Studies of intramolecular alkylidene carbene reactions; an approach to heterocyclic nucleoside bases

Article abstract of DOI:10.1016/S0040-4020(03)00692-6

A series of investigations into the applications of intramolecular cyclisations of alkylidene carbenes are described. The insertion reaction of the carbene generated from 1,4-di(tert-butyldimethylsilyloxy)-3-benzyloxy-butane-2-one to the benzylic position

Full text of DOI:10.1016/S0040-4020(03)00692-6

Tetrahedron 59 (2003) 4739–4748
Studies of intramolecular alkylidene carbene reactions;
an approach to heterocyclic nucleoside bases
Gerard Hobley,a Keith Stuttleb and Martin Willsa
,
*
aDepartment of Chemistry, University of Warwick, Gibbit Hill Road, Coventry CV4 7AL, UK
bAventis Pharma Ltd, Rainham Road South, Dagenham, Essex RM10 7XS, UK
Received 28 February 2003; revised 3 April 2003; accepted 1 May 2003
Abstract—A series of investigations into the applications of intramolecular cyclisations of alkylidene carbenes are described. The insertion
reaction of the carbene generated from 1,4-di(tert-butyldimethylsilyloxy)-3-benzyloxy-butane-2-one to the benzylic position proceeded in
good yield and a diastereoselectivity of 3.6:1. The corresponding insertion process of 1,4-di(tert-butyldimethylsilyloxy)-3-methyloxy-
methyl-butane-2-one gave a mixture of products, including one resulting from a competitive trapping of the carbene by the oxygen atom of a
silyloxy group. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
formation of the carbene by TMSDM (1) is thought to
proceed via addition to the ketone (2), of lithiated anion (3)
generated from the action of n-butyllithium upon the
TMSDM (Scheme 2). This then undergoes a Peterson
elimination to give 4 which is subject to diazo decompo-
sition producing the unsaturated carbene 5.4,20 The base
promoted action of dimethyl-diazomethanephosphonate or
diethyl-diazomethanephosphonate (DAMP) upon a ketone
is thought to proceed in a similar manner.21,22
Alkylidene carbenes undergo intramolecular insertion
reactions into 1,5-CH bonds to form cyclopentenes.1,2
Where heteroatoms are incorporated, heterocycles such as
2,5-dihydrofurans are formed in good yields (Scheme 1).1,
3–8,11,12
A number of methods have been developed for
the generation of alkylidene carbenes. These include; retro-
1,2-shifts in alkynes,9,10 Li/Br exchange in 1,1-dihalo-
alkenes,7,11,12 and base induced a-elimination from terminal
vinylbromides.1,2
TMSDM was first used by Ohira to promote 1,5-CH
insertion reactions4 and its use was extended by Taber
and Meagley.23 When an alkylidene carbene undergoes a
1,5-insertion reaction into a C–H bond at a chiral centre,
retention of the configuration about that centre is
observed.24–27 In 1994 Taber and Meagley reported the
first case of diastereoselectivity in an alkylidene carbene
1,5-CH insertion (Scheme 3).23 Having established 1,3
diastereoselective induction Taber and Yu went on to
demonstrate 1,2 induction of relative stereochemistry in the
synthesis of a-necrodol.28,29 A pseudo chair-like transition
Alkenyl(phenyl)-iodonium tetrafluoroborates and enol tri-
flates have also been used to good effect via addition of soft
nucleophiles to the acetylene bond.13–16,17
Diazoalkenes extrude nitrogen with formation of an
unsaturated carbene. In 1973 Colvin reported the one step
conversion of carbonyl compounds to acetylenes using
lithiated trimethylsilyldiazomethane (TMSDM) or
dimethyl-diazomethane-phosphonate.18,19 Mechanistically,
Scheme 1. Reagents and conditions: (i) TMSDMLi, DME/hexane,
2788C!rt.
Keywords: carbene; alkylidene; insertion; ketone; stereoselective;
cyclisation.
*
Corresponding author. Tel.: þ44-24-7652-3260; fax: þ44-24-7652-4112;
Scheme 2. Reagents and conditions: (i) n-butyllithium, hexane, 2788C!rt;
(ii) 2, 2788C; (iii) warm to rt.
e-mail: m.wills@warwick.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00692-6

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G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
Scheme 3. Reagents and conditions: (i) LiTMSDM, DME, Et2O,
2608C!rt.
Figure 1. Proposed transition state model for diastereoselective 1,5-CH
insertion.
state was assumed, the phenyl group adopting an equatorial
orientation in the proposed model (Fig. 1). The experimental
results obtained were in accordance with this analysis.
Scheme 6. Reagents and conditions: (i) LiAlH4, AlCl3, DCM/Et2O; (ii)
TBSCl, imidazole, DMF, or TBDPS, pyridine, DMAP, DCM; (iii) TPAP,
NMO, DCM; (iv) LiTMSDM, DME/hexane, 2788C!rt.
In 1994, Shiori et al. reported the formal insertion of an
alkylidene carbene into a 1,5-OSi bond to yield 5-tri-
methylsilyl-2,3-dihydrofurans.30 These products could
however have been the result of a ylide intermediate
followed by TMS group migration as was suggested at the
time (Scheme 4). In previously reported work in this group
we extended 2,5-dihydrofuran formation via alkylidene
carbenes to the synthesis of a model of the zaragozic acid
core structure.5,6,31
yield. The esters were reduced and the [1,3]dioxolane ring
system cleaved in one pot by reduction with lithium
aluminium hydride and aluminium chloride in DCM/ether,
to give the triol 9, in 82% yield. The primary alcohols in 9
were then protected with TBS groups (TBSCl, imidazole,
DMF) to give the TBS protected alcohol 10 in 78% yield, or
with TBDPS groups (TBDPSCl, pyridine, DMAP, DCM) to
give the TBDPS protected alcohol 11 in 90% yield. In both
of these compounds the secondary alcohols were oxidised
to the ketones using TPAP and NMO in DCM, furnishing 7
in 87% and 12 in 62% yields. With these substrates in hand
an investigation of the diastereoselectivity in the insertion
process was initiated. When ketone 12 was subjected to the
standard conditions used for the generation of alkylidene
carbenes, only the starting material was recovered from
the crude products upon workup. This was attributed to the
TBDPSO groups in 12 being too bulky to allow attack of
the LiTMSDM nucleophile on the ketone carbon. On the
other hand, when the TBS protected ketone 7 was subjected
to equivalent conditions reaction proceeded smoothly
to give a (major 13 (cis) 3.6: 1 minor 14 (trans)) ratio of
diastereoisomers. The minor diasteroisomer was insepar-
able from a small amount of a third compound and its yield
was calculated from its NMR integrals in this mixture.
The extension of vinylidene carbene insertions to the
construction of the pentose moiety of a functionalised
nucleoside model was therefore considered appealing.32–34
2. Results and discussion
The methodology was first applied to the synthesis of a
model system (Scheme 5). In this example the carbene
inserted cleanly into the methylene CH bond of a benzyl
protecting group to generate dihydrofuran 6. In order to
investigate diastereoselective variations on this reaction
substrate 7 was selected for study and its synthesis was
undertaken (Scheme 6).
Dimethyl (L)-tartrate was condensed with the dimethoxy-
acetal of benzaldehyde in the presence of catalyst p-TSA, to
protect the 1,2-diol functionality, giving product 8, in 89%
Scheme 4. Reagents and conditions: (i) LiTMSDM, THF/hexane, 2788C.
This third component, 15, from examination of its NMR
spectrum, was thought to be the product of an insertion into
the 1,5-OSi bond and is not without precedent (Scheme
4).35,30 Upon standing this third product was found to
rearrange to the furan 16 and benzyl alcohol. Assignment of
the configuration of the two diastereoisomers, 13 and 14,
was made using nuclear Overhauser enhancement spectro-
scopy (NOESY), there being a significant nuclear Over-
hauser effect (nOe) between protons A and B for 13, the
Scheme 5. Reagents and conditions: (i) TMSDMLi, DME/hexane,
2788C!rt.

G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
4741
pseudo chair-like transition state. As the experimental
results suggest this model is substantiated to some extent
and is in accordance with similar findings of Taber et al.
(Scheme 3, Fig. 1).28,29
The insertion process into the methylene CH of a
methoxymethyl (MOM) protecting group in substrate 19
(Scheme 7) was next selected for study, as this would
furnish 20, a nucleoside precursor.
We reasoned that, already having multigram quantities of
the secondary alcohol 7 from the previous synthesis, a
reliable route to the substrate might be to protect this
secondary alcohol with a MOM group, then remove the
benzyl protecting group and oxidise the deprotected alcohol
to the ketone 17. Synthesis of the ketone substrate 17 was
achieved via, MOM protection of the secondary alcohol in 7
with MOMCl and diisopropylethylamine, to give the MOM
protected alcohol 18 in 86% yield. Removal of the benzyl
protecting group using 5% Pd on carbon in ethanol under
hydrogen, gave 19 in 93% yield. Subsequent oxidation of
this secondary alcohol with TPAP and NMO in DCM gave
the ketone 17 in 81% yield (Scheme 7).
Figure 2. Possible transition states in the alkylidene carbene 1,5-CH
insertion reaction on 7.
With this substrate an alkylidene carbene 1,5-CH insertion
reaction was then performed using lithiated TMSDM under
the standard conditions that had been developed. When the
reaction was complete, TLC of the crude reaction mixture
showed the clean formation of two products which were
separated by column chromatography yielding 25% of 20,
and 30% of 21. In this case, the major product 21 appeared
to be the result of an insertion into the 1,5-OSi bond in the
substrate. Why this should form preferentially in this case is
perhaps because insertion into a MOM methylene CH is a
less favourable process and therefore insertion into an
alternative site is permitted kinetically. Insertions into O–Si
bonds have been reported by other groups.35,30
major product, showing that these protons are in close
proximity and therefore cis. This effect is not observed in 14
and thus confirms it as the trans product.
It is thought that free alkylidene carbenes adopt a pseudo
chair-like transition state to bring the carbene centre into
appropriate proximity with the relevant hydrogen atom, then
to undergo a 1,5-CH insertion reaction in a concerted
manner. In the case of substrate 7, this could give four
possible transition states (Fig. 2) labelled TS1–TS4. In this
experiment it was thought that most of the reactant
molecules react via TS1. This was assumed to be the lowest
energy conformation because both the phenyl group and
–CH2–OTBS groups are in equatorial orientations in the
The reason for any MOM methylene deactivation could be
due to there now being an oxygen atom within the substrate
bearing a 1,6-relationship to the carbene centre which could
coordinate to the carbene to form an internal oxonium ylide
thus deactivating 1,5-CH insertion. Evidence for and against
reversible oxonium ylide formation in ethereal solvents has
Figure 3. Proton assignments for nOe of dihydrofuran 20.
Table 1. Summary of nOe effects for dihydrofuran 20
Proton irr
Proton (nOe, %)
Proton irr
Proton (nOe)%
A
A
A
A
B
C
B, 2.03
E, 3.41
F, 1.55
D, 4.87
F, 2.31
A. 1.41
D
D
E
E
F
C, 1.31
B, 1.49
B, 5.18
F, 1.29
A, 2.55
B. 0.80
Scheme 7. Reagents and conditions: (i) MOMCl, diisopropyl-ethylamine;
(ii) 5% Pd/C, EtOH, H2; (iii) TPAP, NMO, DCM; (iv) LiTMSDM,
2788C!rt.
F

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G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
insertion accounts for some of the observed reaction
products.
In conclusion, we have demonstrated that intramolecular
alkylidene carbene C–H insertion reactions exhibit a
complex pattern of reactivity. In certain cases the insertion
is clean and diastereoselective whereas, in contrast, the
presence of oxygen atoms proximal to the insertion position
can result in competing trapping by the heteroatom.
Trapping by the oxygen atom can lead to a synthetically
useful synthesis of dihydrofurans.
Figure 4. Pseudo chair-like transition state in the reaction of ketone 17.
been published by Ochiai et al.36 and separately by Gilbert
et al.37
The minor product 20, although formed in a disappointing
yield, is interesting as it was formed as a single
diastereoisomer. The relative configuration was confirmed
by nOe spectroscopy (Fig. 3 and Table 1). These results
show no nOe between protons A and B and significant nOes
between protons B and F, A and E, thus confirming it as the
trans diastereoisomer. In rationalising this observed dia-
stereoselectivity it is believed that the reaction proceeds via
a similar transition state to that proposed in the previous
section, i.e. a pseudo chair-like transition state (Fig. 4).
However in this case the diastereoselectivity proposed is a
result of preference for an axial orientation of the methoxy
in the transition state due to anomeric stereoelectronic
effects.
3. Experimental
3.1. General
All reactions were carried out in oven or vacuum-flame
dried glassware under nitrogen. All reagents were obtained
from commercial sources and used without purification
unless stated. THF was distilled from sodium using
benzophenone as an indicator under nitrogen. DME was
distilled from calcium hydride under nitrogen. DCM and
methanol were supplied from Romil as Hi-Drye solvents,
DMF from Aldrich as anhydrous in Sure/Seale bottles. All
other solvents were from commercial sources and used
without further preparation unless otherwise stated. Petrol
refers to that fraction of petrol ether which boils in the range
40–608C.
From the previous two alkylidene carbene reactions an order
of insertion site preference was emerging: the alkylidene
carbene appears to prefer to insert into 5,6-bonds in the
following order; benzyl methylene CHqO–TBS.MOM
methylene CH.
Thin layer chromatography (tlc) was performed on
aluminium backed silica gel 60 (F254) plates supplied by
Merck and visualised by UV254, 2,4-dinitrophenylhydrazine
solution, phosphomolybdic acid solution, iodine (adsorbed
onto silica) or potassium permanganate solution. Column
chromatography was carried out on silica gel 40-63U 60A
supplied by Fluorochem Limited. Organic solvents were
removed on a Buchi Rotary Evaporator and then a static oil
pump (2 mm Hg).
To demonstrate that TBS protecting group migration to the
carbene centre is a facile process and therefore, the likely
origin of the products 15 and 21, a simple experiment was
designed and executed. It was reasoned that to demonstrate
1,5-insertion into OTBS bonds would require the synthesis
of a substrate 22 (Scheme 8) in which competing reactions
would not be possible, or very slow. In this ketone there is
no available 1,5-CH insertion site and the possibility of a
1,2-migration to give an alkyne is discouraged by the low
migratory aptitude of the alkyl groups.
Melting points were determined using a Stuart Scientific
SMP1 instrument and are uncorrected. Infrared spectra were
recorded on a Perkin–Elmer 1310 FTIR spectrometer on
sodium chloride plates. Optical rotations were measured
using a Perkin–Elmer 241 polarimeter (sodium D line) at rt
with a 10 cm rotation cell and are reported in 1021 deg
cm2 g21. Nuclear magnetic resonance spectra (NMR) were
recorded on Bruker AC 250 MHz, Bruker ARX-400, Bruker
300 MHz or Bruker 500 MHz spectrometers. Chemical shift
values are quoted in ppm and are relative to the internal
standard tetramethylsilane (TMS) for 1H NMR, or the
middle of the chloroform triplet d 77 for 13C NMR.
Multiplicities are quoted as singlet (s), doublet (d), triplet
(t), quartet (q) or multiplet (m) and coupling constants (J)
are quoted in Hz. Mass Spectra (MS) were recorded on a
Kratos analytical MS80 RFAO spectrometer, except some
high resolution mass determinations (HRMS) which were
obtained from the Swansea EPSRC Mass Spectrometry
Service. Elemental analysis were obtained using a Carlo
Erba 1160 elemental analyser.
The primary alcohol of diol 23 was first protected with a
TBS group by treatment with TBSCl and imidazole in DMF
affording the TBS protected alcohol 24 in 79% yield. This
was treated with TPAP and NMO in DCM to give the ketone
22 in 72% yield. Exposure of 22 to LiTMSDM under the
standard set of conditions employed gave a 50% yield of the
insertion product 25. In this way it was demonstrated that, in
the absence of more favourable reaction pathways, insertion
into OTBS bonds is a facile process and that this kind of
3.1.1.
hydride (4 g, 60% dispersion in mineral oil, 100 mmol)
1,1-Bis(benzyloxymethyl)-ethylene.
Sodium
Scheme 8. Reagents and conditions: (i) TBSCl, imidazole, DMF; (ii) TPAP,
NMO, DCM; (iii) LiTMSDM, DME/hexane, 2788C!rt.

G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
4743
was dispersed in DMF (200 mL) at 08C. To this benzyl
alcohol (10.4 mL, 10.87 g, 100 mmol) was added via
syringe pump over 1 h. After addition was complete
the mixture was stirred for a further 20 min at 08C then
1 h at rt. 3-Chloro-2-chloromethyl-1-propene (4.8 mL,
5.18 g, 41 mmol) was then added and the reaction left for
12 h, after which tlc (1:19, ethyl acetate/petrol) revealed
substantial product formation. The products were poured
into saturated NH4Cl solution (150 mL), and the organics
were extracted into ethyl acetate (4£200 mL). The com-
bined extracts were washed with water (5£200 mL), dried
(MgSO4) and the solvent removed under reduced pressure.
The crude product was purified by column chromatography
(1:19 v/v, ethyl acetate/petrol) yielding the alkene as a
colourless oil (9.40 g, 35 mmol, 88%).6,31 The spectro-
scopic data matched that described in the literature.
EtOH, washed with EtOH and then hexane yielding 8 as
1
white crystals (4.76 g, 17.90 mmol, 89%). The H NMR
spectrum was identical to authentic product.38 The spectro-
scopic data matched that described in the literature.
3.1.5. (2S,3S)-(1)-2-Benzyloxy-1,3,4-butanetriol 9. Alu-
minium trichloride (10.64 g, 80.6 mmol) was dissolved
in diethyl ether (40 mL) at 2208C and to this was added
LiAlH4 (3.73 g, 80 mmol) in diethyl ether (60 mL) at
2208C. This mixture was then diluted with DCM (80 mL)
and whilst maintained at 2208C, (2)-dimethyl-2,3-O-
benzylidene-L-tartrate 8 (3.65 g, 13.72 mmol) in DCM
(80 mL) was added. The reaction mixture was allowed to
warm to rt and then refluxed at 508C for 4 h. After this the
reaction was cooled to 2108C, then diluted with THF
(240 mL) and Na2SO4·10H2O (38 g) was added. This was
then stirred at 2108C for 2 h, allowed to warm to rt and left
for 16 h. The products were filtered through a pad of celite.
After removal of the solvent under reduced pressure the
product was purified by recrystallisation from ethyl acetate
and washed with hexane yielding 9 as fine white crystals
3.1.2. 1,3-Bis(benzyloxy)-2-propanone. 1,1-Bis(benzyl-
oxymethyl)-ethylene (2.84 g, 10.60 mmol) was dissolved
in DCM (10 mL) and cooled to 2788C. Ozone was then
bubbled through this until the reaction mixture adopted a
persistent pale blue coloration. Oxygen was bubbled
through for 10 min and then nitrogen for 30 min. Tri-
phenylphosphine (5.24 g, 20 mmol) was added, the cooling
bath removed and the mixture left for 12 h at rt. The crude
products were adsorbed directly onto silica and the product
purified by column chromatography (1:5 v/v, ethyl acetate/
petrol) yielding the ketone 5 as a colourless oil which
solidifies upon storage (2.36 g, 8.74 mmol, 82%).6,31 The
spectroscopic data matched that described in the literature.
1
(2.37 g, 11.18 mmol, 81.5%). The H NMR spectrum was
identical to authentic product.39
3.1.6. (2S,3S)-(1)-3-Benzyloxy-1,4-bis-(tert-butyl-di-
methyl-silanyloxy)-butan-2-ol 10. (2S,3S)-(þ)-2-Benzyl-
oxy-1,3,4-butanetriol 9 (0.50 g, 2.36 mmol), tert-butyl-
dimethyl-chlorosilane (0.78 g, 5.00 mmol), imidazole
(0.80 g, 11.80 mmol) and DMF (10 mL) were mixed at
2208C, allowed to warm to rt, then stirred for 24 h.
After this time tlc (1:9 v/v, ethyl acetate/petrol) revealed
consumption of the starting materials. The mixture was
poured into water (50 mL) and extracted into diethyl ether
(5£50 mL). The combined organic fractions were dried
(anhydrous MgSO4) and the solvent removed under reduced
pressure. The product was then purified by column
chromatography (1:19 v/v, ethyl acetate/petrol) yielding 9
as a clear oil (0.81 g, 1.84 mmol, 78%);40 CHN requires
C 62.68%, H 10.06%, found C 62.93%, H 10.09%;
[a]D¼þ14.30 (c 1.00, Abs. EtOH); nmax (NaCl)/cm21
2954, 2471, 1256, 1100, 833, 776; dH (250 MHz, CDCl3)
7.35–7.24 (5H, m, PhH), 4.77 (1H, d, JAB¼12 Hz,
Ph–CH2–O–), 4.60 (1H, d, JAB¼12 Hz, Ph–CH2–O–C),
3.87–3.58 (6H, m, Ph–CH2–O–CH(R)CH2–O–Si and
HO–CH(R)–CH2–O–Si), 2.56 (1H, d, J¼6 Hz, HO), 0.90
and 0.89 (18H, 2£s, Si(CH3)2–C(CH3)3), 0.06 and 0.05
(12H, 2£s, Si(CH3)2–C(CH3)3); dC (300 MHz, CDCl3)
138.9 (C ipso), 128.7 (PhCH), 128.3 (PhCH), 128.10
(PhCH), 78.8 (Ph–CH2–O–CH(R)CH2–O), 73.7 (Ph–
CH2–O–C), 72.1 (HO–CH(R)–CH2–O–), 64.1 and 63.5
(Ph–CH2–O–CH(R)CH2–O–Si and HO–CH(R)–CH2–
O–Si), 26.3 (Si(CH3)2–C(CH3)3) 18.6 (Si(CH3)2–
C(CH3)3), 24.9 and 24.0 (2£Si(CH3)2–C(CH3)3); m/z
(CI) 441 [MþH]þ, 383, 309, 108; HRMS (CI) [MþH
(C23H45O4Si2)]þ calculated 441.2856, found 441.2854.
3.1.3. 4-Benzyloxymethyl-2-phenyl-2,5-dihydro-furan 6.
A mixture of TMSDM (1.0 mL, 2 mmol, 2.0 M in hexane)
and DME (1 mL) were cooled to 2788C. To this was added
slowly, n-BuLi (0.84 mL, 2.1 mmol, 2.5 M in hexane), to
give a solution which was stirred for 20 min and then
allowed to warm to rt. The reaction mixture was again
cooled to 2788C and 1,3-bis(benzyloxy-2-propanone
(0.21 g, 0.77 mmol) was added, in a little DME (1 mL).
The reaction was allowed to warm to rt over 4 h and
quenched by the addition of water (5 mL) and extracted into
diethyl ether (3£10 mL). The organic extracts were
combined, dried (anhydrous MgSO4) and the solvent was
removed yielding a crude brown oil. The crude products
were adsorbed onto silica and the product purified by column
chromatography (1:19 v/v, ethyl acetate/petrol) yielding 6 as
an orange oil (0.15 g, 0.56 mmol, 73%).6,31 The spectroscopic
data matched that described in the literature.
3.1.4. (2R,3R)-(2)-Dimethyl-2,3-O-benzylidene-L-tar-
trate 8. Dimethyl-(L)-tartrate (3.56 g, 20 mmol), benzalde-
hyde–dimethylacetal (15 g, 99 mmol) and p-TSA (0.38 g,
2 mmol, 10 mol%) were mixed and stirred under reduced
pressure for 8 h, after which time tlc (1:5 v/v, ethyl acetate/
petrol) revealed complete consumption of the starting
material. The acid catalyst was neutralised with NaHCO3
(1 g), DCM (50 mL) added, and the mixture stirred a further
1 h. The mixture was then diluted with DCM (70 mL),
washed with water (50 mL), then dried (anhydrous MgSO4)
and the solvent removed under reduced pressure. Any
benzaldehyde or benzaldehyde–dimethylacetal were
removed by reduced pressure distillation (408C at
2 mm Hg). The crude product was then recrystallised from
3.1.7. (3R)-(2)-3-Benzyloxy-1,4-bis-(tert-butyl-dimethyl-
silanyloxy)-butan-2-one 7. N-Methylmorpholine oxide
(NMO) (2 g, 14.81 mmol) was dissolved in DCM
(100 mL), dried (anhydrous MgSO4) and filtered. Of this
solution a portion (17 mL) was taken and to it was added
(2S,3S)-(þ)-3-benzyloxy-1,4-bis-(tert-butyl-dimethyl-silanyl-
˚
oxy)-butan-2-ol 10 (0.456 g, 1.06 mmol) and some 2 A

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G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
molecular sieves (1 g). This mixture was stirred gently for
20 min and then tetrapropylammonium perruthenate
(TPAP) (0.018 g, 0.05 mmol, 5 mol%) was added. The
reaction was monitored by tlc (1:19 v/v, ethyl acetate/petrol)
and after 16 h was complete, therefore, the crude products
were adsorbed directly onto silica and the product purified
by column chromatography (1:19 v/v, ethyl acetate/petrol)
yielding 7 as a yellow oil (0.403 g, 0.92 mmol, 87%);40
[a]D¼216.50 (c 0.996, Abs. EtOH); nmax (NaCl)/cm21
2930, 1738, 1471, 1255, 1130, 837; dH (250 MHz, CDCl3)
7.37–7.29 (5H, m, PhH), 4.62 (2H, s, Ph–CH2–O), 4.58
0.02 mmol, 5 mol%) was added. The reaction was moni-
tored by tlc (1:19 v/v, ethyl acetate/petrol) and after 48 h
was complete, therefore, the crude products were adsorbed
directly onto silica and the product purified by column
chromatography (1:19 v/v, ethyl acetate/petrol) yielding 12
as a pale green oil (0.155 g, 0.23 mmol, 62%); nmax (NaCl)/
cm21 3071, 2931, 1739, 1472, 1113, 707; dH (300 MHz,
CDCl3) 7.76–7.11 (25H, m, PhH), 4.61 (1H, d, JAB¼19 Hz,
Ph–CH2–O), 4.54 (1H, d, JAB¼19 Hz, Ph–CH2–O), 4.43
(1H, d, JAB¼12 Hz, OvC(R)–CH2–O–Si), 4.39 (1H, d,
JAB¼12 Hz, OvC(R)–CH2–O–Si), 4.03 (1H, t, JAX
¼
(1H, d, JAB¼19 Hz, OvC(R)–CH2–O), 4.48 (1H, d, JAB
¼
4 Hz, JBX¼4 Hz, Ph–CH2–O–CH(R)–CH2–O–Si), 3.85
(1H, dd, JAB¼11 Hz, JBX¼4 Hz, Ph–CH2–O–CH(R)–
CH2–O–Si), 3.80 (1H, dd, JAB¼11 Hz, JAX¼4 Hz, Ph–
CH2–O–CH(R)–CH2–O–Si), 1.08 (9H, s, Si(Ph)2–
C(CH3)3), 1.00 (9H, s, Si(Ph)2–C(CH3)3); dC (300 MHz,
CDCl3) 208.0 (OvC), 137.7 (C ipso), 136.1 (PhCH), 136.01
(PhCH), 135.98 (PhCH), 133.32 (SiC ipso), 130.26 (PhCH),
130.2 (PhCH), 130.2 (PhCH), 128.8 (PhCH), 128.1 (PhCH),
128.0 (PhCH), 84.1 (Ph–CH2–O–CH), 72.7 (OvC(R)–
CH2–O–Si), 69.4 (Ph–CH2–O), 64.7 (Ph–CH2–O–
CH(R)–CH2–O–Si), 27.1 (Si(Ph)2–C(CH3)3), 19.7 and
19.6 (Si(Ph)2–C(CH3)3); m/z (CI) 704 [MþNH4]þ, 501,
450, 433, 391; HRMS (CI) [MþNH4, (C43H54O4NSi2)]þ
calculated 704.3591, found 704.3591.
19 Hz, OvC(R)–CH2–O–Si), 4.07 (1H, dd, JAX¼4 Hz,
JBX¼5 Hz, Ph–CH2–O–CH(R)–CH2–O–Si), 3.93 (1H,
dd, JAX¼4 Hz, JAB¼11 Hz, Ph–CH2–O–CH(R)–CH2–
O–Si), 3.87 (1H, dd, JBX¼5 Hz, JAB¼11 Hz, Ph–CH2–O–
CH(R)–CH2–O–Si), 0.90 and 0.88 (18H, 2£s,
O–Si(CH3)2–C(CH3)3), 0.07 and 0.06 (12H, 2£s,
Si(CH3)2–C(CH3)3); dC (300 MHz, CDCl3) 208.5 (OvC),
137.5 (C ipso), 128.5 (PhCH), 127.9 (PhCH), 127.8 (PhCH),
83.6 (Ph–CH2–O–CH(R)CH2–O–Si), 72.6 (Ph–CH2–O),
68.8 (OvC(R)–CH2–O–Si), 63.8 (Ph–CH2–O–
CH(R)CH2–O–Si), 25.8 and 25.8 (2£Si(CH3)2–
C(CH3)3), 18.4 and 18.3 (2£Si(CH3)2–C(CH3)3), 25.3
and 25.5 (2£Si(CH3)2–C(CH3)3); m/z (CI) 456
[MþNH4]þ, 391, 331, 273; HRMS (CI) [MþNH4,
(C23H46O4Si2N)]þ calculated 456.2965, found 456.2965.
3.1.10. (2R,5S)-2,3-Bis-(tert-butyl-dimethyl-silanyloxy-
methyl)-5-phenyl-2,5-dihydro-furan 13, (2R,5R)-2,3-bis-
(tert-butyl-dimethyl-silanyloxymethyl)-5-phenyl-2,5-
dihydro-furan 14–16. A mixture of TMSDM (1.3 mL,
2.6 mmol, 2.0 M in hexane) and DME (1.3 mL) were cooled
to 2788C. To this mixture was added slowly, n-BuLi
(1.04 mL, 2.6 mmol, 2.5 M in hexane), which was stirred
for 20 min and then allowed to warm to rt. The reaction
mixture was again cooled to 2788C and a solution of (3R)-
(2)-3-benzyloxy-1,4-bis-(tert-butyl-dimethyl-silanyloxy)-
butan-2-one 7 (0.548 g, 1.25 mmol) dissolved in DME
(1.3 mL) was added dropwise. The reaction was allowed to
warm to rt over 4 h and quenched by the addition of water
(20 mL) to give a mixture which was extracted with ethyl
acetate (3£30 mL). The organic extracts were combined,
dried (anhydrous MgSO4) and the solvent was removed
under reduced pressure. The crude products were then
purified by column chromatography (1:49 v/v, ethyl acetate/
petrol) yielding: 13 the major cis diastereoisomer as a clear
oil (0.273 g, 0.63 mmol, 50%); and 14 the minor trans
diastereoisomer as a clear oil (0.078 g, 0.18 mmol, 14%).
3.1.8. (2S,3S)-3-Benzyloxy-1,4-bis-(tert-butyl-diphenyl-
silanyloxy)-butan-2-ol 11. (2S,3S)-2-Benzyloxy-1,3,4-
butanetriol 9 (0.100 g, 0.472 mmol), tert-butyl-diphenyl-
chlorosilane (0.283 g, 1.030 mmol), dimethylamino pyri-
dine (DMAP) (0.003 g, 0.025 mmol, 5 mol%), pyridine
(1.5 mL) and DCM (2 mL) were mixed at 08C and stirred,
with monitoring by tlc (1:19 v/v, ethyl acetate/petrol). After
24 h the reaction had reached completion and the mixture
was adsorbed directly onto silica and purified by column
chromatography (1:19 v/v, ethyl acetate/petrol) yielding 11
as a yellow oil (0.294 g, 0.427 mmol, 90%); nmax (NaCl)/
cm21 3448, 2931, 1471, 1113, 823, 701; dH (250 MHz,
CDCl3) 7.71–7.18 (25H, m, PhH), 4.65 (1H, d, JAB¼11 Hz,
Ph–CH2–O), 4.44 (1H, d, JAB¼11 Hz, Ph–CH2–O), 3.94–
3.71 (6H, m, Ph–CH2–O–CH(R)CH2–O–Si and
HO–CH(R)–CH2–O–Si), 2.50 (1H, br s, HO), 1.05
(18H, s, Si(Ph)2–C(CH3)3); dC (300 MHz, CDCl3) 138.7
(C ipso), 133.8 (C ipso), 133.7 (C ipso), 136.1–128.1
(PhCH’s), 78.7 (Ph–CH2–O–CH(R)CH2–O–Si or
HO–CH(R)–CH2–O–Si), 73.5 (Ph–CH2–O–CH(R)CH2–
O–Si), 72.0 (Ph–CH2–O–CH(R)CH2–O–Si or HO–
CH(R)–CH2–O–Si), 64.7 and 63.7 (Ph–CH2–O–
CH(R)CH2–O–Si and HO–CH(R)–CH2–O–Si), 27.3
(Si(Ph)2–C(CH3)3), 19.6 (Si(Ph)2–C(CH3)3); m/z (CI) 706
[MþNH4]þ, 365, 129; HRMS (CI) [MþNH4
(C43H56O4NSi2)]þ calculated 706.3748, found 706.3737.
Compound 13 [a]D¼21.86 (c 1.62, Abs. EtOH); nmax
(NaCl)/cm21 2929, 2857, 1471, 1255, 1093, 838; dH
(300 MHz, CDCl3) 7.37–7.25 (5H, m, PhH), 5.77 (1H, m,
CHvC), 5.74 (1H, m, Ph–CH(R)–OR), 4.81 (1H, m, Ph–
CH(R)–O–CH(R)–CH2–OTBS), 4.43 (1H, d, J¼15 Hz,
CHvC(R)–CH2 –OTBS), 4.26 (1H, d, J¼15 Hz,
CHvC(R)–CH2–OTBS), 3.83 (1H, dd, JAX¼3 Hz, JAB
¼
3.1.9. (3R)-3-Benzyloxy-1,4-bis-(tert-butyl-diphenyl-sila-
nyloxy)-butan-2-one 12. NMO (2 g, 14.81 mmol) was
dissolved in DCM (100 mL), dried (anhydrous MgSO4)
and filtered. A portion of this solution (10 mL) was taken
and to it was added (2S,3S)-(þ)-3-benzyloxy-1,4-bis-(tert-
(0.254 g,
10 Hz, O–CH(R)–CH2–OTBS), 3.75 (1H, dd, JBX¼6 Hz,
JAB¼10 Hz, O–CH(R)–CH2–OTBS), 0.91 (9H, s, R–O–
Si(CH3)2 –C(CH3)3), 0.90 (9H, s, R–O–Si(CH3)2 –
C(CH3)3), 0.08, 0.08, 0.06 and 0.05 (12H, 4£s, 4£R–O–
Si(CH3)2 –C(CH3)3); 1H-NOESY (500 MHz, CDCl3).
Irradiation at 5.80 ppm; 7.40 ppm (nOe¼2.45), 4.40 ppm
(nOe¼1.42); irradiation at 5.75 ppm; 7.40 ppm (nOe¼
5.83), 4.86 ppm (nOe¼1.35); irradiation at 4.85 ppm;
butyl-diphenyl-silanyloxy)-butan-2-ol
0.37 mmol) and 2 A molecular sieves (0.5 g). This mixture
was stirred gently for 20 min and then TPAP (0.007 g,
11
˚

G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
4745
5.75 ppm (nOe¼1.71), 4.30 ppm (nOe¼1.48), 3.85 ppm
(nOe¼5.77); dC (300 MHz, CDCl3) 143.3 (C ipso), 142.4
(Ph–CH(OR)–CHvC(R)–CH2–OTBS), 128.7 (PhCH),
128.2 (PhCH), 127.4 (PhCH), 125.0 (Ph–CH(OR)–
CHvC(R)–CH2–OTBS), 87.5 (Ph–CH(OR)–C), 86.6
(Ph–CH(R)–O–CH(R)–CH2–OTBS), 66.0 (O–CH(R)–
CH2 –OTBS), 60.0 (CHvC(R)–CH2 –OTBS), 30.1
(Si(CH3)2 –C(CH3)3), 26.3 (Si(CH3)2 –C(CH3)3), 25.0
(Si(CH3)2 –C(CH3)3); m/z (CI) 452 [MþNH4]þ, 435
propoxymethyl]-benzene 18. (2S,3S)-(þ)-3-Benzyloxy-1,
4-bis-(tert-butyl-dimethyl-silanyloxy)-butan-2-ol 7 (0.602 g,
1.37 mmol), di-isopropylethylamine (3 mL, 2.23 g,
16 mmol) and chloromethyl methyl ether (1 mL, 1.06 g,
13 mmol) were mixed and stirred at 08C for 1 h, then at rt
for 29 h. The mixture was poured into ethyl acetate
(50 mL), washed with water (3£30 mL), brine (30 mL),
dried (anhydrous MgSO4) and the ethyl acetate removed
under reduced pressure. The crude product was purified by
column chromatography (1:32 v/v, ethyl acetate/petrol)
yielding 18 as a clear oil (0.573 g, 1.18 mmol, 86%);
[a]D¼þ1.30 (c 1.02, Abs. EtOH); nmax (NaCl)/cm21 2929,
1471, 1255, 1101, 1036, 837; dH (300 MHz, CDCl3) 7.37–
7.25 (5H, m, PhH), 4.75 (1H, d, J¼7 Hz, CH3–O–CH2–
O–CH), 4.71 (1H, d, J¼11 Hz, Ph–CH2–O), 4.68 (1H, d,
J¼7 Hz, CH3–O–CH2–O–CH), 4.64 (1H, d, J¼11 Hz,
Ph–CH2–O), 3.80–3.64 (6H, m, MOMO–CH(R)–CH2–
OTBS and BnO–CH(R)–CH2–OTBS), 3.36 (3H, s, CH3–
O–CH2–O), 0.89 and 0.88 (18H, 2£s, 2£O–Si(CH3)2–
C(CH3)3), 0.05 and 0.02 (12H, 2£s, 2£O–Si(CH3)2–
C(CH3)3); dC (300 MHz, CDCl3) 139.2 (C ipso), 128.6
(PhCH), 128.5 (PhCH), 127.9 (PhCH), 97.6 (CH3–O–
CH2–O), 79.3 and 78.0 (MOMO–CH(R)–CH2–OTBS and
BnO–CH(R)–CH2–OTBS), 74.0 (Ph–CH2–O), 62.7 and
62.7 (MOMO–CH(R)–CH2–OTBS and BnO–CH(R)–
CH2–OTBS), 56.0 (CH3–O–CH2–O), 26.7 (O–Si(CH3)2–
C(CH3)3), 18.6 (O–Si(CH3)2–C(CH3)3), –5.0 (O–
Si(CH3)2–C(CH3)3); m/z (CI) 502 [MþNH4]þ, 485
[MþH]þ, 453, 380, 361; HRMS (CI) [MþNH4
(C25H52O5Si2N)]þ calculated 502.3384, found 502.3386.
[MþH]þ,
417,
301;
HRMS
(CI)
[MþNH4
(C24H46O3NSi2)]þ calculated 452.3016, found 452.3009.
Compound 14 [a]D¼þ15.7 (c 0.23, Abs. EtOH); nmax
(NaCl)/cm21 2955, 2857, 1471, 1255, 1087, 836; dH
(250 MHz, CDCl3) 7.37–7.24 (5H, m, PhH), 5.78 (2H, m,
CHvC and Ph–CH(R)–OR), 4.94 (1H, m, O–CH(R)–
CH2–OTBS), 4.41 (1H, d, J¼15 Hz, CHvC(R)–CH2–
OTBS), 4.28 (1H, d, J¼15 Hz, CHvC(R)–CH2–OTBS),
3.81 (1H, dd, JAX¼4 Hz, JAB¼11 Hz, O–CH(R)–CH2–
OTBS), 3.75 (1H, dd, JBX¼6 Hz, JAB¼11 Hz, O–CH(R)–
CH2–OTBS), 0.91 (18H, s, O–Si(CH3)2–C(CH3)3), 0.08,
0.07 and 0.06 (12H, 3£s, 3£Si(CH3)2 –C(CH3)3);
1H-NOESY (500 MHz, CDCl3). Irradiation at 5.80 ppm;
7.40 ppm (nOe¼4.08); irradiation at 5.75 ppm; 7.40 ppm
(nOe¼5.83), 4.86 ppm (nOe¼1.35); irradiation at
4.95 ppm; 7.4 ppm (nOe¼1.87), 4.30 ppm (nOe¼1.88),
3.85 ppm (nOe¼5.87); dC (300 MHz, CDCl3) 142.9
(C ipso), 142.4 (CHvC(R)), 128.8 (PhCH), 128.1 (PhCH),
127.4 (PhCH), 125.0 (CHvC(R)), 87.9 (Ph–CH(OR)–
CHvC), 86.7 (Ph–CH(R)–O–CH(R)–CH2 –OTBS),
65.6 (Ph–CH(R)–O–CH(R)–CH2 –OTBS), 60.0 (Ph–
CH(OR)–CHvC(R)–CH2 –OTBS), 31.4 (Si(CH3)2 –
C(CH3)3), 26.3 (Si(CH3)2–C(CH3)3), 24.9 (Si(CH3)2–
C(CH3)3); m/z (CI) 452 [MþNH4]þ, 435 [MþH]þ, 417,
327, 195; HRMS (CI) [MþH (C24H43O3Si2)]þ calculated
435.2751, found 435.2750.
3.1.12. (2S,3S)-1,4-Bis(tert-butyl-dimethyl-silanyloxy)-3-
methoxymethoxy-butan-2-ol 19. (2S,3S)-[3-(tert-Butyl-
dimethyl-silanyloxy)-1-(tert-butyl-dimethyl-silanyloxy)-2-
methoxymethoxy-propoxymethyl]-benzene 18 (0.316 g,
0.65 mmol), ethanol (2 mL) and 5% palladium on carbon
(0.05 g, 0.02 mmol, 3 mol%) were mixed and stirred
vigorously under hydrogen (1 atm) for 3 h. After this time
tlc (1:9 v/v, ethyl acetate/petrol) showed complete con-
sumption of the starting material, so the products were
filtered through celite. After removal of the solvents and
toluene under reduced pressure, 19 was obtained as a
colourless oil (0.239 g, 0.61 mmol, 93%); CHN requires C
54.77%, H 10.73%, found C 54.76%, H 10.69%;
[a]D¼þ9.60 (c 1.09, Abs. EtOH); nmax (NaCl)/cm21
3466, 2954, 1471, 1255, 1101, 1036; dH (250 MHz,
CDCl3) 4.78 (1H, d, J¼7 Hz, CH3–O–CH2–O), 4.71
(1H, d, J¼7 Hz, CH3–O–CH2–O), 3.89–3.66 (6H, m,
MOMO–CH(R)–CH2 –OTBS and HO–CH(R)–CH2 –
OTBS), 3.40 (3H, s, CH3–O–CH2–O), 2.76 (1H, d,
J¼5 Hz, HO), 0.90 (18H, s, O–Si(CH3)2–C(CH3)3), 0.07
(12H, s, O–Si(CH3)2–C(CH3)3); dC (300 MHz, CDCl3)
97.4 (CH3–O–CH2–O), 77.9 (MOMO–CH(R)–CH2 –
OTBS or HO–CH(R)–CH2 –OTBS), 72.3 (MOMO–
CH(R)–CH2–OTBS or HO–CH(R)–CH2–OTBS), 64.0
and 63.8 (MOMO–CH(R)–CH2–OTBS and HO–CH(R)–
CH2–OTBS), 56.1 (CH3–O–CH2–O), 26.2 (O–Si(CH3)2–
C(CH3)3), 18.6 (O–Si(CH3)2–C(CH3)3), 25.0 and 25.1
(2£O–Si(CH3)2–C(CH3)3); m/z (CI) 412 [MþNH4]þ, 395
[MþH]þ, 380, 363, 132.
1
The yield of minor trans product is calculated from H
NMR integrals, it being inseparable from a third product by
column chromatography. The third product 15 rearranges
upon leaving to the furan 16 plus benzyl alcohol (a 1:1
mixture). The presence of the benzyl alcohol was confirmed
1
by spiking the H NMR sample with benzyl alcohol and
observing an increase in the integrals for the peaks
attributed to the benzyl alcohol within the mixture.
Compound 15 dH (250 MHz, CDCl3) 7.32–7.27 (5H, m,
PhH), 4.92 (1H, dd, JAX¼2 Hz, JBX¼7 Hz, Bn–O–CH),
4.52 (1H, d, J¼12 Hz, Ph–CH2–O), 4.46 (1H, d, J¼12 Hz,
Ph–CH2–O), 4.32 (2H, s, CvC(R)–CH2–OTBS), 4.28
(1H, dd, JAX¼2 Hz, JAB¼11 Hz, O–CH2–CH(OBn)), 4.10
(1H, dd, JBX¼7 Hz, JAB¼11 Hz, O–CH2–CH(OBn)), 0.93
and 0.90 (18H, 2£s, 2£Si–(CH3)2–C(CH3)3), 0.17 and 0.18
(12H, 2£s, 2£Si–(CH3)2–C(CH3)3).
Compound 16 dH (250 MHz, CDCl3) 7.56 (1H, d, J¼2 Hz,
O–CHvCH), 6.44 (1H, d, J¼2 Hz, O–CHvCH), 4.61
(2H, s, CH2–OTBS), 0.91 and 0.89 (18H, 2£s, 2£Si–
(CH3)2–C(CH3)3), 0.26 and 0.08 (12H, 2£s, 2£Si–(CH3)2–
C(CH3)3).
3.1.11. (2S,3S)-[3-(tert-Butyl-dimethyl-silanyloxy)-1-
(tert-butyl-dimethyl-silanyloxy)-2-methoxymethoxy-
3.1.13. (3S)-1,4-Bis(tert-butyl-dimethyl-silanyloxy)-3-
methoxymethoxy-butan-2-one
17.
NMO
(2 g,

4746
G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
14.81 mmol) was dissolved in DCM (100 mL). This was
dried (anhydrous MgSO4) and then filtered. Of this solution
a portion (14 mL) was taken and to it added (2S,3S)-1,
4-bis(tert-butyl-dimethyl-silanyloxy)-3-methoxymethoxy-
(1H, d, J¼12 Hz, CH2–OTBS), 4.27 (1H, d, J¼12 Hz,
CH2 –OTBS), 4.24 (1H, dd, JAX¼3 Hz, JAB¼11 Hz,
O–CH2–CH(MOMO)), 4.16 (1H, dd, JBX¼7 Hz, JAB
¼
11 Hz, O–CH2–CH(MOMO)), 3.38 (3H, s, CH3–O–CH2–
O), 0.91 and 0.89 (18H, 2£s, 2£O–Si(CH3)2–C(CH3)3),
0.18 and 0.17 (6H, 2£s, 2£Si(CH3)2–C(CH3)3), 0.07 and
0.05 (6H, 2£s, 2£Si(CH3)2–C(CH3)3); dC (300 MHz,
CDCl3) 154.0 (TBS–C), 96.7 (CH3–O–CH2–O), 81.6
(CH(MOMO)), 76.0 (O–CH2–CH(MOMO)), 56.7 (CH2–
OTBS), 56.1 (CH3–O–CH2–O), 27.0 and 26.6 (2£O–
Si(CH3)2 –C(CH3)3), 18.7 and 17.5 (2£O–Si(CH3)2 –
C(CH3)3), 24.6 (Si(CH3)2–C(CH3)3); m/z (EI) 387, 322,
280, 147, 73; HRMS (EI) [M (C19H40O4Si2)]þ calculated
388.2465, found 388.2446.
˚
butan-2-ol 19 (0.221 g, 0.561 mmol) and 2 A molecular
sieves (0.5 g). This mixture was stirred gently for 20 min
and then TPAP (0.020 g, 0.06 mmol, 11 mol%) was added.
The reaction was monitored by tlc (1:19 v/v, ethyl acetate/
petrol) and after 2 h was complete. The mixture was diluted
with DCM (50 mL), filtered, washed with sodium sulphite
solution (20 mL), brine (20 mL), dried (anhydrous MgSO4),
filtered again and the solvent removed under reduced
pressure. The crude product was purified by column
chromatography (1:9 v/v, ethyl acetate/petrol) yielding 17
as an colourless oil (0.179 g, 0.457 mmol, 81%); CHN
requires C 55.06%, H 10.27%, found C 55.18%, H 10.38%;
[a]D¼20.51 (c 1.24, Abs. EtOH); nmax (NaCl)/cm21 2953,
1738, 1472, 1255, 1123, 1036; dH (250 MHz, CDCl3) 4.74
(1H, d, J¼7 Hz, CH3–O–CH2–O), 4.65 (1H, d, J¼7 Hz,
CH3–O–CH2–O), 4.56 (1H, d, J¼19 Hz, C(vO)–CH2–
OTBS), 4.45 (1H, d, J¼19 Hz, C(vO)–CH2–OTBS), 4.27
(1H, t, J¼4 Hz, MOMO–CH(R)–CH2–OTBS), 3.89 (2H,
d, J¼4 Hz, MOMO–CH(R)–CH2–OTBS), 3.37 (3H, s,
CH3 –O–CH2 –O), 0.92 and 0.87 (18H, 2£s, 2£O–
Si(CH3)2 –C(CH3)3), 0.09 and 0.08 (6H, 2£s, 2£O–
Si(CH3)2 –C(CH3)3), 0.05 and 0.04 (6H, 2£s, 2£O–
Si(CH3)2 – C(CH3)3); dC (300 MHz, CDCl3) 208.3
(C(vO)), 96.8 (CH3 –O–CH2 –O), 81.5 (MOMO–
CH(R)–CH2 –OTBS), 69.2 (R–C(vO)–CH2 –OTBS),
64.2 (MOMO–CH(R)–CH2 –OTBS), 56.3 (CH3 –O–
CH2 – O), 26.2 (O – Si(CH3)2 – C(CH3)3), 18.8 (O –
Si(CH3)2–C(CH3)3), 25.0 (O–Si(CH3)2–C(CH3)3); m/z
(CI) 410 [MþNH4]þ, 395, 280, 220, 148; HRMS (CI)
[MþNH4 (C18H44O5Si2N)]þ calculated 410.2758, found
410.2762.
Compound 20 [a]D¼þ14.95 (c 1.03, Abs. EtOH); nmax
(NaCl)/cm21 2995, 2858, 1472, 1102, 963; dH (250 MHz,
CDCl3) 5.73 (1H, m, CH(O–CH3)), 5.68 (1H, m, CvCH),
4.80 (1H, m, O–C(R)H–CH2–OTBS), 4.39 (1H, d, JAB
16 Hz, TBSO–CH2–C(R)vCH), 4.23 (1H, d, JAB¼16 Hz,
TBSO–CH2 –C(R)vCH), 3.76 (1H, dd, JAB¼11 Hz,
¼
JAX¼4 Hz, O–CH(R)–CH2–OTBS), 3.61 (1H, dd, JAB
¼
11 Hz, JBX¼6 Hz, O–CH(R)–CH2–OTBS), 3.37 (3H, s,
O–CH3), 0.90 and 0.87 (18H, 2£s, 2£Si(CH3)2–C(CH3)3),
0.06 and 0.05 (12H, 2£s, 2£Si(CH3)2 –C(CH3)3);
1H-NOESY (500 MHz, CDCl3). Irradiation at 5.76 ppm;
3.40 ppm (nOe¼4.87); irradiation at 5.71 ppm; 4.33 ppm
(nOe¼1.07), 3.40 ppm (nOe¼1.42); irradiation at
4.83 ppm; 4.27 ppm (nOe¼1.55), 3.78 ppm (nOe¼3.41),
3.64 ppm (nOe¼2.04), 3.40 ppm (nOe¼2.31); irradiation at
4.33 ppm; 5.71 ppm (nOe¼1.31), 4.83 ppm (nOe¼1.49);
irradiation at 3.72 ppm; 4.83 ppm (nOe¼5.18), 3.40 ppm
(nOe¼1.30); irradiation at 3.40 ppm; 5.76 ppm
(nOe¼2.55), 4.83 ppm (nOe¼0.80); dC (300 MHz,
CDCl3) 149.3 (TBSO–CH2–C(R)vCH), 120.7 (TBSO–
CH2–C(R)vCH–CH(O–CH3)), 109.2 (CvCH–CH(O–
CH3)), 85.4 (TBSO–CH2–CH(R)–O), 65.3 (O–CH(R)–
CH2–OTBS), 59.7 (TBSO–CH2–C(R)vCH), 54.2 (O–
CH3), 26.2 (Si(CH3)2 –C(CH3)3), 18.8 (Si(CH3)2 –
C(CH3)3), 25.0 (Si(CH3)2–C(CH3)3); m/z (EI) 387, 357,
299, 225, 82; HRMS (EI) [M (C19H40O4Si2)]þ calculated
388.2465, found 388.2448.
3.1.14. (1R,5R)-2,3-Bis-(tert-butyl-dimethyl-silanyloxy-
methyl)-5-methoxy-2,5-dihydro-furan 20 and 5-(tert-
butyl-dimethyl-silanyl)-4-(tert-butyl-dimethyl-silanyl-
oxy-methyl)-3-methoxymethoxy-2,3-dihydro-furan 21.
A mixture of TMSDM (0.4 mL, 0.08 mmol, 2.0 M in
hexane) and DME (0.4 mL) were cooled to 2788C. To this
was added slowly, n-BuLi (0.32 mL, 0.8 mmol, 2.5 M in
hexane), which was stirred for 20 min and then allowed to
warm to rt. The reaction mixture was again cooled to 2788C
and (3S)-1,4-bis(tert-butyl-dimethyl-silanyloxy)-3-methoxy-
methoxy-butan-2-one 17 (0.157 g, 0.40 mmol) dissolved in
DME (0.4 mL) was added dropwise. The reaction was
allowed to warm to rt over 4 h and quenched by the addition
of water (5 mL), to give a mixture which was extracted into
ethyl acetate (5£5 mL). The organic extracts were com-
bined, dried (anhydrous MgSO4) and the solvent was
removed under reduced pressure. The crude products were
then purified by column chromatography (3:97 v/v, ethyl
acetate/petrol) yielding: 20 as a pale yellow oil (0.046 g,
0.12 mmol, 30%); and 21 as a pale yellow oil (0.038 g,
0.10 mmol, 25%).
3.1.15. 4-(tert-Butyl-dimethyl-silanyloxy)-butan-2-ol 24.
1,3-Butanediol 23 (1 mL, 1.01 g, 11.2 mmol) was dissolved
in DMF (20 mL) and cooled to 2208C. To this was added
tert-butyl-dimethylchlorosilane (2.00 g, 13.4 mmol), imida-
zole (1.76 g, 26.0 mmol) and the resulting mixture was
stirred at 2208C for 20 min, then at rt for 12 h. The mixture
was then poured into water (100 mL) and the organic
components extracted into diethyl ether (5£50 mL). The
combined organic extracts were dried (anhydrous MgSO4)
and the solvent removed under reduced pressure. The crude
product was then purified by column chromatography (1:9
v/v, ethyl acetate/petrol) yielding 24 as a pale yellow oil
(1.82 g, 8.9 mmol, 79%); nmax (NaCl)/cm21 3383, 2929,
1466, 1257, 1097, 834; dH (300 MHz, CDCl3) 4.05–3.99
(1H, m, TBSO–CH2–CH2–CH(OH)–CH3), 3.93–3.77
(2H, m, TBSO–CH2–CH2–CH(OH)–CH3), 3.45 (1H, br
s, TBSO–CH2–CH2–CH(OH)–CH3), 1.72–1.60 (2H, m,
TBSO–CH2–CH2–CH(OH)–CH3), 1.19 (3H, d, J¼6 Hz,
TBSO–CH2–CH2–CH(OH)–CH3), 0.91 (9H, s, Si(CH3)2–
C(CH3)3), 0.08 (6H, s, Si(CH3)2–C(CH3)3); dC (300 MHz,
Compound 21 [a]D¼217.43 (c 1.635, Abs. EtOH); nmax
(NaCl)/cm21 2953, 1625, 1472, 1362, 1253, 1032, 837;
dH (250 MHz, CDCl3) 4.92 (1H, dd, JAX¼3 Hz, JBX¼7 Hz,
O–CH2–CH(OMOM)), 4.71 (1H, d, J¼7 Hz, CH3–O–
CH2–O), 4.66 (1H, d, J¼7 Hz, CH3–O–CH2–O), 4.33

G. Hobley et al. / Tetrahedron 59 (2003) 4739–4748
4747
CDCl3) 68.8 (TBSO–CH2–CH2–CH(OH)–CH3), 63.2
(TBSO–CH2–CH2–CH(OH)–CH3), 40.3 (TBSO–CH2–
CH2–CH(OH)–CH3), 26.2 (Si(CH3)2–C(CH3)3), 23.7
(TBSO–CH2–CH2–CH(OH)–CH3), 18.5 (Si(CH3)2–
C(CH3)3), 25.2 and 25.2 (Si(CH3)2–C(CH3)3); m/z (CI)
222 [MþNH4]þ, 205 [MþH]þ; HRMS (CI) [MþH
(C10H25O2Si)]þ calculated 205.1624, found 205.1625.
Si(CH3)2–C); m/z (EI) 215 [M2HþNH4]þ, 197 [M2H]þ;
HRMS (EI) [M (C11H22OSi)]þ calculated 198.1440, found
198.1429.
Acknowledgements
We thank Avensis for a CASE award (to GH) and Professor
D. Games and Dr B. Stein of the EPSRC National Mass
Spectroscopic service (Swansea) for HRMS analysis of
certain compounds. We wish to acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.41
3.1.16. 4-(tert-Butyl-dimethyl-silanyloxy)-butan-2-one
22. NMO (2 g, 14.81 mmol) was dissolved in DCM
(100 mL). This was dried over anhydrous MgSO4 and
then filtered. To this solution was added 4-(tert-butyl-
dimethyl-silanyloxy)-butan-2-ol 24 (1.12 g, 5.49 mmol) and
˚
some 2 A molecular sieves (2.0 g). This mixture was stirred
gently for 20 min and then TPAP (0.050 g, 0.15 mmol,
3 mol%) was added. The reaction was monitored by tlc (1:9
v/v, ethyl acetate/petrol) and after 14 h was complete. The
mixture was diluted with DCM (50 mL), filtered, washed
with sodium sulphite solution (100 mL), brine (100 mL),
saturated copper sulphate solution (100 mL), dried (anhy-
drous MgSO4), filtered again and the solvent removed under
reduced pressure. The crude product was purified by column
chromatography (1:9 v/v, ethyl acetate/petrol) yielding 22
as a clear oil (0.807 g, 3.96 mmol, 72%); CHN requires C
59.35%, H 10.96%, found C 59.15%, H 10.96%; nmax
(NaCl)/cm21 2955, 2857, 1716, 1472, 1255, 1103; dH
(250 MHz, CDCl3) 3.88 (2H, t, J¼6 Hz, TBSO–CH2–
CH2–C(vO)–CH3), 2.62 (2H, t, J¼6 Hz, TBSO–CH2–
CH2–C(vO)–CH3), 2.19 (3H, s, TBSO–CH2–CH2–
C(vO)–CH3), 0.88 (9H, s, Si(CH3)2–C(CH3)3), 0.05
(6H, s, Si(CH3)2–C(CH3)3); dC (300 MHz, CDCl3) 208.6
(TBSO–CH2–CH2–C(vO)–CH3), 59.2 (TBSO–CH2–
CH2–C(vO)–CH3), 46.9 (TBSO–CH2–CH2–C(vO)–
CH3), 31.3 (TBSO–CH2–CH2–C(vO)–CH3), 26.2
(Si(CH3)2–C(CH3)3), 18.6 (Si(CH3)2–C(CH3)3), 25.1
(Si(CH3)2–C(CH3)3); m/z (CI) 220 [MþNH4]þ, 203
[MþH]þ, 182, 145.
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