Asymmetric synthesis of 1-deoxyazasugars from chiral aziridines

Article abstract of DOI:10.1039/c0ob00730g

A general and facile synthesis of enantiopure 1-deoxyazasugars was achieved from stereoselective dihydroxylation of a common synthetic intermediate, piperidine ring fused oxazolidin-2-one, originating from a commercially available starting substrate, chiral aziridine-2-carboxylate, in high yields. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c0ob00730g

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PAPER
Asymmetric synthesis of 1-deoxyazasugars from chiral aziridines†
Alok Singh,a Bongchan Kim,b Won Koo Lee*b and Hyun-Joon Ha*a
Received 16th September 2010, Accepted 3rd November 2010
DOI: 10.1039/c0ob00730g
A general and facile synthesis of enantiopure 1-deoxyazasugars was achieved from stereoselective
dihydroxylation of a common synthetic intermediate, piperidine ring fused oxazolidin-2-one, originating
from a commercially available starting substrate, chiral aziridine-2-carboxylate, in high yields.
Introduction
Azasugars as structural analogs of true sugars whose ring
oxygen atom is replaced by nitrogen attract great attention due
to their occurrence in nature and their interesting biological
activities. Many polyhydroxylated piperidine alkaloids have been
revealed from diverse natural sources including many different
microorganisms and plants.1 Among them nojirimycin, the closest
analog of pyranose from a structural point of view, was isolated
in 1966.2 However, the hydroxyl group at C-1 causes some
difficulties in isolation and handling. Its deoxy-analogs without
a hydroxyl group at C-1, called deoxynojirimycins, were isolated
and characterized from natural sources.3 On the basis of their
structural similarity to sugar many azasugars have biological
activities in carbohydrate-related metabolic pathways including
glycosidase and glycotransferase and have possible therapeutic
Fig. 1 Some stereoisomers of deoxynojirimycins.
applications as antidiabetic, anticancer and antibacterial agents.4
Many of them are derivatives of deoxynojirimycins with diverse
stereochemistry of the hydroxyl groups along the carbons of the
manner all six D-deoxyazasugars were also synthesized from
(2R)-aziridine-2-carboxylate.
piperidine ring, with representative examples such as miglitol,5
miglustat6 and OGT.7 Though there is a rich literature dealing
For the last several years we have shown that the enantiopure
with asymmetric synthesis of deoxynojirimycins,8,9 an easy and
aziridine-2-carboxylate serves as a starting substrate for the
facile access to their synthesis is still needed, with full control of
asymmetric synthesis of many nitrogen-containing cyclic and
all hydroxy configurations.
In this report, we describe the synthesis of six different stereoiso-
mers of deoxynojirimycins including L-1-deoxyidonojirimycin
(L-Ido-DNJ, 1a), L-1-deoxygalactonojirimycin (L-Galacto-
DNJ, 1b), L-1-deoxygulonojirimycin (L-Gulo-DNJ, 1c), L-
1-deoxynojirimycin (L-DJN, 1d), L-1-deoxyaltronojirimycin
(L-Altro-DNJ, 1e) and L-1-deoxymannojirimycin (L-Manno-
DNJ, 1f) from (2S)-aziridine-2-carboxylate (Fig. 1). In the same
acyclic compounds based on the functional group-transformation
of the carboxylate group and aziridine ring opening in a regio- and
stereoselective manner.10 Based on the same synthetic strategy, we
prepared all six isomers of DNJ starting from the enantiopure
aziridine-2-carboxylate.
The synthetic plan for deoxynojirimycins (1) with complete
control of four stereocenters in the piperidine ring was based
on the stereoselective dihydroxylation of the common synthetic
intermediate 13. Its piperidine ring was formed by ring-closing
metathesis (RCM) between the alkenyl pendent at C-4 and the N-
allyl group present at the ring nitrogen of 3,4-dialkenyl oxazolidin-
2-one (12). The stereochemistry of the hydroxymethyl group at C-2
of the piperidine ring can be pre-determined by the selection of the
starting aziridine-2-carboxylate (2) with the star mark in Scheme
1. Thereby, all six isomers (1a–1f) starting from the same chiral
aziridine-2-carboxylate had the same stereochemistry at C-2 of
the piperidine ring. These isomers (1a–1f) were classified into two
different groups, 1a–1c and 1d–1f, by the stereochemistry at the
aDepartment of Chemistry and Protein Research Centre for Bio-
Industry, Hankuk University of Foreign Studies, Yongin, 449-719, Korea.
E-mail: hjha@hufs.ac.kr; Fax: +82-31-3304566; Tel: +82-31-3304369
bDepartment of Chemistry, Sogang University, Seoul 121-742, Korea.
E-mail: wonkoo@sogang.ac.kr; Fax: +82-2-7010967; Tel: +82-2-7058449
† Electronic supplementary information (ESI) available: Electronic supple-
mentary information (ESI) available: Spectral data for D-deoxyazasugars
and actual 1H and 13C-NMR spectra for all compounds. See DOI:
10.1039/c0ob00730g
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introduce two more hydroxyl groups at the olefin in the piperidine
ring. For the preparation of anti- andsyn diols at C-4 and C-5 of the
piperidine ring two different methods were applied i.e. epoxidation
followed by regioselective hydrolytic epoxide ring opening and the
direct dihydroxylation reaction, respectively. Epoxidation of 13a
R
with oxoneꢀ14 in acetone provided 14a in 71% yield which was
reacted further with acetone in the presence of BF3·Et2O as Lewis
acid to yield diol bound as acetal at C-4 and C-5 of the piperidine
ring (15a). Hydrolytic cleavage of the oxazolidin-2-one ring was
accomplished by LiOH in EtOH with concomitant cleavage of
the TBS protecting group to provide the corresponding amino
alcohol. Finally the acetonide was cleaved with HCl in methanol
followed by treatment with an ion-exchange resin (Amberlite IRA-
410 OH- form) afforded pure L-Ido-DNJ (1a)15 in 96% yield
over two steps. The epoxidation reaction of 16b with MCPBA
after removal of the TBS group from 13a afforded epoxyalcohol
17b, from which L-Galacto-DNJ (1b) was obtained by following
the known procedure.16 Direct dihydroxylation17 of the synthetic
intermediate 13a with OsO4 yielded 18c in quantitative yield with
the right configurations of all hydroxyl groups at C-2 to C-5 for L-
Gulo-DNJ (1c). The same hydrolytic reaction with LiOH in EtOH
yielded L-Gulo-DNJ (1c) in 95% yield (Scheme 3).
Scheme 1 Retrosynthetic analysis of DNJs starting from the enantiopure
aziridine-2-carboxylate bearing the chirality denoted as star mark.
C-3 hydroxy group, with the red color showing its origination from
the hydroxyl group of compound 6. The absolute configuration of
C-3 is controlled by the stereoselective reduction of the carbonyl
functional group at 2-acylaziridine, the alkylated product of
aziridine-2-carboxylate (2), in either an erythro or threo selective
way. In this manner we were able to elaborate all six L-DNJ isomers
starting from (2S)-aziridine-2-carboxylate as shown in Scheme 1.
The same sequential reactions used to introduce the two
hydroxyl groups to 1a, 1b and 1c were applied to the similar olefinic
piperidine intermediate 13b to prepare another set of DNJ isomers
including L-DNJ (1d), L-Altro-DNJ (1e) and L-Manno-DNJ (1f).
Results and discussion
The aziridine-2-yl propynyl ketone (4) was prepared from alkyny-
lation of the corresponding Weinreb amide prepared from ethyl
(2S)-aziridine-2-carboxylate in 95% yield over two steps.11 This
ketone was selectively reduced by non-chelating bulky reducing
R
Direct epoxidation reaction of 13b with Oxoneꢀ and epoxida-
tion with MCPBA after removal of the TBS protecting group
as 16e yielded 14d and 17e in 68% and 77% yields, respectively.
Cleavage of epoxides from 14d and 17e to diols followed by hy-
drolytic removal of oxazoldin-2-one ring and global deprotection
yielded L-DNJ (1d) and L-Altro-DNJ (1e) respectively. The direct
dihydroxylation of 13b yielded 18f which was converted to L-
Manno-DNJ (1f) as in the previous case for 1c in high yield
(Scheme 4).
R
agent L-Selectrideꢀ to provide threo alcohol (5a) exclusively. The
reduction of the same ketone by NaBH4 with ZnCl2 yielded
chelation-controlled product erythro (5b) isomer selectively.11a
Each of the alkynyl alcohols was converted to olefin 6a and 6b by
reduction with LiAlH4 in 94 and 93% yield respectively (Scheme
2).
The hydroxy groups were protected by TBS to 7a and 7b,
which survived throughout the following reactions. The aziridine
rings of 7a and 7b were opened by an oxygen nucleophile,
acetate, to yield 8a and 8b. The acetyl groups in 8a and 8b were
hydrolyzed by KOH in EtOH to give 1,2-hydroxyamines (9a and
9b) in quantitative yield. These were cyclized12 to oxazolidin-
2-ones, 10a and 10b with CDI and DBU in CH2Cl2. The a-
methylbenzyl groups in 10a and 10b were removed by Na in
liquid NH3 at -78 ◦C to afford 11a and 11b in 94 and 93%
yields respectively. Allylation of the ring nitrogen proceeded with
allyl iodide in the presence of NaH as a base to afford 12a
and 12b which were ready for RCM. The piperidine ring fused
oxazolidin-2-ones were formed from 12a and 12b in the presence
of 10 mol% of 1st generation of Grubbs’ catalyst, benzylidene-
bis(tricyclohexylphosphine)dichlororuthenium, to yield 13a and
13b in quantitative yield respectively.13 These bicycles (13a and
13b) were common intermediates for the preparation of DNJs
by introducing two hydroxyl groups to the olefin at C-4 and C-
5 of the piperidine ring in a stereoselective manner. All of the
reactions mentioned above for the formation of 13a and 13b from
chiral aziridine-2-carboxylates proceeded in more than 93% yield
(Scheme 2).
Conclusions
We would like to draw the conclusion that the general and facile
synthesis of enantiopure deoxynojirimycins was achieved from
stereoselective dihydroxylation of a common synthetic intermedi-
ate, piperidine ring fused oxazolidin-2-one 13, originating from
a commercially available starting substrate, chiral aziridine-2-
carboxylate, with full control of all the configurations and in high
yields. On the basis of this synthetic strategy we have synthesized
all six D-enantiomers of 1-deoxynojirimycin starting from (2R)-
aziridine-2-carboxylate instead of (2S)-aziridine-2-carboxylate
which is described fully in the ESI† of this paper.
Experimental
General
All non-aqueous reactions were run in flame-dried glassware
under a positive pressure of nitrogen with exclusion of mois-
ture from reagents and glassware using standard techniques
for manipulating air-sensitive compounds. Anhydrous solvents
were obtained using standard drying techniques. Unless stated
otherwise, commercial grade reagents were used without further
The synthetic intermediate 13a bearing two stereocenters
originating from the chirality of aziridine-2-carboxylate and the
stereoselective reduction of a ketone was utilized as a substrate to
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Scheme 2 Reagents and conditions: (i) isopropylmagnesium chloride, N,O-dimethyl hydroxyl-amine hydrochloride, THF, 0 ◦C, 1 h; (ii) 1-propynyl-
◦
magnesium bromide, THF, -78 C, 1 h, then at rt, 1 h; (iii) L-SelectrideꢀR , THF, -78 ◦C, 0.5 h; (iv) LiAlH4, THF, reflux, 8 h; (v) ZnCl2, MeOH,
-78 ◦C, 0.5 h then NaBH4, -78 ◦C, 1 h; (vi) TBSCl, DMAP, TEA, CH2Cl2, 17 h; (vii) AcOH, CH2Cl2, 15 h; viii) KOH, EtOH, 30 min; (ix) CDI,
DBU, CH2Cl2, 0 ◦C then at rt, 24 h; (x) Na, liq. NH3, THF, -78 ◦C, 30 min; (xi) allyl iodide, NaH, 1,2-dichlorethane, 0 ◦C then reflux, 10 h; (xii)
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (1st generation of Grubbs’ catalyst), CH2Cl2, 24 h.
purification. Both (2R)- and (2S)-1-[(R)-a-methylbenzyl]-2-
aziridinecarboxylate ethyl esters were purchased from Imagene
Co. Ltd. Their methyl esters were also purchased from Aldrich.
Reactions were monitored by analytical thin-layer chromatogra-
phy (TLC) performed on pre-coated, glass-backed silica gel plates.
Visualization of the developed chromatogram was performed
by UV absorbance, ninhydrin, phosphomolybdic acid or iodine.
Flash chromatography was performed on 230–400 mesh silica
gel with the indicated solvent systems. Melting points are uncor-
rected. Routine nuclear magnetic resonance spectra were recorded
either on Varian Gemini 200 (200 MHz) or Varian Gemini 400
(400 MHz) spectrometers. Chemical shifts for H NMR spectra
are recorded in parts per million from tetramethylsilane with
1
the solvent resonance as the internal standard (CDCl3, d 7.27
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elemental analyzer. High resolution mass spectra were recorded on
a 4.7 Tesla IonSpec ESI-FTMS or a Micromass Q-TOF Ultima
Global Mass Spectrometer
(S)-N-methoxy-N-methyl
1-[(R)-1-phenylethyl]aziridine-2-
carboxamide (3). To a stirred solution of 2 (2.46 g, 11.20 mmol)
in anhydrous THF (33 mL) at 0 ◦C, under an inert atmosphere
of N2, were added N,O-dimethyl hydroxyl-amine hydrochloride
(1.64 g, 16.8 mmol) and isopropylmagnesium chloride (2 M in
THF, 16.80 mL, 33.6 mmol). After stirring at 0 ◦C for 1 h and
warming to room temperature the mixture was quenched with
aqueous NH4Cl (10 mL). The reaction mixture was extracted
with ethyl acetate (3 ¥ 50 mL) and the combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (n-hexane–EtOAc = 50 : 50,
v/v) to give 3 (2.61 g, 99% yield) as yellow oil: [a]2D0 = +20.48
(c = 0.649, CHCl3); 1H NMR (200 MHz; CDCl3) d 7.45–7.18 (m,
5H), 3.14 (s, 3H), 3.12 (s, 3H), 2.57 (d, J = 6.4 Hz, 1H), 2.56 (q,
J = 6.4 Hz, 1H), 2.42 (dd, J = 3.1, 1.2 Hz, 1H), 1.76 (dd, J = 6.4,
1.3 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz; CDCl3)
d 23.78, 32.36, 34.10, 35.05, 61.02, 70.53, 126.81, 127.11, 128.53,
144.28, 169.92; HRMS (ESI) calculated for [C13H18N2O2+Na]+:
257.1266, Found 257.1268.
Scheme 3 Reagents and Conditions: (i) OxoneꢀR , NaHCO3, acetone, water,
30 min; (ii) BF3·Et2O, acetone, CH2Cl2, 0 ◦C, 2 h; (iii) LiOH, 30% aq.
EtOH, reflux, 4 h; (iv) HCl, MeOH, reflux, 4 h; (v) TBAF, THF, 0 ◦C, 1 h;
(vi) MCPBA, NaH2PO4, CH2Cl2, 0 ◦C then rt, 3 days; (vii) OsO4, NMO,
CH3CN, H2O, 0 ◦C then rt, 3 h.
1-{(S)-1-[(R)-1-phenylethyl]aziridin-2-yl}but-2-yn-1-one
(4).
To a stirred solution of 3 (1.77 g, 7.55 mmol) in anhydrous THF
(7.5 mL) at -78 ◦C, under an inert atmosphere of N2, was added
1-propynyl magnesium bromide (0.5 M in THF, 22.7 mL, 11.38
◦
mmol). The reaction mixture was then stirred for 1 h at -78 C
and warmed to room temperature and stirred for an additional
1 h before being quenched with water. The reaction mixture was
extracted with ethyl acetate (3 ¥ 25 mL) and combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (n-hexane–EtOAc =
70 : 30, v/v) to give 4 (1.53 g, 95% yield) as yellow oil: [a]D20
=
-148.11 (c = 1.078, CHCl3); 1H NMR (200 MHz; CDCl3) d
7.39–7.17 (m, 5H), 2.62 (q, J = 6.6 Hz, 1H), 2.43 (dd, J = 3.0,
1.2 Hz, 1H), 2.25 (dd, J = 6.5, 3.0 Hz, 1H), 1.99 (s, 3H), 1.86
(dd, J = 6.5, 1.3 Hz, 1H), 1.45 (d, J = 6.6 Hz, 3H); 13C NMR (50
MHz; CDCl3) d 4.24, 23.63, 36.15, 45.31, 69.48, 78.54, 92.16,
126.36, 127.08, 128.63, 143.66, 185.65; HRMS (ESI) calculated
for [C14H15NO+Na]+: 236.1052, Found 236.1051.
Scheme 4 Reagents and Conditions: (i) OxoneꢀR , NaHCO3, acetone, water,
30 min; (ii) BF3·Et2O, acetone, CH2Cl2, 0 ◦C, 2 h; (iii) LiOH, 30% aq.
EtOH, reflux, 4 h; (iv) HCl, MeOH, reflux, 4 h; (v) TBAF, THF, 0 ◦C, 1 h;
(vi) MCPBA, NaH2PO4, CH2Cl2, 0 ◦C then rt, 3 days; (vii) OsO4, NMO,
CH3CN, H2O, 0 ◦C then rt, 3 h.
(S)-1-{(S)-1-[(R)-1-phenylethyl]aziridin-2-yl}but-2-yn-1-ol (5a).
To a stirred solution of 4 (1.53 g, 7.18 mmol) in anhydrous THF
(20.0 mL) at -78 ◦C, under an inert atmosphere of N2, was added
L-Selectride (1 M in THF, 10.8 mL, 10.8 mmol). The reaction
mixture was then stirred for 30 min at -78 ◦C. After the solution
was warmed to room temperature, 10.0 mL of aqueous 10%
aqueous NaOH solution was added. The reaction mixture was
extracted with ethyl acetate (3 ¥ 25 mL) and the combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (n-hexane–EtOAc =
70 : 30, v/v) to give 5a (1.54 g, 99% yield) as brown solid: mp =
ppm; CD3OD d 3.31 ppm; D2O d 4.79 ppm). Data are reported
as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, qn = quintet, m = multiplet, and br =
broad), coupling constant in Hz, and integration. Chemical shifts
for 13C NMR spectra are recorded in parts per million from
tetramethylsilane using the central peak of the solvent resonance as
the internal standard (CDCl3, d 77.00 ppm; CD3OD d 49.15). All
spectra were obtained with complete proton decoupling. Optical
rotations were determined at 589 nm at 20 ◦C. Data are reported
as follows: [a]D, concentration (c in g/100 mL), and solvent.
Elemental analyses were performed using a Carlo Erba EA 1180
◦
1
95 C; [a]2D0 = +121.73 (c = 0.588, CHCl3); H NMR (200 MHz;
CDCl3) d 7.41–7.23 (m, 5H), 4.04–3.91 (m, 1H), 2.57 (q, J =
6.6 Hz, 1H), 2.43 (d, J = 6.5 Hz, 1H), 1.96 (d, J = 3.4 Hz, 1H),
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1.81 (ddd, J = 7.8, 6.4, 4.2 Hz, 1H), 1.63 (d, J = 2.1 Hz, 3H),
1.49 (d, J = 6.4 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H); 13C NMR
(50 MHz; CDCl3) d 3.57, 22.79, 31.00, 42.97, 61.93, 69.34, 78.40,
81.07, 127.15, 127.37, 128.48, 144.11; HRMS (ESI) calculated for
[C14H17NO+H]+: 216.1388, Found 216.1387.
(S)-2-[(S,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]-1-[(R)-1-ph-
enylethyl)aziridine] (7a). To a solution of t-butyldimethylsilyl
chloride (2.01 g, 13.34 mmol) in anhydrous CH2Cl2 (25.0 mL),
under an inert atmosphere of N2, was added DMAP (0.82 g,
6.66 mmol) and TEA (3.70 mL, 26.67 mmol). The mixture was
stirred for 5 min and then treated with 6a (1.45 g, 6.67 mmol)
in 12.5 mL of CH2Cl2. The mixture was stirred for 17 h at
room temperature and was treated with 12.5 mL of saturated
aqueous NaHCO3 solution. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 ¥ 25 mL). The
combined organic extracts were washed with 10 mL of brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(n-hexane–EtOAc = 95 : 5, v/v) to give 7a (2.21 g, 99% yield) as
colorless oil: [a]2D0 = +13.74 (c 0.742, CHCl3); 1H NMR (200 MHz;
CDCl3) d 7.40–7.17 (m, 5H), 5.50 (dq, J = 15.4, 6.5 Hz, 1H), 5.30
(ddq, J = 15.2, 7.6, 1.6 Hz, 1H), 3.71 (t, J = 6.2 Hz, 1H), 2.42 (q,
J = 6.6 Hz, 1H), 1.71 (d, J = 3.5 Hz, 1H), 1.61 (d, J = 6.2 Hz, 3H),
1.60 (d, J = 6.6 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H), 1.33 (d, J =
6.6 Hz, 1H), 0.73 (s, 9H), -0.10 (s, 3H), -0.16 (s, 3H); 13C NMR
(50 MHz; CDCl3) d -4.78, -4.50, 17.57, 18.11, 22.66, 25.84, 30.63,
44.63, 70.09, 75.23, 125.65, 126.93, 127.24, 128.16, 131.69, 144.15;
HRMS (ESI) calculated for [C20H33NOSi+Na]+: 354.2229, Found
354.2223.
(R)-1-{((S)-1-[(R)-1-phenylethyl]aziridin-2-yl)}but-2-yn-1-ol
(5b). To the solution of 4 (1.00 g, 4.60 mmol) in MeOH (30.0 mL)
at -78 ◦C was added ZnCl2 (0.348 g, 6.97 mmol). The solution
was stirred for 30 min, and NaBH4 (0.940 g, 6.90 mmol) was
added at -78 ◦C. The mixture was stirred for an additional 1 h at
-78 ◦C before being quenched with water (30.0 mL). The reaction
mixture was extracted with methylene chloride (3 ¥ 30 mL) and
the combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (n-hexane–EtOAc =
70 :◦30, v/v) to give 5b (0.95 g, 95% yield) as brown solid: mp =
1
89 C; [a]2D0 = +60.34 (c 0.434, CHCl3); H NMR (200 MHz;
CDCl3) d 7.36–7.19 (m, 5H), 4.28–4.19 (m, 1H), 2.61 (q, J =
6.6 Hz, 1H), 2.60 (d, J = 6.5 Hz, 1H), 2.09 (d, J = 3.4 Hz, 1H),
1.82 (ddd, J = 7.2, 6.4, 3.7 Hz, 1H), 1.75 (d, J = 2.2 Hz, 3H),
1.50 (d, J = 6.4 Hz, 1H), 1.43 (d, J = 6.6 Hz, 3H); 13C NMR
(50 MHz; CDCl3) d 3.58, 22.87, 30.59, 42.30, 60.57, 69.20, 77.93,
81.25, 126.76, 127.16, 128.37, 143.97; HRMS (ESI) calculated for
[C14H17NO+H]+: 216.1388, Found 216.1384.
(S)-2-[(R,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]-1-[(R)-1-ph-
enylethyl)aziridine] (7b). The same procedure as for 7a yielded
7b from 6b in quantitative yield. [a]2D0 = +46.90 (c 0.714, CHCl3);
1H NMR (200 MHz; CDCl3) d 7.32–7.21 (m, 5H), 5.40 (dq, J =
15.2, 6.5 Hz, 1H), 4.90 (ddq, J = 15.3, 7.8, 1.6 Hz, 1H), 3.46 (t,
J = 6.4 Hz, 1H), 2.39 (q, J = 6.6 Hz, 1H), 1.83 (d, J = 3.0 Hz,
1H), 1.53 (dd, J = 6.3, 3.3 Hz, 1H), 1.49 (d, J = 2.6 Hz, 1H),
1.42 (d, J = 6.5 Hz, 3H), 1.38 (d, J = 6.6 Hz, 3H), 0.84 (s, 9H),
-0.01 (s, 3H), -0.04 (s, 3H); 13C NMR (50 MHz; CDCl3) d -4.57,
-4.51, 17.43, 18.12, 22.34, 25.83, 33.43, 44.04, 70.07, 75.68, 124.98,
126.99, 127.37, 127.97, 132.44, 143.84; HRMS (ESI) calculated for
[C20H33NOSi+Na]+: 354.2229, Found 354.2232.
(S,E)-1-{(S)-1-[(R)-1-phenylethyl]aziridin-2-yl}but-2-en-1-ol
(6a). To a stirred solution of 5a (1.54 g, 7.17 mmol) in anhydrous
THF (21.3 mL) at 0 ◦C, under an inert atmosphere of N2, was
added LiAlH4. After stirring for 30 min at 0 ◦C, the solution
was warmed to room temperature. Then the reaction mixture was
refluxed for 8 h, then quenched with saturated aqueous KHSO4
solution. The reaction mixture was extracted with ethyl acetate
(3 ¥ 25 mL) and the combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (n-hexane–EtOAc = 70 : 30, v/v) to give 6a (1.45 g,
◦
94% yield) as white solid : mp = 46 C; [a]2D0 = + 94.77 (c 0.673,
1
CHCl3); H NMR (200 MHz; CDCl3) d 7.41–7.23 (m, 5H), 5.54
(2S,3S,E)-3-(t-butyldimethylsilyloxy)-2-[(R)-1-phenylethylami-
no]hex-4-enyl acetate (8a). To a solution of 7a (1.25 g, 3.77
mmol) in anhydrous CH2Cl2 (15.0 mL) under an inert atmosphere
of N2 was added AcOH (1.50 mL, 26.39 mmol). The mixture
was stirred for 15 h and then quenched with 20 mL saturated
aqueous NaHCO3 solution. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 ¥ 20 mL). The
combined organic extracts were washed with 10 mL of brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(n-hexane–EtOAc = 90 : 10, v/v) to give 8a (1.48 g, 99% yield) as
colorless oil: [a]2D0 = +54.14 (c 0.731, CHCl3); 1H NMR (200 MHz;
CDCl3) d 7.35–7.16 (m, 5H), 5.68–5.52 (m, 1H), 5.52–5.28 (m,
1H), 4.14 (dd, J = 11.2, 5.2 Hz, 1H), 4.06 (dd, J = 11.1, 5.0 Hz,
1H), 4.03 (d, J = 5.1 Hz, 1H), 3.90 (dd, J = 11.2, 6.2 Hz, 1H), 2.56
(q, J = 5.2 Hz, 1H), 2.05 (s, 3H), 1.78 (bs, 1H), 1.65 (d, J = 5.6 Hz,
3H), 1.32 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), -0.02 (s, 3H), -0.04 (s,
3H); 13C NMR (50 MHz; CDCl3) d -5.31, -4.43, 17.35, 17.82,
20.56, 24.98, 25.61, 55.62, 58.39, 63.32, 73.75, 126.47, 126.54,
126.58, 127.98, 131.40, 145.39, 170.23; HRMS (ESI) calculated
for [C22H37NO3Si+H]+: 392.2621, Found 392.2628.
(dq, J = 15.4, 6.5 Hz, 1H), 5.08 (ddq, J = 15.3, 8.4, 1.6 Hz, 1H),
3.75–3.57 (m, 1H), 2.51 (q, J = 6.6 Hz, 1H), 1.95 (d, J = 5.6 Hz,
1H), 1.91 (d, J = 3.4 Hz, 1H), 1.58 (dd, J = 6.5, 4.4 Hz, 1H),
1.52 (d, J = 6.5 Hz, 3H), 1.49 (d, J = 6.5 Hz, 1H), 1.45 (d, J =
6.6 Hz, 3H); 13C NMR (50 MHz; CDCl3) d 17.62, 22.54, 31.23,
42.77, 69.46, 71.75, 126.72, 126.97, 127.35, 128.47, 131.44, 144.31;
HRMS (ESI) calculated for [C14H19NO+Na]+: 240.1365, Found
240.1361.
(R,E)-1-{(S)-1-[(R)-1-phenylethyl]aziridin-2-yl}but-2-en-1-ol
(6b). The same procedure as for 6a yielded 6b from 5b in 93%
yield. mp = 58 ◦C; [a]D20 = + 29.47 (c 0.424, CHCl3); 1H NMR (200
MHz; CDCl3) d 7.36–7.23 (m, 5H), 5.63 (dq, J = 15.4, 6.5 Hz, 1H),
5.24 (ddq, J = 15.0, 7.3, 1.6 Hz, 1H), 3.95 (dd, J = 7.3, 3.8 Hz,
1H), 2.61 (q, J = 6.4 Hz, 1H), 2.60 (d, J = 6.4 Hz, 1H), 1.98 (d,
J = 3.6 Hz, 1H), 1.61 (d, J = 6.5 Hz, 3H), 1.60 (d, J = 6.4 Hz, 1H),
1.42 (d, J = 6.6 Hz, 3H), 1.40 (d, J = 6.4 Hz, 1H); 13C NMR (50
MHz; CDCl3) d 17.67, 23.05, 29.97, 41.96, 69.16, 70.07, 126.64,
127.03, 127.91, 128.28, 130.84, 144.19; HRMS (ESI) calculated
for C14H19NO [M+Na]+: 240.1364, Found 240.1360.
1376 | Org. Biomol. Chem., 2011, 9, 1372–1380
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(2S,3R,E)-3-(t-butyldimethylsilyloxy)-2-[(R)-1-phenylethylam-
ino]hex-4-enyl acetate (8b). The same procedure as for 8a yielded
8b from 7b in quantitative yield. [a]2D0 = +30.22 (c 0.695, CHCl3);
1H NMR (200 MHz; CDCl3) d 7.36–7.20 (m, 5H), 5.61 (dq, J =
15.4, 6.5 Hz, 1H), 5.32 (ddq, J = 15.0, 7.4, 1.6 Hz, 1H), 4.19 (dd, J =
11.3, 4.6 Hz, 1H), 4.06 (dd, J = 8.0, 4.2 Hz, 1H), 4.02 (d, J = 4.0 Hz,
1H), 3.89 (q, J = 6.6 Hz, 1H), 2.53 (dd, J = 10.4, 4.2 Hz, 1H), 2.06
(s, 3H), 1.71 (dd, J = 6.3, 1.4 Hz, 3H), 1.64 (bs, 1H), 1.31 (d, J =
6.6 Hz, 3H), 0.83 (s, 9H), 0.02 (s, 3H), -0.04 (s, 3H); 13C NMR
(50 MHz; CDCl3) d -4.96, -4.15, 17.67, 18.10, 20.99, 24.92, 25.83,
55.42, 58.32, 63.15, 74.29, 126.68, 126.83, 128.15, 128.32, 131.73,
145.43, 170.90; HRMS (ESI) calculated for [C22H37NO3Si+H]+:
392.2621, Found 392.2621.
hexane–EtOAc = 90 : 10, v/v) to give 10a (1.37 g, 99% yield) as
colorless oil: [a]2D0 = -36.30 (c = 0.482, CHCl3); 1H NMR (200 MHz;
CDCl3) d 7.42–7.33 (m, 5H), 5.73 (dq, J = 15.4, 6.5 Hz, 1H), 5.46
(ddq, J = 15.2, 7.6, 1.6 Hz, 1H), 5.18 (q, J = 7.2 Hz, 1H), 4.26 (dd,
J = 9.0, 3.6 Hz, 1H), 4.16–4.26 (m, 1H), 4.0 (t, J = 8.8 Hz, 1H), 3.36
(ddd, J = 12.8, 8.7, 3.7 Hz, 1H), 1.73 (ddd, J = 6.4, 2.7, 1.3 Hz, 3H),
1.66 (d, J = 7.2 Hz, 3H), 0.78 (s, 9H), 0.07 (s, 3H), -0.018 (s, 3H); 13C
NMR (50 MHz; CDCl3) d -5.42, -4.99, 17.70, 17.74, 18.72, 25.42,
52.77, 57.86, 62.96, 71.37, 126.07, 127.06, 127.84, 128.57, 129.82,
139.10, 158.32; HRMS (ESI) calculated for [C21H33NO3Si+Na]+:
398.2127, Found 398.2121.
(S)-4-[(R,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]-3-[(R)-1-ph-
enylethyl]oxazolidin-2-one (10b). The same procedure as for 10a
yielded 10b from 9b in quantitative yield. mp = 67 ◦C; [a]D20 = -12.17
(c = 0.419, CHCl3); 1H NMR (200 MHz; CDCl3) d 7.39–7.24 (m,
5H), 5.54 (dq, J = 15.4, 6.5 Hz, 1H), 5.19 (ddq, J = 15.0, 7.4, 1.6 Hz,
1H), 5.21–5.12 (m, 1H), 4.27 (dd, J = 8.3, 4.1 Hz, 1H), 4.17 (d, J =
6.8 Hz, 1H), 4.00 (t, J = 9.0 Hz, 1H), 3.42–3.23 (m, 1H), 1.68 (dd,
J = 6.8 Hz, 3H), 1.59 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 3H),
0.01 (s, 3H); 13C NMR (50 MHz; CDCl3) d -4.91, -3.50, 17.64,
17.98, 18.60, 25.74, 53.14, 59.63, 62.90, 74.11, 127.30, 127.76,
128.60, 129.41, 129.61, 139.65, 158.91; HRMS (ESI) calculated
for [C21H33NO3Si+Na]+: 398.2128, Found 398.2127.
(2S,3S,E)-3-(t-butyldimethylsilyloxy)-2-[(R)-1-phenylethyla-
mino]hex-4-en-1-ol (9a). To a solution of 8a (5.78 g, 14.76 mmol)
in 45.0 mL of EtOH at room temperature was added KOH (4.14
g, 73.81 mmol). The mixture was stirred for 30 min at room
temperature and then quenched with 40.0 mL of water. The
organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (3 ¥ 50 mL). The combined organic extracts were
washed with 30 mL of brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (n-hexane–EtOAc = 80 : 20,
v/v) to give 9a as colorless oil (5.14 g, 99% yield): [a]2D0 = +19.84
(c = 0.695, CHCl3); 1H NMR (200 MHz; CDCl3) d 7.28–7.13 (m,
5H), 5.61 (dq, J = 15.4, 6.5 Hz, 1H), 5.30 (ddq, J = 15.2, 7.6,
1.6 Hz, 1H), 4.01 (t, J = 7.5 Hz, 1H), 3.85 (q, J = 6.6 Hz, 1H), 3.57
(dd, J = 10.7, 4.6 Hz, 1H), 3.36 (dd, J = 10.7, 2.8 Hz, 1H), 2.34
(ddd, J = 7.3, 4.5, 2.8 Hz, 1H), 1.65 (dd, J = 6.4, 1.5 Hz, 3H), 1.34
(S)-4-[(S,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]oxazolidin-
2-one (11a). To a stirred solution of 10a (3.0 g, 7.98 mmol) in
anhydrous THF (25.0 mL) at -78 ◦C, was added freshly cut sodium
metal (0.754 g, 27.95 mmol), and 25.0 mL of liquid ammonia.
Blue color started appearing slowly and in 5 min the reaction
mixture became blue in color. The reaction mixture was stirred
at -78 ◦C for 30 min. As soon as all the starting material was
consumed the mixture was quenched with 15 mL of water. The
reaction mixture was extracted with ethyl acetate (3 ¥ 100 mL)
and combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (n-
hexane–EtOAc = 70 : 30, v/v) to give 11a (2.03 g, 94% yield) as
(d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 3H), -0.019 (s, 3H); 13
C
NMR (50 MHz; CDCl3) d -5.20, -4.30, 17.35, 17.79, 24.74, 25.63,
55.13, 58.97, 60.15, 74.10, 126.23, 126.58, 127.68, 128.09, 131.46,
145.10; HRMS (ESI) calculated for [C20H35NO2Si+H]+: 350.2515,
Found 350.2511.
(2S,3R,E)-3-(t-butyldimethylsilyloxy)-2-[(R)-1-phenylethyla-
mino]hex-4-en-1-ol (9b). The same procedure as for 9a yielded
9b from 8b in quantitative yield. [a]2D0 = -15.8 (c = 0.818, CHCl3);
1H NMR (200 MHz; CDCl3) d 7.38 - 7.20 (m, 5H), 5.59 (dq, J =
15.4, 6.5 Hz, 1H), 5.29 (ddq, J = 15.2, 7.6, 1.6 Hz, 1H), 4.08 (t, J =
6.4 Hz, 1H), 3.88 (q, J = 6.6 Hz, 1H), 3.62 (s, 1H), 3.60 (s, 1H),
2.38 (dd, J = 9.2, 4.2 Hz, 1H), 1.68 (dd, J = 6.3, 0.8 Hz, 3H), 1.33
(d, J = 6.6 Hz, 3H), 0.84 (s, 9H), 0.03 (s, 3H), -0.02 (s, 3H); 13C
NMR (50 MHz; CDCl3) d -5.12, -4.29, 17.45, 17.88, 24.43, 25.67,
54.92, 59.22, 59.72, 75.20, 126.40, 126.77, 127.47, 128.20, 131.97,
145.44; HRMS (ESI) calculated for [C20H35NO2Si+H]+: 350.2515,
Found 350.2518.
◦
1
white solid: mp = 55 C; [a]2D0 = +24.20 (c = 0.537, CHCl3); H
NMR (200 MHz; CDCl3) d 5.75 (dq, J = 15.4, 6.5 Hz, 1H), 5.30
(ddq, J = 15.2, 7.6, 1.6 Hz, 1H), 5.35–5.26 (bs, 1H), 4.33 (t, J =
8.8 Hz, 1H), 4.10 (dd, J = 9.0, 5.0 Hz, 1H), 3.96 (t, J = 7.2 Hz, 1H),
3.71 (ddd, J = 13.5, 7.7, 5.1 Hz, 1H), 1.72 (dd, J = 6.5, 1.6 Hz, 3H),
0.89 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (50 MHz; CDCl3)
d -4.85, -4.06, 17.81, 18.04, 25.78, 57.08, 66.41, 75.51, 128.86,
130.28, 159.90; HRMS (ESI) calculated for [C13H25NO3Si+Na]+:
294.1501, Found 294.1511.
(S)-4-[(S,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]-3-[(R)-1-ph-
enylethyl]oxazolidin-2-one (10a). To a solution of 9a (1.29 g,
3.68 mmol) in anhydrous CH2Cl2 (11.30 mL) at 0 ◦C, under
an inert atmosphere of N2 was added CDI (0.89 g, 5.51 mmol)
and DBU (1.92 mL, 12.87 mmol). The reaction mixture was then
stirred for 1 h at 0 ◦C and warmed to room temperature and
stirred for an additional 24 h before being quenched with water.
The reaction mixture was extracted with CH2Cl2 (3 ¥ 25 mL)
and combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (n-
(S)-4-[(R,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]oxazolidin-2-
one (11b). The same p◦rocedure as for 11a yielded 11b from 10b
in 92% yield. mp = 144 C; [a]2D0 = -57.42 (c = 0.368, CHCl3); 1H
NMR (200 MHz; CDCl3) d 5.74 (dq, J = 15.4, 6.5 Hz, 1H), 5.51
(bs, 1H), 5.32 (ddq, J = 15.0, 7.4, 1.6 Hz, 1H), 4.39 (t, J = 8.6 Hz,
1H), 4.28 (dd, J = 8.8, 4.8 Hz, 1H), 3.97 (t, J = 6.9 Hz, 1H), 3.72
(dt, J = 10.7, 5.6 Hz, 1H), 1.73 (dd, J = 6.4, 1.5 Hz, 3H), 0.88
(s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (50 MHz; CDCl3)
d -5.06, -4.33, 17.54, 17.82, 25.60, 56.86, 66.14, 74.50, 129.27,
129.48, 160.31; HRMS (ESI) calculated for [C13H25NO3Si+Na]+:
294.1501, Found 294.1508.
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(S)-3-allyl-4-[(S,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]oxa-
zolidin-2-one (12a). To a solution of 11a (2.0◦3 g, 7.49 mmol) in
anhydrous ethylene dichloride (24.0 mL) at 0 C, under an inert
atmosphere of N2, was added NaH (1.08 g, 44.94 mmol). The
reaction mixture was then stirred for 1 h at 0 ◦C. Allyl iodide
(2.39 mL, 26.22 mmol) was added to the mixture at 0 ◦C and
warmed to room temperature. The reaction mixture was heated
to reflux for 10 h and cooled to the room temperature, quenched
with aqueous NH4Cl solution (10 mL). The reaction mixture was
extracted with CH2Cl2 (3 ¥ 100 mL) and combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (n-hexane–EtOAc = 90 : 10, v/v) to
give 12a (2.30 g, 99% yield) as colorless oil: [a]2D0 = -104.54 (c =
0.621, CHCl3); 1H NMR (200 MHz; CDCl3) d 5.89–5.64 (m,
2H), 5.45–5.18 (m, 3H), 4.32–4.12 (m, 4H), 3.77 (td, J = 11.0,
5.8 Hz, 1H), 3.60 (dd, J = 15.4, 7.8 Hz, 1H), 1.69 (d, J = 6.5 Hz,
3H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (50 MHz; CDCl3)
d -4.90, -4.30, 17.94, 18.11, 25.79, 45.75, 58.10, 63.55, 72.11,
118.82, 127.50, 130.31, 132.37, 158.35; HRMS (ESI) calculated
for [C16H29NO3Si+Na]+: 334.1814, Found 334.1810.
130.27, 156.97; HRMS (ESI) calculated for [C13H23NO3Si+Na]+:
292.1345, Found 292.1349.
(1aR,6aS,7R,7aS)-7-(t-butyldimethylsilyloxy)tetrahydro-1aH-
oxazolo[3,4-a]oxireno[2,3-d]pyridin-4(2H)-one (14a). To a sus-
pension of the 13a (1.0 g, 3.71 mmol) and sodium hydrogen
carbonate (4.67 g, 55.67 mmol) in acetone (100 mL) and water
(50 mL) was added oxone (11.41 g, 18.55 mmol) over 10 min and
the suspension was stirred for 30 min at room temperature when
TLC indicated complete consumption of the starting material.
The organic phase was extracted into ethyl acetate (3 ¥ 50 mL) and
combined organic extracts were washed with 10% aqueous sodium
bissulfite (50 mL) and water 25 mL, dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (n-hexane–EtOAc =
40 : 60, v/v) to give 14a (0.75 g, 71% yield) as white solid : mp =
◦
1
165 C; [a]2D0 = +34.44 (c = 0.409, MeOH); H NMR (200 MHz;
CD3OD) d 4.36 (t, J = 9.3 Hz, 1H), 4.20 (t, J = 3.0 Hz, 1H),
4.18–4.09 (m, 1H), 4.01–3.84 (m, 3H), 3.70 (dd, J = 12.4, 5.9 Hz,
1H), 3.10 (t, J = 11.6 Hz, 1H), 0.91 (s, 9H), 0.15 (s, 6H); 13C
NMR (50 MHz; CD3OD) d -5.17, -4.20, 18.63, 26.07, 42.14,
54.35, 64.19, 64.76, 71.96, 72.48, 160.20; HRMS (ESI) calculated
for [C13H23NO4Si+H]+: 286.1475, Found 286.1472.
(S)-3-allyl-4-[(R,E)-1-(t-butyldimethylsilyloxy)but-2-enyl]oxa-
zolidin-2-one (12b). The same procedure as for 12a yielded 12b
from 11b in quantitative yield. [a]2D0 = + 5.16 (c = 0.542, CHCl3); 1H
NMR (200 MHz; CDCl3) d 5.89–5.65 (m, 2H), 5.39–5.16 (m, 3H),
4.33–4.14 (m, 4H), 3.72 (dq, J = 8.8, 2.4 Hz, 1H), 3.58 (dd, J = 15.6,
7.6 Hz, 1H), 1.71 (dd, J = 6.5, 0.8 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H),
0.02 (s, 3H); 13C-NMR (50 MHz; CDCl3) d -4.86, -3.86, 17.87,
18.03, 25.76, 45.01, 58.94, 62.97, 71.59, 118.42, 129.23, 129.64,
132.30, 158.53; HRMS (ESI) calculated for [C16H29NO3Si +Na]+:
334.1814, Found 334.1811.
(3aS,8aS,9R,9aR)-9-(t-butyldimethylsilyloxy)-2,2-dimethylte-
trahydro-3aH-[1,3]dioxolo[4,5-d]oxazolo[3,4-a]pyridin-6(4H)-one
(15a). Suspension of 14a (0.75 g, 2.63 mmol) in CH2Cl2
(28.0 mL) and acetone (12.0 mL) at 0 ◦C, was added BF3·Et2O
(1.67 mL, 13.18 mmol). The reaction mixture was stirred for 2 h at
0 ◦C, when TLC indicated complete consumption of the starting
material. The reaction mixture was extracted with CH2Cl2 (3 ¥
30 mL) and the combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel (n-hexane–EtOAc = 80 : 20, v/v) to give 15a (0.859 g,
(8S,8aS)-8-(t-butyldimethylsilyloxy)-8,8a-dihydro-1H-oxazolo-
[3,4-a]pyridin-3(5H)-one (13a). Grubbs’ catalyst benzylidene-
bis(tricyclohexylphosphine)dichlororuthenium (10 mol%, 0.610 g,
0.74 mmol) was added to a solution of 12a (2.31 g, 7.43 mol) in
CH2Cl2 (304 mL) and the mixture was stirred for 24 h at room
temperature. After evaporation, the residue was purified by flash
column chromatography on silica gel (n-hexane–EtOAc = 80 :◦20,
v/v) to give 13a (1.98 g, 99% yield) as brown solid: mp = 49 C;
[a]2D0 = +224.49 (c = 0.514, CHCl3); 1H NMR (200 MHz; CDCl3) d
6.08–5.86 (m, 2H), 4.44 (dd, J = 8.3, 4.7 Hz, 1H), 4.35 (t, J = 8.3 Hz,
1H), 4.22 (td, J = 18.9, 2.3 Hz, 1H), 4.06 (dd, J = 5.6, 2.5 Hz, 1H),
3.81 (ddq, J = 7.7, 4.6, 2.5 Hz, 1H), 3.70 (td, J = 19.0, 1.9 Hz, 1H),
0.88 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (50 MHz; CDCl3)
d -5.24, -4.08, 17.52, 25.23, 40.49, 54.87, 62.77, 63.94, 125.95,
127.16, 157.54; HRMS (ESI) calculated for [C13H23NO3Si+Na]+:
292.1345, Found 292.1341.
◦
94% yield) as white solid : mp = 88 C; [a]2D0 = +42.8 (c = 0.676,
CHCl3); 1H NMR (200 MHz; CDCl3) d 4.47 (td, J = 6.9, 2.5 Hz,
1H), 4.32 (t, J = 10.0 Hz, 1H), 4.07–3.90 (m, 3H), 3.61 (d, J =
14.0 Hz, 1H), 3.60 (d, J = 13.4 Hz, 1H), 3.39 (dd, J = 13.4, 3.4 Hz,
1H), 1.39 (s, 3H), 1.25 (s, 3H), 0.78 (s, 9H), 0.04 (s, 3H), 0.01 (s,
3H); 13C NMR (50 MHz; CDCl3) d -5.24, -4.42, 17.59, 23.84,
25.41, 26.62, 41.90, 51.02, 64.68, 69.69, 70.14, 74.35, 108.75,
159.78; HRMS (ESI) calculated for [C16H29NO5Si+H]+: 344.1893,
Found 344.1898.
(8S,8aS)-8-hydroxy-8,8a-dihydro-1H -oxazolo[3,4-a]pyridin-
3(5H)-one (16b). To a solution of 13a (0.45 g, 1.78 mmol) in
◦
anhydrous THF (6.9 mL) at 0 C, under an inert atmosphere of
N2, was added TBAF (3.56 mL, 3.56 mmol, 1 M in THF). The
reaction mixture was then stirred for 1 h at 0 ◦C then warmed to
room temperature and quenched with saturated aqueous NH4Cl
solution (5.0 mL). The reaction mixture was extracted with ethyl
acetate (3 ¥ 20 mL) and combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (CHCl3–MeOH = 90 : 10, v/v) to give 16b (0.24 g,
(8R,8aS)-8-(t-butyldimethylsilyloxy)-8,8a-dihydro-1H-oxazolo-
[3,4-a]pyridin-3(5H)-one (13b). The same procedure◦as for 13a
yielded 13b from 12b in quantitative yield. mp = 93 C; [a]D20
=
1
-25.58 (c = 0.514, CHCl3); H NMR (200 MHz; CDCl3) d 5.72
(s, 2H), 4.51 (dd, J = 8.9, 8.0 Hz, 1H), 4.22 (dd, J = 9.0, 4.3 Hz,
1H), 4.17 (dd, J = 3.4, 2.5 Hz, 1H), 4.15–4.03 (m, 1H), 3.65 (dd,
J = 18.3, 2.8 Hz, 1H), 3.51 (ddd, J = 7.8, 7.8, 4.3 Hz, 1H), 0.90
(s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (50 MHz; CDCl3)
d -4.85, -4.37, 17.67, 25.46, 40.64, 56.18, 67.01, 68.16, 123.67,
◦
99%) as white solid: mp = 105 C; [a]2D0 = +296.14 (c = 0.315,
MeOH); 1H NMR (200 MHz; CD3OD) d 6.09–5.86 (m, 2H), 4.53
(dd, J = 8.4, 3.0 Hz, 1H), 4.50 (dd, J = 16.6, 8.5 Hz, 1H), 4.21–3.99
(m, 1H), 4.07 (t, J = 2.7 Hz, 1H), 3.94 (ddd, J = 8.5, 5.7, 2.7 Hz,
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1H), 3.73 (td, J = 19.0, 1.9 Hz, 1H); 13C NMR (50 MHz; CD3OD)
d 41.80, 56.44, 62.71, 65.63, 127.21, 128.22, 159.82; HRMS (ESI)
calculated for [C7H9NO3+H]+: 156.0661, Found 156.0656.
2H), 4.13 (dd, J = 9.0, 4.2 Hz, 1H), 3.90 (t, J = 7.2 Hz, 1H), 3.83
(dd, J = 7.7, 4.5 Hz, 1H), 3.73 (dd, J = 9.7, 3.0 Hz, 1H), 2.96 (dd,
J = 13.0, 7.6 Hz, 1H), 1.56 (s, 3H), 1.37 (s, 3H), 0.91 (s, 9H), 0.14
(s, 3H), 0.13 (s, 3H); 13C NMR (50 MHz; CDCl3) d -4.43, -4.01,
18.21, 25.78, 25.94, 28.38, 42.12, 53.27, 66.96, 70.50, 71.36, 76.32,
110.43, 156.82; HRMS (ESI) calculated for [C16H29NO5Si+H]+:
344.1893, Found 344.1899.
(1aS,6aS,7R,7aR) - 7 - hydroxytetrahydro - 1aH - oxazolo[3,4-
a]oxireno[2,3-d]pyridin-4(2H)-one (17b). MCPBA (2.7 g, 12.07
mmol) was added to a suspension of 14b (0.39 g, 2.51 mmol) and
NaH2PO4 (2.08 g, 17.34 mmol) in CH2Cl2 (32.0 mL) at 0 ◦C. After
stirring at room temperature for 3 days, the insoluble materials
were filtered off and filtrate was concentrated. The residue was
purified by flash column chromatography on silica gel (EtOAc–
Me◦OH = 80 : 20, v/v) to give 17b (0.28 g, 67%) as white solid : mp =
(8R,8aS)-8-hydroxy-8,8a-dihydro-1H -oxazolo[3,4-a]pyridin-
3(5H)-one (16e). The same procedure as for 16b yielded 16e
◦
from 13b in quantitative yield. mp = 99 C; [a]2D0 = +26.02 (c =
0.365, MeOH); 1H NMR (200 MHz; CD3OD) d 5.89 (s, 2H), 4.69
(t, J = 8.5 Hz, 1H), 4.45 (dd, J = 8.9, 4.6 Hz, 1H), 4.28–3.98
(m, 2H), 3.74 (dd, J = 18.1, 2.9 Hz, 1H), 3.64 (ddd, J = 11.7,
8.2, 4.6 Hz, 1H); 13C NMR (50 MHz; CD3OD) d 41.67, 57.66,
68.24, 68.99, 124.79, 131.38, 159.35; HRMS (ESI) calculated for
[C7H9NO3+H]+: 156.0661, Found 156.0668.
1
97 C; [a]2D0 = +52.86 (c = 0.087, MeOH); H NMR (400 MHz;
CD3OD) d 4.52 (dd, J = 8.6, 5.4 Hz, 1H), 4.31 (t, J = 8.8 Hz, 1H),
4.01 (d, J = 14.7 Hz, 1H), 3.97 (t, J = 4.7 Hz, 1H), 3.80 (dq, J =
9.3, 4.3 Hz, 1H), 3.46 (dd, J = 5.2, 3.8 Hz, 1H), 3.41 (td, J = 3.8,
1.2 Hz, 1H), 3.37 (dd, J = 14.7, 1.34 Hz, 1H); 13C NMR (100 MHz;
CD3OD) d 40.43, 52.52, 53.05, 56.10, 62.13, 64.14, 160.00; HRMS
(ESI) calculated for [C7H9NO4+H]+: 172.0614, Found 172.0610.
(1aR,6aS,7S,7aR)-7-hydroxytetrahydro-1aH -oxazolo[3,4-a]-
oxireno[2,3-d]pyridin-4(2H)-one (17e). The same procedure as
◦
(6R,7R,8R,8aS)-8-(t-butyldimethylsilyloxy)-6,7-dihydroxy-tet-
rahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (18c). To a solu-
tion of 13a (0.50 g, 1.86 mmol) in CH3CN–H2O = 9 : 1 ratio
(9.0 mL of CH3CN, 1.0 mL of H2O) (45.0 mL) at 0 ◦C, was added
NMO (0.43 g, 3.71 mmol) and OsO4 (4% in water, 0.63 mL, 2.47
mmol). The reaction mixture was then stirred for 10 min at 0 ◦C
and warmed to room temperature and stirred for an additional
3 h before being quenched with saturated aqueous Na2SO3. The
reaction mixture was extracted with CH2Cl2 (3 ¥ 30 mL) and
the combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (n-
hexane–EtOAc = 30 : 60, v/v) to give 18c (0.56 g, 99% yield) as
white solid : mp = 178 ◦C; [a]2D0 = +44.23 (c = 0.391, MeOH); 1H
NMR (200 MHz; CD3OD) d 4.34 (t, J = 9.2 Hz, 1H), 4.25–4.09
(m, 1H), 4.17 (dd, J = 8.8, 3.1 Hz, 1H), 3.95 (dd, J = 5.8, 2.6 Hz,
1H), 3.89 (dd, J = 4.1, 1.4 Hz, 1H), 3.86 (dd, J = 4.1, 1.6 Hz,
1H), 3.67 (dd, J = 12.5, 5.7 Hz, 1H), 3.09 (t, J = 11.7 Hz, 1H),
0.91 (s, 9H), 0.15 (s, 6H); 13C NMR (50 MHz; CD3OD) d -5.14,
-4.18, 18.57, 26.08, 42.08, 54.22, 64.10, 64.67, 71.84, 72.35, 160.03;
HRMS (ESI) calculated for [C13H25NO5Si+H]+: 304.1580, Found
304.1582.
for 17b yielded 17e from 16e in 77% yield. mp = 122 C; [a]D20
=
-47.99 (c = 0.012, MeOH); 1H NMR (400 MHz; CD3OD) d 4.43
(t, J = 8.5 Hz, 1H), 4.27 (dd, J = 8.9, 4.7 Hz, 1H), 3.88 (t, J =
4.6 Hz, 1H), 3.86 (dd, J = 15.0, 3.5 Hz, 1H), 3.70 (ddd, J = 13.4,
8.4, 4.7 Hz, 1H), 3.51 (t, J = 3.8 Hz, 1H), 3.46 (t, J = 13.5 Hz, 1H),
3.37 (t, J = 12.1 Hz, 1H); 13C NMR (100 MHz; CD3OD) d 39.86,
53.69, 54.54, 57.01, 67.68, 70.31, 159.42; HRMS (ESI) calculated
for [C7H9NO4+H]+: 172.0614, Found 172.0619.
(6S,7S,8S,8aS)-8-(t-butyldimethylsilyloxy)-6,7-dihydroxy-tet-
rahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (18f). The same
procedure ◦as for 18c yielded 18f from 13b in quantitative yield.
1
mp = 118 C; [a]2D0 = +29.25 (c = 0.411, MeOH); H NMR (200
MHz; CD3OD) d 4.47 (t, J = 8.4 Hz, 1H), 4.18 (dd, J = 8.7, 5.0 Hz,
1H), 3.93 (dd, J = 4.2, 2.1 Hz, 1H), 3.77 (t, J = 9.0 Hz, 1H), 3.76
(dd, J = 11.6, 2.4 Hz, 1H), 3.59 (ddd, J = 13.2, 8.2, 5.0 Hz, 1H),
3.42 (dd, J = 9.0, 2.9 Hz, 1H), 3.11 (dd, J = 14.0, 1.7 Hz, 1H), 0.89
(s, 9H), 0.17 (s, 3H), 0.15 (s, 3H); 13C NMR (50 MHz; CD3OD) d
-4.79, -3.45, 19.06, 26.44, 46.55, 59.95, 67.77, 70.29, 73.47, 75.27,
159.90; HRMS (ESI) calculated for [C13H25NO5Si+H]+: 304.1580,
Found 304.1587.
L - 1 - deoxyidonojirimycin (L - Ido - DNJ, (2S,3R,4R,5S) - 2-
(hydroxymethyl)piperidine-3,4,5-triol), (1a). To a solution of 15a
(0.20 g, 0.58 mmol) in 20 mL of aq. 30% EtOH at room
temperature was added LiOH (0.70 g, 2.91 mmol). The reaction
mixture was heated to reflux for 4 h and cooled to room
temperature. The insoluble materials were filtered off and the
filtrate was evaporated. The residue was dissolved in 20 mL of
MeOH. Concentrated hydrochloric acid (2.0 mL) was added to the
solution at room temperature. The reaction mixture was heated to
reflux for 4 h and cooled to the room temperature and the solvent
was evaporated. After evaporation of the reaction mixture, the
residue was treated with basic ion-exchange resin (Amberlite IRA-
410 OH- form) using water as eluent to yield 1a (0.90 g, 96% yield)
as white solid: mp = 137 ◦C, [a]D20 = +8.9 (c = 0.726, H2O); 1H NMR
(400 MHz; D2O) d 4.34 (ddq, J = 11.3, 4.8, 3.0 Hz, 1H), 4.30 (d,
J = 4.5 Hz, 1H), 4.17 (t, J = 3.8 Hz, 1H), 4.01 (dd, J = 12.3, 4.8 Hz,
1H), 3.91 (dd, J = 12.3, 8.8 Hz, 1H), 3.66 (dd, J = 7.2, 5.0 Hz,
(1aS,6aS,7S,7aS)-7-(t-butyldimethylsilyloxy)tetrahydro-1aH-
oxazolo[3,4-a]oxireno[2,3-d]pyridin-4(2H)-one (14d). The same
proc◦edure as for 14a yielded 14d from 13b in 68% yield. mp =
1
112 C; [a]2D0 = +14.24 (c = 0.612, MeOH); H NMR (200 MHz;
CD3OD) d 4.44 (t, J = 8.4 Hz, 1H), 4.14 (dd, J = 8.7, 5.0 Hz, 1H),
3.89 (dd, J = 4.6, 2.3 Hz, 1H), 3.74 (dd, J = 14.1, 2.5 Hz, 1H),
3.73 (t, J = 8.8 Hz, 1H), 3.55 (ddd, J = 13.2, 8.2, 5.0 Hz, 1H), 3.34
(dd, J = 9.0, 2.9 Hz, 1H), 3.07 (dd, J = 14.0, 1.7 Hz, 1H), 0.85 (s,
9H), 0.14 (s, 3H), 0.11 (s, 3H); 13C NMR (50 MHz; CD3OD) d
-4.80, -3.46, 19.06, 26.42, 46.55, 59.96, 67.78, 70.31, 73.47, 75.29,
159.92; HRMS (ESI) calculated for [C13H23NO4Si+H]+: 286.1475,
Found 286.1471.
(3aR,8aS,9S,9aS)-9-(t-butyldimethylsilyloxy)-2,2-dimethylt-
etrahydro-3aH - [1,3]dioxolo[4,5 - d]oxazolo[3,4 - a]pyridin - 6(4H)-
one (15d). The same procedure as for 15a yielded 15d from 14d
◦
1
in 97% yield. mp = 72 C; [a]2D0 = +20.08 (c = 0.457, CHCl3); H
NMR (200 MHz; CDCl3) d 4.43 (t, J = 8.4 Hz, 1H), 4.37–4.23 (m,
1H), 3.44 (dd, J = 12.2, 4.9 Hz, 1H), 3.22 (t, J = 11.8 Hz, 1H); 13
C
NMR (50 MHz; D2O) d 46.90, 57.45, 59.46, 65.01, 65.29, 71.51;
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HRMS (ESI) calculated for [C6H13NO4+H]+: 164.0923, Found
164.0929.
Notes and references
1 (a) G. Legler, In Iminosugars as Glycosidase Inhibitors, A. E. Stu¨tz,
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L-1-deoxygulonojirimycin (L-Gulo-DNJ, (2S,3R,4R,5R)-2-
(hydroxymethyl)piperidine-3,4,5-triol (1c). To
a solution of
18c (0.5 g, 1.65 mmol) in 20 mL of aq. 30% EtOH at room
temperature was added LiOH (0.19 g, 8.24 mmol). The reaction
mixture was heated to reflux for 4 h and cooled to the room
temperature. The insoluble materials were filtered off and the
filtrate was evaporated. After evaporation of the reaction mixture,
the residue was treated with basic ion-exchange resin (Amberlite
IRA-410 OH- form) using water as eluent to yield 1c (0.29 g,
95%) as pale yellow oil: [a]2D0 = +14.83 (c = 0.817, H2O); 1H NMR
(400 MHz; D2O) d 4.25 (dq, J = 11.4, 4.8, 2.9 Hz, 1H), 4.12 (dd,
J = 4.6, 1.4 Hz, 1H), 4.05 (t, J = 3.6 Hz, 1H), 3.89 (dd, J = 12.3,
4.8 Hz, 1H), 3.81 (dd, J = 12.1, 9.0 Hz, 1H), 3.53 (ddq, J = 8.5,
4.6, 1.4 Hz, 1H), 3.30 (dd, J = 12.1, 5.0 Hz, 1H), 3.12 (t, J =
11.8 Hz, 1H); 13C NMR (50 MHz; D2O) d 47.0, 59.48, 63.58,
67.37, 72.01, 73.44; HRMS (ESI) calculated for [C6H13NO4+H]+:
164.0923, Found 164.0921.
L-1-deoxynojirimycin (L-DJN, (2S,3S,4S,5R)-2-(hydroxy-
methyl)piperidine-3,4,5-triol) (1d). The same procedure as for
1a yielded 1d from 15d in 95% yield. mp = 194 ◦C, [a]D20 = -40.15
(c = 0.522, H2O); 1H NMR (400 MHz, D2O) d 3.70 (s, 1H), 3.43
(d, J = 12.5 Hz, 1H), 3.34 (dd, J = 10.7, 5.7 Hz, 1H), 3.30 (t, J =
10.0 Hz, 1H), 3.18 (dd, J = 9.6, 2.4 Hz, 1H), 2.82 (d, J = 13.7 Hz,
1H), 2.63 (d, J = 13.7 Hz, 1H), 2.49 (ddd, J = 7.9, 5.6, 2.9 Hz
1H); 13C NMR (50 MHz,D2O) d 52.40, 62.95, 64.96, 70.50, 70.79,
77.0; HRMS (ESI) calculated for C6H13NO4 [M+H]+: 164.0923,
Found 164.0918.
7 (a) M. Weiss, S. Hettmer, P. Smith and S. Ladisch, Cancer Res., 2003,
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Rengasamy, M. J. Curtis-Long, W. D. Seo, S. H. Jeong, I.-Y. Jeong
and K. H. Park, J. Org. Chem., 2008, 73, 2898; (b) N. Palyam and M.
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L-1-deoxymannojirimycin (L-Man-DNJ, (2S,3S,4S,5S)-2-
(hydroxymethyl)piperidine-3,4,5-triol) (1f). The same◦procedure
as for 1c yielded 1f from 18f in 96% yield. mp = 183 C, [a]D20
=
+40.42 (c = 0.728, H2O); 1H NMR (400 MHz; D2O) d 4.23
(ddd, J = 4.3, 2.9, 1.4 Hz, 1H), 3.98 (dd, J = 12.6, 3.3 Hz, 1H),
3.85 (t, J = 10.0 Hz, 1H), 3.86 (dd, J = 12.6, 6.8 Hz, 1H), 3.68
(dd, J = 9.6, 3.1 Hz, 1H), 3.40 (dd, J = 13.6, 3.1 Hz, 1H), 3.23
(dd, J = 13.6, 1.4 Hz, 1H), 3.15 (dq, J = 10.3, 3.3 Hz, 1H); 13C
NMR (50 MHz; D2O) d 51.0, 61.99, 63.70, 69.53, 70.10, 76.26;
HRMS (ESI) calculated for [C6H13NO4+H]+: 164.0923, Found
164.0928.
Acknowledgements
This work was supported by National Research Foundation
(NRF) (Basic Science Research Program, 2010-0008424 and the
Center for Bioactive Molecular Hybrides to HJH) and the HUFS
Grant (2010). WKL also acknowledges the financial support from
KRF-2010-0005538 and KRF-2009-0081956.
16 K. Asano, T. Hakogi, S. Iwama and S. Katsumura, Chem. Commun.,
1999, 41.
17 J. K. Cha, W. J. Christ and Y. Kishi, Tetrahedron Lett., 1983, 24, 3943.
1380 | Org. Biomol. Chem., 2011, 9, 1372–1380
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©