Total synthesis of (-)-sporochnol A, the fish deterrent, from a chiral malonate

Article abstract of DOI:10.1016/S0957-4166(99)00086-5

From a single chiron, the homochiral benzylic malonic acid ester (R)- (+)-2 available with high enantiomeric excess by enzymatic hydrolysis (PLE acetonic powder), enantiomerically pure (-)-sporochnol A 1 was prepared. This versatile method allows preparation of sporochnol 1, via aldehydes 7 and 15, in good overall yield.

Full text of DOI:10.1016/S0957-4166(99)00086-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1153–1162
Total synthesis of (−)-sporochnol A, the fish deterrent, from a
chiral malonate
Antoine Fadel ∗ and Lucie Vandromme
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Received 15 February 1999; accepted 8 March 1999
Abstract
From a single chiron, the homochiral benzylic malonic acid ester (R)-(+)-2 available with high enantiomeric
excess by enzymatic hydrolysis (PLE acetonic powder), enantiomerically pure (−)-sporochnol A 1 was prepared.
This versatile method allows preparation of sporochnol 1, via aldehydes 7 and 15, in good overall yield. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
(+)-Sporochnol A 1, isolated from the Caribbean marine alga Sporochnus bolleanus, has been shown
to exhibit significant feeding deterrence towards herbivorous fish.1
The structure was determined by spectral and chemical methods1 and the absolute configuration
assigned to be (S) for the natural (+)-sporochnol A 1. Few methods for the enantioselective synthesis have
been investigated.2,3 In previous papers, we have described the asymmetric construction of quaternary
benzylic carbons from chiral malonates4–6 and their subsequent transformation into both enantiomers of
(−)-aphanorphine and (+)-eptazocine.7,8 Herein we wish to describe a total synthesis of (−)-sporochnol
∗
Corresponding author. Fax: +33(1)69156278; e-mail: antfadel@icmo.u-psud.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00086-5

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A 1 from a chiral acid ester 2, obtained on a large scale by enantiomeric hydrolysis via the conjugated
ester 3.
2. Results and discussions
The prochiral dimethyl malonate 4, obtained in 92% yield from methyl 4-methoxyphenylacetate by
successive alkylation with methyl iodide and methyl chloroformate, was submitted to enantioselec-
tive enzymatic hydrolysis by pig liver esterase (PLE) to provide (R)-(+)-2 (yield, 93%) in the acid
1
ester.† The enantiomeric excess of 2, determined from the H NMR spectra of its salt with (R)-
(+)-1-naphthylethylamine, was 85% and was raised to 97% after recrystallisation (see Experimental)
[[α]D20=+12 (c=1, CHCl3), ee=97%].
We have previously reported on the chemoselective reduction of acid esters such as 2.6 Thus, reaction
of (R)-(+)-2 with (COCl)2-cat. DMF,9 followed by reduction of the resulting acyl chloride (NaBH4, THF
then MeOH)10 gave the β-hydroxy ester (R)-(+)-5 in 88% overall yield, [α]D20=+65.5 (c=1, CHCl3).
Hydroxy ester (+)-5 was found to be a key intermediate for the preparation of conjugated ester (+)-3.
Thus its protection with chloromethyl methyl ether in the presence of diisopropylethylamine led to the
ester (+)-6 [98% yield; [α]D20=+31 (c=1, CHCl3)]. Its reduction with 2 equiv. of diisobutylaluminium
hydride (DIBAL-H in toluene)‡ at −78°C gave the corresponding alcohol, which was submitted to the
Dess–Martin oxidation11 to furnish aldehyde 7 in 96% overall yield. This aldehyde 7, without further
purification, was treated with methylenetriphenylphosphorane to give olefin 8 [81% yield, [α]D20=−9.5
(c=1, CHCl3)]. At this stage the deprotection of alcohol was carried out in EtOH at 65°C in the presence
of concentrated HCl to afford alcohol 9 in 97% yield. Oxidation with the Dess–Martin reagent,11 followed
by Horner–Emmons reaction of the resulting aldehyde, led to α,β-unsaturated ester (+)-3 in 92% overall
yield. However, oxidation of alcohol 9 with PCC12 furnished, in 92% yield, the expected aldehyde 10
and the byproduct 1113 in a 91:9 ratio.
†
The absolute configuration (R)-(+)-2 was assigned by comparison to other aryl malonic acid ester obtained with PLE,4–6 and
was confirmed, vide infra, by comparison of the sign of (R)-(−)-sporochnol A with that of the literature.2
‡
Use of 1 equiv. of DIBAL-H gave a mixture of alcohol, aldehyde and unreacted ester.

A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
1155
We believe that we have first formation in the chromium(VI) oxidation of chromate ester 12, which
undergoes a normal oxidation to aldehyde 10 (path a), or an unexpected rearrangement via a seven-
membered transition state (path b) to rearranged ester 13. This latter is oxidised to rearranged aldehyde
11. Such rearrangement was known in the oxidation of allyl alcohol using CrO3.14–16 Chemoselective
reduction of the conjugated ester (+)-3 with magnesium in methanol,17–19 gave methyl ester (R)-(−)-
14 in 95% yield. A simple reduction of ester 14 by 1.3 equiv. of DIBAL-H in toluene at −78°C led
to aldehyde (R)-(−)-15 (88% yield) and corresponding alcohol (5%): [[α]D20=−12.5 (c=1, CHCl3), lit.2
[α]D20=−8.7 (c=1.9, CHCl3)].
The aldehyde (R)-(−)-15 underwent the Wittig reaction with isopropyltriphenylphosphorane
(Ph3P+CH(Me)2·I−, t-BuLi) to furnish (R)-(−)-O-methylsporochnol A 16 in 84% yield as a
single product. Finally, to cleave the ether bond, the methyl ether 16 was heated at 180°C with
methylmagnesium iodide20,21 to give (−)-ent-sporochnol A 1 (92% yield). The sign of the specific
rotation of (−)-1 indicated that the configuration is (R) as reported,2 and consequently confirmed our
assignment ((R)-configuration) of acid (+)-2 prepared by enzymatic hydrolysis.
In conclusion, from a readily available chiron 2 (ee >97%), we have developed, by a 10-step reaction
sequence, a rapid and competitive total synthesis of (−)-ent-sporochnol A 1 with 33% overall yield.
Furthermore, we can also emphasise that asymmetric synthesis of the natural product (S)-(+)-1 is
conceivable from the same precursor 2, by converting aldehyde (R)-(+)-7 into ester (R)-(−)-3 just by
inverting the order of the Wittig, Dess–Martin, and Horner–Emmons reactions through the same sequence
proposed herein.

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3. Experimental
Except as otherwise indicated, reactions were carried out under argon, with magnetic stirring. All
reactions were monitored by thin layer chromatography (TLC) using 0.25 mm E. Merck precoated silica
gel plates. Flash chromatography was performed with silica gel 60 (particle size 0.040–0.063 mm).
Yields refer to chromatographically and spectroscopically pure compounds, except as noted. Proton
and 13C NMR spectra were recorded on a Bruker AM250 spectrometer in deuteriochloroform using
the solvent signal as an internal standard, 7.27 ppm. Chemical shifts (δ) are expressed in parts per
million and the coupling constants (J) are given in hertz. IR spectra were recorded on a Perkin–Elmer 682
spectrophotometer. Mass spectra were recorded at an ionising voltage of 70 eV by EI. High resolution
mass spectra were obtained with a MAT 95S spectrometer. Melting points were determined on a Mettler
FP51 capillary melting point apparatus and are uncorrected. Specific rotations were obtained at 20°C
using a Perkin–Elmer 341 polarimeter. Enantiomeric excesses were performed on a GC (Fisons 9130)
chiral column Cydex B (SGE) (25 m, 110°C, 0.8 bar). Elemental analyses were performed by the
microanalytical laboratory of CNRS at Gif (France).
3.1. Dimethyl 2-(4-methoxyphenyl)-2-methylmalonate 4
Prepared from 2-(4-methoxyphenyl)acetic acid (24.9 g, 0.15 mol) following the procedure described
in the literature,6 with 93% overall yield as a colourless oil (35 g).
Data for 4: Rf=0.56 (EtOAc:petroleum ether, 3:7); IR (film, cm−1): 1745, 1620, 1590, 1260; 1H NMR
(CDCl3) δ: 7.35–7.23 (m, 2H), 6.44–6.82 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H, Meester), 1.85 (s, 3H); 13
C
NMR (CDCl3) δ: 172.0 (2s), [6 arom C: 158.7 (s), 129.8 (s), 128.3 (2d), 113.3 (2d)], 57.8 (s, C2), 54.9
(q), 52.5 (2q), 22.0 (q); MS (EI) m/z: 253 (M++1, 5), 252 (M+, 27), 251 (43), 193 (53), 192 (93), 165
(20), 164 (22), 134 (27), 133 (91), 132 (100), 91 (23), 90 (24). HRMS calcd for C13H16O5: 252.0998.
Found: 252.0999. Anal. calcd for C13H16O5: C, 61.90; H, 6.39. Found: C, 62.14; H, 6.58.
3.2. (R)-(+)-2-(Methoxycarbonyl)-2-(4-methoxyphenyl)propionic acid 2
Following the procedure described in the literature:6 to a stirred solution of malonate 4 (25.2 g, 0.1
mol) in water (100 mL) was added, at 25°C, pig liver esterase (5 g, acetonic powder purchased from
Sigma L 8251). The pH of the reaction was kept at 7.0 by regular addition of 2 N aqueous NaOH
via a syringe pump interfaced with a pH controller. After a stirring period of 3 h another portion of
PLE (2×5 g) was added. When 50 mL of aqueous 2 N NaOH (60 h) was added, the enzyme was
eliminated by filtration (addition of Celite to the mixture facilitates the filtration). The precipitate was
washed with water (60 mL) and with ether (100 mL). After separation, the aqueous layer was acidified
(2 N aqueous HCl) until pH=3 and the malonate monoester 2 was extracted with ethyl acetate (6×250
mL). The combined organic extracts were washed with brine, dried and evaporated (T<35°C) to give
23.2 g (97.5%) of crude acid. Product purification was achieved by flash chromatography on silica gel
(elution with EtOAc:petroleum ether, 3:7 to 6:4). Then 22.1 g (92.8%) acid ester (+)-2, was isolated as a
colourless oil, [α]D20=+10.3 (c=1, CHCl3); ee=85% from 1H NMR spectra in the presence of (R)-(+)-1-
naphthylethylamine. Crystallisation of 22 g acid ester from ether:pentane gave 3 g of a solid mixture of
(S):(R) (9:2) and concentration of the mother liquor furnished 19 g (80% yield) of pure acid (+)-2.
Data for (R)-(+)-2: [α]D20=+12 (c=1, CHCl3); ee=97%. Rf=0.16 (EtOAc:petroleum ether, 1:1); IR
1
(film, cm−1): 3600, 3500, 3200, 1745, 1720, 1620, 1590; H NMR (CDCl3, 250 MHz) δ: 10.15 (br s,
1Hacid), 7.40–7.25 (m, 2H), 6.95–6.80 (m, 2H), 3.82 (s, 3H), 3.80 (s, 3H, Meester), 1.90 (s, 3H); 13C

A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
1157
NMR (CDCl3, 50.29 MHz) δ: 177.0 (s, C1 acid), 172.2 (s, C3), [6 arom C: 159.1 (s), 129.3 (s), 128.5
(2d), 113.6 (2d)], 57.8 (s, C2), 55.1 (q), 52.9 (q), 21.7 (q). Anal. calcd for C12H14O5: C, 60.50; H, 5.92.
Found: C, 60.50; H, 5.92.
3.3. Methyl (R)-(+)-3-hydroxy-2-(4-methoxyphenyl)-2-methylpropionate 5
To a stirred solution of acid ester (+)-2 (11.9 g, 50 mmol, 97% ee) and 2 drops of DMF9 in dry CH2Cl2
(90 mL) was added dropwise (COCl)2 (9.6 mL, 110 mmol, 2.2 equiv.). The mixture was stirred at room
temperature for 2 h (complete reaction as evidenced by TLC). The solvent was evaporated to dryness,
which quantitatively gave the corresponding acyl chloride. This was used in the next step without further
purification.
1
Data for acyl chloride: H NMR (CDCl3, 250 MHz) δ: 7.42–7.20 (m, 2H), 7.00–6.80 (m, 2H), 3.85
(s, 3H), 3.83 (s, 3H, Meester), 2.00 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: 173.4 (s, C1), 169.9 (s, C3),
[6 arom C: 159.7 (s), 128.9 (2d), 127.6 (s), 114.0 (2d)], 67.0 (s, C2), 55.3 (q), 53.3 (q), 22.4 (q).
To a cold (−30°C) stirred solution of acyl chloride (50 mmol) in dry THF was added NaBH4 (5.7 g,
150 mmol, 3 equiv.) in one portion, and then MeOH (15 mL)7 was added dropwise over 1 h 30 min.
After stirring at −30°C for 1 h, then at room temperature for 2 h, the reaction mixture was hydrolysed
with 6 N aq. HCl (to pH 2). The hydroxy ester was extracted with CH2Cl2 (4×150 mL). The combined
organic extracts were washed with brine, dried and concentrated. Product purification was achieved by
flash chromatography on silica gel (eluent: ethyl acetate:petroleum ether, 1:9 to 6:4). There was 9.85 g
(88% overall yield from acid 2) hydroxy ester (+)-5 isolated as a colourless oil.
Data for (R)-(+)-5: Rf=0.27 (AcOEt:petroleum ether, 3:7); [α]D20=+65.5 (c=1, CHCl3); ee=97%;
1
IR (film, cm−1): 3500, 1735, 1615, 1590, 1520; H NMR (CDCl3, 200 MHz) δ: 7.30–7.15 (m, 2H),
6.95–6.80 (m, 2H), 3.82 [AB part of ABM system, ∆νAB=87 Hz, 4.05 (dd, A part, JAB=13.6 Hz, JAM=6.3
Hz, 1H), 3.58 (dd, B part, JAB=13.6 Hz, JBM=8.4 Hz, 1H)], 3.80 (s, 3H), 3.72 (s, 3H, Meester), 2.50 (dd,
M part, JAM=6.3 Hz, JBM=8.4 Hz, OH), 1.64 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: 176.4 (s, C1), [6
arom C: 158.5 (s), 132.3 (s), 127.1 (2d), 113.4 (2d)], 69.3 (t, C3), 55.0 (q), 52.0 (q), 51.7 (s, C2), 19.9 (q);
MS (EI) m/z: 225 (M++1, 5.2), 224 (M+, 24), 194 (84), 193 (60), 165 (43), 135 (27), 134 (26), 133 (100),
132 (22), 91 (32), 77 (17), 65 (16), 43 (36). HRMS calcd for C12H16O4: 224.1048. Found: 224.1038.
3.4. Methyl (R)-(+)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2-methylpropionate 6
To a stirred solution of alcohol (+)-5 (8.96 g, 40 mmol) and diisopropylethylamine (21 mL, 120 mmol)
in CH2Cl2 (150 mL) was added chloromethyl methyl ether (MOMCl, 6.06 mL, 80 mmol) at 0°C. The
mixture was stirred at 0°C for 2 h and at room temperature overnight. After addition of water (80 mL) the
mixture was extracted with EtOAc (3×200 mL). The organic layer was dried and concentrated and the
residue purified by flash chromatography on silica gel (using ether:petroleum ether 1:9 to 6:4 as eluent).
Then 10.5 g (98%) of the protected ester 6 was isolated.
Data for (R)-(+)-6: [α]D20=+31.4 (c=1, CHCl3); ee=97%; Rf=0.64 (EtOAc:petroleum ether, 3:7); IR
(film, cm−1): 1740, 1615, 1595, 1520; 1H NMR (CDCl3, 250 MHz) δ: 7.30–7.15 (m, 2H), 6.95–6.80 (m,
2H), 4.65 (A0B0 system like q, JA B =6.4 Hz, 2H), 3.90 [AB system, ∆νAB=95 Hz, JAB=9.5 Hz, 4.12 (d,
A part, JAB=9.5 Hz, 1H), 3.71 (d, B part, JAB=9.5 Hz, 1H)], 3.79 (s, 3H), 3.70 (s, 3H, Meester), 3.31 (s,
3H), 1.65 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: 175.0 (s, C1), [6 arom C: 158.5 (s), 132.9 (s), 127.0
(2d), 113.7 (2d)], 96.5 (t), 73.4 (t, C3), 55.1 (q), 52.0 (q), 50.4 (s, C2), 21.0 (q); MS (EI) m/z: 269 (M++1,
4), 268 (M+, 12), 238 (11), 206 (11), 194 (20), 193 (100), 192 (12), 177 (10), 165 (13), 151 (11), 134
(17), 133 (61), 45 (71), 44 (17). HRMS calcd for C14H20O5: 268.1311. Found: 268.1300.
0
0

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A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
3.5. (R)-(+)-3-(Methoxymethoxy)-2-(4-methoxyphenyl)-2-methylpropanal 7
Preparation of alcohol: To a stirred solution of ester 6 (9.11 g, 34 mmol), in dry CH2Cl2 (100 mL)
was slowly added via cannula at −78°C, a solution of DIBAL-H (1 M solution in toluene, 102 mL, 3
equiv.). The mixture was stirred for 1 h at −78°C before quenching with MeOH (7 mL) then allowed to
warm to room temperature. The solution was poured into a 6:1 mixture of ethyl acetate:potassium sodium
tartrate (140 mL). The organic layer was dried and concentrated to give 7.95 g (97.5%) of alcohol (R)-(+)-
3-(methoxymethoxy)-2-(4-methoxyphenyl)-2-methylpropanol, which was used in the next step without
further purification.
Data for (R)-(+)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2-methylpropanol: [α]D20=+4 (c=1,
1
CHCl3); ee=97%; Rf=0.27 (EtOAc:petroleum ether, 3:7); IR (film, cm−1): 3500, 1620, 1590, 1520; H
NMR (CDCl3, 200 MHz) δ: 7.40–7.23 (m, 2H), 6.98–6.82 (m, 2H), 4.64 (s, 2H), 3.96–3.65 (m, 2H),
3.81 (s, 3H), 3.79 (AB system, ∆νAB=34.8 Hz, JAB=9.4 Hz, 2H), 3.35 (s, 3H), 2.17 (m, OH), 1.34 (s,
3H); 13C NMR (CDCl3, 62.86 MHz) δ: [6 arom C: 157.9 (s), 135.3 (s), 127.4 (2d), 113.6 (2d)], 96.6 (t),
74.2 (t, C3), 69.4 (t, C1), 55.2 (q), 55.0 (q), 43.0 (s, C2), 20.8 (q); MS (EI) m/z: 241 (M++1, 1.9), 240
(M+, 11), 177 (17), 165 (70), 164 (24), 149 (10), 148 (71), 147 (30), 135 (14), 121 (27), 91 (19), 90 (12),
57 (15), 45 (100), 44 (30). HRMS calcd for C13H20O4: 240.1361. Found: 240.1370.
To a stirred suspension of periodinane (Dess–Martin’s reagent)11 (19.1 g, 1.5 equiv.) in CH2Cl2 (120
mL), was added dropwise a solution of crude alcohol (7.2 g, 30 mmol) in 20 mL of CH2Cl2. The mixture
was stirred at room temperature. The reaction was monitored by TLC and was completed after 20 h.
Ether (60 mL) was added and the precipitate was filtered and washed with ether (50 mL). The filtrate
was successively washed with Na2S2O3 solution (50 mL), NaHCO3 saturated solution (5 mL) and brine
(5 mL). The organic layer was dried, filtered, and concentrated to give 7.07 g of aldehyde 7 (99%) used
in the next step without further purification.
Data for (R)-(+)-7: [α]D20=+0.3 (c=1, CHCl3); ee=97%; Rf=0.61 (EtOAc:petroleum ether, 3:7); IR
(film, cm−1): 1740, 1620, 1590, 1520; 1H NMR (CDCl3, 200 MHz) δ: 9.57 (s, 1H), 7.30–7.10 (m, 2H),
7.00–6.82 (m, 2H), 4.60 (m, AB system, 2H), 3.95 [AB system, ∆νAB=60.8 Hz, JAB=9.5 Hz, 4.10 (d, A
part, JAB=9.5 Hz, 1H), 3.79 (d, B part, JAB=9.5 Hz, 1H)], 3.81 (s, 3H), 3.31 (s, 3H), 1.54 (s, 3H); 13C
NMR (CDCl3, 62.86 MHz) δ: 201.2 (d, C1), [6 arom C: 158.8 (s), 129.6 (s), 128.0 (2d), 114.2 (2d)], 96.5
(t), 71.1 (t, C3), 55.2 (q), 55.1 (q), 53.8 (s, C2), 17.8 (q); MS (EI) m/z: 239 (M++1, 1.1), 238 (M+, 5),
179 (14), 177 (11), 163 (23), 148 (20), 135 (20), 45 (100). HRMS calcd for C13H18O4: 238.1205. Found:
238.1194.
3.6. (R)-(+)-4-(Methoxymethoxy)-3-(4-methoxyphenyl)-2-methylbut-1-ene 8
To a stirred suspension of methyltriphenylphosphonium bromide (15 g, 42 mmol) in dry THF (100
mL), was added n-BuLi (1.6 M, 24.3 mL, 38.9 mmol) at 0°C. The resulting yellow suspension was
stirred at room temperature for 1 h. To this suspension was added a solution of crude aldehyde 7 (6.66 g,
28 mmol) in THF (50 mL) at 0°C. The solution was kept at 0°C for 30 min, then allowed to warm to rt
(4 h). The solvent was evaporated and the resulting solid was diluted in ether (200 mL) then filtered on
Celite and the precipitate washed with ether (3×150 mL). The filtrate was concentrated and the resulting
residue purified by flash chromatography on silica gel (elution, EtOAc:petroleum ether, 1:19 to 4:6).
There was 5.35 g (81%) of a pure olefin 8 isolated as a colourless oil and 865 mg (13%) of the unreacted
aldehyde 7.
Data for (R)-(+)-8: Rf=0.75 (AcOEt:petroleum ether, 3:7); [α]D20=−9.4 (c=1, CHCl3); ee=97%; IR
(film, cm−1): 3080, 2940, 1630 (νC_C), 1610, 1580, 1515, 1255, 1115, 1050, 920; 1H NMR (CDCl3, 250

A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
1159
MHz) δ: 7.35–7.20 (m, 2H), 6.92–6.80 (m, 2H), 6.08 (dd, Jcis=10.5 Hz, Jtrans=17.7 Hz, Ha), 5.18 (dd,
Jcis=10.5 Hz, Jgem=2.6 Hz, Hb), 5.11 (dd, Jgem=2.6 Hz, Jtrans=17.7 Hz, Hc), 4.61 (s, like AB system, 2H),
3.80 (s, 3H), 3.73 (m, AB system, 2H), 3.30 (s, 3H), 1.45 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: [6
arom C: 157.8 (s), 137.0 (s), 127.8 (2d), 113.4 (2d)], 144.4 (d, C2), 113.0 (t, C1), 96.6 (t), 75.2 (t, C4),
55.2 (q), 55.1 (q), 44.7 (s, C3), 23.2 (q); MS (EI) m/z: 237 (M++1, 1), 236 (M+, 6), 162 (16), 161 (100),
121 (14), 91 (12), 45 (51). HRMS calcd for C14H20O3: 236.1412. Found: 236.1402.
3.7. Ethyl (S)-(+)-4-(4-methoxyphenyl)-4-methylhexa-2,5-dienoate 3
Deprotection: A stirred solution of olefin 8 (4.72 g, 42 mmol) in ethanol (40 mL) and concentrated
HCl (1 mL), was heated at 65°C for 16 h. After addition of Na2CO3 (solid) to pH=7, the solution was
filtered through Na2CO3 (solid) and the precipitate was washed with ether (2×50 mL). The filtrate was
concentrated and the resulting residue was diluted with ether (50 mL). The organic layer was again
filtered through a silica gel pad. Evaporation of the solvent furnished 3.73 g (97%) crude alcohol 9, used
in the next step without further purification.
1
Data from crude alcohol 9: H NMR (CDCl3) δ: 7.35–7.20 (m, 2H), 6.95–6.80 (m, 2H), 6.07 (dd,
Jcis=10.5 Hz, Jtrans=17.9 Hz, Ha), 5.25 (dd, Jcis=10.5 Hz, Jgem=2.2 Hz, Hb), 5.15 (dd, Jtrans=17.9 Hz,
J
gem=2.2 Hz, Hc), 3.81 (s, 3H), 3.77 (m, 2H), 1.42 (s, 3H).
Oxidation by periodinane: Aldehyde 10 was prepared following the procedure described above for 7,
from a mixture of crude alcohol 9 (3.07 g, 16 mmol), periodinane (10.2 g, 24 mmol) in CH2Cl2 (80 mL).
Usual workup quantitatively gave the corresponding aldehyde 10 which was used in the next step without
further purification.
1
Data from the crude aldehyde 10: H NMR (CDCl3) δ: 9.55 (s, 1H), 7.42–7.22 (m, 2H), 7.03–6.80
(m, 2H), 6.22 (dd, Jcis=10.5 Hz, Jtrans=17.4 Hz, 1H), 5.41 (d, Jcis=10.5 Hz, 1H), 5.18 (d, Jtrans=17.4 Hz,
1H), 3.81 (s, 3H), 1.51 (s, 3H).
Wittig–Horner reaction: Conjugate ester 3 was prepared following the procedure described in the
literature,8 from a mixture of crude aldehyde 10 (3.04 g, 16 mmol), triethyl phosphonoacetate (4.3 g,
19.2 mmol) and n-BuLi (12.4 mL of a 1.55 N solution, 19.2 mmol). Chromatography on silica gel
(EtOAc:petroleum ether, 1:19) furnished 3.83 g (92% overall yield from the olefin 8) as a colourless
oil of the trans-(+)-3.
Data for (S)-(+)-3: Rf=0.70 (AcOEt:petroleum ether, 3:7); [α]D20=+19.6 (c=1, CHCl3); ee=97%; IR
(film, cm−1): 3070, 2970, 1720 (νC_O), 1645 (νC_C conjugated), 1630 (νC_C), 1610, 1580, 1515, 1260,
1185, 1040; 1H NMR (CDCl3, 200 MHz) δ: 7.30–7.10 (m, 2H), 7.18 (d, Jtrans=16.1 Hz, 1H conjugated
olefin), 6.06 (dd, Jcis=10.6 Hz, Jtrans=17.8 Hz, 1H), 5.79 (d, Jtrans=16.1 Hz, 1H conjugated olefin), 5.20
(dd, Jcis=10.6 Hz, Jgem=0.8 Hz, 1H), 5.05 (dd, Jtrans=17.8 Hz, Jgem=0.8 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H),
3.80 (s, 3H), 1.54 (s, 3H), 1.30 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: 166.7 (s, C1), 158.2
(s), 154.4 (d, C3), 143.5 (d, C5), 136.2 (s), 128.1 (2d), 119.5 (d, C2), 113.9 (t, C6), 113.6 (2d), 60.3 (t),
55.1 (q), 47.2 (s, C4), 24.8 (q), 14.2 (q); MS (EI) m/z: 261 (M++1, 7), 260 (M+, 32), 187 (100), 186 (92),
185 (36), 172 (55), 171 (72), 159 (32), 158 (34), 128 (37), 127 (36), 126 (33), 79 (36), 78 (40), 77 (53),
76 (38). HRMS calcd for C16H20O3: 260.1412. Found: 260.1410.
N.B. Oxidation by PCC: Aldehyde 10 was prepared following the procedure described in the
literature,6 from crude alcohol 9 (307 mg, 1.6 mmol), PCC12 (690 mg, 3.2 mmol), Na2HPO4 (0.4 g),
Celite (1 g) and CH2Cl2 (20 mL). After 16 h at room temperature, the usual workup gave 280 mg (92%)
as a mixture of expected aldehyde 10 and conjugated aldehyde 11 in a 9:1 ratio.
The 1H NMR spectrum of conjugated aldehyde 11 read from the mixture (CDCl3) δ: 10.16 (d, J=8 Hz,

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A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
1H), 7.56 (br d, J=9 Hz, 2H), 6.95 (br d, J=9 Hz, 2H), 6.41 (dd, J=8 Hz, J=1.2 Hz, 1H), 3.87 (s, 3H),
2.57 (d, J=1.2 Hz, 3H). Spectral data are identical with those reported.11
3.8. Methyl (R)-(−)-4-(4-methoxyphenyl)-4-methylhex-5-enoate 14
A suspension of conjugated ester 3 (3.38 g, 13 mmol) and Mg (1.56 g, 65 m.atm g) in methanol
(50 mL) was stirred at room temperature for 4 h. The cloudy mixture was neutralised with 2 N HCl
and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried
(MgSO4) and concentrated under vacuum. The resulting residue (3.13 g, 87.2% yield) was purified by
chromatography (SiO2, 70 g, eluent: EtOAc:petroleum ether, 1:19) to furnish ester 14 (3.06 g, 95%) as a
colourless oil.
Data for (R)-(−)-14: [α]D20=−11 (c=1, CHCl3); ee=97%; Rf=0.5 (ether:pentane, 1:3); IR (film, cm−1):
1
3075, 2960, 1740 (νC_O), 1630 (νC_C), 1610, 1580, 1515, 1255, 1185, 1040; H NMR (CDCl3, 250
MHz) δ: 7.35–7.12 (m, 2H), 6.94–6.74 (m, 2H), 5.98 (dd, Jcis=10.6 Hz, Jtrans=16.8 Hz, 1H), 5.13 (d,
Jcis=10.6 Hz, 1H), 5.07 (d, Jtrans=16.8 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H, Meester), 2.32–1.92 (m, 4H),
1.35 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: 174.1 (s, C1), [6 arom C: 157.6 (s), 138.1 (s), 127.4 (2d),
113.4 (2d)], 146.0 (d, C5), 112.0 (t, C6), 54.9 (q), 51.3 (q), 43.0 (s, C4), 35.4 (t, C2), 29.6 (t, C3), 24.7
(q); MS (EI) m/z: 249 (M++1, 2), 248 (M+, 7.8), 162 (16), 161 (100), 160 (61), 146 (7), 145 (6), 91 (6).
HRMS calcd for C15H20O3: 248.1412. Found: 248.1408.
3.9. (R)-(−)-4-(4-methoxyphenyl)-4-methylhex-5-en-1-al 15
To a stirred solution of ester 14 (2.48 g, 10 mmol) in dry CH2Cl2 (20 mL) was slowly added a solution
of DIBALH (1 M in hexane, 13 mL, 13 mmol, 1.3 equiv.) at −78°C. The mixture was stirred for 30 min
at −78°C before quenching with MeOH (5 mL) then allowed to warm to room temperature. The solution
was poured into a 6:1 mixture of EtOAc:potassium sodium tartrate (350 mL). The organic layer was dried
and concentrated and the residue purified by flash chromatography (SiO2, eluent: ether:pentane, 15:85)
to yield 1.92 g (88%) of pure aldehyde (R)-(−)-15 as a colourless oil and the corresponding alcohol (110
mg, 5%).
Data for (R)-(−)-15: [α]D20=−12.5 (c=1, CHCl3); ee=97%; [lit.2 [α]D20=−8.7 (c=1.9, CHCl3)]; Rf=0.5
(ether:pentane, 1:3); IR (film, cm−1): 2960, 1720 (νC_O), 1630 (νC_C), 1608, 1580, 1510, 1255, 1185,
1
1035; H NMR (CDCl3, 250 MHz) δ: 9.70 (t, J=1.5 Hz, 1H), 7.30–7.17 (m, 2H), 6.92–6.80 (m, 2H),
5.99 (dd, Jtrans=17.2 Hz, Jcis=10.8 Hz, 1H), 5.14 (dd, Jcis=10.8 Hz, J=1 Hz, 1H), 5.08 (dd, Jtrans=17.2
Hz, J=1 Hz, 1H), 3.79 (s, 3H), 2.50–2.25 (m, 2H), 2.25–1.95 (m, 2H), 1.35 (s, 3H); 13C NMR (CDCl3,
62.86 MHz) δ: 202.1 (d, C1), [6 arom C: 157.7 (s), 138.1 (s), 127.4 (2d), 113.5 (2d)], 146.1 (d, C5),
112.1 (t, C6), 55.0 (q), 42.9 (s, C4), 39.7 (t), 32.3 (t), 24.9 (q); MS (EI) m/z: 219 (M++1, 2), 218 (M+,
8), 162 (17), 161 (100), 160 (57), 146 (8), 145 (7), 91 (7). HRMS calcd for C14H18O2: 218.1306. Found:
218.1304. All spectral data are identical with those reported.2
1
Data for 4-(4-methoxyphenyl)-4-methylhex-5-en-1-ol: H NMR (CDCl3, 250 MHz) δ: 7.30–7.15 (m,
2H), 6.91–6.75 (m, 2H), 6.02 (dd, Jtrans=17.3 Hz, Jcis=10.7 Hz, 1H), 5.18–5.05 (m, 2H), 3.79 (s, 3H),
3.60 (t, J=6.5 Hz, 2H), 1.92–1.65 (m, 2H), 1.60–1.25 (m, 2H and OH), 1.35 (s, 3H).
3.10. (R)-(−)-3,7-Dimethyl-3-(4-methoxyphenyl)octa-1,6-diene (ent-O-methylsporochnol A) 16
To a stirred solution of isopropyltriphenylphosphonium iodide (2.16 g, 5 mmol) in anhydrous THF (20
mL) was added t-BuLi (1.5 M in pentane, 3.3 mL, 5 mmol) at 0°C and, after 2 h (deep red solution),

A. Fadel, L. Vandromme / Tetrahedron: Asymmetry 10 (1999) 1153–1162
1161
aldehyde 15 (435 mg, 2 mmol) in THF (5 mL) was added at 0°C and the reaction mixture was stirred
at 0°C for 1 h then at room temperature for 10 h. After addition of a saturated aqueous solution of
NH4Cl (20 mL), the mixture was extracted with ether (3×40 mL). The combined extracts were dried
and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 40 g, eluent,
toluene:hexane, 25:75) furnished diene 16 (410 mg, 84%) as a colourless oil.
Data for (R)-(−)-16: [α]D20=−3.7; [α]36520=−15.2 (c=1, CHCl3); ee=97%; [lit.2 [α]D29=−2.3 (c=1.1,
CHCl3)]; Rf=0.42 (toluene:hexane, 3:7); IR (film, cm−1): 2960, 1630 (νC_C), 1610, 1580, 1510, 1250,
1180, 1040; 1H NMR (CDCl3, 250 MHz) δ: 7.25 (br d, J=9 Hz, 2H), 6.85 (br d, J=9 Hz, 2H), 6.03 (dd,
J
trans=17.4 Hz, Jcis=10.8 Hz, 1H), 5.10 (dd, Jcis=10.8 Hz, J=1.2 Hz, 1H), 5.05 (dd, Jtrans=17.4 Hz, J=1.2
Hz, 1H), 5.18–5.04 (m, 1H), 3.80 (s, 3H), 2.00–1.60 (m, 4H), 1.68 (br s, 3H), 1.04 (br s, 3H), 1.37 (s,
3H); 13C NMR (CDCl3, 62.86 MHz) δ: [6 arom C: 157.5 (s), 139.5 (s), 127.6 (2d), 113.3 (2d)], 147.2
(d, C2), 131.2 (s, C7), 124.7 (d, C6), 111.4 (t, C1), 55.1 (q), 43.6 (s, C3), 41.2 (t), 25.7 (q), 25.0 (t), 23.3
(q), 17.5 (q); MS (EI) m/z: 245 (M++1, 1.5), 244 (M+, 6), 162 (27), 161 (100), 160 (33), 146 (7), 91 (9),
83 (9), 55 (17). HRMS calcd for C17H24O1: 244.1827. Found: 244.1820.
All spectral data are identical with those reported.2
3.11. (R)-(−)-3,7-Dimethyl-3-(4-hydroxyphenyl)octa-1,6-diene (ent-(R)-(−)-sporochnol) ent-1
Prepared following the literature:2 To a stirred solution of MeMgI 20,21 (2 M in Et2O: 5 mL, 10 mmol)
was added ether 16 (125 mg, 0.5 mmol) and the solution was evaporated under reduced pressure. The
residue was heated at 180°C for 10 min. The reaction mixture was cooled to 0°C and diluted with ether
(10 mL), then carefully hydrolysed with 1.5 N HCl, and extracted with ether (3×50 mL). The organic
layer was washed with brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by
flash chromatography (SiO2, 30 g, eluent: ether:pentane, 1:9) to give ent-(R)-sporochnol A ent-1 (106
mg, 92%) as a colourless oil.
Data for (R)-(−)-ent-1: [α]D20=−2.5 and [α]36520=−10.3 (c=1, CHCl3); ee=97%; [lit.2 [α]D29=−1.3
(c=0.5, CHCl3), natural1 [α]D=+10 (c=1, CHCl3)]; Rf=0.48 (ether:pentane, 1:3); IR (film, cm−1): 3365,
2980, 1630 (νC_C), 1608, 1590, 1510, 1240, 1176, 930; 1H NMR (CDCl3, 250 MHz) δ: 7.19 (br d, J=9
Hz, 2H), 6.77 (br d, J=9 Hz, 2H), 6.01 (dd, Jtrans=17.2 Hz, Jcis=10.8 Hz, 1H), 5.09 (dd, Jcis=10.8 Hz,
J=1.4 Hz, 1H), 5.03 (dd, Jtrans=17.2 Hz, J=1.4 Hz, 1H), 5.18–5.00 (m, 1H), 4.78 (br s, OH), 2.00–1.58
(m, 4H), 1.66 (br s, 3H), 1.53 (br s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3, 62.86 MHz) δ: [6 arom C:
153.3 (s), 139.7 (s), 127.8 (2d), 114.8 (2d)], 147.1 (d, C2), 131.3 (s, C7), 124.7 (d, C6), 111.4 (t, C1),
43.6 (s, C3), 41.1 (t), 25.6 (q), 25.0 (t), 23.2 (q), 17.5 (q); MS (EI) m/z: 231 (M++1, 2.3), 230 (M+, 9),
148 (31), 147 (100), 146 (26), 120 (11), 107 (10), 83 (18), 55 (38), 54 (23), 41 (45). HRMS calcd for
C16H22O1: 230.1671. Found: 230.1661.
All spectral data are identical with those reported.2
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