The first stereoselective total synthesis of putaminoxin e and its epimer and evaluation of their biological properties

Article abstract of DOI:10.1002/ejoc.201101601

Putaminoxin E, a natural nonanolide, and its C-9 epimer were synthesized for the first time starting from pentane-1,5-diol and butyraldehyde. The synthetic sequences involve Maruoka asymmetric allylation, Sharpless kinetic resolution, and ring-closing metathesis as the key steps. The cytotoxic and antimicrobial activities of these compounds were evaluated. Putaminoxin E, a natural nonanolide, and its C-9 epimer were synthesized for the first time starting from pentane-1,5-diol and butyraldehyde. Copyright

Full text of DOI:10.1002/ejoc.201101601

FULL PAPER
DOI: 10.1002/ejoc.201101601
The First Stereoselective Total Synthesis of Putaminoxin E and Its Epimer and
Evaluation of Their Biological Properties[‡]
Chithaluri Sudhakar,[a] Parigi Raghavendar Reddy,[a] Chityal Ganesh Kumar,[b]
Pombala Sujitha,[b] and Biswanath Das*[a]
Keywords: Natural products / Kinetic resolution / Metathesis / Enantioselectivity / Biological activity
Putaminoxin E, a natural nonanolide, and its C-9 epimer
were synthesized for the first time starting from pentane-1,5-
and ring-closing metathesis as the key steps. The cytotoxic
and antimicrobial activities of these compounds were evalu-
diol and butyraldehyde. The synthetic sequences involve ated.
Maruoka asymmetric allylation, Sharpless kinetic resolution,
Introduction
Results and Discussion
Ten-membered lactonic compounds (nonanolides) are
commonly found as naturally occurring secondary metabo-
lites. Putaminoxins are the recent example of these com-
pounds.[1] Various putaminoxins have been isolated in small
amounts from culture filtrates of Phoma putaminoxum.[1]
This fungus is a causal agent of leaf necrosis of Erigeron
annuus, a weed widely found in fields and pastures. Some
of the putaminoxins are known to possess interesting phy-
totoxic activity.
Retrosynthetic analysis (Scheme 1) revealed that 1 can be
obtained from two fragments: olefinic alcohol 2 and olefinic
acid 3. Fragment 2 can be prepared from butyraldehyde 4,
whereas fragment 3 can be prepared from benzylic ether 5
generated from pentane-1,5-diol (6). Similarly, epimer 1a
can be obtained (Scheme 1) by the coupling of fragment 2a
with the same olefinic acid 3. Fragment 2a can also be pre-
pared from butyraldehyde (4).
In continuation of our work[2] on the stereoselective con-
struction of natural products we were interested in the total
synthesis of putaminoxin E. The structure of the compound
was established as 5-epi-6,7-dihydroputaminoxin (1) having
the stereochemistry of 5S and 9R.[1c,3] The synthesis of this
compound has not yet been reported. Herein we report the
first total synthesis of 1 and its C-9 epimer, 1a, and the
evaluation of their biological properties.
[‡] Synthetic Studies on Natural Products, 53; Part 52: D. B.
Shinde, B. S. Kanth, M. Srilatha, B. Das, Synthesis 2011, in
press.
Scheme 1. Retrosynthetic route to putaminoxin E and its epimer.
[a] Organic Division-I,
Uppal Road, Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: biswanathdas@yahoo.com
[b] Chemical Biology Laboratory,
Indian Institute of Chemical Technology,
Uppal Road, Hyderabad 500007, India
The present synthesis (Scheme 2) started with commer-
cially available butyraldehyde (4), which was subjected to
enantioselective Maruoka allylation[4] with titanium com-
plex (S,S)-I and allyltributyltin to form homoallylic alcohol
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C. Sudhakar, P. R. Reddy, C. G. Kumar, P. Sujitha, B. Das
FULL PAPER
2 with 97%ee (determined by chiral HPLC: Chiralcel OB- Grubbs first generation catalyst under high-dilution condi-
H; iPrOH/hexane, 1:99). When aldehyde 4 was treated with tion to furnish cyclic compound 12 (E:Z = 9:1). The
(R,R)-I and allyltributyltin, homoallylic alcohol 2a was ob- Grubbs first generation catalyst was used here, as the sec-
tained with equal enantioselectivity.
ond generation catalyst is more expensive and improved the
yield of product 12 (derived from 11) only to a small extent
(59% yield, E/Z = 9:1).[6c,6d] When the silyl group of 11 was
deprotected and the corresponding product was subjected
to ring-closing metathesis by using Grubbs first generation
catalyst the yield was also found to be lower (35%) and the
conversion took longer (48 h). Finally, treatment of 12 with
H2 in the presence of Pd/C followed by TBDPS deprotec-
tion with TBAF produced target molecule 1, whose spectral
properties were found to be identical to those of natural
putaminoxin E.[1c] The optical rotation of the compound
was not reported earlier.
Scheme 2. Reagents and conditions: (a) allyltributyltin, (S,S)-I, dry
DCM, –15 to 0 °C, 72 h, 89%; (b) allyltributyltin, (R,R)-I, dry
DCM, –15 to 0 °C, 72 h, 89%.
Olefinic acid fragment 3 was synthesized (Scheme 3) by
converting pentane-1,5-diol (6) into benzylic ether 7 by
treatment with benzyl bromide and NaH. Compound 7
underwent Swern oxidation, and the corresponding alde-
hyde was treated with vinylmagnesium bromide to afford
racemic alcohol 8. The Sharpless kinetic resolution[5] of 8
by using (+)-DET, Ti(OiPr)4, and TBHP produced desired
chiral alcohol 5 with 97%ee (determined by chiral HPLC),
which was separated from the epoxy product by column
chromatography. The hydroxy group of 5 was protected as
the TBDPS ether to form compound 9 upon treatment with
TBDPSCl and imidazole, and subsequently, its benzylic
ether moiety was deprotected with DDQ to produce alcohol
10. Compound 10 was then oxidized with PDC in DMF to
generate required olefinic acid 3.
Scheme 4. Reagents and conditions: (a) DCC, 2, DMAP, DCM,
0 °C to r.t., 3 h, 72%. (b) DCC, 2a, DMAP, DCM, 0 °C to r.t., 3 h,
72%. (c) 1. 12, Grubbs first generation catalyst (5 mol-%), DCM,
reflux, 28 h, 56%, (E/Z = 9:1); 2. 12a, Grubbs first generation cata-
lyst (5 mol-%), DCM, reflux, 22 h, 59%, (E/Z = 9:1). (d) 1. H2/Pd-
C, EtOAc, r.t., 1 h; 2. TBAF, THF, 1 h, overall yield 61%.
Similarly, epimer 1a of putaminoxin E was synthesized
by coupling 3 with alcohol 2a followed by ring-closing me-
tathesis of resulting ester 11a by using Grubbs first genera-
tion catalyst to produce cyclic ester 12a (E/Z = 9:1), which
was subsequently treated with H2 in the presence of Pd/C
followed by TBDPS deprotection with TBAF (Scheme 4).
Scheme 3. Reagents and conditions: (a) NaH, BnBr, dry THF, 0 °C
to r.t., 2 h, 78%. (b) 1. Oxalyl chloride, DMSO, Et3N, –78 °C, 3 h;
2. vinylMgBr, 0 °C to r.t., 2 h, 79%. (c) (+)-DET, Ti(OiPr)4, –20 °C,
TBHP, 45%. (d) TBDPSCl, imidazole, dry DCM, 0 °C to r.t., 2 h,
90%. (e) DDQ, DCM/H2O (19:1) reflux, 2 h, 86%. (f) PDC, DMF,
r.t., 2 h, 78%.
Putaminoxin E (1) and C-9 epimer 1a were examined for
in vitro cytotoxicity against five cancerous cell lines: A-549
(human alveolar adenocarcinoma), MDA-MB-231 (human
breast adenocarcinoma), MCF-7 (human breast adenocar-
cinoma) HeLa (human cervical cancer), and Neuro-2a
The coupling of 3 with alcohol 2 was carried out with (mouse neuroblastoma). Doxorubicin was used as the posi-
DCC and DMAP to afford ester 11 (Scheme 4). Compound tive control. The MTT assay (according to the method of
11 underwent ring-closing metathesis[6] by employing Mosmann[7]) was utilized to evaluate the activity. The IC50
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Stereoselective Total Synthesis of Putaminoxin E and Its Epimer
value for each cell line was determined after four individual
observations (Table 1). The results showed that both 1 and
1a exhibited significant cytotoxic activity against all of the
five cell lines. However, the former showed higher activity
against the MDA-MB-231 cell line, whereas the latter
showed higher activity against A-549, Neuro-2a, and HeLa
cell lines.
Experimental Section
General: All commercially available reagents were used directly
without further purification unless otherwise stated. The solvents
used were all of AR grade and were distilled under a positive pres-
sure of dry nitrogen wherever necessary. The progress of the reac-
tions was monitored by analytical thin-layer chromatography
(TLC) performed on Merck Silica Gel 60 F254 plates. Column
chromatography was carried out by using silica gel 60–120 mesh
(Qingdao Marine Chemical, China). IR spectra were recorded with
a Perkin–Elmer RX1 FTIR spectrophotometer. Mass spectra were
recorded with a VG-Autospec micromass. NMR spectra were re-
corded with a Gemini 200 MHz spectrometer with tetramethylsil-
ane as the internal standard by using CDCl3. Yields are reported
for purified compounds and are not optimized. Optical rotations
were measured with a JASCO DIP 300 digital polarimeter at 25 °C.
Table 1. Cytotoxic activity of 1 and 1a.
Cell line
IC50 [μm]
Epimer
1a
Putaminoxin E
Doxorubicin
(control)
(1)
A-549
Neuro-2a
HeLa
MDA-MB-231
MCF-7
11.27
20.36
37.36
6.79
8.29
10.65
6.97
9.01
24.4
1
1.2
Ͻ1
Ͻ1
1
(R)-Hept-1-en-4-ol (2): To a stirred solution of TiCl4 (0.018 g,
0.10 mmol) in DCM (5 mL) was added dried Ti(OiPr)4 (0.05 g,
0.20 mmol) at 0 °C under an atmosphere of nitrogen. The solution
was warmed to room temperature. After 1 h, silver(I) oxide
(0.048 g, 0.20 mmol) was added at room temperature, and the
whole mixture was stirred for 5 h under exclusion of direct light.
The mixture was diluted with DCM (10 mL) and treated with (S)-
binaphthol (0.118 g, 0.41 mmol) at room temperature over 2 h to
furnish chiral (S,S)-I. In situ generated (S,S)-I was cooled to –15 °C
and treated sequentially with butyraldehyde (0.150 g, 2.08 mmol)
in DCM (50 mL) and allyltributyltin (1.032 g, 3.12 mmol) at
–15 °C. The whole mixture was warmed to 0 °C and stirred for
16 h. The reaction mixture was quenched with saturated NaHCO3
(10 mL) and extracted with diethyl ether (100 mL). The organic
extracts were dried with Na2SO4. Evaporation of the solvents and
purification of the residue by column chromatography (ethyl acet-
ate/hexane, 3:7) afforded pure 2 (0.210 g, 89%) as a yellowish li-
24.4
The antimicrobial activity of putaminoxin E (1) and epi-
mer 1a was also tested against several bacterial organisms:
Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC
121), Staphylococcus aureus MLS16 (MTCC 2940), Micro-
cocus luteus (MTCC 2470), Klebsiella planticola (MTCC
530), Escherichia coli (MTCC 739), and Pseudomonas arru-
ginosa (MTCC 2453) Neomycin was used as the positive
control and microtiter broth dilution method was applied
to determine the activity.[8] The minimum inhibitory con-
centration (MIC) value with each pathogen was evaluated
after four individual observations (Table 2).
quid.[9] [α]2D5 = –17.4 (c = 1.1, CHCl ). IR (neat): ν = 3377, 1623,
˜
3
1
1462, 1341, 1275 cm–1. H NMR (200 MHz, CDCl3): δ = 5.79 (m
Table 2. Antimicrobial activity of 1 and 1a.
1 H), 5.13–5.02 (m, 2 H), 3.58 (m, 1 H), 2.30–2.04 (m, 2 H), 1.48–
1.31 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 134.8, 117.6, 70.1, 41.5, 38.3, 18.2, 13.8 ppm. MS (EI):
m/z = 115 [M + H]+.
Test pathogen
IC50 [μm]
Putaminoxin E Epimer Neomycin
(1)
1a
(control)
S. aureus (MTCC 96)
4.68
–
9.37
–
–
9.37
–
–
–
–
–
–
18.75
18.75
18.75
18.75
18.75
18.75
18.75
(S)-Hept-1-en-4-ol (2a): To a stirred solution of TiCl4 (0.018 g,
0.10 mmol) in DCM (5 mL) was added dried Ti(OiPr)4 (0.05 g,
0.20 mmol) at 0 °C under an atmosphere of nitrogen. The solution
was warmed to room temperature. After 1 h, silver(I) oxide
(0.048 g, 0.20 mmol) was added at room temperature, and the
whole mixture was stirred for 5 h under exclusion of direct light.
The mixture was diluted with DCM (10 mL) and treated with (R)-
binaphthol (0.118 g, 0.41 mmol) at room temperature over 2 h to
furnish chiral (R,R)-I. In situ generated (R,R)-I catalyst was cooled
to –15 °C and treated sequentially with butyraldehyde (0.15 g,
2.08 mmol) in DCM (50 mL) and allyltributyltin (1.032 g,
3.12 mmol) at –15 °C. The whole mixture was warmed to 0 °C and
stirred for 16 h. The reaction mixture was quenched with saturated
NaHCO3 (10 mL) and extracted with diethyl ether (100 mL). The
organic extracts were dried with Na2SO4. Evaporation of the sol-
vents and purification of the residue by column chromatography
(ethyl acetate/hexane, 3:7) afforded pure 2a (210 mg, 89%) as a
yellowish liquid. [α]2D5 = +19.4 (c = 1.1, CHCl3). The characteriza-
tion data (1H NMR, 13C NMR, and MS) of 2a were found to be
the same as those of 2.
B. subtilis (MTCC 121)
S. aureus MLS 16 (MTCC 2940)
M. luteus (MTCC 2470)
K. planticola (MTCC 530)
E. coli (MTCC 739)
–
4.68
P. arruginosa (MTCC 2453)
Putaminoxin E (1) showed impressive activity against
P. arruginosa, whereas epimer 1a showed activity against
S. aureus and E. coli. Thus, it is assumed that the stereo-
chemistry of 1 and 1a at C-9 has an important role on both
the cytotoxicity and microbial activity of these compounds.
Conclusions
In conclusion, we have developed the first total synthesis
of the natural nonanolide putaminoxin E and its C-9 epi-
mer starting from pentane-1,5-diol and butyrolactone in-
volving some simple steps. The cytotoxic and antimicrobial
properties of both of these compounds have also been re-
ported.
5-(Benzyloxy)pentan-1-ol (7): To a stirred solution of NaH in dry
THF (0.276 g, 11.53 mmol) was slowly added alcohol 6 (1 g,
9.61 mmol) in anhydrous THF (15 mL) at 0 °C. After stirring for
10 min, benzyl bromide (1.14 mL, 9.61 mmol) was added dropwise.
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C. Sudhakar, P. R. Reddy, C. G. Kumar, P. Sujitha, B. Das
FULL PAPER
The reaction mixture was stirred at room temperature for 4 h and
then quenched with cold water (20 mL). The mixture was extracted
with EtOAc (3ϫ50 mL), and the combined organic phase was
dried with anhydrous Na2SO4 and concentrated in vacuo. The resi-
due was purified by column chromatography (ethyl acetate/hexane,
azole (0.306 g, 4.5 mmol) in dry DCM (20 mL) was added
TBDPSCl (0.69 mL, 2.7 mmol) portionwise at 0 °C. The mixture
was stirred at room temperature for 2 h and then quenched with
H2O. The DCM layer was separated, and the aqueous layer was
extracted with additional DCM (2ϫ20 mL). The combined or-
ganic layer was washed with H2O (20 mL) and brine (20 mL) and
dried (Na2SO4). The solvent was removed in vacuo, and the residue
was purified by column chromatography (ethyl acetate/hexane, 2:8)
7:3) to afford pure 7 (1.45 g, 78%) as a light yellow oil.[10] IR (neat):
1
ν = 3388, 1454, 1363, 1207 cm–1. H NMR (200 MHz, CDCl ): δ
˜
3
= 7.32–7.18 (m, 5 H), 4.45 (s, 2 H), 3.54 (t, J = 7.0 Hz, 2 H), 3.42
(t, J = 7.0 Hz, 2 H), 2.61 (br. s, 1 H), 1.68–1.34 (m, 6 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 138.5, 128.2, 127.2, 127.1, 72.9, 70.0,
62.9, 32.2, 29.1, 22.2 ppm. MS (ESI): m/z = 195 [M + H]+.
to afford pure 9 (0.927 g, 90%) as a yellowish oil. IR (neat): ν =
˜
1456, 1363, 1251 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.78–7.61
(m, 5 H), 7.43–7.22 (m, 10 H), 5.78 (m, 1 H), 5.01–4.90 (m, 2 H),
4.46 (s, 2 H), 4.13 (m, 1 H), 3.33 (t, J = 7.0 Hz, 2 H), 1.54–1.22
(m, 6 H), 1.09 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
140.9, 138.8, 136.0, 135.9, 134.9, 134.5, 129.9, 129.8, 128.5, 128.1,
128.0, 127.9, 127.8, 114.6, 74.5, 72.8, 70.2, 37.2, 29.8, 27.1, 26.5,
21.1 ppm. MS (ESI): m/z = 476 [M + NH4]+. HRMS (ESI): calcd.
for C30H39O2Si [M + H]+ 459.2721; found 459.2714.
7-(Benzyloxy)hept-1-en-3-ol (8): To a stirred solution of oxalyl
chloride (0.92 mL, 15.10 mmol) in dry DCM (30 mL) was added
DMSO (0.69 mL, 22.65 mmol) at –78 °C, and the mixture was
stirred at the same temperature for 0.5 h. A solution. of 5-phen-
ylpentan-1-ol (7; 1.45 g, 7.55 mmol) in DCM (20 mL) was added
at –78 °C, and the mixture was stirred for 1.5 h at the same tem-
perature. Et3N (5.25 mL, 37.75 mmol) was added at 0 °C, and the
mixture was stirred for an additional 30 min. The mixture was di-
luted with H2O (30 mL) and extracted with DCM (2ϫ50 mL). The
combined organic layer was washed with brine (20 mL), dried
(Na2SO4), and concentrated to give the corresponding aldehyde
(1.21 g, 85%) as a colorless liquid. Because of extensive oxidation
of the aldehyde to the corresponding acid it was used immediately
in the next step. Under a N2 atmosphere, a solution of vinylmagne-
sium bromide (1 m in THF, 7.6 mL) was added to a solution of 5-
phenylpentanal (1.21 g, 6.3 mmol) in dry THF (20 mL) at 0 °C, and
the mixture was allowed to reach room temperature. After stirring
the mixture for 2 h, the reaction was quenched by the addition of
sat. aq. NH4Cl (20 mL). The mixture was extracted with EtOAc
(2ϫ50 mL) and dried (Na2SO4). Evaporation of the solvents re-
sulted in the crude alcohol, which was purified by column
chromatography (ethyl acetate/hexane, 5:5) to afford pure 8 (1.10 g,
(R)-5-(tert-Butyldiphenylsilyloxy)hept-6-en-1-ol (10): To a stirred
solution of 9 (0.927 g, 2.02 mmol) in DCM/water (19:1, 5 mL) was
added DDQ (0.918 g, 4.04 mmol), and the mixture was stirred at
reflux for 4 h. Saturated aq. NaHCO3 (5 mL) was added to the
reaction mixture, which was extracted with DCM (3ϫ10 mL). The
combined organic layer was washed with water (5 mL) and brine
(5 mL), dried with Na2SO4, and concentrated. The crude residue
was purified by column chromatography (ethyl acetate/hexane, 7:3)
to afford pure 10 (0.639 g, 86%) as colorless syrup. IR (neat): ν =
˜
3363, 1426, 1397, 1259 cm–1. 1H NMR (200 MHz, CDCl3): δ =
7.71–7.60 (m, 4 H), 7.45–7.30 (m, 6 H), 5.80 (m, 1 H), 5.05–4.94
(m, 2 H), 4.13 (m, 1 H), 3.49 (t, J = 7.0 Hz, 2 H), 1.51–1.20 (m, 6
H), 1.09 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 139.9,
136.1, 136.0, 134.6, 134.3, 129.8, 129.7, 127.6, 127.5, 114.5, 74.8,
62.9, 37.2, 32.9, 27.4, 19.9, 19.5 ppm. MS (ESI): m/z = 391 [M +
Na]+. HRMS (ESI): calcd. for C23H32O2SiNa [M + Na]+ 391.2064;
found 391.2035.
79%) as a viscous liquid. The characterization data (1H NMR, 13
C
NMR, and MS) of 8 were found to be the same as those of 5.
(R)-5-(tert-Butyldiphenylsilyloxy)hept-6-enoic Acid (3): To a stirred
solution of 10 (0.639 g, 1.7 mmol) in DMF (5 mL) was added PDC
(1.01 g, 3.4 mmol) at room temperature. After 10 h, the mixture
was quenched with cold water (5 mL) and extracted with EtOAc
(3ϫ10 mL). The combined organic layer was washed with KHSO4
(15 mL, 1 mol/L), water (10 mL), and brine (10 mL), dried with
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography (ethyl acetate/hexane, 9:1) to af-
(R)-7-(Benzyloxy)hept-1-en-3-ol (5): To a suspension of powered
molecular sieves (4 Å, 50 mg) in dry DCM (15 mL) was sequen-
tially added Ti(OiPr)4 (0.71 mL, 2.5 mmol) and (+)-DET (0.5 mL,
3 mmol) at –20 °C. After stirring for 30 min, allyl alcohol 8 (1.10 g,
5 mmol) in dry DCM (15 mL) was added, and stirring was contin-
ued for another 30 min at the same temperature. Then, TBHP (4 m
in toluene, 0.68 mL, 2.75 mmol) was added, and after stirring for
another 5 h at the same temperature, the reaction mixture was
quenched by the addition of water (15 mL). It was allowed to re-
main at room temperature with stirring for 30 min. After re-cooling
to 0 °C, an aqueous solution of NaOH (30% w/v, 7 mL saturated
with brine) was added, and the mixture was stirred at 0 °C for 1 h.
The solvent was removed under reduced pressure, and the residue
was extracted with diethyl ether (3ϫ20 mL). The combined or-
ganic extract was washed with brine (2ϫ10 mL), dried with anhy-
drous Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography (ethyl acetate/hexane, 5:5) to afford
ford pure 3 (0.515 g, 78%) as a viscous light yellow liquid. [α]2D5
=
+9.5 (c = 0.4, CHCl ). IR (neat): ν = 3446, 1709, 1426, 1261 cm–1.
˜
3
1H NMR (200 MHz, CDCl3): δ = 7.68–7.60 (m, 4 H), 7.42–7.28
(m, 6 H), 5.75 (m, 1 H), 5.06–4.95 (m, 2 H), 4.12 (m, 1 H), 2.19 (t,
J = 7.0 Hz, 2 H), 1.62–1.41 (m, 4 H), 1.09 (s, 9 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 179.3, 140.5, 136.1, 134.2, 134.1, 129.9,
128.0, 127.9, 115.0, 74.1, 36.9, 34.1, 27.0, 19.8, 19.7 ppm. MS
(ESI): m/z = 405 [M + Na]+. HRMS (ESI): calcd. for C23H30O3-
SiNa [M + Na]+ 405.1861; found 405.1868.
pure compound 5 (0.495 g, 45%) as a viscous yellow liquid. [α]2D5
=
(R)-[(R)-Hept-1-en-4-yl]"Ͼ5-(tert-Butyldiphenylsilyloxy)hept-6-
enoate (11): To a stirred solution of acid 3 (0.25 g, 0.65 mmol) and
DMAP (0.039 g, 0.32 mmol) in anhydrous DCM (15 mL) was
added alcohol 2 (0.148 g, 1.3 mmol) in DCM (4 mL) at room tem-
perature. The reaction mixture was cooled to 0 °C and DCC
(0.401 g, 1.95 mmol) in DCM (3 mL) added. The mixture was
stirred for 10 min at 0 °C and then brought to room temperature
and stirred for 8 h. The white precipitate formed was filtered off
and washed with 2 n HCl, 5% NaHCO3, and finally water. Esterifi-
cation product 11 was purified by column chromatography (ethyl
acetate/hexane, 1:9) to afford pure 11 (0.22 g, 72%) as a colorless
+14.2 (c = 0.6, CHCl ). IR (neat): ν = 3375, 1456, 1353, 1251 cm–1.
˜
3
1H NMR (200 MHz, CDCl3): δ = 7.37–7.20 (m, 5 H), 5.80 (m, 1
H), 5.20 (dd, J = 14.0, 2.0 Hz, 1 H), 5.05 (dd, J = 8.0, 2.0 Hz, 1
H), 4.49 (s, 2 H), 4.05 (m, 1 H), 3.42 (d, J = 7.0 Hz, 2 H), 1.66–
1.41 (m, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 141.1, 138.3,
128.2, 127.9, 127.8, 104.8, 73.0, 72.9, 70.0, 36.4, 29.5, 22.1 ppm.
MS (ESI): m/z = 221 [M + H]+. HRMS (ESI): calcd. for C14H21O2
[M + H]+ 221.1531; found 221.1536.
(R)-[7-(Benzyloxy)hept-1-en-3-yloxy](tert-butyl)diphenylsilane (9):
To a stirred solution of alcohol 5 (0.495 g, 2.25 mmol) and imid-
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Stereoselective Total Synthesis of Putaminoxin E and Its Epimer
syrup. [α]2D5 = +13.3 (c = 0.3, CHCl ). IR (neat): ν = 1736, 1634,
5.75 (m, 1 H), 5.00 (m, 1 H), 4.90 (m, 1 H), 4.20 (m, 1 H), 2.36–
2.21 (m, 2 H), 2.24–2.12 (m, 2 H), 1.72–1.38 (m, 8 H), 1.05 (m, 9
H), 0.79 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 173.0, 140.9, 136.1, 136.0, 134.6, 134.5, 130.0, 129.9, 127.8, 127.7,
115.0, 75.2, 74.0, 37.9, 37.1, 35.0, 34.4, 27.2, 20.9, 19.9, 19.0,
14.2 ppm. MS (ESI): m/z = 473 [M + Na]+. HRMS (ESI): calcd.
for C28H38O3SiNa [M + Na]+ 473.2571; found 473.2487.
˜
3
1450, 1260 cm–1. H NMR (200 MHz, CDCl3): δ = 7.69–7.59 (m,
1
4 H), 7.41–7.28 (m, 6 H), 5.80–5.60 (m, 2 H), 5.08–4.82 (m, 5 H),
4.11 (m, 1 H), 2.24 (t, J = 7.0 Hz, 2 H), 2.10 (t, J = 7.0 Hz, 2 H),
1.60–1.41 (m, 6 H), 1.31 (m, 2 H), 1.06 (m, 9 H), 0.89 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 173.2, 141.0, 136.8,
134.8, 134.7, 134.2, 129.9, 128.0, 127.9, 117.9, 115.1, 74.3, 72.2,
39.0, 37.1, 36.0, 27.1, 20.5, 19.3, 18.4, 13.9 ppm. MS (ESI): m/z =
479 [M + H]+. HRMS (ESI): calcd. for C30H42O3SiNa [M + Na]+
501.2800; found 501.2804.
(6S,10R)-6-Hydroxy-10-propyloxecan-2-one (1): Palladium on char-
coal (10%, 0.03 g) was added to a solution of 12 (0.115 g,
0.25 mmol) in EtOAc (6 mL), and the mixture was hydrogenated
for 1 h. The solution was filtered through Celite and washed well
with EtOAc. The filtrate was concentrated under reduced pressure.
This residue was dissolved in THF and then treated with TBAF in
THF (1 m in THF, 0.5 mL, 0.5 mmol) at 0 °C. The mixture was
stirred for 1 h and then quenched with water (20 mL). The mixture
was extracted with ethyl acetate (50 mL). The organic extracts were
washed with brine (30 mL) and dried with anhydrous Na2SO4, and
the solvent was then evaporated under reduced pressure to yield
the crude product, which was purified by column chromatography
(ethyl acetate/hexane, 4:6) to afford pure 1 (0.033 g, 61%) as a col-
(R)-[(S)-Hept-1-en-4-yl] 5-(tert-Butyldiphenylsilyloxy)hept-6-enoate
(11a): To a stirred solution of acid 3 (0.25 g, 0.65 mmol) and
DMAP (0.039 g, 0.32 mmol) in anhydrous DCM (15 mL) was
added alcohol 2a (0.148 g, 1.3 mmol) in DCM (4 mL) at room tem-
perature. The reaction mixture was cooled to 0 °C and DCC
(0.401 g, 1.95 mmol) in DCM (3 mL) added. The mixture was
stirred for 10 min at 0 °C and then brought to room temperature
and stirred for 8 h. The white precipitate formed was filtered off
and washed with 2 n HCl, 5% NaHCO3, and finally water. Esterifi-
cation product 11a was purified by column chromatography (ethyl
acetate/hexane, 1:9) to afford pure 11a (0.22 g, 72%) as a colorless
orless liquid. [α]2D5 = +14.8 (c = 0.2, CHCl ). IR (neat): ν = 3455,
˜
3
1730, 1449, 1262 cm–1. H NMR (200 MHz, CDCl3): δ = 4.91 (m,
1
syrup. [α]2D5 = +5.6 (c = 0.3, CHCl ). IR (neat): ν = 1736, 1634,
˜
3
1450, 1260 cm–1. H NMR (200 MHz, CDCl3): δ = 7.68–7.60 (m,
1
1 H), 4.08 (m, 1 H), 2.40–2.31 (m, 2 H), 2.08–1.43 (m, 14 H), 1.08
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 172.0,
76.0, 69.9, 35.5, 35.2, 32.0, 29.9, 29.7, 21.0, 20.9, 18.8, 14.1 ppm.
MS (ESI): m/z = 237 [M + Na]+. HRMS (ESI): calcd. for
C12H22O3Na [M + Na]+ 237.1461; found 237.1458.
4 H), 7.41–7.29 (m, 6 H), 5.79–5.62 (m, 2 H), 5.04–4.83 (m, 5 H),
4.12 (m, 1 H), 2.29–2.21 (m, 2 H), 2.11 (t, J = 7.0 Hz, 2 H), 1.56–
1.21 (m, 8 H), 1.07 (m, 9 H), 0.99 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 172.5, 140.8, 136.1, 136.0, 134.1,
134.0, 133.9, 130.0, 129.9, 127.8, 127.7, 117.9, 114.6, 74.1, 72.3,
39.1, 36.9, 36.1, 34.3, 27.1, 20.2, 19.8, 18.8, 14.0 ppm. MS (ESI):
m/z = 479 [M + H]+. HRMS (ESI): calcd. for C30H42O3SiNa [M
+ Na]+ 501.2800; found 501.2804.
(6S,10S)-6-Hydroxy-10-propyloxecan-2-one (1a): Palladium on
charcoal (10%, 0.03 g) was added to a solution of 12a (0.124 g,
0.28 mmol) in EtOAc (6 mL), and the mixture was hydrogenated
for 1 h. The solution was filtered through Celite and washed well
with EtOAc. The filtrate was concentrated under reduced pressure.
This residue was dissolved in THF and then treated with TBAF in
THF (1 m in THF, 0.5 mL, 0.5 mmol) at 0 °C. The mixture was
stirred for 1 h and then quenched with water (20 mL). The mixture
was extracted with ethyl acetate (50 mL). The organic extracts were
washed with brine (30 mL) and dried with anhydrous Na2SO4, and
the solvent was then evaporated under reduced pressure to yield
the crude product, which was purified by column chromatography
(ethyl acetate/hexane, 4:6) to afford pure 1a (0.036 g, 61%) as a
(6R,10R,E)-6-(tert-Butyldiphenylsilyloxy)-10-propyl-3,4,5,6,9,10-
Hexahydro-2H-oxecin-2-one (12): To a stirred solution of bis(tricy-
clohexylphosphanyl)dichlororuthenium(IV) (Grubbs first genera-
tion catalyst; 0.008 g, 5 mol-%) in DCM (40 mL) at 55 °C was
added 11 (0.22 g, 0.46 mmol) dissolved in DCM (10 mL). The re-
sulting mixture was stirred for 28 h, by which time all of the start-
ing material had been consumed (TLC). The solvent was removed
under reduced pressure to yield the crude product, which was puri-
fied by column chromatography (ethyl acetate/hexane, 2:8) to af-
ford pure (E)-12 (0.115 g, 56%) as a yellow oil. [α]2D5 = –12.6 (c =
colorless liquid. [α]2D5 = +8.1 (c = 0.2, CHCl ). IR (neat): ν = 3455,
˜
3
1730, 1449, 1262 cm–1. H NMR (200 MHz, CDCl3): δ = 4.92 (m,
1
0.2, CHCl ). IR (neat): ν = 1736, 1634, 1450, 1260 cm–1. 1H NMR
˜
3
1 H), 4.06 (m, 1 H), 2.39–2.28 (m, 2 H), 2.11–1.38 (m, 14 H), 0.98
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 172.0,
76.1, 69.9, 35.4, 35.2, 32.1, 29.8, 29.7, 21.1, 20.7, 18.9, 14.1 ppm.
MS (ESI): m/z = 237 [M + Na]+. HRMS (ESI): calcd. for
C12H22O3Na [M + Na]+ 237.1461; found 237.1468.
(200 MHz, CDCl3): δ = 7.70–7.59 (m, 4 H), 7.41–7.28 (m, 6 H),
5.74 (m, 1 H), 4.97 (m, 1 H), 4.81 (m, 1 H), 4.12 (m, 1 H), 2.31–
2.16 (m, 2 H), 2.10 (t, J = 7.0 Hz, 2 H), 1.61–1.23 (m, 8 H), 1.08 (m,
9 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 173.0, 140.9, 136.1, 136.0, 134.3, 134.2, 130.0, 129.9, 127.9, 127.8,
115.2, 74.2, 73.1, 37.9, 37.2, 36.2, 34.8, 27.1, 20.2, 19.8, 18.9,
14.1 ppm. MS (ESI): m/z = 473 [M + Na]+. HRMS (ESI): calcd.
for C28H38O3SiNa [M + Na]+ 473.2487; found 473.2571.
Acknowledgments
The authors are thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial support.
(6R,10S,E)-6-(tert-Butyldiphenylsilyloxy)-10-propyl-3,4,5,6-9,10-
hexahydro-2H-oxecin-2-one (12a): To a stirred solution of bis(tricy-
clohexylphosphanyl)dichlororuthenium(IV) (Grubbs first genera-
tion catalyst; 0.008 g, 5 mol-%) in DCM (40 mL) at 55 °C was
added 11a (0.22 g, 0.46 mmol) dissolved in DCM (10 mL). The re-
sulting mixture was stirred for 22 h, by which time all of the start-
ing material had been consumed (TLC). The solvent was removed
under reduced pressure to yield the crude product, which was puri-
fied by column chromatography (ethyl acetate/hexane, 2:8) to af-
ford pure (E)-12a (0.124 g, 59%) as a yellow oil. [α]2D5 = +20.1 (c =
[1] a) A. Evideute, R. Lanzetta, R. Capparo, R. Andolfi, A. Botta-
lico, M. Vurro, M. C. Zonno, Phytochemistry 1995, 40, 1637–
1641; b) A. Evidente, R. Lanzetta, R. Capparo, A. Andolfi, M.
Vurro, M. C. Zonno, Phytochemistry 1997, 44, 1041–1045; c)
A. Evideute, R. Capparo, A. Andolfi, M. Vurro, M. C. Zonno,
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0.2, CHCl ). IR (neat): ν = 1736, 1634, 1450, 1260 cm–1. 1H NMR
˜
3
(200 MHz, CDCl3): δ = 7.69–7.60 (m, 4 H), 7.41–7.30 (m, 6 H),
Eur. J. Org. Chem. 2012, 1253–1258
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1257

C. Sudhakar, P. R. Reddy, C. G. Kumar, P. Sujitha, B. Das
FULL PAPER
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Received: November 4, 2011
Published Online: December 9, 2011
1258
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1253–1258