First total synthesis of fuzanins C, D and their analogues as anticancer agents

Article abstract of DOI:10.1039/c3ra47263a

The first total synthesis of fuzanins C and D, isolated from the culture supernatant of Kitasatospora sp. IFM10917, is described. Key features of this synthetic strategy involve the use of Sharpless asymmetric epoxidation, dihydroxylation, Mitsunobu reaction and Julia-Kocienski olefination. The total synthesis reported herein also confirmed the absolute configuration of fuzanin D. The optical rotations of synthesized fuzanin D and natural product were opposite in sign, leading to a revision of the reported structure as its enantiomer which is further confirmed by molecular modeling studies. In addition, we also synthesized the analogues of fuzanins C, D containing the quinoline nucleus. All of the synthesized compounds were screened for anticancer activity on four cell lines and found to be potent against HT29 colon cancer cell lines, whereas they were found to be less potent against cervical and breast cancer cell lines.

Full text of DOI:10.1039/c3ra47263a

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First total synthesis of fuzanins C, D and their
analogues as anticancer agents†
Cite this: RSC Adv., 2014, 4, 8365
S. Naveen Kumar,a C. H. N. S. Sai Pavan Kumar,a E. Srihari,a Sravani Kancharla,b
b
b
b
abc
*
*
*
Kolupula Srinivas, Shweta Shrivastava, V. G. M. Naidu and V. Jayathirtha Rao
The first total synthesis of fuzanins C and D, isolated from the culture supernatant of Kitasatospora sp.
IFM10917, is described. Key features of this synthetic strategy involve the use of Sharpless asymmetric
epoxidation, dihydroxylation, Mitsunobu reaction and Julia-Kocienski olefination. The total synthesis
reported herein also confirmed the absolute configuration of fuzanin D. The optical rotations of
synthesized fuzanin D and natural product were opposite in sign, leading to a revision of the reported
structure as its enantiomer which is further confirmed by molecular modeling studies. In addition, we
also synthesized the analogues of fuzanins C, D containing the quinoline nucleus. All of the synthesized
compounds were screened for anticancer activity on four cell lines and found to be potent against HT29
colon cancer cell lines, whereas they were found to be less potent against cervical and breast cancer
cell lines.
Received 3rd December 2013
Accepted 13th January 2014
DOI: 10.1039/c3ra47263a
www.rsc.org/advances
Recently, new carbamate or pyridine containing natural
products, fuzanins A (1), B (2), C (3a), and D (4a) were isolated by
Ishibashi et al.11 from the culture supernatant of Kitasatospora
sp. IFM10917 (active strain from 323 actinomycete strains)
obtained from a soil sample collected at Toyama city, Japan
(Fig. 1). In addition, they have also evaluated cytotoxicity against
human colon carcinoma DLD-1 cells, and inhibition of Wnt
signal transcription for the four compounds.
As part of our continuing synthetic efforts towards synthesis
of biologically and pharmaceutically favored heterocycles and
natural products,12 now we became interested in synthesis of
biologically active fuzanin D and its stereo isomer fuzanin C. In
this regard, we report the rst total synthesis of fuzanin C (3a),
D (4a) along with their analogues and also conrmed the
absolute conguration of fuzanin D. Some compounds are
selectively potent against HT29 colon cancer cell line.
Introduction
Organic synthesis is the art of building organic molecules
through chemical reactions. The synthesis of natural products
is one of the most fascinating and challenging areas of research
in chemistry. Further, most of the natural products have been at
the spearhead of merging the elds of organic chemistry and
biology, and the elds will only continue to come together in the
future. Nitrogen containing heterocycles such as pyridine,
quinoline derivatives are among the most omnipresent azahe-
terocycles found in many natural products and have been
claimed to be the most prevalent heterocycles in pharmaceuti-
cally active compounds.1,2 Micrococcin P1, streptonigrin and
nemerelline, etoricoxib, rosuvastatin and imatinib are a few
examples of commercialized drugs bearing the pyridine motif.
The pyridine ring is also ubiquitous in agrochemicals.3 Quinine,
chloroquine, pamaquine, tafenoquine, bulaquine are some of
the active pharmaceuticals containing quinoline nucleus.
Quinoline derivatives exhibit broad range of biological activities
such as antimalarial,4 antimicrobial,5 anticancer,6 antifungal,7
antileishmanial,8 anti-inammatory,9,10 and analgesic activity.10
aCrop Protection Chemicals Division, Indian Institute of Chemical Technology, Uppal
Road Tarnaka, Hyderabad 500007, India. E-mail: jrao@iict.res.in
bNational Institute of Pharmaceutical Education and Research (NIPER), Balanagar,
Hyderabad 500 037, India
cAcSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad-
500007, India
† Electronic supplementary information (ESI) available: 1H NMR spectra and 13
C
NMR spectra for all nal compounds, molecular modeling studies, Cartesian
coordinates of fuzanins C, D, (11R,12S)-fuzanin D. See DOI: 10.1039/c3ra47263a
Fig. 1 Fuzanins A, B, C and D.
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could be prepared efficiently by a Julia-Kocienski olenation
protocol using aldehyde 5a with sulfone 6 and 7 respectively,
The intermediate 5a could be prepared from 2,3-dimethyl
pyridine and compounds 6, 7 from ethyl sorbate (8).
Results and discussion
Fuzanins C (3a) and D (4a) are stereoisomers and differ in
stereochemistry at 11th position. The compounds are similar
with scaffolds, hence similar synthetic strategies were applied
to synthesize them. Retrosynthesis for fuzanins C (3a), D (4a) is
depicted in Scheme 1. The analysis revealed that 3a and 4a
The synthetic strategy for fuzanin C (3a) is described in
Scheme 2. The commercially available starting material ethyl
sorbate 8, was subjected to Sharpless dihydroxylation conditions
using osmium tetraoxide as oxidant and (DHQD)2PHAL as chiral
ligand, giving the diol 9.12a,13 Diol 9 was protected as acetonide
and the ester functionality was reduced using DIBAL-H to obtain
alcohol 10. Mitsunobu reaction of 10 with 1-phenyl-1H-tetrazole-
5-thiol to get sulde, and subsequent oxidation with H2O2 in
presence of a molybdenum(VI) catalyst furnished the desired
sulfone 6 in 82% yield. The vital coupling reaction of 6 and 5a (5a
prepared from SeO2 oxidation of 2,3-dimethyl pyridine14) was
performed by the Julia-Kocienski olenation protocol15 using
KHMDS as base to afford 11 as mixture of E and Z isomers.
The geometrical isomers i.e., E and Z isomers (7 : 3 ratio by
1H NMR) were inseparable at this stage. However, nal aceto-
nide deprotection of 11 with p-TSA afforded fuzanin C (3a) and
Scheme 1 Retrosynthetic analysis of 3a, 4a.
Scheme 2 Synthesis of fuzanin C (3a). Reagents and conditions: (a) (DHQD)2PHAL, OsO4, CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH/H2O (1 : 1),
0 ꢀC, 12 h, 84%; (b) (i) 2,2-Dimethoxypropane, p-TSA (cat), CH2Cl2, rt, 15 min; (ii) DIBAL-H, CH2Cl2, 0 ꢀC, 1 h, 81% (for two steps); (c) (i) 1-phenyl-
1H-tetrazole-5-thiol, PPh3, DIAD, THF, 0 ꢀC, 1 h, 90%; (ii) (NH4)6Mo7O24$4H2O, EtOH, 30% H2O2, rt, 8h, 92%; (d) 5a, KHMDS, THF, :78 ꢀC, 2 h,
81%; (e) p-TSA, MeOH, rt, 12 h, 82% (total yield).
Scheme 3 Synthesis of fuzanin D (4a). Reagents and conditions: (a) TBS-Cl, Et3N, DMAP, CH2Cl2, rt, 24 h, 65%; (b) (i) PPh3, DEAD, HCOOH, rt, 2 h;
(ii) dil. NH4OH/MeOH, 3 h, 55% (for two steps); (c) TBAF, CH2Cl2, 0 ꢀC, 1 h, 85%; (d) (i) 2,2-Dimethoxypropane, p-TSA (cat), CH2Cl2, rt, 15 min; (ii)
DIBAL-H, CH2Cl2, 0 ꢀC, 1 h, 80% (for two steps); (e) (i) 1-phenyl-1H-tetrazole-5-thiol, PPh3, DIAD, THF, 0 ꢀC, 1 h; (ii) (NH4)6Mo7O24$4H2O, EtOH,
30% H2O2, rt, 8 h, 82% (for two steps); (f) 5a, KHMDS, THF, :78 ꢀC, 2 h, 81%; (g) p-TSA, MeOH, rt, 12 h, 82% (total yield).
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Scheme 4 Retrosynthetic analysis of (11R,12S)-4a.
Scheme 5 Synthesis of (11R,12S)-4a. Reagents and conditions: (a) Ti(OiPr)4, (+)-DIPT, anhydrous TBHP, CH2Cl2, :20 ꢀC, 2 h; (b) (i) DMSO,
(COCl)2, Et3N, CH2Cl2, :78 ꢀC, 30 min. (ii) Ph3P]CHCOOEt, CH2Cl2, rt, 24 h, 56% (for two steps); (c) BnOH, BF3$OEt2, DCM, :20 ꢀC, 1 h, 60%; (d)
AlCl3, m-xylene, 0 ꢀC, 15 min, 76%; (e) (i) 2,2-Dimethoxypropane, p-TSA, CH2Cl2, rt, 15 min. (ii) DIBAL-H, CH2Cl2, 0 ꢀC, 1 h, 86% (for two steps); (f)
(i) 1-phenyl-1H-tetrazole-5-thiol, PPh3, DIAD, THF, 0 ꢀC, 1 h. (ii) (NH4)6Mo7O24$4H2O, EtOH, 30% H2O2, rt, 81% (for two steps); (g) 5a, KHMDS,
THF, :78 ꢀC, 2 h, 80%; (h) p-TSA, MeOH, rt, 12 h, 82% (total yield).
its Z-isomer 3b respectively (Scheme 2). All characterization
data for synthesized fuzanin C (3a) (Fig. S2, ESI†) were in good (11R,12S)-fuzanin D [(11R,12S)-4a] is depicted in Scheme 4. We
agreement with those reported by Ishibashi et al.11
envisioned the two stereocenters in (11R,12S)-4a and this could
The retrosynthesis of other enantiomer fuzanin D i.e.,
Synthetic strategy for fuzanin D (4a) is described in be constructed by the Sharpless asymmetric epoxidation. In this
Scheme 3. This synthesis begins with selective protection of regard, the synthesis was started from 2-buten-1-ol, which was
C(5)–OH group of 9 with TBS-Cl in presence of triethylamine subjected to Sharpless epoxidation to afford the epoxy alcohol
and DMAP, provided the desired ether 12.16 Mitsunobu inver- 18 (Scheme 5).18
sion of hydroxyl group in 12 with formic acid in the presence of
Swern oxidation of epoxy alcohol 18 and C2-Wittig homolo-
PPh3, DEAD and subsequent hydrolysis of formyl ester using gation with [(ethoxycarbonyl)methylene]triphenyl-phosphor-
diluted NH4OH–MeOH afforded compound 13 in 55% overall ane, afforded requisite epoxy ester 19.19 The trans regioselective
yield.17 TBS deprotection of 13 in presence of tetrabutylammo-
niumuoride (TBAF) results trans-1,2-diol 14. trans-1,2-Diol 14
is protected as acetonide, DIBAL-H reduction of ester func-
tionality, Julia-Kocienski olenation protocol, and hydrolysis or
deprotection (the same synthetic sequence was followed as in
Scheme 2) provided fuzanin D (4a) and its Z-isomer 4b in 6 : 4
ratio (Scheme 3).
Characterization data for the synthesized fuzanin D (4a)
(Fig. S6, ESI†) were in good agreement with those reported by
Ishibashi et al. except optical rotation. The [a]D of the natural
Fig. 2 Revised structure of fuzanin D.
product is ꢁ32.9 (CHCl3), and synthesized fuzanin D (4a) has
+29.47. The original work by Ishibashi et al.11 mentioned that
fuzanin D as a stereoisomer to fuzanin C and further there was
no attempt made to substantiate the stereochemistry of fuzanin
D. The fuzanin D synthesized in this work exhibited optical
rotation +29.47, whereas the sign of optical rotation is found to
be opposite to the natural product reported by Ishibashi et al. In
order to investigate the absolute conguration of fuzanin D, we
further synthesized the other enantiomer of fuzanin D as given
in Scheme 5.
Fig. 3 Energy minimized geometries of fuzanin D (4a) & (11R,12S)-4a.
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Table 1 Experimental and calculated specific rotations of selected
compounds
(11R,12S)-4a and its Z-isomer (11R,12S)-4b in 6 : 4 ratio
(Scheme 5) (Fig. S11, ESI†).
The optical rotation of (11R,12S)-4a ꢁ26.9, which is in good
accordance with isolated fuzanin D. This lead unambiguously
to the conclusion that the natural product isolated has opposite
conguration to that of reported fuzanin D (Fig. 2).
[a]D (in ꢀ dmꢁ1 gꢁ1 cm3)
Isolation
papera
Synthesized
compounds
Compounds
Calculatedb
This observation was further corroborated by computational
study. Optical rotations (at 589.3 nm) of fuzanin C (3a), fuzanin
D (4a) and (11R,12S)-fuzanin D [(11R,12S)-4a] were computed
using B3LYP/Aug-CC-pVDZ method for geometries obtained at
B3LYP/6-31G(d) basis set (Fig. 3).22 Calculated [a]D for (3a), (4a)
and (11R,12S)-4a are +66.5, +22.4 and ꢁ8.5 degrees[dm(g
cmꢁ3)]ꢁ1 respectively (Table 1). Optical rotations of computa-
tionally calculated fuzanins and synthesized fuzanins were
having same sign (Table 1). The comparison of experimental
and calculated optical rotations allows us to dene the stereo-
chemistry fuzanin D reported by Ishibashi et al. as (11R,12S)-
fuzanin D (Fig. 2).
Fuzanin C (3a)
Fuzanin D (4a)
(11R,12S)-4a
[a]1D5 ¼ +34.5
[a]1D5 ¼ ꢁ32.9
—
[a]2D4 ¼ +39.89
[a]2D4 ¼ +29.47
[a]2D4 ¼ ꢁ26.9
+66.5
+22.4
ꢁ8.5
a
Ref. 11. b Optical rotations were computed using B3LYP/aug-cc-pVDZ//
B3LYP/6-31G(d) basis set in gas phase.
Intrigued by this, we also synthesized different analogues
(3c, 3d, 4c and 4d) using substituted 2-chloroquinoline-3-car-
boxaldehydes (5b and 5c)23 by same synthetic strategy of Julia-
Kocienski olenation protocol, and hydrolysis (Scheme 6)
(Fig. S4, S5, S8 and S9, ESI†).
Furthermore, all the synthesized compounds were subjected
to anticancer activity on various cell lines such as HT29 (Colon
cancer), ME-180 (Cervical cancer), MCF-7 and MDA-MB-453
(Breast cancer) by employing MTT assay (details of bio assay are
presented in Experimental section). For comparison purpose,
the cytotoxicity of salinomycin was evaluated under the same
experimental conditions. The compounds that exhibiting
$50% cell inhibition at 100 mM were considered for determi-
nation of IC50 value, which was calculated from the % cell
viability (from control) versus concentration curves obtained
aer 24 h drug treatment from MTT assay, are shown in Table 2.
All compounds were found to be relatively potent against
colon cancer cell line and less potent against cervical and breast
cancer cell lines. Among all the compounds, quinoline deriva-
tives of fuzanin D (4c, 4d) were found to be potent with an IC50
value of 35.3 ꢂ 0.83, 27.4 ꢂ 0.12 mM respectively. Compound 3c
has exhibited moderate activity. Remaining compounds were
found to be less potent against HT-29 cell lines. The reference
compound salinomycin has IC50 value of 20.5 ꢂ 1.26 mM (Fig. 4).
Scheme 6 Analogues of fuzanins C, D.
opening of epoxide of 19 was accomplished with benzyl alcohol
in presence of BF3$OEt2 as lewis acid catalyst to get benzyl ether
20,20 which was deprotected using AlCl3 to get diol 21.20,21 Ace-
tonide protection of 21, DIBAL-H reduction, Julia-Kocienski
olenation protocol, and hydrolysis or deprotection (the same
synthetic sequence was followed as in Scheme 2) provided
Table 2 IC50 values (mM) of fuzanin compounds and salinomycin
against HT29 human colon cancer cell lines
Conclusion
IC50/mg mLꢁ1
HT-29 (colon cancer)
In conclusion, we have unveiled the rst stereoselective total
synthesis of fuzanins C, D and their analogues. Synthesis of
fuzanin D described here also serves to establish its absolute
conguration. Specic optical rotations of synthesized
compound and reported fuzanin D indicated opposite signs.
This was conrmed by total synthesis of its enantiomer
(11R,12S)-4a. Stereochemistry of reported fuzanin D (4a) should
be 11R,12S instead of 11S,12R conguration. Molecular
modeling studies also supported this observation. Further,
fuzanins C, D and their analogues were screened for anticancer
activity in four cancer cell lines. The compounds were found to
exert cytotoxicity selectively on HT29 cancer cell lines.
Compound
3a
3b
3c
3d
4a
4b
4c
4d
96.2 ꢂ 2.65
85.3 ꢂ 4.72
48.5 ꢂ 2.56
76.2 ꢂ 2.45
77.9 ꢂ 2.95
98.5 ꢂ 1.88
35.3 ꢂ 0.83
27.4 ꢂ 0.12
>100
(11R,12S)-4a
(11R,12S)-4b
Salinomycin
>100
20.5 ꢂ 1.26
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Fig. 4 Dose response of fuzanin compounds against HT-29 cancer cell line.
Quinoline nucleus containing analogues 3c, 4c and 4d are 166.5, 146.6, 122.4, 75.6, 70.2, 60.7, 19.0, 14.1; anal. calcd for
relatively more potent.
C8H14O4 (174.19): C, 55.16; H, 8.10. Found: C, 55.15; H, 8.17%.
Experimental section
(E)-3-((4R,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol
(10)
All reactions were carried out under an inert atmosphere unless
mentioned otherwise, and standard syringe-septa techniques
were followed. Solvents were freshly dried and puried by
conventional methods prior to use. The progress of all reactions
were monitored by TLC, using TLC aluminium backed sheets
precoated with silicagel 60 F254 to a thickness of 0.25 mm
(Merck). Column chromatography was performed on silica gel
(60–120 mesh and 100–200 mesh), and EtoAc, hexane were used
as eluents. Optical rotation values were measured with a Perkin-
Elmer P241 polarimeter and a JASCO DIP-360 digital polarim-
eter, and IR spectra were recorded with a Perkin-Elmer FT-IR
spectrophotometer. 1H and 13C NMR spectra were recorded
with Varian Gemini 200 MHz, Bruker Avance 300 MHz, Varian
Unity 400 MHz or Varian Inova 500 MHz spectrophotometers.
TMS was used as an internal standard in CDCl3. Mass spectra
were recorded with a VG micromass 7070H (EI), QSTAR XL high-
resolution mass spectrophotometer, a Thermo Finnigan ESI Ion
trap Mass spectrophotometer.
To the solution of 9 (3 g, 17.24 mmol) in 30 mL CH2Cl2,
2,2-dimethoxypropane (5.37 g, 51.72 mmol), catalytic amount of
p-TSA were added and stirred for 15 min at rt. The reaction
mixture was washed with saturated aqueous NaHCO3 solution
(10 mL), dried over Na2SO4, concentrated under vacuo. The
crude residue was puried by silica gel column chromatography
(EtOAc–hexane, 1 : 9) to afford cyclic acetonide (3.46 g, 94%) as
colour less oil. To the solution cyclic acetonide (3.2 g,
14.9 mmol) in 30 mL of dry CH2Cl2 at 0 ꢀC, DIBAL-H (21.01 mL,
37.25 mmol, 25% solution in THF) was added, and stirred for
1 h at rt. The reaction mixture was quenched by slow addition of
aq. sodium potassium tartate and stirred for 2 h. Organic layer
was separated and aqueous layer was extracted by chloroform
(20 mL), combined organic layer was dried over Na2SO4, solvent
removed under vacuo. The crude residue was puried by silica
gel column chromatography (EtOAc–hexane, 6 : 4) to afford 10
(2.4 g, 81%) as light yellow, viscous oil; [a]2D4 + 46.01 (c 0.1,
1
CHCl3); IR (Neat): 3395, 2923, 2851, 1449, 1259, 998 cmꢁ1; H
NMR (CDCl3, 300 MHz): d 5.99 (dtd, 1H, J ¼ 15.5, 5.1, 0.7 Hz),
5.70 (tdd, 1H, J ¼ 15.5, 7.5, 1.5 Hz), 4.19 (d, 2H, J ¼ 5.1 Hz), 3.9 (t,
1H, J ¼ 7.5 Hz), 3.84–3.75 (m, 1H), 1.42 (s, 3H), 1.41 (s, 3H), 1.26
(d, 3H, J ¼ 6.0 Hz); 13C NMR (CDCl3, 50 MHz): d 134.2, 127.0,
108.2, 83.1, 76.5, 62.3, 27.2, 26.8, 16.3; anal. calcd for C9H16O3
(172.10): C, 62.77; H, 9.36. Found: C, 62.58; H, 9.57%.
(4R,5R,E)-Ethyl-4,5-dihydroxyhex-2-enoate (9)
To a mixture of K3Fe(CN)6 (28.22 g, 85.71 mmol), K2CO3 (11.80 g,
85.71 mmol), and (DHQD)2PHAL (0.41 g, 0.57 mmol) in 45 mL
of t-BuOH–H2O (1 : 1), was added OsO4 (70.56 mg, 0.28 mmol)
followed by methane sulfonamide (2.71 g, 28.57 mmol) at 0 ꢀC.
Aer stirring for 15 min at 0 ꢀC, ethyl sorbate 8 (4 g, 28.57 mmol)
was added and stirred vigorously at 0 ꢀC for 12 h, and then
quenched with sat. sodium sulte (35 mL). The reaction mixture
was extracted with ethyl acetate (3 ꢃ 40 mL). The organic layer
1-Phenyl-5-(((E)-3-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)-
allyl)sulfonyl)-1H-tetrazole (6)
washed with 2 N KOH (20 mL), brine solution and dried over To a solution of alcohol 10 (0.6 g, 3.48 mmol) and 1-phenyl-1H-
Na2SO4. Solvent removed under vacuo. The crude residue was tetrazole-5-thiol (0.74 g, 4.15 mmol) in 20 mL THF at 0 ꢀC, DIAD
puried by silica gel column chromatography (EtOAc–hexane, (0.82 mL, 4.16 mmol) and triphenyl phosphine (0.84 g, 4.15 mmol)
7 : 3) to afford diol 9 (3.97 g, 84%) as light yellow oil; [a]D25
+
were added, and stirred for 1 h at same temperature. The reaction
50.21 (c 0.1, EtOH); IR (Neat): 3396, 2924, 1704, 1371, 1281, was quenched by addition of saturated aqueous NH4Cl solution,
1036 cmꢁ1; 1H NMR (CDCl3, 300 MHz): d 6.89 (dd, 1H, J ¼ 15.5, extracted with ethyl acetate (2 ꢃ 20 mL), dried over Na2SO4,
5.2 Hz), 6.10 (dd, 1H, J ¼ 15.5, 1.5 Hz), 4.17 (q, 2H, J ¼ 7.5 Hz), concentrated under vacuo. The crude residue was puried by silica
4.02 (brt, 1H, J ¼ 5.2 Hz), 3.75–3.63 (m, 1H), 1.27 (t, 3H, J ¼ gel column chromatography (EtOAc–hexane, 3 : 7) to afford
7.5 Hz), 1.20 (d, 3H, J ¼ 6.0 Hz); 13C NMR (CDCl3, 75 MHz): d sulphide (1.0 g, 90%) as colour less, viscous oil; [a]D24 ꢁ 24.80 (c 0.1,
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CHCl3); IR (Neat): 2923, 1679, 1618, 1185, 1001, 741 cmꢁ1
Paper
;
1H reaction mixture stirred for 12 h at rt, and solvent removed
NMR (CDCl3, 500 MHz): d 7.61–7.55 (m, 5H), 6.05–5.95 (m, 1H), under vacuo. The crude residue was diluted with CH2Cl2 and
5.81 (dd, 1H, J ¼ 15.1, 6.7 Hz), 4.13–3.97 (m, 2H), 3.90 (t, 1H, J ¼ washed with saturated aqueous NaHCO3 solution and the
8.3 Hz), 3.79–3.70 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.22 (d, 3H, J ¼ solvent removed under vacuo. The crude compound was puri-
6.7 Hz); 13C NMR (CDCl3, 50 MHz): d 153.3, 133.4, 132.2, 130.0, ed by silica gel column chromatography (EtOAc–hexane, 1 : 1)
129.6, 127.5, 123.6, 108.4, 82.5, 76.4, 34.4, 27.1, 26.7, 16.2; MS to afford fuzanin C (3a) (0.05 g) as viscous, colour less oil, and
(ESI): m/z 355 (M + Na)+; HRMS (ESI): m/z 355.1200 (M + Na)+ cis isomer 3b (0.02 g) as viscous, colour less oil, (total yield 82%);
(calcd for C16H21N4O2S 355.1199).
[a]2D4 + 39.89 (c 0.055, CHCl3); IR (Neat): 3395, 2923, 1679, 1618,
To a solution of sulphide (0.50 g, 1.50 mmol) and ammo- 772 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.39 (d, 1H, J ¼ 4.7 Hz),
nium heptamolybdate tetrahydrate (0.55 g, 0.45 mmol) in 12 mL 7.42 (d, 1H, J ¼ 7.7 Hz), 7.37 (dd, 1H, J ¼ 15.0, 11.0 Hz), 7.04 (dd,
of ethanol at 0 ꢀC, H2O2 (30% solution in water, 2.04 mL, 18.07 1H, J ¼ 7.7, 4.7 Hz), 6.78 (d, 1H, J ¼ 15.0 Hz), 6.54 (dd, 1H, J ¼
mmol) was added and stirred for 8 h at rt. The reaction mixture 15.3, 11.0 Hz), 5.94 (dd, 1H, J ¼ 15.3, 6.9 Hz), 3.95 (t, 1H, J ¼
was poured in to saturated aqueous NaHCO3 solution (40 mL) 6.9 Hz), 3.68 (q, 1H, J ¼ 6.6 Hz), 2.34 (s, 3H), 1.18 (d, 3H, J ¼ 6.6
and extracted with ethyl acetate (3 ꢃ 30 mL), dried over Na2SO4, Hz); 13C NMR (CDCl3, 100 MHz): d 153.2, 146.8, 138.2, 135.7,
concentrated under vacuo. The crude residue was puried by 133.3, 132.1, 130.8, 128.0, 122.0, 77.1, 70.7, 18.8, 18.6; MS (ESI):
silica gel column chromatography (EtOAc–hexane, 3 : 7) to m/z 220 (M + H)+; HRMS (ESI): m/z 242.1148 (M + Na)+ (calcd for
afford sulphone 4 (0.5 g, 92%) as colour less, viscous oil; [a]D24
ꢁ
C13H17O2NNa 242.1151).
28.70 (c 0.1, CHCl3); IR (Neat): 2922, 1679, 1618, 1222, 741 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): d 7.68–7.59 (m, 5H), 5.98 (dd, 1H,
J ¼ 15.8, 6.0 Hz), 5.93–5.83 (m, 1H), 4.45 (m, 2H), 3.93 (dd, 1H, J
¼ 8.3, 6.0 Hz), 3.77–3.68 (m, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.22
(2R,3R,4E,6Z)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(3b)
(d, 3H, J ¼ 6.0 Hz); 13C NMR (CDCl3, 50 MHz): d 152.8, 140.0, Yield: 0.02 g; [a]D24 + 82.23 (c 0.051, CHCl3); IR (Neat): 3421, 2924,
132.8, 131.4, 129.5, 125.0, 116.6, 108.9, 82.1, 76.4, 59.0, 27.1, 1619, 1449, 772 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.42 (d, 1H,
26.6, 16.3; MS (ESI): m/z 365 (M + H)+; HRMS (ESI): m/z 387.1093 J ¼ 4.7 Hz), 7.45 (d, 1H, J ¼ 7.3 Hz), 7.29 (dd, 1H, J ¼ 15.2,
(M + Na)+ (calcd for C16H20O4N4NaS 387.1097).
11.5 Hz), 7.06 (dd, 1H, J ¼ 7.3, 4.7 Hz), 6.46 (d, 1H, J ¼ 11.5 Hz),
6.38 (t, 1H, J ¼ 11.5 Hz), 5.87 (dd, 1H, J ¼ 15.2, 6.6 Hz), 3.93 (t,
1H, J ¼ 6.6 Hz), 3.66 (quin, 1H, J ¼ 6.2 Hz), 2.31 (s, 3H), 1.17 (d,
3H, J ¼ 6.2 Hz); 13C NMR (CDCl3, 100 MHz): d 154.5, 146.2,
137.8, 136.9, 132.9, 131.9, 129.2, 126.0, 121.8, 76.7, 70.4, 19.0,
18.8; MS (ESI): m/z 220 (M + H)+; HRMS (ESI): m/z 220.1329 (M +
H)+ (calcd for C13H18O2N 220.1332).
3-Methyl-2-((3E)-4-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)
buta-1,3-dien-1-yl)pyridine (11)
To a solution of sulphone 6 (0.40 g, 1.09 mmol) in 10 mL THF at
ꢁ78 ꢀC, potassium bis(trimethylsilyl)amide (0.5 M in THF
solution, 2.85 mL, 1.42 mmol) was added. Aer 30 min of stir-
ring at same temperature, the solution of aldehyde 5a (0.14 g,
1.19 mmol) in 2 mL THF was added. The reaction mixture was
stirred for further 1.5 h at ꢁ78 ꢀC, the reaction allowed to warm
to rt and was stirred for additional 2 h. Brine solution was added
to the reaction mixture and extracted with ethyl acetate (3 ꢃ
10 mL), dried over Na2SO4, concentrated under vacuo. The crude
residue was puried by silica gel column chromatography
(EtOAc–hexane, 1 : 4) to afford 11 (0.23 g, 81%) (inseparable cis,
trans mixture, 3 : 7) as viscous, light yellow oil; IR (Neat): 2984,
(2R,3R,4E,6E)-7-(2-Chloro-6-isopropylquinolin-3-yl)hepta-4,6-
diene-2,3-diol (3c)
According to the procedure 3a, the sulphone 6 (0.10 g,
0.27 mmol) and aldehyde 5b (0.07 g, 0.32 mmol), gave cyclic
acetonide (inseparable cis, trans mixture, 6 : 94 by NMR) as light
yellow oil. Cyclic acetonide dissolved in 10 mL of methanol,
catalytic amount of p-TSA was added and stirred for 30 min at rt,
and solvent removed under vacuo. The crude residue was
diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3 solution and the solvent removed under vacuo. The
crude compound was puried by silica gel column chroma-
tography (EtOAc–hexane, 1 : 1) to afford compound 3c (0.06 g,
70%, for two steps) as white solid; mp 120–122 ꢀC; [a]D24 ꢁ 89.56
(c 0.022, CHCl3); IR (KBr): 3409, 2963, 2926, 1584, 1047,
768 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.19 (s, 1H), 7.89 (d, 1H,
J ¼ 9.0 Hz), 7.60–7.56 (m, 2H), 6.98 (d, 1H, J ¼ 15.9 Hz), 6.83 (dd,
1H, J ¼ 15.9, 10.9 Hz), 6.59 (dd, 1H, J ¼ 14.9, 10.9 Hz), 5.91 (dd,
1H, J ¼ 14.9, 5.9 Hz), 4.01 (t, 1H, J ¼ 5.9 Hz), 3.73 (quin, 1H, J ¼
5.9 Hz), 3.07 (sep, 1H, J ¼ 6.9 Hz), 1.33 (d, 6H, J ¼ 6.9 Hz), 1.24
(d, 3H, J ¼ 5.9 Hz); 13C NMR (CDCl3, 100 MHz): d 149.0, 148.0,
145.5, 134.7, 133.3, 132.3, 131.9, 130.3, 129.5, 127.8, 127.6,
127.3, 123.5, 77.0, 70.8, 34.0, 23.6, 19.0; MS (ESI): m/z 332 [M +
1
2932, 1581, 1498, 1380, 1028, 858 cmꢁ1; H NMR (CDCl3, 300
MHz): d 8.45 (d, 0.3H, J ¼ 4.7 Hz), 8.40 (d, 0.7H, J ¼ 4.1 Hz),
7.45–7.35 (m, 2H), 7.07–7.01 (m, 1H), 6.79 (d, 0.7H, J ¼ 15.1 Hz),
6.60–6.65 (m, 1.5H), 5.92–5.76 (m, 1H), 4.02 (brt, 1H, J ¼ 7.5
Hz), 3.84–3.75 (m, 1.5H), 2.36 (s, 2.1H), 2.31 (s, 0.9H), 1.44 (s,
4.2H), 1.41 (s, 1.8H), 1.29–1.26 (m, 3H); 13C NMR (CDCl3, 50
MHz): d 155.0, 153.4, 147.3, 146.8, 138.3, 137.8, 133.7, 132.8,
132.3, 131.7, 130.9, 129.1, 127.0, 122.3, 122.0, 116.8, 108.7,
108.5, 83.7, 77.7, 77.0, 27.5, 27.1, 19.3, 18.9, 16.8, 16.7; MS (ESI):
m/z 260 (M + H)+; HRMS (ESI): m/z 260.1641 (M + H)+ (calcd for
C
16H22O2N 260.1645).
(2R,3R,4E,6E)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(3a)
To a solution of 11 (0.10 g, 0.38 mmol) in 10 mL methanol, was H]+; HRMS (ESI): m/z 332.1410 (M + H)+ (calcd for C19H23O2NCl
added p-toluenesulphonic acid (1.32 g, 0.77 mmol) and the 332.1411).
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166.3, 145.5, 121.7, 74.8, 70.7, 60.3, 25.7, 17.9, 17.7, 14.2, ꢁ4.4,
ꢁ4.9; MS (ESI): m/z 289 (M + H)+.
(2R,3R,4E,6E)-7-(2-Chloro-7-methylquinolin-3-yl)hepta-4,6-
diene-2,3-diol (3d)
According to the procedure 3c, the sulphone 6 (0.10 g,
0.27 mmol) and requisite aldehyde 5c (0.07 g, 0.35 mmol) gave
the compound 3d (0.06 g, 71%, for two steps) as white solid; mp
130–131 ꢀC; [a]D24 ꢁ 91.18 (c 0.024, CHCl3); IR (KBr): 3397, 2925,
1623, 1049, 756 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.19 (s, 1H),
7.73 (br s, 1H), 7.68 (d, 1H, J ¼ 8.3, Hz), 7.37 (dd, 1H, J ¼ 8.3,
1.13 Hz), 6.99 (d, 1H, J ¼ 15.5 Hz), 6.83 (dd, 1H, J ¼ 15.5,
10.3 Hz), 6.60 (dd, 1H, J ¼ 15.3, 10.3 Hz), 5.91 (dd, 1H, J ¼ 15.3,
6.8 Hz), 4.01 (t, 1H, J ¼ 6.8 Hz), 3.73 (quin, 1H, J ¼ 6.4 Hz), 2.54
(s, 3H), 1.24 (d, 3H, J ¼ 6.4 Hz); 13C NMR (CDCl3, 100 MHz): d
149.8, 146.9, 141.0, 134.5, 133.3, 132.4, 131.7, 129.5, 128.8,
127.8, 127.2, 127.1, 125.4, 77.1, 70.8, 21.9, 19.0; MS (ESI): m/z
304 (M + H)+; HRMS (ESI): m/z 304.1096 [M + H]+ (calcd for
C17H19O2NCl 304.1098).
(4S,5R,E)-Ethyl-4,5-dihydroxyhex-2-enoate (14)
To a solution of 13 (0.5 g, 1.73 mmol) in 10 mL THF at 0 ꢀC, was
added TBAF (1.0 M, 5.2 mL, 5.19 mmol) and the resulting
mixture was stirred for 1 h. The reaction was quenched with
water (25 mL) and extracted with CH2Cl2 (2 ꢃ 25 mL). The
combined organic extracts were dried over Na2SO4, concen-
trated in vacuo. The crude reside was puried by silica gel
column chromatography to yield diol 14 (0.25 g, 85%); [a]D24
ꢁ
9.15 (c 0.047, CHCl3); IR (Neat): 3429, 2981, 2931, 1714, 1659,
1278, 984 cmꢁ1; 1H NMR (CDCl3, 300 MHz): d 6.94 (dd, 1H, J ¼
15.1, 4.5 Hz), 6.11 (d, 1H, J ¼ 15.1 Hz), 4.30 (brs, 1H), 4.20 (q, 2H,
J ¼ 6.8 Hz), 3.99–3.91 (m, 1H), 1.28 (t, 3H, J ¼ 6.8 Hz), 1.16 (d,
3H, J ¼ 6.0 Hz); 13C NMR (CDCl3, 75 MHz): d 166.6, 145.8,
122.37, 74.5, 69.9, 60.6, 17.4, 14.1; anal. calcd for C8H14O4
(174.19): C, 55.16; H, 8.10. Found: C, 55.19; H, 8.14%.
(4R,5R,E)-Ethyl 5-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-
2-enoate (12)
(E)-3-((4S,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol
(15)
To a solution of the diol 9 (3.0 g, 17.5 mmol) in CH2Cl2 (30 mL)
ꢀ
at 0 C, Et3N (4.1 mL, 29.8 mmol), DMAP (1.06 g, 0.88 mmol)
According to the procedure 10, compound 14 (2.4 g, 13.79
mmol) gave alcohol 15 (1.90 g, 80%); [a]2D4 ꢁ 15.1 (c 0.1, CHCl3);
and TBSCl (3.96 g, 26.3 mmol) were added simultaneously, and
the mixture was stirred for 24 h at rt. The reaction mixture was
diluted with CH2Cl2, successively washed with 10% aq. HCl and
sat. NaHCO3, dried over Na2SO4, ltered, and concentrated in
vacuo. The resulting oil was puried by silicagel column chro-
matography (EtOAc–hexane, 1 : 4) to afford the TBS ether (12)
(3.29 g, 65%) as a colorless oil; [a]2D5 ꢁ 0.71 (c 0.051, EtOH); IR
(Neat): 3475, 2932, 2858, 1721, 1257, 838 cmꢁ1; 1H NMR (CDCl3,
300 MHz): d 6.88 (dd, 1H, J ¼ 15.8, 4.5 Hz), 6.10 (dd, 1H, J ¼ 15.8,
1.8 Hz), 4.19 (q, 2H, J ¼ 7.1 Hz), 4.02–3.98 (m, 1H), 3.79–3.71 (m,
1H), 2.57 (brs, 1H), 1.29 (t, 3H, J ¼ 7.1 Hz), 1.20 (d, 3H, J ¼
6.0 Hz), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3,
75 MHz): d 166.2, 147.2, 121.9, 75.2, 71.0, 60.3, 25.7, 20.1, 17.9,
14.2, ꢁ4.3, ꢁ4.9; MS (ESI): m/z 289 (M + H)+.
1
IR (Neat): 3431, 2984, 1380, 1219, 772 cmꢁ1; H NMR (CDCl3,
500 MHz): d 5.90 (td, 1H, J ¼ 15.4, 5.1 Hz), 5.68 (tdd, 1H, J ¼
15.4, 7.7, 1.5 Hz), 4.52 (brt, 1H, J ¼ 7.7 Hz), 4.32 (quin, 1H, J ¼
6.4 Hz), 4.17 (dd, 2H, J ¼ 5.1, 1.5 Hz), 1.47 (s, 3H), 1.35 (s, 3H),
1.13 (d, 3H, J ¼ 6.4 Hz); 13C NMR (CDCl3, 100 MHz): d 133.5,
127.1, 108.0, 79.0, 74.0, 62.8, 28.2, 25.5, 16.1; anal. calcd for
C9H16O3 (172.10): C, 62.77; H, 9.36. Found: C, 62.61; H, 9.59%.
1-Phenyl-5-(((E)-3-((4S,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)-
allyl)sulfonyl)-1H-tetrazole (7)
According to the procedure 6, the alcohol 15 (0.5 g, 2.9 mmol)
gave sulphone 7 (0.86 g, 82%); [a]2D4 ꢁ 3.14 (c 0.05, CHCl3); IR
(Neat): 2922, 1679, 1618, 1524, 1347, 741 cmꢁ1; 1H NMR (CDCl3,
300 MHz): d 7.68–7.56 (m, 5H), 5.96 (dd, 1H, J ¼ 15.8, 6.8 Hz),
5.86–5.76 (m, 1H), 4.54–4.38 (m, 3H), 4.32 (dd, 1H, J ¼ 12.8,
6.7 Hz), 1.45 (s, 3H), 1.34 (s, 3H), 1.03 (d, 3H, J ¼ 6.7 Hz); 13C
NMR (CDCl3, 75 MHz): d 152.9, 140.3, 132.9, 131.4, 129.6, 125.1,
116.1, 108.5, 78.1, 73.8, 59.0, 28.0, 25.3, 15.8; MS (ESI): m/z 365
(M + H)+; HRMS (ESI): m/z [M + H]+ 387.1094 (M + Na)+ (calcu-
lated for C16H20N4O4NaS 387.1097).
(4S,5R,E)-Ethyl-5-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-
2-enoate (13)
Under inert atmosphere, to a solution of PPh3 (0.62 g,
2.38 mmol) in 5 mL benzene at 0 ꢀC, DEAD (0.16 mL, 2.38
mmol), TBS ether (12) (0.274 g, 0.95 mmol) and formic acid
(0.11 mL, 2.85 mmol) were added simultaneously and the
mixture was stirred for 2 h at rt. The solvent was evaporated in
vacuo, and the crude residue was dissolved in NH4OH–MeOH
(1 : 1, 3.0 mL) at 0 ꢀC and stirred for 3 h at rt. This reaction
mixture was diluted with Et2O, successively washed with 10%
3-Methyl-2-((3E)-4-((4S,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)-
buta-1,3-dien-1-yl)pyridine (16)
HCl solution and sat. NaHCO3, dried over Na2SO4, and According to the procedure 11, the sulphone 6 (0.38 g,
concentrated in vacuo. The resulting oil was puried by silica gel 1.04 mmol) and 5a (0.13 g, 1.14 mmol), gave 16 (0.22 g, 81%)
column chromatography (EtOAc–hexane, 1 : 4) to afford alcohol (inseparable cis, trans mixture, 4 : 6) as colourless, viscous oil;
13 (0.15 g, 55%) as a colorless oil; [a]2D5 ꢁ 27.1 (c 0.051, EtOH); IR IR (Neat): 2923, 2851, 1667, 1382, 1048, 771 cmꢁ1
;
1H NMR
(Neat): 3466, 2930, 2857, 1720, 1259, 836 cmꢁ1; 1H NMR (CDCl3, (CDCl3, 300 MHz): d 8.45 (d, 0.4H, J ¼ 4.5 Hz), 8.42 (d, 0.6H, J ¼
300 MHz): d 6.87 (dd, 1H, J ¼ 15.6, 4.6 Hz), 6.08 (dd, 1H, J ¼ 15.6, 4.5 Hz), 7.48–7.36 (m, 2H), 7.08–7.02 (m, 1H), 6.81 (d, 0.6H, J ¼
2.3 Hz), 4.24–4.21 (m, 1H), 4.19 (q, 2H, J ¼ 7.0 Hz), 3.93–3.88 (m, 15.1 Hz), 6.56–6.39 (m, 1.6H), 5.96–5.81 (m, 1H), 4.65–4.59 (m,
1H), 2.43 (brs, 1H), 1.28 (t, 3H, J ¼ 7.0 Hz), 1.08 (d, 3H, J ¼ 1H), 4.41–4.30 (m, 1H), 2.36 (s, 1.8H), 2.30 (s, 1.2H), 1.53 (s,
6.2 Hz), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 70 MHz): d 1.8H), 1.50 (s, 1.2H), 1.39 (s, 1.8H), 1.36 (s, 1.2H), 1.16 (t, 3H,
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24
J ¼ 6.0 Hz); 13C NMR (CDCl3, 75 MHz): d 154.7, 153.2, 146.9, 4d (0.07 g, 70% overall yield); mp 134–136 C; [a]D ꢁ 75.14 (c
ꢀ
1
146.4, 138.1, 137.6, 133.3, 132.8, 132.6, 132.3, 130.9, 128.3, 0.03, CHCl3); IR (Neat): 3418, 2922, 1622, 1337, 986 cmꢁ1; H
126.3, 122.0, 121.7, 108.0, 107.9, 79.4, 79.1, 74.37, 74.32, 28.2, NMR (CDCl3, 500 MHz): d 8.20 (s, 1H), 7.73 (brs, 1H), 7.68 (d,
25.4, 19.0, 18.7, 16.17; MS (ESI): m/z 260 (M + H)+; HRMS (ESI): 1H, J ¼ 8.3 Hz), 7.36 (d, 1H, J ¼ 8.3 Hz), 6.99 (d, 1H, J ¼ 15.1
m/z 260.1640 (M + H)+ (calcd for C16H22O2N 260.1645).
Hz), 6.84 (dd, 1H, J ¼ 15.1, 10.5 Hz), 6.57 (dd, 1H, J ¼ 15.1, 10.5
Hz), 5.98 (dd, 1H, J ¼ 15.1, 6.7 Hz), 4.24 (dd, 1H, J ¼ 6.7, 3.0 Hz),
4.01–3.92 (m, 1H), 2.54 (s, 3H), 1.20 (d, 3H, J ¼ 6.7 Hz); 13C NMR
(CDCl3, 100 MHz): d 149.9, 147.0, 141.0, 133.3, 132.6, 131.8,
129.5, 128.8, 127.8, 127.7, 127.2, 127.1, 126.0, 75.9, 70.3, 21.9,
17.7; MS (ESI): m/z 304 (M + H)+; HRMS (ESI): m/z 304.1097 (M +
H)+ (calculated for C17H18N3O6 304.1098).
(2R,3S,4E,6E)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(4a)
According to the procedure 3a, compound 16 (0.1 g, 0.38 mmol)
gave fuzanin D (4a) (0.05 g) as viscous, colour less oil, and cis
isomer 4b (0.02 g) as viscous, colour less oil, (total yield 82%);
[a]2D4 + 29.47 (c 0.045, CHCl3); IR (Neat): 3424, 2924, 2854, 1621,
1458, 1078, 771 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.40 (d, 1H,
J ¼ 4.1 Hz), 7.45–7.36 (m, 2H), 7.04 (dd, 1H, J ¼ 7.2, 4.1 Hz), 6.79
(d, 1H, J ¼ 14.5 Hz), 6.54 (dd, 1H, J ¼ 14.5, 10.4 Hz), 6.01 (dd,
1H, J ¼ 14.5, 6.2 Hz), 4.20 (dd, 1H, J ¼ 6.2, 4.1 Hz), 3.90 (dd, 1H,
J ¼ 6.2, 4.1 Hz), 2.34 (s, 3H), 1.16 (d, 1H, J ¼ 6.2 Hz); 13C NMR
(CDCl3, 100 MHz): d 153.3, 146.9, 138.2, 134.6, 133.2, 132.3,
130.7, 128.1, 122.0, 75.9, 70.3, 18.7, 17.6; MS (ESI): m/z 242 (M +
(E)-Ethyl-3-((2S,3S)-3-methyloxiran-2-yl)acrylate (19)
To a solution of oxalyl chloride (0.87 mL, 9.96 mmol) in 30 mL of
CH2Cl2 at ꢁ78 ꢀC, DMSO (1.41 mL, 19.92 mmol) was added
dropwise. The solution was stirred for 10 min and a solution of
epoxy alcohol 18 (0.73 mg, 8.3 mmol) in 20 mL of CH2Cl2 was
added. Aer 20 min at same temperature, triethylamine (3.47 mL,
24.7 mmol) was added. Aer 5 min, the reaction mixture of was
allowed to warm to rt during 30 min. A solution of (carbethoxy-
methylene)triphenylphosphorane (7.63 g, 20.8 mmol) in 10 mL of
CH2Cl2 was added and the reaction mixture was stirred for 24 h.
Reaction mixture was quenched with aq. NH4Cl, and extracted
with CH2Cl2 (2 ꢃ 10 mL). The combined organic layer was dried
over Na2SO4, crude residue was puried by silica gel column
chromatography (EtOAc–hexane, 1 : 4) to afford epoxide 19
(0.55 g, 56%); [a]2D4 ꢁ 15.54 (c 0.04, CHCl3); IR (Neat): 2927, 1721,
Na)+; HRMS (ESI): m/z 242.1148 (M
13H17O2NNa 242.1151).
+
Na)+ (calcd for
C
(2R,3S,4E,6Z)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(4b)
Yield: (0.02 g, 90% overall yield); [a]2D4 + 59.15 (c 0.04, CHCl3); IR
(Neat): 3405, 2924, 1449, 995 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d
8.45 (d, 1H, J ¼ 5.2 Hz), 7.46 (d, 1H, J ¼ 7.2 Hz), 7.39 (dd, 1H, J ¼
15.6, 11.4 Hz), 7.07 (dd, 1H, J ¼ 7.2, 5.2 Hz), 6.52 (d, 1H, J ¼
11.4 Hz), 6.44 (t, 1H, J ¼ 11.4 Hz), 5.97 (dd, 1H, J ¼ 15.6, 7.2 Hz),
4.18 (dd, 1H, J ¼ 7.27, 4.1 Hz), 3.9 (dd, 1H, J ¼ 6.2, 4.1 Hz), 2.31
(s, 3H), 1.16 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CDCl3, 100 MHz): d
154.5, 146.2, 138.0, 135.7, 133.1, 132.0, 129.9, 125.9, 121.9, 75.9,
70.1, 19.0, 17.7; MS (ESI): m/z 220 (M + H)+; HRMS (ESI): m/z
220.1329 (M + H)+ (calcd for C13H18O2N 220.1332).
1
1455, 1272, 1178, 772 cmꢁ1; H NMR (CDCl3, 300 MHz): d 6.67
(dd, 1H, J ¼ 15.6, 7.0 Hz), 6.12 (d, 1H, J ¼ 15.6 Hz), 4.20 (q, 2H, J ¼
7.17 Hz), 3.18 (dd, 1H, J ¼ 8.7, 7.0 Hz), 2.97 (qd, 1H, J ¼ 5.1,
2.07 Hz), 1.39 (d, 3H, J ¼ 5.1 Hz), 1.28 (t, 3H, J ¼ 7.17 Hz); 13C
NMR (CDCl3, 75 MHz): d 165.5, 144.5, 123.5, 60.4, 57.2, 57.1, 17.3,
14.0; anal. calcd for C8H12O3 (156.07): C, 61.52; H, 7.74. Found: C,
61.62; H, 7.82%.
(4R,5S,E)-Ethyl-4-(benzyloxy)-5-hydroxyhex-2-enoate (20)
(2R,3S,4E,6E)-7-(2-Chloro-6-isopropylquinolin-3-yl)hepta-4,6-
To a solution of epoxide ester 19 (3.14 g, 20.15 mmol), benzyl
alcohol (4.19 mL, 40.3 mmol) in CH2Cl2 (40 mL) at ꢁ20 ꢀC,
BF3$OEt2 (2.5 mL, 40.3 mmol) was added and whole mixture was
stirred at rt for 1 h, then diluted with H2O and extracted with
ether. The ether layer was washed with saturated brine and dried
over Na2SO4. The organic layer was concentrated under vacuo.
Crude residue was puried by silica gel column chromatography
(EtOAc–hexane, 3 : 2) to afford 20 (3.03 g, 60%) as colorless oil;
[a]2D5 ꢁ 51.51 (c 1.0, CHCl3); IR (Neat): 3508, 2983, 1721, 1264, 836
cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 7.40–7.30 (m, 5H), 6.91 (dd,
1H, J ¼ 15.8, 6.8 Hz), 6.08 (d, 1H, J ¼ 15.8 Hz), 4.66 (d, 1H, J ¼
11.3 Hz), 4.42 (d, 1H, J ¼ 11.3), 4.23 (q, 2H, J ¼ 7.5 Hz), 4.01–3.90
(m, 2H), 1.31 (t, 3H, J ¼ 7.5 Hz), 1.16 (d, 3H, J ¼ 6.0 Hz); 13C NMR
(CDCl3, 75 MHz): d 165.7, 143.8, 137.6, 128.4, 127.8, 127.7, 124.7,
81.9, 71.3, 69.2, 60.6, 17.9, 14.2; anal. calcd for C15H20O4
(264.13): C, 68.16; H, 7.63. Found: C, 68.22; H, 7.69%.
diene-2,3-diol (4c)
According to the procedure 3c, the sulphone 7 (0.10 g,
0.27 mmol) and aldehyde 5b (0.07 g, 0.32 mmol), gave
compound 4c (0.07 g, 70% overall yield); mp 121–122 ꢀC; [a]D24
ꢁ
24.0 (c 0.03, CHCl3); IR (KBr): 3423, 2962, 2924, 1585, 1046, 757
cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.22 (S, 1H), 7.90 (d, 1H, J ¼
8.9 Hz), 7.60–7.58 (m, 2H), 7.01 (d, 1H, J ¼ 15.9 Hz), 6.87 (dd,
1H, J ¼ 15.9, 6.9 Hz), 6.59 (dd, 1H, J ¼ 15.9, 9.8 Hz), 5.99 (dd, 1H,
J ¼ 15.9, 6.7 Hz), 4.24 (dd, 1H, J ¼ 6.7, 4.5 Hz), 3.98–3.94 (m, 1H),
3.08 (sep, 1H, J ¼ 6.9 Hz), 1.34 (d, 6H, J ¼ 6.9 Hz), 1.20 (d, 3H, J ¼
6.9 Hz); 13C NMR (CDCl3, 100 MHz): d 149.1, 148.0, 145.6, 133.4,
133.3, 132.6, 132.0, 130.3, 129.6, 128.0, 127.8, 127.4, 123.5, 75.9,
70.3, 34.0, 23.7, 17.7; MS (ESI): m/z 332 (M + H)+; HRMS (ESI): m/
z 332.1409 (M + H)+ (calcd for C19H23O2NCl 332.1411).
(2R,3S,4E,6E)-7-(2-Chloro-7-methylquinolin-3-yl)hepta-4,6-
diene-2,3-diol (4d)
(4R,5S,E)-Ethyl 4,5-dihydroxyhex-2-enoate (21)
According to the procedure 3c, the sulphone 7 (0.10 g, To a well-stirred solution of AlCl3 (0.99 g, 7.5 mmol) in 10 mL
0.27 mmol) and aldehyde 5c (0.06 g, 0.32 mmol) gave compound CH2Cl2 at 0 ꢀC was added a solution of 20 (0.40 g, 1.5 mmol) in
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5 mL m-xylene and the reaction mixture was stirred for 15 min at
the same temperature. The reaction mixture was poured in ice
cold water and extracted with ether. The ether layer was washed
with saturated NaCl solution and dried over Na2SO4. The ether
layer was concentrated under vacuo. Crude residue was puried
by silica gel column chromatography (EtOAc–hexane, 2 : 1) to
give 21 (0.29 g, 76%) as a colorless viscous oil; [a]2D5 + 9.01 (c
(2S,3R,4E,6Z)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(11R,12S)-4b
Yield: 0.01 g, as viscous, colour less oil; [a]2D4 ꢁ 59.6 (c 0.03,
1
CHCl3); IR (Neat): 3419, 2924, 1628, 1457, 762 cmꢁ1; H NMR
(CDCl3, 500 MHz): d 8.43 (d, 1H, J ¼ 4.0 Hz), 7.46 (d, 1H, J ¼
7.1 Hz), 7.30 (dd, 1H, J ¼ 15.3, 11.2 Hz), 7.07 (dd, 1H, J ¼ 7.1,
4.0 Hz), 6.50 (d, 1H, J ¼ 11.2 Hz), 6.43 (t, 1H, J ¼ 11.2 Hz), 5.97
(dd, 1H, J ¼ 7.1, 15.3 Hz), 4.16 (dd, 1H, J ¼ 6.1, 4.0 Hz), 3.89 (dd,
1H, J ¼ 4.0, 6.1 Hz), 2.30 (s, 3H), 1.15 (d, 3H, J ¼ 6.1 Hz); 13C
NMR (CDCl3, 100 MHz): d 154.6, 146.4, 137.8, 135.3, 132.8,
130.2, 128.5, 126.3, 121.9, 76.0, 70.1, 19.0, 17.8; Mass (ESI-MS):
m/z 220 (M + H)+; HRMS (ESI): m/z 220.1327 (M + H)+ (calculated
for C13H18O2N 220.1332).
1
0.09, CHCl3); IR (Neat): 3417, 2981, 1706, 1276 cmꢁ1; H NMR
(CDCl3, 300 MHz): d 6.94 (dd, 1H, J ¼ 15.6, 5.0 Hz), 6.11 (dd, 1H,
J ¼ 15.6, 1.5 Hz), 4.31–4.27 (m, 1H), 4.20 (q, 2H, J ¼ 7.1 Hz),
3.98–3.90 (m, 1H), 1.29 (t, 3H, J ¼ 7.1 Hz), 1.14 (d, 3H, J ¼
6.6 Hz); 13C NMR (CDCl3, 50 MHz): d 166.5, 145.8, 122.2, 74.5,
69.9, 60.5, 17.2, 14.0; anal. calcd for C8H14O4 (174.19): C, 55.16;
H, 8.10. Found: C, 55.12; H, 8.19%.
Molecular modeling
(E)-3-(4R,5R)-2,2,5-(E)-3-((4R,5S)-2,2,5-Trimethyl-1,3-dioxolan-
4-yl)prop-2-en-1-ol (22)
The calculations of this investigation have been carried out by
following the procedure given below. Fuzanin C (3a), fuzanin D
(4a) and (11R,12S)-4a were considered for computational
prediction of optical rotations. Initially, geometry optimization
was performed at B3LYP/6-31G (d) basis set and frequency
calculations were done for lowest energy conformer in order to
ascertain the minima. Optical rotation was calculated at 589.3
nm using B3LYP/Aug-CC-pVDZ method in gas phase for lowest
energy conformer of respective molecules.24 B3LYP/Aug-CC-
pVDZ method was opted based on the literature.22 The solvent
effect has been omitted for geometry optimizations and optical
rotation calculations, since a methodology does not yet exist
which predicts the solvent effects with uniform reliability.25 All
these calculations were performed using Gaussian 09
soware.26
According to the procedure 10, diol 21 (0.26 g, 1.49 mmol) gave
alcohol 22 (0.21 g, 86%) as colourless, viscous liquid; [a]D24
+
;
21.20 (c 0.1, CHCl3); IR (Neat): 3422, 2985, 1376, 1217, 772 cmꢁ1
1H NMR (CDCl3, 300 MHz): d 5.92 (td, 1H, J ¼ 15.4, 5.1 Hz), 5.70
(tdd, 1H, J ¼ 15.4, 7,7, 1.3 Hz), 4.53 (t, 1H, J ¼ 7.7 Hz), 4.34 (quin,
1H, J ¼ 6.4 Hz), 4.19 (m, 2H), 1.49 (s, 3H), 1.36 (s, 3H), 1.15 (d,
3H, J ¼ 6.4 Hz); 13C NMR (CDCl3, 100 MHz): d 133.5, 127.1,
108.0, 79.0, 74.0, 62.8, 28.2, 25.5, 16.1.
1-Phenyl-5-(((E)-3-((4R,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)-
allyl)sulfonyl)-1H-tetrazole (17)
According to the procedure 6, compound 22 (0.1 g, 0.58 mmol)
gave sulphone 17 (0.17 g, 81%); [a]2D4 + 1.12 (c 0.1, CHCl3); IR
(Neat): 2984, 1497, 1347, 1153, 763 cmꢁ1; 1H NMR (CDCl3, 300
MHz): d 7.69–7.56 (m, 5H), 5.95 (dd, 1H, J ¼ 15.1, 6.0 Hz), 5.85–
5.75 (m, 1H), 4.52–4.42 (m, 3H), 4.32 (t, 1H, J ¼ 6.7 Hz), 1.44 (s,
3H), 1.33 (s, 3H), 1.02 (d, 3H, 6.7 Hz); 13C NMR (CDCl3,
100 MHz): d 152.9, 140.3, 131.4, 129.6, 125.1, 116.1, 108.5, 78.0,
73.8, 59.0, 28.0, 25.3, 15.8; MS (ESI): m/z 364 (M + H)+; HRMS
(ESI): m/z 387.1093 [M + Na]+ (calculated for C16H20N4O4NaS
387.1097).
Biological activity
Cell culture. HT-29 (Colon cancer) cell line was grown as
adherent in RPMI medium, ME-180 (Cervical cancer), MCF-7
(Breast cancer) and MDA-MB-453 (Breast cancer) cell line were
grown as adherent in DMEM medium supplemented with 10%
fetal bovine serum, 100 mg mLꢁ1 penicillin, 200 mg mLꢁ1
streptomycin, 2 mM L-glutamine, and culture was maintained
in a humidied atmosphere with 5% CO2. All in vitro experi-
ments were performed during the exponential phase of cell
growth.
(2S,3R,4E,6E)-7-(3-Methylpyridin-2-yl)hepta-4,6-diene-2,3-diol
(11R,12S)-4a
Preparation of samples for cytotoxicity
According to the procedure 3a, compound 23 (0.05 g, 0.19
mmol) gave (11R,12S)-4a (0.02 g), and cis isomer (11R,12S)-4b
(0.01 g) as viscous, color less oils, (total yield 82%); [a]2D4 ꢁ 26.9
(c 0.04, CHCl3); IR (Neat): 3414, 2924, 2853, 1731, 1617,
995 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 8.42 (d, 1H, J ¼ 4.3 Hz),
7.49–7.40 (m, 2H), 7.06 (dd, 1H, J ¼ 7.5, 4.3 Hz), 6.80 (d, 1H, J ¼
20 mM stock solution for compounds was prepared in DMSO,
from the above stock various dilutions were made with sterile
PBS to get required concentration.
Cytotoxicity screening using MTT assay
15.1 Hz), 6.56 (dd, 1H, J ¼ 15.1, 11.1 Hz), 6.02 (dd, 1H, J ¼ 15.4, MTT assay was performed according to the method of Naidu
6.2 Hz), 4.23 (dd, 1H, J ¼ 6.2, 3.3 Hz), 3.93 (dd, 1H, J ¼ 6.2, et al.27 MTT assay is a standard colorimetric assay for measuring
3.3 Hz), 2.36 (s, 3H), 1.16 (d, 3H, J ¼ 6.2 Hz); 13C NMR (CDCl3, cellular proliferation. MTT is a tetrazolium salt, which is yellow
100 MHz): d 153.2, 146.9, 138.2, 134.3, 133.0, 132.4, 130.8, 128.2, in color and is photosensitive. MTT [3-(4,5-dimethylthiazol-2-yl)-
122.1, 75.9, 70.2, 18.7, 17.6; MS (ESI): m/z 220 (M + H)+; HRMS 2,5-diphenyl tetrazolium bromide] is taken by the living cells and
(ESI): m/z 220.1327 [M + H]+ (calculated for C13H18O2N reduced by a mitochondrial dehydrogenase enzyme to a purple
220.1332).
formazan product that is impermeable to the cell membrane.
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Solubilisation with solvents like DMSO leads to liberation of 12 (a) C. H. Srinivas, C. H. N. S. S. Pavan kumar, B. China Raju,
product and amount of purple formazan product is directly
related to the cell viability. 1 ꢃ 104 cells (counted by trypan blue
exclusion dye method) in 96-well plates were incubated with
series of concentrations of compounds for 48 h at 37 ꢀC in DMEM
with 10% FBS medium. Then the above media was replaced with
90 mL of fresh serum free media and 10 mL of MTT reagent (5 mg
mLꢁ1) and plates were incubated at 37 ꢀC for 4 h, there aer the
above media was replaced with 200 mL of DMSO and incubated at
37 ꢀC for 10 min. The absorbance at 570 nm was measured on a
spectrophotometer (spectra max, Molecular devices). IC50 values
V. Jayathirtha Rao, V. G. M. Naidu, S. Ramakrishna and
P. V. Diwan, Bioorg. Med. Chem. Lett., 2009, 19, 5915; (b)
M. Ravinder, P. S. Sadhu, P. Narender, G. Y. S. K. Swamy,
K. Ravi Kumar and V. Jayathirtha Rao, Synthesis, 2010, 573;
(c) P. A. Kumar, D. Raman, U. S. N. Murthy and
V. Jayathirtha Rao, Bioorg. Chem., 2009, 37, 46; (d)
P. A. Kumar, D. Raman, U. S. N. Murthy and V. Jayathirtha
Rao, Synth. Commun., 2010, 40, 686; (e) C. H. Srinivas,
C. H. N. S. S. Pavan Kumar, B. China Raju and
V. Jayathirtha Rao, Helv. Chim. Acta, 2011, 94, 669.
were determined from plot: % cell viability (from control) versus 13 (a) D. Xu, G. A. Crispino and K. B. Sharpless, J. Am.
concentration.
Chem.Soc., 1992, 114, 7570; (b) S. D. Garaas, T. J. Hunter
and G. A. O'Doherty, J. Org. Chem., 2002, 67, 2682.
14 A. D. Dunn, Org. Prep. Proced. Int., 1999, 31, 120.
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Acknowledgements
The authors thank the Director CSIR-IICT and Project Director
NIPER-Hyderabad for support. VJR thank ORIGIN-0108 for
funding. SNK, CH.N.S.S.P.K, E.S thank CSIR-New Delhi, for the
fellowships. This is main lab project (MLP) of IICT.
¯
R. Masuma, I. Kuwajima and S. Omura, Org. Lett., 2001, 3,
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16 (a) K. Sugimoto, Y. Kobayashi, A. Hori, T. Kondo,
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