Enantioselective synthesis and absolute configurations of aculeatins A, B, D, and 6-epi-aculeatin D

Article abstract of DOI:10.1016/j.tet.2006.07.076

The three naturally occurring, bioactive spiroacetals aculeatins A, B, and D, as well as the non-natural 6-epi-aculeatin D have been synthesized for the first time in enantiopure form using an asymmetric allylation as the only chirality source. A further

Full text of DOI:10.1016/j.tet.2006.07.076

Tetrahedron 62 (2006) 9641–9649
Enantioselective synthesis and absolute configurations
of aculeatins A, B, D, and 6-epi-aculeatin D
a
Paula Alvarez-Bercedo, Eva Falomir, Miguel Carda and J. A. Marco
a,
a
b
ꢀ
*
aDepart. de Q. Inorgaꢀnica y Orgaꢀnica, Universidad Jaume I, Castelloꢀn, E-12080 Castelloꢀn, Spain
bDepart. de Q. Orgaꢀnica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain
Received 17 June 2006; revised 19 July 2006; accepted 25 July 2006
Available online 17 August 2006
Abstract—The three naturally occurring, bioactive spiroacetals aculeatins A, B, and D, as well as the non-natural 6-epi-aculeatin D have been
synthesized for the first time in enantiopure form using an asymmetric allylation as the only chirality source. A further key step was a stereo-
selective aldol reaction with remote induction. The absolute configurations of the natural products have been established and an erroneous
structural assignment has been corrected.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
aculeatins A, B, and D in racemic form.5 Both syntheses re-
lied upon the same type of phenolic oxidation to form the
1,7-dioxadispiro[5.1.5.2]pentadecane system (see below).
In this paper, we present with full detail the first synthesis
of 1, 2, and 4 in enantiopure form.6 Another product gener-
ated in our synthesis was optically pure 6-epi-aculeatin D,
previously synthesized in racemic form5b but not reported
as a natural product so far.
The aculeatins A and B are two epimeric spiroacetals iso-
lated six years ago from the terrestrial plant species Amo-
mum aculeatum Roxb. (fam. Zingiberaceae). They were
assigned structures (relative configurations) 1 and 2, respec-
tively. A more complex variant, aculeatin C-3, was also iso-
lated from the same plant (Fig. 1). Later, the same authors
reported the isolation of a fourth member of this compound
family, named aculeatin D and assigned structure and rela-
tive configuration 4.1,2 These compounds were found to dis-
play antiprotozoal activity against some Plasmodium and
Trypanosoma species. In addition, they showed antibacterial
activity and were cytotoxic against the KB cell line.
The retrosynthetic concept for aculeatins A and B is depicted
in Scheme 1. The dispirocyclic system is generated via
O
O
The aculeatins A–D represent a novel type of natural
compounds displaying the unusual, previously unreported
1,7-dioxadispiro[5.1.5.2]pentadecane system. The observed
biological activity of the aculeatins may be related to the
presence of a Michael acceptor moiety.3 Spiroacetals them-
selves are also interesting molecular fragments, which are
present in many pharmacologically relevant substances
such as macrolide or polyether antibiotics.4 In view of this
and of the aforementioned biological activities, it is not sur-
prising that the aculeatins have already aroused interest in
the synthetic community. As a matter of fact, two papers
have recently appeared, which deal with the synthesis of
O
O
O
O
12
12
OH
OH
1
2
O
O
O
O
O
O
O
O
11
12
OH
OH
OH
6
Keywords: Aculeatins; Absolute configuration; Asymmetric allylation;
Aldol reaction; Remote induction; Spiroacetals; Hypervalent iodine;
Oxidative spiroacetalization.
3
4
* Corresponding author. Tel.: +34 96 3544337; fax: +34 96 3544328;
e-mail: alberto.marco@uv.es
Figure 1. Published structures and relative configurations of the aculeatins
A–D (1–4).
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.076

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P. Alvarez-Bercedo et al. / Tetrahedron 62 (2006) 9641–9649
9642
phenolic oxidation of an appropriately substituted inter-
mediate ketone, related in turn to the protected triol I. The
latter is derived from the aldol reaction of ketone II
with n-tetradecanal. Intermediate II should be obtained
from a suitably protected dihydro-p-coumaraldehyde III
by means of asymmetric allylation and further functional
manipulation.
2. Results and discussion
Scheme 2 shows the details of the synthesis of spiroacetals 1
and 2. Thus, the known 3-(p-benzyloxyphenyl)propanal 57
was subjected to asymmetric allylation using the chiral
allylborane prepared from allylmagnesium bromide and
(ꢀ)-DIP–Cl [(ꢀ)-diisopinocampheylchloroborane].8 In this
way, homoallyl alcohol 6 was obtained in over 96% ee as
judged by NMR examination of the Mosher ester.9 Benzyla-
tion of the hydroxyl group followed by Wacker oxidation10
provided methyl ketone 8. Boron aldol reaction11 of this ke-
tone with n-tetradecanal afforded the desired aldol 9 in 70%
yield as a single diastereomer. The aldol can be then reduced
to the monobenzylated anti,syn-1,3,5-triol 10 but it was
much more expedient to perform the aldol reduction in
situ with LiBH4 to stereoselectively yield 10.12 Protection
of the two free hydroxyl groups as an acetonide followed
by hydrogenolytic debenzylation afforded 12. Swern oxida-
tion of the latter compound furnished ketone 13, which was
then submitted to hydrolytic cleavage of the acetonide moi-
ety. However, while the expected b,d-dihydroxy ketone was
formed, the yield was low (<35%). Fortunately, treatment of
acetonide 12 with phenyliodonium bis(trifluoroacetate) not
only caused the desired phenolic oxidation5,13,14 but also
acetonide hydrolysis and subsequent spiroacetalization.
This cleanly yielded a 5.5:1 mixture of two optically active
products with spectral properties identical to those reported
for aculeatins A and B.1 Intermediates or by-products of 4-
hydroxycyclohexa-2,5-dienone type5b (see Scheme 1) were
not detected.
O
O
11
10
9
12
13
8
1
OH
OH
7 O
2
14
O
O
12
6
12
15
4
5
3
OH
Aculeatins A-B
OH
phenolic
oxidation
OP OH OH
aldol
I
12
PO
OP
O
O
+
II
12
PO
asymmetric allylation
CHO
III
A closer examination of the respective NMR spectral prop-
erties revealed, however, an important issue. The major
product exhibited in fact the optical rotation and spectral
(P = protecting group)
PO
Scheme 1. Retrosynthetic analysis of aculeatins A and B.
OR
OBn
O
CHO
a
c
BnO
BnO
6
R = H
8
BnO
5
b
7
R = Bn
d
e
OR1 OR2
O
OH
OBn
OBn
12
12
10 R1, R2 = H
BnO
BnO
9
f
11 R1, R2 = CMe2
g
OH
O
O
O
O
O
h
12
12
12
13
HO
HO
i
Aculeatin A + Aculeatin B
Scheme 2. Synthesis of aculeatins A and B. Reaction conditions: (a) allylBIpc2 from (ꢀ)-Ipc2BCl and allylmagnesium bromide, Et2O, 3 h, ꢀ90 ꢁC; (b) NaH;
THF, then BnBr, rt, overnight, 85% overall from 5; (c) PdCl2, CuCl2, aq DMF, O2, 2 d, 75%; (d) Bu2BOTf, EtNiPr2, CH2Cl2, ꢀ78 ꢁC, 1 h, followed by addition
of n-tetradecanal, 3 h, ꢀ78 ꢁC, 70%; (e) Bu2BOTf, EtNiPr2, CH2Cl2, ꢀ78 ꢁC, 1 h, followed by addition of n-tetradecanal, 3 h, ꢀ78 ꢁC, then LiBH4, 2 h,
ꢀ78 ꢁC, 65% overall; (f) 2,2-dimethoxypropane, CSA (cat.), Me2CO, rt, 1 d, 72%; (g) H2 (1 atm), 10% Pd–C, EtOAc, rt, 6 h, 70%; (h) (COCl)2, DMSO,
CH2Cl2, ꢀ78 ꢁC, then Et3N, ꢀ78 ꢁC/0 ꢁC, 87% and (i) PhI(OOCCF3)2, Me2CO–H2O (9:1), rt, 24 h, 65% overall, 5.5:1 mixture of aculeatins A and B.
Acronyms: Ipc, isopinocampheyl; CSA, camphorsulfonic acid.

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9643
properties associated with aculeatin A.1 It was stable and
showed no noticeable tendency to isomerize to the minor
stereoisomer. NOE measurements pointed out the absence
of dipolar correlations between the methine proton H-2
and one methylene proton at C-15 (for numbering, see
Scheme 1). This strongly suggests that its configuration cor-
responds to 2 (Fig. 2), not to 1 as proposed.1 In addition,
structure 2 benefits from a favorable anomeric effect,15 in
agreement with the higher stability of aculeatin A. In support
of this reasoning, the minor isomer, which was unstable and
isomerized slowly to the major one, showed a marked NOE
between the methine proton H-2 and one methylene proton
at C-15. These properties, which are associated to aculeatin
B,1a are only compatible with stereostructure 1 (Fig. 2),
which does not exhibit a favorable anomeric effect. A further
support is given by the markedly higher d value of H-2 in
aculeatin A (d 4.10 vs d 3.86 ppm in aculeatin B), which
points to its 1,3-diaxial relation with the anomeric oxygen
atom. In summary, the Swiss workers1 erroneously inter-
changed the relative stereostructures of the aculeatins A
and B, which are therefore 2 and 1, respectively.16 The opti-
cal rotation values of the synthetic compounds were very
similar to those of the natural compounds and the signs are
the same. Our synthesis therefore has led to the natural enan-
tiomers of both aculeatins and permitted the establishment
of their absolute configurations (Fig. 2).
Aculeatin A, (-)-2
Aculeatin B, (+)-1
O
O
O
O
O
O
12
12
OH
OH
H
H
H
H
O
H
O
O
15
H
The same retrosynthetic concept depicted in Scheme 1 was
applied to aculeatin D with only a change, related to the in-
verted configuration at C-4. Thus, aldol 9 was reduced with
TABH17 to stereoselectively afford the expected anti-1,3-
diol 14 (minor isomer not detected by means of NMR), sub-
sequently transformed into its acetonide 15 (Scheme 3).
Problems arose, however, during hydrogenolytic cleavage
of the two benzyl groups. Under all conditions we tried,
2
H
2
H
6
H
H
6
H
H
O
OH
O
15
OH
NOE
H
H
O
Figure 2. Corrected structures and absolute configurations of aculeatins A
and B.
OR1 OR2
OBn
OBn
O
OH
a
12
12
9
BnO
BnO
14 R1, R2 = H
15 R1, R2 = CMe2
b
d
c
OBn
OTBSOTBS
OH
O
O
12
12
16
BnO
HO
HO
HO
+
e
O
O
OH
OH
OTBSOTBS
12
12
17
f
O
O
OH OH
OTBSOTBS
g,h
12
12
HO
HO
18
12
12
O
O
O
O
+
O
O
OH
OH
19, (+)-6-epi-aculeatin D
4, (+)-aculeatin D
Scheme 3. Synthesis of aculeatin D and 6-epi-aculeatin D. Reaction conditions: (a) TABH, AcOH–MeCN, ꢀ30 ꢁC, 12 h, 86%; (b) 2,2-dimethoxypropane, CSA
(cat.), Me2CO, rt, 12 h, 89%; (c) H2 (1 atm), 10% Pd–C, EtOAc, rt, 6 h, 40%; (d) TBSOTf, 2,6-lutidine, CH2Cl2, D, 91%; (e) H2 (1 atm), 10% Pd–C, EtOAc, rt,
15 min, 74%; (f) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, then Et3N, ꢀ78 ꢁC/0 ꢁC, 81%; (g) TASF, DMF, 0 ꢁC, 90 min, then rt, 4 h and (h) PhI(OOCCF3)2,
Me2CO–H2O (9:1), rt, 30 min, 77% overall for the two steps, 2.7:1 mixture of aculeatin D (minor) and 6-epi-aculeatin D (major). Acronyms: TABH, tetra-
methylammonium triacetoxyborohydride; TASF, tris(dimethylamino)sulfonium difluoro-trimethylsilicate; TBSOTf, tert-butyldimethylsilyl triflate.

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9644
6-Epi-aculeatin D, (+)-19
1
Aculeatin D, (+)-4
d 7.25 for H NMR and the triplet centered at 77.00 ppm
for 13C NMR data). Carbon atom types (C, CH, CH2, and
CH3) were determined with the DEPT pulse sequence.
Mass spectra were run by the electron impact (EIMS,
70 eV), the CIMS (CH4 as the gas carrier) or the fast atom
bombardment mode (FABMS, m-nitrobenzyl alcohol
matrix) on a VG AutoSpec mass spectrometer. IR data are
given only for compounds with relevant functions (OH,
C]O, and C^C–H) and were recorded as oily films on
NaCl plates (oils) or as KBr pellets (solids). Optical rotations
were measured at 25 ꢁC. Reactions, which required an inert
atmosphere were carried out under N2 with flame-dried
glassware. Et2O and THF were freshly distilled from
sodium–benzophenone ketyl and transferred via syringe. Di-
chloromethane was freshly distilled from CaH2. Tertiary
amines were freshly distilled from KOH. Toluene was
freshly distilled from sodium wire. Commercially available
reagents were used as received. Unless detailed otherwise,
‘work-up’ means pouring the reaction mixture into brine,
followed by extraction with the solvent indicated in paren-
thesis. If the reaction medium was acidic (basic), an addi-
tional washing with 5% aq NaHCO3 (aq NH4Cl) was
performed. Drying over anhydrous Na2SO4 and elimination
of the solvent under reduced pressure were followed by chro-
matography of the residue on a silica gel column (60–
200 mm) with the indicated eluent. Where solutions were fil-
tered through a Celite pad, the pad was additionally washed
with the same solvent used, and the washings incorporated to
the main organic layer. Reagent acronyms are explained in
the captions of Schemes 2 and 3.
O
O
O
O
O
O
12
12
OH
OH
H
H
H
H
O
H
H
O
O
15
H
H
2
HO
2
HO
6
H
H
6
15
H
H
O
O
H
NOE
H
O
Figure 3. Structures and absolute configurations of aculeatin D 4 and 6-epi-
aculeatin D 19.
partial migration (transacetalization) of the acetonide group
took place with formation in low yield of two isomeric ace-
tonides, the undesired one being the major compound. We
then replaced the acetonide moiety by other protecting
groups such as MOM, MEM or TES (triethylsilyl), all cleav-
able under mild conditions.18 However, no success was
achieved with these groups, either. The acetal-like MOM
or MEM groups were introduced with unsatisfactory yields
and showed a marked tendency to form six-membered form-
aldehyde acetals with the proximal hydroxy group.19 The
TES group behaved better in this aspect but was partially
cleaved under hydrogenolytic conditions. Eventually, the
TBS group proved appropriate. Double silylation of diol
14 worked well, as did the subsequent hydrogenolysis and
oxidation steps, which finally yielded ketone 18. The latter
was desilylated under mild conditions with TASF.20 Without
purification, the intermediate diol was subjected as above to
oxidative spiroacetalization with PhI(OCOCF3)2 to yield
a 2.7:1 mixture of compounds 4 (minor) and 19 (major),
again with no 4-hydroxycyclohexa-2,5-dienone being iso-
lated. Compounds 4 and 19 displayed physical and spectral
features identical to those reported for natural aculeatin D1b
and synthetic 6-epi-aculeatin D,5b respectively. NOE mea-
surements were consistent with the published structures
(Fig. 3). The absolute configuration of natural aculeatin D
turns out to be as depicted in the figure.
4.1.1. (R)-1-(4-Benzyloxyphenyl)hex-5-en-3-ol (6). Allyl-
magnesium bromide (commercial 1 M solution in Et2O,
2.5 mL, 2.5 mmol) was added dropwise under N2 via syringe
to a solution of (ꢀ)-DIP–Cl (0.97 g, 3 mmol) in dry Et2O
(12 mL) cooled in a dry ice-acetone bath. After replacing
the latter by an ice bath, the mixture was stirred for 1 h.
The solution was allowed to stand, whereby precipitation
of magnesium chloride took place. The supernatant solution
was carefully transferred to another flask via cannula. After
cooling this flask at ꢀ90 ꢁC, a solution of freshly prepared7
3-(4-benzyloxyphenyl)-propanal (480 mg, ca. 2 mmol) in
dry Et2O (5 mL) was added dropwise via syringe. The result-
ing solution was further stirred at ꢀ90 ꢁC for 3 h. The reac-
tion mixture was quenched through addition of phosphate
pH 7 buffer solution (12 mL), MeOH (12 mL), and 30%
H2O2 (6 mL). After stirring for 30 min, the mixture was
poured onto satd aq NaHCO3 and worked-up (extraction
with Et2O). For synthetic purposes, the oily residue was
used directly in the next step. For analytical characterization,
an aliquot of the residue was subjected to a careful column
chromatography on silica gel (hexane, then hexane–EtOAc,
19:1 and 9:1) yielding pure 6 (>98:2 mixture of enantiomers
as estimated via the Mosher ester): colorless solid, mp 61–
3. Conclusions
The naturally occurring, bioactive spiroacetals aculeatins A,
B, and D, as well as the hitherto non-natural 6-epi-aculeatin
D, have been synthesized for the first time in enantiopure
form. Their absolute configurations have been established,
and a previous structural misassignment has been corrected.
1
63 ꢁC; [a]D +12.7 (c 1.2, CHCl3); H NMR (500 MHz,
CDCl3) d 7.45–7.30 (5H, m), 7.14 (2H, d, J¼8.5 Hz), 6.93
(2H, d, J¼8.5 Hz), 5.85 (1H, m), 5.20–5.15 (2H, m), 5.06
(2H, s), 3.70 (1H, m), 2.78 (1H, m), 2.67 (1H, m), 2.33
(1H, m), 2.22 (1H, m), 1.80–1.75 (2H, m) (hydroxyl proton
not detected); 13C NMR (125 MHz) d 157.1, 137.2, 134.4
(C), 134.6, 129.3 (ꢂ2), 128.5 (ꢂ2), 127.8, 127.4 (ꢂ2),
114.8 (ꢂ2), 69.9 (CH), 118.2, 70.1, 42.0, 38.6, 31.1
(CH2); IR nmax 3370 (br, OH), 3076, 1513, 1453, 1254,
4. Experimental
4.1. General
1H/13C NMR spectra were measured at 500/125 MHz in
CDCl3 solution at 25 ꢁC. The signals of the deuterated sol-
vent (CDCl3) were taken as the reference (the singlet at

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9645
913 cmꢀ1; HR EIMS m/z (rel int.) 282.1619 (M+, 20),
197 (10), 91 (100). Calcd for C19H22O2, 282.1620. Anal.
Calcd for C19H22O2: C, 80.82; H, 7.85. Found: C, 80.89;
H, 7.83.
quintuplet, Jz6 Hz), 2.82 (1H, dd, J¼15.5, 7 Hz), 2.75–
2.65 (2H, m), 2.59 (1H, dd, J¼15.5, 5 Hz), 2.18 (3H, s),
1.95–1.85 (2H, m); 13C NMR (125 MHz) d 207.3, 157.0,
138.4, 137.2, 134.1 (C), 129.2 (ꢂ2), 128.5 (ꢂ2), 128.3
(ꢂ2), 127.8, 127.7 (ꢂ2), 127.5, 127.4 (ꢂ2), 114.8 (ꢂ2),
74.9 (CH), 71.5, 70.0, 48.4, 36.3, 30.5 (CH2), 31.0
(CH3); IR nmax 3063, 3031, 1714 (C]O), 1610, 1511,
1454, 1239, 1074, 1027, 738 cmꢀ1; HR FABMS m/z
388.2037 (M+). Calcd for C26H28O3, 388.2038. Anal.
Calcd for C26H28O3: C, 80.38; H, 7.26. Found: C, 80.49;
H, 7.33.
4.1.2. (R)-4-Benzyloxy-6-(4-benzyloxyphenyl)hex-1-ene
(7). Solid sodium hydride 95% (125 mg, ca. 5 mmol) was
suspended under N2 in dry THF (5 mL). A solution of the
crude residue of the previous reaction in dry THF (5 mL)
was added. The mixture was stirred at room temperature
for 45 min and treated with tetra-n-butyl ammonium iodide
(18 mg, 0.05 mmol) and benzyl bromide (0.6 mL, ca.
5 mmol). The mixture was stirred overnight at room temper-
ature. Work-up (extraction with Et2O) and column chroma-
tography on silica gel (hexane–EtOAc, 99:1) furnished 7
(630 mg, 85% overall from 5): oil; [a]D +21.7 (c 2.2,
4.1.5. (3R,5R,7R)-3-Benzyloxy-1-(4-benzyloxyphenyl)-
eicosane-5,7-diol (10). A solution of ketone 8 (466 mg,
1.2 mmol) in dry CH2Cl2 (8 mL) was cooled under N2 to
ꢀ78 ꢁC and treated sequentially with diisopropyl ethyl
amine (260 mL, 1.5 mmol) and a 1 M solution of Bu2BOTf
in CH2Cl2 (1.35 mL, 1.35 mmol). The mixture was stirred
for 1 h at the same temp, followed by addition of a solution
of n-tetradecanal (287 mg, 1.35 mmol)21 in dry CH2Cl2
(5 mL). The mixture was stirred at ꢀ78 ꢁC for further 3 h,
treated with a 2 M solution of LiBH4 in THF (1.2 mL,
2.4 mmol), and further stirred at ꢀ78 ꢁC for 2 h. The reac-
tion was quenched by addition of phosphate pH 7 buffer so-
lution (7 mL) and MeOH (7 mL), followed by 30% aq H2O2
solution (3.5 mL). After stirring for 30 min at room temper-
ature, the mixture was worked-up (extraction with CH2Cl2).
Solvent removal in vacuo and column chromatography of
the residue on silica gel (hexane–EtOAc, 9:1) yielded diol
10 (470 mg, 65%): amorphous solid; [a]D ꢀ10.2 (c 0.75,
1
CHCl3); H NMR (500 MHz, CDCl3) d 7.45–7.30 (10H,
m), 7.13 (2H, d, J¼8.5 Hz), 6.94 (2H, d, J¼8.5 Hz), 5.90
(1H, m), 5.15–5.10 (2H, m), 5.08 (2H, s), 4.65 (1H, d,
J¼11.5 Hz), 4.53 (1H, d, J¼11.5 Hz), 3.53 (1H, m), 2.78
(1H, m), 2.66 (1H, m), 2.50–2.40 (2H, m), 1.95–1.85 (2H,
m); 13C NMR (125 MHz) d 157.0, 138.8, 137.3, 134.7 (C),
134.8, 129.3 (ꢂ2), 128.5 (ꢂ2), 128.3 (ꢂ2), 127.8, 127.7
(ꢂ2), 127.5, 127.4 (ꢂ2), 114.8 (ꢂ2), 77.7 (CH), 117.1,
70.9, 70.1, 38.2, 35.9, 30.8 (CH2); IR nmax 3065, 3031,
1511, 1454, 1239, 736 cmꢀ1; HR EIMS m/z (rel int.)
372.2101 (M+, 10), 287 (13), 119 (37), 91 (100). Calcd for
C26H28O2, 372.2089. Anal. Calcd for C26H28O2: C, 83.83;
H, 7.58. Found: C, 83.89; H, 7.50.
1
4.1.3. (R)-4-Benzyloxy-6-(4-benzyloxyphenyl)hexan-2-
one (8). Olefin 7 (615 mg, 1.65 mmol) was dissolved in
DMF containing 10% water (40 mL) and treated with
PdCl2 (90 mg, ca. 0.5 mmol) and CuCl (500 mg, ca.
5 mmol). The mixture was stirred at room temperature under
O2 for 48 h, then poured onto satd aq NH4Cl and worked-up
(extraction with Et2O). Column chromatography on silica
gel (hexane–EtOAc, 9:1) provided 8 (480 mg, 75%): oil;
CHCl3); H NMR (500 MHz, CDCl3) d 7.45–7.30 (10H,
m), 7.08 (2H, d, J¼8.5 Hz), 6.91 (2H, d, J¼8.5 Hz), 5.05
(2H, s), 4.56 (1H, d, J¼11.5 Hz), 4.54 (1H, d, J¼11.5 Hz),
4.18 (1H, m), 3.85 (1H, m), 3.75 (1H, m), 2.70–2.60 (2H,
m), 2.00 (1H, m), 1.85–1.75 (2H, m), 1.65 (1H, ddd,
J¼14.5, 7, 2.5 Hz), 1.55–1.45 (2H, m), 1.40–1.25 (24H, br
m), 0.90 (3H, t, J¼7 Hz) (hydroxyl protons not detected);
13C NMR (125 MHz) d 157.2, 138.1, 137.2, 134.2 (C),
129.3 (ꢂ2), 128.6 (ꢂ2), 128.5 (ꢂ2), 128.1 (ꢂ2), 127.9
(ꢂ2), 127.4 (ꢂ2), 114.9 (ꢂ2), 76.3, 72.7 (CH), 70.7
(CH+CH2), 71.3, 43.4, 40.5, 38.0, 35.5, 31.9, 30.8, 29.6
(several overlapped signals), 29.5 (several overlapped sig-
nals), 29.4, 25.4, 22.7 (CH2), 14.1 (CH3); IR nmax 3420
(br, OH), 3032, 1511, 1455, 1240, 736 cmꢀ1; HR FABMS
m/z 603.4363 (M+H+). Calcd for C40H59O4, 603.4413.
Anal. Calcd for C40H58O4: C, 79.69; H, 9.70. Found: C,
79.79; H, 9.53.
1
[a]D +3.5 (c 1.8, CHCl3); H NMR (500 MHz, CDCl3)
d 7.45–7.30 (10H, m), 7.12 (2H, d, J¼8.5 Hz), 6.94 (2H,
d, J¼8.5 Hz), 5.07 (2H, s), 4.57 (2H, s), 4.00 (1H, br quintu-
plet, Jz6 Hz), 2.82 (1H, dd, J¼15.5, 7 Hz), 2.75–2.65 (2H,
m), 2.59 (1H, dd, J¼15.5, 5 Hz), 2.18 (3H, s), 1.95–1.85
(2H, m); 13C NMR (125 MHz) d 207.3, 157.0, 138.4,
137.2, 134.1 (C), 129.2 (ꢂ2), 128.5 (ꢂ2), 128.3 (ꢂ2),
127.8, 127.7 (ꢂ2), 127.5, 127.4 (ꢂ2), 114.8 (ꢂ2), 74.9
(CH), 71.5, 70.0, 48.4, 36.3, 30.5 (CH2), 31.0 (CH3); IR
nmax 3063, 3031, 1714 (C]O), 1610, 1511, 1454, 1239,
1074, 1027, 738 cmꢀ1; HR FABMS m/z 388.2037 (M+).
Calcd for C26H28O3, 388.2038. Anal. Calcd for C26H28O3:
C, 80.38; H, 7.26. Found: C, 80.49; H, 7.33.
4.1.6. (4S,6R)-4-[(R)-2-Benzyloxy-4-(4-benzyloxyphenyl)
butyl]-2,2-dimethyl-6-n-tridecyl-[1,3]dioxane (11). Diol
10 (452 mg, 0.75 mmol) was dissolved in dry acetone
(15 mL) and treated with camphorsulfonic acid (10 mg, ca.
0.05 mmol) and 2,2-dimethoxypropane (3 mL). After add-
4.1.4. (R)-4-Benzyloxy-6-(4-benzyloxyphenyl)hexan-2-
one (8). Olefin 7 (615 mg, 1.65 mmol) was dissolved in
DMF containing 10% water (40 mL) and treated with
PdCl2 (90 mg, ca. 0.5 mmol) and CuCl (500 mg, ca.
5 mmol). The mixture was stirred at room temperature under
O2 for 48 h, poured onto satd aq NH4Cl and worked-up (ex-
traction with Et2O). Column chromatography on silica gel
(hexane–EtOAc, 9:1) provided 8 (480 mg, 75%): oil; [a]D
˚
ing activated 3 A molecular sieves (0.5 g), the mixture was
stirred overnight at room temperature. The mixture was
then poured onto satd aq NaHCO3 and worked-up (extrac-
tion with CH2Cl2). Column chromatography on silica
gel (hexane–EtOAc, 99:1) furnished 11 (347 mg, 72%):
amorphous solid; [a]D ꢀ12.7 (c 1.6, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.45–7.30 (10H, m), 7.10 (2H, d,
J¼8.5 Hz), 6.91 (2H, d, J¼8.5 Hz), 5.06 (2H, s), 4.58 (1H,
d, J¼11.5 Hz), 4.50 (1H, d, J¼11.5 Hz), 4.10 (1H, m), 3.81
(1H, m), 3.75 (1H, m), 2.66 (2H, m), 1.90–1.85 (2H, m),
1
+3.5 (c 1.8, CHCl3); H NMR (500 MHz, CDCl3) d 7.45–
7.30 (10H, m), 7.12 (2H, d, J¼8.5 Hz), 6.94 (2H, d,
J¼8.5 Hz), 5.07 (2H, s), 4.57 (2H, s), 4.00 (1H, br

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P. Alvarez-Bercedo et al. / Tetrahedron 62 (2006) 9641–9649
9646
1.70–1.65 (2H, m), 1.50 (1H, m), 1.41 (6H, s), 1.40–1.25
(24H, br m), 1.16 (1H, q, J¼11.5 Hz), 0.91 (3H, t,
J¼7 Hz); 13C NMR (125 MHz) d 157.0, 138.9, 137.3,
134.8, 98.4 (C), 129.3 (ꢂ2), 128.6 (ꢂ2), 128.4 (ꢂ2), 127.9
(ꢂ2), 127.8, 127.5, 127.4 (ꢂ2), 114.8 (ꢂ2), 74.7, 69.1,
65.8 (CH), 71.6, 70.1, 42.1, 37.7, 36.6, 36.5, 31.9, 30.3,
29.6 (several overlapped signals), 29.5 (several overlapped
signals), 29.4, 25.0, 22.7 (CH2), 30.4, 20.0, 14.1 (CH3); IR
nmax 3031, 1511, 1455, 1379, 1241, 736 cmꢀ1; HR EIMS
m/z (rel int.) 642.4664 (M+, 1), 627 (14), 584 (5), 476
(59), 197 (33), 91 (100). Calcd for C43H62O4, 642.4648.
Anal. Calcd for C43H62O4: C, 80.33; H, 9.72. Found: C,
80.22; H, 9.84.
445 (8), 402 (18), 107 (100). Calcd for C29H48O4,
460.3552. Anal. Calcd for C29H48O4: C, 75.61; H, 10.50.
Found: C, 75.69; H, 10.63.
4.1.9. (2R,4R,6S)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro
[5.1.5.2]pentadeca-9,12-dien-11-one (aculeatin B) (1)
and (2R,4R,6R)-4-hydroxy-2-tridecyl-1,7-dioxadispiro
[5.1.5.2]pentadeca-9,12-dien-11-one (aculeatin A) (2).
Ketone 13 (140 mg, 0.3 mmol) was dissolved in a 9:1 ace-
tone–water mixture (10 mL) and treated in four portions
with PhI(OCOCF3)2 (430 mg, 1 mmol), each portion being
added every hour. The reaction mixture was stirred overnight
at room temperature in the dark. Work-up (extraction with
EtOAc) and careful column chromatography on silica gel
(hexane–EtOAc, 4:1, then 3:2) yielded 1 (12.5 mg) and 2
(69 mg).
4.1.7. (4S,6R)-4-[(R)-2-Hydroxy-4-(4-hydroxyphenyl)
butyl]-2,2-dimethyl-6-n-tridecyl-[1,3]dioxane (12). Pd–C
10% (50 mg) was suspended in EtOAc (5 mL) and stirred
under an H2 atmosphere for 15 min. Compound 11
(321 mg, 0.5 mmol) dissolved in EtOAc (10 mL) was added
via syringe. The mixture was stirred at room temperature and
ambient pressure for 6 h, and filtered through Celite. Solvent
removal in vacuo and column chromatography on silica gel
(hexane–EtOAc, 4:1) gave 12 (162 mg, 70%): colorless
Aculeatin A (2): oil; [a]D ꢀ5.2 (c 0.9; CHCl3), lit.1a [a]D
ꢀ5.3 (c 0.2, CHCl3); IR nmax 3550 (br, OH), 1673 (ketone
1
C]O) cmꢀ1; H NMR (500 MHz, CDCl3) d 6.85 (1H, dd,
J¼10, 3 Hz), 6.76 (1H, dd, J¼10, 3 Hz), 6.14 (1H, dd,
J¼10, 1.7 Hz), 6.10 (1H, dd, J¼10, 1.7 Hz), 4.15–4.10
(2H, m), 3.35 (1H, br d, J¼10 Hz, OH), 2.38 (1H, m), 2.24
(1H, m), 2.05–2.00 (3H, m), 1.93 (1H, br d, J¼14 Hz),
1.79 (1H, br dd, J¼13.7, 2 Hz), 1.60–1.40 (5H, br m),
1.40–1.20 (20H, br m), 0.88 (3H, t, J¼6.8 Hz); 13C NMR
(125 MHz, CDCl3) d 185.3, 109.2, 79.8 (C), 150.9, 148.7,
127.4, 127.2, 65.4, 64.9 (CH), 39.2, 38.0, 36.0, 34.2, 32.0,
29.7 (several overlapped signals), 29.4, 25.7, 22.7 (CH2),
14.1 (CH3); HR EIMS m/z (rel int.) 418.3117 (M+, 2), 400
(M+ꢀH2O, 6), 310 (6), 236 (25), 165 (100), 107 (73). Calcd
for C26H42O4, M¼418.3083.
1
solid, mp 80–82 ꢁC; [a]D ꢀ1.9 (c 0.9, CHCl3); H NMR
(500 MHz, CDCl3) d 7.04 (2H, d, J¼8.5 Hz), 6.74 (2H, d,
J¼8.5 Hz), 5.40 (1H, br s, OH), 4.20 (1H, m), 3.94 (1H,
m), 3.82 (1H, m), 3.10 (1H, br s, OH), 2.73 (1H, m), 2.59
(1H, m), 1.80–1.50 (6H, br m), 1.45 (3H, s), 1.40 (3H, s),
1.40–1.25 (24H, br m), 0.88 (3H, t, J¼7 Hz); 13C NMR
(125 MHz) d 153.9, 134.2, 98.7 (C), 129.5 (ꢂ2), 115.3
(ꢂ2), 69.2, 68.3, 67.5 (CH), 41.9, 39.3, 36.4, 36.3, 31.9,
31.2, 29.6 (several overlapped signals), 29.5 (several over-
lapped signals), 29.4, 25.0, 22.7 (CH2), 30.3, 19.7, 14.1
(CH3); IR nmax 3370 (br, OH), 1514, 1459, 1262,
828 cmꢀ1; HR EIMS m/z (rel int.) 462.3732 (M+, 1), 447
(14), 386 (16), 107 (100). Calcd for C29H50O4, 462.3709.
Anal. Calcd for C29H50O4: C, 75.28; H, 10.89. Found: C,
75.22; H, 10.84.
Aculeatin B (1): oil; [a]D +53.2 (c 0.4, CHCl3), lit.1a [a]D
+50 (c 0.8, CHCl3); IR nmax 3460 (br, OH), 1670 (ketone
1
C]O) cmꢀ1; H NMR (500 MHz, CDCl3) d 6.99 (1H, dd,
J¼10, 2.9 Hz), 6.77 (1H, dd, J¼10, 2.9 Hz), 6.13 (1H, dd,
J¼10, 1.8 Hz), 6.10 (1H, dd, J¼10, 1.8 Hz), 4.36 (1H,
apparent quintuplet, J¼3.2 Hz), 3.86 (1H, m), 2.68 (1H, br
dd, J¼12.8, 7.2 Hz), 2.30 (1H, td, J¼12.3, 7.2), 2.10–2.00
(2H, m), 1.95–1.85 (2H, m), 1.60–1.40 (8H, br m), 1.40–
1.20 (19H, br m), 0.88 (3H, t, J¼6.9 Hz); 13C NMR
(125 MHz, CDCl3) d 185.7, 108.6, 77.6 (C), 152.2, 149.2,
127.2, 127.1, 69.5, 65.2 (CH), 40.7, 38.0, 35.8, 35.4, 35.3,
31.9, 29.7 (several overlapped signals), 29.4, 29.3, 25.9,
22.7 (CH2), 14.1 (CH3); HR EIMS m/z (rel int.) 418.3108
(M+, 9), 400 (M+ꢀH2O, 24), 310 (16), 235 (85), 165
(100), 107 (23). Calcd for C26H42O4, M¼418.3083.
4.1.8. 1-[(4R,6R)-(2,2-Dimethyl-6-tridecyl-[1,3]dioxan-4-
yl)]-4-(4-hydroxyphenyl)-butan-2-one (13). Oxalyl chlo-
ride (62 mL, ca. 0.7 mmol) was dissolved under N2 in dry
CH2Cl2 (3 mL). After cooling the solution to ꢀ78 ꢁC, dry
DMSO (56 mL, 0.8 mmol) was added dropwise with stirring
for 5 min. A solution of alcohol 12 (162 mg, 0.35 mmol) in
dry CH2Cl2 (1 mL) was added dropwise, with additional stir-
ring for 15 min. Addition of Et3N (210 mL, 1.5 mmol) was
followed by stirring for 15 min at ꢀ78 ꢁC and for further
1 h at 0 ꢁC. Work-up (extraction with CH2Cl2) and column
chromatography on silica gel (hexane–EtOAc, 7:3) gave ke-
tone 13 (140 mg, 87%): colorless solid, mp 53–55 ꢁC; [a]D
4.1.10. (3R,5S,7R)-3-Benzyloxy-1-(4-benzyloxyphenyl)
eicosane-5,7-diol (14). Tetramethylammonium triacetoxy-
borohydride (1.05 g, ca. 4 mmol) was dissolved under N2
in an acetonitrile–acetic acid 1:1 mixture (5 mL). After stir-
ring for 1 h at room temperature, the mixture was cooled to
ꢀ30 ꢁC and treated dropwise with a solution of aldol 9
(300 mg, 0.5 mmol) in dry acetonitrile (3 mL). The solution
was stirred at ꢀ30 ꢁC for 12 h and at 0 ꢁC for further 2 h.
After quenching with aq 1 M sodium potassium tartrate
(2 mL), the mixture was stirred for 1 h at room temperature.
Work-up (extraction with CH2Cl2) and column chromato-
graphy of the residue on silica gel (hexane–EtOAc, 4:1) af-
forded diol 14 (260 mg, 86%): colorless solid, mp 57–59 ꢁC;
1
ꢀ4.2 (c 2.8, CHCl3); H NMR (500 MHz, CDCl3) d 7.00
(2H, d, J¼8.5 Hz), 6.74 (2H, d, J¼8.5 Hz), 5.90 (1H, br s,
OH), 4.32 (1H, m), 3.81 (1H, m), 2.85–2.70 (4H, br m),
2.67 (1H, dd, J¼15.7, 7.2 Hz), 2.40 (1H, dd, J¼15.7,
5.3 Hz), 1.50 (1H, m), 1.42 (3H, s), 1.37 (3H, s), 1.40–
1.25 (24H, br m), 1.11 (1H, q, J¼11.5 Hz), 0.88 (3H, t,
J¼7 Hz); 13C NMR (125 MHz) d 209.0, 154.2, 132.7, 98.8
(C), 129.3 (ꢂ2), 115.4 (ꢂ2), 69.0, 65.9 (CH), 36.8, 36.3,
31.9, 29.6 (several overlapped signals), 29.5 (several over-
lapped signals), 29.3, 24.9, 22.7 (CH2), 30.1, 19.7, 14.1
(CH3); IR nmax 3390 (br, OH), 1712 (C]O), 1614, 1515,
1379, 828 cmꢀ1; HR EIMS m/z (rel int.) 460.3568 (M+, 1),
1
[a]D ꢀ19.6 (c 1.38, CHCl3); H NMR (500 MHz, CDCl3)

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P. Alvarez-Bercedo et al. / Tetrahedron 62 (2006) 9641–9649
9647
d 7.45–7.30 (10H, m), 7.10 (2H, d, J¼8.5 Hz), 6.92 (2H, d,
J¼8.5 Hz), 5.06 (2H, s), 4.63 (1H, d, J¼11 Hz), 4.44 (1H, d,
J¼11 Hz), 4.18 (1H, m), 3.92 (1H, m), 3.78 (1H, m), 2.70–
2.60 (2H, m), 2.00 (2H, br s, OH), 2.00–1.90 (2H, m), 1.70–
1.40 (4H, m), 1.40–1.25 (24H, br m), 0.91 (3H, t, J¼7 Hz);
13C NMR (125 MHz) d 157.1, 137.8, 137.2, 134.2 (C), 129.3
(ꢂ2), 128.6 (ꢂ2), 128.5 (ꢂ2), 128.1 (ꢂ2), 127.9 (ꢂ2), 127.4
(ꢂ2), 114.9 (ꢂ2), 79.2, 69.4, 68.8 (CH), 70.6, 70.1, 43.0,
40.7, 37.6, 35.3, 31.9, 30.0, 29.7 (several overlapped
signals), 29.6 (several overlapped signals), 29.3, 25.7,
22.7 (CH2), 14.1 (CH3); IR nmax 3420 (br, OH), 3063,
3031, 1511, 1455, 1240, 736 cmꢀ1; HR FABMS m/z
603.4401 (M+H+). Calcd for C40H59O4, 603.4413. Anal.
Calcd for C40H58O4: C, 79.69; H, 9.70. Found: C, 79.82;
H, 9.82.
70.8, 70.1, 46.2, 42.7, 37.8, 36.3, 31.9, 30.7, 29.7 (several
overlapped signals), 29.6 (several overlapped signals),
25.0, 22.7 (CH2), 26.0 (ꢂ6), 14.1, ꢀ3.9 (ꢂ2), ꢀ4.0 (ꢂ2)
(CH3); IR nmax 3032, 1511, 1250, 1078, 835 cmꢀ1; HR
EIMS m/z (rel int.) 773.5371 (M+ꢀtBu, 1), 641 (4), 549
(6), 327 (58), 91 (100). Calcd for C52H86O4Si2–tBu,
773.5360. Anal. Calcd for C52H86O4Si2: C, 75.12; H,
10.43. Found: C, 75.24; H, 10.54.
4.1.13. 4-[(3R,5R,7R)-5,7-Bis(tert-butyldimethylsilyl-
oxy)-3-hydroxyeicosyl]phenol (17). Pd–C 10%(250 mg)
was suspended in EtOAc (8 mL) and stirred under H2 atmo-
sphere for 15 min. Compound 16 (233 mg, 0.28 mmol) dis-
solved in EtOAc (5 mL) was added via syringe. The mixture
was stirred at room temperature and ambient pressure for
15 min and filtered through Celite (caution: longer reaction
times lead to partial desilylation!). Solvent removal in vacuo
and column chromatography on silica gel (hexane–EtOAc,
4:1) furnished 17 (135 mg, 74%): oil; [a]D +14 (c 1.5,
CHCl3); 1H NMR (500 MHz, CDCl3) d 7.06 (2H, d,
J¼8.5 Hz), 6.74 (2H, d, J¼8.5 Hz), 4.90 (1H, br s, OH),
3.89 (1H, br quintuplet, Jz5 Hz), 3.78 (1H, m), 3.65 (1H,
br quintuplet, Jz5.5 Hz), 3.30 (1H, br s, OH), 2.70 (1H,
m), 2.61 (1H, m), 1.80–1.55 (6H, m), 1.40–1.25 (24H, br
m), 0.90 (21H, br s), 0.11 (6H, s), 0.05 (6H, s); 13C NMR
(125 MHz) d 153.7, 134.4, 18.1, 17.9 (C), 129.5 (ꢂ2),
115.2 (ꢂ2), 71.7, 70.2, 70.1 (CH), 46.5, 44.3, 39.7, 37.4,
31.9, 30.8, 29.7 (several overlapped signals), 29.6 (several
overlapped signals), 29.4, 25.0, 22.7 (CH2), 26.0 (ꢂ3),
25.9 (ꢂ3), 14.1, ꢀ3.9, ꢀ4.2 (ꢂ2), ꢀ4.3 (CH3); IR nmax
4.1.11. (4R,6R)-4-[(R)-2-Benzyloxy-4-(4-benzyloxy-
phenyl) butyl]-2,2-dimethyl-6-n-tridecyl-[1,3]dioxane
(15). Diol 14 (45 mg, 0.075 mmol) was dissolved in dry ace-
tone (1 mL) and treated with camphorsulfonic acid (1 mg,
ca. 0.005 mmol) and 2,2-dimethoxypropane (0.5 mL). After
˚
adding activated 3 A molecular sieves (50 mg), the mixture
was stirred overnight at room temperature. The mixture was
then poured onto satd aq NaHCO3 and worked-up (extrac-
tion with CH2Cl2). Column chromatography on silica gel
(hexane–EtOAc, 99:1) furnished 15 (43 mg, 89%): oil;
[a]D ꢀ4 (c 2, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.45–7.30 (10H, m), 7.08 (2H, d, J¼8.5 Hz), 6.91 (2H,
d, J¼8.5 Hz), 5.06 (2H, s), 4.53 (1H, d, J¼11.5 Hz), 4.51
(1H, d, J¼11.5 Hz), 3.94 (1H, m), 3.78 (1H, m), 3.55 (1H,
br quintuplet, Jz6 Hz), 2.75–2.65 (2H, m), 2.00 (1H, m),
1.95–1.85 (2H, m), 1.65–1.50 (3H, m), 1.40 (2H, m), 1.37
(3H, s), 1.40–1.25 (25H, br m), 0.92 (3H, t, J¼7 Hz); 13C
NMR (125 MHz) d 157.0, 138.9, 137.3, 134.7, 100.1 (C),
129.3 (ꢂ2), 128.5 (ꢂ2), 128.3 (ꢂ2), 127.9, 127.8, 127.5,
127.4 (ꢂ2), 114.8 (ꢂ2), 74.7, 66.6, 63.7 (CH), 70.6, 70.1,
40.1, 39.0, 36.0, 35.9, 31.9, 30.5, 29.7 (several overlapped
signals), 29.6 (several overlapped signals), 29.5, 29.3,
25.4, 22.7 (CH2), 24.8, 24.7, 14.1 (CH3); IR nmax 3031,
1511, 1455, 1378, 1224, 734 cmꢀ1; HR EIMS m/z (rel int.)
642.4645 (M+, 1), 627 (1), 584 (25), 566 (5), 476 (9), 197
(13), 91 (100). Calcd for C43H62O4, 642.4648. Anal. Calcd
for C43H62O4: C, 80.33; H, 9.72. Found: C, 80.41; H, 9.62.
3380 (br, OH), 1515, 1471, 1463, 1255, 1078, 835 cmꢀ1
;
HR FABMS m/z 651.5209 (M+H+). Calcd for
C38H75O4Si2, 651.5204. Anal. Calcd for C38H74O4Si2: C,
70.09; H, 11.45. Found: C, 69.94; H, 11.54.
4.1.14. (5S,7R)-5,7-Bis(tert-butyldimethylsilyloxy)-1-
(4-hydroxyphenyl)eicosan-3-one (18). Oxalyl chloride
(34 mL, ca. 0.4 mmol) was dissolved under N2 in dry
CH2Cl2 (2 mL). After cooling the solution to ꢀ78 ꢁC, dry
DMSO (35 mL, ca. 0.5 mmol) was added dropwise with stir-
ring for 5 min. A solution of alcohol 17 (130 mg, 0.2 mmol)
in dry CH2Cl2 (0.5 mL) was added dropwise, with additional
stirring for 15 min. Addition of Et3N (120 mL, 0.85 mmol)
was followed by stirring for 10 min at ꢀ78 ꢁC. Work-up (ex-
traction with CH2Cl2) and column chromatography on silica
gel (hexane–EtOAc, 7:3) gave 18 (105 mg, 81%): oil; [a]D
4.1.12. 1-Benzyloxy-4-[(3R,5R,7R)-3-benzyloxy-5,7-bis-
(tert-butyldimethylsilyloxy)eicosyl]benzene (16). Diol 14
(193 mg, 0.32 mmol) was dissolved in dry CH2Cl2 (5 mL)
and treated sequentially with 2,6-lutidine (350 mL,
3 mmol) and TBSOTf (550 mL, ca. 2.5 mmol). The reaction
mixture was stirred at reflux for 6 h and worked-up (extrac-
tion with CH2Cl2). Column chromatography on silica gel
(hexane–EtOAc, 19:1) gave 16 (242 mg, 91%): oil; [a]D
+13.6 (c 1.6, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.45–
7.30 (10H, m), 7.06 (2H, d, J¼8.5 Hz), 6.88 (2H, d,
J¼8.5 Hz), 5.02 (2H, s), 4.54 (1H, d, J¼11.5 Hz), 4.44
(1H, d, J¼11.5 Hz), 3.84 (1H, br quintuplet, Jz6 Hz),
3.72 (1H, br quintuplet, Jz5.5 Hz), 3.57 (1H, br quintuplet,
Jz5.5 Hz), 2.70 (1H, m), 2.58 (1H, m), 1.90–1.75 (3H, br
m), 1.60 (2H, m), 1.40 (1H, m), 1.40–1.25 (24H, br m),
0.86 (21H, br s), 0.05 (3H, s), 0.02 (6H, s), 0.00 (3H, s);
13C NMR (125 MHz) d 157.1, 139.0, 137.3, 134.8, 18.1,
18.0 (C), 129.3 (ꢂ2), 128.6 (ꢂ2), 128.5 (ꢂ2), 128.1 (ꢂ2),
127.9 (ꢂ2), 127.4 (ꢂ2), 114.8 (ꢂ2), 75.7, 70.0, 67.7 (CH),
1
+10.6 (c 1.5, CHCl3); H NMR (500 MHz, CDCl3) d 7.02
(2H, d, J¼8.5 Hz), 6.74 (2H, d, J¼8.5 Hz), 5.50 (1H, br s,
OH), 4.21 (1H, br quintuplet, Jz6 Hz), 3.69 (1H, br quintu-
plet, Jz6 Hz), 2.80 (2H, m), 2.72 (2H, m), 2.60 (1H, dd,
J¼15, 7.5 Hz), 2.60 (1H, dd, J¼15, 4.7 Hz), 1.62 (1H, m),
1.58 (1H, m), 1.42 (2H, m), 1.40–1.25 (22H, br m), 0.89
(12H, br s, overlapping a methyl triplet), 0.86 (9H, s), 0.08
(3H, s), 0.05 (6H, s), 0.03 (3H, s); 13C NMR (125 MHz)
d 209.3, 154.0, 133.0, 18.1, 18.0 (C), 129.4 (ꢂ2), 115.4
(ꢂ2), 70.1, 67.5 (CH), 51.3, 46.4, 45.8, 37.7, 31.9, 30.8,
29.7 (several overlapped signals), 29.6 (several overlapped
signals), 29.4, 25.0, 22.7 (CH2), 26.0 (ꢂ3), 25.9 (ꢂ3),
14.1, ꢀ4.1, ꢀ4.2 (ꢂ2), ꢀ4.4 (CH3); IR nmax 3400 (br,
OH), 1704 (C]O), 1515, 1466, 1362, 1255, 1077,
835 cmꢀ1; HR FABMS m/z 649.5052 (M+H+). Calcd for
C38H73O4Si2, 649.5047. Anal. Calcd for C38H72O4Si2: C,
70.31; H, 11.18. Found, C, 70.44; H, 11.24.

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P. Alvarez-Bercedo et al. / Tetrahedron 62 (2006) 9641–9649
9648
Mayr, S.; Rali, T.; Sticher, O. Phytochemistry 2001, 57,
1281–1285.
4.1.15. (2R,4S,6S)-4-Hydroxy-2-tridecyl-1,7-dioxadis-
piro [5.1.5.2]pentadeca-9,12-dien-11-one (aculeatin D)
(4) and (2R,4S,6R)-4-hydroxy-2-tridecyl-1,7-dioxadis-
piro [5.1.5.2]pentadeca-9,12-dien-11-one (6-epi-aculeatin
D) (19). Ketone 18 (65 mg, 0.1 mmol) was dissolved under
N2 in dry DMF (2 mL), cooled to 0 ꢁC and treated with
TASF (138 mg, 0.5 mmol). The mixture was stirred for
90 min at 0 ꢁC, then for further 4 h at room temperature.
Work-up (extraction with Et2O) and solvent removal invacuo
gave an oily residue, which was directly used in the next step.
2. Confusion has to be avoided between these two compounds and
the coumarin aculeatin, isolated from Toddalia asiatica (T. acu-
leata): Ishii, H.; Kobayashi, J.-I.; Sakurada, E.; Ishikawa, T.
J. Chem. Soc. Perkin Trans. 1 1992, 1681–1684; In addition, the
name aculeatin has also been given to an alkaloid of undefined
ꢀ
structure isolated from Papaver aculeatum: Maturova, M.;
ˇ
ꢀ
ꢀ
ꢀ
Pavlaskova, D.; Santavy, F. Planta Med. 1966, 14, 22–41.
3. For the importance of Michael acceptor moieties for cytotoxic-
ity, see, for example: Buck, S. B.; Hardouin, C.; Ichikawa, S.;
Soenen, D. R.; Gauss, C.-M.; Hwang, I.; Swingle, M. R.;
Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J. Am. Chem.
Soc. 2003, 125, 15694–15695.
The crude material from above was dissolved in a 9:1
acetone–water mixture (10 mL) and treated with PhI-
(OCOCF3)2 (86 mg, 0.2 mmol). The reaction mixture was
stirred at room temperature in the dark until disappearance
of the starting material (ca. 25 min, monitoring with TLC!).
Work-up (extraction with EtOAc) and careful column chro-
matography on silica gel (hexane–EtOAc, 4:1, then 3:2)
yielded 4 (9 mg) and 19 (24 mg).
4. (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–1661;
(b) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041–
ꢁ
2114; (c) Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55,
7661–7706; (d) Thirsk, C.; Whiting, A. J. Chem. Soc. Perkin
Trans. 1 2002, 999–1023; (e) Yeung, K.-S.; Paterson, I.
Angew. Chem. Int. Ed. 2002, 41, 4632–4653; (f) Suenaga, K.
Bull. Chem. Soc. Jpn. 2004, 77, 443–451.
Aculeatin D (4): oil; [a]D +43.5 (c 0.2, CHCl3), lit.1b [a]D
+46.5 (c 1, CHCl3); IR nmax 3430 (br, OH), 1670 (ketone
5. (a) Wong, Y.-S. Chem. Commun. 2002, 686–687; (b) Baldwin,
ꢀ
J. E.; Adlington, R. M.; Sham, V. W.-W.; Marquez, R.; Bulger,
1
C]O) cmꢀ1; H NMR (500 MHz, C6D6) d 6.89 (1H, dd,
P. G. Tetrahedron 2005, 61, 2353–2363.
6. A part of these results has been presented in preliminary form:
J¼10, 3 Hz), 6.21 (1H, dd, J¼10, 2.8 Hz), 6.07 (1H, dd,
J¼10, 1.8 Hz), 6.04 (1H, dd, J¼10, 1.8 Hz), 3.37 (1H, m),
2.95 (1H, m), 1.88 (1H, m), 1.79 (1H, m), 1.73 (1H, m),
1.55 (2H, m), 1.50–1.20 (26H, br m), 1.14 (1H, m), 1.01
(1H, m), 0.91 (3H, t, J¼7 Hz); 13C NMR (125 MHz,
C6D6) d 185.0, 109.6, 78.5 (C), 152.0, 149.0, 127.5, 127.3,
71.8, 66.9 (CH), 44.2, 41.5, 36.5, 35.4, 33.2, 32.5, 30.5
(br, several overlapped signals), 26.5, 23.5 (CH2), 14.8
(CH3); HR EIMS m/z (rel int.) 418.3059 (M+, 2), 400
(M+ꢀH2O, 16), 310 (5), 235 (35), 165 (80), 120 (94), 107
(100). Calcd for C26H42O4, M¼418.3083.
ꢀ
Falomir, E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2005, 46, 8407–8410.
7. Ronald, R. C.; Wheeler, C. J. J. Org. Chem. 1984, 49, 1658–
1660.
8. Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron
Lett. 1997, 38, 2417–2420; For a recent review on asymmetric
allylborations, see: Ramachandran, P. V. Aldrichimica Acta
2002, 35, 23–35.
9. Uray, G. Houben–Weyl’s Methods of Organic Chemistry,
Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Georg Thieme: Stuttgart,
1996; Vol. 1, pp 253–292.
6-Epi-aculeatin D (19): oil; [a]D +5.7 (c 0.3, CHCl3); IR
1
nmax 3430 (br, OH), 1671 (ketone C]O) cmꢀ1; H NMR
10. Tsuji, J. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford, 1993;
Vol. 7, pp 449–468; Experimental procedure based on: Tsuji,
J.; Nagashima, H.; Nemoto, H. Organic Synthesis Collective
Volume VII; Wiley: New York, NY, 1990; pp 137–139.
11. Cowden, C. J.; Paterson, I. Organic Reactions; Paquette, L. A.,
Ed.; Wiley: New York, NY, 1997; Vol. 51, pp 1–200.
12. The aldol addition step of the enolborane of b-alkoxy methyl
ketone 8 to n-tetradecanal takes place with complete stereo-
selectivity, which reflects a high anti-1,5-induction. This re-
mote induction was previously observed by other groups in
related cases: Paterson, I.; Gibson, K. R.; Oballa, R. M.
Tetrahedron Lett. 1996, 37, 8585–8588 and: Evans, D. A.;
(500 MHz, C6D6) d 6.68 (1H, dd, J¼10, 3.2 Hz), 6.15–
6.10 (2H, m), 6.01 (1H, dd, J¼10, 2 Hz), 3.90 (1H, m),
3.70 (1H, m), 2.00 (1H, m), 1.87 (2H, m), 1.65 (1H, m),
1.55 (1H, m), 1.50–1.20 (27H, br m), 1.07 (1H, q,
J¼12 Hz), 0.90 (3H, t, J¼6.9 Hz); 13C NMR (125 MHz,
C6D6) d 185.2, 109.6, 79.7 (C), 151.4, 149.3, 127.5, 127.2,
69.7, 65.7 (CH), 44.3, 41.8, 39.4, 37.0, 35.5, 32.9, 30.5
(br, several overlapped signals), 26.6, 23.5 (CH2), 14.8
(CH3); HR EIMS m/z (rel int.) 418.3068 (M+, 6), 400
(M+ꢀH2O, 23), 310 (27), 235 (35), 165 (100), 107 (70).
Calcd for C26H42O4, M¼418.3083.
Acknowledgements
ˆ ꢀ
Cote, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc.
2003, 125, 10893–10898; The subsequent in situ reduction
of the aldol with LiBH4 gives only a syn-1,3-diol fragment,
as expected: Paterson, I.; Channon, J. A. Tetrahedron Lett.
1992, 33, 797–800.
Financial support has been granted by the Spanish Ministry
of Science and Technology (projects BQU2002-00468,
CTQ2005-06688-C02-01 and CTQ2005-06688-C02-02),
by the BANCAJA-UJI foundation (project P1-1A2005-15)
and by the AVCyT (projects GRUPOS03/180 and GV05/
52). P.A.-B. thanks the Spanish Ministry of Education and
Science for a predoctoral fellowship (FPI program).
13. For general reviews on hypervalent iodine compounds, see: (a)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584;
(b) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903; (c)
Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656–3665; (d)
Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006, ix, 26–58; For
oxidations of phenolic compounds with hypervalent iodine
reagents, see: Moriarty, R. M.; Prakash, O. Organic Reactions;
Overman, L. E., Ed.; Wiley: New York, NY, 2001; Vol. 57,
References and notes
1. (a) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. Helv.
Chim. Acta 2000, 83, 2939–2945; (b) Heilmann, J.; Brun, R.;

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9649
pp 327–415; For reagents of oxidative spiroacetalizations
of arenes, including hypervalent iodine compounds, see:
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Soc. 1988, 110, 3560–3578.
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18. The sensitivity of the b-oxygenated ketone moiety in 18 toward
acidic or basic reagents was a concern here.
14. Spirocyclic amino compounds can also be prepared with this
oxidative methodology. See: Canesi, S.; Belmont, P.;
Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett.
2002, 43, 5193–5195.
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159–349.
16. The way of drawing the aculeatins in Ref. 1 is confusing, as two
spiro connected rings are simultaneously used as reference
rings for stereochemical representation. We prefer the way
depicted in Figure 1, where only the tetrahydropyran moiety
is used as the reference ring.
19. This behavior is well precedented: (a) Herbert, J. M.; Knight,
J. G.; Sexton, B. Tetrahedron 1996, 52, 15257–15266; (b)
Kiyooka, S.; Shahid, K. A.; Goto, F.; Okazaki, M.; Shuto, Y.
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21. Freshly prepared by PCC oxidation of n-tetradecanol.