Towards complete stereochemical control: Complementary methods for the synthesis of six diastereoisomeric monosaccharide mimetics

Article abstract of DOI:10.1039/b202890e

Complementary methods for the synthesis of diastereomeric monosaccharide mimetics are described which rely on the functionalisation of derivatives of 2-butyl-6-methoxy-2,6-dihydropyran-3-one. The stereochemical outcome of dihydroxylation of these derivatives under Upjohn's and Donohoe's (directed) reaction conditions are described. The hydrolyses of diastereomeric 2-butyl-4,5-epoxy-3-hydroxy-6-methoxytetrahydropyrans, generated either by epoxidation with perbenzimidic acid or by cyclisation of the corresponding hydroxy iodides, are described in detail. These methods have enabled stereoselective syntheses of six of a possible eight (ignoring anomers) diastereoisomers of 3,4,5-triacetoxy-2-butyl-6-methoxytetrahydropyran. The power of the general approach lies in the ability to choose at a late stage in the synthesis which diastereoisomer is prepared.

Full text of DOI:10.1039/b202890e

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Towards complete stereochemical control: complementary methods
for the synthesis of six diastereoisomeric monosaccharide mimetics
Robert Hodgson,a Tahir Majidb and Adam Nelson*a
1
a Department of Chemistry, University of Leeds, Leeds, UK LS2 9JT
b Aventis Pharma US, Route 202-206, Bridgewater, New Jersey 08807, USA
Received (in Cambridge, UK) 21st March 2002, Accepted 3rd May 2002
First published as an Advance Article on the web 22nd May 2002
Complementary methods for the synthesis of diastereomeric monosaccharide mimetics are described which rely on
the functionalisation of derivatives of 2-butyl-6-methoxy-2,6-dihydropyran-3-one. The stereochemical outcome
of dihydroxylation of these derivatives under Upjohn’s and Donohoe’s (directed) reaction conditions are described.
The hydrolyses of diastereomeric 2-butyl-4,5-epoxy-3-hydroxy-6-methoxytetrahydropyrans, generated either by
epoxidation with perbenzimidic acid or by cyclisation of the corresponding hydroxy iodides, are described in detail.
These methods have enabled stereoselective syntheses of six of a possible eight (ignoring anomers) diastereoisomers
of 3,4,5-triacetoxy-2-butyl-6-methoxytetrahydropyran. The power of the general approach lies in the ability to
choose at a late stage in the synthesis which diastereoisomer is prepared.
Introduction
The complete control of stereochemistry, that is the ability
to synthesise any stereoisomer at will, is a challenging goal
for the synthetic chemist. Flexible methods for the synthesis of
libraries of stereoisomeric aldoses1 and polyketides2 have
been developed.3 The stereochemical diversity of these libraries
stems, in part, from the control of stereochemistry using
complementary chiral reagents. In contrast, all six conduritol
diastereoisomers have been prepared from common building
blocks using only substrate-controlled diastereoselective reac-
tions.4 An alternative approach, which has been used to syn-
thesise all 16 stereoisomers of a dipeptide mimetic,5 involved
coupling pairs of enantiomerically pure allylic alcohols using
ring-closing metathesis reactions.6 An appreciation of how the
relative stereochemistry of substituents in stereotriads, -tetrads
and -pentads, etc., influences the conformation of molecules is
an essential step towards an understanding of their biological
activity.7
In this paper, we describe methods for the synthesis of pro-
tected versions of the trihydroxylated tetrahydropyrans (THPs)
3 (R = Bu) (Scheme 1).8 The triols 3 are carbohydrate mimetics
the THPs 3 can be considered to be analogues of C-pyranosides
5 in which C-6 has been replaced by a methoxy group.
We envisaged that Sharpless kinetic resolution of the furyl
alcohols 1,10 and protection, would give the optically active
pyranones 2 (Scheme 1). The pyranones 2 are heavily function-
alised and might be functionalised stereoselectively, for example
by reduction and dihydroxylation, to give the triols 3. The aim
of the project was to develop methods which would be suf-
ficiently flexible to allow the synthesis of any stereoisomer 3 by
minor variation of a common reaction scheme.
Synthesis of the starting materials
Sharpless kinetic resolution of the furyl alcohol10 6, followed
by acetalisation, gave the pyranone (2R)-7 as a 70 : 30 mixture
of anomers with 93% enantiomeric excess (Scheme 2).11 In one
experiment, the diastereomeric pyranones 7 were separated
to give trans-7 and cis-7 in 67% and 23% yield, respectively,
from the intermediate hemiacetal. Luche reduction12 (NaBH4,
CeCl3) of the pyranone trans-7 gave the alcohol trans-8 as a
single diastereoisomer, which was acylated to give the optically
active p-methoxybenzoate 9.
Scheme 1
in which C-6 of a monosaccharide has been further substituted.
This substitution pattern is found in the glucose derivative9 4
which is active against six human cancer cell lines. Alternatively,
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This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b202890e

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Scheme 2
A racemic sample of the pyranone 7 (7 : 3 mixture of
Complementary reactions conditions were available, how-
anomers) was synthesised in 89% yield by oxidation of 6 with
tert-butyl hydroperoxide, catalysed by VO(acac)2,13 and protec-
tion; Luche reduction of this diastereomeric mixture gave the
separable alcohols 8. Mitsunobu inversion of the alcohol trans-
8 to give the inverted p-nitrobenzoate, followed by hydrolysis,
gave its diastereoisomer 10. The alcohols 8 and 10 were con-
verted into the racemic p-methoxybenzoate 11 and the racemic
acetate 12.
ever, for the diastereoselective dihydroxylation of alkenes such
as 10, 11 and 12 in which the allylic oxygen substituent adopts a
pseudo-axial orientation (see Fig. 2). Hence, the dihydroxyl-
Control of relative stereochemistry by diastereoselective
dihydroxylation
Fig. 2
Dihydroxylation of the allylic p-methoxybenzoate 9 under
Upjohn’s reaction conditions14 (cat. OsO4, NMO) was highly
diastereoselective, leading to the diol† 13a in 82% yield (crude
ratio of diastereoisomeric products >95 : 5) (Scheme 3). This
observation concurs with earlier investigations14 into the
dihydroxylation of allylic alcohol derivatives: the osmylation
reaction occurred anti to the pseudoequatorial p-methoxy-
benzoyloxy group (Fig. 1). It has previously been shown that
ations of the allylic p-methoxybenzoate 11 and the allylic
acetate 12 under Upjohn’s reaction conditions were anti
diastereoselective. The level of diastereoselectivity observed
depended significantly on the size of the ester substituent. We16
and others17 have previously shown that dihydroxylations of
related allylic alcohols under Upjohn’s conditions also exhibit
moderate levels of anti diastereoselectivity. In contrast, the
dihydroxylation of the allylic alcohol 10 by OsO4ؒTMEDA was
directed efficiently by the pseudo-axial hydroxy group (syn : anti
>95 : 5) to give, after acetylation, the all cis triacetate 15c
1
(Fig. 2). The H NMR spectral data of the triacetates 15 are
summarised in Table 1.§ The ability to alter the sense of the
diastereoselectivity of a functionalisation reaction simply by
changing the reagents used is a valuable feature of these
dihydroxylation reactions.
Fig. 1
it is not possible to direct15 the dihydroxylation of related
pseudoequatorial allylic alcohols using Donohoe’s reaction
conditions (TMEDA, OsO4, CH2Cl2), a process which is
probably prevented by the axial methoxy substituent.16,17
‡
† In this paper, protected versions of the triols 3 (such as 13a) are
labelled a–h according to their relative stereochemistry.
‡ Simple allylic alcohols in which the hydroxy group is conformationally
locked in a pseudo-equatorial position are dihydroxylated under these
reaction conditions with high syn stereoselectivity.15
§ The atoms in the triacetates 15 are labelled as tetrahydropyrans
(i.e. not sugar numbering).
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Table 1 Coupling constants and chemical shifts of the triacetates 15
J(H2H1Ј)/
Hz
J(H2H3)/
Hz
J(H3H4)/
Hz
J(H4H5)/
Hz
J(H5H6)/
Hz
δ (H2)
(ppm)
δ (H3)
(ppm)
δ (H4)
(ppm)
δ (H5)
(ppm)
δ (H6)
(ppm)
Compound
4J/Hz
15a
15b
15c
15d
15e
15f
1.9, 9.8
4.1, 8.8
3.8, 9.3
2.2, 9.6
3.2, 8.8
3.6, 9.5
9.8
2.1
0
9.6
8.8
2.3
9.8
4.1
3.8
9.6
4.0
3.8
3.5
4.1
3.8
10.1
4.0
3.8
1.7
4.1
1.2
3.7
2.0
1.8
—
3.71
4.11
3.91
3.76
3.95
4.10
5.09
4.92
5.22
4.84
4.93
4.85
5.28
5.20
5.26
5.43
5.13
4.97
5.23
5.16
5.10
4.83
4.89
4.82
4.63
4.81
4.76
4.89
4.51
4.68
0.7 (H4H6)
1.2 (H3H5)
—
—
—
Scheme 3
An alternative approach to the triacetate 15c involved revers-
ing the order of the dihydroxylation and reduction steps.
Hence, dihydroxylation of the enone trans-7 was followed by
reduction of the ketone with sodium borohydride and acetyl-
ation (Scheme 4); the triacetate 15c was obtained in 67% yield
Control of relative stereochemistry under Prévost’s reaction
conditions
We have investigated the functionalisation of the diastereo-
meric allylic p-methoxybenzoates 9 and 11 using iodine and
silver benzoate in carbon tetrachloride (Scheme 5).19 In view of
the rigorously dry reaction conditions of these reactions, the
syn stereospecificity of this process (9
17/18; 11
21) and
the absence of benzoate from the products are remarkable.20
Presumably, participation21 of p-methoxybenzoyloxy group
of 9 and 11 gave the dioxonium ions 16 and 20 which were
stable to the reaction conditions;¶ subsequent hydrolysis of
these intermediates, presumably on aqueous work-up, gave the
observed cis hydroxy p-methoxybenzoates. The hydroxy esters
17 and 18 were shown to have the same relative stereochemistry
by conversion into the same diester 23.
The iodides 17/18 (4 : 1 mixture of regioisomers) and 21
were treated with potassium hydoxide in water–THF, and the
products of the reaction were converted into the correspond-
ing peracetates. Hydrolysis of the p-methoxybenzoate ester is
Scheme 4
from the enone trans-7. Dihydroxylations of compounds simi-
lar to the epimeric enone cis-7 have been shown to proceed with
complementary stereoselectivity, that is with dihydroxylation
occurring anti to the C-2 side chain.18
¶ An alternative explanation is that benzoate traps the dioxonium ions
16 and 20 as the corresponding anomeric benzoates.
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Scheme 5
believed to have been followed by epoxide formation ( 19 or
22) and hydrolysis to give the corresponding triols.22 The regio-
selectivity of this ring-opening process deserves further com-
ment. In the major conformer of 19 (conformer 24, Scheme 6),
Scheme 7
allylic p-methoxybenzoates 9 and 11, followed by hydrolysis
and acetetylation. The epoxidations of 9 and 11 with per-
benzimidic acid,25 generated in situ from hydrogen peroxide and
benzonitrile, were anti selective (Scheme 8). It is surprising that
the epoxidation of 11 (anti : syn 70 : 30) was markedly less
stereoselective than that of 9 (anti : syn >95 : 5) given that the
p-methoxybenzoyloxy group of 11 can shield the syn face of the
alkene more effectively. Perhaps, the p-methoxybenzoyloxy
group can direct the epoxidation by perbenzimidic acid to some
extent (Fig. 3).26
Scheme 6
the stereoelectronic preference23 for trans-diaxial opening
(
15e) requires that 24 be opened at the site which is β to the
two oxygens of the acetal; consequently, reaction via the con-
former 25 ( 15d)—that is, away from the two β oxygens24—is
competitive with, and in fact dominates over, this process. After
peracetylation, a 3 : 1 mixture of the triacetates 15d and 15e was
obtained. The diastereomeric epoxy alcohol 22 was, however,
opened with much higher regioselectivity to give, after acetyl-
ation, the triacetate 15f in 87% yield; in this case, the major
conformer (26, Scheme 7) can be opened trans-diaxially at the
carbon which is further from the anomeric centre (Scheme 7).
The conversion of the epoxy ester 29 into the same triacetate
15f (Scheme 8) reinforces the proposal that 22 is an intermediate
Fig. 3
The hydrolyses of the epoxy esters 27b and 28 (Scheme 8)
complement those of the epoxides 19 and 22 (Scheme 5).
Hence, trans-diaxial opening of 27b, that is away from the
anomeric centre (conformer 30, Scheme 9), followed by
acetylation, gave the triacetate 15e, the minor diastereoisomer
obtained from the hydrolysis of 17/18. The hydrolysis of 28 was,
however, much more complicated since not only were the pref-
erences for trans-diaxial opening and substitution away from
the anomeric centre opposed, but the epoxy alcohol 34 was also
in the reaction sequence 21
15f (Scheme 5).
Control of relative stereochemistry by epoxidation and hydrolysis
An alternative approach for controlling the relative stereo-
chemistry of the triacetates 15 would involve epoxidation of the
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454
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Scheme 8
such as 9 and 11, by dihydroxylation, Prévost reaction or
epoxidation. We have shown that asymmetry may be introduced
into the divergent reaction sequence: the common intermediate
7 was synthesised with 93% ee by kinetic resolution of the furyl
alcohol 6.
Scheme 9
Complementary dihydroxylation reactions enabled the syn-
thesis of protected versions of the mimetics 15a–c: it was pos-
sible to direct the dihydroxylation of 10 using OsO4–TMEDA
as an alternative to the usual anti stereoselectivity for this pro-
cess (see Figs. 1 and 2). We were, however, unable to direct the
dihydroxylation of the pseudo-equatorial alcohol trans-8,
which would have been required for the synthesis of the triol
3g. Regioselective ring-openings of diastereomeric hydroxy
epoxides enabled the synthesis of protected versions of the
mimetics 15d–f; unfortunately, the hydroxy epoxide 34 was
susceptible to Payne rearrangement, preventing the synthesis
of the triol 3h using this methodology. On the whole, the
synthetic methods developed were highly diastereoselective
and complemented each other effectively. The divergent
nature of the approach meant that the six diastereomeric
mimetics could be made from a common intermediate by
making minor variations at a relatively late stage in each
synthesis.
prone to Payne rearrangement27 (Scheme 10). In this case, after
acetylation, the triacetates 15b, 15f and 15d were obtained
in 57%, 15% and 9% yield, respectively. Presumably, 15b and
15d were derived from hydrolysis of the Payne-rearranged
epoxy alcohol 33; 15f, on the other hand, was obtained from
trans-diaxial opening of conformer 35 of the epoxy alcohol 34
(Scheme 10). The relative stereochemistry of major product
(15b) was determined by hydrolysis and peracetylation of the
diol 13b of known stereochemistry.
Conclusions
In this paper, we have described methods for the synthesis of six
diastereoisomers (of a possible eight, ignoring anomers) of the
protected monosaccharide mimetics 15. The methods exploited
involved diastereoselective functionalisation of dihydropyrans
Scheme 10
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pyranone10 (1.48 g, 31%, 69 : 31 mixture of anomers), as a
colourless viscous oil, [α]2D0 ϩ34.7 (c 0.78, CHCl3; 93% ee); Rf
0.22 (2 : 8 EtOAc–petrol); νmax/cmϪ1 (thin film) 3431 (O–H),
2958, 2862, 1682 (C᎐O), 1468, 1379, 1158, 1088, 1027; δ (300
᎐
H
MHz; CDCl3) 6.92 (1H, dd, J 10.3 and 1.5, 5-Hmin), 6.90
(1H, dd, J 10.2 and 3.4, 5-Hmaj), 6.14 (1H, dd, J 10.3 and 4JHH
1.6, 4-Hmin), 6.10 (1H, dd, J 10.2 and JHH 0.6, 4-Hmaj), 5.65
4
(1H, m, 6-Hmaj ϩ min), 4.56 (1H, dd, J 8.0 and 3.9, 2-Hmaj), 4.08
(1H, dd, J 8.0 and 3.9, 2-Hmin) 2.0–1.2 (6H, m, butyl), 0.91 (3H,
t, J 7.1, CH3); νC (75 MHz; CDCl3) 197.4 (3-Cmaj), 196.9
(3-Cmin), 148.4 (5-Cmin), 145.0 (5-Cmaj), 127.9 (4-Cmaj), 129.1
(4-Cmin), 91.3 (6-Cmin), 87.9 (6-Cmaj), 79.3 (2-Cmin), 74.6 (2-Cmaj),
29.7 (maj), 30.6 (min), 27.7 (min), 27.5 (maj), 26.9 (maj) and
14.4 (CH3maj ϩ min).
Experimental
All solvents were distilled before use. THF and Et2O were
freshly distilled from lithium aluminium hydride whilst
CH2Cl2 and toluene were freshly distilled from calcium hydride.
Benzophenone was used as indicator for THF. Ether refers to
diethyl ether and petrol refers to petroleum spirit (bp 40–60 ЊC)
unless otherwise stated. Solvents were removed under reduced
pressure using a Büchi rotary evaporator and a Laboport
diaphragm pump. n-Butyllithium was titrated against diphenyl-
aceticacidbeforeuse.Allnon-aqueousreactionswerecarriedout
under argon using oven-dried glassware.
Flash column chromatography was carried out using silica
(35–70 µm particles) according to the method of Still, Kahn
and Mitra.28 Thin layer chromatography was carried out on
commercially available pre-coated plates (Merck silica Kieselgel
60F254). Preparative HPLC was conducted on a Gynkotek
HPLC system with diode array detection using an Econosil
column (silica particle size: 10 µm; 22 × 250 mm). Proton and
carbon NMR spectra were recorded on a Bruker WM 250,
DPX 300 or DRX 500 Fourier transform spectrometers using
an internal deuterium lock. Chemical shifts are quoted in parts
per million downfield of tetramethylsilane and values of coup-
ling constants (J) are given in Hz. The symbol * after the pro-
ton NMR chemical shift indicates that the signal disappears
after a D2O “shake”. Carbon NMR spectra were recorded with
broad band proton decoupling and the DEPT pulse sequence
was routinely used to aid the assignment of spectra.
2-Butyl-2,6-dihydro-6-hydroxypyran-3-one
The furyl alcohol 6 (8.78 g, 57 mmol) and vanadyl acetylaceto-
nate (50 mg, 0.144 mmol) were stirred in dry dichloromethane
(150 ml) at room temperature and tert-butyl hydroperoxide
(62.7 mmol, 14.41 ml as a 4.35 M solution in toluene) was
added. The reaction mixture was stirred for 5 h and quenched
by slow addition of a large excess of saturated aqueous ferrous
sulfate solution. The organic layer was separated, washed with
brine (2 × 50 ml), dried (MgSO4) and the solvent removed
under reduced pressure. The residue was pre-absorbed directly
onto silica gel, and purified by flash chromatography, eluting
with 2 : 8 EtOAc–petrol to give the racemic pyranone10 (9.33 g,
89%; 69 : 31 mixture of anomers) as a colourless viscous oil,
spectroscopically identical to that obtained previously.
(2R,6S)- and (2R,6R)-2-Butyl-6-methoxy-2,6-dihydropyran-3-
one: trans- and cis-7
(2R)-2-Butyl-6-hydroxy-2,6-dihydropyran-3-one (9.00 g, 52.9
mmol) and trimethyl orthoformate (6.97 ml, 63.5 mmol) were
stirred in dry dichloromethane (150 ml) at room temperature
and boron trifluoride–diethyl ether complex (2.6 mmol, 336 µl)
added. The solution was stirred for 2 h and then quenched with
saturated aqueous sodium bicarbonate solution (2 × 50 ml).
The organic layer was washed with brine (50 ml) and dried
(MgSO4). The solvent was removed under reduced pressure and
the residue pre-absorbed directly onto silica gel. Purification by
flash chromatography, eluting with 6 : 94 EtOAc–petrol gave
the pyranone trans-7 (6.53 g, 67%) as a colourless oil, [α]2D0 ϩ84.2
(c 0.32, CHCl3; 93% ee); Rf 0.34 (6 : 94 EtOAc–petrol);
νmax/cmϪ1 (thin film) 2957, 2862, 1695, 1468, 1396, 1101, 1049,
965; δH (300 MHz; CDCl3) 6.85 (1H, dd, J 10.2 and 3.5, 5-H),
6.08 (1H, dd, J 10.2 and 4JHH 0.4, 4-H), 5.11 (1H, d, J 3.5, 6-H),
4.38 (1H, dd, J 8.5 and 3.5, 2-H), 3.52 (3H, s, OCH3), 2.0–1.3
(6H, m, butyl), 0.92 (3H, t, J 7.1, CH3); δC (75 MHz; CDCl3)
197.1 (3-C), 143.5 (5-C), 128.1 (4-C), 94.5 (6-C), 74.3 (2-C), 56.8
(OCH3), 29.5, 27.6, 22.9 and 14.4 (CH3).
Melting points were determined on a Reichert hot stage
apparatus and are uncorrected. Infrared spectra were recorded
on a Nicolet Avatar 360 FT-IR ESP infrared spectrophoto-
meter and signals were referenced to the polystyrene 1601 cmϪ1
absorption. Mass spectra were recorded either on a VG
autospec mass spectrometer, operating at 70 eV, using both the
electron impact and fast atom bombardment methods of ion-
isation, or using a Micromass LCT-KA111 electrospray mass
spectrometer. Accurate molecular weights were generally
obtained using electrospray mass spectrometry using reserpine
as the lock mass and sodium iodide as the standard. The
method used is indicated in each case: electron impact (EI),
fast atom bombardment (FAB) or electrospray (ES). Optical
rotations were recorded for all optically active compounds on a
Perkin Elmer 241 polarimeter (using the sodium D line; 589
nm) and [α]2D0 are given in units of 10Ϫ1 deg cm2 gϪ1
.
(2R)-2-Butyl-2,6-dihydro-6-hydroxypyran-3-one
Also obtained was the pyranone cis-7 (2.63 g, 27%) as a
colourless oil, Rf 0.29 (6 : 94 EtOAc–petrol); δH (300 MHz;
CDCl3) 6.88 (1H, dd, J 10.3 and 1.9, 5-H), 6.13 (1H, dd, J 10.3
and 4JHH 1.6, 4-H), 5.23 (1H, dd, J 1.9 and 4JHH 1.6, 6-H), 4.05
(1H, dd, J 8.7 and 4.1, 2-H), 3.57 (3H, s, OCH3), 2.0–1.3 (6H,
m, butyl), 0.92 (3H, t, J 7.1, CH3); δC (75 MHz; CDCl3) 197.1
(3-C), 146.7 (5-C), 129.0 (4-C), 97.1 (6-C), 79.4 (2-C), 56.7
(OCH3), 31.4, 28.0, 22.8 and 14.4 (CH3).
(Ϫ)--DIPT (15 mole %, 827 µl, 3.90 mmol) and titanium()
isopropoxide (772 µl, 2.60 mmol) were stirred in dry dichloro-
methane (120 ml) at Ϫ40 ЊC over 3 Å molecular sieves (1.2 g)
for 30 min after which a solution of racemic furyl alcohol 6
(4.00 g, 26.0 mmol) in dichloromethane (10 ml) was added.
After a further 10 min of stirring, tert-butyl hydroperoxide
(18.2 mmol, 3.03 ml, 5.0 M solution in decane) was added and
the solution stirred for a further 4 h. This solution was
quenched by slow addition with stirring of a large excess of
saturated aqueous tartaric acid–ferrous sulfate solution. The
organic layer was separated and washed with brine (2 × 50 ml).
The organic layer was dried (MgSO4), after which the solvent
was removed under vacuum and the residue pre-absorbed
directly onto silica gel. Analysis of a portion of the crude
product by 300 MHz 1H NMR spectroscopy indicated that the
reaction had reached 34% completion. Purification by flash
chromatography, eluting with 2 : 8 EtOAc–petrol gave the
(2R,3S)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-ol 8
The pyranone 7 (2.82 g, 15.34 mmol, trans : cis 70 : 30) and
cerium trichloride heptahydrate (6.87 g, 18.4 mmol) were
stirred in absolute ethanol (60 ml) at Ϫ40 ЊC, and sodium
borohydride (583 mg, 15.3 mmol) added slowly and in small
portions. The mixture was stirred for 4 h and allowed to warm
to room temperature before being cautiously quenched with
water (5 ml). After a further 10 min of stirring, the ethanol
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454
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was removed under vacuum and the residue diluted with water
(40 ml). The residue was extracted with chloroform (4 × 60 ml)
and the combined organic extracts dried (MgSO4) and the
solvent removed under reduced pressure to give the alcohol 8
(2.62 g, 92%, 70 : 30 mixture of anomers) as a colourless viscous
oil, [α]2D0 ϩ98.7 (c 0.21, CHCl3; 93% ee); Rf 0.32 (15 : 85 EtOAc–
petrol); νmax/cmϪ1 (thin film) 2453, 2956, 2873, 1651, 1467, 1399,
1043, 1001 and 955; δH (300 MHz; CDCl3) 6.14 (1H, ddd,
1111, 1064; δH (300 MHz; CDCl3) 8.30 (2H, d, J 9.1, Ar), 8.24
(2H, d, J 9.1, Ar), 6.22 (1H, ddd, J 10.0, 5.5 and 4JHH 0.9, 4-H),
6.09 (1H, dd, J 10.0 and 3.0, 5-H), 5.18 (1H, dd, J 5.5 and 2.3,
4
3-H), 5.00 (1H, dd, J 3.0 and JHH 0.5, 6-H), 4.16 (1H, ddd,
J 8.8, 3.9 and 2.3, 2-H), 3.49 (3H, s, OCH3), 1.8–1.5 (3H, m,
butyl), 1.45–1.30 (3H, m, butyl) and 0.90 (3H, t, J 6.9, CH3);
δC (75 MHz; CDCl3) 164.7, 151.1, 135.7, 131.6, 131.3, 125.8,
123.9, 95.6, 69.0, 67.4, 66.6, 56.0, 30.6, 28.2, 22.9 and 14.4.
4
J 10.2, 5.3 and JHH 1.6, 4-Hmin), 5.94 (1H, ddd, J 10.0, 2.6
4
and JHH 1.3, 5-Hmaj), 5.82 (1H, d, J 10.0, 4-Hmaj), 5.75 (1H,
(2R*,3R*,6S*)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-ol
10
4
ddd, J 10.2, 2.8 and JHH 2.1, 5-Hmin), 4.95 (1H, dd, J 2.8
4
and JHH 1.6, 6-Hmin), 4.84 (1H, d, J 1.3, 6-Hmaj), 3.88 (1H, td,
4
(2R*, 3R*, 6S*)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl
4-nitrobenzoate (749 mg, 2.16 mmol) and potassium carbonate
(294 mg, 2.16 mmol) were stirred under nitrogen at room tem-
perature in methanol (20 ml) for 2 days. The solvent was
removed under vacuum and the residue dissolved in chloroform
(30 ml)–water (20 ml). The organic layer was separated and
washed with a further portion of water (2 × 20 ml). The organic
layer was dried (MgSO4) and the solvent removed under
reduced pressure to give the alcohol 10 (399 mg, >98%) as a
viscous colourless oil, Rf 0.35 (15 : 85 EtOAc–petrol); (Found:
MNa 187.1336. C10H18O3 requires MNa, 187.1334); νmax/cmϪ1
3422 (O–H), 2956, 2932, 1651, 1467, 1398, 1187, 1034; δH (300
J 8.9 and JHH 1.3, 3-Hmaj), 3.72 (1H, m, 3-Hmin), 3.48 (1H, m,
ϩ
2-Hmaj min), 1.75 (1H, d, J 11.1, OHmin), 1.64 (1H, d, J 8.9,
OHmaj), 2.0–1.25 (6H, m, butyl) and 0.92 (3H, t, J 7.2, CH3);
m/z 186 (32%), 155 (29), 114 (41), 100 (100), 55(90) and 41 (99).
(2R,3S,6S)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl 4-
methoxybenzoate 9
The alcohol 8 (2.172 g, 11.7 mmol, trans : cis 70 : 30) and
triethylamine (2.604 ml, 18.72 mmol) were stirred in dry
dichloromethane (50 ml) at room temperature and p-anisoyl
chloride (1.75 ml, 12.87 mmol) was added via syringe. The
resulting solution was treated with DMAP (71 mg, 0.585 mmol)
and stirred for 8 h. The solution was quenched with saturated
aqueous sodium bicarbonate solution (20 ml) and diluted with
dichloromethane (100 ml). The organic layer was separated and
washed with a further portion of saturated sodium bicarbonate
solution (2 × 30 ml) followed by a washing with brine (50 ml).
The organic layer was dried (MgSO4) and the solvent removed
under reduced pressure. The crude residue was pre-absorbed
onto silica gel and purified by flash chromatography, eluting
with 1 : 9 EtOAc–petrol to give the ester 9 (2.50 g, 67%) as
a colourless viscous oil, [α]2D0 ϩ147.0 (c 0.68, CHCl3); Rf 0.32
(7 : 93 EtOAc–petrol); (Found MNaϩ 343.1521. C18H24O6
4
MHz; CDCl3) 6.17 (1H, ddd, J 10.0, 5.6 and JHH 0.8, 4-H),
5.89 (1H, dd, J 10.0 and 3.1, 5-H), 4.86 (1H, d, J 3.1, 6-H), 3.91
[1H, ddd, J 7.9 (OH), 5.2 and 2.1 3-H], 3.63 (1H, br, 2-H), 3.43
(3H, s, OCH3), 1.85–1.30 (6H, m, butyl), 0.93 (3H, t, J 7.2,
CH3); δC (75 MHz; CDCl3) 130.9 (4-H), 128.5 (5-H), 95.8 (6-H),
70.9, 63.6, 55.9, 30.6, 28.2, 23.1 and 14.5.
(2R*,3R*,6S*)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl
4-methoxybenzoate 11
p-Anisoyl chloride (1.145 g, 910 µl, 6.70 mmol) was added via
syringe to a stirred solution of alcohol 10 (1.133 g, 6.09 mmol),
triethylamine (1.44 ml, 10.35 mmol) and DMAP (37 mg, 0.305
mmol) in dichloromethane (15 ml) under nitrogen at room
temperature. After being stirred for a further 24 h, the solution
was diluted with chloroform (40 ml) and the organic layer
washed sequentially with saturated sodium bicarbonate (2 ×
20 ml), brine (10 ml) and water (10 ml). The organic layer was
dried (MgSO4) and the solvent removed under reduced
pressure. Purification by flash chromatography (gradient elu-
requires MNa, 343.1520); νmax/cmϪ1 2956, 2954, 2872, 1716 (C᎐
᎐
O), 1606, 1512, 1257, 1168, 1101, 1048, 964, 847; δH (300 MHz;
CDCl3) 7.98 (2H, d, J 9.0, Aryl), 6.92 (2H, d, J 9.0, aryl), 5.97
4
(1H, d, J 10.2, 5-H), 5.84 (1H, ddd, J 10.2, 4.6 and JHH 2.0,
4-H), 5.34 (1H, ddd, J 8.5, 4.6 and 4JHH 1.5, 3-H), 4.92 (1H, s,
6-H), 3.94 (1H, td, J 8.5 and 2.4, 2-H), 3.86 (3H, s, OCH3), 3.48
(3H, s, OCH3), 1.8–1.2 (6H, m, butyl) and 0.87 (3H, t, J 7.1,
CH3); δC (75 MHz; CDCl ) 166.2 (C᎐O), 164.0 (aryl), 132.4
᎐
3
tion: 5 : 95
15 : 85 EtOAc–petrol) gave the ester 11 (1.84 g,
(aryl), 130.7 (4-C), 128.0 (5-C), 122.6 (aryl), 114.1 (aryl), 95.8
(6-C), 70.0 (3-C), 68.9 (2-C), 56.3 (OCH3), 55.9 (OCH3), 30.0,
27.9, 22.9 and 14.4 (CH3); m/z (ES) 343 (100%, MNaϩ).
Also obtained was the ester 4-methoxybenzoic acid (2R,3S,
6R)-2-butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl ester (1.08
g, 29%) as a colourless viscous oil, [α]2D0 Ϫ65.1 (c 0.36, CHCl3);
Rf 0.26 (7 : 93 EtOAc–petrol); δH (300 MHz; CDCl3) 8.03 (2H,
d, J 8.9, Aryl), 6.90 (2H, d, J 8.9, aryl), 6.19 (1H, dd, J 10.2 and
5.2, 4-H), 5.84 (1H, dd, J 10.2 and 1.3, 5-H), 5.24 (1H, m, 3-H),
5.05 (1H, s, 6-H), 3.75 (1H, m, 2-H), 3.86 (3H, s, OCH3), 3.55
(3H, s, OCH3), 1.8–1.2 (6H, m, butyl) and 0.87 (3H, t, J 7.1,
CH3); m/z (ES) 343 (100%, MNaϩ).
95%) as colourless prisms; Rf 0.36 (7 : 93 EtOAc–petrol);
(Found: MNa 343.1528. C18H24O5 requires MNa, 343.1521);
νmax/cmϪ1 2955, 1710 (C᎐O), 1606, 1511, 1257, 1168, 1110, 1044;
᎐
δH (300 MHz; CDCl3) 8.02 (2H, d, J 9.0, Ar), 6.91 (2H, d, J 9.0,
Ar), 6.21 (1H, ddd, J 10.0, 5.5 and 4JHH 0.9, 4-H), 6.04 (1H, dd,
J 10.0 and 3.0, 5-H), 5.13 (1H, dd, J 5.5 and 2.3, 3-H), 4.99 (1H,
d, J 3.0, 6-H), 4.11 (1H, dt, 7.2 and 2.3, 2-H), 3.87 (3H, s,
OCH3), 3.47 (3H, s, OCH3), 1.80–1.30 (6H, m, butyl) and 0.88
(3H, t, J 7.3, CH3); δC (75 MHz; CDCl3) 166.3, 163.9, 132.3,
130.7, 126.8, 122.7, 114.0, 95.7, 69.3, 65.1, 56.0, 55.9, 30.6, 28.2,
22.9 and 14.4; m/z (ES) 343 (100%, MNaϩ).
(2R*,3R*,6S*)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl
4-nitrobenzoate
(2R*,3R*,6S*)-2-Butyl-6-methoxy-3,6-dihydro-2H-pyran-3-yl
acetate 12
A solution of diisopropyl azodicarboxylate (1.629 g, 8.065
mmol) in THF was added dropwise to a solution of alcohol
trans-8 (750 mg, 4.03 mmol), triphenylphosphine (2.112 g,
8.065 mmol) and p-nitrobenzoic acid (1.347 g, 8.065 mmol)
which was stirred under nitrogen at 0 ЊC. After 14 h of stirring
the solvent was removed under vacuum and the residue pre-
absorbed onto silica gel. Purification by flash chromatography
The alcohol 10 (612 mg, 3.29 mmol) was stirred for 4 h at room
temperature in a solvent mixture of acetic anhydride (6 ml) and
pyridine (3 ml). The solvent was removed under high vacuum
and the residue pre-absorbed onto silica gel. Purification by
flash chromatography, eluting with 15 : 85 EtOAc–petrol gave
the acetate 12 (745 mg, >98%) as a colourless oil, Rf 0.29 (7 : 93
EtOAc–petrol); (Found: MNa 251.1260. C12H20O4 requires
(gradient elution: 5 : 95
15 : 85 EtOAc–petrol) gave the ester
MNa, 251.1259); νmax/cmϪ1 2955, 1733 (C᎐O), 1372, 1237, 1187,
᎐
(1.036g, 74%) as colourless prisms, m.p. 74–75 ЊC, Rf 0.31 (7 : 93
EtOAc–petrol); (Found MNaϩ 358.1271. C17H21NO6 requires
MNa, 358.1267); νmax/cmϪ1 2951, 2870, 1717, 1530, 1347, 1274,
1111, 1046, 1023, 960; δH (300 MHz; CDCl3) 6.10 (1H, ddd,
J 10.0, 5.4 and JHH 0.9, 4-H), 6.00 (1H, dd, J 10.0 and 2.9,
5-H), 4.93 (1H, d, J 2.9, 6-H), 4.92 (1H, dd, J 5.4 and 2.3, 3-H),
4
1450
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454

View Article Online
4.03 (1H, dt, 7.2 and 2.3, 2-H), 3.44 (3H, s, OCH3), 2.10 (3H, s,
(2R*,3R*,4S*,5R*,6S*)-2-Butyl-4,5-dihydroxy-6-methoxytetra-
OAc), 1.75–1.30 (6H, m, butyl) and 0.93 (3H, t, J 7.3, CH3);
hydropyran-3-yl acetate 14b
δ (75 MHz; CDCl ) 171.1 (C᎐O), 130.7 (4-C), 126.5 (5-C), 95.6
᎐
C
3
NMO (405 mg, 3.46 mmol) was added to a stirred solution of
the acetate 12 (395 mg, 1.73 mmol) and osmium tetraoxide
(78.7 µmol, 20 mg) in dichloromethane at room temperature
under nitrogen. The solution was stirred for 24 h and the
solvent removed under reduced pressure. The residue was
stirred at room temperature in a mixture of THF (2 ml) and
saturated aqueous sodium sulfite solution (2 ml) for 1 h and the
solvent removed under reduced pressure. The residue was pre-
absorbed onto silica gel and purified by flash chromatography
(6-C), 68.9, 65.0, 56.0, 30.3, 28.1, 22.9, 21.3 and 14.4; m/z (ES)
251 (100%, MNaϩ).
(2R,3S,4R,5S,6S)-2-Butyl-4,5-dihydroxy-6-methoxytetrahydro-
pyran-3-yl 4-methoxybenzoate 13a
The ester 9 (110 mg, 0.344 mmol, >95% ee) and NMO (81 mg,
0.688 mmol) were stirred at room temperature in an 8 : 1
acetone–water mixture (2.4 ml) and osmium tetraoxide (5 mg,
0.02 mmol) was added. After 24 h, the mixture was quenched
with a saturated aqueous sodium sulfite solution (0.5 ml) and
stirred for a further 10 min. The solvent was removed under
reduced pressure and the residue pre-absorbed onto silica gel
before purification by flash chromatography, eluting with 4 : 6
EtOAc–petrol to give the diol 13a (99.6 mg, 82%) as a colour-
less viscous syrup; [α]2D0 ϩ75.0 (c = 0.43, CHCl3); Rf 0.22 (4 : 6
EtOAc–petrol); (Found: MNa 377.1576. C18H26O7 requires
MNa, 377.1576); νmax/cmϪ1 3403 (O–H), 2936, 1716, 1606,
1512, 1463, 1259, 1168, 1105, 1071; δH (300 MHz; CDCl3) 7.97
(2H, d, J 8.9, aryl), 6.90 (2H, d, J 8.9, aryl), 5.00 (1H, t, J 9.5,
3-H), 4.77 (1H, s, 6-H), 3.97 (2H, m, br, 4-H and 5-H), 3.86 (3H,
s, OCH3), 3.78 (1H, td, J 9.0 and 1.4, 2-H), 3.59 (1H, d, JOH
3.6), 3.38 (3H, s, OCH3), 2.97 (1H, br, OH), 1.64–1.46 (3H, m,
CH2), 1.44–1.20 (3H, m, CH2) and 0.91 (3H, t, J 7.1, CH3); m/z
(ES) 377 (100%, MNaϩ).
(gradient elution: 4 : 6
1 : 1 EtOAc–petrol) to give the diol
14b (191 mg, 42%) as a colourless viscous oil, Rf 0.24 (4 : 6
EtOAc–petrol); (Found: MNa 285.1306. C12H22O6 requires
MNa, 285.1314); δH (300 MHz; CDCl3) 5.00 (1H, d, J 2.6, 3-H),
4.81 (1H, d, J 3.7, 6-H), 4.02 (1H, dd, J 8.9 and 3.1, 2-H), 3.89
(1H, m, 4-H), 3.82 (1H, m, 5-H), 3.47 (3H, s, OCH3), 2.12 (1H,
d, J 8.4, OH), 2.82 (1H, br, OH), 1.60–1.25 (6H, m, butyl) and
0.91 (3H, t, J 7.3, CH3); δC (75 MHz; CDCl3) 170.5, 101.3, 73.2,
70.0, 65.8, 64.5, 56.5, 30.0, 28.3, 22.9, 21.3 and 14.4; m/z (ES)
285 (100%, MNaϩ).
Also obtained was the diol 14c (40 mg, 9 %) as a colourless
semi-crystalline solid, Rf 0.33 (4 : 6 EtOAc–petrol); (Found
MNa 285.1320. C12H22O6 requires MNa, 285.1314); νmax/cmϪ1
3288 (O–H), 2940, 1737, 1232, 1117, 1069, 995; δH (300 MHz;
CDCl3) 5.22 (1H, d, J 3.7, 3-H), 4.81 (1H, d, J 1.1, 6-H), 3.95
(1H, dt, J 7.9 and 3.7, 4-H), 3.77 (1H, dd, J 8.7 and 3.2, 2-H),
3.72 (1H, ddd, J 11.0, 3.7 and 1.1, 5-H), 3.38 (3H, s, OCH3),
2.87 (1H, d, J 8.4, OH), 2.52 (1H, d, J 11.0, OH), 2.18 (3H, s,
OAc), 1.70–1.25 (6H, m, butyl) and 0.90 (3H, t, J 7.3, CH3);
δC (75 MHz; CDCl3) 170.8, 102.0, 73.4, 70.2, 68.8, 65.9, 55.6,
30.8, 28.2, 22.9, 21.3 and 14.4; m/z (ES) 285 (100%, MNaϩ).
The diol 13a was shown to have 93% ee by analysis, by
1
500 MHz H NMR spectroscopy, of the mixtures obtained by
derivatisation11 as the corresponding (R)- and (S)-Mosher’s
diesters.
(2R*,3R*,4S*,5R*,6S*)-2-Butyl-4,5-dihydroxy-6-methoxyt-
etrahydropyran-3-yl 4-methoxybenzoate 13b
(2R*,3S*,4S*,5S*,6S*)-4,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-3-yl acetate 15c
NMO (310 mg, 2.644 mmol) was added to a stirred solution
of the ester 11 (423 mg, 1.322 mmol) and osmium tetraoxide
(20 mg, 78.7 µmol) in dichloromethane at room temperature
under nitrogen. The solution was stirred for 24 h and the
solvent removed under reduced pressure. The residue was
stirred at room temperature in a mixture of THF (2 ml) and
saturated aqueous sodium sulfite solution (2 ml) for 1 h and the
solvent removed under reduced pressure. Analysis of the crude
reaction mixture by 300 MHz 1H NMR spectroscopy showed a
93 : 7 mixture of the diols 13b and 13c. The residue was pre-
absorbed onto silica gel and purified by flash chromatography
A solution of the alcohol 10 (113 mg, 0.609 mmol) and
TMEDA (110 µl, 0.731 mmol) in dichloromethane (6 ml) was
cooled to Ϫ78 ЊC under nitrogen. A solution of osmium
tetraoxide (186 mg, 0.731 mmol) in dichloromethane (0.7 ml)
was added and the solution stirred for 8 h at Ϫ78 ЊC. The
solution was allowed to warm to room temperature and
N,N,NЈ,NЈ-tetramethylethane-1,2-diamine added (244 µl, 3.655
mmol) added. The solution was stirred for 24 h before being
poured into brine and extracted with ethyl acetate (4 × 40 ml).
The combined organic extracts were dried (Na2SO4) and the
solvent removed under reduced pressure. The residue was dis-
solved in acetic anhydride–pyridine (3 : 1, 3 ml) and stirred at
room temperature for 4 h. The solvent was removed under
reduced pressure and the crude residue was pre-absorbed onto
silica gel and purified by flash chromatography, eluting with
15 : 85 EtOAc–petrol, to give the triacetate 15c (197 mg, 94%)
as a colourless oil, Rf 0.32 (15 : 85 EtOAc–petrol); (Found MNa
369.1537. C16H26O8 requires MNa, 369.1525); νmax/cmϪ1 2957,
2873, 1744, 1373, 1256, 1227, 1133, 1080, 1023; δH (300 MHz;
CDCl3) 5.26 (1H, t, J 3.7, 4-H), 5.22 (1H, d, J 3.7, 3-H), 5.10
(1H, dt, J 3.7 and 1.1, 5-H), 4.76 (1H, d, J 1.1, 6-H), 3.91 (1H,
dd, J 7.6 and 2.7, 2-H), 3.39 (3H, s, OCH3), 2.16 (3H, s, OAc),
2.09 (3H, s, OAc), 1.99 (3H, s, OAc), 1.80–1.20 (6H, m, butyl)
(gradient elution: 4 : 6
1 : 1 EtOAc–petrol) to give the diol
13b (320 mg, 69%) as a colourless viscous oil, Rf 0.32 (4 : 6
EtOAc–petrol); (Found: MNa 377.1578. C18H26O7 requires
MNa, 377.1576); δH (300 MHz; CDCl3) 7.93 (2H, d, J 8.9, Ar),
6.86 (2H, d, J 8.9, Ar), 5.15 (1H, dd, J 3.1 and 1.8, 3-H), 4.81
(1H, d, J 3.6, 6-H), 4.03 (1H, ddd, J 8.4, 4.6 and 1.8, 2-H), 3.96
(1H, br, 4-H), 3.86 (1H, br, 5-H), 3.79 (3H, s, OCH3), 3.43 (3H,
s, OCH3), 2.82 (1H, br, OH), 1.60–1.24 (6H, m, butyl) and 0.91
(3H, t, J 7.3, CH3); δC (75 MHz; CDCl3) 165.6, 164.1, 132.3,
122.2, 114.2, 101.5, 73.4, 70.2, 69.9, 66.1, 56.5, 55.9, 30.2, 28.4,
23.0 and 14.4; m/z (ES) 377 (100%, MNaϩ).
Also obtained was the diol 13c (23 mg, 5 %) as colourless
prisms, m.p. 119–121 ЊC; Rf 0.37 (4 : 6 EtOAc–petrol); (Found:
MNa 377.1565. C18H26O7 requires MNa, 377.1576); νmax/cmϪ1
3312 (O–H), 2934, 1708, 1607, 1509, 1277, 1255, 1167, 1119 and
1060; δH (300 MHz; CDCl3) 7.91 (2H, d, J 8.9, Ar), 6.85 (2H, d,
J 8.9, Ar), 5.35 (1H, d, J 3.7, 3-H), 4.79 (1H, d, J 1.3, 6-H), 3.96
(1H, dt, J 8.4 and 3.7, 4-H), 3.79 (3H, s, OCH3), 3.79 (1H, m,
2-H), 3.71 (1H, ddd, J 10.2, 3.7 and 1.3, 5-H), 3.33 (3H, s,
OCH3), 2.83 (1H, d, J 8.4, OH), 2.49 (1H, d, J 10.2, OH), 1.60–
1.15 (6H, m, butyl) and 0.79 (3H, t, J 7.3, CH3); δC (75 MHz;
CDCl3) 166.4, 164.2, 132.2, 121.9, 114.3, 102.0, 73.4, 70.2, 69.1,
66.3, 55.9, 55.6, 30.9, 28.3, 22.9 and 14.4; m/z (ES) 377 (100%,
MNaϩ).
and 0.90 (3H, t, J 7.3, CH ); δ (75 MHz; CDCl ) 170.9 (C᎐O),
᎐
3
C
3
170.5 (C᎐O), 170.1 (C᎐O), 99.7 (6-C), 70.0, 68.8, 68.0, 66.5,
᎐
᎐
55.5, 30.6, 28.0, 22.9, 21.4, 21.2, 21.1 and 14.4; m/z (ES) 369
(100%, MNaϩ).
(2R*,3S*,4R*,5S*,6S*)-2-Butyl-4-hydroxy-5-iodo-6-methoxy-
tetrahydropyran-3-yl 4-methoxybenzoate 17 and (2R*,3R*,4R*,
5S*,6S*)-2-butyl-3-hydroxy-5-iodo-6-methoxytetrahydropyran-
4-yl 4-methoxybenzoate 18
A mixture of the ester 9 (170 mg, 0.531 mmol) and freshly
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454
1451

View Article Online
prepared silver benzoate (300 mg, 2.125 mmol, 4 mol equiv.)
was dried azeotropically using toluene and then dissolved in dry
carbon tetrachloride (6 ml). Iodine (270 mg, 1.06 mmol) was
added to the stirred suspension under N2 and the mixture
stirred for a further 4 days with protection from light. The sus-
pension was diluted with chloroform (15 ml) and the silver salts
removed by centrifugation. The organic fraction was washed
with 10% aqueous sodium sulfite solution (2 × 5 ml) and satur-
ated aqueous sodium bicarbonate solution (2 × 5ml), dried
(MgSO4) and the solvent removed under reduced pressure. The
crude residue was pre-absorbed onto silica gel and purified by
flash chromatography, eluting with 15 : 85 EtOAc–petrol, to
give the ester 17 as a colourless oil (182.6 mg, 74%), Rf 0.34
(15 : 85 EtOAc–petrol); (Found MNaϩ 487.0578. C18H25IO6
requires MNa, 487.0594); νmax/cmϪ1 3484, 2956, 2858, 1716
of 15d and 15e. The crude residue was pre-absorbed onto silica
gel and purified by flash chromatography, eluting with 15 : 85
EtOAc–petrol, to give the triacetate 15d (8.3 mg, 74%) as a
colourless viscous oil, Rf 0.21 (15 : 85 EtOAc–petrol); (Found
MNaϩ 369.1529. C16H26O8 requires MNa, 369.1525); δH (300
MHz; CDCl3) 5.43 (1H, t, J 9.5, 4-H), 4.88 (1H, d, J 9.5, 5-H),
4.88 (1H, s, 6-H), 4.85 (1H, t, J 9.5, 3-H), 3.73 (1H, td, 9.5 and
3.2, 2-H), 3.39 (3H, s, OCH3), 2.08 (3H, s, OAc), 2.05 (3H, s,
OAc), 2.01 (3H, s, OAc), 1.65–1.2 (6H, m, butyl) and 0.90 (3H,
t, J 7.1, CH3); m/z (ES) 369 (100%, MNaϩ).
Also obtained was the triacetate 15e (1.2 mg, 11%), spectro-
scopically identical to that obtained from 27b, see below.
(2R*,3S*,4R*,5S*,6S*)-4,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-3-yl acetate 15f
(C᎐O), 1606, 1511, 1258, 1169, 1122, 1030, 847, 769; δ (300
᎐
H
By the same general method, the iodo alcohol 21 (50.2 mg,
108 µmol) gave a crude product residue which was was pre-
absorbed onto silica gel and purified by flash chromatography,
eluting with 15 : 85 EtOAc–petrol, to give triacetate 15f (33 mg,
87%) as a colourless viscous oil, Rf 0.23 (15 : 85 EtOAc–petrol);
(Found MNaϩ 369.1533. C16H26O8 requires MNa, 369.1525);
νmax/cmϪ1 2957, 1746, 1605, 1372, 1224, 1113, 1048; δH (300
MHz; CDCl3) 4.97 (1H, t, J 3.8, 4-H), 4.85 (1H, dd, J 3.8 and
2.3, 3-H), 4.82 (1H, dd, J 3.8 and 1.8, 5-H), 4.68 (1H, d, J 1.8,
6-H), 4.10 (1H, ddd, J 9.5, 3.6 and 2.3, 2-H), 2.13 (3H, s, OAc),
2.10 (3H, s, OAc), 2.09 (3H, s, OAc), 1.72–1.20 (6H, m, butyl)
MHz; CDCl3) 8.00 (2H, d, J 8.9, Ar), 6.92 (2H, d, J 8.9, Ar),
5.50 (1H, dd, J 9.2 and 2.6, 3-H), 5.01 (1H, s, 6-H), 4.31 (1H, d,
J 1.7, 5-H), 4.30, (1H, ddd, J 2.6, 1.7 and JOH 8.9, 4-H), 4.14
(1H, td, J 9.2 and 4.7, 2-H), 3.87 (3H, s, OMe), 3.46, (3H, s,
OMe), 3.41 (1H, d, J 8.9, OH), 1.8–1.2 (6H, m, butyl) and 0.91
(3H, t, J 7.1, CH3); δC (75 MHz; CDCl ) 165.8 (C᎐O), 164.0
᎐
3
(Ar), 132.3 (Ar), 122.4 (Ar), 114.1 (Ar), 102.7 (6-C), 71.6 (4-C),
70.1 (3-C), 67.3 (2-C), 56.2 (OCH3), 55.9 (OCH3), 31.2, 27.8,
25.8, 23.0 and 14.5 (CH3); m/z (ES) 487 (100%, MNaϩ).
Also obtained was the ester 18 as a colourless oil (42 mg,
17%), Rf 0.34 (15 : 85 EtOAc–petrol); (Found MNaϩ 487.0594.
C18H25IO6 requires MNa, 487.0594); νmax/cmϪ1 3459 (O–H),
and 0.91 (3H, t, J 7.3, CH ); δ (75 MHz; CDCl ) 170.5 (C᎐O),
᎐
3
C
3
169.8 (C᎐O), 99.4 (6-C), 69.7, 68.7, 68.1, 66.8, 55.9, 29.9, 28.1,
᎐
2955, 1714 (C᎐O), 1606, 1512, 1257, 1169, 1101 and 1030;
᎐
22.9, 21.3, 21.2 and 14.4; m/z (ES) 369 (100%, MNaϩ).
δH (300 MHz; CDCl3) 8.00 (2H, d, J 8.9, Ar), 6.93 (2H, d, J 8.9,
Ar), 5.40 (1H, t, J 3.9, 4-H), 4.96 (1H, d, J 2.3, 6-H), 4.42 (1H,
dd, J 3.9 and 2.3, 5-H), 4.20, (1H, td, J 9.2 and 3.9, 3-H), 3.98
(1H, td, J 9.2 and 2.9, 2-H), 3.87 (3H, s, OMe), 3.40, (3H, s,
OMe), 2.31 (1H, d, J 9.2, OH), 1.8–1.3 (6H, m, butyl) and 0.92
(2R*,3R*,4S*,5S*,6S*)-4,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-3-yl acetate 15a
By the same general method, the ester 13a (20 mg, 108 µmol)
gave a crude product residue which was was pre-absorbed
onto silica gel and purified by flash chromatography, eluting
with 15 : 85 EtOAc–petrol, to give triacetate 15a (12 mg, 60%)
as a colourless viscous oil, Rf 0.23 (15 : 85 EtOAc–petrol);
(Found MNaϩ 369.1535. C16H26O8 requires MNa, 369.1525);
νmax/cmϪ1 2957, 1746, 1605, 1372, 1224, 1113, 1048; δH (300
MHz; CDCl3) 5.28 (1H, dd, J 9.8 and 3.5, 4-H), 5.23 (1H, dd,
J 3.5 and 1.7, 5-H), 5.09 (1H, t, J 9.8, 3-H), 4.63 (1H, d, J 1.7,
6-H), 3.71 (td, J 9.8 and 1.9, 2-H), 2.14 (3H, s, OAc), 2.10 (6H,
s, OAc), 2.08 (3H, s, OAc), 1.72–1.20 (6H, m, butyl) and 0.91
(3H, t, J 7.3, CH3); m/z (ES) 369 (100%, MNaϩ).
(3H, t, J 7.1, CH3); δC (75 MHz; CDCl ) 166.1 (C᎐O), 164.2
᎐
3
(Ar), 132.4 (Ar), 122.2 (Ar), 114.2 (Ar), 102.2 (6-C), 74.4 (4-C),
70.8 (2-C), 67.6 (3-C), 56.0 (OCH3), 55.9 (OCH3), 31.2, 28.0,
24.8, 23.1 and 14.5 (CH3); m/z (ES) 487 (100%, MNaϩ).
(2R*,3R*,4S*,5R*,6S*)-2-Butyl-5-iodo-6-methoxy-4-hydroxy-
tetrahydropyran-3-yl 4-methoxybenzoate 21
By the same general method, the ester 11 (115 mg, 0.359 mmol)
gave a crude product which was pre-absorbed onto silica gel
and purified by flash chromatography (gradient elution: 8 : 92
15 : 85 EtOAc–petrol) to give the iodo alcohol 21 (87 mg,
52 %) as a colourless oil, Rf 0.35 (15 : 85 EtOAc–petrol); (Found
MNaϩ 487.0594. C18H25IO6 requires MNa, 487.0594); νmax
/
(2R*,3S*,4R*,5S*,6S*)-2-Butyl-4,5-epoxy-6-methoxytetra-
hydropyran-3-yl 4-methoxybenzoate 27b and (2R*,3S*,4R*,5S*,
6R*)-2-butyl-4,5-epoxy-6-methoxytetrahydropyran-3-yl
4-methoxybenzoate 27a
cmϪ1 3473 (O–H), 2955, 2871, 2838, 1713, 1606, 1511, 1463,
1258, 1169, 1122, 1029; δH (300 MHz; CDCl3) 7.97 (2H, d, J 8.9,
Ar), 6.85 (2H, d, J 8.9, Ar), 5.34 (1H, d, J 3.0, 3-H), 4.85 (1H, d,
J 3.0, 6-H), 4.25 (1H, dd, J 11.2 and 3.0, 5-H), 4.18 (1H, dt,
J 11.2 and 3.0, 4-H), 3.93 (1H, dd, 8.5 and 3.2, 2-H), 3.80 (3H, s,
OCH3), 3.37 (3H, s, OCH3), 2.50 (1H, d, J 3.0, OH), 1.60–1.20
(6H, m, butyl) and 0.79 (3H, t, J 7.2, CH3); δC (75 MHz; CDCl3)
Hydrogen peroxide (500 µl, 30% aqueous solution) was added
dropwise to a stirred suspension of the ester 9 (200 mg,
0.625 mmol, 70 : 30 mixture of anomers), benzonitrile (420 µl)
and sodium bicarbonate (170 mg) in methanol (1.5 ml) at 0 ЊC.
The suspension was allowed to warm to room temperature and
stirred for a further 3 days before dilution with brine (5 ml) and
extraction with ethyl acetate (4 × 5 ml). The combined organic
extracts were dried (MgSO4) and the solvent evaporated under
reduced pressure. The crude residue was pre-absorbed onto
silica gel and purified by flash column chromatography, eluting
with 15 : 85 EtOAc–petrol to give the epoxide 27b (141 mg,
67%) as a colourless crystalline solid, m.p. 112–113 ЊC, Rf 0.25
(15 : 85 EtOAc–petrol); (Found MNaϩ 359.1488. C18H24O6
166.9 (C᎐O), 164.2 (Ar), 132.5 (Ar), 122.1 (Ar), 114.1 (Ar),
᎐
101.1 (6-C), 73.1 (3-C), 70.4 (4-C), 69.8 (2-C), 56.4 (OCH3),
55.9 (OCH3), 32.8 (5-C), 30.7, 28.2, 22.9 and 14.6); m/z (ES) 487
(100%, MNaϩ).
(2R*,3R*,4S*,5R*,6S*)-3,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-4-yl acetate 15d
The iodo alcohols 17 and 18 (15 mg, 32.3 µmol, 17 : 18 81 : 19)
were refluxed for 3 days under N2 in aqueous potassium
hydroxide solution (3 ml of a 0.3 M solution). The solvent was
removed under reduced pressure and the crude product was
dissolved in acetic anhydride–pyridine (3 : 1, 3 ml) and stirred at
room temperature for 4 h. The solvent was again removed
under reduced pressure. Analysis of the crude reaction mixture
by 300 MHz 1H NMR spectroscopy revealed a 75 : 25 mixture
requires MNa, 359.1471); νmax/cmϪ1 2954, 2859, 1716 (C᎐O),
᎐
1608, 1255, 1167, 1098, 769; δH (300 MHz; CDCl3) 8.10 (2H, d,
J 9.0, Ar), 6.92 (2H, d, J 9.0, Ar), 5.10 (1H, dd, J 3.5 and 4.8,
5-H), 4.74 (1H, s, 2-H), 3.87 (3H, s, OCH3), 3.73 (1H, dd, J 4.8
and 3.9, 6-H), 3.61 (3H, s, OCH3), 3.54 (1H, m, 4-H), 3.28 (1H,
d, J 3.9, 1-H), 2.0–1.2 (6H, m, butyl) and 0.87 (3H, t, J 7.1,
1452
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454

View Article Online
CH3); δC (75 MHz; CDCl3) 166.6 (Ar), 164.0 (Ar), 132.6 (Ar),
114.0 (Ar), 99.6 (2-C), 76.2 (4-C), 66.3 (5-C), 57.3 (OCH3), 55.9
(OCH3), 52.0 (6-C), 51.4 (1-C), 29.2, 28.2, 22.8 and 14.4 (CH3);
m/z (ES) 359 (100% MNaϩ).
Also obtained was the epoxide 27a (56.9 mg, 27%) as a
colourless oil, Rf 0.52 (15 : 85 EtOAc–petrol); (Found MNaϩ
359.1488. C18H24O6 requires MNa, 359.1471); νmax/cmϪ1 2955,
(1H, dd, J 8.8 and 4.0, 3-H), 4.89 (1H, dd, J 4.0 and 2.0, 5-H),
4.51 (1H, d, J 2.0, 6-H), 3.95 (1H, td, J 8.8 and 3.2, 2-H), 3.33
(3H, s, OCH3), 2.05 (3H, s, OAc), 2.03 (3H, s, OAc), 1.98 (3H,
s, OAc), 1.6–1.1 (6H, m, butyl) and 0.84 (3H, t, J 7.1, CH3);
δC (125 MHz; CDCl3) 98.8 (6-C), 70.1, 69.3, 67.9, 67.2, 56.0
(OCH3), 31.0 (OAc), 21.3 (OAc), 21.3 (OAc), 30.1, 27.8, 23.0
and 14.4 (CH3); m/z (ES) 369 (100%, MNaϩ).
2872, 1717 (C᎐O), 1606, 1512, 1258, 1168, 1082, 1024; δ (300
᎐
H
MHz; CDCl3) 8.02 (2H, d, J 9.0, Ar), 6.95 (2H, d, J 9.0, Ar),
4.93 (1H, s, 2-H), 4.89 (1H, d, J 9.1, 5-H), 3.88 (3H, s, OCH3),
3.76 (1H, td, J 9.1 and 2.4, 4-H), 3.51 (3H, s, OCH3), 3.31 (1H,
d, J 3.5, 6-H), 3.11 (1H, d, J 3.5, 1-H), 2.0–1.2 (6H, m, butyl)
and 0.88 (3H, t, J 7.3, CH3); δC (75 MHz; CDCl3) 165.5
(aryl), 164.1 (aryl), 132.3 (aryl), 114.2 (aryl), 96.5 (2-C), 67.6
(5-C), 66.6 (4-C), 56.2 (OCH3), 55.9 (OCH3), 54.2 (6-C), 49.8
(1-C), 32.4, 27.8, 22.9 and 14.4 (CH3); m/z (ES) 359 (100%
M ϩ Naϩ).
Hydrolysis of the epoxide 28
The epoxide 28 (18.7 mg, 55.6 µmol) was refluxed for 3 days
under N2 in aqueous potassium hydroxide solution (2 ml of a
0.3 M solution). The solvent was removed under reduced pres-
sure and the crude product was dissolved in acetic anhydride–
pyridine mixture (3 : 1, 3 ml) and stirred at room temperature
for 4 h. The solvent was again removed under reduced pressure
and the crude residue was pre-absorbed onto silica gel and
purified by flash chromatography, eluting with 15 : 85 EtOAc–
petrol to give the triacetate 15b (11.0 mg, 57%), as a colourless
oil, Rf 0.26 (15 : 85 EtOAc–petrol); (Found : MNa 369.1517.
C16H26O8 requires MNa, 369.1525); νmax/cmϪ1 2957, 1750, 1372,
1250, 1224, 1045; δH (500 MHz; CDCl3) 5.20 (1H, td, J 4.1 and
4JHH 0.7, 4-H), 5.16 (1H, t, J 4.1, 5-H), 4.92 (1H, dd, J 4.1 and
2.1, 3-H), 4.81 (1H, d, J 4.1, 6-H), 4.11 (1H, ddd, J 8.8, 4.1 and
2.1, 2-H), 2.15 (3H, s, OAc), 2.14 (3H, s, OAc), 2.08 (3H, s,
OAc), 1.55–1.25 (6H, m, butyl) and 0.91 (3H, t, J 7.3, CH3);
(2R*,3R*,4S*,5R*,6S*)-2-Butyl-4,5-epoxy-6-methoxytetra-
hydropyran-3-yl 4-methoxybenzoate 28 and (2R*,3R*,4R*,5S*,
6S*)-2-butyl-4,5-epoxy-6-methoxytetrahydropyran-3-yl
4-methoxybenzoate 29
By the same general method, the ester 11 (116 mg, 0.363 mmol,)
gave a crude product which was pre-absorbed onto silica gel
and purified by flash column chromatography, eluting with
15 : 85 EtOAc–petrol to give a mixture of the epoxides 28 and
29 (108 mg, 89 %, 28 : 29 70 : 30) Separation by preparative
δ (125 MHz; CDCl ) 170.2 (C᎐O), 169.9 (C᎐O), 169.8 (C᎐O),
᎐
᎐
᎐
C
3
97.1 (6-C), 70.5, 67.0, 66.4, 65.4, 55.8, 29.6, 27.9, 22.6, 21.0,
20.9, 20.8 and 14.0; m/z (ES) 369 (100%, MNaϩ).
Also obtained were the triacetates 15f (2.9 mg, 15%) and 15d
(1.7 mg, 9%), spectroscopically identical to those obtained
previously.
HPLC (gradient elution: 100 : 0
94 : 6 hexane–isopropyl
alcohol over 30 min) gave the epoxide 28 (71 mg, 59%) as a
colourless oil, Rf 0.32 (15 : 85 EtOAc–petrol); retention time
25.1 min; (Found MNaϩ 359.1479. C18H24O6 requires MNa,
359.1471); νmax/cmϪ1 2956, 1713, 1606, 1511, 1259, 1168, 1101,
1072; δH (300 MHz; CDCl3) 8.06 (2H, d, J 8.9, Ar), 6.94 (2H, d,
J 8.9, Ar), 5.32 (1H, t, J 1.7, 3-H), 5.05 (1H, d, J 3.2, 6-H), 3.98
(1H, ddd, J 9.1, 2.3 and 1.7, 2-H), 3.88 (3H, s, OCH3), 3.51 (3H,
s, OCH3), 3.49 (1H, dd, J 3.8 and 1.7, 4-H), 3.44 (1H, dd, J 3.8
and 3.2, 5-H), 1.70–1.20 (6H, m, butyl) and 0.86 (3H, t, J 7.3,
CH3); δC (75 MHz; CDCl3) 164.2 (Ar), 132.4 (Ar), 114.2 (Ar),
95.3 (6-C), 67.8 (3-C), 66.7 (2-C), 56.0 (OCH3), 55.9 (OCH3),
51.7 (4-C), 50.9 (5-H), 30.4, 28.2, 22.8 and 14.4; m/z (ES) 359
(100% M ϩ Naϩ).
(2R*,3S*,4R*,5S*,6S*)-4,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-3-yl acetate 15f
By the same general method, the epoxide 29 (12.7 mg, 37.8
µmol) gave a crude product which was pre-absorbed onto silica
gel and purified by flash chromatography, eluting with 15 : 85
EtOAc–petrol to give the triacetate 15f (9.0 mg, 69%), spectro-
scopically identical to that obtained previously.
Also obtained was the epoxide 29 (30 mg, 25%) as a colour-
less oil, Rf 0.32 (15 : 85 EtOAc–petrol); retention time 23.3 min;
(Found MNaϩ 359.1472. C18H24O6 requires MNa, 359.1471);
νmax/cmϪ1 2956, 1713, 1606, 1511, 1259, 1168, 1101, 1072;
δH (300 MHz; CDCl3) 8.07 (2H, d, J 9.0, Ar), 6.93 (2H, d, J 9.0,
Ar), 5.08 (1H, dd, J 5.3 and 3.2, 3-H), 4.98 (1H, d, J 0.4, 6-H),
3.91 (1H, dt, J 8.6 and 3.2, 2-H), 3.87 (3H, s, OCH3), 3.75 (1H,
dd, J 3.6 and 3.2, 4-H), 3.49 (3H, s, OCH3) 3.15 (1H, dd, J 3.6
and 0.4, 5-H), 1.80–1.20 (6H, m, butyl) and 0.88 (3H, t, J 7.3,
(2R*,3R*,4R*,5S*,6S*)-2-Butyl-5-iodo-6-methoxytetrahydro-
pyran-3,4-diyl di(4-methoxybenzoate) 23
The diol 17 (31 mg, 66.8 µmol) and triethylamine (17 µl,
0.120 mmol, 1.8 equiv.) were stirred under N2 in dichloro-
methane (1.1 ml) at room temperature and p-anisoyl chloride
(11 µl, 80 µmol, 1.2 mol equiv.) was added via syringe. The
resulting solution was treated with 4-(dimethylamino)pyridine
(2 mg, 16 µmol) and stirred for 6 h. The solution was quenched
with saturated aqueous sodium bicarbonate solution (5 ml) and
diluted with dichloromethane (20 ml). The organic layer was
separated and washed with a further portion of saturated
sodium bicarbonate solution (2 × 5 ml) followed by a washing
with brine (5 ml). The organic layer was dried (MgSO4) and the
solvent removed under reduced pressure. The crude residue was
pre-absorbed onto silica gel and purified by flash chromato-
graphy, eluting with 1 : 9 EtOAc–petrol to give diester 23 (36.8
mg, 92%) as a colourless oil, Rf 0.42 (15 : 85 EtOAc–petrol);
(Found MNaϩ 621.0961. C16H26O8 requires MNa, 621.0946);
CH ); δ (75 MHz; CDCl ) 166.5 (C᎐O), 164.0 (Ar), 132.4 (Ar),
᎐
3
C
3
122.4 (Ar), 114.1 (Ar), 96.6 (6-C), 67.3 (3-C), 66.7 (2-C), 56.4
(OCH3), 55.9 (OCH3), 50.7 (4-C), 50.7 (5-C), 29.6, 28.3, 22.9
and 14.4; m/z (ES) 359 (100% M ϩ Naϩ).
(2R*,3R*,4R*,5S*,6S*)-4,5-Diacetoxy-2-butyl-6-methoxytetra-
hydropyran-3-yl acetate 15e
The epoxide 27b (12.4 mg, 36.9 µmol) was refluxed for 3 days
under N2 in aqueous KOH (20 mg in 3 ml of water). The solvent
was removed under reduced pressure and the crude product was
dissolved in acetic anhydride–pyridine (3 : 1, 3 ml) and stirred at
room temperature for 4 h. The solvent was again removed
under reduced pressure and the crude residue pre-absorbed
onto silica gel and purified by flash chromatography, eluting
with 15 : 85 EtOAc–petrol to give the triacetate 15e (10.7 mg,
84%) as a colourless viscous syrup, Rf 0.23 (15 : 85 EtOAc–
petrol); (Found MNaϩ 369.1529. C16H26O8 requires MNa,
369.1529); νmax/cmϪ1 2956, 2924, 2856, 1748, 1263, 1371, 1249,
1223, 1050; δH (500 MHz; CDCl3) 5.13 (1H, t, J 4.0, 4-H), 4.93
νmax/cmϪ1 2961, 2871, 2840, 1720 (C᎐O), 1606, 1512, 1260, 1169,
᎐
1095, 1031; δH (300 MHz; CDCl3) 7.97 (2H, d, J 8.9, Ar), 7.89
(2H, d, J 8.9, Ar), 6.91 (2H, d, J 8.9, Ar), 6.86 (2H, d, J 8.9, Ar),
5.64 (1H, dd, J 5.9 and 3.3, 4-H), 5.60 (1H, dd, J 7.1 and 3.3,
3-H), 5.02 (1H, d, J 3.6, 6-H), 4.42 (1H, dd, J 5.9 and 3.6, 5-H),
3.86 (3H, s, OCH3), 3.84 (3H,s, OCH3), 3.49 (3H, s, OCH3),
4.30 (1H, td, J 7.1 and 2.1, 2-H), 1.8–1.2 (6H, m, butyl) and
0.91 (3H, t, J 7.1, CH3); δC (75 MHz; CDCl ) 165.5 (C᎐O),
᎐
3
165.4 (C᎐O), 164.0 (Ar), 132.4 (Ar), 132.0 (Ar), 122.4 (Ar),
᎐
122.3 (Ar), 114.1 (Ar), 114.0 (Ar), 102.2 (6-C), 72.0 (3-C), 70.1
J. Chem. Soc., Perkin Trans. 1, 2002, 1444–1454
1453

View Article Online
9 A. B. Smith III, Q. Lin, G. R. Pettit, J.-M. Chapuis and J. M.
Schmidt, Bioorg. Med. Chem. Lett., 1998, 8, 567.
10 T. Kametani, M. Tsubuki, Y. Tatsuzaki and T. Honda, J. Chem. Soc.,
Perkin Trans. 1, 1990, 639.
(4-C), 69.4 (2-C), 56.5 (OCH3), 55.9 (OCH3), 30.8 (5-C), 27.9,
25.3, 23.0 and 14.5; m/z (ES) 621 (100%, MNaϩ).
11 The enantiomeric excess of 7 was determined by conversion of its
derivative 13a into the corresponding Mosher’s diester: J. A. Dale,
D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34, 2543.
12 J.-L. Luche, J. Am. Chem. Soc., 1978, 100, 2226.
13 S. F. Martin and P. W. Zinke, J. Am. Chem. Soc., 1989, 111, 2311.
14 J. K. Cha, W. J. Christ and Y. Kishi, Tetrahedron, 1984, 40, 2247.
15 T. J. Donohoe, P. R. Moore, M. J. Waring and N. J. Newcombe,
Tetrahedron Lett., 1997, 38, 5027.
Acknowledgements
We thank EPSRC and Aventis for support under the CASE
award scheme for new academic appointees, the Royal Society
for a research grant, and Pfizer and AstraZeneca for strategic
research funding.
16 M. Harding and A. Nelson, Chem. Commun., 2001, 695.
17 M. H. Haukaas and G. A. O’Doherty, Org. Lett., 2001, 3, 3899.
18 J. Ramza and A. Zamojski, Tetrahedron, 1992, 48, 6123.
19 (a) C. Prévost, C. R. Acad. Sci., 1933, 196, 1129; (b) C. Prévost,
C. R. Acad. Sci., 1933, 197, 1661.
20 The dioxonium intermediates in similar reactions can be trapped
in situ by water to give cis hydroxy esters: R. B. Woodward and
F. B. Brutcher Jr., J. Am. Chem. Soc., 1958, 80, 209.
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