 g, 8.82 mmol), and the
solution was stirred at room temperature overnight. After removal
of the solvent, the residue was dissolved in ethyl acetate, washed
with water and brine, dried over MgSO4, and concentrated in
vacuo. The crude product was purified by column
chromatography on silica gel (hexane/ethyl acetate = 90:10) to
CONCLUSION
We have achieved the straightforward and stereoselec-
tive synthesis of two isomers each of 3,4-dihydroxyproline
and 3,4-dihydroxyprolinol. Construction of the D-xylo- and
L-arabino-configured pyrrolidine systems was accom-
plished by a protective group-controlled diastereoselective
cyanation of the chiral iminium intermediate derived from
L-tartaric acid.
EXPERIMENTAL
Melting points were determined with the use of a Yamato MP-
21 melting point apparatus (Tokyo, Japan) in open capillaries and
1
are uncorrected. H and 13C NMR spectra were measured on a
Varian Mercury plus 400 spectrometer (Palo Alto, CA) at 400
and 100 MHz, respectively. All chemical shifts are reported as d
values (ppm) relative to residual chloroform (dH 7.26), HDO
(dH 4.65), the central peak of deuteriochloroform (dC 77.0), or di-
oxane (dC 67.19); J values are expressed in hertz. Mass spectra
were obtained with JEOL JMS-AX-500 or JMS-T100LP Accu-
TOF LC-plus spectrometers (Tokyo, Japan). Optical rotations
were measured on a HORIBA SEPA-200 polarimeter (Kyoto,
Japan). Elemental analyses were performed with the use of a
PerkinElmer 2400 Series II Analyzer (Waltham, MA).
All reagents and solvents were of commercial grade and used
according to supplier instructions unless otherwise mentioned.
(3R,4S,5R)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-5-
cyano-2-pyrrolidinone (6a) and (3R,4S,5S)-1-benzyl-3,4-bis
[(tert-butyldimethylsilyl)oxy]-5-cyano-2-pyrrolidinone (7a). To a
solution of acetoxylactam 4a (1.00 g, 2.03 mmol) and trimethylsilyl
cyanide (377 mL, 3.01 mmol) in toluene (11 mL) was added boron
trifluoride etherate (509 mL, 4.12 mmol) at room temperature under
an argon atmosphere. After it was stirred at room temperature for
1 h, the reaction mixture was quenched with saturated aqueous
Na2CO3 and extracted with ethyl acetate. The organic layer was
dried over MgSO4 and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (hexane/ethyl
acetate = 90:10) to give the title compound 7a (161 mg, 349 mmol,
17%) as colorless needles, mp 63–64ꢀC. [a]D25 +2.19 (c 1.00,
1
CHCl3). H NMR (CDCl3) d 0.10 (s, 3H, Me), 0.13 (s, 3H, Me),
0.17 (s, 3H, Me), 0.22 (s, 3H, Me), 0.84 (s, 9H, tert-Bu), 0.94 (s,
9H, tert-Bu), 3.79 (d, J= 4 Hz, 1H, 5H), 3.98 (d, J= 15 Hz, 1H,
PhCH2), 4.08 (d, J= 4 Hz, 1H, 3H), 4.33 (dd, J= 4 and 4 Hz, 1H,
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Stereoselective Synthesis of 3,4-Dihydroxylated Prolines and Prolinols
Starting from L-Tartaric Acid
241
give the title compound 8 (325 mg, 658mmol, 60%) as a colorless
oil. [a]2D3 +85.26 (c 1.00, CHCl3). 1H NMR (CDCl3) d 0.05
(s, 3H, Si-Me), 0.09 (s, 3H, Si-Me), 0.16 (s, 3H, Si-Me), 0.25 (s,
3H, Si-Me), 0.84 (s, 9H, tert-Bu), 0.94 (s, 9H, tert-Bu), 3.55 (s,
3H, CO2Me), 3.93 (d, J = 8 Hz, 1H, 5H), 4.18 (d, J = 15 Hz, 1H,
PhCH2), 4.26 (dd, J = 8 and 8 Hz, 1H, 4H), 4.45 (d, J = 8 Hz, 1H,
3H), 4.65 (d, J =15Hz, 1H, PhCH2), 7.19–7.35 (m, 5H, Ph). 13C
NMR d À4.76, À4.68, À4.61, À4.01, 17.82, 18.39, 25.68, 25.92,
46.38, 52.22, 61.76, 75.27, 75.69, 128.06, 128.78, 129.02, 135.02,
169.67, 171.89. HRMS (EI) m/z 493.2719 [(M+ H)+, calcd. for
C25H43NO5Si2 493.2719].
and concentrated. The crude product was purified by column
chromatography on silica gel (hexane/ethyl acetate = 90:10) to
give the title compound 11 (485 mg, 1.07 mmol, 84%) as a
1
colorless oil. [a]2D4 +14.54 (c 1.00, CHCl3). H NMR (CDCl3) d
0.01 (s, 3H, Si-Me), 0.05 (s, 3H, Si-Me), 0.10 (s, 3H, Si-Me),
0.11 (s, 3H, Si-Me), 0.87 (s, 9H, tert-Bu), 0.91 (s, 9H, tert-Bu),
2.30 (dd, J = 7 and 10 Hz, 1H, 5H), 2.68 (br s, 1H, OH), 2.92
(ddd, J = 3, 4, and 8 Hz, 1H, 2H), 3.13 (dd, J = 5 and 10 Hz, 1H,
5H), 3.52 (dd, J = 4 and 11 Hz, 1H, CH2OH), 3.62 (d, J = 13 Hz,
1H, PhCH2), 3.65 (dd, J = 3 and 11 Hz, 1H, CH2OH), 3.89 (d,
J = 13 Hz, 1H, PhCH2), 4.08 (ddd, J = 5, 5 and 7 Hz, 1H, 4H),
4.13 (dd, J = 5 and 8 Hz, 1H, 3H), 7.21–7.36 (m, 5H, Ph). 13C
NMR (CDCl3) d À4.69, À4.46, À4.31, À4.24, 18.04, 18.07,
25.94, 26.01, 57.62, 59.89, 60.40, 65.66, 77.51, 80.24, 127.27,
128.50, 129.10, 138.72. Anal. Calcd. for C24H45NO3Si2: C,
63.80; H, 10.04; N, 3.10. Found: C, 64.04; H, 10.21; N, 3.01.
(2R,3S,4S)-3,4-Dihydroxy-2-hydroxymethylpyrrolidine
hydrochloride (12). A mixture of compound 11 (310 mg,
686 mmol), concentrated HCl (2 mL), and MeOH (10 mL) was
stirred at room temperature overnight. After removal of the solvent,
the residue was dissolved in a small amount of H2O and washed
with CHCl3. The aqueous layer was evaporated to give 1-benzyl-
3,4-dihydroxy-2-hydroxymethylpyrrolidine hydrochloride (198 mg,
quant) as a brown oil, which was used for the next step without
further purification.
(2S,3S,4S)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-
2-methoxycarbonylpyrrolidine (9). A solution of borane in
THF (1 M, 12 mL, 12.0 mmol) was added to a solution of
compound 8 (1.14 g, 2.31 mmol) in THF (25mL) under an argon
atmosphere, and the mixture was stirred at room temperature
overnight. The reaction was quenched by addition of methanol
(40mL). After removal of the solvent, the residue was dissolved
in ethyl acetate, washed with water and brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (hexane/ethyl
acetate = 90:10) to give the title compound 9 (892 mg, 1.86 mmol,
1
80%) as a colorless oil. [a]2D3 +26.29 (c 1.01, CHCl3). H NMR
(CDCl3) d 0.02 (s, 3H, Si-Me), 0.03 (s, 3H, Si-Me), 0.05 (s, 3H,
Si-Me), 0.07 (s, 3H, Si-Me), 0.85 (s, 9H, tert-Bu), 0.87 (s, 9H,
tert-Bu), 2.54 (dd, J = 4 and 10 Hz, 1H, 5H), 3.36 (dd, J = 6 and
10Hz, 1H, 5H), 3.61 (s, 3H, CO2Me), 3.69 (d, J = 7 Hz, 1H, 2H),
3.75 (s, 2H, PhCH2), 4.21 (ddd, J = 4, 4, and 6 Hz, 1H, 4H), 4.26
(dd, J = 4 and 7 Hz, 1H, 3H), 7.19–7.36 (m, 5H, Ph). 13C NMR
(CDCl3) d À4.84, À4.54, À4.49, À4.39, 17.98, 18.00, 25.81,
25,97, 51.49, 58.66, 59.06, 69.43, 77.71, 80.10, 127.23, 128.33,
129.33, 138.16, 171.93. Anal. Calcd. for C25H45NO4Si2: C, 62.58;
H, 9.45; N, 2.92. Found: C, 62.28; H, 9.72; N, 2.86.
(2S,3S,4S)-3,4-Dihydroxyproline (10). A mixture of compound
9 (691 mg, 1.44 mmol) and 6 M HCl (30 mL) was heated to reflux
overnight. The cooled solution was washed with CHCl3 and
concentrated to dryness to yield 1-benzyl-3,4-dihydroxyproline
hydrochloride (386 mg, 1.41 mmol, 98%) as a brown solid, mp
215–217ꢀC (dec), which was used for the next step without further
purification.
A mixture of the crude N-benzyl derivative (245mg, 895mmol)
and 10% Pd/C (70 mg) in H2O (10 mL) was hydrogenated at room
temperature overnight. After removal of the catalyst with the use of
a Celite pad, the solvent was evaporated. The residue was sub-
mitted to ion exchange column chromatography on DOWEX
50WX8 and elution with 1 M NH4OH to produce the title
compound 10 (87.0 mg, 591 mmol, 66%) as colorless needles
(H2O–EtOH), mp 254–255ꢀC (dec) (lit [8e], mp 263ꢀC (dec)).
[a]D25 À62.2 (c 1.04, H2O) (lit [8e], [a]D27 À63.2 (c 0.5, H2O)).
1H NMR (D2O) d 3.34 (d, J = 13 Hz, 1H, 5H), 3.70 (dd, J = 13
and 4 Hz, 1H, 5H), 4.37 (d, J = 4 Hz, 1H, 2H), 4.41 (d, J = 4 Hz,
1H, 4H), 4.46 (d, J = 4 Hz, 1H, 3H). 13C NMR (D2O) d 51.58,
65.85, 75.46, 75.89, 171.13.
(2R,3S,4S)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-2-
hydroxymethylpyrrolidine (11). A solution of DIBAL-H in
toluene (1 M, 3.17 mL, 3.17 mmol) was added to a solution of
compound 9 (610 mg, 1.27 mmol) in CH2Cl2 (26 mL) at 0ꢀC
under an argon atmosphere, and the reaction mixture was stirred
for 1 h. Then, the mixture was quenched with methanol (20 mL)
and saturated aqueous NH4Cl. After removal of the insoluble
materials by filtration, the filtrate was extracted with CHCl3.
The organic layer was washed with brine, dried over MgSO4,
A
mixture of the crude N-benzyl derivative (309 mg,
1.29 mmol) and 10% Pd/C (90 mg) in H2O (10 mL) was hydro-
genated at room temperature overnight. After removal of the
catalyst with the use of a Celite pad, evaporation of the solvent
gave the title compound 12 (207mg, quant) as a white solid
(EtOH–acetone), mp 121–122ꢀC (lit [17], mp 127–129ꢀC). [a]
24
D
+10.1 (c 1.0, H2O) (lit [17], [a]2D7 +7.4 (c 0.68, H2O)). 1H
NMR (D2O) d 3.29 (d, J = 13Hz, 1H, 5H), 3.64 (dd, J = 13
and 4 Hz, 1H, 5H), 3.89 (m, 2H, CH2OH), 4.01 (m, 1H, 2H),
4.31 (br s, 1H, 3H), 4.38 (br d, J = 4 Hz, 1H, 4H). 13C NMR
(D2O) d 51.17, 58.29, 63.32, 75.28, 75.36.
(3R,4S,5R)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-
5-methoxycarbonyl-2-pyrrolidinone (13). To a solution of
compound 7b (200 mg, 632 mmol) in methanol (5mL) was added
a solution of 5 M MeONa in MeOH (1.26 mL, 6.32 mmol) at
room temperature. After being stirred for 1 h, the solution was
acidified (pH 1) with 2 M HCl and the resulting mixture was
stirred for 30min. Then, the solvent was evaporated and the
residue was dissolved in DMF (5 mL). To the solution was added
imidazole (267mg, 3.91 mmol) and tert-butyldimethylchlorosilane
(393mg, 2.61 mmol), and the solution was stirred at room
temperature overnight. After removal of the solvent, the residue
was dissolved in ethyl acetate, washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (hexane/ethyl
acetate= 90:10) to give the title compound 13 (191mg, 387 mmol,
61%) as a colorless oil. [a]2D3 +8.38 (c 1.0, CHCl3). 1H NMR
(CDCl3) d 0.02 (s, 3H, Si-Me), 0.08 (s, 3H, Si-Me), 0.15 (s, 3H,
Si-Me), 0.18 (s, 3H, Si-Me), 0.83 (s, 9H, tert-Bu), 0.88 (s, 9H,
tert-Bu), 3.71 (s, 3H, CO2Me), 3.73 (d, J = 2 Hz, 1H, 5H), 3.98 (d,
J = 2 Hz, 1H, 3H), 4.02 (d, J = 15 Hz, 1H, PhCH2), 4.22 (dd, J = 2
and 2 Hz, 1H, 4H), 5.21 (d, J =15Hz, 1H, PhCH2), 7.17–7.32
(m, 5H, Ph). 13C NMR (CDCl3) d À4.96 (overlapped), À4.72,
À4.37, 17.91, 18.18, 25.67, 25.72, 45.25, 52.41, 65.49, 76.65,
77.08, 127.78, 128.29, 128.81, 135.55, 169.95, 172.14. Anal.
Calcd. for C25H43NO5Si2: C, 60.81; H, 8.78; N, 2.84. Found:
C, 60.57; H, 8.65; N, 3.03.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

242
M. Oba, S. Koguchi, and K Nishiyama
Vol 51
(2R,3S,4S)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-2-
(EtOH–acetone), mp 104–105ꢀC (lit [10a], mp 109–111ꢀC). [a]
D
24
methoxycarbonylpyrrolidine (14). According to the procedure
described for the synthesis of compound 9, treatment of the
compound 13 (448 mg, 907 mmol) in THF (10 mL) with a 1M
À36.8 (c 1.01, H2O) (lit [10a], [a]2D0 À34.6 (c 0.37, H2O)).
1H NMR (D2O) d 3.37 (dd, J = 13 and 3 Hz, 1H, 5H), 3.58 (dd,
J = 13 and 5 Hz, 1H, 5H), 3.62 (ddd, J = 8, 5, and 4 Hz, 1H,
2H), 3.84 (dd, J = 12 and 8 Hz, 1H, CH2OH), 3.96 (dd, J = 12
and 5 Hz, 1H, CH2OH), 4.10 (dd, J = 4 and 3 Hz, 1H, 3H), 4.34
(ddd, J = 5, 3, and 3 Hz, 1H, 4H). 13C NMR (D2O) d 50.70,
60.07, 67.01, 75.41, 76.82.
solution of borane in THF (4.6 mL, 4.6 mmol) yielded the title
23
compound 14 (426 mg, 888 mmol, 98%) as a colorless oil. [a]
D
1
À45.0 (c 1.0, CHCl3). H NMR (CDCl3) d À0.01 (s, 3H, Si-Me),
0.01 (s, 3H, Si-Me), 0.03 (s, 3H, Si-Me), 0.07 (s, 3H, Si-Me), 0.85
(s, 9H, tert-Bu), 0.87 (s, 9H, tert-Bu), 2.84 (dd, J= 6 and 10 Hz,
1H, 5H), 2.93 (dd, J= 3 and 10 Hz, 1H, 5H), 3.28 (d, J=4Hz, 1H,
2H), 3.66 (s, 3H, CO2Me), 3.68 (d, J= 13 Hz, 1H, PhCH2), 3.90
(d, J= 13 Hz, 1H, PhCH2), 4.00 (ddd, J= 6, 3, and 3Hz, 1H, 4H),
4.30 (dd, J = 3 and 4 Hz, 1H, 3H), 7.21–7.36 (m, 5H, Ph). 13C
NMR (CDCl3) d À4.80, À4.66, À4.50, À4.43, 17.94, 18.03,
25.83, 25.89, 51.74, 58.80, 58.87, 72.14, 77.86, 82.89, 127.12,
128.26, 129.02, 138.36, 173.03. Anal. Calcd for C25H45NO4Si2: C,
62.58; H, 9.45; N, 2.92. Found: C, 62.34; H, 9.73; N, 3.10.
Acknowledgments. M.O. would like to acknowledge Tokai
University for financial support. We also thank Mr. Kazuki Izawa
for APCI-MS measurements.
REFERENCES AND NOTES
(2R,3S,4S)-3,4-Dihydroxyproline (15). According to the
procedure described for the synthesis of compound 10, treatment
of the compound 14 (818 mg, 1.70 mmol) with 6 M HCl (40mL)
yielded 1-benzyl-3,4-dihydroxyproline hydrochloride (465mg,
1.70mmol, 99%) as a brown solid, mp 175–177ꢀC, which was
used for the next step without further purification.
[1] For the isolation of 3,4-dihydroxyprolinols, see: (a) Asano, N.;
Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron Asymmetry
2000, 11, 1645 and references cited therein; (b) Watson, A. A.; Fleet, G.
W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001,
56, 265 and references cited therein.
[2] For the isolation of 3,4-dihydroxyprolines, see: (a) Nakajima,
T.; Volcani, B. E. Science 1969, 164, 1400; (b) Buku, A.; Faulstich, H.;
Wieland, T.; Dabrowski, J. Proc Natl Acad Sci USA 1980, 77, 2370; (c)
Taylor, S. W.; Waite, J. H.; Ross, M. M.; Shabanowitz, J.; Hunt, D. F. J
Am Chem Soc 1994, 116, 10803.
[3] Rempel, B. P.; Withers, S. G. Glycobiology 2008, 18, 570 and
references cited therein.
[4] Fleet, G. W. J.; Nicholas, S. J.; Smith, P. W.; Evans, S. V.; Fel-
lows, L. E.; Nash, R. J. Tetrahedron Lett 1985, 26, 3127.
Hydrogenolysis of the crude N-benzyl derivative (386 mg,
1.41mmol) in H2O (10 mL) in the presence of 10% Pd/C
(100 mg) followed by ion exchange chromatography on DOWEX
50WX8 produced the title compound 15 (125mg, 850 mmol,
60%) as colorless needles (H2O–EtOH), mp 238–240ꢀC (dec) (lit
[8e], mp 242ꢀC (dec)). [a]D25 +14.3 (c 1.02, H2O) (lit [8e], [a]2D7
1
+15.2 (c 0.4, H2O)). H NMR (D2O) d 3.52 (d, J = 13 Hz, 1H,
[5] (a) Asano, N.; Kizu, H.; Oseki, K.; Tomioka, E.; Matsui, K.;
Okamoto, M.; Baba, M. J Med Chem 1995, 38, 2349; (b) Asano, N.;
Oseki, K.; Kizu, H.; Matsui, K. J Med Chem 1994, 37, 3701.
[6] (a) Andersen, B.; Rassov, A.; Westergaard, N.; Lundgren, K.
Biochem J 1999, 342, 545; (b) Fosgerau, K.; Westergaard, N.; Quistorff,
B.; Grunner, N.; Kristiansen, M.; Lundgren, K. Arch Biochem Biophys
2000, 380, 274.
[7] Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Ada-
chi, I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G. W. J. Tetrahedron
Asymmetry 2005, 16, 223.
[8] For some examples, see: (a) Kahl, J.-U.; Wieland, T. Liebigs
Ann Chem 1981, 1445; (b) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett
1985, 26, 5307; (c) Baird, P. D.; Dho, J. C.; Fleet, G. W. J.; Peach, J.
M.; Prout, K.; Smith, P. W. J Chem Soc Perkin Trans 1 1987, 1785; (d)
Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637; (e) Arakawa, Y.;
Yoshifuji, S. Chem Pharm Bull 1991, 39, 2219; (f) Lee, B. W.; Jeong,
I.-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305;
(g) Fujii, M.; Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046;
(h) Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park, J. H. J Org Chem
2002, 67, 4466; (i) Taylor, C. M.; Jones, C. E.; Bopp, K. Tetrahedron
2005, 61, 9611.
5H), 3.61 (dd, J = 13 and 4 Hz, 1H, 5H), 4.06 (s, 1H, 2H), 4.31
(br d, J = 4 Hz, 1H, 4H), 4.52 (s, 1H, 3H). 13C NMR (D2O) d
51.59, 68.23, 74.62, 79.02, 171.82.
(2S,3S,4S)-1-Benzyl-3,4-bis[(tert-butyldimethylsilyl)oxy]-2-
hydroxymethylpyrrolidine (16). According to the procedure
described for the synthesis of compound 11, treatment of the
compound 14 (872 mg, 1.82 mmol) in CH2Cl2 (37 mL) with a
1 M solution of DIBAL-H in toluene (4.34 mL, 4.34 mmol)
yielded the title compound 16 (572 mg, 1.27 mmol, 70%) as a
23
D
1
colorless oil. [a] À44.93 (c 1.01, CHCl3). H NMR (CDCl3)
d À0.07 (s, 3H, Si-Me), 0.00 (s, 3H, Si-Me), 0.035 (s, 3H, Si-
Me), 0.036 (s, 3H, Si-Me), 0.82 (s, 9H, tert-Bu), 0.84 (s, 9H,
tert-Bu), 2.61 (dd, J = 4 and 10 Hz, 1H, 5H), 2.62 (d, J = 5 Hz,
1H, 2H), 2.75 (d, J = 10 Hz, 1H, 5H), 2.98 (br s, 1H, OH), 3.40
(d, J = 13 Hz, 1H, PhCH2), 3.57 (dd, J = 11 and 2 Hz, 1H,
CH2OH), 3.63 (dd, J = 11 and 3 Hz, 1H, CH2OH), 3.82 (m, 1H,
4H), 3.95 (d, J = 13 Hz, 1H, PhCH2), 4.02 (m, 1H, 3H), 7.14–
7.32 (m, 5H, Ph). 13C NMR (CDCl3) d À4.69, À4.61, À4.52,
À4.38, 16.61, 18.00, 25.84, 25.91, 58.15, 59.17, 59.87, 73.27,
73.31, 81.17, 127.07, 128.38, 128.48, 139.35. HRMS (APCI)
m/z 452.3015 [(M + H)+, calcd. for C24H46NO3Si2 452.3011].
(2S,3S,4S)-3,4-Dihydroxy-2-hydroxymethylpyrrolidine
hydrochloride (LAB-1, 3). According to the procedure
described for the synthesis of compound 12, treatment of the
compound 16 (222mg, 491 mmol) in MeOH (10 mL) with
concentrated HCl (2mL) yielded 1-benzyl-3,4-dihydroxy-2-
hydroxymethylpyrrolidine hydrochloride (135mg, quant) as a
brown oil, which was used for the next step without further
purification.
[9] For review, see: El-Ashry, E. S. H.; Nemr, A. E. Carbohydr
Res 2003, 338, 2265 and references cited therein.
[10] For some pioneering works, see: (a) Fleet, G. W. J.; Smith, P. W.
Tetrahedron 1986, 42, 5685; (b) Ikota, N.; Hanaki, A. Chem Pharm Bull 1987,
35, 2140; (c) Setoi, H.; Kayakiri, H.; Takeno, H.; Hashimoto, M. Chem Pharm
Bull 1987, 35, 3995; (d) Austin, G. N.; Baird, P. D.; Fleet, G. W. J.; Peach, J.
M.; Smith, P. W.; Watkin, D. J. Tetrahedron 1987, 43, 3095.
[11] For recent examples, see: (a) Luo, S.-Y.; Kulkarni, S. S.; Chou,
C.-H.; Liao, W.-M.; Hung, S.-C. J Org Chem 2006, 71, 1226; (b) Laurit-
sen, A.; Madsen, R. Org Biomol Chem 2006, 4, 2898; (c) Kim, I. S.; Zee,
O. P.; Jung, Y. H. Org Lett 2006, 8, 4101; (d) Murruzzu, C.; Riera, A. Tet-
rahedron Asymmetry 2007, 18, 149; (e) Zhou, X.; Liu, W.-J.; Ye, J.-L.;
Huang, P.-Q. Tetrahedron 2007, 63, 6346; (f) Jeon, J.; Lee, J. H.; Kim,
J.-W.; Kim, Y. G. Tetrahedron Asymmetry 2007, 18, 2448; (g) Sugiyama,
M.; Hong, Z.; Liang, P.-H.; Dean, S. M.; Whalen, L. J.; Greenberg, W. A.;
Wong, C.-H. J Am Chem Soc 2007, 129, 14811; (h) Merino, P.; Delso, I.;
Hydrogenolysis of the crude N-benzyl derivative (145 mg,
558 mmol) in H2O (10 mL) in the presence of 10% Pd/C (40 mg)
produced the title compound 3 (101 mg, quant) as a brown solid
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Stereoselective Synthesis of 3,4-Dihydroxylated Prolines and Prolinols
Starting from L-Tartaric Acid
243
[16] Possible rationalization of the cis-effect observed in nucleophilic
additions to acyliminium ions, see: (a) Renaud, P.; Seebach, D. Helv Chim
Acta 1986, 69, 1704; (b) Seebach, D.; Amatsch, B.; Amstutz, R.; Beck,
A. K.; Doler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herradön, B.; Hidber,
P. C.; Irwin, J. J.; Locher, R.; Maestro, M.; Maetzke, T.; Mouriño, A.;
Pfammatter, E.; Plattner, D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.;
Stucky, G.; Petter, W.; Escalante, J.; Juaristi, E.; Quintana, D.; Miravitlles,
C.; Molins E. Helv Chim Acta 1992, 75, 913; (c) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew Chem Int Ed Engl 1996, 35, 2708.
[17] (a) Ikota, N. Chem Pharm Bull 1989, 37, 3399; (b) Buchanan,
J. G.; Lumbard, K. W.; Sturgeon, R. J.; Thompson, D. K.; Wightman, R.
H. J Chem Soc Perkin Trans 1 1990, 699; (c) Van der Klein, P. A. M.;
Filemon, W.; Broxterman, H. J. G.; Van der Marel, G. A.; Van Boom,
J. H. Synthetic Commun 1992, 22, 1763.
Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A.
Eur J Org Chem 2008, 2929; (i) Dangerfield, E. M.; Timmer, M. S. M.;
Stocker, B. L. Org Lett 2009, 11, 535.
[12] (a) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron Lett
2001, 42, 5901; (b) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron
2002, 58, 9359; (c) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron
2004, 60, 8089.
[13] (a) Ryu, Y.; Kim, G. J Org Chem 1995, 60, 103. (b) Szemes,
F., Jr.; Fousse, A.; Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla,
V. Synthesis 2006, 875; (c) Vieira, A. S.; Ferreira, F. P.; Fiorante, P. F.;
Guadagnin, R. C.; Stefani, H. A. Tetrahedron 2008, 64, 3306.
[14] (a) Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett
1991, 32, 3401; (b) Yoda, H.; Kitayama, H.; Yamada, W.; Katagiri, T.;
Takabe, K. Tetrahedron Asymmetry 1993, 4, 1451.
[15] For some examples, see: (a) Thaning, M.; Wistrand, L.-G.
Acta Chem Scand 1989, 43, 290; (b) Schuch, C. M.; Pilli, R. A. Tetrahe-
dron Asymmetry 2000, 11, 753.
[18] (a) Kim, Y. J.; Kido, M.; Bando, M.; Kitahara, T. Tetrahedron
1997, 53, 7501; (b) Huang, Y.; Dalton, D. R.; Carroll, P. J. J Org Chem
1997, 62, 372.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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