Synthesis of polyacetylenic montiporic acids by means of organosilicon compounds

Article abstract of DOI:10.1016/j.jorganchem.2005.03.033

A straightforward synthesis of polyacetylenic montiporic acids A and B has been developed, based upon the selective and sequential substitution of the two trimethylsilyl groups of the readily available 1,4-bis(trimethylsilyl)-1,3- butadiyne.

Full text of DOI:10.1016/j.jorganchem.2005.03.033

Journal of Organometallic Chemistry 690 (2005) 3004–3008
www.elsevier.com/locate/jorganchem
Synthesis of polyacetylenic montiporic acids by means
of organosilicon compounds
*
Vito Fiandanese , Daniela Bottalico, Giuseppe Marchese, Angela Punzi
`
Dipartimento di Chimica, Universita di Bari, via E. Orabona 4, 70126 Bari, Italy
Received 27 January 2005; accepted 18 March 2005
Available online 5 May 2005
Abstract
A straightforward synthesis of polyacetylenic montiporic acids A and B has been developed, based upon the selective and sequen-
tial substitution of the two trimethylsilyl groups of the readily available 1,4-bis(trimethylsilyl)-1,3-butadiyne.
ꢀ 2005 Elsevier B.V. All rights reserved.
Keywords: Silicon compounds; Polyacetylenes; Coupling reactions; Antifungal agents
1. Introduction
So far, in spite of the interesting properties of these
compounds, only one report [2] has described the total
synthesis of montiporic acids A and B, employing two
In recent years, stony corals have been objects of
investigation by organic chemists as sources of interest-
different synthetic strategies for the two products.
ing bioactive natural products. In particular, the stony
coral Montipora sp. is especially rich in acetylenic com-
pounds that have been shown to possess antifungal, anti-
bacterial, ichthyotoxic, and cytotoxic properties [1].
[4], we have recently reported [5] a straightforward and
Recently, two new diacetylenic carboxylic acids, montip-
oric acids A 1 and B 2, have been isolated [1a,1c] from the
eggs of the scleractinian hermaphroditic coral Montipora
digitata and exhibited interesting biological activities,
such as antimicrobial activity against Escherichia coli
and cytotoxicity against P-388 murine leukemia cells.
In connection with our previous studies dealing with
the synthesis of stereodefined conjugated polyunsatu-
rated systems [3] and of a series of natural compounds
general route to a variety of unsymmetrically substituted
conjugated diynes, based upon the selective and sequen-
tial substitution of the trimethylsilyl groups of the read-
ily available 1,4-bis(trimethylsilyl)-1,3-butadiyne with
alkyl, aryl and vinyl groups. Now, we wish to report a
straightforward and expeditious procedure for the total
synthesis of both montiporic acids A 1 and B 2 starting
from a common intermediate and following the same
reaction sequence.
O
CO2H
1 Montiporic Acid A
2. Results and discussion
O
CO2H
2 Montiporic Acid B
Our overall retrosynthesis is summarized in Scheme 1.
Montiporic acids A and B differ in the aliphatic chain
linked to the diyne moiety, a n-heptyl group for
montiporic acid A (1, n = 3) and a 8-nonenyl group
*
Corresponding author. Tel.: +390805442075; fax: +390805442129.
E-mail address: fianda@chimica.uniba.it (V. Fiandanese).
0022-328X/$ - see front matter ꢀ 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.03.033

V. Fiandanese et al. / Journal of Organometallic Chemistry 690 (2005) 3004–3008
3005
of 8 with 1-iodoheptane 6 led to compound 3 in 62%
yield.
O
CO2H
(
)
n
1
2’
The subsequent reaction of compound 3 with ethyl 2-
bromoacetate 5 under phase transfer catalysis condi-
tions [9] gave montiporic acid A in 80% yield.
For the synthesis of montiporic acid B, that was
obtained in 82% yield, the same reaction sequence was
followed employing in the first step a different halide,
9-iodonon-1-ene 7.
1 (n = 3) Montiporic Acid A
13
2 (n = 5, ∆ ) Montiporic Acid B
OH
Br
CO2Et
(
)
+
n
3 (n = 3)
4 (n = 5, ∆
5
13
)
It is noteworthy that also the diacetylene alcohols 3
and 4 are marine metabolites isolated from the stony
coral Montipora sp. and other species of hermatypic cor-
als [1a,1d]. These compounds possess antifungal, anti-
bacterial, ichthyotoxic properties and exhibited
significant cytotoxicity against a small panel of human
solid tumor cell lines.
OH
(
)
+
I
n
8
6 (n = 3)
7 (n = 5, ∆ )
8
Scheme 1.
In conclusion, the procedure described here appears
to be a useful route to polyacetylenic montiporic acids.
A special advantage of our strategy is represented by
the possibility of synthesizing both the montiporic acids
starting from a common intermediate and employing the
same reaction sequence. Moreover, the simplicity of the
operations involved, the mild reactions conditions and
the ready availability of the silyl derivative employed
are additional features making the procedure very
promising.
for montiporic acid B (2, n = 5, D13). Thus, the discon-
0
nection of the O–C2 bond leads to the polyunsaturated
alcohols 3, 4 and to the bromoester 5. A further discon-
nection of the C5–C6 bond leads to the appropriate ha-
lides 6, 7 and to the key intermediate 8.
Accordingly, the synthesis of both the montiporic
acids 1 and 2 can be realized employing the same meth-
odology, starting with a coupling reaction between the
diynol 8 [6] and the readily available halides 6 or 7 which
leads to the polyunsaturated alcohols 3 [1a,2,7] or 4
[1a,1d,2]. The subsequent functionalization with the ha-
lide 5 can directly give both the montiporic acids 1 and
2.
3. Experimental section
The synthesis of the diynol 8 was performed as de-
picted in Scheme 2, in accordance with our recently
published procedure for the synthesis of conjugated
diynes [5], starting from the same intermediate, the
commercially available 1,4-bis(trimethylsilyl)-1,3-but-
adiyne 9.
THF and Et2O were dried before use by distillation
from Na/benzophenone ketyl under nitrogen. All other
solvents were used as obtained. All reactions were car-
ried out under nitrogen in dried glassware. Macherey–
Nagel silica gel (60, particle size 0.040–0.063 mm) for
column chromatography and Macherey–Nagel alumi-
num sheets with silica gel 60 F254 for TLC were used.
GC analysis were performed on a Varian 3900 gas
chromatograph equipped with a J&W capillary column
(DB-1301, 30 m · 0.25 mm i.d.). GC/mass-spectrometry
analysis were performed on a Shimadzu GCMS-
The diyne
9
was selectively desilylated with
MeLi–LiBr complex affording the lithium salt of the
mono-silylated terminal diyne which was coupled with
paraformaldheyde to give the mono-silylated diynol 11
[6b,8] in 86% yield. A further desilylation reaction of
11 with K2CO3 in MeOH led to compound 8 in 80%
yield.
Therefore, the synthesis of montiporic acids A and B
was performed as depicted in Scheme 3.
Both montiporic acids A and B were synthesized
starting from the same compound 8. In the case of mon-
tiporic acid A, the coupling reaction of the lithium salt
QP5000
equipped with a Zebron capillary column (methyl poly-
gas
chromatograph-mass
spectrometer
1
siloxane, 30 m · 0.25 mm i.d.). H NMR spectra were
recorded in deuterochloroform on a Bruker AM 500
spectrometer at 500 MHz. 13C NMR spectra were
recorded in deuterochloroform on a Bruker AM 500
spectrometer at 125.7 MHz. IR spectra were measured
1. MeLi-LiBr
Et2O, r.t.
OH
OH
K2CO3
MeOH, r.t.
80%
Me3Si
SiMe3
Me3Si
2. (CH2O) , Et2O
n
0 C to r.t.
9
11
8
86%
Scheme 2.

3006
V. Fiandanese et al. / Journal of Organometallic Chemistry 690 (2005) 3004–3008
OH
8
1. n-BuLi, -80 ˚C, THF
2.
1. n-BuLi, -80 ˚C, THF
2.
I
I
7
6
HMPA, -30 ˚C to r.t.
HMPA, -30 ˚C to r.t.
62%
59%
OH
OH
3
4
Br
CO2Et
Br
1.
CO2Et
1.
5
5
(n-Bu)4NHSO4, KOH
(n-Bu)4NHSO4, KOH
H2O, benzene, 10 ˚C
H2O, benzene, 10 ˚C
2. HCl
2. HCl
82%
80%
O
CO2H
O
CO2H
2 Montiporic Acid B
1 Montiporic Acid A
Scheme 3.
on a Perkin–Elmer FT-IR 1710 spectrometer. Melting
points (uncorrected) were determined on a Reichert
Microscope. The halide 9-iodonon-1-ene 7 was synthe-
sizing from commercial 1,9-nonandiol using literature
procedures [10,11].
7), 137 (76), 109 (30), 85 (25), 83 (22), 77 (37), 75 (100),
55 (15), 53 (36), 45 (97), 43 (59).
3.2. 2,4-Pentadiyn-1-ol (8) [6a]
K2CO3(1.64 g, 11.87 mmol) was added to a MeOH
solution (15 mL) of compound 11 (1.5 g, 9.85 mmol).
The reaction mixture was stirred for 1 h at room temper-
ature, then quenched with a saturated aqueous solution
of NH4Cl (40 mL), and extracted with ethyl ether
(3 · 50 mL). The organic extracts were washed with a
saturated aqueous solution of NaCl (50 mL), dried over
Na2SO4 and concentrated at atmospheric pressure. Puri-
fication of the residue by percolation on florisil column
with petroleum ether/Et2O (7:3) as eluent led to com-
pound 8 as a yellow-orange oil; yield: 0.635 g (80%).
1H NMR (500 MHz, CDCl3): d = 4.28 (br s, 2H), 2.77
(br s, 1H), 2.18 (t, J = 1.1 Hz, 1H). 13C NMR
(125.7 MHz, CDCl3): d = 74.5, 69.6, 68.3, 67.3, 50.9.
IR (neat): m = 3300, 3290, 2918, 2862, 2220, 2065,
1445, 1385, 1358, 1138, 1015, 631 cmꢀ1. GC–MS: m/z
(%) = 80 (M+, 8), 79 (20), 63 (28), 62 (25), 61 (19), 52
(100), 51 (54), 50 (51), 49 (23).
3.1. 5-Trimethylsilyl-2,4-pentadiyn-1-ol (11) [6b]
MeLi–LiBr complex (1.5 M) in ether (20.6 mL,
30.9 mmol) was added to an ether solution (50 mL) of
1,4-bis(trimethylsilyl)-1,3-butadiyne 9 (5.0 g, 25.7 mmol)
at room temperature under nitrogen. After complete
desilylation (8 h), the reaction mixture was cooled to
0 ꢁC, a suspension of paraformaldheyde (0.773 g,
25.7 mmol) in Et2O (10 mL) was added, then the mixture
was brought to room temperature. After reaction com-
pletion (7 h), the mixture was quenched with a saturated
aqueous solution of NH4Cl (80 mL), and extracted with
ethyl acetate (3 · 80 mL). The organic extracts were
dried over anhydrous Na2SO4 and concentrated under
vacuum. Purification by column chromatography of
the residue with petroleum ether/EtOAc (8:2) as eluent
led to compound 11 as a pale yellow oil; yield: 3.37 g
1
(86%). H NMR (500 MHz, CDCl3): d = 4.29 (s, 2H),
2.34 (br s, 1H), 0.16 (s, 9H). 13C NMR (125.7 MHz,
CDCl3): d = 87.4, 87.2, 75.8, 70.3, 51.0, ꢀ0.6. IR (neat):
m = 3367, 2961, 2901, 2862, 2224, 2108, 1423, 1384, 1252,
1020, 862, 845, 761 cmꢀ1. GC–MS: m/z (%) = 152 (M+,
3.3. 2,4-Dodecadiyn-1-ol (3) [1a,7c]
A solution of n-BuLi 1.6 M in hexane (5.2 mL,
8.32 mmol) was slowly dropped, at ꢀ80 ꢁC, under

V. Fiandanese et al. / Journal of Organometallic Chemistry 690 (2005) 3004–3008
3007
nitrogen, to a solution of 2,4-pentadiyn-1-ol 8 (0.30 g,
3.5. Tetradec-13-en-2,4-diyn-1-ol (4) [1a,1d]
3.75 mmol) in anhydrous THF (10 mL). The resulting
reaction mixture was maintained for 30 min at
ꢀ80 ꢁC, then the reaction temperature was raised to
ꢀ30 ꢁC. After HMPA addition (1.3 mL, 7.50 mmol), a
solution of 1-iodoheptane 6 (0.848 g, 3.75 mmol) in
anhydrous THF (10 mL) was added dropwise, then
the reaction temperature was slowly raised to room tem-
perature. After reaction completion (15 h), the mixture
was quenched with a saturated aqueous solution of
NH4Cl (30 mL) and extracted with ethyl acetate
(3 · 30 mL). The organic extracts were washed with a
saturated aqueous solution of NaCl (3 · 30 mL), dried
over anhydrous Na2SO4 and concentrated under vac-
uum. The residue was purified by column chromatogra-
phy with petroleum ether/EtOAc (8:2) as eluent leading
to compound 3 as a pale yellow solid; yield: 0.414 g
(62%), m.p. 36–38 ꢁC (lit. [7c] 34–36 ꢁC). 1H NMR
(500 MHz, CDCl3): d = 4.27 (s, 2H), 2.24 (t, J = 7.2
Hz, 2H), 1.93 (br s, 1H), 1.50 (quint, J = 7.2 Hz, 2H),
1.39–1.31 (m, 2H), 1.30–1.19 (m, 6H), 0.85 (t, J =
6.9 Hz, 3H). 13C NMR (125.7 MHz, CDCl3): d = 81.9,
73.5, 70.9, 64.3, 51.5, 31.6, 28.8, 28.7, 28.1, 22.6, 19.2,
14.0. IR (neat): m = 3313, 2955, 2929, 2857, 2256,
1466, 1383, 1233, 1026 cmꢀ1. GC–MS: m/z (%) = 149
(2), 145 (2), 135 (7), 117 (8), 107 (14), 105 (10), 91
(39), 79 (58), 77 (41), 67 (26), 65 (27), 55 (45), 51 (25),
43 (60), 41 (100).
A solution of n-BuLi 1.6 M in hexane (3.1 mL,
4.96 mmol) was added dropwise, at ꢀ80 ꢁC, under nitro-
gen, to a solution of compound 8 (0.178 g, 2.23 mmol) in
anhydrous THF (8 mL). The resulting reaction mixture
was maintained for 30 min at ꢀ80 ꢁC, then the reaction
temperature was raised to ꢀ30 ꢁC. After HMPA addi-
tion (0.78 mL, 4.48 mmol), a solution of 9-iodonon-
1-ene 7 (0.562 g, 2.23 mmol) in anhydrous THF (8 mL)
was added dropwise, then the reaction temperature
was slowly raised to room temperature. After reaction
completion (15 h), the mixture was quenched with a sat-
urated aqueous solution of NH4Cl (30 mL) and ex-
tracted with ethyl acetate (3 · 30 mL). The organic
extracts were washed with a saturated aqueous solution
of NaCl (3 · 30 mL), dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by
column chromatography with petroleum ether/EtOAc
(8:2) as eluent leading to compound 4 as a yellow-orange
1
oil; yield: 0.268 g (59%). H NMR (500 MHz, CDCl3):
d = 5.79 (ddt, J = 17.1, 10.2, 6.7 Hz, 1H), 4.97 (ddt,
J = 17.1, 2.2, 1.5 Hz, 1H), 4.91 (ddt, J = 10.2, 2.2,
1.2 Hz, 1H), 4.30 (br s, 2H), 2.26 (tt, J = 7.2, 1.0 Hz,
2H), 2.05–1.99 (m, 2H), 1.63 (br s, 1H), 1.51 (quint,
J = 7.2 Hz, 2H), 1.40–1.32 (m, 4H), 1.31–1.24 (m, 4H).
13C NMR (125.7 MHz, CDCl3): d = 139.0, 114.1, 81.7,
73.6, 70.7, 64.4, 51.3, 33.7, 28.9, 28.8, 28.8, 28.7, 28.0,
19.2. IR (neat): m = 3349, 3076, 2928, 2856, 2256, 1640,
1461, 1384, 1232, 1025, 910 cm ꢀ1. GC–MS: m/z (%)
= 161 (2), 147 (3), 145 (2), 143 (4), 133 (5), 131 (7),
129 (6), 105 (14), 91 (38), 81 (14), 79 (34), 77 (25), 67
(32), 65 (21), 55 (50), 53 (22), 51 (18), 41 (100).
3.4. (Dodeca-2,4-diynyloxy)acetic acid (Montiporic acid
A) (1) [1c]
Ethyl 2-bromoacetate 5 (0.19 mL, 1.70 mmol) was
added at 10 ꢁC to a vigorously stirred mixture of com-
pound 3 (0.20 g, 1.12 mmol) in benzene (6 mL), 50%
aqueous solution of KOH (3 mL) and (n-Bu)4NHSO4
(0.19 g, 0.56 mmol). The stirring was continued for
3 h, then the mixture was quenched with diluted HCl
(30 mL) and extracted with ethyl acetate (4 · 30 mL).
The organic extracts were washed whit water
(3 · 30 mL), dried over anhydrous Na2SO4 and concen-
trated under vacuum. The residue was purified by col-
umn chromatography (petroleum ether/EtOAc 8:2 to
EtOAc/MeOH 9:1 as eluents) leading to montiporic acid
3.6. (Tetradec-13-en-2,4-diynyloxy)acetic acid
(Montiporic acid B) (2) [1c]
Ethyl 2-bromoacetate 5 (0.15 mL, 1.35 mmol) was
added at 10 ꢁC to a vigorously stirred mixture of com-
pound 4 (0.176 g, 0.86 mmol) in benzene (5 mL), 50%
aqueous solution of KOH (2 mL) and (n-Bu)4NHSO4
(0.147 g, 0.43 mmol). The stirring was continued for
4 h, then the mixture was quenched with diluted HCl
(30 mL) and extracted with ethyl acetate (4 · 30 mL).
The organic extracts were washed whit water
(3 · 30 mL), dried over anhydrous Na2SO4 and concen-
trated under vacuum. The residue was purified by col-
umn chromatography (petroleum ether/EtOAc 8:2 to
EtOAc/MeOH 9:1as eluents) leading to montiporic acid
B 2 as a yellow-orange oil; yield: 0.185 g (82%). 1H
NMR (500 MHz, CDCl3): d = 8.90 (br s, 1H), 5.79
(ddt, J = 17.1, 10.2, 6.7 Hz, 1H), 4.97 (ddt, J = 17.1,
2.2, 1.6 Hz, 1H), 4.91 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H),
4.35 (s, 2H), 4.23 (s, 2H), 2.26 (t, J = 7.2 Hz, 2H),
2.05–1.99 (m, 2H), 1.51 (quint, J = 7.2 Hz, 2H), 1.40–
1.32 (m, 4H), 1.31–1.23 (m, 4H). 13C NMR
1
A 1 as a colorless oil; yield: 0.212 g (80%). H NMR
(500 MHz, CDCl3): d = 9.25 (br s, 1H), 4.33 (s, 2H),
4.21 (s, 2H), 2.24 (t, J = 7.2 Hz, 2H), 1.49 (quint,
J = 7.2 Hz, 2H), 1.34 (quint, J = 7.2 Hz, 2H), 1.29–
1.19 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). 13C NMR
(125.7 MHz, CDCl3): d = 175.1, 82.1, 72.8, 69.8, 65.7,
64.1, 58.9, 31.6, 28.7, 28.6, 28.0, 22.5, 19.2, 14.0. IR
(neat): m = 2955, 2929, 2857, 2255, 1734, 1119 cmꢀ1
.
GC–MS: m/z (%) = 235 (M+ ꢀ 1, <1), 207 (2), 177 (2),
152 (7), 131 (15), 117 (25), 105 (18), 91 (47), 79 (36),
77 (36), 76 (29), 67 (28), 65 (24), 55 (49), 51 (33), 50
(23), 43 (70), 41 (100).

3008
V. Fiandanese et al. / Journal of Organometallic Chemistry 690 (2005) 3004–3008
[3] (a) For reviews, see: V. Fiandanese, in: S.G. Pandalai (Ed.),
Recent Research Developments in Organic Chemistry, Conju-
gated Polyunsaturated Silanes as Versatile Building Blocks in
Organic Synthesis, vol. 3, Transworld Research Network, Tri-
vandrum, India, 1999, pp. 177–194;
(125.7 MHz, CDCl3): d = 175.0, 139.0, 114.2, 82.0, 72.8,
69.8, 65.6, 64.2, 58.9, 33.7, 28.9, 28.8, 28.8, 28.7, 28.0,
19.2. IR (neat): m = 3077, 2928, 2855, 2255, 1733, 1640,
1117, 910 cmꢀ1. GC–MS: m/z (%) = 203 (1), 173 (1),
171 (1), 161 (2), 159 (2), 157 (3), 152 (3), 145 (5), 143
(8), 131 (11), 129 (13), 117 (17), 115 (11), 105 (17), 91
(43), 79 (26), 77 (25), 67 (26), 55 (43), 51 (23), 41 (100).
(b) V. Fiandanese, Pure Appl. Chem. 62 (1990) 1987–1992.
[4] (a) F. Babudri, V. Fiandanese, O. Hassan, A. Punzi, F. Naso,
Tetrahedron 54 (1998) 4327–4336;
(b) F. Babudri, V. Fiandanese, G. Marchese, A. Punzi, Tetrahe-
dron 56 (2000) 327–331;
(c) V. Fiandanese, D. Bottalico, G. Marchese, Tetrahedron 57
(2001) 10213–10218;
Acknowledgements
(d) F. Babudri, V. Fiandanese, G. Marchese, A. Punzi, Tetrahe-
dron 57 (2001) 549–554;
This work was financially supported by the Ministero
`
(e) V. Fiandanese, F. Babudri, G. Marchese, A. Punzi, Tetrahe-
dron 58 (2002) 9547–9552.
dellÕIstruzione, dellÕUniversita
e
della Ricerca
(M.I.U.R.), Rome, and the University of Bari (National
Project ‘‘Stereoselezione in Sintesi Organica. Metodolo-
gie ed Applicazioni’’). We thank Dr. L. Valenzano for
preliminary experiments.
[5] V. Fiandanese, D. Bottalico, G. Marchese, A. Punzi, Tetrahedron
Lett. 44 (2003) 9087–9090.
[6] (a) S. Reber, T.F. Knopfel, E.M. Carreira, Tetrahedron 59 (2003)
6813–6817;
(b) B.F. Coles, D.R.M. Walton, Synthesis (1975) 390–391;
(c) E.R.H. Jones, J.M. Thompson, M.C. Whiting, J. Chem. Soc.
(1957) 2012–2017.
References
[7] (a) T.J. Speed, D.M. Thamattoor, Tetrahedron Lett. 43 (2002)
367–369;
[1] (a) N. Alam, B.H. Bae, J. Hong, C.-O. Lee, K.S. Im, J.H. Jung,
J. Nat. Prod. 64 (2001) 1059–1063;
(b) J. Wityak, J.B. Chan, Synth. Commun. 21 (1991) 977–979;
(c) R.E. Doolittle, Synthesis (1984) 730–732.
[8] (a) A.B. Holmes, G.E. Jones, Tetrahedron Lett. 23 (1982) 3203–
3206;
(b) B.H. Bae, K.S. Im, W.C. Choi, J. Hong, C.-O. Lee, J.S. Choi,
B.W. Son, J.-I. Song, J.H. Jung, J. Nat. Prod. 63 (2000) 1511–
1514;
(b) A.B. Holmes, G.E. Jones, Tetrahedron Lett. 21 (1980) 3111–
3112.
(c) N. Fusetani, T. Toyoda, N. Asai, S. Matsunaga, T. Maruy-
ama, J. Nat. Prod. 59 (1996) 796–797;
[9] M. Pietraszkiewicz, J. Jurczak, Tetrahedron 40 (1984) 2967–2970.
[10] Y.-T. He, H.-N. Yang, Z.-J. Yao, Tetrahedron 58 (2002) 8805–
8810.
(d) T. Higa, J. Tanaka, T. Kohagura, T. Wauke, Chem. Lett.
(1990) 145–148.
[2] H.A. Stefani, I.M. Costa, G. Zeni, Tetrahedron Lett. 40 (1999)
9215–9217.
[11] M.C. Roux, R. Paugam, G. Rousseau, J. Org. Chem. 66 (2001)
4304–4310.