Enynone dihydroxylation-cyclisation as a route to densely functionalised 3(2H)-furanone derivatives: An approach to the core of the zaragozic acids

Article abstract of DOI:10.1016/j.tet.2013.05.125

The synthesis of an advanced intermediate is described that could secure the polyoxygenated core of zaragozic acids and related natural products. The key strategy employs a two-step synthesis of the 3(2H)-furanone ring system by catalytic dihydroxylation-

Full text of DOI:10.1016/j.tet.2013.05.125

Tetrahedron 69 (2013) 6639e6647
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enynone dihydroxylationecyclisation as a route to densely
functionalised 3(2H)-furanone derivatives: an approach to the core
of the zaragozic acids
*
Mehrnoosh Ostovar, Charles M. Marson
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of an advanced intermediate is described that could secure the polyoxygenated core of
zaragozic acids and related natural products. The key strategy employs a two-step synthesis of the 3(2H)-
furanone ring system by catalytic dihydroxylation-mercury(II)/acid-catalysed cyclisation with concomi-
tant deprotection. The scope of the 3(2H)-furanone synthesis has been evaluated, and this ring system is
shown to remain intact in multi-step reaction sequences. Access to novel, highly oxygenated 3(2H)-
furanone derivatives has been achieved.
Received 19 March 2013
Received in revised form 15 May 2013
Accepted 28 May 2013
Available online 4 June 2013
Keywords:
Ó 2013 Published by Elsevier Ltd.
3(2H)-Furanone
Dihydroxylation
Cyclisation
Zaragozic acid
1. Introduction
inflammatory activity8 and in a number of naturally occurring
anti-tumour agents9 and bacterial glycosides.10 The 3(2H)-furanone
Natural products containing a tetrahydrofuran ring or a partially
saturated furan core (e.g., Fig. 1) often possess pronounced bi-
ological activity, and include polyether antibiotics, such as mon-
ensin and halichondrin B;1 inhibitors of serine-threonine proteases,
such as the caliculins;2 and inhibitors of squalene synthase, such as
the zaragozic acids.3e6 The 3(2H)-furanone ring system,7 a Michael
acceptor, is present in various sesquiterpenoids possessing anti-
inotilone is a naturally occurring potent COX-2 inhibitor.11
The introduction of densely oxygenated functionalities in mul-
tiple locations on tetrahydropyran and tetrahydrofuran rings still
presents a challenge, and one relevant to many classes of natural
products.1e12 5-exo-Tet cyclisations of epoxy alcohols are often used
to prepare 2-hydroxymethyl-substituted tetrahydrofurans;13
however, the corresponding 5-endo-tet cyclisations to give 3-
O
O
O
O
O
OH
OH
AcO
Ph
O
O
HO2C
HO2C
O
O
O
H
O
Jatrophone
CO2H
OH
HO
OH
HO
Zaragozic acid A
+
HO
O
NMe3
CO2H
Chitaric acid
_
O
O
(+)-Eremantholide A
Cl
(+)-Muscarine
Fig. 1. Some natural products containing 3-oxygenated dihydro- and tetrahydrofuran ring systems.
* Corresponding author. Fax: þ44 (0) 20 7679 7463; e-mail address: c.m.mar-
son@ucl.ac.uk (C.M. Marson).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.05.125

6640
M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
hydroxytetrahydrofurans are disfavoured, as are cyclisations of
hydroxymethyl enones to give 3(2H)-furanones. Moreover, epoxy
alcohol cyclisations afford tetrahydrofurans rather than dihy-
drofuran systems, as present, for example, in the anti-cancer agents
eremantholide A9b,14 and jatrophone9c,15 (Fig. 1). We considered
that limitations on access to 3-oxygenated dihydro- and tetrahy-
drofuran ring systems (Fig. 1) might be countered by catalytic
asymmetric synthesis of 3(2H)-furanones from enynones using
a Sharpless dihydroxylation16ecyclisation protocol17 (Scheme 1),
and wished to explore the extent to which that reaction could be
applied to the synthesis of natural product ring systems. Compared
with other methods for the synthesis of 3(2H)-furanones,18 in-
However, reaction of 12 with PBr3 at 0 ꢀC in diethyl ether gave
rise to extensive decomposition. Since a convergent route to ynone
1 was not available, and in case the alkyne was participating in side-
reactions, the corresponding diester 15 was prepared by reaction of
PBr3 with the BayliseHillman adduct 14. The allylic bromide 15 was
obtained in 69% yield, but displacement with PhCH2ONa gave only
the SN20 product 16, none of the required SN2 product 8 (R¼Bn,
X¼OtBu) being isolated.
These unexpected difficulties led to a revision of the approach
to ynones 1 and consideration of a strategy involving olefination
of a pyruvic ester (Scheme 4). Dihydroxylation of tert-butyl acry-
late afforded 17, which underwent acylation at the primary posi-
tion to give acetate 18, which with BAIBeTEMPO25 afforded
pyruvate ester 19 via a convenient and scaleable route. Wittig
olefination afforded a quantitative yield of a 2.7:1 mixture of the
triesters 8a and 8b, respectively, which were separated by column
chromatography.
cluding acid-catalysed cyclodehydration of
a-hydroxy-1,3-
diketones,19 base-catalysed ring closures,20 and other metal-
catalysed cyclisations,21 the dihydroxylationecyclisation protocol
of Scheme 1 has several notable features, being regioselective,
diastereoselective and in many cases enantioselective.17
O
O
O
OH
R2
R1
R2
R1
4 Mol% HgII in
7 mM H2SO4
Modified
R2
R3
R3
R3
O
R1
HO
AD-mix-α
H
H
OH
H
3
1
2
90-97% e.e.
Scheme 1. Catalytic asymmetric synthesis of substituted 3(2H)-furanones.17
The core of the zaragozic acids was selected, its construction
being envisaged by two cyclisations onto the alkynyl unit, as part of
a synthetic sequence that would also provide a rigorous test of the
scope of the 3(2H)-furanone synthesis (Scheme 1) in multi-step
reactions. Additionally, an achiral enynone of type 1 (Scheme 2)
might be cyclised, modified and a further two chiral, oxygenated
centres created by a second Sharpless asymmetric dihydrox-
ylation22 to give the advanced intermediate 5 (Scheme 2).
Given that appropriate aldehydes were not available, an alkynyl
anion addition would now be to a carboxy group rather than an
aldehyde; a Weinreb amide partner was sought, which from pre-
vious work17 was known to be compatible with the required
dihydroxylationecyclisation protocol of Scheme 1. Hydrolysis of 8a
(1:1 TFA/CH2Cl2, 99%) afforded 20a, which with thionyl chloride
formed quantitatively the unstable acid chloride 21a that was im-
mediately reacted with N,O-dimethylhydroxylamine to give the
O
O
OH
O
OH
O
AcO
OPMB
Ph
HO2C
HO2C
BnO2C
EtO2C
BnO2C
EtO2C
O
O
O
R
OH
O
O
Acid-catalysed
ring closure
CO2H
CO2Me
CO2Et
OH
OH
OH
Zaragozic acid A
4
5
O
O
O
H
RO
EtO2C
RO
RO
EtO2C
HO
O
R
O
R
O
R
EtO2C
Oxidation
Asymmetric
dihydroxylation
Wittig
olefination
O
6
7
3
EtO2C
O
O
H
O
HO
RO
EtO2C
X
RO
RO
EtO2C
R'
R
R'
X=H,MeNOMe,OR"
Catalytic acid-
Hg(II) cyclisation
Alkynylation
then oxidation
Asymmetric
dihydroxylation
EtO2C
HO
1
2
8
Scheme 2. Retrosynthetic analysis for construction of the core of zaragozic acid A via a 3(2H)-furanone. R0¼(CH2)3OPMB.
2. Results and discussion
-Substituted unsaturated esters of type 1 appear to be un-
Weinreb amide 22a (Scheme 5). Unfortunately, this amide proved
resistant to dihydroxylation using AD-mix reagents,26 so a racemic
synthesis was developed. Osmylation under Upjohn conditions27
afforded 23a as a single diastereoisomer, which was protected as
the acetal 24a. Addition of the alkynyl anion of 9 afforded the ynone
25a, which underwent both deprotection and cyclisation when
treated with catalytic quantities of Hg(II) and sulfuric acid, a re-
agent system that also effects cyclisation of 1-alkynyl-2,3-epoxy
alcohols to 2,3-dihydro-4H-pyran-4-ones.28
g
known, and 8 are little known.23 The carbon framework of 1 was
readily assembled by an addition of the alkynyl anion of 9 to
acrolein, followed by oxidation with MnO2 to give 11, which par-
ticipated in a BayliseHillman reaction with ethyl glyoxylate to give
12 (Scheme 3). Such allylic alcohols are known to undergo efficient
SN20 displacement to give the corresponding allyl bromides.24

M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
6641
MnO2
(13 eq.)
9
OH
O
O
OPMB
,
H
CH2Cl2, 54%
n-BuLi, THF, 63%
OPMB
OPMB
OPMB
10
11
O
O
PBr3
Et2O, 0 °C
O
DABCO
(0.1 eq.)
Br
EtO2C
+
H
OPMB
O
dioxane, 69%
decomposition
during work-up
11
EtO2C
OH
O
EtO2C
13
12
O
O
DABCO
(0.1 eq.)
dioxane, 58%
OBut
OBut
Br
OBut
OBut
PBr3
Et2O, 69%
BnOH,
O
+
EtO2C
OH
EtO2C
NaH, THF
0 °C, 59%
EtO2C
OBn
16
EtO2C
H
15
14
Scheme 3. A BayliseHillman approach to
g
-substituted unsaturated esters.
OsO4
(0.1 mol%)
O
O
O
MeCOCl,
OBut
OBut
HO
OBut
AcO
Et3N 74%
NMO,
1:1 acetone:
water 72%
OH
OH
17
18
O
O
O
CO2Et
OBut
CO2Et
Ph3P
BAIB,
AcO
OBut
AcO
AcO
O
OBut
CH2Cl2, reflux
quantitative
TEMPO
81%
+
EtO2C
19
8a
8b
2.7:1
Scheme 4. Synthesis of acetoxymethylmaleate and succinate esters.
O
O
O
O
HO
HO
OsO4
(O.1 mol%) AcO
Me
Me
Me
EtCH(OMe)2,
MeONHMe,
AcO
N
AcO
EtO2C
R
N
AcO
EtO2C
N
O
O
OMe
OMe
pyridine
81%
OMe
NMO,
1:1 acetone:
water 60%
p-TsOH 59%
EtO2C
EtO2C
H
H
8a R=OBut
20a R=OH
21a R=Cl
24a
22a
23a
TFA, quant.
SOCl2, 91%
O
O
O
9
OPMB
,
AcO
0.1 M HgO in
AcO
EtO2C
OPMB
24a
OPMB
O
aq. 2.5% H2SO4
72%
n-BuLi (1 equiv.), THF
EtO2C
HO
O
H
H
42%
3a
25a
Scheme 5. Synthesis of rel-(2S,20S)-2,3-dihydro-3(2H)-furanone 3a.
The same sequence of reactions was performed on the stereo-
isomer 20b, obtained by hydrolysis of 8b, led ultimately to the
3(2H)-furanone 3b (Scheme 6), the diastereoisomer of 3a obtained
above. Schemes 5 and 6 illustrate the reliability and stereointegrity
of these methods for the preparation of polysubstituted 3(2H)-
furanones.
Neither p-TsOH (10 mol %) in CH2Cl2 at reflux, nor AuCl3
(2 mol %) in methanol effected cyclisation. Osmium tetroxide-
catalysed dihydroxylation of the double bond in the ring, which
could have accelerated cyclisation, could not be achieved using
Upjohn conditions.27 A bromo-etherification of the ring double
bond in 5 was attempted using N-bromosuccinimide, and an ep-
oxidation using m-chloroperoxybenzoic acid was also attempted,
but again cyclisation could not be achieved. Nevertheless, pre-
cedent suggests that cyclisation to the desired bicyclo cores should
be achievable, and further investigation is warranted. The meth-
odology presented here would then permit access to a diverse se-
lection of novel compounds containing the 4,8-dioxabicyclo[3.2.1]
octane core.
The a-hydroxy ester 3a was oxidised using the DesseMartin
periodinane to give the unusual and unstable pyruvate ester 7
(Scheme 7), which was subjected to Wittig olefination without
further purification to give the single diastereoisomer 6. This
compound was resistant to dihydroxylation with AD-mix re-
agents, as was the case for diesters 22. However, dihydroxylation
under Upjohn conditions27 afforded
a mixture of the di-
astereoisomers 5a and 5b. The major diastereoisomer was isolated
but could not be unequivocally assigned. Despite the precedent for
the conjugate addition of alcohols to 3(2H)-furanones under
acidic conditions, a variety of reagents did not afford evidence for
the formation of the bicyclo compound 4a, containing the core
oxygenated framework of zaragozic acid, or any other bicyclo
system.
3. Experimental section
3.1. General
All chemicals were used as supplied. Solvents used were reagent
grade, and anhydrous THF, diethyl ether, dichloromethane and

6642
M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
O
O
O
O
O
OsO4
(O.1 mol%)
HO
Me
Me
Me
EtCH(OMe)2,
MeONHMe,
AcO
N
AcO
R
AcO
N
AcO
N
OMe
OMe
CO2Et
OMe NMO,
pyridine
81%
p-TsOH 53%
O
H
H
CO2Et
CO2Et
1:1 acetone:
water 79%
CO2Et
HO
8b R=OBut
20b R=OH
21b R=Cl
24b
22b
23b
TFA, quant.
SOCl2, quant.
O
O
O
9
OPMB
AcO
0.1 M HgO in
,
AcO
24b
OPMB
OPMB
O
n-BuLi (1.5 equiv.), THF
aq. 2.5% H2SO4
67%
EtO2C
H
O
OH
38%
H
CO2Et
3b
25b
Scheme 6. Synthesis of rel-(2S,20R)-2,3-dihydro-3(2H)-furan-2-one 3b.
O
O
Cat. OsO4,
AcO
AcO
OPMB
CO2Et
NMO,
OPMB
O
O
O
Dess-Martin
Ph3P
citric acid (4 eq.)
EtO2C
EtO2C
3a
periodinane
(quantitative)
1:1 acetone:
water 55%
O
66% from 3a
( )-7
( )-6
EtO2C
O
O
AcO
EtO2C
OPMB
AcO
OPMB
AcO
OPMB
O
O
O
O
EtO2C
+
OH
EtO2C
CO2Et
CO2Et
CO2Et
OH
OH
OH
OH
4a
5b
5a
Scheme 7. Progression of (ꢃ)-7 towards the zaragozic acid core.
acetonitrile were obtained from an Anhydrous Engineering (USA)
solvent system after passing through an alumina column. Glass-
ware was flame-dried prior to use. Compound homogeneity was
monitored by ascending thin-layer chromatography, performed on
Merck 0.2 mm aluminium-backed silica gel 60 F254 plates and
visualised using UV radiation at 254 nm or by staining with vanillin,
potassium permanganate, anisaldehyde or ninhydrin. Column
chromatography was performed using Merck 0.040e0.063 mm,
230e400 mesh silica gel. Petroleum ether refers to the 40e60 ꢀC
boiling fraction, unless otherwise stated. Evaporation refers to the
removal of solvent under reduced pressure. Melting points were
determined using an Electrothermal 9100 instrument, and are
uncorrected. Infrared (IR) spectra were recorded on a Shimadzu 100
FT-IR 8700 instrument or a PerkineElmer Precisely Spectrum 100
FT-IT spectrometer with ATR, either as neat powders or as thin
films. 1H NMR spectra were recorded on a Bruker AMX300, AMX-
400, AVANCE-500 and AVANCE-600 spectrometers; chemical
were dried over MgSO4, filtered and evaporated. Chromatography of
the residue on silica gel (1:15 ethyl acetate/petroleum ether) gave 9
(2.40 g, 98%) as a colourless oil; IR nmax (cmꢂ1)3292, 2935, 2857, 2117,
1611; 1H NMR (300 MHz, CDCl3)
d
7.27 (2H, d, J¼8.6 Hz), 6.88 (2H, d,
J¼8.6 Hz), 4.44 (2H, s), 3.80 (3H, s), 3.55 (2H, t, J¼6.2 Hz), 2.31 (2H, td,
J¼7.1, 2.7 Hz), 1.95 (1H, t, J¼2.7 Hz), 1.86e1.78 (2H, m); 13C NMR
(75 MHz, CDCl3)
d 159.2, 130.6, 129.2, 113.8, 84.0, 72.7, 68.5, 68.4,
55.3, 28.7, 15.3; LRMS m/z (þCI, %) 204 (18), 203 (49), 121 (100);
HRMSþCI calcd for C13H16O2 204.1145, found: 204.1145.
3.1.2. 8-(4-Methoxybenzyloxy)-oct-1-en-4-yn-3-ol (10). To a solu-
tion of 1-(4-methoxybenzyloxy)pent-4-yne (9) (2.00 g, 9.79 mmol)
in dry tetrahydrofuran (5 mL) under an atmosphere of nitrogen was
added dropwise n-butyllithium (2.5
M in hexane, 4.85 mL,
12.1 mmol) at ꢂ78 ꢀC over 5 min. After the mixture was stirred at
this temperature for 45 min, acrylaldehyde (0.98 mL, 14.6 mmol)
was added. The mixture was allowed to warm to 20 ꢀC over 30 min.
When no aldehyde remained (45 h, by TLC), the mixture was
quenched with saturated aqueous ammonium chloride (5 mL) and
the organic layer was extracted with diethyl ether (3ꢁ10 mL). The
combined organic layers were washed with brine (10 mL), dried
over MgSO4, filtered and evaporated. Chromatography of the resi-
due on silica gel (1:3 ethyl acetate/petroleum ether) gave 10 (1.6 g,
63%) as a colourless oil; IR nmax (cmꢂ1) 3403, 2934, 2860, 2213,1671,
shifts are reported in
d parts per million (ppm) relative to the in-
ternal reference tetramethylsilane. Mass spectra were obtained on
Micromass 70-SE and MAT 900XP instruments.
The following compounds were prepared according to the lit-
erature: ethyl (triphenylphosphanylidene)acetate.29
3.1.1. 8-(4-Methoxybenzyloxy)-oct-1-en-4-yn-3-ol (9). To a solution
of 4-pentyn-1-ol (1.00 g,11.8 mmol) in dry dichloromethane (10 mL)
20 ꢀC under an atmosphere of nitrogen, was added a solution of
freshly prepared p-methoxybenzyl trichloroacetimidate (6.71 g,
23.7 mmol) in dichloromethane (3 mL) in a slow stream. After 5 min,
pyridiniump-toluenesulfonate (1.49 g, 5.94 mmol) was added in one
portion. The mixture was stirred at room temperature for 3 h and
then quenched with solid sodium hydrogen carbonate followed by
saturated aqueous sodium hydrogen carbonate (10 mL). The
resulting mixture was diluted with dichloromethane (5 mL). The
organic layer was separated, and the aqueous layer was extracted
with dichloromethane (3ꢁ10 mL). The combined organic layers
1611; 1H NMR (300 MHz, CDCl3)
d
7.25 (2H, d, J¼8.6 Hz), 6.87 (2H, d,
J¼8.6 Hz), 5.93 (1H, m), 5.40 (1H, dd, J¼17.0, 1.2 Hz), 5.16 (1H, dd,
J¼10.0, 1.2 Hz), 4.80 (1H, d, J¼3.3 Hz), 4.42 (2H, s), 3.79 (3H, s), 3.51
(2H, t, J¼6.2 Hz), 2.34 (2H, td, J¼7.1, 1.9 Hz), 1.92e1.88 (2H, m); 13C
NMR (75 MHz, CDCl3)
d 159.2, 137.6, 130.5, 129.3, 115.9, 113.8, 86.4,
79.4, 72.6, 68.4, 63.3, 55.3, 28.7, 15.6; LRMS m/z (þCI, %) 243 (5), 121
(100); HRMSþCI calcd for [MꢂOH]þ C16H19O2 243.1385, found:
243.1395.
3.1.3. 8-(4-Methoxybenzyloxy)-oct-1-en-4-yn-3-one (11). A solu-
tion of 8-(4-methoxybenzyloxy)-oct-1-en-4-yn-3-ol (10) (1.20 g,

M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
6643
4.61 mmol) in dichloromethane (3 mL) was added in one portion to
a stirred suspension of manganese dioxide (5.21 g, 60.0 mmol) in
dichloromethane (50 mL) under an atmosphere of nitrogen. Stir-
ring was continued at 20 ꢀC for 24 h. Then the mixture was filtered
through Celite, and the Celite thoroughly washed with dichloro-
methane (25 mL). The combined organic filtrates were evaporated.
Chromatography of the residue (1:22 ethyl acetate/petroleum
ether) gave 11 (0.65 g, 54%) as a yellow oil; IR nmax (cmꢂ1) 2939,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d
164.9, 163.7, 144.2, 127.7,
83.0, 61.2, 27.9, 23.0, 14.1; LRMS m/z (þCI, %) 293 (22), 238 (98), 237
(100); HRMSþCI calcd for C11H18BrO4 293.0389, found: 293.0385.
3.1.7. 4-tert-Butyl-1-ethyl-2-benzyloxy-3-methylene succinate (16).
To a solution of benzyl alcohol (30 mg, 0.28 mmol) in dry tetra-
hydrofuran (2.0 mL) at 0 ꢀC was added sodium hydride (60% in
mineral oil, 14 mg, 0.36 mmol) in one portion. The mixture was
stirred for 1 h, then transferred by means of a double-tipped ended
needle, dropwise over 10 min to a stirred solution of 1-tert-butyl-4-
ethyl-2-bromomethyl-but-2-enedioate (15) (75 mg, 0.26 mmol) in
tetrahydrofuran (2.0 mL), maintained at 0 ꢀC. The mixture was
stirred for 1 h at room temperature and then quenched by dropwise
addition of water (3 mL). The aqueous layer was separated and
extracted with diethyl ether (3ꢁ5 mL). The combined organic layers
were dried over MgSO4, filtered and evaporated. Chromatography
of the residue on silica gel (1:7 ethyl acetate/petroleum ether) gave
16 (48 mg, 59%) as a colourless oil; IR nmax (cmꢂ1) 2979, 2933, 1714;
2217, 1725, 1648, 1612; 1H NMR (600 MHz, CDCl3)
d 7.26 (2H, d,
J¼8.6 Hz), 6.89 (2H, d, J¼8.6 Hz), 6.50 (1H, dd, J¼17.3, 0.9 Hz), 6.38
(1H, m), 6.14 (1H, dd, J¼10.2, 1.0 Hz), 4.42 (2H, s), 3.80 (3H, s), 3.56
(2H, t, J¼6.0 Hz), 2.56 (2H, t, J¼7.0 Hz), 1.92e1.88 (2H, m); 13C NMR
(150 MHz, CDCl3) d 179.1, 159.2, 138.0, 133.4, 130.3, 113.8, 95.0, 78.7,
72.7, 68.0, 55.3, 28.0, 16.0; LRMS m/z (þCI, %) 259 (13), 241 (53), 217
(40), 157 (100), 121 (61); HRMSþCI calcd for C16H19O3 259.1334,
found: 259.1326.
3.1.4. Ethyl 2-hydroxy-9-(4-methoxybenzyloxy)-3-methylene-4-
oxonon-5-ynoate (12). 1,4-Diazabicyclo[2.2.2]octane (4.3 mg,
0.038 mmol) was added in one portion at 0 ꢀC to a solution of 8-(4-
methoxybenzyloxy)-oct-1-en-4-yn-3-one (11) (0.10 g, 0.38 mmol)
and ethyl glyoxylate (0.12 g of 50% w/w solution in toluene,
0.58 mmol) in dioxane (0.4 mL). The mixture was kept at 20 ꢀC for
5 h, thenpoured intohydrochloric acid(0.3 mL,10%)and theaqueous
layer was extracted with ethyl acetate (3ꢁ2 mL). The combined or-
ganic layers were dried over MgSO4, filtered and evaporated. Chro-
matography of the residue on silica gel (1:2 ethyl acetate/petroleum
ether) gave 12 (90 mg, 69%) as a colourless oil; IR nmax (cmꢂ1) 3443,
1H NMR (400 MHz, CDCl3)
d 7.36e7.27 (5H, m), 6.33 (1H, s), 5.91
(1H, s), 4.75 (1H, s), 4.61e4.67 (2H, m), 4.16 (2H, q, J¼7.1 Hz), 1.44
(9H, s), 1.22 (3H, t, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d 170.0,
164.5, 138.1, 137.3, 128.6, 128.1, 128.0, 127.2, 81.7, 76.4, 72.2, 61.4,
28.2, 14.3; LRMS m/z (þES, %) 343 (33), 287 (100); HRMSþES
calcd for C18H24NaO5 343.1521, found: 343.1521.
3.1.8. 4-tert-Butyl
2,3-dihydroxypropionate
(17). N-Methyl-
morpholine-N-oxide (18.4 g, 94.4 mmol), then osmium tetroxide
(0.21 g, 0.1mol %; CAUTION: TOXIC) were added to a solution of tert-
butyl acrylate (11.0 g, 85.8 mmol) in and mixture of acetone
(260 mL) and water (260 mL) at 0 ꢀC. The mixture was stirred at
room temperature for 72 h, after which saturated aqueous sodium
sulfite (170 mL) was added and the mixture then stirred for a fur-
ther 15 min, prior to dilution with water (170 mL). The aqueous
portion was extracted with dichloromethane (3ꢁ300 mL) and the
organic layers were combined, washed with brine (400 mL) and
dried over MgSO4, then evaporated. Chromatography of the residue
on silica gel (1:1 petroleum ether/diethyl ether) gave 17 (10.0 g,
72%) as a colourless oil; IR nmax (cmꢂ1) 3424, 2978, 2931, 1728; 1H
2932, 2857, 2213, 1735,1644, 1512; 1H NMR (600 MHz, CDCl3)
d 7.26
(2H, d, J¼8.6 Hz), 6.89 (2H, d, J¼8.6 Hz), 6.58 (1H, s), 6.27 (1H, s), 4.92
(1H, s), 4.45 (2H, s), 4.24 (2H, q, J¼7.1 Hz), 3.81 (3H, s), 3.55 (2H, t,
J¼5.9 Hz), 2.57 (2H, t, J¼7.1 Hz), 1.92e1.88 (2H, m), 1.23 (3H, t,
J¼7.1 Hz); 13C NMR (150 MHz, CDCl3)
d 177.8, 172.3, 159.2, 146.2,
133.3, 130.2, 129.3, 113.8, 95.8, 78.4, 72.7, 69.7, 68.0, 62.3, 55.3, 27.9,
16.0, 14.1; LRMS m/z (þCI, %) 361 (15), 240 (50), 121 (100), 103 (50);
HRMSþCI calcd for C20H25O6 361.1651, found: 361.1669.
3.1.5. 4-tert-Butyl-1-ethyl-2-hydroxy-3-methylenesuccinate (14).
1,4-Diazabicyclo[2.2.2]octane (0.17 g, 1.56 mmol) was added in one
portion at 0 ꢀC to a solution of tert-butyl acrylate (2.0 g, 15.6 mmol)
and ethyl glyoxylate (4.76 g of a 50% w/w solution in toluene,
23.4 mmol) in dioxane (15 mL). The mixture was kept at room
temperature for 48 h, then poured into hydrochloric acid (5 mL,10%)
and the aqueous layer extracted with ethyl acetate (3ꢁ20 mL). The
combined organic layers were dried over MgSO4, filtered and evap-
orated. Chromatography of the residue on silica gel (1:3 ethyl ace-
tate/petroleum ether) gave 14 (2.08 g, 58%) as a yellow oil; IR nmax
(cmꢂ1) 3499, 2980, 2935,1738,1713,1636; 1H NMR (600 MHz, CDCl3)
NMR (600 MHz, CDCl3)
d
4.14 (1H, t, J¼3.8 Hz), 3.86 (1H, dd, J¼11.6,
3.2 Hz), 3.78 (1H, dd, J¼11.6, 4.1 Hz), 2.85 (2H, br s), 1.49 (9H, s); 13C
NMR (150 MHz, CDCl3)
d 172.3, 83.2, 71.8, 64.3, 28.0; LRMS m/z
(þCI, %) 163 (100), 107 (50); HRMSþCI calcd for C7H15O4 163.0970,
found: 163.0974.
3.1.9. 4-tert-Butyl 3-acetoxy-2-hydroxypropionate (18). To a stirred
solution of tert-butyl 2,3-dihydroxypropionate (17) (10.0 g,
61.6 mmol) in dichloromethane (80 mL) at 0 ꢀC was added trie-
thylamine (11.3 mL, 80.1 mmol) dropwise over 15 min. After 0.5 h,
acetyl chloride (4.8 mL, 68 mmol) was added dropwise over 40 min
at 0 ꢀC. The mixture was stirred for 2 h, then quenched with water
(20 mL). The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3ꢁ20 mL), dried over MgSO4,
filtered and the filtrate evaporated. Chromatography of the residue
on silica gel (1:4 diethyl ether/petroleum ether) gave 18 (9.32 g,
74%) as a white solid, mp 56e58 ꢀC; IR nmax (cmꢂ1) 3443, 2979,
d
6.21 (1H, s), 5.78 (1H, s), 4.73 (1H, s), 4.17 (2H, m), 1.42 (9H, s), 1.20
(3H, t, J¼7.1 Hz); 13C NMR (150 MHz, CDCl3)
d 172.5, 164.3, 139.4,
128.2, 81.8, 71.3, 62.2, 27.9, 14.0; LRMS m/z (þES, %) 254 (45), 197
(100); HRMSþES calcd for C11H18NaO5 253.1052, found: 253.1049.
3.1.6. 4-tert-Butyl-4-ethyl-2-bromomethylbut-2-enedioate (15). To
a
round-bottomed flask containing 4-tert-butyl-1-ethyl-2-
hydroxy-3-methylenesuccinate (14) (1.00 g, 4.34 mmol) in dry
diethyl ether (10 mL) under an atmosphere of nitrogen, was added
phosphorus tribromide (0.42 mL, 4.34 mmol) at 0 ꢀC. The mixture
was stirred for 1 h, then quenched by dropwise addition of water
(10 mL). The organic layer was separated and the aqueous layer was
extracted with diethyl ether (2ꢁ10 mL). The combined organic
layers were dried over MgSO4, filtered and the filtrate evaporated.
Chromatography of the residue on silica gel (20:1 petroleum ether/
ethyl acetate) gave 15 (0.87 g, 69%) as a colourless oil; IR nmax
2936, 1730; 1H NMR (300 MHz, CDCl3)
d 4.37e4.19 (3H, m), 3.25
(1H, br d, J¼5.6 Hz), 2.10 (3H, s), 1.41 (9H, s); 13C NMR (75 MHz,
CDCl3)
d
171.1, 170.6, 83.2, 69.4, 65.7, 27.8, 20.6; LRMS m/z (þFAB, %)
227 (73), 176 (100); HRMSþFAB calcd for C9H16NaO5 227.0895,
found: 227.0892.
3.1.10. 4-tert-Butyl 3-acetoxy-2-oxopropionate (19). To a solution of
tert-butyl 3-acetoxy-2-hydroxypropionate (18) (3.0 g, 14.6 mmol)
in dichloromethane (180 mL) were added TEMPO (0.34 g,
2.2 mmol) and iodobenzene diacetate (7.09 g, 22.0 mmol) at room
temperature. The mixture was stirred for 24 h and then quenched
(cmꢂ1) 2980, 2935, 1716, 1645; 1H NMR (400 MHz, CDCl3)
(1H, s), 4.67 (2H, s), 4.25 (2H, q, J¼7.1 Hz), 1.51 (9H, s), 1.31 (3H, t,
d 6.70

6644
M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
with aqueous sodium thiosulfate (50 mL, 10%). The aqueous layer
was extracted with dichloromethane (3ꢁ50 mL). The combined
organic layers were dried over MgSO4 and the filtered solution was
evaporated. Chromatography of the residue on silica gel (1:4 diethyl
ether/petroleum ether) gave 19 (2.40 g, 81%) as a yellow oil; IR nmax
bonylbut-2-enoate (21a) (0.63 g, 2.68 mmol) in dichloromethane
(10 mL) at 0 ꢀC was added N,O-dimethylhydroxylamine hydro-
chloride (0.44 g, 4.56 mmol) followed by pyridine (0.87 mL,
10.7 mmol). The mixture was stirred at 20 ꢀC; progress of the re-
action was monitored by TLC. On completion, (usually 3 h) the
mixture was acidified using aqueous hydrochloric acid (2 M, 5 mL),
and the aqueous layer was extracted with dichloromethane
(3ꢁ5 mL). The combined organic layers were washed with satu-
rated aqueous sodium hydrogen carbonate (2ꢁ15 mL) followed by
brine (15 mL). The organic layer was dried over MgSO4, filtered and
evaporated. The residue was purified by column chromatography
(1:1 ether/petroleum ether) to give 22a (0.56 g, 81%) as an orange
oil; IR nmax (cmꢂ1) 2982, 2940, 1744, 1716, 1653; 1H NMR (300 MHz,
(cmꢂ1) 2980, 2900, 1729; 1H NMR (400 MHz, CDCl3)
2.16 (3H, s), 1.53 (9H, s); 13C NMR (100 MHz, CDCl3)
d
5.08 (2H, s),
187.5, 170.0,
d
158.3, 85.1, 66.6, 27.7, 20.3; LRMS m/z (þCI, %) 203 (19), 161 (100);
HRMSþCI calcd for C9H15O5 203.0920, found: 203.0902.
3.1.11. (E) and (Z)-1-tert-Butyl 4-ethyl-2-acetoxymethylbut-2-
enedioate (8a) and (8b). To a solution of ethyl (triphenylphospha-
nylidene)-acetate (7.36 g, 21.1 mmol) in dichloromethane (40 mL)
at reflux was added tert-butyl 3-acetoxy-2-oxo-propionate (19)
(2.86 g, 14.1 mmol) in dichloromethane (20 mL) dropwise over
20 min. The mixture was heated at reflux for 2 h; TLC indicated that
no ketone remained and showed two new spots corresponding to
the products (2.7:1 trans- to cis-isomers). The solvent was evapo-
rated and the residue was redissolved in the minimum volume of
dichloromethane and applied to a silica gel column. Chromatog-
raphy of the residue (1:8 diethyl ether/petroleum ether) gave 8a
(2.8 g, 73%) as a yellow oil; IR nmax (cmꢂ1) 2980, 1732, 1716,1655; 1H
CDCl3)
d
5.98 (1H, s), 5.38 (2H, s), 4.17 (2H, q, J¼7.1 Hz), 3.60 (3H, s),
3.20 (3H, s), 1.99 (3H, s), 1.25 (3H, t, J¼7.1 Hz); 13C NMR (75 MHz,
CDCl3)
d 170.0, 168.0, 164.7, 149.0, 120.6, 61.4, 61.0, 60.9, 30.8, 20.6,
14.1; LRMS m/z (þCI, %) 260 (100), 200 (26); HRMSþCI calcd for
C11H18NO6 260.1134, found: 260.1143.
3.1.15. rel-(2S,3S)-Ethyl 3-acetoxymethyl-2,3-dihydroxy-N-methoxy-
N-methylsuccinate (23a). N-Methylmorpholine-N-oxide (0.17 g,
1.27 mmol) then osmium tetroxide (14.7 mg, 5 mol %; CAUTION:
TOXIC) were added to a solution of ethyl (E)-4-acetoxy-3-(methox-
ymethylcarbamoyl)-but-2-enoate (22a) (0.30 g, 1.15 mmol) in
a mixture of acetone (3.5 mL) and water (3.5 mL) at 0 ꢀC. The mixture
was stirred at room temperature for 48 h, after which saturated
aqueous sodium sulfite (3 mL) was added, and the mixture stirred for
a further 15 min, then diluted with water (3 mL). The aqueous por-
tion was extracted with dichloromethane (4ꢁ10 mL), dried over
MgSO4, filtered and evaporated. Chromatography of the residue on
silica gel (2:1 ethyl acetate/petroleum ether) gave 23a (0.20 g, 60%)
as a yellow oil; IR nmax (cmꢂ1) 3423, 2983, 2910,1738,1650; 1H NMR
NMR (400 MHz, CDCl3)
d 6.78 (1H, s), 5.17 (2H, s), 4.40 (2H, q,
J¼7.1 Hz), 2.07 (3H, s), 1.48 (9H, s), 1.28 (3H, t, J¼7.1 Hz); 13C NMR
(100 MHz, CDCl3)
d 170.2, 164.8, 164.3, 141.6, 130.0, 82.5, 61.2, 58.1,
27.9, 20.6, 14.0; LRMS m/z (þFAB, %) 295 (80), 217 (100), 199 (55),
176 (90), 155 (71); HRMSþFAB calcd for C13H20NaO6 295.1158,
found: 295.1159. 2D NOE analysis did not show long-range in-
teraction of the olefinic hydrogen atom with the methylene group.
A reaction using tert-butyl 3-acetoxy-2-oxo-propionate (19)
(0.35 g, 1.73 mmol) was carried out and worked up as above.
Chromatography (1:5 diethyl ether/petroleum ether) gave 8b
(92 mg, 27%) as an orange oil; IR nmax (cmꢂ1) 2981, 1735,1722, 1660;
(500 MHz, CDCl3)
d
4.75 (1H, s), 4.53 (1H, d, J¼11.6 Hz), 4.49 (1H, d,
1H NMR (400 MHz, CDCl3)
d
6.59 (1H, s), 4.74 (2H, s), 4.18 (2H, q,
J¼8.0 Hz), 4.45 (1H, d, J¼11.6 Hz), 4.29e4.25 (2H, m), 3.72 (3H, s),
J¼7.2 Hz), 2.07 (3H, s), 1.47 (9H, s), 1.25 (3H, t, J¼7.2 Hz); 13C NMR
3.26 (3H, s), 1.97 (3H, s), 1.29 (3H, t, J¼7.1 Hz); 13C NMR (125 MHz,
(100 MHz, CDCl3)
d
169.9, 164.9, 164.4, 141.8, 122.4, 83.0, 61.2, 63.1,
CDCl3) d 170.8,170.4,170.1, 79.5, 72.0, 65.6, 62.4, 60.7, 33.7, 21.0,14.1;
61.0, 27.9, 20.6, 14.1; LRMS m/z (þES, %) 295 (20), 239 (100);
HRMSþES calcd for C13H20NaO6 295.1158, found: 295.1156. 2D NOE
analysis showed a long-range interaction of the olefinic hydrogen
atom with the methylene group.
LRMS m/z (þCI, %) 294 (100), 276 (59), 260 (48); HRMSþCI calcd for
C11H20NO8 294.1189, found: 294.1182.
3.1.16. rel-(4S,5S)-Ethyl
5-acetoxymethyl-5-(methoxymethylcarba-
moyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate (24a). To a solu-
tion of (ꢃ)-ethyl 3-acetoxymethyl-2,3-dihydroxy-N-methoxy-N-
methylsuccinate (23a) (0.18 g, 0.61 mmol) in benzene (1.00 mL;
CAUTION: TOXIC) were added 2,2-dimethoxypropane (0.12 g,
1.22 mmol) and p-toluenesulfonic acid monohydrate (5.82 mg,
0.03 mmol). The mixture was heated at reflux for 24 h in a Dean and
3.1.12. (E)-4-Ethyl-2-acetoxymethylbut-2-enedioate (20a). To a solu-
tion of (E)-1-tert-butyl-4-ethyl-2-acetoxymethyl-but-2-enedioate
(8a) (0.80 g, 2.93 mmol) in dichloromethane (10 mL), trifluoro-
acetic acid (10 mL) was added at 0 ꢀC and the mixture was stirred for
2hat20ꢀC.Volatilematerialwasremovedunderreducedpressureto
leave 20a (0.63 g, quantitative) as an orange oil requiring no purifi-
cation; IR nmax (cmꢂ1) 3700e2400, 2983, 1721, 1660; 1H NMR
ꢀ
Stark apparatus containing freshly activated 4 A molecular sieves.
The mixture was concentrated and dried in vacuo. The residue was
purified by silica gel column chromatography (1:1 ethyl acetate and
petroleum ether) to give 24a (0.12 g, 59%) as a yellow oil; IR nmax
(500 MHz, CDCl3)
d
7.00 (1H, s), 5.19 (2H, s), 4.23 (2H, q, J¼7.1 Hz), 2.02
(3H, s),1.30 (3H, t, J¼7.1 Hz); 13C NMR (125 MHz, CDCl3)
d 170.6,169.7,
164.4, 138.7, 133.1, 67.2, 61.5, 20.6, 14.0; LRMS m/z (þCI, %) 217 (46),
(cmꢂ1), 2985, 2940, 1747, 1655; 1H NMR (300 MHz, CDCl3)
d 5.40
157 (100); HRMSþCI calcd for C9H13O6 217.0712, found: 217.0715.
(1H, s), 4.61 (1H, d, J¼11.5 Hz), 4.32 (1H, d, J¼11.5 Hz), 4.20e4.12
(2H, m), 3.71 (3H, s), 3.25 (3H, s),1.99 (3H, s),1.56 (3H, s),1.35 (3H, s),
3.1.13. (E)-4-Ethyl-4-acetoxy-3-chlorocarbonylbut-2-enedioate
(21a). To a solution of (E)-4-ethyl 2-acetoxymethylbut-2-enedioate
(20a) (0.63 g, 2.93 mmol) in dichloromethane (20 mL) cooled in an
ice-bath under nitrogen, was added thionyl chloride (0.57 mL,
7.93 mmol) dropwise with stirring. The mixture was then heated
under nitrogen at reflux at 60 ꢀC. When the reaction was complete,
as indicated by TLC analysis, the solvent and the excess thionyl
chloride were evaporated under reduced pressure at 40 ꢀC to give
21a (0.63 g) as a dark brown oil, which was used directly in the next
step; IR nmax (cmꢂ1) 2981, 2910, 1783, 1726.
1.27 (3H, t, J¼7.1 Hz); 13C NMR (75 MHz, CDCl3)
d 170.8, 169.9, 168.8,
111.7, 85.8, 77.9, 63.1, 61.5, 61.0, 27.2, 27.1, 25.8, 20.6, 14.1; LRMS m/z
(þCI, %) 334 (100), 260 (26); HRMSþCI calcd for C14H24NO8
334.1502, found: 334.1491.
3.1.17. rel-(4S,5S)-Ethyl 5-acetoxymethyl-5-[6-(4-methoxyben-
zyloxy)-hex-2-ynoyl]-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate
(25a). To a solution of 1-(4-methoxybenzyloxy)-pent-4-yne (9)
(1.74 g, 8.55 mmol) in dry THF (30 mL) under nitrogen was added n-
butyllithium (1.6 M in hexane, 5.3 mL, 8.55 mmol) dropwise over
10 min at ꢂ78 ꢀC. The mixture was warmed to ꢂ20 ꢀC for 1 h, then
cooled to ꢂ78 ꢀC. Then the mixture was added to a ꢂ78 ꢀC cold
solution of (ꢃ)-ethyl 5-acetoxymethyl-5-(methoxymethylcar-
3.1.14. (E)-Ethyl-4-acetoxy-3-(methoxymethylcarbamoyl)-but-2-
enoate (22a). To a solution of ethyl (E)-4-acetoxy-3-chlorocar-

M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
6645
bamoyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate (24a) (1.90 g,
5.70 mmol) in dry THF (20 mL) by means of a double-tipped needle.
After stirring the mixture for 3 h at ꢂ78 ꢀC, saturated aqueous
ammonium chloride (15 mL) was added and the mixture was
warmed to room temperature. Water was added until two clear
layers had formed. The aqueous layer was separated and extracted
with diethyl ether (3ꢁ30 mL). The combined organic layers were
dried over MgSO4, filtered and evaporated. Chromatography of the
residue on silica gel (1:4 ethyl acetate/petroleum ether) gave 25a
(1.13 g, 42%) as a yellow oil; IR nmax (cmꢂ1), 3012, 2937, 2839, 2209,
as indicated by TLC analysis, the solvent and the excess thionyl
chloride were evaporated under reduced pressure at 40 ꢀC to give
21b (9.0 g) as a dark brown oil, which was used directly in the next
step; IR nmax (cmꢂ1) 1780.
3.1.21. (Z)-Ethyl-4-acetoxy-3-(methoxymethylcarbamoyl)-but-2-
enoate (22b). To a solution of ethyl (Z)-4-acetoxy-3-chlorocar-
bonylbut-2-enoate (21b) (8.68 g, 37.0 mmol) in dichloromethane
(110 mL) at 0 ꢀC was added N,O-dimethylhydroxylamine hydro-
chloride (6.13 g, 62.8 mmol) followed by pyridine (12 mL, 0.148 mol).
The mixture was stirred at 20 ꢀC; progress of the reaction was
monitored by TLC. On completion, the mixture was acidified using
aqueous hydrochloric acid (2 M, 40 mL), and the aqueous layer was
extracted with dichloromethane (2ꢁ40 mL). The combined organic
layers were washed with saturated aqueous sodium hydrogen car-
bonate (2ꢁ120 mL) followed by brine (15 mL). The organic layer was
dried over MgSO4, filtered and evaporated. The residue was purified
by column chromatography (1:1 ether/petroleum ether) to give 22b
(6.1 g, 81%) as an orange oil; IR nmax (cmꢂ1) 2981, 2943, 1743, 1716,
1745, 1675, 1612; 1H NMR (400 MHz, CDCl3)
d
7.25 (2H, d, J¼8.8 Hz),
6.88 (2H, d, J¼8.8 Hz), 5.00 (1H, s), 4.44 (2H, s), 4.43 (1H, d,
J¼12.0 Hz), 4.35 (1H, d, J¼12.0 Hz), 4.30e4.20 (2H, m), 3.81 (3H, s),
3.54 (2H, t, J¼6.0 Hz), 2.58 (2H, t, J¼7.2 Hz), 2.04 (3H, s), 1.97e1.81
(2H, m), 1.62 (3H, s), 1.48 (3H, s), 1.31 (3H, t, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3)
d 184.1, 170.0, 167.6, 159.2, 130.2, 129.3, 113.9,
113.8, 113.5, 100.2, 87.9, 78.6, 72.7, 67.9, 62.8, 61.9, 55.3, 27.8, 27.4,
26.6, 20.6, 16.3, 14.1; LRMS m/z (þES, %) 499 (100), 396 (70);
HRMSþES calcd for C25H32NaO9 499.1944, found: 499.1953.
1655; 1H NMR (400 MHz, CDCl3)
d 5.95 (1H, s), 5.29 (2H, s), 4.13 (2H,
3.1.18. rel-(2S)-Ethyl {(S)-2-acetoxymethyl-5-[3-(4-methoxybenzyl-
oxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2-hydroxyacetate
(3a). To (ꢃ)-ethyl-5-acetoxymethyl-5-[6-(4-methoxybenzyloxy)-
q, J¼7.1 Hz), 3.56 (3H, s), 3.20 (3H, s), 1.95 (3H, s), 1.23 (3H, t,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d 170.4, 169.9, 164.6, 148.9,
120.3, 69.0, 61.9, 61.2, 60.7, 20.5, 13.9; LRMS m/z (þES, %) 282 (100);
hex-2-ynoyl]-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate
(25a)
HRMSþES calcd for C11H17NaNO6 282.0954, found: 282.0954.
(35 mg, 0.07 mmol) in acetone (5 mL, HPLC grade) was added
acidified mercury(II) oxide solution (0.3 mL, 0.1 M), obtained by
dissolving yellow mercury(II) oxide in aqueous 2.5% sulfuric acid.
The mixture was stirred for 24 h then neutralised by the addition of
powdered sodium hydrogen carbonate. The mixture was stirred for
a further 1.5 h, filtered and the filtrate evaporated. The residue was
dissolved in diethyl ether (10 mL) and the solution was washed with
water (10 mL). The aqueous layer was extracted with ether (2
ꢁ10 mL), and the combined extracts washed with saturated aqueous
sodium hydrogen carbonate (10 mL) then brine (10 mL), and dried
over MgSO4, filtered and evaporated. The residue was purified by
flash column chromatography (1:1 petroleum ether/ethyl acetate)
to give 3a (23 mg, 72%) as a colourless oil; IR nmax (cmꢂ1),
3650e3040, 2935,1742,1704,1594,1512; 1H NMR (300 MHz, CDCl3)
3.1.22. rel-(2S,3S)-Ethyl 3-acetoxymethyl-2,3-dihydroxy-N-methoxy-
N-methylsuccinate (23b). N-Methylmorpholine-N-oxide (4.41 g,
37.6 mmol) then osmium tetroxide (0.31 mg, 5 mol %; CAUTION:
TOXIC) were added to a solution of ethyl (E)-4-acetoxy-3-(methox-
ymethylcarbamoyl)-but-2-enoate (22b) (6.25 g, 25.1 mmol) in
a mixture of acetone (75 mL) and water (75 mL) at 0 ꢀC. The mixture
was stirred at room temperature for 48 h, after which saturated
aqueous sodium sulfite (50 mL) was added, and the mixture stirred
for a further 15 min, then diluted with water (50 mL). The aqueous
portionwas extracted with dichloromethane (4ꢁ150 mL), dried over
MgSO4, filtered and evaporated. Chromatography of the residue on
silica gel (2:1 ethyl acetate/petroleum ether) gave 23b (5.80 g, 79%)
as a yellow oil; IR nmax (cmꢂ1) 3421, 2980, 2909,1736,1648; 1H NMR
d
7.24 (2H, d, J¼8.6 Hz), 6.87 (2H, d, J¼8.6 Hz), 5.47 (1H, s), 4.56 (1H,
(400 MHz, CDCl3)
d
4.78 (1H, s), 4.54 (1H, d, J¼11.3 Hz), 4.50 (1H, d,
d, J¼12.1 Hz), 4.48 (1H, d, J¼8.8 Hz), 4.42 (2H, s), 4.37 (1H, d,
J¼12.1 Hz), 4.28 (2H, q, J¼7.1 Hz), 3.80 (3H, s), 3.62e3.30 (2H, m),
2.62 (2H, t, J¼6.9 Hz), 2.00 (3H, s), 1.97e1.89 (3H, m), 1.31 (3H, t,
J¼8.0 Hz), 4.46 (1H, d, J¼11.3 Hz), 4.30e4.26 (2H, m), 3.73 (3H, s),
3.27 (3H, s), 1.98 (3H, s), 1.30 (3H, t, J¼7.1 Hz); 13C NMR (125 MHz,
CDCl3) d 170.8,170.4,169.9, 79.4, 71.9, 65.5, 62.4, 60.7, 33.7, 20.6,14.0;
J¼7.1 Hz); 13C NMR (150 MHz, CDCl3)
d
200.7, 194.7, 170.4, 170.3,
LRMS m/z (þES, %) 316 (100), 239 (12), 227 (20); HRMSþES calcd for
159.5, 130.2, 129.6, 114.0, 104.7, 89.1, 73.0, 71.0, 68.6, 62.9, 55.5, 28.1,
26.5, 22.6, 20.8, 14.3; LRMS m/z (þES, %) 459 (100), 339 (5);
HRMSþES calcd for C22H28NaO9 459.1631, found: 459.1631.
C11H19NaNO8 316.1008, found: 316.1020.
3.1.23. rel-(4R,5S)-Ethyl 5-acetoxymethyl-5-(methoxymethylcarba-
moyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate (24b). To a solu-
tion of (ꢃ)-ethyl 3-acetoxymethyl-2,3-dihydroxy-N-methoxy-N-
methylsuccinate (23b) (5.0 g, 17 mmol) in benzene (25 mL; CAU-
TION: TOXIC) were added 2,2-dimethoxypropane (5.22 mL,
42.6 mmol) and p-toluenesulfonic acid monohydrate (0.16 g,
0.85 mmol). The mixture was heated at reflux for 48 h in a Dean and
3.1.19. (Z)-4-Ethyl-2-acetoxymethylbut-2-enedioate (20b). To a so-
lution of (E)-1-tert-butyl-4-ethyl-2-acetoxymethyl-but-2-enedi-
oate (8a) (9.00 g, 33.0 mmol) in dichloromethane (90 mL), tri-
fluoroacetic acid (90 mL) was added at 0 ꢀC and the mixture was
stirred for 3.5 h at 20 ꢀC. Volatile material was removed under re-
duced pressure to leave 20b (7.14 g, quantitative) as an orange oil
requiring no purification; IR nmax (cmꢂ1) 3680e2220, 2985, 1717,
ꢀ
Stark apparatus containing freshly activated 4 A molecular sieves.
The mixture was concentrated and dried in vacuo. The residue was
purified by silica gel column chromatography (1:1 ethyl acetate and
petroleum ether) to give 24b (3.0 g, 53%) as a yellow oil; IR nmax
1656; 1H NMR (400 MHz, CDCl3)
d 6.34 (1H, s), 4.87 (2H, s), 4.27
(2H, q, J¼7.1 Hz), 2.10 (3H, s), 1.30 (3H, t, J¼7.3 Hz); 13C NMR
(100 MHz, CDCl3)
d
170.0, 166.7, 166.3, 141.5, 125.2, 63.0, 62.6, 20.7,
(cmꢂ1), 2985, 2940, 1747, 1655; 1H NMR (400 MHz, CDCl3)
d 5.39
13.8; LRMS m/z (þES, %) 239 (46), 157 (100); HRMSþES calcd for
(1H, s), 4.59 (1H, d, J¼11.5 Hz), 4.31 (1H, d, J¼11.5 Hz), 4.28e4.12
C9H12NaO6 239.0532, found: 239.0538.
(2H, m), 3.69 (3H, s), 3.23 (3H, s), 1.97 (3H, s), 1.55 (3H, s), 1.34 (3H,
s), 1.25 (3H, t, J¼7.1 Hz); 13C NMR (75 MHz, CDCl3)
d 169.9, 168.7,
3.1.20. (Z)-4-Ethyl-4-acetoxy-3-chlorocarbonylbut-2-enedioate
(21b). To a solution of (Z)-4-ethyl 2-acetoxymethylbut-2-enedioate
(20b) (8.00 g, 37.0 mmol) in dichloromethane (260 mL) cooled in an
ice-bath under nitrogen, was added thionyl chloride (7.2 mL,
0.10 mol) dropwise with stirring. The mixture was then heated
under nitrogen at reflux at 60 ꢀC. When the reaction was complete,
166.5, 111.6, 85.7, 77.8, 63.0, 61.8, 61.4, 34.0, 27.1, 25.7, 20.5, 14.0;
LRMS m/z (þES, %) 356 (100); HRMSþES calcd for C14H23NaNO8
356.1321, found: 356.1327.
3.1.24. rel-(4S,5S)-Ethyl 5-acetoxymethyl-5-[6-(4-methoxyben-
zyloxy)-hex-2-ynoyl]-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate

6646
M. Ostovar, C.M. Marson / Tetrahedron 69 (2013) 6639e6647
(25b). To a solution of 1-(4-methoxybenzyloxy)-pent-4-yne (9)
(2.70 g, 13.5 mmol) in dry THF (50 mL) under nitrogen was added n-
butyllithium (1.6 M in hexane, 8.4 mL, 13.5 mmol) dropwise over
10 min at ꢂ78 ꢀC. The mixture was warmed to ꢂ20 ꢀC for 1 h, then
cooled to ꢂ78 ꢀC. Then the mixture was added to a ꢂ78 ꢀC cold
solution of (ꢃ)-ethyl 5-acetoxymethyl-5-(methoxymethylcar-
bamoyl)-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate (24b) (3.0 g,
9.0 mmol) in dry THF (20 mL) by means of a double-tipped needle.
After stirring the mixture for 3 h at ꢂ78 ꢀC, saturated aqueous
ammonium chloride (10 mL) and then water (25 mL) were added.
The mixture was allowed to warm to room temperature, then water
was added until two clear layers had formed. The aqueous layer was
separated and extracted with diethyl ether (3ꢁ70 mL). The com-
bined organic layers were dried over MgSO4, filtered and evapo-
rated. Chromatography of the residue on silica gel (1:3 ethyl
acetate/petroleum ether) gave 25b (1.63 g, 38%) as a yellow oil; IR
nmax (cmꢂ1), 3012, 2937, 2839, 2209, 1748, 1675, 1612; 1H NMR
MgSO4, filtered and evaporated. The crude product 7 (40 mg,
quantitative) was very unstable and used directly for the next step
without further purification; IR nmax (cmꢂ1) 2945, 2893, 2832, 1747,
1702, 1601; 1H NMR (600 MHz, CDCl3)
d
7.26 (2H, d, J¼8.6 Hz), 6.89
(2H, d, J¼8.6 Hz), 5.61 (1H, s), 5.52 (1H, d, J¼2.5 Hz), 5.14 (1H, d,
J¼2.5 Hz), 4.45 (2H, s), 4.13 (2H, q, J¼7.1 Hz), 3.82 (3H, s), 3.52 (2H, t,
J¼7.6 Hz), 2.06 (3H, s), 2.00e1.93 (2H, m), 1.26 (3H, t, J¼7.1 Hz); 13C
NMR (150 MHz, CDCl3) d 187.5, 186.1, 171.2, 159.3, 153.4, 130.1, 129.3,
113.8, 105.3, 96.9, 72.7, 26.0, 21.1, 14.2; LRMS m/z (þFAB, %) 457 (32),
433 (30), 335 (44) 274 (52), 241 (100); HRMSþFAB calcd for
C22H26NaO9 457.1474, found: 457.1469.
3.1.27. rel-Diethyl 2-{(R)-2-acetoxymethyl-5-[3-(4-methoxybenzyl-
oxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-(Z)-but-2-enedioate (6).
To
a
solution of crude (ꢃ)-ethyl {2-acetoxymethyl-5-[3-(4-
methoxybenzyloxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2-oxo-
acetate (7) (40 mg, 0.09 mmol) in dichloromethane (2 mL) at room
temperature was added ethyl (triphenylphosphanylidene)acetate
(47 mg, 0.13 mmol). The mixture was stirred for 1 h, after which
time the reaction was shown to be complete by TLC. The solvent
was evaporated and the residue was dissolved in a small amount of
dichloromethane and applied to a silica gel column. Chromatog-
raphy (1:2 ethyl acetate/petroleum ether) afforded 6 (35 mg, 76%
overall, from 3a) as a colourless oil; IR nmax (cmꢂ1) 2977, 2938, 1717,
(400 MHz, CDCl3)
d
7.20 (2H, d, J¼8.6 Hz), 6.83 (2H, d, J¼8.6 Hz),
4.94 (1H, s), 4.38 (2H, s), 4.34 (1H, d, J¼12.1 Hz), 4.27 (1H, d,
J¼12.1 Hz), 4.25e4.15 (2H, m), 3.76 (3H, s), 3.49 (2H, t, J¼5.6 Hz),
2.53 (2H, t, J¼7.2 Hz), 1.98 (3H, s), 1.87e1.78 (2H, m), 1.56 (3H, s),
1.43 (3H, s), 1.29 (3H, t, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d
184.0, 169.9, 167.5, 159.1, 130.1, 129.1, 113.7, 113.4, 100.1, 87.8, 78.5,
76.7, 67.8, 62.7, 61.8, 60.3, 55.1, 27.7, 27.3, 26.4, 20.5, 16.2, 13.9; LRMS
m/z (þES, %) 499 (100), 396 (8); HRMSþES calcd for C25H32NaO9
499.1944, found: 499.1942.
1645, 1601; 1H NMR (400 MHz, CDCl3)
d
7.26 (2H, d, J¼8.6 Hz), 6.89
(2H, d, J¼8.6 Hz), 6.33 (1H, s), 5.48 (1H, s), 4.61 (1H, d, J¼12.0 Hz),
4.44 (2H, s), 4.37 (1 H, d, J¼12.0 Hz), 4.31 (2H, m), 4.19 (2H, q,
J¼7.1 Hz), 3.82 (3H, s), 3.50 (2H, t, J¼6.0 Hz), 2.66 (2H, t, J¼7.6 Hz),
2.04 (3H, s), 1.93 (2H, m), 1.31 (3H, t, J¼7.1 Hz), 1.26 (3H, t, J¼7.1 Hz);
3.1.25. rel-(2R)-Ethyl {(S)-2-acetoxymethyl-5-[3-(4-methoxyben-
zyloxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2-hydroxyacetate
(3b). To (ꢃ)-ethyl-5-acetoxymethyl-5-[6-(4-methoxybenzyloxy)-
13C NMR (100 MHz, CDCl3)
d 197.8, 193.5, 169.8, 164.4, 163.7, 159.3,
hex-2-ynoyl]-2,2-dimethyl-[1,3]-dioxolane-4-carboxylate
(25b)
142.5, 130.1, 129.3, 121.3, 113.8, 103.3, 87.7, 72.7, 68.1, 65.1, 62.0, 61.3,
55.3, 27.6, 26.3, 20.6, 14.0, 13.9; LRMS m/z (þES, %) 457 (32), 527
(100); HRMSþES calcd for C26H32NaO10 527.1893, found: 527.1905.
(0.80 g, 1.67 mmol) in acetone (50 mL, HPLC grade) was added
acidified mercury(II) oxide solution (2.5 mL, 0.1 M), obtained by
dissolving yellow mercury(II) oxide in aqueous 2.5% sulfuric acid.
The mixture was stirred for 24 h then neutralised by the addition of
powdered sodium hydrogen carbonate. The mixture was stirred for
a further 1.5 h, filtered and the filtrate evaporated. The residue was
dissolved in diethyl ether (25 mL) and the solution was washed with
water (40 mL). The aqueous layer was extracted with ether
(2ꢁ25 mL), and the combined extracts washed with saturated
aqueous sodium hydrogen carbonate (50 mL) then brine (50 mL),
and dried over MgSO4, filtered and evaporated. The residue was
purified by flash column chromatography (1:1 petroleum ether/
ethyl acetate) to give 3b (0.49 g, 67%) as a colourless oil; IR nmax
(cmꢂ1), 3650e3040, 2935, 1742, 1704, 1594, 1512; 1H NMR
3.1.28. rel-(2S,3S)-Diethyl 2-{(S)-2-acetoxymethyl-5-[3-(4-methoxy-
benzyloxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2,3-dihydroxysuc-
cinate (5a) or (5b). Citric acid (38 mg, 0.19 mmol) was added to
a solution of (ꢃ)-diethyl 2-{2-acetoxymethyl-5-[3-(4-methoxybe-
nzyloxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-(Z)-but-2-enedio-
ate (6a) (50 mg, 0.10 mmol) in a mixture of acetone (2 mL) and
water (2 mL). Osmium tetroxide (2.5 mg, 0.01 mmol; CAUTION:
TOXIC) was then added, followed by 4-methylmorpholine-N-oxide
(11.6 mg, 0.10 mmol). The mixture was stirred for 4 h at room
temperature. Acetone was removed on a rotary evaporator. Satu-
rated aqueous sodium sulfite (2 mL) was added to the aqueous
residue, which was stirred for 10 min and then extracted with
dichloromethane (4ꢁ8 mL). The combined organic layers were
dried over MgSO4, filtered and evaporated to give a 2:1 mixture of
diastereoisomers, as shown in the 1H NMR spectrum. Chromatog-
raphy of the residue on silica gel (ethyl acetate) gave a single di-
astereoisomer, 5a or 5b (28 mg, 55%) as a colourless oil; IR nmax
(400 MHz, CDCl3)
d
7.19 (2H, d, J¼8.6 Hz), 6.83 (2H, d, J¼8.6 Hz), 5.43
(1H, s), 4.52 (1H, d, J¼12.0 Hz), 4.44 (1H, d, J¼8.8 Hz), 4.40 (2H, s),
4.32 (1H, d, J¼12.0 Hz), 4.25 (2H, q, J¼7.1 Hz), 3.75 (3H, s), 3.60e3.30
(2H, m), 2.58 (2H, t, J¼6.9 Hz), 1.95 (3H, s), 1.90e1.82 (3H, m), 1.27
(3H, t, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d 201.0, 194.4, 170.0,
169.9, 159.1, 129.9, 129.2, 112.9, 104.3, 88.8, 72.6, 70.6, 68.2, 65.5,
55.1, 27.7, 26.1, 22.2, 20.4, 14.0; LRMS m/z (þES, %) 459 (100), 297
(13); HRMSþES calcd for C22H28NaO9 459.1631, found: 459.1617.
(cmꢂ1) 3463, 2937, 1741,1704; 1H NMR (600 MHz, CDCl3)
d 7.26 (2H,
d, J¼8.6 Hz), 6.90 (2H, d, J¼8.6 Hz), 5.54 (1H, s), 4.95 (1H, s), 4.86
(1H, d, J¼12.0 Hz), 4.75 (1H, d, J¼12.0 Hz), 4.45 (2H, s), 4.29e4.18
(4H, m), 3.82 (3H, s), 3.51 (2H, t, J¼6.0 Hz), 2.59 (2H, m), 1.95 (3H, s),
1.90 (2H, m), 1.33 (3H, t, J¼7.1 Hz), 1.26 (3H, t, J¼7.1 Hz); 13C NMR
3.1.26. rel-Ethyl {(R)-2-acetoxymethyl-5-[3-(4-methoxybenzyloxy)-
propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2-oxoacetate (7). To a solu-
tion of rel-(2S)-ethyl {(S)-2-acetoxymethyl-5-[3-(4-methoxyben-
zyloxy)-propyl]-3-oxo-2,3-dihydrofuran-2-yl}-2-hydroxyacetate
(3a) (40 mg, 0.09 mmol) in dichloromethane (2 mL) at room tem-
perature were added sodium hydrogen carbonate (38 mg,
0.45 mmol) and DesseMartin periodinane (58 mg, 0.13 mmol).
After stirring for 2 h, saturated aqueous sodium hydrogen carbon-
ate (2 mL) and saturated aqueous sodium sulfite (2 mL) were added.
The mixture was stirred for 0.5 h, then the aqueous layer was
separated and extracted with dichloromethane (2ꢁ8 mL). The
combined organic layers were washed with brine (4 mL), dried over
(150 MHz, CDCl3)
d 201.7, 193.0, 170.2, 169.9, 169.2, 159.3, 130.1,
129.3, 113.8, 105.3, 90.6, 80.9, 72.8, 72.0, 68.3, 63.8, 63.0, 62.5, 55.3,
27.5, 26.5, 20.6, 14.0; LRMS m/z (þES, %) 561 (100), 539 (5);
HRMSþES calcd for C26H34NaO12 561.1948, found: 561.1953.
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a,b-un-
ꢁ
saturated ketones see: (a) Cox, R. J.; de Andres-Gomez, A.; Godfrey, C. A. Org.
Biomol. Chem. 2003, 18, 3173; (b) Walsh, P. J.; Sharpless, K. B. Synlett 1993, 605.