Biomimetic synthesis of (±)-aculeatin D

Article abstract of DOI:10.1016/j.tet.2005.01.021

A practical, efficient and diastereoselective synthesis of the cytotoxic and antiprotozoal compound aculeatin D (1) is described, employing a biomimetic oxidative cyclisation cascade reaction to generate the tricyclic system of the natural product. The synthesis proceeds in ten steps from commercially available 1-tetradecanol.

Full text of DOI:10.1016/j.tet.2005.01.021

Tetrahedron 61 (2005) 2353–2363
Biomimetic synthesis of (G)-aculeatin D
Jack E. Baldwin,a Robert M. Adlington,a Victoria W.-W. Sham,a Rodolfo Marquezb
and Paul G. Bulgerc,
*
aChemistry Research Laboratory, 12 Mansfield Road, Oxford University, Oxford OX1 3TA, UK
bSchool of Life Sciences, University of Dundee, Nethergate, Dundee DD1 4HN, UK
cThe Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 3 November 2004; revised 13 December 2004; accepted 7 January 2005
Available online 28 January 2005
Abstract—A practical, efficient and diastereoselective synthesis of the cytotoxic and antiprotozoal compound aculeatin D (1) is described,
employing a biomimetic oxidative cyclisation cascade reaction to generate the tricyclic system of the natural product. The synthesis proceeds
in ten steps from commercially available 1-tetradecanol.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The plant from which the aculeatin class of compounds has
been isolated, A. aculeatum, has traditionally been used by
the indigenous people of Papau New Guinea as a folk
medicine against fever and malaria.3 Initial studies have
shown the aculeatin compounds to display an impressive
range of biological effects, including antibacterial activity
against Bacillus cereus and Escherichia coli, and potent
antiprotozoal activity against both the NF54 and the
chloroquine-resistant K1 strains of the malarial parasite
Plasmodium falciparum. Most intriguingly, all four com-
pounds were found to display potent cytotoxicity against a
KB carcinoma cell line (ATCC CCL 17). The relative
stereochemistry of the C-2, C-4 and C-6 tetrahydropyran
ring substituents was found to be important in determining
the relative potency of the compounds; aculeatin D 4 was
found to be the most active in the cytotoxicity assay, with an
During the course of research on novel cytotoxic and
antiprotozoal comounds derived from plants, three novel
compounds, named aculeatins A 1, B 2 and C 3 (Fig. 1) were
isolated by Heilmann and co-workers from the petroleum
ether extracts of the rhizomes of Amomum aculeatum.1
Further investigation of these extracts led to the isolation of
a fourth member, named aculeatin D 4, of this small class of
natural products.2 Common to all four metabolites is the
presence of a unique 1,7-dioxa-dispiro[5.1.5.2]-9,12-dien-
11-one tricyclic ring system, which is without precedent in
the literature, while aculeatin C 3 also contains an additional
cyclohexadienone unit. All four compounds were found to
display optical activity, however, the absolute configuration
of these compounds remains unknown.
Figure 1.
Keywords: Biomimetic synthesis; Aculeatin D; Oxidative cyclisation; Hypervalent iodine reagents.
* Corresponding author. Tel.: C1 858 784 2484; fax: C1 858 784 9527; e-mail: paulb@scripps.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.021

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J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
Scheme 1.
IC50 value of 0.38 mg/mL.2 The structural novelty of these
compounds potentially indicates a hitherto unknown mode
of cytotoxicity.
investigate the viability of the tandem oxidation/double
cyclisation reaction, as at that time there were few reports in
the literature of the intra-molecular oxidative cyclisation of
phenolic compounds employing aliphatic hydroxyl groups
as the capturing nucleophile,7,8 and no examples of tandem
oxidative cyclisations to generate a tricyclic ring system.
A key consideration in designing a synthesis of the generic
aculeatin compound structure involves the stereoselective
construction of the tricyclic spiroketal-containing ring
system. Spiroketal units occur as substructures of a wide
variety of biologically active natural products, and there has
been considerable interest in the synthesis and chemical
reactivity of spiroketal ring systems.4,5 A potentially rapid
biomimetic approach to the synthesis of the aculeatin class
of compounds would involve a formal two-electron
oxidation of the phenol ring in precursors 5 or 6 (Scheme
1) being followed by tandem cationic based intramolecular
cyclisations, to generate the core tricyclic ring system in a
single step from an open chain precursor.
To this end, ketone 10 was prepared from 3-iodo-1-propanol
11, which was initially protected as the corresponding TBS
ether 12 (Scheme 3).9 Selective g-alkylation of the dianion
derived from phosphonate 13 with iodide 12, under the
conditions reported for the corresponding diethyl phospho-
nate homologue,10 then gave b-ketophosphonate 14. The
Wadsworth-Emmons reaction of phosphonate 14 with
aldehyde 15 (readily prepared in one step via the protection
of 4-hydroxybenzaldehyde 1611) then gave alkene 17. A
second product was isolated from this reaction, and this was
determined to be the unexpected desilylated phenol 18.
Optimisation of the reaction conditions revealed that the
yield of the desired alkene 17 was maximised at 74%,
together with 14% of the mono-deprotected side product 18,
if the reaction was quenched 4 h after the addition of
aldehyde 15.
The oxidative double cyclisation of the syn-1,3-diol 5 would
be expected to generate aculeatins A 1 and B 2, which
would arise as the result of cyclisation of the C-2 hydroxyl
group (aculeatin numbering) onto the Re and Si diaster-
eotopic faces of the C-6 ketone group in intermediate 7
respectively. By analogy, the oxidative cyclisation of the
anti-1,3-diol 6 would be expected to generate aculeatin D 4,
as well as, potentially, the corresponding C-6 diastereoi-
somer 8. Following a report by Wong of the synthesis of
racemic aculeatins A 1 and B 2 (Scheme 2),6 in which a
phenolic dithioketal 9 was similarly oxidized, we now
disclose the results of our studies on the synthesis and
oxidative cyclisation of the 1,3-anti diol 6, which has
culminated in the first total synthesis of racemic aculeatin D
4.
While the lability of aryl silyl ethers relative to alkyl silyl
ethers under basic conditions has been documented,12 it was
nevertheless suprising to find that the phenolic silyl ether
could be cleaved under the relatively mild conditions of the
reaction. However, after chromatographic separation, both
the di- and mono-protected compounds 17 and 18 could be
carried through to the next stages of the synthesis. Alkenes
17 and 18 were then separately hydrogenated to give
ketones 19 and 20 respectively; deprotection of either
compound 19 or 20 then gave the desired model cyclisation
precursor 10 in moderate yield.
2. Results and discussion
It was decided to employ hypervalent iodine(III) based
reagents to effect the oxidative cyclisation of the model
We initially decided to pursue a simple model system to
Scheme 2. Reagents and conditions: (a) PhI(O2CCF3)2, MeCN/H2O (6:1 v/v), 0 8C, 5 min (44% (G)-1C15% (G)-2).

J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
2355
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, THF, rt, 2 h (91% for 11/12, 90% for 16/15), (b) 13, NaH, THF, 0 8C, 1.5 h then n-BuLi, 0 8C,
20 min then 12, 0 8C, 1 h (71%), (c) NaH, THF, rt, 1.5 h then 15, rt, 4 h (72% 17C14% 18), (d) H2 (1 atm), cat. Pd/C, EtOAc, rt, 16 h (65% for 17/19, 82%
for 18/20), (e) TBAF, THF, 0 8C/rt, 2 h (48% for 19/10, 25% for 20/10).
1
compound 10, as such iodine reagents are a convenient
alternative to the use of toxic heavy-metal based reagents
(e.g. Pb(OAc)4) for activating hydroxylated aromatic rings
towards oxidative nucleophilic substitution reactions.13,14
Treatment of ketone 10 with PhI(OAc)2 in MeCN led to
clean consumption of starting material and formation of a
single new product, albeit in moderate (unoptimised) yield,
which was shown to be the desired tricyclic compound (G)-
21 (Scheme 4). It was subsequently found that the reaction
yield could be increased dramatically if PhI(O2CCF3)2 was
used as the oxidant.
(Fig. 2). However, the H and 13C NMR spectra of the
product (G)-21 clearly indicated that, in deuterated chloro-
form solution, the compound existed in a single confor-
mation, which was proposed to be (G)-21-A on the basis of
the absence of an observable NOE between the axial C-2
proton and the C-15 methylene protons.
Encouraged by the facile oxidative conversion of ketone 10
to tricyclic compound 21, we then focused our efforts on the
synthesis of the diol 6 required for the formation of
aculeatin D 4. Thus, oxidation of commercially available
1-tetradecanol 22 using PCC afforded the corresponding
aldehyde 23 (Scheme 5),15 then selective g-alkylation of the
dianion of methyl acetoacetate gave racemic alcohol (G)-
24 in good overall yield. Following the Evans’ protocol,
treatment of compound (G)-24 with tetramethylammonium
triacetoxyborohydride resulted in a chemo- and diastereo-
selective reduction of the ketone group;16 500 MHz NMR
analysis of the crude product mixture indicated the
formation of a 95:5 mixture of 1,3-anti-:1,3-syn-diol
products, and a single recrystallisation gave the pure 1,3-
anti product (G)-25 in excellent yield.
Due to the presence of the newly formed anomeric centre at
the C-6 position, the product (G)-21 could potentially exist
in two favoured conformations, (G)-21-A and (G)-21-B
Based upon earlier failures to obtain alkene 26 (Scheme 6)
without hydroxyl group protection, diol (G)-25 was
converted into the acetonide derivative 27 in excellent
yield; analysis of the 13C NMR spectrum of acetonide (G)-
27 confirmed the relative stereochemistry of the 1,3-anti-
diol unit, through the application of the Rychnovsky
protocol for the configurational assignment of 1,3-polyol
chains.17 Treatment of acetonide (G)-27 with a-lithio
methyl phosphonoacetate then gave phosphonate (G)-28.
Scheme 4. Reagents and conditions: (a) PhI(OAc)2, MeCN, rt, 1 h (43%),
(b) PhI(O2CCF3)2, MeCN, rt, 2 h (66%).
Gratifyingly, the Wadsworth–Emmons olefination
between phosphonate (G)-28 and commercially available
4-acetoxybenzaldehyde proceeded efficiently at room
temperature to afford alkene (G)-26 in good yield
(Scheme 6), and exclusively as the (E)-isomer (confirmed
by the measured coupling constant between the alkene
Figure 2.
Scheme 5. Reagents and conditions: (a) PCC, DCM, rt, 2 h (85%), (b) methyl acetoacetate, NaH, THF, 0 8C, 10 min then n-BuLi, 0 8C, 10 min then 23, 20 min
(84%), (c) Me4NBH(OAc)3, MeCN/AcOH (1:1 v/v), K25 8C, 2 h then 0 8C, 3 h (89%).

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J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
Scheme 6. Reagents and conditions: (a) 2,2-dimethoxypropane, CSA, 0 8C, 3 h (98%), (b) dimethyl methylphosphonate, n-BuLi, THF, K78 8C, 30 min then
(G)-27, K78 8C, 20 min (65%), (c) NaH, THF, 0 8C/rt, 40 min then 4-acetoxybenzaldehyde, rt, 24 h (82%), (d) H2 (1 atm), cat. Pd/C, EtOAc, rt, 16 h (76%),
(e) K2CO3, MeOH, rt, 45 min (89%), (f) 0.5 M aq. HCl, THF, 0 8C/rt, 1 h (83%).
protons of 16 Hz). The palladium-catalysed hydrogenation
of alkene (G)-26 then afforded ketone (G)-29, and
subsequent basic cleavage of the acetate group then gave
phenol (G)-30. The acetonide protecting group was then
cleanly removed from ketone (G)-30 under aqueous acidic
conditions. The product was formed as a white solid in good
yield, and was shown to be the cyclic compound (G)-6-A,
however, in solution this material was found to equilibrate
to a mixture of cyclic compound (G)-6-A and the open-
chain derivative (G)-6-B; in deuterated acetone a 2:1
equilibrium mixture of compounds (G)-6-A:(G)-6-B was
formed within 3 h at room temperature.
of the stereochemistry at the C-6 position in compound (G)-
8 was the absence of observable NOEs between the C-15
methylene group and the C-2 and C-4 hydrogens (enhance-
ments which are observed in aculeatin D 42), and the
observation of an NOE between one of the C-15 methylene
protons and the axial methylene proton at the C-5 position
(Fig. 3). The formation of ketone 31 is likely to be due to the
presence of adventitious water in the reaction mixture,
which intercepts the putative phenoxenium cation18 before
the intramolecular cyclisation can occur.
The next conditions attempted were those used by Wong in
the conversion of dithiane (G)-9 to a mixture of racemic
aculeatins A (G)-1 and B (G)-2 (cf. Scheme 2);6 however,
the use of aqueous acetonitrile as the solvent for the
oxidation of phenol (G)-6 did not produce any of
the desired aculeatin D (G)-4, but instead merely increased
the yield of ketone (G)-31 (Table 1).
The oxidative cyclisation of ketone (G)-6 was first
attempted under the conditions that were successful for
the conversion of model precursor 10 into tricyclic
compound (G)-21. Treatment of ketone (G)-6 with
PhI(O2CCF3)2 in MeCN at 0 8C led to the rapid consump-
tion of the starting material, and the formation of two new
products in moderate yield (Scheme 7 and Table 1);
spectroscopic analysis revealed that these two compounds
were tricyclic compound (G)-8 and ketone (G)-31.
Extensive NOE analysis indicated that compound (G)-8
was the C-6 epimer of aculeatin D 4; particularly indicative
After extensive variation of the reaction conditions, it was
found that performing the oxidation in acetone resulted in
the formation of an additional third product, isolated in 11%
yield, which was found to be the desired racemic aculeatin
D (G)-4 (Table 1). The NMR and mass spectrometry data
Scheme 7.
Table 1
Conditions
Yield of (G)-4 (%)
Yield of (G)-8 (%)
Yield of (G)-31 (%)
MeCN, 0 8C, 1 h
0
0
11
19
33
29
40
43
15
44
20
27
MeCN/H2O (6:1 v/v), 0 8C, 1 h6
Acetone, rt, 20 min
Acetone/H2O (9:1 v/v), rt, 20 min

J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
2357
(G)-6-B) to a greater extent than would acetonitrile. A two-
electron oxidation of the phenol ring in compound (G)-6-A
would generate cation 32, which is suitably positioned to
undergo a rapid cyclisation to generate product (G)-8. The
oxidation of compound (G)-6-B, however, could be
expected to lead to both products (G)-4 and (G)-8, via
the double cyclisation of the intermediate cations (G)-33
and (G)-34 respectively. Greater solvent polarity would
thus be expected to increase the proportion of (G)-4 formed
in the reaction, as is observed experimentally. An
alternative pathway for the formation of (G)-4 would be
from compound (G)-6-C (Scheme 8), in a manner
analogous to the proposed formation of (G)-8 from (G)-
6-A. However, this pathway appears to be less likely on the
basis of the fact that compound (G)-6-C (the C-6 epimer of
compound (G)-6-A) could not be detected at any point by
NMR analysis of solutions of the cyclisation precursor, even
after three weeks in deuterated acetone at room temperature.
As an aside, it is possible to speculate that metal ion
coordination could favour the open-chain structure (G)-6-B
(required for formation of aculeatin D (G)-4) over the
cyclic compound (G)-6-A, thus increasing the proportion of
(G)-4 formed during the oxidative cyclisation; however,
this was not investigated experimentally.
Figure 3.
of compound (G)-4 were found to be in excellent
agreement with those reported for the natural product,2
and co-chromatography (TLC) of the synthetic material
with an authentic sample of the natural product revealed that
the two compounds were identical.19 The relative stereo-
chemistry of the spiroacetal ring system in (G)-4 was
confirmed by NOE analysis (Fig. 3). After further
optimization, it was found that using an acetone/water
(9:1 v/v) solvent system for the reaction maximised the
yield of aculeatin D (G)-4 (18%), the proportion of the
desired product (G)-4 ((G)-4:(G)-8:(G)-31 1.0:2.4:1.5)
and also the overall yield of the reaction (88%). It is
interesting to note that the ratio of C-6 anomers 4:(G)-8
obtained under these conditions is almost exactly opposite
the ratio of anomers (G)-1:(G)-2 obtained by Wong in
the deprotection/oxidative cyclisation reaction of dithiane
(G)-9.6
3. Conclusions
The first total synthesis of racemic aculeatin D (G)-4 has
therefore been completed in ten steps from 1-tetradecanol
22, thus confirming the structure and relative stereo-
chemistry of this novel natural product. A number of
analogues and derivatives of the natural product are
potentially available through minor modifications of this
flexible synthetic route. The key feature of the synthesis is
the rapid construction of the tricyclic ring system via an
oxidative cyclisation cascade in the last step. It is intriguing
to speculate as to whether a similar cyclisation pathway is
followed in the biosynthesis of these metabolites within the
producing plant A. aculeatum, and as to whether compound
8 is co-produced with the other aculeatins, but has not been
isolated yet.
It is possible to propose a mechanistic rationale for the
dramatic influence of the nature of the solvent on the
product distribution on the oxidative cyclisation (Scheme 8).
The cyclisation precursor was found to exist as an
equilibrium mixture of the cyclic compound (G)-6-A and
the open-chain compound (G)-6-B in solution (vide supra).
In deuterated acetone the equilibrium ratio of (G)-6-A:
(G)-6-B was shown to be 2:1 (by 500 MHz NMR analysis),
whereas in deuterated acetonitrile compound (G)-6-A was
present almost exclusively ((G)-6-A: (G)-6-B O95:5); this
suggests that the partitioning between (G)-6-A and (G)-6-
B is likely to be due to hydrogen-bonding effects, since
acetone would be expected to stabilize intermolecular
hydrogen bonds (and thus favour the open-chain compound
Scheme 8.

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J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
4. Experimental
5000 full width at half height. Positive ion spectra were
calibrated relative to poly(ethyleneglycol), with tetra-
octylammonium bromide as the internal lock mass.
4.1. General procedures
4.2. Experimental details
All reactions were performed in oven-dried (24 h at 110 8C)
glassware under an argon atmosphere. THF and DCM were
distilled before use. Anhydrous DCM was obtained by
refluxing over calcium hydride for 1 h, followed by
distillation under argon. Anhydrous THF was obtained
by refluxing over sodium-benzophenone for 1 h, followed
by distillation under argon. All reagents were used as
received, unless otherwise stated. Solvents were evaporated
under reduced pressure at 40 8C using a Buchi Rotavapor
RE111. Melting points were obtained using a Cambridge
Instruments microscope with a Reichert–Jung heating
mantle, and are uncorrected.
4.2.1. tert-Butyl-(3-iodopropoxy)dimethylsilane 12.9 To a
stirred solution of 1-iodopropan-3-ol 11 (1.00 g, 5.38 mmol)
in THF (15 ml) was added imidazole (1.10 g, 16.12 mmol,
3.0 equiv) and TBSCl (1.05 g, 7.00 mmol, 1.3 equiv) at rt.
After 2 h H2O (20 ml) was added, and the mixture was
diluted with DCM (20 ml). The layers were separated, and
the aqueous layer was extracted with DCM (3!20 ml). The
combined organic layers were washed with brine (1!
50 ml), dried (MgSO4), filtered and concentrated. Purifi-
cation by flash chromatography (Petrol) gave the title
compound (1.47 g, 91%) as a pale yellow oil: Rf 0.15
(Petrol), dH (200 MHz; CDCl3) 0.03 (6H, s, Si(CH3)2), 0.88
(9H, s, SiC(CH3)3), 1.88–2.04 (2H, m, CH2CH2OTBS),
3.25 (2H, t, JZ6.5 Hz, CH2I), 3.63 (2H, t, JZ5.5 Hz,
CH2OTBS).
Flash chromatography was performed using silica gel
(Prolabo Silica Gel 60, 200–400 mesh) as the stationary
phase. TLC was performed on aluminium sheets pre-coated
with silica (Merck Silica Gel 60 F254), which were
visualised by the quenching of UV fluorescence (lmax
254 nm) and/or by staining with 5% w/v phosphomolybdic
acid in EtOH followed by heating. Retention factor (Rf)
values are quoted to G0.05.
4.2.2. Dimethyl [6-(tert-butyldimethylsilanyloxy-2-oxo-
hexyl)phosphonate 14. To a stirred suspension of NaH
(101 mg of a 60% w/w suspension in mineral oil,
2.52 mmol, 1.8 equiv) in THF (30 ml) was added dimethyl
(2-oxopropyl)phosphonate 13 (233 mg, 1.41 mmol) drop-
wise at 0 8C. The mixture was warmed to rt, stirred for 1.5 h,
then re-cooled to 0 8C, before the addition of n-BuLi
(0.62 ml of a 2.5 M solution in hexanes, 1.55 mmol,
1.1 equiv). After 20 min a solution of iodide 12 (506 mg,
1.68 mmol, 1.2 equiv) in THF (2 ml) was added, and the
mixture was stirred at 0 8C for 1 h, before being quenched
by the cautious addition of sat. aq. NH4Cl (10 ml). The
layers were separated, and the aqueous layer was extracted
with EtOAc (3!20 ml). The combined organic layers were
washed with brine (1!40 ml), dried (MgSO4), filtered and
concentrated. Purification by flash chromatography
(EtOAc) gave the title compound (339 mg, 71%) as a pale
yellow oil: Rf 0.2 (EtOAc); nmax (film)/cmK1 2955 (s), 2857
(m), 1716 (s), 1471 (m); dH (400M Hz; CDCl3) K0.09 (6H,
s, Si(CH3)2), 0.76 (9H, s, SiC(CH3)3), 1.37–1.42 (2H, m,
CH2CH2OTBS), 1.48–1.56 (2H, m, CH2CH2C(]O)), 2.52
(2H, t, JZ7.0 Hz, CH2CH2C(]O)), 2.97 (2H, d, JZ
122.5 Hz, CH2P(]O)(OCH3)2), 3.48 (2H, t, JZ6.0 Hz,
CH2OTBS), 3.66 (6H, d, JZ11.0 Hz, P(]O)(OCH3)2);
dC(100.6 MHz; CDCl3) K5.5 (Si(CH3)2), 18.2 (SiC(CH3)3),
19.7 (CH2CH2C(]O)), 25.8 (SiC(CH3)3), 31.8 (CH2CH2-
OTBS), 41.1 (d, 1J13C–31PZ128.0 Hz, CH2P(]O)(OCH3)2),
IR spectra were recorded either as thin films on NaCl plates,
as KBr discs or as solutions in CHCl3 using a Perkin–Elmer
Paragon 1000 Fourier Transform spectrometer. Only
significant absorptions (nmax) are reported, and all absorp-
tions are reported in wavenumbers (cmK1). The following
abbreviations are used to describe absorption intensity: w,
weak; m, medium; s, strong and br, broad.
Proton magnetic resonance spectra (1H NMR) were
recorded at 200, 400 or 500 MHz using Bruker DPX200,
Bruker DQX400, Bruker DPX400, Bruker DRX500 or
Bruker AMX500 spectrometers. Chemical shifts (dH) are
reported in parts per million (ppm), and are referenced to the
residual protonated solvent peak. COSY, NOE or NOESY
experiments were used in selected cases to aid assignment.
The order of citation in parentheses is (1) number of
equivalent nuclei (by integration), (2) multiplicity (sZ
singlet, dZdoublet, tZtriplet, qZquartet, qnZquintet,
mZmultiplet, brZbroad), (3) coupling constant (J) quoted
in Hertz to the nearest 0.5 Hz, and (4) assignment. Carbon
magnetic resonance spectra (13C) were recorded at 100.6 or
125.7 MHz using Bruker DQX400, Bruker DPX400, Bruker
DRX500 or Bruker AMX500 spectrometers. DEPT-135,
HMBC, HMQC or HSQC experiments were used in
selected cases to aid assignment. Chemical shifts (dC) are
quoted in parts per million (ppm) and are referenced to the
appropriate solvent peak. The assignment is quoted in
parentheses.
3
43.7 (d, J13C–31PZ2.0 Hz, CH2CH2C(]O)), 52.8 (d,
2J13C–31PZ3.0 Hz, P(]O)(OCH3)2), 62.6 (CH2OTBS),
2
201.6 (d, J13C–31PZ6.0 Hz, C]O); m/z(ESC) 361
(100%, MNaC), 339 (15, MHC); HRMS: Found 339.1757
(MHC); C14H32O5PSi requires 339.1757.
Low resolution mass spectra (m/z) were recorded on
Micromass Platform ES (ES) or VG Mass Lab Trio-1 (CI
and EI) spectrometers. Only molecular ions and selected
fragments of molecular ions are reported, with intensities
quoted as percentages of the base peak. High resolution
mass spectra were recorded on a VG AutoSpec spectrometer
by chemical ionisation or on a Micromass LCT electrospray
ionisation mass spectrometer operating at a resolution of
4.2.3. 4-(tert-Butyldimethylsilanyloxy)benzaldehyde
15.11 To a stirred solution of 4-hydroxybenzaldehyde 16
(2.00 g, 16.35 mmol) in THF (40 ml) was added imidazole
(2.45 g, 36.03 mmol, 2.2 equiv) and TBSCl (3.70 g,
24.54 mmol, 1.5 equiv) at rt. After 2 h H2O (40 ml) was
added, and the mixture was diluted with DCM (40 ml). The
layers were separated, and the aqueous layer was extracted
with DCM (3!40 ml). The combined organic layers were

J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
2359
washed with brine (1!50 ml), dried (MgSO4), filtered and
concentrated. Purification by flash chromatography (20:1
petrol/EtOAc) gave the title compound (3.48 g, 90%) as a
pale yellow oil: Rf 0.1 (4:1 petrol/EtOAc); dH (200 MHz;
CDCl3) 0.19 (6H, s, Si(CH3)2), 0.92 (9H, s, SiC(CH3)3),
6.87 (2H, d, JZ8.5 Hz, ArH), 7.72 (2H, d, JZ8.5 Hz, ArH),
9.81 (1H, s, CHO).
solution of alkene 17 (2.76 g, 6.15 mmol) in EtOAc (50 ml)
was added 10% Pd/C (ca. 100 mg) at rt. The flask was
evacuated (water aspirator) and pressurized with H2
(balloon) three time, and the mixture was then stirred for
16 h under H2 (balloon). The mixture was then filtered
through a pad of Celitew, washing thoroughly with EtOAc,
and the filtrate was concentrated. Purification by flash
chromatography (9:1 petrol/EtOAc) gave the title com-
pound (1.81 g, 65%) as a colourless oil: Rf 0.65 (22:3 petrol/
EtOAc); nmax (film)/cmK1 2933 (s), 2859 (m), 1714 (s),
1609 (w), 1567 (m); dH (400 MHz; CDCl3) 0.04 (6H, s,
Si(CH3)2), 0.17 (6H, s, Si(CH3)2), 0.89 (9H, s, SiC(CH3)3),
0.97 (9H, s, SiC(CH3)3), 1.43–1.50 (2H, m, CH2CH2-
OTBS), 1.57–1.64 (2H, m, CH2CH2CH2OTBS, 2.37 (2H, t,
JZ7.5 Hz, CH2CH2CH2CH2OTBS), 2.66 (2H, t, JZ
7.5 Hz, ArCH2CH2C(]O)), 2.80 (2H, t, JZ7.5 Hz, ArCH2-
CH2C(]O)), 3.59 (2H, t, JZ6.0 Hz, CH2OTBS), 6.73 (2H,
d, JZ8.0 Hz, ArH), 7.00 (2H, d, JZ8.0 Hz, ArH); dC
(100.6 MHz; CDCl3) K5.3 (Si(CH3)2), K4.5 (Si(CH3)2),
18.1 (SiC(CH3)3), 18.3 (SiC(CH3)3), 20.8 (CH2CH2CH2-
OTBS), 25.7 (SiC(CH3)3), 25.9 (SiC(CH3)3), 29.0
(ArCH2CH2C(]O)), 32.2 (CH2CH2OTBS), 42.7 (CH2-
CH2CH2CH2OTBS), 44.4 (ArCH2CH2C(]O)), 62.7 (CH2-
OTBS), 129.1 (ArC), 129.9 (ArC), 133.7 (ArC), 153.8
(ArC), 209.8 (C]O); m/z(ESC) 468 (100%, MNH4C), 451
(57, MHC); HRMS: Found 451.3058 (MHC); C25H47O3Si2
requires 451.3064.
4.2.4. 7-(tert-Butyldimethylsilanyloxy)-1-[4-(tert-butyl-
dimethylsilanyloxy)phenyl]hept-1-en-3-one 17 and
7-(tert-butyldimethylsilanyloxy)-1-(4-hydroxyphenyl)-
hept-1-en-3-one 18. To a stirred suspension of NaH (0.47 g
of a 60% w/w suspension in mineral oil, 11.80 mmol,
1.4 equiv) in THF (40 ml) was added a solution of
phosphonate 14 (3.74 g, 11.05 mmol, 1.3 equiv) in THF
(5 ml) dropwise at rt. After 1.5 h a solution of aldehyde 15
(2.01 g, 8.50 mmol) in THF (5 ml) was added dropwise.
After a further 4 h H2O (30 ml) was cautiously added, the
layers were separated, and the aqueous layer was extracted
with Et2O (2!50 ml). The combined organic layers were
washed with brine (1!40 ml), dried (MgSO4), filtered and
concentrated. Purification by flash chromatography (25:1
petrol/EtOAc) gave the title compounds 17 (2.76 g, 72%)
followed by 18 (0.39 g, 14%) as colourless oils.
Data for compound 17: Rf 0.65 (22:3 petrol/EtOAc); nmax
(film)/cmK1 2935 (m), 2910 (s), 1663 (s), 1600 (w), 1508
(m); dH (400 MHz; CDCl3) 0.05 (6H, s, Si(CH3)2), 0.22 (6H,
s, Si(CH3)2), 0.90 (9H, s, SiC(CH3)3), 0.98 (9H, s,
SiC(CH3)3), 1.54–1.61 (2H, m, CH2CH2OTBS), 1.68–1.77
(2H, m, CH2CH2C(]O)), 2.67 (2H, t, JZ7.5 Hz, CH2CH2-
C(]O)), 3.64 (2H, t, JZ6.5 Hz, CH2OTBS), 6.60 (1H, d,
JZ16.0 Hz, ArCH]CHC(]O)), 6.83–6.87 (2H, m, ArH),
7.44–7.46 (2H, m, ArH), 7.50 (1H, d, JZ16.0 Hz,
ArCH]CHC(]O)); dC(100.6 MHz; CDCl3) K5.3
(Si(CH3)2), K4.4 (Si(CH3)2), 18.2 (SiC(CH3)3), 18.3
(SiC(CH3)3), 20.9 (CH2CH2C(]O)), 25.6 (SiC(CH3)3),
26.0 (SiC(CH3)3), 32.4 (CH2CH2OTBS), 40.5 (CH2CH2-
C(]O)), 62.9 (CH2OTBS), 120.5 (ArC), 124.4
(ArCH]CHC(]O)), 127.8 (ArC), 129.8 (ArC), 142.2
(ArCH]CHC(]O)), 158.0 (ArC), 200.3 (C]O); m/z
(CIC) 449 (100%, MHC), 391 (52), 317 (69); HRMS:
Found 449.2889 (MHC); C25H45O3Si2 requires 449.2907.
4.2.6. 7-(tert-Butyldimethylsilanyloxy)-1-(4-hydroxy-
phenyl)hept-1-en-3-one 20. To a stirred solution of alkene
18 (150 mg, 0.45 mmol) in EtOAc (10 ml) was added 10%
Pd/C (ca. 10 mg) at rt. The flask was evacuated (water
aspirator) and pressurized with H2 (balloon) three time, and
the mixture was then stirred for 16 h under H2 (balloon).
The mixture was then filtered through a pad of Celitew,
washing thoroughly with EtOAc, and the filtrate was
concentrated. Purification by flash chromatography (9:1
petrol/EtOAc) gave the title compound (124 mg, 82%) as a
colourless oil: Rf 0.35 (7:3 petrol/EtOAc); nmax (film)/cmK1
3386 (br s), 2933 (s), 1705 (s), 1613 (m), 1514 (m); dH
(400 MHz; CDCl3) 0.04 (6H, s, Si(CH3)2), 0.89 (9H, s,
SiC(CH3)3), 1.43–1.50 (2H, m, CH2CH2OTBS), 1.57–1.64
(2H, m, CH2CH2CH2OTBS), 2.36 (2H, t, JZ7.5 Hz,
CH2CH2CH2CH2OTBS), 2.66 (2H, t, 7.5 Hz, ArCH2CH2-
C(]O)), 2.80 (2H, t, JZ7.5 Hz, ArCH2CH2C(]O)), 3.58
(2H, t, JZ6.0 Hz, CH2OTBS), 6.73 (2H, d, JZ8.5 Hz,
ArH), 7.00 (2H, d, JZ8.5 Hz, ArH); dC (100.6 MHz;
CDCl3) K5.3 (Si(CH3)2), 18.3 (SiC(CH3)3), 20.2 (CH2-
CH2CH2OTBS), 26.0 (SiC(CH3)3), 29.0 (ArCH2CH2-
C(]O)), 32.1 (CH2CH2OTBS), 42.8 (CH2CH2CH2-
CH2OTBS), 44.5 (ArCH2CH2C(]O)), 62.9 (CH2OTBS),
115.4 (ArC), 129.5 (ArC), 132.8 (ArC), 154.2 (ArC), 211.2
(C]O); m/z(ESC) 337 (84%, MHC), 224 (100); HRMS:
Found 337.2195 (MHC); C19H33O3Si requires 337.2199.
Data for compound 18: Rf 0.15 (22:3 petrol/EtOAc); nmax
(film)/cmK1 3266 (br s), 2950 (s), 1589 (s), 1512 (m); dH
(400 MHz; CDCl3) 0.06 (6H, s, Si(CH3)2), 0.90 (9H, s,
SiC(CH3)3), 1.56–1.63 (2H, m, CH2CH2OTBS), 1.71–1.79
(2H, m, CH2CH2C(]O)), 2.70 (2H, t, JZ7.5 Hz, CH2CH2-
C(]O)), 3.66 (2H, t, JZ6.5 Hz, CH2OTBS), 6.62 (1H, d,
JZ16.0 Hz, ArCH]CHC(]O)), 6.80–6.84 (2H, m, ArH),
7.42–7.46 (2H, m, ArH), 7.55 (1H, d, JZ16.0 Hz,
ArCH]CHC(]O)); dC(100.6 MHz; CDCl3) K5.3
(Si(CH3)2), 18.4 (SiC(CH3)3), 21.1 (CH2CH2C(]O)),
26.0 (SiC(CH3)3), 32.2 (CH2CH2OTBS), 40.3 (CH2CH2-
C(]O)), 63.0 (CH2OTBS), 116.2 (ArC), 123.2
(ArCH]CHC(]O)), 126.3 (ArC), 130.4 (ArC), 143.9
(ArCH]CHC(]O)), 159.3 (ArC), 202.2 (C]O); m/z
(ESC) 335 (100%, MHC), 203 (20); HRMS: Found
335.2055 (MHC); C19H31O3Si requires 335.2042.
4.2.7. 7-Hydroxy-1-(4-hydroxyphenyl)heptan-3-one 10.
Method A—from ketone 19. To a stirred solution of ketone
19 (1.80 g, 4.0 mmol) in THF (20 ml) was added TBAF
(12.0 ml of a 1 M solution in THF, 12.0 mmol, 3.0 equiv) at
0 8C. The mixture was warmed to rt, stirred for 2 h, then
quenched by the addition of H2O (10 ml). The mixture was
partitioned between EtOAc (20 ml) and H2O (20 ml), the
layers were separated, and the aqueous layer was extracted
4.2.5. 7-(tert-Butyldimethylsilanyloxy)-1-[4-(tert-butyl-
dimethylsilanyloxy)phenyl]heptan-3-one 19. To a stirred

2360
J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
with EtOAc (2!30 ml). The combined organic layers were
dried (MgSO4), filtered and concentrated. Purification by
flash chromatography (7:3 EtOAc/petrol) gave the title
compound (0.43 g, 48%) as a white solid.
(1H, m, H-2equiv), 3.91 (1H, dt, JZ11.5, 3.0 Hz, H-2ax),
6.08–6.13 (2H, m, H-10 and H-12), 6.77 (1H, dd, JZ10.0,
3.0 Hz, H-9), 6.91 (1H, dd, JZ10.0, 3.0 Hz, H-13);
dC(125.7 MHz; CDCl3) 19.9 (C-4), 25.0 (C-3), 33.7 (C-5),
34.5 (C-15), 38.6 (C-14), 61.7 (C-2), 78.6 (C-8), 107.9
(C-6), 126.9 (C-10 and C-12), 152.0 (C-9), 155.3 (C-13),
185.6 (C-11); m/z (CIC) 221 (70%, MHC), 205 (15), 148
(100); HRMS: Found 221.1168 (MHC); C13H17O3 requires
221.1178.
Method B—from ketone 20. To a stirred solution of ketone
20 (150 mg, 0.45 mmol) in THF (30 ml) was added TBAF
(1.34 ml of a 1 M solution in THF, 1.34 mmol, 3.0 equiv) at
0 8C. The reaction mixture was warmed to rt, stirred for 2 h,
then quenched by the addition of H2O (5 ml). The mixture
was partitioned between EtOAc (10 ml) and H2O (10 ml),
the layers were separated, and the aqueous layer was
extracted with EtOAc (3!10 ml). The combined organic
layers were dried (MgSO4), filtered and concentrated.
Purification by flash chromatography (7:3 EtOAc/petrol)
gave the title compound (25 mg, 25%) as a white solid.
4.2.9. 1-Tetradecanal 23.15 To a stirred suspension of PCC
(15.00 g, 70.0 mmol, 1.5 equiv) in DCM (250 ml) was
added 1-tetradecanol 22 (10.00 g, 46.6 mmol) in one portion
at rt. After 2 h the mixture was diluted with Et2O (400 ml),
and filtered through a pad of Florisil, washing the cake
thoroughly with Et2O. The filtrate was concentrated,
dissolved in Et2O (50 ml), and filtered through a pad of
silica, washing thoroughly with Et2O. The filtrate was
concentrated to afford the title compound (8.43 g, 85%) as a
colourless oil, which was used without further purification
in the next step: Rf 0.45 (23:2 petrol/Et2O).
Data for compound 10. Rf 0.25 (7:3 EtOAc/petrol); mp 75–
76 8C; nmax (KBr)/cmK1 3427 (br s), 1699 (m); dH
(400 MHz; CDCl3) 1.52–1.62 (2H, m, CH2CH2CH2OH),
1.63–1.73 (2H, m, CH2CH2OH), 2.43 (2H, t, JZ7.0 Hz,
CH2CH2CH2CH2OH), 2.67–2.72 (2H, m, ArCH2CH2-
C(]O)), 2.82–2.85 (2H, m, ArCH2CH2C(]O)), 3.61
(2H, t, JZ6.5 Hz, CH2OH), 6.75 (2H, d, JZ8.5 Hz, ArH),
7.45 (2H, d, JZ8.5 Hz, ArH); dC(100.6 MHz; CDCl3) 19.6
(CH2CH2CH2OH), 29.7 (ArCH2CH2C(]O)), 32.0 (CH2-
CH2OH), 42.5 (CH2CH2CH2CH2OH), 44.5 (ArCH2CH2-
C(]O)), 62.3 (CH2OH), 115.3 (ArC), 129.4 (ArC), 133.0
(ArC), 154.0 (ArC), 210.5 (C]O); m/z(CIC) 223 (70%,
MHC), 205 (73), 107 (100); HRMS: Found 223.1337
(MHC); C13H19O3 requires 223.1334.
4.2.10. (G)-Methyl 5-hydroxy-3-oxo-octadecanoate (G)-
24. To a stirred suspension of NaH (1.73 g of a 60% w/w
suspension in mineral oil, 43.2 mmol, 1.2 equiv) in THF
(80 ml) was added methyl acetoacetate (3.90 ml,
36.1 mmol) dropwise at 0 8C. After 10 min n-BuLi
(15.10 ml of a 2.5 M solution in hexanes, 37.8 mmol,
1.05 equiv) was added dropwise. After a further 10 min a
solution of aldehyde 23 (8.40 g, 39.6 mmol, 1.1 equiv) in
THF (25 ml) was added dropwise. After 20 min the reaction
was quenched by the cautious addition of 1 M aq. HCl
(80 ml). The mixture was partitioned between EtOAc
(50 ml) and 1 M aq. HCl (50 ml). The layers were separated,
and the aqueous layer was extracted with EtOAc (2!
70 ml). The combined organic layers were washed with
brine (1!50 ml), dried (MgSO4), filtered and concentrated.
Purification by flash chromatography (18:7 petrol/EtOAc)
gave the title compound (9.94 g, 84%) as an off-white
powder: Rf 0.25 (7:3 petrol/EtOAc); mp 51–53 8C; nmax
(KBr)/cmK1 3401 (s), 2917 (m), 1747 (m), 1709 (m); dH
(400 MHz; CDCl3) 0.88 (3H, t, JZ7.0 Hz, CH2CH3), 1.21–
1.54 (24H, m, CH(OH)(CH2)12CH3), 2.65 (1H, dd, JZ17.5,
9.0 Hz, CH(OH)CH(H)C(]O)), 2.74 (1H, dd, JZ17.5,
3.0 Hz, CH(OH)CH(H)C(]O)), 3.50 (2H, s, CH2CO2CH3),
3.75 (3H, s, CO2CH3), 4.04–4.11 (1H, m, CH(OH));
dC(100.6 MHz; CDCl3) 14.1 (CH2CH3), 29.3, 29.4, 29.5,
29.6, 31.9 (all CH(OH)(CH2)12CH3), 36.4 (CH(OH)CH2-
C(]O)), 49.7 (CH2CO2CH3), 52.5 (CO2CH3), 67.5
(CH(OH)), 167.4 (CO2CH3), 203.7 (CH(OH)CH2C(]O));
m/z(CIC) 329 (8%, MHC), 311 (100), 253 (80); HRMS:
Found 329.2701 (MHC); C19H37O4 requires 329.2692.
4.2.8. 1,7-Dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-
one (G)-21. Method A—using PhI(OAc)2. To a stirred
solution of iodobenzene diacetate (218 mg, 0.68 mmol,
1.51 equiv) in MeCN (15 ml) was added a solution of
ketone 10 (100 mg, 0.45 mmol) in MeCN (3 ml) at rt. After
2 h the reaction was quenched by the addition of sat. aq.
NaHCO3 (20 ml). The layers were separated, and the
aqueous layer was extracted with EtOAc (3!20 ml). The
combined organic layers were dried (MgSO4), filtered and
concentrated. Purification by flash chromatography (2:1
petrol/EtOAc) gave the title compound (43 mg, 43%) as a
colourless oil.
Method B—using PhI(O2CCF3)2. To a stirred solution of
[bis(trifluoroacetoxy)iodo]benzene (126 mg, 0.29 mmol,
1.3 equiv) in MeCN (8 ml) was added a solution of ketone
10 (50 mg, 0.225 mmol) in MeCN (1 ml) at rt. After 2 h the
reaction was quenched by the addition of sat. aq. NaHCO3
(10 ml). The layers were separated, and the aqueous layer
was extracted with EtOAc (3!10 ml). The combined
organic layers were dried (MgSO4), filtered and concen-
trated. Purification by flash chromatography (2:1 petrol/
EtOAc) gave the title compound (33 mg, 66%) as a
colourless oil.
4.2.11. (3S,5R)- and (3R,5S)-Methyl 3,5-dihydroxy-
octadecanoate (G)-25. Tetramethylammonium triacetoxy-
borohydride (4.70 g, 17.9 mmol, 5.0 equiv) was added to a
mixture of MeCN (15 ml) and AcOH (15 ml) at rt. After
10 min the solution was cooled to K25 8C, and a solution of
ketone (G)-24 (1.17 g, 3.6 mmol) in MeCN (8 ml) was
added dropwise. The mixture was stirred at K25 8C for 2 h,
then warmed to 0 8C. After a further 3 h the reaction was
quenched by the addition of 0.5 M aq. sodium potassium
tartrate tetrahydrate (50 ml), then the mixture was poured
Data for compound (G)-21. Rf 0.65 (7:3 EtOAc/petrol);
nmax (film)/cmK1 3584 (br s), 2945 (s), 1671 (s), 1632 (w);
dH (500 MHz; CDCl3) 1.53–1.62 (1H, m, H-3equiv), 1.63–
1.70 (1H, m, H-3ax), 1.71–1.89 (4H, m, H-4ax, H-5ax, H-140
and H-150), 1.91–2.03 (2H, m, H-4equiv and H-5equiv), 2.14–
2.18 (1H, m, H-15), 2.34–2.42 (1H, m H-14), 3.65–3.69

J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
2361
into EtOAc (650 ml). The mixture was washed with sat. aq.
Na2CO3 (2!300 ml), brine (1!200 ml), and the organic
layer was dried (MgSO4), filtered and concentrated to afford
a yellow solid. Purification by recrystallisation from (4:1
hexane/Et2O) gave the title compound (1.05 g, 89%) as a
white powder in two crops: Rf 0.35 (1:1 petrol/EtOAc); mp
63–65 8C; nmax (KBr)/cmK1 3381 (br s), 2917 (m), 1724 (s);
dH (400 MHz; CDCl3) 0.88 (3H, t, JZ7.0 Hz, CH2CH3),
1.26–1.52 (24H, m, CH(OH)(CH2)12CH3), 1.54–1.71 (2H,
m, CH(OH)CH2CH(OH)), 2.38 (1H, d, JZ2.5 Hz,
CH(OH)(CH2)12CH3), 2.52–2.55 (2H, m, CH2CO2CH3),
3.43 (1H, d, JZ3.5 Hz, CH(OH)CH2CO2CH3), 3.73 (3H, s,
CO2CH3), 3.92–3.95 (1H, m, CH(OH)(CH2)12CH3), 4.35–
4.40 (1H, m, CH(OH)CH2CO2CH3); dC (100.6 MHz;
CDCl3) 14.1 (CH2CH3), 29.3, 29.4, 29.6, 29.7, 31.9, 37.5
(all CH(OH)(CH2)12CH3), 41.0 (CH(OH)CH2CH(OH)),
dimethoxypropane (15 ml) was added CSA (ca. 40 mg) at
0 8C. After 3 h the mixture was partitioned between EtOAc
(20 ml) and sat. aq. NaHCO3 (20 ml). The layers were
separated, and the aqueous layer was extracted with EtOAc
(2!20 ml). The combined organic layers were dried
(MgSO4), filtered and concentrated. Purification by flash
chromatography (23:2 petrol/EtOAc) gave the title com-
pound (1.00 g, 98%) as a colourless oil: Rf 0.7 (1:1 petrol/
EtOAc); nmax (film)/cmK1 2925 (s), 1746 (s), 1437 (w);
dH (500 MHz; CDCl3) 0.93 (3H, t, JZ6.5 Hz, CH2CH3),
1.34–1.58 (22H, CHCH2(CH2)11CH3), 1.46 (3H, s,
C(CH3)(CH3)), 1.48 (3H, s, C(CH3)(CH3)), 1.65–1.67
(2H, m, CHCH2(CH2)11CH3), 1.68–1.71 (2H, m, CH2-
CHCH2CO2CH3), 2.48 (1H, dd, JZ8.0, 3.0 Hz,
CH(H)CO2CH3), 2.59 (1H, dd, JZ8.0, 4.5 Hz, CH(H)CO2-
CH3), 3.73 (3H, s, CO2CH3), 3.81–3.83 (1H, m,
CH(CH2)12CH3), 4.28–4.33 (1H, m, CHCH2CO2CH3); dC
(125.7 MHz; CDCl3) 14.5 (CH2CH3), 25.1 (C(CH3)(CH3)),
25.7 (C(CH3)(CH3)), 29.8, 30.0, 30.1, 32.3, 36.3 (all
CH(CH2)12CH3), 38.5 (CH2CHCH2CO2CH3), 41.1 (CH2-
CO2CH3), 52.0 (CO2CH3), 63.9 (CHCH2CO2CH3), 66.9
(CH(CH2)12CH3), 100.9 (C(CH3)2), 171.8 (CO2CH3);
m/z(CIC) 371 (20%, MHC), 355 (90), 313 (100); HRMS:
Found 371.3159 (MHC); C22H43O4 requires 371.3161.
41.9
(CH2CO2CH3),
51.8
(CO2CH3),
65.7
(CH(OH)(CH2)12CH3), 69.0 (CH(OH)CH2CO2CH3), 173.3
(CO2CH3); m/z (ESC) 353 (38%, MNaC), 331 (28, MHC),
248 (100); HRMS: Found 353.2656 (MNaC); C19H38NaO4
requires 353.2668.
4.2.12. (4S,6R)- and (4R,6S)-Methyl 4-[4-(2,2-dimethyl-
6-tridecyl-[1,3]dioxan-4-yl)-3-oxo-butyl-1-ene]phenyl
acetate (G)-26. To a stirred solution of phosphonate (G)-
28 (2.00 g, 4.32 mmol, 1.1 equiv) in THF (20 ml) was added
NaH (0.17 g of a 60% w/w suspension in mineral oil,
4.25 mmol, 1.1 equiv) at 0 8C. The mixture was warmed
to rt and stirred for 40 min, before the addition of
4-acetoxybenzaldehyde (0.55 ml, 3.91 mmol). After 24 h
the reaction was quenched by the cautious addition of H2O
(10 ml), and the mixture was partitioned between Et2O
(20 mL) and brine (20 ml). The layers were separated, and
the aqueous layer was extracted with Et2O (2!20 ml). The
combined organic layers were dried (MgSO4), filtered and
concentrated to afford a white solid. Purification by
recrystallisation (22:3 hexane/EtOAc) gave the title com-
pound (1.61 g, 82%) as a white powder in two crops: Rf 0.4
(22:3 heaxane/EtOAc); mp 85–86 8C; nmax (CHCl3)/cmK1
2928 (s), 2855 (m), 1764 (s), 1686 (m), 1602 (w); dH
(500 MHz; CDCl3) 0.93 (3H, t, JZ7.0 Hz, CH2CH3), 1.31–
1.58 (24H, m, CH(CH2)12CH3), 1.38 (3H, s, C(CH3)(CH3)),
1.41 (3H, s, C(CH3)(CH3)), 1.69–1.81 (2H, m, CH2CHCH2-
C(]O)), 2.36 (3H, s, O2CCH3), 2.74 (1H, dd, JZ16.0,
5.0 Hz, CHCH(H)C(]O)), 3.01 (1H, dd, JZ16.0, 7.5 Hz,
CHCH(H)C(]O)), 3.82–3.86 (1H, m, CHCH2C(]O)),
4.42–4.44 (1H, m, CH(CH2)12CH3), 6.77 (1H, d, JZ
16.0 Hz, ArCH]CHC(]O)), 7.18 (2H, d, JZ8.5 Hz,
ArH), 7.59 (1H, d, JZ16.0 Hz, ArCH]CHC(]O)), 7.61
(2H, d, JZ8.5 Hz, ArH); dC (125.7 MHz; CDCl3) 14.5
(CH2CH3), 23.1 (O2CCH3), 25.2 (C(CH3)(CH3)), 25.8
(C(CH3)(CH3)), 29.8, 30.0, 30.1, 32.4, 36.3 (all CH(CH2)12-
CH3), 38.9 (CH2CHCH2C(]O)), 47.5 (CHCH2C(]O)),
63.9 (CH(CH2)12CH3), 67.0 (CHCH2C(]O)), 100.9
(C(CH3)2), 122.6 (ArC), 127.8 (ArCH]CHC(]O)),
129.9 (ArC), 132.7 (ArC), 142.4 (ArCH]CHC(]O)),
152.7 (ArC), 169.2 (O2CCH3), 198.2 (CHCH2C(]O));
m/z(CIC) 443 (100%, [MHKC3H6O]C). Molecular ion
intensities were too weak to record accurate HRMS data.
4.2.14. (4S,6R)- and (4R,6S)-Dimethyl [3-(2,2-dimethyl-
6-tridecyl-[1,3]dioxan-4-yl)-2-oxo-propyl]phosphate
(G)-28. To a stirred solution of dimethyl methyl-
phosphonate (2.16 ml, 20.0 mmol, 3.0 equiv) in THF
(40 ml) was added n-BuLi (8.00 ml of a 2.5 M solution in
hexanes, 20.0 mmol, 3.0 equiv) dropwise at K78 8C. After
30 min a solution of ester (G)-27 (2.47 g, 6.67 mmol) in
THF (15 ml) was added dropwise. After 20 min the reaction
was quenched by the addition of sat. aq. NH4Cl (40 ml). The
mixture was warmed to rt, and then partitioned between
EtOAc (50 ml) and brine (50 ml). The layers were
separated, and the aqueous layer was extracted with
EtOAc (2!50 ml). The combined organic layers were
dried (MgSO4), filtered and concentrated. Purification by
flash chromatography (5:1 petrol/EtOAc) gave the title
compound (2.01 g, 65%) as a colourless oil: Rf 0.20 (5:1
petrol/EtOAc); nmax (film)/cmK1 2924 (m), 2854 (s), 1717
(s), 1260 (m); dH (500 MHz; CDCl3) 0.91 (3H, t, JZ6.5 Hz,
CH2CH3), 1.33 (3H, s, C(CH3)(CH3)), 1.28–1.53 (24H, m,
CH(CH2)12CH3), 1.37 (3H, s, C(CH3)(CH3)), 1.61–1.69
(2H, m, CH2CHCH2C(]O)), 2.72 (1H, dd, JZ8.5, 2.5 Hz,
CHCH(H)C(]O)), 2.84 (1H, dd, JZ8.5, 4.5 Hz,
CHCH(H)C(]O)), 3.10–3.24 (2H, m, CH2P(]O)-
(OCH3)2), 3.77–3.78 (3H, m, P(]O)(OCH3)(OCH3)),
3.80–3.83 (4H, m, P(]O)(OCH3)(OCH3) and CHCH2-
(CH2)12CH3), 4.21–4.39 (1H, m, CHCH2C(]O)); dC
(125.7 MHz; CDCl3) 14.5 (CH2CH3), 25.2 (C(CH3)-
(CH3)), 25.7 (C(CH3)(CH3)), 29.8, 29.9, 30.0, 30.1, 32.3,
36.2 (all CH(CH2)12CH3), 38.4 (CH2CHCH2C(]O)), 42.4
1
(d, J13C–31PZ106.0 Hz, CH2P(]O)(OCH3)2), 50.2
(CHCH2C(]O)), 53.4 (P(]O)(OCH3)2), 63.5 (CHCH2-
C(]O)), 66.9 (CH(CH2)12CH3), 100.8 (C(CH3)2), 200.4
(C]O); m/z(ESC) 480 (75%, MNHC4 ), 463 (37, MHC),
148 (100); HRMS: Found 485.3008 (MNaC);
C24H47NaO6P requires 485.3008.
4.2.13. (4S,6R)- and (4R,6S)-Methyl (2,2-dimethyl-6-
tridecyl-[1,3]dioxan-4-yl]acetate (G)-27. To a stirred
solution of diol (G)-25 (0.91 g, 2.75 mmol) in 2,2-
4.2.15. (4S,6R)- and (4R,6S)-Methyl 4-[4-(2,2-dimethyl-
6-tridecyl-[1,3]dioxan-4-yl)-3-oxo-butyl]phenylacetate

2362
J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
(G)-29. To a stirred solution of alkene (G)-26 (1.60 g,
3.20 mmol) in EtOAc (40 ml) was added 10% Pd/C (ca.
100 mg) at rt. The flask was evacuated (water aspirator) and
pressurized with H2 (balloon) three time, and the mixture
was then stirred for 16 h under H2 (balloon). The mixture
was then filtered through a pad of Celitew, washing
thoroughly with EtOAc, and the filtrate was concentrated.
Purification by flash chromatography (22:3 petrol/EtOAc)
gave the title compound (1.22 g, 76%) as a colourless oil: Rf
0.45 (22:3 petrol/EtOAc); nmax (film)/cmK1 2925 (s), 2854
(s), 1766 (s), 1717 (s); dH (500 MHz; CDCl3) 0.87 (3H, t,
JZ6.5 Hz, CH2CH3), 1.19–1.42 (24H, m, CH(CH2)12CH3),
1.38 (3H, s, C(CH3)(CH3)), 1.41 (3H, s, C(CH3)(CH3)),
1.52–1.62 (2H, m, CH2CHCH2C(]O)), 2.24 (3H, s,
O2CCH3), 2.39 (1H, dd, JZ15.5, 5.0 Hz, CHCH(H)-
C(]O)), 2.62–2.68 (2H, m, ArCH2CH2C(]O)), 2.64
(1H, dd, JZ15.5, 8.5 Hz, CHCH(H)C(]O)), 2.73–2.76
(2H, m, ArCH2CH2C(]O)), 3.70–3.73 (1H, m, CHCH2-
C(]O)), 4.22–4.29 (1H, m, CH(CH2)12CH3) 6.76 (2H, d,
JZ7.5 Hz, ArH), 7.03 (2H, d, JZ7.5 Hz, ArH); dC
(125.7 MHz; CDCl3) 14.5 (CH2CH3), 23.3 (O2CCH3),
25.0 (C(CH3)(CH3)), 25.7 (C(CH3)(CH3)), 29.1, 29.8,
30.0, 30.1 (all CHCH2(CH2)11CH3), 30.0 (ArCH2CH2-
C(]O)), 32.2 (ArCH2CH2C(]O)), 36.2 (CHCH2(CH2)11-
CH3), 38.7 (CH2CHCH2C(]O)), 49.2 (CHCH2C(]O)),
63.6 (CH(CH2)12CH3), 66.8 (CHCH2C(]O)), 100.7
(C(CH3)2), 121.8 (ArC), 129.7 (ArC), 139.0 (ArC), 149.3
(ArC), 169.8 (O2CCH3), 207.9 (CHCH2C(]O)); m/z(ESC)
520 (80%, MNHC4 ), 148 (100); HRMS: Found 525.3551
(MNaC); C31H50NaO5 requires 525.3556.
4.2.17. (2S,4S,6R)- and (2R,4R,6S)-2-[2-(4-Hydroxy-
phenyl)ethyl]-6-tridecyl-tetrahydropyran-2,4-diol (G)-
6-A and (5S,7R)- and (5R,7S)-dihydroxy-1-(4-hydroxy-
phenyl)icosan-3-one (G)-6-B. To a stirred solution of
acetonide (G)-30 (314 mg, 0.68 mmol) in THF (25 ml) was
added 0.5 M aq. HCl (10 ml) at 0 8C. The mixture was
warmed to rt, stirred for 1 h, then partitioned between
EtOAc (70 ml) and sat. aq. NaHCO3 (70 ml). The layers
were separated, and the aqueous layer was extracted with
EtOAc (3!50 ml). The combined organic layers were
washed with brine (1!50 ml), dried (MgSO4), filtered and
concentrated to afford a white solid. Purification by
recrystallisation (21:4 hexane/EtOAc) gave the title com-
pound (238 mg, 83%) as a white powder: Rf 0.2 (1:1 petrol/
EtOAc); mp 97–98 8C; nmax (CDCl3)/cmK1 3599 (br m),
2928 (m), 2855 (m), 1705 (s), 1612 (w), 1515 (s); NMR
data: If the product was dissolved in acetone-d6, and the
spectra recorded immediately, a single compound ((G)-6-
A) was observed: dH (500 MHz; acetone-d6) 0.90 (3H, t, JZ
6.0 Hz, CH2CH3), 1.07–1.09 1H, m, CH(H)CH
(CH2)12CH3), 1.22–1.31 (23H, m, CCH(H)CH(OH) and
CHCH2(CH2)11CH3), 1.45–1.47 (2H, m, CHCH2(CH2)11-
CH3), 1.86–1.87 (2H, m, ArCH2CH2C), 1.89–1.91 (1H, m,
CH(H)CH
(CH2)12CH3),
2.05–2.07
(1H,
m,
CCH(H)CH(OH)), 2.68–2.71 (2H, m, ArCH2CH2C), 3.61
(1H, d, JZ5.0 Hz, CCH2CH(OH)), 3.87–3.97 (1H, m,
CH(CH2)12CH3), 4.05–4.15 (1H, m, CCH2CH(OH)), 4.18
(1H, s, ArCH2CH2C(OH)), 6.75 (2H, d, JZ8.0 Hz, ArH),
7.05 (2H, d, JZ8.0 Hz, ArH), 7.99 (1H, s, ArOH); dC
(125.7 MHz; acetone-d6) 13.8 (CH2CH3), 28.9 (ArCH2-
CH2C), 29.0, 29.2, 30.0, 32.1 (all CHCH2(CH2)11CH3), 36.4
(CHCH2(CH2)11CH3), 41.9 (CH2 CH(CH2)12CH3), 43.3
(CCH2CH(OH)), 45.9 (ArCH2CH2C), 64.6 (CCH2-
CH(OH)), 68.5 (CH(CH2)12CH3), 97.8 (ArCH2CH2C),
115.5 (ArC), 129.5 (ArC), 133.7 (ArC), 155.7 (ArC).
Within 3hr at rt, the same sample had equilibrated to form a
2:1 mixture of (G)-6-A and (G)-6-B. Although the
4.2.16. (4S,6R)- and (4R,6S)-1-(2,2-Dimethyl-6-tridecyl-
[1,3]dioxan-4-yl)-4-(4-hydroxyphenyl)butan-2-one (G)-
30. To a stirred solution of acetate (G)-29 (1.00 g,
1.99 mmol) in MeOH (40 ml) was added K2CO3 (0.36 g,
2.61 mmol, 1.3 equiv) in one portion at rt. After 45 min the
mixture was partitioned between 50% sat. aq. NH4Cl
(100 ml) and EtOAc (100 ml). The layers were separated,
and the aqueous layer was extracted with EtOAc (3!
100 ml). The combined organic layers were dried (MgSO4),
filtered and concentrated. Purification by flash chromato-
graphy (4:1 petrol/EtOAc) gave the title compound (0.82 g,
89%) as a white solid: Rf 0.25 (2:1 petrol/EtOAc); mp 54–
55 8C, nmax (CHCl3)/cmK1 3597 (br s), 2928 (m), 2855 (s),
1714 (s), 1612 (w); dH (500 MHz; CDCl3) 0.91 (3H, t, JZ
6.5 Hz, CH2CH3), 1.28–1.42 (24H, m, CH(CH2)12CH3),
1.34 (3H, s, C(CH3)(CH3)), 1.35 (3H, s, C(CH3)(CH3)),
1.57–1.64 (2H, m, CH2CHCH2C(]O)), 2.44 (1H, dd, JZ
16.0, 5.0 Hz, CHCH(H)C(]O)), 2.71 (1H, dd, JZ16.0,
8.0 Hz, CHCH(H)C(]O)), 2.74–2.78 (2H, m, ArCH2CH2-
C(]O)), 2.81–2.84 (2H, m, ArCH2CH2C(]O)), 3.72–3.78
(1H, m, CHCH2C(]O)), 4.27–4.37 (1H, m, CH(CH2)12-
CH3), 5.50 (1H, s, OH), 6.73–6.79 (2H, m, ArH), 7.02–7.07
(2H, m, ArH); dC (125.7 MHz; CDCl3) 14.6 (CH2CH3), 25.1
(C(CH3)(CH3)), 25.7 (C(CH3)(CH3)), 29.0, 29.8, 30.0, 30.1
(all CHCH2(CH2)11CH3), 30.1 (ArCH2CH2C(]O)), 32.3
(ArCH2CH2C(]O)), 36.2 (CHCH2(CH2)11CH3), 38.7
(CH2CHCH2C(]O)), 49.3 (CHCH2C(]O)), 63.7
(CHCH2C(]O)), 67.0 (CH(CH2)12CH3), 101.0 (C(CH3)2),
115.7 (ArC), 129.8 (ArC), 133.3 (ArC), 154.5 (ArC), 209.0
(C]O); m/z(CIC) 403 (100%, [MHKC3H6O]C). Molecu-
lar ion intensities were too weak to record accurate HRMS
data.
1
complete assignment of the H NMR spectrum was not
possible due to considerable peak overlap, the 13C NMR
spectra could be completely assigned: 13C NMR data for
(G)-6-B: dC (125.7 MHz; acetone-d6) 13.9 (CH2CH3), 28.9
(ArCH2CH2C(]O)), 29.0, 29.2, 30.0 (all CHCH2(CH2)11-
CH3), 38.4 (CHCH2(CH2)11CH3), 44.2 (CH2CH(CH2)12-
CH3), 45.4 (CH(OH)CH2C(]O)), 50.7 (ArCH2CH2C-
(]O)), 65.5 (CH(OH)CH2C(]O)), 68.2 (CH(CH2)12CH3),
115.5 (ArC), 129.5 (ArC), 132.5 (ArC), 156.0 (ArC), 209.4
(C]O); m/z(ESC) 443 (85%, MNaC), 438 (35, MNHC4 ),
421 (28, MHC), 229 (100); HRMS: Found 443.3140
(MNaC); C26H44NaO4 requires 443.3137.
4.2.18. Aculeatin D (G)-4, (2R,4S,6R)- and (2S,4R,6S)-4-
hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-
9,12-dien-11-one (G)-8 and (5S,7R)- and (5R,7S)-4-(5,7-
dihydroxy-3-oxo-icosyl)-4-hydroxycyclohexa-2,5-die-
none (G)-31. To a stirred solution of compound (G)-6
(216 mg, 0.51 mmol) in acetone/H2O (40 ml of a 9:1 v/v
solution) was added PhI(O2CCF3)2 (258 mg, 0.60 mmol,
1.2 equiv) in one portion at rt. The mixture was stirred for
20 min in the dark, then partitioned between EtOAc (30 ml)
and sat. aq. NaHCO3 (30 ml). The layers were separated,
and the aqueous layer was extracted with EtOAc (2!
20 ml). The combined organic layers were washed with
brine (1!20 ml), dried (MgSO4), filtered and concentrated.

J. E. Baldwin et al. / Tetrahedron 61 (2005) 2353–2363
2363
Purification by flash chromatography (5:4 petrol/EtOAc)
gave the title compounds (G)-8 (92 mg, 43%) followed by
(G)-4 (40 mg, 19%) followed by (G)-31 (60 mg, 27%), all
as colorless oils.
(CH2CH3), 24.6, 30.1, 30.3, 30.4, 32.6, 34.6 (all CHCH2-
(CH2)11CH3), 36.0 (CHCH2(CH2)11CH3), 37.4 (C(OH)CH2-
CH2C(]O)), 39.6 (C(OH)CH2CH2C(]O)), 43.2 (CH2-
CH(OH)CH2C(]O)), 53.7 (CH(OH)CH2C(]O)), 69.3
(CH(OH)CH2C(]O)), 73.0 (C(OH)CH2CH2C(]O)), 75.7
(CH(CH2)12CH3), 128.1 (CCH]CHC(]O)), 131.5
(CCH]CHC(]O)), 145.9 (CCH]CHC(]O)), 153.0
(CCH]CHC(]O)), 184.3 (CCH]CHC(]O)), 206.5
(C(OH)CH2CH2C(]O)); m/z(CIC) 418(100%, [MK
H2O]C). Molecular ion intensities were too weak to record
accurate HRMS data.
Data for compound (G)-8. Rf 0.3 (5:4 petrol/EtOAc); nmax
(film)/cmK1 3400 (br s), 2926 (s), 2854 (m), 1671 (s), 1630
(s), 1457 (m), 1389 (m); dH (500 MHz; CDCl3) 0.91 (3H, t,
JZ7.0 Hz, CH2CH3), 1.05–1.07 (1H, m, H-3ax), 1.33–1.40
(24H, CH(CH2)12CH3), 1.40–1.45 (3H, m, H-5ax, H-140 and
H-150), 1.53–1.62 (1H, m, H-3equiv), 1.85–1.87 (2H, m,
H-5equiv and H-15), 2.00–2.12 (1H, m, H-14), 3.68–3.72
(1H, m, H-2), 3.87–3.94 (1H, m, H-4), 6.02 (1H, dd, JZ8.0,
2.0 Hz, H-12), 6.10–6.15 (2H, m, H-10 and H-13), 6.68 (1H,
dd, JZ10.0, 3.0 Hz, H-9); dC (125.7 MHz; C6D6) 14.6
(CH2CH3), 26.3, 30.1, 30.3, 30.4, 32.6 (all CHCH2(CH2)11-
CH3), 35.1 (C-14), 36.6 (CHCH2(CH2)10CH3), 39.1 (C-15),
41.5 (C-3), 43.7 (C-5), 65.4 (C-4), 69.5 (C-2), 79.4 (C-8),
109.3 (C-6), 127.2 (C-13), 127.6 (C-10), 149.0 (C-12),
151.3 (C-9), 185.0 (C-11); m/z(EIC) 418 (2%, MC),
401(100); HRMS: Found 419.3171 (MHC); C26H43O4
requires 419.3161.
Acknowledgements
We thank the EPSRC for a graduate studentship to PGB. We
also thank Dr. B. Odell and Miss Tina Jackson for assistance
with NMR analyses.
References and notes
Data for compound (G)-4. Rf 0.2 (5:4 petrol/EtOAc); nmax
(film)/cmK1 3418 (br s), 2922 (m), 2853 (s), 1668 (s), 1632
(w), 1455 (s), 1010 (s); dH (500 MHz; C6D6) 0.91 (3H, t, JZ
7.0 Hz, CH2CH3), 1.07–1.14 (1H, m, H-3ax), 1.17–1.23 (1H,
m, H-150), 1.25–1.36 (22H, m, CHCH(H)(CH2)11CH3,
CHCH2CH(H)(CH2)10CH3 and CHCH2CH2(CH2)10CH3)
1.42–1.50 (2H, m, H-140 and CHCH2CH(H)(CH2)10CH3),
1.52–1.58 (1H, m, CHCH(H)(CH2)11CH3), 1.66–1.69 (1H,
m, H-3equiv), 1.78–1.84 (2H, m, H-5ax and H-15), 1.87–1.94
(2H, m, H-5equiv and H-14), 2.96–3.01 (1H, m, H-2), 3.45–
3.51 (1H, m, H-4), 6.04 (1H, dd, JZ9.5, 2.0 Hz, H-12), 6.07
(1H, dd, JZ9.5, 2.0 Hz, H-10), 6.25 (1H, dd, JZ10.0,
3.0 Hz, H-13), 6.90 (1H, dd, JZ10.0, 3.0 Hz, H-9); dC
(125.7 MHz; C6D6) 14.3 (CH2CH3), 23.1 (CH2CH3), 26.2,
(CHCH2CH2(CH2)10CH3), 29.8, 29.9, 30.1, 30.1, 30.1, 32.3
(all CHCH2CH2(CH2)9CH2CH3), 33.1 (C-15), 35.2 (C-14),
36.2 (CHCH2(CH2)11CH3), 41.3 (C-3), 44.1 (C-5), 66.6
(C-4), 71.6 (C-2), 78.1 (C-8), 109.3 (C-6), 127.1 (C-10),
127.3 (C-12), 148.9 (C-13), 151.9 (C-9), 184.9 (C-11); m/z
(CIC) 436 (3%, MNHC4 ), 419 (12, MHC), 401 (14), 163
(48), 155 (100), 107 (58); HRMS: Found 419.3156 (MHC);
C26H43O4 requires 419.3161.
1. Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. Helv.
Chim. Acta 2000, 83, 2939–2945.
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8. Tran-Huu-Dau, M.-E.; Wartchow, R.; Winterfeld, E.; Wong,
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Morrow, G. W. J. Org. Chem. 1993, 58, 3308–3316.
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Data for compound (G)-31. Rf 0.10 (5:4 petrol/EtOAc);
nmax (CHCl3)/cmK1 3394 (br m), 2924 (m), 2854 (m), 1720
(s), 1670 (m), 1513 (m); dH (500 MHz; C6D6) 0.91 (3H, t,
JZ7.0 Hz, CH2CH3), 1.07–1.09 (1H, m, CHCH(H)(CH2)11-
CH3), 1.13–1.23 (1H, m, C(OH)CH(H)CH2C(]O)), 1.32–
1.39 (23H, m, CHCH(H)(CH2)11CH3 and CHCH2(CH2)11-
CH3), 1.54–1.66 (2H, m, CH2CH(OH)CH2C(]O)), 1.72–
1.77 (1H, m, C(OH)CH2CH(H)C(]O)), 1.91–1.97 (1H, m,
C(OH)CH2CH(H)C(]O)), 2.08–2.16 (1H, m, C(OH)CH-
(H)CH2C(]O)), 2.34–2.38 (1H, m, CH(OH)CH-
(H)C(]O)), 2.54–2.58 (1H, m, CH(OH)CH(H)C(]O)),
3.31–3.35 (1H, m, CH(CH2)12CH3), 4.03–4.07 (1H, m,
CH(OH)CH2C(]O)), 5.93 (1H, dd, JZ10.0, 1.0 Hz,
CCH]CHC(]O)), 6.14 (1H, dd, JZ10.5, 1.0 Hz,
CCH]CHC(]O)), 6.24 (1H, dd, JZ10.0, 3.0 Hz,
CCH]CHC(]O)), 6.50 (1H, dd, JZ10.5, 3.0 Hz,
CCH]CHC(]O)); dC (125.7 MHz; C6D6) 14.6
16. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
17. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945–948.
18. For a discussion of the possible mechanisms of oxidation of
phenolic compounds using hypervalent iodine(III) reagents
see: Ku¨rti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus, S.;
Pelter, A. J. Chem. Soc., Pekin Trans. 1 1999, 379–380.
19. We are indebted to Prof. Heilmann for performing the TLC
comparisons, and for kindly supplying copies of the spectra of
natural (K)-aculeatin D 4.