Enantioselective access to benzannulated spiroketals using a chiral sulfoxide auxiliary

Article abstract of DOI:10.1039/c3ob41065j

This article describes our efforts to develop an asymmetric synthesis of bisbenzannulated spiroketals using a chiral sulfoxide auxiliary. Our primary focus was on the synthesis of the 3H-spiro[benzofuran-2,2′-chroman] ring system, the spirocyclic core of the rubromycin family. Our strategy employed the use of lithium-halogen exchange on a racemic bromospiroketal in order to attach a chiral sulfoxide, thus producing two diastereomers. The diastereomers were separable, enabling isolation of each spiroketal enantiomer. Subsequent cleavage of the sulfoxide group from each diastereomer yielded the respective parent spiroketal in high enantiopurity.

Full text of DOI:10.1039/c3ob41065j

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Enantioselective access to benzannulated spiroketals
using a chiral sulfoxide auxiliary†
Cite this: Org. Biomol. Chem., 2013, 11,
5147
Harry R. M. Aitken, Daniel P. Furkert, Jonathan G. Hubert, James M. Wood and
Margaret A. Brimble*
This article describes our efforts to develop an asymmetric synthesis of bisbenzannulated spiroketals
using a chiral sulfoxide auxiliary. Our primary focus was on the synthesis of the 3H-spiro[benzofuran-
2,2’-chroman] ring system, the spirocyclic core of the rubromycin family. Our strategy employed the
use of lithium–halogen exchange on a racemic bromospiroketal in order to attach a chiral sulfoxide, thus
producing two diastereomers. The diastereomers were separable, enabling isolation of each spiroketal
enantiomer. Subsequent cleavage of the sulfoxide group from each diastereomer yielded the respective
parent spiroketal in high enantiopurity.
Received 22nd May 2013,
Accepted 18th June 2013
DOI: 10.1039/c3ob41065j
www.rsc.org/obc
controlled asymmetric spiroketalisation has also been
reported. A chiral iridium(I)–SpinPHOX complex has been
Introduction
The 3H-spiro[benzofuran-2,2′-chroman] ring system present in employed by Ding et al. to effect asymmetric hydrogenation,
the rubromycin family of antibiotics has received significant followed by spontaneous cyclisation9 whilst chiral phosphoric
synthetic attention over the past ten years.1 Previous synthetic acids have been independently used by the Nagory and List
strategies, including cycloadditions,2 haloetherification,3 groups to effect spiroketalisation.10
oxidative cyclisation4 and gold-catalysed hydroalkoxylation5
have only produced racemic spiroketals. We therefore report
an efficient resolution of the 3H-spiro[benzofuran-2,2′-chroman]
Results and discussion
ring system using a chiral sulfoxide auxiliary.
We focused our study on the cyclisation of sulfinyl substituted
Sulfoxide auxiliaries were employed in the current study as
dihydroxyketone 3 to spiroketal 2a. Our proposed synthetic
strategy aimed to access the sulfinyl spiroketal precursor 3
they can be readily introduced and their thiosulfinate precur-
sor can be prepared in high enantiopurity.6 It was anticipated
via a Horner–Wadsworth–Emmons/hydrogenation sequence
that substitution of the chiral sulfoxide at the ortho position
(Scheme 1). This protocol has been successfully employed in
on the benzannulated spiroketal would result in the formation
our group to access the spiroketal core of benzannulated
of two diastereomers and that the thermodynamically favoured
isomer should be formed under equilibrating conditions.
Iwata and co-workers have previously demonstrated the
use of sulfoxide auxiliaries for the asymmetric synthesis of
spiroketals.7 In their work the sulfoxide group directs an intra-
molecular Michael-type addition to facilitate the key spiro-
ketalisation step. Additionally, Uchiyama and co-workers
reported the use of a selenium-based chiral auxiliary to
direct spiroketalisation, albeit with low selectivity.8 Catalyst
Fig. 1 The spirocyclic core of γ-rubromycin.
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland
1142, New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +64 9 3737422;
Tel: +64 9 9238259
†Electronic supplementary information (ESI) available: Copies of the 1H NMR
and 13C NMR spectra for all novel compounds, HPLC traces of 2a, 2b, 27a, and
27b, and crystallographic data in CIF format for 2a and 2b. CCDC 940550 and
940551 for 2a and 2b. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob41065j
Fig. 2 Diastereomeric spiroketals bearing a homochiral sulfoxide.
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afforded disappointing yields of the desired aldehyde 11. The
best yield obtained was only 11% using ethyl formate.
Spiroketal epimerisation strategy
In many cases, spiroketals are known to undergo epimerisa-
tion under acidic conditions via ring opening and recyclisa-
tion. It was thus envisioned that epimerisation of
a
diastereomeric mixture of spiroketals 2a and 2b under acidic
conditions would result in formation of the thermodynami-
cally-favoured diastereomer (Scheme 3).
This revised strategy allowed for late stage appendage of
a chiral sulfoxide auxiliary to racemic bromospiroketal 12,
followed by acid-catalysed epimerisation. It was envisioned
that bromospiroketal precursor 13 could be prepared using a
Horner–Wadsworth–Emmons coupling/hydrogenation strategy
similar to that initially proposed for the preparation of sulfinyl
ketone 3. The requisite HWE coupling partners, bromo-
aldehyde 17 and phosphonate 21, were each prepared in two
and three steps respectively (Scheme 4).
Scheme 1 Retrosynthetic analysis of sulfinyl spiroketal 2a.
natural products.11 It was envisioned that hydrogenation then
deprotection/cyclisation of protected dihydroxyenone 4 would
afford the desired spiroketal 2a. Importantly, the influence
of the chiral sulfoxide auxiliary on the stereocontrol of the spiro-
ketalisation could be investigated. Synthesis of the key
sulfinyl enone 4 required initial access to aldehyde 5 and phos-
phonate 6.
Synthesis of sulfinyl aldehyde
Initial efforts were directed towards the synthesis of sulfinyl
aldehyde 11, which we proposed to prepare via formylation
of aryl sulfinyl bromide 10. Consequently, 10 was readily
prepared from phenol by ortho-dibromination and MOM
protection followed by ortho-lithiation and reaction with
(R)-(+)-tert-butyl tert-butanethiosulfinate (Scheme 2).
With bromosulfoxide 10 in hand, a second lithium–halogen
exchange and trapping with
a formyl electrophile was
then attempted to access aldehyde 11. Despite the successful
synthesis of 10 this subsequent transformation proved fruit-
less. Treatment of 10 with 1.1 equivalents of n-butyllithium
at −78 °C followed by addition of several electrophiles (DMF,
N-formylmorpholine, methyl formate) added in excess, only
Scheme 3 Proposed acid-catalysed epimerisation and retrosynthetic strategy
of sulfinyl spiroketal 2a.
Scheme 2 Attempted synthesis of sulfinyl aldehyde 11 with
a formyl
electrophile.
Scheme 4 Synthesis of HWE coupling partners 17 and 21.
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Scheme 5 Synthesis of ketone 23.
Scheme 7 Synthesis of methyl acetal.
Table 1 Lewis acids screened for cyclisation of acetal 26
Entry
Lewis acid (1.0 eq.)a
Ratio 12 : 25b
1
2
3
4
5
6
7
FeCl3
TiCl4
AlCl3
ZrCl4
BF3
BCl3
InCl3
0 : 100
34 : 66c
43 : 57
47 : 63
54 : 46
77 : 23
91 : 9
Scheme 6 Benzofuran formation during attempted spiroketalisation.
With both aldehyde 17 and phosphonate 21 in hand, the
Horner–Wadsworth–Emmons olefination was carried out
under conditions used previously within our group, to afford
enone 22 in quantitative yield.11 Hydrogenation of 22 proved
to be more challenging than anticipated. When enone 22 was
hydrogenated over catalytic palladium on carbon (10% Pd/C)
both hydrogenation and debromination were observed.
Finally, it was found that use of flow hydrogenation (THALES
H-Cube®, 10% Pd/C, 30 bar) cleanly afforded 23 in a reprodu-
cible 76% yield (Scheme 5).
a Lewis acid (1.0 eq.), CH2Cl2, rt, 3 h. b 100% starting material
conversion to a mixture of 12 and 25, with product ratios determined
based on the crude 1H NMR spectrum. c Significant amounts of
unidentifiable side products observed in the crude 1H NMR spectrum.
Initial deprotection attempts under Brønsted acid con-
ditions resulted in the formation of benzofuran 25 as the
major product. For cyclisations carried out in methanol,
methyl acetal 24 was observed to form prior to benzofuran for-
mation (Scheme 6).
Scheme 8 Synthesis of spiroketals 2a and 2b.
The facile formation of methyl acetal 24 suggested that if
the reaction conditions were tailored to selectively produce
acetal 24 by selective methoxymethyl cleavage, then sub-
sequent tert-butyldimethylsilyl deprotection could be carried
out under mild conditions such as buffered hydrogen fluoride
to give phenol 26. It was then hoped that cyclisation could be
effected by Lewis acids to produce spiroketal 12, thereby avoid-
ing formation of benzofuran 25. With this idea in mind, acetal
26 was prepared over two steps from 23 (Scheme 7).
A range of Lewis acids were then screened to effect the cycli-
sation of methyl acetal 26 to spiroketal 12 (Table 1). Initial
efforts produced substantial amounts of undesired benzofuran
25 (Table 1, entries 1–6), which proved particularly difficult
to separate by chromatography. Pleasingly, use of indium(III)
chloride afforded spiroketal 12 in a 91 : 9 ratio (Table 1,
entry 7) with benzofuran 25, allowing 12 to be prepared in
80% isolated yield.
The chiral sulfoxide was subsequently introduced onto
bromospiroketal 12 by halogen–metal exchange and quenching
with (R)-(+)-tert-butyl tert-butanethiosulfinate (Scheme 8).
Pleasingly, the resultant sulfoxide diastereomers 2a and 2b
were separable by careful flash chromatography. Recrystallisa-
tion and X-ray analysis gave high resolution crystal structures
for both diastereomers. Based on the known sulfoxide stereo-
chemistry it was concluded that the structures of 2a and 2b
were (RS,2S) and (RS,2R) respectively (Fig. 3).
Continuous flow hydrogenation of either sulfoxide 2a or 2b
through a RANEY® nickel cartridge in ethanol at 60 °C for 2 h
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Scheme 10 Attempted epimerisation of spirocyclic diastereomers 2a and 2b.
Fig. 3 Ortep crystal structures of 2a (left) and 2b (right) showing 50% prob-
ability displacement ellipsoids.
Scheme 11 Synthesis of model sulfoxide 29.
Three possible explanations were postulated to explain this
observation: (i) under acidic conditions the chiral sulfoxide is
able to racemise as well as the spirocentre thereby resulting in
the formation of all four possible stereoisomers; (ii) the energy
difference between 2a and 2b may not be sufficient to induce
diastereoselectivity; or (iii) acid-catalysed epimerisation of benz-
annulated spiroketals does not occur as readily as anticipated.
Each of these possibilities was therefore investigated in turn.
Sulfoxide racemisation was investigated using model com-
pound 29 which was prepared from bromobenzene 28 in 80%
yield using standard lithiation conditions (Scheme 11).
For the HPLC analysis, calibration was carried out with
racemic sulfoxide 29. Using conditions identical to those used
to effect the epimerisation of 2a and 2b, namely use of either
pyridinium p-toluenesulfonic acid or camphorsulfonic acid in
dichloromethane for 20 h, resulted in no racemisation of the
sulfoxide being observed by chiral HPLC.
Scheme 9 Synthesis of spiroketals 27a and 27b.
cleanly removed the auxiliary to yield the corresponding spiro-
ketals 27a and 27b in good yield (Scheme 9).
With both spiroketals 27a and 27b successfully prepared,
their enantiopurity was established using chiral HPLC (Chiral-
Pak® AD-H column, n-hexane–propan-2-ol 90 : 10) and it was
determined that both spiroketals were prepared in >97% ee.
HPLC calibration was performed using a sample of racemic 27
prepared in an earlier investigation.11 The optical rotation of
each compound was determined in chloroform at a wavelength
of 570 nm. Isomer (S)-27 was found have a specific rotation of
−218 (c = 0.34, 100% ee), while (R)-27 had a specific rotation of
+195 (c = 0.34, 97% ee). To the best of our knowledge, this rep-
resents the first time the rubromycin core 27 has been pre-
pared asymmetrically and therefore this is the first time that
an optical rotation has been reported for these heterocyclic
systems. It is worth noting that the melting point recorded
for enantiopure 27 is significantly higher than the literature
melting point reported for the racemic product (132 °C vs.
71 °C).11
The next experiments aimed to determine if epimerisation
of the spirocentre of 2a or 2b was possible. It was reasoned
that if epimerisation was occurring and there was no sig-
nificant energy difference between the diastereomers then
treatment of pure 2a or 2b with acid would result in a 1 : 1
ratio of products (Scheme 12).
However, when either 2a or 2b were subjected to standard
epimerisation conditions the only transformation observed
It was next hoped that the mixture of sulfoxide diastereo-
mers 2a and 2b could be converted to the most thermodynami-
cally stable diastereomer by acid-catalysed epimerisation.
After treating a 1 : 1 mixture of the two diastereomers with a
stoichiometric quantity of pyridinium p-toluenesulfonic acid
in dichloromethane for 20 h no epimerisation was observed by
1H NMR analysis (Scheme 10). Further studies using either
excess acetic acid or camphorsulfonic acid in dichloromethane
also showed no variation from the 1 : 1 ratio of diastereomers
(Scheme 10).
Scheme 12 Enantiopure 2a and 2b do not epimerise in the presence of acid.
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alumina gel (20 × 20 cm) thin layer chromatography plates.
Infrared spectra were obtained as indicated using a Perkin-
Elmer Spectrum One FTIR spectrometer on a film ATR
sampling accessory. Absorption maxima are expressed in wave-
numbers (cm−1). Melting points were determined on a Kofler
hot-stage apparatus and are uncorrected. NMR spectra were
recorded as indicated on either the Bruker Avance 300 spectro-
Fig. 4 Benzofurans 25 and 30.
1
meter operating at 300 MHz for H nuclei and 75 MHz for 13C
was the formation of trace amounts of a side product tenta-
tively assigned as benzofuran 30, with no epimerisation taking
place. The structure of benzofuran 25 was determined by com-
parison of the 1H NMR spectrum to the related benzofuran 25.
This compound was not isolated in sufficient quantity for full
characterisation (Fig. 4).
These studies suggest that benzannulated spiroketals such
as the 3H-spiro[benzofuran-2,2′-chroman] ring systems 27a
and 27b do not epimerise as readily as anticipated and that
the stereochemistry generated at the spirocentre will be
retained and will be stable to acidic conditions. This unantici-
pated stability is of potential use for the synthesis of chiral
spiroketals that are present in the rubromycin family of
antibiotics.
nuclei or using the Bruker DRX-400 spectrometer operating at
1
400 MHz for H nuclei, 100 MHz for 13C nuclei. All chemical
shifts are reported in parts per million (ppm) relative to tetra-
methylsilane (1H) or CDCl3 (1H and 13C). 1H NMR data is
reported as chemical shift, relative integral, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; dt, doublet of triplets; ddd, doublet of doublet of
doublets, coupling constant ( J Hz) and assignment. Assign-
ments were made with the aid of DEPT 135, COSY, NOESY
and HSQC experiments where required. High resolution mass
spectra were recorded on a VG-70SE at a nominal accelerating
voltage of 70 eV or on a Bruker micrOTOF-Q II mass
spectrometer.
2,6-Dibromophenol 8. To a solution of phenol (1.5 g,
16 mmol) in dichloromethane (10 mL) was added a solution of
N,N-diisopropylamine (0.44 mL, 3.1 mmol). To this mixture
was added a solution of N-bromosuccinimide (5.7 g, 32 mmol)
in dichloromethane (150 mL) dropwise over 3 h. After stirring
for 1 h at room temperature, aqueous hydrochloric acid (1 M)
was added until the solution became acidic. The organic layer
was washed with water (80 mL), dried over sodium sulfate and
concentrated in vacuo to produce a colourless residue. The
resultant residue was purified by flash column chromato-
graphy using hexanes as eluent afforded the title compound 8
(2.8 g, 11 mmol, 69%) as colourless crystals. M.p. 52–53 °C
(lit. 52–55 °C);12 1H NMR (400 MHz, CDCl3) δ: 5.88 (s, 1H),
6.70 (t, 1H, J = 8.1 Hz), 7.45 (d, 2H, J = 8.1 Hz); 13C NMR
(100 MHz, CDCl3) δ: 111.0, 122.5, 132.1, 149.5; the 1H and
13C NMR data obtained were in agreement with that reported
in the literature.12
Conclusions
Benzannulated sulfinyl spiroketals 2a and 2b have been shown
to be resilient to acid-catalysed epimerisation, suggesting that
any auxiliary-based approach to effect the asymmetric syn-
thesis of benzannulated spiroketals must have the chiral
auxiliary installed prior to cyclisation. This finding also helps
to explain the stability of the rubromycin spirocentre, which is
isolated from nature as a single isomer. The absolute optical
rotation values for the 3H-spiro[benzofuran-2,2′-chroman] ring
systems 27a and 27b have been measured for the first time.
Furthermore, attachment of the tert-butyl sulfoxide auxiliary
ortho to the oxygen has proven to be an efficient way to resolve
racemic bromospiroketal 12.
1,3-Dibromo-2-(methoxymethoxy)benzene 9. To
a stirred
solution of dibromophenol 8 (2.5 g, 10 mmol) in dichloro-
methane (70 mL) was added N,N-diisopropylethylamine
(6.9 mL, 40 mmol) followed by chloromethyl methyl ether
Experimental section
General experimental methods
All reactions were carried out in flame- or oven-dried glassware (1.1 mL, 15 mmol). The reaction was stirred at room temp-
under a dry nitrogen atmosphere. Tetrahydrofuran was dried erature for 18 h and quenched with saturated aqueous sodium
over sodium wire and dichloromethane was dried over calcium bicarbonate (50 mL). The aqueous layer was extracted with
hydride. All solvents were distilled prior to use. Flash chromato- dichloromethane (3 × 70 mL). The combined organic extracts
graphy was carried out using 0.063–0.1 mm silica gel with were washed with saturated sodium chloride (100 mL), dried
the desired solvent. Thin layer chromatography (TLC) was per- over sodium sulfate and the solvent removed in vacuo. The
formed using 0.2 mm Kieselgel F254 (Merck) silica plates and resultant oil was purified by flash chromatography using
compounds were visualised using UV irradiation at 365 nM hexanes–ethyl acetate (90 : 10) as eluent to afford the title com-
and/or staining with: vanillin in methanolic sulfuric acid, a pound 9 (2.8 g, 9.6 mmol, 96%) as a colourless oil. 1H NMR
solution of ammonium heptamolybdate and cerium sulfate in (400 MHz, CDCl3) δ: 3.73 (s, 3H), 5.18 (s, 2H), 6.88 (t, 1H, J =
aqueous sulfuric acid or a solution of potassium permanga- 8.0 Hz), 7.52 (d, 2H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3)
1
nate and potassium carbonate in aqueous sodium hydroxide. δ: 58.5, 99.7, 118.6, 126.5, 132.9, 151.7; the H and 13C NMR
Preparatory TLC was carried out on 500 μm Uniplate™ (Anal- data obtained were in agreement with that reported in the
tech) silica gel (20 × 20 cm) and 500 μm Uniplate™ (Analtech) literature.13
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1
(R)-1-Bromo-3-(tert-butylsulfinyl)-2-(methoxymethoxy)benzene 1066, 930; H NMR (400 MHz, CDCl3) δ: 3.62 (s, 3H), 5.21 (s,
10. To a solution of dibromide 9 (1.6 g, 5.4 mmol) in tetra- 2H), 7.16 (td, 1H, J = 0.8 Hz, 7.8 Hz), 7.80–7.84 (m, 2H), 10.35
hydrofuran (8 mL) was added n-butyllithium (2.5 mL, 2 M in (d, 1H, J = 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ: 58.3, 101.0,
cyclohexane, 4.9 mmol) dropwise at −78 °C. The solution was 118.2, 126.0, 127.7, 131.7, 139.2, 157.3, 189.7; HRMS (ESI+),
stirred for 15 min followed by rapid addition of (R)-(+)-tert- Calculated for C9H9BrO3Na: 266.9627 (M+ + Na); Found
butyl tert-butanethiosulfinate (1.6 g, 8.1 mmol) in tetrahydro- 266.9626.
furan (1.5 mL). The solution was immediately transferred to a
Methyl 2-(2′-hydroxyphenyl)acetate 19. Sulfuric acid (20
−10 °C ice bath and stirred for 4 h. The reaction was quenched drops) was added to a stirred solution of 2-(2′-hydroxyphenyl)-
by addition of saturated aqueous ammonium chloride (8 mL) acetic acid (4.0 g, 26 mmol) in methanol (80 mL) at room
and the aqueous layer was extracted using ethyl acetate temperature. The reaction mixture was heated to reflux for 3 h,
(3 × 10 mL). The combined organic layers were washed with after which it was cooled and filtered through a pad of silica,
saturated sodium chloride (20 mL), dried over sodium sulfate washing with ethyl acetate. The solvent was removed in vacuo
and the solvent removed in vacuo. The crude product was puri- to afford the title compound 19 (4.3 g, 26 mmol, 99%) as white
fied by flash chromatography using hexanes–ethyl acetate crystals. M.p. 61–62 °C (lit. 61–62 °C);15 1H NMR (400 MHz,
(50 : 50) as eluent to afford the title compound 10 (1.2 g, CDCl3) δ: 3.69 (s, 2H), 3.75 (s, 3H), 6.89 (td, 1H, J = 1.2 Hz,
3.9 mmol, 80%) as a pale yellow solid. M.p. 60–62 °C; [α]2D0: 7.5 Hz), 6.93 (dd, 1H, J = 1.2 Hz, 7.5 Hz), 7.11 (dd, 1H, J =
+142 (c = 1.02, CHCl3, 34% ee). IR spectrum (film), cm−1
:
1.7 Hz, 7.5 Hz), 7.19 (td, 1H, J = 1.7 Hz, 7.5 Hz), 7.32 (s, 1H).
1
2957, 1431, 1161, 1066, 1041, 925; H NMR (400 MHz, CDCl3) The 1H NMR data obtained were in agreement with that
δ: 1.20 (s, 9H), 3.66 (s, 3H), 5.17 (s, 2H), 7.22 (t, 1H, J = 7.9 Hz), reported in the literature.15
7.69 (dd, 1H, J = 1.5 Hz, 7.9 Hz), 7.76 (dd, 1H, J = 1.5 Hz, 7.9
Dimethyl (3-(2′-hydroxyphenyl)-2-oxopropyl)phosphonate 20.
Hz); 13C NMR (100 MHz, CDCl3) δ: 23.1, 58.6, 58.7, 100.1, 19) To a stirred solution of dimethyl methylphosphonate
117.3, 126.0, 126.8, 136.4, 137.1, 151.6. HRMS (ESI+), Calcu- (2.0 mL, 18 mmol) in tetrahydrofuran (100 mL) was added
lated for C12H18O3S: 321.0155 (M+); Found 321.0160.
n-butyllithium (11 mL, 1.6 M in hexanes, 18 mmol) dropwise
3-Bromo-2-hydroxybenzaldehyde 16. To a solution of salicyl- at −78 °C. The mixture was stirred at −78 °C for 30 min, fol-
aldehyde (15 g, 0.12 mol) in dichloromethane (150 mL) was lowed by dropwise addition of a solution of ester 19 (1.0 g,
added N,N-diisopropylamine (1.7 mL, 12 mmol) followed by a 6.0 mmol) in tetrahydrofuran (5 mL). The reaction mixture was
solution of N-bromosuccinimide (22 g, 0.12 mol) in dichloro- stirred for 1 h at −78 °C, after which it was quenched with
methane (900 mL) dropwise over 9 h. After stirring for 3 h at saturated ammonium chloride (100 mL) and warmed to room
room temperature, the mixture was acidified to pH 1 with temperature. The resultant mixture was extracted with ethyl
aqueous hydrochloric acid (1 M). The organic layer was separ- acetate (3 × 100 mL), the combined organic extracts washed
ated, washed with water (300 mL), dried over sodium sulfate with saturated sodium chloride (100 mL), dried over mag-
and concentrated in vacuo to produce a yellow residue. Purifi- nesium sulfate and the solvent removed in vacuo. The resultant
cation by flash chromatography using hexanes–ethyl acetate oil was purified by flash chromatography using ethyl acetate–
(95 : 5) as eluent afforded the title compound 16 (17 g, hexanes (2 : 1) as eluent to afford the title compound 20 (1.4 g,
87 mmol, 70%) as yellow crystals. M.p. 50–52 °C (lit. 5.5 mmol, 92%) as a colourless solid. M.p. 78–80 °C; IR spec-
49–52 °C);14 IR spectrum (film), cm−1: 3092, 2852, 1652, 905; trum (film), cm−1: 3200, 2957, 1718, 1598, 1454, 1227, 1028,
1H NMR (400 MHz, CDCl3) δ: 6.95 (t, 1H, J = 7.8 Hz), 7.55 (d, 768; 1H NMR (400 MHz, CDCl3) δ: 3.20 (d, 2H, J = 22.4 Hz),
1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 9.86 (s, 1H), 11.60 (s, 3.78 (d, 6H, J = 11.3 Hz), 3.87 (s, 2H), 6.85 (td, 1H, J = 1.1 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 111.2, 120.8, 121.4, 132.9, 7.4 Hz), 6.92 (dt, 1H, J = 1.1 Hz, 7.4 Hz), 7.08 (dt, 1H, J =
140.0, 158.1, 196.0; HRMS (ESI+), Calculated for C7H5BrO2Na: 1.7 Hz, 7.4 Hz), 7.15 (td, 1H, J = 1.7 Hz, 7.4 Hz), 7.95 (s, 1H);
222.9365 (M+ + Na); Found 222.9373. The data obtained were 13C NMR (100 MHz, CDCl3) δ: 40.1 (d, J = 129 Hz), 46.0, 53.4
in agreement with that reported in the literature.14
(d, J = 6 Hz), 116.7, 120.4, 129.0, 131.4, 154.9, 200.7. HRMS
3-Bromo-2-(methoxymethoxy)benzaldehyde 17. To a stirred (ESI+), Calculated for C11H15O5PNa: 281.0549 (M+ + Na);
solution of phenol 16 (1.5 g, 7.5 mmol) in dichloromethane Found 281.0555.
(30 mL) was added N,N-diisopropylethylamine (5.1 mL,
Dimethyl (3-(2-(tert-butyldimethylsilyloxy)phenyl)-2-oxo-
30 mmol) followed by chloromethyl methyl ether (0.85 mL, propyl)phosphonate 21. To a stirred solution of tert-butyldi-
11 mmol). The reaction was stirred at room temperature for methylsilyl chloride (4.1 g, 27 mmol), imidazole (2.2 g,
18 h then quenched with saturated aqueous sodium bicarbon- 33 mmol), and N,N-dimethyl-4-aminopyridine (0.13 g,
ate (20 mL). The aqueous layer was extracted with dichloro- 1.1 mmol) in dimethylformamide (6 mL) was added a solution
methane (3 × 30 mL). The combined organic extracts were of phenol 20 (2.8 g, 11 mmol) in dimethylformamide (6 mL)
washed with saturated sodium chloride (40 mL), dried over dropwise. The solution was then stirred for 18 h at room temp-
sodium sulfate and the solvent removed in vacuo. The resultant erature and quenched with saturated aqueous sodium bicar-
oil was purified by flash chromatography using hexanes–ethyl bonate (10 mL). The aqueous layer was extracted with ethyl
acetate (90 : 10) as eluent to afford the title compound 17 (1.8 g, acetate (3 × 20 mL). The combined organic layers were washed
7.2 mmol, 97%) as colourless crystals. M.p. 44–45 °C; IR with saturated sodium chloride (10 mL), dried over sodium
spectrum (film), cm−1: 2929, 1685, 1587, 1381, 1241, 1159, sulfate, concentrated in vacuo. The crude residue was purified
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by flash chromatography using ethyl acetate–hexanes (50 : 50) 153.2, 153.8, 207.3. HRMS (ESI+), Calculated for C24H33O4Br-
as eluent to afford the title compound 21 (3.22 g, 8.7 mmol, SiNa: 515.1224 (M+ + Na); Found 515.1227.
80%) as a yellow oil. IR spectrum (film), cm−1: 2955, 2858,
8-Bromo-2-(2′-tert-butyldimethylsilyloxy)benzyl-2-methoxy-
1719, 1493, 1255, 1029, 928, 834; 1H NMR (400 MHz, CDCl3) δ: chroman 24. To a solution of ketone 23 (1.2 g, 2.3 mmol) in
0.24 (s, 6H), 0.98 (s, 9H), 3.06 (d, 2H, J = 22.2 Hz), 3.76 (d, 6H, methanol–tetrahydrofuran (2 : 3, 14 mL) was added camphor-
J = 11.2 Hz), 3.82 (s, 2H), 6.83 (dd, 1H, J = 1.1 Hz, 8.6 Hz), 6.94 sulfonic acid monohydrate (1.1 g, 4.7 mmol) and the solution
(td, 1H, J = 1.1 Hz, 7.5 Hz), 7.15–7.17 (m, 2H); 13C NMR was stirred for 22 h. The reaction was quenched with solid
(100 MHz, CDCl3) δ: −4.2, 18.2, 25.7, 39.7 (d, J = 129 Hz), 46.1 sodium bicarbonate (1.0 g) and filtered through a pad of silica,
(d, J = 2 Hz), 52.8 (d, J = 6 Hz), 118.4, 121.3, 124.7, 128.6, 131.6, washing with ethyl acetate. The solvent was removed in vacuo
153.8, 199.4 (d, 1H, J = 6 Hz). HRMS, Calculated for to afford the title compound 24 which was used as crude.
C17H29O5PSiNa: 395.1414 (M+ + Na); Found 395.1411.
A small analytical sample was prepared by filtering the crude
(E)-4-(3-Bromo-2-(methoxymethoxy)phenyl)-1-(2-(tert-butyl- through silica and washing with hexanes–ethyl acetate
dimethylsilyloxy)phenyl)but-3-en-2-one 22. A solution of phos- (90 : 10). IR spectrum (film), cm−1: 2942, 1452, 1255, 1034,
phonate 21 (2.7 g, 7.3 mmol) in tetrahydrofuran (30 mL) was 835; 1H NMR (400 MHz, CDCl3) δ: 0.29 (d, 6H, J = 8.5 Hz), 1.07
added dropwise to a stirred suspension of sodium hydride (s, 9H), 1.67 (td, 1H, J = 6.0 Hz, 13.5 Hz), 2.03 (ddd, 1H, J =
(0.29 g, 60% in paraffin, 7.3 mmol) in tetrahydrofuran (30 mL) 2.0 Hz, 6.0 Hz, 13.5 Hz), 2.53 (ddd, 1H, J = 2.0 Hz, 6.0 Hz,
at 0 °C. The mixture was stirred at room temperature for 16.1 Hz), 2.99 (ddd, 1H, J = 6.0 Hz, 13.5 Hz, 16.1 Hz), 3.33 (d,
30 min, after which a solution of aldehyde 17 (1.5 g, 2H, J = 4.5 Hz), 3.44 (s, 3H), 6.74 (t, 1H, J = 7.5 Hz), 6.84 (dd,
6.0 mmol) in tetrahydrofuran (60 mL) was added. The reaction 1H, J = 1.3 Hz, 8.9 Hz), 6.94 (td, 1H, J = 1.5 Hz, 7.5 Hz), 6.97 (d,
mixture was stirred at room temperature for 18 h, quenched 1H, J = 7.5 Hz), 7.13 (td, 1H, J = 2.0 Hz, 8.9 Hz), 7.37 (d, 1H, J =
with saturated ammonium chloride (80 mL) and extracted with 7.5 Hz), 7.53 (dd, 1H, J = 2.0 Hz, 7.5 Hz). 13C NMR (100 MHz,
ethyl acetate (3 × 120 mL). The combined organic extracts were CDCl3) δ: −3.9 (d, 1H, J = 18.6 Hz), 18.5, 21.5, 26.1, 28.1, 34.7,
washed with saturated sodium chloride (100 mL), dried over 49.4, 101.4, 111.4, 118.5, 121.3, 124.8, 126.6, 127.7, 128.3,
sodium sulfate and the solvent removed in vacuo. The resultant 130.8, 132.6, 149.2, 154.3; HRMS (ESI+), Calculated for
oil was purified by flash chromatography using hexanes–ethyl C23H31O3BrK: 501.0857 (M+ + K); Found 501.0868.
acetate (90 : 10) as eluent to afford the title compound 22 (3.0 g,
6.0 mmol, 100%) as a yellow oil. IR spectrum (film), cm−1
8-Bromo-2-(2′-hydroxy)benzyl-2-methoxychroman 26 and
2-(2-(benzofuran-2-yl)ethyl)-6-bromophenol 12. To a solution
:
2954, 2858, 1686, 1602, 1452, 1254, 1157, 922; 1H NMR of crude protected phenol 130 (1.1 g) in acetonitrile (100 mL)
(400 MHz, CDCl3) δ: 0.25 (s, 6H), 0.98 (s, 9H), 3.63 (s, 3H), 3.93 was added triethylamine trihydrofluoride (0.77 mL, 2.4 mmol)
(s, 2H), 5.06 (s, 2H), 6.77 (d, 1H, J = 16.1 Hz), 6.86 (dd, 1H, J = dropwise. The reaction mixture was stirred at room temp-
1.1 Hz, 8.6 Hz), 6.94 (td, 1H, J = 1.2 Hz, 7.5 Hz), 7.01 (td, 1H, erature for 3 days, quenched with saturated sodium bicarbonate
J = 0.5 Hz, 7.9 Hz), 7.15–7.17 (m, 2H), 7.47 (dd, 1H, J = 1.5 Hz, (50 mL) and extracted with ethyl acetate (3 × 100 mL). The
6.3 Hz), 7.58 (dd, 1H, J = 1.5 Hz, 7.9 Hz), 7.96 (d, 1H, J = 16.1 combined organic extracts were washed with saturated sodium
Hz); 13C NMR (100 MHz, CDCl3) δ: −4.1, 18.3, 25.8, 43.6, 58.3, chloride (100 mL), dried over sodium sulfate and the solvent
100.5, 118.3, 118.5, 121.3, 125.4, 125.8, 126.5, 127.0, 128.3, removed in vacuo. The resultant oil was purified by flash
131.1, 131.4, 135.1, 137.4, 153.9, 154.0, 197.1. HRMS (ESI+), chromatography using hexanes–ethyl acetate (90 : 10) as eluent
Calculated for C24H31O4BrSiK: 529.0807 (M+ + K); Found to afford the title compound 26 (0.58 g, 1.7 mmol, 72% over two
529.0796.
steps) as colourless crystals and benzofuran 25 (100 mg,
4-(3-Bromo-2-(methoxymethoxy)phenyl)-1-(2-(tert-butyldi- 0.32 mmol, 14% yield over two steps) as a yellow solid.
methylsilyloxy)phenyl)butan-2-one 23. A solution of enone 22
8-Bromo-2-(2′-hydroxy)benzyl-2-methoxychroman
26. M.
(2.1 g, 4.3 mmol) in ethyl acetate (210 mL) was hydrogenated p. 122–124 °C; IR spectrum (film), cm−1: 3441, 2937, 1491,
1
using H-Cube® HC-2 continuous hydrogenation apparatus 1452, 1227, 759; H NMR (400 MHz, CDCl3) δ: 1.75 (ddd, 1H,
(THALES Nanotechnology Inc.) using a 10% palladium on J = 6.2 Hz, 12.5 Hz, 13.8 Hz), 1.99 (ddd, 1H, J = 2.5 Hz, 6.5 Hz,
carbon cartridge at 25 °C and a hydrogen pressure of 30 bar. 13.8 Hz), 2.61 (ddd, 1H, J = 2.5 Hz, 6.2 Hz, 16.5 Hz), 2.85 (d,
The solvent was removed in vacuo and the resulting crude 1H, J = 14.3 Hz), 2.97–3.06 (m, 1H) 3.47 (s, 3H), 3.56 (s, 3H),
product was purified via flash chromatography using hexanes– 3.79 (d, 1H, J = 14.3 Hz), 6.79 (t, 1H, J = 7.9 Hz), 6.88 (td, 1H,
ethyl acetate (90 : 10) as eluent to afford the title compound 23 J = 1.3 Hz, 7.4 Hz), 6.96 (dd, 1H, J = 1.3 Hz, 7.9 Hz), 6.95–7.00
(1.6 g, 3.2 mmol, 76%) as a colourless oil. IR spectrum (film), (m, 1H), 7.10 (dd, 1H, J = 1.6 Hz, 7.4 Hz), 7.14–7.20 (m, 2H),
1
cm−1: 2931, 1714, 1256, 1158, 922; H NMR (400 MHz, CDCl3) 7.37 (d, 1H, J = 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ: 21.4,
δ: 0.23 (s, 6H), 0.98 (s, 9H), 2.75 (t, 2H, J = 8.1 Hz), 2.95 (t, 2H, 28.2, 38.7, 49.5, 102.8, 111.3, 117.9, 120.7, 122.2, 122.5, 124.6,
J = 8.1 Hz), 3.56 (s, 3H), 3.66 (s, 2H), 5.05 (s, 2H), 6.82 (dd, 1H, 128.5, 128.9, 130.8, 132.5, 148.0, 155.1. HRMS (ESI+), Calcu-
J = 1.1 Hz, 8.1 Hz), 6.89 (t, 1H, J = 7.7 Hz), 6.90 (td, 1H, J = lated for C17H17O3BrK: 386.9993 (M+ + K); Found 387.0004.
1.2 Hz, 7.7 Hz), 6.89–6.94 (m, 2H), 7.14 (td, 1H, J = 1.8 Hz,
2-(2-(Benzofuran-2-yl)ethyl)-6-bromophenol
25. M.
7.7 Hz), 7.39 (dd, 1H, J = 1.6 Hz, 8.1 Hz); 13C NMR (100 MHz, p. 49–50 °C IR spectrum (film), cm−1: 3441, 2937, 1491, 1452,
CDCl3) δ: −4.2, 18.2, 25.1, 25.8, 42.1, 45.1, 57.7, 99.9, 117.4, 1227, 759; 1H NMR (400 MHz, CDCl3) δ: 3.06–3.14 (m, 4H),
118.5, 121.3, 125.4, 125.6, 128.3, 129.5, 131.4, 131.6, 137.1, 5.62 (s, 1H), 6.37 (s, 1H), 6.71 (t, 1H, J = 7.8 Hz), 7.04 (dd, 1H,
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J = 1.5 Hz, 7.8 Hz), 7.19 (m, 2H), 7.32 (dd, 1H, J = 1.5 Hz, 7.8 excess (98% ee) was determined by HPLC (Chiracel AD-H
Hz) 7.15–7.23 (m, 1H′′), 7.41–7.47 (m, 1H′′); 13C NMR column, n-hexane–propan-2-ol 90 : 10; flow rate 0.5 mL min−1
(100 MHz, CDCl3) δ: 28.5, 29.5, 102.5, 110.7, 110.9, 120.4, tmajor = 36.7 min, tminor = 55.3 min).
;
121.6, 122.6, 123.4, 128.8, 129.1, 129.9, 130.2, 150.2, 154.8,
158.7; HRMS (ESI+), Calculated for C17H17O3BrK: 386.9993 chroman] 2b. M.p. 157–158 °C; [α]2D0: +347 (c = 0.40, CHCl3,
(M+ + K); Found 387.0004. 97% ee); IR spectrum (film), cm−1: 2960, 1446, 1229, 1171,
(RS,2R)-8′-(tert-Butylsulfinyl)-3H-spiro[benzofuran-2,2′-
2-(2-(Benzofuran-2-yl)ethyl)-6-bromophenol 25. To a solu- 1042, 900; 1H NMR (400 MHz, CDCl3) δ: 0.93 (s, 9H), 2.20–2.28
tion of methyl acetal 26 (0.53 g, 1.5 mmol) in dichloromethane (m, 1H), 2.34 (ddd, 1H, J = 2.5 Hz, 6.0 Hz, 13.4 Hz), 2.88 (ddd,
(20 mL) was added indium chloride (0.34 g, 1.5 mmol). The 1H, 2.5 Hz, 6.0 Hz, 16.5 Hz), 3.25–3.49 (m, 3H), 6.68 (d, 1H, J =
resulting slurry was stirred at room temperature for 3 h. The 6.7 Hz), 6.93 (td, 1H, J = 0.8 Hz, 7.5 Hz), 7.10 (m, 2H), 7.24 (t,
reaction was quenched with solid sodium bicarbonate 2H, J = 6.7 Hz), 7.60 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz,
(0.50 mg) and filtered through a pad of silica, washing with CDCl3) δ: 21.9, 22.8, 29.9, 41.7, 57.5, 109.1, 109.7, 121.4, 121.6,
ethyl acetate. The solvent was removed in vacuo and the 121.8, 125.0, 125.2, 125.7, 128.2, 128.4, 132.1, 150.1, 157.8;
residue was purified by recrystallisation from diethyl ether to HRMS (ESI+), Calculated for C20H23O3S: 343.1362 (M+); Found
afford the title compounds 12 (0.39 g, 1.2 mmol, 80%) as col- 343.1350. The enantiomeric excess (97% ee) was determined
ourless crystals. M.p. 127–129 °C; IR spectrum (film), cm−1
:
by HPLC (Chiral-Pak® AD-H column, n-hexane–propan-2-ol
3666, 2978, 1388, 1247, 1067; 1H NMR (400 MHz, CDCl3) δ: 90 : 10; flow rate 0.5 mL min−1; tminor = 28.0 min, tmajor
2.14–2.22 (m, 1H), 2.34 (ddd, 1H, J = 2.5 Hz, 5.9 Hz, 16.5 Hz), 55.4 min).
=
2.82 (ddd, 1H, J = 2.5 Hz, 5.9 Hz, 16.5 Hz), 3.24–3.33 (m, 1H),
(S)-3H-Spiro[benzofuran-2,2′-chroman] 27a. A solution of
3.33 (d, 1H, J = 16.6 Hz), 3.59 (d, 1H, J = 16.6 Hz), 6.77–6.81 sulfoxide 2a (5.0 mg, 0.015 mmol) in ethanol (10 mL) was
(m, 2H), 6.94 (td, 1H, J = 1.0 Hz, 7.5 Hz), 7.08 (d, 1H, J = hydrogenated under continuous cycle for 2 h using H-Cube®
7.5 Hz), 7.14 (t, 1H, J = 8.0 Hz), 7.25 (d, 1H, J = 7.0 Hz), 7.37 (d, HC-2 continuous hydrogenation apparatus (THALES Nanotech-
1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ: 22.2, 30.5, 41.9, nology Inc.) using a RANEY® nickel cartridge at 60 °C and a
109.9, 121.3, 121.9, 123.4, 124.9, 125.2, 128.1, 128.3, 131.3, hydrogen pressure of 100 bar. The solvent was removed
149.1, 157.7. HRMS (ESI+), Calculated for C16H13O2BrNa: in vacuo and the resulting crude product was filtered through
338.9991 (M+ + Na); Found 338.9996.
silica using hexanes–ethyl acetate (80 : 20) eluent to afford the
(RS,2S)-8′-(tert-Butylsulfinyl)-3H-spiro[benzofuran-2,2′- title compound 27a (2.8 mg, 0.012 mmol, 80%) as colourless
chroman] 2a and (RS,2R)-8′-(tert-butylsulfinyl)-3H-spiro[benzo- crystals. M.p. 132–134 °C (lit. 71–72 °C, racemic);11 [α]D20: −218
furan-2,2′-chroman] 2b. To a solution of bromospiroketal 12 (c = 0.34, CHCl3, 100% ee); 1H NMR (400 MHz, CDCl3) δ:
(80 mg, 0.25 mmol) in tetrahydrofuran (0.8 mL) was added 2.16–2.24 (m, 1H), 2.34 (ddd, 1H, J = 2.7 Hz, 5.9 Hz, 13.4 Hz),
n-butyllithium (0.14 mL, 2 M in cyclohexane, 0.28 mmol) drop- 2.83 (ddd, 1H, 2.7 Hz, 5.9 Hz, 16.4 Hz), 3.21–3.31 (m, 2H), 3.45
wise at −78 °C. The solution was stirred for 10 min followed by (d, 1H, J = 16.4 Hz), 6.80 (dd, 1H, J = 2.5 Hz, 8.1 Hz), 6.92 (t,
addition of (R)-(+)-tert-butyl tert-butanethiosulfinate (59 mg, 1H, J = 7.2 Hz, 2H), 7.13 (m, 2H), 7.24 (t, 1H, J = 8.1 Hz), 7.60
1
0.30 mmol) in tetrahydrofuran (0.2 mL). The solution was (d, 1H, J = 7.2 Hz). The H NMR data obtained was in agree-
allowed to warm to room temperature over 4 h and then ment with that reported in the literature.11 The enantiomeric
quenched by saturated aqueous ammonium chloride (1 mL). excess was determined by HPLC (Chiral-Pak® AD-H column,
The aqueous layer was extracted using ethyl acetate (3 × 2 mL). n- hexane–propan-2-ol 90 : 10; flow rate 0.5 mL min−1; tS
The combined organic layers were washed with saturated 9.7 min, tR = 10.2 min).
=
sodium chloride (3 mL), dried over sodium sulfate and the
(R)-3H-Spiro[benzofuran-2,2′-chroman] 27b. A solution of
solvent removed in vacuo. The crude product was purified by sulfoxide 2b (17 mg, 0.050 mmol) in ethanol (3.5 mL) was
flash chromatography using dichloromethane–ethyl acetate hydrogenated under continuous cycle for 2 h using H-Cube®
(85 : 15) eluent to afford the title compounds 2a (25 mg, HC-2 continuous hydrogenation apparatus (THALES Nanotech-
0.070 mmol, 29%) and 2b (21 mg, 0.060 mmol, 24%) separ- nology Inc.) using a RANEY® nickel cartridge at 60 °C and a
ately as colourless crystals.
hydrogen pressure of 100 bar. The solvent was removed
(RS,2S)-8′-(tert-Butylsulfinyl)-3H-spiro[benzofuran-2,2′- in vacuo and the resulting crude product was filtered through
chroman] 2a. M.p. 135–137 °C; [α]2D0: +125 (c = 0.44, CHCl3, silica using hexanes–ethyl acetate (80 : 20) eluent to afford the
97% ee); IR spectrum (film), cm−1: 2972, 2887, 1378, 1089, title compound 27b (10 mg, 0.042 mmol, 85%) as colourless
1048, 952; 1H NMR (400 MHz, CDCl3) δ: 1.16 (s, 9H), 2.13–2.21 crystals. For both enantiomers: m.p. 132–134 °C (lit. 71–72 °C,
(m, 1H), 2.35 (ddd, 1H, J = 2.5 Hz, 6.0 Hz, 13.4 Hz), 2.87 (ddd, racemic);11 [α]D20: +195 (c = 0.33, CHCl3, 97% ee); 1H NMR
1H, 2.5 Hz, 6.0 Hz, 16.5 Hz), 3.25–3.41 (m, 1H), 6.78 (d, 1H, J = (400 MHz, CDCl3) δ: 2.16–2.24 (m, 1H), 2.34 (ddd, 1H, J =
6.7 Hz), 6.94 (td, 1H, J = 0.8 Hz, 7.6 Hz), 7.10 (t, 1H, J = 7.6 Hz), 2.7 Hz, 5.9 Hz, 13.4 Hz), 2.83 (ddd, 1H, 2.7 Hz, 5.9 Hz, 16.4
7.16 (t, 1H, J = 7.6 Hz), 7.23 (t, 2H, J = 6.7 Hz), 7.61 (d, 1H, J = Hz), 3.21–3.31 (m, 2H), 3.45 (d, 1H, J = 16.4 Hz), 6.80 (dd, 1H,
7.2 Hz); 13C NMR (100 MHz, CDCl3) δ: 22.0, 23.3, 30.5, 41.8, J = 2.5 Hz, 8.1 Hz), 6.92 (t, 1H, J = 7.2 Hz, 2H), 7.13 (m, 2H),
1
57.4, 109.1, 110.2, 121.3, 121.5, 121.9, 124.8 (2C), 125.8, 128.5, 7.24 (t, 1H, J = 8.1 Hz), 7.60 (d, 1H, J = 7.2 Hz). The H NMR
128.6, 132.0, 150.3, 157.8; HRMS (ESI+), Calculated for data obtained was in agreement with that reported in the lit-
C20H23O3S: 343.1362 (M+); Found 343.1350. The enantiomeric erature.11 The enantiomeric excess was determined by HPLC
5154 | Org. Biomol. Chem., 2013, 11, 5147–5155
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(Chiral-Pak® AD-H column, n-hexane–propan-2-ol 90 : 10; flow
rate 0.5 mL min−1; tS = 9.7 min, tR = 10.2 min).
(i) D. C. K. Rathwell, S.-H. Yang, K. Y. Tsang and
M. A. Brimble, Angew. Chem., Int. Ed., 2009, 48, 7996.
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(R)-tert-Butylsulfinyl benzene 29. To a solution of bromo-
benzene (0.55 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was
added n-butyllithium (2.8 mL, 2 M in hexanes, 5.5 mmol)
dropwise at −78 °C. The solution was stirred for 20 min fol-
lowed by addition of (R)-(+)-tert-butyl tert-butanethiosulfinate
(1.0 g, 5.5 mmol). The solution was allowed to warm to room
temperature over 2 h then quenched with saturated aqueous
ammonium chloride (5 mL). The aqueous layer was extracted
with ethyl acetate (3 × 5 mL). The combined organic layers
were washed with saturated sodium chloride (10 mL), dried
over sodium sulfate and the solvent was removed in vacuo. The
crude product was purified by flash chromatography using
hexanes–ethyl acetate (50 : 50) as eluent to afford the title com-
1
pound 29 (0.73 g, 4.0 mmol, 80%) as a colourless oil. H NMR
(400 MHz, CDCl3) δ: 1.17 (s, 9H), 7.48–7.50 (m, 3H), 7.58–7.61
(m, 2H). The 1H NMR data obtained was in agreement with
that reported in the literature.16
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Notes and references
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D. C. K. Rathwell and M. A. Brimble, Synlett, 2009, 793; 12 B. Glettner, F. Liu, X. Zeng, M. Prehm, U. Baumeister,
(d) J. Sperry, Y.-C. Liu, Z. E. Wilson, J. G. Hubert and
M. A. Brimble, Synthesis, 2011, 1383; (e) K.-L. Wu,
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47, 6080.
E. V. Mercado and T. R. R. Pettus, J. Am. Chem. Soc., 2011, 13 P. G. Edwards, S. J. Paisey and R. P. Tooze, J. Chem. Soc.,
133, 6114; (f) S. Akai, K. Kakiguchi, Y. Nakamura, Perkin Trans. 1, 2000, 3122.
I. Kuriwaki, T. Dohi, S. Harada, O. Kubo, N. Morita and 14 M. Kauch and D. Hoppe, Synthesis, 2006, 1578.
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This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 5147–5155 | 5155