A stereodivergent synthesis of β-hydroxy-α-methylene lactones via vinyl epoxides

Article abstract of DOI:10.1039/b802310g

A catalytic diastereoselective sulfonium ylide epoxidation of aldehydes furnished original vinyl epoxides, having an MBH backbone. These highly functionalised building blocks were used for a formal synthesis of the antibiotic conocandin, and opened up a stereodivergent route towards β-hydroxy-α-methylene lactones, core units of naturally occurring compounds. Under acidic conditions, the oxiranes were mainly transformed, with moderate to good yields, into trans β-hydroxy-α-methylene lactones. On the other hand, a user-friendly palladium-catalysed CO₂ insertion and cyclisation sequence gave the cis β-hydroxy-α-methylene lactone counterparts along with an interesting cis-trans equilibration of the π-allyl intermediates. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802310g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A stereodivergent synthesis of b-hydroxy-a-methylene lactones via vinyl
epoxides†
Marion Davoust,a Fre´de´ric Cantagrel,a Patrick Metzner*a and Jean-Franc¸ois Brie`re*a,b,c
Received 12th February 2008, Accepted 12th March 2008
First published as an Advance Article on the web 9th April 2008
DOI: 10.1039/b802310g
A catalytic diastereoselective sulfonium ylide epoxidation of aldehydes furnished original vinyl
epoxides, having an MBH backbone. These highly functionalised building blocks were used for a
formal synthesis of the antibiotic conocandin, and opened up a stereodivergent route towards
b-hydroxy-a-methylene lactones, core units of naturally occurring compounds. Under acidic conditions,
the oxiranes were mainly transformed, with moderate to good yields, into trans b-hydroxy-a-methylene
lactones. On the other hand, a user-friendly palladium-catalysed CO2 insertion and cyclisation
sequence gave the cis b-hydroxy-a-methylene lactone counterparts along with an interesting cis–trans
equilibration of the p-allyl intermediates.
A3 (a trans lactone) and lincomolide B4 (a cis lactone) feature,
Introduction
respectively, potent activity against cancer tumor cell lines and
antitubercular properties.5 In addition, the open-chain diol II
Belonging to the wide-ranging naturally occurring family of a-
methylene-c-butyrolactones, the b-hydroxy-a-methylene lactone
displays the highly synthetically versatile Morita–Baylis–Hillman
(MBH) backbone,6 namely an a-methylene-b-hydroxycarbonyl
structure, which is flanked by an extra alcohol function. These
densely functionalised alk-1-en-3,4-diols have proved to be useful
intermediates in organic synthesis.7
scaffold I is found within compounds having a large array of
biological functions (Fig. 1).1 Their pharmaceutical activities
are related to their structures, from the simpliest motif to some
more elaborate ones. For instance, the simple motif of tulipalin
B2 provides fungicidal activity, whereas the more complex waol
The synthetic endeavours towards b-hydroxy-a-methylene-c-
butyrolactones include the stereochemical control of C-4 and C-5
(in the relative and absolute sense) within such highly decorated
five-membered rings. Early on, the stereoselective synthesis of
these compounds was based on modifications of sugar derivatives.8
In the 1980s, aldolisation reactions of esters derivatives to chiral
aldehydes (with an a-alkoxy group) were developed and furnished
a C–C bond-formation approach via disconnection 1 (I, Fig. 1).
The lactone ring was subsequently formed by cyclisation of the
obtained diol II, from which the alkene moiety was regenerated
by b-elimination of a heteroatom (at the b or a position).9 The
direct inter- and intra-molecular addition of acrylates to chiral
aldehydes in the presence of an amine (MBH reaction) was
achieved with good anti:syn selectivities.10 With respect to these
methods, a chiral acrylamide derived from Oppolzer’s sultam
auxiliary was involved in a highly diastereoselective MBH reaction
to form a readily available precursor of tulipaline B (Fig. 1).2b The
addition of vinyl anion (Br–Li exchange of the corresponding
vinyl bromide) to chiral aldehydes was also studied for the
elaboration of target I in few steps.11 Alternatively, a sequence
involving a diastereoselective Schenck ene-reaction (singlet oxy-
gen) to allylic alcohols was developed in order to introduce
the alcohol at C-4 (disconnection 2).12 On the other hand, the
enantioselective Sharpless dihydroxylation of alkenes turned out
to be the method of choice for the introduction of the diol moiety
(disconnections 2 and 4). In that context, Liu and co-worker
prepared an acetylenic diol from an ene-yne substrate with good
ee. They subsequently performed an elegant cycloalkenation of
the corresponding propargyltungsten intermediate with acetylenic
aldehydes. The obtained oxacarbenium salt was subsequently
Fig. 1 b-Hydroxy-a-methylene lactones.
aLaboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, Uni-
versite´ de Caen, CNRS, 6 Boulevard du Mare´chal Juin, 14050, Caen, France.
E-mail: patrick.metzner@ensicaen.fr; Fax: +33 (0)231452865; Tel: +33
(0)231452885
bINSA de Rouen, IRCOF, rue Tesnie`re, BP 08, 76131, Mont-Saint-
Aignan, France. E-mail: jean-francois.briere@insa-rouen.fr; Fax: +33
(0)235522962; Tel: +33 (0)235522464
cCNRS, Universite´ de Rouen, UMR 6014 COBRA, rue Tesnie`re, 76131,
Mont-Saint-Aignan, France
† Electronic supplementary information (ESI) available: Further experi-
mental details and analytical data for products 10a and 14, and NOE
experiments for 10a, 10g and 17a. See DOI: 10.1039/b802310g
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demetallated to b-hydroxy-a-methylene lactones.13 Bru¨ckner and
successes to develop a route to b-hydroxy-a-methylene lactones via
this epoxidation–cyclisation sequence, providing a stereodivergent
entry to these compounds. The application of this epoxidation
towards a novel formal synthesis of conocadin will also be
described.
co-workers studied a straightforward regioselective dihydroxyla-
ꢀ
tion of a ,bꢀ,a,b-unsaturated esters which led, after cyclisation, to
lactones with moderate to good enantiomeric excesses.14 The cis
and trans derivatives were obtained with respect to the geometry
of the starting dienes. Krische and Rhee have recently described
an effective reductive cyclisation of acetylenic aldehydes catalysed
by enantiopure rhodium complexes (disconnection 1).15 All these
methods have been providing elegant and new approaches to b-
hydroxy-a-methylene lactone scaffolds but, in some cases, they
suffer from a lack of generality due to the specificity of the starting
materials. Moreover, the level of selectivities obtained so far leaves
space for improvement.
Results and discussion
Synthesis of epoxidation precursors
At the onset of this project, we developed a straightforward access
to allylic bromide derivatives 2, our epoxidation precursors. This
synthesis was based on a successful two step MBH–bromination
sequence from the weakly reactive tertiary dimethyl acrylamide
(Scheme 2).16,24 This reaction has been easily extended to morpho-
nyl acrylamide.
We recently became interested in the use of epoxides III (R1 =
NMe2), which are readily available by sulfonium ylide epoxidation
of aldehydes R1CHO (Fig. 1).16 This skeleton displays both a vinyl
epoxide and an MBH building block, which offer many synthetic
transformation opportunities. Moreover, this motif is present
within conocandin (Fig. 1), a potent antibiotic isolated by Mu¨ller
and co-workers in 1976 from a strain of Hormococcus conorum.17
In that context, we envisaged an alternative approach to b-
hydroxy-a-methylene lactone structures based on disconnections 2
and 3. The open-chain intermediate diol II would be formed via a
stereoselective ring-opening transformation of vinyl epoxides III,
to allow a concise access to the lactone ring after cyclisation. To
our knowledge, few publications bring confidence in the feasibility
of this sequence. Kende and Toder described a single example
showing the ability of a trans ester-epoxide III (Y = OEt, R1 =
Me, Fig. 1) to undergo cyclisation to a racemic trans b-hydroxy-
a-methylene lactone in the presence of a Brønsted acid.18 Carlson
and Yang synthesized in situ carboxylic acid derivatives III (Y =
OH, Fig. 1), from epoxidation of the corresponding aldehydes,
which, upon an acidic work-up, furnished the methylene lactone I
with moderate cis and trans ratios.19 These lactonisation sequences
were used as a key step towards bioactive compounds.20
Making use of allylic bromide derivatives having an acrylamide
moiety (Scheme 1),16 we recently described an organocatalytic
sulfonium ylide epoxidation allowing a straightforward connective
formation of vinyl epoxides III (Y = NMe2) via C–C and C–O
bond formation.21–23 We established that the presence of an amide
(instead of an ester or acid) was crucial to preserve the acry-
late moiety integrity, which otherwise underwent polymerisation
events in these basic conditions. But the ability of these robust
epoxy-acrylamides to undergo lactonisation, in a stereospecific
way, is uncertain. We report herein in full our attempts and
Scheme 2 Synthesis of 2-bromomethylacrylamide derivatives.
Sulfonium ylide epoxidation
Both allylic precursors 2a and 2b reacted smoothly in one day
at ambient temperature with various aromatic aldehydes, or cin-
namaldehyde, in the presence of caesium carbonate and a substoi-
chiometric amount of thiolane (Scheme 3).16 This organocatalytic
open-air process furnished the corresponding epoxides 3 with
high trans selectivities (Table 1, entries 1–6) regardless of the
amide moiety (entries 1 vs. 11).22c Aliphatic aldehydes, such as
valeraldehyde, underwent epoxidation in 60 to 78% yield but with
lower diastereoisomeric ratios (entries 7 and 12). Branched (more
hindered) aldehydes gave lower yields due to a slower reaction
of the ylide reagent (entries 8 and 10). Unfortunately, longer
reaction times led only to moderate improvements in yield due
to decomposition of the allylic reactant. Therefore, we used a
stoichiometric amount of sulfonium salt, preformed in situ in water
from 2 (entry 9),25 and improved the yield of epoxide 3h from 51
to 71%, albeit with lower dr.
Scheme 3 Epoxidation of aldehydes (see Table 1).
These outcomes are in agreement with the recently proposed
mechanism by Aggarwal and Harvey explaining the diastere-
oselectivity of the epoxidation of aldehydes by aryl sulfonium
ylides.26–28
Scheme 1 Strategy.
1982 | Org. Biomol. Chem., 2008, 6, 1981–1993
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Table 1 Epoxidation of aldehydes (see Scheme 3)a
Entry
NR2
R1
Product
Yieldsb (%)
dr (trans/cis)
1
2
3
4
5
6
7
8
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NC4H8O
NC4H8O
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3h
3i
90
92
>95 : 5
93 : 7
94 : 6
>95 : 5
95 : 5
92 : 8
77 : 23
78 : 22
63 : 37
62 : 38
>95 : 5
71 : 29
4-CF3C6H4
4-NO2C6H4
4-MeOC6H4
2-Furyl
83
73d (33e)
c
75d
85d (67e)
78
=
PhCH CH
n-Butyl
i-Butyl
i-Butyl
Cy
51
71
39
93
9f
10
11
12
C6H5
3j
3k
n-Butylc
66
a General reaction conditions: 0.25 mmol of benzaldehyde (0.5 M), allylbromide (1.3 eq.), thiolane (0.2 eq.), Cs2CO3 (1.8 eq.), NaI (0.2 eq.), MeCN, rt,
24 h. b Isolated yield after column chromatography on silica gel. c After 48 h. d NMR yield with an internal standard. e Purification on neutral alumina.
f Preformation of the sulfonium salt in water between allylbromide (1 eq.), thiolane (1 eq.) for 5 h, followed by the addition of t-BuOH (9 : 1 t-BuOH–H2O),
aldehyde (1 eq.), NaOH (2 eq.).
Lactonisation of the obtained vinyl epoxides
(entry 4). Much better results were obtained with oxiranes 3g and
3k, having an alkyl chain, which were transformed into the main
trans derivatives 4c in a diastereospecific manner and with more
than 60% yield (entries 5 and 7). We also observed the formation
of the furanone isomer 5 (R1 = n-Bu).30 The amount of this
derivative increased with the reaction time (entry 6). We supposed
that the furanone 5 is the thermodynamic product of the whole
process, coming from the b-hydroxy-a-methylene lactone, via acid-
catalysed isomerisation of the allylic alcohol unit.31 Accordingly,
this forced us to run these reactions for a short period of time
(20 minutes) to minimize the amount of furanone 5.
Having the original epoxides 3 in hand, we undertook the
direct lactonisation reaction under acidic conditions according
to Scheme 4.
This method constitutes a very simple entry to trans b-hydroxy-
a-methylene lactones and affords useful yields with derivatives
having an alkyl group at the 5 position giving, moreover, diastere-
ospecific cyclisations. The access to trans lactones having an aryl
groups at C-5 was limited by poor yields, and/or epimerisation of
the main trans epoxides. In order to get a reasonable working
hypothesis, we established a mechanistic explanation of these
outcomes (Scheme 5).
We assumed that a molecule of water (solvent) adds directly to
the activated allylic carbon under acid catalysis, in an SN2 manner,
to lead to the corresponding diol 6 with inversion of configuration
(trans pathway).32 Although not required, we suppose that an
extra hydrogen bond between the incoming water nucleophile and
the amide could also stabilize the transition state. Then, the diol
easily cyclises into lactone and the cleavage of the robust amide
function is facilitated due to the intramolecular nature of this
step.33 In the case of a phenyl group (R1 = Ph) a carbocation at
Scheme 4 Lactonisation under acidic conditions (see Table 2).
We screened many Brønsted and Lewis acids, eventually finding
that the best conditions involved the use of an aqueous sulfuric
acid solution (Table 2).29 The epoxides 3a and 3j led to the
corresponding major trans lactone 4a (R1 = Ph) in poor yield
irrespective of the amide moiety (entries 1–3). The slow diastere-
ospecific cyclisation at room temperature (entry 1) was speeded
up at 60 ◦C (entries 1 vs. 2–3) but this was detrimental to the
trans/cis ratio. At this stage, the relative stereochemistry was fully
determined by NMR NOE experiments.29 The epimerisation event
was not observed when an electron-poor aryl group was present
Table 2 Lactonisation of epoxides 3 in acidic conditions (see Scheme 4)
Entry
Epoxide 3a (trans/cis)
Time
Temp.
rt
Lactone 4a (trans/cis)
Yieldb(%)
4/5a
1
2
3
4
5
6
7
3a (95 : 5)
3a (95 : 5)
3j (95 : 5)
3b (93 : 7)
3g (78 : 22)
3g (78 : 22)
3k (71 : 29)
21 h
4a (92 : 8)
4a (64 : 36)
4a (72 : 28)
4b (90 : 10)
4c (79 : 21)
4c (76 : 24)
4c (72 : 28)
15
13
24
20
62
30
66
100 : 0
100 : 0
100 : 0
100 : 0
90 : 10
38 : 62
92 : 8
30 min
30 min
60 min
20 min
6.5 h
60 ◦
60 ◦
60 ◦
60 ◦
60 ◦
C
C
C
C
C
20 min
60 ◦C
a Determined by 1H NMR spectroscopy of the crude product. b Isolated yield of both trans and cis lactone.
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formation of the corresponding sulfonium salt 8 in the presence
of water.25 This protocol allowed the subsequent in situ addition
of the other components, and led to an improved yield and
enantioselectivity (Scheme 6). The enantiomeric excess of both
trans and cis vinyl oxiranes 3a (whose absolute configuration was
a priori unknown) was determined by HPLC. We then successfully
carried out Tsuji’s palladium-catalysed reduction on the mixture of
epoxides 3a to form the corresponding secondary alcohol 9.36 This
alcohol underwent smooth cyclisation, with slight racemisation,
into a-methylene lactone 10, for which the absolute configuration
had previously been determined in the literature.37 The addition
of lithium dimethylamide allowed the reverse synthesis of the sec-
ondary alcohol with the same absolute configuration (comparison
of HPLC analysis), showing, thereby, that the lactonisation mainly
took place with a retention of configuration. Therefore, we could
deduce the absolute configuration of the original epoxides 3a.
To explain these results, the lactonisation (9 to 10) should go
mainly through the attack of the alcohol to the amide (retention
of configuration).33 The concomitant formation of the other
enantiomer) occurs likely via the formation of a carbocation
followed by the attack of a molecule of water, which is reminiscent
of the proposal in Scheme 5. On the other hand, we can not rule
out the direct attack of the amide moiety onto the carbocation,
followed by the hydrolysis of the obtained iminium into lactone
10.34 Nevertheless, this shows that the amide bond is easily cleaved
in the presence of a c-hydroxy group, and therefore that our
challenge would be the clean formation of the corresponding diol
6 (Scheme 5) to form a b-hydroxy-a-methylene-c-butyrolactone.
The successful formation of p-allyl intermediates with vinyl
epoxide 3a (Scheme 6) prompted us to envisage a carbon dioxide
insertion into this catalytically formed reagent, as shown in
Scheme 7.38 Thereby, the carbonate derivatives 11 would be
obtained, and this masked diol could easily be cyclised into a
lactone.
Scheme 5 Mechanistic proposal.
the benzylic position would be stabilized for a period of time
long enough to allow the attack of a molecule of water on
either face of the sp2 carbon (trans/cis pathway). Once again,
the diol 6 would easily cyclise into a mixture of trans and cis
lactones with regard to the previous epimerisation event.34 Some
indirect proof of this hypothesis arose from previous studies
that we performed to determine the absolute configuration of
the enantioenriched epoxide 3a (Scheme 6).16 Our first attempts
towards an enantioselective epoxidation gave the best result with
NaOH as a base, but showed that the addition of a bulkier C2-
symmetrical sulfide 7 (with respect to thiolane) to allylic bromide
2a was slow. A moderate yield was obtained (34% yield) and
concurrent side reactions with the unreacted reactants occurred.35
Therefore, we established a user-friendly protocol in order to
preform the sulfonium salt before adding other reagents. It was
shown that a mixture of sulfide 7 and 2a resulted in complete
Scheme 7 CO2 insertion (see Tables 3 and 4).
Our first attempt, with a poorly coordinated phosphite ligand
under CO2 atmosphere, led to the corresponding carbonate 11a
with 63% yield and a very good 92 : 8 ratio of trans/cis isomers
(Table 3, entry 1). However, this process was accompanied by
the formation of ketones 12 (Scheme 7), arising from a b-
elimination reaction. Pleasingly, a much better result was obtained
by making use of bicarbonate as a user-friendly carbon dioxide
surrogate (entry 2), which was originally described by Trost and
McEachern.39 Only traces of 12 could be seen in the NMR of
the crude product. Probing the scope of these conditions, we
observed no reaction with sodium carbonate as a base (entry 3)
Scheme 6 Determination of the absolute configuration of the enantioen-
riched epoxide 3a.
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Table 3 CO2 insertion into epoxide 3a (R1 = Ph)a
Entry
Ligand
CO2 source
Solvent
Conv.b(%)
Yieldb(%)
rd 11ac (trans/cis)
11a : 12a : 12bc
d
1
2
3
4
5
6
7
8
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
PPh3
CO2
CH2Cl2
CH2Cl2
CH2Cl2
THF
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
100
100
7
0
0
90
93
5
63
80
—
—
—
52
—
—
92 : 8
92 : 8
—
—
—
90 : 10
94 : 6
—
84 : 3 : 13
>99 : 1 : 1
—
—
—
76 : 6 : 19
62 : 6 : 32
—
NaHCO3
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
dppe
dppb
a The reactions were performed at rt for 30 hours with the epoxide 3a having a >95 : 5 ratio (trans:cis). b For both trans and cis carbonates. c Determined
on the 1H NMR of the crude product. d Under CO2 atmospheric pressure without water as solvent.
or with more coordinating solvents (entries 4–5). The use of a
more electron-rich phosphine such as PPh3 led to an increase in
side products 12 (entry 6). Eventually, we found that bidentate
phosphine ligands resulted in a slower reaction, or an increase in
b-elimination products, depending on their bite-angle (entries 7
and 8). It seems that a strongly coordinating environment (solvent
or ligand) renders more difficult either the coordination or the
oxidative insertion to the vinyl epoxide moiety, by hindering
and/or saturating the metal. Moreover, for successful p-allyl
derivative formation, the subsequent reaction of CO2 is retarded,
favouring the b-elimination process.40
We next focused on the scope and limitation of this easily
performed reaction with various epoxides 3 (Table 4). The reaction
worked well with both dimethyl or morpholinyl amides (entries 1
and 2). It was found that an electron-withdrawing group on the
Scheme 8 Mechanistic proposal.
aryl moiety slowed down the process (entry 3), or completely
suppressed the CO2 insertion in favour of the b-elimination
reaction (entry 4). This constitutes a chemical limitation of this
metal–ligand couple. However, a very interesting observation
was made with epoxides 3g–i having an alkyl moiety. With n-
butyl (entry 5), i-butyl (entry 6) and cyclohexyl groups (entry
7), a virtually complete re-equilibration of the initial trans/cis
mixture of epoxides into trans carbonates took place. Although
this palladium-promoted isomerisation is well-described with
vinyl aziridines,41 this event has been scarcely reported with
vinyl epoxides.42 In our case, this original process is highly
useful, as the sulfonium ylide epoxidation of aliphatic aldehydes
usually occurs with moderate diastereoselectivities. Therefore,
we achieved an excellent trans/cis ratio for this CO2 insertion
step.
allylpalladium complexes (via p–r–p interconversion), or the
cyclisation transition states thereof, would be dictated by the
minimization of the A(1,3) repulsion between amide and R1 groups
of the cis-carbonate precursor. On one hand, the selectivity would
be controlled by the fastness of the cyclisation step into carbonates
11 and a kinetic dynamic resolution would take place (as long as a
fast equilibrium occurs). On the other hand, the trans and cis ratio
of compounds 11 could also reflect the thermodynamic stability
of both p-allylpalladium intermediates.
We carried out the direct transformation of these masked diols
11 into their corresponding methylene lactones 4. However, under
various conditions (Brønsted and Lewis acids), we obtained the
lactones in low yields. It turned out that the carbonate deprotection
was slower than the diol lactonisation so that the accumulated
lactone 4 decomposed during the reaction time. Therefore, we
An explanation of this phenomenon could stem from the
observation depicted in Scheme 8. The distribution of both p-
Table 4 CO2 insertion into of epoxide 3a
Entry
Epoxide (trans/cis)
R1
NR2
Conv.b(%)
Yieldb (%)
Carbonate 11 (trans/cis)d
1
2
3
4
5
6
7
3a (>95 : 5)
3j (>95 : 5)
3b (93 : 7)
3c (96 : 4)
3g (77 : 23)
3h (78 : 22)
3i (62 : 38)
Ph
Ph
NMe2
NC4H8O
NMe2
NMe2
NMe2
NMe2
NMe2
100
100
45
100
100
100
100
80
77
—
0c
91
85
71
11a (92 : 8)
11j (>95 : 5)
11b (94 : 6)
—
11g (>95 : 5)
11h (95 : 5)
11i (>98 : 2)
4-CF3C6H4
4-NO2C6H4
n-Bu
i-Bu
Cy
a General reaction conditions: 1.15 mmol of epoxides 3, NaHCO3 (6 eq.), Pd2dba3.·CHCl3 (0.5 mol%), P(Oi-Pr3) (3 mol%), CH2Cl2–H2O (5 : 2), rt, 30 h.
b For both trans and cis carbonates. c Exclusive formation of ketones 12. d Determined on the NMR of the crude product.
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focused our attention on a two-step, but one-pot procedure
(Scheme 9).42a
Scheme 10 Formal synthesis of conocandin. Reagents and conditions: a) i.
DHP, p-TSA; ii. MsCl, Et3N; iii. NaI (ref. 46); b) i. Me3Al (3 eq.), Cp2ZrCl2
(0.2 eq.), H2O (1.5 eq.), CH2Cl2, 0 ◦C, 1h; ii. I2, THF (76%), (ref. 45); c)
i. 13 (1.5 eq. with respect to 14), ZnCl2 (1.9 eq.), t-BuLi (6 eq.), ether,
−78 ◦C; ii. 14 (1 eq.), Pd(PPh3)4 (0.02 eq.), ether (73%, estimated with
an NMR internal standard); d) p-TSA, MeOH (50% from 14); e) TPAP,
NMO, acetone (58%); f) i. allyl bromide 2a, thiolane (1 eq.), H2O, rt, 5 h;
ii. Aldehyde 17 (1 eq.), NaOH (2 eq.), t-BuOH (t-BuOH–H2O 9 : 1), rt,
39 h (62%).
Scheme 9 Synthesis of cis lactone.
An easy saponification proceeded in the presence of lithium
hydoxide in water to furnish the desired diol 6 in situ. All attempts
to isolate this compound were unsuccessful due to its high polarity.
The addition of dilute sulfuric acid solution then smoothly
performed the lactonisation into products 4. Once again, the
reaction time for the cyclisation step had to be as short as possible
to prevent a formation of a large amount of furanone 5, likely to
be the thermodynamic product (seen on the NMR of the crude
product). This lactonisation sequence was achieved at 60 ◦C in a
stereospecific fashion even with the phenyl-substituted carbonate.
In contrast to acid-catalysed lactonisation of epoxides 3 (Scheme 5
vs. Scheme 9), one can suppose that the diol 6 ring-closing step is
fast enough to prevent any epimerisation. However, the lactones
4g–h with a 5-alkyl group gave the best results once again, certainly
due to their higher stability in acidic conditions compared to
aryl lactones (Scheme 9). It is noteworthy that the overall process
furnished cis lactones, thanks to the epoxide transformation into
carbonate taking place with retention of configuration. So, this
approach is complementary to the acid-catalysed cyclisation of
vinyl epoxides 3, which mainly afforded trans lactones. Therefore,
we have developed a stereodivergent methodology to both cis and
trans lactones from our trans vinyl oxiranes 3.
a carboalumination–iodation sequence, in the same flask, based
on Wipf’s protocol.45 Then, the known iodide 1346 was expected
to react with vinyl iodide 14 by means of a metal-catalysed
cross-coupling reaction to form the challenging trisubstituted
alkene.43 In our hands, the only successful protocol made use
of the in situ pre-formation of the tert-butyl alkylzinc derivative
from 13 (t-BuR1Zn) according to Smith’s conditions.47 After
optimisation, this reagent allowed a palladium-mediated coupling
process to take place with vinyl iodide 14 to give 15 in 73% yield
(determined by NMR with an internal standard). Nearly 10%
of diene and the hydrolysed C5H11OTHP derivatives were also
formed, and, unfortunately the latter was inseparable from 15 by
column chromatography. However, the THP deprotection led to
the known alcohol 16,17c which was easily purified on silica gel.
TPAP oxidation furnished the aldehyde 17,48 which turned out to
be unstable on silica. Then, 17 was subsequently engaged in the
sulfonium ylide epoxidation reaction to give the target epoxide
18 in 62% yield and a moderate diastereoselectivity in favour
of the trans isomer. Although the epoxidation deserves further
optimisation, this reaction is performed late in the synthesis and
thus allows a convergent strategy towards the precursor aldehyde
17.49 Therefore, the alkyl chains flanking the alkene moiety could
be easily and rapidly modified en route to the elaboration of
analogues of conocandin. The hydrolysis of the amide moiety
is currently under investigation by taking advantage of the
trans-amido-esterification sequence used in the aforementioned
lactonisation.
Synthetic application
The epoxidation methodology allowed us to achieve an alternative
formal synthesis of the naturally occurring metabolite conocandin
(Fig. 1), based on disconnections 1 and 2 (Scheme 10).17 The
elaboration of this potent antibiotic has been studied by two
groups, who have pointed out the challenging stereocontrol of
the trisubstituted C–C double bond and the vinyl epoxide units,43
requiring multi-step strategies. However, the sulfonium ylide
epoxidation of 17 (Scheme 10), at a later stage of the synthesis,
afforded the opportunity of a convergent synthesis of this aldehyde
from commercial pentan-1,5-diol and 1-octyne. For that purpose,
we wanted to use Negishi’s methodologies,44 namely zirconium-
catalysed carboalumination and zinc cross-coupling reactions.
The precursor 14 was readily formed in high regioselectivity by
Conclusions
We have described a straightforward organocatalytic sulfur ylide
epoxidation of aldehydes, furnishing vinyl epoxides with an MBH
backbone. This useful building block allowed a stereodivergent
1986 | Org. Biomol. Chem., 2008, 6, 1981–1993
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synthesis of both cis and trans b-hydroxy-a-methylene lactones,
the core structure of some naturally occurring compounds. The
cis lactones were formed in two steps via the corresponding
carbonates, which were synthesized by a user-friendly palladium-
catalysed carbon dioxide insertion into epoxides making use of
NaHCO3 as a CO2 source. During this process, an interesting
isomerisation of cis oxiranes into trans carbonates was observed,
resulting in a synthesis of cis lactones with high selectivities.
The main trans lactones were obtained by a direct cyclisation
of the corresponding oxiranes functionalised by aryl or alkyl
groups. The latter gave the best results in terms of yields and
diastereospecificity. This study has also pointed out the limitations
of the currently used conditions, by showing that certain aryl-
functionalised epoxides could not be transformed in good yield
(low reactivity or product instability). Seeking to extend the scope
of this methodology, we have also succeeded in the synthesis of
enantioenriched trans (S,S)-vinyl epoxides by a C2 symmetrical
sulfide, but in moderate yields and selectivities so far. We are
currently focusing on the improvement of these results. Indeed,
the non-racemic epoxides would open straightforward enantios-
elective routes towards either trans or cis b-hydroxy-a-methylene
lactones. Moreover, the convergent synthesis of the metabolite
conocandin, achieved in this paper, could be extended to both
enantiomers of this potent antibiotic.
3.05 (t, 1H, J = 5.3 Hz, OH, disappears after D2O exchange).
dC(100 MHz): 169.9 (C), 143.4 (C), 115.6 (CH2), 66.99 (CH2),
66.96 (CH2), 63.9 (CH2), 47.9 (CH2), 42.2 (CH2). mmax/cm−1 (neat)
3313, 2859, 1597, 1431, 1279, 1110, 1068, 1032, 911, 844. MS (ESI)
m/z (%): 172 (37, [M + H]+), 154 (30), 114 (100), 100 (14), 88 (60),
85 (30). Found: C, 55.74; H, 7.61; N, 8.14. Calcd for C8H13NO3:
C, 56.13; H, 7.65; N, 8.18.
4-[2-(Bromomethyl)acryloyl)]morpholine (2b). The alcohol 1b
(644 mg, 3.76 mmol) was dissolved in anhydrous diethyl ether
(3 mL) in a round-bottomed flask under nitrogen pressure.
Dimethylformamide (1.46 mL, 18.90 mmol) was added and the
mixture was cooled to −5 ◦C. A solution of PBr3 (176 lL,
1.90 mmol) in anhydrous diethyl ether (685 lL) was then added
dropwise. A white precipitate then appeared. The reaction was
stirred at room temperature and monitored by TLC (AcOEt–
EtOH 4 : 1). After 15 h, the mixture was quenched by hydrolysis
with water (5 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (3 × 25 mL). The organic layers
were combined and washed with water (2 × 100 mL) to remove
dimethylformamide. Then, the organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (AcOEt–pentane 4 : 1, Rf = 0.33) provided 2b
(595 mg, 68%) as white crystals. Mp 41–43 ◦C. dH(400 MHz): 5.51
(s, 1H), 5.12 (s, 1H), 4.20 (s, 2H), 3.67 (brs, 8H). dC(100 MHz):
168.0 (C), 139.6 (C), 118.2 (CH2), 67.1 (CH2), 66.9 (CH2), 47.8
(CH2), 42.3 (CH2), 33.2 (CH2). mmax/cm−1 (neat): 2855, 1643, 1614,
1433, 1110, 1030, 842. MS (ESI) m/z (%): 234 (12, [M + H]+), 147
(100), 119 (47), 100 (3). (Found: C, 41.03; H, 5.30; N, 6.20. Calc
for C8H12BrNO2: C, 41.05; H, 5.17; N, 5.98).
Experimental
General
NMR spectra were recorded on Bruker DPX 250 (1H: 250 MHz,
13C: 63 MHz) or Bruker DRX 400 (1H: 400 MHz, 13C: 100 MHz)
instruments in CDCl3 unless indicated otherwise. Multiplicities in
13C were determined by DEPT135 experiments. IR spectra were
recorded on a Perkin-Elmer Spectrum-One ATR spectrophotome-
ter. Mass spectra were recorded on a Varian GC/MS/MS instru-
ment equipped with CP 3800 (GC) and Saturn 2000 (MS/MS)
modules. Microanalyses were obtained using a ThermoQuest
instrument. Exact mass spectra were recorded on a Waters Q-
TOF Micro apparatus (LC/MS) with an Xterra MS column.
Purification by flash chromatography of compounds was achieved
with Merck 60 silica gel (40–63 lm). Thin layer chromatography
(TLC) was performed on silica gel 60 F254 (1.1 mm, Merck).
Compounds 1–2a and 3a–g have been previously described.16
All reagents were used without any purification unless noted
otherwise.
General procedure for the synthesis of vinyl epoxides 3. To a
solution of the allylic bromide (0.33 mmol, 1.3 eq.), the aldehyde
(0.25 mmol, 1 eq.) and sodium iodide (7.5 mg, 0.05 mmol, 0.2 eq.)
in acetonitrile (0.5 mL), was added tetrahydrothiophene (4.5 lL,
0.05 mmol, 0.2 eq.). The reaction mixture was stirred for 5 min,
then, caesium carbonate (147 mg, 0.45 mmol, 1.8 eq.) was added.
The resulting mixture was vigorously stirred at 20 ◦C for 24 h. The
salts were filtered and washed with CH2Cl2, and the filtrate was
concentrated in vacuo. Purification by column chromatography
afforded the desired epoxides. Note: the asymmetric synthesis of
vinyl epoxide 3a is described after compound 4c.
N,N-Dimethyl-2-(3-isobutyloxiranyl)acrylamide (3h). After
24 h of reaction and purification by column chromatography
(AcOEt–pentane 1 : 1, Rf = 0.28), the inseparable trans and cis
epoxides (78 : 22) were obtained as a colorless oil (25.2 mg, 51%).
dH(400 MHz): trans 5.40 (s, 1H), 5.14 (s, 1H), 3.13 (d, J = 1.6 Hz,
1H), 3.05–2.86 (m, 7H), 1.80–1.65 (m, 1H), 1.45–1.25 (m, 2H),
0.86–0.84 (m, 6H). cis 5.32 (s, 1H), 5.26 (s, 1H), 3.56 (d, J =
4.4 Hz, 1H), 3.10–3.05 (m, 1H), 3.05–2.86 (m, 6H), 1.80–1.65 (m,
1H), 1.45–1.25 (m, 1H), 1.25–1.15 (m, 1H), 0.86–0.84 (m, 6H).
dC(100 MHz): trans 168.7 (C), 142.4 (C), 116.4 (CH2), 59.6 (CH),
57.9 (CH), 41.0 (CH2), 38.7 (CH3), 34.4 (CH3), 26.2 (CH), 22.8
(CH3), 22.3 (CH3). cis 169.6 (C), 138.7 (C), 117.3 (CH2), 58.5
(CH), 55.7 (CH), 35.2 (CH2), 34.7 (CH3), 34.7 (CH3), 26.4 (CH),
22.64 (CH3), 22.57 (CH3). mmax/cm−1 (neat): 2956, 1643, 1619,
1397, 1111, 905. MS (ESI) m/z (%): 198 (100, [M + H]+), 180 (27),
153 (26), 152 (23), 135 (50), 123 (25), 111 (43), 107 (62), 97 (19).
4-[2-(Hydroxymethyl)acryloyl)]morpholine (1b). Paraformal-
dehyde (901 mg, 30 mmol), DABCO (693 mg, 6 mmol) and phenol
(141 mg, 1.5 mmol) were introduced into a 10 mL flask with a
stirring bar. The vessel was fitted with a septum and gently flushed
with argon. A t-BuOH–H2O (3 : 7) solvent mixture (370 lL) and
4-acryloylmorpholine (780 lL, 6.0 mmol) were then added via a
syringe. The resulting mixture was stirred for 27 h at 55 ◦C (oil bath
temperature) and was then allowed to cool to room temperature.
Water was co-evaporated with toluene under vacuum. The crude
mixture was then filtered over Celite with dichloromethane and
concentrated in vacuo. Purification by column chromatography
(AcOEt–EtOH 5 : 1, Rf = 0.33) afforded the desired product
(688 mg, 67%) as colorless crystals. Mp 91–92 ◦C. dH(250 MHz):
5.49 (s, 1H), 5.17 (s, 1H), 4.28 (d, 2H, J = 5.3 Hz), 3.65 (brs, 8H),
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HRMS (ESI): calcd for C11H20NO2 [M + H]+: 198.1494, found:
198.1485.
7.1 Hz, 3H). cis 5.47 (s, 1H), 5.37 (s, 1H), 3.02 (dd, J = 3.3 and
10.6 Hz, 1H). The other protons could not be observed for the cis
diastereoisomer. dC(100 MHz): trans 167.3 (C), 142.0 (C), 117.2
(CH2), 66.8 (CH2), 66.8 (CH2), 60.3 (CH), 57.8 (CH), 47.6 (CH2),
41.9 (CH2), 31.5 (CH2), 27.8 (CH2), 22.4 (CH2), 13.9 (CH3). cis
168.0 (C), 138.1 (C), 117.7 (CH2), 66.8 (2 CH2), 59.7 (CH), 56.1
(CH), 47.6 (CH2), 41.9 (CH2), 28.3 (CH2), 26.3 (CH2), 22.5 (CH2),
13.9 (CH3). mmax/cm−1 (neat): 2958, 1644, 1619, 1432, 1112, 1031,
844. MS (ESI) m/z (%): 240 (100, [M + H]+), 222 (29), 194 (7), 170
(21), 153 (39), 135 (60), 114 (76), 107 (34), 97 (7). HRMS (ESI):
calcd for C13H22NO3 [M + H]+: 240.1600, found: 240.1606.
Stoichiometric epoxidation protocol for 3h. Thiolane (25 lL,
0.28 mmol) was added to a solution of the allylic bromide (53.1 mg,
0.28 mmol) in water (50 lL) at rt. Under vigorous stirring, the
initial heterogeneous solution became homogeneous after 5 h. t-
BuOH (450 lL), benzaldehyde (25 lL, 0.25 mmol) and NaOH
(20 mg, 0.5 mmol) were subsequently added to the solution.
The mixture was vigorously stirred for 24 h at room temperature
and then diluted with water. The aqueous layer was extracted by
dichloromethane and the combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (AcOEt–pentane = 1 : 1, Rf = 0.28) afforded the
desired epoxides (35 mg, 71%) as an inseparable mixture of trans
and cis diastereoisomers (63 : 37). See above for analyses.
Representative procedure for the lactonisation of vinyl epoxides
3 to 4 under acidic conditions (Table 2). The vinyl epoxide
(0.09 mmol, 1 eq.) and an aqueous solution of H2SO4 (2 mL,
◦
5% v/v) were introduced into a Schlenk flask at 20 C and were
N,N-Dimethyl-2-(3-cyclohexyloxiranyl)acrylamide (3i). After
24 h of reaction and purification by column chromatography
(AcOEt–pentane 1 : 1, Rf(cis) = 0.43, Rf(trans) = 0.37), parts
of the trans and cis epoxides (60 : 40) were obtained separately
as colorless oils (21.9 mg, 39%). dH(400 MHz): trans 5.46 (s, 1H),
5.21 (s, 1H), 3.31 (d, J = 2.0 Hz, 1H), 3.00 (s, 3H), 2.95 (s, 3H),
2.79 (dd, J = 2.0 and 6.7 Hz, 1H), 2.00–1.61 (m, 5H), 1.24–1.06
(m, 6H). cis 5.45 (t, J = 1.3 Hz, 1H), 5.34 (s, 1H), 3.71 (dd, J =
1.3 and 4.4 Hz, 1H), 3.08 (s, 3H), 3.00 (s, 3H), 2.83 (dd, J = 4.4
and 8.5 Hz, 1H), 1.88–1.84 (m, 1H), 1.73–1.62 (m, 4H), 1.20–1.12
(m, 6H). dC(100 MHz): trans 168.9 (C), 142.8 (C), 116.4 (CH2),
65.0 (CH), 56.8 (CH), 40.2 (CH3), 38.9 (CH3), 34.7 (CH), 29.3
(CH2), 28.9 (CH2), 26.3 (CH2), 25.7 (CH2), 25.6 (CH2). cis 169.5
(C), 138.7 (C), 117.5 (CH2), 64.2 (CH), 56.5 (CH), 39.0 (CH3), 35.1
(CH3), 35.1 (CH), 30.4 (CH2), 28.7 (CH2), 26.3 (CH2), 25.5 (CH2),
25.5 (CH2). mmax/cm−1 (neat): 2924, 1644, 1617, 1396, 1102, 870.
MS (ESI) m/z (%): 224 (57, [M + H]+), 206 (52), 161 (100), 133
(63), 128 (34), 97 (24), 91 (15). HRMS (ESI): calcd for C13H22NO2
[M + H]+: 224.1651, found: 224.1649.
stirred at 60 ◦C (oil bath). After allowing to cool, the aqueous
layer was extracted with CH2Cl2 (3 × 2 mL). The combined
organic layers were washed with a saturated aqueous solution of
NaHCO3 (6 mL), dried over MgSO4, filtered and concentrated
in vacuo. Purification by column chromatography (AcOEt–
pentane) provided the desired lactones as a mixture of trans and
cis diastereoisomers.
4-Hydroxy-3-methylene-5-phenyl-c-butyrolactone (4a). After
30 min of reaction with epoxide 3a, purification by column
chromatography (AcOEt–pentane 1 : 1, Rf(trans) = 0.47, Rf(cis) =
0.33) gave the trans and cis lactones 4a partly separated as yellow
oils (24%, 72 : 28 dr). dH(400 MHz): trans 7.41–7.34 (m, 5H), 6.49
(d, J = 2.2 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 5.22 (d, J = 5.2 Hz,
1H), 4.74 (brs, 1H), 2.76 (brs, 1H). cis 7.45–7.30 (m, 5H), 6.52 (d,
J = 2.0 Hz, 1H), 6.02 (d, J = 2.0 Hz, 1H), 5.60 (d, J = 6.1 Hz, 1H),
5.05 (brs, 1H), 1.46 (d, J = 6.1 Hz, 1H). dC(100 MHz): trans 168.5
(C), 138.3 (C), 137.2 (C), 129.1 (CH), 129.0 (CH), 126.1 (CH2),
125.6 (CH), 85.8 (CH), 75.8 (CH). cis 168.9 (C), 137.6 (C), 133.1
(C), 129.4 (CH), 129.1 (CH), 127.2 (CH2), 126.8 (CH), 82.4 (CH),
70.5 (CH). mmax/cm−1 (neat): 3422, 1748, 1146, 1069, 996, 696. MS
(ESI−) m/z (%): 189 (100, [M-H]−), 161 (10), 159 (5), 145 (17), 143
(10), 133 (25), 127 (12), 117 (16), 115 (4). HRMS (ESI−): calcd for
C11H9O3 [M − H]−: 189.0552, found: 189.0549.
4-[2-(3-Phenyloxiranyl)acryloyl]morpholine (3j). After 24 h of
reaction and purification by column chromatography (AcOEt–
pentane 2 : 1, Rf = 0.39), the epoxides were obtained as yellow
crystals (60.3 mg, 93%) as an inseparable mixture of trans and cis
diastereoisomers (95 : 5). dH(400 MHz): trans 7.35–7.27 (m, 5H),
5.61 (s, 1H), 5.36 (s, 1H), 4.00 (d, J = 2.0 Hz, 1H), 3.90–3.53 (m,
8H), 3.52 (d, J = 2.0 Hz, 1H). cis 5.57 (s, 1H), 5.16 (s, 1H), 4.30 (d,
J = 4.5 Hz, 1H), 3.20 (d, J = 4.5 Hz, 1H). The other protons could
not be observed for the cis diastereoisomer. dC(100 MHz): trans
167.1 (C), 141.4 (C), 136.4 (C), 128.7 (CH), 128.6 (CH), 125.7
(CH), 118.2 (CH2), 67.05 (CH2), 67.02 (CH2), 62.1 (CH), 59.9
(CH), 47.8 (CH2), 42.2 (CH2). IR (neat): 2855, 1643, 1615, 1434,
1111, 1031, 844, 754, 698. MS (ESI) m/z (%): 260 (32, [M + H]+),
242 (9), 173 (100), 145 (22), 117 (21), 100 (47), 91 (21), 88 (10).
HRMS (ESI): calcd for C15H18NO3 [M + H]+: 260.1287, found:
260.1279
4-Hydroxy-3-methylene-5-(4-trifluoromethylphenyl)-c-butyro-
lactone (4b). After 60 min of reaction with epoxide 3b, purifica-
tion by column chromatography (AcOEt–pentane 2 : 3, Rf(trans) =
0.32, Rf(cis) = 0.28) gave the trans and cis lactones 4b separately
as colorless oils (20%, dr 90 : 10). dH(250 MHz): trans 7.69 (d,
J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 2.6 Hz,
1H), 6.04 (d, J = 2.6 Hz, 1H), 5.29 (d, J = 5.2 Hz, 1H), 4.73
(brs, 1H), 2.66 (d, J = 6.4 Hz, 1H). cis 6.56 (d, J = 1.7 Hz,
1H), 6.07 (d, J = 1.7 Hz, 1H), 5.64 (d, J = 4.6 Hz, 1H), 5.12
(brs, 1H). The other protons could not be observed for the cis
diastereoisomer. dF(235 MHz): −62.7. dC(100 MHz): trans 167.9
2
4-[2-(3-Butyloxiranyl)acryloyl]morpholine (3k). After 48 h of
reaction and purification by column chromatography (AcOEt–
pentane 2 : 1, Rf = 0.26), the epoxides were obtained as a yellow
oil (39.5 mg, 66%) as an inseparable mixture of trans and cis
diastereoisomers (71 : 29). dH(400 MHz): trans 5.53 (s, 1H), 5.27
(s, 1H), 3.70–3.45 (m, 8H), 3.26 (d, J = 2.1 Hz, 1H), 3.02 (ddd,
J = 2.1, 4.8 and 6.5 Hz, 1H), 1.72–1.30 (m, 6H), 0.91 (t, J =
(C), 141.3 (C), 137.8 (C), 131.3 (q, JC–F = 32.6 Hz, C), 126.6
(CH2), 126.1 (q, 3JC–F = 3.7 Hz, CH), 125.8 (CH), 124.0 (q, 1JC–F
=
272.4 Hz, C), 84.7 (CH), 75.8 (CH). mmax/cm−1 (neat): 3239, 1754,
1330, 1114, 1071, 979, 838. MS (ESI−) m/z (%): 256 (100, [M −
H]−), 229 (16), 213 (67), 201 (27), 193 (28), 165 (30), 145 (16).
HRMS (ESI−): calcd for C12H8O3F3 [M − H]−: 257.0426, found:
257.0419.
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4-Hydroxy-3-methylene-5-butyl-c-butyrolactone (4c). After
20 min of reaction with epoxide 3k and purification by column
chromatography (AcOEt–pentane 2 : 1, Rf = 0.42), the inseparable
trans and cis lactones 4c were obtained as a colorless oil (66%,
72 : 38 dr). dH(400 MHz): trans 6.43 (d, J = 2.2 Hz, 1H), 5.98 (d,
(56 mg, 0.26 mmol, 78% ee for the trans, 30%, ee for the cis)
in THF (0.5 mL) was then added dropwise and the reaction
mixture became yellow. The reaction was stirred at 20 ◦C and
was monitored by TLC (AcOEt–pentane 4 : 1). After 2.5 h, the
solution was passed through a short pad of silica with CH2Cl2,
and the filtrate was concentrated in vacuo. Purification by column
chromatography (AcOEt–pentane 4 : 1, Rf = 0.19) afforded
the desired alcohol 9 (48 mg, 86%, 71% ee) as a colorless oil.
dH(250 MHz): 7.42–7.21 (m, 5H), 5.31 (s, 1H), 5.21 (s, 1H), 5.03
(d, J = 3.4 Hz, 1H), 4.88 (m, 1H, after D2O exchange: dd, J =
2.7 and 9.1 Hz), 3.08 (s, 3H), 3.03 (s, 3H), 2.69 and 2.53 (AB part
of ABX system, 2H, JAX = 2.7, JBX = 9.1 and JAB = 14.0 Hz).
dC(63 MHz): 172.9 (C), 144.3 (C), 140.6 (C), 128.3 (CH), 127.3
(CH), 125.9 (CH), 119.6 (CH2), 74.1 (CH), 44.7 (CH2), 39.4
(CH3), 35.2 (CH3). mmax/cm−1 (neat): 3378, 2931, 1598, 1396, 1057,
700. MS (ESI) m/z (%): 220 (30, [M + H]+), 202 (100), 174 (2),
173 (8), 129 (1). HRMS (ESI): calcd for C13H17NO2Na (MNa+):
242.1157, found: 242.1154. HPLC: AD–H Daicel Chiralpak
column 250 × 4.6 mm, 5 lm. tr = 13.4 and 15.9 min [(S) and
(R) enantiomers]. UV maximum absorption: 202 nm. Absolute
configuration: (R) for the major enantiomer.
3
J = 2.2 Hz, 1H), 4.56–4.50 (m, 1H), 4.26 (ddd, JH–H = 4.4 Hz,
3
1
3JH-CH = 5.4 Hz and JH–CH2 = 7.8 Hz, correlated by H NMR
2
decoupling experiment, 1H), 2.31 (d, J = 6.8 Hz, 1H), 1.85–1.60
(m, 2H), 1.60–1.30 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). cis 6.40 (d,
J = 1.7 Hz, 1H), 5.98 (d, J = 1.7 Hz, 1H), 4.84–4.83 (m, 1H),
4.44 (dt, 3JH-H = JH–CH2 = 5.5 Hz and 3JH–CH2 = 8.4 Hz, correlated
3
by irradiated proton spectra, 1H), 2.21 (brs, 1H), 1.84–1.73 (m,
2H), 1.72–1.26 (m, 4H), 0.94 (t, J = 7.1 Hz, 3H). dC(100 MHz):
trans 168.8 (C), 139.1 (C), 126.0 (CH2), 85.6 (CH), 73.2 (CH),
33.5 (CH2), 27.1 (CH2), 22.5 (CH2), 14.0 (CH3). cis 169.3 (C),
139.1 (C), 126.3 (CH2), 82.5 (CH), 69.5 (CH), 28.4 (CH2), 27.6
(CH2), 22.7 (CH2), 14.0 (CH3). mmax/cm−1 (neat): 3426, 2957,
1740, 1271, 1167, 1112, 984. MS (ESI) m/z (%): 171 (79, [M +
H]+), 153 (80), 135 (77), 125 (19), 111 (79), 109 (16), 107 (100),
101 (11). HRMS (ESI): calcd for C9H15O3 [M + H]+: 171.1021,
found: 171.1020. The furanone side product was also isolated:
3-(hydroxymethyl)-5-butylfuran-2(5H)-one (5). dH(400 MHz):
7.28–7.25 (m, 1H), 4.97 (brt, J = 5.6 Hz, 1H), 4.43 (brs, 1H),
2.46 (brs, 1H), 1.81–1.60 (m, 2H), 1.52–1.28 (m, 4H), 0.91 (t,
J = 6.8 Hz, 3H). dC(100 MHz): 172.9 (C), 149.4 (CH), 133.5 (C),
82.3 (CH), 57.3 (CH2), 33.1 (CH2), 27.3 (CH2), 22.5 (CH2), 14.0
(CH3). mmax/cm−1 (neat): 3435, 1732, 1018. MS (ESI) m/z (%):171
(100, [M + H]+), 153 (61), 135 (31), 111 (34), 107 (49). HRMS
(ESI): calcd for C9H15O3 [M + H]+: 171.1021, found: 171.1019.
3-Methylene-5-phenyl-c-butyrolactone (10). The b-hydroxy-
amide 9 (40 mg, 0.182 mmol) was added to an aqueous solution
of 2 M HCl (4.2 mL). The mixture was warmed to 60 ◦C and
stirred for 2 h. After allowing to cool, the aqueous layer was
extracted with CH2Cl2 (3 × 5 mL). The resulting organic layer
was washed with a saturated aqueous solution of K2CO3 (15 mL),
dried over MgSO4, filtered and concentrated in vacuo. Purification
by column chromatography (AcOEt–pentane 1 : 1, Rf = 0.40)
afforded the lactone (28 mg, 88%, 56% ee) as yellow crystals,
identified by comparing its NMR spectrum with that of the known
compound.37 Mp 54–55 ◦C. dH(250 MHz): 7.40–7.31 (m, 5H), 6.32
(t, J = 2.5 Hz, 1H), 5.70 (t, J = 2.5 Hz, 1H), 5.49 (dd, J = 6.5 and
8.0 Hz, 1H), 3.23 (ddt, J = 2.5, 8.0 and 17.0 Hz, 1H), 2.80 (ddt,
J = 2.5, 6.5 and 17.0 Hz, 1H). [a]1D8 −10.5 (c = 1, CHCl3), lit. (R)
enantiomer [a]1D25 −19.0 (c = 1, CHCl3).37 HPLC: OD-H Daicel
Chiralpak column 250 × 4.6 mm, 5 lm. n-heptane–iso-propanol
95 : 5 at 15 ◦C. tr = 18.5 and 21.3 min [(R) and (S) enantiomers].
UV maximum absorption: 208 nm. Absolute configuration: (R)
for the major enantiomer.
Asymmetric synthesis of N,N-dimethyl-2-(3-phenyloxiranyl)-
acrylamide (3a). A solution of (2R,5R)-2,5-dimethylthiolane 7
(100 mg, 0.86 mmol) with allylic bromide 2a (215 mg, 1.12 mmol)
in water (172 lL) was stirred at 20 ◦C for 24 h. The starting
biphasic mixture became gradually a homogenous solution. t-
BuOH (1.55 mL), benzaldehyde (88 lL, 0.86 mmol), and sodium
hydroxide powder (69 mg, 1.72 mmol) were then added. The
reaction mixture was stirred at 20 ◦C for 3 days. Water (5 mL)
was added and the aqueous layer was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. Purification by column chro-
matography (AcOEt–pentane 3 : 1, Rf = 0.43) afforded the desired
epoxides 3a (81 mg, 43%) as an inseparable mixture of enantio-
enriched trans and cis isomers (88 : 12). The epoxides were then
analyzed by HPLC in order to determine the enantiomeric excess.
HPLC: AS-H Daicel Chiralpak column 250 × 4.6 mm, 5 lm.
tr(trans) = 12.3 and 16.3 min [(S,S) and (R,R) enantiomers]. UV
maximum absorption of trans: 202 nm. Absolute configurations:
3S,2S for the major enantiomer. tr(cis) = 19.5 and 44.4 min [(R,S)
and (S,R) enantiomers]. UV maximum absorption of cis: 202 nm.
Absolute configurations: 3S,2R for the major enantiomer.
4-Hydroxy-N,N-dimethyl-2-methylidene-4-phenylbutanamide
(9) from the lactone 10. Dimethylamine (73 lL, 0.144 mmol,
2.0 M commercial solution in THF) and anhydrous THF
(0.25 mL) were introduced via a syringe into a Schlenk flask
under nitrogen. The mixture was cooled to −78 ◦C and n-BuLi
(64 lL, 0.144 mmol, 2.25 M) was added dropwise. After stirring
for 10 min, a solution of the lactone 10 (25 mg, 0.144 mmol, 56%
ee) in THF (0.5 mL) was dropped into the mixture at −78 ◦C. The
resulting mixture was stirred at −20 ◦C for 2.5 h, and hydrolyzed
with a saturated aqueous solution of NH4Cl (1.2 mL). It was
then allowed to reach room temperature. The aqueous layer was
extracted with CH2Cl2 (3 × 5 mL) and the resulting organic
layer was dried over MgSO4, filtered and concentrated in vacuo.
After purification by column chromatography (AcOEt–pentane
4 : 1, Rf = 0.20), the pure alcohol was obtained (13 mg, 41%).
HPLC analysis showed that the (R)-enantiomer was the major
enantiomer, with 55% ee.
4-Hydroxy-N,N-dimethyl-2-methylidene-4-phenylbutanamide
(9). Pd2(dba)3.CHCl3 (6.6 mg, 6.38 lmol) and tri-n-
butylphosphonium tetrafluoroborate (2 mg, 6.38 lmol) were
introduced into a Schlenk flask under nitrogen. A solution of
formic acid (20 lL, 0.51 mmol) and triethylamine (142 mL,
1.02 mmol) in anhydrous THF (0.5 mL degassed) were added
via a syringe. The resulting purple mixture was stirred for
5–10 min. A solution of the enantioenriched vinylepoxide 3a
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General procedure for the synthesis of vinylcarbonates 11.
Pd2(dba)3·CHCl3 (6 mg, 5.75 lmol, 0.005 eq.) and NaHCO3
(580 mg, 6.9 mmol, 6 eq.) were introduced into a Schlenk flask
under nitrogen. Triisopropylphoshite (9 lL, 34.5 lmol, 0.03 eq.)
was then added via a syringe under nitrogen pressure. These
compounds were dissolved with anhydrous CH2Cl2 (6.5 mL,
degassed). The purple mixture was vigorously stirred at 20 ◦C,
and became bright yellow after 10 min, the time needed for the
complete formation of the organometallic complex. At this stage,
a solution of vinyl epoxide 3 (1.15 mmol, 1 eq.) in anhydrous
CH2Cl2 (5 mL, degassed) was added dropwise via a syringe. Water
(4.6 mL) was◦finally added to the mixture, which was vigorously
stirred at 20 C for 30 h. The biphasic mixture was then passed
through a short pad of (silica/Celite 1 : 9) which was washed with
CH2Cl2. The filtrate was concentrated in vacuo. Purification by
chromatography column afforded the desired carbonate 11. Note:
The products 12a and 12b, which resulted from the b-elimination
pathway, were also obtained in this reaction, depending on
the epoxide (see Table 3): N,N-Dimethyl-2-methylene-4-oxo-4-
phenylbutanamide (12a). dH(250 MHz): 7.95–7.43 (m, 5H), 5.39 (s,
1H), 5.31 (s, 1H), 4.12 (s, 2H), 3.25 (brs, 3H), 3.05 (brs, 3H). MS
(EI) m/z (%): 217 (43, M+), 174 (98), 173 (100), 172 (100), 144 (52),
131 (23), 112 (49), 105 (100), 78 (100), 73 (66). N,N,2-Trimethyl-4-
oxo-4-phenylbut-2-enamide (12b). dH(250 MHz): mixture of E and
Z 7.95–7.43 (m, 5H), 6.84 (s, 1H), 3.06 (s, 3H), 2.92 (s, 3H), 2.34
(d, J = 1.5 Hz, 3H, diastereoisomer A), 2.18 (d, J = 1.5 Hz, 3H,
diastereoisomer B). MS (EI) m/z (%): 217 (43, M+), 174 (98), 173
(100), 172 (100), 144 (52), 131 (23), 112 (49), 105 (100), 78 (100),
73 (66).
N,N-Dimethyl-2-(2-oxo-5-butyl-1,3-dioxolan-4-yl)acrylamide
(11g). After 30 h of reaction and purification by column
chromatography (AcOEt–pentane
3
:
1, Rf
=
0.42), the
inseparable trans and cis carbonates were obtained as a colorless
oil (91%, >95 : 5 dr). dH(400 MHz): trans 5.67 (s, 1H), 5.44 (s,
1H), 4.86–4.84 (m, 2H), 3.11 (s, 3H), 3.02 (s, 3H), 1.85–1.71 (m,
2H), 1.55–1.37 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H). cis 5.89 (s, 1H),
5.61 (s, 1H), the other protons could not be observed for the cis
diastereoisomer. dC(100 MHz): trans 167.7 (C), 154.2 (C), 139.0
(C), 119.2 (CH2), 81.9 (CH), 81.8 (CH), 39.1 (CH3), 35.0 (CH3),
33.4 (CH2), 26.6 (CH2), 22.2 (CH2), 13.8 (CH3). mmax/cm−1 (neat):
2933, 1795, 1618, 1173, 1048, 770. MS (ESI) m/z (%): 242 (100,
[M + H]+), 217 (24), 198 (6), 117 (3). HRMS (ESI): calcd for
C12H20NO4 [M + H]+: 242.1392, found: 242.1389.
N,N-Dimethyl-2-(2-oxo-5-isobutyl-1,3-dioxolan-4-yl)acrylamide
(11h). After 30 h of reaction and purification by column
chromatography (AcOEt–pentane
3
:
1, Rf
=
0.45), the
inseparable trans and cis carbonates were obtained as a colorless
oil (85%, 95 : 5 dr). dH(400 MHz): trans 5.62 (s, 1H), 5.39 (s, 1H),
4.91 (ddd, J = 3.8, 6.8 and 9.4 Hz, 1H), 4.75 (d, J = 6.8 Hz,
1H), 3.06 (s, 3H), 2.97 (s, 3H), 1.86–1.79 (m, 1H), 1.72–1.64 (m,
1H), 1.57–1.51 (m, 1H), 0.93 (d, J = 6.8 Hz, 6H). cis 5.81 (s, 1H),
5.57 (s, 1H), the other protons could not be observed for the cis
diastereoisomer. dC(100 MHz): trans 167.7 (C), 154.2 (C), 138.8
(C), 119.4 (CH2), 82.5 (CH), 80.6 (CH), 42.7 (CH2), 39.1 (CH3),
35.0 (CH3), 24.8 (CH), 22.9 (CH3), 21.8 (CH3). mmax/cm−1 (neat):
2958, 1796, 1618, 1177, 1121, 1047, 770. MS (ESI) m/z (%): 242
(60, [M + H]+), 198 (61), 180 (100), 135 (6). HRMS (ESI): calcd
for C12H20NO4 [M + H]+: 242.1392, found: 242.1380.
N,N-Dimethyl-2-(2-oxo-5-phenyl-1,3-dioxolan-4-yl)acrylamide
(11a). After 30 h of reaction and purification by column
N,N-Dimethyl-2-(2-oxo-5-cyclohexyl-1,3-dioxolan-4-yl)acryla-
mide (11i). After 30 h of reaction and purification by column
chromatography (AcOEt–pentane 3 : 1, Rf = 0.35), the trans
carbonate was obtained as a slightly yellow oil (71%, > 98 : 2 dr).
dH(400 MHz): trans 5.65 (d, J = 1.2 Hz, 1H), 5.42 (s, 1H), 5.00
(d, J = 5.6 Hz, 1H), 4.62 (t, J = 5.6 Hz, 1H), 3.09 (brs, 3H), 3.00
(brs, 3H), 1.81–1.66 (m, 6H), 1.23–1.11 (m, 5H). dC(100 MHz):
trans 167.9 (C), 154.4 (C), 139.8 (C), 119.1 (CH2), 85.0 (CH), 79.4
(CH), 41.3 (CH), 39.2 (CH3), 35.1 (CH3), 27.9 (CH2), 27.0 (CH2),
26.1 (CH2), 25.6 (CH2), 25.4 (CH2). mmax/cm−1 (neat): 2928, 1791,
1618, 1166, 1052, 769. MS (ESI) m/z (%): 268 (41, [M + H]+), 224
(17), 206 (100), 178 (5), 161 (56), 133 (27). HRMS (ESI): calcd for
C14H22NO4 [M + H]+: 268.1549, found: 268.1547.
chromatography (CH2Cl2–EtOH 40
:
1, Rf
=
0.48), the
inseparable trans and cis carbonates 11a were obtained as
a light-brown powder (80%, 92 : 8 dr). dH(400 MHz): trans
7.43–7.40 (m, 5H), 6.00 (d, J = 7.2 Hz, 1H), 5.54 (d, J = 0.8 Hz,
1H), 5.44 (d, J = 0.8 Hz, 1H), 4.99 (dt, J = 0.8 and 7.2 Hz,
1H), 3.10 (s, 3H), 3.03 (s, 3H). cis 7.37–7.31 (m, 3H), 7.25–7.21
(m, 2H), 6.06 (dt, J = 1.8 and 8.2 Hz, 1H), 5.86 (d, J = 8.2 Hz,
1H), 5.79 (d, J = 1.8 Hz, 1H), 5.32 (d, J = 1.8 Hz, 1H), 2.68 (s,
3H), 2.24 (s, 3H). dC(100 MHz): trans 167.7 (C), 154.0 (C), 138.1
(C), 135.6 (C), 129.6 (CH), 129.2 (CH), 126.0 (CH), 120.6 (CH2),
84.9 (CH), 82.2 (CH), 39.1 (CH3), 35.1 (CH3). mmax/cm−1 (neat):
2948, 1804, 1620, 1177, 1042, 761, 699. MS (ESI) m/z (%): 262
(24, [M + H]+), 218 (19), 200 (100), 173 (15), 172 (34), 157 (3),
145 (24), 117 (9). HRMS (ESI): calcd for C14H16NO4 [M + H]+:
262.1079, found: 262.1080. Found: C, 64.57; H, 5.15; N, 5.48.
Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
4-[1-(Morpholin-4-ylcarbonyl)vinyl]-5-phenyl-1,3-dioxolan-2-one
(11j). After 30 h of reaction and purification by column
chromatography (CH2Cl2–EtOH 80
:
3, Rf
=
0.31), the
inseparable trans and cis carbonates were obtained as a yellow oil
(77%, >95 : 5 dr). dH(400 MHz): trans 7.49–7.38 (m, 5H), 5.98 (d,
J = 7.2 Hz, 1H), 5.51 (s, 1H), 5.41 (s, 1H), 4.97 (d, J = 7.2 Hz,
1H), 3.90–3.45 (m, 8H). cis 6.05 (dt, J = 1.6 and 8.2 Hz, 1H),
5.85 (d, J = 8.2 Hz, 1H), 5.83 (d, J = 1.6 Hz, 1H), 5.33 (d, J =
1.6 Hz, 1H). The other protons could not be observed for the cis
diastereoisomer. dC(100 MHz): trans 166.3 (C), 153.8 (C), 137.7
(C), 135.4 (C), 129.7 (CH), 129.3 (CH), 126.0 (CH), 120.8 (CH2),
84.8 (CH), 82.1 (CH), 66.9 (CH2), 66.7 (CH2), 47.9 (CH2), 42.2
(CH2). mmax/cm−1 (neat): 2858, 1798, 1614, 1438, 1269, 1163, 1112,
1030, 698. MS (ESI) m/z (%): 304 (41, [M + H]+), 260 (25), 242
N,N-Dimethyl-2-(2-oxo-5-(4-trifluoromethylphenyl)-1,3-dioxo-
lan-4-yl)acrylamide (11b). After 30 h, the reaction was incom-
plete (45% of conversion, 94 : 6 dr) and the carbonate was not
separable from the starting epoxide. It was thus described from
the crude product. dH(250 MHz): trans 7.69 (d, J = 8.4 Hz, 2H),
7.58 (d, J = 8.4 Hz, 2H), 6.11 (d, J = 7.1, 1H), 5.59 (s, 1H), 5.50
(s, 1H), 4.94 (d, J = 7.1, 1H), 3.12 (s, 3H), 3.05 (s, 3H). cis 6.04
(dt, J = 1.6 and 8.0 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 5.79 (d,
J = 1.6 Hz, 1H). The other protons could not be observed for the
cis diastereoisomer.
1990 | Org. Biomol. Chem., 2008, 6, 1981–1993
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(100), 173 (12), 164 (9), 145 (7), 114 (6). HRMS (ESI): calcd for
C16H18NO5 [M + H]+: 304.1185, found: 304.1170.
aqueous solution of K2CO3 (500 mL). After filtration over a pad of
Celite, the organic layer was separated, washed with brine, dried
over magnesium sulfate and concentrated in vacuo. Purification
by column chromatography (pentane, Rf = 0.75) yielded 14 as a
colorless oil (9.8 g, 78%). dH(400 MHz): 5.84 (q, J = 1.1, 1H),
2.19 (t, J = 6.6 Hz, 2H), 1.80 (d, J = 1.0 Hz, 3H), 1.42 (m, 2H),
1.28–1.18 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H). dC(100 MHz): 148.6
(C), 74.3 (CH), 39.6 (CH2), 31.6 (CH2), 28.7 (CH2), 27.7 (CH2),
23.8 (CH2), 22.6 (CH3), 14.0 (CH3). mmax/cm−1 (neat) 3057, 2955,
2926, 2855, 1617, 1456, 1376, 1271, 1142, 1110, 1017, 892, 838,
765, 724, 680, 666.
Representative procedure for cyclisation of vinylcarbonates 11
to lactones 4. Vinylcarbonate (118 mg, 0.48 mmol) and water
(2.5 mL) were first introduced in a Schlenk flask. Lithium
hydroxide (23.4 mg, 0.98 lmol) was then added and the cloudy
mixture was stirred vigorously at 20 ◦C (the solution became
homogeneous). The carbonate deprotection step was monitored
by TLC (AcOEt–pentane 4 : 1). After complete deprotection, a
solution of sulfuric acid (7.6 mL, 5% v/v) was dropped onto the
solution at 20 ◦C. The reaction mixture was then stirred at 60 ◦C
by putting directly the Schlenk flask into a warm oil bath. The
lactonisation step was also monitored by TLC (AcOEt–pentane
4 : 1). After cooling, the solution was dissolved with water and
extracted with CH2Cl2. The organic layers were washed with a
saturated aqueous solution of NaHCO3 (foam formation), dried
over MgSO4, filtered and concentrated in vacuo. Purification by
column chromatography (AcOEt–pentane) afforded the desired
lactones as a mixture of trans and cis diastereoisomers.
2-[(7-Methyl-tridec-6-en-1-yl)]tetrahydro-2H-pyran (15). ZnCl2
(1 M solution in ether, 0.75 mL, 0.75 mmol) was added to a
solution of alkyl iodide 13 (180 mg, 0.60 mmol) in 0.7 mL of
dry ether at −78 ◦C. The mixture was stirred 30 minutes and
treated dropwise with t-BuLi (1.2 M solution in pentane, 2 mL,
2.4 mmol). The solution was gently allowed to warm to rt, and then
cannulated over a mixture of vinyl iodide 5 (101 mg, 0.4 mmol) and
Pd(PPh3)4 (9 mg, 0.008 mmol) in dry ether. The reaction was stirred
overnight, protected from light. Water was added carefully and the
organic layer was separated. The aqueous layer was extracted by
ether. The combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Rapid column chromatography of the
crude product (Et2O–pentane = 1 : 1, Rf = 0.25) yielded 163 mg of
the coupling product 15 (73% yield determined by NMR with an
internal standard), contaminated with the hydrolyzed side-product
C5H11OTHP. dH(400 MHz): 5.10 (tq, J = 1.1 and 7.1, 1H), 4.58
(dt, J = 2.9 and 4.6, 1H), 3.86 (m, 1H), 3.74 (ddd, J = 6.9, 9.5
and 13.8, 1H), 3.49 (m, 1H), 3.38 (ddd, J = 6.6, 9.3 and 13.3,
1H), 1.96 (m, 4H), 1.57 (m, 2H), 1.57 (m, 5H), 1.44 (m, 6H), 1.25
(m, 10H), 0.88 (t, 3H, J = 6.7). dC(100 MHz): 135.5 (C), 124.4
(CH), 98.9 (CH), 67.8 (CH2), 62.4 (CH2), 39.9 (CH2), 31.9 (CH2),
30.9 (CH2), 29.9 (CH2), 29.8 (CH2), 29.1 (CH2), 28.1 (CH2), 28.0
(CH2), 26.0 (CH2), 25.7 (CH2), 22.8 (CH2), 19.8 (CH2), 16.0 (CH3),
14.2 (CH3). mmax/cm−1 (neat) 2925, 2855, 1668, 1465, 1455, 1441,
1381, 1364, 1352, 1322, 1283, 1260, 1200, 1184, 1164, 1136, 1120,
1078, 1065, 1034, 1022, 988; 974, 905, 869, 844, 816; 727. HRMS
(ESI): calcd for C19H36O2 [M + Na]+: 319.2613, found: 319.2616.
A diene side product 7 was also isolated (Et2O–pent 1 : 4, Rf =
0.80): 10-dimethyl-hexadeca-7,9-diene. dH(400 MHz): 5.99 (s, 2H),
(t, J = 7.1, 4H), 1.72 (s, 6H), 1.42 (m, 4H), 1.26 (m, 12H), 0.89
(t, J = 6.8, 6H). dC(100 MHz): 136.8 (C), 120.8 (CH), 40.5 (CH2),
32.0 (CH2), 29.3 (CH2), 28.2 (CH2), 22.8 (CH2), 16.5 (CH3), 14.3
(CH3). mmax/cm−1 (neat) 2956, 2924, 2855, 1615, 1457, 1379, 1105,
1017, 862, 724. MS (ESI) m/z (%): 250 (M).
4-Hydroxy-3-methylene-5-phenyl-c-butyrolactone (4a). After
4 h for the deprotection step followed by 2 h for the lactonisation,
purification by column chromatography (AcOEt–pentane 1 : 1,
Rf(trans) = 0.47, Rf(cis) = 0.33), provided the trans and cis lactones
separately as yellow oils (56% global yield, 1 : 99 dr). See above
for the analyses.
4-Hydroxy-3-methylene-5-butyl-c-butyrolactone (4g). After
4 h for the deprotection step followed by 50 min for the
lactonisation, purification by column chromatography (AcOEt–
pentane 2 : 1, Rf = 0.42) provided the trans and cis lactones
separately as colorless oils (74%, 5 : 95 dr). See above for the
analyses.
4-Hydroxy-3-methylene-5-isobutyl-c-butyrolactone (4h). After
5 h for the deprotection step followed by 50 min for the
lactonisation, purification by column chromatography (AcOEt–
pentane 2 : 3, Rf = 0.35) provided the inseparable mixture of trans
and cis lactones as a colorless oil (66%, 6 : 94 dr). dH(400 MHz):
trans 6.39 (d, J = 2.4 Hz, 1H), 5.97 (d, J = 2.3 Hz, 1H), 4.49–4.44
(m, 1H), 4.35–4.30 (m, 1H) the other signals overlapped with the
major cis lactone. cis 6.38 (d, J = 1.6 Hz, 1H), 5.98 (d, J = 1.2 Hz,
1H), 4.85–4.75 (brt, 1H), 4.55–4,50 (m, 1H), 2.70 (d, J = 5.6 Hz,
1H), 1.92–1.82 (m, 1H), 1.72–1.65 (m, 1H), 1.60–1.53 (m, 1H),
0.98 (d, J = 4.4 Hz, 3H), 0.97 (d, J = 4.4 Hz, 3H). dC(100 MHz):
cis 169.8 (C), 139.1 (C), 126.0 (CH2), 81.0 (CH), 70.0 (CH), 37.3
(CH2), 24.7 (CH), 23.4 (CH3), 22.0 (CH3). mmax/cm−1 (neat): 3429,
2958, 1742, 1272, 1169, 1121, 986. MS (EI) m/z (%): 171 (59, [M +
H]+), 153 (100), 135 (21), 125 (25), 107 (78). HRMS (ESI): calcd
for C9H15O3 [M + H]+: 171.1021, found: 171.1016.
7-Methyl-tridec-6-en-1-ol(16). p-Toluenesulfonic acid (2.98 mg,
0.016 mmol) was added to the obtained mixture of 15 and
the reduced product (46.6 mg) in methanol (0.5 mL) at room
temperature. The solution was heated at 45 ◦C until complete
conversion (checked by TLC). After addition of ether, the organic
layer was washed with water, an aqueous solution of NaHSO3
and brine. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography
(Et2O—pentane 1 : 2, Rf = 0.31) yielded alcohol 7 in 50% yield
from 14. dH(400 MHz): 5.10 (tq, J = 1.1 and 7.1, 1H), 3.63 (t, J =
6.6, 2H), 1.96 (m, 4H), 1.60–1.55 (m, 2H), 1.57 (s, 4H), 1.43–1.25
(m, 12H), 0.87 (t, J = 6.8, 3H). dC(100 MHz): 135.6 (C), 124.3
1-Iodo-2-methyloct-1-ene (14). According to Wipf’s pro-
tocol,45b Me3Al (75 mL, 2 M solution in toluene, 150 mmol) was
added to a solution of Cp2ZrCl2 (2.92 g, 10 mmol) in 200 mL
of dry dichloromethane at rt. After cooling to 0 ◦C, water was
slowly added dropwise (1.35 mL, 75 mmol). The reaction was
allowed to warm to rt and, after 20 minutes, octyne (5.51 g,
50 mmol) was added. The reaction was stirred for 30 minutes
and treated with a solution of iodine (14.15 g, 60 mmol) in THF
(75 mL). After 30 minutes, the reaction was poured into a saturated
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(CH), 63.2 (CH2), 39.9 (CH2), 32.9 (CH2), 31.9 (CH2), 29.8 (CH2),
29.1 (CH2) 28.1 (CH2), 27.9 (CH2), 25.5 (CH2), 22.8 (CH2), 16.0
(CH3), 14.2 (CH3). mmax/cm−1 (neat) 3323, 2955, 2925, 2855, 1668,
1457, 1379, 1122, 1073, 1055, 1011, 885, 841, 724. The analysis
was in agreement with previous reports.49
2925, 2855, 1646, 1622, 1397, 1105, 924. HRMS (ESI): calcd for
C20H35NO2 [M + H]+: 322.2746, found: 322.2758. MS (ESI) m/z
(%): 172 (37, [M + H]+), 154 (30), 114 (100), 100 (14), 88 (60), 85
(30).
Acknowledgements
7-Methyl-tridec-6-enal (17). Alcoho◦l 16 (70 mg, 0.33 mmol)
was diluted with acetone (10 mL) at 0 C in the presence of N-
methyl-morpholine-N-oxide (117 mg, 1 mmol). Then tetrapropy-
lammonium perruthenate (6 mg, 0.017 mmol) was added and
the reaction mixture was stirred until complete conversion of the
starting material. The solution was concentrated in vacuo and
pentane was added. The obtained crude mixture was filtered over
a pad of Celite. Rapid purification by column chromatography
(Et2O–pentane 1 : 1, Rf = 0.68) gave aldehyde 17 as a light yellow
oil (40 mg, 58%). This unstable aldehyde was subsequently used
in the following epoxidation step. dH(400 MHz): 9.76 (t, J = 1.8,
1H), 5.09 (tq, J = 1.1 and 7.1, 1H), 2.42 (td, J = 1.8 and 7.3,
2H), 2.03–1.93 (m, 4H), 1.67–1.59 (m, 2H), 1.57 (s, 3H), 1.43–1.26
(m, 10H), 0.88 (t, J = 7.1, 3H). dC(100 MHz): 203.0 (C), 136.1
(C), 123.7 (CH), 44.0 (CH2), 39.8 (CH2), 31.9 (CH2), 29.8 (CH2),
29.1 (CH2), 28.1 (CH2), 27.7 (CH2), 22.8 (CH2), 21.8 (CH2), 16.1
(CH3), 14.2 (CH3). mmax/cm−1 (neat) 3323, 2955, 2925, 2855, 1668,
1457, 1379, 1122, 1073, 1055, 1011, 885, 841, 724. The analysis
was in agreement with the previous description.49
We gratefully acknowledge financial support from the “Ministe`re
de la Recherche”, CNRS (Centre National de la Recherche Scien-
tifique), the “Re´gion Basse-Normandie” and the European Union
(FEDER funding). We also warmly thank L. Peauger, M. Avril,
B. Delchambre, A. Hamon, E. Da Silva, and E. Souron for their
contribution in the synthesis of the precursors.
References and notes
1 For reviews on lactones, see: (a) Collins, J. Chem. Soc., Perkin Trans. 1,
2004, 1377; M. I. Konaklieva and B. J. Plotkin, Mini-Rev. Med. Chem.,
2005, 5, 73. For reviews dedicated to a-methylene-c-butyrolactones, see:
(b) N. Petragnani, H. M. C. Ferraz and G. V. J. Silva, Synthesis, 1986,
157; (c) H. M. R. Hoffmann and J. Rabe, Angew. Chem., Int. Ed. Engl.,
1985, 24, 94.
2 (a) P. Barbier and C. Benezra, J. Med. Chem., 1986, 29, 868; (b) L. J.
Brzezinski, S. Rafel and J. W. Leahy, J. Am. Chem. Soc., 1997, 119,
4317; (c) S. Steurer and J. Podlech, Eur. J. Org. Chem., 1999, 1551, and
references cited herein.
3 (a) X. Gao, M. Nakadai and B. B. Snider, Org. Lett., 2003, 5, 451;
(b) X. Gao and B. B. Snider, J. Org. Chem., 2004, 69, 5517.
4 (a) F.-C. Chen, C.-F. Peng, I.-L. Tsai and I.-S. Chen, J. Nat. Prod.,
2005, 68, 1318; (b) For cytotoxic activities, see: I.-L. Tsai, C.-H. Hung,
C.-Y. Duh and I.-S. Chen, Planta Med., 2002, 68, 142.
5 For other selected examples of bio-active b-hydroxy-a-methylene
lactones, see: (a) F. R. Garcez, W. S. Garcez, M. Martins, M. F. C.
Matos, Z. R. Guterres, M. S. Mantovani, C. K. Misu and S. T.
Nakashita, Planta Med., 2005, 71, 923; (b) V. T. Amiguet, P. Petit,
C. A. Ta, R. Nunez, P. Sanchez-Vindas, L. P. Alvarez, M. L. Smith,
J. T. Arnason and T. Durst, J. Nat. Prod., 2006, 69, 1005; (c) H. N.
Kamel, D. Ferreira, L. F. Garcia-Fernandez and M. Slattery, J. Nat.
Prod., 2007, 70, 1223; (d) G.-F. Dai, H.-W. Xu, J.-F. Wang, F.-W. Liu and
H.-M. Liu, Bioorg. Med. Chem. Lett., 2006, 16, 2710; (e) V. T. Amiguet,
P. Petit, C. A. Ta, R. Nunez, P. Sanchez-Vindas, L. P. Alvarez, M. L.
Smith, J. T. Arnason and T. Durst, J. Nat. Prod., 2006, 69, 1005.
6 For recent reviews on MBH reactions and applications, see: (a) D.
Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103,
811; (b) G. Masson, C. Housseman and J. Zhu, Angew. Chem., Int. Ed.,
2007, 46, 4614; (c) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem.
Soc. Rev., 2007, 36, 1581, and references cited therein.
7 For a review on the synthesis and the use of alk-1-en-3,4-diols, see: M.
Lombardo and C. Trombini, Chem. Rev., 2007, 107, 3843.
8 For representative references, see: (a) V. Nair and A. K. Sinhababu,
J. Org. Chem., 1980, 45, 1893; (b) W. W. Wood and G. M. Watson,
J. Chem. Soc., Chem. Commun., 1986, 1599; (c) W. W. Wood and G. M.
Watson, J. Chem. Soc., Perkin Trans. 1, 1987, 2681.
9 From b-nitro ester: (a) D. Seebach, R. Henning and T. Mukhopadhyay,
Chem. Ber., 1982, 115, 1705; (b) S. D. Burke, G. J. Pacofsky and A. D.
Piscopio, J. Org. Chem., 1992, 57, 2228. From b-amino ester: (c) C.
Papageorgiou and C. Benezra, J. Org. Chem., 1985, 50, 157; (d) A.
Bernardi, M. G. Beretta, L. Colombo, C. Gennari, G. Poli and C.
Scolastico, J. Org. Chem., 1985, 50, 4442. From a-sulfide ester: (e) P.
Barbier and C. Benezra, J. Org. Chem., 1983, 48, 2705.
N,N-Dimethyl-2-[3-(6-methyldodec-5-en-1-yl)oxiran-2-yl]-acry-
lamide (18). Thiolane (19 lL, 0.21 mmol) was added to a
solution of allylic bromide 2a (40.1 mg, 0.21 mmol) in water
(40 lL) at rt. With vigorous stirring, the initial heterogeneous
solution became homogenous within 6 h. t-BuOH (360 lL),
aldehyde 17 (40.0 mg, 0.19 mmol) and NaOH (16 mg, 0.40 mmol)
were subsequently added to the solution. The mixture was
vigorously stirred for 39 hours at room temperature and diluted
with water. The aqueous layer was extracted by dichloromethane
and the combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. Purification by column
chromatography (AcOEt–heptane 1 : 1, Rf = 0.32) afforded a
colourless oil corresponding to the desired epoxides (35 mg, 71%)
as an inseparable mixture of trans and cis diastereoisomers (60 :
40). dH(400 MHz): trans 5.49 (s, 1H), 5.24 (s, 1H), 5.07 (t, J =
5.8, 1H), 3.26 (d, J = 2 Hz, 1H), 3.12–2.96 (m, NMe2 and 1H
oxirane, 7H), 2.00–1.91 (m, 4H), 1.71–1.60 (m, 1H), 1.55 (s, 3H),
1.54–1.21 (m, 14H), 0.86 (t, J = 6.8, 3H). cis 5.43 (d, J = 1.2 Hz,
1H), 5.35 (s, 1H), 5.07 (t, J = 5.8 Hz, 1H overlapped with the
trans), 3.68 (dd, J = 1.2 and 4.4 Hz, 1H), 3.12–2.96 (m, NMe2
and 1H oxirane, 7H overlapped with the trans), 2.00–1.91 (m,
4H, overlapped with the trans), 1.71–1.60 (m, 1H, overlapped
with the trans), 1.55 (s, 3H, overlapped with trans), 1.54–1.21
(m, 14H, overlapped with the trans), 0.91 (t, J = 7.6 Hz, 3H).
dC(100 MHz): trans 169.5 (C), 142.7 (C), 135.7 (C), 124.1 (CH),
116.7 (CH2), 60.8 (CH), 58.1 (CH), 39.8 (CH2), 38.9 (CH3), 34.7
(CH3), 31.9 (CH2), 29.7 (CH2), 29.0 (CH2), 28.0 (CH2), 27.8
(CH2), 26.7 (CH2), 25.5 (CH2, 22.7 (CH2), 16.0 (CH3), 14.2 (CH3).
Cis 168.9 (C), 138.8 (C), 135.6 (C), 124.0 (CH), 117.5 (CH2),
59.8 (CH), 56.4 (CH), 39.8 (CH2), 38.9 (CH3), 35.0 (CH3), 32.1
(CH2), 29.8 (CH2), 27.8 (CH2), 26.0 (CH2), 16.0 (CH3 overlapped
with the trans), 14.2 (CH3 overlapped with trans). The chemical
shift of four carbons of the cis isomer could not be determined
because of the overlapping with the trans isomer. mmax/cm−1 (neat)
10 (a) R. S. Porto and F. Coelho, Synth. Commun., 2004, 34, 3037; (b) P. R.
Krishna, V. Kannan and G. V. M. Sharma, J. Org. Chem., 2004, 69,
6467.
11 (a) Z. Su and C. Tamm, Helv. Chim. Acta, 1995, 78, 1278; (b) A.
Sakakura, Y. Takayanagi, H. Shimogawa and H. Kigoshi, Tetrahedron,
2004, 60, 7067.
12 (a) W. Adam, J. Renze and T. Wirth, J. Org. Chem., 1998, 63, 226; (b) W.
Adam and P. Klug, Synthesis, 1994, 567.
13 (a) B. Liu, M.-J. Chen, C.-Y. Lo and R.-S. Liu, Tetrahedron Lett., 2001,
42, 2533; (b) M.-J. Chen, C.-Y. Lo, C.-C. Chin and R.-S. Liu, J. Org.
Chem., 2000, 65, 6362.
1992 | Org. Biomol. Chem., 2008, 6, 1981–1993
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The Royal Society of Chemistry 2008
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14 C. Harcken and R. Bru¨ckner, Tetrahedron Lett., 2001, 42, 3967.
15 J. U. Rhee and M. J. Krishe, J. Am. Chem. Soc., 2006, 128, 10674.
16 M. Davoust, J.-F. Brie`re and P. Metzner, Org. Biomol. Chem., 2006, 4,
3048, and references cited therein.
17 For biological activity of conocandin, see: (a) J. M. Mu¨ller, H. Fuhrer, J.
Gruner and W. Voser, Helv. Chim. Acta, 1976, 59, 2506; (b) F. Molinari,
F. Aragozzini and D. Potenza, Ann. Microbiol. Enzymol., 1996, 46,
57. For the previous synthesis, see: (c) L. Banfi, W. Cabri, G. Poli, D.
Potenza and C. Scolastico, J. Org. Chem., 1987, 52, 5452; (d) K. Tanaka,
H. Horiuchi and H. Yoda, J. Org. Chem., 1989, 54, 63.
Borhan, J. Org. Chem., 2006, 71, 1416; (f) J. R. Falck, S. Manna, A. K.
Siddhanta and J. Capdevila, Tetrahedron Lett., 1983, 24, 5715.
33 For precedents concerning the easy cleavage of an amide bond by
a c-hydroxyl group, see: (a) K. R. Prasad and A. Chandrakumar,
Tetrahedron, 2007, 63, 1798; (b) E. Vedejs and A. W. Kruger, J. Org.
Chem., 1999, 64, 4790; (c) R. B. Martin, R. Hedrick and A. Parcell,
J. Org. Chem., 1964, 29, 158; (d) C. R. Hauser and T. C. Adams, J. Org.
Chem., 1977, 42, 3029.
34 Alternatively, the direct intramolecular addition of the amide moiety
onto the carbocation intermediate in Scheme 5 could be envisaged.
35 When slow epoxidation occurred in the presence of NaOH as a base,
the formation of a Cannizzaro-type product (benzoic acid) and a
Willamson-type product from allylic bromide 2a was observed (see
ESI for details).
36 (a) J. Tsuji and T. Mandai, Synthesis, 1996, 1; (b) J. Tsuji, in Palladium
Reagents and Catalysts, Wiley-VCH, 2004; (c) For related conditions,
see: A. Chau, J.-F. Paquin and M. Lautens, J. Org. Chem., 2006, 71,
1924.
37 (a) P. Bravo, G. Resnati and F. Viani, Tetrahedron Lett., 1985, 26,
2913; (b) R. Csuk, C. Schro¨der, S. Hutter and K. Mohr, Tetrahedron:
Asymmetry, 1997, 8, 1411; (c) K. M. Doxsee, Tetrahedron Lett., 2001,
42, 1411; (d) Chataigner, F. Zammattio, J. Lebreton and J. Villie´ras,
Tetrahedron, 2008, 64, 2441.
38 For the original papers on the palladium-catalysed CO2 insertion of
vinyl epoxides, see: (a) B. M. Trost and S. R. Angle, J. Am. Chem.
Soc., 1985, 107, 6123; (b) T. Fujinami, T. Suzuki, M. Kamiya, S.
Fukuzawa and S. Sakai, Chem. Lett., 1985, 199. For a review, see:
(c) M. Yoshida and M. Ihara, Chem.–Eur. J., 2004, 10, 2886. For a
recent review on p-allyl palladium chemistry, see: (d) B. M. Trost and
D. R. Fandrick, Aldrichimica Acta, 2007, 40, 59, and references cited
therein.
39 (a) B. M. Trost and E. J. McEachern, J. Am. Chem. Soc., 1999, 121, 8649.
For other selected examples of this methodology, see: N. Cheeseman,
M. Fox, M. Jackson, I. C. Lennon and G. Meek, Proc. Natl. Acad. Sci.
U. S. A., 2004, 13, 5396; (b) Z.-X. Jiang and F.-L. Quing, J. Fluorine
Chem., 2003, 123, 57.
18 A. S. Kende and B. H. Toder, J. Org. Chem., 1982, 47, 163.
19 R. M. Carlson and Q. Yang, Tetrahedron Lett., 1994, 35, 7919.
20 (a) F.-D. Boyer and I. Hanna, J. Organomet. Chem., 2006, 691, 5181;
(b) M. Johansson and O. Sterner, J. Antibiot., 2002, 55, 663; (c) M.
Johansson and O. Sterner, Org. Lett., 2001, 3, 2843; (d) C. Lee, K. Y.
Lee, S. J. Kim and J. N. Kim, Bull. Korean Chem. Soc., 2007, 28, 71.
21 For a review on vinyl epoxides, see: B. Olofsson and P. Somfai, in
Aziridines and Epoxides in Organic Synthesis, ed. A. K. Yudin, Wiley-
VCH, Weinheim, 2006, pp. 315; see also ref. 16 for further discussions.
22 For recent reviews on sulfonium ylide epoxidation, see: (a) V. K.
Aggarwal and C. L. Winn, Acc. Chem. Res., 2004, 37, 611; (b) E. M.
McGarrigle, V. K. Aggarwal, in Enantioselective Organocatalysis, ed.
P. I. Dalko, Wiley-VCH, Weinheim, 2007, p. 357; (c) E. M. McGarrigle,
E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches and V. K. Aggarwal,
Chem. Rev., 2007, 107, 5841.
23 For precedents concerning epoxidation mediated by vinyl sulfonium
ylide reagents, see: (a) J. Zanardi, D. Lamazure, S. Minie`re, V. Reboul
and P. Metzner, J. Org. Chem., 2002, 67, 9083; (b) V. K. Aggarwal, E.
Alonso, I. Bae, G. Hynd, K. M. Lydon, M. J. Palmer, M. Patel, M.
Porcelloni, J. Richardson, R. A. Stenson, J. R. Studley, J.-L. Vasse and
C. L. Winn, J. Am. Chem. Soc., 2003, 125, 10926; (c) K. Li, X.-M. Deng
and Y. Tang, Chem. Commun., 2003, 2074; (d) V. K. Aggarwal, I. Bae,
H.-Y. Lee, J. Richardson and D. T. Williams, Angew. Chem., Int. Ed.,
2003, 42, 3274; (e) X.-M. Deng, J. Cai, S. Ye, X.-L. Sun, W.-W. Liao,
K. Li, Y. Tang, Y.-D. Wu and L. X. Dai, J. Am. Chem. Soc., 2006, 128,
9730; (f) see ref. 16 for further discussions.
24 For previous related conditions with primary acrylamides, see: C.
Faltin, E. M. Fleming and S. J. Connon, J. Org. Chem., 2004, 69,
6496.
25 For the use and comments in ylide-promoted epoxidation by a pre-
formed sulfonium salt in water, see: V. Schulz, M. Davoust, M. Lemarie´,
J.-F. Lohier, J. Sopkova de Oliveira Santos, P. Metzner and J.-F. Brie`re,
Org. Lett., 2007, 9, 1745.
40 The reaction between CO2 and a nucleophilic phosphine ligand was
also proposed as an inhibitation process: see ref. 38a.
41 V. B. Reddy Iska, H.-J. Gais and S. K. Tiwari, Tetrahedron, 2007, 48,
7102, and references cited therein.
42 (a) S. Hu, S. Jayaraman and A. C. Oehlschlager, J. Org. Chem., 1999,
64, 2524; (b) For a similar observation with isocyanate, see: B. Olofsson
and P. Somfai, J. Org. Chem., 2002, 67, 8574.
26 (a) V. K. Aggarwal, J. N. Harvey and J. Richardson, J. Am. Chem.
Soc., 2002, 124, 5747; (b) V. K. Aggarwal and J. Richardson, Chem.
Commun., 2003, 2644.
27 For recent experimental insight and alternative explanations, see:
(a) C. M. Crudden and D. R. Edwards, Org. Lett., 2007, 9, 2397;
(b) D. R. Edwards, P. Montoya-Peleaz and C. M. Crudden, Org. Lett.,
2007, 9, 5481.
28 See ref. 16 for further explanations.
29 See ESI for more experimental details.
30 Review on furanone: J. B. Sweeney, A. E. Nadany and N. B. Carter,
J. Chem. Soc., Perkin Trans. 1, 2002, 2324.
43 For a review on the formation of polysubsituted alkenes, see: O. Reiser,
Angew. Chem., Int. Ed., 2006, 45, 2838, and references cited therein.
44 For reviews on Negishi’s methodologies, see: (a) Zirconium-catalysed
carboalumination: E.-I. Negishi, Dalton Trans., 2005, 827; (b) for cross-
coupling reaction of zinc species, see: E.-I. Negishi, X. Zeng, Z. Tan,
M. Qian, Q. Hu and Z. Huang, in Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 2, pp. 815–889;
(c) G. Lessene, Aust. J. Chem., 2004, 57, 107.
45 (a) P. Wipf and S. Lim, Angew. Chem., Int. Ed. Engl., 1993, 32, 1068;
(b) P. Wipf, C. Kendall and C. R. J. Stephenson, J. Am. Chem. Soc.,
2003, 122, 761.
31 When the pure epoxide 3g was heated at 60 ◦C in aqueous H2SO4
(5% v/v), the formation of the furanone 5 was observed, proving that
an equilibrium took place. However, we can not rule out an alternative
direct SN2ꢀ addition of water to the epoxide 3g to give 5 after cyclisation.
32 For selected references concerning the intermolecular ring-opening
reaction of vinyl epoxides by alcohol or water, see: (a) K. Fagnou and
M. Lautens, Org. Lett., 2000, 2, 2319; (b) G. Prestat, C. Baylon, M.-P.
Heck, G. A. Grasa, S. P. Nolan and C. Mioskowski, J. Am. Chem. Soc.,
2004, 69, 5770; (c) M. Ono, C. Saotome and H. Akita, Tetrahedron:
Asymmetry, 1996, 7, 2595; (d) G. Prestat, C. Baylon, M.-P. Heck and C.
Mioskowski, Tetrahedron Lett., 2000, 41, 3829; (e) R. S. Naraya and B.
46 (a) M. Ramaseshan, M. Robitaille, J. W. Ellingboe, Y. L. Dory and P.
Deslongchamps, Tetrahedron Lett., 2000, 41, 4737; (b) K. J. Shea, L. D.
Burke and R. J. Doedens, Tetrahedron, 1986, 42, 1841.
47 A. B. Smith, T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y.
Qiu, H. Arimoto, D. R. Jones and K. Kobayashi, J. Am. Chem. Soc.,
2000, 122, 8654.
48 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994,
639.
49 The synthesis of the aldehyde derivative 17 (via 15 and 16) was
previously described by Scolastico and co-workers in 7 linear steps:
see ref. 17c.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1981–1993 | 1993
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