Synthesis and glycosidase inhibitory studies of pentahydroxyindolizidines: D-glucose-derived aziridine-2-carboxylate approach

Article abstract of DOI:10.1002/ejoc.200700461

D-Glucose-derived aziridine-2-carboxylate 1 was converted into α-amino aldehyde 7, which, after Wittig olefination, asymmetric dihydroxylation, hydrogenation followed by LiAlH₄ reduction, and N-Cbz protection, afforded two diastereomeric pyrrol

Full text of DOI:10.1002/ejoc.200700461

FULL PAPER
DOI: 10.1002/ejoc.200700461
Synthesis and Glycosidase Inhibitory Studies of Pentahydroxyindolizidines:
D
-Glucose-Derived Aziridine-2-carboxylate Approach
K. S. Ajish Kumar,[a] Vinod D. Chaudhari,[a] Vedavati. G. Puranik,[b] and Dilip D. Dhavale*[a]
Keywords: Iminosugars / Indolizidine / Asymmetric dihydroxylation (AD) / N-Methylmorpholine N-oxide (NMO)
D
-Glucose-derived aziridine-2-carboxylate 1 was converted
and reductive amination gave the pentahydroxyindolizidine
alkaloids 6g and 6h, respectively, with (S) absolute configu-
rations at the ring junctions. The glycosidase inhibitory ac-
tivities of these compounds were studied.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
into α-amino aldehyde 7, which, after Wittig olefination,
asymmetric dihydroxylation, hydrogenation followed by
LiAlH4 reduction, and N-Cbz protection, afforded two dia-
stereomeric pyrrolidines 11a and 11b with sugar append-
ages. Removal of the 1,2-acetonide functionality in 11a/11b
Introduction
Among strained ring systems, the three-membered nitro-
gen atom ring compounds – aziridines and aziridinecarbox-
ylates[1] – have found wide utility as intermediates in the
synthesis of a variety of amino compounds, including natu-
ral alkaloids and unnatural analogues. In this context, we
have recently reported the synthesis of the -glucose-
derived aziridinecarboxylate 1, which undergoes highly re-
gioselective nucleophilic ring-opening at the position α to
the carboxylate group under acidic conditions in the pres-
ence of water as nucleophile, to afford aminol 2. This in
turn was elaborated for the synthesis of the piperidine and
pyrrolidine iminosugars 3a/b and 4a/b, respectively
(Scheme 1).[2] As a part of our continuing interest in the
area of iminosugars,[3] we envisioned the potential of azirid-
inecarboxylate 1 in the synthesis of polyhydroxylated indol-
izidine alkaloids. This class of compounds (e.g., castanos-
permine 5; Figure 1) and their analogues[4] have the ability
to inhibit a specific class of hydrolytic enzymes that cleave
different types of glycosidic linkages and have therefore
been found to have applications in the treatment of diabe-
tes, obesity, and viral infection.[5] In the search for struc-
ture–activity relationships and in order to find more potent
and specific glycosidase inhibitors, a number of analogues
of 5 have been either synthesized or isolated from natural
sources and screened in biological assays.
Scheme 1. Piperidine and pyrrolidine alkaloids.
[a] Garware Research Centre, Department of Chemistry, Univer-
sity of Pune,
Figure 1. Indolizidine alkaloids.
Pune-411 007, India
[b] Centre for Material Characterization, National Chemical Labo-
ratory,
Pune-411 008, India
In this context, in 2000 Arisawa et al. isolated uniflor-
ine A from the Paraguayan natural medicine namgapiry –
the leaves of Eugenia uniflora L. – and assigned its structure
E-mail: ddd@chem.unipune.ernet.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 4895–4901
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4895

K. S. Ajish Kumar, V. D. Chaudhari, V. G. Puranik, D. D. Dhavale
FULL PAPER
as (R)-2-hydroxy-1-epi-castanospermine (6a) on the basis of attempted to resolve this ambiguity by synthesizing 6a and
spectral and nOe data.[6] The isolated uniflorine A was its analogues 6e and 6f using 1,3-addition of vinylmagne-
found to be a promising inhibitor of maltase and sucrase, sium bromide to a -glucose-derived nitrone, N-allylation
with IC50 values in the µ range.
and ring-closing metathesis as key steps; however, the ana-
In 2004, Pyne and co-workers reported the total synthe- lytical and spectroscopic data once again did not match
sis of putative uniflorine A using the Petasis reaction, ring- those reported for the isolated uniflorine A.[9] In order to
closing metathesis and asymmetric dihydroxylation as key resolve the structural anomaly of uniflorine A, we thought
steps, and the pentahydroxyindolizidine ring structure 6a of synthesizing new pentahydroxyindolizidine analogues 6g
was confirmed by X-ray crystallographic analysis of its per- and 6h using the -glucose-derived aziridinecarboxylate 1
acetyl derivative.[7] However, the authors have noticed con- as the precursor and of studying their glycosidase inhibitory
1
siderable variation in the H and 13C NMR spectroscopic activities.[10] Regioselective nucleophilic ring-opening of 1,
data for the synthetic and the naturally occurring product. followed by reduction of the ester, protection of the amine
In 2005, in another report, Mariano and co-workers re- and oxidative cleavage of the diol should thus afford aminal
ported the synthesis of 5 and the pentahydroxyindolizidine 7 (Scheme 2) with the -ido configuration at C-5, necessary
alkaloids 6b[8a] and 6c, using a photochemical reaction to for generation of the 8a-epi configuration at the ring junc-
construct a 4-aminocyclopentene-3,5-diol derivative from tion. The Wittig olefination of 7, asymmetric dihydrox-
pyridine as a precursor of the piperidine ring through ring- ylation (AD) and hydrogenation should give access to the
rearrangement metathesis.[8] Both compounds 6b and 6c, pyrrolidine ring skeleton with a sugar appendage and with
however, showed deviation in their spectroscopic data from the requisite relative anti stereochemistry at the pyrrolidine
those for the isolated uniflorine A. Recently, our group have ring, a true intermediate for the synthesis of the pentahy-
droxylated indolizidines 6g and 6h. Our results in the suc-
cessful implementation of this methodology are discussed
here.
Results and Discussion
The aziridinecarboxylate 1 was converted into the aminal
7 as reported earlier by us.[2] The Wittig olefination of 7
with Ph3P=CHCOOEt afforded the γ-amino α,β-unsatu-
rated ester 8 exclusively with the (E) geometry, as confirmed
1
by H NMR studies, which showed a large coupling con-
stant of J = 16.1 Hz for protons 7-H and 6-H (Scheme 2).
Dihydroxylation of 8 with potassium osmate (catalytic) and
N-methylmorpholine N-oxide (NMO) in acetone/water
(8:1) afforded a diastereomeric mixture of the vicinal diols
9a and 9b in a ratio of 7:3 (Table 1).[11] The very similar
Rf values of 9a and 9b did not permit us to separate the
diastereomers by column/flash chromatography. Fortu-
nately, however, crystallization of a diastereomeric mixture
of 9a and 9b from ethyl acetate/hexane (2:8) and keeping
the solution at 5 °C for 12 h afforded 9a as a crystalline
solid.[12] Its single-crystal X-ray analysis (Figure 2) estab-
lished the absolute configurations at the newly generated
stereocenters as (6S) and (7R), so the minor isomer 9b
could then be assigned (6R) and (7S) absolute configura-
tions.[13]
Table 1. Dihydroxylation of 8.
Entry
Ligand
Ratio of 9a/9b Yield [%]
1
2
3
no ligand
(DHQ)2PHAL
(DHQD)2PHAL
70:30
83:17
52:48
91
78
82
The formation of 9a as a major product was against our
expectations (Kishi’s empirical rule, applicable mainly to al-
lylic alcohols), as 9a was obtained by syn-dihydroxylation
from the same side (α-face) as the pre-existing bulky N-
Scheme 2. Synthesis of indolizidine alkaloids 6g and 6h.
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Glycosidase Inhibitory Studies
in THF gave the pyrrolidine, which on treatment with
CbzCl in methanol afforded 11a. In the subsequent steps,
removal of the 1,2-acetonide functionality, followed by hy-
drogenation and purification by chromatography, afforded
1
6g as a white solid. The analytical and H and 13C NMR
spectroscopic data were in accordance with the structure
6g, but the data were not found to be in agreement with
those for the isolated uniflorine A. The structure of 6g was
further confirmed by converting it into the peracetylated
derivative 12a, which also helped in assigning the confor-
mation (vide supra).
The same sequence of reactions was repeated with the
dihydroxylated compound 9b (Scheme 2). The correspond-
ing C-6, C-7 diepimeric compounds 10b and 11b were iso-
lated and characterized by their spectral and analytical
data. Subsequently, the N-Cbz-protected pyrrolidine 11b af-
forded 6h as a thick liquid on removal of the 1,2-acetonide
group with TFA/H2O and reductive aminocyclization by
hydrogenation. To our disappointment, the spectral and the
analytical data for 6h were also inconsistent with those for
the isolated uniflorine A. The pentahydroxyindolizidine 6h
was also further characterized as its pentaacetyl derivative
12b.
Figure 2. ORTEP diagram of the molecule 9a.
(benzyl)benzyloxycarbonyl group, while the minor product
9b was obtained from the side opposite (β-face).[14]Analog-
ous results were observed when we attempted to improve
the diastereoselectivity using cinchona alkaloids as chiral
ligands (Table 1).
Thus, the use of AD-mix-α [10 mol-% (DHQ)2PHAL,
1 mol-% K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2]
in the osmylation afforded only a marginal increase in the
diastereoselectivity in favour of 9a (Entry 2), whereas the
use of AD-mix-β [10 mol-% (DHQD)2PHAL, 1 mol-%
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2] did not
afford any selectivity as determined from the 1H NMR
spectrum of the crude mixture (Entry 3). It is worth men-
tioning that although the presence of the N-(Bn)Cbz func-
tionality hindered the α-face of the double bond, the dihy-
droxylation occurred preferentially from the same side as
this bulky group to give 9a as a major product. We presume
that the amide C–N bond (of the N-Cbz group) has more
double bond character,[15] giving a net negative charge on
the amide oxygen that complexes with potassium osmate
(Figure 3), favouring the dihydroxylation taking place from
the same side as the N-Cbz functionality. However, the
reasons for the loss of diastereoselectivity on using AD-
mix-β and the small increment in selectivity while using
AD-mix-α during the dihydroxylation reaction are not clear
to us.
Conformational Analysis
It is known that 1-deoxycastanospermine (5a) exists in
8
the C5 conformation A (Figure 4) in solution, while its 8a-
5
epimer 5b adopts the C8 conformation B.[3a] We thought
of carrying out a conformational analysis of the newly syn-
thesized pentahydroxyindolizidines 6g and 6h, which have
8a-epi configurations at their ring fusions with relative anti-
hydroxy groups in the pyrrolidine ring. The 1H NMR spec-
troscopic data for 6g and 6h were not informative due to
the broadening of signals, so 6g and 6h were converted into
the corresponding pentaacetyl derivatives 12a and 12b and
the assignments of signals and coupling constant infor-
mation were determined from decoupling experiments
(Table 2). In 12a, the appearance of the C5-methylene pro-
tons as two doublet of doublets at δ = 2.84 and 3.11 ppm
with small coupling constants (J5a,6 = 4.1, J5e,6 = 3.6 Hz)
indicates an equatorial orientation of the 6-H proton. A
doublet of doublets at δ = 3.29 ppm for 8a-H, with J8a,1
=
6.3 and J8a,8 = 3.0 Hz, requires an axial–equatorial relation-
ship between 8a-H and 8-H (small coupling), while the
coupling constant of 6.3 Hz between 8a-H and 1-H indi-
cates a syn relationship with a dihedral angle of ca. 20°.
The initial geometry in the precursor 11a ensures that the
substituents at C6/C7/C8 in the product 12a are trans. As
8-H is equatorial, the protons at 7-H and 6-H should also
be equatorial, and this was confirmed by the low coupling
constants (ca. 3 Hz) observed for these protons. These data
Figure 3. Plausible transition state for the observed selectivity.
indicated the 5C8 conformation of 12a with the (8aS)
1
In the next step, the aminodiol 9a was subjected to hy- absolute configuration. In the H NMR spectrum of 12b
drogenolysis (10% Pd–C and ammonium formate in meth- the appearance of 8a-H at δ = 2.58 ppm (J8a,1 = 8.8 and
anol at reflux) to give the γ-lactam 10a in quantitative yield. J8a,8 = 2.2 Hz) suggests an axial–equatorial relationship be-
Reduction of the lactam functionality in 10a with LiAlH4 tween 8a-H and 8-H, while the large coupling of 8.8 Hz
Eur. J. Org. Chem. 2007, 4895–4901
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. S. Ajish Kumar, V. D. Chaudhari, V. G. Puranik, D. D. Dhavale
FULL PAPER
indicated an anti relationship between 8a-H and 1-H with Table 3. Inhibitory studies with indolizidine alkaloids 6g and 6h.
a dihedral angle of ca. 180°. Both 5-H methylene protons
Enzyme
IC50 [m]
6g
showed small coupling constants with 6-H, suggesting an
equatorial orientation of 6-H. The appearance of 6-H, 7-H
6h
[a]
[a]
α-Mannosidase (jack bean)
β-Glucosidase (sweet almonds)
–
–
and 8-H as narrow multiplets suggested the relative trans
12.35
22.28
5
[a]
[a]
equatorial disposition of these protons, indicating the C8 α-Glucosidase (yeast)
–
–
β-Xylanase (Thermomyces ianug- 51.81
inosus)
0.05
conformation of 12b. As 12a and 12b are acetylated deriva-
tives of 6g and 6h, respectively, the same conformation (5C8)
was assigned to the pentahydroxyindolizidines 6g and 6h.
[a] Inhibition not observed under assay conditions. Data are
averages of three sets of assay performed.
Conclusions
In conclusion, we have successfully demonstrated the
utility of the sugar-derived aziridinecarboxylate 1 as a valu-
able starting material in the synthesis of new pentahy-
droxyindolizidine alkaloids 6g and 6h. The glycosidase in-
hibitory activity studies indicate that 6g and 6h inhibit β-
xylanase and β-glucosidase in the millimolar range. Work
is in progress to utilize 1 in the synthesis of other imi-
nosugars such as lentiginosine and swainsonine and will be
reported in due course.
Figure 4. Conformations of indolizidines.
Experimental Section
Single crystals of compound 9a suitable for X-ray diffraction were
selected directly from the analytical samples.
Table 2. Chemical shifts and coupling constant values for pentaace-
toxy indolizidines 12a and 12b.
Crystal Structure Determination of Compound 9a: C35H41NO10, M
= 635.69, orthorhombic, a = 11.8806(6), b = 11.9104(6), c =
23.6172(11) Å, V = 3341.9(3) Å3, T = 293(2) K, space group
P212121, Z = 4, µ (Mo-Kα) = 0.092 mm–1, 29957 reflections mea-
sured, 5864 unique [IϾ2σ(I)], R value 0.0502, wR2 = 0.1180. The
Flack parameter 0.4251 (with esd 1.091) is inconclusive and there-
fore no conclusions on the absolute structure can be drawn.
Chemical shifts [ppm]
Coupling constants, J [Hz]
12a
12b
12a
12b
1-H
2-H
3-H
3-H
5-H
5-H
5.37 (dd)
5.19 (ddd) 5.08 (ddd)
3.71 (dd)
2.46 (dd)
3.11 (dd)
2.84 (dd)
5.25 (dd)
1-H,2-H
1-H,8a-H 6.3
2-H,3-H
2-H,3-H
8a-H,8-H 3.0
2.7
4.1
8.8
7.7
1.6
2.2
WH
5.4
WH
5.4
WH
5.4
2.7
2.75 (dd)
3.10 (t)
7.4
5.7
2.50 (dd)
8-H,7-H
4.9
4.2
4.1
3.6
=
=
=
General Remarks: Melting points were recorded with a Thomas
Hoover melting point apparatus and are uncorrected. IR spectra
were recorded by FTIR as thin films or in Nujol mulls or as KBr
pellets and are expressed in cm–1. 1H (300 MHz), 13C (100 MHz)
and 13C (75 MHz) NMR spectra were recorded in CDCl3 or D2O
as solvents. Chemical shifts are reported in δ units (ppm) with refer-
ence to TMS as an internal standard, and J values are given in Hz.
Decoupling experiments confirmed the assignments of the signals.
Elemental analyses were carried out with a C,H-analyzer. Optical
rotations were measured with a polarimeter at 25 °C. Thin-layer
chromatography was performed on precoated plates (0.25 mm, sil-
ica gel 60 F254). Column chromatography was carried out with sil-
ica gel (100–200 mesh). The reactions were carried out in oven-
dried glassware under dry N2. Methanol, pyridine and THF were
purified and dried before use. n-Hexane used was the distillation
fraction between 40–60 °C. (DHQD)2PHAL and (DHQ)2PHAL
and Pd-C (10%) were purchased from Aldrich and/or Fluka. After
decomposition of the reaction mixtures with water, the workups
involved washing of the combined organic layers with water and
brine, drying over anhydrous sodium sulfate and evaporation of
solvent at reduced pressure. For enzyme inhibition studies, sub-
strates were purchased from Sigma Chemicals Co., USA. α-Gluco-
sidase from yeast α-mannosidase from jack bean and β-xylanase
from Thermomyces ianuginosus were purchased from Sigma Chemi-
cals Co., USA. β-Glucosidase was extracted and purified from
sweet almonds and used.
6-H
7-H
8-H
4.86 (br. d) 4.85 (narrow 7-H,6-H
multiplet)
5.07–5.12
(m)
5.02 (narrow 6-H,5-H
multiplet)
4.90 (narrow 6-H,5-H
multiplet)
8a-H 3.29 (dd)
2.58 (dd)
3-H,3-H
5-H,5-H
11.0
12.9
11.0
12.9
Glycosidase Inhibitory Activity
The isolated uniflorine A has been found to show inhibi-
tion of maltase and sucrase. In view of the potency of these
types of molecules, we performed a glycosidase inhibition
study with pentahydroxylated indolizidine alkaloids 6g and
6h.
As shown in Table 3, 6g and 6h exhibited selective inhibi-
tion towards β-glucosidase (sweet almonds) and β-xylanase
(Thermomyces ianuginosus) in the millimolar range while no
inhibition was observed with α-glucosidase (yeast) and α-
mannosidase (jack bean) under the assay conditions.
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Glycosidase Inhibitory Studies
CCDC-644419 contains the supplementary crystallographic data
for this paper. Data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
α-L-threo-L-ido-Oct-1,4-furan-8-ulose 10a and α-D-threo-L-ido-Oct-
1,4-furan-8-ulose 10b: A mixture of ammonium formate (0.35 g,
5.60 mmol) and Pd-C (10%, 0.10 g) was added to a solution of 9a/
9b (0.50 g, 0.80 mmol) in dry methanol (15 mL) at reflux and heat-
ing at reflux was continued for 5 h. The reaction mixture was fil-
tered, concentrated and purified by column chromatography.
(E)-Ethyl 3-O-Benzyl-1,2-O-isopropylidene-5-[benzyl(benzyloxycar-
bonyl)amino]-5,6,7-trideoxy-β-L-ido-6-eno-octafuranuronate (8): The
Elution (n-hexane/ethyl acetate, 2:8) gave 10b as a white solid
(0.05 g, 26%), m.p. 190–192 °C. Rf = 0.65 (MeOH/CHCl3, 2:8).
[α]D = +6.4 (c = 0.02, CHCl3). 1H NMR (300 MHz, D2O): δ = 1.37
(s, 3 H, CH3), 1.52 (s, 3 H, CH3), 3.74 (dd, J = 1.3, 7.4 Hz, 1 H,
5-H), 4.12 (t, J = 7.4 Hz, 1 H, 6-H), 4.23 (dd, J = 2.4, 5.5 Hz, 1
H, 4-H), 4.32 (dd, J = 1.3, 7.9 Hz, 1 H, 7-H), 4.37 (d, J = 2.4 Hz,
1 H, 3-H), 4.71 (d, J = 3.5 Hz, 1 H, 2-H), 6.02 (d, J = 3.5 Hz, 1
H, 1-H) ppm. 13C NMR (75 MHz, D2O): δ = 25.3 (CH3), 25.8
(CH3), 53.5 (C-5), 73.5 (C-7), 74.3 (C-3), 75.4 (C-6), 77.7 (C-2),
85.1 (C-4), 104.3 (C-1), 112.6 [(CH3)2C(O)2], 175.9 (C=O) ppm. IR
phosphorane Ph3P=CHCOOEt (0.73 g, 2.08 mmol) was added at
25 °C to a solution of aminoaldehyde 7 (0.92 g, 1.73 mmol) in dry
acetonitrile (20 mL), and the mixture was stirred well for 8 h. It
was then concentrated, and on purification by column chromatog-
raphy (n-hexane/ethyl acetate, 9:1), gave 8 as a thick liquid (0.89 g,
86%). Rf = 0.54 (n-hexane/ethyl acetate, 7:3). [α]D = –18.1 (c =
0.59, CHCl3). 1H NMR (300 MHz, CDCl3; due to doubling of sig-
nals only prominent signals are mentioned): δ = 1.25 (s, 3 H, CH3),
1.28 (t, J = 6.2 Hz, 3 H, OCH2CH3), 1.43 (s, 3 H, CH3), 3.77 (d,
J = 16.1 Hz, 1 H, 5-H), 4.12 (m, 2 H, OCH2CH3), 4.25–4.45 (m, 2
H, NCH2Ph), 4.49–4.90 (m, 5 H, OCH2Ph, 3-H, 4-H, 2-H), 5.12
(d, J = 16.1 Hz, 2 H, NCOOCH2Ph), 5.65 (d, J = 16.1 Hz, 1 H, 6-
H), 5.92 (d, J = 3.6 Hz, 1 H, 1-H), 6.83 (dd, J = 6.7, 16.1 Hz, 1 H,
7-H), 7.13–7.40 (m, 15 H, 15ϫArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.1 (OCH2CH3), 26.3 (CH3), 26.7 (CH3), 51.2
(NCH2Ph), 56.2 (C-5), 57.8 (NCOOCH2Ph), 60.2 (OCH2CH3),
67.1 (OBn), 71.6 (C-3), 81.1 (C-4), 81.6 (C-2), 104.6 (C-1), 111.7
[(CH3)2C(O)2], 124.0 (C-7), 126.9 (ArC), 127.4 (s, 2ϫArC), 127.6
(s, 2ϫArC), 127.7 (s, 2ϫArC), 127.8 (s, 2ϫArC), 127.9 (ArC),
128.1 (s, 3ϫArC), 128.2 (s, 3ϫArC), 136.4 (ArC), 137.7 (ArC),
(neat): ν = 3365, 2983, 1679, 1452 cm–1. C11H17NO7 (275.26):
˜
calcd. C 48.00, H 6.23; found C 47.83, H 6.27.
Further elution with ethyl acetate gave 10a as a white solid (0.14 g,
73 %), m.p. 189–190 °C. Rf = 0.60 (MeOH/CHCl3, 2:8). [α]D
=
1
+20.8 (c = 1.24, CHCl3). H NMR (300 MHz, D2O): δ = 1.36 (s,
3 H, CH3), 1.52 (s, 3 H, CH3), 4.05 (dd, J = 3.4, 6.3 Hz, 1 H, 5-
H), 4.37–4.45 (m, 4 H, 3-H, 4-H, 6-H, 7-H), 4.67 (d, J = 3.8 Hz, 1
H, 2-H), 6.00 (d, J = 3.8 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.3 (CH3), 25.7 (CH3), 55.5 (C-5), 74.4 (C-7), 75.0
(C-3), 76.1 (C-6), 80.2 (C-2), 84.9 (C-4), 104.5 (C-1), 112.7 [(CH3)
141.4 (C-6), 155.4 (CON), 165.5 (COOEt) ppm. IR (neat): ν =
˜
C(O) ], 175.3 (C=O) ppm. IR (neat): ν = 3366, 2984, 1683, 1452,
˜
2
2
2929, 1712 cm–1. C35H39NO8 (601.69): calcd. C 69.87, H 6.53;
found C 69.57, H 6.44.
1074 cm–1. C11H17NO7 (275.26): calcd. C 48.00, H 6.23; found C
47.77, H 6.11.
Ethyl 3-O-Benzyl-5-[benzyl(benzyloxycarbonyl)amino]-5-deoxy-1,2-
α-L-threo-L-ido-Oct-1,4-furanose 11a: A solution of lactam 10a
O-isopropylidene-β-
3-O-Benzyl-5-[benzyl(benzyloxycarbonyl)amino]-5-deoxy-1,2-O-iso-
propylidene-α-D-threo- -ido-heptofuranuronate (9b): A catalytic
L-threo-L-ido-heptofuranuronate (9a) and Ethyl
(0.12 g, 0.44 mmol) in THF (5 mL) was added dropwise at 0 °C to
a slurry of LAH (0.05 g, 1.30 mmol) in THF (6 mL) and the mix-
ture was stirred well. The reaction mixture was brought to room
temperature and heated at reflux for another 3 h. The reaction was
quenched with ethyl acetate (5 mL) and saturated ammonium chlo-
ride solution (1 mL). The reaction mixture was filtered through a
celite bed, concentrated and dried, and MeOH (5 mL), water
(1 mL), NaHCO3 (0.07 g, 0.87 mmol) and CbzCl (0.08 mL,
0.60 mmol) were added at 0 °C. The reaction mixture was stirred
at 25 °C for 3 h. Concentration under vacuum, extraction with
CHCl3, adsorption onto silica and column purification (n-hexane/
ethyl acetate, 8.5:1.5) afforded 11a (0.14 g, 86%) as a thick liquid.
Rf = 0.34 (ethyl acetate). [α]D = +13.0 (c = 0.23, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.38 (s, 3 H, CH3), 1.46 (s, 3 H, CH3), 3.10
(br. d, J = 0.09 Hz, exchangeable with D2O, 3-OH, 3-H), 3.36 (dd,
J = 6.8, 11.2 Hz, 1 H, 8a-H), 3.76 (dd, J = 7.6, 11.2 Hz, 1 H, 8b-
H), 4.20 (t, J = 7.6 Hz, 1 H, 5-H), 4.26 (d, J = 2.3 Hz, 1 H, 3-H),
4.30–4.38 (m, 1 H, 6-H), 4.44 (s, 1 H, 4-H), 4.46–4.52 (m, 1 H, 7-
H), 4.54 (d, J = 3.8 Hz, 1 H, 2-H), 5.15 (ABq, J = 12.3 Hz, 2
H, NCOOCH2Ph), 5.91 (d, J = 3.8 Hz, 1 H, 1-H), 7.38 (s, 5 H,
5ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.9 (CH3), 26.5
(CH3), 50.1 (C-8), 56.9 (C-5), 67.9 (NCOOCH2Ph), 73.6 (C-7), 75.5
(C-3), 76.3 (C-6), 77.2 (C-4), 84.8 (C-2), 104.3 (C-1), 111.5 [(CH3)
2C(O)2], 127.9 (ArC), 128.2 (ArC), 128.5 (s, 3ϫArC), 135.7 (ArC),
L
amount of potassium osmate (0.06 g, 0.017 mmol) was added at
0 °C to a mixture of K3Fe(CN)6 (3.35 g, 10.20 mmol), K2CO3
(3.57 g, 10.20 mmol) and (DHQD)2PHAL or (DHQ)2PHAL
(0.026 g, 0.034 mmol, 1 mol-%) or without ligand in tBuOH/H2O
(1:1, 80 mL), followed by methanesulfonamide (0.32 g, 3.40 mmol).
After stirring for 5 min at 0 °C, compound 8 (2.00 g, 3.40 mmol)
in tBuOH/H2O (1:1, 20 mL) was added over a period of 5 min. The
reaction mixture was stirred at 0 °C for 24 h and quenched with
solid sodium sulfite (3.00 g). The stirring was continued for another
45 min and the reaction mixture was extracted with ethyl acetate
(5ϫ40 mL). The combined organic phase was washed with KOH
(10%) and worked up to afford a diastereomeric mixture of diols
9a and 9b. Recrystallization from n-hexane/ethyl acetate (2:8) gave
9a as a white solid (1.31 g, 71%), m.p. 91–93 °C. Rf = 0.60 (n-
1
hexane/ethyl acetate, 5:5). [α]D = –27.2 (c = 0.52, CHCl3). The H
(300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3) spectra of 9a
were found to be very complicated, due to the doubling of signals
as a result of restricted rotation in the urethane functionality. IR
(neat): ν = 3500, 3141, 1743, 1664, 1448, 1228 cm–1. C H NO
˜
35 41
10
(635.70): calcd. C 66.13, H 6.50; found C 65.96, H 6.37.
Procedure for 9a and 9b with NMO as the Cooxidant: NMO (0.29 g,
2.19 mmol) and potassium osmate (0.012 g) were added at 0 °C to
a solution of conjugate ester 8 (0.60 g, 0.99 mmol) in acetone/water
(8:1, 9 mL), and the system was stirred for 6 h. The reaction mix-
ture was quenched with solid sodium sulfite (1.70 g). The stirring
was continued for another 45 min, and the reaction mixture was
extracted with ethyl acetate (5ϫ20 mL). The combined organic
phase was washed with KOH (10%) and worked up to afford a
diastereomeric mixture of diols 9a and 9b.
157.5 (NCO) ppm. IR (neat): ν = 1676, 1253, 1026 cm–1
.
˜
C19H25NO8 (395.40): calcd. C 57.71, H 6.37; found C 57.52, H
6.26.
α-L-threo-L-ido-Oct-1,4-furanose 11b: A solution of lactam 10b
(0.05 g, 0.19 mmol) in THF (5 mL) was added dropwise at 0 °C to
a slurry of LAH (0.02 g, 1.3 mmol) in THF (6 mL) and the system
was stirred well. The reaction mixture was brought to room tem-
perature and heated at reflux for another 3 h. The reaction was
Eur. J. Org. Chem. 2007, 4895–4901
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4899

K. S. Ajish Kumar, V. D. Chaudhari, V. G. Puranik, D. D. Dhavale
FULL PAPER
quenched and worked up as for 11a. NaHCO3 (0.03 g, 0.40 mmol)
and CbzCl (0.04 mL, 0.26 mmol) were added at 0 °C to the amino
alcohol in MeOH (5 mL) and water (1 mL). The reaction mixture
was stirred at 25 °C for 3 h. Concentration under vacuum, extrac-
tion with CHCl3, adsorption onto silica and column purification
(n-hexane/ethyl acetate, 6:4) afforded 11b (0.06 g, 81%) as a white
solid, m.p. 63–64 °C. Rf = 0.23 (ethyl acetate). [α]D = –68.46 (c =
added and the mixture was extracted with chloroform (3ϫ10 mL).
Usual workup and chromatographic purification (n-hexane/ethyl
acetate, 3:2) afforded the pentaacetate 12a (0.03 g, 77%) as a thick
liquid. Rf = 0.25 (n-hexane/ethyl acetate, 4:6). [α]D = +37.2 (c =
0.19, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 2.04 (s, 3 H,
COCH3), 2.09 (s, 9 H, 3ϫCOCH3), 2.10 (s, 3 H, COCH3), 2.46
(dd, J = 5.7, 11.0 Hz, 1 H, 3e-H), 2.84 (dd, J = 3.6, 12.9 Hz, 1 H,
0.55, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.33 (s, 3 H, CH3), 5e-H), 3.11 (dd, J = 4.1, 12.9 Hz, 1 H, 5a-H), 3.29 (dd, J = 3.0,
1.49 (s, 3 H, CH3), 2.94 (br. s, 3 H, exchangeable with D2O, 3-OH),
3.43 (d, J = 12.0 Hz, 1 H, 8a-H), 4.05 (dd, J = 6.1, 12.7 Hz, 1 H,
8b-H), 4.15 (d, J = 6.1 Hz, 1 H, 7-H), 4.20–4.30 (m, 3 H, 3-H, 4-
H, 5-H), 4.40 (br. s, 1 H, 6-H), 4.50 (d, J = 3.5 Hz, 1 H, 2-H), 5.15
6.3 Hz, 1 H, 8a-H), 3.71 (dd, J = 7.4, 11.0 Hz, 1 H, 3a-H), 4.86
(br. d, J = 3.8 Hz, 1 H, 6-H), 5.07–5.12 (m, 2 H, 7-H, 8-H), 5.19
(ddd, J = 2.7, 5.7, 7.4 Hz, 1 H, 2-H), 5.37 (dd, J = 2.7, 6.3 Hz, 1
H, 1-H) ppm. 1 3 C NMR (75 MHz, CDCl3 ): δ = 20.9 (s,
(ABq, J = 12.4 Hz, 2 H, NCOOCH2Ph), 5.96 (d, J = 3.5 Hz, 1 H, 2ϫCOCH3), 21.0 (COCH3), 21.1 (COCH3), 21.2 (COCH3), 51.2
1-H), 7.28 (s, 5 H, 5ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ
(C-5), 58.2 (C-3), 60.7 (C-8a), 66.9 (C-2), 67.9 (C-6), 68.1 (C-8),
= 26.2 (CH3 ), 26.7 (CH3 ), 54.4 (C-8), 63.8 (C-5), 67.8 77.7 (s, C-7, C-1), 168.7 (COCH3), 169.3 (COCH3), 169.6
(NCOOCH2Ph), 75.1 (C-7), 75.4 (C-6), 77.2 (C-3), 80.5 (C-4), 84.8
(C-2), 104.4 (C-1), 112.0 [(CH3)2C(O)2], 127.8 (s, 2ϫArC), 128.1
(ArC), 128.5 (s, 2 ϫ ArC), 135.8 (ArC), 157.5 (NCO) ppm. IR
(COCH ), 169.7 (COCH ), 170.0 (COCH ) ppm. IR (neat): ν =
˜
3 3 3
1743, 1210 cm–1. C18H25NO10 (415.39): calcd. C 52.05, H 6.07;
found C 52.04, H 6.06.
(neat): ν = 1685, 1232 cm–1. C H NO (395.40): calcd. C 57.71,
˜
19 25
8
(1R,2R,6S,7R,8R,8aS)-1,2,6,7,8-Pentaacetoxyindolizidine (12b):
Acetic anhydride (0.11 mL, 1.21 mmol) and a catalytic amount of
4-(dimethylamino)pyridine were added to an ice-cooled solution of
6h (0.02 g, 0.10 mmol) in dry pyridine (1 mL). The reaction mixture
was stirred at room temperature for 6 h. Ice water (5 mL) was
added and the system was extracted with chloroform (3ϫ10 mL).
Usual workup and chromatographic purification (n-hexane/ethyl
acetate, 3:2) afforded the pentaacetate 12b (0.04 g, 86%) as a thick
liquid. Rf = 0.44 (n-hexane/ethyl acetate, 4:6). [α]D = –0.2 (c = 0.25,
H 6.37; found C 57.48, H 6.22.
(1S,2S,6S,7R,8R,8aS)-1,2,6,7,8-Pentahydroxyindolizidine (6g): A
solution of 11a (0.04 g, 0.11 mmol) in TFA/H2O (3 mL, 2:1) was
stirred at 20 °C for 3 h. Trifluoroacetic acid was co-evaporated with
benzene to furnish a thick liquid. Pd-C (10%, 0.05 g) was added to
a solution of the above product in methanol (5 mL). The solution
was hydrogenated at 80 psi for 24 h. The catalyst was filtered
through a celite bed and washed with methanol (15 mL). The fil-
trate was concentrated, and on column purification afforded 6g
as a crystalline solid (0.018 g, 91%), m.p. 163–165 °C. Rf = 0.20
(chloroform/methanol, 4:6). [α]D = +2.1 (c = 1.93, MeOH). 1H
NMR (300 MHz, D2O): δ = 2.86 (br. d, J = 11.0 Hz, 1 H, 5-Ha),
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 2.04 (s, 3 H, COCH3),
2.06 (s, 3 H, COCH3), 2.09 (s, 6-H, 2ϫCOCH3), 2.10 (s, 3 H,
COCH3), 2.50 (dd, J = 2.7, 12.9 Hz, 1 H, 5e-H), 2.58 (dd, J = 2.2,
8.8 Hz, 1 H, 8a-H), 2.75 (dd, J = 7.7, 11.0 Hz, 1 H, 3a-H), 3.10 (t,
J = 11.0 Hz, 2 H, 3e-H, 5a-H), 4.85 (narrow multiplet, WH
=
3.11–3.36 (m, 2 H, 3a-H, 3b-H), 3.44 (narrow multiplet, WH
=
5.4 Hz, 1 H, 6-H), 4.90 (narrow multiplet, WH = 5.4 Hz, 1 H, 8-
H), 5.02 (narrow multiplet, WH = 5.4 Hz, 1 H, 7-H), 5.08 (ddd, J
= 1.6, 4.1, 7.7 Hz, 1 H, 2-H), 5.25 (dd, J = 4.1, 8.8 Hz, 1 H, 1-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.8 (s, 2ϫCOCH3),
20.9 (COCH3), 21.0 (COCH3), 21.3 (COCH3), 51.9 (C-5), 58.9 (C-
3), 63.4 (C-8a), 65.5 (C-2), 66.2 (C-6), 67.1 (C-8), 75.5 (C-7), 75.6
(C-1), 168.1 (COCH3), 169.7 (COCH3), 169.8 (s, 2 ϫCOCH3),
16.4 Hz, 1 H, 8a-H) 3.70–3.84 (m, 2 H, 5-Hb, 2-H), 3.91 (t, J =
5.2 Hz, 1 H, 7-H), 4.22 (s, WH = 13.7 Hz, 1 H, 8-H), 4.27–4.32 (m,
1 H, 6-H), 4.35 (d, J = 4.1 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz,
D2O): δ = 54.9 (C-3), 60.0 (C-5), 63.2 (C-6), 67.8 (C-8a), 69.1 (C-
2), 69.8 (C-8), 74.7 (C-1), 77.7 (C-7) ppm. IR (KBr): ν = 3400–
˜
3600 (br. band) cm–1. C8H15NO5 (205.21): calcd. C 46.82, H 7.37;
found C 46.68, H 7.27.
170.6 (COCH ) ppm. IR (neat): ν = 1740, 1218 cm–1. C H NO
˜
3
18 25
10
(1R,2R,6S,7R,8R,8aS)-1,2,6,7,8-Pentahydroxyindolizidine (6h): A
solution of 11b (0.05 g, 0.12 mmol) in TFA/H2O (3 mL, 2:1) was
stirred at 25 °C for 2.5 h. Trifluoroacetic acid was co-evaporated
with benzene to furnish a thick liquid. Pd-C (10%, 0.05 g) was
added to a solution of the above product in methanol (5 mL). The
solution was hydrogenated at 80 psi for 24 h. The catalyst was fil-
tered through a celite pad and washed with methanol (15 mL). The
filtrate was concentrated to give a thick light brown liquid of 6h
(0.02 g, 80%). Rf = 0.30 (chloroform/methanol, 4:6). [α]D = +40.0
(c = 0.01, MeOH). 1H NMR (300 MHz, D2O): δ = 3.04–3.18 (m, 2
H, H5a, 3a-H), 3.22–3.40 (m, 3 H, 3b-H, 5b-H, 8a-H), 4.00 (narrow
(415.39): calcd. C 52.05, H 6.07; found C 51.80, H 6.00.
General Procedure for Inhibition Assay: The inhibition potencies of
6g and 6h were determined by measuring the residual hydrolytic
activities of the glycosidases.[16] Substrates purchased from Sigma
Chemicals Co., USA – namely p-nitrophenyl α--glucopyranoside
and p-nitrophenyl β--glucopyranoside – of 2 m concentration
were prepared in 0.025  citrate buffer of pH 6.0. p-Nitrophenyl α-
-mannopyranoside (2 m) was prepared in 0.025  citrate buffer
of pH 4.0. The test compound was preincubated with the appropri-
ate enzyme buffered at the optimal pH for 1 h at 25 °C. The enzyme
reaction was initiated by the addition of substrate (100 µL). Con-
trols were run simultaneously in the absence of test compound. The
reaction was terminated at the end of 10 min by the addition of
borate buffer (0.05 , pH 9.8), and absorbance of the liberated p-
nitrophenol was measured at 405 nm with a Shimadzu Spectropho-
tometer UV-1601. One unit of glycosidase activity is defined as the
amount of enzyme that hydrolysed 1 µmol of p-nitrophenyl pyrano-
side per minute at 25 °C. Xylanase assay was carried out at pH 6.0
by mixing a 2 µ concentration of the enzyme with 0.5 mL of oat
spelt xylan (10 mgmL–1) in a reaction mixture of 1 mL and incu-
bation at 50 °C for 30 min, with the reducing sugar released being
determined by the dinitrosalicylic method.[16b] One unit of xylanase
multiplet, WH = 7.8 Hz, 1 H, 6-H), 4.07 (narrow multiplet, WH
=
5.8 Hz, 2 H, 8-H, 7-H) 4.24 (dd, J = 4.1, 13.2 Hz, 1 H, 2-H), 4.31–
4.35 (m, 1 H, 1-H) ppm. 13C NMR (100 MHz, D2O): δ = 53.7 (C-
5), 59.5 (C-3), 66.7 (C-6/C-2), 66.8 (C-6/C-2), 68.0 (C-8/C-8a), 68.1
(C-8/C-8a), 74.7 (C-7), 76.1 (C-1) ppm. IR (Nujol): ν = 3410–3600
˜
(br. band) cm–1. C8H15NO5 (205.21): calcd. C 46.82, H 7.37; found
C 46.68, H 7.15.
(1S,2S,6S,7R,8R,8aS)-1,2,6,7,8-Pentaacetoxyindolizidine (12a):
Acetic anhydride (0.09 mL, 1.01 mmol) and catalytic 4-(dimeth-
ylamino)pyridine were added to an ice-cooled solution of 6g
(0.02 g, 0.10 mmol) in dry pyridine (1 mL). The reaction mixture
was stirred at room temperature for 6 h. Ice water (5 mL) was activity is defined as the amount of enzyme that produced 1 µmol
4900 Eur. J. Org. Chem. 2007, 4895–4901
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Glycosidase Inhibitory Studies
D. D. Dhavale, Tetrahedron Lett. 2005, 45, 8363–8366; d) D. D.
Dhavale, S. D. Markad, N. S. Karanjule, J. PrakashaReddy, J.
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under assay conditions.
Supporting Information (see also the footnote on the first page of
this article): This include 1H NMR and 13C NMR spectra of com-
pounds 6g, 6h, 8, 10a, 10b, 11a, 11b, 12a and 12b.
Acknowledgments
We are thankful to Dr. Malarao, Head, Biochemical division, and
Dr. V. P. Vinod of the National Chemical laboratory (NCL), Pune
for carrying out glycosidase inhibitory activity studies of our target
molecules. We are grateful to Prof. M. S. Wadia and Dr. K. G. Mar-
athe for helpful discussions. AKKS is thankful to the Council of
Scientific and Industrial Research (CSIR), New Delhi for a Re-
search Fellowship. We gratefully acknowledge the University
Grants Commission (UGC), New Delhi for the grant to purchase
a high-field (300 MHz) NMR spectrometer.
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[11] The NMR spectra of the dihydroxylated products 9a/9b were
very difficult to characterize, due to the doubling of signals as
a result of non-homogeneity in the N–CO bond of the urethane
functionality.
[12] The mother liquor contained 9a and 9b in a 3:7 ratio.
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[15] As a result of delocalization of the lone pair of electrons on
nitrogen bearing the carbonyl group (Cbz) the bulky substitu-
ents (CH2Ph and OCH2Ph) at the nitrogen and carbon orient
syn to each other. The syn orientation of the substituents is
possibly due to the stabilization arising from π-stacking of the
phenyl groups. The presence of two distinct isomers of the con-
jugated ester as a result of delocalization is evident from the
1H NMR spectrum, which showed an isomeric ratio of 58:42.
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Received: May 22, 2007
Published Online: August 8, 2007
Eur. J. Org. Chem. 2007, 4895–4901
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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