The diastereoselective Meth-Cohn epoxidation of camphor-derived vinyl sulfones

Article abstract of DOI:10.1016/j.tetasy.2012.04.014

Some camphor-derived vinyl sulfones bearing an oxygen functionality at the allylic position have been synthesised and their nucleophilic epoxidation reactions under Meth-Cohn conditions have been explored. The γ-oxygenated camphor-derived vinyl sulfones underwent mildly diastereoselective nucleophilic epoxidation reactions, affording the derived sulfonyloxiranes in up to 5.8:1 dr. The diastereoselectivities observed were sensitive to the reaction conditions employed. In contrast, no stereoselectivity was observed in the nucleophilic epoxidation of the corresponding γ-oxygenated isobornyl vinyl sulfone. A tentative mechanism has been proposed to explain the origins of the diastereoselectivity.

Full text of DOI:10.1016/j.tetasy.2012.04.014

Tetrahedron: Asymmetry 23 (2012) 643–649
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The diastereoselective Meth-Cohn epoxidation of camphor-derived
vinyl sulfones
⇑
Frank W. Lewis , David H. Grayson
Centre for Synthesis and Chemical Biology, School of Chemistry, Trinity College, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Some camphor-derived vinyl sulfones bearing an oxygen functionality at the allylic position have been
synthesised and their nucleophilic epoxidation reactions under Meth-Cohn conditions have been
Received 14 March 2012
Accepted 20 April 2012
Available online 2 June 2012
explored. The
c-oxygenated camphor-derived vinyl sulfones underwent mildly diastereoselective
nucleophilic epoxidation reactions, affording the derived sulfonyloxiranes in up to 5.8:1 dr. The diastere-
oselectivities observed were sensitive to the reaction conditions employed. In contrast, no stereoselectiv-
ity was observed in the nucleophilic epoxidation of the corresponding
c-oxygenated isobornyl vinyl
sulfone. A tentative mechanism has been proposed to explain the origins of the diastereoselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
with magnesium bromide affords a
-bromo ketones.13 In addition,
Mori reported the nucleophilic epoxidation of the (Z)-isomer of 3
which afforded the corresponding cis-sulfonyloxiranes.14 Further-
more, an asymmetric variant of this methodology has been devel-
oped, involving diastereoselective nucleophilic epoxidation of
vinyl sulfoximines derived from isopropylideneglyceraldehyde.15
Sulfone 3 could thus be an attractive precursor to 3-O-benzylglyc-
eraldehyde 4 (Fig. 1) using the above methodologies, and we envis-
aged that camphor-derived vinyl sulfones could be potential
Unsaturated sulfones are versatile intermediates in organic syn-
thesis, acting as both electron deficient olefins in a wide range of
cycloaddition processes, and as Michael acceptors with a number
of carbon and heteroatom nucleophiles.1 In recent years, unsatu-
rated sulfones have also been extensively used as substrates in cat-
alytic asymmetric synthesis.2,3 However, although applications of
chiral sulfones in asymmetric synthesis have been reported,4 there
appears to have been no reports on the applications of vinyl sulf-
ones 1, which possess homochiral alkyl groups R* directly attached
to the sulfur atom (Fig. 1). Given the widespread use of camphor
derivatives as chiral auxiliaries,5 we reasoned that vinyl sulfones
bearing the camphorsulfonyl moiety 2 would be promising candi-
dates for the preparation of enantiomerically enriched compounds.6
precursors for the asymmetric synthesis of
a-hydroxy aldehydes
such as 4 using these methodologies.16 Herein, we extend our re-
cent investigations17 on the utility of camphor-derived sulfones
in asymmetric synthesis and report our findings on the use of cam-
phor-derived vinyl sulfones as potential precursors to enantioen-
riched
a
-hydroxy aldehydes such as 4.
Vinyl sulfones also act as synthetic precursors to a-functional-
ised carbonyl compounds. Nucleophilic epoxidation of vinyl sulf-
ones with a metal alkyl peroxide under anhydrous conditions
(Meth-Cohn epoxidation),7 or under classical Weitz–Scheffer con-
ditions8 generates sulfonyloxiranes that react regiospecifically at
the b-position with a range of heteroatom nucleophiles to generate
R
-functionalised carbonyl compounds.9,10 In addition, Sharpless
R*SO2
R* =
a
asymmetric dihydroxylation of vinyl sulfones generates enantioen-
O
-hydroxy aldehydes directly in a single step.11 Jackson pre-
1
2
riched
a
viously reported the synthesis and nucleophilic epoxidation of
achiral (E)-3-benzyloxyprop-1-enyl phenyl sulfone 3 (Fig. 1),12
and showed that subsequent cleavage of related sulfonyloxiranes
O
PhSO2
OBn
4
H
OBn
OH
3
⇑
Corresponding author at present address: Department of Chemistry, University
of Reading, Whiteknights, Reading RG6 6AD, UK.
Figure 1. Homochiral camphor-derived vinyl sulfones and the structures of
(E)-3-benzyloxyprop-1-enyl phenyl sulfone and 3-O-benzylglyceraldehyde.
E-mail addresses: f.lewis@reading.ac.uk, flewis@tcd.ie (F.W. Lewis).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.014

644
F. W. Lewis, D. H. Grayson / Tetrahedron: Asymmetry 23 (2012) 643–649
2. Results and discussion
t-BuOOLi
We began by synthesising camphor-derived vinyl sulfone 7
from sodium (ꢀ)-camphor-10-sulfinate 5,18 which was itself pre-
pared from (+)-camphor-10-sulfonic acid as previously de-
O
THF, –20°C
O
O
RO
S
RO
S
O2
O2
scribed.19 The novel
c-hydroxy vinyl sulfone 7 was prepared in
73% yield by treatment of sodium (ꢀ)-camphor-10-sulfinate 5 with
epichlorohydrin 6 using conditions employed for the synthesis of
the corresponding achiral phenylsulfonyl compound.20 Compara-
ble yields of 7 were also obtained using conditions previously re-
7
12
R = H
R = H 4.7:1 dr
9 R = Bn
13 R = Bn 5.8:1 dr
Scheme 3.
ported by Jackson.13 The free alcohol
7 was subsequently
converted into its benzyl ether 912 by treatment with benzyl-
2,2,2-trichloroacetimidate 8 in DCM/hexane in the presence of an
acid catalyst (Scheme 1).21 As noted earlier,19 attempts to synthe-
sise 9 (and related vinyl sulfones) by iodosulfonylation of allyl ben-
zyl ether with (+)-camphorsulfonyl iodide (generated in situ from
sodium (ꢀ)-camphor-10-sulfinate 5 and iodine) were unsuccess-
ful, and instead led to the formation of (ꢀ)-10-iodocamphor.
ment using two equivalents of reagent, a 2.1:1 diastereomer ratio
of 13 was obtained. The inseparable diastereomers of 13 were
recovered as oils in poor yields (45%) following chromatography.22
It was thus not possible to determine the relative configuration of
the oxirane ring in the major diastereomer. Our studies on the
nucleophilic epoxidation of vinyl sulfones 7, 9 and 10 are summa-
rised in Table 1.
Under similar conditions, nucleophilic epoxidation of the free
alcohol 7 with lithium tert-butyl peroxide afforded, in very low
yield (15%), the sulfonyloxiranes 12 as a 4.7:1 inseparable mixture
of diastereomers as judged by 1H NMR spectroscopy (Scheme 3).
The possibility that the unprotected hydroxyl group of 12
underwent Payne rearrangement with subsequent elimination of
lithium camphor-10-sulfinate under the basic reaction conditions
may account for the low yield of the sulfonyloxiranes 12. Indeed,
evaporation of the aqueous phase afforded a white solid which
was shown by 1H NMR spectroscopy in D2O to contain lithium
camphor-10-sulfinate. In addition to 12, a significant quantity of
the bis-camphorsulfonylmethyl-1,4-dioxane 14 was also obtained
as a pair of diastereomers (ca. 1:1 dr.) from the crude reaction
product (Fig. 2). These are clearly formed by bimolecular Michael
addition to the double bond of 7 of the oxyanion derived from 7,
which is formed under the basic conditions of the epoxidation
reaction.23
The origins of the variable diastereoselectivities in the Meth-
Cohn epoxidation of sulfones 7 and 9 are unclear. Most examples
of diastereoselective nucleophilic epoxidation of chiral electron
deficient olefins involve substrates bearing asymmetric centres at
the allylic position.24 The observed diastereoselectivity is then
influenced by a number of factors, including the conformational
preferences of the substrate, coordination and solvent effects and
the steric bulk and metal counter ion used in the epoxidising re-
agent. Jackson observed high levels of syn-diastereoselectivity in
O
Cl
6
H2O/EtOH
rt, 10 d or
H2O/DMF
Δ, 6 h
O
SO2Na
O
RO
S
O2
NH
8
5
7
R = H
Cl3C
TfOH,
OBn
9 R = Bn
DCM/hexane,
rt, 2 d
Scheme 1.
The presence of a hydroxyl group in the chiral auxiliary pro-
vides the possibility for coordination-controlled stereoselectivity
in the nucleophilic epoxidation reactions of chiral vinyl sulfones
using metal alkyl peroxides. Accordingly, camphor-derived vinyl
sulfone 9 was reduced to the corresponding exo-configured isobor-
nyl vinyl sulfone 10 using either sodium borohydride in methanol,
or DIBAL-H in THF (Scheme 2). In each case, substantial amounts of
the saturated sulfone 11 were also formed via further reduction of
the C–C double bond of 10. No traces of the corresponding
endo-configured bornyl vinyl sulfone were detected in the crude
products of these reactions.
the nucleophilic epoxidation of chiral
c-hydroxy vinyl sulfones
using lithium tert-butyl peroxide in THF; a result attributed to
the coordination of the lithium ion of the reagent to the allylic
oxygen prior to oxygen atom delivery to the olefin.25 Exclusive
syn-diastereoselectivity was also observed in the nucleophilic
We began by studying the nucleophilic epoxidation of vinyl sul-
fone 9 under conditions reported by Meth-Cohn using lithium tert-
butyl peroxide in anhydrous THF.7 Initial experiments conducted
on a small scale using excess (4 equiv) lithium tert-butyl peroxide
in THF gave the product sulfonyloxiranes 13 as 1:1 mixtures of dia-
stereomers, as determined by 1H NMR spectroscopy. However,
when the reaction was conducted on a larger scale using a smaller
excess (3 equiv) of lithium tert-butyl peroxide, a 5.8:1 ratio of the
diastereomers of 13 was obtained (Scheme 3). In another experi-
epoxidation of enantiomerically pure
c-hydroxy-1-arylthio-1-
nitroalkenes.26
In addition, variations in the extent of syn-diastereoselectivity
were observed by Jackson in the nucleophilic epoxidation of -oxy-
genated vinyl sulfoximines depending on the steric bulk of the
c
NaBH4, MeOH
rt, 3.5 h or
+
OH
OH
DIBAL-H, THF,
O
BnO
S
BnO
S
BnO
S
O2
O2
O2
0°-rt, 5 h
9
10
11
Scheme 2.

F. W. Lewis, D. H. Grayson / Tetrahedron: Asymmetry 23 (2012) 643–649
645
Table 1
Studies on the diastereoselective nucleophilic epoxidation reactions of camphor-derived vinyl sulfones 7, 9 and 10
Entry
Vinyl sulfone
Reagent (equiv)
Solvent
Conditions
Yield (%)a (dr)b
1
2
3
4
5
6
7
8
9
9
9
9
7
9
9
9
9
9
t-BuOOLi (4)
t-BuOOLi (3)
t-BuOOLi (2)
t-BuOOLi (3)
Ph3COOLi (2)
t-BuOOLi (3)
t-BuOOLi (4)
t-BuOOLi (4)
HOONa (3)
THF
THF
THF
THF
THF
Toluene
THF
ꢀ20 °C, 3 h
ꢀ20 °C, 3 h
ꢀ20 °C, 2.5 h
ꢀ20 °C, 2 h
ꢀ20 °C, 6 h
ꢀ20 °C, 4 h
13 66 (1:1)
13 70/45 (5.8:1)
13 72 (2.1:1)
12 47/15 (4.7:1)
13 69 (1:1)
13 78/58 (1:1)
13 70 (1:1)
13 63 (1:1)
Ti(Oi-Pr)4, ꢀ20 °C, 2 h
MgCl2, ꢀ20 °C, 2.5 h
40 °C, 3 h
THF
Acetone
Toluene
THF
13 68 (1:1)
15 100/95 (1:1)
15 94/91 (1:1)
10
11
10
10
t-BuOOLi (2)
t-BuOOLi (2)
ꢀ20 °C–rt, 52 h
ꢀ20 °C–rt, 50 h
a
Yield of crude product given first, followed by yield of purified product where appropriate.
Determined from 1H NMR spectroscopy of the crude product.
b
We next examined the nucleophilic epoxidation reaction of 9
O
under classical Weitz–Scheffer conditions.8 Once again, a 1:1 ratio
of diastereomeric sulfonyloxiranes 13 was obtained upon
treatment of 9 with sodium hydroperoxide in acetone. Attempts
to effect an intramolecular epoxidation of 9 by in situ conversion
of the carbonyl group of the auxiliary into a dioxirane moiety using
either oxone/acetonitrile31 or hydrogen peroxide/acetonitrile32
were unsuccessful, and starting material was recovered in each
case. This result is not totally surprising, given that vinyl sulfones
are unreactive towards electrophilic epoxidising reagents.33
In order to shed more light on the role of the camphor auxiliary
in the nucleophilic epoxidations of sulfones 7 and 9, the epoxida-
tion of isobornyl vinyl sulfone 10 was next examined. The reac-
tions of 10 with lithium tert-butyl peroxide in either toluene or
THF were quite slow, and took over 48 h to reach completion.
The rates of these reactions were significantly slower than those
of 7 and 9, and the analogous achiral sulfones.7,12 The sulfonyloxir-
anes 15 were isolated in excellent yields as 1:1 inseparable mix-
tures of diastereomers in each case following chromatography
(Scheme 4). This result suggests that the carbonyl groups of 7
and 9 played a key role in the diastereoselection observed in the
epoxidations of the ketones 7 and 9 in THF, although the reaction
is clearly sensitive to the conditions employed. It should be men-
tioned that the lack of diastereoselection observed in the epoxida-
tion of the alcohol 10 does not rule out lithium ion coordination by
the hydroxyl group of 10. Coordination could have occurred, but
the lack of rotamer control in the sulfonyl side-chain may have
led to the observed lack of diastereoselectivity.
The above results suggest that lithium ion coordination and/or
hydrogen bonding effects are not responsible for the diastereose-
lectivities observed in the nucleophilic epoxidation reactions of
sulfones 7 and 9 with lithium tert-butyl peroxide. A tentative
mechanism has been proposed involving participation of the
carbonyl group of the auxiliary (Scheme 5). The sulfonyl carbanion
formed by the Michael addition of the reagent to the double bond
of either 7 or its benzyl ether 9 could cyclise with the auxiliary,
forming the endo-configured tricyclic oxyanion intermediate 16
as one of two possible diastereomers epimeric at the b-position.34
The collapse of this intermediate and subsequent elimination of
lithium tert-butoxide afford the product sulfonyloxiranes 12 and
13.
O
O2S
SO2
SO2
O2S
O
O
O
O
O
O
14
1:1 dr
Figure 2. Structures of both diastereomers of 1,4-dioxane 14.
reagent (t-BuOOH v Ph3COOH) and the metal counterion used (Li+
v Na+ v K+), with the highest stereoselectivities being observed
with lithium triphenylmethyl peroxide.27 It has also been reported
that protection of the hydroxyl group of
a-(1-hydroxyalkyl) vinyl
sulfones as silyl ethers can switch the mode of diastereoselection
from syn (coordination controlled) to anti (sterically controlled).28
In order to verify if coordination and/or hydrogen bonding ef-
fects were responsible for the diastereoselectivity observed in the
epoxidations of sulfones 7 and 9, the reaction was repeated in tol-
uene, a solvent in which the effects of coordination would be ex-
pected to be enhanced. Higher levels of syn-diastereoselectivity
were observed by Jackson in the nucleophilic epoxidation of c-oxy-
genated-1-arylthio-1-nitroalkenes with lithium tert-butyl peroxide
when toluene was used as the solvent rather than THF.29 Epoxida-
tion of 9 with lithium tert-butyl peroxide in toluene gave a 1:1
mixture of diastereomers, suggesting that coordination and/or
hydrogen bonding effects were not responsible for the diastereose-
lectivity previously observed in THF.
The nucleophilic epoxidation of 9 in THF was then carried out
using the more sterically bulky reagent lithium triphenylmethyl
peroxide.30 Although we anticipated that higher levels of diastere-
oselectivity might be observed with this reagent, a 1:1 mixture of
diastereomers of 13 was still obtained. The nucleophilic epoxida-
tions of 9 were also carried out in the presence of Lewis acids in
an attempt to enforce chelation control by coordination of the car-
bonyl and sulfone oxygens to the Lewis acid. However, no diastere-
oselectivity was observed when either magnesium chloride or
titanium(IV) isopropoxide was employed in the epoxidation
reactions.
With the sulfonyloxiranes 13 in hand, we briefly explored the
hydrolytic ring-opening of 13 with sodium hydroxide. However,
when 13 was hydrolysed using sodium hydroxide in isopropanol
at reflux, benzyl alcohol was obtained as the sole product, presum-
ably arising via b-elimination from the target aldehyde 4 (Fig. 1)
formed in situ. We also briefly explored the non-asymmetric Up-
john dihydroxylation35 of vinyl sulfone 9. In this case, benzyl alco-
hol was also obtained when vinyl sulfone 9 was treated with

646
F. W. Lewis, D. H. Grayson / Tetrahedron: Asymmetry 23 (2012) 643–649
t-BuOOLi
OH
OH
O
THF, –20°C or
BnO
S
BnO
S
toluene, –20°C
O2
O2
10
15 1:1 dr
Scheme 4.
OR
O
O
OOt-Bu
SO2
O-
O2S
t-BuOO-
O2S
O
16
12 R = H
OR
OR
13 R = Bn
Scheme 5.
osmium tetroxide/N-methylmorpholine-N-oxide in acetone/water
at ambient temperature for 6 days. Efforts to find milder conditions
for the preparation of 4 by hydrolysis of 13 and related achiral
arylsulfonyloxiranes (e.g., by using anhydrous hydroxide ion under
Gassman conditions),36 or by asymmetric dihydroxylation of the
drofuran (THF) was dried and distilled over sodium-benzophenone
ketyl prior to use. Toluene was dried over anhydrous calcium chlo-
ride prior to use. All other solvents and reagents were purified by
standard techniques. Organic extracts of reaction products were
dried over anhydrous magnesium sulfate.
corresponding achiral vinyl sulfone
3
have so far been
unsuccessful.37
4.2. (1S,4R)-1-({[(10E)-30-Hydroxyprop-10-enyl]sulfonyl}methyl)-
7,7-dimethylbicyclo[2.2.1]heptan-2-one 7
3. Conclusion
4.2.1. Method A
It has been found that
c-oxygenated camphor-derived vinyl
Sodium sulfinate 5 (9.5 g, 39 mmol) was dissolved in water
(42 mL) and ethanol (10.5 mL), after which epichlorohydrin 6
(6.2 mL, 79 mmol) was added. The solution was stirred at room
temperature for 10 days. The solution was then diluted with water
(100 mL) and extracted with ethyl acetate (3 ꢁ 100 mL). The com-
bined organic extracts were washed with brine (50 mL), dried and
evaporated to yield an oil. Removal of excess epichlorohydrin on an
oil pump (ca. 0.1 mm Hg) afforded the title compound 7 as an oil
(9.65 g, 88%) which slowly crystallised after several days. A small
portion of the product was triturated with a small volume of ether
to afford an analytical sample of the title compound 7 as a white
solid.
sulfones undergo mildly diastereoselective nucleophilic epoxida-
tion reactions under Meth-Cohn conditions. The observed diastere-
oselectivity is sensitive to the reaction conditions employed, with
the highest stereoselectivities being observed using lithium
tert-butyl peroxide (3 equiv) in anhydrous THF. In contrast, no
stereoselectivity was observed in the nucleophilic epoxidations of
a c-oxygenated isobornyl-derived vinyl sulfone. A tentative mech-
anism has been proposed to account for the stereoselectivity,
involving participation of the carbonyl group of the chiral auxiliary.
However, the application of these compounds to the asymmetric
synthesis of 3-O-benzylglyceraldehyde was unsuccessful.
4.2.2. Method B
4. Experimental
4.1. General
Sodium sulfinate 5 (0.95 g, 3.9 mmol) was dissolved in water
(10 mL) and DMF (0.5 mL) and epichlorohydrin
6 (0.62 mL,
7.9 mmol) was added. The solution was heated under reflux for
6 h. The solution was then allowed to cool to room temperature,
diluted with water (50 mL) and extracted with ethyl acetate
(3 ꢁ 50 mL). The combined organic extracts were dried and evapo-
rated to yield an oil. Removal of excess epichlorohydrin on an oil
pump (ca. 0.1 mm Hg) afforded the title compound 7 as an oil
(0.92 g, 85%) which slowly crystallised after several days. Mp
NMR spectra were recorded using a Bruker AVANCE DPX
400 MHz spectrometer (400.1 MHz for 1H and 100.6 MHz for
13C). Chemical shifts are reported in parts per million. Coupling
constants (J) are quoted in Hertz. Optical rotations were measured
using a Perkin–Elmer 141 polarimeter. IR spectra were recorded for
Nujol mulls (N) or liquid films (L) on a Mattson Genesis II FTIR
spectrometer. Mass spectra were obtained under electrospray con-
ditions using a Micromass LCT instrument. Uncorrected melting
points (Mp) were measured in unsealed capillary tubes using a
Griffin melting point apparatus. Anhydrous solutions of tert-butyl
hydroperoxide in benzene were prepared by azeotropic distillation
of commercially available 70% solutions of tert-butyl hydroperox-
ide in water according to the procedure of Sharpless.38 Concentra-
tions were estimated by 1H NMR. Triphenylmethyl hydroperoxide
was prepared according to the procedure of Eberhard.30 Tetrahy-
71 °C (ether). ½a D26
¼ þ26:8 (c 0.5, MeOH). IR mmax (N) 3523 (O–
ꢂ
H), 3061, 2923, 1740 (C@O), 1635 (C@C), 1454, 1414, 1375, 1310
(SO2), 1199, 1130 (SO2), 1104, 1052, 1018, 943, 837, 788,
674 cmꢀ1 1H NMR (CDCl3): 0.86 (s, 3H, 7-CH3), 1.07 (s, 3H, 7-
.
CH3), 1.42–1.48 (m, 1H), 1.70–1.77 (m, 1H), 1.93 (d, 2J = 18.4, 1H,
3-CH2 endo), 2.02–2.08 (m, 1H), 2.12 (t, 3J = 4.5, 1H, 4-CH), 2.37
(dt, 2J = 18.4, 3J = 4.5, 1H, 3-CH2 exo), 2.46 (m, 1H), 2.87 (d,
2J = 15.0, 1H, CH2SO2), 3.44 (d, 2J = 15.0, 1H, CH2SO2), 4.40 (dd,
4
4
3J = 3.4, J = 2.7, 2H, 30-CH2), 6.83 (dt, 3J = 15.0, J = 2.7, 1H, 10-CH),

F. W. Lewis, D. H. Grayson / Tetrahedron: Asymmetry 23 (2012) 643–649
647
3
6.96 (dt, J = 15.0, 3.4, 1H, 20-CH). 13C NMR (CDCl3): 19.2 (7-CH3),
yield two products. The first product to elute was sulfone 10
(0.34 g, 32%) as a colourless oil. The second product to elute was
sulfone 11 (0.50 g, 48%) as a colourless oil.
19.2 (7-CH3), 24.3 (C-5), 26.5 (C-6), 41.9 (C-4), 42.1 (C-3), 48.1
(C-7), 51.4 (CH2SO2), 58.2 (C-1), 60.3 (C-30), 128.8 (C-10), 146.0
(C-20), 214.9 (C-2). HRMS (EI, MeOH) m/z calcd for C13H20O4S
[M+Na]+: 295.0979; found: 295.0930.
4.5. (1S,2R,4R)-1-({[(10E)-30-Benzyloxyprop-10-enyl]sulfonyl}
methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-ol 10
4.3. (1S,4R)-1-({[(10E)-30-Benzyloxyprop-10-enyl]sulfonyl}
methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one 9
½
a 2D5
ꢂ
¼ ꢀ23:7 (c 0.7, MeOH). IR
1640 (C@C), 1601 (Ar C–C), 1495, 1454, 1389, 1307 (SO2), 1123
(SO2), 1075, 1027, 949, 880, 825, 737, 698 cmꢀ1 1H NMR (CDCl3):
mmax (L) 3517 (O–H), 2954, 2879,
Sulfone 7 (2.5 g, 9.1 mmol) was dissolved in dry DCM (40 mL)
and dry hexane (80 mL) and benzyl-2,2,2-trichloroacetimidate 8
(2.5 mL, 13.6 mmol) was added. Trifluoromethanesulfonic acid
(1 mL) was added dropwise and the solution was stirred at room
temperature for 48 h. Hexane (100 mL) was added and the precip-
itated trichloroacetamide was filtered. The filtrate was diluted with
ether (100 mL) and then washed with satd aq sodium hydrogen
carbonate (50 mL) and brine (50 mL), dried and evaporated to yield
an oil. Column chromatography on silica gel, eluting with ethyl
acetate/hexane (1:2) afforded the title compound 9 as a colourless
.
0.82 (s, 3H, 7-CH3), 1.08 (s, 3H, 7-CH3), 1.13–1.18 (m, 1H), 1.55–
1.63 (m, 1H), 1.68–1.84 (m, 5H), 2.86 (d, 2J = 13.5, 1H, CH2SO2),
3.41 (d, 2J = 13.5, 1H, CH2SO2), 4.18 (dd, 3J = 8.0, 4.0, 1H, 2-CH),
4
4.27 (dd, 3J = 3.0, J = 2.0, 2H, 30-CH2), 4.62 (s, 2H, benzyl CH2),
4
6.75 (dt, 3J = 15.0, J = 2.0, 1H, 10-CH), 6.98 (dt, 3J = 15.0, 3.0, 1H,
20-CH), 7.28–7.43 (m, 5H, ArH). 13C NMR (CDCl3): 19.3 (7-CH3),
20.0 (7-CH3), 27.0 (C-5), 30.2 (C-6), 38.5 (C-3), 43.6 (C-4), 48.6
(C-7), 50.3 (C-1), 53.7 (CH2SO2), 67.0 (C-30), 72.8 (benzyl CH2),
75.8 (C-2), 127.2 (Ar C-3), 127.6 (Ar C-4), 128.1 (Ar C-2), 128.9
(C-10), 136.6 (Ar C-1), 143.8 (C-20). HRMS (EI, MeOH) m/z calcd
for C20H28O4S [M+Na]+: 387.1605; found: 387.1606.
oil (2.2 g, 66%). ½a D26
¼ þ27:3 (c 0.57, MeOH). IR mmax (L) 3062,
ꢂ
3029, 2959, 1740 (C@O), 1639 (C@C), 1601 (Ar C–C), 1495, 1454,
1392, 1360, 1314 (SO2), 1279, 1201, 1121 (SO2), 1051, 1026, 945,
908, 831, 784, 739, 699 cmꢀ1
.
1H NMR (CDCl3): 0.87 (s, 3H, 7-
4.6. (1S,2R,4R)-1-({[30-Benzyloxypropyl]sulfonyl}methyl)-7,7-
CH3), 1.09 (s, 3H, 7-CH3), 1.41–1.47 (m, 1H), 1.69–1.74 (m, 1H),
1.93 (d, 2J = 18.5, 1H, 3-CH2 endo), 2.01–2.08 (m, 1H), 2.12 (t,
3J = 4.5, 1H, 4-CH), 2.38 (dt, 2J = 18.5, 3J = 4.5, 1H, 3-CH2 exo), 2.50
(m, 1H), 2.86 (d, 2J = 15.0, 1H, CH2SO2), 3.45 (d, 2J = 15.0, 1H,
dimethylbicyclo[2.2.1]heptan-2-ol 11
½
a 2D5
ꢂ
¼ ꢀ20:0 (c 0.13, MeOH). IR mmax (L) 3512 (O–H), 2954,
2878, 1602 (Ar C–C), 1454, 1370, 1307 (SO2), 1124 (SO2), 1075,
1027, 879, 830, 738, 698 cm–1 1H NMR (CDCl3): 0.83 (s, 3H, 7-
4
CH2SO2), 4.24 (dd, 3J = 3.0, J = 1.5, 2H, 30-CH2), 4.60 (s, 2H, benzyl
.
4
CH2), 6.85 (dt, 3J = 15.0, J = 1.5, 1H, 10-CH), 6.92 (dt, 3J = 15.0, 3.0,
CH3), 1.08 (s, 3H, 7-CH3), 1.13–1.18 (m, 1H), 1.57–1.62 (m, 1H),
1H, 20-CH), 7.31–7.38 (m, 5H, ArH). 13C NMR (CDCl3): 19.2 (7-
CH3), 19.3 (7-CH3), 24.3 (C-5), 26.6 (C-6), 42.0 (C-4), 42.1 (C-3),
47.9 (C-7), 51.3 (CH2SO2), 58.2 (C-1), 67.1 (C-30), 72.5 (benzyl
CH2), 127.2 (Ar C-3), 127.5 (Ar C-4), 128.0 (Ar C-2), 129.9 (C-10),
136.9 (Ar C-1), 142.7 (C-20), 214.3 (C-2). HRMS (EI, MeOH) m/z
calcd for C20H26O4S [M+Na]+: 385.1449; found: 385.1455.
1.70–1.87 (m, 1H), 2.14–2.21 (m, 2H, 20-CH2), 2.85 (d, 2J = 13.5,
3
1H, CH2SO2), 3.19 (app dd, J = 7.5, 6.0, 2H, 10-CH2), 3.40 (d,
3
2J = 13.5, 1H, CH2SO2), 3.62 (t, J = 6.0, 2H, 30-CH2), 4.16 (dd,
3J = 8.5, 4.0, 1H, 2-CH), 4.53 (s, 2H, benzyl CH2), 7.31–7.39 (m,
5H, ArH). 13C NMR (CDCl3): 19.4 (7-CH3), 20.1 (7-CH3), 22.3 (C-
20), 27.0 (C-5), 30.0 (C-6), 38.5 (C-3), 43.6 (C-4), 48.6 (C-7), 50.0
(C-1), 51.2 (C-10), 52.0 (CH2SO2), 67.3 (C-30), 72.6 (benzyl CH2),
75.7 (C-2), 127.2 (Ar C-3), 127.4 (Ar C-4), 128.0 (Ar C-2), 137.3
(Ar C-1). HRMS (EI, MeOH) m/z calcd for C20H30O4S [M+Na]+:
389.1762; found: 389.1743.
4.4. Reduction of vinyl sulfone 9
4.4.1. Method A: with sodium borohydride
Sulfone 9 (0.4 g, 1.1 mmol) was dissolved in methanol (20 mL)
and sodium borohydride (0.16 g, 4.4 mmol) was added. The solu-
tion was stirred at room temperature for 3.5 h. The solution was
then diluted with satd aq ammonium chloride (50 mL) and ex-
tracted with ether (3 ꢁ 50 mL). The combined organic extracts
were washed with brine (50 mL), dried and evaporated to yield
an oil (0.36 g). The crude product was purified by column chroma-
tography on silica gel, eluting with ethyl acetate/hexane (1:3) to
yield two products. The first product to elute was sulfone 10
(0.18 g, 45%) as a colourless oil. The second product to elute was
sulfone 11 (0.13 g, 32%) as a colourless oil.
4.7. Meth-Cohn epoxidation of vinyl sulfones 7, 9 and 10:
general procedure
At first, n-butyllithium (2.4 mL, 2.5 M, 6.0 mmol for sulfone 7,
3.8 mL, 2.5 M, 9.5 mmol for sulfone 9, 0.46 mL, 2.5 M, 1.1 mmol
for sulfone 10) was added dropwise via syringe to a solution of
tert-butyl hydroperoxide (5.0 mL, 1.17 M in benzene, 6.0 mmol
for sulfone 7, 8.0 mL, 1.17 M in benzene, 9.5 mmol for sulfone 9,
0.98 mL, 1.17 M in benzene, 1.1 mmol for sulfone 10) in dry THF
(6 mL for sulfone 7, 7 mL for sulfone 9, 4 mL for sulfone 10) at
ꢀ78 °C under an atmosphere of nitrogen. The solution was allowed
to warm to ꢀ20 °C and a solution of sulfone 7, 9 or 10 (0.55 g,
2.0 mmol for sulfone 7, 1.15 g, 3.1 mmol for sulfone 9, 0.21 g,
0.55 mmol for sulfone 10) in dry THF (8 mL for sulfone 7, 14 mL
for sulfone 9, 4 mL for sulfone 10) was added dropwise via syringe.
The solution was stirred at ꢀ20 °C for 2 h (for sulfone 7), ꢀ20 °C for
2.5 h (for sulfone 9) or ꢀ20 °C for 4 h and then the solution was al-
lowed to warm to room temperature and stirring was continued
for an additional 46 h (for sulfone 10). The solution was then al-
lowed to warm to room temperature, quenched with satd aq so-
dium sulfite (50 mL) and extracted with ether (3 ꢁ 100 mL). The
combined organic extracts were washed with brine (50 mL), dried
over sodium sulfate and evaporated to yield the crude sulfony-
loxiranes 12, 13 or 15 as colourless oils whose diastereomeric ra-
tios were determined by 1H NMR spectroscopy. In some cases,
the crude products were purified by column chromatography on
4.4.2. Method B: with diisobutylaluminium hydride
Sulfone 9 (1.04 g, 2.8 mmol) was dissolved in dry THF (8 mL)
under an atmosphere of nitrogen and cooled to 0 °C. Diisobutylal-
uminium hydride (3.43 mL, 1.5 M in toluene, 5.1 mmol) was added
via syringe and the solution was stirred at 0 °C for 1 h. The solution
was then allowed to warm to room temperature and stirring was
continued for an additional 4 h. The solution was then diluted with
ammonium hydroxide (50 mL) and DCM (100 mL) and the phases
were stirred vigorously for 1.5 h. The combined phases were fil-
tered through CeliteÓ and the filtrate was transferred to a separat-
ing funnel. The phases were mixed and separated and the aqueous
phase was extracted with DCM (50 mL). The combined organic ex-
tracts were washed with brine (50 mL), dried and evaporated to
yield an oil (1.0 g). The crude product was purified by column chro-
matography on silica gel, eluting with ethyl acetate/hexane (1:3) to

648
F. W. Lewis, D. H. Grayson / Tetrahedron: Asymmetry 23 (2012) 643–649
silica gel, eluting with ethyl acetate/hexane (1:2) to afford the pure
sulfonyloxiranes 12, 13 or 15 as colourless oils.
1139 (SO2), 1051, 965, 917, 825, 741, 699 cmꢀ1. Major diastereo-
mer: 1H NMR (CDCl3): 0.91 (s, 3H, 7-CH3), 1.09 (s, 3H, 7-CH3),
1.46–1.52 (m, 1H), 1.78–1.85 (m, 1H), 2.00 (d, 2J = 18.5, 1H, 3-
CH2 endo), 2.04–2.11 (m, 1H), 2.16 (t, 3J = 4.5, 1H, 4-CH), 2.33–
2.44 (m, 2H), 2.92 (d, 2J = 15.0, 1H, CH2SO2), 3.55 (d, 2J = 15.0, 1H,
CH2SO2), 3.67 (dd, 2J = 12.0, 3J = 4.5, 1H, CH2OCH2Ph), 3.80 (app
qu, 3J = 2.0, 1H, 30-CH), 3.93 (dd, 2J = 12.0, 3J = 2.0, 1H, CH2OCH2Ph),
4.49 (d, 3J = 1.5, 1H, 20-CH), 4.58 (s, 2H, CH2OCH2Ph), 7.28–7.40 (m,
5H, ArH). 13C NMR (CDCl3): 19.1 (7-CH3), 19.2 (7-CH3), 24.6 (C-5),
26.5 (C-6), 42.0 (C-3), 42.1 (C-4), 48.0 (C-7), 49.8 (CH2SO2), 54.6
(C-30), 57.9 (C-1), 64.6 (C-20), 66.2 (CH2OCH2Ph), 73.0 (CH2OCH2Ph),
127.3 (Ar C-3), 127.5 (Ar C-4), 128.0 (Ar C-2), 136.7 (Ar C-1), 214.4
(C-2). Minor diastereomer: 1H NMR (CDCl3): 0.91 (s, 3H, 7-CH3),
1.05 (s, 3H, 7-CH3), 1.34–1.52 (m, 2H), 1.96 (d, 2J = 18.5, 1H, 3-
CH2 endo), 2.00–2.11 (m, 1H), 2.15 (t, 3J = 4.5, 1H, 4-CH), 2.24–
2.31 (m, 1H), 2.36–2.45 (m, 1H), 2.89 (d, 2J = 15.0, 1H, CH2SO2),
3.53 (d, 2J = 15.0, 1H, CH2SO2), 3.65 (dd, 2J = 12.0, 3J = 4.5, 1H,
4.8. (1S,4R)-1-({[30-(Hydroxymethyl)oxiran-20-yl]sulfonyl}
methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one 12
Obtained during the nucleophilic epoxidation of vinyl sulfone 7
as a colourless oil (0.09 g, 15%, 4.7:1 dr). IR mmax (L) 3504 (O–H),
2960, 1739 (C@O), 1454, 1394, 1320 (SO2), 1274, 1216, 1137
(SO2), 1054, 916, 881, 826, 734, 678 cmꢀ1. Major diastereomer:
1H NMR (CDCl3): 0.90 (s, 3H, 7-CH3), 1.04 (s, 3H, 7-CH3), 1.46–
1.52 (m, 1H), 1.90–2.01 (m, 1H), 1.96 (d, 2J = 18.5, 1H, 3-CH2 endo),
2.02–2.10 (m, 1H), 2.16 (t, 3J = 4.0, 1H, 4-CH), 2.24–2.31 (m, 1H),
2.41 (dt, 2J = 18.5, 3J = 4.0, 1H, 3-CH2 exo), 2.88 (d, 2J = 15.0, 1H,
2
CH2SO2), 3.53 (d, J = 15.0, 1H, CH2SO2), 3.78–3.80 (m, 1H, 30-CH),
3.87 (dd, 2J = 13.5, 3J = 3.0, 1H, CH2OH), 4.05 (dd, 2J = 13.5, 3J = 2.0,
3
1H, CH2OH), 4.68 (d, J = 1.5, 1H, 20-CH). 13C NMR (CDCl3): 19.0
3
(7-CH3), 19.3 (7-CH3), 25.3 (C-5), 26.6 (C-6), 42.1 (C-4), 42.1 (C-
3), 48.4 (C-7), 49.4 (CH2SO2), 56.9 (C-30), 58.5 (CH2OH), 58.6 (C-
1), 65.2 (C-20), 215.0 (C-2). Minor diastereomer: 1H NMR (CDCl3):
0.89 (s, 3H, 7-CH3), 1.07 (s, 3H, 7-CH3), 1.46–1.52 (m, 1H), 1.75–
1.82 (m, 1H), 1.90–2.01 (m, 1H), 1.96 (d, 2J = 18.5, 1H, 3-CH2 endo),
2.02–2.10 (m, 1H), 2.16 (t, 3J = 4.0, 1H, 4-CH), 2.41 (dt, 2J = 18.5,
3J = 4.0, 1H, 3-CH2 exo), 2.92 (d, 2J = 15.0, 1H, CH2SO2), 3.53 (d,
2J = 15.0, 1H, CH2SO2), 3.73–3.75 (m, 1H, 30-CH), 3.87 (dd,
2J = 13.5, 3J = 3.0, 1H, CH2OH), 4.05 (dd, 2J = 13.5, 3J = 2.0, 1H,
CH2OCH2Ph), 3.85 (app qu, J = 2.0, 1H, 30-CH), 3.92 (dd, 2J = 12.0,
3J = 2.0, 1H, CH2OCH2Ph), 4.59 (s, 2H, CH2OCH2Ph), 4.66 (d,
3J = 2.0, 1H, 20-CH), 7.29–7.39 (m, 5H, ArH). 13C NMR (CDCl3):
19.1 (7-CH3), 19.3 (7-CH3), 25.4 (C-5), 26.6 (C-6), 42.1 (C-3), 42.1
(C-4), 48.3 (C-7), 49.4 (CH2SO2), 55.7 (C-30), 58.6 (C-1), 65.3 (C-
20), 66.2 (CH2OCH2Ph), 73.0 (CH2OCH2Ph), 127.3 (Ar C-3), 127.5
(Ar C-4), 128.0 (Ar C-2), 136.7 (Ar C-1), 214.4 (C-2). HRMS (EI,
MeOH) m/z calcd for
C
20H26O5S [M+Na]+: 401.1398; found:
401.1401.
3
CH2OH), 4.53 (d, J = 1.5, 1H, 20-CH). 13C NMR (CDCl3): not ob-
served. HRMS (EI, MeOH) m/z calcd for C13H20O5S [M+Na]+:
4.11. (1S,2R,4R)-1-({[30-(Benzyloxymethyl)oxiran-20-yl]sulfonyl}
311.0917; found: 311.0928.
methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-ol 15
4.9. (1S,4R)-1,10-[10,40-Dioxane-20,50-diylbis(methylenesulfonyl
methylene)]bis(7,7-dimethylbicyclo[2.2.1]heptan-2-one) 14
Obtained during the nucleophilic epoxidation of vinyl sulfone
10 as a colourless oil (0.21 g, 95%, 1:1 dr). IR mmax (L) 3537 (O–H),
2955, 2880, 1601 (Ar C–C), 1455, 1390, 1372, 1318 (SO2), 1251,
1134 (SO2), 1075, 1026, 916, 878, 739, 699 cmꢀ1. Both diastereo-
mers: 1H NMR (CDCl3): 0.86 (s, 3H, 7-CH3), 0.87 (s, 3H, 7-CH3),
1.09 (s, 3H, 7-CH3), 1.10 (s, 3H, 7-CH3), 1.14–1.19 (m, 2H), 1.54–
1.61 (m, 2H), 1.75–1.88 (m, 10H), 2.98 (d, 2J = 13.5, 1H, CH2SO2),
3.04 (d, 2J = 13.5, 1H, CH2SO2), 3.50 (d, 2J = 13.5, 1H, CH2SO2), 3.56
(d, 2J = 13.5, 1H, CH2SO2), 3.74 (app dt, 2J = 12.0, 3J = 3.5, 2H,
CH2OCH2Ph), 3.84–3.87 (m, 2H, 30-CH), 3.93 (d, 2J = 12.0, 2H,
Obtained as a side-product during the nucleophilic epoxidation
of vinyl sulfone 7 as a white solid (0.15 g, 27%, 1:1 dr). Compound
14 precipitated from the crude product on addition of the chroma-
tography solvent system and was collected by filtration. Mp 211 °C
(ether). IR mmax (N) 2919, 1728 (C@O), 1458, 1376, 1306 (SO2), 1120
(SO2), 1053, 1020, 921, 790, 723, 663 cmꢀ1. Both diastereomers: 1H
NMR (CDCl3): 0.90 (s, 12H, 7-CH3), 1.06 (s, 6H, 7-CH3), 1.09 (s, 6H,
7-CH3), 1.45–1.51 (m, 4H), 1.77–1.84 (m, 2H), 1.90–1.97 (m, 2H),
1.95 (d, 2J = 18.0, 2H, 3-CH2 endo), 1.96 (d, 2J = 18.5, 2H, 3-CH2
endo), 2.03–2.11 (m, 4H), 2.13–2.16 (m, 4H, 4-CH), 2.29–2.48 (m,
8H), 2.89 (d, 2J = 15.0, 2H, 1-CH2SO2), 2.96 (dd, 2J = 14.5, 3J = 4.0,
2H, 20 and 50-CH2SO2), 2.97 (d, 2J = 15.0, 2H, 1-CH2SO2), 3.11 (dd,
2J = 14.5, 3J = 4.0, 2H, 20 and 50-CH2SO2), 3.29 (dd, 2J = 14.5,
3J = 7.5, 2H, 20 and 50-CH2SO2), 3.58 (app t, 2J = 11.5, 3J = 11.5, 4H,
30 and 60-CH2 axial), 3.64 (d, 2J = 15.0, 4H, 1-CH2SO2), 3.76 (dd,
2J = 14.5, 3J = 9.0, 2H, 20 and 50-CH2SO2), 3.91 (dd, 2J = 11.5,
3J = 2.5, 2H, 30 and 60-CH2 equatorial), 3.96 (dd, 2J = 11.5, 3J = 2.5,
2H, 30 and 60-CH2 equatorial), 4.18–4.23 (m, 2H, 20 and 50-CH axial),
4.23–4.29 (m, 2H, 20 and 50-CH axial). 13C NMR (CDCl3): 19.2 (7-
CH3), 19.3 (7-CH3), 19.3 (7-CH3), 19.3 (7-CH3), 24.5 (C-5), 25.2 (C-
5), 26.6 (C-6), 26.7 (C-6), 42.0 (C-4), 42.1 (C-4), 42.1 (C-3), 42.2
(C-3), 48.0 (C-7), 48.2 (C-7), 51.6 (1-CH2SO2), 52.8 (1-CH2SO2),
56.4 (20 and 50-CH2SO2), 56.4 (20 and 50-CH2SO2), 58.3 (C-1), 58.8
(C-1), 69.1 (C-30 and C-60), 69.1 (C-30 and C-60), 69.2 (C-20 and C-
50), 69.7 (C-20 and C-50), 214.6 (C-2), 214.6 (C-2). HRMS (EI, MeOH)
m/z calcd for C26H40O8S2 [M+Na]+: 567.2061; found: 567.2039.
3
CH2OCH2Ph), 4.15 (dd, J = 8.5, 4.0, 2H, 2-CH), 4.27 (s, 2H, 20-CH),
4.58 (s, 4H, CH2OCH2Ph), 7.32–7.40 (m, 10H, ArH). 13C NMR
(CDCl3): 19.4 (7-CH3), 19.4 (7-CH3), 20.0 (7-CH3), 20.0 (7-CH3),
27.0 (C-5), 27.0 (C-5), 30.0 (C-6), 30.0 (C-6), 38.7 (C-3), 38.7 (C-
3), 43.6 (C-4), 43.6 (C-4), 48.7 (C-7), 48.7 (C-7), 49.8 (C-1), 50.0
(C-1), 50.2 (CH2SO2), 50.4 (CH2SO2), 54.8 (C-30), 55.3 (C-30), 64.0
(C-20), 64.1 (C-20), 65.4 (CH2OCH2Ph), 65.4 (CH2OCH2Ph), 73.1
(CH2OCH2Ph), 73.1 (CH2OCH2Ph), 75.7 (C-2), 75.8 (C-2), 127.3 (Ar
C-3), 127.3 (Ar C-3), 127.6 (Ar C-4), 127.6 (Ar C-4), 128.1 (Ar C-
2), 128.1 (Ar C-2), 136.5 (Ar C-1), 136.6 (Ar C-1). HRMS (EI, MeOH)
m/z calcd for C20H28O5S [M+Na]+: 403.1554; found: 403.1550.
Acknowledgments
The authors gratefully acknowledge Dr. John E. O’Brien and Dr.
Manuel Reuther for obtaining NMR spectra and Dr. Martin Feeney
for obtaining mass spectra. One of us (F.W.L.) received financial
support from Trinity College Dublin.
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