Synthesis of sugar-derived spiroaminals via lactamization and metathesis reactions

Article abstract of DOI:10.1039/c0ob00555j

A series of sugar-derived spiroaminals has been synthesized by utilizing cross metathesis, ring closing metathesis and lactamization reactions as key steps from 1-C-alkylated glycosyl azides and important correlations in the spectral data between spiroami

Full text of DOI:10.1039/c0ob00555j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of sugar-derived spiroaminals via lactamization and metathesis
reactions†
Adabala Pal John Pal, Parasuraman Kadigachalam, Asadulla Mallick, Venkata Ramana Doddi and
Yashwant D. Vankar*
Received 9th August 2010, Accepted 12th October 2010
DOI: 10.1039/c0ob00555j
A series of sugar-derived spiroaminals has been synthesized by utilizing cross metathesis, ring closing
metathesis and lactamization reactions as key steps from 1-C-alkylated glycosyl azides and important
correlations in the spectral data between spiroaminals and their respective anomers are reported.
The D-glucopyranose analogue of hydantocidin,3 compound 2
(Fig. 1), is the most powerful inhibitor of glycogen phosphory-
lase (GP), and glucopyranosyl spirodiketopiperazine 3 has been
shown to be a highly specific inhibitor of GP. The anomeric
Introduction
Spiroaminals, also called oxa-aza spirobicyclic frameworks,
spiroaminoketals or spiro-N,O-ketals, are substructures present
spironucleosides,4 which were synthetic derivatives of psiconucle-
osides, were also an important class of spiroaminals for structure–
activity relationship studies. Because of their pharmacological
importance, together with intrinsic complexity in the construction
and the novelty of their frameworks, we planned to synthesize
sugar-derived spiroaminals as potentially biologically important
fused sugars.
The synthesis of sugar-derived oxa-aza spirobicycles, were
reported by Suarez et al.5 and Compain et al.,6 who used an
intramolecular hydrogenabstraction as akeystepinthe promotion
of the cyclisation. In their synthesis, the spiroaminal precursors,
viz. C-glycosyl amines, were synthesized in a multistep process.
We have devised a new strategy, in which we have utilized 1-
C-alkyl glycosyl azides as spiroaminal precursors and mainly
used two main pathways (Scheme 1), viz. reduction of azide,
followedbyspontaneous lactamization andring closing metathesis
reaction for the construction of core oxa-aza spirobicycles. In
our previous communication,7 we reported the 6,5-fused sugar-
derived spiroaminals as glycosidase inhibitors from the azido
esters obtained via the nucleophilic substitution reactions of
unstable Michael adducts derived from 1-nitrosugars. Because of
the significant inhibition activity of spiroaminals, we report herein
a full account of the synthesis of a series of spiroaminals and also
provide some interesting spectral correlations between anomeric
spiroaminals.
in a number of biologically active compounds, viz. marineosins
A and B,1a,b that show significant inhibition of human colon
carcinoma (HCT-116, IC50 = 0.5 mM), crambescidin natural
products,1c that display nanomolar cytotoxicities against several
tumor cell lines, pandamarilactone,1d marine toxin azaspiacids,1e
and immunosuppressant sanglifehrin.1f,g Not only these spiroam-
inals, but the sugar-derived spiroaminoketals or spironucleosides
have gained considerable importance with the discovery of hy-
dantocidin 1 (Fig. 1). Hydantocidin 1 is a natural spiroami-
nal, which was isolated from Streptomyces hygroscopicus and
has unique structural features, that is, a spirohydantoin ring
at the anomeric position of D-ribofuranose. Because of the
unique structural features, potent herbicidal and plant growth
regulatory activities of hydantocidin 1, several reports2 have
appeared for its synthesis and also a wide range of analogues.
Fig. 1 Some important sugar-derived spiroaminal frameworks.
Department of Chemistry, Indian Institute of Technology, Kanpur, 208 016,
India. E-mail: vankar@iitk.ac.in; Fax: +91-512-259 0007; Tel: +91-512-
2597169
† Electronic supplementary information (ESI) available: Copies of 1H
NMR, 13C NMR spectra for all new compounds, and 2D-COSY,
NOE, DEPT-135 spectra of some selected compounds. See DOI:
10.1039/c0ob00555j
Scheme 1 Strategies used to construct the spiroaminals.
Org. Biomol. Chem., 2011, 9, 809–819 | 809
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 2 Synthesis of 6,5-fused bicyclic spirolactams.
first reduced3a to a free amine which undergoes tautomerization
accompanied by pyranose ring opening to form a species having
a free alcohol and an imine B (Scheme 3). Reclosure to form
the pyranose ring leads to two anomeric amines A, C each of
which cyclizes leading to two spiroaminals, viz. 11a and 11b. The
formation of 11a and 11b was confirmed through their spectral
Results and discussion
For the synthesis of 6,5-fused spiroaminals, we chose to utilize
the chemistry of anomeric nitrosugars.8 The required glycosyl
azido esters 9 and 10 were prepared (Scheme 2) from nitrosugars
5 and 6 using our earlier developed method.7 To convert 1-C-
alkyl-1-azido sugars into spirolactams, we studied their reductions
under different conditions. There are only a few reports9 in
the literature regarding the reduction of C-glycosylated-1-azido
sugars. Our initial attempts for the reduction of azide 9 with PPh3
along with H2O10 and Zn-AcOH9a conditions were unsuccessful.
Treatment of ester 9 with Zn-AcOH at room temperature gave
a complex mixture, which is not surprising as earlier reports9a
for the reduction of anomeric azides with Zn-AcOH have led
to N,O-acetals in lower yields. Dondoni et al.9d have reported
the reduction of C-glycosylated-1-azido sugars with Pd/C–H2 in
tBuOH·H2O, and the use of these conditions in the reduction of
9 led to a mixture of products. To overcome these problems we
chose to utilize Pd/CaCO3 as a catalyst11 for the reduction of such
azides. Thus, the treatment of azide 9 with Pd/CaCO3 in EtOH
in the presence of H2 (1 atm) at room temperature afforded the
spiroaminals 11a and 11b (Scheme 2) in 1 : 1 ratio and in 78%
yield. It is likely that under these conditions the azide group gets
1
analysis. Thus, H NMR spectra of 11a and 11b showed –NH
protons as singlets at d 6.94 and 5.92 and IR spectra showed
Scheme 3 Anomerization of glycosyl amine for the formation of
anomeric spiroaminals 11a and 11b.
810 | Org. Biomol. Chem., 2011, 9, 809–819
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 4 Synthesis of 6,6-fused bicyclic spirolactams.
the carbonyl group frequency at 1701 and 1705 cm-1, respectively.
Likewise, reduction of the mannose-derived azido ester 10 in the
presence of Pd/CaCO3 gave a 2 : 1 ratio of products 12a and 12b
in 83% yield.
cross metathesis14 reaction. Thus, the cross metathesis reaction of
allyl azide 19 with methyl acrylate in the presence of 5 mol% of
Grubbs’ second generation catalyst D produced trans azido olefin
1
21 in quantitative yield. The H NMR spectrum of 21 showed
These benzylated spirolactams 11a, 11b, 12a, and 12b were
deprotected using Pd/C in EtOH in the presence of H2 (1 atm)
at room temperature to afford fully deprotected spirolactams 13a,
13b, 14a and 14b, respectively, in quantitative yields, whose struc-
tures were confirmed by the spectral analysis of the corresponding
acetates obtained from acetylation with Ac2O/Py (Scheme 2).
Interestingly, while compound 13b produced a pentaacetate 15b,
other compounds 13a, 14a and 14b gave the tetraacetates 15a, 16a,
and 16b, respectively. All these compounds were characterized by
1H, 13C NMR and COSY spectral data.12
After the successful synthesis of 6,5-fused spiroaminals, our
synthetic plan focused on the construction of 6,6-fused spiroam-
inals. For this purpose we chose D-glucono-1,5-lactone 17 and
D-galactono-1,5-lactone 18 as the starting materials. According to
the literature procedures,13 we have prepared allyl azides 19 and
20 from allyl Grignard addition on lactones 17 and 18, followed
by azidation of the obtained hemiketals (Scheme 4). In order
to extend the aglycon part carbon chain of allyl azides 19 and
20 to construct the 6-membered aza-cycles, we have utilized the
olefinic protons at d 6.94 and d 5.85 with coupling constant J =
15.8 Hz, clearly indicating the trans olefin formation. Similarly,
cross metathesis reaction of allyl azide 20 gave trans azido ester
22 in 78% yield and with 84% conversion. Reduction of the azide
group in azido ester 21 using Pd/CaCO3 in MeOH in the presence
of H2 (1 atm), followed by heating of the crude amine in MeOH at
60 ◦C gave a mixture of spirolactams 23a and 23b in 1 : 1.5 ratio.
Similarly, reduction of azide 22 also gave a mixture of spiroaminals
24a and 24b in 3 : 1 ratio. The global debenzylation of all these
lactams was carried out using Pd(OH)2 in MeOH in the presence
of an H2 (5 psi) atmosphere. Thus, the spirolactams 23a, 23b and
24a successfully produced the hydroxy lactams 25a, 25b and 26a,
respectively. Further, the structures of these hydroxy lactams were
confirmed through their acetates 27a, 27b and 28a, obtained from
the acetylation of aminals 25a, 25b and 26a in the presence of Ac2O
and Py. All these compounds were characterized by 1H, 13C-NMR,
COSY and nOe spectroscopic data.
We also investigated an alternative method for the synthesis
of 6,6-fused spiroaminals (Scheme 5) via ring closing metathesis
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 809–819 | 811
©

View Article Online
Scheme 5 Ring closing metathesis approach for the synthesis of 6,6-fused bicyclic spirolactams.
(RCM). Our attempts to procure the metathesis precursors 32a
and 32b by selective reduction of azide in the presence of a double
bond using the hydrogenation reaction of allyl azide 19 in the
presence of Lindlar catalyst (poisoned with Pb) were unsuccessful
and afforded the N,O-acetal 29 via saturation of the double bond.
However, after examination of different reaction conditions, we
finally obtained the desired aminal 31 upon treatment of the allyl
azide 19 with Zn in MeOH in the presence of NH4Cl.15 The
acroylation reaction of crude amine 31 with acryloyl chloride
furnished the anomeric aminals 32a and 32b in 12 : 1 ratio
in 67% overall yield. The ring closing metathesis reaction of
dienes 32a and 32b using Grubbs’ second generation catalyst D
successfully produced spirolactams 33a and 33b in 91% and 82%
yield, respectively, whose structures were confirmed through their
spectral analysis. Thus, the 1H NMR spectrum of compound 33a
showed characteristic peaks of –NH at d 6.81 as a singlet and
olefinic protons at d 6.55–6.53 and d 5.94 as a multiplet and a
doublet (J = 9.9 Hz), respectively. The global debenzylation along
with saturation of the double bond of 33a and 33b using Pd(OH)2
in MeOH in the presence of H2 (1 atm) afforded fully deprotected
spirolactams 25a and 25b in good yields. The advantage of this
RCM route is that we can get 6,6-fused a-spiroaminal with high
diastereoselectivity.
formation required harsh basic and heating conditions.16 To
overcome these problems in the construction of larger aza-cycles
and due to the above success (Scheme 5), we chose only the
ring closing metathesis approach for the synthesis of 6,7-fused
spiroaminals.
In order to construct the 7-membered aza-cycle at the anomeric
center, the required key intermediate, butenyl glycosyl azide 35
was prepared from benzylated lactone 17. Thus, addition of four
equivalents of vinyl magnesium bromide onto lactone 17 produced
hemiketal 34 in 81% yield.17 The glycosylation of ketose 34 using
TMSN3 in presence of TMSOTf in CH3CN furnished the required
butenyl glycosyl azide35 in 86% yield (Scheme 6). The IR spectrum
of compound 35 showed an intense peak at 2218 cm-1 and the four
1
methylene protons as multiplets at d 2.19–1.90 in its H NMR
spectrum clearly indicating the formation of the product. The
reduction of the glycosyl azide 35 with Zn in presence of NH4Cl,
followed by the acroylation reaction of crude amine with acryloyl
chloride provided inseparable anomeric aminals 36 in 52% overall
yield. Subsequent subjection of the mixture of aminals 36 to RCM
reaction using Grubbs’ second generation catalyst D, in refluxing
methylene chloride, afforded spiroaminals 37a and 37b in 3 : 1 ratio
in 84% yield (Scheme 6). The isomers were separated by column
chromatography and their structures were confirmed through
1
Next we turned our attention to synthesize 6,7-fused spiroam-
inals. Earlier we had observed spontaneous lactamization (in-
tramolecular amine-ester cyclisation) at room temperature in
the construction of 6,5-fused spiroaminals (Scheme 2). But in
the case of 6,6-fused spiroaminals, spontaneous lactamization
was not observed, the lactamization reactions took longer time
(7–8 days) at room temperature, whereas they took 2–3 days
(Scheme 4) at higher temperatures. In general, 7-membered lactam
spectral analysis. Thus, the H NMR spectrum of spirolactam
37b showed the –NH proton appearing at d 6.21 as a singlet,
whereas internal olefinic protons appeared at d 6.36–6.33 and
5.92 as a multiplet and a doublet, respectively. The debenzylation
and saturation of double bonds of spirolactams 37a and 37b with
Pd(OH)2 in MeOH in the presence of H2 (1 atm) gave the fully
deprotected spiroaminals 38a and 38b in quantitative yields. For
the structural confirmation, these free hydroxy compounds 38a
812 | Org. Biomol. Chem., 2011, 9, 809–819
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 6 Synthesis of 6,7-fused bicyclic spirolactams.
and 38b were converted into their acetyl derivatives 39a and 39b
using Ac2O/Py.
The 1H NMR, 2D-COSY and nOe experiments helped to
unambiguously establish the configurations of the newly gener-
ated anomeric center (spiroaminal center) in all the synthesized
spirolactams. To assign the stereochemistry at the anomeric
center, initially we examined the conformation of the pyranose
ring by spectral studies of the all acetylated derivatives. In the
case of glucose-derived spiroaminals 15a, 15b, 27a, 27b, 39a
During these studies it was observed that the glycosyl azido-
alkene 35 was unstable and was easily converted to a new sugar-
derived spiroiminal 40 (Scheme 7), even in the NMR tube in
CDCl3, by merely keeping it at room temperature. The column
chromatography of the crude product gave the spiroiminal 40 as a
major isolable product in 55% yield. The formation of the product
could be explained based on Huisgen intramolecular 1,3-dipolar
cycloaddition18 between the azide and olefin of 35 followed by
the loss of nitrogen from 42 or from the corresponding diradical,
furnishing spiroiminal 40, which was found as a core structure of
biologically active natural products, marineosins A and B.1a–b The
extension of this work is currently in progress.
and 39b, the large coupling constants for J2,3, J3,4 and J4,5
>
9.5 Hz along with positive nOe observations between H-2/H-4
4
unambiguously established the C1 chair conformation19 of the
pyranose ring in these spiroaminals (Fig. 2).12 In case of mannose-
derived spiroaminals 16a and 16b, the large coupling constants
for J7,8 and J8,9 = 10.4 Hz and coupling constant between axial-
equatorial protons, J9,10 = 3.05 Hz with interproton nOe effects
4
between H-7/H-9 clearly established the C1 chair conformation
of the pyranose ring.12 In a similar manner, in galactose-derived
Fig. 2 nOe observations and vicinal proton coupling constants of
compounds 39a and 27b.
Scheme 7 Intramolecular [2 + 3] cycloaddition of azidoolefin 35.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 809–819 | 813
©

View Article Online
mimicking glycosidase inhibitors have been developed.22–24 As part
of our ongoing programme towards the design, synthesis and
biological evaluation of novel carbohydrate entities such as hybrid
sugars,25 iminosugars26and aminocyclitols,27 we became interested
in exploring the glycosidase inhibitory activities of the hydroxy
spiroaminals reported in the present study. Thus, the inhibitory
activities of compounds 13a, 13b, 14a, 14b, 25a, 25b, 26a, 38a and
38b were tested against a few commercially available enzymes.28
However, these molecules showed poor inhibition toward all tested
enzymes.29 But, it is possible that structural variations of these
molecules may improve the activity and selectivity of inhibition.
Table 1 Spectroscopic correlations between a- and b-spirolactams
1H NMR (ppm)
–NH chemical shift
13C NMR (ppm)
anomeric carbon
S. No
Compound
1
2
3
4
5
6
7
8
23a
23b
24a
24b
27a
27b
11a
11b
16a
16b
33a
33b
37a
37b
6.48
6.01
6.51
5.92
6.94
6.43
6.93
5.92
8.9
85.9
87.4
86.5
88.7
85.1
86.6
91.8
92.4
90.7
90.4
86.1
87.9
84.8
85.5
9
10
11
12
13
14
6.5
6.81
5.85
6.41
6.28
Conclusions
In conclusion, we have successfully synthesized a series of
spiroaminals from 1-C-alkyl-1-azido sugars. The synthesis of these
spirolactams was achieved in two main pathways, viz. reduction
of azide, followed by spontaneous lactamization, and ring closing
metathesis reaction to construct the core oxa-aza spirobicycles.
For the synthesis of 6,5-fused spiroaminals, the precursors, azido-
esters, were prepared from 1-nitrosugars, and the precursors for
the synthesis of 6,6 and 6,7-fused spiroaminals were prepared
from sugar-derived d-lactones. Because of the occurrence of
spiroaminal frameworks in natural products of pharmacological
importance, we studied the enzyme inhibition activities of hydroxy
spiroaminals. Further work to extend the scope of the study is in
progress.
spiroaminals 24a and 24b, the large coupling constant for J4,5
>
10.0 Hz and coupling constants between axial-equatorial protons
4
J2,3 and J3,4 < 3.0 Hz confirmed the C1 chair conformation of
their pyranose ring.
In glucose-derived 6,7-fused spiroaminal 39a, irradiation of the
–NH proton signal at d 6.12 enhanced the H-2 proton signal
at d 4.0 and the H-4 proton signal at d 5.24 (2.8% and 11.2%
nOe, respectively, Fig. 2), clearly indicating the axial orientation
of the –NH position in compound 39a. Similarly, we confirmed
the stereochemistry of spiroaminals 15a, 16a, 27a, 24a and 33a as
isomers having the –NH group in the axial position. In the case of
compound 27b, irradiation of the –NH proton at d 6.43 enhanced
only the H-5 proton signal at d 4.97 (14.0% nOe) and irradiation
of the H-2 proton signal at 3.77 enhanced the H-11 proton signal
at d 2.24 and the H-4 proton signal at d 5.32 (9.5% and 4.0%
nOe, respectively, Fig. 2). These results clearly indicated that the
–NH group in spiroaminal 27b was in the equatorial orientation.
In a similar manner the stereochemistry of the anomeric center
of spiroaminals 15b, 16b, 24b, 39b and 33b were also confirmed
as isomers with the –NH group in the equatorial position (see the
ESI†).
An interesting spectral difference was observed between
spiroaminals and their respective anomers. In general, the
spiroaminals, having the –NH group in the axial orientation,
showed the –NH proton chemical shifts at slightly lower fields, and
in their 13C-NMR spectra, anomeric carbon chemical shifts were
observed at slightly higher fields than their respective anomers.
Thus, compound 23a showed the –NH proton as a singlet at d
6.48 and the anomeric carbon peak at d 85.9 ppm. But in the case
of its anomer, viz. compound 23b, the –NH proton peak appeared
at d 6.01 and the anomeric carbon peak at d 87.4. Likewise,
the remaining pairs of anomers showed a similar pattern in
their spectral data. It appears that the stereoelectronic differences
between the anomers directly reflect a regular pattern in spectral
data, from which one can easily predict the stereochemistry of
these spirolactams. These results are summarized in Table 1.
Because of the potential therapeutic applications of glycosidase
inhibitors, in recent years great effort has been made, not only in
the synthesis of naturally occurring glycodiase inhibitors but also
their chemically modified analogues,20 and there are a number of
drugs currently in the market which are used in the treatment
of several diseases.21 As a result, numerous classes of sugar-
Experimental
Infrared spectra were recorded on a Bruker FT/IR Vector 22
spectrophotometer. 1H and 13C NMR spectra were recorded on a
JEOL LA-400 (400 and 100 MHz, respectively) spectrometer or a
JEOL ECX-500 spectrometer (500 and 125 MHz, respectively)
in solutions of CDCl3 using tetramethylsilane as the internal
standard. The mass spectra were recorded on a Waters HAB
213 Q Tof Premier Micromass spectrometer. Optical rotations
were recorded on an Autopol II automatic polarimeter at the
wavelength of sodium D-line (589 nm) at 28 ◦C. Column chro-
matography was performed on silica gel (100–200 mesh) and thin
layer chromatography (TLC) was performed on silica gel plates
made by using grade G silica gel obtained from s.d.fine-chem Ltd.,
Mumbai or on Merck silica gel pre-coated plates. All solvents and
common reagents were purified by established procedures.
General procedure (A). Deprotection of benzyl groups. The
benzyl-protected spiro sugar (0.1 mmol) was dissolved in 2 mL of
MeOH and 20% Pd(OH)2/C (50 mg) was added to it. The reaction
mixture was stirred under 1 atm or 5 psi H2 pressure for 3–4 days
at room temperature. The catalyst was filtered off through Celite,
and concentrated in vacuo to obtain polyhydroxylated spirosugars.
General procedure (B). Acetylation of hydroxy spiro sugars.
Polyhydroxy spiro sugar derivative (20 mg) in acetic anhydride (0.5
mL) and pyridine (0.5 mL) in the presence of a catalytic amount
of DMAP was stirred for 24 h at room temperature. The reaction
mixture was dissolved in CH2Cl2 (3 ¥ 10 mL) and washed with
water (5 mL) and brine (3 mL), dried with MgSO4, concentrated
in vacuo, and purified by silica gel chromatography to give the pure
acetylated spiro sugars.
814 | Org. Biomol. Chem., 2011, 9, 809–819
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(E)-Methyl4-((2S,3R,4S,5R,6R)-2-azido-3,4,5-tris(benzyloxy)-
6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)but-2-enoate (21).
To a solution of azide 19 (100 mg, 0.163 mmol) in anhydrous
CH2Cl2 (3 mL) under N2 atmosphere, was added methyl acrylate
(44 mL, 0.489 mmol, 3 equiv.). Grubbs’ catalyst D (7.0 mg,
0.016 mmol, 0.05 equiv.) was added and the mixture was
heated at 40 ◦C. After 2 h, the solvent was evaporated under
reduced pressure. Purification of the residual product by silica
gel chromatography (AcOEt–petroleum ether) afforded azido
ester 21 (108 mg, quantitative) as a colourless oil. Rf: 0.4
(hexane–ethyl acetate, 9 : 1), [a]2D8 = +61.0 (c 1.0, CH2Cl2). IR
(neat) nmax: 3030, 2920, 2863, 2119, 1724, 1453, 1273, 1090, 735,
697 cm-1.1H NMR (500 MHz, CDCl3): d 7.36–7.19 (m, 20H,
Ar-H), 6.94–6.88 (m, 1H, CH CHCO2Me), 5.83 (d, 1H, J =
15.8 Hz, CH CHCO2Me), 4.95 (d, 1H, J = 11.3 Hz, PhCH),
4.91 (d, 1H, J = 10.6 Hz, PhCH), 4.86–4.82 (m, 2H, 2 ¥ PhCH),
4.65 (d, 1H, J = 11.3 Hz, PhCH), 4.63–4.59 (m, 2H, 2 ¥ PhCH),
4.52 (d, 1H, J = 12.0 Hz, PhCH), 3.99 (t, 1H, J = 9.2 Hz), 3.88
(dd, 1H, J = 1.4, 9.6 Hz), 3.77 (dd, 1H, J = 3.4, 11.0 Hz), 3.71–3.67
(m, 2H), 3.70 (s, 3H, –OCH3), 3.48 (d, 1H, J = 9.3 Hz), 2.83 (dd,
1H, J = 6.9, 14.7 Hz), 2.73 (dd, 1H, J = 7.9, 14.7 Hz). 13C NMR
(125 MHz, CDCl3): d 166.3, 141.4, 138.3, 138.2, 138.0, 137.7,
128.6–127.8 (m, Ar-C), 125.3, 93.2, 83.7, 81.6, 77.7, 75.8, 75.5,
75.2, 74.0, 73.5, 68.3, 51.7, 38.4. HRMS calcd for C39H41N3O7 [M
+ Na]+ 686.2842, Found: 686.2846.
Ar-H), 6.48 (s, 1H, –NH), 4.93 (d, 1H, J = 11.3, PhCH). 4.87–4.79
(m, 3H, 3 ¥ PhCH), 4.68 (d, 1H, J = 11.3 Hz, PhCH), 4.60–4.57
(m, 2H, 2 ¥ PhCH), 4.50 (d, 1H, J = 12.0 Hz, PhCH), 3.77–3.70
(m, 3H), 3.63–3.59 (m, 2H), 3.45 (d, 1H, J = 9.2), 2.47–2.43 (m,
1H), 2.32–2.25 (m, 1H), 2.12–2.09 (m, 1H), 1.87 (dt, 1H, J = 4.4,
13.0), 1.76–1.68 (m, 2H). 13C NMR (125 MHz, CDCl3): d 173.5,
138.0, 137.7, 128.5–127.5 (m, Ar-C), 85.9, 82.9, 82.0, 78.0, 75.6,
74.7, 73.3, 71.3, 68.5, 31.6, 30.9, 15.7. HRMS calcd for C39H41N3O7
[M + Na]+ 686.2842, Found: 686.2840, calcd [M + H]+ 608.3012,
Found: 608.3018.
(2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undecan-8-one (23b). 124 mg, Yield: 53%,
oil, Rf: 0.3 (hexane–ethyl acetate, 3 : 2), [a]2D8 = -12.7 (c 0.55,
CH2Cl2). IR (neat) nmax: 3213, 2923, 2854, 1671, 1495, 1085, 737,
689 cm-1. 1H NMR (500 MHz, CDCl3): d 7.35–7.12 (m, 20H, Ar-
H), 6.01 (s, 1H, –NH), 4.88 (d, 1H, J = 11.0, PhCH). 4.83–4.72
(m, 4H, 4 ¥ PhCH), 4.60 (d, 1H, J = 12.0 Hz, PhCH), 4.53–4.50
(m, 2H, 2 ¥ PhCH), 3.74 (t, 1H, J = 9.2 Hz), 3.69–3.63 (m, 3H),
3.53–3.50 (m, 1H), 3.29 (d, 1H, J = 9.6 Hz), 2.46-2.43 (m, 1H),
2.31–2.24 (m, 1H), 2.04–1.96 (m, 2H), 1.89–1.87 (m, 1H), 1.77–
1.73 (m, 1H). 13C NMR (125 MHz, CDCl3): d 172.9, 138.7, 137.9,
137.6, 128.4–127.7 (m, Ar-C), 87.4, 84.4, 83.0, 77.9, 75.6, 75.0,
73.6, 73.0, 68.9, 31.7, 22.6, 15.6. HRMS calcd for C38H41NO6 [M
+ H]+ 608.3012, Found: 608.3019.
(2R,3S,4S,5R,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undecan-8-one (24a). A procedure similar
to that described for the synthesis of 23a and 23b was employed.
Spiroaminals 24a and 24b were obtained in 3 : 1 ratio (377 mg
from 510 mg, of 22, Yield: 80%). 24a: 283 mg, Yield: 60%, oil, Rf:
0.4 (hexane–ethyl acetate, 3 : 2), [a]2D8 = +40.7 (c 0.65, CH2Cl2). IR
(neat) nmax: 3230, 3063, 2924, 2854, 1662, 1496, 1495, 1454, 1396,
1082, 1026, 734, 697 cm-1.1H NMR (500 MHz, CDCl3): d 7.35–
7.26 (m, 20H, Ar-H), 6.51 (s, 1H, –NH), 4.99 (d, 1H, J = 11.6,
PhCH). 4.91 (d, 1H, J = 11.3 Hz, PhCH), 4.72 (d, 1H, J = 11.6,
PhCH), 4.69 (d, 1H, J = 11.7 Hz, PhCH), 4.64 (d, 1H, J = 11.7 Hz,
PhCH), 4.60 (d, 1H, J = 11.7 Hz, PhCH), 4.46–4.40 (ABq, 2H,
J = 11.7 Hz, PhCH2), 4.02 (d, 1H, J = 1.7 Hz, H-3), 3.89 (d, 1H,
J = 10.3 Hz, H-5), 3.77 (dd, 1H, J = 6.2, 7.5 Hz, H-2), 3.67 (dd,
1H, J = 2.7, 9.9 Hz, H-4), 3.58 (t, 1H, J = 8.9 Hz, CHaHbOBn),
3.45 (dd, 1H, J = 5.5, 8.9 Hz, CHaHbOBn), 2.42 (ddd, 1H, J = 2.7,
6.5, 9.3 Hz), 2.35–2.22 (m, 1H), 2.07–2.00 (m, 1H), 1.89 (td, 1H,
J = 4.8, 13.0 Hz), 1.76–1.72 (m, 1H), 1.75–1.60 (m, 1H). 13C NMR
(125 MHz, CDCl3): d 174.0, 138.6, 138.1, 137.9, 128.6–127.7 (m,
Ar-C), 86.5, 79.9, 78.6, 75.9, 74.7, 73.9, 73.5, 72.5, 69.9, 68.4,
31.7, 30.9, 15.6. HRMS calcd for C38H41NO6 [M + H]+ 608.3012,
Found: 608.3016.
(E)-Methyl4-((2S,3R,4S,5S,6R)-2-azido-3,4,5-tris(benzyloxy)-
6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)but-2-enoate (22).
A procedure similar to that described for the synthesis of 21 was
employed (oil, 170 mg from 200 mg, 0.327 mmol of 20; Yield: 77%).
Rf: 0.4 (hexane–ethyl acetate, 9 : 1), [a]2D8 = +59.5 (c 2.0, CH2Cl2). IR
(neat) nmax: 3088, 3063, 2920, 2867, 2118, 1724, 1659, 1605, 1435,
1273, 1101, 982, 736, 697 cm-1.1H NMR (500 MHz, CDCl3): d
7.35–7.25 (m, 20H, Ar-H), 6.96–6.90 (m, 1H, CH CHCO2Me),
5.83 (d, 1H, J = 14.4 Hz, CH CHCO2Me), 4.98–4.93 (m, 2H, 2 ¥
PhCH), 4.73 (d, 1H, J = 11.3 Hz, PhCH), 4.67 (d, 1H, J = 11.3 Hz,
PhCH), 4.64 (d, 1H, J = 11.3 Hz, PhCH), 4.58 (d, 1H, J = 11.6 Hz,
PhCH), 4.49–4.41 (ABq, 2H, J = 11.7 Hz, PhCH2), 4.01–3.93 (m,
3H), 3.90 (dd, 1H, J = 2.4, 9.6 Hz), 3.69 (s, 3H, -OCH3), 3.59 (dd,
1H, J = 7.6, 9.3 Hz), 3.54 (dd, 1H, J = 5.8, 9.3 Hz), 2.84 (ddd, 1H,
J = 1.7, 7.2, 9.3 Hz, C(HaHb) CHCO2Me), 2.71 (ddd, 1H, J =
1.4, 7.5, 8.9 Hz, C(HaHb) CHCO2Me). 13C NMR (125 MHz,
CDCl3): d 166.3, 141.6, 138.8, 138.1, 137.9, 137.9, 128.6–124.9
(m, Ar-C), 124.9, 93.8, 81.0, 78.3, 75.6, 74.5, 73.9, 73.6, 72.6, 72.5,
68.3, 51.6, 38.6. HRMS calcd for C39H41N3O7 [M + Na]+ 686.2842,
Found: 686.2840.
(2R,3R,4S,5R,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undecan-8-one (23a). To a solution of azido
ester 21 (250 mg, 0.105 mmol) in MeOH (4.0 mL) was added 5%
Pd/CaCO3 (125 mg). The reaction mixture was stirred for 3–4 h
under H2 (1 atm) at rt. The catalyst was filtered through Celite,
washed with EtOAc and the filtrate was concentrated. The crude
amine was dissolved in 5.0 mL of MeOH and heated at 60 ◦C
for 48 h. MeOH was evaporated and purification of the residual
product by silica gel chromatography afforded spiroaminals 23a
and 23b (1 : 1.5) in 89% yield. 23a: (83 mg, yield: 36%, oil) Rf:
0.4 (hexane–ethyl acetate, 3 : 2), [a]2D8 = +40.0 (c 0.75, CH2Cl2). IR
(neat) nmax: 3220, 3063, 2923, 2854, 1669, 1496, 1453, 1363, 1085,
735, 698 cm-1.1H NMR (500 MHz, CDCl3): d 7.34–7.16 (m, 20H,
(2R,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undecan-8-one (24b). 94 mg, Yield: 20%,
oil, Rf: 0.3 (hexane–ethyl acetate, 3 : 2), [a]2D8 = -8.67 (c 0.75,
CH2Cl2). IR (neat) nmax: 3224, 3062, 2923, 2854, 1671, 1453, 1366,
1087, 1025, 734, 697 cm-1.1H NMR (500 MHz, CDCl3): d 7.36–
7.25 (m, 20H, Ar-H), 5.92 (s, 1H, –NH), 4.94 (d, 1H, J = 9.3,
PhCH). 4.83 (d, 1H, J = 10.6 Hz, PhCH), 4.73–4.71 (m, 3H, 3
¥ PhCH), 4.59 (d, 1H, J = 11.3 Hz, PhCH), 4.46 (d, 1H, J =
11.7 Hz, PhCH), 4.40 (d, 1H, J = 11.6 Hz, PhCH), 3.94 (d, 1H,
J = 2.4 Hz, H-3), 3.74 (d, 1H, J = 10.0 Hz, H-5), 3.64 (dd, 1H, J =
2.7, 9.9 Hz, H-4), 3.61–3.57 (m, 2H, H-2, CHaHbOBn), 3.51(dd,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 809–819 | 815
©

View Article Online
1H, J = 4.1, 7.5 Hz, CHaHbOBn), 2.44–2.40 (m, 1H), 2.39–2.23
(m, 1H), 2.04–1.71 (m, 4H). 13C NMR (125 MHz, CDCl3): d 172.9,
138.6, 138.2, 138.0, 137.9, 128.5–127.6 (m, Ar-C), 88.1, 81.2, 80.6,
75.9, 74.8, 74.1, 73.7, 72.9, 72.0, 69.0, 31.9, 22.2, 16.1. HRMS
calcd for C38H41NO6 [M + H]+ 608.3012, Found: 608.3018.
20.7, 20.6, 20.5, 20.5, 15.0. HRMS calcd for C18H25NO10 [M + H]+
416.1557, Found: 416.1554.
(2R,3S,4S,5R,6S)-2-(Acetoxymethyl)-8-oxo-1-oxa-7-aza-spiro-
[5.5]undecane-3,4,5-triyltriacetate (28a). Yield: 71%. Rf: 0.40
(hexane–ethyl acetate, 1 : 4), [a]2D8 = +72.7 (c 0.55, CH2Cl2). IR
(neat) nmax: 3331, 2924, 2853, 1750, 1672, 1436, 1372, 1226, 1129,
1078 cm-1.1H NMR (500 MHz, CDCl3): d 7.59 (s, 1H, -NH),
5.44–5.41 (m, 2H), 5.29 (dd, 1H, J = 1.3, 12.0 Hz), 4.19–4.16 (m,
1H), 4.08–4.07 (m, 2H), 2.51–2.46 (m, 1H), 2.34–2.27 (m, 1H),
2.11–2.06 (m, 1H), 2.14 (s, 3H, COCH3), 2.07(s, 3H, COCH3),
2.02 (s, 3H, COCH3), 1.97 (s, 3H, COCH3), 1.97–1.94 (m, 1H),
1.75–1.62 (m, 2H). 13C NMR (125 MHz, CDCl3): d 173.8, 170.4,
170.3, 170.2, 169.9, 85.6, 69.4, 67.7, 67.2, 61.5, 31.8, 30.9, 20.7,
20.6, 20.5, 15.3. HRMS calcd for C18H25NO10 [M + H]+ 416.1557,
Found: 416.1551.
(2R,3S,4S,5R,6S)-3,4,5-Trihydroxy-2-(hydroxymethyl)-1-oxa-
7-azaspiro[5.5]undecan-8-one (25a). Yield: 85%, oil, [a]2D8 = +50.0
(c 0.4, MeOH). 1H NMR (500 MHz, D2O): d 3.7 (dd, 1H, J = 2.4,
12.0 Hz), 3.63 (t, 1H, J = 10.0 Hz), 3.58 (dd, 1H, J = 5.5, 12.3 Hz),
3.42–3.89 (m, 1H), 3.31–3.20 (m, 2H), 2.32–2.18 (m, 2H), 1.95–
1.87 (m, 2H), 1.67–1.63 (m, 2H). 13C NMR (125 MHz, D2O): d
178.0, 86.0, 74.4, 72.7, 72.5, 69.8, 60.7, 30.8, 30.4, 14.9. HRMS
calcd for C10H17NO6 [M + Na]+ 270.0954, Found: 270.0954.
(2R,3S,4S,5R,6R)-3,4,5-Trihydroxy-2-(hydroxymethyl)-1 - oxa-
7-azaspiro[5.5]undecan-8-one (25b). Yield: quantitative, oil,
1
[a]2D8 = +6.8 (c 1.35, MeOH). H NMR (500 MHz, D2O): d 3.68
N -((3R,4S,5R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-
propyltetrahydro-2H-pyran-2-yl)acetamide (30). To a solution of
azido olefin 19 (70 mg, 0.115 mmol) in EtOH (1.5 mL) was added
5% Lindlar’s catalyst (poisoned with Pb, 35 mg). The reaction
mixture was stirred for 15 h under H2 (1 atm) at rt. The catalyst
was filtered through Celite, washed with EtOAc and the filtrate was
concentrated. Acetylation of the crude amine 29 was carried out
conventionally using acetic anhydride and Et3N, to give glycosyl
acetamide 30. Yield: 72%, oil, Rf: 0.40 (hexane–ethyl acetate, 3 : 2),
[a]2D8 = +31.18 (c 0.85, CH2Cl2). IR (neat) nmax: 3328, 2924, 1672,
1538, 1372, 1496 cm-1.1H NMR (500 MHz, CDCl3): 2 : 1 ratio of
anomers: d 7.34–7.16 (m, 40H, Ar-H, both isomers), 5.93 (s, 1H,
–NH, major), 5.78 (s, 1H, –NH, minor), 4.97 (d, 1H, J = 10.3 Hz,
major), 4.89–4.52 (m, 15H, both isomers), 3.88 (dd, 1H, J = 2.7,
11.7 Hz, major), 3.83–3.59 (m, 11H, both isomers), 2.38–2.36 (m,
1H, major), 2.17–2.07 (m, 2H, both isomers), 1.96 (s, 3H, COCH3,
major), 1.92–1.85 (m, 1H, minor), 1.77 (s, 3H, COCH3, minor),
1.62–1.42 (m, 2H, both isomers), 1.35–1.15 (m, 2H, both isomers),
0.95 (t, 3H, J = 7.5, minor), 0.85 (t, 3H, J = 6.8 Hz, major). 13C
NMR (125 MHz, CDCl3): d 169.4, 169.2, 138.6, 138.5, 138.5,
138.5, 138.1, 137.6, 128.7–127.7 (m, Ar-C), 88.4, 88.1, 84.4, 83.9,
79.9, 79.3, 78.2, 77.6, 75.8, 75.7, 75.1, 74.8, 74.7, 74.5, 73.5, 73.1,
72.3, 69.3, 68.7, 37.6, 32.4, 29.8, 24.9, 24.7, 16.8, 14.9, 14.2. HRMS
calcd for C39H45NO6 [M + H]+ 624.3325, Found: 624.3328.
(d, 1H, J = 12.0 Hz), 3.55 (dd, 1H, J = 4.8, 12.0 Hz), 3.49 (t, 1H,
J = 9.2 Hz), 3.38–3.35 (m, 1H), 3.28–3.24 (m, 2H), 2.28–1.99 (m,
3H), 1.70–1.48 (m, 3H). 13C NMR (125 MHz, D2O): d 177.4, 87.6,
74.9, 73.1, 69.7, 60.9, 30.5, 20.8, 14.5. HRMS calcd for C10H17NO6
[M + Na]+ 270.0954, Found: 270.0955.
(2R,3R,4S,5R,6S)-3,4,5-Trihydroxy-2-(hydroxymethyl)-1-oxa-
7-azaspiro[5.5]undecan-8-one (26a). Yield: 83%, oil, [a]2D8 = +59.0
1
(c 1.0, MeOH). H NMR (500 MHz, D2O): d 3.80 (d, 1H, J =
2.7 Hz), 3.74 (dd, 1H, J = 3.4, 10.3 Hz), 3.62–3.60 (m, 1H), 3.53–
3.50 (m, 3H), 2.24–2.17 (m, 2H), 1.90–1.86 (m, 2H), 1.68–1.58 (m,
2H). 13C NMR (125 MHz, D2O): d 178.1, 86.4, 71.7, 71.4, 69.0,
68.9, 61.3, 30.8, 30.4, 14.9. HRMS calcd for C10H17NO6 [M + Na]+
270.0954, Found: 270.0954.
(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-8-oxo-1-oxa-7-aza-spiro-
[5.5]undecane-3,4,5-triyltriacetate (27a). Yield: 90%, Rf: 0.30
(hexane–ethyl acetate, 1 : 4), [a]2D8 = +38.0 (c 0.5, CH2Cl2). IR (neat)
n
max: 3332, 2923, 2853, 1748, 1673, 1369, 1221, 1033, 901 cm-1. 1H
NMR (500 MHz, CDCl3): d 6.94 (s, 1H, -NH), 5.38 (dd, 1H, J =
9.6, 10.3 Hz, H-4), 5.09 (dd, 1H, J = 4.1, 10.3 Hz, H-3), 5.07 (d,
1H, J = 9.6 Hz, H-5), 4.27 (dd, 1H, J = 4.4, 12.3 Hz, CHaHbOAc),
4.05 (dd, 1H, J = 2.0, 12.3 Hz, CHaHbOAc), 3.93–3.90 (m, 1H,
H-2), 2.52–2.47 (m, 1H), 2.36–2.28 (m, 1H), 2.16–2.07 (m, 1H),
2.06 (s, 3H, COCH3), 2.05(s, 3H, COCH3), 2.01 (s, 3H, COCH3),
1.99 (s, 3H, COCH3) 1.91–1.89 (m, 1H), 1.77–1.73 (m, 1H), 1.67–
1.40 (m, 1H). 13C NMR (125 MHz, CDCl3): d 173.2, 170.6, 170.1,
169.6, 169.4, 85.1, 71.8, 70.4, 68.4, 68.2, 61.9, 31.5, 30.8, 20.7, 20.6,
20.5, 20.4, 15.4. HRMS calcd for C18H25NO10 [M + Na]+ 438.1376,
Found: 438.1376.
N -((2S,3R,4S,5R,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzy-
loxymethyl)tetrahydro-2H-pyran-2-yl)acrylamide (32a). To a so-
lution of azide 19 (300 mg, 0.495 mmol) in methanol (20 ml)
was added NH4Cl (262 mg, 4.95 mmol), and Zn (dust) (575 mg,
4.95 mmol) and the reaction mixture was stirred vigorously for
2 h at room temperature. After completion of the reaction, the
reaction mixture was concentrated, and the residue was triturated
with ether (5 ¥ 30 mL) and the combined ether fractions were
filtered through small pad of silica to afford 245 mg of 31 as
an oil which was used directly in the next step. To a stirred
solution of amine 31 (245 mg, 0.423 mmol) in dry CH2Cl2
(4.0 mL) at 0 ◦C was added dropwise Et3N (0.07 mL, 0.507
mmol) followed by acryloyl chloride (0.04 mL, 0.507 mmol). The
reaction mixture was stirred for 30 min and after completion of
reaction (TLC monitoring), it was extracted with CH2Cl2 (2 ¥
40 mL). Usual work-up gave a crude product which was purified
by column chromatography to give dienes 32a and 32b in 67%
overall yield. 32a: 193 mg, oil, Rf: 0.35 (hexane–ethyl acetate, 7 : 3),
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-8-oxo-1-oxa-7-aza-spiro-
[5.5]undecane-3,4,5-triyltriacetate (27b). Yield: 67%. Rf: 0.30
(hexane–ethyl acetate, 1 : 4), [a]2D8 = - 27.5 (c 0.4, CH2Cl2). IR
(neat) nmax: 2953, 1752, 1682, 1370, 1225, 1036, 822 cm-1.1H NMR
(500 MHz, CDCl3): d 6.43 (s, 1H, -NH), 5.32 (dd, 1H, J = 9.6,
10.3 Hz, H-4), 5.03 (t, 1H, J = 9.6 Hz, H-3), 4.97 (d, 1H, J =
10.3 Hz, H-5), 4.14 (dd, 1H, J = 4.8, 12.0 Hz, CHaHbOAc), 4.09
(dd, 1H, J = 2.7, 12.4 Hz, CHaHbOAc), 3.78–3.75 (m, 1H, H-2),
2.49-2.45 (m, 1H), 2.32–2.23 (m, 2H), 1.91–1.78 (m, 3H), 2.08 (s,
3H, COCH3), 2.04 (s, 3H, COCH3), 2.01 (s, 3H, COCH3), 1.98
(s, 3H, COCH3). 13C NMR (125 MHz, CDCl3): d 175.5, 172.9,
170.6, 170.1, 169.4, 86.6, 72.4, 70.6, 70.1, 68.8, 62.4, 31.2, 22.4,
816 | Org. Biomol. Chem., 2011, 9, 809–819
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
[a]2D8 = +55.0 (c 0.4, CH2Cl2). IR (neat) nmax: 3405, 2921, 1672,
1615, 1497, 1453 cm-1.1H NMR (500 MHz, CDCl3): d 7.37–7.17
(m, 20H, Ar-H), 6.24 (d, 1H, J = 16.8 Hz, –CH CHaHb), 6.08–
6.04 (m, 2H, –NH, –CH CH2), 5.98–5.88 (m, 1H, –CH CH2),
5.62 (d, 1H, J = 9.9 Hz, –CH CHaHb), 5.12 (d, 1H, J = 9.9 Hz,
–CH CHaHb), 5.06 (d, 1H, J = 17.2 Hz, –CH CHaHb), 4.95
(d, 1H, J = 10.7 Hz, PhCH), 4.88 (d, 1H, J = 10.7 Hz, PhCH),
4.81 (d, 1H, J = 11.1 Hz, PhCH), 4.77 (d, 1H, J = 10.7 Hz,
PhCH), 4.74–4.69 (m, 2H, 2 ¥ PhCH), 4.66 (d, 1H, J = 10.3 Hz,
PhCH), 4.56 (d, 1H, J = 11.5 Hz, PhCH), 3.84–3.62 (m, 6H),
3.39 (d, 1H, J = 10.7 Hz, –CHaHbCH CH2), 2.61 (dd, 1H, J =
10.3, 14.5 Hz, –CHaHbCH CH2). 13C NMR (125 MHz, CDCl3):
d 164.7, 138.6, 138.4, 138.0, 137.8, 133.5, 131.4, 128.7–127.6(m,
Ar-C), 127.1, 118.8, 83.3, 84.4, 79.8, 78.0, 75.8, 75.5, 75.1, 73.6,
72.6, 68.6, 40.12. HRMS calcd for C40H43NO6 [M + H]+ 634.3169,
Found: 634.3165.
acetate, 1 : 1), [a]D28 = +12.0 (c 0.25, CH2Cl2). IR (neat) nmax: 3442,
2956, 1687, 1618, 1464, 1363 cm-1. 1H NMR (500 MHz, CDCl3):
d 7.31–7.14 (m, 20H, Ar-H), 6.55–6.52 (m, 1H, –CH CH–), 6.00
(d, 1H, J = 9.9 Hz, –CH CH–), 5.85 (s, 1H, –NH), 4.87 (d, 1H,
J = 11.1 Hz, PhCH), 4.81 (d, 1H, J = 10.7 Hz, PhCH), 4.80 (d, 1H,
J = 11.0 Hz, PhCH), 4.79 (d, 1H, J = 10.7 Hz, PhCH), 4.75 (d, 1H,
J = 11.1 Hz, PhCH), 4.57 (d, 1H, J = 12.2 Hz, PhCH), 4.51(d, 1H,
J = 10.7 Hz, PhCH), 4.49 (d, 1H, J = 12.2 Hz, PhCH), 3.70–3.66
(m, 3H, CHaHbOBn, H-3, H-4), 3.61 (dd, 1H, J = 1.9, 11.1 Hz,
CHaHbOBn), 3.53–3.49 (m, 1H, H-2), 3.33 (d, 1H, J = 9.5 Hz,
H-5), 2.93 (dt, 1H, J = 2.6, 19.1 Hz, –CHaHbCH CH2), 2.66 (dd,
1H, J = 5.7, 19.1 Hz, –CHaHbCH CH2). 13C NMR (125 MHz,
CDCl3): d 166.0, 138.7, 138.3, 138.1, 137.9, 137.5, 128.6–127.8
(m, Ar-C), 123.3, 87.9, 83.9, 82.8, 77.8, 75.7, 75.3, 75.1, 73.2, 68.8,
24.9. HRMS calcd for C38H39NO6 [M + H]+ 606.2856, Found:
606.2855.
(2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
2-(but-3-enyl)tetrahydro-2H-pyran-2-ol (34). To a cold (-78 ◦C)
solution of lactone 17 (2.0 g, 3.72 mmol) in THF (15.0 mL)
under nitrogen atmosphere was added dropwise freshly prepared
vinylmagnesium bromide (1.95 g in 15.0 mL THF, 14.86 mmol).
After 2 h of stirring at -78 ◦C, the reaction mixture was quenched
with saturated NH4Cl and extracted with EtOAc. The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated to give the corresponding hemiketal 34. Yield: 82%
(1.8 g). Rf: 0.5 (hexane–ethyl acetate, 4 : 1), [a]2D8 = +22.94 (c 0.85,
CH2Cl2). IR (neat) nmax: 3440, 3063, 3030, 2923, 2863, 1640, 1453
cm-1. 1H NMR (400 MHz, CDCl3): d 7.85–7.18 (m, 20H, Ar-H),
5.84–5.77 (m, 1H, –CH CH2), 5.00 (dd, 1H, J = 4.0, 16.0 Hz, –
CH CHaHb), 4.96–4.82 (m, 5H, –CH CHaHb, 4¥PhCH), 4.70–
4.52 (m, 4H, 4 ¥ PhCH), 4.02–3.96 (m, 2H), 3.76 (dd, 1H, J = 4.0,
8.0 Hz), 3.69–3.63 (m, 2H), 3.41(d, 1H, J = 8.0 Hz), 2.72 (s, 1H,
OH), 2.24–2.21(m, 1H) 2.13–2.09 (m, 1H), 1.85–1.77 (m, 1H),
1.75–1.69 (m, 1H). 13C NMR (100 MHz, CDCl3): d 138.5, 138.4,
138.3, 128.4–127.5 (m, Ar-C), 114.8, 98.2, 83.8, 81.8, 78.4, 75.6,
75.4, 74.8, 73.3, 71.5, 68.8, 37.4, 26.8. HRMS calcd for C38H42O6
[M + NH4]+ 612.3325, Found: 612.3325.
N -((2R,3R,4S,5R,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzy-
loxymethyl)tetrahydro-2H-pyran-2-yl)acrylamide (32b). 17 mg,
oil, Rf: 0.40 (hexane–ethyl acetate, 7 : 3), [a]2D8 = -4.17 (c 0.6,
CH2Cl2). IR (neat) nmax: 3405, 2924, 1728, 1694, 1453 cm-1.1H
NMR (500 MHz, CDCl3): d 7.45–7.17 (m, 20H, Ar–H), 6.18 (d,
1H, J = 16.9 Hz, –CH CHaHb), 6.08 (s, 1H, –NH), 5.92–5.83
(m, 2H, 2 ¥ CH CH2), 5.55 (d, 1H, J = 10.5 Hz, –CH CHaHb),
5.26–5.24 (m, 1H, –CH CHaHb), 5.23 (d, 1H, J = 11.0 Hz, –
CH CHaHb), 4.82 (d, 1H, J = 11.5 Hz, PhCH), 4.79–4.70 (m,
4H, 4 ¥ PhCH), 4.61–4.52 (m, 3H, 3 ¥ PhCH), 3.81–3.68 (m, 6H),
2.89–2.78 (m, 2H, –CH2CH CH2). 13C NMR (125 MHz, CDCl3):
d 164.7, 138.6, 138.3, 138.1, 131.7, 128.5–127.7 (m, Ar-C), 126.6,
120.3, 87.4, 83.8, 79.2, 77.6, 74.8, 74.7, 74.6, 73.7, 73.4, 69.3, 35.1.
HRMS calcd for C40H43NO6 [M + H]+ 634.3169, Found: 634.3169.
(2R,3R,4S,5R,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undec-9-en-8-one (33a). To a stirred solu-
tion of compound 32a (400 mg, 0.63 mmol) in dry CH2Cl2 (5–
6 mL) at room temperature was added the second generation
Grubbs’ catalyst (26.8 mg, 0.031 mmol). The mixture was refluxed
for 24 h and after completion of reaction, the solvent was evapo-
rated and residue was purified by column chromatography. Yield:
91% (347 mg). Rf: 0.40 (hexane–ethyl acetate, 1 : 1), [a]2D8 = +74.61
(c 0.65, CH2Cl2). IR (neat) nmax: 3241, 2921, 2852, 1678, 1614,
(2S,3R,4S,5R,6R)-2-Azido-3,4,5-tris(benzyloxy)-6-(benzyloxy-
methyl)-2-(but-3-enyl)tetrahydro-2H-pyran (35). The hemiketal
34 (1.2 g, 2.02 mmol) was dissolved in CH2Cl2 (15.0 mL) and
1
1453, 1414 cm-1. H NMR (500 MHz, CDCl3): d 7.32–7.16 (m,
˚
treated with activated 4 A powdered molecular sieves (500 mg). To
20H, Ar-H), 6.81 (s, 1H, –NH) 6.56–6.52 (m, 1H, –CH CH–),
5.94 (d, 1H, J = 9.9 Hz, –CH CH-), 4.96 (d, 1H, J = 11.4 Hz,
PhCH), 4.92 (d, 1H, J = 10.7 Hz, PhCH), 4.85 (d, 1H, J = 10.2 Hz,
PhCH), 4.81 (d, 1H, J = 11.1 Hz, PhCH), 4.69 (d, 1H, J = 11.8 Hz,
PhCH), 4.58 (d, 2H, J = 11.4 Hz, 2 ¥ PhCH), 4.44 (d, 1H, J =
12.2 Hz, PhCH), 3.93 (t, 1H, J = 9.5 Hz, H-4), 3.76 (t, 1H, J =
9.5 Hz, H-3), 3.75–3.71 (m, 2H, CHaHbOBn, H-2), 3.56 (d, 1H,
J = 10.3 Hz, CHaHbOBn), 3.45 (d, 1H, J = 9.5 Hz, H-5), 2.70
(d, 1H, J = 18.3 Hz, –CHaHbCH CH2), 2.31 (dd, 1H, J = 5.7,
17.9 Hz, –CHaHbCH CH2). 13C NMR (125 MHz, CDCl3): d
165.6, 139.9, 138.0, 137.9, 137.8, 137.5, 128.4–127.5 (m, Ar-C),
122.7, 86.1, 82.9, 80.7, 77.9, 75.6, 75.3, 74.6, 73.3, 70.7, 68.2, 33.6.
HRMS calcd for C38H39NO6 [M + H]+ 606.2856, Found: 606.2859.
this reaction mixture, TMSN3 (0.8 mL, 6.06 mmol) and TMSOTf
(0.2 mL, 0.44 mL) were added at -40 ◦C and the reaction
mixture was stirred at the same temperature for 2.0 h. It was
then neutralized with Et3N, diluted with CH2Cl2, filtered through
Celite, and concentrated. Column chromatography of this residue
afforded the desired azide 35. Yield: 86% (1.1 g). Rf: 0.50 (hexane–
ethyl acetate, 9 : 1), [a]2D8 = +68.46 (c 0.65, CH2Cl2). IR (neat) nmax
:
2922, 2118, 1642, 1453 cm-1. 1H NMR (400 MHz, CDCl3): d 7.35–
7.19 (m, 20H, Ar-H), 5.77–5.70 (m, 1H, –CH CH2), 4.98 (d, 1H,
J = 15.8 Hz, –CH CHaHb), 4.94–4.84 (m, 4H, –CH CHaHb 3 ¥
PhCH), 4.81 (d, 1H, J = 10.7 Hz, PhCH), 4.70 (d, 1H, J = 11.2 Hz,
PhCH), 4.63–4.58 (m, 2H, 2 ¥ PhCH), 4.52 (d, 1H, J = 12.2 Hz,
PhCH), 3.99 (t, 1H, J = 9.2 Hz), 3.85 (dd, 1H, J = 1.9, 10.7 Hz),
3.75 (dd, 1H, J = 3.6, 11.2 Hz), 3.69–3.64 (m, 2H), 3.49 (d, 1H, J =
9.2 Hz), 2.19–2.17 (m, 1H), 2.09–2.01 (m, 2H), 1.93–1.88 (m, 1H).
13C NMR (125 MHz, CDCl3): d 138.4, 138.2, 138.1, 137.8, 137.5,
128.6–127.2 (m, Ar-C), 115.2, 93.9, 83.8, 81.8, 77.8, 75.9, 75.5,
2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.5]undec-9-en-8-one (33b). The same proce-
dure was employed, as used for the synthesis of 33a. Yield: 82%
(60 mg from 80 mg, 0.0315 mmol of 32b). Rf: 0.40 (hexane–ethyl
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 809–819 | 817
©

View Article Online
75.2, 73.6, 73.4, 68.4, 34.7, 27.2. HRMS calcd for C38H41N3O5 [M
+ NH4]+ 637.3390, Found: 637.3393.
24.4. HRMS calcd for C39H41NO6 [M + H]+ 620.3012, Found:
620.3015.
(2R,3S,4S,5R,6S)-3,4,5-Trihydroxy-2-(hydroxymethyl)-1-oxa-
7-azaspiro[5.6]dodecan-8-one (38a). Yield: quantitative, oil,
N -((3R,4S,5R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-
(but-3-enyl)tetrahydro-2H-pyran-2-yl)acrylamide (36). A proce-
dure similar to that described for the synthesis of 32a and 32b
was employed. Yield: 52% (oil, 271 mg from 500 mg, 0.807 mmol
of azide 35). Data have given for the major separable isomer. Rf:
0.4 (hexane–ethyl acetate, 7 : 3), [a]2D8 = +40.75 (c 0.75, CH2Cl2).
IR (neat) nmax: 3411, 2924, 1737, 1463 cm-1.1H NMR (500 MHz,
CDCl3): d 7.49–7.17 (m, 20H, Ar-H), 6.23 (d, 1H, J = 16.8 Hz,
–CH CHaHb), 6.10–6.03 (m, 2H, –NH, –CH CH2), 5.79–5.72
(m, 1H, –CH CH2), 5.61 (d, 1H, J = 9.9 Hz, –CH CHaHb),
4.98–4.90 (m, 4H, J = 9.9 Hz, –CH CH2, 2 ¥ PhCH), 4.84 (d,
1H, J = 10.0 Hz, PhCH), 4.77 (d, 1H, J = 10.7 Hz, PhCH), 4.73–
4.70 (m, 2H, 2 ¥ PhCH), 4.66 (d, 1H, J = 10.3 Hz, PhCH), 4.54
(d, 1H, J = 12.2 Hz, PhCH), 3.89–3.76 (m, 4H), 3.63–3.59 (m,
2H), 2.56–2.49 (m, 1H), 2.35–2.30 (m, 1H), 2.02–1.83 (m, 2H).
13C NMR (125 MHz, CDCl3): d 164.4, 138.6, 138.5, 138.1, 138.0,
137.4, 131.5, 128.7–127.6 (m, Ar-C), 126.9, 114.8, 88.3, 84.4, 79.5,
78.0, 75.7, 75.1, 75.1, 73.6, 72.6, 68.6, 34.8, 27.9. HRMS calcd for
C41H45NO6 [M + H]+ 648.3325, Found: 648.3321.
1
[a]2D8 = +39.09 (c 0.55, MeOH). H NMR (500 MHz, D2O): d
3.73 (d, 1H, J = 12.4 Hz), 3.60 (dd, 1H, J = 5.5, 12.4 Hz), 3.46
(t, 1H, J = 9.1 Hz), 3.39–3.36 (m, 1H), 3.28–3.23 (m, 2H), 2.66
(t, 1H, J = 13.3 Hz), 2.13 (dd, 1H, J = 6.4, 13.7 Hz), 1.92–1.85
(m, 2H), 1.76–1.70 (m, 2H), 1.61–1.60 (m, 1H), 1.34–1.29 (m, 1H).
13C NMR (125 MHz, D2O): d 182.2, 85.7, 76.6, 73.1, 72.7, 69.5,
60.4, 36.9, 35.8, 22.6, 22.4. HRMS calcd for C11H19NO6 [M + H]+
262.1291, Found: 262.1292.
(2R,3S,4S,5R,6R)-3,4,5-Trihydroxy-2-(hydroxymethyl)-1-oxa-
7-azaspiro[5.6]dodecan-8-one (38b). Yield: quantitative, oil,
[a]2D8 = -3.33 (c 0.45, MeOH). 1H NMR (500 MHz, D2O): d 3.79
(d, 1H, J = 12.3 Hz), 3.58 (dd, 1H, J = 3.7, 15.1 Hz), 3.52 (t, 1H, J =
10.1 Hz), 3.38–3.21 (m, 3H), 2.70 (t, 1H, J = 13.5 Hz), 2.29–2.23
(m, 1H), 2.12(d, 1H, J = 15.6 Hz), 1.83–1.58 (m, 3H), 1.43–1.37
(m, 1H), 1.19–1.14 (m, 1H). (125 13C NMR MHz, D2O): d 182.0,
86.8, 76.7, 74.0, 73.8, 69.7, 60.8, 36.2, 27.6, 22.3, 21.6. HRMS
calcd for C11H19NO6 [M + H]+ 262.1291, Found: 262.1291.
(2R,3R,4S,5R,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.6]dodec-9-en-8-one (37a). To a stirred solu-
tion of compound 36 (110 mg, 0.17 mmol) in dry CH2Cl2 (2.0 mL)
at room temperature was added the Grubbs’ second generation
catalyst (5 mol%, 7.2 mg). The mixture was refluxed in CH2Cl2 and
stirred for overnight under nitrogen atmosphere. After completion
of the reaction, the solvent was evaporated under reduced pressure
and the column chromatography of the crude product gave two
anomeric spiroaminals 37a and 37b in 3 : 1 ratio with 84% yield.
37a: (51 mg), Rf: 0.25 (hexane–ethyl acetate, 3 : 2), [a]2D8 = +29.41 (c
0.85, CH2Cl2). IR (neat) nmax: 3250, 2920, 1669, 1619, 1453 cm-1.
1H NMR (400 MHz, CDCl3): d 7.34–7.18 (m, 20H, Ar-H), 6.41 (s,
1H, –NH), 6.25 (dt, 1H, J = 3.7, 12.7 Hz, –CH CH–CH2), 5.84
(d, 1H, J = 12.4 Hz, –CH CHCH2), 4.89 (d, 1H, J = 11.2 Hz,
PhCH), 4.87 (d, 1H, J = 10.5 Hz, PhCH), 4.81(d, 2H, J = 10.2 Hz,
2 ¥ PhCH), 4.73 (d, 1H, J = 11.2 Hz, PhCH), 4.60 (d, 1H, J =
10.9 Hz, PhCH), 4.55 (d, 1H, J = 12.4 Hz, PhCH), 4.48 (d, 1H,
J = 12.2 Hz, PhCH), 3.80–3.70 (m, 4H), 3.55 (d, 1H, J = 10.0 Hz),
3.47 (d, 1H, J = 9.0 Hz), 2.79–2.71 (m, 1H), 2.37–2.26 (m, 2H),
1.96–1.92 (m, 1H). 13C NMR (125 MHz, CDCl3): d 169.4, 143.1,
138.3, 138.2, 137.6, 128.6–127.7 (m, Ar-C), 124.1, 84.8, 84.0, 83.8,
78.1, 75.9, 75.8, 74.8, 73.4, 71.6, 68.5, 36.7, 26.8. HRMS calcd for
C39H41NO6 [M + H]+ 620.3012, Found: 620.3011.
(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-8-oxo-1-oxa-7-azaspiro-
[5.6]dodecane-3,4,5-triyl triacetate (39a). Yield: 79%, Rf: 0.35
(hexane–ethyl acetate, 1 : 4), [a]2D8 = +66.0 (c 0.75, CH2Cl2). IR
1
(neat) nmax: 3386, 2926, 1755, 1673, 1434, 1368 cm-1. H NMR
(500 MHz, CDCl3): d 6.15 (s, 1H, –NH), 5.25 (t, 1H, J = 9.6 Hz,
H-4), 5.04 (t, 1H, J = 9.6 Hz, H-3), 5.00 (d, 1H, J = 10.1 Hz, H-5),
4.21 (dd, 1H, J = 5.9, 12.4 Hz, CHaHbOAc), 4.15 (dd, 1H, J = 2.3,
12.4 Hz, CHaHbOAc), 4.02–3.99 (m, 1H, H-2), 2.63 (td, 1H, J =
2.3, 13.3 Hz), 2.42 (dd, 1H, J = 6.0, 13.3 Hz), 2.07–2.02 (m, 1H),
2.07 (s, 3H, COCH3), 2.06 (s, 3H, COCH3), 2.02 (s, 3H, COCH3),
1.97 (s, 3H, COCH3), 1.97–1.94 (m, 1H), 1.87–1.83 (m, 1H), 1.75–
1.68 (m, 2H), 1.54–1.45 (m, 1H). 13C NMR (125 MHz, CDCl3): d
177.6, 170.4, 169.9, 169.5, 168.9, 84.6, 74.3, 70.8, 68.5, 62.1, 37.9,
36.4, 22.9, 20.7, 20.5, 20.4. HRMS calcd for C19H27NO10 [M + H]+
430.1713, Found: 430.1715.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-8-oxo-1-oxa-7-azaspiro-
[5.6]dodecane-3,4,5-triyl triacetate (39b). Yield: 88%, Rf: 0.35
(hexane–ethyl acetate, 1 : 4), [a]2D8 = +15.0 (c 0.3, CH2Cl2). IR (neat)
n
max: 3368, 2922, 1738, 1662, 1459, 1381 cm-1. 1H NMR (500 MHz,
CDCl3): d 6.56 (s, 1H, –NH), 5.35 (t, 1H, J = 9.6 Hz, H-4), 5.00 (t,
1H, J = 9.6 Hz, H-3), 4.93 (d, 1H, J = 9.6 Hz, H-5), 4.21–4.13 (m,
2H, CH2OAc), 3.74–3.72 (m, 1H, H-2), 2.69 (t, 1H, J = 12.8 Hz),
2.46 (dd, 1H, J = 5.9, 14.3 Hz), 2.39 (d, 1H, J = 14.2 Hz), 2.09 (s,
3H, COCH3), 2.08 (s, 3H, COCH3), 2.02 (s, 3H, COCH3), 2.00 (s,
3H, COCH3), 1.91–1.83 (m, 3H), 1.69–1.64 (m, 1H), 1.59–1.52 (m,
1H). 13C NMR (125 MHz, CDCl3): d 177.4, 170.8, 170.6, 170.1,
169.5, 85.9, 75.1, 71.1, 70.0, 69.0, 62.6, 37.2, 29.6, 22.9, 22.6, 20.8,
20.7, 20.6, 20.6. HRMS calcd for C19H27NO10 [M + H]+ 430.1713,
Found: 430.1711.
(2R,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-
1-oxa-7-azaspiro[5.6]dodec-9-en-8-one (37b). 28 mg, Rf: 0.2
(hexane–ethyl acetate, 3 : 2), [a]2D8 = +5.0 (c 0.0.4, CH2Cl2).
IR (neat) nmax: 3397, 2924, 1669, 1618, 1453 cm-1. 1H NMR
(500 MHz, CDCl3): d 7.33–7.15 (m, 20H, Ar-H), 6.36–6.33 (m,
1H, CH CH–CH2), 6.21 (s, 1H, –NH), 5.92 (d, 1H, J = 12.2 Hz,
–CH CH–CH2), 4.88–4.79 (m, 5H, 5¥PhCH), 4.58–4.51 (m, 3H,
3¥PhCH), 3.77 (t, 1H, J = 8.8 Hz, H-4), 3.70 (d, 1H, J = 10.7 Hz,
CHaHbOBn), 3.60–3.57 (m, 2H, H-2, H-3), 3.52 (dd, 1H, J = 4.2,
13.7 Hz, CHaHbOBn), 3.41 (d, 1H, J = 8.8 Hz, H-5), 2.53–2.49 (m,
1H), 2.39–2.38 (m, 2H), 2.26–2.23 (m, 1H). 13C NMR (125 MHz,
CDCl3): d 168.7, 143.4, 138.1, 137.7, 137.4, 128.6–127.6 (m, Ar-C),
125.2, 85.5, 85.2, 83.8, 78.0, 75.7, 75.4, 75.0, 73.4, 73.2, 68.9, 27.2,
(5S,7R,8R,9S,10R)-8,9,10-Tris(benzyloxy)-7-(benzyloxyme-
thyl)-2-methyl-6-oxa-1-azaspiro[4.5]dec-1-ene (40). Yield: 55%,
Rf: 0.4 (hexane–ethyl acetate, 1 : 4), [a]2D8 = +26.25 (c 0.4, CH2Cl2).
IR (neat) nmax: 2918, 1595, 1413 cm-1. 1H NMR (400 MHz, CDCl3):
d 7.35–7.17 (m, 20H, Ar–H), 4.89 (d, 1H, J = 10.72 Hz, PhCH),
4.90–4.83 (m, 3H, 3¥PhCH), 4.65 (d, 1H, J = 11.7 Hz, PhCH),
818 | Org. Biomol. Chem., 2011, 9, 809–819
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
4.62–4.48 (m, 3H, 3¥PhCH), 4.29–4.27 (m, 1H), 4.23 (t, 1H, J =
9.2 Hz), 3.77 (t, 1H, J = 9.5 Hz), 3.71 (dd, 1H, J = 4.6, 11.0 Hz),
3.62 (m, 1H), 3.56 (d, 1H, J = 9.5 Hz), 2.53–2.45 (m, 1H), 2.42–
2.33 (m, 1H), 2.07 (s, 3H, COCH3), 1.89–1.78 (m, 2H). 13C NMR
(125 MHz, CDCl3): d 179.0, 138.9, 138.8, 138.6, 138.3, 128.4–
127.4 (m, Ar-C), 106.9, 84.6, 83.6, 79.2, 75.5, 75.5, 75.4, 74.7,
73.5, 69.1, 39.1, 33.6, 20.5. HRMS calcd for C38H41NO5 [M + H]+
592.3063, Found: 592.3069.
12 For the spectral copies and data of 6,5-fused spiroaminals, see the
supporting information of ref. 7.
13 (a) M. D. Lewis, J. K. Cha and Y. Kishi, J. Am. Chem. Soc., 1982,
104, 4976–4978; (b) Y. Oda and T. Yamanoi, Synthesis, 2007, 3021–
3031.
14 (a) A. K. Chatterjee, T. L. Choi, D. P. Sanders and R. H. Grubbs, J.
Am. Chem. Soc., 2003, 125, 11360–11370; (b) G. Godin, P. Compain
and O. R. Martin, Org. Lett., 2003, 5, 3269–3272.
15 A. N. Rai and A. Basu, Org. Lett., 2004, 6, 2861–2863.
16 (a) C. J. O’Donnell, R. A. Singer, J. D. Brubaker and J. D. McKinley, J.
Org. Chem., 2004, 69, 5756–5759; (b) D. M. Floyd, R. V. Moquin, K. S.
Atwal, S. Z. Ahmed, S. H. Spergel, J. Z. Gougoutas and M. F. Malley,
J. Org. Chem., 1990, 55, 5572–5579.
17 (a) J. Xie, F. Durrat and J.-M. Valeary, J. Org. Chem., 2003, 68, 7896–
7898; (b) L. Cipolla and F. Nicotra, Tetrahedron, 1997, 53, 6163–
6170.
18 (a) A. Hassner, A. S. Amarasekara and D. Andisik, J. Org. Chem.,
1988, 53, 27–30; (b) Y. Zhou and P. V. Murphy, Org. Lett., 2008, 10,
3777–3780.
19 K. Zhang and F. Schweizer, Synlett, 2005, 3111–3115.
20 For some excellent accounts on glycosidases and their inhibitors, see:
(a) B. G. Davis, Tetrahedron: Asymmetry, 2009, 20, 652–671; (b) P.
Compain, V. Chagnault and O. R. Martin, Tetrahedron: Asymmetry,
2009, 20, 672–711; (c) V. H. Lillelund, H. H. Jensen, X. Liang and M.
Bols, Chem. Rev., 2002, 102, 515–553; (d) K. Afarinkia and A. Bahar,
Tetrahedron: Asymmetry, 2005, 16, 1239–1287; (e) D. L. Zechel and S.
G. Withers, Acc. Chem. Res., 2000, 33, 11–18; (f) T. D. Heightman and
A. T. Vasella, Angew. Chem., Int. Ed., 1999, 38, 750–770; (g) G. M.
Gloster and G. J. Davies, Org. Biomol. Chem., 2010, 8, 305–320; (h) Y.
Ichikawa, Y. Igarashi, M. Ichikawa and Y. Suhara, J. Am. Chem. Soc.,
1998, 120, 3007–3018.
21 (a) B. G. Winchester, Tetrahedron: Asymmetry, 2009, 20, 645–651;
(b) D. Sailer and G. Roder, Arzneimittelforschung, 1980, 30, 2182–
2185; (c) N. Katsilambros, P. Philippides, T. Toskas, J. Protopapas, D.
Frangaki, M. Marangos, P. Siskoudis, K. Anastasopoulou, H. Xefteri
and I. Hillebrand, Arzneimittelforschung, 1986, 36, 1136–1138; (d) F.
G. Hayden, J. J. Treanor, R. F. Betts, M. Lobo, J. D. Esinhart and E.
K. Hussey, JAMA, J. Am. Med. Assoc., 1996, 275, 295–299; (e) C. U.
Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S. Swaminathan, N.
Bischofberger, M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver and
R. C. Stevens, J. Am. Chem. Soc., 1997, 119, 681–690.
Acknowledgements
We thank the Council of Scientific and Industrial Research, New
Delhi for financial support [Grant No. 01(2298)/09/EMR-II].
A.P.J.P. thanks the University Grant Commission, New Delhi, for
a Senior Research Fellowship and A.M. thanks the CSIR, New
Delhi, for a Junior Research Fellowship.
Notes and references
1 (a) C. Boonlarppradab, C. A. Kauffman, P. R. Jensen and W. Fenical,
Org. Lett., 2008, 10, 5505–5508; (b) X.-C. Cai, X. Wu and B. B. Snider,
Org. Lett., 2010, 12, 1600–1603; (c) L. E. Overman and Y. H. Rhee,
J. Am. Chem. Soc., 2005, 127, 15652–15658; (d) R. M. Karmer, B.
Johansen, C. Hession and R. B. Pepinsky, Adv. Exp. Med. Biol., 1990,
275, 35–53; (e) M. Satake, K. Ofuji, H. Naoki, K. J. James, A. Furey,
T. McMahon, J. Silke and T. Yasumoto, J. Am. Chem. Soc., 1998, 120,
9967–9968; (f) J.-J. Sanglier, V. Quesniaux, T. Fehr, H. Hofmann, M.
Mahnke, K. Memmert, W. Schuler, G. Zenke, L. Gschwind, C. Mauer
and W. Schilling, J. Antibiot., 1999, 52, 466–473; (g) M. E. Sinibaldi
and I. Canet, Eur. J. Org. Chem., 2008, 4391–4399.
2 (a) S. Moi, R. Inchinose, K. Goto and S. Sugai, Tetrahedron, 1991, 47,
2111–2120; (b) H. Sano and S. Sugai, Tetrahedron, 1995, 51, 4635–4646;
(c) S. Hanessian, J. Y. Sanceau and P. Chemla, Tetrahedron, 1995, 51,
6669–6678.
3 (a) C. J. F. Bichard, E. P. Mitchell, M. R. Wormald, K. A. Watson,
L. N. Johnson, S. E. Zographos, D. D. Koutra, N. G. Oikonomakos
and G. W. J. Fleet, Tetrahedron Lett., 1995, 36, 2145–2148; (b) C. de la
Fuente, T. M. Kru¨lle, K. A. Watson, M. Gregoriou, L. N. Johnson, K.
E. Tsitsanou, S. E. Zographos, N. G. Oikonomakos and G. W. J. Fleet,
Synlett, 1997, 485–487.
4 (a) T. Gimisis, C. Castellari and C. Chatgilialoglu, Chem. Commun.,
1997, 2089–2090; (b) C. Chatgilialoglu, T. Gimisis and G. P. Spada,
Chem.–Eur. J., 1999, 5, 2866–2876.
5 (a) A. Martin, I. Perez-Martin and E. Suarez, Org. Lett., 2005, 7,
2027–2030; (b) R. Freire, A. Martin, I. Perez-Martin and E. Suarez,
Tetrahedron Lett., 2002, 43, 5113–5116.
6 S. Toumieux, P. Compain and O. R. Martin, Tetrahedron Lett., 2005,
46, 4731–4735.
7 A. P. John Pal and Y. D. Vankar, Tetrahedron Lett., 2010, 51, 2519–
2524.
22 A. E. Stuetz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond, Wiley-VCH, Weinheim, Germany, 1999 and see ref. 6a–d.
23 H. Yuasa, M. Izumi and H. Hashimoto, Curr. Top. Med. Chem., 2009,
9, 76–86.
24 A. Berecibar, C. Grandjean and A. Siriwardena, Chem. Rev., 1999, 99,
779–844.
25 (a) B. Gopal Reddy and Y. D. Vankar, Angew. Chem., Int. Ed., 2005, 44,
2001–2004; (b) K. Jayakanthan and Y. D. Vankar, Tetrahedron Lett.,
2006, 47, 8667–8671; (c) V. R. Doddi, H. P. Kokatla, A. P. John Pal,
R. K. Basak and Y. D. Vankar, Eur. J. Org. Chem., 2008, 5731–5739;
(d) A. Kumar, G. K. Rawal and Y. D. Vankar, Tetrahedron, 2008, 64,
2379–2390.
26 (a) V. R Doddi and Y. D. Vankar, Eur. J. Org. Chem., 2007, 5583–5589;
(b) M. A. Alam, A. Kumar and Y. D. Vankar, Eur. J. Org. Chem., 2008,
4972–4980; (c) M. A. Alam and Y. D. Vankar, Tetrahedron Lett., 2008,
49, 5534–5536; (d) P. Gupta and Y. D. Vankar, Eur. J. Org. Chem., 2009,
1925–1933; (e) N. Kumari, B. G. Reddy and Y. D. Vankar, Eur. J. Org.
Chem., 2009, 160–169; (f) A. Kumar, M. A. Alam, S. Rani and Y. D.
Vankar, Carbohydr. Res., 2010, 345, 1142–1148.
27 (a) K. Jayakanthan and Y. D. Vankar, Org. Lett., 2005, 7, 5441–5444;
(b) Y. S. Reddy, P. Kadigachalam, V. R. Doddi and Y. D. Vankar,
Tetrahedron Lett., 2009, 50, 5827–5830; (c) V. R. Doddi, A. Kumar and
Y. D. Vankar, Tetrahedron, 2008, 64, 9117–9122.
28 We have used a-glucosidase (yeast), b-glucosidase (almonds),
a-galactosidase (coffee beans), b-galactosidase (bovine) and a-
mannosidase (jack beans) enzymes for enzyme inhibition studies.
29 Y.-T. Li, S.-C. Li, Methods in Enzymology, ed. V. Ginsberg, Academic
Press, 1972, pp. 702.
8 L. Somsak, Chem. Rev., 2001, 101, 81–135 (In this review, see the
references regarding 1-nitro sugars chemistry).
9 (a) K. Czifrak, P. Szilagyi and L. Somsak, Tetrahedron: Asymmetry,
2005, 16, 127–141; (b) K. Czifrak, L. Kovacs, K. E. Kover and L.
Somsak, Carbohydr. Res., 2005, 340, 2328–2334; (c) L. Somsak, K.
Czifrak and E. Veres, Tetrahedron Lett., 2004, 45, 9095–9097; (d) A.
Dondoni, M. C. Scherrmann, A. Marra and J. L. Delepine, J. Org.
Chem., 1994, 59, 7517–7520.
10 B. Gopal Reddy, K. P. Madhusudanan and Y. D. Vankar, J. Org. Chem.,
2004, 69, 2630–2633.
11 (a) T. Suzuki, S. T. Suzuki, I. Yamada, Y. Kaoshi, K. Yamada and
N. Chida, J. Org. Chem., 2002, 67, 2874–2880; (b) A. Aravind, M. G.
Sankar, B. Varghese and S. Baskaran, J. Org. Chem., 2009, 74, 2858–
2861.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 809–819 | 819
©