Oxygen to carbon rearrangements of anomerically linked alkenols from tetrahydropyran derivatives: An investigation of the reaction mechanism via a double isotopic labelling crossover study

Article abstract of DOI:10.1039/a909300a

A variety of alkenol tetrahydropyran derivatives were prepared and subjected to a tin tetrachloride promoted anomeric oxygen to carbon rearrangement. Using this methodology many of the corresponding carbon-linked structures were synthesised, including alkenes and bicyclic ethers, in good yields. On the basis of an isotopic labelling study using ²H incorporated into the side chain and ring system it is proposed that these reactions proceed via an intermodular pathway. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909300a

View Article Online / Journal Homepage / Table of Contents for this issue
Oxygen to carbon rearrangements of anomerically linked alkenols
from tetrahydropyran derivatives: an investigation of the reaction
mechanism via a double isotopic labelling crossover study
1
Marianne F. Buffet,a Darren J. Dixon,a Gavin L. Edwards,b Steven V. Ley*a and
Edward W. Tatea
a Department of Chemistry, University of Cambridge, Lensfield Rd., Cambridge, UK CB2 1EW
b School of Chemistry, University of New South Wales, Sydney, New South Wales, 2052,
Australia
Received (in Cambridge, UK) 24th November 1999, Accepted 13th April 2000
Published on the Web 25th May 2000
A variety of alkenol tetrahydropyran derivatives were prepared and subjected to a tin tetrachloride promoted
anomeric oxygen to carbon rearrangement. Using this methodology many of the corresponding carbon-linked
structures were synthesised, including alkenes and bicyclic ethers, in good yields. On the basis of an isotopic labelling
study using 2H incorporated into the side chain and ring system it is proposed that these reactions proceed via an
intermolecular pathway.
pathways or via tight ion pair mechanisms. Here we propose a
Introduction
mechanism for these reactions on the basis of a systematic
An abundance of bioactive natural products which contain tetra-
isotopic labelling experiment.
hydropyran and furan ring systems also exhibit carbon sub-
stituents adjacent to the heteroatom. The direct formation of
carbon–carbon bonds at anomeric sites still presents a signifi-
Anomeric oxygen to carbon rearrangements
The starting materials used throughout this investigation were
readily constructed via high yielding acid catalysed addition of
dihydropyrans to appropriate alkenols, which are either com-
mercially available or can be rapidly accessed through short
synthetic routes. For example, for the first rearrangement study
we chose to use tetrahydropyranyl ether 1, which was syn-
thesised by the addition of dihydropyran to a mixture of
2-methylpropen-2-ol and a catalytic amount of camphor-
sulfonic acid (CSA) in dichloromethane to give 1 in 50% yield.
When 1 was exposed to 3.6 equivalents of tin tetrachloride
in dichloromethane at Ϫ30 ЊC it underwent a 1,4 oxygen to
carbon rearrangement resulting in several distinct carbon-
linked products, the diastereoisomeric chlorohydrins 2 (42%
yield) and 3 (17% yield), and aldehyde 4 (26% yield, 2:1 mixture
of diastereoisomers) (Scheme 2).
The formation of these products may be rationalised by con-
sidering the initial generation of a carbocationic intermediate 5.
Three possible reaction pathways are open to 5: i. elimination
from one of the surrounding centres to give an alkene; ii. trap-
ping of the cation by chloride ion to give a chlorohydrin; or iii.
a 1,2-hydride shift to give an aldehyde (Scheme 2). Reaction
pathway (ii) is favoured in this case, in competition with path-
way (iii). In a related reaction Herscovici et al. have used deuter-
ium labelling studies to prove that a 1,2-hydride shift is indeed
the preferred mechanism of aldehyde formation [pathway (iii)]
rather than elimination toward the alcohol to form an enol
followed by tautomerisation.11
cant challenge to synthetic chemists, and several solutions to
this problem have evolved.1 We have shown recently that Lewis
acid promoted oxygen to carbon rearrangement of anomeric-
ally linked nucleophiles can be a powerful reaction for the
introduction of carbon substituents at anomeric sites. Prior to
our work in this area, such rearrangements were restricted
to a limited range of alkenic,2 benzylic3 and aromatic4 ether
systems, and the potential of a general anomeric oxygen to
carbon rearrangement, in which a nucleophile is connected to
the anomeric oxygen via a carbon chain linker, remained largely
untapped. Since we communicated our initial findings on the
rearrangements of anomerically linked alkenols5 the method-
ology has extended to encompass alkynyl stannanes,6 enol
ethers7 and silyl enol ethers8 as the nucleophilic component.
Using an anomeric oxygen to carbon rearrangement as
the key step we have also completed the total synthesis of the
biologically active natural product (ϩ)-Goniodiol.9
In this and the following paper10 we present our investi-
gations into the rearrangement of tetrahydropyran derived
alkenols. In particular we describe in detail studies on the
tin tetrachloride promoted oxygen to carbon rearrangement
of anomeric alkenols, using both ether and ester anomeric
linkages (Scheme 1).
In the initial studies we had no clear evidence as to whether
such rearrangements proceed through inter or intramolecular
With this evidence for a carbocationic intermediate in the
rearrangement reaction, it was hypothesised that the presence
of a trimethylsilyl group adjacent to the cationic centre would
favour the elimination pathway (i) over either (ii) or (iii), leading
to clean formation of a disubstituted allylic alcohol containing
a pendent tetrahydropyran ring. With this in mind, allylsilyl-
alkenol 6 was prepared12 and tetrahydropyranylated under
the usual conditions to give tetrahydropyranyl ether 7 in 50%
yield (Scheme 3). As we anticipated, on exposure to identical
rearrangement conditions (3.6 eq. SnCl4, DCM, Ϫ30 ЊC) 7
Scheme 1
DOI: 10.1039/a909300a
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
This journal is © The Royal Society of Chemistry 2000
1815

View Article Online
Scheme 2
Other experiments have shown that extending the length of
the carbon chain linker in this species leads to some interesting
changes in the preferred reaction pathway. Alkenol 12 was pre-
pared in 66% overall yield via orthoester Claisen rearrange-
ment13 of 2-methylpropen-1-ol with propanoic acid followed by
LiAlH4 reduction, and subsequent tetrahydropyranylation gave
ether 13 in 51% yield. When 13 was rearranged under standard
conditions, we isolated only the linked 6/5 member bicyclic
ether 14 in 83% yield, as an inseparable 9:2 mixture of
diastereoisomers (by proton NMR and GC analysis) (Scheme
5). It seems that the pendent oxygen bearing the Lewis acid in
Scheme 3
underwent a 1,4 anomeric oxygen to carbon rearrangement
with concurrent elimination of the silyl group from the carbo-
cationic intermediate 8 to give the desired allyl alcohol 9 in 43%
yield as the only rearrangement product isolated.
In further experiments we have demonstrated that it is
possible to extend this rearrangement to highly substituted
alkenes, such as tetrahydropyranyl alkenol ether 10, synthesised
by the standard tetrahydropyranylation of cyclopentenyl
methanol in 87% yield (Scheme 4). Rearrangement under
Scheme 5
the intermediate carbocation 15 is still sufficiently nucleophilic
to undergo in situ cyclisation faster than the competing chloride
trap or elimination pathways observed in previous examples
(a 1,2-hydride shift is precluded in this case); the reason for
the diastereoselectivity observed in this reaction remains
unclear.
For the next rearrangement we chose to investigate this
cyclisation reaction pathway with tetrahydropyranyl ether 16
(Scheme 6). The required precursor, 5-methylhexen-1-ol, was
synthesised by the zirconocene dichloride catalysed carbometal-
lation of hexyn-1-ol14 in quantitative yield, and tetrahydro-
pyranylation gave 16 in 81% yield. Under the usual low
temperature conditions 16 undergoes a formal 1,7 oxygen to
carbon rearrangement leading to alkenol 17 as a mixture of E/Z
isomers in 83% yield, without any evidence of products from
cyclisation or trapping by chloride ion. However, treatment
of 16 with SnCl4 at room temperature for 14 hours forms
exclusively the cyclisation products 18 and 19 in 80% combined
yield (18:19 = 1:1).
Scheme 4
the usual conditions gave the linked bicyclic aldehyde 11 (3 dia-
stereomers, 80:12:8 ratio by proton NMR) as the only isolable
product.
1816
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
Scheme 8
introducing further functionality into the system, it is well pre-
cedented that a substituent at the 6-position of a pyranyl ring
system can exert a substantial degree of diastereocontrol in
anomeric oxygen to carbon rearrangements.6–9 The synthesis of
27 proceeds from acrolein dimer 28 via reduction with LiAlH4
to give the alcohol 29 in 85% yield, followed by formation of the
unstable tosylate 30, in 75% yield, by treatment with tosyl chlor-
ide and pyridine (Scheme 9). Copper iodide catalysed displace-
Scheme 6
Intermediate carbocation 20 is presumably the common pre-
cursor to both 18/19 and 17. It is interesting to note that the
moderate diastereoselectivity seen in other rearrangements is
not observed in this case. Regeneration of intermediate 20 by
treating the alkenols 17 with trifluoromethanesulfonic acid in
dichloromethane at room temperature leads to clean form-
ation of an equal quantity of the bicycles 18 and 19 in 97%
combined yield.
In order to investigate still greater lengths of carbon chain
linker, alkenol 21 was synthesised (via three-step homologation
of 5-methylhex-5-en-1-ol) and tetrahydropyranylated to give
ether 22 (Scheme 7). Upon exposure to tin tetrachloride, 22
Scheme 9
ment of the tosylate by phenyllithium gave the dihydropyran 31
in an unoptimised 37% yield, accompanied by small amounts
of the product resulting from attack by iodide ion. Coupling of
31 with the alkenol 12 under standard acid catalysed conditions
gave separable trans-27 and cis-27 in 57% and 34% yield respec-
tively. Tin tetrachloride promoted 1,6 rearrangement of trans-
27 is accompanied by clean 5-member ring closure to give
bicyclic ethers 32 in 76% isolated yield, in a 3:1 diastereoiso-
meric ratio. Remarkably, rearrangement of cis-27 also gives
ethers 32 (59%), in a 3:1 ratio! In each case only two of the
possible four diastereomers are formed, and on the basis of
extensive precedent,15 the ethers 32 are both assigned the trans-
configuration across the pyran ring, and are therefore epimeric
at the tetrahydrofuran ring quaternary centre. The identical
ring stereoselectivity in the rearrangement of both cis- and
trans-27 is discussed in the following section.
Scheme 7
rearranges in a 1,8 sense to give two alkenols 23 and 24 as the
major products in 75% combined yield (2:3 ratio, stereo-
chemistry not determined). In this case formation of a bicyclic
product was not observed, presumably due to the unfavoured
nature of the required 7 member ring cyclisation.
We have discovered that compounds with anomeric leaving
groups other than simple ether linkages also undergo oxygen to
carbon rearrangement to give structurally interesting products.
For example, tetrahydropyranyl ester 25 (synthesised from
the corresponding acid) rearranges in a 1,6 sense on exposure
to tin tetrachloride to give, after intramolecular cyclisation,
lactone 26 in 55% yield (63:37 mixture of diastereoisomers)
(Scheme 8).
The extension of oxygen to carbon rearrangements to
include functionalised tetrahydropyranyl ring systems would
lead to synthetically interesting products, and in order to
investigate this we selected ( )-trans-6-benzyltetrahydropyranyl
ether 27 as a suitable rearrangement substrate. In addition to
Mechanistic studies
We turned our attention next to the detailed mechanism of the
rearrangement reaction. Three distinct possibilities present
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1817

View Article Online
Scheme 10
themselves: i. a concerted process involving simultaneous cleav-
age of the anomeric bond and formation of the carbon–carbon
bond; ii. a stepwise process of initial anomeric bond cleavage to
give a solvent-caged ion pair which rapidly recombines in a
carbon–carbon bond forming step; or iii. an intermolecular
process where anomeric bond cleavage leads to two solvent-
separated fragments which then recombine to give the products
via a carbocationic intermediate (Scheme 10).
With appropriate isotopic tagging of both ring and side chain
in the rearrangement substrate, the extent of label crossover in
the products directly reflects the degree to which mechanism
(iii) (complete scrambling) predominates over mechanisms (i)
and (ii) (no scrambling).
Based on our previous work 27 appears to be a particularly
suitable substrate, as the rearrangement of 27 is both high yield-
ing and selective. Furthermore, it was anticipated that deuter-
ium labels could be straightforwardly introduced into both
the pendent phenyl ring and the alkenol side chain without
significantly influencing the rearrangement reaction rate
through kinetic isotope effects. Indeed, the reduction of ethyl
4-methylpent-4-enoate with lithium aluminium deuteride gave
the deuterium labelled alkenol 33 in 82% yield, and copper
iodide catalysed addition of D5C6MgBr to tosylate 30 produced
the D5 labelled dihydropyran 34 in 5.3% yield (Scheme 11).
Camphorsulfonic acid catalysed coupling of the undeuterated
dihydropyran 31 to the D2 labelled alkenol 33 resulted in trans-
35 (28% yield) along with its cis counterpart, isolated in 6.5%
yield. The rearrangement products of 35 were used to aid the
identification of the crossover rearrangement products. Analo-
gous coupling of 33 and 34 gave tetrahydropyranyl ethers trans-
36 (59% yield) and cis-36 (27% yield).
With cis- and trans-isomers of both unlabelled 27 and the
deuterium labelled 36 in hand, we were in a position to begin
our crossover experiments.
As mentioned earlier, independent rearrangement of the
unlabelled trans-27 and cis-27 diastereomers gave the same
products (trans-32) with almost identical isomer distributions
(approximately 3:1); the diastereoisomeric products were par-
tially separable using LiCl doped silica column chromato-
graphy, but the relative stereochemistry of the epimeric centre
Scheme 11
could not be determined. The non-stereospecific nature of the
reaction suggests that the reactions proceed through similar
intermediates (an oxonium ion or similar species) which elimin-
ates the possibility of concerted anomeric displacement [mech-
anism (i)]. Two crossover experiments were conducted with
the aim of distinguishing between mechanisms (ii) and (iii):
equimolar mixtures of a) the unlabelled cis-27 and the deuter-
ium labelled cis-36 acetals, and b) the unlabelled cis-27 and the
labelled trans-36 acetals, were treated with tin tetrachloride
1818
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
Scheme 12
Scheme 13
and the products isolated (Scheme 12). Proton NMR analysis
the solvent cage after fragmentation had occurred and levels of
revealed that the reactions had given the usual 1,7 anomeric
oxygen to carbon rearrangement coupled with 5-member ring
cyclisation. The products had identical spectra to those
observed for rearrangement of the unlabelled acetals, the
diastereoisomeric ratio being approximately 3:1 in each case,
but with altered integration as expected from deuterium label-
ling. Mass spectrometric analysis (FIB) of both mixtures of
products gave a complicated pattern where MHϩ ions for the
species 32, 37, 38 and 39 were present with significant relative
abundance.
There was almost complete crossover, as determined by the
abundance of the unlabelled 32 and doubly labelled 39 ions
compared with the partially labelled 37 and 38 ions. On the
basis of this result, we propose that the rearrangement proceeds
in two stages: fast (and possibly reversible) fragmentation (with
k1 ≈ kЈ1) into an oxonium ion (or equivalent species) and the
alkenol (with the oxygen bound as a tin alkoxide), followed by a
much slower (and essentially irreversible) carbon–carbon bond
forming process (k2) (Scheme 13). If k2 was very large then
carbon–carbon bond formation would proceed rapidly within
crossover would be minimal. However, this step appears to be
sufficiently slow to allow for diffusion through the solution, and
hence intermolecular crossover occurs. Finally, similar levels of
crossover were observed in the rearrangement of a mixture
of unlabelled cis and the labelled trans species suggest that
k1(trans) and k1(cis) are of similar magnitude, possibly as a
result of the reversibility of the k1 step, and are in any case large
compared with k2 (Scheme 13).
Whilst explaining the observed results, it should be noted
that the mechanism proposed above does not take into account
any reversibility of the initial fragmentation, or retardation of
reaction rates by kinetic isotope effects. However, it is unlikely
that either of these phenomena have significant influence on the
crucial carbon–carbon bond forming step.
Conclusions
We have demonstrated that the oxygen to carbon rearrange-
ment of anomerically linked alkenes can be used in the efficient
synthesis of an interesting range of ether ring systems bearing
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1819

View Article Online
carbon substituents adjacent to the heteroatom. Furthermore,
we have proved that the reaction proceeds by an intermolecular
mechanism. In the following paper we discuss our related find-
ings on the synthesis of monocyclic and fused ring polycyclic
alkenols via the intramolecular ring-opening cyclisation of
anomerically linked alkenes.
1040 (C–O); δH (600 MHz; CDCl3): 3.94 (1H, dd, J 10.6 and
2.2, CHHO), 3.61 (3H, m, OH, CHHOH and OCH), 3.46–3.32
(2H, m, CHHOH and CHHO), 2.12 (1H, dd, J 15.0 and 9.3,
OCHCHH), 1.99 (1H, dd, J 15.0 and 1.7, OCHCHH), 1.89–
1.78 (1H, m, CHH), 1.57 (3H, s, CH3), 1.54–1.23 (5H, m,
2 × CH2 and CHH); δC (150 MHz; CDCl3): 75.0 (OCH), 73.1
(CCH3), 71.5 (CH2O), 68.2 (CH2OH), 48.6 (CH2CCl), 32.5
(CH2CH), 25.9 (CH3), 25.3 (CH2CH2O), 23.4 (CH2CH2CH);
m/z (CI) 215 (10%), 193 (100%, MHϩ), 179 (34%). Found (CI):
MHϩ 193.0999. C9H17O2ClHϩ requires 193.0995. Data for 4,
characterised as a mixture of diastereoisomers in a 2:1 ratio by
integration of the CHO doublets at δH = 9.62 (minor isomer)
and 9.58 (major isomer): νmax (thin film)/cmϪ1 2929, 2842,
Experimental
All reactions were carried out under an atmosphere of argon,
and those not involving aqueous reagents were carried out in
oven-dried glassware, cooled under vacuum. Diethyl ether and
tetrahydrofuran were distilled over sodium benzophenone
ketyl; dichloromethane, methanol and toluene were distilled
over calcium hydride. All other solvents and reagents were used
as supplied, unless otherwise stated. Flash column chromato-
graphy was carried out using Merck Kieselgel (230–400 mesh).
Analytical thin layer chromatography was performed on glass
plates precoated with Merck Kieselgel 60 F254, and visualised
under ultra-violet irradiation, or by staining with aqueous
acidic ammonium molybdate() or acidic potassium man-
ganate(). Microanalyses were performed in the micro-
analytical laboratories at the Department of Chemistry,
Lensfield Road, Cambridge. Optical rotations were measured
on an Optical Activity AA-1000 polarimeter. Infra-red spectra
were obtained on Perkin-Elmer 983G or FTIR 1620 spectro-
meters, from a thin film deposited onto a sodium chloride plate
from dichloromethane. Proton NMR spectra were recorded in
CDCl3, on Bruker AC-200, Bruker DPX-200, Bruker AM-400,
Bruker DPX-400 or Bruker DPX-600 spectrometers, at 200,
400 or 600 MHz, with residual chloroform as the internal refer-
ence (δH = 7.26 ppm). 13C NMR spectra were recorded in
CDCl3, on the same spectrometers, at 50, 100 or 150 MHz, with
the central peak of chloroform as the internal reference. Mass
spectra and accurate mass data were obtained on Micromass
Platform LC-MS, Kratos MS890MS or Bruker BIOAPEX 4.7
T FTICR spectrometers, and at the EPSRC Mass Spectrometry
Service, by electron ionisation, chemical ionisation or fast
atom/ion bombardment techniques. DEPT135 and two dimen-
sional (COSY, HMQC, HMBC) NMR spectroscopy were used,
where appropriate, to aid in the assignment of signals in the
proton and 13C NMR spectra.
1723 (C᎐O), 1084, 1045 (C–O); δ (400 MHz; CDCl3): 9.62
᎐
H
(1H minor, d, J 1.6, CHO), 9.58 (1H major, d, J 2.2, CHO),
3.94–3.89 (1H major, m, CHHO), 3.87–3.83 (1H minor,
CHHO), 3.42–3.20 (2H major and 2H minor, m, CHHO and
OCH), 2.55 (1H major and 1H minor, m, CHCH3), 1.98–1.23
(8H major and 8H minor, m, 4 × CH2), 1.10 (3H minor, d,
J 7.1, CH3), 1.08 (3H major, d, J 7.0, CH3); δC (100 MHz;
CDCl3): 205.0 (CHO, minor), 204.8 (CHO, major), 75.2
(OCH, minor), 75.0 (OCH, major), 68.3 (CH2O, major and
minor), 43.5 (CHCH3, minor), 42.7 (CHCH3, major), 37.6
(CH2, major and minor), 32.2 (CH2, minor), 32.1 (CH2,
major), 25.9 (CH2, major and minor), 23.4 (CH2, major
and minor), 13.8 (CH3, minor), 13.5 (CH3, major); m/z (CI)
157 (100%, MHϩ). Found (CI): MHϩ 157.1231. C9H16O2Hϩ
requires 157.1229.
Trimethyl[2-(tetrahydropyran-2Ј-yloxymethyl)allyl]silane 7
To a stirred solution of 6 (140 mg, 0.98 mmol) and camphor-
sulfonic acid (10 mg) in dichloromethane (5 mL) at 0 ЊC was
added 3,4-dihydro-2H-pyran (98 mg, 1.18 mmol) drop-wise via
syringe. After stirring for 10 minutes at this temperature the
light pink reaction mixture was diluted with ether (20 mL),
washed with saturated sodium bicarbonate (20 mL) and brine
(20 mL), dried (K2CO3), filtered and concentrated in vacuo to
give a brown oil. Purification by flash column chromatography
eluting with 10% diethyl ether–40/60 petroleum ether gave 7
(112 g, 50%) as a colourless oil. νmax (thin film)/cmϪ1 3075, 2948,
2873 (C–H), 1641 (C᎐C), 1085, 1036 (C–O); δ (400 MHz;
᎐
H
CDCl ): 4.93–4.91 (1H, m, C᎐CHH), 4.69–4.61 (2H, m, CH
᎐
3
and C᎐CHH), 4.21–3.80 (3H, m, CHHO and OCH ), 3.56–
᎐
2
2-Chloro-2-methyl-3-(tetrahydropyran-2Ј-yl)propan-1-ols 2 and
3, and 2-methyl-3-(tetrahydropyran-2Ј-yl)propionaldehyde 4
3.47 (1H, m, CHHO), 1.90–1.24 (8H, m, 4 × CH2), 0.03 (9H,
s, Si(CH3)3); δC (100 MHz; CDCl3): 143.7 (quat. C), 108.4
(C᎐CH ), 97.7 (CH), 70.7 (CH ), 62.0 (CH ), 30.5 (CH ), 25.4
᎐
2
2
2
2
To a stirred solution of 1 (302 mg, 1.94 mmol) in dichloro-
methane (3 mL) at Ϫ30 ЊC was added a solution of tin tetra-
chloride in dichloromethane (1.0 M, 6.98 mL, 6.98 mmol)
drop-wise via syringe. After stirring at Ϫ30 ЊC for 15 minutes
the golden brown reaction mixture was quenched by the addi-
tion of aqueous sodium hydroxide solution (2.5 M, 2 mL),
diluted with dichloromethane (10 mL), washed with brine (10
mL), dried (MgSO4), filtered and concentrated in vacuo to leave
a yellow oil. Purification by flash column chromatography, elut-
ing with 20% to 50% diethyl ether–40/60 petroleum ether isol-
ated first 4 (80 mg, 26%), then 2 (157 mg, 42%) and finally 3 (62
mg, 17%) as colourless oils. Data for 2: νmax (thin film)/cmϪ1
3414 (br, O–H), 2929, 2852, 1084, 1045 (C–O); δH (600 MHz;
CDCl3): 3.92 (1H, dd, J 11.3 and 3.5, CHHO), 3.76–3.70 (2H,
m, OH and CHHOH), 3.62 (1H, m, CH), 3.46–3.42 (2H,
m, CHHOH and CHHO), 1.99 (1H, dd, J 15.7 and 9.1,
CHCHHC), 1.82–1.80 (1H, m, CHH), 1.74 (1H, d, J 15.7,
CHCHHC), 1.55 (3H, s, CH3), 1.53–1.42 (4H, m, 2 × CH2),
1.34–1.28 (1H, m, CHH); δC (150 MHz; CDCl3): 74.8 (CH),
71.5 (CCl), 69.3 (CH2O), 68.2 (CH2OH), 47.3 (CHCH2C), 32.2
(CH2CH2CH), 29.8 (CH3), 25.4 (CH2CH2O), 23.3 (CH2CH2-
CH); m/z (CI) 215 (16%), 193 (100%, MHϩ), 179 (20%). Found
(CI): MHϩ 193.0996. C9H17O2ClHϩ requires 193.0995. Data for
3: νmax (thin film)/cmϪ1 3472 (br, O–H), 2930, 2852 (C–H), 1079,
(CH2), 23.3 (CH2), 19.4 (CH2), Ϫ1.4 (Si(CH3)3); m/z (CI)
251 (30%), 229 (100%, MHϩ). Found (CI): MHϩ 229.1630.
C12H24SiO2Hϩ requires 229.1624.
2-(Tetrahydropyran-2Ј-ylmethyl)prop-2-en-1-ol 9
To a stirred solution of 7 (72 mg, 0.32 mmol) in dichloro-
methane (0.6 mL) at Ϫ30 ЊC was added tin tetrachloride (0.13
mL, 1.14 mmol) drop-wise via syringe. After stirring at Ϫ30 ЊC
for 15 minutes the golden brown reaction mixture was
quenched by the addition of sodium hydroxide solution (2.5
M, 2 mL), diluted with dichloromethane (10 mL), washed
with brine (10 mL), dried (MgSO4), filtered and concentrated
in vacuo to leave a yellow oil. Purification by flash column
chromatography, eluting with 30% to 60% ether–40/60 petrol-
eum ether gave 9 (21 mg, 43%) as a colourless oil. νmax (thin
film)/cmϪ1 3420 (br, O–H), 2936, 2850 (C–H), 1648 (C᎐C),
᎐
1086, 1041 (C–O); δ (600 MHz; CDCl ): 5.05 (1H, s, C᎐CHH),
᎐
H
3
4.89 (1H, s, C᎐CHH), 4.05 (2H, s, CH OH), 3.99 (1H, d, J 11.2,
᎐
2
CHHO), 3.44–3.41 (2H, m, CHHO and OCH), 3.26 (1H,
s, OH), 2.31–2.24 (2H, m, CHCH2C), 1.84–1.25 (6H, m,
3 × CH2); δC (150 MHz; CDCl ): 146.4 (C᎐CH ), 113.4
᎐
3
2
(C᎐CH ), 77.7 (OCH), 68.6 (CH ), 68.5 (CH ), 41.2 (CH ),
᎐
2
2
2
2
31.6 (CH2), 25.7 (CH2), 23.4 (CH2); m/z (CI) 179 (100%,
1820
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
MNaϩ). Found (CI): MNaϩ 179.1052. C9H16O2Naϩ requires
179.1048.
cmϪ1 3078, 2980, 2937, 1737, 1651, 1054, 1031; δH (200 MHz;
CDCl ): 4.73 (1H, s, C᎐CHH), 4.69 (1H, s, C᎐CHH), 4.13 (2H,
᎐
᎐
3
q, J 7.1, CH3CH2), 2.33–2.49 (4H, m, 2 × CH2), 1.73 (3H, d,
J 0.4, CH3C), 1.25 (3H, t, J 7.1, CH3CH2); δC (50 MHz; CDCl3):
2-(Cyclopent-1Ј-enylmethoxy)tetrahydropyran 10
173.1 (CO), 144.0 (C᎐CH ), 110.2 (C᎐CH ), 60.2 (OCH ), 32.6
᎐
᎐
2
2
2
To a stirred solution of cyclopentenylmethanol (3.13 g, 31.9
mmol) and camphorsulfonic acid (10 mg) in dichloromethane
(10 mL) at 0 ЊC was added 3,4-dihydro-2H-pyran (2.95 g, 35.1
mmol) drop-wise via syringe. After stirring for 30 minutes at
ambient temperature the light pink reaction mixture was
diluted with ether (20 mL), washed with saturated sodium
bicarbonate (20 mL) and brine (20 mL), dried (K2CO3), filtered
and concentrated in vacuo to give a brown oil. Purification by
flash column chromatography eluting with 15% diethyl ether–
40/60 petroleum ether gave 10 (5.1 g, 87%) as a colourless oil.
νmax (thin film)/cmϪ1 3043, 2938, 2846, 1657 (C᎐C); δ (400
(CH2), 32.6 (CH2), 22.3 (CH3), 14.1 (CH3); m/z (CI) 143 (100%,
MHϩ). Found (CI): MHϩ 143.1095. C8H14O2Hϩ requires
143.1072.
4-Methylpent-4-en-1-ol 12
To a stirred solution of ethyl 4-methylpent-4-enoate (2.0 g, 14.0
mmol) in ether (50 mL) at 0 ЊC was added lithium aluminium
hydride (2.0 M solution in ether, 7.0 mL, 14.0 mmol) drop-wise
via syringe over a period of 5 minutes. After stirring for 15
minutes the highly viscous reaction mixture was cooled to 0 ЊC
and quenched by the cautious addition of water (10 mL) and
aqueous sulfuric acid (1.5 M, 5 mL). The organic residue was
extracted with ether (3 × 40 mL) and the combined fractions
washed with brine (100 mL), dried (MgSO4), filtered and con-
centrated in vacuo to leave a colourless oil. Purification by flash
column chromatography eluting with 25% ethyl acetate–40/60
petroleum ether gave 12 (1.29 g, 93%) as a colourless oil. δH (400
᎐
H
MHz; CDCl ): 5.58–5.57 (1H, m, C᎐CH), 4.56 (1H, t, J 3.3,
᎐
3
OCHO), 4.22–4.15 (1H, m, OCHHC), 4.01–3.94 (1H, m,
OCHHC), 3.87–3.76 (1H, m, CHHO), 3.49–3.38 (1H, m,
CHHO), 2.30–1.43 (12H, m, 6 × CH2); δC (100 MHz; CDCl3):
141.3 (C᎐CH), 126.9 (C᎐CH), 97.5 (OCHO), 65.6 (CH ), 61.8
᎐
᎐
2
(CH2), 32.9 (CH2), 32.2 (CH2), 30.5 (CH2), 25.4 (CH2), 23.2
(CH2), 19.3 (CH2); m/z (CI) 205 (100%, MNaϩ). Found (CI):
MNaϩ 205.1206. C11H18O2Naϩ requires 205.1205.
MHz; CDCl ): 4.64–4.62 (2H, m, C᎐CH ), 3.54–3.50 (2H, m,
᎐
3
2
HOCH2), 3.18 (1H, s, OH), 2.05–1.97 (2H, m, CH2CH2C), 1.66
(3H, s, CH3), 1.70–1.55 (2H, m, CH2CH2CH2); δC (100 MHz;
2-(Tetrahydropyran-2Ј-yl)cyclopentylmethanal 11
CDCl ): 145.3 (C᎐CH ), 109.9 (C᎐CH ), 62.1 (HOCH ), 33.9
᎐
᎐
3
2
2
2
To a stirred solution of 10 (0.10 g, 0.55 mmol) in dichloro-
methane (6 mL) at Ϫ30 ЊC was added a solution of tin tetra-
chloride in dichloromethane (1.0 M, 1.98 mL, 1.98 mmol)
drop-wise via syringe. After stirring at Ϫ30 ЊC for 15 minutes
the golden brown reaction mixture was quenched by the addi-
tion of sodium hydroxide solution (2.5 M, 2 mL), diluted with
dichloromethane (10 mL), washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo to leave a yellow
oil. Purification by flash column chromatography, eluting with
8% diethyl ether–40/60 petroleum ether gave 11, tentatively
assigned as a mixture of three diastereoisomers in a ratio
80:12:8 as determined by integration of the CHO doublets at
9.62 (major isomer), 9.61 and 9.59 (minor isomers 1 and 2) in
the 400 MHz proton NMR spectrum (63 mg, 63%) as a colour-
(CH2), 30.4 (CH2), 22.2 (CH3).
2-(4Ј-Methylpent-4Ј-enyloxy)tetrahydropyran 13
To a stirred solution of 12 (0.55 g, 5.5 mmol) and camphor-
sulfonic acid (5 mg) in dichloromethane (10 mL) at ambient
temperature was added 3,4-dihydro-2H-pyran (0.54 g, 5.5
mmol) drop-wise via syringe. After stirring for 30 minutes the
reaction mixture was diluted with ether (20 mL), washed with
saturated sodium bicarbonate (20 mL) and brine (20 mL), dried
(K2CO3), filtered and concentrated in vacuo to give a colourless
oil. Purification by flash column chromatography eluting with
10% ethyl acetate–40/60 petroleum ether gave 13 (0.52 g, 51%)
as a colourless oil. νmax (thin film)/cmϪ1 3073, 2938, 2870, 2730,
2655, 1649 (C᎐C); δ (400 MHz; CDCl ): 4.53 (2H, s, C᎐CH ),
less oil. νmax (thin film)/cmϪ1 2936, 2852, 1721 (C᎐O), 1088, 1050
᎐
᎐
᎐
H
3
2
(C–O); δH (400 MHz; CDCl3): 9.62 (1H major, d, J 2.8, CHO),
9.61 (1H minor 1, d, J 2.6, CHO), 9.59 (1H minor 2, d, J 2.1,
CHO), 3.97–3.91 (1H major, m, CHHO), 3.36 (1H major, td,
J 11.5 and 2.4, OCH), 3.07–3.02 (1H major, m, CHHO), 2.67–
2.63 (1H major, m, CHCHO), 2.17–1.13 (13H major, m, CH
and 6 × CH2); δC (100 MHz; CDCl3): 204.5 (CHO, major), 81.5
(OCH, major), 68.6 (CH2O, major), 55.6 (CH, major), 47.4
(CH, major), 30.8 (CH2, major), 29.1 (CH2, major), 26.7 (CH2,
major), 26.1 (CH2, major), 25.3 (CH2, major), 23.5 (CH2,
major); further signals for the minor isomers could not be
resolved; m/z (CI) 205 (100%, MNaϩ), 183 (45%). Found (CI):
MNaϩ 205.1209. C11H18O2Naϩ requires 205.1205.
4.41 (1H, t, J 3.2, CH), 3.74–3.51 (2H, m, CHHO and OCHH),
3.37–3.15 (2H, m, CHHO and OCHH), 1.97–1.89 (2H, m,
CH2CH2C), 1.56 (3H, s, CH3), 1.69–1.32 (8H, m, 4 × CH2);
δC (100 MHz; CDCl ): 144.8 (C᎐CH ), 109.7 (C᎐CH ), 98.4
᎐
᎐
3
2
2
(CH), 66.7 (CH2), 61.6 (CH2), 34.1 (CH2), 30.5 (CH2), 27.6
(CH2), 25.4 (CH2), 22.1 (CH3), 19.3 (CH2); m/z (CI) 185
(100%, MHϩ). Found (CI): MHϩ 185.1571. C11H20O2Hϩ
requires 185.1542.
2-(2Ј-Methyltetrahydrofuran-2Ј-ylmethyl)tetrahydropyran 14
To a stirred solution of 13 (100 mg, 0.54 mmol) in dichloro-
methane (3 mL) at Ϫ30 ЊC was added a solution of tin tetra-
chloride in dichloromethane (1.0 M, 1.1 mL, 1.1 mmol)
drop-wise via syringe. After stirring at Ϫ30 ЊC for 15 minutes
the light brown reaction mixture was quenched by the addition
of sodium hydroxide solution (2.5 M, 2.0 mL), diluted with
dichloromethane (10 mL), washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo to leave a yellow
oil. Purification by flash column chromatography eluting with
25% to 50% diethyl ether–40/60 petroleum ether gave 14, as a
9:2 mixture of diastereoisomers by integration of the CH3 sing-
lets at 1.21 (major) and 1.16 (minor) in the proton NMR, and
by GC analysis (2 peaks, retention times 12.52 minutes and
12.78 minutes in a ratio of 2:9) (93 mg, 93%) as a colourless oil.
νmax (thin film)/cmϪ1 2950, 2850, 1084, 1051, 1009; δH (600
MHz; CDCl3): 3.92–3.89 (1H major and 1H minor, m,
CH2CHHO), 3.82–3.72 (2H major and 2H minor, m, COCH2),
3.42–3.36 (2H major and 2H minor, m, CH2CHHO and CH),
Ethyl 4-methylpent-4-enoate
A solution of methallyl alcohol (10 mL, 8.57 g, 0.12 mol) and
propanoic acid (0.6 mL) in triethyl orthoacetate (150 mL) was
heated at reflux for 1 h. Ethanol was removed by fractional
distillation at atmospheric pressure through a Vigreaux column,
and heating was continued for a further hour. The reaction
mixture was cooled to ambient temperature and washed with
cold water (500 mL) containing camphorsulfonic acid (0.4 g).
The organic layer was separated and the aqueous layer
extracted with ether (2 × 200 mL). The combined organic
extracts were washed with saturated sodium bicarbonate
(2 × 300 mL) and brine (300 mL), dried (MgSO4), filtered and
concentrated in vacuo to give a yellow oil. Distillation over a
short path gave ethyl 4-methylpent-4-enoate as a colourless oil
(11.97 g, 71%), bp 156–160 ЊC (760 mmHg); νmax (thin film)/
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1821

View Article Online
1.96–1.23 (12H major and 12H minor, m, 6 × CH2), 1.21 (3H,
s, CH3), 1.16 (3H minor, s, CH3); δC (150 MHz; CDCl3) 81.9
(CCH3, minor), 81.8 (CCH3, major), 75.3 (CH, major), 75.1
(CH, minor), 68.1 (CH2CH2O, major), 66.6 (COCH2, major),
47.5 (CH2, minor), 47.3 (CH2, major), 38.2 (CH2, major), 36.1
(CH2, minor), 33.2 (CH2, major), 27.3 (CH3, minor), 25.9 (CH2,
major), 25.8 (CH2, major), 25.4 (CH3, major), 23.7 (CHCH2C,
major); further signals for the minor isomer could not be
resolved; m/z (CI) 269 (70%), 185 (100%, MHϩ), 85 (30%).
Found (CI): MHϩ 185.1542. C11H20O2Hϩ requires 185.1542.
by integration of the signals in the 400 MHz proton NMR
spectrum at δH = 5.23 (major) and 5.18 (minor) (86 mg, 86%)
as a colourless oil. νmax (thin film)/cmϪ1 3396 (br, O–H), 2935,
2856, 2738, 1666 (C᎐C); δH (400 MHz; CDCl3) 5.23 (1H major,
᎐
t, J 7.3, C᎐CH), 5.18 (1H minor, obs. t, J 7.1, C᎐CH), 3.96–3.90
᎐
᎐
(1H major and 1H minor, m, CHHO), 3.63–3.53 (2H major
and 2H minor, m, CHHO and CHHOH), 3.46–3.30 (2H major
and 2H minor, m, OCH and CHHOH), 1.66 (3H major and
3H minor, s, CH3), 2.47–1.16 (12H major and 12H minor, m,
6 × CH2); δC (100 MHz; CDCl ): 132.4 (C᎐CH , major and
᎐
3
3
minor), 126.7 (C᎐CH, major), 126.4 (C᎐CH, minor), 76.3
᎐
᎐
(OCH, minor), 76.0 (OCH, major), 68.5 (CH2, major), 68.1
(CH2, minor), 62.7 (CH2, major), 61.0 (CH2, minor), 46.8
(CH2, major), 38.8 (CH2, minor), 32.6 (CH2, major and
minor), 31.7 (CH2, major and minor), 26.0 (CH2, major
and minor), 24.7 (CH2, major and minor), 23.5 (CH2, major
and minor), 16.5 (CCH3, major and minor); m/z (CI)
199 (100%, MHϩ). Found (CI): MHϩ 199.1699. C12H22O2Hϩ
requires 199.1698.
2-(5Ј-Methylhex-5Ј-enyloxy)tetrahydropyran 16
To a stirred solution of 5-methylhex-5-en-1-ol (1.5 g, 10.4
mmol) and camphorsulfonic acid (5 mg) in dichloromethane
(10 mL) at ambient temperature was added 3,4-dihydro-2H-
pyran (0.88 g, 10.4 mmol) drop-wise via syringe. After stirring
for 30 minutes the reaction mixture was diluted with ether (20
mL), washed with saturated sodium bicarbonate (20 mL) and
brine (20 mL), dried (MgSO4), filtered and concentrated in
vacuo to give a colourless oil. Purification by flash column
chromatography eluting with 10% ethyl acetate–40/60 petrol-
eum ether gave 16 (1.66 g, 81%) as a colourless oil. νmax (thin
film)/cmϪ1 3073, 2944, 2870, 2729, 2656, 1649 (C᎐C); δ (400
2-(2Ј-Methyltetrahydropyran-2Ј-ylmethyl)tetrahydropyrans 18
and 19
From 16. To a stirred solution of 16 (150 mg, 0.76 mmol) in
dichloromethane (6 mL) at ambient temperature was added a
1.0 M solution of tin tetrachloride in dichloromethane (2.73
mL, 2.73 mmol) drop-wise via syringe. After stirring at ambient
temperature for 14 hours the colourless reaction mixture was
quenched by the addition of sodium hydroxide solution (2.5 M,
2 mL), diluted with dichloromethane (10 mL), washed with
brine (10 mL), dried (MgSO4), filtered and concentrated in
vacuo to leave crude 18 and 19 as a 1:1 mixture of diastereo-
isomers by integration of the CH3 singlets at δH = 1.23 and 1.11
in the 600 MHz proton NMR, as a yellow oil. Purification by
flash column chromatography, eluting with 10% diethyl ether–
40/60 petroleum ether, gave 27 and 28 (120 mg, 80%). νmax (thin
film)/cmϪ1 2933, 2855, 2737, 2668, 1027 (C–O); m/z (CI)
199 (100%, MHϩ). Found (CI) MHϩ 199.1698. C12H22O2Hϩ
requires 199.1698. Further flash column chromatography,
eluting with 10% diethyl ether–40/60 petroleum ether, allowed
separation of a small sample of 27 for spectroscopic analysis.
Data for 18: δH (600 MHz; CDCl3): 3.93–3.91 (1H, m, CHHO),
3.67–3.59 (2H, m, OCH and CHHO), 3.49–3.45 (1H, m,
COCHH), 3.40 (1H, td, J 11.5 and 2.5, COCHH), 1.81–1.37
(14H, m, 7 × CH2), 1.23 (3H, s, CH3); δC (150 MHz; CDCl3):
74.5 (OCH), 72.7 (CCH3), 68.2 (CH2), 61.5 (CH2), 45.7 (CH2),
36.7 (CH2), 33.4 (CH2), 26.0 (CH2), 25.9 (CH2), 23.9 (CH2),
23.6 (CH3), 19.3 (CH2). Data for 19, isolated as a mixture with
27: δH (600 MHz; CDCl3): 3.96–3.92 (1H, m, CHHO), 3.69–
3.63 (2H, m, OCH and CHHO), 3.43–3.37 (2H, m, COCH2),
1.80–1.34 (14H, m, 7 × CH2), 1.11 (3H, s, CH3); δC (150 MHz;
CDCl3): 74.2 (CH), 72.5 (CCH3), 68.1 (CH2), 61.3 (CH2), 45.7
(CH2), 34.2 (CH2), 33.3 (CH2), 26.0 (CH2), 25.9 (CH2), 23.7
(CH2), 19.4 (CH3).
᎐
H
MHz; CDCl ): 4.64–4.62 (2H, m, C᎐CH ), 4.52 (1H, t, J 3.1,
᎐
3
2
CH), 3.86–3.61 (2H, m, CHHO and OCHH), 3.49–3.28 (2H,
m, CHHO and OCHH), 1.98 (2H, t, J 7.4, CH2CCH2), 1.65
(3H, s, CH3), 1.79–1.40 (10H, m, 5 × CH2); δC (100 MHz;
CDCl ): 145.5 (C᎐CH ), 109.8 (C᎐CH ), 98.6 (CH), 67.2 (CH ),
᎐
᎐
3
2
2
2
62.0 (CH2), 37.4 (CH2), 30.6 (CH2), 29.2 (CH2), 25.4 (CH2),
24.1 (CH2), 22.1 (CH3), 19.5 (CH2); m/z (CI) 199 (100%, MHϩ),
102 (61%), 85 (35%). Found (CI): MHϩ 199.1698. C12H22O2Hϩ
requires 199.1698.
5-Methylhex-5-en-1-ol
To a stirred solution of zirconocene dichloride (1.75 g, 6.0
mmol) in dichloroethane (40 mL) at ambient temperature was
added a solution of trimethylaluminium in hexanes (2.0 M,
37.5 mL, 75.0 mmol) drop-wise via syringe. After stirring for
10 minutes a solution of hexyn-1-ol (2.45 g, 25.0 mmol) in
dichloroethane (20 mL) was cautiously added drop-wise via
syringe. The yellow reaction mixture was stirred for 22 hours at
ambient temperature and quenched by the addition of satur-
ated sodium bicarbonate (4 mL) at 0 ЊC. The resulting slurry
was diluted with brine (50 mL), extracted with ether (5 × 50
mL) and the combined organic extracts dried (MgSO4), filtered
and concentrated in vacuo to give a yellow oil. Purification by
flash column chromatography, eluting with 50% diethyl ether–
40/60 petroleum ether gave 5-methylhex-5-en-1-ol (2.85 g,
100%) as a colourless oil. νmax (thin film)/cmϪ1 3358 (br, O–H),
3073, 2932, 1649 (C᎐C); δH (400 MHz; CDCl3): 4.65–4.62 (2H,
᎐
m, C᎐CH ), 3.55 (2H, t, J 6.2, HOCH ), 2.96 (1H, s, OH), 1.97
᎐
2
2
(2H, t, J 7.2, CH2CH2C), 1.65 (3H, s, CH3), 1.59–1.39 (4H,
m, HOCH2CH2 and CH2CH2C); δC (100 MHz; CDCl3): 145.6
(C᎐CH ), 109.8 (C᎐CH ), 62.3 (HOCH ), 37.4 (CH ), 32.2
(CH2), 23.6 (CH2), 22.1 (CH3).
᎐
᎐
2
2
2
2
From 17. To a stirred solution of 17 (51 mg, 0.253 mmol)
in dichloromethane (2 mL) at Ϫ30 ЊC was added trifluoro-
methanesulfonic acid (0.022 mL, 0.253 mmol) drop-wise via
syringe. The reaction mixture was allowed to warm to ambient
temperature, stirred for 16 hours, then diluted with ether (10
mL), washed with saturated sodium bicarbonate (10 mL)
and extracted into ether (3 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo
to leave a colourless oil (49 mg, 97%, 1:1 mixture of diastereo-
mers) as a colourless oil. Spectroscopic data for 18 and 19 were
identical to those reported previously.
5-Methyl-6-(tetrahydropyran-2Ј-yl)hex-4-en-1-ol 17
To a stirred solution of 16 (0.10 g, 0.50 mmol) in dichloro-
methane (6 mL) at Ϫ30 ЊC was added a solution of tin tetra-
chloride in dichloromethane (1.0 M, 1.98 mL, 1.98 mmol)
drop-wise via syringe. After stirring at Ϫ30 ЊC for 10 minutes
the colourless reaction mixture was quenched by the addition
of sodium hydroxide solution (2.5 M, 2 mL), diluted with
dichloromethane (10 mL), washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo to leave a colour-
less oil. Purification by flash gel column chromatography,
eluting with 30% diethyl ether–40/60 petroleum ether gave 17,
tentatively assigned as a 3:1 mixture of E and Z stereoisomers
5-Methylhex-5-enyl toluene-p-sulfonate
To a stirred solution of 5-methylhex-5-en-1-ol (1.0 g, 8.8 mmol)
and toluene-p-sulfonyl chloride (2.7 g, 14.1 mmol) in dichloro-
1822
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
methane (15 mL) at ambient temperature was added triethyl-
amine (8 mL) in one portion. After stirring for 4 hours the
reaction mixture was washed repeatedly with 1.5 M aqueous
hydrochloric acid until the pH of the aqueous washings meas-
ured 1, dried (MgSO4), filtered and concentrated in vacuo to
leave a yellow oil. Purification by flash gel column chromato-
graphy eluting with 15% diethyl ether–40/60 petroleum ether
gave 5-methylhex-5-enyl toluene-p-sulfonate (2.24 g, 95%, con-
taining approximately 15% residual toluene-p-sulfonyl chloride
by 400 MHz proton NMR). δH (400 MHz; CDCl3): 7.71 (2H, d,
mmol) drop-wise via syringe. After stirring for 10 minutes at
ambient temperature the purple reaction mixture was diluted
with dichloromethane (10 mL), washed with saturated sodium
bicarbonate (10 mL) and brine (10 mL), dried (MgSO4), filtered
and concentrated in vacuo to give a black oil. Purification by
flash column chromatography eluting with 10% diethyl ether–
40/60 petroleum ether gave 22 (80 mg, 89%) as a colourless oil.
νmax (thin film)/cmϪ1 3073, 2936, 2656, 1650 (C᎐C), 1076 (C–O);
᎐
δH (400 MHz; CDCl ): 4.68–4.66 (2H, m, C᎐CH ), 4.57 (1H, t,
᎐
3
2
J 3.0, CH), 3.92–3.67 (2H, m, CHHO and OCHH), 3.55–3.33
(2H, m, CHHO and OCHH), 2.01 (2H, t, J 6.7, CH2CH2C),
1.70 (3H, s, CH3), 1.92–1.17 (12H, m, 6 × CH2); δC (100 MHz;
J 8.2, ArH), 7.27 (2H, d, J 8.0, ArH), 4.60 (1H, s, C᎐CHH),
᎐
4.54 (1H, s, C᎐CHH), 3.97 (2H, t, J 6.2, OCH ), 2.36 (3H, s,
᎐
2
ArCH ), 1.88 (2H, t, J 7.4, C᎐CCH ), 1.58 (3H, s, CCH ), 1.56–
CDCl ): 146.0 (C᎐CH ), 109.6 (C᎐CH ), 98.8 (CH), 67.5 (CH ),
᎐ ᎐
3 2 2 2
᎐
3
2
3
1.33 (4H, m, 2 × CH2); δC (100 MHz; CDCl3): 144.71 (quat.
62.3 (CH2), 37.7 (CH2), 30.7 (CH2), 29.6 (CH2), 27.4 (CH2),
25.9 (CH2), 25.5 (CH2), 22.3 (CH3), 19.6 (CH2); m/z (CI)
213 (100%, MHϩ). Found (CI): MHϩ 213.1855. C13H24O2Hϩ
requires 213.1855.
Ph), 144.63 (quat. Ph), 133.1 (CH), 129.8 (CH), 127.7 (C᎐CH ),
᎐
2
110.3 (C᎐CH ), 70.4 (OCH ), 36.8 (CH ), 28.2 (CH ), 23.1
᎐
2
2
2
2
(CH2), 22.0 (CH3), 21.4 (CH3).
(E)- and (Z)-6-Methyl-7-(tetrahydropyran-2Ј-yl)hept-5-en-1-ol
23, 24
6-Methylhept-6-enenitrile
To a stirred solution of 5-methylhex-5-enyl toluene-p-sulfonate
(1.1 g, 4.1 mmol, toluene-p-sulfonyl chloride present as 15%
impurity) in dimethyl sulfoxide (30 mL) at ambient temperature
was added sodium cyanide (400 mg, 8.2 mmol) in one portion.
Stirring was maintained for 24 hours before the light yellow
reaction mixture was quenched by the addition of water (30
mL) and extracted with dichloromethane (3 × 30 mL). The
combined organic extracts were washed with aqueous hydro-
chloric acid (0.1 M, 100 mL), followed by water (100 mL), dried
(MgSO4), filtered and concentrated in vacuo to give 6-methyl-
hept-6-enenitrile (0.50 g, approximately quantitative yield
based on 15% residual toluene-p-sulfonyl chloride in starting
material) as a yellow oil. δH (400 MHz; CDCl3): 4.60 (1H, s,
To a stirred solution of 22 (40 mg, 0.19 mmol) in dichloro-
methane (5 mL) at Ϫ30 ЊC was added a solution of tin tetra-
chloride in dichloromethane (1.0 M, 0.68 mL, 0.68 mmol)
drop-wise via syringe. After 10 minutes at this temperature the
reaction mixture was quenched by the addition of sodium
hydroxide solution (2.5 M, 2 mL), diluted with dichloro-
methane (10 mL), washed with brine (10 mL) and the organic
phase dried (MgSO4), filtered and concentrated in vacuo to
leave a yellow oil. Purification by flash column chromatography,
eluting with 50% diethyl ether–40/60 petroleum ether afforded
23 and 24, tentatively assigned as a 2:3 mixture of E/Z alkene
isomers by integration of the signals at 5.23 (minor) and 5.18
(major) in the proton NMR spectrum, (30 mg, 75%) as a
colourless oil. νmax (thin film)/cmϪ1 3401 (br, O–H), 2901, 2851,
C᎐CHH), 4.56 (1H, s, C᎐CHH), 2.24 (2H, t, J 6.7, NCCH ),
᎐
᎐
2
1.93 (2H, t, J 7.0, CH C᎐C), 1.59 (3H, s, CH ), 1.55–1.38 (4H,
᎐
2
3
1650 (C᎐C); δ (600 MHz; CDCl3): 5.23 (1H minor, t, J 7.1,
᎐
m, 2 × CH2); δC (100 MHz; CDCl ): 144.4 (C᎐CH ), 119.6
H
᎐
3
2
C᎐CH), 5.18 (1H major, t, J 6.9, C᎐CH), 3.94–3.89 (1H major,
᎐
᎐
(CN), 110.5 (C᎐CH ), 36.6 (CH ), 26.2 (CH ), 24.7 (CH ), 22.0
᎐
2
2
2
2
m, CHHO), 3.85–3.81 (1H minor, m, CHHO), 3.66–3.62
(2H major and 2H minor, m, CHHO and CHHOH), 3.43–3.36
(2H major and 2H minor, m, CH and CHHOH), 2.29–1.18
(17H major and 17H minor, m, CH3 and 7 × CH2); δC (150
MHz; CDCl3): 132.2 (quat. C, minor), 132.1 (quat. C, major),
(CH3), 16.8 (CH2).
6-Methylhept-6-en-1-ol 21
To a stirred solution of 1-cyano-6-methylheptene (0.50 g, 4.0
mmol) in toluene (10 mL) at Ϫ78 ЊC was added a 1 M solution
of diisobutylaluminium hydride in toluene (4.0 mL, 4.0 mmol).
Stirring was maintained for 1 hour at this temperature
before the reaction mixture was quenched by the addition of
potassium carbonate solution (5 mL). The presence of the
intermediate aldehyde was tentatively established by thin layer
chromatography (Rf = 0.7 in 30% diethyl ether–40/60 petroleum
ether), and the reaction mixture was extracted with dichloro-
methane (3 × 20 mL). After removal of the volatile components
in vacuo, ethanol (20 mL) was added followed by sodium boro-
hydride (152 mg, 4.0 mmol) and stirring was maintained for
1 hour. The reaction mixture was acidified (concentrated hydro-
chloric acid) to pH 5, extracted with dichloromethane (3 × 20
mL), and the combined organic extracts dried (MgSO4), filtered
and concentrated in vacuo to give a yellow oil. Purification by
flash column chromatography, eluting with 50% diethyl ether–
40/60 petroleum ether afforded 21 (50 mg, 10%) as a colourless
127.2 (C᎐CH, minor), 126.8 (C᎐CH, major), 76.1 (OCH,
᎐
᎐
major), 75.4 (OCH, minor), 68.6 (CH2, major), 68.2 (CH2,
minor), 62.9 (CH2OH, major and minor), 47.0 (CH2, major),
38.9 (CH2, minor), 33.1 (CH2, minor), 32.6 (CH2, major), 32.5
(CH2, minor), 31.8 (CH2, minor), 31.6 (CH2, major), 27.7
(CH2, major), 26.1 (CH2, major), 25.8 (CH2, major), 24.7 (CH2,
minor), 24.5 (CH2, minor), 24.2 (CH3, minor), 23.7 (CH2,
minor), 23.6 (CH2, major), 16.3 (CH3, major); m/z (CI) 213
(100%, MHϩ). Found (CI): MHϩ 213.1859. C13H24O2Hϩ
requires 213.1855.
4-Methylpent-4-enoic acid
To an aqueous solution of lithium hydroxide (1.7 M, 70 mL) at
0 ЊC was added dropwise a solution of ethyl 4-methylpent-4-
enoate (5.6 g, 34.9 mmol) in THF (140 mL). The reaction
mixture was allowed to warm to room temperature and stirred
vigorously for five hours. The solvent was evaporated, the
resulting aqueous solution acidified to pH 1 by the dropwise
addition of hydrochloric acid (3 M), and extracted with diethyl
ether (2 × 50 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4), filtered and concentrated
in vacuo to give a yellow oil which was purified by silica column
chromatography eluting with diethyl ether to give 4-methyl-
pent-4-enoic acid (4.0 g, 83%) as a pale yellow oil. νmax (thin
oil. δH (400 MHz; CDCl ): 4.69 (1H, s, C᎐CHH), 4.65 (1H, s,
᎐
3
C᎐CHH), 3.63 (2H, t, J 6.4, HOCH ), 2.02 (2H, t, J 6.8,
᎐
2
CH C᎐C), 1.70 (3H, s, CH ), 1.65–1.29 (6H, m, 3 × CH );
᎐
2
3
2
δC (100 MHz; CDCl ): 145.9 (C᎐CH ), 109.7 (C᎐CH ), 62.9
(HOCH2), 37.7 (CH2), 32.6 (CH2), 27.3 (CH2), 25.3 (CH2),
22.3 (CH3).
᎐
᎐
3
2
2
2-(6Ј-Methylhept-6Ј-enyloxy)tetrahydropyran 22
film)/cmϪ1 3200 (br, O–H), 2970, 1709, 1654 (C᎐C), 1438, 1376,
᎐
To a stirred solution of 21 (50 mg, 0.40 mmol) and camphor-
sulfonic acid (3 mg) in dichloromethane (2.5 mL) at ambient
temperature was added 3,4-dihydro-2H-pyran (37 mg, 0.44
1290; δH (200 MHz; CD3OD): 5.08 (1H, br s, COOH), 4.72–
4.69 (2H, m, CCH2), 3.75–3.31 (2H, m, CH2CO), 2.47–2.30
(2H, m, CH2CCH2), 1.73 (3H, s, CH3CCH2); δC (200 MHz;
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1823

View Article Online
CD3OD): 175.7 (COOH), 144.1 (CCH2), 109.4 (CCH2), 32.3
(CH2), 32.0 (CH2), 21.3 (CH3).
and 6.5, CHOCHH), 2.79 (1H, dd, J 13.6 and 7.4, PhCHH),
2.64 (1H, dd, J 13.6 and 5.9, PhCHH), 1.93–2.03 (2H, m,
CCH2), 1.71 (3H, s, CH3), 1.28–1.86 (8H, m); δC (50 MHz;
CDCl3): 145.4 (CCH2), 139.0 (q), 129.3 (CH), 128.0 (CH), 126.0
(CH), 109.8 (CCH2), 97.1 (O2CH), 69.8 (OCH), 66.2 (OCH2),
42.8 (CH2C), 34.4 (CH2), 30.9 (CH2), 29.7 (CH2), 27.6 (CH2),
22.4 (CH3), 18.2 (CH2). Further elution gave cis-27 as a colour-
less oil (0.226 g, 34%). Found: C, 79.1; H, 9.45. C18H26O2
requires C, 78.8; H, 9.55%. νmax (thin film)/cmϪ1 3064, 3028,
2941, 2861, 1648, 1495, 1453, 1435, 1373, 1190, 1151, 1070,
1030, 887, 749, 699; δH (200 MHz; CDCl3): 1.21–1.87 (8H, m),
1.72 (3H, s, Me), 2.07 (2H, br t, J 7.5, CCH2), 2.71 (1H, dd,
J 13.7 and 5.8, PhCHH), 2.96 (1H, dd, J 13.7 and 7.3,
PhCHH), 3.38 (1H, dt, J 9.6 and 7.0, OCHH), 3.48–3.61 (1H,
m, 6-H), 3.81 (1H, dt, J 9.6 and 6.7, OCHH), 4.33 (1H, dd,
Jax,ax 8.9, Jax,eq 2.3, 2-H), 4.68 (1H, br s, CCHH), 4.71 (1H, br s,
CCHH), 7.19–7.32 (5H, m, Ph); δC (50 MHz; CDCl3): 145.3
(CH), 138.9 (q), 129.4 (CH), 128.0 (CH), 126.0 (CH), 109.9
(CCH2), 102.2 (O2CH), 77.0 (OCH), 68.2 (OCH2), 42.5
(PhCH2), 34.2 (CH2), 31.1 (CH2), 30.4 (CH2), 27.6 (CH2), 22.4
(CH3), 22.1 (CH2); m/z (FIB) 273 (M ϩ H, 10%).
Tetrahydropyran-2Ј-yl 4-methylpent-4-enoate 25
3,4-Dihydro-2H-pyran (2.4 mL, 26.3 mmol) was added drop-
wise to a stirred solution of 4-methylpent-4-enoic acid (10.6 g,
5.3 mmol) and camphorsulfonic acid (0.012 g, 0.053 mmol) in
dichloromethane (10 mL) at 0 ЊC and stirred for 30 minutes
at room temperature. The reaction mixture was diluted with
diethyl ether (10 mL), washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo to give a yellow oil
which was purified by silica column chromatography, eluting
with 20% diethyl ether–40/60 petroleum ether, to give 25 (4.5 g,
40%) as a pale yellow oil. νmax (thin film)/cmϪ1 3078, 2943, 2850,
1712 (CO), 1651 (C᎐CH ); δ (200 MHz; CDCl3): 4.97–4.93
᎐
2
H
(1H, m, OCHO), 4.83–4.58 (2H, m, CH2C), 4.05–3.70 (1H,
m, ax-CH2O), 3.57–3.37 (1H, m, eq-CH2-O), 2.55–2.46 (2H, m,
CH2CO), 2.37–1.98 (2H, m, CH2C), 1.87–1.43 (6H, m), 1.74
(3H, s, CH3); δC (200 MHz; CDCl3): 178.8 (CO), 143.7 (CCH2),
110.4 (CCH2), 65.8 (CH2O), 62.8 (CH2CO), 32.3 (CH2C), 30.6
(CH2), 25.4 (CH2), 19.64 (CH2), 22.4 (CH3).
2-Hydroxymethyl-3,4-dihydro-2H-pyran 2916
2-(5Ј-Methyl-2Ј-oxotetrahydrofuran-5Ј-ylmethyl)tetrahydro-
Lithium aluminium hydride (55 mL of a 1 M solution in ether,
0.055 mol) was added slowly over 30 min to a stirred, cooled
(0 ЊC) solution of acrolein dimer 28 (11.28 g, 0.101 mol) in
anhydrous ether (50 mL), and the resultant solution was stirred
at 0 ЊC for a further 30 min, at room temperature for 1 h and
finally heated under reflux for 1 h. The mixture was cooled to
0 ЊC and ethyl acetate (20 mL) was added slowly to consume
the excess of LiAlH4. Stirring was continued as the mixture
warmed to room temperature over 30 min, and the reaction was
quenched by the careful sequential addition of water (2 mL),
sodium hydroxide (2 mL of 2.5 M) and water (6 mL), giving a
granular white solid. The solution was filtered and the residue
was washed with ether. The organic solution was washed with
water and brine, dried (MgSO4) and evaporated under reduced
pressure to give the alcohol 29 as a colourless oil (9.73 g, 85%).
νmax (thin film)/cmϪ1 3405 br s, 3059, 2924, 1650, 1449, 1241,
1068, 998, 727; δH (200 MHz; CDCl3): 6.39 (1H, br d, J 6.2,
6-H), 4.67–4.74 (1H, m, 5-H), 3.92 (1H, ddd, J 9.6, 6.6 and 3.4,
2-H), 3.55–3.77 (3H, m, CH2OH), 1.59–2.21 (4H, m); δC (50
MHz; CDCl3): 143.2 (CH), 100.7 (CH), 75.5 (OCH), 65.1
(CH2OH), 23.8 (CH2), 19.3 (CH2).
pyran 26
A solution of tin tetrachloride in dichloromethane (1.0 M,
0.032 mL) was added dropwise to a stirred solution of 25 (0.11
g, 0.59 mmol) in dichloromethane (2.5 mL) at Ϫ78 ЊC, and
stirred at this temperature for 10 minutes. The reaction mixture
was quenched by the rapid addition of an aqueous solution of
sodium hydroxide (2.5 M, 2 mL), diluted with dichloromethane
(10 mL), washed with brine (10 mL), dried (MgSO4), filtered
and concentrated in vacuo to give a brown oil. Purification by
silica column chromatography eluting with 20% diethyl ether–
40/60 petroleum ether gave 26 (0.05 g, 55%, two diastereo-
isomers ratio 5:3 by integration of the CH3 singlets at δH = 1.42
(major) and 1.38 (minor) in the proton NMR) as an orange oil.
νmax (thin film)/cmϪ1 2936, 1770 (C᎐O), 1269 (C–O); δ (200
MHz; CDCl3): 3.93–3.87 (1H, m, ax-CH2O), 3.50–3.28 (1H, m,
eq-CH2O and CHO), 2.62–2.37 (2H, m, CH2CO), 2.29–1.20
(10H, m), 1.42 (3H major, s, CH3), 1.38 (3H minor, s, CH3);
δC (200 MHz; CDCl3): 176.8 (CO), 177.2 (CO), 86.3 (quat.),
85.6 (quat.), 74.5 (OCH), 73.8 (OCH), 68.1 (CH2O THP), 46.9
(CH2CO), 46.8 (CH2CO), 34.3 (CH2), 32.7 (CH2), 32.0 (CH2),
29.0 (CH2), 25.7 (CH2), 23.4 (CH2); m/z (EI) 85 (9%), 199
(27%), 216 (100%).
᎐
H
2-[(p-Tolylsulfonyloxy)methyl]-3,4-dihydro-2H-pyran 30
Toluene-p-sulfonyl chloride (18.05 g, 95 mmol) was added to a
solution of alcohol 29 (8.39 g, 74 mmol) in anhydrous pyridine
(90 mL) at 0 ЊC under an inert atmosphere. The reaction mix-
ture was stirred at 0 ЊC for 3 h and stirred at room temperature
for 3 h, then poured onto ice (300 g). The product was extracted
with ether (2 × 200 mL) and the combined ether extracts were
washed with ice-cold hydrochloric acid (10%, 4 × 100 mL),
saturated sodium bicarbonate (3 × 100 mL), brine (100 mL)
and dried (MgSO4). Evaporation of the volatiles in vacuo and
recrystallisation of the crude product from diethyl ether gave
the tosylate 30 as pale yellow crystals (14.86 g, 75%), which were
stored at Ϫ60 ЊC. δH (200 MHz; CDCl3): 1.50–2.06 (4H, m),
2.44 (3H, s, ArCH3), 3.93–4.10 (3H, m, OCH and CH2OTs),
4.62–4.70 (1H, m, 5-H), 6.25 (1H, dt, J 6.2 and 1.8, 6-H), 7.34
(2H, d, J 8.0, ArH), 7.80 (2H, d, J 8.0, ArH); δC (50 MHz;
CDCl3): 144.9 (q), 142.9 (CH), 132.7 (q), 129.8 (CH), 127.9
(CH), 100.6 (CH), 71.9 (OCH), 71.0 (OCH2), 23.7 (CH2), 21.6
(CH3), 18.7 (CH2).
6-Benzyl-2-[(4-methylpent-4-en-1-yl)oxy]tetrahydropyran cis-27
and trans-27
A catalytic amount of ( )-camphorsulfonic acid was added to a
solution of dihydropyran 31 (0.42 g, 2.4 mmol) and 12 (0.28 g,
2.8 mmol) in anhydrous dichloromethane (10 mL) under an
argon atmosphere. The mixture was stirred at room temper-
ature for 1 h, then quenched by the addition of saturated aque-
ous sodium bicarbonate (50 mL). Additional dichloromethane
(50 mL) was added and the organic layer was separated, washed
successively with saturated sodium bicarbonate (50 mL) and
brine (50 mL), dried (MgSO4) and evaporated under reduced
pressure to give the crude product as a colourless oil; proton
NMR analysis indicated that the crude product was a ca. 2:1
mixture of diastereoisomers. Purification by silica column
chromatography eluting with 0% to 8% diethyl ether–40/60
petroleum ether gave first trans-27 as a colourless oil (0.380 g,
57%). Found: C, 79.1; H, 9.6. C18H26O2 requires C, 78.8; H,
9.55%; νmax (thin film)/cmϪ1 3065, 3027, 2940, 2861, 1649,
1495, 1454, 1441, 1373, 1151, 1071, 1029, 888, 749, 700; δH (200
MHz; CDCl3): 7.15–7.31 (5H, m, Ph), 4.78 (1H, br s, 2-H), 4.70
(1H, br s, CCHH), 4.66 (1H, br s, CCHH), 3.87–3.99 (1H, m, 6-
H), 3.38 (1H, dt, J 9.7 and 6.8, CHOCHH), 3.22 (1H, dt, J 9.7
2-Benzyl-3,4-dihydro-2H-pyran 31
A solution of phenyllithium in hexane–ether (1.8 M, 10 mL)
was added dropwise over 10 min to a stirred slurry of copper()
1824
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
iodide (1.46 g, 7.7 mmol) in ether (10 mL) at 0 ЊC under an
argon atmosphere. The dark solution was stirred at this
temperature for 10 min, and a solution of the tosylate 30 (1.82
g, 6.8 mmol) in ether (20 mL) was added slowly over 10 min.
The reaction mixture was stirred at 0 ЊC for 2 h, and then at
room temperature for 3 h, after which time the mixture was
cooled to 0 ЊC and the reaction was quenched by the addition
of water (5 mL). The organics were separated, filtered through
Celite and the residue washed with ether (20 mL). The filtrate
was washed with cold aqueous ammonium chloride (20 mL),
aqueous ammonia (5 × 20 mL), and brine (20 mL), dried
(MgSO4) and evaporated under reduced pressure to give the
crude product as a partially solidified yellow oil. Purification by
silica column chromatography eluting with 40/60 petroleum
ether gave the dihydropyran 31 as a colourless oil (0.44 g, 37%).
A small sample was purified for analysis by bulb-to-bulb distil-
lation (100 ЊC/0.6 mmHg). Found: C, 82.9; H, 8.1. C12H14O
requires C, 82.7; H, 8.1%; νmax (thin film)/cmϪ1 3060, 3027,
2921, 2848, 1649, 1496, 1454, 1241, 1227, 1068, 1041, 767, 740,
699, 592; δH (200 MHz; CDCl3): 1.59 (1H, dddd, J 13.3, 9.8, 9.7
and 6.4, 3-Ha), 1.81–1.95 (1H, m, 3-Hb), 1.96–2.07 (2H, m, 4-
CH2), 2.78 (1H, dd, J 13.7 and 6.6, PhCHa), 3.01 (1H, dd, J 13.7
and 6.6, PhCHb), 4.04 (1H, dddd, Jax,ax 9.1, JH2,CH(2a) 6.7,
JH2,CH(2b) 6.6, Jax,eq 2.3, 2-H), 4.64–4.72 (1H, m, 5-H), 6.38 (1H,
dt, J 6.2 and 1.8, 6-H), 7.22–7.35 (5H, m, PhH); δC (50 MHz;
CDCl3) 143.7 (CH), 138.1 (q), 129.4 (CH), 128.3 (CH), 126.3
(CH), 100.4 (CH), 75.7 (OCH), 41.6 (PhCH2), 27.0 (CH2),
19.6 (CH2).
(CH2, major diastereoisomer), 27.1 (CH3, minor diastereo-
isomer), 26.1 (CH2, minor diastereoisomer), 25.9 (CH2, major
diastereoisomer), 25.1 (CH3, major diastereoisomer), 18.6
(CH2, both diastereoisomers). The diastereomeric bis-hetero-
cycles 32 could be partially separated on silica gel that had been
doped with lithium chloride (Merck silica gel 9385 was sus-
pended in a solution of LiCl in methanol; after 1 h the silica
was filtered, rinsed with methanol, and dried); while a small
sample of the major diastereoisomer could be obtained in good
1
purity, its H NMR spectrum yielded no further information
(either in CDCl3 or in C6D6) regarding the relative stereo-
chemistry of the molecule. The minor diastereoisomer could
not be obtained pure. Major diastereoisomer: νmax (thin film)/
cmϪ1 3062, 3026, 2933, 2864, 1604, 1496, 1454, 1372, 1264,
1197, 1093, 1042, 740, 700; δH (200 MHz; C6D6): 7.12–7.29 (5H,
m, PhH), 4.12–4.23 (1H, m, OCH), 3.95–4.06 (1H, m, OCH),
3.73–3.81 (2H, m, 2 × OCH), 3.00 (1H, dd, J 13.4 and 6.9,
PhCHH), 2.75 (1H, dd, J 13.4 and 7.0, PhCHH), 2.00 (1H, dd,
J 14.2 and 8.4), 1.33–1.77 (11H, m), 1.29 (3H, s, CH3); δC (50
MHz; CDCl3): 139.1 (quat.), 129.3 (CH), 128.1 (CH), 125.9
(CH), 82.1 (quat.), 72.2 (CH), 68.73 (OCH2), 66.5 (CH), 44.0
(CH2), 40.2 (CH2), 37.5 (CH2), 31.7 (CH2), 29.0 (CH2), 25.9
(CH2), 25.1 (CH3), 18.6 (CH2).
Rearrangement of cis-27
A solution of cis-27 (25.2 mg, 91.8 mmol) in anhydrous dichloro-
methane (0.7 mL) at Ϫ30 ЊC was treated with a solution of
tin() chloride in dichloromethane (1.0 M, 0.34 mL) for 15
minutes and the products isolated and purified according to the
procedure described for the rearrangement of unlabelled trans-
27 to give the bis-heterocycle 32 as a colourless oil (14.9 mg,
59%, a ca. 3:1 mixture of diastereoisomers by integration of
Rearrangement of trans-27 to rel-(2R,6S,2ЈRS)-2-benzyl-6-
[(2Ј-methyltetrahydrofuran-2Ј-yl)methyl]tetrahydropyran 32
A solution of tin() chloride in dichloromethane (1.0 M, 1.6
mL) was added dropwise via syringe to a solution of acetal
trans-27 (117.9 mg, 0.43 mmol) in anhydrous dichloromethane
(3.0 mL) at Ϫ30 ЊC under an atmosphere of argon. The
reaction mixture was stirred for 15 minutes, quenched by the
addition of sodium hydroxide (10%, 2 mL), and stirred vigor-
ously as the mixture warmed to room temperature. Aqueous
sodium hydroxide (10%, 20 mL) and dichloromethane (20 mL)
were added, the organic layer separated and the aqueous resi-
due extracted with dichloromethane (2 × 20 mL). The com-
bined organic extracts were washed with brine (30 mL), dried
(MgSO4), and evaporated under reduced pressure to give a
colourless oil. Purification by silica column chromatography
eluting with 20% to 75% diethyl ether–40/60 petroleum ether
gave the bis-ether 32 as a colourless oil (60.9 mg, 52%, an
inseparable 3:1 ratio of diastereoisomers by integration of the
CH3 singlets in the proton NMR spectrum). νmax (thin film)/
cmϪ1 3026, 2934, 2864, 1604, 1496, 1454, 1370, 1196, 1120,
1092, 1041, 700; δH (600 MHz; CDCl3): 7.26–7.28 (2H, m, PhH
both diastereoisomers), 7.17–7.20 (3H, m, PhH both diastereo-
isomers), 3.71–3.82 (2H, m, OCH2 both diastereoisomers),
3.94–4.03 (2H, m, OCH both diastereoisomers), 1.33–2.00
(12H, m, both diastereoisomers), 2.88–2.92 (1H, m, PhCHH
both diastereoisomers), 2.75–2.82 (1H, m, PhCHH both
diastereoisomers), 1.14 (3H, s, CH3 major diastereoisomer),
1.09 (3H, s, CH3 minor diastereoisomer); δC (50 MHz; CDCl3):
139.1 (quat., both diastereoisomers), 129.3 (CH, both diastereo-
isomers), 128.1 (CH, both diastereoisomers), 125.9 (CH, both
diastereoisomers), 82.1 (quat., both diastereoisomers), 72.2
(CH, major diastereoisomer), 72.0 (CH, minor diastereo-
isomer), 68.7 (OCH2, major diastereoisomer), 68.7 (OCH2,
minor diastereoisomer), 67.1 (CH, minor diastereoisomer),
66.5 (CH, major diastereoisomer), 44.0 (CH2, major diastereo-
isomer), 43.7 (CH2, minor diastereoisomer), 40.4 (CH2, minor
diastereoisomer), 40.2 (CH2, major diastereoisomer), 37.5
(CH2, major diastereoisomer), 35.4 (CH2, minor diastereo-
isomer), 31.9 (CH2, minor diastereoisomer), 31.7 (CH2, major
diastereoisomer), 29.3 (CH2, minor diastereoisomer), 29.0
1
the CH3 singlets), identical (by H NMR spectroscopy) to the
products isolated from the rearrangement of trans-27.
4-Methyl[1,1-2H2]pent-4-en-1-ol 33
A slurry of lithium aluminium deuteride (4.72 g, 0.122 mol) in
anhydrous ether (300 mL) was heated under reflux for 30 min
under an argon atmosphere, then cooled to 0 ЊC. Ethyl 4-
methylpent-4-enoate (12.5 g, 0.088 mol) in anhydrous ether (45
mL) was added slowly over 15 min, and the resulting slurry was
stirred at room temperature for 30 min and then heated under
reflux for 3 h. The reaction mixture was cooled to room tem-
perature and ethyl acetate (10 mL) was added to consume the
excess of LiAlD4. Sequential addition of water (5 mL), aqueous
sodium hydroxide (10%, 7 mL), and water (15 mL) gave a
granular white solid that was separated by filtration. Evapor-
ation of the solvent gave a pale yellow oil which was dissolved
in ether (20 mL), washed successively with water (20 mL) and
brine (20 mL), dried (MgSO4) and concentrated under reduced
pressure. Distillation of the residue through a short Vigreaux
column gave 33 as a colourless liquid (7.36 g, 82%), bp 150–
155 ЊC. νmax (thin film)/cmϪ1 3345 (br), 3074, 2969, 2936, 2194,
2088, 1649, 1445, 1374, 1135, 1101, 965, 888; δH (200 MHz;
CDCl3): 4.68–4.70 (2H, m, CCH2), 2.07 (2H, br t, J 7.6, 3-CH2),
1.87 (1H, br s, OH), 1.72 (3H, s, CH3), 1.67 (2H, br t, J 7.4,
2-CH2); δC (50 MHz; CDCl3): 145.2 (CCH2), 109.8 (CCH2),
61.3 (q, J 21.4, CD2OH), 33.8 (CH2), 30.2 (CH2), 22.1 (CH3).
[phenyl-2H5]-2-Benzyl-3,4-dihydro-2H-pyran 34
A solution of d5-bromobenzene (3.12 g, 19.3 mmol) in
anhydrous THF (25 mL) was added to a slurry of magnesium
powder (1.2 g, 49.4 mmol, preactivated with a crystal of I2) in
THF (10 mL), the mixture heated under reflux for 1 h and
cooled to room temperature. The dark supernatant solution
was added via cannula to a stirred solution of the tosylate 30
(3.14 g, 11.7 mmol) containing copper() iodide (2.46 g, 12.9
mmol) in THF (20 mL) at 0 ЊC, and the mixture stirred at 0 ЊC
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1825

View Article Online
for 3 h and then at room temperature for 6 days. Addition of
water (3 mL) and work-up as described for unlabelled 31
followed by purification by silica chromatography eluting with
0% to 8% diethyl ether–40/60 petroleum ether, gave the title
dihydropyran 34 as a colourless oil (0.1111 g, 5.3%). νmax (thin
film)/cmϪ1 3058, 2920, 2848, 2360, 2273, 1649, 1447, 1435, 1384,
1241, 1226, 1066, 1042, 728; δH (200 MHz; CDCl3): identical to
the 1H NMR spectrum for the unlabelled dihydropyran 31
except that the signal 7.22–7.35 (m) was absent as a result of
deuterium incorporation; δC (50 MHz; CDCl3): 143.7 (CH),
137.9 (q), 129.0 (t, J 23.8, CD), 127.8 (t, J 24.3, CD), 125.8 (t,
J 24.3, CD), 100.4 (CH), 75.7 (OCH), 41.5 (PhCH2), 27.1
(CH2), 19.6 (CH2); m/z (EI) 179 (Mϩ, 1%), 135 (2%), 122 (1%),
96 (3%), 86 (36%), 84 (48%), 51 (35%), 49 (100%). HRMS (EI):
J 24.0, CD), 109.8 (CCH2), 102.1 (O2CH), 76.9 (OCH), 67.5
(qn, J 21.4, OCD2), 42.4 (CH2), 34.1 (CH2), 31.0 (CH2), 30.4
(CH2), 27.4 (CH2), 22.4 (CH3), 22.1 (CH2); m/z (FIB) 280
(MHϩ, 10%).
Rearrangement of trans-35
A solution of tin() chloride in dichloromethane (1.0 M, 1.6
mL) was added slowly drop-wise via syringe to a stirred solution
of D2 labelled trans-35 (125.5 mg, 0.45 mmol) in anhydrous
dichloromethane (3.0 mL) at Ϫ30 ЊC under an argon atmos-
phere. The reaction mixture was stirred at Ϫ30 ЊC for 30 min,
quenched by the addition of aqueous sodium hydroxide (2 M,
1 mL), and stirred vigorously as the mixture warmed to room
temperature. Aqueous sodium hydroxide (2 M, 20 mL) and
dichloromethane (20 mL) were added and the product was
extracted into the organic layer. The organic extract was
washed with sodium hydroxide (2 M, 10 mL) and brine (10
mL), dried (MgSO4), and evaporated under reduced pressure to
give the crude product as a colourless oil. Purification by silica
column chromatography eluting with 0% to 15% diethyl ether–
40/60 petroleum ether gave bicyclic ether 37 as a colourless oil
(95.8 mg, 76%, an inseparable of two diastereoisomers in the
ratio ca. 1:2.8 by integration of the CH3 singlets in the proton
NMR). νmax (thin film)/cmϪ1 3026, 2938, 2865, 2200, 2091,
1604, 1496, 1454, 1371, 1195, 1088, 1038, 1006, 741, 700;
δH (200 MHz; CDCl3): 7.14–7.32 (5H, m, PhH both diastereo-
isomers), 3.91–4.04 (2H, m, both diastereoisomers), 2.71–2.96
(2H, m, PhCH2 both diastereoisomers), 1.26–2.04 (12H, m,
both diastereoisomers), 1.14 (3H, s, CH3 major diastereo-
isomer), 1.09 (3H, s, CH3 minor diastereoisomer); δC (50 MHz;
CDCl3): 139.1 (quat., both diastereoisomers), 129.3 (CH, both
diastereoisomers), 128.2 (CH, both diastereoisomers), 125.9
(CH, both diastereoisomers), 82.1 (quat., both diastereo-
isomers), 72.2 (CH, major diastereoisomer), 72.0 (CH, minor
diastereoisomer), 68.73 (CH, major diastereoisomer), 68.66
(CH, minor diastereoisomer), 44.0 (CH2, major diastereo-
isomer), 43.7 (CH2, minor diastereoisomer), 40.4 (CH2, minor
diastereoisomer), 40.2 (CH2, major diastereoisomer), 37.5
(CH2, major diastereoisomer), 35.4 (CH2, minor diastereo-
isomer), 31.9 (CH2, minor diastereoisomer), 31.7 (CH2, major
diastereoisomer), 29.2 (CH2, minor diastereoisomer), 29.0
(CH2, major diastereoisomer), 27.1 (CH3, minor diastereo-
isomer), 25.9 (CH2, minor diastereoisomer), 25.6 (CH2, major
diastereoisomer), 25.1 (CH3, major diastereoisomer), 18.6
(CH2, both diastereoisomers); m/z (FIB) 277 (M ϩ H,
66%). HRMS (FIB): 277.2136 (MHϩ). Calc. for C18H252H2O2:
277.2137.
2
179.1347. Calc. for C12H9 H5O: 179.1359.
6-Benzyl-2-{[1,1-2H2]-4-methylpent-4-en-1-yl]oxy}tetrahydro-
pyrans cis-35 and trans-35
Addition of the alcohol 33 (0.294 g, 2.88 mmol) to the dihydro-
pyran 31 (0.310 g, 1.78 mmol) according to the protocol
described above for the synthesis of 27 gave, after work-up and
purification by silica column chromatography eluting with 0%
to 8% diethyl ether–40/60 petroleum ether, first trans-35 (138
mg, 28%) as a colourless oil. νmax (thin film)/cmϪ1 3064, 3027,
2938, 2183, 2085, 1649, 1496, 1454, 1440, 1373, 1170, 1125,
1093, 1017, 951, 887, 747, 699. Proton NMR identical to
unlabelled trans-27, but lacking the signals at 3.38 and 3.22
ppm due to deuterium incorporation. δC (50 MHz; CDCl3):
145.4 (CCH2), 139.0 (q), 129.3 (CH), 128.0 (CH), 125.9 (CH),
109.8 (CCH2), 97.1 (O2CH), 69.8 (OCH), 65.5 (qn, J 21.0,
OCD2), 42.8 (CH2C), 34.3 (CH2), 30.9 (CH2), 29.7 (CH2), 27.3
(CH2), 22.4 (CH3), 18.2 (CH2); m/z (FIB) 275 (MHϩ, 10%).
HRMS (FIB): 275.1976 (MHϩ). Calculated for C18H232H2O2:
275.1980. Further elution gave the cis-35 (32.1 mg, 6.5%).
1
δH (200 MHz; CDCl3): identical to the H NMR spectrum for
cis-27 except that the signals 3.38 (dt) and 3.81 (dt) for the
diastereotopic OCH2 were absent as a result of deuterium
incorporation; δC (50 MHz; CDCl3): identical to the 13C NMR
spectrum for cis-27 except that the signal at 68.2 (OCH2) was
absent as a result of deuterium incorporation.
[phenyl-2H5]-6-Benzyl-2-{[1,1-2H2]-4-methylpent-4-en-1-yloxy}-
tetrahydropyran cis-36 and trans-36
Addition of the d2-alcohol 33 (0.301 g, 2.95 mmol) to the d5-
dihydropyran 34 (0.1174 g, 0.655 mmol) according to the
protocol described above for the synthesis of acetal 27 gave,
after work-up and purification by silica column chromato-
graphy eluting with 0% to 8% diethyl ether–40/60 petroleum
ether, first the trans-36 as the first-eluting fraction (108.2 mg,
59%) as a colourless oil. νmax (thin film)/cmϪ1 3073, 2938, 2274,
2183, 2086, 1649, 1570, 1440, 1373, 1350, 1262, 1202, 1170,
1125, 1092, 1013, 950, 887, 844, 820; δH (200 MHz; CDCl3):
identical to the 1H NMR spectrum for trans-27 except that the
signals 3.22 (dt) and 3.38 (dt) for the diastereotopic OCH2, and
7.15–7.31 (m) for PhH, were absent as a result of deuterium
incorporation; δC (50 MHz; CDCl3): 145.4 (CCH2), 138.8 (q),
129.7 (t, J 24.0, CD), 128.3 (t, J 24.2, CD), 126.2 (t, J 24.0, CD),
109.8 (CCH2), 97.1 (O2CH), 69.8 (OCH), 65.9 (qn, J 21.5,
OCD2), 42.7 (CH2), 34.3 (CH2), 30.9 (CH2), 29.7 (CH2), 27.3
(CH2), 22.4 (CH3), 18.2 (CH2); m/z (FIB) 280 (MHϩ, 11%).
Further elution gave cis-36 as a colourless oil (50.5 mg, 27%).
νmax (thin film)/cmϪ1 3073, 2939, 2850, 2274, 2190, 2087,
1649, 1570, 1441, 1392, 1330, 1186, 1156, 1066, 1034, 1022,
Rearrangement of cis-35
Treatment of acetal cis-35 (21.0 mg, 76.0 mmol) with a solution
of tin() chloride in dichloromethane (1.0 M, 0.3 mL) in
anhydrous dichloromethane (0.7 mL) at Ϫ30 ЊC for 30 min fol-
lowed by isolation and purification of the products as described
for trans-35 gave bis-heterocycle 37 as a colourless oil (15.4 mg,
73%, inseparable mixture of two diastereoisomers, dr = 1:2.8
by integration of the CH3 singlets at 1.09 and 1.14 ppm in the
proton NMR spectrum), identical by 1H NMR with the sample
prepared above except for the slight difference in relative
integration between the signals for the major and minor
diastereoisomers.
Crossover experiment: rearrangement of a mixture of cis-27 and
cis-36 acetals
1
932, 887, 845, 821; δH (200 MHz; CDCl3): identical to the H
NMR spectrum for cis-27 except that the signals at 3.38 (dt)
and 3.81 (dt) ppm for the diastereotopic OCH2, and at 7.19–
7.32 (m) ppm for PhH, were absent as a result of deuterium
incorporation; δC (50 MHz; CDCl3): 145.3 (CCH2), 138.7
(quat.), 128.9 (t, J 23.5, CD), 128.0 (t, J 24.5, CD), 125.5 (t,
A solution of tin() chloride in dichloromethane (1.0 M, 0.90
mL) was added dropwise via syringe to a solution of cis-27
(33.7 mg, 0.119 mmol) and cis-36 (33.4 mg, 0.119 mmol) (total
acetal: 0.238 mmol) in anhydrous dichloromethane (2.5 mL) at
Ϫ30 ЊC under an atmosphere of argon. The reaction mixture
1826
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827

View Article Online
Synthesis, CRC Press (Boca Raton), 1995; (c) D. E. Levy and
was stirred at this temperature for 1 h, quenched by the addition
of aqueous sodium hydroxide (10%, 2.5 mL) and allowed to
warm to room temperature. Dichloromethane (20 mL) and
aqueous sodium hydroxide (10%, 10 mL) were added and the
product was extracted into the organic layer. The aqueous layer
was re-extracted with fresh dichloromethane (2 × 20 mL) and
the combined organic layers were washed with aqueous sodium
hydroxide (50 mL) and brine (50 mL), dried (MgSO4) and con-
centrated under reduced pressure to give a yellow oil. Purifi-
cation by silica column chromatography eluting with 5% to 15%
diethyl ether–40/60 petroleum ether gave a mixture of the
bis-heterocycles 32, 37, 38 and 39 as a colourless oil (50.6 mg,
75%, a ca. 1:3 mixture of diastereoisomers). m/z (FIB) 275
[M(d0)Hϩ, 26%], 277 [M(d2)Hϩ, 22%], 280 [M(d5)Hϩ, 24%],
282 [M(d7)Hϩ, 18%].
C. Tang, The Chemistry of C-Glycosides, Pergamon, Oxford, 1995;
(d) P. Sinaÿ, Pure Appl. Chem., 1997, 69, 459; (e) J.-M. Beau and
T. Gallagher, Top. Curr. Chem., 1997, 187, 1.
2 For examples of vinylic and alkenic O- to C- anomeric
rearrangements see: (a) M. Takahashi, H. Suzuki, Y. Moro-oka and
T. Ikawa, Tetrahedron Lett., 1982, 23, 4031; (b) R. Menicagli,
C. Malanga, M. Degl’Innocenti and L. Lardicci, J. Org. Chem.,
1987, 52, 5700; (c) A. Ricci, A. Degl’Innocenti, A. Capperucci,
C. Faggi, G. Seconi and L. Favaretto, Synlett, 1990, 471; (d) K.
Mikami and H. Kishino, Tetrahedron Lett., 1996, 37, 3705.
3 For examples of benzylic O- to C- anomeric rearrangements see:
(a) J. Wennerberg, L. Eklund, M. Polla and T. Frejd, Chem.
Commun., 1997, 445; (b) J. Wennerberg and T. Frejd, Acta Chem.
Scand., 1998, 52, 95.
4 For examples of aryl O- to C- anomeric rearrangements see: (a)
N. G. Ramesh and K. K. Balasubramanian, Tetrahedron Lett.,
1992, 33, 3061; (b) G. Casiraghi, M. Cornia, G. Rassu, L. Zetta,
G. G. Fava and M. F. Belicchi, Tetrahedron Lett., 1988, 29, 3323;
(c) G. Casiraghi, M. Cornia, G. Rassu, L. Zetta, G. G. Fava and
M. F. Belicchi, Carbohydr. Res., 1989, 191, 243.
Crossover experiment: rearrangement of a mixture of cis-27 and
trans-36
5 M. F. Buffet, D. J. Dixon, G. L. Edwards, S. V. Ley and E. W. Tate,
Synlett, 1997, 1055.
6 M. F. Buffet, D. J. Dixon, S. V. Ley and E. W. Tate, Synlett, 1998,
1091.
7 D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans. 1,
1999, 2665.
8 D. J. Dixon, S. V. Ley and E. W. Tate, Synlett, 1998, 1093.
9 D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans. 1,
1998, 3125.
10 See the following paper: D. J. Dixon, S. V. Ley and E. W. Tate,
J. Chem. Soc., Perkin Trans. 1, DOI: 10.1039/a909302h.
11 J. Herscovici, L. Boumaîza and K. Antonakis, J. Org. Chem., 1992,
57, 2476.
12 B. A. Trost and D. M. T. Chan, J. Am. Chem. Soc., 1983, 105,
2315.
13 G. W. Daub, J. P. Edwards, C. R. Okada, J. W. Allen, C. T. Maxey,
M. S. Wells, A. S. Goldstein, M. J. Dibley, C. J. Wang, D. P.
Ostercamp, S. Chung, P. S. Cunningham and M. A. Berliner, J. Org.
Chem., 1997, 62, 1976.
14 P. Wipf and H. Jahn, Tetrahedron, 1996, 52, 12853.
15 The trans-isomer is the predominant or only product seen in
our previous work on oxygen to carbon rearrangements (see refs.
5–9).
A solution of cis-27 (37.6 mg, 0.137 mmol) and trans-36 (37.6
mg, 0.134 mmol) (total acetal: 0.271 mmol) in anhydrous
dichloromethane (2.9 mL) at Ϫ30 ЊC was treated with a solu-
tion of tin() chloride in dichloromethane (1.0 M, 1.0 mL) and
the products isolated and purified according to the crossover
protocol described above to give the rearranged products 32,
37, 38 and 39 as a colourless oil (52.0 mg, 69%, a ca. 1:3 mix-
ture of diastereoisomers). m/z (FIB) 275 [M(d0)Hϩ, 27%], 277
[M(d2)Hϩ, 16%], 280 [M(d5)Hϩ, 20%], 282 [M(d7)Hϩ, 18%].
Acknowledgements
We thank the EPSRC (to E. W. T. and D. J. D.), the Novartis
Research Fellowship (to S. V. L.) and Pfizer inc., Groton,
USA for financial support. G. L. E. contributed to these
studies whilst on sabbatical leave from the University of New
South Wales.
References
1 For reviews, see (a) Y. Du, I. R. Vlahov and R. J. Linhardt,
Tetrahedron, 1998, 54, 9913; (b) M. H. D. Postema, C-Glycoside
16 C. Fehr, J. Galindo and G. Ohloff, Helv. Chim. Acta, 1981, 64,
1247.
J. Chem. Soc., Perkin Trans. 1, 2000, 1815–1827
1827