Enantioselective total synthesis of plakotenin, a cytotoxic metabolite from Plakortis sp

Article abstract of DOI:10.1039/c004199h

The first total enantioselective synthesis of plakotenin is described. This marine natural product was isolated from an Okinawan sponge of the genus Plakortis and shows potent biological activity against several cancerous cell lines. A biomimetic intramolecular Diels-Alder reaction served as a key step in the total synthesis. The synthesis proves the relative and absolute stereochemistry of natural plakotenin. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c004199h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective total synthesis of plakotenin, a cytotoxic metabolite from
Plakortis sp†
Stephanie Arzt, Emmanuel Bourcet, Thierry Muller and Stefan Bra¨se*
Received 16th March 2010, Accepted 13th May 2010
First published as an Advance Article on the web 2nd June 2010
DOI: 10.1039/c004199h
The first total enantioselective synthesis of plakotenin is described. This marine natural product was
isolated from an Okinawan sponge of the genus Plakortis and shows potent biological activity against
several cancerous cell lines. A biomimetic intramolecular Diels–Alder reaction served as a key step in
the total synthesis. The synthesis proves the relative and absolute stereochemistry of natural plakotenin.
Introduction
Nature provides a considerable number of highly functionalised
natural products with great structural divergence. A particular
interesting and biologically active group of natural products is
derived from unsaturated polyketides and a subsequent Diels–
Alder reaction.1
Plakotenin (1) was isolated from an Okinawan marine sponge
of the genus Plakortis (Fig. 1).2 It has a bicyclic system with six
stereogenic centers, one of which is quaternary. Homo-plakotenin
(2)3 and nor-plakotenin (3)3 are related carboxylic acids from the
Palauan sponge Plakortis lita (Fig. 1). They are all optically active
and their absolute stereochemistry was deduced from analogous
compounds and from 2D-NMR analysis.2,3 Compounds 1–3 were
found to significantly reduce proliferation of rheumatoid synovial
fibroblasts3 and show moderate general cytotoxicity.2 Spiculoic
Scheme 1 Hypothetical ring closure of tetraenes (E,E,Z,E)-5a and
(E,E,E,E)-5b.
acid (4), a relative of plakotenin (1) with an additional carbonyl
group isolated from Plakortis angulospiculatus,4 was recently
synthesised (Fig. 1).5–7 Its absolute stereochemistry had to be
revised after total synthesis and is shown in Fig. 1.
a triene–ene, plakotenin needs a diene–diene system. Although,
linear and/or oxidised all (E)-configurated polyketides (e.g.
plakortin)8,10 were often isolated from Plakortis strains and show
interesting biological activity,8 plakotenin (1) necessarily stems
from a rather rare (E,E,Z,E)-tetraene precursor 5a (Scheme 1).10
In order to access plakotenin (1) as well as related diastereomers,
both non linear and linear tetraene systems 5a and 5b have been
considered. The challenge of a total synthesis of plakotenin (1)
stays in the generation of the stereogenic centers and double bonds.
In this manuscript we describe the total synthesis of plakotenin
(1, Fig. 1).11
Results and discussion
Fig. 1 Plakotenin (1) and related compounds.2–4,8
Stereochemical analysis revealed that the tetraene 5 is perfectly
suited for a bidirectional approach using a central C2-symmetrical
dimethyl building block (Scheme 1).
Based on precedence,8,9 we hypothesised that plakotenin stems
from a biosynthetic tetraene precursor 5 (Scheme 1). In contrast to
spiculoic acid whose biosynthetic precursor has been shown to be
The required dimethyl precursor 9a was synthesised by an
asymmetric alkylation approach (Scheme 2). Commercially avail-
able Myers pseudo-ephedrine auxiliary 612,13 was alkylated with
iodide (S)-714—prepared from Roche ester15—to give the amide
8 as a single diastereoisomer. The trityl group was chosen as the
protecting group due to its stability during the reaction sequence
as well as its facile introduction and removal.16 Reduction of amide
8 using lithium amidotrihydroborate gave alcohol 9a. In order to
Institut fu¨r Organische Chemie, Karlsruhe Institute of Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany. E-mail: braese@kit.edu;
Fax: + 49 721 608 8581
† Electronic Supplementary Information (ESI) available: Experimental
procedures and characterisation for compounds S1, S2 and copies of
NMR spectra of compounds 1, 13, 14a, 15a, 16–19 are available. See
DOI: 10.1039/c004199h/
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Scheme 2 Sequence for the generation of alcohol (E,E)-13.
assure that the desired diastereochemistry was achieved during the
asymmetric alkylation, alcohol 9a was deprotected (formic acid)
and the optical rotation of the obtained diol 9b compared with
literature values.17 Oxidation of alcohol 9a delivered aldehyde 10.
Wittig reaction sequence with subsequent leveling of the oxidation
state gave aldehyde 11. Latter was also directly accessible from
aldehyde 10 in comparable yield (63%) in one step by using
silylimine B.18 Extension of 11 via a Julia–Kocienski olefination
approach with tetrazole C19 gave rise to a mixture of inseparable
(E,E)/(Z,E)-dienes 12 in a 10 : 1 ratio. The undesired geometrical
isomer could eventually be removed after cleavage of the trityl
protecting group with camphorsulfonic acid, yielding alcohol
(E,E)-13 as pure isomer in good yield.
With (E,E)-13 in hand, we first explored the route of linear
tetraene precursor 5b. Oxidation of (E,E)-13 with Dess–Martin
periodinane (DMP) furnished the corresponding aldehyde which
was directly used in a classical Wittig reaction (Scheme 3).
However, under the employed reaction conditions (D, toluene,
100 ◦C), cyclisation of intermediate (E,E,E)-14b took place to
give the bicyclic product 15b. The corresponding alcohol 16b was
obtained in good yield after subsequent reduction (43% over three
steps). Its stereochemistry was deduced by 2D-NMR experiments
(Fig. 2, see ESI†). The spectra showed prominent differences with
plakotenin (1) and its congeners, which support the stereochemical
assignment made for plakotenin (1).2 Unfortunately, alcohol 16b
Fig. 2 NOESY correlations for compounds 16a and 16b.
was not suitable for direct extension to plaketonin isomers using
classical olefination chemistry (results not shown).
We then turned to the synthesis of non-linear tetraene precursor
5a. In order to avoid in situ cyclisation of the generated triene, a
mild (Z)-selective variation of the Horner–Wadsworth Emmons
reaction, using phosphonate
E (ethyl 2-((bis(o-tolyloxy))-
phosphoryl)butanoate) was chosen to generate the triene ester
(E,E,Z)-14a required for the plakotenin stereochemistry.20
Thus, (E,E,Z)-isomer 14a was obtained in 64% yield (over two
steps) with a Z : E selectivity of 6 : 1. Both isomers could be
separated by silica column chromatography. The classical HWE
reaction conditions using phosphonate F also proceeded nicely
and, surprisingly delivered again the (E,E,Z)-14a isomer as
the major product with a 4 : 1 ratio in 76% yield over two steps
Scheme 3 Wittig and in situ Diels–Alder reaction yielded 16b.
Scheme 4 HWE reaction followed by Diels–Alder reaction yielded 16a.
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Scheme 5 Sequence to complete (R,R,R,R,R,S)-plakotenin (1).
(Scheme 4). NOESY experiments realised on alcohol 17 (see ESI†)
Experimental
permitted indeed the assignment of the geometry of the double
bonds unambiguously. With the triene in hand, (E,E,Z)-14a
was heated in toluene overnight and cyclisation took place to
deliver the bicycle (R,R,R,R,R,S)-15a in very good yield (85%,
Scheme 4).
General methods
1H and 13C NMR spectra were recorded on a Bruker AM 400
(400 MHz/100 MHz), Bruker DRX 500 (500 MHz/125 MHz)
or Bruker Avance 600 (600 MHz/150 MHz) instrument using
CDCl3 as solvent. Chemical shifts are expressed in parts per
million (ppm, d) downfield from tetramethylsilane (TMS) and
are referenced to CHCl3 (7.26 ppm) as internal standard. All
coupling constants are absolute values and J values are expressed
in Hertz (Hz). For assigning signal separation of 1H NMR spectra
the following abbreviations were used: s = singlet, bs = broad
singlet, d = doublet, t = triplet, q = quartet, sext = sextet,
m = multiplet, dd = doublet of doublets, dq = doublet of
quartets, ddq = doublet of dq and Harom. = aromatic proton. For
assigning signals of 13C NMR spectra the following abbreviations
were used: p = primary (RCH3), s = secondary (R2CH2), t =
tertiary (R3CH), q = quaternary (R4C). The assignment was
supported by analysis of DEPT90 and DEPT135 spectra. MS
(EI) (electron impact mass spectrometry), MS (FAB) (fast atom
bombardment mass spectrometry) and HRMS: Finnigan MAT
90. The molecular fragments are quoted as the relation between
mass and charge (m/z), the intensities as a percentage value
relative to the intensity of the base signal (100%). The molecular
ion obtains the abbreviation [M+]. IR (infrared spectroscopy):
FT-IR Bruker IFS 88. IR spectra of oils were recorded as thin
films on KBr; in the case of solids the neat substance was used. The
deposit of the absorption band is given in wave numbers in cm-1.
Solvents and chemicals used for reactions were purchased from
commercial suppliers. Solvents were dried under standard con-
ditions; chemicals were used without further purification. All the
reactions were performed in standard glassware. All reactions were
carried out under Argon in flame-dried glassware. Evaporation of
solvents and concentration of reaction mixtures were performed
in vacuo on a Bu¨chi rotary evaporator. Column chromatography
was performed using silica gel 60 (purchased from Merck) under
flash conditions. For thin layer chromatography, aluminium foils
The stereochemistry of the product was again deduced by 2D-
NMR spectra (realised on alcohol 16a, obtained by reduction
of ester 15a with LiAlH4) and shows very similar NMR shifts
compared to plakotenin (Fig. 2). Unfortunately, after subsequent
oxidation of 16a, as for 16b, introduction of the last missing
double bond for plakotenin could not be achieved by olefination
reactions (results not shown). Since addition of other nucleophiles
(e.g. Grignard reagents) proceeds smoothly on the corresponding
aldehyde (results not shown), this failure might be attributed
to steric hindrance. Hence, we focused on the strategy of the
biomimetic Diels–Alder reaction of the corresponding tetraene.
Standard reduction of (E,E,Z)-14a using LiAlH4 and subse-
quent oxidation with DMP provided the corresponding aldehyde,
which was directly elongated to the tetraene (E,E,Z,E)-18 using
ester G (Scheme 5). It is noteworthy that compounds 14a,
17 and 18 are very prone to cyclisation and great care must be
taken to store and handle these sensitive compounds in a cold
environment. Indeed, on heating, tetraene (E,E,Z,E)-18 cyclises
smoothly in excellent yield to ester (R,R,R,R,R,S)-19 detected as
single diastereoisomer. Saponification eventually yielded synthetic
plakotenin (1, Scheme 5), which was extensively analysed by
2D-NMR (the same correlations as for compound 16a are
observed, see ESI†). The spectroscopic data (1H-NMR, 13C-NMR
and mass) as well as the optical rotation of synthetic plakotenin
(1) were identical with the reported data of the natural product
(see ESI†).
Conclusions
In summary, we have developed a rapid and very efficient route
to (R,R,R,R,R,S)-plakotenin (1) in 15 steps (14.7% overall yield
from 6) which should also be suitable for the syntheses of
analogous compounds such as 2 and 3. The biological assays and
modelling studies to reveal the transition states are currently being
pursued.
layered with silica gel with fluorescence indicator (silica gel 60 F254
)
produced by Merck were employed. The detection was carried
out with an UV-lamp from Heraeus, model Fluotest. Seebach-
reagent [molybdophosphoric acid (2.5 w%), cerium(IV) sulfate
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tetrahydrate (1.0 w%), H2SO4 conc. (6.0 w%), water (90.5 w %)]
was used as dipping reagent. Specific rotations were determined
using the polarimeter Perkin Elmer 241. Melting points were
registered on a Mel-Temp II melting point microscope from
Laboratory Devices Inc. and are not corrected.
were washed sequentially with 3 M aqueous HCl (10 mL), 2 M
aqueous NaOH (10 mL) and brine (50 mL). The organic layer was
dried (MgSO4) and evaporated under reduced pressure. The crude
product was purified by column chromatography on silica using
cyclohexane/ethyl acetate 9 : 1 to give alcohol 9a (2.03 g, 91%) as
◦
a white solid. Rf 0.18 (cyclohexane/EtOAc 6 : 1). – mp 72 C. –
1
[a]2D0 = +13.0 (0.81 g/100 mL, CHCl3). – H NMR (400 MHz,
(2R,4R)-N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-N,2,4-
trimethyl-5-(trityloxy)pentanamide (8)
CDCl3): d = 0.87 (d, J = 6.6 Hz, 3 H, CH3), 0.93 (d, J = 6.7 Hz,
3 H, CH3), 1.10–1.23 (m, 2 H, CHCH2CH), 1.31 (t, J = 5.5 Hz,
1 H, OH), 1.61–1.69 (m, 1 H, HOCH2CH), 1.79–1.87 (m, 1 H,
TrtOCH2CH), 2.89–2.96 (m, 2 H, TrtOCH2), 3.34–3.46 (m, 2 H,
HOCH2), 7.20–7.31 (m, 9 H, Harom.), 7.43–7.46 (m, 6 H, Harom.).
A solution of n-butyllithium in hexanes (2.5 M, 10.8 mL,
27.0 mmol) was slowly added to a suspension of lithium chloride
(3.64 g, 85.9 mmol) and diisopropylamine (4.10 mL, 3.00 g,
29.0 mmol) in THF (15 mL) at –78 ◦C. The resulting suspension
was warmed to 0 ◦C briefly and was then cooled to –78 ◦C again.
An ice-cooled solution of N-((1S,2S)-1-hydroxy-1-phenylpropan-
2-yl)-N-methylpropionamide (3.14 g, 14.2 mmol) in THF (35 mL)
was added. The mixture was stirred at –78 ◦C for 2 h, at 0 ◦◦C
for 15 min and at rt for 5 min. The mixture was cooled to 0 C
and iodide 7 (2.99 g, 6.76 mmol) in THF (35 mL) was added.
After being stirred for 2 d at 45 ◦C the reaction mixture was
treated with half saturated aqueous NH4Cl (70 mL) and the
resulting mixture was extracted with EtOAc (3 ¥ 40 mL). The
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure. The crude product was purified by
column chromatography on silica using cyclohexane/ethyl acetate
2 : 1 to give amide 8 (3.31 g, 91%)◦ as white foam. Rf 0.22
(cyclohexane/EtOAc 2 : 1). – mp 50 C. – [a]2D0 = +33.5 (0.99
g/100 mL, CHCl3). – 1H NMR (400 MHz, CDCl3): d = 0.92 (d,
J = 2.7 Hz, 3 H), 0.94 (d, J = 2.7 Hz, 3 H), 1.00 (d, J = 6.9 Hz, 3 H),
1.31–1.44 (m, 2 H), 1.50–1.61 (m, 1 H), 2.35–2.43 (m, 1 H), 2.50
(s, 3 H), 2.70 (dd, J = 8.8 Hz, J = 6.0 Hz,1 H), 2.88 (dd, J =
8.8 Hz, J = 4.7 Hz, 1 H), 4.24 (bs, 1 H), 4.49 (t, J = 7.2 Hz, 1 H),
7.11–7.24 (m, 14 H), 7.33–7.39 (m, 6 H). – 13C NMR (100 MHz,
CDCl3): d = 14.3 (p), 17.5 (p), 18.2 (p), 31.7 (t), 34.1 (t), 37.8 (s),
67.4 (s), 76.4 (t), 86.0 (q), 126.1 (t), 126.8 (t), 127.5 (t), 127.6 (t),
–
13C NMR (100 MHz, CDCl3): d = 16.3 (p), 17.1 (p), 31.2 (t),
33.0 (t), 37.2 (s), 68.9 (s), 69.0 (s), 86.2 (q), 126.8 (t), 127.6 (t),
˜
128.7 (t), 144.4 (q). – IR (neat): n = 3299, 3056, 3031, 2958, 2925,
2871, 1595, 1491, 1449, 1387, 1323, 1220, 1177, 1151, 1062, 1033,
985, 949, 931, 897, 821, 765, 752, 709, 697, 648, 632, 540, 484,
422 cm-1. – MS (EI, 70 eV) m/z (%): 374 (1) [M+], 259 (12), 243
(100), 183 (17), 165 (35), 105 (11), 77 (4). – HRMS (C26H30O2):
calc. 374.2246, found 374.2249.
((((2R,4R,5E,7E)-2,4,6-Trimethyl-8-phenylocta-5,7-dien-1-
yl)oxy)methanetriyl)tribenzene (12)
To
a
solution of alcohol (4R,6R,E)-2,4,6-trimethyl-7-
(trityloxy)hept-2-en-1-ol (S2) (201 mg, 485 mmol) in DMSO
(10 mL) was added 2-iodoxybenzoic acid (340 mg, 1.21 mmol).
The reaction mixture was stirred at rt for 1 h, after which it was
diluted with H2O (50 mL) and the resulting precipitate was filtered
off. The aqueous layer was extracted with Et2O (3 ¥ 20 mL). The
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure to yield the crude aldehyde 11 (200 mg,
485 mmol, assumed to be quantitative) as colourless oil, which
was used without further purification for the following olefination
reaction.
128.2 (t), 128.7 (t), 142.5 (q), 144.3 (q), 179.0 (q) (The 1H- and 13
C
To a solution of 5-(benzylsulfonyl)-1-phenyl-1H-tetrazole
NMR spectra are complex due to amide geometrical isomerism). –
(218 mg, 728 mmol) in THF (5 mL) was slowly added lithium
bis(trimethylsilyl)amide (1 M in THF, 600 mL, 600 mmol) at
0 ◦C. After stirring for 20 min at rt, it was cooled to –78 ◦C and a
solution of crude aldehyde 11 (200 mg, 0.485 mmol) in THF (5 mL)
was added. The reaction mixture was stirred overnight while slowly
warming up to rt. It was diluted with Et2O (5 mL) and the reaction
quenched by addition of saturated aqueous NaHCO3 (5 mL).
The aqueous layer was extracted with EtOAc (3 ¥ 15 mL). The
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure. The crude product was purified by column
chromatography on silica using cyclohexane/ethyl acetate 50 : 1 to
give compound 12 (190 mg, 80%) as colourless oil. A 10 : 1 ratio of
E/Z products was obtained. Rf 0.30 (cyclohexane/EtOAc 50 : 1).
˜
IR (neat): n = 3382, 3059, 3030, 2969, 2930, 2871, 1620, 1490, 1449,
1410, 1373, 1318, 1221, 1155, 1070, 988, 926, 899, 839, 764, 747,
705, 648, 633, 506 cm-1. – MS (FAB, Matrix: 3-NBA) m/z (%):
558 [M+Na]+, 536 [M+H]+, 243 (100). – HRMS (FAB, Matrix:
3-NBA) (C36H42NO3): calc. 536.3165, found 536.3167.
(2R,4R)-2,4-Dimethyl-5-(trityloxy)pentan-1-ol (9a)
A solution of n-butyllithium in hexanes (2.5 M, 9.30 mL,
23.0 mmol) was added to a solution of diisopropylamine (3.50 mL,
2.50 g, 25.0 mmol) in THF (30 mL) at –78 ◦C. The resulting
solution was stirred at –78 ◦C for 10 min, was then warmed
to 0 ◦C and held at that temperature for 20 min. Lithium
amidotrihydroborate (819 mg, 23.9 mmol) was added in one
portion. The suspension was stirred at 0 ◦C for 15 min and then
was warmed to rt. After 15 min, the suspension was cooled to
0 ◦C. A solution of amide 8 (3.20 g, 5.97 mmol) in THF (30 mL)
was slowly added. The reaction mixture was warmed to rt, held
at that temperature for 2 h and was then cooled to 0 ◦C where
excess hydride was quenched by careful addition of 3 M aqueous
HCl (70 mL). The mixture was stirred for 10 min at 0 ◦C and
was then extracted with Et2O (3 ¥ 50 mL). The combined extracts
1
– [a]2D0 = –75.0 (0.71 g/100 mL, CHCl3). – H NMR (400 MHz,
CDCl3): d = 0.91 (d, J = 6.6 Hz, 3 H, TrtOCH2CHCH3),
=
1.03 (d, J = 6.7 Hz, 3 H, C CHCHCH3), 1.09–1.16 (m, 1 H,
CHCHAHBCH), 1.45–1.49 (m, 1 H, CHCHAHBCH), 1.63 (s, 3
=
H, PhCH CHCCH3), 1.70–1.80 (m, 1 H, TrtOCH2CH), 2.36–
=
2.47 (m, 1 H, C CHCH), 2.81 (dd, J = 8.6 Hz, J = 6.7 Hz, 1 H,
TrtOCHAHB), 3.02 (dd, J = 8.7 Hz, J = 4.7 Hz, 1 H, TrtOCHAHB),
=
=
5.36 (d, J = 9.6 Hz, 1 H, PhCH CHC CH), 6.38 (d, J = 16.1 Hz,
=
1 H, PhCH), 6.74 (d, J = 15.6 Hz, 1 H, PhCH CH), 7.16–7.24
(m, 5 H, Harom.), 7.26–7.32 (m, 9 H, Harom.), 7.40–7.46 (m, 6 H,
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Harom.). – 13C NMR (100 MHz, CDCl3): d = 12.4 (p), 18.5 (p),
21.0 (p), 30.2 (t), 31.8 (t), 41.7 (s), 67.6 (s), 86.0 (q), 125.6 (t), 126.1
(t), 126.7 (t), 126.8 (t), 127.7 (t), 128.5 (t), 128.8 (t), 132.1 (q), 134.2
cooling to 0 ◦C and addition of the crude aldehyde (310 mg,
1.27 mmol, from previous reaction) in THF (5 mL). The solution
was stirred for 1 h at 0 ◦C, warmed slowly to rt and stirred for
an additional 3 h. The reaction was quenched by pouring on to
saturated aqueous NH4Cl (80 mL). The product was extracted
with Et2O and the combined extracts were dried (MgSO4) and
concentrated. The crude product was then purified by column
chromatography on silica using n-pentane–Et2O 30 : 1 to yield
ester 14a (328 mg, 76%) as a colourless oil. A 4 : 1 ratio of Z/E
products was obtained. Rf 0.50 (cyclohexane/EtOAc = 18 : 1).
˜
(t), 138.0 (q), 140.9 (t), 144.5 (q). – IR (film): n = 3084, 3058, 3025,
2957, 2924, 2866, 2851, 1597, 1560, 1542, 1491, 1448, 1386, 1314,
1220, 1182, 1155, 1070, 1031, 959, 926, 899, 826, 774, 763, 746,
706, 647, 632, 530 cm-1. – MS (EI, 70 eV) m/z (%): 486 (50) [M+],
374 (73), 414 (100), 485 (95). – HRMS (C36H38O): calc. 486.2922,
found 486.2917.
1
– [a]2D0 = –10.0 (1.36 g/100 mL, CHCl3). – H NMR (400 MHz,
(2R,4R,5E,7E)-2,4,6-Trimethyl-8-phenylocta-5,7-dien-1-ol (13)
To a solution of 12 (3.01 g, 6.19 mmol) in CH2Cl2–MeOH
=
=
CDCl3): d = 0.94 (d, J = 6.4 Hz, 3 H, PhCH CHC CHCHCH3),
=
1.00 (d, J = 7.2 Hz, 3 H, EtCO2C CHCHCH3), 1.04 (t,
◦
(200/100 mL) at 0 C camphorsulfonic acid (2.44 g, 10.5 mmol)
J = 7.2 Hz, 3 H, EtCO2CCH2CH3), 1.21 (t, J = 6.8 Hz,
was added in one portion. The mixture was stirred at rt for 90 min
and was then neutralized by the addition of saturated aqueous
NaHCO3 (60 mL). The layers were separated and the aqueous layer
extracted with CH2Cl2 (3 ¥ 50 mL). The combined organic layers
were dried (MgSO4) and then concentrated. The crude product was
then purified by flash chromatography using cyclohexane/ethyl
acetate 6 : 1 to yield alcohol 13 (1.33 g, 88%)◦as colourless solid.
Rf 0.16 (cyclohexane/EtOAc 6 : 1). – mp 43 C. – [a]2D0 = –44.5
(0.92 g/100 mL, CHCl3). – 1H NMR (400 MHz, CDCl3): d = 0.95
(d, J = 6.7 Hz, 3 H, HOCH2CHCH3), 0.99 (d, J = 6.6 Hz, 3 H,
3 H, CO2CH2CH3), 1.29–1.36 (m, 2 H, CHCH2CH), 1.79 (s,
=
3 H, PhCH CHCCH3), 2.22–2.33 (m, 2 H, EtCO2CCH2CH3),
=
=
2.43–2.59 (m, 1 H, PHCH CHC CHCH), 2.98–3.01 (m, 1 H,
=
EtCO2C CHCH), 4.01–4.15 (m, 2 H, CO2CH2CH3), 5.34 (d,
=
=
J = 9.6 Hz, 1 H, PhCH CHC CH), 5.58 (d, J = 9.6 Hz, 1
=
H, EtCO2C CH), 6.41 (d, J = 16.0 Hz, 1 H, PhCH), 6.77 (d, J =
=
16.0 Hz, 1 H, PhCH CH), 7.17–7.21 (m, 1 H, Harom.), 7.28–7.32
(m, 2 H, Harom.), 7.38–7.40 (m, 2 H, Harom.). – 13C NMR (100 MHz,
CDCl3): d = 12.6 (p), 13.9 (p), 14.3 (p), 21.1 (p), 21.5 (p), 27.8
(s), 31.3 (t), 32.0 (t), 45.8 (s), 60.2 (s), 125.7 (t), 126.2 (t), 126.9 (t),
128.6 (t), 132.6 (q), 132.9 (q), 134.3 (t), 138.2 (q), 140.5 (t), 145.9
=
C CHCHCH3), 1.11–1.19 (m, 1 H, CHCHAHBCH), 1.27 (bs, 1
˜
H, OH), 1.39–1.45 (m, 1 H, CHCHAHBCH), 1.63–1.71 (m, 1 H,
(t), 168.3 (q). – IR (film): n = 3027, 2961, 2868, 1727, 1599, 1493,
HOCH2CH), 1.88 (s, 3 H, PhCH CHCCH3), 2.61–2.72 (m, 1 H,
1450, 1381, 1211, 1180, 1030, 1029, 704 cm-1. – MS (EI, 70 eV)
m/z (%): 340 (6) [M+], 267 (14), 171 (8), 91 (6), 43 (100). – HRMS
(C23H32O2): calc. 340.2402, found 340.2400.
=
=
C CHCH), 3.42 (dd, J = 10.5 Hz, J = 6.5 Hz, 1 H, HOCHAHB),
3.53 (dd, J = 10.5 Hz, J = 5.2 Hz, 1 H, HOCHACHB), 5.43 (d,
=
=
J = 9.5 Hz, 1 H, PhCH CHC CH), 6.45 (d, J = 16.1 Hz, 1 H,
=
PhCH), 6.79 (d, J = 16.1 Hz, 1 H, PhCH CH), 7.17–7.21 (m, 1
Compound 15a
H, Harom.), 7.29–7.32 (m, 2 H, Harom.), 7.39–7.41 (m, 2 H, Harom.).
–
13C NMR (100 MHz, CDCl3): d = 12.6 (p), 17.2 (p), 20.8 (p),
A solution of linear ester 14a (100 mg, 294 mmol) in toluene
(30 mL) was heated to reflux and stirred in a sealed vial for 20 h.
The mixture was concentrated. The crude product was purified
by column chromatography on silica using n-pentane–Et2O 40 : 1
to yield cyclic ester 15a (85.0 mg, 85%) as colourless oil. Rf 0.40
(cyclohexane/EtOAc = 18 : 1). – [a]2D0 = +173.5 (0.34 g/100 mL,
CHCl3). – (NMR assignment according to numbering system of
30.3 (t), 33.5 (t), 41.0 (s), 68.1 (s), 125.8 (t), 126.1 (t), 126.9 (t),
˜
128.5 (t), 132.1 (q), 134.1 (t), 137.9 (q), 140.8 (t). – IR (neat): n =
3307, 3078, 3055, 3028, 2959, 2921, 2870, 1658, 1630, 1596, 1575,
1492, 1447, 1370, 1269, 1232, 1153, 1074, 1037, 990, 961, 924, 909,
883, 830, 747, 690, 647, 532, 456, 438, 427, 409 cm-1. – MS (EI, 70
eV) m/z (%): 244 (47) [M+], 171 (100), 143 (29), 129 (31), 99 (37),
91 (31). – HRMS (C17H24O): calc. 244.1827, found 244.1829.
1
plakotenin, see ESI†) H NMR (400 MHz, CDCl3): d = 0.78 (t,
J = 7.2 Hz, 3 H, 17-H), 0.94 (d, J = 6.4 Hz, 3 H, 14-H), 1.00–1.06
(m, 1 H, 11-H), 1.14 (d, J = 6.0 Hz, 3 H, 13-H), 1.19–1.24 (m,
1 H, 11-H), 1.31 (t, J = 7.5 Hz, 3 H, 17-H), 1.52–1.62 (m, 3 H,
3-H and 5-H), 1.80 (bs, 3 H, 15-H), 1.83–1.92 (m, 2 H, 4-H and
7-H), 2.43–2.51 (m, 1 H, 6-H), 4.12 (bs, 1 H, 10-H), 4.22 (ddq, J =
24, 9.6, 7.2 Hz, 2 H, 16-H), 5.28 (s, 1 H, 9-H), 7.22–7.25 (m, 1 H,
Harom.), 7.26–7.30 (m, 4 H, Harom.). – 13C NMR (100 MHz, CDCl3):
d = 9.4 (p), 14.6 (p), 21.6 (p), 22.3 (p), 24.1 (p), 26.8 (s), 31.2 (t),
35.4 (t), 45.0 (s), 48.0 (t), 53.1 (t), 53.6 (t), 54.6 (q), 60.2 (s), 126.2
(t), 126.6 (t), 127.9 (t), 130.8 (t), 136.2 (q), 141.9 (q), 175.7 (q).
(2Z,4R,6R,7E,9E)-Ethyl 2-ethyl-4,6,8-trimethyl-10-
phenyldeca-2,7,9-trienoate (14a)
Dess–Martin periodinane (3.56 mL, 1.65 mmol) was added at 0 ◦C
to a solution of alcohol 13 (310 mg, 1.27 mmol) in CH2Cl2 (15 mL).
After stirring for 2 h at rt, the reaction mixture was quenched by
adding saturated aqueous Na2S2O3 (5 mL) and saturated aqueous
NaHCO3 (5 mL). The layers were separated and the aqueous layer
extracted with CH2Cl2 (4 ¥ 10 mL). The organic layer was dried
(MgSO4) and concentrated to yield the crude aldehyde (310 mg,
1.27 mmol, assumed to be quantitative) as colourless oil, which
was used without further purification for the following olefination
reaction.
To a solution of sodium hydride (60% in mineral oil, 152 mg,
3.87 mmol) in THF (15 mL) at 0 ◦C was added dropwise ethyl
2-(diethoxyphosphoryl)butanoate (960 mg, 3.87 mmol) (or ethyl
2-((bis(o-tolyloxy))phosphoryl)acetate for method according to
ANDO et al.). The solution was stirred at rt for 1 h before
Compound 16a
To a solution of ester 15a (85.0 mg, 250 mmol) in THF (3 mL)
at 0 ◦C was slowly added lithium aluminium hydride (9.70 mg,
255 mmol). After stirring at 0 ◦C to rt overnight the mixture
◦
was quenched carefully at 0 C with H2O followed by Rochelle’s
salt solution. The aqueous layer was extracted with EtOAc (4 ¥
5 mL), the combined organic extracts were dried (MgSO4) and
3304 | Org. Biomol. Chem., 2010, 8, 3300–3306
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©

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=
CDCl3): d = 0.94 (d, J = 6.5 Hz, 3 H, HOCH2C CHCHCH3),
concentrated. The crude product was purified by column chro-
matography on silica using n-pentane–Et2O 9 : 1 to yield alco-
hol 16a (71.0 mg, 95%) as colourless oil. Rf 0.38 (cyclohex-
ane/EtOAc = 6 : 1). – [a]D20 = +184.6 (0.28 g/100 mL, CHCl3). –
(NMR assignment according to numbering system of plakotenin,
see ESI†) 1H NMR (600 MHz, CDCl3): d = 0.82 (t, J = 7.2 Hz, 3
H, 12-H), 0.93 (d, J = 6.6 Hz, 3 H, 14-H), 1.04 (sext, J = 7.2 Hz, 1
H, 11-H), 1.20 (d, J = 5.4 Hz, 3 H, 13-H), 1.28 (bs, 1 H, OH), 1.35
(sext, J = 7.2 Hz, 1 H, 11-H), 1.50–1.54 (m, 1 H, 5-H), 1.57–1.62
(m, 1 H, 5-H), 1.71 (t, J = 10.8 Hz, 1 H, 3-H), 1.83 (s, 3 H, 15-H),
1.86–1.90 (m, 2 H, 4-H and 7-H), 2.17–2.23 (m, 1 H, 6-H), 4.12 (d,
J = 4.2 Hz, 1 H, 10-H), 3.60 (d, J = 11.4 Hz, 1 H, 1-H), 3.84 (d,
J = 10.8 Hz, 1 H, 1-H), 5.19 (d, J = 3.6 Hz, 1 H, 9-H), 7.20–7.23
(m, 1 H, Harom.), 7.25–7.29 (m, 4 H, Harom.). – 13C NMR (100 MHz,
CDCl3): d = 8.8 (p), 21.6 (p), 22.5 (p), 24.0 (p), 25.7 (s), 31.4 (t),
35.2 (t), 43.4 (q), 45.3 (s), 49.8 (t), 51.7 (t), 54.3 (t), 65.2 (s), 126.1
(t), 126.3 (t), 127.7 (t), 130.7 (t), 136.5 (q), 141.3 (q).
=
=
0.97 (d, J = 6.5 Hz, 3 H, PhCH CHC CHCHCH3), 1.05 (t, J =
7.5 Hz, 3 H, HOCH2CCH2CH3), 1.14 (bs, 1 H, OH), 1.27–1.38 (m,
=
2 H, CHCH2CH), 1.80 (s, 3 H, PhCH CHCCH3), 2.14 (q, J =
7.5 Hz, 2 H, HOCH2CCH2CH3), 2.41–2.56 (m, 2 H, CHCH2CH),
=
4.02 (s, 2 H, HOCH2), 5.05 (d, J = 10.0 Hz, 1 H, HOCH2C CH),
=
=
5.41 (d, J = 9.5 Hz, 1 H, PhCH CHC CH), 6.44 (d, J = 16.0 Hz,
=
1 H, PhCH), 6.79 (d, J = 16.0 Hz, 1 H, PhCH CH), 7.19 (t, J =
7.5 Hz, 1 H, Harom.), 7.29–7.32 (m, 2 H, Harom.), 7.40 (d, J = 7.5 Hz,
2 H, Harom.). – 13C NMR (125 MHz, CDCl3): d = 12.7 (p), 13.2 (p),
21.7 (p), 22.7 (p), 28.0 (s), 30.5 (t), 31.2 (t), 46.0 (s), 60.7 (s), 126.2
(t), 126.3 (t), 127.1 (t), 128.7 (t), 133.0 (q), 133.7 (t), 133.9 (t), 138.0
˜
(q), 139.3 (q), 140.8 (t). – IR (film): n = 3343, 3027, 2959, 2923,
1598, 1493, 1450, 1385, 1016, 958, 747, 692 cm-1. – MS (EI, 70 eV)
m/z (%): 298 (67) [M+], 171 (100), 153 (69), 107 (60). – HRMS
(C21H30O): calc. 298.2297, found 298.2296.
(2E,4Z,6R,8R,9E,11E)-Ethyl 4-ethyl-2,6,8,10-tetramethyl-12-
Compound 16b
phenyldodeca-2,4,9,11-tetraenoate (18)
To a solution of ester 15b (85.0 mg, 250 mmol) in THF (3 mL)
at 0 ◦C was slowly added lithium aluminium hydride (9.70 mg,
255 mmol). After stirring at 0 ◦C to rt overnight the mixture was
Dess–Martin periodinane (1.41 mL, 653 mmol) was added at 0 ◦C
to a solution of alcohol 17 (150 mg, 503 mmol) in CH2Cl2 (10 mL).
After stirring for 2 h at rt, the reaction mixture was quenched by
adding saturated aqueous Na2S2O3 (5 mL) and saturated aqueous
NaHCO3 (5 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (4 ¥ 10 mL). The organic layer was dried
(MgSO4) and concentrated to yield the crude aldehyde (150 mg,
503 mmol, assumed to be quantitative) as colourless oil, which
was used without further purification for the following olefination
reaction.
◦
quenched carefully at 0 C with H2O followed by Rochelle’s salt
solution. The aqueous layer was extracted with EtOAc (4 ¥ 5 mL),
dried (MgSO4) and concentrated. The crude product was purified
by column chromatography on silica using n-pentane–Et2O 9 : 1
to yield alcohol 16b (71.0 mg, 95%) as colourless oil. Rf 0.38
(cyclohexane/EtOAc = 6 : 1). – [a]2D0 = +160.3 (0.72 g/100 mL,
CHCl3). – (NMR assignment according to numbering system of
1
plakotenin, see ESI†) H NMR (600 MHz, CDCl3): d = 0.91
To a solution of sodium hydride (60% in mineral oil, 66.0 mg,
1.66 mmol) in THF (10 mL) at 0 ◦C was added dropwise ethyl
2-(diethoxyphosphoryl)propanoate (350 mL, 1.61 mmol). The so-
lution was stirred at rt for 1 h before cooling to 0 ◦C and addition of
crude aldehyde (150 mg, 503 mmol, from previous reaction) in THF
(5 mL). The solution was warmed slowly to rt and after stirring
overnight the reaction was quenched by pouring on to saturated
aqueous NH4Cl (10 mL). The product was extracted with Et2O
and the combined extracts were dried (MgSO4) and concentrated.
The crude product was then purified by column chromatography
on silica using n-pentane–Et2O 40 : 1 to yield ester 18 (169 mg,
88%) as colourless oil. Rf 0.44 (cyclohexane/EtOAc = 18 : 1). –
(d, J = 6.6 Hz, 3 H, 14-H), 1.03 (t, J = 7.2 Hz, 3 H, 12-H), 1.19
(d, J = 5.4 Hz, 3 H, 13-H), 1.55 (t, J = 8.4 Hz, 1 H, 5-H), 1.55–1.60
(m, 1 H, 11-H), 1.61 (sext, J = 7.2 Hz, 1 H, 11-H), 1.61 (t, J =
10.8 Hz, 1 H, 3-H), 1.82–1.87 (m, 4 H, 7-H and 15-H), 1.88–1.92
(m, 1 H, 4-H), 1.96–2.02 (m, 1 H, 6-H), 3.23 (d, J = 8.4 Hz, 1 H,
1-H), 3.33 (d, J = 2.4 Hz, 1 H, 10-H), 3.39 (d, J = 11.4 Hz, 1 H,
1-H), 5.15 (s, 1 H, 9-H), 7.22–7.25 (m, 1 H, Harom.), 7.30–7.31 (m,
4 H, Harom.). – 13C NMR (125 MHz, CDCl3): d = 8.8 (p), 22.0 (p),
22.5 (p), 22.6 (p), 24.4 (s), 31.1 (t), 34.8 (t), 43.2 (q), 45.2 (s), 50.5
(t), 51.0 (t), 52.1 (t), 66.2 (s), 125.0 (t), 126.7 (t), 128.3 (t), 130.2 (t),
˜
136.9 (q), 142.5 (q), 175.7 (q). – IR (film): n = 3471, 3059, 3024,
2930, 2880, 1598, 1490, 1452, 1376, 1032, 702 cm-1. – MS (EI,
70 eV) m/z (%): 298 (26) [M+], 267 (51), 225 (25), 171 (100), 91
(15).
[a]2D0 = +17.3 (0.84 g/100 mL, CHCl3). – H NMR (400 MHz,
1
=
=
CDCl3): d = 0.92 (d, J = 6.4 Hz, 3 H, PhCH CHC CHCHCH3),
=
=
0.93 (d, J = 6.8 Hz, 3 H, EtCO2C CHC CHCHCH3), 0.99
=
(t, J = 7.6 Hz, 3 H, EtCO2C CHCCH2CH3), 1.13 (t, J =
7.2 Hz, 3 H, CO2CH2CH3), 1.30–1.34 (m, 2 H, CHCH2CH),
(2Z,4R,6R,7E,9E)-2-Ethyl-4,6,8-trimethyl-10-phenyldeca-2,7,9-
trien-1-ol (17)
=
1.80 (s, 3 H, EtCO2CCH3), 1.83 (s, 3 H, PhCH CHCCH3),
=
2.13 (q, J = 7.6 Hz, 2 H, EtCO2C CHCCH2CH3), 2.17–
=
=
To a solution of ester 14a (325 mg, 954 mmol) in THF (10 mL)
at 0 ◦C was slowly added lithium aluminium hydride (37.0 mg,
974 mmol). After stirring at◦0 ◦C for 2 h the reaction mixture
was quenched carefully at 0 C with H2O followed by Rochelle’s
salt solution. The aqueous layer was extracted with Et2O (4 ¥
10 mL). The combined organic extracts were dried (MgSO4) and
concentrated. The crude product was then purified by column
chromatography on silica using n-pentane–Et2O 9 : 1 to yield
alcohol 17 (175 mg, 61%). Rf 0.52 (cyclohexane/EtOAc = 6 : 1).
– [a]2D0 = –102.6 (0.61 g/100 mL, CHCl3). – 1H NMR (500 MHz,
2.23 (m, 1 H, EtCO2C CHC CHCH), 2.44–2.55 (m, 1 H,
PhCH CHC CHCH), 3.94–4.08 (m, 2 H, CO2CH2CH3), 5.12
=
=
=
=
(d, J = 10.0 Hz, 1 H, EtCO2C CHC CH), 5.35 (d, J = 9.6 Hz,
=
=
1 H, PhCH CHC CH), 6.41 (d, J = 16.0 Hz, 1 H, PhCH), 6.76
=
=
(d, J = 16.0 Hz, 1 H, PhCH CH), 7.05 (s, 1 H, EtCO2C CH),
7.15 (t, J = 7.2 Hz, 1 H, Harom.) 7.28 (d, J = 8.0 Hz, 2 H, Harom.),
7.39 (d, J = 7.2 Hz, 2 H, Harom.). – 13C NMR (100 MHz, CDCl3):
d = 12.7 (p), 13.4 (p), 14.3 (p), 14.4 (p), 21.1 (p), 21.5 (p), 30.0
(s), 30.9 (t), 31.9 (t), 45.9 (s), 60.7 (s), 125.6 (t), 126.2 (t), 126.9 (t),
128.5 (q), 128.6 (t), 132.6 (q), 134.3 (t), 134.9 (t), 136.3 (q), 138.2
This journal is
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Org. Biomol. Chem., 2010, 8, 3300–3306 | 3305
©

View Article Online
˜
(q), 139.1 (t), 141.0 (t), 168.4 (q). – IR (film): n = 3027, 2962, 2926,
Acknowledgements
2869, 1711, 1631, 1598, 1493, 1450, 1368, 1254, 1115, 1034, 959,
747, 692 cm-1. – MS (EI, 70 eV) m/z (%): 380 (4) [M+], 225 (4), 171
(4), 91 (3), 43 (100). – HRMS (C26H36O2): calc. 380.2715, found
380.2717.
This work has been supported by the KIT, the Landes-
graduiertenfo¨rderung (fellowship to Dr S. Arzt) and the Re´gion
Rhoˆne-Alpes (fellowship to Dr E. Bourcet). We thank Dr
A. Quereshi for copies of NMR spectra and Prof. Sir J. E. Baldwin
as well as Dr D. Keck for valuable advice.
Plakotenin ethyl ester (19)
A solution of linear ester 18 (85.0 mg, 223 mmol) in toluene (20 mL)
was heated to reflux and stirred in a sealed vial for 20 h. The
mixture was concentrated. The crude product was purified by
column chromatography on silica using n-pentane–Et2O 40 : 1 to
yield plakotenin ethyl ester 19 (77.0 mg, 91%) as colourless oil.
Rf 0.42 (cyclohexane/EtOAc = 18 : 1). – [a]2D0 = +203.8 (1.46 g/
100 mL, CHCl3). – (NMR assignment according to numbering
system of plakotenin, see ESI†) 1H NMR (400 MHz, CDCl3): d =
0.77 (t, J = 7.2 Hz, 3 H, 18-H), 0.98 (d, J = 6.0 Hz, 3 H, 15-H),
1.00–1.10 (m, 1 H, 17-H), 1.15 (d, J = 6.0 Hz, 3 H, 14-H), 1.32 (t,
J = 7.5 Hz, 3 H, 20-H), 1.54 (t, J = 8.2 Hz, 2 H, 7-H), 1.72–1.78
(m, 3 H, 5-H, 9-H and 17-H), 1.82 (s, 3 H, 16-H), 1.85–1.92 (m,
2 H, 6-H and 8-H), 2.05 (s, 3 H, 13-H), 3.69 (d, J = 4.0 Hz, 1 H,
12-H), 4.22 (q, J = 7.2 Hz, 2 H, 19-H), 5.23 (d, J = 4.0 Hz, 1 H,
11-H), 6.86 (s, 1 H, 3-H), 7.20–7.24 (m, 1 H, Harom.), 7.28–7.31 (m,
4 H, Harom.). – 13C NMR (100 MHz, CDCl3): d = 9.4 (p), 14.3 (p),
14.4 (p), 21.9 (p), 22.5 (p), 23.3 (p), 27.2 (s), 31.7 (t), 34.7 (t), 45.1
(s), 47.9 (q), 52.3 (t), 52.4 (t), 55.5 (t), 60.8 (s), 125.4 (t), 126.6
(t), 127.8 (t), 128.1 (q), 131.0 (t), 137.1 (q), 142.3 (q), 146.6 (t),
169.5 (q). – MS (EI, 70 eV) m/z (%): 380 (22) [M+], 225 (16), 171
(13), 91 (12), 43 (100). – HRMS (C26H36O2): calc. 380.2715, found
380.2714.
Notes and references
1 (a) K.-i. Takao, R. Munakata and K. Tadano, Chem. Rev., 2005, 105,
4779–4807; (b) M. Stocking and R. M. Williams, Angew. Chem., Int.
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Chem., 1998, 2, 365–394.
2 J. Kobayashi, S. Takeuchi, M. Ishibashi, H. Shigemori and T. Sasaki,
Tetrahedron Lett., 1992, 33, 2579–2580.
3 A. Qureshi, C. S. Stevenson, C. L. Albert, R. S. Jacobs and D. J.
Faulkner, J. Nat. Prod., 1999, 62, 1205–1207.
4 (a) X. Huang, R. van Soest, M. Roberge and RJ. Andersen, Org. Lett.,
2004, 6, 75–78; (b) F. Berrue, O. P. Thomas, R. Laville, S. Prado, J.
Golebiowski, R. Fernandez and P. Amade, Tetrahedron, 2007, 63, 2328–
2334.
5 (–)-Spiculoic acid: (a) J. E. D. Kirkham, V. Lee and J. E. Baldwin,
Chem. Commun., 2006, 2863–2865; (b) G. Mehta and U. K. Kundu,
Org. Lett., 2005, 7, 5569–5572; (c) J. E. D. Kirkham, V. Lee and J. E.
Baldwin, Org. Lett., 2006, 8, 5537–5540; (d) J. S. Crossman and M. V.
Perkins, Tetrahedron, 2008, 64, 4852–4867.
6 (+)-Spiculoic acid: D. Matsumura, T. Toda, T. Hayamizu, K. Sawa-
mura, K. Takao and K. Tadano, Tetrahedron Lett., 2009, 50, 3356–
3358.
7 For related work from our group see: (a) D. Keck, T. Muller and S.
Bra¨se, Synlett, 2006, 3457–3460; (b) D. Keck and S. Bra¨se, Org. Biomol.
Chem., 2006, 4, 3574–3575.
8 F. Rahm, P. Hayes and W. Kitching, Heterocycles, 2004, 64, 523–575.
9 Diels–Alder examples: (a) N. A. Yakelis and W. R. Roush, Org. Lett.,
2001, 3, 957–960; (b) R. Munakata, H. Katakai, T. Ueki, J. Kurosaka,
T. Takao and K. Tadano, J. Am. Chem. Soc., 2004, 126, 11254–
11267.
Plakotenin (1)
10 (a) D. J. Gochfeld and M. T. Hamann, J. Nat. Prod., 2001, 64, 1477–
1479; (b) J. P. John, J. Jost and A. V. Novikov, J. Org. Chem., 2009,
74, 6083–6091; (c) F. Berrue, O. P. Thomas, C. Funel-Le Bon, F. Reyes
and P. Amade, Tetrahedron, 2005, 61, 11843–11849; (d) G. R. Pettit,
T. Nogawa, J. C. Knight, D. L. Doubek and J. N. A. Hooper, J. Nat.
Prod., 2004, 67, 1611–1613; (e) M. Akiyama, Y. Isoda, M. Nishimoto,
M. Narazaki, H. Oka, A. Kuboki and S. Ohira, Tetrahedron Lett., 2006,
47, 2287–2290; (f) H. D. Higgs and D. J. Faulkner, J. Org. Chem., 1978,
43, 3454–3457; (g) E. Manzo, M. L. Ciavatta, D. Melck, P. Schupp, N.
de Voogd and M. Gavagnin, J. Nat. Prod., 2009, 72, 1547–1551.
11 For early approaches: F Ishizaki, Y Hara, S. Kojima and O. Hoshino,
Heterocycles, 1999, 50, 779–790.
12 A. G. Myers, B. H. Yang, H. Chen and J. L. Gleason, J. Am. Chem.
Soc., 1994, 116, 9361–9362.
13 All new compounds were fully characterised. See ESI†.
14 K. Tsunashima, M. Ide, H. Kadoi, A. Hirayama and M. Nakata,
Tetrahedron Lett., 2001, 42, 3607–3611.
15 M. J. Gaunt, A. S. Jessiman, P. Orsini, H. R. Tanner, D. F. Hook and
S. V. Ley, Org. Lett., 2003, 5, 4819–4822.
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17 J. A. Marshall, B. G. Shearer and S. L. Crooks, J. Org. Chem., 1987,
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18 R. Desmond, S. G. Mills, R. P. Volante and I. Shinkai, Tetrahedron
Lett., 1988, 29, 3895–3898.
To a solution of plakotenin ethyl ester 19 (25.0 mg, 66.0 mmol)
in THF–MeOH (1.6/0.8 mL) was added NaOH (2 M) (160 mL,
328 mmol) and the resulting mixture was heated to 40 ◦C and
stirred for 20 h. After cooling to rt, the mixture was acidified
with aqueous HCl (1 M) and then extracted with EtOAc. The
combined organic extracts were backwashed with brine, dried
(MgSO4) and concentrated. The crude product was purified by
column chromatography on silica using n-pentane–Et2O 2 : 1 to
yield plakotenin 1 (20.0 mg, 86%) as colourless oil. Rf 0.40
(cyclohexane/EtOAc = 2 : 1). – [a]2D0 = +212 (0.24 g/100 mL,
CHCl3). – (NMR assignment according to numbering system
1
shown in ESI†) H NMR (500 MHz, CDCl3): d = 0.78 (t, J =
7.0 Hz, 3 H, 18-H), 0.98 (d, J = 6.5 Hz, 3 H, 15-H), 1.03–1.12 (m,
1 H, 17-H), 1.16 (d, J = 6.5 Hz, 3 H, 14-H), 1.56 (t, J = 8.5 Hz,
3 H, 7-H), 1.73–1.80 (m, 3 H, 5-H, 9-H and 17-H), 1.83 (s, 3 H,
16-H), 1.86–1.95 (m, 2 H, 6-H and 8-H), 2.07 (s, 3 H, 13-H), 3.71
(d, J = 4.0 Hz, 1 H, 12-H), 5.23 (s, 1 H, 11-H), 7.03 (s, 1 H, 3-H),
7.21–7.25 (m, 1 H, Harom.), 7.29–7.30 (m, 4 H, Harom.). – 13C NMR
(125 MHz, CDCl3): d = 9.4 (p), 14.0 (p), 21.9 (p), 22.5 (p), 23.3 (p),
27.1 (s), 31.7 (t), 34.7 (t), 45.1 (s), 48.2 (q), 52.2 (t), 52.5 (t), 55.4
(t), 125.3 (t), 126.6 (t), 127.3 (q), 127.9 (t), 131.0 (t), 137.2 (q),
19 P. J. Kocienski, A. Bell and P. R. Blakemore, Synlett, 2000, 365–366.
20 (a) K. Ando, J. Org. Chem., 1997, 62, 1934–1939; (b) K. Ando, J. Org.
Chem., 1998, 63, 8411–8416; (c) K. Ando, J. Org. Chem., 1999, 64,
8406–8408; (d) K. Ando, T. Oishi, M. Himara, H. Ohno and T. Ibuka,
J. Org. Chem., 2000, 65, 4745–4749; (e) For preparation and use of
phosphonate F, see also: L. C. Dias and P. R. R. Meira, J. Org. Chem.,
2005, 70, 4762–4773.
˜
142.1 (q), 149.7 (t), 174.8 (q). – IR (film): n = 2929, 2868, 1683,
1629, 1492, 1451, 1419, 1377, 1281, 877, 762, 745, 703 cm-1. – MS
(EI, 70 eV) m/z (%): 352 (100) [M+], 261 (48), 225 (84), 171 (70).
– HRMS (C24H32O2): calc. 352.2402, found 352.2401.
3306 | Org. Biomol. Chem., 2010, 8, 3300–3306
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