Synthesis of polyhydroxy piperidines and their analogues: A novel approach towards selective inhibitors of α-glucosidase

Article abstract of DOI:10.1039/b804278k

Various polyhydroxy piperidine azasugars have been synthesized from precursors 18a and 18b, obtained in both enantiomeric forms from d-ribose. Out of these polyhydroxy piperidine azasugars, 22, 39 and 20 were found to be potent as well as selective inhibitors of α-glucosidase with K_i values ranging as low as 1.07 μM, 16.4 μM, and 88.2 μM, respectively. Replacement of the hydroxy methylene moiety of 19 (K_i 33% at 1 mM) by an amino methylene moiety (32, K_i 36.8 μM) showed a remarkable increase in the activity (almost 30 times). Furthermore, increasing the lipophilicity of 33 by N-alkylation with a dodecyl group (36) showed a three-fold enhancement in the activity (K_i 217 μM to K_i 72.3 μM). The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b804278k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of polyhydroxy piperidines and their analogues: a novel approach
towards selective inhibitors of a-glucosidase†‡
Ganesh Pandey,*a Kishor Chandra Bharadwaj,a M. Islam Khan,b K. S. Shashidharab and Vedavati G. Puranikc
Received 12th March 2008, Accepted 9th April 2008
First published as an Advance Article on the web 20th May 2008
DOI: 10.1039/b804278k
Various polyhydroxy piperidine azasugars have been synthesized from precursors 18a and 18b,
obtained in both enantiomeric forms from D-ribose. Out of these polyhydroxy piperidine azasugars, 22,
39 and 20 were found to be potent as well as selective inhibitors of a-glucosidase with Ki values ranging
as low as 1.07 lM, 16.4 lM, and 88.2 lM, respectively. Replacement of the hydroxy methylene moiety
of 19 (Ki 33% at 1 mM) by an amino methylene moiety (32, Ki 36.8 lM) showed a remarkable increase
in the activity (almost 30 times). Furthermore, increasing the lipophilicity of 33 by N-alkylation with a
dodecyl group (36) showed a three-fold enhancement in the activity (Ki 217 lM to Ki 72.3 lM).
Introduction
Since the time glycosidases/glycosyl transferases1 were identified
as key carbohydrate processing enzymes, interest in developing
carbohydrate mimics as inhibitors has intensified, because many of
them show promising chemotherapeutic potential in the treatment
of various diseases such as viral infection,2 cancer,3 AIDS,4
and diabetes.5 In this context, iminosugars6 and carbasugars7
have emerged as important compound classes of specific and
competitive inhibitors.
A large number of sugar analogues having a nitrogen atom
in place of the oxygen atom in the ring, such as nojirimycin (1),
deoxynojirimycin (2) and fagomine (3), (Fig. 1) are reported6 to be
glycosidase inhibitors. Similarly, another class of sugar analogues
in which the nitrogen atom is placed at the anomeric carbon, such
as isofagomine8 (4), isogalactofagomine9a (5), isofucofagomine9b,c
(6), 5-hydroxy isofagomine9d (7) and their derivatives,9 have also
emerged as potent glycosidase inhibitors as they are believed
to mimic the oxocarbenium ion transition state.10 Polyhydroxy
piperidines (8–10), isolated by Kusano11 et al. as an active
component of the extract of the plant Eupatorium fortunei used
in folk medicine for various diseases and synthesized by Ganem12
et al. (8–11), have been shown to be potent glycosidase inhibitors.13
Although there are a few good strategies9,13 known for the
synthesis of these inhibitors, they lack generality for diversity
oriented syntheses. Since previously14 we had developed scaffold
12 in both enantiomeric forms starting from the corresponding
Fig. 1 Various potent glycosidase inhibitors.
tartaric acids, utilizing a photoinduced electron transfer (PET)
cyclization as the strategy15 (Fig. 2), in order to synthesize
isofagomine (a mimic of D-glucose) and other piperidinols (8,
10 and 11), we envisaged extending the scope of this strategy to
discover more potent and specific enzyme inhibitors.16
Towards this endeavor, we envisioned that starting with D-ribose
(Scheme 1) and through selective protection and installation of the
acetylenic moiety, it might be possible to obtain two enantiomeric
synthons (A and B) that would allow the synthesis of other
azasugars such as 5 (galacto type), 6 and 9 (fuco type) and other
structural analogues of them. We have explored this aspect in detail
and would like to discuss the findings in this article, along with
enzyme inhibition studies.
aOrganic Chemistry Division, National Chemical Laboratory, Pune-411008,
India. E-mail: gp.pandey@ncl.res.in
bDivision of Biochemical Sciences, National Chemical Laboratory, Pune-
411008, India
cCenter for Material Characterization, National Chemical Laboratory,
Pune-411008, India
† Electronic supplementary information (ESI) available: X-ray crystal
structure analysis for compounds 18a and 18b, general procedure for
the enzyme inhibition assay, general experimental methods, general
procedures for N-debenzylation, acetonide cleavage and the conversion
of the hydroxyl moiety to the amine, and experimental procedures for
compounds 16a, 17, 18a, 21, 38. See DOI: 10.1039/b804278k
Results and Discussion
Initially, we directed our efforts towards synthesizing synthon A
as a proposed precursor for compounds 6 and 9. Towards this
‡ CCDC reference numbers 673352 and 673353. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b804278k
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2587–2595 | 2587
©

View Article Online
Fig. 2 Synthesis of 12.
Scheme 2 Reagents and conditions: (a) (MeO)2P(O)C(N2)COMe, K2CO3,
MeOH, 65 ◦C, 6 h, 70%; (b) MeSO2Cl, Et3N, DCM, 0 ◦C to rt, 5 h,
100%; (c) BnNHCH2TMS, TBAI (cat.), K2CO3, CH3CN, reflux, 96 h, 80%;
(d) hv, DCN, 2-PrOH, 1 h, 60%; (e) OsO4, NMO (50% aq. solution),
t-BuOH, rt, 24 h, 90%.
by irradiating a dilute solution of 16a (2.9 mmol) and 1,4-
dicyanonaphthalene (0.9 mmol) in iso-propanol (200 mL) in a
pyrex vessel, using a 450 W Hanovia medium pressure lamp as
the light source, produced cyclized product 17 in 60% yield. In
1
the H NMR of 17, the coupling constant between protons H3A
and H7A was noticed to be unexpectedly higher in magnitude (J =
9.22 Hz) than expected for the original cis- relationship, indicating
a possible inversion. As it was difficult to prove, beyond doubt, the
stereochemistry of 17 at this stage, we dihydroxylated the olefinic
double bond by using OsO4 in t-BuOH, producing 18a as a single
diastereomer in 90% yield (crystalline solid, m.p.152–154 ◦C).
X-Ray20 (Fig. 3) analysis of 18a established the trans-
stereochemistry between H3A and H7A. The spectral data and
optical rotation ([a]2D9 +24.2 (c 0.6, MeOH)) of 18a also matched
those of the compound previously prepared by us starting from
L-tartaric acid.14d,e
Scheme 1 Proposed route for enantiomeric synthons A and B.
end, the acetonide protected D-ribose (obtained by refluxing D-
ribose with acetone in the presence of a few drops of conc. H2SO4)
(Scheme 2), upon NaBH4 reduction followed by sodium periodate
cleavage of the resultant diol produced lactol 13 in 70% yield.17 The
masked carbonyl group of 13 was converted to the corresponding
acetylenic moiety by the gradual addition of Bestmann–Ohira
reagent18 to obtain 14 in 70% yield.19 The free hydroxyl moiety of
14 was subsequently transformed into mesylate 15 in quantitative
yield, which upon refluxing (96 h) with trimethylsilylmethyl
benzylamine (BnNHCH2TMS) in the presence of anhydrous
K2CO3 gave 16a in 80% yield. Compound 16a, upon photoin-
duced electron transfer (PET) mediated cyclization,15 carried out
Fig. 3 ORTEP diagram of 18a.20 Ellipsoids are drawn at 50% probability.
These observations led us to speculate that the possible step for
inversion could be the reaction of lactol 13 with the Bestmann–
Ohira reagent. Careful literature21 scrutiny revealed a precedence
for such an epimerization. This observed inversion could be
attributed to the greater thermodynamic stability of the trans-
over the cis- structure.
Although this unexpected result was disappointing, nevertheless
the current protocol appeared to be more attractive for the
synthesis of 18a (6 steps) than the earlier one, reported14e by us
2588 | Org. Biomol. Chem., 2008, 6, 2587–2595
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
starting with tartaric acid (11 steps). As the synthesis of other
analogues from 18a and the exploration of their enzyme inhibitory
activity against various other enzymes was forthcoming from our
group, we decided to continue with the existing protocol and
synthesized azasugars such as 22, 20 by following simple synthetic
steps14e as shown in Scheme 3. The major diastereomers of 21,
formed by the sodium borohydride reduction of the corresponding
ketone, were separated after the N-debenzylation during the
synthesis of 22, whereas the corresponding acetate 23 was used
to obtain pure diastereomer for the preparation of 25.
Scheme 4 Reagents and conditions: (a) MeSO2Cl, Py, 0 ◦C to rt, 6 h, 85%;
(b) (i) LiN3, DMF, 110 ◦C, 20 h; (ii) LAH, THF, 12 h, 60% over 2 steps;
(c) (i) Pd(OH)2 on C, H2 (1 atm.), EtOH, rt, 10 h; (ii) HCl, MeOH, rt, 4 h,
100% over 2 steps.
Scheme 3 Reagents and conditions: (a) HCl, MeOH, rt, 4 h, 100%;
(b) (i) Pd(OH)2 on C, H2 (1 atm.), EtOH, rt, 10 h; (ii) HCl, MeOH, rt, 4 h,
100% over 2 steps; (c) (i) NaIO4, EtOH : H2O (4 : 1), rt, 0.5 h; (ii) NaBH4,
MeOH, 0 ◦C to rt, 24 h, 85% over 2 steps, dr 9 : 1; (d) (i) Pd(OH)2 on C,
H2 (1 atm.), EtOH, rt, 10 h; (ii) HCl, MeOH, rt, 4 h, 85% over 2 steps;
(e) AcCl, Py, DCM, 30 h, rt; 80%; (f) K2CO3, MeOH, rt, 12 h, 90%;
(g) HCl, MeOH, rt, 4 h, 90%; (h) HCl, MeOH, rt, 15 min, 100%.
Scheme 5 Reagents and conditions: (a) MeSO2Cl, Et3N, DCM, 0 ◦C to rt,
6 h, 90%; (b) LiN3, DMF, 110 ◦C, 20 h, 90%; (c) LAH, THF, 12 h, 90%;
(d) HCl, MeOH, rt, 4 h, 100%; (e) (i) Pd(OH)2 on C, H2 (1 atm.), EtOH,
rt, 10 h; (ii) HCl, MeOH, rt, 4 h, 100% over 2 steps.
C-3 amine analogue azasugars
In order to create a different class of azasugars having another
basic site6f ,22 for binding to the enzyme, we thought of trans-
forming the hydroxy moiety at C3 of 8 as well as the hydroxy
methylene group at C3 of 19 and 20 into the corresponding amine
functionality (Schemes 4 and 5). Mesylate 26, obtained from 21
(Scheme 4), was purified by column chromatography to obtain
the major diastereomer. Replacement of the mesylate with azide
by using LiN3, followed by reduction of the crude azide with
LAH, furnished 27 as the free amine in 60% yield. Reductive
N-debenzylation followed by acetonide deprotection of 27 gave 28
in quantitative yield.
Scheme 6 Reagents and conditions: (a) C12H25Br, K2CO3, CH3CN : THF
(3 : 1), rt to reflux, 6 h, 70%; (b) HCl, MeOH, rt, 4 h, 70%; (c) (i) Pd(OH)2
on C, H2 (1 atm.), EtOH, rt, 10 h; (ii) HCl, MeOH, rt, 15 min, 100% over
2 steps.
A similar sequence of reactions was also carried out to prepare
amine analogues 32 and 33 from the corresponding diol 18a,
through the synthetic intermediates 29, 30 and 31 (Scheme 5).
Furthermore, in order to increase the lipophilicity of 33 and also
to evaluate the role it plays in the enzyme inhibition, we attached
a long hydrocarbon chain to its primary amine functionality
(Scheme 6).
The alkylation was carried out by refluxing 31 with dodecyl
bromide in the presence of K2CO3 in CH3CN : THF (3 : 1) to
obtain 34 in 70% yield. Acetonide deprotection of 34 yielded 35 in
70% yield, which upon N-debenzylation and salt formation gave
36 in quantitative yield.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2587–2595 | 2589
©

View Article Online
Synthesis of enantiomers 39, 40 and 41
As discussed in Scheme 1, the same reaction sequence (as shown
in Schemes 7 and 8) was repeated to obtain the enantiomers of
the above azasugars. Starting from synthon 37 (prepared from
D-ribose itself),23 the corresponding diol 38 was obtained by
using Bestmann–Ohira reagent18 in 55% yield. As usual in this
case, epimerization was observed at C3A during the course of the
reaction. The diastereomeric ratio was found to be 16 : 1 (deter-
1
mined from the H NMR); the major one being the epimerized
product.24 Sodium periodate cleavage of the diol moiety of 38
gave the corresponding aldehyde, which was converted directly
to 16b by reductive amination25 with BnNHCH2TMS in 50%
yield. Following similar steps as described above, the enantiomeric
compound 18b was obtained (Scheme 7).
Scheme 8 Synthesis of 39, 40 and 41.
Fig. 4 ORTEP diagram of 18b.26 Ellipsoids are drawn at 50% probability.
enzymes and the results are summarized in Table 1. None of the
compounds (except 22) showed any significant activity against
both a- and b-galactosidase as well as mannosidases (from jack
beans). However, all the compounds showed inhibitory activity
against a-glucosidase. Compounds 20, 39, 22, 32, 36 were found
to be anomer specific and inhibited a-glucosidase strongly, with Ki
values (in lM) of 88.2, 16.4, 1.07, 36.8, 72.3, respectively, whereas
there wasn’t any significant inhibition of the corresponding b-
glucosidase. Compounds 25, 28, 33 and 36 proved to be selective
inhibitors of a-glucosidase. This reflects the fact that the current
framework has the potential to inhibit this class of enzyme, and
the results can be explored further and analyzed for further
increases in inhibition and to gain an understanding of the
Scheme 7 Reagents and conditions: (a) (MeO)2P(O)C(N2)COMe, K2CO3,
MeOH, 65 ◦C, 6 h, 55%; (b) (i) NaIO4, EtOH : H2O (4 : 1), rt, 0.5 h;
(ii) Na(OAc)3BH, EDC, BnNHCH2TMS, rt, 24 h, 50% over 2 steps.
The X-ray26 analysis of 18b further confirmed the epimerization
during the acetylenylation step (Fig. 4).
Identical reaction sequences as described earlier led us to
synthesize 39, 40 and 41 from 18b (Scheme 8).
Enzyme inhibition studies
The inhibitory activities of all the final molecules 19, 20, 39,
40, 25, 22, 28, 32, 33, 41, 36 were tested against various
Table 1 Inhibitiona (Ki in lM) of glycosidases by inhibitors
Enzymes (source)
b-Gal. (Aspergillus
oryzaie)
a-Gal. (green
coffee beans)
b-Man.
(snail)
a-Man. (jack
beans)
a-Man. (Aspergillus
fischeri)
Inhibitor
b-Glu. (almond)
a-Glu. (yeast)
19
20
39
40
25
22
28
32
33
41
36
967
NI
NI
NI
6%b
504
NI
NI
NI
NI
NI
NI
NI
NI
NI
890
85
NI
NI
NI
NI
NI
20%b
27%b
NI
NI
NI
578
NI
NI
NI
NI
NI
NI
NI
NI
NI
1066
NI
33%b
88.2
16.4
42%b
210
1.07
153
36.8
217
NI
217
41.4
NI
NI
23%b
991
NI
50%b
325
35%b
37.3
930
NI
456
NI
10%b
14%b
17%b
NI
20%b
NI
NI
NI
34%b
NI
471.3
72.3
35%b
a NI, no inhibition up to 1 mM. b Percent inhibition at 1 mM level.
2590 | Org. Biomol. Chem., 2008, 6, 2587–2595
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
mechanistic pathway. The introduction of a second basic site
in the form of amine functionality proved to be fruitful since
the amine analogue 32 (Ki 36.8 lM and 37.3 lM) proved to be
approximately 30 times more potent against both a-glucosidase
and a-mannosidase (A. fischeri) than its hydroxy analogue 19 (Ki
33%, and no inhibition at 1 mM). However, there was a slight
reduction in the activity of the N-debenzylated analogue (20 vs
33) against both the enzymes and also a decrease in the activity
against a-mannosidase (A. fischeri) when comparing 36 with 20.
Increasing the lipophilicity, was also fruitful as the alkylated
product 36 was not only selective for a-glucosidase but also showed
more activity (3 times) than its non alkylated form 33 (Ki 217 lM to
Ki 72.3 lM). Compound 22 proved to be a very potent inhibitor, in
particular, for a-glucosidases (Ki 1.07 lM) but also exhibited some
inhibition properties for all the other enzymes tested. In addition,
compounds 39 and 32 also displayed good activities (Ki 41.4 lM
and 37.3 lM) against the a-mannosidase that was indigenously
isolated from Aspergillus fischeri.
the residual hydrolytic activities of the glycosidases on the
corresponding p-nitrophenyl glycosides in the presence of the
azasugars. The absorbance of the resulting solution was read at
405 nm.
((4S,5S)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (14)
To a stirring mixture of 13 (10.0 g, 62.5 mmol) and anhydrous
K2CO3 (11.37 g, 81.25 mmol) in dry MeOH (240 mL) at 65 ◦C was
added a solution of Bestmann–Ohira reagent (15.6 g, 81.25 mmol)
in dry MeOH (80 mL) dropwise over a period of 6 h under an argon
atmosphere. After neutralization with acetic acid, the solvent was
removed in vacuo, water was added and the mixture extracted
with ethyl acetate (2 × 100 mL). The combined organic extracts
were dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by column chromatography (pet. ether–ethyl
acetate, 4 : 1) to obtain 14 (6.82 g, 70%) as a colorless liquid.
[a]D27 −8.6 (c 1.0, MeOH); lit.14b [a]2D0 −7.3 (c 2.0, MeOH); anal.
calcd for C8H12O3: C, 61.52; H, 7.74; found: C, 61.79; H, 7.84; IR
(neat) tmax/cm−1, 3452, 3284, 2121, 848, 665; 1H NMR (200 MHz,
CDCl3, D2O exchange), d 1.42 (s, 3H), 1.48 (s, 3H), 2.53 (d, 1H,
J = 2.15 Hz), 3.64 (dd, 1H, J = 12.25, 3.67 Hz), 3.87 (dd, 1H,
J = 12.25, 3.03 Hz), 4.16 (ddd, 1H, J = 7.58, 3.67, 3.03 Hz), 4.56
(dd, 1H, J = 7.57, 2.15 Hz); 13C NMR (50 MHz, CDCl3), d 25.7
(CH3), 26.4 (CH3), 60.4 (CH2), 66 (CH), 74.7 (CH), 80.5 (C), 81.7
(CH), 110.4 (C); mass: m/z (%), 179 (M+ + Na, 100), 157 (M+ +
H, 32), 139 (57).
Conclusion
In conclusion we have developed a versatile strategy for the
synthesis of polyhydroxy azasugars, which we have shown to be
selective inhibitors of a-glucosidase. The utility of this protocol
lies in being diversity oriented yet simple in nature. The reaction
sequence for the various azasugars remains almost similar and
thus doesn’t require a variety of reactions to be tried. The triol 22
showed moderate to good activities against the various enzymes
tested. The new amine analogue azasugars showed promising
activity, introducing another area of research to be explored.
((4S,5S)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl
methanesulfonate (15)
To a stirring solution of 14 (7.0 g, 44.87 mmol) and triethylamine
(6.87 mL, 49.35 mmol) in dry DCM (100 mL) under an ar-
gon atmosphere was added methanesulfonyl chloride (3.82 mL,
49.35 mmol) dropwise at 0 ◦C. The reaction mixture was allowed
to warm to room temp. and stirred for 5 hours. Water was added
and the mixture extracted with DCM (2 × 100 mL). The organic
layer was given a brine wash, dried over anhydrous Na2SO4,
concentrated in vacuo and chromatographed (pet. ether–EtOAc,
4 : 1), to give 15 (10.49 g) as a yellow liquid in quantitative yield.
[a]2D9 −29.36 (c 0.6, CHCl3); anal. calcd for C9H14O5S; C, 46.14; H,
6.02; S, 13.69; found: C, 46.24; H, 5.90; S, 13.66; IR tmax/cm−1 in
Experimental
General experimental methods
Unless mentioned, all reactions were performed under an ar-
gon atmosphere. All commercially available reagents were used
without further purification unless otherwise noted. Enzymes
were purchased from commercial sources. Tetrahydrofuran was
freshly distilled from benzophenone ketyl radical under argon
prior to use. Column chromatography was performed with silica
gel (100–200 and 230–400 mesh). The combined organic layers
were dried over NaSO4. Solvents were evaporated under reduced
pressure. All yields given refer to isolated yields. Melting points
are reported uncorrected. Optical rotations were measured on a
precision automated polarimeter. NMR spectra were recorded
on 200, 400, and 500 MHz spectrometers. Chemical shifts are
reported in ppm. Coupling constants (J values) are reported in
Hertz. 13C peak multiplicity assignments were made based on
DEPT data. IR spectra were recorded on a FT-IR spectrometer.
MS experiments were performed on a low resolution magnetic
sector mass spectrometer. GC analysis was performed on a Varian
CP 3800 GC using a CP-Sil 5CB column. The optical density
measurements were carried out on a Varian CARY-50 BIO UV-
vis spectrophotometer.
1
CHCl3, 3282, 2123, 1359, 1219; H NMR (200 MHz, CDCl3), d
1.42 (s, 3H), 1.49 (s, 3H), 2.58 (d, 1H, J = 2.02 Hz), 3.06 (s, 3H),
4.25–4.44 (m, 3H), 4.54 (dd, 1H, J = 6.82, 2.02 Hz); 13C NMR
(100 MHz, CDCl3), d 26.0 (CH3), 26.6 (CH3), 37.6 (CH3), 66.5
(CH), 67.1 (CH2), 75.5 (CH), 79.1(CH), 79.7(C), 111.5 (C); mass:
m/z (%), 234 (M+, 8), 217 (71), 186 (64), 123 (100).
(3S,4R,5S)-1-Benzyl-3-(hydroxymethyl)piperidine-3,4,5-triol
hydrochloride (19)
Diol 18a (0.025 g, 0.085 mmol), upon acetonide cleavage, afforded
pure 19 (0.024 g) quantitatively as a white solid. [a]2D2 −2.90 (c
1.05, MeOH), ent [a]2D7 +3.73 (c 0.75, MeOH); anal. calcd for
C13H20ClNO4: C, 53.89; H, 6.96; N, 4.83; found: C, 53.69; H, 6.86
N, 4.97; 1H NMR (400 MHz, D2O), d 3.19 (d, 1H, J = 12.80 Hz),
3.30 (d, 1H, J = 12.80 Hz), 3.44 (d, 1H, J = 13.05 Hz), 3.52–3.56
(m, 2H), 3.69 (d, 1H, J = 12.04 Hz), 3.88 (s, 1H), 4.16 (d, 1H, J =
3.26 Hz), 4.45 (d, 1H, J = 13.05 Hz), 4.51 (d, 1H, J = 13.05 Hz),
General procedure for the enzyme inhibition assays
Inhibition assays to determine the inhibitory potencies of the
azasugars were carried out by spectrophotometrically measuring
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2587–2595 | 2591
©

View Article Online
7.57–7.60 (m, 5H); 13C NMR (100 MHz, D2O), d 53.06 (CH2),
53.13 (CH2), 60.8 (CH2), 64.1 (CH2), 65.4 (CH), 67.8 (CH), 72.8
(C), 127.6 (C), 129.3 (CH), 130.4 (CH), 131.7 (CH); mass: m/z
(%), 255 (33), 254 (100), 236 (13).
(3S,5S)-1-Benzylpiperidine-3,4,5-triol (24)
Diastereomerically pure 21 (0.022 g, 0.083 mmol), upon acetonide
cleavage, basic work up and column purification (DCM–MeOH,
92.5 : 7.5), gave 24 as a white solid (0.016 g, 90%). [a]2D3 +26.66 (c
0.3, MeOH); anal. calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27;
1
(3S,4R,5S)-3-(Hydroxymethyl)piperidine-3,4,5-triol hydrochloride
(20)
found: C, 64.44; H, 7.87; N, 6.37; H NMR (400 MHz, CDCl3,
D2O exchange), d 2.04–2.08 (m, 1H), 2.35 (d, 1H, J = 11.80 Hz),
2.91 (d, 1H, J = 9.03 Hz), 2.99 (d, 1H, J = 8.03 Hz), 3.36 (d, 1H,
J = 5.02 Hz), 3.61 (s, 2H), 3.79 (dt, 1H, J = 8.78, 4.77 Hz), 3.91
(s, 1H), 7.28–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3), d 56.5
(CH2), 56.8 (CH2), 61.9 (CH2), 68.3 (CH), 69.5 (CH), 127.5 (CH),
128.5 (CH), 129.1 (CH), 137.3 (C); mass: m/z (%), 246 (M+ + Na,
42), 224 (M+ + H, 100).
Diol 18a (0.02 g, 0.068 mmol), upon N-debenzylation and
acetonide cleavage, afforded pure 20 (0.013 g) quantitatively as
a white solid. [a]2D8 −16.98 (c 0.5, MeOH), ent [a]2D8 +15.47 (c 0.65,
MeOH); lit.14d,e [a]D25 −12.1 (c 0.15, EtOH), ent [a]2D5 +11.0 (c 0.2,
EtOH); anal. calcd for C6H14ClNO4: C, 36.10; H, 7.07; N, 7.02;
1
found: C, 36.23; H, 7.27; N, 7.21; H NMR (400 MHz, D2O), d
3.15 (d, 1H, J = 13.14 Hz), 3.25 (d, 1H, J = 5.56 Hz), 3.32 (d, 1H,
J = 5.18 Hz), 3.43 (dd, 1H, J = 13.39, 2.91 Hz), 3.62 (d, 1H, J =
11.87 Hz), 3.71 (d, 1H, J = 11.88 Hz), 3.85 (d, 1H, J = 4.68 Hz),
4.11 (dd, 1H, J = 7.39, 4.11 Hz). 13C NMR (100 MHz, D2O), d
45.3 (CH2), 46.2 (CH2), 63.7 (CH2), 66.7 (CH), 68.0 (CH), 71.7
(C); mass: m/z (%), 164 (100), 146 (26), 128 (16).
(3aS,7S,7aR)-5-Benzyl-2,2-dimethyl-hexahydro-[1,3]dioxolo[4,5-
c]pyridin-7-yl methanesulfonate (26)
Alcohol 21 (0.1 g, 0.38 mmol), upon mesylation and column
purification of the diastereomers (pet. ether–ethyl acetate, 4 :
1) gave 26 (0.11 g, 85%) as a colorless liquid. [a]2D0 +46.66 (c
0.45, CHCl3); IR (neat) tmax/cm−1, 1361, 738; anal. calcd for
C16H23NO5S: C, 56.29; H, 6.79; N, 4.10; S, 9.39; found: C, 56.18;
(3S,5S)-Piperidine-3,4,5-triol hydrochloride (22)
1
H, 6.75; N, 4.58; S, 9.36; H NMR (200 MHz, CDCl3), d 1.41
Alcohol 21 (0.05 g, 0.19 mmol), upon N-debenzylation, column
purification of the diastereomer (230 : 400 mesh, DCM–MeOH,
95 : 5) and acetonide cleavage, gave 22 (0.027 g, 85% yield) as a
white viscous liquid. [a]D27 +15 (c 0.3, MeOH); lit.12 [a]2D5 +16 (c 0.5,
MeOH); anal. calcd for C5H12ClNO3: C, 35.41; H, 7.13; N, 8.26;
(s, 3H), 1.43 (s, 3H), 2.32 (t, 1H, J = 10.11 Hz), 2.52 (d, 1H,
J = 13.64 Hz), 3.09, (s, 3H), 3.19–3.38 (m, 3H), 3.76 (s, 2H), 4.04
(dt, 1H, J = 9.86, 3.92 Hz), 5.13 (dd, 1H, J = 4.36, 2.34 Hz),
7.26–7.37 (m, 5H); 13C NMR (125 MHz, CDCl3), d 26.3 (CH3),
26.8 (CH3), 38.9 (CH3), 54.2 (CH2), 55.0 (CH2), 61.2 (CH2), 71.1
(CH), 75.1 (CH), 79.2 (CH), 110.9 (C), 127.4 (CH), 128.4 (CH),
128.8 (CH), 137 (C); mass: m/z (%), 342 (M+ + H, 93), 224
(100).
1
found: C, 35.23; H, 7.27; N, 8.21; H NMR (400 MHz, D2O),
d 3.04 (dd, 1H, J = 12.80, 8.28 Hz), 3.28 (dd, 1H, J = 13.05,
2.76 Hz), 3.37 (dd, 1H, J = 13.05, 6.02 Hz), 3.49 (dd, 1H, J =
12.80, 4.01 Hz), 3.86 (dd, 1H, J = 7.78, 3.01 Hz), 4.18 (dt, 1H, J =
8.03, 4.01 Hz), 4.30–4.33 (m, 1H); 13C NMR (100 MHz, D2O), d
45.5 (CH2), 46.0 (CH2), 64.7 (CH), 65.0 (CH), 70.8 (CH); mass:
m/z (%), 132 (100), 107 (45).
(3aS,7R,7aS)-5-Benzyl-2,2-dimethyl-hexahydro-[1,3]dioxolo[4,5-
c]pyridin-7-amine (27)
Mesylate 26 (0.05 g, 0.14 mmol) was converted to azide, which
upon LAH reduction afforded amine 27 as a yellow liquid (0.023 g,
60%). [a]2D2 +14.29 (c 1.4, CHCl3); IR (neat) tmax/cm−1, 3390,
2343, 736; anal. calcd for C15H22N2O2: C, 68.67; H, 8.45; N,
(3aS,7S,7aR)-5-Benzyl-2,2-dimethyl-hexahydro-[1,3]dioxolo[4,5-
c]pyridin-7-yl acetate (23)
1
To a solution of alcohol 21 (0.1 g, 0.38 mmol) and pyridine
(0.036 ml, 0.45 mmol) in dry DCM (2 mL) under an argon
atmosphere, was added acetyl chloride (0.027 ml, 0.38 mmol) and
the reaction mixture was allowed to stir at room temperature for
30 h. After adding a few drops of water, it was extracted with
DCM (2 × 5mL). The combined organic extracts were dried
over anhydrous Na2SO4, concentrated under reduced pressure
and purified by flash column chromatography (silica 230–400, pet.
ether–ethyl acetate, 7 : 3), to give 23 (0.092 g, 80%) as a colorless
liquid. [a]3D1 +60.54 (c 1.85, CHCl3); anal. calcd for C17H23NO4: C,
66.86; H, 7.59; N, 4.59; found: C, 66.53; H, 7.89 N, 4.23; IR (neat)
10.68; found: C, 68.52; H, 8.35; N, 10.77; H NMR (400 MHz,
CDCl3, D2O exchange), d 1.44 (s, 3H), 1.45 (s, 3H), 1.89 (dd,
1H, J = 11.29, 9.28 Hz), 2.22 (t, 1H, J = 10.04 Hz), 2.97 (dd,
1H, J = 11.34, 3.66 Hz), 3.04–3.14 (m, 2H), 3.21 (dd, 1H, J =
9.66, 3.89 Hz), 3.56–3.63 (m, 1H), 3.66 (s, 2H), 7.25–7.35 (m,
5H); 13C NMR (100 MHz, CDCl3), d 26.7 (CH3), 26.8 (CH3),
50.2 (CH), 54.3 (CH2), 59.4 (CH2), 61.7 (CH2), 75.4 (CH), 85.8
(CH), 110.6 (C), 127.3 (CH), 128.3 (CH), 128.9 (CH), 137.8 (C);
mass: m/z (%), 285 (M+ + Na, 5), 263 (M+ + H, 100), 205
(44).
1
tmax/cm−1, 1741, 1217, 756; H NMR (200 MHz, CDCl3), d 1.42
(3S,4S,5R)-5-Aminopiperidine-3,4-diol dihydrochloride (28)
(s, 6H), 2.13 (s, 3H), 2.27 (t, 1H, J = 9.85 Hz), 2.38 (dd, 1H, J =
13.13, 1.90 Hz), 3.08 (d, 1H, J = 13.39 Hz), 3.26–3.38 (m, 2H),
3.70 (s, 2H), 4.05 (dt, 1H, J = 9.72, 3.91 Hz), 5.34 (dd, 1H, J =
4.74, 2.46 Hz) 7.21–7.37 (m, 5H); 13C NMR (50 MHz, CDCl3), d
21.0 (CH3), 26.4 (CH3), 26.8 (CH3), 53.9 (CH2), 54.6 (CH2), 61.5
(CH2), 67.4 (CH), 71.4 (CH), 79.6 (CH), 110.5 (C), 127.3 (CH),
128.3 (CH), 128.9 (CH), 137.2 (C), 170.5 (C); mass: m/z (%), 328
(M+ + Na, 75), 306 (M+ + H, 100), 266 (64), 229 (95).
Amine 27 (0.02 g, 0.075 mmol), upon N-debenzylation and
acetonide cleavage, afforded pure diamine hydrochloride salt 28
(0.015 g) quantitatively as a white viscous liquid. [a]2D5 −1.05 (c
0.95, MeOH); anal. calcd for C5H14Cl2N2O2: C, 29.28; H, 6.88; N,
1
13.66; found: C, 29.38; H, 6.56; N, 13.56; H NMR (400 MHz,
D2O), d 3.11 (dd, 1H, J = 12.80, 10.29 Hz), 3.35 (dd, 1H, J =
10.67, 12.93 Hz), 3.58–3.67 (m, 2H), 3.80–3.85 (m, 2H), 3.93–3.99
2592 | Org. Biomol. Chem., 2008, 6, 2587–2595
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
(m, 1H); 13C NMR (100 MHz, D2O), d 42.8 (CH2), 46.1 (CH2),
48.7 (CH), 66.8 (CH), 70.9 (CH); mass: m/z (%), 133 (100), 116
(81), 102 (20).
(3R,4R,5S)-3-(Aminomethyl)-1-benzylpiperidine-3,4,5-triol
dihydrochloride (32)
Amino alcohol 31 (0.025 g, 0.085 mmol), upon acetonide cleavage,
afforded pure 32 (0.024 g) quantitatively as a white solid. [a]D22
−3.00 (c 1.00, MeOH), ent [a]D28 +4.00 (c 1.00, MeOH); anal. calcd
for C13H22Cl2N2O3: C, 48.01; H, 6.82; N, 8.61; found: C, 48.11;
((3aS,7S,7aS)-5-Benzyl-7-hydroxy-2,2-dimethyl-hexahydro-
[1,3]dioxolo[4,5-c]pyridin-7-yl)methyl methanesulfonate (29)
1
H, 6.52; N, 8.41; H NMR (400 MHz, D2O), d 3.07 (d, 1H, J =
13.30 Hz), 3.31–3.41 (m, 3H), 3.49–3.59 (m, 2H), 3.90 (s, 1H), 4.25
(s, 1H), 4.50 (d, 1H, J = 13.30 Hz), 4.55 (d, 1H, J = 13.30 Hz),
7.60 (s, 5H); 13C NMR (100 MHz, D2O), d 43.4 (CH2), 52.5 (CH2),
53.5 (CH2), 61.0 (CH2), 65.3 (CH), 67.1 (CH), 70.4 (C), 127.4 (C),
129.4 (CH), 130.6 (CH), 131.8 (CH); mass: m/z (%), 254 (28), 253
(100), 206 (12).
Diol 18a (0.2 g, 0.68 mmol) was converted to mesylate 29 (0.23 g,
90%) as a white solid. Mp 100–102 ◦C. [a]D30 +46.52 (c 0.35, CHCl3),
ent [a]3D2 −43.47 (c 1.40, CHCl3); IR (in CHCl3) tmax/cm−1, 2933,
1
1359, 1228; H NMR (200 MHz, CDCl3, D2O exchange), d 1.41
(s, 3H), 1.42 (s, 3H), 2.03 (d, 1H, J = 11.87 Hz), 2.25 (dd, 1H, J =
9.72, 9.61 Hz), 2.95 (s, 3H), 3.00 (dd, 1H, J = 11.88, 1.01 Hz),
3.22 (ddd, 1H, J = 9.60, 3.92, 1.14 Hz), 3.49 (d, 1H, J = 9.60 Hz),
3.59 (dd, 1H, J = 9.6, 3.91 Hz), 3.65 (s, 1H), 3.67 (s, 1H), 4.49
(d, 1H, J = 10.49 Hz), 4.57 (d, 1H, J = 10.23 Hz), 7.21–7.37 (m,
5H); 13C NMR (50 MHz, CDCl3), d 26.45 (CH3), 26.5 (CH3), 37.2
(CH3), 54.6 (CH2), 57.9 (CH2), 61.3 (CH2), 69.2 (CH2), 71.1 (C),
73.1 (CH), 84.5 (CH), 111.1 (C), 127.4 (CH), 128.4 (CH), 128.8
(CH), 137.5 (C); mass: m/z (%), 394 (M+ + Na, 75), 372 (M+ + H,
42), 236 (59%), 229 (100).
(3R,4R,5S)-3-(Aminomethyl)piperidine-3,4,5-triol dihydrochloride
(33)
31 (0.02 g, 0.068 mmol), upon N-debenzylation and acetonide
cleavage, afforded pure 33 (0.016 g) quantitatively as a white solid.
[a]3D1 −8.27 (c 1.45, MeOH); anal. calcd for C6H16Cl2N2O3: C,
1
30.65; H, 6.86; N, 11.92; found: C, 30.66; H, 6.52; N, 11.72; H
NMR (400 MHz, D2O), d 3.14 (d, 1H, J = 13.55 Hz), 3.33 (d,
1H, J = 13.05 Hz), 3.37 (s, 1H), 3.41 (d, 1H, J = 2.51 Hz), 3.43
(d, 1H, J = 3.01 Hz) 3.52 (dd, 1H, J = 13.55, 2.51 Hz), 3.94 (d,
1H, J = 4.01 Hz), 4.22–4.25 (m, 1H); 13C NMR (100 MHz, D2O),
d 43.4 (CH2), 44.6 (CH2), 46.3 (CH2), 66.3 (CH), 66.7 (CH), 69.3
(C); mass: m/z (%), 229 (98), 213 (59), 163 (100).
(3aS,7S,7aS)-7-(Azidomethyl)-5-benzyl-2,2-dimethyl-hexahydro-
[1,3]dioxolo[4,5-c]pyridin-7-ol (30)
Mesylate 29 (0.1 g, 0.27 mmol) was converted to azide 30 (0.077 g,
90%) as a colorless liquid. [a]2D9 +41.86 (c 0.35, CHCl3), ent [a]3D0
−38.41 (c 1.55, CHCl3); anal. calcd for C16H22N4O3: C, 60.36;
H, 6.97; N, 17.60; found: C, 60.56; H, 7.04; N, 17.83; IR (neat)
tmax/cm−1, 2925, 2360, 2102; 1H NMR (200 MHz, CDCl3), d
1.35 (s, 3H), 1.36 (s, 3H), 1.94 (d, 1H, J = 11.75 Hz), 2.15 (dd,
1H, J = 9.85, 9.60 Hz), 2.42 (s, 1H), 2.85 (dd, 1H, J = 11.75,
1.06 Hz), 3.13 (ddd, 1H, J = 9.73, 4.04, 1.27 Hz), 3.39 (d, 1H,
J = 9.60 Hz), 3.50 (dd, 1H, J = 9.60, 3.92 Hz), 3.59 (s, 2H), 3.66
(s, 1H), 3.72 (d, 1H, J = 12.26 Hz), 7.13–7.31 (m, 5H); 13C NMR
(50 MHz, CDCl3), d 26.45 (CH3), 26.5 (CH3), 52.9 (CH2), 54.5
(CH2), 59.0 (CH2), 61.3 (CH2), 71.8 (C), 73.2 (CH), 84.6 (CH),
110.9 (C), 127.4 (CH), 128.3 (CH), 128.6 (CH), 137.5 (C); mass:
m/z (%), 341 (M+ + Na, 56), 319 (M+ + H, 61), 301 (33), 279 (100),
229 (63).
(3aS,7R,7aR)-5-Benzyl-7-((dodecylamino)methyl)-2,2-dimethyl-
hexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol (34)
To a stirring solution of 31 (0.05 g, 0.17 mmol) in dry CH3CN
and THF (3 : 1), (2 mL), was added dodecyl bromide and stirring
continued for 3 h at rt. K2CO3 (0.047 g, 0.34 mmol) was added
and the mixture refluxed for 3 h. Water was added and the mixture
was extracted with ethyl acetate (2 × 5 mL), dried over Na2SO4,
concentrated and purified by column chromatography (pet. ether–
ethyl acetate, 8 : 2), to give 34 (0.055 g, 70%) as a yellow liquid.
1
[a]3D0 +26.66 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3, D2O
exchange), d 0.89 (t, 3H, J = 6.78 Hz), 1.26 (bs, 20H), 1.42–1.43
(m, 8H), 2.10 (d, 1H, J = 11.80 Hz), 2.21 (t, 1H, J = 9.79 Hz),
2.61 (t, 1H, J = 7.03 Hz), 2.69 (d, 1H, J = 11.80 Hz), 2.88 (d, 1H,
J = 12.23 Hz), 3.06 (d, 1H, J = 12.30 Hz), 3.19 (dd, 1H, J = 9.29,
3.89 Hz), 3.49 (d, 1H, J = 9.29 Hz), 3.57 (d, 1H, J = 13.05 Hz),
3.65 (s, 1H), 7.25–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3),
d 14.1 (CH3), 22.7 (CH2), 26.6 (CH3), 26.7 (CH3), 27.0 (CH2),
29.3 (CH2), 29.4 (CH2), 29.6 (CH2),29.7 (CH2), 31.9 (CH2), 50.2
(CH2), 50.3 (CH2), 54.9 (CH2), 61.0 (CH2), 61.5 (CH2), 69.4 (C),
73.4 (CH), 85.4 (CH), 110.5 (C), 127.3 (CH), 128.3 (CH), 128.7
(CH), 138.1 (C); mass: m/z (%), 461 (M+ + H, 100), 403 (34),
229 (12).
(3aS,7R,7aS)-7-(Aminomethyl)-5-benzyl-2,2-dimethyl-hexahydro-
[1,3]dioxolo[4,5-c]pyridin-7-ol (31)
LAH reduction of 30 (0.1 g, 0.31 mmol) gave the corresponding
amine co◦mpound as a white crystalline solid 31 (0.08 g, 90%). Mp
165–168 C (from EtOAc–pet. ether); [a]2D8 +46.67 (c 0.3, CHCl3),
ent [a]2D8 −44.33 (c 0.55, CHCl3); anal. calcd for C16H24N2O3: C,
65.73; H, 8.27; N, 9.58; found: C, 65.63; H, 8.15; N, 9.70; 1H NMR
(400 MHz, CDCl3), d 1.44 (s, 3H), 1.45 (s, 3H), 2.16–2.21 (m, 2H),
2.90 (d, 1H, J = 12.05 Hz), 3.16–3.21 (m, 2H), 3.40 (d, 1H, J =
13.05 Hz), 3.52 (d, 1H, J = 9.53 Hz), 3.60–3.70 (m, 3H), 3.72–3.93
(bs, 3H), 7.26–7.34 (m, 5H); 13C NMR (50 MHz, CDCl3), d 26.6
(CH3), 42.4 (CH2), 54.5 (CH2), 60.1 (CH2), 61.3 (CH2), 70.0 (C),
73.3 (CH), 85.4 (CH), 110.5 (C), 127.2 (CH), 128.3 (CH), 128.6
(CH), 138 (C); mass: m/z (%), 315 (M+ + Na, 6), 293 (M+ + H,
86), 235 (100), 179 (13).
(3R,4R,5S)-1-Benzyl-3-((dodecylamino)methyl)piperidine-3,4,5-
triol (35)
Acetonide deprotection of 34 (0.05 g, 0.108 mmol), basification
and column purification (silica gel, DCM–MeOH, 9 : 1) gave 35
as a yellow liquid (0.032 g, 70%). [a]2D9 +15.10 (c 0.55, CHCl3);
anal. calcd for C25H44N2O3: C, 71.39; H, 10.54; N, 6.66; found:
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2587–2595 | 2593
©

View Article Online
1
C, 71.55; H, 10.65; N, 6.75; H NMR (400 MHz, CDCl3, D2O
Research Fellowships. Financial support by the DBT, New Delhi
is gratefully acknowledged.
exchange), d 0.88 (t, 3H, J = 6.78 Hz), 1.25 (bs, 20H), 1.69 (s, 2H),
2.23 (d, 1H, J = 11.54 Hz), 2.65 (d, 1H, J = 11.04 Hz), 2.84 (d,
1H, J = 12.80 Hz), 2.91–2.95 (m, 2H), 3.45–3.55 (m, 3H), 3.65
(d, 1H, J = 7.78 Hz), 3.72–3.80 (m, 1H), 7.23–7.31 (m, 5H); 13C
NMR (100 MHz, CDCl3), d 14.1 (CH3), 22.7 (CH2), 25.6 (CH2),
26.7 (CH2), 29.2 (CH2), 29.4 (CH2), 29.6 (CH2), 29.6 (CH2), 29.7
(CH2), 31.9 (CH2), 49.1 (CH2), 52.4 (CH2), 61.7 (CH2), 69.4 (CH),
70.9 (C), 127.4 (CH), 128.4 (CH), 129 (CH), 137.6 (C).
Notes and references
1 L. L. Lairson and S. G. Withers, Chem. Commun., 2004, 2243–2248.
2 C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S. Swaminathan,
N. Bischofberge, M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver and
R. C. Stevens, J. Am. Chem. Soc., 1997, 119, 681–690.
3 P. E. Gross, M. A. Baker, J. P. Carver and J. W. Dennis, Clin. Cancer
Res., 1995, 1, 935–944.
4 L. Ratner, N. V. Heyden and D. Dedera, Virology, 1991, 181, 180–
192.
5 (a) P. B. Anzeveno, L. J. Creemer, J. K. Daniel, C.-H. R. King and
P. S. Liu, J. Org. Chem., 1989, 54, 2539–2542; (b) J. A. Balfour and D.
McTavish, Drugs, 1993, 46, 1025.
(3R,4R,5S)-3-((Dodecylamino)methyl)piperidine-3,4,5-triol
dihydrochloride (36)
N-Debenzylation of 35 (0.025 g, 0.059 mmol) followed by diamine
hydrochloride salt formation gave 36 (0.023 g, quantitative)
as a white solid. [a]2D6 +7.27 (c 0.55, MeOH); anal. calcd for
C18H40Cl2N2O3: C, 53.59; H, 9.99; N, 6.94; found: C, 53.79; H,
10.09; N, 6.84; 1H NMR (400 MHz, D2O), d 0.90 (s, 3H), 1.32 (bs,
20H), 1.78 (s, 2H), 3.15 (s, 2H), 3.36–3.52 (m, 4H), 3.96 (s, 1H),
4.23 (s, 1H); 13C NMR (100 MHz, D2O), d 13.6 (CH3), 22.2 (CH2),
25.1 (CH2), 26.0 (CH2), 28.5 (CH2), 28.8 (CH2), 29.1 (CH2), 31.5
(CH2), 44.6 (CH2), 46.4 (CH2), 49 (CH2), 51.1 (CH2), 66.3 (CH),
66.8 (CH), 69.5 (C); mass: m/z (%), 345 (39), 331 (100).
6 (a) B. Ganem, Acc. Chem. Res., 1996, 29, 340–347; (b) A. de Raadt,
C. W. Ekhart, M. Ebner and A. E. Stu¨tz, Top. Curr. Chem., 1997,
187, 157–186; (c) Y. Ichikawa, Y. Igarashi, M. Ichikawa and Y.
Suhara, J. Am. Chem. Soc., 1998, 120, 3007–3018; (d) A. E. Stu¨tz,
Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, Wiley-
VCH, Weinheim, Germany, 1999; (e) N. Asano, R. J. Nash, R. J.
Molyneux and G. W. J. Fleet, Tetrahedron: Asymmetry, 2000, 11, 1645–
1680; (f) V. H. Lillelund, H. H. Jensen, X. Laing and M. Bols, Chem.
Rev., 2002, 102, 515–553; (g) M. S. M. Pearson, M. Math
e´-Allainmat,
V. Fargeas and J. Lebreton, Eur. J. Org. Chem., 2005, 2159–2191; (h) K.
Afarinkia and A. Bahar, Tetrahedron: Asymmetry, 2005, 16, 1239–1287;
(i) L. J. Whalem and C.-H. Wong, Aldrichimica Acta, 2006, 39, 63–71;
(j) C. Gravier-Pelletier and Y. Le Merrer, Curr. Org. Synth., 2007, 4,
1–13; (k) T. M. Wrodnigg, A. J. Steiner and B. J. Bernhard, Anti-Cancer
Agents Med. Chem., 2008, 8, 77–85; (l) X. Song and R. I. Hollingsworth,
Tetrahedron Lett., 2007, 48, 3115–3118; (m) P. Maier, S. M. Andersen
and I. Lundt, Synthesis, 2006, 827–830.
N-Benzyl-((4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)-N-
((trimethylsilyl)methyl)methanamine (16b)
To a solution of 38 (5.0 g, 26.89 mmol) in ethanol–water (100 mL,
4 : 1), was added sodium periodate (6.9 g, 32.25 mmol) gradually.
The white suspension was stirred for 0.5 h at room temperature and
filtered. The filtrate was concentrated and the white pasty mass was
extracted with ethyl acetate (2 × 100 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. To a solution of this aldehyde
in EDC (ethylene dichloride, 90 mL), was added BnNHCH2TMS
(6.25 g, 32.25 mmol) and Na(OAc)3BH (7.98 g, 37.63 mmol) under
an argon atmosphere and stirred for 24 h. The reaction mixture was
quenched with aq. saturated NaHCO3 solution while stirring for
0.5 h then extracted with DCM. The solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (pet. ether–ethyl acetate, 95 : 5) to furnish 16b
(4.45 g, 50% over two steps). [a]2D8 +0.72 (c 1.35, CHCl3); lit.14b
[a]2D0 +1.2 (c 21.2, CHCl3), ent [a]D27 −0.73 (c 0.5, CHCl3); lit14b [a]2D0
−0.7 (c 11.0, CHCl3); anal. calcd for C19H29NO2Si: C, 68.83; H,
8.82; N, 4.22; found: C, 68.63; H, 8.60; N, 4.38; IR tmax/cm−1, in
7 (a) E. Borges de Melo, A. da Silveira Gomes and I. Carvalho,
Tetrahedron, 2006, 62, 10277–10302; (b) O. Arjona, A. M. Go´mez,
J. C. Lo´pez and J. Plumet, Chem. Rev., 2007, 107, 1919–
2036.
8 (a) T. M. Jespersen, W. Dong, M. R. Sierks, T. Skrydstrup, I. Lundt
and M. Bols, Angew. Chem., Int. Ed. Engl., 1994, 33, 1778–1779; (b) I.
Panfil, J. Solecka and M. Chmielewski, J. Carbohydr. Chem., 2006, 25,
673–684.
9 (a) Y. Ichikawa and Y. Igarashi, Tetrahedron Lett., 1995, 36, 4585–
4586; (b) Y. Igarashi, M. Ichikawa and Y. Ichikawa, Bioorg. Med.
Chem. Lett., 1996, 6, 553–558; (c) A. Hansen, T. M. Tagmose and M.
Bols, Chem. Commun., 1996, 2649–2650; (d) M. Ichikawa, Y. Igarashi
and Y. Ichikawa, Tetrahedron Lett., 1995, 36, 1767–1770; (e) M. Bols,
M. P. Persson, W. M. Butt, M. J␾rgensen, P. Christensen and L. T.
Hansen, Tetrahedron Lett., 1996, 37, 2097–2100; (f) G. Zhao, U. C.
Deo and B. Ganem, Org. Lett., 2001, 3, 201–203; (g) M. M. Matin,
T. Sharma, S. G. Sabharwal and D. D. Dhavale, Org. Biomol. Chem.,
2005, 3, 1702–1707; (h) S. D. Markad, N. S. Karanjule, T. Sharma, S. G.
Sabharwal and D. D. Dhavale, Bioorg. Med. Chem., 2006, 14, 5535–
5539.
10 Ref. 6a and (a) P. Sears and C.-H. Wong, Angew. Chem., Int. Ed., 1999,
38, 2300–2324; (b) T. D. Heightman and A. T. Vasella, Angew. Chem.,
Int. Ed., 1999, 38, 750–770.
11 T. Sekioka, M. Shibano and G. Kusano, Nat. Med. (N. Y.), 1995, 49,
332.
1
CHCl3 3307, 1674, 757; H NMR (200 MHz, CDCl3), d 0.00 (s,
9H), 1.29 (s, 3H), 1.39 (s, 3H), 1.95 (d, 1H, J = 14.66 Hz), 2.08 (d,
1H, J = 14.65 Hz), 2.43 (d, 1H, J = 2.02 Hz), 2.51–2.56 (m, 2H),
3.42 (d, 1H, J = 13.64 Hz), 3.64 (d, 1H, J = 13.51 Hz), 4.14–4.23
12 R. C. Bernotas, G. Papandreou, J. Urbach and B. Ganem, Tetrahedron
Lett., 1990, 31, 3393–3396.
(m, 1H), 4.30 (dd, 1H, J = 7.33, 2.03 Hz), 7.12–7.30 (m, 5H); 13
C
13 Ref. 9c and (a) T. Tschamber, F. Backenstrass, M. Neuberger, M.
Zhender and J. Streith, Tetrahedron, 1994, 50, 1135–1152; (b) G. Legler,
A. E. Stu¨tz and H. Immich, Carbohydr. Res., 1995, 272, 17–30; (c) M.
Godskesen, I. Lundt, R. Madsen and B. Winchester, Bioorg. Med.
Chem., 1996, 4, 1857–1865; (d) K. C. Jang, I.-Y. Jeong, M. S. Yang, S. U.
Choi and K. H. Park, Heterocycles, 2000, 53, 887; (e) M. Amat, N. Llor,
M. Huguet, E. Molins, E. Espinosa and J. Bosch, Org. Lett., 2001, 3,
3257–3260; (f) N. T. Patil, S. John, S. G. Sabharwal and D. D. Dhawale,
Bioorg. Med. Chem., 2002, 10, 2155–2160; (g) H. Han, Tetrahedron
Lett., 2003, 44, 1567–1569; (h) M. G. Szczepina, B. D. Johnston, Y.
Yuan, B. Svensson and B. M. Pinto, J. Am. Chem. Soc., 2004, 126,
12458–12469; (i) H. Ouchi, Y. Mihara and H. Takahata, J. Org. Chem.,
2005, 70, 5207–5214; (j) M. S. Reddy, M. Narender and K. R. Rao,
Tetrahedron, 2007, 63, 331–336.
NMR (50 MHz, CDCl3), d −1.4 (CH3), 25.8 (CH3), 26.8 (CH3),
46.9 (CH2), 58.1 (CH2), 62.7 (CH2), 68.6 (CH), 74.3 (CH), 80.4
(CH), 81.3 (C), 110.0 (C), 126.7 (CH), 127.9 (CH), 128.7 (CH),
139.3 (C); mass: m/z (%), 332 (M+ + H, 100), 284 (22), 246 (19),
238 (33).
Acknowledgements
We thank Dr P. R. Rajmohan for special NMR experiments.
K.C.B and K.S.S. thank CSIR, New Delhi for the award of
2594 | Org. Biomol. Chem., 2008, 6, 2587–2595
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
14 (a) G. Pandey and M. Kapur, Tetrahedron Lett., 2000, 41, 8821–8824;
(b) G. Pandey and M. Kapur, Synthesis, 2001, 1263–1267; (c) G.
Pandey and M. Kapur, Org. Lett., 2002, 4, 3883–3886; (d) M. Kapur,
Ph.D. thesis, University of Pune, 2002; (e) G. Pandey, M. Kapur,
M. I. Khan and S. M. Gaikwad, Org. Biomol. Chem., 2003, 1, 3321–
3326.
15 (a) G. Pandey, G. Kumaraswamy and U. T. Bhalerao, Tetrahedron Lett.,
1989, 30, 6059–6062; (b) G. Pandey, G. D. Reddy and G. Kumaraswamy,
Tetrahedron, 1994, 50, 8185–8194.
16 (a) G. Pandey, S. G. Dumbre, M. I. Khan, M. Shabab and V. G. Puranik,
Tetrahedron Lett., 2006, 47, 7923–7926; (b) G. Pandey, S. G. Dumbre,
M. I. Khan and M. Shabab, J. Org. Chem., 2006, 71, 8481–8488; (c) G.
Pandey, S. G. Dumbre, S. Pal, M. I. Khan and M. Shabab, Tetrahedron,
2007, 63, 4756–4761.
19 (a) J.-C. Thie´ry, C. Fre´chou and G. Demailly, Tetrahedron Lett., 2000,
41, 6337–6339; (b) E. Alca´zar, J. M. Pletcher and F. E. McDonald, Org.
Lett., 2004, 6, 3877–3880.
20 CCDC number 673352.
21 F. Dolhem, C. Lie´vre and G. Demailly, Tetrahedron, 2003, 59, 155–164.
22 (a) D.-K. Kim, G. Kim and Y.-W. Kim, J. Chem. Soc., Perkin Trans. 1,
1996, 803–808; (b) A. Kilonda, F. Compernolle, K. Peeters, G. J. Joly, S.
Toppet and G. J. Hoornaert, Tetrahedron, 2000, 56, 1005–1012; (c) E.
Poupon, B.-X. Luong, A. Chiaroni, N. Kunesch and H.-P. Husson,
J. Org. Chem., 2000, 65, 7208–7210; (d) I. McCort, S. Fort, A. Dure´ault
and J.-C. Depezay, Bioorg. Med. Chem., 2000, 8, 135–143; (e) T. Tite,
M.-C. Lallemand, E. Poupon, N. Kunesch, F. Tillequin, C. Gravier-
Pelletie, Y. L. Merrer and H.-P. Hussonc, Bioorg. Med. Chem., 2004,
12, 5091–5097.
17 H. Kotsuki, T. Araki, A. Miyazaki, M. Iwasaki and P. K. Datta, Org.
Lett., 1999, 1, 499–502.
18 (a) S. Mu¨ller, B. Liepold, G. J. Roth and H. Bestmann, Synlett, 1996,
521–522; (b) G. J. Roth, B. Liepold, S. Mu¨ller and H. Bestmann,
Synthesis, 2004, 59–62; (c) J. Pietruszka and A. Witt, Synthesis, 2006,
4266–4268.
23 D. N. Kumar, B. V. Rao and G. S. Ramanjaneyulu, Tetrahedron:
Asymmetry, 2005, 16, 1611–1614.
24 The authors in reference 19b did not observe any epimerization.
25 F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and
R. D. Shah, J. Org. Chem., 1996, 61, 3849–3862.
26 CCDC number 673353.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2587–2595 | 2595
©