Carotenoids and related polyenes. Part 6. Stereoselective synthesis of astaxanthin analogues and their antioxidant activities

Article abstract of DOI:10.1039/b104338m

Astaxanthin analogues having various lengths of polyene chains are stereoselectively synthesized and their singlet-oxygen-quenching activities are examined.

Full text of DOI:10.1039/b104338m

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Carotenoids and related polyenes. Part 6.1 Stereoselective synthesis
of astaxanthin analogues and their antioxidant activities
Yumiko Yamano,a Yuki Sato,a Yasuko Watanabe,a Koshi Namikawa,b Wataru Mikib and
Masayoshi Ito*a
1
a Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558,
Japan
b Suntory Institute for Fundamental Research,Wakayamadai, Shimamoto, Mishima, Osaka,
618-8503, Japan
Received (in Cambridge, UK) 16th May 2001, Accepted 21st June 2001
First published as an Advance Article on the web 31st July 2001
Astaxanthin analogues having various lengths of polyene chains are stereoselectively synthesized and their singlet-
oxygen-quenching activities are examined.
examined their quenching activities against singlet oxygen.
Introduction
These analogues were stereoselectively synthesized using the
C15-building block 3 or 4b, both of which were prepared in a
stereoselective manner via the palladium-catalyzed reaction of
the vinylstannane 9 or the terminal alkyne 6 with the readily
available4 vinyl bromide 10 (Schemes 1 and 2).
Carotenoid pigments are widely distributed in Nature, where
they play an important role in protecting cells and organisms
against photosensitized oxidation.2
Astaxanthin 1 (Fig. 1), one of the dominant carotenoids in
marine animals, has become the center of attention due to its
extremely strong antioxidant activities.3 These strong activities
are considered3 to be profoundly related to the 3-hydroxy-4-
oxo-β-end-groups† conjugated to the polyene system in astaxan-
thin. Antioxidant activity should be also concerned with the
length of the conjugated double-bond system in carotenoids.
Thus, in order to clarify their structure–activity relationships,
especially the relationship between the activity and the length
of the conjugated double-bond system, we have synthesized
astaxanthin analogues 2a–d having various polyene chains and
Results and discussion
Synthesis of 3 and 4 via Stille coupling reaction
Treatment of the known ketone 55 with lithium trimethyl-
silyl(TMS)acetylide followed by deprotection afforded the ter-
minal alkyne 6 as a single product6 in 98% yield (Scheme 1).
Heating the alkyne 6 at 120 ЊC for 2 h with 1.5 equiv. of
tri-n-butyltin hydride in the presence of a catalytic amount
of azoisobutyronitrile (AIBN)7 provided a mixture of the
E-vinylstannane 7a (40%) and its Z-isomer 7b (38%), which
were cleanly separated by column chromatography. The
Z-isomer 7b was converted to a mixture of 7a (67%) and 7b
(22%) by treatment with tri-n-butyltin hydride under the same
conditions. On the other hand, the palladium-catalyzed hydro-
stannylation7 of the alkyne
6 predominantly provided
E-vinylstannane 7a in 68% yield which, on treatment with acid
(92%) followed by acetylation (97%), was converted to com-
pound 9 via 8. The regio- and stereochemical structures of these
1
vinylstannanes 7a, 7b, 8 and 9 were deduced from H NMR
data (see Experimental section), especially from coupling
patterns JHH, J(117SnH), J(119SnH) of the vinylic protons.7,8
Among vinylstannanes 7a, 8 and 9, only the acetate 9 reacted
with the vinyl bromide 104 under the standard conditions
reported by Stille9 (Table 1, run 2) to yield the desired coupled
product 11, stereoselectively. However, in this reaction,
homodimer 12 was a major product, even though the reaction
flask and solvent were carefully deoxygenated. Thus, the reac-
tion conditions (catalyst, ligand, and solvent) were next exam-
ined (Table 1). Pd(PPh3)4 was not effective for this coupling
reaction (run 1). Moderate yields of 11 were achieved by use of
tris(dibenzylideneacetone)dipalladium (Pd2dba3) in N-methyl-
pyrrolidin-2-one (NMP) (run 5) or by combined use of Pd2dba3
and AsPh3 (ligand)10 in either DMF or NMP (run 6, 7).
Oxidation of 11 with active MnO2 (72%) and subsequent
methanolysis (81%) afforded the C15-aldehyde 3 without stereo-
mutation. Direct methanolysis of 11 provided C15-alcohol 14
(57%), which was allowed to react with hydrogen bromide11
Fig. 1
† We have employed the numbering system used in the carotenoids.
1862
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104338m

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Table 1 Coupling reaction of the vinylstannane 9 with the vinyl
bromide 10a
Table 2 Coupling reaction of terminal alkyne 15 with the vinyl
bromide 10a
Yield/%b
Yield/%b
Run
Catalyst(mol%)
Conditions
11
12
Run
Modification
17
18
1
2
3
4
5
6
7
Pd(PPh3)4 (3)
DMF, rt, 24 h
DMF, rt, 24 h
NMP, 50 ЊC, 24 h
DMF, 50 ЊC, 24 h
NMP, 50 ЊC, 24 h
DMF, 50 ЊC, 24 h
NMP, 50 ЊC, 24 h
1
2
3
4
5
none
BHT (20 mol%)
degassing
degassing ϩ BHT (5 mol%)
degassing ϩ BHT (10 mol%)
46
46
67
76
70
43
43
33
24
30
PdCl2(MeCN)2 (10)
PdCl2(MeCN)2 (6)
Pd2dba3 (3)
Pd2dba3 (3)
Pd2dba3 (3), AsPh3 (24)
Pd2dba3 (3), AsPh3 (24)
20
20
19
46
55
54
25
29
17
22
a The reaction was carried out at rt in benzene using 4.5 mol% of
Pd(PPh3)4 and 24 mol% of CuI as catalysts in the presence of Et2NH
(2.3 equiv.). 1.5 equiv. of vinyl bromide 10 were used. b Isolated yield.
a 2 equiv. of vinyl bromide 10 were used. b Isolated yield.
Scheme 2 Reagents and conditions: i, aq. H2SO4; ii, Ac2O, Py; iii, cat.
Pd(PPh3)4, Et2NH, CuI, BHT, degassing; iv, LiAIH4, cat. NaOMe; v,
MnO2.
Synthesis of 3 and 4 via Sonogashira coupling reaction
We first investigated the Sonogashira coupling12 of the terminal
alkyne 15 (Scheme 2), prepared (84%) by acid hydrolysis of 6,
with the vinyl bromide 10 (Table 2). Coupling reaction between
15 and 10 by use of Pd(PPh3)4 (4.5 mol%) and CuI (24 mol%) in
the presence of Et2NH (2.3 equiv.) in benzene gave the cross-
coupling product 17,11 accompanied by a serious amount of
the alkyne dimer 18 (run 1). Negishi13 described how either
degassing via freeze–thaw cycles or addition of an antioxidant
such as 2,6-tert-butyl-4-methylphenol (BHT) was effective in
the formation of cross-coupling products. In our case, addition
of BHT was not so effective (run 2), but degassing apparently
improved the yield of 17 (run 3). The best conditions were
obtained by degassing in the presence of BHT (5 mol%) (run 4).
On the other hand, coupling reaction of the acetate 16 with 10
Scheme 1 Reagents and conditions: i, n-BuLi, TMS-acetylene; then
10% KOH: ii, Bu3SnH, cat. AIBN, 120 ЊC; iii, Bu3SnH, cat. PdCl2-
(PPh3)2; iv, aq. H2SO4; v, Ac2O, Py; vi, cat. NaOMe, MeOH; vii, MnO2;
viii, 48% HBr; then PPh3; ix, 48% HBr; then PBu3.
followed by treatment of the intermediate bromide with tri-
phenylphosphine11 or tri-n-butylphosphine to give the C15-
Wittig salt 4a11 or 4b, respectively.
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869
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under the optimized conditions yielded the cross-coupling
product 19 in high yield (95%) as the sole product. Thus, the
hydroxy group at the C-3 position of the alkyne 15 might cause
the side reaction.
Then, the alkyne 6 reacted with 10 under the optimized con-
ditions to give the cross-coupling product 20 in 86% yield. This
α-acetylenic alcohol 20 was then stereoselectively converted to
the C15-aldehyde 3 (83% from 20 via 21) and the alcohol 14
(65% from 20) via hydroalumination using LiAlH4 in the pres-
ence of 10 mol% of sodium methoxide.14 The alcohol 14 could
be converted to the C15-Wittig salts 4a,b as shown in Scheme 1.
Synthesis of astaxanthin analogues 2a–d
The C15-triphenylphosphonium salt 4a (Fig. 1) was previously
prepared11 in the synthesis of astaxanthin 1. Wittig conden-
sation of the phosphonium salt 4a with 2,7-dimethylocta-
2,4,6-triene-1,8-dial was conducted11 to give a mixture of
E/Z-isomers of astaxanthin, from which the all-E-isomer
has been isolated by isomerization and crystallization. It was
reported15 that Wittig reaction of aldehydes with tri-n-
butylphosphonium salts provided dominantly E-olefins. Thus,
Wittig reaction of the aldehyde 22 with the phosphonium salts
4a and 4b was carried out as a preliminary experiment.
Fig. 2 Singlet oxygen quenching activites of astaxanthin 1 and its
analogues 2a–d.
The triphenylphosphonium salt 4a was condensed with the
aldehyde 22 in the presence of sodium methoxide as a base to
provide a non-separable mixture of isomers 23a and 23b in 85%
yield (Scheme 3). This mixture was acetylated to afford the
Scheme 3
Scheme 4
acetates 24, which could be cleanly separated by preparative
HPLC (pHPLC) to give the all-E-isomer 24a (22% from 22) and
the 11Z-one 24b (22% from 22). In contrast, Wittig conden-
sation of the tri-n-butylphosphonium salt 4b with the aldehyde
22 stereoselectively afforded the all-E-pentaenone 23a in 73%
yield. Therefore, the tri-n-butylphosphonium salt 4b and bis-
(tri-n-butylphosphonium) salts 2515a and 26 were used for the
preparation of astaxanthin analogues 2a–d (Fig. 1) as shown in
Scheme 4.
The analogue 2a was synthesized (70%) by Wittig reaction
between the C15-aldehyde 3 and the C15-phosphonium salt 4b.
Analogues 2b (41%) and 2c (37%) were prepared by conden-
sation of the aldehyde 3 with bis-Wittig salts 2515a -and 26. The
analogue 2d was prepared (42%) by Wittig reaction between the
phosphonium salt 4b and the dialdehyde 27, which was
obtained from the acetal-aldehyde 2816 as shown in Scheme 4.
These analogues 2a–d were all produced in a stereoselective
manner.
lengths were examined according to the method using a
thermodissociable endoperoxide17 of 1,4-dimethylnaphthalene
as a singlet-oxygen-generator3d and 2,2,6,6-tetramethylpiper-
idine (TEMP), a spin-trap agent, as a detector18 of singlet
oxygen.
Results are shown in Fig. 2. Analogues 2b–d showed strong
quenching activities in agreement with astaxanthin 1; however,
analogue 2a, having the shortest polyene chain, revealed low
activity. It is found that the ability of astaxanthin analogues to
quench singlet oxygen is strongly affected by the length of
conjugated polyene chain.
Studies on the antioxidation mechanism of 3-hydroxy-4-oxo-
β-end-groups conjugated to the polyene chain in astaxanthin
are now in progress.
Experimental
Mps were measured on a micro melting-point apparatus
(Yanagimoto) and are uncorrected. UV–visible spectra were
recorded on a JASCO Ubest-55 instrument for ethanol solu-
tions. IR spectra were measured on a Perkin-Elmer FT-IR spec-
Singlet-oxygen-quenching activities of astaxanthin analogues
2a–d
1
Finally, singlet-oxygen-quenching activities of astaxanthin
analogues 2a–d (Fig. 1) having polyene chains of various
trometer, model Paragon 1000, for chloroform solutions. H
NMR spectra at 300 or 500 MHz and 13C NMR spectra at 75 or
1864
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869

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125 MHz were determined on a Varian Gemini-300 or a Varian
VXR-500 superconducting FT-NMR spectrometer, respect-
ively, for deuteriochloroform solutions (tetramethylsilane as
internal reference). J-Values are given in Hz. Mass spectra were
taken on a Hitachi M-4100 spectrometer. Optical rotations
were measured on a JASCO DIP-181 polarimeter ([α]D-values
are in units of 10Ϫ1 deg cm2 gϪ1). EPR spectra were recorded on
a JEOL JES-FR30 spectrometer using the signal given by
paramagnetic resonance of Mn2ϩ as an internal standard.
Column chromatography (CC) was performed on silica gel
(Merck Art. 7734). Short-column chromatography (SCC) was
conducted on silica gel (Merck Art. 7739) under reduced pres-
sure. Preparative HPLC was carried out on a Waters Model 510
instrument with a UV–visible detector.
J 12 and 6, 2-Heq), 4.50 (1H, m, 3-H), 5.93 (1H, d, J 13, J1H–
117Sn 68, J1H–119Sn 72, 8-H), 6.27 (1H, dd-like, J 13 and 1.5,
J1H–117Sn 139, J1H–119Sn 146, 7-H).
Palladium-catalyzed hydrostannylation of terminal alkyne 6
To a solution of alkyne 6 (506 mg, 2.14 mmol) in THF (6 cm3)
was added PdCl2(PPh3)2 (30 mg, 0.04 mmol) followed by tri-n-
butyltin hydride (750 mg, 2.58 mmol) over a period of ca. 1–2
min. After being stirred at room temperature for 10 min, the
reaction mixture was concentrated in vacuo. The residue was
purified by SCC (ether–hexane, 1 : 9) to give the E-vinyl-
stannane 7a (780 mg, 68%).
Isomerization of Z-vinylstannane 7b
All operations were carried out under nitrogen or argon.
Ether refers to diethyl ether except where specified otherwise,
and hexane to n-hexane. NMR assignments are given using the
carotenoid numbering system. Extracts were dried over
anhydrous Na2SO4.
A mixture of Z-vinylstannane 7b (5.00 g, 9.49 mmol) and tri-n-
butyltin hydride (8.28 g, 28.5 mmol) was heated at 120 ЊC for
1 h in the presence of a catalytic amount of AIBN (ca. 50 mg).
The resulting crude product was purified by SCC (ether–
hexane, 1 : 3) to give the E-vinylstannane 7a (3.35 g, 67%) and
the Z-isomer 7b (1.10 g, 22% recovery).
(7aS)-5-Ethynyl-5,6,7,7a-tetrahydro-2,2,4,6,6-pentamethyl-
benzo-1,3-dioxol-5-ol 6
A solution of BuLi (1.50 M in hexane; 21.4 cm3, 32 mmol) was
added to a solution of TMS-acetylene (3.15 g, 32 mmol) in dry
THF (30 cm3) at 0 ЊC and the mixture was stirred for a further
30 min. To this mixture was added dropwise a solution of the
ketone 55 (4.50 g, 21 mmol) in dry THF (30 cm3) at 0 ЊC and the
mixture was stirred at room temperature for 2 h. After being
quenched with saturated aq. NH4Cl, the mixture was extracted
with ether. The extracts were washed with brine, dried and
evaporated to give a residue which, without purification, was
dissolved in methanol (30 cm3). Aq. 10% KOH was added to
this solution at 0 ЊC and the mixture was stirred at room tem-
perature for 30 min. The reaction mixture was diluted with
ether and washed with brine. Evaporation of the dried solution
gave a residue, which was purified by SCC (ether–hexane, 1 : 4)
to afford the terminal alkyne 6 (4.97 g, 98% from 5) as a colour-
less oil; [α]D23 ϩ 178.4 (c 0.97, EtOH); λmax/nm 212; νmax/cmϪ1
(6S)-6-Hydroxy-2,4,4-trimethyl-3-[(E )-2-(tri-n-butylstannyl)-
ethenyl]cyclohex-2-enone 8
Aq. H2SO4 (1.5 M; 50 cm3) was added to a solution of the
E-vinylstannane 7a (5.04 g, 9.6 mmol) in THF (250 cm3) at
0 ЊC. The mixture was stirred at room temperature for 30 min
and neutralized with saturated aq. NaHCO3. The organics were
extracted with ether and washed with brine. Evaporation of the
dried solution gave a residue, which was purified by CC (ether–
hexane, 1 : 4) to provide the hydroxy ketone 8 (4.10 g, 92%) as a
colourless oil; [α]D25 Ϫ102.5 (c 1.06, MeOH); λmax/nm 259;
νmax/cmϪ1 3494 (OH), 1664 (conj. C᎐O), 1590 (C᎐C); δ (300
᎐
᎐
H
MHz) 0.87–0.99 (15H, m, CH2 × 3 and CH2CH3 × 3), 1.15 and
1.29 (each 3H, s, 1-gem-CH3), 1.25–1.39 (6H, m, CH2 × 3),
1.48–1.58 (6H, m, CH2 × 3), 1.80 (1H, t-like, J 14, 2-Hax), 1.85
(3H, d, J 1, 5-CH3), 2.15 (1H, dd, J 12 and 5.5, 2-Heq), 3.68
(1H, s, OH), 4.32 (1H, dd, J 14 and 5.5, 3-H), 6.22 (1H, d, J 20,
J1H–117Sn 69, J1H–119Sn 72, 8-H), 6.46 (1H, dd-like, J 20 and
0.5, J1H–117Sn 62, J 1H–119Sn 65, 7-H).
᎐
᎐
3603 and 3482 (OH), 3305 (᎐C-H), 2110 (C᎐C), 1725 (C᎐C-O);
᎐
᎐
᎐
δH(300 MHz) 1.08 and 1.22 (each 3H, s, 1-gem-CH3), 1.47 and
1.48 [each 3H, s, OC(CH3)2O], 1.77 (3H, s, 5-CH3), 1.81 (1H,
dd, J 12 and 10, 2-Hax), 1.91 (1H, dd, J 12 and 6, 2-Heq), 2.50
(6S)-6-Acetoxy-2,4,4-trimethyl-3-[(E )-2-(tri-n-butylstannyl)-
ethenyl]cyclohex-2-enone 9
ϩ
᎐
(1H, s, C᎐CH), 4.50 (1H, m, 3-H) (Found: M , 236.1422.
᎐
C14H20O3 requires M, 236.1411).
Ac2O (4.5 cm3) was added to a solution of the hydroxy ketone 8
(3.02 g, 6.5 mmol) in pyridine (Py) (16 cm3) and the reaction
mixture was stirred at room temperature for 2 h, poured into
ice–water, and extracted with ether. The extracts were washed
successively with aq. 5% HCl, saturated aq. NaHCO3, and
brine. Evaporation of the dried extracts gave a residue, which
was purified by CC (ether–hexane, 1 : 3) to afford the acetate 9
(3.21 g, 97%) as a colourless oil; [α]2D5 Ϫ87.8 (c 1.11, MeOH);
Radical hydrostannylation of terminal alkyne 6
A mixture of alkyne 6 (3.58 g, 15.2 mmol) and tri-n-butyltin
hydride (6.62 g, 22.7 mmol) was heated at 120 ЊC for 2 h in the
presence of a catalytic amount of AIBN (ca. 30 mg). The result-
ing crude product was purified by SCC (ether–hexane, 1 : 3) to
give the E-vinylstannane 7a (3.17 g, 40%) as a colourless oil and
the Z-isomer 7b (3.06 g, 38%) as a colourless solid.
λmax/nm 265; νmax/cmϪ1 1742 (OAc), 1680 (conj. C᎐O), 1596
᎐
(C᎐C); δH(300 MHz) 0.87–1.00 (15H, m, CH2 × 3 and
᎐
Compound 7a. [α]D25 Ϫ167.4 (c 0.93, MeOH); νmax/cmϪ1 3606
CH2CH3 × 3), 1.17 and 1.32 (each 3H, s, 1-gem-CH3), 1.27–1.39
(6H, m, CH2 × 3), 1.48–1.60 (6H, m, CH2 × 3), 1.81 (3H, d, J 1,
5-CH3), 2.00 (1H, dd, J 13 and 6.5, 2-Heq), 2.10 (1H, t, J 13,
2-Hax), 2.18 (3H, s, OAc), 5.51 (1H, dd, J 13 and 6.5, 3-H), 6.20
(1H, d, J 20, J1H–117Sn 69, J1H–119Sn 72, 8-H), 6.46 (1H,
dd-like, J 20 and 1, J1H–117Sn = J1H–119Sn ≈ 63, 7-H).
and 3499 (OH), 1722 (C᎐C-O), 1590 (C᎐C); δ (300 MHz) 0.84–
᎐
᎐
H
0.92 (18H, m, 1-CH3, CH2 × 3 and CH2CH3 × 3), 1.10 (3H,
s, 1-CH3), 1.23–1.33 (6H, m, CH2 × 3), 1.42–1.56 (6H, m,
CH2 × 3), 1.47 (3H, d, J 1.5, 5-CH3), 1.48 and 1.50 [each 3H, s,
OC(CH3)2O], 1.66 (1H, dd, J 12 and 10.5, 2-Hax), 1.80 (1H, dd,
J 12 and 6, 2-Heq), 4.51 (1H, m, 3-H), 5.84 (1H, d, J 19, J1H–
117Sn 63, J1H–119Sn 66, 7-H or 8-H), 5.99 (1H, d, J 19, J1H–117Sn
69, J1H–119Sn 72, 8-H or 7-H).
Coupling reaction of the vinylstannane 9 with the vinyl bromide
10 (Table 1); representative procedure (Run 6)
Compound 7b. [α]D25 ϩ216.5 (c 1.00, MeOH); νmax/cmϪ1 3616
To a degassed solution of the vinylstannane 9 (217 mg, 0.42
mmol) and the vinyl bromide 10 (128 mg, 0.85 mmol) in DMF
(6 cm3) were added Pd2dba3 (11 mg, 0.012 mmol) and AsPh3
(31 mg, 0.10 mmol) and the mixture was stirred at 50 ЊC for
24 h. After being quenched by addition of aq. 10% NH4OH, the
mixture was extracted with ether. The extracts were washed
and 3500 (OH), 1719 (C᎐C-O), 1594 (C᎐C); δ (300 MHz) 0.84–
᎐
᎐
H
0.91 (18H, m, 1-CH3, CH2 × 3 and CH2CH3 × 3), 1.05 (3H, s,
1-CH3), 1.25–1.37 (6H, m, CH2 × 3), 1.42–1.55 (6H, m,
CH2 × 3), 1.47 and 1.48 [each 3H, s, OC(CH3)2O], 1.49 (3H, d,
J 1.5, 5-CH3), 1.73 (1H, dd, J 12 and 10.5, 2-Hax), 1.88 (1H, dd,
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869
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with brine, dried and evaporated to give a residue, which was
purified by SCC (acetone–ether–hexane, 3 : 10 : 20) to give the
alcohol 11 (68 mg, 55%) and the dimer 12 (16 mg, 17%).
3.70 (1H, br s, OH), 4.32 (1H, m, 3-H), 4.35 (2H, d, J 6.5, 11-
H2), 5.78 (1H, br t, J 6.5, 10-H), 6.17 (1H, br d, J 16.5, 7-H),
6.27 (1H, d, J 16.5, 8-H) (Found: Mϩ, 250.1592. C15H22O3
requires M, 250.1578).
Compound 11. [α]D27 Ϫ156.6 (c 0.97, MeOH); λmax/nm 231,
301; νmax/cmϪ1 3610 and 3468 (OH), 1740 (OAc), 1679 (conj.
Tri-n-butyl{(2E,4E )-5-[(4S)-4-hydroxy-2,6,6-trimethyl-3-
oxocyclohex-1-enyl]-3-methylpenta-2,4-dienyl}phosphonium
bromide 4b
C᎐O), 1612 and 1587 (C᎐C); δ (300 MHz) 1.18 and 1.32 (each
᎐
᎐
H
3H, s, 1-gem-CH3), 1.84 and 1.86 (each 3H, s, 5-CH3 and
9-CH3), 1.99 (1H, dd, J 12.5 and 6.5, 2-Heq), 2.06 (1H, t, J 12.5,
2-Hax), 2.17 (3H, s, OAc), 4.33 (2H, d, J 6.5, 11-H2), 5.51 (1H,
dd, J 12.5 and 6.5, 3-H), 5.76 (1H, br t, J 6.5, 10-H), 6.15 (1H,
br d, J 16, 7-H), 6.26 (1H, d, J 16, 8-H) (Found: Mϩ, 292.1653.
C17H24O4 requires M, 292.1673).
According to the literature procedure,11 aq. 48% HBr (10.6 cm3,
5.1 mmol) was added dropwise to an ice-cooled solution of
the alcohol 14 (1.00 g, 4.0 mmol) in CH2Cl2 (10 cm3) and the
mixture was stirred for further 5 min. After addition of a
small amount of 1,2-epoxybutane, the mixture was poured into
saturated aq. NaHCO3 and extracted with ether. The extracts
were washed with brine, dried, and evaporated to give the brom-
ide which, without purification, was dissolved in ether (15 cm3)
and PBu3 (1.2 cm3, 0.48 mmol) was added to it. After being
stirred at room temperature for 1 h, the resulting precipitate was
filtered off, and washed with ether to provide the phosphonium
salt 4b (1.59 g, 77% from 14); δH(300 MHz) 0.92 (9H, t, J 7,
CH3 × 3) 1.12 and 1.26 (each 3H, s, 1-gem-CH3), 1.49 [12H, m,
(CH2CH2) × 3], 1.76 (1H, t, J 13, 2-Hax), 1.83 (3H, s, 5-CH3),
1.99 (3H, br d, J 3.5, 9-CH3), 2.12 (1H, dd, J 13 and 6, 2-Heq),
2.43 (6H, m, PCH2 × 3), 3.74 (2H, dd, J 16.5 and 7.5, 11-H2),
4.28 (1H, dd, J 13 and 6, 3-H), 5.47 (1H, br q, J 7.5, 10-H), 6.18
(1H, br d, J 16.5, 7-H), 6.25 (1H, d, J 16.5, 8-H).
Compound 12. λmax/nm 225, 328; νmax/cmϪ1 1739 (OAc), 1681
(conj. C᎐O), 1588 (C᎐C); δ (300 MHz) 1.22 and 1.35 (each 6H,
᎐
᎐
H
s, 1-gem-CH3 and 1Ј-gem-CH3), 1.90 (6H, s, 5-CH3 and 5Ј-CH3),
2.01 (2H, dd, J 13 and 6.5, 2Ј-Hax and 2-Hax), 2.07 (2H, t, J 13,
2Ј-Heq and 2-Heq), 2.18 (6H, s, OAc × 2), 5.51 (2H, dd, J 13 and
6.5, 3-H and 3Ј-H), 6.28–6.43 (4H, m, 7-H, 7Ј-H, 8-H and 8Ј-H)
(Found: Mϩ, 442.2354. C26H34O6 requires M, 442.2353).
(2E,4E )-5-[(4S)-4-Acetoxy-2,6,6-trimethyl-3-oxocyclohex-1-
enyl]-3-methylpenta-2,4-dienal 13
The alcohol 11 (532 mg, 1.82 mmol) was dissolved in ether–
hexane (1 : 2) and shaken with active MnO2 (2.7 g) at room
temperature for 1 h. The mixture was filtered through Celite.
Evaporation of the filtrate gave a residue, which was purified by
SCC (acetone–hexane, 1 : 3) to afford the aldehyde 13 (383 mg,
72%) as a pale yellow oil; [α]2D3 Ϫ134.2 (c 1.03, EtOH); λmax/nm
(6S)-3-Ethynyl-6-hydroxy-2,4,4-trimethylcyclohex-2-enone 15
In the same manner as described for the preparation of the
ketone 8, acid hydrolysis of compound 6 (988 mg) followed by
purification by SCC (acetone–hexane, 1 : 6) provided the
ketone 15 (624 mg, 84%) as a colourless oil; [α]2D3 Ϫ195.1 (c 1.02,
250, 300; νmax/cmϪ1 1740 (OAc), 1665 (conj. C᎐O and conj.
᎐
CHO), 1616 and 1596 (C᎐C); δ (300 MHz) 1.21 and 1.37 (each
᎐
H
EtOH); λmax/nm 266; νmax/cmϪ1 3505 (OH), 3301 (᎐C-H), 2092
3H, s, 1-gem-CH3), 1.85 (3H, s, 5-CH3), 2.04 (1H, dd, J 13 and
6.5, 2-Heq), 2.11 (1H, t, J 13, 2-Hax), 2.19 (3H, s, OAc), 2.35 (3H,
s, 9-CH3), 5.53 (1H, dd, J 13 and 6.5, 3-H), 6.02 (1H, br d, J 8,
10-H), 6.35 (1H, d, J 16, 8-H), 6.70 (1H, br d, J 16, 7-H), 10.16
(1H, d, J 8, CHO) (Found: Mϩ, 290.1543. C17H22O4 requires M,
290.1516).
᎐
᎐
᎐
(C᎐C), 1672 (conj. C᎐O), 1586 (C᎐C); δ (300 MHz) 1.29 and
᎐
᎐
᎐
H
1.34 (each 3H, s, 1-gem-CH3), 1.78 (1H, t, J 13, 2-Hax), 2.01
(3H, s, 5-CH3), 2.21 (1H, dd, J 13 and 5.5, 2-Heq), 3.55 (1H, d,
᎐
J 2, OH), 3.79 (1H, s, C᎐CH), 4.33 (1H, ddd, J 13, 5.5 and 2,
᎐
3-H) (Found: Mϩ, 178.1002. C11H14O2 requires M, 178.0993).
(2E,4E )-5-[(4S)-4-Hydroxy-2,6,6-trimethyl-3-oxocyclohex-1-
enyl]-3-methylpenta-2,4-dienal 3
(6S)-6-Acetoxy-3-ethynyl-2,4,4-trimethylcyclohex-2-enone 16
According to the procedure described in the preparation of the
acetate 9, acetylation of the alcohol 15 (2.40 g) followed by
purification by CC (acetone–hexane, 1 : 5) afforded the acetate
16 (2.74 g, 93%) as a colourless oil; [α]2D3 Ϫ166.0 (c 1.03, EtOH);
NaOMe (1.0 M in MeOH; 0.5 cm3, 0.5 mmol) was added to a
solution of the acetate 13 (204 mg, 0.70 mmol) in MeOH (10
cm3) and the mixture was stirred at room temperature for 15
min. To this reaction mixture was added Dowex 50W-X8 (Hϩ)
(500 mg) and the mixture was stirred at room temperature for
10 min. After the Dowex had been filtered off, the filtrate was
evaporated. The residue was purified by SCC (acetone–hexane,
3 : 7) to give the alcohol 3 (141 mg, 81%) as a pale yellow oil;
[α]2D6 Ϫ94.1 (c 1.01, EtOH); λmax/nm 251, 301; νmax/cmϪ1 3495
λmax/nm 267; νmax/cmϪ1 3544 (OH), 3301 (᎐C-H), 2092 (C᎐C),
᎐
᎐
᎐
᎐
1743 (OAc), 1690 (conj. C᎐O), 1587 (C᎐C); δ (300 MHz) 1.30
᎐
᎐
H
and 1.36 (each 3H, s, 1-gem-CH3), 1.97 (3H, s, 5-CH3), 2.03
᎐
(2H, m, 2-H ), 2.16 (3H, s, OAc), 3.79 (1H, s, C᎐CH), 5.49 (1H,
᎐
2
dd, J 12.5 and 7, 3-H) (Found: Mϩ, 220.1085. C13H16O3 requires
M, 220.1099).
(OH), 1666 (conj. C᎐O and conj. CHO), 1616 and 1596 (C᎐C);
᎐
᎐
δH(300 MHz) 1.15 and 1.30 (each 3H, s, 1-gem-CH3), 1.81 (1H,
t, J 13, 2-Hax), 1.85 (3H, s, 5-CH3), 2.15 (1H, dd, J 13 and 6,
2-Heq), 2.31 (3H, s, 9-CH3), 3.61 (1H, br s, OH), 4.32 (1H, ddd,
J 13, 6 and 2, 3-H), 5.98 (1H, br d, J 8, 10-H), 6.32 (1H, d,
J 16.5, 8-H), 6.67 (1H, br d, J 16.5, 7-H), 10.13 (1H, d, J 8,
CHO) (Found: Mϩ, 248.1433. C15H20O3 requires M, 248.1412).
Coupling reaction of terminal alkyne 15 with the vinyl bromide 10
(Table 2); representative procedure (Run 4)
To a stirred, degassed mixture of the vinyl bromide 10 (986 mg,
6.75 mmol), Pd(PPh3)4 (226 mg, 0.20 mmol), Et2NH (1.05 cm3,
10.1 mmol), CuI (200 mg, 1.05 mmol) and BHT (48 mg, 0.22
mmol) in dry benzene (20 cm3) was added dropwise a degassed
solution of alkyne 15 (775 mg, 4.35 mmol) in dry benzene (10
cm3) over a period of 2 h by use of a syringe pump. After being
stirred at room temperature for a further 30 min, the mixture
was diluted with ether and the organic layer was washed succes-
sively with aq. 3% HCl, saturated aq. NaHCO3, and brine.
Evaporation of the dried solvent gave a residue, which was
purified by SCC (acetone–hexane, 1 : 3) to give the alcohol 17
(828 mg, 76%) and the dimer 18 (184 mg, 24%).
(6S)-6-Hydroxy-3-[(1E,3E )-5-hydroxy-3-methylpenta-1,3-
dienyl]-2,4,4-trimethylcyclohex-2-enone 14
According to the procedure described in the preparation of the
alcohol 3, methanolysis of the acetate 11 (334 mg) followed by
purification using SCC (ether–hexane, 4 : 1) gave the diol 14
(164 mg, 57%) as a pale yellow oil; [α]2D5 Ϫ157.6 (c 1.03, EtOH);
λmax/nm 229, 298; νmax/cmϪ1 3611 and 3489 (OH), 1664 (conj.
C᎐O), 1610 and 1595 (C᎐C); δ (300 MHz) 1.17 and 1.30 (each
᎐
᎐
H
3H, s, 1-gem-CH3), 1.81 (1H, t, J 13, 2-Hax), 1.87 and 1.89 (each
3H, s, 5-CH3 and 9-CH3), 2.15 (1H, dd, J 13 and 5.5, 2-Heq),
Compound 17. Mp 86–88 ЊC (from hexane–diisopropyl ether)
(lit.11, 90–92 ЊC); [α]D23 Ϫ199.23 (c 0.99, EtOH) {lit.,11 [α]D20
1866
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869

View Article Online
Ϫ202.6 (c 1.0, EtOH)}; λmax/nm 306; νmax/cmϪ1 3610 and 3494
Preparation of C15-alcohol 14 from ꢀ-acetylenic alcohol 20
᎐
(OH), 2183 (C᎐C), 1665 (conj. C᎐O), 1576 (C᎐C); δ (300 MHz)
᎐
᎐
᎐
H
Reduction of the α-acetylenic alcohol 20 (1.00 g) was carried
out in the same manner as above to afford the crude alcohol 21,
which without purification, was treated with acid according to
the procedure described in the preparation of the ketone 8. The
resulting crude product was purified by SCC (acetone–hexane,
3 : 7) to afford the diol 14 (560 mg, 65% from 20). Spectral
properties of this diol 14 were in agreement with those obtained
by alcoholysis of the acetate 11.
1.29 and 1.34 (each 3H, s, 1-gem-CH3), 1.79 (1H, t, J 13, 2-Hax),
1.92 (3H, s, 9-CH3), 2.00 (3H, s, 5-CH3), 2.21 (1H, dd, J 13 and
5.5, 2-Heq), 3.59 (1H, d, J 1.5, OH), 4.33 (3H, m, 3-H and 11-
H2), 6.14 (1H, tq, J 7 and 1.5, 10-H) (Found: Mϩ, 248.1430.
C15H20O3 requires M, 248.1411).
Compound 18. Mp 180–183 ЊC (from hexane–ether); [α]D23
Ϫ326.7 (c 0.99, EtOH); λmax/nm 228, 265 (sh), 279, 290, 314,
334, 358; νmax/cmϪ1 3499 (OH), 2127 (C᎐C), 1664 (conj. C᎐O),
᎐
(6S)-3-[(1E,3E,5E )-3,8-Dimethylnona-1,3,5,7-tetraenyl]-6-
hydroxy-2,4,4-trimethylcyclohex-2-enone 23a
᎐
᎐
1629 and 1575 (C᎐C); δ (300 MHz) 1.29 and 1.34 (each 6H, s,
᎐
H
1-gem-CH3 and 1Ј-gem-CH3), 1.82 (2H, t, J 13, 2Ј-Hax and
2-Hax), 2.06 (6H, s, 5Ј-CH3 and 5-CH3), 2.23 (2H, dd, J 13 and
6, 2Ј-Heq and 2-Heq), 3.54 (2H, br s, OH × 2), 4.36 (2H, dd, J 13
and 6, 3-H and 3Ј-H) (Found: C, 74.27; H, 7.45; Mϩ, 354.1828.
C22H26O4 requires C, 74.55; H, 7.39%; M, 354.1829).
A solution of NaOMe (1.0 M in MeOH; 2.98 cm3, 2.98 mmol)
was added to an ice-cooled solution of the Wittig salt 4b (1.44
g, 2.98 mmol) and the aldehyde 22 (100 mg, 1.19 mmol) in
CH2Cl2 (20 cm3). After being stirred at room temperature for
40 min, the reaction mixture was diluted with ether. The
organic layer was washed with brine, dried, and evaporated to
give a residue, which was purified by SCC (ether–hexane, 1 : 2)
to afford the all-E pentaenone 23a (260 mg, 73%) as a yellow
(6S)-6-Acetoxy-3-[(3E )-5-hydroxy-3-methylpent-3-en-1-ynyl]-
2,4,4-trimethylcyclohex-2-enone 19
oil; λmax/nm 280, 362; νmax/cmϪ1 3490 (OH), 1659 (conj. C᎐O),
᎐
The coupling reaction of the alkyne 16 (778 mg, 3.53 mmol)
with the vinyl bromide 10 (871 mg, 5.77 mmol) was carried out
in the same manner as above. The resulting crude product was
purified by SCC (acetone–hexane, 1 : 3) to give the alcohol 19
(978 mg, 95%) as a pale yellow oil; [α]2D3 Ϫ183.3 (c 1.02, EtOH);
1610 and 1566 (C᎐C); δ (300 MHz) 1.20, 1.31 (each 3H, s,
᎐
H
1-gem-CH3), 1.80 (1H, m, 2-Hax), 1.81 and 1.84 (each 3H, s,
14-gem-CH3), 1.93 and 1.94 (each 3H, s, 5-CH3 and 9-CH3),
2.15 (1H, dd, J 12.5 and 5.5, 2-Heq), 3.71 (1H, d, J 2, OH), 4.32
(1H, ddd, J 13.5, 5.5 and 2, 3-H), 5.98 (1H, dm, J 10.5, 13-H),
6.16 (1H, br d, J 16, 7-H), 6.26 (1H, br d, J 11, 10-H), 6.40 (1H,
d, J 16, 8-H), 6.46 (1H, dd, J 14.5 and 11, 11-H), 6.56 (1H, dd,
J 14.5 and 10.5, 12-H) (Found: Mϩ, 300.2090. C20H28O2
requires M, 300.2088).
λmax/nm 310; νmax/cmϪ1 3609 and 3480 (OH), 2182 (C᎐C), 1740
᎐
᎐
(OAc), 1681 (conj. C᎐O), 1578 (C᎐C); δ (300 MHz) 1.30 and
᎐
᎐
H
1.37 (each 3H, s, 1-gem-CH3), 1.92 (3H, s, 9-CH3), 1.97 (3H, s,
5-CH3), 2.05 (2H, m, 2-H2), 2.18 (3H, s, OAc), 4.31 (2H, br t,
J 6, 11-H2), 5.51 (1H, dd, J 12 and 7.5, 3-H), 6.14 (1H, tq, J 6
and 1.5, 10-H) (Found: Mϩ, 290.1538. C17H22O4 requires M,
290.1516).
(6S)-6-Acetoxy-3-[(1E,3E,5E/Z )-3,8-dimethylnona-1,3,5,7-
tetraenyl]-2,4,4-trimethylcyclohex-2-enone 24a,b
In the same manner as described above, Wittig reaction of the
phosphonium salt 4a11 (2.05 g, 3.56 mmol) with the aldehyde 22
(100 mg, 1.19 mmol) followed by purification by SCC (ether–
hexane, 1 : 2) provided an isomeric mixture of compound 23
(304 mg, 85%), which without separation was acetylated in the
same manner as described for the preparation of the acetate 9.
The resulting crude products were purified by SCC (acetone–
hexane, 1 : 3) to provide the all-E-pentaenone 24a (90 mg, 22%)
and the 11Z-isomer 24b (90 mg, 22%) each as a yellow oil.
(7aS)-5-[(3E )-5-Hydroxy-3-methylpent-3-en-1-ynyl]-5,6,7,7a-
tetrahydro-2,2,4,6,6-pentamethylbenzo-1,3-dioxol-5-ol 20
According to the procedure described in the preparation of the
alcohol 17, the coupling reaction of the alkyne 6 (3.57 g, 15.1
mmol) with the vinyl bromide 10 (3.57 g, 23.6 mmol) followed
by purification using SCC (acetone–hexane, 1 : 3) provided the
alcohol 20 (5.21 g, 86%) as a pale yellow oil; [α]2D3 ϩ 229.2
(c 0.96, EtOH); νmax/cmϪ1 3610 and 3480 (OH), 2184 (C᎐C),
᎐
᎐
1724 (C᎐C-O), 1663 and 1633 (C᎐C); δ (300 MHz) 1.09 and
᎐
᎐
H
1.21 (each 3H, s, 1-gem-CH3), 1.48 and 1.50 [each 3H, s,
OC(CH3)2O], 1.77 (3H, s, 5-CH3), 1.81 (3H, s, 9-CH3), 1.92 (2H,
m, 2-H2), 4.22 (2H, br t, J 6, 11-H2), 4.52 (1H, m, 3-H), 5.96
(1H, tq, J 6 and 1.5, 10-H) (Found: Mϩ, 306.1823. C18H26O4
requires M, 306.1830).
Compound 24a. λmax/nm 282, 363; νmax/cmϪ1 1740 (OAc), 1675
(conj. C᎐O), 1568 (C᎐C); δ (300 MHz) 1.22 and 1.34 (each 3H,
᎐
᎐
H
s, 1-gem-CH3), 1.81 and 1.84 (each 3H, s, 14-gem-CH3), 1.89
(3H, s, 5-CH3), 1.94 (3H, s, 9-CH3), 2.00 (1H, dd, J 12.5 and 6.5,
2-Heq), 2.07 (1H, t, J 12.5, 2-Hax), 2.19 (3H, s, OAc), 5.52 (1H,
dd, J 12.5 and 6.5, 3-H), 5.98 (1H, dm, J 10.5, 13-H), 6.15 (1H,
br d, J 16, 7-H), 6.25 (1H, br d, J 11, 10-H), 6.37 (1H, d, J 16,
8-H), 6.45 (1H, dd, J 14.5 and 11, 11-H), 6.56 (1H, dd, J 14.5
and 10.5, 12-H) (Found: Mϩ, 342.2185. C22H30O3 requires M,
342.2194).
Preparation of C15-aldehyde 3 from ꢀ-acetylenic alcohol 20
A solution of α-acetylenic alcohol 20 (1.63 g, 5.33 mmol) in
THF (20 cm3) was added dropwise to a stirred suspension of
LiAlH4 (504 mg, 13.3 mmol) and NaOMe (57 mg, 1.06 mmol)
in THF (50 cm3) at 0 ЊC and the mixture was stirred at 0 ЊC for
10 min and at room temperature for 1 h. The excess of LiAlH4
was decomposed by dropwise additon of water. After evapor-
ation of THF, the residue was extracted with ether. The extracts
were washed with brine, dried, and evaporated to afford a
crude alcohol 21, which without purification was dissolved in
ether–hexane (1 : 3) and shaken with active MnO2 (9 g) at
room temperature for 3 h. The mixture was filtered through
Celite. Evaporation of the filtrate gave a residue, which without
purification was treated with acid according to the preparation
of the ketone 8. The resulting crude product was purified by
SCC (acetone–hexane, 1 : 2) to afford the aldehyde 3 (1.09 g,
83% from 20). Spectral properties of this aldehyde 3 were
in agreement with those obtained by alcoholysis of the acetate
13.
Compound 24b. λmax/nm 281, 361; νmax/cmϪ1 1740 (OAc), 1675
(conj. C᎐O), 1607 and 1571 (C᎐C); δ (300 MHz) 1.22 and 1.35
᎐
᎐
H
(each 3H, s, 1-gem-CH3), 1.81 and 1.88 (each 3H, s, 14-gem-
CH3), 1.90 (3H, s, 5-CH3), 1.95 (3H, s, 9-CH3), 2.01 (1H, dd,
J 12.5 and 6.5, 2-Heq), 2.07 (1H, t, J 12.5, 2-Hax), 2.19 (3H, s,
OAc), 5.53 (1H, dd, J 12.5 and 6.5, 3-H), 6.19 (1H, br d, J 16,
7-H), 6.19–6.37 (3H, m, 11-H, 12-H and 13-H), 6.43 (1H, d,
J 16, 8-H), 6.64 (1H, br d, J 11.5, 10-H) (Found: Mϩ, 342.2187.
C22H30O3 requires M, 342.2194).
(2E,4E,6E,8E,10E )-2,11-Dimethyldodeca-2,4,6,8,10-pentaenedial
27
A solution of NaOMe (1.0 M in MeOH; 2.5 cm3, 2.5 mmol)
was added to an ice-cooled solution of the diphosphonium salt
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869
1867

View Article Online
2515a (488 mg, 1.04 mmol) and the aldehyde 2816 (300 mg, 2.08
mmol) in CH2Cl2 (10 cm3). After being stirred at room temper-
ature for 1 h, the reaction mixture was diluted with ether. The
organic layer was sufficiently shaken with aq. 5% HCl and then
washed successively with saturated aq. NaHCO3 and brine.
Evaporation of the dried solution provided a residue, which
was purifed by CC (ether–hexane–CH2Cl2, 1 : 4 : 4) to afford
the dial 27 (121 mg, 54%) as a red solid; λmax/nm 365 (sh), 385,
404; νmax/cmϪ1 1663 (conj. CHO), 1610 (C᎐C); δ (300 MHz)
1.90 (6H, s, 2-CH3 and 11-CH3), 6.60 (2H, m) and 6.68–6.84
(4H, m) (4-H, 5-H, 6-H, 7-H, 8-H and 9-H), 6.91 (2H, br d,
J 10, 3-H and 10-H), 9.48 (2H, s, CHO × 2) (Found: Mϩ,
216.1161. C14H16O2 requires M, 216.1150).
pentaenone 23a, Wittig reaction of diphosphonium salt 2615a
(100 mg, 0.20 mmol) with the aldehyde 3 (100 mg, 0.40 mmol)
and purification of the crude product by CC (acetone–CH2Cl2,
5 : 95) provided the analogue 2c (40 mg, 37%) as an orange
solid; λmax/nm 452; νmax/cmϪ1 3490 (OH), 1660 (conj. C᎐O),
᎐
1611 and 1562 (C᎐C); δ (500 MHz) 1.18 and 1.30 (each 6H,
᎐
H
s, 1-gem-CH3 and 1Ј-gem-CH3), 1.79 (2H, t, J 13.5, 2-Hax and
2Ј-Hax), 1.92 (6H, s, 5-CH3 and 5Ј-CH3), 1.96 (6H, s, 9-CH3
and 9Ј-CH3), 2.13 (2H, dd, J 13 and 5.5, 2-Heq and 2Ј-Heq),
3.66 (2H, d, J 1.5, OH × 2), 4.30 (2H, ddd, J 13.5, 5.5 and
1.5, 3-H and 3Ј-H), 6.20 (2H, br d, J 16, 7-H and 7Ј-H), 6.23
(2H, br d, J 12.5, 10-H and 10Ј-H), 6.39 (8H, m, 8-H, 8Ј-H,
12-H, 12Ј-H, 13-H, 13Ј-H, 14-H and 14Ј-H), 6.61 (2H, m,
11-H and 11Ј-H); δC(75 MHz) 12.51 (9-CH3 and 9Ј-CH3),
13.98 (5-CH3 and 5Ј-CH3), 26.14 and 30.72 (1-gem-CH3 and
1Ј-gem-CH3), 36.79 (C-1 and C-1Ј), 45.40 (C-2 and C-2Ј), 69.22
(C-3 and C-3Ј), 123.77 (C-7 and C-7Ј), 126.92 (C-5 and C-5Ј),
129.57 (C-11 and C-11Ј), 134.12, 134.29 and 134.60 (C-12,
C-12Ј, C-13, C-13Ј, C-14 and C-14Ј), 135.26 (C-9 and C-9Ј),
135.38 (C-10 and C-10Ј), 142.12 (C-8 and C-8Ј), 162.14 (C-6
and C-6Ј), 200.44 (C-4 and C-4Ј) (Found: Mϩ, 542.3393.
C36H46O4 requires M, 542.3394).
᎐
H
3,3Ј-[(1E,3E,5E,7E,9E )-3,8-Dimethyldeca-1,3,5,7,9-pentaene-
1,10-diyl]bis[(6S)-6-hydroxy-2,4,4-trimethylcyclohex-2-enone]
2a
According to the procedure described in the preparation of the
pentaenone 23a, Wittig reaction of phosphonium salt 4b (488
mg, 1.01 mmol) with the aldehyde 3 (100 mg, 0.40 mmol) and
purification of the crude product by CC (EtOAc–benzene, 1 : 4)
gave the analogue 2a (131 mg, 70%) as a yellow oil; λmax/nm 404;
νmax/cmϪ1 3494 (OH), 1661 (conj. C᎐O), 1601 and 1573 (C᎐C);
᎐
᎐
3,3Ј-[(1E,3E,5E,7E,9E,11E,13E,15E,17E,19E,21E )-3,7,16,20-
Tetramethyldocosa-1,3,5,7,9,11,13,15,17,19,21-undecaene-1,22-
diyl]bis[(6S)-6-hydroxy-2,4,4-trimethylcyclohex-2-enone] 2d
δH(500 MHz) 1.21 and 1.32 (each 6H, s, 1-gem-CH3 and 1Ј-gem-
CH3), 1.82 (2H, t, J 13, 2-Hax and 2Ј-Hax), 1.94 (6H, s, 5-CH3
and 5Ј-CH3), 1.99 (6H, s, 9-CH3 and 9Ј-CH3), 2.16 (2H, dd, J 13
and 6, 2-Heq and 2Ј-Heq), 3.68 (2H, d, J 1.5, OH × 2), 4.33 (2H,
ddd, J 13, 6 and 1.5, 3-H and 3Ј-H), 6.24 (2H, br d, J 16, 7-H
and 7Ј-H), 6.32 (2H, br d, J 11, 10-H and 10Ј-H), 6.41 (2H, d, J
16, 8-H and 8Ј-H), 6.71 (2H, m, 11-H and 11Ј-H); δC(75 MHz)
12.55 (9-CH3 and 9Ј-CH3), 14.00 (5-CH3 and 5Ј-CH3), 26.14
and 30.72 (1-gem-CH3 and 1Ј-gem-CH3), 36.82 (C-1 and C-1Ј),
45.41 (C-2 and C-2Ј), 69.25 (C-3 and C-3Ј), 124.16 (C-7 and
C-7Ј), 127.03 (C-5 and C-5Ј), 130.98 (C-11 and C-11Ј), 134.53
(C-10 and C-10Ј), 135.83 (C-9 and C-9Ј), 141.98 (C-8 and C-8Ј),
162.09 (C-6 and C-6Ј), 200.48 (C-4 and C-4Ј) (Found: Mϩ,
464.2938. C30H40O4 requires M, 464.2924).
According to the procedure described in the preparation of
the pentaenone 23a, Wittig reaction of phosphonium salt 4b
(409 mg, 0.84 mmol) with the dial 27 (100 mg, 0.46 mmol)
and purification of the crude product by CC (acetone–
CH2Cl2, 5 : 95) provided the analogue 2d (125 mg, 42%) as
a red solid; λmax/nm 484; νmax/cmϪ1 3492 (OH), 1660 (conj.
C᎐O), 1610, 1576 and 1550 (C᎐C); δ (500 MHz) 1.21 and 1.32
᎐
᎐
H
(each 6H, s, 1-gem-CH3 and 1Ј-gem-CH3), 1.81 (2H, t, J 13,
2-Hax and 2Ј-Hax), 1.94 (6H, s, 5-H and 5Ј-H), 1.98 and 2.00
(each 6H, s, 9-CH3, 9Ј-CH3, 13-CH3 and 13Ј-CH3), 2.15 (2H,
dd, J 13 and 5, 2-Heq and 2Ј-Heq), 3.69 (2H, br s, OH × 2),
4.32 (2H, br dd, J 13.5 and 5.5, 3-H and 3Ј-H), 6.21 (2H, br
d, J 16.5, 7-H and 7Ј-H), 6.25 and 6.29 (each 2H, br d,
J 11.5, 10-H, 10Ј-H, 14-H and 14Ј-H), 6.38–6.48 (8H, m, 8-H,
8Ј-H, 12-H, 12Ј-H, 16-H, 16Ј-H, 17-H and 17Ј-H), 6.63
(4H, m, 11-H, 11Ј-H, 15-H and 15Ј-H); δC (125 MHz) 12.58
(9-CH3 and 9Ј-CH3), 12.80 (13-CH3 and 13Ј-CH3), 14.00 (5-
CH3 and 5Ј-CH3), 26.16 and 30.76 (1-gem-CH3 and 1Ј-gem-
CH3), 36.81 (C-1 and C-1Ј), 45.43 (C-2 and C-2Ј), 69.22 (C-3
and C-3Ј), 123.27 (C-7 and C-7Ј), 124.54 (C-11 and C-11Ј),
126.81 (C-5 and C-5Ј), 130.36 (C-15 and C-15Ј), 133.62, 134.16
and 134.59 (C-14, C-14Ј, C-16, C-16Ј, C-17 and C-17Ј), 134.52
(C-9 and C-9Ј), 135.22 (C-10 and C-10Ј), 136.60 (C-13 and C-
13Ј), 139.77 (C-12 and C-12Ј), 142.38 (C-8 and C-8Ј), 162.26
(C-6 and C-6Ј), 200.43 (C-4 and C-4Ј) (Found: Mϩ, 648.4186.
C44H56O4 requires M, 648.4176).
3,3Ј-[(1E,3E,5E,7E,9E,11E,13E )-3,12-Dimethyltetradeca-
1,3,5,7,9,11,13-heptaene-1,14-diyl]bis[(6S)-6-hydroxy-2,4,4-
trimethylcyclohex-2-enone] 2b
According to the procedure described in the preparation of the
pentaenone 23a, Wittig reaction of diphosphonium salt 2515a
(106 mg, 0.23 mmol) with the aldehyde 3 (112 mg, 0.45 mmol)
and purification of the crude product by CC (EtOAc–benzene,
1 : 4) provided the analogue 2b (48 mg, 41%) as a yellow solid;
λmax/nm 438; νmax/cmϪ1 3502 (OH), 1660 (conj. C᎐O), 1613 and
᎐
1569 (C᎐C); δ (500 MHz) 1.21 and 1.32 (each 6H, s, 1-gem-CH
᎐
H
3
and 1Ј-gem-CH3), 1.81 (2H, t, J 13.5, 2-Hax and 2Ј-Hax), 1.94
(6H, s, 5-CH3 and 5Ј-CH3), 1.98 (6H, s, 9-CH3 and 9Ј-CH3),
2.16 (2H, dd, J 13 and 6, 2-Heq and 2Ј-Heq), 3.68 (2H, d, J 1.5,
OH × 2), 4.32 (2H, ddd, J 13.5, 6 and 1.5, 3-H and 3Ј-H), 6.23
(2H, d, J 16, 7-H and 7Ј-H), 6.26 (2H, d, J 12, 10-H and 10Ј-H),
6.41 (2H, d, J 16, 8-H and 8Ј-H), 6.38–6.46 (4H, m, 12-H, 12Ј-
H, 13-H and 13Ј-H), 6.66 (2H, m, 11-H and 11Ј-H); δC(125
MHz) 12.52 (9-CH3 and 9Ј-CH3), 13.99 (5-CH3 and 5Ј-CH3),
26.15 and 30.73 (1-gem-CH3 and 1Ј-gem-CH3), 36.81 (C-1 and
C-1Ј), 45.42 (C-2 and C-2Ј), 69.22 (C-3 and C-3Ј), 123.85 (C-7
and C-7Ј), 126.95 (C-5 and C-5Ј), 129.76 (C-11 and C-11Ј),
134.36 and 134.54 (C-12, C-12Ј, C-13 and C-13Ј), 135.27 (C-10
and C-10Ј), 135.38 (C-9 and C-9Ј), 142.08 (C-8 and C-8Ј),
162.14 (C-6 and C-6Ј), 200.44 (C-4 and C-4Ј) (Found: Mϩ,
516.3247. C34H44O4 requires M, 516.3236).
Singlet-oxygen-quenching activities
A solution of the endoperoxide3d,17 of 1,4-dimethylnaphthalene
(40 mM in CDCl3; 50 mm3) was added to a mixture of TEMP
(40 mM in CDCl3; 50 mm3), one of the analogues 2a–d (0.01–
10000 µM in CDCl3; 50 mm3) and CDCl3 (50 mm3), and the
mixture was incubated at 37 ЊC for 2 min. Recording of
the EPR spectrum of each mixture was started just after
incubation, and an intensity (designated as S) of a signal
originating from TEMP oxide radical18 was measured. The
intensities of signals from a control without any analogues
(designated as C) and a blank (designated as B) with only
TEMP were also measured. Quenching activity (designated as
Q) of each analogue was calculated using equation (1).
3,3Ј-[(1E,3E,5E,7E,9E,11E,13E,15E )-3,14-Dimethylhexadeca-
1,3,5,7,9,11,13,15-octaene-1,16-diyl]bis[(6S)-6-hydroxy-2,4,4-
trimethylcyclohex-2-enone] 2c
According to the procedure described in the preparation of the
Q (%) = (C Ϫ S)/(C Ϫ B) × 100
(1)
1868
J. Chem. Soc., Perkin Trans. 1, 2001, 1862–1869

View Article Online
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9 J. K. Stille and B. L. Groh, J. Am. Chem. Soc., 1987, 109, 813.
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Acknowledgements
We thank Drs U. Hengartner and K. Bernhard, Hoffmann-La
Roche Ltd. Basel, Switzerland for chemical support.
11 E. Widmer, R. Zell, T. Lukácˇ, M. Casadei, P. Schönholzer and E. A.
Broger, Helv. Chim. Acta, 1981, 64, 2405.
12 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975,
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