A Short and Efficient Synthesis of 2R,3R,4R-3,4-Dihydroxyproline 1,4-Dideoxy-1,4-imino-L-xylitol, 2R,3R,4R,5S-3,4,5-Trihydroxypipecolic Acid, and 1,5-Dideoxy-1,5-imino-L-iditol

Article abstract of DOI:10.1055/s-2000-6408

The syntheses of pyrrolidine alkaloids (-)-1 and (+)-3 were accomplished in 47 percent and 60 percent overall yield from 2-azido-2-deoxy-L-idonate 5, while piperidine alkaloids (-)-2 and (+)-4 were obtained in 51 percent and 53 percent overall yield from the same starting material. Key step includes iodine promoted one-pot cyclization, and selective deprotection of isopropylidene and 9-phenylfluoren-9-yl (Pf) group.

Full text of DOI:10.1055/s-2000-6408

PAPER
1305
A Short and Efficient Synthesis of 2R,3R,4R-3,4-Dihydroxyproline,
1,4-Dideoxy-1,4-imino-L-xylitol, 2R,3R,4R,5S-3,4,5-Trihydroxypipecolic Acid,
and 1,5-Dideoxy-1,5-imino-L-iditol
Byong Won Lee, Ill-Yun Jeong, Min Suk Yang, Sang Uk Choi, Ki Hun Park*
Department of Agricultural Chemistry, Gyeongsang National University, Chinju 660-701, Korea
Fax +82(591)7570178; E-mail: khpark@gshp.gsnu.ac.kr
Received 7 February 2000; revised 24 April 2000
OH
OH
N
Abstract: The syntheses of pyrrolidine alkaloids (-)-1 and (+)-3
were accomplished in 47% and 60% overall yield from 2-azido-2-
deoxy-L-idonate 5, while piperidine alkaloids (-)-2 and (+)-4 were
obtained in 51% and 53% overall yield from the same starting ma-
terial. Key step includes iodine promoted one-pot cyclization, and
selective deprotection of isopropylidene and 9-phenylfluoren-9-yl
(Pf) group.
HO
OH
HO
OH
O
HO
OH
OH
O
HO
OH
OH
OH
OH
N
H
4
N
H
1
N
H
3
H
2
Figure Structures of compounds 1-4 synthesized
Key words: carbohydrates, iodine, amino acids, one-pot cycliza-
tion, azasugars, protecting group
A more efficient synthetic method than the earlier report-
ed ones1-4 should overcome the low overall yield and
nonstereoselectivity. Therefore, the one-pot cyclization
using iodine will be a short sequence for the synthesis of
a pyrrolidine having anti-diol structural unit such as com-
pounds 1 and 3.
The selective and simultaneous derivatization is of con-
siderable importance in design and total synthesis of nat-
ural or synthetic products from carbohydrates. Especially,
the selective transformation is necessary to avoid tedious
protection/deprotection steps and to induce efficient con-
struction of the nitrogen ring of polyhydroxylated pyrroli-
dine and piperidine. Since Paulsen and co-workers1
prepared 1-deoxynojirimycin, a large number of synthetic
routes to piperidine and pyrrolidine alkaloids have been
developed.2 Generally, cyclization has been achieved
through intramolecular N-alkylation, reductive amination,
ring closure using biselectrophile3 (e.g., dimesylates) or
reductive amination employing soluble hydride sources4
(e.g., NaBH3CN). We have recently reported one-pot
intramolecular amination using iodine, and have also
described selective deprotection of isopropylidene and
9-phenylfluoren-9-yl (Pf) group5, 6 (Scheme 1).
As starting material we chose L-gulonic acid g-lactone
which supplies the complete C-unit, stereochemistry, and
functionalities of each final compounds 1-4. The 9-phe-
nylfluoren-9-yl (Pf) group was selected as protecting
group for the amino group since this Pf group has been
shown to inhibit deprotonation at a-position of a-amino
acids.7 The azido idonate 5 as key compound was pre-
pared from L-gulonic acid g-lactone using similar method
as described.8 Since the reported preparation resulted in
some epimerzation of the product and is accompanied by
the difficulty to handle dried Bu4NN3 for transformation
of triflate into 5, a better synthesis is required. Thus, using
a precooled (-15 °C) solution of trifluoromethanesulfonic
anhyhdride in CH2Cl2 for triflation and sodium azide in
DMF for azidation, the azido idonate 5 was obtained in
excellent yield (85%) without any epimerization at a-po-
sition of the amino acid (Scheme 2).
HO
OH
R
O
R
I2/MeOH
MsO
N
H
O
NHPf
syn-diol
trans-diol
OH
Scheme 1
O
O
O
OH
a, b, c
O
O
OH HO
O
OCH3
In this paper, our objective is to develop a short and effi-
cient route of dideoxy-1,4-imino-L-xylitol (1) and 1,5-
dideoxy-1,5-imino-L-iditol (2) as D-azasugar, and
2R,3R,4R-3,4-dihydroxyproline (3) and 2R,3R,4R,5S-
3,4,5-trihydroxypipecolic acid (4) as D-amino acid to em-
phasize the preparative utility of our methodology (Fig-
ure).
O
N3
5
Reagents and conditions: (a) 2,2-dimethoxypropane/TsOH/acetone/
MeOH, r.t., 7 h; (b) Pyridine/Tf2O/CH2Cl2, -15 °C, 10 min; (c) NaN3/
DMF, r.t., 1 h, 85% (overall yield)
Scheme 2
Synthesis 2000, No. 9, 1305–1309 ISSN 0039-7881 © Thieme Stuttgart · New York

1306
B. W. Lee et al.
PAPER
The azido idonate 5 was hydrogenated in the presence of The primary hydroxyl group of diol 7 was selectively
palladium on charcoal, and then the corresponding amine mesylated by treatment of diol 7 with mesyl chloride at
was protected with 9-phenylfluoren-9-yl bromide to give -40 °C in CH2Cl2 to give the corresponding 11 in 95%
idonate 6 in 84% yield (Scheme 3). The terminal isopro- yield (Scheme 4). Although iodine-promoted cyclization
pylidene group was selectively cleaved by treatment of 6 was applied to multiprotected L-idonate 11 to form pipe-
with Dowex 50W-X8 (H+ form) in 90% methanol to give ridine ring, it gave inadequate result (<15%). As an alter-
diol 7 in quantitative yield. The diol 7 was oxidized in the native, N-Pf group of 11 was hydrogenated with
presence of NaIO4; this was followed by sodium borohy- palladium on charcoal followed by the intramolecular
dride reduction of the resulting aldehyde which led to the amination. The resulting L-idonate 12 was readily con-
formation of alcohol 8 in 94% yield. After mesylation of verted by Dowex 50W-X8 to give optically pure
alcohol 8, the resulting mesylate 9 was refluxed with 60% (+)-2R,3R,4R,5S-3,4,5-trihydroxypipecolic acid (4)
(w/w) iodine in methanol for 8 hours. To the reaction mix- {[a]D20 +39.7 (c = 1.1, H2O)} in good yield. The L-idonate
ture was added Dowex 50W-X8, which was then refluxed 12 was reduced by LiAlH4 to afford L-iditol 13 in quanti-
for additional 2 hours to hydrolyze the remaining methyl tative yield. The remaining acetal of 13 was easily cleaved
ester completely. The resin was filtered and washed with with Dowex 50W-X8 in MeOH to give optically pure
methanol, then eluted with a 3 mol/L NH3 solution to af- (-)-1,5-dideoxy-1,5-imino-L-iditol (2) {[a]D20 -15.6 (c =
ford the desired (+)-3 in 83% yield (Scheme 3).
1.1, H2O)} without additional purification. The previous-
ly assigned stereochemistry of target compounds 1-4 was
obtained based on 2D-NOESY experiments of compound
3 which has the same absolute configuration as others.
Strong NOE cross peaks were observed between H2-H3
and H4-H5b, whereas NOE between H3-H4 and H4-H5a
were weak.
O
O
O
O
OH
O
a
b
O
HO
OCH3
OCH3
O
NHPf
7
6
O
NHPf
O
c
H4
OH
H3
HO
O
O
OH
O
a
I2/MeOH
e
MsO
H5α
H
2OH
7
RO
OCH3
4 (13-15%)
OCH3
N
∆
Pf
H
O
NHPf
5β H
O
NHPf
11
O
8: R = H
9: R = Ms
d
3
b
f
HO
OH
O
O
O
g
HO
O
HO
O
OH
MsO
10
OH
d
N
H
O
NHPf
OCH3
OH
1
N
N
H
H
13
12
O
Reagents and conditions: (a) H2/10% Pd-C/EtOAc, r.t., 5 h; PfBr/
Pb(NO3)2/Et3N/CH2Cl2, r.t., 48 h, 84%; (b) Dowex 50W-X8/MeOH,
r.t., 20 h, 95%; (c) NaIO4/EtOH/H2O, r.t., 1 h; NaBH4, 0 °C, 30 min,
94%; (d) MsCl/Et3N/THF, 0 °C,15 min, 96%; (e) I2/MeOH, reflux, 8
h; Dowex 50W-X8/reflux, 2 h, 83%; (f) LiAlH4/THF, 0 °C, 10 min,
97%; (g) I2/MeOH, reflux, 7 h; Dowex 50W-X8, r.t., 1 h, 68%.
c
e
OH
OH
HO
OH
HO
OH
OH
OH
N
H
N
H
Scheme 3
O
2
4
Reagents and conditions: (a) MsCl/Et3N/CH2Cl2, -40 °C,10 min,
95%; (b) H2/Pd-C/ CH3CO2Na/MeOH, 40 °C (6 h) Æ reflux (8 h),
83%; (c) Dowex 50W-X8/THF/H2O, reflux, 9 h, 84%; (d) LiAlH4/
THF, 0 °C,10 min, 92%; (e) Dowex 50W-X8/THF/H2O, reflux, 3 h,
89%
The ester group of mesylate 9 was reduced by LiAlH4 at
0 °C to give compound 10 in 97% yield. The syn-diol 10,
protected by isopropylidene group, was refluxed with
60% (w/w) iodine in methanol for 7 hours and cyclized in
the presence of Dowex 50W-X8 by stirring for 1 hour at
room temperature. The mixture was filtered, washed with
methanol, and then eluted with 3 mol/L NH3 to give the
target compound (-)-1 in 68% yield (Scheme 2). The ring
closure giving trans-3,4-dihydroxy compounds 1, 3 could
be achieved in a one-pot reaction by simultaneous depro-
tection of isopropylidene group, intramolecular amina-
tion, and deprotection of Pf group. The procedure using
iodine reduce a number of tedious steps such as repeated
protection/deprotection and working up water soluble
polyhydroxylated intermediate.
Scheme 4
In summary, using iodine-promoted cyclization, selective
deprotection of isopropylidene and 9-phenylfluoren-9-yl
group, we have accomplished short and efficient synthe-
ses of 1,4-dideoxy-1,4-imino-L-xylitol (1), 1,5-dideoxy-
1,5-imino-L-iditol (2), 2R,3R,4R-3,4-dihydroxyproline
(3), and 2R,3R,4R,5S-3,4,5-trihydroxypipecolic acid (4).
This methodology can also be utilized in the preparation
Synthesis 2000, No. 9, 1305–1309 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Short and Efficient Synthesis of 2R,3R,4R-3,4-Dihydroxyproline
1307
compound 7 (2.63 g, 95%) as colorless needles: mp 61-62 °C;
[a]D16 +275.1 (c = 1.7, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 3 H), 1.49 (s, 3 H), 2.62
(d, J = 2.7 Hz, 1 H), 3.12 (m, 1 H), 3.32 (s, 3 H), 3.53 (dd, J = 18.9,
4.1 Hz, 1 H), 3.59 (dd, J = 11.4, 5.5 Hz, 1 H), 3.96 (dd J = 8.1, 2.9
Hz, 1 H), 4.21 (dd, J = 8.1, 2.4 Hz, 1 H), 7.20-7.66 (m, 13 H).
13C NMR (125 MHz, CDCl3): d = 27.1, 27.3, 51.8, 55.0, 65.1, 69.0,
72.8, 77.9, 78.2, 110.0, 120.0, 120.2, 125.4, 126.0, 127.0, 127.4,
127.4, 128.4, 128.5, 128.7, 140.4, 141.0, 143.8, 147.8, 148.7, 173.9.
of structurally diverse azasugars by employing appropri-
ate carbohydrates as starting material.
Dowex 50W-X8 was purchased from Sigma Chemical Co. All non-
aqueous reactions were carried out under N2. THF was distilled
from Na/benzophenone; MeOH was distilled from Mg; DMF and
CH2Cl2 were distilled from CaH2. Column chromatography was
carried out using 230-400 mesh silica gel. Final solution before
evaporation were dried over anhyd Na2SO4. Mps were measured on
a Thomas-Hoover capillary apparatus and are uncorrected. IR spec-
tra were recorded on Hitachi 270-50. NMR spectra were conducted
on a Bruker AW-500 spectrometer. The chemical shifts are reported
in ppm relative to internal TMS in CDCl3. HRMS (EI) were ob-
tained on a Jeol JMS-700 mass spectrometer. Optical rotaions were
measured on a Jasco DIP-1000 and Perkin-Elmer 343 polarimeters
and [a]D-values are given in units of 10-1 deg cm2g-1.
Anal. calcd for C29H31NO6: C, 71.15; H, 6.38; N, 2.86. Found: C,
71.32; H, 6.50; N, 2.90.
Methyl 2-Deoxy-2-[(9-phenylfluoren-9-yl)amino]-3,4-O-isopro-
pylidene-D-arabinonate (8)
To a solution of 7 (0.9 g, 1.84 mmol) in EtOH/H2O (2:1, 15 mL) was
added NaIO4 (0.39 g, 2.21 mmol) at r.t. After stirring for 1 h, the
mixture was cooled to 0 °C, and then NaBH4 (83 mg, 2.21 mmol)
was added and stirred for 30 min. After evaporation of EtOH, the
mixture was poured into excess of H2O and extracted with EtOAc
(3 × 20 mL). The organic extracts were dried and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography over silica gel with hexane/EtOAc (2:1) as eluent to give
the compound 8 (0.80 g, 94%) as white needles; mp 56-58 °C;
[a]D16 +213.2 (c = 1.3, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.34 (s, 3 H), 1.45 (s, 3 H), 2.68
(d, J = 3.5 Hz, 1 H), 3.30 (dd, J = 12.0, 4.2 Hz, 1 H), 3.32 (s, 3 H),
3.53 (dd, J = 12.0, 4.1 Hz, 1 H), 3.76 (dd, J = 8.3, 3.6 Hz, 1 H), 4.30
(m, 1 H), 7.19-7.68 (m, 13 H).
Methyl 2-azido-2-deoxy-3,4:5,6-O-diisopropylidene-L-idonate (5)
was prepared as described;8 however, no analytical and spectral
data had been reported.
Colorless oil; 85% (overall yield); [a]D20 +41.4 (c = 3.0, CHCl3).
IR (neat): n = 2989, 2118, 1753 cm-1.
1H NMR (500 MHz, CDCl3): d = 1.37-1.50 (m, 12 H), 3.75 (d,
J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.92 (m, 1 H), 4.07 (m, 1 H), 4.24-
4.27 (m, 2 H), 4.46 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 25.1, 26.0, 26.6, 27.1, 53.0, 60.9,
65.5, 74.0, 76.3, 77.6, 110.0, 111.1, 168.8.
Anal. calcd for C13H21N3O6: C, 49.5; H, 6.72; N, 13.33. Found: C,
49.73; H, 6.50; N, 13.59.
13C NMR (125 MHz, CDCl3): d = 27.1, 27.1, 51.8, 55.4, 61.8, 72.9,
76.9, 78.3, 109.4, 120.0, 120.2, 125.5, 126.1, 126.7, 127.4, 127.8,
128.5, 128.6, 128.7, 140.4, 141.0, 143.8, 147.9, 148.6, 173.9.
Methyl 2-Deoxy-2-[(9-phenylfluoren-9-yl))amino]-3,4:5,6-O-di-
isopropylidene-L-idonate (6)
Anal. calcd for C28H29NO5: C, 73.18; H, 6.36; N, 3.05. Found: C,
73.25; H, 6.41; N, 3.31.
A solution of 5 (4.4 g, 13.96 mmol) in EtOAc (30 mL) was hydro-
genated at r.t. over 10% P/C (100 mg) at atmospheric pressure for
5 h. The mixture was filtered and concentrated. To a solution of this
residue (4.0 g, 13.96 mmol) in CH2Cl2 (45 mL) was added PfBr
(6.7 g, 20.94 mmol), Pb(NO3)2 (6.9 g, 20.94 mmol), and Et3N
(3.9 mL, 27.92 mmol). After stirring at r.t. for 48 h, the mixture was
filtered, poured into excess of H2O, and extracted with CH2Cl2. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The organic extracts were dried and con-
centrated under reduced pressure. The residue was purified by
column chromatography over silica gel with hexane/EtOAc (16:1)
as eluent to give the compound 6 (6.14 g, 84%) as colorless needles;
mp 59-63 °C; [a]D16 +200.3 (c = 1.7, CHCl3).
Methyl 2-Deoxy-2-[(9-phenylfluoren-9-yl)amino]-3,4-O-isopro-
pylidene-5-methanesulfonyl-D-arabinonate (9)
To a solution of 8 (0.7 g, 1.52 mmol) in THF (5 mL) was added Et3N
(0.32 mL, 2.28 mmol) and MsCl (0.18 mL, 2.28 mmol) at 0 °C. Af-
ter stirring for 15 min, the mixture was poured into sat. aq NaHCO3
solution. The organic layer was separated, and the aqueous layer
was extracted with EtOAc (3 × 30 mL). The organic extracts were
dried and concentrated under reduced pressure. The residue was pu-
rified by column chromatography over silica gel with hexane/
EtOAc (2:1) as eluent to give the compound 9 (0.76 g, 96%) as
white needles; mp 57-60 °C; [a]D17 +230.2 (c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 3 H), 1.46 (s, 3 H), 2.65
(s, 1 H), 2.99 (s, 3 H), 3.33 (s, 3 H), 3.75 (m, 1 H), 3.87 (dd, J = 11.5,
5.2 Hz, 1 H), 4.20 (dd, J = 11.5, 2.7 Hz, 1 H), 4.47 (m, 1 H), 7.20-
7.67 (m, 13 H).
1H NMR (500 MHz, CDCl3): d = 1.24-1.55 (m, 12 H), 2.54 (s, 1
H), 3.33 (s, 3 H), 3.43 (t, J = 7.8 Hz, 1 H), 3.59 (m, 1 H), 3.77 (m,
1 H), 3.83 (dd, J = 8.0, 2.4 Hz, 1 H), 4.18 (dd, J = 8.0, 2.4 Hz, 1 H),
7.19-7.66 (m, 13 H).
13C NMR (125 MHz, CDCl3): d = 27.0, 27.1, 37.7, 51.9, 55.2, 68.4,
72.9, 74.6, 77.6, 110.3, 120.0, 120.2, 125.3, 126.6, 126.7, 127.4,
127.5, 128.1, 128.5, 128.6, 128.8, 140.3, 141.0, 143.7, 147.8, 148.4,
173.5.
13C NMR (125 MHz, CDCl3): d = 25.7, 26.1, 27.1, 27.4, 51.8, 55.1,
65.5, 72.8, 74.8, 76.3, 78.3, 109.5, 110.0, 119.9, 120.1, 125.7,
126.1, 127.1, 127.3, 127.4, 127.8, 128.4, 128.5, 128.6, 140.3, 141.0,
144.1, 147.8, 148.7, 173.9.
Anal. calcd for C29H31NO7S: C, 64.79; H, 5.81; N, 2.61. Found: C,
64.92; H, 5.97; N, 2.67.
Anal. calcd for C32H35NO6: C, 72.56; H, 6.66; N, 2.65. Found: C,
72.49; H, 6.85; N, 2.90.
2R,3R,4R-3,4-Dihydroxyproline (3)
Methyl 2-Deoxy-2-[(9-phenylfluoren-9-yl)amino]-3,4-O-isopro-
pylidene-L-idonate (7)
A solution of 9 (0.47 g, 0.89 mmol) and I2 (0.2 g) in MeOH (5 mL)
was refluxed for 8 h, and then Dowex 50W-X8 resin (0.2 g) was
added. After refluxing for 2 h, the mixture was filtered and washed
with H2O and MeOH. The remaining residue was eluted with 3 N
NH4OH. The ammoniacal solution was evaporated and co-evapo-
rated with toluene, and the residue was recrystallized (MeOH/H2O)
To a solution of compound 6 (3.0 g, 5.66 mmol) in 90% MeOH
(20 mL) was added Dowex 50W-X8 resin (0.5 g). After stirring at
r.t. for 20 h, the mixture was filtered and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy over silica gel with hexane/EtOAc (2:1) as eluent to give the
Synthesis 2000, No. 9, 1305–1309 ISSN 0039-7881 © Thieme Stuttgart · New York

1308
B. W. Lee et al.
PAPER
to give the compound 3 (85 mg, 83%) as colorless crystals; mp
242 °C (dec); [a]D20 +46.2 (c = 1.0, H2O).
IR (KBr): n = 1632 cm-1.
1H NMR (500 MHz, D2O): d = 3.32 (d, J = 12.9 Hz, 1 H), 3.68 (dd,
J = 12.9, 3.7 Hz, 1 H), 4.36 (d, J = 4.0 Hz, 1 H), 4.39 (m, 1 H), 4.44
(m, 1 H).
13C NMR (125 MHz, D2O): d = 51.4, 65.7, 75.3, 75.7, 170.9.
the compound 11 (2.13 g, 95%) as colorless needles; mp 64-66 °C;
[a]D26 +357.8 (c = 1.3, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.36 (s, 3 H), 1.47 (s, 3 H), 2.62
(d, J = 2.6 Hz, 1 H), 3.04 (s, 3 H), 3.33 (s, 3 H), 3.41 (s, 1 H), 3.93
(dd, J = 8.2, 3.1 Hz, 1 H), 4.10 (dd, J = 10.8, 4.0 Hz, 1 H), 4.18-
4.22 (m, 2 H), 7.19-7.68 (m, 13 H).
13C NMR (125 MHz, CDCl3): d = 27.0, 27.2, 37.7, 51.9, 55.0, 67.5,
71.3, 72.9, 76.0, 77.6, 110.2, 120.0, 120.3, 125.3, 126.0, 126.9,
127.4, 127.5, 128.1, 128.5, 128.6, 128.9, 140.4, 141.6, 143.7, 147.8,
148.6, 173.7.
HRMS: m/z calcd for [C5H9NO4 + H] 148.0610, found 148.0591 (M
+ H)+.
Anal. calcd for C30H33NO7S: C, 65.32; H, 6.03; N, 2.54. Found: C,
65.41; H, 6.35; N, 2.58.
2-Deoxy-2-[(9-phenylfluoren-9-yl)amino]-3,4-O-isopropy-
lidene-5-methanesulfonyl-D-arabinitol (10)
To an ice-cooled solution of LiAlH4 (44 mg, 1.16 mmol) in THF
(3 mL) was added a solution of compound 9 (0.5 g, 0.97 mmol) in
THF (2 mL). After stirring for 10 min, the mixture was quenched by
the sequential addition of H2O (50 µL), 15% aq NaOH solution
(50 µL), and H2O (150 µL). The mixture was filtered and concen-
trated under reduced pressure. The residue was purified by column
chromatography over silica gel with hexane/EtOAc (2:1) as eluent
to give the compound 10 (0.48 g, 97%) as white needles; mp 53-55
°C; [a]D20 +81.6 (c = 1.9, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 3 H), 1.47 (s, 3 H), 2.19
(m, 1 H), 2.78 (m, 1 H), 3.00 (s, 3 H), 3.15 (d, J = 11.4 Hz, 1 H),
3.79 (dd, J = 8.2, 3.9 Hz, 1 H), 3.92 (dd, J = 11.5, 5.5 Hz, 1 H), 4.21
(dd, J = 11.5, 2.7 Hz, 1 H), 4.45 (m, 1 H), 7.22-7.69 (m, 13 H).
2R,3R,4R,5S-3,4,5-Trihydroxypipecolic Acid (4) from 11
A solution of 11 (0.20 g, 0.36 mmol) and I2 (40 mg) in MeOH
(3 mL) was refluxed for 8 h, and then Dowex 50W-X8 resin (0.1 g)
was added. After refluxing for 3 h, the mixture was filtered and
washed with H2O and MeOH. The remaining residue was eluted
with 3 N NH4OH. The ammoniacal solution was evaporated and co-
evaporated with toluene, and the residue was recrystallized (MeOH/
H2O) to give 4 (10 mg, 15%) as white plates; mp 196-197 °C (dec);
[a]D20 +39.7 (c = 1.1, H2O).
IR (KBr): n = 1632 cm-1.
1H NMR (500 MHz, D2O): d = 3.35-3.37 (m, 2 H), 3.93 (d, J = 2.0
Hz, 1 H), 3.99 (s, 1 H), 4.03 (d, J = 3.5 Hz, 1 H), 4.28 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 26.9, 27.2, 37.7, 52.9, 62.8, 68.7,
72.4, 75.3, 80.1, 109.8, 120.1, 120.2, 125.1, 125.5, 126.0, 127.4,
128.0, 128.2, 128.4, 128.6, 128.7, 140.2, 140.6, 144.8, 148.7, 150.6.
13C NMR (125 MHz, D2O): d = 45.2, 58.5, 66.3, 67.9, 68.9, 172.3.
HRMS: m/z calcd for [C6H11NO5 + H] 178.0715, found 178.0717
(M + H)+.
Anal. calcd for C28H31NO6: C, 70.42; H, 6.54; N, 2.93. Found: C,
70.71; H, 6.77; N, 2.98.
2R,3R,4R,5S-3,4,5-Trihydroxypipecolic Acid (4) from 12
To a solution of compound 12 (56 mg, 0.24 mmol) in THF/H2O
(2:1, 1.5 mL) was added Dowex 50W-X8 resin (40 mg). After re-
fluxing for 9 h, the mixture was filtered and washed with H2O and
MeOH. The remaining residue was eluted with 3 N NH4OH. The
ammoniacal solution was evaporated and co-evaporated with tolu-
ene, and the residue was recrystallized (MeOH/H2O) to give 4
(36 mg, 84%).
1,4-Dideoxy-1,4-imino-L-xylitol (1)
A solution of 10 (0.21 g, 0.41 mmol) and I2 (40 mg) in MeOH (3
mL) was refluxed for 7 h, and then Dowex 50W-X8 resin (0.1 g)
was added. After stirring at r.t. for 1 h, the mixture was filtered and
washed with H2O and MeOH. The remaining residue was eluted
with 3 N NH4OH. The ammoniacal solution was evaporated and co-
evaporated with toluene, and the residue was purified by column
chromatography over silica gel with CH2Cl2/MeOH/3 N NH4OH
(5:5:1) as eluent to give 1 (37 mg, 68%) as colorless oil; [a]D31 -4.1
(variable) (c = 1.0, H2O).
1H NMR (500 MHz, D2O): d = 3.16 (d, J = 12.8 Hz, 1 H), 3.58 (ddd,
J = 12.9, 4.5, 1.8 Hz, 1 H), 3.75 (m, 1 H), 3.87 (ddd, J = 11.7, 7.9,
2.1 Hz, 1 H), 3.98 (ddd, J = 11.9, 5.4, 2.1 Hz, 1 H), 4.29 (m, 1 H),
4.35 (m, 1 H).
Methyl 1,5-Dideoxy-1,5-imino-3,4-O-isopropyliden-L-idonate
(12)
A solution of 11 (1.5 g, 2.72 mmol) in MeOH (15 mL) was hydro-
genated at 40 °C over 10% Pd/C (60 mg) at atmospheric pressure
for 6 h. The mixture was filtered and then CH3CO2Na (0.89 g,
10.88 mmol) was added to the filtrate. After refluxing for 8 h, H2O
in excess was added. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2/isopropyl alcohol (IPA)
(3:1) (5 × 20 mL). The organic layers were dried and concentrated
under reduced pressure. The residue was purified by column
chromatography over silica gel with CH2Cl2/IPA (12:1) to give 12
(0.53 g, 83%) as white plates; mp 146-147 °C; [a]D24 -66.3
(c = 0.8, MeOH).
1H NMR (500 MHz, CD3OD): d = 1.34 (s, 3 H), 1.41 (s, 3 H), 2.93-
2.97 (m, 2 H), 3.52 (dd, J = 9.1, 6.0 Hz, 1 H), 3.72 (s, 3 H), 3.67-
3.75 (m, 2 H), 3.96 (d, J = 6.0 Hz, 1 H).
13C NMR (125 MHz, CD3OD): d = 27.1, 27.6, 48.9, 52.5, 57.8, 72.3,
77.2, 80.7, 111.3, 173.3.
13C NMR (125 MHz, D2O): d = 51.1, 58.7, 62.6, 75.7, 75.9;
HRMS: m/z calcd for [C5H11NO3+H] 134.0817, found 134.0824
(M+H)+.
The corresponding hydrochloride was obtained on treatment of the
free base with 6 N HCl and recrystallized from MeOH/H2O;
[a]D20 -7.8 (c = 1.0, H2O) {Lit.9 [a]D20 -8.6 (c = 0.01, H2O).
Methyl 2-Deoxy-2-[(9-phenylfluoren-9-yl)amino]-3,4-O-isopro-
pylidene-6-methanesulfonyl-L-idonate (11)
To a solution of 7 (2.0 g, 4.08 mmol) in CH2Cl2 (15 mL) was added
Et3N (0.57 mL, 4.08 mmol) and MsCl (0.31 mL, 4.08 mmol) at
-40 °C. After stirring for 10 min, the mixture was poured into sat.
aq NaHCO3 solution and extracted with CH2Cl2. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3 × 30 mL). The organic extracts were dried and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography over silica gel with hexane/EtOAc (4:1) as eluent to give
Anal. calcd for C10H17NO5: C, 51.94; H, 7.41; N, 6.06. Found: C,
52.11; H, 7.59; N, 6.25.
1,5-Dideoxy-1,5-imino-3,4-O-isopropyliden-L-iditol (13)
To an ice-cooled suspension of LiAlH4 (31 mg, 0.82 mmol) in THF
(2 mL) was added a solution of 12 (0.16 g, 0.68 mmol) in THF
(1 mL). The mixture was stirred for 10 min, and then quenched by
Synthesis 2000, No. 9, 1305–1309 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Short and Efficient Synthesis of 2R,3R,4R-3,4-Dihydroxyproline
1309
the sequential addition of H2O (30 µL), 15% aq NaOH (30 µL), and
H2O (100 µL). The mixture was filtered, evaporated, and purified
by column chromatography over silica gel with CH2Cl2/IPA (4:1) to
give the compound 13 (0.13 g, 92%) as white plates; mp 137-138
°C; [a]D28 -53.4 (c = 1.8, MeOH).
1H NMR (500 MHz, CD3OD): d = 1.37 (s, 3 H), 1.40 (s, 3 H), 2.48
(dd, J = 13.1, 10.0 Hz, 1 H), 2.92 (dd J = 13.1, 5.2 Hz, 1 H), 3.3 (m,
1 H), 3.46 (m, 1 H), 3.54 (dd, J = 9.7, 5.5 Hz, 1 H), 3.65-3.70 (m,
2 H), 3.74 (dd, J = 11.5, 9.2 Hz, 1 H).
(e) Baxter, E. W.; Reitz, A. B. J. Am. Chem. Soc. 1994, 59,
3175.
(f) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res.
1993, 26, 182.
(g) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem.
Soc. 1994, 116, 5099.
(h) Tschamber, T.; Backenstrass, F.; Neuburger, M.; Zehnder,
M.; Streith, J. Tetrahedron 1994, 50, 1135.
(i) Johnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M.
W.; Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653.
(j) Bernotas, R. C.; Papandreou, G.; Urbach, J.; Ganem, B.
Tetrahedron Lett. 1990, 31, 3393.
13C NMR (125 MHz, CD3OD): d = 27.1, 27.5, 47.3, 57.7, 58.2, 72.6,
78.3, 80.6, 11.0.
(k) For syntheses of pyrrolidines, see:
Anal. calcd for C9H17NO4: C, 53.19; H, 8.43; N, 6.89. Found: C,
53.24; H, 8.46; N, 6.90.
Fleet, G. W. J.; Nicolas, S. J.; Smith, P. W.; Evans, S. V,
Fellows, L. E.; Nash, R. J. Tetrahedron Lett. 1985, 26, 3127.
Asano, A.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem.
1994, 37, 3701.
Asano, N.; Kizu, H.; Oseki, K.; Tomioka, E.; Matsui, K.;
Okamoto, M.; Baba, M. J. Med. Chem. 1995, 38, 2349.
Recent reviews: Scofield, A. M.; Fellows, L. E.; Nash, R. J.;
Fleet, G. W. J. Life Sci. 1986, 39, 645.
1,5-Dideoxy-1,5-imino-L-iditol (2)
To a solution of compound 13 (58 mg, 0.26 mmol) in THF/H2O
(2:1, 1.5 mL) was added Dowex 50W-X8 resin (40 mg). After re-
fluxing for 3 h, the mixture was filtered and washed with H2O and
MeOH. The remaining residue was eluted with 3 N NH4OH. The
ammoniacal solution was evaporated and co-evaporated with tolu-
ene, and the residue was recrystallized (MeOH/H2O) to give 2
(38 mg, 89%) as white plates; mp 125-127 °C; [a]D20 -15.6 (vari-
able) (c = 1.1, H2O).
1H NMR (500 MHz, D2O): d = 2.76 (m, 1 H), 2.98 (m, 1 H), 3.18
(m, 1 H), 3.55-3.63 (m, 2 H), 3.71-3.77 (m, 3 H).
13C NMR (125 MHz, D2O): d = 44.5, 56.8, 58.3, 70.1, 70.7, 72.3.
Sinnott, M. L. Chem. Rev. 1990, 90, 1171.
(3) (a) Masaki, Y.; Oda, H.; Kazuta, K.; Usui, A.; Itoh, A.; Xu, F.
Tetrahedron Lett. 1992, 33, 5089, and references cited therein.
(b) Zou, W.; Szarek, W. A. Carbohydr. Res. 1993, 242, 311.
(4) (a) Di, J.; Rajanikanth, B.; Szarek, W. A. J. Chem. Soc. Perkin
Trans. 1 1992, 2151.
(b) Czollner, L.; Kuszmann, J.; Vasella, A. Helv. Chim. Acta
1990, 73, 1388.
(c) Glanzer, B. I.; Gyorgydeak, Z.; Bernet, B.; Vasella, A.
Helv. Chim. Acta 1991, 74, 343.
HRMS: m/z calcd for [C6H13NO4 + H] 164.0923, found 164.0921
(M + H)+.
The corresponding hydrochloride was obtained on treatment of the
free base with 6 N HCl and recrystallized from MeOH/H2O;
[a]D20 +32.3 (c = 1.0, H2O).
(d) Jones, T. H.; Franko, J. B.; Blum, M. S.; Fales, H. M.
Tetrahedron Lett. 1980, 21, 789.
(e) Abe, K.; Okumura, H.; Tsugoshi, T.; Nakamura, N.
Synthesis 1984, 597.
(f) Kawaguchi, M.; Hayashi, O.; Sakai, N.; Hamada, M.;
Yamamoto, Y.; Oda, J. Agric. Biol. Chem. 1986, 50, 3107.
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Acknowledgement
This work was supported by a grant from High-technology De-
velopment Project for Agriculture, Forestry and Fisheries. We also
thank the financial support of Brain Korea 21 program.
(b) Kim, J. H.; Yang, M. S.; Lee, W. S.; Park, K. H. J. Chem.
Soc., Perkin Trans. 1 1998, 2877.
(6) Kim, J. H.; Lee, W. S.; Yang, M. S.; Lee, S. G.; Park, K. H.
Synlett 1999, 614.
(7) Csuk, R.; Hugener, M.; Vasella, A. Helv. Chim Acta. 1988, 71,
609.
(8) (a) Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R.
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(b) Vanio, A. R.; Szarek, W. A. J. Chem. Soc., Chem.
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Article Identifier:
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Synthesis 2000, No. 9, 1305–1309 ISSN 0039-7881 © Thieme Stuttgart · New York