Enantioselective synthesis of preclavulone A and its methyl ester

Article abstract of DOI:10.1016/j.tet.2007.03.003

A highly enantioselective synthesis of the (8S,12S)-enantiomer of preclavulone A and its methyl ester is described featuring the Julia protocol for installing the (Z)-double bond in the lower chain. This procedure is suitable for the preparation of labele

Full text of DOI:10.1016/j.tet.2007.03.003

Tetrahedron 63 (2007) 3989–3994
Enantioselective synthesis of preclavulone A and its methyl ester
*
Alessio Porta, Savino Re, Giuseppe Zanoni and Giovanni Vidari
Department of Organic Chemistry, University of Pavia, Viale Taramelli, 10, 27100 Pavia, Italy
Received 12 December 2006; revised 13 February 2007; accepted 1 March 2007
Available online 6 March 2007
Abstract—A highly enantioselective synthesis of the (8S,12S)-enantiomer of preclavulone A and its methyl ester is described featuring the
Julia protocol for installing the (Z)-double bond in the lower chain. This procedure is suitable for the preparation of labeled preclavulone
analogues for biosynthetic studies on marine clavulones.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
oxidation of AA to a dienyl hydroperoxide, followed by en-
zymatic cyclization of a derived allene oxide (Scheme 1).5
Marine prostaglandins and related eicosanoids such as clav-
ulones and halogenated clavulones have been found in dif-
ferent species of marine invertebrates and red algae.1 They
have attracted much attention because of their unique struc-
tural features, potent biological activities, including strong
antitumor and antiviral properties, and intriguing biosynthe-
sis.1,2 In fact, although it has been proved that arachidonic
acid (AA) is converted to marine prostaglandins via the
conventional cyclooxygenase route,3 the biogenetic pathway
from AA to clavulones is still under debate.4 In Corey’s
proposed pathway to clavulone I, preclavulone A (1) is a
key intermediate, arising from lipoxygenase mediated
In experiments done with a cell-free extract of the Okinawan
octocoral Clavularia viridis, preclavulone A was, indeed,
obtained from labeled AA as well as from labeled (8R)-
HPETE, however, its enantiomeric purity and absolute con-
figuration could not be determined due to the poor amounts
isolated.6 These stereochemical data are of paramount
importance to support the hypothesis of an enzymatically
stereocontrolled biogenesis of 1. In fact, there is increasing
evidence that various prostanoid-like compounds are formed
also in a non-stereocontrolled fashion by non-enzymatic free
radical oxidation of unsaturated fatty acids in membrane
OOH
O
CO2H
CO2H
CO2H
LOX
AOS
Arachidonic acid
8R-HPETE
Allene oxide
OAc
O
CO2Me
O
AOC
CO2H
AcO
Clavulone I
Preclavulone A (1)
O
CO2Me
2
Scheme 1. Corey’s suggested biosynthesis of clavulones (LOX, lipoxygenase; AOX, allene oxide synthase; AOC, allene oxide cyclase).
Keywords: Preclavulone A; Marine clavulones; Enantioselective synthesis; Julia olefination.
* Corresponding author. Tel.: +39 0382987322; fax: +39 0382987323; e-mail: vidari@unipv.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.003

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A. Porta et al. / Tetrahedron 63 (2007) 3989–3994
lipids, apparently in all mammalian cell types and tissues in
vivo.7 In this regard, the recent isolation by Iguchi of nearly
racemic (8%, ee) methyl ester of preclavulone A (2) along
with its 8-epimer from a methanol extract of C. viridis,8
reinforces uncertainties on the stereospecific biogenesis of
compound 1.
In this paper, we describe the first synthesis of the (8S,12S)-
enantiomer of preclavulone A (1) and the corresponding
methyl ester (8S,12S)-2,12 whose (Z)-olefin in the lower
chain was installed via the corresponding vinylsulfone
(Scheme 3) using the Julia protocol.13 This concise proce-
dure appears, indeed, to be well suitable for the preparation
of more oxidized derivatives and also of labeled preclavulone
analogues since the sulfonyl group can easily be replaced
with deuterium in regio- and stereospecific fashions.14
The major enantiomer (8R,12R)-2 of the natural mixture iso-
lated by Iguchi was first synthesized by Corey and Xiang,9a
and very recently by the Iguchi’s group along with its
(8S,12R)-diastereomer.9b A synthesis of racemic 2 was
reported by Traverso et al. years ago,9c and later by Iguchi.9d
2. Results and discussion
We have recently published the first truly enantioselective
route to (8R,12R)-preclavulone A (1) reporting, for the first
time, its fully spectroscopic characterization, including the
optical rotation.10,11 In this approach, the upper chain was
positioned following the usual Wittig strategy used in
many prostaglandin syntheses, while installation of the
lower side chain was achieved via Knochel coupling of
1-bromoheptyne 4 with the copper/zinc reagent 3 derived
from enantiomerically enriched alcohol 5 (Scheme 2).
Our vinylsulfone based retrosynthetic analysis of preclavu-
lone A 1 is depicted in Scheme 3. The alkylsulfone 8,
required for coupling with hexanal, was envisaged to arise
from monodesulfonylation of the bis-sulfone produced
from the Mitsunobu condensation of hydroxy-lactone ent-5
with bis(phenylsulfonyl)methane 9.15 The starting com-
pound ent-5, [a]2D0 ꢀ4.61 (c 0.8, CH2Cl2), 98% ee (chiral
GC),16 was obtained in 11 steps from racemic cyclopentenyl
carbonate 10 following the same route previously described
for 5,10 enantiodivergence being achieved by using the (R,R)-
antipode of the Trost ligand 11 in the asymmetric step.17
O
O
O
Alkylation of ent-5 with bis-sulfone 9 in the presence of
DEAD and Ph3P18 afforded geminal bis-sulfonyl-lactone
12 in 87% isolated yield (Scheme 4). DIBAL-H reduction
and in situ protection of the obtained lactol readily gave
the corresponding methyl acetal 13 (MeOH, HCl, ꢀ35 ꢁC)
in 93% isolated yield. Subsequent selective monodesulfonyl-
ation of compound 13 proceeded very rapidly at room tem-
perature with SmI2 (4 equiv) in THF,15 delivering sulfone 8
in 87% yield. A highly stereoselective fourstep procedure
developed by Julia and collaborators13,14 allowed coupling
of 8 with hexanal and subsequent stereoconvergent conver-
sion of intermediate stereoisomers 14 to the required Z-ole-
fin 6. Thus, the lithio derivative of phenyl sulfone 8 gave an
adduct with hexanal, which was acetylated in situ to afford
a mixture of diastereomeric b-acetoxysulfones 14 in a grati-
fying 90% isolated yield. Compounds 14 underwent b-elim-
ination readily on exposure to powdered NaOH in dioxane
at rt delivering vinylsulfone 7 as a single stereoisomer (1H
NMR analysis). In the last step of the Julia sequence, the
CO2H
(8R,12R)-1
O
O
O
O
+
C5H11
Br
OH
Cu(CN)ZnI
5
3
4
Scheme 2. Retrosynthesis of preclavulone A (1) based on Knochel’s organo-
zinc chemistry.10
In continuing our efforts in this field, we anticipated possible
difficulties in extending this methodology to the synthesis of
oxidized derivatives of 1, e.g., clavulone I. In addition, in
order to facilitate biosynthetic studies of preclavulones, we
were interested in finding a synthetic route easily extendable
to the preparation of labeled derivatives.
OMe
OMe
O
O
O
Ph
CO2H
O2S
(8S,12S)-1
OMe
6
7
O
O
O
OCO2Me
O
O
SO2Ph
SO2Ph
NH PPh2
NH PPh2
+
OH
SO2Ph
8
ent-5
9
( )−10
+
11
O
Scheme 3. Retrosynthetic analysis of preclavulone A based on Julia vinylsulfone chemistry.

A. Porta et al. / Tetrahedron 63 (2007) 3989–3994
3991
OMe
O
O
OMe
O
O
O
O
a
b
c
SO2Ph
SO2Ph
SO2Ph
SO2Ph
OH
SO2Ph
ent-5
12
13
8
OMe
OMe
O
O
e
Ph
d
f
SO2Ph
O2S
OAc
14
7
OMe
HO
O
O
CO2H
g
h
CO2H
6
15
(8S,12S)--1
O
i
CO2Me
(8S,12S)--2
Scheme 4. Reagents and conditions: (a) (PhSO2)2CH2, Ph3P, DEAD, PhH, rt, 1.5 h, 87%; (b) (i) DIBAL-H, THF, ꢀ78 ꢁC, 1.5 h; (ii) MeOH, HCl (37% solution,
0.05 equiv), ꢀ35 ꢁC, 15 h, 93%; (c) SmI2 (1 M THF solution), THF, rt, 15 min, 87%; (d) (i) n-BuLi, THF, ꢀ78 to ꢀ40 ꢁC, 1 h, followed by addition of hexanal
(THF solution), ꢀ40 ꢁC, 30 min; (ii) Ac2O, rt, 30 min, 90%; (e) NaOH, 1,4-dioxane, rt, 1 h, 90%; (f) Na2S2O4 (15 equiv), NaHCO3 (30 equiv), H2O/EtOH (1:1),
reflux, 2 h, 76%; (g) (i) 0.25 M HCl, THF/H2O (1:1), rt, 5 h, 96%; (ii) BrPh3P(CH2)4CO2H, t-BuOK, THF, rt, 30 min, 96%; (h) Dess–Martin periodinane,
CH2Cl2, rt, 3 h, 96%; (i) CH2N2, Et2O, 0 ꢁC, 97%.
stereospecific desulfonylation of compound 7 smoothly pro-
ceeded on exposure to Na2S2O4 and NaHCO3 in a mixture of
H2O/EtOH (1:1), affording olefin Z-6 in 76% isolated
yield.19
(8R,12R)-2 has been achieved. It features a convergent
sequence of highly stereoselective transformations from
the key chiral building block ent-5, which is available in
multigram amount using an enantioselective organometallic
approach.10 The same strategy opens the way to the prepara-
tion of more oxidized preclavulone derivatives containing
the two Z-olefin structural moieties.1 In addition, labeled
preclavulone analogues for the elucidation of the biosyn-
thetic pathway of clavulones might be obtained according
to a known procedure, labeling being introduced during
the construction of the lower-chain olefin with the Julia
protocol.14
With the stereodefined olefin 6 in hand, the upper side chain
of preclavulone A was then installed via standard Wittig
methodology. Thus, olefination of the carbonyl function
released from acetal 6 with the non-stabilized phosphorane
derived from BrPh3P(CH2)4CO2H, smoothly gave the corre-
sponding Z-olefin 15 in 96% isolated yield.19 With the two
side chains positioned with the required cis-stereochemistry,
completion of the synthesis of preclavulone A 1 required the
mild oxidation of the sensitive cyclopentenol 15 to the cor-
responding stereochemically labile cyclopentenone. In the
event, oxidation of 15 with the Dess–Martin periodinane re-
agent in dichloromethane20 produced the (8S,12S)-enantio-
mer of preclavulone A (1) in 96% isolated yield as
a colorless oil, [a]D20 +126 (c 0.2, CH2Cl2) [lit.10 ꢀ125.6 (c
0.18, CH2Cl2) for (8R,12R)-1]. The corresponding methyl
ester (8S,12S)-2 was readily obtained in quantitative yield
by exposing (8S,12S)-1 to diazomethane in Et2O. The spec-
troscopic data of the ester nicely corresponded with those
reported by Ito and Iguchi for (8R,12R)-2,9b except the oppo-
site sign was observed for the optical rotation, [a]2D0 +136.4
(c 0.17, THF) compared to [a]2D0 ꢀ135.3 (c 0.13, THF),
respectively.9b
4. Experimental
4.1. General
Tetrahydrofuran was distilled over sodium/benzophenone
and methylene chloride was distilled over calcium hydride.
Commercially available reagents were used as supplied
without further purification. All reactions were performed
under a slight positive static pressure of argon in glassware
that had been dried in an oven at 140 ꢁC for at least 3 h prior
to use and allowed to cool in a desiccator over self-indicating
silica gel pellets. Syringes and needles for the transfer of
reagents were dried at 140 ꢁC and allowed to cool in a desic-
cator over P2O5 before use. Routine monitoring of reactions
was performed using GF-254 Merck (0.25 mm), aluminum-
supported SiO2 TLC plates. Compounds were visualized by
UV irradiation at a wavelength of 254 nm or stained by
exposure to a 0.5% solution of vanillin in H2SO4/EtOH
followed by charring. Flash column chromatography was
3. Conclusion
In conclusion, the first asymmetric synthesis of the (8S,12S)-
enantiomer of preclavulone A (1) and its methyl ester

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A. Porta et al. / Tetrahedron 63 (2007) 3989–3994
performed using Kieselgel 60 Merck (40–63 mm). Yields are
reported for chromatographically and spectroscopically pure
isolated compounds. Melting points were determined on
a Fisher-Johns hot plate and are uncorrected. [a]D values
are given in (deg mL)/(g dm); c is in g/100 mL and the
path length l is in decimeters. NMR chemical shifts are re-
ported in d units relative to residual CHCl3 [dH 7.26, dC (cen-
tral line of t) 77.0]; the abbreviations s¼singlet, d¼doublet,
t¼triplet, q¼quartet, qu¼quintuplet, m¼multiplet, and
br¼broad are used throughout. Coupling constants (J) are
given in Hz. The multiplicity of each carbon atom was deter-
mined by DEPT experiments. Infrared absorption spectra
CDCl3) d: 7.54–8.00 (10H, m, Ph), 5.75 (1H, br d, J¼
6.0 Hz), 5.49 (1H, d, J¼6.0 Hz), 5.10 (1H, d, J¼8.0 Hz),
4.93 (1H, d, J¼4.3 Hz), 4.43 (1H, t, J¼6.0 Hz), 3.32 (s,
3H), 3.23–3.29 (m, 1H), 3.11 (1H, ddd, J¼15.0, 12.0,
8.0 Hz), 2.25 (2H, t, J¼6.0 Hz), 1.76 (1H, dd, J¼13.0,
8.0 Hz), 1.51–1.56 (1H, dt, J¼13.0, 4.3 Hz). 13C NMR
(75 MHz, CDCl3) d: 137.6 s, 137.3 s, 134.6 d, 134.5 d,
133.6 d, 133.2 d, 133.0 d, 131.8 d, 129.7 d, 129.6 d, 129.4 d,
129.0 d, 128.9 d, 105.3 d, 88.1 d, 82.3 d, 54.3 q, 43.1 d,
41.2 d, 33.3 t, 26.3 t. HREIMS calcd for C22H24O6S2:
448.1014 (M)+, found: 448.1018. Anal. Calcd for
C22H24O6S2: C, 58.91; H, 5.39. Found: C, 59.06; H, 5.26.
were recorded in the range of 4000–600 cmꢀ1
.
4.1.3. (3aS,4S,6aR)-3,3a,4,6a-Tetrahydro-2-methoxy-4-
(2-(phenylsulfonyl)ethyl)-2H-cyclopenta[b]furan (8). A
solution of compound 13 (70 mg, 0.156 mmol) in dry THF
(3 mL) was added to a 1 M solution of SmI2 in THF
(6.24 mL, 0.62 mmol, 4.0 equiv). The instantaneous reac-
tion was followed by the addition of EtOAc (10 mL) and
a saturated solution of Na2S2O3 (10 mL). The layers were
separated and the aqueous phase was extracted with EtOAc
(3ꢂ10 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by flash chromatography
on silica gel. Elution with CH2Cl2/Et2O (98:2) gave the de-
sired sulfone 8 (42 mg, 87%) as a colorless oil. Rf¼0.31
(CH2Cl2/Et2O, 98:2). IR (liquid film) n cmꢀ1: 3090, 2984,
2948, 2906, 1446, 1152. 1H NMR (300 MHz, CDCl3)
d: 7.50–7.95 (5H, m, Ph), 5.74 (1H, br d, J¼6.0 Hz),
5.53 (1H, d, J¼6.0 Hz), 5.06 (1H, d, J¼7.0 Hz), 4.90 (1H,
d, J¼5.0 Hz), 327 (3H, s), 2.95–3.20 (3H, m), 2.74 (1H,
br q, J¼7.0 Hz), 1.88 (1H, m), 1.72 (1H, dd, J¼12.0,
8.0 Hz), 1.52 (1H, dt, J¼12.0, 5 Hz). 13C NMR (75 MHz,
CDCl3) d: 138.9 s, 133.9 d, 133.7 d, 133.5 d, 133.2 d,
133.1 d, 129.6 d, 129.1 d, 105.3 d, 87.9 d, 55.1 d, 54.2
q, 44.1 d, 41.2 d, 33.1 t, 23.3 t. HREIMS calcd
for C16H20O4S: 308.1082 (M)+, found: 308.1094. Anal.
Calcd for C16H20O4S: C, 62.31; H, 6.54. Found: C, 62.46;
H, 6.46.
4.1.1. (3aS,4S,6aR)-4-(2,2-Bis(phenylsulfonyl)ethyl)-
3a,4-dihydro-3H-cyclopenta[b]furan-2(6aH)-one (12).
Triphenylphosphine (511 mg, 1.95 mmol, 1.5 equiv), bis-
(phenylsulfonyl)methane (385 mg, 1.3 mmol, 1 equiv), and
alcohol ent-5 (200 mg, 1.3 mmol), obtained from racemic
10 following the same route previously described for 5,10
were dissolved in dry benzene (15 mL) under an argon atmo-
sphere. DEAD (0.307 mL, 1.95 mmol, 3 equiv) was added
and the resulting mixture was stirred for 1.5 h, and concen-
trated in vacuo to give a residue, which was purified by flash
chromatography on silica gel. Elution with CH2Cl2/EtOAc
(95:5) gave compound 12 (507 mg, 87%) as a white solid.
Mp 176–178 ꢁC; Rf¼0.28 (CH2Cl2/EtOAc, 95:5); [a]2D0
ꢀ26.8 (c 0.5, CH2Cl2). IR (Nujol) n cmꢀ1: 2881, 1775,
1
1449, 1172, 1327, 1151, 1137, 1076. H NMR (300 MHz,
CDCl3) d: 7.5–8.0 (10H, m, Ph), 5.78 (1H, dt, J¼6.0,
1.0 Hz), 5.72 (1H, br d, J¼6.0 Hz), 5.38 (1H, br d, J¼
7.0 Hz), 4.32 (1H, t, J¼6.0 Hz), 3.32–3.40 (1H, m), 3.16–
3.27 (1H, ddd, J¼14.2, 9.3, 6.7 Hz), 2.31 (1H, dd, J¼17.5,
9.7 Hz), 2.17–2.22 (2H, m), 2.10–2.22 (1H, dd, J¼7.0,
6.0 Hz). 13C NMR (75 MHz, CDCl3) d: 175.8 s, 137.3 s,
137.1 s, 136.8 d, 134.9 d, 129.8 d, 129. 5 d, 129.2 d, 128.2 d,
88.1 d, 82.0 d, 44.1 d, 39.8 d, 28.8 t, 26.9 t. CIMS: m/z
(%): 450 (M+NH4)+, 310 (10), 293 (20), 278 (10), 180
(20), 117 (10). Anal. Calcd for C21H20O6S2: C, 58.32; H,
4.66. Found: C, 58.22; H, 4.72.
4.1.4. 1-((3aS,4S,6aR)-3,3a,4,6a-Tetrahydro-2-methoxy-
2H-cyclopenta[b]furan-4-yl)-2-(phenylsulfonyl)octan-3-
yl acetate (14). n-BuLi (2.3 M in hexane, 0.271 mL,
1.2 equiv) was added to a solution of compound 8
(160 mg, 0.52 mmol) in dry THF (4 mL) at ꢀ78 ꢁC. After
stirring at ꢀ78 ꢁC for 30 min, the reaction mixture was
allowed to warm to ꢀ40 ꢁC, while a yellow color developed.
Hexanal (0.075 mL, 0.62 mmol, 1.2 equiv) in dry THF
(2 mL) was added via cannula, followed, after 30 min, by ex-
cess Ac2O (0.088 mL, 0.93 mmol, 1.8 equiv) and a catalytic
amount of DMAP (4 mg). The resulting mixture was
warmed to rt and stirred for 30 min, followed by the addition
of a saturated solution of NH4Cl (5 mL). The layers were
separated and the aqueous phase was extracted with Et2O
(3ꢂ10 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by flash chromatography
on silica gel. Elution with hexane/EtOAc (8:2) gave the de-
sired diastereomeric mixture 14 (218 mg, 90%) as a colorless
oil, which was immediately submitted to the elimination
step. Rf¼0.22 (hexane/AcOEt, 9:1). IR (liquid film) n
cmꢀ1: 2954, 2926, 1741, 1231, 1148, 1036. CIMS: m/z
(%): 468 (M+NH4)+.
4.1.2. (3aS,4S,6aR)-4-(2,2-Bis(phenylsulfonyl)ethyl)-
3,3a,4,6a-tetrahydro-2-methoxy-2H-cyclopenta[b]furan
(13). DIBAL-H (0.324 mL, 1 M in hexane, 2 equiv) was
added to a solution of lactone 12 (70 mg, 0.16 mmol) in
dry THF (5 mL) cooled to ꢀ78 ꢁC under an argon atmo-
sphere. After 1.5 h MeOH (1 mL) was added and the result-
ing mixture was concentrated under reduced pressure. The
residue was then dissolved in MeOH (10 mL) and 37%
HCl was added to obtain a clear solution. The resulting mix-
ture was stirred at ꢀ35 ꢁC for 15 h. An excess of NaHCO3
was added to quench the residual acid, and the resulting mix-
ture was filtered and concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 (20 mL) and H2O
(30 mL) was added. The layers were separated and the aque-
ous phase was extracted with CH2Cl2 (3ꢂ20 mL). The com-
bined organic phases were dried with MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue
was purified by flash chromatography on silica gel. Elution
with CH2Cl2/Et2O (95:5) gave the desired acetal 13
(65 mg, 93%) as a white solid. Mp 54–55 ꢁC; Rf¼0.22
(CH2Cl2/Et2O, 95:5). IR (Nujol) n cmꢀ1: 3063, 2907,
2830, 1584, 1152, 1078, 1035. 1H NMR (300 MHz,

A. Porta et al. / Tetrahedron 63 (2007) 3989–3994
3993
4.1.5. (3aS,4S,6aR)-3,3a,4,6a-Tetrahydro-2-methoxy-4-
((E)-2-(phenylsulfonyl)oct-2-enyl)-2H-cyclopenta[b]-
furan (7). NaOH (35 mg, 0.88 mmol, 2 equiv) was added to
a solution of compound 14 (200 mg, 0.44 mmol) in 1,4-di-
oxane (2 mL). The resulting mixture was stirred for 1 h
followed by addition of Et2O (20 mL) and H2O (10 mL).
The layers were separated and the aqueous phase was ex-
tracted with Et2O (10 mL). The combined organic phases
were dried with MgSO4, filtered, and concentrated under re-
duced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with hexane/EtOAc
(8:2) gave the desired vinylsulfone 7 (155 mg, 90%) as
a pale yellow oil. Rf¼0.34 (hexane/EtOAc 8:2). IR (liquid
film) n cmꢀ1: 3060, 2954, 2927, 1638, 1446, 1303, 1149,
to yield the corresponding lactol intermediate (28 mg, 96%)
as a colorless oil. Rf¼0.23 (hexane/EtOAc, 8:2). IR (liquid
film) n cmꢀ1: 3405, 2995, 2924, 2855, 1459, 1031. 1H
NMR (300 MHz, CDCl3) d: 5.70–5.80 (1H, m), 5.68 (1H,
d, J¼6.0 Hz), 5.51 (1H, d, J¼3.0 Hz), 5.35–5.45 (2H, m),
5.24 (1H, d, J¼7.3 Hz), 3.15–3.30 (1H, m), 2.75–2.90 (2H,
m), 1.62–2.21 (5H, m), 1.20–1.44 (6H, m), 0.89 (3H, t, J¼
6.5 Hz). 13C NMR (75 MHz, CDCl3) d: 135.9 d, 131.1 d,
130.9 d, 127.5 d, 99.0 d, 88.6 d, 45.0 d, 41.3 d, 34.3 t, 30.2
t, 29.1 t, 28.2 t, 27.3 t, 22.4 t, 13.9 q. t-BuOK (284.8 mg,
2.38 mmol, 8 equiv) was added to a stirred suspension of the
phosphonium salt BrPh3P(CH2)4CO2H (531 mg, 1.20 mmol,
4 equiv) in dry THF (3.5 mL) at rt. The mixture was allowed
to react for 30 min; afterward, to the red suspension of the
resulting ylide, the previously prepared lactol (70.5 mg,
0.3 mmol) in THF (2.5 mL) was added via cannula. The
resulting mixture was stirred for 2 h and then quenched by
the successive addition of a saturated solution of NH4Cl
(20 mL) and AcOH (0.14 mL, 8.4 equiv). The suspension
was diluted with Et2O (15 mL) and the two layers were
separated; the aqueous layer was extracted with Et2O
(3ꢂ20 mL). The combined organic phases were washed
with brine, dried with MgSO4, and evaporated under reduced
pressure. The resulting residue was purified by flash chroma-
tography on silica gel. Elution with hexane/EtOAc (4:1) deliv-
ered compound 15 (92.1 mg, 96%) as a colorless oil, [a]D20
+33 (c 0.3, CH2Cl2); Rf¼0.22 (hexane/EtOAc, 4:1). IR (liquid
film) n cmꢀ1: 3416, 2926, 1708, 1406, 1240, 1049. 1H NMR
(300 MHz, CDCl3) d: 6.14 (1H, dd, J¼5.7, 2.6 Hz), 5.97 (1H,
m), 5.25–5.6 (4H, m), 4.5 (1H, dd, J¼5.8, 2.6 Hz), 2.6 (1H,
m), 2.0–2.5 (11H, m), 1.75 (2H, quintet, J¼7.5 Hz), 1.3
(8H, m), 0.9 (3H, t, J¼7.2 Hz). 13C NMR (75 MHz, CDCl3)
d: 178.9 s, 140.9 d, 131.9 d, 131.3 d, 129.6 d, 129.0 d,
127.4 d, 76.2 d, 46.2 d, 45.5 d, 33.2 t, 31.3 t, 30.0 t, 28.2 t,
27.2 t, 26.5 t, 24.3 t, 23.0 t, 22.3 t, 13.8 q; ESIMS (APCI):
m/z 303 [M+1ꢀH2O]+. HREIMS calcd for C20H32O3:
320.2351 (M)+, found: 320.2355.
1
1036. H NMR (300 MHz, CDCl3) d: 7.40–7.82 (5H, m,
Ph), 6.93 (1H, t, J¼7.3 Hz), 5.64 (1H, d, J¼6.0 Hz), 5.47
(1H, d, J¼6.0 Hz), 5.00 (1H, br d, J¼6.0 Hz), 4.87 (1H, d,
J¼4.0 Hz), 3.24 (3H, s), 2.92–3.05 (2H, m), 2.05–2.30
(4H, m), 1.71–1.87 (1H, m), 1.50–1.60 (1H, m), 1.19–1.25
(6H, m), 0.82 (3H, t, J¼6.5 Hz). 13C NMR (75 MHz,
CDCl3) d: 144.3 s, 143.7 s, 139.6 s, 134.3 d, 133.1 d,
132.9 d, 131.5 d, 130.9 d, 129.0 d, 127.9 d, 105.4 d,
88.0 d, 54.2 q, 44.1 d, 42.2 d, 33.9 t, 28.6 t, 28.5 t, 27.9 t,
22.2 t, 13.8 q. CIMS: m/z (%): 408 (M+NH4)+, 333 (30),
313 (50), 296 (100), 268 (30), 240 (15), 153 (10). Anal.
Calcd for C22H30O4S: C, 67.66; H, 7.74. Found: C, 67.51;
H, 7.85.
4.1.6. (3aS,4S,6aR)-3,3a,4,6a-Tetrahydro-2-methoxy-
4-((Z)-oct-2-enyl)-2H-cyclopenta[b]furan (6). Na2S2O4
(534 mg, 3.07 mmol) and NaHCO3 (517 mg, 6.15 mmol)
were added to a solution of sulfone 7 (80 mg, 0.20 mmol)
in H2O/EtOH 1:1 (5 mL) and the resulting mixture was
heated under reflux for 2 h. EtOH was removed under re-
duced pressure and the aqueous residue was extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic phases were
dried with MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by flash chroma-
tography on silica gel. Elution with hexane/EtOAc (9:1)
gave the desired olefin 6 (38 mg, 76%) as a colorless oil.
4.1.8. (8S,12S)-Preclavulone A (1). Dess–Martin periodi-
nane (75.6 mg, 0.177 mmol, 1.4 equiv) was added to a stirred
solution of alcohol 15 (40.8 mg, 0.127 mmol) in dry CH2Cl2
(3.5 mL) under an argon atmosphere. After 3 h, Et2O
(15 mL) was added and the resulting mixture was filtered
through a pad of Celite. The solution was then concentrated
under reduced pressure at rt. The resulting residue was puri-
fied by flash chromatography on silica gel. Elution with hex-
ane/EtOAc (4:1) delivered compound 1 (38.8 mg, 96%) as
a pale yellow oil, [a]D20 +126 (c 0.2, CH2Cl2) [lit.10 ꢀ125.6
(c 0.18, CH2Cl2) for (8R,12R)-1]; Rf¼0.23 (hexane/EtOAc,
4:1). IR (liquid film) n cmꢀ1: 3600–3100, 2930, 1708,
Rf¼0.31 (hexane/EtOAc, 9:1). IR (liquid film) n cmꢀ1
:
1
2954, 2925, 2855, 1446, 1199, 1038. H NMR (300 MHz,
CDCl3) d: 5.75 (1H, ddd, J¼5.5, 2.5, 2.0 Hz), 5.67 (1H, dt,
J¼5.5, 1.5 Hz), 5.35–5.47 (2H, m), 5.11 (1H, dq, J¼7.0,
1.5 Hz), 4.97 (1H, d, J¼4.5 Hz), 3.32 (3H, s), 3.10 (1H,
ddd, J¼15.2, 10.4, 7.3 Hz), 2.72–2.83 (1H, m), 1.86 (1H, dd,
J¼12.0, 8.0 Hz), 1.70 (4H, m), 1.70 (1H, ddd, J¼12.2,
10.4, 4.5 Hz), 1.20–1.42 (6H, m), 0.88 (3H, t, J¼6.7 Hz).
13C NMR (75 MHz, CDCl3) d: 135.9 d, 131.0 d, 130.9 d,
127.4 d, 105.5 d, 88.3 d, 54.2 q, 45.8 d, 41.6 d, 33.6 t, 31.3
t, 29.5 t, 29.1 t, 28.2 t, 22.4 t, 13.9 q. CIMS: m/z (%): 268
(M+NH4)+, 253 (60), 236 (100), 219 (40). Anal. Calcd for
C16H26O2: C, 76.75; H, 10.47. Found: C, 76.88; H, 10.53.
1
1585, 1198, 737. H NMR (300 MHz, CDCl3) d: 7.7 (1H,
dd, J¼5.7, 2.7 Hz), 6.2 (1H, dd, J¼5.7, 1.8 Hz), 5.5 (4H,
m), 3.1 (1H, m), 2.45–2.55 (3H, m), 2.38 (2H, t, J¼
7.5 Hz), 1.9–2.3 (4H, m), 1.75 (2H, quintet, J¼7.5 Hz),
1.3 (8H, m), 0.9 (3H, t, J¼7.0 Hz). 13C NMR (75 MHz,
CDCl3) d: 208 s, 178.6 s, 165.1 d, 132.0 d, 131.6 d, 129.3
d, 128.7 d, 126.0 d, 48.6 d, 43.6 d, 32.7 t, 31.1 t, 28.8 t,
28.1 t, 27.0 t, 26.2 t, 23.9 t, 23.6 t, 22.2 t, 13.6 q; ESIMS
(APCI): m/z 319 (M+H)+, 301 (M+HꢀH2O)+. HREIMS
calcd for C20H30O3: 318.2195 (M)+, found: 318.2201.
4.1.7. (5Z)-7-((1S,2R,5S)-2-Hydroxy-5-((Z)-oct-2-enyl)-
cyclopent-3-enyl)hept-5-enoic acid (15). Acetal 6 (30 mg,
0.12 mmol) was dissolved in THF/H2O 1:1 (5 mL) and
0.25 N HCl (50 mL) was added. The resulting mixture was
stirred for 5 h followed by addition of excess NaHCO3 to
quench the residual acidity. THF was removed under reduced
pressure and the aqueous phase was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated under reduced pressure
4.1.9. (8S,12S)-Preclavulone A methyl ester (2). An ethe-
real solution of freshly prepared diazomethane was added

3994
A. Porta et al. / Tetrahedron 63 (2007) 3989–3994
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dropwise to an ethereal solution of (8S,12S)-preclavulone
A (1) (5 mg) at 0 ꢁC, until a yellow color persistence, and
the mixture was left at 0 ꢁC for an additional 5 min. Excess
CH2N2 was destroyed with AcOH and volatiles were
removed in vacuo. (8S,12S)-Chromatographically pure
preclavulone A methyl ester (2) was obtained as a color-
less oil in quantitative yields, [a]2D0 +136.4 (c 0.17, THF)
[lit.9b [a]2D0 ꢀ135.3 (c 0.13, THF) for (8R,12R)-2];
Rf¼0.51 (hexane/EtOAc, 4:1). The NMR data of compound
2 were in perfect agreement with those reported in the
literature.8,9a
Acknowledgements
11. It must be stressed that both the Corey’s and Iguchi’s synthe-
ses9a–b are, in the strict sense, merely diastereoselective. In
fact, enantioenriched starting materials were secured, in the
former approach, by a diastereoselective Diel–Alder reaction
whereas, in the other synthesis, a diastereomeric mixture was
separated by preparative HPLC.
This research was supported by Italian MIUR (funds COFIN
and FIRB). We thank Prof. Mariella Mella and Prof. Giorgio
Mellerio for recording NMR and MS spectra, respectively.
12. Since preclavulone A is widespread among coral species,6b and
its biosynthesis seems to be non-stereospecific,8 it is highly
possible that (8S,12S)-1 is the most abundant stereoisomer in
some of them.
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