Synthesis of the phthalide-containing anti-Helicobacter pylori agents CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108

Article abstract of DOI:10.1016/j.tet.2005.08.027

Flexible racemic syntheses of the phthalide-containing antibiotics CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108 that inhibit Helicobacter pylori have been carried out in a convergent fashion by Wittig coupling of a phthalide-containing aldehyd

Full text of DOI:10.1016/j.tet.2005.08.027

Tetrahedron 61 (2005) 10036–10047
Synthesis of the phthalide-containing anti-Helicobacter pylori
agents CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108
*
Margaret A. Brimble, Christopher L. Flowers, James K. Hutchinson, James E. Robinson
and Matthew Sidford
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1000, New Zealand
Received 12 June 2005; revised 18 July 2005; accepted 4 August 2005
Available online 24 August 2005
Abstract—Flexible racemic syntheses of the phthalide-containing antibiotics CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108
that inhibit Helicobacter pylori have been carried out in a convergent fashion by Wittig coupling of a phthalide-containing aldehyde fragment
with an appropriate phosphorous ylide.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
These phthalide-containing compounds provide promising
new leads for the treatment of H. pylori-related diseases.
Helicobacter pylori is a microaerophilic Gram-negative
bacterium that infects over 50% of the human population
worldwide. Infection has been associated with chronic
superficial gastritis, chronic active gastritis, peptic ulcer
disease and gastric cancer in humans.1 As a result of the
latter, the International Agency for Research in Cancer
classified H. pylori as a class I carcinogen in 1994.2
To date, CJ-13,015 3 is the only member of the P. velutina
series of antibiotics to have been synthesized.6 The
synthetic strategy used a 5-methylfuranyl bromide as a
latent 1,4-dicarbonyl system and was efficient requiring
only six steps. However, the synthetic route did not possess
the intrinsic flexibility necessary to access the other
compounds in the series. We herein report a flexible
synthetic strategy that has been used to prepare five of these
antibiotics 3–7 as racemates.
The current first-line triple-therapy for H. pylori-associated
gastrointestinal diseases, using a combination of antibiotics
with a proton-pump inhibitor, fails to fully eradicate
H. pylori in approximately 10–23% of patients. As a result,
second-line or rescue treatments are often required.3
Treatment failure is associated with the emergence of
H. pylori strains that are resistant to the broad-spectrum
antibiotics used.2
Our recent enantioselective total synthesis of spirolaxine
methyl ether 8b7 unequivocally established the absolute
stereochemistry at C-3 of the phthalide unit to be of the (R)-
configuration. It is therefore, likely that C-3 of the phthalide
unit in compounds 1–7 will also exhibit the (R)-configur-
ation. To this end the enantioselective total syntheses of the
more complex and helicobactericidal spiroacetal containing
antibiotics CJ-12,954 1 and CJ-13,014 2, are currently being
investigated.
Consequently, there is an urgent need for the development
of more effective and selective anti-H. pylori agents. In a
screening program designed to discover such compounds,
Dekker et al.4 isolated seven new phthalide antibiotics with
specific anti-H. pylori activity (1–7) from the basidiomycete
Phanerochaete velutina CL6387 (Fig. 1). Two structurally
related compounds, spirolaxine 8a5a and its methyl ether
8b,5b isolated from Sporotrichum laxum, S. pruinosum and
Phanerochaete, chrysosporium have also been reported.
2. Results and discussion
The work reported herein, describes the racemic total
syntheses of five of the P. velutina series of phthalide
antibiotics (3–7). The highly convergent and flexible
synthetic strategy adopted hinged on the Wittig reaction
of a key phthalide aldehyde 9, derived from 2,4-
dimethoxybenzoic acid 10, with the ylide generated from
the appropriate phosphonium salt 11, 12 or 13 (Scheme 1).
Keywords: Phthalides; Helicobacter pylori; Wittig reaction.
*
Corresponding author. Tel.: C64 9 3737599x88259; fax: C64 9
3737599; e-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.027

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10037
Figure 1. Structure and anti-H. pylori activity of phthalide antibiotics (1–7) and spirolaxine 8 isolated from P. velutina.
The alcohol functionality in CJ-13,104 6 was easily
obtained from reduction of the ketone in CJ-13,108 7, that
in turn was derived from the 11-carbon phosphonium salt
13, (Scheme 3). CJ-13,015 3 and CJ-13,102 4 were prepared
from a common hydroxyketone intermediate 14 starting
from the 11-carbon phosphonium salt 11 (Scheme 4). CJ-
13,103 5 was available from the union of the ylide derived
from the 13-carbon phosphonium salt 12 with phthalide
aldehyde 9 (Scheme 5).
began with the preparation of phosphonium salt 13,
obtained from commercially available 10-undecen-1-yl
bromide 19 in 96% yield. Wittig reaction of the ylide
generated from phosphonium salt 13, with aldehyde 9
gave the desired olefin 20 in 86% yield, as a mixture of (E)-
and (Z)-isomers, the relative ratios of which were unable
to be determined. Selective Wacker oxidation of the
terminal olefin afforded methyl ketone 21, which upon
hydrogenation of the internal olefin furnished CJ-13,108
7 in 62% yield. Reduction of the C-130 ketone in CJ-
13,108 7 with sodium borohydride gave CJ-13,104 6 in
95% yield.
2.1. Synthesis of phthalide aldehyde 9
Phthalide aldehyde 9 was the core building block used to
prepare all five of the desired compounds. It was prepared
from commercially available 2,4-dimethoxybenzoic acid 10
(Scheme 2) firstly by conversion to the corresponding amide
15. ortho-Lithiation followed by formylation provided
aldehyde 16, which furnished alkene 17 upon treatment
with but-3-en-1-ylmagnesium bromide. Acid-catalysed
cyclisation furnished phthalide 18 that upon ozonolysis of
the terminal olefin gave the desired phthalide aldehyde 9 in
65% overall yield.
2.3. The synthesis of CJ-13,015 3 and CJ-13,102 4
The synthesis of CJ-13,015 3 and CJ-13,102 4 (Scheme 4)
started from a common hydroxyketone intermediate 14 that
was prepared from commercially available 7-octen-1-ol 22.
Protection of the alcohol as a tert-butyldimethylsilyl ether
23 followed by epoxidation of the terminal olefin provided
oxirane 24 in quantitative yield. Ring-opening of the
epoxide using a higher-order allyl-cuprate afforded alcohol
25, which was protected as a benzyl ether 26. Cleavage of
the tert-butyldimethylsilyl ether yielded alcohol 27 that
underwent conversion to bromide 28 followed by reaction
with triphenylphosphine to furnish the desired phosphonium
2.2. Synthesis of CJ-13,104 6 and CJ-13,108 7
The synthesis of CJ-13,104 6 and CJ-13,108 7 (Scheme 3)

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M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
Scheme 1. Retrosynthetic analysis of CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108.
Scheme 2. Reagents and conditions: (i) SOCl2, reflux, 2.5 h, then Et2NH, CH2Cl2, rt, 12 h, 96%; (ii) t-BuLi (1.1 equiv), THF, K78 8C, 15 min, then DMF, rt,
16 h, 99%; (iii) but-3-en-1-ylmagnesium bromide, Et2O, rt, 30 min; (iv) pTSA, PhMe, reflux, 6 h, 87% from 16; (v) O3, MeOH, K50 8C, 10 min, then Me2S, rt,
1 h, 79%.
Scheme 3. Reagents and conditions: (i) PPh3, MeCN, reflux, 24 h, 96%; (ii) n-BuLi, THF, K78 8C to rt, 30 min, then 9, K78 8C to rt, 2 h, 86% (iii) PdCl2,
CuCl, DMF–H2O (8/1), O2, rt, 3 h, 62%; (iv) 10% Pd/C, H2, EtOAc, rt, 1 h, 100% (v) NaBH4, MeOH, rt, 10 min, 95%.
salt 11 in 34% overall yield (seven steps). Wittig reaction of
the ylide generated from phosphonium salt 11 with phthalide
aldehyde9gaveolefin29in72%yield,asamixtureof(E)-and
(Z)-isomers, the relative ratios of which were unable to be
determined. Selective Wacker oxidation of the terminal olefin
afforded ketone 30 which, upon simultaneous hydrogenation
of the internal olefin and hydrogenation of the benzyl ether,
furnished hydroxyketone 14. Direct acetylation of alcohol 14
provided CJ-13,102 4, whereas TPAP oxidation furnished
the diketone CJ-13,015 3.

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10039
Scheme 4. Reagents and conditions: (i) TBDMSCl, imidazole, DMAP, CH2Cl2, 0 8C, 3 h, 99%; (ii) mCPBA, NaOAc, CH2Cl2, rt, 18 h, 99%; (iii) 5% CuCN,
allylmagnesium bromide, Et2O, K78 8C, 10 h, 55%; (iv) NaH, TBAI, DMF, 0 8C, 75 min, then BnBr, rt, 18 h, 81%; (v) TBAF, THF, 0 8C, 2 h, 97%; (vi) CBr4,
PPh3, MeCN, 0 8C, 30 min, 100%; (vii) PPh3, MeCN, reflux, 26 h, 80%; (viii) n-BuLi, THF, K78 8C to rt, 30 min, then 9, K78 8C to rt, 2 h, 72%; (ix) PdCl2,
CuCl, DMF–H2O (8/1), O2, rt, 3 h, 54%; (x) 10% Pd/C, H2, EtOAc, rt, 3 h; (xi) Ac2O, DMAP, pyridine, rt, 8 h, 83% from 30; (xii) TPAP, NMO, CH2Cl2, rt,
30 min, 37% over two steps.
Scheme 5. Reagents and conditions: (i) TBDMSCl, imidazole, DMAP, CH2Cl2, 0 8C, 3 h, 96%; (ii) O3, MeOH, K50 8C, 10 min, then Me2S, rt, 1 h, 95%; (iii)
but-3-en-1-ylmagnesium bromide, Et2O, rt, 30 min, 96%; (iv) NaH, TBAI, DMF, 0 8C, 75 min, then BnBr, rt, 18 h, 95%; (v) PPh3Br2, CH2Cl2, rt, 24 h, 91%;
(vi) PPh3, MeCN, reflux, 24 h, 80%; (vii) n-BuLi, THF, K78 8C to rt, 30 min, then 9, K78 8C to rt, 2 h, 73%; (viii) PdCl2, CuCl, DMF–H2O (8/1), O2, rt, 3 h,
61% (ix) 10% Pd/C, H2, EtOAc, rt, 3 h; (x) TPAP, NMO, CH2Cl2, rt, 30 min, 44% over two steps.
2.4. Synthesis of CJ-13,103 5
pot desilylation–bromination procedure8 using triphenyl-
phosphine–bromine complex, afforded bromide 36, that
furnished the desired phosphonium salt 12 upon reaction
with triphenylphosphine. Wittig reaction of the ylide
generated from phosphonium salt 12 with phthalide
aldehyde 9 gave olefin 37 in 73% yield, as a mixture of
(E) and (Z) isomers, the relative ratios of which were unable
to be determined. Selective Wacker oxidation of the
terminal olefin afforded ketone 38 which, upon simul-
taneous hydrogenation of the internal olefin and
Following a similar strategy to that used for the synthesis of
CJ-13,015 3, the preparation of CJ-13,103 5 started with
commercially available 9-decen-1-ol 31 (Scheme 5).
Protection of the alcohol as a tert-butyldimethylsilyl ether
32 followed by ozonolysis of the terminal olefin provided
aldehyde 33. Treatment of 33 with but-3-en-1-ylmagnesium
bromide afforded alcohol 34 in quantitative yield. Protec-
tion of the alcohol as a benzyl ether 35 followed by a one-

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hydrogenation of the benzyl ether, furnished hydroxyketone
39. Finally, oxidation of alcohol 39 afforded CJ-13,103 5.
hexanes, 24.15 mmol) was added dropwise to a stirred
solution of N,N-diethyl 2,4-dimethoxybenzamide 15
(5.20 g, 21.91 mmol) in tetrahydrofuran (193 mL) at
K78 8C. After stirring for 25 min, N,N-dimethylformamide
(6.7 mL, 86.16 mmol) was added dropwise. The reaction
mixture was warmed to room temperature, stirred for 12 h
and the solvent removed in vacuo. The residue was
dissolved in dichloromethane (30 mL), washed with brine
(3!15 mL) and the organic layer dried over magnesium
sulfate. Removal of the solvent in vacuo followed by flash
column chromatography using diethyl ether as eluent gave
the title compound 16 (5.71 g, 99%) as a viscous yellow oil.
nmax (film) 2971, 1702, 1633, 1602, 1461, 1320, 1290, 1223,
3. Conclusions
An efficient and flexible strategy has been developed to
prepare five anti-Helicobacter pylori agents (3–7). The
convergent strategy developed, involving union of phthalide
aldehyde 9 with an appropriately functionalized ylide, is
readily amenable to the construction of analogues.
1201, 1155, 1097, 1045, 955, 936 cmK1 1H NMR
;
4. Experimental
4.1. General
(300 MHz, CDCl3) 0.96 (3H, t, JZ7.1 Hz, NCH2CH3),
1.22 (3H, t, JZ7.1 Hz, NCH2CH3), 3.07 (2H, q, JZ7.1 Hz,
NCH2CH3), 3.41–3.55 (1H, m, NCHAHBCH3), 3.58–3.70
(1H, m, NCHAHBCH3), 3.78 (3H, s, OMe), 3.81 (3H, s,
OMe), 6.65 (1H, d, JZ2.3 Hz, 5-H), 6.97 (1H, d, JZ2.3 Hz,
6-H), 9.90 (1H, s, CHO); 13C NMR (75 MHz, CDCl3) 12.6
(CH3, NCH2CH3), 13.7 (CH3, NCH2CH3), 39.0 (CH2,
NCH2CH3), 42.8 (CH2, NCH2CH3), 55.6 (CH3, OMe), 55.9
(CH3, OMe), 102.4 (CH, C-5), 104.7 (CH, C-3), 123.3
(quat., C-1), 134.2 (quat., C-2), 156.8 (quat., C-6), 160.9
(quat., C-4), 165.7 (quat., CONEt2), 190.2 (CH, CHO); m/z
(FABC, %) 266 (MC, 65), 238 (12), 236 (23), 193 (100),
167 (13), 165 (16), 154 (15), 71 (19); HRMS (FABC):
found MHC, 266.1383. C14H19NO4 requires 266.1392.
All reactions were carried out in flame dried or oven dried
glassware under a dry nitrogen atmosphere. Tetrahydro-
furan was distilled from sodium benzophenone while
dichloromethane and N,N-dimethylformamide were dried
over calcium hydride and distilled prior to use. Flash
chromatography was carried out using 0.063–0.1 mm silica
gel with the appropriate solvent. Thin-layer chromato-
graphy was performed using silica coated aluminium plates
(60 F254). Compounds were identified using UV fluor-
escence and or staining with vanillin in ethanolic sulphuric
acid. Low resolution mass spectra were recorded using a
VG-70SE spectrometer operating at a nominal accelerating
voltage of 70 eV. High resolution mass spectra were
recorded at a nominal resolution of 5000–10,000. Infrared
spectra were obtained using a Perkin-Elmer Spectrum 1000
series Fourier Transform IR spectrometer as a thin film
between sodium chloride plates. NMR spectra were
recorded on either the Bruker DRX300 spectrometer
4.2.3. N,N-Diethyl 4,6-dimethoxy-2-(10-hydroxypent-40-
en-10-yl)benzamide 17. A solution of aldehyde 16 (900 mg,
3.39 mmol) in diethyl ether (15 mL) was added dropwise to
the stirred solution of but-3-en-1-ylmagnesium bromide
(11.75 mL of a 0.63 M solution in diethyl ether, 7.41 mmol)
at 0 8C and the reaction mixture allowed to warm to room
temperature. After stirring for 30 min, saturated aqueous
ammonium chloride (20 mL) was added, the reaction
mixture extracted with diethyl ether (3!10 mL) and the
organic layer dried over magnesium sulfate. Removal of the
solvent in vacuo followed by flash column chromatography
using ethyl acetate–hexane (1/1) as eluent afforded the title
compound 17 (1.01 g) as a 1:1 mixture of rotamers and as a
viscous yellow oil. nmax (film) 3390, 2937, 1614, 1455,
1
operating at 300 MHz for H nuclei and 75 MHz for 13C
nuclei or using a Bruker DRX400 spectrometer operating at
400 MHz for 1H nuclei and 100 MHz for 13C nuclei.
Melting points were determined on a Kofler hot-stage
apparatus, and are uncorrected.
4.2. Procedure for the synthesis of phthalide aldehyde 9
4.2.1. N,N-Diethyl 2,4-dimethoxybenzamide 15. A
solution of 2,4-dimethoxybenzoic acid 10 (5.15 g,
28.27 mmol) in thionyl chloride (20 mL) was heated at
reflux for 2.5 h. The solvent was removed in vacuo. Benzene
(3!10 mL) was added to the residue then removed in
vacuo. A solution of diethylamine (9 mL, 87.00 mmol) in
dichloromethane (10 mL) was added dropwise to a stirred
solution of the crude acid chloride in dichloromethane
(40 mL) at 0 8C. After stirring at room temperature for 12 h,
the reaction mixture was diluted with dichloromethane
(50 mL), washed with 10% w/v aqueous sodium bicarbon-
ate (3!10 mL), brine (3!10 mL), and the organic layer
dried over magnesium sulfate. Removal of the solvent in
vacuo followed by flash column chromatography using
diethyl ether–hexane (3/1) as eluent gave the title compound
15 (6.71 g, 96%) as a viscous yellow oil. The 1H NMR data
obtained were in agreement with the literature values.9
1
1317, 1202, 1154, 1049, 912, 732, 635 cmK1; H NMR
(300 MHz, CDCl3) 1.04 (3H, t, JZ7.0 Hz, NCH2CH3), 1.23
(3H, t, JZ7.0 Hz, NCH2CH3), 1.70–2.30 (4H, m, 20-H, 30-
H), 3.15 (2H, q, JZ7.0 Hz, NCH2CH3), 3.47 (2H, t, JZ
7.0 Hz, NCH2CH3), 3.77 (3H, s, OMe), 3.82 (3H, s, OMe),
4.45–4.59 (1H0, m, 10-H), 4.92–5.15 (2H, m, 50-H), 5.74–
5.88 (1H, m, 4 -H), 6.36 (1H, d, JZ2.2 Hz, 5-H), 6.59 (1H,
d, JZ2.2 Hz, 3-H), 6.64 (1H, d, JZ2.2 Hz, 3-H); 13C NMR
(75 MHz, CDCl3) 12.5, 12.6 (CH3, NCH2CH3), 13.6, 15.2
(CH3, NCH2CH3), 30.4 (CH2, C-30), 37.3 (CH2, C-20) 38.7
(CH2, NCH2CH3), 42.8 (CH2, NCH2CH3), 55.3 (CH3,
OMe), 55.4 (CH3, OMe), 69.6, 73.1 (CH, C-10), 97.4, 97.5
(CH, C-5), 102.0, 103.4 (CH, C-3), 114.7, 114.8 (CH2,
C-50), 117.0 (quat., C-1), 138.1, 138.3 (CH, C-40), 144.0
(quat., C-2), 156.1 (quat., C-6), 161.0, 161.2 (quat., C-4),
168.5 (quat., C]O); m/z (EIC, %) 321 (MC, 17), 266 (18),
249 (38), 236 (11), 231 (25), 207 (59), 193 (100), 165 (29),
74 (32), 58 (33), 41 (12); HRMS (EIC): found MC,
321.1938. C18H27NO4 requires 321.1940.
4.2.2. N,N-Diethyl 2-formyl-4,6-dimethoxybenzamide
16. tert-Butyllithium (23 mL of a 1.05 M solution in

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10041
4.2.4. 3-(But-30-en-10-yl)-5,7-dimethoxy-(3H)-isobenzo-
furan-1-one 18. To a crude sample of alcohol 17 (1.10 g,
3.42 mmol) in toluene (20 mL) was added p-toluenesulfonic
acid monohydrate (100 mg, 0.50 mmol). The mixture was
heated under reflux for 6 h. Removal of the solvent in vacuo
followed by flash column chromatography using ethyl
acetate–hexane (1/1) as eluent yielded the title compound
18 (800 mg, 87% over two steps) as a yellow oil. nmax (film)
2942, 1739, 1606, 1463, 1340, 1218, 1160, 1033, 913, 816,
96%) as a viscous colourless oil. The 31P NMR data
obtained was in agreement with the literature value. 31P
NMR (300 MHz, CDCl3) 24.2 (lit. 31P 24.3).10
4.3.2. 5,7-Dimethoxy-3-(tetradec-30,130-dien-10-yl)-(3H)-
isobenzofuran-1-one 20. n-Butyllithium (0.56 mL of a
1.6 M solution in hexanes, 0.90 mmol) was added dropwise
to a stirred solution of triphenyl(undec-10-en-1-yl)-
phosphonium bromide 13 (370 mg, 0.75 mmol) in tetra-
hydrofuran (10 mL) at K78 8C. The resulting deep orange
solution was warmed to room temperature, re-cooled to
K78 8C and a solution of phthalide aldehyde 9 (150 mg,
0.60 mmol) in tetrahydrofuran (5 mL) added dropwise with
stirring. The mixture was warmed to room temperature,
stirred for 2 h and the solvent removed in vacuo. The
resulting residue was dissolved in dichloromethane
(20 mL), washed with brine (3!5 mL) and the organic
layer dried over magnesium sulfate. Removal of the solvent
in vacuo followed by flash column chromatography using
ethyl acetate–hexane (4/1) as eluent afforded the title
compound 20 (200 mg, 86%) as a greasy colourless oil. nmax
(film) 2926, 2853, 1759, 1614, 1463, 1433, 1338, 1217,
732, 670 cmK1 1H NMR (300 MHz, CDCl3) 1.72–1.85
;
(1H, m, 10-HA), 2.02–2.14 (1H, m, 10-HB), 2.20–2.30 (2H,
m, 20-H), 3.90 (3H, s, OMe), 3.95 (3H, s, OMe), 5.00–5.12
(2H, m, 40-H), 5.28–5.35 (1H, m, 3-H), 5.75–5.89 (1H, m,
30-H), 6.43 (1H, s, 6-H), 6.43 (1H, s, 4-H); 13C NMR
(75 MHz, CDCl3) 28.8 (CH2, C-20), 34.0 (CH2, C-10), 55.8
(CH3, OMe), 55.8 (CH3, OMe), 78.9 (CH, C-3), 97.4 (CH,
C-6), 98.6 (CH, C-4), 105.8 (quat., C-7a), 115.7 (CH2,
C-40), 136.8 (CH, C-30), 154.8 (quat., C-3a), 159.5 (quat.,
C-7), 166.6 (quat., C-5), 168.2 (quat., C]O); m/z (EIC, %)
248 (MC, 7), 194 (34), 193 (100), 165 (31), 91 (12); HRMS
(EIC): found MC, 248.1055. C13H14O4 requires 248.1049.
1158, 1056, 1029, 910, 837, 732 cmK1
;
10H NMR
4.2.5. 5,7-Dimethoxy-3-(30-oxoprop-10-yl)-(3H)-iso-
benzofuran-1-one 9. A solution of olefin 18 (200 mg,
0.81 mmol) in methanol (15 mL) was cooled to K50 8C
under nitrogen. Ozone was bubbled through the solution for
10 min at a rate of 1 L/min. The mixture was flushed with
nitrogen and dimethyl sulfide (3 mL) was added. The
resulting mixture was warmed to room temperature, further
dimethyl sulfide added (1 mL) and the mixture stirred for
1 h. The solvent was removed in vacuo and the resulting
yellow residue dissolved in water (5 mL), extracted with
diethyl ether (3!10 mL) and the organic layer dried over
magnesium sulfate. Removal of the solvent in vacuo
followed by flash column chromatography using ethyl
acetate–hexane (1/1) as eluent afforded the title compound 9
(160 mg, 79%) as a yellow oil. nmax (film) 2928, 2951, 1755,
(300 MHz, CDCl3) 1.25–1.42 (12H, m, 60-H, 7 -H, 80-H,
90-H, 100-H, 110-H), 1.62–1.78 (1H, m, 10-HA), 1.91–2.08
(5H, m, 10-HB, 50-H, 120-H), 2.09–2.36 (2H, m, 20-H), 3.89
(3H, s, OMe), 3.94 (3H, s, OMe), 4.90–5.01 (2H, m, 140-H),
5.27–5.48 (3H, m, 3-H, 30-H, 40-H), 5.73–5.87 (1H, m, 130-
H), 6.42 (1H, s, 6-H), 6.42 (1H, s, 4-H); 13C NMR (75 MHz,
CDCl3) 22.5 (CH2, C-20), 27.0 (CH2, C-50), 28.7 (CH2,
C-110), 28.9 (CH2, C-60), 29.1 (CH2, C-100), 29.3 (CH2,
C-90), 29.3 (CH2, C-80), 29.4 (CH2, C-70), 33.6 (CH2,
C-120), 34.8 (CH2, C-10), 55.7 (CH3, OMe), 55.8 (CH3,
OMe), 79.1 (CH, C-3), 97.3 (CH, C-6), 98.5 (CH, C-4),
106.7 (quat., C-7a), 113.9 (CH2, C-140), 127.4 (CH, C-30),
131.6 (CH, C-40), 139.0 (CH, C-130), 154.9 (quat., C-3a),
159.4 (quat., C-7), 166.6 (quat., C-5), 168.2 (quat., C]O);
m/z (EIC, %) 386 (MC, 23), 261 (25), 247 (24), 208 (100),
193 (50); HRMS (EIC): found MC, 386.2457. C24H34O4
requires 386.2451.
1
1602, 1463, 1338, 1218, 1158, 1028, 837, 734 cmK1; H
NMR (300 MHz, CDCl3) 1.88 (1H, dddd, JZ14.4, 8.3, 8.3,
5.1 Hz, 10-HA), 2.44 (1H, dddd, JZ14.4, 7.4, 7.4, 3.2 Hz, 10-
HB), 2.54 (1H, ddd, JZ18.7, 8.2, 5.1 Hz, 20-HA), 2.75 (1H,
td, JZ18.7, 7.4 Hz, 20-HB), 3.88 (3H, s, OMe), 3.94 (3H, s,
OMe), 5.34 (1H, dd, JZ8.3, 3.2 Hz, 3-H), 6.42 (1H, s, 4-H),
6.43 (1H, s, 6-H), 9.80 (1H, apparent s, 30-H); 13C NMR
(75 MHz, CDCl3) 26.9 (CH2, C10), 38.9 (CH2, C20), 56.0
(CH3, OMe), 56.0 (CH3, OMe), 78.4 (CH, C3), 97.4 (CH,
C6), 99.1 (CH, C4), 106.7 (quat., C7a), 154.3 (quat., C3a),
159.7 (quat., C7), 167.0 (quat., C5), 168.0 (quat., C1), 200.7
(CH, C30); m/z (EIC, %) 250 (MC, 30), 206 (61), 193 (100),
165 (21), 135 (20) and 77 (10); HRMS (EIC): found MC,
250.0833. C13H14O5 requires 250.0841.
4.3.3. 5,7-Dimethoxy-3-(130-oxotetradec-30-en-10-yl)-
(3H)-isobenzofuran-1-one 21. Palladium(II) chloride
(46 mg, 0.26 mmol) and copper(I) chloride (61 mg,
0.62 mmol) were added to a stirred solution of diene 20
(200 mg, 0.52 mmol) in N,N-dimethylformamide–water
(4 mL/0.5 mL) at room temperature. The reaction mixture
was bubbled with oxygen gas with stirring for 3 h. The
mixture was filtered through a pad of Celitew and the
solvent removed in vacuo. The resulting residue was
dissolved in dichloromethane (10 mL), washed with brine
(3!2 mL) and the organic layer dried over magnesium
sulfate. Removal of the solvent in vacuo followed by flash
column chromatography using ethyl acetate–hexane (1/1) as
eluent afforded the title compound 21 (130 mg, 62%) as a
greasy colourless oil. nmax (film) 3498, 2926, 2853, 1756,
1712, 1613, 1464, 1432, 1338, 1217, 1158, 1054, 1028, 837,
690 cmK0 1; 1H NMR (300 MHz, CDCl3) 1.22–1.36 (10H, m,
60-H, 7 -H, 80-H, 90-H, 100-H), 1.49–1.62 (2H,0 m, 1100-H),
1.68–1.79 (1H, m, 10-HA), 1.90–2.07 (3H, m, 1 -HB, 5 -H),
2.12 (3H, s, 140-H), 2.15–2.33 (2H, m, 20-H), 2.41 (2H, t,
JZ7.3 Hz, 120-H), 3.89 (3H, s, OMe), 3.94 (3H, s, OMe),
5.26–5.50 (3H, m, 3-H, 30-H, 40-H), 6.42 (1H, s, 6-H), 6.42
4.3. Procedure for the synthesis of CJ-13,104 6 and (G)-
CJ-13,108 7
4.3.1. Triphenyl(undec-10-en-1-yl)phosphonium bromide
13. Triphenylphosphine (3.2 g, 12.3 mmol) was added in
one portion to a solution of 11-bromoundec-1-ene 19
(2.8 mL, 12.9 mmol) in benzene (20 mL). The solution was
heated under nitrogen at reflux for 24 h. The solvent was
removed in vacuo leaving a viscous white residue that was
triturated with diethyl ether (2!5 mL). Removal of the
solvent in vacuo afforded the title compound 13 (6.15 g,

10042
M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
(1H, s, 4-H); 13C NMR (75 MHz, CDCl3) 22.6 (CH2, C-20),
23.7 (CH2, C-110), 27.1 (CH2, C-50), 29.0 (CH2, C-100), 29.0
(CH2, C-90), 29.2 (CH2, C-60), 29.2 (CH2, C-80), 29.5 (CH2,
C-70), 29.7 (CH2, C-140), 34.9 (CH2, C-10), 43.7 (CH2, C-120),
55.8 (CH3, OMe), 55.9 (CH3, OMe), 79.1 (CH, C-3), 97.4
(CH, C-6), 98.6 (CH, C-4), 106.8 (quat., C-7a), 127.5 (CH,
C-30), 131.6 (CH, C-40), 155.0 (quat., C-3a), 159.5 (quat.,
C-7), 166.6 (quat., C-5), 168.3 (quat., C-1), 209.3 (quat.,
C-130); m/z (EIC, %) 402 (MC, 25), 384 (18), 345 (14), 208
(100), 207 (88), 194 (75), 193 (72), 43 (46); HRMS (EIC):
found MC, 402.2403. C24H34O5 requires 402.2406.
C-140), 24.6 (CH2, C-20), 25.7 (CH2, C-110), 29.3 (CH2),
29.4 (CH2), 29.4 (CH2), 29.5 (CH2), 29.5 (CH2) 29.5 (CH2),
29.6 (CH2), 29.6 (CH2), 34.8 (CH2, C-10), 39.3 (CH2,
C-120), 55.9 (CH3, OMe), 55.9 (CH3, OMe), 68.1 (CH,
C-130), 79.9 (CH, C-3), 97.3 (CH, C-6), 98.5 (CH, C-4),
106.9 (quat., C-7a), 155.2 (quat., C-3a), 159.5 (quat., C-7),
166.6 (quat., C-5), 168.5 (quat., C]O); m/z (EIC, %) 406
(MC, 1), 388 (38), 362 (48), 207 (60), 193 (100), 165 (13),
55 (19), 45 (16), 41 (18); HRMS (EIC): found MC,
406.2713. C24H38O5 requires 406.2719.
4.4. Procedure for the synthesis of (G)-CJ-13,015 3 and
CJ-13,102 4
4.3.4. (G)-CJ-13,108 7. Palladium 10% on carbon (20 mg,
0.036 mmol) was added in one portion to a stirred solution
of olefin 21 (130 mg, 0.32 mmol) in ethyl acetate (5 mL) at
room temperature. The reaction mixture was stirred under
an atmosphere of hydrogen for 1 h and filtered through a pad
of Celitew. Removal of the solvent in vacuo followed by
flash column chromatography using ethyl acetate–hexane
(1/1) as eluent afforded the title compound 7 (130 mg,
4.4.1. 1-(tert-Butyldimethylsilyloxy)-oct-7-ene 23. A
solution of 7-octen-1-ol 22 (1.51 g, 11.8 mmol) in dichloro-
methane (10 mL) was added dropwise to a stirred mixture of
imidazole (850 mg, 12 mmol), 4-dimethylaminopyridine
(69 mg, 0.57 mmol) and tert-butyldimethylsilyl chloride
(1.88 g, 12.4 mmol) in dry dichloromethane (30 mL) at
0 8C. After stirring at for 3 h, saturated aqueous sodium
bicarbonate (10 mL) was added, the reaction mixture
extracted with dichloromethane (3!5 mL) and the organic
layer dried over magnesium sulfate. Removal of the solvent
in vacuo followed by flash column chromatography using
heptane–diethyl ether (99/1) as eluent afforded the title
compound 23 (2.74 g, 100%) as a colourless oil. nmax (film)
2955, 2929, 2857, 1641, 1471, 1463, 1414, 1387, 1361,
1255, 1102, 1030, 1005, 993, 937, 909, 836, 811, 775,
1
100%) as a colourless solid. The H and 13C NMR data
obtained were in agreement with the literature values.4 Mp
104–106 8C; nmax (film) 3462, 2915, 1758, 1701, 1600,
1
1469, 1336, 1220, 1162, 1053, 1026, 837 cmK1;0 H NMR
(400 MHz, CDCl3) 1.22–1.36 (16H, m, 30-H, 4 -H, 50-H,
60-H, 70-H, 80-H, 90-H, 100-H), 1.41–1.46 (2H, m, 20-H),
1.52–1.59 (2H, m, 110-H), 1.64–1.73 (1H, m, 10-HA), 1.94–
1.99 (1H, m, 10-HB), 2.13 (3H, s, 140-H), 2.42 (2H, t, JZ
7.4 Hz, 120-H), 3.90 (3H, s, OMe), 3.95 (3H, s, OMe), 5.30
(1H, dd, JZ7.8, 3.9 Hz, 3-H), 6.42 (1H, s, 6-H), 6.42 (1H, s,
4-H); 13C NMR (100 MHz, CDCl3) 23.7 (CH2, C-110), 24.5
(CH2, C-20), 29.0 (CH2), 29.2 (CH2), 29.2 (CH2), 29.3
(CH2), 29.3 (CH2), 29.3 (CH2), 29.4 (CH2), 29.4 (CH2), 29.7
(CH2, C-140), 34.7 (CH2, C-10), 43.6 (CH2, C-120), 55.8
(CH3, OMe), 55.8 (CH3, OMe), 79.8 (CH, C-3), 97.3 (CH,
C-6), 98.4 (CH, C-4), 106.7 (quat., C-7a), 155.1 (quat.,
C-3a), 159.4 (quat., C-7), 166.5 (quat., C-5), 168.4 (quat.,
C-1), 209.3 (quat., C-130); m/z (EIC, %) 404 (MC, 32), 347
(65), 207 (57), 193 (100), 43 (19); HRMS (EIC): found
MC, 404.2559. C24H36O5 requires 404.2563.
660 cmK1 1H NMR (300 MHz, CDCl3) 0.05 (6H, s,
;
SitBuMe2), 0.90 (9H, s, SitBuMe2), 1.27–1.32 (4H, m,
3-H, 4-H), 1.36–1.46 (2H, m, 5-H), 1.50 (2H, quintet, JZ
6.8 Hz, 2-H), 2.05 (2H, dt, JZ7.0, 7.0 Hz, 6-H), 3.60 (2H, t,
JZ6.5 Hz, 1-H), 4.96 (1H, d, JZ11.4 Hz, 8-HA), 4.99 (1H,
d, JZ19.2 Hz, 8-HB), 5.76–5.84 (1H, m, 7-H); 13C NMR
(100 MHz, CDCl3) K5.3 (CH3, SitBuMe2), 17.5 (quat.,
SitBuMe2) 25.0 (CH2, C-3), 25.3 (CH3, SitBuMe2), 28.3
(CH2, C-4), 28.3 (CH2, C-5), 32.2 (CH2, C-2), 33.2 (CH2,
C-6), 63.1 (CH2, C-1), 114.7 (CH2, C-8), 140.0 (CH, C-7);
m/z (CI, NH3, %) 243 (MHC, 100), 202 (4), 185 (29), 132
(12), 91 (13), 71 (12); HRMS (CI, NH3): found MHC,
243.2144. C14H30OSi requires 243.2144.
4.3.5. CJ-13,104 6. Sodium borohydride (116 mg,
3.07 mmol) was added in one portion to a stirred solution
of CJ-13,108 7 (310 mg, 0.77 mmol) in methanol (10 mL) at
0 8C. The reaction mixture was stirred at room temperature
under an atmosphere of nitrogen for 10 min and the solvent
removed in vacuo. The residue was dissolved in dichloro-
methane (10 mL), washed with brine (3!2 mL) and the
organic layer dried over magnesium sulfate. Removal of the
solvent in vacuo followed by flash column chromatography
using ethyl acetate–hexane (1/1) as eluent afforded the title
4.4.2. 1-(tert-Butyldimethylsilyloxy)-7-epoxyoctane 24. A
solution of 1-(tert-butyldimethylsilyloxy)-oct-7-ene 23
(2.79 g, 11.5 mmol) in dry dichloromethane (5 mL) was
added dropwise to a stirred mixture of 3-chloroperoxy-
benzoic acid (3.40 g, 20 mmol) and sodium acetate (2.00 g,
23 mmol) in dichloromethane (50 mL) at 0 8C and the
mixture stirred for 1 h. After stirring at room temperature
for 18 h, the reaction mixture was filtered, washed with
saturated aqueous sodium sulfite (3!10 mL), extracted
with dichloromethane (3!5 mL) and the organic layer
dried over magnesium sulfate. Removal of the solvent in
vacuo followed by flash column chromatography using
hexane–diethyl ether (3/1) as eluent afforded the title
compound 24 (2.77 g, 99%) as a pale yellow oil. nmax (film):
2928, 2856, 1471, 1463, 1409, 1387, 1361, 1255, 1098,
1
compound 6 (296 mg, 95%) as a colourless solid. The H
and 13C NMR data obtained were in agreement with the
literature values.4 Mp 100–102 8C; nmax (film) 3413, 3054,
2928, 2854, 1752, 1604, 1495, 1463, 1422, 1337, 1265,
1219, 1159, 1058, 896, 840, 737, 704 cmK1 1H NMR
;
(400 MHz, CDCl3) 1.18 (3H, d, JZ6.2 Hz, 140-H), 1.20–
1.38 (18H, m, 30-H, 40-H, 50-H, 600-H, 70-H, 80-H, 90-H,
100-H, 110-H), 1.38–1.45 (4H, m, 20 -H, 120-H), 1.67–1.71
(1H, m, 10-HA), 2.00–1.96 (1H, m, 1 -HB), 3.81 (1H, sextet,
JZ6.1 Hz, 130-H), 3.89 (3H, s, OMe), 3.95 (3H, s, OMe),
5.30 (1H, dd, JZ7.9, 3.7 Hz, 3-H), 6.41 (1H, s, 6-H), 6.41
(1H, s, 4-H); 13C NMR (100 MHz, CDCl3) 23.4 (CH3,
1006, 938, 917, 835, 812, 775, 659 cmK1 1H NMR
;
(400 MHz, CDCl3) 0.03 (6H, s, SitBuMe2), 0.88 (9H, s,
SitBuMe2), 1.32–1.34 (4H, m, 3-H, 4-H), 1.43–1.54 (6H, m,
2-H, 5-H, 6-H), 2.45 (1H, dd, JZ5.0, 2.7 Hz, 8-HA), 2.73
(1H, dd, JZ5.0, 4.1 Hz, 8-HB), 2.85–2.88 (1H, m, 7-H),

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10043
3.59 (2H, t, JZ6.5 Hz, 1-H); 13C NMR (100 MHz, CDCl3)
K5.3 (CH3, SitBuMe2), 18.3 (quat., SitBuMe2), 25.8 (CH2),
26.0 (CH3, SitBuMe2), 26.1 (CH2), 29.3 (CH2, C-4), 32.5
(CH2, C-6), 32.8 (CH2, C-2), 47.0 (CH2, C-8), 52.3 (CH,
C-7), 63.2 (CH2, C-1); m/z (CI, NH3, %) 259 (MHC, 100),
243 (6), 127 (19), 109 (13), 92 (12), 71 (7); HRMS (CI,
NH3): found MHC, 259.2087. C14H30O2Si requires
259.2093.
OCH2Ph), 4.94 (1H, dd, JZ8.8, 2.0 Hz, 11-HA), 5.00 (1H,
dd, JZ17.2, 2.0 Hz, 11-HB), 5.77–5.87 (1H, m, 10-H),
7.24–7.38 (5H, m, OCH2Ph); 13C NMR (100 MHz, CDCl3)
K5.3 (CH3, SitBuMe2), 18.4 (quat., SitBuMe2), 25.3 (CH2),
25.8 (CH2), 26.0 (CH3, SitBuMe2), 29.6 (CH2), 29.6 (CH2),
32.8 (CH2), 33.1 (CH2, C-8), 33.7 (CH2), 63.3 (CH2, C-1),
70.8 (CH2, OCH2Ph), 78.4 (CH, C-7), 114.4 (CH2, C-11),
127.4 (CH, OCH2Ph), 127.7 (CH, OCH2Ph), 128.3 (CH,
OCH2Ph), 138.8 (CH, C-10), 139.0 (quat., OCH2Ph); m/z
(CI, NH3, %) 391 (MHC, 7), 283 (17), 216 (28), 108 (18),
92 (45), 91 (100); HRMS (CI, NH3): found MHC, 391.3034.
C24H42O2Si requires 391.3032.
4.4.3. 1-(tert-Butyldimethylsilyloxy)undec-10-en-7-ol 25.
A solution of allylmagnesium bromide (1.53 mL of a 1 M
solution in diethyl ether, 1.53 mmol) was added dropwise to
a stirred suspension of copper(I) cyanide (37.6 mg,
0.33 mmol) in diethyl ether (4 mL) at K78 8C. To the
resulting stirred cuprate reagent was added a solution of
epoxide 24 (198 mg, 0.77 mmol) in diethyl ether (6 mL) at
K78 8C. After stirring for 10 h, saturated aqueous
ammonium chloride (30 mL) was added and the mixture
allowed to warm to room temperature. The reaction mixture
was extracted with diethyl ether (3!20 mL) and the organic
layer dried over magnesium sulfate. Removal of the solvent
in vacuo followed by flash column chromatography using
hexane–diethyl ether (4/1) as eluent gave the title compound
25 (1.02 g, 55%) as a pale yellow oil. nmax (film) 3350,
3077, 2929, 2856, 1641, 1471, 1463, 1412, 1388, 1360,
4.4.5. 7-(Benzyloxy)undec-10-en-1-ol 27. Tetrabutyl-
ammonium fluoride (4.13 mL of a 1 M solution in
tetrahydrofuran, 4.13 mmol) was added dropwise to a
stirred mixture of silyl ether 26 (1.08 g, 2.75 mmol) and
˚
4 A molecular sieves (200 mg) in tetrahydrofuran (15 mL)
at 0 8C. After stirring for 2 h, saturated aqueous ammonium
chloride (10 mL) was added, the reaction mixture extracted
with diethyl ether (3!5 mL) and the organic layer dried
over magnesium sulfate. Removal of the solvent in vacuo
followed by flash column chromatography using hexane–
diethyl ether (4/1) as eluent gave the title compound 27
(613 mg, 97%) as a yellow oil. nmax (film): 3368, 3065,
3030, 2931, 2857, 1640, 1496, 1454, 1414, 1396, 1350,
1307, 1257, 1206, 1067, 1028, 994, 910, 735, 697 cmK1; 1H
NMR (400 MHz, CDCl3) 1.30–1.44 (6H, m, 3-H, 4-H, 5-H),
1.50–1.70 (6H, m, 2-H, 6-H, 8-H), 2.11–2.15 (2H, m, 9-H),
3.40 (1H, quintet, JZ5.8 Hz, 7-H), 3.63 (2H, t, JZ6.6 Hz,
1-H), 4.50 (2H, s, OCH2Ph), 4.95 (1H, dd, JZ10.2, 1.6 Hz,
11-HA), 5.01 (1H, dd, JZ17.2, 1.6 Hz, 11-HB), 5.77–5.85
(1H, m, 10-H), 7.25–7.36 (5H, m, OCH2Ph); 13C NMR
(100 MHz, CDCl3) 25.2 (CH2), 25.7 (CH2), 29.6 (CH2),
29.6 (CH2, C-9), 32.7 (CH2), 33.1 (CH2, C-8), 33.7 (CH2),
63.0 (CH2, C-1), 70.8 (CH2, OCH2Ph), 78.3 (CH, C-7),
114.4 (CH2, C-11), 127.4 (CH, OCH2Ph), 127.8 (CH,
OCH2Ph), 128.3 (CH, OCH2Ph) 138.8 (CH, C-10), 139.0
(quat., OCH2Ph); m/z (EIC, %) 276 (MC, 1), 175 (4), 107
(9), 92 (10), 91 (100), 65 (4), 55 (5), 41 (4); HRMS (EIC):
found MC, 276.2089. C18H28O2 requires 276.2089.
1255, 1100, 1005, 938, 910, 836, 812, 775, 710, 661 cmK1
;
1H NMR (400 MHz, CDCl3) 0.03 (6H, s, SitBuMe2), 0.88
(9H, s, SitBuMe2), 1.26–1.37 (6H, m, 3-H, 4-H, 5-H), 1.38–
1.61 (6H, m, 2-H, 6-H, 8-H), 2.09–2.23 (2H, m, 9-H), 3.59
(2H, t, JZ6.6 Hz, 1-H), 3.53–3.62 (1H, m, 7-H), 4.96 (1H,
dd, JZ10.2, 1.7 Hz, 11-HA), 5.04 (1H, dd, JZ17.1, 1.7 Hz,
11-HB), 5.78–5.89 (1H, m, 10-H); 13C NMR (100 MHz,
CDCl3) K5.3 (CH3, SitBuMe2), 18.4 (quat., SitBuMe2),
25.6 (CH2), 25.8 (CH2) 26.0 (CH3, SitBuMe2), 29.5 (CH2),
30.1 (CH2, C-9), 32.8 (CH2, C-2), 36.5 (CH2), 37.4 (CH2),
63.2 (CH2, C-1), 71.5 (CH, C-7), 114.7 (CH2, C-11), 138.6
(CH, C-10); m/z (CI, NH3, %) 301 (MHC, 18), 283 (20), 151
(14), 109 (50), 95 (100), 83 (20), 81 (42), 75 (49); HRMS
(CI, NH3): found MHC, 301.2561. C17H36O2Si requires
301.2563.
4.4.4.
7-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)
undec-10-ene 26. A solution of alcohol 25 (161 mg,
0.53 mmol) in N,N-dimethylformamide (1 mL) was added
dropwise to a stirred suspension of sodium hydride (15 mg,
0.64 mmol) and tetrabutylammonium iodide (51 mg,
0.15 mmol) in N,N-dimethylformamide (1 mL) at 0 8C.
After stirring for 75 min, benzyl bromide (0.08 mL,
0.64 mmol) was added dropwise and the reaction mixture
stirred at room temperature for 18 h. Saturated aqueous
ammonium chloride (5 mL) was added, the reaction mixture
extracted with diethyl ether (3!5 mL) and the organic layer
dried over magnesium sulfate. Removal of the solvent in
vacuo followed by flash column chromatography using
hexane–diethyl ether (49/1) as eluent gave the title
compound 26 (170 mg, 81%) as a yellow oil. nmax (film)
3065, 3030, 2929, 2857, 1640, 1496, 1471, 1462, 1454,
1387, 1360, 1254, 1206, 1098, 1071, 1028, 1005, 994, 938,
4.4.6. 7-(Benzyloxy)-1-bromoundec-10-ene 28. A solution
of carbon tetrabromide (1.44 g, 4.34 mmol) in acetonitrile
(2 mL) was added dropwise to a stirred mixture of alcohol
27 (0.60 g, 2.17 mmol) and triphenylphosphine (1.14 g,
4.34 mmol) in acetonitrile (20 mL) at 0 8C. After stirring the
reaction mixture at room temperature for 30 min, saturated
aqueous sodium bicarbonate (10 mL) was added and the
reaction mixture extracted with diethyl ether (3!5 mL).
The organic layer was washed with brine (2!10 mL) and
dried over magnesium sulfate. Removal of the solvent in
vacuo followed by flash column chromatography using
hexane–diethyl ether (49/1) as eluent gave the title
compound 28 (0.72 g, 98%) as a colourless oil. nmax
(film): 3064, 3029, 2933, 2857, 1640, 1496, 1453, 1349,
1306, 1260, 1206, 1093, 1067, 1028, 993, 910, 734,
1
697 cmK1; H NMR (400 MHz, CDCl3) 1.25–1.47 (6H,
1
910, 836, 813, 775, 734, 696 cmK1; H NMR (400 MHz,
m, 3-H, 4-H, 5-H), 1.48–1.70 (4H, m, 6-H, 8-H), 1.83 (2H,
quintet, JZ7.2 Hz, 2-H), 2.08–2.22 (2H, m, 9-H), 3.37–3.43
(3H, m, 1-H, 7-H), 4.49 (2H, s, OCH2Ph), 4.95 (1H, dd, JZ
10.2, 1.6 Hz, 11-HA), 5.01 (1H, dd, JZ17.2, 1.6 Hz, 11-
HB), 5.77–5.85 (1H, m, 10-H), 7.25–7.36 (5H, m, OCH2Ph);
CDCl3) 0.05 (6H, s, SitBuMe2), 0.90 (9H, s, SitBuMe2),
1.25–1.43 (6H, m, 3-H, 4-H, 5-H), 1.46–1.65 (6H, m, 2-H,
6-H, 8-H), 2.01–2.17 (2H, m, 9-H), 3.39 (1H, quintet, JZ
5.9 Hz, 7-H), 3.60 (2H, t, JZ6.6 Hz, 1-H), 4.49 (2H, s,

10044
M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
13C NMR (100 MHz, CDCl3) 25.1 (CH2), 28.1 (CH2), 28.9
(CH2), 29.6 (CH2, C-9), 32.7 (CH2), 33.1 (CH2, C-8), 33.6
(CH2), 33.9 (CH2, C-1), 70.8 (CH2, OCH2Ph), 78.3 (CH,
C-7), 114.5 (CH2, C-11), 127.4 (CH, OCH2Ph), 127.7 (CH,
OCH2Ph), 128.3 (CH, OCH2Ph), 138.7 (CH, C-10), 139.0
(quat., OCH2Ph); m/z (EIC, %) 339 (MC, 0.1), 175 (9), 107
(9), 92 (10), 91 (100), 65 (4), 55 (5), 41 (5); HRMS (EIC):
found MC, 338.1243, 340.1219. C18H27BrO requires
338.1245, 340.1225.
20-HA, 120), 2.22–2.35 (1H, m, 20-HB), 3.40 (1H, quintet,
JZ5.8 Hz, 100-H), 3.86 (3H, s, OMe), 3.92 (3H, s, OMe),
4.49 (2H, s, OCH2Ph), 4.94 (1H, dd, JZ10.2, 1.8 Hz, 140-
HA), 5.00 (1H, dd, JZ17.2, 1.8 Hz, 140-HB), 5.22–5.28 (1H,
m,0 3-H), 5.30–5.47 (2H, m, 30-H, 40-H), 5.72–5.88 (1H, m,
13 -H), 6.40 (2H, br s, 4-H, 6-H), 7.21–7.36 (5H, m,
13
OCH2Ph); C NMR (100 MHz, CDCl3) 22.8 (CH2, C-20),
25.2 (CH2, C-80), 27.2 (CH2, C-50), 29.4 (CH2), 29.6 (CH2),
29.6 (CH2, C-120), 33.1 (CH2, C-110), 33.7 (CH2, C-90), 35.0
(CH2, C-10), 55.9 (CH3, OMe), 56.0 (CH3, OMe), 70.8
(CH2, OCH2Ph), 78.4 (CH, C-100), 79.3 (CH, C-3), 97.3
(CH, C-6), 98.7 (CH, C-4), 106.9 (quat., C-7a), 114.4 (CH2,
C-140), 127.4 (CH, OCH2Ph), 127.6 (CH, C-30), 127.7 (CH,
OCH2Ph), 128.3 (CH, OCH2Ph), 131.7 (CH, C-40), 138.8
(quat., OCH2Ph), 139.0 (CH, C-130), 155.1 (quat., C-3a),
159.6 (quat., C-7), 166.7 (quat., C-5), 168.5 (quat., C]O);
m/z (FABC, %) 493 (MHC, 9), 385 (8), 219 (5), 120 (11),
91 (22); HRMS (FAB): found MHC, 493.2953. C31H40O5
requires 493.2954.
4.4.7. [7-(Benzyloxy)undec-10-en-1-yl]triphenylphos-
phonium bromide 11. Triphenylphosphine (1.18 g,
4.51 mmol) was added in one portion to a stirred solution
of bromide 28 (765 mg, 2.26 mmol) in acetonitrile (10 mL)
at room temperature. The mixture was heated under an
atmosphere of nitrogen at reflux for 26 h. Removal of the
solvent in vacuo followed by flash column chromatography
using dichloromethane–methanol (19/1) as eluent gave the
title compound 11 (1.08 g, 80%) as a wax. nmax (film) 3377,
3055, 3031, 3007, 2989, 2934, 2859, 2791, 1639, 1618,
1587, 1495, 1485, 1453, 1438, 1413, 1344, 1315, 1273,
4.4.9. 3-(100-Benzyloxy-130-oxotetradec-30-en-10-yl)-5,7-
dimethoxy-(3H)-isobenzofuran-1-one 30. Palladium(II)
chloride (11 mg, 0.06 mmol) and copper(I) chloride
(15 mg, 0.16 mmol) were added in one portion to a stirred
solution of diene 29 (64 mg, 0.13 mmol) in N,N-dimethyl-
formamide–water (4 mL/0.5 mL) at room temperature. The
reaction mixture was bubbled with oxygen gas with stirring
for 3 h. The mixture was filtered through Celitew and the
solvent removed in vacuo. The resulting residue was
dissolved in dichloromethane (10 mL), washed with brine
(3!2 mL) and dried over magnesium sulfate. Removal of
the solvent in vacuo followed by flash column chromato-
graphy using hexane–ethyl acetate (1/1) as eluent afforded
the title compound 30 (35 mg, 54%) as a viscous colourless
oil. nmax (film) 3503, 3061, 3005, 2930, 2855, 1755, 1713,
1605, 1494, 1456, 1432, 1359, 1338, 1271, 1217, 1158,
1190, 1161, 1113, 1066, 1027, 996, 912, 788, 725, 693 cmK1
;
1H NMR (400 MHz, CDCl3) 1.20–1.36 (4H, m, 4-H, 5-H),
1.41–1.68 (8H, m, 2-H, 3-H, 6-H, 8-H), 2.04–2.17 (2H, m,
9-H), 3.35 (1H, quintet, JZ5.8 Hz, 7-H), 3.84–3.91 (2H, m,
1-H), 4.45 (2H, s, OCH2Ph) 4.94 (1H, dd, JZ10.2, 1.6 Hz,
11-HA), 4.99 (1H, dd, JZ17.1, 1.6 Hz, 11-HB), 5.74–5.85
(1H, m, 10-H), 7.25–7.31 (5H, m, OCH2Ph), 7.65–7.89
(15H, m, PPh3); 13C NMR (100 MHz, CDCl3) 22.5 (CH2, d,
JZ7 Hz, C-2), 22.7 (CH2, d, JZ49 Hz, C-1), 24.8 (CH2,
C-5), 29.4 (CH2, C-4), 29.6 (CH2, C-9), 30.3 (CH2, d, JZ
15 Hz, C-3), 33.0 (CH2, C-8), 33.6 (CH2, C-6), 70.7 (CH2,
OCH2Ph), 78.2 (CH, C-7), 114.4 (CH2, C-11), 118.4 (quat.,
d, JZ85 Hz, PPh3), 127.4 (CH, OCH2Ph), 127.7 (CH,
OCH2Ph), 128.3 (CH, OCH2Ph), 130.4 (CH, d, JZ12 Hz,
PPh3), 133.7 (CH, d, JZ10 Hz, PPh3), 134.9 (CH, PPh3)
138.7 (CH, C-10), 139.0 (quat., OCH2Ph); m/z (FABC, %)
521 (MCKBr, 100), 429 (4), 413 (5), 373 (6), 275 (4), 262
(8), 183 (6), 91 (15); HRMS (FAB): found MCKBr,
521.2965. C36H42BrOP requires 521.2973.
1108, 1062, 1028, 972, 837, 735, 698 cmK1 1H NMR
;
(300 MHz, CDCl3) 1.20–1.50 (6H, m, 60-H, 70-H, 80-H),
1.53–1.65 (2H, m, 90-H), 1.67–1.78 (2H, m, 10-HA, 110-HA),
1.82–1.93 (1H, m, 110-HB), 1.94–2.05 (3H, m, 10-HB, 50-H),
2.11 (3H, s, 140-H), 2.13–2.23 (1H, m, 20-HA,), 2.23–2.35
(1H, m, 20-HB), 2.48–2.53 (2H, m, 120-H), 3.38–3.40 (1H,
m, 100-H), 3.89 (3H, s, OMe), 3.95 (3H, s, OMe), 4.43 (1H,
d, JZ11.5 Hz, OCHAHBPh), 4.51 (1H, d, JZ11.5 Hz,
OCHAHBPh), 5.28–5.30 (1H, m, 3-H), 5.35–5.45 (2H, m,
30-H, 40-H), 6.41 (1H, s, 4-H), 6.42 (1H, s, 6-H), 7.30–7.34
(5H, m, OCH2Ph); 13C NMR (100 MHz, CDCl3) 22.8 (CH2,
C-20), 25.2 (CH2, C-80), 27.2 (CH2, C-50), 27.5 (CH2,
C-110), 29.4 (CH2), 29.6 (CH2), 30.0 (CH3, C-140), 33.7
(CH2, C-90), 35.0 (CH2, C-10), 39.3 (CH2, C-120), 55.9
(CH3, OMe), 56.0 (CH3, OMe), 70.8 (CH2, OCH2Ph), 77.9
(CH, C-100), 79.3 (CH, C-3), 97.3 (CH, C-6), 98.7 (CH,
C-4), 106.9 (quat., C-7a), 127.5 (CH, OCH2Ph), 127.6 (CH,
C-30), 127.8 (CH, OCH2Ph), 128.3 (CH, OCH2Ph), 131.7
(CH, C-40), 138.8 (quat., OCH2Ph), 155.1 (quat., C-3a),
159.6 (quat., C-7), 166.7 (quat., C-5), 168.5 (quat., C-1),
209.1 (quat., C-130); m/z (FABC, %) 509 (MHC, 2), 401
(9), 219 (4), 124 (7), 120 (8), 91 (19), 89 (22); HRMS
(FABC): found MHC, 509.2904. C31H40O6 requires
509.2903.
4.4.8. 3-(100-Benzyloxytetradec-30,130-dien-10-yl)-5,7-
dimethoxy-(3H)-isobenzofuran-1-one 29. n-Butyllithium
(0.23 mL of a 1.6 M solution in hexanes, 0.37 mmol) was
added dropwise to a stirred solution of phosphonium salt 11
(200 mg, 0.33 mmol) in dry tetrahydrofuran (5 mL) at
K78 8C. The resulting deep orange solution was warmed to
room temperature, re-cooled to K78 8C, and a solution of
phthalide aldehyde 9 (69 mg, 0.28 mmol) in dry tetrahydro-
furan (2 mL) was added dropwise with stirring. The mixture
was warmed to room temperature, stirred for 2 h and the
solvent removed in vacuo. The resulting residue was
dissolved in dichloromethane (20 mL), washed with brine
(3!5 mL) and the organic layer dried over magnesium
sulfate. Removal of the solvent in vacuo followed by flash
column chromatography using hexane–diethyl ether (4/6) as
eluent gave the title compound 29 (98 mg, 72%) as a viscous
colourless oil. nmax (film) 3505, 3065, 3005, 2931, 2855,
1759, 1639, 1613, 1495, 1462, 1455, 1432, 1360, 1338,
1216, 1158, 1108, 1062, 1028, 911, 837, 735, 6970cmK1; 1H
NMR (300 MHz, CDCl3) 1.23–1.46 (6H, m, 6 -H, 70-H,
800-H), 1.48–1.66 (4H, m, 90-H, 1100-H), 1.67–1.78 (1H, m,
1 -HA), 1.94–2.05 (3H, m, 10-HB, 5 -H), 2.09–2.21 (3H, m,
4.4.10. 5,7-Dimethoxy-3-(100-hydroxy-130-oxotetradec-
10-ly)-(3H)-isobenzofuran-1-one 14. Palladium 10% on

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10045
carbon (20 mg, 0.036 mmol) was added in one portion to a
stirred solution of benzyl ether 30 (35 mg, 0.07 mmol) in
ethyl acetate (5 mL) at room temperature. The reaction
mixture was bubbled with hydrogen gas for 3 h and filtered
through a pad of Celitew. Removal of the solvent in vacuo
afforded the title compound 14 as a colourless oil (25 mg)
that was not purified further before use in the subsequent steps.
155.2 (quat., C-3a), 159.6 (quat., C-7), 166.6 (quat., C-5),
168.6 (quat., C-1), 170.9 (quat., OAc), 208.0 (quat., C-130);
m/z (FABC, %) 463 (MHC, 3), 403 (11), 120 (15), 89 (23),
73 (12); HRMS (FABC): found MHC, 463.2703.
C26H38O7 requires 463.2696.
4.5. Procedure for the synthesis of (G)-CJ-13,103 5
4.5.1. 1-(tert-Butyldimethylsilyloxy)dec-9-ene 32. Using a
similar method to that described above for the preparation of
sily ether 23, alcohol 31 (3.6 g, 23.04 mmol) was reacted
with tert-butyldimethylsilyl chloride (5.53 g, 29.90 mmol)
to afford the the title compound 32 (6.00 g, 96%) as a
colourless oil. The 1H and 13C NMR data obtained were in
agreement with the literature values.11
4.4.11. (G)-CJ-13,015 3. Tetra-n-propylammonium per-
ruthenate (5 mg, 0.01 mmol) and N-methylmorpholine
N-oxide (10 mg, 0.09 mmol) were added to a stirred
solution of crude alcohol 14 (11 mg) in dichloromethane
(2 mL) at room temperature. The reaction mixture was
stirred for 30 min then filtered through a pad of silica.
Removal of the solvent in vacuo followed by flash column
chromatography using hexane–ethyl acetate (1/1) as eluent
afforded the title compound 3 (4 mg, 37% over two steps) as
a colourless solid. The 1H and 13C NMR data obtained were
in agreement with the literature values.4 Mp 103–104 8C;
nmax (film) 3584, 2925, 2852, 1756, 1710, 1603, 1494, 1465,
1431, 1413, 1360, 1337, 1218, 1159, 1099, 1053, 1028, 836,
689 cmK0 1; 1H NMR (400 MHz, CDCl3) 1.18–1.39 (10H, m,
30-H, 4 -H, 50-H, 600-H, 70-H), 1.37–1.52 (2H, m, 20-H),
1.52–1.74 (3H, m, 1 -HA, 80-H), 1.92–2.03 (1H, m, 10-HB),
2.19 (3H, s, 0140-H),02.44 (2H, t, JZ7.4 Hz, 90-H), 2.67–2.72
(4H, m, 11 -H, 12 -H), 3.90 (3H, s, OMe), 3.95 (3H, s,
OMe), 5.30 (1H, dd, JZ7.9, 3.7 Hz, 3-H), 6.41 (1H, s, 4-H),
6.42 (1H, s, 6-H); 13C NMR (100 MHz, CDCl3) 23.8 (CH2,
C-80), 24.6 (CH2, C-20), 29.1 (CH2), 29.3 (CH2), 29.3 (CH2),
29.3 (CH2), 29.3 (CH2), 30.0 (CH3, C-140), 34.8 (CH2,
C-10), 36.0 (CH2, C-120), 36.9 (CH2, C-110), 42.8 (CH2,
C-90), 55.9 (CH3, OMe), 56.0 (CH3, OMe), 79.9 (CH, C-3),
97.3 (CH, C-6), 98.6 (CH, C-4), 106.9 (quat., C-7a), 155.2
(quat., C-3a), 159.6 (quat., C-70), 166.6 (quat., C-5),0 168.6
(quat., C-1), 207.4 (quat., C-13 ), 209.7 (quat., C-10 ); m/z
(FABC, %) 419 (MHC, 5), 403 (73), 120 (14), 89 (19);
HRMS (FABC): found MHC, 419.2431. C24H34O6
requires 419.2434.
4.5.2. 9-(tert-Butyldimethylsilyloxy)nonanal 33. A
solution of alkene 32 (5.00 g, 18.5 mmol) in methanol
(20 mL) was cooled to K50 8C under nitrogen. Ozone was
bubbled through the solution for 10 min at a rate of 1 L/min.
The mixture was flushed with nitrogen and dimethyl sulfide
(5 mL) was added. The resulting mixture was warmed to
room temperature, further dimethyl sulfide added (2 mL)
and the mixture stirred for 1 h. The solvent was removed in
vacuo and the resulting yellow residue dissolved in water
(5 mL), extracted with diethyl ether (3!10 mL) and the
organic layer dried over magnesium sulfate. Removal of the
solvent in vacuo followed by flash column chromatography
using ethyl acetate–hexane (1/1) as eluent afforded the title
1
compound 33 (4.80 g, 95%) as an oil. The H NMR data
obtained was in agreement with the literature values.12
4.5.3. 1-(tert-Butyldimethylsilyloxy)tridec-12-en-9-ol 34.
A solution of aldehyde 33 (5.00 g, 18.3 mmol) in diethyl
ether (15 mL) was added dropwise to a stirred solution of
but-3-en-1-ylmagnesium bromide (56 mL of 0.5 M solution
in diethyl ether, 28 mmol) at 0 8C and the reaction mixture
allowed to warm to room temperature. After stirring for
30 min, saturated aqueous ammonium chloride (20 mL) was
added, the reaction mixture extracted with diethyl ether (3!
10 mL) and the organic layer dried over magnesium sulfate.
Removal of the solvent in vacuo followed by flash column
chromatography using ethyl acetate–hexane (1/1) as eluent
afforded the title compound 34 as a yellow oil. nmax (film)
3361, 2929, 2856, 1641, 1471, 1463, 1387, 1361, 1255,
1100, 1006, 938, 909, 835, 775 cmK1; 1H NMR (400 MHz,
CDCl3) 0.02 (6H, s, SitBuMe2), 0.87 (9H, s, SitBuMe2),
1.22–1.34 (8H, m, 3-H, 4-H, 5-H, 6-H), 1.38–1.66 (8H, m,
2-H, 7-H, 8-H, 10-H), 2.10–2.20 (2H, m, 11-H), 3.56–3.59
(3H, m, 1-H, 9-H), 4.94 (1H, d, JZ10.2 Hz, 13-HA), 5.02
(1H, d, JZ17.2 Hz, 13-HB), 5.78–5.85 (1H, m, 12-H); 13C
NMR (100 MHz, CDCl3) K5.3 (CH3, SitBuMe2), 18.3
(quat., SitBuMe2), 25.6 (CH2), 25.7 (CH2), 25.9 (CH3,
SitBuMe2), 29.3 (CH2), 29.6 (CH2), 29.6 (CH2), 30.0 (CH2,
C-11), 32.8 (CH2, C-2), 36.4 (CH2), 37.4 (CH2), 63.2 (CH2,
C-1), 71.5 (CH, C-7), 114.7 (CH2, C-11), 138.6 (CH, C-10);
m/z (FABC, %) 329 (MHC, 27), 311 (17), 123 (14), 115
(16), 109 (21), 95 (40), 89 (27), 81 (37), 75 (83); HRMS
(FABC): found MHC, 329.2883. C19H40O2Si requires
329.2876.
4.4.12. CJ-13,102 4. Acetic anhydride (2 mL, 21.16 mmol)
was added dropwise to a stirred mixture of crude alcohol 14
(11 mg) and N,N-dimethyl-4-aminopyridine (5 mg,
0.04 mmol) in pyridine (2 mL) at room temperature. The
reaction mixture was stirred for 8 h and the solvent removed
in vacuo. Flash column chromatography using hexane–ethyl
acetate (1/1) as eluent afforded the title compound 4 (10 mg,
1
83% over two steps) as a colourless oil. H and 13C NMR
data obtained were in agreement with the literature values.4
nmax (film) 3504, 2927, 2853, 1756, 1718, 1603, 1494, 1464,
1432, 1359, 1337, 1241, 1218, 1159, 1104, 1052, 1028, 837,
732, 690 cmK1 1H NMR (400 MHz, CDCl3) 1.20–1.35
;
(10H, m, 30-H, 40-H, 50-H, 60-H, 70-H), 1.35–1.58 (4H, m,
80-H, 20-H), 1.61–1.80 (3H, m, 10-HA, 90-H), 1.84–2.02 (3H,
m, 10-HB, 110-H), 2.05 (3H, s, OAc) 2.15 (3H, s, 140-H), 2.45
(2H, t, JZ7.4 Hz, 120-H), 3.90 (3H, s, OMe), 3.95 (3H, s,
OMe), 4.82–4.88 (1H, m, 100-H), 5.29 (1H, dd, JZ7.8,
3.7 Hz, 3-H), 6.41 (1H, s, 4-H), 6.42 (1H, s, 6-H); 13C NMR
(100 MHz, CDCl3) 21.2 (CH3, OAc), 24.6 (CH2, C-20), 25.2
(CH2, C-80), 27.9 (CH2, C-110), 29.3 (CH2), 29.3 (CH2),
29.4 (CH2), 29.4 (CH2), 29.4 (CH2) 30.0 (CH3, C-140), 34.2
(CH2, C-90), 34.8 (CH2, C-10), 39.5 (CH2, C-120), 55.9
(CH3, OMe), 56.0 (CH3, OMe), 73.5 (CH, C-100), 80.0 (CH,
C-3), 97.3 (CH, C-6), 98.6 (CH, C-4), 106.9 (quat., C-7a),
4.5.4. 9-Benzyloxy-1-(tert-butyldimethylsilyloxy)tridec-
12-ene 35. Using a similar method to that described above

10046
M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
for the preparation of benzyl ether 26, alcohol 34 (944 mg,
2.87 mmol) was reacted with benzyl bromide (0.48 mL,
4.02 mmol) to afford the title compound 35 (1.14 g, 95%) as
a yellow oil. nmax (film) 3065, 3031, 2929, 2856, 1641,
1496, 1471, 1462, 1454, 1387, 1360, 1306, 1254, 1207,
1098, 1071, 1028, 1005, 938, 909, 835, 814, 775, 733,
H, 80-H), 1.72–2.36 (4H, m, 100-H, 110-H), 3.35–3.45 (1H,
m, 9-H), 3.64–3.82 (2H, m, 1-H), 4.48 (2H, s, OCH2Ph),
4.89–5.07 (2H, m, 13-H), 5.71–5.89 (1H, m, 12-H), 7.20–
7.40 (5H, m, OCH2Ph), 7.65–7.94 (15H, m, PPh3); 13C
NMR (75 MHz, CDCl3) 22.3 (CH2, d, JZ9 Hz, C-2), 22.6
(CH2, d, JZ46 Hz, C-1), 24.8 (CH2), 27.1 (CH2), 28.7
(CH2), 28.8 (CH2), 29.3 (CH2, d, JZ5 Hz, C-4), 30.1 (CH2,
d, JZ16 Hz, C-3), 32.8 (CH2), 33.4 (CH2), 70.4 (CH2,
OCH2Ph), 78.1 (CH, C-9), 114.1 (CH2, C-13), 118.0 (quat.,
d, JZ86 Hz, PPh3), 127.0 (CH, OCH2Ph), 127.4 (CH,
OCH2Ph), 127.9 (CH, OCH2Ph), 130.2 (CH, d, JZ13 Hz,
PPh3), 133.3 (CH, d, JZ10 Hz, PPh3), 134.8 (CH, d, JZ
3 Hz, PPh3), 138.4 (CH, C-12), 138.7 (quat., OCH2Ph); m/z
(FABC, %) 549 (MCKBr, 100), 523 (28), 521 (28), 459
(18), 441 (92), 401 (51), 275 (12), 262 (27), 183 (15),
91 (14).
696 cmK1 1H NMR (400 MHz, CDCl3) 0.05 (6H, s,
;
SitBuMe2), 0.90 (9H, s, SitBuMe2), 1.22–1.38 (8H, m,
3-H, 4-H, 5-H, 6-H), 1.44–1.70 (8H, m, 2-H, 7-H, 8-H,
10-H), 2.10–2.29 (2H, m, 11-H), 3.38–3.47 (1H, m, 9-H),
3.59–3.67 (2H, m, 1-H), 4.53 (2H, s, OCH2Ph) 4.88–5.05
(2H, m, 13-H), 5.87–5.92 (1H, m, 12-H), 7.27–7.38 (5H, m,
OCH2Ph); 13C NMR (100 MHz, CDCl3) K5.3 (CH3,
SitBuMe2), 18.3 (quat., SitBuMe2), 25.2 (CH2), 25.7
(CH2), 25.9 (CH3, SitBuMe2), 29.3 (CH2), 29.6 (CH2),
29.6 (CH2), 29.7 (CH2), 32.8 (CH2), 33.1 (CH2), 33.7 (CH2),
63.2 (CH2, C-1), 70.7 (CH2, OCH2Ph), 78.3 (CH, C-9),
114.4 (CH2, C-13), 127.3 (CH, OCH2Ph), 127.7 (CH,
OCH2Ph), 128.2 (CH, OCH2Ph), 138.7 (CH, C-12), 139.0
(quat., OCH2Ph); m/z (FABC, %) 419 (MHC, 5), 311 (11),
95 (13), 91 (100), 89 (14), 81 (13), 75 (81); HRMS (FABC):
found MHC, 419.3341. C26H46O2Si requires 419.3345.
4.5.7. 3-(120-Benzyloxyhexadec-30,150-dien-10-yl)-5,7-
dimethoxy-(3H)-isobenzofuran-1-one 37. Using a similar
method to that described above for the preparation of diene
29, phosphonium salt 12 (300 mg, 0.48 mmol) was reacted
with phthalide aldehyde 9 (120 mg, 0.48 mmol) to afford the
title compound 37 (181 mg, 73%) as a viscous colourless
oil. nmax (film) 3514, 3075, 3006, 2927, 2853, 1759, 1640,
1614, 1495, 1463, 1455, 1434, 1360, 1338, 1217, 1158,
4.5.5. 1-Bromo-9-(benzyloxy)tridec-12-ene 36. Bromine
(1.71 mL, 33.4 mmol) was added dropwise to a stirred
solution of triphenylphosphine (8.89 g, 33.9 mmol) in
dichloromethane (100 mL) at 0 8C. The mixture was
warmed to room temperature resulting in formation of a
white suspension to which was added a solution of silyl
ether 35 (2.00 g, 4.78 mmol) in dichloromethane dropwise
with stirring. The resulting mixture was stirred for 24 h at
room temperature then filtered through a plug of silica using
hexane–ethyl acetate (9/1) as eluent, affording the title
compound 36 (1.60 g, 4.40 mmol) as a colourless oil. nmax
(film) 3064, 3029, 2929, 2854, 1639, 1496, 1453, 1349,
1305, 1252, 1206, 1093, 1067, 1027, 994, 910, 733, 696,
669 cmK1; 1H NMR (400 MHz, CDCl3) 1.25–1.32 (6H, m,
40-H, 50-H0, 60-H),01.34–1.45 (4H, m, 30-H, 70-H), 1.46–4.70
(4H, m, 8 -H, 10 -H), 1.84 (2H, quintet, JZ7.2 Hz, 2-H),
2.06–2.20 (2H, m, 11-H), 3.35–3.43 (3H, m, 1-H, 9-H), 4.49
(2H, s, OCH2Ph), 4.93–4.96 (1H, m, 13-HA), 5.01 (1H, dd,
JZ17.2, 1.6 Hz, 13-HB), 5.78–5.85 (1H, m, 10-H), 7.22–
7.36 (5H, m, OCH2Ph); 13C NMR (100 MHz, CDCl3) 25.1
(CH2), 28.1 (CH2), 28.6 (CH2), 29.3 (CH2), 29.6 (CH2), 29.6
(CH2), 32.7 (CH2), 33.0 (CH2), 33.6 (CH2), 34.0 (CH2, C-1),
70.7 (CH2, OCH2Ph), 78.3 (CH, C-9), 114.4 (CH2, C-13),
127.3 (CH, OCH2Ph), 127.7 (CH, OCH2Ph), 128.2 (CH,
OCH2Ph), 138.7 (CH, C-12), 139.0 (quat., OCH2Ph); m/z
(EIC, %) 368 (MC, 0.1), 366 (MC, 0.1), 175 (11), 92 (11),
91 (100); HRMS (EIC): found MC, 366.1550, 368.1537.
C20H31BrO requires 366.1558, 368.1538.
1109, 1061, 1029, 912, 837, 735, 696 cmK1 1H NMR
;
(300 MHz, CDCl3) 1.22–1.42 (10H, m, 60-H, 70-H, 80-H,
90-H, 100-H), 1.45–1.88 (5H, m, 10-HA, 110-H, 130-H),
1.92–2.07 (3H, m, 10-HB, 50-H), 2.08–2.21 (3H, m, 20-HA,
140-H), 2.22–2.37 (1H, m, 20-HB), 3.37–3.43 (1H, m,
120-H), 3.89 (3H, s, OMe), 3.95 (3H, s, OMe), 4.49 (2H,
OCH2Ph), 4.89–5.11 (2H, m, 160-HA), 5.29 (1H, dd, JZ8.5,
3.3 Hz, 3-H), 5.33–5.48 (2H, m, 30-H, 40-H), 5.71–5.87 (1H,
m, 150-H), 6.41 (2H, br s, 4-H, 6-H), 7.22–7.37 (5H, m,
OCH2Ph); 13C NMR (75 MHz, CDCl3) 22.7 (CH2), 25.2
(CH2), 27.2 (CH2), 27.4 (CH2), 29.2 (CH2), 29.5 (CH2), 29.6
(CH2), 31.6 (CH2), 33.1 (CH2), 33.7 (CH2), 34.9 (CH2,
C-10), 55.8 (CH3, OMe), 55.9 (CH3, OMe), 70.7 (CH2,
OCH2Ph), 78.4 (CH, C-120), 79.2 (CH, C-3), 97.3 (CH,
C-6), 98.6 (CH, C-4), 106.9 (quat., C-7a), 114.3 (CH2,
C-160), 127.3 (CH, OCH2Ph), 127.5 (CH, C-30), 127.7 (CH,
OCH2Ph), 128.2 (CH, OCH2Ph), 131.7 (CH, C-40), 138.7
(CH, C-150), 139.0 (quat., OCH2Ph), 155.0 (quat., C-3a),
159.6 (quat., C-7), 166.6 (quat., C-5), 168.3 (quat., C]O);
m/z (FABC, %) 521 (MHC, 12), 413 (24), 373 (10), 207
(10), 193 (10), 120 (12), 91 (30); HRMS (FABC): found
MHC, 521.3260. C33H44O5 requires 521.3267.
4.5.8. 3-(120-Benzyloxy-150-oxohexadec-30-en-10-yl)-5,7-
dimethoxy-(3H)-isobenzofuran-1-one 38. Using a similar
method to that described above for the preparation of methyl
ketone 30, Wacker oxidation of alkene 37 (111 mg,
0.21 mmol) afforded the title compound 38 (70 mg, 61%)
as a viscous colourless oil. nmax (film) 2928, 2853, 1755,
1713, 1676, 1613, 1494, 1463, 1433, 1339, 1217, 1159,
4.5.6. [9-(Benzyloxy)tridec-12-en-1-yl]triphenylphos-
phonium bromide 12. Using a similar method to that
described above for the preparation of phosphonium salt 11,
bromide 36 (730 mg, 1.99 mmol) was reacted with
triphenylphosphine (680 mg, 2.58 mmol) to afford the title
compound 12 (1.0 g, 80%) as a wax. nmax (film) 3390, 3056,
3007, 2989, 2928, 2856, 2792, 2174, 1639, 1615, 1587,
1485, 1463, 1454, 1439, 1413, 1340, 1317, 1271, 1190,
1059, 1029, 914, 837, 733, 697, 5000 cmK1
;
1H0 NMR
(300 MHz, CDCl3) 1.20–1.48 (10H, m, 6 -H, 70-H, 8 -H, 90-
H, 100-H), 1.49–1.62 (2H, m, 110-H), 1.65–1.90 (3H, m, 10-
HA, 130-H), 1.92–2.08 (3H, m, 10-HB, 50-H), 2.10 (3H, s,
160-H), 2.12–2.22 (1H, m, 20-HA), 2.23–2.35 (1H, m, 20-
HB), 2.42–2.53 (2H, m, 140-H), 3.35–3.42 (1H, m, 120-H),
3.89 (3H, s, OMe), 3.95 (3H, s, OMe), 4.42 (1H, d, JZ
11.6 Hz, OCHAHBPh), 4.50 (1H, d, JZ11.6 Hz,
1162, 1113, 1069, 1027, 996, 923, 787, 723, 691, 638 cmK1
;
1H NMR (300 MHz, CDCl3) 1.16–1.36 (8H, m, 30-H, 40-H,
50-H, 60-H), 1.41–1.56 (2H, m, 70-H), 1.57–1.71 (4H, m, 20-

M. A. Brimble et al. / Tetrahedron 61 (2005) 10036–10047
10047
OCHAHBPh), 5.29 (1H, d, JZ8.6, 3.3 Hz, 3-H), 5.33–5.48
(2H, m, 30-H, 40-H), 6.41 (1H, s, 4-H), 6.42 (1H, s, 6-H),
7.30–7.37 (5H, m, OCH2Ph); 13C NMR (75 MHz, CDCl3)
22.7 (CH2, C-20), 25.3 (CH2), 27.2 (CH2), 27.5 (CH2), 29.2
(CH2), 29.5(CH2), 29.6 (CH2), 29.7 (CH2), 29.9 (CH3,
C-140), 33.7 (CH2), 35.0 (CH2, C-10), 39.3 (CH2, C-140),
55.9 (CH3, OMe), 56.0 (CH3, OMe), 70.7 (CH2, CH2Ph),
77.9 (CH, C-120), 79.3 (CH, C-3), 97.4 (CH, C-6), 98.7 (CH,
C-4), 106.9 (quat., C-7a), 127.5 (CH, OCH2Ph), 127.5 (CH,
C-30), 127.8 (CH, OCH2Ph), 128.3 (CH, OCH2Ph), 131.7
(CH, C-40), 138.8 (quat., OCH2Ph), 155.1 (quat., C-3a),
159.6 (quat., C-7), 166.7 (quat., C-5), 168.4 (quat., C-1),
208.9 (quat., C-150); m/z (FABC, %) 537 (MHC, 5), 429
(75), 389 (10), 207 (11), 191 (17), 165 (10), 120 (11), 91
(52), 89 (32); HRMS (FABC): found MHC, 537.3226.
C33H44O6 requires 537.3216.
C-3a), 159.6 (quat., C-7), 166.6 (quat., C-5),0168.6 (quat.,
C-1), 207.4 (quat., C-150), 209.8 (quat., C-12 ); m/z (EIC,
%) 446 (MC, 9), 428 (18), 375 (23), 348 (12), 333 (87), 207
(46), 193 (100), 165 (14), 99 (17), 71 (11), 57 (12), 55 (20),
43 (27); HRMS (EIC): found MC, 446.2678. C26H38O6
requires 446.2668.
Acknowledgements
The authors thank the University of Auckland Medical
Research foundation for financial support.
4.5.9. 5,7-Dimethoxy-3-(120-hydroxy-150-oxohexadec-1-
yl)-(3H)-isobenzofuran-1-one 39. Using a similar method
to that described above for the preparation of alcohol 14,
benzyl ether 38 (60 mg, 0.11 mmol) was reacted with
hydrogen over 10% palladium on charcoal to afford the title
compound 39 as a colourless oil (48 mg) that was not
purified further before use in the subsequent steps.
References and notes
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1
solid. H and 13C NMR data obtained were in agreement
with the literature values.4 Mp 103–104 8C; nmax (film)
2921, 2848, 2100, 1757, 1641, 1470, 1337, 1218, 1160, 837,
667 cmK1; 1H NMR (400 MHz, CDCl3) 1.20–1.37 (14H, m,
300-H, 40-H, 50-H, 60-H, 70-H, 80-H, 90-H), 1.38–1.49 (2H, m,
2 -H), 1.52–1.61 (2H, m, 100-H), 1.64–1.75 (1H, m, 10-HA),
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JZ7.4 Hz, 110-H), 22.66–2.72 (4H, m, 130-H, 140-H), 3.89
(3H, s, OMe), 3.95 (3H, s, OMe), 5.30 (1H, dd, JZ8.0,
3.7 Hz, 3-H), 6.41 (1H, s, 4-H), 6.41 (1H, s, 6-H); 13C NMR
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29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.4 (CH2), 29.4 (CH2),
29.5 (CH2), 29.5 (CH2) 30.0 (CH3, C-160), 34.8 (CH2, C-10),
36.0 (CH2, C-140), 36.9 (CH2, C-130), 42.8 (CH2, C-110),
55.9 (CH3, OMe), 56.0 (CH3, OMe), 80.0 (CH, C-3), 97.4
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