Stereocontrolled Total Synthesis of Nonenolide

Article abstract of DOI:10.1021/acs.jnatprod.8b00001

Nonenolide (1) was first isolated from the entomopathogenic fungus Cordyceps militaries BCC2816 and exhibited good antimalarial activity against Plasmodium falciparum K1. Structurally, it features a decanolide with a trans-double bond attached to two chir

Full text of DOI:10.1021/acs.jnatprod.8b00001

Article
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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Stereocontrolled Total Synthesis of Nonenolide
Purushotham Reddy Sudina,† Damoder Reddy Motati,*,†,‡ and Aravind Seema*,§
†Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
§Department of Chemistry, Osmania University, Hyderabad-500007, India
S
* Supporting Information
ABSTRACT: Nonenolide (1) was first isolated from the entomopathogenic
fungus Cordyceps militaries BCC2816 and exhibited good antimalarial activity
against Plasmodium falciparum K1. Structurally, it features a decanolide with a
trans-double bond attached to two chiral hydroxy groups, making the total
synthesis of the exclusive isomer of 1 more difficult. Herein, we report the
successful synthesis of 1 by employing a MacMillan α-hydroxylation to generate
three chiral centers in both the key fragments, starting from 1,6-hexanediol and
1,4-butanediol, followed by Steglich esterification of compounds 2 and 3. The exclusive E-isomer was obtained via a ring-closing
metathesis of the mono-PMB-protected diene 19. Deprotection provided the required natural product 1.
aturally occurring 10-membered macrolides, commonly
known as nonenolides or decanolides, have attracted
profile in combination with the novel structural features of 1
made it a highly attractive target for total synthesis. The first
total synthesis of 1 was reported by Grubbs et al. in 2007.9 For
the construction of the 10-membered lactone, Yamaguchi
esterification followed by RCM reaction was carried out, giving
a mixture of E- and Z-isomers. Deprotection of the p-
methoxybenzyl ether (PMB) groups provided an inseparable
mixture of 1 with the E-isomer as a major product. An extensive
study of RCM reaction conditions with the PMB-protected
substrate and other model substrates gave the exclusive Z-
isomer of 1 and exclusive isomers of desmethyl nonenolide
molecules. In 2008, the She group reported the synthesis of 1
as a major isomer obtained using RCM conditions after
investigating a range of protecting groups.10 Furthermore,
Meshram et al. reported11 the synthesis of two key fragments
from L-(−)-malic acid following the reported procedure for the
RCM reaction by Grubbs,9 which provided an inseparable
mixture of E- and Z-isomers of 1. Additionally, the Willis group
reported the synthesis of 1 from an iodoalkene via the
diastereoselective Nozaki−Hiyama−Kishi cyclization method
as a key ring-closing reaction.12 Here we report an expedient
and stereocontrolled synthesis of 1 using an approach that
combines the MacMillan α-hydroxylation and RCM reaction.
The synthesis of fragments (2 and 3) was carried out from the
inexpensive, achiral starting materials 1,6-hexanediol and 1,4-
butanediol.
N
considerable attention owing to their interesting and potent
biological properties1,2 that include antimalarial activity,1b
cholesterol biosynthesis inhibition,1d and antibacterial,1a anti-
inflammatory,1g cytotoxic,2c,d and herbicidal activity.1f The
majority of these compounds were isolated as secondary
metabolites from terrestrial and marine source.1a,b,d,f−h The first
natural 10-membered lactone, jasmine ketolactone, was isolated
in 1942 from the essential oil of Jasminum grandiflorium.3 The
first bioactive 10-membered macrolide, diplodialide A, which
was isolated in 1975, exhibited steroid hydroxylase inhibitory
activity.4 Moreover, the most popular method for the synthesis
of macrolides was lactonization until the discovery of ring-
closing metathesis (RCM) reactions.5 The utilization of the
RCM reactions for the construction of a broad range of
lactones increased significantly.6 Despite these advances,
stereoselectivity in RCM reactions remains a significant
challenge, particularly in the synthesis of decanolides.6c−f
Nonenolide (1) is a 10-membered lactone, isolated as a
white solid from the entomopathogenic fungus Cordyceps
militaries BCC2816 in 2004.1b The structural elucidation of 1
was secured by spectroscopic, chemical, and single-crystal X-ray
diffraction analyses. This molecule has been shown to exhibit
significant antimalarial activity against multidrug-resistant
Plasmodium falciparum K1.1b Malaria is a devastating infectious,
parasitic disease. In 2016, an estimated 216 million cases of
malaria were diagnosed in 91 countries,7 and 445 000 malaria
deaths were reported. The majority of deaths occur in children
under five,7c,e,f and efforts to develop a vaccine have been
ineffective, but drugs are able to cure infections. Moreover,
malaria imposes a substantial social burden that has delayed
economic development in countries where it is endemic.7c,f,g
Additionally, drug resistance is also a serious concern. To
combat this, new antimalarial drugs are necessary. There are
several natural products, particularly heterocycle and carbocycle
derivatives, that exhibit antimalarial activity.8 The biological
RESULTS AND DISCUSSION
■
Retrosynthetic analysis of the asymmetric total synthesis of 1 is
delineated in Scheme 1. The target molecule could possibly be
constructed through esterification and ring-closing metathesis
of the two key fragments 2 and 3. The key fragment 2, with two
chiral centers, could be generated via the MacMillan α-
Received: January 1, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b00001
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Scheme 1. Retrosynthetic Analysis of Nonenolide 1
Scheme 3. Synthesis of Acid Fragment 3
by MacMillan α-hydroxylation, afforded the diol 13.
Furthermore, the epoxide intermediate 14 was obtained from
13, and the epoxide 14 was converted to the allyl alcohol 15.
Protection of alcohol 15 gave silyl ether 16, which was then
subjected to PMB deprotection to generate primary alcohol 17.
Finally, oxidation of the resulting alcohol provided the desired
acid 3.
With the requisite alcohol 2 and carboxylic acid 3 in hand, we
then turned our attention to the coupling reaction and
construction of the lactone ring (Scheme 4). In the synthesis
hydroxylation reaction and functional group modifications of
alcohol substrate 4. Another key fragment (3) would be
accessible from epoxide 14 by a series of interconversions that
would install the carboxylic acid moiety. Compound 14 could
be prepared from the MacMillan α-hydroxylation reaction of
the 1,4-butanediol derivative 12.
Scheme 4. Coupling of Fragments 3 and 4 to Nonenolide
As outlined in Scheme 2, the synthesis of fragment 2 began
with the preparation of the known mono-PMB-protected 1,6-
Scheme 2. Synthesis of Alcohol Fragment 2
of nonenolide, Steglich esterification18 proceeded smoothly,
and the corresponding ester was obtained in 84% yield. The
construction of a lactone ring with exclusive selectivity of the E-
isomer was troublesome,9−11,13,19 since the RCM did not
proceed with diene 18 in the presence of Grubb’s second-
generation catalyst (G-II) presumably due to steric hindrance
of the two allylic chiral centers containing PMB and TBS
protecting groups. We envisioned that removal of one of the
protecting groups might reduce the steric crowding and
facilitate the RCM reaction. Thus, silyl deprotection of 18
gave the alcohol 19. The RCM reaction was accomplished in
the presence of G-II catalyst, providing exclusively the E-
olefinic lactone 20 in 72% yield. Finally, removal of the PMB
group in 20 using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) completed the total synthesis of nonenolide. The
structure of 1 was confirmed by spectral analysis and single-
hexanediol 4.13 Alcohol 4 was converted into the corresponding
aldehyde and was treated under MacMillan α-hydroxylation
conditions to give the 1,2-diol 5.14 Compound 5 was converted
into the desired chiral secondary alcohol 6 via an epoxide
intermediate.15 Protecting group modifications of 6 gave the
alcohol 8. Oxidation and MacMillan α-hydroxylation of 8
generated diol 9. Selective protection of the secondary alcohol
of 9 with the PMP-acetal (p-methoxyphenyl) and subsequent
reduction gave compound 10 in good yield.16 The oxidation
and Wittig reaction of 10 gave the olefinic compound 11.17
Finally, removal of the tert-butyldimethylsilyl (TBS) group
afforded the fragment 2.
The synthesis of carboxylic acid fragment 3 commenced
from alcohol 12 (Scheme 3). Initially, oxidation of 12, followed
B
DOI: 10.1021/acs.jnatprod.8b00001
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Journal of Natural Products
Table 1. Comparison of the 13C and H NMR Data of Synthesized 1 with Literature Data
Article
1
13C NMR (δC)
1H NMR (δH)
a
b
c
a
b
c
no.
compound 1
nonenolide (ref 1b) nonenolide (ref 12)
compound 1
nonenolide (ref 1b)
nonenolide (ref 12)
1
2
170.3
44.0
170.3
44.0
171.8
45.6
2.51 (dd, 12.1, 3.9)
2.49 (dd, 12.0, 3.5)
4.65−4.61 (m)
5.75 (dd, 15.9, 2.8)
5.63 (ddd, 15.9, 8.3, 1.1)
4.16−4.04 (m)
2.02−1.86
2.53 (dd, 12.0, 3.9)
2.48 (dd, 12.0, 3.6)
4.63 (m)
2.44 (dd, 12.0, 3.7)
2.40 (dd, 12.0, 3.4)
4.51−4.55 (m)
5.65 (dd, 16.0, 3.0)
5.56 (dd, 16.0, 8.3)
4.03 (td, 8.3, 2.8)
1.90−1.83
3
4
5
6
7
66.9
133.1
130.4
74.3
66.8
133.0
130.3
74.3
68.4
134.4
132.0
74.4
5.76 (d, 16.0, 3.0)
5.63 (ddd, 16.0, 8.1, 1.2)
4.12 (m)
37.0
37.0
38.5
1.96, 1.66 (m)
1.66−1.52 (m)
1.84−1.69
1.45−1.59 (m)
1.67−1.71
8
31.4
31.3
32.8
1.77, 1.57 (m)
1.66−1.52 (m)
4.81−4.71 (m)
1.14 (d, 6.4)
1.45−1.59 (m)
4.66−4.74 (app. qui, 6.5)
9
72.9
20.6
72.9
20.6
75.8
22.1
4.77 (m)
10
1.14 (d,6.0)
1.06 (d, 6.4)
a
b
c
Data recorded in CD3OD at 300 and 75 MHz. Data obtained from an isolation paper (ref 1b) recored in CD3OD at 500 and 125 MHz. Data
obtained from ref 12 recorded in CD3OD at 500 and 126 MHz.
(S)-6-((4-Methoxybenzyl)oxy)hexane-1,2-diol (5).20 To a
stirred solution of 2-iodoxybenzoic acid (IBX) (7.05 g, 25.21 mmol)
in dry DMSO (7 mL) was added a solution of 4 (4 g, 16.80 mmol) in
dry CH2Cl2 (30 mL) at room temperature (rt) and stirred for 3 h at
the same temperature. After completion of the reaction, the mixture
was filtered, diluted with water (10 mL), and extracted with CH2Cl2 (2
× 30 mL). The combined organic extract was washed with brine (20
mL), dried over anhydrous Na2SO4, and concentrated under vacuum
to give the crude aldehyde, which was used in the next step without
further purification. The crude aldehyde (3.6 g, 15.25 mmol) was
added dropwise to a solution of nitrosobenzene (1.63 g, 15.25 mmol)
and D-proline (0.70 g, 6.101 mmol) in chloroform (9 mL) at 0 °C, and
the solution was vigorously stirred at 0 °C for 2 h. The reaction
mixture was transferred dropwise to a solution of sodium borohydride
(0.58 g, 15.25 mmol) in ethanol (90 mL) at 0 °C, and the solution was
stirred at 0 °C for 2 h, then concentrated. Saturated NaHCO3 solution
(90 mL) was added, and the mixture was extracted with ethyl acetate
(3 × 50 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated. The residue was dissolved in 3:1
ethanol−acetic acid (40 mL) and treated with zinc powder (3.3 g,
50.72 mmol). The reaction mixture was stirred at rt for 12 h, then
filtered through Celite and concentrated. The crude residue was
purified by column chromatography using hexanes−EtOAc (4:6) to
give the diol 5 (2.5 g, 65%) as a colorless oil. The enantiomeric excess
was determined by chiral HPLC column (CHIRAL IA: 250 × 4.6 mm,
5 μm); mobile phase: 15% isopropyl alcohol (IPA) in hexane, flow
rate: 1 mL/min, detection: 210 nm, tR: 17.32 min, 98% ee.
crystal X-ray diffraction. Data were identical to those reported
in the original isolation paper.
CONCLUSIONS
■
In summary, we have accomplished an efficient, stereo-
controlled total synthesis of nonenolide (1). The key
transformations include a MacMillan α-hydroxylation to
generate three chiral centers in fragments 2 and 3, starting
from 1,6-hexanediol and 1,4-butanediol, and Steglich ester-
ification followed by RCM involving mono-PMB-protected
diene precursor 19 (12 linear steps, 10.4% overall yield from
alcohol 4). In comparison with the reported synthesis of 1, the
present synthesis provides the exclusive stereoisomer of 1 in the
RCM reaction and used inexpensive, achiral starting materials.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Glassware was dried in an
oven (120 °C), heated under reduced pressure, and cooled under
argon before use. Unless otherwise noted, materials obtained from
commercial suppliers were used without further purification. 1H NMR
and 13C NMR spectra were recorded in CDCl3 on a Bruker 300 MHz
(Avance) and Varian Unity 500 MHz (Innova) spectrometer at
ambient temperature. Chemical shifts are reported in ppm relative to
tetramethylsilane as internal standard. FTIR spectra were recorded on
a PerkinElmer 683 infrared spectrophotometer, neat or as thin films in
KBr. Optical rotations were measured on an Anton Paar MLP 200
modular circular digital polarimeter using a 2 mL cell with a path
length of 1 dm. Low-resolution MS were recorded on an Agilent
Technologies LC-MSD trap SL spectrometer. Column chromatog-
raphy was carried out on silica gel (60−120 mesh) packed in glass
columns.
(R)-6-((4-Methoxybenzyl)oxy)hexan-2-ol (6).21 To a cooled (0
°C) solution of diol 5 (2.4 g, 9.523 mmol), a catalytic amount of
dibutyl tin oxide (5 mg), and Et3N (2.64 mL, 21.046 mmol) in
CH2Cl2 (15 mL) was added p-TsCl (1.81 g, 9.523 mmol) portionwise
at 0 °C, and the mixture was stirred at rt for 12 h. After completion of
the reaction, the mixture was diluted with water and extracted with
CH2Cl2 (3 × 50 mL). The organic layer was washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
give the crude residue, which was purified on a silica gel column,
eluting with hexanes−EtOAc (75:25), to afford the mono-tosylated
product (3.1 g, 80%) as a viscous liquid. To a stirred suspension of
LiAlH4 (0.56 g, 14.705 mmol) in dry THF (30 mL) was added
dropwise a solution of the mono-tosylated derivative (3.0 g, 7.35
mmol) in dry THF (30 mL) at 0 °C under nitrogen, and the mixture
was stirred at reflux for 12 h. The reaction mixture was cooled to 0 °C,
treated with saturated aqueous Na2SO4 solution (25 mL), filtered, and
concentrated in vacuo. The crude residue was purified by column
chromatography, using hexanes−EtOAc (8:2), to give 6 (1.38 g, 79%)
as a colorless liquid.
6-((4-Methoxybenzyl)oxy)hexan-1-ol (4).15a To a solution of
1,6-hexanediol (4a, 8.0 g, 67.79 mmol) in dry THF (100 mL) was
added NaH (60% in mineral oil, 2.44 g, 45.76 mmol) at 0 °C. The
reaction mixture was stirred for 30 min at the same temperature. Then
PMB bromide (9.55 g, 61.01 mmol) was added slowly at 0 °C
followed by tetrabutylammonium iodide (TBAI) (cat.) with stirring at
rt for 1 h. After completion, the mixture was quenched with cold water
at 0 °C, the two layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with water and brine, dried over anhydrous Na2SO4, and
concentrated under vacuum. The residue was purified by silica gel
column chromatography using hexanes−EtOAc (7:3) as eluent to
furnish the mono-PMB-protected alcohol 4 (13.08 g, 83%) as a
(R)-tert-Butyl((6-((4-methoxybenzyl)oxy)hexan-2-yl)oxy)-
colorless oil.
dimethylsilane (7).20,21 To a solution of the alcohol 6 (1.3 g, 5.46
̀
C
DOI: 10.1021/acs.jnatprod.8b00001
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Journal of Natural Products
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mmol) in dry CH2Cl2 (15 mL) was added imidazole (0.743 g, 10.92
mmol), and the mixture was stirred for 10 min at 0 °C. To this
solution TBS-Cl (0.983 g, 6.55 mmol) was added at 0 °C, and the
mixture was stirred at rt for 6 h. After completion of the reaction, the
mixture was diluted with water and extracted with CH2Cl2 (3 × 20
mL). The combined extract was washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
crude residue was purified by column chromatography, using
hexanes−EtOAc (95:5), to give pure compound 7 (1.76 g, 92%) as
a colorless liquid.
was extracted with ether (2 × 30 mL). The combined extracts were
washed with brine (20 mL), dried over anhydrous Na2SO4, and
concentrated. The residue was purified by column chromatography,
using hexanes−EtOAc (95:5), to afford 11 (1.37 g, 77%) as a yellow
syrup.
(2R,5R)-5-((4-Methoxybenzyl)oxy)hept-6-en-2-ol (2).26 To a
solution of 11 (1.0 g, 2.74 mmol) in dry tetrahydrofuran (THF) (5
mL) was added tetrabutylammonium fluoride (TBAF) (3.3 mL, 1.0 M
solution in THF) with stirring for 2 h at rt. After completion, the
reaction was quenched with saturated NaHCO3 solution and extracted
with EtOAc (2 × 20 mL). The organic layer was washed with brine
solution, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude residue was purified by silica gel column
chromatography, using hexanes−EtOAc (7:3), to give alcohol 2 (0.63
g, 92%) as a colorless liquid.
(R)-5-((tert-Butyldimethylsilyl)oxy)hexan-1-ol (8).21,22 To a
cooled (0 °C) solution of 7 (1.7 g, 4.83 mmol) in CH2Cl2 (15 mL)
and H2O (1.5 mL) was added DDQ (2.2 g, 9.71 mmol), and the
mixture was stirred at rt for 2 h. After completion of the reaction,
saturated NaHCO3 solution was added, and the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL). The combined organic extract
was dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude residue was purified by column chromatography, using
hexanes−EtOAc (7:3), to give product 8 (1.04 g, 93%) as a colorless
liquid.
4-((4-Methoxybenzyl)oxy)butan-1-ol (12).13,27 The same
procedure as described for the preparation of compound 4 (mono-
PMB protection), 1,4-butanediol 12a (2 g, 22.22 mmol), NaH (60%,
1.06 g, 44.44 mmol), p-methoxybenzyl bromide (4.44 g, 22.22 mmol),
and TBAI (cat.) was used. Mono-PMB-protected alcohol 12 was
obtained in 3.73 g, 80% yield as a colorless oil.
(2R,5R)-5-((tert-Butyldimethylsilyl)oxy)hexane-1,2-diol (9).23
Same procedure was used as described for the preparation of
compound 5 (IBX oxidation), IBX (1.80 g, 6.46 mmol), and
compound 8 (1.0 g, 4.31 mmol). The crude aldehyde was directly
used in the next step. The aldehyde (0.8 g, 3.478 mmol) was added
dropwise to a solution of nitrosobenzene (0.372 g, 3.478 mmol) and L-
proline (0.16 g, 1.391 mmol) in dry DMSO (0.5 mL) at rt, and the
solution was vigorously stirred at rt for 30 min. The reaction mixture
was transferred dropwise to a solution of sodium borohydride (0.132
g, 3.478 mmol) in ethanol (15 mL) at 0 °C, and the solution was
stirred at 0 °C for 2 h and then concentrated. Saturated NaHCO3
solution (10 mL) was added, and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated under vacuum. The residue was
dissolved in MeOH (10 mL) and treated with CuSO4·5H2O (0.26 g,
1.043 mmol), and the reaction mixture was stirred at rt for 12 h, then
filtered through Celite and concentrated. The crude residue was
purified by column chromatography, using hexanes−EtOAc (6:4) to
give the diol 9 as the exclusive product (0.49 g, 57%) as a colorless oil.
tert-Butyl(((2R)-4-((4R)-2-(4-methoxyphenyl)-1,3-dioxolan-4-
yl)butan-2-yl)oxy)dimethylsilane (10a).24 To a stirred solution of
9 (2.72 g, 10.96 mmol) in CH2Cl2 (30 mL) were added subsequently
anisaldehyde dimethyl acetal (2.5 mL, 15.32 mmol) and a catalytic
amount of pyridinium p-toluenesulfonate. The mixture was stirred at rt
for 1 h. After completion, the reaction was quenched with Et3N (two
drops). The mixture was concentrated, and the residue was purified by
column chromatography to afford the acetal 10a (3.4 g, 85%).
(2R, 5R)-5-((tert -B utyld im ethylsilyl)oxy)-2-((4-
methoxybenzyl)oxy)hexan-1-ol (10).24 To a stirred solution of
10a (2.4 g, 6.56 mmol) in CH2Cl2 (30 mL) was added dropwise
DIBAL−H (13.1 mL, 1 M in toluene, 13.10 mmol) at −78 °C. The
mixture was stirred at −20 °C for another 1 h. After completion of the
reaction, the excess DIBAL−H was quenched with 10% Rochelle’s salt
solution, and the mixture was stirred at rt for 2 h. The two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30
mL). The combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography, using hexanes−EtOAc (8:2), to afford the desired
compound 10 (2.1 g, 86%) as a colorless liquid.
(S)-4-((4-Methoxybenzyl)oxy)butane-1,2-diol (13).28 The
same procedure was used as described for the preparation of
compound 5 (IBX oxidation and MacMillan-α-hydroxylation), IBX
(6.0 g, 21.42 mmol), and compound 12 (3.0 g, 14.28 mmol). The
crude aldehyde was used in the next step without further purification.
The aldehyde (1.9 g, 9.13 mmol), nitrosobenzene (0.977 g, 9.13
mmol), D-proline (0.42 g, 3.653 mmol), sodium borohydride (0.347 g,
9.13 mmol), and zinc powder (1.98 g, 30.32 mmol) were used. The
crude product was purified by column chromatography, using
hexanes−EtOAc (4:6 to give the diol 13 (1.42 g, 69%), as a colorless
oil. The enantiomeric excess was determined by chiral HPLC
(CHIRAL PAK-OD-H: 250 × 4.6 mm, 5 μm); mobile phase: 8%
IPA in hexane, flow rate: 1 mL/min, detection: 210 nm, tR: 16.74 min,
99% ee.
(S)-2-(2-((4-Methoxybenzyl)oxy)ethyl)oxirane (14).13,15a
A
solution of diol 13 (0.92 g, 4.04 mmol) in THF (10 mL) was
added to NaH (0.392 g, 16.28 mmol) in THF (20 mL) at 0 °C. The
resulting mixture was then warmed to rt and stirred for 40 min. The
mixture was then cooled to 0 °C, and tosylimidazole (1.12 g, 4.88
mmol) was added in one portion. The reaction mixture was allowed to
warm to rt with stirring for 1 h. The reaction was quenched with water
(20 mL) and extracted with EtOAc (2 × 20 mL). The combined layers
were washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography, using hexanes−EtOAc (95:5), to give
oxirane 14 (0.724 g, 86%) as a colorless oil.
(S)-5-((4-Methoxybenzyl)oxy)pent-1-en-3-ol (15).13 A solution
of trimethylsulfonium iodide (1.96 g, 9.61 mmol) in THF (30 mL)
was cooled to −20 °C, n-BuLi (2.5 M solution in hexane, 2.9 mL, 7.21
mmol) was added dropwise, and the resulting solution was stirred for
1 h at −20 °C. A solution of the epoxide 14 (0.5 g, 2.40 mmol) in
THF (10 mL) was added, and a cloudy suspension formed. The
stirring was continued for another 1 h at −20 °C. The reaction mixture
was warmed to 0 °C and quenched with saturated, aqueous NH4Cl
(20 mL). The layers were separated, and the aqueous layer was
extracted with diethyl ether (2 × 50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated. The crude
product was purified by silica gel column chromatography, using
hexanes−EtOAc (9:1), to give alcohol 15 (0.48 g, 90%) as a pale,
yellow oil.
(S)-tert-Butyl((5-((4-methoxybenzyl)oxy)pent-1-en-3-yl)oxy)-
dimethylsilane (16).15a To a 0 °C solution of 15 (0.45 g, 2.02
mmol) in CH2Cl2 (8 mL) were added imidazole (0.48 g, 4.04 mmol)
and TBS-Cl (0.51 g, 2.23 mmol). The mixture was stirred at 0 °C for 2
h and diluted with CH2Cl2 (15 mL). The organic phase was washed
with a saturated solution of NaHCO3 (20 mL) and brine (15 mL),
dried over anhydrous Na2SO4, and evaporated in vacuo. The residue
was purified by column chromatography, using hexanes−EtOAc
(97:3), to give 16 (0.6 g, 88% yield) as a colorless oil.
tert-Butyl(((2R,5R)-5-((4-methoxybenzyl)oxy)hept-6-en-2-yl)-
oxy)dimethylsilane (11).25 The same procedure as described for the
synthesis of compound 5 (IBX oxidation), IBX (2.074 g, 7.4 mmol),
and compound 10 (800 mg, 4.92 mmol) was used. The crude
aldehyde was used in the next step without further purification. To a
solution of CH3P(C6H5)3I (3.97 g, 9.83 mmol) in dry THF (20 mL)
was added n-BuLi (6.14 mL, 9.83 mmol, 1.6 M) at 0 °C, and the
mixture was stirred for 1 h at rt. The mixture was cooled to 0 °C, an
aldehyde solution (1.8 g, 4.91 mmol) in dry THF (5 mL) was added,
and the mixture was stirred for an additional 12 h at rt. The reaction
was quenched with saturated NH4Cl (5 mL) solution, and the mixture
D
DOI: 10.1021/acs.jnatprod.8b00001
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(S)-3-((tert-Butyldimethylsilyl)oxy)pent-4-en-1-ol (17).10 To a
solution of 16 (0.5 g, 1.50 mmol) in CH2Cl2 (5 mL) and H2O (0.5
mL) was added DDQ (0.405 g, 1.775 mmol) at 0 °C. The mixture was
stirred for 30 min at rt. After completion, saturated NaHCO3 solution
was added and reaction mixture was extracted with CH2Cl2 (2 × 15
mL). The combined organic extracts were washed with aqueous
NaHCO3 (10 mL), dried, and concentrated. The residue was purified
by column chromatography, using hexanes−EtOAc (8:2), to give
alcohol 17 (0.3 g, 93%) as a colorless oil.
*E-mail: aravind.iict@gmail.com.
ORCID
Damoder Reddy Motati: 0000-0002-4000-1548
Present Address
‡Department of Pharmaceutical Sciences, College of Pharmacy,
Union University, Jackson, Tennessee 38305, United States (D.
R. Motati).
(S)-3-((tert-Butyldimethylsilyl)oxy)pent-4-enoic acid (3).10
To a solution of alcohol 17 (250 mg, 1.16 mmol) in CH2Cl2−H2O
(1:1, 4 mL) were added 2,2,6,6-tetramethyl-1-piperidinyloxyl (52 mg,
0.35 mmol) and [bis(acetoxy)iodo]benzene (1.12 g, 3.48 mmol). After
stirring at rt for 2 h, the mixture was diluted with CH2Cl2 (5 mL) and
then washed with saturated aqueous Na2S2O3 (10 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated to give the
crude carboxylic acid, which was purified by silica gel column
chromatography, using hexanes−EtOAc (6:4), to give acid 3 (230 mg,
86%) as a colorless oil.
(S)-(2R,5R)-5-((4-Methoxybenzyl)oxy)hept-6-en-2-yl 3-((tert-
butyldimethylsilyl)oxy)pent-4-enoate (18). To a cooled (0 °C)
solution of acid 3 (200 mg, 0.86 mmol), DCC (180 mg, 0.86 mmol),
and 4-dimethylaminopyridine (106 mg, 0.86 mmol) in dry CH2Cl2 (10
mL) was added alcohol 2 (218 mg, 0.86 mmol) in 5 mL of dry
CH2Cl2, and the mixture was stirred at rt for 12 h. After completion,
the mixture was diluted with water (15 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried and
concentrated. The crude product was purified by silica gel column
chromatography, using hexanes−EtOAc (96:4), to give 18 (337 mg,
84%) as a colorless liquid.
(S)-(2R,5R)-5-((4-Methoxybenzyl)oxy)hept-6-en-2-yl 3-hy-
droxypent-4-enoate (19). The same procedure as described for
the preparation of compound 2 (TBS deprotection) was used.
Compound 18 (140 mg, 0.303 mmol) and TBAF (0.36 mL, 0.36
mmol, 1.0 M in THF) were used. The residue was purified by column
chromatography on silica gel using hexanes−EtOAc (7:3) to give
alcohol 19 (98 mg, 93%) as a colorless liquid.
(4S,7R,10R,E)-4-Hydroxy-7-((4-methoxybenzyl)oxy)-10-
methyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-one (20). Grubbs’
second-generation catalyst (10.9 mg, 0.013 mmol) was dissolved in
dry, deoxygenated CH2Cl2 (120 mL). After heating the solution to
reflux, diene 19 (45 mg, 0.13 mmol) dissolved in dry, deoxygenated
CH2Cl2 (30 mL) was added dropwise over 30 min. The mixture was
then stirred at reflux for 1 h. After cooling to rt, all volatiles were
removed under reduced pressure. The residue was purified by silica gel
column chromatography using hexanes−EtOAc (85:15) to give 20
(29.8 mg, 72%) as a colorless oil.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors P.R.S. and D.R.M. thank the Director for support
and encouragement and the Centre for X-ray Crystallography
for providing X-ray crystallographic data, CSIR-Indian Institute
of Chemical Technology. This article is dedicated to the fond
memory of the late Dr. Yenamandra Venkateswarlu for his
support and encouragement and his contribution to natural
products chemistry. We gratefully acknowledge the valuable
help given by Prof. E. Blake Watkins, Union University College
of Pharmacy, for assisting with English language editing.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00001.
1
Copies of H and 13C{1H} NMR spectra and details of
X-ray crystallography (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: dreddy@uu.edu.
■
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DOI: 10.1021/acs.jnatprod.8b00001
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
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DOI: 10.1021/acs.jnatprod.8b00001
J. Nat. Prod. XXXX, XXX, XXX−XXX