Selectivity in the cycloadditions of carbonyl ylides with glyoxylates: An approach to the zaragozic acids-squalestatins

Article abstract of DOI:10.1039/b004870o

Reaction of diazodiketoester 8 with glyoxylates in the presence of catalytic rhodium(n) acetate generates 6,8-dioxabicyclo[3.2.1]octanes 9 and 11 in good yield. Elaboration of 9 provides a suitable alcohol 25 for acid-catalysed rearrangement to give the 2,8-dioxabicyclo[3.2.1]octane skeleton 26 of the zaragozic acids-squalestatins. More substituted diazodiketoesters 36 and 40 also undergo highly regio- and diastereoselective cycloaddition with glyoxylates to give the cycloadducts 41,43 and 44. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004870o

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Selectivity in the cycloadditions of carbonyl ylides with
glyoxylates: an approach to the zaragozic acids—squalestatins
David M. Hodgson,*ab James M. Bailey,ab Carolina Villalonga-Barber,a Michael G. B. Drewb
and Timothy Harrisonc
1
a Dyson Perrins Laboratory, Department of Chemistry, University of Oxford, South Parks
Road, Oxford, UK OX1 3QY†
b Department of Chemistry, University of Reading, Whiteknights, Reading, UK RG6 2AD
c Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park,
Harlow, Essex, UK CM20 2QR
Received (in Cambridge, UK) 19th June 2000, Accepted 16th August 2000
First published as an Advance Article on the web 3rd October 2000
Reaction of diazodiketoester 8 with glyoxylates in the presence of catalytic rhodium(II) acetate generates 6,8-dioxa-
bicyclo[3.2.1]octanes 9 and 11 in good yield. Elaboration of 9 provides a suitable alcohol 25 for acid-catalysed
rearrangement to give the 2,8-dioxabicyclo[3.2.1]octane skeleton 26 of the zaragozic acids—squalestatins. More
substituted diazodiketoesters 36 and 40 also undergo highly regio- and diastereoselective cycloaddition with
glyoxylates to give the cycloadducts 41, 43 and 44.
Introduction
Cardiovascular disease is one of the leading causes of death
in the developed world, nearly double that of all forms of
cancer combined.1 In addition to clinical treatments presently
available, the development of new leads targeting endogenous
cholesterol inhibition—a major cause of coronary heart
disease—is of vital importance to overcome this mortality rate.
In recent years, several new classes of natural compounds
have been shown to inhibit the enzyme squalene synthase,
the last committed step on the biosynthetic pathway towards
cholesterol production. One of the most notable of these leads
are the zaragozic acids (also known as squalestatins).2–5 This
novel mode of action amongst cholesterol inhibitors is desirable
over the currently favoured methods of HMG-CoA reductase
inhibition and bile acid sequestration, which may interfere with
other important biochemical processes. This paper details
our early studies towards the synthesis of zaragozic acid
A/squalestatin S1 1—the first isolated member of this novel
class of fungal metabolites, which all contain the complex
2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core.6
Our strategic analysis of the anhydrofuranose core of acid
1 is detailed in Scheme 1. We reasoned that the bicyclic ketal
might be formed from acid-catalysed rearrangement of the
isomeric anhydropyranose core 2. This in turn could arise from
1,3-dipolar cycloaddition reaction of carbonyl ylide 3 (PG =
protecting group) with a suitable glyoxylate dipolarophile,
followed by introduction of the C-5 acid (zaragozic acid
numbering). The ylide precursor, diazodiketoester 4, points to
Scheme 1
(ϩ)-tartaric acid as a suitable starting material from the chiral
pool.
and a simplified 6,8-dioxabicyclo[3.2.1]octane skeleton has been
prepared by carbonyl ylide cycloaddition chemistry en route to
the naturally occurring pheromone brevicomin.9 Preparation
of the known deoxy cycloaddition precursor 8 was carried out
essentially using the route outlined by Padwa et al.10 although
4-oxopentanal was best prepared by ozonolysis of heptenone
511 (Scheme 2). Alternatively, Masamune homologation12 of
levulinic acid using the magnesium salt of ethyl hydrogen
malonate gave the intermediate diketoester 6 in one step (49%).
Diazoester 8 could also be obtained in a two-step procedure
from commercially available γ-valerolactone. Lithiated ethyl
diazoacetate was added to the lactone to give alcohol 7 in
Results and discussion
We chose to examine the proposed chemistry first in a racemic
model study towards the core of 6,7-dideoxysqualestatin
H5 (C-1 alkyl chain = Me).7 The use of ylide cycloaddition
chemistry for the preparation of functionalised bicyclic hetero-
cycles has been examined in detail by Padwa and co-workers,8
† Address for correspondence.
3432
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004870o

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Table 1 Effect of experimental conditions on the yields and ratio of cycloadducts 9/10 and 11/12 from diazoester 8
Glyoxylate
ester
9/10 or 11/12
Entry
Solvent
T/ЊC
endo:exoa
Yields (%)b
1
2
3
4
5
6
7
8
9
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
tert-Butyl
tert-Butyl
CH2Cl2
PhMe
PhMe
C6H6
C6H6
Et2O
Hexane
Hexane
PhMe
Hexane
25
110
25
70
25
35
70
25
110
70
2.4:1
2.5:1
2:1
3:1
3:1
1.4:1
1:1
1.7:1
3:1
50/0
60/10
36/13
72/15
54/20
33/21
43/35
47/18
61/11
46/8
10
3:1
a As determined by integration of methine signals in the crude 1H-NMR spectra. b Isolated yields of individual isomers.
Fig. 1 Molecular structure of 9 with ellipsoids at 30% probability.
entry 7). Using the more sterically demanding tert-butyl
glyoxylate16 gave no change in stereoselectivity (entries 9
and 10).
Consistently good yields for this cycloaddition contrast with
a related study,17 where the methyl ester analogue of diazoester
8 and aromatic aldehydes gave only low yields (<20%) of
the desired cycloadducts. The use of a highly electron deficient
aldehyde dipolarophile suggests that the favourable interaction
in our case will be between the dipolarophile LUMO and dipole
HOMO.18 Houk and co-workers have shown that electron
withdrawing substituents on the dipolarophile reduce both the
HOMO and LUMO of the system.19 The low lying orbitals of
Scheme 2 Reagents and conditions: i, O3, CH2Cl2, Ϫ78 ЊC, then
N2CHCO2Et, SnCl2 (cat.), CH2Cl2, 25 ЊC (76% from 5); ii, carbonyldi-
imidazole, THF, 25 ЊC, then Mg(O2CCH2CO2Et)2, THF, 25 ЊC, then
H3Oϩ (49%); iii, MeSO2N3, Et3N, MeCN, 25 ЊC (75%); iv, LiC(N2)-
CO2Et, THF, Ϫ90 to Ϫ78 ЊC (51%); v, PCC, NaOAc, CH2Cl2 (88%); vi,
methyl or tert-butyl glyoxylate, Rh2(OAc)4 (cat.) (see Table 1).
the aldehyde C᎐O π-bond further reduce the overall energy of
᎐
51% yield.13 Alcohol 7 was then oxidised using PCC14 to the
diazoester 8 in 88% yield.
the dipolarophile, thus bringing its LUMO into an energetically
favourable interaction with the dipole HOMO. The observed
endo selectivity in the reaction of diazoester 8 could be attribut-
able to favourable secondary orbital overlap between the
carbonyl of the glyoxylate ester (in the lower energy s-trans
conformation)20 and the ketone group of the ylide.
Ylide formation and cyclisation were initially investigated
using conditions developed previously by Padwa et al. for
tandem decomposition–intermolecular cycloaddition reac-
tions.10 Reaction of diazoester 8 and freshly distilled methyl
glyoxylate15 with catalytic Rh2(OAc)4 in toluene at reflux, gave
Although incorrect relative stereochemistry between C-1 and
C-7 for zaragozic acid/squalestatin synthesis was present
in cycloadduct 9, the good yield and selectivity in the cyclo-
addition step suggested that a modified strategy would be worth
pursuing with this substrate. This would first require intro-
duction of a masked acid nucleophile to the ketone of 9 from
the lower face, followed by inversion of stereochemistry at C-1
(vide infra). Our first effort focused on the addition of trimeth-
ylsilyl cyanide to cycloadduct 9 to generate a protected cyano-
hydrin which could then be hydrolysed to reveal the desired
hydroxyacid moiety (Scheme 3).21 Reaction of 9 with TMSCN
and catalytic zinc(II) iodide gave TMS cyanohydrin 13 in good
yield (76%) as a single isomer. The stereochemistry at C-2 was
not determined at this point, but presence of the endo CO2Me
substituent together with the normal propensity for axial attack
1
a mixture of cycloadducts (2.5:1 by H NMR analysis of the
crude reaction mixture) from which the major endo isomer 9
was isolated in 60% yield. Although none of the exo isomer 10
was observed initially, later studies have shown that small
amounts of this cycloadduct (≤10%) can also be isolated from
these reaction conditions. Provisional stereochemical assign-
ments were made from NOE experiments on both isomers.
X-Ray crystallographic analysis of cycloadduct 9 (Fig. 1)
subsequently confirmed that it possessed endo stereochemistry
with respect to the ylide-containing ring.
A subsequent solvent study showed that the endo isomer 9
was predominant under all conditions examined (Table 1);
the desired exo isomer 10 was at best formed in a 1:1 ratio
(exo:endo) using hexanes at reflux (35% isolated yield of 10,
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
3433

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Scheme 4 Reagents and conditions: i, 50% MCPBA, CH2Cl2, then KF,
0 ЊC; ii, 2% HCl–MeOH, 25 ЊC (51%, 2 steps).
Scheme 3 Reagents and conditions: i, TMSCN, ZnI (cat.), CH2Cl2,
᎐
25 ЊC (76%); ii, 40% HF, MeCN, 25 ЊC (93%); iii, TMSC᎐CH, BuLi,
᎐
THF, Ϫ78 ЊC (80%).
by a simple intramolecular ‘SN2’ opening of the epoxide at the
tertiary position by the ketone group, our results do not prove
configurational instability at the tertiary centre in this system.
Finding the 6,8- rather than the 2,8-dioxygenated skeleton
was favoured in this system was an additional concern to
us in the context of our zaragozic acid/squalestatin synthesis.
However, Nicolaou and co-workers have reported that more
functionalised/oxidised systems favour the 2,8-structure.28
The isolation of an intermediate 6,8-dioxabicyclo[3.2.1]octane
skeleton from their reaction mixture before formation of the
correct core also provided good precedent for our proposed
transketalisation reaction (cf. 2 to 1, Scheme 1).
by sterically small nucleophiles in conformationally biased
cyclohexanones strongly suggested that 13 had the configur-
ation as drawn. Desilylation was best achieved using 40%
aqueous HF in acetonitrile to provide cyanohydrin 14 in 93%
yield. The use of a plastic/polypropylene vessel for this reaction
was important; glass flasks or beakers gave lower yields. A
similar observation has been reported previously by Schreiber
and co-workers.22 Efforts to hydrolyse the nitrile to acid, amide
or ester functionality (e.g. under basic peroxide or acidic con-
ditions)23 afforded only decomposition products. Carreira
and Du Bois have also investigated cyanohydrin formation for
ketone to hydroxy acid synthesis in the zaragozic acid series,
although conditions for nitrile hydrolysis were not reported.24
Attempts to add a suitable ethoxycarbonyl anion equivalent
such as lithiated ethyl vinyl ether,25 or the less basic cerium
reagent generated by transmetallation with CeCl3,26 to ketone
9 were also unsuccessful. Similarly, addition of vinylmagnesium
bromide or lithium acetylide to ketone 9 gave a complicated
mixture of products. We were eventually successful employing
lithiated trimethylsilylacetylene, addition of which to ketone
9 gave lactone 15 in 80% yield after careful quenching of the
reaction mixture (1 M aq. HCl,Ϫ78 ЊC).
With this information in hand, lactone 15 was required to be
converted to a suitable substrate to examine the epimerisation–
rearrangement chemistry. To this end lactone 15 was desilylated
to give alkyne 22 in 98% yield (Scheme 5). K2CO3 in DMF
With lactone 15 in hand (which contains all the required
functionality of the dideoxy core of squalestatin H-5 and the
correct relative stereochemistry at C-2 and C-7), inversion of
the C-1 quaternary stereocentre was now required (as well
as the originally planned 6,8- to 2,8-dioxabicyclo[3.2.1]octane
rearrangement). The work of Johnston and Oehlschlager
towards frontalin indicated that configurational instability-
inversion at such a position might be achieved under acid
catalysis.27
On treatment of the labile epoxide 17 with MeOH–cat.
SOCl2, Johnston and Oehlschlager observed two products
(ratio reported after 1 h at rt, 1.5:1; after 18 h at rt, 15:1) which
they assigned to an isomeric axial/equatorial alcohol mixture
18 with the major isomer not specified (Scheme 4). We inter-
preted this mixture 18 to consist of alcohols 19 and 20, since
configurational instability (if it occurred) would have been
expected at the tertiary (rather than the secondary) centre. We
repeated their work but isolated only one product, which gave
1H NMR data consistent with those published for the major
isomer. Attempts to prepare a crystalline derivative for X-ray
analysis failed, but the dinitrobenzoate ester 21 (3,5-dinitro-
benzoyl chloride, Et3N, CH2Cl2, 57% yield) proved a suitable
substrate for NMR NOE studies; a strong enhancement
between C-2 H and one H of C-7 CH2 confirmed the relative
stereochemistry at C-2. This result provided a possible prece-
dent in our system for equilibration to the desired axial alcohol
(compare anhydropyranose 2 in Scheme 1). However, since
the relative configuration between C-1 and C-2 in the 6,8-
dioxabicyclo[3.2.1]octane 19 could arise from the epoxide 17
Scheme 5 Reagents and conditions: i, K2CO3, DMF, 25 ЊC (98%); ii, H2
(1 atm), Pd/C (cat.), pyridine, 25 ЊC (quant.); iii, LiAlH4, Et2O, 25 ЊC
(60%); iv, NaH (2 equiv.), NaI (cat.), BnCl (2 eq.), MeO(CH2)2OMe,
0 to 25 ЊC (52%); v, Hϩ (see Table 2).
was found to be superior to K2CO3 in MeOH,29 as it avoided
capricious methanolysis of the lactone ring. LiAlH4 reduction
of the terminal acetylene proved difficult, affording no discern-
ible products from the crude reaction mixture. The matter was
resolved by partial hydrogenation of the alkyne using Pd on
charcoal in pyridine to afford the alkene 23 quantitatively,
which was subjected to further reduction using LiAlH4 under
carefully controlled conditions to reproducibly provide triol
24 in satisfactory yields (60%). The oily triol was not purified
further but immediately benzylated to give dibenzyl ether 25 in
an unoptimised 52% yield.
Although the vinyl group in ether 25 was projected to
become the third carboxylic acid group of the zaragozic acid/
3434
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Table 2 Effect of experimental conditions on the yield of ketal 26
26/25
Entry
Reagents
T/ЊC
Time/h
Yields (%)a
1
2
3
4
5
6
7
8
2% HCl–MeOH
2% HCl–MeOH
2% HCl–MeOH
CSA (cat.)–CH2Cl2
CSA (cat.)–MeOH
TFA–CH2Cl2 (1:1)
TFA–CH2Cl2 (1:1)
TFA–CH2Cl2– H2O (10:20:1)
68
25
0
0 to 40
0 to 68
0
40
40
1
59/26
64/25
61/18
65/34
67/33
traceb/89
0c
0.1
0.1
12/6
12/6
12
2
2
0c
a Isolated, chromatographically homogeneous yields. b By crude 1H-NMR analysis. c No products isolated.
squalestatin core, further manipulation of this group was
postponed until after our investigation of the crucial C-1
epimerisation–skeletal rearrangement chemistry. For epimerisa-
tion to take place, a group capable of stabilising a potential
carbocation at C-1 should prolong the existence of such an
intermediate such that inversion might occur. The more polar,
electron deficient groups destined to replace vinyl at C-2 would
undoubtedly destabilise this charged intermediate more, a
premise demonstrated effectively in HeathcockЈs studies on
the acid-catalysed rearrangement of anhydrofuranoses.26
In the event, after treatment of ether 25 under the rearrange-
ment conditions of Nicolaou and co-workers (2% HCl in
MeOH, 25 ЊC)28 no inversion of stereochemistry at C-1 was
seen, but the rearranged alcohol 26 was reproducibly isolated in
60% yield, along with recovered starting material (20%). The
structure of alcohol 26 was assigned on the basis of extensive
1H-NMR studies. Notably, the coupling constants trans 3J
of 5.0 and 4.5 Hz in the dimethylene bridge are consistent
with the conformation of a five- (rather than six-) membered
ring.30 A NOESY spectrum showed cross peaks between one
H of both C-6 and C-7 in the dimethylene bridge and C-3 H,
and between H C᎐CH and one H of the C-4 CH OBn. No
᎐
2
2
cross peaks were seen between the dimethylene bridge and
either of the CH2OBn groups, confirming the structure of 26
as shown.
Scheme 6 Possible mechanism of acid-catalysed rearrangement 25 to
26. Protons omitted for clarity.
A range of other acidic conditions were examined for the
rearrangement of ether 25 (Table 2). Trifluoroacetic acid proved
to be unsuitable and only decomposition was observed at high-
er temperatures, no reaction occurring at lower temperatures.
Entries 2 and 3 are notable in that equilibrium is reached within
5 minutes, even at reduced temperatures. CSA gave clean con-
version in both CH2Cl2 (entry 4) or MeOH (entry 5), although
elevated temperatures were required to reach equilibrium. In
no case was there any indication of stereochemical lability at
C-1. In a related model study by Armstrong and Barsanti,
configurational instability also does not appear to have been
seen where it might potentially have occurred.31 That true
equilibrium had been reached in our system was established by
returning alcohol 26 to the reaction conditions (entry 2) which
resulted in the same ratio of products.
A probable mechanism for the acid-catalysed rearrangement
of 25 is shown in Scheme 6, and, whilst formation of oxonium
ion 28 (Path a) is favoured on stereoelectronic grounds,32 27
(Path b) cannot be ruled out at this time.28b The six-membered
ring oxonium ion 28, if formed, evidently does not undergo
the desired epimerisation. Equilibration to 26 from 28 could
then proceed via the comparatively strained 2,7-dioxabicyclo-
[2.2.1]heptane 29. Clearly the factors governing selectivity in
the rearrangement of 25 to 26 are complex: Dominey and
Goodman report that molecular mechanics force fields are
unable to cope with the prediction of the position of equi-
librium for competitive acetal formation in simple models of
the zaragozic acid core, because there is competition between
five- and six-membered cyclic acetals.33 Evans34 and Myles35
have also reported computer modelling studies which suggest
that the natural core of the squalestatins is some 2.6 kcal
molϪ1 higher in energy than the alternative 6,8-core. This effect
can be seen clearly in ArmstrongЈs preliminary studies, where
his cyclisation precursor closes under thermodynamic con-
ditions to give a 1:1 mixture of the 2,8- and the 6,8-dioxa-
bicyclo[3.2.1]octanes.31 HashimotoЈs synthesis of zaragozic
acid C however, utilises a differentially protected substrate
which can first undergo kinetic cyclisation to form the furanose
ring of the correct core, which ultimately results in formation of
a 10:1 (2,8-:6,8-) ratio after hydrolysis of a C-3–C-4 aceto-
nide.36 Armstrong et al. were later able to utilise this same
kinetic control in their total synthesis of zaragozic acid C,
simply by changing the order of events from the initial model
study.37 These results further support the proposed mechanism
in the present study, whereby the 2,7-dioxabicyclo[2.2.1]heptane
system 29 ring opens to reveal the anhydrofuranose ring of the
squalestatin core. It should be noted, however, that the presence
of a functionalised C-1 side chain rather than a simple model
alkyl group at C-1 can also effect the outcome of such ketalis-
ation reactions.38
As communicated previously,6 the evidence presented
here strongly suggests that the minor isomer observed by
Oehlschlager in his frontalin studies is in fact the rearranged
1
2,8-core 31. Our initial analysis of the reported H-NMR data
is supported by the recent synthesis of frontalin by Majewski
and Nowak,39 where they prepare equatorial alcohol 20 and
report data different to those of both isomers prepared by
Oehlschlager and ourselves.
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
3435

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At this point it was clear that influencing the initial cyclo-
addition reaction by substrate manipulation would be required
to solve the stereochemical problems seen in our racemic study.
The use of a tartrate-derived carbonyl ylide, with the 6,7-diol
unit of the natural product already in place, was considered
a viable strategy to effect cycloaddition such that the exo
cycloadduct might be preferred. It was hoped that the presence
of the protected diol unit would provide suitable steric con-
gestion over the endo or back-side of the ylide ring, thus forcing
the dipolarophile away from the ring to give the exo cyclo-
adduct. If the exo product was formed, but facial selectivity was
not in the desired sense, then the use of a chiral Rh(II) catalyst40
or employment of chiral auxiliaries was anticipated to provide
solutions to this latter issue.
Scheme
8
Reagents and conditions: i, TBDMSOTf, 2,6-lutidine,
CH2Cl2, 0 to 25 ЊC (88%); ii, N2CHCO2Et, LDA, THF, Ϫ90 to Ϫ78 ЊC
(50% ϩ 42% 38); iii, Dess–Martin periodinane, CH2Cl2, 25 ЊC (60%).
have reported that PCC oxidation of related diazoalcohols
proceeds in good yield (see also 7→8, Scheme 2), with the
present substrate only 3% of the desired ketone 40 was
obtained, along with 10% of bisether 38. TPAP–NMO was only
a slightly better oxidant,44 giving the ketone 40 in 15% yield,
and again bisether 38 was observed (16% yield). The Dess–
Martin45 reagent, however, cleanly gave ketone 40 as the sole
isolated material (60%).
TBDMS ethers were considered as the protecting group of
choice for the vicinal diol unit in cycloaddition substrate 4
(PG = TBDMS), due to their steric bulk conferring a conform-
ational bias upon cyclohexyl (chair type) systems, by orienting
themselves trans-diaxially thus minimising steric interactions
between the two groups.41 It was hoped that a similar conform-
ational preference in our system would help bias the approaching
dipolarophile to react exo with respect to these axial blocking
groups. However, due to ease of synthesis, the acetonide-
protected diazoketoester 36 was first prepared for examination
(and eventual comparison with the di-TBDMS protected
system).
Diazoacetonide 36 (Scheme 9) was found to be much less
Hydrogenolysis of the known42 benzyl ether 32 in EtOH
proceeded quantitatively to give ketoalcohol 33. (Scheme 7). A
Scheme 9 Reagents and conditions: i, methyl glyoxylate, PhMe, reflux,
then Rh2(OAc)4 (cat.) (>98%, crude); ii, CDCl3, 25 ЊC (>98%).
reactive than diazoester
8 under similar conditions for
cyclisation–cycloaddition, presumably due to steric congestion
within 36. After much experimentation, it was found that the
best reaction conditions were to conduct the cyclisation at
higher concentrations (1.0 to 0.5 M in toluene for both the
diazoacetonide 36 and dipolarophile), with premixing of the
freshly distilled aldehyde (1.5 equiv.) and substrate at 110 ЊC
before catalyst addition. This protocol reproducibly gave
quantitative yields (by 1H NMR) of a single crude cycloadduct
diastereomer 41, with unreacted glyoxylate as the only other
detectable material. Whilst some of the residual glyoxylate
could be removed under vacuum, further purification by
chromatography or distillation resulted in degradation of the
cycloadduct 41—presumably due to strain engendered by the
trans-fused dioxolane. Nevertheless, structural identification of
the cycloadduct 41 could be accomplished directly on the crude
material using NMR techniques. Dissolution in CDCl3 pro-
vided a complicated spectrum due to overlapping signals.
Also, the slightly acidic nature of CDCl3 resulted in recovery
after evaporation of a more polar material lacking the iso-
propylidene group which was assigned as diol 42. Using
Scheme 7 Reagents and conditions: i, H2 (1 atm), Pd(OH)2/C (cat.),
EtOH, 25 ЊC (>98%); ii, (a) (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC then
Et3N, Ϫ78 to 0 ЊC, (b) N2CHCO2Et, SnCl2 (cat.), CH2Cl2, 25 ЊC (51%,
2 steps); iii, 4-NO2C6H4SO2N32, Et3N, MeCN, 0 ЊC (94%).
range of oxidation procedures were screened for conversion of
ketoalcohol 33 to the sensitive aldehyde 34, the Swern method
proving most effective in our hands. Tin(II) chloride-catalysed
homologation of the crude aldehyde 34 gave diketoester 35 in
51% yield (2 steps). Diazotransfer with 4-nitrobenzenesulfonyl
azide then provided cycloaddition precursor 36 in 94% yield.
Synthesis of the di-TBDMS analogue began with the
known tartrate-derived lactone diol 37 (Scheme 8).43 Silylation
with TBDMSOTf–2,6-dimethylpyridine gave bisether 38
(88%). Following MoodyЈs protocol,13 addition of lithiated
ethyl diazoacetate furnished the desired α-diazo-β-ketoester
39 (50%, 85% based on recovered 38). Although Padwa et al.14
3436
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2/3
Table 3 Comparison of
J
values for C-7 H in the cycloadducts
CH
d6-benzene as solvent allowed irradiation of the peaks during
NOE experiments on 41,‡ indicating that the stereochemistry
of 41 is as shown in Scheme 9. Specifically, C-4 H irradiation
enhanced C-7 H and methyl ester protons much more than
irradiating C-3 H on the top face of the 6-membered ring, thus
assigning the glyoxylate bridge to the lower face of the
substrate, which likely forces the six-membered ring into a boat
conformation to accommodate the trans-fused acetonide ring.
A small NOE between C-7 H and ethyl ester methylene groups
suggested that C-7 H was disposed exo to the ylide-containing
ring; this was further confirmed by the strong interaction
between C-4 H and the methyl ester CH3, compared to that
between C-4 H and C-7 H. Had the H and CO2Me groups at
C-7 been reversed then a much stronger interaction between
C-4 H and C-7 H would be expected, and most likely, no
enhancement of the methyl ester signal upon irradiation of C-4
H. Further evidence in support of 41 having the structure
shown in Scheme 9 was provided by the CDCl3 decomposition
nJCH/Hz
Entry
Substrate
C-1
C-1Ј
C-2
C-5
C-7Ј
1
2
3
4
5
6
7
9
10
11
12
41
43
44
4.2
0
4.1
0
5.0
4.9
4.9
2.8
0.9
2.8
0.9
2.7
3.8
2.9
5.9
3.3
6.1
3.5
4.8
5.0
5.0
0.9
3.9
0.9
3.9
0.9
0
2.6
1.9
2.6
1.6
2.0
2.8
1.8
1.5
3
product 42. The JH3H4 coupling constant was reduced from
9.5 in 41 to 7.0 Hz in 42, reflecting a reduction of the dihedral
angle between the two protons consistent with a change in
conformation from boat for 41 to chair for 42.
Fig. 2
Repeating the cycloaddition with the di-TBDMS protected
substrate 40 and methyl glyoxylate using the optimised con-
ditions for 36 gave a single cycloadduct diastereomer 43 in
42% yield after chromatography (Scheme 10), this product
proving much more stable than the acetonide analogue 41.
Using the more sterically demanding tert-butyl glyoxylate as
the dipolarophile did not modify the selectivity of the cyclo-
addition reaction, from which a single diastereoisomer 44 was
isolated (58%, Scheme 10). Similar NOE’s were observed with
lower face of the intermediate dipole in each case providing
a less-hindered approach to the incoming dipolarophile, when
the glyoxylate ester is experiencing secondary orbital overlap
with the ylide ketone group (although analysis of molecular
models does not obviously indicate this to be the case).
Although the cycloadditions do not provide the desired selec-
tivity for a projected zaragozic acid/squalestatin synthesis,
the present study does serve to demonstrate the ability of
more highly substituted diazoketones to successfully participate
in carbonyl ylide cycloadditions and that high levels of
stereochemical control can be achieved.46 Building on the
study reported herein, a second generation approach involving
modification of the ketone group of the ylide has recently led to
the core of the zaragozic acids/squalestatins with the correct
triacid stereochemistry47 and these results will be reported in
full in due course.
Scheme 10 Reagents and conditions: i, (R = Me) methyl glyoxylate,
PhMe, 80 ЊC, then Rh2(OAc)4 (cat.) (42%); ii, (R = But) tert-butyl
glyoxylate, PhMe, 110 ЊC, then Rh(OAc)4 (cat.) (58%).
Experimental
General details
All reactions requiring anhydrous conditions were conducted in
flame- or oven-dried apparatus under an atmosphere of argon.
Syringes and needles for the transfer of reagents were dried
at 140 ЊC and allowed to cool in a desiccator over P2O5 before
use. Ethers were distilled from sodium benzophenone ketyl;
(chlorinated) hydrocarbons, amines, DMSO and DMF from
CaH2. Reactions were monitored by TLC using commercially
available glass-backed plates, pre-coated with a 0.25 mm layer
of SiO2 containing a fluorescent indicator (Merck). Column
chromatography was carried out on Kieselgel 60 (40–63 µm).
Light petroleum refers to the fraction with bp 40–60 ЊC. [α]D
Values are given in 10Ϫ1 deg cm2 gϪ1. IR spectra were recorded
as thin films unless stated otherwise. 1H- and 13C- NMR spectra
were recorded in CDCl3 unless stated otherwise with Varian
Gemini 200, Bruker AC200, Bruker WM250, Bruker WH300,
JEOL EX400, Bruker AM500 or Bruker AMX500 spectro-
meters. Chemical shifts are reported relative to CHCl3 [δH 7.26,
δC(central line of t) 77.0]. Coupling constants (J) are given
in Hz.
compounds 43 and 44 to those found for cycloadduct 41,
suggesting that they all share the same relative configuration.
To provide further evidence for these stereochemical con-
2
3
clusions, a comparison of the JCH and JCH values for C-7 H
in cycloadducts 9 and 10 (and the cycloadducts 11 and 12
obtained from reaction of 8 with tert-butyl glyoxylate), with
cycloadducts 41, 43 and 44 was carried out using the SIMBA
method.§ Similar J values for the endo isomer 9 compared with
11, 41, 43 and 44, and which are different to those seen for
the exo isomers 10 and 12, support the assignments of the
structures as shown (Table 3 and Fig. 2).
The observed selectivity in the cycloadditions of ketones
36 and 40 is most straightforwardly explained in terms of the
‡ NOE’s conducted were not 1D difference experiments but 1D
NOESY spectra. Therefore exact values (%) are not available for the
enhancement between signals after irradiation.
§ The SIMBA experiment is, in essence, a 13C-selective 1D heteronuclear
multiple-bond correlation (HMBC) experiment. The experiment util-
ises proton observation for optimum sensitivity, and reveals the long-
range coupling to the selectively excited carbon centre as an antiphase
doublet splitting. The original sequence (R. Crouch and G. E. Martin,
J. Magn. Reson., 1991, 92, 189) was modified for the current work by
the inclusion of pulsed field gradients for signal selection, as applied in
the conventional gradient-selected 2D HMBC experiment. The gradi-
ents provided complete suppression of the unwanted parent 1H–13C
resonance and revealed the required long-range coupling in the absence
of artefacts.
Ethyl 3,6-dioxoheptanoate 6
A mixture of O2 and O3 was bubbled through a solution of 6-
methylhept-5-en-2-one (7.62 g, 60.4 mmol) in CH2Cl2 (120 cm3)
at Ϫ78 ЊC for 2.5 h, until the colourless solution turned blue.
The system was then flushed with oxygen and argon to remove
excess ozone. The colourless solution was allowed to warm to
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
3437

View Article Online
3
Ϫ3
¯
V = 682.7 Å , space group P1, Z = 2, Dc = 1.324 mg m ,
room temperature before the solvent was evaporated to yield
white crystals in a colourless oil. The crystals were filtered, and
the filtrate was diluted with CH2Cl2 (25 cm3) and then slowly
added to a stirred solution of ethyl diazoacetate (6.89 g, 60.4
mmol) and anhydrous SnCl2 (500 mg, cat.) in CH2Cl2 (80 cm3)
at 25 ЊC. After 60 h the mixture was diluted with water (30 cm3)
to yield a yellow precipitate, heptanoate 6. This was filtered off,
the filtrate evaporated and the resultant dark yellow oil purified
by column chromatography (25% EtOAc in light petroleum) to
give a second crop as a yellow oil (8.59 g in total, 76%). This
material was identical in all respects to that prepared by Padwa
and co-workers.9
µ = 0.110 mmϪ1, F(000) 288. 1863 independent reflections were
measured on a MAR research Image Plate using 95 frames at
2Њ intervals each measured for 2 min. Data analysis was carried
out using the XDS program.48 The structure was solved by
direct methods using SHELX-86.49 All non-hydrogen atoms
were given anisotropic thermal parameters and hydrogen
atoms included in calculated positions given isotropic thermal
parameters. The structure was refined on F2 using SHELXL-
9350 to give conventional R factors of 0.0645, wR2 = 0.1822 for
1595 observed reflections [I>2σ(I)]. The largest peak and hole
in the final difference map were 0.214 andϪ0.252 e ÅϪ3. CCDC
reference number 207/472. See http://www.rsc.org/suppdata/p1/
b0/b004870o for crystallographic files in .cif format.
Ethyl 2-diazo-3,6-dioxoheptanoate 8
To a stirred solution of heptanoate 6 (1.4 g, 7.5 mmol) and
MsN3 (0.71 cm3, 8.3 mmol) in MeCN (20 cm3) at 0 ЊC was
added Et3N (2.1 cm3, 30 mmol) dropwise. After 3 h, the reaction
mixture was diluted with CH2Cl2 (20 cm3) and washed with 20%
aq. NaOH (3 × 20 cm3). The aq. phase was extracted with
CH2Cl2 (20 cm3), and the combined organic extracts were dried
and evaporated to give a yellow oil. Column chromatography
(25% EtOAc in light petroleum) gave a yellow oil, diazodione
ester 8 (1.20 g, 75%). This material was identical in all respects
to that prepared by Padwa and co-workers.9
Ethyl ( )-endo-7-tert-butoxycarbonyl-5-methyl-2-oxo-6,8-dioxa-
bicyclo[3.2.1]octane-1-carboxylate 11 and ethyl ( )-exo-7-tert-
butoxycarbonyl-5-methyl-2-oxo-6,8-dioxabicyclo[3.2.1]octane-
1-carboxylate 12
Rhodium(II) acetate (cat.) was added to a stirred solution of
diazoester 8 (160 mg, 0.75 mmol) and freshly distilled tert-butyl
glyoxylate16 (147 mg, 1.13 mmol) in toluene (1.5 cm3) at 110 ЊC.
Nitrogen evolution was observed, and after 30 min the reac-
tion mixture was filtered through Celite, evaporated and the
resultant oil purified by column chromatography (20% Et2O in
light petroleum). First to elute was a white solid, cycloadduct 11
(144 mg, 61%); mp 62–64 ЊC (from Et2O–light petroleum)
(Found: C, 57.29; H, 7.10. C15H22O7 requires C, 57.30; H,
7.06%); Rf 0.54 (50% Et2O in light petroleum); νmax/cmϪ1
2984m, 1757s, 1737s, 1383m, 1313m and 1150s; δH(400 MHz)
4.57 (1 H, s, CH), 4.38–4.29 (2 H, m, OCH2), 2.89–2.76 (1 H, m,
CH2), 2.57 (1 H, ddd, J 3.5, 9 and 18, CH2), 2.38–2.22 (2 H, m,
CH2), 1.67 (3 H, s, Me), 1.47 (9 H, s, CMe3) and 1.33 (3 H, t, J 7,
CH2Me); δC(100 MHz) 199.1 (C, quat.), 166.6 (C, quat.), 164.0
(C, quat.), 111.6 (C, quat.), 89.2 (C, quat.), 83.4 (C, quat.),
Ethyl ( )-endo-7-methoxycarbonyl-5-methyl-2-oxo-6,8-dioxabi-
cyclo[3.2.1]octane-1-carboxylate 9 and ethyl ( )-exo-7-
methoxycarbonyl-5-methyl-2-oxo-6,8-dioxabicyclo[3.2.1]octane-
1-carboxylate 10
Rh2(OAc)4 (cat.) was added to a stirred solution of diazoester
8 (0.35 g, 1.65 mmol) and freshly distilled methyl glyoxylate15
(0.62 g, 7.04 mmol) in toluene (5 cm3) at 80–85 ЊC. Nitrogen
evolution was observed, and after 1 h the reaction mixture was
filtered through Celite, evaporated and the resultant oil purified
by column chromatography (50% Et2O in light petroleum).
First to elute was a white crystalline solid, dioxabicyclo[3.2.1]-
octane 9 (268 mg, 60%); mp 114–116 ЊC (from EtOAc–light
petroleum) (Found: C, 52.85; H, 6.0. C12H16O7 requires C,
52.95; H, 5.9%); Rf 0.48 (50% Et2O in light petroleum);
νmax(paraffin)/cmϪ1 2925, 2865, 1770 and 1745; δH(400 MHz)
4.73 (1 H, s, CH), 4.26–4.40 (2 H, m, OCH2), 3.79 (3 H, s,
OMe), 2.85 (1 H, ddd, J 18, 9 and 4, CHH), 2.61 (1 H, ddd,
J 18, 9 and 7.5, CHH), 2.25–2.39 (2 H, m, CH2), 1.69 (3 H, s,
Me) and 1.33 (3 H, t, J 7, CH2Me); δC(100 MHz) 199.3 (C,
quat.), 168.1 (C, quat.), 163.9 (C, quat.), 111.0 (C, quat.), 89.1
(C, quat.), 78.5 (CH), 62.6 (OCH2), 52.9 (OMe), 34.0 (CH2),
33.1 (CH2), 24.2 (Me) and 13.9 (Me); m/z (EI) 273 (M ϩ Hϩ,
20%), 184 (30), 99 (90) and 43 (100) (Found: M ϩ Hϩ,
273.0974. C12H17O7 requires M, 273.0974).
79.2 (CH), 62.4 (OCH2), 34.1 (CH2), 33.2 (CH2), 27.7 (CMe3),
ϩ
,
24.3 (Me) and 14.0 (Me); m/z (CI, NH3) 332 (M ϩ NH4
95%), 315 (10) and 276 (100) (Found: M ϩ NH4ϩ, 332.1711.
C15H26NO7 requires M, 332.1709). Second to elute was a clear
oil, cycloadduct 12 (27 mg, 11%); Rf 0.26 (50% Et2O in light
petroleum); νmax/cmϪ1 2982w, 1745s, 1370m, 1305m, 1156m and
1097m; δH(400 MHz) 4.60 (1 H, s, CH), 4.40–4.20 (2 H, m,
OCH2), 2.70–2.50 (2 H, m, CH2), 2.40–2.20 (2 H, m, CH2), 1.72
(3 H, s, Me), 1.45 (9 H, s, CMe3) and 1.31 (3 H, t, J 7, CH2Me);
δC(100 MHz) 198.3 (C, quat.), 166.8 (C, quat.), 163.5 (C, quat.),
111.0 (C, quat.), 89.8 (C, quat.), 82.7 (C, quat.), 78.9 (CH),
62.3 (OCH2), 36.3 (CH2), 30.7 (CH2), 27.7 (CMe3), 23.5 (Me)
and 13.9 (Me); m/z (APCI) 337 (M ϩ Naϩ, 75%), 281 (40), 250
(70), 229 (100) and 213 (55).
Second to elute was a white crystalline solid, dioxabicy-
clo[3.2.1]octane 10 (45 mg, 10%); mp 62–64 ЊC (from EtOAc–
light petroleum) (Found: C, 52.84; H, 5.97. C12H16O7 requires
Ethyl (1R*,2R*,5R*,7S*)-2-cyano-7-methoxycarbonyl-5-
methyl-2-(trimethylsilyl)oxy-6,8-dioxabicyclo[3.2.1]octane-1-
carboxylate 13
C, 52.92; H, 5.93%); Rf 0.19 (50% Et2O in light petroleum); νmax
/
TMSCN (60 µl, 0.45 mmol) in CH2Cl2 (2 cm3) was added to a
stirred solution of ketone 9 (100 mg, 0.37 mmol) and anhydrous
ZnI2 (ca. 10 mg, catalytic) in CH2Cl2 (3 cm3) at 25 ЊC. After
3 h, a further equivalent of TMSCN (50 µl, 0.37 mmol) in
CH2Cl2 (2 cm3) was added. After 18 h the reaction mixture
diluted with water (10 cm3), extracted with CH2Cl2 (20 cm3),
and the combined organic layers dried (MgSO4) and evaporated
under reduced pressure. The resultant solid was triturated
with EtOH and filtered to give trimethylsilylcyanohydrin 13.
The yellow filtrate was evaporated and purified by column
chromatography (50% Et2O in light petroleum) to yield a
second crop (104 mg in total, 76%); mp 74–76 ЊC (from Et2O-
light petroleum); νmax(KBr)/cmϪ1 2960, 2245, 1745, 1450, 1245
and 1215; δH(250 MHz) 5.10 (1 H, s, CH), 4.30–4.44 (2 H, m,
OCH2), 3.75 (3 H, s, OMe), 2.85–2.91 (1 H, m, CHH), 2.19–
2.25 (1 H, m, CHH), 2.03–2.14 (2 H, m, CH2), 1.59 (3 H, s, Me),
cmϪ1 2987, 1752, 1265 and 1100; δH(400 MHz) 4.73 (1 H, s,
CH), 4.40–4.20 (2 H, m, CH2Me), 3.75 (3 H, s, C(O)Me), 2.65–
2.55 (2 H, m, CH2), 2.40–2.20 (2 H, m, CH2), 1.73 (3 H, s,
Me) and 1.29 (3 H, t, J 7, CH2Me); δC(100 MHz) 198.2
(C, quat.), 168.4 (C, quat), 163.4 (C, quat), 111.4 (C, quat.), 89.9
(C, quat.), 77.9 (CH), 62.5 (OCH2), 52.6 (OMe), 35.9 (CH2),
32.9 (CH2), 23.4 (Me) and 13.9 (Me); m/z (EI) 273 (M ϩ Hϩ,
1%) and 99 (100) (Found: M ϩ Hϩ, 273.0974. C12H17O7
requires M, 273.0974).
X-Ray structure determination of ethyl ( )-endo-7-methoxy-
carbonyl-5-methyl-2-oxo-6,8-dioxabicyclo[3.2.1]octane-1-
carboxylate 9
C12H16O7, M = 272.24. Triclinic, a = 8.405(9), b = 9.044(9),
c = 10.192(12) Å, α = 69.55(1), β = 76.80(1), γ = 71.60(1)Њ,
3438
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443

View Article Online
1.37 (3 H, t, J 7, CH2Me) and 0.25 (9 H, s, SiMe3); δC(50 MHz)
was evaporated to give a dark residue which was purified by
᎐
167.6 (C, quat.), 164.3 (C, quat.), 119.5 (C᎐N, quat.), 111.6
column chromatography (40% EtOAc in light petroleum) to
give alcohol 19 (284 mg, 51%). This material was identical in all
respects to the major isomer prepared by the same method by
Johnston and Oehlschlager.27
᎐
(C, quat.), 85.9 (C, quat.), 79.1 (CH), 70.2 (CCN, quat.),
62.8 (OCH2), 52.3 (OMe), 33.8 (CH2), 33.2 (CH2), 23.3 (Me),
13.8 (Me) and 1.1 (SiMe3); m/z (EI) 371 (Mϩ, 75%), 188 (43)
and 156 (100) (Found: Mϩ, 371.1404. C16H25NO7Si requires M,
371.1400).
(1R*,2S*,5R*)-1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octan-2-yl
3,5-dinitrobenzoate 21
Ethyl (1R*,2R*,5R*,7S*)-2-cyano-2-hydroxy-7-methoxy-
3,5-Dinitrobenzoyl chloride (497 mg, 2.16 mmol) in CH2Cl2
(4 cm3) was added dropwise to a stirred solution of alcohol 19
(284 mg, 1.80 mmol) and Et3N (300 µl, 2.16 mmol) in CH2Cl2
(6 cm3) at 25 ЊC. The reaction mixture was stirred for 6 h before
water (10 cm3) was added. The organic phase was washed with
saturated aq. NaHCO3 (15 cm3), dried (MgSO4) and evaporated
to give a dark orange oil. Purification of the residue by column
chromatography (gradient elution, 30 to 60% Et2O in light
petroleum) gave the yellow crystalline benzoate 21 (360 mg,
57%); mp 124–127 ЊC (from Et2O–light petroleum); νmax(KBr
disc)/cmϪ1 1730, 1630, 1545, 1285, 1165, 730 and 720; δH(500
MHz) 9.26 (1 H, m, Ar), 9.21 (2 H, m, Ar), 5.08 (1 H, app.
d, J 4.5 and 1.5, CH), 3.98 (1 H, d, J 8, CHH), 3.60 (1 H, d,
J 8, CHH), 2.18–2.39 (1 H, m, CHH), 1.83–1.98 (2 H, m, CH2),
1.72 (1 H, dd, J 13 and 7, CHH), 1.56 (3 H, s, Me) and 1.37
(3 H, s, Me); δC(125 MHz) 162.3 (C, quat.), 148.8 (2 × Ar,
quat.), 133.9 (Ar, quat.), 129.5 (2 × Ar), 122.6 (Ar), 108.5
(C, quat.), 80.8 (C, quat.), 73.0 (CH2O), 72.9 (CH), 31.3 (CH2),
24.3 (Me), 23.8 (CH2) and 19.2 (Me); m/z (APCI) 375
(M ϩ Naϩ, 100%) (Found: M ϩ Hϩ, 353.0985. C15H17N2O8
requires M, 353.0985).
carbonyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate
14
HF (40% in water, 0.5 cm3) was added to a stirred solution
of trimethylsilylcyanohydrin 13 (41 mg, 0.11 mmol) in MeCN
(4.5 cm3) in a polypropylene beaker. After 24 h, another portion
of HF (0.5 cm3) was added. After a further 24 h, all the solvent
had evaporated to leave a white solid. This was dissolved
in CH2Cl2 (5 cm3), washed with saturated aq. NaHCO3 (2 ×
5 cm3) and evaporated under reduced pressure. Purification
of the residue by column chromatography (60% Et2O in light
petroleum) gave cyanohydrin 14 (31 mg, 93%); νmax(CH2Cl2)/
cmϪ1 3430, 2960, 1750, 1470, 1255 and 1205; δH(250 MHz) 4.72
(1 H, s, CH), 4.40–4.53 (2 H, m, OCH2), 3.76 (3 H, s, OMe),
2.57–2.65 (1 H, m, CHH), 2.18–2.23 (1 H, m, CHH), 2.03–2.08
(2 H, m, CH2), 1.65 (3 H, s, Me) and 1.40 (3 H, t, J 7, CH2Me);
᎐
δ (125 MHz) 167.8 (C, quat.), 164.5 (C, quat.), 115.0 (C᎐N,
᎐
C
quat.), 111.1 (C, quat.), 86.8 (C, quat.), 78.6 (CH), 78.8
(C, quat.), 62.7 (OCH2), 53.0 (OMe), 34.0 (CH2), 33.1 (CH2),
24.5 (Me) and 14.0 (Me); m/z (CI, NH3) 317 (M ϩ NH4ϩ, 30%)
and 300 (M ϩ Hϩ, 100) (Found: M ϩ Hϩ, 300.1083. C13H18-
NO7 requires M, 300.1083).
Ethyl (1R*,4S*,7S*,8R*)-4-ethynyl-1-methyl-6-oxo-5,9,10-tri-
oxatricyclo[5.2.1.04,8]decane-8-carboxylate 22
Ethyl (1R*,4S*,7S*,8R*)-1-methyl-6-oxo-4-[2-(trimethysilyl)-
ethynyl]-5,9,10-trioxatricyclo[5.2.1.04,8]decane-8-carboxylate 15
Lactone 15 (35 mg, 0.10 mmol) and anhydrous K2CO3 (ca. 10
mg, 70 µmol) were stirred in wet DMF (5 cm3) at room tem-
perature for 3 h. The solvent was evaporated, and the resultant
oil dissolved in CH2Cl2 (10 cm3). The solution was filtered
and the filtrate purified by dry-column flash chromatography
(Et2O), to give desilylated lactone 22 (27 mg, 98%); mp 108–
110 ЊC (from Et2O); νmax(CH2Cl2)/cmϪ1 2255, 1795, 1765, 1270
and 910; δH(400 MHz) 4.51 (1 H, s, CH), 4.29–4.43 (2 H, m,
To a stirred solution of trimethylsilylacetylene (35 µl, 0.236
mmol) in THF (5 cm3) at Ϫ78 ЊC, was added BunLi (2.5 mol
dmϪ3 in hexanes; 100 µl, 0.24 mmol) dropwise. After 15 min,
ketone 9 (50 mg, 0.184 mmol) in THF (4 cm3) was added. After
1 h saturated aq. NH4Cl (5 cm3) was added to the reaction
mixture which was then warmed to room temperature and then
evaporated under reduced pressure. The yellow residue was
acidified with 1 M HCl (5 cm3), until the solution turned colour-
less and then extracted with Et2O (3 × 20 cm3). The combined
organic layers were dried (MgSO4) and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (50% Et2O in light petroleum) gave a white solid,
lactone 15 (50 mg, 80%); mp 75–76 ЊC; νmax(CHCl3)/cmϪ1 2960,
2175, 1795, 1770, 1255, 1245 and 850; δH(400 MHz) 4.50 (1 H, s,
CH), 4.23–4.42 (2 H, m, OCH2), 2.04–2.27 (3 H, m, CH2CHH),
1.76–1.84 (1 H, m, CHH), 1.66 (3 H, s, Me), 1.35 (3 H, t, J 7,
᎐
OCH ), 2.79 (1 H, s, ᎐CH), 2.21–2.27 (1 H, m, CH ), 2.06–2.16
᎐
2
2
(2 H, m, CH2), 1.78–1.86 (1 H, m, CHH), 1.67 (3 H, s, Me)
and 1.35 (3 H, t, J 7.5, CH2Me); δC(50 MHz) 165.0 (C, quat.),
169.7 (C, quat.), 111.1 (C, quat.), 88.1 (C, quat.), 80.7 (C,
᎐
quat.), 78.4 (C, quat.), 77.8 (᎐CH), 75.4 (OCH), 62.8 (OCH ),
᎐
2
30.9 (CH2), 29.9 (CH2), 24.5 (Me) and 14.0 (Me); m/z (CI, NH3)
284 (M ϩ NH4ϩ, 100%) and 267 (M ϩ Hϩ, 10) (Found:
M ϩ Hϩ, 267.0869. C13H15O6 requires M, 267.08686).
CH2Me) and 0.17 (9 H, s, SiMe3); δC(63 MHz) 169.8 (C, quat.),
Ethyl (1R*,4S*,7S*,8R*)-4-ethenyl-1-methyl-6-oxo-5,9,10-tri-
oxatricyclo[5.2.1.04,8]decane-8-carboxylate 23
᎐
165.0 (C, quat.), 111.0 (C, quat.), 99.0 (C, quat.), 95.1 (C᎐,
᎐
᎐
᎐
quat.), 88.4 (᎐C-TMS, quat.), 81.2 (C-᎐, quat.), 75.4 (CH),
᎐
᎐
To a solution of acetylene 22 (30 mg, 0.113 mmol) in pyridine
(1 cm3) was added 10% Pd on carbon (5 mg, cat.). The reaction
mixture was stirred vigorously under 1 atmosphere of H2 for
2 h. The mixture was then diluted with Et2O (10 cm3) and
filtered through a pad of Celite before evaporation to give a
cloudy green oil. Purification by column chromatography
(Et2O), gave alkene 23 (30 mg, 100%); νmax(CH2Cl2)/cmϪ1 1790,
1760, 1315 and 480; δH(400 MHz) 5.83 (1 H, dd, J 17 and 11,
᎐CH), 5.42 (1 H, dd, J 17 and 0.5, CH ᎐), 5.22 (1 H, dd, J 11
62.4 (OCH2), 31.1 (CH2), 30.0 (CH2), 24.5 (Me), 14.0 (Me) and
0.0 (SiMe3); m/z (CI, NH3) 339 (M ϩ Hϩ, 5%), 310 (25), 295
(15), 249 (18) and 180 (51) (Found: M ϩ Hϩ, 339.1264.
C16H23O6Si requires M, 339.1264).
(1R*,2S*,5R*)-1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octan-2-ol
19
To a stirred solution of enol 1627 (500 mg, 3.52 mmol) in
CH2Cl2 (40 cm3) at 0 ЊC, was added MCPBA (50% w/w pure;
1.23 g, 3.56 mmol) portionwise. After 1 h, anhydrous KF (5 g)
was added, and the suspension was stirred for a further 1 h. The
reaction mixture was then filtered, the remaining white solid
washed with CH2Cl2 (3 × 30 cm3) and the solvent evaporated to
give a clear yellow oil, epoxide 17, which was used in the next
step without further purification. The crude oil was stirred at
room temperature in 2% HCl in MeOH for 22 h. The solvent
᎐
᎐
2
and 0.5, CH ᎐), 4.46 (1 H, s, CH), 4.12–4.23 (2 H, m, OCH ),
᎐
2
2
2.03 (1 H, m, CHH), 1.76–1.95 (3 H, m, CHHCHH), 1.60 (3 H,
s, Me) and 1.14 (3 H, t, J 7, CH2Me); δC(50 MHz) 170.5
(C, quat.), 165.3 (C, quat.), 134.3 (CH᎐), 117.1 (᎐CH ), 110.7
᎐
᎐
2
(C, quat.), 87.9 (C, quat.), 87.3 (C, quat.), 76.0 (OCH), 62.2
(OCH2), 30.1 (CH2), 28.9 (CH2), 24.4 (Me) and 13.9 (Me); m/z
(EI) 268 (Mϩ, 20%) and 184 (30) (Found: Mϩ, 268.0947.
C13H16O6 requires M, 268.0947).
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
3439

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(1R*,2S*,5R*,7R*)-1,7-Bis(benzyloxymethyl)-2-ethenyl-5-
methyl-6,8-dioxabicyclo[3.2.1]octan-2-ol 25
[(4R,5S)-5-Hydroxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]-
ethanone 33
LiAlH4 (0.45 mol dmϪ3 in Et2O; 3 cm3, 1.35 mmol) was added
dropwise to a stirred solution of alkene 23 (165 mg, 0.62 mmol)
in THF (8 cm3) at 25 ЊC. After 24 h the reaction mixture was
Pd(OH)2 on carbon (20 mg) was added to ketone 3242 (510 mg,
1.93 mmol) in EtOH (5 cm3) at 25 ЊC. The flask, with vigorous
stirring, was evacuated, then filled with H2. This procedure was
repeated three times in total and then stirred for 14 h under H2.
The suspension was then diluted with CH2Cl2 (5 cm3), then
filtered through Celite and evaporated to give a colourless oil,
ketoalcohol 33 (335 mg, 100%); [α]2D3 ϩ42.5 (c 1.08 in CHCl3);
νmax/cmϪ1 3485, 2935, 1615, 1455, 1300, 1250 and 1170; δH(500
MHz) 4.22 (1 H, d, J 7.5, H-4), 4.07 (1 H, app. quintet, J 4.5,
H-5), 3.87 (1 H, dd, J 11.5 and 4.5, CH2), 3.70 (1 H, dd, J 11.5
and 4, CH2), 2.62 (1 H, br s, OH), 2.28 (3 H, s, Me), 1.45 (3 H,
s, CMe) and 1.39 (3 H, s, CMe); δC (125 MHz) 208.9 (C,
quat.), 110.6 (CMe2, quat.), 81.4 (CH), 78.2 (CH), 62.0 (CH2),
27.0 (Me), 26.6 (CMe) and 26.0 (CMe); m/z (CI, NH3) 192
(M ϩ NH4ϩ, 100%) and 175 (M ϩ Hϩ, 22) (Found: M ϩ Hϩ,
175.0970. C8H15O4 requires M, 175.0970).
cooled (0 ЊC) then water (50 µl), aq. NaOH (1.5 mol dmϪ3
;
50 µl) and finally water (150 µl) were added, and the resultant
white suspension stirred vigorously at room temperature for
1 h. MeOH (15 cm3) was then added to the mixture, and the
solution was preadsorbed onto SiO2 and purified by filtration
through a pad of SiO2 (10% MeOH in CH2Cl2) to give a pale
yellow oil, triol 24 (86 mg, 60%), which was used without
further purification; δ (50 MHz) 140.5 (CH᎐), 112.9 (᎐CH ),
᎐
᎐
C
2
107.4 (C, quat.), 84.7 (CH), 82.5 (C, quat.), 74.3 (C, quat.), 64.1
(CH2), 60.2 (CH2), 34.0 (CH2), 32.7 (CH2) and 23.9 (Me).
NaH (19 mg, 0.785 mmol) was added to a stirred solution of
triol 24 (86 mg, 0.374 mmol) in DME (7 cm3) at 0 ЊC. After 20
min BnCl (91 µl, 0.785 mmol) and NaI (56 mg, 0.374 mmol)
were added and the reaction mixture allowed to warm to room
temperature. After 22 h water (5 cm3) was added and the prod-
uct extracted with CH2Cl2 (2 × 15 cm3). The combined organic
layers were washed with saturated aq. NaHCO3 (15 cm3), dried
(MgSO4) and evaporated under reduced pressure. Purification
of the residue by column chromatography (40% Et2O in
pentane) gave dibenzyl ether 25 (79 mg, 52%); νmax/cmϪ1 3500,
2925, 1455, 2365, 1205, 1075 and 700; δH(500 MHz) 7.26–7.40
(8 H, m, Ar), 7.12–7.17 (2 H, m, Ar), 6.40 (1 H, dd, J 17 and 11,
Ethyl 3-{(4R,5R)-2,2-dimethyl-5-[1-(oxo)ethyl]-1,3-dioxolan-4-
yl}-3-oxopropanoate 35
A solution of (COCl)2 (1.06 cm3, 12.12 mmol) in CH2Cl2 (20
cm3) at Ϫ78 ЊC was treated dropwise with DMSO (1.72 cm3,
24.24 mmol) and stirred for 15 min after which time keto-
alcohol 33 (1.92 g, 11 mmol) in CH2Cl2 (5 cm3) was added.
After 1 h Et3N (3.37 cm3, 24.24 mmol) was added and the
temperature raised to 0 ЊC for 1 h before quenching with pH
7.0 aq. phosphate buffer (20 cm3). The aq. phase was extracted
with CH2Cl2 (2 × 20 cm3) and the combined organic layers
were dried (MgSO4) and evaporated to give a pale yellow oil,
aldehyde 34 that was used directly.
A stirred solution of the above aldehyde 34 in CH2Cl2
(30 cm3) at 25 ЊC was treated with ethyl diazoacetate (1.16 cm3,
11.05 mmol) and anhydrous SnCl2 (cat.). After 24 h water
(10 cm3) was added and the organic phase washed with water
(2 × 25 cm3), brine (25 cm3), dried (MgSO4) and evaporated
under reduced pressure. Purification of the residue by column
chromatography (gradient elution, 10 to 20% Et2O in light
petroleum) gave a colourless oil, diketoester 35 (1.45 g, 51%);
[α]2D3 ϩ20.8 (c 1.50 in CHCl3); νmax/cmϪ1 2990, 1735, 1720,
1375, 1215, 1090 and 860; δH(300 MHz) 4.66 (1 H, d, J 6, H-5Ј),
4.55 (1 H, d, J 5.5, H-4Ј), 4.10–4.17 (2 H, m, CH2Me), 3.61
(2 H, s, CH2), 2.24 (3 H, s, Me), 1.34 (3 H, s, CMe), 1.38 (3 H,
s, CMe) and 1.21 (3 H, t, J 7, CH2Me); δC(125 MHz) 206.0
(C, quat.), 201.6 (C, quat.), 166.6 (C, quat.), 112.5 (CMe2,
quat.), 83.5 (CH), 76.1 (CH), 61.3 (CH2), 45.5 (CH2), 26.4 (Me),
26.2 (Me), 25.8 (Me) and 13.8 (Me); m/z (CI, NH3) 276
(M ϩ NH4ϩ, 100%) and 259 (M ϩ Hϩ, 37) (Found: M ϩ Hϩ,
259.1181. C12H19O6 requires M, 259.1182).
CH᎐), 5.33 (1 H, dd, J 17 and 1.5, CH ᎐), 5.12 (1 H, dd, J 11
᎐
᎐
2
and 1.5, CH ᎐), 4.75 (1 H, d, J 12.5, OCH Ar), 4.55 (1 H, d,
᎐
2
2
J 12.5, OCH2Ar), 4.39 (2 H, s, OCH2Ar), 4.23 (1 H, s, CH2CH),
4.21 (1 H, app. q, J 9.5, CHHCH), 3.99 (1 H, d, J 9.5,
CHHCH), 3.80 (1 H, d, J 9, CHHO), 3.47 (1 H, s, OH), 3.43
(1 H, d, J 9, CHHO), 2.28 (1 H, dt, J 12 and 7, CHHCH2),
1.72–1.83 (2 H, m, CH2CH2), 1.55–1.65 (1 H, m, CHH) and
1.49 (3 H, s, Me); δ (125 MHz) 140.9 (᎐CH), 138.1 (Ar, quat.),
᎐
C
136.7 (Ar, quat.), 128.5 (2 × Ar), 128.3 (2 × Ar), 128.1 (Ar),
127.8 (4 × Ar), 127.6 (Ar), 112.6 (H C᎐), 107.7 (C, quat.), 85.4
᎐
2
(CHCH2O), 81.5 (C, quat.), 74.1 (CH2OBn), 74.0 (C, quat.),
73.3 (ArCH2), 72.8 (ArCH2), 69.1 (OCH2CH), 33.8 (CH2), 32.7
(CH2) and 24.1 (Me); m/z (APCI) 433 (M ϩ Naϩ, 100%)
(Found: M ϩ Hϩ, 411.2172. C25H31O5 requires M, 411.2172).
(1R*,3S*,4S*,5R*)-3,4-Bis(benzyloxymethyl)-5-ethenyl-1-
methyl-2,8-dioxabicyclo[3.2.1]octan-4-ol 26
A solution of alcohol 25 (17.0 mg, 41.5 µmol) in 2% HCl in
MeOH (1.5 cm3) was stirred at 68 ЊC for 1 h. The reaction
mixture was evaporated under reduced pressure and the resi-
due purified by column chromatography (gradient elution, 40
to 50% Et2O in pentane) to give recovered alcohol 25 (4.4 mg,
26%) and the rearranged alcohol 26 (10.0 mg, 59%); νmax/cmϪ1
3435, 2925, 1645, 1455 and 695; δH(500 MHz) 7.25–7.34 (10 H,
Ethyl 3-{(4R,5R)-2,2-dimethyl-5-[1-(oxo)ethyl]-1,3-dioxolan-4-
yl}-2-diazo-3-oxopropanoate 36
m, Ar), 6.19 (1 H, dd, J 17.5 and 11, CH᎐), 5.27 (1 H, dd,
᎐
J 17.5 and 2, CHH᎐), 5.14 (1 H, dd, J 11 and 2, CHH᎐), 4.54
᎐
᎐
(1 H, d, J 12, OCH2Ar), 4.50 (1 H, d, J 11.5, OCHHAr), 4.46
(1 H, d, J 12, OCHHAr), 4.46 (1 H, d, J 11.5, OCHHAr), 3.96
(1 H, dd, J 7 and 4, CHCH2O), 3.85 (1 H, d, J 10, CH2O), 3.80
(1 H, dd, J 10 and 4, CHCH2O), 3.61 (1 H, d, J 10, CHHO),
3.49 (1 H, dd, J 10 and 7, CHCHHO), 3.19 (1 H, s, OH), 2.52
(1 H, ddd, J 13, 9.5 and 5, CHH), 2.14 (1 H, ddd, J 13.5,
9.5 and 4.5, CHH), 1.95 (1 H, ddd, J 13, 13 and 5, CHH),
1.71 (1 H, ddd, J 13, 13, and 4.5, CHH) and 1.54 (3 H, s,
Me); δC(125 MHz) 138.2 (Ar, quat.), 137.7 (Ar, quat.), 136.8
Et3N (0.5 cm3) was added to a stirred solution of diketoester
35 (960 mg, 3.72 mmol) and 4-nitrobenzenesulfonyl azide (856
mg, 3.76 mmol) in MeCN (7 cm3) at 0 ЊC. After 4 h the mixture
was diluted with CH2Cl2 (10 cm3) and washed with saturated
aq. NH4Cl (2 × 10 cm3), brine (10 cm3), dried (MgSO4) and
evaporated under reduced pressure. Purification of the residue
by column chromatography (30% EtOAc in light petroleum)
gave a yellow glassy solid, diazoester 36 (995 mg, 94%); mp
57–59 ЊC; [α]2D3 Ϫ41.7 (c 1.03 in CHCl3); νmax(KBr)/cmϪ1 2990,
2165, 1730, 1715, 1655, 1370, 1315, 1070 and 1020; δH(500
MHz) 5.48 (1 H, d, J 6, H-5Ј), 4.70 (1 H, d, J 6, H-4Ј), 4.26–4.31
(2 H, m, CH2Me), 2.32 (3 H, s, Me), 1.49 (3 H, s, CMe),
1.48 (3 H, s, CMe) and 1.32 (3 H, t, J 7, CH2Me); δC(125
MHz) 206.5 (C, quat.), 188.3 (C, quat.), 161.0 (C, quat.), 113.8
(CMe2, quat.), 83.0 (CH), 78.4 (CH), 62.4 (CH2), 27.3 (CMe),
26.8 (CMe), 26.6 (Me) and 14.7 (Me); m/z (CI, NH3) 302
(᎐CH), 128.4 (2 × Ar), 128.3 (2 × Ar), 127.8 (5 × Ar), 127.5
᎐
(Ar), 113.5 (H C᎐), 106.6 (C, quat.), 87.2 (C, quat.), 75.6
᎐
2
(CHCH2O), 73.6 (ArCH2), 73.4 (ArCH2), 69.7 (OCH2CH),
69.5 (C, quat.), 68.7 (CH2OBn), 34.9 (CH2), 31.9 (CH2) and
23.6 (Me); m/z (CI, NH3) 428 (M ϩ NH4ϩ, 54%) and 411
(M ϩ Hϩ, 100) (Found: M ϩ Hϩ, 411.2171. C25H31O5 requires
M, 411.217145).
3440
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443

View Article Online
(M ϩ NH4ϩ, 36%), 285 (M ϩ Hϩ, 28), 276 (100), 190 (84) and
160 (91) (Found: M ϩ Hϩ, 285.1086. C12H17N2O6 requires M,
285.1087).
was stirred at 25 ЊC. After 1 h a solution of sodium thiosulfate
(0.12 g) in saturated aq. NaHCO3 (5 cm3) was added. The
aqueous layer was separated and the organic layer was washed
with sat. aq. NaHCO3, dried (MgSO4) and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (10% Et2O in light petroleum) gave ketone 40 (6.5 mg,
60%); Rf 0.59 (20% Et2O in light petroleum); [α]2D5 ϩ47.0 (c 1.01
in CHCl3); νmax/cmϪ1 2954m, 2930m, 2859m, 2136s, 1716s,
1674m, 1305s, 1130m and 839s; δH(400 MHz) 5.23 (1 H, br s,
CHOTBDMS), 4.41 (1 H, d, J 3, CHOTBDMS), 4.37–4.29
(2 H, m, CO2CH2), 2.25 (3 H, s, Me), 1.34 (3 H, t, J 7, CH2Me),
0.91 (9 H, s, SiCMe3), 0.88 (9 H, s, SiCMe3), 0.05 (3 H, s, SiMe),
0.04 (3 H, s, SiMe), 0.00 (3 H, s, SiMe) and Ϫ0.04 (3 H, s,
SiMe); δC(100 MHz) 188.9 (C, quat.), 161.1 (C, quat.), 79.4
(2R,3S,4S)-2,3-Bis(tert-butyldimethylsilyloxy)-4-methylbutyro-
lactone 38
2,6-Dimethylpyridine (0.13 cm3, 1.13 mmol) was added to a
stirred solution of (2R,3S,4S)-2,3-dihydroxy-4-methylbutyro-
lactone43 37 (0.037 g, 0.28 mmol) in CH2Cl2 (0.5 cm3). The
solution was cooled to 0 ЊC and TBDMSOTf (0.195 cm3,
0.85 mmol) was added dropwise. The reaction mixture was
stirred for 3 h at 25 ЊC before adding water (5 cm3). The organic
layer was separated and the aqueous layer extracted with
CH2Cl2 (3 × 5 cm3). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. Purification
of the residue by column chromatography (20% Et2O in light
petroleum) gave a white solid, lactone 38 (88 mg, 88%); Rf 0.54
(10% Et2O in light petroleum); mp 39–43 ЊC (from Et2O–light
petroleum) (Found: C, 55.73; H, 10.06. C17H36O4Si2 requires C,
56.62; H, 10.06%); [α]2D5 ϩ13.7 (c 1.09 in CHCl3); νmax/cmϪ1
2955s, 2930s, 2886m, 1857s, 1805s, 1254s and 1073s; δH(400
MHz) 4.29 (1 H, d, J 7.5, CHOTBDMS), 4.15 (1 H, dq, J 6.5
and 6.5, CHMe), 3.90 (1 H, dd, J 7.5 and 7.5, CHOTBDMS),
1.42 (3 H, d, J 6.5, Me), 0.93 (9 H, s, SiCMe3), 0.90 (9 H,
s, SiCMe3), 0.21 (3 H, s, SiMe), 0.14 (3 H, s, SiMe), 0.13 (3 H,
s, SiMe) and 0.11 (3 H, s, SiMe); δC(100 MHz) 173.3 (C,
quat.), 80.6 (OCH), 77.7 (OCH), 76.1 (OCH), 25.7 (CMe3), 25.6
(CMe3), 18.2 (Me), 18.1 (CSi, quat.), 17.8 (CSi, quat.), Ϫ4.0
(SiMe), Ϫ4.4 (2 × SiMe2) and Ϫ4.8 (SiMe); m/z (CI, NH3) 378
(M ϩ NH4ϩ, 30%), 246 (45), 132 (35) and 53 (100) (Found:
M ϩ NH4ϩ, 378.2492. C17H40Si2NO4 requires M, 378.2496).
(CH), 61.7 (OCH ), 27.8 (MeC᎐O), 25.7 (CMe ), 25.6 (CMe ),
᎐
2
3
3
18.3 (CMe3), 18.0 (CMe3), 14.8 (Me), Ϫ4.8 (SiMe), Ϫ4.9
(SiMe), Ϫ5.4 (SiMe) and Ϫ5.6 (SiMe); m/z (CI, NH3) 473
(M ϩ Hϩ, 10%), 206 (70), 132 (100), 91 (95) and 74 (93)
(Found: M ϩ Hϩ, 473.2494. C21H41Si2N2O6 requires M,
473.2503).
Ethyl (1R,2R,6R,8R,9R)-9-methoxycarbonyl-1,4,4-trimethyl-
7-oxo-3,5,10,11-tetraoxatricyclo[6.2.1.02,6]undecane-8-
carboxylate 41
Diazoester 36 (46.0 mg, 0.162 mmol) was added to a stirred
solution of freshly distilled methyl glyoxylate15 (22.0 mg, 0.250
mmol) in toluene (0.25 cm3) and the mixture warmed to 110 ЊC.
Rh2(OAc)4 (cat.) was then added initiating N2 evolution. After
1 h the mixture was cooled, diluted with Et2O (2 cm3) and filtered
through Celite with Et2O (5 × 10 cm3), followed by CH2Cl2
(2 × 5 cm3) washings. The filtrate was evaporated under reduced
pressure to give a yellow oil, tricyclic ester 41 (63.5 mg, quant.);
νmax/cmϪ1 1755, 1225, 1110 and 855; δH(500 MHz) 5.03 (1 H, d,
J 9.5, H-3), 5.03 (1 H, s, H-10), 4.50 (1 H, d, J 9.5, H-7), 4.34–
4.37 (2 H, m, CHMe), 3.84 (3 H, s, OMe), 1.82 (3 H, s, Me),
1.56 (6 H, s, 2 × Me) and 1.38 (3 H, t, J 7.0, CH2Me); δC(125
MHz) 196.6 (C, quat.), 168.5 (C, quat.), 162.7 (C, quat.), 115.9
(CMe2, quat.), 111.7 (C2, quat.), 90.3 (C, quat.), 81.5 (CH),
79.8 (CH), 79.4 (CH), 63.5 (CH2), 53.1 (OMe), 26.7 (CMe),
26.3 (CMe), 17.5 (Me) and 13.9 (Me); m/z (CI, NH3) 362
Ethyl (4R,5S,6S)-4,5-bis(tert-butyldimethylsilyloxy)-2-diazo-6-
hydroxy-3-oxoheptanoate 39
BunLi (2.3 mol dmϪ3 in hexanes; 382 µl, 0.88 mmol) was added
to a solution of diisopropylamine (123 µl, 0.88 mmol) in THF
at Ϫ78 ЊC. After 30 min the reaction mixture was cooled to
Ϫ90 ЊC and ethyl diazoacetate (92 µl, 0.88 mmol) was added
dropwise to give an orange solution. After 20 min a solution of
lactone 38 (0.29 g, 0.80 mmol) in THF (3 cm3) was added and
after 1 h at Ϫ90 ЊC the reaction mixture was allowed to warm to
Ϫ78 ЊC. After 5 h at Ϫ78 ЊC a mixture of glacial acetic acid and
water was added and the reaction was then warmed to 25 ЊC
and extracted with Et2O. The combined organic layers were
dried (MgSO4), evaporated under reduced pressure and the
residue purified by column chromatography (10% Et2O in light
petroleum). First to elute was recovered lactone 38 (0.122 g,
42%). Second to elute was diazoketoester 39 (0.164 g, 50%);
Rf 0.32 (20% Et2O in light petroleum); [α]2D5 Ϫ35.0 (c 1.01 in
CHCl3); νmax/cmϪ1 3514w, 2955s, 2931s, 2859s, 2136s, 2110s,
1715s, 1678m, 1306s, 1115s and 837s; δH(400 MHz) 5.48 (1 H, d,
J 3, CHOTBDMS), 4.30–4.20 (3 H, m, CH2Me and CHMe),
3.66 (1 H, dd, J 3 and 6.5, CHOTBDMS), 3.22 (1 H, br, OH),
1.31 (3 H, t, J 7, CH2Me), 1.20 (3 H, d, J 6.5, Me), 0.91 (9 H, s,
SiCMe3), 0.85 (9 H, s, SiCMe3), 0.10 (3 H, s, SiMe), 0.07 (3 H, s,
SiMe), 0.05 (3 H, s, SiMe) and 0.04 (3 H, s, SiMe); δC(100 MHz)
191.7 (C, quat.), 161.2 (C, quat.), 76.5 (C, quat.), 76.5 (OCH),
75.7 (OCH), 69.7 (OCH), 61.5 (OCH2), 25.7 (2 × CMe3), 20.1
(Me), 18.0 (CSi, quat.), 17.9 (CSi, quat.), 14.3 (Me), Ϫ4.5
(SiMe), Ϫ4.9 (SiMe), Ϫ5.0 (SiMe) and Ϫ5.3 (SiMe); m/z
(CI, NH3) 457 ([M ϩ H Ϫ H2O]ϩ, 8%), 378 (100), 246 (100) and
132 (95) (Found: [M ϩ H Ϫ H2O]ϩ, 457.2555. C21H41Si2N2O5
requires M, 457.2554).
(M ϩ NH4ϩ, 20%), 345 (M ϩ Hϩ, 10), 322 (100) and 216 (50)
ϩ
(Found: M ϩ NH4
, 362.1451. C15H24NO9 requires M,
362.1451).
Ethyl (1R,3R,4R,5R,7S)-7-methoxycarbonyl-3,4-dihydroxy-5-
methyl-2-oxo-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate 42
Crude tricyclic ester 41 (25 mg, 0.073 mmol) was dissolved in
CDCl3 (0.5 cm3). After standing for 1 h at 25 ЊC, the solvent was
evaporated under reduced pressure at 40 ЊC to afford diol 42
as a pale yellow oil (22 mg, quant.); νmax/cm1 3490, 1755, 1370,
1220, 1075 and 855; δH(500 MHz) 4.76 (1 H, s, H-7), 4.54 (1 H,
d, J 7, H-3), 4.31 (2 H, q, J 7, CH2Me), 3.93 (1 H, d, J 7, H-4),
3.76 (3 H, s, OMe), 1.69 (3 H, s, Me) and 1.30 (3 H, t, J 7,
CH2Me); δC(125 MHz) 203.5 (C, quat.), 167.9 (C, quat.),
162.1 (C, quat.), 114.1 (C, quat.), 88.7 (C, quat.), 79.8 (CH),
78.0 (CH), 77.2 (CH), 63.3 (CH2), 53.1 (OMe), 19.7 (Me) and
13.8 (Me); m/z (CI, NH3) 322 (M ϩ NH4ϩ, 20%), 276 (100) and
192 (40) (Found: M ϩ NH4ϩ, 322.1138. C12H20NO9 requires M,
322.1138).
Ethyl (1R,3R,4R,5R,7S)-3,4-bis(tert-butyldimethylsilyloxy)-7-
methoxycarbonyl-5-methyl-2-oxo-6,8-dioxabicyclo[3.2.1]octane-
1-carboxylate 43
Rh2(OAc)4 (cat.) was added to a solution of diazoketoester
40 (51 mg, 0.10 mmol) and freshly distilled methyl glyoxylate15
(38 mg, 0.43 mmol) in toluene (1 cm3) at 80 ЊC. After 4 h the
reaction was cooled, diluted with Et2O (1 cm3), filtered through
Celite and evaporated under reduced pressure. Purification of
Ethyl (4R,5R)-4,5-bis(tert-butyldimethylsilyloxy)-2-diazo-3,6-
dioxoheptanoate 40
A mixture of the alcohol 39 (11 mg, 0.024 mmol) and Dess–
Martin periodinane45 (30 mg, 0.072 mmol) in CH2Cl2 (5 cm3)
J. Chem. Soc., Perkin Trans. 1, 2000, 3432–3443
3441

View Article Online
the residue by column chromatography (10% EtOAc in
light petroleum) gave a yellow oil, cycloadduct 43 (22 mg,
42%); Rf 0.45 (20% Et2O in light petroleum); [α]2D4 Ϫ23.1 (c 1.12
in CHCl3); νmax/cmϪ1 2931s, 2858s, 1763s, 1473m, 1260s, 1097s
and 839s; δH(400 MHz) 4.81 (1 H, s, CH), 4.70 (1 H, d, J 7,
Duhamel (Rouen) is thanked for additional information con-
cerning the synthesis of lactone diol 37.
References
CHC᎐O), 4.41–4.29 (2 H, m, CO CH Me), 3.91 (1 H, d, J 7,
᎐
2
2
1 Statistical Abstract of the United States: 1994, 114th edn., U.S.
Bureau of Census, Washington, DC, 1994, Tables 125 and 130.
2 M. J. Dawson, J. E. Farthing, P. S. Marshall, R. F. Middleton,
M. J. O’Neill, A. Shuttleworth, C. Stylli, R. M. Tait, P. M. Taylor,
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648.
CH), 3.80 (3 H, s, CO2Me), 1.68 (3 H, s, Me), 1.34 (3 H, t,
J 7, Me), 0.99 (9 H, s, SiCMe3), 0.98 (9 H, s, Si CMe3), 0.20 (6
H, s, 2 × SiMe,), 0.10 (3 H, s, SiMe) and 0.05 (3 H, s, SiMe);
1H NOE experiments: irradiation δ 4.81 saw enhancement at
3.91 (1.0%), at 1.68 (1.8%) and at 1.34 (1.0%); irradiation at
δ 4.70 saw enhancement at 3.91 (3.2%); irradiation at δ 3.91 saw
enhancement at 4.81 (1.0%), 4.70 (4.2%) and at 1.68 (2.5%);
irradiation at δ 1.68 saw enhancement at 4.81 (4.1%), 4.70
(3.0%), at 3.91 (4.5%), at 0.99 (6.5%) and at 0.20 (9%); δC(100
MHz) 203.2 (C, quat.), 167.1 (CO2Me, quat.), 162.6 (CO2Et,
quat.), 114.6 (C, quat.), 88.5 (C, quat.), 79.4 (CH), 78.9
(CH), 78.0 (CH), 63.0 (CH2), 52.7 (CO2Me), 26.1 (CMe3), 25.9
(CMe3), 21.1 (C-5 Me), 18.4 (CMe3), 17.9 (CMe3), 13.8 (Me),
Ϫ3.5 (SiMe), Ϫ3.6 (SiMe), Ϫ4.1 (SiMe) and Ϫ4.9 (SiMe); m/z
(CI) 550 (M ϩ NH4ϩ, 18%), 533 (M ϩ Hϩ, 5%), 313 (25), 132
(65) and 91 (100) (Found: M ϩ Hϩ, 533.2594. C24H45Si2O9
requires M, 533.2602).
3 K. Hasumi, K. Tachikawa, K. Sakai, S. Murakawa, N. Yoshikawa,
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Ethyl (1R,3R,4R,5R,7S)-7-tert-butoxycarbonyl-3,4-bis(tert-
butyldimethylsilyloxy)-5-methyl-2-oxo-6,8-dioxabicyclo[3.2.1]-
octane-1-carboxylate 44
Rh2(OAc)4 (cat.) was added to a solution of diazoester 40
(64 mg, 0.13 mmol) and freshly distilled tert-butyl glyoxylate16
(26 mg, 0.20 mmol) in toluene (1 cm3) at 110 ЊC. After 2.5 h the
reaction was cooled, diluted with Et2O (1 cm3), filtered through
Celite and evaporated under reduced pressure. Purification of
the residue by column chromatography (10% EtOAc in
light petroleum) gave a clear oil, cycloadduct 44 (43 mg, 58%);
Rf 0.42 (10% Et2O in light petroleum); [α]2D5 Ϫ20.2 (c 1.0 in
CHCl3); νmax/cmϪ1 2931s, 2858s, 1754s, 1473m, 1257s, 1097s and
839s; δH(400 MHz, C6D6) 5.01 (1 H, s, CH), 4.88 (1 H, d, J 7.5,
CH), 4.35 (1 H, d, J 7.5, CH), 3.99–3.80 (2 H, m, CO2CH2),
1.73 (3 H, s, Me), 1.45 (9 H, s, CMe3), 1.17 (9 H, s, CMe3), 1.02
(9 H, s, CMe3), 0.99 (3 H, t, J 7, Me), 0.19 (3 H, s, SiMe), 0.18
(3 H, s, SiMe), 0.17 (3 H, s, SiMe) and 0.09 (3 H, s, SiMe); 1H
NMR NOE experiments: irradiation at δ 5.01 saw enhance-
ments at 4.35 (1.4%), at 1.73 (1.0%) and at 1.45 (1.0%); irradi-
ation at δ 4.88 saw enhancements at 4.35 (4.0%) and at 0.19
(6.4%); irradiation at δ 4.35 saw enhancements at 5.01 (1.0%),
at 4.88 (3.0%), at 1.73 (1.8%), at 1.45 (2.2%), at 0.19 (3.2%) and
at 0.09 (4.3%); δC(100 MHz, C6D6) 203.2 (C, quat.), 165.7
(C, quat.), 162.9 (C, quat.), 114.6 (C, quat.), 89.3 (C, quat.),
82.5 (C, quat.), 82.5 (CH), 80.2 (CH), 78.8 (CH), 62.3 (CH2),
27.5 (CMe3), 26.2 (CMe3), 25.9 (CMe3), 21.2 (C(5)Me), 18.4 (C,
quat.), 17.8 (C, quat.), 13.4 (Me), Ϫ3.6 (SiMe), Ϫ3.7 (SiMe),
ϩ
Ϫ4.5 (SiMe) and Ϫ4.9 (SiMe); m/z (CI) 592 (M ϩ NH4
,
18%), 443 (10) and 313 (100) (Found: M ϩ NH4ϩ, 592.3329.
C27H54NO9Si2 requires M, 592.3337).
20 E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of
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Acknowledgements
We thank the EPSRC for a Research Grant (GR/J84267) and
an Earmarked Studentship and the EPSRC and Merck Sharp
& Dohme for converting the Studentship into a CASE award
(to J. M. B.). We also thank Dr R. Mortishire-Smith (Merck
Sharp & Dohme) and Dr T. D. W. Claridge (Oxford) for expert
assistance with the determination of stereochemistry using
NMR, the EPSRC National Mass Spectrometry Service Centre
for mass spectra and Zeneca (Strategic Research Fund) and
Pfizer for additional financial support. We also thank A. W.
Johans for his assistance with the crystallographic investi-
gations and the University of Reading together with the
EPSRC for funds for an Image Plate System. Professor L.
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