Preliminary investigations on novel camphor-derived chiral sulfones: Completely stereoselective formation of tricyclic β-hydroxy sulfones from 8- and 10-functionalized camphor derivatives

Article abstract of DOI:10.1016/j.tet.2011.07.081

Some camphor-derived chiral allylic and benzylic sulfones in which the sulfonyl group is located at the C-10, C-9 or C-8 methyl groups of (+)-camphor were synthesized. The C-9 and C-8 substituted sulfones were obtained via Wagner-Meerwein rearrangements of the bicyclic camphor framework. On treatment with LDA, the C-10 and C-8 substituted sulfones cyclized with complete stereoselectivity, affording tricyclic β-hydroxy sulfones whose relative configurations were determined by X-ray crystallography. Tricyclic sulfones 23 and 24 underwent both β-elimination and retro-aldol reactions on further exposure to base. Reduction of the carbonyl group of the C-10 substituted sulfones afforded exo-configured isobornyl sulfones with high stereoselectivity. Reaction of the lithiated isobornyl benzyl sulfone 32 with benzaldehyde generated all four of the possible product diastereomers, of which three were isolated pure by chromatography. Attempted desulfonylation of these diastereomers failed to generate the desired optically active homobenzylic alcohols but the same sulfonyl carbanion trapping/desulfonylation sequence was successful in a model achiral series of compounds.

Full text of DOI:10.1016/j.tet.2011.07.081

Tetrahedron 67 (2011) 7517e7528
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preliminary investigations on novel camphor-derived chiral sulfones: completely
stereoselective formation of tricyclic
functionalized camphor derivatives
b-hydroxy sulfones from 8- and 10-
,
Frank W. Lewis y, Thomas C. McCabe, 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:
Received 10 May 2011
Received in revised form 10 July 2011
Accepted 26 July 2011
Available online 31 July 2011
Some camphor-derived chiral allylic and benzylic sulfones in which the sulfonyl group is located at
the C-10, C-9 or C-8 methyl groups of (þ)-camphor were synthesized. The C-9 and C-8 substituted
sulfones were obtained via WagnereMeerwein rearrangements of the bicyclic camphor framework.
On treatment with LDA, the C-10 and C-8 substituted sulfones cyclized with complete stereo-
selectivity, affording tricyclic
X-ray crystallography. Tricyclic sulfones 23 and 24 underwent both
b
-hydroxy sulfones whose relative configurations were determined by
-elimination and retro-aldol
b
Keywords:
Sulfones
Camphor
Asymmetric synthesis
Chiral auxiliary
Carbanion
reactions on further exposure to base. Reduction of the carbonyl group of the C-10 substituted sul-
fones afforded exo-configured isobornyl sulfones with high stereoselectivity. Reaction of the lithiated
isobornyl benzyl sulfone 32 with benzaldehyde generated all four of the possible product di-
astereomers, of which three were isolated pure by chromatography. Attempted desulfonylation of
these diastereomers failed to generate the desired optically active homobenzylic alcohols but the
same sulfonyl carbanion trapping/desulfonylation sequence was successful in a model achiral series of
compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The rigid bicyclic nature of the camphor skeleton is an attractive
structural feature for chiral auxiliary applications.1 As a result,
many derivatives of camphor have found widespread use as chiral
auxiliaries in asymmetric synthesis.2 The most widely used auxil-
iary is Oppolzer’s sultam 13 (Fig. 1), which has been employed in an
impressive range of reactions since its introduction in 1984.4 In
addition, 10-mercaptoisoborneol 2 has been used in a tandem Mi-
chael addition/MeerweinePonndorfeVerley (MPV) reduction with
enones.5 Many camphor derivatives have also been employed as
chiral reagents and catalysts.6 For example, amino-alcohol 3 gives
high levels of stereoinduction when it is used as a chiral ligand in
the asymmetric addition of dialkylzinc reagents to aldehydes,7 and
in asymmetric Reformatsky reactions.8 Furthermore, sulfonium
ylides derived from sulfide 4 have been used in asymmetric Cor-
eyeChaykovsky reactions,9 and in the asymmetric cyclo-
propanation of electron-deficient olefins.10
NH
SO2
OH
SH
NMe2
OH
SMe
OMe
Fig. 1. Important camphor-derived chiral auxiliaries and reagents.
In recent decades, there has been a dramatic increase in the
use of the sulfonyl functional group in organic synthesis.11
However, in contrast to the sulfinyl group,12 relatively little
work has been carried out on the use of chiral sulfones in
asymmetric synthesis.13 A search of the literature reveals rela-
tively few examples where camphor-derived chiral sulfones have
been employed.5,14 On the other hand, camphor-derived chiral
* Corresponding author. Tel.: þ44 (0) 118 378 7417; fax: þ44 (0) 118 378 6121;
e-mail address: f.lewis@reading.ac.uk (F.W. Lewis).
y
Present address: Department of Chemistry, University of Reading, White-
knights, Reading RG6 6AD, UK.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.081

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F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
sulfoxides have been widely used in asymmetric synthesis.15 We
considered that a chiral auxiliary approach to asymmetric syn-
thesis using camphor-derived chiral sulfones would be a particu-
larly attractive option, based on the variety of methods available
for the introduction of the sulfonyl group and the ability to
remove it after the asymmetric synthetic step has been per-
formed. We have recently demonstrated the utility of the
camphorsulfonyl-group as a recyclable chiral auxiliary in asym-
metric DielseAlder reactions.16 In this paper, we describe the
results of our investigations into the feasibility of employing the
camphorsulfonyl-group as a recyclable chiral auxiliary in a dif-
ferent context.
PhCH2Cl
Ph
DMSO, 80° 78 %
or MeCN, 75 %
O
O
O
S
O2
SO2Na
5
6
Br
DMSO, 80° 65 %
or MeCN, 74 %
O
S
O2
SO2Na
5
7
2. Results and discussion
Scheme 2.
Initially, we wished to examine the reactions of aldehydes
with the anions derived from enantiopure camphor-based allylic
and benzylic sulfones, and then to examine the reductive
desulfonylation of the derived b-hydroxy sulfones as a means of
Sulfones 17 and 22 were obtained by the regioselective func-
tionalization of (þ)-camphor at either its C-9 or its C-8 methyl
group, respectively. The functionalization of these methyl groups
occurs via WagnereMeerwein rearrangements of the bicyclic
framework of camphor.20 The method of Kipping and Pope was
used to install the C-9 sulfonyl functionality of 17.21 Reaction of
endo-(þ)-3-bromocamphor 11 (prepared by the bromination22 of
(þ)-camphor 10) with chlorosulfonic acid afforded ammonium
sulfonate salts 12 and 13 after neutralization.21,23 Debromination of
12 using zinc dust in ammonium hydroxide afforded ammonium
sulfonate 14, which was then converted into sulfonyl chloride 15
using phosphorus pentachloride.23 Reduction of 15 with sodium
sulfite in the presence of sodium hydrogen carbonate gave the
sodium sulfinate 16 contaminated with ca. 10% (1H NMR spec-
troscopy) of the corresponding sodium sulfonate. This mixture was
used without purification. Alkylation of 16 with benzyl chloride in
acetonitrile19 afforded the novel benzyl sulfone 17 in 69% yield
(Scheme 3).
preparing enantiomerically enriched homoallylic and homo-
benzylic alcohols. Thus, alkylation of sodium camphor-10-
sulfinate 517 with an allylic or benzylic halide would afford
sulfones 6 or 7. Treatment of 6 or 7 with a suitable base, fol-
lowed by an aldehyde may afford diastereomeric adducts 8.
Desulfonylation with a suitable reagent (e.g.,: sodium amalgam
or samarium(II) iodide) would potentially yield the product
homoallylic or homobenzylic alcohol 9, together with a metal
sulfinate salt, which could then be recovered and recycled for
further use (Scheme 1).
R1CH2X
R1
O
O
(X = Cl/Br)
S
O2
SO2Na
6 R1 = phenyl
7 R1 = vinyl
5
recycle
LDA
R2CHO
SO3
NH4
O3S
NH4
metal
sulfinate
+
1: ClSO3H
2: NH4OH
+
R
Br
O
O
O
Br
OH
SmI2
Br2
AcOH
82 %
R1
10 R = H
12 22 %
13
R1
R2
R2
11 R = Br
Zn
*
O
S
NH4OH 80 %
O2
9
OH
8
ClO2S
O3S
NH4
Scheme 1.
PCl5
19 %
O
O
15
14
Na2SO3
NaHCO3
H2O/Me2CO 96 %
Accordingly, we proceeded to synthesize a number of regioiso-
meric sulfones where one of the three methyl groups of (þ)-cam-
phor was functionalized with a sulfonyl group. Sodium sulfinate 5
was synthesized from (þ)-camphor-10-sulfonic acid as previously
described.18 Treatment of sodium (ꢀ)-camphor-10-sulfinate 5 with
benzyl chloride or allyl bromide in DMSO at 80 ꢁC, or in acetonitrile
at reflux,19 afforded the novel sulfones 6 and 7 in good yields
(Scheme 2). None of the corresponding sulfinate esters (which
could be obtained by O-alkylation of 5) were formed in these
reactions.
NaO2S
Ph
S
O2
PhCH2Cl
MeCN,
69 %
O
O
16
17
Scheme 3.

F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
7519
Sulfone 22 was obtained by utilising the regiospecific C-8
LDA
THF
functionalization of (þ)-camphor developed by Money.24 Using the
method of Money, 3,3-dibromocamphor 1825 (obtained by bromi-
nation of either (þ)-camphor 10 or endo-(þ)-3-bromocamphor 11)
was treated with bromine and chlorosulfonic acid to afford 3,3,8-
tribromocamphor 19. Regioselective C-3 debromination of 19
with zinc dust in acetic acid gave enantiopure (þ)-8-
bromocamphor 20 in 62% yield.24,26 Despite its neopentyl struc-
ture, the bromo-substituent of 20 was smoothly displaced by the
sodium salt of benzyl mercaptan to give the sulfide 21 in 93%
yield.27 Oxidation of sulfide 21 with either m-CPBA in DCM, or with
KMnO4 in DCM/AcOH,28 afforded the sulfone 22 in good yield
(Scheme 4).
R
_
60°
R
O
S
SO2
O2
OH
6 R = phenyl
7 R = vinyl
23 R = phenyl 76 %
24 R = vinyl 70 %
Scheme 5.
The outcome of these cyclization reactions suggests that the
carbanions derived from 6 and 7 are in equilibrium with the tri-
cyclic oxyanions leading to 23 and 24. The fact that 7 cyclizes to
a greater extent than 6 under the same conditions may be due to
the greater steric effect of the bulky phenyl group in 6. The relative
stereochemistry of tricyclic sulfone 23 was unambiguously estab-
lished by single crystal X-ray crystallography (Fig. 2). We were
somewhat surprised to find that the hydroxyl group of 23 was in
the endo-configuration, indicating that the carbanion derived from
6 underwent 5-exo trig cyclization with the carbonyl group from
the more hindered top face. This is in contrast to the known pre-
cedent for stereoselective additions of metal hydrides and organ-
ometallic reagents to camphor, which give predominantly exo-
configured products via axial attack from the less hindered bottom
face.29
Br
Br2
R
O
Br
O
84-98 %
10 R = H or
11 R = Br
18
Br2
ClSO3H 60 %
Br
Br
Br
Zn
Br
O
AcOH
62 %
O
20
19
PhCH2SNa
EtOH, 93 %
m-CPBA
DCM 83 %
or
S
Ph
S
Ph
O2
KMnO4
DCM/AcOH
87 %
O
O
21
22
Scheme 4.
With the regioisomeric sulfones 6, 7, 17 and 22 in hand, we
proceeded to explore the reactions of the sulfonyl-stabilized carb-
anions derived from benzyl sulfone 6 and allyl sulfone 7 with
electrophiles. Treatment of either allyl sulfone 7 or benzyl sulfone 6
with LDA in anhydrous THF at ꢀ60 ꢁC, followed by the addition of
benzaldehyde gave, after acidic quench and standard work up, an
intractable mixture of products, which could not be cleanly sepa-
rated by column chromatography. Intractable mixtures were also
obtained when iodomethane was used as the electrophile. In order
to verify if the anions derived from these sulfones were undergoing
intramolecular 5-exo trig cyclization with the C-2 carbonyl group,
we repeated these reactions in the absence of an electrophile. Thus,
treatment of allyl sulfone 7 with LDA in THF at ꢀ60 ꢁC gave, after
acidic quench, tricyclic sulfone 24 as a single diastereomer (de-
termined by 1H NMR spectroscopy) in 70% yield, together with
a small amount of unchanged sulfone 7. Similarly, treatment of
benzyl sulfone 6 under identical conditions gave tricyclic sulfone
23, also as a single diastereomer, in lower yield, together with
a significant amount (52%) of unreacted starting sulfone 6 (Scheme
5). The yield of 23 was improved to 76% by allowing the reaction
mixture to warm to room temperature prior to quenching.
Fig. 2. Molecular structure in the crystal of sulfone 23 (CCDC: 822432). One of the two
asymmetric units is omitted for clarity.
The finding that the sulfonyl-stabilized carbanions derived from
6 and 7 cyclized in a completely stereoselective manner prompted
an investigation into the chemistry of these novel tricyclic com-
pounds. Sulfone 24 in particular was of interest by virtue of the
potential additional functionalization of its double bond. Henbest
et al. discovered that epoxidation of cyclic allylic alcohols with
peroxybenzoic acid occurs on the same side as the hydroxyl group
to give cis epoxy alcohols.30 We postulated that an analogous hy-
droxyl group-directed epoxidation of 24 would be possible. We
were pleased to find that treatment of tricyclic sulfone 24 with m-
CPBA in chloroform did indeed furnish the oxiranyl sulfone 25 as
a single diastereomer. On the other hand, treatment of 24 with
bromine in DCM gave both diastereomers of dibromosulfone 26 in
ca. 1:1 ratio (1H NMR spectroscopy), which were separable by
chromatography. Regioselective ring-opening of the oxiranyl ring of
25 with sodium thiophenolate afforded the sulfonyldiol 27 as
a single stereoisomer in good yield (Scheme 6).

7520
F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
which the bulky phenyl group is held away from the C-1 methyl
group (Fig. 4).
m-CPBA
S
Ph
O
LDA
THF
CHCl3,
45 %
O2
SO2
Ph
SO2
SO2
OH
24
OH
25
_
60°
O
75 %
OH
Br2
PhSNa
22
28
DCM 69 % 1:1 dr
THF 71 %
Scheme 7.
Br
SPh
Br
OH
SO2
SO2
OH
OH
26
27
Scheme 6.
The relative configurations of the three new stereocentres of
oxiranyl sulfone 25 were established by X-ray crystallography
(Fig. 3). It is evident that the base-mediated 5-exo trig cyclization
reaction of sulfone 7 proceeded with the same stereochemical
outcome as that of sulfone 6. Also evident is the configuration of the
oxiranyl group at C-4, held away from the bulky 10-syn methyl
group. The configuration of the oxiranyl-ring carbon indicates that
epoxidation of 24 occurred from the side of the double bond closest
to the hydroxyl group. As suggested by the X-ray structure of 25, the
most stable conformation of alkene 24 is most likely one where the
alkenyl-group is pointing up away from the sterically crowded endo
face. The hydroxyl group of 24 then directs O-atom transfer to the
side of the double bond facing the hydroxyl group.
Fig. 4. Molecular structure in the crystal of sulfone 28 (CCDC: 822435). A single
asymmetric unit is shown for clarity.
In view of the differing reactivities of sulfones 6 and 7 towards
aldol cyclization, it was of interest to examine if and to what extent
the tricyclic b-hydroxy sulfones 23 and 24 would undergo retro-
aldol reactions31 on treatment with a suitable base, followed by
acidic quenching. This would give some indication of the feasibility
of trapping the intermediate sulfonyl-stabilized carbanions with
electrophiles. Thus, the reaction of sulfone 23 with sodium hydride
in THF in the absence of an electrophile was first explored in order
to provide an indication of the position of equilibrium of the anion
formed by deprotonation of the hydroxyl group of 23.
Treatment of tricyclic sulfone 23 with sodium hydride in THF at
0
ꢁC, followed by warming to room temperature and acidic
quenching gave two products. Separation by column chromatog-
raphy yielded benzyl sulfone 6 as the major product (76%) together
with a minor amount (21%) of the tricyclic vinyl sulfone 29 (Scheme
8). Vinyl sulfone 29 is most likely formed by deprotonation at the
benzylic position followed by
b
-elimination of hydroxide ion.
NaH
THF
Ph
+
Ph
O
S
SO2
Ph
S
O2
OH
O2
23
29 21 %
6 76 %
Fig. 3. Molecular structure in the crystal of sulfone 25 (CCDC: 822431).
Scheme 8.
We also found that the sulfonyl-stabilized carbanion derived
from C8-substituted benzyl sulfone 22 cyclized in a completely
stereoselective manner. Treatment of 22 with LDA in THF led, after
acidic quenching and work-up, to a single diastereomer (1H NMR
spectroscopy) of the tricyclic sulfone 28 in 75% yield (Scheme 7).
Once again, the relative stereochemistries at the two newly-formed
stereocentres of 28 were determined by X-ray crystallography.
Apart from the expected endo-configuration of the hydroxyl group
(attack of the sulfonyl carbanion is only possible from the top face),
a notable feature is the configuration of the benzylic carbon in
In contrast, treatment of 24 under identical conditions gave two
products. Sulfonyldiene 30 was obtained as the major product
(83%) in addition to a minor amount of (E)-propenyl sulfone 31
(Scheme 9). The sulfone 31 is clearly formed via retro-aldol reaction
of the initially formed oxyanion of 24 and subsequent double bond
isomerization prior to quenching. This result, in which the
b-
elimination reaction that yields 30 is the major pathway, contrasts
with the result obtained for sulfone 23, in which the retro-aldol
reaction leading back to the parent sulfone 6 dominates. As

F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
7521
LDA (2 eq)
PhCHO
Ph
NaH
THF
+
OH
OH
Ph
THF
Ph
O
S
S
S
SO2
_
S
O2
60°
O2
O2
OH
OH
O2
32
36 87 %
24
30 83 %
31 15 %
threo 1:1 dr
erythro 3.8:1 dr
Scheme 9.
Scheme 11.
mentioned earlier, this may be due to a greater steric effect in 23
where the derived tricyclic oxyanion opens more readily than that
obtained from 24, to give the corresponding bicyclic sulfonyl
carbanion in order to relieve steric strain. The formation of 6 and 31
by retro-aldol reactions of 23 and 24, respectively, is further evi-
dence that the carbanions derived from sulfones 6 and 7 equilibrate
with the tricyclic oxyanions derived from 23 and 24 (Scheme 5).
Disappointingly, attempts to trap intermediate sulfonyl carbanions
by repeating the retro-aldol reactions of 23 and 24 in the presence
of benzaldehyde or iodomethane met with no success.
The carbonyl group present in sulfones 6 and 7 was sub-
sequently manipulated in order to remove the internal electrophile
and allow for potential reactions of the lithiated sulfones with ex-
ternal electrophiles. Ketosulfones 6 and 7 were reduced to the
corresponding exo-hydroxysulfones 32 and 34 using sodium bo-
rohydride in methanol. These reactions proceeded with high ster-
eoselectivity, giving the exo-configured isobornyl sulfones 32 and
34 as the major products and the endo-configured bornyl sulfones
33 and 35 as minor products (Scheme 10). The two pairs of di-
astereomers were readily separated by column chromatography in
each case. The major and minor isomers were identified by com-
parison of their 1H and 13C NMR data with those of isoborneol and
borneol, respectively.32 The high stereoselectivity observed for the
exo-configured alcohols 32 and 34 (15.7:1 dr for 6, 16.5:1 dr for 7) is
in keeping with that observed for the reduction of camphor with
metal hydrides, which affords isoborneol as the major stereoisomer
via axial attack from the less hindered endo face.29
Integration of the relevant signals in the 1H NMR spectrum of
the crude product showed that the reaction was mildly threo se-
lective (1.5:1 ratio), in agreement with previous observations on
analogous achiral sulfones.34 In addition, the pseudo-enantiomeric
threo isomers were present in ca. 1:1 ratio, whereas the erythro
isomers were present in ca. 3.8:1 ratio as determined by 1H NMR.
Thus, the aldol reaction of sulfone 32 with benzaldehyde proceeded
with little or no stereoselectivity. Fortunately, three of the four
diastereomers of 36 could be separated by careful column chro-
matography (the minor erythro diastereomer could not be isolated).
The relative configuration of one of the threo diastereomers 36C
was determined by X-ray crystallography. The molecular structure
in the crystal revealed that the configurations at the two newly
formed asymmetric centres were 10S,20S (Fig. 5). With this in-
formation, and the relative stereochemistry known from the vicinal
coupling constant in the 1H NMR spectrum, the relative configu-
ration of the second threo diastereomer 36B was determined as
10R,20R. The isobornylsulfonyl group and the phenyl group on the
adjacent carbon are anti, placing the vicinal methine protons in an
antiperiplanar relationship, in agreement with the conformational
preference exhibited by the analogous arylsulfonyl compounds,33
and with the large vicinal coupling constant (J 9.5 Hz) observed
NaBH4
+
OH
MeOH
R
R
R
O
S
S
S
OH
O2
O2
O2
6 R = phenyl
7 R = vinyl
32 R = phenyl 71 %
34 R = vinyl 76 %
33 R = phenyl 9 %
35 R = vinyl 4 %
Scheme 10.
With sulfones 32 and 34 in hand, we initially explored the re-
action of the sulfonyl-stabilized carbanion derived from 32 with
benzaldehyde. Treatment of sulfone 32 with LDA (2 equiv), fol-
lowed by benzaldehyde gave a crude product whose 1H NMR
spectrum showed the presence of all four diastereomers of b-hy-
droxy sulfone 36, in addition to a minor amount of unreacted
starting material (Scheme 11). The 1H NMR spectrum of the crude
product showed a pair of closely spaced doublets at ca.
each with a coupling constant of 9.5 Hz and another pair at ca.
6.0 ppm, each with a coupling constant of 3.5 Hz. These reso-
d 5.6 ppm,
d
nances were assigned to the pairs of pseudo-enantiomeric threo
and erythro diastereomers of 36, respectively. It has been shown
that the analogous achiral arylsulfonyl compounds reside in a pre-
ferred conformation in which the arylsulfonyl group and the phenyl
group on the adjacent carbon are antiperiplanar, enabling the two
diastereomers to be distinguished from the magnitude of their
vicinal coupling constants.33
Fig. 5. Molecular structure in the crystal of sulfone 36C (CCDC: 822433).

7522
F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
in the 1H NMR spectrum. Similarly, the relative configuration of the
major erythro diastereomer 36A was determined by X-ray crystal-
lography. The molecular structure in the crystal shows that the
configurations at the sulfonyl side-chain are 10S,20R (Fig. 6). Hence
the relative configuration of the minor erythro diastereomer (which
is pseudo-enantiomeric at the sulfonyl side-chain) must be 10R,20S.
PhCH2Cl or
Br
MeCN,
SO2Na
S
R
O2
37
38 R = phenyl 97 %
39 R = vinyl 93 %
BuLi, PhCHO
_
THF, 40°
R
SmI2
THF/HMPA
OH
Ph
R
+
R
S
Ph
Ph
O2
OH
44 R = phenyl 31 % 42 R = phenyl 40 %
40 R = phenyl 71 %
41 R = vinyl 38 %
45 R = vinyl 18 %
43 R = vinyl 63 %
Scheme 12.
The desulfonylation reactions of 40 and 41 with samarium(II)
iodide were then examined. Treatment of 41 with excess samar-
ium(II) iodide in THF/HMPA at ꢀ20 ꢁC for 5 h gave a mixture of the
desired homoallylic alcohol 43 and 1-phenylbuta-1,3-diene 45 in
ca. 4:1 ratio. The homoallylic alcohol 43 was isolated in reasonable
yield (63%) following column chromatography. Similarly, treatment
of 40 with samarium(II) iodide led to a ca. 1.2:1 ratio of homo-
benzylic alcohol 42 (isolated in 40% yield) and trans-stilbene 44
(Scheme 12). Alternative desulfonylation procedures applied to 40
and 41 were less successful. Sulfones 40 and 41 were unreactive
towards free-radical desulfonylation conditions using tri-n-butyltin
hydride/AIBN,38 whilst the attempted desulfonylation of 40 and 41
39
with NaBH4 in the presence of Pd(PPh3)4 produced a mixture of
benzyl alcohol and sulfones 38 and 39, respectively, via retro-aldol
reactions of 40 and 41. The relative success of the desulfonylation
step of achiral arylsulfones 40 and 41 compared to the chiral dia-
lkylsulfones 36 could be due to the greater reactivity of arylsulfones
towards reduction caused by delocalization into the aromatic ring
of the intermediate radical anion formed by electron transfer.40
Fig. 6. Molecular structure in the crystal of sulfone 36A (CCDC: 822434).
We then proceeded to examine the desulfonylation of each of
the three isolated diastereomers of b-hydroxy sulfone 36. Although
3. Conclusions
sodium amalgam is the reducing agent typically used for the
desulfonylation of arylsulfonyl compounds,35 we anticipated that
this would lead exclusively to the corresponding olefins via Julia-
type elimination, with subsequent loss of stereochemistry.36 On
the other hand, samarium(II) iodide in THF/HMPA has been used for
the desulfonylation of a variety of phenylsulfonyl compounds in-
We have carried out preliminary studies on the feasibility of
employing the camphorsulfonyl-group as a recyclable chiral aux-
iliary in asymmetric synthesis. Lithiated C-10 and C-8 substituted
sulfones failed to react with external electrophiles but reacted in-
stead with the carbonyl group of the auxiliary to generate tricyclic
products with complete stereoselectivity. The lithiated C-10
substituted isobornyl sulfone 32 reacted with benzaldehyde to
generate all of the four possible hydroxy sulfone product di-
astereomers and three of these were obtained pure by chroma-
tography. X-ray crystallography established the relative
configurations of the products. Attempted cleavage of the auxiliary
by desulfonylation with samarium(II) iodide failed to generate the
desired optically active homobenzylic alcohols. However, this re-
action sequence was successful with the corresponding achiral p-
tolyl sulfones, indicating a difference in reactivity between the two
classes of sulfone towards reductive desulfonylation.
cluding b
-hydroxy sulfones.37 We consequently chose this reagent
for the desulfonylation step. Unfortunately, each of the three di-
astereomers of 36 failed to react on treatment with an excess
(10 equiv) of samarium(II) iodide in THF/HMPA, and were re-
covered unchanged.
Inordertocomparetheabovedesulfonylationstepwiththatofthe
corresponding achiral arylsulfones, we carried out the same sulfonyl
carbanion alkylation/desulfonylation sequence on the corresponding
achiral arylsulfonyl compounds 38 and 39 (Scheme 12). Alkylation of
sodium p-toluenesulfinate 37 with benzyl chloride or with allyl bro-
mide afforded sulfones 38 and 39, respectively. Lithiated benzyl p-
tolyl sulfone 38reactedwithbenzaldehydetoform b-hydroxysulfone
adducts 40 as a mixture of threo/erythro diastereomers (71%) in ca.
2.2:1 ratio. Thesecould notbeseparatedby recrystallizationand were
contaminated with a trace amount of unreacted sulfone 38. Similarly,
lithiated allyl p-tolyl sulfone 39 on treatment with benzaldehyde
formed a mixture of separable diastereomeric adducts 41 (38%) in ca.
2.6:1 ratio. A significant amount of double bond isomerization oc-
curred during this reaction giving rise to the corresponding propenyl
sulfone 46 in 16% yield (see Supplementary data).
4. Experimental
4.1. General procedures
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

F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
7523
constants (J) are quoted in Hertz. Assignments were verified by
appropriate 1He1H COSY, 13Ce1H COSY and 13C-DEPT experiments.
Optical rotations were measured using a PerkineElmer 141 polar-
imeter. IR spectra were recorded for Nujol mulls (N) or for neat
liquid films (L) between sodium chloride plates using a Matteson
Genesis II FTIR spectrometer. Uncorrected melting points (Mp)
were measured in unsealed capillary tubes using a Griffin melting
point apparatus. Mass spectra were obtained under electrospray
conditions using a Micromass LCT instrument. Tetrahydrofuran
(THF) was dried and distilled over sodium-benzophenone ketyl.
Diisopropylamine was dried and distilled over calcium hydride. All
solvents and reagents were purified by standard techniques. Or-
ganic extracts of reaction products were dried over anhydrous
magnesium sulfate.
4.1.2.2. Method B. Sodium (ꢀ)-camphor-10-sulfinate 5 (0.94 g,
3.9 mmol) was suspended in acetonitrile (15 mL) and triethylhex-
ylammonium bromide (0.21 g, 20 mol %) was added. Allyl bromide
(0.38 mL, 4.3 mmol) was added and the mixture was heated under
reflux for 24 h. The mixture was allowed to cool to room temper-
ature, diluted with water (50 mL) and extracted with diethyl ether
(3ꢂ50 mL). The combined organic extracts were washed with brine
(50 mL), dried and evaporated to yield an oil. Column chromatog-
raphy on silica gel eluting with ethyl acetate/hexane (1:2) afforded
the title compound as a colourless oil (0.75 g, 74%). ½a D22
þ19.2 (c
ꢃ
0.51 in MeOH); vmax (L)/cmꢀ1 3087, 2961, 1744 (C]O), 1638 (C]C),
1455, 1417, 1394, 1317 (SO2), 1245, 1201, 1133 (SO2), 1051, 994, 937,
876, 820, 773, 676; dH (400.1 MHz; CDCl3; Me4Si) 0.89 (3H, s, 7-
CH3), 1.07 (3H, s, 7-CH3), 1.44e1.50 (1H, m), 1.81e1.89 (1H, m),
1.95 (1H, d, 2J 18.4, 3-CH2 endo), 2.01e2.11 (1H, m), 2.14 (1H, t, 3J 4.5,
4-CH), 2.36e2.45 (2H, m), 2.75 (1H, d, 2J 15.0, alkyl CH2SO2), 3.47
(1H, d, 2J 15.0, alkyl CH2SO2), 3.80 (1H, dd, J 14.0 and 7.5, allyl
CH2SO2), 4.12 (1H, dd, J 14.0 and 7.5, allyl CH2SO2), 5.52 (2H, m,
CH]CH2), 6.01 (1H, ddt, J 17.3, 10.0 and 7.5, CH]CH2); dC
(100.6 MHz; CDCl3; Me4Si) 19.2 (7-CH3), 19.3 (7-CH3), 24.9 (C-5),
26.6 (C-6), 42.1 (C-4), 42.2 (C-3), 48.2 (C-7), 48.6 (alkyl CH2SO2),
58.5 (C-1), 59.9 (allyl CH2SO2), 124.4 (CH]CH2), 124.8 (CH]CH2),
215.0 (C-2); m/z (CI) 279.1027 ([MþNa]þ); C13H20O3SNa requires
279.1030.
4.1.1. (1S,4R)-1-[(Benzylsulfonyl)methyl]-7,7-dimethylbicyclo-[2.2.1]
heptan-2-one (6). 4.1.1.1. Method A. Sodium (ꢀ)-camphor-10-
sulfinate 5 (5.00 g, 21 mmol) and sodium iodide (0.6 g, 20 mol %)
were dissolved in DMSO (75 mL). The flask was warmed to 40 ꢁC to
dissolve the solids and benzyl chloride (3.14 mL, 27.2 mmol) was
added. The solution was warmed at 80 ꢁC for 12 h. The solution was
then allowed to cool to room temperature, diluted with water
(200 mL) and extracted with diethyl ether (2ꢂ200 mL). The com-
bined organic extracts were washed with satd aq sodium sulfite
(100 mL) and brine (50 mL), dried and evaporated to yield an oil,
which later crystallized. Recrystallization from ethyl acetate affor-
ded the title compound as a white solid (5.01 g, 78%).
4.1.3. Sodium (1R,4R,7R)-(1,7-dimethyl-2-oxobicyclo[2.2.1]hept-7-yl)
methanesulfinate (16). Sulfonyl chloride 15 (0.63 g, 2.5 mmol) in
dry acetone (10 mL) was added dropwise over 1 h to a solution of
sodium sulfite (0.63 g, 5.0 mmol) and sodium hydrogen carbonate
(0.42 g, 5.0 mmol) in water (10 mL) maintained at 70 ꢁC. The
mixture was stirred for an additional 1 h at 70 ꢁC and was then
allowed to cool to room temperature and left stirring overnight. The
mixture was evaporated to yield a white solid, which was taken up
in boiling ethanol (50 mL) and filtered through CeliteÒ. The filtrate
was evaporated to afford the title compound as a white solid
(0.58 g, 96%) together with ca. 10% (by 1H NMR) of the corre-
sponding sodium sulfonate. vmax (N)/cmꢀ1 3344, 3188, 2921, 1739
(C]O), 1458, 1377, 1204, 1026 (S]O), 971 (S]O), 850, 721; dH
(400.1 MHz; D2O) 0.77 (3H, s, 1-CH3), 0.92 (3H, s, 7-CH3), 1.27e1.38
(2H, m), 1.65e1.73 (1H, m), 1.89 (1H, d, 2J 19.0, 3-CH2 endo),
1.94e2.01 (1H, m), 2.17 (1H, d, 2J 13.5, CH2SO2Na), 2.36 (1H, dt, J
19.0 and 4.5, 3-CH2 exo), 2.45 (1H, d, 2J 13.5, CH2SO2Na), 2.55 (1H, t,
3J 4.5, 4-CH); dC (100.6 MHz; D2O) 7.9 (1-CH3), 16.5 (7-CH3), 25.3 (C-
5), 28.5 (C-6), 39.9 (C-4), 41.9 (C-3), 47.6 (C-7), 59.6 (C-1), 64.7
(CH2SO2Na), 225.8 (C-2).
4.1.1.2. Method B. Sodium (ꢀ)-camphor-10-sulfinate 5 (0.94 g,
3.9 mmol) was suspended in acetonitrile (15 mL) and trie-
thylhexylammonium bromide (0.21 g, 20 mol %) was added.
Benzyl chloride (0.5 mL, 4.3 mmol) was added and the mixture
was heated under reflux for 24 h. The mixture was allowed to cool
to room temperature, diluted with water (50 mL) and extracted
with diethyl ether (3ꢂ50 mL). The combined organic extracts were
washed with brine (50 mL), dried and evaporated to yield an oil,
which later crystallized. Recrystallization from ethyl acetate
afforded the title compound as a white solid (0.91 g, 75%). Mp
68e69 ꢁC (from EtOAc); ½a 2D2
þ21.0 (c 0.48 in MeOH); vmax (N)/
ꢃ
cmꢀ1 2945, 1737 (C]O), 1455, 1411, 1375, 1314 (SO2), 1263, 1198,
1153, 1118 (SO2), 1052, 1029, 965, 931, 879, 857, 793, 744, 720, 701;
dH(400.1 MHz; CDCl3; Me4Si) 0.85 (3H, s, 7-CH3), 1.02 (3H, s, 7-
CH3), 1.44e1.51 (1H, m), 1.89e1.97 (1H, m), 1.97 (1H, d, 2J 18.5, 3-
CH2-endo), 2.02e2.09 (1H, m), 2.13 (1H, t, 3J 4.5, 4-CH),
2.32e2.45 (2H, m), 2.68 (1H, d, 2J 15.0, alkyl CH2SO2), 3.40 (1H, d,
2J 15.0, alkyl CH2SO2), 4.36 (1H, d, 2J 13.5, benzyl CH2SO2), 4.72
(1H, d, 2J 13.5, benzyl CH2SO2), 7.38e7.41 (3H, m, AreH), 7.46e7.49
(2H, m, ArH); dC(100.6 MHz; CDCl3; Me4Si) 19.2 (7-CH3), 19.3 (7-
CH3), 25.2 (C-5), 26.6 (C-6), 42.1 (C-4), 42.2 (C-3), 48.2 (C-7),
48.9 (alkyl CH2SO2), 58.7 (C-1), 61.6 (benzyl CH2SO2), 127.9 (Ar C-
1), 128.4 (Ar C-3), 128.4 (Ar C-4), 130.5 (Ar C-2), 215.1 (C-2); m/z
(CI) 329.1173 ([MþNa]þ); C17H22O3SNa requires 329.1187.
4.1.4. (1R,4R,7R)-7-[(Benzylsulfonyl)methyl]-1,7-dimethylbicyclo-
[2.2.1]heptan-2-one (17). Sodium sulfinate 16 (0.36 g, 1.51 mmol)
was suspended in acetonitrile (10 mL) and triethylhexylammonium
bromide (0.08 g, 20 mol %) was added. Benzyl chloride (0.19 mL,
1.66 mmol) was added and the mixture was heated under reflux for
24 h. The mixture was allowed to cool to room temperature, diluted
with water (50 mL) and extracted with diethyl ether (3ꢂ50 mL).
The combined organic extracts were dried and evaporated to yield
an oil. Column chromatography on silica gel eluting with ethyl
acetate/hexane (1:3) afforded the title compound as a white solid
4.1.2. (1S,4R)-1-[(Allylsulfonyl)methyl]-7,7-dimethylbicyclo-[2.2.1]
heptan-2-one (7). 4.1.2.1. Method A. Sodium (ꢀ)-camphor-10-
sulfinate
5 (5.36 g, 22 mmol) and sodium iodide (0.67 g,
20 mol %) were dissolved in DMSO (50 mL). The mixture was
warmed to 40 ꢁC to dissolve the solids and allyl bromide (2.92 mL,
33 mmol) was added. The solution was warmed at 60 ꢁC for 6 h. The
solution was then allowed to cool to room temperature, diluted
with water (200 mL) and extracted with diethyl ether (3ꢂ100 mL).
The combined organic extracts were washed with satd aq sodium
sulfite (100 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 as a colourless oil (3.77 g,
65%).
(0.32 g, 69%). Mp 93e94 ꢁC (from EtOAc/hexane); ½a 1D9
þ75.8 (c
ꢃ
0.39 in CHCl3); vmax (N)/cmꢀ1 2923, 1737 (C]O), 1602, 1459, 1377,
1296 (SO2), 1203, 1132 (SO2), 1078, 1044, 950, 828, 753, 727, 698; dH
(400.1 MHz; CDCl3; Me4Si) 0.87 (3H, s, 1-CH3), 1.16 (3H, s, 7-CH3),
1.35e1.46 (3H, m), 1.72e1.80 (1H, m), 1.90 (1H, d, 2J 18.5, 3-CH2
endo), 2.38 (1H, dt, J 18.5 and 4.5, 3-CH2 exo), 2.72 (1H, d, 2J 13.5,
alkyl CH2SO2), 2.97 (1H, t, 3J 4.5, 4-CH), 3.07 (1H, d, 2J 13.5, alkyl
CH2SO2), 4.25 (1H, d, 2J 14.0, benzyl CH2SO2), 4.28 (1H, d, 2J 14.0,
benzyl CH2SO2), 7.44 (5H, s, AreH); dC (100.6 MHz; CDCl3; Me4Si)
8.9 (1-CH3), 17.0 (7-CH3), 25.9 (C-5), 28.8 (C-6), 39.9 (C-4), 42.0 (C-

7524
F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
3), 48.5 (C-7), 52.1 (alkyl CH2SO2), 59.5 (C-1), 62.3 (benzyl CH2SO2),
127.8 (Ar C-1), 128.6 (Ar C-3), 128.7 (Ar C-4), 130.0 (Ar C-2), 216.0
(C-2); m/z (CI) 329.1187 ([MþNa]þ); C17H22O3SNa requires
329.1186.
4.1.7. (1S,4S,5S,7R)-10,10-Dimethyl-4-phenyl-3-thiatricyclo-[5.2.1.01,5
]
decan-5-ol 3,3-dioxide (23). n-Butyllithium (2.61 mL, 2.5 M,
6.5 mmol) was added to a solution of dry diisopropylamine (1.19 mL,
8.5 mmol) in dry tetrahydrofuran (10 mL) at ꢀ60 ꢁC under an at-
mosphere of nitrogen. The solution was allowed to warm to 0 ꢁC and
then recooled to ꢀ60 ꢁC. A solution of sulfone 6 (2.0 g, 6.5 mmol) in
dry tetrahydrofuran (15 mL) was added dropwise via syringe and the
solution was stirred at ꢀ60 ꢁC for 15 min and then allowed to warm
to room temperature and stirred for a further 3 h. The solution was
then quenched with satd aq ammonium chloride (50 mL) and
extracted with diethyl ether (3ꢂ50 mL). The combined organic ex-
tracts were washed with brine (50 mL), dried and evaporated to
yield an oil (1.89 g). Column chromatography on silica gel eluting
with ethyl acetate/hexane (1:3) afforded the title compound as
a white solid (1.53 g, 76%), followed by unchanged starting sulfone 6
4.1.5. (1R,4R,7S)-7-[(Benzylthio)methyl]-1,7-dimethylbicyclo-[2.2.1]
heptan-2-one (21). Freshly cut sodium metal (0.10 g, 4.67 mmol)
was dissolved in isopropanol (10 mL) and benzyl mercaptan
(0.73 mL, 6.23 mmol) was added. A solution of 8-bromocamphor
20 (0.36 g, 1.55 mmol) in isopropanol (5 mL) was added and the
solution was heated under reflux for 4 days. The solution was
allowed to cool to room temperature, diluted with water (50 mL)
and extracted with diethyl ether (3ꢂ50 mL). The combined or-
ganic extracts were washed with 0.1 M aq potassium hydroxide
(2ꢂ50 mL), dried and evaporated to yield an oil. Column chro-
matography on silica gel eluting with ethyl acetate/hexane (1:10)
(0.28 g). Mp 83 ꢁC (from EtOAc/hexane); ½a 2D2
þ4.4 (c 0.93 in MeOH);
ꢃ
afforded the title compound as a clear oil (0.40 g, 93%). ½a D21
ꢃ
þ19.7
vmax (N)/cmꢀ1 3515 (OeH), 2929, 1601, 1499, 1455, 1376, 1300 (SO2),
1247, 1222, 1183, 1117 (SO2), 1077, 1027, 944, 832, 794, 738, 716, 694;
dH (400.1 MHz; CDCl3; Me4Si) 1.07 (3H, s, 10-CH3), 1.23 (3H, s, 10-
CH3), 1.49 (1H, d, 2J 13.5, 6-CH2 endo), 1.53e1.58 (1H, m), 1.70e1.77
(1H, m), 1.87e1.90 (1H, m), 1.93 (1H, t, 3J 3.5, 7-CH), 2.36 (1H, dt, J
13.5 and 3.5, 6-CH2 exo), 2.44 (1H, m), 3.17 (1H, d, 2J 14.5, 2-CH2), 3.21
(1H, d, 2J 14.5, 2-CH2), 4.38 (1H, s, 4-CH), 7.41 (3H, t, 3J 2.5, AreH),
7.64e7.67 (2H, m, AreH); dC (100.6 MHz; CDCl3; Me4Si) 21.6 (10-
CH3), 21.6 (10-CH3), 26.1 (C-8), 26.9 (C-9), 42.3 (C-6), 43.9 (C-7), 50.3
(C-10), 51.4 (C-2), 56.2 (C-1), 71.9 (C-4), 81.9 (C-5), 126.8 (Ar C-1),
128.2(Ar C-3), 128.5 (Ar C-4), 130.2 (Ar C-2); m/z (CI) 329.1196
([MþNa]þ); C17H22O3SNa requires 329.1186.
(c 1.01 in CHCl3); vmax (L)/cmꢀ1 3060, 3027, 2958, 1741 (C]O),
1601, 1492, 1450, 1413, 1380, 1282, 1240, 1200, 1154, 1069, 1040,
924, 759, 701; dH (400.1 MHz; CDCl3; Me4Si) 0.89 (3H, s, 1-CH3),
1.04 (3H, s, 7-CH3), 1.31e1.46 (2H, m), 1.67e1.74 (1H, m), 1.82 (1H,
d, 2J 18.5, 3-CH2 endo), 1.86e1.93 (1H, m), 2.11e2.18 (1H, m, 3-CH2
exo), 2.14 (1H, d, 2J 12.0, alkyl CH2S), 2.30 (1H, d, 2J 12.0, alkyl
CH2S), 2.35 (1H, t, 3J 4.5, 4-CH), 3.66 (1H, d, 2J 13.5, benzyl CH2S),
3.71 (1H, d, 2J 13.5, benzyl CH2S), 7.24e7.37 (5H, m, AreH); dC
(100.6 MHz; CDCl3; Me4Si) 8.8 (1-CH3), 15.6 (7-CH3), 26.2 (C-5),
29.8 (C-6), 36.8 (alkyl CH2S), 37.1 (benzyl CH2S), 39.8 (C-4), 42.2
(C-3), 49.8 (C-7), 58.4 (C-1), 126.6 (Ar C-4), 128.0 (Ar C-3), 128.2
(Ar C-2), 137.6 (Ar C-1), 218.4 (C-2); m/z (CI) 297.1297 ([MþNa]þ);
C17H22OSNa requires 297.1288.
4.1.8. (1S,4S,5S,7R)-10,10-Dimethyl-4-vinyl-3-thiatricyclo-[5.2.1.01,5
]
decan-5-ol3,3-dioxide(24). n-Butyllithium (0.80 mL, 2.5 M, 1.9 mmol)
was added to a solution of dry diisopropylamine (0.36 mL, 2.5 mmol)
in dry tetrahydrofuran (5 mL) at ꢀ60 ꢁC under an atmosphere of
nitrogen. The solution was allowed to warm to 0 ꢁC and then recooled
to ꢀ60 ꢁC. A solution of sulfone 7 (0.51 g, 1.9 mmol) in dry tetrahy-
drofuran (4 mL) was added dropwise via syringe and the solution was
stirred at ꢀ60 ꢁC for 90 min. The solution was then allowed to warm
to room temperature, quenched with satd aq ammonium chloride
(50 mL) and extracted with diethyl ether (3ꢂ50 mL). The combined
organic extracts were washed with brine (50 mL), dried and evapo-
rated to yield an oil (0.41 g). Column chromatography on silica gel
eluting with ethyl acetate/hexane (1:2) afforded the title compound
as a white solid (0.36 g, 70%), followed by unchanged starting sulfone
4.1.6. (1R,4R,7S)-7-[(Benzylsulfonyl)methyl]-1,7-dimethylbicyclo-[2.2.1]
heptan-2-one (22). 4.1.6.1. Method A. Sulfide 21 (0.15 g, 0.54 mmol)
was dissolved in dichloromethane (10 mL) and cooled to 0 ꢁC. A so-
lution of m-CPBA (0.296 g, 70%, 1.2 mmol) in dichloromethane (5 mL)
was added dropwise over 15 min. The solution was stirred at 0 ꢁC for
4 h. The solution was allowed to warm to room temperature and
diluted with dichloromethane (100 mL). The solution was washed
with satd aq sodium sulfite (50 mL) and satd aq sodium hydrogen
carbonate (50 mL), dried and evaporated to yield an oil. Column
chromatography on silica gel eluting with ethyl acetate/hexane (1:3)
afforded the title compound as an oil (0.14 g, 83%), which crystallized
on standing overnight.
7 (0.03 g). Mp 89e91 ꢁC (from EtOAc/hexane); ½a 2D2
ꢀ74.8 (c 1.11 in
ꢃ
4.1.6.2. Method B. Sulfide 21 (0.33 g, 1.2 mmol) was dissolved in
dichloromethane (10 mL) and acetic acid (2 mL) and finely pow-
dered potassium permanganate (0.38 g, 2.4 mmol) was added in
small portions over 5 min. The mixture was stirred at room tem-
perature for 5 h. The mixture was then diluted with dichloro-
methane (100 mL) and filtered and the filtrate was washed with
water (3ꢂ50 mL), satd aq sodium sulfite (50 mL) and satd aq so-
dium hydrogen carbonate (50 mL) and then dried and evaporated
to yield an oil (0.32 g, 87%), which crystallized on standing over-
MeOH); vmax (N)/cmꢀ1 3507 (OeH), 3465 (OeH), 2918, 1634 (C]C),
1461, 1409, 1375, 1300 (SO2), 1221, 1182, 1116 (SO2), 1023, 994, 931,
859, 831, 786, 741, 645; dH (400.1 MHz; CDCl3; Me4Si) 1.02 (3H, s, 10-
CH3), 1.12 (3H, s, 10-CH3), 1.48 (1H, d, 2J 13.5, 6-CH2 endo), 1.49e1.56
(1H, m), 1.66e1.72 (1H, m), 1.84e1.91 (2H, m), 2.22 (1H, dt, J 13.5 and
2
3.5, 6-CH2 exo), 2.33e2.39 (1H, m), 3.06 (1H, d, J 14.5, 2-CH2), 3.13
(1H, d, 2J 14.5, 2-CH2), 3.74 (1H, d, 3J 8.5, 4-CH), 5.57 (1H, d, 3J 17.0,
CH]CH2), 5.61 (1H, d, 3J 10.5, CH]CH2), 6.02 (1H, ddd, J 17.0,10.5 and
8.5, CH]CH2); dC (100.6 MHz; CDCl3; Me4Si) 21.4 (10-CH3), 21.4 (10-
CH3), 26.1 (C-8), 26.7 (C-9), 41.9 (C-6), 43.7 (C-7), 50.3 (C-10), 51.0 (C-
2), 56.5 (C-1), 72.7 (C-4), 82.1 (C-5), 122.7 (CH]CH2), 125.2 (CH]
CH2); m/z (CI) 279.1035 ([MþNa]þ); C13H20O3SNa requires 279.1030.
night. Mp 78e79 ꢁC (from EtOAc/hexane); ½a 1D5
þ21.8 (c 0.33 in
ꢃ
CHCl3); vmax (N)/cmꢀ1 2923, 2854, 1732 (C]O), 1603, 1459, 1376,
1313 (SO2), 1263, 1202, 1120 (SO2), 1073, 927, 888, 787, 723, 696; dH
(400.1 MHz; CDCl3; Me4Si) 0.87 (3H, s, 1-CH3), 1.25 (3H, s, 7-CH3),
1.38e1.45 (1H, m), 1.62e1.71 (2H, m), 1.90 (1H, d, 2J 19.0, 3-CH2
endo), 1.95e2.00 (1H, m), 2.27 (1H, dt, J 19.0 and 4.0, 3-CH2 exo),
2.54 (1H, d, 2J 14.0, alkyl CH2SO2), 2.74 (1H, d, 2J 14.0, alkyl CH2SO2),
2.95 (1H, t, 3J 4.5, 4-CH), 4.20 (2H, s, benzyl CH2SO2), 7.36e7.43 (5H,
m, AreH); dC (100.6 MHz; CDCl3; Me4Si) 8.7 (1-CH3), 16.0 (7-CH3),
26.5 (C-5), 27.8 (C-6), 39.4 (C-4), 42.5 (C-3), 48.6 (C-7), 53.2 (alkyl
CH2SO2), 60.2 (C-1), 61.9 (benzyl CH2SO2), 127.4 (Ar C-1), 128.7 (Ar
C-3), 128.8 (Ar C-4), 130.0 (Ar C-2), 217.6 (C-2); m/z (CI) 329.1185
([MþNa]þ); C17H22O3SNa requires 329.1186.
4.1.9. (1S,4S,5S,7R,20S)-10,10-Dimethyl-4-oxiran-20-yl-3-thiatricyclo
[5.2.1.01,5]decan-5-ol 3,3-dioxide (25). Sulfone 24 (0.25 g, 0.97 mmol)
was dissolved in chloroform (5 mL) and a solution of m-CPBA (0.48 g,
70%, 1.95 mmol) in chloroform (5 mL) was added dropwise. The so-
lution was heated under reflux for 4 h and then allowed to cool to
room temperature and left stirring overnight. The mixture was di-
luted with chloroform (100 mL) and then washed with satd aq so-
dium hydrogen carbonate (2ꢂ50 mL) and brine (50 mL), dried and
evaporated to yield a white solid (0.32 g). Column chromatography

F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
7525
on silica gel eluting with ethyl acetate/hexane (1:2) afforded the title
compound as a white solid (0.12 g, 45%). Mp 152 ꢁC (from EtOAc/
(1H, dd, J 12.0 and 2.5, 20-CH2), 4.12 (1H, dd, J 12.0 and 4.5, 20-CH2),
3
4.78 (1H, ddd, J 10.5, 4.5 and 2.5, 10CH); dC (100.6 MHz; CDCl3;
hexane); ½a 2D6
ꢃ
ꢀ40.0 (c 0.09 in MeOH); vmax (N)/cmꢀ1 3506 (OeH),
Me4Si) 21.1 (10-CH3), 21.1 (10-CH3), 25.7 (C-8), 26.9 (C-9), 37.7 (C-6),
44.2 (C-7), 45.4 (C-10), 47.2 (C-20), 49.8 (C-10), 52.7 (C-2), 56.7 (C-1),
71.6 (C-4), 83.6 (C-5); m/z (CI) 438.9332 ([MþNa]þ); C13H20
O3SBr2Na requires 439.1598. The second product to elute was di-
astereomer 26B as a white solid (0.12 g, 38%). Mp 172 ꢁC (from
2908,1461,1376, 1303 (SO2), 1253, 1179, 1125 (SO2),1037, 878, 732; dH
(400.1 MHz; CDCl3; Me4Si) 1.02 (3H, s, 10-CH3), 1.07 (3H, s, 10-CH3),
1.52e1.58 (1H, m), 1.66 (1H, d, 2J 13.5, 6-CH2 endo), 1.69e1.75 (1H, m),
3
1.85e1.89 (1H, m), 1.92 (1H, t, J 4.0, 7-CH), 2.35e2.41 (1H, m), 2.44
(1H, dt, J 13.5 and 3.5, 6-CH2 exo), 2.88 (1H, d, 3J 7.0, 4-CH), 2.94 (1H,
dd, J 4.5 and 2.5, 30-CH2 anti), 2.98 (1H, app t, J 4.5 and 4.0, 30-CH2 syn),
3.08 (1H, d, 2J 14.5, 2-CH2), 3.12 (1H, br s, OH), 3.13 (1H, d, 2J 14.5, 2-
CH2), 3.58 (1H, qu, 20-CH); dC (100.6 MHz; CDCl3; Me4Si) 21.2 (10-
CH3), 21.4 (10-CH3), 26.0 (C-8), 26.6 (C-9), 42.9 (C-6), 44.1 (C-30), 44.1
(C-7), 44.5 (C-20), 50.3 (C-10), 51.9 (C-2), 56.8 (C-1), 71.1 (C-4), 81.8 (C-
5); m/z (CI) 295.0985 ([MþNa]þ); C13H20O4SNa requires 295.0979.
EtOAc/hexane); ½a D27
ꢃ
ꢀ58.8 (c 0.36 in MeOH); vmax (N)/cmꢀ1 3419
(OeH), 2924, 1607, 1461, 1376, 1308 (SO2), 1246, 1178, 1120 (SO2),
1028, 740; dH (400.1 MHz; CDCl3; Me4Si) 1.01 (3H, s, 10-CH3), 1.15
(3H, s, 10-CH3), 1.45e1.50 (1H, m), 1.51 (1H, d, 2J 13.0, 6-CH2 endo),
1.66e1.74 (1H, m), 1.82e1.90 (1H, m), 1.93 (1H, t, 3J 4.5, 7-CH),
2.18e2.24 (1H, m), 2.82 (1H, dt, J 13.0 and 3.5, 6-CH2 exo), 3.16 (1H,
d, 2J 14.5, 2-CH2), 3.20 (1H, d, 2J 14.5, 2-CH2), 3.74 (1H, d, 3J 10.5, 4-
CH), 3.95 (1H, dd, J 11.5 and 3.0, 20-CH2), 4.02 (1H, dd, J 11.5 and 3.0,
20-CH2), 4.80 (1H, dt, 3J 10.5 and 3.0, 10-CH); dC (100.6 MHz; CDCl3;
Me4Si) 20.9 (10-CH3), 21.2 (10-CH3), 25.9 (C-8), 26.6 (C-9), 38.4 (C-
6), 43.1 (C-7), 43.4 (C-20), 44.1 (C-10), 50.4 (C-10), 52.2 (C-2), 55.4 (C-
1), 71.7 (C-4), 83.6 (C-5); m/z (CI) 438.9332 ([MþNa]þ);
C13H20O3SBr2Na requires 439.1598.
4.1.10. (1S,4S,5S,7R,10S)-10,10-Dimethyl-4-[10-hydroxy-20-(phenylthio)
ethyl]-3-thiatricyclo[5.2.1.01,5]decan-5-ol 3,3-dioxide (27). Thiophenol
(0.076 mL, 0.73 mmol) was added to a suspension of sodium hydride
(0.03 g, 60%, 0.73 mmol) in dry tetrahydrofuran (3 mL) at 0 ꢁC under
an atmosphere of nitrogen. After the evolution of hydrogen had
ceased (ca. 5 min), a solution of sulfone 25 (0.10 g, 0.36 mmol) in dry
tetrahydrofuran (4 mL) was added dropwise. The solution was
allowed to warm to room temperature and stirred for 5 h. The so-
lution was quenched with satd aq ammonium chloride (50 mL) and
extracted with diethyl ether (3ꢂ50 mL). The combined organic ex-
tracts were washed with brine (50 mL), dried and evaporated to
yield a semi-solid (0.27 g). Column chromatography on silica gel
eluting with ethyl acetate/hexane (1:2) afforded the title compound
4.1.12. (1R,2S,5R,6S,8R)-1,2-Dimethyl-5-phenyl-4-thiatricyclo-
[4.4.0.02,8]decan-6-ol 4,4-dioxide (28). n-Butyllithium (0.42 mL,
2.5 M, 1.04 mmol) was added to a solution of dry diisopropylamine
(0.2 mL, 1.35 mmol) in dry tetrahydrofuran (5 mL) at ꢀ60 ꢁC under
an atmosphere of nitrogen. The solution was allowed to warm to
0
ꢁC and then recooled to ꢀ60 ꢁC. A solution of sulfone 22 (0.32 g,
1.04 mmol) in dry tetrahydrofuran (6 mL) was added dropwise via
syringe and the solution was stirred at ꢀ60 ꢁC for 30 min and then
allowed to warm to room temperature and stirred for a further 3.5 h.
The solution was then quenched with satd aq ammonium chloride
(50 mL) and extracted with diethyl ether (3ꢂ50 mL). The combined
organic extracts were washed with brine (50 mL), dried and evap-
orated to yield a yellow solid (0.27 g). Column chromatography on
silica gel eluting with ethyl acetate/hexane (1:2) afforded the title
compound as a white solid (0.24 g, 75%). Also eluted was unchanged
as a white solid (0.10 g, 71%). Mp 124 ꢁC (from EtOAc/hexane); ½a 2D6
ꢃ
ꢀ93.7 (c 0.35 in MeOH); vmax (N)/cmꢀ1 3407 (OeH), 2922, 1582,
1460, 1376, 1280 (SO2), 1214, 1118 (SO2), 1076, 984, 804, 735, 692; dH
(400.1 MHz; CDCl3; Me4Si) 1.02 (3H, s, 10-CH3), 1.15 (3H, s, 10-CH3),
1.47e1.53 (1H, m),1.57 (1H, d, 2J 14.0, 6-CH2 endo), 1.61e1.68 (1H, m),
1.81e1.85 (1H, m), 1.89 (1H, t, 3J 4.5, 7-CH), 2.38 (1H, m), 2.52 (1H, dt,
J 14.0 and 3.0, 6-CH2 exo), 3.12 (1H, dd, J 14.3 and 7.5, 20-CH2), 3.17
(2H, s, 2-CH2), 3.25 (1H, br s, OH), 3.49 (1H, d, 3J 8.0, 4-CH), 3.56
(1H, br s, OH), 3.58 (1H, dd, J 14.3 and 3.5, 20-CH2), 4.46e4.54 (1H, m,
10-CH), 7.23 (1H, t, 3J 7.5, 4-AreH), 7.32 (2H, t, 3J 7.5, 3-AreH), 7.44
(2H, d, 3J 7.5, 2-AreH); dC (100.6 MHz; CDCl3; Me4Si) 21.2 (10-CH3),
21.3 (10-CH3), 25.9 (C-8), 26.3 (C-9), 38.8 (C-20), 44.7 (C-7), 46.0 (C-6),
49.7 (C-10), 52.9 (C-2), 56.7 (C-1), 65.9 (C-10), 71.5 (C-4), 83.1 (C-5),
126.4 (Ar C-4), 128.7 (Ar C-2), 129.3 (Ar C-3), 133.6 (Ar C-1); m/z (CI)
405.1154 ([MþNa]þ); C19H26O4S2Na requires 405.1169.
starting sulfone 22 (0.02 g). Mp 171 ꢁC (from EtOAc/hexane); ½a 1D5
ꢃ
þ37.5 (c 0.37 in CHCl3); vmax (N)/cmꢀ1 3435 (OeH), 2921, 1600,1459,
1377, 1289 (SO2),1217, 1105 (SO2),1055, 983, 924, 855, 786, 732, 693;
dH (400.1 MHz; CDCl3; Me4Si) 1.05 (3H, s, 1-CH3), 1.20 (3H, s, 2-CH3),
1.40 (1H, d, 2J 14.0, 7-CH2 endo), 1.44e1.50 (2H, m), 1.84e1.92 (1H,
m), 2.17 (1H, t, 3J 4.5, 8-CH), 2.37e2.44 (1H, m), 3.34 (1H, d, 2J 15.0, 3-
CH2), 3.52 (1H, d, 2J 15.0, 3-CH2), 3.64 (1H, ddd, J 14.0, 4.5 and 3.5, 7-
CH2 exo), 4.58 (1H, s, 5-CH), 7.43e7.46 (3H, m, AreH), 7.52e7.55 (2H,
m, AreH); dC (100.6 MHz; CDCl3; Me4Si) 11.1 (1-CH3), 19.3 (2-CH3),
28.1 (C-9), 29.7 (C-10), 39.6 (C-7), 45.0 (C-8), 50.2 (C-2), 50.5 (C-1),
60.7 (C-3), 72.0 (C-5), 79.0 (C-6), 128.7 (Ar C-3), 129.2 (Ar C-2), 131.0
(Ar C-4), 131.1 (Ar C-1); m/z (CI) 329.1174 ([MþNa]þ); C17H22O3SNa
requires 329.1186.
4.1.11. (1S,4R,5S,7R)-10,10-Dimethyl-4-(10,20-dibromoethyl)-3-thia-
tricyclo[5.2.1.01,5]decan-5-ol 3,3-dioxide (26). Sulfone 24 (0.20 g,
0.78 mmol) was dissolved in dichloromethane (5 mL) and the so-
lution was cooled to 0 ꢁC. A solution of bromine in dichloromethane
(2.2 mL, 0.39 M, 0.85 mmol) was added dropwise and the solution
was stirred at 0 ꢁC for 30 min and then allowed to warm to room
temperature and stirred for an additional 3 h. Water (50 mL) was
added and the mixture was extracted with diethyl ether (3ꢂ50 mL).
The combined organic extracts were washed with satd aq sodium
sulfite (50 mL) and brine (50 mL), dried and evaporated to yield
a white solid (0.29 g) whose 1H NMR spectrum showed it to consist
of two diastereomers of 26 in ca. 1:1 ratio. Column chromatography
on silica gel eluting with ethyl acetate/hexane (1:2) yielded two
products. The first product to elute was diastereomer 26A as
4.2. Retro-aldol reactions of tricyclic
and (24): general procedure
b-hydroxy sulfones (23)
A solution of sulfone 23 or 24 (0.30 g, 0.98 mmol) in dry tetra-
hydrofuran (8 mL) was added dropwise to a suspension of sodium
hydride (0.043 g, 60%, 1.07 mmol) in dry tetrahydrofuran (6 mL) at
0
ꢁC under an atmosphere of nitrogen. The mixture was stirred at
0 ꢁC for 30 min and then allowed to warm to room temperature and
stirred for an additional 90 min. The mixture was then quenched
with satd aq ammonium chloride (50 mL) and extracted with
diethyl ether (3ꢂ50 mL). The combined organic extracts were
washed with brine (50 mL), dried and evaporated to yield an oil.
Column chromatography on silica gel eluting with ethyl acetate/
hexane (1:3) afforded the unsaturated sulfone 29 (0.06 g, 21%) or 30
(0.10 g, 83%) as a white solid, followed by benzyl sulfone 6 (0.23 g,
76%) or vinyl sulfone 31 (0.02 g, 15%), respectively.
a white solid (0.10 g, 31%). Mp 134 ꢁC (from EtOAc/hexane); ½a 2D7
ꢃ
ꢀ5.4 (c 0.33 in MeOH); vmax (N)/cmꢀ1 3419 (OeH), 2924, 1607, 1461,
1376, 1308 (SO2), 1246, 1178, 1120 (SO2), 1028, 740; dH (400.1 MHz;
CDCl3; Me4Si) 1.03 (3H, s, 10-CH3), 1.18 (3H, s, 10-CH3), 1.46e1.52
(1H, m), 1.59 (1H, d, 2J 14.5, 6-CH2 endo), 1.64e1.72 (1H, m),
1.82e1.88 (1H, m), 1.91 (1H, t, 3J 4.5, 7-CH), 2.36 (1H, m), 2.66 (1H,
dt, J 14.5 and 3.5, 6-CH2 exo), 2.81 (1H, br s, OH), 3.16 (1H, d, 2J 14.0,
2-CH2), 3.21 (1H, d, 2J 14.0, 2-CH2), 3.83 (1H, d, 3J 10.5, 4-CH), 4.02

7526
F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
4.2.1. (1S,7R)-10,10-Dimethyl-4-phenyl-3-thiatricyclo[5.2.1.01,5]-dec-
(3H, s, 7-CH3), 1.02 (3H, s, 7-CH3), 1.12e1.17 (1H, m), 1.57e1.62 (1H,
m), 1.65e1.84 (5H, m), 2.76 (1H, d, 2J 13.0, alkyl CH2SO2), 3.31 (1H, d,
2J 13.0, alkyl CH2SO2), 4.15 (1H, dd, J 8.0 and 4.5, 2-CH), 4.28 (1H, d,
2J 14.5, benzyl CH2SO2), 4.31 (1H, d, 2J 14.5, benzyl CH2SO2), 7.44
(5H, s, AreH); dC (100.6 MHz; CDCl3; Me4Si) 19.3 (7-CH3), 20.0 (7-
CH3), 26.9 (C-5), 29.9 (C-6), 38.5 (C-3), 43.6 (C-4), 48.6 (C-7), 49.7
(alkyl CH2SO2), 50.0 (C-1), 61.3 (benzyl CH2SO2), 75.7 (C-2), 127.3
(Ar C-1), 128.6 (Ar C-3), 128.7 (Ar C-4), 130.1 (Ar C-2); m/z (CI)
331.1333 ([MþNa]þ); C17H24O3SNa requires 331.1343.
ꢁ
4-ene 3,3-dioxide (29). White solid (0.06 g, 21%). Mp 97e99
C
(from EtOAc/hexane); ½a D25
ꢃ
ꢀ69.2 (c 0.53 in MeOH); vmax (N)/cmꢀ1
2919, 1720, 1649 (C]C), 1598, 1459, 1410, 1376, 1293 (SO2), 1209,
1153, 1120 (SO2), 756, 686; dH (400.1 MHz; CDCl3; Me4Si) 0.91 (3H,
s, 10-CH3), 1.09 (3H, s, 10-CH3), 1.38e1.44 (1H, m), 1.89e1.95 (1H,
m),1.98e2.13 (2H, m), 2.16 (1H, t, 3J 4.5, 7-CH), 2.40 (1H, d, 2J 18.0, 6-
CH2 endo), 2.85 (1H, dt, J 18.0 and 3.5, 6-CH2 exo), 3.23 (1H, d, 2J 13.0,
2-CH2), 3.28 (1H, d, 2J 13.0, 2-CH2), 7.33e7.38 (1H, m, AreH),
7.41e7.44 (2H, m, AreH), 7.66e7.68 (2H, m, AreH); dC (100.6 MHz;
CDCl3; Me4Si) 18.5 (10-CH3), 18.6 (10-CH3), 26.7 (C-8), 30.9 (C-9),
34.4 (C-6), 44.9 (C-7), 47.7 (C-10), 53.1 (C-2), 54.4 (C-1), 126.7 (Ar C-
3), 127.6 (Ar C-1),128.2 (Ar C-4),128.4 (Ar C-2) 130.6 (C-4), 156.3 (C-
5); m/z (CI) 311.1079 ([MþNa]þ); C17H20O2SNa requires 311.1080.
4.3.2. (1S,2S,4R)-1-[(Benzylsulfonyl)methyl]-7,7-dimethylbicyclo-
[2.2.1]heptan-2-ol (33). White solid (0.1 g, 9%). Mp 88e90 ꢁC (from
EtOAc/hexane); ½a D26
ꢃ
þ19.6 (c 0.27 in MeOH); vmax (N)/cmꢀ1 3513,
3433 (OeH), 2925, 2855, 1456, 1375, 1296 (SO2), 1259, 1113 (SO2),
1066, 1020, 770, 696; dH (400.1 MHz; CDCl3; Me4Si) 0.86 (3H, s, 7-
CH3), 0.88 (3H, s, 7-CH3), 1.14 (1H, dd, J 13.3 and 3.0, 3-CH2 endo),
1.40e1.47 (1H, m), 1.50e1.58 (1H, m), 1.66 (1H, t, 3J 4.5, 4-CH),
1.78e1.87 (1H, m), 2.26e2.34 (1H, m), 2.50e2.56 (1H, m), 2.96 (1H,
d, 2J 14.0, alkyl CH2SO2), 2.99 (1H, d, 2J 14.0, alkyl CH2SO2), 4.29 (1H,
dt, J 10.0 and 2.5, 2-CH), 4.29 (1H, d, 2J 13.5, benzyl CH2SO2), 4.33 (1H,
d, 2J 13.5, benzyl CH2SO2), 7.43 (5H, s, AreH); dC (100.6 MHz; CDCl3;
Me4Si) 18.4 (7-CH3), 20.0 (7-CH3), 23.4 (C-5), 27.8 (C-6), 37.5 (C-3),
43.3 (C-4), 50.9 (C-7), 51.6 (C-1), 54.4 (alkyl CH2SO2), 60.8 (benzyl
CH2SO2), 74.5 (C-2), 128.0 (Ar C-1), 128.6 (Ar C-3), 128.8 (Ar C-4),
130.3 (Ar C-2); m/z (CI) 331.1328 ([MþNa]þ); C17H24O3SNa requires
331.1343.
4.2.2. (1S,7R)-10,10-Dimethyl-4-vinyl-3-thiatricyclo[5.2.1.01,5]dec-4-
ene 3,3-dioxide (30). White solid (0.10 g, 83%). Mp 137 ꢁC (de-
composition); ½a D26
ꢃ
ꢀ62.7 (c 0.29 in CHCl3); vmax (N)/cmꢀ1 2923,
1666 (C]C), 1457, 1375, 1288 (SO2), 1155, 1116 (SO2), 981, 923, 742;
dH (400.1 MHz; CDCl3; Me4Si) 0.83 (3H, s, 10-CH3), 1.04 (3H, s, 10-
CH3), 1.31e1.36 (1H, m), 1.78e1.83 (1H, m), 1.92e2.06 (2H, m),
2.11 (1H, t, 3J 4.5, 7-CH), 2.19 (1H, d, 2J 18.5, 6-CH2 endo), 2.63 (1H,
dd, J 18.5 and 4.5, 6-CH2 exo), 3.11 (1H, d, 2J 13.5, 2-CH2), 3.16 (1H, d,
2J 13.5, 2-CH2), 5.45 (1H, d, 3J 11.0, CH]CH2), 5.83 (1H, d, 3J 18.0,
CH]CH2), 6.25 (1H, dd, J 18.0 and 11.0, CH]CH2); dC (100.6 MHz;
CDCl3; Me4Si) 18.4 (10-CH3), 18.5 (10-CH3), 26.6 (C-8), 30.6 (C-9),
32.8 (C-6), 44.8 (C-7), 47.9 (C-10), 53.1 (C-2), 54.2 (C-1), 118.7 (CH]
CH2), 121.2 (CH]CH2), 129.5 (C-4), 157.3 (C-5); m/z (CI) 261.0936
([MþNa]þ); C13H18O2SNa requires 261.0924.
4.3.3. (1S,2R,4R)-1-[(Allylsulfonyl)methyl]-7,7-dimethylbicyclo-[2.2.1]
heptan-2-ol (34). White solid (0.33 g, 76%). Mp 49e50 ꢁC (from
EtOAc/hexane); ½a D26
ꢃ
ꢀ26.4 (c 0.25 in MeOH); vmax (N)/cmꢀ1 3424
4.2.3. (1S,4R)-1-({[(10E)-Prop-10-enyl]sulfonyl}methyl)-7,7-dimethyl-
(OeH), 2927, 1638 (C]C), 1456, 1374, 1312 (SO2), 1240, 1197, 1122
(SO2), 1075, 1027, 996, 943, 879, 829, 721; dH (400.1 MHz; CDCl3;
Me4Si) 0.84 (3H, s, 7-CH3), 1.08 (3H, s, 7-CH3), 1.14e1.19 (1H, m),
1.59e1.66 (1H, m), 1.70e1.88 (5H, m), 2.86 (1H, d, 2J 13.0, alkyl
CH2SO2), 3.38 (1H, d, 2J 13.0, alkyl CH2SO2), 3.78 (2H, d, 3J 7.5, allyl
CH2SO2), 4.17 (1H, dd, J 8.0 and 4.0, 2-CH), 5.51 (1H, dd, J 17.3 and
1.0, CH]CH2 trans), 5.55 (1H, dd, J 10.0 and 1.0, CH]CH2 cis), 5.99
(1H, ddt, J 17.3, 10.0 and 7.5, CH]CH2); dC (100.6 MHz; CDCl3;
Me4Si) 19.8 (7-CH3), 20.5 (7-CH3), 27.4 (C-5), 30.4 (C-6), 38.9 (C-
3), 44.0 (C-4), 49.1 (C-7), 50.0 (alkyl CH2SO2), 50.3 (C-1), 60.0
(allyl CH2SO2), 76.1 (C-2), 124.9 (CH]CH2), 125.0 (CH]CH2); m/z
(CI) 281.1188 ([MþNa]þ); C13H22O3SNa requires 281.1186.
bicyclo[2.2.1]heptan-2-one (31). Colourless oil (0.02 g, 15%). ½a D25
ꢃ
þ34.5 (c 0.9 in MeOH); vmax (L)/cmꢀ1 2960, 1744 (C]O), 1641 (C]
C), 1440, 1393, 1315 (SO2), 1216, 1131 (SO2), 1051, 956, 828, 806, 678;
dH (400.1 MHz; CDCl3; Me4Si) 0.87 (3H, s, 7-CH3),1.09 (3H, s, 7-CH3),
1.42e1.49 (1H, m), 1.68e1.75 (1H, m), 1.93 (1H, d, 2J 18.5, 3-CH2
endo), 1.96 (3H, dd, J 7.0 and 1.5, 30-CH3), 2.01e2.10 (1H, m), 2.13
(1H, t, 3J 4.5, 4-CH), 2.38 (1H, dt, J 18.5 and 4.0, 3-CH2 exo),
2.46e2.53 (1H, m), 2.84 (1H, d, 2J 15.0, CH2SO2), 3.43 (1H, d, 2J 15.0,
CH2SO2) 6.55 (1H, dq, J 15.0 and 1.5, 10-CH), 6.89 (1H, dq, J 15.0 and
7.0, 20-CH); dC (100.6 MHz; CDCl3; Me4Si) 16.8 (C-30), 19.2 (7-CH3),
19.3 (7-CH3), 24.2 (C-5), 26.6 (C-6), 42.0 (C-4), 42.1 (C-3), 47.9 (C-7),
51.4 (CH2SO2), 58.2 (C-1), 131.3 (C-10), 142.5 (C-20), 214.5 (C-2); m/z
(CI) 279.1021 ([MþNa]þ); C13H20O3SNa requires 279.1030.
4.3.4. (1S,2S,4R)-1-[(Allylsulfonyl)methyl]-7,7-dimethylbicyclo-[2.2.1]
heptan-2-ol (35). Colourless oil (0.02 g, 4%). ½a D26
þ22.5 (c 0.16 in
ꢃ
4.3. Reduction of sulfones (6) and (7) with sodium
borohydride: general procedure
MeOH); vmax (L)/cmꢀ1 3483 (OeH), 2953, 1639 (C]C), 1452, 1391,
1310 (SO2), 1262, 1126 (SO2), 1069, 1020, 938, 874, 792; dH
(400.1 MHz; CDCl3; Me4Si) 0.91 (3H, s, 7-CH3), 0.93 (3H, s, 7-CH3),
1.14 (1H, dd, J 13.0 and 3.0, 3-CH2 endo), 1.41e1.47 (1H, m), 1.50e1.58
(1H, m), 1.68 (1H, t, 3J 4.5, 4-CH), 1.79e1.88 (1H, m), 2.29e2.36 (1H,
m), 2.48e2.54 (1H, m), 3.01 (1H, d, 2J 13.5, alkyl CH2SO2), 3.08 (1H, d,
2J 13.5, alkyl CH2SO2), 3.80 (2H, d, 3J 7.5, allyl CH2SO2), 4.34 (1H, dt, J
9.8 and 2.5, 2-CH), 5.50 (1H, dd, J 17.0 and 1.0, CH]CH2 trans), 5.55
(1H, dd, J 10.0 and 1.0, CH]CH2 cis), 5.97 (1H, ddt, J 17.0, 10.0 and 7.5,
CH]CH2); dC (100.6 MHz; CDCl3; Me4Si) 18.4 (7-CH3), 20.0 (7-CH3),
23.3 (C-5), 27.8 (C-6), 37.5 (C-3), 43.3 (C-4), 50.8 (C-7), 51.6 (C-1),
54.2 (alkyl CH2SO2), 59.1 (allyl CH2SO2), 74.5 (C-2), 124.4 (CH]CH2),
124.6 (CH]CH2); m/z (CI) 281.1183 ([MþNa]þ); C13H22O3SNa re-
quires 281.1186.
Sulfone 6 or 7 (1.00 g, 3.26 mmol) was dissolved in methanol
(25 mL) and sodium borohydride (0.49 g, 13.0 mmol) was added.
The solution was stirred at room temperature for 6 h. The solution
was then diluted with satd aq ammonium chloride (50 mL) and
extracted with diethyl ether (3ꢂ50 mL). The combined organic
extracts were washed with brine (50 mL), dried and evaporated to
yield a solid product (0.86 g) whose 1H NMR spectrum showed it to
consist of two diastereomers in approx.15.7:1 (32/33) or 16.5:1 (34/
35) ratio. The crude product was purified by chromatography on
silica gel, eluting with ethyl acetate/hexane (1:3) to yield two
products. The first product to elute was exo-sulfone 32 or 34. The
second product to elute was endo-sulfone 33 or 35.
4.4. Aldol reaction of sulfone (32) with benzaldehyde
4.3.1. (1S,2R,4R)-1-[(Benzylsulfonyl)methyl]-7,7-dimethylbicyclo-
[2.2.1]heptan-2-ol (32). White solid (0.72 g, 71%). Mp 107e108 ꢁC
n-Butyllithium (0.6 mL, 2.5 M, 1.49 mmol) was added to a solu-
tion of dry diisopropylamine (0.23 mL, 1.64 mmol) in dry tetrahy-
drofuran (6 mL) at ꢀ60 ꢁC under an atmosphere of nitrogen. The
solution was allowed to warm to 0 ꢁC and then recooled to ꢀ60 ꢁC.
(from EtOAc/hexane); ½a D26
ꢃ
ꢀ38.4 (c 0.44 in MeOH); vmax (N)/cmꢀ1
3494 (OeH), 2919, 1456, 1376, 1299 (SO2), 1267, 1208, 1143, 1106
(SO2), 1029, 982, 884, 792, 698; dH (400.1 MHz; CDCl3; Me4Si) 0.78

F.W. Lewis et al. / Tetrahedron 67 (2011) 7517e7528
7527
A solution of sulfone 32 (0.22 g, 0.71 mmol) in dry tetrahydrofuran
(8 mL) was added dropwise via syringe. After 20 min, freshly dis-
tilled benzaldehyde (0.08 mL, 0.78 mmol) was added and the so-
lution was stirred at ꢀ60 ꢁC for 3 h. The solution was then allowed
to warm to room temperature, quenched with satd aq ammonium
chloride (50 mL) and extracted with diethyl ether (3ꢂ50 mL). The
combined organic extracts were washed with brine (50 mL), dried
and evaporated to yield an oil. The crude product was purified by
chromatography on silica gel, eluting with ethyl acetate/hexane
(1:3) to yield three diastereomers. The first diastereomer to elute
was sulfone 36A. The second diastereomer to elute was sulfone
36B. The third diastereomer to elute was sulfone 36C. Sulfones 36A
and 36B were contaminated with minor traces of unreacted start-
ing sulfone 32.
for obtaining mass spectra. One of us (F.W.L.) received financial
support from Trinity College Dublin.
Supplementary data
Procedures and characterization data for known compounds.
Details of X-ray crystallographic structure determination. Mol files
of new compounds. Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 822431e822435. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk). Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2011.07.081. These data include MOL files and InChiKeys of the
most important compounds described in this article.
4.4.1. (1S,2R,4R,10S,20R)-1-{[(10,20-Diphenyl-20-hydroxyethyl)-sulfo-
nyl]methyl}-7,7-dimethylbicyclo[2.2.1]heptan-2-ol (36A). Colourless
oil (0.08 g, 27%). vmax (N)/cmꢀ1 3485 (OeH), 3432 (OeH), 2924,
1602, 1455, 1375, 1309 (SO2), 1248, 1126 (SO2), 1056, 1025, 877, 805,
697; dH (400.1 MHz; CDCl3; Me4Si) 0.62 (3H, s, 7-CH3), 0.90 (3H, s,
7-CH3), 1.54e1.80 (7H, m), 2.62 (1H, d, 2J 13.0, CH2SO2), 3.03 (1H, d,
2J 13.0, CH2SO2), 4.14 (1H, dd, J 7.8 and 4.5, 2-CH), 4.23 (1H, d, 3J 3.5,
References and notes
1. For recent reviews on chiral auxiliaries, see: (a) Roos, G. Compendium of Chiral
Auxiliary Applications; Academic: New York, NY, 2002; (b) Adam, W.; Zhang, A.
Synlett 2005, 1047; (c) Gnas, Y.; Glorius, F. Synthesis 2006, 1899; (d) Pellissier, H.
3
10-CH), 5.96 (1H, d, J 3.5, 20-CH), 7.17e7.28 (5H, m, AreH),
€
Tetrahedron 2006, 62, 1619; (e) Evans, D. A.; Helmchen, G.; Ruping, M. In
7.33e7.46 (5H, m, AreH); dC (100.6 MHz; CDCl3; Me4Si) 19.2 (7-
CH3), 19.9 (7-CH3), 26.9 (C-5), 29.9 (C-6), 38.5 (C-3), 43.5 (C-4), 48.6
(C-7), 50.1 (C-1), 50.3 (CH2SO2), 70.6 (C-10), 75.7 (C-2), 75.8 (C-20),
125.8 (Ar C-3),127.6 (Ar C-4),127.9 (Ar C-3),128.1 (Ar C-2),128.7 (Ar
C-1), 128.8 (Ar C-4), 130.2 (Ar C-2), 139.2 (Ar C-1); m/z (CI) 437.1770
([MþNa]þ); C24H30O4SNa requires 437.1761.
€
Asymmetric Synthesis: The Essentials, 2nd ed.; Christmann, M., Brase, S., Eds.;
Wiley-VCH: Weinheim, 2008; pp 3e9; (f) Meggers, E. Chem.dEur. J. 2010, 16,
752.
2. (a) Oppolzer, W. Tetrahedron 1987, 43, 1969; (b) Polywka, M. E. C. Chim. Oggi
1992, 10, 33; (c) Liu, W. In Handbook of Chiral Chemicals, 2nd ed.; Ager, D., Ed.;
CRC LLC: Boca Raton, 2006; pp 59e74; (d) Langlois, Y.; Kouklovsky, C. Synlett
2009, 3065.
3. (a) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241; (b) Kim, B. H.; Curran, D. P.
Tetrahedron 1993, 49, 293.
4.4.2. (1S,2R,4R,10R,20R)-1-{[(10,20-Diphenyl-20-hydroxyethyl)-sulfo-
nyl]methyl}-7,7-dimethylbicyclo[2.2.1]heptan-2-ol (36B). Colourless
oil (0.10 g, 33%). vmax (L)/cmꢀ1 3482 (OeH), 3063, 3031, 2954, 1953,
1890, 1804, 1719, 1602, 1493, 1455, 1390, 1292 (SO2), 1117 (SO2),
1056, 1026, 912, 879, 790, 731, 698; dH (400.1 MHz; CDCl3; Me4Si)
0.82 (3H, s, 7-CH3), 1.00 (3H, s, 7-CH3), 1.08e1.19 (1H, m), 1.57e1.83
(6H, m), 3.35 (1H, d, 2J 14.0, CH2SO2), 3.39 (1H, d, 2J 14.0, CH2SO2),
4.14 (1H, dd, J 7.8 and 4.5, 2-CH), 4.44 (1H, d, 3J 9.5, 10-CH), 5.57 (1H,
4. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397.
5. Nishide, K.; Ozeki, M.; Kunishige, H.; Shigeta, Y.; Patra, P. K.; Hagimoto, Y.; Node,
M. Angew. Chem., Int. Ed. 2003, 42, 4515.
6. (a) Chelucci, G. Chem. Soc. Rev. 2006, 35, 1230; (b) Pellissier, H. Tetrahedron
2007, 63, 1297.
7. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 5551;
(b) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605.
8. Kloetzing, R. J.; Thaler, T.; Knochel, P. Org. Lett. 2006, 8, 1125.
9. (a) Aggarwal, V. K.; Hynd, G.; Picoul, W.; Vasse, J.-L. J. Am. Chem. Soc. 2002, 124,
9964; (b) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.;
Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.; Vasse, J.-L.; Winn, C. L. J. Am. Chem.
Soc. 2006, 128, 2105.
3
d, J 9.5, 20-CH), 7.16 (5H, s, AreH), 7.22 (5H, s, AreH); dC
(100.6 MHz; CDCl3; Me4Si) 19.3 (7-CH3), 20.1 (7-CH3), 27.0 (C-5),
29.8 (C-6), 38.5 (C-3), 43.6 (C-4), 48.8 (C-7), 50.6 (C-1), 53.3
(CH2SO2), 74.2 (C-10), 75.8 (C-2), 76.1 (C-20) 126.5 (Ar C-3), 127.8 (Ar
C-4), 127.8 (Ar C-3), 128.3 (Ar C-2), 128.7 (Ar C-4), 129.4 (Ar C-2),
130.0 (Ar C-1), 139.5 (Ar C-1); m/z (CI) 437.1770 ([MþNa]þ);
C24H30O4SNa requires 437.1761.
10. Huang, K.; Huang, Z.-Z. Synlett 2005, 1621.
11. For leading reviews, see: (a) Magnus, P. D. Tetrahedron 1977, 33, 2019; (b) Trost,
B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107; (c) Simpkins, N. S. Sulphones in Organic
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ꢀ
12. (a) Chiral Sulfur Reagents; Miko1ajczk, M., Drabowicz, J., Kie1basinski, P., Eds.;
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agorda, M.; Urbano, A. Chem. Commun. 2009, 6129.
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4.4.3. (1S,2R,4R,10S,20S)-1-{[(10,20-Diphenyl-20-hydroxyethyl)-sulfonyl]
methyl}-7,7-dimethylbicyclo[2.2.1]heptan-2-ol (36C). White solid
~
1695; (b) Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paixao, M. W.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2010, 49, 2668; (c) Alba, A.-N. R.; Companyo, X.; Rios, R.
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(0.08 g, 27%). Mp 168 ꢁC (from EtOAc/hexane); ½a 2D2
ꢀ10.4 (c 0.25 in
ꢃ
CHCl3); vmax (N)/cmꢀ1 3473 (OeH), 3345 (OeH), 2924, 1954, 1887,
1803, 1601, 1455, 1375, 1299 (SO2), 1249, 1119 (SO2), 1047, 942, 880,
826, 762, 698; dH (400.1 MHz; CDCl3; Me4Si) 0.77 (3H, s, 7-CH3), 1.06
(3H, s, 7-CH3), 1.10e1.16 (1H, m), 1.56e1.61 (1H, m), 1.69e1.78 (5H,
m), 2.93 (1H, d, 2J 13.5, CH2SO2), 3.92 (1H, d, 2J 13.5, CH2SO2), 4.21
(1H, dd, J 7.8 and 4.5, 2-CH), 4.44 (1H, d, 3J 9.5, 10-CH), 5.58 (1H, d, 3J
9.5, 20-CH), 7.17 (5H, s, AreH), 7.23 (5H, s, AreH); dC (100.6 MHz;
CDCl3; Me4Si) 19.4 (7-CH3), 20.0 (7-CH3), 27.0 (C-5), 30.0 (C-6), 38.3
(C-3), 43.7 (C-4), 48.7 (C-7), 50.6 (C-1), 53.8 (CH2SO2), 74.4 (C-10),
76.0 (C-2), 76.0 (C-20), 126.5 (Ar C-3), 127.7 (Ar C-4), 127.8 (Ar C-3),
128.2 (Ar C-2), 128.4 (Ar C-4), 129.4 (Ar C-2), 129.9 (Ar C-1), 139.6 (Ar
C-1); m/z (CI) 437.1757 ([MþNa]þ); C24H30O4SNa requires 437.1761.
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The authors gratefully acknowledge Dr. John E. O’Brien and Dr.
Manuel Reuther for obtaining NMR spectra and Dr. Martin Feeney

7528
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~
ꢀ
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