Towards the biosynthesis of the aromatic products of the Mediterranean mollusc Scaphander lignarius: isolation and synthesis of analogues of lignarenones

Article abstract of DOI:10.1016/j.tet.2007.04.061

Secondary metabolites of the Mediterranean mollusc Scaphander lignarius from different collection sites have been investigated, proving the constant presence of a number of minor metabolites correlated to the already known lignarenones. Complete character

Full text of DOI:10.1016/j.tet.2007.04.061

Tetrahedron 63 (2007) 7256–7263
Towards the biosynthesis of the aromatic products of the
Mediterranean mollusc Scaphander lignarius: isolation and
synthesis of analogues of lignarenones
a,
Giorgio Della Sala,a Adele Cutignano,b Angelo Fontana,b, Aldo Spinella,
*
*
Gianpiero Calabrese,a Anna Domenech Coll,b Giuliana d’Ippolito,b
Carmela Della Monicaa and Guido Ciminob
aUniversitaꢀ degli Studi di Salerno, Dipartimento di Chimica, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
bIstituto di Chimica Biomolecolare del CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy
Received 5 January 2007; revised 29 March 2007; accepted 19 April 2007
Available online 25 April 2007
Abstract—Secondary metabolites of the Mediterranean mollusc Scaphander lignarius from different collection sites have been investigated,
proving the constant presence of a number of minor metabolites correlated to the already known lignarenones. Complete characterization of
the new metabolites has been supported by enantioselective synthesis. The data are consistent with the origin of this unique class of u-phenyl-
octanoids from a common polyketide pathway.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
u-phenyl alkenyl 2-hydroxy and 2-keto derivatives 7–11. All
these compounds are ascribable to a single biosynthetic path-
way of which the aldehyde 12, also isolated and characterized
from the mollusc extracts, could be a potential intermediate.
The absolute stereochemistry of the chiral metabolites 8 and
10 has been proven by enantioselective synthesis.
A few species of marine molluscs of the order Cephalaspidea
(Gastropoda, Opisthobranchia) produce a structurally ho-
mogenous group of oxygenated aryl-alkenyl compounds
(e.g., 1–4), which in some cases, have been proven to func-
tion as alarm pheromones in intra-specific communication.1
The biosynthesis of these molecules is basically unknown,
even if they all are notional products of a PKS-like pathway
involving branched aryl residues as starter units and acetate,
or metabolic equivalents, for the elongation steps.2 A first
piece of evidence in support to this biogenesis comes from
our recent finding that the 3-alkylpyridine motif of haminols
(e.g., 4) derives from sequential condensation of malonyl-
Co-A onto nicotinic acid.3 Scaphander lignarius, a deep
water cephalaspidean mollusc, contains an unusual group
of branched phenyloctanoids named lignarenones (5 and 6)
differing in the double bond configuration at the trienic
chain.4 In order to approach the biosynthesis of lignarenones,
we have re-collected the organisms from different sites and
analyzed the metabolite content as a function of the geo-
graphic variability. In this manuscript, we report the result
of this study that shows the unvarying presence of the previ-
ously described lignarenones 5 and 6, together with minor
O
O
OH
1
2
OAc
O
N
N
3
4
2. Results and discussion
In addition to lignarenones A and B (5 and 6), lipophilic ex-
tracts of S. lignarius from different sites of Italy and Spain
(see Section 4), revealed the presence of a mixture of minor
compounds (7–11). In particular, specimens collected along
the southern coasts of Italy gave variable mixtures of 5 and 6,
as major components, together with a new derivative (7) here
named lignarenone C. Except for the presence of the ethyl
group (d 2.46 and 1.14) a to the carbonyl moiety, this last
Keywords: Structure elucidation; Stereochemistry; Natural products; Bio-
synthesis; Chemical ecology.
* Corresponding authors. Fax: +39 0818041770 (A.F.); fax: +39 089969585
(A.S.); e-mail addresses: afontana@icmib.na.cnr.it; spinella@unisa.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.061

G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
7257
O
B (6), which represented 90% of the pheromone mixture,
contained dihydrolignarenone B (8) and a significant amount
of a 9:1 mixture of the E/Z isomeric alcohols 10 and 11. In
the COSY spectrum, both these compounds, named dihydro-
lignarenol B and dihydrolignarenol A, respectively, revealed
a methyl doublet at about d 1.20 (see Section 4) coupled to
a downshifted signal at about d 3.80. The other 1H NMR sig-
nals were consistent with the depicted structures, showing
major differences only due to the coupling constant between
H-5 and H-6 (15.6 Hz in 10 and 10.6 Hz in 11). The presence
of the hydroxyl group at C-2 was also consistent with the
APCI+ MS molecular ion (m/z 217) of both products and
with the resonance of the alcoholic carbon at 70.8 ppm in
the 13C NMR spectrum of the major isomer 10. Furthermore,
oxidation of this latter compound with tetra-n-propylammo-
nium perruthenate (TPAP) and N-methylmorpholine N-
oxide (NMO)5 gave quantitatively dihydrolignarenone B (8).
As shown in Figure 1, the CD spectra of the oxidation prod-
uct of 10 and natural 8 were identical, thus proving that the
two molecules share the same configuration at C-3.
O
6
5
O
O
6'
3
3
10
2
2
5
7
1
9
2'
4'
7
8
OH
O
10
9
CHO
OH
11
12
compound showed spectroscopic data identical to those of
lignarenone B (6),4 with an extended conjugation (lmax
In order to determine the absolute stereochemistry of di-
hydrolignarenones and dihydrolignarenols we designed an
enantioselective synthesis based on Suzuki coupling be-
tween trans-phenylvinylboronic acid (13) and the chiral vi-
nyl iodide 14 obtainable in three steps from 16 (Scheme 1).
All possible diasteroisomers of this last compound are acces-
sible from the synthetic procedure proposed by Brown and
Bhat6 through the reaction of ethanal with chiral crotyldi-
alkylborane prepared from (Z or E) 2-butene and (+ or ꢀ)
b-methoxydiisopinocampheylborane (Ipc2BOMe).
¼
348 nm) involving a linear triene system (see Section 4).
The molluscs collected along the Italian coasts also
contained 3,4-dihydroderivatives of 6 and 7, here named
dihydrolignarenone B (8) and dihydrolignarenone C (9),
together with very minor amounts of the alcohol 10.
Compounds 8 and 9 shared the presence of NMR signals of
one (E,E)-1,3-butadiene group (d 5.73, dt, H-5; d 6.22, dd,
H-6; d 6.48, d, H-8; d 6.72, dd, H-7) and one methyl doublet
(d 1.12, H3-9), but as for the unsaturated homologues 6 and
7, they differed in the terminal alkyl residues, a methyl group
for 8 (d 2.17, s) and an ethyl group for 9 (d 1.05, t, J¼7.2 Hz;
d 2.48, m). The 1H NMR spectrum of the alcohol 10, on the
contrary, was characterized by two methyl doublets at d 1.19
and 0.93, together with one hydroxymethine signal at d 3.78.
These data were suggestive of the presence of one hydroxy
group at C-2 of the lignarenone skeleton. The definitive
demonstration of the structure was achieved only after ex-
traction of S. lignarius from the eastern coast of Spain. In
fact, these molluscs, in addition to lignarenones A (5) and
OTBDPS
B(OH)2
*
10
+
I
*
14
13
OH
OTBDPS
O
H
H
O
16
15
Scheme 1. Retrosynthesis of lignarenones in S. lignarius.
Figure 1. CD spectra of: (A) dihydrolignarenone B (8) and (B) the oxidation product of dihydrolignarenol B (10). Spectra were recorded in MeOH at concen-
tration of 10ꢀ5 mg/L.

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G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
OH
OTBDPS
OTBDPS
ref. 5
OHC
BH3
TBDPSCl
imidazole
DMF
HO
Me2S
16a
17a
18a
OTBDPS
OR
OTBDPS
13, Pd(PPh3)4
CrCl2
CHI3
PDC
I
1M KOH aq, THF
15a
14a
O
TPAP, NMO
8
19a R= TBDPS
10 R = H
TBAF/
THF
Scheme 2. Enantioselective synthesis of syn (2S,3S)-dihydrolignarenone B (10).
Table 1. NMR chemical shifts of natural and synthetic samples of dihydrolignarenol B (10)a
Position
Natural compound (10)
2S,3S Synthetic
2R,3S Synthetic
d
1H
d
13C
d
1H
d
13C
d
1H
d
13C
1
2
3
4
5
0.93
3.78
14.0
70.8
40.0
36.4
0.93
3.78
1.61
2.02 and 2.33
5.82
14.0
70.8
40.1
36.5
0.92
3.68
1.63
2.04 and 2.36
5.83
15.0
71.5
40.5
36.3
1.60b
2.02 and 2.32
5.82
134.0
134.0
134.0
Data were recorded in CDCl3.
The remaining signals are identical in the three samples.
Partially overlapped by the DHO signal.
a
b
For the synthesis of 2S,3S stereoisomer (Scheme 2), asym-
metric crotylation of (Z)-2-butene with (+)-Ipc2BOMe
gave a chiral crotyldiisopinocampheylborane that, after re-
action with ethanal at ꢀ78 ꢁC, afforded the expected homo-
allylic alcohol with S,S stereochemistry (16a, 72% yield,
98% de, 92% ee). After protection of the hydroxyl group,
the terminal alkene 17a was hydroborated by BH3$Me2S
to provide first the primary alcohol (18a) and, after Cr(VI)
oxidation, the aldehyde 15a (50% yield, three steps). Con-
version of aldehyde to vinyl iodide 14a occurred via a Takai
reaction7 in 57% yield. Finally, Suzuki coupling of iodide
14a and trans-phenylvinylboronic acid (13) afforded com-
pound 19a whose deprotection gave a dihydrolignarenol
synthesis of the anti isomer (10b), (2R,3S) 8-phenyl-2-
methyl-octa-5,7-dien-2-ol, from (E)-2-butene (Scheme 3).
In fact, the chemical shifts of a few NMR signals of this
last compound were diagnostically different to conclude that
the natural product could not have the same configuration
of the synthetic 2R,3S material (Table 1), thus establishing
unambiguously the configuration of dihydrolignarenol B
(10) as 2S,3S.
OH
OH
ref. 5
16b
10b
1
showing that H and 13C NMR spectra were identical to
Scheme 3. Enantioselective synthesis of anti (2R,3S)-dihydrolignarenone B
(10b). The synthetic steps are identical to those described in Scheme 2.
that of the natural product 10 (see Section 4). The subsequent
oxidation at C-3 of this compound with tetra-n-propyl-
ammonium perruthenate (TPAP) and N-methylmorpholine
N-oxide (NMO) afforded in good yield a keto derivative
showing that NMR and CD spectra were identical to the
natural dihydrolignarenone B (8) (synthetic q297¼1764.6,
3. Conclusions
Extracts of S. lignarius from Mediterranean sites contain
a unique family of aryl-alkenyl compounds embracing the
known lignarenones 5 and 6 and the unprecedented ana-
logues 7–11. In comparison with lignarenones A and B (5
and 6) that constitute about 14ꢂ6% of the lipophilic extract
in every group of animals studied here, the structures of the
minor metabolites (on the whole, 2.1ꢂ1.1% of the lipophilic
extract) differ for one of these three major aspects: (a) pres-
ence of an alkyl chain of nine carbon atoms (7 and 9), (b) re-
duction of the carbonyl group (10 and 11) and (c) absence of
C-3–C-4 double bond (8 and 11). As outlined in Scheme 4,
all these changes are consistent with the origin of the prod-
ucts of S. lignarius from a single PKS pathway based on
q268¼ꢀ97.3, c 12 mg/mL; natural q297¼2143.3, q267
126.4, c 10 mg/mL).
¼
This proved the 3S configuration for the chiral centre not
only of dihydrolignarenone B (8) but also of dihydrolign-
arenone C (9), as the two compounds had very similar po-
larimetric values ([a]D23 +8.8 for synthetic 8; [a]2D3 +11.4 for
natural 8; [a]2D3 +7.4 for 9). On the other hand, considering
1
the strong similarities of the H and 13C NMR spectra of
natural and synthetic products, the above synthesis was
also suggestive of 2S,3S stereochemistry for dihydrolign-
arenol B (10). This hypothesis was rigorously proven by

G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
7259
CO2
-
CO2
malonyl-CoA
polyketide
O
assembly
S-Enz
or
O
5
-
CO2
1
5
3
CHO
trapped
(CET-PPh3)
CoA-SH
12
5
3
1
CO2Et
12a
Scheme 4. Proposed biogenesis of lignarenones via polyketide pathway.
benzoic or cinnamic acid as a starter unit and elongation
rounds of malonyl-coenzyme-A. The metabolic connection
of Scaphander metabolites is supported by the stereochem-
ical correlations between dihydrolignarenones (8 and 9) and
dihydrolignarenols (10 and 11), whereas the finding of
5-phenyl-2E,4E-pentadienal (12), a potential intermediate
derivative of the emerging molecule, in the extracts of
the molluscs appears as an indirect evidence in support of
the processive mechanism (Scheme 4). The aromatic alde-
hyde (12) was characterized as ethyl ester derivative 7-phenyl-
2E,4E,6E-heptatrienoic acid (12a) by a trapping approach
involving treatment of aldehyde-containing fractions with
carbethoxyethylidene-triphenylphosphorane (CET-TPP).8
Microanalyses were performed on a ThermoFinnigan Ele-
mental Analyser EA 1112. GC–MS spectra were recorded
on a GC Trace 2000 SERIES connected to Finnigan Thermo-
quest GLQ Plus 2000 spectrometer with an ion trap detector.
Optical rotations were measured with a JASCO DIP-1000
polarimeter. All the moisture or air sensitive reactions were
carried out in anhydrous solvents and flame-dried glassware
under dry nitrogen or argon. Reactions were monitored by
TLC, using silica gel 0.25 mm plates (Merck). Yields refer
to isolated pure products.
4.2. Collection, extraction and fractionation
S. lignarius was collected from Malgrat (22 specimens) and
Blanes (82 specimens) (Southeast of Spain), Gulf of Naples
(Southwest of Italy) (600 specimens) and Crotone (South
east of Italy) (170 specimens) by dredging (around 80 m
of depth). Samples were kept frozen at ꢀ20 ꢁC till the anal-
yses. Released mucus was recovered by a Pasteur pipette and
frozen at ꢀ20 ꢁC immediately after dredging. The frozen
animals and mucus were extracted with acetone (1.5 mL/
animal and 3 mL, respectively). After removing the organic
solvent, the aqueous residues were diluted with fresh water
(0.4 mL/animal) and partitioned with Et2O (0.8 mL/animal).
The ether extracts were then fractionated by LH-20 (MeOH)
and the products of interest were further purified by SiO2 gel
column (polarity-increasing gradient of petroleum ether/di-
ethyl ether) followed by SiO2 rotatory TLC (n-hexane/ethyl
acetate 80:20) to give 5–12. Final purification of the prod-
ucts was achieved by normal phase HPLC (m-Porasil) using
n-hexane/EtOAc (85:15) as an isocratic eluant (flow 3.5 mL/
min, Detector UV 256 nm).
Despite minor variation in the metabolic content from the
three collection sites, the molluscs examined in this study
show an uniform composition of the aromatic metabolites
that in addition to the arguments of Andersen and Faulkner9
may imply the origin of lignarenones in the molluscan tis-
sues. This hypothesis needs experimental confirmation but
it would be consistent with the recent studies on opistho-
branch biosynthesis, which indicates the ability of these
marine organisms to produce de novo ecological mediators
through PKS-like pathways.2 Feeding experiments are cur-
rently in progress to confirm the proposed biogenesis.
4. Experimental section
4.1. General
SiO2 rotatory TLC was carried out on ChromatotronÒ
(Harrison Research, Palo Alto, California). MS analyses
were carried out with Micromass Qtof micro equipped
with APCI (RP-18 column), MeOH/H2O 87:13, flow
0.7 mL/min. NMR spectra were recorded on Bruker AMX
300 (300 MHz) and Avance DRX 400 (400 MHz). Chemical
shifts are referenced to residual C6D5H (d 7.16 and
128.0 ppm were taken as reference) or residual CHCl3 (d
7.26 and 77.0 ppm were taken as reference). Enantiomeric
excesses of alcohols 16a and 16b were determined by capil-
lary GC analysis of (S)-a-methoxy-a-(trifluoromethyl)-
phenylacetic acid ester derivatives, using a methylsilicon
column, 30 mꢃ0.25 mm (100 ꢁC isotherm; tR¼101.35 and
104.20 min, respectively, for the major and minor of the
two MTPA ester diastereomers derived from 16a and
tR¼98.25 and 101.70 min, respectively, for the major and mi-
nor of the two MTPA ester diastereomers derived from 16b).
4.2.1. Lignarenone C (7). Yield 5.2 mg, UV (MeOH)
lmax¼348 nm (3¼40,500), IR (film) nmax¼1710 cmꢀ1
,
FAB+ MS m/z 226 [M]+, 211 [MꢀCH3]+, 197 [MꢀEt]+;
APCI+ MS m/z 227.1 [M+H]+; HRMS APCI+ m/z
227.1440 [M+H]+ (227.1436 calculated for C16H19O+); H
1
NMR (400 MHz, CDCl3) d 1.13 (3H, t, JH,H¼7.2 Hz, H3-
10), 1.96 (3H, s, H3-9), 2.46 (2H, q, JH,H¼7.2 Hz, H2-1),
6.71 (3H, m, H-5, H-6 and H-8), 6.93 (1H, dd, JH,H¼15.5
and 9.6 Hz, H-7), 7.13 (1H, d, JH,H¼9.2 Hz, H-4), 7.27
(1H, d, JH,H¼7.4 Hz, H-40), 7.34 (2H, t, JH,H¼7.4 Hz, H-30
and H-50), 7.44 (2H, t, JH,H¼7.4 Hz, H-20 and H-60); 13C
NMR (100.6 MHz, CDCl3) d 202.1 (C-2), 139.6 (C-4),
137.7 (C-6), 136.7 (C-3), 135.9 (C-8), 135.7 (C-10), 128.7
(C-30, C-40 and C-50), 128.4 (C-5), 128.2 (C-7), 126.6 (C-
20 and C-60), 30.5 (C-1), 11.8 (C-10), 8.8 (C-9).

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G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
4.2.2. Dihydrolignarenone B (8). Yield 3.1 mg, [a]2D3 +11.4
(c 0.24), UV (MeOH) lmax¼287 nm (3¼20,990), IR (film)
m, phenyl protons); 1H NMR (400 MHz, C6D6) d 0.88
(3H, d, JH,H¼6.8 Hz, H3-9), 0.94 (3H, d, JH,H¼6.4 Hz,
H3-1), 1.38 (1H, d, JH,H¼6.7 Hz, H-3), 2.10 (1H, d,
JH,H¼7.5 Hz, H-4a), 2.43 (1H, br d, JH,H¼7.5 Hz, H-4b),
3.51 (1H, m, H-2), 5.48 (1H, dt, JH,H¼10.6, 7.5 and
7.5 Hz, H-5), 6.51 (1H, d, JH,H¼15.6 Hz, H-8), 6.74 (1H,
dd, JH,H¼11.0 and 10.6 Hz, H-6), 7.25 (1H, dd, JH,H¼15.6
and 11.0 Hz, H-7), 7.10–7.30 (5H, m, phenyl protons).
nmax¼1710 cmꢀ1
,
FAB+ MS m/z 214 [M]+, 171
[MꢀC2H3O]+, 143 [MꢀC4H7O]+; APCI+ MS m/z 215.1
[M+H]+; HRMS APCI+ m/z 215.1431 [M+H]+ (215.1436
calculated for C15H19O+); 1H NMR (400 MHz, CDCl3)
d 1.12 (3H, s, H3-9), 2.17 (3H, s, H3-1), 2.21 (1H, m, H-
4a), 2.48 (1H, m, H-4b), 2.61 (1H, m, H-3), 5.73 (1H, m,
H-5), 6.22 (1H, dd, JH,H¼15.6 and 11.2 Hz, H-6), 6.48
(1H, d, JH,H¼15.6 Hz, H-8), 6.72 (1H, dd, JH,H¼15.6 and
11.2 Hz, H-7), 7.16–7.39 (5H, m, phenyl protons); 13C
NMR (100.6 MHz, CDCl3) d 211.5 (C-2), 137.2 (C-10),
132.6 (C-5), 131.5 (C-6), 131.0 (C-8), 128.7 (C-7), 128.5
(C-40), 127.1 (C-20 and C-60), 126.2 (C-30 and C-50), 47.0
(C-3), 36.1 (C-4), 28.3 (C-1), 15.9 (C-9); 13C NMR
(100.6 MHz, C6D6) d 209.7, 133.4, 132.1, 131.4, 131.0,
129.2, 128.8, 127.3, 46.9, 36.1, 27.9, 16.0.
4.2.6. Conversion of dihydrolignarenol B (10) to dihydro-
lignarenone B (8). To a solution of compound 10 (1.6 mg,
0.04 mmol) in dry methylene chloride (1 mL) under argon,
tetrapropylammonium perruthenate (TPAP, 0.004 mmol)
and N-methylmorpholine N-oxide (0.08 mmol) were added.
The mixture was stirred for 2 h at room temperature then fil-
tered through a pad of silica gel and the bed was washed with
ethyl acetate (2ꢃ20 mL). The filtrate was concentrated in
vacuo to give 0.7 mg of 8. 1H and 13C NMR spectra of this
product were identical to those of natural dihydrolignare-
none B.
4.2.3. Dihydrolignarenone C (9). Yield 2.6 mg, [a]2D3 +7.4
(c 0.24, MeOH), UV (MeOH) lmax¼289 nm (3¼21,960),
IR (film) nmax¼1710 cmꢀ1, FAB+ MS m/z 228 [M]+, 199
[MꢀC2H5]+, 171 [MꢀC3H5O]+; APCI+ MS m/z 229.1
[M+H]+; HRMS APCI+ m/z 229.1585 (229.1592 calculated
for C16H21O+); 1H NMR (400 MHz, CDCl3) d 1.05 (3H, d,
JH,H¼7.2 Hz, H3-1), 1.12 (3H, d, JH,H¼7.2 Hz, H3-9), 2.19
(1H, m, H-4a), 2.48 (3H, m, H-4b and H2-1), 2.64 (1H, br
q, JH,H¼7.1 Hz, H-3), 5.72 (1H, dt, JH,H¼15.1, 7.6 and
7.6 Hz, H-5), 6.21 (1H, dd, JH,H¼15.1 and 10.4 Hz, H-6),
6.45 (1H, d, JH,H¼15.6 Hz, H-8), 6.72 (1H, dd, JH,H¼15.6
and 10.4 Hz, H-7), 7.16–7.39 (5H, m, benzene protons).
4.2.7. (S)-MTPA ester of alcohol 16a. To a solution of
homoallylic alcohol 16a5 (40 mg, 0.4 mmol) and 4-(di-
methylamino)pyridine (54 mg, 0.44 mmol) in THF (3 mL)
was added (R)-MTPA–Cl (111 mg, 0.44 mmol) dropwise.
The solution was stirred at room temperature overnight.
Then, the solution was diluted with dichloromethane (5 mL)
and washed with water (2ꢃ5 mL). The filtrate was concen-
trated and the residue was filtered through a short column of
neutral alumina with pentane. Concentration of the filtrate pro-
vided MTPA ester (113.8 mg, 90% yield). 1H NMR analysis
integration of the vinylic protons of the two diastereomeric
(S)-MTPA esters (d 5.75 (m, 1H) for the (3S,4S)-16a isomer
and 5.64 (m, 1H) for the (3R,4R)-16a minor isomer) con-
firmed the enantiomeric purity determined by GC analysis.
4.2.4. Dihydrolignarenol B (10). Yield 1.1 mg, [a]2D3 ꢀ3.0
(c 0.05, MeOH), UV (MeOH) lmax¼287 nm (3¼22,900),
IR (film) nmax¼3352 cmꢀ1; APCI+ MS m/z 217 [M+H]+,
199 [MꢀH2O+H]+; HRMS APCI+ m/z 217.1601 [M+H]+
1
(217.1592 calculated for C15H21O+); H NMR (400 MHz,
CDCl3) d 0.93 (3H, d, JH,H¼6.4 Hz, H3-9), 1.19 (3H, d,
JH,H¼6.4 Hz, H3-1), 1.71 (1H, m, H-3a), 2.02 (1H, m, H-
4a), 2.32 (1H, m, H-4b), 3.78 (1H, m, H-2), 5.82 (1H, m,
H-5), 6.23 (1H, dd, JH,H¼15.6 and 11.2 Hz, H-6), 6.47
(1H, d, JH,H¼15.6 Hz, H-8), 6.77 (1H, dd, JH,H¼15.6 and
11.2 Hz, H-7), 7.20–7.38 (5H, m, benzene protons); 1H
NMR (400 MHz, C6D6) d 0.84 (3H, d, JH,H¼6.8 Hz,
H3-9), 0.95 (3H, d, JH,H¼6.4 Hz, H3-1), 1.37 (1H, br d,
JH,H¼6.8 Hz, H-3), 1.88 (1H, m, H-4a), 2.24 (1H, m, H-
4b), 3.51 (1H, m, H-2), 5.67 (1H, ddd, JH,H¼15.1, 7.5 and
7.3 Hz, H-5), 6.16 (1H, dd, JH,H¼15.1 and 10.4 Hz, H-6),
6.39 (1H, d, JH,H¼15.4 Hz, H-8), 6.74 (1H, dd, JH,H¼15.4
and 10.4 Hz, H-7), 7.04–7.29 (5H, m, benzene protons);
13C NMR (100.6 MHz, CDCl3) d 138.5 (C-10), 134.3 (C-
5), 132.4 (C-6), 130.8 (C-8), 130.1 (C-7), 126.6 (C-40),
70.8 (C-2), 40.4 (C-3), 36.9 (C-4), 20.6 (C-1), 14.0 (C-9).
4.2.8. (3S,4S)-4-tert-Butyldiphenylsilyloxy-3-methyl-
pent-1-ene (17a). To a solution of homoallylic alcohol 16a
(510 mg, 5.09 mmol) in dry DMF (2 mL), stirred under an
argon atmosphere at room temperature, tert-butylchlorodi-
phenylsilane (TBDPSCl, 3.50 g, 12.7 mmol) and imidazole
(1.73 g, 25.5 mmol) were added. The reaction mixture was
stirred for 24 h and then quenched with 0.2 N aqueous HCl
solution (65 mL). The resulting mixture was extracted with
diethyl ether (3ꢃ20 mL), and the organic layers were dried
over MgSO4, filtered and concentrated under reduced pres-
sure. Purification by flash chromatography using n-pentane
as an eluant afforded 1.12 g (65% yield) of compound 17a
as a colourless oil: Rf (n-hexane) 0.2; [a]2D5 ꢀ23.2 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.72–7.65 (m, 4H),
7.45–7.33 (m, 6H), 5.93 (ddd, J¼17.1, 10.7 and 6.7 Hz,
1H), 5.04–4.96 (m, 2H overlapped), 3.77 (m, 1H), 2.29 (m,
1H), 1.04 (s, 9H), 0.94 (d, J¼6.1 Hz, 3H), 0.93 (d,
J¼6.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 140.9,
136.0 (ꢃ2), 135.0, 134.3, 129.5 (ꢃ2), 129.4 (ꢃ2), 127.5
(ꢃ2), 127.4 (ꢃ2), 114.2, 73.0, 44.7, 27.1, 19.8, 19.4, 15.1.
EIMS (70 eV) m/z: 338 [M]+, 281, 203, 177. Anal. Calcd
for C22H30OSi: C, 78.05; H, 8.93. Found: C, 78.09; H, 8.88.
4.2.5. Dihydrolignarenol A (11). Yield 0.1 mg; APCI+ MS
m/z 217 [M+H]+, 199 [MꢀH2O+H]+; HRMS APCI+ m/z
1
217.1584 [M+H]+ (217.1592 calculated for C15H21O+); H
NMR (400 MHz, CDCl3) d 0.94 (3H, d, JH,H¼6.8 Hz,
H3-9), 1.21 (3H, d, JH,H¼6.4 Hz, H3-1), 1.38 (1H, d,
JH,H¼6.7 Hz, H-3), 2.10 (1H, d, JH,H¼7.5 Hz, H-4a), 2.43
(1H, br d, JH,H¼7.5 Hz, H-4b), 3.81 (1H, m, H-2), 5.53
(1H, dt, JH,H¼10.6, 7.5 and 7.5 Hz, H-5), 6.23 (1H, t,
JH,H¼10.6 Hz, H-8), 6.53 (1H, d, JH,H¼15.6 Hz, H-8),
7.07 (1H, dd, JH,H¼15.6 and 10.6 Hz, H-7) 7.20–7.42 (5H,
4.2.9. (3S,4S)-4-tert-Butyldiphenylsilyloxy-3-methyl-pen-
tan-1-ol (18a). A solution of compound 17a (36 mg,
0.106 mmol) in dry hexane (2 mL) under an argon atmo-
sphere was cooled to 0 ꢁC and BH3$SMe2 (0.160 mL,

G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
7261
0.319 mmol, 2 M solution in THF) was added. The mixture
was warmed to room temperature and stirred for 26 h, then
treated with 3 M aqueous NaOH solution (0.88 mL,
2.64 mmol) and H2O2 (0.135 mL, 35% w/w aqueous solu-
tion). After stirring overnight at room temperature, the mix-
ture was extracted with diethyl ether (3ꢃ20 mL), dried over
Na2SO4, filtrated and concentrated in vacuo, giving a crude
product, which was purified by flash chromatography (gradi-
ent elution with petroleum ether/diethyl ether mixtures from
100:0 to 60:40). Alcohol 18a of 32 mg (85% yield) was ob-
tained, as a colourless oil: Rf (30% Et2O/n-pentane) 0.25;
(100.6 MHz, CDCl3) d 145.9, 135.9 (ꢃ2), 134.7, 134.1,
129.6 (ꢃ2), 129.5 (ꢃ2), 127.6 (ꢃ2), 127.4 (ꢃ2), 74.9,
72.0, 39.6, 38.7, 27.1, 19.4 (2C overlapped), 14.5. m/z: 478
[M]+, 421, 217, 199. Anal. Calcd for C23H31IOSi: C,
57.73; H, 6.53. Found: C, 58.02; H, 6.42.
4.2.12. (1E,3E,6S,7S)-7-tert-Butyldiphenylsilyloxy-6-
methyl-1-phenylocta-1,3-diene (19a). A mixture of vinylic
iodide 14a (41 mg, 0.085 mmol), Pd(PPh3)4 (10 mg,
0.0085 mmol) and trans-2-phenylvinylboronic acid (13,
25 mg, 0.17 mmol) in THF/KOH 2 M aqueous 4:1
(1.25 mL) was stirred under nitrogen at 50 ꢁC for 4 h. Then
the THF was removed in vacuo and the suspension was ex-
tracted with methylene chloride (3ꢃ10 mL). The combined
organic extracts were dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography using
petroleum ether as an eluant gave 26 mg of coupling product
19a (67% yield) as a colourless oil: Rf (n-pentane) 0.50; [a]D25
ꢀ64.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.74–
7.67 (m, 4H), 7.47–7.35 (m, 8H), 7.31 (m, 2H), 7.21 (m,
1H), 6.74 (dd, J¼15.6 and 10.5 Hz, 1H), 6.42 (d,
J¼15.6 Hz, 1H), 6.16 (dd, J¼15.3 and 10.5 Hz, 1H), 5.74
(m, 1H), 3.84 (m, 1H), 2.47 (m, 1H), 1.96 (m, 1H), 1.62
(m, 1H), 1.09 (s, 9H), 1.00 (d, J¼6.3 Hz, 3H), 0.87 (d,
J¼6.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 137.7,
135.9 (ꢃ2), 135.1, 134.5, 134.2, 131.5 (ꢃ2), 129.8 (ꢃ2),
129.4 (ꢃ2), 129.3 (ꢃ2), 128.4, 127.4 (ꢃ2), 127.3 (ꢃ2),
126.9, 126.3, 126.0, 72.6, 40.6, 35.6, 27.0, 19.5, 19.3, 14.6.
m/z: 454 [M]+, 397, 199. Anal. Calcd for C31H38OSi: C,
81.88; H, 8.42. Found: C, 81.90; H, 8.39.
1
[a]2D5 ꢀ1.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3)
d 7.71–7.65 (m, 4H), 7.47–7.34 (m, 6H), 3.79 (dq, J¼6.4
and 3.0 Hz, 1H), 3.68 (m, 1H), 3.63 (m, 1H), 2.20 (m,
1H), 1.80 (m, 1H), 1.73 (m, 1H), 1.40 (m, 1H), 1.06 (s,
9H), 0.98 (d, J¼6.4 Hz, 3H), 0.80 (d, J¼6.9 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 135.9 (ꢃ2), 134.4, 133.9,
129.7 (ꢃ2), 129.6 (ꢃ2), 127.6 (ꢃ2), 127.4 (ꢃ2), 73.3,
61.9, 42.5, 35.0, 27.0, 19.2, 18.3, 16.6. m/z: 356 [M]+, 299,
199, 139. Anal. Calcd for C22H32O2Si: C, 74.10; H, 9.05.
Found: C, 74.35; H, 8.82.
4.2.10. (3S,4S)-4-tert-Butyldiphenylsilyloxy-3-methyl-
pentan-1-al (15a). To a solution of compound 18a (59 mg,
0.166 mmol) in dry methylene chloride (2 mL) under an
argon atmosphere, pyridinium dichromate (125 mg,
˚
0.331 mmol) and activated 4 A molecular sieves (112 mg)
were added. The reaction mixturewas stirred at room temper-
ature for 3 h, diluted with diethyl ether (4 mL) and stirred
again for 30 min. The resulting suspension was filtered
through a pad of silica gel/CaSO4 (9:1, 1.5 g) and the bed
was washed with diethyl ether (3ꢃ10 mL). The filtrate was
concentrated in vacuo giving 53 mg of aldehyde 15a (90%
yield) as a colourless oil: Rf (30% Et2O/n-pentane) 0.70;
4.2.13. (2S,3S)-Dihydrolignarenol B (10). To a solution of
compound 19a (17 mg, 0.037 mmol) in dry THF (0.5 mL)
under argon, TBAF (0.30 mL, 0.30 mmol, 1 M solution in
THF) was added. The mixture was stirred at room tempera-
ture for 24 h then quenched by adding water (2 mL). The
THF was removed in vacuo and the resulting suspension
was extracted with ethyl acetate (3ꢃ3 mL). The combined
organic extracts were dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography (gradi-
ent elution with petroleum ether/diethyl ether mixtures from
100:0to8:2) afforded8 mgofalcohol10(98%yield)asacol-
ourless oil: Rf (30% Et2O/petroleum ether) 0.65; [a]2D5 ꢀ1.4
1
[a]2D5 ꢀ1.1 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3)
d 9.71 (m, 1H), 7.70–7.62 (m, 4H), 7.47–7.34 (m, 6H),
3.82 (dq, J¼6.3 and 3.2 Hz, 1H), 2.66 (m, 1H), 2.29–2.14
(m, 2H overlapped), 1.05 (s, 9H), 0.95 (d, J¼6.3 Hz, 3H),
0.85 (d, J¼6.7 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
d 202.6, 135.8 (ꢃ2), 134.4, 133.9, 129.7 (ꢃ2), 129.6 (ꢃ2),
127.7 (ꢃ2), 127.5 (ꢃ2), 72.2, 46.3, 35.0, 27.1, 20.5, 19.3,
15.7. m/z: 354 [M]+, 297, 219, 199. Anal. Calcd for
C22H30O2Si: C, 74.53; H, 8.53. Found: C, 74.58; H, 8.42.
1
(c 0.6, CHCl3); H NMR (400 MHz, CDCl3) d 7.38 (m,
4.2.11. (1E,4S,5S)-5-tert-Butyldiphenylsilyloxy-1-iodo-4-
methyl-hex-1-ene (14a). To a cooled solution (0 ꢁC) of an-
hydrous CrCl2 (110 mg, 0.897 mmol) in dry THF/dioxane
1:6 (2.4 mL) under nitrogen, a solution of aldehyde 15a
(53 mg, 0.150 mmol) and iodoform (118 mg, 0.299 mmol)
in dry THF/dioxane 1:6 (1.2 mL) was added slowly. The re-
action mixture was stirred at 0 ꢁC for 24 h then quenched
with saturated aqueous NH4Cl solution (20 mL), extracted
with petroleum ether (3ꢃ30 mL), dried over MgSO4, filtered
and concentrated under reduced pressure. Purification by
flash chromatography (gradient elution with petroleum
ether/diethyl ether mixtures from 100:0 to 95:5) afforded
41 mg of iodoalkene 14a (57% yield) as a colourless oil:
2H), 7.30 (m, 2H), 7.20 (m, 1H), 6.76 (dd, J¼15.6 and
10.4 Hz, 1H), 6.45 (d, J¼15.6 Hz, 1H), 6.23 (dd, J¼15.1
and 10.4 Hz, 1H), 5.82 (dt, J¼15.1 and 7.4 Hz, 1H), 3.78
(m, 1H), 2.33 (m, 1H), 2.02 (m, 1H), 1.61 (m, 1H), 1.19
(d, J¼6.5 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 137.5, 134.0, 132.0, 130.3, 129.1,
128.5, 127.2, 126.1, 70.8, 40.1, 36.5, 20.4, 14.0. Anal. Calcd
for C15H20O: C, 83.28; H, 9.32. Found: C, 82.99; H, 9.40.
4.2.14. (3S)-Dihydrolignarenone B (8). To a solution of
compound 10 (9 mg, 0.04 mmol) in dry methylene chloride
(1 mL) under argon, tetrapropylammonium perruthenate
(1.5 mg, 0.004 mmol), N-methylmorpholine N-oxide
1
Rf (n-hexane) 0.50; [a]2D5 ꢀ23.5 (c 1.0, CHCl3); H NMR
(10 mg, 0.08 mmol) and activated 4 A molecular sieves
˚
(400 MHz, CDCl3) d 7.67–7.65 (m, 4H), 7.42–7.37 (m,
6H), 6.41 (ddd, J¼14.2, 7.3 and 7.3 Hz, 1H), 5.88 (d,
J¼14.2 Hz, 1H), 3.79 (dq, J¼12.5 and 6.2 Hz, 1H), 2.33
(m, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1.05 (s, 9H), 0.96
(d, J¼6.2 Hz, 3H), 0.82 (d, J¼6.8 Hz, 3H); 13C NMR
were added. The mixture was stirred at room temperature
for 90 min then filtered through a pad of silica gel and the
bed was washed with ethyl acetate (3ꢃ30 mL). The filtrate
was concentrated in vacuo. Purification by flash chromato-
graphy using petroleum ether/diethyl ether 8:2 as an eluant

7262
G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
afforded 7 mg of ketone 8 (82% yield) as a colourless oil: Rf
(30% Et2O/petroleum ether) 0.85; [a]3D5 +8.8 (c 0.4, CHCl3);
Rf (1H and 13C NMR data (400 MHz, CDCl3)) were identical
to those of the natural product 8. Anal. Calcd for C15H18O:
C, 84.07; H, 8.47. Found: C, 84.01; H, 8.51.
6.5 mmol) was treated with anhydrous CrCl2 (4.8 g,
39 mmol) and iodoform (5.1 g, 13.0 mmol) in dry THF/di-
oxane 1:6 (17 mL) as described for 18a. Purification by flash
chromatography (gradient elution with petroleum ether/
diethyl ether mixtures from 100:0 to 95:5) afforded 2.4 g
of iodoalkene 14b (78% yield) as a colourless oil: Rf (10%
1
4.2.15. (3S,4R)-4-tert-Butyldiphenylsilyloxy-3-methyl-
pent-1-ene (17b). A solution of homoallylic alcohol 16b
(6.5 g, 62 mmol) in dry DMF (35 mL) was treated with tert-
butylchlorodiphenylsilane (TBDPSCl, 42.9 g, 156 mmol)
and imidazole (21.1 g, 310 mmol) as described for 16a.
Purification by flash chromatography using n-pentane as an
eluant afforded 14.4 g (68% yield) of compound 17b as
a colourless oil: Rf (n-hexane) 0.50; [a]2D5 ꢀ1.9 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.69 (m, 4H),
7.45–7.33 (m, 6H), 5.74 (ddd, J¼17.2, 10.5 and 7.4 Hz,
1H), 4.95 (m, 1H), 4.90 (m, 1H), 3.82 (m, 1H), 2.23 (m,
1H), 1.06 (s, 9H), 1.03 (d, J¼6.9 Hz, 3H), 0.95 (d,
J¼6.3 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 141.0,
135.9 (ꢃ2, overlapped), 134.9, 134.3, 129.5 (ꢃ2), 129.4
(ꢃ2), 127.5 (ꢃ2), 127.3 (ꢃ2), 114.4, 72.6, 44.8, 27.0, 19.4,
19.3, 14.3. m/z: 338 [M]+, 281, 203. Anal. Calcd for
C22H30OSi: C, 78.05; H, 8.93. Found: C, 78.00; H, 9.12.
Et2O/n-pentane) 0.94; [a]2D5 +9.5 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) d 7.66 (m, 4H), 7.47–7.34 (m, 6H),
6.29 (ddd, J¼14.4, 7.5 and 7.5 Hz, 1H), 5.86 (ddd,
J¼14.4, 1.5 and 1.3 Hz, 1H), 3.73 (dq, J¼12.5 and 6.2 Hz,
1H), 2.05 (m, 1H), 1.82 (m, 1H), 1.60 (m, 1H), 1.05 (s,
9H), 0.96 (d, J¼6.2 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 145.4, 135.9 (ꢃ2), 134.7,
134.1, 129.6 (ꢃ2), 129.5 (ꢃ2), 127.6 (ꢃ2), 127.4 (ꢃ2),
74.9, 72.1, 39.4, 27.0, 19.3, 18.8, 14.2. m/z: 478 [M]+, 421,
199. Anal. Calcd for C23H31IOSi: C, 57.73; H, 6.53; I,
26.52. Found: C, 57.51; H, 6.66; I, 26.83.
4.2.19. (1E,3E,6S,7R)-7-tert-Butyldiphenylsilyloxy-6-
methyl-1-phenylocta-1,3-diene (19b). A solution of vinylic
iodide 14b (0.22 g, 0.46 mmol) in THF/KOH 2 M aqueous
4:1 (6 mL) was treated with Pd(PPh3)4 (80 mg,
0.069 mmol) and trans-2-phenylvinylboronic acid (13,
0.20 g, 1.38 mmol) as described for 14a. Purification by
flash chromatography (gradient elution with petroleum
ether/diethyl ether mixtures from 100:0 to 97:3) gave
0.155 g of coupling product 19b (74% yield) as a colourless
oil: Rf (1% Et2O/n-pentane) 0.50; [a]2D5 +26.6 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) d 7.80–7.69 (m, 4H), 7.55–7.37
(m, 9H), 7.29 (m, 1H), 7.26 (m, 1H), 6.75 (dd, J¼15.6 and
10.4 Hz, 1H), 6.46 (d, J¼15.6 Hz, 1H), 6.17 (dd, J¼15.3
and 10.4 Hz, 1H), 5.65 (ddd, J¼15.2, 7.6 and 7.6 Hz, 1H),
3.86 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H), 1.75 (m, 1H),
1.15 (s, 9H), 1.07 (d, J¼6.4 Hz, 3H), 1.00 (d, J¼6.8 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) d 137.7, 136.0 (ꢃ2),
135.0, 134.5, 134.4, 131.6 (ꢃ2), 129.9 (ꢃ2), 129.6 (ꢃ2),
129.5 (ꢃ2), 128.6, 127.6, 127.5 (ꢃ2), 127.1 (ꢃ2), 126.4,
126.2, 72.4, 40.5, 36.5, 27.1, 19.4, 18.5, 14.3. m/z: 408
[M]+, 401, 202. Anal. Calcd for C31H38OSi: C, 81.88; H,
8.42. Found: C, 81.76; H, 8.68.
4.2.16. (3S,4R)-4-tert-Butyldiphenylsilyloxy-3-methyl-
pentan-1-ol (18b). A solution of compound 17b (1.4 g,
4.1 mmol) in dry hexane (40 mL) was treated with
BH3$SMe2 (6.0 mL, 12 mmol, 2 M solution in THF) and
then with 3 M aqueous NaOH solution (33 mL, 99 mmol)
and H2O2 (5.1 mL, 35% w/w aqueous solution) as described
for 16a. Purification by flash chromatography (gradient elu-
tion with petroleum ether/diethyl ether mixtures from 95:5
to 80:20) gave 0.99 g of alcohol 18b (69% yield) as a colour-
less oil: Rf (20% Et2O/n-pentane) 0.38; [a]2D5 ꢀ1.0 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.69 (m, 4H), 7.46–
7.34 (m, 6H), 3.77 (m, 1H), 3.58 (m, 1H), 3.49 (m, 1H), 1.64
(m, 1H), 1.52 (m, 1H), 1.46–1.33 (m, 2H overlapped), 1.06
(s, 9H), 1.00 (d, J¼6.3 Hz, 3H), 0.94 (d, J¼6.9 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) d 135.9 (ꢃ2), 134.7,
134.1, 129.6 (ꢃ2), 129.4 (ꢃ2), 127.5 (ꢃ2), 127.4 (ꢃ2),
72.7, 60.8, 36.6, 35.4, 27.0, 19.3, 18.7, 14.4. m/z: 356
[M]+, 299, 199, 139. Anal. Calcd for C22H32O2Si: C,
74.10; H, 9.05. Found: C, 73.90; H, 9.03.
4.2.20. (2R,3S)-Dihydrolignarenol B (10b). A solution of
compound 19b (0.78 g, 1.7 mmol) in dry THF (25 mL)
was treated with TBAF (7.0 mL, 7.0 mmol, 1 M solution
in THF) as described for 19a. Purification by flash chroma-
tography (gradient elution with petroleum ether/diethyl
ether mixtures from 9:1 to 6:4) afforded 0.32 g of alcohol
10b (87% yield) as a colourless oil; [a]2D5 ꢀ8.0 (c 1.0,
4.2.17. (3S,4R)-4-tert-Butyldiphenylsilyloxy-3-methyl-
pentan-1-al (15b). A solution of compound 18b (0.86 g,
2.4 mmol) in dry methylene chloride (30 mL) was treated
with pyridinium dichromate (1.8 g, 4.8 mmol) and activated
1
4 A molecular sieves (1.7 g) as described for 18a. Aldehyde
CHCl3); H and 13C NMR data (400 MHz, CDCl3) d 7.39
˚
15b of 0.58 g (68% yield) was obtained as a colourless oil: Rf
(30% Et2O/n-pentane) 0.71; [a]2D5 +11.8 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) d 9.66 (dd, J¼2.8 and 1.5 Hz, 1H),
7.67 (m, 4H), 7.48–7.34 (m, 6H), 3.73 (m, 1H), 2.52 (ddd,
J¼16.2, 4.5 and 1.5 Hz, 1H), 2.21 (ddd, J¼16.2, 8.8 and
2.8 Hz, 1H), 2.12 (m, 1H), 1.05 (s, 9H), 0.98 (d, J¼6.3 Hz,
3H), 0.96 (d, J¼6.8 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) d 202.8, 135.9 (ꢃ2), 134.5, 133.8, 129.7 (ꢃ2),
129.6 (ꢃ2), 127.6 (ꢃ2), 127.5 (ꢃ2), 72.6, 46.9, 35.4, 27.0,
19.9, 19.4, 15.9. m/z: 358 [M]+, 301, 223, 199. Anal. Calcd
for C22H30O2Si: C, 74.53; H, 8.53. Found: C, 74.89; H, 8.26.
(m, 2H), 7.31 (m, 2H), 7.21 (m, 1H), 6.78 (dd, J¼15.6 and
10.5 Hz, 1H), 6.46 (d, J¼15.6 Hz, 1H), 6.24 (dd, J¼15.0
and 10.4 Hz, 1H), 5.83 (dt, J¼15.0 and 7.4 Hz, 1H), 3.68
(m, 1H), 2.36 (m, 1H), 2.04 (m, 1H), 1.63 (m, 1H), 1.18
(d, J¼6.3 Hz, 3H), 0.92 (d, J¼6.9 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 137.5, 134.0, 132.0, 130.3, 129.2,
128.6, 127.2, 126.1, 71.5, 40.5, 36.3, 19.9, 15.0. Anal. Calcd
for C15H20O: C, 83.28; H, 9.32. Found: C, 83.21; H, 9.38.
4.2.21. Trapping reaction with carbethoxyethylidene
(CET)-triphenylphosphorane. Compound 12 was obtained
by SiO2 chromatography (petroleum ether/diethyl ether
85:15) on extracts of animals from Malgrat (Spain). The
product was then derivatized with carbethoxyethylidene
4.2.18. (1E,4S,5R)-5-tert-Butyldiphenylsilyloxy-1-iodo-
4-methyl-hex-1-ene (14b). Compound 15b (2.3 g,

G. D. Sala et al. / Tetrahedron 63 (2007) 7256–7263
7263
1865–1874; (c) Sleeper, H. L.; Paul, V. J.; Fenical, W. J.
Chem. Ecol. 1980, 6, 57–70; (d) Spinella, A.; Alvarez, L. A.;
Passeggio, A.; Cimino, G. Tetrahedron 1993, 49, 1307–1314;
(e) Spinella, A.; Alvarez, L. A.; Cimino, G. Tetrahedron Lett.
1998, 39, 2005–2008; (f) Marin, A.; Alvarez, L. A.; Cimino,
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(CET)-triphenylphosphorane in 0.5 mL CH2Cl2 at room
temperature per 2 h. The reaction mixture was dried at re-
duced pressure and the oily residue was purified to give
0.4 mg of 12a. Compound 12a: GC–MS m/z 242 [M+H]+,
1
213 [MꢀEt+H]+, 197 [MꢀOEt+H]+; H NMR (400 MHz,
C6D6) d 1.05 (3H, t, JH,H¼7.2 Hz, Et), 2.01 (3H, s, Me),
4.09 (2H, q, JH,H¼7.2 Hz, Et), 6.34 (1H, dd, JH,H¼14.5 and
9.7 Hz, H-3), 6.39 (1H, dd, JH,H¼14.5 and 10.7 Hz, H-2),
6.40 (1H, d, JH,H¼15.6 Hz, H-5), 6.66 (1H, dd, JH,H¼15.6
and 10.2 Hz, H-4), 7.03–7.28 (5H, m, phenyl protons), 7.54
(1H, br d, JH,H¼10.7 Hz, H-1).
2. Fontana, A. Marine Molecular Biotechnology; Cimino, G.,
Gavagnin, M., Eds.; Series Progress in Molecular and
Subcellular Biology; Springer: Heidelberg, 2006; Molluscs,
pp 303–332.
3. (a) Cutignano, A.; Tramice, A.; De Caro, S.; Villani, G.; Cimino,
G.; Fontana, A. Angew. Chem., Int. Ed. 2003, 2633–2636; (b)
Cutignano, A.; Cimino, G.; Giordano, A.; d0Ippolito, G.;
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1990, 5, 162–163.
Acknowledgements
The authors are grateful to Mr. Antonio Maiello and Mr. Car-
mine Iodice for the technical assistance. Special thanks are
due to Mrs. Dominique Melck for the NMR spectra. The
5. Griffiths, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13–19.
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5919–5923.
ꢀ
authors acknowledge the financial support from Universita
di Salerno and ‘Dipartimento di Progettazione Molecolare’
of Consiglio Nazionale delle Ricerche.
7. Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
8. d’Ippolito, G.; Iadicicco, O.; Romano, G.; Fontana, A.
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References and notes
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