Synthesis of naturally occurring polyacetylenes via a bis-silylated diyne

Article abstract of DOI:10.1016/j.tet.2006.03.043

A straightforward synthesis of a series of naturally occurring polyacetylenes has been developed, including the montiporynes A and C, possessing cytotoxic activity against several human solid tumor cells, the atractylodin, with antibiotic activity against Escherichia coli, and triynes, which display insecticidal activities, starting from the readily available 1,4-bis(trimethylsilyl)-1,3-butadiyne.

Full text of DOI:10.1016/j.tet.2006.03.043

Tetrahedron 62 (2006) 5126–5132
Synthesis of naturally occurring polyacetylenes via
a bis-silylated diyne
*
Vito Fiandanese, Daniela Bottalico, Giuseppe Marchese and Angela Punzi
`
Dipartimento di Chimica, Universita di Bari, via E. Orabona 4, 70126 Bari, Italy
Received 15 December 2005; revised 23 February 2006; accepted 9 March 2006
Available online 17 April 2006
Abstract—A straightforward synthesis of a series of naturally occurring polyacetylenes has been developed, including the montiporynes A
and C, possessing cytotoxic activity against several human solid tumor cells, the atractylodin, with antibiotic activity against Escherichia coli,
and triynes, which display insecticidal activities, starting from the readily available 1,4-bis(trimethylsilyl)-1,3-butadiyne.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently reported successfully the applications of
our methodology,9 which led to the synthesis of a variety
of unsymmetrically substituted conjugated diynes, to the
preparation of a series of natural diacetylenic compounds,
such as xerulins,10 which are potent inhibitors of the bio-
synthesis of cholesterol, montiporic acids,11 possessing
antibacterial and cytotoxic properties, and virol C and
1-dehydroxyvirol A,12 congeners of cicutoxin and isolated
from Cicuta virosa. In connection with our ongoing work,
we now wish to report the total synthesis of a series of
naturally occurring polyacetylenes.
Polyynes and acetylenic arrays are readily found in a series
of natural products and exhibit a broad distribution in plant
species1 and stony corals2 and display a wide range of bio-
logical activity for their antibacterial,3 antifungal,3,4 and
pesticidal properties.5 In particular the montiporynes,6 pos-
sessing cytotoxic activity against human solid tumor cells,
have been isolated from stony corals Montipora sp., whereas
atractylodin, isolated from the roots of Atractylis cancel-
lata,7 is phototoxic and antibiotic against Escherichia
coli.8 Moreover, other acetylenic products, with a conjugated
triyne structure,1,8 isolated from various plant species, re-
vealed to be extremely phototoxic toward mosquito larvae.
Consequently, the search for improved synthetic methodolo-
gies for well-defined polyynes continues to expand.
As reported in Scheme 1, we have devised a common strat-
egy for the preparation of all these naturally occurring acet-
ylenes. In particular the synthesis of the montiporynes A, C
(2, 3)6 and the atractylodin 48 can be realized starting
O
CH3
7
O
O
Me3Si
Me3Si
CH3
CH3
CH3
5
8
6
SiMe3
1
O
4 Atractylodin
2
Montiporyne A
O
3
Montiporyne C
Scheme 1.
Keywords: Silicon and compounds; Polyacetylenes; Coupling reactions; Bioactive products.
* Corresponding author. Tel./fax: +39 080 5442075; e-mail: fianda@chimica.uniba.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.043

V. Fiandanese et al. / Tetrahedron 62 (2006) 5126–5132
5127
Br
O
O
directly from the same bis-silylated diyne 1, whereas the pre-
cursor for the synthesis of compounds 6–88 can be achieved
from the mono-silylated pentadiyne 5.
COOH
LiBr, Oxone, Na2CO3
CH3CN:H2O/3:2
14
15 (52%)
0 °C
Scheme 3.
2. Results and discussion
The synthetic approach leading to the montiporynes 2, 3 and
to atractylodin 4 was based upon the selective and sequential
substitution of the two silyl groups of the diyne 1. Indeed, the
montiporynes A 2 and C 3 differ in the aliphatic chain linked
to the diyne moiety, a n-heptyl group for montiporyne A and
a 8-nonenyl group for montiporyne C, and, therefore, the
same strategy has been devised for the synthesis of both
the montiporynes.
.
1. MeLi LiBr/Et2O
+
2. H
Me3Si
SiMe3
Me3Si
1
3.
17 (65%)
Br
16
PdCl2(PPh3)2, CuI,
Et3N, THF
O
Br
O
15
Pd(PPh3)4, Ag(I)
K2CO3, MeOH, DMF
Atractylodin
As depicted in Scheme 2, we started with a coupling reaction
between the readily available iodides 9 or 10 and the lithium
salt of the mono-silylated terminal diyne, obtained by selec-
tive desilylation of the diyne 1 with MeLi–Libr complex.13
The coupling products were desilylated with K2CO3 in
MeOH leading to the diyne 11 in 69% yield or to the
enediyne 12 in 57% yield. Finally, a Sonogashira14 cross-
coupling reaction of the diyne 11 with the bromovinyl
ketone 1315 of E-configuration led to the montiporyne A in
77% yield, whereas the reaction of the enediyne 12 with
the same halide 13 led to the montiporyne C in 71% yield.
4 (66%)
Scheme 4.
direct cross-coupling reaction9,12,19 of the silylated enediyne
17 with the bromoderivative 15 in the presence of a Pd(0)
catalyst led to atractylodin 4 in 66% yield. It is noteworthy
that, notwithstanding the ꢀ85:15 mixture of compound 15,
essentially all E product 4 was isolated by chromatography.
As reported in Scheme 1, the key intermediate for the syn-
thesis of triynes 6, 7, and enediyne 8, a potential mosquito
larvicidal agent, is mono-silylated pentadiyne 5. This inter-
mediate was readily prepared20,21 in 55% yield (Scheme 5)
by a coupling reaction between the lithium salt of the diyne
1 and methyl iodide.
Following the same synthetic approach, in order to prepare
atractylodin 4, it was necessary to form the appropriate
halovinyl intermediate possessing a furyl moiety. Thus,
(Scheme 3), the bromoderivative 15 was synthesized,
through modification of literature procedures,16–18 in 52%
yield (E:Zꢀ85:15) by halodecarboxylation of commercially
available (2E)-3-(2-furyl)acrylic acid 14.
Therefore, (Scheme 4), we began from diyne 1, which was
selectively desilylated with the MeLi–LiBr complex. The
mono-silylated diyne was isolated and reacted with (E)-1-
bromopropene 16 in the presence of a Pd(II) catalyst, leading
to compound 17 in an overall 65% yield.10 A further and
.
1. MeLi LiBr/THF
SiMe3
Me3Si
CH3
Me3Si
2. MeI/THF
-80 °C to r.t.
1
5 (55%)
Scheme 5.
Me3Si
SiMe3
1
.
.
1. MeLi LiBr, Et2O, r.t.
1. MeLi LiBr, Et2O, r.t.
2.
2.
I
I
10
9
HMPA, -80 °C to r.t.
3. K2CO3, MeOH, r.t.
HMPA, -80 °C to r.t.
3. K2CO3, MeOH, r.t.
11 (69%)
12 (57%)
Br
Br
13
13
O
O
PdCl2(PPh3)2, CuI, Et3N
THF, r.t.
PdCl2(PPh3)2, CuI, Et3N
THF, r.t.
2
Montiporyne A
3
Montiporyne C
O
O
(77%)
(71%)
Scheme 2.

5128
V. Fiandanese et al. / Tetrahedron 62 (2006) 5126–5132
The strategy employed for the synthesis of the triynes 6 and
7 was based upon the conversion of this mono-silylated
diyne 5 into the 1-bromo-1,3-pentadiyne, which was sub-
jected to a coupling reaction with the appropriate acetylenic
intermediates, the phenylacetylene for the synthesis of com-
pound 6 and the 2-[(1E)-but-1-en-3-ynyl]furan for the syn-
thesis of compound 7. The furyl intermediate was prepared
according to Scheme 6, through a coupling reaction of bromo-
vinylfuran 15 with trimethylsilylacetylene, in the presence
of a Pd(II) catalyst, which led to the mono-silylated enyne
18, and subsequently, after a desilylation reaction with
K2CO3 in MeOH, to the desired enyne 19.
3. Experimental
Macherey–Nagel silica gel (60, particle size 0.040–
0.063 mm) for column chromatography and Macherey–
Nagel aluminum sheets with silica gel 60 F254 for TLC
were used. GC analysis was performed on a Varian 3900
gas chromatograph equipped with a J & W capillary column
(DB-1301, 30 mꢁ0.25 mm i.d.). GC/mass spectrometry
analysis was performed on a Shimadzu GCMS-QP5000
gas chromatograph–mass spectrometer equipped with a
Zebron capillary column (methyl polysiloxane, 30 mꢁ
1
0.25 mm i.d.). H NMR spectra were recorded in deutero-
chloroform or CD3OD on a Bruker AM 500 spectrometer
at 500 MHz. 13C NMR spectra were recorded in deutero-
chloroform or CD3OD on a Bruker AM 500 spectrometer
at 125.7 MHz. IR spectra were recorded on a Perkin–Elmer
FTIR—Spectrum One and on a Shimadzu IR Prestige 21
spectrometers. Solvents were dried before use as follows:
tetrahydrofuran was distilled from sodium, N,N-dimethyl-
formamide and acetonitrile were distilled over molecular
sieves. Melting points (uncorrected) were determined on
a Reichert Microscope. The halide 9-iodonon-1-ene 10
was synthesized from commercial 1,9-nonandiol using liter-
ature procedures.23,24
Therefore, the synthesis of all acetylenic products 6–8 is
outlined in Scheme 7.
Both triynes 6 and 7 were obtained following the same reac-
tion sequence. In particular the diyne 5 was converted by
NBS, in the presence of AgF in acetonitrile,22 to the corre-
sponding bromoderivative, which, without isolation, was
directly coupled with phenylacetylene 20, in the presence
of a Pd(0) catalyst, to afford the triyne 6 in an overall 60%
yield, or with the enyne 19 to lead to triyne 7 in an overall
72% yield. Finally, the enediyne 8 was obtained in 65% yield
by a direct coupling reaction between the silylated diyne 5
and the bromovinyl derivative 15 in the presence of
a Pd(0) catalyst.
3.1. General procedure for the synthesis of monti-
porynes A 2 and C 3
In summary, our synthetic approach to naturally occurring
acetylenes compares favorably with other procedures. A
special advantage of our strategy is represented by the pos-
sibility of preparing different acetylenes starting from the
same compound and following the same reaction sequence.
Moreover, the simplicity of the operations involved and the
ready availability of the starting materials are additional
features making the procedure useful.
MeLi–LiBr complex (1.5 M) in ether (1.1 equiv) was added,
under nitrogen, to a THF (0.5 M) solution of 1,4-bis(tri-
methylsilyl)-1,3-butadiyne 1 (1.0 equiv) at room tempera-
ture. After complete monodesilylation (3–5 h), the reaction
mixture was cooled to ꢂ80 ꢃC. A solution of 1-iodoheptane
9 or 9-iodonon-1-ene 10 (1.1 equiv) in THF (1.1 M) and
HMPA (2.0 equiv) were slowly dropped at the same temper-
ature, then the mixture was slowly brought to room
O
O
O
Br
SiMe3
K2CO3
MeOH
Me3Si
Pd(II), CuI, Et3N/THF
19 (83%)
15
18 (65%)
Scheme 6.
1. NBS, AgF/CH3CN
2.
CH3
Ph
20
Pd(0), (i-Pr)2NH, DMF
1-Phenylhepta-1,3,5-triyne
6 (60%)
1. NBS, AgF/CH3CN
O
O
CH3
Me3Si
CH3
O
2.
5
2-[(1E)-Non-1-en-3,5,7-triynyl]furan
7 (72%)
19
Pd(0), (i-Pr)2NH, DMF
O
Br
CH3
15
Pd(0), Ag(I), K2CO3
MeOH, DMF
2-[(1E)-Hept-1-en-3,5-diynyl]furan
8 (65%)
Scheme 7.

V. Fiandanese et al. / Tetrahedron 62 (2006) 5126–5132
5129
temperature. After reaction completion (18 h), MeOH
(10 mL) and K2CO3 (1.2 equiv) were added, then the reaction
mixture was stirred for 1 h at room temperature. A saturated
aqueous solution of NH4Cl (100 mL) was added and then the
reaction mixture extracted with ethyl acetate (3ꢁ50 mL).
The organic extracts were washed with water (3ꢁ50 mL),
dried over Na2SO4, and concentrated under vacuum. The
residue was purified by column chromatography leading to
the compounds 11 or 12. A solution of diyne 11 or 12
(1.0 equiv) in THF (0.2 M) was added at room temperature,
under nitrogen, to a stirred mixture of 13 (1.0 equiv), PdCl2
(PPh3)2 (0.02 equiv), CuI (0.04 equiv), and Et3N (1.5 equiv)
in THF (0.2 M). After reaction completion (1 h), the mixture
was quenched with a saturated aqueous solution of NH4Cl
(100 mL) and extracted with ethyl acetate (3ꢁ50 mL). The
organic extracts were washed with a saturated aqueous solu-
tion of NaCl (50 mL), dried over Na2SO4, and concentrated
under vacuum. The residue was purified by column chro-
matography leading to title compounds 2 and 3.
J¼16.1, 1.0 Hz, 1H), 6.61 (d, J¼16.1 Hz, 1H), 2.44 (td,
J¼7.0, 1.0 Hz, 2H), 2.31 (s, 3H), 1.61 (quintet, J¼7.0 Hz,
2H), 1.50–1.42 (m, 2H), 1.41–1.31 (m, 6H), 0. 96 (t,
J¼6.9 Hz, 3H); dC (125.7 MHz, CD3OD) 199.3, 141.6,
124.5, 90.8, 85.3, 73.0, 65.9, 33.2, 30.2, 30.2, 29.5, 27.8,
24.0, 20.5, 14.7; MS m/z 216 (M+, <1), 187 (1), 173 (2),
159 (2), 145 (4), 131 (6), 117 (4), 115 (4), 105 (3),
103 (3), 91 (7), 77 (5), 63 (4), 62 (3), 55 (7), 43 (100), 41
(17%).
3.1.4. (3E)-Heptadeca-3,16-dien-5,7-diyn-2-one (3)
(Montiporyne C).6 Compound 3 was prepared from tri-
dec-12-en-1,3-diyne 12 (0.341 g, 1.96 mmol) in accordance
with general procedure. Purification by column chromato-
graphy (silica gel, 5% ethyl acetate/petroleum ether) gave
compound 3 (0.337 g, 71% yield) as a yellow oil. nmax
(neat) 3075, 2928, 2855, 2228, 2139, 1694, 1676, 1638,
1589, 1458, 1424, 1360, 1248, 1234, 1171, 957, 910; dH
(500 MHz, CD3OD) 6.76 (dt, J¼16.1, 1.1 Hz, 1H), 6.61
(d, J¼16.1 Hz, 1H), 5.85 (ddt, J¼17.1, 10.2, 6.7 Hz, 1H),
5.03 (ddt, J¼17.1, 2.2, 1.5 Hz, 1H), 4.96 (ddt, J¼10.2, 2.2,
1.2 Hz, 1H), 2.44 (td, J¼7.1, 1.1 Hz, 2H), 2.31 (s, 3H),
2.13–2.07 (m, 2H), 1.61 (quintet, J¼7.1 Hz, 2H), 1.50–
1.41 (m, 4H), 1.41–1.35 (m, 4H); dC (125.7 MHz,
CD3OD) 199.3, 141.5, 140.3, 124.5, 115.1, 90.8, 85.3,
73.0, 65.9, 35.1, 30.3, 30.3, 30.3, 30.2, 29.5, 27.8, 20.5;
MS m/z 199 (2), 185 (1), 159 (2), 145 (4), 143 (3), 131
(5), 129 (5), 117 (5), 115 (4), 105 (3), 103 (3), 95 (3), 91
(8), 79 (5), 77 (6), 67 (6), 55 (10), 43 (100), 41 (29%).
3.1.1. Undeca-1,3-diyne (11).25 Compound 11 was pre-
pared from 1,4-bis(trimethylsilyl)-1,3-butadiyne 1 (1.00 g,
5.16 mmol) and 1-iodoheptane 9 (1.28 g, 5.67 mmol) in
accordance with general procedure. Purification by column
chromatography (silica gel, petroleum ether) gave com-
pound 11 (0.527 g, 69% yield) as a pale yellow oil. nmax
(neat) 3310, 2955, 2930, 2857, 2297, 2224, 1458, 1425,
1375, 1244, 613; dH (500 MHz, CDCl3) 2.22 (td, J¼7.0,
1.1 Hz, 2H), 1.92 (t, J¼1.1 Hz, 1H), 1.51 (quintet,
J¼7.0 Hz, 2H), 1.39–1.32 (m, 2H), 1.31–1.20 (m, 6H),
0.86 (t, J¼6.9 Hz, 3H); dC (125.7 MHz, CDCl3) 78.5,
68.5, 64.6, 64.4, 31.6, 28.7, 28.7, 28.0, 22.6, 19.0, 14.0;
MS m/z 133 (1), 119 (5), 105 (29), 91 (68), 79 (30), 78
(31), 77 (18), 67 (14), 65 (16), 63 (31), 55 (48), 51 (24),
43 (62), 41 (100%).
3.2. Synthesis of the intermediates 15, 18, 19
3.2.1. 2-[(E)-2-Bromovinyl]furan (15).16–18 Lithium bro-
mide (3.74 g, 43.48 mmol) and sodium carbonate (1.54 g,
14.49 mmol) were added to a stirred solution of carboxylic
acid 14 (2 g, 14.49 mmol) in 50 mL of CH3CN–H2O (3:2
v/v) at 0 ꢃC, and then followed by the addition in one portion
of a solution of Oxone (4.45 g, 7.25 mmol) in 24 mL of
H2O. After reaction completion (5 min), the mixture was
quenched with a saturated aqueous solution of NH4Cl
(50 mL) and extracted with ethyl acetate (3ꢁ50 mL). The
organic extracts were washed with a saturated aqueous solu-
tion of NaOH (10%, 3ꢁ50 mL) dried over Na2SO4, and
concentrated under vacuum. The residue was purified by
percolation on a florisil column (petroleum ether) affording
0.65 g (52% yield) of compound 15 as a yellow oil. nmax
(neat) 3078, 1629, 1477, 1014, 926, 788, 771, 737, 689;
dH (500 MHz, CDCl3) (E+Z isomer): (E isomer) 7.37
(d, J¼1.8 Hz, 1H), 6.89 (d, J¼13.9 Hz, 1H), 6.72 (d,
J¼13.9 Hz, 1H), 6.38 (dd, J¼3.3, 1.8 Hz, 1H), 6.26 (d,
J¼3.3 Hz, 1H), (Z isomer)26 7.44 (d, J¼1.8 Hz, 1H), 7.10
(d, J¼3.3 Hz, 1H), 7.06 (d, J¼8.3 Hz, 1H), 6.50–6.47 (m,
1H), 6.31 (d, J¼8.3 Hz, 1H); dC (125.7 MHz, CDCl3)
151.1, 142.6, 125.4, 111.3, 108.6, 105.3; MS m/z 174
(M+2, 55), 172 (M+, 58), 145 (10), 143 (10), 119 (3), 117
(3), 93 (12), 87 (7), 86 (7), 65 (100), 64 (15), 63 (34), 62
(15), 61 (8), 50 (8%).
3.1.2. Tridec-12-en-1,3-diyne (12). Compound 12 was pre-
pared from 1,4-bis(trimethylsilyl)-1,3-butadiyne 1 (1.00 g,
5.16 mmol) and 9-iodonon-1-ene 10 (1.429 g, 5.67 mmol)
in accordance with general procedure. Purification by col-
umn chromatography (silica gel, petroleum ether) gave com-
pound 12 (0.512 g, 57% yield) as a pale yellow oil. [Found:
C, 89.50; H, 10.43. C13H18 requires C, 89.59; H, 10.41%];
nmax (neat) 3308, 3076, 2974, 2928, 2855, 2297, 2224,
1640, 1458, 1425, 1246, 995, 910, 617; dH (500 MHz,
CDCl3) 5.78 (ddt, J¼17.1, 10.2, 6.7 Hz, 1H), 4.97 (ddt,
J¼17.1, 2.2, 1.6 Hz, 1H), 4.91 (ddt, J¼10.2, 2.2, 1.2 Hz,
1H), 2.23 (td, J¼7.1, 1.1 Hz, 2H), 2.05–1.99 (m, 2H), 1.93
(t, J¼1.1 Hz, 1H), 1.51 (quintet, J¼7.1 Hz, 2H), 1.41–1.32
(m, 4H), 1.31–1.25 (m, 4H); dC (125.7 MHz, CDCl3)
139.0, 114.2, 78.4, 68.5, 64.7, 64.4, 33.7, 28.9, 28.8, 28.8,
28.7, 27.9, 18.9; MS m/z 145 (3), 131 (11), 117 (19), 105
(15), 91 (51), 79 (24), 78 (15), 77 (16), 67 (22), 65 (14),
63 (23), 55 (35), 51 (20), 41 (100%).
3.1.3. (3E)-Pentadec-3-en-5,7-diyn-2-one (2) (Monti-
poryne A).6 Compound 2 was prepared from undeca-1,3-
diyne 11 (0.423 g, 2.86 mmol) in accordance with general
procedure. Purification by column chromatography (silica
gel, 5% ethyl acetate/petroleum ether) gave compound 2
(0.476 g, 77% yield) as a yellow oil. nmax (neat) 2955,
2928, 2857, 2228, 2139, 1694, 1676, 1589, 1466, 1424,
1360, 1248, 1171, 957; dH (500 MHz, CD3OD) 6.76 (dt,
3.2.2. 2-[(1E)-4-Trimethylsilylbut-1-en-3-ynyl]furan
(18).
A solution of trimethylsilylacetylene (0.445 g,
4.528 mmol) in THF (5 mL) was added at room tem-
perature, under nitrogen, to a stirred mixture of bromovinyl-
furan 15 (0.649 g, 3.773 mmol), PdCl2(PPh3)2 (0.053 g,

5130
V. Fiandanese et al. / Tetrahedron 62 (2006) 5126–5132
0.075 mmol), CuI (0.0287 g, 0.151 mmol), and Et3N
(0.573 g, 5.660 mmol) in THF (7 mL). After reaction com-
pletion (1 h), the mixture was quenched with a saturated
aqueous solution of NH4Cl (20 mL) and extracted with ethyl
acetate (3ꢁ20 mL). The organic extracts were washed with
H2O (3ꢁ20 mL) dried over Na2SO4, and concentrated under
vacuum. The residue was purified by column chromato-
graphy (petroleum ether) leading to 0.47 g of compound
18 (65% yield) as a pale yellow oil. [Found: C, 69.50; H,
7.36. C11H14OSi requires C, 69.42; H, 7.41%]; nmax (neat)
2959, 2897, 2115, 1481, 1251, 1086, 1065, 1015, 944,
844, 760, 738; dH (500 MHz, CDCl3) 7.35 (d, J¼1.8 Hz,
1H), 6.72 (d, J¼16.0 Hz, 1H), 6.37 (dd, J¼3.4, 1.8 Hz,
1H), 6.30 (d, J¼3.4 Hz, 1H), 6.05 (d, J¼16.0 Hz, 1H), 0.2
(s, 9H); dC (125.7 MHz, CDCl3) 152.0, 143.1, 129.3,
111.8, 110.3, 106.1, 104.3, 97.7, –0.1; MS m/z 190 (M+,
78), 175 (100), 160 (12), 147 (45), 145 (48), 131 (16), 116
(26), 115 (82), 105 (16), 91 (21), 88 (51), 75 (25), 73 (24),
67 (16), 59 (20), 53 (45), 45 (81), 43 (78%).
3.3.2. 2-[(1E,7E)-Nona-1,7-dien-3,5-diynyl]furan (4)
(Atractylodin).8 To a solution of bromovinylfuran 15
(0.238 g, 1.389 mmol) in anhydrous DMF (3.5 mL) at
room temperature, under nitrogen, were successively added
Pd(PPh3)4 (0.08 g, 0.0694 mmol), AgCl (0.0398 g,
0.278 mmol), and K2CO3 (1.533 g, 11.11 mmol). The result-
ing mixture was stirred for 5 min, then MeOH (0.355 g,
11.11 mmol) was added followed by a solution of mono-
silylated enediyne 17 (0.225 g, 1.39 mmol) in anhydrous
DMF (3.5 mL). The reaction mixture was warmed to
40 ꢃC and stirred at same temperature. After reaction com-
pletion (1 h), the mixture was quenched with a saturated
aqueous solution of NH4Cl (20 mL) and extracted with ethyl
acetate (3ꢁ20 mL). The organic extracts were washed with
a saturated aqueous solution of NaCl (3ꢁ20 mL), dried over
Na2SO4, and concentrated under vacuum. The residue was
purified by column chromatography (petroleum ether) lead-
ing to 0.17 g of compound 4 (66% yield) as a yellow solid
(mp 49–51 ꢃC). nmax (KBr) 3133, 2964, 2929, 2852, 2194,
2126, 1616, 1475, 1440, 1261, 1096, 1016, 943, 802, 742;
dH (500 MHz, CDCl3) 7.37–7.35 (m, 1H), 6.77 (d,
J¼16.0 Hz, 1H), 6.40 (dd, J¼3.4, 1.8 Hz, 1H), 6.35 (dd,
J¼3.4, 0.5 Hz, 1H), 6.31 (dq, J¼15.8, 6.9 Hz, 1H), 6.09
(d, J¼16.0 Hz, 1H), 5.61–5.50 (m, 1H), 1.81 (dd, J¼6.9,
1.8 Hz, 3H); dC (125.7 MHz, CDCl3) 151.9, 143.6, 143.5,
130.7, 112.1, 111.1, 109.9, 104.8, 81.9, 80.2, 77.2, 72.5,
18.9; MS m/z 182 (M+, 100), 181 (14), 153 (46), 152 (89),
151 (21), 139 (15), 127 (13), 126 (13), 115 (12), 113 (8),
102 (9), 98 (8), 91 (7), 89 (8), 87 (14), 86 (10), 77 (21), 76
(55), 75 (23), 74 (22), 64 (26), 63 (36), 62 (14), 52 (11),
51 (32), 50 (18%).
3.2.3. 2-[(1E)-But-1-en-3-ynyl]furan (19). K2CO3
(0.358 g, 2.589 mmol) was added to a MeOH solution
(4 mL) of silylated compound 18 (0.41 g, 2.158 mmol).
The reaction mixture was stirred for 1 h at room temperature,
then quenched with H2O (30 mL), and extracted with ethyl
acetate (30 mL). The organic extracts were dried over
Na2SO4 and concentrated under vacuum leading to com-
pound 19 as a pale yellow oil; 0.212 g, yield 83%. [Found:
C, 81.38; H, 5.10. C8H6O requires C, 81.34; H, 5.12%];
nmax (neat) 3294, 2095, 1624, 1479, 1373, 1246, 1045,
1016, 947, 741; dH (500 MHz, CDCl3) 7.36 (d, J¼1.8 Hz,
1H), 6.75 (d, J¼16.0 Hz, 1H), 6.49 (dd, J¼3.4, 1.8 Hz,
1H), 6.33 (d, J¼3.4 Hz, 1H), 6.01 (dd, J¼16.0, 2.5 Hz,
1H), 3.07 (dd, J¼2.5, 0.6 Hz, 1H); dC (125.7 MHz,
CDCl3) 151.7, 143.2, 130.1, 111.8, 110.4, 105.0, 82.8,
80.0; MS m/z 118 (M+, 75), 90 (67), 89 (100), 64 (19),
63 (64), 62 (23), 59 (12), 51 (27), 50 (25), 45 (24), 40 (11%).
3.4. Synthesis of compounds 5–8
3.4.1. 1-Trimethylsilyl-1,3-pentadiyne (5).20,21 MeLi–
LiBr complex (1.5 M) in ether (18.9 mL, 28.350 mmol)
was slowly dropped, under nitrogen, to a THF solution
(50 mL) of 1,4-bis(trimetilsilyl)-1,3-butadiyne
1 (5 g,
3.3. Synthesis of the atractylodin 4
25.773 mmol) at room temperature. After complete mono-
desilylation (5 h), the reaction mixture was cooled to a
ꢂ80 ꢃC and a solution of methyl iodide (4 g, 28.350 mmol)
in THF (40 mL) was slowly dropped at the same tempera-
ture, then the mixture was slowly brought to room tempera-
ture. After reaction completion (2 h), the mixture was
quenched with a saturated aqueous solution of NH4Cl
(100 mL) and extracted with ethyl ether (3ꢁ30 mL). The
organic extracts were washed with water (3ꢁ30 mL), dried
over Na2SO4, and concentrated under vacuum. The residue
was purified by column chromatography (petroleum ether)
leading to 1.93 g of compound 5 (55% yield) as a pale yellow
oil. nmax (neat) 2961, 2232, 2113, 1251, 1196, 870, 844, 760;
dH (500 MHz, CDCl3) 1.92 (s, 3H), 0.17 (s, 9H); dC
(125.7 MHz, CDCl3) 88.5, 82.2, 75.5, 64.7, 4.0, ꢂ0.5; MS
m/z 136 (M+, 14), 121 (100), 107 (3), 105 (3), 93 (9), 91
(7), 79 (7), 77 (15), 53 (20), 43 (22%).
3.3.1. (5E)-1-Trimethylsilyl-hept-5-en-1,3-diyne (17).10
MeLi–LiBr complex (1.5 M) in ether (20.6 mL,
30.93 mmol) was added to an ether solution (40 mL) of
1,4-bis(trimethylsilyl)-1,3-butadiyne 1 (4 g, 20.57 mmol)
at room temperature. After reaction completion (4 h), the
mixture was quenched with a saturated aqueous solution of
NH4Cl (20 mL) and extracted with ethyl ether (3ꢁ20 mL).
The organic extracts were washed with water (3ꢁ20 mL),
dried over Na2SO4, and concentrated under vacuum. The
mono-silylated diyne 1-trimethylsilyl-1,3-butadiyne 1a
was purified by distillation (2.0 g, 79% yield). A THF solu-
tion (20 mL) of diyne 1a (1.21 g, 9.92 mmol) was added at
room temperature, under nitrogen, to a stirred mixture of
(E)-1-bromopropene 18 (1.0 g, 8.26 mmol), Et3N (1.25 g,
12.40 mmol), CuI (0.063 g, 0.33 mmol), and Pd(PPh3)2Cl2
(0.116 g, 0.165 mmol) in THF (12 mL). After reaction com-
pletion (12 h), the mixture was quenched with a saturated
aqueous solution of NH4Cl (20 mL) and extracted with ethyl
acetate (3ꢁ20 mL). The organic extracts were washed with
water (3ꢁ20 mL), dried over Na2SO4, and concentrated
under vacuum. Purification by column chromatography
(petroleum ether) led to the title compound 17 as a yellow
oil (1.1 g, 82% yield).
3.4.2. 1-Phenylhepta-1,3,5-triyne (6).8,27 To a solution
of the mono-silylated diyne 5 (0.345 g, 2.537 mmol) in
anhydrous CH3CN (4 mL) were added NBS (0.542 g,
3.044 mmol) and AgF (0.383 g, 3.044 mmol) in the dark.
The resulting mixture was stirred for 1 h at room tempera-
ture; after reaction completion (1 h), the mixture was di-
rectly percolated on a florisil column with DMF (30 mL)

V. Fiandanese et al. / Tetrahedron 62 (2006) 5126–5132
5131
as eluent. To this mixture of bromodiyne in DMF, were
added at room temperature, under nitrogen, Pd(PPh3)4
(0.147 g, 0.127 mmol) and i-Pr2NH (0.51 g, 5.073 mmol)
followed by a solution of phenylacetylene 20 (0.26 g,
2.537 mmol) in anhydrous DMF (3 mL). After reaction
completion (70 h), the mixture was quenched with a satu-
rated aqueous solution of NH4Cl (50 mL) and extracted
with ethyl acetate (3ꢁ30 mL). The organic extracts were
washed with a saturated aqueous solution of NaCl
(3ꢁ30 mL) dried over Na2SO4, and concentrated under vac-
uum. The residue was purified by column chromatography
(petroleum ether) leading to 0.25 g of compound 6 (overall
60% yield) as a white solid (mp 56–58 ꢃC). nmax (KBr)
2957, 2924, 2853, 2219, 1490, 1440, 1425, 1024, 756,
689, 525; dH (500 MHz, CDCl3) 7.51–7.47 (m, 2H), 7.39–
7.34 (m, 1H), 7.33–7.28 (m, 2H), 1.99 (s, 3H); dC
(125.7 MHz, CDCl3) 132.9, 129.5, 128.4, 121.1, 78.3,
75.2, 74.6, 67.4, 64.9, 58.9, 4.6; MS m/z 164 (M+, 100),
163 (63), 138 (48), 137 (15), 110 (8), 98 (7), 88 (7), 87
(11), 86 (13), 82 (50), 74 (6), 69 (16), 67 (8), 63 (11), 55
(9), 51 (6), 50 (6%).
mixture was warmed to 40 ꢃC and stirred at same tempera-
ture. After reaction completion (1 h), the mixture was
quenched with a saturated aqueous solution of NH4Cl
(20 mL) and extracted with ethyl acetate (3ꢁ20 mL). The or-
ganic extracts were washed with a saturated aqueous solution
of NaCl (3ꢁ20 mL), dried over Na2SO4, and concentrated
under vacuum. The residue was purified by column chroma-
tography (petroleum ether) leading to 0.126 g of compound
8 (65% yield) as a yellow oil. nmax (neat) 3146, 3119, 3046,
2911, 2841, 2230, 2137, 1618, 1481, 1385, 1262, 1016, 941,
926, 883, 741; dH (500 MHz, CDCl3) 7.36 (d, J¼1.8 Hz,
1H), 6.76 (d, J¼16.0 Hz, 1H), 6.39 (dd, J¼3.4, 1.8 Hz,
1H), 6.33 (d, J¼3.4 Hz, 1H), 6.03 (d, J¼16.0 Hz, 1H),
1.99 (s, 3H); dC (125.7 MHz, CDCl3) 151.9, 143.3, 130.7,
112.0, 110.8, 104.9, 81.4, 77.4, 73.8, 64.6, 4.7; MS m/z
156 (M+, 100), 155 (19), 128 (32), 127 (51), 126 (18), 102
(40), 101 (12), 87 (8), 78 (27), 77 (25), 76 (17), 75 (25), 74
(20), 64 (21), 63 (39), 62 (17), 51 (82), 50 (57%).
Acknowledgments
This work was financially supported by the Ministero dell’Is-
`
3.4.3. 2-[(1E)-Non-1-en-3,5,7-triynyl]furan (7).8 To a solu-
tion of the mono-silylated diyne 5 (0.244 g, 1.797 mmol) in
anhydrous CH3CN (3 mL) were added NBS (0.384 g,
2.156 mmol) and AgF (0.272 g, 2.156 mmol) in the dark.
The resulting mixture was stirred for 1 h at room tempera-
ture; after reaction completion (1 h), the mixture was di-
rectly percolated on a florisil column with DMF (21 mL)
as eluent. To this mixture of bromodiyne in DMF, were
added at room temperature, under nitrogen, Pd(PPh3)4
(0.104 g, 0.090 mmol) and i-Pr2NH (0.363 g, 3.593 mmol)
followed by a solution of the 2-[(1E)-but-1-en-3-ynyl]furan
19 (0.212 g, 1.797 mmol) in anhydrous DMF (2 mL). After
reaction completion (70 h), the mixture was quenched with
a saturated aqueous solution of NH4Cl (30 mL) and ex-
tracted with ethyl acetate (3ꢁ30 mL). The organic extracts
were washed with a saturated aqueous solution of NaCl
(3ꢁ30 mL), dried over Na2SO4, and concentrated under vac-
uum. The residue was purified by column chromatography
(petroleum ether) leading to 0.233 g of compound 7 (overall
72% yield) as a pale yellow solid (mp 59–62 ꢃC). nmax (KBr)
2955, 2913, 2852, 2219, 2203, 2166, 1613, 1479, 1282,
1261, 1051, 938, 927, 804, 740; dH (500 MHz, CDCl3)
7.37 (d, J¼1.6 Hz, 1H), 6.83 (d, J¼15.9 Hz, 1H), 6.41 (dd,
J¼3.4, 1.6 Hz, 1H), 6.39 (dd, J¼3.4, 0.5 Hz, 1H), 6.03
(dd, J¼15.9, 0.5 Hz, 1H), 1.98 (s, 3H); dC (125.7 MHz,
CDCl3) 151.6, 143.8, 132.3, 112.2, 111.7, 103.8, 79.0,
77.6, 75.1, 68.6, 65.0, 59.2, 4.6; MS m/z 180 (M+, 100),
179 (6), 152 (38), 151(67), 150 (35), 126 (33), 102 (8),
100 (8), 99 (16), 98 (20), 90 (19), 87 (14), 86 (14), 77
(13), 76 (31), 75 (30), 74 (38), 63 (56), 62 (22), 51 (25),
50 (24%).
truzione, dell’Universita e della Ricerca (M.I.U.R.), Rome,
and the University of Bari (National Project ‘Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni’).
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