Novel squalestatin derivatives arising from reactions at the allylic centre of the C1-side chain

Article abstract of DOI:10.1039/a704363e

Reaction of 2 with Ac₂O-TMSOTf gives the triacetate 5, which on further reaction gives isomer 6, arising from an allylic rearrangement, whereas reaction of 2 with Et₃SiH-TMSOTf gives tricycle 7 arising from addition of the C7-OH to the allylic centre. Attempted ionic reduction of triacetate 5 gives benzocycloheptene 8, arising from Friedel-Crafts alkylation of the phenyl ring by the allylic centre. Similar alkylation has been obtained with analogue 9, and with the trifluoromethanesulfonate ester of the allylic alcohol 13. Attempted ionic reduction of 17, lacking the allylic centre, gives 20 arising from ester hydrolysis at C4.

Full text of DOI:10.1039/a704363e

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Novel squalestatin derivatives arising from reactions at the allylic
centre of the C1-side chain
Panayiotis A. Procopiou,* Brian W. Dymock, Graham G. A. Inglis,
Michael G. Lester, Andrew D. Roberts, Philip J. Sidebottom,
Stephen J. Spooner, Anton R. P. Srikantha and Nigel S. Watson
Glaxo Wellcome Research and Development Limited, Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY
Reaction of 2 with Ac2O–TMSOTf gives the triacetate 5, which on further reaction gives isomer 6, arising
from an allylic rearrangement, whereas reaction of 2 with Et3SiH–TMSOTf gives tricycle 7 arising from
addition of the C7-OH to the allylic centre. Attempted ionic reduction of triacetate 5 gives benzocyclo-
heptene 8, arising from Friedel-Crafts alkylation of the phenyl ring by the allylic centre. Similar alkylation
has been obtained with analogue 9, and with the trifluoromethanesulfonate ester of the allylic alcohol 13.
Attempted ionic reduction of 17, lacking the allylic centre, gives 20 arising from ester hydrolysis at C4.
In 1992 we described the isolation1,2 and structure elucidation3
of the squalestatins, a novel group of fungal metabolites iso-
lated from a previously unknown Phoma species (coelomycetes).
Squalestatin S1 (1) is a potent and selective inhibitor of both rat
Heathcock29 groups and of zaragozic acid C by the Carreira30
and Evans31 groups. A second review dealing with the chem-
istry and biology of these exciting molecules has been published
by Nicolaou.32
In order to probe the role of the complex 2,8-dioxabicyclo-
[3.2.1]octane core of the squalestatins in securing potent SQS
activity, we were interested in cleaving of the C1᎐O2 bond to
generate novel monocyclic tetrahydrofuran analogues. This was
complementary to our studies on the preparation of mono-
cyclic 1,3-dioxane analogues,19 via fission of the C6᎐C7 bond,
and on the cleavage of the 6,8-dioxabicyclo[3.2.1]octane ring
system obtained by rearrangement of the S1 core.22 In this
paper, we report our attempts towards C1᎐O2 cleavage and the
resulting novel squalestatin analogues modified in the C1-side
chain.
O
HO2C
HO
6
O
OH
HO2C
5
O
7
4
3
1
HO2C
O
S1(1)
AcO
and Candida squalene synthase (SQS); 50% inhibition of rat
liver microsomal SQS activity is observed in vitro at a concen-
tration of 12 nmol dmϪ3. Furthermore when S1 is administered
orally to marmosets, a 50% reduction in serum cholesterol
levels is observed at a dose of 10 mg kgϪ1 dayϪ1 for 7 days.4 S1
has a profound and extended effect on lipids (50–60% decrease
in serum cholesterol levels during 7 days after a single intraven-
ous dose of 1 mg kgϪ1 in marmosets).5 At the end of 1992 a
group at Merck published the isolation6–9 of the zaragozic
acids, the structure of zaragozic acid A being identical with that
of S1. In 1993 a group at Tokyo Noko University-Mitsubishi10
isolated S1 from another organism, Setosphaeria khartoumen-
sis, and more recently a group at Pfizer have also isolated S1
from an unidentified fungus.11
As a part of our chemical programme aimed at the modifi-
cation of the complex squalestatin structure and the identi-
fication of the key structural features responsible for the
biological activity, we have reported on the C1 chain-length
requirements;5,12 on the role of the tricarboxylic acid moiety;13
on C6 and C7 modifications,14 on the C6,C7-dideoxy,15 C3-
decarboxy,16,17 C4-decarboxy and C4-deoxy,17 C4-carbox-
amide,18 monocyclic,19,20 acyclic,21,22 C3-hydroxymethyl,23 C3-
heterocyclic24 and other C3 modified analogues,25 and on
modifications at the allylic centre in the C1 side chain.26 In
addition a detailed review bringing together all the published
structure-activity relationships of the squalestatins and the
zaragozic acids has been published.27 Apart from our own and
Merck’s studies there has been a tremendous flurry of activity
by the scientific community on the squalestatins/zaragozic acids
culminating in the total synthesis of S1 by the Nicolaou28 and
In one of our earlier communications16 we have reported
on the preparation of the C3-decarboxy squalestatin 2 which
provided a structurally simplified model substrate for this
work. When compound 2 is redrawn as in structure 2a it
can be considered as an anhydro-sugar. Fraser-Reid has
reported33 the use of triethylsilyl trifluoromethanesulfonate
and acetic anhydride as a powerful reagent for the ring open-
ing of 1,6-anhydro-sugars providing diacetate esters. We
envisaged reacting compound 2 with trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) and acetic anhydride (Ac2O)
according to the above method to form ketal acetate 3, fol-
lowed by reduction with triethylsilane in the presence of a
Lewis acid34,35 to give tetrahydrofuran 4 (Scheme 1). The
attempted acetolysis of 2 in Ac2O as solvent at 0 ЊC and
using a catalytic amount of TMSOTf (3.3 mol%) gave almost
immediately the 4,7-diacetate squalestatin derivative 5 (94%;
Scheme 2). A literature search revealed only two references
from a French group36,37 on the use of Ac2O–TMSOTf for
the selective cleavage of the ring carbon–oxygen bond of
methyl β--glycopyranosides, and for the replacement of the
anomeric methoxy group of α--pyranosides where these
transformations were accompanied by peracetylation of all
unprotected hydroxy groups. Taking advantage of the mild-
ness, speed and efficiency of this reaction we have developed
it into a very powerful esterification procedure for a variety
of complex, functionalised and sterically hindered alcohols.38
Further reaction of 5 under the same conditions at room
temperature for 5 days led to the slow generation of a new
product 6 (11%) which was regioisomeric with the starting
J. Chem. Soc., Perkin Trans. 1, 1998
327

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gests that the new esterification procedure (Ac2O–TMSOTf)
will be of particular use in acid sensitive allylic alcohols.
O
MeO2C
HO
MeO2C
In order to avoid esterification of the C7-hydroxy group we
attempted an ionic reduction of the C1 ketal by treating 2 with
TMSOTf and triethylsilane in dichloromethane.39 A new prod-
uct was generated, identified as the tricyclic product 7 (23%).
Clearly the tricycle 7 is formed by intramolecular attack of the
C7-hydroxy group onto the olefin in the C1 side chain, followed
by elimination of acetic acid. A similar reaction has been
reported by the Merck group9 where S1 was heated in aqueous
sulfuric acid and tetrahydrofuran at 40 ЊC for 1 h, followed by
esterification of the tricarboxylic acid moiety to provide the
crystalline tris-tert-butyl ester, whose structure was confirmed
by an X-ray diffraction study. The geometry of the newly gen-
erated exocyclic olefin in 7 was assigned as E based on the
chemical shift of C3 (23.5 ppm).2 It is also noteworthy that one
of the protons attached to C2 appeared at 0.27 ppm and this is
consistent with the phenyl ring being in close proximity to this
proton in solution as it is in the solid state.9
O
OH
O
O
AcO
2
O
O
OH
OH
–OTf
O
O
TMSOTf
+
O
MeO2C
MeO2C
MeO2C
MeO2C
O
O
OTMS
OH
OH
2a
Ac2O
Ionic reduction using TMSOTf as the Lewis acid and tri-
ethylsilane as the reducing agent39 was attempted once more,
but this time the 4,7-diacetate derivative 5 was used in place
of 2 in order to block participation of the hydroxy groups.
After 23 h a new product 8 had formed and was isolated in
O
O
OH
OH
TMSOTf–Et3SiH
O
O
MeO2C
MeO2C
MeO2C
MeO2C
1
O
O
OAc
16% yield. The H NMR spectrum of 8 indicated the pres-
OAc
OAc
ence of only 4 aromatic protons and a single olefinic proton
which appeared as a singlet at 6.34 ppm and showed a strong
NOE to an aromatic proton. Saturation transfer experiments
showed no exchangeable protons to be present. The olefinic
protons in the C1 side chain and allylic acetate were clearly
OH
OH
4
3
Scheme 1
material. In the 1H NMR spectrum of 6 the two singlets
corresponding to the olefinic protons in the C1 side chain of 5
(4.94 and 5.00 ppm) disappeared and were replaced by a single
olefinic proton appearing as a doublet at 5.31 ppm. Further-
more a primary allylic acetate methylene was observed as a two
proton AB quartet at 4.42 ppm instead of the usual secondary
allylic acetate methine present in the starting material as a one
proton doublet at 5.09. Other data (1H and 13C) were consistent
with structure 6. In particular the chemical shift of C2Ј (29.3
ppm) was characteristic of the Z geometry of the C1 side-chain
double bond observed in other naturally occurring squalestat-
ins.2 Key long range 1H–13C correlations are summarised in Fig.
1. The formation of compound 6 from 5 can be rationalised by
an allylic rearrangement brought about by TMSOTf. However,
the extent of the rearrangement (only 11% after 5 days) sug-
O
MeO2C
AcO
MeO2C
O
OAc
O
O
O
O
Fig. 1 Key long range 1H–13C correlations
MeO2C
HO
MeO2C
O
MeO2C
AcO
MeO2C
O
O
MeO2C
9
HO
MeO2C
8
O
OH
O
OAc
O
iii
O
i
O
O
O6
7
10
11
1
5
O
O
O
4
2
3
AcO
AcO
Ph
2
5
7
ii
O
MeO2C
AcO
MeO2C
O
OAc
O
O
MeO2C
AcO
MeO2C
iii
5
O
OAc
O
O
OAc
O
8
6
Scheme 2 Reagents and conditions: i, TMSOTf, Ac2O, 0 ЊC, 10 min, 94%; ii, TMSOTf, Ac2O, 20 ЊC, 11%; iii, TMSOTf, Et3SiH
328
J. Chem. Soc., Perkin Trans. 1, 1998

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O
O
MeO2C
AcO
MeO2C
MeO2C
AcO
MeO2C
O
OAc
O
OAc
O
O
O
MeO2C
O
AcO
9
i
Fig. 2 Key long range 1H–13C correlations
O
MeO2C
AcO
O
OAc
MeO2C
absent, whereas the remainder of the molecule was intact. The
molecular formula of C38H50O12 was obtained from the high
resolution mass spectrum and confirmed the loss of C2H4O2
(acetic acid). The 13C NMR and DEPT spectra confirmed the
presence of an additional methylene, a disubstituted phenyl
ring and a trisubstituted double bond. These data together with
O
MeO2C
O
1
long range H–13C couplings (Fig. 2) established the structure
as that of the benzocycloheptene 8. Mechanistically, this is the
result of electrophilic intramolecular attack by the phenyl ring
of the C1-side chain onto an allylic cation generated by the
TMSOTf, in a Friedel-Crafts fashion. The benzocycloheptene 8
was of sufficient novelty to warrant biological evaluation and
thus preparation of the corresponding S1 analogue was under-
taken. The previously described 4,7-diacetate-3,4,5-trimethyl
ester of S1 93 was treated with TMSOTf in dichloromethane
for 13 days to give a mixture which had a major component by
HPLC (48%; Scheme 3). This was isolated in 25% yield and
identified as the benzocycloheptene 10. Deprotection of ester
10 with excess lithium iodide in 2,4,6-trimethylpyridine40 at
45 ЊC for 24 h removed not only the methyl esters, but also
resulted in cleavage of the O-acetyl ester at C7 together with
partial cleavage of the C6-ester side chain. Purification of this
reaction mixture by preparative HPLC gave the tricarboxylic
acid 11 (4%) and the 3,5-dicarboxylic acid-4-methyl ester 12
(10%). The position of the methyl ester at the C4-carboxylic
acid was assumed based on previous findings showing that
the C4 ester was the most resistant ester to hydrolysis and
dealkylation.13,23–25
10
ii
O
HO2C
HO
HO2C
O
OH
O
HO2C
O
11
+
O
HO2C
HO
MeO2C
O
OH
O
HO2C
O
It was of interest to investigate the formation of the benzo-
cycloheptene ring under different conditions (non-Lewis acid
catalysed) and from other substrates, for example using the tri-
fluoromethanesulfonate ester of the allylic alcohol 13. Allylic
alcohol 13 which was previously used in the preparation of
allylic ethers26 was prepared from S1 according to Scheme 4.
Reaction of S1 in methanol and in the presence of concentrated
hydrochloric acid introduced the methyl ester at the C3-
carboxylic acid and concurrently converted the allylic acetate
to the allylic alcohol.2 Esterification of this product with N,N-
dimethylformamide di-tert-butyl acetal in toluene gave ester 14
(32% overall from S1). Acetylation of 14 with excess Ac2O and
triethylamine in dichloromethane gave predominantly ester 13
(54%) and diacetate 15 (14%), separable by chromatography.
Treatment of the allylic alcohol 13 with trifluoromethane-
sulfonic anhydride in the presence of 2,4,6-trimethylpyridine in
dichloromethane for 2 h at 20 ЊC gave benzocycloheptene 16
(26%). Interestingly the double bond in the cycloheptene ring
of 16 was not conjugated with the phenyl ring, unlike that in
benzocycloheptene 10. This could be explained by the initial
formation of the non-conjugated olefin as the kinetic product,
followed by equilibration with time under the reaction condi-
tions to the thermodynamic conjugated olefin (cf. formation of
16 2 h; formation of 10 13 days). However, we have not
attempted deliberate equilibration of 16 to the corresponding
conjugated olefin.
12
Scheme 3 Reagents and conditions: i, TMSOTf, CH2Cl2, 0 ЊC, 13 d,
25%; ii, LiI, 2,4,6-trimethylpyridine, 45 ЊC
promising substrate for further work. This compound was
readily prepared by converting the previously reported tri-
carboxylic acid5 18 (as a 1:1 mixture of diastereoisomers) into
its trimethyl ester 19 (81%), followed by protection of the C4-
and C7-hydroxy groups as the diacetate 17 (66%) using our
newly developed acetylation procedure (Scheme 5).38 Treatment
of 17 with either triethylsilane and a catalytic amount of
TMSOTf in dichloromethane at 20 ЊC for 7 days or with
triethylsilane and a catalytic amount of boron trifluoride–
diethyl ether in dichloromethane at 20 ЊC for 11 days, gave the
partially deprotected analogue 20 (78%) as the only isolated
product.
Compounds 11 and 12 were tested in our mammalian
squalene synthase inhibition screen and found to be consider-
ably weaker inhibitors than S1 in vitro. Thus the IC50 value for
the inhibition of cholesterol biosynthesis from [14C]farnesyl
diphosphate using male rat liver microsomes as enzyme source
was 500 nmol dmϪ3 for both compounds.
Given the incompatibility of the allylic centre to the reaction
conditions employed for the cleavage of the C1᎐O2 bond, the
tetrahydro-desacetoxy analogue 17 was identified as a more
In conclusion the present study has demonstrated the
robustness of the squalestatin core to cleavage and has led to
J. Chem. Soc., Perkin Trans. 1, 1998
329

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ButO2C
HO
O
ButO2C
O
OH
O
i, ii
S1 (1)
MeO2C
O
OH
14
iii
ButO2C
HO
ButO2C
HO
ButO2C
O
O
ButO2C
O
OAc
O
OAc
O
O
MeO2C
O
MeO2C
O
OAc
OH
13
15
iv
ButO2C
HO
ButO2C
O
O
OAc
O
MeO2C
O
16
Scheme 4 Reagents and conditions: i, HCl, MeOH; ii, N,N-dimethylformamide di-tert-butyl acetal, PhMe, 32%; iii, Ac2O, Et3N, CH2Cl2, 54%;
iv, Tf2O, 2,4,6-trimethylpyridine, CH2Cl2, 20 ЊC, 2 h, 26%
the identification of a powerful acetylation reaction of alcohols
with Ac2O–TMSOTf. In addition novel squalestatin derivatives
were obtained, arising from allylic rearrangement or from
intramolecular reaction of an allylic cation in the C1 side chain
with either the C7-hydroxy group or with the phenyl ring when
the C7-OH is protected. The intramolecular cycloaddition reac-
tions of allylic cations have very recently been reviewed by
Harmata.41
lution mass spectrometry were conducted on a VG Autospec
spectrometer.
(1S,4S,5R,6R,7R)-Dimethyl 4,7-diacetoxy-1-{3-[(1S,2R)-1-
acetoxy-2-methyl-3-phenylpropyl]but-3-enyl}-6-{[(4S,6S,2E)-
4,6-dimethyloct-2-enoyl]oxy}-2,8-dioxabicyclo[3.2.1]octane-4,5-
dicarboxylate 5
A solution of the dimethyl ester 2 (100 mg, 0.15 mmol) in acetic
anhydride (2 cm3) was treated with TMSOTf (0.001 cm3, 0.005
mmol) at 0 ЊC for 5 min under nitrogen. The reaction mixture
was treated with saturated aqueous sodium hydrogen carbonate
(60 cm3), stirred for 10 min and extracted with ethyl acetate
(3 × 20 cm3). The combined organic phases were washed with
saturated aqueous sodium hydrogen carbonate (20 cm3) and
brine (20 cm3), then dried and evaporated to a gum (106 mg,
95%) [Found: (CI) (M ϩ H)ϩ, 759.3592. C40H55O14 requires
(M ϩ H), 759.3596]; analytical HPLC tr 4.98 min 94% (column
A; 80% MeCN–H2O); νmax(CHBr3)/cmϪ1 1744, 1649, 1241 and
1228; δH(250 MHz; CDCl3) 0.8–0.9 (9H, m, CH3), 1.02 (3H, d,
J 7, ᎐CHCHCH ), 2.09, 2.17 and 2.19 (3s, 3H each, AcO),
Experimental
Organic solutions were dried over MgSO4 and column chrom-
atography was performed on silica gel 60 (Merck, Art no. 9385).
Analytical HPLC was performed on a Spherisorb 5 ODS-2
column (15 × 0.46 cm) using MeCN–H2O as eluent, at a flow
rate of 2 cm3 minϪ1 and detecting at 210 nm (column A) or on a
Spherisorb 5 ODS-2 column (25 × 0.46 cm) using MeCN–H2O
as eluent, at a flow rate of 1.5 cm3 minϪ1 and detecting at 210
nm (column B). Preparative HPLC was conducted on a
Spherisorb 5 ODS-2 column (25 × 2.2 cm) using MeCN–H2O
as eluent, at a flow rate of 15 cm3 minϪ1 and detecting at 210
nm. The appropriate fractions from each run were combined,
the acetonitrile was removed under reduced pressure (bath
temperature <40 ЊC), and the remainder extracted with ethyl
acetate. The combined extracts were washed with brine, dried
and evaporated to dryness. IR spectra were recorded on a
Nicolet 5SXC or a Bio-Rad FTS-7 FTIR spectrometer. NMR
spectra were recorded on a Bruker AM 500, AM 250 or Varian
VXR 400 spectrometers using standard pulse sequences. Chem-
ical shifts are expressed as parts per million downfield from
internal tetramethylsilane. All J values are in Hz. Positive
ammonia chemical-ionisation (CI), desorption chemical-
ionisation (DCI), fast-atom-bombardment (FAB) or high reso-
᎐
3
2.70 (1H, dd, J 13 and 5, CH2Ph), 3.73 and 3.81 (2s, 3H each,
CO2CH3), 4.58 and 4.89 (2d, 1H each, J 14, OCH2), 4.94 and
5.00 (2s, 1H each, ᎐CH ), 5.09 (1H, d, J 5, CHOAc), 5.23 (1H,
᎐
2
d, J 2, 7-H), 5.72 (1H, d, J 16, OCOCH᎐CH), 6.18 (1H, d, J 2,
᎐
6-H), 6.83 (1H, dd, J 16 and 8, OCOCH᎐CH) and 7.1–7.3 (5H,
᎐
m, Ph); m/z (DCI–NH3) 776 (M ϩ NH4)ϩ.
(1S,4S,5R,6R,7R)-Dimethyl 4,7-diacetoxy-1-[(5R,3Z)-3-
acetoxymethyl-5-methyl-6-phenylhex-3-enyl]-6-{[(4S,6S,2E)-
4,6-dimethyloct-2-enoyl]oxy}-2,8-dioxabicyclo[3.2.1]octane-4,5-
dicarboxylate 6
A solution of triacetate 5 (22.7 mg, 0.03 mmol) in acetic
anhydride (0.5 cm3) was cooled to 0 ЊC under nitrogen and
330
J. Chem. Soc., Perkin Trans. 1, 1998

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of TMSOTf (0.002 cm3, 0.01 mmol) in dichloromethane (0.5
cm3) under nitrogen at 0 ЊC, followed by compound 2 (25 mg,
0.037 mmol). The resulting clear solution was stirred at 0 ЊC for
0.5 h and then allowed to warm to 20 ЊC and stirred for a fur-
ther 96 h. The reaction mixture was treated with saturated
aqueous sodium hydrogen carbonate (15 cm3) and extracted
with ethyl acetate (3 × 5 cm3). The combined organic extracts
were washed with saturated aqueous sodium hydrogen carbon-
ate (5 cm3), brine (5 cm3), then dried and evaporated under
reduced pressure. The residue was purified by preparative
reversed-phase HPLC eluting with 73% MeCN–H2O to give
compound 7 (5.2 mg, 23%) as a colourless gum. Analytical
HPLC tr 9.80 min 98.2% (column A; 70% MeCN–H2O)
[Found: (CI) (M ϩ H)ϩ, 615.3187. C34H47O10 requires (M ϩ H),
615.3169]; νmax(CHBr3)/cmϪ1 3445, 1740 and 1650; δH(400
O
KO2C
HO
KO2C
O
OH
O
KO2C
O
18
i
O
MeO2C
HO
O
OH
MeO2C
O
MeO2C
O
MHz; CDCl ) 0.27 (1H, m, CH CH C᎐), 0.8–0.9 (6H, m, CH ),
᎐
3
2
2
3
19
1.03 [3H, d, J 6, CH(CH )Bn], 1.05 (3H, d, J 7, ᎐CHCHCH ),
᎐
3
3
ii
1.10–1.20 (2H, m), 1.25–1.47 (3H, m), 1.80–1.95 (2H, m), 2.35–
2.52 (3H, m), 2.63 [1H, m, CH(CH3)Bn], 2.73 (1H, dd, J 12 and
4, CH2Ph), 3.70 (1H, d, J 2.5, 7-H), 3.78 and 3.86 (2s, 3H each,
CO2CH3), 3.82 (1H, s, OH), 4.18 and 4.26 (2d, 1H each, J 8,
O
MeO2C
AcO
O
MeO2C
O
OAc
OCH C᎐CH), 3.77 and 4.54 (2d, 1H each, J 12, 11-H), 5.33 (1H,
᎐
2
d, J 10, OCH C᎐CH), 5.82 (1H, d, J 16, OCOCH᎐CH), 6.27
MeO2C
O
᎐
᎐
2
(1H, d, J 2.5, 8-H), 6.91 (1H, dd, J 16 and 8, OCOCH᎐CH),
᎐
17
(100 MHz, CDCl3)
7.06 (2H, m, Ph) and 7.2–7.3 (3H, m, Ph); δC
169.5 (CO), 165.4 (CO), 164.2 (CO), 156.2 (d), 140.4 (s), 139.1
(d), 133.3 (s), 128.4 (d), 128.1 (d), 126.0 (d), 118.2 (d), 106.0 (s),
89.0 (s), 82.7 (d), 76.9 (d), 76.8 (t), 73.8 (s), 68.0 (t), 53.1 (q),
52.1 (q), 43.5 (t), 42.9 (t), 35.9 (d), 34.1 (t), 33.9 (d), 31.6 (d),
29.4 (t), 23.5 (t), 20.8 (q), 20.0 (q), 18.4 (q) and 10.7 (q); m/z
(CI–NH3) 632 [(M ϩ NH4)ϩ, 100%], 615 [(M ϩ H)ϩ, 20%].
iii
O
MeO2C
HO
MeO2C
O
O
OAc
MeO2C
O
(1S,4S,5R,6R,7R)-Dimethyl 4,7-diacetoxy-6-{[(4S,6S,2E)-4,6-
dimethyloct-2-enoyl]oxy}-1-{2-[(6S)-6-methyl-6,7-dihydro-5H-
benzocyclohepten-8-yl]ethyl}-2,8-dioxabicyclo[3.2.1]octane-3,5-
dicarboxylate 8
20
Scheme 5 Reagents and conditions: i, MeI, NaHCO3, DMF, 20 ЊC,
81%; ii, TMSOTf, Ac2O, 0 ЊC, 5 min, 66%; iii, BF3ؒOEt2, Et3SiH,
CH2Cl2, 20 ЊC, 11 d, 56%
Triethylsilane (0.0058 cm3, 0.036 mmol) was added at 0 ЊC
under nitrogen to a solution of TMSOTf (0.001 cm3, 0.005
mmol) in dichloromethane (0.5 cm3), followed by the triacetate
5 (25 mg, 0.033 mmol). The reaction mixture was stirred at 0 ЊC
for 0.5 h and at 20 ЊC for 23 h. The reaction was then diluted
with aqueous saturated sodium hydrogen carbonate (15 cm3)
and ethyl acetate (5 cm3). The aqueous phase was extracted with
ethyl acetate (2 × 5 cm3) and the combined organic extracts
were washed with aqueous saturated sodium hydrogen carbon-
ate (5 cm3), brine (5 cm3), then dried and evaporated to a pale
yellow gum (17.8 mg). This was purified by preparative
reversed-phase HPLC eluting with 80% MeCN–H2O collecting
fractions with a tr 25 min, to give a clear colourless gum (3.8
mg, 16%). Analytical HPLC tr 5.075 min 95.6% (column A;
90% MeCN–H2O) [Found: (CI) (M ϩ H)ϩ, 699.3371. C38H51-
O12 requires (M ϩ H), 699.3380]; νmax(CHBr3)/cmϪ1 1745, 1645
and 1220; δH(500 MHz; CDCl3) 0.8–0.9 (6H, m, CH3), 1.02 [3H,
treated with TMSOTf (0.001 cm3, 0.005 mmol). The solution
was allowed to warm to 20 ЊC and stirred for 5 days. The reac-
tion mixture was stirred with saturated aqueous sodium hydro-
gen carbonate (20 cm3) and extracted with ethyl acetate (3 × 7
cm3). The combined organic extracts were washed with aqueous
sodium hydrogen carbonate (7 cm3), brine (7 cm3), then dried
and purified by preparative HPLC 73% MeCN–H2O to give
compound 6 as a colourless gum (2.5 mg, 11%) [Found: (CI)
(M ϩ H)ϩ, 759.3592. C40H55O14 requires (M ϩ H), 759.3596];
δH(500 MHz; CDCl3) 0.81–0.84 (6H, m, CH3), 0.98 [3H, d, J 7,
CH(CH )Bn], 1.02 (3H, d, J 7, ᎐CHCHCH ), 1.06–1.17 (2H,
᎐
3
3
m), 1.23–1.44 (4H, m), 1.73 (1H, m), 2.03 (1H, m), 2.07, 2.17
and 2.18 (3s, 3H each, AcO), 2.20 (1H, m), 2.41 (1H, m), 2.48–
2.62 (2H, m, CH2Ph), 2.73 (1H, m), 3.73 and 3.80 (2s, 3H each,
CO2CH3), 4.37 and 4.46 (2d, 1H each, J 12.5, CH2OAc), 4.55
and 4.88 (2d, 1H each, J 14, 3-H), 5.12 (1H, d, J 2.5, 7-H), 5.32
[1H, d, J 10, ᎐CHCH(CH )Bn], 5.74 (1H, dd, J 15.5, 1, OCO-
d, J 7, CH(CH )CH Ar], 1.03 (3H, d, J 7, ᎐CHCHCH ), 1.05–
᎐
3
2
3
᎐
3
1.18 (2H, m), 1.23–1.41 (3H, m), 1.86 [1H, dd, J 16 and 9,
CH᎐CH), 6.15 (1H, d, J 2.5, 6-H), 6.85 (1H, dd, J 15.5 and 8,
᎐
᎐CCH CH(CH )], 2.05–2.21 (3H, m), 2.19 and 2.23 (2s, 3H
OCOCH᎐CH), 7.11–7.16 (3H, m, Ph) and 7.23 (2H, t, J 7.5,
᎐
2
3
᎐
each, AcO), 2.25–2.52 (5H, m), 2.69 (1H, dd, J 14 and 4,
CH2Ar), 3.74 and 3.82 (2s, 3H each, CO2CH3), 4.63 and 4.92
(2d, 1H each, J 14, 3-H), 5.31 (1H, d, J 2, 7-H), 5.72 (1H, d,
Ph); δC(125 Hz, CDCl3), 170.4 (CO), 169.5 (CO), 168.9 (CO),
166.0 (CO), 164.2 (CO), 163.9 (CO), 156.6 (d), 140.0 (s), 136.1
(d), 131.7 (s), 128.9 (d), 127.6 (d), 125.4 (d), 117.7 (d), 104.6 (s),
87.6 (s), 79.0 (d), 78.3 (s), 76.1 (d), 67.9 (t), 62.9 (t), 52.8 (q),
52.0 (q), 43.3 (t), 42.8 (t), 34.2 (t), 34.0 (d), 33.9 (d), 31.5 (d),
29.3 (t), 21.1 (q), 20.6 (q), 20.4 (q), 20.2 (q), 19.8 (q), 18.5 (q),
10.7 (q). Selected long range 1H–13C couplings are shown
schematically in Fig. 1.
J 16, OCOCH᎐CH), 6.20 (1H, d, J 2, 6-H), 6.34 (1H, s,
᎐
C᎐CHAr), 6.85 (1H, dd, J 16 and 8, OCOCH᎐CH), 7.03–7.12
᎐
᎐
(3H, m, Ar) and 7.16 (1H, m, Ar); δC(125 MHz; CDCl3) 170.0
(CO), 169.5 (CO), 166.4 (CO), 164.6 (CO), 164.3 (CO), 157.1
(d), 142.4 (s), 139.4 (s), 137.6 (s), 129.5 (d), 129.1 (d), 125.9 (d),
125.8 (d), 118.0 (d), 105.3 (s), 88.1 (s), 79.3 (d), 78.7 (s), 76.4 (d),
63.4 (t), 53.3 (q), 52.6 (q), 43.2 (t), 42.0 (t), 40.7 (t), 37.0 (d), 35.0
(t), 34.4 (d), 33.0 (t), 31.8 (d), 29.7 (t), 22.0 (q), 21.5 (q), 20.9 (q),
20.2 (q), 18.9 (q), 11.1 (q); m/z (DCI–NH3) 716 (M ϩ NH4)ϩ.
(1S,7R,8R,9R,10S)-Dimethyl 8-{[(4S,6S,2E)-4,6-dimethyloct-2-
enoyl]oxy}-10-hydroxy-4-[(2R,E)-2-methyl-3-phenylpropylid-
ene]-6,12,13-trioxatricyclo[7.3.1.01,7]tridecane-9,10-dicarb-
oxylate 7
1
Selected long range H–13C couplings are shown schematically
Triethylsilane (0.0065 cm3, 0.041 mmol) was added to a solution
in Fig. 2.
J. Chem. Soc., Perkin Trans. 1, 1998
331

View Article Online
(1S,3S,4S,5R,6R,7R)-Trimethyl 7-acetoxy-6-{[(4S,6S,2E)-4,6-
dimethyloct-2-enoyl]oxy}-4-hydroxy-1-{2-[(6S)-6-methyl-6,7-
dihydro-5H-benzocyclohepten-8-yl]ethyl}-2,8-dioxabicyclo-
[3.2.1]octane-3,4,5-tricarboxylate 10
OCOCH᎐CH), 6.30 (1H, s), 6.41 (1H, s), 6.85 (1H, dd, J 16 and
᎐
9, OCOCH᎐CH) and 7.00–7.11 (4H, m, Ar); m/z (DCI–NH )
᎐
3
662 (M ϩ NH4)ϩ.
A solution of triacetate 9 (1.42 g, 1.74 mmol) in dichloro-
methane (25 cm3) was treated with TMSOTf (0.057 cm3, 0.31
mmol) under nitrogen at 0 ЊC. The reaction mixture was
allowed to warm to 20 ЊC and stirred for 13 days. Saturated
aqueous sodium hydrogen carbonate (150 cm3) was added and
the mixture was extracted with ethyl acetate (3 × 50 cm3). The
combined organic extracts were washed with further saturated
aqueous sodium hydrogen carbonate (50 cm3), brine (50 cm3),
then dried and evaporated under reduced pressure to a gum
(1.161 g) which was purified by preparative reversed-phase
HPLC eluting with 75% MeCN–H2O collecting fractions with a
tr 22 min, to give the acetate 10 as a colourless gum (329 mg,
25%). Analytical HPLC tr 16.82 min 97.9% (column B; 70%
MeCN–H2O) [Found: (CI) (M ϩ H)ϩ, 715.3329. C38H51O13
requires (M ϩ H), 715.3333]; νmax(CHBr3)/cmϪ1 1770, 1745,
1646 and 1222; δH(250 MHz, CDCl3) 0.8–0.92 (6H, m, CH3),
1.02 (6H, d, J 6, CH3), 2.20 (3H, s, AcO), 2.69 (1H, dd, J 14 and
4, CH2Ar), 3.74, 3.79 and 3.96 (3s, 3H each, CO2CH3), 5.14
(1H, s, 3-H), 5.35 (1H, d, J 2, 7-H), 5.70 (1H, d, J 16, OCO-
(1S,3S,4S,5R,6R,7R)-4,5-Di-tert-butyl 3-methyl 6-{[(4S,6S,2E)-
4,6-dimethyloct-2-enoyl]oxy}-4,7-dihydroxy-1-{3-[(1S,2R)-1-
hydroxy-2-methyl-3-phenylpropyl]but-3-enyl}-2,8-dioxabicyclo-
[3.2.1]octane-3,4,5-tricarboxylate 14
A solution of tricarboxylic acid 1 (10 g, 14.5 mmol) in methanol
(1 dm3) and conc. hydrochloric acid (12.5 cm3) was stood at
20 ЊC for 2 days. The solution was concentrated under reduced
pressure to half volume and poured into water (2 dm3). The
resulting mixture was extracted with ethyl acetate (3 dm3), the
extracts were dried and evaporated under reduced pressure to a
very pale brown foam (10.18 g). The residue was dissolved in
toluene (100 cm3) and heated to 80 ЊC under nitrogen. N,N-
Dimethylformamide di-tert-butyl acetal (31 cm3, 129 mmol) was
added over 30 min and the mixture was heated to 80 ЊC for 3 h.
The reaction mixture was allowed to cool to room temperature
and diluted with diethyl ether (600 cm3). The organic solution
was washed with brine (500 cm3), dried and evaporated to a
brown gum (13.2 g), which was purified by column chrom-
atography. Elution of the column with ethyl acetate–
cyclohexane (1:5→2:1) gave the 3-methyl-4,5-di-tert-butyl
ester 14 (3.596 g, 32%) as a yellow foam (Found: C, 64.6; H, 8.1.
C42H62O13ؒ0.25H2O requires C, 64.72; H, 8.08%); νmax(CHBr3)/
cmϪ1 3535, 1770, 1741, 1706 and 1648; δH(250 MHz; CDCl3)
CH᎐CH), 6.35 (1H, d, J 2, 6-H), 6.36 (1H, s, C᎐HAr), 6.82 (1H,
᎐
᎐
dd, J 16 and 8, OCOCH᎐CH) and 7.00–7.2 (4H, m, Ar); m/z
᎐
(DCI–NH3) 732 (M ϩ NH4)ϩ.
(1S,3S,4S,5R,6R,7R)-6-{[(4S,6S,2E)-4,6-Dimethyloct-2-
enoyl]oxy}-4,7-dihydroxy-1-{2-[(6S)-6-methyl-6,7-dihydro-5H-
benzocyclohepten-8-yl]ethyl}-2,8-dioxabicyclo[3.2.1]octane-
3,4,5-tricarboxylic acid 11 and (1S,3S,4S,5R,6R,7R)-6-
{[(4S,6S,2E)-4,6-dimethyloct-2-enoyl]oxy}-4,7-dihydroxy-4-
methoxycarbonyl-1-{2-[(6S)-6-methyl-6,7-dihydro-5H-benzo-
cyclohepten-8-yl]ethyl}-2,8-dioxabicyclo[3.2.1]octane-3,5-
dicarboxylic acid 12
0.8–0.9 (9H, m, CH ), 1.03 (3H, d, J 7, ᎐CHCHCH ), 1.47 and
᎐
3 3
1.60 (2s, 9H each, tert-BuO), 2.78 (1H, dd, J 14 and 6, CH2Ph),
3.17 (1H, d, J 5, 7-OH), 3.74 (3H, s, CO2CH3), 3.95 (1H, s,
4-OH), 4.06 (2H, m, 7-H, ᎐CCHOH), 5.04 and 5.13 (2s, 1H
᎐
each, ᎐CH ), 5.27 (1H, s, 3-H), 5.76 (1H, d, J 16, OCO-
᎐
2
CH᎐CH), 5.97 (1H, d, J 2, 6-H), 6.89 (1H, dd, J 16 and 9,
᎐
OCOCH᎐CH) and 7.12–7.30 (5H, m, Ph); m/z (DCI–NH ) 792
᎐
3
(M ϩ NH4)ϩ.
A mixture of ester 10 (320 mg, 0.45 mmol) and lithium iodide
(3.25 g, 24.28 mmol) in 2,4,6-trimethylpyridine (15 cm3) was
heated to 45 ЊC under nitrogen for 24 h. The mixture was
allowed to cool, filtered and the solid was washed with toluene
(100 cm3). The filtrate and washings were evaporated under
reduced pressure. The residue was redissolved in toluene (100
cm3) and re-evaporated under reduced pressure. The process of
dissolving in toluene and evaporating was repeated three times
to remove 2,4,6-trimethylpyridine. The residue was dissolved in
ethyl acetate (150 cm3), washed with dilute hydrochloric acid
(3 × 100 cm3), 5% aqueous sodium metabisulfite (2 × 100 cm3),
brine (100 cm3), then dried and evaporated to dryness. The
resulting orange foam was then purified by preparative
reversed-phase HPLC (60% MeCN–H2O containing 0.15 cm3
concentrated H2SO4 dmϪ3). The appropriate fractions were
combined and the acetonitrile was removed under reduced
pressure. The aqueous phase was extracted with ethyl acetate
and the organic solution was dried and then evaporated under
reduced pressure. The first compound to be eluted off the
column was obtained as a white foam (12 mg, 4%) identified as
the tricarboxylic acid 11, analytical HPLC tr 11.94 min 95%
(column B; 60% MeCN–H2O containing 1 cm3 trifluoroacetic
acid dmϪ3) [Found: (LSIMS Ϫve) (M Ϫ H)Ϫ, 629.2607. C33H41-
O12 requires (M Ϫ H), 629.2598]; δH(250 MHz; CDCl3 ϩ
CD3OD) 0.8–0.9 (6H, m, CH3) 1.02 (6H, d, J 6, CH3) 2.69 (1H,
dd, J 14 and 4, CH2Ar), 4.17 (1H, s, 7-H), 5.32 (1H, s, 3-H),
(1S,3S,4S,5R,6R,7R)-4,5-Di-tert-butyl 3-methyl 7-acetoxy-
6-{[(4S,6S,2E)-4,6-dimethyloct-2-enoyl]oxy}-4-hydroxy-1-
{3-[(1S,2R)-1-hydroxy-2-methyl-3-phenylpropyl]but-3-enyl}-
2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 13 and
(1S,3S,4S,5R,6R,7R)-4,5-di-tert-butyl 3-methyl 7-acetoxy-6-
{[(4S,6S,2E)-4,6-dimethyloct-2-enoyl]oxy}-4-hydroxy-1-{3-
[(1S,2R)-1-acetoxy-2-methyl-3-phenylpropyl]but-3-enyl}-2,8-
dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 15
A solution of alcohol 14 (10.701 g, 13.8 mmol) in dichloro-
methane (107 cm3) and triethylamine (30 cm3, 214 mmol) was
treated with acetic anhydride (17.12 cm3, 181 mmol) at 20 ЊC
and stirred for 20 h. The reaction mixture was diluted with
diethyl ether and poured into dilute hydrochloric acid (200
cm3). The organic phase was washed with aqueous sodium
hydrogen carbonate (2 × 200 cm3), brine (200 cm3), then dried
and concentrated under reduced pressure. The residue was
chromatographed on silica gel eluting with ethyl acetate–
cyclohexane (2:3) to give the diacetate 15 as a white foam
(1.671 g, 14%) (Found: C, 64.5; H, 8.05. C46H66O15 requires C,
64.32; H, 7.74%); νmax(CHBr3)/cmϪ1 3540, 1770, 1733 and 1645;
δH(250 MHz; CDCl3) 0.8–0.9 (9H, m, CH3), 1.03 (3H, d, J 7,
᎐CHCHCH ), 1.43 and 1.65 (2s, 9H each, tert-BuO), 2.10 (3H,
᎐
3
s, AcO), 2.14 (3H, s, AcO), 2.73 (1H, dd, J 14 and 5, CH2Ph),
3.76 (3H, s, CO2CH3), 4.05 (1H, s, 4-OH), 4.98 and 5.00 (2s, 1H
each, ᎐CH ), 5.12 (1H, d, J 5, CHOAc), 5.16 (1H, s, 3-H), 5.20
᎐
2
5.78 (1H, d, J 16, OCOCH᎐CH), 6.09 (1H, s), 6.37 (1H, s), 6.88
(1H, d, J 2, 7-H), 5.77 (1H, d, J 16, OCOCH᎐CH), 6.45 (1H, d,
᎐
᎐
(1H, dd, J 16 and 8, OCOCH᎐CH) and 7.02–7.19 (4H, m, Ar);
J 2, 6-H), 6.92 (1H, dd, J 16 and 8, OCOCH᎐CH) and 7.1–
᎐
᎐
m/z (FAB Ϫve) 629 (M Ϫ H)Ϫ. The second compound to be
eluted off the column was obtained as a white foam (28 mg,
10%) identified as the dicarboxylic acid 12, analytical HPLC tr
16.97 min, 89% (column B; 60% MeCN–H2O containing 1 cm3
trifluoroacetic acid dmϪ3); δH(250 MHz; CDCl3 ϩ CD3OD)
0.8–0.9 (6H, m, CH3), 1.03 (6H, d, J 6, CH3), 3.82 (3H, s,
CO2CH3), 4.20 (1H, s, 7-H), 5.22 (1H, s, 3-H), 5.76 (1H, d, J 16,
7.3 (5H, m, Ph); m/z (DCI–NH3) 876 (M ϩ NH4)ϩ; and the
monoacetate 13 as a white foam (6.109 g, 54%) (Found: C, 64.8;
H, 8.1. C44H64O14 requires C, 64.69; H, 7.90%); νmax(CHBr3)/
cmϪ1 3530, 1765, 1740 and 1647; δH(250 MHz; CDCl3) 0.8–0.9
(9H, m, CH ), 1.03 (3H, d, J 7, ᎐CHCHCH ), 1.42 and 1.63 (2s,
᎐
3
3
9H each, tert-BuO), 2.14 (3H, s, AcO), 2.80 (1H, dd, J 14 and 6,
CH2Ph), 3.75 (3H, s, CO2CH3), 3.98 (1H, s, 4-OH), 4.10 (1H, d,
332
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
J 5, CHOH), 5.02 (1H, s, ᎐CH ), 5.13 (2H, s, 3-H, ᎐CH ), 5.22
cm3), brine (25 cm3), then dried and evaporated to a gum (89.1
᎐
᎐
2
2
(1H, d, J 2, 7-H), 5.76 (1H, d, J 16, OCOCH᎐CH), 6.44 (1H, d,
mg). This was purified by column chromatography on silica
gel eluting with ethyl acetate–cyclohexane (1:4) to give the
diacetate 17 as a colourless gum (70.1 mg, 66%) [Found: (CI)
(M ϩ H)ϩ, 763.3931. C40H59O14 requires (M ϩ H), 763.3904];
analytical HPLC tr 11.042 min, 95.2% (column A; 80% MeCN–
H2O); νmax(CHBr3)/cmϪ1 1770, 1749 and 1220; δH(250 MHz;
CDCl3) 0.76–0.93 (15H, m, CH3), 2.10 and 2.16 (2s, 3H each,
AcO), 2.58 (0.5H, dd, J 13 and 6, CH2Ph), 2.68 (0.5H, dd, J 13
and 5, CH2Ph), 3.77, 3.79 and 3.89 (3s, 3H each, CO2CH3), 5.07
(1H, s, 3-H), 5.20 (1H, m, 7-H), 6.43 (1H, d, J 2, 6-H) and 7.10–
7.32 (5H, m, Ph); m/z (DCI–NH3) 780 (M ϩ NH4)ϩ.
᎐
J 2, 6-H), 6.90 (1H, dd, J 16 and 8, OCOCH᎐CH) and 7.1–7.3
᎐
(5H, m, Ph); m/z (DCI–NH3) 834 (M ϩ NH4)ϩ.
(1S,3S,4S,5R,6R,7R)-4,5-Di-tert-butyl 3-methyl 7-acetoxy-
6-{[(4S,6S,2E)-4,6-dimethyloct-2-enoyl]oxy}-4-hydroxy-1-{2-
[(8R)-8-methyl-8,9-dihydro-5H-benzocyclohepten-6-yl]ethyl}-
2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 16
A solution of allylic alcohol 13 (200 mg, 0.24 mmol) in dichloro-
methane (3 cm3) was treated with dry 2,4,6-trimethylpyridine
(0.14 cm3, 1.06 mmol) and trifluoromethanesulfonic anhydride
(0.12 cm3, 0.71 mmol) at 20 ЊC under nitrogen. After 2 h stir-
ring, the mixture was diluted with diethyl ether and washed
with dilute hydrochloric acid, saturated sodium hydrogen car-
bonate, then dried and evaporated. The residue was chromato-
graphed on silica gel eluting with ethyl acetate–light petroleum
(1:3) to give compound 16 (50 mg, 26%), as a foam (Found: C,
65.9; H, 7.9. C44H62O13 requires C, 66.14; H, 7.76%); δH(500
MHz; CDCl3) 0.82–0.86 (6H, m, CH3), 0.97 [3H, d, J 7,
(1S,3S,4S,5R,6R,7R)-Trimethyl 7-acetoxy-6-{[(4R,6S)-4,6-
dimethyloctanoyl]oxy}-1-[(3RS,5S)-3,5-dimethyl-6-phenyl-
hexyl]-4-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarb-
oxylate 20
Boron trifluoride–diethyl ether (0.001 cm3, 0.008 mmol) was
added to a solution of diacetate 17 (14.6 mg, 0.019 mmol) and
triethylsilane (0.0022 cm3, 0.014 mmol) in dichloromethane (0.5
cm3) and the mixture was stirred for 0.5 h at 0 ЊC and 11 days at
20 ЊC. The mixture was then treated with aqueous sodium
hydrogen carbonate (15 cm3) and ethyl acetate (15 cm3). The
aqueous phase was extracted with ethyl acetate (3 × 5 cm3) and
the combined organic extracts were washed with aqueous
sodium hydrogen carbonate (5 cm3), brine (5 cm3), then dried
and evaporated to a gum. This was chromatographed on silica
gel eluting with ethyl acetate–cyclohexane (1:2) to give alcohol
20 (7.7 mg, 56%), as a white foam (Found: C, 63.4; H, 7.9.
C38H56O13 requires C, 63.32; H, 7.83%); analytical HPLC tr
3.124 min 96.7% (column A; 90% MeCN–H2O); νmax(CHBr3)/
cmϪ1 3496, 1768, 1746 and 1222; δH(250 MHz; CDCl3) 0.78–
0.95 (15H, m, CH3), 2.17 (3H, s, AcO), 2.58 (0.5H, dd, J 13 and
6, CH2Ph), 2.68 (0.5H, dd, J 13 and 5, CH2Ph), 3.76, 3.77 and
3.95 (3s, 3H each, CO2CH3), 5.08 (1H, s, 3-H), 5.21 (1H, m,
7-H), 6.28 (1H, d, J 2, 6-H) and 7.08–7.30 (5H, m, Ph); m/z
(FAB ϩve) 721 [(M ϩ H)ϩ, 40%], 743 [(M ϩ Na)ϩ, 20%].
CH(CH )CH Ar], 1.02 (3H, d, J 7, CH᎐CHCHCH ), 1.05–1.18
᎐
3
2
3
(2H, m), 1.20–1.50 (3H, m), 1.42 and 1.63 (2s, 9H each, tert-
BuO), 2.05–2.20 (2H, m), 2.15 (3H, s, AcO), 2.30–2.48 (3H, m),
2.78 [1H, dd, J 16 and 9, CH(CH3)CH2Ar], 2.94 [1H, dd, J 16
and 4, CH(CH3)CH2Ar], 3.31 and 3.47 (2d, 1H each, J 16,
᎐CCH Ar), 3.77 (3H, s, CO CH ), 4.01 (1H, s, 4-OH), 5.16 (1H,
᎐
2
2
3
s, 3-H), 5.17 (1H, d, J 4, C᎐CHCH ), 5.26 (1H, d, J 2, 7-H), 5.75
᎐
2
(1H, d, J 16, OCOCH᎐CH), 6.44 (1H, d, J 2, 6-H), 6.92 (1H,
᎐
dd, J 16 and 9, OCOCH᎐CH) and 7.06–7.15 (4H, m, Ar);
᎐
δC(125 MHz; CDCl3) 169.3 (CO), 167.9 (CO), 167.1 (CO),
164.5 (CO), 163.3 (CO), 157.0 (d), 141.4 (s), 139.9 (s), 134.4 (s),
129.7 (d), 128.9 (d), 127.7 (d), 126.2 (d), 125.9 (d), 118.4 (d),
104.4 (s), 89.6 (s), 86.0 (s), 84.4 (s), 80.4 (d), 75.9 (d), 75.7 (d),
74.0 (s), 52.3 (q), 43.2 (t), 39.4 (t), 36.9 (t), 34.5 (t), 34.5 (t), 34.4
(d), 33.5 (d), 31.8 (d), 29.7 (t), 28.0 (q), 27.8 (q), 22.3 (q), 20.7
(q), 20.2 (q), 18.9 (q) and 11.1 (q).
(1S,3S,4S,5R,6R,7R)-Trimethyl 6-{[(4R,6S)-4,6-dimethyl-
octanoyl]oxy}-1-[(3RS,5S)-3,5-dimethyl-6-phenylhexyl]-4,7-
dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 19
A mixture of tripotassium salt 18 (150 mg, 0.20 mmol), sodium
hydrogen carbonate (252 mg, 3.0 mmol) and methyl iodide
(0.075 cm3, 1.2 mmol) was stirred in DMF (2 cm3) for 23 h at
20 ЊC. The suspension was poured into water (15 cm3) and
extracted with diethyl ether (50 cm3). The organic phase was
washed with aqueous sodium hydrogen carbonate (3 × 15 cm3),
water (15 cm3), brine (15 cm3), then dried and evaporated to a
gum (112 mg). This was purified by column chromatography on
silica gel eluting with ethyl acetate–cyclohexane (1:3) to give
the trimethyl ester 19 as a white foam (110 mg, 81%) [Found:
(CI) (M ϩ H)ϩ, 679.3711. C36H55O12 requires (M ϩ H),
679.3693]; analytical HPLC tr 5.23 min, 97.7% (column A; 80%
MeCN–H2O); νmax(CHBr3)/cmϪ1 3550, 1769, 1736 and 1251;
δH(250 MHz; CDCl3) 0.76–0.95 (15H, m, CH3), 2.57 (0.5H, dd,
J 13 and 6, CH2Ph), 2.68 (0.5H, dd, J 13 and 5, CH2Ph), 3.13
(1H, t, J 2.5, 7-OH), 3.76, 3.80 and 3.92 (3s, 3H each, CO2CH3),
3.77 (1H, s, 4-OH), 4.00 (1H, m, 7-H), 5.23 (1H, s, 3-H), 5.75
(1H, m, 6-H) and 7.10–7.32 (5H, m, Ph); m/z (DCI–NH3) 696
(M ϩ NH4)ϩ.
Acknowledgements
We are indebted to Dr C. Chan for providing us with a sample
of compound 2, Mr K. Brinded for conducting the mass
spectrometry determinations and Mrs S. Faulks and Mrs J. F.
Roberts for expert technical assistance in conducting the rat
enzyme inhibition assays.
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Paper 7/04363E
Received 20th June 1997
Accepted 29th August 1997
334
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