Enantioselective synthesis of the dioxabicyclo[3.2.1]octane core of the zaragozic acids via intramolecular Wacker-type cyclisation reactions.

Article abstract of DOI:10.1039/b406280a

Wacker-type cyclisation reactions provide an effective entry into the dioxabicyclo[3.2.1]octane core of the zaragozic acid analogues.

Full text of DOI:10.1039/b406280a

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A R T I C L E
Enantioselective synthesis of the dioxabicyclo[3.2.1]octane core
of the zaragozic acids via intramolecular Wacker-type cyclisation
reactions
Patrick Perlmutter,* Walailak Selajerern and Filisaty Vounatsos
School of Chemistry, Monash University, PO Box 23, 3800, Australia.
E-mail: Patrick.Perlmutter@sci.monash.edu.au; Fax: (+61 3) 9905 4597; Tel: (+61 3) 9905 4522
Received 26th April 2004, Accepted 3rd June 2004
First published as an Advance Article on the web 13th July 2004
Wacker-type cyclisation reactions provide an effective entry into the dioxabicyclo[3.2.1]octane core of the zaragozic
acid analogues.
Introduction
The zaragozic acids (also referred to as squalestatins) are a class
of fungal metabolites that exhibit picomolar inhibition of the
enzyme squalene synthase (EC 2.5.1.21) and hence, of cholesterol
biosynthesis.1,2 The highly functionalised 2,8-dioxabicyclo[3.2.1]-
octane core common to all the zaragozic acids (e.g. zaragozic acid
C, Fig. 1) presents the most significant synthetic challenge of these
natural products.3
Aldol addition of the (Z)-diethylboron enolate4 of 3a to alde-
hyde 4a proceeded with essentially complete diastereoselectivity
(Scheme 1). Subjection of compound 6 to a Wacker cyclisation5
reaction, involving its treatment with a mixture of PdCl2, CuCl2, O2
at 60 °C, resulted in the smooth formation of 7 incorporating the
dioxabicyclo[3.2.1]octane framework. A single X-ray crystal struc-
ture of 7 provided unambiguous confirmation of its structural and
stereochemical assignment.3n Whilst deprotection of the silylated
alcohol 5 was initially effected with HCl–THF (1:10)6 prior to
cyclisation, the need for such a conversion was obviated since the
direct ring closure of mono-silyl ether 5 proceeded as efficiently as
that for 6.
Fig. 1 Zaragozic acid C.
To date these natural products have not been successfully
developed into a useful therapeutic. One reason for this is the
lack of rapid means of assembling the unusual bicyclic core. In
their review of this class of natural products Nadin and Nicolaou1a
highlighted those features identified through SAR studies which
are critical for biological activity. These features included the C5
carboxylic acid as well as the hydrophobic chain attached to C1
and C6. Significantly the C6 oxygen was found to be unnecessary
for activity. Taking this information into account we selected 2 as
a plausible target (we have reported3o a similar approach to C5-
substituted derivatives). Hence in the first part of this report we
provide full details of an earlier communication on the construction
and intramolecular Wacker-type cyclisation reactions of precursors
of type 5.
Scheme 1 Reagents and conditions: (i) (a) Et2BOTf, Et2(i-Pr)N, CH2Cl2,
0 °C, 20 min then −78 °C; (b) 4a, −78 °C, 3 h, 95%; (ii) conc. HCl–THF
(1:10), rt, 2 h, 74%; (iii) PdCl2 (5 mol%), CuCl2, DME, O2, 65 °C, 12 h,
60%.
With these results in hand we coupled 3a to aldehydes 4a–d and
3b to 4a (see Table 1). All these aldol reactions proceeded with
essentially complete diastereoselectivity.7 Each of the adducts was
then subjected to the ring closing conditions described above. In each
case the bicyclic product was produced in good yield. Significantly,
this process was successful with secondary as well as primary silyl
ethers (entries 3 and 4) allowing the introduction of substituents at
C3 and C4. Most important, ring closure of the internal alkene 14 was
also successful (entry 5) although in relatively modest yields. This
last example, which is not optimised at this stage, provides access to
2,8-dioxabicyclo[3.2.1]octanes bearing functionalised substituents
The second part of this paper describes the application of an
intramolecular Wacker-type cyclisation reaction to a carbohydrate-
derived precursor resulting in the synthesis of a 6,7-dioxygenated
dioxabicyclo[3.2.1]octane.
Results and discussion
Initial efforts in this laboratory were directed towards the synthesis
of precursors via asymmetric aldol coupling of 3a with 4a–d and
3b to 4a.
2 2 2 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1
Entry
Reactants
Aldol adduct
Yield (%)
95
Ring closed Product
Yield (%)
60
1
2
3a + 4a
3a + 4b
3a + 4c
94
95
60
65
3
4
5
3a + 4d
95
71
50
39
3b + 4a
at C1, and is of great value in the design and synthesis of zaragozic
acid and its analogues. To the best of our knowledge this is also the
first example of an intramolecular Wacker oxidation of an internal
alkene.8 Reductive removal of the auxiliary with LiAlH4 (Scheme 2),
provided its corresponding primary alcohol in excellent yield.
Treatment of ester 22 with DIBAL-H in CH2Cl2 at −78 °C
resulted in the smooth formation of compound 23.15 Subsequently,
this pivotal diol was subjected to a Wacker reaction5 (using PdCl2,
CuCl2, O2 at 60 °C as before) furnishing the corresponding cyclisa-
tion product 24 in excellent yield (89%).15
Conclusions
The successful application of intramolecular Wacker-type
cyclisation reactions to a variety of alkenediols offers a powerful
technologyforthepreparationoffunctionalizeddioxabicyclo[3.2.1]-
octanes of relevance to the zaragozic acids.
Scheme 2 Reagents and conditions: (i) LiAlH4, Et2O, 0 °C, 45 min, 87%.
Experimental
Whilst the method described above delivers the bicyclic core
efficiently and rapidly we were interested in preparing analogues
which contained the C6 and C7 hydroxy groups with correct
absolute stereochemistry. In order to achieve this the synthesis
of a more highly functionalised precursor, 23, was developed
commencing with 17, available in four steps from D-xylose.9 The
primary alcohol of 17 was selectively protected as its TBS-ether
under standard silylating conditions. Hydrolysis of 18 using HgCl2,
HgO in acetone–water (10:1) at 40 °C resulted in the formation of
19 which existed predominantly in the lactol form shown.10 Wittig
methylenation next gave compound 20 in 80% yield.11 -Hydroxy
ester 22 was obtained as a 3:1 mixture12 in 96% yield over two
steps via oxidation of the secondary alcohol with Dess–Martin
periodinane,13 followed by a zinc mediated Reformatsky reaction.14
The stereochemistry of the newly formed quaternary centre of the
major product was deduced by NOESY experiments on 24. A 5.8%
enhancement was observed as indicated in Scheme 3.
Melting points were conducted on a Kofler hotstage and are
uncorrected. Elemental microanalyses were performed by
the Australian Microanalytical Service, National Analytical
Laboratories, Melbourne or the University of Otago, Dunedin, New
Zealand. Optical rotations were recorded on a Perkin Elmer Model
141 Polarimeter and are reported as follows: []D, concentration,
c (g/100 mL) and solvent. Infrared (IR) spectra were recorded on
a Perkin-Elmer 1600 Series Fourier Transform spectrophotometer
1
−
(cm scale) and refer to thin films of liquids (neat) or paraffin (Nujol)
mulls of solids between NaCl plates. High-resolution hydrogen-1
nuclear magnetic resonance (1H NMR) spectra were recorded at
200 MHz on a Bruker AC-200 spectrometer; 300 MHz on a Varian
Mercury, Bruker AM-300 spectrometer or DPX-300 spectrometer;
1
400 MHz on a Bruker Avance DRX 400 spectrometer. The H
NMR spectral data refer to deuteriochloroform solutions (CDCl3)
using tetramethylsilane (TMS) as internal reference ( 0.00 ppm),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8
2 2 2 1

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containing UV254 fluorescent indicator and inspected under
ultraviolet light, stained with iodine or sprayed with ammonium
molybdate/cerium sulfate solution. Preparative TLC was performed
on glass plates (20 × 20 cm), coated with 0.5 mm of silica gel
(Merck 70–230 mesh, No. 7747), which were activated at 100 °C for
at least 1 h before use. Flash chromatography was performed using
Kieselgel 60 silica gel (Merck 230–400 mesh, No. 9385). Hexane
refers to the hydrocarbon fraction boiling between 40–60 °C.
Tetrahydrofuran (THF) and diethyl ether (ether) were distilled from
sodium metal/benzophenone ketyl under nitrogen atmosphere prior
to use. Toluene and dichloromethane were distilled from calcium
hydride under nitrogen atmosphere prior to use. Methanol was
distilled from magnesium methoxide under a nitrogen atmosphere
prior to use. N,N-Dimethylformamide (DMF) was of analytical
purity and stored over 4 Å molecular sieves. Dimethoxyethane
(DME) was distilled from calcium hydride and stored over 4 Å
molecular sieves. Triethylamine was distilled from and stored
over potassium hydroxide pellets. Trifluoromethanesulfonic acid
(triflic acid) was distilled from phosphorus pentoxide (P2O5) under
a nitrogen atmosphere prior to use.
Preparation of aldehydes 4a–4d
General procedure for silylation of 1,n-diols. tert-Butyl-
dimethylsilyl chloride (1 eq.) was added in portions to a cold
(−25 °C) solution of diol (2.4 eq.) in dry DMF (0.25 mL/1 mmol
of diol). After 1 h, the reaction mixture was warmed to 0 °C and
stirred at this temperature for 4 h. The reaction mixture was diluted
with n-pentane, washed with water (6×), dried (MgSO4), filtered
and the solvent removed in vacuo. Flash chromatography (ethyl
acetate–hexane, 1:9) provided the silyloxy alcohols.
Scheme 3 Reagents and conditions: (i) TBSCl, DMAP, Im, DMF, rt, 5 h,
95%; (ii) HgCl2, HgO, acetone–water (10:1), 40 °C, 3 h; (iii) Ph3PCH2,
THF, HMPA, 0 °C to rt, 4 h, 80% over two steps; (iv) Dess–Martin, CH2Cl2,
rt, 2.5 h, 91%; (v) -methyl bromoacetate, Zn, THF, 60 °C, 30 min, 96%;
(vi) DIBAL, CH2Cl2, −78 to 0 °C, 2 h, 79%; (vii) PdCl2 (5 mol%), CuCl2,
DME, O2, 50 °C, 3 h, 89%.
General procedure for DIBAL-H reduction of esters. Astirred
solution of ester (1 eq.) in dry toluene (3 mL/1 mmol of the ester)
was cooled to −78 °C under a nitrogen atmosphere, DIBAL-H in
toluene solution was added dropwise and the reaction mixture was
stirred at this temperature until TLC analysis showed no starting
material. Acetone was added dropwise to the mixture followed
by the rapid addition of water, the reaction mixture then warmed
to room temperature and salts were filtered off. The aldehyde
was extracted with diethyl ether, and the organic phase was dried
(MgSO4), filtered and the solvent removed in vacuo. Distillation
under reduced pressure or flash chromatography provided the
aldehyde.
unless otherwise stated. Each resonance was assigned according
to the following convention: chemical shift () measured in parts
per million (ppm) downfield from TMS, multiplicity, observed
coupling constant (J Hz), number of hydrogens, and assignment.
Multiplicities are denoted as s (singlet), d (doublet), t (triplet), q
(quartet), quin (quintet), m (multiplet) and br (broad). Carbon-13
nuclear magnetic resonance (13C NMR) spectra were recorded at
50 MHz on a Bruker AC-200 spectrometer; 75 MHz on a Bruker
APX-300 or Varian Mercury spectrometer; 100 MHz on a Bruker
Advance DRX 400 spectrometer and refer to deuteriochloroform
solutions with the central peak of the CDCl3 triplet (77.0 MHz)
used as the reference. The program of the spin-echo for 13C nuclei
coupling to proton (JMOD 13C NMR) was used for most samples in
order to determine the number of hydrogens attached. 13C chemical
shifts () are reported and assignments for identifiable carbons
are given where pronticity is defined as C = quaternary; CH =
methine; CH2 = methylene; CH3 = methyl; C or CH2 = quaternary
or methylene; CH or CH3 = methine or methyl. Mass spectrometry
(ESI) was performed using samples in MeOH on a Micromass
Platform QMS spectrometer. High-resolution mass spectra (HRMS)
for accurate mass determinations were recorded on a Bruker
BioApex 47e FTMS fitted with an Analytical electrospray source
using NaI for accurate mass calibration (accuracy ±3 ppm). Low-
resolution mass spectra were recorded on a VG micromass 70/70F
or a VG TRIO-1 mass spectrometer with an ion source temperature
of 200 °C and electron impact energy (70 eV). Chemical ionisation
mass spectra (CI) were obtained using methane as the reagent
gas. The principal ion peaks (m/z) are reported together with their
intensities (in parentheses) expressed as percentages of the base
peak (usually) greater than 10% and M+ denotes the molecular
ion. X-Ray crystallography was performed on a Nonius Kappa
CCD. Analytical thin layer chromatography (TLC) was performed
on Polygram Sil G/UV 254 plastic sheets coated with silica gel
General procedure for Swern oxidation of alcohols. Dimethyl
sulfoxide (2.2 eq.) was added to a solution of oxalyl chloride
(1.1 eq.) in dry dichloromethane (2 mL/1 mmol of oxalyl chloride)
at −70 °C under a nitrogen atmosphere and the reaction mixture was
stirred at this temperature for 30 min. A solution of silyloxy alcohol
(1 eq.) in dry dichloromethane (5 mL/1 mmol of alcohol) was added
dropwise and stirring was continued for a further 1 h. Triethylamine
(5 eq.) was then added, and the mixture was stirred for 10 min then
quenched with water. The organic layer was washed with saturated
aqueous NaCl, dried (MgSO4), filtered and the solvent removed in
vacuo to furnish the aldehyde.
General procedure for asymmetric Aldol reactions. Freshly
distilled trifluoromethanesulfonic acid (2 eq.) was added drop-
wise to triethylborane (1 M in hexane, 2 eq.) with strong stirring
under an atmosphere of nitrogen at room temperature for 30 min
(warmed to 40 °C for 30 min to effect homogeniety if necessary)
and the reaction was cooled to −5 °C. Acyl sultam (1 eq.) in dry
dichloromethane (4 mL/1 mmol of the acyl sultam) was added
dropwise and the reaction mixture was stirred at this tempera-
ture for 5 min. Diisopropylethylamine (1 M in dichloromethane,
2.2 eq.) was added dropwise followed by stirring at −3 °C to −5 °C
for 30 min. The reaction mixture was cooled to −78 °C and the
required aldehyde (2 eq.) in dry dichloromethane (3 mL/1 mmol
of aldehyde) was added dropwise followed by stirring at −78 °C
until TLC analysis indicated no starting material. The reaction was
2 2 2 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8

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quenched with aqueous phosphate buffer (pH 7, 1 eq.) and allowed
to warm to room temperature. The layers were partitioned and the
dichloromethane layer separated. Products were extracted from the
aqueous layer with dichloromethane (5×), the organic layers were
combined, washed with saturated aqueous ammonium chloride
solution, dried (MgSO4), filtered and concentrated in vacuo. The
crude product was subjected to flash chromatography to provide
the pure aldol adduct.
4-(Benzyloxy)-1-butanal. Using the general Swern oxidation
procedure described in general remarks, a solution of DMSO
(8.60 g, 7.8 mL, 110 mmol) in dry dichloromethane (100 mL) was
added to a stirred cold (−70 °C) solution of oxalyl chloride (6.98 g,
4.8 mL, 55 mmol) in dry dichloromethane (140 mL) followed by
the addition of a solution of the above alcohol (9.0 g, 50 mmol) in
dry dichloromethane (250 mL). The reaction mixture was stirred
at −78 °C for 2 h and work-up provided the title compound (8.8 g,
99%) as a yellow liquid. The aldehyde was used in the next step
without further purification: IR (neat): max 2945, 1958, 1869,
1818, 1725, 1477, 1256, 1100, 836, 774 cm ; H NMR (200 MHz,
CDCl3):  1.90–1.99 (2H, m), 2.55 (2H, dt, J 1.6 and 7.1 Hz), 3.51
(2H, t, J 6.1 Hz), 4.49 (2H, s), 7.27–7.37 (5H, m), 9.78 (1H, t, J
1.6 Hz); 13C NMR (50 MHz, CDCl3):  22.6, 40.9, 69.1, 72.9, 127.5,
127.6, 128.3, 128.4, 138.3, 202.1.
General procedure for Wacker reaction. A mixture of
PdCl2 (0.05 eq.) and anhydrous CuCl2 (0.236 eq.) in dry DME
(1 mL/1 mmol of CuCl2) was stirred and heated at 65 °C. Oxygen
was bubbled through the mixture, a solution of the cyclisation
precursor (1 eq.) in dry DME (4 mL/1 mmol of the cyclisation
precursor) was added dropwise. Oxygen bubbling was continued,
the reaction mixture stirred at 65 °C and judged to be complete
by TLC. The reaction mixture was cooled to room temperature,
diethyl ether added, the mixture filtered (sintered glass funnel), then
passed through a short column of neutral alumina and the solvent
concentrated in vacuo. The resulting yellow residue was purified by
preparative TLC or flash chromatography.
1
1
−
(3-Ethoxycarbonylprop-1-yl)triphenylphosphonium
bromide. A solution of ethyl 4-bromobutyrate (19.5 g, 0.1 mol)
and triphenylphosphine (26.2 g, 0.1 mol) in dry toluene (100 mL)
was stirred and heated under reflux for 24 h. After cooling the reac-
tion mixture to room temperature the insoluble white precipitate
was filtered off and washed with toluene (40 mL). The filtrate and
washings were combined and heated under reflux for a further 24 h
then filtered and washed. The second crop was combined with the
first and dried under reduced pressure (4 mmHg, 24 h) to give the
title compound (33 g, 72%) as a white powder: mp 172–174 °C; 1H
NMR (200 MHz, CDCl3):  1.23 (3H, t, J 7.1 Hz), 1.85–2.05 (2H,
m), 2.86 (2H, t, J 5.5 Hz), 3.93–4.08 (2H, m), 4.09 (2H, q, J 7.1 Hz),
7.65–7.95 (15H, m).
4-Pentenoyl chloride. Oxalyl chloride (0.9 mL, 10.8 mmol) was
added dropwise to 4-pentenoic acid (1.0 mL, 9.8 mmol) at 0 °C
and the reaction was warmed to room temperature and stirred for
3 h. The acid chloride was used without purification. 1H NMR and
IR spectra of the acid chloride were obtained to ensure complete
conversion: IR (neat): max 2983, 1798, 1643, 1409, 1132, 1042,
1
1
−
958m, 920, 724 cm ; H NMR (200 MHz, CDCl3):  2.40–2.48
(2H, m), 2.99 (2H, t, J 7.2 Hz), 5.05–5.16 (2H, m), 5.79 (1H, ddt, J
6.5, 10.2 and 16.8 Hz).
Ethyl (Z)-8-(benzyloxy)-4-octenoate. Sodium bis(trimethyl-
silyl)amide (1 M, 45 mL, 45 mmol) was added dropwise to a
suspension of the above phosphonium salt (20.57 g, 45 mmol) in
dry THF (18 mL) under nitrogen atmosphere at 0 °C. The result-
ing orange solution was stirred for 20 min and cooled to −78 °C.
A solution of freshly prepared 4-benzyloxy-1-butanal (5.31 g,
30 mmol) in dry THF (30 mL) was added dropwise and stirring
was continued for an additional 1.5 h. The reaction mixture was
warmed to 0 °C, quenched by addition of water (30 mL) and poured
into ethyl acetate–water (300/90 mL). The organic layer was sepa-
rated, dried (MgSO4), filtered and the filtrate concentrated in vacuo.
Flash chromatography (ethyl acetate–hexane, 1:9) afforded the title
compound (5.4 g, 65%) as a yellow oil: IR (Nujol): max 3448, 2351,
(2R)-N-(4-Pentenoyl)bornane-10,2-sultam 3a. n-Butyllithium
(2.14 M, 7.3 mL, 15.7 mmol) was added via a dropping funnel to
a cold (0 °C) solution of (2R)-N-(4-pentenoyl)bornane-10,2-sultam
(2.74 g, 12.7 mmol) in dry toluene (34 mL). The reaction mixture
was stirred for 2 h whilst warming to room temperature. Freshly
prepared 4-pentenoyl chloride in dry toluene (10 mL) was added
dropwise to the reaction mixture and the reaction mixture stirred at
room temperature overnight. The reaction mixture was quenched
with saturated NH4Cl solution (27 mL). The toluene layer was sepa-
rated and the aqueous layer extracted with diethyl ether (3 × 10 mL).
The organic layers were combined, dried (MgSO4), filtered and the
filtrate concentrated in vacuo to give the crude product as a yellow
solid. Dry column chromatography (diethyl ether–hexane) followed
by recrystallisation (hexane) provided the title compound as colour-
less crystals (2.50 g, 66%): IR (Nujol): max 2968, 2853, 2341, 1694,
1
1
−
2342, 1950, 1868, 1715, 1734, 1451, 1370, 1161, 736 cm ; H
NMR (200 MHz, CDCl3):  1.25 (3H, t, J 7.0 Hz), 1.61–1.72 (2H,
m), 2.10–2.19 (2H, m), 2.30–2.39 (4H, m), 3.42–3.49 (2H, m), 4.12
(2H, q, J 7.0 Hz), 4.50 (2H, s), 5.33–5.45 (2H, m), 7.26–7.39 (5H,
m); 13C NMR (50 MHz, CDCl3):  14.3, 22.8, 23.9, 29.6, 34.4, 60.3,
69.7, 72.9, 127.3, 127.5, 127.9, 128.2, 130.4, 138.4, 172.9. HRMS:
Calc. C17H24O3: [M + Na]+ m/z 299.1623. Found: 299.1620.
1
−
1
1121, 1135, 806, 721 cm ; H NMR (200 MHz, CDCl3):  0.85 (3H,
s), 1.02 (3H, s), 1.12–1.42 (2H, m), 1.73–1.85 (3H, m), 1.86–2.02
(2H, m), 2.23–2.49 (2H, m), 2.55–2.77 (2H, m), 3.31 and 3.41 (2H,
AB quartet, J 13.9 Hz), 3.73 (1H, dd, J 5.5 and 7.3 Hz), 4.82–4.98
(2H, m), 5.70 (1H, ddt, J 6.4, 10.3, 16.9 Hz); 13C NMR (50 MHz,
CDCl3):  19.5, 20.5, 26.1, 27.9, 32.4, 34.1, 38.1, 44.3, 47.4, 48.1,
52.5, 64.8, 115.3, 136.2, 170.7.
(4Z)-8-(Benzyloxy)-4-octenoic acid. A solution of the above
ester (2.76 g, 10 mmol) in THF (20 mL) was added to a solution
of NaOH (1 M, 40 mL). The reaction mixture was stirred at room
temperature overnight and extracted with diethyl ether (2 × 20 mL).
The aqueous layer was acidified with aqueous HCl (5 M) to pH 3
and extracted with dichloromethane (3 × 20 mL), dried (MgSO4),
filtered and the filtrate concentrated under reduced pressure to give
the title compound (2.4 g, 97%) as a colourless oil: IR (Nujol): max
3350, 1928, 1949, 1873, 1713, 1708, 1496, 1453, 1364, 1208w,
4-(Benzyloxy)-1-butanol. 1,4-Butanediol (8.11 g, 90 mmol) was
added dropwise to NaH (2.16 g, 90 mmol) in dry DMF (56 mL)
at 0 °C under a nitrogen atmosphere. Benzyl chloride (12.32 g,
97 mmol) was then added and the stirred reaction mixture allowed to
warm to room temperature. The reaction mixture was stirred at room
temperature for a further 2 days then poured into ethyl acetate–water
(200/200 mL). The organic layer was separated and the aqueous layer
extracted with ethyl acetate (100 mL), dried (MgSO4), filtered and
the solvent removed under reduced pressure. The resulting yellow
oil was subjected to flash chromatography (ethyl acetate–hexane,
1:3) providing the title compound (12.2 g, 75%) as a yellow oil: IR
(neat): max 3418, 2865, 1953, 1873, 1812, 1719, 1667, 1455, 1362,
1311, 1098, 958, 737, 699, 612 cm−1; 1H NMR (200 MHz, CDCl3): 
1.65–1.73 (4H, m), 2.48 (1H, br s), 3.52 (2H, t, J 5.9 Hz), 3.63 (2H, t,
J 6.0 Hz), 4.52 (2H, s, 2H), 7.27–7.53 (5H, m); 13C NMR (200 MHz,
CDCl3):  26.6, 30.0, 62.6, 70.3, 72.9, 127.6, 127.7, 128.4, 138.1.
1
1103, 736, 698 cm−1; H NMR (200 MHz, CDCl3):  1.63–1.70
(2H, m), 2.15 (2H, q, J 6.8 Hz), 2.34–2.41 (4H, m), 3.47 (2H, t, J
6.5 Hz), 4.50 (2H, s), 5.32–5.48 (2H, m), 7.27–7.38 (5H, m); 13C
NMR (50 MHz, CDCl3):  22.5, 23.9, 29.6, 33.9, 69.6, 72.9, 127.4,
127.6, 127.9, 128.3, 128.4, 138.5, 178.6. HRMS: Calc. C15H20O3:
[M + Na]+ m/z 271.1310. Found: 271.1303.
(4Z)-8-(Benzyloxy)-4-octenoyl chloride. Oxalyl chloride
(0.86 mL, 9.9 mmol) was added dropwise to the above acid
(2.23 g, 9.0 mmol) at 0 °C and the reaction was warmed to room
temperature and stirred at this temperature for a further 3 h. The
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8
2 2 2 3

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1
acid chloride was not isolated and used immediately. H NMR
chromatography (dichloromethane–hexane, 1:1) provided the
title compound (3.5 g, 83%) as a colourless oil. Specific rotation:
[]D −23.6 (c 4.0, MeOH); IR (neat): max 2954, 2771, 1747, 1471,
1435, 1389, 1362, 1257, 1198, 1096, 1025, 1006, 990, 939, 837,
and IR spectra of acid chloride were obtained to ensure complete
conversion: IR (Nujol): max 2936, 2857, 1794, 1453, 1401, 1364,
1102, 957, 735, 697 cm−1; 1H NMR (200 MHz, CDCl3):  1.63–1.71
(2H, m), 2.11–2.18 (2H, m), 2.20–2.26 (2H, m), 2.89–2.94 (2H, m),
3.46 (2H, t, J 6.5 Hz), 4.50 (2H, s), 5.31 (1H, m), 5.44–5.62 (1H,
m), 7.27–7.40 (5H, m).
1
777, 665 cm−1; H NMR (200 MHz, CDCl3):  0.02 (6H, s), 0.85
(9H, s), 1.12 (3H, d, J 7.0 Hz), 2.63 (1H, ddq, J 6.0, 6.9 and 7.0 Hz),
3.61 (1H, dd, J 6.0 and 9.7 Hz), 3.65 (3H, s), 3.76 (1H, dd, J 6.9
and 9.7 Hz); 13C NMR (50 MHz, CDCl3):  −5.4, 13.5, 18.3, 25.8,
42.6, 51.6, 65.3, 175.5. All spectral data compare favourably with
the literature.16
(2R)-N-[(4Z)-8-Benzyloxyocten-1-oyl)bornane-10,2-sultam
3b. n-Butyllithium (2.5 M solution in hexane, 5.76 mL, 14.4 mmol)
was added via a dropping funnel to a cooled (0 °C) solution of the
sultam (2.52 g, 11.7 mmol) in dry toluene (30 mL). The reaction
mixture was allowed to warm to room temperature and stirred at
this temperature for 2 h. A solution of the above acid chloride in dry
toluene (9 mL) was added dropwise, the reaction mixture allowed
to warm to room temperature and stirring was continued overnight.
Saturated NH4Cl solution (25 mL) was added and the toluene layer
was separated. The aqueous layer was extracted with diethyl ether
(3 × 8 mL) and the organic layers were combined, dried (MgSO4),
filtered and the filtrate concentrated in vacuo to afford the crude acyl
sultam as a brown residue. Flash chromatography (ethyl acetate–
hexane, 1:4) provided the title compound (3.18 g, 79%) as a yellow
oil: IR (neat): max 2958, 2360, 2341, 1952, 1870, 1716, 1697, 1454,
1330, 1272, 737, 699 cm−1; 1H NMR (200 MHz, CDCl3):  0.96 (3H,
s), 1.14 (3H, s), 1.30–1.40 (2H, m), 1.61–1.68 (2H, m), 1.85–2.10
(5H, m), 2.18–2.25 (2H, m), 2.36–2.42 (2H, m), 2.76 (2H, t, J
6.6 Hz), 3.41 and 3.49 (2H, AB quartet, J 13.8 Hz), 3.46 (1H, t, J
6.6 Hz), 3.86 (1H, dd, J 5.4 and 7.3 Hz), 4.50 (2H, s), 5.32–5.45
(2H, m), 7.24–7.35 (5H, m); 13C NMR (50 MHz, CDCl3):  19.9,
20.8, 22.3, 23.8, 26.4, 29.6, 32.8, 35.3, 38.5, 44.6, 47.7, 48.4, 52.9,
65.2, 69.8, 72.9, 127.4, 127.6, 128.3, 130.5, 138.4, 171.1. HRMS:
Calc. C25H35NO4S: [M + Na]+ m/z 468.2184. Found: 468.2192.
(R)-3-[(tert-Butyldimethylsilyloxy)-2-methyl]propional 4b.
Using the general DIBAL-H reduction procedure described in
general remarks, DIBAL-H solution (1.5 M, 4.0 mL, 6.0 mmol)
was added to a stirred cold (−78 °C) solution of the above ester
(1.16 g, 5.0 mmol) in dry toluene (15 mL). The reaction mixture
was stirred at this temperature for 2 h. The resulting yellow oil
obtained upon work-up was subjected to flash chromatography
(dichloromethane) providing the title compound (1.01 g, 62%)
as a colorless oil. Specific rotation: []D −36.7 (c 1.0, CH2Cl2);
IR (neat): max 2956, 2931, 2858, 2713, 2362, 1734, 1473, 1389,
1362, 1257, 1100, 1033, 837, 777, 668 cm−1; 1H NMR (300 MHz,
CDCl3):  0.05 (6H, s), 0.88 (9H, s), 1.09 (3H, d, J 7.0 Hz), 2.49–
2.56 (1H, m), 3.80 (1H, dd, J 6.3 and 10.2 Hz), 3.86 (1H, dd, J 5.3
and 10.2 Hz), 9.68 (1H, d, J 1.6 Hz); 13C NMR (75 MHz, CDCl3):
 −5.6, −5.5, 10.3, 18.2, 25.7, 48.8, 63.5, 204.6. All spectral data
compare favourably with the literature.17
Ethyl (R)-3-(tert-butyldimethylsilyloxy)butyrate. Using the
general silylation procedure described in general remarks, a mixture
of ethyl (R)-(−)-3-hydroxybutyrate (1.0 g, 7.6 mmol), TBSCl
(1.22 g, 8.1 mmol), DMAP (65 mg, 0.5 mmol) and imidazole
(0.61 g, 8.9 mmol) in dry DMF (4 mL) was stirred under a nitrogen
atmosphere at room temperature overnight. The resulting yellow
oil obtained upon work-up was subjected to flash chromatography
(dichloromethane) providing the title compound (1.257 g, 68%) as
a colourless oil. Specific rotation: []D −25.5 (c 1.0, CH2Cl2); IR
(neat): max 2957, 2858, 1740, 1472, 1376, 1300, 1256, 1183, 1139,
1083, 1034, 1003, 939, 836, 776 cm−1; 1H NMR (200 MHz, CDCl3):
 0.04 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.19 (3H, d, J 6.1 Hz),
1.26 (3H, t, J 7.2 Hz), 2.35 (1H, dd, J 5.4 and 14.5 Hz), 2.47 (1H,
dd, J 7.4 and 14.5 Hz), 4.10 (2H, q, J 7.2 Hz), 4.27 (1H, ddq, J 5.4,
6.1 and 7.4 Hz); 13C NMR (50 MHz, CDCl3):  −5.0, −4.5, 14.2,
17.9, 23.9, 25.7, 45.0, 60.3, 65.9, 171.6. All spectral data compare
favourably with the literature.18
3-(tert-Butyldimethylsilyloxy)-1-propanol. Using the general
procedure for silylation described in general remarks, TBSCl (7.8 g,
53 mmol) was added in portions to a cold (−25 °C) solution of 1,3-
propanediol (9.7 g, 127 mmol) and imidazole (7.5 g, 110 mmol)
in dry DMF (30 mL) under a nitrogen atmosphere. After 1 h, the
reaction mixture was warmed to 0 °C and stirred at this temperature
for 4 h. The yellow oil obtained upon work-up was subjected to
flash chromatography (ethyl acetate–hexane, 1:9) providing the
title compound as a colourless oil (7.0 g, 69%): IR (neat): max
3356, 2930, 2858, 1471, 1388, 1362, 1256, 1097, 1006, 961, 836,
776, 718, 662 cm−1; H NMR (200 MHz, CDCl3):  0.05 (6H, s),
0.87 (9H, s), 1.75 (2H, quin, J 5.7 Hz), 2.76 (1H, br s), 3.76 (2H, t, J
5.7 Hz), 3.80 (2H, t, J 5.7 Hz); 13C NMR (50 MHz, CDCl3):  −5.6,
18.1, 25.8, 34.2, 62.1, 62.7.
1
(R)-3-(tert-Butyldimethylsilyloxy)butanal 4c. Using the general
DIBAL-H reduction procedure described in general remarks,
DIBAL-H solution (1.5 M in toluene, 4.0 mL, 6.0 mmol) was
added to a stirred solution of the above ester (1.23 g, 5.0 mmol) in
dry toluene (15 mL) at −78 °C and the reaction mixture was stirred
at this temperature for 2 h. The resulting yellow oil obtained upon
work-up was subjected to fractional distillation to yield the title
compound (660 mg 65%) as a colourless oil. Aldehyde 4c was used
immediately in the next step. Specific rotation: []D −11.3 (c 1.0,
CH2Cl2); IR (neat): max 2957, 2858, 1728, 1472, 1376, 1256, 1099,
1028, 1005, 836 cm−1; 1H NMR (300 MHz, CDCl3):  0.06 (3H, s),
0.08 (3H, s), 0.87 (9H, s), 1.23 (3H, d, J 6.2 Hz), 2.46 (1H, ddd, J
2.1, 5.0 and 15.7 Hz), 2.55 (1H, ddd, J 2.8, 6.8 and 15.7 Hz), 4.25
3-(tert-Butyldimethylsilyloxy)propanal 4a. Using the general
Swern oxidation procedure described in general remarks, DMSO
(3.61 g, 3.3 mL, 46 mmol) in dry dichloromethane (18 mL) was
added to a stirred cold (−70 °C) solution of oxalyl chloride (2.93 g,
2.0 mL, 23 mmol) in dry dichloromethane (46 mL) followed by
the addition of the above alcohol (4.0 g, 21 mmol) in dry dichloro-
methane (105 mL). The reaction mixture was stirred at −70 °C for
a further 1 h and work-up to furnish the title compound (3.96 g,
100%) as a yellow oil. The aldehyde 4a was used in the next
reaction without purification: IR (neat): max 2955, 2857, 2730,
1728, 1472, 1464, 1389, 1361, 1256, 1099, 1099, 1006, 971, 939,
836, 774 cm−1; H NMR (200 MHz, CDCl3):  0.00 (6H, s), 0.81
(1H, ddq, J 5.0, 6.2 and 6.8 Hz), 9.80 (1H, dd, J 2.1 and 2.8 Hz); 13
C
1
(9H, s), 2.52 (2H, dt, J 2.1 and 6.0 Hz), 3.92 (1H, t, J 6.0 Hz), 9.73
(1H, t, J 2.1 Hz); 13C NMR (50 MHz, CDCl3):  −5.0, −5.6, 18.1,
25.7, 46.5, 57.3, 201.5.
NMR (75 MHz, CDCl3):  −4.9, −4.3, 17.9, 24.2, 25.7, 53.0, 64.6,
202.0. All spectral data compare favourably with the literature.18
Ethyl (S)-3-(tert-butyldimethylsilyloxy)butyrate. Using
the general silylation procedure described in general remarks, a
mixture of ethyl (S)-(+)-3-hydroxybutyrate (2.0 g, 15.1 mmol),
TBSCl (2.24 g, 16.2 mmol), DMAP (0.13 g, 1.9 mmol) and
imidazole (1.22 g, 17.9 mmol) in dry DMF (8 mL) was stirred
under a nitrogen atmosphere at room temperature overnight. The
resulting yellow oil obtained upon work-up was subjected to flash
chromatography (dichloromethane) providing the title compound
Methyl (R)-3-[(tert-butyldimethylsilyloxy)-2-methyl]propio-
nate. Using the general procedure for silylation described in general
remarks, (2S)-methyl 3-hydroxy-2-methylpropionate (2.14 g,
18.0 mmol), TBSCl (2.92 g, 19.4 mmol), DMAP(0.16 g, 1.3 mmol)
and imidazole (1.46 g, 21.4 mmol) in dry DMF (9 mL) was stirred
under a nitrogen atmosphere at room temperature overnight. The
resulting yellow oil obtained upon work-up was subjected to flash
2 2 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8

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(2R)-N-[(2R)-2-{(1S,2S)-3-tert-Butyldimethylsilyloxy)-1-
hydroxy-2-methylprop-1-yl}-4-penten-1-oyl]bornane-10,2-
sultam 8. Using the general aldol reaction procedure described
in general remarks, aldol addition of acyl sultam 3a (1 mmol)
to aldehyde 4b with the reaction time of 3 h afforded upon
work-up crude product as a yellow solid. Purification by flash
chromatography (ethyl acetate–hexane; 1:90) followed by
recrystallisation (diethyl ether–hexane) provided adduct 8 (470 mg,
95%) as colourless crystals: mp 137–139 °C. Specific rotation:
[]D −68.0 (c 1.0, CH2Cl2); IR (Nujol): max 3508, 2953, 2358,
1698, 1457, 1332, 1258, 1068, 835, 721 cm−1; 1H NMR (200 MHz,
CDCl3):  0.04 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 0.95 (3H, s),
1.00 (3H, d, J 7.0 Hz), 1.15 (3H, s), 1.34–1.41 (2H, m), 1.70–1.77
(1H, m), 1.83–1.94 (3H, m), 1.98–2.02 (2H, m), 2.51–2.55 (1H,
m), 2.63–2.74 (1H, m), 3.32–3.39 (1H, m), 3.40 and 3.49 (2H, AB
quartet, J 13.8 Hz), 3.66 (1H, dd, J 3.9 and 10.1 Hz), 3.71–3.91
(2.98 g, 80%) as a colourless oil. Specific rotation: []D +23.7
(c 1.0, CH2Cl2); IR (neat): max 2958, 2858, 1739, 1472, 1376, 1300,
1249, 1183, 1130, 1084, 1034, 1003, 939, 836, 776 cm−1; 1H NMR
(200 MHz, CDCl3):  0.04 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.19
(3H, d, J 6.1 Hz), 1.24 (3H, t, J 7.2 Hz), 2.35 (2H, dd, J 5.4 and
14.5 Hz), 2.47 (2H, dd, J 7.5 and 14.5 Hz), 4.12 (1H, q, J 7.2 Hz),
4.27 (1H, ddq, J 5.4, 6.1 and 7.5 Hz); 13C NMR (50 MHz, CDCl3):
 −5.0, −4.5, 14.2, 17.9, 23.9, 25.7, 44.9, 60.3, 65.9, 171.7. All
spectral data compare favourably with the literature.19
(S)-3-(tert-Butyldimethylsilyloxy)butanal 4d. Using the
general DIBALH reduction procedure described in general remarks,
DIBALH solution (1.5 M in toluene, 4.0 mL, 6.0 mmol) was added
to a stirred cold (−78 °C) solution of the above ester (1.23 g,
5.0 mmol) in dry toluene (15 mL). The reaction mixture was stirred
at this temperature for 2 h. The resulting yellow oil obtained upon
work-up was subjected to fractional distillation to yield the title
compound (720 mg, 71%) as a colourless oil.Aldehyde 4d was used
immediately in the next step. Specific rotation: []D +11.0 (c 1.0,
CH2Cl2); IR (neat): max 2957, 2858, 2365, 1729, 1473, 1376, 1255,
1099, 1029, 836 cm−1; 1H NMR (300 MHz, CDCl3):  0.06 (3H, s),
0.08 (3H, s), 0.88 (9H, s), 1.24 (3H, d, J 6.2 Hz), 2.46 (1H, ddd, J
2.1, 5.1 and 15.7 Hz), 2.55 (1H, ddd, J 2.8, 6.9 and 15.7 Hz), 4.25
(3H, m), 4.95–5.09 (2H, m), 5.85 (1H, ddt, J 6.5, 10.3, 17.1 Hz); 13
C
NMR (50 MHz, CDCl3):  −5.7, −5.6, 14.4, 18.1, 19.9, 20.7, 25.8,
26.4, 32.3, 32.8, 36.9, 38.4, 44.5, 47.3, 47.7, 48.1, 53.1, 65.2, 65.9,
73.3, 117.3, 134.9, 174.7. HRMS: Calc. C25H45NO5SSi: [M + Na]+
m/z 522.269. Found: 522.269.
(2R)-N-[(1S,4R,5S,6R)-1,4-Dimethyl-2,8-dioxabicyclo[3.2.1]-
octanyl-6-carbonyl]bornane-10,2-sultam 9. Using the general
Wacker reaction procedure described in general remarks, Pd(II)-
catalysed cyclisation of aldol adduct 8 (0.1 mmol scale) for 3 h
afforded, upon work-up, a yellow residue which was purified
by flash chromatography (ethyl acetate–hexane, 1:3) followed
by crystallisation (diethyl ether) providing the title compound
(23–36 mg, 60–93%) as colourless crystals: mp 190–191 °C.
Specific rotation: []D −53.1 (c 1.0, CH2Cl2). Analysis (%): Calc.
for C19H29NO5S: C 59.50, H 7.63, N 3.65. Found: C 59.22, H 7.75,
N 3.57; IR (Nujol): max 2850, 2725, 1695, 1570, 1456, 1377, 1165,
720 cm−1; 1H NMR (300 MHz, CDCl3):  0.97 (3H, s), 1.15 (3H, s),
1.25 (3H, d, J 7.0 Hz), 1.30–1.44 (2H, m), 1.50 (3H, s), 1.54–1.64
(1H, m), 1.86–1.92 (3H, m), 2.07–2.11 (2H, m), 2.18 (1H, dd, J
4.8 and 13.6 Hz), 2.43 (1H, dd, J 9.0 and 13.6 Hz), 3.45 and 3.52
(2H, AB quartet, J 13.8 Hz), 3.54 (1H, dd, J 1.3 and 12.0 Hz), 3.61
(1H, dd, J 4.8 and 9.0 Hz), 3.89 (1H, dd, J 5.5 and 5.6 Hz), 4.04
(1H, dd, J 4.0 and 12.0 Hz), 4.40 (1H, br s); 13C NMR (75 MHz,
CDCl3):  16.5, 19.8, 20.9, 23.8, 26.3, 32.7, 32.8, 38.5, 38.6, 44.6,
47.7, 48.1, 48.4, 53.1, 65.4, 65.7, 82.8, 106.0, 172.3. HRMS: Calc.
C19H29NO5S: [M + Na]+ m/z 406.166. Found: 406.165.
(1H, ddq, J 5.1, 6.2 and 6.9 Hz), 9.79 (1H, dd, J 2.1 and 2.8 Hz); 13
C
NMR (75 MHz, CDCl3):  −4.9, −4.4, 17.9, 24.2, 25.7, 53.0, 64.6,
202.1. All spectral data compare favourably with the literature.20
(2R)-N-[(2R)-2-{(1S)-3-(tert-Butyldimethylsilyloxy)-1-
hydroxyprop-1-yl}-4-penten-1-oyl]bornane-10,2-sultam
5.
Using the general aldol reaction procedure described in general
remarks, aldol addition of acyl sultam 3a (4 mmol) to aldehyde
4a with the reaction time of 3 h afforded upon work-up crude
product as a yellow residue. Purification by dry column chromato-
graphy (diethyl ether–hexane) followed by recrystallisation
(hexane) provided adduct 5 (1.85 g, 95%) as colourless crystals:
mp 108–109 °C. Specific rotation: []D −59.9 (c 1.0, CH2Cl2).
Analysis (%): Calc. C24H43NO5SSi: C 59.35, H 8.93, N 2.89. Found:
C 59.51, H 9.19, N 2.94; IR (Nujol): max 3480, 2918, 2360, 2354,
1
1694, 1483, 1376, 1312, 1165, 1072, 973, 838, 781, 721 cm−1; H
NMR (400 MHz, CDCl3):  0.06 (6H, s), 0.89 (9H, s), 0.96 (3H,
s), 1.16 (3H, s), 1.31–1.41 (2H, m), 1.64–1.70 (1H, m), 1.76–1.80
(2H, m), 1.81–1.91 (2H, m), 2.01–2.03 (2H, m), 2.55–2.64 (2H, m),
3.23–3.29 (1H, m), 3.42 and 3.50 (2H, AB quartet, J 13.8 Hz), 3.66
(1H, br s), 3.76–3.81 (1H, m), 3.83–3.89 (2H, m), 4.09–4.14 (1H,
m), 4.95–5.10 (2H, m), 5.86 (1H, ddt, J 6.5, 10.3 and 17.0 Hz); 13
C
(2R)-N-[(2R,3S,5R)-2-Allyl-5-(tert-butyldimethylsilyloxy)-
hexan-1-oyl]bornane-10,2-sultam 10. Using the general aldol
reaction procedure described in general remarks, aldol addition of
acyl sultam 3a (1 mmol) to aldehyde 4c with the reaction time of 3 h
afforded upon work-up crude product as a yellow residue. Purifica-
tion by flash chromatography (ethyl acetate–hexane, 1:9) followed
by recrystallisation (diethyl ether–hexane) provided adduct 10
(475 mg, 95%) as colourless crystals: mp 138–140 °C. Specific
rotation: []D −69.0 (c 1.18, CH2Cl2); IR (Nujol): max 3487, 3077,
2957, 2856, 1694, 1463, 1333, 1210, 1133, 1065, 836, 775 cm−1;
1H NMR (200 MHz, CDCl3):  0.05 (3H, s), 0.06 (3H, s), 0.87 (9H,
s), 0.95 (3H, s), 1.14 (3H, s), 1.19 (3H, d, J 6.3 Hz), 1.27–1.38
(2H, m), 1.43–1.54 (1H, m), 1.65–1.78 (1H, m), 1.81–1.92 (3H,
m), 1.98–2.01 (2H, m), 2.46–2.66 (2H, m) 3.16–3.31 (1H, m), 3.40
and 3.50 (2H, AB quartet, J 13.8 Hz), 3.74 (1H, br s), 3.88 (1H, t,
J 6.3 Hz) 4.08–4.47 (2H, m), 4.93–5.10 (2H, m), 5.86 (1H, ddt,
J 6.5, 10.3, 17.1 Hz); 13C NMR (50 MHz, CDCl3):  −5.1, −4.6,
17.9, 19.9, 20.8, 22.9, 25.8, 26.4, 32.9, 33.8, 38.4, 42.0, 44.6, 47.7,
48.0, 50.4, 53.3, 65.3, 67.0, 67.7, 117.3, 135.1, 174.2. HRMS: Calc.
C25H45NO5SSi: [M + Na]+ m/z 522.269. Found: 522.268.
NMR (100 MHz, CDCl3):  −5.5, 18.2, 19.9, 20.9, 25.9, 26.5, 33.0,
33.7, 36.4, 38.5, 44.7, 47.7, 48.1, 50.3, 53.3, 62.2, 64.2, 70.8, 117.3,
135.0, 174.0. HRMS: Calc. C24H43NO5SSi: [M + Na]+ m/z 486.271.
Found: 486.271.
(2R)-N-[(1S,5S,6R)-1-Methyl-2,8-dioxabicyclo[3.2.1]octanyl-
6-carbonyl]bornane-10,2-sultam 7. Using the general Wacker
reaction procedure described in general remarks, Pd(II)-catalysed
cyclisation of aldol adduct 5 (0.25 mmol scale) for 3 h afforded,
upon work-up, a yellow residue, which was purified by preparative
TLC (ethyl acetate–hexane, 1:1). Extraction of the major chromo-
phoric band at Rf 0.40 followed by crystallisation (2-propanol–
dichloromethane) provided the title compound (55 mg, 60%) as
colourless crystals. Specific rotation: []D −65.6 (c 1.4, CH2Cl2).
Analysis (%): Calc. for C18H27NO5S: C 58.51, H 7.37, N 3.79.
Found: C 58.44, H 7.27, N 3.83; IR (Nujol): max 2923, 2852, 1687,
1463, 1377, 1333, 1215, 1133, 1083, 949, 833, 722 cm−1; 1H NMR
(400 MHz, CDCl3):  0.98 (3H, s), 1.16 (3H, s), 1.32–1.47 (3H,
m), 1.51 (3H, s), 1.87–1.97 (3H, m), 2.05–2.20 (3H, m), 2.23 (1H,
dd, J 4.7 and 13.7 Hz), 2.46 (1H, dd, J 9.1 and 13.7 Hz), 3.45 and
3.52 (2H, AB quartet, J 13.8 Hz), 3.62 (1H, dd, J 4.7 and 9.1 Hz),
3.88–4.00 (3H, m), 4.73 (1H, br s); 13C NMR (100 MHz, CDCl3): 
19.9, 20.9, 24.0, 26.4, 29.5, 32.9, 38.5, 39.4, 44.6, 47.1, 47.8, 48.5,
53.1, 59.7, 65.7, 78.2, 105.9, 172.3. HRMS: Calc. C18H27NO5S:
[M + Na]+ m/z 370.169. Found: 370.169.
(2R)-N-[(1S,3R,5S,6R)-1,3-Dimethyl-2,8-dioxabicyclo[3.2.1]-
octanyl-6-carbonyl]bornane-10,2-sultam 11. Using the general
Wacker reaction procedure described in general remarks, Pd(II)-
catalysed cyclisation of aldol adduct 10 (0.1 mmol scale) for 3 h
afforded, upon work-up, a yellow residue which was purified
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8
2 2 2 5

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by flash chromatography (ethyl acetate–hexane, 1:4) followed
by crystallisation (diethyl ether) providing the title compound
(25–34 mg, 65–89%) as colourless crystals: mp 147–148 °C.
Specific rotation: []D −61.0 (c 1.0, CH2Cl2). Analysis (%): Calc.
for C19H29NO5S: C 59.5, H 7.63, N 3.65. Found: C 59.50, H 7.85,
N 3.57; IR (Nujol): max 2852, 2360, 1686, 1460, 1377, 1329, 1211,
1210, 1134, 838, 776, 735, 698 cm−1; 1H NMR (200 MHz, CDCl3):
 0.06 (6H, s), 0.88 (9H, s), 0.93 (3H, s), 1.12 (3H, s), 1.19–1.40
(2H, m), 1.56–1.69 (4H, m), 1.79–1.96 (3H, m), 1.99–2.04 (2H, m),
2.07–2.30 (2H, m), 2.38–2.56 (1H, m), 2.61–2.75 (1H, m), 3.19–
3.30 (1H, m), 3.35–3.52 (4H, m), 3.70–3.88 (3H, m), 4.05–4.13
(1H, m), 4.48 (2H, s), 5.32–5.52 (2H, m), 7.13–7.33 (5H, m); 13C
NMR (50 MHz, CDCl3):  −5.6, 18.0, 19.8, 20.7, 23.6, 25.8, 26.3,
26.8, 29.4, 32.8, 36.2, 38.3, 44.5, 47.5, 47.9, 50.2, 53.1, 62.0, 65.0,
69.7, 70.7, 72.7, 125.9, 127.3, 127.5, 127.6, 128.2, 130.5, 131.4,
138.5, 171.2. HRMS: Calc. C34H55NO6SSi: [M + Na]+ m/z 656.342.
Found: 656.339.
1
1162, 1136, 1069, 953, 770, 722, 653 cm−1; H NMR (300 MHz,
CDCl3):  0.96 (3H, s), 1.13 (3H, s), 1.17 (3H, d, J 6.1 Hz), 1.23–1.44
(2H, m), 1.50 (3H, s), 1.56 (1H, ddd, J 2.0, 3.8 and 13.3 Hz), 1.68
(1H, ddd, J 3.6, 10.9 and 13.3 Hz), 1.80–1.96 (3H, m), 2.03–2.12
(2H, m), 2.17 (1H, dd, J 4.8 and 13.6 Hz), 2.42 (1H, dd, J 9.1 and
13.6 Hz), 3.44 and 3.51 (2H, AB quartet, J 13.8 Hz), 3.55 (1H, dd,
J 4.8 and 9.1 Hz), 3.87 (1H, dd, J 5.4 and 7.2 Hz), 3.91–3.98 (1H,
m), 4.69 (1H, br s); 13C NMR (75 MHz, CDCl3):  19.8, 20.9, 21.7,
24.1, 26.3, 32.9, 37.3, 38.5, 39.8, 44.6, 47.5, 47.7, 48.5, 53.1, 65.2,
65.7, 77.9, 105.7, 172.3. HRMS: Calc. C19H29NO5S: [M + Na]+ m/z
406.166. Found: 406.165.
(2R)-N-[(1S,5S,6R)-1-{4-Benzyloxybut-1-yl}-2,8-dioxabicyclo-
[3.2.1]octanyl-6-carbonyl]bornane-10,2-sultam 15. Using the
general Wacker reaction procedure described in general remarks,
Pd(II)-catalysed cyclisation of aldol adduct 14 (0.1 mmol scale) for
8 h afforded, upon work-up, a yellow residue which was purified
by flash chromatography (ethyl acetate–hexane, 1:1) providing
the title compound (20 mg, 39%) as colourless oil: IR (neat): max
2945, 1949, 1872, 1715, 1690, 1268, 1210, 1130, 774, 690 cm−1; 1H
NMR (300 MHz, CDCl3):  0.98 (3H, s), 1.16 (3H, s), 1.25–1.42
(2H, m), 1.43–1.60 (6H, m), 1.69–1.90 (5H, m), 2.02–2.12 (2H, m),
2.24 (1H, dd, J 4.6 and 13.7 Hz), 2.38 (1H, dd, J 9.0 and 13.7 Hz),
3.42–3.55 (4H, m), 3.60 (1H, dd, J 4.6 and 9.0 Hz), 3.87–3.96 (3H,
m), 4.49 (2H, s), 4.72 (1H, br s), 7.27–7.33 (5H, m); 13C NMR
(75 MHz, CDCl3):  18.9, 19.5, 19.9, 25.4, 28.8, 28.9, 31.9, 36.5,
36.9, 37.6, 43.6, 45.7, 46.8, 47.5, 52.2, 58.6, 64.8, 69.3, 71.8, 77.2,
106.6, 126.4, 126.6, 127.3, 137.7, 171.4. HRMS: Calc. C28H39NO6S:
[M + Na]+ m/z 540.240. Found: 540.238.
(2R)-N-[(2R,3S,5S)-2-Allyl-5-(tert-butyldimethylsilyloxy)-
hexan-1-oyl]bornane-10,2-sultam 12. Using the general aldol
reaction procedure described in general remarks, aldol addition
of acyl sultam 3a (1 mmol) to aldehyde 4d with the reaction time
of 3 h afforded upon work-up crude product as a yellow residue.
Purification by flash chromatography (ethyl acetate–hexane)
followed by recrystallisation (diethyl ether–hexane) provided
adduct 12 (467 mg, 94%) as colourless crystals: mp 138–141 °C.
Specific rotation: []D −61.0 (c 1.0, CH2Cl2); IR (Nujol): max
3499, 2960, 1699, 1462, 1335, 1265, 1210, 1133, 1065, 990, 836,
1
778 cm−1; H NMR (300 MHz, CDCl3):  0.08 (3H, s), 0.09 (3H,
s), 0.85 (9H, s), 0.95 (3H, s), 1.15 (3H, s), 1.16 (3H, d, J 6.0 Hz),
1.21–1.42 (2H, m), 1.54 (1H, ddd, J 2.0, 4.6 and 14.3 Hz), 1.69
(1H, ddd, J 8.7, 9.6 and 14.3 Hz), 1.82–1.96 (3H, m), 1.99–2.09
(2H, m), 2.53–2.69 (2H, m), 3.17–3.24 (1H, m), 3.42 and 3.50 (2H,
AB quartet, J 13.8 Hz), 3.88 (1H, t, J 6.3 Hz), 4.00–4.11 (2H, m),
4.94–5.09 (2H, m), 5.58 (1H, ddt, J 6.2, 10.0 and 16.6 Hz); 13C
NMR (75 MHz, CDCl3):  −4.8, −4.1, 17.9, 19.9, 20.8, 24.0, 25.0,
26.4, 32.9, 33.8, 38.4, 43.7, 44.6, 47.7, 48.0, 50.6, 53.3, 65.2, 69.6,
70.3, 117.3, 135.0, 174.2. HRMS: Calc. C25H45NO5SSi: [M + Na]+
m/z 522.269. Found: 522.268.
(1R,3S,5R,6S)-1,3-Dimethyl-6-hydroxymethyl-2,8-dioxa-
bicyclo[3.2.1]octane 16. A solution of LiAlH4 (4 mg, 0.1 mmol) in
diethyl ether (1 mL) was stirred under a nitrogen atmosphere and
cooled to 0 °C while a solution of 7 (82 mg, 0.21 mmol) in diethyl
ether (2 mL) was added dropwise. The reaction mixture was stirred
at this temperature for 45 min and water (20 L) was added. The
mixture was warmed to room temperature, filtered through a bed of
MgSO4 and the filtrate concentrated in vacuo. The resulting yellow
oil was purified by flash chromatography (ethyl acetate–dichloro-
methane, 1:4) to afford the title compound (32 mg, 87%) as a
colourless oil: 1H NMR (300 MHz, CDCl3):  1.18 (3H, d, J 6.1 Hz),
1.23–1.42 (2H, m), 1.46 (3H, s), 1.67–1.76 (1H, m), 2.02 (1H, br s),
2.21–2.34 (2H, m), 3.52 (2H, d, J 5.7 Hz), 3.91–4.08 (1H, m) and
4.35 (1H, br s); 13C NMR (75 MHz, CDCl3):  21.9, 24.6, 37.9, 38.0,
44.5, 65.3, 65.6, 77.4, 105.4. HRMS: Calc. C9H16O3: [M + Na]+ m/z
195.0997. Found: 195.0993.
(2R)-N-[(1S,3S,5S,6R)-1,3-Dimethyl-2,8-dioxabicyclo[3.2.1]-
octanyl-6-carbonyl]bornane-10,2-sultam 13. Using the general
Wacker reaction procedure described in general remarks, Pd(II)-
catalysed cyclisation of aldol adduct 12 (0.1 mmol scale) overnight
afforded, upon work-up, a yellow residue which was purified by
flash chromatography (ethyl acetate–hexane, 1:4) providing the
title compound (19 mg, 50%) as a white solid: IR (Nujol): max
2932, 2359, 1688, 1460, 1377, 1326, 1159, 1133, 953, 770, 722,
2,3-Bis(phenylmethyloxy)-5-[(1,1-dimethylethyl)dimethyl-
silyloxy]-D-xylose 18. tert-Butyldimethylsilyl chloride (7.25 g,
48 mmol) was added to a magnetically stirred solution of 2,3-
di-O-benzyl-D-xylose diethyl dithioacetal 17 (17.5 g, 40 mmol)
and imidazole (3.55 g, 52 mmol) in anhydrous DMF (50 mL)
maintained at rt under an atmosphere of nitrogen. After 12 h the
reaction mixture was poured into water (500 mL) and extracted
with CH2Cl2 (3 × 300 mL). The combined organic phases were
washed with water (400 mL) and brine (400 mL) before being
dried (MgSO4), filtered and concentrated under reduced pressure
to afford a light yellow oil. Flash chromatography (5–25% v/v
ethyl acetate–hexane elution) gave the title compound (20.9 g,
95%) as a yellow oil. Specific rotation: []D −5.1 (c 1.1, CHCl3);
IR (neat): max 3450, 3063, 2949, 1497, 1454, 1389, 1254, 1121,
842 cm−1; 1H NMR (300 MHz):  0.05 (3H, s), 0.06 (3H, s), 0.90
(9H, s), 1.22 (6H, m), 2.72 (4H, m), 3.51 (1H, d, J 9.8), 3.53 (1H,
d, J 9.8), 3.65 (1H, d, J 9.7), 3.77 (1H, ddd, J 8.5, 6.6 and 2.0 Hz),
4.04 (2H, m), 4.14 (1H, d, J 3.0 Hz), 4.62 (1H, d, J 11.1 Hz), 4.83
(1H, d, J 11.1 Hz), 4.87 (2H, AB system, J 11 Hz), 7.24–7.37
(10H, m); 13C NMR (75 MHz):  −5.1 (2 × CH3, coincident),
14.6 (CH3), 14.7 (CH3), 25.4 (C), 26.1 (3 × CH3, coincident),
26.2 (2 × CH2, coincident), 53.6 (CH), 64.1 (CH2), 71.7 (CH),
75.5 (CH2), 75.7 (CH2), 79.7 (CH), 83.7 (CH), 127.7 (CH), 128.0
(2 × CH, coincident), 128.2 (2 × CH, coincident), 128.4 (2 × CH,
1
653 cm−1; H NMR (300 MHz, CDCl3):  0.95 (3H, s), 1.12 (3H,
s), 1.16 (3H, d, J 6.1 Hz), 1.22–1.42 (2H, m), 1.50 (3H, s), 1.57
(1H, ddd, J 2.0, 3.7 and 13.3 Hz), 1.69 (1H, ddd, J 3.6, 10.9 and
13.3 Hz), 1.83–1.95 (3H, m), 2.02–2.12 (2H, m), 2.16 (1H, dd, J 4.8
and 13.6 Hz), 2.40 (1H, dd, J 9.1 and 13.6 Hz), 3.45 and 3.50 (2H,
AB quartet, J 13.8 Hz), 3.54 (1H, dd, J 4.7 and 9.1 Hz), 3.81–3.89
(1H, m), 3.90–3.96 (1H, m), 4.69 (1H, br s); 13C NMR (75 MHz,
CDCl3):  19.8, 20.8, 21.5, 24.0, 26.4, 32.8, 37.4, 38.4, 40.4, 44.6,
47.4, 47.7, 48.5, 53.2, 65.0, 65.6, 78.1, 105.9, 172.3. HRMS: Calc.
C19H29NO5S: [M + Na]+ m/z 406.166. Found: 406.165.
(2R)-N-[(4Z)-{(1S)-3-(tert-Butyldimethylsilyloxy)-1-
hydroxyprop-1-yl)-8-benzyloxyocten-1-oyl]bornane-10,2-
sultam 14. Using the general aldol reaction procedure described in
general remarks, acyl sultam 3b (223 mg, 0.5 mmol) in dry dichloro-
methane (2 mL) was reacted with freshly prepared diethylboron
triflate (1 mmol) at −10 °C to give the corresponding diethylboron
enolate which was cooled to −78 °C.Aldehyde 4a (188 mg, 1 mmol)
was added and the reaction mixture stirred at this temperature for
5 h. The resulting yellow residue obtained upon work-up was
subjected to flash chromatography (ethyl acetate–hexane, 1:3)
to provide the title compound (225 mg, 71%) as a yellow oil: IR
(neat): max 3490, 2954, 1950, 1870, 1717, 1694, 1454, 1335, 1267,
2 2 2 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8

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coincident), 128.5 (2 × CH, coincident), 128.6 (CH), 138.6 (C),
138.8 (C). HRMS: Calc. C29H46O4S2Si: [M + Na]+ m/z 573.2504.
Found: 573.2485.
(signal due to CO and C not observed). HRMS: Calc. C26H36O4Si:
[M + Na]+ m/z 463.2281. Found: 465.2283.
(3R,4R,5S)-4,5-Bis(phenylmethyloxy)-3-[(1,1-dimethylethyl)-
dimethylsilyloxy]-3-hydroxyhept-6-enoic acid methyl ester 22.
A solution of 21 (2.47 g, 5.61 mmol) and methyl bromoacetate
(1.28 g, 8.42 mmol) in THF (2 mL) were added, dropwise, to Zn
dust (550 mg, 8.42 mmol) and heated to reflux under a nitrogen
atmosphere. The reaction mixture was refluxed for a further 20 min
then allowed to warm to rt over 1 h before being treated with H2SO4
(20 mL of a 2 M aqueous solution). The resulting mixture was
extracted with diethyl ether (3 × 20 mL) and the combined organic
extracts were washed with brine (1 × 100 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford a pale yellow oil. Flash chromatography (5–15% v/v ethyl
acetate–hexane elution) gave the title compound (2.69 g, 96%) as a
clear colorless oil. Spectroscopic data for the major diastereomer:
IR (neat) 3465, 2925, 2858, 1763, 1740, 1642, 1350, 1254, 1110,
814, 762 cm−1; 1H NMR (300 MHz):  −0.002 (3H, s), 0.01 (3H, s),
0.86 (9H, s), 2.68 (2H, AB system, J 15.2 Hz), 3.60 (3H, s), 3.71
(2H, AB system, J 1.8 Hz), 4.05 (1H, d, J 4.4 Hz), 4.14 (1H, dd, J
7.9 and 3.1 Hz), 4.31 (1H, d, 11.8 Hz), 4.63 (1H, d, J 11.9 Hz), 4.71
(2H, s), 5.27–5.36 (2H, m), 5.95–6.07 (1H, m), 7.25–7.34 (10H,
m) (signal due to OH not observed); 13C NMR (75 MHz):  −5.5
(2 × CH3), 18.2 (C), 25.8 (3 × CH3), 38.3 (CH2), 51.4 (CH3), 66.1
(CH), 70.1 (CH), 75.8 (CH), 76.87 (C), 80.2 (CH), 83.4 (CH), 118.2
(CH2), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.0 (CH), 128.1
(2 × CH), 128.2 (2 × CH), 128.3 (2 × CH), 136.4 (CH), 137.7 (C),
138.3 (C), 172.8 (C). HRMS: Calc. C29H42O6Si: [M + Na]+ m/z
537.2648. Found: 537.2641.
(2R,3S,4S)-3,4-Bis(phenylmethyloxy)-1-[(1,1-dimethylethyl)-
dimethylsilyloxy]hex-5-en-2-ol 20. Compound 18 (5.47 g,
9.9 mmol) was dissolved in acetone–water (40 mL of a 10:1
solution) and HgO (4.98 g, 23.0 mmol) was added in one portion,
followed by HgCl2 (2.96 g, 10.5 mmol). The reaction mixture was
heated to 60 °C for 3 h, then filtered through a bed of Celite™.
The solvent was concentrated under reduced pressure and the
residue was diluted with CH2Cl2 (100 mL), then washed with
potassium iodide (3 × 70 mL of a 1 M aqueous solution) and
brine (1 × 100 mL), before being dried (MgSO4), filtered and
concentrated under reduced pressure to afford 2,3-di-O-benzyl-5-
O-tert-butyldimethylsilyl-D-xylose (18) as a pale yellow oil. This
material was used, without purification, in the next step of the
reaction sequence. n-BuLi (50.04 mL of a 1.6 M solution in hexane,
80.76 mmol) was added, dropwise, to a solution of methyltriphen
ylphosphonium bromide (27.41 g, 76.72 mmol) in anhydrous THF
(85 mL) containing HMPA (30 mL) maintained at 0 °C under an
atmosphere of nitrogen. The resulting yellow solution was allowed
to warm to rt over 1 h then re-cooled to 0 °C. A solution of lactol 19
(3.42 g, 7.67 mmol) in THF (25 mL) was then added, dropwise, to
the reaction mixture. After 4 h at rt the reaction mixture was treated
sequentially with NaHCO3 (100 mLof a saturated aqueous solution)
and water (200 mL). The resulting mixture was extracted with
diethyl ether (3 × 200 mL) and the combined organic extracts were
washed with water (2 × 200 mL) and brine (2 × 300 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a light brown oil. Flash chromatography (5–15%
v/v ethyl acetate–hexane elution) gave the title compound (2.74 g,
80%) as a clear colourless oil. Specific rotation: []D −1.0 (c 1.75,
CHCl3); IR (neat): max 3465, 3031, 2953, 1654, 1253, 1096, 836,
777, 734, 697 cm−1; 1H NMR (300 MHz):  0.03 (6H, s), 0.88 (9H,
s), 3.55 (2H, m), 3.65 (1H, dd, J 6.0 and 2.3 Hz), 3.74 (1H, br s),
4.13 (1H, AB system, J 7.0 Hz), 4.42 (1H, d, J 11.7 Hz), 4.65 (2H,
d, J 11.4 Hz), 4.91 (1H, d, J 11.1 Hz), 5.29–5.42 (2H, complex m),
5.87 (1H, m), 7.26–7.41 (10H, m) (signal due to OH not observed);
13C NMR (75 MHz):  −5.1 (2 × CH3, coincident), 26.1 (3 × CH3,
coincident), 29.9 (C), 64.1 (CH2), 70.9 (CH2), 71.6 (CH), 75.3 (CH2),
79.9 (CH), 82.5 (CH), 119.5 (CH2), 127.7 (2 × CH, coincident),
127.9 (2 × CH, coincident), 128.1 (2 × CH, coincident), 128.4
(2 × CH, coincident), 128.5 (2 × CH, coincident), 135.6 (CH),
138.7 (2 × C, coincident). HRMS: Calc. C26H38O4Si: [M + Na]+ m/z
465.2437. Found: 465.2421.
(3R, 4R, 5S)-4, 5-Bis(phenylmethyloxy)-3-[(1, 1-
dimethylethyl)dimethylsilyloxy]hept-6-ene-1,3-diol
23.
DIBAL-H (2.87 mL of a 1 M solution in toluene, 2.87 mmol) was
added, dropwise, to a solution of ester 22 (740 mg, 1.43 mmol)
in CH2Cl2 (15 mL) maintained at −78 °C under an atmosphere
of nitrogen. The reaction mixture was allowed to warm to 0 °C
over 2 h, then treated with tartaric acid (75 mL of a 1 M aqueous
solution) and allowed to warm to rt. The resulting mixture was
extracted with CH2Cl2 (3 × 40 mL) and the combined organic
extracts were washed with brine (1 × 75 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford a light yellow oil. Flash chromatography (5–25% v/v
ethyl acetate–hexane elution) gave the title compound (550 mg,
79%) as a clear colourless oil. Spectroscopic data for the major
diastereomer: IR (neat) 3465, 3340, 1654, 1254, 1105, 821,
754 cm−1; 1H NMR (300 MHz):  0.04 (s, 6H), 0.97 (s, 9H), 1.75
(AB system, 1H, J 3.8 Hz), 1.81 (dd, 1H, J 8.9 and 4.4 Hz), 3.22
(dd, 1H, J 7.7 and 3.1 Hz), 3.55 (m, 1H), 3.56 (d, 1H, J 10.0 Hz),
3.69 (d, 1H, J 10.0 Hz), 3.87 (s, 2H), 4.20 (dd, 1H, J 8.1 and
3.2 Hz), 4.34 (d, 1H, 11.7 Hz), 4.65 (d, 1H, 11.7 Hz), 4.71 (d, 2H,
J 2.4 Hz), 5.31–5.36 (m, 2H), 5.96–6.08 (m, 1H), 7.25–7.37 (m,
10H) (signal due to OH not observed); 13C NMR (75 MHz):  −5.6
(CH3), −5.4 (CH3), 18.0 (C), 25.8 (3 × CH3), 35.2 (CH2), 59.0
(CH2), 64.1 (CH2), 70.1 (CH2), 75.9 (CH2), 78.5 (C), 80.7 (CH),
82.6 (CH), 118.9 (CH2), 127.6 (CH), 127.8 (2 × CH), 127.9 (CH),
128.3 (2 × CH), 128.4 (2 × CH), 128.5 (2 × CH), 136.0 (CH),
137.3 (C), 138.1 (C). HRMS: Calc. C28H42O5Si: [M + Na]+ m/z
509.2699. Found: 509.2695.
(3R,4S)-3,4-Bis(phenylmethyloxy)-1-[(1,1-dimethylethyl)-
dimethylsilyloxy]hex-5-en-2-one 21. Dess–Martin periodinane
(7.84 g, 18.47 mmol) was added, in portions, to a stirred solution
of alcohol 20 (2.74 g, 6.15 mmol) in CH2Cl2 (62 mL) at rt under
an atmosphere of nitrogen. After 2.5 h the reaction mixture was
treated with sodium thiosulfate (60 mL of a 1 M aqueous solution)
and NaHCO3 (60 mL of a saturated aqueous solution). After being
stirred vigorously for 20 min, the reaction mixture was extracted
with CH2Cl2 (2 × 200 mL) and the combined organic extracts were
washed with brine (1 × 200 mL) before being dried (MgSO4),
filtered and concentrated under reduced pressure to afford a light
yellow oil. Flash chromatography (5–15% v/v ethyl acetate–hexane
elution) gave the title compound (2.47 g, 91%) as a clear colorless
oil. Specific rotation: []D +12.1 (c 1.2, CHCl3); IR (neat): max
3031, 2928, 2856, 1736, 1655, 1497, 1455, 1254, 1115, 838, 779,
697 cm−1; 1H NMR (300 MHz):  0.007 (s, 6H), 0.86 (s, 9H), 4.09
(d, 1H, J 3.5 Hz), 4.20 (dd, 1H, J 7.7 and 3.6 Hz), 4.30 (d, 1H, J
12 Hz), 4.40 (s, 2H), 4.52 (d, 1H, J 12 Hz), 4.60 (d, 1H, J 12 Hz),
4.65 (d, 1H, J 12 Hz), 5.28–5.40 (complex m, 2H), 5.91 (m,
1H), 7.24–7.36 (m, 10H); 13C NMR (75 MHz):  −5.3 (2 × CH3,
coincident), 26.0 (3 × CH3, coincident), 69.3 (CH2), 70.9 (CH2),
74.3 (CH2), 80.7 (CH), 85.4 (CH), 119.8 (CH2), 127.9 (CH), 128.0
(3 × CH, coincident), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 128.5 (CH), 128.7 (CH), 134.5 (CH), 137.2 (C), 137.9 (C)
(3R,6R,7R)-(6,7-Bis(phenylmethyloxy)-1-methyl-2,8-
dioxabicyclo[3.2.1]oct-5-ylmethoxy)(1,1-dimethylethyl)di-
methylsilyloxy 24. A solution of 23 (40 mg, 0.08 mmol) in DME
(2 mL) was added, dropwise, to a stirred suspension of PdCl2
(0.73 mg, 4.11 × 10−3 mmol), CuCl2 (2.6 mg, 0.02 mmol) in DME
(2 mL) maintained at 50 °C under a stream of oxygen. After 3 h
the reaction mixture was cooled and filtered through a short pad of
silica, which was subsequently washed with diethyl ether (15 mL).
The combined filtrates were concentrated under reduced pressure
to afford a light brown oil. Flash chromatography (5–15% v/v ethyl
acetate–hexane elution) gave the title compound (34 mg, 89%) as a
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 2 0 – 2 2 2 8
2 2 2 7

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1992, 33, 7739; (b) N. T. Byrom, R. Grigg, B. Kongkathip, G. Reimer
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clear colorless oil. Spectroscopic data for the major diastereomer:
IR (neat) 2943, 1648, 1267, 1138, 818, 746 cm−1; 1H NMR
(300 MHz):  0.06 (3H, s), 0.07 (3H, s), 0.89 (9H, s), 1.45 (3H,
s), 1.69 (1H, dd, J 13.2 and 3.9 Hz), 2.01 (1H, app. dt, J 13.2 and
6.9 Hz), 3.53 (1H, d, J 9.8 Hz), 3.90 (1H, d, J 2.4 Hz), 3.96 (1H, m),
4.01 (1H, d, J 9.8 Hz), 4.30 (1H, app. dt, J 12.6 and 3.9 Hz), 4.00
(1H, d, J 2.1 Hz), 4.55 (1H, d, J 11.6 Hz), 4.58 (1H, d, J 11.8 Hz),
4.63 (1H, d, J 11.6 Hz), 4.71 (1H, d, J 11.8 Hz), 7.29–7.35 (10H, m);
13C NMR (75 MHz):  −5.2 (2 × CH3), 18.4 (C), 24.2 (CH3), 26.1
(3 × CH3), 31.5 (CH2), 60.4 (CH2), 64.0 (CH2), 72.6 (CH2), 72.7
(CH2), 83.5 (C), 86.5 (CH), 91.3 (CH), 102.8 (C), 127.5 (2 × CH),
127.6 (2 × CH), 127.7 (2 × CH), 127.8 (2 × CH), 128.3 (CH), 128.4
(CH), 138.0 (C), 138.4 (C). HRMS: Calc. C28H40O5Si: [M + Na]+
m/z 507.2543 Found: 507.2541.
Acknowledgements
6 S. Bond and P. Perlmutter, J. Org. Chem., 1997, 62, 6397.
7 The stereochemistry of aldol adducts 8, 10, 12 and 14 were assigned by
analogy to the result obtained for 5.
Financial support from theAustralian Research Council is gratefully
acknowledged for W. S. and F. V.
8 S.-K. Kang, K.-Y. Jung, J.-U. Chung, E.-Y. Namkoong and T.-H. Kim,
J. Org. Chem., 1995, 60, 4678.
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