Asymmetric synthesis of tetrahydrofurans by competitive [1,2]-phenylsulfanyl (PhS) migrations under thermodynamic control

Article abstract of DOI:10.1039/b208556a

Asymmetric synthesis of tetrahydrofurans (THF) by competitive [1,2]-phenylsulfanyl (PhS) migrations under thermodynamic control was discussed. Triols were prepared in enantiomerically enriched form by a short route that included a Sharpless asymmetric dihydroxylation. Treatment of these triols with toluene-p-sulfonic acid gave THFs as thermodynamic products.

Full text of DOI:10.1039/b208556a

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Asymmetric synthesis of tetrahydrofurans by competitive [1,2]-
phenylsulfanyl (PhS) migrations under thermodynamic control
Lorenzo Caggiano,a David J. Fox,b David House,c Zoe A. Jones,b Fraser Kerrd
and Stuart Warren*b
1
a Università degli Studi di Milano, Dipartimento di Chimica Organica e Industriale,
Via Venezian 21, 20133 Milano, Italy
b University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: sw134@cam.ac.uk
c Dyson Perrins Laboratory, South Parks Road, Oxford, UK 0X1 3QY
d AstraZeneca, Hurdsfield Industrial Estate, Macclesfield, Cheshire, UK SK10 2NA
Received (in Cambridge, UK) 3rd September 2002, Accepted 2nd October 2002
First published as an Advance Article on the web 7th November 2002
Triols were prepared in enantiomerically enriched form by a short route that included a Sharpless asymmetric
dihydroxylation; treatment of these triols with toluene-p-sulfonic acid gave THFs as thermodynamic products.
In a short series of papers1 we reported the outcome of
sulfanyl2 mediated competitive cyclisations between two
hydroxy groups of 2,4,5-triols (bearing a phenylsulfanyl group
at C-1). For these types of compounds four modes of cyclis-
ation are conceptually possible: routes A to D (Scheme 1).
Three sets of diastereomeric 2,4,5-triols were prepared so
that their cyclisations could be studied. Each of the three
sets had a different migration origin in order that we could
demonstrate the generality of the cyclisation outcome. In the
first series (triols 5 and 8) the sulfanyl group was bound to a
gem-dimethyl substituted carbon atom (Fig. 1). The second pair
Fig. 1 2,4,5-Triols for cyclisation reactions.
of triols (6 and 9) had a cyclohexane ring present and the final
set (triols 7 and 10) had a THP ring present in order that we
could prepare some unusual dioxaspirocycles that are not trivial
to prepare by other routes.7 The triols could be synthesised
asymmetrically: Sharpless asymmetric dihydroxylation (AD)8
of a homoallylic ketone being the key step in our route to these
compounds.
Scheme 1 Reagents: i, TsOH, CH2Cl2.
In each case the synthesis started from an α-phenylsulfanyl
aldehyde (11, 12 or 13), compounds which were easily syn-
thesised on a large scale by sulfenylation of the appropriate silyl
enol ethers with phenylsulfenyl chloride (Scheme 3).9 Addition
of allylmagnesium bromide to each of the aldehydes to give the
homoallylic alcohols (14–16) was followed by oxidation with
Corey’s PCC reagent10 to give good yields of the homoallylic
ketones (17–19). We were pleased to observe that no trace of
double bond isomerisation to give the conjugated enones was
observed.
The AD reaction gave optimum enantiomeric excess (73–
84%) for the diols (20–22) when Sharpless’ PYR ligand was
used.11a Reaction using the commercially available AD mixes
(which contain the PHAL ligand11b) resulted in much lower
enantioselectivities (typically 30%). The final stage of the stereo-
controlled triol synthesis was a 1,3-diastereoselective reduction
Route A could be ignored because oxetanes (e.g. 1) are too high
in energy to be isolated from these cyclisation reactions.3 We
wished to ascertain which of the modes of cyclisation, B (to
give the ‘unrearranged’4 THF 2), C (to give the ‘rearranged’4
THF 3) or D (to give the rearranged THP 4) would be operative
under acid catalysis. In a closely related study Gruttadauria
has reported the outcome of selenium-mediated competitive
cyclisations, with the observation that THFs were formed under
kinetic conditions but these THFs slowly equilibrated (E) to
THPs (Scheme 2).5 More recently Borhan has examined the
same problem in the context of epoxide opening and showed
that THFs are produced under kinetic conditions. By incorpor-
ation of a phenylsulfanyl group the regiochemistry of the
epoxide opening could be reversed (cf. F and G, Scheme 2) to
give isomeric THFs.6
2634
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b208556a

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Scheme 2 Reagents: i, HClO4, CH2Cl2, rt; ii, BF3ؒOEt2, Et2O, 0 ЊC to rt; iii, Ac2O, pyridine, 60 ЊC.
Scheme 3 Reagents: i, CH2᎐᎐CHCH2MgBr, Et2O, rt; ii, PCC, CH2Cl2, rt; iii, K2OsO2(OH)4, chiral ligand, K2CO3, K3Fe(CN)6, ButOH–H2O, 0 ЊC; iv,
Me4Nϩ BH(OAc)3Ϫ, AcOH–MeCN, Ϫ20 ЊC, 7 days; v, Et2BOMe, THF–MeOH, Ϫ78 ЊC then NaBH4. *Chiral ligand used was either: (1)
(DHQD)2PHAL or (2) (DHQD)2PYR.
to give either the 2,4-anti12 (5–7) or the 2,4-syn13 diastereo-
isomers (8–10) of each triol. Racemic standards of the triols
could also be prepared in large quantities by racemic dihydroxyl-
ation14 of the homoallylic alcohols (14–16) and straightforward
separation of the 2,4-related diastereoisomers by column
chromatography. Little diastereoselection was observed in the
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
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Table 1 Product distribution for the acid catalysed rearrangement of
triol 6
Table 3 Summary of crystal data, data collection, structure solution
and refinement data for compound 30
Reaction time/hours
Product ratio, THF 23:THP 24
Empirical formula
Formula weight (M)
Crystal system
C20H20N2O7S
432.44 g molϪ1
Orthorhombic
a = 8.527(2) Å, α = 90Њ
b = 21.517(3) Å, β = 90Њ
c = 22.053(3) Å, γ = 90Њ
4046.2(12) Å3
0.167
1.25
24
56:44
66:34
96:4
Unit cell dimensions
48
>98:2
Volume
Temperature
Space group
Z
Absorption coefficient (µ)
Reflections collected
Independent reflections
Final R indices [I>2σ(I )]
R indices (all data)
210(2) K
Pbca
Table 2 Product distribution for the acid catalysed rearrangement of
triol 9
8
1.830 mmϪ1
Reaction time/hours
Product ratio, THF 25:THP 26
3905
2511 (Rint = 0.0249)
R1 = 0.0434, wR2 = 0.0897
R1 = 0.0724, wR2 = 0.1006
0.167
1.33
24
63:37
71:29
89:11
>98:2
48
racemic dihydroxylation reaction but in this way large quan-
tities of the triols were made available to study the cyclisations.
To begin with, the triols 6 and 9 (from the second set) were
subjected to our standard conditions for cyclisation: a ten-
minute reflux with five mol% toluene-p-sulfonic acid in dichloro-
methane. To our initial disappointment triol 6 gave a 56:44 mix-
ture of THF 23 and THP 24 (Scheme 4, Table 1). Previously we
have shown that these cyclisation reactions are under thermo-
dynamic control,15,16 so resubmitting this mixture to the reac-
tion conditions, or taking a fresh sample of the triol 6, and
heating to reflux in dichloromethane for 48 hours led to the
complete conversion into the spirocyclic THF 23 (Scheme 4).
Similarly, the syn-triol 9 gave an initial product distribution of
63:37 THF 25:THP 26, but after a prolonged reflux (48 hours)
gave only THF 25 (Scheme 4, Table 2).
Scheme 5 Reagents: i, TsOH, CH2Cl2, 40 ЊC, 48 h.
Scheme 4 Reagents: i, TsOH, CH2Cl2, 40 ЊC.
Rearrangement of the two other structurally related sets of
triols (5 and 8) and (7 and 10) again led to THF–THP mixtures
after short reaction times. Longer reaction times (48 hours)
gave the rearranged THFs 3 and 27 (for the second series) and
28 and 29 (for the third series) (Scheme 5).
Fig. 2 X-Ray crystal structure of the 3,5-dinitrobenzoate derivative 30
of the syn-THP 4 formed by rearrangement of anti-triol 5.
1
The THFs and THPs are clearly distinguished by their H
NMR spectra. The methine proton on the carbon atom bound
to the PhS group appears as a double doublet for the THPs
It was possible to follow the course of the [1,2]-PhS rearrange-
ment in CDCl3 over a period of 24 hours by NMR. Fig. 3
shows the 3.0–5.0 ppm region for a selection of 1H NMR
spectra recorded during this period. The initial spectrum (top
of Fig. 3) is that of the triol 5. After two hours at 40 ЊC the
spectrum clearly shows a mixture of four compounds: the triol
5, and each of the three cyclisation products 2, 3 and 4 (i.e.
resulting from cyclisations B, C and D, Scheme 1). At much
longer reaction times (e.g. 9 hours) almost none of the unrear-
ranged THF 2 remains, but THF 3 and THP 4 are still present
in a ratio of 1:1. The final spectrum, recorded after 36 hours,
3
3
(with typical Jax-ax and Jax-eq coupling constants), whereas for
the THFs this methine signal appears as a triplet (or at least a
double doublet with very similar coupling constants). We were
also able to prove unambiguously that the stereochemistry in
the triol precursor is faithfully translated into the cyclised
product (i.e. with stereochemical inversion taking place at C-2).
This proof was obtained by single crystal X-ray diffraction on
the 3,5-dinitrobenzoate ester 30 (Fig. 2, Table 3) of the syn-THP
4 (derived from anti-triol 5).
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J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645

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Table 4 Molecular modelling data obtained using MOPAC software with PM3 parameters
Compound number
Compound type
Energy range/kcal molϪ1
1
2
4
3
Oxetane
Ϫ82.9 to Ϫ77.2
Ϫ98.1 to Ϫ95.0
Ϫ101.0 to Ϫ98.2
Ϫ103.9 to Ϫ97.8
Unrearranged THF
Rearranged THP
Rearranged THF
shows that most of the THP 4 has now disappeared, a clear
demonstration that the rearranged THF 3 is the thermo-
dynamic cyclisation product.
We used semi-empirical molecular orbital calculations to
model the products of these cyclisations given their fairly low
molecular complexity. We calculated a number of minimum
energy conformations for each of the products using PM3
parameters. The data are summarised in Table 4. The model-
ling data is in good agreement with the actual experimental
outcome and these results gave us the confidence to use com-
puter modelling to make predictions about the cyclisations of
other closely related compounds.
In contrast to other systems we have studied,17 ring-size has
become more important than the relative stereochemistry
(Scheme 6): triols 31 and 32 rearrange to give 3,4-anti THP 33
and 3,4-anti THF 34, respectively. That a 2,4-syn THF (e.g. 25)
is preferred to the alternative 2,4-anti THP (e.g. 26, Scheme 4,
where one of the two substituents would enter an axial
environment) is perhaps not surprising. However, the 2,4-anti
THF (e.g. 23) is preferred to the 2,4-syn THP (e.g. 24, Scheme
4), where both groups could now be equatorial. We presume
that the factor governing the cyclisation outcome for the 2,4,5-
triols (the degree of substitution being equal for both ring sizes)
is the gem-disubstituted migration origin. In the THPs one of
the C–C bonds is forced to be axial; presumably the 1,3-diaxial
interactions are too severe and the flatter THF rings are
preferred.
In order to demonstrate further the important role of the
sulfanyl group in determining the outcome of these cyclisations,
we prepared the triol 35 in racemic form, to compare the acid
catalysed cyclisation of this triol with the results obtained for
the sulfanyl compounds. Triol 35 was prepared by addition of
but-3-enyl-1-magnesium bromide to cyclohexanone, followed
by racemic dihydroxylation of the alkene 36 (Scheme 7). A
prolonged reflux (3 days) of triol 35 with toluene-p-sulfonic
acid in dichloromethane was required for the starting material
to be consumed. Analysis of the crude reaction mixture
revealed the presence of three products: the THF 37 and the
two elimination products 38 and 39, which we were unable to
separate by chromatography. No THP could be detected. Acid
catalysed diol cyclisations are well known to be complicated by
competing mechanisms and often result in poor yields;18 this
cyclisation was no exception. A combination of stepwise and
concerted substitution pathways is likely to occur, and when
Fig. 3 1H NMR spectra recorded in CDCl3 at 40 ЊC at specified
intervals to show the rearrangement of triol 5 under equilibrating
conditions. Spectrum 1 shows triol 5 immediately after addition
of TsOH (OH couplings removed); spectrum 2 shows four com-
pounds present: triol 5 (δH ∼ 4.0), unrearranged THF 2 (δH ∼ 4.5),
THF 3 (δH ∼ 4.2) and THP 4 (δH ∼ 3.1); spectrum 4 reveals only two
major components present: THF 3 and THP 4; and finally spectrum 5
shows equilibration nearing completion: THF 3 is now the major
component [note the presence of the characteristic THF signal δH
∼
3.45 (1 H, t)].
Scheme 6 Reagents: i, TsOH, C6H6, 80 ЊC; ii, TsOH, CH2Cl2, 40 ЊC.
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
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Scheme 7 Reagents: i, Mg, Et2O; ii, cyclohexanone; iii, K2OsO2(OH)4, quinuclidine, K3Fe(CN)6, K2CO3, ButOH–H2O; iv, TsOH, CH2Cl2, 40 ЊC,
3 days.
the stepwise mechanism operates a competing E1 pathway is
generally found. This reaction demonstrates the importance
of sulfur in our cyclisation reactions; the phenylsulfanyl
group plays a vital role in controlling the mechanism of the
reaction. Stereochemical inversion is always observed even
where the electrophilic carbon atom may display a near planar
geometry. For this reason no departure from stereospecific
cyclisation has ever been observed for cyclisations with [1,2]-
PhS migration.
In summary we have demonstrated a viable route for the
asymmetric synthesis of 2,4,5-triols and provided firm evidence
that [1,2]-PhS rearrangements are under thermodynamic con-
trol. For a simple class of triols 5–10 the most stable products
are the THFs 3,23,25 and 27–29 (Schemes 4 and 5). We believe
that the difference in product stability between the 5- and
6-membered rings can be attributed to the gem-disubstituted
migration origin. In other cases we have investigated whether
the relative stability of products may be dependent on ring-size,
stereochemistry or a thermodynamic Thorpe–Ingold effect.19,20
We are now looking at applying these cyclisation reactions
to the synthesis of C2-symmetrical bis-THFs (e.g. 40) and bis-
THPs (e.g. 41), which may be interesting compounds in their
own right (Fig. 4).
are quoted in parts per million (ppm) downfield of tetramethyl-
silane. Coupling constants J are quoted in Hz and are not
rationalised. The symbol* after the proton NMR chemical
shift indicates that the signal disappears after a D2O “shake”.
Carbon NMR spectra were recorded with broad band proton
decoupling and Attached Proton Test. The symbols and
after the carbon NMR chemical shift indicate odd and even
numbers of attached protons respectively.
ϩ
Ϫ
Melting points were measured on a Stuart Scientific SMP1
melting point apparatus and are uncorrected. Infrared spectra
were recorded on
a Perkin–Elmer 1600 FTIR spectro-
photometer. Electron Impact (EI) mass spectra were recorded
on a Kratos double focusing magnetic sector instrument using
a DS503 data system for high-resolution analysis. Fast atom
bombardment (FAB) mass spectra were obtained from a
Kratos MS 890 instrument. Electrospray (ϩES) mass spectra
were recorded using a Brucker Bio-Apex FT-ICR instrument
and LCMS using a Hewlett Packard HPLC system, eluting
with an acetonitrile-water gradient, in conjunction with positive
and negative ion electrospray mass spectrometry.
Optical rotations were recorded on a Perkin–Elmer 241
polarimeter (using the sodium D line; 589 nm) and [α]D are
given in units of 10Ϫ1 deg dm2 gϪ1
.
(3RS,5SR)-2,2-Dimethyl-3-phenylsulfanyltetrahydrofuran-5-
ylmethanol 3
Toluene-p-sulfonic acid (1.7 mg, 9.0 µmol, 5 mol%) was added
to a stirred solution of the anti-triol 5 (50 mg, 195 µmol) in
dichloromethane (2.5 cm3). The reaction temperature was
raised to 50 ЊC to initiate reflux and heating continued for
48 hours. The mixture was cooled to room temperature and
then filtered through a short plug of silica, eluting with dichloro-
methane, and the solvent was evaporated under reduced
pressure to give a crude product. Purification by column
chromatography [light petroleum (bp 40–60 ЊC)–diethyl ether,
1:1] gave the 3,5anti-tetrahydrofuran 3 (42 mg, 90%) after 48
hours as an oil; Rf[light petroleum (bp 40–60 ЊC)–diethyl ether,
1:1] 0.12; νmax(CH2Cl2)/cmϪ1 3593 (O–H), 3052, 2978, 2929,
2879, 1583, 1480, 1420, 1382, 1369, 1142, 1091, 1034 and 896;
δH(250 MHz; CDCl3) 7.44–7.19 (5 H, m, PhS), 4.17 (1 H, dtd,
J 8.3, 4.8 and 3.3 Hz, CH–O), 3.68 (1 H, ddd, J 11.5, 5.3 and 3.0
Hz, CHAHBOH), 3.46 (1 H, ddd, J 11.8, 7.3 and 4.8 Hz, CHA-
HBOH), 3.36 (1 H, dd, J 9.5 and 8.5 Hz, CHSPh), 2.34 (1 H,
ddd, J 13.0, 8.3 and 4.8 Hz, CHAHB), 2.13 (1 H, ddd, J 13.0, 9.3
and 8.5 Hz, CHAHB), 2.03* (1 H, dd, J 7.0 and 5.8 Hz, OH),
1.29 (3 H, s, MeA) and 1.27 (3 H, s, MeB); δC(100.6 MHz;
CDCl3) 135.6Ϫ (i-PhS), 131.2ϩ, 129.0ϩ, 126.9ϩ (p-PhS), 83.6Ϫ
(C–O), 75.6ϩ (CHOH), 65.2Ϫ (CH2OH), 55.1ϩ (CHSPh), 35.7Ϫ
(CH2), 27.5ϩ (Me) and 22.2ϩ (Me); m/z (EI) 238 (41%, Mϩ),
207 (22, Mϩ Ϫ CH2OH), 180 (94, Mϩ Ϫ Me2CO), 169 (26), 149
(100, C3H4SPhϩ), 131 (82) and 119 (61); (Found: Mϩ, 236.1027.
C13H18O2S requires M, 238.1027).
Fig. 4 C2-symmetrical bis-THF and THPs.
Experimental
All solvents were distilled before use. Tetrahydrofuran and
diethyl ether were freshly distilled from lithium aluminium
hydride whilst dichloromethane and acetonitrile were freshly
distilled from calcium hydride. Triphenylmethane was used as
an indicator for tetrahydrofuran. Pyridine was dried by distil-
lation from calcium hydride and was stored over 4 Å molecular
sieves. All non-aqueous reactions were carried out under argon
using oven-dried glassware.
Flash column chromatography was carried out using Merck
Kieselgel 60 (230–400 mesh). Thin layer chromatography was
performed on commercially available pre-coated plates (Merck
silica Kieselgel 60F254). Preparative HPLC was performed using
a Zorbax SIL prepacked silica column (21.2 mm id × 25 cm)
with a Gilson model 303 pump and a Cecil Instruments CE
212A UV detection system measuring the absorbance at 254
nm. Analytical HPLC was performed using either a Zorbax
RX-C8 prepacked reverse phase silica column or a Daicel
Chiralpak AD column with a Spectra-Physics SP8800 pump, a
Spectra-Physics SP8450 UV detection system and a ChromJet
single channel integrator.
(2R,4R)-5-Methyl-5-phenylsulfanylhexane-1,2,4-triol 5
Proton and carbon NMR spectra were recorded on Bruker
DPX 250, AM 400, DRX 400 or DRX 500 Fourier transform
spectrometers using an internal deuterium lock. Chemical shifts
Glacial acetic acid (20 cm3) was added to a stirred suspension
of tetramethylammonium triacetoxyborohydride12 (8.0 g, 30.4
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mmol, 10 eq.) in acetonitrile (20 cm3) and the resulting mixture
stirred for 30 minutes at room temperature to give a colourless
solution. This solution was cooled to Ϫ30 ЊC and a solution of
β-hydroxyketone 20 (1.00 g, 3.93 mmol) in acetonitrile (5 cm3)
was added. The solution was then transferred to a freezer
(–25 ЊC) for 1 week. The reaction was quenched by addition of
aqueous sodium potassium tartrate solution (1.0 mol dmϪ3, 10
cm3) and the mixture allowed to warm slowly to room temper-
ature. The reaction mixture was then diluted with dichloro-
methane (10 cm3) and washed with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted with
dichloromethane (4 × 10 cm3), the combined organic layers
dried over anhydrous magnesium sulfate and the solvent
removed under vacuum to give a crude product. Purification by
column chromatography (silica, ethyl acetate) gave syn-triol 8
(56 mg, 6%) as an oil, Rf(ethyl acetate) 0.23 (see below) and
anti-triol 5 (880 mg, 87%) as a white amorphous solid; Rf(ethyl
acetate) 0.13; retention time/min (isocratic HPLC 62:38
MeCN:H2O; 0.1% CF3CO2H, 0.1% Et3N; flow rate 1 cm3
minϪ1) 5.58; νmax(CH2Cl2)/cmϪ1 3615 (O–H), 3472 (O–H), 3059,
2934 and 2856; δH(400 MHz; CDCl3) 7.54–7.46 (2 H, m, PhS),
7.42–7.29 (3 H, m, PhS), 4.02–3.93 (1 H, m, CHOH), 3.66 (1 H,
ddd, J 10.9, 6.7 and 3.6 Hz, CHAHBOH), 3.61 (1 H, dt, J 10.4
and 2.2 Hz, PhSCCHOH), 3.54 (1 H, ddd, J 11.3, 6.8 and 5.1
Hz, CHAHBOH), 3.23* (1 H, s, OH), 2.59* (1 H, d, J 5.5 Hz,
OH), 2.14* (1 H, t, J 5.8 Hz, CH2OH ), 1.66 (1 H, ddt, J 13.9,
7.8 and 2.0 Hz, CHAHB), 1.56 (1 H, ddd, J 14.1, 10.4 and 4.2
Hz, CHAHB), 1.25 (3 H, s, MeA) and 1.21 (3 H, s, MeB); δC(100.6
MHz; CDCl3) 137.4ϩ (m-PhS), 130.1Ϫ (i-PhS), 129.4ϩ (p-PhS),
128.9ϩ (o-PhS), 71.7ϩ (CHOH), 70.2ϩ (CHOH), 66.8Ϫ
(CH2OH), 55.2Ϫ (CSPh), 33.4Ϫ (CH2), 25.7ϩ (Me) and 22.0ϩ
(Me); m/z (ϩFAB) 279 (20%, MNaϩ), 257 (17, MHϩ), 239 (94),
154 (97), 151 (100, Me2CSPhϩ), 136 (82), 129 (100) and 110 (37,
PhSHϩ); (Found: MNaϩ, 279.1014. C13H20O3SNa requires
279.1025).
as an oil (90 mg, 27%); Rf(ethyl acetate–methanol, 49:1) 0.28;
[α]D ϩ8.8 (c. 0.49 in CHCl3; 78% ee); νmax(CH2Cl2)/cmϪ1 3610
(O–H), 3472 (O–H), 2961 (C–H), 2869 (C–H), 1582 (PhS) and
1102 (C–O); δH(400 MHz; CDCl3) 7.52–7.45 (2 H, m, PhS),
7.38–7.30 (3 H, m, PhS), 4.05 (1 H, dd, J 11.5 and 2.0 Hz,
OCHeqHax), 4.00–3.97 (2 H, m, OCHeqHax), 3.83–3.77 (2 H, m,
CHOHCH2CHOH), 3.66 (1 H, dd, J 7.5 and 3.5 Hz,
CHAHBOH) 3.69 (1 H, br dd, J 10.5 and 2.0 Hz, OCHeqHax),
3.54 (1 H, dd, J 11.0 and 7.5 Hz, CHAHBOH), 3.30 (1 H, br s,
OH), 2.83 (1 H, br s, OH), 2.47 (1 H, br s, OH), 1.95 (1 H, ddd,
J 14.5, 11.5 and 5.0 Hz, CCHeqHax), 1.83–1.78 (2 H, m,
CH2CHOH), 1.62 (1 H, ddd, J 14.5, 10.5 and 4.0 Hz,
CCHeqHax), 1.48 (1 H, br dd, J 14.5 and 2.0 Hz, CCHeqHax) and
1.31 (1 H, br dd, J 14.5 and 2.0 Hz, CCHeqHax); δC(100.6 MHz;
CDCl3) 137.9ϩ (PhS), 130.2Ϫ (i-PhS), 129.7ϩ (p-PhS), 129.4ϩ
(PhS), 72.5ϩ (CHOH), 70.2ϩ (CHOH), 67.4Ϫ (CH2OH),
64.1Ϫ(CH2OCH2), 64.0Ϫ (CH2OCH2), 57.2Ϫ (CSPh), 34.0Ϫ
(CH2CHOH), 30.4Ϫ (CH2CCH2); m/z (EI) 298 (36%, Mϩ), 193
(Mϩ–C4H9O3), 153 (96, Mϩ–PhS–2 × H2O), 135 (56, Mϩ–PhS–3
× H2O); (Found: Mϩ, 298.1238. C15H22O4S requires M,
298.1239).
(2R,4S )-5-Methyl-5-phenylsulfanylhexane-1,2,4-triol 8
A 1.0 mol dmϪ3 solution of diethylmethoxyborane13 in tetra-
hydrofuran (2.0 cm3, 0.3 mmol) was added to a solution of
β-hydroxyketone 20 (500 mg, 1.97 mmol) in tetrahydrofuran–
methanol (4:1) (50 cm3) at Ϫ78 ЊC, under an atmosphere of
argon. The mixture was stirred for 5 minutes and then sodium
borohydride (94.6 mg, 2.50 mmol) was added and the solution
allowed to stir for 8 hours. Glacial acetic acid (3 cm3) was added
and stirring continued for a further 5 minutes. The solution was
then neutralised with saturated aqueous sodium bicarbonate
solution (30 cm3) and extracted with diethyl ether (3 × 15 cm3).
The organic extracts were dried over anhydrous magnesium
sulfate and the solvent was removed under reduced pressure to
give a crude product. This product was redissolved in methanol
(5 cm3) and stirred for 5 minutes before removing the methanol
under reduced pressure. This cycle was repeated until TLC
showed no spots with Rf(diethyl ether) > 0.5. The crude product
was purified by column chromatography (silica, ethyl acetate)
to give anti-triol 5 (54 mg, 11%) as a white solid, Rf(ethyl
acetate) 0.13 (see above) and syn-triol 8 (399 mg, 79%) as an oil;
Rf(ethyl acetate) 0.24; retention time/min (isocratic HPLC 62:38
MeCN:H2O; 0.1% CF3CO2H, 0.1% Et3N; flow rate 1 cm3
minϪ1) 6.75; νmax(CH2Cl2)/cmϪ1 3486 (O–H), 3057, 2982, 2931,
2874 and 1422; δH(400 MHz; CDCl3) 7.55–7.46 (2 H, m, PhS),
7.44–7.28 (3 H, m, PhS), 3.94* (1 H, s, OH), 3.93–3.83 (1 H, m,
CHOH), 3.65* (1 H, s, OH), 3.65–3.53 (2 H, m, CHAHBOH and
PhSCCHOH), 3.48 (1 H, dt, J 11.3 and 5.7 Hz, CHAHBOH),
2.25* (1 H, t, J 6.2 Hz, CH2OH ), 1.67–1.53 (2 H, m, CHAHB
and CHAHB), 1.26 (3 H, s, MeA) and 1.19 (3 H, s, MeB); δC(100.6
MHz; CDCl3) 137.4ϩ (m-PhS), 129.9Ϫ (i-PhS), 129.4ϩ (p-PhS),
128.9ϩ (o-PhS), 75.4ϩ (CHOH), 72.2ϩ (CHOH), 66.7Ϫ
(CH2OH), 55.1Ϫ (CSPh), 32.8Ϫ (CH2), 25.6ϩ (Me) and 21.8ϩ
(Me); m/z (ϩFAB) 279 (100%, MNaϩ), 257 (3, MHϩ), 239
(27), 151 (38, Me2CSPhϩ), 129 (33), 110 (15, PhSHϩ) and 77
(25); (Found: MNaϩ, 279.1015. C13H20O3SNa requires
279.1025).
(1R,3R)-[1-(Phenylsulfanyl)cyclohexyl]butane-1,3,4-triol 6
By the method described for compound 5, glacial acetic acid
(7.5 cm3), tetramethylammonium triacetoxyborohydride (3.58
g, 13.6 mmol, 8 eq.) in acetonitrile (7.5 cm3) and β-hydroxy-
ketone 21 (500 mg, 1.70 mmol) in acetonitrile (2 cm3) gave a
crude product after one week. Purification by column chrom-
atography (silica, ethyl acetate) gave syn-triol 9 (see below) (40
mg, 8%) as an oil; Rf(ethyl acetate) 0.22 and anti-triol 6 (437 mg,
87%) as an amorphous white solid; Rf(ethyl acetate) 0.32;
retention time/min (isocratic HPLC 62:38 H2O:MeCN; 0.1%
CF3CO2H, 0.1% Et3N; flow rate
1 ) 14.01;
cm3 minϪ1
νmax(CH2Cl2)/cmϪ1 3615 (O–H), 3472 (O–H), 3069, 2936 and
2856; δH(400 MHz; CDCl3) 7.54–7.50 (2 H, m, PhS), 7.43–7.30
(3 H, m, PhS), 4.01–3.93 (1 H, m, CHOH), 3.64 (1 H, ddd,
J 11.0, 6.8 and 3.6 Hz, CHAHBOH), 3.61 (1 H, dt, J 10.6 and 2.3
Hz, PhSCCHOH), 3.53 (1 H, ddd, J 11.8, 6.9 and 5.2 Hz,
CHAHBOH), 3.24* (1 H, s, OH), 2.59* (1 H, d, J 5.5 Hz, OH);
2.14* (1 H, t, J 6.0 Hz, OH), 2.06–1.14 (12 H, m); δC(100.6
MHz; CDCl3) 137.2ϩ, 129.9Ϫ (i-PhS), 129.2ϩ, 129.0ϩ, 71.4ϩ
(CHOH), 70.3ϩ (CHOH), 66.8Ϫ (CH2OH), 61.4Ϫ (CSPh),
33.4Ϫ, 30.5Ϫ, 29.6Ϫ, 26.2Ϫ, 21.8Ϫ and 21.8Ϫ; m/z (EI) 296 (5%,
Mϩ), 278 (12), 191 (100, C6H10SPhϩ), 181 (33), 169 (37), 149
(19), 131 (76), 119 (56) and 110 (52, PhSHϩ); (Found: Mϩ,
296.1443. C16H24O3S requires M, 296.1446).
(1S,3R)-[1-(Phenylsulfanyl)cyclohexyl]butane-1,3,4-triol 9
By the method described for compound 8, diethylmethoxy-
borane (1.1 cm3 of a 1.0 mol dmϪ3 solution in tetrahydrofuran,
1.1 mmol), β-hydroxyketone 21 (300 mg, 1.02 mmol) in
tetrahydrofuran–methanol (4:1) (20 cm3) and sodium boro-
hydride (76.5 mg, 2.03 mmol) gave a crude product. Purification
by column chromatography (silica, ethyl acetate) gave anti-triol
6 (45 mg, 15%) as an oil; Rf(ethyl acetate) 0.30 and syn-triol 9
(226 mg, 75%) as an oil; Rf(ethyl acetate) 0.22; retention time/
min (isocratic HPLC 62:38 H2O:MeCN; 0.1% CF3CO2H, 0.1%
(1R,3R)-1-[4-(Phenylsulfanyl)tetrahydropyran-4-yl]butane-
1,3,4-triol 7
By the method described for compound 5, glacial acetic acid
(5 cm3), tetramethylammonium triacetoxyborohydride (2.35 g,
8.96 mmol, 8 eq.) in acetonitrile (5 cm3) and β-hydroxyketone
22 (330 mg, 1.12 mmol) in acetonitrile (1.6 cm3) gave a crude
product after one week. Purification by column chromato-
graphy (silica, ethyl acetate–methanol 49:1) gave the anti-triol 7
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
2639

View Article Online
Et3N; flow rate 1 cm3 minϪ1) 17.77; νmax(CH2Cl2)/cmϪ1 3686
(O–H), 3599 (O–H), 3056, 2986, 2937, 2860, 1605, 1474 and
1394; δH(400 MHz; CDCl3) 7.53–7.47 (2 H, m, PhS), 7.42–7.31
(3 H, m, PhS), 3.94* (1 H, s, OH), 3.90–3.83 (1 H, m, CHOH),
3.75* (1 H, s, OH), 3.62 (1 H, ddd, J 10.9, 6.3 and 3.8 Hz,
CHAHBOH), 3.58–3.52 (1 H, m, PhSCCHOH), 3.49 (1 H, dt,
J 11.3 and 5.8 Hz, CHAHBOH), 2.14* (1 H, t, J 6.2 Hz,
CH2OH ), 2.02 (1 H, qt, J 12.8 and 3.9 Hz), 1.89–1.52 (8 H, m)
and 1.45–1.14 (3 H, m); δC(100.6 MHz; CDCl3) 137.3ϩ, 129.7Ϫ
(i-PhS), 129.3ϩ, 129.0ϩ, 75.1ϩ (CHOH), 72.4ϩ (CHOH), 66.8Ϫ
(CH2OH), 61.3Ϫ (CSPh), 32.8Ϫ, 30.2Ϫ, 29.2Ϫ, 26.2Ϫ, 21.8Ϫ and
21.7Ϫ; m/z (ϩFAB) 296 (16%, Mϩ), 279 (64, Mϩ Ϫ OH), 169
(73), 154 (100) and 109 (34); (Found: Mϩ, 296.1446. C16H24O3S
requires M, 296.1446).
acetate) 0.24, spectroscopically identical to the enantiomeric-
ally enriched sample and anti-triol 5 (2.98 g, 43%) as a white
amorphous solid. Crystallisation from chloroform gave anti-
triol 5 as needles, mp 108–109 ЊC (from chloroform); Rf(ethyl
acetate) 0.13, spectroscopically identical to the enantiomeric-
ally enriched sample.
(2RS,4SR)-[1-(Phenylsulfanyl)cyclohexyl]butane-1,2,4-triol 6
and (2RS,4RS )-[1-(Phenylsulfanyl)cyclohexyl]butane-1,2,4-triol
9
By the method described for triols 5 and 8, potassium ferri-
cyanide (1.86 g, 5.66 mmol, 3 eq.), potassium carbonate (0.782 g,
5.66 mmol, 3 eq.), osmium() chloride hydrate (4.2 mg, 14
µmol, 0.7 mol%), quinuclidine (7.4 mg, 67 µmol, 3.5 mol%) and
alkene 15 (500 mg, 1.91 mmol) in 2-methylpropan-2-ol (10 cm3)
and water (10 cm3) gave a crude product. Analytical HPLC
(isocratic 38:62 MeCN:H2O; 0.1% CF3CO2H, 0.1% Et3N;
flow rate 1 cm3 minϪ1) indicated an syn:anti mixture of 58:42
(retention times: 4.20 min, 4.74 min, respectively). Purification
by column chromatography (silica, ethyl acetate) gave anti-triol
6 (215 mg, 38%) as a white amorphous solid; Rf(ethyl acetate)
0.32, spectroscopically identical to the enantiomerically
enriched sample and syn-triol 9 (288 mg, 51%) as an oil; Rf(ethyl
acetate) 0.22, spectroscopically identical to the enantiomeri-
cally enriched sample.
(1S,3R)-1-[4-(Phenylsulfanyl)tetrahydropyran-4-yl]butane-
1,3,4-triol 10
By the method described for compound 8, diethylmethoxy-
borane (2.3 cm3 of a 1.0 mol dmϪ3 solution in tetrahydrofuran,
2.3 mmol), β-hydroxyketone 22 (599 mg, 2.10 mmol) in
tetrahydrofuran–methanol (4:1) (40 cm3) and sodium boro-
hydride (159 mg, 4.20 mmol) gave a crude product after 8 hours.
Purification by column chromatography (silica, ethyl acetate,
4% methanol) gave the syn-triol 10 as an oil (0.21g, 33%);
Rf(ethyl acetate–methanol, 24:1) 0.40; [α]D Ϫ10.7 (c. 0.6 in
CHCl3; 78% ee); νmax(CH2Cl2)/cmϪ1 3610 (O–H), 2962 (C–H),
2870 (C–H) and 1103 (C–O); δH(400 MHz; CDCl3) 7.49–7.43
(2 H, m, PhS), 7.36–7.27 (3 H, m, PhS), 4.03 (1 H, dd, J 11.5
and 2.0 Hz, OCHaxHeq), 3.96 (1 H, dd, J 11.5 and 2.0 Hz,
OCHaxHeq), 3.91–3.84 (1 H, m, CH2CHOH), 3.80–3.72 (2 H, m,
OCHaxHeq), 3.83–3.74 (2 H, m, CHAHBOH and CCHOH), 3.49
(1 H, dd, J 11.0 and 6.0 Hz, CHAHBOH), 1.96 (1 H, ddd, J 14.0,
12.0 and 5.5 Hz, CHAHBCHOH), 1.83 (1 H, br d, J 14.0 Hz,
CHAHBCHOH), 1.83 (1 H, ddd, J 14.0, 12.0 and 5.0 Hz,
CCHAHB), 1.63 (1 H, dt, J 14.0 and 10.0 Hz, CCHaxHeq), 1.40
(1 H, dd, J 12.0 and 1.5 Hz, CCHaxHeq) and 1.23 (1 H, dd,
J 14.5 and 1.5 Hz, CCHaxHeq); δC(100.6 MHz; CDCl3) 136.5ϩ
(PhS), 128.5Ϫ (i-PhS), 128.4ϩ (p-PhS), 128.1ϩ (PhS), 74.5ϩ
(CH2CHOH), 71.5ϩ (CCHOH), 65.7Ϫ (CH2OH), 62.8Ϫ
(CH2OCH2), 62.5Ϫ (CH2OCH2), 56.2Ϫ (CSPh), 28.8Ϫ
(CH2CCH2) and 28.5Ϫ (CH2CCH2); m/z (ϩES) 321 (100%,
MNaϩ); (Found: MNaϩ, 321.1144. C15H22O4SNa requires M,
321.1137).
(3RS )-2-Methyl-2-phenylsulfanylhex-5-en-3-ol 14
A solution of allylmagnesium bromide in diethyl ether (1.0 mol
dmϪ3, 56 cm3, 56 mmol) was added to a stirred solution of
aldehyde 11 (9.92 g, 55 mmol) in diethyl ether (100 cm3) at 0 ЊC
under an atmosphere of argon. After the addition was complete
the reaction was allowed to warm to room temperature and
stirring continued for 2 hours. Saturated aqueous ammonium
chloride solution (80 cm3) was added and the product was
extracted with diethyl ether (3 × 50 cm3). The combined organic
extracts were washed with water (70 cm3) and saturated brine
(70 cm3) and dried over anhydrous magnesium sulfate. The
solvent was removed under reduced pressure to give a crude
product which was purified by column chromatography [silica,
light petroleum (40–60 ЊC)–diethyl ether, 9:1] to give the alcohol
14 (12.1 g, 99%) as a pale yellow oil; Rf[light petroleum (bp 40–
60 ЊC)–diethyl ether, 9:1] 0.17; νmax(CH2Cl2)/cmϪ1 3478 (O–H),
3078, 2934, 2856, 1640 (C᎐C) and 1583 (PhS); δ (250 MHz;
᎐
H
CDCl3) 7.55–7.51 (2 H, m, PhS), 7.39–7.30 (3 H, m, PhS),
(2RS,4SR)-5-Methyl-5-phenylsulfanylhexane-1,2,4-triol 5 and
(2RS,4RS )-5-Methyl-5-phenylsulfanylhexane-1,2,4-triol 8
5.90–5.81 (1 H, m, CH᎐CH ), 5.16–5.06 (2 H, m, CH᎐CH ),
᎐
᎐
2
2
3.38 (1 H, td, J 10.0 and 2.4 Hz, CHOH), 2.83* (1 H, dd, J 2.2
and 1.3 Hz, OH), 2.35–2.23 (1 H, m, CH H CH᎐CH ), 2.21–
Potassium ferricyanide (26.4 g, 80.0 mmol, 3 eq.), potassium
carbonate (11.1 g, 80.0 mmol, 3 eq.), osmium() chloride
hydrate (59.4 mg, 20 µmol, 0.7 mol%) and quinuclidine (105
mg, 944 µmol, 3.5 mol%) were placed in a round bottom flask
and stirred gently. Water (140 cm3) and 2-methylpropan-2-ol
(140 cm3) were added, the flask was sealed and the solution
stirred vigorously. Once the solids had completely dissolved
the alkene 14 (6.00 g, 27.0 mmol) was added in one portion.
Stirring was continued until TLC or LCMS indicated complete
consumption of starting material. Sodium sulfite was then
added in one portion (121 g, 960 mmol) and stirring continued
for a further 30 minutes. The solution was transferred to a
separating funnel, diluted with ethyl acetate (200 cm3) and the
aqueous layer separated. The aqueous layer was then extracted
with ethyl acetate (3 × 150 cm3). The combined organic extracts
were washed with water (200 cm3) and brine (200 cm3), dried
over anhydrous magnesium sulfate and finally, the solvent was
evaporated under reduced pressure to give a crude product.
Analytical HPLC (isocratic 38:62 MeCN:H2O; 0.1%
CF3CO2H, 0.1% Et3N; flow rate 1 cm3 minϪ1) indicated an
anti:syn mixture of 43:57 (retention times: 5.66 min, 6.64 min,
respectively). Purification by column chromatography (silica,
ethyl acetate) gave syn-triol 7 (3.53 g, 51%) as an oil; Rf(ethyl
᎐
A
B
2
2.14 (1 H, m, CH H CH᎐CH ), 1.28 (3 H, s, Me ) and 1.23
᎐
A
B
2
A
(3 H, s, MeB); δC(100.6 MHz; CDCl3) 137.5ϩ, 136.1ϩ, 130.4Ϫ
(i-PhS), 129.2ϩ, 128.8ϩ, 117.0Ϫ (CH᎐CH ), 74.6ϩ (COH), 55.0Ϫ
᎐
2
(CSPh), 35.5Ϫ (CH CH᎐CH ), 25.6ϩ (MeA) and 22.5ϩ (MeB);
᎐
2
2
m/z (EI) 222 (10%, Mϩ), 181 (9, Me2C(SPh)CHOHϩ), 151 (100,
Me2CSPhϩ), 110 (91, PhSHϩ), 95 (26) and 71 (29); (Found: Mϩ,
222.1078. C13H18OS requires M, 222.1078).
(1RS )-1-[1-(Phenylsulfanyl)cyclohexyl]but-3-en-1-ol 15
By the method described for compound 14, a solution of
allylmagnesium bromide in diethyl ether (1.0 mol dmϪ3, 40 cm3,
40 mmol) and aldehyde 12 (8.80 g, 40 mmol) in diethyl ether
(150 cm3) gave a crude product which was purified by column
chromatography [silica, light petroleum (bp 40–60 ЊC)–diethyl
ether, 9:1] to give the alcohol 15 (10.06 g, 96%) as a pale yellow
oil; Rf[light petroleum (bp 40–60 ЊC)–diethyl ether, 9:1] 0.17;
νmax(CH2Cl2)/cmϪ1 3495 (O–H), 3074, 2971, 2931, 2870, 1641
(C᎐C) and 1582 (PhS); δ (500 MHz; CDCl ) 7.55–7.50 (2 H, m,
᎐
H
3
PhS), 7.39–7.29 (3 H, m, PhS), 5.89 (1 H, ddt, J 17.1, 10.1
and 6.9 Hz, CH᎐CH ), 5.11 (1 H, dd, J 17.3 and 1.5 Hz, CH᎐
᎐
᎐
2
CHtransH ), 5.08 (1 H, d, J 10.6 Hz, CH᎐CHtransHcis), 3.35 (1 H,
᎐
cis
2640
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645

View Article Online
d, J 10.0 Hz, CHOH), 2.89* (1 H, s, OH), 2.47 (1 H, dd, J 14.1
and 5.4 Hz, CHAHB), 2.25–2.17 (1 H, m, CHAHB) 1.97 (1 H, qt,
J 12.9 and 3.8 Hz), 1.85 (1 H, qt, J 12.2 and 3.4 Hz), 1.79–1.48
(6 H, m, 6 × CH2), 1.44–1.36 (1 H, m) and 1.23 (1 H, qt, J 12.5
and 3.8 Hz); δC(100.6 MHz; CDCl3) 137.3ϩ, 136.5ϩ, 130.2Ϫ
(i-PhS), 129.0ϩ, 128.9ϩ, 116.8Ϫ (CH᎐CH ), 74.3ϩ (COH), 60.9Ϫ
38 mmol) and pyridinium chlorochromate (10.8 g, 50 mmol) in
dichloromethane (100 cm3) gave a crude product as a pale green
oil. Purification by column chromatography [silica, light petrol-
eum (bp 40–60 ЊC)–diethyl ether, 9:1] gave the ketone 18 (8.04 g,
81%) as an oil; Rf[light petroleum (bp 40–60 ЊC)–diethyl ether,
9:1] 0.39; νmax(CH2Cl2)/cmϪ1 3052, 2838, 2858, 1697 (C᎐O) and
᎐
᎐
2
(CSPh), 35.5Ϫ, 30.5Ϫ, 29.9Ϫ, 26.2Ϫ and 21.8Ϫ; m/z (EI) 262 (3%,
Mϩ), 203 (3), 191 (66, C6H10SPhϩ), 135 (27), 110 (73, PhSHϩ)
and 83 (100) and 91 (98); (Found: Mϩ, 262.1387. C16H22OS
requires M, 262.1391).
1641 (C᎐C); δ (250 MHz; CDCl ) 7.34–7.24 (5 H, m, PhS), 6.03
᎐
H
3
(1 H, ddt, J 17.1, 10.3 and 6.9 Hz, CH᎐CH ), 5.21 (1 H, dd,
᎐
2
J 10.1 and 1.4 Hz, CH᎐CHtransHcis), 5.19 (1 H, dd, J 17.1 and
᎐
1.6 Hz, CH᎐CH H ), 3.57 (2 H, dt, J 6.8 and 1.0 Hz, CH C᎐
᎐
᎐
2
trans cis
O), 1.99–1.91 (2 H, m, CH2), 1.82–1.64 (4 H, m, 2 × CH2), 1.49–
1.38 (2 H, m, CH2) and 1.38–1.26 (2 H, m, CH2); δC(100.6 MHz;
(1RS )-1-[4-(Phenylsulfanyl)tetrahydropyran-4-yl]but-3-en-1-ol
16
CDCl3) 204.4Ϫ (C᎐O), 136.5ϩ, 132.0ϩ, 130.0Ϫ (i-PhS), 129.3ϩ,
᎐
128.8ϩ, 118.1Ϫ (CH᎐CH ), 61.2Ϫ (CSPh), 41.0Ϫ, 32.5Ϫ, 25.5Ϫ
᎐
2
By the method described for compound 14, allylmagnesium
bromide in diethyl ether (1.0 mol dmϪ3, 35 cm3, 0.035 mol,
1.2 eq.) and aldehyde 13 (6.39g, 0.029 mol) in dry tetrahydro-
furan (120 cm3) gave a crude product which was recrystallised
from chloroform to give the alcohol 16 as prisms (5.15g, 68%),
mp 84–86 ЊC (chloroform); Rf[light petroleum (bp 40–60 ЊC)–
diethyl ether, 1:1] 0.21; νmax(CH2Cl2)/cmϪ1 3579 (O–H), 3070
and 23.1Ϫ; m/z (EI) 260 (4%, Mϩ), 191 (100, C6H10SPhϩ), 123
(16), 110 (9, PhSHϩ) and 81 (44); (Found: Mϩ, 260.1242.
C16H20OS requires M, 260.1235).
1-[4-(Phenylsulfanyl)tetrahydropyran-4-yl]but-3-en-1-one 19
By the method described for compound 17, the alcohol 16
(2.21 g, 8.4 mmol) and pyridinium chlorochromate (2.71 g,
12.5 mmol) in dichloromethane (25 cm3) gave a crude product.
Purification by column chromatography [silica, light petroleum
(bp 40–60 ЊC)–diethyl ether, 9:1] gave the ketone 19 as an oil
(1.709 g, 78%); Rf[light petroleum (bp 40–60 ЊC)–diethyl ether,
3:1] 0.23; νmax(CH2Cl2)/cmϪ1 3073 (C–H), 3041 (C–H), 2931
(C–H), 3040 (C–H), 2962 (C–H), 2867 (C–H), 1640 (C᎐C) and
᎐
1104 (C–O); δH(400 MHz; CDCl3) 7.50–7.48 (2 H, m, PhS),
7.36–7.25 (3 H, m, PhS), 5.87 (1 H, dddd, J 16.0, 10.0, 7.0 and
7.0 Hz, HC᎐CH ), 5.16–5.10 (2 H, m, HC᎐CH ), 4.04–3.98
᎐
᎐
2
2
(2 H, m, CHAHBO), 3.83–3.80 (2 H, m, CHAHBO), 3.39 (1 H,
dt, J 10.0 and 3.0 Hz, CHOH), 2.74 (1 H, d, J 3.0 Hz, OH), 2.55
(1 H, br dd, J 14.0 and 6.0 Hz, CHCHAHB), 2.26–2.17 (1 H,
m, CHCHAHB), 2.02 (1 H, ddd, J 14.5, 11.5 and 5.0 Hz,
CCHaxHeq), 1.86 (1 H, ddd, J 14.5, 11.5 and 5.0 Hz, CCHaxHeq),
1.48 (1 H, dd, 14.5 and 2.0 Hz, CCHaxHeq) and 1.34 (1 H, dd,
J 14.5 and 2.0 Hz, CCHaxHeq); δC(100.6 MHz; CDCl3), 137.9ϩ
(PhS), 136.4ϩ (CH᎐CH ), 130.1Ϫ (i-PhS), 129.7ϩ (p-PhS),
(C–H), 2867 (C–H), 1699 (C᎐O), 1641 (C᎐C), 1576 (PhS) and
᎐
᎐
1104 (C᎐O); δ (400 MHz; CDCl ) 7.34–7.25 (5 H, m, PhS), 6.00
᎐
H
3
(1 H, ddt, J 17.0, 10.0 and 7.0 Hz, CHCH2), 5.21 (1 H, dd,
J 10.0 and 1.5 Hz, C᎐CH H ), 5.19 (1 H, dd, J 17.0 and 1.5 Hz,
᎐
A
B
C᎐CH H ), 3.94 (2 H, ddd, J 12.0, 7.5 and 3.5 Hz, OCH H ),
᎐
A
B
ax eq
᎐
3.58–3.52 (4 H, m, OCHaxHeq and CHCH2), 2.01 (2 H, ddd,
J 14.0, 7.5 and 3.5 Hz, CCHaxHeq) and 1.84 (2 H, ddd, J 14.0,
7.0 and 3.5 Hz, CCHaxHeq); δC(100.6 MHz; CDCl3) 203.9Ϫ
(C᎐O), 136.9ϩ (PhS), 136.9Ϫ (i-PhS), 131.8ϩ (CH᎐CH ), 130.0ϩ
2
129.4ϩ (PhS), 117.7Ϫ (CH᎐CH ), 75.0ϩ (CHOH), 64.2Ϫ
᎐
2
(CH2OCH2), 64.0Ϫ (CH2OCH2), 57.8Ϫ (CSPh), 35.9Ϫ
(CH2CHOH), 30.6Ϫ (CH2CCH2) and 30.3Ϫ (CH2CCH2);
m/z (EI) 264 (46%, Mϩ), 193 (100, Mϩ Ϫ C4H6O), 137 (47,
Mϩ Ϫ PhS Ϫ H2O), 109 (45, PhSϩ) and 83 (39, C5H7Oϩ);
(Found: Mϩ, 264.1194. C15H20O2S requires M, 264.1184);
(Found: C, 68.19; H, 7.58. C15H20O2S requires C, 68.15; H,
7.63%).
᎐
᎐
2
(p-PhS), 129.4ϩ (PhS), 119.0Ϫ (HC᎐CH ), 64.7Ϫ (CH2OCH2),
᎐
2
58.8Ϫ (CSPh), 41.4Ϫ (CH C᎐O), and 32.3Ϫ (CH2CCH2);
᎐
2
m/z (EI) 262.1 (18%, Mϩ), 193 (100, C5H8OSPhϩ) and 109
(12, PhSϩ); (Found: Mϩ, 262.1019. C15H18O2S requires M,
262.1027).
2-Methyl-2-phenylsulfanylhex-5-en-3-one 17
(5R)-5,6-Dihydroxy-2-methyl-2-phenylsulfanylhexan-3-one 20
Alcohol 14 (8.00 g, 36.0 mmol) was added in one portion, under
argon at 0 ЊC to a stirred solution of pyridinium chloro-
chromate (PCC)10 (10.1 g, 46.8 mmol) in dichloromethane
(150 cm3). The solution was allowed to warm to room temper-
ature and stirred until the reaction was judged complete by
TLC. Dry diethyl ether (50 cm3) was added and the supernatant
liquor decanted from a black gum. The insoluble residues were
washed 5 times with ether (50 cm3) and the combined ethereal
extracts were filtered through a plug of florisil, which was
washed with more diethyl ether. The solvent was removed under
reduced pressure to give a crude product as a pale yellow–green
oil. Purification by column chromatography [silica, light petrol-
eum (bp 40–60 ЊC)–diethyl ether, 9:1] gave the ketone 17 (6.66 g,
84%) as an oil; Rf[light petroleum (bp 40–60 ЊC)–diethyl ether,
Alkene 17 (3.10 g, 14.1 mmol) was added to a vigorously stirred
solution of AD-mix-β (19.7 g) in a mixture of 2-methylpropan-
2-ol (70 cm3) and water (70 cm3). The reaction was stirred at
room temperature† until judged complete by TLC or LCMS.
Sodium sulfite (7.50 g, 59.3 mmol, 12 eq.) was then added and
stirring continued for 30 minutes. The mixture was transferred
to a separating funnel and ethyl acetate (50 cm3) was added.
The solution was extracted a further three times with ethyl
acetate (25 cm3). The combined organic extracts were washed
with water (25 cm3), saturated brine (25 cm3) and dried over
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure to give a crude product which was puri-
fied by column chromatography (silica, ethyl acetate) to give
the diol 20 (3.57 g, 77%) as an oil; Rf(ethyl acetate) 0.42;
νmax(CH2Cl2)/cmϪ1 3591 (br, O–H), 3057, 2972, 2931, 2876,
9:1] 0.35; νmax(CH2Cl2)/cmϪ1 3080, 2972, 2931, 1701 (C᎐O),
᎐
1642 (C᎐C) and 1584 (PhS); δ (250 MHz; CDCl ) 7.38–7.25
᎐
H
3
1691 (C᎐O), 1541, 1474, 1439, 1385, 1367, 1102, 1051, 1026
᎐
(5 H, m, PhS), 6.05–5.92 (1 H, m, CH᎐CH ), 5.23–5.14 (2 H, m,
᎐
2
and 909; retention time/min (Chiralpak AD column; hexane–
ethanol, 9:1) 15.5 (63.6%) and 17.3 (36.4); δH(250 MHz; CDCl3)
7.39–7.27 (5 H, m, PhS), 4.23–4.12 (1 H, m, CHOH), 3.71 (1 H,
ddd, J 11.1, 6.0 and 3.7 Hz, CHAHBOH), 3.56 (1 H, dt, J 11.3
and 5.6 Hz, CHAHBOH), 3.39* (1 H, d, J 3.1 Hz, CHOH ), 3.04
CH᎐CH ), 3.59 (2 H, dt, J 6.8 and 1.5 Hz, CH CO) and 1.40
᎐
2
2
(6 H, s, 2 × Me); δ (100.6 MHz; CDCl ) 205.7Ϫ (C᎐O), 136.2ϩ,
᎐
C
3
131.8ϩ, 131.0Ϫ (i-PhS), 129.3ϩ, 129.0ϩ, 118.2Ϫ (CH᎐CH ), 56.4Ϫ
᎐
2
(CSPh), 41.0Ϫ (CH C᎐O) and 24.3ϩ (2 × Me); m/z (EI) 220 (8%,
᎐
2
Mϩ), 151 (100, Me2CSPhϩ), 110 (14, PhSHϩ), 109 (14, PhSϩ),
84 (35) and 73 (17); (Found: Mϩ, 220.0923. C13H16OS requires
M, 220.0922).
(1 H, dd, J 17.7 and 3.8 Hz, CH H C᎐O), 2.95 (1 H, dd, J 17.7
᎐
B
A
and 8.3 Hz, CH H C᎐O), 2.07* (1 H, br t, J 6.1 Hz, CH OH ),
᎐
A
B
2
1.44 (3 H, s, MeA) and 1.41 (3 H, s, MeB); δC(100.6 MHz;
1-[1-(Phenylsulfanyl)cyclohexyl]but-3-en-1-one 18
† When the temperature was reduced to 0 ЊC only a small improvement
in enantiomeric excess was noticed.
By the method described for compound 17, alcohol 15 (10.0 g,
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
2641

View Article Online
Table 5 Effect of varying ligand8,11 and temperature on the enantiomeric excess of the AD reaction of alkene 17
Ligand
Temperature
Peaks
Enantiomeric excess
CLB8
25 ЊC
25 ЊC
25 ЊC
25 ЊC
25 ЊC
10 ЊC
0 ЊC
15.4 (55.1%) and 17.2 (44.9)
15.8 (63.6%) and 17.7 (36.4)
15.5 (67.2%) and 17.3 (32.8)
15.5 (61.3%) and 17.3 (38.7)
15.7 (80.3%) and 17.6 (19.7)
16.4 (83.9%) and 18.6 (16.1)
16.9 (86.3%) and 19.0 (13.7)
10.2%
27.2%
34.4%
22.6%
60.6%
67.8%
72.6%
PHAL (AD-mix-β)11b
PHAL
PHN11c
PYR11a
PYR
PYR
Table 6 Comparison of enantiomeric excess in the AD reaction of alkene 18 using the PYR ligand and the standard PHAL ligand
Ligand
Temperature
Peaks
Enantiomeric Excess
PHAL (AD-mix-β)
PYR
25 ЊC
0 ЊC
13.8 (64.4%) and 15.0 (35.6)
14.4 (91.8%) and 15.8 (8.2)
29.0%
83.6%
CDCl3) 208.9Ϫ (C᎐O), 136.3ϩ (m-PhS), 130.7Ϫ (i-PhS), 129.5ϩ
acetate (4 × 50 cm3). The combined organic extracts were
washed with water (50 cm3), then brine (50 cm3), and finally
dried over sodium sulfate. The solvent was removed under
reduced pressure to give the crude diol 20 which was analysed
by Chiral HPLC (Chiralpak AD column; eluting with hexane–
ethanol, 9:1; flow rate 1 cm3 minϪ1).
᎐
(p-PhS), 128.9ϩ (o-PhS), 68.8ϩ (CHOH), 66.0Ϫ (CH2OH), 56.2Ϫ
(CSPh), 38.8Ϫ (CH2), 24.3ϩ (Me) and 24.2ϩ (Me); m/z (EI) 254
(5%, Mϩ), 151 (82, Me2CSPhϩ) and 109 (100, PhSϩ); (Found:
Mϩ, 254.0971. C13H18O3S requires M, 254.0977).
(3R)-3,4-Dihydroxy-1-[1-(phenylsulfanyl)cyclohexyl]butan-1-one
21
(3R)-3,4-Dihydroxy-1-[1-(phenylsulfanyl)cyclohexyl]butan-1-one
21
By the method described for compound 20, alkene 18 (3.00 g,
11.5 mmol) and AD-mix-β (16.5 g) in 2-methylpropan-2-ol
(75 cm3) and water (75 cm3) gave a crude product which was
purified by column chromatography (silica, ethyl acetate) to
give the diol 21 (3.07 g, 91%) as a pale yellow oil; Rf(ethyl
acetate) 0.42; νmax(CH2Cl2)/cmϪ1 3584 (br, O–H), 3056, 3048,
By the previous method described for compound 20, alkene 18
(52.0 mg, 0.20 mmol), osmium tetroxide (2% w/v solution in
water, 25 µl, 2 µmol, 1 mol%), ligand (10 µmol, 5 mol%), potas-
sium ferricyanide (198 mg, 0.6 mmol) and potassium carbonate
(83.0 mg, 0.6 mmol) in a mixture of 2-methylpropan-2-ol
(2 cm3) and water (2 cm3) gave the crude diol 21 which was
analysed by Chiral HPLC (Chiralpak AD column; hexane–
ethanol, 9:1) (Table 6).
3987, 2938, 2859, 1685 (C᎐O), 1621, 1586, 1541, 1474, 1382,
᎐
1102, 1069, 1055, 1025 and 909; δH(250 MHz; CDCl3) 7.38–7.26
(5 H, m, PhS), 4.20 (1 H, ddq, J 9.0, 6.2 and 3.1 Hz, CHOH),
3.71 (1 H, ddd, J 11.1, 6.0 and 3.6 Hz, CHAHBOH), 3.54 (1 H,
dt, J 11.4 and 5.7 Hz, CHAHBOH), 3.53* (1 H, d, J 2.8 Hz,
(3R)-3,4-Dihydroxy-1-[4-(phenylsulfanyl)tetrahydropyran-4-
yl]butan-1-one 22
CHOH ), 3.03 (1 H, dd, J 17.7 and 2.9 Hz, CH H C᎐O), 2.89
᎐
B
A
(1 H, dd, J 17.7 and 9.1 Hz, CH H C᎐O), 2.13* (1 H, br t, J 5.3
᎐
B
A
By the previous method described for compound 20, alkene 19
(500 mg, 1.9 mmol), osmium tetroxide (2% w/v solution in
water, 240 µl, 19 µmol, 1 mol%), (DHQD)2PYR (84 mg,
95 µmol, 5 mol%), potassium carbonate (790 mg, 5.7 mmol)
and potassium ferricyanide (1.88 g, 5.7 mmol) in a mixture of
water (20 cm3) and 2-methylpropan-2-ol (20 cm3) at 0 ЊC gave a
crude product. Purification by column chromatography (silica,
ethyl acetate) gave the diol 22 as a viscous oil (410 mg, 73%);
Rf(ethyl acetate) 0.38; retention time/min (Chiralpak AD
column; hexane–ethanol, 9:1, flow rate 1 cm3 minϪ1) 34.3 (89%)
and 37.4 (11); [α]D ϩ13.0 (c. 1.23 in CHCl3; 78% ee);
νmax(CH2Cl2)/cmϪ1 3593 (O–H), 2967 (O–H), 2868 (C–H), 2868
(C–H), 2868 (C–H), 1691 (C᎐O) and 1104 (C–O); δ (400 MHz;
Hz, CH2OH ) and 2.04–1.23 (10 H, m); δC(100.6 MHz; CDCl3)
207.8Ϫ (C᎐O), 136.5ϩ, 129.7Ϫ (i-PhS), 129.6ϩ, 128.9ϩ, 68.8ϩ
᎐
(CHOH), 66.0Ϫ (CH2OH), 60.9Ϫ (CSPh), 38.7Ϫ (CH C᎐O),
᎐
2
32.6Ϫ, 32.4Ϫ, 25.4Ϫ, 23.2Ϫ and 23.0Ϫ; m/z (EI) 294 (4%, Mϩ), 191
(100, C6H10SPhϩ), 149 (5), 123 (15) and 81 (46); (Found: Mϩ,
294.1287. C16H22O3S requires M, 294.1290).
(3S )-3,4-Dihydroxy-1-[4-(phenylsulfanyl)tetrahydropyran-4-
yl]butan-1-one ent-22
By the method described for compound 20, alkene 19 (50 mg,
0.19 mmol) and AD-mix-α (283 mg) in 2-methylpropan-2-ol
(1.5 cm3) and water (1.5 cm3) gave a crude product after 24
hours which was purified by column chromatography (silica,
ethyl acetate) to give the diol ent-22 (35 mg, 63%) as a yellow oil;
Rf(ethyl acetate) 0.38; retention time/min (Chiralpak AD
column; hexane:ethanol, 9:1, flow rate 1 cm3 minϪ1) 33.4 (37%)
and 36.3 (63); [α]D Ϫ0.5 (c. 0.88 in CHCl3; 26% ee), spectro-
scopically identical to 22.
᎐
H
CDCl3) 7.36–7.24 (5 H, m, PhS), 4.18–4.26 (1 H, m, CHOH),
4.20–3.91 (2 H, m, CHAHBO), 3.71 (2 H, dd, J 11.5 and 3.5 Hz,
CH2OH), 3.58–3.53 (2 H, m, CHAHBO), 2.94 (1 H, dd, J 17.5
and 7.0 Hz, O᎐CCH H ), 2.93 (1 H, dd, J 17.5 and 5.0 Hz,
᎐
A
B
O᎐CCH H ), 2.00–1.97 (2 H, m, CCH H ) 1.83 (1 H, ddd,
᎐
A
B
ax eq
J 13.0, 5.0 and 3.5 Hz, CCHaxHeq) and 1.79 (1 H, ddd, J 12.5,
5.0 and 3.0 Hz, CCHaxHeq); δC(100.6 MHz; CDCl3) 204.6Ϫ
(C᎐O), 134.6ϩ (PhS), 127.9ϩ (p-PhS), 127.2ϩ (PhS), 127.1Ϫ
(5R)-5,6-Dihydroxy-2-methyl-2-phenylsulfanylhexan-3-one 20
᎐
(i-PhS),66.8ϩ(CH2CHOH),64.1Ϫ( CH2OH),62.3ϩ(CH2OCH2),
62.1ϩ (CH2OCH2), 56.3Ϫ (CSPh), 37.1ϩ (CH C᎐O), 20.9Ϫ
The alkene 17 (42.0 mg, 200 µmol) was added to a stirred
solution of osmium tetroxide (2% w/v solution in water, 25 µl,
2 µmol, 1 mol%), ligand (10 µmol, 5 mol%; see Table 5), potas-
sium carbonate (83 mg, 600 µmol) and potassium ferricyanide
(198 mg, 600 µmol) dissolved in a mixture of water (2 cm3) and
2-methylpropan-2-ol (2 cm3). The reaction mixture was
excluded from light and stirred for 36 hours at the appropriate
temperature (0–25ЊC). Sodium sulfite (250 mg, 1.98 mmol) was
added and stirring continued for 30 minutes. The organic layer
was separated and the aqueous layer was washed with ethyl
᎐
2
(CH2CCH2) and 29.7Ϫ (CH2CCH2); m/z (EI) 296 (38%, Mϩ),
193 (100, Mϩ–C4H7O3) and 109 (22, PhSϩ); (Found: Mϩ,
296.1093. C15H20O4S requires M, 296.1082).
(2RS,4SR)-(4-Phenylsulfanyl-1-oxaspiro[4.5]dec-2-yl)methanol
23
By the method described for compound 3, toluene-p-sulfonic
acid (4.8 mg, 25 µmol) and a solution of anti-triol 6 (70 mg,
2642
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645

View Article Online
0.240 mmol) in dichloromethane (2 cm3) gave the 2,4anti-
tetrahydrofuran 23 (59 mg, 90%) after 48 hours as an oil;
Rf[light petroleum (bp 40–60 ЊC)–diethyl ether, 1:1] 0.18;
νmax(CH2Cl2)/cmϪ1 3591 (O–H), 3056, 2986, 2938, 2861, 1584,
1480, 1448, 1439, 1146, 1090, 1039, 1026, 964 and 909; δH(250
MHz; CDCl3) 7.44–7.36 (3 H, m, PhS), 7.33–7.16 (2 H, m,
PhS), 4.20 (1 H, dddd, J 7.9, 6.0, 4.7 and 3.2 Hz, CH–O), 3.71
(1 H, ddd, J 11.5, 5.6 and 3.2 Hz, CHAHBOH), 3.45 (1 H, ddd,
11.7, 7.2 and 4.7 Hz, CHAHBOH), 3.36 (1 H, t, J 7.9 Hz,
CHSPh), 2.32 (1 H, ddd, J 13.0, 8.0 and 6.0 Hz, CHAHB), 2.10
(1 H, dt, J 13.0 and 7.9 Hz, CHAHB), 1.90* (1 H, dd, J 7.2 and
5.7 Hz, OH) and 1.76–1.14 (10 H, m); δC(100.6 MHz; CDCl3)
135.9Ϫ (i-PhS), 131.0ϩ, 129.0ϩ, 126.7ϩ, 84.5Ϫ (C–O), 75.6ϩ
(CH–O), 65.2Ϫ (CH2OH), 55.2ϩ (CHSPh), 37.0Ϫ, 35.5Ϫ, 30.9Ϫ,
25.6Ϫ, 23.3Ϫ and 22.2Ϫ; m/z (EI) 278 (18%, Mϩ), 180 (56, Mϩ Ϫ
C6H10O), 149 (100, C3H4SPhϩ) and 110 (15, PhSHϩ); (Found:
Mϩ, 278.1343. C16H22O2S requires M, 278.1340).
(PhS) and 1106 (C–O); δH(400 MHz; CDCl3) 7.41 (2 H, dd,
J 8.0 and 1.5 Hz, PhS), 7.31–7.22 (3 H, m, PhS), 4.20 (1 H, dtd,
J 11.0, 5.5 and 3.5 Hz, OCH), 3.82 (1 H, ddd, J 11.0, 5.0 and 2.5
Hz, OCH2), 3.80–3.68 (4 H, m, OCH2), 3.51–3.44 (1 H, m,
OCH2), 3.37 (1 H, t, J 8.0 Hz, CHSPh), 2.34 (1 H, ddd, J 13.0,
8.0 and 7.0 Hz, CH2), 2.10 (1 H, dt, J 13.0 and 8.5 Hz, CH2),
1.96 (1 H, ddd, J 13.5, 11.0 and 4.5 Hz, CHeqHax), 1.90 (1 H,
ddd, J 13.5, 11.0 and 5.5 Hz, CHeqHax), 1.59 (1 H, dq, J 13.5
and 2.5 Hz, CHeqHax) and 1.38 (1 H, dq, J 13.5 and 2.5 Hz,
CHeqHax); δC(100.6 MHz; CDCl3) 134.2Ϫ (i-PhS), 130.4ϩ (PhS),
128.1ϩ (PhS), 126.0ϩ (p-PhS), 80.9Ϫ (OCq), 74.9ϩ (OCHCH2),
64.1Ϫ (OCH2), 63.8Ϫ (OCH2), 63.2Ϫ (OCH2), 54.2ϩ (CHSPh),
35.9Ϫ (CH2), 33.9Ϫ (CH2) and 30.3Ϫ (CH2); m/z (EI) 280 (31%,
Mϩ), 251 (3), 201 (5), 151 (9), 119 (36), 100 (5) and 69 (100);
(Found: Mϩ, 280.1120. C15H20O3S requires M, 280.1133).
(2R,4R)-2-Hydroxymethyl-4-phenylsulfanyl-1,8-dioxaspiro-
[4.5]decane 29
(2RS,4RS )-(4-Phenylsulfanyl-1-oxaspiro[4.5]dec-2-yl)methanol
By the method described for compound 28, Amberlyst®
(0.35 g) and a solution of the triol 10 (67 mg, 0.22 mmol) in dry
dichloromethane (20 cm3) gave a crude product after heating to
reflux for 24 hours. The filtered residue was purified by column
chromatography (silica, diethyl ether) to give the 2,4syn-tetra-
hydrofuran 29 as an oil (52 mg, 87%); Rf(diethyl ether) 0.33; [α]D
ϩ1.5 (c. 1.18 in CHCl3; 78% ee); νmax(CH2Cl2)/cmϪ1 3267
(O–H), 2818 (C–H), 1582 (PhS) and 1103 (C–O); δH(400 MHz;
CDCl3) 7.45–7.39 (2 H, m, PhS), 7.33–7.20 (3 H, m, PhS), 4.10
(1 H, dtd, J 12.0, 6.5 and 3.5 Hz, OCH), 3.82 (1 H, ddd, J 11.0,
5.0 and 2.5 Hz, OCH2), 3.78–3.67 (4 H, m, OCH2), 3.55 (1 H,
dt, J 11.5 and 5.5 Hz, OCH2), 3.46 (1 H, t, J 7.5 Hz, CHSPh),
2.40 (1 H, dt, J 13.5 and 7.0 Hz, CH2), 2.05–1.90 (2 H, m, CH2),
1.81 (1 H, ddd, J 13.5, 10.5 and 6.5 Hz, CHeqHax), 1.60 (1 H, dq,
J 13.5 and 2.5 Hz, CHeqHax) and 1.48 (1 H, dq, J 13.5 and 2.5
Hz, CHeqHax); δC(100.6 MHz; CDCl3) 135.4Ϫ (i-PhS), 132.1ϩ
(PhS), 129.5ϩ (PhS), 127.6ϩ (p-PhS), 81.8Ϫ (OCq), 77.2ϩ
(OCHCH2), 65.5Ϫ (OCH2), 65.1Ϫ (OCH2), 64.8Ϫ (OCH2), 56.1ϩ
(CHSPh), 36.6Ϫ (CH2), 35.4Ϫ (CH2) and 34.5Ϫ (CH2); m/z (EI)
280 (21%, Mϩ), 251 (2), 222 (4), 169 (48), 119 (37), 100 (5)
and 69 (100); (Found: Mϩ, 280.1143. C15H20O3S requires M,
280.1133).
25
By the method described for compound 3, toluene-p-sulfonic
acid (5.0 mg, 26 µmol) and a solution of syn-triol 9 (62.2 mg,
0.210 mmol) in dichloromethane (2 cm3) gave the 2,4syn-tetra-
hydrofuran 25 (53 mg, 92%) after 48 hours as an oil; Rf[light
petroleum (bp 40–60 ЊC)–diethyl ether, 1:1] 0.17; νmax(CH2Cl2)/
cmϪ1 3589 (O–H), 1584, 1480, 1448, 1146, 1091, 1025, 958 and
908; δH(250 MHz; CDCl3) 7.45–7.37 (2 H, m, PhS), 7.34–7.17
(3 H, m, PhS), 4.08 (1 H, dddd, J 8.6, 6.8, 5.4 and 3.2 Hz,
CH–O), 3.72 (1 H, ddd, J 11.5, 6.2 and 3.3 Hz, CHAHBOH),
3.54 (1 H, ddd, J 11.7, 6.5 and 5.4 Hz, CHAHBOH), 3.46 (1 H,
dd, J 8.7 and 7.1 Hz, CHSPh), 2.38 (1 H, dt, J 12.9 and 6.9 Hz,
CHAHB), 2.01 (1 H, t, J 6.6 Hz, OH), 1.96 (1 H, dt, J 12.9 and
8.7 Hz, CHAHB) and 1.77–1.11 (10 H, m); δC(100.6 MHz;
CDCl3) 135.6Ϫ (i-PhS), 131.4ϩ, 129.0ϩ, 126.9ϩ, 83.9Ϫ (C–O),
76.5ϩ (CH–O), 65.2Ϫ (CH2OH), 55.8ϩ (CHSPh), 36.1Ϫ, 35.4Ϫ,
33.6Ϫ, 25.6Ϫ, 23.1Ϫ and 22.4Ϫ; m/z (EI) 278 (25%, Mϩ), 180 (82,
Mϩ Ϫ C6H10O), 149 (100, C3H4SPhϩ), 131 (22) and 110 (24,
PhSHϩ); (Found: Mϩ, 278.1347. C16H22O2S requires M,
278.1340).
(3RS,5RS )-2,2-Dimethyl-3-phenylsulfanyltetrahydrofuran-
5-ylmethanol 27
(3RS,5SR)-2,2-Dimethyl-3-phenylsulfanyltetrahydropyran-5-yl
3,5-dinitrobenzoate 30 and (3RS,5SR)-2,2-Dimethyl-3-phenyl-
sulfanyltetrahydrofuran-5-ylmethyl 3,5-dinitrobenzoate
By the method described for compound 3, toluene-p-sulfonic
acid (1.7 mg, 9.0 µmol) and a solution of syn-triol 8 (50 mg, 195
µmol) in dichloromethane (2.5 cm3) gave the 3,5syn-tetrahydro-
furan 27 (44 mg, 95%) after 48 hours as an oil; Rf[light petrol-
eum (bp 40–60 ЊC)–diethyl ether, 1:1] 0.09; νmax(CH2Cl2)/cmϪ1
3593 (O–H), 3054, 2978, 2881, 1584, 1480, 1422, 1142, 1091 and
1034; δH(400 MHz; CDCl3) 7.46–7.23 (5 H, m, PhS), 4.12–4.04
(1 H, m, CH–O), 3.70 (1 H, ddd, J 11.5, 6.0 and 3.3 Hz, CHA-
HBOH), 3.52 (1 H, ddd, J 11.5, 6.5 and 5.3 Hz, CHAHBOH),
3.49 (1 H, dd, J 10.3 and 6.8 Hz, CHSPh), 2.36 (1 H, dt, J 13.0
and 6.5 Hz, CHAHB), 1.97 (1 H, dt, J 13.0 and 10.1 Hz,
CHAHB), 1.31 (3 H, s, MeA) and 1.29 (3 H, s, MeB); δC(100.6
MHz; CDCl3) 135.6Ϫ (i-PhS), 131.6ϩ, 129.1ϩ, 126.7ϩ (p-PhS),
83.5Ϫ (C–O), 75.8ϩ (CHOH), 64.9Ϫ (CH2OH), 56.0ϩ (CHSPh),
35.6Ϫ (CH2), 27.8ϩ (Me) and 25.1ϩ (Me); m/z (EI) 238 (43%,
Mϩ), 136 (100), 135 (34) and 110 (24, PhSϩ); (Found: Mϩ,
238.1022. C13H18O2S requires M, 238.1027).
A 1:1 mixture of alcohols 3 and 4 (98 mg, 412 µmol) was dis-
solved in pyridine (2.5 cm3) and 3,5-dinitrobenzoyl chloride
(97 mg, 421 µmol) was added. The resulting pale yellow solu-
tion was stirred under argon for 1 hour and diluted with diethyl
ether (4 cm3), at which point a cloudy white precipitate was
formed. Dilute hydrochloric acid (15 cm3, 2.0 mol dmϪ3) was
added and the aqueous layer extracted twice with diethyl ether
(10 cm3). The combined organic fractions were dried over
anhydrous magnesium sulfate and the solvent evaporated under
reduced pressure to give a crude product as a pale yellow solid.
The residue was purified by column chromatography [silica,
light petroleum (bp 40–60 ЊC)–diethyl ether, 4:1] to give the
tetrahydropyran 30 (51 mg, 29%) as bright yellow needles which
were recrystallised from hexane–chloroform (9:1), mp 128–130
ЊC (from hexane–chloroform); Rf[light petroleum (bp 40–60
ЊC)–diethyl ether, 4:1] 0.25; νmax(CH2Cl2)/cmϪ1 3101, 2880, 1735
(2R,4S )-2-Hydroxymethyl-4-phenylsulfanyl-1,8-dioxaspiro-
[4.5]decane 28
(C᎐O), 1628, 1549 (NO ), 1478, 1462, 1346 (NO ), 1290, 1256,
᎐
2
2
1169, 1138, 1088 and 990; δH(400 MHz; CDCl3) 9.23 (1 H, t,
J 2.2 Hz, p-Ar), 9.13 (2 H, d, J 2.1 Hz, o-Ar), 7.48–7.43 (2 H, m,
PhS), 7.36–7.26 (3 H, m, PhS), 5.10 (1 H, tt, J 10.2 and 5.1 Hz,
CH–O), 3.95 (1 H, ddd, J 11.2, 5.3 and 2.0 Hz, CHeqHaxO), 3.67
(1 H, dd, J 11.1 and 10.1 Hz, CHeqHaxO), 3.18 (1 H, dd, J 12.3
and 4.2 Hz, CHSPh), 2.48 (1 H, dtd, J 12.8, 4.7 and 2.0 Hz,
CHeqHax), 2.07 (1 H, dt, J 12.5 and 11.0 Hz, CHeqHax), 1.48
(3 H, s, MeA) and 1.40 (3 H, s, MeB); δC(100.6 MHz; CDCl3)
Amberlyst® (0.35 g) was added to a solution of the triol 7 (53
mg, 0.18 mmol) in dry dichloromethane (20 cm3). The solution
was heated to reflux for 48 hours and the residue was filtered
and purified by column chromatography (silica, diethyl ether)
to give the 2,4anti-tetrahydrofuran 28 as an oil (42 mg, 83%);
Rf(diethyl ether) 0.36; [α]D ϩ4.2 (c. 0.7 in CHCl3; 78% ee);
νmax(CH2Cl2)/cmϪ1 3348 (O–H), 2785 (C–H), 2654 (C–H), 1584
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
2643

View Article Online
161.6Ϫ (C᎐O), 148.7Ϫ (C–NO ), 134.6Ϫ, 133.6Ϫ, 132.3ϩ, 129.5ϩ,
71.4Ϫ (C–OH), 41.4Ϫ, 37.5Ϫ, 27.5Ϫ, 25.8Ϫ and 22.2Ϫ; m/z (EI)
᎐
2
129.3ϩ, 127.6ϩ, 122.6ϩ, 75.4Ϫ (C–O), 70.6ϩ (CH–O), 62.1Ϫ
(CH2O), 53.1ϩ (CSPh), 33.4Ϫ (CH2), 28.4ϩ (CH3) and 18.4ϩ
(CH3); m/z (EI) 432 (100%, Mϩ), 220 (19), 195 (37), 162 (20)
and 136 (56); (Found: Mϩ, 432.0971. C20H20N2O7S requires M,
432.0991) CCDC 192684. See http://www.rsc.org/suppdata/p1/
b2/b208556a/ for crystallographic files in .cif or other electronic
format. Also, the tetrahydrofuran (42 mg, 24%) as pale yellow
needles which were recrystallised from hexane–chloroform
(9:1), mp 141–142 ЊC (from hexane–chloroform); Rf[light
petroleum (bp 40–60 ЊC)–diethyl ether, 4:1] 0.15; νmax(CH2Cl2)/
cmϪ1 3112, 2859, 1734 (C᎐O), 1628, 1549 (NO ), 1481, 1347
136 (2%, Mϩ Ϫ H O), 99 (52, Mϩ Ϫ CH CH CH᎐CH ), 84 (42),
᎐
2
2
2
2
55 (78, CH CH CH᎐CH ϩ) and 49 (100).
᎐
2
2
2
(2RS )-(1-Oxaspiro[4.5]dec-2-yl)methanol 37, (2RS )-4-Cyclo-
hexylidenebutane-1,2-diol 38 and (2RS )-4-(Cyclohex-1-ene)-
butane-1,2-diol 39
By the method described for compound 23, triol 35 (143 mg,
761 µmol) and toluene-p-sulfonic acid (20 mg, 106 µmol) in
dichloromethane (5 ml) gave a crude product after three days
whose 1H NMR spectrum indicated the presence of three com-
ponents. Purification by column chromatography [silica, light
petroleum (bp 40–60 ЊC)–diethyl ether, 9:1] gave the tetrahydro-
furan 37 (67 mg, 47%) as an oil; Rf[light petroleum (bp 40–60
ЊC)–diethyl ether, 9:1] 0.25; νmax(CH2Cl2)/cmϪ1 3583 (O–H),
3056, 2934, 2858, 1449, 1401, 1361, 1331, 1311, 1093, 1068,
1039, 1023 and 908; δH(250 MHz; CDCl3) 4.15–4.03 (1 H, m,
CH–O), 3.67 (1 H, ddd, J 11.3, 6.0 and 3.5 Hz, CHAHBOH),
3.45 (1 H, dt, 11.5 and 6.0 Hz, CHAHBOH), 2.05* (1 H, t, J 6.3
Hz, OH) and 2.02–1.26 (14 H, m); δC(100.6 MHz; CDCl3) 83.4Ϫ
(C–O), 78.1ϩ (CH–O), 65.3Ϫ (CH2OH), 38.4Ϫ, 37.3Ϫ, 36.0Ϫ,
27.1Ϫ, 25.7Ϫ, 24.1Ϫ and 23.7Ϫ; m/z (EI) 170 (25%, Mϩ), 139 (100,
Mϩ–CH2OH), 127 (81), 121 (69), 114 (14), 95 (32), 83 (31), 81
(32) and 67 (30); (Found: Mϩ, 170.1310. C10H18O2 requires M,
170.1307) and the alkenes endo-38 and exo-39 (16 mg, 11%; 2:1,
endo:exo) as an oil; Rf[light petroleum (bp 40–60 ЊC)–diethyl
ether, 9:1] 0.06; νmax(CH2Cl2)/cmϪ1 3585 (br, O–H), 2931, 2857
᎐
2
(NO2), 1290 and 991; δH(400 MHz; CDCl3) 9.24 (1 H, t, J 2.1
Hz, p-Ar), 9.16 (2 H, d, J 2.2 Hz, o-Ar), 7.45–7.41 (2 H, m,
PhS), 7.32–7.21 (3 H, m, PhS), 4.52–4.36 (3 H, m, CH–O,
CHAHBO and CHAHBO), 3.43 (1 H, t, J 9.0 Hz, CHSPh),
2.40–2.25 (2 H, m, CHAHB and CHAHB), 1.32 (3 H, s, MeA) and
1.31 (3 H, s, Me ); δ (100.6 MHz; CDCl ) 162.5Ϫ (C᎐O), 148.7Ϫ
᎐
B
C
3
(C–NO2), 135.1Ϫ, 133.7Ϫ, 131.6ϩ, 129.5ϩ, 129.2ϩ, 127.3ϩ,
122.5ϩ, 84.1Ϫ (C–O), 72.8ϩ (CH–O), 68.9Ϫ (CH2O), 55.3ϩ
(CSPh), 36.3Ϫ (CH2), 27.8ϩ (CH3) and 22.4ϩ (CH3); m/z (ϩES)
455 (8%, MNaϩ), 413 (36), 373 (35), 316 (16) and 261
(100); (Found: MNaϩ, 455.0893. C20H20N2O7SNa requires
455.0883).
(3RS )-1-(Cyclohexan-1-ol)butane-3,4-diol 35
By the method described for compound 5, potassium ferri-
cyanide (6.40 g, 19.4 mmol), potassium carbonate (2.68 g, 19.4
mmol), osmium() chloride hydrate (5.6 mg, 65.4 µmol, 0.7
mol%), quinuclidine (104 mg, 0.930 mmol, 3.5 mol%) and
alkene 36 (1.0 g, 6.48 mmol) in 2-methylpropan-2-ol (35 cm3)
and water (35 cm3) gave a crude product. Purification by col-
umn chromatography (silica, ethyl acetate) gave triol 35 (940
mg, 77%) as an oil; Rf(ethyl acetate) 0.10; νmax(CH2Cl2)/cmϪ1
3595 (O–H), 3396 (br, O–H), 2935, 2859, 1449, 1390 and 1348;
δH(200 MHz; CDCl3) 3.79–3.57 (2 H, m, CHOH and CHA-
HBOH), 3.47 (1 H, dd, J 8.4 and 5.6 Hz, CHAHBOH), 2.86*
(3 H, br s, 3 × OH), 1.69–1.21 (14 H, m); δC(100.6 MHz; CDCl3)
72.7ϩ (CH–OH), 71.3Ϫ (C–OH), 66.7Ϫ (C–OH), 37.9Ϫ, 37.8Ϫ,
37.1Ϫ, 26.5Ϫ, 25.8Ϫ, 22.3Ϫ and 22.2Ϫ; m/z (ϩFIB) 189 (20%,
MHϩ), 171 (54), 154 (100), 137 (70), 136 (86) and 107 (28);
(Found: MHϩ, 189.1497. C10H20O3 requires M, 189.1491).
and 1642 (C᎐C); δ (200 MHz; CDCl ) 5.44 (1 H, br s, endo
᎐
H
3
CH᎐C), 5.09 (1 H, br t, J 7.6 Hz, exo CH᎐C), 3.78–3.58 (4 H,
᎐
᎐
m), 3.54–3.38 (2 H, m) and 2.43–1.39 (24 H, m); δC(100.6 MHz;
CDCl ) 143.8Ϫ (exo CH᎐C), 137.3Ϫ (endo CH᎐C), 121.6ϩ (endo
᎐
᎐
3
CH᎐C), 115.7ϩ (exo CH᎐C), 72.2ϩ (endo and exo CH–OH),
᎐
᎐
66.8Ϫ (endo CH2OH), 66.3Ϫ (exo CH2OH), 37.3Ϫ (exo CH2),
34.1Ϫ (endo CH2), 31.2Ϫ (exo CH2), 31.0Ϫ (endo CH2), 28.8Ϫ
(exo CH2), 28.7Ϫ (exo CH2), 28.2Ϫ (endo CH2), 27.9Ϫ (exo CH2),
26.8Ϫ (exo CH2), 25.2Ϫ (endo CH2), 22.9Ϫ (endo CH2) and 22.5Ϫ
(endo CH2); (Found: MNaϩ, 193.1192. C10H18O2Na requires M,
193.1199).
Acknowledgements
We thank the EPSRC for grants to LC and DH, and
AstraZeneca for extra support to DH. We are very grateful
to Dr J. E. Davies and Dr N. Feeder for the single crystal X-ray
diffraction analysis.
1-(Cyclohexan-1-ol)but-3-ene 36
4-Bromobut-1-ene (5.0 g, 3.76 cm3, 37.0 mmol) was slowly
added to a stirred suspension of magnesium turnings (0.99 g,
40.7 mmol, 1.1 eq.) and one small crystal of iodine in diethyl
ether (50 cm3) at 0 ЊC under argon. The solution was allowed to
warm to room temperature once the addition was complete and
stirred for 2 hours. The reaction was again cooled to 0 ЊC and
cyclohexanone (3.99 g, 4.22 cm3, 40.7 mmol) in diethyl ether
(5 cm3) slowly added. Once the addition was complete the
mixture was warmed to ambient temperature and stirring con-
tinued for 1 hour. Saturated aqueous ammonium chloride
solution was then slowly added and the mixture transferred to a
separating funnel. The aqueous layer was extracted three times
with diethyl ether (30 cm3) and the combined organic extracts
washed with water (30 cm3), saturated brine (30 cm3) and dried
over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. Purification by
column chromatography [silica, light petroleum (bp 40–60ЊC)–
diethyl ether, 4:1] gave the alkene 36 (2.88 g, 50%) as an oil;
Rf[light petroleum (bp 40–60ЊC)–diethyl ether, 4:1] 0.16;
Notes and references
1 (a) D. House, F. Kerr and S. Warren, Chem. Commun., 2000, 1779;
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2 Selenium and iodine electrophiles have been used to great effect in
the stereoselective synthesis of oxygen heterocycles. For leading
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‘rearranged’ heterocycle is one formed by [1,2]-PhS migration.
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a [1,2] migration. Conversely, a
νmax(CH2Cl2)/cmϪ1 3596 (O–H), 2926, 2857, 1639 (C᎐C), 1449,
᎐
1382, 1346 and 1148; δH(400 MHz; CDCl3) 5.86 (1 H, ddt,
J 16.8, 10.1 and 6.6 Hz, CH᎐CH ), 5.04 (1 H, dq, J 17.1 and
᎐
2
1.7 Hz, CHtransH ᎐CH), 4.99–4.91 (1 H, m, CH H ᎐CH),
᎐
᎐
trans cis
cis
2.25–2.09 (2 H, m, CH CH᎐CH ) and 1.94–1.17 (13 H, m);
᎐
2
2
δC(100.6 MHz; CDCl3) 139.3ϩ (CH᎐CH ), 114.3Ϫ (CH᎐CH ),
᎐
᎐
2
2
2644
J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645

View Article Online
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J. Chem. Soc., Perkin Trans. 1, 2002, 2634–2645
2645