Palladium mediated spiroketal synthesis: Application to pheromone synthesis

Article abstract of DOI:10.1016/j.tet.2005.09.055

Stereospecific Stille coupling reactions of 2-metallo-dihydropyrans with Z-vinyl iodo alcohols and subsequent cyclisation provides rapid access to 1,7-dioxaspiro[5.5]undecane family of spiroketals.

Full text of DOI:10.1016/j.tet.2005.09.055

Tetrahedron 61 (2005) 11910–11923
Palladium mediated spiroketal synthesis: application to
pheromone synthesis
a
b,†
Jeremy C. Conway,a Peter Quayle,a, Andrew C. Regan and Christopher J. Urch
*
aSchool of Chemistry, University of Manchester, Manchester M13 9PL, UK
bSyngenta, Jealott’s Hill International Research Station, Bracknell, Berkshire RG42 6EY, UK
Received 7 July 2005; revised 1 September 2005; accepted 15 September 2005
Available online 6 October 2005
Dedicated to Professor S. V. Ley on the occasion of his 60th birthday
Abstract—Stereospecific Stille coupling reactions of 2-metallo-dihydropyrans with Z-vinyl iodo alcohols and subsequent cyclisation
provides rapid access to 1,7-dioxaspiro[5.5]undecane family of spiroketals.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
We1 and others2 have previously reported on the Stille
coupling of tri-butylstannyldihydrofuran and -pyran deriva-
tives. This methodology provides rapid access to a variety of
C-glycosides,2 heterosubstituted dienes1 and has been
employed in the synthesis of benzofused spiroketal-contain-
ing systems.3 Herein we report an extension of this
chemistry leading to the rapid synthesis of simple
spirocyclic systems which are ubiquitous as pheromones4a
and is a structural motif present in an ever expanding
number of biologically active molecules.4b Our basic
strategy centred upon the use of Stork’s Wittig method-
ology5 for the synthesis of Z-vinyl iodides 1 followed by a
Stille coupling6 (retention of alkene geometry) with an
appropriately metallated enol ether 2 to afford a diene 3
which would undergo cyclisation to afford the desired
spiroketal 4, Scheme 1.
Oxidation of the readily available mono-protected diol 57a
using Swern’s procedure afforded the aldehyde 67b in
excellent yield (92%). Olefination5 (Ph3P]CHI, 1.2 equiv;
THF; K78 8C) generated 7 which on deprotection (CSA, cat.;
MeOH; 25 8C; 78%) led to the isolation of the vinyl iodide
8
Z,E, as a mixture of geometrical isomers8 (Z:EZ6.4:1). With
the key intermediate 8Z,E in hand, its palladium-mediated
couplingwithdihydropyran-derivedorganometallicswasnext
investigated. Reaction of the iodide 8Z,E (1.1 equiv) with the
stannane 9 (1 equiv) in the presence of Pd(OAc)2 (5 mol%)
and tri-o-tolyl phosphine (10 mol%) dissolved in acetonitrile
containing triethylamine (Et3N/CH3CN; 2.5% v/v) at 80 8C
for 1.5 h afforded the labile diene alcohols 10Z,E in moderate
yield (33%). As anticipated the coupling reaction proceeds
with retention of olefin geometry, generating the dienes
10Z,E as a 6:1 mixture of geometrical isomers.
Scheme 1.
Keywords: Spiroketal; Palladium; Stille; Vinyl iodide; Stork; Selenium.
*
Corresponding author. Tel.: C44 161 275 4619; fax: C44 161 275 4598; e-mail: peter.quayle@manchester.ac.uk
† Present address: Glycoform Limited, Unit 44C, Milton Park, Abingdon, Oxon OX14 4RU, UK.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.055

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11911
Substantially higher yields (71 and 72%, respectively) of the
dienes 10 were obtained under milder reaction conditions
(0–10 8C; THF; 1 h) from the coupling reaction of the zinc
reagent9 11 with the iodide 8Z,E using either ‘Pd(PPh3)2’10
or Pd(PPh3)4 as catalyst. Exposure of the diene-alcohol
10Z,E to a catalytic quantity of CSA in CH2Cl2 at ambient
temperature resulted in the isolation of the unsaturated
spiroketal 1211 in 82% yield. A common feature of these
spiroketalisation reactions is that, although enriched
Z/E-mixtures of the precursor alcohols were usually
employed in the cyclisation reaction, none of the acyclic
E-double bond isomers could be detected by 1H NMR
spectroscopy at the end of reaction.12 Presumably acid
catalysed isomerisation of the unreactive E-isomer to the
Z-isomer and subsequent cyclisation is responsible for this
observation. Catalytic hydrogenation (H2, 1 atm; 5% Pd/C;
EtOAc; 25 8C) of 12 afforded the racemic spiroketal 13, the
pheromone13 of Dacus oleae, D. cacumintus, in 93% yield.
Alternatively, cyclisation3b,14 of the alcohol 10Z,E with
PhSeCl (1.1 equiv; pyridine, 3 equiv; CH2Cl2; K78–20 8C)
mixture of diastereoisomers. Exposure of the alcohols 19Z,E
to camphorsulfonic acid (0.1 equiv) in CH2Cl2 at ambient
temperature brought about immediate cyclisation to the
spiroketal 20, which was isolated in 58% yield after
chromatography. Catalytic hydrogenation of 20 afforded
the spiroketal 21, which upon fluoride-induced deprotection
afforded the functionalised spiroketal 2218 in 82% overall
yield. Stereochemical assignments in this cyclisation
sequence are based on stereoelectronic arguments (vide
infra) and are supported by spectroscopic data, most
cogently illustrated by the excellent correlation of the 13C
NMR of 22 with the published data for this compound.18b
Alternatively, reaction of the dienes 19Z,E with PhSeCl-
pyridine, as above, afforded a diastereoisomeric mixture of
the selenides 23 and 24 (57% yield; 23:24Z2:1), in which
the major diasteroisomer 23 possesses an equatorial
phenylseleno-substituent at C5 (H5: d 3.24 ppm; dd, JZ
12.5, 4.5 Hz). Removal of the phenylseleno-group was
readily accomplished in our standard, two step procedure,
affording the unsaturated spiroketal 25, as a single
diastereoisomer, in 73% yield, Scheme 3.
afforded the diastereoisomerically pure selenide 14 (H11
d
3.21 ppm; dd, JZ12.5, 4.5 Hz) in good isolated yield
(73%). Finally oxidation of 14 followed by in situ
thermolysis3b (2-benzenesulfonyl-3-phenyloxaziridine,
‘Davis oxaziridine’,15 1.1 equiv; pyridine; CHCl3; 80 8C)
afforded the doubly unsaturated spiroketal 1516 in 62%
yield, Scheme 2.
The preparation of branched-chain vinyl iodides and their
utilisation in this coupling-cyclisation procedure is also
possible, Scheme 4. Reduction of the protected ester 26 to
the aldehyde 2719 (Dibal-H, 1.6 equiv; toluene; K78 8C;
1 h; 88%) followed by Stork olefination afforded the vinyl
iodides20 29Z,E in 73% overall yield (Z:EZ8.2:1). In our
hands the alternate route to aldehyde 27, via alcohol 28, was
not as amenable to scale-up when compared to the direct
reduction of ester 26, with the caveat that due care was
exercised in quenching the Dibal-H reduction (10% aqueous
citric acid). Deprotection of the ethers 29Z,E to the partially
separable alcohols21 30Z,E proceeded smoothly (CSA,
0.1 equiv; MeOH; 25 8C, 85%), albeit with a slight erosion
of stereochemical integrity about the olefinic centre (Z:EZ
6.4:1). Palladium-mediated cross coupling of the
This basic synthetic strategy was next applied to the
protected dihydropyran 16. Lithiation of 16 using Boeck-
man’s conditions17 (tBuLi, 2.2 equiv; THF; K78 to 0 8C),
transmetallation (ZnCl2, 1.1 equiv; THF; 2 h) to the
organozinc 18 and coupling with the vinyl iodides 8Z,E
[‘Pd(PPh3)2’, 5 mol%; THF; 5–20 8C, 1 h] afforded the
diene-alcohols 19Z,E in 72% isolated yield. Again, the
coupling reaction proceeded with retention of configuration
of double bond geometry as 19Z,E was isolated as a 8:1
Scheme 2. Reagents and conditions: (i) (COCl)2 (1.1 equiv), DMSO (2.2 equiv), CH2Cl2, K78 8C; (ii) Ph3P]CHI (1.2 equiv), THF, K78 8C; (iii) CSA
(0.1 equiv), MeOH, 20 8C, 15 h; (iv) a. tBuLi (1 equiv), THF, K78 8C to 0 8C, b. Bu3SnCl (0.75 equiv), K78 8C; (v) a. tBuLi (1 equiv), THF, K78 to 0 8C, b.
ZnCl2 (1.2 equiv), 0–20 8C, 2 h; (vi) 9 (1 equiv), (o-Tol)3P (10 mol%), Pd(OAc)2 (5 mol%), Et3N, CH3CN, 80 8C, 1.5 h; (vii) 11 (2 equiv), ‘(Ph3P)2Pd’
(5 mol%), THF, 0 8C, 1 h; (viii) (11) (2 equiv), Pd(Ph3P)4 (5 mol%), THF, 0 8C, 1 h; (ix) CSA (0.1 equiv), CH2Cl2, 20 8C; (x) 5% Pd/C, H2, EtOAc, 1 atm., 6 h;
(xi) pyridine (3 equiv), PhSeCl (1.1 equiv), CH2Cl2, K78 to 20 8C, 1 h; (xii) Davis oxaziridine (1.1 equiv), pyridine (5 equiv), CHCl3, 80 8C, 15 h.

11912
J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
t
Scheme 3. Reagents and conditions: (i) a. BuLi (2.2 equiv), THF, K78–0 8C; b. THF (excess); (ii) ZnCl2 (1.1 equiv); THF, 0 8C, 2 h; (iii) 8, Pd(PPh3)4
(5 mol%) or ‘Pd(PPh3)2’ (5 mol %); see text for conditions; (iv) CSA (0.1 equiv), CH2Cl2; (v) 5% Pd/C, H2, EtOAc, 1 atm.; (vi) TBAF (1 equiv), THF, 20 8C,
12 h; (vii) pyridine (3 equiv), PhSeCl (1.1 equiv), CH2Cl2, K78–20 8C, 1 h; (viii) Davis oxaziridine (1.1 equiv), pyridine (5 equiv), CHCl3, 80 8C, 15 h.
geometrically pure Z-isomer 30Z with the zinc reagent 11
proved uneventful, affording the diene-alcohol 31Z in 76%
yield. Acid promoted cyclisation of the alcohol 31Z
generated the spiroketal 3222 as a single diastereoisomer
(66% yield), which on catalytic hydrogenation afforded the
racemic pheromone of epeolus cruciger 3323 in 74% yield.
Cyclisation of the alcohol 31Z using PhSeCl-pyridine again
afforded only two of the possible four diastereoisomeric
selenides 34 and 35 (anomeric carbons in 13C NMR
{75 MHz CDCl3} at d 95.02, 95.39 ppm) in a ratio of
7:11. Inspection of the 1H NMR spectra of these compounds
indicated that the major product 35 possessed an equator-
ially disposed selenide group (H11: d 3.16 ppm, dd, JZ13,
4.5 Hz) whereas that of 34 was axially disposed (H11: d
3.40 ppm, tr. JZ4.5 Hz). Furthermore dissolution of an
enriched mixture of 34 and 35 (34:35Z1:2) in CDCl3 at
ambient temperature effected complete isomerisation of this
mixture to 35 over a period of 3 days. Notably cyclisation of
both 19 (to give 23 and 24) and 31 (to give 34 and 35)
afforded only two of the possible four diastereoisomeric
selenides. Molecular mechanics calculations24 suggest that
in each case the thermodynamically more stable
Scheme 4. Reagents and conditions: (i) TBDMSCl (1.1 equiv), DBU (1 equiv), CH2Cl2, 20 8C; (ii) a. Dibal-H (1.6 equiv), toluene, K78 8C, b. citric acid,
K78 8C; (iii) a. Dibal-H (3.0 equiv), toluene, K78–20 8C; b. (COCl)2 (1.1 equiv), DMSO (2.2 equiv), K78 8C; (iv) Ph3P]CHI (1.2 equiv); (v) CSA
(0.1 equiv), MeOH, 20 8C; (vi) 11, (2 equiv), Pd(PPh3)4 (5 mol%), THF, 5 8C, 1 h; (vii) CSA (cat.), CH2Cl2, 20 8C; (viii) 5% Pd/C, H2, EtOAc, 1 atm., 6 h;
(ix) pyridine (3 equiv), PhSeCl (1 equiv), CH2Cl2, K78–20 8C, 1 h; (x) ‘CDCl3’, 20 8C; (xi) Davis oxaziridine (1.1 equiv), pyridine (5 equiv), CHCl3, 80 8C.

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11913
Scheme 5.
diastereoisomers are isolated: the equatorial selenide 23
being more stable than the axial selenide 24 by ca.
12.5 kJ molK1 whilst 35 is more stable than 34 by ca.
as a mixture of geometric isomers (Z:EZ6:1) in 41%
overall yield from the ester 38.
11.2 kJ molK1
.
Deprotection of 41E,Z to 42Z (77% yield) was best
accomplished using aqueous hydrogen fluoride in aceto-
nitrile31 and was then treated with an excess of the
organozinc reagent 11 (ca. 4 equiv) in the presence of
Pd(PPh3)4 to afford the diene 43, as a single geometrical
isomer, in 72% yield. The diene 43 was very sensitive to
traces of acid and occasionally underwent spirocyclisation
The equilibration of 34 and 35 can be explained by invoking
a reversible25 ring opening of the selenides 34 and 35 via the
oxonium cations 37. Cation 37 is presumably in equilibrium
with the enol ether 370 thereby providing a pathway for the
epimerisation26 at C11. Ring closure under conditions of
thermodynamic control (i.e., maximum anomeric effect in
which both exocyclic oxygen substituents are axial with
respect to each of the pyranose rings27) would account for
the interconversion of 34 into the more stable diastereo-
isomer 35, Scheme 5. The fact that epimerisation at C11 had
occurred in this particular reaction is further substantiated
by the observation that oxidation of the diastereoisomeric
mixture of selenides 34 and 35 (34:35Z7:11) followed by
mild thermolysis afforded the doubly-unsaturated sprioketal
36 as a single diastereoisomer in 73% isolated yield.
1
in CDCl3 when trying to obtain its H NMR spectrum.
Cyclisation of 43 on a preparative scale was best
accomplished using camphorsulfonic acid as promoter
(0.1 equiv) in dichloromethane enabling isolation of the
volatile spiroketal 4432 in 42% yield.
Presumably cyclisation under these conditions is again
subject to thermodynamic control: diastereoisomer 44
benefits from a maximum exo anomeric effect (each oxygen
is axial to the adjacent pyranose ring) which is augmented
by the diequatorial disposition of the methyl groups at C2
and C3, Scheme 6. As an excess (ca. 4 equiv) of the
organozinc reagent 11 was used in this coupling sequence
(1 equiv just serves to deprotonate the free hydroxyl group
of 42), which is obviously wasteful if more elaborate
organometallics were to be employed, in situ protection of
the hydroxyl group was briefly investigated. Germane to this
discussion is Negishi’s33 observation that alkoxyzincs,
generated in situ from (Z)-iodo-2-buten-1-ol by reaction
with EtZnCl, undergo efficient cross-coupling reactions
Finally, the synthesis of spiroketal 44, which serves as a
model for more complex systems present in a number of
natural products,28 has also been achieved using this basic
strategy. Protection (DBU, TBDMSCl, dichloromethane;
87% yield) of the hydroxyl group of ethyl (3R*,2R*)-3-
hydroxy-2-methylbutanoate29 38 (95% de) and reduction of
the ester group with Dibal-H afforded the known aldehyde
40.30 The unstable aldehyde 40 was used immediately in
Stork’s Wittig olefination sequence affording, without any
detectable epimerisation, the light-sensitive vinyl iodide 41
with organometallic reagents, providing
a highly
Scheme 6. Reagents and conditions: (i) TBDMSCl (1.1 equiv), DBU (1 equiv), CH2Cl2, 0 8C, 3 h; (ii) Dibal-H (1.6 equiv), toluene, K80 8C, 1 h; (iii) Ph3P]
CHI (1.2 equiv); (iv) 60% HFaq in CH3CN; (v) 11, (4 equiv), Pd(PPh3)4 (5 mol%), THF, 5 8C, 1 h; (vi) CSA (0.1 equiv), CH2Cl2, 20 8C; (vii) a. EtZnCl
(1 equiv), K78–20 8C; b. 11, Pd(PPh3)4 (5 mol%), THF, 5 8C, 1 h; (viii) a. Dibal-H (1 equiv), K78–20 8C; b. 11, Pd(PPh3)4 (5 mol%), THF, 5 8C, 1 h.

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J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
stereoselective procedure for the synthesis of (Z)-3-methyl-
2-alken-1-ols. Unfortunately, this modification was not
successful in our hands. We did observe however that prior
treatment of 42 with Dibal-H (1 equiv), followed by
reaction with the vinylzinc reagent 11, as previously
described, afforded the coupled product 45 (19% yield) in
which transfer of an iso-butyl group from aluminium34
rather than cross coupling with the zinc reagent 11 had taken
place, Scheme 6.
out on plates precoated with Kieselgel 60 F254 silica.
Visualisation was achieved by ultraviolet absorption or
treatment with an ethanolic solution of dodecamolybdo-
phosphoric acid followed by heating.
4.1.1. 3-(t-Butyldimethylsilyloxy)propan-1-ol, 5.7a
Sodium hydride (80% suspension in oil) (1.5 g,
49.8 mmol) was suspended in THF (100 mL) after being
washed with hexane. 1,3-Propanediol (3 mL, 3.16 g,
41.5 mmol) was added to the mixture at room temperature
and stirred for 45 min, after which time an opaque white
precipitate had formed. t-Butyldimethylsilyl chloride
(6.26 g, 41.5 mmol) was then added, and vigorous stirring
was continued for 45 min. The mixture was poured into
ether (100 mL), washed with 10% potassium carbonate
(30 mL) and brine (30 mL), dried (MgSO4) and concen-
trated in vacuo. The resulting oil was purified by flash
column chromatography using ethyl acetate/petrol (1:4) as
eluent to afford the title compound 5 (6.3 g, 80%) as a
colourless oil; nmax (film) 3353, 2930, 2858, 1472, 1389,
3. Conclusion
In conclusion, this study illustrates that the 1,7-dioxa-
spiro[5.5]undec-4-ene system is readily accessible using a
Wittig–Stille route, and that application of this strategy to
the synthesis of more elaborate spiroketals of biological
inteserest28 should be possible. Further studies in this area
are in progress the results of which will be reported at a
future date.
1362, 1256, 1097, 1008, 963, 837, 777, 720 and 663 cmK1
;
dH (300 MHz, CDCl3): 0.09 (6H, s, MeSi), 0.9 (9H, s, tBuSi),
1.77 (2H, quintet, JZ5.5 Hz, 2-H), 2.60 (1H, br s, OH), 3.80
(2H, t, JZ5.5 Hz, 1-H), 3.82 (2H, t, JZ5.5 Hz, 3-H); dC
(75 MHz, CDCl3): K5.50 (MeSi), 18.17 (CMe3), 25.67
(CMe3), 34.29 (C-2), 62.27 (C-1), 62.77 (C-3); m/z (CI)
191 {[MCH]C, 100%}. Found: m/z 191.1465. C9H23O2Si
{[MCH]C} requires m/z 191.1467.
4. Experimental
4.1. General
All non-aqueous reactions were performed under an
atmosphere of dry nitrogen at temperatures which were
those of the external bath. Proton and carbon nuclear
magnetic resonance (1H and 13C NMR) spectra were
recorded on Bruker AC 300, Varian XL 300, Varian
Gemini 200 spectrometers, with residual non-deuterated
solvent as internal standard. All chemical shifts are quoted
in parts per million downfield from tetramethylsilane. J
values are given in Hz. Splitting patterns were abbreviated
as follows: singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), broad (br). Infrared spectra were recorded on
a Perkin–Elmer 1710 FT spectrometer as evaporated films
unless otherwise stated. Absorption maxima (nmax) were
reported in wavenumber (cmK1). Mass spectra were
recorded on Kratos MS20 and MS25 spectrometers. The
modes of ionisation used were electron impact (EI) and
chemical ionisation (CI). Microanalysis was performed at
the University of Manchester. Melting points were recorded
on a Kofler heated stage microscope, and are uncorrected.
Petrol refers to that fraction of light petroleum ether which
distils between 40 and 60 8C, and was redistilled prior to
use. Tetrahydrofuran (THF) was dried over sodium/
benzophenone ketyl and distilled under an atmosphere of
dry nitrogen. Dichloromethane was dried over phosphorus
pentoxide and distilled. Methanol was dried over mag-
nesium methoxide and distilled. Triethylamine was dried
over potassium hydroxide pellets and distilled. Pyridine was
dried over potassium hydroxide pellets and redistilled under
nitrogen. Dimethyl sulfoxide was dried over calcium
hydride and redistilled at atmospheric pressure. Toluene
was dried over sodium and redistilled under nitrogen.
Where ether is mentioned it refers to diethyl ether.
n-Butyllithium was supplied as solution in hexanes and
t-butyllithium as a solution in pentane. Chromatography
refers to flash column chromatography and was carried out
using Merck silica gel 60H (40–63 mm, 230–400 mesh) as
stationary phase. Thin layer chromatography was carried
4.1.2. 3-(t-Butyldimethylsilyloxy)propanal, 6.7b The title
compound was prepared from the alcohol 5 (10.43 g,
54.9 mmol) using method A as above. Purification by
flash chromatography afforded 6 as a colourless oil (9.46 g,
92%); nmax (film) 2956, 2930, 2858, 1728, 1473, 1390,
1390, 1362, 1257, 1100, 1007, 972, 837 and 778 cmK1; dH
(300 MHz, CDCl3) 0.09 (6H, s, MeSi), 0.90 (9H, s, tBuSi),
2.59 (2H, dt, JZ6, 2 Hz, 2-H), 3.98 (2H, t, JZ6.5 Hz, 3-H),
9.80 (1H, t, JZ2 Hz, 1-H); dC (75 MHz) K5.46 (MeSi),
18.20 (CMe3), 25.80 (CMe3), 46.57 (C-2), 57.41 (C-3),
201.68 (C-1); m/z (CI) 189 {[MCH]C, 100%}. Found m/z
189.1310. C9H21O2Si {[MCH]C} requires m/z 189.1311.
4.1.3. Iodomethyltriphenylphosphonium iodide.36 To a
suspension of triphenylphosphine (60 g, 0.23 mol) in
toluene (60 mL) was added methylene iodide (24 mL,
0.3 mol). The mixture was kept at 45–50 8C for 15 h after
which time the crystals were collected, washed with toluene
(3!100 mL), and dried in vacuo (0.1 mmHg) for 4 h
affording the title compound (111.2 g, 91.2%) as a white
solid, mp 230 8C (dec) [Lit.35 228–230 8C (dec)]; nmax (KBr
disc) 2919, 2849, 1639, 1618, 1586, 1499, 1482, 1438,
1318, 1111, 1084, 997, 785, 727, 689, 566, 508 and
484 cmK1. dH (300 MHz, d6-DMSO): 5.15 (2H, d,
2J{P–H}Z9 Hz), 7.95 (15H, s, Ar). Found: C, 43.4; H,
3.35; I, 47.4; P, 5.7. C19H17I2P requires: C, 43.0; H, 3.25; I,
47.9; P, 5.85%.
4.1.4. 2-Tri-n-butylstannyl-5,6-dihydro-2H-pyran, 9.35
A
solution of t-butyl lithium (17.5 mL, 1.7 M solution in
pentane) was added dropwise to a stirred solution of 2,3-
dihydro-2H-pyran (2.5 g, 2.7 mL, 29.7 mmol) in THF
(10 mL) at K78 8C. The mixture was allowed to warm up
to 0 8C and was stirred at this temperature for 30 min, then

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11915
recooled to K78 8C. Tri-n-butyltin chloride (6 mL,
22.3 mmol) was added dropwise and the resulting mixture
was allowed to warm up to room temperature and to stir for
2 h. After quenching with aq. ammonium chloride, the
product was extracted into ether (3!30 mL), the ethereal
extracts dried (MgSO4) and evaporated and the residue
purified by column chromatography (triethylamine/petrol
1:19) to afford the title compound 9 (7.23 g, 87%) as a
colourless oil; nmax (film) 2955, 2926, 2854, 1606, 1464,
1377, 1221, 1070, 1054, 898, 839, 780 and 666 cmK1; dH
(300 MHz, CDCl3): 0.91 (15H, m, SnCH2– and –CH3), 1.33
(6H, m, –CH2–, JZ7.5 Hz), 1.50 (6H, m, –CH2–, JZ
7.5 Hz), 1.85 (2H, m, 4-H, JZ5 Hz), 2.01 (2H, m, JZ4 Hz,
3-H), 3.90 (2H, t, JZ5 Hz, 5-H), 4.72 (1H, t, JZ3.5 Hz,
MeSi), 0.07 (3H, s, MeSi), 0.85 (9H, s, tBuSi), 1.19 (3H, d,
JZ6 Hz, 4-H), 1.25 (3H, t, JZ7 Hz, OCH2CH3), 2.35 (1H,
dd, JZ14, 5.5 Hz, 2-H), 2.46 (1H, dd, JZ14, 7.5 Hz, 2-H),
4.11 (2H, m, OCH2), 4.27 (1H, m, 3-H); dC (75 MHz,
CDCl3) K5.03, K4.51 (Me2Si), 14.21 (OCH2CH3), 17.96
(Me3C), 23.93 (C-4), 25.73 (Me3C), 44.96 (C-2), 60.25
(C-3), 65.67 (OCH2), 171.67 (C-1); m/z (EI) 161 [MCK
TBDMS, 100%]. (CI) 45 {[(CH3)H2Si]C, 82.1%}. Found:
m/z, 189.0950. C8H17SiO3 [MCKtBu] requires 189.0947.
Found: C, 58.7; H, 10.4; Si, 11.7. C12H26O3Si requires: C,
58.5; H, 10.6; Si, 11.4%.
4.1.7. (G)-3-(t-Butyldimethylsilyloxy)butanal, 27.19
Method A. A solution of oxalyl chloride (0.9 mL,
10 mmol) in dichloromethane (100 mL) was cooled to
K78 8C to which was added dropwise freshly dried
dimethyl sulfoxide (1.5 mL, 20.8 mmol). After 15 min. at
K78 8C a solution of (G)-3-(t-butyldimethylsilyloxy)buta-
nol 2836 (1.75 g, 8.58 mmol) in dichloromethane (20 mL)
was added dropwise and the reaction mixture stirred at
K78 8C for 25 min. The reaction was quenched by the
addition of triethylamine (6 mL) and allowed to warm to
room temperature. After 1 h the reaction was poured into
saturated aqueous sodium bicarbonate solution (50 mL).
The layers were separated and the aqueous layer extracted
with dichloromethane. The combined organic layers were
washed with brine (50 mL), dried (MgSO4) and concen-
trated in vacuo. The residue was diluted with hexane
(30 mL), washed with water (20 mL), dried (MgSO4) and
concentrated in vacuo. Flash column chromatography of the
residue using 1:19 ethyl acetate:petrol as eluent, gave the
title compound 27 as a colourless oil (1.34 g, 77%).
3
2-H, J{H–Sn}Z30 Hz); m/z (EI) 317 [[MCKBu], 120Sn
100%], 315 {[MCKBu], 118Sn 73%}. (CI) 375 {[MCH]C,
120Sn 100%}, 373 {[MCH]C, 118Sn 76%}.
4.1.5. (G)-2-(t-Butyldiphenylsilyloxymethyl)-3,4-dihy-
dro-2H-pyran, 16. Sodium hydride (80% suspension in
mineral oil) (2.12 g, 70.6 mmol) was suspended in THF
(100 mL) after being washed with hexane. 2-(Hydroxy-
methyl)-3,4-dihydro-2H-pyran (6.71 g, 58.8 mmol) was
added to the mixture at room temperature and left to stir
at this temperature for 45 min during which time a light
brown precipitate had formed. t-Butyldiphenylsilyl chloride
(11.76 g, 42.8 mmol) was then added, and vigorous stirring
was continued for 40 h. The mixture was poured into ether
(100 mL), washed with ammonium chloride, dried (MgSO4)
and concentrated in vacuo. The resulting oil was purified by
flash column chromatography using ethyl acetate/petrol
(1:99) as eluent to afford the title compound 16 (12.53 g,
83%) as a colourless, viscous oil; nmax (film) 3070, 2930,
2857, 1650, 1472, 1428, 1391, 1362, 1242, 1188, 1136,
Method B. Dibal-H in toluene (1 M, 47.3 mL) was added
dropwise to a cooled (K80 8C) solution of ethyl (G)-3-(t-
butyldimethylsilyloxy)butanoate 26 (7.27 g, 29.55 mmol) in
anhydrous toluene (210 mL). After 1 h at K78 8C the
reaction was quenched by the dropwise addition of
methanol (30 mL) whilst keeping the temperature below
K78 8C. Citric acid (10% aqueous solution, 300 mL) was
then added, the mixture was allowed to warm to room
temperature, the organic phase was decanted and the
aqueous layer was extracted with dichloromethane (3!
100 mL). The combined organic phases were dried
(MgSO4), the solvent was removed under reduced pressure
and the residue purified by flash chromatography (ethyl
acetate/petrol 1:19) to afford the title compound 27 (5.26 g,
88%); nmax (film) 2957, 2931, 2896, 2858, 2721, 1730,
1473, 1464, 1377,1363, 1257, 1219, 1186, 1138, 1100,
1030, 940, 904, 837, 811 and 777 cmK1; dH (300 MHz,
CDCl3): 0.06 (3H, s, MeSi), 0.08 (3H, s, MeSi), 0.85 (9H, s,
tBuSi), 1.24 (3H, d, JZ6 Hz, 4-H), 2.45 (1H, ddd, JZ15, 5,
2 Hz, 2-H), 2.55 (1H, ddd, JZ15, 7, 3 Hz, 2-H), 4.35 (1H,
sextet, JZ5.5 Hz, 2-H), 9.80 (1H, t, JZ2.5 Hz, 1-H); dC
(75 MHz, CDCl3): K4.48, K3.90 (Me2Si), 18.43 (Me3C),
24.66 (C-4), 26.2 (Me3C), 53.45 (C-2), 65.02 (C-3), 202.74
(C-1); m/z (EI) 145 [MCKtBu, 100%], (CI) 203 {[MC
H]C, 100%}. Found: m/z (CI) 220.1742. C10H26NSiO2
{[MCNH4]C} requires m/z 220.1733. Found: C, 59.1; H,
11.1. C10H22O2Si requires: C, 59.4; H, 10.8%.
1112, 1071, 1005, 939, 909, 824, 798, 740 and 702 cmK1
;
t
dH (300 MHz, CDCl3) 1.15 (3H, s, BuSi), 1.70–1.85 (1H,
m, 3-H), 1.95–2.20 (3H, m, 4-H, 30-H), 3.76 (1H, dd, JZ10,
5.5 Hz, CH2OSi), 3.88 (1H, dd, JZ10, 5 Hz, CH2OSi),
3.90–4.00 (1H, m, 2-H), 4.70 (1H, br s, 5-H), 6.43 (1H, d,
JZ6.5 Hz, 6-H), 7.40–7.80 (10H, m, Ar); dC (75 MHz,
CDCl3) 19.27 (C-4), 19.36 (CMe3), 24.49 (CMe3), 66.11,
75.38 (C-1), 100.35 (C-5), 127.69, 129.68, 133.69, 135.69
(Ar), 143.64 (C-6); m/z (CI) 275 {[MCKPh], 100%}; m/z (EI)
295 [[MCKtBu], 65.1%]. Found: m/z (CI); 353.1935 {[MC
H]C}. C22H29O228Si {[MCH]C} requires m/z 353.1937.
4.1.6. Ethyl (G)-3-(t-butyldimethylsilyloxy)butanoate,
26.19 To a solution of racemic ethyl-3-hydroxybutanoate
(7.12 g, 53.9 mmol) in dichloromethane (10 mL) was added
1,8-diazobicyclo[5,4,0]undec-7-ene (8.9 mL, 59.25 mmol)
at 0 8C followed by a solution of t-butyldimethylsilyl
chloride (8.53 g, 56.56 mmol) in dichloromethane (10 mL).
After 3 h at room temperature, the mixture was poured into
water (100 mL) and extracted into ether (100 mL). The
organic extracts were washed with water (50 mL), hydro-
chloric acid (0.1 M, 50 mL), water (50 mL), saturated
sodium bicarbonate (50 mL) and water (50 mL). The
organic layer was dried (MgSO4), concentrated in vacuo,
and the residue chromatographed (1:19 ethyl acetate petrol)
to afford the title compound, 26 (13.12 g, 99%) as a
colourless oil; nmax (film) 2958, 2931, 2858, 1740, 1474,
1377, 1301, 1256, 1184, 1140, 1084, 1035, 1003, 940, 837,
811 and 777 cmK1; dH (300 MHz, CDCl3): 0.03 (3H, s,
4.1.8. (G)-3-(t-Butyldimethylsilyloxy)butan-1-ol, 28.37
To a solution of ethyl (G)-3-(t-butyldimethylsilyloxy)butanoate

11916
J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
t
25 (3.02 g, 12.3 mmol) in THF (10 mL) was added Dibal-H
(1 M solution in toluene, 27.0 mmol) at K78 8C. The
mixture was allowed to warm up to room temperature and
stirred for 2–3 h. The reaction was quenched with water
(1 mL), poured into diethyl ether (100 mL), sodium
hydroxide (3 M, 1 mL) was added and the mixture was
stirred until the aluminium salts had precipitated. The
supernatant was filtered through celitew and the celitew pad
washed with ether (3!30 mL). The combined organic
extracts were dried (MgSO4), concentrated and the residue
purified by column chromatography (ethyl acetate/petrol
1:4) to afford the title compound (28) (1.95 g, 78%) as a
colourless oil. nmax (film) 3356, 2957, 2930, 2858, 1473,
1376, 1256, 1141, 1100, 1060, 1030, 943, 904, 837, 776,
718 and 664 cmK1; dH (300 MHz, CDCl3): 0.05 (6H, s,
Me2Si), 0.88 (9H, s, tBuSi), 1.22 (3H, d, JZ6 Hz, 4-H), 1.62
(1H, m, 2-H), 1.75 (1H, m, 2-H), 2.70 (1H, s, OH), 3.70 (1H,
m, 1-H), 3.80 (1H, m, 1-H), 4.1 (1H, m, 3-H); dC (75 MHz):
K4.96, K4.36 (Me2Si), 17.94 (Me3C), 23.44 (C-4), 25.80
(Me3C), 40.57 (C-2), 60.41 (C-1), 68.25 (C-3); m/z (EI) 75
[[(CH3)2HSi–O]C, 100%], (CI) 205 {[MCH]C,100%}
Found: m/z (CI) 205.1625. C10H25O2Si {[MCH]C}
requires m/z 205.1624. Found: C, 58.7; H, 12.2; Si, 14.2.
C10H24O2Si requires C, 58.8; H, 11.8; Si, 13.7%.
s, BuSi), 2.36 (2H, m, 4-H), 3.70 (2H, t, JZ6.5 Hz, 3-H),
6.29 (2H, m, 1-H, 2-H); E-isomer 0.08 (6H, s, MeSi), 0.90
(9H, s, BuSi), 2.26 (2H, m, 4-H), 3.65 (2H, t, JZ6.5 Hz,
3-H), 6.02 (1H, d, JZ14.5 Hz, 1-H), 6.54 (1H, dt, JZ14.5,
7.5 Hz, 2-H); dC (75 MHz, CDCl3) Z-isomer K5.27 (MeSi),
18.33 (CMe3), 25.93 (CMe3), 38.37 (C-3), 61.2 (C-4), 83.62
(C-1), 138.31 (C-2); E-isomer K5.27, 18.33, 25,93, 39.39,
61.68, 83.63, 143.33; m/z (EI) 255 [MCKtBu, 100%] (CI)
313 {[[MCH]C, 100%}. Found: m/z (CI) 313.0485.
C10H22IOSi requires m/z 313.0486.
t
4.1.11. (Z,E)-4-Hydroxy-1-iodobutene, 8. The title com-
pounds were prepared from the vinyl iodide 7 (2.48 g,
7.95 mmol) using the method above. Flash chromatography
afforded the iodide as a colourless, light-sensitive oil38
(1.23 g, 78%), (Z:EZ6.4:1); nmax (film) 3338, 3066, 3948,
2880 1610, 1423, 1336, 1307, 1284, 1254, 1165, 1040, 946,
883, 852 and 691 cmK1; dH (300 MHz, CDCl3) Z-isomer
1.75 (1H, s, OH), 2.44 (2H, dq, JZ6.5, 1 Hz, 3-H), 3.75
(2H, t JZ6.5 Hz, 4-H), 6.28 (1H, q, JZ7 Hz, 2-H), 6.37
(1H, td, JZ7, 1 Hz, 1-H); E-isomer 1.75 (1H, s, OH), 2.32
(2H, dq, JZ6.5, 1 Hz, 3-H), 3.68 (2H, t, JZ6.5 Hz, 1-H),
6.16 (1H, td, JZ14.5, 1 Hz, 1-H), 6.55 (1H, dt, JZ14.5,
7 Hz, 2-H); dC (75 MHz, CDCl3): Z-isomer 38.11 (C-3),
60.96 (C-4), 84.74 (C-1), 137.68 (C-2); E-isomer 39.16
(C-3), 61.01 (C-4), 84.74 (C-1), 142.68 (C-2); m/z (EI) 198
[MC, 32.7%]. Found: m/z 197.9544. C4H7IO [MC] requires
197.9543.
4.1.9. (G)-(Z,E)-4-(t-Butyldimethylsilyloxy)-1-iodopent-
1-ene, 29. To a suspension of iodomethyltriphenylphos-
phonium iodide (16.35 g, 30.85 mmol) in THF (16 mL) at
room temperature was slowly added sodium hexamethyldi-
silazide (1 M solution in THF, 32.4 mL). After stirring for
10 min, the dark red-coloured solution of the yield was
cooled to K78 8C and (G)-3-(t-butyldimethylsilyloxy)bu-
tanal 28 (4.99 g, 24.7 mmol) was added slowly. The mixture
was allowed to warm up to room temperature and, after
30 min, the solvent was removed in vacuo. The residue was
triturated with petrol (3!50 mL) and the combined extracts
filtered through celitew to remove triphenylphosphine
oxide. The combined organic extracts were concentrated
in vacuo and the residue purified by column chromato-
graphy (dichloromethane/hexane 1:19) to afford the title
compound 29 (6.7 g, 83%) as a light-sensitive colourless38
oil, (Z:EZ8.2:1); nmax (film) 2956, 2929, 2894, 2857, 1611,
1472, 1377, 1361, 1308, 1256, 1131, 1089, 1022, 836, 808
and 776 cmK1; dH (300 MHz, CDCl3): Z-isomer; 0.07 (6H,
4.1.12. (G)-(Z,E)-4-Hydroxy-1-iodopentene, 30. To a
solution of (G)-(Z,E)-4-(t-butyldimethylsilyloxy)-1-iodo-
pentene 29 (1.68 g, 5.15 mmol) in methanol (10 mL) was
added camphorsulfonic acid (30 mg) and mixture stirred for
15 h at ambient temperature after which time anhydrous
potassium carbonate (0.15 g) was added and stirring was
continued for 15 min. The mixture was filtered and
concentrated in vacuo. The residue was dissolved in
dichloromethane (50 mL), washed with saturated aqueous
sodium hydrogencarbonate solution, dried (MgSO4), con-
centrated in vacuo and the residue chromatographed (1:4
ethyl acetate petrol) to afford the title compound 30 (0.93 g,
85%) as a colourless, light-sensitive oil38 (Z:EZ6.4:1); nmax
(film) 3340, 2967, 2925, 1609, 1456, 1376, 1307, 1262,
1121, 1081, 973, 943 and 844 cmK1; dH (300 MHz, CDCl3):
Z-isomer 1.25 (3H, d JZ6.5 Hz, 5-H), 2.34 (2H, t, JZ
6.5 Hz, 3-H), 3.98 (1H, sextet, JZ6.5 Hz, 4-H), 6.29 (1H, q,
JZ7 Hz, 2-H), 6.36 (1H, distorted d, JZ8 Hz, 1-H);
E-isomer 1.20 (3H, d, JZ6.5 Hz), 2.10 (2H, t, JZ6.5 Hz),
3.87 (1H, sextet, JZ6.5 Hz), 6.13 (1H, d, JZ15 Hz, 1-H),
6.55 (1H, dt, JZ15, 7.5 Hz, 2-H); dC (75 MHz, CDCl3):
Z-isomer 23.20 (C-5), 44.10 (C-3), 66.89 (C-4), 84.80 (C-1),
137.56 (C-2); E-isomer 22.87, 45.50, 66.58, 84.90, 142.60;
m/z (EI) 212 [MC,11.6% (CI) 230 {[MCNH4]C, 100%}.
Found: m/z (CI) 211.9704. C5H9IO [MC] requires m/z
211.9700.
t
s, Me2Si), 0.90 (9H, s, BuSi), 1.19 (1H, d, JZ6 Hz, 5-H),
2.31 (2H, distorted triplet, 3-H), 3.98 (1H, sextet, JZ6 Hz,
4-H), 6.28 (2H, m, 2-H). E-isomer 0.07 (6H, s, Me2Si), 0.90
t
(9H, s, BuSi), 1.15 (1H, d, JZ6 Hz, 5-H), 2.18 (2H,
distorted triplet, 3-H), 3.86 (1H, sextet, JZ6 Hz, 4-H), 6.03
(1H, d, JZ14.5 Hz, 1-H), 6.55 (1H, dt, JZ14.5, 7.5 Hz,
2-H). dC (75 MHz, CDCl3): Z-isomer K4.69, K4.46
(Me2Si), 18.11 (Me3C), 23.59 (C-5), 25.88 (Me3C), 44.55
(C-3), 67.30 (C-4), 83.69 (C-1), 138.33 (C-2). m/z (EI) 269
[MCKtBu, 100%] (CI) m/e 327 {[MCH}C, 48%]. Found:
m/z (CI) 327.0643. C11H24IOSiO requires m/z 327.0655.
4.1.10. (Z,E)-4-(t-Butyldimethylsilyloxy)-1-iodobut-1-
ene, 7. The title compound was prepared from the aldehyde
6 (5.21 g, 27.7 mmol) using the method described above.
Isolated as a light-sensitive, colourless, oil38 (6.71 g, 78%;
Z:EZ7.6:1); nmax (film) 2954, 2929, 2857, 1610, 1472,
1385, 1287, 1257, 1103, 939, 836 and 777 cmK1; dH
(300 MHz, CDCl3): Z-isomer 0.09 (6H, s, MeSi), 0.90 (9H,
4.1.13. (G)-(4Z,E)-5-(3,4-Dihydro-2H-6-pyranyl)-4-pen-
ten-2-ol, 31. Method A. To a stirred mixture of palladium(II)
acetate (41 mg, 5 mol%), tri-(o-tolyl)phosphine (77 mg,
10 mol%) and triethylamine (0.25 mL) in acetonitrile
(10 mL) was added 2-tri-n-butylstannyl-5,6-dihydro-2H-
pyran 9 (1.22 g, 3.22 mmol) followed by (G)-(Z,E)-4-
hydroxy-1-iodopentene 30 (0.73 g, 3.44 mmol). The

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11917
reaction mixture was brought to reflux for 1.5 h, cooled to
ambient temperature and saturated aqueous potassium
fluoride in 10% ammonium hydroxide was added. The
resulting mixture was filtered and extracted with ether (3!
30 mL). The combined organic extracts were dried
(MgSO4), concentrated in vacuo, and the residue chromato-
graphed (3:1:16 ethyl acetate/triethylamine/petrol) to afford
the title compound 31 (261 mg, 48%, colourless oil) as an
inseparable mixture of isomers (Z:EZ6:1).
method A (using 0.5 g, 2.52 mmol vinyl iodide 8) afforded
10 (127 mg, 33%); method B (using 0.75 g, 3.79 mmol of
the iodide 8) gave 10 (395 mg, 71%) whilst method C (same
scale as in method B) afforded the diene 10 in 72% yield
(Z:EZ6:1); nmax (film) 3357, 3020, 2930, 2875, 1656, 1612,
1466, 1435, 1414, 1352, 1310, 1234, 1163, 1087, 1060, 966,
934, 890, 865 and 784 cmK1; dH (300 MHz, C6D6) Z-isomer
1.44 (2H, quintet, JZ5.5 Hz, 3-H), 1.83 (2H, dt, JZ6, 4 Hz,
4-H), 2.81 (2H, q, JZ6.5 Hz, 20-H), 3.6 (2H, t, JZ6.5 Hz,
10-H), 3.75 (2H, t, JZ5 Hz, 2-H), 04.71 (1H, t, JZ4 Hz,
5-H), 5.40 (1H, dt, JZ12, 7 Hz, 3 -H), 5.82 (1H, d, JZ
12 Hz, 40-H); E-isomer 1.52 (2H, quintet, JZ5.5 Hz, 3-H),
1.90 (2H, dt, JZ6, 4 Hz, 4-H), 2.21 (2H, q, JZ6.5 Hz,
20-H), 3.45 (2H, t, JZ6.5 Hz, 10-H), 3.85 (2H, t, JZ5 Hz,
2-H), 4.68 (1H, t, JZ4 Hz, 5-H), 5.87 (1H, d, JZ15.5 Hz,
40-H), 6.22 (1H, dt, JZ15.5, 7.5 Hz, 30-H); dC (75 MHz;
C6D6) Z-isomer 20.96 (C-3), 22.22 (C-4), 32.98 (C-20),
62.58 (C-10), 65.61 (C-2), 103.08 (C-5), 127.11, 127.19
(C-30, C-40), 153.00 (C-6); E-isomer 21.01 (C-3), 22.66
(C-4), 36.31 0(C-20), 62.08 (C-10), 65.86 (C-2), 100.88 (C-5),
124.97 (C-3 ), 128. 82 (C-40), 153.0 (C-6); m/z (CI) 155
{[MCH]C, 100%}. Found: m/z (CI) 154.0990. C9H14O2
[MC] requires m/z 154.0994.
Method B. A solution of t-butyl lithium (7.4 mL, 1.7 M
solution in pentane) was added dropwise to a stirred solution
of 2,3-dihydro-2H-pyran (1.15 mL, 12.6 mmol) in THF
(8 mL) at K78 8C. The mixture was allowed to warm to
0 8C and was stirred at this temperature for 30 min, then
recooled to K78 8C. Zinc chloride (1 M solution in ether,
13.8 mL) was added dropwise and the resulting mixture was
allowed to warm up to room temperature and to stir for 2 h.
Catalyst generation: in a separate flask, Dibal-H (1 M solution
in toluene, 0.33 mL) was added dropwise to PdCl2(PPh3)2
(116 mg, 0.16 mmol, 5 mol%) in THF (5 mL) at 0 8C and the
resulting mixture was stirred for 30 min. The solution
containing the catalyst was then transferred by canula under
nitrogen to the solution of the vinyl zinc intermediate 11 at
5–10 8C, followed by a solution of (Z,E)-4-hydroxy-1-
iodopentene 30 (0.72 g, 3.4 mmol) in THF (2 mL) and
resulting mixture was stirred for 1 h at ambient temperature.
After quenching with sodium hydroxide (10 mL), the product
was extracted into ether (3!30 mL), the ethereal extracts
dried (MgSO4), concentrated in vacuo, and column chroma-
tography (3:1:16 ethyl acetate/triethylamine/petrol) of the
residue afforded the title compound 30 (400 mg, 74%;
Z:EZ6:1) as a mobile oil.
4.1.15. (2R*,6S*)-2-Methyl-1,7-dioxaspiro[5.5]undec-4-
ene, 3222 To a solution of (Z,E)-4-(3,4-dihydro-2H-6-
pyranyl)-3-buten-1-ol, 31 (261 mg, 1.55 mmol) in dichloro-
methane (5 mL) was added camphorsulfonic acid (30 mg)
and the mixture stirred at room temperature for 1 h. After
quenching with saturated sodium bicarbonate, the product
was extracted into ether (2!20 mL), the ethereal extracts
dried (MgSO4), and evaporated and the residue purified by
column chromatography (ethyl acetate/petrol 1:19) to afford
the title compound 32 (172 mg, 66%) as a colourless oil;
nmax (film) 2940, 1658, 1397, 1270, 1201, 1186, 1101,
1072,1046, 1002, 953, 899 and 808 cmK1; dH (300 MHz,
CDCl3): 1.27 (3H, d, JZ6.5 Hz, Me), 1.50–1.65 (5H, m, 9-
H, 10-H, 11-H), 1.90–2.00 (3H, m, 3-H, 110-H), 3.60 (1H, br
d, JZ10 Hz, 8eq-H), 3.85 (1H, dt, JZ11.5, 2.5 Hz, 8ax-H),
4.01 (1H, ddq, JZ10, 6, 4.5 Hz, CHMe), 5.61 (1H, ddd, JZ
10, 2.5, 1 Hz, 5-H), 5.89 (1H, ddd, JZ10, 5, 2.5 Hz, 4-H);
dC (50 MHz, CDCl3) 19.01 (C-10), 21.60 (C-Me), 25.59
(C-11), 32.79 (C-9), 35.39 (C-3), 61.18 (C-8), 63.54 (C-2),
94.49 (C-6), 128.31 (C-5), 130.79 (C-4); m/z (EI) 168 [MC,
79.2%]; (CI) 169 {[MCH]C, 87.9%}. Found: m/z (CI)
168.1146. C10H16O2 [MC] requires m/z 168.1150.
Method C. The title compound 31 was prepared in exactly
the same way as in method B except that freshly prepared
Pd(PPh3)4 (192 mg, 5 mol%) was used as the catalyst. (G)-
(Z,E)-4-hydroxy-1-iodopentene 30 (0.72 g, 3.4 mmol)
afforded 31 (413 mg, 76%; Z:EZ6:1); nmax (film) 3379,
2967, 2929, 1656, 1612, 1414, 1374, 1352, 1310, 1234,
1165, 1122, 1085, 1060, 1002, 922, 886, 846, 814 and
781 cmK0 1; dH (300 MHz, C6D6) Z-isomer 1.23 (3H, d, JZ
6 Hz, 1 -H), 1.45 (2H, quintet, JZ5.5 Hz, 3-H), 1.85 (2H,
m, 4-H), 2.05–2.15 (1H, br s, OH), 2.73 (1H, dt, JZ15,
7 Hz, 30-H), 02.82 (1H, dt, JZ15, 7 Hz, 30-H), 3.76 (1H, t,
JZ6.5 Hz, 2 -H), 3.85 (2H, t, JZ6.5 Hz, 2-H), 4.72 (1H, t,
JZ4 Hz, 5-H), 5.48 (1H, dt, JZ12, 6 Hz, 40-H), 5.82 (1H, d,
JZ12 Hz, 50-H); E-isomer 1.12 (3H, d, JZ6 Hz, 10-H), 1.32
(2H, quintet, JZ5.5 Hz, 3-H), 1.91 (2H, m, 4-H), 2.15–2.30
(3H, m, 30-H, OH), 3.70 (1H, t, JZ6.5 Hz, 20-H), 3.89 (2H,
t, JZ6.5 Hz, 2-H), 4.69 (1H, t, JZ4 Hz, 5-H), 5.900 (1H, d,
JZ15.5 Hz, 50-H), 6.27 (1H, dt, JZ15.5, 7.5 Hz, 4 -H); dC
(75 MHz, C6D6) Z-isomer 20.98 (Me), 22.23 (C-4), 23.39
(C-3), 39.010(C-30), 65.61 (C-20), 67.91 (C-2), 103.11 (C-5),
127.02 (C-4 ), 127.15 (C-50), 153.03 (C-6);0E-isomer 21.03
(Me), 22.23 (C-4), 22.66 (C-3), 42.65 (C-3 ), 65.87 (C-200),
67.35 (C-2), 100.96 (C-5), 125.06 (C-40), 129.09 (C-5 ),
153.03 (C-6); m/z (EI) 168 [MC, 42.3%] (CI) 169 {[MC
H]C, 8.4%}. Found m/z (CI) 168.1146. C10H16O2 [MC]
requires m/z 168.1150.
4.1.16. (G)-1,7-Dioxaspiro[5.5]undec-4-ene, 12.11 The
title compound was prepared using the method above
from the diene 10 (359 mg, 2.33 mmol) as a colourless oil
(293 mg, 82%); nmax (film) 3040, 2940, 2874, 1656, 1428,
1398, 1379, 1353, 1335, 1273, 1201, 1184, 1160, 1138,
1096, 1069, 1053, 1039, 953, 897, 868, 812, 769, 722 and
689 cmK1; dH (300 MHz, CDCl3) 1.4–1.65 (5H, m, 10-H,
11-H, 9ax-H), 1.70–1.90 (2H, m, 9eq-H, 3eq-H), 2.23 (1H,
dddt, JZ18, 10, 5.5, 2.5 Hz, 3ax-H), 3.53–3.60 (1H, m, 8eq-
H), 3.70 (1H, dd, JZ11.5, 6.5 Hz, 2eq-H), 3.80 (1H, dt, JZ
12, 3 Hz, 8ax-H), 3.87 (1H, dt, JZ12, 3.5 Hz, 2ax-H), 5.64
(1H, ddd, JZ10, 3, 1.5 Hz, 5-H), 5.87 (1H, dd, JZ10, 5 Hz,
4-H); dC (75 MHz, CDCl3) 18.53 (C-10), 24.71 (C-3), 24.98
(C-8), 34.79 (C-11), 57. 56 (C-2), 60.78 (C-8), 92.78 (C-6),
127.58 (C-5), 130.66 (C-4); m/z (CI) 155 {[MCH]C,
4.1.14. (Z,E)-4-(3,4-Dihydro-2H-6-pyranyl)-3-buten-1-
ol, 10. The following coupling procedures were attempted:

11918
J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
100%}; (EI) 154 [MC, 75.1%]. Found: (CI) m/z 154.1001.
C9H14O2 [MC] requires m/z 154.0993.
JZ10, 2 Hz, 5-H), 5.98–6.12 (1H, m, 4-H), 6.36 (7/18H, dt,
JZ10, 2 Hz, 5-H), 7.25–7.62 (5H, m, Ar); Equilibrated
(essentially 35) dH 1.30 (3H, d, JZ6.5 Hz, Me), 1.50–1.80
(3H, m, 9-H, 3ax-H), 1.95–2.10 (2H, 10eq-H, 3eq-H), 2.28
(1H, qd, JZ13, 4.5 Hz, 10ax-H), 3.16 (1H, dd, JZ13,
4.5 Hz, 11-H), 3.62–3.76 (1H, m, 8eq-H), 3.87–3.90 (1H, dt,
JZ11, 3 Hz, 8ax-H), 4.04 (1H, sextet, JZ6.5 Hz, 2-H), 5.71
(1H, dt, JZ10, 2 Hz, 5-H), 6.05 (1H, dt, JZ9.5, 4 Hz, 4-H),
7.20–7.65 (5H, m, Ar); dC (75 MHz; CDCl3): Initially
21.01, 22.48, 26.63, 27.40, 28.34, 32.09, 31.14, 49.63,
50.21, 60.16, 61.03, 63.84, 64.31, 95.90, 96.09, 126.85,
126.98, 127.17, 128.07, 128.89, 128.96, 129.13, 129.13,
129.32, 130.23, 130.93, 133.38, 134.30; Equilibrated 21.01
(Me), 27.40 (C-9), 28.34 (C-3), 32.09 (C-7), 49.63 (C-11),
60.16 (C-8), 63.84 (C-2), 96.10 (C-6), 127.17, 127.74,
128.88, 129.19 (Ar), 129.13, 129.32 (C-4, C-5), 131.57,
134.30, 134.37 (Ar); m/z (EI) 324 [MC, 80Se 47.5%]; (CI)
325 {[MCH]C, 80Se 38.3%}. Found: m/z 324.0616.
C16H20O820Se [MC] requires m/z 324.0628.
4.1.17. (2R*,6S*)-2-Methyl-1,7-dioxaspiro[5.5]undecane,
a
33.23 To
solution of (2R*,6S*)-2-methyl-1,7-
dioxaspiro[5.5]undec-4-ene, 32 (228 mg, 1.34 mmol) in
ethyl acetate (20 mL) was added 5% palladium on carbon
(30 mg) and the mixture was hydrogenated at 1 atm for 6 h
at room temperature. The catalyst was removed by filtration
through celitew, the celitew pad washed with ethyl acetate
(25 mL) and the combined organic extracts were concen-
trated in vacuo. The residue was purified by column
chromatography (ethyl acetate/petrol 3:97) to afford the
title compound 33 (171 mg, 74%) as a colourless oil; nmax
(film) 2939, 2870, 1449, 1384, 1349, 1282, 1257, 1231,
1214, 1182, 1138, 1095, 1065, 1048, 999, 965, 948, 926,
897, 845 and 804 cmK1; dH (300 MHz, CDCl3) 1.15 (3H, d,
JZ6 Hz), 1.20–2.00 (12H, m), 3.50–3.80 (3H, m, 2-H, 8-
H); dC (75 MHz, CDCl3) 18.57, 18.89 (C-10, C-4), 21.79
(Me), 25.42 (C-9), 32.69 (C-3), 35.08, 35.83 (C-5, C-7),
60.23 (C-8), 65.10 (C-1), 95.54 (C-6); m/z (EI) 169
{[MKH]C, 86.2%}. Found: m/z (CI) 169.1225. C10H17O2
{[MKH]C} requires m/z 169.1228.
4.1.20. (6S*,11S*)-11-Phenylselenyl-1,7-dioxaspiro[5.5]
undec-4-ene, 14. The title compound was prepared from
the diene 10 (382 mg, 2.48 mmol) using the method above
and isolated, after flash chromatography, as essentially a
single diastereoisomer (559 mg, 73%); nmax (film) 3042,
2935, 2876, 1658, 1599, 1477, 1437, 1395, 1377, 1344,
1316, 1283, 1229, 1209, 1177, 1145, 1070, 1036, 993, 949,
929, 888, 853, 772, 743, 713, 693 and 671 cmK1; dH
(300 MHz, CDCl3) 1.55–1.80 (2H, m, 9-H), 1.90–2.10 (2H,
m, 3eq-H, 10eq-H), 2.23 (1H, dq, JZ13, 4.5 Hz, 10ax-H),
2.41 (1H, dddt, JZ18, 9, 5.5, 2.5 Hz, 3ax-H), 3.21 (1H, dd,
JZ12.5, 4.5 Hz, 11-H), 3.67 (1H, br dd, JZ11, 5 Hz, 8eq-
H), 3.80–4.03 (3H, m, 2-H, 8ax-H), 5.74 (1H, ddd, JZ10, 3,
1 Hz, 5-H), 6.12 (1H, dd, JZ10, 5.5 Hz, 4-H), 7.24–7.62
(10H, m, Ar); dC (75 MHz, CDCl3) 24.52 (C-3), 27.29
(C-9), 28.83 (C-10), 49.45 (C-11), 58.12 (C-4), 60.32 (C-8),
94.92 (C-6), 127.28, 128.93 (Ar), 129.12 (C-5), 129.60
(C-6), 129.95, 133.45, 134.33, 134.40 (Ar); m/z (CI) 311
{[MCH], 100%]}. Found: m/z 310.0473. C15H18O820Se
[MC] requires m/z 310.0472.
4.1.18. (G)-1,7-Dioxaspiro[5.5]undecane, 1313 The title
compound was prepared using the method above from the
spiroketal 12 (226 mg, 1.46 mmol) as a colourless oil
(213 mg, 93%); nmax (film) 2948, 2870, 1452, 1384, 1280,
1256, 1230, 1208, 1179, 1096, 1068, 991, 935, 913, 876 and
796 cmK1; dH (300 MHz, CDCl3) 1.40–2.00 (12H, m),
3.60–3.80 (4H, m, 2-H, 8-H); dC (75 MHz) 18.54 (C-4,
C-10), 25.33 (C-5, C-11), 35.76 (C-3, C-9), 60.37 (C-2, C-
8), 95.01 (C-6); m/z (EI) 155 {[MKH]C, 32.1%}. Found:
m/z (CI) 155.1068. C9H15O2 {[MKH]C} requires m/z
155.1072.
4.1.19. (2R*,6R*,11S*)-2-Methyl-11-phenylselenyl-1,7-
dioxaspiro[5.5]undec-4-ene, 34 and (2R*,6R*,11R*)-2-
methyl-11-phenylselenyl-1,7-dioxaspiro[5.5]undec-4-
ene, 35. To a solution of (4Z,E)-5-(3,4-dihydro-2H-6-
pyranyl)-4-penten-1-ol, 31 (0.36 g, 2.14 mmol) in dichloro-
methane (5 mL) was added pyridine (0.2 mL, 6.4 mmol).
The mixture was cooled to K78 8C, phenylselenyl chloride
(0.45 g, 2.35 mmol) was added and the reaction was allowed
to warm to room temperature and stir for 1 h. After
quenching with ice cold aqueous sodium hydrogencarbo-
nate, the product was extracted into dichloromethane (3!
30 mL), the combined extracts dried (MgSO4), and
evaporated and residue purified by column chromatography
(ethyl acetate/petrol 3:97) to afford the title compounds 34
and 35 (458 mg, 66%) as an inseparable mixture (34:35Z
7:11). The diastereoisomers equilibrated in CDCl3 after
3 days at 20 8C to 35 as a single diastereoisomer. Mixture:
nmax (film) 3053, 2931, 2874, 1658, 1579, 1478, 1437,
1396,1342, 1282, 1231, 1188, 1133, 1101, 1064, 1023, 991,
949, 932, 893, 845, 742 and 709 cmK1; dH (300 MHz,
CDCl3): Initially 1.30 (33/18H, d, JZ6.5 Hz, Me), 1.32 (21/
18H, d, JZ6.5 Hz, Me), 1.50–1.80 (3H, m, 9-H, 3ax-H),
1.90–2.10 (2H, m, 10eq-H, 3eq-H), 2.28 (11/18H, qd, JZ
13, 4.5 Hz, 10ax-H), 2.50–2.65 (7/18H, m, 10ax-H), 3.16
(11/18H, dd, JZ13, 4.5 Hz, 11-H), 3.40 (7/18H, t, JZ
4.5 Hz, 11-H), 3.62–3.76 (1H, m, 8eq-H), 3.87–4.00 (1H, m,
8ax-H), 4.06 (1H, sextet, JZ6.5 Hz, 2-H), 5.71 (11/18H, dt,
4.1.21. (2R*,6S*)-2-Methyl-1,7-dioxaspiro[5.5]undec-4,
10-diene, 36. The diastereomeric mixture of the selenides
34 and 35 (0.39 g, 1.22 mmol) was dissolved in chloroform
(5 mL) to which was added pyridine (0.5 mL, 6.02 mmol)
and 2-benzenesulfonyl-3-phenyloxaziridine15 (413 mg,
1.58 mmol) and the reaction mixture brought to a gentle
reflux 15 h. The solvent was removed in vacuo and the
residue chromatographed (2:3 dichloromethane/petrol) to
afford the title compound 35 (147 mg, 73%) as a yellow oil;
nmax (film) 3041, 2974, 2931, 2895, 2828, 1656, 1462, 1446,
1425, 1398, 1386, 1367, 1339, 1270, 1214, 1201, 1183,
1135, 1100, 1076, 1048, 1021, 980, 928, 903, 874, 851, 819,
769, 730 and 701 cmK1; dH (300 MHz, CDCl3) 1.25 (3H, d,
JZ6.5 Hz, Me), 1.80–2.00 (3H, m, 3-H, 9eq-H), 2.29 (1H,
dddt, JZ18, 9, 6, 3 Hz, 9ax-H), 3.76 (1H, dd, JZ12, 6 Hz,
8eq-H), 4.02 (1H, dt, JZ12, 3.5 Hz, 8ax-H), 4.00–4.15 (1H,
m, 2-H), 5.59 (2H, br d, JZ10 Hz, 5-H, 11-H), 5.99 (2H, m,
4-H, 10-H); dC (75 MHz, CDCl3) 21.29 (Me), 24.53 (C-9),
31.95 (C-3), 58.25 (C-2), 64.01 (C-8), 92.07 (C-6), 128.27,
128.35, 128.54, 129.11 (C-4, C-5, C-10, C-11); m/z (CI) 167
{[MCH]C, 72.2%}. Found: m/z 166.0993. C10H14O2 [MC]
requires m/z 166.0994.

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11919
4.1.22. (G)-1,7-Dioxaspiro[5.5]undec-4,10-diene, 15.16
The title compound was prepared from the selenide 14
(532 mg, 1.71 mmol) using the method described above.
Flash chromatography (1:1 dichloromethane/petrol)
afforded the title compound as a yellow oil (161 mg,
62%); nmax (film) 3041, 2965, 2933, 2878, 2830, 1654,
1463, 1426, 1395, 1368, 1335, 1271, 1201, 1185, 1157,
1119, 1075, 1023, 901, 862, 778, 735 and 705 cmK1; dH
(300 MHz, C6D6) 1.50 (2H, ddd, JZ18, 5, 3 Hz, 9eq-H,
3eq-H), 2.10 (2H, dddt, JZ18, 12, 6, 2 Hz, 3ax-H, 9ax-H),
3.67 (2H, dd, JZ10, 6 Hz, 2eq-H, 8eq-H), 4.07 (2H, dt, JZ
11, 3.5 Hz, 2ax-H, 8ax-H), 5.75 (2H, dd, JZ10, 3 Hz, 5-H,
11-H), 5.82 (2H, dd, JZ10, 5 Hz, 4-H, 10-H); dC (75 MHz,
C6D6) 24.81 (C-3, C-9), 58.33 (C-2, C-8), 91.36 (C-6),
127.82 (C-4, C-10), 130.08 (C-5, C-11); m/z (EI) 152 [MC,
35.5%]. Found: m/z 152.0834. C9H12O2 [MC] requires m/z
152.0837.
CH2OSi), 3.80–3.90 (1H, m, CH2OSi), 3.90–4.00 (1H, m,
2-H), 4.68 (1H, t, JZ4 Hz, 5-H), 5.91 (1H, d, JZ15.5 Hz,
40-H), 6.25 (1H, dt, JZ15.5, 7.5 Hz, 30-H), 7.30–8.00 (10H,
m, Ar); dC (75 MHz, C6D6) Z-isomer: 19.45 or 19.51
(CMe3), 20.75 (C-4), 23.84 (C-3), 26.95 or 27.03 (CMe3),
33.13 (C-20), 62.54 (C-10), 66.69 (CH2OSi), 76.12 (C-2),
102.64 (C-5), 126.76 (C-30), 127.80 (C-40), 128.06, 128.09,
130.01, 133.83, 135.97, 136.01 (Ar), 152.63 (C-6);
E-isomer: 19.45 or 19.51 (CMe3), 20.75 (C-4), 24.34
(C-3), 26.95 or 27.03 (CMe3), 36.44 (C-20), 62.05 (C-10),
66.69 (CH2OSi), 75.97, (C-6), 100.97 (C-5), 125.18 (C-30),
126.76 (C-40), 128.06, 128.09, 130.01, 133.83, 135.97,
136.01 (Ar), 151.14 (C-6); m/z (CI) 345 {[[MCKPh],
100%}. Found: m/z (CI) 423.2358. C26H35O238Si {[MC
H]C} requires m/z 423.2355.
4.1.24. (2R*,6S*)-2-(t-Butyldiphenylsilyloxymethyl)-1,7-
dioxa-spiro[5.5]undec-10-ene, 20. The title compound was
prepared from the diene 19 (0.908 g, 2.15 mmol) using the
method described above for 32. Isolated as a colourless,
viscous oil after flash chromatography (1:99 ethyl acetate/
petrol); yield 0.53 g, (58%); nmax (film) 3071, 3046, 2933,
2858, 1657, 1590, 1473, 1428, 1361, 1273, 1206, 113, 1079,
1029, 998, 958, 919, 904, 889, 862, 824, 805, 739 and
4.1.23.
(Z,E)-4-[(2R*)-2-(t-Butyldiphenylsilyloxy-
methyl)-3,4-dihydro-2H-6-pyranyl]-3-buten-1-ol, 19.
Method A. A solution of t-butyllithium (20.6 mL, 1.7 M
solution in pentane) was added dropwise to a stirred solution
of 2-(t-butyldiphenylsilyloxymethyl)-3,4-dihydro-2H-pyran
16 (5.61 g, 15.94 mmol) in THF (8 mL) at K78 8C. The
mixture was allowed to warm up to 0 8C and was stirred at
this temperature for 2 h, then recooled to K78 8C (excess
t-butyllithium was destroyed by adding more THF
[30 mL]). Zinc chloride (1 M solution in ether, 16.9 mL)
was added dropwise and the resulting mixture was allowed
to warm up to room temperature and to stir for 2 h. In a
separate flask, Dibal-H (1 M solution in toluene, 0.4 mL)
was added dropwise to PdCl2(PPh3)2 (133 mg, 0.19 mmol,
5 mol%) in THF (5 mL) at 0 8C and the resulting mixture
was stirred for 30 min. The solution containing the Pd(0)
catalyst was then added to the vinyl zinc at 5–10 8C,
followed by a solution of (Z,E)-4-hydroxy-1-iodobut-1-ene
8 (0.69 g, 3.48 mmol) in THF (2 mL) and resulting mixture
was stirred for 1 h at 0 8C. After quenching with sodium
hydroxide (10 mL), the product was extracted into ether
(3!30 mL), the ethereal extracts dried (MgSO4), concen-
trated in vacuo. The residue was chromatographed (3:1:16
ethyl acetate/triethylamine/petrol) to afford the title
compound 19 (1.08 g, 72%; mobile oil) as an inseparable
mixture of geometrical isomers (Z:EZ8:1)
t
704 cmK1; dH (300 MHz, CDCl3) 1.13 (9H, s, BuSi), 1.28
(1H, dq, JZ12, 3.5 Hz, 3ax-H), 1.58 (1H, dt, JZ13, 5 Hz,
5eq-H), 1.65–2.05 (4H, m, 4-H, 9eq-H, 3eq-H, 5ax-H), 2.35
(1H, dddt, JZ18, 9, 5.5, 2.5 Hz, 9ax-H), 3.62 (1H, dd, JZ
10, 6 Hz, CH2OSi), 3.70–3.85 (2H, m, CH2OSi, 8eq-H),
3.90–4.05 (2H, m, 8ax-H, 2ax-H), 5.67 (1H, br d, JZ10 Hz,
11-H), 5.99 (1H, br dt, JZ10, 5 Hz, 10-H), 7.30–7.80 (10H,
m, Ar); dC (75 MHz, CDCl3) 18.54 (C-4), 19.33 (CMe3),
24.80 (C-9), 26.82 (CMe3), 27.13 (C-3), 34.67 (C-5), 57.58
(C-8), 67.72 (CH2OSi), 70.57 (C-2), 93.43 (C-6), 127.58
(Ar), 129.54 (C-10), 130.89 (Ar), 133.93 (C-11), 135.67,
135.75 (Ar); m/z (CI) 423 {[MCH]C, 67%} (EI) 365
{[MKtBu]C, 58.6%}. Found: (CI) m/z 423.2339 {[MC
H]C}. C26H35O3Si requires m/z 423.2355.
4.1.25. (2R*,6R*)-2-(t-Butyldiphenylsilyloxymethyl)-1,7-
dioxaspiro[5.5]undecane, 21. The title compound 21 was
prepared from the spiroketal 20 (369 mg, 0.87 mmol) using
the method above. Isolated after flash chromatography (1:99
ethyl acetate/petrol) as a colourless, viscous oil (345 mg,
94%); nmax (film) 2937, 2858, 1428, 1386, 1280, 1229,
1211, 1112, 1086, 994, 951, 932, 875, 824, 800, 739 and
702 cmK1; dH (300 MHz, CDCl3) 1.13 (9H, s, tBuSi), 1.20–
1.70 (10H, m, 3-H, 4-H, 5-H, 9-H, 10-H, 11-H), 1.83–2.10
(2H, m, 9-H, 10-H), 3.64 (1H, dd, JZ10, 5 Hz, CH2OSi),
3.58–3.67 (1H, m, 8-H), 3.75 (1H, dd, JZ10, 6 Hz,
CH2OSi), 3.80–3.90 (2H, m, 2-H, 8-H) 7.4–7.85 (10H, m,
Ar); dC (75 MHz, CDCl3) 18.55 (C-4, C-10), 19.27 (CMe3),
25.39 (C-3), 26.61 (CMe3), 27.18 (C-9), 35.45, 35.78, (C-5,
C-11), 60.25 (CH2OSi), 67.55 (C-8), 70.15 (C-2), 95.50
(C-6), 127.60, 129.52, 129.55, 133.96, 135.69, 135.73, (Ar);
m/z (CI) 442 [[MCNH4]C,100%]. Found: m/z 425.2516.
C26H37O238Si {[MCH]C} requires m/z 425.2512.
Method B. The title compound 19 was prepared from (Z,E)-
4-hydroxy-1-iodobut-1-ene 8 (0.75 g, 3.79 mmol) in exactly
the same way as method A except that freshly prepared
Pd(PPh3)4 (213 mg, 5 mol%) was used as the catalyst.
Work-up and chromatography (3:1:16 ethyl acetate/triethyl-
amine/petrol) afforded the title compound (1.06 g, 70%,
colourless oil), as a mixture of geometrical isomers (Z:EZ
8:1); nmax (film) 3385, 2930, 2857, 1655, 1613, 1590, 1472,
1428, 1112, 1068, 1006, 824, 789, 741 and 703 cmK1; dH
t
(300 MHz, C6D6) Z-isomer: 1.25 (9H, s, BuSi), 1.49–1.58
(2H, m, 3-H), 1.85–1.95 (2H, m,04-H), 2.90 (2H, q, JZ7 Hz,
30-H), 3.66 (2H, t, JZ6 Hz, 1 -H), 3.77 (1H, dd, JZ10,
4.5 Hz, CH2OSi), 3.80–3.90 (1H, m, CH2OSi), 3.88–4.00
(1H, m, 2-H), 4.72 (1H, t, JZ4 Hz, 5-H), 5.50 (1H, dt, JZ
12, 8 Hz, 20-H), 5.85 (1H, d, JZ12 Hz, 10-H), 7.30–8.00
4.1.26.
(2R*,6R*)-2-(Hydroxymethyl)-1,7-dioxa-
spiro[5.5]-undecane, 22.18 To a solution of the TBDPS-
protected alcohol 21 (275 mg, 0.65 mmol) under nitrogen in
THF (10 mL) at ambient temperature was added TBAF
(1 M in THF, 1.3 mL) and the resulting pale green solution
t
(10H, m, Ar); E-isomer: 1.27 (9H, s, BuSi), 1.40–1.6 (2H,
m, 3-H), 1.61–1.81 (2H, 0m, 4-H), 2.30 (2H, q, JZ7 Hz, 20-
H), 3.50–3.58 (2H, m, 1 -H), 3.77 (1H, dd, JZ10, 4.5 Hz,

11920
J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
was stirred at this temperature for 16 h. Ether (30 mL) was
added and the organic solution was washed with saturated
aqueous ammonium chloride (2!15 mL) and brine (1!
15 mL), then dried (MgSO4), and concentrated in vacuo.
Flash chromatography (2:3 ethyl acetate/petrol) of the
residue afforded the title compound 22 (105 mg, 87%) as a
colourless, viscous oil; nmax (film) 3425, 2941, 2871, 1440,
1384, 1281, 1228, 1210, 1182, 1094, 1077, 1049, 1022, 992,
951, 928, 894, 875 and 808 cmK1; dH (300 MHz, CDCl3)
1.20–1.70 (10H, m, 3-H, 4-H, 5-H, 9-H, 10-H, 11-H), 1.78–
2.00 (2H, m, 9-H, 10-H), 2.10 (1H, br s, OH), 3.54 (1H, dd,
JZ11, 7 Hz, CH2OH), 3.65 (1H, dt, JZ11, 3 Hz, 8ax-H),
3.60–3.70 (2H, m, CH2OH and 8eq-H), 3.73–3.83 (1H, m,
2-H); dC (75 MHz, CDCl3) 18.18, 18.61 (C-4, C-10), 25.21
(C-3), 26.46 (C-9), 35.42, 35.59 (C-5, C-11), 60.43
(CH2OH), 66.31 (C-8), 69.67 (C-2), 95.51 (C-6); m/z (CI)
187 [[MCH]C, 100%]. Found: m/z 186.1252. C10H18O3
[MC] requires m/z 186.1256.
(1H, dt, JZ12, 3.5 Hz, 8ax-H), 4.20 (1H, dq, JZ10, 5 Hz,
2-H), 5.60–5.70 (2H, m, 5-H, 11-H), 6.12–6.22 (2H, m, 4-H,
10-H), 7.30–7.80 (10H, m, Ar); dC (75 MHz, CDCl3) 19.03
(CMe3), 24.53 (C-9), 26.64 (CMe3), 27.08 (C-3), 58.32
(C-8), 66.90 (CH2OSi), 68.66 (C-2), 91.89 (C-6), 127.61,
127.72, 127.80 (Ar), 127.88, 128.15 (C-4, C-10), 128.24,
128.71 (C-5, C-11), 129.57, 129.60, 133.72, 135.50, 135.62,
135.69, 135.76; m/z (EI) 362 [MCKtBu, 61%] (CI) 421
[[MCH]C, 100%]. Found: (CI) m/z 421.2185.
C26H33O238Si {[MCH]C} requires m/z 421.2200.
4.1.29. Ethyl (2R*,3R*)-3-(t-butyldimethylsilyloxy)-2-
methylbutanoate, 39.30 To a solution of ethyl (2R*,3R*)-
3-hydroxy-2-methylbutanoate 38 (9.95 g, 68.1 mmol) in
dichloromethane (10 mL) was added 1,8-diazobicyclo-
[5,4,0]undec-7-ene (10.2 mL, 65.6 mmol) at 0 8C followed
by t-butyldimethylsilyl chloride (9.89 g, 65.6 mmol) in
dichloromethane (10 mL). After 3 h at room temperature the
mixture was poured into water (100 mL), extracted into
ether (100 mL) and washed with water (50 mL), hydro-
chloric acid (0.1 M, 50 mL), water (50 mL), saturated
sodium bicarbonate (50 mL) and water (50 mL). The
organic layer was dried (MgSO4), concentrated in vacuo,
and the residue was purified by flash column chromato-
graphy (1:19 ethyl acetate petrol) to afford the title
compound 39 (14.02 g, 87%) as a colourless oil; nmax
(film) 2958, 2931, 2858, 1737, 1474, 1376, 1320, 1256,
4.1.27.
(2R*,5S*,6R*)-2-(t-Butyldiphenylsilyloxy-
methyl)-5-phenylselenyl-1,7-dioxaspiro[5.5]-undec-10-
ene, 23 and (2R*,5R*,6R*)-2-(t-butyldiphenylsilyloxy-
methyl)-5-phenylselenyl-1,7-dioxaspiro[5.5]undec-10-
ene, 24. The title compounds were prepared from the diene
19 (0.94 g, 2.23 mmol) using the standard cyclisation
procedure. Isolated as a 2:1 (23:24) mixture of diastereo-
isomers (0.74 g, 57%) after flash chromatography (1:99
ethyl acetate/petrol); nmax (film) 3071, 3049, 2997, 2931,
2857, 1657, 1579, 1475, 1428, 1392, 1361, 1339, 1300,
1271, 1235, 1210, 1189, 1113, 1079, 999, 909, 824, 739 and
1185, 1113, 1068, 1039, 982, 953, 839, 811 and 776 cmK1
;
dH (300 MHz, CDCl3): 0.06 (3H, s, CH3Si), 0.09 (3H, s,
CH3Si), 0.90 (9H, s, CH3CSi), 1.11 (3H, d, JZ7 Hz, C2–
Me), 1.16 (3H, d, JZ6 Hz, H-4), 1.25 (3H, t, JZ7 Hz,
OCH2CH3), 2.51 (1H, quintet JZ7 Hz, H-2), 3.95–4.15
(1H, m, H-3), 4.13 (2H, q, JZ7 Hz, OCH2); dC (75 MHz)
K5.12, K4.32, 12.68, 14.19, 17.92, 20.24, 25.72, 48.15,
60.12, 70.15, 175.15; m/z (CI) 261 [MCH]C, 100%], 203
[MCKtBu, 20%]. Found: (CI) m/z 261.1884. C13H29O238Si
{[MCH]C} requires m/z 261.1886.
t
705 cmK1; dH (300 MHz, CDCl3): 1.18 (6H, s, BuSi, eq.
t
isomer, 23), 1.21 (3H, s, BuSi, ax. isomer, 24), 1.70–1.80
(2/3H, m), 1.80–2.04 (2H, m), 2.04–2.22 (1H, m), 2.22–2.60
(2H, m), 2.62–2.78 (1/3H, m), 3.24 (2/3H, dd, JZ12.5,
4.5 Hz, 5-H), 3.46 (1/3H, br s, 5-H), 3.60–4.20 (5H, m, 2-H,
8-H, CH2OSi), 5.80 (2/3H, d, JZ10 Hz, 11-H), 6.02–6.10
(1/3H, m, 10-H), 6.12–6.20 (2/3H, m, 10-H), 6.49 (1/3H, d,
JZ10 Hz, 11-H), 7.25–7.85 (15H, m, Ar); dC (75 MHz,
CDCl3) Equatorial isomer, 23: 19.37 (CMe3), 24.62 (C-3),
26.97 (CMe3), 28.37 (C-9), 29.65 (C-10), 49.37 (C-11),
58.09 (C-2), 67.33 (CH2OSi), 70.27 (C-8), 95.39 (C-6),
127.80 (Ar), 128.92 (C-4), 129.01, 129.11, 129.66 (Ar),
129.84 (C-6), 133.17, 134.51, 135.81 (Ar); Axial isomer,
24: 19.41 (CMe3), 23.73 (C-9), 26.16 (C-9), 26.89 (C-4),
26.97 (CMe3), 50.16 (C-5), 58.44 (C-8), 67.48 (CH2OSi),
70.53 (C-2), 95.02 (C-6), 127.80 (Ar), 128.59 (C-10),
129.01, 129.11, 129.66 (Ar), 129.92 (C-11), 133.92, 133.17,
134.51, 135.81 (Ar); m/z FAB 579 {[MCH]C, 4.2%}.
Found: m/z 579.1856. C32H39O830Se28Si {[MCH]C}
requires 579.1834.
4.1.30. (1ZE,3S*,4R*)-4-(t-Butyldimethylsilyloxy)-1-
iodo-3-methylpentene, 41. Dibal-H (1 M in toluene,
15.7 mL, 15.7 mmol) was added dropwise to a cooled
(K78 8C) and stirred solution of ethyl (2R*,3R*)-3-(t-
butyldimethylsilyloxy)-2-methylbutanoate 39 (2.42 g,
9.83 mmol) in anhydrous toluene (100 mL). After being
stirred at K80 8C for 1 h the reaction was quenched by
dropwise addition of methanol (10 mL) keeping the
temperature below K78 8C. Citric acid (10% aqueous
solution, 80 mL) was then added, the mixture was allowed
to warm to room temperature, the organic phase was
decanted and the aqueous layer was extracted with
dichloromethane (3!100 mL). The combined organic
phases were dried (MgSO4), the solvent was removed
under vacuum. The crude aldehyde 4030 {dH (300 MHz,
CDCl3): 0.04 (3H, s, CH3Si), 0.05 (3H, s, CH3Si), 0.90 (9H,
s, CH3CSi); 1.10 (3H, d, JZ7.5 Hz, C2–Me), 1.25 (3H, d,
JZ6 Hz, 4-H), 2.30–2.40 (1H, m, H-2); 4.05 (1H, quintet,
JZ6 Hz, H-3), 9.85 (1H, d, JZ2.5 Hz, H-1)} was used
immediately in the next reaction.
4.1.28. (2R*,6R*)-2-(t-Butyldiphenylsilyloxymethyl)-1,7-
dioxaspiro[5.5]undec-4,10-diene, 25. The title compound
was prepared from the diastereomeric mixture of selenides
23 and 24 (503 mg, 0.87 mmol). Isolated as a single isomer,
a pale yellow oil, (265 mg, 73%) after flash chromatography
(1:99 ethyl acetate/petrol); nmax (film) 3044, 2930, 2857,
1657, 1473, 1428, 1389, 1201, 1113, 1077, 1020, 908, 824,
796, 740 and 702 cmK1; dH (300 MHz, CDCl3): 1.10 (9H, s,
tBuSi), 1.90 (1H, dt, JZ18, 4.5 Hz, 9eq-H), 2.00–2.10 (2H,
m, 3-H), 2.35 (1H, dddt, JZ18, 9, 5.5, 3 Hz, 9ax-H), 3.70
(1H, dd, JZ10, 5.5 Hz, CH2OSi), 3.80 (1H, dd, JZ11,
6 Hz, 8eq-H), 3.87 (1H, dd, JZ10, 5 Hz, CH2OSi), 4.10
To a suspension of iodomethyltriphenylphosphonium iodide
(6.51 g, 12.3 mmol) in THF (27 mL) at room temperature
was slowly added sodium hexamethyldisilazide (1 M
solution in THF, 11.3 mL). After stirring for 10 min, the

J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
11921
dark-coloured solution of the yield was cooled to K78 8C
and crude (2R*,3R*)-3-(t-butyldimethylsilyloxy)-2-methyl-
butanal 40 in THF (10 mL) was added slowly. The mixture
was allowed to warm to room temperature and after 30 min,
the solvent was removed in vacuo. The residue was washed
with 3!(50 mL 50:1 petrol/diethyl ether) and the super-
natant filtered through celitew to remove triphenylphos-
phine oxide. The combined eluents were concentrated in
vacuo and the residue purified by flash column chromato-
graphy (dichloromethane /hexane 1:19) to afford the title
compound 41 as a light sensitive, colourless, oil38 (1.38 g,
41% overall yield from 39; E:ZZ6:1). Z-isomer; nmax (film)
2957, 2927, 2885, 2857, 1608, 1472, 1462, 1375, 1259,
1152, 1086, 1064, 1027, 1007, 956, 850, 837, 802, 775, 745,
699 and 665 cmK1; dH (300 MHz, CDCl3): 0.10 (3H, s,
CH3Si), 0.11 (3H, s, CH3Si), 0.93 (9H, s, CH3CSi), 1.05
(3H, d, JZ7 Hz, C3–Me), 1.12 (3H, d, JZ6.5 Hz, 5-H),
2.50–2.56 (1H, m, 3-H), 3.80–3.88 (1H, m, 4-H), 6.15 (1H,
dd, JZ9, 7.5 Hz, 2-H), 6.25 (1H, d, JZ7 Hz, 1-H); dC
(75 MHz; CDCl3): K4.75, K4.23, 15.76, 18.07, 21.45,
25.87, 49.65, 70.87, 81.90, 143.41; m/z (CI) 341 [[MC
H]C,34%]. Found: m/z (CI) 341.0804. C12H25IO28Si {[MC
H]C} requires m/z 341.0798. E-isomer nmax (film) 2957,
2929, 2885, 2857, 1603, 1552, 1472, 1462, 1374, 1361,
1253, 1188, 1157, 1128, 1102, 1064, 1029, 1007, 988, 956,
837, 806, 775 and 663 cmK1; dH (300 MHz, CDCl3): 0.10
(6H, s, CH3Si), 0.95 (9H, s, CH3CSi), 1.02 (3H, d, JZ
6.5 Hz, C3–Me), 1.11 (3H, d, JZ6 Hz, 5-H), 2.15–2.25 (1H,
m, 3-H), 3.65–3.72 (1H, m, 4-H), 6.02 (1H, dd, JZ14.5,
0.5 Hz, H-1), 6.52 (1H, dd, JZ14.5, 8.5 Hz, H-2); dC
(75 MHz, CDCl3): K4.78, K4.35, 15.69, 18.07, 21.24,
25.86, 48.37, 71.23, 74.73, 149.04; m/z (CI) 341 {[MCH]C,
36%}. Found: m/z (CI) 341.0807. C12H25IO28Si {[MC
H]C} requires m/z 341.0798.
temperature for 30 min, then re-cooled to K78 8C. Zinc
chloride (1 M solution in ether, 9.8 mL) was added
dropwise and the resulting mixture was allowed to warm
up to room temperature and to stir for 2 h, generating a stock
solution of the zinc reagent 11. A solution of (2R*,3S*,4Z)-
5-iodo-3-methyl-4-penten-2-ol 42 (500 mg, 1.17 mmol) and
Pd(PPh3)4 (127 mg, 5 mol%) in THF (5 mL) was added to
the vinylzinc 11 at 5–10 8C, and resulting mixture was
stirred for 1 h. After quenching with sodium hydroxide
(10 mL), the product was extracted with ether (3!30 mL),
the ethereal extracts dried (MgSO4), concentrated in vacuo,
and the residue was purified by flash column chromato-
graphy (3:1:16 ethyl acetate/triethylamine/petrol) to afford
the title compound 43 as a colourless oil (290 mg, 72%);
nmax (film) 3412, 2969, 2930, 2874, 1723, 1656, 1610, 1450,
1394, 1375, 1353, 1311, 1274, 1234, 1153, 1086, 1060, 999,
972, 936, 893, 862 and 787 cmK1; dH (200 MHz, C6D6)
1.03 (3H, d, JZ6 Hz, C-30Me), 1.18 (3H, d, JZ6 Hz, H-10),
1.35 (2H, apparent quintet, J0Z6 Hz, 3-H), 1.76–1.90 0(2H,
m, 4-H), 3.30–3.50 (1H, m, 3 -H), 3.45–3.55 (1H, m, 2 -H),
3.68 (2H, t, JZ6 Hz, 2-H), 4.66 (1H, t, JZ4 Hz, 5-H), 5.15–
5.30 (1H, m, 40-H), 5.75 (1H, d, JZ12 Hz, 50-H); m/z (CI)
183 [[MCH]C, 100%]. Found m/z (CI) 182.1301.
C11H18O2 [MC] requires m/z 182.1307.
4.1.33. (2R*,3S*,6S*)-2,3-Dimethyl-1,7-dioxaspiro[5.5]
undec-4-ene, 44. To a solution of (2R*,3S*,4Z)-5-(3,4-
dihydro-2H-6-pyranyl))-3-methyl-4-penten-2-ol 43 (247 mg,
1.35 mmol) in dichloromethane (5 mL) was added cam-
phorsulfonic acid (30 mg) and the mixture stirred at room
temperature for 1 h. After quenching with saturated sodium
bicarbonate (15 mL), the reaction mixture was extracted
with ether (2!20 mL), the ethereal extracts dried (MgSO4),
and evaporated and the residue purified by flash column
chromatography (ethyl acetate/petrol 1:19) to afford the title
compound 44 (105 mg, 42%) as a colourless oil; nmax (film)
3034, 2939, 2872, 1657, 1450, 1398, 1378, 1269, 1225,
1204, 1186, 1169, 1106, 1091, 1074, 1055, 1002, 954, 923,
896, 813 and 723 cmK1; dH (300 MHz, CDCl3): 0.92 (3H, d,
JZ6 Hz, Me) 1.23 (3H, d, JZ6.5 Hz, Me), 1.45–1.65 (5H,
m, 10-H, 11-H, 9ax-H), 1.80–2.00 (2H, m, 3-H, 9eq-H),
3.50–3.61 (2H, m, 8eq-H, 2-H), 3.80 (1H, dt, JZ11, 3 Hz,
8ax-H), 5.54 (1H, dd, JZ10, 2 Hz, 5-H) 5.64 (1H, dd, JZ
10, 1.5 Hz, 4-H); dC (75 MHz, CDCl3) 16.73, 18.52, 19.14,
25.13, 34.88, 36.22, 60.75, 69.46, 93.59, 129.39, 134.42;
m/z (CI) 182 [MC, 100%]. Found: m/z (CI) 183.1386.
C11H19O2 {[MCH]C} requires m/z 183.1386.
4.1.31. (2R*,3S*,4Z)-5-Iodo-3-methyl-4-penten-2-ol, 42.
To a solution of (1ZE,3S*,4R*)-4-(t-butyldimethyl-sily-
loxy)-3-methyl-1-iodopentene 41 (1.29 g, 3.79 mmol) in
acetonitrile (67 mL) was added 60% aqueous hydrogen
fluoride (2.25 mL). The mixture was stirred for 10 min at
ambient temperature after which time the reaction mixture
was diluted with water (50 mL) and extracted with
chloroform (2!50 mL). The combined organic extracts
were dried (MgSO4), concentrated in vacuo and the residue
purified by flash column chromatography (1:4 ethyl acetate
petrol) to afford the title compound 42 (0.66 g, 77%) as a
light sensitive, colourless, oil38; nmax (film) 3376, 3064,
2969, 2929, 1609, 1452, 1376, 1352, 1262, 1200, 1152,
1112, 1085, 1045, 1015, 995, 929, 886, 797 and 702 cmK1
;
4.1.34. (2R*,3S*,4Z)-3,7-Dimethyl-4-octen-2-ol, 45.
Dibal-H (2.5 mL of a 1 M solution in toluene) was added
to the vinyl iodide 42 (570 mg, 2.5 mmol) at K78 8C and
then allowed to warm up to room temperature. This solution
was then added, via cannula, to a mixture of the zinc reagent
11 (2.5 mmol) and Pd(PPh3)4 (5 mol%) in THF. After 1 h at
5 8C work-up and chromatography as above afforded the
title compound 45 as a colourless oil (75 mg, 19%); nmax
(film) 3363, 2958, 2871, 1465, 1368, 1164, 1091, 1044,
1014, 924, 877, 831 and 792 cmK1; dH (300 MHz, CDCl3):
0.95–1.10 (9H, m, 3!Me), 1.22 (3H, d, JZ7 Hz, Me), 1.65
(1H, apparent septet, JZ6.5 Hz, 7-H), 1.82 (1H, br d s, OH),
2.00–2.20 (2H, m, 6-H), 2.45–2.60 (1H, m, 3-H), 3.52 (1H,
quintet, JZ6.5 Hz, 2-H), 5.28–5.40 (1H, m, 4-H), 5.59 (1H,
dt, JZ11, 7 Hz, 5-H); dC (50 MHz, CDCl3) 16.9, 20.0, 22.1,
dH (300 MHz, CDCl3): 1.08 (3H, d, JZ7 Hz, 30-H), 1.24
(3H, d, JZ6.5 Hz, 1-H), 2.42–2.56 (1H, m, 3-H), 3.81 (1H,
quintet, JZ6 Hz, 2-H), 6.15 (1H, dd, JZ9, 7 Hz, 4-H), 6.36
(1H, d, JZ7.5 Hz, 5-H); dC (75 MHz, CDCl3): 15.65, 20.85,
46.70, 70.90, 83.35, 142.86. m/z (CI) 244 [[MCNH4]C,
100%]. Found: m/z (CI) 244.0204. C6H15INO {[MC
NH4]C} requires m/z 244.0198.
4.1.32. (2R*,3S*,4Z)-50-(30,40-Dihydro-2H-6-pyranyl))-3-
methyl-4-penten-2-ol, 43. A solution of t-butyllithium
(5.8 mL, 1.7 M solution in pentane) was added dropwise to
a stirred solution of 2,3-dihydro-2H-pyran (0.8 mL,
9.36 mmol) in THF (5 mL) at K78 8C. The mixture was
allowed to warm up to 0 8C and was stirred at this

11922
J. C. Conway et al. / Tetrahedron 61 (2005) 11910–11923
22.5, 28.6, 36.8, 39.9, 71.6, 131.3, 132.4; m/z (CI) 156 [MC,
38%], 174 [[MCNH4]C, 100%]. Found: m/z (CI) 174.1855.
C10H24NO {[MCNH4]C} requires m/z 174.1858.
Vilcachagu, J. D.; Nigsch, F. J. Org. Chem. 2005, 70,
2225–2234.
¨
6. For reviews see: Schoter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245–2267. Mitchell, T. N. In Metal-catalyzed
Cross-coupling Reactions; De Meijere, A., Diederich, F., Eds.
2nd ed.; Wiley-VCH: Weinheim, 2004; pp 125–161. Jutand,
A. Appl. Organomet. Chem. 2004, 18, 574–582. Espinet, P.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
4704–4734. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986,
25, 508. Mitchell, T. N. Synthesis 1992, 803–825. Farina, V.;
Krishnammurthy, V.; Scott, W. J. Org. React. (N. Y.) 1997, 50,
1. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235. Franzen, R. Can J. Chem. 2000, 78, 957.
For recent mechanistic investigations see: Casado, A. L.;
Espinet, P.; Gallego, A. M.; Martinez-Ilarduya, J. M. Chem.
Commun. 2001, 339–340. For recent applications of this
methodology to diene synthesis see: Mulzer, J.; Berger, M. J.
Org. Chem. 2004, 69, 891–898. Munoz, D. M.; Passey, S. C.;
Simpson, T. J.; Willis, C. L.; Campbell, J. B.; Rosser, R. Aust.
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Acknowledgements
We thank Syngenta and the EPSRC for support of this work.
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