Enantioselective Synthesis and Antifungal Activity of C18 Polyacetylenes

Article abstract of DOI:10.1021/acs.jafc.9b07967

Fungal pathogens cause serious crop diseases and decrease crop yields and quality. Polyacetylene alcohols are plant secondary metabolites and bioactive against various pathogenic fungi. They are, however, difficult to synthesize. In the present study, an efficient and highly enantioselective method (>98% ee) was established and employed to achieve the synthesis of the natural C18 polyacetylenes (S,E)-octadeca-1,9-dien-4,6-diyn-3-ol 1, (3R,10R,E)-octadeca-1,8-dien-4,6-diyne-3,10-diol 2, and their analogs. The title compounds were structurally characterized and biologically evaluated for fungicidal activities. The compounds exhibited high potencies against eight pathogenic fungal species tested, such as Colletotrichum gloeosporioiles, Bipolaris sorokiniana, Fusarium graminearum, and Fusarium pseudograminearum, with half-maximum effective concentrations ranging from 8 to 425 μg/mL, being similar to those of the fungicide thiophanate-methyl (3-408 μg/mL). These compounds are potential natural fungicides and fungicide lead candidates for further structural and property improvements.

Full text of DOI:10.1021/acs.jafc.9b07967

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Bioactive Constituents, Metabolites, and Functions
Enantioselective Synthesis and Antifungal Activity of C18 Polyacetylenes
Jia Liu, Shichao Lu, Jiayang Feng, Changkai Li, wenliang wang, Yiming
Pei, Shengli Ding, Meng Zhang, Honglian Li, Risong Na, and Qing X. Li
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b07967 • Publication Date (Web): 27 Jan 2020
Downloaded from pubs.acs.org on January 29, 2020
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Enantioselective Synthesis and Antifungal Activity of C18 Polyacetylenes
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Jia Liu, Shichao Lu, Jiayang Feng, Changkai Li, Wenliang Wang, Yiming Pei, Shengli
Ding, Meng Zhang, Honglian Li, Risong Na,1, * and Qing X. Li2
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College of Plant Protection, Henan Agricultural University, Wenhua Road No. 95, Zhengzhou,
450002, China
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Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa,
1955 East-West Road, Honolulu, HI 96822, USA
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* Corresponding Author
Email address: nrs@henau.edu.cn
honglianli@sina.com
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Abstract
Fungal pathogens cause serious crop diseases and decrease crop yields and quality.
Polyacetylene alcohols are plant secondary metabolites and bioactive against various pathogenic
fungi. They are, however, difficult to synthesize. In the present study, an efficient and highly
enantioselective method (> 98% ee) was established and employed to achieve the synthesis of
the natural C18 polyacetylenes (S, E)-octadeca-1,9-dien-4,6-diyn-3-ol 1, (3R, 10R, E)-octadeca-
1,8-dien-4,6-diyne-3,10-diol 2 and their analogs. The title compounds were structurally
characterized and biologically evaluated for fungicidal activities. The compounds exhibited high
potencies against eight pathogenic fungal species tested, such as Colletotrichum gloeosporioiles,
Bipolaris sorokiniana, Fusarium graminearum and Fusarium pseudograminearum, with half-
maximum effective concentrations ranging from 8 to 425 μg/mL, being similar to those of the
fungicide thiophanate-methyl (3 - 408 μg/mL). These compounds are potential natural fungicides
and fungicide lead candidates for further structural and property improvements.
Key words: Antifungal, Asymmetric synthesis, Fungicide, Panax Stipuleanatus, Polyacetylene
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INTRODUCTION
Fungal pathogens are widely distributed and cause serious damage to crops. Many plants
secrete secondary metabolites to defend against pathogenic invasion. Those metabolites reveal
antifungal effects,1-5 which indicate a great potential for the development of fungicides. A classic
example is the discovery of strobilurins from Strobilurus tenacellus, which opened the door for
the development of one of the best salable fungicides – azoxystrobin.6-9 Pyrethroid and
neonicotinoid insecticides are also good examples of pesticides developed from natural
products.10-11
Polyacetylene alcohols are widespread defensive secondary metabolites in plants such as
Umbelliferae and Araliaceae. In an early report in 1978, falcarindiol, a C17 polyacetylene
alcohol, was discovered to exhibit antifungal activity to Uromyces fabae and Colletotrichum
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lagenarium. In 2012, Kim’s group found two new C18 polyacetylenes from Panax
stipuleanatus,13-14 which showed biological activities against HCT-116 cancer cell better than
mitoxantrone. Further studies have shown that polyacetylene alcohols have beneficial effects on
acute alcohol-induced oxidative stress and liver damage as well as antioxidant activity, intensive
cell differentiation activity and exhibited dose-dependent inhibitory effects on the cancer cell
proliferation.15-20 The diverse biological activities indicate that polyacetylene alcohols have the
potential to be developed as natural product drugs and fungicides, especially as natural
fungicides from plant origin.19
However, the unique structures of chiral conjugated diynol make the compounds difficult to
store and synthesize, which restrict the development and application of polyacetylene alcohols.21
Those limitations prompted us to develop an efficient and highly enantioselective method and to
employ it for the synthesis of these natural products with a large structural diversity.
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In 2016, our group achieved the C17 polyacetylenes virol A and C by using chiral alkynols,
which was proved to be a reasonable synthetic block for the preparation of polyacetylene
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alcohols (Figure 1). In the present study, a general method was established to synthesize the
natural C18 polyacetylenes (S, E)-octadeca-1,9-dien-4,6-diyn-3-ol 1 and (3R, 10R, E)-octadeca-
1,8-dien-4,6-diyne-3,10-diol 2 and their analogs with a large structural diversity. The synthetic
compounds inhibited eight pathogenic fungal species tested, such as Colletotrichum
gloeosporioiles, Bipolaris sorokiniana, Fusarium graminearum and Fusarium
pseudograminearum. The half-maximum effective concentrations (EC ) of the synthetic
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polyacetylene alcohols ranged from 8 to 425 μg/mL, which are comparable to the potencies, but
differ in the anti-fungal spectrum of the commercial fungicide thiophanate-methyl. Those
polyacetylene alcohols can be fungicide lead candidates.
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MATERIALS AND METHODS
General Information. All reactions were performed under argon atmosphere. Solvents were
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dried according to standard procedures and distilled prior to use. All reagents were purchased
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commercially and used without further purification unless stated otherwise. H, C and 2D
NMR data were recorded with a Bruker AvanceTM III 400MHz spectrometer (Billerica, MA).
High-resolution mass spectra were recorded on an Agilent 6224 TOF instrument (Santa Clara,
CA) by the TOF MS technique. The fused silica capillary column was a DB-5MS column
(Agilent Technologies). Electron impact (70 eV) mass spectra were recorded from m/z 50 to 550.
Enantiomeric excess (ee) was determined by chiral HPLC (Prominence LC-20A, Kyoto, Japan)
analyses using a chiral column (Chiralpak OD-H), and elution with isopropanol-hexane.
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Chiralcel OD: 0.8 ml/min, Hexane/2-propanol (65/35), 220 nm. The optical rotations were
measured on a Perkin Elmer 341 Polarimeter (Waltham, MA).
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Antifungal activity assay. All seven compounds were tested against eight food and cash
crop fungal pathogens,24-25 according to published procedure. The compound (10 mg) was
dissolved in 0.5 mL of DMSO and then diluted with distilled water containing 0.1% Tween-80 to
a concentration of 200 μg/mL. The solution was then diluted to 1.56, 3.12, 6.25, 12.5, 25, 50, and
100 μg/mL. The fungicidal activity was determined as the rate of mycelial growth inhibition.26
Thiophanate-methyl is a broad-spectrum systemic commercial fungicide. It was used as a
positive control to compare the antifungal potencies of the newly synthesized compounds.
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Statistics and EC calculations. Data were presented as the means ± standard deviations
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(SD) for at least three independent experiments. Statistical significance (***p < 0.001, **p <
0.01, *p < 0.05) was assessed using Student’s t-test or one-way analysis of variance (ANOVA)
coupled with Dunnett’s t-test.
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General synthetic method of target compounds. To a blue solution of CuCl (2.9 mg, 0.03
mmol) in degassed 30% n-BuNH solution (2.2 mL) was added aqueous NH OH-HCl to
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discharge the blue color at 0 C. A solution of terminal alkyne (1.50 mmol) in methanol (MeOH)
(1.0 mL) was then added. After the resulting mixture was stirred for 1 min, bromohydrocarbon
(1.00 mmol) in MeOH (1.0 mL) was added slowly. The reaction mixture was stirred for 30 min
before it was quenched with water. The aqueous phase was extracted with dichloromethane. The
combined organic phases were washed with saturated brine solution, dried over anhydrous
Na SO , and concentrated under reduced pressure. The residue was purified by silica gel
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chromatography.
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RESULTS AND DISCUSSION
The retrosynthetic analysis of (S, E)-1 and (3R, 10R, E)-2 (Figure 2) led to four different
fragments: the terminal alkyne 8 and chiral alkynols (S)-12, (R)-12, and 18. All the chiral
alkynols could be generated from a chiral alkynol ester, a classic product synthesized from the
asymmetric addition of methyl propiolate to aldehydes with the enantioselectivity up to 98%
purity. Terminal alkyne 8 could be synthesized by desiliconization of enyne 7, which could be
accomplished by the Cu-catalyzed cross-coupling reaction.
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The synthesis of 8 started from the preparation of the long-chain propargyl alcohol 4
(Scheme 1). Under the effect of n-butyllithium, propargyl alcohol reacted with 1-bromooctane to
afford 4 with 95% yield. Then, 4 was treated with LiAlH to generate enol 5 with 91% yield.
4
Bromohydrocarbon 6 was prepared in 99% yield by the substitution of enol 5 with carbon
tetrabromide and triphenylphosphine. The key intermediate 7 was achieved by the cross-coupling
of bromohydrocarbon 6 with trimethylsilyacetylene in 83% yield under room temperature. After
the desiliconization of enyne 7, the terminal alkyne 8 was synthesized in 90% yield.
Synthesis of the chiral alkynol (S)-12 was consisted of two parts (Scheme 2). Under the
effect of prophenol-triphenylphosphine oxide-zinc complex, the asymmetric addition of methyl
propiolate 10 to acrolein 9 was achieved to afford (S)-11 with 65% yield and 99% ee.27-28 The
second part was the decarboxylation and substitution of (S)-11. (S)-11 was treated with LiOH,
CuCl, NBS and AgNO to afford chiral alkynol (S)-12 in 71% yield. The synthesis of the chiral
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alkynol (R)-12 was similar to that of (S)-12 with the compound (S)-19 instead of (R)-19.
The synthesis of the chiral enol 18 started from the preparation of the chiral propargyl
alcohol (R)-15 (Scheme 3). Under the same condition of the synthesis of (R)-12, (R)-15 was
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achieved in 73% yield. (R)-15 was then treated with LiAlH and AlCl to afford the bromoenol
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16 in 91% yield. The key intermediate 17 was achieved by cross-coupling 16 with
trimethylsilyacetylene in 87% yield at room temperature. After the desiliconization of 17, the
terminal alkyne 18 was synthesized in 91% yield.
The natural product (S, E)-1 was synthesized by the Cadiot-Chodkiewicz cross-coupling of
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the terminal alkyne 8 and the alkynol (S)-12 in 87% yield. The natural product (3R, 10R, E)-2
was achieved by the across-coupling of chiral enol 18 and (R)-12 in 87% yield (Scheme 4). After
(S, E)-1 and (3R, 10R, E)-2 were synthesized, we intended to test the antifungal activity of the
new C18 structures having different double bonds and chiral alkynol centers. A new Z-
configuration terminal alkyne 23 was then synthesized in order to achieve a series of (S, E)-1
analogs.
The synthesis of the terminal alkyne 23 started from 4 (Scheme 5). The propargyl alcohol 4
was treated with carbon tetrabromide and triphenylphosphine to generate the bromohydrocarbon
20 in 98% yield. The intermediate 21 was achieved by cross-coupling 20 with
trimethylsilyacetylene in 85% yield under nitrogen atmosphere. 22 was selectively reduced by
the Raney Nickel in 81% yield. After the desiliconization of the enyne 22, the terminal alkyne 23
was synthesized in 91% yield.
Five isomers of (S, E)-1 were achieved by the same synthetic strategy as (S, E)-1 (Scheme
6). (R, E)-1 was synthesized by the Cadiot-Chodkiewicz cross-coupling of 8 and (R)-12 in 85%
yield. Rac-(E)-1 was accomplished by the cross-coupling of 8 and rac-12 in 83% yield. Cross-
coupling of 23 with (R)-12, rac-12 and (S)-12 afforded in (R, Z)-1, Rac-(Z)-1 and (S, Z)-1,
respectively, in 87%, 87% and 85% yields.
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Structural characterization: Table 1 shows H NMR spectroscopic data (δ in ppm, J in
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Hz) of, (S, E)-1 (R, Z)-1 and (3R, 10R, E)-2 (400 MHz, CDCl3). (S, E)-octadeca-1,9-dien-
4,6-diyn-3-ol, (S, E)-1, [α]D20 = + 11.2 (c = 0.10, CHCl ), lit [α] = + 11.2 (c = 0.10, CHCl3).
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The molecular formula is C H O. HRMS ESI [M-H] calcd for C H O 257.1911, found
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257.1913. The H-NMR spectrum contained alkenyl proton signals H-1 at δ 5.47 (dt, J = 17.0,
1.3 Hz, 1H) and 5.24 (dt, J = 10.1, 1.3 Hz, 1H). The HMBC and DEPT spectra showed an
oxygenated H-3 proton signal at δ 4.93 (d, J = 5.0 Hz, 1H), olefinic protons (H-2, H-9, H-10) at δ
5.94 (ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.39 – 5.30 (m, 1H), 5.67 (dtt, J = 15.3, 6.8, 1.8 Hz, 1H),
and alkyl protons (H-17, H-16, H-15, H-14, H-13, H-12, H-11, and H-8) at δ 1.37 – 1.32 (m,
2H), 1.26 (s, 10H), 2.03 – 1.98 (m, 2H), 3.00 (dt, J = 5.7, 1.4 Hz, 2H), and a methyl proton (H-
12) at 0.88 (t, J = 6.8 Hz, 3H). The δ 2.10 (d, J = 5.6 Hz, 1H) showed no correlation with any
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carbon in the HSQC spectrum; it was assigned to the hydroxy group (H-19). The C-NMR
spectrum contained four olefinic carbon signals (C-2, C-10, C-9, and C-1) at δ 136.1, 133.6,
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122.0, and 117.0, one oxygenated sp carbon signal (C-3) at δ 63.5, four alkyne carbon signals
(C-4, C-5, C-6, and C-7) at δ 79.6, 65.7, 71.2, 74.5, seven alkyl carbon signals (C-8, C-17, C-16,
C-15, C-14, C-13, C-12, and C-11) at 22.4, 31.9, 29.4, 29.2, 29.2, 29.1, 22.6, and 32.3, and one
methyl carbon signal (C-18) at 14.1. The NOESY-NMR spectrum correlation between H-8 (δ
3.00 (dt, J = 5.6, 1.4 Hz, 2H)) and H-11 (δ 2.03 – 1.98 (m, 2H)) revealed that C-9 and C-10 were
trans-configured.
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(R, Z)-Octadeca-1,9-dien-4,6-diyn-3-ol, (R, Z)-1, [α]D20 = - 30.9 (c = 0.10, CHCl ). The
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molecular formula is C H O. HRMS ESI [M-H] calcd for C H O 257.1911, found 257.1912.
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The H-NMR spectrum contained alkenyl proton signals (H-1) at δ 5.49 - 5.44 (m, 1H), 5.41 –
5.34 (m, 1H). The HMBC and DEPT spectra showed an oxygenated (H-3) proton signal at δ 4.91
(dt, J = 5.4, 1.3 Hz, 1H), olefinic proton signals (H-2, H-10, H-9) located separately at δ 5.94
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(ddd, J = 17.1, 10.2, 5.4 Hz, 1H), 5.51 (dt, J = 9.0, 1.7 Hz, 1H), 5.24 (dt, J = 10.2, 1.2 Hz, 1H),
and alkyl proton signals (H-8, H-11, H-12, H-13, H-14, H-15 ,H-16, and H-17) at δ, 2.02 (qd, J =
7.3, 1.5 Hz, 2H), 3.03 (dt, J = 7.0, 1.1 Hz, 2H), 1.35 (q, J = 7.0 Hz, 2H), 1.27 (s, 10H), and a
methyl proton signal (H-18) at 0.87 (t, J = 6.7 Hz, 3H). The δ 2.02 signal (qd, J = 7.3, 1.5 Hz,
1H) showed no correlation with any carbon in the HSQC spectrum; it was assigned to the
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hydroxy group (H-19). The C-NMR spectrum contained four olefinic carbon signals (C-2, C-
10, C-9, and C-1) at δ 136.1, 133.1, 121.9, and 117.0, and one oxygenated sp3 carbon signal (C-
3) at δ 63.5, four alkyne carbon signals (C-4, C-5, C-6, and C-7) at δ 80.3, 64.0, 71.3, and 74.2,
seven alkyl carbon signals (C-8, C-11, C-12, C-13, C-14, C-15, C-16, and C-17) at δ 17.7, 27.2,
29.2, 29.2, 29.3, 29.4 22.7, and 31.8, and one methyl carbon signal (C-18) at 14.1. The NOESY-
NMR spectrum correlation between H-11 (δ 3.03 (dt, J = 7.0, 1.1 Hz, 2H)) and H-8 (2.02 (qd, J
= 7.3, 1.5 Hz, 3H)) revealed that C-9 and C-10 were cis-configured.
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(3R, 10R, E)-Octadeca-1,8-dien-4,6-diyne-3,10-diol, (3R, 10R, E)-2 was obtained as yellow
oil with [α]D20 = - 38.4 (c = 0.70, CHCl ), lit [α] = - 38.5 (c = 0.70, CHCl ). The molecular
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formula is C H O . HRMS ESI [M-H] calcd for C H O 273.1860, found 273.1863. The H-
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NMR spectrum contained alkenyl proton signals (H-1) at δ 5.47 (dd, J = 17.1, 1.4 Hz, 1H) and
5.25 (dd, J = 10.1, 1.4 Hz, 1H). The HMBC and DEPT spectra showed two oxygenated proton
signals (H-3 and H-10) located separately at δ 4.97 (d, J = 5.0 Hz, 1H), 4.18 (q, J = 6.2 Hz, 1H),
and three olefinic proton signals (H-9, H-2, H-8) located separately at δ 6.33 (ddd, J = 15.9, 5.7,
1.5 Hz, 1H), 5.99 – 5.89 (m, 1H), and 5.76 (d, J = 15.9 Hz, 1H), and alkyl proton signals (H-11,
H-12, H-13, H-14, H-15, H-16, and H-17) at δ 1.52 (t, J = 6.7 Hz, 2H) and δ 1.27 (q, J = 5.4, 4.5
Hz, 12H), and one methyl proton signal (H-18) at 0.87 (t, J = 6.8 Hz, 3H). The signals at δ 2.52
(d, J = 6.2 Hz, 1H) and 1.92 (s, 1H) showed no correlation with any carbon in the HSQC
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spectrum; it was assigned to the hydroxy group (H-19 and H-20). The C-NMR spectrum
contained four olefinic carbon signals (C-9, C-2, C-1, and C-8) at δ 149.8, 135.9, 117.2, 108.1,
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and two oxygenated sp carbon signals (C-3, C-10) at δ 63.5 and 72.0, four alkyne carbon signals
(C-4, C-5, C-6, and C-7) at δ 80.4, 70.9, 73.5, and 77.5, seven alkyl carbon signals (C-11, C-12,
C-13, C-14, C-15, C-16, and C-17) at δ 22.6, 31.8, 29.5, 29.4, 29.2, 25.2, and 36.8, and one
methyl carbon signal (C-18) at δ 14.1. The NOESY-NMR spectrum correlation between H-9 (δ
6.33 (ddd, J = 15.9, 5.7, 1.5 Hz, 1H)) and H-11 (δ 1.55 – 1.49 (m, 2H)) revealed that H-9 and H-
11 were trans-configured.
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(S, E)-1 and (3R, 10R, E)-2 showed good antifungal activities (Table 2). The antifungal
activities of (R, E)-1, rac-(E)-1, (S, Z)-1, (R, Z)-1 and rac-(Z)-1 were also shown in Table 2. It
is very interesting that the newly synthesized polyacetylene alcohols show half-maximum
effective concentrations (EC ) between 8 and 425 μg/mL. Such potencies are in a similar range
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as those of thiophanate-methyl (EC , 3 and 408 μg/mL), whereas the anti-fungal spectra of the
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polyacetylene alcohols largely differ among themselves and from those of thiophanate-methyl.
Thiophanate-methyl is the most potent (3 µg/mL) against M. fructigena among the eight fungal
pathogens tested. Among the seven tested pure isomers or racemic mixtures and eight fungal
species, rac-(E)-1 was the most potent against B. sorokiniana.
The EC value of (S, E)-1 against B. sorokiniana was 36-, 3- and 8-times smaller (i.e.,
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more potent) than that of (R, E)-1, (S, Z)-1 and (3R, 10R, E)-2, respectively. The EC value of
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(S, E)-1 against C. gloeosporioides was 7-, 2- and 2-times smaller than that of (R, E)-1, (S, Z)-1
and (3R, 10R, E)-2, respectively. The EC value of (S, E)-1 against Phytophthora capsici was
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2-, 5- and 4-times smaller than (R, E)-1, (S, Z)-1 and (3R, 10R, E)-2, respectively. The EC of
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(S, E)-1 against F. graminearum was 3-times smaller than both rac-(E)-1, and (R, Z)-1,
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228
229
230
231
232
233
234
respectively. The EC of (S, E)-1 against A. kikuchiana Tanaka was 3-, 2- and 3-times smaller
5
0
than rac-(E)-1, rac-(Z)-1, and (3R, 10R, E)-2, respectively. The EC of (3R, 10R, E)-2 against
5
0
Rhizoctonia cerealis was 8-, 4-, and 3-times smaller than (S, E)-1, (S, Z)-1, and rac-(E)-1,
respectively. The EC of (S, E)-1 against F. pseudograminearum was similar to that of (3R,
5
0
10R, E)-2, but 4-times smaller than rac-(E)-1 and (R, Z)-1. The EC of (S, Z)-1 against M.
5
0
fructigena was 7-, 6- and 3-times smaller than (S, E)-1, rac-(Z)-1 and (3R, 10R, E)-2,
respectively.
The results may indicate that the fungicidal potency is related to the chiral center
configurations and geometric isomerism. The bioassay results of the eight fungal species suggest
that (S, E)-1 and (R, E)-1, (S, Z)-1 and (R, Z)-1 are mostly antagonistic. However, (S, E)-1 and
(R, E)-1, (S, Z)-1 and (R, Z)-1 had low activity against B. sorokiniana. (S, E)-1 and (R, E)-1 had
low activity against P. capsica and M. fructigena, and were synergistic against Rhizoctonia
cerealis. (S, Z)-1 and (R, Z)-1 were synergistic against P. capsica.
Compounds having the S optical configuration and the E configuration seem to have greater
antifungal potential. The spatial structure and activity information may lay a good foundation for
the study of the structure-activity relationship of polyacetylenes in the future.
In conclusion, an efficient and highly enantioselective general method (> 98% ee, 32-56%
yield) was established to synthesize C18 polyacetylenes (S, E)-octadeca-1,9-dien-4,6-diyn-3-ol,
(3R, 10R, E)-octadeca-1,8-dien- 4,6-diyne-3,10-diol and their analogs for the first time. The
configuration of the double bond and the chiral alkynol centers have shown varying selectivity
against the tested fungi. The EC values ranged from 8 to 425 μg/mL. The EC values of (S,
5
0
50
E)-1, rac-(E)-1, (S, Z)-1, rac-(Z)-1, and (3R, 10R, E)-2 against B. sorokiniana were 9, 8, 26, 24,
and 74 μg/mL, respectively, which provide useful information to the structural optimization of
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new polyacetylene fungicide candidates.
ACKNOWLEDGEMENTS
2
2
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38
39
40
This work was supported in part by the Special Fund for the National Natural Science
Foundation of China (No. 21602043, 21702048 and U1904111), National key research and
development program (SQ2017YFNC050081-04), and USDA (HAW5032-R)
2
41
242
243
244
SUPPORTING INFORMATION
1
13
H and C NMR, 2D NMR spectra, HPLC chromatograms of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
2
45
46
REFERENCES
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248
249
250
251
252
253
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255
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264
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266
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26. Obydennov, K. L.; Khamidullina, L. A.; Galushchinskiy, A. N.; Shatunova, S. A.; Kosterina,
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Journal of Agricultural and Food Chemistry
1
Table 1. H NMR spectroscopic data (δ in ppm, J in Hz) of (S, E)-1, (R, Z)-1 and (3R, 10R, E)-2.
H
(400 MHz, CDCl3)
20
8
10
12
14
16
8
11
13
15
17
OH
18
8
12
14
16
18
18
10
5
7
9
11
13
15
17
5
7
9
10
12
14
16
6
2
6
2
6
7
9
11
13
15
17
3
3
2
4
4
3
5
1
1
4
1
OH
OH
19
OH
1
(3R, 10R, E)-2
19
(S, E)-1
(R, Z)-1
9
Noa
1
δ
δ
(J in Hz)
HMBC
δ
δ
(J in Hz)
HMBC
δ
δ
(J in Hz)
HMBC
C
H
C
H
C
H
117.0,
CH
H
a
5.47 dt,
H
a
2, 3,
117.0,
CH
H
a
5.49 –
5.44, m
H
a
2, 3
2, 3
117.2
CH
H
a
5.47, dd
H
a
2, 3, 4
3, 4
2
4, 5
2
2
(17.1, 1.4)
(
17.0, 1.3)
5.24 dt,
10.1, 1.3)
5.94 ddd,
H
b
H
b
H
4
b
2, 3,
H
b
5.41 –
5.34, m
H 5.25, dd
(10.1, 1.4)
b
H
b
(
2
3
136.1,
CH
3, 4
136.1,
CH
5.94, ddd
3, 4, 5
135.9,
CH
5.99 – 5.89,
m
1, 3, 4
1, 2, 4,
(17.0, 10.1,
(17.1, 10.2)
5
.3)
63.5,
CH
4.93 d, (5.0)
1, 2, 4,
5
63.5,
CH
4.91, dt
1, 2, 4,
5
63.5,
CH
4.97, d (5.0)
(5.4, 1.3)
4
5
6
7
8
79.6, C
65.7, C
71.2, C
74.5, C
22.4,
80.3,
C
80.4, C
70.9, C
73.5, C
77.5, C
64.0,
C
71.3,
C
74.2,
C
3.00 dt, (5.6,
1.4)
3, 4, 5,
6, 7, 9,
17.7,
CH
2
2.02, qd
7.3, 1.5)
5.24, dt
10.2, 1.2)
6, 7, 9,
10
108.1,
CH
5.76, d (15.9)
6, 7, 9, 10
CH
2
(
1
0, 11
9
122.0,
CH
5.39 – 5.30, m
7, 8, 10,
11
121.9,
CH
7, 8,
10, 11
149.8,
CH
6.33, ddd
(15.9, 5.7,
7, 8, 10, 11
8, 9, 11
(
1
.5)
1
1
0
1
133.6,
CH
5.67 dtt,
7, 9, 11,
12
133.1,
CH
5.51, dt
(9.0, 1.7)
3.03, dt
7, 8, 9,
11,12
72.0,
CH
4.18, q (6.2)
(15.3, 6.8, 1.8)
32.3,
2.03 – 1.98, m
11, 12,
13, 14,
27.2,
9, 10,
12, 13,
14, 15
36.8,
CH
2
1.55 – 1.49,
m
8, 9, 10, 12,
13, 14, 15,
16
CH
2
CH
2
(7.0, 1.1)
1
6, 17
1
1
2
3
22.6,
CH
1.26, s
11, 12,
13, 14,
29.2,
CH
1.27, s
9, 10,
11, 13,
14, 15
25.2,
CH
1.27, q
11, 13, 15,
16, 17
2
2
2
(
5.4, 4.5)
1.27, q
5.4, 4.5)
1
6, 17
29.1,
CH
1.26, s
11, 12,
14, 15,
29.2,
CH
1.27, s
11, 12,
14, 15,
16
29.2,
CH
10, 11, 12,
14, 15, 16,
17
2
2
2
(
1
6, 17
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1
1
1
1
4
5
6
7
8
29.2,
CH
1.26, s
11, 12,
13, 15,
29.3,
CH
1.27, s
11, 12,
13, 15,
16, 17
29.4,
CH
1.27, q
5.4, 4.5)
1.27, q
5.4, 4.5)
1.27, q
5.4, 4.5)
1.27, q
5.4, 4.5)
11, 12, 13,
15, 16, 17
2
2
2
(
1
6, 17
29.2,
CH
1.26, s
11, 12,
13, 14,
29.4,
CH
1.27, s
12, 13,
14, 16,
17
29.5,
CH
11, 13, 14,
16, 17, 18
2
2
2
(
1
6, 17
29.4,
CH
1.26, s
12, 13,
14, 15,
22.7,
CH
1.27, s
12, 13,
14, 15,
17, 18
31.8,
CH
11, 12, 13,
14, 15, 17,
18
2
2
2
(
1
7, 18
31.9,
CH
1.37 – 1.32, m
0.88 t, (6.8)
2.10 d, (5.6)
12, 13,
14, 15,
31.8,
CH
1.35, q (7.0)
0.87, t (6.7).
2.02, qd
12, 13,
14, 15,
16, 18
22.6,
CH
11, 12, 13,
14, 15, 16,
18
2
2
2
(
1
6, 18
14.1,
CH
9, 13,
14, 15,
14.1,
CH
13, 14,
15, 16,
17
14.1,
CH
0.87, t (6.8).
13, 14, 15,
16, 17
3
3
3
1
6, 17
1
2
9
0
2.52, d (6.2)
1.92, s
(7.3, 1.5)
a
Carbon position.
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Journal of Agricultural and Food Chemistry
Table 2. Antifungal activity of (3R, 10R, E)-2 and all the isomers of natural product 1.
Fungus
Compound
Toxicity regression
equation
R2
EC50
(µg/mL)
B. sorokiniana
(S, E)-1
y=6.87+0.61x
y=6.23+0.83x
y=6.47+0.47x
y=6.55+0.60x
y=6.28+0.64x
y=6.47+0.56x
y=7.94+1.38x
y=5.50+0.36x
y=6.75+0.75x
y=6.22+0.84x
y=6.69+0.90x
y=7.54+1.21x
y=6.79+0.87x
y=6.90+0.96x
y=6.32+0.63x
y=6.67+0.97x
y=6.88+0.87
y=5.85+0.48x
y=6.35+0.63x
y=5.79+0.54x
y=6.33+0.97x
y=6.61+0.85x
y=6.47+0.94x
y=7.13+0.71x
y=6.52+0.71x
y=6.05+0.49x
y=6.60+0.96x
y=6.19+0.59x
y=6.53+0.94x
y=5.77+0.41x
y=6.66+0.76x
y=8.24+1.20x
y=6.75+0.73x
0.983
0.956
0.966
0.984
0.968
0.978
0.986
0.976
0.991
0.982
0.989
0.970
0.969
0.991
0.960
0.993
0.991
0.993
0.997
0.994
0.979
0.973
0.975
0.981
0.951
0.966
0.969
0.984
0.969
0.980
0.964
0.963
0.992
9
(R, E)-1
330
8
rac-(E)-1
(
S, Z)-1
R, Z)-1
26
(
100
24
rac-(Z)-1
3R, 10R, E)-2
(
74
Thiophanate-methyl
408
46
C. gloeosporioides
Phytophthora capsica
F. graminearum
(S, E)-1
(R, E)-1
353
133
80
rac-(E)-1
(
S, Z)-1
R, Z)-1
(
88
rac-(Z)-1
3R, 10R, E)-2
105
80
(
Thiophanate-methyl
190
69
(S, E)-1
(R, E)-1
169
72
rac-(E)-1
(
S, Z)-1
R, Z)-1
344
425
128
273
10
(
rac-(Z)-1
3R, 10R, E)-2
(
Thiophanate-methyl
(S, E)-1
72
(R, E)-1
72
rac-(E)-1
216
96
(
S, Z)-1
R, Z)-1
(
236
132
66
rac-(Z)-1
3R, 10R, E)-2
(
Thiophanate-methyl
200
41
A. kikuchiana Tanaka
(S, E)-1
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(
R, E)-1
y=6.17+0.51x
y=6.08+0.57x
y=6.39+0.64x
y=6.76+0.76x
y=6.45+0.73x
y=5.89+0.475x
y=9.90+2.01x
y=5.73+0.48x
y=5.72+0.39x
y=6.44+0.74x
y=6.38+0.72x
y=6.33+0.65x
y=6.53+0.77x
y=6.58+0.65x
y=6.39+0.67x
y=6.12+0.46x
y=6.86+0.83x
y=6.11+0.64x
y=6.90+0.83x
y=6.14+0.63
0.988
0.982
0.971
0.984
0.987
0.994
0.984
0.968
0.989
0.981
0.978
0.990
0.992
0.987
0.987
0.885
0.978
0.990
0.989
0.987
0.986
0.968
0.942
0.969
0.994
0.985
0.993
0.971
0.993
0.948
0.949
51
rac-(E)-1
127
67
(
S, Z)-1
R, Z)-1
(
48
rac-(Z)-1
3R, 10R, E)-2
103
134
37
(
Thiophanate-methyl
Rhizoctonia cerealis
F. pseudograminearum
M. fructigena
(S, E)-1
301
143
113
121
90
(R, E)-1
rac-(E)-1
(
S, Z)-1
R, Z)-1
(
rac-(Z)-1
3R, 10R, E)-2
103
37
(
Thiophanate-methyl
84
(S, E)-1
37
(R, E)-1
57
rac-(E)-1
184
51
(
S, Z)-1
R, Z)-1
(
155
130
44
rac-(Z)-1
3R, 10R, E)-2
y=6.00+0.53x
y=6.98+0.84x
y=8.26+1.20x
y=5.73+0.50x
y=6.38+0.66x
y=6.46+0.70x
y=6.33+0.59x
y=7.01+0.99x
y=6.10+0.74x
y=6.06+0.601x
y=7.20+0.610x
(
Thiophanate-methyl
19
(S, E)-1
347
81
(R, E)-1
rac-(E)-1
82
(
S, Z)-1
R, Z)-1
56
(
93
rac-(Z)-1
3R, 10R, E)-2
Thiophanate-methyl
326
172
3
(
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Journal of Agricultural and Food Chemistry
Figure and scheme captions
Figure 1. Structures of strobilurin’s family and polyacetylenes.
Figure 2. Retrosynthetic analysis of (S, E)-1 and (3R, 10R, E)-2.
Scheme 1. Synthesis of the terminal alkyne 8.
Scheme 2. Synthesis of (S)-12 & (R)-12.
Scheme 3. Synthesis of (R, E)-tridec-3-en-1-yn-5-ol 18.
Scheme 4. Synthesis of (S, E)-1 and (3R, 10R, E)-2.
Scheme 5. Synthesis of the terminal alkyne 23.
Scheme 6. Synthesis of (S, E)-1 analogs.
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Page 20 of 28
OH
C7H15
3
8 17
C H
O
OMe
C3H7
OMe
Panaxjapyne A
3
Strobilurin A
OH
OH
Cicutoxin OH
OH
OH
C7H15
3
(S, E)-octadeca-1,9-dien-4,6-diyn-3-ol
O
OMe
Cl
C5H11
OH
2
OMe
OMe
Falcarinol
OH
Virol A
Virol C
8 17
C H
OH
Strobilurin B
OH
3
C7H15
O
OMe
C7H15
OH
(3R, 10R, E)-octadeca-1,8-dien-
,6-diyne-3,10-diol
O
OMe
Falcarindiol
OH
4
Strobilurin C
OH
New Polyacetylenes
from Panax stipuleanatus
Strobilurin's Family
Falcarinol's Family
Cicutoxin's Family
Figure 1. Structures of strobilurin’s family and polyacetylenes.
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Journal of Agricultural and Food Chemistry
C H
7
C H
7
15
15
8
C H
8
7
17
TMS
+
Br
COOMe
OH
(S, E)-1
(S)-12
OH
OH
(S)-11
Br
COOMe
OH
C H
8
17
( )-
R 12
OH
OH
(R)-11
+
OH
C H
COOMe
OH
(3R, 10R, E)-2
8
17
C H
7 15
(
R)-14
18
OH
Figure 2. Retrosynthetic analysis of (S, E)-1 and (3R, 10R, E)-2.
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Scheme 1. Synthesis of the terminal alkyne 8
OH
C H
7
n-BuLi, Propargyl alcohol, HMPA
C H
7
LAlH4, THF
reflux, 12 h
15
CBr4, Ph3P
15
OH
C H17Br
8
o
o
THF, 25 C, 12 h
DCM, 25 C, 0.5 h
3
4 95% yield
5 91% yield
C H
7
C H
7 15
C H
7
CuI, Bu NCl, Na CO
4
2
3
15
K CO , MeOH
2
3
15
Br
o
o
DMF, 25 C, 24 h
25 C, 24 h
6
99% yield
7 83% yield
TMS
8 90% yield
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Journal of Agricultural and Food Chemistry
Scheme 2. Synthesis of (S)-12 and (R)-12.
Ph
Ph
OH
Ph
OH
) LiOH, THF, 25 o
OH
1
2
C
R)-19,TPPO, Me2Zn
) CuCl, CH3CN, 25 oC
N
N
OH
OH
N
(
CHO
+
HO
Ph
COOMe
10
Toluene, 0 oC, 24 h
3) NBS, AgNO3, acetone
COOMe
Br
9
(
S)-11 65% yield, 99% ee
(S)-12 71% yield
(S)-19
1) LiOH, THF, 25 o
OH
Ph
Ph
HO
OH
Ph
Ph
OH
C
2) CuCl, CH3CN, 25 oC
N
(
S)-19, TPPO, Me2Zn
Toluene, 0 oC, 24 h
CHO
+
COOMe
10
3) NBS, AgNO3, acetone
COOMe
Br
9
(
R)-11 65% yield, 99% ee
(R)-12 71% yield
(R)-19
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Scheme 3. Synthesis of (R, E)-tridec-3-en-1-yn-5-ol, 18.
1) LiOH, THF, 25 o
C
OH
OH
S-Ligand, TPPO, Me2Zn
Toluene, 0 oC, 24 h
2) CuCl, CH CN, 25 oC
3
8 17
C H
C7H15
CHO
+
C8H17
COOMe
3) NBS, AgNO3, acetone
Br
R)-14
COOMe
(
13
10
(R)-15 73% yield
69% yield, 99% ee
OH
OH
OH
LiAlH4, AlCl3, THF
reflux,12 h
CuCl, trimethylsilylacetylene, piperidine
Toluene, 25 oC, 4 h
K CO , MeOH
2
3
C8H17
Br
C8H17
25 oC, 6 h
C8H17
TMS
1
6 91% yield
17 87% yield
18 91% yield
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Scheme 4. Synthesis of (S, E)-1 and (3R, 10R, E)-2.
OH
C H
8
C H
8 17
17
8
CuCl, n-BuNH , H O, 0 oC, 0.5 h
(S, E)-octadeca-1,9-dien-4,6-diyn-3-ol (S, E)-1
Br
2
2
(
(
S)-12 71% yield
87% yield
OH
OH
OH
OH
C H
8 17
OH
C H
8
17
18
CuCl, n-BuNH2, H2O, 0 oC, 0.5 h
(
3R, 10R, E)-octadeca-1,8-dien-4,6-diyne-3,10-diol (3R, 10R, E)-2
Br
R)-12 71% yield
87% yield
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Scheme 5. Synthesis of the terminal alkyne 23.
OH
CBr , Ph P
CuI, Bu4NCl, Na2CO3
4
3
Br
C H
7
C H
7
15
C H
7
o
15
o
15
DMF, 25 C, 24 h
DCM, 25 C, 0.5 h
TMS
4
20 98% yield
21 85% yield
C H
7
15
C H
7
15
Ni(OAc) , NaBH , Ethylenediamine
K2CO3, MeOH
2
4
o
o
EtOH, 25 C, 4 h
25 C, 24 h
TMS
22 81% yield
23 91% yield
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Scheme 6. Synthesis of (S, E)-1 analogs.
OH
OH
C8H17
C8H17
Br
Br
Br
(
R)-12
(R)-12
(R, Z)-1 87% yield
OH
OH
OH
OH
C8H17
(
R, E)-1 85% yield
7 15
C H
C7H15
+
rac-(Z)-1 87% yield
rac-12
+
8
OH
23
OH
C8H17
8
C H
17
Br
rac-12
Br
(
S)-12
OH
(
S, Z)-1 85% yield
rac-(E)-1 83% yield
OH
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Table of Contents
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