Design, synthesis and evaluation of tetrahydropyran based COX-1/-2 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2008.08.008

Chiral tetrahydropyrans were designed and synthesized by allylations of enantiomerically enriched β-hydroxy ketones followed by iodocyclisations and nucleophilic replacement of iodo group with C₂H₅S^- and SCN-. In vitro COX-1/-2 inhibitory activities and the docking studies of these compounds identify some of them as moderate inhibitors of COX-1 and COX-2 enzymes.

Full text of DOI:10.1016/j.ejmech.2008.08.008

European Journal of Medicinal Chemistry 44 (2009) 1278–1287
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and evaluation of tetrahydropyran based
COX-1/-2 inhibitors
,
a
b
a
Palwinder Singh a , Atul Bhardwaj , Satwinderjeet Kaur , Subodh Kumar
*
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b Department of Botanical & Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2008
Received in revised form 13 July 2008
Accepted 19 August 2008
Available online 3 September 2008
Chiral tetrahydropyrans were designed and synthesized by allylations of enantiomerically enriched b-
hydroxy ketones followed by iodocyclisations and nucleophilic replacement of iodo group with C2H5Sꢀ
and SCNꢀ. In vitro COX-1/-2 inhibitory activities and the docking studies of these compounds identify
some of them as moderate inhibitors of COX-1 and COX-2 enzymes.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords:
Arachidonic acid metabolism
Cyclooxygenases
Tetrahydropyrans
Enantioselective synthesis
COX-1/-2 inhibitors
1. Introduction
of selective/non-selective COX-1 inhibitors [23–27] which might be
due to the gastrointestinal ulcerations (GI) associated with COX-1
Two isoforms of enzyme cyclooxygenase viz. COX-1 and COX-2
perform key roles in arachidonic acid metabolism [1,2]. The induc-
ible enzyme COX-2 [3] also constitutively expressed in human
kidney and brain is found in inflamed and neoplastic tissues; takes
part in the production of inflammatory prostaglandins, responsible
for promoting cancer [4–7] and in the development of multidrug
resistance [8–10] and it continues to be a target of a large number of
anti-inflammatory drugs. However, higher inhibition of COX-2 shifts
the arachidonic acid metabolism to lipoxygenase pathwayand leads
to more production of leukotrienes, responsible for cancer induction
[11,12]. Moreover, COX-2 inhibitors are also responsible for neph-
rotoxicity and cardiovascular risks [13–17]. The prostaglandins
produced from arachidonic acid through the participation of COX-1
are mainly responsible for gastrointestinal (GI) protection, induction
of labor pains and blood clotting [18]. Higher inhibition of COX-1, by
the use of non-selective COX-1/2 inhibitors, leads to thinning of
blood. Keeping in mind the functions of these two isoforms of
cyclooxygenase, the development of new molecules with optimum
inhibition of both COX-1 and COX-2 seems to be desirable. Struc-
turally, the COX-2 inhibitors consist of two aryl rings on the adjacent
sp2 hybridized carbons of an acyclic template as well as on 3-, 4-, 5-,
6-membered carbocyclic/heterocyclic moieties [19–22]. However,
a few reports are available for the rational design and development
inhibition. Further investigations indicate that it is not only the
inhibition of COX-1 which is responsible for GI ulcerations but the
inhibition of COX-2 also [27].
Based upon the flexible and the chiral natures of COX-1 and
COX-2 active sites (so is the case for every other enzyme), it was
envisaged that the central template with asymmetric carbons could
adapt more conveniently in the active sites of these enzymes and
could prove as better inhibitors (only S-ibuprofen is active [28]).
Moreover, non-selective COX-1/-2 inhibitors require an optimum
size so that they could be accommodated in the active sites of both
COX-1 and COX-2 (due to the small difference in the size of the
active site cavities of COX-1 and COX-2). Keeping both these factors
in mind and the reports available on the COX-2 inhibitory activities
of pyran-2/4-ones [29–31], in the present investigations, chiral
tetrahydropyrans (Fig.1) with an aryl ring at C-2 and an appropriate
substituent at C-6 have been synthesized. In vitro bio-evaluations
(supported by dockings) of these molecules have identified two
molecules as moderate inhibitors of COX-1 and COX-2.
2. Results and discussion
2.1. Chemistry
Considerable attention has been paid for the synthesis of
substituted tetrahydropyrans, with well defined stereochemistry at
* Corresponding author. Tel.: þ91 183 2258802x3495; fax: þ91 183 2258819.
E-mail address: palwinder_singh_2000@yahoo.com (P. Singh).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.08.008

P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
1279
HO
CH3
X
O
H
H
R
1: R = NO2, F, Cl, Br
X = I, SC2H5, SCN
Fig. 1. Design of tetrahydropyrans.
Fig. 2. ORTEP view of 2 (R ¼ NO2).
the ring carbons, starting from simple acyclic compounds [32–34],
by ring enlargement [35], via hetero Diels–Alder reaction [36,37],
olefin metathesis [38] and recently an increasing interest has been
shown for the synthesis of stereo-controlled tetrahydropyrans by
Prins cyclization [39–43]. Here, the stereoselective synthesis of
polysubstituted tetrahydropyrans has been achieved by the allyla-
(0.4 mmol) in dry THF, was added 2 (R ¼ NO2, 1 equiv). Stirring the
reaction mixture at room temperature, after usual work up and
column chromatography provided a mixture of two diastereomers
3a and 3b (88%, Mþ m/z 251) which in 1H NMR spectrum clearly
shows two sets of signals in the ratio 7:3 (Scheme 1). Under the
same reaction conditions, the treatment of 2 (R ¼ F, Cl, Br) with pre-
generated reagent In2(allyl)3Br3 gave the corresponding
compounds 4, 5 and 6 as a mixture of two diastereomers (a and b)
in the ratio 5:4, 2:1 and 7:3, respectively (Scheme 1).
tions of enantiomerically enriched
diastereoselective iodocyclisations.
b-hydroxy ketones followed by
2.1.1. Enantioselective synthesis of
b-hydroxy ketones
It has been observed that the diastereoselectivity of the allylated
b-Hydroxy ketones have been procured stereoselectively
products (3–6) formed from
compared to the high diastereoselectivity of the allylations of
hydroxy ketones [49]. This might be attributed to the formation of
a relatively flexible six-membered transition state during the ally-
lation of 2 (Fig. 3) in contrast to the five-membered transition state
formed in the case of allylations of
formation of the syn- and anti-diastereomer could be visualized
through the existence of Cram’s chelation models A and B (Fig. 3).
b-hydroxy ketones (2) is lower as
through the reactions of appropriate aldehydes and ketones
mediated by small organic molecules viz. proline and its derivatives
[44–48]. Here, improved over the reported procedures for the
a
-
synthesis
of
4-hydroxy-4-(4-nitrophenyl)-butan-2-one
(2,
R ¼ NO2) [44] (entry 1, Table 1), it has been synthesized (72%,
[a]
D
¼ þ44ꢁ and 72% ee) by the reaction of 4-nitrobenzaldehyde
a-hydroxy ketones. The
with acetone (as solvent) using proline as catalyst (entry 3, Table 1).
The reaction of 4-nitrobenzaldehyde with acetone in 1:1 mixture of
DMSO and water yielded compound 2 (R ¼ NO2) (80%) with poor
optical rotation and enantioselectivity (entry 2, Table 1). Under the
reaction conditions as mentioned in entry 3 (Table 1), the treatment
of other benzaldehydes (entries 4–8, Table 1) with acetone
2.1.3. Diastereoselective conversion of allylated products to
tetrahydropyrans
Treatment of diastereomeric mixture of 3 with iodine in dry
CH3CN using NaHCO3 provided a mixture of two compounds (2:1,
1H NMR spectrum) which after purification with column chroma-
provided the corresponding
b-hydroxy ketones in comparable
yields and enantioselectivities as reported using DMSO/acetone as
the solvent and ‘proline derivatives’ as the catalysts. The R-config-
uration at the chiral center of these hydroxy ketones has been
confirmed from the X-ray structure of 2 (R ¼ NO2) (Fig. 2).
tography have been identified as compounds 7 (40%, [
a]
¼ þ43.3ꢁ)
D
and 8 (20%, [
compounds 9 (35%, [
a
]
¼ þ41ꢁ). Similar reactions of 4, 5 and 6 provided
D
a
]D ¼ þ40ꢁ), 10 (30%, [
a]
¼ þ35ꢁ); 11 (35%,
D
[
a
]
¼ þ47ꢁ), 12 (30%, [
a]
¼ þ48ꢁ) and 13 (32%, [
a
]D ¼ þ41.2ꢁ), 14
D
D
(21%, [
a
]D ¼ þ40ꢁ), respectively (Scheme 2).
2.1.2. Allylation of b-hydroxy ketones
To the cooled solution of the reagent In2(allyl)3Br3, generated by
refluxing the mixture of allyl bromide (0.5 mmol) and indium metal
The relative stereochemistries at the various asymmetric
carbons of compounds 7–14 have been ascertained on the basis of
Table 1
Reaction conditions, percentage yields, optical rotation and ee values for 2
OH
O
O
CHO
L-Proline
CH
3
H C
CH
3
+
3
solvent, temp.
time
R
R
2
Entry
R
Solvent
Temperature (ꢁC)
Time (h)
% Yield
[a
]
D (ꢁ)
eea
%
1 [44]
NO2
NO2
NO2
F
Cl
Br
DMSO
0
25
25
25
25
25
25
25
8
6
76
80
72
70
68
75
64
55
þ46
76
35
72
74
77
60
60
58
2
3
4
5
6
7
8
DMSO/H2O
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
þ22
10
10
11
10
15
30
þ44
þ49
þ51
þ40.4
þ43.6
þ41.4
OCH3
SCH3
a
Enantiomeric excess was determined by 1H NMR experiments using Eu(hfc)3 chiral shift reagent.

1280
P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
OH
O
OH OH
OH OH
CH3
CH3
CH3
R
2
R
R
Pre-generated In2(allyl)3Br3,
THF, stir, rt
3-6
I2, NaHCO3
CH3CN, stir
OH OH
OH OH
HO CH3
4
HO
CH3
CH3
CH3
+
5
3
+
R
R
I
I
2
6
O
O
a
b
1
3-6
syn-
anti-
R
R
yield
88%
86%
80%
70%
dr(a:b)
70:30
56:44
67:33
70:30
8,10, 12,14
7, 9, 11,13
3, R = NO2
4, R = F
5, R = Cl
6, R = Br
7, 8: R = NO2
9, 10: R = F
11, 12: R = Cl
13, 14: R = Br
Scheme 1.
Scheme 2.
NOE experiments (Fig. 4) and X-ray structure of 13 (Fig. 5). The
observation of NOE between 2-H and 6-H in the case of compounds
7, 9, 11 and 13 indicates the syn orientation of these hydrogens.
The X-ray structure of 13 (Fig. 5) shows the equatorial orientation of
phenyl ring, CH2I and OH groups and supports the stereochemistries
observed for these compounds on the basis of NMR experiments.
Compounds 15–22 (analogues of 7, 9,11 and 13)withstereochemistries
at various asymmetric carbons as shown in Fig. 5 are used for docking
studies while in the case of compounds 23–30 (analogues of 8, 10, 12
and 14), the stereochemistry at C-6 of tetrahydropyran is reversed.
inhibitor screening assay kits (Cayman Chemicals, Cat. No. 560101)
with 96 well plates following the standard procedure [51]. On the basis
of the results of docking studies, compounds 23–30 which show very
poor or no interactions with the enzymes are not included in the
experimental investigations. For compounds 15–22, almost no differ-
ence in the COX-2 inhibitory activities between compounds 15 and 16;
17 and 18; 21 and 22 has been observed which indicates that CH2SC2H5
and SCN groups may contribute equally towards the activity of these
compounds. It was also found during the docking studies that the S
atom of both these substituents approaches to R120 in the active site of
COX-2. Compounds 17 and 18 with F on the aryl ring showconsiderably
2.1.4. Replacement of iodo group with other nucleophiles
It has been found [50,51] that the groups like CH2SCH2CH3,
CH2SCN, etc., when present at five-membered cyclic template, are
suitable for interacting with the guanidine moiety of R120, an
amino acid present in the active site of COX-2. In order to introduce
such groups on tetrahydropyrans, equimolar quantities of 7/9/11/13
and C2H5SH/KSCN were stirred in CH3CN using K2CO3 as base which
provided the respective compounds 15–22 (Scheme 3).
higher inhibition of COX-2 (IC50 w 1 mM) as compared to other
compounds with NO2, Cl andBr substitutedaryl rings. Moreover,17 and
18 exhibit lower inhibition of COX-1 incomparisontoibuprofen(anon-
selective COX-1/2 inhibitor). Therefore, in addition to the identification
of 17 and 18 as suitable candidates for further refinement to develop as
COX-1/2 inhibitors, these investigations also justify the design of these
molecules.
Therefore, starting from b-hydroxy ketones, following a two step
synthetic approach viz. allylation and iodocyclisation, polysubstituted
tetrahydropyrans have been procured in moderate to high yields.
NOE
I
H
2.2. Biology
(3.30)
H
He
(1.90)
C
Compounds 15–22 (except 20) were evaluated in duplicate at
10ꢀ5 M and 10ꢀ6 M concentrations for COX-2 inhibition and 10ꢀ5 M
concentration for COX-1 inhibition (Table 2) using COX (ovine)
Hc(1.90)
5
1
Hd
O
(1.59)
6
3
2
4
H3C
L
L
HO
Ph-NO2
(1.59)
H3C
(3.5)
In
Hf
In
O
O
L
Hb
L
In
OH
OH
NOE
H
OH
C
H
Ha
O
H
NOE
(4.60)
H
H
H3C
(1.48)
R
R
R
J
a-b = 2.1 Hz, Ja-c = 11.7 Hz, Jd-f = 2.1 Hz, Je-f = 11.4 Hz
B
A
Fig. 4. Orientation of the groups at each carbon of 7 as depicted from 1H decoupling
Fig. 3. Transition state during allylations of 2 and Cram’s chelation model.
and NOE experiments. 1H chemical shifts are given in brackets.

P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
1281
Table 2
In vitro percentage inhibition of COX-1 and COX-2 by compounds 15–22
Compound
Percentage inhibition
COX-2
IC50 (mM)
COX-1
COX-2
COX-1
10ꢀ5 M
10ꢀ6 M
10ꢀ5 M
15
16
17
18
19
20
21
22
37
35
56
49
34
nd
30
28
76
37
34
55
47
30
nd
30
26
87
34
29
42
34
34
nd
24
32
96
>10
>10
<1
1
>10
–
>10
>10
>10
>10
>10
–
>10
>10
>10
>10
Ibuprofen [25]
Aspirin (IC50) [26]
2.4
0.35
nd – Not done.
between the dockings of two sets of diastereomers (15–22 and 23–
30), compounds 23–30 were also included for docking studies. All
the compounds were built with specific stereochemistry at the
different asymmetric centers and energy minimized before their
dockings in the active sites of COX-1 and COX-2. Crystal coordinates
of COX-2 with SC-558 in the active site pocket were downloaded
from protein data bank (Pdb ID 6COX) and refined as reported
previously [52]. The crystal structure of COX-1 (Pdb ID 1EQG) has
ibuprofen in the active site pocket. The docking program [53] was
validated by docking ibuprofen in the active site of COX-1 and
a close overlapping of the docked ibuprofen with the one present in
the crystal structure of the enzyme was observed (Fig. 6).
Compounds 15–22, like ibuprofen, aspirin and diclofenac,
exhibit negative docking scores (Table 3) for COX-2 and COX-1
indicating their significant interactions with active site amino acids
of these enzymes. Compounds 17 and 18, which show best exper-
imental results in this series of compounds, also exhibit better
docking score in comparison to other compounds. Docking scores
of other compounds, except 19, follow almost parallel trend with
the experimental results (inhibition of both COX-1 and COX-2 by
these compounds). Interestingly, the dockings of compounds 23–
30 in the active sites of both COX-1 and COX-2 show positive
docking scores (Table 3) indicating their poor or no interactions
Fig. 5. ORTEP diagram of 13.
2.3. Dockings of tetrahydropyrans in the active sites of COX-1 and
COX-2
In order to get further insight into the nature of interactions
between the tetrahydropyrans and the amino acids of COX-1, COX-2
active sites, the dockings of compounds 15–22 in the active sites of
COX-1 and COX-2 were performed. For making a comparison
HO
CH3
I
O
7, 9, 11, 13
R
i, ii
HO
HO
CH3
CH3
Nu
Nu
O
O
R
R
15-22
23-30
15, 23: R = NO2, Nu = SC2H5
16, 24: R = NO2, Nu = SCN
17, 25: R = F, Nu = SC2H5
18, 26: R = F, Nu = SCN
19, 27: R = Cl, Nu = SC2H5
20, 28: R = Cl, Nu = SCN
21, 29: R = Br, Nu = SC2H5
22, 30: R = Br, Nu = SCN
Scheme 3. Reagents and reaction conditions: (i) C2H5SH, K2CO3, CH3CN, stir, rt; (ii)
Fig. 6. A close overlapping between the two Ibuprofen molecules validates the docking
KSCN, K2CO3, CH3CN, stir, rt.
programme.

1282
P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
Table 3
Docking scores (kcal/mol) of compounds 15–30 when docked in the active sites of
COX-1 and COX-2
Compound
Docking score (kcal/mol)
COX-2
COX-1
15
16
17
18
19
20
21
22
23
24
25
26
ꢀ37
ꢀ45
ꢀ50
ꢀ49
ꢀ50
ꢀ40
ꢀ38
ꢀ40
103
32
ꢀ20
ꢀ30
ꢀ24
ꢀ33
ꢀ25
ꢀ26
ꢀ3
ꢀ26
72
100
ꢀ7.4
36
64
74
27
32
27
28
29
ꢀ18
6.8
43
69
30
89
46
Ibuprofen
Aspirin
Diclofenac
ꢀ47
ꢀ62
ꢀ27
ꢀ21
ꢀ60
ꢀ41
Fig. 8. Compound 15 docked in the active site of COX-1.
with these enzymes and also indicates that the stereochemistry at
C-6 of tetrahydropyran significantly affects the interactions of these
compounds in the active sites of COX-1 and COX-2.
The optimum size and appropriate stereochemistry of these
molecules allow them to enter the active sites of COX-1 as well
as COX-2, thereby inhibiting both these enzymes. The close
parallelism between the docking results and the experimental
results could be helpful in further refinements of these
molecules.
During the docking of compound 15 in the active site of COX-2
(Fig. 7), the nitro group present at the phenyl ring shows H-bonding
with H90 residue and the S atom present at C-6 substituent
approaches R120 (the amino acid active during the metabolic phase
of COX-2) at a distance of 2.7 Å.
When 15 is docked in the active site of COX-1 (Fig. 8), the C-6
substituent (CH2SC2H5) is placed in the hydrophobic sub-pocket of
COX-1 active site constituted by Y385, W387, F381 and F518 resi-
dues. The nitrophenyl group present at C-2 of 15 is oriented
towards the polar sub-pocket comprising R120, V116, Y355 resi-
dues. A similar placement of molecules 16–22 has been observed
during their dockings in the active sites of COX-1 and COX-2.
3. Conclusions
Rationally designed tetrahydropyrans, with asymmetric centers
and appropriate substituents, were synthesized by the allylations of
enantioselective
b-hydroxy ketones followed by the iodocyclisa-
tions. The in vitro investigations of these molecules identify
compounds 17 and 18 as moderate inhibitors of COX-1/-2 enzymes.
The dockings of these molecules in the active sites of COX-1 and
COX-2 indicate their significant interactions with the active site
amino acid residues of these enzymes.
4. Experimental
4.1. General details
Melting points were determined in capillaries and are uncor-
rected. 1H and 13C NMR spectra were run on JEOL 300 MHz and
75 MHz NMR spectrometer, respectively, using CDCl3 as solvent.
Chemical shifts are given in parts per million with TMS as an
internal reference. J values are given in hertz. Chromatography was
performed with silica 100–200 mesh and reactions were monitored
by thin layer chromatography (TLC) with silica plates coated with
silica gel HF-254. In 13C NMR spectral data, þve, ꢀve terms corre-
spond to CH3, CH, CH2 signals in DEPT-135 NMR spectra.
4.2. General procedure for the synthesis of
b-hydroxy ketones
To the solution of 4-substituted benzaldehyde (0.4 mmol) in
10 ml acetone was added L-proline (20 mol%) and the resulting
mixture was stirred at 25 ꢁC for 8–13 h. The reaction mixture was
treated with saturated ammonium chloride solution, the layers
were separated and aqueous layer was extracted with ethyl acetate
Fig. 7. Compound15 docked in the active site of COX-2. One of the oxygens of the nitro
group of 15 forms H-bond with H90 while
S atom present at C-6 substituent
approached R120 at a distance of 2.7 Å.

P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
1283
(3 ꢂ 25 ml) and combined organic layers were dried over anhy-
4.2.6. (4R)-4-Hydroxy-4-(4-methylsulfanylphenyl)-butan-2-one
(2f)
drous Na2SO4. Ethyl acetate was distilled off and the residue was
purified by column chromatography using ethyl acetate and hexane
(1:2) as eluents.
4-Methylsulfanylbenzaldehyde was allowed to react with
acetone as described in the general procedure to give 2f as thick
liquid, 55% yield; 1H NMR (CDCl3)
d 2.15 (s, 3H, CH3), 2.45 (s, 3H,
4.2.1. (4R)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (2a)
CH3), 2.73 (dd, J ¼ 17.1 Hz, J ¼ 3.6 Hz, 1H, 1H of CH2), 2.84 (dd,
J ¼ 17.1 Hz, J ¼ 9.0 Hz, 1H, 1H of CH2), 3.55 (br, 1H, OH), 5.06 (dd,
J ¼ 9.0 Hz, J ¼ 3.6 Hz, 1H, CH), 7.18–7.28 (m, 4H, ArH); 13C NMR
4-Nitrobenzaldehyde was allowed to react with acetone as
described in the general procedure to give 2a as white crystalline
solid, 72% yield, mp 60 ꢁC; nmax (CHCl3): 1705 (C]O), 3580
(normal/DEPT-135) (CDCl3)
d
15.75 (þve, CH3), 30.71 (þve, CH3),
(OH) cmꢀ1; 1H NMR (CDCl3)
d
2.23 (s, 3H, CH3), 2.87 (d, J ¼ 6 Hz, 2H,
51.82 (ꢀve, CH2), 69.32 (þve, CH), 126.03 (þve, ArCH), 126.45 (þve,
CH2), 5.27 (t, J ¼ 6 Hz, 1H, CH), 7.54 (d, J ¼ 6.9 Hz, 2H, ArH), 8.20
ArCH), 137.46 (absent, ArC), 139.64 (absent, ArC), 208.78 (absent,
(d, J ¼ 6.9 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
C]O); FAB mass m/z 210 (Mþ); [
a
]D ¼ þ41.4ꢁ (c 1, CHCl3).
d
30.64 (þve, CH3), 51.39 (ꢀve, CH2), 68.83 (þve, CH), 123.70 (þve,
ArCH), 126.33 (þve, ArCH), 147.30 (absent, ArC), 149.88 (absent,
4.3. General procedure for allylation of b-hydroxy ketones
ArC), 208.56 (absent, CO); FAB mass m/z 209 (Mþ); [
a]
¼ þ44ꢁ (c 1,
D
CHCl3).
To the magnetically stirred solution of allyl bromide (0.5 mmol) in
dry THF was added indium metal (0.4 mmol) and mixture was refluxed
for 30 min. During this period indium was dissolved. To the cooled
4.2.2. (4R)-4-(4-Fluorophenyl)-4-hydroxybutan-2-one (2b)
4-Fluorobenzaldehyde was allowed to react with acetone as
described in the general procedure to give 2b as white crystalline
solid, 70% yield, mp 55 ꢁC; nmax (CHCl3): 1700 (C]O), 3640
solution was added a solution of b-hydroxy ketone (0.5 mmol) in dry
THF. The reaction mixture was stirred at room temperature for 6–10 h
(TLC). The reaction mixture was treated with saturated solution of
ammonium chloride and extracted with ethyl acetate (3 ꢂ 25 ml),
dried over anhydrous Na2SO4. Removal of ethyl acetate by distillation
and the purification of the residue by column chromatography using
ethyl acetate and hexane as eluents (1:5) gave a mixture of two dia-
stereomers (a and b) for compounds 3–6. The assignments of the
signals to various Hs’ in the 1H NMR experiments are based upon the
decoupling, 1H–13C HETCOR, NOE experiments.
(OH) cmꢀ1; 1H NMR (CDCl3)
d
2.19 (s, 3H, CH3), 2.81 (d, J ¼ 6 Hz, 2H,
CH2), 5.13 (dd, J ¼ 8.4 Hz, J ¼ 3.9 Hz, 1H, CH), 7.02 (t, J ¼ 8.7 Hz, 2H,
ArH), 7.31 (m, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d
30.67 (þve, CH3), 51.85 (ꢀve, CH2), 69.11 (þve, CH), 115. 92, (þve,
ArCH, ortho to F, JC–F ¼ 21.0 Hz), 127.28 (þve, ArCH, meta to F, JC–
¼ 8.02 Hz), 138.46 (absent, ArC, para to F, JC–F ¼ 1.87 Hz), 162.14
F
(mid point of two peaks at 160.52 and 163.76) (absent, ArC–F, JC–
¼ 243.5 Hz), 209.00 (absent, C]O); FAB mass m/z 182 (Mþ);
F
[
a
]
¼ þ49ꢁ (c 1, CHCl3).
4.3.1. 3-Methyl-1-(4-nitrophenyl)-hex-5-ene-1,3-diols (3a þ 3b)
Compound 2a was allowed to react with allyl bromide as
described in the general procedure to give 3a and 3b as thick
creamish white liquid, 88% yield; mixture of two diastereomers
designated as major and minor, 7:3 (1H NMR integration); nmax
D
4.2.3. (4R)-4-(4-Chlorophenyl)-4-hydroxy-2-butanone (2c)
4-Chlorobenzaldehyde was allowed to react with acetone as
described in the general procedure to give 2c as white crystalline
solid, 68% yield, mp 45 ꢁC; nmax (CHCl3): 1715 (C]O), 3540
(CHCl3): 3720 (OH), 3780 (OH) cmꢀ1; 1H NMR (CDCl3)
d 1.22 (s, 3H,
(OH) cmꢀ1; 1H NMR (CDCl3)
d
2.14 (s, 3H, CH3), 2.80 (d, J ¼ 6 Hz, 2H,
CH2), 5.13 (dd, J ¼ 8.1 Hz, J ¼ 4 Hz, 1H, CH), 7.21–7.32 (m, 4H, ArH);
13C NMR (normal/DEPT-135) (CDCl3)
CH3major), 1.44 (s, 3H, CH3minor), 1.62–1.77 (m, 2H, 1H of
CH2major þ 1H of CH2minor), 1.80–1.88 (m, 2H, 1H of CH2major þ 1H of
CH2minor), 2.25 (d, J ¼ 7.5 Hz, 2H, CH2minor), 2.52 (d, J ¼ 7.5 Hz, 2H,
CH2major), 5.09–5.21 (m, 6H, 2H of ]CH2major þ 2H of
]CH2minor þ 1H of CH–OHmajor þ 1H of CH–OHminor), 5.82–5.91 (m,
2H, 1H of ]CHmajor þ 1H of ]CHminor), 7.48 (d, J ¼ 7.2 Hz, 2H, ArH),
7.51 (d, J ¼ 6.6 Hz, 2H, ArH), 8.15 (d, J ¼ 8.7 Hz, 2H, ArH), 8.15 (d,
d
30.66 (þve, CH3), 51.73 (ꢀve,
CH2), 69.05 (þve, CH), 126.95 (þve, ArCH), 128.56 (þve, ArCH),
133.23 (absent, ArC), 141.22 (absent, ArC), 208.80 (absent, C]O);
FAB mass m/z 198 (Mþ); [
a
]D ¼ þ51ꢁ (c 1, CHCl3).
4.2.4. (4R)-4-(4-Bromophenyl)-4-hydroxybutan-2-one (2d)
4-Bromobenzaldehyde was allowed to react with acetone as
described in the general procedure to give 2d as white crystalline
J ¼ 8.7 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3):
d 25.35
(þve, CH3minor), 28.87 (þve, CH3major), 29.61 (ꢀve, CH2minor), 44.66
(ꢀve, CH2major), 48.32 (ꢀve, CH2major), 48.42 (ꢀve, CH2minor), 70.66
(þve, CHmajor), 70.93 (þve, CHminor), 73.39 (Cmajor), 73.43 (Cminor),
119.34 (ꢀve, ]CH2major), 119.79 (ꢀve, ]CH2minor), 123.59 (þve,
ArCHmajor), 124.13 (þve, ArCHminor), 126.13 (þve, ArCHmajor), 126.35
(þve, ArCHminor), 128.78 (þve, ArCHmajor), 130.24 (þve, ArCHminor),
132.61 (þve, CHmajor), 133.40 (þve, CHminor), 146.97 (ArC), 152.13
solid, 75% yield, mp 57 ꢁC; 1H NMR (CDCl3)
d 2.10 (s, 3H, CH3), 2.66
(dd, J ¼ 17.1 Hz, J ¼ 3.6 Hz, 1H, 1H of CH2), 2.78 (dd, J ¼ 17.1 Hz,
J ¼ 9.0 Hz, 1H, 1H of CH2), 4.07 (br, 1H, OH), 5.01 (br d, J ¼ 9.0 Hz),
7.15 (d, J ¼ 8.1 Hz, 2H, ArH), 7.39 (d, J ¼ 8.1 Hz, 2H, ArH); 13C NMR
(normal/DEPT-135) (CDCl3)
d
30.63 (þve, CH3), 51.78 (ꢀve, CH2),
68.94 (þve, CH), 120.78 (absent, ArC), 127.10 (þve, ArCH), 131.04
(ArCmajor), 152.19 (ArCminor); FAB mass m/z 251 (Mþ); [
(c 1, CHCl3). (Found C 62.43, H 6.48, N 5.17; C13H17NO4 requires C
a
]D ¼ þ34.3ꢁ
(þve, ArCH), 141.90 (absent, ArC), 206.14 (absent, C]O); FAB mass
m/z 242 (Mþ); [
a]
¼ þ40.4ꢁ (c 1, CHCl3).
62.14, H 6.82, N 5.57).
D
4.2.5. (4R)-4-Hydroxy-4-(4-methoxyphenyl)-butan-2-one (2e)
4-Methoxybenzaldehyde was allowed to react with acetone as
described in the general procedure to give 2e as thick liquid, 64%
yield; nmax (CHCl3): 1705 (C]O), 3580 (OH) cmꢀ1; 1H NMR (CDCl3)
4.3.2. 1-(4-Fluorophenyl)-3-methylhex-5-ene-1,3-diols (4a þ 4b)
Compound 2b was allowed to react with allyl bromide as
described in the general procedure to give 4a and 4b as thick
creamish white liquid, 86% yield; mixture of two diastereomers,
d
2.12 (s, 3H, CH3), 2.69 (dd, J ¼ 16.8 Hz, J ¼ 3.6 Hz, 1H, 1H of CH2),
56:44 (1H NMR integration); nmax (CHCl3) 3500–3560 (OH) cmꢀ1
;
2.84 (dd, J ¼ 16.2 Hz, J ¼ 9.0 Hz, 1H, 1H of CH2), 3.75 (s, 3H, OCH3),
5.03 (dd, J ¼ 9.0 Hz, J ¼ 3.6 Hz, 1H, CH), 6.84 (d, J ¼ 6.6 Hz, 2H, ArH),
7.21 (d, J ¼ 6.6 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
1H NMR (CDCl3)
d 1.17 (s, 3H, CH3major), 1.27 (s, 3H, CH3minor), 1.54–
1.69 (m of 8 lines, 2H, 1H of CH2major þ 1H of CH2minor), 1.80–1.88 (m
of 8 lines, 2H, IH of CH2major þ 1H of CH2minor), 2.20 (d, J ¼ 7.5 Hz,
2H, CH2minor), 2.43 (d, J ¼ 7.2 Hz, 2H, CH2major), 4.97–5.03 (m, 2H,1H
of CHmajor þ 1H of CHminor), 5.09–5.19 (m, 4H, 2H of ]CH2major þ 2H
of ]CH2minor), 5.76–5.86 (m, 2H, 1H of ]CHmajor þ 1H of ]CHmi-
nor), 6.95–7.23 (m, 4H, ArH), 7.23–7.29 (m, 4H, ArH); 13C NMR
d
30.67 (þve, CH3), 51.92 (ꢀve, CH2), 55.16 (þve, CH3), 69.38 (þve,
CH), 113.77 (þve, ArCH), 126.86 (þve, ArCH), 134.96 (absent, ArC),
158.88 (absent, ArC), 208.95 (absent, CO); FAB mass m/z 194 (Mþ);
[
a]
¼ þ43.6ꢁ (c 1, CHCl3).
D

1284
P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
(normal/DEPT-135) (CDCl3)
d
25.35 (þve, CH3minor), 28.57 (þve,
column chromatography using ethyl acetate and hexane as eluents
provided the two diastereomers of tetrahydropyrans. The
numbering of the six atoms of tetrahydropyran is as per Fig. 4.
CH3major), 29.60 (ꢀve CH2minor), 44.81 (ꢀve, CH2major), 48.39
(ꢀve, CH2major), 48.43 (ꢀve, CH2minor), 70.87 (þve, CHmajor), 71.14
(þve, CHminor), 73.06 (Cmajor), 73.08 (Cminor), 115.06 (mid of two
peaks at 114.92 and 115. 20) (þve ArCH, ortho to F, JC–F ¼ 21.6 Hz),
118.59 (ꢀve, ]CH2major), 118.97 (ꢀve, ]CH2minor), 127.07 (þve,
ArCH, meta to F, JC–F ¼ 8.10 Hz), 127.21 (þve, ArCH, meta to F, JC–
4.4.1. (2R,4S,6S)-2-Iodomethyl-4-methyl-6-(4-nitrophenyl)-
tetrahydropyran-4-ol (7)
Compound 3a þ 3b was allowed to undergo iodocyclisation as
described in the general procedure to give 7 and 8 as thick liquids
which were separated by column chromatography. 40% yield; 1H
¼ 7.42 Hz), 133.20 (þve, ]CHminor), 133.93 (þve, ]CHmajor),
F
140.40 (absent, ArC, para to F, JC–F ¼ 3.15 Hz), 140.48 (absent, ArC,
para to F, JC–F ¼ 3.07 Hz), 161.94 (mid point of two peaks at 160.32
and 163.56) (absent, ArC–F, JC–F ¼ 242.9 Hz); FAB mass m/z 224
NMR (CDCl3)
d
1.48 (s, 3H, CH3), 1.51–1.62 (m, 2H, H-3 þ H-5), 1.90–
1.99 (m, 2H, H-3 þ H-5), 3.30 (dd, J ¼ 14.1 Hz, J ¼ 6.0 Hz, 1H, 1H of
CH2I), 3.35 (dd, J ¼ 14.1 Hz, J ¼ 4.5 Hz, 1H, 1H of CH2I), 3.54 (m of 16
lines, 1H, H-6), 4.69 (dd, J ¼ 11.7 Hz, J ¼ 2.1 Hz, 1H, H-2), 7.56 (d,
J ¼ 9.0 Hz, 2H, ArH), 8.23 (d, J ¼ 8.7 Hz, 2H, ArH); 13C NMR (normal/
(Mþ); [
a]
¼ þ23.2ꢁ (c 1, CHCl3). (Found C 69.80, H 7.23; C13H17FO2
D
requires C 69.62, H 7.64).
4.3.3. 1-(4-Chlorophenyl)-3-methylhex-5-ene-1,3-diols (5a þ 5b)
Compound 2c was allowed to react with allyl bromide as
described in the general procedure to give 5a and 5b as thick
creamish white liquid, 80% yield; mixture of two diastereomers, 7:3
DEPT-135) (CDCl3)
d
8.92 (ꢀve, CH2I), 26.06 (þve, CH3), 45.4 (ꢀve,
CH2), 47.5 (ꢀve, CH2), 69.23 (C-4), 74.42 (þve, C-2), 75.9 (þve, C-6),
123.69 (þve, ArCH), 126.45 (þve, ArCH), 147.60 (absent, ArC),
149.00 (absent, ArC); In the decoupling NMR experiments, irradi-
(1H NMR integration); 1H NMR (CDCl3)
d
1.12 (s, 3H, CH3major), 1.17
ation of signal at
1.51–1.62 and 1.90–1.99 indicating the presence of two H-5
protons in each one of these multiplets. Similarly, the irradiation of
dd at 4.69 changes the multiplicity of both the multiplets at
1.51–1.62 and 1.90–1.99 which shows the presence of two C-3
d 3.54 changes the multiplicity of the multiplets at
(s, 3H, CH3minor), 1.53–1.59 (m, 2H, 1H of CH2major þ 1H of CH2minor),
1.64–1.81 (m, 2H, 1H of CH2major þ 1H of CH2minor), 2.16 (d,
J ¼ 7.5 Hz, 2H, CH2minor), 2.39 (d, J ¼ 6.9 Hz, 2H, CH2major), 4.89–5.24
(m, 6H, 2H of ]CH2major þ 2H of ]CH2minor þ 1H of CHmajor þ 1H of
CHminor), 5.70–5.84 (m, 2H, 1H of ]CHmajor þ 1H of ]CHminor),
7.15–7.25 (m, 8H, 4H of ArHmajor þ 4H of ArHminor); 13C NMR
d
d
d
protons one each in the two multiplets. These two decoupling
experiments indicate the non-equivalence of the protons present at
C-3 and C-5 of tetrahydropyran (axial and equatorial protons). This
observation has also been confirmed from the IH–13C HETCOR
experiment in which the C-3 and C-5 carbons show correlations
(normal/DEPT-135) (CDCl3)
d
25.34 (þve, CH3minor), 28.58 (þve,
CH3major), 44.80 (þve, CH2minor), 48.26 (ꢀve, CH2major), 48.34 (ꢀve,
CH2major), 48.68 (ꢀve, CH2minor), 70.82 (þve, CHmajor), 71.15
(þve, CHminor), 73.09 (Cmajor), 73.11 (Cminor), 118.67 (ꢀve, ]CH2mi-
nor), 119.06 (ꢀve, ]CH2major), 126.83 (þve, ArCHmajor), 126.98 (þve,
ArCHminor), 128.41 (þve, ArCHmajor), 132.79 (ArC), 133.12 (þve,
]CHminor), 133.86 (þve, ]CHmajor), 143.12 (ArCminor), 143.20
with both the multiplets present at
NMR spectrum. NOE experiments: the irradiation of proton at
4.69 (H-2) shows NOE effect on the signal at 3.54 (H-6); irra-
3.54 shows NOE effect on CH3 at 1.48, the
3.30 and H-2 signal
d
1.51–1.62 and 1.90–1.99 in 1H
d
d
diation of signal at
multiplet signal at
at
d
d
(ArCmajor); FAB mass m/z 240 (Mþ); [
a
]D ¼ þ34ꢁ (c 1, CHCl3). (Found
d
1.51–1.62, CH2I protons at d
C 64.38, H 7.15; C13H17ClO2 requires C 64.86, H 7.12).
d
4.60 indicating the placement of H-6, one H-5, one H-3, H-2 and
CH3 protons syn to one another; FAB mass m/z 378 (Mþ);
4.3.4. 1-(4-Bromophenyl)-3-methylhex-5-ene-1,3-diols (6a þ 6b)
Compound 2d was allowed to react with allyl bromide as
described in the general procedure to give 6a and 6b as thick
creamish white liquid, 70% yield; mixture of two diastereomers, 7:3
[a
]D ¼ þ43.3ꢁ (c 1, CHCl3). (Found C 41.59, H 4.47, N 3.83;
C13H16INO4 requires C 41.40, H 4.28, N 3.71).
4.4.2. (2R,4S,6R)-2-Iodomethyl-4-methyl-6-(4-nitrophenyl)-
tetrahydropyran-4-ol (8)
(1H NMR integration); 1H NMR (CDCl3)
d 1.14 (s, 3H, CH3major), 1.32
(s, 3H, CH3minor), 1.55–1.82 (m, 4H, CH2major þ CH2minor), 2.18 (d,
J ¼ 7.2 Hz, 2H, CH2minor), 2.41 (d, J ¼ 7.5 Hz, 2H, CH2major), 4.91–5.16
(m, 6H, 2H of ]CH2major þ 2H of ]CH2minor þ 1H of CHmajor þ 1H of
CHminor), 5.72–5.86 (m, 2H, 1H of ]CHmajor þ 1H of ]CHminor),
7.11–7.16 (d, J ¼ 8.4 Hz, 4H, ArHmajor þ ArHminor), 7.40 (d, J ¼ 8.4 Hz,
4H, ArHmajor þ ArHminor); 13C NMR (normal/DEPT-135) (CDCl3)
20% Yield; 1H NMR (CDCl3)
d 1.48 (s, 3H, CH3), 1.51–1.62 (m, 2H,
H-3 þ H-5), 1.79–1.88 (m, 2H, H-3 þ H-5), 3.27–3.39 (m, 2H, CH2I),
4.95 (m, 1H, H-6), 4.97 (dd, J ¼ 11.4 Hz, J ¼ 2.4 Hz, 1H, H-2), 7.61 (d,
J ¼ 8.7 Hz, 2H, ArH), 8.17 (d, J ¼ 8.7 Hz, 2H, ArH); 13C NMR (normal/
DEPT-135) (CDCl3)
d
14.75 (ꢀve, CH2I), 27.01 (þve, CH3), 42.99 (ꢀve,
CH2), 46.09 (ꢀve, CH2), 68.61 (C-4), 74.14 (þve, C-2), 77.02 (þve, C-
6), 123.35 (þve, ArCH), 126.33 (þve, ArCH), 146.60 (absent, ArC),
d
25.35 (þve, CH3minor), 28.50 (þve, CH3major), 44.82 (þve, CH2mi-
nor), 48.08 (ꢀve, CH2major), 48.17 (ꢀve, CH2minor), 48.65 (ꢀve,
CH2major), 70.82 (þve, CHmajor), 71.14 (þve, CHminor), 70.70 (Cmajor),
71.07 (Cminor), 118.56 (ꢀve, ]CH2major), 118.90 (ꢀve, ]CH2minor),
120.78 (ArC), 131.34 (þve, ArCHmajor), 133.23 (þve, ]CHminor),
133.96 (þve, ]CHmajor), 143.59 (ArCminor), 143.68 (ArCmajor); FAB
149.76 (absent, ArC); FAB mass m/z 378 (Mþ); [
a
]D ¼ þ41ꢁ (c 1,
CHCl3). (Found C 41.78, H 4.25, N 3.90; C13H16INO4 requires C 41.40,
H 4.28, N 3.71).
4.4.3. (2R,4S,6S)-2-(4-Fluorophenyl)-6-iodomethyl-4-
methyltetrahydropyran-4-ol (9)
Compound 4a þ 4b was allowed to undergo iodocyclisation as
described in the general procedure to give 9 and 10 as thick liquids
which were separated by column chromatography. 35% yield; 1H
mass m/z 285 (Mþ); [
a]
¼ þ38ꢁ (c 1, CHCl3). (Found C 54.50, H 6.30;
D
C13H17BrO2 requires C 54.75, H 6.01).
4.4. Iodine mediated cyclization of 3–6
NMR (CDCl3)
d
1.47 (s, 3H, CH3), 1.51–1.59 (m, 2H, H-3 þ H-5), 1.70–
To the ice cold solution of diastereomeric mixtures of 3–6
(0.5 mmol) in dry CH3CN was added sodium hydrogen carbonate
(0.6 mmol) and the resulting suspension was stirred for 10 min at
0 ꢁC. Iodine (0.7 mmol) was added to the above reaction mixture
and stirring was continued for 12–17 h (TLC monitoring). The
reaction mixture was diluted with water and extracted with ethyl
acetate (3 ꢂ 25 ml). The organic layer was washed with saturated
aqueous sodium thiosulphate and dried over anhydrous sodium
sulphate. Removal of the solvent and purification of the residue by
1.98 (m, 2H, H-3 þ H-5), 3.30 (m, 2H, CH2–I), 3.82 (m, 16 lines, 1H,
H-6), 4.83 (dd, J ¼ 11.7 Hz, J ¼ 1.8 Hz, 1H, H-2), 7.01–7.07 (m, 2H,
ArH), 7.34–7.37 (m, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d
10.41 (ꢀve, CH2I), 31.42 (þve, CH3), 43.75 (ꢀve, CH2), 45.83 (ꢀve,
CH2), 68.48 (C-4), 71.98 (þve, C-2), 74.20 (þve, C-6), 114.84 (mid of
two peaks at 114.87 and 115.01, þve, ArCH, ortho to F, JC–
¼ 21.6 Hz), 127.41 (þve, ArCH, meta to F, JC–F ¼ 8.10 Hz), 138.05
F
(absent, ArC, para to F, JC–F ¼ 3.15 Hz), 161.93 (mid point of two
peaks at 160.31 and 163.55) (absent, ArC–F, JC–F ¼ 243.0 Hz); FAB

P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
1285
mass m/z 350 (Mþ); [
4.32; C13H16IFO2 requires C 44.59, H 4.61).
a
]D ¼ þ40ꢁ (c 1, CHCl3). (Found C 44.98, H
CH2), 47.40 (ꢀve, CH2), 69.31 (C-4), 72.27 (þve, C-2), 74.25 (þve, C-
6), 121.36 (absent, ArC), 127.49 (þve, ArCH), 131.43 (þve, ArCH),
141.40 (absent, ArC); FAB mass m/z 411 (Mþ); [
a]
¼ þ40ꢁ (c 1,
D
4.4.4. (2R,4S,6R)-2-(4-Fluorophenyl)-6-iodomethyl-4-
methyltetrahydropyran-4-ol (10)
CHCl3). (Found C 37.80, H 4.05; C13H16IBrO2 requires C 37.98, H
3.92).
30% Yield; 1H NMR (CDCl3)
d 1.48 (s, 3H, CH3), 1.52–1.67 (m, 2H,
H-3 þ H-5), 1.80–1.94 (m, 2H, H-3 þ H-5), 3.22–3.31 (dd, J ¼ 14.1 Hz,
J ¼ 6.0 Hz, 1H, 1H of CH2I), 3.42–3.50 (m of 16 lines, 1H, H-6), 4.42
(dd, J ¼ 11.4 Hz, J ¼ 2.1 Hz, 1H, H-2), 7.56 (d, J ¼ 9.0 Hz, 2H, ArH),
8.23 (d, J ¼ 8.7 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
4.5. Reactions of 7, 9, 11, 13 with C2H5SH and KSCN
A solution of 7/9/11/13 (0.5 mmol), ethanthiol/KSCN (0.5 mmol),
K2CO3 (0.7 mmol) in CH3CN (20 ml) was stirred at room tempera-
ture for 2 h. The reaction mixture after filtration and evaporation of
the solvent was column chromatographed to get pure compounds
15–22.
d
9.82 (ꢀve, CH2I), 25.97 (þve, CH3), 45.34 (ꢀve, CH2), 47.46 (ꢀve,
CH2), 69.23 (C-4), 74.42 (þve, C-2), 75.9 (þve, C-6), 115.16 (þve, JC–
¼ 21.0 Hz, ArCH), 127.38 (þve, JC–F ¼ 8.0 Hz, ArCH), 137.33 (þve, JC–
F
¼ 3.0 Hz, ArC), 161.94 (absent, JC–F ¼ 243 Hz, ArC); FAB mass m/z
F
350 (Mþ); [
a
]D ¼ þ35ꢁ (c 1, CHCl3). (Found C 44.76, H 4.66;
4.5.1. 2-Ethylsulfanylmethyl-4-methyl-6-(4-nitrophenyl)-
tetrahyropyran-4-ol (15)
C13H16IFO2 requires C 44.59, H 4.61).
Compound 7 was allowed to react with ethanthiol as described
4.4.5. (2R,4S,6S)-2-(4-Chlorophenyl)-6-iodomethyl-4-
methyltetrahydropyran-4-ol (11)
Compound 5a þ 5b was allowed to undergo iodocyclisation as
described in the general procedure to give 11 and 12 as thick liquids
which were separated by column chromatography. 35% yield; 1H
in the general procedure to give 15 as thick liquid, 65% yield; 1H
NMR (CDCl3)
d
1.27 (t, J ¼ 3.1 Hz, 3H, CH3), 1.47 (s, 3H, CH3), 1.51–
1.65 (m, 2H, H-3 þ H-5),1.79–2.13 (m, 2H, H-3 þ H-5), 2.58–2.69 (m,
2H, SCH2), 2.75–2.82 (m, 2H of CH2), 4.1 (m, 1H, H-6), 4.69 (dd,
J ¼ 11.7 Hz, J ¼ 2.1 Hz, 1H, H-2), 7.52 (d, J ¼ 8.4 Hz, 1H, ArH), 7.70 (d,
NMR (CDCl3)
d
1.45 (s, 3H, CH3), 1.53 (m, 2H, CH2), 1.72–1.87 (m, 2H,
J ¼ 8.1 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d 26.38
CH2), 3.24 (m, 2H, CH2–I), 3.43 (m, 1H, H-6), 4.42 (dd, J ¼ 11.7 Hz,
(ꢀve, S–CH2), 31.28 (þve, CH3), 31.38 (þve, CH3), 39.16 (ꢀve, CH2–
S), 43.83 (ꢀve, CH2), 45.73 (ꢀve, CH2), 68.45 (C-4), 71.94 (þve, C-2),
73.91 (þve, C-6), 123.31 (þve, ArCH), 123.51 (þve, ArCH), 126.38
(þve, ArCH), 126.84 (þve, ArCH), 149.45 (absent, ArC), 149.99
J ¼ 2.1 Hz,1H, H-2), 7.20–7.31 (m, 4H, ArH); 13C NMR (normal/DEPT-
135) (CDCl3)
d
9.68 (ꢀve, CH2I), 25.97 (þve, CH3), 45.34 (ꢀve, CH2),
47.42 (ꢀve, CH2), 69.12 (C-4), 74.15 (þve, C-2), 76.21 (þve, C-6),
126.95 (þve, ArCH), 127.19 (þve, ArCH), 128.47 (þve, ArCH), 132.76
(absent, ArC); FAB mass m/z 311 (Mþ); [
a
]D ¼ þ36.72ꢁ (c 1, CHCl3).
(ArC), 140.0 (ArC); FAB mass m/z 366 (Mþ); [
a
]
¼ þ47ꢁ (c 1, CHCl3).
(Found C 58.11, H 6.77, N 4.66; C15H21NO4S requires C 57.86, H 6.80,
N 4.50).
D
(Found C 42.35, H 4.38; C13H16IClO2 requires C 42.59, H 4.40).
4.4.6. (2R,4S,6R)-2-(4-Chlorophenyl)-6-iodomethyl-4-
methyltetrahydropyran-4-ol (12)
4.5.2. 4-Methyl-2-(4-nitrophenyl)-6-
thiocyanatomethyltrtrahydropyran-4-ol (16)
30% Yield; 1H NMR (CDCl3)
d
1.44 (s, 3H, CH3), 1.54 (m, 2H, CH2),
Compound 7 was allowed to react with KSCN as described in the
1.71–1.87 (m, 2H, CH2), 3.23 (m, 2H, CH2–I), 3.77 (m, 1H, H-6), 4.76
general procedure to give 16 as thick liquid; 80% yield; 1H NMR
(dd, J ¼ 11.2 Hz, J ¼ 2.4 Hz, 1H, H-2), 7.20–7.28 (m, 2H, ArH), 7.31–
(CDCl3)
d
1.46 (s, 3H, CH3), 1.50-1.65 (m, 2H, H-3 þ H-5), 1.72-1.91
7.45 (m, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d
9.77 (ꢀve,
(m, 2H, H-3 þ H-5), 3.19 (m, 2H, CH2), 4.28 (m, 1H, H-6), 4.98 (dd,
CH2I), 25.97 (þve, CH3), 45.31 (ꢀve, CH2), 47.42 (ꢀve, CH2), 69.0 (C-
4), 74.13 (þve, C-2), 76.09 (þve, C-6), 126.96 (þve, ArCH), 127.18
(þve, ArCH), 128.39 (ArC), 140.0 (ArC); FAB mass m/z 366 (Mþ);
J ¼ 11.7 Hz, J ¼ 2.1 Hz, 1H, H-2), 7.53 (d, J ¼ 8.7 Hz, 2H, ArH), 8.20 (d,
J ¼ 8.7 Hz, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d 31.18
(þve, CH3), 39.09 (ꢀve, CH2S), 42.08 (ꢀve, CH2), 45.69 (ꢀve, CH2),
68.65 (C-4), 71.69 (þve, C-2), 74.23 (þve, C-6), 112.86 (absent,
C^N), 123.43 (þve, ArCH), 123.53 (þve, ArCH), 126.22 (þve, ArCH),
126.68 (þve, ArCH), 147.12 (absent, ArC), 149.32 (absent, ArC); FAB
[
a
]
¼ þ48ꢁ (c 1, CHCl3). (Found C 42.65, H 4.56; C13H16IClO2
D
requires C 42.59, H 4.40).
4.4.7. (2R,4S,6S)-2-(4-Bromophenyl)-6-
iodomethyltetrahydropyran-4-ol (13)
mass m/z 308 (Mþ); [
a]
¼ þ35.62ꢁ (c 1, CHCl3). (Found C 54.49, H
D
5.40, N 9.17; C14H16N2O4S requires C 54.53, H 5.29, N 9.08).
Compound 6a þ 6b was allowed to undergo iodocyclisation as
described in the general procedure to give 13 as solid and 14 as
thick liquid which were separated by column chromatography. 32%
4.5.3. 2-Ethylsulfanylmethyl-6-(4-fluorophenyl)-4-
methyltetrahyropyran-4-ol (17)
yield; mp 68 ꢁC; 1H NMR (CDCl3)
d
1.44 (s, 3H, CH3), 1.53–1.62 (m,
Compound 9 was allowed to react with ethanthiol as described
2H, H-3 þ H-5), 1.69–1.99 (m, 2H, H-3 þ H-5), 3.27 (m, 2H, CH2I),
3.82 (m, 16 lines, 1H, H-6), 4.93 (dd, J ¼ 11.4 Hz, J ¼ 3.6 Hz, 1H, H-2),
7.25 (d, J ¼ 8.1 Hz, 2H, ArH), 7.44 (d, J ¼ 8.7 Hz, 2H, ArH); 13C NMR
in the general procedure to give 17 as thick liquid; 78% yield; 1H
NMR (CDCl3)
d
1.24 (t, J ¼ 6.6 Hz, 3H, CH3), 1.48 (s, 3H, CH3), 1.49–
1.55 (m, 2H, H-3 þ H-5), 1.79–1.81 (m, 2H, H-3 þ H-5), 2.59–2.58
(m, 2H, SCH2), 2.75–2.82 (m, 2H of CH2), 3.28(m, 1H, H-6), 4.79 (dd,
J ¼ 11.7 Hz, J ¼ 1.8 Hz, 1H, H-2), 6.69–7.07 (m, ArH), 7.30–7.49 (m,
(normal/DEPT-135)
d
10.33 (ꢀve, CH2I), 31.44 (þve, CH3), 43.71
(ꢀve, CH2), 45.78 (ꢀve, CH2), 68.67 (C-4), 72.00 (þve, C-2), 74.24
(þve, C-6), 121.04 (absent, ArC), 127.52 (þve, ArCH), 131.44 (þve,
ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d
26.95 (ꢀve, S–CH2),
ArCH), 141.40 (absent, ArC); FAB mass m/z 411 (Mþ); [
a
]D ¼ þ41.2ꢁ
31.46 (þve, CH3), 36.92 (þve, CH3), 39.60 (ꢀve, CH2–S), 43.74 (ꢀve,
CH2), 45.83 (ꢀve, CH2), 68.46 (C-4), 71.99 (þve, C-2), 73.43 (þve, C-
6), 115.04 (þve, JC–F ¼ 21.0 Hz, ArCH), 127.50 (þve, JC–F ¼ 8.0 Hz,
ArCH), 137.52 (þve, JC–F ¼ 3.0 Hz, ArC), 161.91 (absent, JC–F ¼ 243 Hz,
(c 1, CHCl3). (Found C 37.62, H 4.35; C13H16IBrO2 requires C 37.98, H
3.92).
4.4.8. (2R,4S,6R)-2-(4-Bromophenyl)-6-
iodomethyltetrahydropyran-4-ol (14)
ArC); FAB mass m/z 284 (Mþ); [
a]
¼ þ39.72ꢁ (c 1, CHCl3). (Found C
D
63.11, H 7.28, S 11.16; C15H21FO2S requires C 63.35, H 7.44 S 11.28).
21% Yield; 1H NMR (CDCl3)
d 1.44 (s, 3H, CH3), 1.50–1.63 (m, 2H,
H-3 þ H-5), 1.70–2.04 (m, 2H, H-3 þ H-5), 3.23 (m, 2H, CH2I), 3.64
(m, 16 lines, 1H, H-6), 4.93 (dd, J ¼ 14.1 Hz, J ¼ 11.7 Hz, 1H, H-2), 7.25
(d, J ¼ 7.2 Hz, 2H, ArH), 7.46 (d, J ¼ 8.4 Hz, 2H, ArH); 13C NMR
4.5.4. 2-(4-Fluorophenyl)-4-methyl-6-
thiocyanatomethyltetrahydropyran-4-ol (18)
Compound 9 was allowed to react with KSCN as described in the
(normal/DEPT-135)
d
9.40 (ꢀve, CH2I), 25.97 (þve, CH3), 45.27 (ꢀve,
general procedure to give 18 as thick liquid; 71% yield; 1H NMR

1286
P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
(CDCl3)
d
1.44 (s, 3H, CH3), 1.54–1.68 (m, 2H, H-3 þ H-5), 1.78–1.92
13C NMR (normal/DEPT-135) (CDCl3)
d
31.20 (þve, CH3), 39.31 (ꢀve,
(m, 2H, H-3 þ H-5), 3.15 (m, 2H, CH2S), 3.83 (m, 1H, H-6), 4.98 (dd,
CH2S), 42.17 (ꢀve, CH2), 45.68 (ꢀve, CH2), 67.76 (C-4), 71.58 (þve, C-
2), 74.44 (þve, C-6), 112.82 (absent, C^N), 127.44 (þve, ArCH),
127.80 (þve, ArCH), 131.34 (þve, ArCH), 131.39 (þve, ArCH), 139.78
(absent, ArC), 140.88 (absent, ArC); FAB mass m/z 342 (Mþ);
J ¼ 11.7 Hz, J ¼ 2.1 Hz, 1H, H-2), 6.99–7.05 (m, 2H, ArH), 7.28–7.33
(m, 2H, ArH); 13C NMR (normal/DEPT-135) (CDCl3)
d
25.83 (þve,
CH3), 39.11 (ꢀve, CH2S), 43.96 (ꢀve, CH2), 47.38 (ꢀve, CH2), 69.06
(C-4), 73.41 (þve, C-2), 76.57 (þve, C-6), 112.66 (absent, C^N),
115.18 (mid of two peaks at 115.04 and 115.33, þve, ArCH, ortho to F,
JC–F ¼ 21.6 Hz), 127.40 (þve, ArCH, meta to F, JC–F ¼ 8.02 Hz), 136.89
(absent, ArC, para to F, JC–F ¼ 3.15 Hz), 162.11 (mid point of two
peaks at 160.49 and 163.74, absent, ArC) (absent, ArC–F, JC–
[
a
]D ¼ þ37.62ꢁ (c 1, CHCl3). (Found C 50.55, H 5.01, N 3.90, S 8.92;
C14H16BrNO2S requires C 49.13, H 4.71, N 4.09, S 9.37).
4.6. X-ray crystal data for 2a and 13
¼ 243.0 Hz); FAB mass m/z 281 (Mþ); [
a]
¼ þ37.84ꢁ (c 1, CHCl3).
F
D
X-ray crystal data was measured by using q–2q scan mode. The
(Found C 59.60, H 5.70, N 4.98, S 11.20; C14H16FNO2S requires C
59.77, H 5.73, N 4.92, S 11.40).
structure was solved by using direct method SHELX-97. For 2a,
molecular formula C10H11NO4; space group P21, a ¼ 7.1698 Å,
b ¼ 5.6136 Å, c ¼ 12.6297 Å;
a
¼ 90.00ꢁ,
b
¼ 103.042ꢁ,
g
¼ 90.00ꢁ;
V ¼ 495.213 Å3; Z ¼ 2, Z0 ¼ 0, R-factor ¼ 3.7. For 13, molecular
4.5.5. 2-(4-Chlorophenyl)-6-ethylsulfanylmethyl-4-
methyltetrahyropyran-4-ol (19)
formula C13H14BrIO2; space group P21, a ¼ 6.0080 Å, b ¼ 8.0672 Å,
c ¼ 14.788 Å;
a
¼ 90.00ꢁ,
b
¼ 101.72ꢁ,
g
¼ 90.00ꢁ; V ¼ 701.799 Å3;
Compound 11 was allowed to react with ethanthiol as described
in the general procedure to give 19 as thick liquid; 71% yield; 1H
Z ¼ 2, Z0 ¼ 0; R-factor ¼ 3.81.
NMR (CDCl3)
d
1.26 (t, J ¼ 5.8 Hz, 3H, CH3), 1.44 (s, 3H, CH3), 1.49 (m,
2H, H-3 þ H-5), 1.72–1.81 (m, 2H, H-3 þ H-5), 2.56–2.59 (m, 2H,
SCH2), 2.61–2.76 (m, 2H of CH2), 3.27 (m, 1H, H-6), 4.79 (dd,
J ¼ 10.5 Hz, J ¼ 2.4 Hz, 1H, H-2), 7.28–7.30 (m, 4H, ArH); 13C NMR
Acknowledgements
We thank UGC, New Delhi; CSIR, New Delhi and DST, New Delhi
for the research grants. Atul thanks ‘Prof. Harjit Singh Foundation
for Promotion of Chemical Sciences’ Guru Nanak Dev University,
Amritsar and DST, New Delhi for the fellowship. X-ray national
facility at IIT Bombay, Mumbai is gratefully acknowledged for X-ray
structure analysis.
(normal/DEPT-135) (CDCl3)
d
26.97 (ꢀve, S–CH2), 31.38 (þve, CH3),
31.57 (þve, CH3), 39.49 (ꢀve, CH2–S), 43.24 (ꢀve, CH2), 45.77 (ꢀve,
CH2), 68.63 (C-4), 72.02 (þve, C-2), 74.19 (þve, C-6), 127.00 (þve,
ArCH), 128.47 (þve, ArCH), 132.76 (ArC), 140.8 (ArC); FAB mass m/z
300 (Mþ); [
a]
¼ þ41.26ꢁ (c 1, CHCl3). (Found C 59.90, H 7.14, S
D
10.70; C15H21ClO2S requires C 59.88, H 7.04, S 10.66).
References
4.5.6. 2-(4-Chlorophenyl)-4-methyl-6-
thiocyanatomethyltetrahydropyran-4-ol (20)
[1] J.L. Marnett, S.W. Rowlinson, D.C. Goodwin, A.S. Kalgutkar, C.A. Lanzo, J. Biol.
Chem. 274 (1999) 22903–22906.
[2] W.J. Smith, R.M. Garavito, D.L. DeWitt, J. Biol. Chem. 271 (1996) 33157–33160.
[3] D.A. Kujubu, B.S. Fletcher, B.C. Vernum, R.W. Rim, H.R. Herschman, J. Biol.
Chem. 266 (1991) 12866–12872.
[4] Y.T. Jeon, Y.S. Song, Mini-Rev. Med. Chem. 6 (2006) 827–833 and references
therein.
[5] F.H. Sarkar, S. Adsule, Y. Li, S. Padhye, Mini-Rev. Med. Chem. 7 (2007) 599–608
and references therein.
[6] C.H. Liu, S.-H. Chang, K. Narko, O.C. Trifan, M.-T. Wu, E. Smith, C. Haudenschild,
T.F. Lane, T. Hla, J. Biol. Chem. 276 (2001) 18563–18569.
[7] J.-B. Meric, S. Rottey, K. Olaussen, J.-C. Soria, D. Khayat, O. Rixe, J.-P. Spano, Crit.
Rev. Oncol./Hematol. 59 (2006) 51–64.
[8] A. Sorokin, Curr. Pharm. Des. 10 (2004) 647–657.
[9] P. Surowiak, V. Materna, R. Matkowski, K. Szczuraszek, J. Kornafel, A. Wojnar,
M. Pudelko, M. Dietel, C. Denkert, M. Zabel, H. Lage, Breast Cancer Res. 7
(2005) R862.
[10] V.A. Patel, M.J. Dunn, A. Sorokin, J. Biol. Chem. 277 (2002) 38915–38920.
[11] C.P. Schroeder, P. Yang, R.A. Newman, R. Lotan, J. Exp. Ther. Oncol. 6 (2007)
183–192.
[12] H. Ikawa, H. Kamitani, B.F. Calvo, J.F. Foley, T.E. Eling, Cancer Res. 59 (1999)
360–366.
[13] J.-M. Dogne, C.T. Supuran, D. Pratico, J. Med. Chem. 49 (2005) 2251–2257.
[14] S.B. Jeffrey, S.S. Lee, Arthritis Res. Ther. 7 (2005) S14–S22.
[15] G. Tilo, F. Susanne, A.F. Garret, J. Clin. Invest. 116 (2006) 4–15.
[16] C.H. Raymond, D.B. Matthew, Clin. J. Am. Soc. Nephrol. 1 (2006) 236–245.
[17] R.M. Longford, V. Mehta, Biomed. Pharmacother. 60 (2006) 323–328.
[18] L. Crofford, J. Rheumatol. 24 (1997) 15.
[19] G. Dannhardt, W. Kiefer, Eur. J. Med. Chem. 36 (2001) 109–126.
[20] C.R. Rodrigues, M.P. Veloso, H. Verli, C.A.M. Fraga, A.L.P. Miranda, E.J. Barreiro,
Med. Chem. Rev. 1 (2004) 73–90.
[21] E.F.F. da Cunha, T.C. Ramalho, D. Josa, M.S. Caetano, T.C.S. de Souza, Recent Pat.
Inflamm. Allergy Drug Dis. 1 (2007) 108–123.
[22] P. Singh, A. Mittal, Mini-Rev. Med. Chem. 8 (2008) 73–90.
[23] M. Martic, I. Tatic, S. Markovic, N. Kujundzic, S. Kostrum, Eur. J. Med. Chem. 39
(2004) 141–151.
Compound 11 was allowed to react with KSCN as described in
the general procedure to give 20 as thick liquid; 67% yield; 1H NMR
(CDCl3)
d
1.46 (s, 3H, CH3), 1.53–1.67 (m, 2H, H-3 þ H-5), 1.77–2.02
(m, 2H, H-3 þ H-5), 3.14 (m, 2H, CH2), 4.18 (m, 1H, H-6), 4.78 (dd,
J ¼ 11.4 Hz, J ¼ 1.8 Hz, 1H, H-2), 7.23 (m, 2H, ArH), 7.39 (m, 2H, ArH);
13C NMR (normal) (CDCl3)
d
31.33 (þve, CH3), 39.11 (CH2S), 42.45
(CH2), 45.57 (CH2), 68.09 (C-4), 71.95 (C-2), 76.57 (þve, C-6), 112.86
(C^N), 127.26 (ArCH), 127.62 (ArCH), 131.14 (ArCH), 131.18 (ArCH),
139.76 (ArC), 140.85 (ArC); FAB mass m/z 298 (Mþ); [
a
]D ¼ þ36.61ꢁ
(c 1, CHCl3). (Found C 56.40, H 5.41, N 4.69, S 10.72; C14H16ClNO2S
requires C 56.46, H 5.42, N 4.70, S 10.77).
4.5.7. 2-(4-Bromophenyl)-6-ethylsulfanylmethyl-4-
methyltetrahyropyran-4-ol (21)
Compound 13 was allowed to react with ethanthiol as described
in the general procedure to give 21 as thick liquid; 80%; 1H NMR
(CDCl3)
d
1.23 (t, J ¼ 7.3 Hz, 3H, CH3), 1.38 (s, 3H, CH3), 1.50 (m, 2H,
H-3 þ H-5), 1.77–1.89 (m, 2H, H-3 þ H-5), 2.43–2.59 (m, 2H, S–CH2),
2.61–2.78 (m, 2H of CH2), 3.25 (m, 1H, H-6), 4.37 (dd, J ¼ 11.7 Hz,
J ¼ 1.8 Hz, 1H, H-2), 7.30 (m, 2H, ArH), 7.43 (m, 2H, ArH); 13C NMR
(normal/DEPT-135) (CDCl3)
d
25.87 (þve, CH3), 25.96 (þve, CH3),
37.09 (ꢀve, S–CH2), 44.86 (ꢀve, CH2–S), 45.36 (ꢀve, CH2), 47.41
(ꢀve, CH2), 69.03 (C-4), 74.17 (þve, C-2), 76.15 (þve, C-6), 127.48
(þve, ArCH), 127.51 (þve, ArCH), 131.33 (þve, ArCH), 131.39 (þve,
ArCH), 140.62 (absent, ArC), 141.98 (absent, ArC); FAB mass m/z 345
(Mþ); [
a]
¼ þ38.6ꢁ (c 1, CHCl3). (Found C 52.10, H 5.09, S 9.28;
D
C15H21BrO2S requires C 52.18, H 5.13, S 9.29).
[24] A. Zarghi, T. Zebardast, F. Hakimion, F.H. Shirazi, P.N.P. Rao, E.E. Knaus, Bioorg.
Med. Chem. 14 (2006) 7044–7050.
[25] G. Dannhardt, B.L. Fiebich, J. Schweppenhauser, Eur. J. Med. Chem. 37 (2002)
147–161.
[26] R. Anana, P.N.P. Rao, Q.-H. Chen, E.E. Knaus, Bioorg. Med. Chem. 14 (2006)
5259–5265.
[27] H. Kakuta, X. Zheng, H. Oda, S. Harada, Y. Sugimoto, K. Sasaki, A. Tai, J. Med.
Chem. 51 (2008) 2400–2411 and references therein.
4.5.8. 2-(4-Bromophenyl)-4-methyl-6-
thiocyanatomethylterahydropyran-4-ol (22)
Compound 13 was allowed to react with KSCN as described in
the general procedure to give 22 as thick liquid; 78%; 1H NMR
(CDCl3)
d
1.47 (s, 3H, CH3), 1.52–1.69 (m, 2H, H-3 þ H-5), 1.76–2.03
(m, 2H, H-3 þ H-5), 3.13 (m, 2H, CH2), 4.19 (m, 1H, H-6), 4.79 (dd,
J ¼ 11.5 Hz, J ¼ 2.4 Hz, 1H, H-2), 7.27 (m, 2H, ArH), 7.45 (m, 2H, ArH);
[28] M. Cleij, A. Archelas, R. Furstoss, J. Org. Chem. 64 (1999) 5029–5035 and
references therein.

P. Singh et al. / European Journal of Medicinal Chemistry 44 (2009) 1278–1287
1287
[29] P.N.P. Rao, M. Amini, H. Li, A.G. Habeeb, E.E. Knaus, Bioorg. Med. Chem. Lett. 13
(2003) 2205–S2209.
[42] K.-P. Chan, A.-H. Seow, T.-P. Loh, Tetrahedron Lett. 48 (2007) 37–41.
[43] J.S. Yadav, B.V.S. Reddy, G.G.K.S.N. Kumar, T. Swamy, Tetrahedron Lett. 48
(2007) 2205–2208.
[44] K. Sakthivel, W. Notz, T. Bui, C.F. Barbas III, J. Am. Chem. Soc. 123 (2001)
5260–5267.
[45] Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, J. Am.
Chem. Soc. 127 (2005) 9285–9289 and references therein.
[46] W. Notz, F. Tanaka, C.F. Barbas III, Acc. Chem. Res. 37 (2004) 580–591.
[47] Z. Tang, F. Jiang, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Y.-D. Wu, Proc. Natl.
Acad. Sci. U.S.A. 101 (2004) 5755–5760.
[30] F. Caturla, J.-M. Jimenez, N. Godessart, M. Amat, A. Cardenas, L. Soca, J. Beleta,
H. Ryder, M.I. Crespo, J. Med. Chem. 47 (2004) 3874–3886.
[31] P.N.P. Rao, M.J. Uddin, E.E. Knaus, J. Med. Chem. 47 (2004) 3972–3990.
[32] S. Roth, C.B.W. Stark, Angew. Chem., Int. Ed. 45 (2006) 6218–6221.
[33] A. Blanc, F.D. Toste, Angew. Chem., Int. Ed. 45 (2006) 2096–2099.
[34] M.C. Carreno, R.D. Mazery, A. Urbano, F. Colobert, G. Solladie, J. Org. Chem. 68
(2003) 7779–7787.
[35] J.C. Estevez, A.J. Fairbanks, G.W.J. Fleet, Tetrahedron 54 (1998) 13591–13620.
[36] L.F. Titze, G. Kettschau, J.A. Gewert, A. Schuffenlavee, Curr. Org. Chem. 2 (1998)
19–62.
[37] R.R. Schmidt, Acc. Chem. Res. 19 (1986) 250–259.
[38] D.G. Gillingham, O. Kataoka, S.B. Garber, A.H. Hoveyda, J. Am. Chem. Soc. 126
(2004) 12288–12290 and references therein.
[39] X.-F. Yang, J.T. Mague, C.-J. Li, J. Org. Chem. 66 (2001) 739–747.
[40] K. Kataoka, Y. Ode, M. Matsumoto, J. Nokami, Tetrahedron 62 (2006) 2471–2483.
[41] B. Patterson, S.D. Rychnovsky, Synlett 3 (2004) 543–545.
[48] B. List, Tetrahedron 58 (2002) 5573–5590.
[49] S. Kumar, P. Kaur, A. Mittal, P. Singh, Tetrahedron 62 (2006) 4018–4026.
[50] L. Navidpour, H. Shafaroodi, K. Abdi, M. Amini, M.H. Ghahremani,
A.R. Dehpour, A. Shafiee, Bioorg. Med. Chem. 14 (2006) 2507–2517.
[51] P. Singh, A. Mittal, S. Kaur, S. Kumar, Bioorg. Med. Chem. 14 (2006) 7910–7916.
[52] P. Singh, P. Kaur, Anu, S. Kumar, Indian J. Chem., Sect. B 45 (2005) 1692–1698.
[53] Dockings were performed in the ‘Dock in active site’ module of BioMed CaChe
version 7.0.5.85.