Efficient synthesis of (+)-1,8,8a-tri-epi-swainsonine, (+)-1,2-di-epi- lentiginosine, (+)-9a-epi-homocastanospermine and (-)-9-deoxy-9a-epi- homocastanospermine from a d-glucose-derived aziridine carboxylate, and study of their glycosidase inhibitory activities

Article abstract of DOI:10.1039/b712753g

The utility of a d-glucose-derived aziridine carboxylate was demonstrated for the synthesis of polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed by two-carbon homologation by the Wittig reaction afforded γ,δ-aziridino-α,β-unsaturated ester 9, which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or hydrogenation afforded δ-lactams 11/16-true synthons for the synthesis of four structurally different iminosugars, namely quinolizidine alkaloids 5b/5c, swainsonine 6b and lentiginosine 7b analogues. Glycosidase inhibitory activities of these iminosugars were investigated. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b712753g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient synthesis of (+)-1,8,8a-tri-epi-swainsonine, (+)-1,2-di-epi-
lentiginosine, (+)-9a-epi-homocastanospermine and (−)-9-deoxy-9a-epi-
homocastanospermine from a D-glucose-derived aziridine carboxylate, and
study of their glycosidase inhibitory activities†
K. S. Ajish Kumar, Vinod D. Chaudhari and Dilip D. Dhavale*
Received 17th August 2007, Accepted 16th October 2007
First published as an Advance Article on the web 3rd January 2008
DOI: 10.1039/b712753g
The utility of a D-glucose-derived aziridine carboxylate was demonstrated for the synthesis of
polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed
by two-carbon homologation by the Wittig reaction afforded c,d-aziridino-a,b-unsaturated ester 9,
which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or
hydrogenation afforded d-lactams 11/16—true synthons for the synthesis of four structurally different
iminosugars, namely quinolizidine alkaloids 5b/5c, swainsonine 6b and lentiginosine 7b analogues.
Glycosidase inhibitory activities of these iminosugars were investigated.
more rapidly with hydride donors like LiAlH4 and DIBAL-H
than non-activated aziridines (e.g. those having a benzyl group
Introduction
on nitrogen).3,4h In such cases, chemoselective reduction of the
carboxylate group to an alcohol/aldehyde functionality, keeping
the aziridine functionality intact, could be achieved under kinet-
ically controlled reaction conditions. This type of chemoselective
functional group transformation protocol, with initial reaction at
the carboxylate functionality, followed by regio-selective aziridine
ring opening giving access to distinct building blocks that are
necessary for the synthesis of complex natural products, has
received limited attention.4,5 Recently, we reported the synthesis
of D-glucose-derived aziridine carboxylate 1, and demonstrated
that exclusive aziridine ring opening at the C2 position, using
water as a nucleophile in the presence of TFA, resulted in the
formation of a-hydroxy b-amino ester 2, which was then elaborated
to the piperidine and pyrrolidine iminosugars 3a/3b and 4a/4b,
respectively (Scheme 2).5c,d
Among the functionalized three-membered cyclic compounds,
aziridines and aziridine carboxylates have been considered to be
prominent precursors in the synthesis of natural and unnatural
amino compounds due to their inherent ability to undergo regio-
and chemo-selective reactions as well as cycloaddition pathways.1
For example, aziridine carboxylates of type A are prone to regio-
controlled nucleophilic ring opening either at C2 or at C3, leading
to the formation of b- or a-amino esters,2a–l,r,s while cycloaddition
reactions with doubly activated olefins afford pyrrolidines2m–q,t
(Scheme 1). In addition, the presence of two electrophilic func-
tionalities (aziridine and ester) in A offers flexibility to achieve
chemoselective transformations under diverse reaction conditions.
Scheme 1 Reactivity of aziridine carboxylates of type A.
In general, it is observed that aziridine carboxylates in which
the ring nitrogen is activated by an electron-withdrawing group
(R2 = electron withdrawing group like Cbz, tosyl etc.) react
Scheme 2 Piperidine and pyrrolidine alkaloids.
Iminosugars,6 in particular polyhydroxylated indolizidine7 and
quinolizidine alkaloids, namely naturally occurring (+)-castano-
spermine 5a, (−)-swainsonine 6a and (+)-lentiginosine 7a (Fig. 1),
are promising glycosidase inhibitors8 and show exceptional ability
to inhibit the glycoprotein-processing enzymes useful in studies on
Garware Research Centre, Department of Chemistry, University of Pune,
Pune, 411 007, India. E-mail: ddd@chem.unipune.ernet.in
† Electronic supplementary information (ESI) available: Detailed experi-
mental procedures, and copies of 1H and 13C NMR spectra of compounds
5b, 5c, 6b, 7b and 8–19. See DOI: 10.1039/b712753g
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the effect of oligosaccharide structure on glycoprotein function.8e–g
In the search for better inhibitors toward specific classes of hy-
drolytic enzymes, a number of stereochemically different hydroxyl-
substituted and ring-expanded analogues9 of these iminosugars
have been synthesized and evaluated for glycosidase inhibitory
and immunosupressive activities.8h–k As a continuation of our
interest in this area,10 we envisioned that the presence of a
non-activated aziridine functionality in 1 will allow us to ex-
plore kinetically controlled chemoselective transformations at the
carboxylate functionality to obtain c,d-aziridino-a,b-unsaturated
ester 9 (Scheme 3).
the following types: 8a-epi-homocastanospermine 5b; 1-deoxy-8a-
epi-homocastanospermine 5c; 1,8,8a-tri-epi-swainsonine 6b; and
1,2-di-epi-lentiginosine 7b; to the best of our knowledge, has not
been reported so far. Our efforts in this direction are discussed
herein.
Results and discussion
Aziridine carboxylate 1 was prepared from D-glucose as reported
earlier by us.5c Treatment of 1 with DIBAL-H in CH2Cl2 at −78 ◦C
resulted in the chemoselective formation of aziridine aldehyde
8, which was subjected to the two-carbon homologation using
=
Ph3P CHCOOEt to afford an inseparable E/Z mixture of c,d-
aziridino-a,b-unsaturated ester 9 in the ratio 8.5 : 1.5 as evident
from the 1H NMR of the crude product (Scheme 4). A mixture of
9 was treated with TFA (2 equiv.) in CH3CN–H2O (8 : 1) to afford
c-hydroxy-d-amino-a,b-conjugated ester 10 as the major E-isomer
in 74% yield.12 Assignment of structure 10 was made by using
1H NMR data and decoupling experiments, wherein H5 showed a
doublet of doublets (J5,6 = 8.8 Hz and J4,5 = 3.5 Hz) at d 3.39 while
H6 appeared at d 4.45 as a doublet of doublet of doublets (J =
8.8, 3.8, and 2.2 Hz). This indicated that aziridine ring opening
in 9 took place regioselectively at C6 leading to the formation of
d-amino ester 10.
Fig. 1 Indolizidine and quinolizidine alkaloids.
Scheme 3 Retrosynthetic analysis.
The regioselective aziridine ring opening at C6 either by a
hydroxyl- or hydrogen-equivalent will give access to two different
d-lactams 11 and 16, with a sugar appendage required to generate
the polyhydroxylated framework. Lactams 11 and 16 can be
common intermediates for the synthesis of polyhydroxylated
quinolizidine 5b and 5c and indolizidine alkaloids 6b and 7b. A few
reports are available on the use of sugar aziridines in the synthesis
of iminosugars;11 however, the applicability of aziridine carboxy-
late 1 in the synthesis of quinolizidine and indolizidine alkaloids of
Scheme 4 Reagents and conditions: (a) DIBAL-H, CH2Cl2, −78 ◦C, 2.5 h,
79%; (b) Ph3P CHCOOEt, CH3CN, 30 ◦C, 6 h, 77%; (c) TFA (2 equiv.),
=
CH3CN–H2O (8 : 1), 15 ◦C to 30 ◦C, 6 h, 80%; (d) HCOONH4, 10% Pd/C,
MeOH, reflux, 3 h, 90%; (e) NaH, BnBr, THF, 0 ◦C to reflux, 2.5 h, 90%;
(f) LAH, THF, 0 ◦C to reflux, 3 h, 85%; (g) i) TFA–H2O (7 : 3), 0 ◦C to
20 ◦C, 3 h; ii) H2 (80 psi), 10% Pd/C, MeOH, 24 h, 96%; (h) Ac2O, Py,
DMAP, 30 ◦C, 6 h; (i) i) TFA–H2O (7 : 3), 0 ◦C to 20 ◦C, 3 h; ii) NaIO4,
acetone–water (4 : 1); (j) H2 (80 psi), 10% Pd/C, MeOH, 30 ◦C, 24 h, 81%.
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The observed stereo- and regioselectivity in 10 (with a 5S,6R
absolute configuration) could be explained by the preferential SN2
attack at the C6 carbon atom of the aziridine ring, rather than at
C5, which is hindered due to the b-oriented C3-OBn group. In the
next step, d-amino ester 10 was subjected to hydrogenation using
10% Pd/C in methanol to give d-lactam 11 in quantitative yield.
−1
=
Formation of d-lactam was confirmed by IR (C O, 1628 cm )
and NMR spectral data.13 This one-pot three-step process involves
=
reduction of C C, removal of N/O-benzyl groups and cyclization.
Subsequently, reaction of 11 with benzyl bromide and sodium
hydride in THF gave tribenzylated lactam 12, which on treatment
with LiAlH4 in THF afforded tribenzylated piperidine 13 in good
yield. Finally, opening of the 1,2-acetonide functionality in 13 with
TFA–H2O (7 : 3) to give a hemiacetal followed by hydrogenation
using 10% Pd/C in MeOH and purification by chromatography
afforded quinolizidine alkaloid 5b as a white solid. The structure
of 5b was confirmed by converting it to peracetylated derivative
14. The analytical and spectral data of both the compounds were
found to be in accordance with the assigned structures 5b and 14.
With the indolizidine alkaloid target 6b in mind, compound 13 was
treated with TFA–H2O (to cleave the 1,2-acetonide group) to give
a hemiacetal, and oxidative cleavage with NaIO4 afforded the one-
carbon-degraded product (as evident from the NMR of the crude
product), which was immediately subjected to hydrogenation
with 10% Pd/C in MeOH to give 1,8,8a-tri-epi-swainsonine 6b
as a thick liquid. Peracetylation of 6b using Ac2O in pyridine
gave triacetyl derivative 15. The analytical and spectral data
were found to be in agreement with the assigned structures 6b
and 15.
Scheme 5 Reagents and conditions: (a) H2 (80 psi), 10% Pd/C, MeOH,
30 ◦C, 12 h, then, NaOAc, MeOH, reflux, 1.5 h, 74% (over two steps); (b)
NaH, BnBr, THF, 0 ◦C to reflux, 2.5 h, 96%; (c) LAH, THF, 0 ◦C to reflux,
3 h, 89%; (d) i) TFA–H2O (7 : 3); ii) NaIO4, acetone–water (4 : 1); (e) H2
(80 psi), 10% Pd/C, MeOH, 30 ◦C, 24 h, 69%; (f) Ac2O, Py, DMAP (cat.),
30 ◦C, 6 h; (g) i) TFA–H2O (7 : 3), 0 ◦C to 20 ◦C, 3 h; ii) H2 (80 psi), 10%
Pd/C, MeOH, 24 h, 96%.
It is known that small structural modifications of the natural
indolizidine alkaloids such as swainsonine and lentiginosine
induce significant changes in their specificity and potency to
inhibit various glycosidases.7r,x In view of this, the synthetic
potentiality of c,d-aziridino ester 9 was further demonstrated
by transforming it to 1,2-di-epi-lentiginosine and 9-deoxy-9a-epi-
homocastanospermine (Scheme 5).
At this stage, we thought of reductive aziridine ring opening in
9, keeping the ester functionality intact. There exists a possibility
to achieve this transformation under hydrogenation conditions.
In general, hydrogenation of aziridine carboxylates of type A
occurs at C3, affording a-amino esters in good yield.14 However,
compound 9, on hydrogenation (10% Pd/C, MeOH)15 followed
by treatment with sodium acetate in methanol, afforded d-lactam
16 and not the c-lactam. This two-step process probably involves
Scheme 6 Plausible pathway for the hydrogenation reaction.
thought of using benzyl protection of d-lactam 16 (to give a
product benzylated on the nitrogen and C3 oxygen), to give access
to quinolizidine as well as indolizidine alkaloids.17
=
reduction of C C, N/O-debenzylation, regioselective aziridine
ring opening at C6 and the formation of the d-lactam. The spectral
and analytical data of 16 was fo◦und to be identical to that reported
by us previously [mp 156–157 C; lit.9d mp 157 ◦C; [a]D = −12.3
(c 2.51, CHCl3), lit.9d [a]D = −11.5 (c 2.35, CHCl3)].
Thus, as shown in Scheme 5, benzylation of 16 with benzyl
bromide (using NaH in THF) afforded piperidone 17, which
on LiAlH4 reduction afforded dibenzylated piperidine compound
18. In the subsequent steps, 1,2-acetonide cleavage (TFA–H2O)
followed by hydrogenation (10% Pd/C, MeOH) and purification
by chromatography afforded quinolizidine alkaloid 5c as a thick
The formation of the d-lactam rather than the c-lactam is
interesting. We believe that the reductive aziridine ring opening
is assisted by the conjugated double bond,16 wherein initial
abstraction of the hydrogen is followed by migration of the double
bond and aziridine ring opening to give an allylamine. This is
further reduced to a d-amino ester and cyclizes to give the d-lactam
16, as shown in Scheme 6.
1
liquid. The analytical and H NMR and 13C NMR data of 5c
were in consonance with the reported data [[a]D = −75.9 (c
0.13, MeOH), lit.9d [a]D = −80.0 (c 0.1, MeOH)]. On the other
hand, 1,2-acetonide deprotection followed by oxidative cleavage
(NaIO4) and hydrogenation (10% Pd/C, MeOH) afforded 1,2-
di-epi-lentiginosine 7b as a crystalline solid in good yield. The
spectral and analytical data of 7b was found to be identical with
We previously reported the transformation of d-lactam 16 to
quinolizidine alkaloid 5c using reduction of the lactam function-
ality followed by N-Cbz protection.9d However, at this stage we
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Table 1 Inhibition potencies of quinolizidines 5b and 5c and indolizidines
6b and 7b
Experimental
General methods
IC50/mM
Melting points were recorded with Thomas Hoover melting point
apparatus and are uncorrected. IR spectra were recorded with
an FTIR spectrometer as a thin film, in Nujol mull, or using
KBr pellets, and are expressed in cm−1. dH (300 MHz) and dC
(75 and 100 MHz) NMR spectra were recorded using CDCl3
or D2O/CD3OD as a solvent. Chemical shifts were reported in
d units (ppm) with reference to TMS as an internal standard,
and J values are given in Hz. Decoupling and DEPT experiments
confirmed the assignments of the signals. Elemental analyses were
carried out with a C,H-analyzer. Optical rotations were measured
using a polarimeter at 25 ◦C. Thin layer chromatography was
performed on pre-coated plates (0.25 mm, silica gel 60 F254).
Column chromatography was carried out with silica gel (100–
200 mesh). The reactions were carried out in oven-dried glassware
under dry N2. Methanol, pyridine, THF, were purified and dried
before use. The n-hexane used was the fraction distilling between
40–60 ◦C. TFA and 10% Pd/C were purchased from Aldrich
and/or Fluka. After decomposition of the reaction with water, the
work-up involves: washing of combined organic layers with water,
brine, drying over anhydrous sodium sulfate and evaporation of
solvent under reduced pressure.
Enzyme
5b
5c
6b
7b
a
a-Amylase (ex-porcine)
b-Glucosidase (sweet almonds)
a-Mannosidase (jack bean)
—
NIb
629
1.23
NIb
1109
0.75
NIb
79.80 372
NIb
—
a
b-Xylanase (Thermomyces lanuginosus) 1.80
0.26 10.70 6.50
a Inhibition was not studied. b No inhibition under the assay conditions.
that reported [mp 133–135 ◦C; lit.7w,10e mp (not reported); [a]D
+3.8 (c 0.43, MeOH), lit.7w,10e [a]D = +4.2 (c 0.51, MeOH)]. The
dihydroxy indolizidine 7b was further characterized as its diacetyl
derivative 19.
=
Glycosidase inhibitory activity
Using standardized assay techniques,18 the inhibitory activities
of 5b, 5c, 6b, and 7b were screened with different enzymes,
namely a-amylase (ex-porcine), b-glucosidase (sweet almonds), a-
mannosidase (jack bean), and b-xylanase (Thermomyces lanugi-
nosus) and results are summarized in Table 1. The data clearly
indicates that quinolizidines 5b/5c and indolizidines 6b/7b are
weak inhibitors of a-amylase. 9-Deoxyquinolizidine analogue 5c
was found to be a selective inhibitor of b-xylanase, with a ∼10-fold
increase in activity compared to that of 5b. Thus, the presence of
a hydroxyl functionality in the six-membered ring of quinolizidine
5b reduces the activity (towards b-xylanase) and also the specificity
of the inhibitor as noted from the structure–activity relationship
with 5c. This observation is analogous to that of Pearson and
coworkers,9a who found that ring homologues of swainsonine were
found to be poor inhibitors of glycosidases. Natural (−)-swainso-
nine 6a is a potent inhibitor of a-D-mannosidase and mannosidase
II, while the antipode (+)-swainsonine is a selective and potent
inhibitor of naringinase (L-rhamnosidase).8f –l However, the new
analogue 1,8,8a-tri-epi-swainsonine 6b did not show any inhibition
towards a-mannosidase, probably due to the anti-orientation of
the hydroxyl functionalities at C1 and C3 in the pyrrolidine ring
of the indolizidine skeleton.
General procedure for inhibition assay
Inhibition potencies of 5b/5c, and 6b/7b were determined by
measuring the residual hydrolytic activities of the glycosidases.18
The substrates (purchased from Sigma Chemicals Co., USA),
namely p-nitrophenyl-a-D-glucopyranoside and p-nitrophenyl-
b-D-glucopyranoside, of 2 mM concentration, were prepared
in 0.025 M citrate buffer with pH 6.0. p-Nitrophenyl-a-D-
mannopyranosideof 2 mM concentration was prepared in 0.025M
citrate buffer with pH 4.0. The test compound was preincubated
with the respective enzyme buffered at their optimal pH, for 1 h
at 25 ◦C. The enzyme reaction was initiated by the addition
of 100 lL substrate. Controls were run simultaneously in the
absence of test compound. The reaction was terminated after
10 min by the addition of 0.05 M borate buffer (pH 9.8), and
absorbance of the liberated p-nitrophenol was measured at 405 nm
using a spectrophotometer. One unit of glycosidase activity is
defined as the amount of enzyme hydrolyzing 1 lmol of (p-
nitrophenyl)pyranoside in 1 min at 25 ◦C. The xylanase assay was
carried out at pH 6.0 by mixing 2 mM of the enzyme with 0.5 cm3
of oat spelt xylan◦(10 mg cm−3) in 1 cm3 of reaction mixture and
incubation at 50 C for 30 min; the reducing sugar released was
determined by the dinitrosalicylic method.18b One unit of xylanase
activity is defined as the amount of enzyme producing 1 lmol of
xylose equivalent per unit using oat spelt xylan as the substrate
under assay conditions.
Interestingly, 6b showed moderate inhibition toward b-
glucosidase as well as b-xylanase. Lentiginosine analogue 7b
displayed similar activity to that of 6b (in the millimolar range),
indicating that the presence of the C8 hydroxyl functionality in 6b
has little influence on the specificity and potency.
Conclusion
In conclusion, we have demonstrated chemo- and regio-selective
transformations of D-glucose-derived aziridine carboxylate 1 and
its versatility in the efficient synthesis of iminosugars of biological
interest, namely (+)-1,8,8a-tri-epi-swainsonine 6b, (+)-1,2-di-epi-
lentiginosine 7b, (+)-9a-epi-homocastanospermine 5b, and its 9-
deoxy analogue 5c. A structure–activity relationship study of
target molecules indicates that the small structural changes have
a noticeable effect on the potency as well as the specificity of the
inhibitor.
1,2-O-Isopropylidine-3-O-benzyl-5,6-dideoxy-5,6-N-benzyl-
E-aziridino-b-L-ido-1,4-furan-7-al (8)
To a solution of aziridine ester 1 (1.41 g, 3.09 mmol) in dry
dichloromethane (20 cm3) at −78 ◦C was added DIBAL-H (20%
solution in hexane) (4.35 cm3, 6.18 mmol) over 15 min, and the
mixture stirred for 2.5 h. The reaction mixture was quenched using
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ethyl acetate (5 cm3) and sat. NH4Cl (1 cm3) and filtered through
Celite, concentrated, adsorbed on silica and purified by column
chromatography (n-hexane–ethyl acetate = 9 : 1), to give 8 as a
white solid (1.01 g, 79.3%): mp 95–96 ◦C; (found: C, 70.31; H, 6.49.
Calc. for C24H27NO5: C, 70.40; H, 6.65); Rf = 0.40 (n-hexane–ethyl
acetate = 7 : 3); [a]D = −29.10 (c 0.05, CHCl3); mmax(KBr)/cm−1
2920, 1726, 1666, 1074, 1022; dH (300 MHz, CDCl3) (the 1H and
13C NMR spectra showed additional signals corresponding to
aldehydes and aziridine protons and carbons—we are unable to
explain these features) 1.24 (3H, s, CH3), 1.38 (3H, s, CH3), 2.54
(1H, bs, H-5), 2.91 (1H, bs, H-6), 3.91 (2H, bs, NCH2Ph), 4.12–
4.40 (2H, m, H-4, H-3), 4.46 (1H, d, J = 11.0 Hz, OCH2Ph), 4.65
(1H, d, J = 3.8 Hz, H-2), 4.67 (1H, d, J = 11.0 Hz, OCH2Ph), 6.00
(1H, d, J = 3.8 Hz, H-1), 7.14–7.27 (10H, m, ArH), 9.40 (1H, s,
CHO); dC (75 MHz, CDCl3) 26.2, 26.8 (2 × CH3), 43.2 (C-6), 48.7
(C-5), 56.3 (NCH2Ph), 71.8 (OCH2Ph), 75.7 (C-3), 82.0 (C-2), 82.7
(C-4), 105.3 (C-1), 111.7 (OCO), 127.1 (ArC), 127.7 (ArC), 128.0
(ArC), 128.3 (strong, 4 × ArC), 128.4 (strong, 3 × ArC), 137.8
(ArC), 197.2 (CHO).
10 (0.72 g, 80.4%) as a thick liquid: (found: C, 67.83; H, 7.05.
Calc. for C28H35NO7: C, 67.59; H, 7.09); Rf = 0.30 (n-hexane–ethyl
acetate = 7 : 3); [a]D = −11.53 (c 0.26, CHCl3); mmax(neat)/cm−1
3080–3700 (broad), 1714, 1654; dH (300 MHz, CDCl3) 1.28 (3H,
t, J = 6.8 Hz, OCH2CH3) 1.33 (3H, s, CH3), 1.49 (3H, s, CH3),
2.80 (2H, bs, exchanges with D2O, NHBn, OH) 3.39 (1H, dd, J =
8.8 and 3.5 Hz, H-5), 3.87 (1H, d, J = 3.0 Hz, H-3), 3.89 (2H,
ABq, J = 12.0 Hz, NCH2Ph), 4.19 (1H, dd, J = 3.5 and 3.0 Hz,
H-4), 4.20 (2H, q, J = 6.8 Hz, OCH2CH3), 4.45 (1H, ddd, J =
8.8, 3.8 and 2.2 Hz, H-6), 4.58 (2H, ABq, J = 11.2 Hz, OCH2Ph),
4.65 (1H, d, J = 3.8 Hz, H-2), 5.89 (1H, d, J = 3.8 Hz, H-1), 6.22
(1H, dd, J = 15.6 and 2.2 Hz, H-8), 6.90 (1H, dd, J = 15.6 and
3.5 Hz, H-7), 7.22–7.42 (10H, m, ArH); dC (75 MHz, CDCl3) d 14.3
(OCH2CH3), 26.3 (CH3), 26.7 (CH3), 52.0 (C-5), 59.6 (NCH2Ph),
60.4 (OCH2CH3), 68.0 (OCH2Ph), 71.2 (C-3), 78.5 (C-6), 81.9
(strong, C-2 and C-4), 103.8 (C-1), 111.6 (OCO), 121.3 (C-8),
127.1 (ArC), 127.6 (strong, 2 × ArC), 127.9 (ArC), 128.2 (strong,
2 × ArC), 128.3 (strong, 2 × ArC), 128.4 (strong, 2 × ArC), 137.0
(ArC), 139.1 (ArC), 146.0 (C-7), 166.1 (COOCH2CH3).
(E)-Ethyl-3-O-benzyl-5,6-dideoxy-5,6-N-benzyl-E-aziridino-
1,2-O-isopropylidine-b-L-ido-nona-7-eno-furanuronate (9)
1,2-O-Isopropylidine-3,6-di-hydroxy-5,7,8-tri-deoxy-b-L-glycero-
5,9-imino-b-L-ido-furan-9-ulose (11)
To a solution of aziridine aldehyde 8 (0.97 g, 2.37 mmol)
in dry acetonitrile (15 cm3) was added (carboethoxymethy-
lene)triphenylphosphorane (1.07 g, 3.08 mmol), and the reaction
mixture was stirred for 6 h at 30 ◦C. The acetonitrile was evapo-
rated and the reaction mixture was adsorbed on silica. Purification
by column chromatography (n-hexane–ethyl acetate = 9 : 1) gave
9 (mixture of E and Z isomers) as a thick liquid (0.87 g, 77.7%):
(found: C, 69.97; H, 6.86. Calc. for C28H33NO6: C, 70.13; H, 6.94);
Rf = 0.40 (n-hexane–ethyl acetate = 7 : 3); mmax(neat)/cm−1 1718,
To a stirred solution of hydroxyl amino ester 10 (0.66 g, 1.32 mmol)
in methanol (15 cm3) at reflux was added ammonium formate
(0.41 g, 6.63 mmol) and 10% Pd/C (100 mg), and the mixture
refluxed for 3 h. The reaction mixture was filtered through Celite,
concentrated and purified by column chromatography (n-hexane–
ethyl acetate = 2 : 8) to afford 11 as a white solid (0.30 g, 90%); mp
182 ◦C: (found: C, 52.61; H, 7.30. Calc. for C12H19NO6: C, 52.74;
H, 7.01); Rf = 0.83 (CHCl3–MeOH = 7 : 3); [a]D = −5.40 (c 0.36,
CHCl3); mmax(KBr)/cm−1 3325, 1628, 1076 cm−1; dH (300 MHz,
CD3OD) 1.30 (3H, s, CH3), 1.46 (3H, s, CH3), 1.79–1.92 (1H, m,
H-7a), 1.99–2.08 (1H, m, H-7b) 2.27–2.50 (2H, m, H-8), 3.57 (1H,
dd, J = 6.7 and 3.5 Hz, H-5), 3.88 (1H, ddd, J = 9.1, 6.7 and
3.2 Hz, H-6), 4.20 (1H, d, J = 2.7 Hz, H-3), 4.25 (1H, t, J =
3.5 Hz, H-4), 4.49 (1H, d, J = 3.8 Hz, H-2), 4.62 (1H, bs, NH),
5.91 (1H, d, J = 3.8 Hz, H-1) (Note: In the 1H NMR spectrum OH
protons are exchanged with CD3OD); dC (75 MHz, CD3OD) 26.4
(CH3), 27.1 (CH3), 28.8 (C-7), 28.9 (C-8), 59.5 (C-5), 66.3 (C-6),
77.3 (C-3), 79.8 (C-2), 86.8 (C-4), 105.9 (C-1), 112.7 (OCO), 174.3
(COOCH2CH3).
1
1624, 1217, 1076; dH (300 MHz, CDCl3) (the H and 13C NMR
spectra showed an additional signal due to the minor Z-isomer
(∼15%)) 1.31 (3H, t, J = 7.1 Hz, OCH2CH3), 1.32 (3H, s, CH3),
1.44 (3H, s, CH3), 2.45 (1H, dd, J = 7.1 and 3.0 Hz, H-5), 2.59
(1H, dd, J = 9.9 and 3.0 Hz, H-6), 3.72 (1H, d, J = 14.0 Hz,
NCH2Ph), 3.86 (1H, d, J = 3.3 Hz, H-3), 3.96 (1H, d, J = 14.0 Hz,
NCH2Ph), 4.15–4.27 (3H, m, OCH2CH3, H-4), 4.44 (1H, d, J =
12.1 Hz, OCH2Ph), 4.61 (1H, d, J = 3.8 Hz, H-2), 4.66 (1H, d, J =
12.1 Hz, OCH2Ph), 5.98 (1H, d, J = 3.8 Hz, H-1), 6.04 (1H, d, J =
15.4 Hz, H-8), 6.89 (1H, dd, J = 15.4 and 9.9 Hz, H-7), 7.16–7.37
(10H, m, ArH); dC (75 MHz, CDCl3) d 14.3 (OCH2CH3), 26.3
(CH3), 26.8 (CH3), 39.9 (C-5), 47.0 (C-6), 56.9 (NCH2Ph), 60.5
(OCH2CH3), 71.7 (OCH2Ph), 81.9 (C-3), 82.0 (C-2), 82.7 (C-4),
105.2 (C-1), 111.6 (OCO), 125.2 (C-8), 126.8 (ArC), 127.7 (strong,
2 × ArC), 127.8 (strong, 2 × ArC), 127.9 (ArC), 128.1 (strong, 2 ×
ArC), 128.3 (strong, 2 × ArC), 136.8 (ArC), 138.4 (ArC), 142.9
(C-7), 165.2 (COOCH2CH3).
1,2-O-Isopropylidine-3,6-di-O-benzyl-5,7,8-tri-deoxy-b-L-glycero-
5,9-N-(benzyl)imino-b-L-ido-furan-9-ulose (12)
To a slurry of NaH (0.29 g, 0.74 mmol) in dry THF (5 cm3) at 0 ◦C
was added a solution of lactam 11 (0.50 g, 0.18 mmol) in THF
(10 cm3), and the mixture stirred for five minutes. Benzyl bromide
(0.86 cm3, 0.74 mmol) in THF (5 cm3) was added dropwise, and
stirred well while warming to room temperature, before being
refluxed for 2.5 h. Usual workup and purification by column
chromatography (n-hexane–ethyl acetate = 8.5 : 1.5) yielded 12
as a thick liquid (0.90 g, 90%): (found: C, 73.11; H, 7.02. Calc. for
C33H37NO6: C, 72.91; H, 6.86); Rf = 0.43 (n-hexane–ethyl acetate =
6.5 : 3.5); [a]D = +50.00 (c 0.2, CHCl3); mmax(neat)/cm−1 2925, 1627,
1217, 1078; dH (300 MHz, CDCl3) 1.32 (3H, s, CH3), 1.50 (3H, s,
CH3), 1.79–2.12 (2H, m, H-8), 2.48 (1H, dd, J = 18.1 and 7.4 Hz,
(E)-Ethyl-3-O-benzyl-5-N-(benzyl)amino-1,2-O-isopropylidine-
b-L-glycero-L-ido-nona-7-eno-furanuronate (10)
To a solution of aziridine ester 9 (0.85 g, 1.77 mmol) in acetonitrile–
◦
water (8 : 1, 20 cm3) at 15 C was added TFA (0.40 cm3, 3.54
mmol). The reaction mixture was allowed to warm to room
temperature, stirred for 6 h, and neutralized with Indion-860
resin. Filtration, evaporation of solvent at rotary evaporator and
column chromatography (n-hexane–ethyl acetate = 4 : 1) afforded
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H-7), 2.67–2.79 (1H, m, H-7), 3.49 (1H, bs, H-6), 3.79 (1H, d, J =
2.7 Hz, H-3), 3.89 (2H, s, OCH2Ph), 3.99 (1H, bd, J = 9.3 Hz,
H-5), 4.13 (1H, dd, J = 9.3 and 2.7 Hz, H-4), 4.23 (1H, d, J =
15.1 Hz, NCH2Ph), 4.29 (1H, d, J = 12.1 Hz, OCH2Ph), 4.61 (1H,
d, J = 3.8 Hz, H-2), 4.62 (1H, d, J = 12.1 Hz, OCH2Ph), 5.66
(1H, d, J = 15.1 Hz, NCH2Ph), 5.99 (1H, d, J = 3.8 Hz, H-1),
6.92–6.95 (2H, m, ArH), 7.11–7.30 (13H, m, ArH); dC (75 MHz,
CDCl3) 23.5 (C-7), 26.0 (CH3), 26.6 (CH3), 27.0 (C-8), 49.0 (C-
5), 56.1 (NCH2Ph), 69.2 (C-6), 70.5 (OCH2Ph), 71.2 (OCH2Ph),
80.5 (C-3), 81.5 (C-2), 83.1 (C-4), 104.5 (C-1), 111.5 (OCO), 126.4
(strong, ArC), 126.5 (ArC), 127.0 (ArC), 127.3 (strong, 2 × ArC),
127.9 (ArC), 128.0 (strong, 2 × ArC), 128.1 (strong, 2 × ArC),
128.2 (strong, 2 × ArC), 128.3 (strong, 2 × ArC), 136.3 (ArC),
137.5 (ArC), 137.8 (ArC), 169.5 (CONH).
156–157 ◦C; lit.9d mp 157 ◦C]; (found: C, 56.29; H, 7.57. Calc. for
C12H19NO5: C, 56.02; H, 7.44); Rf = 0.35 (n-hexane–ethyl acetate =
5 : 5); [[a]D = −12.3 (c 2.51, CHCl3), lit.9d [a]D = −11.5 (c 2.35,
CHCl3)]; mmax(KBr)/cm−1 1624, 1076; dH (300 MHz, CDCl3) 1.28
(3H, s, CH3), 1.45 (3H, s, CH3), 1.64–1.79 (2H, m, H-7), 1.80–1.98
(2H, m, H-6), 2.26–2.38 (2H, m, H-8), 3.72–3.79 (1H, m, H-5),
3.93 (1H, dd, J = 3.2 and 2.7 Hz, H-4), 4.22 (1H, d, J = 2.7 Hz,
H-3), 4.50 (1H, d, J = 3.6 Hz, H-2), 5.50–5.89 (1H, bs, exchangable
with D2O, OH), 5.93 (1H, d, J = 3.6 Hz, H-1), 7.10–7.16 (1H, bs,
exchangable with D2O, NH); dC (75 MHz, CDCl3) 20.1 (CH3), 26.2
(CH3), 26.5 (C-7), 27.1 (C-6), 31.2 (C-8), 52.9 (C-5), 76.0 (C-3),
81.6 (C-4), 85.5 (C-2), 104.9 (C-1), 111.8 (OCO), 173.4 (CONH).
1,2-O-Isopropylidine-3-O-benzyl-5,6,7,8-tetradeoxy-b-L-glycero-
5,9-N-(benzyl)imino-b-L-ido-1,4-furan-9-ulose (17)
1,2-O-Isopropylidine-3,6-di-O-(benzyl)-5,7,8-tri-deoxy-b-L-
glycero-5,9-N-(benzyl)imino-b-L-ido-1,4-furanose (13)
To a suspension of NaH (0.07 g, 1.71 mmol) in dry THF (3 cm3) at
0 ◦C were added a solution of lactam 16 (0.20 g, 0.77 mmol) in THF
(10 cm3) and benzyl bromide (0.19 cm3, 1.71 mmol) in THF (3 cm3)
successively. The reaction was refluxed for 3 h. Usual workup and
purification by column chromatography (n-hexane–ethyl acetate =
8.5 : 1.5) yielded dibenzylated lactam 17 as a thick liquid (0.33 g,
96%): (found: C, 71.18; H, 7.20. Calc. for C26H31NO5: C, 71.37; H,
7.14); Rf = 0.58 (n-hexane–ethyl acetate = 4 : 6); [a]D = +12.84
(c 0.19, CHCl3); mmax(CDCl3)/cm−1 2925, 1627, 1217, 1073; dH
(300 MHz, CDCl3) 1.32 (3H, s, CH3), 1.48 (3H, s, CH3), 1.52–1.85
(4H, m, H-6, H-7), 2.48–2.52 (2H, m, H-8), 3.74–3.78 (1H, m,
H-5), 3.85 (1H, d, J = 3.0 Hz, H-4), 4.25 (1H, d, J = 15.4 Hz,
NCH2Ph), 4.31 (1H, dd, J = 6.7 and 3.0 Hz, H-3), 4.38 (1H, d,
J = 11.8 Hz, NCH2Ph), 4.59 (1H, d, J = 3.8 Hz, H-2), 4.64 (1H, d,
J = 11.8 Hz, OCH2Ph), 5.56 (1H, d, J = 15.4 Hz, NCH2Ph), 5.98
(1H, d, J = 3.8 Hz, H-1), 7.16–7.29 (10H, m, ArH); dC (75 MHz,
CDCl3) 17.9 (C-7), 25.1 (C-6), 26.1 (CH3), 26.6 (CH3), 31.2 (C-
8), 49.3 (C-5), 53.6 (NCH2Ph), 71.4 (OCH2Ph), 80.6 (C-3), 81.6
(C-2), 83.2 (C-4), 104.9 (C-1), 111.5 (OCO), 126.6 (ArC), 127.5
(strong, 2 × ArC), 127.8 (strong, 2 × ArC), 127.9 (ArC), 128.1
(strong, 2 × ArC), 128.3 (strong, 2 × ArC), 136.5 (ArC), 138.6
(ArC), 169.9 (CONH).
To an ice-cooled suspension of LAH (0.02 g, 0.04 mmol) in
dry THF (4 cm3) was added tribenzylated lactam 12 (0.09 g,
0.16 mmol) in dry THF (10 cm3) at 0 ◦C, and the mixture
stirred for 10 min. The reaction mixture was slowly warmed
to room temperature, refluxed for 3 h and quenched with ethyl
acetate (10 cm3), followed by an aqueous solution of ammonium
chloride (2 cm3). Filtration through Celite, concentration under
vacuum and purification by column chromatography (n-hexane–
ethyl acetate = 9 : 1) gave 13 as a thick liquid (0.06 g, 85.0%):
(found: C, 74.71; H, 7.33. Calc. for C33H39NO5: C, 74.83; H, 7.42);
Rf = 0.82 (n-hexane–ethyl acetate = 7 : 3); [a]D = +13.33 (c 0.15,
CHCl3); mmax(neat)/cm−1 1610, 1416; dH (300 MHz, CDCl3) 1.20–
1.74 (2H, m, H-8), 1.32 (3H, s, CH3), 1.52 (3H, s, CH3), 1.79–2.00
(2H, m, H-7), 2.46–2.65 (1H, m, H-9), 2.66–2.84 (1H, m, H-9),
3.42 (1H, bd, J = 3.3 Hz, H-6), 3.60 (1H, dd, J = 9.3 and 2.7 Hz,
H-5), 3.79 (1H, d, J = 2.7 Hz, H-3), 3.86 (1H, d, J = 14.3 Hz,
NCH2Ph), 4.05 (1H, d, J = 14.3 Hz, NCH2Ph), 4.31 (1H, d, J =
11.8 Hz, OCH2Ph), 4.36 (1H, d, J = 12.1 Hz, OCH2Ph), 4.42 (1H,
d, J = 11.8 Hz, OCH2Ph), 4.52–4.66 (3H, m, H-2, H-4, OCH2Ph),
5.97 (1H, d, J = 3.8 Hz, H-1), 7.13–7.32 (13H, m, ArH), 7.41 (2H,
d, J = 7.1 Hz, ArH); dC (75 MHz, CDCl3) 19.4 (C-8), 26.2 (CH3),
26.8 (CH3), 26.9 (C-7), 44.9 (C-9), 58.4 (C-5), 58.5 (NCH2Ph), 69.6
(OCH2Ph), 71.3 (OCH2Ph), 73.0 (C-6), 76.2 (C-3), 81.2 (C-2), 82.7
(C-4), 104.3 (C-1), 111.1 (OCO), 126.1 (ArC), 126.9 (strong, 2 ×
ArC), 127.2 (strong, 2 × ArC), 127.6 (strong, 2 × ArC), 127.7
(strong, 2 × ArC), 127.9 (strong, 2 × ArC), 128.2 (strong, 2 ×
ArC), 128.4 (strong, 2 × ArC), 137.1 (ArC), 138.9 (ArC), 140.9
(ArC).
1,2-O-Isopropylidine-3-O-benzyl-5,6,7,8-tetradeoxy-b-L-glycero-
5,9-N-(benzyl)imino-b-L-ido-1,4-furanose (18)
To an ice-cooled suspension of LAH (0.24 g, 6.40 mmol) in
dry THF (4 cm3) was added dibenzylated lactam 17 (0.70 g,
1.60 mmol) in dry THF (10 cm3) at 0 ◦C, and the mixture stirred
for 10 min. The reaction mixture was slowly warmed to room
temperature and refluxed for 3 h. The reaction was quenched
by adding ethyl acetate (10 cm3) and an aqueous solution of
ammonium chloride (2 cm3), and was then filtered through Celite.
The filtrate was concentrated under vacuum and purified by
column chromatography (n-hexane–ethyl acetate = 9 : 1) to give 18
as a thick liquid (0.61 g, 89%): (found: C, 73.85; H, 7.78. Calc. for
C26H33NO4: C, 73.73; H, 7.85); Rf = 0.61 (n-hexane–ethyl acetate =
6 : 4); [a]D = −33.33 (c 2.15, CHCl3); mmax(neat)/cm−1 1620, 1410;
dH (300 MHz, CDCl3) 1.31 (3H, s, CH3), 1.36–1.66 (6H, m, H-6,
H-7, H-8), 1.49 (3H, s, CH3), 2.26–2.33 (1H, m, H-9), 2.69–2.74
(1H, m, H-9), 3.09–3.13 (1H, m, H-5), 3.63 (1H, d, J = 13.7 Hz,
NCH2Ph), 3.86 (1H, d, J = 2.7 Hz, H-3), 4.08 (1H, d, J = 13.7 Hz,
1,2-O-Isopropylidine-5,6,7,8-tetra-deoxy-5,9-imino-b-L-ido-
1,4-furan-9-ulose (16)
A solution of aziridine ester 9 (0.62 g, 1.29 mmol) and 10% Pd/C
(70 mg) in methanol (15 cm3) was hydrogenated (80 psi) at 30 ◦C
for 12 h. The reaction mixture was filtered through Celite. Sodium
acetate (0.12 g, 1.55 mmol) was added to the filtrate and the
mixture refluxed for 1.5 h. The reaction mixture was concentrated
under vacuum, extracted using CHCl3 (3 × 15 cm3) and dried
over anhydrous sodium sulfate. The combined organic layer was
concentrated and purified by column chromatography (n-hexane–
ethyl acetate = 7 : 3) to give 16 as a white solid (0.25 g, 74%): [mp
708 | Org. Biomol. Chem., 2008, 6, 703–711
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NCH2Ph), 4.42 (1H, d, J = 11.5 Hz, OCH2Ph), 4.47 (1H, dd, J =
6.5 and 2.7 Hz, H-4), 4.57 (1H, d, J = 3.8 Hz, H-2), 4.66 (1H, d, J =
11.5 Hz, OCH2Ph), 5.96 (1H, d, J = 3.8 Hz, H-1), 7.13−7.35 (10H,
m, ArH); dC (75 MHz, CDCl3) 22.8 (C-7), 24.2 (C-8), 26.3 (C-6),
26.6 (CH3), 26.7 (CH3), 48.7 (C-9), 57.8 (C-5), 58.9 (NCH2Ph),
71.4 (OCH2Ph), 79.6 (C-3), 80.6 (C-4), 82.6 (C-2), 104.7 (C-1),
111.1 (OCO), 126.1 (ArC), 127.4 (strong, 2 × ArC), 127.6 (ArC),
127.7 (strong, 2 × ArC), 128.2 (strong, 2 × ArC), 128.6 (strong,
2 × ArC), 137.1 (ArC), 140.7 (ArC).
H-6b), 2.83–2.95 (2H, m, H-3, H-5a), 3.35 (1H, bd, J = 11.8 Hz,
H-5b), 3.42 (1H, dd, J = 10.1 and 2.7 Hz, H-8a), 3.76–3.90 (2H,
m, H-1, H-3), 4.14–4.19 (2H, m, H-8, H-2); dC (75 MHz, D2O) 21.9
(C-6), 31.0 (C-7), 51.9 (C-5), 59.8 (C-3), 64.0 (C-8a), 71.1 (C-8),
73.4 (C-2), 74.2 (C-1).
(1R,2R,3S,9S,9aS)-1,2,3,9-Tetraacetoxyquinolizidine (14)
A solution of quinolizidine alkaloid 5b (0.017 g, 0.08 mmol) in
pyridine (1.50 cm3), acetic anhydride (0.06 cm3, 0.66 mmol) and
DMAP (cat.) was stirred for 6 h. The reaction mixture was concen-
trated under vacuum and purified by column chromatography (n-
hexane–ethyl acetate = 3 : 7) to afford tetraacetoxyquinolizidine
alkaloid 14 as a semi-solid (0.023 g, 74%): (found: C, 55.30; H,
7.11. Calc. for C17H25NO8: C, 54.98; H, 6.79); Rf = 0.30 (ethyl
acetate); [a]D = +40.0 (c 0.15, CHCl3); mmax(CDCl3)/cm−1 1727,
1210; dH (300 MHz, CDCl3) 1.21–1.82 (4H, m, H-7, H-8), 2.03
(3H, s, CH3), 2.09 (3H, s, CH3), 2.10 (3H, s, CH3), 2.15 (3H, s,
CH3), 2.63–2.78 (1H, dt, J = 12.9 and 3.0 Hz, H-3), 3.56 (1H,
dd, J = 10.1 and 4.1 Hz, H-6), 4.42–4.54 (3H, m, H-9a, H-4),
4.58 (1H, dd, J = 12.6 and 4.1 Hz, H-6), 4.59–4.69 (1H, dt, J =
11.0 and 4.9 Hz, H-9), 4.56–5.41 (1H, m, H-2), 5.66 (1H, d, J =
4.1 Hz, H-1); dC (75 MHz, CDCl3) 20.6 (CH3), 20.7 (CH3), 20.9
(CH3), 22.3 (CH3), 29.4 (C-7), 44.3 (C-8), 60.4 (C-6), 61.3 (C-4),
61.6 (C-9a), 67.6 (C-9), 69.3 (C-3), 74.0 (C-2), 77.2 (C-1), 169.9
(COCH3), 170.0 (COCH3), 170.2 (COCH3), 170.4 (COCH3).
(+)-(1R,2R,3S,9S,9aS)-1,2,3,9-Tetrahydroxyquinolizidine (5b)
A solution of 13 (0.03 g, 0.14 mmol) in TFA–H2O (3 cm3, 2 : 1) was
stirred at 15 ◦C for 3 h. The trifluoroacetic acid was co-evaporated
with benzene to furnish a thick liquid. A solution of this liquid
in methanol (5 cm3) and 10% Pd/C (0.05 g) was hydrogenated at
80 psi for 24 h. The catalyst was filtered through Celite, washed
with methanol, and the filtrate concentrated to give 5b as a solid
(0.015 g, 96%): mp 207 ◦C; (found: C, 53.50; H, 8.70 Calc. for
C9H17NO4: C, 53.19; H, 8.43); Rf = 0.27 (chloroform–methanol =
4 : 6); [a]D = +66.66 (c 0.15, MeOH); mmax(neat)/cm−1 3400–3600
(broad); dH (300 MHz, D2O) 1.48–1.64 (1H, m, H-7a), 1.65–1.84
(1H, m, H-7b), 1.86–1.98 (1H, bd, J = 14.3 Hz, H-8a), 2.07–2.19
(1H, bd, J = 12.1 Hz, H-8b) 2.88–3.34 (2H, m, H-4a, H-6b), 3.25–
3.44 (3H, m, H-4b, H-6a, H-9a), 3.83–3.94 (1H, m, H-9), 3.98
(1H, bs, H-3), 4.03 (1H, bs, H-2), 4.20 (1H, bs, H-1); dC (75 MHz,
D2O) 20.4 (C-1), 30.9 (C-8), 54.8 (C-6), 55.9 (C-4), 63.8 (C-9a),
64.8 (C-9), 65.7 (C-3), 66.3 (C-1), 67.1 (C-2).
1,8,8a-Triacetoxy-tri-epi-swainsonine (15)
Reaction of tri-epi-swainsonine 6b (0.023 g, 0.13 mmol) with
pyridine (2 cm3), acetic anhydride (0.09 cm3, 0.93 mmol) and
DMAP (cat.) for 6 h afforded triacetoxy-tri-epi-swainsonine 15 as
a thick liquid (0.033 g, 82%): (found: C, 55.94; H, 6.89. Calc. for
C14H21NO6: C, 56.18; H, 7.07); Rf = 0.35 (n-hexane–ethyl acetate =
6 : 4); [a]D = −25.8 (c 0.13, CHCl3); mmax(neat)/cm−1 1721, 1204;
dH (300 MHz, CDCl3) 1.54–1.62 (2H, m, H-6), 1.68–1.78 (2H, m,
H-7), 1.98 (3H, s, CH3), 2.06 (6H, s, 2 × CH3), 2.07–2.14 (2H, m,
H-3), 2.31 (1H, dd, J = 9.3 and 4.4 Hz, H-8a), 3.01 (1H, d, J =
9.7 Hz, H-5), 3.69 (1H, dd, J = 9.3 and 8.9 Hz, H-5), 4.82 (1H,
m, H-8), 4.94 (1H, t, J = 6.6 Hz, H-2), 5.33 (1H, d, J = 4.4 Hz,
H-1); dC (75 MHz, CDCl3) 20.8 (CH3), 21.1 (CH3), 23.6 (CH3),
29.9 (C-6), 44.8 (C-7), 51.7 (C-5), 59.5 (C-3), 67.9 (C-8a), 68.3 (C-
8), 75.6 (C-2), 76.8 (C-1), 169.7 (COCH3), 169.8 (COCH3), 169.9
(COCH3).
(−)-(1R,2R,3S,9aS)-1,2,3-Trihydroxyquinolizidine (5c)
Reaction of 18 (0.25 g, 0.57 mmol) with TFA–H2O (6 cm3, 7 :
3) and hydrogenation as in the case of 5b afforded 5c as a thick
liquid (0.08 g, 80%): Rf = 0.27 (chloroform–methanol = 4 : 6);
[[a]D = −75.9 (c 0.13, MeOH), lit.9d [a]D = −80.0 (c 0.1, MeOH)];
mmax(neat)/cm−1 3190–3645 (broad); dH and dC values were in
agreement with those reported.
(+)-1,8,8a-Tri-epi-swainsonine (6b)
A solution of 13 (0.25 g, 0.47 mmol) in TFA–H2O (6 cm3, 7 : 3) was
stirred at 15 ◦C for 4 h. The trifluoroacetic acid was co-evaporated
with benzene to give a thick liquid (0.17 g, 0.34 m◦mol), which was
dissolved in acetone–water (5.00 cm3, 4 : 1) at 0 C, treated with
sodium metaperiodate (0.09 g, 0.41 mmol) and stirred at 15 ◦C for
1 h. The reaction was quenched using ethylene glycol (0.01 cm3),
concentrated, extracted with CH2Cl2 (3 × 10 cm3) and dried over
sodium sulfate. The combined organic layer was concentrated and
dried to afford aldehyde (1.28 g, 0.27 mmol). The crude aldehyde
was dissolved in methanol (15 cm3), and hydrogenated at 80 psi
using 10% Pd/C (40 mg) at 30 ◦C for 24 h. The reaction mixture
was filtered through Celite, concentrated, and purified by column
chromatography to afford 1,8,8a-tri-epi-swainsonine 6b as a thick
liquid (0.04, 81%): (found: C, 55.11; H, 8.51.Calc. for C8H15NO3:
C, 55.47; H, 8.73); Rf = 0.40 (chloroform–methanol 7 : 3); [a]D =
+42.42 (c 0.66, MeOH); mmax(neat)/cm−1 3390–3610 (broad); dH
(300 MHz, D2O) 1.46–1.59 (1H, m, H-6a), 1.65–1.81 (1H, m, H-
7a), 1.98–2.02 (1H, bd, J = 12.1 Hz, H-7b), 2.16–2.60 (1H, m,
(+)-1,2-Di-epi-lentiginosine (7b)
Reaction of 18 (0.60 g, 1.43 mmol) with TFA–H2O (6 cm3, 7 : 3),
as in the case of 6b, followed by treatment with NaIO4 (0.55 g, 1.38
mmol) in acetone–water (8 cm3, 4 : 1) afforded an aldehyde (0.49 g,
1.30 mmol). The aldehyde, on hydrogenation using 10% Pd/C (50
mg) and column purification, afforded 1,2-di-epi-lentiginosine 7b
◦
as a white solid (0.15 g, 69%): [mp 133–135 C; lit.7w,10e mp (not
reported)]; Rf = 0.26 (chloroform–methanol 7 : 3); [[a]D = +3.8
(c 0.43, MeOH), lit.10e [a]D = +4.2 (c 0.51, MeOH), lit.7w [a]D
=
+3.4 (c 0.51, MeOH)]; mmax(neat)/cm−1 3390–3609 (broad); the dH
and dC values are in agreement with those reported by us10e and
Shibasaki et al.7w
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1,2-Diacetoxy-di-epi-lentiginosine (19)
3 (a) K. Fugami, K. Miura, Y. Morizawa, K. Oshima, K. Utimoto and H.
Nozaki, Tetrahedron, 1989, 45, 3089–3098; (b) I. Funaki, P. L. Bell, L.
Thijs and B. Zwanenburg, Tetrahedron, 1996, 52, 12253–12274; (c) D.
Tanner and P. Somfai, Tetrahedron Lett., 1987, 28, 1211–1214.
4 (a) T. Tanaka, K. Nakajima and K. Okawa, Bull. Chem. Soc. Jpn., 1980,
53, 1352–1354; (b) P. Deshong and D. A. Kell, Tetrahedron Lett., 1986,
27, 3979–3982; (c) J. Legters, L. Thijs and B. Zwanenburg, Tetrahedron,
1991, 47, 5287–5294; (d) A. P. Patwardhan, V. R. Pulgam, Yu. Zhang
and W. D. Wulff, Angew. Chem., Int. Ed., 2005, 44, 6169–6172; (e) J. J.
Caldwell and D. Craig, Angew. Chem., Int. Ed., 2007, 46, 2631–2634;
(f) P. Righi, N. Scardovi, E. Marotta, P. Holte and B. Zwanenburg,
Org. Lett., 2002, 4, 497–500; (g) D. Savoia, G. Alvaro, R. DiFabio
and A. Gualandi, J. Org. Chem., 2007, 72, 3859–3862; (h) K. Fugami,
K. Miura, Y. Morizawa, K. Oshima, K. Utimoto and H. Nozaki,
Tetrahedron, 1989, 45, 3089–3098.
5 (a) For sugar aziridines: J. M. J. Tronchet and M. A. M. Massoud,
Heterocycles, 1989, 29, 418–426; (b) J. M. J. Tronchet, E. Winter-Mihaly,
M. A. M. Massoud, O. R. Martin, F. Barbalat-Rey, J. Ojha-Poncet and
J. Giust, Helv. Chim. Acta, 1981, 64, 2350–2354 and references cited
therein; (c) D. D. Dhavale, K. S. Ajish Kumar, V. D. Chaudhari, S. G.
Sabharwal, T. Sharma and J. PrakashaReddy, Org. Biomol. Chem.,
2005, 3, 3720–3726; (d) For a recent report on the application of
aziridine carboxylate 1 in the synthesis of pentahydroxyindolizidines,
see: K. S. Ajish Kumar, V. D. Chaudhari, D. D. Dhavale and V. G.
Puranik, Eur. J. Org. Chem., 2007, 4895–4901.
Acetylation of di-epi-lentiginosine 7b (0.02 g, 0.13 mmol) with
pyridine (2 cm3), acetic anhydride (0.04 cm3, 0.38 mmol) and
DMAP (cat.) as in case of 15, after purification by column chro-
matography (n-hexane–ethyl acetate = 8 : 2) afforded diacetoxy-
di-epi-lentiginosine 19 as a thick liquid (0.025 g, 83%): (found: C,
60.01; H, 8.20. Calc. for C12H19NO4: C, 59.73; H, 7.94); Rf = 0.20
(n-hexane–ethyl acetate = 6 : 4); [a]D = −37.7 (c 0.26, CHCl3);
mmax(neat)/cm−11725, 1210; dH (300 MHz, CDCl3) 1.20–1.40 (2H,
m, H-7, H-6), 1.42–1.84 (4H, m, H-6, H-7, H-8), 2.06 (3H, s, CH3),
2.10 (3H, s, CH3), 2.12–2.27 (3H, m, H-3, H-5), 3.11 (1H, bd, J =
11.0 Hz, H-3), 3.64 (1H, dd, J = 9.9 and 7.1 Hz, H-8a), 4.99 (1H,
t, J = 7.4 Hz, H-2), 5.16 (1H, d, J = 4.6 Hz, H-1); dC (75 MHz,
CDCl3) 20.9 (strong, C-6 and C-7), 23.7 (C-8), 24.8 (CH3), 24.9
(CH3), 53.1 (C-5), 59.7 (C-3), 65.7 (C-8a), 76.9 (C-1), 78.8 (C-2),
169.9 (COCH3), 170.2 (COCH3).
Acknowledgements
6 For a review of iminosugars, see: (a) P. C. Tyler and B. G. Winchester,
Iminosugars as Glycosidase Inhibitors, 1999, 125–156; (b) P. Sears and
C.-H. Wong, Angew. Chem., Int. Ed., 1999, 38, 2300–2324; (c) K.
Burgess and I. Henderson, Tetrahedron, 1992, 48, 4045–4066; (d) L. E.
Fellows, G. C. Kite, R. J. Nash, M. S. J. Simmonds and A. M. Scofield,
Recent Adv. Phytochem., 1989, 23, 395–427; (e) Y. Chen and P. Vogel,
J. Org. Chem., 1994, 59, 2487–2496.
We are thankful to Dr MalaRao, Head of the Biochemical
Division, and Dr V. P. Vinod of the National Chemical laboratory
(NCL), Pune, for carrying out glycosidase inhibitory activity stud-
ies of our target molecules. We are grateful to Prof. M. S. Wadia
and Dr K. G. Marathe for helpful discussion. AKKS is thankful
to CSIR, New Delhi, for a Research Fellowship. We gratefully
acknowledge DST, New Delhi, for the research fund SR/S1/OC-
21/2005.
7 (a) For castanospermine: A. D. Elbein and R. J. Molyneux, in
Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier,
Wiley-Interscience, New York, 1987, vol. 5; A. S. Howard and J. P.
Michael, in The Alkaloids, ed. A. Brossi, Academic Press, New York,
1986, vol. 28, ch. 3; (b) J. P. Michael, Nat. Prod. Rep., 1990, 9, 485–523;
(c) For selected syntheses of castanospermine, see:J. P. Michael, Nat.
Prod. Rep., 2004, 21, 625–649; (d) P. Somfai, P. Marchand, S. Torsell and
U. M. Lindstrom, Tetrahedron, 2003, 59, 1293–1299; (e) H. Zhao and
D. R. Mootoo, J. Org. Chem., 1996, 61, 6762–6763; (f) S. E. Denmark
and B. Herbert, J. Org. Chem., 2000, 65, 2887–2896; (g) For a review
on synthesis of stereoisomers of swainsonine and lentiginosine, see:
A. E. Nemr, Tetrahedron, 2000, 56, 8579–8629; (h) For recent reports
on the synthesis of swainsonine, lentiginosine and their analogues, see:
J. Ceccon, A. E. Greene and J.-F. Poisson, Org. lett., 2006, 8, 4739–
4742; (i) L. Song, E. N. Duesler and P. S. Mariano, J. Org. Chem., 2004,
69, 7284–7293; (j) N. Buschmann and A. Ruckert Blechert, J. Org.
Chem., 2002, 67, 4325–4329; (k) H. Zhao, S. Hans, X. Cheng and D. R.
Mootoo, J. Org. Chem., 2001, 66, 1761–1767; (l) H. Razavi and R. Polt,
J. Org. Chem., 2000, 65, 5693–5706; (m) H. G. A. Guo and O’Doherty,
Org. Lett., 2006, 8, 1609–1612; (n) K. B. Lindsay and S. G. Pyne,
J. Org. Chem., 2002, 67, 7774–7780; (o) G. Heimgartner, D. Raatz and
O. Reiser, Tetrahedron, 2005, 61, 643–655; (p) V. Cere, S. Pollicino and
A. Ricci, J. Org. Chem., 2003, 68, 3311–3314; (q) C. W. G. Au and S. G.
Pyne, J. Org. Chem., 2006, 71, 7097–7099; (r) A. T. Carmona, J. Fuentes,
I. Robina, E. R. Garcia, R. Demange, P. Vogel and A. L. Winters,
J. Org. Chem., 2003, 68, 3874–3883; (s) M. O. Rasmussen, P. Delair
and A. E. Greene, J. Org. Chem., 2001, 66, 5438–5443; (t) R. Martin,
C. Murruzzu, M. A. Pericas and A. Riera, J. Org. Chem., 2005, 70,
2325–2328; (u) K. B. Lindsay and S. G. Pyne, Aust. J. Chem., 2004, 57,
669–672; (v) W. H. Pearson, Y. Ren and J. D. Powers, Heterocycles, 2002,
58, 421–430; (w) S. Nakui, M. Sodeoka, H. Sasai and M. Shibasaki,
J. Org. Chem., 1995, 60, 398–404; (x) A. Brandi, S. Cicchi, F. M.
Cordero, R. Frignoli, A. Goti, S. Picasso and P. Vogel, J. Org. Chem.,
1995, 60, 6806–6812; (y) R. Giovannini, E. Marcantoni and M. Petrini,
J. Org. Chem., 1995, 60, 5706–5707; (z) For the enantiomer of 7b see: C.
Paolucci, L. Musiani, F. Venturelli and A. Fava, Synthesis, 1997, 1415–
1419.
References and notes
1 (a) For a recent account of aziridines, see: I. D. G. Watson, L. Yu and
A. K. Yudin, Acc. Chem. Res., 2006, 39, 194–206; (b) For a review on
aziridine carboxylic esters, see:D. Tanner, Angew. Chem., Int. Ed. Engl.,
1994, 33, 599–619 and references cited therein; (c) J. S. Yadav, B. V. S.
Reddy, P. N. Reddy and M. S. Rao, Synthesis, 2003, 1387–1390; (d) B.
Zwanenburg and P. ten Holte, Top. Curr. Chem., 2001, 216, 93–124;
(e) Aziridines and Epoxides in organic synthesis ed. A. K. Yudin, Wiley-
VCH, Weinheim, 2006; (f) J. B. Sweeney, Chem. Soc. Rev., 2002, 31,
247–258; (g) W. McCoull and F. A. Davis, Synthesis, 2000, 1347–1365.
2 (a) For a review on nucleophilic ring opening of aziridines, see: X. E.
Hu, Tetrahedron, 2004, 60, 2701–2743; (b) B. Zwanenburg, Pure Appl.
Chem., 1999, 71, 423–430 and references therein; (c) F. A. Davis, H.
Liu, P. Zhou, T. Fang, G. V. Reddy and Y. Zhang, J. Org. Chem.,
1999, 64, 7559–7567; (d) P. Dauban, L. Dubois, E. T. H. Dau and
R. H. Dodd, J. Org. Chem., 1995, 60, 2035–2043; (e) Z. Bouayed, J.
Chanet-Ray, S. Ducher and R. Vessiere, J. Heterocycl. Chem., 1991, 28,
1757–1767; (f) J. Legters, L. Thijs and B. Zwanenburg, Tetrahedron,
1991, 47, 5287–5294; (g) O. Ploux, M. Caruso, G. Chassaing and A.
Marquet, J. Org. Chem., 1988, 53, 3154–3158; (h) K. J. Shaw, J. R.
Luly and H. Rapoport, J. Org. Chem., 1985, 50, 4515–4523; (i) K.
Nakajima, F. Takai, T. Tanaka and K. Okawa, Bull. Chem. Soc. Jpn.,
1978, 51, 1577–1578; (j) K. Nakajima, M. Neya, S. Yamada and K.
Okawa, Bull. Chem. Soc. Jpn., 1982, 55, 3049–3050; (k) Nakajima, H.
Oda and K. Okawa, Bull. Chem. Soc. Jpn., 1983, 56, 520–522; (l) Chem.
Abstr., 1974, 80, 70734t; (m) For the synthesis of pyrrolidines, see: M.
Fremery, Angew. Chem., Int. Ed. Engl., 1966, 5, 975–975; (n) H. W.
Heine, R. Peavy and A. J. Durbetaki, J. Org. Chem., 1966, 31, 3924–
3927; (o) P. B. Woller and N. H. Cromwell, J. Org. Chem., 1970, 35,
888–898; (p) I. Funaki, L. Thijs and B. Zwanenburg, Tetrahedron, 1996,
52, 9909–9924; (q) R. Huisgen, W. Scheer and H. Huber, J. Am. Chem.
Soc., 1967, 89, 1753–1755; (r) For a recent report on the nucleophilic
ring opening of aziridines, see: S. Minakata, Y. Okada, Y. Oderaotoshi
and M. Komatsu, Org. Lett., 2005, 7, 3509–3512; (s) Y. K. Liu, R. Li,
L. Yue, B. J. Li, Y. C. Chen, Y. Wu and L. S. Ding, Org. Lett., 2006, 8,
1521–1524; (t) O. Kitagawa, S. Miyahi, Y. Yamada, H. Fujiwara and
T. Taguchi, J. Org. Chem., 2003, 68, 3184–3189.
8 (a) M. L. Sinot, Chem. Rev., 1990, 90, 1171–1202; (b) M. Bols, Acc.
Chem. Res., 1998, 31, 1–8; (c) For recent reviews on glycosidase
mechanisms, see: D. L. Zechel and S. G. Withers, Acc. Chem. Res., 2000,
33, 11–18; (d) T. D. Heightman and A. Vasella,T., Angew. Chem., Int.
Ed., 1999, 38, 750–770; (e) For glycoprotein enzyme inhibition studies,
see: A. D. Elbein, FASEB J., 1991, 5, 3055–3063; (f) B. Winchester and
710 | Org. Biomol. Chem., 2008, 6, 703–711
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
G. W. J. Fleet, Glycobiology, 1992, 2, 199–210; (g) P. E. Goss, C. L.
Reid, D. Bailey and J. W. Dennis, Clin. Cancer Res., 1997, 3, 11077–
11086; (h) For immunosuppressive activity, see: P. M. Grochowicz,
A. D. Hibberd, Y. C. Smart, K. M. Bowen, D. A. Clark, W. B. Cowden
and D. O. Qwillenborg, Transplant Immunol., 1996, 4, 275–285; (i) S.
Walter, K. Fassbender, E. Gulbins, Y. Liu, M. Rieschel, M. Herten, T.
Bertsch and B. Engelhardt, J. Neuroimmunol., 2002, 132, 1–10; (j) K. A.
Wall, J. D. Pierce and A. D. Elbein, Proc. Natl. Acad. Sci. U. S. A., 1988,
85, 5644–5648; (k) X.-S. Ye, F. Sun, M. Liu, Q. Li, Y. Wang, G. Zhang,
L.-H. Zhang and X.-L. Zhang, J. Med. Chem., 2005, 48, 3688–3691;
(l) B. Davis, A. A. Bell, R. J. Nash, A. A. Watson, R. C. Griffiths,
M. G. Jones, C. Smith and G. W. J. Fleet, Tetrahedron Lett., 1996, 37,
8565–8568.
9 (a) W. H. Pearson and E. J. Hembre, J. Org. Chem., 1996, 61, 5537–5545;
(b) W. H. Pearson and E. J. Hembre, Tetrahedron Lett., 2001, 42, 8273–
8276; (c) W. H. Pearson, L. Guob and T. M. Jewell, Tetrahedron Lett.,
2002, 43, 2173–2178; (d) D. D. Dhavale, S. M. Jachak, N. P. Karche and
C. Trombini, Tetrahedron, 2004, 60, 3009–3016; (e) N. S. Kumar and
B. M. Pinto, J. Org. Chem., 2006, 71, 1262–1264; (f) J. P. Michael, Nat.
Prod. Rep., 2000, 17, 579–602; (g) P. Gebarowski and W. Sas, Chem.
Commun., 2001, 915–916; (h) J. C. Carretero, R. G. Arrayas and I. S.
Garcia, Tetrahedron Lett., 1997, 38, 8537–8540; (i) U. K. Pandit, H.
Overleeft, B. C. Borer and H. Bieraugel, Eur. J. Org. Chem., 1999, 959–
968; (j) H. Hamana, N. Ikota and B. Ganem, J. Org. Chem., 1987, 52,
5492–5494; (k) G. Gradnig, A. Berger and A. Stutz, Tetrahedron Lett.,
1991, 32, 4889–4892; (l) P. Liu, R. Rogers, M. Kang and P. Sankara,
Tetrahedron Lett., 1991, 32, 5853–5856; (m) P. Herczegh, I. Kovacs, L.
Szilagyi and F. Sztaricskai, Tetrahedron, 1995, 51, 2969–2978; (n) H.
Overkleeft, P. Bruggeman and U. K. Pandit, Tetrahedron Lett., 1998,
39, 3869–3872.
Dhavale, Tetrahedron, 2006, 62, 4349–4354 and references sited therein;
(f) N. S. Karanjule, S. D. Markad and D. D. Dhavale, J. Org. Chem.,
2006, 71, 6273–6276 and references cited therein.
11 (a) G. J. Jolly, K. Peeters, H. Mao, T. Brossette, G. J. Hoornaert and
F. Compernolle, Tetrahedron Lett., 2000, 41, 2223–2226; (b) T. K.
Chakraborty and S. Jayaprakash, Tetrahedron Lett., 1997, 38, 8899–
8902; (c) For iminosugar derived aziridines, see: J.-Y. Goujon, D.
Gueyrard, P. Compain, O. R. Martin and N. Asano, Tetrahedron:
Asymmetry, 2003, 14, 1969–1972; (d) O. L. Lopez, J. G. Fernandez-
Bolanos, V. H. Lillelund and M. Bols, Org. Biomol. Chem., 2003, 1,
478–482.
12 A minor amount of ring-opened product with Z-geometry is observed
(<6%). The major isomer was separated by flash chromatography and
characterized using 1H and 13C NMR spectra; however, due to the close
Rf values we could not separate the Z-isomer in a pure form.
13 This observation also supports the aziridine ring opening in 9 occurring
exclusively at the C6 position.
14 (a) F. A. Davis, P. Zhou and G. V. Reddy, J. Org. Chem., 1994, 59,
3244–3245; (b) F. A. Davis, G. V. Reddy and H. Liu, J. Am. Chem. Soc.,
1995, 117, 3651–3652; (c) W. J. Kruper and A. H. Emmons, J. Org.
Chem., 1991, 56, 3323–3329; (d) H. Yakawa and S. Kimura, Nippon
Kagaku Zasshi, 1955, 78, 454–458.
15 The product after hydrogenation was a mixture of d-amino saturated
ester (80%) and cyclized d-lactam (∼20%) as indicated by the 1H NMR
spectra. The mixture was therefore subjected to sodium acetate in
methanol to afford d-lactam as the only product.
16 Our assumption was supported by the fact that when aziridine car-
boxylate 1 was subjected to hydrogenation, under conditions identical
to those for 9, an N/O-debenzylated aziridine ester was obtained,
indicating high stability of the aziridine ring in 1 to the hydrogenation.
For mechanistic aspects in hydrogenation, see: I. Horiuti and M.
Polanyi, Trans. Faraday Soc., 1934, 30, 1164–1167.
17 Protection of C3–OH group is essential for the removal of the C1
carbon atom required for the synthesis of indolizidine alkaloids.
18 (a) Y.-T. Li and S.-C. Li in Methods in Enzymology, ed. V. Ginsberg,
Academic Press, New York, 1972, vol. 28, Part B, p. 702; (b) G. L.
Miller, Anal. Chem., 1959, 31, 426–428.
10 (a) N. T. Patil, J. N. Tilekar and D. D. Dhavale, J. Org. Chem., 2001,
66, 1065–1074; (b) N. S. Karanjule, S. D. Markad, T. Sharma, S. G.
Sabharwal, V. G. Puranik and D. D. Dhavale, J. Org. Chem., 2005,
70, 1356–1363; (c) V. D. Chaudhari, K. S. Ajish Kumar and D. D.
Dhavale, Tetrahedron Lett., 2005, 45, 8363–8366; (d) D. D. Dhavale,
S. D. Markad, N. S. Karanjule and J. PrakashaReddy, J. Org. Chem.,
2004, 69, 4760–4766; (e) V. D. Chaudhari, K. S. Ajish Kumar and D. D.
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The Royal Society of Chemistry 2008
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