An efficient total synthesis of (+)-varitriol from D-ribonolactone

Article abstract of DOI:10.1055/s-0030-1258201

A short and efficient total synthesis of cytotoxic natural (+)-varitriol has been accomplished in eight steps from γ-D-ribonolactone and 2,3-dimethylanisole in 41% overall yield. The key features include a highly stereoselective introduction of methyl at a carbonyl group and installation of the side chain with the aromatic portion by Julia-Kocieski olefination at C5 of the starting carbon skeleton. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258201

PAPER
3449
An Efficient Total Synthesis of (+)-Varitriol from D-Ribonolactone
Total
S
ynthesis of
l
(+)-V
a
’
ritriol fr
o
g
m
D
-Ribono
a
lactone Karlubíková, Miroslav Palík, Angelika Lásiková, Tibor Gracza*
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovak Republic
E-mail: tibor.gracza@stuba.sk
Received 11 May 2010; revised 24 June 2010
ported.11 In addition, the impressive biological activity of
(+)-varitriol initiated the synthesis of its analogues and
their testing for pharmacological properties.12 A synthetic
route that allows for the rapid construction of varitriol an-
Abstract: A short and efficient total synthesis of cytotoxic natural
(+)-varitriol has been accomplished in eight steps from g-D-ribono-
lactone and 2,3-dimethylanisole in 41% overall yield. The key fea-
tures include a highly stereoselective introduction of methyl at a
carbonyl group and installation of the side chain with the aromatic alogues with variable side chain is therefore desirable. In
portion by Julia–Kocieński olefination at C5 of the starting carbon
skeleton.
this communication we wish to report a short and efficient
synthesis of (+)-1 offering a reliable access to its ana-
logues from a single chiral pool material, g-D-ribonolac-
tone.
Key words: natural products, varitriol, stereoselective synthesis,
diastereoselectivity, chiral pool
The key operation in the retrosynthetic analysis of varitri-
ol is the coupling of sulfone 2 and aldehyde 3 via a
Kocieński–Julia olefination13 (Scheme 1).
The tetrahydrofuran backbone is a frequently found het-
erocyclic unit in a number of biologically active natural
products such as Annonaceae acetogenins1 and ionophore
antibiotics.2 Varitriol [(+)-1], isolated from a marine-de-
rived strain of the fungus Emericella variecolor, is anoth-
er type of low-molecular-weight cytotoxic compound
containing a polysubstituted tetrahydrofuran ring.3 Partic-
ularly, (+)-1 demonstrated a more than 100-fold increased
potency over the mean toxicity towards cell lines RXF
393 (renal cancer, GI50 = 1.63 × 10–7 M), TD-47 (breast
cancer, GI50 = 2.10 × 10–7 M), and SNB (CNS cancer,
GI50 = 2.44 × 10–7 M).3,4 The noteworthy cytotoxic activ-
ity of (+)-1 and the unknown mode of its action generated
considerable interest among synthetic chemists.5–9,11 Five
syntheses of (+)- and (–)-varitriol have been reported, and
a formal approach has also been disclosed.9 At first, two
synthetic approaches to unnatural varitriol (–)-1 were
published. Jennings et al.5 achieved the total synthesis of
(–)-1 using cross metathesis to link together the carbohy-
drate and aromatic moieties of the molecule. Taylor’s
group reported a flexible route to (–)-1 applying the
HWE/conjugate addition/Ramberg–Bäcklund rearrange-
ment sequence.6 Both syntheses utilized D-ribose as start-
ing material for construction of the furanoside part of (–)-
1 (Scheme 1). Shaw and Kumar7 accomplished the first
synthesis of naturally occurring (+)-1 from methyl a-D-
mannopyranoside. The approach is based on an alkene
metathesis of the corresponding styrene and tetrahydrofu-
ran subunits. We described the synthesis of (+)-1 starting
with dimethyl L-tartrate8 and D-glucose,9 respectively.
Both routes used our bicyclization strategy10 for the con-
struction of the tetrahydrofuran subunit. Very recently,
the syntheses of (+)-1 and 5-epi-varitriol, and their enan-
HO
OH
HO
OH
O
O
HO
HO
OMe
OMe
(–)-1
varitriol (+)-1
O
O
M. P. Jennings5
R. J. K. Taylor6
O
+
SO2PT
AcO
O
OMe
3
2
HO
OH
HO
OH
OH
HO
1
1
5
5
OH
O
O
O
OMe
D-ribose
γ-D-ribonolactone
Scheme 1 Retrosynthetic analyses of varitriol
Fragment 3,14 2-(acetoxymethyl)-3-methoxybenzalde-
hyde, was easily available8 from 2,3-dimethylanisole.
Variation in the structure of substituted benzaldehyde 3
would provide an array of varitriol analogues. In contrast
to the reported syntheses5,6 the tetrahydrofuran subunit 2
with the configuration of natural enantiomer (+)-1 could
be accessible from g-D-ribonolactone by diastereoselec-
tive introduction of the methyl group at C1 and the sulfo-
nyl moiety at C5, i.e. at the opposite ends of carbon chain
of the starting block.
tiomers, from D-mannitol using the Heck reaction were re- The synthesis began with nucleophilic displacement of
the primary hydroxy group of commercially available ac-
etonide g-D-ribonolactone 4 with 1-phenyl-1H-tetrazole-
5-thiol (PTSH) using the Mitsunobu protocol15 to provide
sulfide 6, which was used in the next step without further
purification (Scheme 2). Alternatively, analytically pure 6
SYNTHESIS 2010, No. 20, pp 3449–3452
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258201; Art ID: T10310SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3450
O. Karlubíková et al.
PAPER
1. DIBAL-H, THF, –50 °C, 8 h
2. Ac2O, DMAP, CH2Cl2, 0 °C, 12 h
3. Me3Al, CH2Cl2, –30 to –18 °C, 6 d
70%, from 4 over 4 steps
O
O
O
O
O
O
PTSH, Ph3P, DIAD
THF, 0 °C, 1 h
N
N
N
OR
S
S
N
O
O
O
O
O
N
N
N
N
6
Ph
Ph
4 R = H
7
MsCl, pyridine,
CH2Cl2, 0 °C to r.t., 2 d
79%
KSPT, DMF, r.t., 8 h
65%
5 R = Ms
1. 3, KHMDS, DME, –55 °C to r.t., 10 h
2. NaOMe, MeOH, r.t., 4 h
3. HCl, THF, r.t., 4 h
O
O
HO
OH
Mo(VI)/H2O2, THF
EtOH, r.t., 24 h
O
O
N
S
N
64%, 3 steps
91%
O
O
N
N
HO
Ph
2
(+)-1
OMe
Scheme 2 Synthesis of (+)-varitriol
was obtained in 51% yield in two steps; mesylation of free steps of the route include a highly stereoselective intro-
hydroxy followed by displacement of the leaving group duction of the methyl group at C1 and installation of the
using potassium thiolate. A highly stereoselective incor- side chain with the aromatic portion by Julia–Kocieński
poration of the exo-methyl group at C1 was then possible olefination at C5 of the starting carbon skeleton. In this
using a three-step sequence. Partial reduction of the lac- reversed arrangement of events, compared to the
tone 6 using diisobutylaluminum hydride (2 equiv) in tet- Jennings5 and Taylor6 syntheses, in fact D-ribose has be-
rahydrofuran at –50 °C afforded a crude mixture of lactols come a useful template for the synthesis of both enan-
that in turn was treated with acetic anhydride (2 equiv) tiomers.
and 4-(dimethylamino)pyridine (3 equiv) in dichlo-
romethane at 0 °C to give a mixture of the corresponding
anomeric acetates. Low temperature treatment of this ma-
Moreover, a rapid access to key fragments, furan subunit
2 and substituted aldehyde 3, respectively, as well as the
late stage of convergence of the synthesis make the strat-
terial with trimethylaluminum (3 equiv) in dichlo-
egy suitable for the synthesis of substantial amounts of a
romethane followed by flash chromatography purification
variety of analogues for investigation of biological activi-
ty and SAR studies.
on silica gel then afforded the desired exo-methylated
compound 7 in 70% overall yield. No endo-diastereomer
The application of this strategy towards the synthesis of
novel analogues of varitriol and SAR study is under
progress and will be presented in due course.
was observed in the 1H NMR spectra of the crude reaction
mixture. This three-step protocol in one pot required only
one purification step and efficiently introduced the methyl
group with high stereoselectivity in the C–C bond forma-
tion step.
All reactions involving organometallic or moisture-sensitive re-
agents were carried out under argon atmosphere using standard vac-
uum line techniques and glassware that was flame dried and cooled
under argon before use. Commercial reagents were used without
further purification. All solvents were distilled before use. Hexanes
refer to the fraction boiling at 60–65 °C. Flash column liquid chro-
matography was performed on silica gel Kieselgel 60 (40–63 mm,
230–400 mesh) and analytical TLC was performed on aluminum
plates pre-coated with either 0.2 mm (DC-Alufolien, Merck) or 0.25
mm silica gel 60 F254 (Alugram SIL G/UV254, Macherey-Nagel).
The compounds were visualized by UV fluorescence and by dip-
ping the plates in Ce(SO4)2/(NH4)6Mo7O24·4 H2O in aq H2SO4 soln
followed by charring with a heat gun.
Oxidation of 7 with hydrogen peroxide–ammonium mo-
lybdate completed the construction of sulfone 2 in 91%
(64% from 4) yield. The crucial Kocieński–Julia
olefination13 between the furanoside fragment 2 and the
aromatic aldehyde 38 was achieved using potassium hexa-
methyldisilazanide (1.8 equiv) in 1,2-dimethoxyethane to
give a mixture of E/Z-isomeric olefins (E/Z, 6:1), which
was subjected to final deprotection. The treatment of the
crude mixture with sodium methoxide in methanol fol-
lowed by acidic hydrolysis with hydrogen chloride in tet-
rahydrofuran and, finally, flash chromatography
purification furnished the target compound (+)-1 in 64%
Elemental analyses were run on a Fisons EA1108 instrument. Melt-
ing points were obtained using a Boecius apparatus (uncorrected).
Optical rotations were measured with a Polar L-mP polarimeter (IBZ
20
yield over the last three steps. Synthetic (+)-1, [a]D
+41.6 (c 0.18, MeOH) [Lit.8 [a]D20 +43.4 (c 0.53, MeOH), Messtechnik) with a water-jacketed 10.000-cm cell at the wave-
Lit.6 [a]D20 –40.6 (c 1.6, MeOH) for (–)-1] showed physi-
length of NaD line (l = 589 nm). Specific rotations are reported in
10–1 deg cm2 g–1 and concentrations in g 100 cm–3. FT-IR spectra
cal and spectroscopic data corresponding to the reported
were obtained on a Nicolet 5700 spectrophotometer (Thermo Elec-
values.8
tron) equipped with a Smart Orbit (diamond crystal ATR) accesso-
ry, using the reflectance technique (4000–400 cm–1).
In conclusion, a short and effective synthesis of natural
varitriol has been achieved from g-D-ribonolactone and
dimethylanisole (8 steps, 41% overall yield). The key
1H and 13C NMR spectra were recorded on either 300 (75) MHz
MercuryPlus or 600 (150) MHz Unity Inova spectrometers from
Synthesis 2010, No. 20, 3449–3452 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-Varitriol from D-Ribonolactone
3451
Varian and referenced to TMS as internal standard. HRMS were re-
corded on a Q-Tof PremierTM mass spectrometer with nanoAcquity
UPLCTM (Waters), and are accurate to 3 ppm.
1,4-Anhydro-5-deoxy-2,3-O-isopropylidene-1-methyl-5-(1-phe-
nyl-1H-tetrazol-5-ylsulfanyl)-D-galacto-pentitol (7)
The crude lactone 6 (3.456 g) was dissolved in anhyd THF (100
mL), cooled to –50 °C and 1 M DIBAL in toluene (25 mL, 10.5
mmol, 2 equiv) was slowly added with vigorous stirring. The mix-
ture was stirred at –50 °C for 8 h and then carefully quenched with
3 M HCl (10 mL) while the temperature rose to r.t. (30 min). Then
H2O (100 mL) and Et2O (50 mL) were added, phases were separated
and aqueous layer was extracted with Et2O (2 × 50 mL). The com-
bined organic extracts were washed with brine (50 mL), dried
(MgSO4), and evaporated in vacuo. The mixture of anomeric lactols
was dried in vacuo and immediately used in the subsequent acetyla-
tion reaction. Thus, the crude oil was dissolved in anhyd CH2Cl2 (50
mL), cooled to 0 °C, and DMAP (1.954 g, 16 mmol, 3 equiv) was
added under argon with vigorous stirring. Then Ac2O (1.0 mL, 10.5
mmol, 2 equiv) was slowly added at 0 °C and the mixture was
stirred at this temperature for 12 h, diluted with CH2Cl2 (100 mL),
and washed with H2O (50 mL) and brine (50 mL). The organic layer
was dried (MgSO4) and evaporated to give a crude mixture of ano-
meric acetates that was dried in vacuo and immediately used for the
subsequent methylation. Thus, the crude yellow oil was dissolved in
anhyd CH2Cl2 (25 mL), cooled to –30 °C under argon and 2 M
Me3Al in heptane (8 mL, 16 mmol, 3 equiv) was slowly added drop-
wise. The mixture was stirred at –30 to –18 °C for 6 h and then the
reaction was carefully quenched with 5% aq citric acid soln (100
mL) and extracted with Et2O (3 × 30 mL). The combined organic
layers were dried (MgSO4) and evaporated in vacuo. The purifica-
tion by flash column chromatography (silica gel, 10% Et2O–hex-
anes) gave 7 (1.352 g, 70% from 4, over 4 steps) as a colorless oil;
Rf = 0.6 (hexanes–EtOAc, 1:1).
2,3-O-Isopropylidene-5-O-mesyl-g-D-ribonolactone (5)
A soln of MsCl (0.43 mL, 639 mg, 5.58 mmol, 1.05 equiv) was
slowly added to a stirred soln of 4 (1.00 g, 5.31 mmol) and pyridine
(1.56 mL, 1.538 g, 9.45 mmol, 1.7 equiv) in CH2Cl2 (30 mL) at 0
°C. The mixture was stirred at r.t. for 2 d and then concentrated in
vacuo. The residual white solid was redissolved in CH2Cl2 (80 mL)
and washed with H2O (2 × 40 mL) and brine (40 mL). The organic
layer was dried (MgSO4), concentrated, and purified by flash chro-
matography (silica gel, 30 g, 40% EtOAc–hexanes) to afford mesy-
late 5 (1.118 g, 79%) as a white solid; mp 64–66 °C; Rf = 0.4
(hexanes–EtOAc, 1:1).
[a]D25 –34.7 (c 0.78, MeOH).
IR (ATR): 3026, 2952, 1792, 1466, 1389, 1331, 1277, 1237, 1212,
1183, 1157, 1077, 1051, 954, 925, 850, 833, 789, 535, 512 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 3.07 (s, 3 H, CH3), 4.75 (dd, J = 0.9, 2.5 Hz, 2 H, CH2OMs),
4.79–4.85 (m, 3 H, H2, H3, H4).
13C NMR (75 MHz; CDCl3): d = 25.5, 26.6, 37.6, 68.2, 74.9, 77.4,
79.3, 114.0, 173.2.
Anal. Calcd for C9H14O7S: C, 40.60; H, 5.30. Found: C, 40.76; H,
5.32.
5-Deoxy-2,3-O-isopropylidene-5-(1-phenyl-1H-tetrazol-5-ylsul-
fanyl)-g-D-ribonolactone (6) from Mesylate 5
Mesylate 5 (1.04 g, 3.91 mmol) was added to a soln of potassium 1-
phenyl-1H-tetrazole-5-thiolate (0.93 g, 4.3 mmol, 1.1 equiv) in
DMF (60 mL) at r.t. and the mixture was stirred for 8 h. The mixture
was concentrated in vacuo (rotavapor, 40 °C/6.7 mbar) and the
crude residue was partially dissolved in refluxing EtOAc (100 mL),
filtered, concentrated to 30 mL, and allowed to crystallize. Crystal-
line product was filtered off and washed with small amount of
EtOAc affording 6 (0.89 g, 65%) as a white solid; mp 136–138 °C;
Rf = 0.3 (hexanes–EtOAc, 1:1).
[a]D20 +28.9 (c 0.36, CHCl3).
IR (ATR): 2979, 1579, 1499, 1456, 1381, 1267, 1240, 1240, 1210,
1074, 1014, 862, 761, 694, 552, 511 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J1,Me = 6.4 Hz, 3 H, CH3),
1.32 (s, 3 H, CH3), 1.52 (s, 3 H, CH3), 3.62 (dd, JA,4 = 6.7 Hz,
JA,B = 13.3 Hz, 1 H, CH2ASPT), 3.79 (dd, JB,4 = 5.2 Hz, JA,B = 13.3
Hz, 1 H, CH2BSPT), 3.99 (dq, J1,2 = 4.8 Hz, J1,Me = 6.4 Hz, 1 H, H1),
4.21 (ddd, J3,4 = 4.9 Hz, JB,4 = 5.1 Hz, JA,4 = 6.7 Hz, 1 H, H4), 4.30
(dd, J1,2 = 4.8 Hz, J2,3 = 7.0 Hz, 1 H, H2), 4.56 (dd, J3,4 = 4.6 Hz,
J2,3 = 7.0 Hz, 1 H, H3), 7.56–7.61 (m, 5 H, Ph).
13C NMR (75 MHz, CDCl3): d = 18.9, 25.4, 27.3, 36.1, 80.7, 81.8,
84.1, 86.1, 115.1, 123.9, 129.8, 130.1, 130.1, 133.6, 153.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H21N4O3S: 349.1329;
found: 349.1158.
[a]D20 +3.9 (c 0.33, MeOH).
IR (ATR): 2991, 1770, 1595, 1499, 1391, 1378, 1354, 1276, 1242,
1214, 1187, 1069, 1035, 981, 956, 881, 852, 765, 696, 689, 551, 514
cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.26 (s, 3 H, CH3), 1.29 (s, 3
H, CH3), 3.70 (ddd, JA,4 = 5.9 Hz, JB,4 = 7.1 Hz, JA,B = 14.3 Hz, 2 H,
CH2SPT), 4.83–4.87 (m, 2 H, H3, H4), 4.98 (d, J2,3 = 5.8 Hz, 1 H,
H2), 7.62 (s, 5 H, Ph).
Anal. Calcd for C16H20N4O3S: C, 55.15; H, 5.79; N, 16.08. Found:
C, 55.14; H, 5.81; N, 15.99.
13C NMR (75 MHz, acetone-d6): d = 16.4, 17.8, 25.8, 65.3, 69.5,
71.5, 104.1, 116.1, 121.4, 122.1, 124.3, 144.9, 165.0.
1,4-Anhydro-5-deoxy-2,3-O-isopropylidene-1-methyl-5-(1-phe-
nyl-1H-tetrazol-5-ylsulfonyl)-D-galacto-pentitol (2)
Anal. Calcd for C15H16N4O4S: C, 51.71; H, 4.63; N, 16.08. Found:
C, 51.66; H, 4.65; N, 16.01.
To a soln of sulfide 7 (0.79 g, 2.17 mmol) in a mixture of EtOH (30
mL) and THF (30 mL) was added a mixture of 35% aq H2O2 (4.82
mL, 63.62 mmol, 29.3 equiv) and (NH4)2MoO4 (482 mg, 0.386
mmol, 0.18 equiv) at 0 °C. The mixture was stirred at r.t. overnight
and then diluted with H2O (60 mL) and CH2Cl2 (60 mL). The layers
were separated and the aqueous layer was extracted with CH2Cl2
(5 × 30 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification by chromatography
(silica gel, 30 g, EtOAc–hexanes, 3:7) provided 2 (0.785 g, 91%) as
a white solid; mp 109–110 °C.
5-Deoxy-2,3-O-isopropylidene-5-(1-phenyl-1H-tetrazol-5-ylsul-
fanyl)-g-D-ribonolactone (6) from Protected Ribonolactone 4
1-Phenyl-1H-tetrazole-5-thiol (1.989 g, 11.16 mmol, 2.1 equiv) was
added to a soln of 4 (1.0 g, 5.314 mmol) in THF (50 mL) at r.t. and
mixture was cooled to 0 °C. Then PPh3 (2.09 g, 7.97 mmol, 1.5
equiv) and DIAD (1.88 mL, 9.56 mmol, 1.8 equiv) were consecu-
tive added. The mixture was stirred for 1 h and then it was parti-
tioned between Et2O (2 × 50 mL) and brine (50 mL). The combined
organic layers were dried (MgSO4), concentrated, and passed
through a column of silica gel (20% EtOAc–hexanes) to afford sul-
fide 6 (3.456 g), which was used without further purification in the
next step.
[a]D20 +47.6 (c 0.43, CHCl3).
IR (ATR): 2989, 2982, 1496, 1461, 1381, 1375, 1353, 1259, 1237,
1211, 1152, 1114, 1077, 1062, 1016, 869, 846, 818, 770, 759, 693,
683, 531, 451, 413 cm–1.
Synthesis 2010, No. 20, 3449–3452 © Thieme Stuttgart · New York

3452
O. Karlubíková et al.
PAPER
1H NMR (600 MHz, CDCl3): d = 1.13 (d, J1,Me = 6.5 Hz, 3 H, CH3),
1.30 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 3.85–3.94 (m, 3 H, H1,
CH2SO2PT), 4.22–4.29 (m, 2 H, H2, H4), 4.54 (dd, J3,4 = 5.3 Hz,
J2,3 = 6.9 Hz, 1 H, H3), 7.58–7.64 (m, 5 H, Ph).
13C NMR (150 MHz, CDCl3): d = 18.7, 25.4, 27.2, 58.8, 77.9, 81.0,
83.8, 85.5, 115.7, 125.6, 129.5, 131.4, 133.6, 153.8.
References
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1999, 62, 504. (c) Cave, A.; Figadère, B.; Laurens, A.;
Cortes, D. Acetogenines from Annonaceae, In Progress in
the Chemistry of Organic Natural Products, Vol. 70; Herz,
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(d) McLaughlin, J. L.; Chang, C.-J.; Smith, D. L. Stud. Nat.
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HRMS (ESI): m/z [M + H]+ calcd for C16H21N4O5S: 381.1277;
found: 381.1076.
Anal. Calcd for C16H20N4O5S: C, 50.52; H, 5.30; N, 14.73. Found:
C, 50.66; H, 5.27; N, 14.78.
(+)-Varitriol [(+)-1]
To a stirred soln of sulfone 2 (70 mg, 0.184 mmol) and aldehyde 3
(192 mg, 0.922 mmol, 5 equiv) in DME (6 mL) was added 15%
KHMDS in toluene (0.50 mL, 0.331 mmol, 1.8 equiv) at –55 °C.
The mixture was allowed to warm slowly to r.t. and stirred for 10 h.
The reaction was then quenched by addition of H2O (0.5 mL) and
concentrated in vacuo. The crude product of the olefination was dis-
solved in MeOH (4 mL) and freshly prepared 0.6 M NaOMe in
MeOH (1.5 mL) was added. The mixture was allowed to stir for 4 h
[TLC (EtOAc–hexanes, 3:7) monitoring]. The mixture was concen-
trated in vacuo and remainder dissolved in THF (10 mL). Aq 1 M
HCl (10 mL) was added the mixture was stirred for 4 h. Solvents
were removed in vacuo and residue was purified by flash chroma-
tography (silica gel, 10 g, CH2Cl2–acetone, 3:2) to give (+)-1 (33
mg, 64%) as a white solid; mp 109–110 °C [colorless needles by re-
crystallization (EtOAc–hexanes, 1:1)]; Rf = 0.3 (CH2Cl2–acetone,
3:2).
[a]D20 +41.6 (c 0.18, MeOH) [Lit.3 [a]D25 +18.5 (c 2.3, MeOH), Lit.7
28
20
[a]D +19.4 (c 0.16, MeOH), Lit.8 [a]D +43.4 (c 0.53, MeOH),
Lit.11 [a]D +40.0 (c 0.21, MeOH), Lit.5 [a]D –18.2 (c 0.0033,
28
25
(10) (a) Babjak, M.; Remeň, ; Szolcsányi, P.; Zálupský, P.;
Miklóš, D.; Gracza, T. J. Organomet. Chem. 2006, 691,
928. (b) Babjak, M.; Remeň, ; Karlubíková, O.; Gracza, T.
Synlett 2005, 1609.
MeOH) for (–)-1, Lit.6 [a]D20 –40.6 (c 1.6, MeOH) for (–)-1].
HRMS (ESI): m/z [M + H]+ calcd for C15H21O5: 281.1384; found:
281.1539.
(11) Ghosh, S.; Pradhan, T. K. J. Org. Chem. 2010, 75, 2107.
(12) (a) Nagarapu, L.; Paparaju, V.; Satyender, A. Bioorg. Med.
Chem. Lett. 2008, 18, 2351. (b) Senthilmurugan, A.;
Aidhen, I. S. Eur. J. Org. Chem. 2010, 555.
(13) (a) Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley,
A. Synlett 1998, 26. (b) Julia, M.; Paris, J.-M. Tetrahedron
Lett. 1973, 14, 4833. (c) Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563.
Anal. Calcd for C15H20O5: C, 64.27; H, 7.19. Found: C, 64.02; H,
7.17.
The spectroscopic data of (+)-1 were in good agreement with those
reported.8
Acknowledgment
(14) Box, V. G. S.; Yianikorous, G. P. Heterocycles 1990, 31,
1261.
(15) (a) Loibnen, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100.
(b) Mitsunobu, O. Synthesis 1981, 1.
This work was supported by Slovak Grant Agencies (VEGA, Slo-
vak Academy of Sciences and Ministry of Education, Bratislava,
projects No. 1/0115/10, 1/0236/09, and APVV, Bratislava, project
No. LPP-0071-09).
Synthesis 2010, No. 20, 3449–3452 © Thieme Stuttgart · New York