Carboxylate-stabilised sulfur ylides (thetin salts) in asymmetric epoxidation for the synthesis of glycidic acids. Mechanism and implications

Article abstract of DOI:10.1039/b418740g

The reaction of carboxylate-stabilised sulfur ylides (thetin salts) with aldehydes and ketones has been investigated. Using both achiral and chiral sulfur ylides, good yields were obtained with dimsylsodium or LHMDS as bases in DMSO or THF-DMSO mixtures.

Full text of DOI:10.1039/b418740g

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A R T I C L E
Carboxylate-stabilised sulfur ylides (thetin salts) in asymmetric
epoxidation for the synthesis of glycidic acids. Mechanism and
implications
Varinder K. Aggarwal* and Christina Hebach
University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS.
E-mail: V.Aggarwal@Bristol.ac.uk; Fax: 44 (0)117 929 8611; Tel: 44 (0)117 954 6315
Received 14th December 2004, Accepted 22nd February 2005
First published as an Advance Article on the web 18th March 2005
The reaction of carboxylate-stabilised sulfur ylides (thetin salts) with aldehydes and ketones has been investigated.
Using both achiral and chiral sulfur ylides, good yields were obtained with dimsylsodium or LHMDS as bases in
DMSO or THF–DMSO mixtures. However, the enantioselectivities observed with a camphor-based sulfide were only
moderate (up to 67%). The reaction was studied mechanistically by independent generation of the betaine (via the
hydroxyl sulfonium salt) in the presence of a more reactive aldehyde, which resulted in incorporation of the more
reactive aldehyde and showed that betaine formation was reversible. Thus, the moderate enantiomeric excess
observed is a consequence of the enantiodifferentiating step being the ring closure step rather than the betaine
forming step. We had expected betaine formation might be non-reversible because a carboxylate-stabilised ylide has
only slightly higher stability than a phenyl-stabilised ylide, which does largely react non-reversibly with aldehydes.
Evidently, a carboxylate-stabilised ylide is significantly more stable than a phenyl-stabilised ylide and as such reacts
reversibly with aldehydes.
Introduction
Glycidic acids, esters and amides are extremely useful synthetic
intermediates since they can be opened by nucleophiles with
complete stereo- and often excellent regio-control to give
highly functionalised compounds.1 The most direct route
to such compounds is via a Darzens-type reaction. This
reaction involves an initial aldol reaction and it is therefore
not surprising that the widespread asymmetric developments
in the aldol area have been extended to Darzens reactions.
Indeed, high enantioselectivity has been achieved by employing
either chiral auxiliaries,2 chiral reagents3 or chiral catalysts.4
Invariably, these reactions involve two discrete steps: the aldol
reaction, followed by ring closure. In contrast, sulfur ylides
react directly with aldehydes to give epoxides5 and, recently,
high enantioselectivity (95%–>99% ee) has been achieved with
tertiary amide-stabilised ylides leading to an enantioselective
route to glycidic amides (Fig. 1).6 However, tertiary amides are
difficult to convert into other acid derivatives. As such, we have
investigated alternative ylides and in this paper we describe our
studies employing carboxylate-stabilised sulfur ylides.
Scheme 1 Epoxidation using optimised sulfide A.
In contrast, reversible formation of betaines derived from ter-
tiary amide-stabilised ylides again gave excellent results (between
95%–>99% ee). Only the trans-diastereomer was formed when
aromatic aldehydes were employed, but this turned out to be a
special case. In this unique case, high enantioselectivity was the
result of one diastereomer of the betaine undergoing ring closure
more rapidly than the other (Fig. 1, lower pathway). In designing
chiral sulfides for asymmetric epoxidation reactions it is very
difficult to engineer features that affect the rates of ring closure
of diastereomeric betaines. It is much easier to incorporate
features that control which betaine diastereomer is formed, as
demonstrated in the case with phenyl-stabilised ylides. Thus, if
betaine formation could be made non- or partially reversible, our
current optimum sulfide A should deliver high enantioselectivity.
The degree of reversibility of betaine formation relates to ylide
stability, a measure of which can be obtained from pKa values
of the corresponding sulfonium salts. We obviously needed a
carbonyl group that stabilised the ylide to a similar extent
as a phenyl group. We particularly considered a carboxylate
group because such ylides had previously been employed in
epoxidations with both aldehydes and ketones.8 However, no
pKa values were available for this system and in fact very few
pKa’s of sulfonium salts have been measured (Table 1).
In order to determine the relative stabilities of various ylides,
we calculated the equilibrium between the trimethylsulfonium
ylide and substituted sulfonium salts using the B3LYP 6-31G*
base set with THF as solvent (Table 1). In descending the
table betaine formation becomes more reversible, ylide stability
increases and, ultimately, no reaction is observed (Table 1, entry
6, 7) as the ylide is too stable. This clearly showed the relationship
between ylide stability and reversibility in betaine formation. It
also showed that a sodium-carboxylate substituted ylide was the
closest in stability to a phenyl substituted ylide. We therefore
Fig. 1 Epoxidation by tertiary amide-stabilised ylides.
Our detailed mechanistic analysis of phenyl-stabilised ylides B
has shown that partially reversible formation of the syn-betaine
and non-reversible formation of the anti-betaine contributed to
the excellent selectivities observed (up to >99% ee and 95% dr)
(Scheme 1).7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7
1 4 1 9
©

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Table 1 Relative stability of ylides and their reactivitya
Entry
Substituent
pKa
DE/kcal mol−1
Reactivity/explanation [towards aldehydes]
1
2
3
4
5
6
7
H
Ph
—
0.00
Epoxide formation; betaine formation non-reversible
Epoxide formation; betaine formation partially-reversible
Epoxide formation known
Epoxide formation known
Epoxide formation; betaine formation fully reversible
No reaction (ylide too stable)
17.9b9
—
−9.90
CO2Na
CO2Li
CON(CH3)2
CO2CH3
C(O)Ph
−11.85
−17.22
−21.74
−27.58
−30.07
—
—
—
8.45 c10
No reaction (ylide too stable)
a Calculations carried out with a B3LYP 6-31G* base set. b In DMSO. c In 80% EtOH.
Table 2 Scope of electrophiles
Entry
Carbonyl compound
R1
R2
Yield (%)
Ester
1
2
3
4
Cyclohexyl-carboxaldehyde
Pentanal
Trifluoromethyl-benzaldehyde
Cyclohexanone
Cy
H
H
H
98
73
75
68
2
3
4
5
CH3(CH2)3
pCF3(Ph)
(CH2)5
considered the use of carboxylate-stabilised ylides in order
to broaden the scope of our asymmetric epoxidation process
(Scheme 2).
a-bromo-acetate had been previously reported,11 the sulfides
were always utilised in excess, even as the solvent, which was
not appropriate in this case. In our synthesis of the sulfonium
salts, the use of only one equivalent of the chiral sulfide A and an
easy exchange of the counter ion (Br− versus BF4 or PF6−) are
−
particularly noteworthy. The hygroscopic thetin salts 7 are prone
to decarboxylate.12 In fact, Forbes et al. applied this thermally
induced loss of carbon dioxide to generate methylsulfonium salts
for base-free epoxidations.13 We found it more convenient to
store the stable, less hygroscopic esters 6 at room temperature
and convert them into the thetin salts 7 when needed. Structure
determination was substantiated by X-ray crystallography of
7b†‡ (Fig. 2).
Scheme 2 General reaction pathway for the formation of glycidic acids.
Results and discussion
In our initial studies we prepared tetrahydrothiophene thetin
salts in order to optimise the reaction conditions and to establish
the range of electrophiles suitable for this transformation
(Table 2). Excellent yields of the trans-substituted glycidic esters
could be obtained with a wide range of electrophiles, including
a-branched aliphatic (Table 1, entry 1), unbranched aliphatic
(Table 1, entry 2) and aromatic aldehydes (Table 1, entry 3), as
well as ketones (Table 1, entry 4), using dimsylsodium as a base in
DMSO at room temperature followed by esterification. This re-
action was highly diastereoselective, furnishing thetrans-epoxide
only. Having established conditions and suitable substrates for
the epoxidation we sought to render the reaction asymmetric
and turned to our camphor-derived sulfide A (Scheme 3). The
required sulfonium salts 7 bearing different counter ions were
prepared as shown in Scheme 3.
Fig. 2 X-ray structure of (+)-7b [ORTEP].
Scheme 3 Synthesis of the sulfonium salt 7.
Commercially available a-bromo-tert-butyl-acetate was re-
acted with sulfide A in a biphasic environment (with aqueous
saturated salt solutions to achieve concomitant counter ion
exchange) and the sulfonium salts 6 were obtained in high
yields. Although the direct formation of the sulfonium salt with
† CCDC reference number 258338. See http://www.rsc.org/suppdata/
ob/b4/b418740g/ for crystallographic data in CIF or other electronic
format.
‡ The salt for X-ray structure determination was obtained from the
opposite enantiomer of A.
1 4 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7

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Table 3 Darzens-type reaction of 7b
Entry
Base (2.5 eq.)
Solvent
Temp./◦C
Yield (%)
dr
Enantiomeric excess (%)a
1
2
3
4
5
DMSONa
DMSO
THF–DMSO
THF
THF–DMSO
THF
20
0
−40
−45
−45
80
82
8
9
10
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
25
33
56
58
59
LHMDS in toluene
LHMDS in toluene
KHMDS in THF
KHMDS with 18-crown-6
a Determined by chiral GC, absolute stereochemistry of major product is shown in Scheme 4.
Table 4 Darzens-type reaction of 7c
Entry
Base (2.5 eq.)
Solventa
Temp./◦C
Yield (%)
dr
Enantiomeric excess (%)
1
2
3
4
P2base
DCM
THF
−80 to 0
−50
15 ◦C then 0 ◦
9
8
9
>99 : 1
>99 : 1
>99 : 1
>99 : 1
53
67
54
35
LHMDS
LDA
THF
−75
KHMDSb
toluenec–dioxane
C
64
a Concentration 0.04 (mol l−1). b 2.5eq. 18-crown-6 was used as additive. c Concentration was 0.02 (mol l−1).
Asymmetric epoxidation process
Initial investigations were carried out with salt 7b using cy-
clohexanecarboxaldehyde (CyCHO) as the electrophile with
a variety of bases and solvents (Table 3). It was found that
Scheme 4 Determination of absolute stereochemistry of 8.
the highest yields were obtained in the dipolar aprotic solvent
DMSO (Table 3, entry 1, 2), but enantiomeric excesses were
low. By using a mixture of THF and DMSO (1 : 1) with a
lithium base, we were able to conduct the reaction at lower
temperatures which led to a small increase in enantiomeric excess
(Table 3, entry 2). Further temperature reduction was possible
using THF alone (Table 3, entry 3). Under these conditions,
the ylide was not completely in solution and it proved difficult
to obtain good yields. The expected increase in enantiomeric
excess by employing potassium ylides was not realised (Table 3,
entry 4, 5), as the potassium ylides were expected to react
less reversibly because the potassium carboxylate is less anion
stabilised than other metal carboxylates (see Table 1, entry 3,
4). Other variations in reaction parameters, including change
of solvent, temperature and additives, did not lead to further
improvements in yield or enantiomeric excess.§
understanding of the processes occurring during analysis and
establishing for the first time the absolute stereochemistry of the
glycidic esters obtained. A detailed explanation of the origin of
our enantioselectivity is given in Scheme 5 and is discussed later.
The lower than expected level of asymmetric induction ob-
served in our epoxidations could result from either poor control
in ylide conformation or reversibility in betaine formation
(Scheme 5). We felt that ylide conformation would be well
controlled because A-values¶ of a carboxylate and a phenyl
group are comparable.15 Since the conformation of the phenyl
substituted ylide is well controlled,7 we would therefore expect
that the conformation of the carboxylate-stabilised ylide would
be similarly well controlled. We therefore focussed on exam-
ining whether betaine formation was reversible or not.16 This
was achieved by independent preparation of the intermediate
betaines and examining the stereospecificity of ring closure and
carrying out cross-over experiments.17
As the BF4 salt 7b showed limited solubility, the PF6 salt 7c
was also examined to see if yield or enantioselectivity could be
improved by changing the counter ion. However, no significant
improvements in either were observed (Table 4).
Synthesis of the betaines
Without a strong chromophore in epoxide 2, we had to resort
to GC/MS and chiral GC analysis to determine enantioselectiv-
ity. The results from GC/MS indicated that decarboxylation had
occurred during analysis (most probably in the injector port) as
the molecular ion peak of the terminal epoxide 8 was observed
(Scheme 4).
To verify this, (R)-8 was synthesised by an independent route
using the Jacobsen protocol and the retention times of (R)-8 and
2 were compared.14 These were identical, thus confirming our
The syn- and anti-sulfonium salts were synthesised as shown
in Scheme 6. Substitution of the commercially available a-
bromo-acetic-tert-butyl ester with sodium thiomethoxide gave
a-thiomethoxy-acetic-tert-butylester (9) in 93% yield. An aldol
reaction with cyclohexylcarboxaldehyde furnished a separable
2.4 : 1 mixture of diastereo isomers in favour of the anti-
adduct 10. The relative stereochemistry of the aldol adducts
§ No product formation was observed in acetonitrile and dimethylfor-
mamide as solvent or when other bases, such as Grignard reagents, were
employed. Chelating salts, such as MgBr2 and ZnCl2, did not lead to
product formation either.
¶
◦
Definition: A-value = −DGꢀ: APh (−100 C): 2.8 (kcal mol−1);
ACOOH (25 ◦C): 1.4 (kcal mol−1); ACOO (25 ◦C): 2.0 (kcal mol−1).
−
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7
1 4 2 1

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Scheme 5 Origin of enantioselectivity.
Scheme 6 Synthesis of hydroxyl dimethylsulfonium salts 10.
were determined by comparison of the NMR J-values*16 and
diastereomeric ratios (anti : syn, 2 : 1)17 by analogy to literature
known compounds.
Alkylation of the sulfides (syn)-10 and (anti)-10 with Meer-
wein’s reagent gave the sulfonium salts 11 (Scheme 7). It was
critical to avoid traces of water, as the acid generated from
its reaction with Meerwein’s salt caused partial cleavage of
the tert-butyl ester. An acid catalysed cleavage of the ester 11
yielded 12 quantitatively. As these salts were hygroscopic and
difficult to analyse, small amounts of 12 were derivatised with
diazomethane into the corresponding methyl esters 13 to prove
their structure.
Scheme 8 Stereospecificity of ring closure.
investigate whether reversion to the starting materials (aldehyde
and ylide) is faster than ring closure to the epoxide (Scheme 9).
Scheme 9 Origin of diastereoselectivity.
Scheme 7 Synthesis of hydroxy dimethylsulfonium salts 12.
In a control experiment, the tetrahydrothiophene thetin
sulfonium salt was treated with base and a mixture of two
eq. of the more reactive aromatic aldehyde and one eq. of
cyclohexanecarboxaldehyde (Scheme 10).
Mechanistic studies and results of the cross-over experiment
Before carrying out cross-over experiments, the syn- and anti-
sulfonium salts 12 were treated with 2.5 eq. of base. If betaine
formation was non-reversible, one would observe a stereospe-
cific ring closure to give exclusively cis- and trans-epoxides,
respectively.17 In practice, the anti-betaine 12 gave (trans)-2, but
treatment of the (syn)-12 salt did not yield any of the expected cis-
epoxide 2 (Scheme 8). The lack of formation of the cis-epoxide
was frustrating but could be the result of decarboxylation of the
epoxy-acid (a common side reaction), which is likely to be more
facile for the cis-isomer. Indeed, only few examples of cis-epoxy
acids are known in the literature, most of them derived from
oxidation of the corresponding epoxy alcohol.18
Scheme 10 Control experiment, maximal ratio of product.
A 19 : 81 ratio of the two epoxides (2 : 4) was obtained,
incorporating the more reactive aromatic substituent preferen-
tially. This result indicates that if the betaine formation is fully
reversible, this is the maximum ratio one would expect in a cross-
over experiment.
The cross-over experiments itself were conducted under the
same reaction conditions as employed above to determine
whether solvent polarity affected the outcome of the experiment.
In DMSO a 20 : 80 ratio of epoxides (2 : 4) was obtained, showing
that the reaction was fully reversible (Table 5, entry 1). Even
using potassium salts in a mixture of less polar solvents (Table 5,
To investigate the level of reversibility of the trans-betaine
formation, a cross-over experiment was carried out using a
more reactive aromatic trifluoromethyl benzaldehyde as the
second competing electrophile. This experiment was designed to
* trans Reported: 6.0 Hz, found 6.6 Hz; cis reported: 4.0 Hz, found
5.5 Hz.
1 4 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7

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Table 5 Cross-over experiment
Entry
Base (2.5 eq.)
Solvent
Temp./◦C
Yield (%)
Ratio 2 : 4
1
2
3
NaDMSO
KHMDSa
KHMDSa
DMSO
THF–DMSO
THF
Rt
0
−40
89
63
62
20 : 80
33 : 77
29 : 71
a In toluene using 2.5 eq. 18-crown-6 as additive.
entry 2) with crown ether to capture the potassium ion at reduced
temperatures (Table 5, entry 3) still resulted in substantial
reversibility and incorporation of the more reactive aldehyde.
For obvious reasons, we did not carry out the cross-over
experiments with the syn-betaine 12, since no product formation
was obtained even under the most suitable reaction conditions
(dimsylsodium as base at rt) without any competing electrophile.
The reversibility in betaine formation implicates either bond
rotation or the ring closure step as the enantiodifferentiating
step. In related reactions involving amide-stabilised ylides, we
have found that the ring closure step is most likely the rate
determining step and so we assume that a similar scenario
applies in this case. Thus, the overall mechanistic picture of
the ylide reaction is best described by Scheme 5. A series of
reversible steps leads to an equilibrium mixture of betaines Y and
Z and the ratio of epoxides obtained depends on their relative
concentration and rates of the ring closure (Curtin–Hammett).
using a Bruker Daltonics (Billerica, MA, USA) ApexIV 7Tesla
FT-ICR-MS with Apollo Electrospray source. As a X-ray
generator was used a standard water cooled W-filament source,
which produces Mo K-alpha radiation and is typically used at 50
kV and 40 mA (2 kW power). The CCD (charge-coupled device)
area detector has a two-dimensional array of photodiodes
(1024 × 1024 elements) coupled by fibre-optics. The analytical
data of literature known compounds were in good agreement
with the data reported. Diastereomeric ratios were determined
from the crude proton NMR spectra and enantiomeric excesses
were determined by chiral GC (Supelco 120, gamma dex;
30 m × 0.25 mm × 0.25 lm). A gradient method was applied,
◦
70 C isotherm for 10 minutes and then heating with a rate of
1 ◦C per minute to 140 ◦C.
1-Carboxymethyl-tetrahydro-thiophenium bromide (1). Tetra-
hydrothiophene (19.4 ml, 220 mmol) and bromo-acetic acid
(27.79 g, 200 mmol) were stirred in acetone (75 ml) under a
nitrogen atmosphere for two days. The precipitate formed in
acetone was collected by filtration, washed with cold diethyl
ether (3 × 15 ml) and dried under a vacuum to give 1 as a white
crystalline solid in 82% yield (37.21 g, 164.0 mmol). Mp 96–
99 ◦C (decomp.); (found: M+, 147.0473. C6H11O2SBr 147.0479);
(found C, 32.00; H, 5.04; S, 13.99%. C6H11BrO2S required C,
31.73; H, 4.80; S, 14.12%); mmax (neat)/cm−1 2805, 1714; dH
(400 MHz, CD3OD) 2.21–2.31 (4H, m, SCH2CH2), 3.48–3.57
(4H, m, SCH2CH2), 4.35 (2H, s, SCH2CO2). dC (101 MHz,
CD3OD) 28.2 (CH2), 42.6 (CH2), 50.0 (CH2), 167.5 (C).
Conclusions
Carboxylate-stabilised ylides react with aldehydes to give epox-
ides in good yields. The reaction can be rendered asymmetric
using chiral sulfides, although enantioselectivities are relatively
moderate. Detailed analysis of the reaction mechanism, primar-
ily from generating the intermediate betaines in the presence of
a more reactive aldehyde and observing cross-over products,
has shown that betaine formation is fully reversible. This
accounts for the low enantioselectivity observed. Thus, under
our reaction conditions and irrespective of the counter ion
employed, carboxylate-stabilised ylides should be regarded in
the class of stabilised ylides rather than semi-stabilised ylides as
the latter class react non- or partially reversibly with aldehydes
whilst stabilised ylides react reversibly.
Method A. Standard epoxidation procedure with DMSONa
as base: to a stirred solution of DMSONa (freshly prepared
according to the literature procedure)19 in 1 ml DMSO un-
der nitrogen was added 113 mg carboxymethyl-tetrahydro-
thiophenium bromide over a period of five minutes. After stirring
for 30 minutes the ylide was a pale solution and the electrophile
(0.5 mmol) was added in one portion via a syringe. After 18 hours
stirring at rt, the reaction mixture was diluted with diethyl ether
and poured onto ice. After phase separation, the organic layer
was washed once with ice cold saturated NaHCO3 solution.
The combined basic layers were acidified with ice cold 1 N HCl
aq. to a pH of 2–3 and the product was re-extracted in the
organic layer (three times) with diethyl ether. The combined
organic layers were dried over MgSO4, filtered and exposed to
an etherial solution of CH2N2 until no more nitrogen evolution
was observed. The solvent was evaporated at a reduced pressure
to yield aromatic-smelling oils. If purification was necessary, a
Kugelrohr-distillation gave the final product.
Experimental
General
Reactions requiring anhydrous conditions were performed in
vacuum-dried glassware under an argon atmosphere using
standard canula techniques. The solvents were purified after
standard procedures. Liquid starting materials were distilled
before use and solid compounds were used as supplied. P2-base
(1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2l5,4l5-catenadi
(phosphazene)) was supplied from Aldrich and used without
purification. Chromatographic purification was achieved on
silica gel (Merck, Kieselgel 60, 230–400 mesh) and the reactions
were monitored by TLC on alumina backed silica plates (60F254
,
0.2 mm). Infrared spectra were recorded on a Perkin-Elmer
1
Spectrum One FT-IR spectrometer. H spectra were recorded
at 400 MHz on a Jeol Eclipse 400 instrument. Chemical shifts
(d) are quoted in ppm and are referenced to TMS or, in the
absence of the latter, to the solvent peak; J values are given in
Hz. 13C NMR spectra were recorded to 101 MHz on the same
instrument and are referenced to the appropriate solvent peak.
Elemental microanalyses were carried out using a Perkin Elmer
2400 CHN elemental analyser. HR-mass spectra were recorded
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7
1 4 2 3

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3-Cyclohexyl-oxirane-carboxylic-acid-methylester (2)20. This
compound was prepared according to method A as colourless
oil in 98% yield (83 mg, 0.49 mmol). mmax (neat)/cm−1 1746; dH
(400 MHz, CDCl3) 1.15–1.26 (5H, m, Cy), 1.69–1.77 (6H, m,
Cy), 2.99 (1H, dd, J = 6.4 Hz, J = 2.0 Hz, CHCy), 3.29 (1H,
d, J = 2.0 Hz, CHCO), 3.79 (3H, s, CO2CH3). dC (101 MHz,
CDCl3) 25.4 (CH2), 25.5 (CH2), 26.1 (CH2), 28.8 (CH2), 29.3
(CH2), 39.5 (CH), 51.9 (CH3), 52.4 (CH), 62.6 (CH), 170.1 (CO).
GC-analysis: tR (R): 79.51; tR (S): 79.98.
(1S,3S,4R)-2-tert-Butyloxymethyl-3-[(1S,4R)-7,7-dimethyl-2-
oxobicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane tetra-
fluoroborate (6b). To a stirred solution of the chiral sulfide
A (1.02 g, 4.03 mmol) in 1.4 ml DCM was added a-bromo-
tert-butyl-acetate (4.55 ml, 28.2 mmol) in one portion. 3.096 g
(28.2 mmol) of NaBF4 dissolved in 4 ml water (saturated
solution) were added and the reaction mixture was stirred
vigorously at rt and monitored by TLC for two days. After
consumption of the sulfide, the reaction mixture was diluted
with DCM and water. The resulting phases were separated
and the water layer was washed with DCM (3 × 10 ml). The
combined organic washings were washed with brine (1 × 15 ml),
dried over MgSO4, filtered and the solvent was evaporated
under a vacuum to yield 1.50 g (3.35 mmol, 83% of the theory)
of a white crystalline product. Rf = 0.03 (6 : 4 petrol–EtOAc);
(found: M+, 365.2143 C21H33O3S requires 365.2145); mp
102–103 ◦C; mp 104–105 ◦C; [a]2D3 = −53.4 (c = 1.0); (found C,
55.74; H, 7.33%; C21H33BF4O3S requires C, 55.76; H, 7.33%);
mmax (neat)/cm−1 2967, 1733, 1041; dH (500 MHz, CD3OD,
TOCSY, Jres.COSY) 1.02 (6H, s, C16H3), 1.39 (1H, m, C5HH),
1.39 (9H, s, C18H3), 1.54–1.67 (2H, m, C9H2), 1.75 (1H, ddd,
J = 13.2 Hz, J = 8.9 Hz, J = 4.0 Hz, C5HH), 1.90 (1H, d, J =
18.6 Hz, C2HH), 1.93 (1H, m, C4HH), 2.00 (1H, m, C4HH),
2.07 (1H, t, J = 4.5 Hz, C3HH), 2.09–2.14 (2H, m, C10H2),
2.19 (1H, dt, J = 12.6 Hz, J = 2.1 Hz, C12HH), 2.25 (1H, t,
J = 12.8 Hz, C12HH), 2.56 (1H, ddd, J = 18.6 Hz, J = 4.9 Hz,
J = 2.8 Hz, C2HH), 3.12 (1H, br. s, C8H), 4.02 (1H, dd, J =
3.4 Hz, J = 1.5 Hz, C7H), 4.33 (1H, br. s, C11H). dC (125 MHz,
CD3OD) 19.8 (CH3), 22.4 (CH3), 25.6 (CH2), 27.7 (CH2), 27.9
(CH2), 28.3 (3 × CH3), 35.1 (CH2), 42.1 (CH2), 44.8 (CH), 45.0
(CH2), 46.8 (CH), 49.8 (CH2), 51.2 (C), 61.5 (C), 61.6 (CH),
70.8 (CH), 86.8 (C), 165.2 (CO), 217.2 (CO).
3-Butyl-oxirane-2-carboxylic-acid-methylester (3)20. This com-
pound was prepared according to method A as colourless oil
in 73% yield (58 mg, 0.37 mmol). mmax (neat)/cm−1 2975, 2929,
2862, 1758, 1742; dH (400 MHz, CDCl3) 0.93 (3H, t, J = 7.3 Hz,
CH3CH2), 1.31–1.69 (6H, m, CH2), 3.16 (1H, m, CH2CHO),
3.23 (1H, d, J = 1.9 Hz, CHOCO2), 3.79 (3H, s, CO2CH3). dC
(101 MHz, CDCl3) 13.9 (CH3), 22.4 (CH2), 27.8 (CH2), 31.2
(CH2), 52.4 (CH3), 53.0 (CH), 58.6 (CH), 170.0 (CO).
3,4-(Trifluoromethyl-phenyl)-oxirane-2-carboxylic-acid-methyl-
ester (4)21. This compound was prepared according to method
A as colourless oil in 75% yield (92 mg, 0.38 mmol). dH
(400 MHz, CDCl3) 3.49 (1H, d, J = 1.7 Hz, PhCH), 3.83 (3H, s,
CO2CH3), 4.17 (1H, d, J = 1.5 Hz, CH), 7.42 (2H, d, J =
8.3 Hz, CF3CCHCH), 7.63 (2H, d, J = 8.3 Hz, CF3CCH). dC
(101 MHz, CDCl3) 52.7 (CH3), 56.7 (CH), 57.1 (CH), 125.7
(C), 126.1 (2 × CH), 131.2 (CF3, JCF = 33.1 Hz), 138.9 (C),
168.1 (CO).
1-Oxa-spira[2,5]octane-2- carboxylic-acid-methylester (5)8,22
.
This compound was prepared according to method A as
colourless oil [bp 138–142 ◦C; 20 mbar] in 68% yield (58 mg,
0.34 mmol). dH (400 MHz, CDCl3) 1.38–1.78 (10H, m, Cy), 3.27
(1H, s, CHO), 3.71 (3H, s, CH3). dC (101 MHz, CDCl3) 24.8
(CH2), 25.0 (CH2), 25.3 (CH2), 28.8 (CH2), 34.9 (CH2), 52.2
(CH3), 59.4 (CH), 64.9 (C), 168.9 (CO)..
(1S,3S,4R)-2-tert-Butyloxymethyl-3-[(1S,4R)-7,7-dimethyl-2-
oxobicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane hexa-
fluorophosphate (6c). To a stirred solution of the chiral sulfide
A (507 g, 2.00 mmol) in 1.4 ml DCM was added a-bromo-
tert-butyl-acetate (2.28 ml, 14.1 mmol) in one portion. An
aqueous solution of KPF6 (2.590 g, 14.1 mmol) in 4 ml water
was added and the reaction mixture was stirred vigorously at
rt and monitored by TLC for four days. After consumption
of the sulfide, the reaction mixture was diluted with DCM
and water. The resulting phases were separated and the water
layer was washed with DCM (3 × 20 ml). The combined
organic washings were washed with brine (1 × 15 ml), dried
over MgSO4, filtered and the solvent was evaporated under a
vacuum to yield 772 mg (1.70 mmol, 85% of the theory) of an
(1S,3S,4R)-2-tert-Butyloxymethyl-3-[(1S,4R)-7,7-dimethyl-
2-oxobicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane bro-
mide (6a). To a stirred suspension of sulfide A (253 g,
1.00 mmol) in 1.4 ml of DCM and 2 ml of water was added
a-bromo-tert-butyl-acetate (1.14 ml, 4.00 mmol) in one portion.
The reaction mixture was stirred vigorously at rt and monitored
by TLC for two days. After consumption of the sulfide, the
reaction mixture was diluted with DCM and water (20 ml each).
The resulting phases were separated, and the water layer was
washed with DCM (3 × 10 ml). The combined organic washings
were washed with brine (1 × 15 ml), dried over MgSO4, filtered
and the solvent was evaporated under a vacuum to yield 351 mg
(0.79 mmol, 79% of the theory) of a white solid. Rf = 0.11
23
off-white solid. Rf = 0.05 (9 : 1 DCM–MeOH); [a]D = −60.0
(c = 1.0); (found: M+, 365.2148; C21H33O3S requires 365.2150);
mp 101–102 ◦C; mmax (neat)/cm−1 3002, 2967, 1733, 1726, 1042;
dH (400 MHz, CD3OD) 1.12 (3H, s, C16H3), 1.22 (3H, s, C16H3),
1.40–1.54 (10H, m, 3 × C18H3, C5HH), 1.64–1.73 (3H, m,
C5HH, C9H2), 2.00 (1H, d, J = 18.8 Hz, C2HH), 2.11–2.27 (6H,
m, C4H2, C3H, C10H2, C12HH), 2.34 (1H, m, C12HH), 2.57–2.64
(1H, ddd, J = 18.8 Hz, J = 4.6 Hz, J = 2.2 Hz, C2HH), 3.18
(1H, br. s, C8H), 3.87 (1H, d, J = 17.7 Hz, C13HH), 4.22 (1H,
d, J = 17.7 Hz, C13HH), 4.23 (1H, br. s, C7H), 4.42 (1H, d, J =
5.1 Hz, C11H). dC (101 MHz, CDCl3) 19.1 (CH3), 21.9 (CH3),
24.3 (CH2), 26.7 (CH2), 26.8 (CH2), 27.8 (3 × CH3), 33.4 (CH2),
40.8 (CH2), 43.1 (CH), 44.0 (CH2), 45.0 (CH), 45.7 (CH2), 50.1
(C), 59.6 (C), 60.2 (CH), 68.2 (CH), 86.5 (C), 163.3 (CO), 215.6
(CO).
(75 : 25 petrol–EtOAc); mp 104–105 ◦C; [a]23 = −48.0 (c =
D
1.0); (found: M+, 365.2148 C21H33O3S requires 365.2150); mmax
(neat)/cm−1 3002, 2967, 1733, 1042; dH (401 MHz, CDCl3)
1.12 (3H, s, C16H3), 1.23 (3H, s, C16H3), 1.39–1.53 (10H, m,
C5HH, C18H3), 1.55–1.78 (3H, m, C5HH, C9H2), 1.98 (1H, d,
J = 18.6 Hz, C2HH), 2.09–2.38 (6H, m, C3HH, C4H2, C10H2,
C12HH), 2.60 (1H, dd, J = 18.6 Hz, J = 3.7 Hz, C2HH), 2.75
(1H, br. d, J = 13.2 Hz, C12HH), 3.19 (1H, br. s, C8H), 3.95 (1H,
d, J = 17.1 Hz, C13HH), 4.36 (1H, dd, J = 17.1 Hz, C13HH),
4.42 (1H, br. s, C7H), 4.46 (1H, d, J = 5.4 Hz, C11HH). dC
(125 MHz, CD3OD) 19.2 (CH3), 22.9 (CH3), 24.3 (CH2), 26.7
(CH2), 26.8 (CH2), 27.8 (3 × CH3), 33.2 (CH2), 40.8 (CH2), 43.1
(CH), 44.0 (CH2), 45.0 (CH), 45.6 (CH2), 50.0 (C), 59.6 (C),
60.2 (CH), 67.4 (CH), 86.1 (C), 163.5 (CO), 215.7 (CO).
1 4 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7

View Online
Standard procedure for ester cleavage
freshly prepared LDA was allowed to stir for 15 minutes. In the
meantime, 136 mg of 1 (0.33 mmol), which has been under a high
vacuum for one hour prior to use, was suspended at rt in 5.5 ml
dry THF in a 15 ml schlenk equipped with a magnetic stirrer
bar. The schlenk was cooled down to −78 ◦C and the base was
added dropwise over a period of ten minutes. After 12 minutes,
34 ll cyclohexyl-carboxaldehyde (0.33 mmol) were added in one
portion and the reaction was stirred at −78 ◦C for six hours.
The reaction mixture was diluted with diethyl ether, quenched
with ca. 0.5 ml of methanol and 3 ml of water was added at
0 ◦C temperature. After phase separation, the organic layer was
washed once with ice cold saturated NaHCO3 solution. The
combined basic layers were acidified with ice cold 1 N HCl aq.
to pH = 2–3 and the product was re-extracted in the organic layer
(three times) with diethyl ether and the combined organic layers
were dried over MgSO4, filtered and exposed to an etherial solu-
tion of CH2N2, until no more nitrogen evolution was observed.
The solvent was evaporated at a reduced pressure to yield 5 mg
(0.027 mmol, 9%) of an aromatic-smelling, colourless oil.
0.3 mmol of 6a were dissolved in 0.15 ml of DCM under an argon
atmosphere, before 0.10 ml of trifluoroacetic acid was added via
a syringe in one portion. The reaction mixture was allowed to
stir at rt for one hour. The crude mixture was diluted with diethyl
ether until the product precipitated. After filtration of the ether
under a protection atmosphere, the product was dried on a high
vacuum pump, resulting in the desired products quantitatively
as white, hygroscopic solids.
(1S,3S,4R)-2-Carboxymethyl-3-[(1S,4R)-7,7-dimethyl-2-oxo-
bicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane bromide
(7a). According to the standard procedure, 116 mg (0.3 mmol)
of 7a were obtained of 134 mg (0.3 mmol) 6a as a white solid;
(found: M+, 309.1518; M + Na, 331.1340 C17H25O3S requires
309.1519, M + Na, 331.1338); mp 90–95 ◦C (decomp.); mmax
(neat)/cm−1 3457, 2970, 1749; dH (400 MHz, CD3OD) 1.08
(3H, s, C16H3), 1.09 (3H, s, C16H3), 1.47 (1H, m, C5HH),
1.68–1.86 (3H, m, C5HH, C9H2), 2.00–2.42 (8H, m, C4H2,
C2HH, C3H, C10H2, C12H2), 2.65 (1H, ddd, J = 7.6 Hz, J =
2.0 Hz, J = 0.9 Hz, C2HH), 3.23 (1H, br. s, C8H), 4.24 (1H,
dd, J = 3.3 Hz, J = 1.8 Hz, C7H), 4.31 (1H, d, J = 16.6 Hz,
C13HH), 4.40 (1H, d, J = 16.6 Hz, C13HH), 4.48 (1H, br. s,
C11H). dC (101 MHz, CD3OD) 17.7 (CH3), 20.2 (CH3), 22.3
(CH2), 23.4 (CH2), 25.6 (CH2), 25.7 (CH2), 32.8 (CH2), 39.9
(CH2), 42.6 (CH), 42.8 (CH2), 44.6 (CH), 49.0 (C), 59.1 (C),
59.3 (C), 68.1 (CH), 165.2 (CO), 214.9 (CO).
(R/S)-Cyclohexyloxirane (8)23. According to the literature,
a solution of 0.05 M Na2HPO4 (5 ml) was added to a 12.5 ml
solution of undiluted bleach. The pH was 12.0. This solution
was cooled down to 0 ◦C and was added in one portion to an ice
cold suspension of 127 mg of (R/R) Jacobsen catalyst and 684 ll
(5 mmol) of vinylcyclohexene in 5 ml of DCM. The two-phase
mixture was stirred vigorously and the ice bath was removed
after 20 minutes. After 12 hours the reaction was quenched with
50 ml of water and 50 ml of hexane. After phase separation,
the organic layer was washed with water (two times), brine
(two times), dried over MgSO4 and the solvent was removed
under a vacuum. The NMR spectra were in agreement with
the literature. The product was analysed via GC after filtration.
c-column tR (R): 79.53; tR (S): 79.98. dH (400 MHz, CDCl3):
1.01–1.32 (6H, m, CH2), 1.61–1.80 (4H, m, CH2), 1.90 (1H, m,
CparaH), 2.51 (1H, m, COH), 2.70 (2H, m, COH2). dC (101 MHz,
CDCl3) 25.4 (CH2), 25.5 (CH2), 26.1 (CH2), 28.2 (CH2), 29.5
(CH2), 40.2 (CH), 45.7 (CH2), 56.4 (CH).
(1S,3S,4R)-2-Carboxymethyl-3-[(1S,4R)-7,7-dimethyl-2-oxo-
bicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane tetraflu-
oroborate (7b). According to the standard procedure, 119 mg
(0.3 mmol) 7b were obtained from 136 mg (0.3 mmol) of 6b
as a white solid;† mp 91–95 ◦C (decomp.); mmax (neat)/cm−1
3224, 2980, 1736; (found: M+, 309.1522; M + Na, 331.1344
C17H25O3S requires 309.1519, M + Na, 331.1338); dH (400 MHz,
CD3OD) 1.16 (6H, s, C16H3), 1.47 (1H, m, C5HH), 1.68–1.86
(2H, m, C5HH, C9HH), 1.84 (1H, td, J = 13.0 Hz, J = 3.9 Hz,
C9HH), 2.04 (1H, d, J = 18.8 Hz, C2HH), 2.07–2.26 (6H, m,
C4H2, C3H, C10H2, C12HH), 2.35 (1H, dt, J = 13.0 Hz, 1.0 Hz,
C12HH), 2.65 (1H, ddd, J = 18.8 Hz, J = 4.9 Hz, J = 2.2 Hz,
C2HH), 3.21 (1H, br. s, C8H), 4.10 (1H, br. s, C7H), 4.20 (1H,
d, J = 16.9 Hz, C13HH), 4.29 (1H, dd, J = 16.9 Hz, C13HH),
4.45 (1H, br. s, C11H). dC (101 MHz, CD3OD) 19.8 (2 × CH3),
22.4 (CH2), 25.3 (CH2), 27.8 (CH2), 27.9 (CH2), 35.0 (CH2),
40.1 (CH2), 41.9 (CH), 44.8 (CH2), 45.0 (CH), 49.3 (C), 51.3
(C), 61.2 (C), 61.5 (CH), 165.8 (CO), 212.0 (CO).
a-Thiomethoxy-acetic-tert-butylester (9)24. To a stirred sus-
pension of 4.205 g of sodium thiomethoxide (60 mmol) in 80 ml
of acetone was added via a dropping funnel 8.08 ml of a-
bromoacetic-tert-butylester, diluted with 20 ml of acetone. The
temperature rose during the addition to 40 ◦C. One cone end
of a spatula with ammoniumtetramethyl iodide was added as a
catalyst. The reaction was allowed to stir at 55 ◦C (oil bath) for
200 minutes. After cooling to rt, 100 ml of diethylester and 50 ml
of water were added and the water layer was extracted three times
with diethyl ether (25 ml each). The combined organic layers
were washed with brine, dried over MgSO4 and the solvent was
removed under a vacuum. Distillation of the crude residue at
54–55 ◦C/20 mbar afforded traces of the starting material and
5.880 g (93%, 46.6 mmol) of the product distilled over at 57–
(1S,3S,4R)-2-Carboxymethyl-3-[(1S,4R)-7,7-dimethyl-2-oxo-
bicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane hexaflu-
orophosphate (7c). According to the standard procedure,
136 mg (0.3 mmol) of 7c were obtained from 153 mg (0.3 mmol)
of 6c as a white solid; (found: M+, 309.1529; M + Na
331.1350; M + K 347.1091 C17H25O3S requires 309.1524); mp
89–94 ◦C (decomp.); mmax (neat)/cm−1 2975, 1736; dH (400 MHz,
CD3OD) 1.16 (3H, s, C16H3), 1.17 (3H, s, C16H3), 1.28 (2H, s,
H2O), 1.47 (1H, m, C5HH), 1.65–1.87 (3H, m, C5HH, C9H2),
2.01 (1H, d, J = 18.8 Hz, C2HH), 2.07–2.23 (6H, m, C4H2,
C3H, C10H2, C12HH), 2.27 (1H, dt, J = 12.7 Hz, J = 2.2 Hz,
C12HH), 2.39 (1H, br. d, J = 12.9 Hz, C12HH), 2.65 (1H, ddd,
J = 18.8 Hz, J = 4.6 Hz, J = 2.0 Hz, C2HH), 3.21 (1H, br. s,
C8H), 4.16 (1H, dd, J = 3.2 Hz, 1.5 Hz, C7H), 4.20 (less than
1H, br. s, C13HH), 4.29 (less than 1H, br. s, C13HH), 4.45 (1H,
br. s, C11H). dC (101 MHz, CD3OD) 17.7 (CH3), 20.2 (CH3),
22.3 (CH2), 23.4 (CH2), 25.6 (CH2), 25.7 (CH2), 32.8 (CH2),
39.9 (CH2), 42.6 (CH), 42.8 (CH2), 44.5 (CH), 49.0 (C), 58.9
(C), 59.4 (C), 67.7 (CH), 168.9 (CO), 215.0 (CO).
◦
60 C/20 mbar as a colourless, smelly liquid. mmax (neat)/cm−1
1722, 905; Rf = 0.29 (petrol–EtOAc 7 : 3); dH (400 MHz, CDCl3)
1.48 (s, 9H, C(CH3)3), 2.21 (s, 3H, SCH3), 3.10 (s, 2H, CH2).
dC (101 MHz, CDCl3) 24.4 (CH3), 26.6 (CH3), 26.7 (CH3), 30.1
(CH3), 56.7 (C), 195.0 (CO), 207.0 (CO).
syn–anti-3-Cyclohexyl-3-hydroxy-2-methylsulfanyl-propionic-
acid-tert-butylester (10). To
a
stirred solution of
diisopropylamine (1.18 ml, 8.43 mmol) in 14 ml of THF
(abs.) was added at −35 ◦C 4.83 ml of n-BuLi (1.6 molar
solution in hexane). The fresh prepared pale yellow LDA was
allowed to stir for five minutes, before the cool bath was cooled
down to −78 ◦C. 1.09 g (7.03 mmol) of a-thiomethoxyacetic-
tert-butylester was dissolved in 20 ml THF in a second schlenk
at a low temperature. The base was added dropwise over a
period of ten minutes via a canula. The colour changed after
addition of 1 eq. to orange. After addition of 935 ll (7.73 mmol)
cyclohexylcarboxaldehyde, the colour of the mixture brightened
Method B. Standard epoxidation procedure with LDA as
base: to a solution of 131 ll of diisopropylamine (0.750 mmol)
in 1.5 ml of THF at −78 ◦C was added dropwise 422 ll of
a 1.6 molar solution of BuLi (0.675 mmol) in hexane. The
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 1 9 – 1 4 2 7
1 4 2 5

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up to result in a yellow solution. The reaction was stirred at
−78 ◦C for 1.45 hours and quenched with 3.85 ml of a 2 molar
HCl solution in diethyl ether. The reaction was diluted with
diethyl ether before removal of the ice bath. After addition
of water, the phases were separated (aq. layer pH = 10) and
the organic layer was washed with 0.1 molar aq. solution of
KHSO4 (two times), brine (once) and dried over MgSO4. After
filtration of the inorganic salts and evaporation of the solvent
under a vacuum, the crude product was purified by column
chromatography to result in 1.68 g of colourless oil. The dr
(31.5 : 68.5) was determined by NMR proton spectrum of the
crude product.
(syn)-10. Rf = 0.25 (petrol–EtOAc 9 : 1); mmax (neat)/cm−1
3507, 2977, 2924, 2852, 1718; (found C, 61.55; H, 9.52; S,
11.79%. C14H26O3S required C, 61.28; H, 9.55; S, 11.68%); dH:
(400 MHz, CDCl3) 1.06–1.90 (20H, m, Cy, C(CH3)3), 2.19 (3H, s,
SCH3), 3.04 (1H, d, J = 2.0 Hz, OH), 3.18 (1H, d, J = 5.8 Hz,
CHCHOH), 3.64 (1H, ddd, J = J = 5.5 Hz, J = 1.5 Hz
CHCHOH). dC: (101 MHz, CDCl3) 13.9 (CH3), 26.0 (CH2),
26.3 (CH2), 27.1 (CH2), 27.7 (CH2), 27.9 (3 × CH3), 29.8 (CH2),
40.4 (CH), 52.1 (CH), 73.2 (CH), 81.9 (C), 171.1 (CO).
(anti)-10. Rf = 0.16 (petrol–EtOAc 9 : 1); mmax (neat)/cm−1
3508, 2977, 2853, 2924, 1714; (Found C, 61.60; H, 9.57; S,
11.41%. C14H26O3S required C, 61.28; H, 9.55; S, 11.68%. dH
(400 MHz, CDCl3) 1.10–1.80 (20H, m, Cy, C(CH3)3), 2.18 (3H, s,
SCH3), 2.68 (1H, d, J = 7.6 Hz, OH), 3.25 (1H, br. d, J = 6.6 Hz,
CHCHOH), 3.62 (1H, dd, J = 12.5 Hz, J = 6.6 Hz CHCHOH).
dC (101 MHz, CDCl3) 14.6 (CH3), 25.9 (CH2), 26.3 (CH2), 26.3
(CH2), 27.1 (CH2), 30.0 (CH2), 28.1 (3 × CH3), 40.9 (CH), 50.8
(CH), 75.9 (CH), 80.2 (C), 171.6 (CO).
was stirred overnight at rt. The resultant solution was frozen
with liquid nitrogen and the solvent was removed under a high
vacuum, to yield quantitatively an air sensitive white powder.
mmax (CD3OD)/cm−1 3558, 3022, 2931, 2859, 1702; dH (400 MHz,
CD3OD) 0.90–1.38 (5H, m, Cy), 1.67–1.91 (5H, m, Cy), 2.12
(1H, br. s, CyCHCHOH), 2.97 (3H, s, SCH3), 3.01 (3H, s,
SCH3), 3.77 (1H, J = 8.8 Hz, J = 2.9 Hz, CHOH), 4.70 (1H,
d, J = 2.5 Hz, CHS(CH3)2). dC (101 MHz, CDCl3) 23.4 (CH2),
25.1 (CH2), 26.7 (2 × CH3), 27.1 (CH2), 29.9 (CH2), 30.5 (CH2),
42.6 (CH), 65.0 (CH), 74.1 (CH), 167.3 (CO).
syn-Carboxy-2-cyclohexyl-2-hydroxy-ethyl)-dimethylsulfonium
tetrafluoroborate (anti)-(12). As described above, the title
compound was obtained quantitatively without further
purification (NMR pure). mmax (CD3OD)/cm−1 3339, 2469,
2243, 2216, 2070, 972; (found: M+, 233.1206; C11H21O3S
requires 233.1206); dH (400 MHz, CD3OD) 0.75–1.85 (11H,
m, Cy), 2.91 (3H, s, SCH3), 2.93 (3H, s, SCH3), 3.92 (1H, d,
J = 7.8 Hz, J = 5.1 Hz, CHOH), 4.48 (1H, d, J = 7.6 Hz,
CHS(CH3)2). dC (101 MHz, CDCl3) 22.5 (CH2), 24.6 (CH2),
25.9 (CH2), 26.2 (CH3), 26.3 (CH3), 26.7 (CH2), 29.5 (CH2),
42.6 (CH), 60.6 (CH), 73.7 (CH), 166.7 (CO).
anti-Methoxycarbonyl-2-cyclohexyl-2-hydroxy-ethyl)-dimeth-
ylsulfonium tetrafluoroborate (anti)-(13). The solvent of the
NMR sample (anti)-12was removed under a high vacuum,
the salt dissolved in few drops of acetic acid ethyl ester and
acetone (1 : 1 mixture) and a freshly prepared etherical solution
of CH2N2 was added until the yellow colour of the CH2N2
remained. The solution was stirred for 15 minutes and the
solvent was removed under a high vacuum at rt; (found: M+,
247.1367 C12H23O3S requires 247.1368); mmax (neat)/cm−1 3463,
3017, 2970, 2857, 1741; dH (400 MHz, CD3OD) 0.98–1.37 (5H,
m, Cy), 1.68–1.89 (5H, m, Cy), 2.07 (1H, br. s., CyCHCHOH),
2.99 (3H, s, SCH3), 3.02 (3H, s, SCH3), 3.79 (1H, dd, J =
9.3 Hz, J = 2.9 Hz, CHOH), 3.91 (3H, s, COOCH3), 4.76
(1H, d, J = 2.9 Hz, CHS(CH3)2). dC (101 MHz, CDCl3) 22.7
(CH2), 24.4 (CH2), 26.1, (CH3), 26.5 (2 × CH3), 29.4 (CH2),
29.9 (CH2), 42.0 (CH), 64.4 (CH), 73.4 (CH3), 73.5 (CH), 166.9
(CO).
anti-tert-Butoxycarbonyl-2-cyclohexyl-2-hydroxy-ethyl)-dimeth-
ylsulfonium tetrafluoroborate (anti)-(11). Under argon, 74 mg
of trimethyloxonium-tetrafluoroborate were weighed out in
a glove box in a schlenk and were suspended in 2.5 ml dry
DCM. In a second oven dried flask was dissolved 124 mg of
syn-3-cyclohexyl-3-hydroxy-2-methylsulfanyl-propionicacid-tert-
butylester (0.5 mmol) in 3 ml of dry DCM under an argon
atmosphere. The reaction was stirred overnight at rt. The
resultant solution was frozen with liquid nitrogen and the
solvent was removed under a high vacuum, to yield quanti-
tatively an air sensitive white powder. The ester was over 95%
pure and therefore was used in the next step without further
purification and full characterisation. dH (400 MHz, CD3OD)
0.89–2.24 (20H, m, Cy, C(CH3)3), 2.97 (3H, s, SCH3), 3.00
(3H, s, SCH3), 3.78 (1H, dd, J = 9.0 Hz, J = 2.5 Hz, CHS),
4.68 (1H, d, J = 2.7 Hz, CHOH).
Acknowledgements
We thank the DTI, Avecia, Syngenta, Johnson Matthey, for
financial support; A. Kantacha for determining the X-ray
structure of 7b and Raphae¨l Robiette for carrying out the
calculations. The authors acknowledge the University of Bristol
Proteomics group (School of Medical Sciences) for access to the
FT-ICR instrument.
syn-tert-Butoxycarbonyl-2-cyclohexyl-2-hydroxy-ethyl)-dimeth-
ylsulfonium tetrafluoroborate (syn)-(11). Under argon, 74 mg
of trimethyloxonium-tetrafluoroborate were weighed out
in a glove box in a schlenk and were suspended in 2.5 ml
of dry DCM. In a second oven dried flask was dissolved
124 mg of syn-3-cyclohexyl-3-hydroxy-2-methylsulfanyl-
propionicacid-tert-butylester (0.5 mmol) in 3 ml of dry DCM
under argon atmosphere. The reaction was stirred overnight
at rt. The resultant solution was frozen with liquid nitrogen
and the solvent was removed under a high vacuum, to yield
quantitatively an air sensitive white powder. The ester was
over 95% pure and therefore was used in the next step without
further purification and full characterisation. dH (400 MHz,
CD3OD) 0.75–2.12 (20H, m, Cy, C(CH3)3), 2.91 (3H, s, SCH3),
2.93 (3H, s, SCH3), 3.92 (1H, dd, J = 7.8 Hz, J = 5.1 Hz,
CHOH), 4.68 (1H, d, J = 7.6 Hz, CHS).
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