Synthesis of the Northern hemisphere of the briaranes

Article abstract of DOI:10.1016/j.tet.2010.04.003

A highly functionalized fragment corresponding to the Northern hemisphere of the briaranes has been synthesized employing a sulfonyl diene Diels-Alder reaction, oxidative desulfonylation, Eschenmoser rearrangement and Keck radical allylation.

Full text of DOI:10.1016/j.tet.2010.04.003

Tetrahedron 66 (2010) 6340–6348
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Synthesis of the Northern hemisphere of the briaranes
*
Roderick W. Bates , Attapol Pinsa, Ximin Kan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, 21 Nanyang Link, Nanyang Technological University, Singapore 637371
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly functionalized fragment corresponding to the Northern hemisphere of the briaranes has been
synthesized employing a sulfonyl diene Diels–Alder reaction, oxidative desulfonylation, Eschenmoser
rearrangement and Keck radical allylation.
Received 22 January 2010
Received in revised form 15 March 2010
Accepted 1 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 8 April 2010
Keywords:
Diels–Alder
Sulfone
Oxidation
Allylation
Cyclolactonisation
1. Introduction
Various members of the family, as well as analogues,3 have been
screened for biological activity, and a range of properties has been
A review published in 1999 reported 299 natural products in the
briarane family, isolated from marine organisms from a variety of
locations around the world including the coast of Taiwan, the
Caribbean Sea and the Ligurian Sea.1 Since then, numerous addi-
tions to the family have been made, bringing the total to well over
300.2 The briarane skeleton is characterized by a six-membered
ring fused to a ten-membered ring and often with a butenolide or
derivative attached to the latter, as in brianthein W (Fig. 1). The
basic skeleton always includes unsaturation and bears various
methyl groups, especially one at the C1 quaternary centre, hydroxy
groups and, sometimes ether linkages including epoxides, and
halogen atoms.
reported. Despite this combination of structural challenge and bi-
ological activity, there has been little synthetic work reported for
this family of compounds.4 We wish to report an approach to what
might be termed the briarane Northern hemisphere, in racemic
form: C1 to C6 and the cyclohexane moiety.
2. Results and discussion
A challenge anticipated early was the quaternary centre at C1.
We planned to employ a sigmatropic rearrangement to install this
quaternary centre, starting from an allylic alcohol. This led us to
a crotonate Diels–Alder reaction as the method for formation of
the six-membered ring. Crotonate derivatives are often reluctant
dienophiles and, therefore, we sought a robust functionalized diene
that would permit conversion to the desired allylic alcohol after the
cycloaddition. Ba¨ckvall has reported the use of sulfonyl dienes even
in reactions with electron poor dienophiles.5 As various methods
are available for subsequent desulfonylation,6 this route was se-
lected. The required sulfonyl diene 3 was synthesized from crotyl
chloride (E/Z mixture) (Scheme 1). This was converted to a crotyl
sulfone 1 by reaction with toluene sulfinic acid sodium salt under
van Leusen’s phase transfer conditions.7 Deprotonation with n-
butyl lithium and quenching with paraformaldehyde gave the
alcohol 2, which was dehydrated in one pot by treatment with
mesyl chloride and excess triethylamine to give the sulfonyl diene 3
as a single geometrical isomer. Diene 3 is unstable, undergoing
a Diels–Alder dimerisation if stored in its pure form, as has also
OAc
AcO
15
1
14
11
20
2
16
13
12
5
6
H
O
O
17
18
O
O
Figure 1. The briarane skeleton and brianthein W.
* Corresponding author. Tel.: þ65 6316 8907; fax: þ65 6791 1961; e-mail
address: roderick@ntu.edu.sg (R.W. Bates).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.003

R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
6341
been observed for related esters and nitriles.8 Thus, sulfonyl diene 3
CO2Me
AlCl3, CH2Cl2
62% (2 steps)
p-TolSOn
was handled as a solution in dichloromethane and stored at ꢀ80 ꢁC.
p-TolSOn
p-TolSO2
n-BuLi, (CH2O)n
CO2Me
X
3 n = 2
5 n = 1
9
n = 2
10 n = 1
HO
2
X = Cl
p-TolSO2Na,
n-Bu4NBr
p-TolSO2
1 X = SO2p-Tol
p-TolSO2
11 R = H
12 R = TBS
TBSCl, Et3N,
DMAP
DIBAL
96%
p-TolSO2
92%
OR
MsCl, Et3N
Scheme 3. Sulfonyl and sulfinyl diene Diels–Alder reactions.
3
4
SO2p-Tol
Scheme 1. Sulfonyl diene synthesis and dimerisation.
The dimer 4 proved to be crystalline, and the structure was
confirmed by X-ray crystallography (Fig. 2).9
Figure 3. alcohol 11.
Oxidative desulfonylation of the vinyl sulfone 12 proved to be
troublesome (Scheme 4). Attempts at either electrophilic epoxi-
dation (mcpba) or nucleophilic (Weitz–Scheffer) epoxidation13
(t-BuOOLi or H2O2, NaOH) failed, as did attempts to oxidize the
double bond using osmium tetroxide under either Upjohn14 or
Figure 2. diene dimer 4.
The corresponding sulfoxide 5 was also prepared, but by
a modification of the method of Maignan (Scheme 2).10 The 2-
ethoxyethylsulfoxide 6 (prepared from the readily available vinyl
sulfoxide11) was deprotonated with LDA and the resulting anion
was quenched with propionaldehyde. Dehydration of the resulting
alcohol 7 to give the diene was effected in two steps: formation of
mesylate 8 and elimination with DBU. In contrast to sulfone 3,
sulfoxide 5 did not dimerise during isolation or storage.
Tsuji15 conditions. Attempts at
g-deprotonation with either LDA or
n-BuLi were, likewise, fruitless. During epoxidation studies, it was
noticed that prolonged treatment of alcohol 11 with sodium hy-
droxide in hot methanol resulted in isomerisation of the double
bond, cleanly giving the b,g-unsaturated sulfone 13 as a mixture of
diastereoisomers. The identity of the major isomer could not be
determined due to overlapping 1H NMR signals. After silylation of
the free alcohol, oxidative desulfonylation16 could be achieved by
treatment with an excess of LDA and MoOPD (MoO5$Py$DMPU)17
to give cyclohexenone 15. To obtain an optimum yield of cyclo-
hexenone 15, it was necessary to limit the reaction time. An
extended reaction time resulted in significant over-oxidation,
O
S
O
S
OR
1. LDA, THF, -78°C
2. CH3CH2CHO
p-Tol
p-Tol
OEt
6
7 R = H
MsCl, Et3N
O
8 R = Ms
DBU, CH2Cl2, Δ
S
p-Tol
yielding some of the
isomer.18 The observation of a 12.3 Hz coupling constant between
the and -protons indicated that the new hydroxyl group was
a-hydroxylated enone 16 as a single stereo-
5
a
b
Scheme 2. Sulfinyl diene synthesis.
equatorial, corresponding to approach of the MoOPD reagent to the
face opposite the methyl group.
While sulfonyl diene 3 undergoes cycloaddition with methyl
acrylate quite rapidly giving the expected cycloadduct in 4 h using
aluminium trichloride as a Lewis acid catalyst,12 the reaction with
methyl crotonate is sluggish, requiring 7 days in dichloromethane
at reflux. Despite the harsh reaction conditions, the Diels–Alder
adduct 9 was isolated in 62% yield over two steps, as a single
(racemic) stereoisomer, accompanied by a small amount (5% yield)
of dimer 4 (Scheme 3). The Diels–Alder reaction of the corre-
sponding sulfoxide 5, proved to be even slower and resulted in the
formation of an inseparable mixture of stereoisomers due to the
chiral centre at sulfur. The approach using the sulfoxide was not,
therefore, pursued further. Reduction of the ester group of sulfone 9
with DIBAL yielded the primary alcohol 11. Crystals of this alcohol
suitable for X-ray analysis were obtained, allowing confirmation of
the structure (Fig. 3). The stereochemistry was, as anticipated, in
accordance with the Alder cis-endo rule. The free alcohol was then
protected as its TBS ether 12.
p-TolSO2
p-TolSO2
NaOH, MeOH
95%
11
OR
OH
13 R = H
TBSCl, Et3N
14 R = TBS
92%
O
O
LDA, MoOPD
84%
+
HO
16
15
OTBS
OTBS
Scheme 4. Oxidative desulfonylation.
Cyclohexenone 15 was reduced with sodium borohydride to
give the equatorial alcohol 17 (15:1 ratio of diastereoisomers)

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R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
NMe2
O
O
HO
NaBH4, CeCl3.7H2O
MeOH
CH3C(NMe2)(OMe)2
CONMe2
I2, aq. THF
93%
Δ
I
49%
96% (15:1)
15
17
18
20
OTBS
OTBS
OTBS
OTBS
O
O
O
O
I
O
O
O
O
O
OR
IBX,
LiHMDS,
MoOPD
87%
I
CONMe2
DMSO
DBU
94%
84%
OTBS
19
21
22
25
OTBS
+
OTBS
OTBS
OTBS
23 R = H
24 R = TMS
HO
OH
O
OTs
OH
O
TsCl, DMAP,
Et3N
HO
OH
O
NaBH4,
MeOH
98%
OH
28
29
OH
LiAlH4
77%
OTBS
NaI, NaHCO3,
Na2SO3, acetone
OTBS
50% + 21%
PPh3, I2,
C3H4N2
26
27
OTBS
OTBS
HO
OH
HO
OH
67%
Snn-Bu3
ACN, C6H6, Δ
58%
I
30
31
OTBS
OTBS
Scheme 5. Completion of the synthesis of the Northern hemisphere fragment.
(Scheme 5). Addition of cerium trichloride19 was unnecessary in
obtaining exclusive 1,2-addition, but a slight improvement in the
stereoselectivity was found when this additive was employed.
Several methods were tried for introducing the briarane C1
quaternary centre by a [3,3]-sigmatropic rearrangement.20 Use of
Johnson’s modification of the Claisen rearrangement21 (triethyl
orthoacetate and propionic acid at reflux) gave none of the de-
sired product, neither did conversion of the alcohol to its acetate
ester, followed by attempted Ireland–Claisen rearrangement.
Treatment of 17 with ethyl vinyl ether and mercuric acetate,22
followed by heating did give some of the rearranged aldehyde
by 1H NMR, but this material could not be isolated. Attempts to
obtain the same aldehyde by the method of Mandai,23 involving
oxa-Michael addition of 17 to an aryl vinyl sulfoxide, were simi-
larly unsuccessful.24 Finally, employing Eschenmoser’s variation
of the Claisen rearrangement,25 heating with dimethylacetamide
dimethyl acetal in xylene at reflux, gave the desired rearranged
amide 18 in modest but useable yield (Scheme 5).26 This reaction
was most effectively carried out in a microwave. The difficulty in
achieving this transformation can be attributed to the equatorial
disposition of the alcohol. While amides are less susceptible to
nucleophilic attack than other carboxyl derivatives, they are more
susceptible to electrophilic attack. Amide 18 was, therefore,
subjected to cycloiodination27 to give iodolactone 19 as a single
isomer. Curiously, if the reaction was quenched and worked up as
soon as TLC indicated disappearance of the starting material, then
a low yield of iodolactone 19 was obtained, accompanied by
unreacted starting material 18. On prolonged reaction, however,
an almost quantitative yield of iodolactone 19 could be obtained.
We attribute this to fast iodocyclisation, but slow hydrolysis of
intermediate 20, with the iodocyclisation reversing under the
work up conditions. A minor by-product of the cycloiodination
was assigned structure 21. This by-product was obtained as a
single diastereoisomer, although it was not possible to determine
which one.28 Elimination of the iodine from lactone 19 was
achieved by heating with DBU in THF. An X-ray structure of the
elimination product 22 was obtained (Fig. 4). This compound
represents a highly functionalized intermediate for the briarane
ready for further manipulation to introduce different cyclohexane
substitution patterns.
Figure 4. lactone 22.
Nevertheless, introduction of the remaining portion of the
Northern hemisphere required further elaboration of lactone 22. At
this point, we opted to introduce the briarane C2 hydroxyl group.
Attempts to do this using LDA and MoOPD led to recovery of
starting material. Reasoning that the bulk of LDA was preventing
removal of the crowded proton
to other bases. The use of an excess of LiHMDS, followed by MoOPD
gave an excellent yield of the -hydroxylated lactone 23 as a single
stereoisomer. Interestingly, use of KHMDS gave only a modest yield
a to the lactone carbonyl, we turned
a

R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
6343
of the desired
a
-hydroxylated lactone 23, accompanied by a small
and Z isomers); mp 32–34 ꢁC; Rf¼0.26 (25% ethyl acetate/hexane);
nmax/cmꢀ1 1666, 1597, 1433, 1396, 1315, 1300, 1143, 1087, 968, 929,
815, 723, 624; dH (400 MHz; CDCl3) 7.86 (d, 2H, J¼8.1 Hz, Ar–H, cis
and trans), 7.29 (d, 2H, J¼8.1 Hz, Ar–H, cis and trans), 5.77 (dq, 1H,
J¼10.8, 7.0 Hz, CHCH3, cis), 5.52 (dq, 1H, J¼15.3, 6.4 Hz, CHCH3,
trans), 5.36 (dtq, 1H, J¼15.3, 7.3, 1.5 Hz, CH]CHCH3, cis and trans),
3.79 (d, 2H, J¼7.9 Hz, SO2CH2, cis), 3.67 (d, 2H, J¼7.3 Hz, SO2CH2,
trans), 2.39 (s, 3H, CH3, cis and trans),1.62 (app.d, 3H, J¼6.4 Hz, CH3,
trans), 1.31 (app.d, 3H, J¼7.0 Hz, CH3, cis); dC (100 MHz; CDCl3)
144.6, 136.3, 135.6, 129.6 (2C), 128.4 (2C), 117.1, 60.1, 21.6, 18.1; m/z,
211 (MþHþ, 100%), 210, 195; HRMS found 211.0785 (MþHþ,
C11H14O2S requires 211.0793).
amount of the TMS ether 24,29 presumably due to the hexame-
thyldisilylamine by-product acting as a silylating agent for the re-
active potassium alkoxide.
Inspection of molecular models, supported by NOE studies, in-
dicated that hydroxylation occurred on the convex face of the
enolate of 22, syn to the methyl group. This is opposite to the ste-
reochemistry required for the natural products. The hydroxyl group
was inverted by oxidation to the ketolactone 25 with an excess of
IBX,30 followed by sodium borohydride reduction, giving alcohol
26, diastereoisomeric with 23. This reduction was completely
stereoselective. Further reduction with lithium aluminium hydride
yielded triol 27. In order to introduce the remaining Northern
hemisphere carbon atoms, we attempted to convert the primary
alcohol group of triol 27 into a leaving group. Tosylation proceeded
in modest yield and was accompanied by in situ formation of the
tetrahydrofuran 29.31 Attempts at a Finkelstein reaction of tosylate
28 (sodium iodide, sodium bicarbonate and sodium sulfite) resul-
ted in the formation of additional amounts of this tetrahydrofuran
and none of the desired iodide. The desired iodide 30 could, how-
ever, be obtained directly from the triol 27 by treatment with iodine
and triphenylphosphine in the presence of imidazole,32 although
a small amount of the tetrahydrofuran 29 was also obtained. The
key difference between the two iodination methods appears to be
the reaction temperature. With iodide 30 in hand, the remainder of
the Northern hemisphere was installed by free radical Keck ally-
lation33 using methallyltri-n-butyltin in the presence of 1,10-azo-
bis(cyclohexanecarbonitrile) (ACN) as initiator, giving a highly
functionalised Northern hemisphere fragment 31. During the free
radical methallylation, no intramolecular attack on the cyclohexene
double bond was noted, presumably due to the equatorial dispo-
sition of the radical containing side-chain.
4.1.2. 2-(p-Tolylsulfonyl)pent-3-en-1-ol (2). n-BuLi (21.8 mL of
a 1.6 M solution in hexanes, 32.7 mmol) was added over 5 min to
a
suspension of sulfones 1 (4.91 g, 23.4 mmol) and para-
formaldehyde (1.40 g, 46.7 mmol) in THF (70 mL) at ꢀ78 ꢁC under
nitrogen. After stirring at this temperature for 1 h, the temperature
was allow to rise to ꢀ25 ꢁC over a period of 5 h. The reaction
mixture was quenched with saturated aq NH4Cl (30 mL) and
extracted with Et2O (50 mLꢂ3). The combined organic layers were
washed with water and brine and dried over anhydrous MgSO4.
After removal of solvent under reduced pressure, the residue was
purified by column chromatography (SiO2, 50% EtOAc in hexanes)
to give sulfonyl alcohols 2 (3.60 g, 14.98 mmol, 64%) as a colourless
oil (64:36 mixture of E and Z isomers); Rf¼0.25 (50% ethyl acetate/
hexane); nmax/cmꢀ1 3458, 3030, 2920, 1643, 1597, 1494, 1444, 1300,
1141, 966, 815, 709; dH (400 MHz; CDCl3) 7.73 (d, 2H, J¼8.2 Hz, Ar–
H, cis), 7.70 (d, 2H, J¼8.2 Hz, Ar–H, trans), 7.34 (d, 2H, J¼8.2 Hz, Ar–
H, cis and trans), 5.81 (dq, 1H, J¼10.8, 7.0 Hz, CHCH3, cis), 5.54 (dq,
1H, J¼15.3, 6.5 Hz, CHCH3, trans), 5.53–5.10 (m, 1H, CH]CHCH3, cis
and trans), 4.30–3.60 (m, 2H, CH2OH, cis and trans), 2.98 (dt, 1H,
J¼4.6, 3.1 Hz, SO2CH2, cis), 2.88 (dt,1H, J¼5.6, 2.1 Hz, SO2CH2, trans),
2.45 (s, 3H, CH3, cis and trans), 1.66 (dd, 3H, J¼6.5, 1.4 Hz, CH3,
trans), 1.31 (dd, 3H, J¼7.0, 1.7 Hz, CH3, trans); dC (100 MHz; CDCl3)
145.1, 136.1, 134.1, 129.7, 129.6, 129.1 (2C), 119.1, 70.4, 60.9, 21.7, 18.3;
m/z, 263 (MþNaþ, 100%) 258; HRMS found 263.0713 (MþNaþ,
C12H16O3S requires 263.0718).
3. Conclusion
We have completed a viable route to the Northern hemisphere
to give a highly functionalized intermediate. Studies on the in-
stallation of a butenolide, and closure of the ten-membered ring are
in progress.
4.1.3. 2-(p-Tolylsulfonyl)penta-1,3-diene (3). Triethylamine (4.0 mL,
28.6 mmol) and methanesulfonyl chloride (2.2 mL, 28.6 mmol)
were added dropwise and sequentially to a solution of alcohol 2
(3.43 g, 14.3 mmol) in dichloromethane (42 mL) at 0 ꢁC under
nitrogen. The reaction mixture was stirred at 0 ꢁC for 30 min, then
allowed to warm slowly to room temperature and stirred for an
additional for 4 h. The reaction mixture was diluted with H2O
(30 mL) and extracted with CH2Cl2 (100 mLꢂ2). The combined
organic layers were washed with water and brine and dried over
anhydrous MgSO4. The solution of diene 3 was stored at (–78 ꢁC) or
used directly in the next step without concentration or isolation;
Rf¼0.33 (25% ethyl acetate/hexane); dH (400 MHz; CDCl3) 7.72
(app.d, 2H, J¼7.9 Hz, Ar–H), 7.32 (app.d, 2H, J¼7.9 Hz, Ar–H), 6.17
(br s, 1H, C]CHH), 6.13 (dq, 1H, J¼15.8, 6.5 Hz, CH]CHCH3), 6.01
(app.d, 1H, J¼15.8 Hz, CH]CHCH3), 5.83 (br s, 1H, C]CHH),
2.42 (s, 3H, Ar–CH3), 1.74 (d, 3H, J¼6.5 Hz, CH3); dC (75 MHz;
CDCl3) 148.4, 144.4, 136.4, 133.5, 129.7 (3C), 128.0, 121.9, 121.3,
21.5, 18.5.
4. Experimental
4.1. General procedures
All reactions were carried out under a nitrogen atmosphere
using oven-dried glassware (120 ꢁC), which was cooled under
vacuum. All commercially obtained reagents were used as received.
Analytical TLC was carried out on precoated plates (silica gel 60,
F254). Column chromatography was performed with silica gel 60
(230–400 mesh). 1H NMR spectra were recorded in CDCl3 at 300 or
400 MHz; chemical shifts are expressed in parts per million relative
to an internal standard. Peaks are assigned by consideration of
chemical shift values and coupling patterns. Melting points are
uncorrected. Infrared spectra were recorded as Nujol mulls or neat.
4.1.1. 1-(p-Tolylsulfonyl)-but-2-ene (1). Crotyl chloride (7.86 mL,
80.1 mmol, E/Z mixture) was added to a suspension of sodium p-
toluenesulfinate (15.77 g, 88.2 mmol) and tetra-n-butyl ammo-
nium bromide (1.29 g, 4.0 mmol) in 1,2-dimethoxyethane (70 mL).
The mixture was heated at reflux for 30 min, then cooled to room
temperature, diluted with water (20 mL) and extracted with Et2O
(50 mLꢂ3). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 25% EtOAc in hexanes) to give sulfone 1
(14.41 g, 68.53 mmol, 86%) as a colourless solid (72:28 mixture of E
4.1.4. 2-(p-Tolylsulfinyl)pent-1-en-3-ol (7). A solution of 1-(2-
ethoxyethylsulfinyl)-4-methylbenzene 6 (2.76 g, 13 mmol) in THF
(25 mL) was added dropwise at ꢀ78 ꢁC to a solution of lithium
diisopropylamide (LDA) under nitrogen [prepared by reacting dii-
sopropylamine (5.85 mL, 32.5 mmol) in THF (32 mL) with n-BuLi
(17.9 mL of a 1.6 M solution in hexane, 28.6 mmol) at ꢀ78 ꢁC for
30 min]. After stirring at ꢀ78 ꢁC for 1 h, propionaldehyde (1.12 mL,
15.6 mmol) was added. The mixture was stirred at ꢀ78 ꢁC for 3 h,

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R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
and then quenched with saturated NH4Cl (30 mL). The mixture was
diluted with water (50 mL) and extracted with Et2O (30 mLꢂ3). The
combined organic layers were washed with water and brine and
dried over anhydrous MgSO4. After removal of solvent under re-
duced pressure, the residue was purified by column chromatogra-
phy (SiO2, 50% EtOAc in hexanes) to give sulfoxide 7 (0.81 g,
3.64 mmol, 28% yield) as a colourless oil; Rf¼0.17 (50% ethyl ace-
tate/hexane); nmax/cmꢀ1 3003, 2872, 1643, 1633, 1492, 1377, 1354,
1215, 1107, 1085, 1041, 806, 754; dH (500 MHz; CDCl3) 7.55 (d, 2H,
J¼8.1 Hz, Ar–H, minor), 7.52 (d, 2H, J¼8.1 Hz, Ar–H, major), 7.31 (d,
2H, J¼8.1 Hz, Ar–H, major), 7.27 (d, 2H, J¼8.1 Hz, Ar–H, minor), 6.07
(s, 1H, C]CHH, minor), 6.06 (s, 1H, C]CHH, major), 5.85 (s, 1H,
C]CHH, major), 5.84 (s, 1H, C]CHH, minor), 4.15–4.03 (m, 1H,
CHOH, major and minor), 2.41 (s, 3H, CH3, major), 2.40 (s, 3H, CH3,
minor), 1.75–1.46 (m, 2H, CH2CH3, major and minor), 0.86 (t, 3H,
J¼7.4 Hz, CH3, minor), 0.80 (t, 3H, J¼7.4 Hz, CH3, major); dC
(100 MHz; CDCl3) 156.9 (minor), 156.1 (major), 142.0 (major), 141.9
(minor), 139.7 (minor), 138.9 (major), 130.1 (2C) (major), 130.0 (2C)
(minor), 125.5 (2C) (minor), 125.2 (2C) (major), 117.5 (major), 117.3
(minor), 70.7 (minor), 69.7 (major), 29.4 (minor), 28.4 (major), 21.5
(major and minor), 9.7 (minor), 9.5 (major); m/z, 225 (MþHþ,
100%), 208, 207, 206, 189, 163, 157, 141, 139, 131; HRMS found
225.0945 (MþHþ, C12H17O2S requires 225.0949).
1303, 1178, 1082, 1051, 960, 912, 810; dH (300 MHz; CDCl3) 7.52
(d, 2H, J¼8.1 Hz, Ar–H), 7.25 (d, 2H, J¼8.1 Hz, Ar–H), 6.10–5.80
(m, 3H, C]CH2 and CH]CHCH3), 5.69 (s, 1H, CH]CHCH3), 2.36
(s, 3H, CH3), 1.68 (d, 3H, J¼5.5 Hz, CH3); dC (75 MHz; CDCl3) 151.1,
141.8, 140.2, 131.4, 129.9 (2C), 125.6, 123.5 (2C), 114.9, 21.4, 18.7; m/z,
207 (MþHþ, 100%), 189, 186, 183, 171, 165, 159, 157, 149, 143; HRMS
found 207.0840 (MþHþ, C12H15OS requires 207.0844).
4.1.7. (1R
*
,2R
*
*
,6S )-Methyl
2,6-dimethyl-4-tosylcyclohex-3-ene-
carboxylate (9). AlCl3 (9.53 g, 71.5 mmol), CH2Cl2 (70 mL) and
methyl crotonate (7.6 mL, 71.5 mmol) were stirred under nitrogen
until a homogeneous solution was formed. A solution of dienyl
sulfone 3 (14.3 mmol) in CH2Cl2 (125 mL) was added over 5 min.
The mixture was heated at reflux for 7 days, then cooled to 0 ꢁC,
quenched with sat NH4Cl (50 mL) and extracted with CH2Cl2
(50 mLꢂ3). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 25% EtOAc in hexanes) to give cyclohexenyl
sulfone 9 (2.86 g, 8.86 mmol, 62%) as a colourless solid and dimer 4
(0.33 g, 0.74 mmol, 5%) as a colourless solid. Cyclohexenyl sulfone
9: mp 95–96 ꢁC; Rf¼0.26 (25% ethyl acetate/hexane); nmax/cmꢀ1
2954, 2931, 1732, 1651, 1597, 1454, 1435, 1371, 1300, 1220, 1145,
1089, 1010, 906, 815, 665; dH (500 MHz; CDCl3) 7.70 (d, 2H,
J¼8.2 Hz, Ar–H), 7.31 (d, 2H, J¼8.2 Hz, Ar–H), 6.92 (app.d, 1H,
J¼3.9 Hz, SO2C]CH), 3.64 (s, 3H, OCH3), 2.85–2.74 (m, 1H,
C]CHCHCH3), 2.42 (s, 3H, CH3), 2.35 (app.t, 1H, J¼6.1 Hz,
CHCO2CH3), 2.33 (app.d, 1H, J¼5.6 Hz, SO2CCHH), 2.10–1.93 (m, 1H,
CH2CHCH3), 1.73 (dddd, 1H, J¼16.8, 9.6, 2.1, 2.1 Hz, SO2CCHH), 0.98
(d, 3H, J¼7.3 Hz, CH3), 0.96 (d, 3H, J¼6.5 Hz, CH3); dC (75 MHz;
CDCl3) 173.3, 144.3, 140.4, 138.3, 136.1, 129.8 (2C), 128.0 (2C), 51.4,
49.2, 31.9, 30.3, 25.5, 21.6, 19.6, 16.1; m/z, 345 (MþNaþ, 100%) 323,
281, 139. Anal. Calcd for C17H22O4S: C, 63.33; H, 6.88. Found: C,
63.12; H, 6.98.
4.1.5. 2-(p-Tolylsulfinyl)pent-1-en-3-yl methanesulfonate (8). A so-
lution of methanesulfonyl chloride (0.37 mL, 4.81 mmol) in CH2Cl2
(1 mL) was added to a solution of sulfoxide 7 (0.83 g, 3.70 mmol)
and triethylamine (0.67 mL, 4.81 mmol) in CH2Cl2 (18.5 mL) at 0 ꢁC
under nitrogen. The reaction mixture was allowed to warm slowly
to room temperature and stirred for 16 h. The mixture was diluted
with NH4Cl (10 mL) and water (10 mL), and extracted with Et2O
(3ꢂ25 mL). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 50% EtOAc in hexanes) to give mesylate 8
(1.11 g, 3.67 mmol, 99% yield) as a yellow oil; Rf¼0.37 (50% ethyl
acetate/hexane); nmax/cmꢀ1 3024, 2976, 2937, 1629, 1595, 1492,
1454, 1352, 1174, 1080, 1047, 914, 850, 812; dH (300 MHz; CDCl3)
7.55 (d, 2H, J¼8.1 Hz, Ar–H, minor), 7.51 (d, 2H, J¼8.1 Hz, Ar–H,
major), 7.32 (d, 2H, J¼8.1 Hz, Ar–H, major and minor), 6.32 (d, 1H,
J¼0.9 Hz, C]CHH, minor), 6.27 (d, 1H, J¼0.9 Hz, C]CHH, major),
6.03 (d, 1H, J¼0.9 Hz, C]CH2, major and minor), 5.02–4.85 (m, 1H,
CH–OMs, major and minor), 2.89 (s, 3H, CH3, major), 2.60 (s, 3H,
CH3, minor), 2.40 (s, 3H, CH3, major and minor), 1.92–1.68 (m, 1H,
CHHCH3, major), 1.63–1.31 (m, 3H, CHHCH3, minor and CHHCH3,
major and minor), 0.85 (t, 3H, J¼7.3 Hz, CH3, major), 0.85 (t, 3H,
J¼7.3 Hz, CH3, minor); dC (75 MHz; CDCl3) 152.6 (major), 152.4
(minor), 142.64 (major), 142.59 (minor), 138.7 (minor), 138.1
(major), 130.3 (2C) (major), 130.2 (2C) (minor), 125.6 (2C) (minor),
125.1 (2C) (major), 120.71 (major), 120.67 (minor), 78.8 (minor),
77.4 (major), 38.4 (major), 38.3 (minor), 29.4 (major), 29.0 (minor),
21.5 (major and minor), 9.4 (minor), 9.0 (major); m/z, 303 (MþHþ,
100%), 302, 300, 295, 291; HRMS found 303.0724 (MþHþ,
C13H19O4S2 requires 303.0725).
4.1.8. (1S
*
,2S
*
,6R )-Methyl 2,6-dimethyl-4-(p-tolylsulfinyl) cyclohex-
*
3-enecarboxylate (10). AlCl3 (2.21 g, 16.6 mmol), CH2Cl2 (32 mL)
and methyl crotonate (3.5 mL, 33.2 mmol) were mixed and stirred
under nitrogen until a homogeneous solution formed. A solution of
dienyl sulfoxide 5 (0.69 g, 3.3 mmol) in CH2Cl2 (6.6 mL) was added
and the mixture was heated at reflux for 10 days. The reaction was
cooled to 0 ꢁC, quenched with saturated aq NH4Cl (30 mL) and
extracted with CH2Cl2 (50 mLꢂ3). The combined organic layers
were washed with water and brine and dried over anhydrous
MgSO4. After removal of solvent under reduced pressure, the resi-
due was purified by column chromatography (SiO2, 50% EtOAc in
hexanes) to give cyclohexenyl sulfoxide 10 (0.57 g, 1.85 mmol, 56%)
as a colourless oil (3:1 mixture of two diastereoisomers); Rf¼0.38
(50% ethyl acetate/hexane); nmax/cmꢀ1 2956, 2927, 2874,1733,1453,
1433, 1216, 1158, 1082, 1044, 1014, 809, 620; dH (300 MHz; CDCl3)
7.27 (d, 2H, J¼8.0 Hz, Ar–H, major and minor), 7.10 (d, 2H, J¼8.0 Hz,
Ar–H, major and minor), 6.39 (app.s, 1H, SO2C]CH, major and
minor), 3.47 (s, 3H, OCH3, minor), 3.46 (s, 3H, OCH3, major), 2.72–
2.50 (m, 1H, C]CHCHCH3, major and minor), 2.25 (dd, 1H, J¼10.1,
5.8 Hz, CHCO2CH3, major and minor), 2.21 (s, 3H, CO2CH3, major
and minor), 1.93–1.66 (m, 2H, CH2CHCH3 and SO2CCHH, major and
minor), 1.42 (ddd, 1H, SO2CCHH, major and minor), 0.84 (d, 3H,
J¼6.6 Hz, CH3, minor), 0.82 (d, 3H, J¼6.7 Hz, CH3, major), 0.75
(d, 3H, J¼6.7 Hz, CH3, major), 0.74 (d, 3H, J¼6.6 Hz, CH3, minor);
dC (75 MHz; CDCl3) 173.54 (major), 173.48 (minor), 141.5 (major
and minor), 141.4 (major and minor), 139.2 (major and minor),
136.5 (minor), 135.4 (major), 129.9 (2C) (major), 129.8 (2C) (minor),
125.0 (2C) (major), 124.8 (2C) (minor), 51.3 (major and minor),
50.4 (minor), 50.0 (major), 32.5 (minor), 32.0 (major), 27.9 (major),
26.8 (minor), 25.8 (major), 25.4 (minor), 21.4 (major and minor),
19.7 (major), 19.6 (minor), 16.6 (major), 16.5 (minor); m/z, 307
4.1.6. (E)-1-Methyl-4-(penta-1,3-dien-2-ylsulfinyl)benzene (5). DBU
(1.94 mL, 13.0 mmol) was added slowly to a solution of mesylate 8
(1.96 g, 6.5 mmol) in CH2Cl2 (32.5 mL) under nitrogen. The mixture
was heated at reflux for 2 h, then diluted with saturated aq NH4Cl
(10 mL) and extracted with Et2O (3ꢂ25 mL). The combined organic
layers were washed with water and brine and dried over anhydrous
MgSO4. After removal of solvent under reduced pressure, the resi-
due was purified by column chromatography (SiO2, 50% EtOAc
in hexanes) to give dienyl sulfoxide 5 (0.86 g, 4.2 mmol, 64%) as
a yellow solid; mp 59–60 ꢁC; Rf¼0.54 (50% ethyl acetate/hexane);
nmax/cmꢀ1 3020, 2992, 2850, 1643, 1595, 1492, 1446, 1398, 1377,

R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
6345
(MþHþ, 100%), 306, 299, 295, 289, 284; HRMS found 307.1363
(MþHþ, C17H23O3S requires 307.1368).
reduced pressure, the residue was purified by column chromatog-
raphy (SiO2, 50% EtOAc in hexanes) to give cyclohexenyl sulfone 13
(2.28 g, 7.74 mmol, 95%) as a yellow oil; Rf¼0.25 (50% ethyl acetate/
hexane); nmax/cmꢀ1 3435, 3419, 3020, 2958, 1637, 1597, 1448, 1379,
1286, 1217, 1143, 1085, 754, 665; dH (400 MHz; CDCl3) 7.66 (d, 2H,
J¼8.2 Hz, Ar–H), 7.28 (d, 2H, J¼8.2 Hz, Ar–H), 5.53 (br s, 1H,
CH]CCH3), 3.66 (br s, 1H, SO2CH), 3.53 (dd, 1H, J¼11.1, 3.2 Hz,
CHHOH), 3.33 (dd, 1H, J¼11.1, 6.8 Hz, CHHOH), 2.38 (s, 3H, CH3),
2.25 (br s, 1H, OH), 2.22–2.14 (m, 1H, CHCH3), 1.92 (ddd, 1H, J¼13.4,
8.0, 4.4 Hz, SO2CHCHH), 1.77 (br s, 1H, CHCH2OH), 1.72 (s, 3H, CH3),
1.52 (ddd, 1H, J¼13.4, 6.7, 6.7 Hz, SO2CHCHH), 0.86 (d, 3H, J¼6.9 Hz,
CH3); dC (100 MHz; CDCl3) 144.7, 141.9, 134.3, 129.6 (2C), 129.0 (2C),
115.0, 62.7, 60.7, 48.5, 26.7, 26.1, 23.0, 21.6, 19.6; m/z, 317 (MþNaþ,
100%), 295, 157; HRMS found 317.1183 (MþNaþ, C16H22O3SNa re-
quires 317.1187).
4.1.9. ((1R
*
,2R
*
,6S )-2,6-Dimethyl-4-tosylcyclohex-3-enyl)methanol
*
(11). A solution of DIBAL in toluene (65.6 mL of a 1 M solution,
65.6 mmol) was added over 30 min to a solution of cyclohexenyl
sulfone 9 (5.74 g, 18.7 mmol) in dry CH2Cl2 (95 mL) at ꢀ78 ꢁC under
nitrogen. The mixture was stirred for a further 3 h at ꢀ78 ꢁC, then
the reaction was quenched with a solution of Rochelle’s salt (1.2 M
aq potassium sodium tartrate, 50 mL). The viscous mixture was
stirred vigorously for 1 h, allowed to stand until two clear phases
formed. The reaction mixture was extracted with CH2Cl2
(3ꢂ50 mL). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 50% EtOAc in hexanes) to give alcohol 11
(5.30 g, 18.0 mmol, 96%) as a colourless solid; mp 104–105 ꢁC;
Rf¼0.25 (50% ethyl acetate/hexane); nmax/cmꢀ1 3441, 1643, 1595,
1300, 1286, 1273, 1149, 1105, 1082, 1004, 806, 669, 623; dH
(400 MHz; CDCl3) 7.70 (d, 2H, J¼8.1 Hz, Ar–H), 7.30 (d, 2H, J¼8.1 Hz,
Ar–H), 6.94 (app.d, 1H, J¼4.1 Hz, SO2C]CH), 3.68 (dd, 1H, J¼10.1,
6.1 Hz, CHHOH), 3.51 (dd, 1H, J¼10.1, 10.1 Hz, CHHOH), 2.80–2.66
(m, 1H, C]CHCHCH3), 2.42 (s, 3H, CH3), 2.27 (app.d, 1H, J¼12.2 Hz,
SO2CCHH), 1.85–1.67 (m, 2H, SO2CCHH and CH2CHCH3), 1.63–1.46
(m, 1H, CHCH2OH), 1.01 (d, 3H, J¼7.3 Hz, CH3), 0.87 (d, 3H, J¼6.2 Hz,
CH3); dC (100 MHz; CDCl3) 144.1, 142.4, 138.0, 136.3, 129.8 (2C),
127.9 (2C), 61.7, 43.6, 30.8, 30.7, 26.0, 21.6, 18.7, 14.5; m/z, 295
(MþHþ, 100%), 280, 279, 260, 255, 238, 204, 180, 167, 163, 150. Anal.
Calcd for C16H22O3S: C, 65.27; H, 7.53. Found: C, 65.33; H, 7.58.
4.1.12. t-Butyl(((1R
*
,6S )-2,6-dimethyl-4-tosylcyclohex-2-enyl)me-
*
thoxy) dimethylsilane (14). A solution of t-butyldimethylsilyl chlo-
ride (0.81 g, 5.4 mmol) in THF (6.7 mL) was added dropwise to
a solution of alcohol 13 (0.66 g, 2.2 mmol), triethylamine (0.48 mL,
3.34 mmol) and 4-(dimethylamino)pyridine (0.03 g, 0.22 mmol) in
THF (6.7 mL) at 0 ꢁC. The mixture was allowed to warm slowly to
room temperature and stirred for an additional 20 h. The reaction
mixture was quenched with saturated aq NH4Cl (15 mL) and
extracted with Et2O (25 mLꢂ3). The combined organic layers were
washed with water and brine and dried over anhydrous MgSO4.
After removal of solvent under reduced pressure, the residue was
purified by column chromatography (SiO2, 25% EtOAc in hexanes)
to give silyl ether 14 (0.84 g, 2.06 mmol, 92%) as a colourless solid;
mp 62–64 ꢁC; Rf¼0.44 (25% ethyl acetate/hexane); nmax/cmꢀ1 1286,
1255,1220,1126,1083, 879, 837, 812, 773, 673, 599, 574, 557, 511; dH
(500 MHz; CDCl3) 7.71 (d, 2H, J¼8.1 Hz, Ar–H, minor), 7.68 (d, 2H,
J¼8.1 Hz, Ar–H, major), 7.31 (d, 2H, J¼8.1 Hz, Ar–H, minor), 7.30 (d,
2H, J¼8.1 Hz, Ar–H, major), 5.64 (br s, 1H, CH]CCH3, minor), 5.58
(br s, 1H, CH]CCH3, major), 3.74 (dd, 1H, J¼11.3, 2.7 Hz, SO2CH,
major), 3.62 (dd, 1H, J¼10.4, 2.7 Hz, SO2CH, minor), 3.39 (dd, 1H,
J¼9.9, 4.4 Hz, CHHOTBS, major and minor), 2.85 (dd, 1H, J¼9.9,
9.9 Hz, CHHOTBS, major and minor), 2.41 (s, 3H, CH3, minor), 2.40
(s, 3H, CH3, major), 2.23–2.12 (m, 1H, CHCH3, major and minor),
1.83–1.50 (m, 3H, SO2CH and SO2CHCH2, major and minor), 1.72 (s,
3H, CH3, major and minor), 0.95 (d, 3H, J¼6.6 Hz, CH3, minor), 0.85
(d, 3H, J¼7.1 Hz, CH3, major), 0.82 (s, 9H, SiC(CH3)3, major), 0.80 (s,
9H, SiC(CH3)3, minor), ꢀ0.03 (s, 6H, Si(CH3)2, minor), ꢀ0.06 (s, 6H,
Si(CH3)2, major); dC (100 MHz; CDCl3) 144.4, 141.0, 133.8, 129.6,
129.4 (2C), 129.1, 114.4, 64.0, 60.6, 48.5, 28.5, 25.9 (2C), 25.8, 24.1,
23.7, 21.6, 18.6, 18.2, ꢀ5.4, ꢀ5.5; m/z, 431 (MþNaþ, 100%), 409, 271,
209; HRMS found 431.2048 (MþNaþ, C22H36O3SSiNa requires
431.2052).
4.1.10. t-Butyl(((1S
*
,2S
*
,6R )-2,6-dimethyl-4-tosylcyclohex-3-enyl)-
*
methoxy) dimethylsilane (12). A solution of t-butyldimethylsilyl
chloride (0.42 g, 2.77 mmol) in THF (8 mL) was added dropwise to
a solution of alcohol 11 (0.54 g, 1.85 mmol), 4-(dimethylamino)-
pyridine (45.0 mg, 0.37 mmol) and triethylamine (0.36 mL,
2.59 mmol) in THF (9.0 mL) at 0 ꢁC under nitrogen. The reaction
mixture was stirred at 0 ꢁC for 30 min, then allowed to warm up
slowly to room temperature and stirred for an additional 20 h. The
reaction mixture was quenched with NH4Cl (15 mL) and extracted
with Et2O (20 mLꢂ3). The combined organic layers were washed
with water and brine and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure, and the residue was purified
by column chromatography (SiO2, 25% EtOAc in hexanes) to give
silyl ether 12 (0.69 g, 1.68 mmol, 91%) as a colourless solid; mp 70–
72 ꢁC; Rf¼0.44 (25% ethyl acetate/hexane); nmax/cmꢀ1 1641, 1597,
1467, 1454, 1377, 1300, 1290, 1149, 1112, 1083, 885, 837, 813, 775,
667, 619; dH (500 MHz; CDCl3) 7.71 (d, 2H, J¼8.1 Hz, Ar–H), 7.31 (d,
2H, J¼8.1 Hz, Ar–H), 6.45 (app.d, 1H, J¼4.3 Hz, SO2C]CH), 3.58 (dd,
1H, J¼9.9, 6.0 Hz, CHHOTBS), 3.45 (dd, 1H, J¼9.9, 9.9 Hz, CHHOTBS),
2.75–2.63 (m, 1H, C]CHCHCH3), 2.42 (s, 3H, Ar–CH3), 2.26 (app.d,
1H, J¼12.3 Hz, SO2CCHH), 1.82–1.66 (m, 2H, SO2CCHH and
CH2CHCH3), 1.58–1.46 (m, 1H, CHCH2OTBS), 0.99 (d, 3H, J¼7.3 Hz,
CH3), 0.86 (d, 3H, J¼8.6 Hz, CH3), 0.85 (s, 9H, SiC(CH3)3), 0.00 (s, 3H,
SiCH3), 0.01 (s, 3H, SiCH3); dC (100 MHz; CDCl3) 144.0, 142.7, 138.0,
136.5, 129.7 (2C), 128.0 (2C), 61.8, 43.7, 31.1, 31.0, 25.82 (3C), 25.77,
21.6, 18.6, 18.1, 14.5, ꢀ5.4, ꢀ5.5; m/z; 431 (MþNaþ, 100%), 409, 389,
357, 339, 335, 279, 254, 233, 222, 206, 166, 140; HRMS found
431.2054 (MþNaþ, C22H36O3SSiNa requires 431.2052).
4.1.13. (4R
*
,5S )-4-((t-Butyldimethylsilyloxy)methyl)-3,5-dime-
*
thylcyclohex-2-enone (15). A solution of lithium diisopropylamide
[prepared by reacting diisopropylamine (5.05 mL, 28.0 mmol) in
THF (50 mL) with n-BuLi (1.6 M in hexane, 17.5 mL, 28.0 mmol) at
ꢀ78 ꢁC for 30 min] was added dropwise to a suspension of sulfone
14 (1.91 g, 4.67 mmol) and MoOPD (6.72 g, 17.5 mmol) in THF
(55 mL) at ꢀ78 ꢁC under nitrogen. The mixture was stirred at
ꢀ78 ꢁC for 3 h, then quenched with 2 M HCl (30 mL), and extracted
with Et2O (3ꢂ75 mL). The combined organic layers were washed
with water and brine and dried over anhydrous MgSO4. After re-
moval of solvent under reduced pressure, the residue was purified
by column chromatography (SiO2, 25% EtOAc in hexanes) to give
enone 15 (1.06 g, 3.94 mmol, 84%) as a colourless oil; Rf¼0.43 (25%
ethyl acetate/hexane); nmax/cmꢀ1 2954, 2927, 1647, 1629, 1460,
1438, 1375, 1300, 1251, 1105, 1004, 991, 835, 775; dH (500 MHz;
CDCl3) 5.91 (s, 1H, C]CH), 3.80 (app.d, 1H, J¼1.3 Hz, CHHOTBS),
3.79 (app.d, 1H, J¼2.5 Hz, CHHOTBS), 2.60 (dd, 1H, J¼16.9, 5.1 Hz,
4.1.11. ((1R
*
,6S )-2,6-Dimethyl-4-tosylcyclohex-2-enyl)methanol
*
(13). Sodium hydroxide (2.27 g, 56.77 mmol) was added to a solu-
tion of alcohol 11 (2.39 g, 8.1 mmol) in MeOH (40 mL). The mixture
was heated at reflux for 7 h, then cooled to room temperature,
neutralised with 2 M HCl and extracted with CH2Cl2 (50 mLꢂ3).
The combined organic layers were washed with water and brine
and dried over anhydrous MgSO4. After removal of solvent under

6346
R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
COCHH), 2.48–2.35 (m, 1H, CHCH3), 2.17–2.06 (m, 2H, COCHH and
CHCH2OTBS), 1.99 (s, 3H, CH3), 1.05 (d, 3H, J¼7.0 Hz, CH3), 0.87
(s, 9H, SiC(CH3)3), 0.052 (s, 3H, SiCH3), 0.050 (s, 3H, SiCH3); dC
(125 MHz; CDCl3) 199.2, 161.1, 127.8, 62.7, 49.8, 41.9, 30.2, 25.8 (3C),
23.5, 20.0, 18.2, ꢀ5.49, ꢀ5.52; m/z, 269 (MþHþ, 100%), 268, 239,
223, 185, 137, 107; HRMS found 269.1934. (MþHþ, C15H29O2Si re-
quires 269.1937).
layers were washed with water and brine and dried over anhydrous
MgSO4. After removal of solvent under reduced pressure, the resi-
due was purified by column chromatography (SiO2, 25% EtOAc in
hexanes) to give iodide 19 (0.98 g, 2.23 mmol, 93%) as a colourless
solid and iodide 21 (0.01 g, 0.02 mmol, 1%) as a yellow oil. Iodide 19:
mp 77–79 ꢁC; Rf¼0.57 (25% ethyl acetate/hexane); nmax/cmꢀ1 3020,
2954, 2927,1784,1637,1462,1388,1327,1257,1215,1195,1143,1097,
993, 837, 756; dH (500 MHz; CDCl3) 4.66 (d, 1H, J¼2.8 Hz, CHI), 4.53
(s, 1H, CHO), 3.81 (dd, 1H, J¼10.6, 3.7 Hz, CHHOTBS), 3.67 (dd, 1H,
J¼10.6, 7.6 Hz, CHHOTBS), 2.97 (d,1H, J¼7.2 Hz, CHHCO), 2.37 (d,1H,
J¼7.2 Hz, CHHCO), 2.08–1.93 (m, 2H, CHCH3 and CHICHH),1.92–1.77
(m, 1H, CHICHH), 1.50 (s, 3H, CH3), 1.41–1.27 (m, 1H, CHCH2OTBS),
1.02 (d, 3H, J¼6.3 Hz, CH3), 0.92 (s, 9H, SiC(CH3)3), 0.08 (s, 6H,
Si(CH3)2); dC (75 MHz; CDCl3) 174.6, 88.6, 61.6, 47.1, 45.4, 42.7, 39.7,
26.1, 25.9 (3C), 22.1, 21.9, 19.3, 18.1, ꢀ5.6, ꢀ5.8; m/z, 461 (MþNaþ,
100%), 439, 414, 413, 403, 393, 344, 330, 275, 257, 223, 209, 180;
HRMS found 461.0990 (MþNaþ, C17H31O3SiINa requires 461.0985).
4.1.14. (4R
*
,5S )-4-((t-Butyldimethylsilyloxy)methyl)-3,5-dime-
*
thylcyclohex-2-enol (17). Sodium borohydride (0.67 g, 17.75 mmol)
was added portionwise to a solution of CeCl3$7H2O (1.98 g,
5.33 mmol) and enone 15 (0.95 g, 3.55 mmol) in methanol (50 mL)
at ꢀ78 ꢁC under nitrogen. The temperature was allowed to increase
slowly to ꢀ40 ꢁC. Stirring was continued at this temperature for an
additional 15 h. The reaction mixture was then quenched with
saturated aq NH4Cl solution (20 mL). HCl (aq, 2 M) was added until
the reaction mixture became clear, and it was extracted with Et2O
(3ꢂ75 mL). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 25% EtOAc in hexanes) to give alcohol 17
(0.87 g, 3.23 mmol, 91%) as a colourless oil (95:5 mixture of di-
astereoisomers); Rf¼0.25 (25% ethyl acetate/hexane); nmax/cmꢀ1
3348, 3331, 2954, 2927, 2856, 1718, 1664, 1469, 1462, 1384, 1361,
1253, 1112, 1095, 1029, 987, 875, 837, 773; dH (300 MHz; CDCl3) 5.51
(s, 1H, C]CH), 4.18 (br s, 1H CHOH), 3.71 (dd, 1H, J¼6.1, 2.3 Hz,
CHHOTBS), 3.65 (dd, 1H, J¼6.1, 1.9 Hz, CHHOTBS), 2.02–1.94 (m, 1H,
CHHCHCH3), 1.91–1.80 (m, 1H, CHCH3), 1.72 (s, 3H, CH3), 1.68 (br d,
1H, J¼3.9 Hz, CHCH2OTBS), 1.40 (br s, 1H, OH), 1.28–1.18 (m, 1H,
CHHCHCH3), 1.03 (d, 3H, J¼4.0 Hz, CH3), 0.86 (s, 9H, SiC(CH3)3), 0.02
(s, 6H, Si(CH3)2); dC (125 MHz; CDCl3) 137.0, 128.5, 67.3, 61.1, 49.2,
40.5, 27.8, 25.8 (3C), 21.5, 20.5, 18.2, ꢀ5.5 (2C); m/z, 293 (MþNaþ,
100%), 269, 253, 251, 247, 239, 236, 228, 222, 217, 212, 207, 192;
HRMS found 293.1917 (MþNaþ, C15H30O2SiNa requires 293.1913).
4.1.17. (3aS
*
,4R
*
,5S
*
,7aR
*
)-4-((t-Butyldimethylsilyloxy)methyl)-3a,5-
(22). DBU
dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-one
(0.92 mL, 6.2 mmol) was added to a solution of iodide 19 (0.68 g,
1.55 mmol) in THF (7.8 mL) under nitrogen. The mixture was heated
at reflux for 2 h, then the reaction was quenched with saturated aq
NH4Cl (5 mL) and extracted with Et2O (3ꢂ10 mL). The combined
organic layers were washed with water and brine and dried over
anhydrous MgSO4. After removal of solvent under reduced pres-
sure, the residue was purified by column chromatography (SiO2,
25% EtOAc in hexanes) to give cyclohexene 22 (0.45 g, 1.45 mmol,
94%) as a colourless solid; mp 97–98 ꢁC; Rf¼0.49 (25% ethyl acetate/
hexane); nmax/cmꢀ1 2956, 2927, 2881, 2854, 1762, 1745, 1460, 1384,
1249, 1222, 1197, 1170, 1126, 993, 833, 773; dH (400 MHz; CDCl3)
5.91 (d, 1H, J¼10.0 Hz, CH]CH), 5.79 (ddd, 1H, J¼10.0, 4.6, 2.5 Hz,
CH]CH), 4.28 (d, 1H, J¼4.6 Hz, CHO), 3.79 (dd, 1H, J¼11.3, 3.3 Hz,
CHHOTBS), 3.75 (dd, 1H, J¼11.3, 5.5 Hz, CHHOTBS), 2.96 (d, 1H,
J¼17.4 Hz, CHHCO), 2.39 (d, 1H, J¼17.4 Hz, CHHCO), 2.32–2.18 (m,
1H, CHCH3), 1.37–1.23 (m, 1H, CHCH2OTBS), 1.11 (s, 3H, CH3), 1.10 (d,
3H, J¼6.0 Hz, CH3), 0.89 (s, 9H, SiC(CH3)3), 0.06 (s, 6H, Si(CH3)2); dC
(100 MHz; CDCl3) 176.0, 141.0, 119.3, 82.5, 61.1, 44.3, 43.0, 41.2, 29.1,
25.8 (3C), 19.4, 18.9, 18.1, ꢀ5.6, ꢀ5.7; m/z, 333 (MþNaþ, 100%), 311,
310, 295, 276, 231, 223, 210, 187, 177, 159, 150; HRMS found
333.1853 (MþNaþ, C17H30O3SiNa requires 333.1862).
4.1.15. 2-((1R
*
,5S
*
,6R )-6-((t-Butyldimethylsilyloxy)methyl)-1,5-di-
*
methylcyclohex-2-enyl)-N,N-dimethylacetamide (18). Allylic alcohol
17 (3.93 g, 14.5 mmol) and N,N-dimethylacetamide dimethyl acetal
(4.25 mL, 29.07 mmol) were heated by microwave irradiation
employing 150 ꢁC, 150 W and a pressure of 150 psi for 1 h. The
volatiles were evaporated and the residue was purified by column
chromatography (SiO2, 25% EtOAc in hexanes) to give amide 18
(2.28 g, 6.73 mmol, 46%, 49% conversion from dr96:4) as a colour-
less solid; mp 65–67 ꢁC; Rf¼0.30 (25% ethyl acetate/hexane);
nmax/cmꢀ1 1653, 1620, 1307, 1253, 1193, 1105, 1058, 991, 862, 837,
773, 719; dH (500 MHz; CDCl3) 5.61 (ddd, 1H, J¼10.0, 5.2, 1.5 Hz,
CH]CH), 5.53 (d, 1H, J¼10.0 Hz, CH]CH), 3.83 (dd, 1H, J¼10.8,
3.5 Hz, CHHOTBS), 3.77 (dd, 1H, J¼10.8, 5.5 Hz, CHHOTBS), 3.04 (s,
3H, NCH3), 2.95 (s, 3H, NCH3), 2.54 (s, 2H, CH2N(CH3)3), 2.10–1.95
(m, 1H, CH]CHCHH), 1.88–1.73 (m, 2H, CH]CHCHH and CHCH3),
1.72–1.63 (m, 1H, CHCH2OTBS), 1.10 (s, 3H, CH3), 1.01 (d, 3H,
J¼6.0 Hz, CH3), 0.91 (s, 9H, SiC(CH3)3), 0.073 (s, 3H, SiCH3), 0.069 (s,
3H, SiCH3); dC (75 MHz; CDCl3) 171.7, 136.1, 124.3, 61.6, 48.9, 43.5,
39.1, 38.3, 35.4, 35.1, 27.3, 25.9 (3C), 23.9, 19.8, 18.1, ꢀ5.6, ꢀ5.7; m/z,
340 (MþHþ, 100%), 328, 317, 295, 279, 264, 246, 237, 223, 209, 208,
195, 181; HRMS found 340.2675 (MþHþ, C19H38NO2Si requires
340.2672).
4.1.18. (3S
*
,3aR
*
,4R
*
,5S
*
,7aR )-4-((t-Butyldimethylsilyloxy)methyl)-
*
3-hydroxy-3a,5-dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-one
(23). Lithium bis(trimethylsilyl)amide (1.32 mL of a 1 M solution in
THF, 1.32 mmol) was added to a suspension of lactone 22 (0.20 g,
0.66 mmol) and MoOPD (0.50 g, 1.32 mmol) in THF (6.5 mL) at
ꢀ78 ꢁC under nitrogen. The mixture was allowed to warm slowly to
ꢀ40 ꢁC and stirring was continued for 30 min at this temperature.
The mixture was allowed to warm to ꢀ10 ꢁC and stirring was
continued for 18 h at this temperature. The mixture was quenched
with saturated aq NH4Cl solution, and extracted with Et2O
(3ꢂ20 mL). The combined organic layers were washed with water
and brine and dried over anhydrous MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column
chromatography (SiO2, 25% EtOAc in hexanes) to give hydrox-
ylactone 23 (0.17 g, 0.52 mmol, 79%) as a colourless solid; mp 96–
98 ꢁC; Rf¼0.59 (50% ethyl acetate/hexane); nmax/cmꢀ1 3400, 2954,
2929,1759,1666,1512,1462,1359,1251,1215,1116, 991, 835, 752; dH
(500 MHz; CDCl3) 5.86 (dd, 1H, J¼10.1, 2.0 Hz, CH]CH), 5.72 (ddd,
1H, J¼10.1, 2.9, 2.9 Hz, CH]CH), 4.62 (app.s, 1H, CHOCO), 4.44 (d,
1H, J¼3.5 Hz, CHOH), 3.81 (dd, 1H, J¼10.5, 3.5 Hz, CHHOTBS), 3.66
(dd, 1H, J¼10.5, 4.5 Hz, CHHOTBS), 2.72 (d, 1H, J¼3.5 Hz, CHOH),
2.37–2.22 (m, 1H, CHCH3), 1.49 (app.q, 1H, J¼4.5 Hz, CHCH2OTBS),
1.17 (d, 3H, J¼7.4 Hz, CH3), 1.12 (s, 3H, CH3), 0.87 (s, 9H, SiC(CH3)3),
0.05 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); dC (100 MHz; CDCl3) 176.6,
4.1.16. (3aS
*
,4R
*
,5S
*
,7S
*
,7aS )-4-((t-Butyldimethylsilyloxy)methyl)-
*
7-iodo-3a,5-dimethylhexahydrobenzofuran-2(3H)-one (19). Iodine
(1.22 g, 4.81 mmol) was added to a solution of amide 18 (0.82 g,
2.40 mmol) in THF–H2O (9.6 mL: 9.6 mL) at 0 ꢁC. The mixture was
allowed to warm slowly to room temperature and stirred for an
additional 30 h, then the reaction was quenched with saturated aq
Na2S2O3 solution until the mixture became colourless. The mixture
was extracted with Et2O (3ꢂ20 mL), and the combined organic

R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
6347
138.3, 120.6, 81.0, 74.3, 63.7, 43.9, 43.7, 31.6, 25.8 (3C), 21.0, 18.1,
14.8, ꢀ5.6, ꢀ5.7; m/z, 349 (MþNaþ, 100%), 327, 323, 311, 280, 251,
240, 224, 195, 177, 159, 149, 131; HRMS found 349.1810 (MþNaþ,
C17H30O4SiNa requires 349.1811).
with water and brine and dried over anhydrous MgSO4. After re-
moval of solvent under reduced pressure, the residue was purified
by column chromatography (SiO2, 50% EtOAc in hexanes) to give
triol 27 as a colourless solid (23.9 mg, 0.07 mmol, 77%); mp 118–
120 ꢁC; Rf¼0.21 (50% ethyl acetate/hexane); nmax/cmꢀ1 3368, 2955,
2928, 2884, 2857, 1461, 1253, 1103, 1066, 1026, 995, 864, 834, 774;
dH (300 MHz; CDCl3) 5.73 (ddd, 1H, J¼9.8, 5.4, 1.8 Hz, CH]CH), 5.65
(dd, 1H, J¼9.8, 1.9 Hz, CH]CH), 4.58 (app.d, 1H, J¼5.1 Hz, CHOH-
CH2OH), 4.12 (br s, 1H, OH), 3.97–3.65 (m, 6H, CH2OH, CH2OTBS,
CHOH, OH), 2.47 (br s, 1H, OH), 2.10–1.87 (m, 2H, CHCH3,
CHCH2OTBS), 1.14 (d, 3H, J¼6.5 Hz, CHCH3), 0.90 (s, 9H, SiC(CH3)3),
0.76 (s, 3H, CH3), 0.111 (s, 3H, SiCH3), 0.106 (s, 3H, SiCH3); dC
(125 MHz; CDCl3) 136.3, 125.8, 78.3, 71.3, 62.3, 61.2, 42.4, 40.8, 30.6,
25.8 (3C), 19.6, 18.1, 16.3, ꢀ5.58, ꢀ5.63; m/z, 353 (MþNaþ, 100%),
314, 313, 306, 299, 294; HRMS 353.2129 (MþNaþ, C17H34O4SiNa
requires 353.2124).
4.1.19. (3aS
*
,4R
*
,5S
*
,7aR )-4-((t-Butyldimethylsilyloxy)methyl)-3a,5-
*
dimethyl-4,5-dihydrobenzofuran-2,3(3aH,7aH)-dione (25). 2-Iodox-
ybenzoic acid (0.18 g, 0.63 mmol) was added to a solution of
hydroxylactone 23 (17.9 mg, 0.055 mmol) in DMSO (1 mL) at room
temperature. The mixture was stirred at room temperature for 4
days, then the reaction mixture was diluted with saturated NaHCO3
solution (10 mL), and extracted with Et2O (3ꢂ15 mL). The com-
bined organic layers were washed with water and brine and dried
over anhydrous MgSO4. After removal of solvent under reduced
pressure, the residue was purified by column chromatography
(SiO2, 25% EtOAc in hexanes) to give ketone 25 (15.0 mg,
0.046 mmol, 84%) as a colourless solid; mp 74–75 ꢁC; Rf¼0.61 (25%
ethyl acetate/hexane); nmax/cmꢀ1 2955, 2929, 2884, 2857, 1787,
1461, 1249, 1110, 990, 952, 909, 832, 775, 675; dH (300 MHz; CDCl3)
6.06 (dd, 1H, J¼10.1, 1.5 Hz, CH]CH), 5.90 (ddd, 1H, J¼10.1, 4.3,
2.5 Hz, CH]CH), 4.59 (d, 1H, J¼4.3 Hz, CHOCO), 3.69 (dd,1H, J¼11.3,
3.5 Hz, CHHOTBS), 3.65 (dd, 1H, J¼11.3, 3.0 Hz, CHHOTBS), 2.60–
2.40 (m, 1H, CHCH3), 1.43 (ddd, 1H, J¼9.3, 3.5, 3.3 Hz, CHCH2OTBS),
1.24 (s, 3H, CH3), 1.13 (d, 3H, J¼7.1 Hz, CHCH3), 0.88 (s, 9H,
SiC(CH3)3), 0.08 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); dC (125 MHz;
CDCl3) 197.9, 160.8, 142.1, 119.0, 79.2, 58.7, 48.3, 41.1, 28.5, 25.8 (3C),
19.0, 18.1, 13.7, ꢀ5.7, ꢀ5.8; m/z, 347 (MþNaþ, 100%), 325, 324, 311,
306, 298, 280, 278, 266, 261, 257, 242, 238; HRMS found 347.1651
(MþNaþ, C17H28O4SiNa requires 347.1655).
4.1.22. (R
*
)-2-((1R
*
,2S
*
,5R
*
,6S )-6-((t-Butyldimethylsilyloxy)
*
methyl)-2-hydroxy-1,5-dimethyl-cyclohex-3-enyl)-2-hydroxyethyl 4-
methylbenzenesulfonate (28). Triethylamine (0.04 mL, 0.31 mmol)
was added to a solution of triol 27 (92.5 mg, 0.28 mmol), 4-
(dimethylamino)pyridine (7 mg, 0.06 mmol) and p-TsCl (80 mg,
0.42 mmol) in CH2Cl2 (2.8 mL) at 0 ꢁC under nitrogen. The reaction
mixture was allowed to warm slowly to room temperature (5 h).
The mixture was diluted with saturated aq NH4Cl (5 mL) and water
(10 mL), and extracted with CH2Cl2 (3ꢂ10 mL). The combined or-
ganic layers were washed with water and brine and dried over
anhydrous Na2SO4. After removal of solvent under reduced pres-
sure, the residue was purified by column chromatography (SiO2,
25% EtOAc in hexanes) to give tosylate 28 as a colourless oil
(67.8 mg, 50%) and tetrahydrofuran 29 (18.8 mg, 21%) as a colourless
solid. Tosylate 28: Rf¼0.57 (25% ethyl acetate/hexane); nmax/cmꢀ1
3369, 2962, 2926, 2879, 1457, 1357, 1174, 1033, 1009, 970, 814, 682,
665, 553; dH (500 MHz; CDCl3) 7.81 (d, 2H, J¼8.2 Hz, Ar–H), 7.33 (d,
2H, J¼8.2 Hz, Ar–H), 5.76–5.60 (m, 2H, CH]CH), 4.46 (dd, 1H,
J¼10.6, 2.1 Hz, CHHOTs), 4.28 (dd, 1H, J¼10.6, 8.1 Hz, CHHOTs), 3.96
(dd, 1H, J¼8.1, 2.1 Hz, CHOHCH2OTs), 3.77 (app.d, 1H, J¼10.8 Hz,
CHHOTBS), 3.73 (app.d, 1H, J¼5.2 Hz, CH]CHCHOH), 3.69 (dd, 1H,
J¼10.8, 6.6 Hz, CHHOTBS), 2.44 (s, 3H, Ar–CH3), 2.08–1.88 (m, 2H,
CHCH3 and CHCH2OTBS), 1.11 (d, 3H, J¼6.4 Hz, CHCH3), 0.89 (s, 9H,
SiC(CH3)3), 0.77 (s, 3H, CH3), 0.09 (s, 6H, Si(CH3)2); dC (75 MHz;
CDCl3), 144.7, 138.7, 134.3, 129.9 (2C), 127.7 (2C), 121.2, 86.5, 79.7,
71.6, 61.6, 47.1, 44.8, 30.5, 25.8 (3C), 21.7, 19.6, 18.1, 12.1, ꢀ5.5, ꢀ5.6;
m/z, 507 (MþNaþ, 100%), 485; HRMS 507.2223 (MþNaþ,
C24H40O6SiSNa requires 507.2213).
4.1.20. (3R
*
,3aS
*
,4S
*
,5R
*
,7aS )-4-((t-Butyldimethylsilyloxy)methyl)-
*
3-hydroxy-3a,5-dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-one
(26). Sodium borohydride (93 mg, 2.46 mmol) was added por-
tionwise to a solution of ketone 25 (0.16 g, 0.49 mmol) in methanol
(5 mL) at ꢀ78 ꢁC. The temperature was allowed to rise gradually to
0 ꢁC and the mixture was stirred at this temperature for an addi-
tional 2 h, then quenched with saturated aq NH4Cl solution, and
extracted with Et2O (3ꢂ20 mL). The combined organic layers were
washed with water and brine and dried over anhydrous MgSO4.
After removal of solvent under reduced pressure, the residue was
purified by column chromatography (SiO2, 25% EtOAc in hexanes)
to give hydroxylactone 26 (0.16 g, 0.48 mmol, 98%) as a colourless
solid; mp 92–94 ꢁC; Rf¼0.26 (50% ethyl acetate/hexane); nmax/cmꢀ1
3381, 3305, 3018, 2956, 2929, 2883, 2856, 1774, 1462, 1255, 1215,
1141, 958, 835, 756; dH (300 MHz; CDCl3) 5.91 (dd, 1H, J¼9.9, 1.9 Hz,
CH]CH), 5.81 (ddd, 1H, J¼9.9, 5.1, 2.3 Hz, CH]CH), 5.73 (app.d, 1H,
J¼10.0 Hz, OH), 4.23–4.12 (m, 2H, CHOCO and CHOH), 3.82 (dd, 1H,
J¼11.3, 1.8 Hz, CHHOTBS), 3.74 (dd, 1H, J¼11.3, 7.7 Hz, CHHOTBS),
2.05–1.87 (m, 1H, CHCH3), 1.42 (ddd, 1H, J¼10.0, 7.7, 1.8 Hz,
CHCH2OTBS),1.15 (s, 3H, CH3),1.13 (d, 3H, J¼7.0 Hz, CH3), 0.91 (s, 9H,
SiC(CH3)3), 0.11 (s, 6H, Si(CH3)2); dC (125 MHz; CDCl3) 175.6, 141.0,
118.9, 79.4, 77.1, 61.0, 45.2, 44.4, 29.7, 25.7 (3C), 19.9, 18.1, 15.9, ꢀ5.4,
ꢀ5.6; m/z, 349 (MþNaþ, 100%), 326, 311, 279, 274, 256, 240, 220,
213, 200, 180, 177; HRMS 349.1814 (MþNaþ, C17H30O4SiNa requires
349.1811).
4.1.23. (1S
*
,4R
*
,5S
*
,6R
*
)-5-((t-Butyldimethylsilyloxy)methyl)–1-hy-
(30). Imidazole
droxy-2-iodoethyl)-4,6-dimethylcyclohex-2-enol
(15 mg, 0.21 mmol) followed by a solution of triphenylphosphine
(19 mg, 0.07 mmol) in CH2Cl2 was slowly added to a solution of triol
27 (21.2 mg, 0.064 mmol) in CH2Cl2 (0.5 mL) at ꢀ30 ꢁC under ni-
trogen. A solution of iodine (18 mg, 0.07 mmol) in CH2Cl2 (0.5 mL)
was added dropwise to the stirred reaction mixture. The mixture
was stirred at this temperature for 2 h, then quenched with satu-
rated aq Na2S2O3 (5 mL) and extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic layers were washed with water and brine and
dried over anhydrous Na2S2O4. After removal of solvent under re-
duced pressure, the residue was purified by column chromatogra-
phy (SiO2, 25% EtOAc in hexanes) to give iodide 30 (18.9 mg,
0.043 mmol, 67%) as a colourless oil and tetrahydrofuran 29 (3.1 mg,
0.01 mmol, 15%) as a colourless solid. Iodide 30: Rf¼0.27 (25% ethyl
acetate/hexane); nmax/cmꢀ1 3387, 2922, 2851, 1448, 1416, 1374,
1259, 1092, 1031, 987, 892, 838, 578, 553; dH (300 MHz; CDCl3) 5.75
(ddd, 1H, J¼9.8, 5.4, 2.0 Hz, CH]CH), 5.71 (dd, 1H, J¼9.8, 2.0 Hz,
CH]CH), 4.68 (br s, 1H, OH), 4.45 (br s, 1H, OH), 4.05 (dd, 1H, J¼9.5,
4.5 Hz, CHHI), 3.96 (dd, 1H, J¼8.2, 4.5 Hz, CHHOTBS), 3.84–3.56 (m,
4.1.21. (R
*
)-1-((1R
*
,2S
*
,5R
*
,6S )-6-((t-Butyldimethylsilyloxy)methyl)-
*
2-hydroxy-1,5-dimethylcyclohex-3-enyl)ethane-1,2-diol (27). A so-
lution of hydroxylactone 26 (30.8 mg, 0.09 mmol) in THF (1 mL)
was slowly added to a suspension of LiAlH4 (10.7 mg, 0.28 mmol) in
THF (0.5 mL) at 80 ꢁC under nitrogen. After heating at reflux for 2 h,
the reaction mixture was cooled to 0 ꢁC, and quenched with satu-
rated aq NH4Cl (3 mL) and water (5 mL) and stirred for an addi-
tional 5 min. The insoluble materials were removed by filtration
through Celite, washing with THF, and the filtrate was extracted
with Et2O (3ꢂ10 mL). The combined organic layers were washed

6348
R.W. Bates et al. / Tetrahedron 66 (2010) 6340–6348
16.8; m/z, 467 (MþNaþ, 100%) 445, 413, 391, 363, 287, 205, 167, 149, 131. Anal.
Calcd for C24H28O4S2: C, 64.38; H, 6.53. Found: C, 64.72; H, 6.54.
10. (a) Alexandre, C.; Belkadi, O.; Maignan, C. Synthesis 1992, 547; (b) Bonfand, E.;
Gosselin, P.; Maignan, C. Tetrahedron Lett. 1992, 33, 2347.
11. Paquette, L. A.; Carr, R. V. C. Org. Synth. Coll. Vol. 1990, 7, 453.
12. Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436.
4H, CHOH, CHOHCH2I, CHHI and CHHOTBS), 1.90–1.79 (m, 1H,
CHCH2OTBS), 1.72 (app.d, 1H, J¼7.1 Hz, CHCH3), 1.13 (d, 3H, J¼7.1 Hz,
CHCH3), 0.92 (s, 9H, SiC(CH3)3), 0.82 (s, 3H, CH3), 0.11 (s, 6H,
Si(CH3)2); dC (125 MHz; CDCl3) 137.8, 116.2, 75.3, 70.3, 63.0, 47.4,
42.1, 30.6, 29.7, 25.9 (3C), 19.9, 18.2, 12.0, ꢀ5.3, ꢀ5.4; m/z, 441
(MþHþ, 100%), 428, 427, 390, 312, 294, 277, 251, 212, 180, 162, 146;
HRMS 441.1326 (MþHþ, C17H34O3SiI requires 441.1322).
13. Weitz, E.; Scheffer, A. Ber. Dtsch. Chem. Ges. 1921, 54, 2327.
14. VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Synth. Coll. Vol. 1988, 6, 342;
VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.
15. Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
16. Little, R. D.; Myong, S. O. Tetrahedron Lett. 1980, 21, 3339.
4.1.24. (1S
*
,4R
*
,5S
*
,6S
*
)-5-((t-Butyldimethylsilyloxy)methyl)-6-((S )-
*
17. Anderson, J. C.; Smith, S. C. Synlett 1990, 107.
18. Data for hydroxyketone 16: mp 47–48 ꢁC; Rf¼0.34 (25% ethyl acetate/hexane);
nmax/cmꢀ1 3479, 2957, 2928, 2887, 2856, 1657, 1461, 1376, 1251, 1085, 986, 882,
833, 772, 681; dH (500 MHz; CDCl3) 6.03 (s, 1H, C]CH), 3.99 (dd, 1H, J¼10.6, 2.
0 Hz, CHHOTBS), 3.81 (dd, 1H, J¼10.6, 1.8 Hz, CHHOTBS), 3.81 (br s, 1H, OH), 3.
80 (d, 1H, J¼12.3 Hz, CHOH), 2.18–2.08 (m, 2H, CHCH3 and CHCH2OTBS), 2.04 (s,
3H, CH3), 1.23 (d, 3H, J¼6.0 Hz, CH3), 0.84 (s, 9H, SiC(CH3)3), 0.05 (s, 3H, SiCH3),
0.04 (s, 3H, SiCH3); dC (125 MHz; CDCl3) 199.2, 164.6, 125.4, 76.7, 59.3, 49.4, 37.9,
25.7 (3C), 22.1, 18.1, 15.7, ꢀ5.6, ꢀ5.7; m/z, 285 (MþHþ, 100%), 284, 270, 269, 266,
255, 237, 231, 206, 171, 155, 151; HRMS found 285.1887. (MþHþ, C15H29O3Si
requires 285.1886).
19. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
20. Dauben, W. G.; Dietsche, T. J. J. Org. Chem 1972, 37, 1212.
21. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.;
Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741.
22. (a) Bennett, G. B. Synthesis 1977, 9, 589; (b) Watanabe, W. H.; Conlon, L. E. J. Am.
Chem. Soc. 1957, 79, 2828; (c) Johnson, W. S.; Li, T.-T.; Harbert, C. A.; Bartlett, W.
R.; Herrin, T. R.; Staskun, B.; Rich, D. H. J. Am. Chem. Soc. 1970, 92, 4463.
23. Mandai, T.; Ueda, M.; Hasegawa, S.-i.; Kawada, M.; Tsuji, J.; Saito, S. Tetrahedron
Lett. 1990, 31, 4041; Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9, 2417.
24. Interestingly, a low yield of cyclohexenone 15 could be isolated from the re-
action mixture.
25. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425.
26. Some of the acetate of compound 17 could also be isolated from the reaction
mixture: Rf¼0.37 (25% ethyl acetate/hexane); nmax/cmꢀ1 2954, 2927, 2856,
1735, 1469, 1462, 1373, 1242, 1114, 1099, 1026, 873, 837, 775; dH (500 MHz;
CDCl3) 5.47 (s, 1H, CH]C), 5.29 (br s, 1H, CHOCO), 3.69 (app.d, 2H, J¼3.1, Hz,
CH2OTBS), 2.10–2.20 (m, 1H, CHHCHCH3), 2.05 (s, 3H, OCOCH3), 2.10–1.90 (m,
1H, CHCH3), 1.76 (br s, 4H, CHCH2OTBS and CH]CCH3), 1.43–1.31 (m, 1H,
CHHCHCH3), 1.04 (d, 3H, J¼6.7 Hz, CH3), 0.88 (s, 9H, SiC(CH3)3), 0.04 (s, 6H,
Si(CH3)2); dC (100 MHz; CDCl3) 170.9, 138.9, 123.7, 69.9, 61.3, 49.0, 35.3, 27.4, 25.
8 (3C), 21.8, 21.5, 20.2, 18.2, ꢀ5.5 (2C); m/z, 335 (MþNaþ, 100%) 237, 208, 194,
191; HRMS found 335.2020 (MþNaþ, C17H32O3SiNa requires 335.2018).
27. For reviews of cyclofunctionalisation, see Corey, E. J.; Shibasaki, M.; Knolle, J.
Tetrahedron Lett. 1977, 19, 1625; Cardillo, G.; Orena, M. Tetrahedron 1990, 46,
3321; Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997, 29, 33.
28. Data for iodide 21: Rf¼0.55 (25% ethyl acetate/hexane); nmax/cmꢀ1 3018, 2954,
2929, 1782, 1643, 1462, 1388, 1257, 1215, 1097, 989, 837, 748, 665; dH (500 MHz;
CDCl3) 5.79 (app.d, 1H, J¼10.2 Hz, CH]CH), 5.68–5.57 (m, 1H, CH]CH), 5.20 (s,
1H, CHI), 3.76 (dd, 1H, J¼10.8, 3.6 Hz, CHHOTBS), 3.64 (dd, 1H, J¼10.8, 6.3 Hz,
CHHOTBS), 3.02 (s, 3H, NCH3), 2.89 (s, 3H, NCH3), 1.97 (dt, 1H, J¼16.8, 4.3 Hz,
CH]CHCHH), 1.83 (dt, 1H, J¼10.6, 2.3 Hz, CHCH3), 1.81–1.65 (m, 2H,
CH]CHCHH and CHCH2OTBS), 1.12 (s, 3H, CH3), 0.95 (d, 3H, J¼6.0 Hz, CH3), 0.
88 (s, 9H, SiC(CH3)3), 0.054 (s, 3H, SiCH3), 0.052 (s, 3H, SiCH3); dC (100 MHz;
CDCl3) 169.8, 136.1, 123.6, 62.3, 44.9, 41.2, 38.2, 38.1, 36.5, 34.6, 29.0, 26.0 (3C),
25.8, 19.8, 18.4, ꢀ5.4, ꢀ5.5; m/z, 466 (MþHþ, 100%), 414, 413, 392, 391, 341, 340,
311, 279, 257, 205, 180, 149; HRMS found 466.1628 (MþHþ, C19H37NO2SiI re-
quires 466.1638).
1-hydroxy-4-methylpent-4-enyl)-4,6-dimethylcyclohex-2-enol
(31). Methallyltri-n-butyltin (0.42 g, 0.12 mmol) was added to
a solution of 30 (13.2 mg, 0.30 mmol) and 1,10-azobis(cyclohex-
anecarbonitrile) (3.0 mg, 0.009 mmol) in benzene (1 mL) at room
temperature under nitrogen. The mixture was heated at reflux for
6 h, then allowed to cool to room temperature. DBU (0.2 mL) was
added and the mixture was stirred for an additional 1 h, then di-
luted with water (10 mL) and extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic layers were washed with water and brine and
dried over anhydrous NaSO4. After removal of solvent under re-
duced pressure, the residue was purified by column chromatogra-
phy (SiO2, 10% EtOAc in hexanes) to give alkene 31 (6.4 mg,
0.017 mmol, 58%) as a colourless oil; Rf¼0.46 (25% ethyl acetate/
hexane); nmax/cmꢀ1 3397, 2956, 2929, 2884, 2857, 1729, 1649, 1461,
1253,1102,1072, 993, 862, 832, 774; dH (300 MHz; CDCl3) 5.79 (ddd,
1H, J¼9.8, 5.5, 2.0 Hz, CH]CH), 5.63 (dd,1H, J¼9.8, 2.2 Hz, CH]CH),
4.72 (br s, 2H, CH]CHH and OH), 4.71 (s, 1H, C]CHH), 4.41 (d, 1H,
J¼4.4 Hz, OH), 3.99 (d, 1H, J¼5.5 Hz, CH]CHCHOH), 3.73 (dd, 1H,
J¼10.6,1.7 Hz, CHHOTBS), 3.70–3.53 (m, 2H, CCHOH and CHHOTBS),
2.39 (ddd, 1H, J¼14.4, 7.1, 7.1 Hz, CHOHCH2CHH), 2.18–2.02 (m, 2H,
CHOHCH2CHH and CHOHCHHCH2), 1.93–1.77 (m, 3H, CHCH3,
CHOHCHHCH2 and CHCH2OTBS), 1.74 (s, 3H, CH3), 1.15 (d, 3H,
J¼6.8 Hz, CH3), 0.91 (s, 9H, SiC(CH3)3), 0.68 (s, 3H, CH3), 0.11 (s, 3H,
Si(CH3)), 0.10 (s, 3H, Si(CH3)); dC (100 MHz; CDCl3) 145.8, 135.8,
126.5, 110.3, 76.9, 70.8, 61.7, 42.8, 41.7, 35.2, 31.2, 27.7, 25.9 (3C),
22.6, 19.8, 18.2, 16.1, –5.6 (2C); m/z, 391 (MþNaþ, 100%), 368, 352,
351, 330, 314, 279, 278, 238, 218, 216, 198, 178; HRMS 391.2653
(MþNaþ, C21H40O3SiNa requires 391.2644).
Acknowledgements
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 2 (grant
T206B1220RS) for support of this work. XK thanks NTU for a URECA
scholarship.
29. Data for TMS ether 24: mp 47–49 ꢁC; Rf¼0.64 (25% ethyl acetate/hexane); nmax
/
References and notes
cmꢀ1 2956, 2929, 2883, 2856, 1778, 1660, 1512, 1462, 1404, 1359, 1251, 1228,
1097, 989, 939, 837, 775; dH (500 MHz; CDCl3) 5.87 (dd, 1H, J¼10.0, 2.2 Hz,
CH]CH), 5.76 (ddd, 1H, J¼10.0, 4.6, 2.4 Hz, CH]CH), 4.54 (d, 1H, J¼4.6 Hz,
CHOCO), 4.35 (s, 1H, CHOTMS), 3.74 (d, 2H, J¼4.0 Hz, CH2OTBS), 2.35–2.22 (m,
1H, CHCH3), 1.17 (dt, 1H, J¼8.9, 4.0 Hz, CHCH2OTBS), 1.06 (d, 3H, J¼7.2 Hz, CH3),
1.00 (s, 3H, CH3), 0.89 (s, 9H, SiC(CH3)3), 0.19 (s, 9H, Si(CH3)3), 0.06 (s, 3H,
SiCH3), 0.05 (s, 3H, SiCH3); dC (125 MHz; CDCl3) 175.2, 140.2, 119.5, 80.3, 75.3,
62.0, 44.7, 42.9, 30.1, 25.8 (3C), 19.9, 18.1, 12.5, 0.07 (3C), ꢀ5.5, ꢀ5.6; m/z, 421
(MþNaþ, 100%), 399, 391, 349, 327, 267, 249, 221, 195, 177, 159, 146, 131; HRMS
found 421.2207 (MþNaþ, C20H38O4Si2Na requires 421.2206).
1. Sung, P.-J.; Sheu, J.-H.; Xu, J.-P. Heterocycles 2002, 57, 535.
2. Sung, P.-J.; Chang, P.-C.; Fang, L.-S.; Sheu, J.-H.; Chen, W.-C.; Chen, Y.-P.; Lin, M.-
R. Heterocycles 2005, 65, 195; Sung, P.-J.; Sheu, J.-H.; Wang, W.-H.; Fang, L.-S.;
Chung, H.-M.; Pai, C.-H.; Su, Y. D.; Tsai, W.-T.; Chen, B.-Y.; Lin, M.-R.; Li, G.-Y.
Heterocycles 2008, 75, 2627.
3. Cronan, J. M.; Lee, A.; Liang, J.; Clardy, J.; Cardellina, J. H., II, J. Nat. Prod 2010, 73,
346.
4. For an example, see Iwasaki, J.; Ito, H.; Nakamura, M.; Iguchi, K. Tetrahedron Lett.
2006, 47, 1483.
5. Ba¨ckvall, J.-E.; Juntunen, S. K. J. Am. Chem. Soc. 1987, 109, 6396.
6. Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547; Simpkins, N. S. Sulfones in Or-
ganic Synthesis; Pergamon: Oxford, 1983.
7. Wildeman, J.; van Leusen, A. M. Synthesis 1979, 733.
8. Poly, W.; Schomburg, D.; Hoffmann, H. M. R. J. Org. Chem. 1988, 53, 3701;
Marvel, C. S.; Brace, N. O. J. Am. Chem. Soc. 1949, 71, 37.
30. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
31. None of the alternative epoxide product could be detected. Data for tetrahy-
drofuran 29: mp 63–65 ꢁC; Rf¼0.36 (25% ethyl acetate/hexane); nmax/cmꢀ1
3408, 2954, 2928, 2880, 2857, 1461, 1252, 1097, 1074, 1037, 1004, 985, 833, 774;
dH (500 MHz; CDCl3) 5.84 (ddd, 1H, J¼10.0, 3.5, 2.6 Hz, CH]CH), 5.65 (d, 1H,
J¼10.0 Hz, CH]CH), 4.45 (dd, 1H, J¼4.5, 1.6 Hz, OH), 3.96 (dt, 1H, J¼4.5, 4.5 Hz,
CHOH), 3.93–3.86 (m, 2H, OCHH and CHHOTBS), 3.81 (ddd, 1H, J¼9.4, 4.5, 1.
6 Hz, OCHH), 3.65–3.52 (m, 2H, CHOCH2, CHHOTBS), 1.93 (dd, 1H, J¼10.3, 3.9 Hz,
CHCH2OTBS), 1.90–1.82 (m, 1H, CHCH3), 1.09 (d, 3H, J¼6.7 Hz, CH3), 0.97 (s, 3H,
CH3), 0.93 (s, 9H, SiC(CH3)3), 0.13 (s, 6H, Si(CH3)2); dC (125 MHz; CDCl3) 136.6,
123.9, 83.3, 81.1, 72.7, 62.8, 45.7, 41.2, 29.7, 25.8 (3C), 20.3, 18.6, 18.1, ꢀ5.6, ꢀ5.7;
m/z, 313 (MþHþ, 100%), 312, 292, 262, 251, 227, 198, 180, 162; HRMS 313.2200
(MþHþ, C17H33O3Si requires 313.2199).
9. Other data for dimer 4: mp 142–143 ꢁC; Rf¼0.13 (25% ethyl acetate/hexane);
nmax/cmꢀ1 1645, 1595, 1288, 1151, 1139, 1091, 970, 800, 707, 655, 594; dH
(300 MHz; CDCl3) 7.66 (d, 2H, J¼8.2 Hz, Ar–H), 7.54 (d, 2H, J¼8.2 Hz, Ar–H), 7.26
(app.t, 4H, J¼7.9 Hz, Ar–H), 6.74 (app.d, 1H, J¼2.4 Hz, SO2C]CH), 5.51 (dd, 1H,
J¼16.0, 1.3 Hz, CH]CHCH3), 5.30 (dq, 1H, J¼16.0, 6.3 Hz, CH]CHCH3), 3.35–3.15
(m, 1H, CHCH3), 2.38 (s, 6H, CH3 (2C)), 2.28–2.00 (m, 2H, SO2CCH2), 1.97–1.78
(m, 2H, SO2CCH2CH2), 1.61 (dd, 3H, J¼6.3, 1.3 Hz, CH]CHCH3), 1.39 (d, J¼7.4 Hz,
CH3); dC (75 MHz; CDCl3) 144.9, 144.3, 141.1, 137.7, 135.8, 133.2, 131.9, 130.6, 129.
7 (2C), 129.1 (2C), 127.9 (2C), 121.9 (2C), 67.8, 33.8, 25.6, 21.59, 21.56, 20.5, 18.5,
32. Inoue, M.; Yamashita, S.; Ishihara, Y.; Hirama, M. Org. Lett. 2006, 8, 5805.
33. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.