A new access to polyhydroxy piperidines of the azasugar class: Synthesis and glycosidase inhibition studies

Article abstract of DOI:10.1039/b307455b

A new synthetic strategy has been devised to access a variety of polyhydroxylated piperidines belonging to the azasugar class of glycosidase inhibitors. The key precursor (3aR, 7aR)-5-benzyl-2,2-dimethyl-7-methylenehexahydro[1,3]dioxo[4,5-c]pyridine is obtained by photoinduced electron transfer (PET) cyclization of the corresponding α-trimethylsilylmethylamine radical cation to the tethered acetylene functionality. The new molecules have been evaluated for inhibitory properties for certain β-glycosidases and have been found to be moderate to weak inhibitors of the enzymes under study.

Full text of DOI:10.1039/b307455b

View Article Online / Journal Homepage / Table of Contents for this issue
A new access to polyhydroxy piperidines of the azasugar class:
synthesis and glycosidase inhibition studies
Ganesh Pandey,*a Manmohan Kapur,a M. Islam Khanb and Sushama M. Gaikwadb
a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411008,
India. E-mail: pandey@ems.ncl.res.in; Fax: ϩ91-20-5893153; Tel: ϩ91-20-5893300
b Division of Biochemical Sciences, National Chemical Laboratory, Pune-411008, India
Received 1st July 2003, Accepted 18th August 2003
First published as an Advance Article on the web 10th September 2003
A new synthetic strategy has been devised to access a variety of polyhydroxylated piperidines belonging to the
azasugar class of glycosidase inhibitors. The key precursor (3aR, 7aR)-5-benzyl-2,2-dimethyl-7-methylenehexa-
hydro[1,3]dioxo[4,5-c]pyridine is obtained by photoinduced electron transfer (PET) cyclization of the corresponding
α-trimethylsilylmethylamine radical cation to the tethered acetylene functionality. The new molecules have been
evaluated for inhibitory properties for certain β-glycosidases and have been found to be moderate to weak inhibitors
of the enzymes under study.
Although tremendous effort has been put into the develop-
Introduction
ment of synthetic routes towards these piperidines,9,10 these
Polyhydroxy piperidines, also characterized as inhibitors of
deceptively simple looking molecules have not been easy to syn-
glycosidases, have found widespread interest,1 especially, after
thesize. Barring a few approaches, most of the groups rely upon
being postulated as possible therapeutics in the treatment of
carbohydrates as starting materials for the polyhydroxy frame-
a variety of carbohydrate mediated diseases.2 These low-
work. The construction of the aminomethylene moiety in the
molecular weight entities, also termed as “azasugars”, are
neighborhood of a stereocenter and the lack of suitably sub-
suggested to bind to glycosidases by mimicking the shape and
stituted carbohydrates make the approaches towards these
charge of the postulated oxo-carbenium ion intermediate for
molecules lengthy and rather tedious. In this context, other than
the glycosidic bond cleavage reaction.3 Based on the studies on
the approaches of the groups of Ganem9c and Nishimura,6d
the relationship between structure and inhibitory activity in
a general and flexible synthetic route towards this class of
inhibitors is unknown. As a part of our ongoing interest in the
polyhydroxy piperidines, we envisioned an entity of type 11
glycosidase inhibitors, the research groups of Bols,4 Ichikawa5
and Nishimura6 have developed a new class of sugar mimic
inhibitor having a nitrogen atom at the anomeric position.
(Chart 2) as a general representative synthon for an easy access
These designed azasugars have displayed high inhibitory
to these classes of compounds.11 This design was surmised
potencies towards β-glycosidases, whose substrates they have
keeping in mind the general substitution pattern of the aza-
sugars of type 12.
mimicked. In particular, isofagomine4a (1, R1 = CH2OH, R2 =
H), isoglucuronofagomine5d (2, R1 = COOH, R2 = H), 5-
hydroxy isofagomine5c (3, R1 = CH2OH, R2 = OH), noeuromy-
cin4d (4, R1 = CH2OH, R2 = H), isogalactofagomine5b (5) and
isofucofagomine5a,4b (6) have been found to be extremely potent
and selective inhibitors of β-glycosidases (Chart 1).
Chart 2
These substituted piperidines (11) were envisaged to be
accessed utilizing our methodology developed for the synthesis
of cyclic amines via the photoinduced electron transfer (PET)
mediated cyclization of α-trimethylsilylmethylamine radical
cation to a tethered acetylene functionality.12 The acetonide
moiety was chosen in order to lock the conformation for better
diastereoselection during the functionalization of the exocyclic
olefin. We report herein the full details13 on the synthesis of a
variety of the azasugars through the general route as depicted
retrosynthetically in Scheme 1, as well as the evaluation of the
glycosidase inhibitory properties of some of the new molecules.
Chart 1 Azasugar type glycosidase inhibitors.
Results and discussion
3,4,5-Trihydroxy piperidines (7–10), first synthesized by
Ganem et al., are also shown to exhibit moderate to good glyco-
sidase inhibitory activity.7 These compounds (7–9) were sub-
sequently, isolated from Eupatorium Fortunei TURZ by Kusano
and co-workers8 and were shown to be active components of
the extracts of this plant which had been used traditionally in
Chinese and Japanese folk medicine for a variety of disorders.
As a part of our broad research program aimed at the design,
synthesis and evaluation of new glycosidase inhibitors of the
azasugar class, we initially chose isofagomine (1) as our target.
This compound was synthesized11 (Scheme 2) by the hydro-
boration of the -threo precursor 15 using 9-BBN followed by
the removal of the protecting groups. The key precursor
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3321

View Article Online
Scheme
3
Reagents and conditions: (a) OsO4, NMO, pyridine,
acetone–water (9 : 1), from 0 ЊC to rt, 24 h, 95%; (b) Pd(OH)2, H2,
EtOH, 65 psi, 6 h, 90%; (c) HCl, MeOH, rt, 4 h, quant.
lowed by the reduction of the corresponding ketone (Scheme 4),
failed to give a good yield of the expected alcohol 20. Therefore,
we reverted back to 17 once again.
Scheme 1
Scheme 4 Reagents and conditions: (a) (Boc)2O, TEA, DCM, from 0
ЊC to rt, overnight, 80%; (b) (i) NaIO4, EtOH–H2O (4 : 1), rt, 30 min,
70%; (ii) NaBH4, MeOH, rt, 36 h, then saturated NaCl, rt, 24 h, 25%.
The diol 17 upon periodate oxidation afforded 21 (Scheme 5),
which was quickly subjected to sodium borohydride reduction
resulting in the formation of 22 in 85% yield. The diastereo-
meric ratio (9 : 1), was determined by the capillary GC analysis
(Varian CP-Sil 5CB, 30 m, 0.25 mm i.d. column). These
diastereomers were found to be non-separable at this stage.
One pot N-debenzylation and acetonide removal afforded 10
as a hydrochloride salt. Purification of the crude 10 was carried
out by column chromatography as a free base, which was
reconverted back to its hydrochloride salt for spectral charac-
terization. The stereochemistry of 10 was determined by COSY
experiments. The optical rotation ([α]2D5 = Ϫ12 (c 0.15, MeOH);
lit7 [α]2D5 = Ϫ16 (c 0.9, MeOH)) and spectral characteristics for
10ؒHCl were found to be in close agreement with those reported
in literature.7
Scheme 2 Synthesis of isofagomine.
(3aR, 7aR)-5-benzyl-2,2-dimethyl-7-methylenehexahydro[1,3]-
dioxo[4,5-c]pyridine (15) was obtained in 60% yield by the
PET cyclization12 of 16 which in turn was synthesised from ()-
tartaric acid by following simple synthetic steps.11 Hydro-
boration of 15 took place selectively from the α-face, possibly
due to the preferential low energy equatorial orientation of the
bulky bicyclic boron in the four membered transition state. In a
similar fashion (Ϫ)-isofagomine was also synthesized starting
from the -threo precursor (ent-15)
This success prompted us to go in for the further develop-
ment of our strategy and we took up the preparation of 5-
hydroxy-5-epi-isofagomine (13) (Scheme 3). Osmium tetroxide
dihydroxylation of 15 afforded 17 as a single diastereomer. The
stereochemistry of the product was adjudged by HETCOR and
COSY experiments. Although, 13 could be obtained by a one-
pot hydrogenation of 17 in acidic medium, we failed to purify it
by any of the available means. Therefore, a two-step sequence,
N-debenzylation followed by acetonide deprotection, was
adopted to obtain 13 in a pure state.
Subsequently, it was visualized that the corresponding syn-
thesis of piperidines 8–10 could also be achieved from the
- and -threo precursors. Towards the planned synthesis of
des(hydroxymethyl)-deoxymannojirimycin (10), the diol 17 was
first subjected to N-debenzylation to obtain 18 and was repro-
tected as N-Boc derivative 19. This deprotection–protection
sequence was performed to avoid any possible complications
during periodate oxidation. The periodate oxidation of 19 fol-
Scheme 5 Reagents and conditions: (a) NaIO4, EtOH–H2O (4 : 1), rt, 1
h, 80%; (b) NaBH4, MeOH, rt, 40 h, then saturated NaCl, rt, 24 h, 85%;
(c) Pd(OH)2 on C, HCl, MeOH, H2, 1 atm, rt, 36 h, quant; silica gel
chromatography, 88%.
Next, we targeted the synthesis of meso-des(hydroxymethyl)-
deoxynojirimycin (8). It was visualized that 8 could be accessed
easily by inverting the stereochemistry of the free hydroxy
group either in 22 or 23 (ent-22). Mitsunobu esterification14 of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3322

View Article Online
23 followed by the cleavage of the p-nitrobenzoate and aceto-
nide deprotection as well as N-debenzylation afforded 8 as its
hydrochloride salt (Scheme 6). Usual purification of the basified
material by column chromatography afforded pure 8. Spectral
characteristics of 8ؒHCl were found to be in excellent agree-
ment with reported values.7
Scheme
6
Reagents and conditions: (a) (i) diisopropyl azodi-
carboxylate, PPh3, p-nitrobenzoic acid, THF, rt, overnight; (ii) LiOH,
MeOH, 60% over two steps; (b) Pd(OH)2 on C, HCl, MeOH, H2, 1 atm,
rt, 20 h, quant; silica gel chromatography, 90%.
Scheme 8 Reagents and conditions: (a) (i) PPh3, n-BuLi, THF, Ϫ15 ЊC
to rt, 16 h, 60%; (ii) TBAF, THF, rt, 4 h, 90%; (b) (i) TsCl, pyridine,
DCM, rt, 24 h, 95%; (ii) PhCH2NHCH2TMS, Cs2CO3, TBAI, CH3CN,
reflux, 72 h, 58%; (c) hν, DCN, 2-PrOH, 2 h, 55%; (d) Pd(OH)2 on C,
HCl, MeOH, H2, 1 atm, 28 h, quant.
Further, we adopted a one-pot strategy for the synthesis of
5Ј-deoxy-5-epi-isofagomine (14) (Scheme 7).
This effort was prompted by the fact that the fucose analog
6 was found to be an extremely potent inhibitor of fuco-
sidases.5a,4b Therefore, it was decided to evaluate 14, the C-3
epimer of 6 and compare its activity with the dihydroxy analog
13. The catalytic hydrogenation of 15, N-debenzylation as well
as acetonide removal afforded 14 in a 4 : 1 diastereomeric ratio
(as determined by NMR). The free amines were not separable
and therefore, were converted to the corresponding N-Boc
derivatives. Careful column chromatography afforded the
major diastereomer as a pure compound. The stereochemistry
of the 5-methyl group was adjudged by the coupling constants
for H4, which was observed as a dd (J = 6.8, 4.0 Hz) at δ 3.63.
The N-Boc moiety was cleaved to afford 14 as a hydrochloride
salt.
Chart 3 The azasugars obtained from -threo precursor.
The new compounds were tested for inhibitory activities
of β-glucosidase and β-mannosidase. The results of the study
are summarized in Table 1. The compounds tested exhibited
moderate to weak inhibition for the glycosidases under study.
The dihydroxy compound 13 and the 5Ј-deoxy compound 14,
both derived from the -threo precursor 15, displayed moderate
inhibition for β-glucosidase. Surprisingly 14, which lacks the
hydroxy group at the 5-position was found to be a better
inhibitor than 13. The iminosugar 14, however, did not inhibit
β-mannosidase. The corresponding enantiomers, derived from
-threo precursor, were found to be weak inhibitors of β-
glucosidase. Substrate 29 inhibited β-mannosidase to some
extent. We also tested the N-benzyl derivatives of the corre-
sponding dihydroxy compounds but no general trend was
observed for these compounds.
The moderate diastereoselectivity in the synthesis of 14,
encouraged us to improve upon it by attempting the direct PET
cyclization of 27 (Scheme 8).
In conclusion, a new synthetic strategy to access polyhydroxy
piperidines of the 1-N-iminosugar type has been generalized by
synthesizing a variety of 1-N-iminosugars. It is quite obvious
that this methodology can easily be extended to derive other
azasugars in which the C-3 and C-4 hydroxy are syn, utilizing
precursors of the - and -erythro type.
Scheme 7 Reagents and conditions: (a) (i) Pd/C, MeOH, HCl, H2,
1 atm, rt, 12 h, 89%; (ii) (Boc)2O, TEA, DCM, rt, 48 h, 75%; (b) HCl,
MeOH, from 0 ЊC to rt, 4 h, quant.
Towards this end, the efforts began by deriving the alcohol 26
from -tartaric acid. Wittig olefination of the aldehyde 25,15
followed by TBS removal afforded 26, data for which is in
accordance with that reported in literature for its enantiomer.16
Nucleophilic displacement of the corresponding tosylate using
PhCH2NHCH2TMS, afforded 27. This amine, when irradiated
under PET cyclization conditions, yielded 28 as almost a single
diastereomer (>97% as determined by GC). The stereo-
chemistry of the methyl group was ascertained by the coupling
constants for H7a (δ 3.24, ddd, J = 9.9, 4.0, 1.2 Hz). A small
coupling constant of 4.0 Hz pointed to the axial–equatorial
relationship of H7a and H7. The coupling constant of 1.2 Hz
was attributed to long range coupling, probably with one of H6
protons. The protecting groups were removed to afford 14ؒHCl.
In a manner similar to that described earlier, utilizing the -
threo precursor, we prepared the corresponding enantiomeric
azasugars, 29 (ent-13), 30 (ent-14) and des(hydroxymethyl)-
deoxygalactonojirimycin (9) (Chart 3).
Experimental
General methods
All reagents were used as supplied. Unless otherwise men-
tioned, all reactions involving sensitive reagents and anhydrous
solvents, were carried out under an argon atmosphere. The
boiling point range of the petroleum ether referred to through-
out the Experimental section was 60–80 ЊC. Melting points
reported are uncorrected. 1H and 13C NMR spectra were
run on Bruker AC 200 and DRX 500 instruments. GC-MS
was performed on Shimadzu QP 5000 GC/MS coupled to
Shimadzu 17A GC using a DB1 column. GC analysis was
performed on a Varian CP 3800 GC using CP-Sil 5CB column.
ESI (Electrospray Ionization) HRMS spectra were obtained on
QSTAR PULSAR LC-MS/MS-TOF using an infusion
method. Optical rotations were measured on a Jasco P1030
polarimeter in units of 10Ϫ1 deg cm2 gϪ1. The glycosidases and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3323

View Article Online
Table 1 Enzyme inhibition studies
Ki/µM
Glycosidase
13
14
N-Bn-13
29
30
N-Bn-29
ꢀ-Glucosidase (37 ЊC, pH 6.0)
ꢀ-Mannosidase (25 ЊC, pH 4.0)
96
30
590
NT
580
290
370
NI
300
1500
NTa
NIb
a NT = not tested. b NI = no inhibition up to 2 mM.
the corresponding p-nitrophenyl β--glycosides were purchased
from Sigma. The optical density measurements were carried out
on a Varian CARY-50 BIO UV-VIS spectrophotometer.
49.6 (C6, CH2), 46.0 (C4, CH2), 25.4 (2 × CH3); ESI HRMS
found 204.1236, C9H18NO4 requires 204.1236.
(3R,4S,5R)-3-(Hydroxymethyl)piperidine-3,4,5-triol, hydro-
chloride salt (13ؒHCl). To a solution of substrate 18 (0.025 g,
0.12 mmol) in distilled methanol (0.5 mL) was added conc.
HCl (2 drops) and the reaction mixture was stirred at rt for
approximately 4 h. The solvent was evaporated to dryness and
the residue dissolved in water (1 mL) and lyophilized to afford
13ؒHCl (0.024 g, ∼100%) as an amorphous solid. [α]2D5 ϩ11.0
(c = 0.2, EtOH); δH (500 MHz, D2O) 4.11 (m, 1H, H3), 3.85 (d,
J 4.4 Hz, 1H, H4), 3.71 (d, J 12.0 Hz, 1H, CH2OH), 3.64 (d,
J 12.0 Hz, 1H, CH2OH), 3.43 (d, J 13.6 Hz, 1H, H6eq), 3.30 (m,
2H, H2), 3.16 (d, J 13.6 Hz, 1H, H6ax); δC (125 MHz, D2O) 71.5
(C5, –C–), 68.1 (C3, CH), 66.6 (C4, CH), 63.6 (CH2OH, CH2),
46.1 (C2, CH2), 45.2 (C6, CH2); ESI HRMS found 164.0916,
C6H14NO4 requires 164.0923.
For the synthesis of the D- and L-threo precursors (15 and ent-15
respectively) and the preparation of isofagomine, see ref. 11
General procedure for the PET cyclization. A typical PET
cyclization procedure involves irradiation of a solution con-
taining the substrate (1 mmol) and a catalytic amount of 1,4-
dicyanonaphthalene (DCN) (0.15–0.30 mmol) in 2-propanol
(0.5 mL per mg of substrate), in an open vessel, using a 450 W
Hanovia medium pressure mercury vapor lamp as the light
source. The lamp is housed in a Pyrex water-jacketed immer-
sion well so as to allow only the wavelengths greater than
280 nm to pass through. The reaction is monitored by TLC or
GC and when the consumption of the starting material is found
to be complete (>90%), the irradiation is discontinued. The
solvent is removed under reduced pressure and the photolysate
is purified by column chromatography.
(3aR,7aS )-5-Benzyl-2,2-dimethyltetrahydro[1,3]dioxolo-
[4,5-c]pyridin-7(4H)-one (21). To a solution of 17 (0.100 g,
0.34 mmol) in ethanol–water (2 mL, 8 : 2), was added sodium
periodate (0.090 g, 0.4 mmol) in three portions over a period
of 15 min. The white suspension was stirred for an additional
hour and filtered. The solvent was evaporated off and the white
pasty mass was extracted into ethyl acetate (3 × 3 mL). The
combined organic extracts were dried over anhydrous Na2SO4
and the solvent was removed under reduced pressure. Column
chromatography (silica, pet. ether–ethyl acetate, 4 : 1) of the
crude mixture afforded pure 21 (0.071 g, 80%) as a colorless
liquid. δH (200 MHz, CDCl3) 7.30 (m, 5H, Ar), 4.26 (dd, J 10.2,
1.5 Hz, 1H, H7a), 3.90 (ddd, J 10.0, 9.8, 4.4 Hz, 1H, H3a), 3.75
(m, 2H, N–CH2Ph), 3.40 (dd, J 10.3, 4.4 Hz, 1H, H4eq), 3.25
(d, J 14.2 Hz, 1H, H6), 3.05 (d, J 14.2 Hz, 1H, H6), 2.72 (dd like
t, J 10.2, 9.8 Hz, 1H, H4ax), 1.50 (s, 3H, CH3), 1.49 (s, 3H, CH3).
(3aR,7R,7aS )-5-Benzyl-7-(hydroxymethyl)-2,2-dimethylhexa-
hydro[1,3]dioxolo[4,5-c]pyridin-7-ol (17). To a solution of 15
(0.119 g, 0.46 mmol) in acetone–water (3 mL, 9 : 1) was added
pyridine (40 µL, 0.46 mmol), followed by N-methylmorpholine-
N-oxide (0.108 g, 0.92 mmol). The reaction mixture was cooled
to 0 ЊC and to it was added a catalytic amount of osmium
tetroxide (0.002 g). The reaction mixture was allowed to come
to rt and was stirred for 24 h. It was passed through a short pad
of Celite and the solvent evaporated off. The crude reaction
mixture upon column chromatography (silica, pet. ether–ethyl
acetate, 3 : 2) afforded the diol 17 as a colorless solid (0.128 g,
95%). Mp 150–152 ЊC; [α]2D5 Ϫ21.6 (c = 1.4, MeOH); δH
(500 MHz, CDCl3) 7.40 (m, 5H, Ar), 4.25 (d, J 11.5 Hz, 1H,
CH2–OH), 3.85 (ddd, J 9.9, 9.7, 4.3 Hz, 1H, H3a), 3.78 (d, J 11.5
Hz, 1H, CH2–OH), 3.76 (d, J 13.8 Hz, 1H, N–CH2–Ph), 3.71
(d, J 13.8 Hz, 1H, N–CH2–Ph), 3.61 (d, J 9.7 Hz, 1H, H7a), 3.30
(dd, J 9.7, 4.3 Hz, 1H, H4eq), 2.92 (d, J 11.7 Hz, 1H, H6eq), 2.31
(dd like t, J 10.1, 9.9 Hz, 1H, H4ax), 2.21 (d, J 12.0 Hz, 1H,
H6ax), 1.50 (s, 6H, 2 × CH3); δC (50 MHz, CDCl3) 137.7, 128.6,
128.3, 127.3 (Ar), 110.7 (C2, –C–), 86.2 (C7a, CH), 73.6 (C3a,
CH), 71.5 (C7, –C–), 65.0 (CH2OH, CH2), 61.5 (N–CH2Ph,
CH2), 59.3 (C6, CH2), 54.5 (C4, CH2), 26.5 (2 × CH3); m/z (%)
293 (Mϩ)(5), 235 (25), 134 (45), 120 (41), 91 (100).
(3aR,7R,7aR)-5-Benzyl-2,2-dimethylhexahydro[1,3]dioxolo-
[4,5-c]pyridin-7-ol (22). Sodium borohydride (0.009 g, 0.23
mmol) was added to a solution of 21 (0.050 g, 0.019 mmol) in
methanol (0.5 mL). The resulting mixture was stirred for 48 h
and then quenched by the adding a saturated solution of NaCl
in excess. The resultant white suspension was stirred overnight
and then extracted into ethyl acetate (4 × 3 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and the
solvent evaporated off. The residue was purified using column
chromatography (silica, pet. ether–ethyl acetate, 3 : 2) to afford
22 (0.043 g, 85%) as a colorless oil (9 : 1 mixture of dia-
stereomers). [α]2D5 Ϫ36.2 (c = 0.13, CHCl3); δH (200 MHz,
CDCl3) 7.35 (m, 5H, Ar), 4.30 (m, 1H, H7), 4.10 (ddd, J 10.3,
9.7, 4.4 Hz, 1H, H3a), 3.87 (d, J 13.7 Hz, 1H, N–CH2Ph), 3.79
(d, J 13.7 Hz, 1H, N–CH2Ph), 3.45–3.30 (m, 2H, H7a, H4eq),
(3aR,7R,7aS )-7-(Hydroxymethyl)-2,2-dimethylhexahydro-
[1,3]dioxolo[4,5-c]pyridin-7-ol (18). An ethanolic solution
(2 mL) of the diol 17 (0.100 g, 0.34 mmol) was hydrogenated
for 6 h in the presence of Pd(OH)2 on charcoal (20%) (0.005 g)
at 60 psi. The catalyst was filtered off and the solvent removed
in vacuo. The crude reaction mixture was purified using column
chromatography (silica, chloroform–methanol, 9 : 1) to afford
pure 18 (0.063 g, 90%) as a colorless gum. [α]2D5 Ϫ24.7 (c = 0.9,
MeOH); δH (500 MHz, D2O) 3.81 (d, J 12.1 Hz, 1H, CH2OH),
3.79 (d, J 12.1 Hz, 1H, CH2OH), 3.69 (ddd, J 10.0, 9.9, 4.4 Hz,
1H, H3a), 3.62 (d, J 9.5 Hz, 1H, H7a), 3.35 (dd, J 11.9, 4.0 Hz,
1H, H4eq), 3.24 (d, J 13.9 Hz, 1H, H6eq), 2.70 (dd like t, J 11.1,
10.3 Hz, 1H, H4ax), 2.37 (d, J 13.9 Hz, 1H, H6ax), 1.43 (s, 3H,
CH3), 1.42 (s, 3H, CH3); δC (125 MHz, D2O) 110.2 (C2, –C–),
84.1 (C7a, CH), 73.7 (C7, –C–), 72.9 (C3a, CH), 60.0 (CH2OH),
3.20 (m, 1H, H6eq), 2.80 (br s, 1H, OH ), 2.40 (m, 2H, H4ax
,
H6ax), 1.50 (s, 3H, CH3), 1.49 (s, 3H, CH3); δC (125 MHz,
CDCl3) 137.2, 128.7, 128.1, 127.1 (Ar), 110.1 (C2, –C–), 81.4
(C7, CH), 70.6 (C7a, CH), 65.7 (C3a, CH), 61.5 (N–CH2Ph), 56.5
(C4, CH2), 54.7 (C6, CH2), 26.5 (CH3), 26.3 (CH3); GC/MS: m/z
(%) 263 (Mϩ)(<1%), 207 (3), 172 (7), 149 (20), 91 (100).
(3R,5R)-Piperidine-3,4,5-triol, hydrochloride salt (des-
(hydroxymethyl)deoxy-mannojirimycin) (10ؒHCl). To a solution
of 22 (0.030 g, 0.11 mmol) in distilled methanol (0.5 mL) was
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3324

View Article Online
added conc. HCl (2 drops), followed by Pd(OH)2 on C (20%)
(0.003 g) and the reaction mixture was hydrogenated at atmos-
pheric pressure for approximately 16 h. After passing through a
short pad of Celite, the solvent evaporated off to dryness to
afford 10ؒHCl (19 mg, ∼100%). Pure 10 was obtained by
column chromatography of the corresponding free base (silica,
chloroform–2-propanol–aq. NH3, 8.5 : 1.5 : 0.5). The combined
fractions containing the compound were pooled together and
concentrated. Water (2 mL) was added and the solution con-
centrated. The residue was dissolved in water (0.5 mL) and
hydrochloric acid (1 mL, 6 M) was added. This solution was
concentrated and the residue lyophilized from water to yield
10ؒHCl (0.0167 g, 88%) as a white solid. [α]2D5 Ϫ12 (c = 0.15,
MeOH); lit7 [α]2D5 Ϫ16 (c = 0.9, MeOH); For des(hydroxy-
methyl)deoxygalactonojirimycin, 9ؒHCl, [α]2D5 ϩ18 (c = 0.14,
MeOH); lit7 [α]2D5 ϩ16 (c = 0.5, MeOH); δH (500 MHz, D2O)
4.20 (m, 1H, H5), 4.06 (ddd, J 8.3, 7.8, 3.9 Hz, 1H, H3), 3.75 (dd,
J 7.6, 3.2 Hz, 1H, H4), 3.37 (dd, J 13.2, 3.9 Hz, 1H, H2eq), 3.26
(dd, J 12.9, 5.9 Hz, 1H, H6eq), 3.18 (m, 1H, H6ax), 2.92 (dd,
J 12.7, 8.4 Hz, 1H, H2ax); δC (125 MHz, D2O) 70.7 (C5, CH),
65.0 (C4, CH), 64.6 (C3, CH), 45.9 (C2, CH2), 45.4 (C6, CH2);
ESI HRMS found 134.0813, C5H12NO3 requires 134.0817.
analysis of the crude mixture indicated it to be a mixture of
diastereomers in a ratio of 4 : 1, which were non-separable. This
salt was basified using conc. NH4OH and the excess ammonia
was evaporated off. This was dissolved in DCM (1 mL) and
triethyl amine (0.1 mL, 0.7 mmol) was added and the resulting
mixture was cooled to 0 ЊC. (Boc)2O (35 µL, 0.15 mmol) was
added and the reaction mixture was stirred at rt for 48 h. The
excess triethyl amine was removed at the pump and the crude
mixture upon column chromatography (silica, pet. ether–ethyl
acetate, 3 : 2) afforded pure 24 (0.030 g, 70 %) as a gummy mass.
25
D
[α] ϩ50 (c = 0.1, MeOH); δH (500 MHz, CDCl3) 3.82 (dd,
J 2.4, 1.0 Hz, 1H, H2eq), 3.72 (ddd, J 10.8, 6.8, 4.0 Hz, 1H, H3),
3.63 (dd, J 6.8, 4.0 Hz, 1H, H4), 3.43 (dd, J 13.3, 6.7 Hz,
1H, H6eq), 3.29 (dd, J 13.1, 2.8 Hz, 1H, H6ax), 3.18 (dd, J 13.5,
6.7 Hz, 1H, H2ax), 2.15 (m, 3H, 2H D2O exchangeable, H5, 2 ×
OH ), 1.50 (s, 9H, tBu), 0.98 (d, J 7.1 Hz, 3H, CH3); δC (75 MHz,
CDCl ) 155.7 (C᎐O), 80.0 (O–C(CH ) ), 74.0 (C , CH), 68.4
᎐
3
3
3
4
(C3, CH), 46.7 (C4, C6, 2 × CH2), 32.5 (C5, CH), 28.4 (tBu, 3 ×
CH3), 12.1 (CH3); GC/MS: m/z 231(Mϩ), 207, 186, 175, 158,
145, 57.
(3R,4R,5R)-5-Methylpiperidine-3,4-diol, hydrochloride salt
(14ؒHCl). To a solution of 24 (0.032 g, 0.13 mmol) in distilled
methanol (0.5 ml) was added conc. HCl (100 µL) at 0 ЊC. The
reaction mixture was stirred at rt for about 4 h and the solvent
evaporated to dryness. The residue was lyophilized from water
(1 mL) to afford 14ؒHCl (0.021 g, ∼100%) as a colorless solid
mass. [α]2D5 ϩ 7.7 (c = 0.2, MeOH); δH (500 MHz, D2O) 4.01 (m,
1H, H3), 3.76 (m, 1H, H4), 3.25 (dd, J 13.3, 1.7 Hz, 1H, H2eq),
3.17 (dd, J 14.7, 1.2 Hz, 1H, H2ax), 3.07 (dd, J 12.7, 4.3 Hz, 1H,
H6eq), 2.87 (dd like t, J 12.7, 12.4 Hz, 1H, H6ax), 2.30 (m,
1H, H5), 0.9 (d, J 7.1 Hz, 3H, CH3); δC (125 MHz, D2O) 68.2
(C4, CH), 65.4 (C3, CH), 43.9 (C2, CH2), 43.8 (C6, CH2), 27.3
(C5, CH), 12.9 (CH3); ESI HRMS found 132.1021, C6H14NO2
requires 132.1025.
(3R,5S )-Piperidine-3,4,5-triol, hydrochloride salt (des-
(hydroxymethyl)deoxy-nojirimycin) (8ؒHCl). To a solution of 23
(0.090 g, 0.34 mmol) in dry THF (2 mL) was added triphenyl
phosphine (0.099 g, 0.38 mmol) and p-nitrobenzoic acid
(0.063 g, 0.38 mmol). The resulting reaction mixture was cooled
to 0 ЊC and to it was added diisopropyl azodicarboxylate
(81 µL, 0.41 mmol). The reaction mixture was allowed to warm
to rt and was stirred overnight. This was followed by extraction
into DCM (5 mL) with sodium bicarbonate washes ( 2 M, 3 ×
3 mL). The organic layer, after drying over anhydrous Na2SO4,
was concentrated under reduced pressure. This residue was
dissolved in a minimum quantity of DCM and to it was added
petroleum ether to precipitate out the phosphine oxide. The
resulting slurry was loaded onto a column of silica gel and
eluted. The combined fractions were concentrated in vacuo to
afford the benzoate. This benzoate was dissolved in distilled
methanol (2 mL) and to it was added lithium hydroxide
(0.016 g, 0.68 mmol) and the reaction mixture was stirred at
rt for about 6 h. Water (5 mL) was added, followed by ethyl
acetate (6 mL) and the layers were separated. The organic layer
was dried (anhydrous Na2SO4) and concentrated under reduced
pressure to afford the alcohol (0.054 g, 60%).
This alcohol was dissolved in distilled methanol (1.5 mL)
and conc. HCl (2 drops) was added and the resulting reaction
mixture was hydrogenated at atmospheric pressure in the
presence of Pd(OH)2 on carbon (20%) (0.002 g), for about 7 h.
The catalyst was filtered off and the filtrate evaporated to dry-
ness to afford 8 as a hydrochloride salt (0.035 g, ∼100%), which
was further purified by column chromatography as a free base
(silica, chloroform–2-propanol–aq. NH3, 8.5 : 1.5 : 0.5).
Utilizing exactly the same procedure as described for com-
pound 10, the triol 8 was reconverted back to its hydrochloride
salt for spectral characterization (0.0315 g, 90%). [α]2D5 0.0
(c = 0.2, MeOH); δH (500 MHz, D2O) 3.72 (ddd, J 10.2, 8.4, 4.4
Hz, 2H, H3, H5), 3.46 (t, J 8.4 Hz, 1H, H4), 3.40 (dd, J 12.7,
N-Benzyl-N-[(trimethylsilyl)methyl]-N-{[(4R,5R)-2,2-di-
methyl-5-vinyl-1,3-dioxolan-4-yl]methyl}amine (27). Pyridine
(0.23 mL, 2.85 mmol) was added to a solution of 26 (0.300 g,
1.89 mmol) in dry DCM (3 mL) at 0 ЊC. To this was added p-
toluene sulfonyl chloride (0.434 g, 2.28 mmol) in portions over
a period of 30 min. The reaction mixture was stirred overnight
at rt and worked up by extraction in DCM. The combined
organic extracts were dried over anhydrous Na2SO4 and con-
centrated in vacuo. The residue upon column chromatography
(silica, pet. ether–ethyl acetate, 19 : 1) afforded pure tosylate
(0.562 g, 95%) as a colorless oil. [α]2D5 ϩ 8.4 (c = 1.0, CHCl3);
δH (200 MHz, CDCl3) 7.75 (d, J 8.3 Hz, 2H, Ar), 7.35 (d, J 8.3
Hz, 2H, Ar), 5.75 (m, 1H, CH᎐CH2), 5.25 (m, 2H, CH᎐CH2),
᎐
᎐
4.25–4.0 (m, 3H, H4, H5, one of CH2OTs), 3.85 (m, 1H, CH2-
OTs), 2.45 (s, 3H, Ar–CH3), 1.40 (s, 3H, CH3), 1.35 (s, 3H,
CH ); δ (50 MHz, CDCl ) 144.8 (Ar), 134.0 (CH᎐CH , CH),
᎐
3
C
3
2
132.3 (Ar), 129.7 (Ar), 127.7 (Ar), 119.5 (CH᎐CH , CH ), 109.7
᎐
2
2
(C2, –C–), 78.5 (C4, CH), 77.7 (C5, CH), 67.7 (CH2–OTs), 26.7
(gem CH3), 26.4 (gem CH3), 21.4 (Ar–CH3); GC/MS: m/z (%)
297 (Mϩ Ϫ 15) (8), 155 (34), 98 (29), 83 (53), 43 (100).
A mixture of the tosylate (0.325 g, 1.041 mmol), PhCH2-
NHCH2TMS (0.402 g, 2.083 mmol), anhydrous cesium carb-
onate (1.696 g, 5.2 mmol), and tetra-n-butyl ammonium iodide
(0.020 g) in dry CH3CN (4 mL) was refluxed under an inert
atmosphere for about 72 h. The reaction mixture was filtered
and the solvent evaporated off. The crude residue upon column
chromatography (silica, pet. ether–ethyl acetate, 98 : 1) afforded
27 (0.201 g, 58%) as a colorless oil. [α]2D5 ϩ28.3 (c = 1.5, CHCl3);
4.3 Hz, 2H, H2eq, H6eq), 2.86 (dd, J 12.7, 10.3 Hz, 2H, H2ax
,
H6ax); δC (125 MHz, D2O) 74.3 (C4, CH), 66.5 (C3, C5, 2 × CH),
45.9 (C2, C4, 2 × CH2); ESI HRMS found 134.0822, C5H12NO3
requires 134.0817.
tert-Butyl (3R,4R,5R)-3,4-dihydroxy-5-methylpiperidine-1-
carboxylate (24). To an ethanolic solution (1 mL) of 15 (0.040
g, 0.15 mmol), was added conc. HCl (50 µL) followed by Pd/C
(10%) (0.005 g) and the mixture was hydrogenated at atmos-
pheric pressure for over 12 h. The suspension was passed
through a short pad of Celite and the mixture evaporated to
dryness to afford the hydrochloride salt (0.023 g, 89%). NMR
δ (200 MHz, CDCl ) 7.30 (m, 5H, Ar), 5.75 (m, 1H, CH᎐CH ),
᎐
H
3
2
5.25 (m, 2H, CH᎐CH ), 4.0 (m, 1H, H ), 3.88 (m, 1H, H ),
᎐
2
4
5
3.75 (d, J 13.7 Hz, 1H, N–CH2Ph), 3.45 (d, J 13.7 Hz, 1H,
N–CH2Ph), 2.60 (dd, J 13.2, 4.1 Hz, 1H, CH2–N–), 2.53 (dd,
J 13.2, 5.9 Hz, 1H, CH2–N–), 2.13 (d, J 14.6 Hz, 1H,
N–CH2TMS), 2.01 (d, J 14.6 Hz, 1H, N–CH2TMS), 1.42 (s,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3325

View Article Online
3H, CH3), 1.38 (s, 3H, CH3), 0.05 (s, 9H, 3 × CH3, –SiMe3); δC
(50 MHz, CDCl ) 139.6 (Ar), 135.4 (CH᎐CH , CH), 128.8
We also thank Mrs S. S. Kulkarni for the GC-MS analysis.
MK thanks CSIR, New Delhi, for a Research Fellowship grant.
᎐
3
2
(Ar), 127.9 (Ar), 126.6 (Ar), 117.9 (CH᎐CH , CH ), 108.7 (C ,
᎐
2
2
2
–C–), 80.9 (C4, CH), 79.8 (C5, CH), 62.6 (N–CH2Ph, CH2), 58.1
(–CH2–N–, CH2), 46.9 (–N–CH2TMS), 27.0 (CH3), 26.7
(CH3), Ϫ1.35 (3 × CH3); GC/MS: m/z (%) 333 (Mϩ) (<1%),
260 (<1%), 206 (57), 134 (12), 91 (100), 73 (10).
References
1 (a) B. Ganem, Acc. Chem. Res., 1996, 29, 340; (b) A. de Raadt,
C. W. Ekhart, M. Ebner and A. E. Stütz, Top. Curr. Chem., 1997,
187, 157; (c) A. E. Stütz, Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond, Wiley-VCH, Weinheim, Germany, 1999;
(d ) V. H. Lillelund, H. H. Jensen, X. Laing and M. Bols, Chem. Rev.,
2002, 102, 515 and references therein; (e) Y. Ichikawa, Y. Igarashi,
M. Ichikawa and Y. Suhara, J. Am. Chem. Soc., 1998, 120, 3007.
2 N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet,
Tetrahedron: Asymmetry, 2000, 11, 1645.
3 For some reviews on this topic see: (a) D. L. Zechel and S. G.
Withers, Acc. Chem. Res., 2000, 33, 11; (b) P. Sears and C.-H. Wong,
Angew. Chem., Int. Ed., 1999, 38, 2300; (c) T. D. Heightman and
A. T. Vasella, Angew. Chem., Int. Ed., 1999, 38, 750.
4 (a) T. M. Jespersen, W. Dong, M. R. Sierks, T. Skrydstrup, I. Lundt
and M. Bols, Angew. Chem., Int. Ed. Engl., 1994, 33, 1778;
(b) A. Hansen, T. M. Tagmose and M. Bols, Chem. Commun., 1996,
2649; (c) M. Bols, R. G. Hazell and Ib B. Thomsen, Chem. Eur. J.,
1997, 3, 940; (d ) H. Liu, X. Liang, H. H. Søhoel, A. Bülow and
M. Bols, J. Am. Chem. Soc., 2001, 123, 5116; (e) H. Søhoel, X. Liang
and M. Bols, J. Chem. Soc., Perkin Trans. 1, 2001, 1584.
5 See ref. 1(e) and (a) Y. Igarashi, M. Ichikawa and Y. Ichikawa,
Bioorg. Med. Chem. Lett., 1996, 6, 553; (b) Y. Ichikawa and
Y. Igarashi, Tetrahedron Lett., 1995, 36, 4585; (c) M. Ichikawa,
Y. Igarashi and Y. Ichikawa, Tetrahedron Lett., 1995, 36, 1767;
(d ) Y. Igarashi, M. Ichikawa and Y. Ichikawa, Tetrahedron Lett.,
1996, 37, 2707.
6 (a) Y. Nishimura, T. Kudo, S. Kondo and T. Takeuchi, J. Antibiot.,
1994, 47, 101; (b) Y. Nishimura, Studies in Natural Products
Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1995, vol 16,
p 75; (c) Y. Nishimura, T. Satoh, T. Kudo, S. Kondo and T. Takeuchi,
BioMed. Chem., 1996, 4, 91; (d ) Y. Nishimura, E. Shitara,
H. Adachi, M. Toyoshima, M. Nakajima, Y. Okami and T. Takeuchi,
J. Org. Chem., 2000, 65, 2; (e) E. Shitara, Y. Nishimura, F. Kojima
and T. Takeuchi, Bioorg. Med. Chem., 2000, 8, 343.
7 R. C. Bernotas, G. Papandreou, J. Urbach and B. Ganem,
Tetrahedron Lett., 1990, 31, 3393.
8 T. Sekioka, M. Shibano and G. Kusano, Nat. Med., 1995, 49,
332.
(3aR,7R,7aR)-5-Benzyl-2,2,7-trimethylhexahydro[1,3]-
dioxolo[4,5-c]pyridine (28). A solution containing 27 (0.200 g,
0.6 mmol) and 1,4-dicyanonaphthalene (DCN) (0.015 mg,
0.08 mmol) in 2-propanol (100 mL) was irradiated using a
450 W Hanovia medium pressure mercury vapor lamp as the
light source. After about 2 h, when most of the starting material
(>90%) had reacted, the irradiation was discontinued and the
solvent was removed under reduced pressure. The crude photo-
lysate was purified using column chromatography (silica, pet.
ether–acetone, 99 : 1) to afford 28 (0.086 g, 55%) as a colorless
oil. [α]2D5 Ϫ8.0 (c = 0.2, CHCl3); δH (500 MHz, CDCl3) 7.30 (m,
5H, Ar), 3.65 (m, 2H, N–CH2Ph), 3.59 (ddd, J 10.3, 8.7, 4.0 Hz,
1H, H3a), 3.24 (ddd, J 9.9, 4.0, 1.2 Hz, 1H, H7a), 2.97 (dd, J 10.6,
8.9 Hz, 1H, H4eq), 2.87 (dd, J 11.7, 3.8 Hz, 1H, H6eq), 2.18 (t,
J 9.9 Hz, 1H, H4ax), 2.0 (m, 1H, H7), 1.82 (t, J 11.1 Hz, 1H,
H6ax), 1.46 (s, 3H, gem CH3), 1.44 (s, 3H, gem CH3), 1.0 (d, J 6.8
Hz, 3H, CH3); δC (125 MHz, CDCl3) 137.8, 128.7, 128.0,
126.9 (Ar), 109.7 (C2, –C–), 85.3 (C3a, CH), 76.3 (C7a), 61.7
(N–CH2Ph, CH2), 58.8 (C4, CH2), 54.5 (C6, CH2), 33.7 (C7,
CH), 26.7 (gem CH3), 26.5 (gem CH3), 15.2 (CH3); GC/MS
m/z 261 (Mϩ), 246, 203, 134, 120, 91.
Preparation of 14ؒHCl from 28. To a solution of 28 (0.021 g,
0.077 mmol) in distilled MeOH (0.5 mL) was added conc. HCl
(2 drops) and the reaction mixture was hydrogenated for 7 h at
atmospheric pressure in the presence of Pd(OH)2 on charcoal
(20%) (0.001 g). The reaction mixture was passed through a
short pad of Celite and the solvent was removed under reduced
pressure to afford 14ؒHCl (0.013 g, ∼100%) as an amorphous
solid.
9 For 1-N-iminosugar syntheses see refs 4–6 and (a) G. Guanti and
R. Riva, Tetrahedron Lett., 2003, 44, 357; (b) J. Andersch and
M. Bols, Chem. Eur. J., 2001, 7, 2744; (c) G. Zhao, U. C. Deo
and B. Ganem, Org. Lett., 2001, 3, 201; (d ) Y. J. Kim, M. Ichikawa
and Y. Ichikawa, J. Org. Chem., 2000, 65, 2599; (e) G. Mehta and
N. Mohal, Tetrahedron Lett., 2000, 41, 5747; ( f ) U. Kazmaier and
C. Schneider, Tetrahedron Lett., 1998, 39, 817; (g) X. Liang,
A. Lohse and M. Bols, J. Org. Chem., 2000, 65, 7432; (h) M. Bols,
Tetrahedron Lett., 1996, 37, 2097.
10 For 3,4,5-piperidine triol syntheses, see refs 5(a), 7 and (a) H. Han,
Tetrahedron Lett., 2003, 44, 1567; (b) N. T. Patil, S. John,
S. G. Sabharwal and D. D. Dhawale, Bioorg. Med. Chem., 2002, 10,
2155; (c) M. Amat, N. Llor, M. Huguet, E. Molins, E. Espinosa
and J. Bosch, Org. Lett., 2001, 3, 3257; (d ) K. C. Jang, I.-Y. Jeong,
M. S. Yang, S. U. Choi and K. H. Park, Heterocycles, 2000, 53,
887; (e) M. Godskesen, I. Lundt, R. Madsen and B. Winchester,
Bioorg. Med. Chem., 1996, 4, 1857; ( f ) G. Legler, A. E. Stütz and
H. Immich, Carbohydr. Res., 1995, 272, 17; (g) D. Sames and R. Polt,
Synlett, 1995, 552; (h) T. Tschamber, F. Backenstrass, M. Neuberger,
M. Zhender and J. Streith, Tetrahedron, 1994, 50, 1135.
General procedure for enzyme inhibition assay. The inhibitory
potencies of the azasugars were determined spectrophoto-
metrically, by carrying out the inhibition assay of the glyco-
sidases in the presence of the azasugars utilizing the corre-
sponding p-nitrophenyl glycosides as the substrates.
In the case of β-glucosidase, each assay was performed in a
citrate buffer (100 mM, pH 6.0) with p-nitrophenyl β--gluco-
side as the substrate. Varying concentrations of the substrate
and the iminosugar were employed. The reaction was initiated
by the addition of 100 µL of appropriately diluted enzyme and
the reaction mixture, which had a final volume of 1 mL, was
incubated at 37 ЊC, for 10 min. Thereupon, it was quenched by
the addition of 2 mL of 1 M Na2CO3 solution and the optical
density of the resulting solution was read at 405 nm.
In the case of β-mannosidase, the assay was performed in an
acetate buffer (100 mM, pH 4.0). The reaction was carried out
at 25 ЊC for 20 min and then quenched by Na2CO3 solution. The
Ki values were determined from the Lineweaver–Burke double
reciprocal plots of 1/v vs. 1/[S]. Ki for competitive inhibition was
determined using the formula:10f Ki = [I]/{(Slope (I )/ Slope
(0))Ϫ1}.
11 (a) G. Pandey and M. Kapur, Tetrahedron Lett., 2000, 41, 8821;
(b) G. Pandey and M. Kapur, Synthesis, 2001, 1263.
12 (a) G. Pandey, G. Kumaraswamy and U. T. Bhalerao, Tetrahedron
Lett., 1989, 30, 6059; (b) G. Pandey, G. D. Reddy and
G. Kumaraswamy, Tetrahedron, 1994, 50, 8185.
13 G. Pandey and M. Kapur, Org. Lett., 2002, 4, 3883.
14 (a) O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn., 1967,
40, 2380; (b) O. Mitsunobu, Synthesis, 1981, 1; (c) D. L. Huges,
R. A. Reamer, J. J. Bergan and E. J. J. Grabowski, J. Am. Chem. Soc.,
1988, 110, 6487.
15 H. Iida, N. Yamazaki and C. Kibayashi, J. Org. Chem., 1987, 52,
3337.
Acknowledgements
We thank Ms Rupali Bhagwat, Dr P. R. Rajmohanan and Mrs
U. D. Phalgune for the special NMR experiments. We thank
Dr M. Vairamani, IICT, Hyderabad, for the HRMS analysis.
16 S. K. Kang and S. B. Lee, Chem. Commun., 1998, 761.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 2 1 – 3 3 2 6
3326