Synthesis of highly oxygenated decalins from sugar allyltins: An access to sulfur and phosphorus derivatives

Article abstract of DOI:10.1016/j.tetasy.2012.09.015

A sugar allyltin derivative (with the d-gluco-configuration) was converted into d-xylo-dienoaldehyde and then into several bicyclic highly oxygenated compounds. The proposed methodology allows for a convenient synthesis of such derivatives containing heteroatoms other than oxygen. Molecular docking studies employing AutoDock 4.2 and AutoDock Vina were conducted in order to evaluate their activity as glycosidase inhibitors.

Full text of DOI:10.1016/j.tetasy.2012.09.015

Tetrahedron: Asymmetry 23 (2012) 1501–1511
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of highly oxygenated decalins from sugar allyltins: an access
to sulfur and phosphorus derivatives
⇑
Marcin Nowogródzki, Michał Malik, Sławomir Jarosz
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 September 2012
Accepted 25 September 2012
A sugar allyltin derivative (with the D-gluco-configuration) was converted into D-xylo-dienoaldehyde and
then into several bicyclic highly oxygenated compounds. The proposed methodology allows for a conve-
nient synthesis of such derivatives containing heteroatoms other than oxygen. Molecular docking studies
employing AutoDock 4.2 and AutoDock Vina were conducted in order to evaluate their activity as glyco-
sidase inhibitors.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecular Diels–Alder (IMDA) cyclization of the correspond-
ing triene 1 was a key step, while Mulzer11 applied the ring closing
Cyclic polyhydroxylated compounds, which are structurally
similar to carbohydrates, act as glycomimetics; they are recognized
by appropriate enzymes but due to them not being metabolized,
block their active center(s).1 Usually, they have a mono- or bi-het-
erocyclic structure or a mono-carbocyclic structure. Most known
derivatives of this type are iminosugars2 (inhibitors of glycosi-
dases); representatives of this class (Glyset™, Zavesca™) have
found application in clinical use. Simple monocarbocyclic deriva-
tives (conduritols,3 cyclophellitols,4 inositols,5 and carbasugars6)
also possess potent biological activities.
Much less is known about the synthesis and properties of poly-
hydroxylated bicyclic derivatives, although such compounds can
act as sugar mimics.7,8 The bicyclic structure can also be found in
some antibiotics (e.g., nodusmicin, nargenicin, and branimycin).9–11
Most common bicyclic structures are represented by decalin
and hydrindane scaffolds (although derivatives with bicyclo-
[4.2.0]octane12a and bicyclo[2.2.2]octane12b skeletons are also
known) which strongly resemble natural inhibitors of glycosidases
(Fig. 1).7c,8,13 Polyhydroxylated bicyclic derivatives may also be re-
garded as carbasugars with a rigid structure.
metathesis reaction (RCM) in the synthesis of branimycin (Fig. 2).
The trienes used in the syntheses of Roush and Mulzer were
prepared in a number of steps from simple synthons (D-glyceralde-
hyde and quinic acid). It seems however, to be more convenient to
initiate the synthesis from simple sugars. For the construction of
precursors of type 1, Herczegh applied pentoses or hexoses, which
by using classical sugar chemistry, were converted into the target
trienes as a mixture of geometrical isomers (Fig. 3).16
Our approach to such bicyclic systems was based on a stereo-
controlled fragmentation of sugar allyltins 2, which provided the
corresponding dienoaldehydes 3 exclusively with the E-geometry
across the double bond.17 The reaction of such synthons with
stabilized Wittig reagent afforded trienes which underwent the
IMDA reaction under high pressure to afford perhydroindenes 5
(Fig. 4).18,19
Alternatively, aldehyde 3 was converted into phosphonate 4,
which when reacted with an aldehyde furnished another triene
undergoing spontaneous cyclization to decalin 5.19,20 Both syn-
thons are convenient starting materials for the preparation of fully
hydroxylated decalins and perhydroindanes. In order to achieve
this goal, an oxidation of the allylic position is required, as well
as the oxidation of the double bond and replacement of the C-sub-
stituent for a heteroatom. As we have found, direct oxidation of the
allylic position was not possible, however oxidation of the double
bond (epoxidation, cis-dihydroxylation) of both types of synthons
provided the corresponding derivatives in good yield.21
Very often such products are prepared as a racemic mixture.14
Much more valuable, however, are enantiomerically pure deriva-
tives. There are two routes to such compounds. In the first one,
the optically inactive material is converted into pure enantiomers
either by kinetic resolution of a racemate15 or desymmetrization
of meso-derivatives at the early stage of the synthesis. The second,
the more convenient method involves the application of enantio-
merically pure substrates. In the Roush10 synthesis of nargenicins,
Precursor 720 can be selectively converted either into cis-diol 8
or a mixture (2:1) of epoxides.21 The introduction of the oxygen
functionality at the allylic position was done ‘indirectly’, that is,
by reaction of the epoxides with selenide followed by oxidative
work-up (Scheme 1).22 Herein, further functionalization of
compounds of type 6 will be presented. Furthermore, molecular
⇑
Corresponding author. Fax: +48 22 632 66 81.
E-mail address: slawomir.jarosz@icho.edu.pl (S. Jarosz).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.015

1502
M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
OH
OH
HO
OH
OH
H
N
HO
HO
HO
HO
HO
HO
OH
N
OH
HO
HO
carbocyclic
castanospermine
castanospermine
analogue
analogue
HO
OH
OH
OH
HO
OH
H
N
HO
HO
H
N
HO
OH
HO
HO
HO
OH
OH
HO
HO
tetrahydroxy
quinolizidine
quinolizidine
analogue
carbocyclic
analogue
Figure 1. Similarity of the polyhydroxylated carbobicyclic derivatives to bicyclic iminosugars and monocyclic carbasugars with rigid structure.
SnBu3
O
O
O
H
H
ref. 17
O
O
sugar
BnO
BnO
OR
Roush
R
MeO2C
OBn
2
R
Me
ZnCl2
Me
E/Z ~5:1
MeO2C
O
1
O
D
-glyceraldehyde
O
O
P
OR
OR
BnO
BnO
O
BnO
BnO
PMBO
BnO
OBn
OBn
3
PMBO
OBn
H
OBn
4
Mulzer
H
H
OMe
1. Ph3P=CHCOR
2. 10 kbar
OMe
RCHO, PTC
(-)-quinic
acid
H
OBn
OBn
BnO
BnO
BnO
CO2Me
Figure 2. Approach to highly functionalized decalins by Roush and Mulzer.
OBn
OBn
R
O
6
5
Herczegh
Figure 4. Synthesis of highly oxygenated bicycles from sugar allyltins.
approach
conversion
into olefin
pentoses
to hydrolysis. The expected compound 14 seemed to be a conve-
nient precursor of the target olefin 17; moreover, the carbonyl
group in the intermediate compound 16 could be cleaved under
the Baeyer Villiger conditions to afford the C-9 hydroxylated
derivative.
or
CH(SEt)2
hexoses
1
5 (or 6)
CHO
RO
However, treatment of olefin 13 with dilute sulfuric acid affor-
ded cyclic derivative 15 as the main product and only relatively
small amounts of the expected diol 14 were obtained (Scheme 2).
The structure of this unexpected tricyclic derivative was eluci-
dated on the basis of the NOESY spectra in which the cross-peaks
between H8–H9, H10–H10, and H5–H10 were observed (Fig. 5)
The synthesis of compound 17 was therefore realized via an
alternative route (Scheme 3). Hydrolysis of the isopropylidene
unit in compound 7 afforded the corresponding diol 18 which
was subjected to periodate cleavage to provide aldehyde 19.
Reduction of this compound furnished alcohol 20, and then finally
converted into 21, which was stable under basic conditions.
Oxidation of the allylic position in 21 was also performed ‘indi-
rectly’ as for compound 7. Epoxidation of the double bond under
standard conditions provided two epoxides: 22 and 23 in a 1:1 ra-
tio; both oxiranes were converted into the allylic alcohols 24 and
conversion
into diene
RO
E/Z ~2:3
IMDA
bicycles
Figure 3. Herczegh approach to highly oxidized bicycles from sugars.
docking studies allowed for a preliminary evaluation of the com-
pounds obtained as glycosidase inhibitors.
2. Results and discussion
Functionalization of precursor 11 requires oxidation of the dou-
ble bond and cleavage of the terminal diol grouping (C10–C20).
Thus, alcohol 11 was protected as benzyl ether 13 and subjected

M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
1503
H
H
HO
OBn
OBn
H
H
H
H
HO
OBn
OBn
OBn
OBn
BnO
5
H
H
OBn
4
H
OBn
6
7
a), b)
a), c)
H
1
H
2
OBn
10
9
R
OH
O
H
O
H
8
8
O
H
7
H
1'
O
OAc
H
OBn
OBn
2'
O
H
H
O
H
H
15-Ac
OBn
OBn
OBn
OBn
Figure 5. Important NOESY interactions in the acetate 15-Ac.
+
R
OBn
R
OBn
10
R
OBn
9
OBn
H
OBn
OBn
H
H
OBn
O
d)
d)
a
b
O
9
H
H
OBn
HO
R
OBn
OBn
OBn
OBn
H
OBn
HO 1'
HO
2'
OBn
OBn
OBn
O
7
HO
19
18
c
OBn
H
H
R
OBn
OBn
OBn
OBn
12
11
H
H
H
OBn
OBn
OBn
OBn
d
Scheme 1. (a) NaBH4; (b) OsO4 (cat.), NMMO; (c) (i) BnBr, NaH, DMF; (ii) mCPBA;
(d) PhSeSe/PhNaBH4 then H2O2.
H
OBn
1'
1'
HO
BnO
BnO
OBn
20
21
H
OBn
OBn
a)
5
Scheme 3. (a) HCl, EtOH, H2O, and THF (71%); (b) (i) NaIO4/SiO2, CH2Cl2; (ii) NaBH4,
11
10
1
MeOH (86%); (c) NaH, BnBr, and THF (90%).
H
H
O
OBn
2'
1'
13
H6 proton correlated to H5 and, which is most important, to H4.
The latter correlation confirmed the proposed structure. A correla-
tion between the protons from the acetyl group at C-6 and the
benzyl group at C-10 was also observed (Fig. 6).
O
b)
BnO
OBn
BnO
OBn
H
H
H
OBn
OBn
OBn
OBn
possible
route
9
H
H
H
H
H
OBn
OBn
H
O
5
3
HO
BnO
H
16
14
(25%)
AcO
OBn
4
HO
OBn
6
H
1
2
10
9
OBn
+
7
H
OBn
H
H
BnO
H
OBn
8
H
H
H
H
OBn
OBn
OBn
OBn
24-Ac
H
1'
H
OBn
O
H
H
OBn
H
OBn
OH
H
BnO
H
3
17
5
15
(61%)
BnO
6
OBn
4
OBn
7
H
b
H
Scheme 2. (a) BnBr, NaH, and DMF (60%); (b) H2SO4, H2O, and THF.
1
AcO
10
2
OBn
H
8
9
H
1'
a
25, respectively, by reaction with the selenide anion followed by
oxidative work-up (Scheme 4).
H
H
25-Ac
OBn
The structures of these allylic alcohols were also proven by the
NOESY NMR spectra of their acetates. In the spectrum of 24-Ac, the
Figure 6. Important NOESY interactions in the acetates 24-Ac and 25-Ac.

1504
M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
21
H
H
H
AcO
OBn
OBn
a
OBn
6
O
OBn
H
H
O
5
H
1
OBn
OBn
4
OBn
OBn
H
H
OBn
10
H
BnO
H
+
7
H
H
AcO
H
OBn
b
OBn
23
8
BnO
BnO
9
H
H
22
b
H
1
R
ratio ~ 1 : 1
AcO
O
R
10
OBn
H
9
OH
OBn
H
7
HO
AcO
4
OBn
H
5
OBn
8
R =
6
H
AcO
or -CH2OBn
OBn
H
OBn
H
O
OBn
OAc
H
OBn
BnO
twisted chair conformation
BnO
25
of left ring
24
Figure 7. Important NOESY interactions in the triacetates 26-Ac3 and 27-Ac3.
Scheme 4. (a) m-CPBA, CH2Cl2, 3 °C, 67%; (b) (i) PhSeSePh, NaBH4; (ii) H2O2.
be much smaller than that observed (6.5 Hz). On the other hand,
the H8 and H9 protons in the chair conformation would be axial,
so the J8,9 value should be about 10 Hz. We observed, however,
J = 6.7 Hz, which seems to prove the proposed distortion of the ‘left
ring’.
The other set of stereoisomeric compounds of this type was
available by inversion of the configuration at the carbinol center
under Mitsunobu conditions. Treatment of allylic alcohols 12 with
p-nitrobenzoic acid, DIAD, and triphenylphosphine afforded the
expected SN2 product 29. Similarly, treatment of alcohol 25 led
to 28 (Scheme 6).
AcO
OBn
H
H
HO
HO
OBn
OBn
6
a
24-Ac
OBn
BnO
26
(65%)
HO
OBn
OBn
OBn
H
H
6
ArCOO
OBn
OBn
HO
OBn
H
a
25
a
OBn
HO
11
H
OBn
BnO
O
28
(31% + 62% recovery
of the substrate)
O
27
(60%)
OBn
Scheme 5. (a) OsO4 (cat), NMMO, THF, and t-BuOH.
ArCOO
OBn
a
12
OBn
The structure of the 25-Ac was proposed on the basis of the ob-
served cross peaks between pairs: H7–H8b and H8a–H9, which
strongly suggested that they were in the cis-relationship.
Functionalization of the double bond in olefins 11 and 24-Ac
provided the polyhydroxylated derivatives 26 and 27 (Scheme 5)
as single products. This was rather surprising since the stereoselec-
tivity of the cis-dihydroxylation of the double bond is usually sen-
H
O
H
OBn
Ar = p-NO2Ph-
O
29 (25% + 60% recovery
of the substrate)
sitive to the oxygen functionality at the
a-position (the alkoxy or
Scheme 6. (a) p-NO2C6H4COOH, DIAD, and PhP3.
hydroxy groups usually secure a much higher selectivity than the
Although in such complex products (e.g., 11) an SN20 process
might be observed22 under Mitsunobu conditions, both reactions
performed for 12 and 25 afforded only the SN2 products (albeit
in low yield: ꢀ60% of the starting material was recovered in both
cases). No SN20 products were formed probably because of the hin-
dered syn trajectory required for this substitution of the double
bond.23
ester functions,23 that is, at the C-6 position).
The structures of both compounds 26 and 27 were assigned
from advanced NMR experiments. We have observed the NOE
interaction between H7 and H10. This strongly suggested that
two new hydroxyls were introduced (Fig. 7) from ‘the bottom’ of
the molecule, since in the alternative structure, such a correlation
is not possible.
The configuration of products obtained was confirmed by the
NOESY correlations (Fig. 8). Two systems of correlating protons
were detected for both products 28 and 29: H-8b, H-10, and H-1
and the second one: H7, H8a, H9, and H2. Such correlations fully
support the proposed structures.
Moreover, the distance between these two protons in 26 or 27
in the chair conformation is rather large; thus the presence of this
interaction suggests that the ‘left’ ring is distorted. This assumption
was supported by coupling constants. The J6,7 value in the chair
conformation (where both H6 and H7 would be equatorial) should

M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
1505
H
HO
HO
OBn
OBn
OBn
H
H
H
H
H
OBn
OBn
OBn
OBn
H
NCS
HS
HO
ArCOO
a)
a)
3
5 BnO
6
OBn
4
OBn
7
H
b
H
R
1
10
9
2
H
OBn
R
OBn
R
H
8
H
30
34 (69%)
OBn
H
a
HS
H
H
NCS
OBn
H
OBn
OBn
OBn
HO
28 R = CH2OBn 29 R =
O
OBn
O
H
H
R
OBn
R
OBn
Figure 8. Diagnostic NOESY interactions in derivatives 28 and 29.
31
35 (67%)
Scheme 8. (a) LiAlH4, THF.
The highly regioselective opening of the oxirane ring in com-
pounds 9 and 10 might open up a convenient route to derivatives
containing heteroatoms other than oxygen or nitrogen placed on
the decalin ring; we decided to check the possibility of introducing
sulfur and phosphorus nucleophiles. The treatment of epoxide 9
with an ether solution of HSCN24 afforded thiocyanate 30 as the
single product (Scheme 7).
Alternatiꢁvely, opening of the oxirane ring with the phosphide
anion [(PPh2 )25] provided the corresponding phosphine. Although
this reaction was performed under an argon atmosphere, we ob-
served the formation of significant amounts of the phosphine
oxide.26 After exposing the reaction mixture to air, the full conver-
sion to phosphine oxide 32 (Scheme 7) was noted.
It is reported that the treatment of thiocyanates with Grignard
reagents provides the corresponding dialkyl sulfides in good yields.
This methodology was successfully applied to the preparation of
glycosyl sulfides, important starting materials in the synthesis of
oligosaccharides.28a However, this reaction, besides the desired
dialkyl sulfides, also afforded significant amounts of the thiols
(resulting from reductive removal of the CN moiety).28a,b
In order to avoid the formation of a mixture (thiol/dialkyl sul-
fide), an alternative transformation can be used which is based
on the reduction of thiocyanates with lithium aluminum hydride.
Treatment of bicyclic derivatives 30 and 31 with LiAlH4 afforded
the desired thiols 34 and 35 in good yields (Scheme 8).
In the NMR spectra of 30, 31, 32, 34, and 35 recorded at room
temperature, broad signals were observed due to relatively slow
conformational changes, which disappeared at an elevated
(80 °C) temperature (see Section 4).
Since in the ‘right’ ring all of the benzyloxy groups are equato-
rial, it seems rather unlikely for the whole molecule to undergo
typical cis-decalin ring inversion, so this phenomenon results
(most probably) rather from the conformational mobility (chair
and twisted chair) of the ‘left’ ring.
The same sequence of reactions performed on the diastereoiso-
meric epoxide 10 provided the thio-cyanate 31 and phosphine
oxide 33, respectively. The determination of the configurations of
all compounds was based on 1D NOE experiments.
As expected on the basis of the Fürst/Plattner rule,27 the config-
uration of the products was trans-diaxial; the attack of the nucleo-
phile (either SCNꢁ or Ph2P–) occurred at the C7 carbon atom in
epoxide 9 and at the C6 atom in the alternative oxirane 10. This
regioselectivity of the opening of the three membered ring in sim-
ilar cis-decalins has been previously observed.21
OBn
OBn
2.1. Molecular docking
O
H
O
H
OBn
OBn
OBn
OBn
6
4
1
a)
7
a)
Compounds 27, 32, 33, 34, and 35 can be regarded as precursors
for structures 27a, 32a, 33a, 34a, and 35a (Fig. 9) which can be seen
as potential glycosidase inhibitors. The AutoDock 4.229 and Auto-
Dock Vina30 programs were used to perform docking studies (see
Section 4) on several human glycosidases which structures were
found at http://www.pdb.org. For our studies, we chose those al-
ready containing a ligand known for its inhibitory activity. The
most promising results were obtained for human pancreatic
lase (PDB ID:1U33), human lysosomal acid-b-glucosidase (PDB
ID:2NSX), and 3GXF) and human ER -mannosidase I (PDB ID:1FO3)
b)
b)
H
H
R
OBn
R
OBn
NCS
9
10
HO
OBn
OBn
H
H
OBn
OBn
OBn
NCS
HO
a-amy-
OBn
a
H
H
R
OBn
R
OBn
(Table 1). The ligands present in these structures were also subjected
to docking (‘ligand’, Table 1).
R
30
31
(71%)
(93%)
Comparing the results from AutoDock 4.2, 32a, and 33a gave
significantly better results than the other derivatives. They showed
slightly smaller (1U33, 2NSX, and 3GXF) or even higher (1FO3)
affinities than known inhibitors. A similar tendency was observed
using AutoDock Vina: again, 32a and 33a seemed to be the best
binding derivatives.à Most probably, the phenyl rings present in
these structures contribute significantly to the van der Waals term
in AD’s free energy force field. Visual analysis of the lowest energy
O
O
O
O
HO
OBn
Ph2P
OBn
H
H
H
H
Ph2P
OBn
OBn
HO
OBn
OBn
R
OBn
R
OBn
32 (71%)
33 (92%)
The ligand was assumed to be bound in the enzyme’s active site.
Differences in energy values result from the fact that Vina uses different scoring
à
Scheme 7. (a) (i) Ph2PK, THF; (ii) O2 (air); (b) HSCN, Et2O.
functions than AD 4.2.

1506
M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
O
HO
Ph2P
OH
OH
O
OH
OH
HO
OH
OH
H
H
H
H
H
HO
Ph2P
OH
OH
OH
OH
HO
HO
OH
OH
H
HO
27a
HO
HO
32a
33a
HS
OH
OH
HO
OH
OH
H
H
OH
OH
HO
OH
OH
HS
H
H
HO
HO
34a
35a
Figure 9. Structures subjected to molecular docking.
Table 1
Results of the molecular docking studies
1U33
2NSX
1FO3
3GXF
AD 4.2
Vina
AD 4.2
Vina
AD 4.2
Vina
AD 4.2
Vina
Liganda
27a
32a
33a
34a
ꢁ8.66b (ꢁ7.15c)
ꢁ6.45 (ꢁ5.20)
ꢁ8.47 (ꢁ7.41)
ꢁ7.78 (ꢁ6.74)
ꢁ7.21 (ꢁ5.55)
ꢁ7.19 (ꢁ5.64)
ꢁ9.2d
ꢁ7.3
ꢁ8.1
ꢁ7.9
ꢁ6.7
ꢁ7.0
ꢁ8.05 (ꢁ7.67)
ꢁ5.92 (ꢁ4.73)
ꢁ7.74 (ꢁ6.21)
ꢁ7.90 (ꢁ6.53)
ꢁ6.64 (ꢁ5.81)
ꢁ6.79 (ꢁ5.21)
ꢁ5.8
ꢁ6.6
ꢁ7.5
ꢁ8.0
ꢁ6.4
ꢁ6.1
ꢁ6.02 (ꢁ5.03)
ꢁ6.39 (ꢁ4.93)
ꢁ7.77 (ꢁ7.10)
ꢁ7.64 (ꢁ6.37)
ꢁ6.43 (ꢁ5.75)
ꢁ5.85 (ꢁ5.17)
ꢁ6.8
ꢁ7.5
ꢁ7.8
ꢁ7.4
ꢁ6.7
ꢁ6.5
ꢁ8.29 (ꢁ7.86)
ꢁ6.43 (ꢁ4.49)
ꢁ7.88 (ꢁ6.12)
ꢁ8.15 (ꢁ6.69)
ꢁ6.67 (ꢁ4.79)
ꢁ6.86 (ꢁ4.94)
ꢁ5.9
ꢁ6.6
ꢁ7.6
ꢁ8.0
ꢁ5.9
ꢁ6.1
35a
All values are presented in kcal/mol. Structures 2NSX and 3GXF represent the same enzyme complexed with isofagomine but at different pH values (4.5 and 7.5, respectively).
Standard error is ꢀ2.5 kcal/mol.
a
Binding energy of the ligand present in the PDB structure.
The lowest binding energy obtained.
Mean binding energy of the lowest energy cluster.
For Vina, only the best result is presented.
b
c
d
binding poses demonstrates that compounds 27a and 32a–35a bind
in the same pocket as the ligand from the PDB structure. The only
exception was observed in case of 3GXF for 33a when using Vina.
Overall, the docking studies indicated that structures 32a and
33a, among those shown in Table 1, seem to be especially good
inhibitors of human enzymes related to carbohydrate metabolism.
Optical rotations were measured with a Jasco P 1020 polarimeter
(sodium light). The IR spectra were recorded with a Perkin Elmer
Spectrum 2000 instrument. All MS spectra were recorded with a
Mariner PerSeptive Biosystems spectrometer. Thin layer chroma-
tography was performed on pre-coated plates (0.25 mm, silica
gel 60 F254). Column chromatography was carried out with silica
gel (230–400 mesh).
3. Conclusion
4.2. (1R,2R,3S,4R,5R,6R,9S,10R)-1,2,3,4,6-Pentabenzyloxy-9-
[(40R)-20,20-di methyl-10,30-dioxolane-40-yl]bicyclo[4.4.0]dec-7,8-
ene 13
In conclusion, we have demonstrated a useful methodology,
which allows us to prepare, in a predictable way, highly oxygen-
ated decalins from convenient precursors obtained directly from
sugar allyltins. Using the route presented herein, derivatives con-
taining phosphorus or sulfur units are made available. Further-
more, we have demonstrated, via molecular docking studies, that
the latter can be regarded as potential glycosidase inhibitors.
To a vigorously stirred solution of 11 (178 mg, 0.26 mmol) in
DMF (5 mL), imidazole (3 mg, 45 lmol) and sodium hydride were
added in one portion (11 mg, 0.52 mmol). After 15 min. benzyl bro-
mide (0.1 mL, 1 mmol) was added, the mixture was stirred for 1 h
at rt (TLC monitoring in hexane/EtOAc, 3:1) after which the reac-
tion was quenched with saturated aqueous NaHCO3 (15 mL). The
product was extracted with EtOAc (4 ꢂ 30 mL), the organic layer
was washed with brine (30 mL), dried, and concentrated. Purifica-
tion of the residue by column chromatography (hexane/EtOAc,
10:1) afforded compound 13 as a colorless oil (118 mg, 60%).
4. Experimental
4.1. General experimental methods
The NMR spectra were recorded with a Varian 600 MHz or Bru-
ker 500 MHz in CDCl3 at 25 °C unless otherwise stated. The struc-
tures were assigned, whenever necessary, with the help of 2D
correlation experiments (COSY, HSQC, HMBC, and NOESY). Chemi-
cal shifts were reported with reference to TMS (1H) or H3PO4 (31P).
½
a 2D2
ꢃ
¼ ꢁ11:2 (c 1, CHCl3); m/z = 789.4 ([M+Na]+); 1H NMR
(500 MHz) d: 6.05 (1H, dd, J8,7 = 10.2 Hz, J8,9 = 2.9 Hz, H-8), 5.86
(1H, m, H-7), 5.04 (1H, m, H-10), 4.93–4.36 (10H, OCH2Ph), 4.04
(1H, dd, J = 5.4 Hz, J = 2.1 Hz, H-6), 3.84–3.78 (2H, d and d,

M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
1507
J = 9.9 Hz, J = 6.9 Hz, H-2, H-20a), 3.70 (1H, app. t, J = 7.4 Hz, H-20b),
4.4.2. (1R,2R,3S,4R,5R,9S,10R)-1,2,3,4-Tetrabenzyloxy-9-
3.48–3.54 (1H, dd, J1,10 = 6.8 Hz, J1,2 = 10.2 Hz, H-1), 3.53 (1H, app.
t, J2,3 = 10.1 Hz, H-3), 3.34 (1H, dd, J3,4 = 11.5 Hz, J4,5 = 9.1 Hz, H-
4), 2.72 (1H, m, H-9), 2.17 (1H, dt, J5,10 = 6.4 Hz, J9,10 = 10.6 Hz, H-
10), 1.93 (1H, m, H-5), 1.42 and 1.19 ppm (6H, 2 ꢂ s, C(CH3)2).
13C NMR (125 MHz, CDCl3, 25 °C) d: 130.5 (C-8), 126.4 (C-7),
108.4 (C(CH3)2), 86.6 (C-3), 83.9 (C-1), 82.7 (C-2), 78.7 (C-4),
75.99 (C-10), 75.96, 75.8, 75.1, 73.6, and 70.3 (5 ꢂ OCH2Ph), 69.3
(C-6), 64.9 (C-20), 41.6 (C-5), 37.1 (C-9), 32.1 (C-10), 26.0 and
24.4 ppm (C(CH3)2). Anal. Calcd for C50H54O7: C 78.3, H 7.1. Found:
C 78.3, H 6.9%.
hydroxymethylbicyclo[4.4.0]dec-6,7-ene 20
To a vigorously stirred solution of the diol 18 (2.71 g, 4.4 mmol)
in dichloromethane (100 mL) containing small amounts of water
(1 mL), NaIO4 adsorbed on silica gel (11.5 g of SiO2, with approxi-
mately 7 mmol of NaIO4)31 was added in portions and stirring
was continued for 4 h (TLC monitoring in hexane/EtOAc, 3:1). Next,
the solid was filtered off and the filtrate was concentrated to afford
crude aldehyde 19 (2.31 g), which was used directly in the next
step.
Aldehyde 19 (2.31 g, 3.93 mmol) was dissolved in a THF/meth-
anol/water mixture (30 + 30 + 5 mL) to which NaBH4 (260 mg,
7 mmol) was added in portions. After 3 h (TLC monitoring in hex-
ane/EtOAc, 3:1) saturated aqueous NaHCO3 (20 mL) was added and
the solvent was removed in vacuo. The residue was partitioned be-
tween water (50 mL) and EtOAc (30 mL), the organic phase was
separated, and aqueous phase extracted with EtOAc (3 ꢂ 30 mL).
The combined organic solutions were washed with brine, dried,
and the product was isolated by column chromatography (hex-
ane/EtOAc, 4:1–3:1) to afford 20 as a colorless oil (2.27 g, 86% from
the diol), which was characterized as acetate 20-Ac.
4.3. Removal of the isopropylidene protecting group from 13
To a solution of 13 (118 mg, 0.154 mmol) in THF (15 mL), H2SO4
(17% aqueous solution, 6 mL) was added slowly and the mixture
was heated at reflux until all of the starting materials were con-
sumed (5 h; TLC monitoring). The reaction was quenched with sat-
urated aqueous NaHCO3 (50 mL) and the product was extracted
with EtOAc (5 ꢂ 20 mL). The organic layer was washed with brine
(30 mL), dried, concentrated, and the residue was purified by col-
umn chromatography (hexane/EtOAc, 3:1) to afford compound
14 (28 mg, 25%) and compound 15 (58 mg, 61%), characterized as
acetate 15-Ac, as a colorless oil.
4.4.3. (1R,2R,3S,4R,5R,9S,10R)-1,2,3,4-Tetrabenzyloxy-9-
acetyloxymethyl bicyclo[4.4.0]dec-6,7-ene 20-Ac
½
a 2D2
ꢃ
¼ þ103:7 (c 1, CHCl3); m/z = 655.5 ([M+Na]+). 1H NMR
4.3.1. (1R,2R,3S,4R,5R,6S,9S,10R)-1,2,3,4,6-Pentabenzyloxy-9-
[(40R)-10,20-dihydroxyeth-10-yl]bicyclo[4.4.0]dec-7,8-ene 14:
m/z = 749.8 ([M+Na]+)
(500 MHz) d: 5.96 (1H, m, H-6), 5.73 (1H, m, H-7), 4.74–4.65 (3H,
m, H-1a0,OCH2Ph), 4.09 (1H, dd, J9,1 b = 7.3 Hz, J1 a,1 b = 11 Hz, H-
1b0), 3.85 (1H, m, J1,2 = 9.2 Hz, H-2), 3.61–3.53 (3H, m, H-1, H-3,
H-4), 2.36–2.28 (1H, m, H-8a), 2.25–2.15 (3H, m, H-5, H-9, H-10),
1.95 (3H, s, COCH3), 1.94–1.87 ppm (1H, m, H-8b). 13C NMR
(125 MHz; CDCl3, 25 °C) d: 171.1 (COCH3), 128.3 (C-5), 126.9 (C-
6), 128.4–127.2 (C arom.), 86.6 (C-1), 84.8 (C-3), 83.5 (C-4), 81.6
(C-2), 67.4 (C-10), 39.9 (C-5), 38.3(C-10), 32.5 (C-9), 30.7 (C-8),
20.8 ppm (COCH3). Anal. Calcd for C39H42O5 + H2O: C 77.0, H 7.3.
Found: C 76.8, H 7.1%.
0
0
0
Compound 15-Ac:
½
a 2D2
ꢃ
¼ þ171:2 (c 1, CHCl3); m/z = 683.3
([M+Na]+). 1H NMR (600 MHz) d: 6.20 (1H, ddd, J6,8 = 1 Hz,
J6,5 = 5.9 Hz, J6,7 = 9.9 Hz, H-6), 5.99 (1H, m, H-10), 5.91 (1H, dd,
J7,8 = 3.9 Hz, H-7), 4.39 (1H, t, J8,9 = 4.7 Hz, H-8), 4.09 (1H, dd,
J1 ,2 = 4.6 Hz, J2 ,2 = 10.6 Hz, H-20), 3.98 (1H, t, J2,3 = J1,2 = 9.5 Hz, H-
0
0
0
0
2), 3.75–3.25 (1H, dd, J1 ,2 = 1.9 Hz, H-20), 3.64 (1H, dd,
J1,10 = 4.6 Hz, J1,2 9.9 Hz, H-1), 3.55 (1H, t, J3,4 = 9.1 Hz, H-3), 3.39
0
0
0
(1H, dd, J4,5 = 10.9 Hz, H-4), 2.45 (1H, ddd, J1 ,9 = 5.8 Hz,
J9,10 = 12.8 Hz, H-9), 2.22 (1H, m, H-5), 2.03 (3H, s, CH3CO),
2.02 ppm (1H, m, H-10). 13C NMR (150 MHz) d: 170.4 (CH3CO),
132.7 (C-6), 125.9 (C-7), 86.4 (C-3), 83.5 (C-4), 82.9 (C-1), 81.9
(C-2), 78.6 (C-10), 73.6 (C-8), 71.1 (C-20), 42.8 (C-9), 39.2 (C-5),
34.1 (C-10), 21.1 ppm (CH3CO).
4.4.4. (1R,2R,3S,4R,5R,9S,10R)-1,2,3,4,Tetrabenzyloxy-9-
benzyloxymethylbicyclo[4.4.0]dec-6,7-ene 21
To a vigorously stirred solution of 20 (2.27 g, 3.84 mmol) in
DMF (30 mL) imidazole (15 mg, 225 lmol) and sodium hydride
(163.5 mg, 7.7 mmol) were added in one portion. After 15 min.
benzyl bromide (1.5 mL, 15 mmol) was added and the mixture
was stirred for 1 h (TLC monitoring in hexane/EtOAc, 3:1). Satu-
rated aqueous NaHCO3 (15 mL) was added, the product was ex-
tracted with EtOAc (4 ꢂ 30 mL), the organic layer was washed
with brine (30 mL), dried, and concentrated. Purification of the res-
idue by column chromatography (hexane/EtOAc, 10:1) afforded
4.4. Removal of the isopropylidene protecting group from 7
To a solution of 7 (4.11 g, 6.23 mmol) in THF (50 mL), 5% aque-
ous HCl (20 mL) was slowly added and the reaction mixture was
heated at reflux. After 3 h (TLC monitoring), the reaction was
quenched with saturated aqueous NaHCO3 (30 mL) and the prod-
uct was extracted with EtOAc (3 ꢂ 30 mL). The organic layer was
washed with brine (30 mL), dried, concentrated, and the product
was purified by column chromatography (hexane/EtOAc, 3:1) to af-
ford diol 18 as a colorless oil (2.71 g, 71%), which was characterized
as a diacetate.
compound 21 as a colorless oil (2.36 g, 90%). ½a D22
¼ þ71:0 (c 1,
ꢃ
CHCl3); m/z = 703.4 ([M+Na]+), 1H NMR (500 MHz) d: 5.93 (1H,
m, H-6), 5.76 (1H, m, H-7), 4.03–3.95 (1H, m, H-10a), 3.81–3.76
(1H, t, J1,2 = J2,3 = 9.7 Hz, H-2), 3.61–3.52 (3H, m, H-1,3,4), 3.46–
3.41 (1H, m, H-10b), 2.54–2.47 (1H, m, H-8a), 2.22–2.15 (3H, m,
H-5, H-9, H-10), 1.98–1.90 (1H, m, H-8b). 13C NMR (125 MHz) d:
128.3–127.2 (C-5, C-6, C arom.), 86.7 (C-1), 84.9 (C-2), 83.7 (C-3),
81.4 (C-4), 73.0 (C-10), 40.0 (C-5), 38.2 (C-9), 33.7 (C-10),
31.2 ppm (C-8).
4.4.1. (1R,2R,3S,4R,5R,9S,10R)-1,2,3,4-Tetrabenzyloxy-9-((10R)-
10,20-diacetyloxy-eth-10-yl)bicyclo[4.4.0]dec-6,7-ene 18-(Ac)2:
m/z = 643.3 ([M+Na]+)
Anal. Calcd for C46H48O5: C 81.2, H 7.1. Found: C 81.1, H 7.3%.
1H NMR (500 MHz) d: 5.98–5.90 (2H, m, H-6, H-10), 5.75–5.70
(1H, m, H-7), 5.06–4.55 (8H, OCH2Ph), 4.18–4.10 (3H, m, 2 ꢂ H-
20, H-2), 3.61 (1H, dd, J1,10 = 4.2 Hz, J1,2 = 10.3 Hz, H-1), 3.57–3.48
(2H, m, H-3,4), 2.35–2.20 (4H, m, H-5, H-8a, H-9, H-10), 2.09 (3H,
s, CH3CO), 1.97–1.85 (1H, m, H-8b), 1.78 ppm (3H, s, CH3CO). 13C
NMR (125 MHz) d: 128.3–127.7 (C-5,6 and C arom.), 86.8 and
84.8 (C-3,4), 83.4 (C-1) 81.8 (C-2), 75.7, 75.6, 75.5, and 75.1
(4 ꢂ OCH2Ph), 72.8 (C-10), 63.1 (C-20), 40.6 (C-5), 39.3 (C-9), 35.6
(C-10), 26.7 (C-8), 21.2 and 20.7 ppm (2 ꢂ CH3CO).
4.5. Epoxidation of 21
To a stirred and cooled to 4 °C solution of 21 (1.25 g, 1.84 mmol)
in dichloromethane (20 mL), 55% 3-chloroperbenzoic acid (800 mg,
3.5 mmol) was added and the mixture was kept for 24 h at rt. The
reaction was quenched with 2% aqueous NaOH (100 mL), the layers
were separated, and the aqueous one extracted with CH2Cl2
(3x20 mL). Combined organic solutions were washed with brine,

1508
M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
dried, concentrated, and the residue was purified by column chro-
matography (hexane/EtOAc, 4:1) to afford a 1:1 mixture of 22 and
23 (0.86 g, 67%). m/z = 719.5 ([M+Na]+). 1H NMR (500 MHz) d:
3.89–3.86 (H-10), 3.79–3.75 (H-10), 3.97–3.92, 3.73–3.65, 3.61–
3.56, 3.46–3.38 (H-1, H-2, H-3, H-4), for 22: 3.29 (H-6), 2.94 (H-
7); for 23: 3.39 (H-6), 3.33 (H-7), 3.26–3.22 (H-10), 2.54–2.48,
2.25–2.10, 1.98–1.78, 1.67–1.55 ppm (H-5, H-8, H-9, H-10). 13C
NMR (125 MHz) d: 87.1, 86.5, 83.7, 81.4, 79.9, 79.2 (C-1, C-2, C-3,
C-4), 71.9 (C-10), for 22: 53.9 (C-7), 51.5 (C-6), for 23: 53.7 (C-7),
53.0 (C-6), 38.9, 37.7, 32.9, 31.6, 30.06 (C-5, C-9, C-10), 31.0, and
27.7 ppm (C-8). Anal. Calcd for C46H48O6 + 1 4H2O: C 78.8, H 7.0.
Found: C 78.9, H 6.9%.
BuOH; 0.1 mL, 10 lmol) and the mixture was stirred for 5 days at
rt (TLC monitoring in hexane/EtOAc, 2:1). Methanol (10 mL) was
added followed by saturate aqueous NaHSO3 (3 mL). The mixture
was filtered through Celite, and the filtrate was partitioned be-
tween water (30 mL) and EtOAc (30 mL). The aqueous phase was
extracted with EtOAc (3 ꢂ 30 mL), the combined organic solutions
were washed with brine (40 mL), dried, and concentrated. Column
chromatography (hexane/EtOAc 6:1–3:1) afforded product 26
(37 mg, 65%), which was characterized as a triacetate.
4.7.1. (1R,2R,3S,4R,5R,6S,7R,8S,9S,10R)-1,2,3,4-Tetrabenzyloxy-
6,7,8-triacetyloxy-9-benzyloxymethylbicyclo[4.4.0]decane 26-
(Ac)3
4.6. Isomerization of epoxides 22 and 23
½
a 2D2
ꢃ
¼ ꢁ34:5 = (c 1, CHCl3); m/z = 879.5 ([M+Na]+). 1H NMR
(600 MHz) d: 5.49 (1H, dd, J5,6 = 2.0 Hz, J6,7 = 3.0 Hz, H-6), 5.39
(1H, dd, J7,8 = 3.6 Hz, H-7), 5.31 (1H, dd, J8,9 = 10.8 Hz, H-8), 4.09
(1H, d, J4,3 = 9.2 Hz, H-4), 4.07 (1H, d, J50a,50b = 9.0 Hz, H-50a), 3.8
(1H, dd, J = 9.3 Hz, J = 10.3 Hz, H-2), 3.56–3.51 (2H, m, H-1, H-3),
3.48 (1H, dd, J40,50b = 2.6 Hz, H-50b), 2.78–2.73 (1H, m, H-10),
2.14 (1H, m, H-9), 1.87 (1H, m, H-5), 2.12, 2,05, and 1.78 ppm
(9H, 3 ꢂ s, 3 ꢂ CH3CO). 13C NMR (150 MHz) d: 169.7, 169.2, and
169.1 (3 ꢂ COCH3), 87.3 (C-1), 83.5 (C-3), 81.3 (C2), 78.0 (C-4),
69.4 (C-8), 68.9 (C-6, C-7), 65.1 (C-10), 42.8 (C-5), 35.4 (C-9), 32.7
(C-10), 21.2, 21.1, and 20.7 ppm (3 ꢂ COCH3). Anal.: Calcd for
C52H56O11 + ½H2O: C 72.1, H 6.63. Found: C 72.2, H 6.9%.
To a solution of diphenyl diselenide (64 mg, 0.2 mmol) in anhy-
drous ethanol (5 mL), sodium borohydride (37 mg, 1.0 mmol) was
added in portions under an argon atmosphere until the disappear-
ance of the yellow color. After 5 min. a solution of a mixture of
epoxides 22 and 23 (204 mg, 0.29 mmol) in anhydrous ethanol/
THF (2 mL; 1:1 v/v) was added. The mixture was then heated at re-
flux for 2 h, then diluted with THF (10 mL), and cooled to 0 °C (ice-
bath). Hydrogen peroxide (0.5 mL of a 30% solution in water,
4.4 mmol) was added dropwise, and the mixture was then allowed
to warm to rt., and then kept at this temperature overnight. Satu-
rated aqueous Na2SO4 (100 mL) and diethyl ether (20 mL) were
added, the layers were separated and the aqueous phase extracted
with diethyl ether (3 ꢂ 20 mL). The combined organic solutions
were washed with saturated aqueous Na2CO3 (50 mL), dried, con-
centrated, and the products were isolated by column chromatogra-
phy (hexane/EtOAc, 4:1–3:1) to afford 24 (68.7 mg, 32%) and 25
(43.5 mg, 20%) which were characterized as acetates.
4.8. The cis-dihydroxylation of 11
Compound 11 (36.6 mg, 54 lmol) was dissolved in THF (4 mL)
to which t-BuOH (0.4 mL), water (0.05 mL), and N-methyl-morpho-
line-N-oxide (40 mg, 0.3 mmol) were added, followed by OsO4
(2.5% solution in t-BuOH; 0.1 mL, 10 lmol), and the mixture was
stirred for 5 days at rt (TLC monitoring in hexane/EtOAc, 2:1).
Methanol (10 mL) was then added followed by saturated aqueous
NaHSO3 (3 mL), the mixture was filtered through Celite, and the fil-
trate was partitioned between water (30 mL) and EtOAc (30 mL).
The aqueous phase was extracted with EtOAc (3 ꢂ 30 mL), the
combined organic layers were washed with brine (40 mL), dried,
and concentrated. Column chromatography (hexane/EtOAc 6:1–
3:1) afforded product 27 (26.6 mg, 60%), which was characterized
as a triacetate.
4.6.1. (1R,2R,3S,4R,5R,6R,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
acetyloxy-9-benzyloxymethylbicyclo[4.4.0]dec-7,8-ene 24-Ac
½
a 2D2
ꢃ
¼ ꢁ12:5 (c 1, CHCl3); m/z = 719.4 ([M+Na]+). 1H NMR
(500 MHz) d: 6.07 (1H, dd, J7,8 = 10.0 Hz, J8,9 = 2.3 Hz, H-8), 5.79–
5.75 (1H, m, H-7), 5.43–5.40 (1H, dd, J6,7 = 1.5 Hz, J5,6 = 5.3 Hz,
H-6), 4.41 (2H, m, H-10, OCH2Ph), 4.00 (1H, dd, J9,1 = 3.3 Hz,
0
J1 ,1 = 8.7 Hz, H-10), 3.80 (1H, t, J1,2 = J2,3 = 9.5 Hz, H-2), 3.61–3.55
(2H, m, H-1,3), 3.55–3.51 (1H, m, H-10), 3.39 (1H, dd, J4,5 = 9.2 Hz,
J3,4 = 10.2 Hz, H-4), 2.58–2.52 (1H, m, H-10), 2.52–2.46 (1H, m, H-
9), 1.99 (3H, s, CH3CO), 1.88–1.84 ppm (1H, m, H-5). 13C NMR
(125 MHz) d: 170.2 (CH3CO), 138.7–138.6 (C-arom), 135.6 (C-8),
128.4–127.2 (C-arom), 122.4 (C-7), 86.4 (C-1), 83.9 (C-2), 82.5 (C-
3), 78.3 (C-4), 72.91 (C-10), 66.4 (C-6), 41.5 (C-5), 35.9 (C-9), 30.7
(C-10), 21.2 (CH3CO). Anal. Calcd for C48H50O7: C 78.0, H 6.8.
Found: C 77.9, H 6.9%.
0
0
4.8.1. (1R,2R,3S,4R,5R,6S,7R,8S,9S,10R)-{1,2,3,4-Tetrabenzyloxy-
6,7,8-triacetyloxy-9-[(40R)-20,20-dimethyl-[10,30]-dioxolan-40-
yl]}bicyclo[4.4.0]decane 27-Ac3
m/z = 859.7 ([M+Na]+). 1H NMR (600 MHz) d: 5.62 (1H, dd,
J7,8 = 3.7 Hz, J8,9 = 6.7 Hz, H-8), 5.43 (1H, m, H-6), 5.09 (1H, dd,
J6,7 = 6.5 Hz, H-7), 4.67–4.64 (1H, m, C-40), 3.99–3.95 (1H, t,
J3,4 = J4,5 = 9.2 Hz, H-4), 3.95–3.91 (1H, t, J = 6.5 Hz, H-5a0), 3.87
(1H, t, J = 7.5 Hz, H-2), 3.67–3.61 (3H, m, H-5b,1,3), 2.45–2.41
(1H, m, H-5) 2.42–2.37 (1H, m, H-10), 2.18–2.13 (1H, m, H-9),
1.99–1.97 (6H, m, 2 ꢂ COCH3), 1.94 (3H, s, COCH3), 1.39–1.36
(3H, s, C(CH3)2), 1.27–1.24 ppm (3H, s, C(CH3) 2). 13C NMR
(150 MHz) d: 170, 169.5 and 169.5 (3 ꢂ COCH3), 108.5 (C(CH3)2),
85.9 (C-1), 81.7 (C-3), 81.3 (C-2), 78.6 (C-4), 75.4 (C-10), 73.5 (C-
7), 72.4 (C-8), 68.8 (C-6), 66.4 (C-20), 43.2 (C-5), 39.9 (C-9), 34.1
(C-10), 26.2 and 25.2 (C(CH3)2), 21.1 and 20.8 ppm (3 ꢂ COCH3).
4.6.2. (1R,2R,3S,4R,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-7-
acetyloxy-9-benzyloxymethyl-bicyclo[4.4.0]dec-5,6-ene 25-Ac
½
a 2D2
ꢃ
¼ ꢁ7:1 (c 1, CHCl3); m/z = 719.5 ([M+Na]+). 1H NMR
(500 MHz) d: 6.07 (1H, m, H-6), 5.33 (1H, m, H-7), 4.28 (1H, d,
J3,4 = 7.8 Hz, H-4), 3.82–3.77 (3H, m, H-1, H-2, H-3), 3.24–3.15
(2H, m, H-10), 2.51–2.49 (1H, m, H-10), 2.22–2.14 (1H, m, H-9),
2.02 (3H, s, COCH3), 2.01–1.95 (1H, m, H-8a), 1.73–1.66 ppm (1H,
m, H-8b). 13C NMR (125 MHz) d: 170.7 (CH3CO), 141.3 (C-5),
122.7 (C-6), 82.0 (C-1), 79.9 (C-2), 78.6 (C-4), 76.2 (C-3), 72.2 (C-
10), 66.7 (C-7), 37.9 (C-10), 31.5 (C-8), 30.9 (C-9), and 21.4 (CH3CO).
Anal. Calcd for C48H50O7: C 78.0, H 6.8. Found: C 77.8, H 6.9%.
4.9. Mitsunobu reaction of 12
(This reaction was conducted under an argon atmosphere) To a
4.7. The cis-dihydroxylation of 24-Ac
solution of 12 (21 mg, 30 lmol) in dry THF (5 mL), p-nitrobenzoic
acid (16.8 mg, 0.1 mmol) and Ph3P (26.3 mg, 0,1 mmol) were
added followed by DIAD (20 mg, 0.1 mmol). The mixture was
heated at reflux for 6 h, cooled to rt, and quenched with saturated
aqueous NaHCO3 (10 mL). Next it was partitioned between water
To a solution of 24-Ac (54.1 mg, 73.2 lmol) in THF (4 mL), t-
BuOH (0.4 mL), and water (0.05 mL), N-methylmorpholine-N-oxide
(40 mg, 0.3 mmol) was added, followed by OsO4 (2.5% solution in t-

M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
1509
(30 mL) and EtOAc (20 mL), the organic phase was separated, and
the aqueous one extracted with EtOAc (3 ꢂ 30 mL). The combined
organic solutions were washed with brine (30 mL), dried, concen-
trated, and the residue was purified by column chromatography
(hexane/EtOAc 5:1–2:1) to afford 28 (8 mg, 31%) and unreacted
substrate 12 (13 mg, 62%).
formation of a new slightly more polar product. The reaction mix-
ture was quenched with saturated aqueous NaHCO3 (10 mL) and
partitioned between ethyl acetate (20 mL) and water (20 mL).
The organic layer was separated, and the aqueous one extracted
with EtOAc (2 ꢂ 20 mL). The combined organic solutions were
washed with water (15 mL) and brine (15 ml), dried, concentrated,
and the product was isolated by column chromatography (hexane/
ethyl acetate, 4:1–3:1) to afford thiocyanate 31 (from 10;
106.5 mg, 71%) or 30 (from 9; 143.5 mg, 93%) as amorphous solids.
These compounds were characterized as acetates.
4.9.1. (1R,2R,3S,4R,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-9-
benzyloxymethylbicyclo[4.4.0]-dec-5,6-en-7-yl 4-nitrobenzoate
28
½
a 2D2
ꢃ
¼ þ35:2 (c 1, CHCl3); m/z = 868.5 [M+Na]+). 1H NMR
(600 MHz) d: 6.01 (1H, s, H-6), 5.75 (1H, m, H-7), 4.21 (1H, d,
J3,4 = 6.6 Hz, H-4), 3.86–3.82 (1H, m, H-3), 3.76 (2H, m, H-1,2),
3.23–3.16 (2H, m, H-10), 2.72–2.68 (1H, d, J10,9 = 7.3 Hz, H-10),
2.36–2.35 (1H, m, H-8a), 2.26–2.24 (1H, m, H-9), 1.70–1.67 ppm
(m, 1H, H-8b). 13C NMR (150 MHz) d: 164.3 [OC(O)C6H4-p-NO2],
150.4 (C-5), 125.4 (C-6), 80.9 (C-3), 78.7 (C-4), 78.4 (C-2), 76,0
(C-1), 72.4 (C-10), 72.0 (C-7), 37.1 (C-10), 33.8 (C-9), 31.7 (C-8).
Anal.: Calcd for C53H51O9N + 1/2H2O: C 74.5, H 6.1, N 1.6. Found:
C 74.3, H 6.1, N 1.6%.
4.11.1. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
acetyloxy-7-thiocyano-9-[(40R)-20,20-dimethyl-10,30-dioxolan-40-
ylo]bicyclo[4.4.0]decane 30-Ac
½
a 2D2
ꢃ
¼ þ16:6 (c 1, CHCl3); m/z: 800.3193; Calcd for C46H51NO8S-
Na (M+Na+): 800.3228. IR (CHCl3 film)
: 2153 (SCN), 1741, 1454,
1370, 1225, 1069, 736, 698 cmꢁ1 1H NMR (600 MHz, DMSO-d6,
m
.
80 °C) d: 5.55 (1H, app. t, H-6, J = 10.0 Hz), 4.68–4.46 (8H, m,
OCH2Ph), 4.31 (1H, app. dd, H-10, J = 14.2, 6.7 Hz), 4.00 (1H, dd,
H-20a, J = 7.9, 6.5 Hz), 3.78 (1H, m, H-2), 3.71 (4H, m, H-1, H-3, H-
4, H-7), 3.53 (1H, m, H-20b), 2.61 (1H, m, H-10), 2.38 (2H, m, H-5,
H-8a), 1.90 (3H, s, CH3CO), 1.84 (2H, m, H-8b, H-9), 1.30 and
1.27 ppm (2 ꢂ s, 6H, (CH3)2C). 13C NMR (150 MHz, DMSO-d6,
80 °C) d: 169.2 (CH3CO), 110.5 (SCN), 108.0 (C-40), 81.7 (C-1),
79.2 (C-3), 77.9 (C-2), 76.3 (C-4), 75.8 (C-10), 73.8 (C-6), 67.0 (C-
20), 49.2 (C-7), 41.2 (C-5), 40.0 (C-9) 31.9 (C-10), 31.6 (C-8), 26.2
and 25.0 ((CH3)2C), 20.0 ppm (CH3CO).
4.10. Mitsunobu reaction of 25
(This reaction was conducted under an argon atmosphere) To a
solution of 25 (96.4 mg, 143 lmol) in dry THF (5 mL), p-nitroben-
zoic acid (50.1 mg, 0.29 mmol), and Ph3P (78.6 mg, 0.29 mmol)
were added followed by DIAD (20 mg, 0.1 mmol). The mixture
was heated at reflux for 4 h, cooled to rt., and quenched with sat-
urated aqueous NaHCO3 (10 mL). Next, it was partitioned between
water (30 mL) and EtOAc (20 mL), the organic phase was sepa-
rated, and the aqueous one extracted with EtOAc (3 ꢂ 30 mL).
The combined organic solutions were washed with brine (30 mL),
dried, concentrated, and the residue was purified by column chro-
matography (hexane/EtOAc 5:1–2:1) to afford 29 (30 mg, 25%) and
unreacted substrate 25 (58 mg, 60%).
4.11.2. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
thiocyano-7-acetyloxy-9-[(40R)-20,20-dimethyl-10,30-dioxolan-40-
yl]bicyclo[4.4.0]decane 31-Ac
½
a 2D2
ꢃ
¼ ꢁ1:4 (c 1, CHCl3); m/z: 800.3190; Calcd for C46H51NO8S
(M+Na+): 800.3228. IR (CHCl3 film)
: 2152 (SCN), 1742, 1454,
1370, 1230, 1068, 736, 698 cmꢁ1 1H NMR (600 MHz, DMSO-d6,
m
.
80 °C) d: 5.04 (td, 1H, H-7, J = 8.6, 5.0 Hz), 4.65–4.51 (m, 8H,
OCH2Ph), 4.30 (dd, 1H, H-10, J = 13.4, 6.6 Hz), 4.10 (m, 1H, H-4),
4.06 (m, 1H, H-6), 3.90 (m, 2H, H-2, H-20a), 3.80 (app. t, 1H, H-3,
J = 5.3 Hz), 3.74 (app. t, 1H, H-1, J = 3.4 Hz), 3.54 (dd, 1H, H-20b),
2.57 (m, 1H, H-10), 2.36 (app. dt, 1H, H-5, J = 10.4, 5.4 Hz), 2.15
(ddd, 1H, H-8a, J = 14.0, 8.8, 5.4 Hz), 2.02 (m, 1H, H-9), 2.00 (s,
3H, CH3CO), 1.69 (app. dt, 1H, H-8b, J = 13.6, 5.0 Hz), 1.29 and
1.23 ppm (2 ꢂ s, 6H, (CH3)2C). 13C NMR (150 MHz, DMSO-d6,
80 °C) d: 168.8 (CH3CO), 110.2 (SCN), 107.9 (C-40), 81.3 (C-1),
79.0 (C-3), 76.5 (C-2), 76.3 (C-4), 75.9 (C-10), 71.7 (C-7), 66.3 (C-
20), 51.4 (C-6), 39.1 (C-5), 37.2 (C-9), 32.7 (C-10), 29.5 (C-8), 26.2
and 25.0 ((CH3)2C), 20.2 ppm (CH3C(O)).
4.10.1. (1R,2R,3S,4R,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-9-[(40R)-
20,20-dimethyl-10,30-dioxolan-40-yl]bicyclo[4.4.0]-dec-5,6-en-7-yl
4-nitrobenzoate 29
½
a 2D2
ꢃ
¼ þ80:7 (c 1, CHCl3); m/z = 848.5 ([M+Na]+). 1H NMR
(600 MHz) d: 6.01 (1H, s, H-6), 5.71 (1H, m, H-7), 4.17 (1H, d,
J3,4 = 6.4 Hz, H-4), 4.06 (1H, m, H-1), 3.95–3.1 (2H, m, H-40,50),
3.83–3.81 (1H, dd, J2,3 = 4.1 Hz, H-3), 3.76–3.72 (1H, dd,
J1,2 = 1.9 Hz, H-2), 3.56–3.52 (1H, m, H-50), 2.72–2.69 (1H, m, H-
10), 2.28–2.22 (1H, m, H-9), 2.20–2.17 (1H, m, H-8a), 1.47–1.42
(1H, m, H-8b), 1.36 and 1.25 ppm (3H, 2 ꢂ s, C(CH3)2). 13C NMR
(150 MHz) d: 164.2 [OC(O)C6H4–4-NO2], 150.5 (C-5), 109.0
(C(CH3)2), 71.3 (C-7), 125.9 (C-6), 80.6 (C-3), 78.7 (C-4), 78.4 (C-
40), 77.8 (C-2), 77.1 (C-2), 67.6 (C-50), 38.1 (C-10), 35.9 (C-9), 29.5
(C-8), 26.7, and 25.7 ppm (C(CH3)2). Anal. Calcd for C50H51O10N +
2H2O: C 69.67, H 6.43, N 1.62. Found: C 69.4, H 6.21, N 1.94.
4.12. Reaction of oxiranes 9 and 10 with the phosphide anion
General procedure: To a stirred solution of epoxide 9 or 10
(50 mg, 0.073 mmol) in dry THF (30 mL, distilled over sodium prior
to use), under an argon atmosphere, potassium diphenylphosphide
[Ph2PK; 0.37 ml of a 0.5 M solution in THF] was added at room tem-
perature. After 40 min., the solution changed color from orange to
pale yellow and TLC analysis (hexane/ethyl acetate, 3:1) indicated
the disappearance of the starting material. The crude reaction mix-
ture (composed of the phosphine and phosphine oxide) was ex-
posed to air; after 1.5 h TLC confirmed the full conversion of the
phosphine into the phosphine oxide. The mixture was partitioned
between water (50 mL) and ethyl acetate (30 mL); the organic layer
was separated, and the aqueous one extracted with EtOAc
(2 ꢂ 30 mL). The combined organic solutions were washed with
water (15 mL) and brine (15 ml), dried, concentrated, and the prod-
uct was isolated by column chromatography (hexane/ethyl acetate,
3:1) to afford 33 (from 10; 59 mg, 92%) or 32 (from 9; 42 mg, 71%) as
amorphous solids. Compound 32 was characterized as an acetate.
4.11. Reaction of oxiranes 9 and 10 with HSCN
General procedure: An ether solution of HSCN was prepared
according to the literature.24 Six drops of concentrated ortho-phos-
phoric acid were added to a saturated aqueous solution of KSCN
(20 mL) and the in situ formed HSCN was extracted with diethyl
ether (10 mL), providing a crude pink solution, which was used di-
rectly in the next step.
This mixture was added to a stirred and cooled (0 °C) solution of
the epoxide (140 mg, 0.21 mmol) in ether (20 mL), containing
small amounts of hydroquinone as stabilizer, until the solution be-
came pink. The cooling bath was removed and the solution was
kept overnight at room temp. TLC analysis (hexane/ethyl acetate,
3:1) indicated the disappearance of the starting material and the

1510
M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
4.12.1. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
acetyloxy-7-diphenylphosphoryl-9-[(40R)-20,20-dimethyl-10,30-
dioxolan-40-yl]bicyclo[4.4.0]-decane 32-Ac
(2 mL) was added. After 5 min. TLC analysis (hexane/ethyl acetate,
3:1) showed the disappearance of the starting material and the for-
mation of a new, slightly less polar product. The reaction was
quenched with water (1 mL) and partitioned between water
(10 mL) and ethyl acetate (15 mL). The phases were separated
and the aqueous one extracted with ethyl acetate (2 ꢂ 15 mL).
The combined organic solutions were washed with brine (5 mL),
dried, and concentrated, and the crude product was purified via
preparative TLC (hexane-ethyl acetate, 2:1) to afford a pale yellow,
amorphous solid: 34 (24.7 mg, 69%) or 35 (24 mg, 67%).
½
a 2D6
ꢃ
¼ ꢁ1:7 (c 1, CHCl3); m/z: 943.3973; Calcd for C57H61O9PNa
(M+Na+): 943.3945. 1H NMR (600 MHz, DMSO-d6, 80 °C) d: 5.76
(m, 1H, H-6), 4.79–4.48 (8H, OCH2Ph), 4.55 (m, 1H, H-10), 4.29
(app. t, 1H, H-4, J = 8.7 Hz), 4.04 (dd, 1H, H-2, J = 14.2, 7.1 Hz),
3.68 (app. t, 1H, H-20a, J = 7.5 Hz), 3.62 (app. t, 1H, H-1,
J = 7.4 Hz), 3.58 (m, 1H, H-3), 3.42 (m, 1H, H-20b), 3.11 (m, 1H, H-
7), 2.27 (m, 1H, H-10), 2.22 (m, 1H, H-9), 2.13 (m, 1H, H-5), 2.02
(m, 1H, H-8a), 1.52 (s, 3H, CH3C(O)), 1.41 (m, 1H, H-8b), 1.19 and
1.01 ppm (2 ꢂ s, 6H, (CH3)2C); 13C NMR (150 MHz, DMSO-d6,
80 °C) d: 168.3 (CH3C(O)), 107.1 (C-40), 84.7 (C-3), 82.3 (C-1), 80.8
(C-2), 76.3 (C-4), 75.3 (C-10), 68.8 (C-5), 64.5 (C-20), 43.0 (C-5),
36.6 and 36.1 (d, C-7, JCP = 69 Hz), 35.2 (C-9 and C-10), 25.4 and
24.4 ((CH3)2C), 21.1 (C-8), 20.0 ppm (CH3C(O)). 31P NMR
(243 MHz, DMSO-d6, 80 °C) d: 31.4 ppm.
4.13.1. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
hydroxy-7-sulfanyl-9-[(40R)-20,20-dimethyl-10,30-dioxolan-40-
ylo]bicyclo[4.4.0]decane 34
½
a 2D2
ꢃ
¼ þ20:5 (c 1, CHCl3); m/z: 733.3169, Calcd for C43H50O7SNa
(M+Na+): 733.3170. 1H NMR (600 MHz, DMSO-d6, 80 °C) d: 4.67–
4.50 (m, 7H, OCH2Ph), 4.47 (d, 1H, OH, J = 6.3 Hz), 4.32 (app. dd,
1H, H-10, J = 14.1, 6.8 Hz), 4.02 (m, 1H, H-4), 3.92 (dd, 1H, H-20a,
J = 8.0, 6.3 Hz), 3.80 (m, 1H, H-6), 3.77 (m, 1H, H-2), 3.67 (app. t,
1H, H-3, J = 6.6 Hz), 3.62 (app. t, 1H, H-1, J = 3.9 Hz), 3.52 (m, 1H,
H-20b), 3.49 (dd, 1H, H-1, J = 8.1, 6.9 Hz), 2.97 (ddd, 1H, H-7,
J = 12.4, 9.9, 4.5 Hz), 2.51 (m, 1H, H-10), 2.19 (d, 1H, SH,
J = 4.6 Hz), 2.08 (m, 1H, H-8a), 1.97 (m, 1H, H-5), 1.84 (app. td,
1H, H-9, J = 8.8, 4.6 Hz), 1.62 (app. dt, 1H, H-8b, J = 13.7, 4.4 Hz),
1.29 and 1.23 ppm (2 ꢂ s, 6H, (CH3)2C). 13C NMR (150 MHz,
DMSO-d6, 80 °C) d: 107.5 (C-40), 83.0 (C-1), 81.5 (C-3), 79.1 (C-2),
77.9 (C-4), 75.7 (C-10), 73.4 (C-6), 66.6 (C-20), 44.0 (C-5), 41.6 (C-
7), 40.8 (C-10), 38.4 (C-9), 33.2 (C-8), 26.2 and 25.0 ppm ((CH3)2C).
4.12.2. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
diphenylphosphoryl-7-hydroxy-9-[(40R)-20,20-dimethyl-10,30-
dioxolan-40-yl]bicyclo-[4.4.0]decane 33
½
a 2D2
ꢃ
¼ ꢁ1:4 (c 1, CHCl3); m/z: 901.3818; Calcd for C55H59O8P-
Na (M+Na+): 901.3840. 1H NMR (600 MHz, C6D6, 25 °C) d: 5.32
(app. dd, 1H, H-10), 5.22–4.48 (9H, m, OCH2Ph, H-4), 4.36 (1H, H-
7), 4.30 (m, 2H, H-20a, OCH2Ph), 4,09 (dd, 1H, H-20b, J = 8.4,
7.3 Hz), 3,88 (dd, 1H, H-2, J = 10.4, 9.2 Hz), 3.50 (app. d, 1H, H-6,
J = 11.8 Hz), 3,24 (m, 2H, H-1, H-3), 2.97 (dt, 1H, H-10, J = 12.3,
4.1 Hz), 2.74 (m, 1H, H-9), 2.38 (m, 1H, H-8a), 2.28 (1H, m, H-
m
8b), 2.17 (m, 1H, H-5), 1.51 and 1.35 ppm (2 ꢂ s, 6H, ðCH3Þ2 , C).
13C NMR (150 MHz, C6D6, 25 °C) d: 107.9 (C-40), 88.2 (C-3), 84.0
(C-1), 82.2 (C-2, C-4), 75.6 (C-10), 66.2 (C-7), 64.6 (C-20), 39.2 (C-
10), 38.7 (C-5), 38.4 and 37.9 (d, C-6, JCP = 69 Hz), 31.7 (C-8),
31.2 (C-9), 26.3 and 24.5 ppm ((CH3)2C). 31P NMR (243 MHz,
C6D6) d: 32.6 ppm.
4.13.2. (1R,2R,3S,4R,5R,6S,7S,9S,10R)-1,2,3,4-Tetrabenzyloxy-6-
sulfanyl-7-hydroxy-9-[(40R)-20,20-dimethyl-10,30-dioxolan-40-
ylo]bicyclo[4.4.0]decane 35
½
a 1D9
ꢃ
¼ þ14:5 (c 1, CHCl3); m/z: 733.3201, Calcd for C43H50O7SNa
(M+Na+): 733.3170. 1H NMR (600 MHz, DMSO-d6, 80 °C) d: 4.98 (m,
1H, OH), 4.74–4.61 (m, 9H, OCH2Ph, H-10), 4.26 (m, 1H, H-4), 3.82
(m, 1H, H-7), 3.79 (m, 1H, H-2), 3.68 (dd, 1H, H-20a, J = 8.0,
7.0 Hz), 3.62 (m, 1H, H-20b), 3.55 (m, 1H, H-6), 3.49 (m, 1H, H-1),
3.44 (m, 1H, H-3), 2.63 (d, 1H, SH, J = 7.2 Hz), 2.25 (m, 2H, H-9,
H-10), 1.86 (m, 2H, H-5, H-8a), 1.61 (m, 1H, H-8b), 1.31 and
1.18 ppm (2 ꢂ s, 6H, (CH3)2C). 13C NMR (150 MHz, DMSO-d6,
4.13. Reduction of the thiocyanates 30 and 31 with LiAlH4
General procedure: (This reaction was performed under an argon
atmosphere): To a stirred solution of the thiocyanate (37 mg,
0.05 mmol) in dry THF (3 mL), a solution of LiAlH4 (8 mg) in THF
Figure 10. The lowest energy binding poses for (red: AD4.2, green: Vina): (a) 32a in 1U33; (b) 33a in 2NSX; (c) 32a in 1FO3; and (d) 33a in 3GXF (yellow: ligand/isofagomine).
The hydrophobicity surface of the receptor is shown.

M. Nowogródzki et al. / Tetrahedron: Asymmetry 23 (2012) 1501–1511
1511
80 °C) d: 106.8 (C-40), 85.4 (C-3), 83.0 (C-1), 80.3 (C-2), 79.3 (C-4),
74.7 (C-10), 70.7 (C-7), 63.8 (C-20), 45.0 (C-5), 40.3 (C-6), 35.1 (C-9)
32.2 (C-10), 27.3 (C-8), 25.6 and 24.1 ((CH3)2C), 20.1 ppm (C-8).
5. (a) Berridge, M. J.; Irvine, R. F. Nature 1989, 341, 197–205; (b) Berridge, M. J.
´
Nature 1993, 361, 315–325; (c) Hinterding, K.; Dıaz, D. A.; Waldmann, H.
Angew. Chem., Int. Ed. 1998, 37, 688–749; (d) Kilbas, B.; Balci, M. Tetrahedron
Lett. 2011, 67, 2355–2389.
6. (a) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–
2036; (b) Kobayashi, Y. Carbasugars: Synthesis and Functions. In Glycoscience;
Fraser-Reid, B., Tatsuta, K., Eds.; Springer: Berlin, Heidelberg, 2008; pp 1915–
1998.
4.14. Molecular docking
7. (a) Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 2429–2430; (b) Mehta, G.;
Ramesh, S. S. Tetrahedron Lett. 2001, 42, 1987–1990; (c) Mehta, G.; Ramesh, S. S.
Can. J. Chem. 2005, 83, 581–594.
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9144.
9. Kallmerten, J. The Chemistry of the Nargenicin Macrolides. In: Studies in Natural
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3851; (c) Marchart, S.; Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813–816.
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The potential inhibitory activities of the obtained compounds
were examined by using AutoDock 4.2 and AutoDock Vina. Auto-
Dock Tools 1.5.4 was used to prepare docking input files and to
evaluate the results. In order to prepare a receptor for docking,
all small molecules, ions, and ligands were removed, then, polar
hydrogen atoms were added, whereas the non-polar ones were
merged. Gasteiger charges were computed. The B3LYP/6-31G(d)
geometry optimization (Gaussian03) of 27a, 32a, 33a, 34a, and
35a allowed us to find the lowest-energy conformers (those shown
in the Fig. 10). Subsequently, partial charges and polar hydrogen
atoms were added to them.
In case of Autodock 4.2, AutoGrid was launched prior to dock-
ing, using a grid box 60–60–60 with a spacing of 0.375 Å, centered
at the position of the initial PDB ligand. For docking, the Lamarck-
ian GA-LS was used (number of runs: 250, population size: 250,
RMSD tolerance for cluster analysis: 3 Å, other parameters kept de-
fault). Whenever several clusters were obtained, the docking was
redone with the number of runs reduced to 100, and the number
of energy evaluation number increased to 25 ꢂ 106. The first two
changes significantly reduced the process time, whereas the latter
gave a better result convergence.
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When AutoDock Vina was employed, all docking parameters
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Acknowledgments
Support from Grant: POIG.01.01.02-14-102/09 (part-financed
by the European Union within the European Regional Development
Fund) is acknowledged. We are thankful to Mr. Tomasz Grining
from Quantum Chemistry Laboratory (University of Warsaw,
Department of Chemistry) for his support concerning the computa-
tional work.
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