Synthesis, structure and reactivity of some chiral benzylthio alcohols, 1,3-oxathiolanes and their S-oxides

Article abstract of DOI:10.1080/17415993.2020.1754418

A series of amino acid-derived chiral benzylthio alcohols have been prepared and characterized. A chiral mercapto alcohol derived from S-leucine has been used to form three chiral 2,4-disubstituted 1,3-oxathiolanes. One of these has been oxidized to the S-oxide and another to the S,S-dioxide. The cis and trans isomers have been characterized by ¹H NMR in each case and it appears that thermal epimerisation at C-2 is possible at the sulfoxide oxidation state. The X-ray structure of major trans diastereomer of 2-phenyl-4-isobutyl-1,3-oxathiolane S,S-dioxide shows an envelope conformation with oxygen at the flap and an internal angle at sulfur of just 93.8°. This compound fragments upon flash vacuum pyrolysis at 700°C to give SO₂, benzaldehyde and 4-methylpent-1-ene.

Full text of DOI:10.1080/17415993.2020.1754418

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Synthesis, structure and reactivity of some chiral
benzylthio alcohols, 1,3-oxathiolanes and their S-
oxides
R. Alan Aitken, Philip Lightfoot & Andrew W. Thomas
To cite this article: R. Alan Aitken, Philip Lightfoot & Andrew W. Thomas (2020): Synthesis,
structure and reactivity of some chiral benzylthio alcohols, 1,3-oxathiolanes and their S-oxides,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2020.1754418
To link to this article: https://doi.org/10.1080/17415993.2020.1754418
View supplementary material
Published online: 24 Apr 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gsrp20

JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1754418
Synthesis, structure and reactivity of some chiral benzylthio
alcohols, 1,3-oxathiolanes and their S-oxides
R. Alan Aitken, Philip Lightfoot and Andrew W. Thomas
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, UK
ABSTRACT
ARTICLE HISTORY
Received 24 February 2020
Accepted 6 April 2020
A series of amino acid-derived chiral benzylthio alcohols have been
prepared and characterized. A chiral mercapto alcohol derived from
S-leucine has been used to form three chiral 2,4-disubstituted 1,3-
oxathiolanes. One of these has been oxidized to the S-oxide and
another to the S,S-dioxide. The cis and trans isomers have been
KEYWORDS
1,3-oxathiolane; pyrolysis;
sulfoxide; sulfone; X-ray
structure
1
characterized by H NMR in each case and it appears that thermal
epimerisation at C-2 is possible at the sulfoxide oxidation state. The
X-ray structure of major trans diastereomer of 2-phenyl-4-isobutyl-
1,3-oxathiolane S,S-dioxide shows an envelope conformation with
oxygen at the flap and an internal angle at sulfur of just 93.8°. This
compound fragments upon flash vacuum pyrolysis at 700°C to give
SO2, benzaldehyde and 4-methylpent-1-ene.
1. Introduction
Some time ago we were interested in preparing chiral 1,4,2-oxathiaphosphorinanes as
potential chiral acyl anion equivalents. Although a wide range of heterocyclic acyl and
formyl anion equivalents have been developed [1], to the best of our knowledge this ring
system exemplified by A (Figure 1), which is a hybrid between a Wadsworth-Emmons
reagent and a 1,3-dithiane, is not known. As shown, we envisaged forming the ring by an
intramolecular Arbuzov process on a substrate readily derived from a chiral (benzylthio)
alcohol B, itself readily accessible in a few conventional steps from an α-amino acid. The
related heterocyclic phosphonium salts C are known from a single publication [2] but are
CONTACT R. Alan Aitken
raa@st-and.ac.uk
EaStCHEM School of Chemistry, University of St Andrews, St
Andrews, UK
This article makes reference to supplementary material available on the publisher’s website at
https://doi.org/10.1080/17415993.2020.1754418
© 2020 Informa UK Limited, trading as Taylor & Francis Group

2
R. A. AITKEN ET AL.
difficult to prepare and have not been exploited synthetically. We recently reported the syn-
thesis, structure and reactivity of some 2-substituted 1,3-oxathiolanes and their S-oxides D
[3]. In this paper we describe the synthesis and characterization of a series of the benzylthio
alcohols B and also the formation, structure and reactivity of some chiral 2,4-disubstituted
1,3-oxathiolanes and their S-oxides E. As shown these are also derived via the mercapto
alcohol from amino acids.
2. Results and discussion
Our synthesis started by diazotization of the amino acids leucine, valine and isoleucine
bearing bulky alkyl side chains in the presence of 3–6 equivalents of potassium bromide
[4] to afford the α-bromo acids 1–3 (Scheme 1). These showed good agreement of boiling
point and optical rotation with literature values. An attempt was then made to introduce
sulfur by addition of potassium ethyl xanthate to a solution of the α-bromo acids in aqueous
sodium carbonate. This proved to be highly effective in the case of bromo acid 1 to afford
the previously unknown derivative 4 in almost quantitative yield. However, as previously
documented [5], the corresponding reaction with the more sterically hindered bromo acids
2 and 3 failed. Direct reduction of the xanthate 4 with lithium aluminium hydride gave a
mixture of mercapto alcohol and mercapto acid in both THF and diethyl ether, so the acid
group was first converted into the ethyl ester to give 5, which was then efficiently reduced
to afford the mercapto alcohol 6 as an intensely unpleasant smelling oil. To give the first
target benzylthio alcohol 7, this was S-benzylated by treatment with sodium ethoxide in
ethanol followed by benzyl bromide.
In order to access the full range of target benzylthio alcohols B we adopted the
more direct approach of initial nucleophilic displacement using sodium benzylthiolate
(Scheme 2). Thus the bromo acids 1–3 afforded the benzylthio acids 8–10 in good yield.
Of these three compounds, only 9 has been previously reported [6] and it showed good
agreement with literature NMR data although, as noted in the experimental section, there
is a slight error in the literature interpretation. The three acids were then readily esteri-
fied to give the benzylthio esters 11–13 in almost quantitative yield. Again two of these
three compounds are previously unknown and only compound 11 is briefly mentioned
in the literature [7] with no characterization data. The final reduction to the target ben-
zylthio alcohols 7, 14, and 15 was achieved in high yield with lithium aluminium hydride in
Figure 1. Retrosynthetic analysis of target heterocycles A and structure of related compounds.

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 1. First approach to benzylthio alcohols.
Scheme 2. Second approach to benzylthio alcohols.
diethyl ether. Of these three compounds, the valine-derived example 14 has been reported
by Evans [8] and used to form mixed P/S ligands for palladium catalysis. In his study,
installation of an additional stereocentre adjacent to OH was followed by reaction with
Ar2PCl to give a phosphinite much as suggested in Figure 1. Importantly however, our opti-
cal rotation value for 14 is roughly half that reported by Evans and also for the isoleucine
derived compounds 10, 13 and 15 with a second and presumably invariant stereocentre
present, diastereomeric mixtures were evident by NMR, thus pointing to a degree of racem-
ization, most likely at the stage of the initial sodium benzylthiolate substitution. Clearly this
problem would need to be addressed for effective implementation of the strategy outlined
in Figure 1. However, in the mean time, progress in this direction was halted by the discov-
ery that treatment of the benzylthio alcohols 7, 14 and 15 with sodium hydride followed by
diethyl chlorophosphite gave not the expected phosphites F but rather the isomeric chlo-
rides G formed via an intermediate thiiranium salt (Scheme 3). This will be described in
detail elsewhere.
The chiral mercapto alcohol 6 is a member of a potentially useful but uncommon
class of compounds, although it might be noted that there is one paper [9] involving use
of the isopropyl analogue derived from (S)-valine as a chiral auxiliary. We realized that

4
R. A. AITKEN ET AL.
Scheme 3. Undesired reactivity of sulfide-containing phosphites.
Scheme 4. Preparation and oxidation of 1,3-oxathiolanes.
reaction of compound 6 with aldehydes would give a range of chiral 2,4-disubstituted-
1,3-oxathiolanes. The stereoselectivity of the ring closure process, leading to cis and trans
isomers, is of interest and, after S-oxidation, there is one report of such an (achiral) system
acting as a formyl anion equivalent [10]. Substituted 1,3-oxathiolanes have been prepared
in a variety of ways including by 1,3-dipolar cycloaddition, either of carbonyl ylides to
thioketones [11], or of thiocarbonyl ylides to carbonyl compounds [12,13]. Reaction of
compound 6 with pivalaldehyde and benzaldehyde in boiling diethyl ether with addition
of boron trifluoride etherate gave the 1,3-oxathiolanes 16 and 17, respectively, in high yield
as inseparable mixtures of diastereomers. In the case of phenylgloxal, reaction with 6 catal-
ysed by p-toluenesulfonic acid in toluene gave the diastereomers 18a and 18b which were
separated by chromatography (Scheme 4).
With a view to developing potential chiral acyl anion equivalents, we attempted to oxi-
dize the oxathiolanes 16 and 17 to the corresponding sulfones. Treatment with two equiv-
alents of meta-chloroperbenzoic acid in diethyl ether cleanly gave only mono-oxidation to
the sulfoxide 19 in the case of the tert-butyl compound 16, presumably due to steric hin-
drance, whereas the phenyl compound 17 did undergo full oxidation to the desired sulfone

JOURNAL OF SULFUR CHEMISTRY
5
Table 1. Observed 1H NMR chemical shifts (ppm) and coupling contants (Hz) for the cis and trans 1,3-
oxathiolanes 16–20 as well as comparison compound 21 [20].
Compd
Ratio
H-2
H-4
H-5c
H-5t
J(4-5t)
J(4-5c)
J(5t-5c)
cis-16
trans-16
cis-17
trans-17
cis-18
trans-18
cis-21
trans-21
cis-19
trans-19
cis-20
66
34
52
48
75
25
—
—
61
39
13
87
4.88
4.95
6.18
6.12
5.20
5.08
5.04
5.14
4.03
4.03
5.23
5.10
3.45
3.44
3.91
3.76
4.00
3.98
3.58
3.62
3.12
2.52
3.35
3.35
3.78
4.31
4.03
4.51
3.66
4.34
3.83
4.27
4.23
4.41
4.32
4.71
3.98
3.35
4.15
3.61
4.04
3.66
3.89
3.38
4.33
3.84
4.49
3.84
2
9
3
7
3
10
2.6
8.5
4
10
6
6
6
4
5
5
10
9.3
7
7
12
12
9.1
9.0
10
10
9
4
5.1
5.6
0
6
3
trans-20
11
8
11
20. The structure of the new oxathiolane compounds 16–20 was now examined by NMR
and in the case of 20 X-ray diffraction.
The application of 1H NMR to conformational analysis of substituted 1,3-oxathiolane
systems is well established and has been summarized in various review series covering this
ring system [14–16]. Early studies on 2-substituted 1,3-oxathiolanes [17,18] were followed
by detailed analysis of examples including 2,4-dialkyl systems [19,20] and in later papers
the S-oxidised systems are also included [21,22]. The data collected for the compounds
involved here is presented in Table 1 and conforms to a logical pattern, both in terms of
chemical shift and coupling constants. In particular, the fact that the chemical shifts for
the two H-5 protons are widely separated for the trans isomer and those for H-5 of the cis
isomer are closer and in fact come between those for trans, is fully consistent with the liter-
ature pattern for other 2,4-dialkyl-1,3-oxathiolanes [20]. Similarly, the coupling constants
between H4 and H5 (cis) are fairly equal between cis and trans isomers in each case, but
the value of the coupling constant between H4 and H5 (trans) is much greater for the trans
isomers (7–11 Hz) than the corresponding cis isomers (2–6 Hz), again fully consistent with
the literature pattern [20] and in fact this allowed us to confidently assign signals to cis and
trans isomers in the case of 17 where they were present in almost a 1:1 ratio. To illustrate
the point, literature data [20] for 2-ethyl-4-methyl-1,3-oxathiolane are included in Table
1 for comparison. When we come to the S-oxidised systems 19 and 20, the same pattern
of chemical shifts is observed although the coupling constants are now more unequal for
both cis and trans somers.
Since the enhanced acidity of H-2 expected for the S,S-dioxide 20 together with the
known propensity of this ring system to fragment thermally with loss of SO2 and an alkene

6
R. A. AITKEN ET AL.
Figure 2. X-Ray structure of trans-20 (ORTEP diagram, 50% probability level). Selected bond lengths
and angles: O1-C2 1.404(4), C2-S3 1.822(3), S3-C4 1.818(3), C4-C5 1.510(4), C5-O1 1.454(4) Å; C2-O1-C5
106.9(2), O1-C2-S3 103.3(2), C2-S3-C4 93.8(2), S3-C4-C5 102.6(2), C4-C5-O1 109.2(3)°.
[10] suggested that this compound might act as an effective chiral benzoyl anion equiva-
lent, the relative configuration of the major and minor diastereomers of this compound
was clearly of interest. Fortunately the major diastereomer was readily obtained in pure
form by recrystallisation from ethyl acetate. A single crystal X-ray diffraction study showed
this to be the trans isomer (Figure 2) showing an obvious ‘envelope’ conformation with
the ring oxygen out of the plane of the remaining four essentially coplanar ring atoms
and a ring angle of only 93.8° at sulfur. The angle between the ring plane and flap of the
envelope is 47.8°. This is highly consistent with the structure of 2-benzyl-1,3-oxathiolane
S,S-dioxide 22 from our previous paper [3] and the only two previous X-ray structures of
1,3-oxathiolane S,S-dioxides: the carbohydrate-derived compounds 23 [23,24] and 24 [25]
(Figure 3). These all show very similar envelope conformations and the bond lengths and
−
angles within the ring are very similar to those observed for 20. The values for the C(2) S
−
− −
and S C(4) bond lengths as well as the C(2) S C(4) angle also agree well with those
observed for the few unsaturated 1,3-oxathiole S,S-dioxides 25 [26,27] and 26 and 27 [28]
to be crystallographically characterized although in all these cases the oxathiolane ring is
planar.
The fact that oxidation of the 2-phenyl-1,3-oxathiolane 17 which was a 52:48 mixture of
cis and trans isomers gives the corresponding sulfone 20 as a 13:87 mixture of cis and trans
isomers requires some explanation. Although the isomer ratio of the 2-tert-butyl com-
pound 16 was essentially the same as that of the final sample obtained for its S-oxide 19,
the behavior of the latter gave a valuable clue as to what may be going on. As described
in the experimental section, the oxidation of 16 (66:34 cis/trans) initially gave the sulfox-
ide 19 as a 34:66 cis/trans mixture after distillation, but this was progressively transformed
upon repeated vacuum distillation first to 55:45 cis/trans and finally to a 61:39 cis/trans
ratio. The fact that thermal epimerisation is possible at the sulfoxide stage may be due to

JOURNAL OF SULFUR CHEMISTRY
7
Figure 3. 1,3-Oxathiolane and 1,3-oxathiole S,S-dioxides previously characterized by X-ray crystallog-
raphy with CCDC Reference Codes.
Scheme 5. Possible epimerisation mechanism of 1,3-oxathiolane S-oxides.
ring opening and re-closure as shown in Scheme 5 and the occurence of a similar process
at the intermediate stage in the oxidation of 17 may explain the dramatic change in the
isomer ratio.
We now examined the pyrolysis behavior of the S,S-dioxide 20 under flash vacuum
pyrolysis (FVP) conditions. Thermal extrusion of SO2 from five-membered ring hetero-
cycles is well known [29], but we are only aware of two previous reports describing such
extrusion from 1,3-oxathiolane 3,3-dioxides. In the first [10] 4,4-dimethyl-1,3-oxathiolane
3,3-dioxide was found to fragment cleanly into SO2, isobutene and formaldehyde. This
allowed Gokel and coworkers to use the compound as a formyl anion equivalent, by depro-
tonation and alkylation with an alkyl halide, RX, at C-2 followed by thermal fragmentation
to generate the corresponding aldehyde RCHO. In our own recent study [3], both 2-benzyl-
and 2-benzylidene-1,3-oxathiolane S,S-dioxide were found to fragment cleanly with loss
of SO2 and ethene to give, respectively, phenylacetaldehyde and products derived from

8
R. A. AITKEN ET AL.
Scheme 6. FVP behavior of sulfone 20.
phenylketene. Consistent with this pattern, FVP of compound 20 resulted in complete
reaction at 700°C with loss of SO2 to afford benzaldehyde (60%) and the expected alkene
4-methylpent-1-ene (78%) (Scheme 6). While there are various mechanistic possibilities
for this process, we believe it most likely proceeds by extrusion of benzaldehyde to give
2-isobutylthiirane S,S-dioxide which rapidly decomposes to the alkene and SO2. In our
previous study [3] significant evidence was obtained for formation of thiirane S-oxide by
extrusion of phenylacetaldehyde from 2-benzyl-1,3-oxathiolane. Unfortunately conditions
have not so far been found for efficient deprotonation and alkylation at C-2 of the sulfone
20 thus frustrating its potential use as a chiral benzoyl anion equivalent.
3. Conclusion
Although the initial objective of developing effective chiral acyl anion equivalents starting
from amino acids has not been realized, several new chiral sulfur containing alcohols and
derived 1,3-oxathiolanes have been obtained and characterized. The structure of the latter
has been studied by 1H NMR of the cis and trans isomers giving results in good agreement
with literature precedent for achiral systems. The first gas phase fragmentation of a chiral
1,3-oxathiolane S,S-dioxide leading to loss of SO2 and formation of an aldehyde and an
alkene is reported.
4. Experimental section
4.1. General
Melting points were determined on a Reichert hot-stage microscope and are uncorrected.
1
NMR spectra were recorded for H at 300 or 200 MHz and for 13C at 75 or 50 MHz on
Bruker instruments. Spectra were obtained for solutions in CDCl3 with Me4Si as internal
reference and coupling constants are given in Hz. IR spectra were measured on a Perkin
Elmer 1420 spectrophotometer as Nujol mulls for solids and thin films for liquids. Low
and high resolution mass spectra were run on an AEI Kratos MS50 spectrometer. Elemen-
tal analysis was performed on a Carlo-Erba 1106 elemental analyser. Optical rotations were
recorded on an Optical Activity AA1000 digital polarimeter and are given in units of 10–1
deg cm2 g–1. Flash vacuum pyrolysis was conducted using a conventional flow system with
the sample being volatilized from an electrically heated inlet tube through a horizontal
quartz reactor tube (30 × 2.5 cm) heated externally by a laboratory tube furnace, and con-
nected via a liquid nitrogen-cooled product collection trap to a rotary vacuum pump. The

JOURNAL OF SULFUR CHEMISTRY
9
system was maintained at pressures in the range 10–3–10–2 Torr corresponding to a contact
time in the hot zone of 1–10 ms. Full details of the procedure are given in a recent publica-
tion [30]. CCDC 1861140 (trans-20) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1. Preparation of α-bromo acids 1–3
These compounds were prepared by modification of the method of Izumiya [4]. To a
stirred solution of an α-amino acid (1 eq.) containing potassium bromide (3 eq.) in sulfuric
acid (1.5 M) at 0 °C was added sodium nitrite (1.2 eq.) portionwise over a 30 min period
maintaining the temp. at or near 0 °C. The resulting solution was stirred for 1 h and then
extracted with ethyl acetate (3 × 40 mL). The organic extract was dried and evaporated to
give the product which was purified as stated.
a. (S)-2-Bromo-4-methylpentanoic acid 1
Reaction as above using (S)-leucine (31.0 g, 240 mmol), sulfuric acid (1.5, 160 mL),
potassium bromide (85.6 g, 720 mmol) and sodium nitrite (19.9 g, 288 mmol) afforded the
title compound (44.9 g, 96%) as a colourless oil after Kugelrohr distillation, bp (oven temp.)
74–75 °C at 0.04 Torr (lit. [31] bp 94 °C at 0.2–0.4 Torr). [α]D24 –56.3 (c 1.5 in CHCl3) [lit.
24
[32] [α]D –56.1 (c 1.2 in CHCl3)]. νmax/cm–1 3500–2400, 1710. 1H NMR (300 MHz):
9.75 (1 H, br s, CO2H), 4.30 (1 H, t, J 7, CHBr), 1.93 (2 H, t, J 7, CH2), 1.82 (1 H, m,
CHMe2), 0.97 (3 H, d, J 7, CHMe), 0.93 (3 H, d, J 7, CHMe). 13C NMR (75 MHz): 176.6
=
(C O), 44.0 (CHBr), 43.2 (CH2), 26.3 (CHMe2), 22.3, 21.5 (Me).
b. (S)-2-Bromo-3-methylbutanoic acid 2
Reaction as above using (S)-valine (10.0 g, 90 mmol), sulfuric acid (1.5, 100 mL), potas-
sium bromide (64.3 g, 540 mmol) and sodium nitrite (8.2 g, 120 mmol) afforded the title
compound (10.1 g, 62%) as a colourless oil after Kugelrohr distillation, bp (oven temp.) 86
°C at 0.04 Torr (lit. [33] bp 119–120 °C at 14 Torr), or low melting crystals mp 41–42 °C
(hexane). [α]D24 –20.8 (c 1.2 in Et2O) [lit. [34] [α]D24 –16.7 (c 5 in 1 M NaOH)]. νmax/cm–1
3600–2400, 1705. 1H NMR (300 MHz): 11.20 (1 H, br s, CO2H), 4.09 (1 H, d, J 7, CHBr),
2.26 (1 H, m, CHMe2), 1.12 (3 H, d, J 7, CHMe), 1.08 (3 H, d, J 7, CHMe). 13C NMR
=
(75 MHz): 176.1 (C O), 54.1 (CHBr), 32.2 (CHMe2), 20.2, 19.8 (Me).
c. (S,S)-2-Bromo-3-methylpentanoic acid 3
Reaction as above using (S,S)-isoleucine (50.0 g, 380 mmol) in sulfuric acid (1.5,
200 mL) containing potassium bromide (135.7 g, 1.1 mol) and sodium nitrite (36.8 g,
530 mmol) afforded the title compound (44.9 g, 96%) as a colourless oil after Kugelrohr dis-
24
tillation, bp (oven temp.) 80 °C at 0.1 Torr (lit. [35] bp 93–95 °C at 1.0 Torr); [α]D +10.4
(c 1.5 in MeOH) [lit. [36] [α]D +9.3 (MeOH)]; νmax/cm–1 3600–2400, 1700. 1H NMR
27
(300 MHz): 9.50 (1 H, br s, CO2H), 4.13 (1 H, d, J 7, CHBr), 1.75 (1 H, m, CHCH2Me), 1.34
(2 H, m, CH2Me), 1.06 (3 H, d, J 7, CHMe), 0.92 (3 H, t, J 7, CH2Me). 13C NMR (75 MHz):
=
175.3 (C O), 52.6 (CHBr), 38.1 (CHMe), 26.2 (CH2), 16.2 (CHMe), 10.5 (CH2Me).
2. Preparation of potassium O-ethyl dithiocarbonate
A solution of potassium ethoxide was prepared by dissolving KOH (42.0 g, 0.75 mol)
in dry ethanol (150 mL) and heating the resulting mixture under reflux for 1 h. After
cooling, the solution was filtered. The filtrate was cooled in an ice bath and carbon disul-
fide (45 mL, 0.75 mol) was added dropwise with constant shaking of the reaction flask.

10
R. A. AITKEN ET AL.
The solid formed was filtered off and washed with ether (3 × 25 mL) to afford potassium
O-ethyldithiocarbonate (potassium ethyl xanthate) (80.0 g, 76%) as colourless crystals, mp
>200 °C (dec.) [lit. [37] mp 190 °C (dec.)] which were recrystallised from ethanol.
3. Preparation of (R)-2-Ethoxythiocarbonylthio-4-methylpentanoic acid 4
Following the method of Levene [38], a stirred solution of (S)-2-bromo-4-
methylpentanoic acid 1 (16.0 g, 82 mmol) in water (70 mL) at 0 °C was neutralized by
addition of sodium carbonate (8.7 g, 82 mmol) which was followed by addition of potas-
sium O-ethyl dithiocarbonate (13.1 g, 82 mmol). This solution was maintained at 0 °C
for 8 h and then acidified with cold concentrated hydrochloric acid (11 mL). The mixture
was extracted with ether (3 × 40 mL) and the combined extracts washed with brine (2 ×
15 mL), dried and evaporated. Kugelrohr distillation afforded the title compound (18.6 g,
96%) as a clear light yellow oil after Kugelrohr distillation, bp (oven temp.) 130 °C at 0.3
Torr (Found: C, 45.98; H, 6.88. C9H16O3S2 requires C, 45.74; H, 6.82%). HRMS (EI) m/z
22
calcd for C9H17O3S2: 237.0619, found: 237.0628 [M + H]. [α]D +65.3 (c 1.1 in CH2Cl2).
ν
max/cm–1 3500–2400, 1700. 1H NMR (300 MHz): 9.00 (1 H, br s, CO2H), 4.67 (2 H, q, J
7, CH2), 4.43 (1 H, t, J 7, SCH), 1.80 (1 H, m, CHMe2), 1.70 (2 H, m, CH2CH), 1.44 (3 H,
t, J 7, CH2Me), 1.00 (3 H, d, J 7, CHMe), 0.95 (3 H, d, J 7, CHMe). 13C NMR (75 MHz):
=
=
211.6 (C S), 177.8 (C O), 70.8 (OCH2), 50.4 (CHS), 39.4 (CH2), 26.1 (CHMe2), 22.3,
22.2 (CHMe), 13.6 (CH2Me). m/z (CI) 237 (M + H+, 100%), 133 (28), 123(86), 117 (63).
4. Preparation of (R)-Ethyl 2-ethoxythiocarbonylthio-4-methylpentanoate 5
A solution of (R)-2-ethoxythiocarbonylthio-4-methylpentanoic acid 4 (14.1 g,
100 mmol) in ethanol (70 mL) containing concentrated sulfuric acid (0.2 mL) was heated
under reflux for 6.5 h. After cooling, the solution was partly evaporated. Water (50 mL)
was added and the mixture extracted with ether (2 × 50 mL), which was dried and evapo-
rated to give the product. Kugelrohr distillation afforded the title compound (15.3 g, 97%)
as a light yellow liquid, bp (oven temp.) 140 °C at 2.0 Torr (Found: C, 50.21; H, 7.35.
25
C11H20O3S2 requires C, 49.97; H, 7.62%); [α]D +59.5 (c 1.4 in CH2Cl2). νmax/cm–1
1700. 1H NMR (300 MHz): 4.62 (2 H, q, J 7, MeCH2OCS2), 4.35 (1 H, t, J 7, CHS), 4.19
(2 H, q, J 7, CO2CH2), 1.75 (1 H, m, CHMe2), 1.71 (2 H, m, CH2CH), 1.41 (3 H, t, J 7,
MeCH2OCS2), 1.27 (3 H, t, J 7, CO2CH2Me), 0.97 (3 H, d, J 7, CHMe), 0.93 (3 H, d, J
7, CHMe). 13C NMR (75 MHz): 212.4 (C S), 171.5 (C O), 70.3 (OCH2), 61.6 (OCH2),
50.8 (CHS), 40.1 (CH2), 26.2 (CH), 22.3, 22.2 (CHMe), 14.1, 13.6 (CH2Me). m/z (EI) 265
(M + H+, 17%), 219 (18), 143 (100), 133 (16), 120 (20), 115 (60), 101 (38), 87 (24), 69 (48).
=
=
5. Preparation of (R)-2-Mercapto-4-methylpentan-1-ol 6
A solution of (R)-ethyl 2-ethoxythiocarbonylthio-4-methylpentanoate 5 (8.7 g,
33 mmol) in dry THF (50 mL) was added dropwise with stirring over a 1 h period to a
suspension of lithium aluminium hydride (1.8 g, 49 mmol) in dry THF (50 mL) under
nitrogen and the resulting mixture was heated under reflux for 7 h. After cooling, ace-
tone (30 mL) was added to destroy the excess reagent followed by the addition of sulfuric
acid (1.5, 40 mL). The THF layer was separated and the product extracted from it with
potassium hydroxide (10%, 3 × 40 mL). The combined alkali extracts were acidified with
hydrochloric acid (2 M) and the mixture extracted with ether (4 × 25 mL). The combined
ether extracts were washed with water (4 × 15 mL), dried and evaporated to afford the
title compound (3.9 g, 88%) as a colourless foul smelling liquid after Kugelrohr distillation,
bp (oven temp.) 50 °C at 0.1 Torr (Found: C, 53.38; H, 10.46. C6H14OS requires C, 53.69;

JOURNAL OF SULFUR CHEMISTRY
11
17
H, 10.51%). HRMS (EI) m/z calcd for C6H14OS: 134.0765, found: 134.0762 [M]. [α]D
+31.0 (c 1.1 in CH2Cl2). νmax/cm–1 3600–3100. 1H NMR (300 MHz): 3.68 (1 H, half AB
pattern of d, J 11, 5, CH2OH), 3.41 (1 H, half AB pattern of d, J 11, 7, CH2OH), 2.94 (1 H,
m, CHS), 2.64 (1 H, br s, OH), 1.86 (1 H, m, CHMe2), 1.39 (2 H, m, CH2CH), 1.30 (1 H,
d, J 7, SH), 0.91 (3 H, d, J 7, CHMe), 0.87 (3 H, d, J 7, CHMe). 13C NMR (75 MHz): 68.3
(OCH2), 43.8 (CH2), 42.1 (CHS), 25.4 (CH), 23.0, 21.6 (Me). m/z (EI) 134 (M+, 5%), 115
(5), 103 (22), 100 (24), 83 (47), 69 (100), 61 (50), 57 (51), 43 (74).
6. Preparation of (R)-2-Benzylthio-4-methylpentan-1-ol 7
A solution of (R)-2-mercapto-4-methylpentan-1-ol 6 (8.5 g, 63 mmol) in ethanol
(25 mL) was slowly added to a solution of sodium ethoxide (70 mmol) in ethanol (50 mL).
After stirring for 15 min, benzyl bromide (12.0 g, 8.3 mL, 70 mmol) was added, dropwise,
and after 1 h at RT the mixture was filtered to remove the precipitate of sodium bro-
mide and then evaporated. The residue was dissolved in water (30 mL) and the mixture
extracted with ether (3 × 20 mL). The combined organic extracts were washed with water
(30 mL), dried and evaporated to give the crude product. Kugelrohr distillation afforded
the title compound (6.0 g, 60%) as a pale yellow oil, bp (oven temp.) 175 °C at 0.5 Torr
(Found: C, 69.85; H, 9.18. C13H20OS requires C, 69.59; H, 8.99%). HRMS (EI) m/z calcd
25
for C13H20OS: 224.1235, found: 224.1239 [M]. [α]D +50.1 (c 1.2 in CH2Cl2). νmax/cm–1
3600–3100. 1H NMR (200 MHz): 7.4–7.2 (5 H, m, Ph), 3.71 (2 H, s, PhCH2S), 3.64 (1 H,
half AB pattern of d, J 11, 5, CH2OH), 3.45 (1 H, half AB pattern of d, J 11, 7, CH2OH),
2.75 (1 H, m, CHS), 2.07 (1 H, br s, OH), 1.76 (1 H, m, CHMe2), 1.38 (2 H, m, CH2CH),
0.86 (3 H, d, J 7, CHMe), 0.76 (3 H, d, J 7, CHMe). 13C NMR (50 MHz): 138.3 (Ph-C1),
128.8 (Ph, 2CH), 128.6 (Ph, 2CH), 127.1 (Ph-C4), 64.0 (OCH2), 46.6 (CHS), 40.5 (CH2),
34.5 (CH2S), 25.2 (CH), 22.9, 21.9 (Me); m/z (EI) 224 (M+, 41%), 193 (43), 137 (51), 123
(14), 91 (100), 65 (16).
7. Preparation of α-benzylthio acids 8–10
To a stirred solution of the α-bromo acid (1 eq.) containing sodium hydroxide (1 eq.) in
water, was added dropwise, a solution of benzyl mercaptan (1 eq.) and sodium hydroxide (1
eq.) in water (50 mL). The resulting mixture was heated under reflux for 7 h. After cooling,
the solution was washed with ether (20 mL) and this extract discarded. The aqueous phase
was acidified with hydrochloric acid (2 M) and then extracted with ether (3 × 50 mL). The
combined organic extracts were dried and evaporated and the products purified as stated.
a. (R)-2-Benzylthio-4-methylpentanoic acid 8
Reaction as above using (S)-2-bromo-4-methylpentanoic acid 1 (19.6 g, 100 mmol)
and sodium hydroxide (4.0 g, 100 mmol) in water (50 mL) and benzyl mercaptan (12.4 g,
11.7 mL, 100 mmol) and sodium hydroxide (4.0 g, 100 mmol) in water (50 mL) afforded
the title compound (21.4 g, 90%) as a clear colourless liquid after removal of the α-
hydroxyalcohol by Kugelrohr distillation (Found: C, 65.47; H, 7.87. C13H18O2S requires
C, 65.51; H, 7.61%). HRMS (EI) m/z calcd for C13H18O2S: 238.1028, found: 238.1022 [M].
[α]D +170.5 (c 1.4 in CH2Cl2). νmax/cm–1 3400–2400, 1705. 1H NMR (200 MHz): 11.18
22
(1 H, br s, CO2H), 7.4–7.2 (5 H, m, Ph), 3.90 and 3.82 (2 H, AB pattern, J 14, PhCH2S),
3.19 (1 H, t, J 7, CHS), 1.70 (2 H, m, CH2CH), 1.50 (1 H, m, CHMe2), 0.83 (3 H, d, J 7,
CHMe), 0.71 (3 H, d, J 7, CHMe). 13C NMR (50 MHz): 180.0 (C O), 137.5 (Ph-C1), 129.4
=
(Ph, 2CH), 128.7 (Ph, 2CH), 127.5 (Ph-C4), 43.7 (CHS), 39.5 (CH2), 36.3 (CH2S), 25.9

12
R. A. AITKEN ET AL.
(CH), 22.5 (Me), 22.1 (Me). m/z (EI) 238 (M+, 29%), 123 (100), 113 (11), 91 (100), 65 (22),
45 (25).
b. (R)-2-Benzylthio-3-methylbutanoic acid 9
Reaction as above using (S)-2-bromo-3-methylbutanoic acid 2 (19.4 g, 110 mmol) and
sodium hydroxide (4.3 g, 110 mmol) in water (50 mL) and benzyl mercaptan (13.3 g,
12.5 mL, 110 mmol) and sodium hydroxide (4.3 g, 110 mmol) in water (50 mL) afforded
the title compound (18.5 g, 75%) as a clear colourless liquid after Kugelrohr distillation, bp
135 °C at 2.5 Torr (Found: C, 63.84; H, 7.46%. C12H16O2S requires C, 64.25; H, 7.19%).
22
HRMS (EI) m/z calcd for C12H16O2S: 224.0871, found: 224.0866 [M]. [α]D +67.7 (c 1.2
in CH2Cl2). νmax/cm–1 3500–2400, 1680. 1H NMR (200 MHz): 9.00 (1 H, br s, CO2H),
7.40–7.20 (5 H, m, Ph), 3.86 (2 H, s, PhCH2S), 2.92 (1 H, d, J 7, SCH), 2.08 (1 H, m,
CHMe2), 1.02 (3 H, d, J 7, CHMe), 1.00 (3 H, d, J 7, CHMe) [good agreement with lit. [6]
except that there the 4 signals constituting the two Me doublets have been mis-paired to
give a false coupling constant of 2.9 Hz]. 13C NMR (50 MHz): 179.0 (C O), 137.4 (Ph-C1),
=
129.3 (Ph, 2CH), 128.6 (Ph, 2CH), 127.4 (Ph-C4), 53.6 (CHS), 36.2 (CH2S), 29.3 (CH), 20.7
(Me), 19.8 (Me) [good agreement with lit. [6]]. m/z (EI) 224 (M+, 33%), 179 (3), 140 (30),
138 (29), 123 (100), 91 (100), 76 (52) 73 (48), 43 (35).
c. (3S)-2-Benzylthio-3-methylpentanoic acid 10
Reaction as above using (S,S)-2-bromo-3-methylpentanoic acid 3 (37.7 g, 193 mmol)
and sodium hydroxide (7.7 g, 193 mmol) in water (75 mL) and benzyl mercaptan (24.0 g,
22.7 mL, 193 mmol) and sodium hydroxide (7.7 g, 193 mmol) in water (75 mL), followed
by distillation using a Vigreux column afforded the title compound (38.5 g, 84%), as a
54: 46 mixture of 2 diastereomers, as a clear colourless liquid, bp 170 °C at 2.0 Torr
(Found: C, 65.49; H, 7.98. C13H18O2S requires C, 65.51; H, 7.61%). HRMS (EI) m/z calcd
1
for C13H18O2S: 238.1028, found: 238.1027 [M]. νmax/cm–1 3600–2300, 1705. H NMR
(300 MHz): 10.35 (1 H, br s, CO2H), 7.32 (5 H, m, Ph), 3.88 and 3.78 (2 H, AB pattern, J
14, PhCH2S), 3.01 and 2.99 (1 H, d, J 7, CHS), 1.86 and 1.72 (1 H, m, CHCH2), 1.40 and
1.20 (2 H, m, CH2Me), 1.00 (3 H, d, J, CHMe), 0.80 and 0.79 (3 H, t, J 7, CH2Me). 13
C
=
NMR (75 MHz): major diastereomer 179.4 (C O), 137.5 (Ph-C1), 129.4 (Ph, 2CH), 128.6
(Ph, 2CH), 127.4 (Ph-C4), 51.9 (CHS), 36.1 (CH2S), 35.6 (CH), 27.4 (CH2), 16.1 (Me), 11.3
=
(Me); minor diastereomer 179.1 (C O), 137.5 (Ph-C1), 129.3 (Ph, 2CH), 128.6 (Ph, 2CH),
127.4 (Ph-C4), 52.0 (CHS), 36.2 (CH2S), 35.3 (CH), 26.0 (CH2), 16.8 (Me), 10.5 (Me). m/z
(EI) 238 (M+, 10%), 123 (100), 91 (87), 65 (9).
8. Preparation of α-benzylthio esters 11–13
A stirred solution of an α-benzylthio acid (1 eq.) in excess ethanol containing sulfu-
ric acid (0.5 mL) was heated under reflux for 6.5 h. After cooling, the excess ethanol was
removed at the water pump. Water (50 mL) was added and the mixture extracted with
ether (4 × 40 mL). The ether extracts were washed with a saturated solution of sodium
bicarbonate (2 × 30 mL), dried and evaporated to give the product which was purified as
stated.
a. (R)-Ethyl 2-benzylthio-4-methylpentanoate 11
Reaction as above using (R)-2-benzylthio-4-methylpentanoic acid 8 (25.0 g, 105 mmol)
and ethanol (100 mL) afforded the title compound (26.5 g, 95%) as a light yellow liq-
uid after Kugelrohr distillation, bp (oven temp.) 150 °C at 2.0 Torr (Found: C, 67.56; H,

JOURNAL OF SULFUR CHEMISTRY
13
8.16. C15H22O2S requires C, 67.63; H, 8.32%). HRMS (EI) m/z calcd for C15H22O2S:
22
1
266.1341, found: 266.1348 [M]. [α]D +144.4 (c 1.1 in CH2Cl2). νmax/cm–1 1725. H
NMR (300 MHz): 7.40–7.25 (5 H, m, Ph), 4.16 (2 H, q, J 7, CH2Me), 3.82 and 3.77 (2 H,
AB pattern, J 13, PhCH2S), 3.20 (1 H, t, J 7, CHS), 1.77–1.44 (3 H, m, CH2CH), 1.28 (3 H, t,
J 7, CH2Me), 0.83 (3 H, d, J 7, CHMe), 0.74 (3 H, d, J 7, CHMe). 13C NMR (75 MHz): 173.1
=
(C O), 137.8 (Ph-C1), 129.2 (Ph, 2CH), 128.6 (Ph, 2CH), 127.2 (Ph-C4), 61.0 (OCH2),
44.2 (CHS), 39.8 (CH2), 35.8 (CH2S), 25.9 (CH), 22.3 (Me), 22.0 (Me), 14.2 (Me). m/z (EI)
266 (M+, 33%), 210 (7), 193 (9), 144 (57), 137 (16), 123 (64), 101 (76), 91 (100), 73 (18),
65 (20).
b. (R)-Ethyl 2-benzylthio-3-methylbutanoate 12
Reaction as above using (R)-2-benzylthio-3-methylbutanoic acid 9 (13.0 g, 60 mmol)
and ethanol (50 mL) afforded the title compound (15.1 g, 100%) as a colourless liquid
after Kugelrohr distillation, bp (oven temp.) 150 °C at 4.0 Torr (Found: C, 67.11; H,
8.26%. C14H20O2S requires C, 66.63; H, 7.99%). HRMS (EI) m/z calcd for C14H20O2S:
252.1184, found: 252.1191 [M]. [α]D +55.3 (c 1.3 in CH2Cl2). νmax/cm–1 1720. 1H NMR
24
(300 MHz): 7.40–7.25 (5 H, m, Ph), 4.19 (2 H, q, J 7, CH2Me), 3.79 (2 H, s, PhCH2S), 2.90
(1 H, d, J 11, CHS), 2.06 (1 H, m, CHMe2), 1.29 (3 H, t, J 7, CH2Me), 1.00 (3 H, d, J 7,
CHMe), 0.95 (3 H, d, J 7, CHMe). 13C NMR (75 MHz): 172.7 (C O), 137.8 (Ph-C1), 129.2
=
(Ph, 2CH), 128.6 (Ph, 2CH), 127.3 (Ph-C4), 60.9 (OCH2), 54.2(CHS), 36.0 (CH2S), 29.6
(CH), 20.7 (Me), 20.0 (Me), 14.2 (CH2Me). m/z (EI) 252 (M+, 41%), 179 (30), 130 (57),
123 (67), 91 (100), 65 (20).
c. (3S)-Ethyl 2-benzylthio-3-methylpentanoate 13
Reaction as above using (3S)-2-benzylthio-3-methylpentanoic acid 10 (25.5 g,
110 mmol) and ethanol (60 mL) afforded the title compound (26.2 g, 92%), as a 65:35 mix-
ture of diastereomers, as a colourless liquid after Kugelrohr distillation, bp (oven temp.)
130 °C at 2.0 Torr (Found: C, 67.32; H, 8.50. C15H22O2S requires C, 67.63; H, 8.32%).
ν
max/cm–1 1720. major diastereomer 1H NMR (300 MHz): 7.40–7.25 (5 H, m, Ph), 4.18 (2
H, q, J 7, CH2Me), 3.78 (2 H, s, PhCH2S), 3.02 (1 H, d, J 7, CHS), 1.86 (1 H, m, CHCH2),
1.28 (3 H, t, J 7, CH2Me), 1.18 (2 H, m, CH2Me), 0.98 (3 H, d, J 7, CHMe), 0.81 (3 H, t, J 7,
CH2Me). 13C NMR (75 MHz): 172.9 (C O), 137.8 (Ph-C1), 129.3 (Ph, 2CH), 128.6 (Ph,
=
2CH), 127.3 (Ph-C4), 60.9 (CH2), 52.6 (CHS), 35.9 (CH2S), 35.8 (CH), 27.4 (CH2), 16.3
(Me), 14.2 (Me), 11.3 (Me); minor diastereomer 1H NMR (300 MHz): 7.40–7.25 (5 H, m,
Ph), 4.18 (2 H, q, J 7, CH2Me), 3.77 (2 H, s, PhCH2S), 3.01(1 H, d, J 7, CHS), 1.66 (1 H,
m, CHCH2), 1.42 (2 H, m, CH2Me), 1.28 (3 H, t, J 7, CH2Me), 0.93 (3 H, d, J 7, CHMe),
0.78 (3 H, t, J 7, CH2Me). 13C NMR (75 MHz): 172.7 (C O), 137.8 (Ph-C1), 129.3 (Ph,
=
2CH), 128.6 (Ph, 2CH), 127.3 (Ph-C4), 60.9 (CH2), 52.4 (CHS), 36.0 (CH2S), 35.6 (CH),
26.1 (CH2), 16.8 (Me) 14.2 (Me), 10.5 (Me). m/z (EI) 266 (M+, 49%), 193 (14), 144 (57),
123 (59), 115 (86), 91 (100).
9. Preparation of α-benzylthio alcohols from the esters
A solution of an α-benzylthio ester (1 eq.) in dry ether was added to a suspension of
excess lithium aluminium hydride in dry ether under nitrogen and the resulting mixture
heated under reflux for 3 h. After cooling, acetone was added to destroy the excess reagent
followed by the addition of sulfuric acid. The mixture was extracted with ether which was
separated, dried and evaporated to give the product which was purified as stated.

14
R. A. AITKEN ET AL.
a. (R)-2-Benzylthio-4-methylpentan-1-ol 7
Reaction was carried out as above using (R)-ethyl 2-benzylthio-4-methylpentanoate
11 (17.0 g, 103 mmol) and dry ether (50 mL) and lithium aluminium hydride (4.9 g,
130 mmol) in dry ether (140 mL). After cooling, acetone (50 mL) and sulfuric acid (1.5
M, 60 mL) were added. Kugelrohr distillation afforded the title compound (13.9 g, 97%) as
25
a colourless liquid, bp (oven temp.) 135 °C at 0.2 Torr; [α]D +52.5 (c 1.4 in CH2Cl2); For
further characterization see 6.
b. (R)-2-Benzylthio-3-methylbutan-1-ol 14
Reaction was carried out as above using (R)-ethyl 2-benzylthio-3-methylbutanoate 12
(8.0 g, 32 mmol) in dry ether (20 mL) and lithium aluminium hydride (1.4 g, 36 mmol) in
dry ether (100 mL). After cooling, acetone (50 mL) and sulfuric acid (1.5 M, 60 mL) were
added. Kugelrohr distillation afforded the title compound (6.0 g, 90%) as a colourless liq-
uid, bp (oven temp.) 120 °C at 0.2 Torr (Found: C, 68.33; H, 8.94%. C12H18OS requires C,
68.52; H, 8.63%). HRMS (EI) m/z calcd for C12H18OS: 210.1078, found: 210.1087 [M].
[α]D +11.6 (c 1.2 in CH2Cl2) [lit. [8] [α]D +22.9 (c 0.93 in CH2Cl2)]. νmax/cm–1
22
23
1
3600–3100. H NMR (300 MHz): 7.40–7.25 (5 H, m, Ph), 3.76 and 3.72 (1 H, AB pat-
tern, J 13, PhCH2S), 3.68 (1 H, half AB pattern of d, J 12, 4, CH2OH), 3.51 (1 H, half AB
pattern of d, J 12, 8, CH2OH), 2.53 (1 H, d of t, J 8, 5, CHS), 2.09 (1 H, br s, OH), 1.89
(1 H, m, CHMe2), 0.95 (6 H, d, J 7, CHMe2) [good agreement with lit. [8]]. 13C NMR
(75 MHz): 138.5 (Ph-C1), 128.9 (Ph-C4), 128.6 (Ph, 2CH), 127.1 (Ph, 2CH), 62.8 (OCH2),
56.2 (CHS), 36.4 (CH2S), 29.8 (CH), 20.4 (Me), 19.5 (Me) [good agreement with lit. [8]].
m/z (EI) 210 (M+, 25%), 179 (33), 145 (12), 123 (16), 91 (100), 65 (19).
c. (R)-2-Benzylthio-3-methylpentan-1-ol 15
Reaction was carried out as above using (R)-ethyl 2-benzylthio-3-methylpentanoate 13
(6.0 g, 23 mmol) in dry ether (20 mL) and lithium aluminium hydride (0.9 g, 24 mmol) in
dry ether (80 mL). After cooling, acetone (30 mL) and sulfuric acid (1.5 M, 50 mL) were
added. The ether layer was separated, dried and evaporated to give the title compound
(5.0 g, 100%) as a 74:26 mixture of diastereomers as a colourless liquid (Found: C, 69.84; H,
9.06. C13H20OS requires C, 69.59; H, 8.99%). νmax/cm–1 3500–3050. major diastereomer
1H NMR (300 MHz): 7.40–7.25 (5 H, m, Ph), 3.72 (2 H, s, PhCH2S), 3.66 (1 H, half AB
pattern of d, J 12, 4, CH2OH), 3.52 (1 H, half AB pattern of d, J 12, 8, CH2OH), 2.55 (1
H, d of t, J 8, 5, CHS), 2.35 (1 H, br s, OH), 1.66 (1 H, m, CHMe), 1.20 (2 H, m, CH2Me),
0.90 (3 H, d, J 7, CHMe), 0.80 (3 H, t, J 7, CH2Me). 13C NMR (75 MHz): 138.3 (Ph-C1),
128.8 (Ph-C2,C6), 128.4 (Ph-C3,C5), 127.0 (Ph-C4), 63.4 (CH2), 54.5 (CHS), 36.6 (CH),
36.4 (CH2S), 27.0 (CH2), 16.2 (Me), 11.6 (Me); minor diastereomer 1H NMR (300 MHz):
7.40–7.25 (5 H, m, Ph), 3.72 (2 H, s, PhCH2S), 3.64 (1 H, half AB pattern of d, J 12, 4,
CH2OH), 3.50 (1 H, half AB pattern of d, J 12, 8, CH2OH), 2.52 (1 H, d of t, J 8, 5, CHS),
2.35 (1 H, br s, OH), 1.42 (1 H, m, CHMe), 1.22 (2 H, m, CH2Me), 0.88 (3 H, d, J 7, CHMe),
0.79 (3 H, t, J 7, CH2Me). 13C NMR (75 MHz): 138.5 (Ph-C1), 128.8 (Ph, 2CH), 128.4 (Ph,
2CH), 127.0 (Ph-C4), 62.0 (CH2), 53.8 (CHS), 36.2 (CH2S), 36.1 (CH), 26.3 (CH2), 15.6
(Me), 11.6 (Me). m/z (EI) 224 (M+, 35%), 193 (40), 137 (15), 122 (28), 91 (100).
10. Preparation of chiral 1,3-oxathiolanes
To a stirred boiling solution of the mercapto alcohol (1 eq.) containing an aldehyde
(1 eq.) in dry ether or THF was added dropwise over 1 h boron trifluoride diethyl etherate
(1 eq.) in dry ether or THF. This solution was heated for the time stated after addition was

JOURNAL OF SULFUR CHEMISTRY
15
complete. The cooled solution was then washed twice with sodium bicarbonate (0.1 M, 2 ×
15 mL) and with a saturated brine solution (2 × 20 mL). The organic extract was then dried
and evaporated to leave a colourless liquid with a very potent aroma purified as stated.
a. 2-(RS)-tert-Butyl-4-(R)-isobutyl-1,3-oxathiolane 16
Reaction was carried out as above using (R)-2-mercapto-4-methylpentan-1-ol 6
(780 mg, 5.8 mmol), pivalaldehyde (0.5 g, 0.6 mL, 5.8 mmol) in dry ether (7 mL) and boron
trifluoride diethyl etherate (0.8 g, 0.7 mL, 5.8 mmol) in dry ether (3 mL) for 1 h. Kugelrohr
distillation afforded the title compound (950 mg, 81%) as a colourless liquid, bp (oven
temp.) 45 °C at 0.35 Torr as a 66:34 mixture of two diastereomers (Found: C, 64.71; H,
11.03%. C11H22OS requires C, 65.29; H, 10.96%). HRMS (EI) m/z calcd for C11H22OS:
202.1391, found: 202.1395 [M]. νmax/cm–1 2930, 1450. major diastereomer cis-16 1H NMR
(300 MHz): 4.88 (1 H, s, CHBut), 3.98 (1 H, half AB pattern of d, J 10, 2, CH2O), 3.78 (1 H,
half AB pattern of d, J 10, 6, CH2O), 3.45 (1 H, m, CHS), 1.63 (1 H, m, CHMe2), 1.44 (2 H,
m, CHCH2CH), 0.97 (9 H, s, CMe3), 0.89 (6 H, d, J 7, CHMe2); 13C NMR (75 MHz): 96.8
(CHO), 76.8 (CH2O), 46.8 (CHS), 45.4 (CH2), 34.7 (CMe3), 26.7 (CH), 26.0 (CMe3), 23.0
(Me), 21.8 (Me); minor diastereomer trans-16 1H NMR (300 MHz): 4.95 (1 H, s, CHBut),
4.31 (1 H, d of d, J 9.3, 6, CH2O), 3.44 (1 H, m, CHS), 3.35 (1 H, d of d, J 9.3, 9, CH2O),
1.63 (1 H, m, CHMe2), 1.44 (2 H, m, CHCH2CH), 0.95 (9 H, s, CMe3), 0.86 (6 H, d, J 7,
CHMe2). 13C NMR (75 MHz): 96.5 (CHO), 77.5 (CH2O), 47.7 (CHS), 42.5 (CH2), 35.2
(CMe3), 28.2 (CH), 25.8 (CMe3), 23.0 (Me), 22.1 (Me). m/z (EI) 222 (M+, 35%), 116 (44),
105 (25), 82 (46), 75 (100).
b. 4-(R)-Isobutyl-2-(RS)-phenyl-1,3-oxathiolane 17
Reaction was carried out as above using (R)-2-mercapto-4-methylpentan-1-ol 6 (1.9 g,
14 mmol), benzaldehyde (1.5 g, 1.4 mL, 14 mmol) in dry THF (35 mL) and boron triflu-
oride diethyl etherate (2.0 g, 1.7 mL, 14 mmol). This solution was heated for 1 h. Kugel-
rohr distillation afforded the title compound (3.2 g, >99%) as a colourless liquid, bp
(oven temp.) 140 °C at 0.3 Torr as a 52:48 diastereomeric mixture. (Found: C, 69.44; H,
8.18%. C13H18OS requires C, 70.23; H, 8.16%). HRMS (EI) m/z calcd for C13H18OS:
222.1078, found: 222.1086 [M]. νmax/cm–1 2930, 1450. major diastereomer cis-17 1H NMR
(300 MHz): 7.60–7.50 (2 H, m, Ph), 7.45–7.30 (3 H, m, Ph), 6.18 (1 H, s, PhCH), 4.15 (1 H,
half AB pattern of d, J 7, 3, CH2O), 4.03 (1 H, half AB pattern of d, J 7, 4, CH2O), 3.91 (1 H,
m, CHS), 1.70 (2 H, m, CHCH2CH), 1.62 (1 H, m, CHMe2), 1.00 (6 H, d, J 7, CHMe2). 13
C
NMR (75 MHz): 139.9 (Ph-C1), 128.8 (Ph, 2CH), 128.6 (Ph, 2CH), 126.8 (Ph-C4), 87.7
(CHO), 77.5 (CH2O), 49.4 (CHS), 43.3 (CH2), 28.2 (CH), 23.1 (Me), 22.2 (Me); minor
1
diastereomer trans-17 H NMR (300 MHz): 7.60–7.50 (2 H, m, Ph), 7.45–7.30 (3 H, m,
Ph), 6.12 (1 H, s, PhCH), 4.51 (1 H, d of d, J 7, 5, CH2O), 3.76 (1 H, m, CHS), 3.61 (1 H, t,
J 7, CH2O), 1.70 (2 H, m, CHCH2CH), 1.62 (1 H, m, CHMe2), 1.00 (6 H, d, J 7, CHMe2).
13C NMR (75 MHz): 139.6 (Ph-C1), 128.6 (Ph, 2CH), 127.0 (Ph, 2CH), 126.8 (Ph-C4), 87.2
(CHO), 76.8 (CH2O), 49.7 (CHS), 45.7 (CH2), 27.2 (CH), 23.2 (Me), 22.0 (Me). m/z (EI)
202 (M+, 10%), 145 (100), 83 (25).
c. Preparation of 2-(R)- and 2-(S)-benzoyl-4-(R)-isobutyl-1,3-oxathiolane 18
A solution of (R)-2-mercapto-4-methylpentan-1-ol 6 (200 mg, 1.5 mmol), phenylgly-
oxal monohydrate (227 mg, 1.5 mmol) and a catalytic quantity of p-toluenesulfonic acid
monohydrate (5 mg) in dry toluene (50 mL) was heated under reflux for 9 h. After cool-
ing the toluene was evaporated and the residue added to ether (20 mL). This was washed

16
R. A. AITKEN ET AL.
with saturated aqueous sodium hydrogen carbonate (2 × 25 mL), dried and evaporated.
Purification by chromatography eluting with light petroleum/ether (4: 1) afforded two
diastereomers of the title compound:
The 2,4-cis diastereomer 18a (120 mg, 32%), Rf 0.48. HRMS (EI) m/z calcd for
C14H19O2S: 251.1106, found: 251.1112 [M + H]. νmax/cm–1 1705. 1H NMR (300 MHz):
7.38 (5 H, m, Ph), 5.20 (1 H, s, PhCH), 4.04 (1 H, half AB pattern of d, J 12, 3, CH2O), 3.94
(1 H, m, CHS), 3.66 (1 H, half AB pattern of d, J 12, 5, CH2O), 1.80 (1 H, m, CHMe2), 1.52
(2 H, t, J 7, CHCH2CH), 0.98 (6 H, d, J 7, CHMe). 13C NMR (75 MHz): 198.6 (C O), 136.1
=
(Ph-C1), 128.7 (Ph-C4), 128.7 (Ph, 2CH), 128.0 (Ph, 2CH), 89.0 (CHO), 65.9 (CH2O), 43.5
(CHS), 43.4 (CH2), 22.9 (CH), 22.8 (Me), 21.9 (Me). m/z (EI) 251 (M + H+, 80%), 222 (95),
116 (75), 105 (95), 75 (100).
The 2,4-trans diastereomer 18b (43 mg, 11%), Rf 0.50. HRMS (EI) m/z calcd for
C14H19O2S: 251.1106, found: 251.1111 [M + H]. νmax/cm–1 1705. 1H NMR (300 MHz):
7.40–7.35 (5 H, m, Ph), 5.08 (1 H, s, PhCH), 4.34 (1 H, d of d, J 12, 4, CH2O), 4.00 (1
H, m, CHS), 3.66 (1 H, d of d, J 12, 10, CH2O), 1.72 (1 H, m, CHMe2), 1.52 (2 H, t, J 7,
CHCH2CH), 0.98 (6 H, d, J 7, CHMe2). 13C NMR (75 MHz): 199.0 (C O), 136.3 (Ph-C1),
=
128.9 (Ph-C4), 128.7 (Ph, 2CH), 127.9 (Ph, 2CH), 86.9 (CHO), 70.3 (CH2O), 43.7 (CHS),
41.7 (CH2), 25.0 (CH), 22.9, 21.9 (Me). m/z (EI) 251 (M + H+, 7%), 222, 116 (80), 105
(65), 75 (100); (CI) 251 (M + H+, 100%), 235 (10), 221 (45), 209 (20), 159 (6).
11. Oxidation of chiral 1,3-oxathiolanes
a. 2-(RS)-tert-Butyl-4-(R)-isobutyl-1,3-oxathiolane S-oxide 19
A solution of 2-(RS)-tert-butyl-4-(R)-isobutyl-1,3-oxathiolane 16 (360 mg, 1.8 mmol)
in dry ether (5 mL) was added dropwise to a solution of m-CPBA (70–75%, 440 mg,
3.6 mmol) in dry ether (10 mL) stirred at 0 °C. After 3 h this was allowed to warm up
to RT and stirred for a further 60 h. The mixture was then washed with saturated aque-
ous sodium bicarbonate (4 × 100 mL), dried and evaporated. Kugelrohr distillation of the
residue afforded the title compound (370 mg, 85%) as a colourless liquid, bp (oven temp.)
120 °C at 0.5 Torr (Found: C, 59.85; H, 10.19. C11H22O2S requires C, 60.51; H, 10.16%) as
a 34:66 mixture of two diastereomers. This compound showed a peculiar behavior upon
distillation and gave a complete reversal of the diastereomeric ratio:- 2nd distillation bp
(oven temp.) 120 °C at 0.5 Torr gave a 55: 45 mixture of two diastereomers; 3rd distillation
bp (oven temp.) 120 °C at 0.5 Torr gave a 61: 39 mixture of two diastereomers; νmax/cm–1
2950, 1430. major diastereomer cis-19a (after 3rd distillation) 1H NMR (300 MHz): 4.33
(1 H, half AB pattern of d, J 10, 4, CH2O), 4.23 (1 H, half AB pattern, J 10, CH2O), 4.03
(1 H, s, CHBut), 3.12 (1 H, t of d, J 8, 4, CHSO), 1.78 (2 H, m, CHCH2CH), 1.35 (1 H,
m, CHMe2), 1.11 (9 H, s, CMe3), 0.99 (6 H, d, J 7, CHMe2). 13C NMR (75 MHz): 121.5
(CHO), 73.2 (CH2O), 65.5 (CHSO), 36.6 (CH2), 33.2 (CMe3), 26.9 (CH), 26.6 (CMe3),
22.6, 22.3 (Me); minor diastereomer trans-19b 1H NMR (300 MHz): 4.41 (1 H, d of d, J 10,
6, CH2O), 4.03 (1 H, s, CHBut), 3.84 (1 H, t, J 10, CH2O), 2.52 (1 H, m, CHSO), 1.78 (2
H, m, CHCH2CH), 1.35 (1 H, m, CHMe2), 1.09 (9 H, s, CMe3), 0.94 (6 H, d, J 7, CHMe2).
13C NMR (75 MHz): 121.2 (CHO), 73.2 (CH2O), 60.3 (CHSO), 33.8 (CMe3), 30.4 (CH2),
30.0 (CH), 26.3 (CMe3), 22.6, 22.4 (Me).
b. 4-(R)-Isobutyl-2-(RS)-phenyl-1,3-oxathiolane S,S-dioxide 20
A solution of 4-(R)-isobutyl-2-(RS)-phenyl-1,3-oxathiolane 17 (1.6 g, 7 mmol) in dry
ether (20 mL) was added dropwise to a solution of m-CPBA (70–75%, 3.5 g, 14 mmol)

JOURNAL OF SULFUR CHEMISTRY
17
in dry ether (30 mL) at 0 °C. This was allowed to warm up to RT and after 40 h work
up as above afforded the title compound as a 87:13 mixture of two diastereomers (4.6 g,
85%) as colourless needles, mp 119.5–120.5 °C. Recrystallisation from ethyl acetate–ether
gave needles, mp 121–122 °C, of the pure major diastereomer trans-20 suitable for X-Ray
determination (Found: C, 61.25; H, 7.02% C13H18O3S requires C, 61.39; H, 7.13%). HRMS
(EI) m/z calcd for C13H19O3S: 255.1055, found: 255.1062 [M + H]. νmax/cm–1 1455, 1305;
major diastereomer trans-20 1H NMR (300 MHz): 7.42 (5 H, m, Ph), 5.10 (1 H, s, PhCH),
4.71 (1 H, d of d, J 11, 8, CH2O), 3.84 (1 H, t, J 11, CH2O), 3.35 (1 H, m, CHS), 1.95–1.75
(2 H, m, CHCH2CH), 1.47 (1 H, m, CHMe2), 1.00 (6 H, d, J 7, CHMe2). 13C NMR
(75 MHz): 130.4 (Ph-C4), 129.5 (Ph-C1), 128.9 (Ph, 2CH), 127.6 (Ph, 2CH), 94.2 (CHO),
70.8 (CH2O), 56.3 (CHS), 34.8 (CH2), 26.2 (CH), 22.6, 22.4 (Me); minor diastereomer cis-
20 1H NMR (300 MHz): 7.42 (5 H, m, Ph), 5.24 (1 H, s, PhCH), 4.49 (1 H, half AB pattern
of d, J 9, 6, CH2O), 4.32 (1 H, half AB pattern of d, J 9, 3, CH2O), 3.35 (1 H, m, CHS),
1.95–1.75 (2 H, m, CHCH2CH), 1.47 (1 H, m, CHMe2), 1.00 (6 H, d, J 7, CHMe2). 13
C
NMR (75 MHz): 130.4 (Ph-C4), 129.5 (Ph-C1), 128.9 (Ph, 2CH), 127.5 (Ph, 2CH), 93.9
(CHO), 70.4 (CH2O), 55.8 (CHS), 36.7 (CH2), 26.2 (CH), 22.7, 22.1 (Me). m/z (CI) 255
(M + H+, 100%), 107 (9), 83 (4).
12. Pyrolysis of 4-(R)-isobutyl-2-(RS)-phenyl-1,3-oxathiolane S,S-dioxide 20
FVP of the title compound (53 mg, 700 °C, 8.0 × 10–3 Torr) gave a liquid in the cold
1
trap which consisted of benzaldehyde (60%) and 4-methylpent-1-ene (78%) by H and
13C NMR and GCMS. PhCHO 1H NMR (300 MHz): 10.03 (1 H, s), 7.92–7.85 (2 H, m),
7.68–7.50 (3 H, m); 13C NMR (75 MHz): 192.9 (CO), 136.9 (C), 135.0 (CH), 130.2, 129.5
(2CH); i-BuCH CH2 1H NMR (300 MHz): 5.88–5.68 (1 H, m), 5.06–4.95 (2 H, m), 1.93
=
(2 H, t, J 7), 1.62 (1 H, septet, J 7), 0.88 (6 H, d, J 7); 13C NMR (75 MHz): 138.4 (CH), 115.8,
43.8 (CH2), 28.5 (CH), 22.7 (2CH3).
13. X-Ray structure determination
A colourless tablet (0.40 × 0.30 × 0.15 mm) of trans-20 suitable for X-ray diffraction
was obtained by recrystallisation from diethyl ether–ethyl acetate. The following data
were obtained: C13H18SO3, M = 254.34. Triclinic space group P1 (No. 1), a = 5.952(2),
b = 10.920(3), c = 5.580(2) Å, α = 100.49(3), β = 108.52(3), γ = 93.05(3)°,
V =335.7(2) Å3, Z = 1, Dc = 1.258 g/mL, R = 0.029, Rw = 0.023 for 1247 observed
reflections with I > 3σ(I) and 152 parameters. Data were recorded at 293 K using MoKα
radiation and the structure was solved by direct methods and refined using full-matrix least
squares analysis.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
[1] Aitken RA, Thomas AW. Heterocyclic acyl and formyl anion equivalents. Adv Heterocycl
Chem. 2001;79:89–114.
[2] Isslieb K, Hannig H-J. 1,3-Thiaphosphorinane. Z Anorg Allgem Chem. 1973;402:189–192.
[3] Aitken RA, Henderson S, Slawin AMZ. Structure and thermal reactivity of some 2-substituted
1,3-oxathiolane S-oxides. J Sulfur Chem. 2018;39:422–434.

18
R. A. AITKEN ET AL.
[4] Izumiya N, Nagamatsu A. Walden Inversion of amino acids. VI. The synthesis of D-Surinamine
(N-Methyl-D-tyrosine). Bull Chem Soc Jpn. 1952;25:265–267.
[5] Levene PA, Mori T, Mikeska LA. On Walden inversion: X. On the oxidation of 2-thiolcarboxylic
acids to the corresponding sulfonic acids and on the Walden inversion in the series of
2-hydroxycarboxylic acids. J Biol Chem. 1927;75:337–365.
[6] Naksomboon K, Valderas C, Gómez-Martínez M, et al. S,O-Ligand-promoted palladium-
catalyzed C–H functionalization reactions of nondirected arenes. ACS Catal. 2017;7:
5342–6346.
[7] Umezu S, Shindo M. α-Substituent effect on olefination of ester carbonyl groups with ynolates.
Tetrahedron Lett. 2013;54:6871–6873.
[8] Evans DA, Campos KR, Tedrow JS, et al. Application of chiral mixed phosphorus/sulfur ligands
to palladium-catalyzed allylic substitutions. J Am Chem Soc. 2000;122:7905–7920.
[9] Kurth MJ, Tahir SH, Olmtead MM. A thioxanone-based chiral template: asymmetric induction
in the [2,3]-sigmatropic rearrangement of sulfur ylides. Enantioselective preparation of Cα-
chiral pent-4-enoic acids. J Org Chem. 1990;55:2286–2288.
[10] Gokel GW, Gerdes HM, Miles DE, et al. Sulfur heterocycles 1. Use of 4,4-dimethyl-
1,3-oxathiolane 3,3-dioxide as a carbonyl anion equivalent. Tetrahedron Lett. 1979;20:
3375–3378.
[11] Hojo M, Ishibashi N, Hosomi A. Versatile reactivities of carbonyl ylids toward unactivated
alkenes and heterodipolarophiles, and their synthetic use. Synlett. 1996: 234–236.
[12] Mloston G, Gendek T, Heimgartner H. Synthese von Trifluoromethyl-substituierten Schwefel-
Heterocyclen unter Verwendung von 3,3,3-Trifluorobrenztraubensäure-Derivaten. Helv Chim
Acta. 1996;79:1537–1548.
[13] Mloston G, Huisgen R, Polborn K. Cycloadditions of adamantanethione S-methylide to
heteromultiple bonds. Tetrahedron. 1999;55:11475–11494.
[14] Aitken RA, Hill L. 1,3-Dioxoles and 1,3-oxathioles. Compr Heterocycl Chem II. 1996;3:
525–567.
[15] Aitken RA, Power LA. 1,3-Dioxoles and 1,3-oxathioles. Compr Heterocycl Chem III.
2008;4:841–891.
[16] Aitken RA, Power LA. Recent advances in the chemistry of 1,3-dioxoles and 1,3-oxathioles: an
update. Adv Heterocycl Chem. 2013;108:163–193.
[17] Pasto DJ, Klein FM, Doyle TW. Analysis of the nuclear magnetic resonance spectra of 2-
substituted 1,3-oxathiolanes. determination of the conformation of the oxathiolane ring system
and the conformational free energy values for the 2-alkyl substituents. J Am Chem Soc.
1967;89:4368–4374.
[18] Wilson Jr GE, Huang MG, Bovey FA. Nuclear magnetic resonance studies on the conformations
of 2-substituted 1,3-oxathiolanes. J Am Chem Soc. 1970;92:5907–5911.
[19] Pihlaja K, Nurmi T, Pasanen P. Conformational analysis. Part XVII. A simple application
of the Karplus equation to study the preferred conformations of the ethyl group in some
alkylsubstituted 4-ethyl-1,3-oxathiolanes. Acta Chem Scand B. 1977;31:895–898.
[20] Keskinen R, Nikkilä A, Pihlaja K, et al. Properties and reactions of 1,3-oxathiolanes. Part IV.
conformational analysis of 2-alkyl-4-methyl- and 2-alkyl-2,4-dimethyl-1,3-oxathiolans with
the aid of 1H nuclear magnetic resonance spectroscopy and chemical equilibration. J Chem
Soc Perkin Trans 2. 1974: 466–472.
[21] Teodori E, Melani F, Gualtieri F. 13C NMR spectra of 1,3-oxathiolane, 1,3-oxathiolane 3- oxide
and 1,3-oxathiolane 3,3-dioxide derivatives. J Heterocycl Chem. 1986;23:1487–1490.
[22] Pihlaja K, Sinkkonen J, Stájer G. 3-Oxo-1,3-oxathiolanes - synthesis and stereochemistry. Magn
Reson Chem. 2008;46:244–249.
[23] Skelton BW, Stick RV, Tilbrook DMG, et al. Investigations into the chemistry of some 1,6-
epithio and 1,6-episeleno α-D-glucopyranoses. Aust J Chem. 2000;53:389–397.
[24] Budesinsky M, Polakova J, Hamernikova M, et al. 1,6-Anhydro-1-thio-α-D-glucopyranose
(Thiolevoglucosan) and the corresponding sulfoxides and sulfone. Collect Czech Chem Com-
mun. 2006;71:311–336.

JOURNAL OF SULFUR CHEMISTRY
19
[25] Sivapriya K, Hariharaputran S, Suhas VL, et al. Conformationally locked thiosugars as potent
α-mannosidase inhibitors: synthesis, biochemical and docking studies. Bioorg Med Chem.
2007;15:5659–5665.
[26] Block E, Aslam M, Iyer R, et al. α-Haloalkanesulfonyl bromides in organic synthesis 3. α-
Alkylidene ketones and 1,3-oxathiole 3,3-dioxides from trimethylsilyl enol ethers. J Org Chem.
1984;49:3664–3666.
[27] Block E, Aslam M, Eswarakrishnan V, et al. α-Haloalkanesulfonyl bromides in organic syn-
thesis 5. Versatile reagents for the synthesis of conjugated polyenes, enones, and 1,3-oxathiol
1,1-dioxides. J Am Chem Soc. 1986;108:4568–4580.
[28] Friedrich M, Meichle W, Bernhard H, et al. Sulfogriseofulvin derivatives. synthesis by
[4 + 2] cycloaddition, structure, properties, crystal structure analysis, and antifungal activity
of spiro[1,3-benzoxathiole-2,1’-cyclohex-2’-en]-4’-one 3,3-dioxides. Arch Pharm (Weinheim
Ger). 1996;329:361–370.
[29] Aitken RA, Gosney I, Cadogan JIG. Extrusion of SO2 from heterocyclic compounds, part 2:
five-membered rings. Prog Heterocycl Chem. 1993;5:1–33.
[30] Aitken RA, Horsburgh CER. Flash vacuum pyrolysis of o-phenylene sulfite: formation and
purification of cyclopentadienone dimer. In: Afonso CAM, Candeias NR, Simao DP, Trinidade
AF, Coelho JAS, Tan B, Franzén R, editor. Comprehensive organic chemistry experiments for
the laboratory classroom. Cambridge: RSC; 2017. p. 690–693.
[31] Fischer E. Zur Kenntnis der Waldenschen Umkehrung. Ber Dtsch Chem Ges.1907;40:489–508.
[32] Watabe K, Chang S-C, Gil-Av E, et al. The determination of small amounts of enantiomeric
impurities in α-halo carboxylic acids. Synthesis (Mass). 1987: 225–228.
[33] Fischer E, Scheibler H. Zur Kenntnis der Waldenschen Umkehrung II. Ber Dtsch Chem Ges.
1908;41:2891–2902.
[34] Schreiber H, Wheeler AS. Zur Kenntnis der Waldenschen Umkehrung VII. Optischaktiv
Leucinsäure (α-Oxy-isocapronsäure) und ihre Verwandlung in α-Brom-isocapronsäure. Ber
Dtsch Chem Ges. 1911;44:2684–2690.
[35] Fischer E, Carl H. Zerlegung der α-Brom-isocapronsäure und der α-Brom-hydrozimtsäure in
die optisch-activen Componenten. Ber Dtsch Chem Ges. 1906;39:3996–4003.
[36] Abderhalden E, Zeisset W. Über die konfigurativen Beziehungen der aus den optischen Iso-
meren des Isoleucins und des Alloisoleucins gewinnbaren α-Bromsäuren zu den aus diesen bei
der Aminierung hervorgehenden Aminosüauren. Ein Beitrag zum Problem der Waldenschen
Umkehrung. Z Physiol Chem. 1931;200:179–190.
[37] Millican RJ, Angelopoulos M, Bose A, et al. Uncatalyzed and general acid catalyzed decom-
position of alkyl xanthates and monothiocarbonates in aqueous solutions. J Am Chem Soc.
1983;105:3622–3630.
[38] Levene PA, Mikeska LA. On Walden inversion: III. Oxidation of optically active thiosuccinic
acid and thiosuccinimide to the corresponding sulfo acids. J Biol Chem. 1924;60:685–692.