Exploratory studies toward the synthesis of the peroxylactone unit of plakortolides

Article abstract of DOI:10.1016/j.tet.2012.03.024

Our efforts in construction the 1,2-dioxane ring of plakortolides through two approaches are described. The first one involved as a key step an acid catalyzed 6-endo ring closure of β-hydroperoxy trans-epoxides directed by a vinyl group adjacent to the ep

Full text of DOI:10.1016/j.tet.2012.03.024

Tetrahedron 68 (2012) 3717e3724
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploratory studies toward the synthesis of the peroxylactone unit
of plakortolides
*
ꢀ
Bogdan Barnych, Jean-Michel Vatele
ˇ
ꢁ
ꢁ
ꢁ
Universite Lyon 1, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS), UMR 5246 CNRS, Equipe SURCOOF, bat. Raulin 43, Bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Our efforts in construction the 1,2-dioxane ring of plakortolides through two approaches are described.
The first one involved as a key step an acid catalyzed 6-endo ring closure of b-hydroperoxy trans-ep-
Received 13 February 2012
Received in revised form 6 March 2012
Accepted 7 March 2012
oxides directed by a vinyl group adjacent to the epoxide function. By this route, an advanced in-
termediate of plakortolides was obtained in six steps and 35% overall yield. The second approach
featured a 1,2-dioxane ring forming by a double opening of bis-epoxides by ethereal hydrogen peroxide.
This reaction did not proceed in the expected sense and exclusive formation of hydroperoxy tetrahy-
dropyran derivatives was observed via a tandem oxacyclizationehydroperoxidation sequence.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 13 March 2012
Keywords:
Cyclization
Endoperoxides
Hydroperoxides
Hydroperoxysilylation
Plakortolides
1. Introduction
H
O
O
2
3
4
O
6
Marine sponges of the family Plakinidae have been reported to
be a rich source of cyclic peroxides, many of which exhibit anti-
microbial, antitumor, antifungal, and antiparasitic activities.1 The
majority of these natural products contain six-membered peroxide
rings (1,2-dioxane). In addition, a few 1,2-dioxolane carboxylates
with methyl substituents at the C3, C5 positions have been reported.
Plakortolides, one of the family of secondary metabolites found in
these sponges, have for most of them, an aromatic ring connected
via a methylene chain to a 4,6-dimethyl peroxylactone ring.2 They
differ in absolute configuration at C3, C4, C6, the substituted pattern,
the level of unsaturation and the chain length. A representative
sample of plakortolides is depicted in Fig. 1.
The first total synthesis of racemic plakortolide I was achieved
by the Jung group using a [2þ4] photocycloaddition of a singlet
oxygen to a diene and iodolactonization as key steps.3 We recently
reported the synthesis of (ꢀ)-ent-plakortolide I involving the
elaboration of the 1,2-dioxane ring by intramolecular Michael ad-
dition of an hydroperoxide to a butenolide.4
R2
O
R1
R2 = (CH2)8Ph
R1 = Me
Plakortolide E 1
Plakortolide I 2
Plakortolide M 3
6-(epi)-1
R2 = (CH2)10p-PhOH
R1 = Me
R1 = Me
Plakortolide O 4
R2 =
Ph
6
Fig. 1. Representative examples of plakortolides.
application of this concept to forge the 1,2-dioxane ring system of
plakortolides from b-hydroperoxy vinyl cis-trisubstituted epoxides.
Unfortunately, the vinyl group had no directing effect and the
cyclization followed Baldwin’s rules to give exclusively five-
membered peroxides (1,2-dioxolanes).6 Assuming that the cis
configuration of epoxides disfavored the 6-endo ring closure due to
steric congestions in the transition state,7 we decided to modify our
strategy by using vinyl trans-1,2-disubstituted epoxides known to
afford predominately in the majority of cases 6-endo cyclized
products7 and we describe here the results of this study.
Our retrosynthetic analysis, summarized in Scheme 1, was dic-
tated in part by our strategy of 1,2-dioxane ring forming and with
the goal of using a common precursor for the synthesis of pla-
kortolides 1e4. Disconnection of 1e4 at the lactone function and
the C7eC8 bond led to common intermediate 5. Methyl group at C4
As a part of an ongoing project devoted to the directing effect of
a double bond in the regiocontrol of intramolecular opening of
vinyl epoxides with nucleophiles via disfavored 5- or 6-endo
modes,5 we have recently reported
a study concerning the
* Corresponding author. Tel.: þ33 472431151; e-mail address: vatele@uni-
ꢀ
v-lyon1.fr (J.-M. Vatele).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.024

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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3718
could be installed via a diastereoselective addition of an organo-
metallic reagent to the corresponding ketone of alcohol 6. Guided
by our approach of 1,2-dioxane ring forming based on anti-Baldwin
triphenylphosphine dibromide in the presence of imidazole.14
Cu(II)-catalyzed coupling between propargyl alcohol and allylic
bromide 10b afforded the enyne 8b in good yield, which, in the
presence of LiAlH4 or Red-Al, again decomposed. We next explored
another strategy for synthesizing the diene 13a, which is based on
indium-mediated anti-Markovnikov allylation of alkynols.15 To our
dismay, treatment of propargyl alcohol with an excess of the allylic
iodide 14 and indium metal provided the desired product 13 in low
yield accompanied by 14 dimer.
6-endo cyclization of b-hydroperoxy vinyl epoxides, disconnection
of C3eO bond within 6 revealed the trans epoxide 7. This latter
could arise from 8 via regioselective hydroperoxysilylation de-
veloped by Mukaiyama and Isayama8 and conventional functional
manipulations.
Scheme 3. Hypothetic fragmentation pathway of 8a.
The inability to synthesize 1,4-dienols 13a,b forced us to revise
our synthetic plan and especially that of the advanced precursor 6
(Scheme 1). As seen in Scheme 4, we envisioned that the 1,2-
dioxane 6 should be accessible by an acid catalyzed double open-
ing of the bis-epoxide 15 by hydrogen peroxide. Although no study
was reported on the synthesis of 1,2-dioxanes from diepoxides, this
approach appeared for us viable since C2 and C5, the required attack
sites of H2O2, are the most reactive centers in 15. Pursuing the
retrosynthetic analysis, vinyl bis-epoxide 15 could arise from the
known unsaturated epoxy alcohol 16 by conventional functional
manipulations.
Compound 16 was obtained, via a slightly modified literature
procedure,16 by Cu(II)-catalyzed coupling between propargyl alco-
hol and methallyl chloride 17, under Jeffery conditions,17 hydride
reduction and Sharpless epoxidation in 53% over three steps
(Scheme 5). Exposure of 16 to mCPBA afforded the diepoxy alcohol
20 as a mixture of 1/1 diastereomers, which was subsequently
transformed to the requisite target 15 by TEMPO/BAIB oxidation
and Wittig olefination in 70% overall yield. With bis-epoxide 15 in
hand, we study the tandem epoxide opening-cyclization reaction
with anhydrous hydrogen peroxide in acid media (Scheme 6).18
Scheme 1. Retrosynthetic analysis for plakortolides 1e4.
2. Results and discussion
The synthesis of enyne 8a (PG¼PMB) started by the reaction of
commercially available allyl dichloride 9 with sodium p-methox-
ybenzyl alcoholate to afford mainly the monosubstitution product
10a in 64% yield (Scheme 2).9 The coupling of 10a with propargyl
alcohol was best realized using stoichiometric amounts of CuI and
NaI in DMF to produce the monoprotected enyne diol 8a in 62%
yield.10 Unfortunately, all attempts to perform the reduction of the
triple bond of 8a to trans alkene 13a with LiAlH4 or Red-Al led to
decomposition to give p-methoxybenzyl alcohol as the sole iden-
tified product in the 1H NMR spectrum of the reaction mixture.
Other reducing agents, such as nBuLieDIBAL11 and chromium(II)
chloride12 gave rise to, respectively, no reaction or very slow re-
duction [61% yield (83% conversion) after 21 days].
Scheme 2. Attempts synthesis of dienol 13.
In the presence of aluminum hydrides, we supposed that the
propargylic alcohol 8a formed the cyclic organoaluminium com-
pound 15, which then gave a Grob fragmentation type reaction
facilitated by the activation of the p-methoxybenzyl group by
electrophilic species present in the medium (Scheme 3). Assuming
that replacing the PMB protecting group by a non-chelating group,
such as TBS group will avoid the fragmentation, the mono TBS
protected 1,4-enyne diol 8b was prepared starting from the Bay-
liseHilmann adduct 11.13 This compound was transformed in three
steps and 66% yield to the allylic bromide 10b by successive pro-
tection of the alcohol function as a TBS group, reduction of the ester
function and bromination of the resulting alcohol 12 employing
Whatever the conditions used, the hydroperoxide 22 was isolated
as a major product. In the optimized conditions, namely in the
presence of a large excess of hydrogen peroxide and a catalytic
amount of phosphomolybdic acid, 22 was obtained in 40% yield as
a 1/1 mixture of diastereomers separable by flash chromatography.
The structure of 22a,b was ascertained by 1D and 2D NMR spec-
troscopy and the most representative NOE correlations are pre-
sented in Fig. 2. Based on the mechanism of oxacyclization of
polyepoxides to fused polycyclic ether natural product skeletons
reported by McDonald and co-workers,19 we hypothesized that
formation of tetrahydropyran compounds 22a,b began by acid co-
ordination to the vinyl epoxide followed by nucleophilic addition of

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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3719
the second epoxide to form an epoxonium intermediate 24
(Scheme 6). Addition of H2O2 to the most highly substituted carbon
of bridged oxonium ion 24 afforded the hydroperoxide 22. A con-
certed oxacyclization process rather than a stepwise mechanism is
not excluded.
Scheme 7. Tandem oxacylisationeperoxidation on compound 25.
approach and searched in the literature for intermediate 13
(Scheme 2) substitutes accessible in a few steps and in a stereo-
selective fashion. Fortunately, we found a good candidate corre-
sponding to our demand, compound 29, the superior homolog of
13.21 Except for the elaboration of the side chain, the synthetic
strategy for plakortolides from 29 was essentially the same than
that depicted in Scheme 1 (Scheme 8).
Scheme 4. Second retrosynthetic analysis for 1,2-dioxane 6.
Scheme 8. A third synthetic approach for plakortolides 1e4.
Scheme 5. Synthesis of diepoxide 15 from methallyl chloride.
The synthesis of dienol 29 started by the reported EtAlCl2-cat-
alyzed ene reaction between methyl propiolate and the TIPS ether
of commercially available 3-methyl-3-buten-1-ol, compound 30
(Scheme 9). Our initial attempts to reproduce this ene reaction,
gave invariably low yields of the desired ester (35e55%).21
Scheme 6. Tandem oxacylisationeperoxidation on compound 15.
Fig. 2. Key NOE correlations observed for 22a,b.
Scheme 9. Synthesis of the peroxide 28 via an ene reaction.
The applicability of this acid catalyzed oxacycliza-
tionehydroperoxydation reaction was tested on another substrate,
compound 25 prepared by epoxidation of commercially available
2,5-dimethyl-1,5-hexadiene.20 In the same reaction conditions than
compound 15, diepoxide 25 yielded the hydroperoxy tetrahy-
dropyran derivative 26 in 45% yield via very likely the same mech-
anistic pathway than for 15 (Scheme 7). If this unprecedented study
of the addition of hydrogenperoxide to 1,4 and 1,5-bis-epoxides was
worth it, it did not lead to the desired 1,2-dioxane ring system.
Consequently, a new synthetic strategy for plakortolides was
required. We turned back our attention to the first synthetic
On a larger scale (w15 mmol) using freshly doubly distilled
dichloromethane and ethyl propiolate as enophile, the yield could
be increased to 77%. After reduction of the ester function of 31 with
DIBAL, the resulting allylic alcohol 29 was subjected to Sharpless
asymmetric epoxidation to generate compound 32 in 80% for the
two steps. The stage was now set up for MukaiyamaeIsayama
hydroperoxysilylation of the double bond of 32. Regioselective
peroxidation of 32 with triethylsilane and oxygen catalyzed by
bis(1-morpholinocarbamoyl-4,4-dimethyl-1,3-pentadionate) Co(II)
[Co(modp)2]22 provided the tertiary protected hydroperoxide 28 in
only 41% as a 1:1 mixture of diastereomers. Following literature

ꢀ
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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
Table 1
precedent that the hydroperoxysilylation may be improved by
protection of alcohols,23 compound 29 was acetylated and sub-
mitted to peroxidation conditions to afford compound 33 in nearly
quantitative yield (Scheme 10). Prior to the introduction of the
Study of the regioselective oxidation of diene 34
double bond in the
a position of the oxirane, the acetyl protecting
group had to be cleaved. In the presence of a catalytic amount of
potassium carbonate in methanol, deprotection of both acetyl and
triethylsilyl functions occurred followed by 5-exo-tet cyclization to
give the 1,2-dioxolane 34. In the reductive conditions (DIBAL) the
desired alcohol 28 was obtained in low yield (Scheme 11).
Entry
Catalyst
Time (h)
Yield (%)
1
2
3
4
Co(acac)2
Co(modp)2
Co(mopd)2
Co(thd)2
7
ꢁ24
10
19a
ꢁ36
45
b
2
62
a
Determined by 1H NMR (71% conversion).
One drop of TBHP (5.5 M) was added.
b
which could be separated by column chromatography. The struc-
ture of each diastereomer of 27 was determined by 1D and 2D NMR
experiments (HSQC, HMBC) and relative stereochemistry by anal-
ysis of NOE interactions, represented in Fig. 3.
Scheme 10. Attempted improvement of the peroxidation of 32 by protection of the
primary alcohol.
Fig. 3. Key correlations observed for 27a,b.
At the stage of the synthesis our plan called for the installation
of a methyl group in C4 of 27 by first oxidation of the secondary
alcohol in this position. Surprisingly, treatment of diastereomeric
mixture of 27 with TEMPO/BAIB led the starting material un-
changed. Hypervalent iodine oxidizing agents (IBX, DMP) gave
a mixture of compounds, which did not contain any of the desired
ketone 38. In the presence of PDC or PCC, compound 27 gave the
fragmentation product 37 as a sole isolable compound in, re-
spectively, 36 and 15% (w50% conversion) (Scheme 12). Again,
compound 38 was not observed in the 1H NMR spectrum of the
crude mixture.
Scheme 11. Synthesis of 1,2-dioxane 27 from epoxy alcohol 32.
Faced with the inefficiency of peroxide 28 preparation methods,
we decided to install the vinyl group prior to the peroxidation.
Based on the study of Masuyama and co-workers concerning the
relative reactivity of alkenes in the Co(II)/O2/Et3SiH peroxidation,24
we were confident that the gem-disubstituted double bond within
35 should be more reactive than the vinyl group. After introduction
of the double bond within 32 via TEMPO/BAIB oxidation and Wittig
olefination, the peroxidation of the resulting diene 35 was in-
vestigated in the presence of three bis (1,3-diketonato)Co(II) com-
plexes and the results of this study are summarized in Table 1.
Co(acac)2 was found as a poor catalyst for this reaction because the
yield of 36 was estimated to be 19% by 1H NMR of the crude mixture
(entry 1). With Co(modp)2 used as catalyst, the peroxidation was
not reproducible due to important variations in the induction pe-
riod (entry 2). Conversely, addition of a drop of tBuOOH, known as
an effective initiator for this reaction,8b allowed the peroxidation of
35 to be efficiently effected in the presence of Co(modp)2 albeit in
moderate yield (entry 3). The use of bis(2,2,6,6-tetramethyl-3,5-
Scheme 12. Fragmentation of alcohol 27 in the presence of Cr(VI) reagents.
To explain these results, we speculated that after oxidation of
the secondary alcohol, the resulting ketone underwent an E1cB
fragmentation via deprotonation in the
a position of the carbonyl
function followed by retroaldol reaction (Scheme 12). This in-
stability of the 1,2-dioxan-4-one 38 toward bases is similar to that
observed for 2-peroxyaldehydes in the presence of organometallic
reagents.26 In light of these last disappointing findings and the
failure of the different approaches studied, we decided to not
pursue our investigation to fashion the peroxylactone skeleton of
plakortolides in this direction.
25
heptanedoinato)Co(II) Co(thd)2 increased the yield (62% vs 45%)
and shortened the reaction time (2 h vs 10 h) in comparison with
Co(modp)2 and furthermore no initiator was needed (entry 4).
Amberlyst-15 mediated triethylsilyl peroxy ether cleavage and
subsequent cyclization within 36 provided exclusively the 6-endo
cyclized product 27 in good yield as a 1:1 mixture of diastereomers,

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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3721
3. Conclusion
CuI (0.17 g, 0.88 mmol) were suspended in dry DMF (10 mL). Sub-
sequently, propargyl alcohol (80 L, 1.3 mmol, 1.5 equiv) was added
m
Two strategies to gain access to the peroxylactone core of pla-
kortolides were studied. In the first one, based on 6-endo cycliza-
tion of b-quaternary hydroperoxy vinyl epoxide, different routes for
at once and kept stirring for 15 min. After, 1-(((2-(chloromethyl)
allyl)oxy)methyl)-4-methoxybenzene (10a)9 (0.2 g, 0.88 mmol) in
DMF (1 mL) was added dropwise and the suspension was stirred at
room temperature under argon atmosphere for 24 h, then
quenched with saturated aqueous solution of ammonium chloride,
extracted with diethyl ether (3ꢂ10 mL), dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (Et2O/petroleum ether¼1:1) to yield
8a (135 mg, 62%) as a colorless oil. IR (neat): 1515, 1586, 1614, 1657,
2225, 2286, 2839, 2860, 2915, 2932, 2999, 3406. 1H NMR (300 MHz,
the elaboration of this key precursor were studied. A first method to
prepare an intermediate of this vinyl epoxide, a monoprotected 1,4-
diene diol, via reduction of the corresponding enyne, failed. A
second approach of the diene diol utilizing an ene reaction allowed
its elaboration in two steps and 66% yield. Prior to a vinyl moiety
introduction and after peroxidation of a gem-disubstituted olefin,
attempted cleavage of an acetyl group, in basic medium, furnished
unexpectively a 1,2-dioxolane. A modification of the strategy by
introduction of the vinyl group before the chemoselective perox-
idation of the other double bond present in the molecule autho-
rized the synthesis of the 1,2-dioxane ring system of plakortolides
in a good yield. All attempts to oxidize the secondary alcohol in the
CDCl3):
d
¼2.68 (br s, 1H, OH), 3.04 (s, 2H), 3.80 (s, 3H), 3.99 (s, 2H),
4.25 (t, J¼2.1 Hz, 2H), 4.41 (s, 2H), 5.15 (m, 1H), 5.27 (d, J¼1.5 Hz,
1H), 6.88 (d, J¼8.7 Hz, 2H), 7.26 (d, J¼8.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3):
d
¼23.4, 51.3, 55.4, 71.6, 72.2, 81.1, 82.7, 113.9 (2C), 114.1,
129.5 (2C), 130.2, 140.9, 159.3. HRMS (ESI): calculated for
C15H18NaO3 (MNaþ) 269.1148, found 269.1155.
b
position of the oxygen ring of the endoperoxide failed due to
a fragmentation reaction. A second-generation strategy for a 1,2-
dioxane formation based on a double opening of a 1,4-diepoxide
with hydrogen peroxide, was elaborated. Unforeseen outcomes
were obtained since a hydroperoxy tetrahydropyran derivative was
isolated in 40% yield showing that the intramolecular attack of the
first epoxy group to the other one activated by protonation was
much faster than the external attack by hydrogen peroxide.
4.3.2. 5-(((tert-Butyl(dimethyl)silyl)oxy)methyl)hex-5-en-2-yn-1-ol
(8b). The same protocol was used than for the preparation of 8a
starting from 1.4 mmol of 10b.14 The residue was purified by flash
column chromatography (Et2O/petroleum ether¼1:1) to yield 8b
(254 mg, 74%) as a colorless oil. IR (neat): 1660, 2227, 2288, 2858,
2885, 2930, 2955, 3339. 1H NMR (300 MHz, CDCl3):
d
¼0.05 (s, 6H),
0.89 (s, 9H), 2.35 (br s, 1H, OH), 2.97 (s, 2H), 4.11 (s, 2H), 4.25 (t,
4. Experimental
4.1. Caution
J¼2.3 Hz, 2H), 5.10 (d, J¼1.5 Hz, 1H), 5.12 (d, J¼1.5 Hz, 1H). 13C NMR
(75 MHz, CDCl3):
d
¼ꢀ5.3 (2C), 18.4, 22.9, 26.0 (3C), 51.3, 65.6, 80.9,
82.8, 111.0, 143.4. HRMS (CI): calculated for C13H24O2Si (MHþ)
241.1624, found 241.1624.
Organic peroxides are potentially hazardous compounds and
must be handled with great care: avoid direct exposure to strong
heat or light, mechanical shock, oxidizable organic materials, or
transition-metal ions. A safety shield should be used for all re-
actions involving large quantities of organic peroxides or H2O2.
4.3.3. (2E)-5-(((4-Methoxybenzyl)oxy)methyl)hexa-2,5-dien-1-ol
(13a). (a) By indium-mediated allylation of propargyl alcohol. Indium
powder (60 mg, 0.52 mmol, 1.2 equiv) was placed in a reaction vial
under argon, followed by the addition of THF (1 mL), of 14 (276 mg,
0.87 mmol, 2 equiv) and propargyl alcohol (25 mL, 0.43 mmol). The
4.2. General experimental detail
reaction mixture was stirred at room temperature for 30 h,
quenched with a few drops of diluted hydrochloric acid (1 M). The
resulting mixture was stirred for 10 min, and extracted with Et2O
(3ꢂ3 mL), dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (Et2O: petroleum ether¼1:1) to yield 13a (20 mg, 19%) as
a colorless oil. IR (neat): 1514, 1586, 1614, 1651, 2838, 2858, 2909,
NMR spectra were recorded at ambient probe temperature on
Bruker AC 300, AM 300, AM 400, and AV 500 spectrometers.
Multiplicity is described by the following abbreviations: s¼singlet,
d¼doublet, t¼triplet, q¼quadruplet, m¼multiplet, br¼broad.
Chemical shifts are given in parts per million. 1H NMR spectra were
referenced to the residual solvents peaks at
(C6H6), 2.50 (DMSO-d6), 3.31 (CD3OD), 5.32 (CD2Cl2). 13C NMR
spectra were referenced to the solvent peak at
¼77.16 (CDCl3),
d
¼7.26 (CDCl3), 7.16
2933, 3000, 3396. 1H NMR (300 MHz, CDCl3):
d
¼1.94 (br s, 1H, OH),
2.82 (d, J¼4.5 Hz, 2H), 3.80 (s, 3H), 3.93 (s, 2H), 4.08 (d, J¼4.5 Hz,
2H), 4.42 (s, 2H), 4.95 (s, 1H), 5.08 (s, 1H), 5.69 (m, 2H), 6.88 (d,
J¼8.7 Hz, 2H), 7.26 (d, J¼8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d
53.80 (CD2Cl2), 49.00 (CD3OD). High resolution mass spectrometry
(HRMS) analyses were conducted using a Thermofinigan-MAT 95
XL instrument. IR spectra were recorded on a PerkineElmer one
spectrometer and are reported in wave numbers (cmꢀ1). Optical
rotations were measured on a PerkineElmer 343 apparatus at the
sodium D line (598 nm). Reagents and solvents were purified by
standard means. Tetrahydrofuran and diethyl ether were distilled
from sodium wire/benzophenone and stored under a nitrogen at-
mosphere. Dichloroethane, dichloromethane, dimethylformamide,
pyridine were distilled from calcium hydride. Analytical thin-layer
chromatography (TLC) was performed on Merck silica gel 60 F254
plates. Flash chromatography was performed on silica gel
(230e400 mesh) from Macherey Nagel. Preparative thin-layer
chromatography (PTLC) was performed on Silicycle plates (F-254,
1000 microns).
d
¼36.2, 55.4, 63.6, 71.7, 72.6, 113.0, 113.9 (2C), 129.5 (2C), 129.8,
130.5, 131.2, 144.7, 159.3. HRMS (ESI): calculated for C15H20NaO3
(MNaþ) 271.1305, found 271.1312.
(b) By reduction of the enyne 8a. CrCl2 (270 mg, 2.1 mmol,
8 equiv) and sodium sulfate (150 mg, 1.1 mmol, 4 equiv) were
dissolved in degassed water (1 mL), and solution of the 5-(((4-
methoxybenzyl)oxy)methyl)hex-5-en-2-yn-1-ol 8a (65 mg,
0.26 mmol) in degassed DMF (1 mL) was added. Hydrochloric acid
(35%, 55 mg, 0.53 mmol, 2 equiv) was then added and the reaction
mixture was stirred for 21 days. The solution was extracted by Et2O
(3ꢂ10 ml) dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (Et2O/petroleum ether¼1:1) to yield 13a (40 mg, 61%) as
a colorless oil. Its spectroscopic data are in accordance with those
described above. Further elution provided the starting material 8a
(11 mg, 17%).
4.3. Experimental procedures
4.3.1. 5-(((4-Methoxybenzyl)oxy)methyl)hex-5-en-2-yn-1-ol
4.3.4. 1-(((2-(Iodomethyl)prop-2-enyl)oxy)methyl)-4-methoxy ben-
(8a). K2CO3 (0.18 g, 1.3 mmol, 1.5 equiv), NaI (0.13 g, 0.88 mmol),
zene (14). To a solution of 10a (0.47 g, 2.07 mmol) in acetone was

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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3722
added sodium iodide (0.47 g, 3.11 mmol). The mixture was stirred
for 24 h at room temperature. Then water was added, extracted
with hexane (4ꢂ10 ml), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (Et2O/petroleum ether¼1:12) to yield 14 (567 mg, 86%)
as a colorless oil. IR (neat): 1614, 2836, 2855, 2908, 2934, 2954,
1.23 mmol, 1 equiv) and ethereal H2O2 (1.26 M, 4.9 mL, 6.1 mmol,
5 equiv). The reaction mixture was stirred at room temperature for
1 h, filtered through a short pad of silica gel and evaporated. The
residue after evaporation was purified by flash column chroma-
tography on silica gel (Et2O/petroleum ether¼2:1) to give first pure
22a (2R,3S,5S) (13.3 mg) as a colorless oil. IR (neat): 1647, 2853,
2999, 3033, 3079. 1H NMR (300 MHz, CDCl3):
d
¼3.81 (s, 3H), 3.99 (s,
2932, 2977, 3318. 1H NMR (500 MHz, CD2Cl2):
d¼1.19 (s, 3H), 1.45
2H), 4.15 (s, 2H), 4.46 (s, 2H), 5.20 (m, 1H), 5.40 (br s, 1H), 6.89 (d,
(dd, J¼13.8, 11.2 Hz, 1H), 1.89 (d, J¼3.5 Hz, 1H, OH), 2.26 (ddd,
J¼13.8, 4.9, 2.7 Hz, 1H), 3.24 (d, J¼12.7 Hz, 1H), 3.43 (dd, J¼9.5,
7.0 Hz, 1H, H), 3.55 (m, 1H), 4.05 (dd, J¼12.7, 2.7 Hz, 1H), 5.29e5.32
(m, 1H), 5.38 (d, J¼17.3 Hz, 1H), 5.88 (s, 1H, OOH). 13C NMR
J¼8.7 Hz, 2H), 7.28 (d, J¼8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d
¼6.3, 55.4, 70.6, 72.2, 114.0 (2C), 115.9, 129.5 (2C), 130.2, 143.7,
159.4.
(126 MHz, CD2Cl2):
d
¼20.7, 40.5, 66.4, 70.5, 81.6, 83.8, 119.1, 136.1.
4.3.5. ((2S,3S,5RS)-3-((2-Methyloxiran-2-yl)methyl)oxiran-2-yl)
MS (CI): 127, 141 (MHþꢀH2O2), 145, 157 (MHþꢀH2O), 175 (MHþ).
HRMS (CI): calculated for C8H14NaO4 (MNaþ) 197.0784, found
197.0.782.
methanol (20). To
a
cooled (0 ꢃC) mixture of ((2S,3S)-3-(2-
methylallyl)oxiran-2-yl)methanol 1616 (0.58 g, 4.55 mmol,
1 equiv), NaHCO3 (2.29 g, 27.3 mmol, 6 equiv), and CH2Cl2 (45 mL)
was added mCPBA (2.35 g, 6.82 mmol, 1.5 equiv). The mixture was
stirred for 5 h, evaporated and the residue washed with Et2O and
filtered. The filtrate was evaporated and the residue was purified by
flash column chromatography (AcOEt/petroleum ether¼4:1) to
yield 20 (0.58 g, 88%, dr¼1:1) as a colorless oil. IR (neat): 2874,
The second fraction contains pure 22b (2S,3R,5S) (20 mg). IR
(neat): 1647, 2853, 2932, 2977, 3318. 1H NMR (500 MHz, CD2Cl2):
d
¼1.28 (s, 3H), 1.85 (dd, J¼13.2, 7.9 Hz, 1H), 1.96 (ddd, J¼13.2, 4.3,
1.1 Hz,1H), 2.54 (br s,1H, OH), 3.55 (br s,1H), 3.61 (d, J¼11.7 Hz,1H),
3.66 (dd, J¼11.5, 1.0 Hz, 1H), 3.80 (dd, J¼6.1, 6.1 Hz, 1H), 5.31e5.38
(m, 2H), 5.88 (ddd, J¼17.0, 10.8, 5.9 Hz, 1H), 8.15 (br s, 1H, OOH). 13C
2928, 2985, 3048, 3434. 1H NMR (300 MHz, CDCl3):
d¼1.31 (s, 1.5H),
NMR (126 MHz, CD2Cl2):
d¼21.2, 38.2, 68.3, 69.5, 80.7, 82.2, 118.9,
1.34 (s, 1.5H), 1.64e1.91 (m, 2H), 2.58 (d, J¼5.4 Hz, 1H), 2.63 (d,
J¼4.8 Hz, 0.5H), 2.72 (d, J¼4.5 Hz, 0.5H), 2.86 (m, 1H), 2.92 (ddd,
J¼1.8, 3.9, 6.9 Hz, 0.5H), 2.92 (ddd, J¼2.3, 4.8, 7.0 Hz, 0.5H), 3.22 (br
s, 1H, OH), 3.55 (m, 1H), 3.80 (d, J¼12.6 Hz, 0.5H), 3.81 (d, J¼12.6 Hz,
135.5. MS (CI): 127, 141 (MHþꢀH2O2), 145, 157 (MHþꢀH2O), 175
(MHþ). HRMS (CI): calculated for C8H14NaO4 (MNaþ) 197.0784,
found 197.0.788. A mixture of 22a,b (52.8 mg) was also obtained
(overall yield 40%, dr¼1:1).
0.5H). 13C NMR (75 MHz, CDCl3):
53.1, 53.9, 55.4, 55.6, 57.9, 58.1, 61.54, 61.55. HRMS (ESI): calculated
for C7H12NaO3 (MNaþ) 167.0679, found 167.0675.
d
¼21.2, 21.9, 38.3, 39.2, 52.3, 52.8,
4.3.8. rac-(5-Hydroperoxy-2,5-dimethyltetrahydro-2H-pyran-2-yl)
methanol (26a,b). A mixture of 1,2-bis(2-methyloxiran-2-yl)ethane
2520 (134 mg, 0.94 mmol, 1 equiv), ethereal H2O2 (1.15 M, 2.3 mL,
4.3.6. 2-Methyl-2-(((2S,3S)-3-vinyloxiran-2-yl)methyl)oxirane
(15). To a solution of ((2S,3S,5RS)-3-((2-methyloxiran-2-yl)methyl)
oxiran-2-yl)methanol 20 (0.46 g, 3.2 mmol, 1 equiv) in CH2Cl2
(32 mL) were added successively at 0 ꢃC TEMPO (50 mg, 0.32 mmol,
0.1 equiv) and BAIB (1.34 g, 4.16 mmol, 1.3 equiv). The reaction
mixture was stirred for 20 h at room temperature, evaporated, and
the residue was purified by flash column chromatography (AcOEt/
petroleum ether¼3:1) to give the aldehydo derivative (0.45 g, 99%,
dr¼1:1), which was used in the next step. IR (neat): 1732, 2838,
2.65 mmol, 2.8 equiv), and PMA (13.5 mg, 7.4 mmol, 0.008 equiv)
was stirred at ambient temperature for 1 h and chromatographed
(Et2O/Et2O/petroleum ether¼10:1) to give first pure 26a (2S*,5S*)
(26 mg) obtained as a colorless oil. IR (neat): 2873, 2935, 2974, 3311.
1H NMR (500 MHz, CD3OD):
d
¼1.17 (s, 3H), 1.20 (s, 3H),1.59 (m, 3H),
1.87 (m, 1H), 3.39 (d, J¼11.4 Hz, 1H), 3.47 (d, J¼12.1 Hz, 1H), 3.57 (d,
J¼11.4 Hz, 1H), 3.70 (d, J¼12.1 Hz, 1H). 13C NMR (75 MHz, CD3OD):
d
¼21.0, 22.1, 28.9, 29.1, 66.5, 67.1, 74.7, 79.1. MS (CI): 129, 143 (MHþ-
H2O2), 159 (MHþꢀH2O), 161, 177 (MHþ). HRMS (CI): calculated for
2930, 2985, 3048, 3444. 1H NMR (300 MHz, CDCl3):
d¼1.37 (s, 1.5H),
C8H16NaO4 (MNaþ) 199.0941, found 199.0941.
1.41 (s, 1.5H), 1.76e2.10 (m, 2H), 2.65 (m, 1.5H), 2.79 (d, J¼4.5 Hz,
0.5H), 3.13 (2dd, J¼2.1, 6.2 Hz, 1H), 3.26 (ddd, J¼2.0, 3.8, 7.4 Hz,
0.5H), 3.37 (ddd, J¼1.9, 4.3, 7.1 Hz, 0.5H), 8.99 (2d, J¼6.0 Hz, 1H). 13C
The second fraction is composed of the other diastereomer 26b
(2S*,5R*) (8.7 mg). IR (neat): 2871, 2934, 2972, 3327. 1H NMR
(500 MHz, CD3OD):
d
¼1.14 (s, 3H), 1.17 (s, 3H), 1.17e1.23 (m, 1H),
NMR (75 MHz, CDCl3):
58.2, 58.5, 55.0, 55.2, 197.8 (2C).
d
¼21.2, 21.9, 37.9, 38.9, 53.0, 53.8, 53.1, 53.7,
1.67e1.73 (m,1H), 1.82e1.90 (m, 2H), 3.37 (d, J¼11.1 Hz,1H), 3.40 (d,
J¼11.1 Hz, 1H), 3.47 (d, J¼12.6 Hz, 1H), 3.76 (dd, J¼12.7, 2.2 Hz, 1H).
A solution of NaHMDS (2 M, 6.48 mL, 13.4 mmol, 4 equiv) was
added to the suspension of Ph3PMeBr (5.76 g,16.2 mmol, 5 equiv) in
45 mL of freshly distilled THF at 0 ꢃC under stirring. After 30 min,
a solution of the above prepared aldehyde (0.45 g, 3.24 mmol,
1 equiv) in THF (18 mL) was added and the resulting mixture was
stirred for 1 h, quenched with water (27 mL) and extracted with
Et2O/petroleum ether¼2:1 (5ꢂ10 mL). The combined organic ex-
tracts were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (Et2O/petroleum ether¼1:2) to yield 15 (0.36 g, 81%, dr¼1:1) as
a colorless oil. IR (neat): 1624, 2923, 2984, 3045. 1H NMR (300 MHz,
13C NMR (75 MHz, CD3OD):
d
¼18.0, 21.3, 27.6, 28.9, 66.1, 70.5, 74.6,
78.7. MS (CI): 129, 143 (MHþꢀH2O2), 159 (MHþꢀH2O), 161, 177
(MHþ). HRMS (CI): calculated for C8H16NaO4 (MNaþ) 199.0941,
found 199.0940. A mixture of 26a,b was also obtained (40.3 mg;
overall yield 45%).
4.3.9. (E)-Ethyl 5-methylene-7-((triisopropylsilyl)oxy)hept-2-enoate
(31). To
a
vigorously stirred solution of triisopropyl((3-
methylbut-3-en-1-yl)oxy)silane 3021 (3.5 g, 14.5 mmol, 1 equiv)
and ethyl propiolate (1.47 mL, 14.5 mmol, 1 equiv) in freshly doubly
distilled CH2Cl2 (from P2O5 followed by final distillation from CaH2)
(50 mL), was added at 0 ꢃC, EtAlCl2 (1 M, 14.8 mL, 14.8 mmol,
1.02 equiv). The reaction mixture was stirred at room temperature
for 7 days and then poured into ice-water. The aqueous layer was
extracted with AcOEt (4ꢂ10 mL) and the combined organic layers
were washed with brine, dried with Na2SO4, and evaporated. Flash
chromatography (Et2O/petroleum ether¼1:10) of the residue gave
pure 31 (3.8 g, 77%) as a colorless oil. IR (neat): 1652, 1724, 2867,
CDCl3):
d
¼1.39 (s, 1.5H), 1.42 (s, 1.5H), 1.71e2.00 (m, 2H), 2.64 (d,
J¼4.7 Hz, 1H), 2.69 (d, J¼4.7 Hz, 0.5H), 2.80 (d, J¼4.7 Hz, 0.5H), 2.89
(ddd, J¼2.2, 4.2, 7.1 Hz, 0.5H), 2.98 (ddd, J¼2.1, 4.9, 6.9 Hz, 0.5H),
3.11 (2dd, J¼1.7, 6.7 Hz, 1H), 5.27e5.31 (m, 1H), 5.45e5.64 (m, 2H).
13C NMR (75 MHz, CDCl3):
d
¼21.4, 22.1, 38.8, 39.7, 53.3, 53.9, 55.4,
55.5, 56.6, 57.2, 58.0, 58.4, 119.68, 119.69, 135.22, 135.25.
4.3.7. (2R,3S,5RS)-5-Hydroperoxy-5-methyl-2-vinyltetrahydro-2H-
pyran-3-ol (22a,b). Phosphomolybdic acid (PMA) (11.5 mg,
2944, 3079. 1H NMR (300 MHz, CDCl3):
J¼7.2 Hz, 2H), 2.28 (t, J¼6.6 Hz, 2H), 2.94 (d, J¼7.2 Hz, 2H), 3.78 (t,
J¼6.6 Hz, 2H), 4.18 (q, J¼7.2 Hz, 2H), 4.82 (m, 1H), 4.87 (s, 1H), 5.84
d
¼1.05 (m, 21H), 1.28 (t,
6.2
mmol, 0.005 equiv) was added to diepoxide 15 (173 mg,

ꢀ
B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3723
(dt, J¼15.3, 1.5 Hz, 1H), 6.96 (dt, J¼15.6, 7.2 Hz, 1H). 13C NMR
the alcohol 28 (104 mg, 0.33 mmol, 1 equiv) in pyridine (0.45 mL)
was added acetic anhydride (0.094 mL, 0.99 mmol, 3 equiv). After
being stirred at room temperature for 4 h the solution was cooled in
an ice bath and 10% HCl (0.8 mL) was added to quench the reaction.
Aqueous solution was extracted with Et2O (5ꢂ1 mL). The combined
organic extracts were dried with Na2SO4 and evaporated. Flash
chromatography (Et2O/petroleum ether¼1:2) of the residue affor-
ded the acetate (117 mg, 99%) as a colorless oil. IR (neat): 1647, 1748,
(75 MHz, CDCl3):
d
¼12.1 (3C), 14.4, 18.2 (6C), 39.5, 39.6, 60.3, 62.6,
113.4, 122.9, 143.8, 146.5, 166.6. HRMS (ESI): calculated for
C19H36NaO3Si (MNaþ) 363.2326, found 363.2325.
4.3.10. (E)-5-Methylene-7-((triisopropylsilyl)oxy) hept-2-en-1-ol
(29). DIBAL (1 M, 10.8 mL, 10.8 mmol, 2.3 equiv) was added over
10 min to a stirred solution of 31 (1.59 g, 4.68 mmol, 1 equiv) in THF
(12 mL) at ꢀ78 ꢃC. After 2 h the reaction mixture was warmed to
2867, 2893, 2944, 3079. 1H NMR (300 MHz, CDCl3):
d¼1.05 (m,
0
ꢃC, stirred for 30 min, carefully quenched with a Rochelle salt
21H), 2.08 (s, 3H), 2.31 (m, 4H), 2.98 (m, 2H), 3.79 (t, J¼6.9 Hz, 2H),
solution and extracted with Et2O (4ꢂ10 mL). The combined organic
extracts were dried with Na2SO4 and evaporated. The residue was
purified by flash column chromatography (Et2O/petroleum
ether¼1:2) to give pure 29 (1.19 g, 85%) as a colorless oil. IR (neat):
1646, 2867, 2893, 2943, 3078, 3331. 1H NMR (300 MHz, CDCl3):
3.96 (dd, J¼12.3, 6.0 Hz, 1H), 4.36 (dd, J¼12.3, 3.0 Hz, 1H), 4.89 (s,
1H), 4.90 (s, 1H). 13C NMR (75 MHz, CDCl3):
20.9, 38.7, 40.1, 55.3, 55.4, 62.5, 64.7, 113.2, 143.0, 170.9.
d
¼12.1 (3C), 18.1 (6C),
The corresponding acetate of 32 (117 mg, 0.33 mmol, 1 equiv),
Co(modp)2 (18 mg, 0.033 mmol, 0.1 equiv) and dichloroethane
(2.5 mL) were placed into the flask. The flask was charged with O2
and Et3SiH (0.105 mL, 0.66 mmol, 2 equiv) was added. After stirring
for 5 h, the reaction mixture was evaporated. Flash chromatography
(Et2O/petroleum ether¼1:2) of the residue led to 33 (157 mg, 95%,
dr¼1:1) as a colorless oil. IR (neat): 1750, 2868, 2875, 2944, 2956.
d
¼1.06 (m, 21H), 1.57 (br s, 1H, OH), 2.28 (t, J¼6.9 Hz, 2H), 2.79 (d,
J¼4.8 Hz, 2H), 3.78 (t, J¼6.9 Hz, 2H), 4.12 (m, 2H), 4.80 (s, 2H), 5.70
(m, 2H). 13C NMR (75 MHz, CDCl3):
d
¼12.2 (3C), 18.2 (6C), 39.5, 39.7,
62.7, 63.8, 111.9, 130.6, 130.9, 145.6. HRMS (CI): calculated for
C17H34O2Si (MHþ) 299.2406, found 299.2406.
1H NMR (300 MHz, CDCl3):
d
¼0.68 (m, 6H), 0.97 (t, J¼7.8 Hz, 9H),
4.3.11. ((2S,3S)-3-(2-Methylene-4-((triisopropylsilyl)oxy) butyl)ox-
1.06 (m, 21H), 1.27 (s, 1.5H), 1.29 (s, 1.5H), 1.71e2.06 (m, 4H), 2.08 (s,
3H), 2.97 (m, 1H), 3.03 (m, 1H), 3.79 (t, J¼6.6 Hz, 1H), 3.81 (t,
J¼6.6 Hz,1H), 3.92 (dd, J¼12.3, 6.3 Hz,1H), 4.38 (dm, J¼12.3 Hz,1H).
iran-2-yl)methanol (32). To a cooled (ꢀ25 ꢃC) mixture of 29 (1.2 g,
ꢂ
4.02 mmol, 1 equiv), 4 A MS (240 mg) in CH2Cl2 (11 mL) were added
Ti(OiPr)4 (0.24 mL, 0.803 mmol, 0.2 equiv) and a solution of (þ)-DET
(0.17 mL, 0.964 mmol, 0.24 equiv) in CH2Cl2 (1 mL) and the
resulting mixture was stirred for 30 min. A solution of TBHP in
decane (5.5 M, 1.46 mL, 8.03 mmol, 2 equiv) was then added and
the reaction mixture was placed in a freezer (ꢀ25 ꢃC) for 2 days. The
reaction was quenched with water (2 mL), allowed to warm up to
room temperature and then stirred for 30 min. 30% NaOH aqueous
solution saturated with NaCl (0.5 mL) was added and the resulting
mixture was stirred for 30e40 min then 10 mL of water was in-
troduced. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (5ꢂ8 mL). The combined organic ex-
tracts were washed once with water (15 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography (Et2O/petroleum ether¼1:1) to yield the epoxy
13C NMR (75 MHz, CDCl3):
d
¼3.9 (3C), 6.8 (3C), 12.0 (3C), 18.1 (6C),
20.8, 22.2, 23.0, 39.85, 39.95, 40.00, 40.88, 53.2, 53.3, 55.0, 55.3,
59.37, 59.38, 64.7, 82.88, 82.92, 170.7. HRMS (ESI): calculated for
C25H52O6Si2Na (MNaþ) 527.3200, found 527.3197.
4.3.14. (S)-1-((3R,5R,S)-5-Methyl-5-(2-((triisopropylsilyl) oxy)ethyl)-
1,2-dioxolan-3-yl)ethane-1,2-diol (34a,b). To an ice-cooled solution
of 33 (43 mg, 0.8 mmol) in methanol (1 mL) was added K2C03
(2.1 mg, 0.02 equiv). The solution was stirred at 0 ꢃC for 90 min and
evaporated. Flash chromatography (Et2O/petroleum ether¼1:1) of
the residue afforded first 34a (5R) (12.5 mg, 40%), as a colorless oil.
½
a 2D0
ꢄ
¼ꢀ28.2 (c 1.59, CHCl3). IR (neat): 2867, 2892, 2943, 3390. 1H
NMR (400 MHz, CDCl3):
d
¼1.05 (m, 21H, H), 1.35 (s, 3H), 1.89 (t,
J¼6.6 Hz, 2H), 2.39 (br s, 1H, OH), 2.42 (dd, J¼12.3, 8.1 Hz, 1H), 2.58
(dd, J¼12.3, 6.0 Hz, 1H), 2.83 (br s, 1H, OH), 3.62 (dd, J¼11.4, 6.0 Hz,
1H), 3.71 (dd, J¼11.4, 3.0 Hz, 1H), 3.82 (m, 3H), 4.33 (dt, J¼8.0,
alcohol 32 (1.19 g, 94%) as a colorless oil. ½a D20
ꢄ ¼ꢀ8.6 (c 0.69, CHCl3).
IR (neat): 1647, 2867, 2893, 2943, 3426. 1H NMR (300 MHz, CDCl3):
d
¼1.06 (m, 21H), 1.70 (dd, J¼7.1, 5.6 Hz, 1H, OH), 2.25e2.41 (m, 4H),
5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
40.7, 47.0, 59.9, 63.5, 72.4, 81.4, 85.3.
d
¼12.0 (3C), 18.1 (6C), 24.3,
2.95 (ddd, J¼4.7, 2.5, 2.5 Hz, 1H), 3.09 (td, J¼5.8, 5.8, 2.3 Hz, 1H),
3.65 (ddd, J¼12.0, 7.5, 4.5 Hz, 1H), 3.80 (t, J¼6.8 Hz, 2H), 3.93 (ddd,
J¼12.6, 5.3, 2.6 Hz, 1H), 4.89 (s, 1H), 4.91 (m, 1H). 13C NMR (75 MHz,
The second fraction was composed of compound 34b (5S)
(12.5 mg, 40%) obtained as a colorless oil. ½a D20
ꢄ ¼ꢀ45.9 (c 1.28,
CDCl3):
d¼12.1 (3C), 18.2 (6C), 38.8, 40.1, 54.8, 58.4, 61.7, 62.6, 113.1,
CHCl3). IR (neat): 2867, 2892, 2943, 3386. 1H NMR (400 MHz,
143.1. MS (CI) forC17H34O3Si: 337 (MNaþ), 383, 399.
CDCl3):
d
¼1.05 (m, 21H), 1.37 (s, 3H), 1.87 (dt, J¼13.9, 6.9 Hz, 1H),
1.91 (dt, J¼12.5, 6.2 Hz, 1H), 2.36 (dd, J¼12.2, 5.8 Hz, 1H), 2.37 (br s,
1H, OH), 2.70 (dd, J¼12.2, 8.2 Hz, 1H), 2.83 (br s, 1H, OH), 3.62 (dd,
J¼11.4, 6.1 Hz, 1H), 3.72 (dd, J¼11.4, 3.4 Hz, 1H), 3.82 (t, J¼6.5 Hz,
2H), 3.82 (m, 1H), 4.28 (dt, J¼8.1, 5.6 Hz, 1H). 13C NMR (101 MHz,
4.3.12. ((2S,3S)-3-(2-Methyl-2-((triethylsilyl)peroxy)-4((triisopro-
pylsilyl)oxy)butyl)oxiran-2-yl)methanol
(28). Compound
32,
(120 mg, 0.38 mmol, 1 equiv), Co(modp)2 (21 mg, 0.038 mmol,
0.1 equiv), and dichloroethane (4 mL) were placed into the flask.
The flask was charged with O2 and Et3SiH (0.12 mL, 0.76 mmol,
2 equiv) was added. After stirring for 4 h, the reaction mixture was
evaporated. Flash chromatography (Et2O/petroleum ether¼1:1) of
the residue gave 28 (73 mg, 41%, dr¼1:1) as a colorless oil. IR (neat):
CDCl3):
d¼12.0 (3C), 18.2 (6C), 23.2, 41.5, 46.9, 59.8, 63.5, 72.4, 81.7,
85.2; HRMS (ESI) (mixture of diastereomers): calculated for
C17H36O5SiNa (MNaþ) 371.2230, found 371.2233.
4.3.15. Triisopropyl ((3-(((2S,3S)-3-vinyloxiran-2-yl)methyl)but-3-
en-1-yl)oxy)silane (35). To a solution of the epoxy alcohol 32
(1.08 g, 3.42 mmol, 1 equiv) in CH2Cl2 (34 mL), TEMPO (57 mg,
0.342 mmol, 0.1 equiv) and BAIB (1.44 g, 4.56 mmol, 1.3 equiv) were
added successively at 0 ꢃC. The reaction mixture was stirred for 6 h
at room temperature, quenched with saturated aqueous solution of
Na2SO3 (1 mL) and extracted with Et2O (5ꢂ1 mL). The combined
organic extracts were dried with Na2SO4 and evaporated. The res-
idue was purified by flash column chromatography (Et2O/petro-
leum ether¼1:8) to yield the epoxy aldehyde (0.92 g, 85%) as
a colorless oil. IR (neat): 1648, 1732, 2867, 2893, 2944. 1H NMR
2868, 2944, 2957, 3434. 1H NMR (300 MHz, CDCl3):
d
¼0.66 (q, 6H,
J¼7.8 Hz), 0.97 (t, 9H, J¼7.8 Hz), 1.05 (m, 21H), 1.27 (s, 1.5H, H8), 1.29
(s, 1.5H), 1.74e2.02 (m, 5H), 2.91 (m, 1H), 3.10 (m, 1H), 3.59 (m, 1H),
3.80 (t, J¼6.4 Hz, 2H), 3.91 (m, 1H). 13C NMR (75 MHz, CDCl3):
¼4.0
d
(2ꢂ 3C), 6.9 (2ꢂ 3C), 12.1 (2ꢂ 3C), 18.2 (2ꢂ 6C), 22.3, 23.1, 39.9,
40.04, 40.06, 41.0, 52.8, 52.9, 58.3, 58.6, 59.4, 61.88, 61.94, 82.95,
83.00. HRMS (ESI): calculated for C23H50NaO5Si2 (MNaþ) 485.3089,
found 485.3098.
4.3.13. ((2S,3S)-3-(2-Methyl-2-((triethylsilyl)peroxy)-4((triisopro-
pylsilyl)oxy)butyl)oxiran-2-yl)methyl acetate (33). To a solution of
(300 MHz, CDCl3):
d
¼1.05 (m, 21H), 2.32 (t, J¼6.6 Hz, 2H), 2.42 (m,

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B. Barnych, J.-M. Vatele / Tetrahedron 68 (2012) 3717e3724
3724
2H), 3.17 (dd, J¼6.0,1.8 Hz,1H), 3.37 (ddd, J¼6.0, 5.1,1.8 Hz,1H), 3.81
(t, J¼6.6 Hz, 2H), 4.94 (s, 2H), 9.03 (d, J¼6.3 Hz, 1H). 13C NMR
J¼10.6, 0.7 Hz, 1H), 5.49 (d, J¼17.3 Hz, 1H), 5.72 (ddd, J¼17.7, 10.6,
7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3):
38.8, 42.2, 59.5, 66.3, 82.0, 86.8, 122.1, 132.1. HRMS (ESI): calculated
for C18H36NaO4Si (MNaþ) 367.2275, found 367.2287.
d
¼12.1 (3C), 18.2 (6C), 25.3,
(75 MHz, CDCl3):
d
¼12.0 (3C), 18.1 (6C), 38.2, 39.9, 55.6, 59.0, 62.5,
114.0, 142.3, 198.2. HRMS (ESI): calculated for C17H32O3Si (MHþ)
313.2199, found 313.2199.
A solution of NaHMDS (2 M, 5.9 mL, 11.8 mmol, 4 equiv) was
added to the suspension of Ph3PMeBr (4.42 g, 12.4 mmol, 4.2 equiv)
in 50 mL of freshly distilled THF at 0 ꢃC under stirring. After 30 min,
a solution of the above prepared aldehyde (0.92 g, 2.95 mmol,
1 equiv) in THF (2 mL) was added and the resulting mixture was
stirred for 1 h, quenched with water (40 mL) and extracted with
Et2O/petroleum ether¼2:1 (5ꢂ20 mL). The combined organic ex-
tracts were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (Et2O/petroleum ether¼1:9) to yield the epoxy diene 35
Acknowledgements
ꢀ
B.B. thanks the “ French Ministere de la Recherche et de l’En-
ꢁ
seignement Superieur” for a PhD grant.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.024.
(0.911 g, 99.6%) as a colorless oil. ½a D20
ꢄ ¼þ1.0 (c 0.92, CHCl3). IR
(neat): 1645, 2867, 2893, 2943, 2958, 3085. 1H NMR (300 MHz,
References and notes
CDCl3):
d
¼1.06 (m, 21H), 2.24e2.41 (m, 4H), 2.95 (ddd, J¼5.7, 5.7,
2.2 Hz,1H), 3.12 (dd, J¼7.2, 2.1 Hz, 1H), 3.80 (t, J¼6.9 Hz, 2H), 4.88 (s,
1H), 4.91 (m, 1H), 5.26 (m, 1H), 5.46 (dd, J¼17.2, 1.8 Hz, 1H), 5.60
1. (a) Casteel, A. N. Nat. Prod. Rep. 1998, 16, 55e73; (b) Rahm, F.; Hayes, P. Y.;
Kitching, W. Heterocycles 2004, 523e575.
(ddd, J¼17.2, 9.9, 7.2 Hz, 1H). 13C NMR (75 MHz, CDCl3):
¼12.1 (3C),
d
2. (a) Davidson, B. S. Tetrahedron Lett. 1992, 32, 7167e7170; (b) Horton, P. A.;
Longley, R. E.; Kelly-Borges, M.; McConnell, O. J.; Ballas, L. M. J. Nat. Prod. 1994,
57, 1374e1381; (c) Varoglu, M.; Peters, B. M.; Crews, P. J. Nat. Prod. 1995, 58,
27e36; (d) Qureshi, A.; Salva, J.; Harper, M. K.; Faulkner, D. J. J. Nat. Prod. 1998,
61, 1539e1542; (e) Williams, D. E.; Allen, T. M.; Van Soest, R.; Behrisch, H. W.;
Andersen, R. J. J. Nat. Prod. 2001, 64, 281e285; (f) Perry, T. L.; Dickerson, A.;
Khan, A. A.; Kondru, R. K.; Beratan, D. N.; Wipf, P.; Kelly, M.; Hamann, M. T.
Tetrahedron 2001, 57, 1483e1487; (g) Chen, Y.; Killday, K. B.; McCarthy, P. J.;
Schemoler, R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S. A.; Wright, A. E. J. Nat.
Prod. 2001, 64, 262e264; (h) Rudi, A.; Afanii, R.; Gravalos, L. G.; Aknin, M.;
Gaydou, E.; Vacelet, J.; Kashman, Y. J. Nat. Prod. 2003, 66, 682e685; (i) Jimenez-
Romero, C.; Ortiz, I.; Vincente, J.; Vera, B.; Rodrigue, A. D.; Nam, S.; Jove, R. J. Nat.
Prod. 2010, 73, 1694e1700; (j) Yong, K. W. L.; De Voss, J. J.; Hooper, J. N. A.;
Garson, M. J. J. Nat. Prod. 2011, 74, 194e207.
18.1 (6C), 39.2, 40.1, 58.8, 59.2, 62.6, 113.1, 119.3, 135.7, 143.1. HRMS
(ESI): calculated for C18H34O2SiNa (MNaþ) 333.2226, found
333.2226.
4.3.16. 3,3-Diethyl-10,10-diisopropyl-6,11-dimethyl-6-(((2S,3S)-3-
vinyloxiran-2-yl)methyl)-4,5,9-trioxa-3,10-disiladodecane (36). To
a solution of diene epoxide 35 (70 mg, 0.226 mmol, 1 equiv) in
dichloroethane (1.5 mL) was added Co(thd)2 (10 mg, 0.023 mmol,
0.1 equiv) and the flask was charged with O2. Et3SiH (0.072 mL,
0.45 mmol, 2 equiv) was added and the reaction mixture was
stirred under O2 atmosphere until the reaction was finished (by
TLC, w1.5 h). Evaporation and flash chromatography (Et2O/petro-
leum ether¼1:10) of the residue gave 36 (64 mg, 62%, dr¼1:1) as
a colorless oil. IR (neat): 1644, 2868, 2944, 2957. 1H NMR (300 MHz,
3. Jung, M.; Ham, J.; Song, J. Org. Lett. 2002, 4, 2763e2765.
ꢀ
4. Barnych, B.; Vatele, J.-M. Org. Lett. 2012, 14, 564e567.
ꢀ
5. Doan, H. D.; Gallon, J.; Piou, A.; Vatele, J.-M. Synlett 2007, 983e985.
ꢀ
6. Barnych, B.; Vatele, J.-M. Synlett 2011, 1912e1916; For the pioneering work on
the construction of the 1,2-dioxane skeleton via cyclization of hydroperoxy
epoxides, see: Xu, X.-X.; Dong, H.-Q. J. Org. Chem. 1995, 60, 3039e3044.
7. (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc.
1989, 111, 5330e5334; (b) Ha, J. D.; Shin, E. Y.; Chung, Y.; Choi, J.-K. Bull. Korean
Chem. Soc. 2003, 24, 1567e1568.
CDCl3):
d
¼0.68 (m, 6H), 0.97 (m, 9H, H13), 1.06 (m, 21H), 1.27 (s,
1.5H), 1.29 (s, 1.5H), 1.76e2.01 (m, 4H), 2.98 (m, 1H), 3.08 (m, 1H),
3.80 (t, J¼6.9 Hz, 1.5H), 3.82 (t, J¼6.9 Hz, 1H), 5.25 (dd, J¼9.9, 1.9 Hz,
1H), 5.44 (dd, J¼17.2, 1.8 Hz, 1H), 5.57 (ddd, J¼17.1, 9.9, 7.2 Hz, 1H).
8. (a) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 573e575; (b) Isayama, S. Bull.
Chem. Soc. Jpn. 1990, 63, 1305e1310.
13C NMR (75 MHz, CDCl3):
d¼4.0 (3C), 4.1 (3C), 6.9 (3C), 7.0 (3C),
9. Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J. Org. Chem. 2000, 65, 4145e4152.
10. (a) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis 1993, 65e66; (b)
Bruno, G.; Caruso, T.; Peluso, A.; Spinella, A. Phytochem. Rev. 2004, 417e422.
11. For an example of hydroalumination of alkynyl alcohols with BuLi-DIBAL, see:
Ohmori, K.; Hachisu, Y.; Suzuki, T.; Suzuki, K. Tetrahedron Lett. 2002, 43,
1031e1034.
12.1 (2ꢂ 3C), 18.2 (2ꢂ 6C), 26.3 (2C), 40.2, 40.4, 57.2, 58.6, 58.9, 59.5,
82.96, 83.04, 119.16, 119.18, 135.93, 135.95. HRMS (ESI): calculated
for C24H50NaO4Si2 (MNaþ) 481.3140, found 481.3126.
12. Castro, C. E.; Stephens, R. D. J. Am. Chem. Soc. 1964, 86, 4358e4363.
13. Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Synth. Commun. 2000, 30,
2061e2069.
4.3.17. (3R,4S,6RS)-6-Methyl-6-(2-((triisopropylsilyl)oxy)ethyl)-3-
vinyl-1,2-dioxan-4-ol (27a,b). Amberlyst-15 (20 mg, 94
mmol,
€
14. Brass, S.; Gerber, H.-D.; Dorr, S.; Diederich, W. E. Tetrahedron 2006, 62,
0.45 equiv) was added to a solution of hydroperoxy vinyl epoxide
36 (95 mg, 0.207 mmol, 1 equiv) in dichloromethane (4 mL). The
mixture was stirred for 5 h, filtered and evaporated. The residue
was purified by flash column chromatography (Et2O/petroleum
ether¼1:2) to yield 1,2-dioxane 27a (6R) (24 mg, 33.5%) as a color-
1777e1786.
15. (a) Ranu, B. C.; Majee, A. Chem. Commun. 1997, 1225e1226; (b) Klaps, E.;
Schmid, W. J. Org. Chem. 1999, 64, 7537e7546.
16. Alegret, C.; Santacana, F.; Riera, A. J. Org. Chem. 2007, 72, 7688e7692.
17. Jeffery, T. Tetrahedron Lett. 1989, 30, 2225e2228.
18. For the preparation of anhydrous ethereal hydrogen peroxide, see: Nagata, R.;
Saito, I. Synlett 1990, 291e300.
19. (a) McDonald, F. E.; Wang, X.; Do, B.; Hardcastle, K. I. Org. Lett. 2000, 2,
2917e2919; (b) Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816e1828.
20. Lee, S. H.; Kohn, H. J. Org. Chem. 2002, 67, 1692e1695.
21. Mikami, K.; Koizumi, Y.; Osawa, A.; Terada, M.; Takayama, H.; Nakagawa, K.;
Okano, T. Synlett 1999, 1899e1902.
22. For the preparation of Co(modp)2, see: Wang, J.; Morra, N. A.; Zhao, H.; Gor-
man, J. S. T.; Lynch, V.; McDonald, R.; Reichman, J. F.; Pagenkopf, B. L. Can. J.
Chem. 2009, 87, 328e334.
less oil. ½a 2D0
ꢄ ¼ꢀ71.8 (c 0.73, CHCl3). IR (neat): 2867, 2892, 2944,
3446. 1H NMR (500 MHz, CDCl3):
d
¼1.03e1.13 (m, 21H), 1.41 (s, 3H),
1.71 (dd, J¼12.8, 10.2 Hz, 1H), 1.74e1.94 (m, 3H), 2.08 (dd, J¼12.9,
5.1 Hz, 1H), 3.77e3.85 (m, 3H), 4.20 (t, J¼7.9 Hz, 1H), 5.41 (d,
J¼10.7 Hz, 1H), 5.48 (dt, J¼17.4, 1.1 Hz, 1H), 5.78 (ddd, J¼17.6, 10.6,
7.2 Hz, 1H). 13C NMR (125 MHz, CDCl3):
d¼12.1 (3C), 18.2 (6C), 22.7,
41.0, 43.2, 58.8, 66.3, 81.7, 87.0, 121.7, 132.3. HRMS (ESI): calculated
for C18H36NaO4Si (MNaþ) 367.2275, found 367.2290.
23. See for example: Silva, E. M. P.; Pye, R. J.; Cardin, C.; Harwood, L. M. Synlett 2010,
509e513.
24. Tokuyasu, T.; Kunikawa, S.; McCullough, K. J.; Masuyama, A.; Nojima, M. J. Org.
The next fraction was constituted of diastereomer 27b (24 mg)
(6S) (clear oil). ½a D20
ꢄ ¼ꢀ111.2 (c 0.7, CHCl3). IR (neat): 1643, 2867,
Chem. 2005, 70, 251e260.
2892, 2943, 3436. 1H NMR (500 MHz, CDCl3):
d
¼1.05e1.14 (m, 21H),
25. O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.; Park, B. K.; Kapu, D.
S.; Ward, S. A.; Stocks, P. A. Tetrahedron Lett. 2003, 44, 8135e8138.
26. (a) Dussault, P. H.; Eary, C. T.; Woller, K. R. J. Org. Chem. 1999, 64, 1789e1797 See
also: (b) Dussault, P.; Sahli, A. Tetrahedron Lett. 1990, 31, 5117e5120; (c) Dus-
sault, P.; Sahli, A.; Westermeyer, T. J. Org. Chem. 1993, 58, 5469e5474.
1.23 (s, 3H), 1.54 (dd, J¼12.8, 10.9 Hz, 1H), 1.64 (br s, 1H, OH), 2.01
(dt, J¼14.1, 7.1 Hz, 1H), 2.09 (dt, J¼12.6, 6.3 Hz, 1H), 2.26 (dd, J¼12.8,
5.2 Hz, 1H), 3.80e3.85 (m, 3H), 4.17 (t, J¼16.5 Hz, 1H), 5.42 (dd,