Enantioselective synthesis of benzomorphan analogues by intramolecular oxa-Pictet-Spengler cyclization

Article abstract of DOI:10.1016/j.tetasy.2013.12.016

A new strategy toward biologically active enantiomerically pure benzomorphan analogues is described. The key steps in the synthesis are the l-proline catalyzed asymmetric α-aminooxylation of an aldehyde and the titanium tetrachloride promoted intramolecular oxa-Pictet-Spengler cyclization of (4R)-2-(bromomethyl)-4-(2,5-dimethoxybenzyl)-1,3-dioxolane. In the intramolecular oxa-Pictet-Spengler cyclization, cis-pyran 8a (71%) formed over the trans-pyran 8b (14%). Computational modeling studies provided an insight into the stereoselectivity of the products. Docking studies of benzomorphan derivatives indicated that compound 6c had the best binding efficiency, and that it formed extensive hydrogen bonding with TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of the μ-opioid receptor, which belong to the G-protein coupled receptor super family.

Full text of DOI:10.1016/j.tetasy.2013.12.016

Tetrahedron: Asymmetry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of benzomorphan analogues
by intramolecular oxa-Pictet–Spengler cyclization
Viraj P. Patil a, Anirban Ghosh b, Uddhavesh Sonavane b, Rajendra Joshi b, Rajiv Sawant a, Satish Jadhav a,
Suresh B. Waghmode a,
⇑
a Department of Chemistry, University of Pune, Ganeshkhind, Pune 411 007, India
b Bioinformatics Group, Centre for Development of Advanced Computing, Pune 411 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy toward biologically active enantiomerically pure benzomorphan analogues is described.
The key steps in the synthesis are the L-proline catalyzed asymmetric a-aminooxylation of an aldehyde
and the titanium tetrachloride promoted intramolecular oxa-Pictet–Spengler cyclization of (4R)-2-
(bromomethyl)-4-(2,5-dimethoxybenzyl)-1,3-dioxolane. In the intramolecular oxa-Pictet–Spengler
cyclization, cis-pyran 8a (71%) formed over the trans-pyran 8b (14%). Computational modeling studies
provided an insight into the stereoselectivity of the products. Docking studies of benzomorphan
derivatives indicated that compound 6c had the best binding efficiency, and that it formed extensive
Received 26 October 2013
Accepted 19 December 2013
Available online xxxx
hydrogen bonding with TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of the
receptor, which belong to the G-protein coupled receptor super family.
l-opioid
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
modifications include the synthesis of a simple tricyclic system,
ring size variation,5 nitrogen atom repositioning,6 and synthesis
of the 5-arylmorphan skeleton.7 A substituted benzomorphan
scaffold has potential as a lead structure in the search for new drug
candidates with selective activity on opioid receptors.
Opioid alkaloids and related pharmaceuticals are the most
effective analgesics for the treatment of acute and chronic pain.
The active alkaloids in opium are morphine 1a and codeine 1b,
which act on the central nervous system of humans to produce a
wide range of effects such as analgesia, euphoria, sedation, respira-
tory depression, and cough suppression, and have peripheral
effects such as constipation. The management of pain, acute
pulmonary edema, coughs, diarrhea, and shivering is mainly
Since the stereochemistry of
a drug strongly influences
pharmacological activity, nowadays one of the major challenges
organic chemists face is, the synthesis of chiral molecules in
efficient and economical ways. In this context, the organocatalytic
L
-proline catalyzed a
-aminooxylation of an aldehyde8 and the
controlled by the
l
-opioid receptor (
l
-OR).1 It is one of the family
oxa-Pictet–Spengler rearrangement of 6-aryl 1,3-dioxolane
provide a means to improve the chemical transformations and thus
the synthetic efficiency for novel tricyclic benzomorphan
analogues. A convenient, straightforward, and practical route to
the synthesis of benzomorphan analogues from prochiral starting
materials is highly desirable. Since a part of our research program
was aimed toward the synthesis of biologically active compounds
and their key intermediates9 by using the proline-catalyzed
members of the class A G-protein-coupled receptors (GPCRs)2 and
the most important signaling receptors of the central nervous
system.3 The majority of opioid alkaloids, such as morphine and
codeine, function by binding to and activating
upon the substitution on N of the tricyclic ring system, it interacts
with the (Opioid), d receptor, and phenacyclidine binding site
of the NMDA (N-methyl-
-aspartate) receptor.4 These compounds
l-OR. Depending
l, j
D
consist of a basic skeleton of benzomorphan (2-phenyl ethylamine
substructure Fig. 1, structures 1 to 5). However, the highly
addictive nature of opioid drugs makes it necessary to develop
some new forms of opioid drugs which might help in reducing
dependence while increasing efficiency. Structural modification
asymmetric
to design
a
a
-aminooxylation of aldehydes,8 we were encouraged
short and effective route for the synthesis of
benzomorphan analogues. In order to search for a novel receptor
of the benzomorphan analogues, tricyclic amines with
a
2-phenylethylamine substrate were envisaged. Herein we report
a novel enantioselective synthesis of benzomorphan analogues by
can reduce this problem to
a considerable degree. These
employing an L-proline-catalyzed asymmetric a-aminooxylation
of an aldehyde and a titanium tetrachloride promoted intramolec-
⇑
Corresponding author. Tel.: +91 20 2560 1394x585; fax: +91 20 25691728.
E-mail address: suresh@chem.unipune.ac.in (S.B. Waghmode).
ular oxa-Pictet–Spengler cyclization10 as the key steps for chirality
http://dx.doi.org/10.1016/j.tetasy.2013.12.016
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

2
V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
NMe
H
N
O
N
H
N
R
RO
O
OH
N
H
1a
1b
: R = H
4
5
: R = Me
3
2
Figure 1. Structure of benzomorphan with planned tricyclic amine and prominent analogues.
induction. In order to understand the stability of the isomers and
binding efficiency of benzomophan compounds with -opioid
receptors, optimization by DFT calculations and docking studies
8a and 8b. In this reaction, we presume that the Re and Si attack of
the nucleophile gives the cis- and trans-pyran through transition
state 15a and 15b, respectively. The product distribution may be
due to the fact that the cis-isomer 8a has both of its methyl alcohol
and methyl bromide groups adopting a pseudoequatorial orienta-
tion 15a, which minimizes the 1,3-diaxial interaction across the
oxygen in the 6 membered oxonium transition state. The trans-
isochroman would result from the oxonium transition state 15b
where the methyl bromide group is in a pseudoaxial position, a
feature already observed in other pyran derivatives.11
The relative stereochemistry of isochroman 8a was ascertained
by a 2D-NOE correlation experiment. The 1,3-trans pyran showed a
strong NOE correlation between the proton H3 and the bromo-
methyl protons (Fig. 3). The stereochemistry at the C1 position
was further confirmed by carrying out the cyclization of isochro-
mans 8a and 8b. The cis-isochroman cyclized to the tricyclic ben-
zomorphan, while the trans-isochroman did not cyclize. These
experimental results helped to fix the stereochemistry of 8a and
8b isochromans as (1S,3R) and (1R,3R), respectively.
The major cis-configured pyran was subjected to tosylation by
using p-toluenesulfonyl chloride, Et3N, and DMAP in CH2Cl2 to
afford the desired 1,3-disubstituted bromotosylate 7a in 71% yield.
The one step nucleophilic substitution of various benzyl amine
derivatives 16a–i was performed using K2CO3 in CH3CN at 80 °C,
to afford tricyclic benzomorphan derivatives. Benzyl amine gave
81% yield, whereas halogen substituted benzyl amines gave yields
between 71% and 85% (Table 1, entries 1–4). When electron
donating para-methoxy benzyl amine was subjected to nucleo-
philic substitution, the desired product was obtained in 90% yield.
Heterocyclic pyridin-4-ylmethanamine gave 77% yield (entry 6).
Homobenzyl amines gave the desired product in 60–65% yield
(Table 1, entries 7 and 8). This is due to the decrease in the nucleo-
philic character of the amine. The same methodology was applied
for the trans-isomer 8b, but we were unable to obtain the cyclized
product, since in structure 8b, the –CH2Br adopts a pseudoaxial
position 15b, so that the nucleophilic attack by an amine is not
feasible; this also reveals the trans-geometry of 8b.
l
were carried out, respectively.
2. Results and discussion
2.1. Synthesis of benzomorphan analogues
Our plan for the synthesis of enantiomerically pure tricyclic
benzomorphan analogues is shown in Scheme 1. The retrosynthet-
ic scheme is centered on the organocatalytic enantioselective syn-
thesis of the cis-1,3-dimethylpyran containing key intermediate
while its analogues were developed in our laboratory.9c The one
step nucleophilic substitution of tosylate by various benzyl amines
to deliver tricyclic benzomorphans has been envisaged. The tosyl-
ate 7 itself can be obtained by tosylation of alcohol 8, formed via
intra-molecular pyran formation by the diastereoselective intra-
molecular oxa-Pictet–Spengler cyclization of bromomethyl-1,3-
dioxolane 9.
The synthesis of benzomorphan analogues started with (R)-diol
10, which was prepared in 98% ee by following an organocatalytic
approach based on the L-proline catalyzed asymmetric a-amino-
oxylation of aldehydes.9c,d Diol 10 was reacted with 2-bromo-
1,1-diethoxyethane in the presence of p-toluenesulfonic acid in
CH2Cl2 and gave bromomethyl-1,3-dioxolane 9 in excellent yield.
Bromomethyl-1,3-dioxolane 9 was subjected to intramolecular
oxa-Pictet–Spengler cyclization with TiCl4 (2 equiv) in dry CH2Cl2
at ꢀ30 °C to afford cis- and trans-pyran 8a and 8b. The TiCl4 pro-
moted intramolecular oxa-Pictet–Spengler cyclization gave the
cis-pyran (71%) as the major product over the trans-pyran (14%)
(Scheme 2).
In Fig. 2, the cyclization of the acetals presumably starts by alk-
oxide abstraction by the Lewis acid (TiCl4) from 9, leaving a stabi-
lized oxocarbocation 12, which undergoes an electrophilic attack
on the aromatic ring to afford intermediate species 13 and 14.
The final elimination of a proton produces the isochroman nucleus
Br
O
Br
OMe
Br
OMe
OMe
OMe
R
N
O
O
O
O
OH
OTs
OMe
OMe
OMe
OMe
OMe
OMe
9
8
6
7
OH
OH
10
Scheme 1. Retrosynthetic analysis of benzomorphan analogues.
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
3
OEt
OMe
Br
OMe
Br
OMe
OMe
OEt
Ref. 9d
OH
O
OH
O
PTSA,
CH2Cl2,
0 °C
CHO
OMe
rt,
OMe
4h, 90%
9
10
2,5-dimethoxybenzaldehyde
OMe
OMe
Br
R
OMe
OMe
N
Br
OMe
O
NH2
p-TsCl
R
O
O
OTs
K2CO3, CH3CN,
80 °C, 12h
CH2Cl2,
0 °C
12h, 72%
OH
OH
rt,
not formed
TiCl4
7b
OMe
8b
(14%)
Br
6'
9
CH2Cl2,
-30 °C,
3h.
Br
OMe
OMe
OMe
R
NH2
R
N
p-TsCl
O
O
O
OTs
K2CO3, CH3CN,
80 °C, 12h
CH2Cl2,
0 °C
12h, 71%
rt,
OMe
OMe
OMe
8a
(71%)
7a
Scheme 2. Synthesis of benzomorphan analogues.
6
OMe
OMe
OMe
OMe
OMe
CH2Br
O
Br
Br
O
O
O
O
O
TiCl4
TiCl4
TiCl4
12
OMe
11
9
(Re attack)
(Si attack)
OMe
OMe
CH2Br
O
CH2Br
O
Br
H
H
OMe
(Si attack)
Cl4TiO
O
O
O
TiCl4
TiCl4
MeO
15a
OMe
OMe
OMe
OMe
13
14
CH2Br
O
CH2Br
O
OMe
Cl4TiO
O
(Re attack)
OH
OH
MeO
Br
15b
8b (14%)
8a (
OMe
OMe
71%)
Figure 2. Plausible reaction mechanism for the oxa-Pictet–Spengler cyclization.
of these isomers by using DFT calculations. We observed that
trans-8b was more stable (0.66744 kcal/mol) compared to cis-8a.
Experimentally obtained result suggested that the cis-isomer was
a kinetically controlled product. In this reaction, the transition
state (Fig. 2) of the product formation played an important role,
whereas the quasi 1,3-diaxial interactions were minimized (Fig. 4).
Br
Br
OMe
OMe
H
H
OMe
OMe
H
1
H
H
H
H
H
2
2
O
3
O
3
1
OH
OH
8b
8a
2.3. Docking studies
Figure 3. 2D-NOE correlation observed in cis-8a and trans-8b.
Using the recently solved crystal structure of
l-OR (PDB ID:
4DKL), bound to an irreversible benzomorphan antagonist, b-fun-
altrexamine (b-FNA), docking studies were carried out. The binding
efficiencies of these new compounds were compared with those of
2.2. DFT calculations
b-FNA, which was redocked to
tions based on the calculated binding energy for each of the com-
pounds with -OR are listed in Table 2. From Table 2, it can be
l-OR. The best docked conforma-
The oxa-Pictet–Spengler reaction of compound 9 gave two
isomers 8a and 8b in 71% and 14% yields, respectively. In order
to determine the reason for this, we performed an optimization
l
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

4
V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
Table 1
Summary of one step nucleophilic substitution of bromotosylate 7 with various benzyl amines
NH2
Br
R
OMe
OMe
OMe
R
16a-i
N
O
O
K2CO3,
CH3CN,
80 °C,
12 h
OTs
OMe
6a-i
7
Entry
1
Benzyl amines
NH2
Product
Yield (%)
81
OMe
N
O
16a
6a
OMe
OMe
NH2
N
O
O
O
O
Cl
2
3
4
5
6
7
76
71
85
90
77
60
Cl
Cl
16b
Cl
6b
OMe
OMe
NH2
N
Cl
Cl
16c
OMe
OMe
6c
NH2
N
F
16d
F
6d
OMe
OMe
NH2
N
MeO
OMe
16e
6e
OMe
OMe
NH2
N
N
O
O
N
16f
6f
OMe
OMe
NH2
N
N
H
HN
16g
OMe
OMe
6g
MeO
MeO
NH2
N
O
8
9
65
88
16h
OMe
OMe
OMe
6h
OMe
N
NH2
O
16i
6i
OMe
clearly seen that b-FNA, which was present in the crystal structure,
has a minimum free energy of binding of ꢀ11.84 kcal/mol. It forms
a hydrogen bond with LEU219 on extracellular loop 2 (ECL2).
Among the synthesized compounds it was found that compound
6c had the best binding efficiency with a binding free energy of
ꢀ8.30 kcal/mol. It formed extensive hydrogen bonding with
TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of
the receptor (Fig. 5).
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
5
synthesis of tricyclic benzomorphan derivatives using chiral diol
10 as a building block. This route is practical since it uses the chi-
ral diol 10, which can be readily synthesized by using an
L-proline
catalyzed asymmetric -aminooxylation of aldehyde. The present
a
methodology should gain importance, as it provides a route for
the synthesis of tricyclic benzomorphan derivatives, which are
important moieties in medicinal chemistry and bioactive natural
products. The biological activity of synthesized compound is un-
der investigation. The trend observed in the docking study is
helpful in designing and synthesizing new benzomorphan ana-
logues, which have more binding efficiency with a receptor.
cis pyran 8a
trans pyran 8b
4. Experimental
4.1. General
Figure 4. DFT optimized structures of 8a and 8b.
Melting points were recorded with a Thomas Hoover Capillary
melting point apparatus. Thin-layer chromatography was per-
formed on Merck 60F254 silica gel plates, and visualization was
accomplished by irradiation with UV light and/or by treatment
with a solution of phosphomolybdic acid (1.25 g) and Ce(SO4)2ꢁH2O
(0.5 g) in concentrated H2SO4/H2O (3.47 mL) followed by heating.
Crude products were purified by column chromatography on silica
gel of 100–200 mesh. IR spectra were recorded with a Shimadzu
FTIR 8400 in CHCl3 or as KBr pellets. Optical rotations were ob-
tained with Jasco P-1020 digital polarimeter. 1H and 13C NMR spec-
tra were recorded with a Varian Mercury spectrometer at 300 and
75 MHz, respectively, by using CDCl3 as a solvent. Chemical shifts
are reported in d units (ppm) with reference to TMS as an internal
standard. LC mass spectra were obtained with a Shimadzu LC–MS-
2010ev spectrometer. All solvents were purified and dried by stan-
dard procedures prior to use.
Table 2
Binding free energies of the native ligands and the ligand derivatives with
obtained after docking
l-OR
Compound
Binding energy (kcal/mol)
Crystal ligands
b-FNA
Morphine
ꢀ11.84
ꢀ10.55
Ligand derivatives
6a0
6a
6b
6c
6d
6e
6f
6g
6h
6i
ꢀ8.11
ꢀ8.26
ꢀ7.89
ꢀ8.30
ꢀ7.94
ꢀ6.99
ꢀ8.16
ꢀ7.87
ꢀ6.99
ꢀ7.00
3. Conclusion
4.2. Methodology for the DFT calculations
In conclusion we have reported on
methodology for the stereoselective synthesis of benzomorphan
analogues through -proline catalyzed -aminooxylation of an
aldehyde and intramolecular oxa-Pictet–Spengler cyclization.
The oxa-Pictet–Spengler reaction gave cis-pyran as the major
product. The versatility of our new approach is shown with the
a concise and easy
We used the Gaussian0912,13 software packages for our calcula-
tions. The computational studies of the benzomorphan isomers
were carried out using Density Functional Theory (DFT).12 The
DFT calculations were subjected to unrestricted energy optimiza-
tion and single point energy calculations. Geometry optimizations
L
a
Figure 5.
l-OR-ligand interactions. (A) Shows the hydrogen bond network (seen from the extracellular side of the receptor) formed by the native ligand b-FNA with the l-OR
molecule after re-docking. The higher number of hydrogen bonds formed explains the lowest free energy of binding (ꢀ11.84 kcal/mol) with the receptor. (B) Depicts the
hydrogen bond network between the best ligand derivative 6c, with the lowest free energy of binding (ꢀ8.30 kcal/mol) with
l-OR. The residues involved in the formation of
the hydrogen bonds with the ligands belong to TM3 and TM6 of the receptor.
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

6
V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
were performed by using the hybrid-DFT B3LYP14 exchange corre-
lation functionals and the double-f 6-311++G(d,p) basis set for all
of the atoms. Normal self-consistent field (SCF) and geometry con-
vergence criteria were employed throughout using C1 symmetry.
The calculated geometries with all bond lengths and bond angles
are within the standard errors expected for geometry optimiza-
tions using the B3LYP exchange correlation functionals and the
6-311++G(d,p) basis set.
under a nitrogen atmosphere, a TiCl4 solution (691.38 lL,
6.329 mmol) was added dropwise in dry CH2Cl2 (4 mL) over
5 min, and the mixture was stirred at the same temperature for
3 h. The reaction was quenched with saturated aqueous NH4Cl
solution and extracted with CH2Cl2 of (3 ꢂ 15 mL). The combined
organic layer was washed with brine, dried with anhydrous
Na2SO4, and concentrated under reduced pressure to afford a mix-
ture of 8a and 8b, which was purified by column chromatography
(EtOAc/hexane, 1.8:8.2) to give nonpolar trans-isomer 8b (28 mg,
4.3. Methodology for the docking studies
14%) as a white solid. ½a D23
ꢃ
¼ ꢀ23:4 (c 1, CHCl3); FTIR (KBr cmꢀ1):
788, 1062, 1084, 1128, 1257, 1481, 2929, 3265; 1H NMR
(300 MHz, CDCl3) d: 6.72 (d, J = 9.1 Hz, ArH); 6.66 (d, J = 9.1 Hz,
1H, ArH), 5.12 (dd, J = 10.9 and 3.2 Hz, 1H, CH), 3.91–3.98 (m, 2H,
CH), 3.80 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.59–3.74 (m, 2H,
CH), 2.66 (dd, J = 3.6 and 17.0 Hz, 1H, CH), 2.35–2.45 (m, 2H, CH),
1.57 (s, 1H, OH), 13C NMR (75 MHz, CDCl3) d: 151.1, 149.5, 123.8,
123.3, 108.9, 107.5, 71.3, 67.7, 65.7, 55.6, 55.4, 32.8, 23.9. Further
elution (EtOAc/hexane, 1.8:8.2) gave 8a (142 mg 71%) as white so-
Docking was carried out using the AutoDock (version 4.2.5.1)
package.15 The receptors and ligands were initially prepared by
adding hydrogen atoms, with partial charges being calculated with
Gasteiger’s method using the AutoDock software tools. The docking
protocol was carried out, and the results were in good agreement
with the experimental results.16–21 The binding pocket was based
on the ligand binding site of receptor crystal structures. The ligand
was kept flexible along with some of the residues in the receptor
binding pocket based on the crystal structure. Auto Grid was used
for generating the grid parameter files and atom-specific affinity
maps. While carrying out the docking of all of the compounds, 4 res-
lid. ½a 2D5
ꢃ
¼ þ185:4 (c 1, CHCl3); FTIR (KBr cmꢀ1): 788, 1062, 1084,
1128, 1257, 1481, 2929, 3265; 1H NMR (300 MHz, CDCl3) d:
6.58–6.67 (m, 2H, ArH), 5.13 (br s, 1H, CH), 3.95 (dd, J = 8.5 and
3.8 Hz, 1H, CH), 3.93 (dd, J = 6.5 and 3.0 Hz, 1H, CH), 3.80 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 3.73 (br d, J = 7.3 Hz, 1H, CH) 3.63 (t,
J = 10.9 Hz, 1H, CH), 2.66 (dd, J = 17.0 and 3.6 Hz, 1H, CH), 2.40
(dd, J = 17.3 and 11.4 Hz, 1H, CH), 2.34 (br s, 1H, OH); 13C NMR
(75 MHz, CDCl3) d: 151.1, 149.5, 123.8, 123.3, 108.9, 107.5, 71.3,
67.7, 65.7, 55.6, 55.4, 32.8, 23.9.
idues (ASP147, TYR148, LYS233, and HIS297) of
lOR, which are
known to be present in the ligand binding pocket of the receptor
and directly interact with b-FNA, were set as flexible residues while
the rest of the protein was kept as rigid. The roots of the torsion
were selected individually for all of the ligands. AutoGrid 4.2 was
used to generate the grid parameter files and atom-specific affinity
maps. Grid points for the map files were generated with dimensions
of 48 ꢂ 48 ꢂ 48 (Å) with a grid spacing of 0.375 Å and centered at
the crystallographic binding site, which is conserved among all
the class A GPCR molecules. Docking simulations were carried out
using Lamarkian Genetic Algorithm with maximum number of iter-
ations set to 10 and a population size of 150. Maximum number of
energy evaluations was set to 2,500,000. Other AutoDock parame-
ters were set to default values. Finally, ranked cluster analysis
was performed to sort out the docked poses.
4.6. ((1S,3R)-1-(Bromomethyl)-5,8-dimethoxyisochroman-3-yl)
methyl 4-methylbenzene-sulfonate 7a
To a stirred solution of alcohol 8a (123 mg, 0.3892 mmol) in dry
CH2Cl2 (10 ml), under a nitrogen atmosphere were added Et3N
(55.71 ll, 0.3971 mmol), p-toluene sulphonyl chloride (75.44 mg,
0.3971 mmol), and DMAP at 0 °C, and mixture was stirred at room
temperature for 12 h. The reaction mixture was then quenched
with aq NH4Cl and extracted with CH2CI2 (3 ꢂ 25 ml). The com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure, and the
residue was purified by column chromatography (EtOAc/hexane,
0.5:9.5) to afford pure tosylate 7a, 187 mg (71.12%) as a white so-
lid. FTIR (KBr cmꢀ1): 790, 833, 977, 1084, 1130, 1180, 1255, 1356,
1481, 1599, 2835, 2939; 1H NMR (300 MHz, CDCl3) d: 7.85 (d,
J = 8.2 Hz, 2H, ArH), 7.36 (d, J = 8.2 Hz, 2H, ArH), 6.72 (q,
J = 8.8 Hz, 1H, ArH), 6.66 (d, J = 8.8 Hz, 1H, ArH), 5.12 (br s, 1H,
CH), 4.17 (m, 3H, CH), 3.88 (dd, J = 10.4 and 4.9 Hz, 1H, CH), 3.74
(br d, J = 2.2 Hz, 1H, CH), 3.77 (br s, 6H, OCH3), 2.74 (dd, J = 17.6
and 4.0 Hz, 1H, CH), 2.44 (s, 3H, CH3), 2.37 (dd, J = 17.2 and
6.6 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.46, 149.72,
144.75, 132.09, 129.82, 128.06, 124.78, 123.87, 108.88, 108.03,
73.06, 71.87, 70.69, 55.63, 55.48, 37.04, 25.19, 21.62.
4.4. (R)-4-(2,5-Dimethoxybenzyl)-2-(bromomethyl)-1,3-dioxo-
lane 9
To a stirred solution of (R)-3-(2,5-dimethoxyphenyl) propane-1,
2-diol 10 (500 mg, 2.358 mmol) and (2-bromo-1-ethoxy)ethane
(1.064 ml 7.075 mmol) in 15 mL of CH2CI2 was added p-toluenesul-
fonic acid (44 mg 0.235 mmol) at 0 °C and the mixture was stirred
at room temperature for 4 h. The reaction was then quenched with
saturated aqueous NaHCO3 solution and extracted with CH2Cl2
(3 ꢂ 5 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(EtOAc/hexane, 2:8) to afford pure 9 (698 mg, 90%) as a brown li-
quid. 1H NMR (300 MHz, CDCl3) d: 6.76 (m, 3H, ArH), 5.13 (t,
J = 3.8 Hz, 1H, CH), 4.40 (quint, J = 6.7 Hz, 1H, CH), 3.94 (t,
J = 6.7 Hz, 1H, CH), 3.77 (s, 3H, OCH3), 3.75 (br s, 4H, OCH3 and
CH), 3.35–3.43 (m, 2H, CH), 3.00 (dd, J = 6.2 and 13.3 Hz, 1H, CH),
2.86 (dd, J = 6.7 and 13.4 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3)
d: 153.3, 151.6, 126.4, 117.3, 112.0, 111.0, 102.1, 76.5, 69.8, 55.7,
55.6, 34.1, 32.6.
4.7. (1S,5R)-3-Aryl-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-
epoxybenzo[d]azocine 6a–i
To a stirred solution of tosylate 7a (50 mg, 0.1036 mmol) in
CH3CN (10 ml), benzyl amine 16a–i (0.1554 mmol) and K2CO3
(35.80 mg, 0.2590 mmol) were added at reflux, (reaction was mon-
itored by TLC). The reaction mixture was quenched with aq NH4Cl
and extracted with EtOAc. The combined organic layer was washed
with brine solution, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford a crude product,
which was purified by column chromatography (EtOAc/hexane,
0.2:9.8) to afford 6a–i (60–90%).
4.5. (R)- and (S)-1-(Bromomethyl)-3,4-dihydro-5,8-dimethoxy-
1H-isochromen-3-yl)methanol 8a and 8b
To a stirred solution of (R)-4-(2,5-dimethoxybenzyl)-2-(bromo-
methyl)-1,3-dioxolane 9 (200 mg 0.6079 mmol) in CH2Cl2 (30 mL)
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
7
4.7.1. (+)-(1S,5R)-3-Benzyl-7,10-dimethoxy-1,2,3,4,5,6-hexahy-
dro-1,5-epoxybenzo[d] azocine 6a
66.3, 61.5, 58.9, 56.1, 55.7, 55.5, 55.2, 29.7, 27.1; LC–MS (ESI
M+1): 356.10.
White solid (27.5 mg, 81%); ½a D26
¼ þ37:5 (c 1, CHCl3); FTIR (KBr,
ꢃ
cmꢀ1): 1074, 1251, 1481, 1600, 2798, 2928; 1H NMR (300 MHz,
CDCl3) d: 7.06–7.08 (m, 3H, ArH), 6.8–6.9 (m, 2H, ArH), 6.35 (d,
J = 8.8 Hz, 1H, ArH), 6.55 (d, J = 8.9 Hz, 1H, ArH), 5.01 (s, 1H, CH),
4.23–4.26 (m, 1H, CH), 3.75 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),
3.34 (ABq, J = 13.7 Hz, 2H, CH2), 3.01 (dd, J = 8.0 and 17.7 Hz, 1H,
CH), 2.70 (br d J = 11.3 Hz, 1H, CH), 2.62 (br d, J = 11.3 Hz, 1H,
CH), 2.54 (br d, J = 4.8 Hz, 1H, CH), 2.49 (br d, J = 4.3 Hz, 1H, CH),
2.42 (dd, J = 11.0 and 3.3 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3)
d: 150.5, 148.6, 138.4, 128.2, 127.8, 127.9, 126.6, 125.3, 107.8,
106.6, 67.6, 66.3, 62.1, 59.1, 56.1, 55.7, 55.5, 27.1; LC-MS (ESI
M+1): 326.45.
4.7.6. (+)-(1S,5R)-7,10-Dimethoxy-3-(pyridin-4-ylmethyl)-1,2,3,
4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 9f
White solid (26.6 mg, 77%); ½a D26:3
¼ þ32:2 (c 1, CHCl3); FTIR
ꢃ
(KBr, cmꢀ1): 1072, 1256, 1485, 1602, 2799, 2927; 1H NMR
(300 MHz, CDCl3) d: 8.28 (d, J = 4.6 Hz, 1H, ArH), 6.76 (d,
J = 5.6 Hz, 1H, ArH), 6.66 (d, J = 8.8 Hz, 1H, ArH), 6.63 (d,
J = 9.1 Hz, 1H, ArH), 5.02 (br d, J = 1.2 Hz, 1H, CH), 4.28 (dd, J = 2.4
and 5.9 Hz, 1H, CH), 3.77 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.33
(ABq, J = 14.5 Hz, 2H, CH2), 3.04 (dd, J = 7.9 and 17.8 Hz, 1H, CH),
2.52–2.65 (m, 4H, CH), 2.43 (dd, J = 3.0 and 10.9 Hz 1H, CH); 13C
NMR (75 MHz, CDCl3) d: 150.4, 149.3, 148.5, 148.1, 127.1, 125.1,
123.1, 107.7, 106.6, 104.9, 67.4, 66.2, 60.7, 59.3, 55.8, 55.6, 55.5,
27.1; LC–MS (ESI M+1): 327.10.
4.7.2. (+)-(1S,5R)-3-(3,4-dichlorobenzyl)-7,10-dimethoxy-1,2,3,
4,5,6-hexahydro-1,5-epoxybenzo[d] azocine 6b
White solid (31.1 mg, 76%); ½a D22:3
ꢃ
¼ þ29:4 (c 1, CHCl3); FTIR
4.7.7. (+)-(1S,5R)-3-(2-(1H-Indol-3-yl)ethyl)-7,10-dimethoxy-1,2,
3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6g
(KBr, cmꢀ1): 1075, 1254, 1473, 2891, 2944, 3004; 1H NMR
(300 MHz, CDCl3) d: 7.19 (d, J = 8.2 Hz, 1H, ArH), 6.92 (d,
J = 1.5 Hz, 1H, ArH), 6.70–6.77 (m, 2H, ArH), 6.63 (d, J = 8.8 Hz,
1H, ArH), 5.07 (s, 1H, CH), 4.32 (d, J = 7.9 Hz, 1H, CH), 3.82 (s, 3H,
OCH3), 3.68 (s, 3H, OCH3), 3.33 (ABq, J = 14.3 Hz, 2H, CH), 3.08
(dd, J = 8 and 17.9 Hz, 1H, CH), 2.56–2.70 (m, 4H, CH), 2.48 (dd,
J = 3.2 and 11.1 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.4,
148.4, 139.1, 132.1, 130.2, 129.9, 129.8, 127.2, 127.1, 125.1,
107.8, 106.8, 67.5, 66.3, 60.4, 59.2, 55.7, 55.6, 55.5, 27.1; LC–MS
(ESI M+1): 395.15.
White solid (23.1 mg, 60%); ½a D24
¼ þ15:8 (c 1.35, CHCl3); FTIR
ꢃ
(KBr, cmꢀ1): 1078, 1258, 1485, 1605, 2851, 2923, 3215; 1H NMR
(300 MHz, CDCl3) d: 7.8 (s, 1H, NH), 7.47 (d, J = 7.9 Hz, 1H, ArH),
7.25 (d, J = 8.2 Hz, 1H, ArH), 7.01–7.14 (m, 2H, ArH), 6.56–6.68
(m, 3H, ArH), 5.1 (s, 1H), 4.37 (br d, J = 5.6 Hz, 1H, CH), 3.77 (s,
3H, OCH3), 3.72 (s, 3H, OCH3), 3.1 (dd, J = 7.9 and 17.9 Hz, 1H,
CH), 2.91 (dd, J = 11.1 and 16.7 Hz, 2H, CH), 2.75 (t, 6.8 Hz, 2H,
CH), 2.53–2.64 (m, 5H, CH); 13C NMR (75 MHz, CDCl3) d: 150.5,
148.6, 135.8, 127.6, 127.5, 125.2, 122.0, 121.5, 118.9, 118.6,
114.1, 110.8, 107.5, 106.7, 67.4, 66.1, 59.2, 58.6, 56.3, 55.5, 27.1,
21.5; LC–MS (ESI M+1): 379.15.
4.7.3. (+)-(1S,5R)-3-(2-Chlorobenzyl)-7,10-dimethoxy-1,2,3,4,5,
6-hexahydro-1,5-epoxybenzo[d]azocine 6c
White solid (27.05 mg, 71%); ½a D26:4
¼ þ26:5 (c 0.5, CHCl3); FTIR
ꢃ
4.7.8. (+)-(1S,5R)-3-(3,4-Dimethoxyphenethyl)-7,10-dimethoxy-
1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6h
(KBr, cmꢀ1): 1078, 1256, 1483, 2802, 3004; 1H NMR (300 MHz,
CDCl3) d: 7.22 (d, J = 7.9, 1H, ArH), 7.03 (t, J = 7.6 Hz, 1H, ArH),
6.93 (t, J = 7.1 Hz, 1H, ArH), 6.76 (d, J = 6.6 Hz, 1H, ArH), 6.69 (d,
J = 8.7 Hz, 1H, ArH), 6.62 (d, J = 8.8 Hz, 1H, ArH), 5.08 (s, 1H, CH),
4.34 (br d, J = 7.5 Hz, 1H, CH), 3.8 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 3.49 (ABq, J = 15.4 Hz, 2H, CH), 3.09 (dd, J = 7.9 and
17.6 Hz, 1H, CH), 2.71 (m, 4H, CH), 2.55 (dd, J = 12.9 and 5.4 Hz
1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.50, 148.6, 146.6, 136.0,
133.5, 129.5, 128.9, 127.4, 126.2, 125.4, 107.8, 106.6, 67.6, 66.3,
59.4, 58.3, 56.0, 55.6, 55.5, 27.1; LC–MS (ESI M+1): 360.10.
White solid (27.5 mg, 65%); ½a D23
¼ þ3:8 (c 1, CHCl3); FTIR (KBr)
ꢃ
cmꢀ1: 1078, 1258, 1484, 1605, 2852, 2924; 1H NMR (300 MHz,
CDCl3) d: 6.61–6.68 (m, 4H, ArH), 6.53 (d, J = 7.9 Hz, 1H, ArH),
5.10 (s, 1H, CH), 4.36 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.10 (dd, J = 8.2 and
17.9 Hz, 1H, CH), 2.84 (dd, J = 10.9 and 19.1 Hz, 2H, CH), 2.41–
2.59 (m, 7H, CH); 13C NMR (75 MHz, CDCl3) d: 150.4, 148.6,
148.5, 146.9, 133.2, 127.6, 125.0, 120.5, 111.8, 110.9, 107.4,
106.5, 67.4, 66.0, 60.2, 59.4, 56.5, 55.7, 55.6, 55.5, 55.3, 32.1,
27.0; LC–MS (ESI M+1): 400.19.
4.7.4. (+)-(1S,5R)-3-(4-Fluorobenzyl)-7,10-dimethoxy-1,2,3,4,5,
6-hexahydro-1,5-epoxy-benzo[d]azocine 6d
White solid (31 mg, 85%); ½a D26
¼ þ22:8 (c 1, CHCl3); FTIR (KBr,
ꢃ
4.7.9. (+)-(1S,5R)-7,10-Dimethoxy-3-((S)-1-phenylethyl)-1,2,3,4,
5,6-hexahydro-1,5-epoxybenzo[d]azocine 6i
cmꢀ1): 1150, 1257, 1494, 1603, 2932; 1H NMR (300 MHz, CDCl3) d:
6.80–6.92 (m, 4H, ArH), 6.71 (d, J = 8.8 Hz, 1H, ArH), 6.62 (d,
J = 9.1 Hz, 1H, ArH), 5.08 (s, 1H, CH), 4.33 (br d, J = 5.9 Hz, 1H,
CH), 3.83 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.36 (s, 2H, CH), 3.09
(dd, J = 8.2 and 18.1 Hz, 1H, CH), 2.45–2.75 (m, 5H, CH); 13C NMR
(75 MHz, CDCl3) d: 150.5, 148.6, 134.1, 129.6, 129.5, 127.5, 125.3,
114.8, 114.5, 107.7, 106.6, 67.5, 66.3, 61.2, 59.1, 56.0, 55.6, 55.5,
29.6, 27.1; LC–MS (ESI M+1): 344.10.
White solid (32 mg, 88%); ½a D26:7
¼ þ27:8 (c 1, CHCl3); FTIR (KBr)
ꢃ
cmꢀ1: 1149, 1256, 1484, 1603, 2794, 2928; 1H NMR (300 MHz,
CDCl3) d: 7.02 (t, J = 2.9 Hz, 3H, ArH), 6.76 (m, 2H, ArH), 6.64 (d,
J = 8.8 Hz, 1H, ArH), 6.51 (d, J = 9.1 Hz, 1H, ArH), 4.92 (s, 1H, CH),
4.29 (m, 1H, CH), 3.77 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.2 (q,
J = 6.7 Hz, 1H, CH), 3.03 (dd, J = 8 and 17.9 Hz, 1H, CH), 2.81 (d,
J = 10.8 Hz, 1H, CH), 2.51–2.58 (m, 3H, CH), 2.32 (dd, J = 2.9 and
11.1 Hz, 1H, CH), 1.09 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3) d: 150.4, 148.7, 145.5, 144.8, 127.8, 127.1, 126.3, 125.4,
107.6, 106.6, 67.8, 66.6, 63.4, 55.6, 55.4, 54.5, 31.9, 29.6, 27.3,
19.5, 14.1; GC–MS: m/z 339 (M+).
4.7.5. (+)-(1S,5R)-7,10-Dimethoxy-3-(4-methoxybenzyl)-1,2,3,4,
5,6-hexahydro-1,5-epoxybenzo[d]azocine 6e
White solid (34 mg, 90%); ½a D23
¼ þ17:0 (c 1, CHCl3); FTIR (KBr)
ꢃ
cmꢀ1: 1074, 1251, 1481, 1600, 2798, 2928; 1H NMR (300 MHz,
CDCl3) d: 6.89 (d, J = 8.6 Hz, 2H, ArH), 6.68–6.72 (m, 3H, ArH),
6.61 (d, J = 8.6 Hz, 1H, ArH), 5.08 (s, 1H, CH), 4.31 (dd, J = 1.9 and
7.6 Hz, 1H, CH), 3.82 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.69 (s,
3H, OCH3), 3.35 (q, J = 13.4 Hz, 2H, CH), 3.07 (dd, J = 8.1 and
18.1 Hz, 1H, CH), 2.76 (d, J = 11 Hz, 1H, CH), 2.67 (d, J = 11 Hz, 1H,
CH), 2.46–2.59 (m, 3H, CH); 13C NMR (75 MHz, CDCl3) d: 158.4,
150.5, 148.7, 130.3, 129.4, 127.6, 125.4, 113.4, 107.8, 106.6, 67.6,
Acknowledgments
We are thankful to the Department of Science and Technology
(DST) (Project No. SR/FT/CS-015/2010), UGC, New Delhi, for finan-
cial support. V.P.P. is thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, for
fellowship.
a junior research
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

8
V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx
411; (d) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 2, 187; (e) Giles, R. G. F.;
References
McManus, J. D. Tetrahedron Lett. 2009, 50, 6361. and references cited therein.
11. For a reference proposing a boat transition state for ring closure, see: Mohler,
D. L.; Thompson, D. W. Tetrahedron Lett. 1987, 28, 2567.
12. Koch, W.; Holthausen, M. C. A. Chemists Guide to Density Functional Theory, 2nd
ed.; Wiley-VCH: Weinheim, Germany, 2001.
1. (a) Katzung, B. G. In Basic and Clinical Pharmacology; LANGE McGraw Hill
Medical, 2007. 10th ed.; (b) Lednicer, D.; Mitscher, L. A. The Organic Chemistry
of Drug Synthesis; John Wiley & Sons: New York, 1977. pp. 286–312; Lednicer,
D. Central Analgesics; John Wiley & Sons: New York, 1982. pp 137–213.
2. Lord, J. A.; Waterfield, A. A.; Hughes, J.; Kosterlitz, H. W. Nature 1977, 267, 495.
3. Matthes, H. W.; Maldonado, R.; Simonin, F.; Valverde, O.; Slowe, S.; Kitchen, I.;
Befort, K.; Dierich, A.; Le Meur, M.; Dollé, P.; Tzavara, E.; Hanoune, J.; Roques, B.
P.; Kieffer, B. L. Nature 1996, 383, 819.
4. (a) Carroll, F. I.; Abraham, P.; Parham, K.; Bai, X.; Zhang, X.; Brine, G. A.;
Mascarella, S. W.; Martin, B. R.; May, E. L.; Sauss, C.; Di Paolo, L.; Wallace, P.;
Walker, J. M.; Bowen, W. D. J. Med. Chem. 1992, 35, 2812; (b) May, E. L.; Aceto,
M. D.; Bowman, E. R.; Bentley, C.; Martin, B. R.; Harris, L. S.; Medzihradsky, F.;
Mattson, M. V.; Jacobson, A. E. J. Med. Chem. 1994, 37, 3408.
5. Kometani, T.; Shiotani, S. J. Med. Chem. 1978, 21, 1105.
6. Mitsuhashi, K.; Shiotani, S.; Oh-uchi, R.; Shiraki, K. Chem. Pharm. Bull. 1969, 17,
434.
7. Carroll, F. I.; Melvin, M. S.; Nuckols, M. C.; Mascarella, S. W.; Navarro, H. A.;
Thomas, J. B. J. Med. Chem. 2006, 49, 1781.
8. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293; (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; Macmillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 10808; (c) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
9. (a) Sawant, R. T.; Waghmode, S. B. Tetrahedron 2009, 65, 1599; (b) Sawant, R. T.;
Waghmode, S. B. Tetrahedron 2010, 66, 2010; (c) Sawant, R. T.; Jadhav, S. G.;
Waghmode, S. B. Eur. J. Org. Chem. 2010, 4442; (d) Sawant, R. T.; Waghmode, S.
B. Synth. Commun. 2010, 40, 2269; (e) Sawant, R. T.; Waghmode, S. B. Synth.
Commun. 2011, 41, 2385.
10. For intramolecular oxa-Pictet–Spengler cyclization, see: (a) Giles, R. G. F.;
Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1 1997, 3361; (b)
Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1
1998, 3949; (c) Bianchi, D. A.; Rua, F.; Kaufman, T. S. Tetrahedron Lett. 2004, 45,
13. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T., ; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision
A.02; Gaussian, Inc: Wallingford CT, 2009.
14. (a) Lee, C.; Yang, W.; Parr, R. Phys. Rev. B 1988, 37, 785; (b) Becke, A. D. J. Chem.
Phys. 1993, 98, 5648.
15. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D.
S.; Olson, A. J. J. Comput. Chem. 2009, 30, 2785.
16. Smith, D. M.; Daniel, K. G.; Wang, Z.; Guida, W. C.; Chan, T. H.; Dou, Q. P.
Proteins 2004, 54, 58.
17. Rao, M. S.; Olson, A. J. Proteins 1999, 34, 173.
18. Dym, O.; Xenarios, I.; Ke, H.; Colicelli, J. Mol. Pharmacol. 2002, 61, 20.
19. Harriman, D. J.; Deslongchamps, G. J. Comput. Aided Mol. Des. 2004, 18, 303.
20. Fra˛czek, T.; Siwek, A.; Paneth, P. J. Chem. Inf. Model. 2013. http://dx.doi.org/
10.1021/ci400427a.
21. Bitomsky, W.; Wade, R. C. J. Am. Chem. Soc. 1999, 121, 3004.
Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016