Toward the total synthesis of klaivanolide: Complete reinterpretation of its originally assigned structure

Article abstract of DOI:10.1002/ejoc.201402741

Klaivanolide is an antiparasitic natural product isolated from Uvaria klaineana, whose structure was originally assigned as a seven-membered lactone ring. Attempts towards the total synthesis of klaivanolide led us to revise its original structural assignment based on both experimental evidence and spectroscopic data. The isolated compound was revealed to be a known molecule, acetylmelodorinol, originally isolated from Melodorum fruticosum. Vibrational circular dichroism simulation of the reassigned structure was also performed to reinvestigate our previous studies on the determination of the absolute configuration of klaivanolide.

Full text of DOI:10.1002/ejoc.201402741

FULL PAPER
DOI: 10.1002/ejoc.201402741
Toward the Total Synthesis of Klaivanolide: Complete Reinterpretation of Its
Originally Assigned Structure
Laurent Ferrié,*[a] Sabrina Ferhi,[a] Guillaume Bernadat,[a] and Bruno Figadère*[a]
Keywords: Lactones / Vibrational spectroscopy / Density functional calculations / Total synthesis / Structure elucidation
Klaivanolide is an antiparasitic natural product isolated from
Uvaria klaineana, whose structure was originally assigned as
a seven-membered lactone ring. Attempts towards the total
synthesis of klaivanolide led us to revise its original structural
assignment based on both experimental evidence and spec-
troscopic data. The isolated compound was revealed to be a
known molecule, acetylmelodorinol, originally isolated from
Melodorum fruticosum. Vibrational circular dichroism simu-
lation of the reassigned structure was also performed to rein-
vestigate our previous studies on the determination of the
absolute configuration of klaivanolide.
duced by a selective allylic oxidation of unsaturated lactone
2. The enantioenriched lactone (S)-2 could be prepared
through two different strategies. The first approach involves
a ruthenium-catalyzed ring-closing metathesis (RCM) reac-
tion of diene 3 (Pathway A). The second strategy involves
benzoylation of lactone 4 followed by introduction of the
unsaturation (Pathway B). Lactone 4 could be prepared
through Baeyer–Villiger oxidation and organocatalytic
formylation of cyclohexanone as the key steps.
Introduction
Uvaria klaineana, a Gabonese Annonaceae, is a source
of promising antiparasitic natural products, and stem ex-
tracts of this plant have shown in vitro activities against
acari,[1] Leishmania donovani promastigote forms, and
Trypanosoma brucei brucei trypomastigote forms. Bio-
guided MeOH/CH2Cl2 extraction of a sample of Uvaria
klaineana afforded a crystalline compound that was charac-
terized as a new seven-membered lactone and named klaiv-
anolide.[2] Determination of the absolute configuration of
klaivanolide was accomplished by vibrational circular di-
chroism (VCD) spectroscopy, by analysis of experimental
data and density functional theory calculated spectra.[3]
Klaivanolide was also isolated from another Annonaceae,
Mitrella mesnyi,[4] based on the spectroscopic data disclosed
in the original report.[2]
Because of the promising antileishmanial activity of the
isolated product klaivanolide, we initiated a scientific pro-
gram with the aim to provide synthetic samples of this mo-
lecule and structurally related analogues. Herein we present
our synthetic efforts toward the preparation of klaivanolide,
which led us to re-assign its structure.
Results and Discussion
To synthesize klaivanolide, we anticipated that the enol
acetate moiety in the natural product could derive from
ketone 1 (Scheme 1). The carbonyl group could be intro-
Scheme 1. Retrosynthetic analysis of klaivanolide through Path-
ways A or B.
Racemic trityl glycidyl ether 5 was used as starting mate-
rial to test pathway A. Epoxide 5 was opened by allyl-
magnesium bromide at –30 °C in the presence of CuI to
afford dihomoallyl alcohol 6 in 76% yield. Subsequent
acryloylation of the hydroxy group gave diene 3 in 80%
yield. The key step of this route was a formation of the
seven-membered ring by RCM. Nevertheless, previous
[a] Faculté de Pharmacie, UMR CNRS 8076, LERMIT, Université
Paris-Sud,
5 rue J-B Clément, 92296 Châtenay-Malabry, France
E-mail: laurent.ferrie@u-psud.fr
bruno.figadere@u-psud.fr
http://www.biocis.u-psud.fr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402741.
Eur. J. Org. Chem. 2014, 6183–6189
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L. Ferrié, S. Ferhi, G. Bernadat, B. Figadère
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works reported that this transformation is generally diffi-
Pathway B began with an organocatalyzed aldol reaction
cult,[5] and we observed that dilution is crucial to prevent between cyclohexanone and formaldehyde in the presence
the formation of polymeric materials. By applying these of threonine in tetrahydrofuran (THF).[7] After 4 d of stir-
conditions (5ϫ10–4 m) in the presence of 15 mol-% of 2nd- ring at room temperature, α-(hydroxymethyl)cyclohexanone
generation Grubbs catalyst, racemic lactone 7 was obtained (8) was isolated in 57% yield and 90% ee.[8] The next step
in moderate yield (55%). The synthesis of racemic com- was the Baeyer–Villiger oxidation of chiral cyclohexanone 8
pound 2 was then performed in two more steps after hydrol- with meta-chloroperoxybenzoic acid (m-CPBA), which gave
ysis of the trityl group[6] and benzoylation (Scheme 2, Path- regioselectively and stereospecifically[9] the expected seven-
way A). However, by working on a gram-scale synthesis, the membered lactone 4 in 85% yield. Subsequent benzoylation
RCM reaction is almost impractical owing to the high cata- of 4 afforded compound 9 in nearly quantitative yield. The
lyst loading, modest yield and high dilution. We turned unsaturation of the lactone was introduced by a selenoxyeli-
then our attention to a second strategy to prepare com- mination in two steps.[10]
pound 2 more conveniently (Scheme 3, Pathway B).
First, the lithium enolate of 9 was trapped with phenyl-
selenium bromide to yield selenide 10 (95%). Then, oxi-
dation of 10 with hydrogen peroxide in the presence of am-
monium dimolybdate produced the corresponding interme-
diate selenoxide that underwent spontaneous elimination to
afford unsaturated lactone (S)-2 with 75% yield. Pathway B
has the advantage of providing efficiently the desired inter-
mediate (S)-2 from cheap reagents (Scheme 3).
The next critical reaction was the introduction of the
carbonyl group in the allylic position. Among all the direct
or indirect methods that we tested to perform this transfor-
mation, only the use of chromic anhydride in combination
with acetic anhydride/acetic acid in benzene allowed us to
isolate ketone 1, albeit with a moderate 65% yield.[11] At
this point, we expected the synthesis to be almost finished
by considering the last step as a simple functional-group
transformation. Unfortunately, it was not the case, and
whatever the reaction conditions used [propenyl acetate/
p-toluenesulfonic acid (PTSA), lithium diisopropylamide
(LDA)/AcCl], we were not able to obtain or to observe any
trace of the supposed structure of klaivanolide (Scheme 4).
Indeed, compound 1 is unstable to weakly basic conditions,
such as neutral alumina or triethylamine, and moderately
stable to silica gel chromatography or aqueous treatment,
because the compound has a high tendency to undergo eli-
mination at the β-position of the ketone, driven by the
strain in the seven-membered ring to yield compound 11.
Scheme 2. Pathway A based on an RCM reaction for the synthesis
of klaivanolide.
Scheme 4. Endgame and attempts to obtain synthetic klaivanolide.
PTSA = p-toluenesulfonic acid.
As a result of the observation of the instability of (S)-1
towards various conditions, we questioned that klaivanolide
could be isolated by usual extractive techniques on a several
hundred milligram scale. We were brought to reinvestigate
Scheme 3. Pathway B based on an organocatalytic aldol reaction
and a Baeyer–Villiger oxidation.
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Toward the Synthesis of Klaivanolide and Structure Reinterpretation
the structure reported for klaivanolide, as we understood
that such an unstable molecule could hardly be isolated by
1
usual means. A careful look at the H NMR spectroscopic
data of isolated klavanolide showed that the value of the
coupling constant of the ethylene protons in positions 3 and
4 is smaller than expected (J3,4 = 5.5 Hz)[2] relative to a
classical value of J = 10–11 Hz for a (Z) double bond in an
acyclic system. In contrast, compound 1 shows a slightly
larger coupling constant (J3,4 = 12.1 Hz). These differences
could be a result of the size of the ring, which distorts the
ethylene moiety and changes the corresponding dihedral
angle. Figure 1 shows the value of reported coupling con-
stants for vicinal ethylene protons of α,β-unsaturated lact-
ones or cyclic ketones as a function of the ring size and
emphasizes that the ring strain has a strong influence on
this variable, because cyclobutenone,[12] butenolide,[13] pent-
enolide,[14] hexenolide,[15] and heptenolide[16] exhibit vicinal
coupling constants for ethylene protons of 2.3, 5.8, 9.5, 12.4
and 13.0 Hz, respectively. By comparing vicinal coupling
constants of ethylene protons of compound 1 and isolated
klaivanolide, 12.1 and 5.5 Hz, respectively, we could postu-
late that isolated klaivanolide contains a butenolide rather
than a hexenolide.
Figure 2. Structure of the originally assigned klaivanolide and re-
vised structure 12 known as acetylmelodorinol.
viously recorded experimental spectrum.[20] A preliminary
conformation sampling on a model of compound 12 was
performed by random (Monte-Carlo) torsional search and
subsequent minimization with the OPLS[21] molecular me-
chanics force field. Lowest-energy conformations found
were then subjected to geometry optimization at the
B3LYP/6-31G* level and yielded 27 unique structures. The
six first geometries ranked by ascending energy covered
more than 90% of conformational population within the
conformational space explored, over a 1.29 kcal/mol energy
range (Figure 3). These were retained for VCD calculation
at the same level. Overlay of the weighted average theoreti-
cal spectrum with previously reported experimental data[3]
is plotted in Figure 4. In particular, the spectroscopic signa-
ture in the 1290–1180 cm–1 band is in good accordance with
experimental data, and confirms with a high level of confi-
dence that the absolute configuration for acetylmelodorinol
(12) isolated from Uvaria klaineana at C7 is (S).
Figure 1. Influence of the ring size on the reported coupling con-
stant of vicinal ethylene protons of α,β-unsaturated cycloesters/
ketones.
Reassignment of the structure of klaivanolide led us to
propose structure 12, which is already known in the litera-
ture as acetylmelodorinol, originally isolated from Melodo-
rum fruticosum[17] and later from other Annonaceae such as
Mitrella kentii[18] and Artabotrys madagascaiensis.[19] Analy-
sis of the NMR spectroscopic data between isolated “klaiv-
anolide” and acetylmelodorinol showed that they are iden-
tical. Therefore, we conclude that the isolated compound
from Uvraria klaineana is not klaivanolide as reported but
acetylmelodorinol. (Figure 2).
As a corollary, our previous work on the determination
of the absolute configuration by VCD spectroscopy of klai-
vanolide[3] must be discussed, because the structure was
completely revised. We followed the same approach, and a
new spectrum was predicted in the density functional
Figure 3. Lowest-energy conformations found for compound 12 at
the B3LYP/6-31G* level, sorted by ascending energy (calculated
theory (DFT) framework and analyzed relative to the pre- populations: a: 42%, b: 14%, c: 12%, d: 11%, e: 6%, f: 5%).
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L. Ferrié, S. Ferhi, G. Bernadat, B. Figadère
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acid/acetic acid in EtOH, KMnO4/K2CO3 in H2O or ammonium
molybdate/sulfuric acid in water followed by heating. Flash
chromatography was performed with silica gel (230–400 mesh). All
the reactions were carried out under N2 unless specified otherwise.
Acrylate 3: To a solution of compound 6 (3.17 g, 8.88 mmol,
1 equiv.) and triethylamine (17.7 mmol, 2 equiv.) in Et2O (30 mL)
at –20 °C was added dropwise acryloyl chloride (0.9 mL,
11.5 mmol, 1.3 equiv.). After stirring for 1 h, the reaction was
quenched by addition of a saturated NaHCO3 aqueous solution.
The organic layer was extracted with Et2O and washed with satu-
rated NH4Cl aqueous solution and brine. The organic solution was
then dried with MgSO4, filtered and concentrated under reduced
pressure to afford the crude product, which was purified by flash
chromatography on silica gel (Et2O/petroleum ether, 96:4) to afford
compound 3 (1.43 g, 39%). IR (ATR): ν = 3056, 1724, 1492, 1449,
˜
1405, 1196, 1078, 765, 747, 707, 633 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 7.43 (m, 6 H), 7.33–7.18 (m, 9 H), 6.46 (dd, J =
17.1, 1.8 Hz, 1 H), 6.19 (dd, J = 17.1, 10.4 Hz, 1 H), 5.87 (d, J =
10.4, 1.8 Hz, 1 H), 5.75 (ddt, J = 16.7, 10.4, 6.5 Hz, 1 H), 5.17
(dtd, J = 7.6, 5.7, 4.0 Hz, 1 H), 4.94 (dq, J = 16.7, 1.5 Hz, 1 H),
4.93 (dq, J = 10.4, 1.5 Hz, 1 H), 3.20 (dd, J = 9.9, 4.0 Hz, 1 H),
3.14 (dd, J = 9.9, 5.7 Hz, 1 H), 2.01 (m, 2 H), 1.85–1.70 (m, 2 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 165.7, 143.9, 137.6, 130.6,
128.7, 127.8, 127.0, 115.1, 86.4, 72.9, 64.7, 30.1, 29.4 ppm. HRMS
(ESI): calcd. for C28H28O3Na [M + Na]+ 435.1936; found 435.1927.
Figure 4. Overlay of an experimental VCD spectrum for acetyl-
melodorinol (12) isolated from Uvaria klaineana (in green) with the
corresponding (downshifted by 25 cm–1) conformationally
weighted spectrum calculated at the B3LYP/6-31G* level (in red).
Conclusions
We discovered that the originally assigned structure of
klaivanolide was wrong. The difficulties experienced in the
synthesis of this uncommon “natural” seven member-ring
product led us to reconsider its structure as a butyrolactone,
confirmed by NMR spectroscopy.
We also tried to revise the absolute configuration of
“klaivanolide” by VCD spectroscopy, now revised as known
acetylmelodorinol (12). This work concludes that the theo-
retical VCD spectrum of klaivanolide reported in our pre-
vious communication[3] is very similar to that obtained here
for acetylmelodorinol (12). This observation can be ration-
alized by the fact that the VCD phenomenon ensues from
infrared absorption properties of functional groups (unsat-
uration, ester groups) that are identical in both compounds,
and is strongly correlated to their relative arrangement
around the stereogenic center C7, which remains (S) in both
structures.
Racemic Lactone 7: To a solution of compound 3 (621 mg,
1.5 mmol, 1 equiv.) in technical-grade CH2Cl2 (3 L), was added
2nd-generation Grubbs catalyst (192.4 mg, 0.226 mmol, 15 mol-%).
After the solution had been heated to reflux for 24 h, the solvent
was removed by distillation, and the residue was purified by silica
gel chromatography (ethyl acetate/petroleum ether 20:80) to afford
compound 7 (312.6 mg, 54%). IR (ATR): ν = 3020, 1696, 1489,
˜
1
1448, 1397, 1281, 1190, 1091, 1053, 1018, 750, 698 cm–1. H NMR
(CDCl3, 300 MHz): δ = 7.46 (m, 6 H), 7.40–7.20 (m, 9 H, Ar), 6.41
(dt, J = 12.3, 4.6 Hz, 1 H), 6.00 (dt, J = 12.3, 1.9 Hz, 1 H), 4.28
(dddd, J = 8.6, 6.1, 5.6, 1.4 Hz, 1 H), 3.46 (dd, J = 9.7, 5.6 Hz, 1
H), 3.22 (dd, J = 9.7, 6.1 Hz, 1 H), 2.60–2.30 (m, 2 H), 2.20 (br.
dt, J = 15.4, 5.3 Hz, 1 H), 1.99 (dtd, J = 15.4, 8.8, 6.6 Hz, 1 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 168.0, 143.7, 143.6, 128.6,
127.8, 127.1, 122.2, 86.8, 65.0, 29.4, 29.0 ppm. HRMS (ESI): calcd.
for C26H24O3Na [M + Na]+ 407.1623; found 407.1621.
Benzoylated Lactone 2 from Compound 7: A solution of compound
7 (266 mg, 0.693 mmol) in a mixture of formic acid/Et2O (1:1;
2 mL, 2 mL) was stirred at room temperature for approximately
3 h, until no starting materiel was left as monitored by TLC. The
reaction mixture was then poured carefully into a saturated aque-
ous solution of NaHCO3, and extracted with 1-butanol (3ϫ). The
organic layer was dried with MgSO4, filtered, concentrated under
vacuum, and the residue purified by flash chromatography on silica
gel (CH2Cl2/methanol, 99:1) to afford the intermediate unsaturated
Experimental Section
General Experimental Procedure: Infrared (IR) spectra were re-
corded with an FTIR apparatus. H NMR spectra were recorded
1
at 300 MHz in CDCl3, and data are reported as follows: chemical
shift relative to tetramethylsilane (TMS) with the solvent as an in-
ternal standard (CHCl3: δ = 7.26 ppm), multiplicity (br. = broad,
s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet,
m = multiplet or overlap of non-equivalent resonances), and inte-
(hydroxymethyl)caprolactone (53.7 mg, 55%). IR (ATR): ν = 3500
˜
(br.), 1698, 1452, 1050 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 6.44
gration. 13C NMR spectra were recorded at 75 MHz in CDCl3, and (dt, J = 12.3, 4.6 Hz, 1 H), 5.99 (dt, J = 12.3, 1.8 Hz, 1 H), 4.39
data are reported as follows: chemical shift relative to TMS with
the solvent as an internal standard (CDCl3: δ = 77.0 ppm). HRMS
data were recorded by electrospray ionization (ESI). CH2Cl2, Et2O,
and toluene were dried by filtration through activated molecular
sieves. THF was distilled from sodium/benzophenone ketyl radical.
Other reagents or solvents were obtained from commercial suppli-
ers and used as received. Analytical thin layer chromatography
(TLC) was performed on silica gel plates visualized either with a
UV lamp (254 nm), or by using solutions of p-anisaldehyde/sulfuric
(tt, J = 6.8, 3.5 Hz, 1 H), 3.76 (dd, J = 12.1, 6.8 Hz, 2 H), 3.69
(dd, J = 12.1, 3.7 Hz, 1 H), 2.60–2.34 (m, 2 H), 2.55 (br. s, 1 H,
OH), 2.00 (m, 2 H) ppm. HRMS (ESI): calcd. for C7H10O3Na [M
+ Na]+ 165.0528; found 165.0521. To a solution of the unsaturated
(hydroxymethyl)caprolactone (53 mg, 0.373 mmol, 1 equiv.) in pyr-
idine (3 mL) at 0 °C was added benzoyl chloride (65 μL,
0.56 mmol, 1.5 equiv.). The reaction mixture was quenched by ad-
dition of a saturated aqueous solution of NaHCO3, the organic
layer was extracted with ethyl acetate, washed twice with a satu-
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Toward the Synthesis of Klaivanolide and Structure Reinterpretation
1
rated copper sulfate aqueous solution and brine. The organic solu-
tion was dried with MgSO4, filtered, concentrated under vacuum,
and the residue was purified by flash chromatography on silica gel
(EtOAc/petroleum ether, 30:70) to afford racemic compound 2
(59.0 mg, 64%).
3400 (br.), 1716, 1185, 1105 cm–1. H NMR (CDCl3, 300 MHz): δ
= 4.30 (m, 1 H), 2.80 (br. s, 1 H, OH), 3.66 (dd, J = 11.9, 7.4 Hz,
1 H), 3.58 (dd, J = 11.9, 4.5 Hz, 1 H), 2.59 (m, 2 H), 1.79–1.98 (m,
3 H), 1.40–1.60 (m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
175.6, 80.8, 64.8, 34.6, 30.3, 27.6, 22.7 ppm. HRMS (ESI): calcd.
for C7H12O3Na [M + Na]+ 167.0679; found 167.0676.
Benzoylated Lactone 2 from Compound 10: To a solution of com-
pound 10 (8.0 g, 19.8 mmol, 1 equiv.) and ammonium dimolybdate
(50 mg) in EtOH (30 mL) was added dropwise at 0 °C hydrogen
peroxide (3.38 mL, 29.7 mmol, 1.5 equiv., 30% in water). After
90 min, the reaction mixture was diluted with water, and the or-
ganic layer was extracted with Et2O, then washed with a sodium
thiosulfate aqueous solution, dried with MgSO4, filtered through a
pad of silica gel and concentrated under vacuum to afford hexenol-
ide (S)-2 (3.65 g, 75%). [α]2D0 = +31.1 (c = 2.70, CHCl3). IR (ATR):
Benzoate 9: To a solution of compound 4 (680 mg, 4.72 mmol,
1 equiv.) in CH2Cl2 (10 mL) at 0 °C was added pyridine (1.12 mL,
14.16 mmol, 3 equiv.) followed by benzoyl chloride (995 μL,
7.08 mmol, 1.5 equiv.). After stirring at room temp. for 1 h, the
reaction mixture was diluted with ethyl acetate, quenched and
washed with a saturated aqueous NaHCO3 solution, washed twice
with a saturated copper sulfate aqueous solution and brine. The
organic solution was dried with MgSO4, filtered, concentrated un-
der vacuum and the residue purified by flash chromatography on
silica gel (EtOAc/petroleum ether, 70:30) to afford benzoate 9
ν = 1718, 1452, 1271, 1128, 1026, 710 cm–1. 1H NMR (CDCl3,
˜
300 MHz): δ = 8.05 (dd, J = 7.8, 1.3 Hz, 2 H), 7.57 (dt, J = 7.8,
1.3 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 2 H), 6.44 (dt, J = 12.1, 4.6 Hz,
1 H), 6.02 (dt, J = 12.1, 2.0 Hz, 1 H), 4.65 (m, 1 H), 4.52 (dd, J =
11.8, 6.0 Hz, 1 H), 4.47 (dt, J = 11.8, 4.7 Hz, 1 H), 2.70–2.40 (m,
2 H), 2.25–2.00 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 167.4, 166.2, 143.5, 133.3, 129.7, 129.5, 128.4, 75.7, 65.7, 29.0,
28.6 ppm. HRMS (ESI): calcd. for C14H14O4Na [M + Na]+
269.0790; found 269.0788.
(1.14 g, 97%). [α]2D0 = +29.0 (c = 3.24, CHCl ). IR (ATR): ν = 1716,
˜
3
1272, 1096, 711 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.05 (dd,
1
J = 7.8, 1.3 Hz, 2 H), 7.57 (dt, J = 7.8, 1.3 Hz, 1 H), 7.44 (t, J =
7.8 Hz, 2 H), 4.65 (dt, J = 8.3, 5.7 Hz, 1 H), 4.45 (dd, J = 11.6,
6.3 Hz, 1 H), 4.39 (dt, J = 11.6, 5.0 Hz, 1 H), 2.73 (br. dd, J =
14.2, 7.0 Hz, 1 H), 2.62 (ddd, J = 14.2, 12.0, 2.5 Hz, 1 H), 2.15–1.85
(m, 3 H), 1.85–1.45 (m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 174.4, 166.2, 133.2, 129.7, 129.6, 128.4, 77.5, 66.4, 34.8, 31.1,
27.9, 22.9 ppm. HRMS (ESI): calcd. for C14H16O4Na [M + Na]+
271.0941; found 271.0940.
(S)-Hydroxymethylcyclohexanone 8: To a solution of l-threonine
(1.2 g, 10 mmol, 0.1 equiv.) in formaldehyde (8.7 mL, 100 mmol,
1 equiv., 35% wt. in H2O) was added THF (100 mL) followed by
cyclohexanone (20 mL, 200 mmol, 2 equiv.) and MgSO4 (12 g,
100 mmol, 1 equiv.). After 4 d of stirring at room temperature, the
reaction mixture was filtered, and the solids were washed with ethyl
acetate. Saturated aqueous NH4Cl solution (50 mL) was added to
the filtrate, and the solution was stirred for another 10 min. The
organic phase was separated, and the aqueous phase was extracted
twice with ethyl acetate. The combined organic phases were washed
with brine (50 mL) and dried with MgSO4. After filtration, the
solvents were evaporated under reduced pressure, and the crude
product was purified by flash chromatography with silica gel
(EtOAc/petroleum ether, 40:60 to 80:20) to afford compound 8
(7.33 g, 57%, 90% ee). The enantiomeric excess of product 8 was
determined by chiral HPLC analysis of the benzoate derivative[22]
(from reaction with benzoyl chloride in pyridine). HPLC (Daicel
Chiralcel AD 4.6ϫ250 mm; hexanes/iPrOH, 90:10 isocratic; flow
rate = 1.0 mL/min; λ = 225 nm): tr = 13.6 [major, (S)], 16.9 [minor,
Phenylselenide 10: To a solution of compound 9 (298 mg, 1.2 mmol,
1 equiv.) in THF (3 mL) was added dropwise lithium bis(trimethyl-
silyl)amide (1.44 mL, 1.44 mmol, 1.2 equiv., 1 m in THF) at –78 °C.
After 30 min of stirring at this temperature, phenylselenyl bromide
(1.44 mmol, 1.2 equiv.) was added [prepared from diphenyl diselen-
ide (224 mg, 0.72 mmol, 0.6 equiv.) and bromine (37 μL,
0.72 mmol, 0.6 equiv.) in THF (1 mL)]. The reaction was quenched
by the addition of an aqueous HCl solution (1 m, 5 mL), and the
organic layer was extracted with ethyl acetate (3ϫ). The combined
organic layers were washed with a saturated NaHCO3 solution,
brine, then dried with MgSO4, filtered and concentrated under vac-
uum. The crude product was purified by flash chromatography
with silica gel (EtOAc/petroleum ether, 20:80) to afford compound
10 (293 mg, 95%) as a 80:20 mixture of diastereoisomers. [α]2D0
=
+61.4 (c = 2.95, CHCl ). IR (ATR): ν = 1716, 1272, 1096,
˜
3
711 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.1 (m, 2 H), 7.60 (m,
1
(R)] min. [α]2D0 = +10.1 (c = 2.98, CHCl ). IR (ATR): ν = 3400
˜
3
3 H), 7.48 (m, 2 H), 7.28 (m, 3 H), 5.39 (dt, J = 9.9, 4.7 Hz, 0.8
H), 4.70 (dt, J = 9.6, 5.1 Hz, 0.2 H), 4.53–4.40 (m, 2 H), 4.30 (dt,
J = 4.4, 1.4 Hz, 1 H), 2.18 (m, 2 H), 2.09 (m, 1 H), 1.94 (m, 2 H),
1.75 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 171.5, 166.2,
134.6, 133.2, 129.7, 129.6, 129.4, 128.7, 128.4, 127.7, 77.1, 66.6,
46.6, 31.3 (1JSe-C = 115.5 Hz), 28.7, 24.4 ppm. HRMS (ESI): calcd.
for C20H20O4NaSe [M + Na]+ 427.0424; found 427.0419.
(br.), 1702, 1044 cm–1. H NMR (CDCl3, 300 MHz): δ = 3.77 (dd,
1
J = 11.9, 7.5 Hz, 1 H), 3.59 (dd, J = 11.9, 4.1 Hz, 1 H), 2.75 (br.
s, 1 H, OH), 2.56–2.43 (m, 1 H), 2.43–2.20 (m, 1 H), 2.15–1.97 (m,
2 H), 1.93–1.85 (m, 2 H), 1.76–1.55 (m, 2 H), 1.49–1.36 (m, 1 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 214.8, 62.4, 52.1, 42.0, 29.9,
27.3, 24.5 ppm. HRMS (ESI): calcd. for C7H12O2Na [M + Na]+
151.0730; found 151.0728.
Caprolactone 4: To a solution of compound 8 (1.0 g, 7.8 mmol,
4-Oxohexenolide (S)-1: To a solution of Ac2O (2.5 mL) and AcOH
1 equiv.) in CH2Cl2 (40 mL) at 0 °C were added solid NaHCO3
(5 mL) at 0 °C was added CrO3 (812 mg, 8.12 mmol, 4 equiv.) fol-
(0.98 g, 11.7 mmol, 1.5 equiv.) and m-CPBA (1.6 g, 9.37 mmol, lowed by benzene (5 mL). After 15 min, a solution of hexenolide 2
1.2 equiv., 70–75% purity). The reaction mixture was then allowed
to reach room temperature and was vigorously stirred for 3 h, then
diluted with dichloromethane (20 mL), and quenched by addition
of a saturated aqueous sodium thiosulfate solution. The organic
layer was extracted with EtOAc (3ϫ), and the combined organic
phases were dried with MgSO4. After filtration and evaporation
of the solvents, purification on silica gel by flash chromatography
(EtOAc/petroleum ether, 50:50 to 80:20) afforded compound 4
(500 mg, 2.03 mmol, 1 equiv.) in benzene (2 mL) was added drop-
wise. After 1 h at this temperature, the reaction mixture was poured
carefully into a saturated aqueous solution of NaHCO3, and the
organic layer was extracted with EtOAc (3ϫ). The combined or-
ganic extracts were washed with a sodium metabisulfite solution,
then dried with MgSO4, filtered and concentrated under vacuum.
The residue was purified by silica gel chromatography (short col-
umn) with pure EtOAc to afford 4-oxohexenolide 1 (350 mg, 65%).
(960 mg, 85%). [α]2D0 = +34.0 (c = 3.95, CHCl ). IR (ATR): ν =
[α]2D0 = +11.3 (c = 3.56, CHCl ). IR (ATR): ν = 1718, 1269, 1114,
˜
3
˜
3
Eur. J. Org. Chem. 2014, 6183–6189
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6187

L. Ferrié, S. Ferhi, G. Bernadat, B. Figadère
FULL PAPER
1069, 710 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.05 (m, 1 H),
1
[7] A. Chen, J. Xu, W. Chiang, C. L. L. Chai, Tetrahedron 2010,
66, 1489–1495.
[8] The measured enantiomeric excess of 8 was consistent with that
reported by Chen et al.; see ref.[7] The enantiomeric excess was
measured on the benzoyl derivative.
[9] M. Renz, B. Meunier, Eur. J. Org. Chem. 1999, 737–750.
[10] K. Lal, R. G. Salomon, J. Org. Chem. 1989, 54, 2628–2632.
[11] a) M. Nakayama, S. Shinke, Y. Matsushita, S. Ohira, S. Haya-
shi, Bull. Chem. Soc. Jpn. 1979, 52, 184–185; b) F. Busqué, P.
Cid, P. de March, M. Figueredo, J. Font, Heterocycles 1995,
40, 387–399.
7.60 (tt, J = 7.3, 1.4 Hz, 1 H), 7.46 (m, 2 H), 6.65 (d, J = 12.5 Hz,
1 H), 6.50 (ddd, J = 12.5, 1.4, 0.5 Hz, 1 H), 5.15 (dddd, J = 10.6,
6.0, 4.7, 1.4 Hz, 1 H), 4.60 (dd, J = 12.0, 6.0 Hz, 1 H), 4.53 (dd, J
= 12.0, 4.7 Hz, 1 H), 3.15 (ddd, J = 19.1, 10.6, 0.5 Hz, 1 H), 3.00
(dt, J = 19.1, 1.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
196.1, 166.0, 163.8, 136.7, 130.5, 129.8, 129.1, 128.6, 72.9, 64.5,
45.7 ppm. HRMS (ESI): calcd. for C14H11O5 [M – H]– 259.0606;
found 259.0611: calcd. for C15H14O6 [(M + MeOH) – H]– 291.0874;
found 291.0872.
[12] X. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 11004–
Molecular Modeling: Coordinates for an arbitrary conformation of
acetylmelodorinol (12) were subjected to random torsional sam-
pling by using the Monte Carlo Multiple Minima algorithm[23] fol-
lowed by minimization with the OPLS 2005 force field[24] in vacuo
and conjugated gradient algorithm[25] as implemented in Macro-
Model 9.9.[26] The number of repetitions was set to 10000, and the
energy window for saving conformations was set to 5 kcal/mol,
which resulted in 45 fully minimized conformations, with a
0.05 kcalmol–1 Å–1 gradient convergence criterion. Corresponding
coordinates were then fully optimized without constraint by using
a DFT[27] method with the hybrid Becke-3-parameter-Lee–Yang–
Parr exchange-correlation functional[28] and the 6-31G* base[29] as
implemented in the Gaussian 09 software package.[30] Vibrational
analyses within the harmonic approximation were performed at the
same level of theory upon geometrical optimization convergence.
Local minima were characterized by the absence of imaginary fre-
quency. Populations were calculated by using Maxwell–Boltzmann
statistics. Vibrational rotational strengths within the harmonic
approximation were calculated at the same level for the 6 confor-
mations with the lowest free-energy conformations, and used for
VCD spectra simulation with a 4 cm–1 width at half height.[31] Spec-
tra were plotted with gnuplot.[32] Figures were rendered with UCSF
Chimera.[33]
11005.
[13] R. Garzelli, S. Samaritani, C. Malanga, Tetrahedron 2008, 64,
4183–4186.
[14]
a) G. Asensio, M. A. Miranda, M. J. Sabater, J. Perez-Prieto,
A. Simon-Fuentes, R. Mello, J. Org. Chem. 2000, 65, 964–968;
b) A. D’Annibale, L. Ciaralli, M. Bassetti, C. Pasquini, J. Org.
Chem. 2007, 72, 6067–6074.
[15]
[16]
[17]
S. E. Denmark, N. D. Gould, L. M. Wolf, J. Org. Chem. 2012,
76, 4260–4336.
E. Fouque, G. Rousseau, J. Seyden-Penne, J. Org. Chem. 1990,
55, 4807–4817.
a) J. H. Jung, S. Pummangura, C. Chaichantipyuth, C. Patara-
panich, P. E. Fanwick, C.-J. Chang, J. L. McLaughlin, Tetrahe-
dron 1990, 46, 5043; b) J. H. Jung, C.-J. Chang, D. L. Smith,
J. L. McLaughlin, S. Pummangura, C. Chaichantipyuth, C. Pa-
tarapanich, J. Nat. Prod. 1991, 54, 500–505; c) P. Tuchinda,
J. Udchachon, V. Reutrakul, T. Santisuk, W. C. Taylor, N. R.
Famsworth, J. M. Pezzuto, D. Kinghom, Phytochemistry 1991,
30, 2685–2689.
[18]
[19]
S. Saadawi, J. Jalil, M. Jasamai, I. Jantan, Molecules 2012, 17,
4824–4835.
B. T. Murphy, S. Cao, P. J. Brodie, J. S. Miller, F. Ratovoson,
C. Birkinshaw, E. Rakotobe, V. E. Rasamison, K. Tendyke,
E. M. Suh, D. G. I. Kingston, Nat. Prod. Res. 2008, 22, 1169–
1175.
[20]
[21]
[22]
[23]
[24]
T. B. Freedman, X. Cao, R. K. Dukor, L. A. Nafie, Chirality
2003, 15, 743–758.
W. L. Jorgensen, D. S. Maxwell, J. Tirado-Rives, J. Am. Chem.
Soc. 1996, 118, 11225–11236.
S. Ishikawa, T. Hamada, K. Manabe, S. Kobayashi, J. Am.
Chem. Soc. 2004, 126, 12236–12237.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectroscopic data for new synthesized compounds 1–
10; chiral HPLC data for compound 8; NMR spectroscopic data of
isolated “klaivanolide” and acetylmelodorinol (12); computational
data for the DFT calculation of acetylmelodorinol (12).
G. Chang, W. Guida, W. C. Still, J. Am. Chem. Soc. 1989, 111,
4379–4386.
For a description of the OPLS_2005 parameters, see: J. L.
Banks, H. S. Beard, Y. Cao, A. E. Cho, W. Damm, R. Farid,
A. K. Felts, T. A. Halgren, D. T. Mainz, J. R. Maple, R. Mur-
phy, D. M. Philipp, M. P. Repasky, L. Y. Zhang, B. J. Berne,
R. A. Friesner, E. Gallicchio, R. M. Levy, J. Comput. Chem.
2005, 26, 1752–1780.
E. Polak, G. Ribière, Rev. Fr. Inform. Rech. O. 1969, 16, 35–
43.
MacroModel, version 9.9, Schrödinger, LLC, New York, NY,
2011.
a) W. Kohn, L. J. Sham, Phys. Rev. 1965, 140, A1133–A1138;
b) P. Hohenberg, W. Kohn, Phys. Rev. 1964, 136, B864–B871.
a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee,
W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
W. J. Hehre, L. Radom, P. v. R. Schleyer, J. A. Pople, Ab initio
Molecular Orbital Theory, Wiley, New York, 1986.
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
Acknowledgments
We thank the IT Department of Université Paris-Sud for providing
computing resources. We thank also Karine Leblanc and Claire
Troufflard from their analytical services that provided HRMS and
chiral HPLC data for our compounds. We thank Tomoki Tsuchiya,
Bayer Cropsciences, for discussions regards writing.
[25]
[26]
[27]
[28]
[29]
[30]
[1] B. Akendengue, E. Ngou-Milama, H. Bourobou-Bourobou, J.
Essouma, F. Roblot, C. Gleye, A. Laurens, R. Hocquemiller,
P. M. Loiseau, C. Bories, Phytother. Res. 2003, 17, 364–367.
[2] B. Akendengue, F. Roblot, P. M. Loiseau, C. Bories, E. Ngou-
Milama, A. Laurens, R. Hocquemiller, Phytochemistry 2002,
59, 885–888.
[3] F. J. Devlin, P. J. Stephens, B. Figadère, Chirality 2009, 21, 48–
53.
[4] J.-B. Galle, M. Leti, S. Kim, A. Mandeau, Biochem. Syst. Ecol.
2013, 48, 9–11.
[5] K. Nakashima, M. Imoto, T. Miki, T. Miyake, N. Fujisaki, S.
Fukunaga, R. Mizutani, M. Sono, M. Tori, Heterocycles 2002,
56, 85–89.
[6] M. Bessodes, D. Komiotis, K. Antonakis, Tetrahedron Lett.
1986, 27, 579–580.
6188
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6183–6189

Toward the Synthesis of Klaivanolide and Structure Reinterpretation
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, Re-
vision A.02. Gaussian, Inc., Wallingford, CT, 2009.
[32] T. Williams, C. Kelley, Gnuplot 4.6: An Interactive Plotting Pro-
gram, http://gnuplot.sourceforge.net/, 2012.
[33] Chimera is developed by the Resource for Biocomputing, Visu-
alization, and Informatics at the University of California, San
Francisco, with support from the National Institutes of Health
(National
Center
for
Research
Resources
grant
2P41RR001081, National Institute of General Medical Sci-
ences grant 9P41GM103311).
[31] J. R. Cheeseman, M. J. Frisch, F. J. Devlin, P. J. Stephens,
Chem. Phys. Lett. 1996, 252, 211–220.
Received: June 11, 2014
Published Online: August 20, 2014
Eur. J. Org. Chem. 2014, 6183–6189
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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