Synthesis of sporochnol A, a marine fish deterrent

Article abstract of DOI:10.1081/SCC-200063941

A synthesis of the methyl ether of the fish-deterrent sporochnol A is described. The route involves the application of Claisen ortho-ester rearrangement to generate the key quaternary carbon. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200063941

Synthetic Communicationsw, 35: 1769–1779, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063941
Synthesis of Sporochnol A, a Marine
Fish Deterrent
Bidyut Biswas and Ramanthapuram V. Venkateswaran
Department of Organic Chemistry, Indian Association for the Cultivation
of Science, Jadavpur, Kolkata 700 032, India
Abstract: A synthesis of the methyl ether of the fish-deterrent sporochnol A is
described. The route involves the application of Claisen ortho-ester rearrangement to
generate the key quaternary carbon.
Keywords: Claisen ortho-ester rearrangement, fish deterrent, sporochnols
INTRODUCTION
Sporochnol A 1, along with its congeners sporochnol B and C, 2, 3, constitute
a group of substituted monoterpenoid phenolic constitutents isolated from the
Caribbean marine alga Sporochnus bolleanus.[1] These have been reported to
significantly deter feeding by herbivorous fish. The structural assignment of
sporochnol A relied on chemical and spectroscopic analysis.[1] However,
the absolute configuration of the lone asymmetric centre as S was based on
the asymmetric synthesis of the ent-isomer.[2] The pronounced biological
activity of 1 has prompted its many synthesis in both racemic and optically
active forms.[3] We report a facile synthesis of 1 employing Claisen ortho-
ester rearrangement[4] to generate the key quaternary carbon center.
Received in India February 2, 2005
Address correspondence to Ramanthapuram V. Venkateswaran, Department of
Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Kolkata 700 032 , India. Fax: þ91-33-24732805; E-mail: ocrvv@mahendra.iacs.res.in
1769

1770
B. Biswas and R. V. Venkateswaran
RESULTS AND DISCUSSION
Alkylation of the lithium enolate of 4-methoxy acetophenone 4 with prenyl
bromide furnished the prenylated ketone 5 in 60% yield. Condensation of
this ketone with triethyl phosphonoacetate afforded the a,b-unsaturated
ester(s) 6 in very good yield as a mixture of geometrical isomers. Although
there was no need to separate the isomers in view of the subsequent steps,
chromatographic purification to recover the traces of the starting ketone 5
led to an efficient separation affording the isomers 6a and 6b in 2 : 1 pro-
portion. The structural assignment followed from spectral characteristics of
1
the isomers. In the H NMR of 6a, the methylene protons adjacent to the
styrenoid double bond appeared as a triplet at d3.02, the ester function
causing a downfield shift compared with the same protons in 6b appearing
at d2.37. The olefinic proton, proximal to the aromatic ring, experiencing a
deshielding effect, appeared at d5.92 (br s) as against the same proton in 6b
appearing at d5.77. Furthermore, the peri-hydrogen in the benzene ring of
isomer 6b showed a pronounced upfield shift consequent on the shielding
by the ester function and showed as a doublet at d7.04 compared with the
same hydrogen in 6a, a doublet at d7.32. The protons of the ethyl group in
isomer 6b also displayed a similar upfield shift compared with the same
protons in 6a. Reduction of the major ester 6a with lithium aluminium
hydride produced the allylic alcohol 7. This allylic alcohol, on refluxing with
triethyl orthoacetate in presence of a catalytic amount of propionic acid, under-
went a facile Claisen ortho-ester rearrangement to afford the diene-ester 8 in a
moderate yield. In subsequent experiments the combined mixture of isomers
6a and 6b was reduced with lithium aluminium hydride and subjected to the
Claisen ortho-ester rearrangement and furnished the same diene-ester 8. This
ester incorporated all the requisite features of the target compound and it was
anticipated that a ready decarboxylative degradation of the acetate side chain
would yield the methyl ether of sporochnol A. However, all efforts to effect
this degradation proved futile. The efforts involved decarbonylation experi-
ments of the corresponding aldehyde 9, obtained from hydride reduction of
the ester 8 to an alcohol followed by oxidation. Decarbonylation attempts
were carried out employing Wilkinson’s catalyst and also photolytic con-
ditions. Direct decarboxylation of the corresponding acid 10, obtained from
hydrolysis of 8, was also attempted under photolytic conditions. In all cases
only a complex product profile resulted and no product corresponding to the
desired O-methyl sporochnol A could be traced (Scheme 1).
In view of these failures in the final phase of the synthesis, the approach
was modified at the initial stage, but once again using the Claisen ortho-ester
rearrangement to generate the quaternary carbon center. The starting point was
the a,b-unsaturated ester 11, obtained as a mixture of isomers in excellent
yield on condensation of 4-methoxy acetophenone with triethyl phosphono-
acetate following the reported procedure.[5] This ester was expeditiously
reduced with lithium aluminiumhydride to the allylic alcohol(s) 12.

Synthesis of Sporochnol A, a Marine Fish Deterrent
1771
Scheme 1. Reagents and conditions: (i) LDA, (CH3)2C55CHCH2Br, THF, 2208C;
(ii) (C2H5O)2P(O)CH2CO2Et, NaH, THF, reflux, 20 h; (iii) LAH, Et2O, 2208C, 4 h;
(iv) CH3C(OEt)3, C2H5CO2H, Hg(OAc)2, 2008C, 24 h; (v) a. LAH, THF, reflux, 2 h;
b. (COCl)2, DMSO, Et3N, 2788C; (vi) KOH, EtOH, reflux, 12 h.
Treatment of this alcohol(s) with triethyl orthoacetate at reflux temperature in
the presence of a catalytic amount of propionic acid effected a facile ortho-
ester rearrangement to afford the olefinic ester 13 in very good yield, incorpo-
rating the elusive geminal vinyl and methyl groups and an acetate side chain
for further elaboration. This was readily achieved through a one-carbon homo-
logation. Lithium aluminium hydride–induced reduction of the ester 13
yielded the alcohol 14 in near quantitative yield. The corresponding tosylate,
obtained from interaction with toluene-p-sulfonyl chloride, on treatment with
potassium cyanide in dimethyl sulfoxide afforded the nitrile 15 in an overall
yield of 64%. Alkaline hydrolysis of this nitrile furnished the carboxylic

1772
B. Biswas and R. V. Venkateswaran
acid 16. This acid had previously been synthesized by Ohira et al.[3g] and taken
to sporochnol A. However, for the purpose of spectral comparison, we carried
out the reported steps and converted this acid to the aldehyde 17, which was
subjected to a Wittig reaction with isopropylidene triphenylphosphorane
to finally afford O-methyl sporochnol A 18 (Scheme 2). The spectral data
(1H NMR and 13C NMR) of our 18 fully matched the reported values.[2,3b]
Deprotection of 18 to sporochnol A 1 has already been carried out[3b] and
hence, the present efforts concluded a synthesis of this marine antifeedent.
Because sporochnol A has been converted to sporochnols B 2 and C 3,[3g]
this also constitutes a formal synthesis of these compounds.
In summary, we have described a synthesis of the important fish deterrent
sporochnol A, employing readily available materials and simple reaction con-
ditions. The crucial step of generating the quaternary carbon center involved
the application of Claisen ortho-ester rearrangement.
EXPERIMENTAL
Melting points are uncorrected. Purity of the products was routinely monitored
by TLC. Preparative TLC was performed with silica-gel 60 HF254 plates
of 1 mm in thickness. The petroleum ether that was used has a bp 60–808C.
Scheme 2. Reagents and conditions: (i) (C2H5O)2P(O)CH2CO2C2H5, NaH, THF,
reflux, 6 h; (ii) LAH, Et2O, 2208C, 2 h; (iii) CH3C(OEt)3, C2H5CO2H, 138–1428C,
5 h; (iv) LAH, THF, reflux, 3 h; (v) a. p-TsCl, Py, 12 h, rt, 2 h, 60–708C; b. KCN,
DMSO, 1608C, 14 h; (vi) KOH, CH2(OH)CH2OH, 1808C, 24 h; (vii) a. LAH,
THF, reflux, 8 h; b. (COCl)2, DMSO, Et3N, 2788C; (viii) (CH3)2CHPPh3I, n-BuLi,
THF, 08C.

Synthesis of Sporochnol A, a Marine Fish Deterrent
1773
Na2SO4 was used to dry organic extracts. The IR spectra are of CHCl3
1
solutions. H NMR spectra of CDCl3 solutions were recorded at 300 MHz
and 13C NMR spectra at 75 MHz.
4-Methoxy-(3-methyl)-but-2-enyl acetophenone (5). To a well-stirred
solution of LDA [prepared from n-butyllithium (1.4 mL of 1.6 M solution in
hexane, 2.24 mmol) and diisopropylamine (0.32 mL, 2.3 mmol)] in THF at
2208C, a solution of p-methoxyacetophenone 4 (300 mg, 2.00 mmol) in
THF (2 mL) was added in drops. After 30 min, prenyl bromide (0.28 mL,
2.41 mmol) was added and stirring was continued at 2208C for 45 min and
at rt for 4 h. The reaction mixture was then quenched with saturated
aqueous NH4Cl solution and extracted with ether (15 mL ꢀ 2). The combined
ethereal extracts were washed with water, dried, and the solvent removed. The
residual oil was subjected to column chromatography over silica gel. Elution
with ethyl acetate–petroleum ether (1 : 49) afforded the prenylated ketone 5 as
colorless oil (260 mg, 60%). IR 1678 cm21; dH (300 MHz, CDCl3) 1.64
(s, 3H), 1.70 (s, 3H), 2.38–2.45 (m, 2H), 2.95 (t, J ¼ 7.4 Hz, 2H), 3.87
(s, 3H), 5.18 (t, J ¼ 7.1 Hz, 1H), 6.93 (d, J ¼ 8.7 Hz, 2H), 7.95
(d, J ¼ 8.7 Hz, 2H); dC (75 MHz, CDCl3) 18.0, 23.5, 26.1, 38.8, 55.8,
113.9, 122.1, 123.5, 130.7, 133.0, 163.7, 199.0. Anal. calcd. for C14H18O2:
C, 77.03; H, 8.31. Found: C, 77.15; H, 8.27.
Ethyl 3-(4-methoxyphenyl)-7-methyl-octa-2,6-dienoate(s) (6a and 6b).
Triethyl phosphonoacetate (0.72 mL, 3.60 mmol) was added dropwise to a
stirred slurry of sodium hydride (72 mg, 3.00 mmol, freed from oil) in THF
(4 mL) and stirring continued at rt for 40 min. The ketone 5 (200 mg,
0.92 mmol) in THF (2 mL) was then added dropwise and stirring continued
for 2 h at ambient temperature. Then, the reaction mixture was refluxed for
20 h. It was then cooled and poured into saturated aqueous NH4Cl solution
and extracted with ether (5 mL ꢀ 2). The combined ethereal extracts were
washed with brine, dried, and concentrated. The residual oil was purified by
column chromatography over silica gel. Elution with ethyl acetate–
petroleum ether (1 : 49) furnished the diene-ester 6a (110 mg, 42%) as colorless
oil. IR 1712 cm21; dH (300 MHz, CDCl3): 1.21 (t, J ¼ 7.1 Hz, 3H), 1.44 (s, 3H),
1.56 (s, 3H), 1.99–2.07 (m, 2H), 3.02 (t, J ¼ 7.4 Hz, 2H), 3.73 (s, 3H), 4.11
(q, J ¼ 7.1 Hz, 2H), 5.07 (t, J ¼ 7.2 Hz, 1H), 5.92 (s, 1H), 6.79
(d, J ¼ 8.8 Hz, 2H), 7.32 (d, J ¼ 8.8 Hz, 2H); dC (75 MHz, CDCl3)
14.7, 18.0, 26.0, 28.2, 31.2, 55.6, 60.0, 114.2, 116.0, 124.0, 128.4, 132.4,
133.7, 159.8, 160.7, 167.0. Anal. calcd for C18H24O3: C, 74.97; H, 8.39.
Found: C, 74.93; H, 8.41.
Continued elution afforded starting material 5 (40 mg, 20%). Further
elution with ethyl acetate–petroleum ether (1 : 19) afforded the isomer 6b
(60 mg, 23%) as colorless liquid. IR 1712 cm21; dH (300 MHz, CDCl3):
1.04 (t, J ¼ 7.1 Hz, 3H), 1.44 (s, 3H), 1.59 (s, 3H), 1.94–2.01 (m, 2H), 2.37
(t, J ¼ 7.2 Hz, 2H), 3.73 (s, 3H), 3.94 (q, J ¼ 7.1 Hz, 2H), 4.98

1774
B. Biswas and R. V. Venkateswaran
(t, J ¼ 7.2 Hz, 1H), 5.77 (s, 1H), 6.79 (d, J ¼ 8.7 Hz, 2H), 7.04 (d, J ¼ 8.7 Hz,
2H); dC (75 MHz, CDCl3) 14.4, 18.1, 26.0, 26.6, 40.8, 55.5, 60.1, 113.6, 117.1,
123.3, 129.1, 132.2, 132.9, 159.4, 159.6, 166.6. Anal. calcd for C18H24O3: C,
74.97; H, 8.39. Found: C, 74.81; H, 8.37.
3-(4-Methoxyphenyl)-7-methyl-octa-2,6-dien-1-ol (7). A suspension of
LAH (180 mg, 4.74 mmol) in ether (8 mL) was stirred for 0.5 h and allowed
to settle. The clear solution (7 mL) was removed via syringe and added
dropwise to a stirred and cooled (2208C) solution of the ester 6a (0.70 g,
2.43 mmol) in ether (8 mL). After stirring for 4 h at this temperature, the
reaction mixture was quenched by addition of aqueous saturated Na2SO4
solution. The ether layer was carefully decanted and concentrated, and the
residue subjected to column chromatography. Elution with ethyl acetate–
petroleum ether (1 : 1) furnished the alcohol 7 (540 mg, 90%) as a gummy
oil. dH (300 MHz, CDCl3) 1.53 (s, 3H), 1.69 (s, 3H), 2.00–2.07 (m, 2H),
2.55 (t, J ¼ 7.4 Hz, 2H), 3.83 (s, 3H), 4.31 (d, J ¼ 7.0 Hz, 2H), 5.12
(t, J ¼ 7.4 Hz, 1H), 5.86 (t, J ¼ 7.0 Hz, 1H), 6.88 (d, J ¼ 8.7 Hz, 2H), 7.33
(d, J ¼ 8.7 Hz, 2H); dC (75 MHz, CDCl3) 18.1, 26.0, 27.5, 30.3, 55.7, 60.0,
114.1, 124.0, 126.1, 127.9, 133.0, 134.7, 142.8, 159.3. Anal. calcd for
C16H22O2: C, 78.01; H, 9.00. Found: C, 78.12; H, 8.91.
Ethyl 3-(4-methoxyphenyl)-7-methyl-3-vinyl-oct-7-enoate (8). A mixture
of the alcohol 7 (200 mg, 0.81 mmol), triethyl orthoacetate (1.48 mL,
8.1 mmol), propionic acid (6 mg, 0.08 mmol), and mercuric acetate (20 mg)
was placed in a sealed tube and heated at 2008C for 24 h. Then, it was
cooled and the excess orthoester and propionic acid were removed by distilla-
tion under reduced pressure (ꢀ50–608C at 20 mmHg) and the residue purified
by column chromatography over silica gel. Elution with ethyl acetate–
petroleum ether (1 : 19) furnished the diene-ester 8 (100 mg, 39%) as
colorless oil; IR 1732 cm21; dH (300 MHz, CDCl3) 1.09 (t, J ¼ 7.1 Hz, 3H),
1.52 (s, 3H), 1.65 (s, 3H), 1.82–2.03 (m, 4H), 2.77 (s, 2H), 3.78 (s, 3H),
3.97 (q, J ¼ 7.1 Hz, 2H), 5.05–5.11 (m, 2H), 5.20 (d, J ¼ 10.9 Hz, 1H),
6.03 (dd, J ¼ 10.9, 17.4 Hz, 1H), 6.83 (d, J ¼ 8.7 Hz, 2H), 7.20
(d, J ¼ 8.7 Hz, 2H); dC (75 MHz, CDCl3) 14.5, 17.9, 23.3, 26.1, 37.9, 42.9,
46.5, 55.6, 60.4, 113.3, 113.7, 124.6, 128.4, 132.0, 137.0, 145.0, 158.2,
171.8. Anal. calcd for C20H28O3: C, 75.91; H, 8.92. Found: C, 75.73; H, 8.89.
3-(4-Methoxyphenyl)-7-methyl-3-vinyl-oct-6-enal (9). To a magnetically
stirred suspension of LAH (20 mg, 0.53 mmol) in THF (2 mL), the ester 8
(120 mg, 0.38 mmol) in THF (2 mL) was added dropwise at 08C. Then, it
was brought to room temperature and stirred for 30 min. The reaction
mixture was then refluxed for 2 h. It was cooled and decomposed with
saturated aqueous Na2SO4 solution. The organic layer was separated and
the aqueous layer extracted with ether (5 mL ꢀ 2). The combined organic
extracts were dried and concentrated. The residue after purification over

Synthesis of Sporochnol A, a Marine Fish Deterrent
1775
silica-gel column chromatography and eluting with ethyl acetate–petroleum
ether (2 : 5) furnished alcohol (100 mg, 96%) as a very viscous liquid; dH
(300 MHz, CDCl3) 1.53 (s, 3H), 1.68 (s, 3H), 1.73–1.82 (m, 4H), 2.04–2.16
(m, 2H), 3.52 (t, J ¼ 7.5 Hz, 2H), 3.79 (s, 3H), 5.10–5.17 (m, 2H), 5.22
(d, J ¼ 10.9 Hz, 1H), 5.95 (dd, J ¼ 10.9, 17.6 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz,
2H), 7.23 (d, J ¼ 8.8 Hz, 2H); dC (75 MHz, CDCl3) 17.9, 23.1, 26.0, 38.5,
40.4, 46.1, 55.5, 59.8, 113.1, 113.8, 124.8, 128.3, 131.8, 137.7, 145.7, 158.0.
Anal. calcd for C18H26O2: C, 78.79; H, 9.55. Found: C, 78.81; H, 9.52
To a magnetically stirred and cooled (2788C) solution of oxalyl chloride
(0.11 mL, 1.26 mmol) in dichromethane (2 mL), a solution of DMSO (0.2 mL,
2.81 mmol) in dichloromethane (1 mL) was added dropwise. After stirring at
2788C for 15 min, a solution of this alcohol (180 mg, 0.66 mmol) in dichloro-
methane (2 mL) was added and stirred for 45 min at this temperature. Triethyl-
amine (0.64 mL, 4.59 mmol) was then added and the reaction mixture allowed
to attain rt and was stirred for 2 h. The reaction mixture was poured into cold
water and the organic layer separated. The aqueous part was extracted with
dichloromethane (5 mL ꢀ 2). The combined organic layers were washed
with water, dried, and concentrated. The residual oil was subjected to column
chromatography. Elution with ethyl acetate–petroleum ether (1 : 19) afforded
the aldehyde 9 (160 mg, 90%) as a colorless oil; IR 1720 cm21; dH (300 MHz,
CDCl3) 1.50 (s, 3H), 1.64 (s, 3H), 1.78–1.87 (m, 4H), 2.76 (dd, A of ABX,
JAB ¼ 15.3 Hz, 1H), 2.80 (dd, B of ABX, JBA ¼ 15.3 Hz, 1H), 3.78 (s, 3H),
5.03–5.16 (m, 2H), 5.29 (d, J ¼ 10.7 Hz, 1H), 6.08 (dd, J ¼ 10.7, 17.4 Hz,
1H), 6.86 (d, J ¼ 8.7 Hz, 2H), 7.22 (d, J ¼ 8.7 Hz, 2H), 9.52 (t, X of ABX,
JAX ¼ JBX ¼ 3.0 Hz, 1H); dC (75 MHz, CDCl3) 17.9, 23.0, 26.0, 39.7, 45.9,
50.7, 55.5, 114.1, 114.4, 124.1, 128.3, 132.3, 136.3, 144.2, 158.4, 203.7.
Anal. calcd for C18H24O2: C, 79.37; H, 8.88. Found: C, 79.28; H, 8.91.
3-(4-Methoxyphenyl)-7-methyl-3-vinyl-oct-6-enoic acid (10). The ester 8
(100 mg, 0.32 mmol) was taken in 20% ethanolic KOH (3 mL) and heated
under reflux for 12 h. The reaction mixture was then diluted with ice-cold
water and extracted once with ether. The aqueous part was acidified with
cold dilute HCl (6 N) and extracted with ether (5 mL ꢀ 2). The combined
ethereal extracts were washed with saturated brine, dried, and concentrated
to afford the acid 10 (85 mg, 93%) as a thick mass; IR 1708 cm21; dH
(300 MHz, CDCl3) 1.50 (s, 3H), 1.65 (s, 3H), 1.77–2.00 (m, 4H), 2.82
(s, 2H), 3.79 (s, 3H), 5.06–5.12 (m, 2H), 5.21 (d, J ¼ 10.7 Hz, 1H), 6.04
(dd, J ¼ 10.7, 17.4 Hz, 1H), 6.83 (d, J ¼ 8.7 Hz, 2H), 7.20 (d, J ¼ 8.7 Hz,
2H); dC (75 MHz, CDCl3) 17.9, 23.3, 26.0, 38.0, 42.6, 46.3, 55.5, 113.5,
113.8, 124.5, 128.3, 132.1, 136.7, 144.8, 158.2, 176.9. Anal. calcd. for
C18H24O3: C, 74.97; H, 8.39. Found: C, 74.89; H, 8.41.
3-(4-Methoxyphenyl)-but-2-en-1-ol(s) (12). A suspension of LAH (170 mg,
4.47 mmol) in ether (10 mL) was stirred for 0.5 h and was allowed to settle.
The clear solution (9 mL) was removed via syringe and was added dropwise

1776
B. Biswas and R. V. Venkateswaran
to a stirred and cooled (2208C) solution of the ester 11 (500 mg, 2.27 mmol)
in ether (10 mL). After stirring for 2 h at this temperature, the reaction mixture
was quenched by dropwise addition of saturated Na2SO4 solution. The ether
layer was carefully decanted and concentrated, and residue subjected to
column chromatography over silica gel. Elution with ethyl acetate–
petroleum ether (1 : 3) furnished the alcohol 12 as a white crystalline solid.
Crystallised from ether–petroleum ether (340 mg, 85%), mp 59–608C; dH
(300 MHz, CDCl3) 1.98 (s, 3H), 3.74 (s, 3H), 4.27 (d, J ¼ 6.6 Hz, 2H), 5.83
(t, J ¼ 6.6 Hz, 1H), 6.79 (d, J ¼ 8.7 Hz, 2H), 7.28 (d, J ¼ 8.7 Hz, 2H); dC
(75 MHz, CDCl3) 16.3, 55.7, 60.3, 114.0, 125.2, 127.2, 135.6, 137.8, 159.3.
Anal. calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.24; H, 8.02.
Ethyl 3-(4-methoxyphenyl)-3-methylpent-4-enoate (13). A mixture of the
allylic alcohol 12 (710 mg, 3.98 mmol), triethyl orthoacetate (7.29 mL,
39.8 mmol), and propionic acid (29 mg, 0.39 mmol) was heated with stirring
to keep the temperature of the liquid at 138–1428C. Heating was continued
for 5 h; the reaction mixture was allowed to cool to rt and excess orthoacetate
was removed by distillation under reduced pressure (ꢀ50–608C at 20 mmHg).
The residue was purified by column chromatography. Elution with ethyl
acetate–petroleum ether (1 : 19) afforded the ester 13 (690 mg, 70%) as
colorless oil. IR 1734 cm21; dH (300 MHz, CDCl3) 1.13 (t, J ¼ 7.1 Hz, 3H),
1.56 (s, 3H), 2.74, 2.78 (ABq, J ¼ 13.9 Hz, 2H), 3.80 (s, 3H), 4.02
(q, J ¼ 7.1 Hz, 2H), 5.08 (d, J ¼ 17.5 Hz, 1H), 5.14 (d, J ¼ 10.7 Hz, 1H),
6.15 (dd, J ¼ 10.7, 17.5 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 2H), 7.26
(d, J ¼ 8.8 Hz, 2H); dC (75 MHz, CDCl3) 14.5, 25.9, 43.2, 46.2, 55.6, 60.4,
112.3, 113.8, 127.8, 138.4, 146.2, 158.2, 171.7. Anal. calcd for C15H20O3:
C, 72.55; H, 8.12. Found: C, 72.76; H, 8.03.
3-(4-Methoxyphenyl)-3-methyl-pent-4-en-1-ol (14). To a magnetically
stirred suspension of LAH (40 mg, 1.05 mmol) in THF (3 mL), the ester 13
(220 mg, 0.89 mmol) in THF (5 mL) was added dropwise at 08C. Then, it
was brought to rt and stirred for 30 min. The reaction mixture was then refluxed
for 3 h, cooled, and quenched with saturated aqueous solution of Na2SO4. The
organic layer was decanted, dried, and concentrated and the residue purified
by column chromatography. Elution with ethyl acetate–petroleum ether
(1 : 3) afforded the alcohol 14 (180 mg, 98%) as a colorless viscous liquid. dH
(300 MHz, CDCl3) 1.38 (s, 3H), 1.99–2.13 (m, 2H), 3.54–3.63 (m, 2H), 3.78
(s, 3H), 5.06 (d, J ¼ 17.4 Hz, 1H), 5.10 (d, J ¼ 10.7Hz, 1H), 6.02 (dd,
J ¼ 10.7, 17.4 Hz, 2H), 6.85 (d, J ¼ 8.8 Hz, 2H), 7.24 (d, J ¼ 8.8 Hz, 2H); dC
(75 MHz, CDCl3) 25.8, 42.9, 43.8, 55.6, 60.3, 112.1, 113.9, 127.8, 139.3, 147.2,
158.1. Anal. calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.58; H, 8.91.
4-(4-Methoxyphenyl)-4-methyl-hex-5-enonitrile (15). To a cold solution of
the alcohol 14 (220 mg, 1.07 mmol) in pyridine (5 mL), toluene-p-sulphonyl
chloride (244 mg, 1.28 mmol) was added and the mixture stirred overnight

Synthesis of Sporochnol A, a Marine Fish Deterrent
1777
at rt. Then, it was warmed at 60–708C for 2 h. The reaction mixture was
diluted with ice water, saturated with NaCl, and extracted with ether. The
ethereal extract was washed with an ice-cold solution of HCl (10%) and
brine, and then dried. The residue after evaporation was chromatographed
over silica gel. Elution with ethyl acetate–petroleum ether (1 : 4) afforded
the corresponding tosylate as a gummy liquid (290 mg, 76%). dH (300 MHz,
CDCl3) 1.31 (s, 3H), 2.07–2.17 (m, 2H), 2.44 (s, 3H), 3.78 (s, 3H), 3.91–
3.97 (m, 2H), 4.98 (d, J ¼ 17.4 Hz, 1H), 5.07 (d, J ¼ 10.7 Hz, 1H), 5.88
(dd, J ¼ 10.7, 17.4 Hz, 1H), 6.79 (d, J ¼ 8.8 Hz, 2H), 7.11 (d, J ¼ 8.8 Hz,
2H), 7.31 (d, J ¼ 8.2 Hz, 2H), 7.72 (d, J ¼ 8.2 Hz, 2H); dC (75 MHz,
CDCl3) 22.0, 25.8, 39.5, 42.7, 55.6, 68.4, 112.7, 114.0, 127.6, 128.2, 130.2,
133.5, 138.1, 145.1, 146.0, 158.3.
A solution of tosylate (240 mg, 0.67 mmol) in DMSO (3 mL) was added
dropwise to a stirred suspension of KCN (53 mg, 0.80 mmol) in DMSO (3 mL)
maintained at 130–1358C. The reaction mixture was then heated at 1608C for
14 h. Then, it was cooled and poured into cold water (30 mL) and extracted
with ether (15 mL ꢀ 3). The combined ethereal extracts were washed with
brine, dried, and concentrated. The residual oil was subjected to column
chromatography over silica gel. Elution with ethyl acetate–petroleum ether
(1 : 7) furnished the nitrile 15 as a viscous oil (120 mg, 84%); IR
2246 cm21; dH (300 MHz, CDCl3) 1.37 (s, 3H), 2.06–2.20 (m, 4H), 3.79
(s, 3H), 5.07 (d, J ¼ 17.4 Hz, 1H), 5.18 (d, J ¼ 10.7 Hz, 1H), 5.95 (dd,
J ¼ 10.7, 17.4 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 2H), 7.19 (d, J ¼ 8.8 Hz, 2H);
dC (75 MHz, CDCl3) 13.3, 25.0, 36.8, 43.7, 55.6, 113.4, 114.2, 120.6, 127.8,
137.3, 145.4, 158.5. Anal. calcd. for C14H17NO: C, 78.10; H, 7.96; N, 6.51.
Found: C, 77.94; H, 7.92; N, 6.49.
4-(4-Methoxyphenyl)-4-methyl-hex-5-enoic acid (16). A mixture of the
nitrile 15 (120 mg, 0.56 mmol) and potassium hydroxide in ethylene glycol
(3 mL, 20%) was heated under reflux for 24 h. The cooled reaction mixture
was diluted with ice-cold water and extracted once with ether. The aqueous
alkaline portion was acidified with cold dilute HCl (6 N) and extracted with
ether (10 mL ꢀ 3). The combined ethereal extracts were washed with brine,
dried, and concentrated to afford the acid 16 as a gummy liquid (120 mg,
92%); IR 1708 cm21; dH (300 MHz, CDCl3) 1.35 (s, 3H), 2.02–2.26
(m, 4H), 3.79 (s, 3H), 5.07 (d, J ¼ 17.4 Hz, 1H), 5.13 (d, J ¼ 10.7 Hz, 1H),
5.98 (dd, J ¼ 10.7, 17.4 Hz, 1H), 6.85 (d, J ¼ 8.8 Hz, 2H), 7.23
(d, J ¼ 8.8 Hz, 2H); dC (75 MHz, CDCl3) 25.3, 30.2, 35.7, 43.5, 55.6,
112.7, 114.0, 127.9, 138.6, 146.4, 158.2, 180.6. Anal. calcd for C14H18O3:
C, 71.77; H, 7.74. Found: C, 71.65; H, 7.63.
4-(4-Methoxyphenyl)-4-methyl-hex-5-en-1-al (17). A solution of the acid 16
(120 mg, 0.51 mmol) in THF (3 mL) was added to magnetically stirred slurry
of LAH (60 mg, 1.58 mmol) in THF (4 mL). After addition the reaction
mixture was refluxed for 8 h. The reaction mixture was then cooled and

1778
B. Biswas and R. V. Venkateswaran
decomposed with saturated aqueous Na2SO4 solution. The organic layer was
separated and the aqueous layer extracted with ether (10 mL ꢀ 2). The
combined ethereal extracts were washed with saturated NaHCO3 and brine
and dried. The residual oil after removal of solvent was chromatographed
over silica gel. Elution with ethyl acetate–petroleum ether (1 : 3) furnished
the corresponding alcohol (110 mg, 97%) as a viscous liquid. dH (300 MHz,
CDCl3) 1.36 (s, 3H), 1.38–1.51 (m, 2H), 1.68–1.84 (m, 2H), 3.58
(t, J ¼ 6.5 Hz, 2H), 3.78 (s, 3H), 5.03 (d, J ¼ 17.4 Hz, 1H), 5.08
(d, J ¼ 10.7 Hz, 1H), 6.01 (dd, J ¼ 10.7, 17.4 Hz, 1H), 6.84 (d, J ¼ 8.8 Hz,
2H), 7.23 (d, J ¼ 8.8 Hz, 2H); dC (75 MHz, CDCl3) 25.4, 28.4, 37.5, 43.7,
55.6, 63.8, 112.0, 113.8, 127.9, 139.6, 147.4, 158.0. Anal. calcd for
C14H20O2: C, 76.32; H, 9.15. Found: C, 75.89; H, 9.35.
To a magnetically stirred and cooled (2788C) solution of oxalyl chloride
(0.08 mL, 0.91 mmol) in dichloromethane (1 mL), a solution of DMSO
(0.14 mL, 1.97 mmol) in dichloromethane (1 mL) was added dropwise. After
stirring at 2788C for 15 min, a solution of this alcohol (100 mg, 0.45 mmol)
in dichloromethane (2 mL) was added and stirred for 45 min. Triethylamine
(0.4 mL, 2.86 mmol) was then added and the reaction mixture allowed to attain
rt and stirred for 4 h. The reaction mixture was poured into cold water and the
organic layer separated. The aqueous part was extracted with dichloromethane
(5 mL ꢀ 2). The combined organic layers were washed with water, dried, and
concentrated. The residue after column chromatography over silica gel using
ethyl acetate–petroleum ether (1 : 5) afforded the aldehyde 17 (95 mg, 96%) as
a colorless oil. IR 1720 cm21; dH (300 MHz, CDCl3) 1.35 (s, 3H), 1.98–2.16
(m, 2H), 2.27–2.35 (m, 2H), 3.79 (s, 3H), 5.06 (d, J ¼ 17.4 Hz, 1H), 5.12
(d, J ¼ 10.7 Hz, 1H), 5.98 (dd, J ¼ 10.4, 17.4 Hz, 1H), 6.84 (d, J ¼ 8.8 Hz,
2H), 7.21 (d, J ¼ 8.8 Hz, 2H), 9.69 (t, J ¼ 1.5 Hz, 1H); dC (75 MHz, CDCl3)
25.4, 32.9, 40.3, 43.4, 55.6, 112.7, 113.8, 127.9, 138.6, 146.5, 158.2, 202.7.
Anal. calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.98; H, 8.25.
3-(4-Methoxyphenyl)-3,7-dimethyl-1,6-octadiene (O-methylsporochnol A)
(18). The aldehyde 17 was converted to O-methylsporochnol A 18 following
literature procedure[3b] and was obtained in 76% yield as a colorless oil. dH
(300 MHz, CDCl3) 1.28 (s, 3H), 1.44 (s, 3H), 1.58 (s, 3H), 1.61–1.75
(m, 4H), 3.72 (s, 3H), 4.92–5.02 (m, 3H), 5.93 (dd, J ¼ 10.7, 17.5 Hz, 1H),
6.76 (d, J ¼ 8.8 Hz, 2H), 7.15 (d, J ¼ 8.8 Hz, 2H). dC (75 MHz, CDCl3)
16.5, 22.3, 24.0, 24.6, 40.2, 42.6, 54.2, 110.4, 112.3, 123.7, 126.7, 130.3,
138.5, 146.2, 156.5.
The spectral data of 18 were identical with the reported values.[2,3b]
ACKNOWLEDGMENTS
B.B. thanks the Council of Scientific & Industrial Research, New Delhi, India,
for a fellowship.

Synthesis of Sporochnol A, a Marine Fish Deterrent
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1779
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