Total synthesis of (+)-varitriol

Article abstract of DOI:10.1002/ejoc.200801070

The total synthesis of natural (+)-varitriol (1) was accomplished by starting from dimethyl L-tartrate. The key features were a substrate selective and diastereoselective Pd^II-catalysed bicyclisation of unsaturated protected triol 9 followed by regioselective ring-opening of bicyclic skeleton 10. The absolute configuration of the target was confirmed by single-crystal X-ray analysis for the first time.

Full text of DOI:10.1002/ejoc.200801070

FULL PAPER
DOI: 10.1002/ejoc.200801070
Total Synthesis of (+)-Varitriol
[a]
[a]
[a]
[b]
ˇ ˇ
Miroslav Palík, Ol’ga Karlubíková, Angelika Lásiková, Jozef Kozísek, and
Tibor Gracza*[a]
Dedicated to Professor Hans-Ulrich Reissig on the occasion of his 60th birthday
Keywords: Natural products / Total synthesis / Homogeneous catalysis / Palladium
The total synthesis of natural (+)-varitriol (1) was ac- 10. The absolute configuration of the target was confirmed
complished by starting from dimethyl
L-tartrate. The key
by single-crystal X-ray analysis for the first time.
features were a substrate selective and diastereoselective
PdII-catalysed bicyclisation of unsaturated protected triol 9
followed by regioselective ring-opening of bicyclic skeleton
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Horner–Wadsworth–Emmons/conjugate addition/Ramberg–
Bäcklund rearrangement sequence. Both syntheses utilised
-ribose to construct the furanoside portion of (–)-1. Very
recently, the paper describing the first total synthesis of nat-
ural varitriol [(+)-1] appeared in the literature.[7] The ap-
proach is based on a cross metathesis reaction of the corre-
sponding styrene and tetrahydrofuran subunits, for which
the latter was obtained from methyl α--mannopyranoside.
In addition, impressive biological activity of (+)-varitriol
initiated the synthesis of its analogues and their testing for
pharmacological properties.[8]
In the course of our long-term programme directed
towards the application of PdII-catalysed bicyclisation of
unsaturated polyols[9] to natural products synthesis, we de-
veloped the total syntheses of goniofufurone,[10] gonio-
thalesdiol[11] and erythroskyrine.[12] Herein, we report on
the total synthesis of natural varitriol.
Introduction
In the last decade, increased interest in the chemistry of
fungi isolated from the marine environment has been indi-
cated.[1] Marine fungi are interesting organisms from an
ecological point of view, because they are significant patho-
gens in the marine environment.[2] Furthermore, because
many can be cultured, they represent an important biomed-
ical resource. Recently, a new natural tetrahydrofuran deriv-
ative, (+)-varitriol (1), was isolated from a marine-derived
strain of fungus Emericella variecolor and has been revealed
to have significant activity against a variety of tumours. In
particular, (+)-1 showed notably increased potency towards
selected renal, CNS and breast cancer cell lines, although
its mode of action has not yet been established.[3,4] The
structure and relative stereochemistry of 1 was assigned on
the basis of NMR spectroscopy and the absolute configura-
tion was determined in the course of the synthesis of its
unnatural enantiomer (–)-1.[5]
Recently, two synthetic approaches to unnatural (–)-1
varitriol were published. Jennings et al.[5] achieved the total
synthesis of (–)-1 by utilising alkene metathesis to link to-
gether the carbohydrate and aromatic moieties of the mole-
cule. The group of Taylor[6] reported a short and flexible
route to (–)-1 by applying their methodology featuring the
Results and Discussion
Our analysis of the synthetic problem suggested the
coupling of fragments 2 and 3 as the key step; namely, suit-
ably protected furan derivative 2 bearing a sulfonyl group
and substituted benzaldehyde through Kocien´ski–Julia ole-
fination[13] (Scheme 1). Intermediate 3[14] in turn was clearly
available from 2,3-dimethylanisole, whereas subunit 2 could
be prepared from dimethyl tartrate by employing our bi-
cyclisation strategy developed for the construction of 2,3-
trans-substituted tetrahydrofurans.[9b,9c] Thus, sulfone 2
with the correct configuration of the target molecule could
be accessible from key intermediate -xylo-9 by PdCl2/
CuCl2-catalysed bicyclisation followed by regioselective ring
opening of 10 and inversion of configuration at C3.
[a] Department of Organic Chemistry, Institute of Organic Chem-
istry, Catalysis and Petrochemistry, Slovak University of Tech-
nology,
Radlinského 9, 81237 Bratislava, Slovakia
Fax: +421752968560
E-mail: tibor.gracza@stuba.sk
[b] Department of Physical Chemistry, Institute of Physical Chem-
istry and Chemical Physics, Slovak University of Technology,
Radlinského 9, 81237 Bratislava, Slovakia
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2009, 709–715
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
709

M. Palík, O. Karlubíková, A. Lásiková, J. Kozísˇek, T. Gracza
ˇ
FULL PAPER
The mixture of diastereomers -lyxo-9/-xylo-9 (69:31)
was subjected to the crucial transformation of the synthesis:
a two-step sequence to convert protected triol -xylo-9 into
tetrahydrofuran 11 with the trans relationship of C4–C5
substituents (Scheme 3). The present approach takes advan-
tage of recent work[9b,9c] showing that unsaturated polyols
undergo PdII–CuII-catalysed bicyclisation to yield 1,4:2,5-
dianhydroalditols with high xylo-substrate preference and
excellent threo diastereoselectivity (concerning the newly
formed stereocentre at C2 relative to the hydroxy group at
C4).
Scheme 1. Retrosynthetic analysis of (+)-1.
The key intermediate for bicyclisation, protected triol 9,
was obtained by using standard carbohydrate chemistry
(Scheme 2). Known protected triol 5 was easily prepared
from dimethyl -tartrate (4) by using a published procedure
involving acetonide formation,[15] ester reduction,[16] selective
monotosylation[17] and hydride displacement (51% overall
yield). Swern oxidation of 5 afforded aldehyde 6, which was
subjected without further purification to Grignard addition
with vinylmagnesium bromide in THF. A diastereomeric
mixture of partially protected triols -xylo-7/-lyxo-7 in a
69:31 ratio and 63% yield was obtained. Finally, benzylation
Scheme 3. Synthesis of sulfone 14. Reagents and conditions:
of the free hydroxy function of 7 and acidic hydrolysis of the (a) PdCl2 (0.1 equiv.), CuCl2 (3 equiv.), AcONa (3 equiv.), AcOH,
room temp., 12 h; (b) TMSCl, TBAI, HCI, CH2CI2, room temp.,
acetonide protecting group furnished the required intermedi-
ate for bicyclisation, α-benzyl-protected 9, with the -xylo
configuration along with its diastereomer -lyxo-9.
2 d, 61% from -xylo-9; (c) DIAD (5 equiv.), Ph3P (5 equiv.), p-
NBA (5 equiv.), reflux, 2 h, 57%; (d) KSPT, DMF, room temp.,
8 h, 76%; (e) MoVI/H2O2, EtOH, THF, 0 °C to room temp., 10 h,
89%. TMSCl = trimethylsilyl chloride, TBAI = tetrabutylammo-
nium iodide, DIAD = diisopropyl azodicarboxylate, p-NBA = p-
nitrobenzoic acid, KSPT = potassium 1-phenyl-1H-tetrazol-5-
thiolate, PNB = p-nitrobenzoyl.
The reaction was carried out under standard conditions
with PdCl2 as catalyst (0.1 equiv.), CuCl2 as oxidant
(3 equiv.) and NaOAc (3 equiv.) in acetic acid as buffer at
room temperature. Only -xylo-9 diastereomer was trans-
formed into required bicycle 10, with high substrate and
threo selectivity as expected.[9b,9c] The products of the trans-
formation of the other diastereomer were not identified.
Treatment of the crude material with TBAI/TMSCl/HCl in
CH2Cl2 at room temperature furnished iodide 11 (61%
yield from -xylo-9), as a product of the exo-regioselective
ring-opening reaction of bicyclic skeleton 10.
Next, the configuration at C3 was inverted by Mitsunobu
reaction with DIAD/PPh3/p-nitrobenzoic acid in THF to
afford iodide 12 (57%). Nucleophilic displacement of iodine
with potassium thiolate efficiently installed the phenyl-
tetrazole sulfide moiety (88% yield) and subsequent oxi-
dation with hydrogen peroxide/ammonium molybdate com-
pleted the construction of sulfone 14 in 89% yield. Single-
crystal X-ray analysis[18] secured the structure of 14 with
correct absolute configuration of all stereogenic centres
(Figure 1).
Scheme 2. Synthesis of -lyxo-9/-xylo-9. Reagents and conditions:
(a) ref.[15] DMP, PTSA, benzene, 98%; (b) ref.[16] NaBH4, MeOH,
80%; (c) ref.[17] TsCI, Bu4NHSO4, 15% NaOH, CH2Cl2, 86%;
(d) ref.[17] LAH, Et2O, 76%; (e) (COCl)2, DMSO, Et3N, CH2CI2,
–78 °C to room temp., 2 h; (f) vinylmagnesium bromide, THF, 0 °C
to room temp., 12 h, 63% from 5 (anti/syn, 69:31); (g) BnBr, NaH,
DMF, 0 °C to room temp., 12 h, 76%; (h) 60% AcOH, room temp.,
10 h, 83%. DMP = 2,2-dimethoxypropane, PTSA = p-toluenesul-
fonic acid.
710
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 709–715

Total Synthesis of (+)-Varitriol
Figure 1. An ORTEP view of the crystal and molecular structure
of sulfone 14.
In the next steps of the synthesis, the set up of the free
hydroxy groups was required. Because many attempts using
various protocols for debenzylation of the hydroxy function
at C4 had failed, this seemed to be a dead end to this ap-
proach. Fortunately, removal of the benzyl protecting group
of iodide 12 was successfully achieved by smooth reaction
with BCl3 in CH2Cl2 at –50 °C,[19] even though concomitant
partial migration of the p-nitrobenzoyl moiety (Scheme 4)
took place; a mixture of isomers 15 and 16 in a 71:29 ratio
and 81% yield was obtained. As the protecting groups for
the OH functionalities were to be removed in the final step,
the synthesis continued with the acetylation of the 15/16
mixture by using acetic anhydride and pyridine in the pres-
ence of DMAP to afford corresponding acetates 17/18
(90%, 1:1 ratio). Finally, the suitably protected sulfone frag-
ment 2 for the Kocien´ski–Julia olefination was prepared as
described above. A two-step substitution/oxidation se-
quence completed the synthesis of 21/22 as an equimolar
mixture.
Scheme 4. Synthesis of varitriol [(+)-1]. Reagents and conditions:
(a) BCl3, CH2Cl2, –50 °C, 50 min, 81% (71:29); (b) Ac2O, DMAP,
pyridine, room temp., 3 h, 90% (50:50); (c) KSPT, DMF, room
temp., 8 h, 84% (50:50); (d) MoVI/H2O2, EtOH, THF, 0 °C to room
temp., 10 h, 87% (50:50); (e) KHMDS (1.4 equiv.), DME, –55 °C
to room temp., 10 h; (f) NaOMe, MeOH, room temp., 4 h, 63%
over 2 steps. DMAP = 4-(dimethylamino)pyridine, KHMDS = po-
tassium hexamethyldisilazane.
= 0.53, MeOH)} closely matched the value reported by Tay-
lor et al.[6] for unnatural (–)-1 {[α]2D0 = –40.6 (c = 1.6,
MeOH)}. However, it was substantially distinct from all
other values reported in the literature {ref.[3] [α]D25 = +18.5
(c = 2.3, MeOH), ref.[7] [α]2D8 = +19.4 (c = 0.16, MeOH),
ref.[5] [α]2D5 = –18.2 (c = 0.0033, MeOH). Therefore, we de-
cided to definitively clear the situation regarding the abso-
lute configuration and corresponding specific rotation of
natural varitriol. Thus, we performed a single-crystal X-ray
analysis[18] of the obtained compound (Figure 2) and mea-
sured its optical activity. On the basis of the results, the
absolute configuration was determined as to be the same as
published by Malmstrøm.[3] Hence we believe we have fi-
nally set straight the correct specific rotation for varitriol.
Fragment 3, 2-formyl-6-methoxybenzyl acetate, was pre-
pared in 88%[20] yield from 2,3-dimethylanisole by adopting
a known three-step procedure.[14]
With both key fragments in hand we then looked at the
key Kocien´ski–Julia olefination[13] of aldehyde 3 with the
mixture of sulfones 21/22. The coupling was performed un-
der various reaction conditions by using different bases and
solvents. The best result, in terms of both E selectivity (only
the E isomer was observed) and yield was achieved with
KHMDS (1.4 equiv.) in dimethoxyethane by adopting the
so-called Barbier protocol.[13c] The base was added to the
mixture of sulfones 21/22 and an excess amount of aldehyde
3 (5 equiv.) at –55 °C, and the mixture was stirred at room
temperature for 10 h. The final global removal of the acetyl
and benzoyl protecting groups with NaOMe in MeOH ap-
plied on the crude mixture of isomers furnished the desired
natural varitriol. Purification by flash chromatography pro-
vided analytically pure (+)-1 as a white solid in 63% yield,
which was crystallised from EtOAc/hexanes (1:1) to furnish
colourless needles. The spectroscopic data of (+)-1 were in
good agreement with those obtained from a natural
Figure 2. An ORTEP view of the crystal and molecular structure
of natural (+)-varitriol [(+)-1].
Conclusions
In summary, natural varitriol was synthesised in 17 steps
source,[3] as well as with the synthetic probes.[5–7] Our mea- from commercially available dimethyl -tartrate and di-
sured value of specific rotation for (+)-1 {[α]2D0 = +43.4 (c methylanisole. Tetrahydrofuran derivative 11 with a trans
Eur. J. Org. Chem. 2009, 709–715
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
711

M. Palík, O. Karlubíková, A. Lásiková, J. Kozísˇek, T. Gracza
ˇ
FULL PAPER
phase was extracted with Et2O (5ϫ250 mL). The combined or-
ganic phase was dried with Na2SO4 and concentrated. The residue
arrangement of the substituents at C4–C5 was constructed
by using a bicyclisation strategy in two steps, namely, sub-
strate and diastereoselective PdII–CuII-catalysed bicycli-
sation of -lyxo-9/-xylo-9 unsaturated polyols followed by
exo-regioselective ring opening of bicyclic dianhydroalditol
10. The furanoside subunit of 1 with correct stereochemis-
try at all stereogenic centres was achieved by inversion of
configuration at C3 by using the Mitsunobu reaction. For
the first time the absolute configuration of natural (+)-vari-
triol was confirmed by X-ray analysis.
was distilled with
0.15 Torr) to afford 7 (9.14 g, 63% after two steps) as a mixture of
diastereomers -lyxo-7/-xylo-7 (69:31, GC–MS). Rf 0.64
a Kugelrohr (bath temp. 120–130 °C/0.1–
=
1
(EtOAc/hexanes, 1:1). Data for the mixture of isomers: H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.28 (d, J1,2 = 6.04 Hz, 3 H, 1-H,
minor), 1.30 (d, J1,2 = 6.04 Hz, 3 H, 1-H, major), 1.41, 1.43 (all s,
4ϫ3 H, all CH3), 2.48 (br. s, 2ϫ1 H, 2ϫOH), 3.55 (dd, J = 4.7,
8.1 Hz, 1 H, 3-H, minor), 3.62 (dd, J = 4.1, 8.1 Hz, 1 H, 3-H,
major), 3.96–4.14 (m, 3 H), 4.32–4.37 (m, 1 H), 5.20–5.45 (m, 4
H, 2ϫ6A-H, 6B-H), 5.80–5.95 (m, 2 H, 2ϫ5-H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 18.2 (q, 1-C, minor), 19.19 (q, 1-C,
major), 26.8, 27.4 (2ϫq, 2ϫCH3, major), 26.9, 27.4 (2ϫq,
2ϫCH3, minor), 71.6, 72.5 (2ϫd, 2-C, 4-C, major), 72.5, 73.3 (all
d, 2-C, 4-C, minor), 84.3 (d, 3-C, major), 84.8 (d, 3-C, minor),
109.4 [s, C(CH3)2, major], 110.2 [s, C(CH3)2, minor], 116.8 (t, 6-C,
major), 117.1 (t, 6-C, minor), 135.6 (d, 5-C, major), 136.9 (d, 5-C,
minor) ppm.
Experimental Section
General Procedure: 1H (13C) NMR spectra were recorded with
either a 300 (75) MHz or 600 (150) MHz Varian spectrometer.
Chemical shifts (δ) are quoted in ppm and are referenced to tet-
ramethylsilane (TMS) as internal standard. High-resolution mass
spectra (HRMS) were recorded with a Kratos Concept-IS mass
spectrometer and are accurate to Ϯ0.001. Optical rotations were
measured with a POLAR -µP polarimeter (IBZ Messtechnik) with
a water-jacketed 10.000 cm cell at the wavelength of the sodium D
line (λ = 589 nm). Elemental analyses were run with a FISONS
EA1108 instrument. Infrared spectra were recorded with either a
Philips Analytical PU9800 FTIR spectrometer or a Perkin–Elmer
1750 FTIR spectrophotometer as KBr discs or as thin films on
KBr plates (film). Melting points were obtained by using a Boecius
apparatus and are uncorrected. 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 chromatography (FLC) was performed on silica gel Kieselgel
60 (40–63 µm, 230–400 mesh), and analytical thin-layer chromatog-
raphy (TLC) was performed on aluminum plates precoated 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 visualised by UV fluorescence and by dipping the plates in an
aqueous H2SO4 solution of cerium sulfate/ammonium molybdate
followed by charring with a heat gun.
L-lyxo-8 and L-xylo-8: A suspension of hexanes-washed NaH (60%
in paraffin, 6.1 g, 151 mmol, 1.3 equiv.) in dry DMF (100 mL) was
cooled to 0 °C and a solution of -lyxo-7/-xylo-7 (69:31, 19.981 g,
116 mmol) in DMF (120 mL) was added dropwise over 45 min.
The resulting mixture was stirred for 15 min and benzyl bromide
(25.83 g, 151 mmol, 1.3 equiv.) was added in one portion by sy-
ringe. The reaction mixture was left to stir at room temperature
overnight and it was then quenched with MeOH (10 mL). The vol-
atiles were removed in vacuo, and the residue was dissolved in water
(80 mL) and extracted with EtOAc (5ϫ130 mL). The combined
organic phase was dried (Na2SO4). After concentration at 30–
40 °C/15 Torr, the remaining residue was purified by flash
chromatography (EtOAc/hexanes, 1:10) to afford 8 (23.1 g, 76%)
as a colourless oil and as a mixture of isomers -lyxo-8/-xylo-8
(69:31). Rf = 0.72 (EtOAc/hexanes, 1:8). Data for the mixture of
isomers: 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.24 (d, J5,6
=
6.0 Hz, 3 H, 1-H, minor), 1.32 (d, J5,6 = 6.1 Hz, 3 H, 1-H, major),
1.36, 1.41 (all s, 4ϫ3 H, all CH3), 3.62–3.69 (m, 2 H), 3.78–4.05
(m, 4 H), 4.41 (d, J = 12.2 Hz, 1 H, CH2Ph, major), 4.45 (d, J =
12.2 Hz, 1 H, CH2Ph, minor), 4.65 (d, J = 12.2 Hz, 1 H, CH2Ph,
major), 4.69 (d, J = 12.2 Hz, 1 H, CH2Ph, minor), 5.28–5.41 (m, 4
H, 2ϫ6A-H, 6B-H), 5.72–5.92 (m, 2 H, 2ϫ5-H), 7.25–7.37 (m,
2ϫ5 H, 2ϫPh) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 18.6
(q, 1-C, minor), 19.0 (q, 1-C, major), 26.7, 27.38 (all q, 2ϫCH3,
major), 26.8, 27.4 (all q, 2ϫCH3, minor), 70.1 (t, CH2Ph, minor),
71.5 (t, CH2Ph, major), 73.2, 80.0, 83.8 (all d, 2-C, 3-C, 4-C,
minor), 74.9, 80.8, 83.8 (all d, 2-C, 3-C, 4-C, major), 108.40 [s,
C(CH3)2, minor], 108.5 [s, C(CH3)2, major], 119.5 (t, 6-C, major),
119.6 (t, 6-C, minor), 127.4, 127.5, 127.6, 127.8, 128.2, 128.3 (all
d, Ph), 134.5 (d, 5-C, minor), 135.1 (d, 5-C, major), 138.1 (s, i-Ph,
major), 138.3 (s, i-Ph, minor) ppm.
6: A solution of DMSO (14.81 g, 189.6 mmol, 2.25 equiv.) in
CH2Cl2 (130 mL) was slowly added to a solution of oxalyl chloride
(15.939 g, 126.6 mmol, 1.5 equiv.) in CH2Cl2 (130 mL) at –78 °C
and stirred for 30 min under an atmosphere of argon. A solution
of 5 (12.335 g, 84.3 mmol) in CH2Cl2 (130 mL) was added dropwise
at –78 °C. After 30 min stirring at –78 °C, Et3N (47.1 mL,
337.2 mmol, 4 equiv.) was added. After 1 h at –78 °C, the mixture
was warmed to room temperature over 1 h. The mixture was con-
centrated in vacuo, diluted with diethyl ether and filtered through
a silica gel pad. The filtrate and washings were combined and con-
centrated under reduced pressure. The crude product (17.9 g) was
used without further purification in the next step. Rf = 0.57
(EtOAc/hexanes, 1:1)
L-lyxo-9 and L-xylo-9: A solution of diastereomers -lyxo-8/-xylo-
8 (69:31) (22 g, 83.86 mmol) dissolved in 60% AcOH (10 mL) was
left to stir at room temperature for 10 h. The solvents were removed
in vacuo, and the crude product was purified by FLC (EtOAc/hex-
anes, 1:8). Yield: 15.49 g (83%); colourless viscous oil. Data for the
L-lyxo-7 and L-xylo-7: A dry flask was charged with Mg turnings
(3.15 g, 134.6 mmol, 1.59 equiv.) and a few crystals of iodine and
then heated under an atmosphere of argon until the iodine started
1
to sublime.
A
solution of vinyl bromide (10 mL, 15.17 g,
mixture of isomers: H NMR (300 MHz, CDCl3, 25 °C): δ = 1.18
141.2 mmol, 1.67 equiv.) in dry THF (80 mL) was added dropwise
to start a vigorous exothermic reaction. The reaction mixture was
left at reflux for 1 h, until no magnesium remained in the flask and
subsequently cooled to 0 °C. Crude aldehyde 6 (17.5 g) in THF
(120 mL) was added, and the solution was left to stand overnight
(12 h) and then quenched with saturated solution of NH4Cl
(20 mL). Ether (100 mL) was added, and the separated aqueous
(d, J1,2 = 6.4 Hz, 3 H, 1-H, major), 1.19 (d, J1,2 = 6.4 Hz, 3 H, 1-
H, minor), 2.30–2.71 (br. s, 4 H, 4ϫOH), 3.30–3.35 (m, 1 H,
minor), 3.38–3.43 (m, 1 H, major), 3.80–4.07 (m, 4 H), 4.34 (d, J
= 11.7 Hz, 1 H, CH2Ph, minor), 4.39 (d, J = 11.6 Hz, 1 H, CH2Ph,
major), 4.65 (d, J = 11.6 Hz, 1 H, CH2Ph, major), 4.66 (d, J =
11.6 Hz, 1 H, CH2Ph, minor), 5.33–5.44 (m, 4 H, 2ϫ6A-H, 6B-
H), 5.78–5.92 (m, 2 H, 2ϫ5-H), 7.26–7.38 (m, 10 H, 2ϫPh) ppm.
712
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 709–715

Total Synthesis of (+)-Varitriol
13C NMR (300 MHz, CDCl3, 25 °C): δ = 19.2 (q, 1-C, major), 19.9
(q, 1-C, minor), 66.4, 75.8, 81.8 (all d, 2-C, 3-C, 4-C, major), 67.4,
75.9, 81.9 (all d, 2-C, 3-C, 4-C, minor), 70.3 (t, CH2Ph, minor),
J4,5 = 6.7 Hz, 1 H, 5-H), 3.98 (dd, J3,4 = 5.6 Hz, J4,5 = 6.6 Hz, 1
H, 4-H), 4.34 (dq, J2,3 = 4.2 Hz, JMe,2 = 6.5 Hz, 1 H, 2-H), 4.52
(d, J = 11.4 Hz, 1 H, CH2Ph), 4.59 (d, J = 11.4 Hz, 1 H, CH2Ph),
71.0 (t, CH2Ph, major), 119.9 (t, 6-C, major), 120.3 (t, 6-C, minor), 5.12 (dd, J2,3 = 4.2 Hz, J3,4 = 5.5 Hz, 1 H, 3-H), 7.23–7.26 (m, 5
127.8, 127.9, 127.9, 128.0, 128.6, 128.5 (all d, Ph), 134.6 (d, 5-C, H, Ph), 8.21 (d, Jo,m = 9.0 Hz, 2 H, o-NO2C6H4), 8.29 (d, Jo,m
major), 137.9 (d, 5-C, minor), 137.6 (s, i-Ph, minor), 137.6 (s, i-Ph, 9.0 Hz, 2 H, m-NO2C6H4) ppm. 13C NMR (75 MHz, CDCl3,
=
major) ppm.
25 °C): δ = 7.6 (t, CH2I), 19.5 (q, Me), 73.3 (t, CH2Ph), 77.6, 78.2,
80.0, 80.9 (all d, 2-C, 3-C, 4-C, 5-C), 123.6, 128.0, 128.2, 128.5,
130.9 (all d, C6H4NO2), 135.1, 137.1, 150.7 (all s, i-C6H4NO2),
164.1 (s, CO) ppm. C20H20INO6 (497.28): calcd. C 48.31, H 4.05,
N 2.82; found C 49.12, H 4.12, N 2.81.
10: A mixture of -lyxo-9/-xylo-9 (2.656 g, 11.95 mmol, 69:31),
PdCl2 (212 mg, 1.19 mmol, 0.1 equiv.), anhydrous CuCl2 (4.822 g,
35.84 mmol, 3 equiv.) and anhydrous AcONa (2.94 g, 35.84 mmol,
3 equiv.) in glacial AcOH (75 mL) was stirred at 25–30 °C under
an atmosphere of argon for 12 h. The solvent was evaporated in
vacuo, and the residue was distributed between an aqueous solu-
tion of ammonia (10%, 250 mL) and AcOEt (100 mL). The water
phase was extracted with AcOEt (4ϫ200 mL). The combined or-
ganic extract was dried with sodium sulfate, filtered and concen-
trated under reduced pressure. Purification of the resultant residue
by FLC (160 g of silica gel; AcOEt/hexanes, 3:7) yielded bicycle 10
along with two other compounds (1.05 g) as a slightly yellow oil,
which was used in the next step as such.
13: Potassium 1-phenyl-1H-tetrazol-5-thiolate (48 mg, 0.221 mmol,
1.1 equiv.) was added to a solution of iodide 12 (100 mg, 0.2 mmol)
in DMF (5 mL) at room temperature. After stirring for 8 h, the
reaction mixture was concentrated in vacuo (20–30 °C/5 Torr), and
the crude residue was purified by flash chromatography (20 g of
silica gel; AcOEt/hexanes, 3:7) to afford sulfide 13 (96 mg, 88%) as
a yellow oil. Rf = 0.6 (EtOAc/toluene, 1:3). [α]D20 = +44.2 (c = 1.52,
CHCl ). IR (film): ν = 3056 (s), 3015 (s), 2976 (m), 2952 (s), 2873
˜
3
(m), 1728 (s), 1606 (m), 1597 (s), 1528 (s), 1500 (s), 1417 (s), 1386
(s), 1276 (s), 1130 (s), 1102 (s), 1014 (s), 984 (m), 912 (m), 873 (m),
1
760 (s), 721 (s), 695 (s) cm–1. H NMR (300 MHz, CDCl3, 25 °C):
11: A mixture of derivative 10 (1.05 g), trimethylsilyl chloride
(0.6 mL, 442 mg, 4.1 mmol, 1.1 equiv.), tetrabutylammonium io-
dide (2.715 g, 8.1 mmol, 2.2 equiv.) and aqueous concentrated HCl
(1.5 mL) was stirred in CH2Cl2 (14 mL) at room temperature for
2 d. The mixture was diluted with CH2Cl2 (40 mL) and washed
with an aqueous solution of Na2S2O3 (10%, 25 mL). The organic
phase was dried with MgSO4 and concentrated. The crude oil was
purified by flash chromatography (300 g of silica gel; toluene/
EtOAc, 3:1). Pure iodide 11 was isolated as a colourless oil
(787 mg, 61% after two steps corrected to the amount of pure -
xylo-9). Rf = 0.48 (toluene/EtOAc, 4:1), [α]2D0 = +14.2 (c = 0.6,
δ = 1.35 (d, JMe,2 = 6.6 Hz, 3 H, Me), 3.59 (dd, A of ABX, J5,HA
= 6.3 Hz, JHA,HB = 13.5 Hz, 1 H, CH2S), 3.86 (dd, B of ABX, J5,HB
= 4.2 Hz, JHA,HB = 13.5 Hz, 1 H, CH2S), 4.10 (dd, J3,4 = 6.0 Hz,
J4,5 = 7.2 Hz, 1 H, 4-H), 4.27 (dq, J2,3 = 3.9 Hz, JMe,2 = 6.3 Hz, 1
H, 2-H), 4.35 (ddd, X of ABX, J5,HB = 4.2 Hz, J5,HA = 6.6 Hz, J4,5
= 7.5 Hz, 1 H, 5-H), 4.50 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.57 (d, J
= 11.4 Hz, 1 H, CH2Ph), 5.12 (dd, J2,3 = 3.9 Hz, J3,4 = 5.7 Hz, 1
H, 3-H), 7.19 (s, 5 H, Ph), 7.55 (s, 5 H, Ph), 8.20 (d, Jo,m = 9.0 Hz,
2 H, o-C6H4NO2), 8.27 (d, Jo,m = 9.0 Hz, 2 H, m-C6H4NO2) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 19.5 (q, Me), 35.9 (t,
CH2S), 73.2 (t, CH2Ph), 77.3, 78.5, 79.2, 79.3 (all d, 2-C, 3-C, 4-C,
5-C), 123.5, 123.7, 128.3, 128.4, 129.8, 130.2, 130.9 (all d, NO2C6H4,
Ph), 133.4, 134.9, 136.9, 150.6, 153.9 (all s, i-C6H4NO2, i-Ph, i-Tetr),
164.0 (s, CO) ppm. C27H25N5O6S (547.58): calcd. C 59.22, H 4.60,
N 12.79, S 5.86; found C 59.42, H 4.65, N 12.67, S 5.77.
CHCl ). IR (film): ν = 3443 (s), 3030 (m), 2975 (m), 2931 (s), 2871
˜
3
(m), 1714 (w), 1454 (s), 1119 (s), 1071 (s), 1012 (s), 984 (s), 739 (s),
698 (s) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.29 (d, JMe,2
= 6.5 Hz, 3 H, Me), 1.89 (d, 1 H, OH), 3.28 (dd, B of ABX, J5,HB
= 4.9 Hz, JHA,HB = 10.3 Hz, 1 H, CH2I), 3.36 (dd, A of ABX, J5,HA
= 6.8 Hz, JHA,HB = 10.3 Hz, 1 H, CH2I), 3.80 (dd, J3,4 = 0.7 Hz,
J4,5 = 3.0 Hz, 1 H, 4-H), 3.89 (ddd, X of ABX, J4,5 = 3.0 Hz, J5,HB
= 4.9 Hz, J5,HA = 6.8 Hz, 1 H, 5-H), 4.02–4.07 (m, 1 H, 3-H), 4.15
(dq, J2,3 = 3.2 Hz, JMe,2 = 6.5 Hz, 1 H, 2-H), 4.63 (s, 2 H, CH2Ph),
7.35 (br. s, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
7.8 (t, CH2I), 13.5 (q, Me), 71.9 (t, CH2Ph), 77.0, 78.1, 82.8, 89.5
(all d, 2-C, 3-C, 4-C, 5-C), 127.9 (d, p-Ph), 127.8, 128.5 (all d, Ph),
137.5 (s, i-Ph) ppm. C13H17IO3 (348.18): calcd. C 44.84, H 4.92;
found C 44.74, H 4.95.
14: To a solution of sulfide 13 (96 mg, 0.18 mmol) in a mixture of
EtOH (3 mL) and THF (3 mL) was added a mixture of 35% aque-
ous H2O2 (0.4 mL, 5.28 mmol, 29.3 equiv.) and ammonium molyb-
date (40 mg, 0.032 mmol, 0.18 equiv.) at 0 °C. After stirring over-
night at room temperature, the reaction was diluted by the addition
of water (4 mL) and CH2Cl2 (5 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (5ϫ5 mL). The
combined organic layer was dried with MgSO4, filtered and con-
centrated in vacuo. Purification on silica gel (30 g; EtOAc/hexanes,
3:7) provided 14 (93 mg, 89%) as a white solid. Rf = 0.6 (EtOAc/
toluene, 1:3). M.p. 107–108 °C, colourless needles were obtained by
recrystallisation from EtOAc/hexanes (1:3). [α]2D0 = +32.6 (c = 1.3,
12: Diisopropyl azodicarboxylate (232 mg, 1.171 mmol, 1.2 equiv.)
was added to a solution of Ph3P (301 mg, 1.171 mmol, 2 equiv.) in
dry THF (3 mL) under an atmosphere of argon. After 1 h stirring
at room temperature,
a
solution of alcohol 11 (204 mg,
CHCl ). IR (KBr): ν = 3064 (w), 3030 (w), 2975 (m), 2931 (m),
˜
3
0.585 mmol) in THF (3 mL) and p-nitrobenzoic acid (192 mg,
1.171 mmol, 2 equiv.) was added. After 2 h at reflux, the solvent
was evaporated in vacuo (20–30 °C/10 Torr), and the crude residue
was purified by flash chromatography (50 g of silica gel, toluene)
to afford 12 (167 mg, 57%) as a yellow solid. Rf = 0.6 (EtOAc/
toluene, 1:3). M.p. 49–52 °C. [α]2D0 = +57.9 (c = 0.58, CHCl3). IR
1728 (s), 1672 (m), 1607 (m), 1529 (s), 1497 (w), 1448 (s), 1349 (s),
1308 (s), 1275 (s), 1103 (s), 1015 (m), 873 (m), 753 (s), 719 (s), 700
1
(s) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.20 (d, JMe,2
=
6.5 Hz, 3 H, Me), 3.71–3.73 (m, J = 2.7 Hz, J = 4.2 Hz, 2 H,
CH2SO2), 3.99 (dd, J3,4 = 5.7 Hz, J4,5 = 7.8 Hz, 1 H, 4-H), 4.16
(dq, J2,3 = 3.3 Hz, JMe,2 = 6.5 Hz, 1 H, 2-H), 4.35 (ddd, X of ABX,
(KBr): ν = 3435 (s), 3113 (w), 2970 (m), 2926 (m), 2851 (w), 1719 J5,HB = J5,HA = 4.8 Hz, J4,5 = 7.8 Hz, 1 H, 5-H), 4.39 (d, J =
˜
(s), 1608 (m), 1524 (s), 1350 (s), 1279 (s), 1269 (s), 1133 (s), 1123 11.7 Hz, 1 H, CH2Ph), 4.58 (d, J = 11.6 Hz, 1 H, CH2Ph), 5.06
1
(s), 1106 (s), 1015 (s), 870 (m), 754 (m), 719 (s), 702 (s) cm–1. H (dd, J2,3 = 3.5 Hz, J3,4 = 5.4 Hz, 1 H, 3-H), 7.20–7.25 (m, 5 H, Ph),
NMR (300 MHz, CDCl3 25 °C): δ = 1.42 (d, JMe,2 = 6.5 Hz, 3 H,
Me), 3.23 (dd, A of ABX, J5,HA = 4.6 Hz, JHA,HB = 10.9 Hz, 1 H,
CH2I), 3.39 (dd, B of ABX, J5,HB = 4.2 Hz, JHA,HB = 10.9 Hz, 1
H, CH2I), 3.80 (dddd, X of ABX, J5,HB = 4.3 Hz, J5,HA = 4.5 Hz,
7.58 (s, 5 H, Ph), 8.17 (d, Jo,m = 8.9 Hz, 2 H, o-C6H4NO2), 8.27 (d,
Jo,m = 8.9 Hz, 2 H, m-C6H4NO2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 19.4 (q, Me), 58.7 (t, CH2SO2), 73.4 (t, CH2Ph), 75.0,
76.0, 79.4, 79.5 (all d, 2-C, 3-C, 4-C, 5-C), 123.6, 125.6, 128.0,
Eur. J. Org. Chem. 2009, 709–715
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
713

M. Palík, O. Karlubíková, A. Lásiková, J. Kozísˇek, T. Gracza
ˇ
FULL PAPER
128.4, 128.6, 129.5, 130.9, 131.5 (all d, C6H4NO2, Ph), 133.0, 134.7,
136.7, 150.6, 153.9 (all s, i-C6H4NO2, i-Ph, i-Tetr), 163.9 (s, CO)
ppm. C27H25N5O8S (579.58): calcd. C 55.95, H 4.35, N 12.08, S
5.53; found C 55.75, H 4.41, N 11.96, S 5.48.
(2ϫq, COCH3), 74.8, 75.6, 76.2, 77.7, 80.2, 80.3, 80.6, 80.7 (all d,
2ϫ2-C, 3-C, 4-C, 5-C), 123.7, 123.7, 130.7, 130.8 (all d, C6H4NO2),
134.6, 134.7, 151.5, 151.9 (2ϫs, i-C6H4NO2), 163.5, 163.6 (2ϫs,
COC6H4NO2), 169.6, 169.7 (2ϫs, COCH3) ppm.
15 and 16: To a solution of 12 (1.474 g, 2.96 mmol) in CH2Cl2
(30 mL) at –50 °C was added BCl3 (0.236  in CH2Cl2, 50 mL,
11.84 mmol, 4 equiv.) dropwise by syringe. After 50 min at –50 °C,
the reaction was quenched by the addition of MeOH (10 mL) and
then concentrated in vacuo. The residual oil was purified by flash
column chromatography (40 g of silica gel; EtOAc/hexanes, 3:7) to
afford a mixture of 15 and 16 as a colourless oil (780 mg, 81%,
19 and 20: To a stirred solution of isomeric iodides 17/18 (1:1,
935 mg, 2.08 mmol) in DMF (40 mL) was added potassium 1-
phenyl-1H-tetrazolyl-5-thiolate (495 mg, 2.28 mmol, 1.1 equiv.) at
room temperature. After stirring overnight, the mixture was con-
centrated in vacuo and purified by flash chromatography (30 g sil-
ica gel; EtOAc/hexanes, 3:7) to afford a mixture of sulfides 19 and
20 as a colourless oil (874 mg, 84%, mixture of isomers in a 50:50
ratio by 1H NMR spectroscopy). Rf = 0.2 (EtOAc/hexanes, 2:8).
1
mixture of isomers in a 71:29 ratio by H NMR spectroscopy). Rf
= 0.3 (EtOAc/hexanes, 3:7). IR (film): ν = 3504 (m), 3111 (w), 2974 IR (film): ν = 2975 (m), 1747 (s), 1733 (s), 1606 (m), 1526 (s), 1499
˜
˜
(m), 1727 (s), 1607 (m), 1527 (s), 1349 (s), 1275 (s), 1126 (s), 1105
(s), 1349 (s), 1272 (s), 1120 (s), 1105 (s), 1015 (s), 873 (m), 763 (m),
(s), 1104 (m), 873 (m), 783 (w), 718 (s) cm–1. Data for the major
719 (s) cm–1. HRMS (ESI+): calcd. for C22H22N5O7S [M + H]+
1
isomer: H NMR (300 MHz, CDCl3, 25 °C, mixture of 15/16): δ = 500.1234; found 500.1236. Data for the major isomer: 1H NMR
1.43 (d, JMe,2 = 6.4 Hz, 3 H, Me), 2.07 (br. s, 1 H, OH), 3.38 (dd,
A of ABX, J5,HA = 4.9 Hz, JHA,HB = 10.8 Hz, 1 H, CH2I), 3.49
(dd, B of ABX, J5,HB = 4.6 Hz, JHA,HB = 10.8 Hz, 1 H, CH2I), 3.76
(ddd, X of ABX, J5,HB = 4.7 Hz, J5,HA = 4.9 Hz, J4,5 = 6.7 Hz, 1
(300 MHz, CDCl3, 25 °C, mixture of 19/20 in a 58:42 ratio): δ =
1.38 (d, JMe,2 = 6.4 Hz, 3 H, Me), 2.01 (s, 3 H, COCH3), 3.66 (dd,
A of ABX, J5,HA = 6.5 Hz, JHA,HB = 13.9 Hz, 1 H, CH2S), 3.93
(dd, B of ABX, JHA,HB = 14.0 Hz, 1 H, CH2S), 4.24 (dq, J2,3
=
=
H, 5-H), 4.27 (dd, J3,4 = 6.2 Hz, J4,5 = 6.7 Hz, 1 H, 4-H), 4.32 (dq, 4.2 Hz, JMe,2 = 6.4 Hz, 1 H, 2-H), 4.45 (dddd, X of ABX, J2,5
J2,3 = 4.6 Hz, JMe,2 = 6.4 Hz, 1 H, 2-H), 5.01 (dd, J2,3 = 4.6 Hz, 1.9 Hz, J4,5 = 4.2 Hz, J5,HA = 6.4 Hz, 1 H, 5-H), 5.17 (m, 2 H, 3-
J3,4 = 6.0 Hz, 1 H, 3-H), 8.23 (d, Jo,m = 9.0 Hz, 2 H, o-NO2C6H4), H, 4-H), 7.58–7.61 (m, 5 H, Ph), 8.20 (d, Jo,m = 9.1 Hz, 2 H, o-
8.31 (d, Jo,m = 9.0 Hz, 2 H, m-NO2C6H4) ppm. Data for the minor
isomer: H NMR (300 MHz, CDCl3, 25 °C, mixture of 15/16): δ = for the minor isomer: H NMR (300 MHz, CDCl3, 25 °C, mixture
NO2C6H4), 8.31 (d, Jo,m = 9.0 Hz, 2 H, m-NO2C6H4) ppm. Data
1
1
1.42 (d, JMe,2 = 6 Hz, 3 H, Me), 2.07 (br. s, 1 H, OH), 3.39 (dd, A
of ABX, J5,HA = 5.4 Hz, JHA,HB = 10.7 Hz, 1 H, CH2I), 3.45 (dd,
of 19/20 in a 58:42 ratio): δ = 1.35 (d, JMe,2 = 6.4 Hz, 3 H, Me),
2.00 (s, 3 H, COCH3), 3.69 (dd, A of ABX, J5,HA = 6.4 Hz, JHA,HB
B of ABX, J5,HB = 4.6 Hz, JHA,HB = 10.8 Hz, 1 H, CH2I), 4.06– = 14.0 Hz, 1 H, CH2S), 3.91 (d, B of ABX, JHA,HB = 14.0 Hz, 1
4.14 (m, 3 H, 2-H, 3-H, 5-H), 5.17 (dd, J4,5 = 3.9 Hz, J3,4 = 6.0 Hz,
1 H, 4-H), 8.23 (d, Jo,m = 9.0 Hz, 2 H, o-NO2C6H4), 8.31 (d, Jo,m
H, CH2S), 4.14 (dq, J2,Me = 6.4 Hz, J2,3 = 6.0 Hz, 1 H, 2-H), 4.54
(ddd, J2,5 = 4.1 Hz, J4,5 = 6.0 Hz, J5,HA = 6.4 Hz, 1 H, 5-H), 5.00
= 9.0 Hz, 2 H, m-NO2C6H4) ppm. Data for the major isomer: 13C (dd, J3,4 = 5.8 Hz, J4,5 = 5.9 Hz, 1 H, 4-H), 5.37 (dd, J3,4 = 5.9 Hz,
NMR (75 MHz, CDCl3, 25 °C, mixture of 15/16): δ = 7.0 (t, CH2I), J2,3 = 6.0 Hz, 1 H, 3-H), 7.56–7.57 (m, 5 H, Ph), 8.20 (d, Jo,m
=
19.3 (q, Me), 74.6, 77.7, 79.6, 81.5 (all d, 2-C, 3-C, 4-C, 5-C), 123.7, 9.1 Hz, 2 H, o-NO2C6H4), 8.31 (d, Jo,m = 9.0 Hz, 2 H, m-NO2C6H4)
130.8, (all d, C6H4NO2), 134.7, 150.8 (all s, i-C6H4NO2), 164.4 (s, ppm. 13C NMR (75 MHz, CDCl3, 25 °C, mixture of 19/20 in a
CO) ppm. Data for the minor isomer: 13C NMR (75 MHz, CDCl3,
25 °C, mixture of 15/16): δ = 6.7 (t, CH2I), 18.1 (q, Me), 75.8, 78.8,
58:42 ratio): δ = 18.7, 19.0 (2ϫq, Me), 20.4, 20.5 (2ϫq, COCH3),
35.6, 35.7 (2ϫt, CH2S), 72.9, 74.4, 75.5, 76.9, 78.2, 78.4, 78.6, 78.9
79.0, 80.5 (all d, 2-C, 3-C, 4-C, 5-C), 123.7, 130.9, (all d, (all d, 2ϫ2-C, 3-C, 4-C, 5-C), 123.7, 123.8, 123.9, 124.2, 129.7,
C6H4NO2), 134.6, 150.2 (all s, i-C6H4NO2), 164.4 (s, CO) ppm.
129.8, 129.9, 130.2, 130.7, 130.8 (all d, C6H4NO2, Ph), 133.4, 133.5,
134.4, 134.6, 150.8, 150.9, 153.7, 153.8 (all s, 2ϫi-C6H4NO2, i-
Ph, i-Tetr), 163.5, 163.6 (2ϫs, COC6H4NO2), 169.6, 169.6 (2ϫs,
COCH3) ppm.
17 and 18: To a stirred solution of 15/16 (71:29, 948 mg, 2.32 mmol)
in CH2Cl2 (50 mL) was added acetanhydride (0.44 mL, 4.65 mmol,
2 equiv.), pyridine (0.18 mL, 2.32 mmol, 1 equiv.) and DMAP
(3 mg, 0.02 mmol, 0.008 equiv.) at room temperature under an at-
mosphere of argon. The mixture was allowed to stir for 3 h, by
which time TLC (EtOAc/hexanes, 3:7) showed complete conversion
of the starting material. The solvent was then evaporated in vacuo.
Flash chromatography (35 g silica gel; EtOAc/hexanes, 3:7) af-
forded 17 and 18 as a colourless oil (941 mg, 90%, mixture of iso-
mers in a 50:50 ratio by 1H NMR spectroscopy). Rf = 0.6 (EtOAc/
21 and 22: Ammonium molybdate (355 mg, 0.287 mmol,
0.17 equiv.) and hydrogen peroxide (35% solution in H2O, 2.9 mL,
33.8 mmol, 25 equiv.) were combined at 0 °C and stirred for
15 min. This bright yellow solution was added dropwise to a cooled
(0 °C) solution of starting sulfides 19/20 (1:1, 844 mg, 1.69 mmol)
in the mixture of EtOH (15 mL) and THF (15 mL). The mixture
was allowed to stir overnight at room temperature and then concen-
hexanes, 3:7). IR (film): ν = 2977 (m), 1734 (s), 1608 (m), 1528 (s), trated in vacuo. The residue was partitioned between dichlorometh-
˜
1350 (s), 1227 (s), 1121 (s), 1105 (s), 1104 (m), 873 (m), 783 (w),
ane (25 mL) and water (15 mL). The water layer was washed with
dichloromethane (4ϫ20 mL). The combined organic phase was
718 (s) cm–1. Data for a 1:1 mixture of 17/18: 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 1.42 (d, JMe,2 = 6.2 Hz, 3 H, Me), 1.46 (d, JMe,2 dried with MgSO4 and concentrated under reduced pressure. Flash
= 6.3 Hz, 3 H, Me), 2.00 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3),
3.37–3.48 (m, J5,HA = 4.3 Hz, J5,HA = 4.9 Hz, J5,HB = 5.0 Hz,
JHA,HB = 9.8 Hz, JHA,HB = 10.9 Hz, 4 H, CH2I), 3.98 (ddd, J5,HA
= 4.9 Hz, J5,HB = J4,5 = 5.0 Hz, 1 H, 5-H), 4.09 (ddd, J5,HB = J5,HA
chromatography (30 g silica gel; EtOAc/hexanes, 3:7) afforded 21/
22 as a colourless viscous oil (779 mg, 87%, mixture of isomers in
a 50:50 ratio by 1H NMR spectroscopy). Rf = 0.5 (EtOAc/hexanes,
4:6). IR (film): ν = 2975 (m), 2931 (m), 1728 (s), 1672 (s), 1607 (m),
˜
= J4,5 = 4.9 Hz, 1 H, 5-H), 4.20 (dq, JMe,2 = J2,3 = 6.3 Hz, 1 H, 2- 1529 (s), 1448 (s), 1349 (s), 1319 (s), 1308 (s), 1275 (s), 1148 (s),
H), 4.29 (dq, J2,3 = 5.3 Hz, JMe,2 = 6.4 Hz, 1 H, 2-H), 4.99 (dd,
J2,3 = J3,4 = 6.4 Hz, 1 H, 3-H), 5.12–5.21 (m, J = 5.9 Hz, J =
5.3 Hz, 2 H, 3-H, 4-H), 5.33 (dd, J3,4 = 4.7 Hz, J2,3 = 6.1 Hz, 1 H,
1132 (s), 1015 (m), 873 (w), 753 (s), 719 (s) cm–1. HRMS (ESI+):
calcd. for C22H25N6O9S [M + NH4]+ 549.1398; found 549.1406.
Data for the major isomer: 1H NMR (300 MHz, CDCl3, 25 °C,
mixture of 21/22 in a 56:44ratio): δ = 1.26 (d, JMe,2 = 6.4 Hz, 3 H,
4-H), 8.20 (d, Jo,m = 9.1 Hz, 4 H, o-NO2C6H4), 8.33 (d, Jo,m
=
8.9 Hz, 4 H, m-NO2C6H4) ppm. 13C NMR (75 MHz, CDCl3, Me), 1.99 (s, 3 H, COCH3), 3.97–4.18 (m, 3 H, CH2SO2, 2-H), 4.46
25 °C): δ = 6.0, 6.2 (2ϫt, CH2I), 18.4, 18.8 (2ϫq, Me), 20.5, 20.6
714
(ddd, J5,HA = 3.2 Hz, J5,HB = 5.1 Hz, J4,5 = 6.3 Hz, 1 H, 5-H), 5.06
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 709–715

Total Synthesis of (+)-Varitriol
(dd, J2,3 = 5.9 Hz, J3,4 = 6.1 Hz, 1 H, 3-H or 4-H), 5.18 (dd, J3,4
= 5.9 Hz, J4,5 = 6.1 Hz, 1 H, 4-H or 3-H), 7.59–7.66 (m, 5 H, Ph),
8.19 (d, Jo,m = 9.0 Hz, 2 H, o-NO2C6H4), 8.32 (d, Jo,m = 8.9 Hz, 2
H, m-NO2C6H4) ppm. Data for the minor isomer: 1H NMR
(300 MHz, CDCl3, 25 °C, mixture of 21/22 in a 56:44ratio): δ =
1.23 (d, JMe,2 = 6.3 Hz, 3 H, Me), 2.03 (s, 3 H, COCH3), 3.97–4.18
(m, 3 H, CH2SO2, 2-H), 4.56 (ddd, J5,HA = 3.9 Hz, J5,HB = 4.7 Hz,
J4,5 = 5.8 Hz, 1 H, 5-H), 4.88 (dd, J2,3 = 6.1 Hz, J3,4 = 6.4 Hz, 1
H, 3-H or 4-H), 5.35 (dd, J4,5 = 5.9 Hz, J3,4 = 6.0 Hz, 1 H, 4-H or
3-H), 7.59–7.66 (m, 5 H, Ph), 8.16 (d, Jo,m = 8.9 Hz, 2 H, o-
NO2C6H4), 8.32 (d, Jo,m = 8.9 Hz, 2 H, m-NO2C6H4) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C, mixture of 21/22 in a 1:1 ratio): δ =
18.3, 18.6 (2ϫq, Me), 20.4, 20.5 (2ϫq, COCH3), 58.7, 58.8 (2ϫt,
CH2SO2), 73.2, 74.5, 74.8, 75.7, 75.8, 75.9, 78.3, 78.6 (all d, 2ϫ2-
C, 3-C, 4-C, 5-C), 123.7, 123.8, 125.4, 125.5, 129.6, 130.7, 130.8,
131.5 (all d, C6H4NO2, Ph), 133.0, 133.1, 134.0, 134.3, 143.2, 143.8,
153.8, 153.9 (all s, i-Ph, i-C6H4NO2, i-Tetr), 163.6, 163.7 (2ϫs,
COC6H4NO2), 169.6, 170.8 (2ϫs, COCH3) ppm.
Acknowledgments
This work was supported by Slovak Grant Agencies (VEGA, Slo-
vak Academy of Sciences and Ministry of Education, Bratislava,
project 1/3549/06 and 1/0817/08, APVV, Bratislava, project APVV-
20-000305), as well as the Structural Funds, Interreg IIIA for pur-
chasing the diffractometer. The authors are grateful to fy. Tau-
Chem. Ltd. (Bratislava) for supplying the chemicals. We thank Dr.
Peter Szolcsányi and Dr. Peter Zálupský for their help with the
preparation o the manuscript.
[1] D. Faulkner, J. Nat. Prod. Rep. 2000, 17, 7–55.
[2] W. Fenical, P. R. Jensen in Marine Biotechnology (Eds.: D. H.
Attaway, O. K. Zaborsky), Plenum Press, New York, 1993, vol.
1, pp. 419–457.
[3] J. Malmstrøm, C. Christophersen, A. F. Barrero, J. E. Oltra, J.
Justicia, A. Rosales, J. Nat. Prod. 2002, 65, 364–367.
[4] A. M. S. Mayer, K. R. Gustafson, Eur. J. Cancer 2004, 40,
2676–2704.
(+)-Varitriol {(+)-1}: To a stirred solution of 21/22 (65 mg,
0.122 mmol) and aldehyde 3 (127 mg, 0.608 mmol, 5 equiv.) in di-
methoxyethane (5 mL) was added KHMDS (15% in toluene,
0.260 mL, 0.170 mmol, 1.4 equiv.) at –55 °C. The reaction mixture
was warmed slowly to room temperature and stirred for 10 h. The
reaction was then quenched by the addition of water (0.2 mL) and
concentrated in vacuo. The crude product was dissolved in MeOH
(3 mL) and freshly prepared sodium methoxide (0.6  in MeOH,
1 mL) was added. The mixture was allowed to stir for 4 h, by which
time TLC (EtOAc/hexanes, 3:7) showed complete conversion of the
starting material. Strong acidic DOWEX (2 g) was added, and the
mixture was stirred for 30 min until the pH of the mixture was
neutral. The resin was filtered off, and the mixture was concen-
trated in vacuo. Purification (10 g silica gel; CH2Cl2/acetone, 3:2)
provided [(+)-1] (21.5 mg, 63%) as a white solid. Rf = 0.3 (CH2Cl2/
acetone, 3:2). M.p. 109–112 °C, colourless needles by recrystalli-
sation from EtOAc/hexanes, 1:1. [α]2D0 = +43.4 (c = 0.53, MeOH)
{ref.[3] [α]2D5 = +18.5 (c = 2.3, MeOH), ref.[7] [α]2D8 = +19.4 (c = 0.16,
MeOH), ref.[5] [α]2D5 = –18.2 (c = 0.0033, MeOH), ref.[6] [α]2D0 = –40.6
[5] R. T. Clemens, M. P. Jennings, Chem. Commun. 2006, 2720–
2721.
[6] G. D. McAllister, J. E. Robinson, R. J. K. Taylor, Tetrahedron
2007, 63, 12123–12130.
[7] V. Kumar, A. K. Shaw, J. Org. Chem. 2008, 73, 7526–7531.
[8] L. Nagarapu, V. Paparaju, A. Satyender, Bioorg. Med. Chem.
Lett. 2008, 18, 2351–2354.
[9] a) T. Gracza, T. Hasenöhrl, U. Stahl, V. Jäger, Synthesis 1991,
ˇ
1108–1118; b) M. Babjak, L. Remenˇ, P. Szolcsányi, P.
Zálupský, D. Miklosˇ, T. Gracza, J. Organomet. Chem. 2006,
ˇ
691, 928–940; c) M. Babjak, L. Remenˇ, O. Karlubíková, T.
Gracza, Synlett 2005, 1609–1611.
[10] a) T. Gracza, V. Jäger, Synlett 1992, 191–193; b) T. Gracza, V.
Jäger, Synthesis 1994, 1359–1368.
[11] a) M. Babjak, P. Kapitán, T. Gracza, Tetrahedron Lett. 2002,
43, 6983–6985; b) M. Babjak, P. Kapitán, T. Gracza, Tetrahe-
dron 2005, 61, 2471–2479.
[12] D. J. Dixon, S. V. Ley, T. Gracza, P. Szolcsányi, J. Chem. Soc.
Perkin Trans. 1 1999, 839–841.
[13] a) P. R. Blakemore, W. J. Cole, P. J. Kocien´ski, A. Morley, Syn-
lett 1998, 26–28; b) M. Julia, J.-M. Paris, Tetrahedron Lett.
1973, 14, 4833–4836; c) P. R. Blakemore, J. Chem. Soc. Perkin
Trans. 1 2002, 2563–2585.
[14] V. G. S. Box, G. P. Yianikorous, Heterocycles 1990, 31, 1261–
1270.
[15] M. Carmack, J. Ch. Kelley, J. Org. Chem. 1968, 33, 2171–2173.
[16] A. S. Batsanov, M. J. Begley, R. J. Fletcher, J. H. Murphy, M. S.
Sherbrun, J. Chem. Soc. Perkin Trans. 1 1995, 1281–1294.
[17] S. Valverde, B. Herradon, R. M. Rabanal, M. Martin-Lomas,
Can. J. Chem. 1987, 65, 332–338.
(c = 1.6, MeOH) for (–)-1}. IR (nujol): ν = 3385 (s), 2968 (m), 2929
˜
(m), 1597 (w), 1578 (s), 1472 (s), 1456 (m), 1439 (m), 1255 (s), 1091
1
(s), 1004 (s), 974 (m), 799 (w), 748 (w) cm–1. H NMR (300 MHz,
[D6]acetone, 25 °C): δ = 1.27 (d, JMe,2 = 6.2 Hz, 3 H, Me), 3.69
(dd, J2,3 = J3,4 = 5.7 Hz, 1 H, 3-H), 3.82 (s, 3 H, OCH3), 3.83 (dq,
J2,3 = 5.9 Hz, J2,Me = 6.2 Hz, 1 H, 2-H), 3.90 (dd, J3,4 = J4,5
5.6 Hz, 4-H), 4.28 (ddd, J5,2Ј = 1.2 Hz, J4,5 = 5.4 Hz, J5,1Ј = 6.5 Hz,
1 H, 5-H), 4.71 (s, 2 H, OCH2), 6.20 (dd, J1Ј,5 = 6.5 Hz, J1Ј,2Ј
=
=
15.8 Hz, 1 H, 1Ј-H), 6.89 (dd, J6Ј,8Ј = 1.1 Hz, J6Ј,7Ј = 8.0 Hz, 1 H,
6Ј-H), 7.13 (dd, J6Ј,8Ј = 1.1 Hz, J7Ј,8Ј = 8.0 Hz, 1 H, 8Ј-H), 7.13 (dd,
[18] CCDC-702733 (for 14) and -702734 [for (+)-1] contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[19] G. B. Jones, G. Hynd, J. M. Wright, A. Sharma, J. Org. Chem.
2000, 65, 263–265.
J5,2Ј = 1.2 Hz, J1Ј,2Ј = 15.8 Hz, 1 H, 2Ј-H), 7.19 (dd, J6Ј,7Ј = J7Ј,8Ј
=
8.0 Hz, 1 H, 7Ј-H) ppm. 13C NMR (75 MHz, [D6]acetone, 25 °C): δ
= 19.5 (q, Me), 55.2 (t, CH2OH), 56.1 (q, OCH3), 76.5 (d, 4-C),
77.2 (d, 3-C), 80.1 (d, 2-C), 85.4 (d, 5-C), 110.7 (d, 6Ј-C), 119.4 (d,
8Ј-C), 128.1 (s, 4Ј-C), 129.3 (d, 7Ј-C), 129.4 (d, 2Ј-C), 132.6 (d, 1Ј-
C), 139.1 (s, 3Ј-C), 159.0 (s, 5Ј-C) ppm. C15H20O5 (280.32): calcd.
C 64.27, H 7.19; found C 63.86, H 7.26.
[20] Synthesis of 3:
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental procedures and physical and spectro-
scopic data; structure refinement details of 14 and (+)-1; 1H and
13C NMR spectra for all new compounds.
Received: October 28, 2008
Published Online: January 7, 2009
Eur. J. Org. Chem. 2009, 709–715
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
715