1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine

Article abstract of DOI:10.1016/j.tetasy.2015.05.008

Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.

Full text of DOI:10.1016/j.tetasy.2015.05.008

Tetrahedron: Asymmetry 26 (2015) 657–661
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
1,3-Oxazine as a chiral building block used in the total synthesis
of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-
dihydroxypyrrolidine
⇑
Seok-Hwi Park , Ji-Yeon Kim , Jin-Seok Kim, Changyoung Jung, Dong-Keun Song, Won-Hun Ham
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-
dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate.
The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucle-
ophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-
butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2%
overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 4 April 2015
Accepted 8 May 2015
Available online 23 May 2015
1. Introduction
OH
HO
OH
HO
OH
Polyhydroxylated alkaloids isolated from plants and micro-or-
ganisms are worthy of close attention since they can function as
glycosidase inhibitors by mimicking natural sugar substrates,
which may allow the development of new antiviral, antidiabetic,
and anticancer drugs.1 Among over two hundred of these
naturally-occurring alkaloids, (+)-1-deoxynojirimycin 1 is a well-
HO
OH
OH
N
H
N
H
(+)-1-deoxynojirimycin 1
(+)-DMDP 2
Figure 1. Structures of (+)-1-deoxynojirimycin and (+)-DMDP.
known piperidine alkaloid and is a potent inhibitor of
a-glucosi-
via Miyashita C-2 selective endo-mode azide opening of an epoxy
alcohol, followed by Sharpless asymmetric dihydroxylation.6d Li
et al. reported a short synthesis of 1 via a diastereoselective syn-
coupling reaction of Cbz-protected (S)-isoserinal acetonide and a
vinylzinc nucleophile.6e Davies et al’s. approach commenced with
dihydroazepine6f,g while Aerts and Overkleeft’s approach started
dases. It was first isolated from the roots of the mulberry tree in
1976,2a after having been synthesized by Paulsen in 1966.2b The
inhibitory activity of this compound has been employed in the
azasugar drugs miglitol (GlysetÒ) and miglustat (ZavescaÒ),
which are synthesized N-alkylated derivatives of 1, and have
been approved for the treatment of type 1 diabetes, Gaucher’s
disease, and other lysosomal storage disorders.3 Meanwhile,
from 2,3,4,6-tetra-O-benzyl-D
-glucopyranose.6h,k In 2014, Bouillon
et al. reported the facile synthesis of (+)-DMDP, which relied on a
Petasis borono–Mannich reaction for the key nitrogen
introduction.8a Ishikawa et al. reported an enantioselective synthe-
sis of 2 via a guanidinium ylide-mediated asymmetric aziridina-
(2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine
[(+)-
DMDP] 2 is another polyhydroxylated alkaloid and is a representa-
tive pyrrolidine alkaloid. It was first found in Derris elliptica leaves
and is a widespread secondary metabolite.4 This compound is also
known to be a selective inhibitor of glycosidases and has proven to
have potential as an antiviral and anticancer agent (Fig. 1).5
The promising biological activities and four contiguous stere-
ogenic centers of these compounds have prompted the develop-
ment of many synthetic approaches.6–8 For example, in 2012, Rao
et al. reported an asymmetric synthesis of (+)-1-deoxynojirimycin
tion.8c Cheng et al. started from
D
-arabinose8d while Goti et al.
also commenced with
D
-arabinose.8e
Recently, we have reported a facile strategy for the preparation
of anti,syn-oxazines9 via a stereoselective palladium(0)-catalyzed
reaction for the total synthesis of biologically active natural and
synthetic compounds. Using versatile oxazine chiral building
blocks, piperidine alkaloid
D
-fagomine,9d pyrrolidine alkaloid
DAB-1,9d and indolizidine alkaloid (ꢀ)-lentiginosine9b were
⇑
Corresponding author. Tel.: +82 31 290 7706.
E-mail address: whham@skku.edu (W.-H. Ham).
successfully
synthesized.
Herein
we
report
highly
stereocontrolled total syntheses of (+)-1-deoxynojirimycin 1 and
These authors contributed equally.
http://dx.doi.org/10.1016/j.tetasy.2015.05.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

658
S.-H. Park et al. / Tetrahedron: Asymmetry 26 (2015) 657–661
TBS
O
OH
OH
OMs
HO
OH
TBSO
N
O
OH
TBS
N
OTBS
O
O
OH
N
H
Ph
TBSO
TBSO
1
3
N
O
TBS
N
Ph
Ph
O
OMs
HO
OH
5
6
TBSO
HO
OH
O
N
H
Ph
2
4
Scheme 1. Retrosynthesis.
(+)-DMDP
2
via straightforward procedures that rely on an
TBS groups using 1 M HCl in methanol followed by neutralization
anti,syn-oxazine as a chiral building block.
with an ion-exchange resin afforded 1 in 85% yield. Meanwhile,
mesylation of
5 gave secondary mesylate 4 in 91% yield.
Ozonolysis of 4 followed by a reductive workup and hydrogenoly-
sis yielded protected 10 in 70% yield. Finally, acid-promoted
hydrolysis cleaved the silyl groups, and subsequent neutralization
with an acidic resin afforded 2 in 88% yield (Scheme 4).
2. Results and discussion
Our retrosynthesis (Scheme 1) suggested that 1 and 2 could be
obtained from primary and secondary mesylates 3 and 4, respec-
tively, via intramolecular SN2 reactions. Conveniently, mesylates 3
and 4 could all be obtained from allylic alcohol 5. The synthesis of
this compound could be accomplished by diastereoselective vinyl
addition into the corresponding aldehyde, which could be derived
from conversion of the terminal olefin of anti,syn-oxazine 6.
3. Conclusion
In conclusion, we have reported a new method for the diastere-
oselective vinyl addition to an anti,syn-oxazine. The key features in
this strategy are the use of 1,3-oxazine as a chiral building block
and diastereoselective vinyl addition. Starting from readily avail-
able 7, (+)-1-deoxynojirimycin 1 was obtained in 11 steps and
26.2% overall yield and (+)-DMDP 2 was obtained in 11 steps and
27.1% overall yield. Meanwhile, starting from oxazine 6 as a chiral
building block, 1 was afforded in 6 steps and 46.0% overall yield
and 2 was afforded in 6 steps and 47.6% overall yield. Using similar
protocols, our syntheses of castanospermine and australine are
currently in progress.
The synthesis of 6 began with readily available protected D-ser-
ine or (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)
oxy)propanoate 7 and proceeded in 56.8% yield over five steps.1b,d
After many unsuccessful attempts, a reaction was carried out with
the oxazine-derived aldehyde and divinylzinc to afford syn-alcohol
5 as a single diastereomer by chelation control in 85% yield over
two steps.10 No trace of the minor isomer could be detected in a
number of repeated experiments without using any external chiral
ligand or catalyst (Scheme 2). anti-Alcohol 50 was prepared
from the aldehyde and vinylmagnesium bromide (Scheme 3).
Fortunately, diastereomers 5 and 50 were chromatographically sep-
arable and the ratios were determined by 1H NMR peak intensities
of crude reaction mixtures.
4. Experimental
4.1. General
Diol 8 was generated in 85% yield by treating 5 with ozone and
sodium borohydride. Subsequent primary mesylation and catalytic
hydrogenation provided protected 9 in 75% yield. The removal of
Flash chromatography was carried out using a Merck Kiesegel
60 (230–400 mesh) stationary phase and mixtures of ethyl acetate
and hexanes as the eluents. Ethyl acetate and hexanes were dried
TBS
OTBS
O
OH
1. O3, MeOH, –78 °C;
O
DMS
Ref. 9b,d
TBSO
TBSO
TBSO
OCH3
N
O
N
O
2. divinylzinc, THF
–78 °C to rt
56.8% (5 steps)
NHBz
Ph
Ph
7
85% (2 steps)
5
6
Scheme 2. Synthesis of 5.
TBS
N
TBS
O
OH
O
OH
OTBS
1. O3, MeOH, –78 °C;
DMS
TBSO
TBSO
TBSO
+
O
N
O
N
O
2. vinyl–MgBr, THF, rt
78% (2 steps)
syn/anti = 1.3:1
Ph
Ph
Ph
5
5'
6
Scheme 3. Synthesis of minor isomer 50.

S.-H. Park et al. / Tetrahedron: Asymmetry 26 (2015) 657–661
659
TBS
TBS
N
O
OH
O
OH
OH
1. MsCl (1.1 equiv.)
TEA, CH2Cl2, 0 °C
OH
HO
OTBS
OTBS
1 M HCl, MeOH
O3, MeOH, –78 °C
TBSO
TBSO
1
O
N
O
then NaBH4
85%
2. Pd(OH)2/C, H2
MeOH, rt
rt
N
H
85%
Ph
Ph
75% (2 steps)
9
5
8
TBS
N
TBS
N
O
OMs
O
OH
HO
OTBS
OTBS
1. O3, MeOH, –78 °C
1 M HCl, MeOH
TBSO
MsCl, TEA
CH2Cl2, 0 °C
91%
TBSO
then NaBH4
HO
2
O
O
N
2. Pd(OH)2/C, H2
MeOH, rt
rt
H
88%
Ph
Ph
10
70% (2 steps)
4
5
Scheme 4. Syntheses of 1 and 2.
and purified by distillation prior to use. Tetrahydrofuran and
diethyl ether were distilled over sodium and benzophenone (indi-
cator). Dichloromethane was distilled with calcium hydride.
Commercially available compounds were used without further
purification. 1H and 13C NMR spectra were obtained at the Center
for Cooperative Research Facility at Sungkyunkwan University on
FT-NMR 500 and 700 MHz spectrometers. Chemical shifts are
reported as d values in ppm relative to the CHCl3 residual peak
(7.26 ppm in CDCl3). IR spectra were measured on a Bruker FT-IR
spectrometer. Optical rotation was measured on a JASCO DIP
1020 digital polarimeter. Mass spectra data were measured at
the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high
resolution mass spectrometer.
133.9, 135.7, 155.7; HRMS (FAB) m/z: [M+H]+ calcd for
C26H46O4NSi2 492.2965, found 492.2968.
4.2.2. (R)-1-((4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-4-
(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-
4H-1,3-oxazin-6-yl)prop-2-en-1-ol 50
Yield 85%; ratio syn/anti = >20:1; white solid; mp 106–110 °C;
Rf = 0.53 (1:6 ethyl acetate/hexanes); [
IR (neat) 699, 778, 836, 937, 1033, 1118, 1256, 1280, 1651, 2934,
2951, 3358 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.03 (s, 3H), 0.07
a]
25 = +21.6 (c 0.6, CHCl3);
D
;
(s, 3H), 0.16 (s, 3H), 0.17 (s, 3H), 0.87 (s, 9H), 0.89 (s, 9H), 2.74
(d, J = 5.0 Hz, 1H), 3.58 (dd, J = 10.5, 7.0 Hz, 1H), 3.67–3.70 (m,
1H), 3.96 (dd, J = 10.5, 3.5 Hz, 1H), 4.05 (dd, J = 8.0, 2.5 Hz, 1H),
4.47 (t, J = 2.5 Hz, 1H), 4.51–4.56 (m, 1H), 5.33 (dt, J = 12.0,
1.5 Hz, 1H), 5.45 (dt, J = 19.0, 1.5 Hz, 1H), 6.06–6.13 (m, 1H),
7.23–7.43 (m, 3H), 7.90–7.92 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d ꢀ5.2, ꢀ4.3, 18.2, 18.4, 26.0, 60.8, 64.6, 71.6, 75.4, 117.1, 127.6,
128.2, 130.7, 133.7, 137.8, 155.4; HRMS (FAB) m/z: [M+H]+ calcd
for C26H46O4NSi2 492.2965, found 492.2963.
4.2. Experimental procedures
4.2.1. (S)-1-((4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-4-
(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-
4H-1,3-oxazin-6-yl)prop-2-en-1-ol 5
Oxazine 6 (50 mg, 0.108 mmol) was dissolved in dry methanol
(2.16 mL) and cooled to ꢀ78 °C. Ozone was then passed through
the solution until the reaction was complete. The reaction mixture
was quenched with methyl sulfide (0.08 mL) and allowed to warm
to rt. The solvent was evaporated off under reduced pressure, and
the crude aldehyde was immediately used in the next step without
further purification. Vinylmagnesium bromide (1.0 M solution in
diethyl ether, 0.64 mL, 0.648 mmol) was added to a solution of zinc
chloride (1.0 M solution in diethyl ether, 0.32 mL, 0.324 mmol) in
THF (0.76 mL) at rt and stirred for 0.5 h. A solution of the aldehyde
in THF (0.32 mL) was added to this white suspension at ꢀ78 °C and
allowed to warm to rt. After 3 h, the reaction was quenched with
saturated NH4Cl. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined organic layer
was washed with saturated NaHCO3 and brine, dried over MgSO4,
and filtered. The filtrate was concentrated in vacuo. Purification
4.2.3. (S)-1-((4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-4-
(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-
4H-1,3-oxazin-6-yl)ethane-1,2-diol 8
Alkene 5 (220 mg, 0.447 mmol) was dissolved in dry methanol
(15.0 mL) and cooled to ꢀ78 °C. Ozone was then passed through
the solution until the reaction was complete. Next, NaBH4
(25 mg, 0.677 mmol) was added to the reaction mixture, which
was then warmed to rt. The reaction mixture was washed with sat-
urated NH4Cl, saturated NaHCO3, and brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo. Purification using
silica gel column chromatography gave diol
0.380 mmol); Yield 85%; colorless liquid; Rf = 0.52 (1:2 ethyl
acetate/hexanes); [
25 = +21.5 (c 1.0, CHCl3); IR (neat) 672, 778,
836, 1091, 1114, 1257, 1452, 1652, 2045, 2525, 2832, 2945,
3354 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.03 (s, 3H), 0.07 (s, 3H),
8
(188 mg,
a]
D
;
using silica gel column chromatography gave
0.091 mmol); Yield 85%; Ratio syn/anti = >20:1; white solid; mp
115–132 °C; Rf = 0.50 (1:6 ethyl acetate/hexanes); [
25 = +40.1 (c
1.0, CHCl3); IR (neat) 698, 777, 836, 937, 1110, 1161, 1256, 1279,
1638, 2855, 2928, 2955, 3387 cmꢀ1 1H NMR (CDCl3, 500 MHz) d
0.02–0.03 (m, 3H), 0.06–0.07 (m, 3H), 0.12–0.15 (m, 6H), 0.86–
0.88 (m, 18H), 3.04 (d, J = 2.0 Hz, 1H), 3.45 (dd, J = 10.5, 8.0 Hz,
1H), 3.71 (ddd, J = 7.0, 3.5, 1.0 Hz, 1H), 3.97 (dd, J = 10.5, 3.5 Hz,
1H), 4.05 (dd, J = 6.0, 1.0 Hz, 1H), 4.30 (t, J = 2.0 Hz, 1H), 4.55–
4.57 (m, 1H), 5.35 (dt, J = 9.0, 1.5 Hz, 1H), 5.52 (dt, J = 11.0,
1.5 Hz, 1H), 5.97–6.02 (m, 1H), 7.36–7.45 (m, 3H), 7.91–7.93 (m,
2H); 13C NMR (CDCl3, 125 MHz) d ꢀ5.3, ꢀ5.2, ꢀ4.3, ꢀ3.9, 18.2,
18.4, 26.0, 61.3, 65.0, 65.7, 72.8, 76.4, 118.2, 127.5, 128.3, 130.7,
5
(44.6 mg,
0.15 (s, 6H), 0.87 (s, 9H), 0.88 (s, 9H), 3.27 (s, 1H), 3.51 (dd,
J = 10.5, 7.5 Hz, 1H), 3.69 (ddd, J = 5.5, 3.5, 2.0 Hz, 1H), 3.84 (d,
J = 5.0 Hz, 1H), 3.96 (dd, J = 10.5, 3.5 Hz, 1H), 4.12 (q, J = 5.0 Hz,
1H), 4.27 (dd, J = 2.0, 4.5 Hz, 1H), 4.32 (t, J = 2.0 Hz, 1H), 7.36–
7.45 (m, 3H), 7.90–7.92 (m, 2H); 13C NMR (CDCl3, 125 MHz) d
ꢀ5.3, ꢀ5.2, ꢀ4.5, ꢀ4.0, 18.2, 18.4, 25.9, 26.1, 61.1, 63.3, 64.9,
66.6, 72.5, 73.2, 127.5, 128.3, 130.8, 133.8, 155.6; HRMS (FAB)
m/z: [M+H]+ calcd for C25H46O5NSi2 496.2915, found 496.2912.
a
]
D
;
4.2.4. (3S,4R,5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-(((tert-
butyldimethylsilyl)oxy)methyl)piperidine-3,4-diol 9
Triethylamine (22
lL, 0.161 mmol) and MsCl (14 lL,
0.177 mmol) were successively added to a solution of diol 8

660
S.-H. Park et al. / Tetrahedron: Asymmetry 26 (2015) 657–661
(80 mg, 0.161 mmol) in dichloromethane (3.2 mL) at 0 °C. The
reaction mixture was stirred at 0 °C for 1 h, and then distilled
water was added. The organic layer was separated and the aqueous
layer was extracted with dichloromethane. The combined organic
layer was washed with saturated NH4Cl, saturated NaHCO3, and
brine, dried over MgSO4, and filtered. The filtrate was concentrated
in vacuo. Purification using silica gel column chromatography gave
primary mesylate 3 (81 mg, 0.141 mmol) as a white solid. A solu-
tion of 3 in MeOH (1.28 mL) was hydrogenated overnight in the
presence of 20% Pd(OH)2/C (0.1 g) at rt. The catalyst was removed
by filtration through Celite and the filtrate was concentrated in
vacuo. Purification using silica gel column chromatography gave
protected 9 (47.4 mg, 0.121 mmol); Yield 75% for two steps; color-
75.0, 82.3, 123.0, 127.6, 128.4, 130.6, 130.9, 133.8, 155.7; HRMS
(FAB) m/z: [M+H]+ calcd for C27H48O6NSi2S 570.2741, found
570.2742.
4.2.7. (2R,3R,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-
butyldimethylsilyl)oxy)methyl)-2-(hydroxymethyl)pyrrolidin-
3-ol 10
Mesylate 4 (108 mg, 0.190 mmol) was dissolved in dry metha-
nol (3.8 mL) and cooled to ꢀ78 °C. Ozone was then passed through
the solution until the reaction was complete. Next, NaBH4 (11 mg,
0.284 mmol) was added to the reaction mixture, which was then
warmed to rt. The reaction mixture was washed with saturated
NH4Cl, saturated NaHCO3, and brine, dried over MgSO4, and fil-
tered. The filtrate was concentrated in vacuo. Purification using sil-
ica gel column chromatography gave an alcohol (90 mg,
0.157 mmol) as a white solid. A solution of the alcohol in MeOH
(1.57 mL) was hydrogenated overnight in the presence of 20%
Pd(OH)2/C (0.1 g) at rt. The catalyst was removed by filtration
through Celite, and the filtrate was concentrated in vacuo.
Purification using silica gel column chromatography gave pro-
tected 10 (52 mg, 0.133 mmol); Yield 70% for two steps; colorless
less liquid; Rf = 0.28 (1:9 methanol/chloroform); [
0.1, CHCl3); IR (neat) 674, 779, 837, 1033, 1054, 1108, 1255,
1363, 1469, 1738, 2858, 2930, 2954, 3365 cmꢀ1 1H NMR (CDCl3,
a]
25 = +55.5 (c
D
;
500 MHz) d 0.06 (s, 3H), 0.07 (s, 3H), 0.10 (s, 3H), 0.14 (s, 3H),
0.9 (s, 18H), 2.54 (m, 2H), 3.22 (dd, J = 12.0, 5.0 Hz, 1H), 3.31 (m,
2H), 3.51 (m, 1H), 3.58 (dd, J = 9.5, 6.5 Hz, 1H), 3.85 (dd, J = 9.5,
3.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d ꢀ5.2, ꢀ5.1, ꢀ4.4, ꢀ3.6,
18.5, 26.2, 49.7, 62.2, 63.8, 72.2, 73.7, 80.7; HRMS (FAB) m/z:
[M+H]+ calcd for C18H42O4NSi2 392.2652, found 392.2649.
liquid; Rf = 0.19 (1:9 methanol/chloroform); [
a]
25 = +11.6 (c 0.5,
D
CHCl3); IR (neat) 654, 1029, 1454, 1652, 2833, 2945, 3355 cmꢀ1
;
4.2.5. (2R,3R,4R,5S)-2-(Hydroxymethyl)piperidine-3,4,5-triol
[(+)-1-deoxynojirimycin] 1
1H NMR (CDCl3, 500 MHz) d 0.09 (s, 3H), 0.10 (s, 6H), 0.11 (s,
3H), 0.89 (s, 9H), 0.92 (s, 9H), 3.07 (dt, J = 4.5, 3.0 Hz, 1H), 3.23
(dt, J = 6.0, 4.5 Hz, 1H), 3.56 (dd, J = 11.0, 5.0 Hz, 1H), 3.63 (dd,
J = 11.0, 6.5 Hz, 1H), 3.71 (d, J = 3.0 Hz, 2H), 3.83 (t, J = 4.0 Hz,
1H), 3.97 (t, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d ꢀ5.3,
ꢀ4.6, ꢀ4.2, 18.1, 15.6, 25.9, 26.1, 62.8, 62.9, 66.3, 66.4, 80.4, 80.6;
HRMS (FAB) m/z: [M+H]+ calcd for C18H42O4NSi2 392.2652, found
392.2653.
A solution of protected 9 (37 mg, 0.095 mmol) in 1 M HCl
(0.5 mL) was stirred at rt for 12 h. The reaction mixture was evap-
orated to dryness to give 1ꢁHCl; 1H NMR (D2O, 500 MHz) d 2.91 (t,
J = 12.0 Hz, 1H), 3.10 (m, 1H), 3.45 (m, 2H), 3.54 (t, J = 10.0 Hz, 1H),
3.72 (m, 1H), 3.81 (dd, J = 12.5, 5.0 Hz, 1H), 3.88 (dd, J = 13.0,
3.0 Hz, 1H); 13C NMR (D2O, 125 MHz) d 46.0, 57.8, 60.1, 67.1,
67.9, 76.3. Further purification by treatment of the salt with ion-
exchange resin (DOWEX 50 W ꢂ 8) afforded
0.080 mmol); Yield 85%; white solid; mp 195–197 °C; Rf = 0.23
(1:1 methanol/chloroform); [
25 = +40.8 (c 0.8, H2O); IR (neat)
658, 1033, 1452, 1666, 2833, 2946, 3361 cmꢀ1
500 MHz) d 2.79 (s, 1H), 2.96 (d, J = 13.7 Hz, 1H), 3.17 (dd,
J = 15.4, 0.9 Hz, 1H), 3.57 (dd, J = 9.6, 3.3 Hz, 1H), 3.75 (dd,
J = 12.2, 5.9 Hz, 1H), 3.84 (d, J = 11.8 Hz, 1H), 4.08 (s, 1H); 13C
NMR (D2O, 175 MHz) d 47.9, 60.3, 60.4, 69.8, 70.5, 77.8; HRMS
(FAB) m/z: [M+H]+ calcd for C6H14NO4 164.0923, found 164.0921.
1
(13 mg,
4.2.8. (2R,3R,4R,5R)-2,5-Bis(hydroxymethyl)pyrrolidine-3,4-diol
[(+)-DMDP] 2
a
]
D
A solution of protected 10 (30 mg, 0.077 mmol) in 1 M HCl
(0.4 mL) was stirred at rt for 12 h. The reaction mixture was evap-
orated to dryness to give 2ꢁHCl; 1H NMR (D2O, 500 MHz) d 3.51 (m,
2H), 3.80 (dd, J = 12.5, 6.0 Hz, 2H), 3.87 (dd, J = 13.0, 3.5 Hz, 2H),
4.02 (dt, J = 8.0, 4.5 Hz, 2H); 13C NMR (D2O, 125 MHz) d 61.4,
62.0, 77.3. Further purification by treatment of the salt with ion-
;
1H NMR (D2O,
exchange resin (DOWEX 50 W ꢂ 8) afforded
0.067 mmol); Yield 88%; colorless oil; Rf = 0.1 (1:1 methanol/chlo-
roform); [
25 = +55.2 (c 0.9, H2O); IR (neat) 658, 1032, 1114, 1453,
1650, 2833, 2946, 3382 cmꢀ1
2
(11 mg,
4.2.6. (S)-1-((4R,5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-4-
(((tert-butyldimethylsilyl)oxy)methyl)-2-phenyl-5,6-dihydro-
4H-1,3-oxazin-6-yl)allyl methanesulfonate 4
a]
D
;
1H NMR (D2O, 500 MHz) d 3.02 (m,
2H), 3.58 (dd, J = 11.5, 6.5 Hz, 2H), 3.66 (dd, J = 12.0, 4.0 Hz, 2H),
3.79 (dd, J = 5.5, 1.5 Hz, 2H); 13C NMR (D2O, 125 MHz) d 61.8,
61.9, 77.7; HRMS (FAB) m/z: [M+H]+ calcd for C6H14O4N
164.0923, found 164.0922.
Triethylamine (27 lL, 0.345 mmol) and MsCl (35 lL,
0.253 mmol) were successively added to a solution of allylic alco-
hol 5 (110 mg, 0.223 mmol) in dichloromethane (4.6 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 1 h, and then distilled
water was added. The organic layer was separated and the aqueous
layer was extracted with dichloromethane. The combined organic
layer was washed with saturated NH4Cl, saturated NaHCO3, and
brine, dried over MgSO4, and filtered. The filtrate was concentrated
in vacuo. Purification using silica gel column chromatography gave
secondary mesylate 4 (116 mg, 0.204 mmol); Yield 91%; colorless
Acknowledgements
This research was supported by the Basic Science Research
Program of the National Research Foundation of Korea (NRF),
which is funded by the Ministry of Education, Science and
Technology (2010-0022900, 2011-0029199) and by the Yonsung
Fine Chemicals Corporation. S.H.P. also gratefully acknowledges
the Global Ph.D. Fellowship Grant.
liquid; Rf = 0.5 (1:6 ethyl acetate/hexanes); [
CHCl3); IR (neat) 698, 837, 1032, 1114, 1454, 1651, 2832, 2948,
3382, 3733 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.02 (s, 3H), 0.06
a]
25 = +11.2 (c 0.47,
D
;
(s, 3H), 0.09 (s, 3H), 0.12 (s, 3H), 0.87 (s, 9H), 0.87 (s, 9H), 3.05 (s,
3H), 3.46 (dd, J = 10.5, 8.0 Hz, 1H), 3.74 (ddd, J = 7.0, 4.0, 1.0 Hz,
1H), 3.97 (dd, J = 10.5, 4.0 Hz, 1H), 4.21 (t, J = 2.0 Hz, 1H), 4.25 (d,
J = 9.0 Hz, 1H), 5.41 (t, J = 8.0 Hz, 1H), 5.56 (d, J = 10.5 Hz, 1H),
5.69 (d, J = 17.0 Hz, 1H), 5.92–5.99 (m, 1H), 7.36–7.39 (m, 2H),
7.41–7.45 (m, 1H), 7.90–7.91 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d ꢀ5.3, ꢀ5.2, ꢀ4.1, ꢀ3.6, 18.3, 18.4, 26.0, 39.3, 60.8, 63.8, 64.7,
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