Stereoselectivity of intramolecular cyclisations of nitrones derived from 3-oxahept-6-enals

Article abstract of DOI:10.1039/a905802h

Intramolecular [l,3]-dipolar cycloadditions of nitrones 33, derived from 3-oxahept-6-enals 7, substituted at either the 4- or 5-position and prepared using a variety of approaches, give good to excellent yields of the cycloadducts 34-37, with good levels

Full text of DOI:10.1039/a905802h

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Stereoselectivity of intramolecular cyclisations of nitrones derived
from 3-oxahept-6-enals
Michael B. Gravestock,a David W. Knight,*b † Jennifer S. Lovellb and Steven R. Thorntonb
a Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
b Chemistry Department, University Park, Nottingham, UK NG7 2RD
Received (in Cambridge, UK) 19th July 1999, Accepted 1st September 1999
Intramolecular [1,3]-dipolar cycloadditions of nitrones 33, derived from 3-oxahept-6-enals 7, substituted at either the
4- or 5-position and prepared using a variety of approaches, give good to excellent yields of the cycloadducts 34–37,
with good levels of stereoselectivity, especially when the substituent is adjacent to the alkene. The cyclisations appear
to proceed via well-defined transition state conformations which should be of predictive value.
Amino sugars occupy a central position in Nature as ubiqui-
tous components of glycoproteins. Of special interest is their
association with both immune responses and infection mechan-
isms; especially prominent in this class are N-acetylmuramic
acid 1, a key component of the ‘muramyl dipeptide’, the mini-
mum structural component of various bacterial cell walls1 and
neuraminic acid 2, the parent member of the sialic acids,2 which
possessing many of the other structural and stereochemical
features of the natural compounds. Such compounds might be
expected to be recognized as amino sugars but then to interfere
with processes such as cell wall assembly, particularly due to the
absence of the anomeric group. The synthetic utility of [1,3]-
dipolar cycloadditions has been amply demonstrated over the
past three decades and intramolecular versions in particular
have been employed as key steps in many elegant syntheses.6
The idea of generating such bicyclic systems using intra-
molecular dipolar cycloadditions was first demonstrated by
LeBel and co-workers who showed that such a process is well-
suited to the preparation of cis-bicyclo[3.3.0]octanes although,
in highly hindered cases, the isomeric bicyclo[3.2.1]octanes are
also formed.7 Later, this methodology was used to prepare
sugar-like carbocycles.8 The idea of incorporating ether oxy-
gens into the chain connecting the two reacting functional
groups has been extensively studied by Aurich and co-workers9
in the elaboration of dioxabicyclo[3.3.0]octanes, from often
spontaneous cycloadditions at ambient temperature. This
group also found that isomeric dioxabicyclo[3.2.1]octanes were
formed from some hindered substrates and that, perhaps not
surprisingly, substituents exerted the greatest degree of stereo-
is often found at the termini of glycoproteins. Amino glycosides
can also show broad-spectrum antibiotic activity, especially
against Gram-negative bacteria,3 while a number of examples
of desoxyamino sugars occur as isolated residues in non-
carbohydrate molecules which also exhibit useful antibiotic
activities, exemplified by galantinic acid and relatives, com-
ponents of galantin 1 and spicamicin.4 Perhaps the best known
of this class of compounds is ()-daunosamine which occurs in
almost all of the important anthracycline antibiotics and which
is considered essential for their biological activity.5
As a preliminary to synthetic studies towards these classes
of amino sugars, we became interested in the prospects for
employing intramolecular [1,3]-dipolar cycloadditions of
nitrones 3, derived from 3-oxahept-6-enals, to access the aza
control when positioned adjacent to the reaction groups.10
A
brief study of the preparation of some examples of dioxa-
bicyclo[4.3.0]nonanes, isomeric with our target compounds 4,
has also been reported by the Aurich group,11 but only with
methyl substituents and bulky N-tert-butyl or aryl groups.
Again, formation of the isomeric bridged products, dioxa-
bicyclo[4.2.1]nonanes, was observed in some cases.
It was against this background that we began our studies
with a trial sequence, to test that the planned strategy leading to
nitrones 3 was viable.12 This consisted of O-alkylation of a
homoallylic alcohol 5, conversion of the resulting esters or
acids 6 into the corresponding aldehydes 7 and condensation
with an N-alkylhydroxylamine (Scheme 1). But-3-enol was
dioxabicyclo[4.3.0]nonanes 4. This approach was especially
suited to our initial aim, which was the elaboration of relatives
of amino sugars lacking an anomeric hydroxy function, but
Scheme 1
alkylated using sodium bromoacetate, formed in situ using
sodium hydride,13 and the resulting acid 8a was esterified
using acidic methanol (Scheme 2). Reduction of the ester 8b
† Present address: Chemistry Department, Cardiff University, P.O. Box
912, Cardiff, UK CF10 3TB.
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This journal is © The Royal Society of Chemistry 1999
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Scheme 4
(Scheme 4).16 The 2-silyloxymethyl alcohol, as its lithium salt
23, was obtained by [2,3]-Wittig rearrangement17 of the alkyl-
lithium derived from the stannane 22, which was itself prepared
by alkylation of the monoprotected butenediol 21a18 by
iodomethyltributylstannane (Scheme 5).19 The lower homo-
Scheme 2
using lithium aluminium hydride gave the alcohol 9 and thence
the sensitive aldehyde 10, following oxidation with pyridinium
chlorochromate.14 This was immediately converted into the
N-benzyl nitrone 11 which required heating in toluene to effect
the dipolar cycloaddition, resulting in the isolation of only the
cis-azadioxabicyclo[4.3.0]nonane 12 in moderate yield [traces
(<5%) of other apparent products were not isolated]. Despite
some signal overlap, 1H NMR data showed complete dis-
appearance of the alkene function and provided, along with the
13C NMR data, excellent evidence for this structure. Double
irradiation experiments allowed a full assignment of the spec-
tral data. In particular, a dddd pattern with only one large
trans-diaxial coupling constant at δH 2.89 was assigned to 6-H
while an apparent dt pattern centred at δH 3.07 due to 1-H
having relatively small coupling constants (≤6.3 Hz), suggested
that this proton was equatorial to a first approximation. A
coupling of 6.3 Hz (J1,6) across the ring junction confirmed a cis
ring fusion and suggested conformation 13 for the product.
We therefore required a representative series of homoallylic
alcohols to probe the overall utility and stereochemical features
of the cyclisation. These were obtained as follows: the 4-methyl
derivative 14a is commercially available and the 4-phenyl homo-
logue 14b was obtained by a Grignard reaction between allyl-
Scheme 5
logue 26 was prepared starting with butadiene monoepoxide,
hydration of which using aqueous sulfuric acid20 gave but-2-
ene-1,2-diol which was selectively silylated at the primary
position to give alcohol 24; formation of the benzyl ether 25
and desilylation completed the sequence (Scheme 6). Finally,
Scheme 6
the dioxolane 30 was prepared starting from the ester 27
derived from solketal (2,2-dimethyl-1,3-dioxolane-4-methanol)
by sequential oxidation with basic potassium permanganate21
and esterification under basic conditions.22 The ethenyl group
was then constructed by condensation between the lithium
enolate of ester 27 and phenylselenoacetaldehyde.23 The result-
ing seleno-alcohol 28 was mesylated, resulting in elimination
to the ethenyl-ester 29 which was then reduced to the target
alcohol 30 (Scheme 7). Conversion of these various alcohols
into the 3-oxahept-6-enoic acids or esters 31 was achieved in a
number of ways. Initially, alkylation using sodium bromo-
acetate13 (see above) was used, although in some examples,
yields were poor and only viable in the case of acid 31ba when
DMPU was added, presumably due to lower nucleophilicity of
the alkoxide because of electron withdrawal by the phenyl sub-
stituent. Similar alkylations using ethyl bromoacetate (e.g. for
esters 31cc and 31dc), although quoted in the Experimental
section as giving reasonable isolated yields (>60%) were, how-
ever, rather capricious. We subsequently found that sodium
iodoacetate was much more suitable, routinely giving high
yields of the acids 31a. In the case of the Wittig rearrangement
magnesium chloride and benzaldehyde. Displacement of
tosylate from the glycidyl tosylate 15 using sodium benzyloxide
gave the epoxy-ether 16 and thence the 4-O-benzylmethyl alco-
hol 17 by copper-catalysed coupling15 with vinylmagnesium
bromide (Scheme 3). In the second series, which have substitu-
Scheme 3
ents adjacent to the alkene, the 2-methyl derivative 18 is com-
mercially available and the 2-phenyl analogue 20 was obtained
by the addition of vinylmagnesium bromide to styrene oxide 19
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chloroform, the protons at C-5 were almost coincident. Fortu-
nately, a spectrum obtained in d6-DMSO showed these and
other obscured signals as well-resolved resonances. The pres-
ence of only one large coupling constant (Jgem = 12.8 Hz) for
both of the C-2 protons indicated that the adjacent ring junc-
tion proton, 1-H, at δH 2.79, was positioned equatorially, which
was confirmed by the absence of any large couplings in its ddd
pattern. In contrast 4-H, at δH 3.39, was evidently axial (J4ax,5ax
12.0 Hz), confirmed by the presence of three large couplings (all
ca. 12.0 Hz) in the resonance for 5-Hax at δH 1.32 in DMSO,
assigned to J4ax,5ax, Jgem and J5ax,6ax, showing that the other ring
junction proton, 6-H, was positioned axially. Hence the overall
ring system in product 34a was cis-fused, which is also consist-
ent with a coupling constant between 1-H and 6-H of 5.2 Hz.
Another feature of the spectrum was the rather small couplings
between one of the protons at position 7 in the five-membered
ring and 6-H, a phenomenon common to many of the related
derivatives obtained later. These data suggest a conformation
based upon that (13) proposed for the model compound 12, but
having an additional equatorial 4-methyl group and doubtless
some twisting of the six-membered ring from a regular cyclo-
hexane shape. In a similar manner, the overall structure of the
minor azadioxa[4.3.0]nonane was found to be the alternative
cis-fused isomer 35a. Following full assignment of the 1H NMR
data, using both decoupling and COSY experiments, 2-Hax was
found to have two large coupling constants (J = 10.8 Hz), show-
ing that 1-H was also axial. Similarly, a large (10.6 Hz) coupling
contained in the resonance for 4-H showed that this too was
positioned axially but the adjacent axial proton, 5-Hax, had
only two large couplings (14.3 and 10.5 Hz), assigned to J4ax,5ax
and Jgem, implying that 6-H was equatorial and certainly not
axial. Further, a very small (unmeasurable) coupling between 1-
H and 6-H again indicated a cis ring fusion and the conform-
ation 40. All other data were consistent with this formulation;
in this and related isomers, both protons at position 7 were
strongly coupling to 6-H. The final minor product was readily
identified as the isomeric azadioxa[4.2.1]nonane 36a, firstly by
the occurrence in its 13C NMR spectrum of two methylene
resonances at 32.1 and 42.7 ppm due to C-5 and C-9; in the
isomers 34a and 35a, only one methylene resonated below 60
ppm. Conversely, there was no methine resonance at around 40
ppm, as was the case in both 34a and 35a due to the 6-CH
group, but an additional methine resonance above 60 ppm, due
to this carbon in structure 36a. Clearly, coupling constant data
is nothing like as informative in this case and hence the stereo-
chemical assignment to structure 36a is based on literature
precedent,6,7,11 as well as being the most likely transition state
Scheme 7
approach to acid 31fa, the intermediate lithium salt 23 was
directly alkylated using sodium iodoacetate. Esterification and
reduction then provided the alcohols 32 which were oxidized to
the aldehydes 7a–d,h using Swern oxidation24 or using tetra-
propylammonium perrhuthenate (TPAP)25 in the case of alde-
hyde 7b. A more rapid, if sometimes capricious method, was
direct reduction of the esters 31xb to the aldehydes 7b,e–g using
diisobutylaluminium hydride in hexanes. Finally, the nitrones
33 were formed by condensation with N-benzylhydroxylamine
at 0–20 ЊC then isolated and immediately heated in toluene
1
(Scheme 8). Some of these were characterized by H NMR
spectroscopy and found to be single geometric isomers in every
case, presumably the more stable (Z)-isomers as depicted.6
There is, of course, no guarantee that these isomers are the ones
which react in the cycloadditions (see below).
The results obtained from the [1,3]-dipolar cycloadditions
are collected in Schemes 9 and 10. In general, isomer ratios were
determined by careful integration of a 1H NMR spectrum
of the crude product, prior to separation. These, rather than
isolated yields, which can vary from run to run, are quoted in
Schemes 9 and 10. In all examples, all analytical data were
consistent with the proposed structures; the stereochemical
determinations were based largely on detailed analyses of
NMR data. In the case of the 4-methyl nitrone 33a, three
separable products were isolated in a ratio 70:19:11 in 72%
overall yield. The major component was identified as the all-cis
isomer 34a mainly on the basis of 1H NMR coupling constant
data. A combination of decoupling and COSY experiments
allowed full assignment of the spectrum, although in deuterio-
Scheme 8
Scheme 9
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Scheme 10
conformation (see below) in which the substituent is again posi-
C-2 were clearly coupled to an equatorially positioned 1-H (J1,2
tioned equatorially,7 and in which the nitrone oxygen manages
to react, despite the ring constraint, in the usually preferred
manner in which it becomes bonded to the more substituted
carbon of the alkene.6
3.3 and 2.4 Hz); hence, the ring fusion must be cis. The proton
at position 5 was in an axial position, indicated by the two large
coupling constants associated with 4-Hax (J = 11.5 and 10.5
Hz), showing that the substituent methyl group is positioned
equatorially and hence anti to the five-membered ring. These
conclusions are also consistent with the stereochemistry deter-
mined for the minor [4.3.0] isomer 37d. In this case, both 2- and
4-Hax showed second large couplings of 11.3 and 11.5 Hz, in
addition to Jgem (also 11.3 and 11.5 Hz respectively), establish-
ing that both 1- and 5-H were positioned axially. Further,
analysis of the pattern displayed by 1-H showed a coupling
across the ring junction of 6.2 Hz and hence cis fusion with the
5-methyl group syn to the five-membered ring, which is consist-
ent with the minor product 37d and its relatives discussed below
adopting conformation 41.
Cyclisation of the 5-phenyl nitrone 33e led to essentially a
single isomer, identified as 38e, together with only traces of
other components. In this example, it was clear from the coup-
ling constant data, obtained in a mixture of CDCl3–C6H6,
which gave much better signal resolution, that the molecule was
distorted from the normal chair conformation of the six-
membered pyran ring. The close proximity of relevant signals
precluded the use of NOE measurements. However, a J1,6 value
of 8.8 Hz indicated a typical cis ring fusion but the similar
J values for the surrounding protons did not allow a definite
assignment of the relative stereochemistry of the 5-phenyl
substituent. Further, the data is very similar to that displayed
by the related silyloxymethyl analogue 38f and the major
5-benzyloxy isomer 38g. It does seem highly likely, as this is
almost the exclusive product, that the phenyl group is posi-
tioned anti to the five-membered ring as shown in Scheme 10.
This is also consistent with the somewhat unexpected chem-
ical shifts of the 4-CH2 at δH 2.70 and 2.96; presumably the
proximity of the 5-phenyl group is responsible for this. Great
care had to be taken with intermediates 20, 31eb, 7e and 33e as
each readily underwent partial or complete isomerization of the
alkene into conjugation with the phenyl group to give isomers
42. The key cyclisation was therefore carried out at 60 ЊC; at
higher temperatures, significant quantities of the 5,5-fused
compound 449–11 were isolated (Scheme 11), presumably from
cyclisation of nitrone 43.
The 4-phenyl nitrone 33b underwent a similar cyclisation to
again give three products which were similarly identified as 34b,
35b and 36b in the same way, in a slightly less useful ratio of
50:33:17. In the major product, coupling constant data estab-
lished that 4-H was axial and coupled to a 5-H which showed
three large coupling constants; hence, 6-H was also axial. The
relative narrowness of 1-H, together with a ring junction coup-
ling of 6.4 Hz between 1- and 6-H revealed a cis-ring fusion.
Other features corresponded to those in the foregoing example.
Similarly, the minor [4.3.0]nonane isomer 35b showed features
related to the minor 4-methyl isomer 35a; in particular, a ring
junction coupling of 6.6 Hz confirmed a cis geometry, with
1-H now in an axial position. Again, the overall structure
of the least abundant product was readily identified as the
[4.2.1]nonane 36b, especially with 13C NMR data, and the
stereochemistry shown again based on transition state specu-
lation and previous precedent. Cyclisation of the 4-benzyloxy-
methyl nitrone 33c, somewhat to our surprise, proved more
selective in favour of the usual major isomer 34c and a slightly
enhanced quantity of the bridged [4.2.1] isomer 36c, at the
expense of the minor [4.3.0] isomer 35c. The identity of the
major isomer 34c was based on comparative data, using
relatively poor 1H NMR data, which was not improved by
changes in solvent. However, characteristically very small
couplings between 1-H and the protons at 2-CH2, together with
the absence of significant coupling between one of the 7-CH2
protons and 6-H indicated that 1-H was equatorial and 6-H
axial, which is also consistent with the narrow multiplet shown
by the former and the broader resonance for the latter.
Not unexpectedly, a different pattern of selectivity was found
in cyclisations of the related 5-substituted nitrones 33d–h
(Scheme 10). Double irradiation and COSY data again allowed
assignment of the 1H NMR spectra of the 5-methyl-substituted
products 37d–39d. Although overlapping signals prevented
meaningful analysis of the resonances for 1-, 5- and 6-H, suf-
ficient data was available to allow assignment of the cis-fused,
anti-stereochemistry 38d as the major product. Both protons at
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the basis of these results, should be useful in planning appli-
cations of this chemistry to the synthesis of amino-sugar
analogues and related species.
Experimental
General details
Scheme 11
Melting points were determined on a Köfler hot stage appar-
atus and are uncorrected. Optical rotations were measured
using an Optical Activity AA-10 polarimeter. Infrared spectra
were recorded using a Perkin-Elmer 1600 series Fourier trans-
form spectrometer using thin films between sodium chloride
The situation was clearer with the product from cyclisation
of the silyloxymethyl nitrone 33f. Again, virtually a single
1
product was isolated. H NMR data established two features:
firstly, the ring fusion was again cis (J1,6 = 5.5 Hz) and the
5-substituent was positioned equatorially (J4ax,5ax = 13.3 Hz).
Similarly, the major 5-benzyloxy product 38g was cis-fused
(J1,6 = 6.2 Hz) while the 1-H was evidently not in an axial
position lending strong support to this structural assignment.
In contrast, the minor isomer 37g clearly had 1-H in an axial
position. The final example, nitrone 33h, was studied to show
that such a dioxolane function could be taken through the
overall sequence. The lack of stereoselection is not too surpris-
ing; presumably, the major isomer 38h is that with the larger
methylene group of the dioxolane anti to the isoxazolidine ring
(see below).
Likely transition states consistent with these observations are
based upon a chair-like pyran ring, leading to only cis-fused
products.7,11 Thus, conformation 45 with the substituent posi-
tioned equatorially would account for the formation of the
major 4-substituted isomers 34a–c (Scheme 12). A somewhat
1
plates, unless otherwise stated. H NMR spectra were deter-
mined using a Perkin-Elmer R32 operating at 90 MHz, a
Bruker WM-250, a JEOL EX-270 or a Bruker AM-400 spec-
trometer, operating at the frequencies indicated (i.e (90) refers
to 90 MHz etc.). 13C NMR spectra were determined using any
of the latter three instruments, operating at 62.5, 67.5 and 100.1
MHz respectively, as indicated after δC. Unless otherwise
stated, all spectra were determined using dilute solutions in
deuteriochloroform and tetramethylsilane as internal standard.
J Values are expressed in Hertz. Mass spectra were measured
using either an AEI MS902 or a VG 7070E instrument, both
operating in the electron impact mode, unless otherwise stated;
high resolution mass measurements were obtained using the
latter instrument or from the EPSRC Mass Spectrometer
Service, Swansea University.
Unless otherwise stated, all reactions were carried out under
dry nitrogen in anhydrous solvents which were obtained by the
usual methods.26 Standard work-up involved partitioning of the
reaction mixture or residue between appropriate and equal
volumes of water and ether (or another named solvent). The
separated aqueous layer was extracted twice with ether and
the combined ether solutions washed with water (1 × ) and
brine (1 × ). All organic solutions from work-ups were dried by
brief exposure to dried magnesium sulfate followed by filtra-
tion. Solvents were removed by rotary evaporation. CC refers
to column chromatography over Merck 9385 flash silica gel
using the eluants specified. Petrol refers to light petroleum
of bp 40–60 ЊC and ether refers to diethyl ether. THF refers to
tetrahydrofuran. DMPU refers to 1,3-dimethyl-3,4,5,6-tetra-
hydropyrimidin-2(1H)-one.
Methyl 3-oxahept-6-enoate 8b
A solution of but-3-enol (1.00 g, 1.2 ml, 13.87 mmol) in THF
(5 ml) was added dropwise to an ice-cold, stirred suspension of
sodium hydride (1.46 g of a 50% suspension in oil, 30.51 mmol)
in THF (100 ml). After 0.5 h, a solution of bromoacetic acid
(2.12 g, 15.26 mmol) in THF (5 ml) was added dropwise.13 The
resulting mixture was refluxed for 6 h then stirred overnight
without further heating and finally diluted with ether (100 ml)
and water (100 ml). Stirring was continued until all solids had
dissolved then the aqueous layer was separated, washed with
ether (2 × 40 ml), acidified with concentrated hydrochloric acid
and extracted with ethyl acetate (3 × 50 ml). The combined
extracts were dried and evaporated to leave 3-oxahept-6-enoic
Scheme 12
less favourable conformation 46, again with an equatorial sub-
stituent, then explains the formation of the less abundant iso-
mers 35a–c (Scheme 12). Although not proven with certainty,
the more likely stereochemistry7 of the bridged isomers 36a–c
arises from conformation 47 (Scheme 12), in which, despite
additional strain, the more normal reactivity6 of simple mono-
substituted alkenes with nitrones when the nitrone oxygen
becomes bonded to the inner carbon of the alkene, is followed.
Similar arguments account for the formation of the major
5-substituted isomers 38d–h. In these cases, the greater prox-
imity of the substituent to the reacting sites means that the
conformation 48 is more favoured relative to the alternate 49,
especially when the substituent is relatively large, resulting
in much higher stereoselections (e.g. 38e and 38f). Presumably,
this proximity renders formation of the bridged isomers 39
especially unfavourable.
acid 8a as a viscous brown oil (1.58 g, 88%) which showed νmax
/
cmϪ1 3700–2300, 1720 and 1640; δH (250) 2.41 (2H, app. qt,
J 6.7 and ca. 1, 5-CH2), 3.65 (2H, t, J 6.7, 4-CH2), 4.14 (2H, s,
2-CH2), 5.05–5.21 (2H, m, 7-CH2), 5.83 (1H, ddt, J 16.7, 10.0
and 6.7, 6-H) and 8.42 (1H, br s, OH); δC (62.5) 33.8 (5-CH2),
67.7 (CH2), 71.2 (CH2), 116.9 (7-CH2), 134.5 (6-CH) and 175.0
(CO).
A solution of the foregoing acid 8a (4.19 g, 32 mmol) in
methanol (50 ml) was treated with acetyl chloride (0.50 ml) then
refluxed for 2 h. The cooled solution was evaporated and the
residue dissolved in ether (100 ml). The resulting solution was
washed with water (30 ml), saturated aqueous sodium hydrogen
carbonate (30 ml), water (30 ml) and brine (30 ml) then dried,
In conclusion, these pathways represent useful approaches to
these compounds, especially when a substituent is incorporated
at a site adjacent to the reacting centres, leading to high levels
of stereoselection, and offer a variety of options for further
homologation. The transition state conformations, deduced on
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filtered through a silica gel plug and evaporated to leave the
ester 8b (3.31 g, 72%) as a pale oil; νmax/cmϪ1 3080, 1745
and 1640; δH (90) 2.25 (2H, br q, J 6, 5-CH2), 3.48 (2H, t, J 6,
4-CH2), 3.61 (3H, s, OMe), 3.94 (2H, s, 2-CH2), 4.82–5.12 (2H,
m, 7-CH2) and 5.75 (1H, ddt, J 17, 10 and 6, 6-H); δC (62.5) 33.6
(5-CH2), 51.3 (OMe), 67.8, 70.7 (both CH2), 116.2 (7-CH2),
134.4 (6-CH) and 170.6 (CO); m/z 103 (Mϩ Ϫ allyl, 19%), 75
(20), 74 (12), 71 (13), 61 (84), 59 (20) and 55 (100) [Found:
Mϩ Ϫ allyl, 103.0375. C4H7O3 requires M, 103.0393].
chloride (3 ml), a standard work-up gave the alcohol 17 (0.147
mg, 66%)28 as a pale yellow oil; νmax/cmϪ1 3360, 3060, 3020,
1635, 1495 and 1450; δH (250) 2.23 (2H, br t, J 6.6, 3-CH2), 2.58
(1H, br s, OH), 3.32 (1H, dd, J 9.5 and 6.9, 1-Ha), 3.49 (1H, dd,
J 9.5 and 3.7, 1-Hb), 3.63–3.99 (1H, m, 2-H), 4.52 (2H, s,
PhCH2), 4.94–5.20 (2H, m, 5-CH2), 5.83 (1H, ddt, J 17.0, 10.0
and 6.9, 4-CH) and 7.31 (5H, s, Ph); δC (100) 37.9 (3-CH2), 69.7
(2-CH), 73.3 (1-CH2), 73.9 (PhCH2), 117.5 (5-CH2), 127.8,
128.3, 128.9 (all PhCH), 134.6 (4-CH) and 138.1 (Ph); m/z 192
(Mϩ, 7%), 151 (9), 107 (31), 92 (68), 91 (100) and 71 (31)
[Found: Mϩ, 192.1151. C12H16O2 requires M, 192.1150].
3-Oxahept-6-en-1-ol 9
A solution of the foregoing ester 8b (1.06 g, 7.36 mmol) in ether
(20 ml) was added dropwise to an ice-cold, stirred slurry of
lithium aluminium hydride (0.28 g, 7.36 mmol) in ether (15 ml).
The resulting mixture was stirred for 2 h at this temperature
then quenched by the careful addition of 0.5 M aqueous
sodium hydroxide (4 ml). The resulting grey suspension was
filtered through Celite and the solid washed with ether. The
combined filtrates were evaporated to leave the alcohol 9
(0.66 g, 77%) as a colourless oil; νmax/cmϪ1 3400, 3090 and 1640;
δH (250) 2.22 (1H, br s, OH), 2.37 (2H, app qt, J 6.7 and ca. 1,
5-CH2), 3.50–3.61 (4H, m, 2- and 4-CH2), 3.74 (2H, t, J 7.0,
1-CH2), 5.03–5.18 (2H, m, 7-CH2) and 5.84 (1H, ddt, J 16.7,
10.0 and 6.7, 6-H); m/z 116 (Mϩ, 1%), 75 (52), 55 (39) and 45
(100) [Found: Mϩ, 116.0828. C6H12O2 requires M, 116.0834].
(Z)-6-(tert-Butyldimethylsilyloxy)-1-tributylstannyl-2-oxahex-
4-ene 22
The monosilylated diol 21b (2.50 g, 12.4 mmol, prepared18 from
(Z)-but-2-ene-1,4-diol 21a) in THF (2 ml) was added dropwise
to a suspension of sodium hydride (0.35 g, 14.2 mmol) in THF
(50 ml) at ambient temperature. After 1 h, a solution of
(iodomethyl)tributylstannane (5.34 g, 12.4 mmol)19 in THF (10
ml) was slowly added. The resulting mixture was stirred for 24
h, quenched with methanol (2 ml) and poured into petrol (200
ml). The resulting solution was washed with water (150 ml) then
dried and evaporated. CC [EtOAc–petrol (1:8)] of the residue
separated the stannane 22 (3.08 g, 44%) as a colourless oil, Rf
0.70; δH (250) 0.00 (6H, s, 2 × MeSi), 0.85 (9H, s, ButSi), 1.21–
1.29 (9H, m, 3 × Me), 1.39–1.49 (18H, m, 9 × CH2), 3.63 (2H, s,
1-CH2), 3.87 (2H, d, J 8.3, 6-CH2) and 5.48–5.56 (2H, m, 4- and
5-H); m/z 449 (Mϩ Ϫ Bu, 6%), 447 (5), 291 (86), 289 (59), 235
(56), 233 (43), 184 (64), 188 (58), 120 (15), 118 (12), 97 (12)
and 73 (100) [Found: 449.1894. C19H41O2SiSn requires M,
449.1898].
(1RS,6RS)-9-Benzyl-9-aza-3,8-dioxabicyclo[4.3.0]nonane 12
A solution of the foregoing alcohol 9 (0.624 g, 5.38 mmol) in
dichloromethane (20 ml) was added slowly to an ice-cold,
stirred suspension of pyridinium chlorochromate (3.48 g, 16.13
mmol), 3 Å molecular sieves (6.7 g) and sodium acetate (4.41 g,
53.8 mmol) in dichloromethane (20 ml).14 After 2 h at this tem-
perature, the mixture was poured onto a pad of silica and eluted
with a gradient solvent system of ether–petrol [1:1] increasing
to neat ether. The major fraction was evaporated to leave the
aldehyde 10 (0.58 g, 95%) as a pale yellow oil, Rf 0.26 [ether–
petrol (1:1)]; νmax/cmϪ1 3090, 1740 and 1640; δH (90) 2.37 (2H,
br q, J 6, 5-CH2), 3.58 (2H, t, J 6, 4-CH2), 4.05 (2H, s, 2-CH2),
4.90–5.15 (2H, m, 7-CH2), 5.82 (1H, ddt, J 16, 10 and 6, 6-H)
and 9.22 (1H, app s, CHO).
An ice-cold, stirred solution of the foregoing aldehyde
10 (0.58 g, 5.10 mmol) in ether (20 ml) was treated with
N-benzylhydroxylamine (0.66 g, 5.34 mmol) and the resulting
yellow solution stirred for 1 h then evaporated. The residue,
consisting mainly of the nitrone 11, was dissolved in toluene (15
ml) and the resulting solution refluxed for 20 h then cooled and
evaporated. CC [EtOAc–petrol (3:10)] of the residue separated
Methyl 5-(tert-butyldimethylsilyloxymethyl)-3-oxahept-6-enoate
31fb
Butyllithium (3.10 ml of a 1.5 M solution in hexanes, 4.95
mmol) was added to a stirred solution of the stannane 22 (2.25
g, 4.50 mmol) in THF (40 ml), maintained at Ϫ78 ЊC. After 1 h
at this temperature,17 solid sodium iodoacetate (0.94 g, 4.50
mmol) was added in one portion, the cooling bath was removed
and the mixture stirred overnight then quenched by the addi-
tion of methanol (5 ml), followed by 2 M aqueous sodium
hydroxide (30 ml) and ether (100 ml). Ether (50 ml) and 2 M
hydrochloric acid (50 ml) were added to the separated aqueous
layer. After mixing, the organic layer was separated, dried and
evaporated to leave the acid 31fa (0.48 g, 39%) as a colourless
oil; νmax/cmϪ1 3600–3200, 1710 and 1640; δH (90) 0.00 (6H, s,
2 × MeSi), 0.81 (9H, s, ButSi), 2.45 (1H, app tq, J 8 and 6, 5-H),
3.57 (2H, d, J 8, CH2OSi), 3.63 (2H, d, J 6, 4-CH2), 4.08 (2H, s,
2-CH2), 5.09 (1H, br d, J 17, 7-Ht), 5.15 (1H, br d, J 10, 7-Hc),
5.70 (1H, ddd, J 17, 10 and 8, 6-H) and 9.11 (1H, br s, OH). The
the bicyclo[4.3.0]nonane 12 (0.48 g, 43%) as an oil, Rf 0.20; νmax
/
cmϪ1 3070, 3040, 1600, 1490 and 1450; δH (400) 1.82 (2H, m,
5-CH2), 2.89 (1H, br dddd, J 13.4, 7.6, 6.3 and 5.5, 6-Hax), 3.07
(1H, ddd, J 6.3, 5.0 and 5.0, 1-Heq), 3.46 (1H, dd, J 12.2 and 6.6,
4-Heq), 3.50–3.75 (4H, m, 2-CH2, 4-Hax and 7-Ha), 3.87 (1H, d,
J 12.9, PhCHaHb), 4.03 (1H, d, J 12.9, PhCHaHb), 4.18 (1H, dd,
J 7.6 and 7.6, 7-Hb) and 7.24–7.41 (5H, Ph); δC (100) 25.2
(5-CH2), 38.0 (6-CH), 61.0 (1-CH), 61.2, 64.5, 66.7, 69.9 (all
CH2), 127.4, 128.4, 129.1 (all CH) and 137.0 (C); m/z 220
(Mϩ ϩ H, 8%), 219 (Mϩ, 54), 161 (20), 92 (29) and 91 (100)
[Found: Mϩ, 219.1259. C13H17NO2 requires M, 219.1255].
1
sample was pure according to this H NMR data and was not
purified further but immediately dissolved in ether (5 ml) and
added to a solution diazomethane (ca. 10 mmol) in ether (100
ml). The resulting solution was left overnight then evaporated.
CC [EtOAc–petrol (1:6)] of the residue gave the ester 31fb
(0.47 g) as a colourless oil [Found: C, 58.3; H, 9.6. C14H28O4Si
requires C, 58.3; H, 9.8%]; νmax/cmϪ1 1741 and 1643; δH (250)
0.00 (6H, s, 2 × MeSi), 0.85 (9H, s, ButSi), 2.49 (1H, tq, J 7.9
and 6.3, 5-H), 3.51–3.58 (2H, m, CH2OSi), 3.60 (2H, d, J 6.3,
4-CH2), 3.71 (3H, s, OMe), 4.06 (2H, s, 2-CH2), 5.07 (1H, ddd,
J 10.4, 1.8 and 0.9, 7-Hc), 5.11 (1H, ddd, J 17.4, 1.8 and 1.2,
7-Ht) and 5.76 (1H, ddd, J 17.4, 10.4 and 7.9, 6-H).
1-Phenylmethoxypent-4-en-2-ol 17
Vinylmagnesium bromide (2.32 mmol as a 1 M solution in
THF) was added dropwise to a stirred suspension of copper()
iodide (44 mg) in THF (15 ml), maintained at Ϫ25 ЊC. The
resulting dark-green solution was stirred for 10 min then a solu-
tion of benzyloxymethyloxirane 16 (0.19 g, 1.16 mmol)27 in
THF (2 ml) was added dropwise, the cooling bath removed and
stirring of the now black mixture continued for 2 h.15 After
quenching by the addition of saturated aqueous ammonium
2-Benzyloxybut-3-en-1-ol 26
But-3-ene-1,2-diol (3.13 g, 35.5 mmol)20 was added to a solu-
tion of tert-butyldimethylsilyl chloride (5.62 g, 37.3 mmol), tri-
ethylamine (5.19 ml, 37.3 mmol) and 4-(dimethylamino)-
pyridine (50 mg) in dichloromethane (50 ml) and the resulting
3148
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155

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solution stirred at ambient temperature for 24 h. 2 M Hydro-
chloric acid (50 ml) was then added, the phases mixed and the
organic layer separated, washed successively with water (50 ml)
and brine (50 ml), then dried and evaporated. CC [EtOAc–
petrol (1:8)] of the residue separated 1-(tert-butyldimethyl-
silyloxy)but-3-en-2-ol 24 (3.79 g, 53%) as a colourless oil, Rf
0.38; νmax/cmϪ1 3700–3300 and 1642; δH (90) 0.00 (6H, s,
2 × MeSi), 0.78 (9H, s, ButSi), 2.77 (1H, br s, OH), 3.48 (2H, m,
1-CH2), 4.05 (1H, m, 2-H), 5.08 (1H, d, J 10, 4-Hc), 5.23 (1H, d,
J 17, 4-Ht) and 5.70 (1H, ddd, J 17, 10 and 5, 3-H).
Butyllithium (12.2 ml of a 1.56 M solution in hexanes, 19.1
mmol) was added dropwise to a stirred solution of the fore-
going alcohol 24 (3.51 g, 17.3 mmol) in hexane (50 ml) main-
tained at Ϫ78 ЊC followed, after 10 min, by benzyl bromide
(2.97 g, 17.3 mmol), which was added at such a rate that the
temperature remained below Ϫ70 ЊC. The resulting solution
was allowed to warm to ambient temperature during 1 h then
refluxed for 12 h. The cooled solution was quenched with water
(0.5 ml), the mixture dried, filtered and the solvent evaporated
to leave the doubly protected butene-1,2-diol 25 (5.01 g, >95%)
as a colourless oil; νmax/cmϪ1 1642; δH (90) 0.02 (6H, s,
2 × MeSi), 0.85 (9H, s, ButSi), 3.59 (1H, m, 2-H), 4.40 (2H, m,
1-CH2), 5.08 (2H, s, PhCH2), 5.16 (1H, d, J 10, 4-Hc), 5.27 (1H,
d, J 17, 4-Ht), 5.68 (1H, ddd, J 17, 10 and 6, 3-H) and 7.10–7.35
(5H, m, Ph).
2-Me), 1.53 (3H, s, 2-Me), 3.84 (3H, s, OMe), 3.93 (1H, d, J 8.0,
5-Ha), 4.54 (1H, d, J 8.0, 5-Hb), 5.33 (1H, dd, J 10.0 and 2.2,
1Ј-Hc), 5.59 (1H, dd, J 17.0 and 2.2, 1Ј-Ht) and 6.15 (1H, dd,
J 17.0 and 10.0, ᎐CH); δ (67.5) 26.1 (2 × 2-Me), 52.7 (5-CH ),
᎐
C
2
72.9 (OMe), 84.5 (4-C), 111.9 (2-C), 116.5 (᎐CH ), 135.3 (᎐CH)
᎐
᎐
2
and 172.5 (CO); m/z 171 (Mϩ Ϫ Me, 16%), 129 (17), 127 (60),
97 (24), 69 (52) and 43 (100).
2,2-Dimethyl-4-ethenyl-1,3-dioxolane-4-methanol 30
A solution of the foregoing ester 29 (2.78 g, 14.9 mmol) in ether
(50 ml) was added dropwise to an ice-cold, stirred suspension of
lithium aluminium hydride (0.57 g, 14.9 mmol) in ether (50 ml).
The resulting mixture was stirred at ambient temperature for
20 h then quenched by the careful addition of water and the
resulting grey suspension filtered through silica gel. Standard
work-up of the filtrate gave the alcohol 30 (1.77 g, 75%) as a
colourless oil; νmax/cmϪ1 3440; δH (250) 1.41 (3H, s, 2-Me), 1.44
(3H, s, 2-Me), 2.78 (1H, br s, OH), 3.52 (2H, br s, 4-CH2O),
3.83 (1H, d, J 8.0, 5-Ha), 4.07 (1H, d, J 8.0, 5-Hb), 5.20 (1H, dd,
J 10.0 and 2.2, 1Ј-Hc), 5.36 (1H, dd, J 17.0 and 2.2, 1Ј-Ht) and
5.95 (1H, dd, J 17.0 and 10.0, ᎐CH); m/z 157 (Mϩ Ϫ H, 8%),
᎐
143 (66), 84 (31), 69 (77), 59 (38) and 57 (25) [Found: Mϩ Ϫ H,
157.0885. C8H13O3 requires M, 157.0865].
4-Methyl-3-oxahept-6-enoic acid 31aa
Tetrabutylammonium fluoride (17.1 ml of a 1 M solution in
THF, 17.1 mmol) was added slowly to a stirred solution of the
foregoing protected diol 25 (5.01 g, 17.1 mmol) in THF (20 ml)
at ambient temperature. After 10 min, saturated aqueous
ammonium chloride (20 ml) and ether (100 ml) were added.
Standard work-up left a residue which was purified by CC
[EtOAc–petrol (1:4)] to give the alcohol 26 (3.10 g, 95%) as a
colourless oil, Rf 0.20; νmax/cmϪ1 3700–3200 and 1653; δH (90)
2.65 (1H, br s, OH), 3.48 (2H, d, J 6, 1-CH2), 3.84 (1H, q, J 6,
2-H), 4.33 (1H, d, J 12, PhCHaHb), 4.57 (1H, d, J 12, PhCHa-
Hb), 5.23 (1H, d, J 10, 4-Hc), 5.33 (1H, d, J 17, 4-Ht), 5.68 (1H,
ddd, J 17, 10 and 6, 3-H) and 7.20–7.35 (5H, m, Ph); m/z 147
(Mϩ Ϫ CH2OH, 33%), 107 (11), 91 (100) and 77 (29) [Found:
Mϩ Ϫ CH2OH, 147.0808. C10H11O requires M, 147.0810].
Pent-4-en-2-ol (1.60 g, 18.6 mmol; Aldrich) was alkylated with
bromoacetic acid as described above for the preparation of acid
8a, except that the final reaction mixture was refluxed for 2 h, to
give the acid 31aa (2.59 g, 97%) as a viscous oil; νmax/cmϪ1 3700–
2300, 1720 and 1640; δH (90) 1.24 (3H, d, J 6, 4-Me), 2.35 (2H,
m, 5-CH2), 3.63–3.73 (1H, m, 4-H), 4.24 (2H, s, 2-CH2), 5.13–
5.24 (2H, m, 7-CH2) and 5.94 (1H, ddt, J 17, 10 and 6, 6-H);
δC (67.5) 19.1 (4-Me), 40.6 (5-CH2), 65.6 (2-CH2), 76.5 (4-CH),
117.5 (7-CH2), 134.2 (6-CH) and 175.1 (CO); m/z 103 (Mϩ Ϫ
allyl, 61%), 75 (47), 69 (19), 45 (100), 43 (13) and 41 (49)
[Found: Mϩ Ϫ allyl, 103.0434. C4H7O3 requires M, 103.0395].
Methyl 4-methyl-3-oxahept-6-enoate 31ab
A stirred solution of the acid 31aa (2.86 g, 19.8 mmol) in acet-
one (230 ml) was treated with anhydrous potassium carbonate
(8.22 g, 59.5 mmol) and dimethyl sulfate (2.07 ml, 21.8 mmol)
and the resulting mixture was refluxed for 20 h then cooled,
filtered and evaporated.22 A standard work-up of the residue,
with additional washings with aqueous 2 M ammonium
hydroxide (3 × ), gave the ester 31ab (2.80 g, 89%) as a colour-
less oil; νmax/cmϪ1 3095, 1750 and 1640; δH (90) 1.21 (3H, d, J 6,
4-Me), 2.34 (2H, m, 5-CH2), 3.63–3.73 (1H, m, 4-H), 3.81 (3H,
s, OMe), 4.18 (2H, s, 2-CH2), 5.01–5.30 (2H, m, 7-CH2) and
5.93 (1H, ddt, J 17, 10 and 6, 6-H); δC (67.5), 19.0 (4-Me), 40.5
(5-CH2), 51.5 (OMe), 65.9 (2-CH2), 76.0 (4-CH), 117.0 (7-CH2),
134.4 (6-CH) and 171.0 (CO); m/z 117 (Mϩ Ϫ allyl, 58%), 69
(19), 59 (100), 45 (17), 43 (13) and 41 (29) [Found: Mϩ Ϫ allyl,
117.0546. C5H9O3 requires M, 117.0549].
Methyl 2,2-dimethyl-4-ethenyl-1,3-dioxolane-4-carboxylate 29
Methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate 27 was pre-
pared by oxidation of solketal using potassium permanganate
in aqueous potassium hydroxide21 followed by esterification of
the resulting carboxylic acid using dimethyl sulfate and potas-
sium carbonate in acetone (see preparation of ester 31ab).22
The ester 27 (0.231 g, 1.44 mmol) in ether (2 ml) was added
dropwise to a stirred solution of lithium diisopropylamine
[from butyllithium (1 ml of 1.58 M solution in hexanes, 1.58
mmol) and diisopropylamine (0.24 ml, 1.73 mmol)] in ether (4
ml) maintained at Ϫ78 ЊC. After 10 min, a solution of phenyl-
selenoacetaldehyde (0.288 g, 1.44 mmol) in ether (1 ml)
was added dropwise and, after 10 min, the cooling bath
was removed and the resulting colourless solution stirred for
0.5 h then quenched by the addition of saturated aqueous
ammonium chloride (3 ml).23 Standard work-up gave the
crude hydroxy selenide 28 which was immediately dissolved in
dichloromethane (5 ml). The resulting solution was stirred in an
ice bath for 5 min before the addition of triethylamine (1 ml)
followed by a solution of methanesulfonyl chloride (0.33 ml)
in dichloromethane (30 ml), which was added dropwise during
1.5 h. The resulting dark solution was then warmed to ambient
temperature and washed with water (3 × 10 ml). The aqueous
washings were extracted with dichloromethane (10 ml) and the
combined organic solutions washed with brine (10 ml) then
dried and evaporated to leave a dark oil. CC [ether–petrol (3:7)]
separated the ethenyl ester 29 (0.19 g, 70%) as a colourless oil,
Rf 0.43 [Found: C, 57.8; H, 7.7. C9H14O4 requires C, 58.0; H,
7.6%]; νmax/cmϪ1 3090, 1740 and 1640; δH (250) 1.48 (3H, s,
4-Methyl-3-oxahept-6-en-1-ol 32a
The ester 31ab (2.50 g) was reduced using lithium aluminium
hydride as described for the ester 9 to give the alcohol 32a (1.71
g, 83%) as a colourless oil; νmax/cmϪ1 3420, 3080 and 1640;
δH (90) 1.19 (3H, d, J 6, 4-Me), 2.29 (2H, br q, J 6, 5-CH2), 2.81
(1H, br s, OH), 3.47–3.84 (5H, m, 1- and 2-CH2 and 4-H), 4.96–
5.08 (2H, m, 7-CH2) and 5.94 (1H, ddt, J 17, 10 and 6, 6-H);
δC (67.5) 19.4 (4-Me), 40.8 (5-CH2), 61.9 (2-CH2), 69.5 (1-CH2),
74.4 (4-CH), 116.9 (7-CH2) and 134.9 (6-CH); m/z 89 (Mϩ Ϫ
allyl, 86%), 69 (32), 55 (13), 45 (100) and 41 (56) [Found:
Mϩ Ϫ allyl, 89.0601. C4H9O2 requires M, 89.0603].
4-Phenyl-3-oxahept-6-enoic acid 31ba
Method A. A solution of 1-phenylbut-3-en-1-ol 14b [6.17 g,
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155
3149

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41.65 mmol; prepared from allylmagnesium chloride and benz-
aldehyde] in THF (20 ml) was added dropwise to an ice-cold,
stirred suspension of sodium hydride (2.19 g, 91.6 mmol) in
THF (250 ml) and DMPU (20 ml). The cooling bath was
removed and the darkening mixture stirred for 1 h before the
dropwise addition of bromoacetic acid (5.79 g, 41.65 mmol) in
THF (25 ml). The resulting pale yellow mixture was refluxed for
20 h then cooled and quenched by the addition of methanol (25
ml). The mixture was concentrated and worked up as described
fied by CC [EtOAc–petrol (1:4)] to give the ethyl ester 31cc (2.54
g, 61%) as a colourless oil, Rf 0.60 [Found: C, 69.2; H, 8.1.
C16H22O4 requires C, 69.0; H, 8.0%]; νmax/cmϪ1 3080, 3040,
3000, 1745, 1640, 1490 and 1455; δH (90) 1.27 (3H, t, J 7,
OCH2CH3), 2.40 (2H, br t, J 6, 5-CH2), 3.52–3.89 (3H, m, 4-H
and CH2OBn), 4.23 (2H, q, J 7, OCH2CH3), 4.31 (2H, s,
2-CH2), 4.59 (2H, s, PhCH2), 5.02–5.33 (2H, m, 7-CH2), 5.97
(1H, ddt, J 17, 10 and 6, 6-H), and 7.42 (5H, s, Ph); δC (67.5)
15.9 (Me), 38.1 (5-CH2), 62.4, 69.6, 74.4, 75.1 (all CH2), 81.0
(4-CH), 118.9 (7-CH2), 127.8, 129.3, 130.0 (all PhCH), 136.0
(6-CH), 139.9 (PhC) and 172.4 (CO); m/z 143 (14%), 107 (27),
91 (100), 85 (19) and 68 (34).
above to give the acid 31ba (5.48 g, 64%) as a viscous oil; νmax
/
cmϪ1 3700–2200, 1715, 1590 and 1540; δH (90) 2.53–2.62 (2H,
m, 5-CH2), 3.85 (1H, d, J 16, 2-Ha), 4.00 (1 H, d, J 16, 2-Hb),
4.45 (1H, t, J 6, 4-H), 4.94–5.26 (2H, m, 7-CH2), 5.54–6.12 (1H,
m, 6-H) and 7.22–7.39 (5H, br s, Ph); m/z 165 (Mϩ Ϫ allyl,
97%), 131 (35), 115 (13), 107 (100), 91 (39), 79 (30) and 77 (58)
[Found: Mϩ Ϫ allyl, 165.0567. C9H9O3 requires M, 165.0552].
4-Benzyloxymethyl-3-oxahept-6-en-1-ol 32c
The ester 31cc (0.55 g) was reduced using lithium aluminium
hydride as described for the ester 8b to give the alcohol 32c (0.41
g, 87%) as a colourless oil; νmax/cmϪ1 3380, 3060, 3020, 1640,
1490 and 1450; δH (90) 2.23 (2H, br t, J 6, 5-CH2), 3.37–3.71
(7H, m, 1- and 2-CH2, CH2OBn and 4-H), 4.46 (2H, s, PhCH2),
4.91–5.20 (2H, m, 7-CH2) and 5.82 (1H, ddt, J 17, 10 and 6,
6-H); δC (67.5) 35.7 (5-CH2), 61.2, 70.9, 71.7, 72.7 (all CH2),
78.1 (4-CH), 116.6 (7-CH2), 127.1, 127.8, 127.9 (all PhCH),
134.0 (6-CH) and 137.6 (PhC); m/z 236 (Mϩ, 1%), 195 (1), 152
(5), 107 (23), 91 (100) and 71 (19) [Found: Mϩ, 236.1395.
C14H20O3 requires M, 236.1407].
Method B. A solution of 1-phenylbut-3-en-1-ol 14b (1.17 g,
7.90 mmol) in THF (10 ml) was added dropwise to an ice-cold,
stirred suspension of sodium hydride (0.42 g, 17.4 mmol) in
THF (60 ml). After 1 h, sodium iodoacetate (1.64 g, 7.90 mmol)
was added in one portion. The resulting mixture was allowed to
warm to ambient temperature then refluxed for 2 h. The cooled
mixture was quenched by the addition of methanol (2 ml), then
the solvents were evaporated and the residue worked up in the
usual manner to leave the acid 31ba (1.55 g, 95%) which exhib-
ited spectral and analytical data identical with the foregoing
example.
Ethyl 5-methyl-3-oxahept-6-enoate 31dc
Alkylation of 2-methylbut-3-en-1-ol 18 (1.67 g) with ethyl
bromoacetate as described for ester 31cc, without DMPU but
with a reflux period of 20 h, delivered, after CC [ether–petrol
(1:9)], the ethyl ester 31dc (2.10 g, 63%) as a colourless oil, Rf
0.50 [Found: C, 62.8; H, 9.6. C9H16O3 requires C, 62.8; H,
9.4%]; νmax/cmϪ1 3090, 1740 and 1640; δH (90) 1.05 (3H, d, J 7,
5-Me), 1.27 (3H, t, J 7, OCH2CH3), 2.50 (1H, br sept, J 7, 5-H),
3.38–3.46 (2H, m, 4-CH2), 4.06 (2H, s, 2-CH2), 4.21 (2H, q, J 7,
OCH2CH3), 4.92–5.20 (2H, m, 7-CH2) and 5.82 (1H, ddd, J 17,
10 and 7, 6-H); δC (67.5) 14.0 (5-CH3), 16.3 (OCH2CH3), 37.6
(5-CH), 60.4 (OCH2CH3), 68.4, 76.3 (both CH2O), 114.1
(7-CH2), 140.7 (6-CH) and 170.2 (CO); m/z 172 (Mϩ, 1%), 127
(34), 117 (100), 113 (54), 89 (30), 69 (97), 68 (66) and 55 (19)
[Found: Mϩ, 172.1101. C9H16O3 requires M, 172.1099].
Methyl 4-phenyl-3-oxahept-6-enoate 31bb
Esterification of the foregoing acid 31ba (4.13 g) using dimethyl
sulfate, as described for acid 31aa, gave the ester 31bb (3.56 g,
81%) as a colourless oil [Found: C, 70.9; H, 7.5. C13H16O3
requires C, 70.9; H, 7.3%]; νmax/cmϪ1 3090, 3050, 1745, 1640,
1490 and 1440; δH (90) 2.53–2.62 (2H, m, 5-CH2), 3.75 (3H, s,
OMe), 3.90 (1H, d, J 16, 2-Ha), 4.00 (1H, d, J 16, 2-Hb), 4.51
(1H, t, J 6, 4-H), 4.97–5.24 (2H, m, 7-CH2), 5.91 (1H, ddt,
J 17, 10 and 6, 6-H) and 7.28–7.48 (5H, br s, Ph); δC (100) 42.2
(5-CH2), 51.5 (OMe), 65.6 (2-CH2), 81.2 (4-CH), 116.9 (7-CH2),
126.9, 127.9, 128.4 (all ArCH), 134.3 (6-CH), 140.5 (ArC) and
170.7 (CO); m/z 179 (Mϩ Ϫ allyl, 100%), 131 (23), 121 (89), 105
(16), 91 (31), 77 (13) and 73 (15) [Found: Mϩ Ϫ allyl, 179.0679.
C10H11O3 requires M, 179.0708].
5-Methyl-3-oxahept-6-en-1-ol 32d
Alternatively, esterification using diazomethane (see ester
31fb) gave an identical product in 90% isolated yield.
The ester 31dc (3.27 g) was reduced using lithium aluminium
hydride as described for the ester 8b to give the alcohol 32d (2.32
g, 94%) as a colourless oil; νmax/cmϪ1 3400, 3080 and 1650;
δH (90) 1.13 (3H, d, J 6, 5-Me), 2.49 (1H, br s, OH), 2.61 (1H, m,
5-H), 3.43–3.99 (6H, m, 1-, 2- and 4-CH2), 5.09–5.38 (2H, m,
7-CH2) and 5.98 (1H, ddd, J 17, 10 and 6, 6-H); δC (67.5) 16.5
(5-CH3), 37.7 (5-CH), 61.7, 72.1, 75.9 (all CH2O), 114.2 (7-CH2)
and 141.2 (6-CH); m/z 99 (Mϩ Ϫ Me, 10%), 75 (100), 69 (37), 68
(60), 56 (18) and 55 (13) [Found: Mϩ Ϫ Me, 99.0816. C6H11O
requires M, 99.0810].
4-Phenyl-3-oxahept-6-en-1-ol 32b
The ester 31bb (3.30 g) was reduced using lithium aluminium
hydride as described for the ester 9 to give the alcohol 32b (2.35
g, 81%) as a colourless oil; νmax/cmϪ1 3420, 3080, 3020, 1640,
1490 and 1450; δH (90) 2.34–2.80 (2H, m, 5-CH2), 3.42–3.91
(4H, m, 1- and 2-CH2), 4.40 (1H, t, J 6, 4-H), 5.02–5.31 (2H, m,
7-CH2), 5.93 (1H, ddt, J 17, 10 and 6, 6-H) and 7.46 (5H, s, Ph);
δC (67.5) 42.5 (5-CH2), 61.8 (2-CH2), 70.0 (1-CH2), 82.4 (4-CH),
117.1 (7-CH2), 126.7, 127.7, 128.4 (all PhCH), 134.8 (6-CH)
and 141.7 (PhC); m/z 151 (Mϩ Ϫ allyl, 82%), 131 (16), 107 (100)
and 91 (14) [Found: Mϩ Ϫ allyl, 151.0766. C9H11O2 requires M,
151.0759].
Methyl 5-phenyl-3-oxahept-6-enoate 31eb
2-Phenylbut-3-en-1-ol 2016 (3.0 g, 20 mmol) in THF (2 ml) was
added slowly to a stirred suspension of sodium hydride (1.01 g,
42 mmol) in THF (50 ml), cooled in an ice bath. After 1 h,
sodium iodoacetate (4.15 g, 20 mmol) was added in one portion
and the resulting mixture stirred without further cooling for 16
h. 2 M Aqueous sodium hydroxide was then added followed by
ether (50 ml). The separated aqueous layer was washed with
ether (100 ml) then adjusted to pH 3 using 2 M hydrochloric
acid. The resulting mixture was extracted with ether (2 × 100
ml) and the combined extracts washed with brine (30 ml) then
dried and evaporated to leave 5-phenyl-3-oxahept-6-enoic acid
31ea (2.73 g, 66%) as a colourless oil; νmax/cmϪ1 3700–3100 and
1740–1720; δH (250) 3.75 (1H, dd, J 13.7 and 6.7, 4-Ha), 3.82
Ethyl 4-benzyloxymethyl-3-oxahept-6-enoate 31cc
A solution of the alcohol 17 (2.87 g, 14.95 mmol) in THF (20
ml) was added dropwise to a stirred suspension of sodium
hydride (0.45 g, 17.9 mmol) in THF (150 ml) and DMPU (3.6
ml). The mixture was stirred at 60 ЊC for 1 h, then cooled to
ambient temperature and ethyl bromoacetate (2.0 ml, 17.9
mmol) added dropwise. The resulting yellow suspension was
refluxed for 4 h then cooled, quenched with methanol (15 ml)
and concentrated. Standard work-up left an oil which was puri-
3150
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155

View Article Online
(1H, d, J 13.7 and 6.7, 4-Hb), 4.12 (1H, d, J 16.3, 2-Ha), 4.17
(1H, m, 5-H), 4.20 (1H, d, J 16.3, 2-Hb), 5.14 (1H, dd, J 17.1
and 0.7, 7-Ht), 5.19 (1H, dd, J 10.3 and 1.0, 7-Hc), 6.10 (1H,
ddd, J 17.1, 10.3 and 8.0, 6-H) and 7.25–7.45 (5H, m, Ph); m/z
206 (Mϩ, 12%), 147 (22), 130 (71), 117 (26), 91 (100) and 77 (24)
[Found: Mϩ, 206.0947. C12H14O3 requires M, 206.0943].
The acid 31ea (1.0 g) was esterified using diazomethane and
the resulting product purified as described for ester 31fb to give
the methyl ester 31eb (1.01 g, 95%) as a colourless oil [Found:
C, 70.8; H, 7.3. C13H16O3 requires C, 70.9; H, 7.3%]; νmax/cmϪ1
1747 and 1638; δH (250) 2.85 (1H, dd, J 13.7 and 6.7, 4-Ha), 3.06
(1H, dd, J 13.7 and 6.7, 4-Hb), 3.71 (3H, s, OCH3), 4.00 (1H, d,
J 16.4, 2-Ha), 4.02 (1H, m, 5-H), 4.10 (1H, d, J 16.4, 2-Hb), 5.12
(1H, dd, J 17.1 and 0.7, 7-Ht), 5.19 (1H, dd, J 10.3 and 1.0,
7-Hc), 5.69 (1H, ddd, J 17.1, 10.3 and 8.0, 6-H) and 7.20–7.40
(5H, m, Ph); m/z 131 (100%), 117 (13), 91 (69) and 77 (11).
J 8.0, 5-Hb), 4.23 (2H, s, CH2CO2), 5.29 (1H, br d, J 10.0,
᎐CH H ), 5.51 (1H, br d, J 17.0, ᎐CH H ), 6.09 (1H, dd, J 17.0
᎐
᎐
c
t
c
t
and 10.0, ᎐CH) and 8.30 (1H, br s, OH).
᎐
The acid 31ha (1.40 g) was immediately dissolved in acetone
and esterified using dimethyl sulfate, as described for ester 31ab.
After reflux for 5 h, standard work-up gave the methyl ester
31hb (1.38 g) as a yellow oil; δH (90) 1.42 (3H, s, 2-Me), 1.48
(3H, s, 2-Me), 3.57 (2H, br s, 4-CH2O), 3.76 (3H, s, OCH3), 3.85
(1H, d, J 8.0, 5-Ha), 4.19 (2H, s, CH2CO2), 4.21 (1H, d, J 8.0,
5-H ), 5.23 (1H, dd, J 10 and 2, ᎐CH H ), 5.48 (1H, dd, J 17 and
᎐
b
c
t
2, ᎐CH H ) and 6.09 (1H, dd, J 17 and 10, ᎐CH).
᎐
᎐
c
t
The foregoing ester 31hb (1.38 g) was reduced using lithium
aluminium hydride as described for ester 8b, and the crude
product purified by CC using ether–petrol (1:1), to give the
alcohol 32h (1.13 g, 70%) as a colourless oil; νmax/cmϪ1 3440 and
1640; δH (90) 1.41 (3H, s, 2-Me), 1.46 (3H, s, 2-Me), 3.38–3.86
(6H, m, 3 × CH2O), 3.81 (1H, d, J 8.6, 5-Ha), 4.10 (1H, d, J 8.6,
5-H ), 5.20 (1H, dd, J 10 and 2, ᎐CH H ), 5.41 (1H, dd, J 17 and
᎐
5-Benzyloxy-3-oxahept-6-enoic acid 31ga
b
c
t
2, ᎐CH H ) and 6.00 (1 H, dd, J 17 and 10, ᎐CH); δ (67.5) 26.2
᎐
᎐
c
t
C
Butyllithium (5.8 ml of a 1.56 M solution in hexanes, 9.0 mmol)
was added dropwise to a stirred, ice-cooled solution of the
alcohol 26 (1.46 g, 8.2 mmol) in THF (50 ml). After 10 min,
sodium iodoacetate (1.71 g, 8.2 mmol) was added in one por-
tion and the resulting mixture warmed to ambient temperature
during 0.5 h then refluxed for 2 h. The cooled solution was
quenched with methanol (2 ml) and the solvents evaporated.
The residue was dissolved in 2 M aqueous sodium hydroxide
(50 ml) and ether (50 ml). The separated aqueous layer was
washed with ether (50 ml) then acidified to pH 4 using 2 M
hydrochloric acid and extracted with ether (2 × 100 ml). The
combined extracts were washed with brine (50 ml) then dried
and evaporated to leave the acid 31ga (1.73 g, 89%) as a colour-
less oil; Rf 0.42 [EtOAc–petrol (1:1)] [Found: C, 66.4; H, 7.1.
C13H16O4 requires C, 66.1; H, 6.8%]; νmax/cmϪ1 3600–3000 and
1740–1710; δH (90) 3.50 (2H, d, J 6, 4-CH2), 4.05 (1H, m, 5-H),
4.14 (2H, s, 2-CH2), 4.40 (1H, d, J 12, PhCHa), 4.65 (1H, d,
J 12, PhChb), 5.29 (1H, br d, J 10, 7-Hc), 5.34 (1H, br d, J 17,
7-Ht), 5.80 (1H, ddd, J 17, 10 and 7, 6-H), 7.25–7.35 (5H, m,
Ph) and 10.20 (1H, br s, OH); m/z 147 (8%), 107 (14), 105 (15),
91 (100) and 77 (13).
(2-CH3), 27.0 (2-CH3), 61.7, 70.9, 73.1, 74.9 (all CH2O), 82.9
(4-C), 110.3 (2-C), 115.1 (᎐CH ) and 138.5 (᎐CH); m/z 202 (Mϩ,
᎐
᎐
2
1%), 187 (6), 127 (100), 83 (32), 69 (97), 45 (28) and 43 (53)
[Found: Mϩ, 202.1180. C10H18O4 requires M, 202.1200].
(1RS,4SR,6RS)- and (1SR,4SR,6SR)-9-Benzyl-4-methyl-9-aza-
3,8-dioxabicyclo[4.3.0]nonane 34a and 35a and (1RS,4RS,6SR)-
8-benzyl-4-methyl-8-aza-3,7-dioxabicyclo[4.2.1]nonane 36a
Dimethyl sulfoxide (0.85 ml, 12.0 mmol) in dichloromethane (2
ml) was added dropwise to a stirred solution of freshly distilled
oxalyl chloride (0.48 ml, 5.5 mmol) in dichloromethane (10 ml),
maintained at Ϫ78 ЊC. After 6 min, a solution of the alcohol
32a (0.325 g, 2.49 mmol) in dichloromethane (2 ml) was added
dropwise. After 1 h at the same temperature, triethylamine (1.74
ml, 12.5 mmol) was added dropwise and the resulting white
suspension allowed to warm spontaneously to ambient tem-
perature.24 Water (20 ml) was added, the layers separated and
the aqueous layer extracted with dichloromethane (2 × 5 ml).
The combined organic solutions were washed successively with
10 ml portions of 2 M hydrochloric acid, water, saturated aque-
ous sodium hydrogen carbonate, water and brine then dried and
evaporated to leave the aldehyde 7a (0.27 g, 85%); νmax/cmϪ1
3090, 1740 and 1645; δH (90) 1.21 (3H, d, J 6, 4-CH3), 2.10–2.48
(2H, m, 5-CH2), 3.60–3.66 (1H, m, 4-H), 4.15 (2H, s, 2-CH2),
5.02–5.30 (2H, m, 7-CH2), 5.93 (1H, ddt, J 17, 10 and 7, 6-H)
and 9.87 (1H, br s, 1-H).
The crude aldehyde 7a was immediately dissolved in ice
cooled ether (15 ml) and the solution stirred with N-benzyl-
hydroxylamine (0.27 g, 2.21 mmol) for 1 h then evaporated to
leave the nitrone 33a; δH (90) 1.11 (3H, d, J 6, 4-CH3), 2.08–2.37
(2H, m, 5-CH2), 3.46–3.54 (1H, m, 4-H), 4.44 (2H, br d, J 4,
2-CH2), 4.85 (2H, br s, PhCH2), 4.93–5.24 (2H, m, 7-CH2), 5.83
(1H, ddt, J 17, 10 and 7, 6-H), 6.93 (1H, t, J 4, 1-H) and 7.25–
7.56 (5H, m, Ph).
Methyl 5-benzyloxy-3-oxahept-6-enoate 31gb
The foregoing acid 31ga (1.72 g) was esterified using diazo-
methane, as described for the ester 31fb, to give the methyl ester
31gb (1.70 g, 93%) as a colourless oil [Found: C, 67.3; H, 7.1.
C14H18O4 requires C, 67.2; H, 7.3%]; νmax/cmϪ1 1735 and 1644;
δH (90) 3.65 (2H, d, J 6, 4-CH2), 3.70 (3H, s, OCH3), 4.08 (1H,
m, 5-H), 4.20 (2H, br s, 2-CH2), 4.48 (1H, d, J 13, PhCHa), 4.68
(1H, d, J 13, PhCHb), 5.32 (1H, br d, J 10, 7-Hc), 5.38 (1H, br d,
J 17, 7-Ht), 5.80 (1H, ddd, J 17, 10 and 7, 6-H), and 7.35–7.45
(5H, m, Ph).
2,2-Dimethyl-4-ethenyl-4-(4-hydroxy-2-oxabutyl)-1,3-dioxolane
32h
The crude nitrone was immediately dissolved in toluene (10
ml) and the resulting solution stirred at 80 ЊC for 20 h, then
cooled and evaporated. CC [EtOAc–petrol (1:4)] separated i)
the (1RS,4SR,6RS)-bicyclo[4.3.0]nonane 34a (251 mg, 51%) as
a colourless oil with Rf 0.25; νmax/cmϪ1 3090, 3080, 3040, 1495,
1450 and 1120; δH (400) 1.21 (3H, d, J 6.2, 4-CH3), 1.58–1.66
(2H, m, 5-CH2), 2.65 (1H, app dddd, J 12.0, 6.1, ca. 5.2 and 5.2,
6-H), 2.79 (1H, ddd, J 5.2, 2.7 and 1.0, 1-H), 3.39 (1H, br dq,
J 12.0 and 6.2, 4-Hax), 3.59 (1H, br d, J ca. 7.4, 7-Ha), 3.63 (1H,
dd, J 12.8 and 2.7, 2-Ha), 3.77 (1H, br d, J 12.8, 2-Hb), 3.98 (1H,
d, J 13.0, PhCHaHb), 4.03 (1H, partly obscured but containing
d, J 5.2, 7-Hb), 4.04 (1H, d, J 13.0, PhCHaHb) and 7.23–7.42
(5H, m, Ph); δH (400; d6-(CH3)2SO; selected resonances) 1.32
(1H, app q, J 12.0, 5-Hax), 1.60 (1H, dddd, J 12.0, 6.2, 6.2 and
1.5, 5-Heq), 3.34 (1H, dqd, J 12.0, 6.2 and 1.5, 4-Hax) and 3.96
(1H, dd, J 7.4 and 5.2, 7-Hb); δC (100) 21.7 (4-CH3), 34.2
A solution of 2,2-dimethyl-4-ethenyl-1,3-dioxolane-4-methanol
30 (1.27 g, 8.01 mmol) in THF (5 ml) was added dropwise to a
stirred, ice-cold suspension of sodium hydride (0.42 g, 17.6
mmol) in THF (80 ml). After 1 h, a solution of bromoacetic
acid (1.11 g, 8.01 mmol) in THF (15 ml) was added dropwise
and the resulting mixture refluxed for 20 h then cooled to
ambient temperature, quenched by the addition of methanol
(10 ml) and the solvents evaporated. The residue was par-
titioned between water (50 ml) and ether (50 ml). The separated
aqueous layer was washed with ether (50 ml) then acidified with
excess solid citric acid and extracted with ether (3 × 30 ml). The
combined extracts were washed with brine (30 ml) then dried
and evaporated to leave the acid 31ha (1.40 g, 81%) as a thick,
colourless oil; δH (90) 1.45 (3H, s, 2-Me), 1.50 (3H, s, 2-Me),
3.63 (2H, s, 4-CH2O), 3.87 (1H, d, J 8.0, 5-Ha), 4.22 (1H, d,
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155
3151

View Article Online
(5-CH2), 41.3 (6-CH), 62.2 (PhCH2), 62.5 (1-CH), 66.0, 71.0
(both CH2O), 72.0 (4-CH), 127.4, 128.3, 129.5 (all PhCH)
and 136.9 (PhC); m/z 233 (Mϩ, 13%), 174 (24), 161 (12), 107
(12), 106 (20), 92 (13) and 91 (100) [Found: Mϩ, 233.1407.
C14H19NO2 requires M, 233.1416]; ii) the (1SR,4SR,6SR)-
bicyclo[4.3.0]nonane 35a (64 mg, 13%) also a colourless oil, Rf
0.29; νmax/cmϪ1 3090, 3070, 3040, 1490, 1450 and 1100; δH (400)
1.17 (3H, d, J 6.1, 4-CH3), 1.64 (1H, ddd, J 14.3, 10.5 and 5.3,
5-Hax), 1.76 (1H, ddd, J 14.3, 2.7 and 2.7, 5-Heq), 3.08–3.15 (1H,
m, 6-H), 3.24 (1H, app dd, J 10.8 and 5.5, 1-H), 3.34 (1H, dd,
J 10.8 and 10.8, 2-Hax), 3.57 (1H, dqd, J 10.5, 6.1 and 2.7,
4-Hax), 3.76 (1H, d, J 12.7, PhCHaHb), 3.79 (1H, dd, J 9.3 and
7.5, 7-Ha), 3.85 (1H, dd, J 10.8 and 5.5, 2-Heq), 4.06 (1H, d,
J 12.7, PhCHaHb), 4.31 (1H, dd, J 9.6, and 7.5, 7-Hb) and 7.24–
7.35 (5H, m, Ph); δC (100) 21.4 (4-CH3), 31.3 (5-CH2), 36.8
(6-CH), 59.0 (1-CH), 60.6, 67.1, 69.5 (all CH2), 68.5 (4-CH),
127.4, 128.4, 128.9 (all PhCH) and 137.1 (PhC); m/z 233 (Mϩ,
26%), 174 (14), 161 (23), 92 (16) and 91 (100) [Found: Mϩ,
233.1404] and iii) the (1RS,4RS,6SR)-bicyclo[4.2.1]nonane 36a
(43 mg, 8%) as a colourless oil, Rf 0.40; νmax/cmϪ1 3090, 3060,
3030, 1490 and 1450; δH (400) 1.16 (3H, d, J 6.4, 4-CH3), 1.30
(1H, ddd, J 14.2, 11.0 and 1.2, 5-Ha), 1.77 (1H, ddd, J 14.2, 4.8
and 2.0, 5-Hb), 2.29–2.33 (2H, m, 9-CH2), 3.37 (1H, ddd, J 5.5,
5.5 and 3.1, 1-H), 3.61 (1H, app d, J 12.5, 2-Ha), 3.75 (1H, dd,
J 12.5 and 5.5, 2-Hb), 3.76 (1H, d, J 12.8, PhCHaHb), 3.83 (1H,
m, 4-H), 4.13 (1H, d, J 12.8, PhCHaHb), 4.64 (1H, ddd, J 8.7,
4.8 and ca. 1, 6-H) and 7.23–7.40 (5H, m, Ph); δC (100) 22.4
(4-CH3), 32.1 (5-CH2), 42.7 (9-CH2), 64.2 (CH), 64.3 (CH2),
72.1 (CH), 74.3 (CH2), 76.7 (6-CH), 127.4, 128.5, 129.2 (all
PhCH) and 137.5 (PhC); m/z 233 (Mϩ, 12%), 160 (20), 92 (11)
and 91 (100) [Found: Mϩ, 233.1423].
mmol) and dried magnesium sulfate (1.0 g) in ice-cold ether
(50 ml). After 1 h at 0 ЊC, the mixture was allowed to warm
to ambient temperature, filtered and the filtrate evaporated to
leave the nitrone 33b (0.87 g, 98%) as a colourless oil; νmax/cmϪ1
1641 and 1604; δH (90) 2.35–2.45 (2H, m, 5-CH2), 3.63–3.67
(1H, m, 4-H), 4.25 (2H, d, J 4, 2-CH2), 4.78 (2H, s, PhCH2),
4.92 (1H, d, J 1, 7-Hc), 4.97 (1H, d, J 17, 7-Ht), 5.88 (1H, ddt,
J 17, 10 and 7, 6-H), 6.73 (1H, t, J 4, 1-H) and 7.20–7.40 (10H,
m, Ph); m/z 295 (Mϩ, 8%), 161 (18), 107 (10), 105 (13), 91 (100)
and 77 (10) [Found: Mϩ, 295.1573. C19H21NO2 requires M,
295.1572].
The nitrone 33b (0.87 g) was heated in toluene (20 ml) at
60 ЊC for 10 h. The cooled solution was evaporated and
the residue separated by CC [petrol–EtOAc–triethylamine
(6:1:0.1)] to give i) the (1RS,4RS,6RS)-bicyclo[4.3.0]nonane
34b (330 mg, 38%) as a colourless oil with Rf 0.23; νmax/cmϪ1
3090, 1954, 1883, 1813 and 914; δH (400) 1.88 (1H, ddd, J 13.3,
6.4 and 2.0, 5-Heq), 2.04 (1H, app br q, J ca. 11.7, 5-Hax), 2.86
(1H, br dq, J 11.7 and 6.4, 6-H), 2.87–2.96 (1H, m, ω1/2 22,
1-H), 3.65 (1H, br d, J 7.8, 7-Ha), 3.84 (1H, dd, J 12.9 and 2.3,
2-Ha), 4.02 (1H, d, J 13.3, PhCHaHb), 4.06 (1H, d, J 13.3,
PhCHaHb), 4.04–4.14 (2H, m, 2-Hb and 7-Hb), 4.33 (1H, dd,
J 11.6 and 2.0, 4-Hax) and 7.07–7.46 (10H, m, Ph); δC (100) 34.7
(5-CH2), 41.9 (6-CH), 62.2 (2-CH2), 62.6 (1-CH), 66.6 (PhCH2),
71.3 (7-CH2), 78.3 (4-CH), 126.2, 127.7, 127.8, 128.5, 128.6,
129.6 (all PhCH), 137.0 and 142.6 (both PhC); m/z 295 (Mϩ,
19%), 161 (44), 105 (16), 91 (100) and 77 (17) [Found: Mϩ,
295.1563]; ii) the (1SR,4RS,6SR)-bicyclo[4.3.0]nonane 35b (250
mg, 29%), Rf 0.38, as colourless crystals, mp 107–109 ЊC (aq.
MeOH) [Found: C, 77.4; H, 7.3; N, 4.7. C19H21NO2 requires C,
77.3; H, 7.2; N, 4.7%]; νmax/cmϪ1 3090, 1956, 1880, 1818 and
914; δH (400) 1.94–2.04 (2H, m, 5-CH2), 3.18–3.27 (1H, m, ω1/2
20, 6-H), 3.37 (1H, ddd, J 10.7, 6.6 and 6.6, 1-H), 3.52 (1H, dd,
J 11.8 and 10.7, 2-Hax), 3.81 (1H, d, J 12.7, PhCHaHb), 3.96
(1H, br t, J 8.3, 7-Ha), 4.02 (1H, dd, J 11.8 and 6.6, 2-Heq), 4.11
(1H, d, J 12.7, PhCHaHb), 4.39 (1H, dd, J 9.3 and 7.9, 7-Hb),
4.51 (1H, dd, J 9.6 and 4.6, 4-Hax) and 7.16–7.38 (10H, m, Ph);
δH (400; d6-(CH3)2SO; selected resonances) 1.86 (1H, ddd,
J 14.0, 11.6 and 5.4, 5-Hax) and 2.00 (1H, br d, J 14.0, 5-Heq);
δC (100) 31.8 (5-CH2), 37.2 (6-CH), 59.0 (2-CH2), 60.7 (1-CH),
67.5 (PhCH2), 69.5 (7-CH2), 74.7 (4-CH), 125.7, 127.6, 128.4,
128.5, 129.1 (all PhCH), 137.0 and 142.0 (both PhC); m/z 295
(Mϩ, 21%), 161 (53), 105 (12) and 91 (100) [Found: Mϩ,
295.1575] and iii) the (1RS,4SR,6SR)-bicyclo[4.2.1]nonane 36b
(138 mg, 16%) as a colourless oil; Rf 0.50; νmax/cmϪ1 2857, 1953,
1881, 1811, 1495 and 917; δH (400) 1.62 (1H, dd, J 13.9 and
11.8, 5-Ha), 2.01 (1H, dd, J 13.9 and 4.1, 5-Hb), 2.36 (1H, dd,
J 11.7 and 7.7, 7-Ha), 2.42 (1H, d, J 7.7, 7-Hb), 3.46 (1H, ddd,
J 11.7, 6.5 and 6.5, 1-H), 3.72 (1H, d, J 12.7, 2-Ha), 3.81 (1H, d,
J 12.9, PhCHaHb), 3.90 (1H, dd, J 12.7 and 5.7, 2-Hb), 4.18 (1H,
d, J 12.9, PhCHaHb), 4.72 (1H, m, 4-H), 4.97 (1H, m, 6-H)
and 7.10–7.41 (10H, m, PhH); δC (100) 32.3 (9-CH2), 43.0
(5-CH2), 64.0 (1-CH), 64.3 (PhCH2), 74.9 (2-CH2), 76.6 (4-CH),
77.7 (6-CH), 127.1, 127.5, 128.3, 128.4, 128.5, 129.2 (all PhCH),
137.4 and 143.4 (PhC); m/z 295 (Mϩ, 4%), 160 (26), 106 (81),
91 (100), 77 (31) and 70 (29) [Found: Mϩ, 295.1562].
(1RS,4RS,6RS)- and (1SR,4RS,6SR)-9-Benzyl-4-phenyl-9-aza-
3,8-dioxabicyclo[4.3.0]nonane 34b and 36b and (1RS,4SR,6SR)-
8-benzyl-4-phenyl-8-aza-3,7-dioxabicyclo[4.2.1]nonane 36b
i) Formation of 4-phenyl-3-oxahept-6-enal 7b:-
a) Swern oxidation of the 4-phenylhept-6-enol 32b (0.601 g),
as described for aldehyde 7a above, gave crude aldehyde 7b
(0.585 g, 98%) as a colourless oil; νmax/cmϪ1 3090, 3040, 1737,
1642, 1490 and 1455; δH (90) 2.26–2.77 (2H, m, 5-CH2), 3.88
(1H, d, J 16, 2-Ha), 3.95 (1H, d, J 16, 2-Hb), 4.34 (1H, dd, J 10
and 7, 4-H), 5.01 (1H, d, J 10, 7-Hc), 5.06 (1H, d, J 17, 7-Ht),
5.88 (1H, ddt, J 17, 10 and 7, 6-H), 7.27 (5H, app br s, Ph) and
9.66 (1H, t, J ca. 1, 1-H); m/z 149 (42%), 131 (14), 107 (40), 91
(100) and 77 (19). The sample was ca. 90% pure according to
the 1H NMR data.
b) Tetrapropylammonium perrhuthenate (0.16 g, 0.45 mmol)
was added in one portion to a stirred mixture of the alcohol 32b
(0.94 g, 4.9 mmol), N-methylmorpholine N-oxide (0.91 g, 7.8
mmol) and powdered 4 Å molecular sieves (2.6 g) in acetonitrile
(20 ml) at ambient temperature.25 After 25 min, the solvent
was evaporated and the residue stirred with dichloromethane
(50 ml). The resulting mixture was filtered through a pad of
Kieselruhr gel and the filtrate evaporated to leave the aldehyde
7b (0.72 g, 78%; ca. 95% pure) which showed data identical to
the foregoing.
c) Diisobutylaluminium hydride (4.0 ml of a 1 M solution in
hexanes, 4.0 mmol) was added dropwise to a stirred solution of
the ester 31bb (0.80 g, 3.6 mmol) in hexane (40 ml), maintained
at Ϫ78 ЊC. After 1 h at this temperature, the mixture was
quenched by the addition of aqueous methanol (1:9, 1 ml) and
then warmed to ambient temperature. The resulting mixture
was dried, filtered through a pad of silica and the solid washed
with dichloromethane (2 × 50 ml). Evaporation of the com-
bined filtrates left the aldehyde 7b (0.67 g, 98%) as a colourless
oil of >95% purity according to the 1H NMR data, which was
identical to the foregoing.
(1RS,4RS,6RS)-9-Benzyl-4-benzyloxymethyl-9-aza-3,8-dioxa-
bicyclo[4.3.0]nonane 34c and 35c and (1RS,4SR,6SR)-8-benzyl-
4-benzyloxymethyl-8-aza-3,7-dioxabicyclo[4.2.1]nonane 36c
The 4-benzyloxymethylhept-6-enol 32c (0.28 g) was oxidized
using the Swern method and the resulting aldehyde condensed
immediately with N-benzylhydroxylamine to give the nitrone
33c, exactly as described for the 4-methyl derivative 33a. The
nitrone 33c was immediately dissolved in toluene (10 ml) and
the resulting solution stirred at 80 ЊC for 20 h. The cooled solu-
tion was evaporated and the residue separated by CC [EtOAc–
petrol (2:3)] to give i) the (1RS,4RS,6RS)-bicyclo[4.3.0]nonane
34c (148 mg, 41%) as a colourless oil; νmax/cmϪ1 3090, 3060,
N-Benzylhydroxylamine (0.37 g, 3.0 mmol) was added to a
stirred mixture of freshly prepared aldehyde 7b (0.57 g, 3.0
3152
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155

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3030, 1490, 1450, 1115 and 1100; δH (400) 1.63–1.67 (2H, m,
5-CH2), 2.62–2.71 (1H, m, 6-H), 2.80–2.85 (1H, m, 1-H), 3.37–
3.44 (1H, m, 4-H), 3.50–3.56 (2H, m, CH2OBn), 3.59 (1H,
app d, J 7.8, 7-Ha), 3.65 (1H, dd, J 12.7 and 3.0, 2-Ha), 3.81
(1H, dd, J 12.7 and 1.0, 2-Hb), 3.98 (1H, d, J 13.3, PhCHaHbN),
4.02 (1H, d, J 13.3, PhCHaHbN), 4.03 (1H, dd, J 7.8 and 5.1,
7-Hb), 4.51 (1H, d, J 12.2, PhCHaHbO), 4.61 (1H, d, J 12.2,
PhCHaHbO) and 7.23–7.40 (10H, m, Ph); δC (100) 29.0 (5-CH2),
40.8 (6-CH), 62.1 (CH2), 62.7 (1-CH), 65.8, 71.0, 73.3, 74.9 (all
CH2), 127.4, 127.6, 127.8, 128.3, 129.4 (all PhCH), 136.8 and
138.2 (both PhC); m/z 339 (Mϩ, 2%), 160 (10), 92 (18) and 91
(100) [Found: Mϩ, 339.1831. C21H25NO3 requires M, 339.1834]
and ii) the (1RS,4SR,6SR)-bicyclo[4.2.1]nonane 36c (58 mg,
16%) as a colourless oil; νmax/cmϪ1 3090, 3060, 3030, 1490, 1450
and 1095; δH (400) 1.44 (1H, ddd, J 14.0, 11.6 and 1.2, 5-Ha),
1.67–1.76 (1H, m, 5-Hb), 2.28–2.34 (2H, m, 9-CH2), 3.64 (1H, d,
J 12.5, 2-Ha), 3.77 (1H, d, J 12.9, PhCHaHbN), 3.84 (1H, dd,
J 12.5 and 5.7, 2-Hb), 3.91–3.98 (1H, m, 1-H), 4.13 (1H, d,
J 12.9, PhCHaHbN), 4.54 (1H, d, J 12.5, PhCHaHbO), 4.58
(1H, d, J 12.5, PhCHaHbO), 4.67–4.71 (1H, m, 6-H) and 7.24–
7.38 (10H, m, Ph); δC (100) 32.3 (5-CH2), 37.3 (9-CH2), 64.1
(CH), 64.3, 73.2, 73.6, 74.8 (all CH2), 75.1 (CH), 76.4 (6-CH),
127.4, 127.5, 127.6, 128.3, 128.4, 129.2 (all PhCH), 137.5 and
138.5 (both PhC); m/z 174 (Mϩ, 4%), 107 (15), 91 (100) and 71
(26).
2.28–2.36 (2H, m, 9-CH2), 3.30–3.36 (1H, m, 1-H), 3.38 (1H,
dd, J 12.0 and 11.0, 4-Ha), 3.56 (1H, d, J 12.6, PhCHaHb), 3.69
(1H, dd, J 12.0 and 4.8, 4-Hb), 3.73 (1H, dd, J 12.8 and 6.2,
2-Ha), 3.75 (1H, d, J 12.8, 2-Hb), 4.41 (1H, ddd, J 4.5, 4.5 and
1.0, 6-H) and 7.24–7.44 (5H, m Ph); δC (100) 13.7 (5-CH3),
32.2 (9-CH2), 39.3 (5-CH), 62.9 (1-CH), 64.0, 72.0, 75.5 (all
CH2), 81.7 (6-CH), 127.4, 128.4, 129.2 (all PhCH) and 137.4
(PhC); m/z 233 (Mϩ, 16%), 160 (28), 91 (100) and 81 (21)
[Found: Mϩ, 233.1411].
(1RS,5SR,6RS)-9-Benzyl-5-phenyl-9-aza-3,8-dioxabicyclo-
[4.3.0]nonane 38e
The ester 31eb (0.60 g) was reduced to the aldehyde 7e directly
using DIBAL-H, exactly as described for the preparation of
aldehyde 7b, method c), and was isolated as a colourless oil
(0.46 g, 90%) and showed νmax/cmϪ1 1737; δH (90) 2.90 (1H, dd,
J 13.7 and 6.7, 4-Ha), 2.95 (1H, dd, J 13.7 and 6.7, 4-Hb), 3.95
(1H, m, 5-H), 4.00 (2H, s, 2-CH2), 5.15 (1H, dd, J 17.1 and 0.7,
7-Ht), 5.20 (1H, dd, J 10.3 and 1.0, 7-Hc), 5.72 (1H, ddd, J 17.1,
10.3 and 8.0, 6-H), 7.20–7.35 (5H, m, Ph) and 9.78 (1H, br s,
CHO); m/z 190 (Mϩ, 6%), 130 (97), 130 (50), 117 (27), 91 (100)
and 77 (23) and was used immediately. Both TLC and 1H NMR
analysis indicated ca. 95% purity.
The foregoing aldehyde 7e (0.46 g) was converted into the
corresponding nitrone 33e as described for the preparation of
nitrone 33b. The crude nitrone 33e was heated in toluene at
60 ЊC for 12 h and the cooled solution evaporated. CC [EtOAc–
petrol (1:4)] of the residue gave the (1RS,5SR,6RS)-bicyclo-
[4.3.0]nonane 38e (350 mg, 46%), Rf 0.36, as a colourless
oil; νmax/cmϪ1 3085, 3061, 3027, 1495, 1454 and 920; δH (400;
CDCl3–C6H6) 2.70 (1H, dd, J 13.8 and 7.2, 4-Ha), 2.84 (1H,
dddd, J 8.8, 6.5, 6.5 and 2.4, 6-H), 2.96 (1H, dd, J 13.8 and 6.5,
4-Hb), 3.35 (1H, dd, J 9.1 and 2.4, 7-Ha), 3.49 (1H, dd, J 9.4 and
6.1, 2-Ha), 3.63 (1H, d, J 12.8, PhCHaHb), 3.68 (1H, ddd, J 8.8,
7.2 and 6.1, 1-H), 3.82 (1H, dd, J 9.1 and 6.5, 7-Hb), 3.85 (1H,
ddd, J 7.2, 6.5 and 6.5, 5-H), 3.99 (1H, dd, J 9.4 and 7.2, 2-Hb)
and 7.09–7.42 (10H, m, Ph); δC (100), 40.6 (4-CH2), 53.9
(6-CH), 60.0 (PhCH2), 69.2 (7-CH2), 71.5 (1-CH), 72.1 (2-CH2),
85.8 (5-CH), 128.5, 128.9, 129.0, 129.2, 129.9, 130.0 (all PhCH),
136.9 and 137.4 (both PhC); m/z 295 (Mϩ, 8%), 204 (14), 174
(81), 148 (32), 106 (30), 91 (100) and 77 (12) [Found: Mϩ,
295.1572. C19H21NO2 requires M, 295.1572].
Also isolated in variable amounts (see discussion) was
(1RS,5SR,6RS)-2-benzyl-4-methyl-5-phenyl-2-aza-3,7-dioxa-
bicyclo[3.3.0]octane 44 as a viscous, colourless oil [Found: C,
77.2; H, 7.5; N, 4.5. C19H21NO2 requires C, 77.3; H, 7.2; N,
4.7%]; νmax/cmϪ1 3090, 3030, 1495, 1454, 1378, 1077 and 1029;
δH (400) 1.41 (3H, d, J 6.3, 4-CH3), 3.70 (1H, m, 1-H), 3.78 (1H,
d, J 9.5, 6-Ha), 3.90–4.10 (2H, m, 8-CH2), 4.00 (1H, d, J 12.8,
PhCHaHb), 4.19 (1H, d, J 12.8, PhCHaHb), 4.28 (1H, d, J 9.5,
6-Hb), 4.72 (1H, q, J 6.3, 4-H) and 7.02–7.41 (10H, m, Ph-H);
δC (100) 12.6 (4-CH3), 59.3 (PhCH2), 62.0 (5-C), 65.6 (8-CH2),
70.8 (6-CH2), 75.8 (1-CH), 78.5 (4-CH), 125.4, 125.8, 126.3,
127.8, 128.2, 128.3 (all PhCH), 135.9 and 141.6 (both PhC); m/z
295 (Mϩ, 15%), 174 (3), 149 (11), 130 (6), 117 (5), 105 (6), 103
(8), 92 (9), 91 (100) and 77 (6).
(1SR,5RS,6SR)- and (1RS,5RS,6RS)-9-Benzyl-5-methyl-9-aza-
3,8-dioxabicyclo[4.3.0]nonane 37d and 38d and (1RS,5RS,6SR)-
8-benzyl-5-methyl-8-aza-3,7-dioxabicyclo[4.2.1]nonane 39d
The 5-methylhept-6-enol 32d (0.22 g) was oxidized using the
Swern method and the resulting aldehyde condensed immedi-
ately with N-benzylhydroxylamine to give the nitrone 33d,
exactly as described for the 4-methyl derivative 33a. The inter-
mediate aldehyde 7d showed δH (90) 1.08 (3H, d, J 7, 5-CH3),
2.46–2.74 (1H, m, 5-H), 3.33–3.75 (2H, m, 4-CH2), 4.15 (2H, s,
2-CH2), 5.00–5.34 (2H, m, 7-CH2), 5.94 (1H, ddd, J 17, 10 and
7, 6-H) and 9.89 (1H, br s, CHO). The nitrone 33d was immedi-
ately dissolved in toluene (10 ml) and the resulting solution
stirred at 80 ЊC for 20 h. The cooled solution was evaporated
and the residue separated by CC [EtOAc–petrol (1:5)] to give i)
the (1RS,5RS,6RS)-bicyclo[4.3.0]nonane 38d (143 mg, 36%), Rf
0.24, as a colourless oil; νmax/cmϪ1 3090, 3060, 3030, 1450 and
1115; δH (400) 0.86 (3H, d, J 6.8, 5-CH3), 1.91–1.99 (1H, m,
5-H), 2.19–2.24 (1H, m, 6-H), 2.85–2.92 (1H, m, 1-H), 3.02 (1H,
dd, J 11.5 and 10.5, 4-Hax), 3.56 (1H, dd, J 12.6 and 3.3, 2-Ha),
3.65 (1H, dd, J 12.6 and 2.4, 2-Hb), 3.69 (1H, dd, J 7.7 and 2.5,
7-Ha), 3.79 (1H, dd, J 11.5 and 4.1, 4-Heq), 3.94 (2H, s, PhCH2),
4.02 (1H, dd, J 7.7 and 6.0, 7-Hb) and 7.21–7.43 (5H, m, PhH);
δC (100) 16.5 (5-CH3), 30.3 (5-CH), 47.4 (6-CH), 61.7 (2-CH2),
62.4 (1-CH), 66.1 (PhCH2), 69.3, 71.6 (both CH2), 127.2, 128.2,
129.1 (all PhCH) and 137.1 (PhC); m/z 233 (Mϩ, 36%), 188
(24), 161 (12), 92 (13) and 91 (100) [Found: Mϩ, 233.1423.
C14H19NO2 requires M, 233.1416], ii) the (1SR,5RS,6SR)-
bicyclo[4.3.0]nonane 37d (33 mg, 9%), Rf 0.29, as a colourless
oil; νmax/cmϪ1 3090, 3070, 3040, 1490, 1455 and 1105; δH (400)
0.89 (3H, d, J 7.1, 5-CH3), 2.17–2.25 (1H, m, 5-H), 3.07–
3.21 (1H, m, 6-H), 3.15 (1H, dd, J 11.5 and 11.5, 4-Hax),
3.19 (1H, dd, J 11.3 and 11.3, 2-Hax), 3.31 (1H, ddd, J 11.3,
6.2 and 6.2, 1-H), 3.64 (1H, dd, J 11.5 and 5.0, 4-Heq), 3.77
(1H, d, J 12.6, PhCHaHb), 3.80 (1H, dd, J 11.3 and 6.2, 2-Heq),
3.86 (1H, dd, J 9.8 and 7.7, 7-Ha), 4.07 (1H, d, J 12.6,
PhCHaHb), 4.17 (1H, dd, J 9.8 and 7.9, 7-Hb) and 7.25–7.38
(5H, m, Ph); δC (100) 15.4 (5-CH3), 29.5 (5-CH), 42.6 (6-CH),
60.0 (1-CH), 60.7, 65.7, 66.8, 68.7 (all CH2), 127.5, 128.5, 129.0
(all PhCH) and 137.2 (PhC); m/z 233 (Mϩ, 54%), 188 (44), 161
(15), 92 (18) and 91 (100) [Found: Mϩ, 233.1414] and iii) the
(1RS,5RS,6SR)-bicyclo[4.2.1]nonane 39d (36 mg, 10%), Rf, as
a colourless oil; νmax/cmϪ1 3090, 3070, 3040, 1490 and 1455;
δH (400) 0.87 (3H, d, J 7.1, 5-CH3), 1.70–1.79 (1H, m, 5-H),
(1RS,5RS,6RS)-9-Benzyl-5-(tert-butyldimethylsilyloxymethyl)-
9-aza-3,8-dioxabicyclo[4.3.0]nonane 38f
The ester 31fb was reduced to the aldehyde 7f directly using
DIBAL-H, exactly as described for the preparation of aldehyde
7b, method c), and was isolated as a colourless oil (90–93%);
νmax/cmϪ1 1740 and 1640; δH (250) 0.00 (6H, s, 2 × SiCH3), 0.84
(9H, s, SiC(CH3)3), 2.47 (1H, m, 5-H), 3.40–3.65 (6H, m, 2- and
4-CH2 and CH2Si), 5.09 (1H, dd, J 11.6 and 1.2, 7-Hc), 5.13 (1H,
dd, J 17.4 and 1.2, 7-Ht), 5.75 (1H, ddd, J 17.4, 11.6 and 7.9,
6-H) and 9.70 (1H, t, J 0.9, CHO) and was used immediately
1
as it proved to be rather sensitive. Both TLC and H NMR
analysis indicated ca. 95% purity.
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155
3153

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The foregoing aldehyde 7f (55 mg, 0.21 mmol) was added to a
suspension of N-benzylhydroxylamine hydrochloride (34 mg,
0.21 mmol) and anhydrous potassium carbonate (43 mg, 0.35
mmol) in toluene (20 ml) maintained at 0 ЊC. After 2 h, the
mixture was filtered and evaporated to leave the crude nitrone
33f (71 mg); νmax/cmϪ1 1642 and 1605; δH (250) 0.00 (6H, s,
2 × SiCH3), 0.87 (9H, s, SiC(CH3)3), 2.47 (1H, m, 5-H), 3.46–
3.58 (4H, m, 4-CH2 and CH2OSi), 4.40 (2H, d, J 4.7, 2-CH2),
4.55 (2H, s, PhCH2), 5.06 (1H, d, J 10.9, 7-Hc), 5.08 (1H, d,
J 17.2, 7-Ht), 5.72 (1H, ddd, J 17.2, 10.9 and 7.8, 6-H), 6.80
(1H, t, J 4.7, 1-H) and 7.14–7.20 (5H, m, Ph). A sample
(63 mg) was immediately heated in toluene (10 ml) at 57 ЊC for
18 h and the cooled solution evaporated. CC [EtOAc–petrol
(1:4)] of the residue gave the (1RS,5RS,6RS)-bicyclo[4.3.0]-
nonane 38f (37 mg, 58%), Rf 0.21, as a colourless oil; νmax/cmϪ1
3090, 3030, 1495 and 920; δH (400) 0.00 (6H, s, 2 × SiCH3),
0.84 (9H, s, SiC(CH3)3), 1.94–1.99 (1H, m, 5-H), 2.65 (1H,
ddd, J ca. 6.5, 5.5 and 4.2, 6-H), 2.96 (1H, app br q, J ca. 5.5,
1-H), 3.22 (1H, app dd, J 13.3 and 11.7, 4-Hax), 3.36 (1H,
dd, J 11.7 and 8.3, 4-Heq), 3.46 (1H, d, J 7.6, 7-Ha), 3.57 (1H,
dd, J 9.8 and 5.0, CHaHbOSi), 3.72 (1H, dd, J 7.7, and 5.6,
2-Ha), 3.76 (1H, dd, J 9.8 and 4.9, CHaHbOSi), 3.81 (1H, dd,
J 7.6 and 4.2, 7-Hb), 3.91 (1H, d, J 13.3, PhCHaHb), 3.95 (1H, d,
J 13.3, PhCHaHb), 4.12 (1H, dd, J 7.7 and 5.6, 2-Hb) and
7.18–7.38 (5H, m, Ph); δC (67.5) Ϫ0.3, Ϫ0.1 (both SiCH3),
18.2 (SiC), 25.8 (SiC(CH3)3), 37.7 (6-CH), 40.7 (5-CH), 61.1
(1-CH), 61.3 (PhCH2), 63.6 (CH2OSi), 66.6 (4-CH2), 67.3
(2-CH2), 69.7 (7-CH2), 127.4, 128.4, 129.2 (all PhCH) and
136.9 (PhC); m/z 363 (Mϩ, 9%), 160 (14), 91 (100), 73 (21)
and 57 (19) [Found: Mϩ, 363.2232. C20H33NO3Si requires M,
363.2226].
requires M, 325.1678] and ii) the (1RS,5RS,6RS)-bicyclo-
[4.3.0]nonane 38g (26 mg, 30%), Rf 0.23, as a viscous oil [Found:
C, 73.6; H, 6.8; N, 3.9. C20H23NO3 requires C, 73.8; H, 7.1; N,
4.3%]; νmax/cmϪ1 3090, 3030, 1490 and 927; δH (400) 2.72 (1H,
app br qd, J ca. 7 and 3.7, 6-H), 3.17 (1H, dd, J 6.2, 3.9 and 3.9,
1-H), 3.35 (1H, dd, J 11.4 and 7.9, 4-Hax), 3.55 (1H, dd, J 12.6
and 3.9, 2-Ha), 3.65 (1H, dd, J 12.6 and 3.9, 2-Hb), 3.70 (1H,
ddd, J 7.9, 7.9 and 4.0, 5-H), 3.81 (1H, dd, J 8.0 and 3.7, 7-Ha),
3.92 (1H, d, J 13.1, PhCHaHbN), 3.97 (1H, dd, J 11.4 and 4.0
4-Heq), 3.98 (1H, d, J 13.1, PhCHaHbN), 4.12 (1H, dd, J 8.0 and
6.6, 7-Hb), 4.53 (1H, d, J 11.7, PhCHaHbO), 4.63 (1H, d, J 11.7,
PhCHaHbO) and 7.11–7.42 (10H, m, Ph); δC (100) 46.5 (6-CH),
61.7 (PhCH2N), 62.9 (1-CH), 66.5 (7-CH2), 67.5 (2-CH2), 68.8
(4-CH2), 71.9 (PhCH2O), 73.1 (5-CH), 127.6, 127.8, 128.0,
128.5, 128.6, 129.3 (PhCH), 136.7 and 138.1 (PhC); m/z 280
(2%), 219 (12), 106 (7), 91 (100) and 77 (8) [Found: Mϩ Ϫ 45,
280.1340. C18H18NO2 requires M, 280.1338].
Spiro-dioxolanes 37h and 38h
The dioxolane alcohol 32h (290 mg) was oxidized using the
Swern method to give the aldehyde 7h (245 mg), exactly as
described for the 4-methyl derivative 33a, which showed δH (90)
1.41 (3H, s, 2-Me), 1.46 (3H, s, 2-Me), 3.64 (2H, s, 4-CH2O),
3.92 (1H, d, J 9, 5-Ha), 4.25 (1H, d, J 9, 5-Hb), 4.26 (2H, br s,
CH CHO), 5.23–5.66 (2H, m, ᎐CH ), 6.15 (12H, dd, J 17 and
᎐
2
2
10, ᎐CH) and 9.89 (1H, s, CHO) and which was condensed
᎐
immediately with N-benzylhydroxylamine to give the nitrone
33h, also as described for the 4-methyl derivative 33a. This was
immediately dissolved in toluene (10 ml) and the resulting solu-
tion stirred at 80 ЊC for 20 h. The cooled solution was evapor-
ated and the residue separated by CC [ETOAc–petrol (3:7)] to
give i) 37h (71 mg, 16%), Rf 0.36, as a colourless solid, mp 126–
128 ЊC (ether–petrol) [Found: C, 66.9; H, 7.8; N, 4.7. C17H23-
NO4 requires C, 66.9; H, 7.6; N, 4.6%]; νmax/cmϪ1 (CHCl3) 1605,
1450, 1380, 1100 and 1050; δH (400) 1.25 (3H, s, CCH3), 1.41
(3H, s, CCH3), 3.15–3.25 (2H, m, 2-Ha and 6-H), 3.32 (1H, ddd,
J 10.8, 6.6 and 6.6, 1-H), 3.40 (1H, dd, J 11.4 and 1.0, 4-Ha),
3.57 (1H, d, J 11.4, 4-Hb), 3.75 (1H, d, J 12.8, PhCHaHb), 3.80
(1H, dd, J 11.5 and 6.6, 2-Hb), 3.84 (1H, dd, J 8.7 and 1.0,
O(C)CHaHbO), 4.06 (1H, d, J 12.8, PhCHaHb), 4.09 (1H, dd,
J 8.6 and 8.6, 7-Ha), 4.12 (1H, d, J 8.7, O(C)CHaHbO), 4.32
(1H, dd, J 9.4 and 8.6, 7-Hb) and 7.23–7.38 (5H, m, Ph);
δC (100) 27.0, 27.2 (both CH3), 47.3 (6-CH), 60.0 (CH2), 61.1
(1-CH), 67.3, 67.7, 68.9, 74.9 (all CH2), 77.9 (5-C), 109.8
(OCO), 127.7, 128.6, 128.9 (all PhCH) and 136.8 (PhC); m/z
305 (Mϩ, 48%), 216 (23), 161 (27), 92 (23) and 91 (100) [Found:
Mϩ, 305.1619. C17H23NO4 requires M, 305.1627] and ii) 38h
(135 mg, 31%), Rf 0.26, as a colourless oil [Found: C, 66.7; H,
8.1; N, 4.5]; δmax/cmϪ1 (CHCl3) 1605, 1450, 1380; δH (90) 1.38
(3H, s, CCH3), 1.43 (3H, s, CCH3), 3.28–4.44 (12H, m) and
7.24–7.39 (5H, m Ph); δC (100) 26.6, 27.5 (both CH3), 47.7
(6-CH), 60.6 (CH2), 61.3 (1-CH), 66.0, 66.5, 69.6, 70.8 (all
CH2), 78.1 (5-C), 109.6 (OCO), 127.4, 128.8, 129.3 (all PhCH)
and 136.9 (PhC); m/z 305 (Mϩ, 15%), 126 (20), 161 (33), 92 (43)
and 91 (100) [Found: Mϩ, 305.1622].
(1RS,5SR,6RS)- and (1RS,5RS,6RS)-9-Benzyl-5-benzyloxy-9-
aza-3,8-dioxabicyclo[4.3.0]nonane 37g and 38g
The ester 31gb (0.50 g) was reduced to the aldehyde 7g directly
using DIBAL-H, exactly as described for the preparation of
aldehyde 7b, method c), and was isolated, after CC [EtOAc–
petrol (1:2)], as a colourless oil (180 mg, 41%) along with
recovered ester 31gb (235 mg, 47%). The aldehyde 7g showed
νmax/cmϪ1 1737 and 1644; δH (90) 3.63 (2H, d, J 6, 4-CH2), 4.04–
4.11 (1H, m, 5-H), 4.14 (2H, br s, 2-CH2), 4.45 (1H, d, J 12,
PhCHaHb), 4.68 (1H, d, J 12, PhCHaHb), 5.32 (1H, d, J 11,
7-Hc), 5.38 (1H, d, J 17, 7-Ht), 5.80 (1H, ddd, J 17, 11 and 7,
6-H) and 9.70 (1H, t, J 1, CHO) and was used immediately.
Both TLC and 1H NMR analysis indicated ca. 95% purity.
The foregoing aldehyde 7g (65 mg) was converted into the
nitrone 33g (86 mg, 88%), as described in the foregoing example
(33f); νmax/cmϪ1 1645 and 1604; δH (250) 3.53 (2H, d, J 6.2,
4-CH2), 3.95 (2H, d, J 4.3, 2-CH2), 3.93–3.99 (1H, m, 5-H), 4.40
(1H, d, J 12.1, PhCHaHbO), 4.61 (1H, d, J 12.1, PhCHaHbO),
4.81 (2H, s, PhCH2), 5.29 (1H, d, J 10.9, 7-Hc), 5.30 (1H, d,
J 16.9, 7-Ht), 5.75 (1H, ddd, J 16.9, 10.9 and 7.3, 6-H), 6.82
(1H, t, J 4.3, 1-H) and 7.25–7.40 (10H, m, Ph).
The crude nitrone 33g (86 mg) was heated in toluene
(10 ml) at 55 ЊC for 21 h. After evaporation, CC [EtOAc–petrol
(1:2)] of the residue separated i) the (1RS,5SR,6RS)-bicyclo-
A small quantity (12 mg, 3%) of the bicyclo[4.2.1]nonane
isomer 39h, of unknown stereochemistry at the dioxolane
centre, was also isolated, Rf 0.24, and identified by δC (100) 26.3,
27.4 (both CH3), 37.8 (9-CH2), 62.8 (1-CH), 63.9, 69.4, 73.3,
75.6 (all CH2), 82.3 (5-C), 83.2 (6-CH), 110.3 (OCO), 127.6,
128.4, 129.2 (all PhCH) and 137.0 (PhC); m/z 305 (Mϩ, 10%),
161 (40), 92 (61) and 91 (100) [Found: Mϩ, 305.1624].
[4.3.0]nonane 37g (11 mg, 13%), Rf 0.29, as a viscous oil; νmax
/
cmϪ1 3090, 3030, 1495 and 920; δH (400) 3.23 (1H, br dd, J 10.7
and 10.7, 2-Hax), 3.27 (1H, m, 6-H), 3.39–3.56 (2H, m, 1- and
5-H), 3.74 (1H, d, J 12.7, PhCHaHbN), 3.81 (1H, dd, J 11.7
and 6.8, 2-Heq), 3.87 (1H, dd, J 12.0 and 5.2, 7-Ha), 3.90 (1H,
dd, J 12.0 and 5.2, 7-Hb), 4.06 (1H, d, J 12.7, PhCHaHbN), 4.14
(1H, dd, J 8.7 and 8.7, 4-Heq), 4.27 (1H, dd, J 9.2 and 8.7, 4-Hax),
4.57 (2H, s, PhCH2O) and 7.09–7.41 (10H, m, Ph); δC (100) 42.0
(6-CH), 60.0 (PhCH2N), 61.1 (1-CH), 65.3 (7-CH2), 66.1
(2-CH2), 67.4 (4-CH2), 71.2 (PhCH2O), 71.9 (5-CH), 127.6,
127.7, 128.0, 128.6, 129.1 (PhCH), 137.1 and 138.2 (PhC); m/z
325 (Mϩ, 4%), 280 (3), 234 (5), 219 (15), 161 (4), 159 (4), 106
(15), 91 (100) and 77 (8) [Found: Mϩ, 325.1668. C20H23NO3
Acknowledgements
We are very grateful to the EPSRC Mass Spectrometry Service,
Swansea University for the provision of some high resolution
mass spectral data and to Zeneca Pharmaceuticals and the
EPSRC for financial support through the CASE Scheme.
3154
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155

View Article Online
F. Biesemeier and K. Harms, J. Chem. Soc., Perkin Trans. 1, 1998,
References
3717; H. G. Aurich, M. Geiger, C. Gentes, K. Harms and H. Köster,
Tetrahedron, 1998, 54, 3181.
1 P. Lefrancier, Forschr. Chem. Org. Naturst., 1981, 40, 1; E. Ellouz,
A. Adam, R. Ciorbaru and E. Lederer, Biochem. Biophys. Res.
Commun., 1974, 59, 1317.
2 M. A. Sparks, K. W. Williams, C. Lukacs, A. Schrell, G. Priebe,
A. Spaltenstein and G. M. Whitesides, Tetrahedron, 1993, 49, 1;
M. P. DeNinno, Synthesis, 1991, 583 and references cited therein.
3 P. M. Colman, Pure Appl. Chem., 1995, 67, 1683 and references cited
therein.
4 T. Wakamiya, T. Ando, T. Teshima and T. Shiba, Bull. Chem.
Soc. Jpn., 1984, 57, 142; Y. Hayakawa, M. Nakagawa, H. Kawai,
K. Tanabe, H. Nakayama, A. Shimazu, H. Seto and H. Otake,
Agric. Bio. Chem., 1985, 49, 2685.
5 F. M. Hauser and S. R. Ellenberger, Chem. Rev., 1986, 86, 35 and
references cited therein.
6 J. J. Tufariello, [1,3]-Dipolar Cycloaddition Chemistry, ed. A. Padwa,
Wiley Interscience, New York, 1984, ch. 9; P. A. Wade,
Comprehensive Organic Synthesis, eds. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, vol. 4, p. 1113; K. B. G. Torssell,
Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, VCH
Publishers Inc., Weinheim, 1988, ch. 5; W. Carruthers, Cycloaddition
Reactions in Organic Synthesis, Pergamon Press, Oxford, 1990;
E. Breuer, H. G. Aurich and A. Nielsen, Nitrones, Nitronates and
Nitroxides, eds. S. Patai and Z. Rappoport, John Wiley and Sons,
Chichester, 1989.
7 N. A. LeBel, M. E. Post and J. J. Whang, J. Am. Chem. Soc., 1964,
86, 3759; N. A. LeBel and E. G. Banucci, J. Org. Chem., 1971, 36,
2440.
8 B. Bernat and A. Vassella, Helv. Chim. Acta, 1979, 62, 2400 and
2411.
9 H. G. Aurich and K.-D. Möbus, Tetrahedron, 1989, 45, 5815;
H. G. Aurich and F. Biesemeier, Synthesis, 1995, 1171; H. G. Aurich,
F. Biesemeier and M. Boutahar, Chem. Ber., 1991, 124, 2329. See
also S. Baskaran and H. G. Aurich, Synlett, 1998, 277; H. G. Aurich,
G. Frenzen and C. Gentes, Chem. Ber., 1993, 126, 787.
10 H. G. Aurich, M. Geiger and U. Sievers, Synlett, 1997, 1004;
H. G. Aurich, F. Biesemeier, M. Geiger and K. Harms, Liebigs Ann./
Recl., 1997, 423.
12 For
a preliminary communication, see M. B. Gravestock,
D. W. Knight, J. S. Lovell and S. R. Thornton, J. Chem. Soc., Perkin
Trans. 1, 1994, 1661.
13 Cf. B. B. Snider and R. A. H. F. Hui, J. Org. Chem., 1985, 50, 5167.
14 J. Herscovici, M.-J. Egron and K. Antonakis, J. Chem. Soc., Perkin
Trans. 1, 1982, 1967.
15 C. Huynh, F. Derguini-Boumechal and G. Linstrumelle,
Tetrahedron Lett., 1979, 1503.
16 Cf. C. B. Rose and C. W. Smith, J. Chem. Soc., Chem. Commun.,
1969, 248.
17 T. Nakai and K. Mikami, Chem. Rev., 1986, 86, 885; Org. React.,
1994, 46, 105.
18 M. Sodeoka, H. Yamada and M. Shibasaki, J. Am. Chem. Soc.,
1990, 112, 4906; H. M. Hull and D. W. Knight, J. Chem. Soc., Perkin
Trans. 1, 1997, 857.
19 W. C. Still, J. Am. Chem. Soc., 1978, 100, 1481; D. Seyferth and
S. B. Andrews, J. Organomet. Chem., 1971, 30, 151.
20 D. Carpita and A. Rossi, Synthesis, 1982, 469.
21 T. Reichstein, A. Pedolin and A. Grussner, Helv. Chim. Acta, 1935,
18, 598.
22 J. Grundy, B. G. James and G. Pattenden, Tetrahedron Lett., 1972,
757.
23 D. L. J. Clive and C. G. Russell, J. Chem. Soc., Chem. Commun.,
1981, 434.
24 D. Swern, A. J. Mancuso and S.-L. Huang, J. Org. Chem., 1978, 43,
2480.
25 W. P. Griffith and S. V. Ley, Aldrichimica Acta, 1990, 23, 13;
S. V. Ley, J. Norman, W. P. Griffiths and S. P. Marsden, Synthesis,
1994, 639.
26 W. L. F. Armarego and D. D. Perrin, Purification of Laboratory
Chemicals, Butterworth Heinemann, Oxford, 1996.
27 G. Hirth and R. Barner, Helv. Chim. Acta, 1982, 65, 1059;
J. M. Klunder, S. Y. Ko and K. B. Sharpless, J. Org. Chem., 1986, 51,
3710.
28 Cf. B. H. Lipschutz, R. Moretti and R. Crow, Org. Synth., 1990, 69,
80.
11 H. G. Aurich, M. Boutahar, H. Köster, K.-D. Möbus and L. Ruiz,
Chem. Ber., 1990, 123, 1999. See also S. Baskaran, H. G. Aurich,
Paper 9/05802H
J. Chem. Soc., Perkin Trans. 1, 1999, 3143–3155
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