A short synthesis of (±)-sporochnol A, a chemical fish deterrent from a Caribbean marine alga

Article abstract of DOI:10.1081/SCC-200048943

A short formal synthesis of (±)-sporochnol A (1) is described. In this synthesis, the quaternary carbon center is formed by successive alkylations of the carbanion a to the nitrile in an arylacetonitrile derivative, followed by conversion of the nitrile g

Full text of DOI:10.1081/SCC-200048943

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A Short Synthesis of
(±)‐Sporochnol A, A Chemical
Fish Deterrent from a
Caribbean Marine Alga
J. Gustavo Ávila‐Zárraga a , Mario Barroso a , Adrián
Covarrubias‐Zúñiga b & Moisés Romero‐Ortega c
a División de Estudios de Posgrado, Facultad de
Química, Circuito Interior , Universidad Nacional
Autónoma de México , Ciudad Universitaria,
Coyoacan, 04510, México D. F., México
b Instituto de Química , Universidad Nacional
Autónoma de México , Ciudad Universitaria, México
D. F., México
c Facultad de Química , Universidad Autónoma del
Estado de México , Paseo Colon/Paseo Tollocan,
Toluca Estado de México, México
Published online: 28 Jul 2007.
To cite this article: J. Gustavo Ávila‐Zárraga , Mario Barroso , Adrián
Covarrubias‐Zúñiga & Moisés Romero‐Ortega (2005) A Short Synthesis of
(±)‐Sporochnol A, A Chemical Fish Deterrent from a Caribbean Marine Alga, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:3, 389-395, DOI: 10.1081/SCC-200048943
To link to this article: http://dx.doi.org/10.1081/SCC-200048943

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Synthetic Communicationsw, 35: 389–395, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048943
A Short Synthesis of (+)-Sporochnol A,
A Chemical Fish Deterrent from a
Caribbean Marine Alga
´
J. Gustavo Avila-Zarraga and Mario Barroso
´
Facultad de Quımica, Universidad Nacional Autonoma de Mexico, Ciudad
´ ´
Universitaria, Mexico D. F., Mexico
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´
´
Adrian Covarrubias-Zun˜iga
´ ´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico,
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´ ´
Ciudad Universitaria, Mexico, D. F., Mexico
´
Moises Romero-Ortega
´ ´
Facultad de Quımica, Universidad Autonoma del Estado de Mexico,
´
´
´
Paseo Colon/Paseo Tollocan, Toluca Estado de Mexico, Mexico
Abstract: A short formal synthesis of (+)-sporochnol A (1) is described. In this
synthesis, the quaternary carbon center is formed by successive alkylations of the
carbanion a to the nitrile in an arylacetonitrile derivative, followed by conversion of
the nitrile group to a vinyl group. The quaternary carbon center derivatives obtained
in each step were characterized by spectroscopy.
Keywords: Sporochnols, quaternary carbon, alkylation, carbanion, Wittig reaction
INTRODUCTION
Various marine plants and algae contain agents that act as chemical deterrents
against herbivores. One such organism is the alga Sporochnus bolleanus,
Received in the USA October 24, 2004
´
Address correspondence to J. Gustavo Avila-Zarraga, Division de Estudios de Pos-
´
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grado, Facultad de Quımica, Circuito Interior, UNAM, Ciudad Universitaria, Coyoacan,
´
´ ´
04510, Mexico D. F., Mexico. E-mail: gavila@correo.unam.mx

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J. G. Avila-Zarraga et al.
390
which contains three compounds that act as fish deterrents: sporochnol A (1),
as a major component (0.5% dry wt), and sporochnols B (2) and C (3) as minor
metabolites (0.004% dry wt).[1]
The sporochnols have a prenylated phenol structure (C16) with a quatern-
ary carbon center whose substituents are phenol, methyl, isoprenyl, and vinyl
groups. The absolute configuration is S-(þ)-.[2]
Sporochnols have been synthesized via several routes. Sporochnol A (1)
has been synthesized in racemic[3,4] form, in the naturally occuring S-(þ)-
sporochnol form[5,6] and as the R-(2) enantiomer.[7] Sporochnols B (2) and
C (3) have also been synthesized.[8,9]
In the syntheses of compounds with quaternary carbons reported to date, a
variety of stabilized carbanions have been used as reactive intermediates for
C-C bond construction. Among these carbanions, the nitrile-stabilized
anions occupy a unique position in that they are particularly powerful
nucleophiles ideally suited for installing sterically hindered quaternary
centers.[10–14] Here we report a simple route for the synthesis of (1) that the
exploits anionic arylacetonitrile species as intermediates.

Short Synthesis of (+)-Sporochnol
391
RESULTS AND DISCUSSION
The goal of our study was to construct a quaternary benzylic carbon through
two successive alkylations of the anion a to arylacetonitrile. In the two
alkylations we introduced first the prenyl chain and then the methyl group,
and finally we converted the nitrile group to a vinyl group to give racemic
sporochnol A (1) (Scheme 1).
To perform the first alkylation, the arylacetonitrile derivative, 4, in dry
THF at 2788C was treated with lithium pyrrolidide (pyrrolidine and
n-BuLi) followed by 5-iodo-2methyl-pent-2-ene.[15–17] The carbanion a to
arylacetonitrile can also be prepared by treating LDA or LHDS; however,
Scheme 1. Reagents and conditions: (a) Lithium pyrrolidide, 5-iodo-2-methyl-pent-
2-ene, THF, 2788C; (b) NaH, MeI, THF, 08C; (c) DIBAL, toluene, 08C, then H3Oþ,
r.t.; (d) PH3PCH3Br, n-BuLi, THF, 08C.

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J. G. Avila-Zarraga et al.
392
treatment with lithium pyrrolidide gives better results. The desired monoalky-
lated product (5) was obtained in 77%. The second alkylation was performed
by reacting 5 with NaH and MeI in dry THF. The compound 6 was obtained in
95% yield. Compound 6 was obtained in similar yield when lithium pyrroli-
dide was used instead of sodium hydride. When we attempted to prepare
the dialkylated compound by performing the two alkylation reactions as a
one-pot reaction, a complex mixture was obtained and 6 was isolated in low
yield. The structures of 5 and 6 were confirmed by spectroscopy.
The last step of synthesis was the conversion of the nitrile group in 6 to a
vinyl group. First, 6 was reduced[18] by reaction with diisobutylaluminum
hydride in toluene at 08C overnight, and because the resulting aldehyde decom-
posed when we attempted to isolate it, we proceeded without further purification
of the sample. Thus, we used the Wittig reaction to convert the aldehyde to
a methylene.[19,20] Briefly, we treated the raw product with methyltriphenyl-
phosphonium bromide and then n-BuLi in THF at 08C for 3 h. Compound 7
was purified from the resulting mixture by chromatography on silica gel in
50% yield over the two steps. Analytical and spectroscopic data for 7 were in
accordance with those previously reported by Takahashi[2] (Scheme 1).
In conclusion, we have presented an easy and short formal synthesis of
sporochnol A (1) that exploits successive alkylations involving carbanions a
to arylacetonitrile as intermediates.
The route presented here could potentially be applied in the enantioselective
synthesis of sporochnols and other compounds with chiral quatenary centers.
EXPERIMENTAL SECTION
Thin-layerchromatographywasperformedonsilicagel 60F254 andvisualizedby
UV irradiation. Infrared spectra were recorded on Perkin Elmer 1600 FT spec-
trometer. 1H NMR spectra were recorded at 300 MHz; while 13C NMR spectra
were run at 75MHz in CDCl3 solution on Oxford NMR 300 spectrometer.
The chemical shifts were expressed in ppm (d) down field from TMS. Mass
spectra were measured at 70eV (EI) on JEOL SX-102. Elemental analysis
were performed on FISONS Instruments EA1108/CHNS-O.
2-(4-Methoxy-phenyl)-6-Methyl-hept-5-enenitrile (5)
To a stirred solution of lithium pyrrolidide [prepared in situ by treating pyrro-
lidine (0.53 g, 7.48 mmol) in dry THF (20 mL) with n-BuLi (0.48 g, 7.5 mmol)
at 2788C for 5 min], under N2 atmosphere, 4-methoxyphenyl acetonitrile
(1.0 g, 6.8 mmol) in THF (5 mL) was added drop-wise, and the mixture was
stirred for 10 min. A solution of 5-iodo-2-methyl-pent-2-ene (1.57 g,
7.47 mmol) in THF (3 mL) was then added drop-wise to the mixture at
2788C. After stirring for 40 min, the temperature was raised to room

Short Synthesis of (+)-Sporochnol
393
temperature. After 20 min at room temperature the reaction were quenched by
addition of saturated aqueous NH4Cl (20 mL). The mixture was extracted with
AcOEt (5 ꢀ 10 mL) and the organic layer was washed with brine
(2 ꢀ 10 mL), dried (anhydrous Na2SO4), filtered, and concentrated. The
residue was purified by column chromatography (SiO2; eluent: ethyl
acetate/hexane, 1 : 9) to give the nitrile 5 (1.2 g, 77%) as a colourless oil.
IR (film, cm21). 2932, 2240, 1672, 1613, 1585, 1514; 1H NMR (CDCl3,
300 MHz) d 7.23 (d, J ¼ 8.4 Hz, 2H), 6.90 (d, J ¼ 8.4 Hz, 2H), 5.06 (t, J ¼ 7.2
Hz, 1H), 3.80 (s, 3H), 3.72 (dd, J ¼ 6.3 Hz, 1H), 2.19 (m, 2H), 2.05–1.78 (m.
2H), 1.70 (d, J ¼ 0.9 Hz 3H), 1.60 (d, J ¼ 0.60 Hz 3H); 13C NMR (CDCl3,
75.5 MHz) d 159.21, 133.90, 128.35, 127.88, 121.89, 121.17, 114.32, 55.27,
35.90, 35.72, 25.69, 25.33, 17.78; MS (EI) m/z (abun. rel.): 229 (71), 159
(100), 146 (63); HRMS (EI): m/z calcd. for C15H19NO: 229.1467; found
229.1460; Anal. calcd. for C15H19NO: C, 78.56; H, 8.35; N, 6.11; Found:
C, 78.43; H, 8.40; N, 6.21.
2-(4-Methoxy-phenyl)-2,6-Dimethyl-hept-5-enenitrile (6)
To a stirred suspension of NaH (60% in oil: 31mg, 1.3 mmol) in dry THF at 08C,
under N2 atmosphere, 5 (200mg, 8.7 mmol) in THF (2 mL) was added and the
mixture was stirred for 30min at the same temperature. MeI (148mg,
1.0 mmol) was then added to the mixture and the temperature was raised to
room temperature. After stirring the mixture overnight, the reaction was
quenched by addition of NH4Cl (5mL) and the mixture was extracted with
AcOEt (4 ꢀ 5 mL). The extract was washed with brine, dried (anhydrous
Na2SO4), evaporated under reduced pressure, and chromatographed (SiO2;
eluent: ethyl acetate/hexane 5 : 95) affording the dialkylated compound 6
(200 mg, 95%) as a colorless oil. IR (film): 2926, 2855, 2235, 1674, 1610, and
1
1582. 1513 cm21; H NMR d ppm 7.34 (d, J ¼ 9 Hz, 2H), 6.90 (d, J ¼ 9 Hz,
2H), 5.03 (t, J ¼ 6.9 Hz, 1H), 3.81 (s, 3H), 2.13–1.80 (m, 4H), 1.68 (s, 3H),
1.64 (s, 3H), 1.52 (s, 3H); 13C NMR d ppm 158.92, 132.90, 132.18, 126.56,
123.62, 122.37, 114.11, 55.30, 42.11, 41.65, 27.94, 27.58, 24.24, 17.59; MS
m/z (relative intensity): 243 Mþ (29), 160 (100), 83 (80), 55 (51); HRMS (EI):
m/z calcd. for C16H21N1O1: 243.1623; found 243.1616; Anal. Calcd. for
C16H21NO: C, 78.97; H, 8.70; N, 5.76; Found: C, 78.85; H, 8.92; N, 5.64.
1-(1,5-Dimethyl-1-vinyl-hex-4-enyl)-4-Methoxy-benzene (7)
To a stirred solution of 6 (200 mg, 0.82 mmol) in dry Toluene (5 mL) at 08C,
a solution of DIBAL-H (1.5 M solution in toluene, 2.74 mL, 4 mmol) was
slowly added and the mixture was stirred for 2 h at the same temperature,
after which it was allowed to warm to room temperature and then stirred
overnight. The mixture was then quenched with EtOH (2 mL) at 08C, after
which dilute aqueous H2SO4 (10 mL) was added and the resulting mixture

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J. G. Avila-Zarraga et al.
394
was stirred for 40 min at 08C. Finally, the mixture was extracted with AcOEt
(4 ꢀ 4 mL). The extract was washed with aqueous NAHCO3 followed by
brine, dried (anhydrous Na2SO4), and evaporated under reduced pressure to
give the aldehyde (200 mg, 99%) as a colorless oil, which was used in the
next step without further purification.
To a solution of methyltriphenylphosphonium bromide (1.54 g, 4.3 mmol)
in THF (10 mL) was added n-BuLi (1.3 M, in hexan; 3.12 mL, 4 mmol) at 08C
and, after 90 min, a solution of the aldehyde (200 mg, 0.81 mmol) in THF
(5 mL) was added at the same temperature and stirring as continued for 3 h.
The reaction was quenched by addition of saturated aqueous NH4Cl (5 mL)
and the mixture was extracted with AcOEt (5 ꢀ 5 mL). The extract was
washed with brine, dried (anhydrous Na2SO4), evaporated under reduced
pressure, and purified by chromatography (SiO2; eluent ethyl acetate/
hexane, 5 : 95), to give the diene 7 (100 mg, 50%) as a colorless oil. IR
(film): 3056, 2965, 2926, 2834, 1633, 1609, 1580, 1511, 1467, 1438, 1373,
1
1294, 1182, 1037 cm21. H NMR d ppm 7.23 (br d, J ¼ 9 Hz, 2H), 6.84 (br
d, J ¼ 9 Hz, 2H), 6.00 (dd, Jtrans ¼ 17.6 Hz, Jcis10.8 Hz, 1H), 5.07 (dd,
Jcis ¼ 10.4 Hz, J ¼ 1.2 Hz, 1H), 5.02 (dd, Jtrans ¼ 17.2 Hz, J ¼ 1.2 Hz, 1H),
5.24–5.05 (m, 1H), 3.79 (s, 3H), 2.9–2.65 (m, 4H), 1.63 (br s, 3H), 1.45
(br s, 3H), 1.35 (s, 3H), 13C NMR d ppm 157.50, 139.50, 127.58, 113.33,
147.19, 131.30, 124.70, 111.40, 55.19, 43.63, 41.15, 25.67, 24.98, 23.27,
17.56. Ms m/z (relative intensity): 244 Mþ (5), 162 (20), 161 (100), 146
(6), 121 (6). HRMS (EI) m/z calcd. For C17H24O1: 244.1827. Found 244.1826
ACKNOWLEDGMENTS
We are grateful to Georgina Durate, Margarita Guzman, Oscar Yan˜ez, Rosa
I. Del Villar, and Maricela Gutierrez for their assistance in acquiring
´
spectral data. We also thank DGAPA-UNAM, Mexico for financial support.
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