The synthesis of water soluble decalin-based thiols and S-nitrosothiols - Model systems for studying the reactions of nitric oxide, with protein thiols

Article abstract of DOI:10.1039/b503758a

The syntheses of three decalin-based tert-thiols displaying varying degrees of solubility in aqueous milieu are described. The 5-nitroso derivatives of these compounds have also been prepared and the structures of two of these determined by single crystal

Full text of DOI:10.1039/b503758a

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A R T I C L E
The synthesis of water soluble decalin-based thiols and
S-nitrosothiols—model systems for studying the reactions of nitric
oxide with protein thiols
Alan C. Spivey,*a Jacqueline Colley,b Lindsey Sprigens,b Susan M. Hancock,b
D. Stuart Cameron,b Kordi I. Chigboh,a Gemma Veitch,a Christopher S. Framptonc and
Harry Adamsb
a Department of Chemistry, Imperial College, South Kensington campus, London, UK SW7 2AZ
b Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, UK S3 7HF
c Pharmorphix Ltd., 250 Cambridge Science Park, Milton Road, Cambridge, UK CB4 0WE
Received 14th March 2005, Accepted 5th April 2005
First published as an Advance Article on the web 19th April 2005
The syntheses of three decalin-based tert-thiols displaying varying degrees of solubility in aqueous milieu are
described. The S-nitroso derivatives of these compounds have also been prepared and the structures of two of these
determined by single crystal X-ray diffraction. These compounds have been designed for studying the interaction of
nitric oxide (NO) with thiols under physiological conditions.
shielding of the sulfur centre. This is apparent from the few
Introduction
examples of S-nitrosothiols (1–7)17–24 and sulfenic acids (8–
Nitric oxide (NO) is an important redox messenger in many
cellular signal transduction pathways and has been shown to
11)25–29 in the Cambridge crystallographic database (CCDC),
most of which contain these functional groups in highly hindered
be intimately involved in a host of regulatory roles including
environments (Fig. 1).
control of vasodilation, platelet aggregation, neurotransmission
We therefore sought to design a thiol located within a
and in the immune system.1,2 Signalling is achieved primarily
by three types of post-translational protein modifications:
molecular scaffold that would provide an appropriately hindered
environment to allow formation of stable S-nitrosothiol and
sulfenic acid derivatives that would be soluble in physiologically
compatible aqueous milieu and that would also be amenable to
the introduction of pendent peptidic chains, to allow study of
the reactions of the derivatives with side chain functional groups.
To this end we were particularly interested in the synthesis by
Yoshimura et al. of trans-decalin sulfenic acid 12, which was
nitrosylation of metal centres (e.g. Fe in the heam unit of
guanylate cyclase),3 nitrosation/nitration of aromatic rings of
aromatic amino acids (e.g. Tyr-385 in prostaglandin-H2 (PGH2)
synthase)4 and nitrosation/oxidation of the sulfur atom of
cysteine residues (e.g. Cys-34 in human serum albumin (HSA)).5
Interactions with cysteine residues are particularly interesting
because a wide range of oxidised products, including S-
nitrosothiol (RSNO), disulfide (RSSR’), sulfenic acid (RSOH),
sulfinic acid (RSO2H) and sulfonic acid (RSO3H) derivatives,
reported to be a stable crystalline solid (although no X-ray
crystal structure was obtained).30,31 We envisaged that the rigid
trans-decalin ring system could provide a useful framework
are formed following nitrosative stress.6 These modifications can
for incorporation of both water solubilising substituents and
dynamically mediate a diverse array of perturbations of protein
peptide chains in a spatially well-defined manner relative to
structure and function.7 However, despite intensive research
the hindered thiol group. Consequently, we identified molecules
efforts, the molecular mechanisms by which these modifications
based on functionalised decalin I as our target model thiol.
are effected remain contentious8 and a concensus has yet to
Based on the work of Kelly et al.32 we envisaged employing
emerge as to the relative importance of various putative NO-
derived oxidising/nitrosating species in vivo (and their mode of
oxyacetate groups to impart aqueous solubility, although it was
unclear at the outset how many of these groups would need to
formation and transport).9–11 A significant factor confounding
be incorporated (Fig. 2).
progress in this area is that the primary derivatives, RSNOs12
Our initial approach to the synthesis of this type of molecule
is shown in Scheme 1. Epoxy bis-alkene 13 was prepared
and RSOHs,13 are both highly susceptible towards further
transformations (e.g. to give disulfides) and do not have strong
from naphthalene by Birch reduction (Na–NH3; 74%) then
spectroscopic fingerprints, making them difficult to identify
epoxidation (CH3CO3H; 87%).33,34 Ring-opening of this epoxide
and monitor in proteins.14–16 We have initiated a program to
with benzylthiol in ethylene glycol35 afforded thioether bis-
develop small molecule model systems on which to study the
formation and reactivity of these important derivatives under
physiologically compatible conditions in order to gain insight
into the factors that control specificity and reactivity in partic-
ular cellular microenvironments. Here we describe the synthesis
of a class of aqueous soluble tert-decalin thiols for which the
alkene 14a (78%). The plan was to chemo- and stereoselectively
oxidise this thioether bis-alkene to the corresponding bis-
epoxide using the axial tert-alcohol at C10 to direct epoxidation
onto the a-face.36 However, in the event we were unable to
delineate conditions to achieve this bis-epoxidation without
prior/concomitant oxidation of the benzyl thioether group.
S-NO derivatives display sufficient kinetic stability to allow
Oxidation of the thioether bis-alkene 14a with VO(acac)2-tert-
isolation and full characterisation and for which the scaffold
butyl hydroperoxide (TBHP, 2 eq.)37 in CH2Cl2 at various
offers opportunities for introducing proximal functionality (e.g.
pendent peptides) to study further transformations.
1
temperatures resulted in complex reaction mixtures that by H
NMR did not look promising for further investigation. The use
of Mo(CO)6–TBHP (2 eq.)38 in CH2Cl2 at 0 ◦C, or excess DMD39
◦
in acetone–benzene at 0 C, or m-CPBA (1.5 eq.)40 in CH2Cl2
Results and discussion
at rt gave mixtures of sulfoxide bis-alkene 15a and sulfone bis-
alkene 15b. Reaction with m-CPBA (3 eq.) in CH2Cl2 at rt gave
the sulfone mono-epoxide 16 as the major product (89%) and
Although S-nitrosothiols and sulfenic acids are generally very
labile, kinetic stability can be imparted to both species by steric
1 9 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
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
©

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Fig. 1 Structures of all reported S-nitrosothiol and sulfenic acid containing compounds characterised by single crystal X-ray diffraction.
Fig. 2 Yoshimura’s trans-decalin-9-sulfenic acid 12 and proposed target thiol I.
use of excess m-CPBA in CH2Cl2 at rt gave sulfone bis-epoxide
benzyl thiol in the original ring-opening reaction the resulting
thioether would be less susceptible to oxidation at sulfur, we
prepared bis-alkenyl thioether 14b by ring-opening of epoxide 13
with tert-butylthiol in ethylene glycol (85%). Although treatment
of bis-alkenyl thioether 14b with m-CPBA (2 eq.) or MMPP
(2 eq.)41 in CH2Cl2 at rt again resulted in preferential oxidation
at sulfur, oxidation with VO(acac)2–trityl hydroperoxide (THP,
4 eq.) in CH2Cl2 at rt gave thioether mono-epoxide 18 cleanly
(80%). However, if the temperature was raised to 80 ◦C (in
benzene) to try to induce bis-epoxide formation the only isolated
17 as the major product (56%). The sulfone bis-epoxide 17 could
also be obtained by oxidation of sulfone bis-alkene 15b with
VO(acac)2–TBHP (2 eq.) in CH2Cl2 at rt (79%, Scheme 1).
The sulfone bis-epoxide 17 did not prove to be a productive
intermediate for preparation of the target structures as we
were unable to convert it into the corresponding sulfone triol
using hydride reducing agents (e.g. LiAlH4 or DIBAL-H) or the
corresponding thiol triol using Birch reduction (Li/NH3–THF).
Reasoning that if we employed a more bulky thiol in place of
Scheme 1 Reagents and conditions: a) BnSH, NaOH, HOCH2CH2OH, 100 ◦C [78%]; b) DMD, acetone–benzene [15a 67% + 15b 33%]; c) m-CPBA
(3 eq.), CH2Cl2 [16 89% from 15a]; d) m-CPBA (5 eq.), CH2Cl2 [17 56% from 15a]; e) VO(acac)2, TBHP, CH2Cl2 [17 79% from 15b; 19 77%]; f) tBuSH,
NaOH, HOCH2CH2OH, 100 ◦C [14b 85%; 21 80%]; g) VO(acac)2, THP, CH2Cl2 [18 80%]; h) VO(acac)2, THP, benzene [19 69%]; i) PtO2, H2, Et2O
[90%]; j) PtO2, H2, EtOAc [83%]; k) NaH, ClCH2CO2H, THF, 70 ◦C [65%].
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
1 9 4 3

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Fig. 3 ORTEP diagram of sulfate ester 19 and a proposed pathway for its formation.
product was sulfate ester 19 (69%). This compound was also
the exclusive product (77%) when employing VO(acac)2–TBHP
(4 eq.) in CH2Cl2 at rt. The identity of the unexpected sulfate
ester 19 was secured by single crystal X-ray diffraction; its
structure and a possible pathway for the formation of this
product are shown in Fig. 3.
by hydrogenolysis. This chemistry proved very efficient: thus,
ring-opening of epoxide 20 with benzylthiol in ethylene glycol
gave decalin benzyl thioether 23 (72%), which was converted
to oxyacetate 24 using chloroacetic acid–sodium hydride (52%)
and the benzyl group removed under Birch reductive conditions
to give the desired thiol 25 (95%, Scheme 2).
It appears that following initial a-face alkene epoxidation
to give thioether mono-epoxide 18 further oxidation occurs at
sulfur rather that at the other alkene. The resulting sulfoxide
(or sulfone) then undergoes a rearrangement in which the
C10 tert-alcohol displaces the sulfoxide (or sulfone) to form
a C9–C10 tetrasubstituted a-epoxide and the sulfoxide (sulfone)
oxygen ring-opens the C2–C3 disubstituted a-epoxide at C3
to give a sulfenate (or sulfinate) intermediate, which is then
further oxidised to the sulfate ester 20. That ring-opening of the
epoxide occurs to give the di-equatorial product suggests that
the intermeduate epoxy sulfoxide (sulfone) occupies a non-chair
conformation.
Pleasingly, treatment of thiol 25 with a slight excess of tert-
butyl nitrite in CH2Cl2 at rt resulted in a clean and rapid
conversion into the S-nitroso derivative 26, which crystallised
as small pale green plates and proved suitable for a single crystal
X-ray structure determination (see later, Fig. 4). Although
this compound exhibited good stability both in solution and
in the solid-state, as expected from the work of Yoshimura
et al.,30,31 the aqueous solubility of parent thiol 25 was not
as high as we had hoped (see Table 1). Consequently, we
decided to prepare a closely related analogue containing two
oxyacetate solubilising groups; compound 33. The synthesis of
this derivative was achieved by allylation of alcohol 23 using
nBuLi–allyl bromide in THF at 50 ◦C to give thioether allyl ether
27 (75%). Selective oxidation of the terminal double bond in the
presence of the benzyl ether was achieved using an epoxidation
protocol employed by Anderson et al.44 for a similar purpose,
involving conversion to the bromohydrin using NBS and ring-
closure to the thioether terminal epoxide 28 with K2CO3 in
MeOH (55% overall). Subsequent BF3·Et2O promoted ring-
opening with water gave the thioether diol 29. Conversion of
this diol directly to the corresponding thioether bis-oxyacetate
32 was achieved on one occasion using chloroacetic acid–sodium
hydride (79%); however, this method proved capricious on a
larger scale and so a two step method was developed involving
reaction with tert-butyl bromoacetate under phase transfer
conditions (50% aqueous NaOH, CH2Cl2, nBu4NBr, 29%),45
then saponification of the resulting bis-tert-butyloxyacetate 31
(LiOH, THF–MeOH)46 to give thioether bis-oxyacetate 32
(100%). As before, the benzyl group was cleanly removed under
Birch reductive conditions to give the desired thiol 33 (100%). A
related thiol, compound 36, having a methyl ether in place of the
primary oxyacetate group (cf. thiol 33) was also prepared using
an analogous sequence following ring-opening of (unisolated)
epoxide 28 by methanol (27 → 30 → 34 → 35 → 36, Scheme 2).
As with thiol 25, treatment of thiols 33 and 36 with an
excess of tert-butyl nitrite in CH2Cl2 at rt resulted in a
rapid conversion to the corresponding S-nitroso derivatives 37
Several attempts were made to effect conversion of the isolated
thioether mono-epoxide 18 to the desired diepoxide using m-
R
CPBA, MMPP and oxoneꢀ but to no avail; complex mixtures
of uncharacterised products were formed. Consequently, we
decided to direct our effort towards the preparation of a less
highly functionalised target structure lacking functionality on
the decalin rings. To access this framework, the two alkenes
in thioether bis-alkene 14b were hydrogenated (PtO2–H2) to
give decalin thioether 21 (83%). This compound could also
be obtained by hydrogenation of epoxy bis-alkene 13 (PtO2–
H2), to give volatile epoxide 20 (90%), then ring opening with
tert-butyl thiol (80%). The tert-alcohol function in thioether
21 was smoothly converted to the oxyacetate function (→ 22)
by treatment with chloroacetic acid and excess sodium hydride
(65%) but, unfortunately, deprotection of the tert-butyl group
to give the free thiol proved problematic. The use of mercuric
acetate–TFA–anisole according to the method of Nishimura
and coworkers42 appeared to be successful as the crude 1H
NMR showed complete disappearance of the tert-butyl signal
at d 1.40 and no signals in the alkene region, but we were
unable to isolate any of the desired thiol following work-up.
Notwithstanding the possibility to access the sulfenic acid by a
thermolysis reaction on the sulfoxide derivative43 of thioether
22, we decided to revert to the use of a benzyl protected
thiol so as to allow final deprotection to give the free thiol
1 9 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2

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Scheme 2 Reagents and conditions: a) BnSH, NaOH, HOCH2CH2OH, 100 ◦C [72%]; b) NaH, ClCH2CO2H, THF, 70 ◦C [52%]; c) Na, NH3–THF,
◦
t
n
n
=
−33 C [25 95%; 33 100%; 36 50%]; d) BuONO, CH2Cl2 [26 57%; 37 56% from 33; 38 69% from 36]; e) BuLi, Bu4NI, CH2 CHCH2Br, THF [75%];
t
f) (i) NBS, THF–H2O, (ii) K2CO3, MeOH [28 55%; 30 83%]; g) BF3·Et2O, THF–H2O [29 92%]; h) NaOH, nBu4NBr, BrCH2CO2 Bu, CH2Cl2–H2O
[31 29% from 29; 34 64% from 30]; i) LiOH, MeOH–THF [32 100%; 35 100%].
Fig. 4 ORTEP diagrams of S-nitrosothiols 26 and 38.
and 38, respectively, both of which were crystalline. Crystals
suitable for single crystal X-ray structure determination could
be obtained for S-nitrosothiol 38 but not S-nitrosothiol 37
(Fig. 4).
These conformational preferences are in accord with hybrid
DFT calculations by Houk et al.21 who showed that for primary
and secondary S-nitrosothiols the s-cis conformation is electron-
ically preferred due to an nS → r*NO anomeric interaction (cf. in
alkyl esters)47, whereas competing steric effects cause tertiary S-
nitrosothiols to prefer an s-trans conformation. S-Nitrosothiols
display significant barriers to rotation about the S–N bond (46–
50 kJ mol−1)21 as the result of strong nS → p*NO delocalisation,
which imparts p-bond character to the S–N bond. The overall
weakness of the S–N bond is believed to result from a strong
nO → r*SN anomeric effect.48
The structures of the S-nitrosothiol groups in compounds 26
and 38 are closely similar: both occupy an s-trans conformation
about the S–N bond, which is aligned parallel to the C8-C9 bond
(the decalin ring fusion). Comparison of these structures with
those of the five previous aliphatic S-nitrosothiols in the CCDC
(structures 1–5, Fig. 1) reveals that this anti-conformation is
also found in all four previously reported tert-thiol derived S-
nitrosothiols (structures 1–4), whereas an s-cis-conformation
is adopted by the primary thiol derived S-nitrosocaptopril 5
(Table 2).
As expected,49 the solubility of thiol bis-oxyacetate 33 in
aqueous solution was significantly higher than either of the thiol
mono-oxyacetates 25 or 36, being soluble in phosphate buffered
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
1 9 4 5

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˚
Table 1 Measured solubility of thiols 25, 33 and 36
before use and stored over activated 4 A molecular sieves,
unless otherwise indicated. Anhydrous CH2Cl2 was obtained
by refluxing over CaH2. Anhydrous THF and Et2O were
obtained by distillation, immediately before use, from sodium–
benzophenone ketyl under an inert atmosphere of nitrogen.
Anhydrous DMF was obtained by distillation from CaH2 under
a reduced pressure. Ethylene glycol was distilled immediately
prior to use. Petrol refers to the fraction of light petroleum
boiling between 40–60 ◦C. NMR J values are given in Hz.
High Resolution Mass Spectrometry (HRMS) measurements
are valid to 5 ppm.
Soluble?
Buffer
PBSa
KRBb
H2O
Concentration/mM
25
33
36
4
20
4
20
4
yes
no
partially
no
yes
yes
yes
yes
yesc
yes
yes
yes
no
yes
no
yes
no
20
no
a Buffer was made up using (× 10−2 mol dm−3): phosphate buffer
1.0, NaCl 1.37 and KCl 0.27 in water. b Buffer was made up using
(× 10−3 mol dm−3): NaCl 118.9, CaCl2 1.2, NaHCO3 20.4, K2HPO4 2.4,
KH2PO4 0.6, MgCl2 1.2 and glucose 10 in water adjusted to pH 7.4 by
bubbling a gaseous mixture of 95% O2 and 5% CO2 through the solution
for 5 min. c Brief sonication required to achieve complete dissolution.
9b-Benzylthio-10a-hydroxy-1,4,5,8,9,10-hexahydronaphtha-
lene 14a. To a suspension of epoxy bis-alkene 13 (100 mg,
0.676 mmol) and powdered NaOH (270 mg, 6.76 mmol) in
ethylene glycol (10 cm3) was added benzyl thiol (790 cm3,
6.76 mmol, CAUTION stench) and the resulting mixture heated
at 100 ◦C for 2 h. An aqueous solution of saturated Na2SO4
(5 cm3) was then added dropwise and the phases separated. The
aqueous phase was extracted further with EtOAc (2 × 15 cm3),
dried (MgSO4) and concentrated in vacuo to give a cloudy oil.
Purification by flash chromatography (petrol–EtOAc, 9 : 1) gave
thioether 14a as a clear oil (143 mg, 78%). Rf (petrol–EtOAc, 4 :
1) 0.40; mmax/cm−1 (CHCl3) 3483 (OH), 3026, 2897, 1653, 1494,
saline (PBS), Krebs–Ringer bicarbonate buffer (KBS) and water
in concentrations up to 20 mM (Table 1).
Conclusions
The preparation of tert-thiol 33 has been achieved in nine steps
and ∼5% overall yield from naphthalene. This compound has
been shown to have significant solubility in water and buffered
aqueous solutions at pH 7.4 and to form a relatively stable S-
nitroso derivative 37, analogues of which (i.e. S-nitrosothiols
26 and 38) have been characterised by X-ray crystallography.
It is anticipated that these features will make this compound a
useful model for studying the S-nitrosation and related oxidation
processes under aqueous conditions. Experiments to prepare
and characterise the sulfenic acid derivative of this thiol and
to probe the reactivity of this thiol towards NO and putative
NO-donors under physiologically compatible conditions are
currently underway and will be reported in due course.
ꢀ
1241, 869; dH (250 MHz, CDCl3) 2.08–2.20 (2H, CH2 s), 2.10
(1H, bs, OH), 2.38–2.42 (4H, 2 × CH2), 2.47–2.61 (2H, CH2),
3.75 (2H, s, CH2Ph), 5.67 (4H, m, 2 × CH2), 7.18–7.35 (5H,
Ph); dC (63 MHz, CDCl3) 33.5 (2 × t), 34.8 (2 × t), 36.9 (t), 49.7
(s), 71.0 (s), 124.4 (2 × d), 124.6 (2 × d), 126.9 (s), 128.4 (2 ×
d), 129.1 (2 × d), 137.9 (s); m/z (EI+) 272 (M+, 19%), 181 (100),
148 (27), 94 (80); found: m/z (EI+) M+ 272.1227, C17H20OS
requires 272.1235 (D = −2.9 ppm).
9b-Benzylsulfinyl-10a-hydroxy-1,4,5,8,9,10-hexahydronaphtha-
lene 15a and 9b-benzylsulfonyl-10a-hydroxy-1,4,5,8,9,10-hexa-
hydronaphthalene 15b. To a solution of thioether bis-alkene
14a (100 mg, 0.37 mmol) in benzene (5 cm3) at 0 ◦C was added
a solution of dimethyldioxirane51 in acetone (∼0.1 M, 7.4 cm3,
∼0.74 mmol) dropwise. After 30 min the volatiles were removed
in vacuo and the residue purified by flash chromatography
(EtOAc–petrol, 2 : 3 → 4 : 1) to give:
Experimental
General directions
All reactions were performed under anhydrous conditions and
an inert atmosphere of nitrogen in the oven-dried glassware.
Yields refer to chromatographically and spectroscopically (1H
NMR) homogenous materials, unless otherwise indicated.
Reagents were used as obtained from commercial sources or
purified according to known procedures.50 Flash chromatogra-
phy was carried out using Merck Kiesegel 60 F254 (230–400 mesh)
silica gel. Only distilled solvents were used as eluents. Thin layer
chromatography (TLC) was performed on Merck DC-Alufolien
or glass plates precoated with silica gel 60 F254 which were
Sulfoxide 15a as a white crystalline solid (71 mg, 67%). Mp 45–
51 ◦C (EtOAc); Rf (EtOAc–petrol, 2 : 1) 0.15; mmax/cm−1 (CHCl3)
3014, 1496, 1454; dH (250 MHz, CDCl3) 2.20–2.35 (2H, CH2),
2.40–2.45 (2H, CH2), 2.50–2.65 (5H, 2 × CH2 + OH), 2.77–2.9
(2H, CH2), 3.94 and 3.77 (2H, ABq JAB 11.9, CH2Ph), 5.60–5.75
=
(4H, 4 × CH), 7.27–7.40 (5H, Ph); dc (63 MHz, CDCl3) 29.4
(t), 30.0 (t), 37.2 (t), 37.3 (t), 54.8 (s), 63.0 (s), 69.0 (s), 124.2
(d), 125.2 (d), 125.6 (d), 125.7 (d), 128.2 (s), 128.8 (2 × s), 130.5
(2 × s), 131.7 (s); m/z (CI+) 289 (MH+, 34%), 263 (9), 231 (13),
158 (27); found: m/z (CI+) MH+ 289.1268, C17H21O2S requires
289.1262 (D = +2.1 ppm).
visualised either by quenching of ultraviolet fluorescence (kmax
=
254 nm) or by charring with 5% w/v phosphomolybdic acid in
95% EtOH, 10% w/v ammonium molybdate in 1M H2SO4, or
10% KMnO4 in 1M H2SO4. Observed retention factors (Rf) are
quoted to the nearest 0.05. All reaction solvents were distilled
Sulfone 15b as a white solid (36 mg, 33%). Mp 176–178 ◦C
(EtOAc); Rf (EtOAc–petrol, 2 : 1) 0.60; mmax/cm−1 (CHCl3) 3019,
ꢀ
1494, 1434; dH (250 MHz, CDCl3) 2.20–2.55 (5H, CH2 s + OH),
2.72–2.81 (2H, CH2), 2.84–2.87 (2H, CH2), 4.22 (2H, s, CH2Ph),
Table 2 Comparison of X-ray crystal data of S-nitrosothiols 26 and 38 and previously reported S-nitrosothiols
Bond Lengths
◦
˚
˚
˚
=
N O/A
=
=
Structure
Conformation C–S–N
O
Torsion Angle C–S–N O/
C–S/A
S–N/A
26 (tertiary)
38 (tertiary)
122–24 (tertiary)
217 (tertiary)
322 (tertiary)
420 (tertiary)
521 (primary)
s-trans
179.3
175.0
176.3
178.6
175.7
179.6a
0.68
1.875
1.815
1.841
1.828
1.867
1.841a
1.800
1.744
1.703
1.771
1.755
1.792
1.781a
1.766
1.307
1.231
1.214
1.207
1.177
1.205a
1.206
s-trans
s-trans
s-trans
s-trans
s-trans : s-cis (7 : 3)
s-cis
a Data for the s-trans isomer.
1 9 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2

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=
5.65–5.78 (4H, 4 × CH), 7.25–7.35 (5H, Ph); dc (63 MHz,
(s), 123.9 (2 × d), 124.9 (2 × d); m/z (EI+) 238 (M+, 39%),
t
CDCl3) 32.1 (2 × t), 36.9 (2 × t), 57.3 (t), 67.5 (s), 68.8 (s), 124.0
(2 × d), 125.3 (2 × d), 126.7 (s), 128.4 (2 × s), 128.7 (s), 131.5
(2 × s); m/z (EI+) 304 (M+, 7%), 157 (10), 149 (48), 131 (48);
found: m/z (EI+) M+ 304.1134, C17H20O3S requires 304.1133
(D = +0.3 ppm).
181 (M+ − Bu, 91), 148 (100), 131 (88); found: m/z (EI+) M+
238.1395, C14H22OS requires 238.1391 (D = +1.7 ppm).
9b-tert-Butylthio-(2a,3a)-oxido-10a-hydroxy-1,2,3,4,5,8,9,10-
octahydronaphthalene 18. To a solution of thioether bis-alkene
14b (50 mg, 0.21 mmol) and vanadyl bis(acetylacetonate) (3 mg,
0.011 mmol, 0.05 eq.) in CH2Cl2 (3 cm3) was added trityl
hydroperoxide (230 mg, 0.84 mmol, 4 eq.) and the resulting
mixture stirred at rt for 14 h. A saturated aqueous solution
of Na2S2O5 (5 cm3) was added, the organic phase separated
and the aqueous phase extracted with CHCl3 (3 × 10 cm3).
The combined organic extracts were washed with a saturated
aqueous solution of Na2S2O5 (10 cm3), dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash
chromatography (petrol–EtOAc, 4 : 1 → 2 : 1) to give thioether
mono-epoxide 18 as white needles (45 mg, 80%). Mp 92–95 ◦C
(EtOAc); Rf (petrol–EtOAc, 1 : 1) 0.80; mmax/cm−1 (CH2Cl2)
3594, 3482, 2964, 2907, 1461, 1425, 1366, 1158, 1074, 1020; dH
(250 MHz, CDCl3) 1.41 [9H, s, C(CH3)3], 1.95–2.10 (2H, CH2),
2.13–2.28 (2H, CH2 + OH), 2.30–2.38 (2H, CH2), 2.40–2.60
(2H, CH2), 2.70–2.80 (1H, CH2), 3.39–3.45 (2H, 2 × CHO),
9b-Benzylsulfonyl-(2a,3a)-oxido-10a-hydroxy-1,2,3,4,5,8,9,10-
octahydronaphthalene 16. To a solution of thioether bis-alkene
14a (100 mg, 0.37 mmol) in CH2Cl2 (5 cm3) was added m-CPBA
(420 mg, 1.11 mmol) and the resulting mixture stirred for
15 min. The reaction was then quenched by addition of a
saturated aqueous solution of Na2S2O5 (5 cm3) and the resulting
reaction mixture extracted with CH2Cl2 (3 × 10 cm3). The
organic extracts were dried (MgSO4), concentrated in vacuo and
the residue purified by flash chromatography (EtOAc–petrol, 3 :
7) to give sulfone mono-epoxide 16 as a white solid (106 mg,
89%). Mp 119–125 ◦C (EtOAc); Rf (EtOAc–petrol, 1 : 1)
0.30; mmax/cm−1 (CHCl3) 3372, 2921, 1439, 1260, 1061, 746;
ꢀ
dH (250 MHz, CDCl3) 2.17–2.40 (3H, CH2 s), 2.52–2.65 (3H,
ꢀ
CH2 s), 2.65–2.87 (2H, CH2), 3.40–3.52 (2H, 2 × CHO),
4.21 and 4.31 (2H, ABq JAB 12.5, CH2Ph), 4.45 (1H, s, OH),
=
5.55–5.63 (2H, 2 × CH); dC (63 MHz, CDCl3) 32.9 (2 × q),
=
5.65–5.75 (2H, 2 × CH), 7.36–7.44 (5H, Ar); dc (63 MHz,
33.0 (t), 34.8 (t), 35.1 (t), 36.9 (t), 46.1 (s), 50.5 (s), 51.9 (d),
54.3 (d), 71.3 (s), 123.6 (d), 123.8 (d); m/z (EI+) 254 (M+, 14%),
197 (37), 181 (4), 165 (15); found: m/z (EI+) M+, 254.1338,
C14H22O2S requires 254.1341 (D = −1.2 ppm).
CDCl3) 31.4 (t), 32.2 (t), 33.5 (t), 38.0 (t), 51.9 (d), 55.5 (d), 56.8
(t), 66.6 (s), 70.0 (s), 121.6 (2 × d), 126.3 (2 × d), 128.7 (2 ×
s), 129.1 (s), 131.6 (2 × s); m/z (CI+) 321 MH+, 6%), 231 (7),
165 (69), 147 (40); found: m/z (CI+) MH+ 321.1154, C17H21O4S
requires 321.1161 (D = −2.2 ppm).
2a-Hydroxy-3b-O-tert-butylsulfonyl-(9a,10a)-oxido-1,2,3,4,5,
8,9,10-octahydronaphthalene 19. To a solution of thioether bis-
alkene 14b (100 mg, 0.42 mmol) and vanadyl bis(acetyl-
acetonate) (6 mg, 0.022 mmol, 0.05 eq.) in CH2Cl2 (5 cm3)
was added a solution of TBHP in toluene (550 mm3, 3.05 M,
1.68 mmol, 4 eq.) dropwise and the resulting solution was
stirred at rt for 15 h. The reaction mixture was concentrated
in vacuo and the residue was purified by flash chromatography
(petrol–EtOAc, 3 : 2) to give the sulfonate ester 19 as off-white
needles (98 mg, 77%). Mp 178.5–181 ◦C (EtOAc); Rf (petrol–
EtOAc, 1 : 1) 0.40; mmax/cm−1 (CH2Cl2) 3589, 3488, 2929, 1427,
1321, 1270, 1145; dH (250 MHz, CDCl3) 1.44 [9H, s, C(CH3)3],
2.08–2.35 (4H, 2 × CH2), 2.36–2.73 (4H, 2 × CH2), 3.30 (1H,
9b-Benzylsulfonyl-(2a,3a),(6a,7a)-dioxido-10a-hydroxy-1,2,3,
4,5,6,7,8,9,10-decahydronaphthalene 17. To
a solution of
thioether bis-alkene 14a (100 mg, 0.37 mmol) in CH2Cl2
was added m-CPBA (560 mg, 1.85 mmol) and the resulting
mixture stirred stirred for 2 h. The reaction was then quenched
by addition of a saturated aqueous solution of Na2S2O5
(10 cm3) and the resulting reaction mixture extracted with
CH2Cl2 (3 × 10 cm3). The organic extracts were washed with
a saturated aqueous solution of NaHCO3 (10 cm3), dried
(MgSO4), concentrated in vacuo and the residue purified by
flash chromatography (EtOAc–petrol, 1 : 1 → 2 : 1) to give
sulfone bis-epoxide 17 as a white solid (70 mg, 56%). Mp
◦
184–186 C (EtOAc); Rf (EtOAc–petrol, 1 : 1) 0.10; mmax/cm−1
m, CHOH), 3.91 (1H, s, CHOH), 4.85 (1H, dd, J 9.4 and 4.4,
t
=
CHOSO2Bu ), 5.43–5.49 (2H, 2 × CH); dC (63 MHz, CDCl3)
(nujol) 3398, 1459, 1376, 1120; dH (250 MHz, CDCl3) 2.23–2.34
(4H, 2 × CH2), 2.38–2.53 (4H, 2 × CH2), 3.27 (2H, m, 2 ×
CHO), 3.38 (2H, m, 2 × CHO), 4.24 (1H, s, OH), 4.35 (2H, s,
CH2Ph), 7.38–7.47 (5H, Ph); dc (63 MHz, CDCl3) 31.3 (2 × t),
35.2 (2 × t), 49.9 (2 × d), 54.0 (2 × d), 56.7 (t), 64.9 (s), 71.4
(s), 126.4 (s), 129.0 (2 × s), 129.4 (s), 131.3 (2 × s); m/z (EI+)
336 (M+, 6%), 245 (14), 216 (5), 181 (29); found: m/z (EI+) M+
326.1032, C17H20O5S requires 326.1031 (D = +0.3 ppm).
24.5 (3 × q), 30.7 (t), 31.3 (t), 32.8 (t), 33.3 (t), 59.3 (s), 60.7 (s),
62.0 (d), 67.3 (d), 76.9 (d), 121.9 (d), 122.0 (d); m/z (EI+) 164
(M+ − BuSO3H, 38%), 146 (26), 120 (36), 108 (93).
t
Single crystals of sulfonate ester 19 suitable for X-ray
diffraction were obtained by re-crystallisation (CH2Cl2–hexane),
mounted in inert oil and transferred to the cold gas stream of the
diffractometer. Crystal data: C14H22O5S1, M = 302.38, triclinic,
˚
a = 6.8076(9), b = 9.3008(12), c = 12.2010(18) A, a = 96.400(8),
◦
3
˚
b = 105.284(9), c = 92.286(9) , U = 738.62(17) A , T = 123 K,
9b-tert-Butylthio-10a-hydroxy-1,4,5,8,9,10-hexahydronaphtha-
lene 14b. To a suspension of epoxy bis-alkene 13 (100 mg,
0.68 mmol) and powdered NaOH (270 mg, 6.8 mmol, 10 eq) in
ethylene glycol (10 cm3) was added tert-butyl thiol (380 mm3,
3.4 mmol, 5 eq., CAUTION stench) and the resulting mixture
heated at 100 ◦C for 16 h. Excess tert-butyl thiol was removed in
vacuo and the remaining reaction mixture partitioned between
EtOAc (10 cm3) and H2O (10 cm3). The aqueous phase was
extracted with EtOAc (4 × 10 cm3) and the combined organic
extracts washed with saturated brine (10 cm3), dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography (petrol–EtOAc, 9 : 1) to give thioether bis-
alkene 14b as off-white needles (137 mg, 85%). Mp 56.5–58.5 ◦C
(EtOAc); Rf (petrol–EtOAc, 4 : 1) 0.45; mmax/cm−1 (CH2Cl2)
3578, 3030, 2970, 2902, 1460, 1425, 1366, 1270; dH (250 MHz,
CDCl3) 1.42 [9H, s, C(CH3)3], 1.98–2.11 (2H, CH2), 2.09 (1H,
bs, OH), 2.33–2.48 (2H, CH2), 2.49–2.61 (2H, CH2), 2.62–2.75
l
˜
¯
space group P1, (Ci, no. 2), Z = 2, Mo-Ka radiation (k =
−1
˚
0.71073 A), l(Mo–Ka) = 0.235 mm , 6317 reflections measured,
2987 unique, (Rint = 0.0182). Refinement converged, (D/r, max,
mean = 0.000, 0.000 respectively), with final wR(F2) = 0.1012,
(all data), R1 = 0.0368, S = 1.008 for 2426 reflections with I >
2r(I) and 188 parameters.†
(9a,10a)-Oxido-1,2,3,4,5,6,7,8,9,10-decahydronaphthalene
2052. To a solution of epoxy bis-alkene 13 (5.10 g, 34.4 mmol)
in Et2O (30 cm3) was added PtO2 (Adams’ catalyst, 600 mg,
2.64 mmol, 0.08 eq.) and the resulting suspension stirred
vigorously under an atmosphere of hydrogen for 14 h. The
R
reaction mixture was filtered through a pad of celiteꢀ and the
solvent removed by careful distillation at atmospheric pressure
† CCDC reference numbers 266148, 266149 and 266150. See http://
www.rsc.org/suppdata/ob/b5/b503758a/ for crystallographic data in
CIF or other electronic format.
=
(2H, CH2), 5.63–5.75 (4H, 4 × CH); dC (63 MHz, CDCl3)
33.2 (3 × q), 35.2 (2 × t), 36.6 (2 × t), 45.8 (s), 50.9 (s), 70.8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
1 9 4 7

View Article Online
to leave epoxide 20 as a colourless oil (4.71 g, 90%) which was
used directly without further purification. Rf (EtOAc–petrol,
1 : 19) 0.70; mmax/cm−1 (neat) 2934, 2857, 1449; dH (250 MHz,
CDCl3) 1.13–1.27 (4H, 2 × CH2), 1.32–1.48 (4H, 2 × CH2),
1.49–1.62 (4H, 2 × CH2), 1.74–1.87 (4H, 2 × CH2); dC (63 MHz,
CDCl3) 20.5 (4 × t), 31.0 (4 × t), 62.2 (2 × s); m/z (EI+) 152
(M+, 50%), 111 (100), 62 (95); found: m/z (EI+) M+ 152.1203,
C10H16O requires 152.1201 (D = +1.3 ppm).
9b-Benzylthio-10a-hydroxy-1,2,3,4,5,6,7,8,9,10-decahydrona-
phthalene 23. To a suspension of saturated epoxide 20 (1.49 g,
10.0 mmol) and powdered NaOH (4.0 g, 100 mmol, 10.0 eq.)
in ethylene glycol (25 cm3) was added benzyl thiol (12.4 cm3,
100 mmol, 10.0 eq., CAUTION stench) and the resulting
mixture heated at 100 ◦C for 15 h. A deep orange colour
developed. The reaction mixture was partitioned between H2O
(60 cm3) and Et2O (40 cm3), the phases separated and the
organic phase washed with H2O (3 × 40 cm3). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo
to give a yellow oil. Purification by flash chromatography
(EtOAc–petrol, 1 : 19 → 1 : 9 → EtOAc) gave decalin
thioether 23 as a pale yellow amorphous powder (1.99 g, 72%).
Mp 69.4–70.6 ◦C (pentane); Rf (EtOAc–petrol, 1 : 19) 0.15;
mmax/cm−1 (CHCl3) 3616 (OH), 2940, 1602, 1495; dH (CDCl3,
250 MHz) 1.14–1.33 (4H, 2 × CH2), 1.41–1.82 (8H, 4 ×
CH2), 1.87–2.02 (2H, CH2), 2.06–2.25 (2H, CH2), 3.48 (2H, s,
SCH2Ph), 7.17–7.36 (5H, Ph), OH absent; dC (CDCl3, 63 MHz)
20.8 (2 × t), 20.9 (2 × t), 30.9 (2 × t), 32.2 (t), 34.5 (2 × t), 56.5
(s), 72.6 (s), 126.9 (d), 128.5 (2 × d), 129.2 (2 × d), 138.0 (s); m/z
(EI+) 276 (M+, 46%), 153 (M+ − SCH2Ph, 89), 135 (100) 111
(89); found: m/z (EI+) M+ 276.1544, C17H24SO requires M+,
276.1548 (D = −1.4 ppm).
9b-tert-Butylthio-10a-hydroxy-1,2,3,4,5,6,7,8,9,10-decahydro-
naphthalene 21.
Method 1. To a solution of saturated epoxide 20 (1.52 g,
10.0 mmol) and powdered NaOH (4.0 g, 100.0 mmol, 10 eq.) in
ethylene glycol (25.0 cm3) was added tert-butyl thiol (5.60 cm3,
50 mmol, 5 eq., CAUTION stench) and the resulting mixture
heated at 100 ◦C for 48 h. The reaction mixture was partitioned
between H2O (30 cm3) and Et2O (30 cm3) and the phases
separated. The organic phase was washed with H2O (20 cm3)
and the combined aqueous phases re-extracted with Et2O (2 ×
20 cm3). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography (petrol → EtOAc–petrol, 1 : 4) to give decalin
◦
thioether 21 as colourless needles (1.94 g, 80%). Mp 64–65 C
(EtOAc); Rf (EtOAc–petrol, 1 : 9) 0.50; mmax/cm−1 (CHCl3) 3687,
3614, 2946, 2861, 1461, 1364, 1256, 1153; dH (250 MHz, CDCl3)
1.06–1.18 (2H, CH2), 1.38 [9H, s, C(CH3)3], 1.45 (1H, s, OH),
1.52–1.67 (6H, 3 × CH2), 1.71–1.82 (4H, 2 × CH2), 2.03 (2H,
td, J 13.0 and 6.0, CH2), 2.16–2.37 (2H, CH2); dC (100 MHz,
CDCl3) 21.0 (2 × t), 21.1 (2 × t), 32.2 (2 × t), 33.4 (3 × q), 34.2
(2 × t), 46.9 (s), 59.0 (s), 73.1 (s); m/z (EI+) 242 (M+, 81%), 153
[M+ − SC(CH3)3, 93], 135 (100); found: m/z (EI+) M+ 242.1697,
C14H26OS requires 242.1704 (D = −2.9 ppm).
(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-10a-
yloxy)-acetic acid 24. To a suspension of sodium hydride
(319 mg, 13.3 mmol, 4 eq.) in THF (6 cm3) was added a solution
of thioether alcohol 23 (915 mg, 3.32 mmol) in THF (5 cm3)
and chloroacetic acid (345 mg, 3.6 mmol, 1.1 eq.). The resulting
mixture was heated to reflux for 1.5 h before removing the
solvent under a stream of N2 and heating the residual solid at
85 ◦C for a further 48 h. The residue was allowed to cool to rt,
resuspended in THF (20 cm3), H2O (2 cm3) added dropwise and
the resulting solution concentrated in vacuo. The residue was
partitioned between CH2Cl2 (20 cm3) and an aqueous solution
of sodium hydroxide (10 cm3, 1 M), the phases separated, the
aqueous phase acidified to pH 1 with an aqueous solution of
hydrochloric acid (1 M) and extracted with CHCl3 (3 × 10 cm3).
The organic extracts were dried (MgSO4) and concentrated in
vacuo to give thioether oxyacetate 24 as a white amorphous
powder (578 mg, 52%). Mp 154–156 ◦C (pentane); mmax/cm−1
Method 2. To a solution of thioether bis-alkene 14b (59 mg,
247 lmol) in EtOAc (3 cm3) was added PtO2 (Adams’ catalyst,
6 mg, 26 lmol, 0.1 eq.) and the resulting suspension stirred
vigorously under an atmosphere of hydrogen for 14 h. The
R
reaction mixture filtered through a pad of celiteꢀ and the
filtrate concentrated in vacuo. The residue was purified by flash
chromatography (petrol–EtOAc, 16 : 1) to give thioether alcohol
21 as white needles (50 mg, 83%). Spectroscopic data as above.
(9b-tert-Butylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-acetic acid 22. To a suspension of sodium hydride
(39 mg, 1.547 mmol) in THF (3 cm3) was added a solution of
thioether alcohol 21 (150 mg, 0.619 mmol) in THF (3 cm3) and
the resulting mixture heated to reflux for 1 h. A solution of
chloroacetic acid (55 mg, 0.582 mmol, 0.94 eq.) in THF (3 cm3)
was then added and the reaction mixture stirred at reflux for
a further 12 h. The reaction mixture was then allowed to cool
to rt, H2O (5 cm3) added dropwise and the resulting solution
concentrated in vacuo. The residue was partitioned between
CHCl3 (10 cm3) and an aqueous solution of citric acid (10 cm3,
1 M), the phases separated and the the aqueous phase extracted
with CHCl3 (2 × 10 cm3). The combined organic extracts were
dried (Na2SO4) and evaporated to give a white solid which was
dissolved in CH2Cl2 (10 cm3) and extracted with an aqueous
solution of NaOH (3 × 10 cm3, 1 M). The aqueous extracts
were acidified to pH 1 with an aqueous solution of HCl (1 M)
and extracted with CHCl3 (3 × 10 cm3). The organic extracts
were dried (MgSO4) and concentrated in vacuo to give thioether
oxyacetate 22 as white needles (120 mg, 65%). Mp 178–180 ◦C
(EtOAc); Rf (CH2Cl2–HCO2H, 50 : 1) 0.60; mmax/cm−1 (CHCl3)
3686, 3523, 3395, 2944, 2863, 1785, 1459, 1365, 1159, 1087;
dH (250 MHz, CDCl3) 1.24–1.36 (4H, 2 × CH2), 1.40 [9H, s,
C(CH3)3], 1.45–1.58 (4H, 2 × CH2), 1.68–1.80 (2H, CH2),
1.81–2.00 (4H, 2 × CH2), 2.14–2.36 (2H, CH2), 3.85 (2H, s,
OCH2CO2H), CO2H absent; dC (63 MHz, CDCl3) 20.9 (2 × t),
21.0 (2 × t), 27.9 (2 × t), 32.1 (2 × t), 33.4 (3 × q), 47.1 (s), 57.6
(t), 59.1 (s), 79.4 (s), 173.4 (s); m/z (EI+) 300 (M+, 20%), 238
(11), 211 (M+ − SC(CH3)3, 22), 135 (100); found: m/z (EI+) M+
300.1747, C16H28O3S requires 300.1759 (D = −4.0 ppm).
=
(CHCl3) 2800 (OH), 2936, 1729 (C O), 1602, 1495; dH (CDCl3,
250 MHz) 1.32–1.60 (10H, 5 × CH2), 1.74–1.94 (4H, 2 ×
CH2), 2.05–2.26 (2H, CH2), 3.51 (2H, s, SCH2Ph), 3.90 (2H, s,
OCH2CO2H), 7.19–7.35 (5H, Ph), OH absent; dC (CDCl3,
63 MHz) 20.7 (2 × t), 20.8 (2 × t), 28.2 (2 × t), 30.7 (2 × t),
32.0 (t), 56.7 (s), 57.9 (t), 79.1 (s), 127.1 (d), 128.5 (2 × d),
129.2 (2 × d), 137.5 (s), 172.4 (s); m/z (EI+) 334 (M+, 26%), 135
(100), 91 (M+ − C12H19SO3, 76); found: m/z (EI+)M+ 334.1587,
C19H26SO3 requires M+, 334.1603 (D = −4.8 ppm).
(9b-Mercapto-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-10a-
yloxy)-acetic acid 25. To a solution of thioether oxyacetate
24 (257 mg, 0.75 mmol) in THF (1 cm3) in a two-necked
flask fitted with a cold-finger condenser was condensed NH3
(10 cm3). Sodium metal (220 mg, 10 mmol, 13 eq.) was then
added and the resulting deep blue solution stirred for 4 h at
−33 ◦C. Solid ammonium chloride was then added until the
solution went clear and the NH3 allowed to evaporate. The
residue was concentrated in vacuo and then partitioned between
CHCl3 (10 cm3) and an aqueous solution citric acid (10 cm3, of
1 M). The phases were separated and the organic phase dried
(MgSO4) and concentrated in vacuo to give thiol oxyacetate
25 as an off-white amorphous powder (176 mg, 95%). Mp
152–154 ◦C (CHCl3); mmax/cm−1 (CHCl3) 3200 (OH), 2895,
=
2578, 1729 (C O); dH (CDCl3, 250 MHz) 1.21–1.67 (10H,
5 × CH2), 1.75–1.92 (4H, 2 × CH2), 2.01–2.16 (2H, CH2), 3.89
(2H, s, OCH2CO2H), SH and OH absent; dC (CDCl3, 63 MHz)
20.5 (2 × t), 21.1 (2 × t), 28.2 (2 × t), 36.7 (2 × t), 54.0 (s),
58.6 (t), 79.8 (s), 171.7 (s); m/z (EI+) 244 (M+, 10%), 212 (20),
1 9 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2

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168 (100); found: m/z (EI+) M+ 244.1121, C12H20O3S requires
244.1133 (D = −4.9 ppm).
in vacuo to give the crude bromohydrin [Rf (EtOAc–petrol, 1 :
19) 0.20] which was directly dissolved in dry MeOH (26.0 cm3)
and K2CO3 (3.12 g, 22.6 mmol) added. After stirring at rt for
1 h, the resulting suspension was filtered under suction and
the filtrate concentrated in vacuo and the residue partitioned
between brine (15 cm3) and EtOAc–petrol (50 : 50, 25 cm3). The
phases were separated and the aqueous phase extracted with
further EtOAc–petrol (50 : 50, 25 cm3). The combined organic
extracts were then dried (MgSO4), filtered and concentrated
in vacuo to give thioether epoxide 28 as a yellow oil (1.0 g,
55%) which was used directly without further purification. Rf
(EtOAc–petrol, 1 : 19) 0.30; mmax/cm−1 (CHCl3) 3007, 2934,
2860, 1495, 1456; dH (250 MHz, CDCl3) 1.32–1.59 (10H, 5 ×
CH2), 1.59–1.80 (2H, CH2), 1.87–2.22 (4H, 2 × CH2) 2.69
(1H, dd, J 5.2 and 2.4, CCOHH), 2.83 (1H, dd, J 5.2 and 3.2,
CCOHH), 3.13–3.19 (1H, OCH2CHOC), 3.20 and 3.48 (2H,
ABq, JAB 7.2, OCH2CHOC), 3.50 (2H, s, SCH2Ph), 7.19–7.39
(5H, Ph); dC (100 MHz, CDCl3) 20.7 (2 × t), 21.0 (2 × t), 27.9
(t), 28.2 (t), 30.4 (2 × t), 31.9 (t), 44.6 (t), 51.4 (d), 57.5 (s), 60.1
(s), 76.5 (t), 126.9 (d), 128.4 (2 × d), 129.2 (2 × d), 138.0 (s);
m/z (EI+) 332 (M+, 50%), 209 (55), 136 (84), 135 (100), 91(67),
57 (33); found: m/z (EI+) M+ 332.1824, C20H28O2S requires
332.1810 (D = +4.2 ppm).
3-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-propane-1,2-diol 29. To a solution of thioether
epoxide 28 (1.0 g, 3.0 mmol) in THF (16.0 cm3) and H2O
(16.0 cm3) was added BF3·Et2O (3.20 cm3, 10% vol.) dropwise
and the solution stirred for 1 h at rt. A saturated aqueous
solution of NaHCO3 (10 cm3) was added and the resulting
reaction mixture extracted with Et2O (4 × 25 cm3), the
combined organic extracts dried (MgSO4) and concentrated in
vacuo. Purification by flash chromatography (EtOAc–petrol,
1 : 4 → 2 : 3) gave diol 29 as a colourless oil (970 mg, 92%).
Rf (EtOAc–petrol, 1 : 1) 0.30; mmax/cm−1 (CHCl3) 3580, 3009,
2936, 2862, 1454, 1186; dH (250 MHz, CDCl3) 1.36–1.57 (10H,
5 × CH2), 1.65–1.92 (4H, 2 × CH2), 2.05–2.22 (2H, CH2),
3.22 (1H, dd, J 6.1 and 4.5, CHHOH), 3.26 (1H, dd, J 6.1
and 4.5, CHHOH), 3.50 (2H, s, SCH2Ph), 3.64 [1H, dd, J
11.5 and 4.5, OCHHCH(OH)], 3.71 [1H, dd, J 11.5 and 4.5,
OCHHCH(OH)], 3.87–3.96 [1H, OCH2CH(OH)], 7.19–7.34
(5H, Ph), 2 × OH absent; dC (100 MHz, CDCl3) 20.7 (2 × t),
20.7 (2 × t), 27.9 (t), 27.9 (t), 30.6 (t), 30.7 (t), 31.9 (t), 57.2 (s),
60.6 (s), 64.5 (t), 71.1 (d), 76.8 (t), 126.9 (d), 128.5 (2 × d), 129.2
(2 × d), 138.1 (s); m/z (EI+) 350 (M+, 22%), 227 (25), 153 (24),
136 (100), 135 (79), 91 (49); found: m/z (EI+) M+ 350.1909,
C20H30O3S requires 350.1916 (D = −2.0 ppm).
S-Nitroso-(9b-mercapto-1,2,3,4,5,6,7,8,9,10-decahydronaph-
thalen-10a-yloxy)-acetic acid 26. To a solution of thiol
oxyacetate 25 (50 mg, 0.20 mmol) in CH2Cl2 (3.0 cm3) was
added tert-butyl nitrite (27 mm3, 0.23 mmol). After 20 min the
reaction was concentrated in vacuo to give the S-nitrosothiol
oxyacetate 26 as pale green plates (32 mg, 57%). Mp 144–146 ◦C
(CH2Cl2–hexane, 1 : 4); mmax/cm−1 (CHCl3) 3421, 2941, 2866,
1781, 1624, 1521; dH (250 MHz, CDCl3) 1.17–2.66 (16H, 8 ×
CH2), 3.92 (1H, s, OH), 4.04 (2H, s, OCH2CO2H); dC (100 MHz,
CDCl3) 20.4 (2 × t), 20.5 (2 × t), 29.4 (2 × t), 33.6 (2 × t), 57.2
(s), 57.9 (t), 67.6 (s) 173.2 (s); m/z (ES+) 296 (MNa+, 23%), 260
(29), 257 (39), 219 (45), 193 (100); Found: m/z (ES−) M − H−
272.0960, C12H18O4SN requires 272.0957 (D = +1.1 ppm).
Single crystals of S-nitrosothiol oxyacetate 26 suitable for
X-ray diffraction were obtained by recrystallisation (CH2Cl2–
hexane). Crystal data: C12H18NO4S; M = 273.33, monoclinic,
◦
˚
a = 10.927(8), b = 8.372(2), c = 14.620(10) A, b = 96.444(14) ,
3
2
˚
U = 1329.1(16) A , T = 150 K, space group P21 (C2 No.4),
−1
˜
˚
Mo–Ka radiation (k = 0.71073 A), l(Mo–Ka) = 0.250 mm ,
7349 reflections measured, 2394 unique, (Rint = 0.1197) all of
which were corrected for Lorentz and polarisation effects and
for absorption by semi empirical methods based on symmetry-
equivalent and repeated reflections (minimum and maximum
transmission coefficients 0.9001 and 0.9925) 3499 independent
reflections exceeded the significance level |F|/r(|F|) > 4.0. N1A
and O4A where found to be disordered and refined to an
occupancy of 67% to 33%. Refinement converged, (D/r, max,
mean = 0.000, 0.000 respectively), with final wR(F2) = 0.2352,
(all data), R1 = 0.0842, S = 0.927 for 2394 reflections with I >
2r(I) and 345 parameters Flack parameter value 0.0(2).†
9b-Benzylthio-10a-allyloxy-1,2,3,4,5,6,7,8,9,10-decahydrona-
phthalene 27. To a solution of thioether alcohol 23 (2.56 g,
9.40 mmol) in THF (25.0 cm3) at 0 ◦C was added a solution
of nBuLi (4.10 cm3, 2.5 M in hexanes, 10.0 mmol) and the
solution stirred for 30 min at this temperature before adding
nBu4NI (342 mg, 0.94 mmol) and then allyl bromide (2.40 cm3,
28.1 mmol) dropwise. The reaction mixture was heated at
◦
50 C for 48 h, H2O (10 cm3) was added and the resulting
solution extracted with CH2Cl2 (3 × 30 cm3). The combined
organic phases were washed with H2O (20 cm3), dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography (petrol → EtOAc–petrol, 1 : 4) to give allyl
ether 27 as a yellow oil (2.23 g, 75%). Rf (EtOAc–petrol, 1 : 19)
0.80; mmax/cm−1 (CHCl3) 3009, 2934, 2860, 1723, 1644, 1602,
1494, 1453; dH (250 MHz, CDCl3) 1.34–1.62 (10H, 5 × CH2),
1.66–1.85 (2H, CH2), 1.96–2.27 (4H, 2 × CH2), 3.53 (2H, s,
[2-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-tert-butoxycarbonylmethoxymethylethoxy]-acetic
acid tert-butyl ester 31. To a solution of diol 29 (982 mg,
2.80 mmol) and nBu4NBr (140 mg, 4.20 mmol) in CH2Cl2
=
SCH2Ph), 3.69–3.77 (2H, OCH2CH CH2), 5.15 (1H, app dq,
J 10.4 and 2.0, OCH2CH CHH), 5.39 (1H, app dq, J 17.1
=
◦
(3.37 cm3) at 0 C was added a 50% w/v aqueous solution of
=
and 2.0, OCH2CH CHH), 6.00 (1H, ddt, J 17.1, 10.4 and 7.0,
OCH2CH CH2), 7.20–7.40 (5H, Ph); dC (100 MHz, CDCl3)
NaOH (3.37 cm3) and then tert-butyl bromoacetate (0.87 cm3,
=
5.90 mmol) dropwise. The reaction mixture was stirred at
20.9 (2 × t), 21.1 (2 × t), 28.2 (2 × t), 30.5 (2 × t), 32.0 (t),
57.7 (s), 59.9 (s), 76.3 (t), 114.5 (t), 126.8 (d), 128.4 (2 × d),
129.2 (2 × d), 135.9 (t),138.1 (s); m/z (EI+) 316 (M+, 52%), 259
(77), 136 (100), 135 (53), 91(85), 67 (32); found: m/z (EI+) M+
316.1854, C20H28OS requires 316.1861 (D = −2.2 ppm).
0
◦C for 3 h, partitioned between H2O (15.0 cm3) and petrol
(25.0 cm3) and the phases separated. The aqueous layer was
extracted further with petrol (2 × 25 cm3) and then the
combined organic phases washed with saturated brine (10 cm3),
dried (MgSO4) and concentrated in vacuo. Purification by flash
chromatography (petrol → EtOAc–petrol, 1 : 4) gave diester
31 as a clear oil (472 mg, 29%). Rf (EtOAc–petrol, 1 : 9) 0.40;
2-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-oxirane 28. To a solution of allyl ether 27 (1.79 g,
◦
5.64 mmol) in THF (21.0 cm3) and H2O (7.0 cm3) at 0 C was
mmax/cm−1 (CHCl3) 3008, 2982, 2934, 2861, 1742 (C O), 1369;
=
added N-bromosuccinimide (1.50 g, 8.46 mmol) portionwise
dH (250 MHz, CDCl3) 1.29–2.18 (16H, 8 × CH2), 1.47 [18H, s,
2 × C(CH3)3], 3.24–3.42 (2H, OCH2CH), 3.47 (2H, s, SCH2Ph),
3.63–3.88 (3H, CHCH2O), 4.02, 4.08 (2H, ABq JAB 17.5,
OCH2COtBu), 4.24, 4.26 (2H, ABq JAB 17.5, OCH2COtBu),
7.16–7.35 (5H, Ph); dC (100 MHz, CDCl3) 20.6 (t), 20.7 (t), 20.9
(2 × t), 27.8 (t), 27.9 (t), 28.1 (6 × q), 30.5 (2 × t), 31.9 (t), 57.4
(s), 59.4 (s), 68.7 (t), 69.4 (t), 72.6 (t), 76.5 (t), 78.9 (d), 81.3 (s),
81.5 (s), 126.8 (d), 128.4 (2 × d), 129.2 (2 × d), 137.9 (s), 169.5
◦
and the reaction mixture stirred at 0 C for 3 h. The reaction
mixture was then concentrated in vacuo and the residue
partitioned between brine (15 cm3) and Et2O (25 cm3). The
phases were separated and the aqueous phase extracted with
further Et2O (3 × 25 cm3). The combined organic extracts were
washed with a saturated aqueous solution of NaHCO3 (30 cm3)
and brine (10 cm3), dried (MgSO4), filtered and concentrated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
1 9 4 9

View Article Online
(s), 167.0 (s); m/z (EI+) 579 (2%), 578 (M+, 5), 321 (35), 265
(42), 259 (88), 209 (100), 136 (73),135 (63); found: m/z (EI+) M+
578.3276, C32H50O7S requires 578.3277 (D = −0.2 ppm).
S-Nitroso-[1-carboxymethoxymethyl-2-(9b-mercapto-1,2,3,4,
5,6,7,8,9,10-decahydronaphthalen-10a-yloxy)-ethoxy]-acetic acid
37. To a solution of thiol bis-oxyacetate 33 (50 mg, 0.13 mmol)
in CH2Cl2 (2.0 cm3) was added tert-butyl nitrite (49 mm3,
0.41 mmol). After 40 min the reaction was concentrated in
vacuo to give the S-nitrosothiol oxyacetate 37 as a pale green
[2-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-carboxymethoxymethylethoxy]-acetic acid 32.
Method 1. To a suspension of sodium hydride (30 mg,
1.1 mmol) in THF (1 cm3) was added a solution of diol 29 (32 mg,
0.09 mmol) in THF (5 cm3) and the resulting reaction mixture
oil (30 mg, 56%). mmax/cm−1 (CH2Cl2), 2934, 2863, 1735 (C O),
=
1496, 1452; dH (270 MHz, CDCl3) 1.24–1.75 (12 C 6 × CH2),
2.38–2.49 (4H, 2 × CH2), 3.30–3.40 (2H, OCH2CH), 3.75–4.00
(3H, OCH2CH), 4.20–4.55 (4H, 2 × O CH2COOH); dC
(270 MHz, CDCl3) 20.4 (2 × t), 21.2 (2 × t), 29.1 (t), 29.2 (t),
33.6 (t), 33.7 (t), 59.2 (s), 68.0 (s), 68.4 (t), 68.5 (t), 72.5 (t), 75.9
(t), 80.4 (d), 174.5 (s), 174.7 (s); m/z (ES−) 404 (M − H, 20%),
374 (50), 341 (55%), 75 (100).
◦
heated at 60 C for 1 h. The reaction mixture was then cooled
to 0 ◦C and chloroacetic acid (20 mg, 2.0 mmol) was added
portionwise. The reaction mixture was then heated to reflux for
24 h, the solution allowed to cool to rt, H2O (2 cm3) added
dropwise and the resulting solution concentrated in vacuo. The
residue was partitioned between CH2Cl2 (5 cm3) and an aqueous
solution of NaOH (5 cm3, 1 M), the phases separated and the
aqueous phase washed with CH2Cl2 (2 × 5 cm3) and acidified
to pH 1 with an aqueous solution of hydrochloric acid (1 M).
The resulting solution was extracted with CHCl3 (3 × 5 cm3),
the organic extracts dried (MgSO4) and concentrated in vacuo
to give bis-oxyacetate 32 as a clear oil (33 mg, 79%). mmax/cm−1
3-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-O-methyl-propane-1,2-diol 30. Obtained using
the same method as described above for the preparation of
thioether epoxide 28 employing allyl ether 27 (2.53 g, 8.0 mmol),
N-bromosuccinimide (2.13 g, 12 mmol), MeOH (30 cm3) and
K2CO3 (4.42 g, 32 mmol) but employing a reaction time
of 12 h (cf. 1 h) for the second step. Purification by flash
chromatography (EtOAc–petrol, 1 : 4) gave methyl ether 30
as a yellow oil (2.41 g, 83%). Rf (EtOAc–petrol, 1 : 9) 0.20;
mmax/cm−1 (CHCl3) 3500, 2948, 2910, 2862, 1458, 1192; dH
(250 MHz, CDCl3) 1.32–1.52 (10H, 5 × CH2), 1.63–1.91 (4H,
2 × CH2), 2.04–2.18 (2H, CH2), 2.31 (1H, bs, OH), 3.24 (2H,
d, J 6.5, CH2OMe), 3.39 (3H, s, OMe), 3.47 [1H, dd, J 11.5
and 4.5, OCHHCH(OH)], 3.50 (2H, s, SCH2Ph), 3.52 [1H, dd,
J 11.5 and 4.5, OCHHCH(OH)], 3.95 [1H, app quintet, J 7.0,
OCH2CH(OH)], 7.17–7.36 (5H, Ph); dC (100 MHz, CDCl3)
20.7 (2 × t), 21.0 (2 × t), 28.0 (2 × t), 30.6 (2 × t), 32.0 (t), 57.4
(s), 59.3 (s), 60.0 (t), 70.0 (d), 74.2 (q), 76.4 (t), 127.0 (d), 128.5
(2 × d), 129.3 (2 × d), 137.9 (s); m/z (CI+) 365 (4%), 364 (M+,
5), 259 (100), 241 (55), 135 (55); found: m/z (CI+) M+ 364.2073,
C21H32O3S requires 364.2072 (D = +0.3 ppm).
=
=
(CHCl3) 3690, 2936, 2861, 1766 (C O), 1732 (C O), 1454; dH
(250 MHz, CDCl3) 1.29–1.54 (10H, 5 × CH2), 1.63–1.90 (4H,
2 × CH2), 1.99–2.19 (2H, CH2), 3.20–3.37 (2H, OCH2CH), 3.48
(2H, s, SCH2Ph), 3.67 (1H, CHCHHO), 3.83 (2H, CHCHHO),
4.17, 4.19 (2H, ABq JAB 16.5, OCH2COtBu), 4.31, 4.44 (2H,
ABq JAB 17.5, OCH2COtBu), 7.16–7.35 (5H, Ph), 8.39 (2H, bs,
2 × CO2H); dC (63 MHz, CDCl3) 20.7 (t), 20.8 (t), 20.9 (2 ×
t), 27.8 (t), 27.9 (t), 30.6 (2 × t), 32.0 (t), 57.2 (s), 59.1 (s), 68.3
(t), 68.4 (t), 72.5 (t), 77.2 (t), 80.5 (d), 126.9 (d), 128.5 (2 × d),
129.2 (2 × d), 137.8 (s), 174.0 (s), 174.4 (s); m/z (ES+) 490 (9%),
489 (MNa+, 100), 260 (3), 259 (68); found: m/z (ES+) MNa+
489.1918, C24H34O7NaS requires 489.1923 (D = −1.0 ppm).
Method 2. To a solution of diester 31 (445 mg, 0.77 mmol) in
THF (4 cm3) and MeOH (4 cm3) was added an aqueous solution
of LiOH (4 cm3, 2 M). The reaction mixture was stirred at rt for
48 h, acidified to pH 1 with aqueous hydrochloric acid (1 M)
and extracted with EtOAc (3 × 10 cm3). The combined organic
extracts were washed with brine (10 cm3), dried (MgSO4) and
concentrated in vacuo to give bis-oxyacetate 32 as a clear oil
(359 mg, 100%). Spectroscopic data as above.
[2-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-methoxymethylethoxy]-acetic acid tert-butyl ester
34. To a solution of methyl ether 30 (1.98 g, 5.43 mmol) and
nBu4NBr (1.99 g, 5.98 mmol) in CH2Cl2 (5 cm3) at 0 ◦C was
added a 50% w/v aqueous solution of NaOH (5 cm3) and then
tert-butyl bromoacetate (0.88 cm3, 5.90 mmol) dropwise. The
reaction mixture was stirred at 0 ◦C for 5 h, partitioned between
H2O (21.0 cm3) and petrol (35.0 cm3) and the phases separated.
The aqueous layer was extracted further with petrol (4 ×
30 cm3) and then the combined organic phases washed with
saturated brine (50 cm3), dried (Na2SO4), and concentrated in
vacuo. Purification by flash chromatography (EtOAc–petrol, 1 :
9) gave ester 34 as a clear oil (1.83 g, 64%). Rf (EtOAc–petrol, 1 :
[1-Carboxymethoxymethyl-2-(9b-mercapto-1,2,3,4,5,6,7,8,9,
10-decahydronaphthalen-10a-yloxy)-ethoxy]-acetic acid 33.
To a solution of bis-oxyacetate 32 (310 mg, 0.66 mmol) in
THF (5 cm3) in a two-necked flask fitted with a cold-finger
condenser was condensed NH3 (10 cm3). Sodium metal (199 mg,
8.64 mmol) was then added and the resulting deep blue solution
◦
stirred for 4 h at −33 C. Solid ammonium chloride was then
added until the solution went clear and the NH3 allowed to
evaporate. The residue was concentrated in vacuo and then
partitioned between CH2Cl2 (10 cm3) and an aqueous solution
of NaOH (10 cm3, 1 M). The phases were separated and the
aqueous phase was washed with CH2Cl2 (2 × 10 cm3) before
being acidified to pH 1 with a saturated aqueous solution of
citric acid. The aqueous phase was then extracted with CHCl3
(3 × 10 cm3) and the combined organic extracts dried (MgSO4)
and concentrated in vacuo to give thiol bis-oxyacetate 33 as a
thick clear oil (227 mg, 100%). mmax/cm−1 (CHCl3) 3690, 3026,
4) 0.80; mmax/cm−1 (CHCl3) 2930, 2860, 1748 (C O), 1454, 1136;
=
dH (250 MHz, CDCl3) 1.32–1.51 (10H, 5 × CH2), 1.46 [9H, s,
C(CH3)3], 1.58–1.72 (2H, CH2), 1.77–1.93 (2H, CH2), 2.00–2.15
(2H, CH2), 3.23–3.40 (2H, CH2OMe), 3.37 (3H, s, OMe),
3.45 (2H, s, SCH2Ph), 3.52–3.66 (2H, CHCH2O), 3.68–3.75
(1H, CHCH2O), 4.18, 4.22 (2H, ABq JAB 17.5, OCH2COtBu),
7.18–7.33 (5H, Ph); dC (63 MHz, CDCl3) 20.7 (t), 20.8 (t), 21.0
(2 × t), 27.9 (2 × t), 28.2 (3 × q), 30.6 (2 × t), 32.0 (t), 57.4
(s), 59.3 (s), 59.3 (t), 68.5 (d), 73.6 (q), 76.6 (t), 78.7 (t), 81.4
(s), 126.9 (d), 128.5 (2 × d), 129.2 (2 × d), 138.0 (s), 170.0 (s);
=
3016, 2936, 1767 (C O), 1602; dH (250 MHz, CDCl3) 1.26–1.60
(10H, 5 × CH2), 1.64–1.94 (4H, 2 × CH2), 2.04 (2H, app tt, J
13.4 and 3.7, CH2), 3.22 (1H, dd, J 11.8 and 5.8, OCHHCH),
3.26 (1H, dd, J 11.8 and 5.8, OCHHCH), 3.66 (1H, dd, J
9.4 and 7.6, CHCHHO), 3.75–3.86 (2H, CHCHHO), 4.16,
4.24 (2H, ABq JAB 16.8, OCH2COH), 4.28, 4.43 (2H, ABq JAB
17.4, OCH2COH), 9.37 (2H, bs, 2 × CO2H), SH absent; dC
(100 MHz, CDCl3) 20.5 (2 × t), 21.3 (2 × t), 27.8 (t), 27.9 (t),
36.5 (t), 36.6 (t), 54.6 (s), 59.8 (s), 68.2 (2 × t), 72.3 (t), 77.6 (t),
80.4 (d), 174.3 (s), 174.6 (s); m/z (ES+) 400 (6%), 399 (MNa+,
100), 367 (4); found: m/z (ES+) MNa+ 399.1459, C17H28O7NaS
requires 399.1453 (D = +1.5 ppm).
m/z (CI+) 496 (MNH4 , 15%), 355 (15), 259 (100); found: m/z
+
(CI+) MNH4 496.3100, C27H46O5SN requires 496.3097 (D =
+
+0.6 ppm).
[2-(9b-Benzylthio-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-methoxymethylethoxy]-acetic acid 35. To
a
solution of ester 34 (1.75 g, 3.66 mmol) in THF (15 cm3) and
MeOH (15 cm3) was added an aqueous solution of LiOH
(15 cm3, 2 M). The reaction mixture was stirred at rt for 14 h,
acidified to pH 1 with aqueous hydrochloric acid (1 M) and
extracted with EtOAc (3 × 40 cm3). The combined organic
1 9 5 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2

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extracts were washed with brine (40 cm3), dried (Na2SO4) and
concentrated in vacuo to give oxyacetate 35 as a thick, clear
oil (1.54 g, 100%). mmax/cm−1 (CHCl3) 3260, 2930, 2861, 1762
0.2950, (all data), R1 = 0.0943, S = 1.010 for 2778 reflections
with I > 2r(I) and 223 parameters.†
=
(C O), 1454, 1188; dH (250 MHz, CDCl3) 1.32–1.54 (10H, 5 ×
Acknowledgements
CH2), 1.65–1.88 (4H, 2 × CH2), 2.02–2.17 (2H, CH2), 3.15–3.26
(2H, CH2OMe), 3.48 (3H, s, OMe), 3.49 (2H, s, SCH2Ph),
3.50–3.60 (2H, CHCH2O), 3.68–3.77 (1H, CHCH2O), 4.22,
4.41 (2H, ABq JAB 17.5, OCH2CO2H), 7.18–7.33 (5H, Ph),
CO2H absent; dC (63 MHz, CDCl3) 20.7 (t), 20.8 (t), 20.9 (2 × t),
27.8 (t), 27.9 (t), 30.5 (t), 30.6 (t), 32.0 (t), 57.3 (s), 59.4 (s), 59.4
(t), 69.3 (d), 72.8 (q), 77.2 (t), 81.2 (t), 127.0 (d), 128.6 (2 × d),
Grateful acknowledgement is made to the ESPRC for a Quota
studentship (J. C.) and Pfizer Ltd for a Summer Scholarship
(K. I. C.). Merck Sharp & Dohme Ltd and Pfizer Ltd are also
thanked for unrestricted research funds.
+
129.3 (2 × d), 137.7 (s), 172.0 (s); m/z (CI+) 440 (MNH4 , 3%),
References
1 D. L. H. Williams, Org. Biomol. Chem., 2003, 1, 441.
2 C. Nathan, J. Clin. Invest., 2003, 111, 769.
3 A. J. Hobbs and L. J. Ignarro, in Methods in enzymology: nitric
oxide: part B physiological and pathological processes, ed. L. Packer,
Academic Press, New York, 1996, vol. 269, pp. 134–148.
4 A. van der Vliet, J. P. Eiserich, M. K. Shigenaga and C. E. Cross,
Am. J. Resp. Crit. Care, 1999, 160, 1.
5 J. S. Stamler, S. Lamas and F. C. Fang, Cell, 2001, 106, 675.
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7 C. Jacob, G. I. Giles, N. M. Giles and H. Sies, Angew. Chem., Int.
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423 (MH+, 1), 259 (100), 182 (76); found: m/z (CI+) MNH4
+
440.2471, C23H38O5SN requires 440.2471 (D = 0.0 ppm).
[2-(9b-Mercapto-1,2,3,4,5,6,7,8,9,10-decahydronaphthalen-
10a-yloxy)-1-methoxymethylethoxy]-acetic acid 36. To
a
solution of oxyacetate 35 (1.45 g, 3.43 mmol) in THF (20 cm3)
in a two-necked flask fitted with a cold-finger condenser was
condensed NH3 (150 cm3). Sodium metal (1.03 g, 44.6 mmol)
was then added and the resulting deep blue solution stirred
for 4 h at −33 ◦C. Solid ammonium chloride was then added
until the solution went clear and the NH3 allowed to evaporate.
The residue was concentrated in vacuo and then partitioned
between CH2Cl2 (50 cm3) and an aqueous solution of NaOH
(50 cm3, 1 M). The phases were separated and the aqueous
phase was washed with CH2Cl2 (2 × 40 cm3) before being
acidified to pH 1 with a saturated aqueous solution of citric
acid. The aqueous phase was then extracted with CHCl3 (4 ×
50 cm3) and the combined organic extracts dried (Na2SO4) and
concentrated in vacuo to give thiol oxyacetate 36 as a thick clear
oil (640 mg, 50%). mmax/cm−1 (CHCl3) 3200, 2934, 1860, 1763
8 A. J. Hobbs, M. T. Gladwin, R. P. Patel, D. L. H. Williams and A. R.
Butler, Trends Pharmacol. Sci., 2002, 23, 406.
9 J. B. Mannick and C. M. Schonhoff, Arch. Biochem. Biophys., 2002,
408, 1.
10 S. R. Jaffrey, M. Fang and S. H. Snyder, Chem. Biol., 2002, 9, 1329.
11 M. T. Gladwin and A. N. Schechter, Circ. Res., 2004, 94, 851.
12 D. L. H. Williams, Acc. Chem. Res., 1999, 32, 869.
13 A. Claiborne, T. C. Mallett, J. I. Yeh, J. Luba and D. Parsonage,
Adv. Protein Chem., 2001, 58, 215; L. B. Poole, P. A. Karplus and A.
Claiborne, Annu. Rev. Pharmacol. Toxicol., 2004, 44, 325.
14 R. Marley, M. Feelisch, S. Holt and K. Moore, Free Radical Res.,
2000, 32, 1.
15 H. R. Ellis and L. B. Poole, Biochemistry, 1997, 36, 15013.
16 J. S. Stamler and M. Feelisch, in Methods in Nitric Oxide Research,
ed. M. Feelisch and J. S. Stamler, John Wiley and Sons Ltd, New
York, 1996, pp. 521–539.
17 J. Lee, G.-B. Li, D. R. Powell, M. A. Khan and G. B. Richter-Addo,
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18 M. Itoh, K. Takenaka, R. Okazaki, N. Takeda and N. Tokitoh, Chem.
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19 G. Goto, Y. Hino, Y. Takahashi, T. Kawashima, G. Yamamoto, N.
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8479.
=
(C O), 1452, 1188; dH (250 MHz, CDCl3) 1.26–1.57 (10H, 5 ×
CH2), 1.63–1.89 (4H, 2 × CH2), 2.02 (2H, app td, J 13.5 and
3.6, CH2), 3.17 (1H, dd, J 11.6 and 3.9, OCHHCH), 3.22 (1H,
dd, J 11.6 and 3.9, OCHHCH), 3.42 (3H, s, OMe), 3.46–3.57
(2H, CHCH2O), 3.64–3.72 (1H, CHCH2O), 4.20, 4.38 (2H,
ABq JAB 16.5, OCH2CO2H), CO2H and SH absent; dC (63 MHz,
CDCl3) 20.5 (2 × t), 21.4 (2 × t), 27.8 (t), 27.9 (t), 36.6 (t), 36.7
(t), 54.7 (s), 59.3 (s), 60.2 (q), 69.0 (t), 72.9 (t), 77.6 (t), 80.8
+
(d), 172.6 (s); m/z (CI+) 350 (MNH4 , 20%), 294 (100), 278
(32); found: m/z (CI+) MNH4 350.1989, C16H32O5SN requires
+
350.2001 (D = −3.4 ppm).
S-Nitroso-[2-(9b-mercapto-1,2,3,4,5,6,7,8,9,10-decahydrona-
phthalen-10a-yloxy)-1-methoxymethylethoxy]-acetic acid 38.
To a solution of thiol oxyacetate 36 (60 mg, 0.18 mmol)
in CH2Cl2 (3.0 cm3) was added tert-butyl nitrite (170 mm3,
1.43 mmol). After 20 min the reaction was concentrated in
vacuo to give the S-nitrosothiol oxyacetate 38 as a pale green
oil (45 mg, 69%). mmax/cm−1 (CH2Cl2.) 3427, 2933, 2862, 1731
21 M. D. Bartberger, K. N. Houk, S. C. Powell, J. D. Mannion, K. Y.
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5889.
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1978, B34, 2645.
25 T. Saiki, K. Goto, N. Tokitoh, M. Goto and R. Okazaki,
J. Organomet. Chem., 2000, 611, 146.
=
=
(C O), 1503 (N O), 1453; dH (250 MHz, CDCl3) 1.37–1.72
(12H, 6 × CH2), 2.38–2.49 (4H, 2 × CH2), 3.30–3.40 (2H,
OCH2CH), 3.44 (3H, s, OMe), 3.52–3.66 (2H, CHCH2O),
3.76–3.87 (1H, CHCH2O), 4.28, 4.41 (2H, ABq JAB 16.0,
OCH2CO2H), 8.96 (1H, bs, CO2H); dC (270 MHz, CDCl3) 20.4
(2 × t), 21.2 (2 × t), 29.1 (t), 29.2 (t), 33.6 (t), 33.7 (t), 59.4 (q),
68.0 (s), 69.2 (t), 72.8 (t), 75.9 (s), 77.6 (t), 80.9 (d), 172.2 (s);
m/z (ES−) 360 (M − H, 20%), 330 (50), 297 (100%).
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1460.
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12836.
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Single crystals of sulfonate ester 37 suitable for X-ray
diffraction were obtained by recrystallisation (CH2Cl2–hexane),
mounted in inert oil and transferred to the cold gas stream of
the diffractometer. Crystal data: C16H27N1O6S1, M = 361.45,
˚
monoclinic, a = 15.095(1), b = 10.338 (6), c = 11.718 (5) A, b =
◦
3
˚
97.582(4) , U = 1812.7(18) A , T = 120 K, space group P21/c,
5
˜
˚
(C2k, No. 14), Z = 4, Mo-Ka radiation (k = 0.71073 A), l(Mo–
Ka) = 0.209 mm−1, 22 881 reflections measured, 3744 unique,
(Rint = 0.1151). Structure was discovered in the latter stages
of refinement to be a non-merohedral twin with a dominant
domain. Refinement on this single domain converged, (D/r,
max, mean = 0.005, 0.001 respectively), with final wR(F2) =
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2
1 9 5 1

View Article Online
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49 Calculated log octanol–water partition coefficients (cLogP) for
compounds 25, 33 and 36 are 2.93, 2.58 and 2.23, respectively;
the corresponding values corrected for ionisation at pH 7.4 [cLogD,
where logD = logP log(1 + 10pH − pK )] are −0.95, −0.94 and −2.67
a
(calculations performed using ACD labs software version 5.09).
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1 9 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 4 2 – 1 9 5 2