Synthesis of 2,5-dihydrofurans via alkylidene carbene insertion reactions

Article abstract of DOI:10.1039/b111097g

The insertion reaction of alkylidene carbenes is demonstrated to be an effective method for the synthesis of 2,5-dihydrofuran ring systems. The best results have been obtained on substrates containing electron-withdrawing substituents, which appear less prone to the competing rearrangement reaction. This insight has led to the development of a new method for the synthesis of the core structure of the squalestatin-zaragozic acid natural products.

Full text of DOI:10.1039/b111097g

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Synthesis of 2,5-dihydrofurans via alkylidene carbene insertion
reactions
Louise F. Walker,a Ahmed Bourghida,a Stephen Connollyb and Martin Wills*a
1
a Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL
b Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough,
Leicestershire, UK LE11 5RH
Received (in Cambridge, UK) 5th December 2001, Accepted 1st February 2002
First published as an Advance Article on the web 28th February 2002
The insertion reaction of alkylidene carbenes is demonstrated to be an effective method for the synthesis of 2,5-
dihydrofuran ring systems. The best results have been obtained on substrates containing electron-withdrawing
substituents, which appear less prone to the competing rearrangement reaction. This insight has led to the
development of a new method for the synthesis of the core structure of the squalestatin–zaragozic acid natural
products.
Introduction
Alkylidene carbenes 1 represent a class of valuable synthetic
intermediates which have been employed in a number of total
syntheses of challenging natural products.1–17 The formation
of these reactive species may be achieved by a number of
methods,2–17 including treatment of vinyl halides with a strong
base,2–5 nucleophilic addition to alkynyliodonium salts,6 and by
the reaction of a carbonyl compound with diazomethylphos-
phonate7,8 or lithio(trimethylsilyl)diazomethane (LTDM).9–13
Although carbenes 1 (R = H, RЈ = alkyl) undergo rapid
rearrangement to alkynes,18 substrates lacking a hydrogen atom
adjacent to the carbene are known to participate in insertion
reactions with appropriate functional groups. Intramolecular
trapping of the carbene with hydroxy or amino groups provides
a convenient method for the synthesis of heterocycles,2,9,14,15
Scheme 1 Reagents and conditions: i) TMSDM, nBuLi, DME–hexane.
and insertion of the carbenes into proximal C–H bonds pro-
vides
a convenient method for the synthesis of cyclo-
C(5)–H bond would be expected to increase the rate of
insertion.11b,20,21 Generally, electron donating groups activate
C–H bonds towards insertion and electron withdrawing groups
deactivate. Aldehyde 2 was synthesised from ( )-mandelic acid†
(Scheme 2). The methyl ester of mandelic acid 3 was prepared
under standard esterification conditions then protected with a
pentenes,4,6,7,10,16,17 or heterocyclic products.5,8,10,13,17 In our
studies on the total synthesis of neohalicholactone, a 2,5-
dihydrofuran side product was obtained via the insertion of
a vinylidene carbene generated from a 1,1-dibromoalkene.19
Intrigued by this latter result, we chose to pursue a systematic
investigation into the scope and limitations of alkylidene
insertion reactions as a method for 2,5-dihydrofuran syn-
thesis. Throughout our work we chose to use the commercially
available reagent (trimethylsilyl)diazomethane (TMSDM),9–13
lithiation of which with nBuLi generates the active reagent
LTDM. The proposed mechanism for the generation of an
alkylidene carbene by the reaction of lithiated TMSDM and a
carbonyl compound is shown in Scheme 1. It was also our
intention to study the diastereoselectivity of the reaction with
respect to 2,5-disubstituted-2,5-dihydrofurans and examine the
nature of the stereochemical induction. We also wished to
explore the application of this methodology in natural product
synthesis.
Scheme 2 Reagents and conditions: i) AcCl, MeOH. ii) (MeO)2CH2,
P2O5, CHCl3. iii) LiAlH4, Et2O, reflux, iv) DMSO, ClCOCOCl, NEt3,
DCM. v) MeMgBr, THF, rt, overnight.
The first 2,5-dihydrofuran precursor we selected for study
was the aldehyde 2 which, on reaction with LTDM, would yield
an alkylidene carbene. The two heteroatoms adjacent to the
† The IUPAC name for mandelic acid is phenylglycolic acid.
DOI: 10.1039/b111097g
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This journal is © The Royal Society of Chemistry 2002
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methoxymethyl (MOM) protecting group using dimeth-
oxymethane and catalytic phosphorus pentaoxide in chloro-
form.22 Reduction of the ester 4 with lithium aluminium
hydride followed by Swern oxidation led to the generation of
2-phenyl-2-methoxymethoxyethanal 2. Aldehyde 2 was treated
with LTDM and an alkyne 6 was obtained as the exclusive
product in good yield as the result of a 1,2-hydrogen shift
(Scheme 3) with no evidence of the corresponding 2,5-dihydro-
Fig. 1 Electron-donating nature of β-substituents.
carbene might prevent migration. To test this speculation a
series of ketones which had electron withdrawing α-alkoxy-
substituents were synthesised. These were prepared by a variety
of methods.
Symmetrical ketones 15–17 were formed by reaction of 1,3-
dichloropropan-2-ol 18 and the appropriate sodium alkoxide
followed by oxidation of the corresponding alcohols 19–21 by
PCC oxidation.24a The synthesis of 1,3-bis(benzyloxy)propan-
2-one 22 was achieved by reaction of 3-chloro-2-chloromethyl-
prop-1-ene with sodium benzyl oxide followed by ozonolysis of
the double bond in the product 23 to give the ketone. 1,3-Bis(p-
methoxyphenylmethoxy)propan-2-one 24 was synthesised from
( )-glycidol (Scheme 5). The alcohol was deprotonated and
Scheme 3 Reagents and conditions: i) TMSDM, nBuLi, DME–hexane.
furan 7. It was therefore clear that hydrogen migration was
always likely to outpace any attempted insertion reaction in
an aldehyde-derived system. The methyl ketone 8 was therefore
synthesised from aldehyde 2 by a Grignard reaction with
methylmagnesium bromide and oxidation of the resulting
alcohol 9 (Scheme 2). Treatment of 7 with LTDM resulted in
the formation of 2,5-dihydrofuran 10 by a C(5)–H insertion
Scheme 5 Reagents and conditions: i) NaH, RX, DMF, ii) LiClO4,
RЈOH, MeCN, reflux, iii) PCC, ClCOCOCl, NEt3, DCM.
1
reaction, which appeared to be a single diastereoisomer by H
reacted with p-methoxybenzyl chloride. Epoxide 25 was then
opened with p-methoxybenzyl alcohol in the presence of cat-
alytic lithium perchlorate.24b Finally oxidation of this alcohol 26
by PCC gave the desired ketone 24. The same method was
employed for the synthesis of a series of unsymmetrical ketones
27–29 (Scheme 5). The results of insertion reactions on these
compounds would provide evidence of the relative rates of
insertion into different C(5)–H bonds adjacent to benzyl,
methyl, ethyl and p-methoxyphenylmethyl (MPM). One final
ketone 30 was synthesised by deprotonation of cyclopentanol
with sodium hydride and subsequent reaction with 3-bromo-2-
methylpropene in DMF. The double bond of the resulting
alkene was then ozonolised to give ketone 30.
NMR (Scheme 3). There was no evidence of formation of the
corresponding alkyne 11
In order to facilitate a shorter synthesis of analogues of
ketone 8 we examined the direct conversion of a methyl ester
to ketones via a Weinreb amide intermediate. We elected to
use the method reported by Williams and co-workers in which a
Grignard reagent is employed as both the base and the organo-
metallic reagent.23 A combination of bases and Grignard
reagents were experimented with but only one combination
proved successful in our hands; the use of isopropylmagnesium
chloride as both the base and Grignard reagent (Scheme 4).
Scheme 4 Reagents and conditions: i) PrMgBr, Me(MeO)NHؒHCl,
THF.
This resulted in the formation of an isopropyl ketone 12 which
on treatment with LTDM gave a mixture of products, the major
(63%) being alkyne 13, the product of an 1,2-alkyl shift and the
minor (ca. 4%) being the desired 2,5-dihydrofuran 14, formed
as a single diastereoisomer (Scheme 3).
If we consider the later two results in terms of the electron
donating nature of the β-alkyl substituents, we can see that the
methyl group is electron donating but does not migrate whereas
the greater electron donating ability of the isopropyl group
resulted in its migration (Fig. 1). Therefore, it might be expected
that an electron withdrawing group in the β-position to the
Each symmetrical ketone was then treated with LTDM
at Ϫ78 ЊC and allowed to warm to rt over 4 h (Scheme 6 and
Table 1). The reaction of 1,3-dimethoxy- 15 and 1,3-diiso-
propoxypropan-2-one 17 with LTDM resulted in poor yields
of insertion products 31 and 35. In the case of diisoprop-
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Table 1 Alkylidene carbene insertion reactions
Substrate
R
RЈ
Product
Yield (%)
15
16
22
24
17
H
H
H
H
H
Me
Ph
31
32
33
34
35
14
55
70
61
27
Fig. 2 Proposed mode of formation of 10 and 37.
p-(MeO)C6H4
Me
Me
catalytic PTSA. Upon reaction with LTDM, this ketone gave
2,5-dihydrofuran 37 as a 3 : 1 mixture of diastereoisomers of
which the major isomer was predicted to be the cis-isomer
(Scheme 8) by considering the predicted transition state for its
formation, i.e. bearing pseudo-equatorial substituents (Fig. 3).
Table 2 Alkylidene carbene insertion reactions of unsymmetrical
ketones
Substrate
R
Ratio A : B
Yield (%)
27
28
29
H
Me
1 : 2
5 : 3
1 : 1
34
52
32
p-(MeO)C6H4
Scheme 8 Reagents and conditions: i) BnOH, PTSA, toluene, reflux. ii)
TMSDM, nBuLi, DME–hexane.
Scheme 6 Reagents and conditions: i) TMSDM, nBuLi, DME–hexane.
oxypropan-2-one, starting material was also recovered from the
reaction indicating that the reaction did not reach completion
in 4 h. Ketones 16, 22 and 24 all gave good yields of 2,5-
dihydrofuran products 32–34. The presence of an adjacent
aromatic group appears to result in activation of the C(5)–H
bond in the same way as the α oxygen.21 On reaction with
LTDM a spiro-2,5-dihydrofuran 36 was formed from ketone 30
in 57% yield.
Fig. 3 Compounds related to 10, 14 and 37 demonstrated to be cis-by
NOE measurements.
The measurement of nuclear Overhauser effects (NOE) pro-
vides a means for the assignment of relative stereochemistry in
compounds of rigid structure, such as heterocycles. Although
NOE studies were not carried out during the course of this
study on compounds 10, 14 and 37 due to the lack of a suitable
facility, two closely related compounds, illustrated in Fig. 3,
have been made in our group via identical insertion reactions.
In both cases analysis exhibited a strong NOE between
the protons at the 2 and 5 positions of the dihydrofuran ring.25
This suggests a cis-relationship between these protons in the
illustrated compounds and, by analogy, in the rings of com-
pounds 10, 14 and 37.
There was generally little selectivity between the different
C(5)–H bonds in the unsymmetrical ketones examined (Scheme
7, Table 2). Although yields of products were poor, which limits
Scheme 7 Reagents and conditions: i) TMSDM, nBuLi, DME–hexane.
the validity of the data, there appears to be a potential order of
insertion preference of methoxy > OBn = OMPM > ethoxy.
However, other factors may be significantly more important to
the regioselectivity. Indeed an observation by Taber17b indicates
that the environment of the activating group may be of less
significance than the method employed to prepare the carbene.
Insertion products 10 and 14 may possess trans or cis relative
stereochemistry. In the two examples described so far both
products appeared to be formed as single diastereoisomers. For
2-methoxy-4-methyl-5-phenyl-2,5-dihydrofuran (10) we have
tentatively assigned this to be cis, based on a consideration of
the likely transition states that have been postulated (Fig. 2),6a,11b
to predict the diastereoselective outcome of such reactions. 2,5-
Dihydrofuran 14 was formed along with the alkyne 13. This
2,5-dihydrofuran was also obtained as a single diastereoisomer
to which we also tentatively assign the same relative stereo-
chemistry. We followed these results with one further example
to investigate the diastereoselectivity of the reaction. Pyruv-
aldehyde dibenzyl acetal was prepared by reacting the corre-
sponding dimethyl acetal with benzyl alcohol in the presence of
The squalestatin–zaragozic acid class of natural products
(e.g. zaragozic acid C 38) have been a subject of great interest
to synthetic organic chemists on account of their biological
activity and complex structure.26 Though their synthesis has
been realised by a number of groups, each synthesis utilises an
acid catalysed ketalisation reaction in order to close the bicyclic
core. We set out to synthesise the bicylic core by an alkylidene
carbene C(5)–H insertion reaction (Scheme 9). We envisioned
construction of the six-membered ketal followed by generation
of an alkylidene carbene that would insert into the C(3)–
or C(3Ј)–H axial bond to give the five-membered ring of the
bicyclic core.
Whilst devising a model system for the key cyclisation step,
we considered that a methyl group at the C(1) position would be
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Scheme 9 Proposed synthetic approach to squalestatins–zaragozic
acid core.
product 48. In this case this is almost certainly because there is
required to force the less bulky sp2 ketone into the axial position
where it would readily insert into the corresponding axial C(3)–
or C(3Ј)–H bond. The synthesis of ketal 39 was achieved by
heating butane-2,3-dione with propane-1,3-diol and PTSA
(Scheme 10). This ketone was then treated with LTDM under
no group that may be eliminated from the C(5) position result-
ing in aromatisation. The exact structure of the bicyclic product
obtained was confirmed by a 3-bond correlation NMR study.
As expected, ketal 46, bearing axial methyl groups at C(3)
and C(3Ј), gave no insertion product. Ketal 45 was treated
with LTDM, and once again the crude NMR spectrum showed
that the reaction had given the insertion product 49. Upon
purification by column chromatography a rearrangement
had taken place leading to 50 (45% overall yield), analogous to
that observed with ketal 44. In the case of this ketal there
is no diaxial interaction between the C(3) methyl and the
five-membered ring but despite this the rearrangement still pro-
ceeded.
Scheme 10 Reagents and conditions: i) propane-1,3-diol, PTSA,
toluene, 90 ЊC. ii) TMSDM, nBuLi, DME–hexane. iii) silica gel or
alumina.
1
the standard conditions described above. H NMR analysis of
the crude product from this reaction showed that the insertion
reaction had indeed been successful and the bicyclic product 40
had been formed exclusively. Unfortunately, attempted purifi-
cation of this product by column chromatography on silica gel
or alumina resulted in rearrangement to give a furan 41 which
was isolated in good yield. The rearrangement is likely to pro-
ceed via an acid-catalysed opening of the six-membered ring
followed loss of a proton from C(5) resulting in aromatisation
to the furan. This type of rearrangement has been observed
before by a team at GlaxoSmithKline.27 When a squalestatin
analogue 42 was treated with acid, it underwent ring opening
with elimination, yielding furan 43.
As all attempts to abate the rearrangement process by placing
groups at the C(3) and C(3Ј) positions of the ketal had failed,
we next chose to carry through the crude insertion products to
the next step of the sequence toward the squalestatin–zaragozic
acid core. The insertion reaction proceeded well so our next
tasks were to convert the methyl and double bond groups into
the required ester and alcohol groups with appropriate stereo-
chemistry. We achieved this by epoxidation of the double bond,
ring opening of the epoxide and esterification of the alcohol
followed by simple ozonolysis of the double bond and reduc-
tion of the ketone product (Scheme 11). This sequence was
carried out on the simplest crude bicyclic core 40 with the first
step, epoxidation, first using MCPBA (m-chloroperbenzoic
acid). Unfortunately no desired product was obtained in the
reaction, and furan 41 was obtained as the major product.
Using dimethyldioxirane,28 a neutral epoxidising reagent, the
epoxidation reaction was successful but the product 51 was
formed in low yield. It is also interesting to note that only
one product was formed in this reaction which we believe was
probably due to attack from the less hindered exo face giving
the relative stereochemistry required at the C(6) position. The
next step in this sequence was ring opening of the epoxide with
base. LDA failed to give any of the desired product therefore
the use of dilithiated (1S,2R)-norephedrine was investigated.
This particular base was chosen as it has been used effectively
in the enantioselective rearrangement of epoxides to allylic
alcohols.29 In the event, the rearrangement of epoxide 5130 pro-
ceeded smoothly in reasonable yield to give the racemic allylic
alcohol 52 (Scheme 11).
A further set of ketals were synthesised by the independent
reactions of (R,R)-(Ϫ)-pentane-2,4-diol and meso-pentane-2,4-
diol with butane-2,3-dione and PTSA. This resulted in the
preparation of three ketals 44–46. The relative stereochemistry
in the ketals 45 (40%) and 46 (15%) prepared from meso-
pentane-2,4-diol was assigned following reaction with LTDM
as only 45 would be predicted to be able to form the desired
product by alkylidene carbene insertion into the axial C(5)–H
bond.
Each ketal in turn was then treated with LTDM. The ketal
44 gave the expected insertion product 47 in a crude form
but attempted purification by column chromatography resulted
in rearrangement, not to the furan, but to the fused bicyclic
The next two steps were a simple coupling between the
alcohol and 3-bromobenzoic acid with DCC and DMAP31 and
ozonolysis of the double bond to give ketone 54. 3-Bromo-
benzoic acid was used to form the ester 53 (48% yield) as it was
hoped this would lead to a crystalline compound suitable for
X-ray analysis. This would establish without doubt the relative
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with this route is the potentially wasteful removal of the result-
ing chain at C(7) in the bicyclic core after the insertion reaction
has been performed. In this step half of the original ketone is
cleaved in the ozonolysis which, in a more complex analogue
would lead to the loss of a chain of considerable complexity.
However this route will hopefully demonstrate that the inser-
tion reaction will still occur predominantly into the C(5)–H of
the ketal and not into the C(1) side chain.
The starting material for this synthesis was 3-phenylpropyl-
(triphenyl)phosphonium bromide which was used in a Wittig
reaction with hydrocinnamaldehyde to give alkene 55. This
alkene was reacted with catalytic osmium tetraoxide in a
dihydroxylation32 and then the resulting diol 56 oxidised by a
Swern oxidation to give 1,6-diphenylhexane-3,4-dione 57. Ketal
formation proceeded cleanly to give the desired ketal 58, which
was treated with LTDM. The insertion reaction proceeded with
exclusive insertion into the desired C(5)–H bond yielding the
crude bicyclic core 59 which was directly epoxidised to 60 using
dimethyldioxirane. This reaction also resulted in the formation
of some furan 61, which is as a result of the starting material
rearranging as we have seen before. With the epoxide 60 in
hand an attempt to deprotonate and ring open the epoxide was
carried out using lithiated (1S,2R)-norephedrine. However we
did not obtain any of the desired product in the reaction and no
starting material was retrieved.
In summary we have demonstrated that the insertion
reactions of alkylidene carbenes with proximal C–H bonds
represent a valuable method for the formation of heterocyclic
systems. We are currently extending our investigations to more
complex systems, including carbohydrates, and these results will
be reported in due course.
Scheme 11 Reagents and conditions: i) dimethyldioxirane, acetone. ii)
(1R, 2S)-Norephedrine, n-BuLi, THF, PhH. iii) DCC, DMAP, m-
BrC6H4CO2H, DCM. iv) Ozone, DCM, Me2S.
stereochemistry at C(6). Unfortunately neither the alkene nor
the ketone 54 (formed from 53 in 40% yield) were solids.
We also investigated the synthesis of a more complex inter-
mediate for the squalestatin–zaragozic acid synthesis (Scheme
12). This was designed to facilitate the incorporation of a more
complex chain at the ketal of the bicyclic product; an essential
requirement for the total synthesis. However a disadvantage
Experimental
All reactions were carried out in vacuum-flame-dried or oven-
dried glassware under nitrogen unless otherwise stated.
Reagents were obtained from commercial sources and were
either used directly or purified by standard methods. THF
and diethyl ether were freshly distilled from sodium using
benzophenone as an indicator; DCM from calcium hydride;
toluene from sodium. DMF, DMSO and acetonitrile were dis-
tilled from calcium hydride under reduced pressure and DME
was distilled from calcium hydride. All the above purifications
were carried out under nitrogen. Petroleum ether refers to that
fraction which boils in the range 40–60 ЊC.
The reactions were monitored by TLC using aluminium
backed silica gel 60 (F254) plates, pre-coated with a layer of silica
(Merck), and these were visualised with UV (λ = 254 nm) and
then phosphomolybdic acid solution, potassium permanganate
solution or 2,4-dinitrophenylhydrazine solution. All organic
layers were concentrated by rotary evaporation on a Büchi
rotary evaporator, the final traces of solvents being removed
on a static oil pump (2 mmHg). Column chromatography was
carried out on silica gel 60 (40–63 µm).
Melting points were measured on a Stuart Scientific SMP1
instrument and are uncorrected. Infrared spectra (IR) were
recorded on a Perkin–Elmer 1310 FTIR spectrometer for
samples between sodium chloride plates with peak intensities
specified as strong (s), medium (m), weak (w) and broad (br).
Optical rotations were measured on a Perkin-Elmer 241 pol-
arimeter (sodium D line) at ambient temperature with a 1 cm
rotation cell. [α]D values are reported in 10Ϫ1 deg cm2 gϪ1
.
Nuclear magnetic resonance spectra (NMR) were recorded on
a Bruker AC 250 MHz, Bruker ARX-400, Bruker 300 MHz or
Bruker 500 MHz spectrometer. The chemical shift values are
quoted in ppm and these are relative to the standard tetra-
1
methylsilane (TMS) for H NMR and to the centre line of the
Scheme 12 Reagents and conditions: i) NMO, OsO4, MeSO2NH2,
acetone–H2O. ii) ClCOCOCl, DMSO, Et3N, DCM. iii) Propane-1,3-
diol, PTSA, toluene, reflux, 15 h. iv) TMSDM, n-BuLi, DME–hexanes.
v) Dimethyldioxirane, acetone.
chloroform triplet δ 77.0 for 13C NMR. The peak multiplicities
are specified as singlet (s), doublet (d), double-doublet (dd),
triplet (t), quartet (q) or septet (sept) and coupling constants
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(J) quoted in Hz. Mass spectra (MS) were obtained with a
Kratos analytical MS80 RFAO spectrometer and high reso-
lution determinations were obtained from the EPSRC Mass
Spectrometry Service Centre, Swansea. Elemental analyses
were performed with a Carlo Erba 1106 elemental analyser.
Determination of enantiomeric excesses by HPLC analysis
was achieved using a Waters 501 HPLC pump, Waters 486
tuneable absorbance detector, Waters 746 data module and a
Chiralcel OD column.
(18), 151 ([M Ϫ CO2Me]ϩ, 50), 124 (45), 105 (15), 94 (10), 77
([Ph]ϩ, 6), 62 (9), 45 ([MeOCH2]ϩ, 100).
Preparation of 2-(methoxymethoxy)-2-phenylethanol 5
Lithium aluminium hydride (3.0 g, 80 mmol) was stirred in
diethyl ether (50 ml) at 0 ЊC and to this suspension methyl
2-(methoxymethoxy)-2-phenylethanoate 4 (2.76 g, 13.1 mmol)
in diethyl ether (15 ml) was added dropwise over 30 min. The
reaction was refluxed for 3 h and cooled, after which water
(3 ml), 15% sodium hydroxide solution (3 ml) and further water
(9 ml) were added. The solid was filtered off and the solvent
removed by evaporation. Purification by column chroma-
tography eluting with 10–25% ethyl acetate–petroleum ether
gave the product as a colourless oil (1.77 g, 74%). Rf 0.45 (20%
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3434 (s), 3029
(w), 2932 (s), 2888 (s), 1736 (w); δH(CDCl3, 250.1 MHz) 7.37–
7.22 (5H, m, aryl CH ), 4.72–4.67 (1H, dd, J 4.0 and 8.0, CH ),
4.61 (2H, s, OCH2O), 3.73 (1H, dd, JAB 11.9 and JAX 8.0,
CHHЈOH), 3.64 (1H, dd, JAB 11.9 and JBX 4.0, CHHЈOH), 3.35
(3H, s, OCH3), 3.26 (1H, s, OH ); δC(CDCl3, 62.9 MHz) 138.6
(aryl Ci), 128.4 (aryl Cm), 128.0 (aryl Cp), 127.0 (aryl Co), 94.8
(MeOCH2O), 79.9 (CH), 67.1 (CH2OH), 55.5 (CH3); m/z (CI)
200 ([M ϩ NH4]ϩ, 100%), 182 ([M]ϩ, 9), 170 (56), 156 (21), 151
([M Ϫ MeO]ϩ, 51), 138 (35), 124 (20), 45 ([MeOCH2]ϩ, 52);
Found: 200.1287, [C10O14O3 ϩ NH4]ϩ requires 200.1287.
General experimental for the generation of alkylidene carbenes
TMSDM (trimethylsilyldiazomethane, 2.0 mmol, 2.0 M in
hexanes) was stirred in DME (3 ml) at Ϫ78 ЊC and to this n-
butyllithium (1.0 mmol, 2.5 M in hexanes) was added dropwise.
Once the addition was complete the reaction was stirred for 20
min and allowed to warm until a clear solution was observed
(Ϫ10 ЊC). The reaction was cooled to Ϫ60 ЊC and the ketone
(1.0 mmol) in DME (3 ml) was added slowly. Once the addition
was complete the reaction was stirred, allowed to come to rt
over 4 h and quenched by the addition of water (5 ml). The
reaction was extracted with ethyl acetate (3 × 5 ml), the com-
bined organic layers were dried over sodium sulfate and filtered,
and the solvent removed by rotary evaporation. Purification by
column chromatography followed or use of crude product in
the next step.
Preparation of ( )-methyl phenylglycolate 3
Preparation of 2-(methoxymethoxy)-2-phenylethanal 2
Methanol (50 ml) was stirred at 0 ЊC and to this, acetyl chloride
(3.0 ml, 42 mmol) was added dropwise. Once the addition was
complete, the cooling bath was removed and the reaction was
stirred at rt for 30 min. The reaction was cooled once more to
0 ЊC, as was a solution of ( )-mandelic acid (5.0 g, 33 mmol)
in methanol (6 ml). The 0.84 M solution of acetyl chloride–
methanol was added to the mandelic acid and the reaction
stirred overnight at rt. The solvent was removed by rotary
evaporation and the product was obtained as a white solid
(5.1 g, 92%), mp 57–58.5 ЊC (lit.,33 58 ЊC) with no further
purification required. Rf 0.70 (10% ethyl acetate–petroleum
ether); δH(CDCl3, 250.1 MHz) 7.44–7.26 (5H, m, aryl CH ),
5.28 (1H, d, J 5.8, CH ), 3.76 (3H, s, CH3), 3.52 (1H, d, J 5.8,
OH ); δC(CDCl3, 62.9 MHz) 174.1 (CO2R), 138.2 (aryl Ci),
128.6 (aryl Cm), 128.5 (aryl Cp), 126.6 (aryl Co), 72.8 (CH), 53.0
(CH3); m/z (CI) 184 ([M ϩ NH4]ϩ, 100%), 166 ([M]ϩ, 38), 149
([M Ϫ OH]ϩ, 28), 124 (7), 107 ([M Ϫ CO2Me]ϩ, 33), 94 (9),
79 (22).
Oxalyl chloride (0.66 ml, 1.32 mmol) was stirred in DCM
(2.5 ml) at Ϫ78 ЊC and to this DMSO (0.19 ml, 2.64 mmol) in
DCM (3 ml) was added over 5 min. The reaction was stirred for
a further 15 min before the addition of 2-(methoxymethoxy)-2-
phenylethanol 5 (0.15 g, 0.80 mmol) in DCM (3 ml). Once again
the reaction was stirred for 15 min after which time triethyl-
amine (0.76 ml, 5.50 mmol) was added and the cooling bath
removed. After 30 min stirring at rt and the addition of water
(5 ml), the aqueous layer was extracted with DCM (4 × 10 ml).
The combined organic layers were dried over sodium sulfate,
filtered and the solvent removed. Purification of the residue
by column chromatography eluting with 10% ethyl acetate–
petroleum ether gave the product as a colourless oil (0.13 g,
88%). Rf 0.43 (20% ethyl acetate–petroleum ether); νmax(neat)/
cmϪ1 3028 (w), 2943 (m), 2886 (m), 1738 (s); δH(CDCl3, 250.1
MHz) 9.61 (1H, d, J 7.8, CHO), 7.42–7.28 (5H, m, aryl CH ),
5.04 (1H, d, J 7.8, CH ), 4.78 (1H, d, JAB 6.7, OCHHЈO), 4.75
(1H, d, JAB 6.7, OCHHЈO), 3.42 (3H, s, CH3); δC(CDCl3,
62.9 MHz) 197.8 (C᎐O), 133.5 (aryl C ), 129.0 (aryl C ), 128.9
᎐
i
m
(aryl Cp), 127.6 (aryl Co), 95.1 (MeOCH2O), 83.1 (CH), 55.9
(CH3O). The aldehyde was prone to rapid oxidation and was
not fully characterised but used directly in the next step.
Preparation of methyl 2-(methoxymethoxy)-2-phenylethanoate 4
Methyl mandelate 3 (4.0 g, 24 mmol) and dimethoxymethane
(130 ml, 1.60 mol) were stirred vigorously in chloroform
(130 ml) at 0 ЊC. To this solution, phosphorus pentaoxide (70 g,
0.49 mol) was added and the reaction stirred for 2 h at rt. The
reaction was quenched at 0 ЊC with saturated sodium carbonate
solution (100 ml) and the chloroform removed by rotary
evaporation. The aqueous layer was extracted with diethyl ether
(4 × 120 ml), the combined organic layers were dried over
magnesium sulfate and filtered, and the solvent removed. Puri-
fication by column chomatography eluting with 7% ethyl
acetate–petroleum ether gave the product as a colourless oil
(4.57 g, 91%). Found: C 62.74% H 6.72%, C11H14O4 requires
C 62.86% H 6.67%. Rf 0.55 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 2954 (m), 2894 (m), 1753 (s), 1714 (m);
δH(CDCl3, 250.1 MHz) 7.48–7.28 (5H, m, aryl CH ), 5.18 (1H,
s, CH ), 4.74 (1H, d, JAB 6.8, MeOCHHЈO), 4.68 (1H, d, JAB 6.8,
MeOCHHЈO), 3.69 (3H, s, CO2CH3), 3.37 (3H, s, OCH3);
δC(CDCl3, 62.9 MHz) 170.8 (CO2Me), 135.8 (aryl Ci), 128.4
(aryl Cp), 128.3 (aryl Cm), 127.1 (aryl Co), 94.7 (MeOCH2O),
76.3 (CH), 55.5 (OCH3), 51.9 (CO2CH3); m/z (CI) 228 ([M ϩ
NH4]ϩ, 15%), 211 ([M ϩ H]ϩ, 9), 179 ([M Ϫ OMe]ϩ, 88), 166
Preparation of 3-(methoxymethoxy)-3-phenylpropyne 6
TMSDM (1.5 ml, 3.1 mmol) was lithiated with n-butyllithium
(1.2 ml, 3.0 mmol) and this reacted with 2-(methoxymethoxy)-
2-phenylethanal 2 (0.13 g, 0.72 mmol) in DME (5 ml) under the
standard conditions described. Purification by column chrom-
atography eluting with 5% ethyl acetate–petroleum ether gave
the product as a pale yellow oil (0.09 g, 70%). Rf 0.68 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3288 (m), 3033 (w),
2953 (m), 2890 (m); δH(CDCl3, 250.1 MHz) 7.56–7.34 (5H,
m, aryl CH ), 5.43–5.42 (1H, m, PhCH ), 5.03 (1H, d, J 6.7,
MeCHHЈO), 4.66 (1H, d, J 6.7, MeOCHHЈO), 3.44 (3H, s,
CH3O), 2.63 (1H, d, J 2.1, CCH ); δC(CDCl3, 62.9 MHz) 137.9
(aryl Ci), 128.6 (aryl C), 127.4 (aryl C), 93.8 (MeOCH2O), 81.3
(PhCH), 75.3 (PhCHCCH), 67.0 (PhCHCCH), 55.8 (CH3O);
m/z (CI) 194 ([M ϩ NH4]ϩ, 12%), 164 (10), 144 (41), 132 (75),
115 ([M Ϫ MeOCH2O]ϩ, 89), 89 (10), 63 (9), 45 ([MeOCH2]ϩ,
49), 18 (100); Found: 194.1181, [C11H12O2 ϩ NH4]ϩ requires
194.1181.
970
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

View Article Online
Preparation of 1-(methoxymethoxy)-1-phenylpropan-2-ol 9
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3063 (m), 3030
(m), 2981 (s), 2891 (s), 2825 (m), 1648 (w); δH(CDCl3, 250.1
MHz) 7.45–7.17 (5H, m, aryl CH ), 5.92–5.88 (1H, dq, J 3.8 and
2-(Methoxymethoxy)-2-phenylethanal 2 (0.5 g, 2.8 mmol) was
stirred in THF (20 ml) at Ϫ78 ЊC and to this solution methyl-
magnesium bromide (2.4 ml, 3.3 mmol) was added. The cooling
bath was removed once the addition was complete and the reac-
tion was stirred at rt overnight. The reaction was quenched by
the addition of saturated ammonium chloride solution (25 ml)
and extracted with diethyl ether (3 × 30 ml). The combined
organic extracts were dried over magnesium sulfate and filtered,
and the solvent removed by rotary evaporation. The crude
residue was purified by column chromatography eluting with
10–20% ethyl acetate–petroleum ether. The product was
obtained as a mixture of diastereoisomers in a ratio of 3 : 1 and
as a colourless oil (0.46 g, 84%). Rf 0.17 (15% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 3447 (br), 3029 (w), 2934 (m),
2888 (m); δH(CDCl3, 250.1 MHz) 7.38–7.26 (5Hmaj ϩ 5Hmin, m,
1.2, C᎐CH ), 5.61–5.57 (2H, m, PhCH and MeOCH ), 3.45 (3H,
᎐
s, CH O), 1.60 (3H, dd, J 1.5 and 1.2, CH C᎐CH); δ (CDCl ,
᎐
3
3
C
3
62.9 MHz) 145.5 (MeC᎐CH), 139.4 (aryl C ), 128.6 (aryl
᎐
i
C ), 128.2 (aryl C ), 127.0 (aryl C ), 120.9 (C᎐CH), 109.3
᎐
m
p
o
(MeOCH), 89.5 (PhCH), 54.6 (CH O), 12.4 (CH C᎐CH);
᎐
3
3
m/z (EI) 190 ([M]ϩ, 15%), 159 ([M Ϫ MeO]ϩ, 60), 129 (56), 91
(64), 57 (17), 51 (23), 45 (100); Found: 190.0994, [C12H14O2]ϩ
requires 190.0994.
Preparation of 1-(methoxymethoxy)-3-methyl-1-phenylbutan-2-
one 12
N,O-Dimethylhydroxylamine hydrogen chloride (70 mg,
0.74 mmol) was stirred as a slurry in THF (0.95 ml) at Ϫ20 ЊC
and to this solution isopropylmagnesium chloride (0.72 ml,
1.4 mmol, 2 M in THF) was added dropwise. Methyl 2-(meth-
oxymethoxy)-2-phenylethanoate 4 (0.10 g, 0.48 mmol) was then
added and the reaction stirred for 30 min. The reaction was
quenched by the addition of dilute ammonium chloride solu-
tion (5 ml) and extracted with diethyl ether (4 × 6 ml). The
combined organic extracts were dried over magnesium sulfate
and filtered, and the solvent removed by rotary evaporation.
Purification by column chromatography eluting with 10% ethyl
acetate–petroleum ether gave the product as a pale yellow oil
(0.06 g, 53%). Rf 0.39 (20% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 3062 (w), 3030 (w), 2970 (s), 2933 (m), 2890 (m),
2824 (w), 1726 (s); δH(CDCl3, 250.1 MHz) 7.38–7.35 (5H, m,
aryl CH ), 5.26 (1H, s, PhCH ), 4.67 (1H, d, JAB 7.3, MeO-
CHHЈO), 4.65 (1H, d, JAB 7.3, MeOCHHЈO), 3.36 (3H, s,
CH3O), 2.85 [1H, sept, J 6.8, (CH3)2CH], 1.06 [3H, d, J 6.8,
CH3C(H)CHЈ3], 0.94 [3H, d, J 6.8, CH3C(H)CHЈ3]; δC(CDCl3,
aryl CH ), 4.60 (1Hmin, d, JAB 6.8, MeOCHHЈO), 4.57 (1Hmin
,
d, JAB 6.8, MeOCHHЈO), 4.56 (2Hmaj, s, MeOCH2O), 4.51
(1Hmin, d, J 4.9, PhCH ), 4.31 (1Hmaj, d, J 7.9, PhCH ), 4.00–
3.85 (1Hmin ϩ 1Hmaj, m, MeCHOH), 3.39 (3Hmin, s, CH3O), 3.38
(3Hmaj, s, CH3O), 3.11 (1Hmaj, br s, OH ), 2.40 (1Hmin, br d,
J 4.9, OH ), 1.15 (3Hmin, d, J 6.4, CH3CH), 1.00 (3Hmaj, d, J 6.4,
CH3CH); δC(CDCl3, 62.9 MHz) 138.3 (aryl Ci)1Cmaj, 138.0 (aryl
Ci)1Cmin, 126.3 (aryl Cm2Cmaj, 128.1 (aryl Cm)2Cmin, 128.0 (aryl
Cp)1Cmaj, 127.7 (aryl Cp)1Cmin, 126.6 (aryl Co)2Cmaj ϩ 2Cmin
94.6 (CH2)1Cmin, 94.2 (CH2)1Cmaj, 83.7 (PhCH)1Cmaj, 82.2
(PhCH)1Cmin, 70.9 (MeCHOH)1Cmaj, 70.5 (MeCHOH)1Cmin
,
,
;
55.6 (CH3O)1Cmaj ϩ 1Cmin, 18.2 (CH3CH)1Cmaj ϩ 1Cmin
m/z (CI) 214 ([M ϩ NH4]ϩ, 100%), 198 (29), 184 (37), 170 (17),
152 ([M Ϫ MeOCH]ϩ, 65), 135 ([M Ϫ MeOCH2O]ϩ, 12), 120
(16), 105 ([M Ϫ PhCH2]ϩ, 19), 91 ([PhCH2]ϩ, 13), 52 (41), 47
(24); Found: 214.1443, [C11H16O3 ϩ NH4]ϩ requires 214.1443.
62.9 MHz) 211.0 (C᎐O), 135.5 (aryl C ), 128.8 (aryl C ), 128.7
Preparation of 1-(methoxymethoxy)-1-phenylpropan-2-one 8
᎐
i
p
(aryl Cm), 128.0 (aryl Co), 94.6 (OCH2O), 81.6 (PhCH), 55.8
(OCH3), 36.7 [(CH3)2CH], 19.1 [CH3(Me)CH], 18.8 [Me(CH3)
CH]; m/z (CI) 240 ([M ϩ NH4]ϩ, 100%), 223 ([M ϩ H]ϩ, 12),
191 ([M Ϫ MeO]ϩ, 100), 180 (45); Found: 223.1329, [C13H18O3
ϩ H]ϩ requires 223.1334.
Oxalyl chloride (1.41 ml, 2.82 mmol) was stirred at Ϫ78 ЊC in
DCM (6 ml) and to this solution DMSO (0.40 ml, 5.64 mmol)
was added in DCM (6 ml). The reaction was stirred for 20 min
before the addition of 1-(methoxymethoxy)-1-phenylpropan-
2-ol 9 (0.46 g, 2.35 mmol) in DCM (6 ml). Once more the
reaction was stirred for 20 min and then triethylamine (1.60 ml,
11.8 mmol) was added. The cooling bath was removed and the
reaction stirred for 30 min at rt. The reaction was quenched by
the addition of water (25 ml) and extracted with DCM (3 ×
25 ml). The combined organic extracts were dried over mag-
nesium sulfate and filtered, and the solvent removed. Purifica-
tion of the residue by column chromatography eluting with 7%
ethyl acetate–petroleum ether gave the product as a colourless
oil (0.27 g, 59%). Rf 0.47 (20% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 3059 (m), 2948 (m), 2824 (w), 1722 (s);
δH(CDCl3, 250.1 MHz) 7.43–7.27 (5H, m, aryl CH ), 5.10 (1H,
s, PhCH ), 4.70 (1H, d, J 6.7, MeOCHHЈO), 4.66 (1H, d, J 6.7,
MeOCHHЈO), 3.38 (3H, s, CH3O), 2.13 (3H, s, CH3C);
Preparation of 1-(methoxymethoxy)-4-methyl-1-phenylpent-2-
yne 13 and 4-isopropyl-2-methoxy-5-phenyl-2,5-dihydrofuran 14
TMSDM (0.45 ml, 0.90 mmol) was lithiated with n-butyl-
lithium (0.53 ml, 0.90 mmol) and reacted with 1-(methoxy-
methoxy)-3-methyl-1-phenylbutan-2-one 12 (50 mg, 0.22
mmol) in DME (3 ml) under the standard conditions described.
Purification by column chromatography eluting with 5%
ethyl acetate–petroleum ether gave the products 13 : 14 as an
inseparable mixture in a ratio of 16 : 1 in the form of a pale
yellow oil (0.03 g, 67%). Rf 0.60 (20% ethyl acetate–petroleum
ether); δH(CDCl3, 250.1 MHz) 7.41–7.22 (5Hmaj ϩ 5Hmin, m,
aryl CH ), 5.94–5.91 (1Hmin, m, C᎐CH ), 5.79–5.75 (1Hmin, m,
᎐
δ (CDCl , 62.9 MHz) 205.7 (C᎐O), 135.6 (aryl C ), 128.8 (aryl
MeOCH ), 5.59–5.56 (1Hmin, m, PhCH ), 5.59–5.56 (1Hmaj
,
᎐
C
3
i
Cm), 128.6 (aryl Cp), 127.4 (aryl Co), 94.7 (OCH2O), 83.4
(PhCH), 55.9 (OCH3), 25.7 (CH3C); m/z (CI) 212 ([M ϩ
NH4]ϩ, 67%), 180 (8), 168 (22), 163 ([M Ϫ MeO]ϩ, 100), 152
(13), 122 (7), 105 (19), 94 (11), 78 (8), 58 (12), 52 (42), 44 (15);
Found: 212.1287, [C11H14O3 ϩ NH4]ϩ requires 212.12867.
m, PhCH ), 5.12 (1Hmaj, d, J 6.2, MeOCHHЈ), 4.78 (1Hmaj, d,
J 6.2, MeOCHHЈ), 3.46 (3Hmin, s, CH3O), 3.35 (3Hmaj, s,
CH3O), 2.18–1.95 [1Hmaj ϩ 1Hmin, m, (CH3)2CH], 1.02 (3Hmaj
,
t, J 6.9, CH3CHCHЈ3), 0.85 (3Hmaj, d, J 6.3, CH3CHCHЈ3),
0.80 [6Hmin, dd, J 5.2 and 2.5, (CH3)2CH].
Preparation of 2-methoxy-4-methyl-5-phenyl-2,5-dihydrofuran
10
Preparation of 1,3-dimethoxypropan-2-ol 1934
Methanol (100 ml) was stirred at 0 ЊC and to this pieces of
sodium metal (0.60 g, 26.1 mmol) were added over 1 h. Once all
the sodium was consumed 1,3-dichloropropan-2-ol 18 (1.00 ml,
10.5 mmol) was added and the cooling bath removed. The
reaction was stirred at rt for 1.5 h and the sodium chloride
removed by filtration. Water (100 ml) was added to the reaction
and the aqueous methanol layer extracted with diethyl ether
(3 × 100 ml). The combined organic layers were dried over
TMSDM (1.13 ml, 2.26 mmol) was lithiated with n-butyl-
lithium (0.90 ml, 2.26 mmol) and reacted with 1-(methoxy-
methoxy)-1-phenylpropan-2-one (0.11 g, 0.57 mmol) in DME
(4 ml) under the standard conditions described. Purification
by column chromatography eluting with 5% ethyl acetate–
petroleum ether gave the product as an apparent single
diastereoisomer as a pale yellow oil (60 mg, 59%). Rf 0.68 (20%
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981
971

View Article Online
magnesium sulfate and filtered, and the solvent removed. The
crude residue was purified by column chromatography eluting
with 8–20% methanol-DCM and the product obtained as
a colourless oil (0.62 g, 49%). Rf 0.18 (60% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 3426 (br), 2982 (m), 2892 (s),
2822 (m); δH(CDCl3, 250.1 MHz) 4.00–3.94 (1H, m, CHOH),
3.50–3.38 (4H, m, OCH2CHCH2O), 3.39 (6H, s, OCH3), 2.72
(1H, br s, OH ); δC(CDCl3, 62.9 MHz) 73.5 (OCH2), 68.6 (CH),
58.5 (OCH3); m/z (CI) 138 ([M ϩ NH4]ϩ, 39%), 121 ([M ϩ H]ϩ,
13), 106 (30), 91 (42), 74 (100), 58 (54); Found: 138.1134,
[C5H12O3 ϩ NH4]ϩ requires 138.1130.
Preparation of 1,3-diethoxypropan-2-one 1637
1,3-Diethoxypropan-2-ol 20 (4.00 g, 27 mmol) was stirred
in DCM (150 ml) at rt with silica (11.7 g) and sodium acetate
(4.5 g, 54 mmol). To this PCC (11.7 g, 54.0 mmol) was added in
portions over 20 min and the reaction stirred overnight at rt.
The reaction was filtered through silica and the silica washed
with DCM (3 × 100 ml). The solvent was removed by rotary
evaporation, the crude residue purified by column chroma-
tography eluting with 20% ethyl acetate–petroleum ether and
the product obtained as a colourless oil (2.43 g, 62%). Rf 0.41
(40% ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 2978 (m),
2851 (m), 1730 (s); δH(CDCl3, 250.1 MHz) 4.23 [4H, s, CH2-
Preparation of 1,3-dimethoxypropan-2-one 1535
C(᎐O)CH ], 3.56 (4H, q, J 7.0, CH CH O), 1.25 (6H, t, J 7.0,
᎐
2
3
2
CH CH O); δ (CDCl , 62.9 MHz) 206.4 (C᎐O), 74.3 [OCH -
᎐
Sodium acetate (0.82 g, 10.0 mmol), silica (2.16 g) and 1,3-
dimethoxypropan-2-ol 19 (0.60 g, 5.0 mmol) were stirred at
0 ЊC in DCM (25 ml). PCC (2.16 g, 10.0 mmol) was added in
portions over 5 min and the reaction stirred for a further
10 min. The cooling bath was removed and the reaction stirred
at rt overnight. The reaction was filtered through silica, the
silica washed with DCM (3 × 30 ml) and the solvent removed
from the combined filtrate and washings. Purification of the
residue by column chromatography eluting with 40% ethyl
acetate–petroleum ether gave the product as a colourless oil
(0.21 g, 36%). Rf 0.36 (40% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 2999 (m), 2940 (m), 2835 (m), 1731 (s);
3
2
C
3
2
C(᎐O)CH O], 67.2 (MeCH O), 14.9 (CH ); m/z (CI) 164 ([M ϩ
᎐
2
2
3
NH4]ϩ, 76%), 149 (71), 147 ([M ϩ H]ϩ, 55), 103 (23), 87 ([M Ϫ
EtOCH2]ϩ, 12), 59 ([EtOCH2]ϩ, 100), 47 (22); Found: 164.1287,
[C7H14O3 ϩ NH4]ϩ requires 164.1286.
Preparation of 4-ethoxymethyl-2-methyl-2,5-dihydrofuran 32
TMSDM (1.20 ml, 2.40 mmol) was lithiated with n-butyl-
lithium (0.95 ml, 2.40 mmol) and reacted with 1,3-diethoxy-
propan-2-one 16 (0.18 g, 1.20 mmol) in DME (10 ml) under
the standard conditions described. Purification by column
chromatography eluting with 0–5% ethyl acetate–petroleum
ether gave the product as a pale yellow oil (0.09 g, 55%). Rf 0.65
(20% ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 2976 (m),
2931 (m), 2871 (m), 1654 (w); δH(CDCl3, 250.1 MHz) 5.67–5.64
δ (CDCl , 250.1 MHz) 4.19 [4H, s, OCH C(᎐O)CH O], 3.42
᎐
H
3
2
2
(6H, s, CH O); δ (CDCl , 62.9 MHz) 205.1 (C᎐O), 75.3
᎐
3
C
3
(OCH2CCH2O), 58.7 (CH3O); m/z (CI) 136 ([M ϩ NH4]ϩ,
100%), 106 (24), 77 (32), 74 (30), 58 (29); Found: 136.0975,
[C5H10O3 ϩ NH4]ϩ requires 136.0974.
(1H, m, C᎐CH ), 4.98–4.91 (1H, m, MeCH ), 4.70–4.52 (2H,
᎐
m, OCH C᎐CH), 4.06 (2H, d, J 0.9, OCH OEt), 3.48 (2H, q,
᎐
2
2
J 7.0, MeCH2O), 1.25 (3H, d, J 6.4, CH3CH), 1.20 (3H, t,
J 7.0, CH CH O); δ (CDCl , 62.9 MHz) 137.6 (C᎐CH), 127.3
Preparation of 3-methoxymethyl-2,5-dihydrofuran 3136
᎐
3
2
C
3
TMSDM (1.27 ml, 2.54 mmol) was lithiated with n-butyl-
lithium (1.01 ml, 2.54 mmol) and reacted with 1,3-dimeth-
oxypropan-2-one 15 (0.15 g, 1.27 mmol) in DME (10 ml) under
the standard conditions described. Purification by column
chromatography eluting with 0–5% ethyl acetate–petroleum
ether gave the product as a pale yellow oil (0.02 g, 14%). Rf 0.70
(20% ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 2859 (m),
2928 (m); δH(CDCl3, 250.1 MHz) 4.66–4.70 (5H, m, furan CH2
and CH ), 3.55–3.59 (2H, m, MeOCH2), 3.35 (3H, s, CH3O);
(C᎐CH), 82.3 (MeCH), 74.9 (furan CH ), 66.0 (EtOCH ), 65.9
(MeCH2O), 21.7 (CH3CH), 15.1 (CH3CH2O).
᎐
2
2
Preparation of 1,3-diisopropoxypropan-2-ol 21
Isopropyl alcohol (125 ml) was stirred at rt and to this pieces of
sodium (2.80 g, 122 mmol) were added over a period of 8 h.
Once all the sodium was consumed 1,3-dichloropropan-2-ol 18
(4.0 ml, 42 mmol) was added and the reaction stirred overnight
at rt. Water (100 ml) was added to the reaction which was then
extracted with diethyl ether (3 × 100 ml). The combined organic
extracts were dried over magnesium sulfate and filtered, and the
solvent evaporated off. Purification of the residue by column
chromatography eluting with 20% ethyl acetate–petroleum
ether gave the product as a colourless oil (4.14 g, 56%). Rf 0.46
(20% ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3440 (br),
2983 (m), 2862 (m), 1650 (w); δH(CDCl3, 250.1 MHz) 3.83–3.90
(1H, m, CHOH), 3.60 [2H, sept, J 6.1, CH(CH3)2], 3.49 (2H,
dd, JAB 9.6 and JAX 4.8, OCHHЈCHCHHЈO), 3.43 (2H, dd,
JAB 9.6 and JBX 6.1, OCHHЈCHCHHЈO), 2.78 (1H, br d, J 4.4,
OH ), 1.16 [12H, d, J 6.1, (CH3)2CH]; δC(CDCl3, 62.9 MHz)
71.9 [(CH3)2CHO], 69.6 (OCH2CHCH2O), 69.1 (CHOH), 21.8
(CH3); m/z (CI) 194 ([M ϩ NH4]ϩ, 8%), 177 ([M ϩ H]ϩ,
100), 135 (47), 117 ([M Ϫ (CH3)2CHO]ϩ, 6), 100 (14), 85 (11), 73
{[(CH3)2CHOCH2]ϩ, 30}, 43 {[(CH3)2CH]ϩ, 12}; Found:
194.1752, [C9H20O3 ϩ NH4]ϩ requires 194.1756.
δ (CDCl , 62.9 MHz) 155.8 (R C᎐CH), 129.6 (OCH C᎐CH),
᎐
᎐
2
C
3
2
120.5 (R C᎐CH), 115.3 (OCH CH᎐CR ), 59.3 (MeOCH ),
᎐
᎐
2
2
2
2
14.1 (CH3O).
Preparation of 1,3-diethoxypropan-2-ol 2034
Ethanol (200 ml) was stirred at rt and to this sodium (3.50 g,
152 mmol) was added in portions with occasional cooling.
Once addition of the sodium was completed the reaction was
stirred for a further 30 min and then 1,3-dichloropropan-2-ol 18
(5.00 ml, 52.4 mmol) was added. The reaction was stirred over-
night and then water (150 ml) was added. The majority of the
ethanol was removed and then the aqueous layer was extracted
with diethyl ether (3 × 150 ml). The combined organic layers
were dried over magnesium sulfate and filtered, and the solvent
removed. Purification of the residue by column chromato-
graphy eluting with 60% ethyl acetate–petroleum ether gave
the product as a colourless oil (4.57 g, 59%). Rf 0.51 (70% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3446 (br), 2973 (m),
2868 (m); δH(CDCl3, 250.1 MHz) 3.98–3.91 (1H, br m, CHOH),
3.52 (4H, q, J 7.0, MeCH2), 3.50 [2H, dd, JAB 9.7 and JAX 3.7,
OCHHЈCH(OH)CHHЈO], 3.45 [2H, dd, JAB 9.7 and JBX 6.4,
OCHHЈCH(OH)CHHЈO], 2.76 (1H, br d, J 2.4, CHOH ), 1.21
(6H, t, J 7.0, CH3CH2O); δC(CDCl3, 62.9 MHz) 77.6 (OCH-
2CHCH2O), 69.3 (CHOH), 66.6 (MeCH2O), 14.9 (CH3CH2O);
m/z (CI) 166 ([M ϩ NH4]ϩ, 48%), 149 ([M ϩ H]ϩ, 100), 103
([M Ϫ OCH2CH3]ϩ, 13), 87 (72), 59 ([CH3CH2OCH2]ϩ, 65);
Found: 149.1178, [C7H16O3 ϩ H]ϩ requires 149.1178.
Preparation of 1,3-diisopropoxypropan-2-one 17
Silica (3.7 g), sodium acetate (1.40 g, 17.0 mmol) and 1,3-
diisopropoxypropan-2-ol 21 (1.50 g, 8.51 mmol) were stirred at
0 ЊC in DCM (30 ml) and to this PCC (3.70 g, 17.0 mmol) was
added in portions over 10 min. Once the addition was complete
the cooling bath was removed and the reaction stirred overnight
at rt. The reaction was filtered through silica, the silica washed
with DCM (3 × 50 ml) and the solvent removed by rotary
evaporation. Purification of the residue by column chromato-
972
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

View Article Online
graphy eluting with 10% ethyl acetate–petroleum ether gave
the product as a colourless oil (0.89 g, 55%). Rf 0.55 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 2974 (s), 2933 (m),
2877 (m), 1738 (s); δH(CDCl3, 250.1 MHz) 4.23 [4H, s, CH2-
2876 (m), 1727 (s); δH(CDCl3, 299.9 MHz) 7.42–7.28 (10H, m,
aryl CH ), 4.57 (4H, s, PhCH2O), 4.24 [4H, s, OCH2C(O)-
CH O]; δ (CDCl , 75.4 MHz) 205.6 (C᎐O), 137.0 (aryl C ),
᎐
2
C
3
i
128.5 (aryl Cm), 128.0 (aryl Co), 127.9 (aryl Cp), 73.6 (CH2), 73.5
(CH2); m/z (CI) 288 ([M ϩ NH4]ϩ, 100%), 182 (29), 108 (41), 91
([PhCH2]ϩ, 22); Found: 288.1590, [C17H18O3 ϩ NH4]ϩ requires
288.1600.
C(᎐O)CH ], 3.63 [2H, sept, J 6.1, (CH ) CHO], 1.20 [12H, d,
᎐
2
3 2
J 6.1, (CH ) CH]; δ (CDCl , 62.9 MHz) 207.0 (C᎐O), 72.7
᎐
3
2
C
3
(Me CH), 72.2 [OCH C(᎐O)CH O], 21.7 (CH ); m/z (CI) 192
᎐
2
2
2
3
([M ϩ NH4]ϩ, 100%), 175 ([M ϩ H]ϩ, 88), 150 (25), 136 (96),
117 (22), 101 {[M Ϫ (CH3)2CH]ϩ, 64}, 58 (22), 47 (30); Found:
192.1560, [C9H18O3 ϩ NH4]ϩ requires 192.1560.
Preparation of 4-(benzyloxymethyl)-2-phenyl-2,5-dihydrofuran
33
TMSDM (1.85 ml, 3.70 mmol) was lithiated with n-butyl-
lithium (1.48 ml, 3.70 mmol) and reacted with 1,3-bis(benzyl-
oxy)propan-2-one 22 (0.50 g, 1.90 mmol) in DME (12 ml)
under the standard conditions described. Purification by
column chromatography eluting with 0.5% ethyl acetate–
petroleum ether gave the product as a pale yellow oil (0.36 g,
70%). Rf 0.41 (20% ethyl acetate–petroleum ether); νmax(neat)/
cmϪ1 3062 (w), 3028 (w), 2853 (m); δH(CDCl3, 250.1 MHz)
7.35–7.21 (10H, m, aryl CH ), 5.84–5.79 (2H, m, PhCH
Preparation of 4-isopropoxymethyl-2,2-dimethyl-2,5-dihydro-
furan 35
TMSDM (1.10 ml, 2.20 mmol) was lithiated with n-butyl-
lithium (0.88 ml, 2.20 mmol) and reacted with 1,3-diisoprop-
oxypropan-2-one 17 (0.19 g, 1.10 mmol) in DME (4 ml) under
the standard conditions described. Purification by column
chromatography eluting with 5% ethyl acetate–petroleum ether
gave the product as a pale yellow oil (0.05 g, 27%). Rf 0.54 (20%
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 2973 (s), 2932
(m), 2872 (m), 2247 (w); δH(CDCl3, 250.1 MHz) 5.50–5.48
and CH᎐C), 4.92–4.84 (1H, m, OCHHЈ), 4.81–4.73 (1H, m,
᎐
OCHHЈ), 4.53 (2H, s, PhCH2O), 4.16–4.20 (2H, m, BnO-
(1H, m, C᎐CH ), 4.49–4.47 (2H, m, CH᎐CCH O), 3.93–3.91
CHHЈ); δ (CDCl , 62.9 MHz) 141.9 (C᎐CH), 138.1 (aryl C ),
᎐
C 3 i
᎐
᎐
2
[2H, m, (CH3)2CHOCH2C], 3.52–3.46 [1H, m, (CH3)2CH], 1.18
(6H, s, CH3CCH3), 1.03 (3H, d, J 6.1, CH3CH), 1.00 (3H, d,
137.8 (aryl Ci), 128.4 (aryl Cm), 127.8 (aryl Cp), 127.7 (aryl Co),
127.6 (aryl Cp), 126.3 (aryl Co), 88.2 (PhCH), 75.8 (furan CH2),
J 6.1, CH CH); δ (CDCl , 62.9 MHz) 136.7 (R C᎐CH), 130.7
72.4 (PhCH ), 65.5 (BnOCH C᎐C); m/z (CI) 266 ([M]ϩ, 9),
᎐
᎐
3
C
3
3
2
2
(R C᎐CH), 87.9 [R C(CH ) ], 74.0 (furanCH ), 72.5 [CH-
58 (48), 145 (13), 122 (33), 115 (17), 105 (100), 91 ([PhCH2]ϩ,
100), 77 ([Ph]ϩ, 90), 69 (15), 65 (27), 51 (62), 43 (12); Found:
266.1307, [C18H18O2]ϩ requires 266.13068.
᎐
3
2
3
2
2
(CH3)2], 64.7 (PrOCH2O), 27.7 (CH3CCH3), 22.0 [CH3(Me)-
CH], 21.9 [Me(CH3)CH].
Preparation of 1,1-bis(benzyloxymethyl)ethylene 23
Preparation of ( )-2-( p-methoxyphenylmethoxymethyl)oxirane
25 (R ؍ MPM)
Sodium hydride (4.00 g, 0.10 mol) was stirred in DMF (200 ml)
at 0 ЊC and to this benzyl alcohol (10.4 ml, 0.10 mol) was added
dropwise. Once the addition was complete the reaction was
stirred for 20 min, the cooling bath was removed and stirring
continued for a further h at rt. 3-Chloro-2-chloromethylprop-1-
ene (4.8 ml, 40 mmol) was added and the reaction stirred over-
night. Saturated ammonium chloride solution (150 ml) was
added to quench the reaction and then the aqueous mixture was
extracted with ethyl acetate (4 × 200 ml). The combined organic
layers were dried over magnesium sulfate, filtered and concen-
trated. Purification of the residue by column chromatography
eluting with 10–20% ethyl acetate–petroleum ether gave the
product as a colourless oil (10.4 g, 97%). Found: C 80.62% H
7.82%, C18H20O2 requires C 80.60% H 7.46%. Rf 0.58 (30% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3087 (m), 3030 (m),
2926 (s), 2858 (s); δH(CDCl3, 299.9 MHz) 7.37–7.25 (10H, m,
Sodium hydride (0.84 g, 21 mmol) was stirred in DMF (30 ml)
at 0 ЊC and to this ( )-glycidol (1.13 ml, 17.0 mmol) was added
dropwise. The cooling bath was removed once the addition was
complete and the reaction stirred for 1 h at rt. The reaction
was cooled to 0 ЊC once more and p-methoxybenzyl chloride
(2.6 ml, 19 mmol) and tetrabutylammonium iodide (0.24 g,
0.87 mmol, 5%) added. The reaction was stirred for 3 days at rt,
quenched with saturated ammonium chloride solution (50 ml)
and extracted with diethyl ether (2 × 100 ml). The combined
organic layers were washed with water (5 × 100 ml), dried
over magnesium sulfate and filtered, and the solvent removed.
Purification of the residue by column chromatography eluting
with 10–20% ethyl acetate–petroleum ether gave the product as
a colourless oil (1.97 g, 60%). Rf 0.56 (20% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 3000 (m), 2934 (m), 2862 (m)
2838 (m); δH(CDCl3, 250.1 MHz) 7.30–7.24 (2H, m, aryl CH β
to COMe), 6.91–6.85 (2H, m, aryl CH α to COMe), 4.51 (2H,
dd, JAB 11.3, aryl CH2O), 3.80 (3H, s, CH3O), 3.72 (1H, dd,
JAB 11.3 and JAX 3.0, aryl OCHHЈ), 3.41 (1H, dd, JAB 11.3 and
JBX 5.8, aryl OCHHЈ), 3.20–3.14 (1H, m, CH ), 2.79 (1H, dd,
JAB 5.1 and JAX 4.2, RCHCHHЈ), 2.60 (1H, dd, JAB 5.1 and JBX
2.9, RCHCHHЈ); δC(CDCl3, 62.9 MHz) 159.1 (aryl CiOMe),
129.8 (aryl CCH2O), 129.3 (aryl CH β to COMe), 113.6 (aryl
CH α to COMe), 72.8 (aryl CH2O), 70.4 (CH2OCH2Ar), 55.1
(OCH3), 50.7 (CH), 44.2 (OCH2CH); m/z (EI) 194 ([M]ϩ,
100%), 163 ([M Ϫ OMe]ϩ, 6), 122 (69), 78 (22); Found:
194.0950, [C11H14O3]ϩ requires 194.0943.
aryl CH ), 5.26 (2H, d, J 0.9, CH ᎐CR ), 4.52 (4H, s, PhCH ),
᎐
2
2
2
4.07 [4H, d, J 0.9, OCH C(᎐CH )CH O]; δ (CDCl , 75.4 MHz)
᎐
2
2
2
C
3
142.6 (CH ᎐CR ), 138.2 (aryl C ), 128.3 (aryl C ), 127.6 (aryl
᎐
2
2
i
m
C ), 127.5 (aryl C ), 114.3 (CH ᎐CR ), 72.2 (CH ), 70.9 (CH );
᎐
o
p
2
2
2
2
m/z (CI) 286 ([M ϩ NH4]ϩ, 36%), 269 ([M ϩ H]ϩ, 59), 233
(53), 198 (26), 177 ([M Ϫ PhCH2]ϩ, 57), 131 (48), 108 (67), 91
([PhCH2]ϩ, 100), 65 (33).
Preparation of 1,3-bis(benzyloxy)propan-2-one 22
1,1-Bis(benzyloxymethyl)ethylene 23 (3.12 g, 11.6 mmol) was
stirred in DCM (40 ml) at Ϫ60 ЊC. An empty trap followed by
a trap containing a solution of 5% potassium iodide in 50%
acetic acid–water were connected to the outlet. Ozone was
passed through the reaction mixture for 35 min by which time
the solution appeared pale blue. Oxygen was bubbled through
the solution for 10 min followed by nitrogen for 20 min. Tri-
phenylphosphine (4.60 g, 17.5 mmol) was added and the cooling
bath removed. The reaction was stirred overnight, the solvent
removed and purified by column chromatography eluting with
10–25% ethyl acetate–petroleum ether yielding the product as a
white solid (3.02 g, 96%). Rf 0.25 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 3087 (w), 3063 (m), 3031 (m), 2936 (m),
Preparation of 1,3-bis( p-methoxyphenylmethoxy)propan-2-ol 26
(R ؍ RЈ ؍ MPM)
( )-2-(p-Methoxyphenylmethoxymethyl)oxirane 25 (R
=
MPM) (0.5 g, 2.6 mmol) was stirred in acetonitrile (7 ml)
with p-methoxybenzyl alcohol (0.39 ml, 3.10 mmol). Lithium
perchlorate (0.55 g, 5.20 mmol) was added and the reaction
heated at 95 ЊC overnight. Water (15 ml) was added to the
cooled reaction, which was then extracted with diethyl ether
(3 × 15 ml). The combined organic layers were dried over
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981
973

View Article Online
magnesium sulfate and filtered, and the solvent removed by
evaporation. The residue was purified by column chromato-
graphy eluting with 0–40% ethyl acetate–petroleum ether to
give the product as a colourless oil (0.26 g, 36%). Rf 0.27 (20%
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3438 (br), 3003
(w), 2926 (m), 2855 (w); δH(CDCl3, 250.1 MHz) 7.25–7.29 (4H,
m, aryl CH β to COMe), 6.85–6.89 (4H, m, aryl CH α to
COMe), 4.47 (4H, s, aryl CH2O), 4.02–3.94 (1H, m, OCH2CH-
CH2O), 3.80 (6H, s, CH3O), 3.51 (2H, dd, JAB 9.6 and JAX 4.7,
OCHHЈCHCHHЈO), 3.48 (2H, dd, JAB 9.6 and JBX 6.1, OCH-
HЈCHCHHЈO), 2.28 (1H, s, CHOH ); δC(CDCl3, 62.9 MHz)
159.2 (aryl CiOMe), 130.0 (aryl CiC), 129.4 (aryl CH β to
COMe), 113.8 (aryl CH α to COMe), 73.1 (arylCH2O), 71.0
(OCH2CHCH2O), 69.6 (CHOH), 55.2 (OCH3); m/z (CI) 350
([M ϩ NH4]ϩ, 4%), 211 ([M Ϫ MeOC6H4CH2]ϩ, 4), 154 (19),
138 (32), 136 (20), 121 ([MeOC6H4CH2]ϩ, 100); Found:
350.1962, [C19H24O5 ϩ NH4]ϩ requires 350.1967.
Preparation of ( )-2-benzyloxymethyloxirane 25 (R ؍ Bn)
Sodium hydride (1.05 g, 43.7 mmol) was stirred in THF (25 ml)
at 0 ЊC and to this ( )-glycidol (2.42 ml, 36.0 mmol) was
added slowly over 10 min. The reaction was stirred at rt for
1 h before cooling once more to 0 ЊC. Benzyl bromide (5.20 ml,
43.7 mmol) was added and the reaction stirred overnight at rt.
The reaction was quenched by the addition of saturated
ammonium chloride solution (30 ml) and extracted with diethyl
ether (3 × 30 ml). The organic layers were combined, dried over
magnesium sulfate and filtered, and the solvent removed by
rotary evaporation. Purification of the residue by column
chromatography eluting with 5% ethyl acetate–petroleum ether
gave the product as a colourless oil (4.44 g, 74%). Found: C
72.69% H 7.24%, C10H12O2 requires C 73.17% H 7.32%. Rf 0.58
(20% ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3060 (w),
3029 (w), 2997 (w), 2861 (m); δH(CDCl3, 250.1 MHz) 7.37–7.25
(5H, m, aryl CH ), 4.60 (1H, d, JAB 11.9, PhCHHЈO), 4.56 (1H,
d, JAB 11.9, PhCHHЈO), 3.76 (1H, dd, JAB 11.3 and JAX 3.1,
BnOCHHЈ), 3.43 (1H, dd, JAB 11.3 and JAX 5.9, BnOCHHЈ),
3.22–3.16 (1H, m, CH ), 2.79 (1H, dd, JAB 4.9 and JAX 4.1,
CHCHHЈ), 2.61 (1H, dd, JAB 4.9 and JAX 2.8, CHCHHЈ);
δC(CDCl3, 62.9 MHz) 137.8 (aryl Ci), 128.4 (aryl Cm), 127.7
(aryl Co ϩ p), 73.2 (PhCH2O), 70.8 (BnOCH2), 50.8 (CH), 44.2
(OCH2CH); m/z (EI) 164 ([M]ϩ, 23%), 107 ([PhCH2O]ϩ, 92), 91
([PhCH2]ϩ, 100), 84 (34), 79 (70), 65 (55), 57 ([epoxideCH2]ϩ,
32), 51 (32), 43 (47).
Preparation of 1,3-bis( p-methoxyphenylmethoxy)propan-2-one
24
1,3-Bis(p-methoxyphenylmethoxy)propan-2-ol 26 (R = RЈ =
MPM) (0.36 g, 1.1 mmol), silica (0.5 g) and sodium acetate
(0.18 g, 2.2 mmol) were stirred in DCM (10 ml) at 0 ЊC. To
this solution PCC (0.5 g, 2.2 mmol) was added and after 30 min
the cooling bath was removed. The reaction was stirred over-
night and filtered through silica. The silica was washed with
DCM (3 × 20 ml) and the solvent removed by evaporation.
After purification of the residue by column chromatography
eluting with 20–30% ethyl acetate–petroleum ether the product
was obtained as a colourless oil (0.14 g, 39%) which was a white
solid at Ϫ18 ЊC. Rf 0.35 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 3002 (w), 2936 (m), 2837 (m), 1732 (s);
δH(CDCl3, 250.1 MHz) 7.28–7.22 (4H, m, aryl CH α to
COMe), 6.90–6.95 (4H, m, aryl CH β to COMe), 4.49 (4H,
Preparation of 1-benzyloxy-3-methoxypropan-2-ol 26 (R ؍ Bn,
RЈ ؍ Me)
2-Benzyloxymethyloxirane 25 (R = Bn) (1.5 g, 9.2 mmol) was
stirred in methanol (40 ml) at rt and to this solution lithium
perchlorate (1.95 g, 18.3 mmol) was added and the reaction
refluxed for 3 days. After cooling to rt the reaction was
quenched by the addition of water (40 ml) and extracted with
diethyl ether (3 × 40 ml). The combined organic layers were
dried over magnesium sulfate and filtered, and the solvent
evaporated off. Purification of the residue by column chromato-
graphy eluting with 5–10% ethyl acetate–petroleum ether gave
the product as a colourless oil (1.25 g, 69%). Rf 0.30 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3429 (br), 3062 (w),
3029 (w), 2894 (m); δH(CDCl3, 250.1 MHz) 7.35–7.28 (5H,
m, aryl CH ), 4.56 (2H, s, PhCH2), 4.01–3.97 (1H, m, CH ),
3.59–3.41 [4H, m, CH2CH(OH)CH2], 3.37 (3H, s, CH3O), 2.67
(1H, br s, OH ); δC(CDCl3, 62.9 MHz) 137.9 (aryl Ci), 128.4
(aryl Cm), 127.7 (aryl Co ϩ p), 73.7 (CH2OMe), 73.4 (OCH2Ph),
71.3 (CH2OBn), 69.4 (CHOH), 59.1 (OCH3); m/z (EI) 196
([M]ϩ, 36%), 107 (73), 91 ([PhCH2]ϩ, 100), 72 ([MeOCH2-
HCHCH2]ϩ, 81), 65 (63), 58 ([MeOCH2CH]ϩ, 21), 51 (29), 45
([MeOCH2]ϩ, 81); Found: 196.1100, [C11H16O3]ϩ requires
196.10995.
s, aryl CH O), 4.19 [4H, s, OCH C(᎐O)CH O], 3.80 (6H, s,
᎐
2
2
2
CH O); δ (CDCl , 62.9 MHz) 205.8 (C᎐O), 159.3 (aryl
᎐
3
C
3
CiOMe), 129.5 (aryl CiC), 128.8 (aryl CH β to COMe), 113.7
(aryl CH α to COMe), 73.0 (CH2), 72.9 (CH2), 55.1 (OCH3);
m/z (EI) 330 ([M]ϩ, 4%), 267 (54), 241 (16), 209 ([M Ϫ MeO-
C6H4CH2]ϩ, 76), 195 (57), 149 (17), 137 ([MeOC6H4CH2O]ϩ,
76), 121 ([MeOC6H4CH2]ϩ, 100), 109 (38), 91 (52), 78 (72), 65
(32), 51 (42), 39 (29); Found: 330.1439, [C19H22O5]ϩ requires
330.1467.
Preparation of 2-( p-methoxyphenyl)-4-( p-methoxyphenyl-
methoxymethyl)-2,5-dihydrofuran 34
TMSDM (0.43 ml, 0.86 mmol) was lithiated with n-butyl-
lithium (0.38 ml, 0.86 mmol) and reacted with 1,3-bis(p-meth-
oxyphenylmethoxy)propan-2-one 24 (0.14 g, 0.43 mmol) in
DME (5 ml) under the standard conditions described. Purifica-
tion by column chromatography eluting with 5% ethyl acetate–
petroleum ether gave the product as a pale yellow oil (0.09 g,
61%); mp 38.5–39.0 ЊC; Rf 0.23 (20% ethyl acetate–petroleum
ether); νmax(hexachlorobuta-1,3-diene)/cmϪ1 >3000 (w), 2997
(w), 2951 (m), 2835 (m), 1652 (w); δH(CDCl3, 250.1 MHz) 7.28–
7.20 (4H, m, aryl CH β COMe), 6.92–6.84 (4H, m, aryl CH α to
Preparation of 1-benzyloxy-3-methoxypropan-2-one 27
Oxalyl chloride (1.80 ml, 2.47 mmol) was stirred at Ϫ78 ЊC in
DCM (3 ml) and to this DMSO (0.35 ml, 4.94 mmol) in DCM
(3 ml) was added dropwise. The reaction was stirred for 20 min
before the addition of 1-benzyloxy-3-methoxypropan-2-ol 26
(R = Bn, RЈ = Me) (0.40 g, 1.90 mmol) in DCM (3 ml). Once
more the reaction was stirred for 20 min and then triethylamine
(1.43 ml, 10.3 mmol) was added and the cooling bath removed.
The reaction was stirred for 40 min at rt and then quenched by
the addition of water (12 ml). The layers were separated and the
aqueous layer extracted with DCM (3 × 10 ml). The combined
organic layers were dried over magnesium sulfate and filtered,
and the solvent removed. The product was isolated by column
chromatography eluting with 10% ethyl acetate–petroleum
ether as a colourless oil (0.37 g, 89%). Rf 0.56 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3062 (w), 3029 (w),
2974 (m), 2894 (m), 1730 (s); δH(CDCl3, 250.1 MHz) 7.38–7.29
COMe), 5.78–5.75 (2H, m, ArCHO and R C᎐CH ), 4.88–4.79
᎐
2
(1H, dm, OCHHЈC᎐CH), 4.76–4.68 (1H, dm, OCHHЈC᎐CH),
᎐
᎐
4.48 (2H, s, ArCH2O), 4.18 (2H, m, ArCH2OCH2), 3.80 (3H, s,
OCH3), 3.79 (3H, s, OCH3); δC(CDCl3, 62.9 MHz) 159.3 (aryl
CiOMe), 159.2 (aryl CiOMe), 138.1 (aryl CiC), 133.8 (aryl CiC),
129.7 (R C᎐CH), 129.2 (aryl CH β to COMe), 127.7 (aryl CH
᎐
2
β to COMe), 126.2 (C᎐CH), 113.7 (aryl CH α to COMe),
᎐
87.7 (ArCH), 75.5 (furan CH2), 72.0 (ArCH2O), 65.1 (ArCH2-
OCH C᎐C), 55.1 (OCH ); m/z (CI) 327 ([M ϩ H]ϩ, 4%), 188
᎐
2
3
(7), 159 (4), 135 (22), 121 ([MeOC6H4CH2]ϩ, 100), 115 (24), 108
(4), 91 (9), 78 (6), 58 (4); Found: 327.1596, [C20H22O4 ϩ H]ϩ
requires 327.1596.
974
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

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(5H, m, aryl CH ), 4.59 (2H, s, PhCH2), 4.22 (2H, s, BnOCH2),
4.21 (2H, s, MeOCH2), 3.40 (3H, s, CH3O); δC(CDCl3, 62.9
were dried over magnesium sulfate and filtered, and the solvent
removed. Purification of the residue by column chromato-
graphy eluting with 10% ethyl acetate–petroleum ether gave
the product as a colourless oil (0.26 g, 66%). Rf 0.65 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3071 (m), 3030 (m),
2976 (m), 2914 (m), 1732 (s); δH(CDCl3, 250.1 MHz) 7.40–7.30
(5H, m, aryl CH ), 4.59 (2H, s, PhCH2), 4.24 (2H, s, BnO-
CH2C), 4.23 (2H, s, EtOCH2C), 3.53 (2H, q, J 7.0, MeCH2O),
1.23 (3H, t, J 7.0, CH3CH2O); δC(CDCl3, 62.9 MHz) 206.0
MHz) 205.6 (C᎐O), 136.9 (aryl C ), 128.5 (aryl C ), 128.0 (aryl
᎐
i
m
Cp), 127.9 (aryl Co), 76.1 (PhCH2O), 73.5 [CH2C(O)CH2], 73.4
[CH2C(O)CH2], 59.4 (CH3O); m/z (CI) 212 ([M ϩ NH4]ϩ,
14%), 122 (5), 108 (43), 91 ([PhCH2]ϩ, 100), 78 (15), 65 (4), 58
(7), 51 (4), 45 ([MeOCH2]ϩ, 19); Found: 212.1282, [C11H14O3 ϩ
NH4]ϩ requires 212.1287.
(C᎐O), 137.0 (aryl C ), 128.5 (aryl C ), 128.0 (aryl C ), 127.8
᎐
Preparation of 4-(methoxymethyl)-2-phenyl- (A) and 3-(benzyl-
oxymethyl)-2,5-dihydrofurans (B) from 27
i
m
p
(aryl Co), 74.3 (PhCH2O), 73.5 [CH2C(O)CH2], 73.4 [CH2C-
(O)CH2], 67.2 (MeCH2O), 14.9 (CH3); m/z (CI) 226 ([M ϩ
NH4]ϩ, 50%), 195 (18), 184 (33), 195 (50), 138 (14), 120 (27),
108 (85), 91 ([PhCH2]ϩ, 100), 76 (46), 65 (23), 59 ([EtOCH2]ϩ,
78), 47 (68); Found: 226.1443, [C12H16O3 ϩ NH4]ϩ requires
226.1443.
TMSDM (1.03 ml, 2.06 mmol) was lithiated with n-butyl-
lithium (0.82 ml, 2.06 mmol) and reacted with 1-benzyloxy-3-
methoxypropan-2-one (0.20 g, 1.03 mmol) in DME (8 ml)
under the standard conditions described. Purification by col-
umn chromatography eluting with 5% ethyl acetate–petroleum
ether gave the products as an inseparable mixture in a 2 : 1 ratio
(0.07 g, 34%) in the form of a yellow oil. Rf 0.45 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3029 (w), 2923 (m),
Preparation of 4-ethoxymethyl-2-phenyl- (A) and 4-(benzyloxy-
methyl)-2-methyl-2,5-dihydrofuran (B) from 28
TMSDM (2.00 ml, 4.00 mmol) was lithiated with n-butyl-
lithium (1.6 ml, 4.0 mmol) and reacted with 1-benzyloxy-3-
ethoxypropan-2-one (0.26 g, 1.26 mmol) in DME (6 ml) under
the standard conditions described. Purification by column
chromatography eluting with 1–10% ethyl acetate–petroleum
ether gave the products as an inseparable mixture in a 5 : 3 ratio
(0.14 g, 52%) in the form of a pale yellow oil. Rf 0.52 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3036 (w), 3000 (w),
2956 (m), 2931 (m), 2837 (m); δH(CDCl3, 250.1 MHz) 7.71–7.16
2851 (m); δH(CDCl3, 250.1 MHz) 7.36–7.18 (5Hmin ϩ 5Hmaj
,
m, aryl CH ), 5.85–5.77 (1Hmin ϩ 2Hmaj, m, C᎐CH and C᎐
᎐
᎐
CHCHPh), 4.90–4.72 (2Hmaj, m, CH2OCH), 4.71–4.63 (4Hmin
m, CH2OCH2), 4.52 (2Hmin, s, PhCH2), 4.14–4.13 (2Hmin, m,
BnOCH2), 4.11–4.10 (2Hmaj, m, MeOCH2), 3.38 (3Hmaj, s,
,
CH O); δ (CDCl , 62.9 MHz) 141.8 (C᎐CH)1C , 137.9 (C᎐
᎐
᎐
3
C
3
min
CH)1Cmaj, 137.8 (aryl Ci)1Cmin, 137.4 (aryl Ci)1Cmaj, 129.5 (aryl
Cp)1Cmaj, 128.5 (aryl Cm)2Cmaj, 128.4 (aryl Cm)2Cmin, 127.8 (aryl
Cp)1Cmin, 127.7 (aryl Co)2Cmin, 126.3 (aryl Co)2Cmaj, 122.8 (C᎐
᎐
(5Hmaj ϩ 5Hmin, m, aryl CH ), 5.85–5.76 (2Hmin, m, PhCHCH᎐
᎐
CH)1Cmaj, 120.2 (C᎐CH)1Cmin, 88.2 (PhCH)1Cmaj, 75.8 (furan
᎐
C), 5.73–.69 (1Hmaj, m, C᎐CH ), 5.08–4.95 (1Hmaj, m, MeCH ),
᎐
CH2), 75.7 (furan CH2), 75.5 (furan CH2), 72.3 (PhCH2)1Cmin
,
4.92–4.72 (2Hmin, m, OCH C᎐CH), 4.76–4.57 (2Hmaj, m,
᎐
2
68.0 (MeOCH C᎐C)1C , 65.5 (BnOCH C᎐C)1Cmin, 58.3
᎐
᎐
2
2
maj
(OCH3)1Cmaj; m/z (CI) 208 ([M ϩ NH4]ϩ, 41%), 191 ([M ϩ H]ϩ,
100), 173 (17), 159 (39), 141 (17), 129 (18), 117 (16), 105 (91), 91
([PhCH2]ϩ, 86), 84 (30), 65 (18), 45 ([MeOCH2]ϩ, 45); Found:
191.1072, [C12H14O2 ϩ H]ϩ requires 191.1072.
2
CH C᎐CH), 4.51–4.55 (2Hmaj, m, PhCH2), 4.17 (2Hmin, s,
᎐
EtOCH2), 4.12 (2Hmaj, s, BnOCH2), 3.53 (2Hmin, q, J 7.0,
MeCH2O), 1.28 (3Hmaj, d, J 6.4, CH3CH), 1.25 (3Hmin, t, J 7.0,
CH3CH2O); δC(CDCl3, 62.9 MHz) 137.7 (aryl Ci)1Cmin, 137.3
(aryl Ci)1Cmaj, 129.6 (aryl C), 128.4 (aryl C), 127.8 (aryl C),
127.7 (aryl C), 126.3 (aryl C), 88.2 (PhCH)1Cmin, 82.4
Preparation of 1-benzyloxy-3-ethoxypropan-2-ol 26 (R ؍ Bn,
RЈ ؍ Et)
(MeCH)1Cmaj, 75.9 (furan CH2)1Cmin, 74.9 (furan CH2)1Cmaj
72.4 (Ph CH2)1Cmaj, 66.0 (EtOCH C᎐CH and MeCH O)2C
min
,
,
᎐
2
2
2-Benzyloxymethyloxirane 25 (R = Bn) (1.5 g, 9.2 mmol) was
stirred in ethanol (40 ml) at rt and lithium perchlorate (1.95 g,
18.3 mmol) added. The reaction was refluxed for 3 days,
quenched by the addition of water (50 ml) at rt and extracted
with diethyl ether (3 × 50 ml). The combined organic layers
were dried over magnesium sulfate, filtered and concentrated.
Purification of the residue by column chromatography eluting
with 10% ethyl acetate–petroleum ether gave the product as a
colourless oil (1.2 g, 62%). Rf 0.41 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 3443 (br), 3062 (w), 3029 (w), 2974 (m),
2865 (s); δH(CDCl3, 250.1 MHz) 7.36–7.28 (5H, m, aryl CH ),
4.56 (2H, s, PhCH2O), 4.04–3.94 (1H, m, CH ), 3.59–3.42 [6H,
m, MeCH2OCH2CH(OH)CH2], 2.62 (1H, d, J 4.3, OH ), 1.20
(3H, t, J 7.0, CH3CH2O); δC(CDCl3, 62.9 MHz) 137.9 (aryl
Ci), 128.4 (aryl Cm), 127.7 (aryl Co), 73.4 (PhCH2O), 71.6
(EtOCH2), 71.3 (BnOCH2), 69.5 (CHOH), 66.8 (MeCH2O),
15.1 (CH3); m/z (EI) 210 ([M]ϩ, 36%), 164 (36), 107
([PhCH2O]ϩ, 67), 91 ([PhCH2]ϩ, 100), 61 (79), 43 (56); Found:
210.1256, [C12H18O3]ϩ requires 210.1256.
65.6 (BnOCH C᎐CH)1Cmaj, 22.7 (CH3CH)1Cmaj, 15.1 (CH3-
᎐
2
CH2O)1Cmin; m/z (CI) 222 ([M ϩ NH4]ϩ, 77%), 205 ([M ϩ H]ϩ,
84), 187 (53), 159 ([M Ϫ EtO]ϩ, 70), 113 ([M Ϫ Bn]ϩ, 58), 105
(74), 95 (67), 91 ([PhCH2]ϩ, 100), 85 (35), 81 (43), 59
([EtOCH2]ϩ, 43), 41 (35); Found: 205.1229, [C13H16O2 ϩ NH4]ϩ
requires 205.1228.
Preparation of 1-benzyloxy-3-( p-methoxybenzyloxy)propan-2-ol
26 (R ؍ MPM, RЈ ؍ Bn)
2-(p-Methoxybenzyloxymethyl)oxirane 25 (R = MPM) (1.00 g,
5.16 mmol) was stirred in benzyl alcohol (8 ml, excess) at rt and
to this lithium perchlorate (1.09 g, 10.3 mmol) was added. The
reaction was stirred at 60 ЊC for 4 days, water (20 ml) added
and the mixture extracted with ethyl acetate (3 × 30 ml). The
combined organic layers were dried over magnesium sulfate
and filtered, and the solvent removed by rotary evaporation.
Purification of the residue by column chromatography eluting
with 10–40% ethyl acetate–petroleum ether gave the product as
a colourless oil (1.38 g, 89%). Rf 0.14 (20% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 3442 (br), 3062 (w), 3002 (w),
2907 (s), 2861 (s); δH(CDCl3, 250.1 MHz) 7.37–7.28 (5H, m,
phenyl CH ), 7.27–7.21 (2H, m, aryl CH β to COMe), 6.90–6.84
(2H, m, aryl CH α to COMe), 5.54 (2H, s, MeOC6H4CH2), 4.47
(2H, s, PhCH2), 4.04–3.96 (1H, m, CHOH), 3.79 (3H, s, OCH3),
3.58–3.45 (4H, m, OCH2CHCH2O), 2.57 (1H, br s, CHOH );
δC(CDCl3, 62.9 MHz) 159.2 (aryl CiOMe), 137.9 (phenyl CiC),
130.0 (aryl CiC), 129.3 (aryl CH β to COMe), 128.4 (phenyl
Preparation of 1-benzyloxy-3-ethoxypropan-2-one 28
Oxalyl chloride (1.70 ml, 2.47 mmol) was stirred in DCM (3 ml)
at Ϫ78 ЊC and DMSO (0.35 ml, 4.94 mmol) in DCM (3 ml) was
added dropwise. The reaction was stirred for 20 min and then
1-benzyloxy-3-ethoxypropan-2-ol 26 (R = Bn, RЈ = Et) (0.40 g,
1.90 mmol) in DCM (3 ml) was added. Once more the reaction
was stirred for 20 min, triethylamine (1.43 ml, 10.3 mmol)
added and the cooling bath removed. The reaction was stirred
for 40 min at rt, quenched by the addition of water (12 ml) and
extracted with DCM (3 × 10 ml). The combined organic layers
Cm), 127.7 (phenyl Cp o), 113.8 (aryl CH α to COMe), 73.4
ϩ
(PhCH2O), 73.0 (ArCH2O), 71.3 (BnOCH2), 70.9 (ArOCH2),
69.5, (CH) 55.2 (CH3O); m/z (EI) 302 ([M]ϩ, 7%), 21 ([M Ϫ
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981
975

View Article Online
PhCH2]ϩ, 70), 181 ([M Ϫ MeOC6H4CH2]ϩ, 60), 137 ([MeO-
C6H4CH2O]ϩ, 86), 121 ([MeOC6H4CH2]ϩ, 100), 91 ([PhCH2]ϩ,
92), 77 ([Ph]ϩ, 67), 65 (62), 51 (58); Found: 302.1527,
[C18H22O4]ϩ requires 302.1518.
was quenched by the addition of saturated ammonium chloride
solution (150 ml), extracted with ethyl acetate (3 × 150 ml)
and the combined organic layers were washed with water (4 ×
150 ml), dried over magnesium sulfate, filtered and concen-
trated. Purification of the residue by column chromatography
eluting with 5–10% ethyl acetate–hexane gave the product as a
colourless oil (3.87 g, 56%). Rf 0.78 (30% ethyl acetate–
petroleum ether). Found: C 77.40% H 11.41%, C9H16O requires
C 77.14% H 11.43%. νmax(neat)/cmϪ1 2959 (s), 2915 (s), 1454
Preparation of 1-benzyloxy-3-( p-methoxybenzyloxy)propan-2-
one 29
1-Benzyloxy-3-(p-methoxybenzyloxy)propan-2-ol 26 (R
=
MPM, RЈ = Bn) (1.00 g, 3.31 mmol), silica (1.43 g) and sodium
acetate (0.54 g, 6.62 mmol) were stirred in DCM (20 ml) at 0 ЊC.
PCC (1.43 g, 6.62 mmol) was added in portions over 10 min
and cooling was maintained for a further 20 min. The reaction
was stirred for 48 h at rt and then filtered through silica. The
silica was washed with DCM (2 × 50 ml) and the solvent
removed from the combined filtrate and washings by rotary
evaporation. Purification of the residue by column chromato-
graphy eluting with 5–20% ethyl acetate–petroleum ether gave
the product as a colourless oil (0.28 g, 28%). Rf 0.32 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3063 (w), 3031 (w),
3004 (w), 2935 (m), 2864 (m), 2837 (m), 1735 (s); δH(CDCl3,
250.1 MHz) 7.39–7.30 (5H, m, phenyl CH ), 7.28–7.22 (2H,
m, aryl CH β to COMe), 6.91–6.85 (2H, m, aryl CH α to
COMe), 4.56 (2H, s, ArCH2O), 4.49 (2H, s, PhCH2O), 4.23 [2H,
(m); δH (CDCl , 299.9 MHz) 4.97–4.95 (1H, m, C᎐CHHЈ),
᎐
3
4.87–4.85 (1H, m, C᎐CHHЈ), 3.95–3.88 (1H, m, CH CHCH ),
᎐
2
2
3.83 (2H, s, OCH C᎐CH ), 1.77–1.59 [6H, m, OCHCH (CH-
᎐
2
2
2
HЈ)2CH2], 1.73 (3H, s, CH3), 1.55–1.49 [2H, m, OCH2(CH-
HЈ) CH ]; δ (CDCl , 75.4 MHz) 142.9 (CH C᎐C), 111.4
᎐
3
2
2
C
3
(CH ᎐C), 80.6 (CH), 72.6 (CCH O), 32.2 (CH C), 23.5
᎐
2
2
3
(OCHCH2CH2CH2CH2), 19.6 (OCHCH2CH2CH2CH2).
Preparation of 1-cyclopentyloxypropan-2-one 30
1-Cyclopentyloxy-2-methylpropene (1.50 g, 10.7 mmol) was
stirred in DCM (20 ml) at Ϫ60 ЊC. An empty trap followed by
a trap containing a solution of 5% potassium iodide in 50%
acetic acid–water were connected to the outlet and then ozone
bubbled through the reaction for 30 min. Air and nitrogen were
bubbled through for a further 30 min each and then triphenyl-
phosphine (4.22 g, 16.1 mmol) was added. The cooling bath was
removed and the reaction stirred overnight at rt. The solvent
was removed by evaporation and purification of the residue by
column chromatography eluting with 10% ethyl acetate–
petroleum ether gave the product as a colourless oil (1.36 g,
90%). Rf 0.44 (30% ethyl acetate–petroleum ether); νmax(neat)/
s, ROCH C(᎐O)CH ORЈ], 4.20 [2H, s, ROCH C(᎐O)CH ORЈ],
᎐
᎐
2
2
2
2
3.79 (3H, s, CH O); δ (CDCl , 62.9 MHz) 205.8 (C᎐O), 159.4
᎐
3
C
3
(aryl CiOMe), 136.9 (phenyl Ci), 129.6 (aryl Ci), 128.5 (aryl C β
to COMe), 127.9 (phenyl Cp), 128.9 (phenyl Cm), 128.0 (phenyl
Co), 113.8 (aryl CH α to COMe), 73.5 (CH2), 73.4 (CH2), 73.2
(CH2), 73.1 (CH2), 55.2 (CH3O); m/z (CI) 318 ([M ϩ NH4]ϩ,
41), 138 (35), 121 ([MeOC6H4CH2]ϩ, 100); Found: 318.1712,
[C18H20O4 ϩ NH4]ϩ requires 318.1705.
cmϪ1 2957 (s), 2871 (m), 1719 (s) C᎐O; δ (CDCl , 299.9 MHz)
᎐
H
3
3.98 [2H, s, MeC(᎐O)CH O], 3.97–3.91 (1H, m, CH ), 2.17 (3H,
᎐
2
s, CH C᎐O), 1.78–1.65 [6H, m, CHCH (CHHЈ) CH ], 1.60–
᎐
Preparation of 4-( p-methoxybenzyloxymethyl)-2-phenyl- (A)
and 4-(benzyloxymethyl)-2-( p-methoxyphenyl)-2,5-dihydrofuran
(B) from 29
3
2
2
2
1.52 [2H, m, CHCH2(CHHЈ2)2CH2]; δC(CDCl3, 75.4 MHz)
207.8 (C᎐O), 82.3 (OCH), 74.6 (CCH O), 31.2 (CH C᎐O), 26.4
᎐
᎐
3
2
(OCH2CH2CH2CH2), 23.4 (OCH2CH2CH2CH2); m/z (EI) 160
([M ϩ NH4]ϩ, 73%), 143 ([M ϩ H]ϩ, 78), 116 (73), 99 ([M Ϫ
CH C᎐O]ϩ, 82), 85 ([M Ϫ CH C᎐OCH ]ϩ, 77), 75 (84), 69
TMSDM (0.83 ml, 1.67 mmol) was lithiated with n-butyl-
lithium (0.67 ml, 1.67 mmol) and reacted with 1-benzyloxy-3-
(p-methoxybenzyloxy)propan-2-one 29 (0.25 g, 0.83 mmol) in
DME (4 ml) under the standard conditions described. Purifica-
tion by column chromatography eluting with 5% ethyl acetate–
petroleum ether gave the products as an inseparable mixture in
a ratio of 1 : 1 as a pale yellow oil (0.08 g, 32%). Rf 0.52 (20%
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3062 (w), 3030
(w), 3003 (w), 2850 (m); δH(CDCl3, 250.1 MHz) 7.38–7.20 (7HA
ϩ 7HB, m, aryl CH ), 6.91–6.85 (2HA ϩ 2HB, m, aryl CH α to
COMe), 5.84–5.77 (2HA ϩ 2HB, m, 4 × CH ), 4.88–4.71 (2HA ϩ
2HB, m, furan CH2), 4.56 (2HA, s, ArCH2O), 4.48 (2HB, s,
PhCH2O), 4.22–4.20 (2H, m, ArCH2OCH2), 4.18–4.16 (2H,
m, ArCH2OCH2), 3.80 (3H, s, OCH3), 3.79 (3H, s, OCH3);
δC(CDCl3, 62.9 MHz) 159.3 (aryl CiOMe)1CA ϩ 1CB, 138.2
᎐
᎐
3
3
2
([CH C᎐OCH O]ϩ, 98), 58 (100); Found: 160.1338, [C H O ϩ
᎐
3
2
8
14
2
NH4]ϩ requires 160.13375.
Preparation of 3-methyl-1-oxaspiro[4.4]non-3-ene 36
TMSDM (6.0 ml, 12 mmol) was lithiated with n-butyllithium
(4.8 ml, 12 mmol) and reacted with 1-cyclopentyloxypropan-2-
one 30 (0.85 g, 6.00 mmol) in DME (20 ml) under the standard
conditions described. Purification by column chromatography
eluting with 0.5% ethyl acetate–petroleum ether gave the
product as a pale yellow oil (0.47 g, 57%). Rf 0.62 (15% ethyl
acetate–hexane); νmax(neat)/cmϪ1 3074 (w), 2961 (m), 2874 (m);
δ (CDCl , 299.9 MHz) 5.36–5.32 (1H, m, C᎐CH ), 4.44 (2H,
᎐
H
3
(R C᎐CH)1C ϩ 1CB, 134.0 (aryl Ci)1CA ϩ 1CB, 129.4 (aryl
dd, J 1.0, OCH C᎐C), 1.80–1.72 (4H, m, CCH CH CH CH ),
᎐
2 2 2 2 2
᎐
2
A
CH β to COMe), 128.5 (aryl C), 127.8 (aryl C), 127.7 (C᎐CH),
1.73 (3H, dd, J 1.0, CH C᎐C), 1.68–1.59 (4H, m, CCH -
᎐
3 2
᎐
126.4 (C᎐CH), 126.3 (aryl C), 113.8 (aryl CH α to CO-
CH CH CH ); δ (CDCl , 75.4 MHz) 134.8 (CH C᎐C), 127.1
᎐
2 2 2 C 3 3
᎐
Me)1CA ϩ 1CB, 88.2 (PhCH)1CA, 87.8 (ArCH)1CB, 75.9
(furan CH2)1CA, 75.6 (furan CH2)1CB, 72.4 (PhCH2)1CB, 72.1
(CH᎐C), 98.6 (OCR3), 76.6 (OCH C᎐C), 38.4 (CCH2-
᎐ ᎐
2
CH CH CH ), 24.3 (CCH CH CH CH ), 12.3 (CH C᎐C);
᎐
3
2
2
2
2
2
2
2
(ArCH )1C , 65.5 (BnOCH C᎐C)1C , 65.2 (ArCH OCH -
m/z (EI) 138 ([M]ϩ, 31%), 123 ([M Ϫ CH3]ϩ, 49), 95 (93), 81
(92), 79 (61), 67 (71), 55 (100), 53 (62); Found: 138.1045,
[C9H14O]ϩ requires 138.10447.
᎐
2
A
2
B
2
2
C᎐C)1C , 55.2 (OCH )1C ϩ 1CB; m/z (EI) 296 ([M]ϩ, 32%),
᎐
A
3
A
173 (23), 158 (68), 145 (23), 135 (96), 121 ([MeOC6H4CH2]ϩ,
100), 91 ([PhCH2]ϩ, 95), 84 (72), 77 ([Ph]ϩ, 74), 65 (24), 51 (24),
43 (30); Found: 296.1412, [C19H20O3]ϩ requires 296.1213.
Preparation of pyruvaldehyde dibenzyl acetal
Pyruvaldehyde dimethyl acetal (4.0 ml, 33 mmol) was stirred in
benzyl alcohol (20 ml) and PTSA (0.63 g, 3.3 mmol) added. The
reaction was heated at 80 ЊC for 20 h and then cooled to rt.
Water (50 ml) and DCM (60 ml) were added and then the
aqueous layer extracted with DCM (3 × 60 ml). The organic
layers were combined, dried over magnesium sulfate and
filtered, and the solvent removed by rotary evaporation. Purifi-
cation of the residue by column chromatography eluting with
Preparation of 1-cyclopentyloxy-2-methylpropene
Sodium hydride (3.0 g, 74 mmol) was stirred in DMF (100 ml)
at 0 ЊC and to this cyclopentanol (6.7 ml, 74 mmol) was added
carefully over 10 min. The cooling bath was removed once the
addition was completed and the reaction stirred for 1 h at rt.
3-Bromo-2-methylpropene (6.62 g, 49.0 mmol) was then added
dropwise and the reaction stirred overnight at rt. The reaction
976
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

View Article Online
5% ethyl acetate–petroleum ether gave the product as a colour-
less oil (2.92 g, 33%). Rf 0.76 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 3061 (m), 3029 (m), 2934 (m), 2874 (m),
1729 (s); δH(CDCl3, 250.1 MHz) 7.34–7.30 (10H, m, aryl CH ),
4.73 (1H, s, CH ), 4.67 (2H, d, JAB 11.8, PhCHHЈO), 4.59 (2H,
d, JAB 11.8, PhCHHЈO), 2.24 (3H, s, CH3); δC(CDCl3, 62.9
(OCH2CH2), 24.0 (R3CCH3); m/z (CI) 162 ([M ϩ NH4]ϩ, 87%),
145 ([M ϩ H]ϩ, 100), 111 (16), 101 ([M Ϫ CH C᎐O]ϩ, 78), 86
᎐
3
(24), 58 (16), 44 (27); Found: 162.1130, [C9H14O ϩ NH4]ϩ
requires 162.1130.
Preparation of 1,7-dimethyl-2,8-dioxabicyclo[3.2.1]oct-6-ene 40
and rearrangement to 5-(2-hydroxyethyl)-2,3-dimethylfuran 41
MHz) 203.8 (C᎐O), 136.8 (aryl C ), 128.5 (aryl C ), 128.0 (aryl
᎐
i
m
Co ϩ p), 100.9 (CH), 69.2 (PhCH2O), 25.0 (CH3); m/z (CI) 288
([M ϩ NH4]ϩ, 83%), 212 (49), 181 (12), 108 (86), 91 ([PhCH2]ϩ,
100); Found: 288.1600, [C17H18O3 ϩ NH4]ϩ requires 288.1600.
TMSDM (13.0 ml, 27.8 mmol) was lithiated with n-butyl-
lithium (11.1 ml, 27.8 mmol) and reacted with 2-acetyl-2-
methyl-1,3-dioxane 39 (2.00 g, 13.9 mmol) in DME (30 ml)
under the standard conditions described. The crude residue was
carried through without further purification as an orange oil
Preparation of 2-(benzyloxy)-3-methyl-5-phenyl-2,5-dihydro-
furan 37
(2.24 g). δ (CDCl , 299.9 MHz) 6.07–6.06 (1H, m, HC᎐CMe),
᎐
H
3
TMSDM (3.70 ml, 7.41 mmol) was lithiated with n-butyl-
lithium (2.90 ml, 7.41 mmol) and reacted with pyruvaldehyde
dibenzyl acetal (1.00 g, 3.70 mmol) in DME (30 ml) under the
standard conditions described. Purification by column chrom-
atography eluting with 10% ethyl acetate–petroleum ether gave
the products as an inseparable mixture in a 3 : 1 ratio (0.67 g,
68%) in the form of a pale yellow oil. Rf 0.47 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3061 (m), 3028 (m),
2934 (m), 2869 (m); δH(CDCl3, 250.1 MHz) 7.42–7.23 (10Hmaj
4.64 (1H, br d, J 0.6, HCR3), 3.91 (1H, td, J 4.4 and 11.3,
OCHaHeCH2), 3.82 (1H, ddd, J 4.6, 0.8 and 11.3, OCHa-
H CH ), 2.32–2.21 (1H, m, OCH CH H ), 1.80 (3H, t, J 1.1, C᎐
᎐
e
2
2
a
e
CCH3), 1.45 (3H, s, CH3CR3), 1.25–1.23 and 1.21–1.16 (1H, m,
OCH CH H ); δ (CDCl , 100.6 MHz) 138.9 (C᎐CMe), 128.6
᎐
2
a
e
C
3
(C᎐CH), 109.3 (R C), 78.4 (HCR ), 61.8 (OCH CH ), 29.4
᎐
4
3
2
2
(OCH CH ), 22.6 (C᎐CH ), 13.0 (CH ).
᎐
2
2
3
3
Attempted purification of this compound by column
chromatography eluting with 20% ethyl acetate–hexane resulted
in a rearrangement product, 41, obtained as a pale orange oil
(0.62 g, 64%). Rf 0.35 (20% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 3402 (br), 2954 (s), 2912 (m), 1761 (m), 1261
(m); δH(CDCl3, 400.0 MHz) 5.88 (1H, s, CH ), 3.83 (2H, t, J 6.1,
CH2OH), 2.86 (2H, t, J 6.1, CH2CH2OH), 2.17 (3H, s, CH3OC),
ϩ 10Hmin, m, aryl CH ), 5.92 (1Hmin, d, J 4.0, C᎐CH ), 5.88–5.85
᎐
(1Hmin, m, PhCH ), 5.82–5.80 (1Hmin, m, BnOCH ), 5.77–
5.74 (2Hmaj, m, CH ), 5.68–5.66 (1Hmaj, m, CH ), 4.86 (1Hmaj
,
d, J 11.9, PhCHHЈO), 4.81 (1Hmin, d, J 11.9, PhCHHЈO), 4.65
(1Hmin, d, J 11.9, PhCHHЈO), 4.63 (1Hmaj, d, J 11.9,
PhCHHЈO), 1.84–1.82 (3Hmin, m, CH3), 1.82–1.80 (3Hmaj, m,
CH3); δC(CDCl3, 62.9 MHz) 141.1 (aryl C), 138.3 (aryl C),
135.7 (aryl C), 135.2 (aryl C)1Cmaj, 128.7–126.5 (aryl C)10maj ϩ
1.90 (3H, s, CH C᎐CO), 1.66 (1H, br s, OH ); δ (CDCl , 100.6
᎐
3
C
3
MHz) 149.6 (OCCH CH OH), 146.3 (OCMe), 114.5 (OC᎐
᎐
2
2
CMe), 109.9 (C᎐CH), 61.3 (CH CH OH), 31.6 (OCCH -
᎐
2
2
2
10min
,
109.6 (BnOCH)1Cmin
,
109.4 (BnOCH)1Cmaj
,
87.3
CH OH), 11.3 (CH CO), 9.9 (CH C᎐CO); m/z (EI) 140 ([M]ϩ,
᎐
2 3 3
(PhCH)1Cmaj, 86.9 (PhCH)1Cmin, 69.5 (PhCH2)1Cmaj ϩ 1Cmin
,
70%), 109 ([M Ϫ CH2OH]ϩ, 100), 95 ([M Ϫ CH2CH2OH]ϩ, 17),
79 (35), 73 (46), 65 ([M Ϫ 2CH3 and CH2CH2OH]ϩ, 36); Found:
141.0917, [C8H12O2 ϩ H]ϩ requires 141.0916.
11.9 (CH C᎐CH)1C ϩ 1Cmin; m/z (CI) 281 ([M ϩ NH4 Ϫ
᎐
3
maj
H]ϩ, 13%), 265 ([M ϩ H Ϫ H2]ϩ, 27), 249 (17), 205 (10), 188
(33), 175 ([M Ϫ Bn]ϩ, 60), 159 ([M Ϫ BnO]ϩ, 100), 147 (50);
Found: 265.1229, [C18H18O2 ϩ H Ϫ H2]ϩ requires 265.1229.
Preparation of 2-acetyl-2,4,4,6-tetramethyl-1,3-dioxane
Butane-2,3-dione (2.6 ml, 29 mmol) was stirred in DCM (50 ml)
with 2-methylpentane-2,4-diol and PTSA (1.38 g, 7.30 mmol)
and refluxed for 20 h. The reaction was cooled to rt, after which
the solvent and excess butane-2,3-dione were removed by rotary
evaporation. Purification of the residue by column chromato-
graphy eluting with 15% ethyl acetate–petroleum ether gave
the product as a colourless oil (1.02 g, 19%). Rf 0.62 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 2976 (s), 1736 (s);
δH(CDCl3, 299.9 MHz) 4.16–4.09 (1H, m, CHe), 2.24 [3H, s,
Preparation of 1,3-dioxane-2-carbaldehyde
Pyruvaldehyde dimethyl acetal (2.00 ml, 16.0 mmol) and
propane-1,3-diol (1.40 ml, 19.2 mmol) were stirred in toluene
(5 ml) and PTSA (0.15 g, 0.80 mmol) was added. The reaction
was heated at 80 ЊC for 5 h and, after cooling, the solvent
was removed by rotary evaporation. Purification of the residue
by column chromatography eluting with 5% ethyl acetate–
petroleum ether gave the product as a colourless oil (1.05 g,
51%). Rf 0.54 (20% ethyl acetate–petroleum ether); νmax(neat)/
cmϪ1 2962 (m), 2868 (m), 1733 (s); δH(CDCl3, 250.1 MHz)
4.76 (1H, s, CH), 4.25–4.18 (2H, m, OCHaHeCH2), 3.91–3.81
(2H, m, OCHaHeCH2), 2.23 (3H, s, CH3), 2.26–2.14 (1H, m,
OCH2CHaHe), 1.48–1.39 (1H, m, OCH2CHaHe); δC(CDCl3,
C(᎐O)CH ], 1.57 (1H, dd, J 13.5 and JAX 3.3, CHCHaHe),
᎐
3
AB
1.47 (1H, dd, JAB 13.5 and JBX 11.5, CHCHaHe), 1.46 [3H,
s, MeC(᎐O)CCH ], 1.36 [3H, s, R C(CH )CH Ј], 1.31 (3H, d,
᎐
3
2
3
3
J 11.5, CH3CH), 1.31 [3H, s, R2C(CH3)CH3Ј]; δC(CDCl3, 75.4
MHz) 206.6 (C᎐O), 98.9 [MeC(᎐O)CR ], 72.1 [R C(CH ) ],
᎐
᎐
2
2
3 2
62.9 MHz) 201.8 (C᎐O), 100.3 (CH), 66.9 (CH O), 25.5 (CH ),
24.8 (OCH2CH2).
62.8 (CH), 43.2 (CH ), 32.2 [C(᎐O)CH ], 28.3 [MeC(᎐O)-
᎐ ᎐
2 3
᎐
2
3
CCH3], 23.4–22.0–20.9 (CH3); m/z (CI) 204 ([M ϩ NH4]ϩ,
29%), 187 ([M ϩ H]ϩ, 46), 169 (12), 143 ([M Ϫ CH C᎐O]ϩ, 80),
᎐
3
131 (67), 118 (12), 104 (45), 83 (100), 55 (66), 43 ([CH C᎐O]ϩ,
᎐
Preparation of 2-acetyl-2-methyl-1,3-dioxane 39
3
86); Found: 187.1334, [C10H18O3 ϩ H]ϩ requires 187.1334.
Butane-2,3-dione (5.1 ml, 58 mmol) was stirred in toluene
(100 ml) and propane-1,3-diol (4.2 ml, 58 mmol) and PTSA
(0.55 g, 2.90 mmol) were added. The reaction was heated at
90 ЊC for 16 h and cooled to rt. The solvent and excess butane-
2,3-dione were removed by rotary evaporation and the crude
residue was purified by column chromatography eluting with
20% ethyl acetate–hexane. The product was obtained as a col-
ourless oil (6.1 g, 73%). Rf 0.61 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 2969 (s), 2886 (m), 1728 (s); δH(CDCl3,
299.9 MHz) 4.02–3.95 (2H, m, OCHaHeCH2CHaHeO), 3.82–
Preparation of (4R,6R)-1-(2,4,6-trimethyl-1,3-dioxan-2-yl)-
ethanone 44
Butane-2,3-dione (0.25 ml, 2.90 mmol), (R,R)-(Ϫ)-pentane-2,4-
diol and PTSA (0.4 g, 0.2 mmol) were stirred in toluene (10 ml)
and refluxed for 2 h. The reaction was allowed to cool to rt
and the solvent and excess butane-2,3-dione were removed by
rotary evaporation. Purification of the residue by column
chromatography eluting with 10% ethyl acetate–hexane gave the
product as a colourless oil (0.23 g, 70%). Rf 0.53 (40% ethyl
acetate–hexane); νmax(neat)/cmϪ1 2975 (s), 2934 (s), 1732 (s);
δH(CDCl3, 299.9 MHz) 4.15–4.08 [1H, m, OCHa(Me)CH2-
CHe(Me)O], 3.91–3.84 [1H, m, OCHa(Me)CH2CHe(Me)O],
3.73 (2H, m, OCH H CH CH H O), 2.25 [3H, s, C(᎐O)CH ],
᎐
a
e
2
a
e
3
2.12–1.96 (1H, m, OCH2CHaHeCH2O), 1.46–1.38 (1H, m,
OCH2CHaHeCH2O), 1.41 (3H, s, CH3CR3); δC(CDCl3, 75.4
MHz) 208.2 (C᎐O), 100.8 (CR ), 62.6 (OCH ), 25.0 (CH ), 24.9
᎐
4
2
3
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981
977

View Article Online
2.25 (3H, s, CH CC᎐O), 1.71–1.62 [1H, m, OCH(Me)CH H ],
13.0 and JAX 2.5, CHCHaHeCH), 1.49 (3H, s, CH3CR3), 1.31–
1.19 (1H, m, CHCHaHeCH), 1.21 (6H, d, J 6.2, CH3CHCH2-
CHCH ); δ (CDCl , 75.4 MHz) 204.8 (C᎐O), 99.2 [MeC-
᎐
3
a
e
1.59–1.50 [1H, m, OCH(Me)CH H ], 1.38 [3H, s, MeC(᎐O)-
᎐
a
e
CCH3], 1.25 (3H, d, J 2.3, CH3CHCH2CHMe), 1.23 (3H, d,
J 2.3, MeCHCH CHCH ); δ (CDCl , 75.4 MHz) 208.2 (C᎐O),
᎐
3
C
3
(OR) C], 65.8 (MeCHO), 40.5 (CH ), 23.2 (CH C᎐O), 22.0
᎐
᎐
3
2
3
C
3
2
2
100.5 (CR4), 65.0 (CH), 64.5 (CЈH), 39.3 (CH2), 25.0 (CH3-
C᎐O), 22.6 [MeC(᎐O)CCH ], 21.6 (CH CH), 21.1 (CЈH CH);
(CH3CR3), 15.2 (CH3CH); m/z (CI) 173.2 ([M ϩ H]ϩ, 100%);
Found: 173.1178, [C9H18O3 ϩ H]ϩ requires 173.1178.
᎐
᎐
3
3
3
m/z (CI) 190 ([M ϩ NH4]ϩ, 32%), 173 ([M ϩ H]ϩ, 100), 155
([M Ϫ OH]ϩ, 5), 129 ([M Ϫ MeC᎐O]ϩ, 94), 104 (33), 86 {[M Ϫ
᎐
Preparation of 1,3,5,7-tetramethyl-2,8-dioxabicyclo[3.2.1]oct-
6-ene 49 and rearrangement to 1,3,4,7-tetramethyl-2,6-dioxa-
bicyclo[3.3.0]oct-3-ene 50
MeC(᎐O)C(–O)Me]ϩ or [MeC(᎐O)C(–O)Me]ϩ, 55}, 69 (63),
᎐
᎐
60 (11), 43 ([MeC᎐O]ϩ, 42); Found: 173.1178, [C H O ϩ H]ϩ
᎐
9
16
3
requires 173.11778.
TMSDM (1.74 ml, 3.49 mmol) was lithiated with n-butyl-
lithium (1.40 ml, 3.49 mmol) and reacted with 2-acetyl-2,4,6-
trimethyl-1,3-dioxane 45 (0.30 g, 1.74 mmol) in DME (16 ml)
under the standard conditions described. The crude residue
was obtained as an orange oil (0.36 g). δH(CDCl3, 299.9 MHz)
Preparation of 1,3,5,7-tetramethyl-2,8-dioxabicyclo[3.2.1]oct-
6-ene 47 and rearrangement to 1,3,4,7-tetramethyl-2,6-dioxa-
bicyclo[3.3.0]oct-3-ene 48
TMSDM (1.10 ml, 2.20 mmol) was lithiated with n-butyl-
lithium (0.90 ml, 2.20 mmol) and reacted with (4R,6R)-2-
acetyl-2,4,6-trimethyl-1,3-dioxane 44 (0.19 g, 1.10 mmol) in
DME (12 ml) under the standard conditions described. The
crude residue was obtained as an orange oil (0.23 g). δH(CDCl3,
5.80 (1H, q, J 1.5, C᎐CH), 3.82–3.70 (1H, m, MeCH CH ), 1.75
᎐
a
2
(3H, d, J 1.6, CH C᎐CH), 1.54–1.42 (1H, m, CHCH H C), 1.47
᎐
3
a
e
[3H, s, CH3C(OR)2C], 1.32 [3H, s, CH3C(OR)R2], 1.26–1.15
(1H, m, CHCHaHeC), 1.19 (3H, d, J 6.3, CH3CH); δC(CDCl3,
100.6 MHz) 140.6 (MeC᎐C), 133.6 (MeC᎐CH), 110.5
᎐
᎐
299.9 MHz) 5.71 (1H, q, J 1.6, MeC᎐CH ), 4.29–4.18 (1H, m,
᎐
[MeC(OR)2R], 84.9 [MeC(OR)R2], 69.0 (MeCH), 44.2 (CH2),
25.5 (CH3CH), 24.2 [CH3C(OR)2R], 23.7 [CH3C(OR)R2], 13.9
MeCHe), 2.18 (1H, dd, JAB 13.0 and JAX 8.6, CHCHaHe), 1.78
(3H, d, J 1.6, CH C᎐CH), 1.43 (3H, s, CH CR ), 1.43–1.42 and
᎐
3
3
3
(CH C᎐C). Attempted purification of this compound by col-
᎐
3
1.38–1.37 (1H, m, CHCHaHe) 1.35 (3H, s, CH3CR3), 1.28 (3H,
d, J 7.1, CH CH); δ (CDCl , 75.4 MHz) 142.4 (MeC᎐C), 133.1
umn chromatography eluting with 20% ethyl acetate–hexane
resulted in a rearrangement product 50 obtained as a pale
orange oil (0.14 g, 45%). Rf 0.64 (30% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 2973 (m), 2908 (m), 2838 (w); δH(CDCl3,
299.9 MHz) 4.37 (1H, br s, OCHCCH3), 3.97–3.86 (1H, m,
MeCHaCH2), 2.14 (1H, dd, JAB 12.6 and JAX 5.3, CHCHaHe),
1.84 (1H, dd, JAB 12.6 and JAX 9.3, CHCHaHe), 1.74 (3H, t,
᎐
3
C
3
(MeC᎐CH), 107.1 [MeC(OR) R], 82.0 [MeC(OR)R ], 67.9
᎐
2
2
(MeCH), 37.0 (CH2), 24.4 (CH3CH), 23.7 [CH3C(OR)2R],
21.6 [CH C(OR)R ], 12.0 (CH C᎐C). Attempted purification
᎐
3
3
2
of this compound by column chromatography eluting with 20%
ethyl acetate–hexane resulted in a rearrangement product 48
obtained as a pale orange oil (50 mg, 29%). Rf 0.71 (40% ethyl
acetate–hexane); νmax(neat)/cmϪ1 2970 (m), 2911 (m), 2838 (w);
δH(CDCl3, 500.1 MHz) 4.58 (1H, s, OCHCCH3), 3.88 (1H, ddq,
J 11.1, 4.8 and 6.0, CHCH2), 2.15 (1H, dd, JAB 12.9 and JAX 4.2,
J 0.9, OCCH ), 1.68 (3H, d, J 0.9, OC᎐CCH ), 1.37 (3H, s,
᎐
3
3
R3CCH3), 1.27 (3H, d, J 6.2, CHCH3); δC(CDCl3, 75.4 MHz)
152.5 [MeC᎐C(Me)O], 106.1 [MeC᎐C(Me)O], 96.6 (R C), 75.9
᎐
᎐
4
(MeCH), 50.8 (CH2), 26.1 (CH3CR3), 22.3 (CH3CH), 14.0
CHCH H ), 1.75 [3H, s, CH C(OR)᎐C], 1.62 (3H, s, CH C᎐C–
᎐
᎐
a
e
3
3
[MeC᎐C(CH )O], 12.0 [MeC᎐C(CH )O]; m/z (CI) 169 ([M ϩ
᎐ ᎐
3 3
H]ϩ, 62%), 152 ([M Ϫ CH3]ϩ, 3), 151 ([M Ϫ CH4]ϩ, 100);
Found: 169.1229, [C10H16O2 ϩ H]ϩ requires 169.1229.
OR), 1.46 (1H, dd, JAB 12.9 and JAX 11.1, CHCHaHe), 1.43 (3H,
s, CH3CR3), 1.25 (3H, d, J 6.0, CH3CH); δC(CDCl3, 75.4 MHz)
151.5 [MeC᎐C(Me)–O], 101.8 [MeC᎐C(Me)–O], 94.2 (Me-
᎐
᎐
Preparation of 1,8-dimethyl-2,7,9-trioxatricyclo[3.3.1.06,8]-
nonane 51
CCH), 90.7 (R4C), 72.3 (MeCH), 48.4 (CH2), 23.6 (CH3CR3),
19.1 (CH CH), 11.5 [MeC᎐C(CH )OR], 9.7 [CH C᎐C(Me)-
᎐
᎐
3
3
3
OR]; m/z (CI) 169 ([M ϩ H]ϩ, 33%), 152 ([M Ϫ CH3]ϩ, 11), 151
([M Ϫ CH4]ϩ, 100); Found: 169.1229, [C10H16O2 ϩ H]ϩ requires
169.1229.
Freshly prepared dimethyldioxirane solution8b (140 ml) was
added directly to a stirred solution of 1,7-dimethyl-2,8-dioxa-
bicyclo[3.2.1]oct-6-ene 40 (1.00 g, 7.14 mmol) in acetone (20 ml)
cooled at Ϫ78 ЊC. The reaction was allowed to come to rt over-
night and then concentrated. The crude residue was purified by
column chromatography eluting with 25–30% ethyl acetate–
petroleum ether and the product 51 was obtained as a colour-
less oil (0.32 g, 28%). Rf 0.45 (20% ethyl acetate–petroleum
ether); νmax(neat)/cmϪ1 2966 (s), 2879 (m), 2838 (m); δH(CDCl3,
299.9 MHz) 4.27 (1H, d, J 3.9, CH2CH ), 4.06 (1H, ddd, JAB
12.0, JAX 7.2 and JAXЈ 0.7, OCHaHe), 3.85 (1H, dd, JAB 12.0 and
JAX 4.8, OCHaHe), 3.52 (1H, s, epoxide CH ), 2.40–2.30 (1H, m,
OCH2CHaHe), 1.58 (3H, s, CH3 β to epoxide), 1.48–1.42 (1H,
m, OCH2CHaHe), 1.36 (3H, s, CH3 α to epoxide); δC(CDCl3,
75.4 MHz) 102.4 (R4C α to 2O’s), 71.2 (CH2CH), 59.8 (OCH2),
58.8 (CH2CHCHO), 58.4 (R4C of epoxide), 25.5 (CH2CH2O),
17.9 (R3CCH3), 10.6 (CHCCH3); m/z (CI) 174 ([M ϩ NH4]ϩ,
2%), 157 ([M ϩ H]ϩ, 100), 96 (10), 81 (16); Found: 157.0865,
[C8H12O3 ϩ H]ϩ requires 157.08647.
Preparation of 2-acetyl-2,4,6-trimethyl-1,3-dioxane 45 and 46
Butane-2,3-dione (1.01 ml, 11.5 mmol), meso-pentane-2,4-diol
(0.8 g, 7.7 mmol) and PTSA (0.15 g, 0.77 mmol) were refluxed
in toluene (20 ml) for 5 h. The reaction was cooled to rt, after
which the solvent and excess butane-2,3-dione were removed by
rotary evaporation. Purification of the residue by column
chromatography eluting with 5–10% ethyl acetate–hexane gave
the products as colourless oils (0.20 g, 15% and 0.53 g, 40%).
The major product 45 gave the following data: Rf 0.46 (40%
ethyl acetate–hexane); νmax(neat)/cmϪ1 2975 (s), 2937 (m), 1728
(s); δH(CDCl3, 299.9 MHz) 3.79–3.68 (2H, m, MeCHaCH2-
CH Me), 2.22 [3H, s, C(᎐O)CH ], 1.47 (1H, dt, J 13.3 and
᎐
a
3
AB
JAX 2.5, CHCHaHeCH), 1.42 (3H, s, R3CCH3), 1.24 (1H, dd,
J 11.2, CHCHaHeCH), 1.23 (6H, d, J 6.0, CH3CHCH2CH-
CH ); δ (CDCl , 75.4 MHz) 208.8 (C᎐O), 101.7 [MeC(OR) C],
᎐
3
C
3
2
68.5 (CH), 39.4 (CH ), 25.2 [CH C(OR) C], 25.1 (CH C᎐O),
᎐
3
2
3
2
21.7 (CH3CH); m/z (CI) 190 ([M ϩ NH4]ϩ, 21%), 173 ([M ϩ
H]ϩ, 100), 155 ([M Ϫ OH]ϩ, 21), 129 ([M Ϫ MeCO]ϩ, 87), 101
(15), 86 {[MeCH(O)CH CHMe]ϩ or [MeC(᎐O)C(O)Me]ϩ, 15},
Preparation of 6-hydroxy-1-methyl-7-methylene-2,8-dioxa-
bicyclo[3.2.1]octane 52
᎐
2
69 (22), 43 ([MeC᎐O]ϩ, 27); Found: 173.1178, [C H O ϩ H]ϩ
(1S,2R)-Norephedrine (0.66 g, 4.36 mmol) was stirred in THF
(13 ml) and benzene (20 ml) at 0 ЊC and to this solution
n-butyllithium (3.49 ml, 8.72 mmol) was added slowly over
5 min. The cooling bath was removed after a further 5 min
and the reaction stirred at rt for 30 min. The cooling bath was
replaced and 1,8-dimethyl-2,7,9-trioxatricyclo[3.3.1.06,8]nonane
᎐
9
16
2
requires 173.1178.
Data for the minor product 46: Rf 0.53 (40% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 2976 (s), 2915 (m), 1737 (s);
δH(CDCl3, 299.9 MHz) 4.05 (2H, ddd, J 2.5, 6.1 and 5.5,
MeCH CH CH Me), 2.26 (3H, s, CH C᎐O), 1.58 (1H, dt, J
᎐
e
2
e
3
AB
978
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

View Article Online
51 (0.20 g, 1.28 mmol) was added in THF (7 ml). The reaction
was then stirred overnight at rt, quenched by the addition of
methanol (13 ml) and filtered through Celite. The solvent was
removed by rotary evaporation and purification of the residue
by column chromatography eluting with 2% methanol–DCM
gave the product as a pale yellow oil (0.12 g, 62%). Rf 0.22 (10%
methanol–dichloromethane); νmax(hexachlorobuta-1,3-diene)/
cmϪ1 3426 (br), 2966 (m); δH(CDCl3, 250.1 MHz) 5.63 (1H,
d, J 1.3, C᎐CHHЈ), 5.40 (1H, d, J 1.3, C᎐CHHЈ), 4.47 (1H, t,
JAB 12.8, JAX 7.9 and JAXЈ 1.0, OCHaHe), 3.98 (1H, dd, JAB 12.8
and JAX 3.7, OCHaHe), 2.67–2.51 (1H, m, OCH2CHaHe), 2.05
(3H, s, CH3CR3), 1.87–1.84 and 1.82–1.79 (1H, m, OCH2-
CH H ); δ (CDCl , 100.6 MHz) 206.8 (C᎐O), 164.5 (ArCO R),
᎐
a
e
C
3
2
136.6 (aryl CH α to CBr), 132.8 (aryl CH α to CBr and
CCO2R), 130.4 (arylCCCO2R), 130.0 (aryl CH β to CBr and
CCO2R), 128.5 (aryl CH α to CCO2R), 122.5 (aryl CBr), 99.2
(MeCR ), 76.7 (OCH), 72.4 (CHC᎐O), 61.3 (OCH ), 27.7
᎐
3
2
(OCH2CH2), 18.7 (CH3); m/z (CI) 343 ([MH, 81Br]ϩ, 47%), 341
([MH, 79Br]ϩ, 46), 263 (37), 252 (15), 185 ([M Ϫ BrC6H4]ϩ, 16),
176 (100), 160 (41), 159 (79), 143 (50), 122 (22), 114 (18), 105
(22), 52 (25), 44 (21); Found: 341.0024, [C14H1379BrO5 ϩ H]ϩ
requires 341.0025.
᎐
᎐
J 1.2, CHOH), 4.31–4.29 (1H, m, CH2CH ), 3.86–3.69 (2H, m,
OCHaHe), 2.31–2.16 (1H, m, OCH2CHaHe), 1.57 (3H, s, CH3),
1.43–1.41 and 1.38–1.35 (1H, m, OCH2CHaHe); δC(CDCl3, 62.9
MHz) 153.6 (R C᎐CH ), 112.4 (C᎐CH ), 104.3 (MeCR ),
᎐
᎐
2
2
2
3
80.9 [CH(OH)], 74.9 (CH2CH ), 60.1 (CH2CH2O), 27.5 (CH2-
CH2O), 22.3 (CH3); m/z (EI) 157 ([M]ϩ, 100%), 137 ([M Ϫ
OH]ϩ, 41), 126 (27), 112 (29), 97 (42); Found: 157.0865,
[C8H12O3]ϩ requires 157.08647.
Preparation of 1,6-diphenylhex-3-ene 5538
3-Phenylpropyl(triphenyl)phosphonium bromide (10.0 g, 21.7
mmol) was stirred in THF (50 ml) at 0 ЊC and n-butyllithium
(8.67 ml, 21.7 mmol) was added dropwise. Once addition was
complete the reaction was stirred for 30 min at rt and dihydro-
cinnamaldehyde (3.43 ml, 26.0 mmol) in THF (50 ml) was
added. The reaction was stirred for 3 h, quenched by the
addition of water (80 ml) and extracted with diethyl ether
(3 × 100 ml). The combined organic layers were dried over
magnesium sulfate, filtered and concentrated. Purification of
the residue by column chromatography eluting with 10% ethyl
acetate–petroleum ether gave the product as an inseparable
mixture of isomers in a ratio of 4 : 1 in the form of a colourless
oil (3.68 g, 72%). Rf 0.66 (20% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 3081 (w), 3059 (m), 3023 (s), 2921 (s), 2852 (m);
δH(CDCl3, 250.1 MHz) 7.30–7.13 (10Hmaj ϩ 10Hmin, m, aryl
Preparation of 6-(3-bromobenzoyloxy)-1-methyl-7-methylene-
2,8-dioxabicyclo[3.2.1]octane 53
6-Hydroxy-1-methyl-7-methylene-2,8-dioxabicyclo[3.2.1]octane
52 (0.10 g, 0.64 mmol) was stirred in DCM (20 ml) at 0 ЊC with
3-bromobenzoic acid (0.39 g, 1.92 mmol) and DMAP (0.07 g,
0.58 mmol). To this solution DCC (0.15 g, 0.71 mmol) was
added. The cooling bath was removed after 10 min and the
reaction stirred for 24 h at rt. The dicyclohexylurea was
removed by suction filtration and the filtrate washed with 0.5 M
hydrochloric acid (50 ml) and saturated sodium hydrogen
carbonate solution (50 ml). The organic layer was dried over
magnesium sulfate and filtered, and the solvent removed by
rotary evaporation. Purification by column chromatography
eluting with 50% ethyl acetate–petroleum ether gave the
product as a colourless oil (0.11 g, 48%). Rf 0.30 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3054 (w), 2969 (m),
2870 (w), 1719 (s); δH(CDCl3, 250.1 MHz) 8.17 (1H, t, J 1.5,
aryl CH α to Br and CO2R), 7.98 (1H, dt, J 1.5 and 7.9, aryl CH
α to CO2R), 7.70 (1H, dq, J 0.9 and 7.9, β to Br), 7.33 (1H, t,
CH ), 5.49–5.45 (2Hmin, m, RCH᎐CHR), 5.44–5.39 (2Hmaj, m,
᎐
RCH᎐CHR), 2.68–2.62 (4Hmin, m, PhCH2), 2.60–2.53 (4Hmaj
,
᎐
m, PhCH2), 2.33–2.25 (4Hmaj ϩ 4Hmin, m, CH C᎐CCH );
δC(CDCl3, 62.9 MHz) 141.9 (aryl Ci)2Cmaj, 141.5 (aryl Ci)2Cmin
᎐
2
2
,
130.0 (CH᎐CH)2C , 129.3 (CH᎐CH)2Cmaj, 128.3 (aryl C)-
᎐
᎐
min
4Cmaj ϩ 4Cmin, 128.1 (aryl C)4Cmaj ϩ 4Cmin, 125.6 (aryl Cp)-
2Cmaj, 125.2 (aryl Cp)2Cmin, 35.9 (PhCH2)2Cmin, 35.7 (PhCH2)-
J 7.9, β to Br and CO R), 5.78 (1H, t, J 1.22, C᎐CHHЈ), 5.73
2Cmaj, 34.3 (CH C᎐CCH )2C , 29.0 (CH C᎐CCH )2C
;
᎐
᎐
᎐
2
2
2
2
min
2
maj
(1H, d, J 1.2, C᎐CHHЈ), 5.50 (1H, d, J 1.5, RCO CH ), 4.50–
m/z (EI) 236 ([M]ϩ, 50%), 145 ([M Ϫ Bn]ϩ, 56), 131 ([M Ϫ
PhCH2CH2]ϩ, 42), 117 (61), 104 (49), 91 ([PhCH2]ϩ, 100), 77
([Ph]ϩ, 25), 65 (55), 51 (24), 41 (28); Found: 236.1565, [C18H18]ϩ
requires 236.1565.
᎐
2
4.48 (1H, m, RCO2CHCH ), 3.92–3.87 (2H, m, CHaHeO), 2.38–
2.23 (1H, m, CHaHeCH2O), 1.62 (3H, s, CH3), 1.60–1.52 (1H,
m, CHaHeCH2O); δC(CDCl3, 62.9 MHz) 165.2 (ArCO2R),
148.9 (CH ᎐CR ), 136.1 (BrCCHCH), 132.5 (BrCCHCCO ),
᎐
2
2
2
131.5 (CCO2R), 129.8 (ArCHCHCH), 128.2 (CHCO2H), 122.3
(CBr), 114.6 (C᎐CH ), 104.4 (MeCR ), 78.2 (CHC᎐CH ), 76.8
Preparation of 1,6-diphenylhexane-3,4-diol 56
᎐
᎐
2
3
2
N-Methylmorpholine N-oxide (1.54 g, 13.1 mmol) was stirred
in water (16 ml) and acetone (8.0 ml) and to this mixture 1,6-
diphenylhex-3-ene 55 (2.82 g, 12.0 mmol) and osmium tetra-
oxide (0.03 ml, 0.12 mmol) were added. Methanesulfonamide
(1.14 g, 12.0 mmol) was added to the reaction, which was then
heated at 60 ЊC for 2 days. After cooling to rt sodium hydro-
sulfite (0.20 g) was added followed by a slurry of Florisil (2 g) in
water (10 ml). The reaction was stirred for 10 min and filtered
through Florisil. The Florisil was washed with acetone which
was then neutralised (pH 7) with 6 M sulfuric acid. The acetone
was removed and the pH of the resulting aqueous solution
adjusted to pH 2. The acidic aqueous layer was extracted with
DCM (4 × 50 ml), the combined organic layers were dried
over magnesium sulfate and filtered, and the solvent removed
by rotary evaporation. Purification of the residue by column
chromatography eluting with 20–50% ethyl acetate–petroleum
ether gave the major product as white crystals (2.24 g, 69%)
after recrystallisation from hexane. Mp 132–135 ЊC; Rf 0.32
(60% ethyl acetate–petroleum ether); νmax(Nujol mull)/cmϪ1
3236 (m), 3026 (m), 2922 (s), 2854 (s); δH(DMSO, 250.1 MHz)
7.30–7.11 (10H, m, aryl CH ), 4.20 [2H, br s, CH(OH )CH-
(OH )], 3.29–3.21 (2H, br m, CHOHCHOH), 2.85–2.73 (2H,
m, PhCHHЈ), 2.61–2.52 (2H, m, PhCHHЈ), 1.92–1.81 (2H, m,
CHCHHЈ), 1.63–1.48 (2H, m, CHCHHЈ); δC(DMSO, 62.9
MHz) 142.9 (aryl Ci), 128.4 (aryl C), 128.3 (aryl C), 125.6 (aryl
(OCH), 60.0 (CH2CH2O), 27.4 (CH2CH2O), 22.0 (CH3);
m/z (CI) 358 ([M ϩ NH4, 81Br]ϩ, 2%), 356 ([M ϩ NH4, 79Br]ϩ,
2), 341 ([M ϩ H, 81Br]ϩ, 4), 339 ([M ϩ H, 79Br]ϩ, 4), 158 (6), 156
(46), 141 (68), 139 (100); Found: 338.0154, [C15H1579BrO4]ϩ
requires 338.0154.
Preparation of 6-(3-bromobenzoyloxy)-1-methyl-2,8-dioxa-
bicyclo[3.2.1]octan-7-one 54
1-Methyl-6-(3-bromobenzoyloxy)-7-methylene-2,8-dioxabi-
cyclo[3.2.1]octane 53 (73 mg, 0.22 mmol) was stirred in DCM
(10 ml) at Ϫ60 ЊC and ozone was bubbled through the solution.
The reaction was warmed to ∼0 ЊC to effect solution of the
alkene and the reaction continued for 30 min. Dimethyl sulfide
(30 µl, 0.32 mmol) was added, the cooling bath removed and
the reaction stirred overnight. The solvent was removed under
reduced pressure. Purification by column chromatography eluting
with 20–60% ethyl acetate–petroleum ether gave the product as
a colourless oil (30 mg, 40%). Rf 0.30 (20% ethyl acetate–
petroleum ether); νmax(neat)/cmϪ1 3066 (w), 2961 (w), 2866 (w),
1780 (m), 1730 (s); δH(CDCl3, 250.1 MHz) 8.17 (1H, t, J 1.8,
aryl CH α to Br and CO2R), 7.98 (1H, dq, J 1.0 and 7.0, aryl
CH α to CO2R), 7.74 (1H, dq, J 1.0 and 7.9, aryl CH β to Br),
7.34 (1H, t, J 7.9, aryl CH β to Br and CO2R), 5.23 (1H,
s, RCO2CH ), 4.65 (1H, d, J 4.0, RCO2CHCH ), 4.10 (1H, dd,
J. Chem. Soc., Perkin Trans. 1, 2002, 965–981
979

View Article Online
Cp), 73.3 (CHOH), 35.1 (PhCH2), 31.8 (PhCH2CH2CH); m/z
(CI) 288 ([M ϩ NH4]ϩ, 15%), 253 ([M Ϫ OH]ϩ, 50), 235 (56),
208 (32), 145 (18), 130 (70), 117 (92), 104 (61), 91 ([PhCH2]ϩ,
100), 78 (24), 65 (39); Found: 288.1964, [C18H22O2 ϩ NH4]ϩ
requires 288.19635.
1.32–1.30 (1H, dm, OCH2CHaHe); δC (62.9 MHz, CDCl3) 209.2
(C᎐O), 141.4 (aryl C ), 140.9 (aryl C ), 128.4 (aryl C), 128.3
(aryl C), 128.2 (aryl C), 126.1 (aryl Cp), 125.8 (aryl Cp),
101.9 (R4C), 62.5 (OCH2), 39.2 (PhCH2), 38.8 (PhCH2), 29.4
᎐
i
i
(CH CR ), 28.2 (CH C᎐O), 24.9 (OCH CH CH O); m/z (CI)
᎐
2
3
2
2
2
2
342 ([M ϩ NH4]ϩ, 100%), 325 ([M ϩ H]ϩ, 27), 266 (10),
249 (14), 191 ([M Ϫ PhCH2CH2C᎐O]ϩ, 73), 91 ([PhCH2]ϩ, 7);
᎐
Preparation of 1,6-diphenylhexane-3,4-dione 5739
Found: 342.2084, [C21H24O3 ϩ NH4]ϩ requires 342.2069.
Oxalyl chloride (4.0 ml, 8.0 mmol) was stirred at Ϫ78 ЊC in
DCM (20 ml) and to this DMSO (1.13 ml, 16.0 mmol) in DCM
(20 ml) was added dropwise over 5 min and the reaction stirred
for a further 20 min. 1,6-Diphenylhexane-3,4-diol 56 (0.90 g,
3.33 mmol) in DCM (30 ml) was then added slowly over 10 min.
Once the addition was complete the reaction was stirred for 20
min and then triethylamine (4.63 ml, 33.3 mmol) was added and
the cooling bath removed. The reaction was left to come to rt
over 30 min, then quenched by the addition of water (100 ml)
and extracted with DCM (3 × 100 ml). The organic layers were
combined, dried over magnesium sulfate and filtered, and the
solvent removed by rotary evaporation. The crude residue was
purified by column chromatography eluting with 10% ethyl
acetate–petroleum ether and the product isolated as bright
yellow crystals (0.60 g, 67%). Found: C 80.91% H 6.81%,
C18H18O2 requires C 81.20% H 6.77%; mp 91–92.5 ЊC; Rf 0.60
(40% ethyl acetate–petroleum ether); νmax(Nujol mull)/cmϪ1
2923 (s), 2853 (s), 1706 (m); δH(CDCl3, 250.1 MHz) 7.30–7.14
Preparation of 1,7-bis(2-phenylethyl)-2,8-dioxabicyclo[3.2.1]oct-
6-ene 59
TMSDM (1.54 ml, 3.09 mmol) was lithiated with n-butyl-
lithium (1.23 ml, 3.09 mmol) and reacted with 2-(2-phenyl-
ethyl)-2-(3-phenylpropanoyl)-1,3-dioxane 58 (0.50 g, 1.54
mmol) in DME (15 ml) under the standard conditions
described. The crude residue was carried through without
further purification as an orange oil (0.84 g). δH(CDCl3, 250.1
MHz) 7.32–7.13 (10H, m, aryl CH ), 6.17 (1H, q, J 1.8, C᎐CH ),
᎐
4.73–4.77 (1H, m, CHCH2CH2O), 3.94–3.78 (2H, m, OCHa-
H CH ), 2.96–2.88 (2H, m, PhCH CH C᎐C), 2.84 (1H, dd,
᎐
2
e
2
2
J 5.2 and 12.2, PhCHHЈ), 2.60 (1H, ddd, J 5.2, 12.2 and 14.0,
PhCHHЈ), 2.46–2.37 (2H, m, PhCH CHHC᎐C), 2.34–2.22
᎐
2
(1H, m, OCH2CHaHe), 2.14 (1H, ddd, J 5.5, 12.2 and 14.0, Ph-
CH2CHHЈCR3), 1.96 (1H, ddd, J 5.2, 12.2 and 14.0, PhCH2-
CHHЈCR3), 1.27–1.26 and 1.22–1.20 (1H, m, OCH2CHaHe).
This compound was used in the next step without further
purification due its instability to silica gel and alumina.
(10H, m, aryl CH ), 3.08–3.02 (4H, m, CH C᎐O), 2.94–2.84
᎐
2
(4H, m, PhCH ); δ (CDCl , 62.9 MHz) 198.5 (C᎐O), 140.2
᎐
2
C
3
(aryl Ci), 128.4 (aryl C), 128.2 (aryl C), 126.2 (aryl Cp), 37.5
Preparation of 1,8-bis(2-phenylethyl)-2,7,9-trioxatricyclo-
[3.3.1.06,8]nonane 60 and 5-(2-hydroxyethyl)-2,3-bis(2-phenyl-
ethyl)furan 61
(PhCH ), 28.0 (CH C᎐O); m/z (EI) 266 ([M]ϩ, 70%), 224
᎐
2
2
(19), 175 ([M Ϫ PhCH ]ϩ, 19), 133 ([PhCH CH C᎐O]ϩ, 81), 105
᎐
2
2
2
([PhCH2CH2]ϩ, 100), 91 ([PhCH2]ϩ, 95), 83 (33), 77 ([Ph]ϩ, 69),
65 (52), 55 (16), 51 (48), 43 (37).
At Ϫ78 ЊC, a solution of freshly prepared dimethyldioxirane
solution (140 ml) was added to a stirred solution of 1,7-
bis(2-phenylethyl)-2,8-dioxabicyclo[3.2.1]oct-6-ene 59 (0.78 g,
∼1.54 mmol) in acetone (15 ml). The reaction was stirred and
allowed to warm to rt overnight. The solvent was removed by
rotary evaporation and purification of the residue by column
chromatography gave two products of which one was the
desired product as a colourless oil (0.14 g, 27%). The other was
a result of rearranged starting material, 2,3-bis(2-phenylethyl)-
5-(2-hydroxyethyl)furan, as a pale yellow oil (74 mg, 15%).
Epoxide 60: Rf 0.55 (60% ethyl acetate–petroleum ether);
νmax(neat)/cmϪ1 3061 (w), 3026 (w), 2957 (m), 2873 (w);
δH(CDCl3, 250.1 MHz) 7.33–7.09 (10H, m, aryl CH ), 4.34 (1H,
d, J 3.4, OCH2CH2CH ), 4.00 (1H, td, JAB 11.9 and JAX 4.6,
OCHaHeCH2), 3.85 (1H, dd, JAB 11.9 and JBX 7.4, OCHaHe-
CH2), 3.62 (1H, s, epoxide CH ), 2.86–2.73 (3H, m, PhCH2
and PhCHHЈ), 2.67–2.55 (1H, m, PhCHHЈ), 2.48–2.26 (3H,
m, PhCH2CH2 and OCH2CHaHe), 2.01–1.94 (2H, m, PhCH2-
CHH), 1.44–1.37 (1H, m, OCH2CHaHe); δC(CDCl3, 62.9
MHz) 141.9 (aryl Ci), 140.9 (aryl Ci), 128.4 (aryl C), 128.2 (aryl
C), 128.1 (aryl C), 126.1 (aryl Cp), 125.7 (aryl Cp), 103.2 (R4C),
71.2 (CHCH2CH2O), 61.2 (epoxide R4C), 59.7 (CH2O), 56.2
(epoxide CH), 34.6 (PhCH2), 30.2 (PhCH2), 28.6 (PhCH2-
CH2CR3), 25.5 (OCH2CH2), 25.2 (PhCH2CH2–epoxide); m/z
(CI) 354 ([M ϩ NH4]ϩ, 31%), 337 ([M ϩ H]ϩ, 100), 186 (15);
Found: 337.1817, [C22H24O3 ϩ H]ϩ requires 337.1804.
Data for minor product where mono-oxidation resulted
in the formation of 1,6-diphenyl-4-hydroxyhexan-3-one, which
was obtained as a pale yellow oil (0.23 g, 26%). Rf 0.45 (40%
ethyl acetate–petroleum ether); νmax(neat)/cmϪ1 3471 (br m),
3085 (w), 3062 (w), 3027 (m), 2927 (m), 2862 (w), 1711 (s);
δH(CDCl3, 250.1 MHz) 7.30–7.12 (10H, m, aryl CH ), 4.09 (1H,
t, J 4.2, CHOH), 3.33 (1H, br s, OH ), 2.93–2.84 (2H, m, CH2-
C᎐O), 2.78–2.61 (4H, m, PhCH ), 2.14–2.00 (1H, m, PhCH-
᎐
2
HЈCHOH), 1.83–1.68 (1H, m, PhCHHЈCHOH); δC(CDCl3,
62.9 MHz) 210.2 (C᎐O), 139.9 (aryl C ), 139.4 (aryl C ), 127.5
᎐
i
i
(aryl C), 127.3 (aryl C), 125.3 (aryl Cp), 125.1 (aryl Cp), 74.7
(CHOH), 38.5 (PhCH CH C᎐O), 34.4 (PhCH CH CH), 30.0
᎐
2
2
2
2
(PhCH CH CH), 28.4 (PhCH CH C᎐O); m/z (CI) 286 ([M ϩ
᎐
2
2
2
2
NH4]ϩ, 69%), 269 ([M ϩ H]ϩ, 64), 251 ([M Ϫ OH]ϩ, 47), 233
(58), 181 (48), 164 (82), 134 (69), 117 (61), 105 ([PhCH2CH2]ϩ,
79), 91 ([PhCH2]ϩ, 100), 78 (50), 65 (72); Found: 286.1807,
[C18H20O2 ϩ NH4]ϩ requires 286.1807.
Preparation of 2-(2-phenylethyl)-2-(3-phenylpropanoyl)-1,3-
dioxane 58
1,6-Diphenylhexane-3,4-dione 57 (1.00 g, 3.76 mmol) was
stirred in toluene (50 ml) with propane-1,3-diol (0.27 ml, 3.76
mmol) and PTSA (0.18 g, 0.94 mmol) and the reaction refluxed
overnight. The reaction was cooled, after which water (50 ml)
was added and the layers separated. The aqueous layer was
extracted with ethyl acetate (2 × 50 ml) and the organic layers
were combined, dried over magnesium sulfate, filtered and
concentrated. Purification of the residue by column chrom-
atography eluting with 5% ethyl acetate–petroleum ether gave
the product as a yellow oil (0.52 g, 42%). Rf 0.43 (20% ethyl
acetate–petroleum ether); νmax(neat)/cmϪ1 3060 (w), 3024 (w),
2962 (m), 2926 (m), 1723 (s); δH (250.1 MHz, CDCl3) 7.30–7.07
(10H, m, aryl CH ), 3.99–3.91 (2H, m, OCHaHeCH2CHaHe),
3.73–3.63 (2H, m, OCHaHeCH2CHaHeO), 2.89–2.93 (4H,
Furan 61: Rf 0.27 (60% ethyl acetate–petroleum ether);
δmax(neat)/cmϪ1 3410 (br), 3084 (w), 3060 (w), 3026 (m), 2934
(m); δH(CDCl3, 250.1 MHz) 7.32–7.12 (10H, m, aryl CH ), 5.99
(1H, t, J 1.2, CH ), 3.85 (2H, t, J 6.4, CH2OH), 3.05 (2H, dd,
J 9.1 and 7.0, PhCH2CH2CO), 2.85–2.68 (6H, m, CH2CH2-
OH, PhCH CH C᎐CO and BnCH CO), 2.52–2.46 (2H, m,
᎐
2
2
2
BnCH C᎐CO); δ (CDCl , 62.9 MHz) 149.9 (OCCH CH OH),
᎐
2
C
3
2
2
149.0 (OCCH2Bn), 141.7 (aryl Ci), 141.3 (aryl Ci), 126.1 (aryl
C), 125.8 (aryl C), 125.7 (aryl C), 125.6 (aryl C), 117.2
(C᎐CCH Bn), 108.2 (CH), 61.0 (CH OH), 36.5 (PhCH CH -
᎐
2
2
2
2
m, PhCH ), 2.63–2.57 (2H, m, CH C᎐O), 2.11–1.92 (1H, m,
CO), 34.8 (PhCH CH C᎐CO), 31.5 (CCH CH OH), 27.9
᎐
2 2 2 2
᎐
2
2
OCH2CHaHe), 1.90–1.83 (2H, m, CH2CR3), 1.38–1.36 and
(BnCH CO), 26.7 (BnCH C᎐CO).
᎐
2 2
980 J. Chem. Soc., Perkin Trans. 1, 2002, 965–981

View Article Online
13 H. Ogawa, T. Aoyama and T. Shioiri, Heterocycles, 1996, 42, 75.
14 (a) F. E. McDonald and A. K. Chatterjee, Tetrahedron Lett., 1997,
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15 S. Kim, J.-K. Yoon and C. M. Cho, Chem. Commun., 1996, 909.
16 S. Kim and C. M. Cho, Tetrahedron Lett., 1994, 35, 8405.
17 (a) M. Kunishima, K. Hioki, S. Tani and A. Kato, Tetrahedron Lett.,
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18 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769.
19 D. J. Critcher, S. Connolly and M. Wills, J. Org. Chem., 1997, 62,
6638.
Acknowledgements
We thank AstraZeneca for a CASE award (to L. F. W.) and
Professor D. Games and Dr B. Stein of the EPSRC National
Mass Spectroscopic Service (Swansea) for HRMS analysis of
certain compounds. M. W. thanks Dr A. M. Kawamoto for
assistance in the preparation of this manuscript. We wish to
acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.40
20 P. Wang and J. Adams, J. Am. Chem. Soc., 1994, 116, 3296.
21 D. M. Spero and J. Adams, Tetrahedron Lett., 1992, 33, 1143.
22 K. Fuji, S. Nakano and E. Fujita, Synthesis, 1975, 276.
23 J. M. Williams, R. B. Jobson, N. Yasuda, G. Marchesini,
U.-H. Doiling and E. J. J. Grabowski, Tetrahedron Lett., 1995, 36,
5461.
24 (a) M. Chini, P. Crotti, C. Gardelli and F. Macchia, Synlett, 1992,
673; (b) G. Piancatelli, A. Scettri and M. D’Auria, Synthesis, 1982,
245.
25 In each case the diastereoisomeric compounds (i.e. of trans-relative
configuration) exhibited no NOE between the corresponding
protons; M. Wills, A. Bourghida and G. Hobley, unpublished
results.
26 (a) Review on zaragozic acids–squalestatins: A. Nadin and K. C.
Nicolaou, Angew. Chem., Int Ed. Engl., 1996, 35, 1622; (b) an
ingenious and closely related ‘desymmetrisation’ approach utilising
insertion reactions of α-keto carbenes was reported after our
preliminary publication: D. J. Wardrop, A. L. Velter and R. E.
Forslund, Org. Lett., 2001, 3, 2261.
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