Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: Total synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (-)-1-deoxynojirimycin, (-)-1-deoxy-altro-nojirimycin, and related diversity

Article abstract of DOI:10.1016/j.tet.2013.11.074

Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (-)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (-)-1-deoxynojirimycin, (-)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation.

Full text of DOI:10.1016/j.tet.2013.11.074

Tetrahedron 70 (2014) 1363e1374
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Tetrahedron
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Synthesis of polyhydroxylated indolizidines and piperidines from
Garner’s aldehyde: total synthesis of (ꢀ)-swainsonine, (þ)-1,2-di-
epi-swainsonine, (þ)-8,8a-di-epi-castanospermine, pentahydroxy
indolizidines, (ꢀ)-1-deoxynojirimycin, (ꢀ)-1-deoxy-altro-
nojirimycin, and related diversity
*
Priyanka Singh, Sudipta Kumar Manna, Gautam Panda
Medicinal and Process Chemistry Division, CSIR e Central Drug Research Institute, Lucknow 226031, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2013
Received in revised form 11 November 2013
Accepted 16 November 2013
Available online 1 December 2013
Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been
described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into
(ꢀ)-swainsonine, (þ)-1,2-di-epi-swainsonine, (þ)-8,8a-di-epi-castanospermine, pentahydroxy in-
dolizidines, (ꢀ)-1-deoxynojirimycin, (ꢀ)-1-deoxy-altro-nojirimycin, and related diversity. The key steps
were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective
dihydroxylation.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
responsible for the anti-mannosidase activity.12 It has been sug-
gested that their rigid, bicyclic structures are responsible for their
New applications of natural and synthetic glycosidase in-
hibitors continue to mount interest in basic research and medi-
cine. Swainsonine,1 Castanospermine,2 and their derivatives
belong to indolizidine class of glycosidase inhibitors, and have
generated much interest due to their potent and selective glyco-
sidase inhibition activities and consequently exhibit significant
anticancer, antitumor,3 antimetastatic, immunoregulating,4 and
anti-HIV5 properties. In addition to this, it was established that
structural modifications in iminosugars induce significant changes
in their biological activity, their potency, or their specificity as
inhibitors of immunomodulators6 as well as glycosidases.7
Therefore several analogues have been synthesized and used as
biochemical tools and have been examined as chemotherapeutic
agents against diabetes,8 cancers,9 and HIV.10 It is believed that
their activity is the result of their ability to mimic the transition
state involved in substrate hydrolysis. For example, the similarity
of the six-membered ring of castanospermine to the glucosyl
cation, is responsible for the activity of castanospermine against
glucosidases.11 In a less evident way, resemblance of the five
membered ring of swainsonine to the mannosyl cation is
potent activity. 1-Deoxynojirimycin (DNJ)13 belongs to poly-
hydroxylated piperidine class of glycosidase inhibitors and inhibits
a
-glucosidases I and II.14 In addition to this, it also exhibits
promising antiviral15 and anticancer activities. Miglitol16 and
Miglustat,17 two of these synthetic analogues of polyhydroxylated
piperidines are drugs against type-2 diabetes and Gaucher’s dis-
ease, respectively. (ꢀ)-1-Deoxy-altro-nojirimycin; an analogue of
nojirimycin, also shows modest activity towards glycosidases.18
The biological activity of these above mentioned indolizidine
and piperidines, coupled with their complex structural features,
have led to many stereoselective syntheses of these natural alka-
loids to date. Majority of syntheses of these alkaloids involve
chemical transformations of monosaccharides, however, with the
development in field of enantioselective synthesis, non-
carbohydrate syntheses have also been reported.19e21 Even
though, the development of new expeditious stereodivergent ap-
proaches furnishing compounds in enantiomerically pure form
from a common precursor remains a worthwhile job.
Recently, we reported,22 the total syntheses of natural alkaloids
Epiquinamide and Conhydrin, using ring-closing metathesis.23,24 We
envisaged that key intermediate 1, readily prepared in a few steps
from Garner aldehyde24 derived from
L-serine, could be a versatile
precursor for the diastereoselective total synthesis of the natural
isomer of swainsonine. We also demonstrate here that compound 1 is
* Corresponding
gautam_panda@cdri.res.in (G. Panda).
author.
E-mail
addresses:
gautam.panda@gmail.com,
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.074

1364
P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
a versatile precursor for the diastereoselective synthesis of the alka-
loids (þ)-8,8a-di-epi-castanospermine, (þ)-1,2-di-epi-swainsonine,
(1S,2R,6S,7R,8S,8aS)-ctahydroindolizidine-1,2,6,7,8-pentol, (1R,2S,6S,
with 47% and 3% overall yield, respectively, from 1. The exact ste-
reochemistry of compound 6 was confirmed from the ultimate
conversion of major intermediate 6 into
With compound 6 and 7 in hand, we proceeded towards total
synthesis of -altro-1-deoxy-nojirimycin and -1-deoxy-nojir-
L-altro-deoxynojirimycin.
7R,8S,8aS)-octahydroindolizidine-1,2,6,7,8-pentol,
altro-nojirimycin, N-(3-hydroxypropyl)-altro-DNJ, N-(2-hydroxye
thyl)-altro-DNJ and N-butyl-altro-DNJ, and (ꢀ)-1-deoxynojirimycin.
(ꢀ)-1-deoxy-
L
L
imycin. Removal of N-Boc of 6 by acid treatment provided amino
28
alcohol 8 (Scheme 3), which on hydrogenolysis with PdCl2/H2
afforded
NMR, IR, and mass spectra of
those reported earlier.20 Using the similar synthetic sequence, mi-
nor isomer 7 was converted in
-DNJ in 85% yield from 7. The 1H, 13
-1-DNJ were in agreement with those
L
-altro-1-DNJ in 29% overall yield from 1. The 1H, 13C
2. Results and discussions
L
-altro-1-DNJ were in agreement with
The synthesis of (þ)-8,8a-di-epi-castanospermine, (ꢀ)-1-deoxy-
altro-nojirimycin, N-(3-hydroxypropyl)-altro-DNJ, N-(2-hydroxye
L
C
NMR, IR, and mass spectra of
reported earlier.20
L
thyl)-altro-DNJ and N-butyl-altro-DNJ and (ꢀ)-1-deoxynojirimycin,
L-
altro-deoxy-nojirimycin, (1S,2R,6S,7R,8S,8aS)-octahydroindolizidine-
1,2,6,7,8-pentol, and (1R,2S,6S,7R,8S,8aS)-octahydroindolizidine-1,2,6,
7,8-pentol commenced from 1.
Our first aim was to introduce epoxy functionality on the double
bond of 1, while it yielded a complex mixture of products under
standard conditions, (Scheme 1). The silyl ether 1, upon desilylation
followed by NaH treatment at 0 ꢁC furnished oxazolidinone 3,
which on stereoselective epoxidation via in situ generated dime-
thyldioxirane (DMDO)25 gave mixture of epoxides 426 (overall yield
85.7% from 1), (Scheme 2). 1H NMR spectra of 4 showed that di-
astereomers were in 70:30 ratios. As the diastereoisomers were
inseparable, the stereochemistry of epoxidation was determined
from the subsequent steps.
Scheme 3. Synthesis of L-altro-1-DNJ and L-DNJ.
Synthesis of N-butyl-altro-DNJ, N-(2-hydroxyethyl)-altro-DNJ,
and N-(3-hydroxypropyl)-altro-DNJ were easily achieved in two
steps from amino alcohol 8 (Scheme 4). N-Butyl-DNJ was obtained
through N-alkylation of 8 with n-butyl bromide giving 9 followed
by hydrogenolysis with PdCl2/H2 in 85% yield after ion-exchange
chromatography. Similarly N-(2-hydroxyethyl)-DNJ and N-(3-
hydroxypropyl)-DNJ were obtained by N-alkylation of 8 with 2-
bromoethanol and 3-bromo propanol providing 10 and 11, re-
spectively, followed by hydrogenolysis in 82% and 85% yields, re-
spectively, after ion-exchange chromatography.
Scheme 1.
Scheme 2. Conversion of 1 to advanced precursor 6.
Scheme 4. Synthesis of L-altro-DNJ analogues.
With the mixture of epoxides in hand, opening of this ring was
explored. Towards this objective, use of BF3$OEt2 and benzyl alco-
hol in DCM on epoxides 4 was unsuccessful. On the other hand,
NaHSO4 and water treatment on epoxides 4 led to the recovery of
starting material. It was decided that more strongly acidic condi-
tions were necessary to provide the desired products. Treatment of
epoxides 4 with sulfuric acid (1 M) in a 1:1 water/dioxane27 mix-
ture afforded the diols, which were protected as benzyl ethers 5 in
75% yields. 1H NMR spectra of 5 showed the mixture of di-
astereomers. Moreover, diastereomers were inseparable at this
stage as well, thus we proceeded further with the mixture of di-
astereomers. Hydrolysis of the oxazolidinone 5 under basic condi-
tion followed by protection of amine using Boc anhydride furnished
two pure diastereomers 6 and 7 (95:5) in seven synthetic steps
Next, we turned our attention to conversion of 6 into (þ)-8,8a-
di-epi-castanospermine containing stereochemically well-defined
hydroxylated carbon center C-1. Thus, the construction of pyrroli-
dine ring was initiated through intramolecular aminomercuration
strategy.29
The synthesis commenced with oxidation of alcohol 6 to cor-
responding aldehyde 12 by the use of DesseMartin periodinane30
(DMP) as an oxidant in basic media, followed by addition of vinyl
magnesium bromide at ꢀ78 ꢁC furnishing separable diastereomeric
mixture (3:1) of anti/syn products31 13 and 14 (Scheme 5). In order
to establish the stereochemistry of newly generated carbinol in 13,
it was converted into oxazolidinone 16 and its 2D NMR studies
confirmed the structure of 13 (Scheme 6).

P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1365
Scheme 5. Synthesis of (þ) 8,8a-di-epi-castanospermine.
Scheme 6. Stereochemical assignment of 13.
Treatment of 13 under acidic condition provided b-hydroxy-g-
alkenylamine, which on exposure with mercury (II) acetate in THF/
water at room temperature, followed by the reductive demercu-
ration with NaBH4, afforded exclusively 5-endo-trig-cyclized prod-
uct 15 in 71% yield. Similar treatment on 14 did not yield any
cyclized product because of unfavorable conformation. It could be
explained by the fact that products were formed due to hydroxyl
directed mercuration.32 The reactivity difference towards mercu-
ration of compounds 13 and 14 may depend on the possible tran-
sition states arising from amines derived from 13 and 14,
respectively.33 As shown in hydroxyl directed mercuration (Fig. 1),
Hg2þ approaches from the same side of hydroxyl in 13 and 14 but
experiences less steric interaction in 13 compared to 14. Sub-
sequently, from the opposite side, nucleophilic attack of secondary
amine in 13 furnished compound 15 whereas 14 did not.
Scheme 7. Synthesis of pentahydroxylated indolizidines.
In Kishi’s empirical model, the substrate reacts in such conforma-
tion that minimizes A1,3 strain. For 13, conformation I is highly fa-
vored as there is no A1,3 strain, yielding only one diastereoisomer.
Whereas in 14, conformation II is disfavored due to A1,3 strain fur-
nishing two diastereomers (4:1), Fig. 2.
OH
OH
H
O
H
H
H
H
H
O
N
H
H
OsO4
A1,3 strain
maximized
O
N
OsO4
I
O
II
Fig. 2. Conformational model of 13 and 14.
Fig. 1. Possible transition states of amines derived from 13 and 14.
Treatment of triol 17 with trifluoroacetic acid resulted in N-Boc
hydrolysis and gave the amino triol 18 in 76% yields, which was
further used in next step without purification. Finally under Mit-
sunobu reaction conditions36 with pyridine as the solvent, 18 un-
derwent cyclization to give indolizidine 19 in a combined yield of
39.7% from 13 after purification of the crude reaction mixture by
column chromatography. Hydrogenolysis of 19 under conditions
using PdCl2/H2 gave 21 in 86% yields after ion-exchange chroma-
tography. A similar reaction sequence, with triol 22, afforded 26. The
target molecules were characterized by spectral and analytical
techniques.
The stereochemistry of final compounds was confirmed on the
basis of NOESY spectrum of acetylated products 20 and 25. The
significant NOESY correlations are shown in Fig. 3. In 20, H-1
showed the NOESY correlation to H-2 and H-8 whereas in 25 H-1
showed the NOESY correlation with H-2 and H-8a. All these cor-
relations confirmed the stereochemistry of final compounds.
Hydrogenolysis of 15 with PdCl2/H2 furnished (þ) 8,8a-di-epi-
castanospermine with 82% yields after ion-exchange chromatog-
raphy and overall 15% yield from intermediate 1. The 1H, 13C NMR,
IR, and mass were in agreement with those reported earlier.21
A modified strategy is required for the synthesis of pentahy-
droxylated indolizidine derivatives as they have one extra hydroxyl
group at 2-position of indolizidine ring than castanospermine,
Scheme 7. To achieve this goal allylic alcohol 13 and 14 underwent
dihydroxylation34 reaction using Upjohn condition to furnish triol
17 as the only isolable diastereomer in case of 13 in 78% yield and
the major diastereomers 22 along with its minor isomer in ratio 4:1
in case of 14.
The stereochemical outcome of this dihydroxylation (DH) re-
action could be explained by Kishi’s model.35 Addition of bulky
osmium reagent occurred from the face opposite to the hydroxy
group because of the repulsion of the oxygen lone pairs with OsO4.

1366
P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
Fig. 3. NOESY correlation for 20 and 25.
The synthetic sequences involved the selective double bond
reduction through hydrogenation using H2/10% PdeC/triethyl
amine followed by desilylation of TBS ether of 27. The resulting
alcohol 28 was oxidized to the corresponding aldehyde, which on
addition of vinyl magnesium bromide at ꢀ78 ꢁC, afforded the
separable diastereomeric mixture (3:1) of anti/syn products 29 and
30, respectively, in good yields (Scheme 8).
Scheme 10. Synthesis of (þ)-1,2-di-epi-swainsonine and (ꢀ)-swainsonine.
Mitsunobu reaction conditions36 with pyridine as solvent produced
the desired indolizidine products 34 and 37 in 65% yields. Hydro-
genolysis of 34 and 37 by PdCl2/H2 gave (þ)1,2-di-epi-swainsonine
and (ꢀ)-Swainsonine in 86% and 85% yield, respectively, after ion-
exchange chromatography and overall 23% and 7% from in-
termediate 1. The 1H and 13C NMR spectral data were in consonance
with that reported in the literature.12 The stereochemistry was also
determined by 2D NMR spectra of their acetate derivatives 35 and
38. The stereochemical outcome of this DH reaction could be
explained by the same way as has been described in 13 and 14.
Scheme 8. Conversion of compound 1 into key intermediates 28 and 29.
Now having the intermediate 29 with all the stereocenters in
place as of the target molecule, we set out to prepare for the cy-
clization followed by dihydroxylation (Scheme 9). The palladium-
catalyzed intramolecular amination are very much known in lit-
erature so we thought to use this methodology for cyclization.
Hydroxy group of intermediate 29 was converted to its acetate
derivative 31. Acidic hydrolysis of N-Boc carbamate gave 32. The
intramolecular amination of amine 32 by using [Pd(PPh3)4], tri-
phenylphosphine and triethyl amine as the base at 80 ꢁC in ace-
tonitrile was unsuccessful. Whereas use of Pd(PPh3)4 and
trimethylguanidine as base in THF under nitrogen atmosphere at
40e55 ꢁC led to recovery of starting material.37 However use of
strong basic condition, PdCl2 and tetrabutylammonium bromide
(TBAB) as a stabilizer in the presence of Cs2CO3 led to de-
composition of starting material.38 Disappointing with these re-
sults, we planned to modify our strategy. Modified synthetic plan
involved, dihydroxylation of intermediate followed by cyclization.
3. Conclusions
Diverse and straightforward syntheses of (ꢀ)-swainsonine,
(þ)-1,2-di-epi-swainsonine, (þ)-8,8a-di-epi-castanospermine, (1S,
2R,6S,7R,8S,8aS)-octahydroindolizidine-1,2,6,7,8-pentol and (1R,2S,
6S,7R,8S,8aS)-octahydroindolizidine-1,2,6,7,8-pentol, (ꢀ)-1-deoxy
nojirimycin, (ꢀ)-1-deoxy-altro-nojirimycin, N-(3-hydroxypropyl)-
altro-DNJ, N-(2-hydroxyethyl)-altro-DNJ, and N-butyl-altro-DNJ
have been described from easily accessible common chiral in-
termediate. Hydroxy directed intramolecular aminomercuration,
and diastereoselective dihydroxylation were the key easily exe-
cutable synthetic sequences, which gave access to a large number
of polyhydroxylated indolizidines, piperidines, and their related
diversity. Bioevaluation of this series is underway.
4. Experimental
4.1. General methods
Organic solvents were dried by standard methods. All the
products were characterized by 1H, 13C, two-dimensional homo-
nuclear COSY (correlation spectroscopy), heteronuclear single
quantum coherence (HSQC), Nuclear Overhauser effect spectros-
copy (NOESY), IR, ESI-MS, HRMS (direct analysis in real time, DART),
and HRMS (quadrupole time of flight, Q-TOF). Analytical TLC was
performed using 2.5ꢂ5 cm plates coated with a 0.25 mm thickness
of silica gel (60F-254) using UV light as visualizing agent and an
acidic solution of ninhydrin, and heat as developing agents. Column
chromatography was performed using silica gel (60e120 and
100e200 mesh). NMR spectra were recorded on 300 MHz (1H) and
50, 75 MHz (13C). Experiments were recorded in CDCl3 and D2O at
Scheme 9. Attempted cyclization of 29.
Application of Upjohn dihydroxylation (DH)32 on another key
intermediate 29, furnished the triol 33 as the only isolable di-
astereomer in 78% yield whereas 30 gave triol 36 as major product
(85%) along with its minor diastereomeric triol (15%). With N-Boc
cleavage of triols 33 and 36 under acidic condition (TFA/DCM)
yielded corresponding amino triols, which were further used in
subsequent steps without purification (Scheme 10). Nevertheless,
our effort to cyclize the amino-triol under Appel cyclization re-
action conditions39 were unsuccessful and resulted into a complex
mixture of products. Finally treatment of amino triols under
25 ꢁC. Chemical shifts are given on the
d scale and are referenced to

P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1367
the TMS at 0.00 ppm for proton and 0.00 ppm for carbon. For 13C
NMR reference CDCl3 appeared at 77.00 ppm. IR spectra were
recorded on FT-IR spectrophotometers. Optical rotations were de-
termined by using a 1 dm cell at 25 ꢁC in chloroform, methanol, and
water as the solvents; concentrations mentioned are in g/100 mL.
slowly added, and the resulting aqueous phase was extracted with
Et2O. The combined organic fractions were washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography to
furnish 5 as a white semi solid (553 mg, 75%). Eluent for column
chromatography: EtOAc/Hexane (10/40, v/v); Rf 0.35 (1.5/3.5 EtOAc/
4.1.1. (8R,8aS)-8-(Benzyloxy)-8,8a-dihydro-1H-oxazolo[3,4-a]pyr-
idin-3(5H)-one: 3. To a cooled (0 ꢁC) solution of alcohol 2 (50.0 mg,
0.15 mmol) in dry THF (2.25 mL) was added sodium hydride
(7.48 mg, 0.31 mmol), in one portion, under nitrogen atmosphere
and allowed to stir for 1 h at same temperature. After completion of
reaction, it was quenched by addition of saturated aqueous NH4Cl,
and extracted with ethyl acetate (3ꢂ5 mL). The combined organic
phase was dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by silica gel flash column chroma-
tography to afford 3 (36.43 mg, 95%) as a white semi solid. Eluent
Hexane); 1H NMR (300 MHz, CDCl3)
d 7.34e7.23 (15H, m, ArH),
4.73e4.61 (2H, m, OCH2Ph), 4.54 (2H, d, J¼11.1 Hz, OCH2Ph),
4.38e4.29 (m, 3H, OCH2Ph, CHAHBO), 4.06e4.01 (m, 1H, CHOBn),
3.99e3.75 (m, 3H, 2CHOBn, CHAHBO), 3.74e3.68 (2H, m, NCHAHB,
CHN), 3.20 (1H, dd, J¼14.3, 1.4 Hz, NCHAHB); 13C NMR (50 MHz,
CDCl3)
d 158.0, 137.8, 137.5, 137.3, 128.5, 128.4, 128.0, 127.9, 127.8,
127.77,127.73,127.6, 75.5, 73.3, 72.9, 72.7, 71.3, 70.8, 65.7, 52.9, 38.6;
IR (neat, cmꢀ1) 3398, 3020, 2363, 1752, 1218, 1077, 766; mass (ESI-
MS) m/z 460 [MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd for C28H30NO5
[MþH]ꢄþ: 460.21240, measured 460.21250.
for column chromatography: EtOAc/Hexane (17.5/32.5, v/v), ½a D28
ꢃ
ꢀ1.5 (c 0.37, CH3OH); Rf 0.50 (1/1 EtOAc/Hexane) 1H NMR
4.1.4. (2S,3S,4R,5S)-tert-Butyl
3,4,5-tris(benzyloxy)-2-(hydroxyme
(300 MHz, CDCl3)
d
7.37e7.31 (5H, m, ArH), 5.98e5.79 (2H, m, CH]
thyl)piperidine-1-carboxylate: 6. To the solution of oxazolidinone 5
(1 g, 2.18 mmol) in EtOH (7.72 mL), an aqueous solution of KOH
(2 M, 7.72 mL) was added. The mixture was allowed to reflux for
12 h. After completion of reaction, it was cooled to room temper-
ature, diluted with water, and extracted with ethyl acetate. The
combined organic fraction was washed with water, followed by
brine, and dried over anhydrous Na2SO4. Then organic fraction was
concentrated under reduced pressure to give colorless oil. The
residue was used without further purification. To the solution of
crude amino alcohol (946 mg, 2.18 mmol) in water (2.18 mL),
(Boc)2O (2.62 mmol, 0.60 mL) was added, and allowed to stir for 1 h.
The reaction mixture was diluted with water, and extracted with
ethyl acetate (35 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated under vacuo.
Purification by flash chromatography afforded compound 6 as
major (850 mg, 73.2%) and 7 as minor products (44 mg, 3.8%).
For 6: white gum, eluent for column chromatography: EtOAc/
CH), 4.72 (1H, d, J¼11.6 Hz, OCH2Ph), 4.54e4.43 (2H, m, OCH2Ph,
CHAHBO), 4.13e4.06 (2H, m, 2CHAHBO, CHOBn), 3.95e3.92 (1H, m,
CHN), 3.69e3.57 (2H, m, NCH2); 13C NMR (75 MHz, CDCl3)
d 157.2,
137.3, 128.6, 128.2, 127.9, 126.4, 124.9, 74.0, 71.2, 67.4, 54.5, 40.9,
29.6; IR (neat, cmꢀ1) 3021, 2365, 1752, 1520, 1426, 1216, 1087, 763,
671; mass (ESI-MS) m/z 246 [MþH]ꢄþ; HRMS (DART) calcd for
C
14H16NO3 [MþH]ꢄþ: 246.11302, measured 246.11522.
4.1.2. (6aS,7S)-7-(Benzyloxy)tetrahydro-1aH-oxazolo[3,4-a]oxireno
[2,3-d]pyridin-4(2H)-one: 4. To a stirred mixture of 3 (860 mg,
3.51 mmol), NaHCO3 (4.42 g, 52.60 mmol), acetone (75.57 mL), and
water (37.74 mL), oxone (10.82 g, 17.60 mmol) was added in por-
tions over half an hour at 0 ꢁC. The resulting mixture was stirred at
room temperature, for four hours. After completion of reaction, it
was diluted with ethyl acetate and washed with water followed by
brine. The organic layer was dried over Na2SO4. The solvent was
evaporated, and the residue was purified by silica gel column
chromatography to furnish 4 (870 mg, 95%) as white semi solid.
Eluent for column chromatography EtOAc/Hexane (30/20, v/v); Rf
0.55 (EtOAc); IR (Neat, cmꢀ1) 3428, 3022, 2364, 1744, 1652, 1522,
Hexane (13/37, v/v); ½a D28
þ2.2 (c 0.94, MeOH); Rf 0.48 (2/3 EtOAc/
ꢃ
Hexane); IR (neat, cmꢀ1) 3442, 2926, 1671, 1419, 1368, 1107, 745,
698; 1H NMR (300 MHz, CDCl3)
d 7.37e7.23 (15H, m, ArH),
4.74e4.55 (6H, m, OCH2Ph), 4.50 (1H, s, CHAHBOH), 4.4e4.26 (1H,
m, CHAHBOH), 3.91 (1H, q, J¼13.3 Hz, CHOBn), 3.79 (1H, t, J¼2.6 Hz,
CHOBn), 3.71e3.64 (1H, m, OH), 3.56 (2H, m, CHN, NCHAHB), 2.78
(1H, t, J¼10.9 Hz, NCHAHB), 1.42 (9H, s, CMe3); 13C NMR (75 MHz,
1427, 1216, 765, 672; 1H NMR (300 MHz, CDCl3)
d 7.38e7.35 (m, 5H,
ArH), 4.80 (1H, dd, J¼11.8, 2.0 Hz, OCH2Ph), 4.6 (1H, m, OCH2Ph)
4.30e4.10 (1H, m, CHAHBO), 4.06e3.70 (m, 3H, CHAHBO, CHN,
NCHAHB), 3.57e3.40 (m, 3H, NCHAHB, CHO), 3.36e3.29 (m, 1H,
CDCl3)
d 155.8, 138.4, 138.1, 128.3, 128.2, 127.8, 127.6, 127.58, 127.5,
CHO); 13C NMR (75 MHz, CDCl3)
d
157.0, 137.0, 136.6, 128.8, 128.7,
127.4, 80,4, 79.1, 74.7, 73.7, 72.9, 72.3, 71.5, 59.9, 55.9, 42.9, 28.3;
128.5, 128.4, 128.1, 128.0, 75.4, 73.0, 72.1, 71,5, 67.3, 65.9, 53.9, 52.8,
mass (ESI-MS) m/z 556 [MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd for
52.6, 52.5, 51.6, 49.6, 39.5, 38.8; mass (ESI-MS) m/z found 262
C
32H39NNaO6 [MþNa]þ: 556.26751, measured 556.26621.
þ
[MþH]ꢄþ, HRMS (ESI TOF (þ)): calcd for C14H16NO4 [MþH]ꢄ
:
262.10793, measured 262.10723.
4.1.5. (2S,3S,4S,5R)-tert-Butyl 3,4,5-tris(benzyloxy)-2-(hydroxymet
hyl)piperidine-1-carboxylate: 7. White gum, eluent for column
4.1.3. (8S,8aS)-6,7,8-Tris(benzyloxy)tetrahydro-1H-oxazolo[3,4-a]
pyridin-3(5H)-one: 5. To the solution of 4 (420 mg, 1.60 mmol) in
a mixture of dioxane and water (1:1, 80 mL), an aqueous H2SO4
solution (1 M, 4.8 mL, 4.81 mmol) was added, and the mixture was
allowed to stir at 80 ꢁC for 12 h. A saturated aqueous NaHCO3 so-
lution (50 mL) was added, and the mixture was stirred at room
temperature for 10 min. The aqueous phase was extracted with
ethyl acetate. The combined organic extracts were washed with
brine, and dried over Na2SO4. The organic fraction was concen-
trated in vacuo to give diols as a white gum. The residue was used
without further purification. To a solution of the crude diols
(426 mg, 1.52 mmol) in dry DMF (20 mL), NaH (182.9 mg, 60%
mineral oil dispersion, and 7.62 mmol) was slowly added at 0 ꢁC.
The suspension was stirred at 0 ꢁC until the evolution of H2 had
chromatography: EtOAc/Hexane (13/37, v/v); ½a D28
þ0.6 (c 1.04,
ꢃ
MeOH); Rf 0.47 (2/3 EtOAc/Hexane); IR (neat, cmꢀ1) 3442, 2926,
1671, 1419, 1368, 1107, 745, 698; 1H NMR (300 MHz, CDCl3)
d
7.32e7.29 (15H, m, ArH), 4.77e4.64 (5H, m, OCH2Ph), 4.54 (d,
J¼11.7 Hz, 1H, OCH2Ph), 3.85 (m, 1H, CHAHBOH), 3.78e3.75 (m, 1H,
CHOBn), 3.73e3.65 (m, 2H, CHOBn, CHAHBOH), 3.62e3.55 (m, 3H,
CHOBn, CHN, NCHAHB), 3.16 (m, 1H, NCHAHB), 1.42 (9H, s, CMe3);
13C NMR (50 MHz, CDCl3)
d 155.7, 138.1, 138.08, 138.04, 128.4, 128.3,
127.9, 127.8, 127.7, 83.3, 80.6, 77.9, 76.0, 73.6, 73.5, 71.2, 61.5, 59.3,
43.2, 28.3; mass (ESI-MS) m/z 556 [MþNa]þ; HRMS (ESI TOF (þ)):
calcd for C32H39NNaO6 [MþNa]þ: 556.26751, measured 556.26621.
4.1.6. ((2S,3S,4R,5S)-3,4,5-Tris(benzyloxy)piperidin-2-yl)methanol:
8. To a stirred solution of compound 6 (150 mg, 0.34 mmol) in dry
DCM (15 mL), 50% TFA in DCM was added at 0 ꢁC. After completion
of the reaction, it was quenched by saturated solution of NaHCO3,
and aqueous layer was extracted with DCM. The combined organic
ceased (10 min) followed by the addition of benzyl bromide (400 ml,
3.35 mmol), and the mixture was allowed to stir at room temper-
ature for 3 h. At 0 ꢁC, saturated aqueous NH4Cl solution (30 mL) was

1368
P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated under vacuo to a colorless oil, which on column
chromatographic purification gave the pure compound 8 (white
gum, 87 mg, 72%). Eluent for column chromatography: MeOH/
J¼7.19 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3)
d 138.6, 138.5, 138.3,
128.3, 127.9, 127.6, 75.1, 74.8, 73.6, 72.5, 72.3, 71.5, 60.6, 57.9, 53.4,
49.0, 28.2, 20.5, 13.9; (ESI-MS) m/z 490 [MþH]ꢄþ; EI-HRMS: calcd
þ
for C31H40NO4 [MþH]ꢄ 490.29573, measured 490.29383.
CHCl3 (2.5/47.5, v/v). ½a D28
ꢀ2.5 (c 1.0, MeOH); Rf 0.5 (1/9, MeOH/
ꢃ
CHCl3); IR (neat, cmꢀ1) 3449, 2925, 2856, 2364, 1688, 1218, 1094,
4.1.10. (2S,3S,4R,5S)-1-Butyl-2-(hydroxymethyl)
piperidine-3,4,5-
771; 1H NMR (300 MHz, CDCl3)
d
7.33e7.23 (15H, m, ArH),
triol: (N-butyl, -altro-DNJ). To a solution of compound 9 (50 mg,
L
4.67e4.39 (6H, m, OCH2Ph), 4.07 (1H, t, J¼6.5 Hz, CHAHBOH), 3.98
(1H, d, J¼1.2 Hz, CHOBn), 3.80e3.69 (3H, m, OH, 2CHOBn),
3.65e3.59 (1H, m, CHAHBOH), 3.07e2.99 (1H, m, CHN), 2.89 (1H,
dd, J¼11.9, 3.1 Hz, NCHAHB), 2.66 (1H, dd, J¼11.9, 2.3 Hz, NCHAHB),
0.102 mmol) in MeOH (1 mL) was added catalytic amount of PdCl2.
The mixture was stirred at room temperature under an atmosphere
of H2 (balloon) for 3 h. The mixture was filtered through a Celite pad
and the filtrates were evaporated in vacuo, then the residue was
dissolved in water (1 mL) and applied to a column of Amberlyst
IRA-100 basic ion-exchange resin. Elution with water (30 mL) fol-
lowed by evaporation of the eluent in vacuo gave the title product
2.27 (1H, br s, NH); 13C NMR (75 MHz, CDCl3)
d 138.3, 138.1, 137.9,
128.4, 128.3, 128.2, 127.7, 127.6, 85.6, 75.0, 73.8, 72.8, 71.7, 71.4, 69.6,
59.3, 46.5; (ESI-MS) m/z 434 [MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd
for C27H32NO4 [MþH]ꢄþ 434.23313, measured 434.23093.
(19.0 mg, 85%) as a white foam. ½a D28
ꢃ
þ1.8 (c 0.24, H2O); IR (neat,
cmꢀ1) 3600e3200; 1H NMR (300 MHz, D2O)
d
4.06 (1H, t, J¼4.6 Hz,
4.1.7. (2S,3S,4R,5S)-2-(Hydroxymethyl)piperidine-3,4,5-triol [
L
-altro-
CHAHBOH), 3.93e3.87 (2H, m, CHOH, CHAHBOH), 3.81e3.75 (2H, m,
CHOH), 2.94e2.93 (1H, m, CHN), 2.86 (1H, dd, J¼12.5, 4.3 Hz,
NCHAHBCHOH), 2.69 (2H, t, J¼7.5 Hz, NCH2CH2, NCHAHBCHOH),
2.63e2.56 (1H, m, NCHAHBCHOH), 1.56e1.48 (2H, m, CH2CH2),
1.41e1.31 (2H, m, CH2CH3), 0.95 (3H, s, CH3); 13C NMR (75 MHz,
1-deoxynojirimycin]. To solution of compound (50 mg,
a
8
0.11 mmol) in MeOH (1 mL) was added catalytic amount of PdCl2.
The mixture was stirred at room temperature under an atmosphere
of H2 (balloon) for 1 h. The mixture was filtered through a Celite
pad, and the filtrates were evaporated in vacuo. The residue was
dissolved in water (1 mL), and applied to a column of Amberlite
IRA-400 basic ion-exchange resin. Elution with water (30 mL) fol-
lowed by evaporation of the eluent in vacuo, gave the title product
D2O)
d
71.5, 68.6, 6þ7.6, 62.2, 56.8, 53.1, 51.9, 27.6, 20.2,13.3; (ESI-MþS)
m/z 220 [MþH]ꢄ
;
EI-HRMS: calcd for C10H22NO4 [MþH]ꢄ
:
220.15488, measured 220.15368.
L
-altro-1-deoxynojirimycin (16 mg, 85%). ½a D28
ꢃ
ꢀ3.73 (c 0.2, H2O);
4.1.11. 2-((2S,3S,4R,5S)-3,4,5-Tris(benzyloxy)-2-(hydroxymethyl)pi-
peridin-1-yl)ethanol: 10. To the stirred solution of compound 8
(55 mg, 0.126 mmol) in dry acetone (8 mL) was added 2-
bromoethanol (17.43 mg, 0.139 mmol), K2CO3 (26.12 mg,
0.189 mmol), and catalytic amount of KI (2.09 mg, 0.0126 mmol).
The reaction mixture was allowed to reflux for overnight. After
completion of reaction it was cooled to room temperature and
acetone was removed in vacuum, diluted with water, and extracted
with ethyl acetate (5 mLꢂ3). The combined organic layer was
washed with brine and dried over anhydrous Na2SO4 and concen-
trated under vacuum to colorless oil, which on column chromato-
graphic purification gave the pure compound (white gum, 55 mg,
90.9%).
1H NMR (300 MHz, D2O)
d 3.87 (1H, m, CHAHBOH), 3.82 (1H, m,
CHAHBOH), 3.75 (1H, dd, J¼9.4, 2.8 Hz, CHOH), 3.69e3.68 (2H, m,
CHOH), 2.81 (1H, dd, J¼14.2, 1.87 Hz, CHN), 2.77e2.67 (2H, m,
CH2N); 13C NMR (75 MHz, D2O)
d 70.7, 69.4, 66.4, 60.9, 55.7, 44.6; IR
(neat, cmꢀ1) 3600e3200; (ESI-MS) m/z 164 [MþH]ꢄþ; HRMS (ESI
TOF (þ)): calcd for C6H14NO4 [MþH]ꢄþ: 164.09228, measured
164.09258.
4.1.8. (2S,3S,4S,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol
(L-
DNJ). Reaction was performed in same manner as for compound 8
and
L
-DNJ, compound 7 (50 mg, 0.115 mmol), afforded L-DNJ.
(16 mg, 85%). ½a 2D8
ꢃ
ꢀ10.7 (c 0.6, H2O); IR (neat, cmꢀ1) 3600e3200;
1H NMR (300 MHz, D2O)
d
3.71 (dd, J¼11.8, 3.0 Hz, 1H, CHAHBOH),
White semi solid, eluent for column chromatography: EtOAc/
3.52 (dd, J¼11.3, 6.0 Hz, 1H, CHAHBOH), 3.42e3.34 (m, 1H, CHOH),
3.21 (t, J¼9.3 Hz, 1H, CHOH), 3.12 (t, J¼9.3 Hz, 1H, CHOH), 3.05 (dd,
J¼12.3, 5.0 Hz, 1H, CHN); 2.49e2.46 (m, 1H, NCHAHBOH), 2.37 (dd,
Hexane (25/25, v/v). ½a D28
ꢀ2.6 (c 0.82, MeOH); Rf 0.3 (1/1 EtOAc/
ꢃ
Hexane); IR (neat, cmꢀ1) 3416, 2925, 2856, 2364, 1647, 1454, 1218,
1094, 768; 1H NMR (300 MHz, CDCl3)
d 7.35e7.25 (15H, m, ArH),
J¼12.2, 11.0 Hz, 1H, NCHAHBOH); 13C NMR (75 MHz, D2O)
d
81.1,
4.67e4.30 (9H, m, 3OCH2Ph, 2OH, CHOBn), 3.98 (1H, dd, J¼11.56,
3.51 Hz, CHAHBOH), 3.79 (t, J¼2.91 Hz, 1H, CHOBn), 3.67e3.54 (m,
4H, CHAHBOH, CHOBn, CH2OH), 2.69e2.62 (2H, m, NCHAHBCH2OBn,
CHN), 2.57e2.53 (2H, m, NCHAHBCH2OH, NCHAHBCH2OBn), 2.27 (d,
74.2, 73.6, 64.1, 63.3, 51.4; (ESI-MS) m/z 164 [MþH]ꢄþ; HRMS (ESI
TOF (þ)): calcd for C6H14NO4 [MþH]ꢄþ: 164.09228, measured
164.09258.
J¼10.9 Hz, 1H, NCHAHBCH2OH); 13C NMR (75 MHz, CDCl3)
d 138.3,
4.1.9. ((2S,3S,4R,5S)-3,4,5-Tris(benzyloxy)-1-butylpiperidin-2-yl)
methanol: 9. To the stirred solution of compound 8 (42 mg,
0.0968 mmol) in dry acetone (6 mL) was added 1-bromobutane
(0.0156 mL, 0.1453 mmol), K2CO3 (26.75 mg, 0.1936 mmol), and
catalytic amount of KI (1.6 mg, 0.00968 mmol). The reaction mix-
ture was allowed to reflux for overnight. After completion of re-
action, it was cooled to room temperature and acetone was
removed in vacuum, diluted with water, and extracted with ethyl
acetate (5 mLꢂ3). The combined organic layer was washed with
brine and dried over anhydrous Na2SO4 and concentrated under
vacuum to colorless oil, which on column chromatographic puri-
fication gave the pure compound (white gum, 36 mg, 75.9%).
White semi solid, eluent for column chromatography: EtOAc/
138.1, 137.9, 128.4, 127.9, 127.7, 127.6, 76.1, 73.9, 72.6, 71.8, 71.4, 71.2,
64.4, 63.1, 62.5, 57.7, 52.2; (ESI-MS) m/z 478 [MþH]ꢄþ; EI-HRMS:
calcd for C29H36NO5 [MþH]ꢄþ 478.25935, measured 478.25815.
4.1.12. (2S,3S,4R,5S)-1-(2-Hydroxyethyl)-2-(hydroxymethyl)piperi-
dine-3,4,5-triol: N-(2-hydroxyethyl)-altro-DNJ. To
a solution of
compound 10 (50 mg, 0.105 mmol) in MeOH (1 mL) was added
catalytic amount of PdCl2. The mixture was stirred at room tem-
perature under an atmosphere of H2 (balloon) for 3 h. The mixture
was filtered through a Celite pad and the filtrates were evaporated
in vacuo, then the residue was dissolved in water (1 mL) and ap-
plied to a column of Amberlyst IRA-100 basic ion-exchange resin.
Elution with water (30 mL) followed by evaporation of the eluent in
Hexane (7/43, v/v). ½a D28
ꢃ
4.6 (c 1.55, MeOH); Rf 0.8 (1/1, EtOAc/
vacuo gave the title product (17.8 mg, 82%) as a colorless solid. ½a D28
ꢃ
Hexane); IR (neat, cmꢀ1) 3473, 2949, 2839, 1649, 1454, 1024, 751;
ꢀ1.8 (c 0.23, H2O); IR (neat, cmꢀ1) 3600e3200; 1H NMR (300 MHz,
1H NMR (300 MHz, CDCl3)
d
7.32e7.28 (15H, m, ArH), 4.65e4.46
D2O)
d
4.15e4.06 (2H, m, CHAHBOH, CHOH), 4.01 (d, J¼3.5 Hz, 1H,
(6H, m, 3OCH2Ph), 3.87 (1H, d, J¼7.18 Hz, CHAHBOH), 3.78e3.69 (m,
4H, CHAHBOH, 3CHOBn), 2.85e2.69 (m, 5H, NCH2CHOBn, NCH2CH2,
OH), 2.56 (m, 1H, CHN), 1.45e1.38 (m, 4H, CH2CH2CH3), 0.90 (t,
CHOH), 3.98 (d, J¼2.5 Hz, 1H, CHOH), 3.95 (br s, 2H, CHAHBOH,
CHAHBOHCH2), 3.57 (s, 1H, CHAHBOHCH2), 3.35 (d, J¼12.5 Hz, 1H,
NCHAHBCHOBn, CHN), 3.26e3.24 (m, 2H, NCHAHBCH2,

P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1369
NCHAHBCHOBn), 3.12 (d, J¼12.5 Hz, 1H, NCHAHBCH2); 13C NMR
layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated under vacuo to a colorless oil, which on column
chromatographic purification, gave the pure compound Colorless
oil, 13 (118 mg, 56%). Eluent for column chromatography: EtOAc/
(75 MHz, D2O)
d 68.4, 66.4, 63.9, 62.5, 59.0, 58.4, 54.1, 43.9; (ESI-
MS) m/z 208 [MþH]þ; EI-HRMS: calcd for C8H15NO5 [MþH]þ:
208.11850, measured 208.11891.
Hexane (6.5/43.5, v/v); ½a D28
þ9.8 (c 1.08, CHCl3); Rf 0.4 (2/8, EtOAc/
ꢃ
4.1.13. 3-((2S,3S,4R,5S)-3,4,5-Tris(benzyloxy)-2-(hydroxymethyl)pi-
peridin-1-yl)propan-1-ol: 11. To the stirred solution of compound 8
(40 mg, 0.09 mmol) in dry acetone (8 mL) was added 3-chloro
propanol (0.007 mL, 0.10 mmol), K2CO3 (19.07 mg, 0.14 mmol),
and catalytic amount of KI (1.52 mg, 0.01 mmol). The reaction
mixture was allowed to reflux for overnight. After completion of
reaction it was cooled to room temperature and acetone was re-
moved in vacuum, diluted with water, and extracted with ethyl
acetate (5 mLꢂ3). The combined organic layer was washed with
brine and dried over anhydrous Na2SO4, and concentrated under
vacuum to colorless oil, which on column chromatographic puri-
fication gave the pure compound (white gum, 35 mg, 77%).
Hexane); IR (neat, cmꢀ1) 3451, 2921, 2858, 2348, 1680, 1218, 1102,
769; 1H NMR (300 MHz, CDCl3)
d 7.35e7.24 (15H, m, ArH),
5.86e5.79 (1H, m, CH]CH2), 5.23e5.12 (2H, m, CH2]CH),
4.78e4.74 (1H, m, CHOH), 4.67e4.50 (6H, m, 3OCH2Ph), 4.26e4.22
(2H, m, 2CHOBn), 4.08 (1H, s, CHOBn), 3.97 (1H, br s, OH), 3.76e3.74
(1H, m, CHN), 2.69e2.49 (2H, m, CH2NBoc), 1.42 (9H, s, CMe3); 13
C
NMR (75 MHz, CDCl3) d 155.2, 138.6, 138.5, 138.3, 137.9, 128.3, 128.2,
127.7, 127.6, 127.4, 117.2, 80.2, 79.2, 74.7, 73.2, 72.1, 71.6, 71.3, 57.9,
42.5, 28.3; (ESI-MS) m/z 582 [MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd
for C34H42NO6 [MþH]ꢄþ: 560.30121, measured 560.30120.
4.1.16. (2S,3S,4R,5S)-tert-Butyl 3,4,5-tris(benzyloxy)-2-((R)-1-
hydroxyallyl)piperidine-1-carboxylate: 14. Colorless oil, (39 mg,
19%) eluent for column chromatography: EtOAc/Hexane (7/43, v/v);
Off white semi solid, eluent for column chromatography: EtOAc/
Hexane (25/25, v/v). ½a D28
ꢀ2.6 (c 0.82, MeOH); Rf 0.35 (3/2, EtOAc/
ꢃ
Hexane); IR (neat, cmꢀ1) 3391, 2925, 2363, 1588, 1217, 1091, 771; 1H
½
a 2D8
ꢃ
þ3.7 (c 0.98, CHCl3); Rf 0.35 (2/8, EtOAc/Hexane); IR (neat,
cmꢀ1) 3747, 2925, 2860, 2365, 1684, 1219, 1102, 769; 1H NMR
(300 MHz, CDCl3) 7.34e7.24 (15H, m, ArH), 5.65e5.53 (1H, m,
NMR (300 MHz, CDCl3)
d 7.32e7.25 (15H, m, ArH), 4.69e4.40 (6H,
m, 3OCH2Ph), 3.92e3.88 (2H, m, CH2OH), 3.85e3.76 (2H, m,
CH2OH), 3.69e3.68 (1H, m, CHOBn), 3.62 (1H, br s, CHOBn),
3.15e3.05 (1H, m, CHOBn), 2.98e2.83 (4H, m, CHN, CH2N),
2.72e2.64 (1H, m, CHAHBN), 2.54e2.59 (1H, m, CHAHBN),
d
CH]CH2), 5.07e4.99 (2H, m, CH2]CH), 4.76 (1H, br s, CHOH),
4.68e4.40 (6H, m, OCH2Ph), 4.21e4.12 (1H, m, CHOBn), 4.06 (1H, t,
J¼7.9 Hz, CHOBn), 3.94 (1H, br s, CHOBn), 3.67 (1H, t, J¼2.8 Hz,
CHN), 3.52 (1H, d, J¼6.2 Hz, OH), 2.75e2.66 (2H, m, CH2NBoc), 1.43
2.05e2.00 (2H, m, CH2CH2OH); 13C NMR (75 MHz, CDCl3)
d 138.5,
138.3, 138.0, 128.4, 128.38, 128.36, 128.3, 128.1, 127.71, 127.67,
127.62, 74.7, 73.8, 72.9, 72.6, 72.3, 71.5, 71.4, 63.2, 62.4, 52.6, 50.1,
33.8; (ESI-MS) m/z 492 [MþH]ꢄþ; EI-HRMS: calcd for C30H38NO5
[MþH]ꢄþ 492.27500, measured 492.27540.
(9H, s, CMe3); 13C NMR (75 MHz, CDCl3)
d 155.8, 138.5, 138.4, 137.9,
128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 118.1, 80.6, 78.5, 74.8,
73.2, 72.2, 70.4, 71.5, 71.3, 58.0, 43.5, 28.2; (ESI-MS) m/z 582
þ
[MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd for C34H42NO6 [MþH]ꢄ
:
560.30121, measured 560.30121.
4.1.14. (2S,3S,4R,5S)-2-(Hydroxymethyl)-1-(3-hydroxypropyl)piperi-
dine-3,4,5-triol: (N-(3-hydroxypropyl)-altro-DNJ). To a solution of
compound 11 (50 mg, 0.10 mmol) in MeOH (1 mL) was added
catalytic amount of PdCl2. The mixture was stirred at room tem-
perature under an atmosphere of H2 (balloon) for 3 h. The mixture
was filtered through a Celite pad and the filtrates were evaporated
in vacuo, then the residue was dissolved in water (1 mL) and ap-
plied to a column of Amberlyst IRA-100 basic ion-exchange resin.
Elution with water (30 mL) followed by evaporation of the eluent in
4.1.17. (1S,6S,7R,8S,8aS)-6,7,8-Tris(benzyloxy)octahydroindolizin-1-
ol: 15. To a stirred solution of compound 13 (150 mg, 0.26 mmol) in
dry DCM (15 mL), 50% TFA in DCM was added at 0 ꢁC. After com-
pletion of the reaction, it was quenched by saturated solution of
NaHCO3, and aqueous layer was extracted with DCM. The combined
organic layer was washed with brine and dried over anhydrous
Na2SO4. After concentration in vacuo, the crude amine was used in
the next step without further purification. To a stirred solution of
amine (100 mg, 0.21 mmol) in THF/water (1:1, 1.6 mL) was added
Hg(OAc)2 (138.8 mg, 0.43 mmol), and the reaction mixture was
vacuo gave the title product (19.1 mg, 85%) as a colorless foam. ½a D28
ꢃ
ꢀ1.4 (c 0.4, H2O); IR (neat, cmꢀ1) 3600e3200; 1H NMR (300 MHz,
D2O)
d
4.05 (1H, m, CHAHBOH), 3.92e3.89 (m, 2H, CHAHBOH,
stirred at room temperature for 3 h. Sodium borohydride
CHOBn), 3.82e3.76 (m, 2H, 2CHOBn), 3.70 (2H, t, J¼6.0 Hz, CH2OH),
2.92 (2H, m, CHAHBN,CHN), 2.81 (2H, t, J¼7.8 Hz, NCH2CH2),
2.63e2.57 (1H, m, CHAHBN), 1.85e1.76 (2H, m, CH2CH2OH); 13C
(32.95 mg, 0.87 mmol) was added over a period of 10 min. THF was
removed under reduced pressure, and the residue was extracted
with chloroform. The combined organic portion was washed with
brine, dried over anhydrous Na2SO4, and concentrated under vac-
uum to a colorless oil, which on column chromatographic purifi-
cation gave the pure compound 15 (87.5 mg, 71%).
NMR (75 MHz, D2O)
d 71.5, 68.6, 67.58, 62.9, 60.7, 56.8, 51.6, 50.6,
21.9; (ESI-MS) m/z 222 [MþH]ꢄþ; EI-HRMS: calcd for C9H20NO5
[MþH]ꢄþ: 222.13415, measured 222.13155.
White gum, eluent for column chromatography: EtOAc/Hexane
4.1.15. (2S,3S,4R,5S)-tert-Butyl 3,4,5-tris(benzyloxy)-2-((S)-1-
hydroxyallyl)piperidine-1-carboxylate: 13. To a solution of alcohol
6 (200 mg, 0.37 mmol) in anhydrous CH2Cl2 (20 mL) under a ni-
trogen atmosphere, was added DesseMartin periodinane
(238.4 mg, 0.56 mmol) at 0 ꢁC. The reaction mixture was allowed to
stir at ambient temperature for 30 min. Then, the reaction was
quenched with aqueous saturated Na2S2O3 (10 mL), the organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine
(15 mL), dried over Na2SO4, and concentrated under vacuo to obtain
the aldehyde 12, which was used as such for the next step without
purification. To a solution of aldehyde in dry THF under N2 atmo-
sphere at ꢀ78 ꢁC, vinyl magnesium bromide was added and
allowed to stir for one hour at same temperature. After completion
of reaction, it was quenched with saturated solution of NH4Cl, and
extracted with ethyl acetate (10 mLꢂ3). The combined organic
(36/14, v/v). ½a D28
þ2.1 (c 0.26, MeOH); Rf 0.35 (EtOAc); IR (neat,
ꢃ
cmꢀ1) 3416, 2925, 2856, 2364, 1647, 1454, 1218, 1094, 768; 1H NMR
(300 MHz, CDCl3)
d 7.34e7.24 (15H, m, ArH), 4.61e4.36 (6H, m,
OCH2Ph), 4.15e4.07 (m, 1H, CHOH), 3.78e3.73 (m, 2H, 2CHOBn),
3.58 (1H, d, J¼2.3 Hz, CHOBn), 2.99 (1H, dt, J¼8.5, 2.21 Hz, CHN), 2.89
(1H, dd, J¼12.0, 1.7 Hz, CHAHBN), 2.51e2.39 (3H, m, CH2N, CHAHBN),
2.32e2.22 (1H, m, CHAHBCHOH), 1.63e1.54 (1H, m, CHAHBCHOH);
13C NMR (75 MHz, CDCl3)
d 138.4, 138.3, 137.9, 128.6, 128.4, 128.3,
127.9, 127.8, 127.7, 127.6, 79.5, 75.4, 74.9, 72.5, 72.1, 71.8, 70.9, 67.1,
52.1, 51.5, 30.5; (ESI-MS) m/z 460 [MþH]ꢄþ; HRMS (ESI TOF (þ)):
calcd for C29H34NO4 [MþH]ꢄþ 460.2487, measured 460.2475.
4.1.18. (1S,6S,7R,8S,8aS)-Octahydroindolizine-1,6,7,8-tetraol [(þ)-8-
8a-di-epi-castanospermine]. To a solution of compound 15 (50 mg,
0.11 mmol) in methanol (1 mL) was added catalytic amount of
PdCl2. The mixture was stirred at room temperature under an

1370
P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
atmosphere of H2 (balloon) for 1 h. The mixture was filtered
through a Celite pad, and the filtrates were evaporated in vacuo,
then the residue was dissolved in water (1 mL) and applied to
a column of Amberlyte IRA-400 basic ion-exchange resin. Elution
with water (35 mL) followed by evaporation of the eluent in vacuo
gave the title product (þ)-8,8a-di-epi-castanospermine (16.8 mg,
compound 17 (500 mg, 0.84 mmol) in dry DCM (5 mL), 50% TFA in
DCM was added. After completion of the reaction, the mixture was
basified at 0 ꢁC with aqueous NH3 solution (28%). The mixture was
extracted with DCM, dried over Na2SO4, and concentrated under
vacuo to give crude amine 18, which was further used without puri-
fication. To a solution of triol amine (315 mg, 0.64 mmol) in pyridine,
under nitrogen atmosphere at 0 ꢁC was added triphenylphosphine
(199.3 mg, 0.76 mmol) and diisopropyl azodicarboxylate (0.12 mL,
0.76 mmol). The mixture was stirred at same temperature for 1 h.
After completion of reaction, solvent was removed under vacuo to
give crude indolizidine (203 mg, 67%). To the stirred solution of 19
(203 mg, 0.47 mmol) in pyridine (10 mL) at 0 ꢁC was added acetic
anhydride (239.9 mg, 2.35 mmol) and catalytic amount of dimethy-
laminopyridine. The mixture was stirred at room temperature for
overnight. The usual workup followed by separation by column
chromatography afforded diacetate 20 (195.9 mg, 82%); Rf 0.6 (1:1
EtOAc/Hexane); IR (neat, cmꢀ1) 2364, 1742, 1617, 1225, 1098, 769; 1H
82%). ½a 2D8
ꢃ
þ13.8 (c 0.15, H2O); IR (neat, cmꢀ1) 3600e3200; 1H NMR
(300 MHz, D2O)
d 4.29 (1H, m, CHOH), 4.00 (1H, m, CHOH), 3.98
(1H, br s, CHOH), 3.89 (1H, dd, J¼9.0, 3.0 Hz, CHOH), 3.01 (1H, dt,
J¼9.5, 2.1 Hz, CHN), 2.94 (1H, dd, J¼12.4, 2.3 Hz, CHAHBN),
2.67e2.56 (2H, m, CH2N), 2.36 (1H, t, J¼9.0 Hz, CHAHBN), 2.28e2.25
(1H, m, CHAHBCHOH), 1.67e1.64 (1H, m, CHAHBCHOH); 13C NMR
(75 MHz, D2O) d 76.3, 73.4, 72.3, 72.0, 70.2, 54.6, 53.7, 33.6; (ESI-MS)
m/z 190 [MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd for C8H17NO4
[MþH]ꢄþ: 190.10793, measured 190.10813.
4.1.19. (1S,6S,7R,8S,8aS)-6,7,8-Tris(benzyloxy)-1-vinyltetrahydro-
1H-oxazolo[3,4-a]pyridin-3(5H)-one: 16. To a cooled (0 ꢁC) solution
of 13 (50 mg, 0.11 mmol) in dry THF (1.5 mL) was added sodium
hydride in one portion under nitrogen atmosphere (5.21 mg,
0.22 mmol), and the suspension was allowed to reflux for 1 h,
quenched by addition of saturated aqueous NH4Cl, and extracted
with ethyl acetate (3ꢂ10 mL). The combined organic phase was
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography to
afford 16 (41 mg, 95%) as a white gum.
NMR (300 MHz, CDCl3) d 7.23e7.15 (15H, m, ArH), 5.19e5.12 (2H, m,
CHOAc), 4.61 (1H, d, J¼12.6 Hz, OCH2Ph), 4.45e4.28 (5H, m, OCH2Ph),
3.69e3.66 (1H, m, CHOBn), 3.63 (1H, br s, CHOBn), 3.49 (2H, br s,
CHOBn, CHN), 2.84e2.81 (2H, m, NCHAHB), 2.55e2.47 (1H, m,
NCHAHB), 2.28e2.56 (1H, m, NCHAHB),1.95 (3H, s, CH3CO), 1.83 (3H, s,
CH3CO); 13C NMR (75 MHz, CDCl3)
d 170.0, 169.8, 138.4, 138.2, 138.1,
128.4, 128.3, 128.29, 127.85, 127.82, 127.7, 127.6, 78.7, 74.6, 73.5, 72.9,
72.5, 71.7, 71.4, 68.7, 61.4, 58.1, 50.5, 20.7, 20.6; (ESI-MS) m/z 560
[MþH]ꢄþ; EI-HRMS: calcd for C33H38NO7 [MþH]ꢄþ: 560.26480, mea-
sured 560.26370.
Colorless oil, eluent for column chromatography: EtOAc/Hexane
(7/43, v/v); ½a 2D8
þ5.1 (c 0.67, CHCl3); Rf 0.5 (3/7, EtOAc/Hexane); IR
ꢃ
(neat, cmꢀ1) 3021, 2365, 1752, 1216, 763; 1H NMR (300 MHz, CDCl3)
4.1.22. (1R,2S,6S,7R,8S,8aS)-Octahydroindolizine-1,2,6,7,8-pentaol:
21. To a solution of compound 19 (50 mg, 0.10 mmol) in MeOH
(1 mL) was added catalytic amount of PdCl2. The mixture was
stirred at rt under an atmosphere of H2 (balloon) for 3 h. The
mixture was filtered through a Celite pad and the filtrates were
evaporated in vacuo, then the residue was dissolved in water (1 mL)
and applied to a column of Amberlyst IRA-100 basic ion-exchange
resin. Elution with water (30 mL) followed by evaporation of the
eluent in vacuo gave the title product 21 (18.5 mg, 86%) as a white
d
7.23e7.12 (15H, m, ArH), 5.92e5.81 (1H, m, CH]CH2), 5.45 (1H, d,
J¼17.1 Hz, CH2]CH), 5.20 (1H, d, J¼10.9 Hz, CH2]CH), 5.0 (1H, t,
J¼6.5 Hz, CHN), 4.66 (1H, d, J¼11.9 Hz, OCHAHBPh), 4.56 (1H, d,
J¼11.9 Hz, OCHAHBPh), 4.43 (1H, d, J¼11.9 Hz, OCHAHBPh),
4.35e4.20 (3H, m, OCHAHBPh, OCH2Ph), 4.08e4.01 (1H, m, CHOH),
3.92e3.87 (2H, m, CHAHBN, CHOH), 3.69 (1H, dd, J¼10.3, 2.3 Hz,
CHAHBN), 3.60 (1H, d, J¼3.9 Hz, CHOH), 3.14 (1H, d, J¼13.6 Hz,
CHOH); 13C NMR (75 MHz, CDCl3)
d 157.5, 137.8, 137.6, 137.3, 131.2,
128.4, 128.37, 127.8, 127.6, 117.4, 76.2, 73.1, 73.0, 72.6, 72.5, 70.6,
70.4, 56.6, 38.7; (ESI-MS) m/z 486 [MþH]ꢄþ; HRMS (ESI TOF (þ)):
calcd for C30H32NO5 [MþH]ꢄþ: 486.22805, measured 486.23105.
foam. ½a 2D8
ꢃ
þ0.3 (c 0.7, D2O); IR (neat, cmꢀ1) 3600e3200; 1H NMR
(300 MHz, D2O)
d 4.28e4.25 (1H, m, CHOH), 3.98 (3H, br s, CHOH),
3.87 (1H, d, J¼9.3 Hz, CHOH), 3.58e3.41 (2H, m, CHN, NCHAHB),
2.90 (1H, d, J¼11.9 Hz, NCHAHB), 2.62 (1H, d, J¼12.6 Hz, NCHAHB),
2.43 (1H, t, J¼9.3 Hz, NCHAHB), 2.36e2.31 (1H, m, NCHAHB); 13C
4.1.20. (2S,3S,4R,5S)-tert-Butyl
3,4,5-tris(benzyloxy)-2-((1R,2S)-
1,2,3-trihydroxypropyl)piperidine-1-carboxylate: 17. To a solution of
allylic alcohol 13 (175 mg, 0.38 mmol) in a 10:1 mixture of acetone/
H2O (4.15 mL) was added N-methylmorpholine N-oxide (61.68 mg,
0.526 mmol) and 4% aqueous OsO4, (1.1 mL). The reaction mixture
was stirred at room temperature for 3 h. After addition of aqueous
NaHSO3 solution (1 mL), the mixture was stirred for an additional
1 h at room temperature and extracted with EtOAc (3ꢂ10 mL). The
combined organic layer was washed with brine and dried over
anhydrous Na2SO4 and concentrated under vacuum to a colorless
oil, which on column chromatographic purification gave the pure
compound 17 (colorless thick liquid, 105 mg, 78%).
NMR (75 MHz, D2O)
d
73.5, 71.0, 70.2, 69.5, 67.3, 65.1, 59.5, 52.þ2;
(ESI-MS) m/z 206 [MþH]ꢄþ; EI-HRMS: calcd for C8H16NO5 [MþH]ꢄ
:
206.1028, measured 206.1038.
4.1.23. (2S,3S,4R,5S)-tert-Butyl
3,4,5-tris(benzyloxy)-2-((1S,2R)-
1,2,3-trihydroxypropyl)piperidine-1-carboxylate: 22. The reaction of
N-methylmorpholine N-oxide (61.68 mg, 0.53 mmol) and OsO4
(1.0 mL) with allylic alcohol (120 mg, 0.26 mmol) was performed
under similar reaction conditions as described for 17 followed by
purification by column chromatography gave pure product 22
(colorless thick liquid, 75 mg, 80%).
Colorless oil, eluent for column chromatography: EtOAc/Hexane
Colorless thickliquid, eluent for column chromatography: EtOAc/
(30/20, v/v); ½a D28
þ27.2 (c 0.32, CHCl3); Rf 0.6 (EtOAc); IR (neat,
ꢃ
Hexane (25/25, v/v); Rf 0.5 (EtOAc); IR (neat, cmꢀ1) 3470, 3394, 2927,
cmꢀ1) 3470, 3394, 2927, 1722, 1640, 1217, 768; 1H NMR (300 MHz,
1722,1640,1217, 768; 1H NMR (300 MHz, CDCl3)
d 7.24e7.18 (15H, m,
CDCl3)
d
7.24e7.18 (15H, m, ArH), 4.6e4.45 (6H, m, OCH2Ph), 4.36
ArH), 4.60e4.45 (6H, m, OCH2Ph), 4.36 (1H, br s, CHAHBOH), 4.23
(1H, t, J¼6.4 Hz, CHOH), 4.14 (1H, dd, J¼5.8, 3.4 Hz, CHAHBOH),
4.02e4.00 (1H, m, CHOH), 3.91 (1H, br s, CHOBn), 3.88 (1H, br s,
CHOBn), 3.70 (4H, m, CHOBn), 3.37e3.36 (1H, m, CHN), 2.98 (1H, t,
J¼12.3 Hz, NCHAHB), 2.23 (1H, t, J¼7.2 Hz, NCHAHB), 1.34 (9H, s,
CMe3); (ESI-MS) m/z 593; found 616 [MþNa]ꢄþ; EI-HRMS: calcd for
(1H, br s, CHAHBOH), 4.23 (1H, t, J¼6.4 Hz, CHOH), 4.14 (1H, dd,
J¼5.8, 3.4 Hz, CHAHBOH), 4.02e4.00 (1H, m, CHOH), 3.91 (1H, br s,
CHBn), 3.88 (1H, br s, CHBn), 3.70 (4H, m, CHBn), 3.37e3.36 (1H, m,
CHN), 2.98 (1H, t, J¼12.3 Hz, NCHAHB), 2.23 (1H, t, J¼7.20 Hz,
NCHAHB), 1.34 (9H, s, CMe3); (ESI-MS) m/z 616 [MþNa]ꢄþ; EI-HRMS:
calcd for C34H43NO8 [M]ꢄþ: 593.29887, measured 593.30817.
C
34H43NO8 [M]ꢄþ: 593.29882, measured 593.30812.
4.1.21. (1R,2S,6S,7R,8S,8aR)-6,7,8-Tris(benzyloxy)octahy-
4.1.24. (1S,2R,6S,7R,8S,8aR)-6,7,8-Tris(benzyloxy)octahydroindolizine-
droindolizine-1,2-diyl diacetate: 20. To the stirred solution of
1,2-diyl diacetate: 25. Reaction was performed in same manner as for

P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1371
compound 20 (165 mg, 32% over four steps). Yellowish liquid, eluent
chromatography: EtOAc/Hexane (13.5/26.5, v/v). ½a D28
ꢃ
þ1.4 (c 0.83,
for column chromatography: EtOAc/Hexane (12/38, v/v); ½a D28
ꢃ
ꢀ18.5
MeOH); Rf 0.3 (1/1 EtOAc/Hexane); IR (neat, cmꢀ1) 3418, 2936,
(c 0.39, CHCl3); Rf 0.4 (3:7 EtOAc/Hexane); IR (neat, cmꢀ1) 2364, 1742,
2364, 1654, 1433, 1057, 745; 1H NMR (300 MHz, CDCl3)
d 7.33e7.24
1617, 1225, 1098, 769; 1H NMR (300 MHz, CDCl3)
d
7.25e7.11 (15H, m,
(5H, m, ArH), 4.62 (1H, d, J¼11.8 Hz, OCH2Ph), 4.51e4.47 (2H, m,
OCH2Ph, CHAHBOH), 3.98 (1H, d, J¼12 Hz, CHAHBOH), 3.75 (1H, t,
J¼8.2 Hz, NCHAHB), 3.64e3.57 (2H, m, NCHAHB), 2.9e2.82 (1H, m,
CHN), 2.30 (1H, br s, OH), 1.96e1.85 (2H, m, CH2CHOBn), 1.66e1.53
(2H, m, CH2CH2NBoc), 1.45 (9H, s, CMe3); 13C NMR (50 MHz, CDCl3)
ArH), 5.45e5.44 (1H, m, CHOAc), 5.20 (1H, t, J¼6.3 Hz, CHOAc),
4.49e4.46 (2H, m, OCH2Ph), 4.39e4.32 (2H, m, OCH2Ph), 4.29e4.23
(2H, m, OCH2Ph), 3.92 (1H, d, J¼7.9 Hz, CHOBn), 3.70 (1H, t, J¼2.8 Hz,
CHOBn), 3.50 (1H, br s, CHOBn), 2.95e2.91 (2H, m, CHN, NCHAHB),
2.68 (m, 1H, NCHAHB), 2.58 (m, 1H, NCHAHB), 2.34 (d, J¼9.4 Hz, 1H,
NCHAHB), 1.95 (3H, s, CH3CO), 1.92 (3H, s, CH3CO); 13C NMR (75 MHz,
d
156.4,138.6,128.3,127.4, 79.9, 71.5, 70.1, 60.7, 55.7, 39.6, 28.4, 25.3,
þ
19.4; (ESI-MS) m/z 322 [MþH]ꢄ
; HRMS (DART): calcd for
CDCl3)
d
170.3, 170.1, 138.25, 138.23, 137.9, 128.4, 128.3, 127.9, 127.8,
C
18H28NO4 [MþH]ꢄþ 322.20183, measured 322.20179.
127.7, 127.6, 74.2, 74.0, 72.7, 72.2, 71.5, 71.46, 71.3, 70.2, 63.1, 58.9, 51.0,
20.6; (ESI-MS) m/z 560 [MþH]ꢄþ; EI-HRMS: calcd for C33H38NO7
[MþH]ꢄþ: 560.26483, measured 560.26373.
4.1.28. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((S)-1-hydroxyallyl)piper-
idine-1-carboxylate: 29. To a solution of 28 (180 mg, 0.56 mmol) in
anhydrous CH2Cl2 (15 mL), under a nitrogen atmosphere was added
DesseMartin periodinane (356.28 mg, 0.84 mmol) at 0 ꢁC and the
reaction mixture was allowed to stir at ambient temperature for
30 min. Then, the reaction was quenched with aqueous solution of
saturated Na2S2O3 (10 mL), the organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine (15 mL), dried over Na2SO4, and
concentrated under vacuo to obtain the aldehyde, which was used
as such for the next step without purification. To a solution of al-
dehyde in dry THF, under N2 atmosphere at ꢀ78 ꢁC, vinyl magne-
sium bromide (1 M solution in THF, 1.68 mL) was added and
allowed to stir for one hour at same temperature. After completion
of reaction, it was quenched with saturated solution of NH4Cl, and
extracted with ethyl acetate (10 mLꢂ3). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated under vacuo to a colorless oil, which on column
chromatographic purification gave the pure compound 29 (color-
less oil, 109 mg, 56.2% in two steps). Eluent for column chroma-
4.1.25. (1S,2R,6S,7R,8S,8aS)-Octahydroindolizine-1,2,6,7,8-pentaol:
26. To a solution of compound 25 (50 mg, 0.11 mmol) in MeOH
(1 mL) was added catalytic amount of PdCl2. The mixture was
stirred at rt under an atmosphere of H2 (balloon) for 3 h. The
mixture was filtered through a Celite pad and the filtrates were
evaporated in vacuo, then the residue was dissolved in water (1 mL)
and applied to a column of Amberlyst IRA-100 basic ion-exchange
resin. Elution with water (30 mL) followed by evaporation of the
eluent in vacuo gave the title product 26 (18.2 mg, 85%) as a color-
less foam. IR (neat, cmꢀ1) 3600e3200; 1H NMR (300 MHz, D2O)
d
4.38e4.32 (1H, m, CHOH), 4.2e4.18 (1H, m, CHOH), 4.06 (1H, dd,
J¼10.3, 3.3 Hz, CHOH), 3.95 (1H, t, J¼3.3 Hz, CHOH), 3.89e3.88 (1H,
m, CHOH), 2.88 (m, 1H), 2.84 (1H, m, CHN), 2.60e2.54 (1H, m,
NCHAHB), 2.44 (1H, d, J¼1.6 Hz, NCHAHB), 2.40 (1H, d, J¼1.6 Hz,
NCHAHB), 2.33 (1H, dd, J¼10.2, 3.7 Hz, NCHAHB); 13C NMR (75 MHz,
D2O)
d 70.6, 70.1, 69.6, 69.2, 65.3, 65.1, 59.9, 51.9; (ESI-MS) m/z 206
[MþH]ꢄþ; EI-HRMS: calcd for C8H16NO5 [MþH]ꢄþ: 206.10285,
measured 206.10315.
tography: EtOAc/Hexane (7/43, v/v); ½a D28
ꢃ
þ17.5 (c 5.10, CHCl3); Rf
0.4 (1.2/7.8, EtOAc/Hexane); 1H NMR (300 MHz, CDCl3)
d
7.25e7.16
4.1.26. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((tert-butyl dimethylsily-
loxy)methyl)piperidine-1-carboxylate: 27. To a solution of com-
pound 1 (668.0 mg, 1.54 mmol) in methanol, catalytic amount of
triethyl amine (31.17 mg, 0.04 mL, 0.31 mmol) and 10% Pd/C was
added, and the solution was stirred under the pressure of H2 at-
mosphere in balloon at room temperature for 4 h. After completion
of the reaction, it was filtered through Celite, and the solvent was
evaporated under vacuum, which on column chromatographic
provided the pure product 27 (665 mg, 99%) as colorless oil. Eluent
(5H, m, ArH), 5.83 (1H, m, CH]CH2), 5.18 (1H, d, J¼17.3 Hz, CH2]
CH), 5.08 (1H, d, J¼10.3 Hz, CH2]CH), 4.55 (1H, d, J¼11.9 Hz,
OCH2Ph), 4.39 (1H, d, J¼11.9 Hz, OCH2Ph), 4.22 (2H, m, CHOH,
CHOBn), 4.00 (1H, br s, OH), 3.83 (1H, m, CHN), 2.64 (br s, 1H,
NCHAHB), 2.08 (br s, 1H, NCHAHB), 1.83e1.68 (m, 4H, CH2CHOBn,
CH2CH2NBoc), 1.35 (9H, s, CMe3); 13C NMR (300 MHz, CDCl3)
d
155.6, 138.9, 128.4, 128.1, 127.2, 116.8, 79.5, 71.1, 70.0, 57.2, 39.2,
28.4, 24.8, 19.4; (ESI-MS) m/z 370 [MþNa]ꢄþ; HRMS (ESI TOF (þ)):
calcd for C20H29NNaO4 [MþNa]ꢄþ: 370.19943, measured 370.19833.
for column chromatography: EtOAc/Hexane (2/48, v/v). ½a D28
þ2.2
ꢃ
(c 0.24, MeOH); Rf 0.5 (1/9 EtOAc/Hexane); IR (neat, cmꢀ1) 3441,
4.1.29. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((R)-1-hydroxyallyl)piper-
3020, 2364, 1676, 1216, 762, 670; 1H NMR (300 MHz, CDCl3)
idine-1-carboxylate: 30. Colorless oil (36.5 mg, 18.8%) eluent for
d
7.35e7.28 (5H, m, ArH), 4.64 (1H, d, J¼10.4 Hz, OCH2Ph),
column chromatography: EtOAc/Hexane (8/42, v/v); ½a D28
þ10.8 (c
ꢃ
4.52e4.35 (2H, m, OCH2Ph), 4.08 (1H, br s, CHAHBO), 3.74e3.68 (3H,
m, NCHAHB, CHN, CHAHBO), 2.79 (1H br s, NCHAHB), 1.87e1.68 (4H,
m, CH2CHOBn, CH2CH2NBoc), 1.47 (9H, s, CMe3), 0.89 (9H, s,
2.92, CHCl3); Rf 0.35 (1.2/7.8, EtOAc/Hexane); IR (neat, cmꢀ1) 3399,
2928, 2360, 1665, 1424, 1150, 769; 1H NMR (300 MHz, CDCl3)
d
7.35e7.24 (5H, m, ArH), 5.91e5.79 (1H, m, CH]CH2), 5.26 (1H, d,
SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (75 MHz, CDCl3)
d
155.5,
J¼17.2 Hz, CH2]CH), 5.15 (1H, d, J¼10.3 Hz, CH2]CH), 4.63 (1H, d,
J¼11.8 Hz, OCH2Ph), 4.47 (1H, d, J¼11.8 Hz, OCH2Ph), 4.29 (2H, m,
CHOBn, CHOH), 4.07 (1H, br s, CHN), 3.90 (1H, m, NCHAHB), 2.72
(1H, m, NCHAHB), 1.91e1.71 (4H, m, CH2CHOBn, CH2CH2NBoc), 1.53
138.8, 128.2, 127.3, 79.3, 71.2, 69.9, 61.1, 55.1, 39.1, 28.4, 25.8, 24.6,
19.4, 18.1, ꢀ5.4, ꢀ5.5; (ESI-MS) m/z 436 [MþH]ꢄþ, 336 [M-Boc];
þ
HRMS (DART): calcd for C24H42NO4Si [MþH]ꢄ 436.28831, mea-
sured 436.28781.
(9H, s, CMe3); 13C NMR (50 MHz, CDCl3)
d 155.6, 138.9, 138.4, 128.2,
127.2, 116.8, 79.5, 71.1, 70.0, 57.0, 39.2, 28.4, 24.8, 19.4; (ESI-MS) m/z
370 [MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd for C20H29NNaO4
[MþNa]ꢄþ: 370.19943, measured 370.19833.
4.1.27. (2S,3R)-tert-Butyl
3-(benzyloxy)-2-(hydroxymethyl)piperi-
dine-1-carboxylate: 28. To a cooled solution of 27 (890 mg,
2.04 mmol) in dry THF (10 mL), solution of TBAF (1.0 M in THF,
5.0 mL) was added, and allowed to stir for 30 min. After completion
of the reaction, mixture was concentrated in vacuo, the residue was
diluted with ethyl acetate. The combined organic layer was washed
with water followed by brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated under vacuum to colorless oil,
which on column chromatographic purification gave the pure
compound 28 as white gum (636 mg, 95%). Eluent for column
4.1.30. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((1R,2S)-1,2,3-
trihydroxypropyl)piperidine-1-carboxylate: 33. To a solution of 29
(146 mg, 0.42 mmol) in a 10:1 mixture of acetone/H2O (6.6 mL) was
added N-methylmorpholine N-oxide (98.51 mg, 0.84 mmol) and 4%
aqueous OsO4, (1.0 mL). The reaction mixture was stirred at room
temperature for 3 h. After addition of aqueous NaHSO3 solution
(1 mL), the mixture was stirred for an additional 1 h at room

1372
P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
temperature, and extracted with EtOAc (3ꢂ10 mL). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuo to a colorless oil, which on column
chromatographic purification gave the pure compound 33 (color-
less oil, 125 mg, 78%). Eluent for column chromatography: EtOAc/
in MeOH (1 mL) was added catalytic amount of PdCl2. The mixture
was stirred at room temperature under an atmosphere of H2 (bal-
loon) for 1 h. The mixture was filtered through a Celite pad and the
filtrates were evaporated in vacuo, then the residue was dissolved
in water (1 mL) and applied to a column of Amberlyte IRA-100 basic
ion-exchange resin. Elution with water (30 mL) followed by evap-
oration of the eluent in vacuo gave the title product (þ)-1,2-di-epi-
Hexane (35/15, v/v); ½a D28
þ5.0 (c 1.04, CHCl3); Rf 0.7 (EtOAc); IR
ꢃ
(neat, cmꢀ1) 3417, 2370, 1629, 1219, 771; 1H NMR (300 MHz, CDCl3)
d
7.32e7.23 (5H, m, ArH), 4.62 (1H, d, J¼11.7 Hz, OCH2Ph), 4.47 (1H,
swainsonine (28.3 mg, 86%) as a colorless solid. ½a D28
þ6 (c 2.25,
ꢃ
d, J¼11.7 Hz, OCH2Ph), 4.38 (1H, br s, CHAHBOH), 4.08 (1H, d,
J¼6.99 Hz, CHOH), 3.94 (2H, m, CHOH, CHAHBOH), 3.86e3.84 (1H,
m, CHOBn), 3.71 (1H, m, CHN), 3.58 (1H, brs, NCHAHB), 2.77 (1H, t,
J¼12.4 Hz, NCHAHB), 1.90e1.72 (4H, m, CH2CH2N, CH2CHOBn), 1.42
(9H, s, CMe3); (ESI-MS) m/z 404 [MþNa]ꢄþ; HRMS (ESI TOF (þ)):
calcd for C20H31NNaO6 [MþNa]ꢄþ: 404.20491, measured 404.20521.
MeOH); IR (neat, cmꢀ1) 3600e3200; 1H NMR (300 MHz, D2O)
d
4.22 (1H, q, J¼13.0 Hz, CHOH), 3.97 (1H, t, J¼7.4 Hz, CHOH),
3.61e3.53 (1H, m, CHOH), 3.43 (1H, dd, J¼7.4, 2.8 Hz, CHAHB), 2.96
(1H, d, J¼9.32 Hz, CHAHB), 2.33e2.27 (1H, m, CHAHB), 2.19e1.99
(3H, m, CHAHB, CHN, CHAHB), 1.80 (1H, d, J¼12.6 Hz, CHAHB), 1.63
(1H, m, CHAHB), 1.43e1.31 (1H, m, CHAHB); 13C NMR (75 MHz, D2O)
d
73.7, 72.0, 71.2, 67.1, 59.4, 51.0, 32.7, 23.1; (ESI-MS) m/z 174
þ
4.1.31. (1R,2S,8R,8aS)-8-(Benzyloxy)octahydroindolizine-1,2-diol:
34. To the stirred solution of compound 33 (500 mg, 1.31 mmol) in
dry DCM (5 mL), 50% TFA in DCM was added. After completion of
the reaction, the mixture was basified at 0 ꢁC with aqueous NH3
solution (28%). The mixture was extracted with EtOAc, dried over
Na2SO4, and concentrated under vacuo to give crude amine, which
was further used without purification. To a solution of triol amine
(0.792 g, 1.14 mmol) in pyridine, under nitrogen atmosphere at 0 ꢁC
was added triphenylphosphine (0.301 g, 1.15 mmol) and diiso-
propyl azodicarboxylate (0.56 mL, 2.84 mmol). The mixture was
stirred at same temperature for 1 h. After completion of reaction,
solvent was removed under vacuo to give crude indolizidine, which
on column chromatographic purification gave the pure compound
34 (colorless oil, 224 mg, 65%). Eluent for column chromatography:
[MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd for C8H16NO3 [MþH]ꢄ
:
174.11302, measured 174.11242.
4.1.34. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((1S,2R)-1,2,3-
trihydroxypropyl)piperidine-1-carboxylate: 36. To a solution of al-
lylic alcohol 30 (146 mg, 0.42 mmol) in a 10: 1 mixture of acetone/
H2O (6.6 mL) was added N-methylmorpholine N-oxide (98.51 mg,
0.84 mmol) and 4% aqueous OsO4 (1.0 mL). The reaction mixture
was stirred at room temperature for 3 h. After addition of aqueous
NaHSO3 solution (1 mL), the mixture was stirred for an additional
1 h at room temperature and extracted with EtOAc (3ꢂ10 mL). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, and concentrated under vacuo to colorless oil, which
on column chromatographic purification gave the pure compound
(colorless oil, 125 mg, 80%). Colorless oil, eluent for column chro-
EtOAc/Hexane (3.5/46.5, v/v); ½a D28
ꢀ1.3 (c 0.82, MeOH); Rf 0.5 (1:4
ꢃ
MeOH:CHCl3); IR (neat, cmꢀ1) 3417, 2370, 1629, 1219, 771; 1H NMR
matography: EtOAc/Hexane (30/20, v/v); ½a D28
þ4.5 (c 1.23, CHCl3);
ꢃ
(300 MHz, CDCl3)
d
7.35e7.34 (5H, m, ArH), 4.72 (1H, d, J¼11.6 Hz,
Rf 0.5 (EtOAc); IR (neat, cmꢀ1) 3417, 2370, 1629, 1219, 771; 1H NMR
OCH2Ph), 4.51 (1H, d, J¼11.6 Hz, OCH2Ph), 4.21e4.15 (1H, m, CHOH),
3.88e3.83 (1H, m, CHOH), 3.50e3.36 (2H, m, CHOBn, CHN), 2.89
(1H, br d, J¼8.9 Hz, NCHAHBCHOH), 2.66 (2H, brs, OH), 2.33e2.23
(300 MHz, CDCl3)
d
7.33e7.25 (5H, m, ArH), 4.59 (1H, d, J¼12 Hz,
OCHAHBPh), 4.51 (1H, d, J¼12 Hz, OCHAHBPh), 4.44 (1H, m, CHN),
3.97 (1H, d, J¼11 Hz, CHAHBOH), 3.83e3.81 (3H, m, CHAHBOH,
CHOH, CHAHBN), 3.69 (1H, br s, OH), 3.48 (1H, m, CHOH), 3.17 (1H,
m, CHAHBN), 2.88 (1H, br s, OH), 2.62e2.46 (1H, m, CHOBn),
(2H, m, NCHAHBCH2, NCHAHBCHOH), 2.08e2.03 (2H, m, CHAHB
-
CHOBn, NCHAHBCH2), 1.77e1.72 (1H, m, CHAHBCHOBn), 1.58e1.47
(2H, m, CH2CH2N); 13C NMR (75 MHz, CDCl3)
d
138.8, 128.6, 128.3,
2.04e1.81 (4H, m, CH2CH2), 1.46 (9H, s, CMe3); (ESI-MS) m/z 404
þ
127.6, 73.2, 72.4, 71.0, 70.0, 69.1, 62.1, 52.0, 33.8, 23.2; (ESI-MS) mþ/z
[MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd for C20H31NNaO6 [MþNa]ꢄ
:
264 [MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd for C15H22NO3 [MþH]ꢄ
:
404.20491, measured 404.20901.
264.15997, measured 264.16077.
4.1.35. (1S,2R,8R,8aR)-8-(Benzyloxy)octahydroindolizine-1,2-diyl di-
acetate: 38. Reaction was performed in same manner as for com-
pound 34 and 35, compound 36 (500 mg, 1.31 mmol, 1.18 mmol),
afforded diacetate 38 (276 mg 55% over three steps); colorless oil,
eluent for column chromatography: EtOAc/Hexane (16/24, v/v);
4.1.32. (1R,2S,8R,8aR)-8-(Benzyloxy)octahydroindolizine-1,2-diyl di-
acetate: 35. To the stirred solution of 34 (50 mg, 0.19 mmol) in
pyridine (2 mL) at 0 ꢁC was added acetic anhydride (58.2 mg,
0.57 mmol) and catalytic amount of DMAP. The mixture was stirred
at room temperature for overnight. The usual workup followed by
separation by column chromatography afforded diacetate 35
(56 mg, 85%). Colorless, eluent for column chromatography: EtOAc/
½
a 2D8
ꢃ
ꢀ101 (c 2.01, CHCl3); Rf 0.4 (1:1 EtOAc/Hexane); 1H NMR
(300 MHz, CDCl3)
d 7.32e7.28 (m, 5H), 5.56 (m, 1H), 5.29 (m, 1H),
4.58 (d, J¼11.6 Hz, 1H), 4.42 (d, J¼11.6 Hz, 1H), 3.63 (m, 1H),
3.07e3.0 (m, 2H), 2.57 (dd, J¼11.1, 7.8 Hz, 1H), 2.31e2.28 (m, 1H),
2.07 (m, 1H), 2.01 (s, 6H), 1.90 (m, 1H), 1.80e1.5 (m, 2H), 1.28e1.1
Hexane (16/24, v/v); ½a D28
þ5.0 (c 1.04, CHCl3); Rf 0.4 (1:1 EtOAc/
ꢃ
Hexane); IR (neat, cmꢀ1) 3417, 2370, 1629, 1219, 771; 1H NMR
(300 MHz, CDCl3)
d
7.23e7.19 (5H, m, ArH), 5.18e5.07 (2H, m,
(m, 1H); 13C NMR (75 MHz, CDCl3)
d 170.1, 138.1, 128.4, 127.8, 127.7,
2CHOAc), 4.54 (1H, d, J¼11.1 Hz, OCH2Ph), 4.32 (1H, d, J¼11.1 Hz,
OCH2Ph), 3.47 (1H, dd, J¼9.7, 6.5 Hz, CHOBn), 3.30 (1H, ddd, J¼12.8,
9.8, 4.3 Hz, NCHAHBCH2), 2.86 (1H, br d, J¼10.2 Hz, CHN), 2.28e2.17
72.9, 71.1, 70.5, 70.1, 69.8, 59.6, 52.1, 33.8, 23.3, 20.7, 20.6; IR (neat,
þ
cmꢀ1) 3417, 2370, 1629, 1219, 771; (ESI-MS) m/z 348 [MþH]ꢄ
;
HRMS (ESI TOF (þ)): calcd for C19H26NO5 [MþH]ꢄþ: 348.1811,
(3H, m, NCH2CH2, NCHAHBCHOAc), 2.07e2.01 (1H, m, CHAHB
measured 348.1802.
-
CHOBn), 1.95 (3H, s, CH3CO), 1.83 (3H, s, CH3CO), 1.65 (1H, br d,
J¼12.8 Hz, CHAHBCHOBn), 1.56e1.48 (1H, m, CHAHBCH2N),
4.1.36. (1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol [(ꢀ)-swainso-
nine]. To a solution of compound 37 (50 mg, 0.11 mmol) in MeOH
(1 mL) was added catalytic amount of PdCl2. The mixture was
stirred at room temperature under an atmosphere of H2 (balloon)
for 1 h. The mixture was filtered through a Celite pad and the fil-
trates were evaporated in vacuo, then the residue was dissolved in
water (1 mL) and applied to a column of Amberlyte IRA-400 basic
ion-exchange resin. Elution with water (35 mL) followed by evap-
oration of the eluent in vacuo gave the title product
1.32e1.16 (1H, m, CHAHBCH2N); 13C NMR (50 MHz, CDCl3)
d 169.9,
169.7,138.4,128.3,127.8, 127.6, 78.8, 73.6, 70.8, 68.4, 68.2, 58.2, 51.5,
29.9, 23.6, 20.6, 20.5; (ESI-MS) m/z 348 [MþH]ꢄþ; HRMS (ESI TOF
þ
(þ)): calcd for
C
19H26NO5 [MþH]ꢄ
:
348.18110, measured
348.18020.
4.1.33. (1R,2S,8R,8aR)-Octahydroindolizine-1,2,8-triol
epi-swainsonine]. To a solution of compound 34 (50 mg, 0.19 mmol)
[(þ)-1,2-di-

P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1373
(ꢀ)-swainsonine (28 mg, 85%) as a white solid; mp 140e141 ꢁC ½a D28
ꢃ
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ꢀ68 (c 0.46, MeOH); IR (neat, cmꢀ1) 3367, 2944, 2800, 2723, 1347,
1127, 1073; 1H NMR (300 MHz, D2O)
d 4.27e4.21 (m, 1H, CHOH),
4.16e4.14 (m, 1H, CHOH), 3.69 (ddd, J¼13.6, 10.8, 4.48 Hz, 1H,
CHOH), 2.80e2.75 (m, 2H, CHN), 2.52e2.38 (m, 1H, CHAHBN),
1.98e1.78 (m, 3H, CHAHB, CH2N), 1.62e1.58 (m, 1H, CHAHB),
1.50e1.37 (m, 1H, CHAHBN), 1.13 (m, 1H, CHAHBN); 13C NMR
(75 MHz, D2O) d 71.8, 68.7, 68.0, 65.4, 59.6, 50.7, 31.5, 22.2; (ESI-MS)
m/z 174 [MþH]ꢄþ; HRMS (ESI TOF (þ)): calcd for C8H16NO3
[MþH]ꢄþ: 174.11302, measured 174.11242.
Acknowledgements
The authors P.S. and S.K.M. cordially thank CSIR for providing
fellowships (NET-SRFs). Financial support from DST is acknowl-
edged. This has CDRI communication no 8570/2013/GP.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.074.
References and notes
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