A new synthesis of (-)-epipyriculol: a phytotoxic metabolite

Article abstract of DOI:10.1016/j.tet.2008.01.115

A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.

Full text of DOI:10.1016/j.tet.2008.01.115

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4711e4717
www.elsevier.com/locate/tet
A new synthesis of (ꢀ)-epipyriculol: a phytotoxic metabolite
*
Antonio Leyva, Francesca E. Blum, Steven V. Ley
Department of Chemistry, The University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom
Received 20 August 2007; received in revised form 27 September 2007; accepted 17 October 2007
Available online 2 February 2008
Abstract
A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl L-tartrate. The synthetic
strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Epipyriculol; BDA methodology; Palladium catalysis; Natural product synthesis
1. Introduction
Here we describe a new route to epipyriculol that should also
be general for the synthesis of all four stereoisomers. Our work
starts from the single and cheap chiral source L-tartrate. The
natural product 2 was obtained after 17 steps and only five chro-
matographic separations. The use of butanediacetal (BDA) as
a 1,2-diol protecting group for methyl L-tartrate9e12 (Scheme
1) allows us to have a convenient scaffold upon which to build
the rest of the molecule by appropriate side chain modifications.
BDA-protected 1,2-diols have shown particularly good flexibil-
ity and robustness as building blocks in other synthesis pro-
grammes.13e19 Moreover, desymmetrisation of this common,
now commercially available, precursor 310 and interchange of
the alkenyl side chains in principle determines the isomer that
will be ultimately obtained, giving potential access to all four
stereoisomers of pyriculol.
Pyriculol (1), first isolated in 1969 by Iwasaki et al. from
a culture broth of Pyricularia oryzae Cavara,1 is a phytotoxic
metabolite that has been shown to cause dark necrotic spots on
rice leaves. This is one of the symptoms of rice blast fungus,
a crippling disease that also damages the collar, node and pan-
icle of the plants and impairs the growth of seedlings.2 A wide
range of related structures have been isolated later,3e6 many of
which are known to be phytotoxic metabolites. Its S(C10)-epi-
mer, epipyriculol (2), was obtained in 1991 from the same fun-
gus and showed even stronger inhibition activity than pyriculol
in spore germination bioassays (Fig. 1).4
To date, only one synthesis of epipyriculol has been de-
scribed.7,8 In that work, the syntheses of all four stereoisomers
of pyriculol, including epipyriculol, were reported in 20 steps.8
OH
OH
O
MeO2C
O
R
R'
R'
S
MeO2C
MeO2C
Ref. 10
O
O
O
R
R
O
MeO2C
R'
OH
Pyriculol 1
OH
R'
CHO
O
CHO
Epipyriculol 2
O
4
3
OH
OH
Figure 1. Phytotoxic metabolites that contribute to the symptoms of rice blast
disease.
(Altering the order of the sidechain formation)
(S,S) or (R,R)
Scheme 1. Strategy to obtain all four isomers of 1 from the common precursor 3.
(S,R) or (R,S)
* Corresponding author. Tel.: þ44 1223 336398; fax: þ44 1223 336442.
E-mail address: svl1000@cam.ac.uk (S.V. Ley).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.115

4712
A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
2. Results and discussion
Accordingly, the BDA-protected boronate 12 was prepared
from 5 in 47% overall yield over 7 steps and without need for
column chromatography. Diol 5 was protected as butanediacetal
3, which after reduction of the two ester groups to alcohols and
mono-silyl protection of one of them afforded alcohol 8. After
forming aldehyde 9 by Swern oxidation, CoreyeFuchs homo-
logation to obtain the alkyne 11 and hydroboration of this
yielded the vinyl boronate 12 after removal of the pinacol by
sublimation. The other partner for the first Suzuki reaction,
namely triflate 7, was obtained from 6 in 49% yield over two
steps, using a more practical procedure to that previously re-
ported,21,22 and again without chromatographic purification.
At this point, the Suzuki coupling between 12 and 7 was attemp-
ted. Not many examples of couplings between aromatic triflates
and vinyl boronates can be found in the literature.23,24 In gen-
eral, the method of choice for the coupling of triflates with
boronic derivatives involves a Pd-phosphine catalyst in combi-
nation with inorganic bases such as K2CO3 or K3PO4, in hot
dioxane as solvent.25,26 In our particular case, the following
issues were addressed after experimentation under several con-
ditions: (a) Pd(PPh3)4 was found to be a superior catalyst com-
pared to PdCl2(dppf)$CH2Cl2 or Pd(OAc)2ePCy3 (CsF as base)
under similar conditions; (b) longer reaction times than 2 h did
not improve the yield; (c) when anhydrous dioxane was used as
solvent, 3 equiv of base were necessary to bring the reaction to
completion, however, amounts of phenol (coming from the
hydrolysis of 7, CeOSO2CF3 to CeOH) were found in the mix-
ture; (d) when DMF (dry)/EtOH (4:1 volume)24 was used, only
1.5 equiv of base were needed to complete the reaction. Curi-
ously, the by-product formed exclusively from 7 under these
conditions was the benzene-derivative (CeOSO2CF3 to CeH).
The latter route gave the coupling product 14 in moderate yield
after purification by column chromatography.
Our proposed route to epipyriculol 2 is shown in Scheme 2.
The strategy is based on the BDA protecting group method,
developed in our laboratories14,18,13 and by others,11,12,20 in
combination with Pd-catalysed cross-coupling reactions. It
was anticipated that the introduction of the E-propenyl side
chain would eventually proceed better using a Takai olefina-
tion rather than further Suzuki coupling.
Alternative
olefination
Suzuki coupling
O
O
O
Epipyriculol 2
O
O
O
O
Suzuki coupling
Y1
O
O
Y1= OSO CF3
X1= Bpin 2
X2= I
X2
X1
Y2
O
O
O
O
Y2= B(OR)2
O
7
OH
O
OH
CO2Me
OH
OH
2,6-dihydroxybenzoic acid 6
MeO2C
OH
L-tartrate 5
Scheme 2. Proposed retrosynthesis to epipyriculol 2.
Thus, starting from methyl L-tartrate 5, we expected the
boronate precursor (X1¼BPin) to engage in the first Suzuki
coupling with the triflate 7 obtained from 2,6-dihydroxybenz-
oic acid 6. After this coupling, the resulting product could be
further functionalised (X2¼I) to obtain a second partner for
another Suzuki reaction or, alternatively, directly olefinated
through a Takai reaction. Epipyriculol 2 would be achieved
after removal of the two protecting groups.
The synthesis also allows access to each isomer selectively
early on in the pathway. A drawback in the previous reported
route8 relies on the enantiomeric differentiation. Diastereo-
meric mixtures (ca. 1:1), arising from nucleophilic addition of
an acetylide anion to a chiral aldehyde, were chromatographi-
cally separated, each of which was further elaborated to give
an isomer of pyriculol. Moreover, this chiral approach can be
readily adapted to give access to the other three stereoisomers.
Thus, desymmetrisation of the equatorialeequatorial precursor
3 to the corresponding equatorialeaxial 4 would eventually
give the (S,S)-isomer (2) and the (S,R)-isomer (Scheme 1).
The other two stereoisomers (R,R)- and (R,S)-(1) would be
obtained after reversing the coupling operations.
The final stages of the synthesis are shown in Scheme 4.
In spite of the difficulties found in the first Suzuki coupling,
we tested the possibility of forming the remaining E-alkenyl
moiety by a better-known second Suzuki coupling, in this
case with the methylboronic acid derivative 18.27
The formation of the vinyl iodide 17 for the second Suzuki
coupling was carried out in good yield by deprotection of the
silyl protecting group of 14, Swern oxidation of the resulting
alcohol 1519 and Takai homologation28 of the aldehyde 16 to
obtain 17 as a 9:1 (E/Z) molar ratio mixture. It is important to
note that the silyl deprotection of 14 has to be accomplished
at ꢀ10 ꢁC, otherwise isomerisation was observed. In a same
way, quenching the Swern oxidation of 15 with Et3N to obtain
aldehyde 16 has to be addressed carefully, since reaction times
longer than 20 min cause isomerisation. These two features sug-
gest a particular sensitivity of the scaffold to isomerise. This be-
haviour could be explained by the increased acidity of the allylic
proton due to the presence of a highly conjugated system. This
fact could impart a certain instability to the system under basic
conditions, which could be a drawback for the subsequent Su-
zuki coupling. Indeed, the coupling of 17 with trimethylborox-
ine proceeded as expected with total retention of configuration
but in a poor 20% yield after column chromatography. A mix-
ture of by-products coming from the BDA-scaffold, including
Following the analysis described above, we began the syn-
thesis of epipyriculol 2 by installing the aromatic side chain.
The results obtained are depicted in Scheme 3.

A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
4713
ref. 9
O
OH
O
i) DMSO, CH2Cl2,
oxalyl chloride
-78 °C, 90 min
ii) Et3N, r.t.
TBDMSO
O
(3 as first
intermediate)
60 %
TBDMSO
HO
PPh3, CH2Cl2, CBr4
0 °C r.t , 2 h
84 %
CO2Me
O
O
O
MeO2C
O
OH
O
9
O
8
5
over 3 steps
99 %
O
O
OTBDMS
BH
O
O
B
O
TBDMSO
TBDMSO
Br
O
O
n-BuLi, THF
-78 °C r.t.
99 %
O
O
O
O
O
O
100 °C, 24 h
O
O
Br
O
12
10
11
99 %
Pd(PPh3)4 (15 mol%)
K2CO3
DME, DMAP
acetone
thionyl chloride
20 °C, 3 h
63 %
OH
O
py, Tf2O
0 °C, 10 min,
77 %
OTf
O
OH
O
O
O
OH
OH
solvent
100 °C, 2 h
O
O
6
13
7
O
OTBDMS
O
O
Solvent
7 (eq.)
K2CO3(eq.) 14 (isolated
yield, %)
O
O
1,4-dioxane
DMF/EtOH (4:1)
1.5
2.0
3
39
54
14
O
O
1.5
Scheme 3. Synthesis of 14.
O
O
O
HO
DMSO, CH2Cl2,
Bu4NF (2.5. eq.)
THF
O
O
O
oxalyl chloride, -78 °C, 90 min.
O
14
-10 °C, 82 (13)a
%
O
then alcohol in CH2Cl2, 90 min
then Et3N, 20 min., r.t.
80 (20)a
%
O
O
O
16
15
O
O
O
O
O
B
18
(1.5 eq.)
O
B
O
O
O
CrCl2 (18 eq.),
CHI3(6 eq.), THF,
r.t., 24 h
B
O
I
O
O
O
O
O
PdCl2(dppf) CH2Cl2 (2.5 eq.)
19
·
O
O
O
O
79 (10)a
%
3 eq. K2CO3,
1,4 -dioxane, 110 °C
20 %
17
O
O
16
O
S
O
N
N
N
N
Et
Ph
20
KHMDS
DME, -60 °C
50 %, 4:1 (E:Z)
19
O
OH
i) DIBAL-H (3 eq.), CH2Cl2
-78 °C, 90 min.
O
O
AcOH:THF:H2O (4:2:1)
19
HO
OH
Epipyriculol 2
O
CHO
CrCl2 (12 eq.),
CH3CHI2 (4 eq.),
THF, r.t., 24 h
ii) MnO2, CH2Cl2, r.t., 45 min.
70 °C, 14 h
70 %
21
O
H
OH
84 % over 2 steps
65 %, 10:1 (E:Z)
a
Scheme 4. Completion of the synthesis of epipyriculol 2. In brackets, recovered starting material.
homocoupling, were unavoidably formed in the reaction. More-
over, Pd loadings >2.5% generated significant amounts of
terminal alkene. Therefore, other approaches were screened to
install the E-propenyl chain.
In the literature, one of the most used methods to install a
E-propenyl moiety is the JuliaeKociensky olefination, using
the sulfone 20.29,30 However, the poor 4:1 (E/Z) molar ratio ob-
tained under the optimal reaction conditions reported30 forced

4714
A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
us to seek for other conditions. Given the fact that the Takai ole-
fination proceeded smoothly to form the E-vinyl iodide 17, and
with high stereocontrol, we examined the same reaction31 with
the aldehyde 16 but using CH3CHI2.32,33 Pleasingly, the reac-
tion yielded a reasonable 65% of 19 with a 10:1 (E/Z) molar
ratio. Although the presence of small amounts of the alcohol
did not interfere in the formation of 17, it was found that, in
this particular case, the purification of the aldehyde (alcohol
<5%) is crucial in order to obtain good yields of 19.
constant J in hertz). Residual protic solvent was used as the in-
ternal reference, setting chloroform to d 7.26. Carbon magnetic
resonance spectra (13C NMR) were recorded at 100 MHz on
a Bruker DPX-400. Chemical shifts are quoted in parts per
million, referenced to the appropriate solvent peak, taking chlo-
roform as d 77.0. Assignments were made using DEPT 135
experiments. Elemental analysis was carried out, unless the
compound could not be isolated in sufficient purity, at the
Department of Chemistry, University of Cambridge. High-reso-
lution mass spectrometry (HRMS) was carried out on a Waters
LCT Premier XE Spectrometer using electrospray ionisation
(ESI) at the Department of Chemistry, University of Cambridge.
With compound 19 in hand, we only needed to remove both
the cyclic ester and the BDA to obtain the natural product.
DIBAL-H reduction of the ester34 and treatment of the resulting
8
products with MnO2 gave the desired aldehyde 21. The re-
moval of the BDA group was attempted under different condi-
tions including: TFA,16 TiCl420 and BF3/ethanedithiol,10 all of
them failed to give 2. However, a combination of AcOH/THF/
H2O (4:2:1 in volume)35 at 70 ꢁC rendered our target compound
epipyriculol 2 in satisfactory yields and identical in all respects
to the reported natural product.
4.1.1. 5-Hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (13)
Following the literature procedure,21 a solution of 2,6-dihy-
droxybenzoic acid (16.28 g, 105.6 mmol) in DME (35 mL) was
dried over MgSO4 at rt overnight. To the filtered solution was
added DMAP (665 mg, 5.5 mmol) and acetone (10 mL,
140 mmol). The solution was cooled to 20 ꢁC and a solution
of thionyl chloride (18 g, 151 mmol) in DME (5 mL) was added
over 2 h. The solution was stirred for 1 h. The mixture was then
passed through a pad of silica, eluting with CH2Cl2 (1 L) after
which water (1 L) was added to the filtrate and the aqueous
phase further extracted with CH2Cl2 (2ꢂ500 mL). The organic
fractions were combined and washed with water (2ꢂ500 mL)
and brine (500 mL), then dried over Na2SO4, filtered and con-
centrated in vacuo to give 13 as a brown oil, which crystallised
upon cooling (12.81 g, 66.06 mmol, 63%).
3. Conclusions
The synthesis of epipyriculol 2 has being completed. Our
route involves 17 steps in a 9.1% overall yield for the longest
linear sequence (14 steps). Only five chromatographic separa-
tions are needed throughout the synthesis. All other stereoiso-
mers as well as derivatives could, in principle, be prepared
using a related synthetic route.
4. Experimental
1H NMR d: 10.04 (1H, br s), 7.32 (1H, dd, J¼8, 8), 6.53
(1H, d, J¼8), 6.35 (1H, d, J¼8), 1.65 (6H, s). 13C NMR d:
165.3, 161.3, 155.5, 137.9, 110.68, 107.2, 107.1, 99.3, 25.5.
4.1. General methods
All reactions were performed in oven-dried glassware, under
an inert argon atmosphere. All solvents used were reagent grade
and distilled by standard procedures. All aqueous solutions were
saturated unless otherwise indicated and all reactions were mag-
netically stirred and monitored by GCeMS, on a PerkineElmer
AutoSystem XL GC/TurboMass GCeMS spectrometer. Where
sealed microwave tubes were used, thesewere sealed with Suba-
Seal septa. Analytical TLC was carried out with precoated
glass-backed plates (Merck Keiselgel 60 F254 plates), visualised
by UV fluorescence (l¼254 nm) and stained with aqueous
acidic ammonium molybdate(IV). Flash column chromatogra-
phy and purification through silica pads were carried out using
Merck Keiselgel (230e400 mesh). P.E. refers to petroleum
ether, 40e60 ꢁC boiling point.
Optical rotations were measured, unless the compound could
not be isolated in sufficient purity, on a PerkineElmer Model
343 Polarimeter with a sodium lamp at 25 ꢁC. [a]D25 are given
in 10ꢀ1 deg cm2 gꢀ1 and concentrations, c, are reported in
g/100 mL. IR spectra were recorded on a PerkineElmer Spec-
trum One FT-IR Spectrometer and selected characteristic absor-
bances are reported neat, in cmꢀ1 (abs). Proton magnetic
resonance spectra (1H NMR) were recorded at 400 MHz on
a Bruker DPX-400 and are reported as follows: chemical shift
d in parts per million (number of protons, multiplicity, coupling
4.1.2. 2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-5-yl
trifluoromethanesulfonate (7)
Following the procedure,22 triflic anhydride (5.0 g,
17.72 mmol) was added to a solution of 13 (2.862 g,
14.75 mmol) in pyridine (25 mL) at 0 ꢁC. The solution was
stirred for 10 min then quenched with NaHCO3 (aq) (15 mL).
The mixture was repeatedly extracted with ether and the com-
bined organic fractions were washed with water, dried over
Na2SO4 and concentrated in vacuo. The residue was dissolved
in P.E. and the filtrate was concentrated in vacuo to give 7 as
a pale orange solid (1.07 g, 3.28 mmol, 22%). The residue
remaining from dissolution in P.E. was dissolved in ether and
the filtrate was concentrated in vacuo to give additional 7 as
an orange solid (2.64 g, 8.10 mmol, 55%).
1H NMR d: 7.60 (1H, dd, J¼8, 8), 7.06 (1H, d, J¼8), 7.00
(1H, d, J¼8), 1.75 (6H, s). 13C NMR d: 157.4, 157.0, 148.7,
117.8, 116.6, 116.5, 108.3, 106.8, 25.5.
4.1.3. (2R,3S,5R,6R)-3-((tert-Butyldimethylsilyloxy)methyl)-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (9)
Prepared according to a previous procedure.36 A solution of
DMSO (1.58 mL, 22.31 mmol) in CH2Cl2 (30 mL) was added to
a solution of oxalyl chloride (1.41 g, 11.13 mmol) in CH2Cl2
at ꢀ78 ꢁC and stirred for 30 min. A solution of 8 (3.0 g,

A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
4715
8.57 mmol) in CH2Cl2 (65 mL) was added over 30 min. The so-
4.1.6. tert-Butyl(((2S,3S,5R,6R)-5,6-dimethoxy-5,6-dimethyl-
lution was stirred at ꢀ78 ꢁC for 90 min then Et3N (4.17 mL,
29.94 mmol) was added over 15 min. The solution was allowed
to warm to rt over 20 min, then diluted with CH2Cl2 (300 mL)
and washed with water (2ꢂ250 mL) and brine (250 mL). The
organic fractions were dried over MgSO4 and concentrated in
vacuo to give 9 as a yellow oil (2.98 g, 8.57 mmol, 100%).
1H NMR d: 9.64 (1H, d, J¼1.5), 4.12 (1H, dd, J¼10, 1.5),
3.76e3.85 (3H, m), 3.26 (6H, s), 1.36 (3H, s), 1.29 (3H, s),
0.87 (9H, s), 0.05 (6H, s).
3-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
vinyl)-1,4-dioxan-2-yl)methoxy)dimethylsilane (12)
Alkyne 11 (1.741 g, 5.06 mmol) was added to pinacolborane
(1.762 mL, 12.14 mmol) and the mixture was heated at 100 ꢁC
in a sealed tube for 24 h. Then, the crude mixture was heated to
110 ꢁC under high vacuum (<2 Torr) overnight. After this treat-
ment, pure 12 was obtained in the flask as a yellow oil (2.39 g,
5.06 mmol, 100%).
[a]2D5 ꢀ89.6 (c 0.875, CDCl3). IR (neat, cmꢀ1): 2953, 1644,
1
1372, 1254, 1120, 1038. H NMR d: 6.59 (1H, dd, J¼18, 6),
4.1.4. tert-Butyl(((2S,3S,5R,6R)-3-(2,2-dibromovinyl)-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)methoxy)-
dimethylsilane (10)
5.81 (1H, dd, J¼18, 1), 4.12 (1H, ddd, J¼9, 6, 1), 3.64 (2H, d,
J¼5), 3.56 (1H, dt, J¼10, 5), 3.21 (3H, s), 3.19 (3H, s), 1.27
(3H, s), 1.24 (3H, s), 1.22 (12H, s), 0.85 (9H, s), 0.04 (3H, s),
0.03 (3H, s). 13C NMR d: 147.8, 132.0, 98.5, 83.2, 72.1, 71.5,
63.2, 47.7, 47.6, 25.9, 24.8, 18.2, 17.6, 17.5, ꢀ5.3 (2C). E.A.
Calcdfor C23H45BO7Si:C58.47, H9.60. Found:C58.32,H 8.96.
Carbon tetrabromide (5.697 g, 17.18 mmol) was added to
a solution of triphenylphosphine (9.015 g, 34.37 mmol) in
CH2Cl2 (120 mL) at 0 ꢁC and stirred for 15 min. The ice-bath
was removed and the mixture was stirred for another 15 min.
A solution of 9 (2.99 g, 8.59 mmol) in CH2Cl2 (60 mL) was
added and the mixture was stirred for 3 h. Hexane (120 mL)
was added whereupon a precipitate was formed. The mixture
was filtered and the filtrate was washed again with hexane
(120 mL) and refiltered. The solvent was removed in vacuo
and the resulting crude 10 was redissolved in hexane
(120 mL) and placed in the fridge overnight, after which the
mixture was filtered once more and the solvent removed again
in vacuo to yield pure 10 as a brown oil (3.63 g, 7.22 mmol,
84%).
4.1.7. 5-((E)-2-((2S,3S,5R,6R)-3-((tert-Butyldimethylsilyloxy)-
methyl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)vinyl)-
2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (14)
Vinyl boronate 12 (47.2 mg, 0.1 mmol), triflate 7 (65.2 mg,
2 equiv), Pd(PPh3)4 (17.3 mg, 15 mol %) and K2CO3 (19.8 mg,
1.5 equiv) were placed in a sealed tube under argon and dry
DMF (0.4 mL) and absolute ethanol (0.1 mL) were added. The
mixture was heated at 100 ꢁC for 2 h. After this time the mixture
was concentrated under vacuum and the crude was separated by
column chromatography (7% Et2O/P.E., then 15 and 30%) to ob-
tain the coupling product 14 as an oil (28.2 mg, 0.054 mmol,
54%).
Rf (20% Et2O in P.E.): 0.65. [a]2D5 ꢀ94.0 (c 0.205, CDCl3).
1
IR (neat, cmꢀ1): 2929, 1629, 1253, 1116, 1037. H NMR d:
6.45 (1H, d, J¼9), 4.41 (1H, dd, J¼9, 9), 3.69 (1H, dt, J¼9,
5), 3.63 (2H, dd, J¼5, 2), 3.33 (3H, s), 3.26 (3H, s), 1.29
(3H, s), 1.28 (3H, s), 0.89 (9H, s), 0.08 (3H, s), 0.06 (3H,
s). 13C NMR d: 134.9, 98.8, 98.6, 95.2, 71.4, 70.9, 63.1,
48.3, 47.9, 25.8, 18.3, 17.5, 17.5, ꢀ5.4 (2C). E.A. Calcd for
C17H32Br2O5Si: C 40.49, H 6.40, Br 31.69. Found: C 41.09,
H 6.21, Br 31.77.
Rf (10% Et2O in P.E.): 0.14. [a]2D5 ꢀ76.2 (c 1.56, CHCl3). IR
(neat, cmꢀ1): 2948, 1741, 1576, 1319, 1272, 1128, 1042, 836,
1
779. H NMR d: 7.76 (1H, d, J¼16), 7.42 (1H, t, J¼8), 7.26
(1H, dd, J¼8, 1), 6.85 (1H, dd, J¼8, 1), 6.17 (1H, dd, J¼16,
7), 4.29 (1H, t, J¼8), 3.71 (3H, m), 3.30 (3H, s), 3.29 (3H, s),
1.72 (3H, s), 1.70 (3H, s), 1.32 (3H, s), 1.30 (3H, s), 0.85 (9H,
s), 0.04 (3H, s), 0.02 (3H, s) 13C NMR d: 160.0, 156.7, 141.1,
135.0, 132.3, 129.8, 121.6, 116.5, 111.0, 105.2, 98.6 (2C), 72,
5, 71.2, 63.3, 48.0, 47.8, 26.0, 25.8 (3C), 25.3, 18.2, 17.7,
17.6, ꢀ5.2, ꢀ5.3. HRMS (ESI) m/z 545.2569 [(MþNa)þ; calcu-
lated for C27H42O8SiNa: 545.2547].
4.1.5. tert-Butyl(((2R,3S,5R,6R)-2-ethynyl-5,6-dimethoxy-
5,6-dimethyltetrahydro-2H-pyran-3-yl)methoxy)-
dimethylsilane (11)
n-BuLi (7.91 mL, 12.65 mmol, 1.6 M in hexanes) was added
dropwise over 15 min to a solution of 10 (2.55 g, 5.06 mmol) in
THF (70 mL) at ꢀ78 ꢁC. The solution was allowed to warm up
to rt over 30 min, after which NH4Cl (aq) (40 mL) was added
and the aqueous layer was extracted with ether (2ꢂ60 mL).
The organic fractions were combined and washed with water
(2ꢂ40 mL) and brine (40 mL), then dried (MgSO4), filtered
and concentrated in vacuo to give 11 as a yellow oil (1.741 g,
5.06 mmol, 100%).
4.1.8. 5-((E)-2-((2S,3S,5R,6R)-3-(Hydroxymethyl)-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)vinyl)-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (15)
A solution of Bu4NF 1.0 M in THF (2.97 mL, 2.975 mmol,
2.5 equiv) was added dropwise to 14 (620 mg, 1.19 mmol) dis-
solved in THF (12 mL) at ꢀ10 ꢁC under argon. The solution
was magnetically stirred for 3 h 30 min. After this time the so-
lution was passed through a pad of silica, washing with a 1:1
solution of ether/petroleum ether and then pure ether. The sol-
vents were removed under vacuum and the remaining mixture
was purified by column chromatography (25% ether/P.E, then
50%) to give 15 as a white solid after complete solvent re-
moval (400 mg, 0.98 mmol, 82%). The remaining starting ma-
terial was recovered after washing the column with pure ether
[a]2D5 ꢀ93.0 (c 0.835, CDCl3). IR (neat, cmꢀ1): 3260, 2929,
1
2344, 1252, 1118, 1036. H NMR d: 4.42 (1H, dd, J¼10, 2),
3.77 (3H, m), 3.26 (3H, s), 3.24 (3H, s), 2.47 (1H, d, J¼2),
1.30 (3H, s), 1.25 (3H, s), 0.88 (9H, s), 0.07 (3H, s), 0.06
(3H, s). 13C NMR d: 98.9, 98.7, 79.7, 75.0, 72.4, 62.9, 60.1,
48.1, 47.8, 25.8, 18.3, 17.5 (2C), ꢀ5.3 (2C). E.A. Calcd for
C17H32O5Si: C 59.27, H 9.36. Found: C 58.75, H 8.94.

4716
A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
(79 mg, 0.15 mmol, 13%) alongside some amounts of the
silanol.
Rf (20% Et2O in P.E.): 0.29. [a]2D5 ꢀ119.3 (c 0.80, CHCl3). IR
(neat, cmꢀ1): 2992, 2949, 1732 (vs), 1600, 1578, 1477, 1377,
Rf (Et2O): 0.51. [a]D25 ꢀ86.6 (c 0.65, CHCl3). IR (neat, cmꢀ1):
1318, 1271, 1208, 1141 (vs), 1120 (vs), 1078, 1040. H NMR
1
3508, 2949, 1734 (vs), 1600, 1578, 1477, 1378, 1320, 1272,
1
1208, 1124 (vs), 1081, 1040 (vs). H NMR d: 7.66 (1H, d,
d: 7.75 (1H, d, J¼16), 7.45 (1H, t, J¼8), 7.21 (1H, dd, J¼7,
1), 6.88 (1H, dd, J¼8, 1), 6.57 (2H, m), 6.04 (1H, dd, J¼16,
8), 4.26 (1H, ddd, J¼10, 8, 1), 4.14 (1H, dd, J¼10, 4), 3.31
(3H, s), 3.28 (3H, s), 1.72 (3H, s), 1.70 (3H, s), 1.34 (6H, s).
13C NMR d: 160.1, 156.8, 141.1, 140.8, 135.2, 133.5, 128.3,
121.6, 116.8, 111.1, 105.4, 99.0, 98.7, 81.0, 73.7, 72.1, 48.3,
48.2, 25.9, 25.5, 17.7 (2C). HRMS (ESI) m/z 553.0724
[(MþNa)þ; calculated for C22H27IO7Na: 553.0699].
J¼16), 7.45 (1H, t, J¼8), 7.22 (1H, d, J¼7), 6.88 (1H, dd, J¼
8, 1), 6.08 (1H, dd, J¼16, 8), 4.39 (1H, t, J¼9), 3.75 (3H, m),
3.32 (3H, s), 3.30 (3H, s), 2.20 (1H, OH, t, J¼6), 1.72 (3H, s),
1.69 (3H, s), 1.35 (3H, s), 1.34 (3H, s). 13C NMR d: 160.3,
156.7, 140.9, 135.4, 133.3, 129.1, 121.8, 116.7, 111.0, 105.4,
98.8, 98.7, 71.4, 71.0, 62.3, 48.1, 48.0, 26.1, 25.1, 17.7, 17.6.
HRMS (ESI) m/z 431.1665 [(MþNa)þ; calculated for
C21H28O8Na: 431.1682].
4.1.11. 5-((E)-2-((2S,3S,5R,6R)-5,6-Dimethoxy-5,6-
dimethyl-3-((E)-prop-1-enyl)-1,4-dioxan-2-yl)vinyl)-
4.1.9. (2R,3S,5R,6R)-3-((E)-2-(2,2-Dimethyl-4-oxo-4H-
benzo[d][1,3]dioxin-5-yl)vinyl)-5,6-dimethoxy-5,6-
dimethyl-1,4-dioxane-2-carbaldehyde (16)
2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (19)
Heck coupling: vinyl iodide 17 (103 mg, 0.19 mmol),
PdCl2(dppf)$CH2Cl2 (3.75 mg, 0.0046 mmol, 2.5 mol %) and
K2CO3 (75 mg, 0.54 mmol, 3 equiv) wereplaced in athick-glass
sealed tube and purged with argon. 1,4-Dioxane (750 mL) and
trimethylboroxine (38.5 mL, 0.28 mmol, 1.5 equiv) were added
and the mixture was heated at 105 ꢁC for 2 h. The completion of
the reaction was judged by TLC. After this time the mixture was
diluted in ether and filtered, the solvents were removed under
vacuum and the crude was purified by column chromatography
(30% Et2O/P.E.) to give 19 as an oil (14.6 mg, 20%).
JuliaeKociensky olefination: a 0.5 M solution of KHMDS in
toluene (1.920 mL, 0.96 mmol) was placed under vacuum. Af-
ter removal of the toluene, the dry KHMDS was redissolved in
DME (700 mL). A portion of this fresh solution (200 mL,
0.27 mmol, ca. 4 equiv) was added bysyringe pump to asolution
of the mixture aldehyde 16/alcohol 15 (4:1 mol ratio, 26 mg,
0.064 mmol) and sulfone 20 (46 mg, 0.192 mmol, 3 equiv) in
DME (300 mL) at ꢀ60 ꢁC over 1 h. After this time water
(100 mL) was added and the mixture left to reach rt. The mixture
was eluted with Et2O and extracted with water. The aqueous
phasewas further extracted with ether and the combined organic
phases were washed water and brine, dried over Na2SO4 and
concentrated. The residue was purified by column chromatogra-
phy (10% Et2O/P.E., then 20% and pure ether) to give alkene 19
(12 mg, 44%) as a 4:1 (E/Z molar ratio) mixture (determined by
1H NMR) alongside sulfone 19; and the starting mixture alde-
hyde/alcohol (10 mg, 38%).
A solution of DMSO (102 mL, 1.44 mmol, 4.5 equiv) in
CH2Cl2 (1 mL) was added dropwise to a solution of oxalyl chlo-
ride (84 mL, 0.96 mmol, 3 equiv) in CH2Cl2 (2 mL) at ꢀ78 ꢁC
and stirred for 90 min. A solution of 15 (130 mg, 0.32 mmol)
in CH2Cl2 (2.5 mL) was added over 1 h. The solution was stirred
at ꢀ78 ꢁC for 1 h and then Et3N (334 mL, 2.4 mmol, 7.5 equiv)
was added over 10 min. The solution was allowed to warm to rt
over 20 min, then diluted with CH2Cl2 (30 mL) and washed with
water (30 mL). The aqueous phases were further extracted
with CH2Cl2 (30 mL) and the combined organic phases washed
with water (2ꢂ50 mL) and brine (50 mL). The organic fraction
was dried over MgSO4 and concentrated in vacuo to give a mix-
1
ture 4:1 (determined by H NMR) of the aldehyde 16 and the
starting material alcohol 15 as an oil (128 mg, 98%). The mix-
ture could be separated by column chromatography (40%
Et2O in P.E., then 60, 80 and 100% Et2O).
Rf (80% Et2O in P.E.)¼0.24. 1H NMR d: 9.66 (1H, d, J¼1),
7.76 (1H, d, J¼16), 7.44 (1H, t, J¼8), 7.25 (1H, d, J¼8), 6.87
(1H, d, J¼8), 6.19 (1H, dd, J¼16, 7), 4.49 (1H, ddd, J¼10, 7,
1), 4.16 (1H, dd, J¼10, 4), 3.32 (3H, s), 3.29 (3H, s), 1.69 (3H,
s), 1.68 (3H, s), 1.40 (3H, s). 1.35 (3H, s).
4.1.10. 5-((E)-2-((2S,3S,5R,6R)-3-((E)-2-Iodovinyl)-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)vinyl)-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (17)
A mixture of aldehyde 16 and alcohol 15 (4:1 molar ratio,
205 mg, 0.42 mmol respect to aldehyde) and CHI3 (993 mg,
2.52 mmol, 6 equiv) were dissolved in THF (2 mL) under ar-
gon. This solution was added dropwise to a magnetically stirred
dispersion of CrCl2 (930 mg, 7.56 mmol, 18 equiv) in THF
(4 mL) at rt and the mixture was stirred for 24 h. After this
time the mixture was poured into water (25 mL) and extracted
with ether (25 mL). The aqueous phase was further extracted
with ether (25 mL) and CH2Cl2 (25 mL). The combined or-
ganic phases were dried over MgSO4, filtered and the solvents
removed under vacuum. The remaining crude was purified by
column chromatography (20% Et2O in P.E., then 100% Et2O)
to give the iodide 17 as a 9:1 (E/Z molar ratio) mixture
(177 mg, 0.33 mmol, 79%) and the starting mixture (22 mg,
10%).
Takai olefination: pure aldehyde 16 (20 mg, 0.05 mmol)
and CH3CHI2 (56.4 mg, 0.2 mmol, 4 equiv) were dissolved
in THF (0.4 mL) under argon. This solution was added drop-
wise to a magnetically stirred dispersion of CrCl2 (74 mg,
0.6 mmol, 12 equiv) in THF (0.4 mL) at rt and the mixture
was stirred for 24 h. After this time the mixture was poured
into water (4 mL) and extracted with ether (10 mL). The aque-
ous phase was further extracted with ether (6 mL) and CH2Cl2
(6 mL). The combined organic phases were dried over
MgSO4, filtered and the solvents removed under vacuum.
The remaining crude was purified by column chromatography
(10% Et2O in P.E., then 20%) to give the alkene 19 as a 10:1
(E/Z molar ratio) mixture (14 mg, 0.033 mmol, 65%).
Rf (20% Et2O in P.E.): 0.23. [a]2D5 ꢀ78.5 (c 1.00, CHCl3). IR
(neat, cmꢀ1): 1733 (vs), 1599, 1577, 1475, 1376, 1316, 1270,

A. Leyva et al. / Tetrahedron 64 (2008) 4711e4717
4717
1204, 1119 (vs), 1039. 1H NMR d: 7.72 (1H, d, J¼16), 7.43 (1H,
Acknowledgements
t, J¼8), 7.22 (1H, d, J¼8), 6.86 (1H, d, J¼8), 6.05 (1H, dd,
J¼16, 7), 5.82 (1H, dq, J¼15, 7), 5.49 (ddd, J¼16, 8, 1), 4.28
(1H, dd, J¼10, 8), 4.09 (1H, t, J¼8), 3.33 (3H, s), 3.30 (3H,
s), 1.71 (6H, m), 1.68 (3H, s), 1.35 (3H, s), 1.34 (3H, s). 13C
NMR d: 160.1, 156.7, 141.2, 135.1, 132.4, 131.6, 129.5,
127.0, 121.6, 116.5, 111.0, 105.2, 98.7, 98.6, 72.7, 72.6, 48.1,
48.0, 26.0, 25.2, 18.0, 17.8 (2C). HRMS (ESI) m/z 441.1898
[(MþNa)þ; calculated for C23H30O7Na: 441.1889].
We thank EPSRC (A.L.) and the BP Endowment (S.V.L.)
for financial support.
References and notes
1. Suzuki, M.; Sugiyama, T.; Watanabe, M.; Yamashita, K. Agric. Biol.
Chem. 1986, 2159.
2. Iwasaki, S.; Nozoe, S.; Okuda, S.; Sato, Z.; Kozaka, T. Tetrahedron Lett.
1969, 1, 3977.
4.1.12. 2-((E)-2-((2S,3S,5R,6R)-5,6-Dimethoxy-5,6-
dimethyl-3-((E)-prop-1-enyl)-1,4-dioxan-2-yl)vinyl)-
6-hydroxybenzaldehyde (21)
3. Kim, J.; Mi, J.; Kim, H.; Cho, K.; Yu, S. Biosci. Biotechnol. Biochem.
1998, 173.
4. Kono, Y.; Sekido, S.; Yamaguchi, I.; Kondo, H.; Suzuki, Y.; Neto, G. C.;
Sakurai, A.; Yaegashi, H. Agric. Biol. Chem. 1991, 2785.
5. Nukina, M.; Sassa, T.; Ikeda, M.; Umezawa, T.; Tasaki, H. Agric. Biol.
Chem. 1981, 2161.
DIBAL-H (1 M in CH2Cl2, 165 mL, 0.165 mmol, 3 equiv)
was added to a solution of the alkene 19 (23 mg, 0.055 mmol)
in CH2Cl2 (300 mL) at ꢀ78 ꢁC and the solution was stirred
for 90 min. After this time MeOH (150 mL) and aqueous 1 M
HCl (165 mL) were added and the mixture was left to reach rt.
The mixture was diluted with ether and washed with water.
The aqueous phase was further extracted with ether (ꢂ3) and
the combined organic phases were washed with water (ꢂ2)
and brine, dried over MgSO4 and concentrated. The resulting
crude was redissolved in dry CH2Cl2 (1.2 mL) and added to ac-
tivated MnO2 (160 mg). The mixture was magnetically stirred
at rt under argon for 45 min, then filtered through a pad of Celite
under vacuum. After removal of the solvent, aldehyde 21 was
obtained (17 mg, 0.046 mmol, 84% over two steps).
Rf (50% Et2O in P.E.): 0.69. [a]2D5 ꢀ72.4 (c 0.50, CHCl3). IR
(neat, cmꢀ1): 1645, 1610, 1570, 1450, 1119. 1H NMR d: 11.84
(1H, s), 10.27 (1H, s), 7.44 (1H, t, J¼8), 7.16 (1H, d, J¼15),
6.89 (1H, d, J¼7), 6.88 (1H, d, J¼8), 5.97 (1H, dd, J¼15, 7),
5.84 (1H, dq, J¼15, 7), 5.48 (ddd, J¼15, 8, 1), 4.26 (1H, ddd,
J¼10, 6, 1), 4.03 (1H, t, J¼9), 3.31 (3H, s), 3.29 (3H, s), 1.73
(3H, dd, J¼7, 1), 1.36 (3H, s), 1.34 (3H, s). 13C NMR d:
195.5, 162.7, 142.4, 137.1, 133.1, 132.4, 127.2, 126.8, 119.0,
117.3, 117.1, 98.8, 98.7, 73.2, 72.0, 48.1, 48.0, 18.1, 17.8,
17.7. HRMS (ESI) m/z 385.1629 [(MþNa)þ; calculated for
C20H26O6Na: 385.1627].
6. Umetsu, N.; Kaji, J.; Tamari, K. Agric. Biol. Chem. 1972, 859.
7. Suzuki, M.; Sugiyama, T.; Watanabe, M.; Murayama, K. M.; Yamashita,
K. Agric. Biol. Chem. 1987, 1121.
8. Suzuki, M.; Sugiyama, T.; Watanabe, M.; Murayama, K. M.; Yamashita,
K. Agric. Biol. Chem. 1987, 2161.
9. Barlow, J. S.; Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D. J.
J. Chem. Soc., Perkin Trans. 1 1999, 1627.
10. Dixon, D. J.; Foster, A. C.; Ley, S. V. Can. J. Chem. 2001, 1668.
11. Berens, U.; Leckel, D.; Oepen, S. C. J. Org. Chem. 1995, 60, 8204.
12. Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996,
61, 3897.
13. Ley, S. V.; Sheppard, T. D.; Myers, R. M.; Chorghade, M. S. Bull. Chem.
Soc. Jpn. 2007, 80, 1.
14. Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. Rev. 2001, 101, 53.
15. Michel, P.; Ley, S. V. Angew. Chem., Int. Ed. 2002, 41, 3898.
16. Ley, S. V.; Diez, E.; Dixon, D. J.; Guy, R. T.; Michel, P.; Nattrass, G. L.;
Sheppard, T. D. Org. Biomol. Chem. 2004, 2, 3608.
17. Ley, S. V.; Michel, P. Synthesis 2004, 147.
18. Ley, S. V.; Polara, A. J. Org. Chem. 2007, 72, 5943.
19. Milroy, L.-G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.; Gunarat-
nam, M.; Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46, 2493.
20. Austin, K. A. B.; Banwell, M. G.; Loong, D. T. J.; Rae, A. D.; Willis,
A. C. Org. Biomol. Chem. 2005, 3, 1081.
21. Hadfield, A.; Schweitzer, H.; Trova, M. P.; Green, K. Synth. Commun.
1994, 1025.
22. Furstner, A.; Konetzki, I. Tetrahedron 1996, 15071.
¨
23. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324.
24. Ghosh, S.; Kinney, W. A.; Gauthier, D. A.; Lawson, E. C.; Hudlicky, T.;
Maryanoff, B. E. Can. J. Chem. 2006, 84, 555.
4.1.13. Epipyriculol 2 (2-((1E,3S,4S,5E)-3,4-dihydroxy-
hepta-1,5-dienyl)-6-hydroxybenzaldehyde)
25. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
AcOH (0.3 mL) and water (0.075 mL) were added to a solu-
tion of compound 21 (2 mg, 0.0055 mmol) in THF (0.15 mL)
at rt and the mixture was heated at 70 ꢁC for 14 h. The initial
blurred solution became gradually transparent and the progress
of the reaction was monitored by TLC. After completion, the
solvents were removed under vacuum and the remaining mix-
ture was purified by preparative TLC (70% Et2O in P.E.) to
give epipyriculol (0.95 mg, 0.0038 mmol, 70%). The charac-
terisation data (1H NMR, IR, optical rotation) are identical
to those previously reported.8
Rf (80% Et2O in P.E.): 0.27. [a]2D5 ꢀ50 (c 0.025, CHCl3). IR
(neat, cmꢀ1): 2925, 1643, 1450. 1H NMR d: 11.85 (1H, s), 10.30
(1H, s), 7.45 (1H, t, J¼8), 7.19 (1H, d, J¼15), 6.90 (1H, d, J¼7),
6.89 (1H, d, J¼8), 6.08 (1H, dd, J¼16, 6), 5.84 (1H, dq, J¼15,
6), 5.55 (ddq, J¼15, 7, 1), 4.22 (1H, t, J¼6), 4.03 (1H, t, J¼7),
1.75 (3H, dd, J¼7, 1).
26. Kamisuki, S.; Takahashi, S.; Mizushina, Y.; Hanashima, S.; Kuramochi,
K.; Kobayashi, S.; Sakaguchi, K.; Nakata, T.; Sugawara, F. Tetrahedron
2004, 60, 5695.
27. Najera, C.; Gil-Molto, J.; Karlstroem, S. Adv. Synth. Catal. 2004, 346, 1798.
28. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 7408.
29. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
30. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc.,
Perkin Trans. 1 1999, 955.
31. Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951.
32. Friedrich, E. C.; Falling, S. N.; Lyons, D. E. Synth. Commun. 1975, 5, 33. A
modification to the original procedure was made: the reaction crude was fil-
tered through a pad of silica (previous or later to the distillation, elution with
5% Et2O/P.E.) as acetaldehyde hydrate co-distilled with CH3CHI2. The
synthesis reported in this reference was preferred to others due to the avail-
ability of the reagents. For a more high-yielding method (67%) see Ref. 33.
33. Letsinger, R. L.; Kammeyer, C. W. J. Am. Chem. Soc. 1951, 73, 4476.
34. Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 3646.
35. Ueki, T.; Kinoshita, T. Org. Biomol. Chem. 2005, 3, 295.
36. Barlow, J. S. Thesis, The University of Cambridge, 1998.