Total synthesis of cytotoxic sponge alkaloids hachijodines F and G

Article abstract of DOI:10.1016/S0040-4020(03)00115-7

The total synthesis of two cytotoxic sponge alkaloids hachijodines F and G has been achieved. The synthesis of both compounds utilises a common intermediate alkyne. By comparison of spectra the structure of the natural product has been confirmed.

Full text of DOI:10.1016/S0040-4020(03)00115-7

Tetrahedron 59 (2003) 1719–1729
Total synthesis of cytotoxic sponge alkaloids hachijodines F and G
*
William R. F. Goundry, Jack E. Baldwin and Victor Lee
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 25 October 2002; revised 17 December 2002; accepted 16 January 2003
Abstract—The total synthesis of two cytotoxic sponge alkaloids hachijodines F and G has been achieved. The synthesis of both compounds
utilises a common intermediate alkyne. By comparison of spectra the structure of the natural product has been confirmed. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
alkaloids from two marine sponges of the genera
Xestospongia and Amphimedon. The sponges were collected
off Hachijo-jima, Japan and the alkaloids were subsequently
named hachijodines A–G. Their structures were determined
on the basis of NMR spectroscopy and mass spectrometry
measurements. Hachijodines F (1) and G (2) (Fig. 1) share
the same acetylene moiety and were both isolated from
the sponge Amphimedon (0.0058 and 0.017% yield, wet
weight, respectively). They exhibit moderate toxicity
against P388 murine leukaemia cells with IC50 values
of 1.0–2.3 mg/ml. We have previously communicated the
synthesis of these two compounds.5 Herein we disclose the
full details of our investigation. Retrosynthetic analysis
shows that the alkaloids can be synthesised via a common
alkyne intermediate 3.
Marine sponges (Phylum Porifera) are an extremely rich
source of novel secondary metabolites, many of which
display potent biological activities. One major category of
such compounds is the 3-alkylpyridine alkaloids.1 – 3
Recently Fusetani4 et al. isolated seven 3-alkylpyridine
2. Results and discussion
2.1. Synthesis of 5-(pyridin-3-yl)-hex-1-yne (3)
The synthesis commenced with 5-bromopent-1-ene 4 being
subjected to SN2 displacement by the anion derived from
3-picoline6 to give the 5-(pyridin-3-yl)-hex-1-ene 57
(Scheme 1). Deprotonation of 3-picoline was affected by
Figure 1. Hachijodines F (1) and G (2). Common intermediate 3.
t
Scheme 1. Reagents and conditions: (i) LDA, DMPU, 3-picoline, THF, 70%; (ii) OsO4, NaIO4, BuOH, H2O, 73%; (iii) K2CO3, MeOH, dimethyldiazo-2-
oxopropylphosphonate 7, 79%.
Keywords: marine sponge alkaloid; Sonogashira coupling.
*
Corresponding author. Tel.: þ44-1865-275693; fax: þ44-1865-275632; e-mail: victor.lee@chem.ox.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00115-7

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W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
Table 1. Range of conditions for Lemieux–Johnson oxidation
Table 2. Conditions for coupling of 3 and 11, showing the amount of
starting material recovered
Co-solvent
NaIO4 (equiv.)
Yield of aldehyde 6 (%)
Iodide
DMPU
nBuLi
Alkyne (%)
Iodide (%)
12 (%)
Et2O
Et2O
THF
tBuOH
tBuOH
tBuOH
3.0
6.0
3.0
3.0
4.5
6.0
47
57
44
44
73
49
1.5
2.6
2.7
5.0
5.0
6.0
1.1
1.2
1.5
0
12
32
34
27
63
42
48
36
diazo-2-oxopropylphosphonate 7 and aldehyde 6 in anhy-
drous methanol. Dimethyldiazo-2-oxopropylphosphonate 7
was prepared according to the literature from tosyl azide
and the commercially available dimethyl-2-oxopropylphos-
phonate.11
using lithium diisopropylamine (LDA) in THF with 1,3-di-
methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).
The reaction proceeded in 55–70% yield depending on
the scale. The lowering of the yield on a large-scale
preparation of 5 is probably due to a competing elimination
reaction to give 1,5-pentadiene. When the reaction mixture
was left for 60 h (20 h in excess of the literature precedent),
it was observed that isomerisation of the product to give
the thermodynamically stable internal double bond occurred
in about 50% (estimated by 1H NMR spectroscopy).
The amount of lithiated 3-picoline affects the outcome of
the reaction greatly. Too little and the yield is low, but too
much and degradation of product occurs. The reaction time
was limited to less than 18 h to avoid isomerisation and
the quantity of lithiated 3-methyl picoline was optimised.
Reactions with 1.5 equiv. of the anion were found to give
the best results with no isomerisation product as detected
2.2. Synthesis of hachijodine F (1)
The synthesis of hachijodine F 1 commenced with the
selective monobromination12 of octane-1,8-diol 8 to give
8-bromooctan-1-ol 9 in 95% yield (Scheme 2). Experi-
mentally, concentrated hydrobromic acid was added to a
mixture of the diol 8 in toluene and the mixture was heated
under gentle reflux. In the original protocol, the reaction
was conducted as an open system, but we found this
produced low yields presumably due to the loss of HBr. The
yield of this reaction was greatly improved by conducting
the reaction in a closed system at atmospheric pressure.
Less than 1% of dibrominated product was isolated when
the reaction was carried out on a large scale.
1
by H NMR spectroscopy, with a reasonable yield of 5.
Oxidation of compound 5 was first attempted using
ozonolysis,8 however yields of aldehyde 6 were low,
with a range of unidentified degradation products. As an
alternative approach compound 5 was subjected to the
Lemieux–Johnson oxidation.9 Osmium tetroxide was added
to a homogeneous mixture of water and a co-solvent,
containing the alkene 5 and sodium periodate, then stirred at
room temperature for one hour. The reaction was attempted
with several organic solvents, Et2O, THF and tBuOH and a
different amount of sodium periodate equivalents (Table 1).
The best yield of 6 (73%) was obtained using 4.5 equiv. of
Compound 9 was converted to its tert-butyldiphenylsilyl
ether 10 in 89% yield by reaction with imidazole and tert-
butyldiphenylsilyl chloride (TBDPSCl) in THF.13 Iodide 11
was obtained in 95% yield via a Finklestein14 reaction, with
bromide 10 and 5 equiv. of NaI in acetone at reflux.
Iodide 11 was reacted with the acetylide anion generated
n
from 3 (3þ BuLi in THF/DMPU)15 to deliver the coupled
compound 12. We found that following the method of
Liljefors, by adding nBuLi to 3 followed by DMPU and 11
produced low yields of 12. However by adding the DMPU
first followed by nBuLi gave much better results. The
amounts of DMPU, iodide and nBuLi were varied, to
optimise the reaction and the best yield achieved was 48%
(Table 2). In this reaction remaining 3 and 11 were both
recovered and recycled.
t
NaIO4 with BuOH as co-solvent. Care was taken in the
reaction work-up since the aldehyde 6 was quite water-
soluble.
Conversion to the acetylene 3 was effected in 79% yield
by use of the Bestmann procedure.10 The alkyne forming
reaction was performed as a one-pot procedure by adding
anhydrous potassium carbonate to a solution of dimethyl-
Deprotection of 12 was affected by the method of Zhang,
with ammonium fluoride in methanol16 to afford alcohol 13
Scheme 2. Reagents and conditions: (i) HBr(aq), toluene, reflux, 95%; (ii) TBDPSCl, imidazole, THF, 89%; (iii) NaI, acetone, reflux, 95%; (iv) 3, nBuLi,
DMPU, 48%; (v) NH4F, MeOH, 90%; (vi) TsCl, Et3N, CH2Cl2, 67%; (vii) Et4NI, Et3N, MeNHOH·HCl, DMPU, 61%.

W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
1721
Scheme 3. Reagents and conditions: (i) DMPU, E3N, 67%.
in 90% yield. Reaction of alcohol 13 with p-toluenesulpho-
nyl chloride and triethylamine17 gave tosylate 14 in 67%
yield. Next, the introduction of the hydroxylamino group
was investigated. Mukiyama et al.18 examined the best
solvent for the reaction of N-alkylhydroxylamines with
bromides and found hexamethylphosphoric triamide
(HMPA) gave the best yields. However, as HMPA is
carcinogenic and can cause heritable genetic damage, it was
decided to test if DMPU could be used as a HMPA
substitute in this particular reaction.15,19 A trial reaction was
carried out between N-methylhydroxylamine (as the
hydrochloride) and iododecane in DMPU with triethyl-
amine, giving the expected product 1-(N-methylhydroxyl-
amine)-decane 15 in 67% yield (Scheme 3). Thus
compound 14 was subjected to nucleophilic displacement
with N-methylhydroxylamine under the modified
Mukiyama conditions (triethylamine and a catalytic amount
of tetraethylammonium iodide in DMPU) to afford
hachijodine F (1) in 61% yield.
protocol, but it could be conjectured that the diol 16 initially
resides in the diisopropylethylamine (DIEA) phase and
upon monoprotection moves into the dimethyl sulfoxide
(DMF) phase. If the TBDPSCl remains in the DIEA phase
then little diprotection would occur. As the volume of the
solution increases the surface to volume ratio decreases,
hence the diffusion rate decreases and more diprotection
occurs.
The oxidation of 17 to aldehyde 19 was effected in 83%
yield by treating monoprotected diol 16 with 2-iodoxyben-
zoic acid (IBX)21,22 in a mixture of DMSO and THF.
Compound 19 was converted into cis-vinyl iodide 20 by
using the Stork and Zhao olefination protocol.23 Again
DMPU successfully replaced HMPA as reported by Holmes
et al.24 The required Wittig reagent [Ph3PCH2Iþ]2 21 was
prepared in 96% yield by refluxing triphenylphosphine with
diiodomethane in benzene at 1008C.25 The aldehyde 19 was
then reacted with the ylide generated from 21 with sodium
bis(trimethylsilyl)amide to afford the vinyl iodide 20 in 65%
yield. The geometry of the alkene was confirmed as Z by
measuring the vincinal-coupling constant of the vinyl
2.3. Synthesis of hachijodine G (2)
1
The synthesis of hachijodine G (2) began with the selective
monoprotection20 of nonanediol 16. A mild and convenient
biphasic process was employed according to Yu et al.
(Scheme 4). The diol 16 was dissolved in a biphasic mixture
of diisopropylethylamine and N,N-dimethylformamide.
tert-Butyldiphenylsilylchloride was added dropwise into
the mixture at room temperature and stirred vigorously for
28 h. On a small scale yields of 75% of the 9-(tert-
butyldiphenylsilyloxy)-nonan-1-ol 17 were achieved,
however on a large scale the yield of 17 was just 55%
with the di-protected diol 18 isolated in a 20% yield. No
mechanistic rationale or working model was given in the
hydrogens in the H NMR spectrum (J¼7.0 Hz).
The projected Sonogashira26 coupling of compounds 3 and
20 was found to be non-trivial. A range of conditions was
screened (Table 3). Using Sonogashira’s methodology
(experiment 1)27 no desired product was formed and the
spectroscopic data suggested that the iodine had been
replaced. Unfortunately the due to the rapid fragmentation
of this molecule in mass spectrometry measurements, we
were unable to fully determine what this side product was,
solely on the basis of NMR spectroscopy. Using Et3N
instead of Et2NH has been successful in the coupling of
Scheme 4. Reagents and conditions: (i) iPr2Et, DMF, TBDPSCl, 55%; (ii) IBX, DMSO, THF, 83%; (iii) NaN(TMS)2, [PH3PCH2I]þI2, THF, DMPU, 65%;
(iv) Pd(PPh3)4, pyrrolidine, CuI, 3, 87%; (v) NH4F, MeOH, 92%; (vi) TsCl, Et3N, DCM, 81%; (vii) Et4NI, Et3N, MeNHOH·HCl, DMPU, 46%.
Table 3. Reagents and conditions for the Sonogashira coupling
Experiment
Reagents and conditions
Yield
1
2
3
4
Pd(PPh3)4, CuI, Et2NH, rt, 39 h
Side product
No reaction
No reaction
90% 22
Cl2Pd(PPh3)2, CuI, Et3N, DCM, reflux 508C, 22 h
Pd(PPh3)4, CuI, BnEt3NþCl2, 10% NaOH(aq), rt, 22 h
Pd(PPh3)4, CuI, pyrrolidine, rt, 20 h

1722
W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
product. This protocol was adopted for experiment 3 but
again no coupling was observed. Following the work of
Alami,29 when pyrrolidine was used as solvent, 87% of the
desired coupling product 22 was formed. No reaction was
observed until the copper (I) iodide was added showing that
it plays a key role in the mechanism.
Compound 22 was deprotected with ammonium fluoride in
methanol16 to deliver the alcohol 23 in 92% yield. Alcohol
23 was then converted to its tosylate 24 in 81% yield with
p-toluenesulphonyl chloride and triethylamine.17 Com-
pound 24 was treated with N-methylhydroxylamine18 under
our modified conditions, to give hachijodine G 2 in 46% yield.
3. Conclusion
Figure 2. Proton NMR spectrum of authentic hachijodine F.
The 1H NMR data of hachijodines F (1) and G (2) (in CDCl3
with traces of trifluoroacetic acid added) are consistent with
the literature data (Figs. 2–5). The structures of the natural
products have been confirmed, and efficient syntheses of
1 (7%), and 2 (9%) have been developed via the common
intermediate 3.
alkynes and bromoalkenes,7 but when applied in this
reaction (experiment 2) only the starting materials were
recovered. Rossi28 reported the use of phase transfer
conditions to avoid the production of a diethylamine side
Figure 3. Proton NMR spectrum of synthetic hachijodine F.
Figure 4. Proton NMR spectrum of authentic hachijodine G.

W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
1723
Figure 5. Proton NMR spectrum of synthetic hachijodine G.
4. Experimental
maxima (nmax) of the major peaks are reported in
wavenumbers (cm21).
4.1. General experimental
Melting points were measured using a Cambridge Instru-
ments Gallene III hot stage melting point apparatus and are
uncorrected.
Proton magnetic resonance spectra were recorded on a
Varian Gemini 200 (200 MHz), Bru¨ker DPX200
(200 MHz), Bru¨ker DPX400 (400 MHz), and Bru¨ker
AMX500 (500 MHz) spectrometers at ambient tempera-
Thin layer chromatography (TLC) was performed using
Merck aluminium foil backed plates pre-coated with
silica gel 60 F254 (1.05554). Visualisation was affected by
quenching of UV fluorescence (lmax¼254 nm), staining
with 10% w/v ammonium molybdate in 1 M sulphuric acid,
followed by heating. Retention factors (Rf) are reported to
two decimal places.
1
tures. Proton spectra assignments are supported by H–1H
COSY where necessary. Chemical shifts (dH) are reported in
parts per million (ppm) and are referenced to the residual
solvent peak. Coupling constants (J) are recorded to the
nearest 0.5 Hz.
Carbon magnetic resonance spectra were recorded on
Varian Gemini 200 (50.3 MHz), Bru¨ker DPX200
(50.3 MHz), Bru¨ker DPX400 (100.6 MHz), and Bru¨ker
AMX500 (125.8 MHz), spectrometers at ambient tempera-
tures. Chemical shifts (dC) are reported in parts per million
(ppm) and are referenced to the residual solvent peak.
Carbon spectra assignments are supported by DEPT
analysis and 13C–1H correlations where necessary.
Column chromatography was performed using ICN silica
˚
¨
32–63, 60 A. Kugelrohr distillations were performed
using Bu¨chi Glass Oven B-580 distillation apparatus at the
temperature and pressure specified.
Anhydrous diethyl ether, and THF were obtained by
distillation from sodium/benzophenone ketyl under nitro-
gen, anhydrous dichloromethane (DCM) was distilled from
calcium hydride under nitrogen. PE refers to the fraction of
light petroleum ether boiling between 40 and 608C, and was
distilled before use. IPA refers to isopropyl alcohol.
All water used was distilled except where otherwise
indicated. Solvents were evaporated on a Bu¨chi R110
Rotavaporator.
Low resolution mass spectra were recorded using a TRIO-1
GCMS spectrometer, a Micromass Platform (APCI)
Spectrometer, Micromass Autospec spectrometer (CIþ)
and a micromass ZAB spectrometer (CIþ, EI). Only
molecular ions (Mþ), fragments from molecular ions and
other major peaks are reported. High-resolution mass
spectra were recorded on a Micromass Autospec spectro-
meter and are accurate to ^10 ppm.
Diisopropylamine, diisopropylethylamine (DIEA), diethyl-
amine, triethylamine, dimethyl formamide (DMF), dimethyl
sulfoxide, pyrrolidine, 1,3-dimethyl-3,4,5,6.tetrahydro-
2(1H)-pyrimidinone (DMPU), benzene, EtOH, and MeOH
were distilled from calcium hydride under argon or reduced
Microanalyses were carried out by Elemental Microanalysis
Limited, and are quoted to the nearest 0.1% for all elements
except hydrogen which is quoted to the nearest 0.05%.
˚
pressure and stored over 4 A molecular sieves under argon
until used. Toluene and dimethylacetylmethylphosphonate
Infrared spectra were recorded on a Perkin–Elmer Paragon
1000 Fourier Transform spectrometer as a thin film between
NaCl plates, and where necessary as KBr discs. Absorption
˚
were dried over 4 A molecular sieves under argon.
Anhydrous K2CO3 was flame dried and cooled under

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W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
argon before use. 2-Iodobenzoic acid was recrystallised
from acetone/water.
7.14 (1H, dd, J1¼5.0 Hz, J2¼7.5 Hz, H-50), 7.45 (1H, dt,
J1¼8.0 Hz, J2¼2.0 Hz, H-40), 8.30–8.47 (2H, br s, H-20,
H-60), 9.69 (1H, t, J¼1.5 Hz, H-1); dC (50.3 MHz, CDCl3)
21.4 (CH2), 30.4 (CH2), 32.6 (CH2), 43.5 (1C, C-2), 123.3
(1C, C-500), 0135.8 (1C, C-40), 137.1 (1C, C-30), 147.2, 149.7
(2C, C-2 ,6 ), 202.1 (1C, C-1).
4.2. Experimental procedure
4.2.1. Preparation of 5-(pyridin-3-yl)-hex-1-ene (5). To a
stirred solution of diisopropylamine (0.84 ml, 6.00 mmol) in
n
THF (5 ml) at 08C under argon was added BuLi (2.65 ml,
4.2.3. Preparation of dimethyldiazo-2-oxopropylphos-
phonate (7). Sodium hydride (2.64 g, 60% in oil,
66.3 mmol) was washed with THF (anhydrous, 2£15 ml)
under argon. To a cold suspension (0–58C) of NaH in
benzene (100 ml) and THF (20 ml) was added dimethyl
acetylmethylphosphonate (8.60 ml, 62.0 mmol) in anhy-
drous THF (7.5 ml) via cannula. After stirring for 1 h at 08C,
tosylazide (13.0 g, 10.1 ml, 66.0 mmol) was added in
anhydrous THF (7.5 ml) via cannula. The solution was
allowed to warm to room temperature with stirring over
18 h. The mixture was filtered through a celite pad and the
pad was washed with benzene (3£20 ml) and EtOAc
(14£30 ml). Removal of solvent in vacuo afforded the
crude product which was purified by flash chromatography
(100% EtOAc) to yield dimethyldiazo-2-oxopropylphos-
phonate 7 (10.4 g, 87%) as a bright yellow oil; Rf¼0.28
(100% EtOAc); nmax/cm21 (thin film) 3496 (w, br), 3302
(w), 3007 (w), 2960 (m), 2856 (w), 2415 (w), 2344 (w),
2224 (w), 2125 (s), 1660, (s), 1462 (m), 1366 (m), 1272 (s,
br), 1183 (s), 1028 (s, br), 971 (m), 929 (w), 837 (s), 804 (s),
784 (m); m/z Probe CIþ (NH3) 193.0 (Mþ 13%), 183.4
(38%), 173.8 (100%), 149.1 (26%), 128.0 (16%), 111.0
(14%), 57.9 (14%); dH (400 MHz, CDCl3) 2.20 (3H, s, H-1),
3.78 (6H, d, J¼12.0 Hz, OMe); dC (100.6 MHz, CDCl3),
27.0 (1C, C-1), 53.5 (2C, d, J¼5.0 Hz, OMe), 63.4 (1C, d,
J¼222.5 Hz, C-3), 189.8 (1C, d, J¼13.0 Hz, C-2).
2.29 M, 6.00 mmol) in hexanes via a syringe. The resulting
pale yellow solution was maintained at 08C for 30 min, then
treated with DMPU (0.72 ml, 6.00 mmol). The yellow
solution was stirred at 08C for 15 min then treated with
3-methylpyridine (0.58 ml, 6.00 mmol) over 10 min to give
a deep red solution. After 30 min at 08C, the mixture
containing the lithiated 3-methylpyridine was cooled to
2788C and treated with 5-bromo-1-pentene 4 (0.60 ml,
5.00 mmol). The resulting solution was stirred for 17 h,
being allowed to gradually warm to room temperature. The
mixture was quenched with water (20 ml) and NH4Cl(aq)
(sat., 20 ml), then extracted into Et2O (3£30 ml). The
combined organic extracts were washed with brine (sat.,
15 ml) and dried over Na2SO4. Removal of solvent in vacuo
afforded the crude product which was purified by flash
chromatography (20% PE, 80% Et2O) to yield 5-(pyridin-3-
yl)-hex-1-ene 5 (4.69 g, 63%) as a yellow/brown oil;
Rf¼0.35 (20% PE, 80% Et2O); nmax/cm21 (thin film)
3077 (m), 3028 (m), 2995 (m), 2977 (m), 2932 (s), 2858 (s),
1641 (m), 1592 (w), 1575 (m), 1478 (m), 1462 (m), 1438
(m), 1422 (s), 1190 (w), 1110 (w), 1026 (m), 993 (s), 911
(s), 796 (m), 714 (s), 629 (m); m/z Probe APCI 162.16
([MH]þ 100%); HRMS found [MH]þ¼162.1282, C11H15N
requires [MH]þ¼162.1283; dH (200 MHz, CDCl3) 1.40
(2H, qui, J¼7.0 Hz, H-4), 1.60 (2H, qui, J¼7.0 Hz, H-5),
2.04 (2H, q, J1¼7.0 Hz J2¼6.0 Hz, H-3), 2.56 (2H, t,
J¼7.5 Hz, H-6), 4.83–5.04 (2H, m, H-1), 5.60–5.87 (1H,
m, H-2), 7.15 (1H, dd, J1¼5.0 Hz, J2¼8.0 Hz, H-5), 7.45
(1H, dt, J1¼8.0 Hz, J2¼2.0 Hz, H-40), 8.32–8.49 (2H, m,
H-20,60); dC (50.3 MHz, CDCl3) 28.3 (CH2), 30.5 (CH2),
32.8 (CH2), 33.4 (CH2), 114.6 (1C, C-1), 123.2 (1C, C-50),
135.7 (1C, C-400), 0137.7 (1C, C-30), 138.5 (1C, C-2), 147.2,
149.9 (2C, C-2 ,6 ).
4.2.4. Preparation of 5-(pyridin-3-yl)-hex-1-yne (3). To
a stirred solution of the aldehyde 6 (1.07 g, 6.56 mmol)
and dimethyl-1-diazo-2-oxopropylphosphonate 7 (1.52 g,
7.92 mmol) in anhydrous methanol (5 ml), was added
anhydrous K2CO3 (1.88 g, 13.6 mmol). The resulting pale
yellow solution was stirred for 22 h. The mixture was
quenched with water (40 ml) and extracted with Et2O
(4£25 ml). The combined extracts were washed with
NaHCO3(aq) (sat., 10 ml) and brine (sat., 10 ml), then
dried over Na2SO4. Removal of solvent in vacuo afforded
the crude product which was purified by flash chroma-
tography (20% PE, 80% Et2O) to yield 3-hex-5-ynyl-
pyridine 3 (824 mg, 79%) as a pale yellow oil; Rf¼0.36
(20% PE, 80% Et2O); nmax/cm21 (thin film) 3305 (s), 3030
(w), 2941 (s), 2862 (m), 2217 (w), 2117 (w), 1592 (w), 1576
(m), 1479 (m), 1462 (m), 1423 (s), 1328 (w), 1190 (w), 1106
(w), 1026 (m), 912 (m), 795 (m), 733 (s), 714 (s), 644 (m);
m/z Probe APCI 160.08 (MHþ 100%); HRMS found
MHþ¼160.1133, C11H13N requires [MH]þ¼160.1126; dH
(200 MHz, CDCl3) 1.44–1.62 (2H, m, H-4), 1.62–1.81
(2H, m, H-5), 1.94 (1H, t, J¼2.5 Hz, H-1), 2.20 (2H, dt,
J1¼3.0 Hz J2¼7.0 Hz, H-3), 2.60 (2H, t, J¼7.5 Hz, H-6),
7.18 (1H, dd, J1¼7.0 Hz, J2¼5.0 Hz, H-50), 7.43–7.53 (1H,
m, H-40), 8.35–8.50 (2H, m, H-20,60); dC (50.3 MHz,
CDCl3) 18.1 (CH2), 27.7 (CH2), 30.0 (CH2), 32.4 (1C,
C-6), 68.6 (1C, C-1), 84.0 (1C, C-2), 123.2 (1C, C-500), 135.7
(1C, C-40), 137.3 (1C, C-30), 147.3, 149.8 (2C, C-2 ,60).
4.2.2. Preparation of 5-(pyridin-3-yl)-pentanal (6). To a
stirred solution of the alkene 5 (300 mg, 1.86 mmol) in
tBuOH/H2O (8 ml/2.67 ml) was added a catalytic amount of
osmium tetroxide. To the resulting brown solution was
added NaIO4 (3£600 mg, 8.38 mmol) at intervals of 15 min.
The reaction was allowed to stir under argon for 1 h. The
mixture was quenched with water (80 ml), then extracted
with DCM /IPA mixture (9:1, 6£25 ml). The combined
organic extracts were washed with Na2S2O3(aq) (sat., 10 ml)
and brine (sat., 10 ml), then dried over Na2SO4. Removal of
solvent in vacuo afforded the crude product which was
purified by flash chromatography (40% EtOAc, 60% Et2O)
to yield 5-(pyridin-3-yl)-pentanal 6 (220 mg, 73%) as a
yellow oil; Rf¼0.38 (40% EtOAc, 60% Et2O); nmax/cm21
(thin film) 3420 (w), 3029 (w), 2937 (s), 2861 (m), 2724 (w),
1926 (w, br), 1723 (s), 1576 (m), 1479 (m), 1461 (m), 1423
(m), 1391 (w), 1270 (w), 1189 (w), 1127 (w), 1108 (w),
1027 (m); m/z Probe APCI 164.02 ([MH]þ 100%); HRMS
found [MH]þ¼164.1075, C10H13NO requires [MH]þ¼
164.1075; dH (200 MHz, CDCl3) 1.46–1.72 (4H, m, H-4,
H-3), 2.30–2.49 (2H, m, H-2), 2.60 (2H, t, J¼7.5 Hz, H-5),
4.2.5. Preparation of 8-bromooctan-1-ol (9). To 1,9-octane

W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
1725
diol 8 (5.2 g, 35.6 mmol) in toluene (80 ml) was added
concentrated HBr (5 ml, 45 mmol, 48% 9 M aq). The
heterogeneous mixture was heated at reflux for 21 h (with a
rubber balloon fitted to the condenser). The reaction mixture
was diluted with water (50 ml), and extracted with Et2O
(2£40 ml). The combined organics were then washed with
NaOH(aq) (1 M, 30 ml), and brine (sat., 40 ml), dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by flash chromatography (40% PE, 60% Et2O) to
give 8-bromooctan-1-ol 9 as a colourless oil (7.00 g, 95%);
Rf¼0.30 (40% PE, 60% Et2O); nmax/cm21 (thin film) 3339
(br, s), 2930 (s), 2856 (s), 2361 (w), 1654 (w), 1464 (m),
1246 (m), 1057 (m), 878 (w), 724 (w); dH (200 MHz,
CDCl3) 1.21–1.60 (10H, m, H-2, 3, 4, 5, 6), 1.81 (2H, qui,
J¼7.0 Hz, H-7), 3.37 (2H, t, J¼7.0 Hz, H-8), 3.57 (2H, t,
J¼6.5 Hz, H-1); dC (50.3 MHz, CDCl3) 25.7 (CH2), 28.1
(CH2), 28.7 (CH2), 29.2 (CH2), 32.6 (CH2), 32.8 (CH2), 34.0
(1C, C-8), 62.7 (1C, C-1).
495.2 ([MH]þ, 47%), 368.4 ([MH2I]þ, 100%), 328.3 (25%);
HRMS found [MH]þ¼495.1591, C24H35OSiI requires
[MH]þ¼495.1580; dH (200 MHz, CDCl3) 1.09 (9H, s,
C(CH3)3), 1.22–1.50 (8H, m, H-3, 4, 5, 6), 1.50–1.68 (2H,
m, H-2), 1.82 (2H, qui, J¼7.0 Hz, H-7), 3.20 (2H, t, J¼
7.0 Hz, H-8), 3.67 (2H, t, J¼6.5 Hz, H-1), 7.32–7.48 (6H,
m, o, p-Ph), 7.65–7.74 (4H, m, m-Ph); dC (50.3 MHz,
CDCl3) 7.4 (1C, C-8), 19.3 (1C, C(CH3)3), 25.7 (CH2), 26.9
(3C, C(CH3)3), 28.5 (CH2), 29.2 (CH2), 30.5 (CH2), 32.5
(CH2), 33.6 (CH2), 64.0 (1C, C-1), 127.6 (4C, o-Ph), 129.5
(2C, p-Ph), 134.2 (2C, i-Ph), 135.6 (4C, m-Ph).
4.2.8. Preparation of 14-(pyridin-3-yl)-1-tert-butyldi-
phenylsilyloxy-tetradec-9-yne (12). To a stirred solution
of 5-(pyridin-3-yl)-hex-1-yne 3 (78.3 mg, 0.49 mmol) in
THF (1 ml) was added DMPU (300 ml, 314 mg, 2.45 mmol)
and the solution was cooled to 2788C. After 10 min to this
was added nBuLi in hexanes (250 ml, 0.58 mmol, 2.3023 M)
with a colour change from pale yellow to orange. After
30 min 8-iodo-1-(tert-butyldiphenylsilyloxy)-octane 11
(635 mg, 1.29 mmol) was added via cannula in THF
(2£1 ml). The reaction mixture was left stirring for 17.5 h
and warmed to room temperature. The reaction mixture was
diluted with water (10 ml) and extracted with PE (3£10 ml).
The organics were washed with brine (sat., 10 ml), then
dried over Na2SO4 and filtered. Removal of solvent in vacuo
afforded the crude product which was purified by flash
chromatography (60% PE, 40% Et2O) to yield 14-(pyridin-
3-yl)-1-tert-butyldiphenylsilyloxy-tetradec-9-yne 12 as a
colourless oil (124 mg, 48%); Rf¼0.25 (60% PE, 40%
Et2O); nmax/cm21 (thin film) 3071 (w), 3050 (w), 2998 (w),
2931 (s), 2857 (s), 1590 (w), 1576 (w), 1473 (m), 1463 (m),
1428 (s), 1390 (w), 1361 (w), 1332 (w), 1189 (w), 1112 (s),
1026 (w), 1008 (w), 940 (w), 824 (m), 793 (w), 741 (m), 703
(s), 688 (m); Microanalysis found C 80.0%, H 9.50%,
C35H47NOSi requires C 79.9%, H 9.00%; m/z Probe
electrospray 548.18 (15%, [MþNa]þ) 526.23 (100%,
[MþH]þ); HRMS found [MH]þ¼526.3497, C35H47NOSi
requires [MH]þ¼526.3505; dH (200 MHz, CDCl3) 1.05
(9H, s, C(CH3)3), 1.20–1.65 (14H, m, H-2, 3, 4, 5, 6, 7, 12),
1.65–1.85 (2H, m, H-13), 2.08–2.26 (4H, m, H-8,11), 2.63
(2H, t, J¼8.0 Hz, H-14), 3.65 (2H, t, J¼6.5 Hz, H-1), 7.16–
7.24 (1H, m, H0-50), 7.31–7.45 (6H, m, o, p-Ph), 7.50 (1H, d,
J¼7.5 Hz,0H-4 ), 7.62–7.72 (4H, m, m-Ph), 8.40–8.47 (2H,
m, H-20,6 ); dC (100.6 MHz, CDCl3) 18.6 (CH2), 18.8
(CH2), 19.3 (1C, C(CH3)3), 25.8 (CH2), 26.9 (3C, C(CH3)3),
28.5 (CH2), 28.9 (CH2), 29.2 (CH2), 29.3 (CH2), 30.2 (CH2),
32.5 (CH2), 32.6 (CH2), 64.0 (1C, C-1), 79.6, 80.8 (2C, C-9,
10), 123.3 (1C, C-50), 127.6 (4C, o-Ph), 129.5 (2C, p-Ph),
134.2 (2C, i-Ph), 135.6 (4C, m-Ph), 135.8 (1C, C-4000), 137.6
(1C, C-30), 147.3 (1C, C-60), 150.0 (1C, C-2 ). Also
recovered were 8-iodo-1-(tert-butyldiphenylsilyloxy)-
octane (171.2 mg, 27%) and 5-(pyridin-3-yl)-hex-1-yne
(18.3 mg, 12%).
4.2.6. Preparation of 8-bromo-1-(tert-butyldiphenylsilyl-
oxy)-octane (10). To 8-bromooctan-1-ol
9 (6.84 g,
32.7 mmol) in THF (70 ml) was added imidazole (6.65 g,
97.7 mmol) and tert-butyldiphenylsilyl chloride (10.3 g,
10.7 ml, 39 mmol). The solution was stirred at room
temperature for 3.5 h. The reaction mixture was diluted
with NH4Cl(aq) (sat., 30 ml), and extracted with a 50% PE
50% Et2O mixture (3£60 ml). The combined extracts were
washed with brine (sat., 40 ml), dried over MgSO4, and
concentrated in vacuo. The crude material was purified by
flash chromatography (100% PE) to give 1-bromo-8-(tert-
butyldiphenylsilyloxy)-octane 10 as a colourless oil (13.0 g,
89%); Rf¼0.20 (100% PE); nmax/cm21 (thin film) 3071 (s),
3850 (m), 2999 (m), 2931 (s), 2857 (s), 2739 (w), 1959 (w),
1890 (w), 1825 (w), 1655 (w), 1590 (m), 1472 (s), 1428 (s),
1390 (s), 1361 (m), 1250 (m), 1226 (w), 1188 (w), 1111 (s),
1008 (m), 998 (m), 939 (w), 824 (s), 740 (s), 703 (s), 688 (s),
614 (s); m/z Probe CIþ (NH3) 464.2, 466.2 (15%, [MNH4]þ,
Br79, Br81), 447.4, 449.4 (100%, MHþ, Br79, Br81); HRMS
found [MH]þ¼447.1704, C24H35OSiBr requires [MH]þ¼
447.1719; dH (200 MHz, CDCl3) 1.09 (9H, s, C(CH3)3),
1.22–1.50 (8H, m, H-3, 4, 5, 6), 1.50–1.69 (2H, m, H-2),
1.88 (2H, qui, J¼8.0 Hz, H-7), 3.43 (2H, t, J¼7.0 Hz, H-8),
3.70 (2H, t, J¼6.5 Hz, H-1), 7.35–7.48 (6H, m, o, p-Ph),
7.67–7.77 (4H, m, m-Ph); dC (50.3 MHz, CDCl3) 19.3 (1C,
C(CH3)3), 25.7 (CH2), 26.9 (3C, C(CH3)3), 28.2 (CH2), 28.8
(CH2), 29.2 (CH2), 32.6 (CH2), 32.9 (CH2), 34.1 (1C, C-8),
64.0 (1C, C-1), 127.6 (4C, o-Ph), 129.6 (2C, p-Ph), 134.2
(2C, i-Ph), 135.6 (4C, m-Ph).
4.2.7. Preparation of 8-iodo-1-(tert-butyldiphenylsilyl-
oxy)-octane (11). To 1-bromo-8-tert-butyldiphenylsilyl-
oxy-octane 10 (2.02 g, 4.52 mmol) in acetone (dry, 15 ml)
was added NaI (3.27 g, 21.8 mmol) and the solution was
refluxed for 20 min. The reaction mixture was diluted with
Et2O and then filtered to give the crude product. The crude
product was purified by flash chromatography (90% PE,
10% Et2O), to give 1-iodo-8-(tert-butyldiphenylsilyloxy)-
octane 11 as a colourless oil (2.11 g, 95%); Rf¼0.8 (90%
PE, 10% Et2O); nmax/cm21 (thin film) 3071 (m), 2999 (m),
2930 (s), 2856 (s), 2739 (w), 1958 (w), 1888 (w), 1823 (w),
1658 (w), 1590 (w), 1472 (m), 1428 (s), 1390 (m), 1361 (m),
1260 (w), 1193 (m), 1111 (s), 1007 (m), 824 (s), 740 (s), 702
(s), 614 (s); m/z Probe CIþ (NH3) 512.3 ([MNH4]þ, 5%),
4.2.9. Preparation of 14-(pyridin-3-yl)-tetradec-9-yne-1-
ol (13). To a stirred solution of 14-(pyridin-3-yl)-1-tert-
butyldiphenylsilyloxy-tetradec-9-yne 12 (477 mg, 0.9 mmol)
in methanol (5 ml) was added ammonium fluoride (635 mg,
17 mmol). The mixture was kept at 708C for 3 h under
argon. The reaction was quenched with NaHCO3(aq) (sat.,
40 ml) and water (40 ml) and extracted with EtOAc
(3£50 ml). The organics were washed with brine (sat.,

1726
W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
40 ml), then dried over Na2SO4. Removal of solvent in
vacuo afforded the crude product which was purified by
flash chromatography (Gradient eluted, 50% PE, 50%
EtOAc to 95% EtOAc, 5% MeOH) to afford 14-(pyridin-
3-yl)-tetradec-9-yne-1-ol 13 (234 mg, 90%) as a colourless
oil; Rf¼0.20 (50% PE, 50% EtOAc); nmax/cm21 (thin film)
3326 (br, m), 3031 (w), 2930 (s), 2857 (s), 2360 (w), 1672
(w), 1594 (w), 1577 (m), 1479 (m), 1462 (m), 1424 (s), 1368
(w), 1332 (m), 1190 (w), 1058 (s), 1028 (s), 795 (m), 714
(s), 637 (m); m/z Probe CIþ (NH3) 289.40 (33%), 288.21
(100%, MHþ); HRMS found [MH]þ¼288.2325, C19H29NO
requires [MH]þ¼288.2327; dH (200 MHz, CDCl3) 1.20–
1.64 (14H, m, 2, 3, 4, 5, 6, 7, 12), 1.74 (2H, qui, J¼7.0 Hz,
H-13), 2.08–2.28 (4H, m, H-8, 11), 2.63 (2H, t, J¼7.5 Hz,
H-14), 3.64 (2H, t, J¼6.5 Hz, H-1), 7.21 (1H, dd, J1¼
8.0 Hz, J2¼5.0 Hz, H-50), 7.51 (1H, dt, J1¼8.0 Hz, J2¼
2.0 Hz, H-40), 8.36–8.55 (2H, m, H-20,60); dC (125.7 MHz,
CDCl3) 19.0, 19.1 (2C, C-8,13), 26.1 (CH2), 28.9 (CH2),
29.2 (CH2), 29.5 (2C, CH2), 29.7 (CH2), 30.6 (CH2), 33.0,
33.2 (2C, C-2,14), 63.3 (1C, C-1), 80.0, 81.1 (2C, C-9, 10),
123.8 (1C, C-50), 136.3 (1C, C-40), 138.1 (1C, C-30), 147.6
(1C, C-60), 150.2 (1C, C-20).
brine (sat., 15 ml), then dried over Na2SO4. Removal of
solvent in vacuo afforded the crude product which was
purified by flash chromatography (50% PE, 50% EtOAc) to
yield 1-(N-methylhydoxylamine)-decane 15 (47 mg, 83%)
as a white powder, mp 57–588C; Rf¼0.38 (50% PE, 50%
EtOAc); nmax/cm21 (thin film) 3192 (s, br), 3010 (s), 2925
(s), 2854 (s), 1466 (s), 1378 (m), 1216 (s), 1143 (w), 1040
(w), 958 (w), 758 (s), 668 (s); m/z Probe APCI 188.13
(100%, MHþ), 172.1 (89%), 170.1 (24%); HRMS found
MHþ¼188.2009, C11H26NO requires MHþ¼188.2014;
microanalysis found H¼13.40, C¼70.2, N¼7.3, C11H25NO
requires H¼13.45, C¼70.5, N¼7.5; dH (200 MHz, CDCl3)
0.94 (3H, t, J¼6.5 Hz, H-1), 1.27–1.48 (14H, m, H-2, 3, 4,
5, 6, 7, 8), 1.51–1.70 (2H, m, H-9), 2.56–2.70 (5H, m,
H-10, N(CH3)), 4.98 (1H, br, s, OH); dC (50.3 MHz, CDCl3)
14.9, 24.2, 28.8, 28.8, 30.9, 31.2, 33.5 (9CH2), 49.4 (1C,
C–NCH3), 63.9 (1C, C-1).
4.2.12. Preparation of hachijodine F (1). To a mixture of
N-methylhydroxylamine hydrochloride (67 mg, 0.8 mmol)
and tetraethylammonium iodide (8.7 mg, 0.03 mmol) in
DMPU (1 ml) was added a mixture of 14-(pyridin-3-yl)-1-
tosyl-tetradec-9-yne 14 (70.6 mg, 0.21 mmol) and Et3N
(225 ml, 1.61 mmol) in DMPU (1.5 ml) under an argon
atmosphere. The mixture was left stirring for 41 h. The
reaction mixture was diluted with water (20 ml), then
extracted with Et2O (3£20 ml). The combined organic
extracts were washed with water (2£20 ml), brine (sat.,
15 ml), then dried over Na2SO4. Removal of solvent in
vacuo afforded the crude product which was purified by
flash chromatography (gradient eluted, 100% Et2O to 100%
EtOAc) to yield hachijodine F (1) (30.9 mg, 61%) as a
colourless oil; Rf¼0.26 (100% Et2O); nmax/cm21 (thin film)
3228 (m, br), 2931 (s), 2856 (s), 1739 (m), 1576 (m), 1527
(m), 1479 (w), 1462 (m), 1423 (m), 1371 (w), 1332 (w),
1318 (w), 1253 (w), 1190 (w), 1132 (w), 1106 (w), 1046
(w), 1027 (m), 796 (m), 755 (w), 715 (s); m/z Probe APCI
3.17.2 (100%, [MH]þ), 301.2 (95%); HRMS found
MHþ¼317.2595, C22H35N2O requires MHþ¼317.2593;
dH (200 MHz, CDCl3) 1.20–1.62 (14H, m, H-2, 3, 4, 5, 6,
7, 12), 1.69 (2H, qui, J¼7.5 Hz, H-13), 2.05–2.24 (4H, m,
H-8, 11), 2.52–2.68 (7H, m, H-1,14, NCH3), 7.19 (1H, dd,
J1¼8.0 Hz, J2¼5.0 Hz, H-50), 7.49 (1H, dt, J1¼8.0 Hz, J2¼
2.0 Hz, H-4), 8.39–8.48 (2H, m, H-20,60); dC (125.7 MHz,
CDCl3) 18.5, 18.7 (2C, CH2), 27.2 (CH2), 27.3 (CH2), 28.5
(CH2), 28.8 (CH2), 29.1 (2C, CH2), 29.5 (CH2), 30.2, 32.6
(2C, CH2), 48.6 (1C, NCH3), 62.3 (1C, C-1), 79.6 (1C,
C-10), 80.7 (1C, C-9), 123.3 (1C,0 C-50), 135.9 (1C, C-40),
137.6 (1C, C-30), 147.2 (1C, C-6 ), 149.8 (1C, C-20); dH
(400 MHz, CDCl3, doped with TFA) 1.20–1.40 (10H, m,
CH2), 1.45 (2H, qui, J¼7.5 Hz, H-7), 1.56 (2H, qui, J¼
7.5 Hz, H-12), 1.64–1.86 (4H, m, H-2, 13), 2.13 (2H, tt,
J1¼7.0 Hz, J2¼2.5 Hz, H-8), 2.23 (2H, tt, J1¼7.0 Hz, J2¼
2.5 Hz, H-11), 2.86 (2H, t, J¼8.0 Hz, H-14), 3.05 (3H, s,
N(CH3)), 3.21 (2H, t, J¼8.5 Hz, H-1), 7.80 (1H, dd, J1¼
8.0 Hz, J2¼6.0 Hz, H-50), 8.19 (1H, d, J¼8.0 Hz, H-40),
8.73–8.76 (2H, m, H-20,60).
4.2.10. Preparation of 14-(pyridin-3-yl)-1-tosyl-tetradec-
9-yne (14). To a solution of 14-(pyridin-3-yl)-tetradec-9-
yne-1-ol 13 (90.0 mg, 0.31 mmol) in anhydrous DCM
(2 ml) under an argon atmosphere was added Et3N (87 ml,
0.62 mmol), and tosyl chloride (90 mg, 0.47 mmol). The
reaction was stirred at 08C for 19 h under argon. The
reaction was diluted with Na2CO3(aq) (sat., 20 ml) and
extracted with DCM (3£20 ml). The organics were washed
with brine (sat., 20 ml), then dried over Na2SO4. Removal of
solvent in vacuo afforded the crude product which was
purified by flash chromatography (100% Et2O) to yield
14-(pyridin-3-yl)-1-tosyl-tetradec-9-yne 14 (90.6 mg, 67%)
as a pale orange oil; Rf¼0.27 (100% Et2O); nmax/cm21 (thin
film) 3022 (m), 2919 (s), 2849 (s), 1593 (m), 1570 (m), 1459
(m), 1430 (m), 1360 (s), 1180 (s), 1105 (m), 1028 (w), 942
(m), 814 (m), 721 (m), 669 (s); m/z Probe APCI
442.20 (100%, MHþ); HRMS found [MH]þ¼442.2428,
C26H35NO3S requires [MH]þ¼442.2416; dH (200 MHz,
CDCl3) 1.13–1.85 (16H, m, H-2, 3, 4, 5, 6, 7, 12, 13), 2.03–
2.27 (4H, m, H-8, 11), 2.45 (3H, s, C(CH3)), 2.63 (2H, t,
J¼7.5 Hz, H-14), 4.01 (2H,0t, J¼6.5 Hz, H-1), 7.21 (1H, dd,
J1¼8.0 Hz, J2¼5.0 Hz, H-5 ), 7.44 (2H, d, J¼8.5 Hz, m-Ph),
7.50 (1H, dt, J1¼8.5 Hz, J2¼2.0 Hz, H-40), 7.86 (2H,
d, J¼8.0 Hz, o-Ph), 8.40–8.50 (2H, m, H-20,60); dC
(125.7 MHz, CDCl3) 18.4, 18.6 (2C), 21.5 (1C, C(CH3)),
25.2 (CH2), 28.3 (CH2), 28.6 (CH2), 28.7 (2C, CH2), 28.8
(CH2), 28.9 (CH2), 30.0, 32.4 (2C, C-2, 14), 70.5 (1C, C-1),
79.5, 80.5 (2C, C-9, 10), 123.2 (1C, C-50), 127.8 (2C, o-Ph),
129.7 (2C, m-Ph), 133.1 (1C, p-Ph), 135.7 (1C, C-40), 137.5
(1C0, C-30), 144.5 (1C, i-Ph), 147.2 (1C, C-60), 149.8 (1C,
C-2 ).
4.2.11. Preparation of 1-(N-methylhydroxylamine)-
decane (15). To a solution of N-methylhydroxylamine
hydrochloride (34.0 mg, 0.41 mmol) in DMPU (1.5 ml)
with Et3N (120 ml, 0.86 mmol) under argon was added
1-iododecane (50 ml, 0.377 mmol). The mixture was left
stirring for 48 h. The reaction mixture was diluted with
water, then extracted with Et2O (3£20 ml). The combined
organic extracts were washed with water (2£15 ml), and
4.2.13. Preparation of 9-(tert-butyldiphenylsilyloxy)-
nonan-1-ol (17). A solution of 1,9-nonanediol 16 (1.46 g,
0.91 mmol) in anhydrous DMF (1.5 ml) was charged with
DIEA (1.2 mmol, 2.1 ml) forming a biphasic mixture at
room temperature. TBDPSCl (1.05 mmol, 0.28 ml) was

W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
1727
added dropwise into the biphasic mixture with vigorous
stirring under argon. The resulting solution was stirred for
40 h. The mixture was quenched with water (20 ml) and
extracted with Et2O (3£30 ml). The combined extracts
were washed with HCl(aq) (2 M, 2£15 ml), NaHCO3(aq)
(sat., 20 ml) and brine (sat., 15 ml), then dried over Na2SO4.
Removal of solvent in vacuo afforded the crude product
which was purified by flash chromatography (80% PE, 20%
Et2O) to yield 9-(tert-butyldiphenylsilyloxy)-nonan-1-ol 16
(2.03 g, 55%) as a colourless oil; Rf¼0.29 (40% PE, 60%
Et2O); nmax/cm21 (thin film) 3338 (br, m), 3071 (w), 2931
(s), 2857 (s), 2362 (w), 1590 (w), 1472 (m), 1428 (m), 1390
(w), 1361 (w), 1188 (w), 1112 (s), 938 (w), 824 (m), 740
(m), 702 (s), 614 (s); m/z Probe CIþ (NH3) 416 (MNH4þ
70%), 321 ([MH2PhH]þ 100%), 216 (26%); HRMS found
[MNH4]þ¼416.2980, C25H38O2Si requires [MNH4]þ¼
416.2985; dH (200 MHz, CDCl3) 1.06 (9H, s, C(CH3)3),
1.21–1.40 (10H, m, H-3, 4, 5, 6, 7), 1.45–1.68 (4H, m,
H-2,8), 3.64 (2H, t, J¼6.5 Hz, H-9), 3.66 (2H, t, J¼6.5 Hz,
H-1), 7.32–7.50 (6H, m, o, p-Ph), 7.63–7.73 (4H, m, m-Ph);
dC (50.3 MHz, CDCl3) 19.2 (1C, C(CH3)3), 25.7 (CH2),
26.9 (3C, C(CH3)3), 29.3 (CH2), 29.4 (CH2), 32.6, 32.8 (2C,
C-2, 8), 63.1, 64.0 (1C, C-1, 9), 127.6 (4C, o-Ph), 129.5 (2C,
p-Ph), 134.2 (2C, i-Ph), 135.6 (4C, m-Ph).
m, H-2,7), 2.43 (2H, dt, J1¼7.5 Hz, J2¼2.0 Hz, H-8) 3.68
(2H, t, J¼6.5 Hz, H-1), 7.35–7.50 (6H, m, o, p-Ph), 7.65–
7.75 (4H, m, m-Ph), 9.78 (1H, t, J¼1.5 Hz, H-9); dC
(50.3 MHz, CDCl3) 19.2 (1C, C(CH3)3), 22.1, 25.7, 26.9,
29.1, 29.3, 32.5 (9C, C-2, 3, 4, 5, 6, 7, C(CH3)3), 43.9 (1C,
C-8), 63.9 (1C, C-9), 127.6 (4C, o-Ph), 129.5 (2C, p-Ph),
134.1 (2C, i-Ph), 135.6 (4C, m-Ph), 202.9 (1C, C-9).
4.2.15. Preparation of (iodomethyl)triphenylphospho-
nium iodide (21). A solution of triphenylphosphine (6.01 g,
22.9 mmol) and diiodomethane (2.46 ml, 29.7 mmol) in
benzene (10 ml) under argon and protected from light, was
heated under reflux at 1008C for 20 h. After this time
white crystals had formed. The white crystals were washed
with cold benzene (50 ml) and dried in vacuo to yield
(iodomethyl)triphenylphosphonium iodide 21 (11.7 g, 96%)
as crystals; mp 2288C (lit.¼228–2308C); m/z Probe
Electrospray þve 403.15 ([M]2I 100%); microanalysis
found H¼3.20, C¼43.1, C16H17PI2 requires H¼3.25, C¼
43.0; dH (200 MHz, DMSO-d6) 5.06 (2H, d, J¼8.5 Hz,
CH2I), 7.74–8.00 (15H, m, Ph); dC (50.3 MHz, DMSO-d6)
214.3 (1C, d, J¼50.5 Hz, CH2I), 119.3 (3C, d, J¼90.5 Hz,
i-Ph), 131.1 (6C, d, J¼15.0 Hz, m-Ph), 134.7 (6C, d, J¼
10.0 Hz, o-Ph), 136.1 (3C, s, p-Ph).
In addition 1,9-(tert-butyldiphenylsilyloxy)-nonane 18 was
isolated (1.43 g, 25%) as a colourless oil; Rf¼0.31 (80% PE,
20% toluene); nmax/cm21 (thin film) 3071 (m), 2931 (s),
2857 (s), 2361 (w), 1742 (m), 1590 (m), 1472 (m), 1428 (s),
1390 (m), 1361 (w), 1240 (w), 1188 (w), 1112 (s), 1008 (m)
938 (w), 823 (m), 739 (m), 701 (s), 613 (m); m/z Probe CIþ
(NH3) 654.5 (MNHþ4 100%), 637.5 (MHþ, 16%), 501.3
(16%), 381.3 (20%); HRMS found [MNH4]þ¼654.4167,
C41H56O2Si2 requires [MNH4]þ¼654.4163; dH (200 MHz,
CDCl3) 1.07 (18H, s, C(CH3)3), 1.20–1.40 (10H, m, H-3, 4,
5, 6, 7), 1.49–1.63 (4H, m, H-2,8), 3.66 (4H, t, J¼6.5 Hz,
H-1,9), 7.33–7.48 (12H, m, o, p-Ph), 7.65–7.75 (8H, m,
m-Ph); dC (50.3 MHz, CDCl3) 19.2 (2C, C(CH3)3), 25.7
(3C, C-4,5,6), 26.9 (6C, C(CH3)3), 29.3 (2C, C-3,7), 32.6
(2C, C-2,8), 64.0 (2C, C-1,9), 127.5 (8C, o-Ph), 129.5 (4C,
p-Ph), 134.2 (4C, i-Ph), 135.6 (8C, m-Ph).
4.2.16. Preparation of Z-10-iodo-1-(tert-butyldiphenyl-
silyloxy)-dec-9-ene (20). To a suspension of iodomethyl-
triphenylphosphonium iodide 21 (200 mg, 0.38 mmol) in
THF (3 ml) at 208C was slowly added sodium bis-(tri-
methylsilyl)amide in THF (0.40 ml, 0.943 M). After stirring
for 5 min the solution was cooled to 2788C and DMPU
(0.23 ml, 1.90 mmol) was added. After a further 15 min
aldehyde 19 (100 mg, 0.25 mmol) in THF (1 ml) at 2788C
was added via cannula. This was rinsed in with a further
0.5 ml of THF. The reaction was maintained at 2788C for
1hour then was allowed to warm to room temperature. The
reaction mixture was diluted with cyclohexane (20 ml). The
mixture was filtered through a cellulose pad, and the pad
then washed with cyclohexane (8£0 ml). The combined
organics were washed with NH4Cl(aq) (sat., 20 ml), and
brine (sat., 20 ml), then dried over Na2SO4. Removal of
solvent in vacuo afforded the crude product which was
purified by flash chromatography (10% benzene, 90%
cyclohexane) to yield Z-10-iodo-1-(tert-butyldiphenylsilyl-
oxy)-dec-9-ene 20 (85.6 mg, 65%) as a colourless oil;
Rf¼0.34 (10% benzene, 90% cyclohexane); nmax/cm21
(thin film) 3071 (m), 3046 (m), 2930 (s), 2856 (s), 1610 (w),
1590 (w), 1472 (m), 1428 (s), 1389 (m), 1361 (w), 1283 (m),
1189 (w), 1112 (s), 1008 (w), 998 (w), 939 (w), 824 (m), 740
(m), 702 (s), 614 (s); m/z Probe CIþ (NH3) 521.0 (100%,
[MH]þ), 480.0 (35%), 395.2 (95%), 354.1 (27%), 337.1
(21%), 256.1 (16%), 216.0 (15%), 199.0 (20%); HRMS
found [MH]þ¼521.1727, C26H36OSiI requires [MH]þ¼
521.1737; dH (400 MHz, C6D6) 1.08–1.18 (6H, m), 1.20
(9H, s, C(CH3)3), 1.26–1.37 (4H, m,), 1.56 (2H, qui, J¼
7.0 Hz, H-2), 2.02 (2H, q, J¼7.0 Hz, H-8), 3.68 (2H, t,
J¼6.5 Hz, H-1), 5.74 (1H, q, J¼7.0 Hz, H-9), 5.89 (1H, d,
J¼7.5 Hz, H-10), 7.20–7.29 (6H, m, o, p-Ph), 7.76–7.84
(4H, m, m-Ph); dC (50.3 MHz, C6D6) 19.7 (1C, C(CH3)3),
26.3 (CH2), 27.3 (3C, C(CH3)3), 28.4 (CH2), 29.5 (CH2),
29.8 (CH2), 29.9 (CH2), 33.2 (1C, C-2), 35.2 (1C, C-8), 64.5
(1C, C-1), 82.6 (1C, C-10), 128.2 (4C, o-Ph), 130.1 (2C,
p-Ph), 134.7 (2C, i-Ph), 136.2 (4C, m-Ph), 141.6 (1C, C-9).
4.2.14. Preparation of 1-(tert-butyldiphenylsilanyloxy)-
nonanal (19). To a stirred solution of IBX (1.06 g,
3.79 mmol) in DMSO (8 ml) under argon was added via
cannula alcohol 17 (1.00 g, 2.51 mmol) in THF (1 ml,
followed by THF 3£0.5 ml). The reaction was left stirring
for 2.5 h. The reaction mixture was diluted with water
(60 ml) and filtered through a sintered glass funnel, and the
residue was washed with EtOAc (30 ml). The combined
organics were extracted with EtOAc (3£50 ml), then
washed with brine (sat., 20 ml), dried over Na2SO4 and
filtered. Removal of solvent in vacuo afforded the crude
product which was purified by flash chromatography (50%
PE, 50% DCM) to yield 1-(tert-butyldiphenylsilanyloxy)-
nonanal 19 (0.826 g, 83%) as a pale yellow oil; Rf¼0.31
(80% PE, 20% toluene); nmax/cm21 (thin film) 3072 (m),
2931 (s), 2857 (s), 2714 (w), 1727 (s), 1590 (w), 1472 (m),
1428 (s), 1390 (m), 1361 (w), 1261 (w), 1188 (w), 1112 (s),
1008 (w), 938 (w), 824 (m), 741 (m), 703 (s), 614 (s); m/z
Probe CIþ (NH3) 339.1 ([MH2tBu]þ, 40%), 319.18
(100%), 199.0 (41%); dH (200 MHz, CDCl3) 1.08 (9H, s,
C(CH3)3), 1.23–1.47 (8H, m, H-3, 4, 5, 6), 1.49–1.60 (4H,

1728
W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
4.2.17. Preparation of Z-16-(pyridin-3-yl)-1-tert-butyldi-
phenylsilyloxy-hexadec-11-yne-9-ene (22). To a stirred
solution of iodoalkene 20 (480 mg, 0.92 mmol), Pd(PPh3)4
(20 mg, 0.017 mmol), and CuI (16 mg, 0.013 mmol) in
pyrrolidine (4 ml), under an argon atomosphere, was added
via cannula a solution of alkyne 3 (143 mg, 0.90 mmol) in
pyrrolidine (3 ml). The reaction was left stirring for 22 h.
The reaction mixture was diluted with NH4Cl(aq) (sat.,
40 ml) and extracted with Et2O (3£50 ml). The organics
were washed with brine (sat., 20 ml), then dried over
Na2SO4 and filtered. Removal of solvent in vacuo afforded
the crude product which was purified by flash chroma-
tography (80% PE, 20% EtOAc) to yield Z-16-(pyridin-3-
yl)-1-tert-butyldiphenylsilyloxy-hexadec-11-yne-9-ene 21
(432 mg, 87%) as a colourless oil; Rf¼0.34 (80% PE,
20% EtOAc); nmax/cm21 (thin film) 3071 (m), 3021 (m),
2930 (s), 2857 (s), 2361 (w), 1590 (w), 1575 (w), 1473 (m),
1462 (m), 1428 (s), 1390 (w), 1361 (w), 1329 (w), 1261 (w),
1189 (w), 1112 (s), 1026 (w), 1008 (w), 998 (w), 939 (w),
824 (m), 793 (w), 740 (m), 703 (s), 614 (s); m/z Probe APCI
552.4 (100%, [MH]þ), 474.4 (20%), 314.4 (20%); HRMS
found [MH]þ¼552.3665, C37H49NOSi requires [MH]þ¼
552.3662; dH (400 MHz, CDCl3) 1.06 (9H, s, C(CH3)3),
1.20–1.45 (10H, m, H-3,4,5,6,7), 1.50–1.65 (4H, m,
H-2,14), 1.77 (2H, qui, J¼8.0 Hz, H-15), 2.27 (2H, q,
J¼7.5HZ, H-8), 2.39 (2H, dt, J1¼7.0 Hz, J2¼2.0 Hz, H-13),
2.65 (2H, t, J¼7.5 Hz, H-16), 3.66 (2H, t, J¼6.5 Hz, H-1),
5.43 (1H, dt, J1¼1.5 Hz, J2¼10.5 Hz, H-10), 5.83 (1H, dt,
J1¼7.5 Hz, J2¼10.5 Hz, H-9), 7.17–7.24 (1H, m, H-50),
7.37–7.48 (6H, m, o, p-Ph), 7.50 (1H, d, J¼7.5 Hz, H-40),
7.65–7.73 (4H, m, m-Ph), 8.46 (2H, br s, H-20,60); dC
(100.6 MHz, CDCl3) 19.2 (1C, C(CH3)3), 19.3 (1C, C-13),
25.7 (CH2), 26.8 (3C, C(CH3)3), 28.2 (1C, C-14), 28.9
(CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 30.1, 30.2 (2C,
C-8,15), 32.5, 32.6 (2C, C-16,2), 64.0 (1C, C-1), 77.8 (1C,
C-12), 93.6 (1C, C-11), 109.1 (1C, C-10), 123.3 (1C, C-50),
127.5 (4C, o-Ph), 129.5 (2C, p-Ph), 134.1 (2C, i-Ph), 135.5
(4C, m-Ph), 135.7 (10C, C-40), 137.5 (1C, C-30), 142.9 (1C,
C-9), 147.3 (1C, C-6 ), 149.9 (1C, C-20).
J¼6.5 Hz, H-1), 5.38 (1H, apparent d, J¼10.5 Hz, H-10),
5.77 (1H, dt, J1¼7.5 Hz, J2¼10.5 Hz, H-9), 7.17 (1H, dd,
J1¼5.0 Hz, J2¼7.5 Hz, H-50), 7.47 (1H, dd, J1¼8.0 Hz, J2¼
1.5 Hz, H-4), 8.30–8.43 (2H, m, H-20,60); dC (100.6 MHz,
CDCl3) 19.2 (1C, C-13), 25.8 (CH2), 28.1 (1C, C-14), 28.9
(CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 30.0, 30.1 (2C,
C-8,15), 32.4, 32.8 (2C, C-2,16), 62.5 (1C, C-1), 77.8 (1C,
C-12), 93.6 (1C, C-11), 109.0 (1C, C-10), 123.3 (1C, C-50),
135.9 (1C, C-40), 137.6 (1C, C-30), 142.8 (1C, C-9), 147.0
(1C, C-60), 149.6 (1C, C-20).
4.2.19. Preparation of Z-16-(pyridin-3-yl)-1-tosyl-hexa-
dec-11-yne-9-ene (24). To a solution of alcohol 23
(80.0 mg, 0.26 mmol) in anhydrous DCM (8 ml) under an
argon atmosphere was added Et3N (71 ml, 0.51 mmol), and
tosyl chloride (71 mg, 0.372 mmol). The reaction was
stirred at 08C for 3 days. The reaction was diluted with
Na2CO3(aq) (sat., 30 ml) and extracted with DCM (3£30 ml).
The organics were washed with brine (sat., 30 ml), then
dried over Na2SO4. Removal of solvent in vacuo afforded
the crude product which was purified by flash chroma-
tography (100% Et2O) to yield Z-16-(pyridin-3-yl)-1-tosyl-
hexadec-11-yne-9-ene 24 (98.8 mg, 83%) as a pale orange
oil; Rf¼0.27 (100% Et2O); nmax/cm21 (thin film) 3022 (m),
2930 (s), 2857 (s), 2211 (w), 1922 (w), 1598 (m), 1575 (m),
1462 (m), 1423 (m), 1360 (s), 1189 (s), 1177 (s), 1098 (s),
1026 (w), 956 (m), 816 (m), 734 (m), 664 (m); m/z Probe
APCI 468.28 (100%, MHþ); HRMS found [MH]þ¼
468.2586, C28H37NO3S requires [MH]þ¼468.2572; dH
(400 MHz, CDCl3) 1.15–1.45 (10H, m, H-3,4,5,6,7),
1.51–1.70 (4H, m, H-2,14), 1.76 (2H, q, J¼7.5 Hz, H-15),
2.26 (2H, q, J¼7.0 Hz, H-8), 2.39 (2H, dt, J1¼1.5 Hz,
J2¼7.0 Hz, H-13), 2.45 (3H, s, C(CH3)), 2.65 (2H, t,
J¼7.5 Hz, H-16), 4.02 (2H, t, J¼6.5 Hz, H-1), 5.43 (1H, d,
J¼10.5 Hz, H-10), 5.81 (1H, dt, J1¼7.5 Hz, J2¼10.5 Hz,
H-9), 7.19–7.25 (1H, m, H-50), 7.35 (2H, d, J¼8.0 Hz,
m-Ph), 7.51 (1H, d, J¼8.00Hz, H-4), 7.79 (2H, d, J¼8.0 Hz,
o-Ph), 8.46 (2H, br s, H-2 ,60); dC (50.3 MHz, CDCl3) 19.2
(1C, C-13), 21.5 (1C, C(CH3)), 25.2 (CH2), 28.1 (1C, C-14),
28.7, 28.9, 29.1 (3C, CH2), 29.9, 30.1 (2C, CH2), 32.4 (2C,
CH2), 70.7 (1C, C-1), 77.4 (1C, C-12), 93.8 (1C, C-11),
109.4 (1C, C-10), 123.4 (1C, C-50), 128.0 (1C, o-Ph), 130.0
(1C, m-Ph), 133.4 (1C, p-Ph), 136.0 (1C, C-40), 137.7 (1C,
C-30), 142.9 (1C, C-9), 144.9 (1C, i-Ph), 147.6 (1C, C-60),
150.2 (1C, C-20).
4.2.18. Preparation of Z-16-(pyridin-3-yl)-hexadec-11-
yne-9-ene-1-ol (23). To a stirred solution of Z-16-(pyridin-
3-yl)-1-tert-butyldiphenylsilyloxy-hexadec-11-yne-9-ene 22
(430 mg, 0.78 mmol) in methanol (5 ml) was added
ammonium fluoride (580 mg, 15.6 mmol). The mixture
was kept at 708C for 7 h under argon. The reaction was
quenched with NaHCO3(aq) (sat., 40 ml) and water (40 ml)
and extracted with EtOAc (3£50 ml). The organics were
washed with brine (sat., 30 ml), then dried over Na2SO4.
Removal of solvent in vacuo afforded the crude product
which was purified by flash chromatography (gradient
eluted, 50% PE, 50% EtOAc to 100% EtOAc) to afford
Z-16-(pyridin-3-yl)-hexadec-11-yne-9-ene-1-ol 23 (224 mg,
92%) as a colourless oil; Rf¼0.34 (80% PE, 20% EtOAc);
4.2.20. Preparation of hachijodine G (2). To a mixture of
N-methylhydroxylamine hydrochloride (88 mg, 1.06 mmol)
and tetraethylammonium iodide (10.3 mg, 0.04 mmol) in
DMPU (1 ml) was added a mixture of tosylate 24 (98.8 mg,
0.21 mmol) and Et3N (308 ml, 2.24 mmol) in DMPU
(1.5 ml) under an argon atmosphere. The mixture was left
stirring for 47 h. The reaction mixture was diluted with
water (20 ml), then extracted with Et2O (3£20 ml). The
combined organic extracts were washed with water
(2£20 ml), brine (sat., 20 ml), then dried over Na2SO4.
Removal of solvent in vacuo afforded the crude product
which was purified by flash chromatography (PE–EtOAc–
Et3N, 1:1:1) to yield hachijodine G (2) (33.8 mg, 46%) as a
n
max/cm21 (thin film) 3326 (br, m), 3021 (m), 2928 (s), 2855
(s), 2211 (w), 1578 (m), 1479 (m), 1462 (m), 1424 (m), 1329
(w), 1190 (w), 1058 (m), 1028 (m), 795 (w), 714 (s); m/z
Probe APCI 314.38 (100%, [MH]þ); HRMS found
[MH]þ¼314.2495, C21H33NO requires [MH]þ¼314.2484;
dH (400 MHz, CDCl3) 1.20–1.45 (10H, m, H-3,4,5,6,7),
1.45–1.60 (4H, m, H-2,14), 1.72 (2H, qui, J¼7.5 Hz, H-15),
2.22 (2H, q, J¼7.5 Hz, H-8), 2.38 (2H, dt, J1¼7.0 Hz,
J2¼2.0 Hz, H-13), 2.60 (2H, t, J¼7.5 Hz, H-16), 3.58 (2H, t,
colourless oil; Rf¼0.38; (PE–EtOAc–Et3N, 1:1:1); nmax
/
cm21 (thin film) 3222 (m, br), 3020 (m), 2928 (s), 2855 (s),
2211 (w), 1739 (m), 1576 (m), 1479 (m), 1462 (s), 1424 (s),
1372 (m), 1329 (w), 1241 (w), 1191 (w), 1136 (w), 1105

W. R. F. Goundry et al. / Tetrahedron 59 (2003) 1719–1729
1729
6. Baldwin, J. E.; Spring, D. R.; Atkinson, C. E.; Lee, V.
Tetrahedron 1998, 54, 13655–13680.
(w), 1046 (w), 1027 (m), 957 (w), 795 (m), 714 (s); m/z
Probe APCI 343.3 ([MH]þ 70%), 327.3 (100%), HRMS
found [MH]þ¼343.2751, C22H34N2O requires [MH]þ¼
343.2749; dH (500 MHz, CDCl3) 1.20–1.42 (10H, m, H-3,
4, 5, 6, 7), 1.50–1.65 (4H, m, H-2,14), 1.77 (2H, qui,
J¼7.5 Hz, H-15), 2.26 (2H, q, J¼7.0 Hz, H-8), 2.39 (2H, dt,
J1¼7.0 Hz, J2¼2.0 Hz, H-13), 2.55–2.70 (7H, m, H-1,16,
NCH3), 5.43 (1H, d, J¼10.5 Hz, H-10), 5.82 (1H, dt, J1¼
7.5 Hz, J2¼10.5 Hz, H-9) 7.21 (1H, dd, J1¼7.5 Hz, J2¼
5.0 Hz,0H-50), 7.51 (1H, d, J¼8.0 Hz, H-4), 8.41–8.48 (2H,
m, H-2 ,60); dC (125.7 MHz, CDCl3) 19.8 (1C, CH2), 27.7
(CH2), 27.9 (CH2), 28.7 (CH2), 29.3 (CH2), 29.6 (CH2), 29.8
(CH2), 30.0 (CH2), 30.5 (CH2), 30.6 (CH2), 33.0 (CH2), 49.1
(1C, C–NCH3), 62.8 (1C, C-1), 78.3 (1C, C-12), 94.1 (1C,
C-11), 109.6 (1C0, C-10), 123.8 (1C, C-50), 136.3 (1C, C-40),
138.0 0 (1C, C-3 ), 143.3 (1C, C-9), 147.7, 150.3 (2C,
C-20,6 ); dH (500 MHz, CDCl3, doped with TFA) 1.20–
1.42 (10H, m, CH2), 1.65 (2H, qui, J¼7.0 Hz, H-14), 1.73
(1H, m, H-2), 1.81 (1H, m, H-2), 1.88 (2H, qui, J¼7.5 Hz,
H-15), 2.25 (2H, q, J¼7.0 Hz, H-8), 2.44 (2H, dt, J1¼
7.0 Hz, J2¼2.0 Hz, H-13), 2.91 (2H, t, J¼8.0 Hz, H-16),
3.09 (3H, s, N(CH3), 3.24 (2H, t, J¼8.0 Hz, H-1), 5.43 (1H,
d, J¼11.0 Hz, H-10), 5.83 (1H, dt, J1¼7.5 Hz, J2¼10.5 Hz,
H-9), 7.87 (1H, dd, J1¼8.0 Hz, J2¼5.5 Hz, H-50), 8.26 (1H,
d, J¼8.0 Hz, H-4), 8.73–8.83 (2H, m, H-20,60).
7. Tilley, J. W.; Coffen, D. L.; Schaer, B. H.; Lind, J. J. Org.
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Acknowledgements
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1999, 64, 4537–4538.
We thank Professor Nobuhiro Fusetani for providing us with
the spectra of hachijodines F (1) and G (2).
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