Synthetic approaches to phomactins: on the stereoselectivity of some [2,3]-Wittig rearrangements

Article abstract of DOI:10.1016/j.tet.2015.04.005

On treatment with n-butyllithium, 4-alkoxy- and 4-silyloxy-2-(tributylstannylmethoxymethyl)-1,6-dimethyl-1-(phenylsulfonylmethyl)cyclohex-2-enes undergo tin-lithium exchange followed by [2,3]-Wittig rearrangements to give 3-alkoxy- and 3-silyloxy-2-hydroxymethyl-5,6-dimethyl-1-methylene-6-(phenylsulfonylmethyl)cyclohexanes in which the 2-hydroxymethyl and 6-phenylsulfonylmethyl residues are cis-disposed about the six-membered ring. In contrast, the corresponding 1-(phenylsulfanylmethyl)cyclohexenes give mainly methylenecyclohexanes with the 2-hydroxymethyl and 6-phenylsulfanylmethyl groups trans-disposed about the six-membered ring. This stereoselectivity is independent of the nature of the alkoxy- or silyloxy-substituent and configuration at C4. The 3-tert-butyldiphenylsilyloxy-1-methylene-6-(phenylsulfonylmethyl)cyclohexane was converted into a macrocyclic precursor of the phomactins.

Full text of DOI:10.1016/j.tet.2015.04.005

Tetrahedron xxx (2015) 1e17
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approaches to phomactins: on the stereoselectivity
of some [2,3]-Wittig rearrangements
*
Timothy J. Blackburn, Michael J. Kilner, Eric J. Thomas
The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
On treatment with n-butyllithium, 4-alkoxy- and 4-silyloxy-2-(tributylstannylmethoxymethyl)-1,6-
dimethyl-1-(phenylsulfonylmethyl)cyclohex-2-enes undergo tinelithium exchange followed by [2,3]-
Wittig rearrangements to give 3-alkoxy- and 3-silyloxy-2-hydroxymethyl-5,6-dimethyl-1-methylene-6-
(phenylsulfonylmethyl)cyclohexanes in which the 2-hydroxymethyl and 6-phenylsulfonylmethyl residues
are cis-disposed about the six-membered ring. In contrast, the corresponding 1-(phenylsulfanylmethyl)
cyclohexenes give mainly methylenecyclohexanes with the 2-hydroxymethyl and 6-phenylsulfanylmethyl
groups trans-disposed about the six-membered ring. This stereoselectivity is independent of the nature of
the alkoxy- or silyloxy-substituent and configuration at C4. The 3-tert-butyldiphenylsilyloxy-1-methylene-
6-(phenylsulfonylmethyl)cyclohexane was converted into a macrocyclic precursor of the phomactins.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 26 January 2015
Received in revised form 28 March 2015
Accepted 2 April 2015
Available online xxx
Keywords:
[2,3]-Wittig rearrangements
Stereoselectivity
Natural products
Total synthesis
Macrocycle
1. Introduction
on the Still [2,3]-Wittig rearrangement,7 together with further
studies of the stereoselectivity of the [2,3]-Wittig process (Fig. 1).5c
The phomactins are diterpenes with distinctive structures and
interesting biological activities that have provided challenging
targets for synthetic organic chemists.1 Several total syntheses,
including syntheses of phomactin A 1,2 together with other novel
synthetic approaches,3 have been developed to date. Aspects of this
chemistry have been reviewed.4
2. Results and discussion
2.1. Preliminary investigations of alternative approaches
The racemic keto-ester 7, as a 75: 25 mixture of epimers at C6,5a
was converted into the 2-(hydroxmethyl)cyclohexene 17 and the
corresponding 2-(bromomethyl)cyclohexene 18, see Scheme 1. O-
Silylation of the ketoester 7 gave the dienyl enol ether 8 and this
was oxidized using methyl(trifluoromethyl)dioxirane8 generated in
situ to give the 2-(hydroxymethyl)cyclohexenone 9 after desilyla-
tion during work-up, still as a mixture of C6 epimers, see Scheme 1.
This mixture was protected as its tert-butyldimethylsilyl ether 10
that was reduced under Luche’s conditions to give the C6 epimeric
alcohols 11 and 13 that now could be separated. The configuration
of the major product 11 at C4 was established by NOE studies and
was confirmed later by X-ray diffraction. This structure was con-
sistent with pseudo-axial attack on the preferred conformation of
the major enone, away from the axial 1-methyl substituent. The
structure of the minor alcohol 13 was assigned by analogy.
In our approach to the phomactins,5 a key step was the [2,3]-
Wittig rearrangement of the alkynylmethyl ether 2. This gave
a mixture of the epimeric alcohols 3 in which the side-chain at C2
was cis-disposed to the phenylsulfonylmethyl substituent at C6 for
both epimers.5b This stereoselectivity had not been observed in
earlier analogous [2,3]-Wittig rearrangements.5a The mixture of
epimers was then converted into the bis-(E)-triene 4 that was taken
through to the bicyclic triene 5, a promising macrocyclic in-
termediate for the synthesis of phomactins.5b
In this work, the alkynylmethyl ether 2 was used rather than the
bis(alkenylmethyl) ether 6, as preliminary studies had indicated it
would be difficult to direct the regioselectivity of deprotonation of
the bis(alkenylmethyl) ether.6 However, several steps were re-
quired to convert the alkyne 3 into the (E)-alkene 4 and this re-
stricted the amount of material that could conveniently be taken
through the synthesis. We now report a modified approach based
Following protection of the alcohol 11 as its trimethylsilyle-
thoxymethyl (SEM) ether 12, reduction of the ester using Super-
HydrideÔ gave the alcohol 14. This was converted into the analo-
gous phenylthioether 15 via the corresponding methanesulfonate,
and selective oxidation on sulfur9 gave the sulfone 16. Desilylation
* Corresponding author. Tel.: þ44 (0) 161 275 4613; e-mail address: e.j.thomas@
manchester.ac.uk (E.J. Thomas).
http://dx.doi.org/10.1016/j.tet.2015.04.005
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
bases to remove the less hindered, albeit less acidic, proton at C10,
the alcohol 17 was alkylated using geranyl bromide to give the
bis(alkenylmethyl) ether 19, see Scheme 2. However, initial at-
tempts to effect a [2,3]-Wittig rearrangement on this substrate
using various bases, e.g., sec-butyllithium, gave either unchanged
starting material or complex mixtures of products.
Scheme 2. Preparation of the model bis(alkenylmethyl) ether 19 Reagents and con-
n
ditions. i, NaH, Bu4NI, THF, 0 ꢁC, 20 min, 15-c-5, geranyl bromide, rt, 16 h (80%).
It has been shown that carbanion stabilising groups can control
the deprotonation of bis(alkenylmethyl) ethers leading to regiose-
lective [2,3]-Wittig rearrangements.6,10 Since the stereoselective
introduction of a vinylic methyl group by substitution of a phenyl-
thio substituent had proved useful in earlier studies,5b the control of
the regioselectivity of the Wittig rearrangement by a phenylthio
group was briefly evaluated. The stereoselective addition11 of thi-
ophenol to the pentynyl ester 20 gave the thioether 21 that was
reduced to the alcohol 22. Alkylation of this using 1-(bromomethyl)
cyclohexene gave the bis(alkenylmethyl) ether 23 that on treatment
with n-butyllithium underwent a regioselective Wittig rearrange-
ment to give the ketone 24 after oxidation of the intermediate al-
cohols. However, despite this promising model study, preliminary
studies of the [2,3]-Wittig rearrangement of the more complex
ether 25, prepared by alkylation of the alcohol 22 using the bromide
18, were unsuccessful in that either unchanged starting materials or
complex mixtures of products were obtained, see Scheme 3.
Fig. 1. The earlier [2,3]-Wittig rearrangement based synthesis of the phomactin core 5.
Scheme 3. Synthesis and rearrangement of phenylthio-substituted alkenyl ethers
Reagents and conditions. i, NaOMe, PhSH, MeOH, rt, 16 h (85%); ii, DIBAL-H, THF,
ꢀ78 ꢁC, 3 h (88%); iii, 22, NaH, nBu4NI, 0 ꢁC, 20 min, 15-c-5, 1-(bromomethyl)cyclo-
hexene, THF, rt, 24 h (93%); iv, (a) nBuLi, THF, ꢀ60 ꢁC, 0.5 h; (b) IBX, DMSO, rt, 3 h (72%);
Scheme 1. Synthesis of the 1-(phenylsulfonylmethyl)-2-(hydroxymethyl)cyclohex-2-
ene 17 Reagents and conditions. i, Et3N, tBuMe2SiOTf, DCM, 0 ꢁC, 20 h (65%); ii,
Na2EDTA, CF3COCH3, oxoneÔ, NaHCO3, ꢀ10 ꢁC, 1.5 h (68%); iii, tBuMe2SiCl, imid., DCM,
n
v, NaH, Bu4NI, THF, 0 ꢁC, 20 min, 15-c-5, 18, THF, rt, 16 h (71%).
i
2.2. Use of the Still [2,3]-Wittig rearrangement
rt, 24 h (92%); iv, CeCl3.7H2O, NaBH4, ꢀ78 ꢁC, 2 h (11, 63%; 13, 18%); v, Pr2NEt, SEMCl,
DCM, 0 ꢁC to rt, 20 h (80%); vi, LiEt3BH, THF, 0 ꢁC to rt, 4 h (82%); vii, (a) Et3N, MsCl,
DCM, 0 ꢁC, 2 h; (b) NaH, PhSH, DMF, 0 ꢁC, 20 min, add mesylate, heat under reflux, 20 h
(73%); viii, (NH4)2MoO4, H2O2, EtOH, 0 ꢁC to rt, 24 h (71%); ix, TBAF, THF, rt, 16 h (85%);
x, MsCl, Et3N, THF, 0 ꢁC, 45 min, LiBr, THF, 0 ꢁC, 1 h (86%).
Although further studies into the [2,3]-Wittig rearrangement of
the substituted bis(alkenylmethyl) ether 25 could have been car-
ried out, it was decided instead to look at the simpler [2,3]-Still
process7 since an efficient incorporation of the products into the
macrocyclisation precursor 4 could be envisaged.
Alkylation of the alcohol 17 using iodomethyl(tributyl)stannane
gave the ether 26. On treatment with 2 equiv of n-butyllithium at
ꢀ50 ꢁC, this was converted into the [2,3]-Wittig product 27 that was
isolated in a modest yield of 35%, together with the methyl ether 28,
presumably formed by protonation of the intermediate from the
gave the primary alcohol 17 and this was converted into the bro-
mide 18, see Scheme 1.
[2,3]-Wittig rearrangements of bis(alkenylmethyl) ethers usu-
ally proceed with deprotonation of the more acidic methylene
group next to the ethereal oxygen.6 To check whether this prefer-
ence could be overturned in the present case, e.g. by using bulky
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T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
3
tinelithium exchange. The use of more vigorous conditions led to
the formation of additional side-products that were not fully
characterised and when only 1 equiv of n-butyllithium was used,
90% of unchanged starting material was obtained, see Scheme 4.
correlation with the rearranged sulfone 27, the minor rearrange-
ment product 31 from the sulfide 29 giving the sulfone 27 on oxi-
dation, whereas the major rearrangement product gave a new
sulfone 32, see Scheme 5.
The contrasting stereoselectivities observed for the Wittig
rearrangements of the sulfone 26 and sulfide 29 were interesting
and so it was decided to study the [2,3]-rearrangements of some
analogous substrates. The epimeric substrates were prepared
starting with alcohol 11. Inversion to the epimeric alcohol 34 was
carried out using a Mitsunobu reaction followed by hydrolysis
of the intermediate ester 33. After the SEM-protection, reduction of
the ester gave the primary alcohol 35 that was converted into the
thioether 36. Oxidation gave the sulfone 37 and desilylation and O-
alkylation of the sulfone 37 and sulfide 36 gave the [2,3]-
rearrangement precursors 38 and 39, see Scheme 6.
Scheme 4. Preparation and [2,3]-rearrangement of the sulfone 26 Reagents and con-
ditions i, NaH, THF, rt, 5 min, nBu3SnCH2I, rt, 24 h (78%); ii, nBuLi (2 equiv), THF, ꢀ78 ꢁ
C
toꢀ50 ꢁC, 24 h (27, 35%; 28, 60%).
The 35% yield of the [2,3]-Wittig product 27 was disappointing
but it was formed essentially as a single diastereoisomer. This was
identified as having the 2-(hydroxymethyl) and 6-(phenyl-
sulfonylmethyl) substituents cis-disposed about the six-membered
ring on the basis of a significant NOE between 2-H and the 6-methyl
substituent. As 2 equiv of base were required for the rearrange-
ment, it was inferred that deprotonation of the phenylsulfonyl-
methylene group was taking place under the reaction conditions.
To check whether this was influencing the [2,3]-Wittig reaction, it
was decided to check the behaviour of the analogous, but less
acidic, sulfide 29. This was prepared by desilylating the tert-
butyldimethylsilyl ether 15 followed by alkylation of the resulting
alcohol and was found to rearrange efficiently on treatment with
1 equiv of n-butyllithium. Two diastereoisomeric rearrangement
products 30 and 31 were isolated, ratio 89: 11, in which the major
product 30 had the 2-(hydroxymethyl) and 6-(phenyl-
sulfanylmethyl) groups trans-disposed about the six-membered
ring. The structures of these products were established by
Scheme 6. Preparation of the rearrangement precursors 38 and 39 Reagents and
conditions i, Ph3P, DIAD, PhCO2H, THF, 0 ꢁC, 4 h; ii, NaOH, MeOH, rt, 30 min (94% two
steps); iii, (a) iPr2NEt, SEMCl, DCM, 0 ꢁC to rt, 2 d; (b) LiEt3BH, THF, 0 ꢁC to rt, 4 h (74%);
iv, (a) Et3N, MsCl, DCM, 0 ꢁC, 2 h; (b) NaH, PhSH, DMF, 0 ꢁC, 20 min, add mesylate, heat
under reflux, 4 h (75%); v, (NH4)2MoO4, H2O2, EtOH, 0 ꢁC to rt, 24 h (73%); vi, (a) TBAF,
THF, rt, 18 h; (b) NaH, THF, 5 min, nBu3SnCH2I, rt, 24 h (38, 76%; 39, 74%).
The Wittig rearrangements of the substrates 38 and 39 followed
the pattern set by their epimers 26 and 29. The rearrangement of
the sulfone 38 was highly stereoselective in favour of the un-
saturated alcohol 40 in which the 2-(hydroxymethyl) and 6-(phe-
nylsulfonylmethyl) groups were cis to each other with respect to
the six-membered ring albeit only a 37% yield was obtained. The
rearrangement of the sulfide 39 was more efficient but gave
a mixture of epimeric products 41 and 42, ratio 92:8, in which the
major product had the 2-(hydroxymethyl) and 6-(phenyl-
sulfanylmethyl) groups trans-disposed with respect to the six-
membered ring. The structures of these products were confirmed
later but products from these reactions were correlated with each
other in that oxidation of the minor product 42 from rearrange-
ment of the sulfide 39 gave the product 40 obtained by rear-
rangement of the sulfone 38 whereas oxidation of the major
product 41 from the rearrangement of the sulfide 39 gave a differ-
ent sulfone 43, see Scheme 7.
Scheme 5. Preparation and [2,3]-rearrangement of the sulfide 29 Reagents and con-
The influence of the protecting group of the allylic alcohol on the
stereoselectivity of the [2,3]-rearrangement was investigated by
protecting the hydroxy-ester 11 as its bulky tert-butyldiphenylsilyl
ditions i, (a) TBAF, THF, rt, 16 h; (b) NaH, THF, rt, 5 min, nBu3SnCH2I, rt, 24 h (69%); ii,
nBuLi, THF, ꢀ78 ꢁC toꢀ50 ꢁC, 24 h (30, 81%; 31, 10%); iii, (NH4)2MoO4, H2O2, EtOH, 0 ꢁ
to rt, 24 h (32, 86%; 27, 86%).
C
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T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
Scheme 7. [2,3]-Rearrangements of the sulfone 38 and sulfide 39 Reagents and con-
n
ditions i, BuLi, THF, ꢀ78 ꢁC to ꢀ50 ꢁC, 24 h (40, 37% using 2 equiv nBuLi; 41, 81%; 42,
7%); ii, (NH4)2MoO4, H2O2, EtOH, 0 ꢁC to rt, 24 h (40, 88%; 43, 84%).
ether 44. Reduction of the ester gave the alcohol 45 that was con-
verted into the phenylthioether 46 via the corresponding mesylate.
Oxidation of the thioether gave the sulfone 48. The thioether 46
and sulfone 48 were selectively monodesilylated and the primary
alcohols 47 and 49 so formed were alkylated using iodomethyl
(tributyl)stannane to give the stannylmethyl ethers 51 and 50,
respectively. These were subjected to the [2,3]-Wittig rearrange-
ments under the usual conditions. The rearrangement of the sul-
fone 50 was highly stereoselective and gave the homoallylic alcohol
52 in which the 2-(hydroxymethyl) and 6-(phenylsulfonylmethyl)
groups were cis-disposed about the six-membered ring in an im-
proved yield of 65%. As before, rearrangement of the thioether 51
was more efficient but again gave two products 53 and 54, ratio
92:8. The major product was shown to be the epimer 53 in which
the 2-(hydroxymethyl) and 6-(phenylsulfanylmethyl) groups are
trans-disposed about the six-membered ring because oxidation
gave a new sulfone 55. Oxidation of the minor sulfide rearrange-
ment product 54 gave sulfone 52, see Scheme 8.
Scheme 8. Preparation and [2,3]-rearrangement of tert-butyldiphenylsilyloxysub-
stituted stannanes 50 and 51 Reagents and conditions i, tert-butyldiphenylsilyl chlo-
ride, imid., DCM, 0 ꢁC to rt, 24 h (96%); ii, LiEt3BH, THF, 0 ꢁC to rt, 4 h (88%); iii, (a) Et3N,
MsCl, DCM, 0 ꢁC, 2 h; (b) NaH, PhSH, DMF, 0 ꢁC, 20 min, add mesylate, heat under
reflux, 4 h (81%); iv, (NH4)2MoO4, H2O2, EtOH, 0 ꢁC to rt, 24 h (48, 88%; 52, 86% from
54; 55, 86% from 53); v, conc. aq HCl, EtOH, rt, 1 h (47, 95%; 49, 95%); vi, NaH, THF,
The structures of the [2,3]-rearrangements products prepared in
this work had been established by oxidation of the products ob-
tained from the sulfides into the sulfones and by 1H NMR studies.
However, the homoallylic alcohol 52, prepared by rearrangement of
the sulfone 50, was crystalline. Its structure was confirmed un-
ambiguously by X-ray diffraction, see Fig. 2.12
n
5 min, nBu3SnCH2I, rt, 24 h (50, 83%; 51, 83%); vii, BuLi, THF, ꢀ78 ꢁC to ꢀ50 ꢁC, 24 h
(52, 65% using 2 equiv nBuLi; 53, 86%; 54, 7%).
As the structure of the rearranged sulfone 52 was now secure, it
was possible to confirm the structures assigned to the products in the
other series. Deprotection of the crystalline sulfone 52 gave the diol
56 in which the 2-(hydroxymethyl) and 6-(phenylsulfonylmethyl)
substituents must be cis to each other across the six-membered ring.
The same diol was prepared by deprotection of the product 27 from
rearrangement of the SEM-protected sulfone 26 so confirming the
structure of this product as shown. S-Oxidation and deprotection of
the major product 53 from rearrangement of the sulfide 51 gave diol
57 that was distinguishable from its epimer 56 by NMR. Oxidation of
the major product 41 from rearrangement of the SEM-protected
sulfide 39 had given the sulfone 43 that was benzoylated to give the
benzoate 58. Deprotection gave the alcohol 59 and inversion of the
configuration at C3 via a Mitsunobu reaction with a final saponifica-
tion of both esters, also gave the diol 57, see Scheme 9. This sequence
confirmed the stereochemistry assigned to the rearrangement
product 41. The oxidations of the sulfides had related the structures of
the sulfides and sulfones within the series and so the structures of all
productswerenowconfirmed. Itwouldappearthatthe4-alkoxy-and
Fig. 2. An ORTEP projection of the [2,3]-rearrangement product 52 as established by X-
ray diffraction.12
4-silyloxy-2-(tributylstannylmethoxymethyl)-1,6-dimethyl-1-(phe-
nylsulfonylmethyl)cyclohexenes had rearranged to give the products
with the 6-(phenylsulfonylmethyl) and 2-(hydroxymethyl) sub-
stituents cis-disposed about the six-membered ring irrespective of
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T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
5
Scheme 9. Correlation of the products in the different series via the diols 56 and 57
Reagents and conditions i, TBAF, THF, rt, 24 h (83% from 52); ii, MgBr2, Et2O, nitro-
methane, rt, 1 h (76% from 27); iii, (a) (NH4)2MoO4, H2O2, EtOH, 0 ꢁC to rt, 24 h; (b)
TBAF, THF, rt, 24 h (69%); iv, PhCOCl, DMAP, py, rt, 3 h; v, MgBr2, Et2O, nitromethane, rt,
1 h; vi, (a) Ph3P, DIAD, THF, PhCO2H, 0 ꢁC, 4 h; (b) NaOH, MeOH, rt, 30 min (40% of 57
from 41).
the nature of the substituent or the configuration at C4. Moreover, the
analogous sulfides rearranged with the opposite stereoselectivity.
Scheme 10. Synthesis of a macrocyclic precursor of the phomactins Reagents and
conditions i, Cl2ZrCp2, AlMe3, DCM, rt, 2 d, 0 ꢁC, I2, THF, rt, 5 h (62%); ii, tBuMe2SiCl,
i
imid., rt, 24 h (96%); iii, Pr2NEt, py.SO3, DMSO, DCM, 0 ꢁC, 15 min (91%); iv, 62, tBuLi,
2.3. Synthesis of the core of the phomactins
THF, pentane, ꢀ78 ꢁC, 1 h, then add to Yb(OTf)3, THF, ꢀ78 ꢁC, 30 min, add to 63 in THF,
ꢀ78 ꢁC, 3 h (85%); v, BOMCl, iPr2NEt, nBu4NI, THF, rt, 16 h (82%); vi, AcOH, water, THF, rt,
2 d (91%); vii, Et3N, MsCl, THF, 0 ꢁC, 45 min, LiBr, THF, 0 ꢁC, 1 h (86%); viii, NaHMDS,
THF, 0 ꢁC, add via a syringe pump over 40 min, 0 ꢁC, 30 min (72%).
The tert-butyldiphenylsilyl protected diol 52 was selected for
incorporation into a synthesis of a macrocyclic precursor of pho-
mactin A 1 and was oxidized to the corresponding aldehyde 63. The
hydroxyheptadienyl iodide 61 was prepared from the alkyne 6013
using Negishi conditions14 and protected as its tert-butyldime-
thylsilyl ether 62. The addition of organometallic reagents gener-
ated from the vinyl iodide 62 to the aldehyde 63 was then
investigated. Initial studies with the vinyllithium reagent generated
from the iodide 62 using tert-butyllithium to effect the iodide-
lithium exchange, gave only modest yields of the adduct 64.
Slightly better yields were obtained if equimolar amounts of vinylic
iodide and tert-butyllithium were employed but any excess of tert-
butyllithium over the iodide resulted in a lower yield. The use of
three molar equivalents each of iodide 62 and tert-butyllithum gave
an optimised yield of 48%. These difficulties were attributed to the
sensitivity to base of the bg-unsaturated aldehyde 63. Slightly im-
proved yields were obtained when cerium(III) chloride15 or anhy-
drous zinc(II) bromide16 was added to the vinyllithium reagent
before addition to the aldehyde, but the best yield, 85%, was ach-
ieved using ytterbium(III) triflate,17,18 when a single adduct was
isolated that was subsequently shown to be the alcohol 64, see
Scheme 10. The stereoselectivity of this reaction may be due to the
organometallic reagent approaching the less hindered face of the
co-ordinated aldehyde away from the bulky tert-butyldiphenylsi-
lyloxy substituent, see Fig. 3.
Fig. 3. Stereoselectivity of addition to the aldehyde 63.
Following protection of the alcohol 64 as its benzyloxymethyl
(BOM) ether 65, selective removal of the tert-butyldimethylsilyl
group using acetic acid gave the alcohol 66. This was converted into
the bromide 67 via its mesylate, and an efficient cyclisation of the
bromide using sodium hexamethyldisilazide as base gave the
macrocycle 68 as a single epimer at C10. This was crystalline and its
structure was confirmed by X-ray diffraction, see Fig. 4.12 This X-ray
structure confirmed the stereoselectivity of the addition of the
vinylic organometallic reagent to the aldehyde 63 and established
Fig. 4. An ORTEP projection of the macrocyclic compound 68 as determined by X-ray
diffraction.12
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6
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
the configuration of the sulfone bearing stereogenic centre at C10,
see Scheme 10.
spectrometers with residual non-deuterated solvent as the in-
ternal standard. Only distinguishable peaks are reported for mi-
nor isomers in isomeric mixtures. IR spectra were recorded on an
ATI Mattson Genesis FTIR as thin films produced by evaporation
of a dichloromethane solution on sodium chloride plates unless
otherwise stated. Mass spectra were recorded on Fison VG Trio
2000 and Kratos Concept spectrometers. For compounds con-
taining tin only peaks corresponding to 120Sn are reported and
for bromine containing compounds 79Br. Chemical ionisation (CI)
was performed using ammonia. Chromatography refers to flash
column chromatography using Merck silica gel 60H (230e300
mesh). Tetrahydrofuran (THF) was dried and distilled from so-
dium metal using benzophenone as an indicator under an at-
mosphere of nitrogen. Dichloromethane was dried and distilled
from calcium hydride under an atmosphere of nitrogen. Ether
refers to diethyl ether, which was dried and distilled from so-
dium metal using benzophenone as an indicator under an at-
mosphere of nitrogen. Light petroleum refers to the fraction that
distilled between 40 and 60 ꢁC. Benzene and hexane were dried
over sodium metal. Butyllithium (1.6 M in hexanes) was titrated
against a solution of propan-2-ol in xylene with 2,20-bipyridine
as an indicator. Triethylamine and di-isopropylamine were dried
over potassium hydroxide pellets. Brine refers to saturated
aqueous sodium chloride.
3. Summary and conclusions
Macrocycle 68 has a structure that corresponds to the bicyclic
core structure of the phomactins. Indeed it corresponds to the in-
termediate 5 prepared earlier, apart from the protecting group at
C14 and the configuration at C2 (phomactin numbering), but is
more accessible as the chemistry outlined in Scheme 10 is ame-
nable to scale-up.
In the present work, it is of interest that the sulfones 26, 38 and
50, all rearranged with excellent stereoselectivity to give the prod-
ucts 27, 40, and 52, inwhich the 2-(hydroxymethyl) groups were cis-
disposed about the six-membered ring relative to the 6-(phenyl-
sulfonylmethyl) substituents as had been observed earlier for the
rearrangement of the phenylsulfonyl substituted alkynylmethyl
ether 2.5b In contrast the corresponding sulfides 29, 39 and 51
rearranged to give predominantly [2,3]-rearrangement products
in which the 2-(hydroxymethyl) and 6-(phenylsulfanylmethyl)
substituents were trans-disposed about the six-membered ring.
This remote substituent effect involving a reversal of the stereo-
selectivity of these rearrangement processes dependent on the ox-
idation state of the sulfur-containing substituent was not expected.
The stereoselectivity of the rearrangement of the sulfone 2 had
been explained in terms of deprotonation of the sulfone to give
a bis-lithiated intermediate following tinelithium exchange. It was
suggested that in this intermediate the migrating alkoxy group is co-
ordinated to the lithiated sulfone and so is directed to the same face
of the six-membered ring as the phenylsulfonylmethyl group. It
would appear that this process is also taking place during the
rearrangements of the phenylsulfones 26, 38 and 50, possibly via
transition structure 69, see Fig. 5. This explanation is consistent with
the need for 2 equiv of n-butyllithium for these rearrangements
4.2. Experimental procedures
4.2.1. Methyl 4-tert-butyldimethylsilyloxy-1,6-dimethyl-2-
methylenecyclohex-3-ene-1-carboxylate
(8). Triethylamine
(1.56 mL, 11.19 mmol) followed by tert-butyldimethylsilyl tri-
fluoromethanesulphonate (2.49 mL, 10.84 mmol) were added at
0
ꢁC to the enone 75a as a 75:25 mixture of epimers at C6 (1.42 g,
7.24 mmol) in dichloromethane (7 mL). After 20 h, dichloro-
methane (20 mL) was added and the mixture washed with satu-
rated aqueous sodium bicarbonate (10 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was dissolved in
ether, separated from the insoluble triethylammonium tri-
fluoromethanesulphonate and the solution concentrated under
reduced pressure. Chromatography of the residue on silica using 2%
ether in light petroleum as eluent gave the title compound 8 (1.45 g,
65%) as a colourless oil, a 75: 25 mixture of diastereoisomers, Rf¼0.7
þ
(10% ether in light petroleum) (Found:
C
M
Na, 333.1843.
17H30O3NaSi requires M, 333.1856); nmax/cmꢀ1 2955, 2931, 2858,
Fig. 5. Possible transition structures for the [2,3]-Wittig rearrangements.
1732, 1643, 1461, 1372, 1254, 1194, 1105, 1000, 890, 839 and 781; dH
(300 MHz, CDCl3) major epimer 5.47 (1H, s, 3-H), 4.71 and 4.49
(each 1H, s, 2-CH), 3.73 (3H, s, OCH3), 2.48 (1H, m, 6-H), 2.20 (1H, m,
5-H), 1.88 (1H, m, 5-H0), 1.22 (3H, s, 1-CH3), 0.95 [9H, s, Si(CH3)3],
0.88 (3H, d, J 7.0, 6-CH3) and 0.19 (6H, s, 2ꢂSiCH3); minor epimer
5.53 (1H, s, 3-H), 4.87 and 4.81 (each 1H, s, 2-CH), 3.65 (3H, s, 1-
OCH3), 1.44 (3H, s, 1-CH3) and 1.05 (3H, d, J 7.0, 6-CH3); dC
(75 MHz, CDCl3) 176.9, 174.8, 153.8, 153.2, 147.8, 146.6, 109.6, 108.4,
107.0, 106.2, 52.2, 51.8, 51.4, 48.8, 37.5, 37.0, 35.6, 34.7, 25.9, 25.9,
25.8, 22.4, 18.3, 17.8, 17.1, 16.3, ꢀ3.9, ꢀ4.0, ꢀ4.1 and ꢀ4.1; m/z (ESþ)
333 (Mþþ123, 100%).
For the sulfides, the rearrangements need just 1 equiv of n-
butyllithium and so deprotonation of the methylene group next to
the sulfide is not competing with tinelithium exchange. The ster-
eoselectivities of these rearrangements are consistent with the
participation of transition structures analogous to 70, see Fig. 5, in
which the new carbonecarbon bond formation is taking place by
axial attack on the carbonecarbon double-bond in the preferred
conformation of the six-membered ring in which most of the
substituents are equatorial. Analogous stereoselectivity has been
observed in other systems.19 In the case of sulfide 39, it may be that
steric hindrance due to the bulk of the protected 3-OH is also in-
volved as implicated in earlier cases.5c Solvent effects on the ster-
eoselectivities of these rearrangements were not investigated.
Further work is concerned with developing the chemistry of the
macrocycle 68 to complete a synthesis of phomactin A 1.5c,20
4.2.2. Methyl 2-hydroxymethyl-1,6-dimethyl-4-oxocyclohex-2-ene-
1-carboxylate (9). Aqueous Na2EDTA (95 mL, 0.0004 M) was added
to the silyl ether 8 (5.94 g,19 mmol) in acetonitrile (140 mL) and the
solution cooled to ꢀ10 ꢁC. Trifluoroacetone (19.1 mL, 213 mmol)
was added using a pre-cooled syringe followed by a mixture of
oxoneÒ (58.6 g, 95.3 mmol) and sodium bicarbonate (12.4 g,
147 mmol) over a period of 1 h. The suspension was stirred at
ꢀ10 ꢁC for 1.5 h then filtered, and the filtrate was extracted with
dichloromethane (4ꢂ100 mL), dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue on silica
using 30e90% ether in light petroleum gave the title compound 9
4. Experimental
4.1. General experimental procedures
1H and 13C NMR spectra were recorded on Varian Unity 500,
Varian Unity Inova 400 and Varian Unity Inova 300
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T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
7
(2.62 g, 68%) as
a
colourless oil,
a
75:25 mixture of di-
1088, 1048, 836 and 778; dH (300 MHz, CDCl3) 5.82 (1H, s, 3-H), 4.21
(1H, m, 4-H), 4.04 (2H, s, 2-CH2), 3.62 (3H, s, OCH3), 2.58 (1H, br s,
OH), 1.71e1.67 (3H, m, 6-H and 5-H2), 1.25 (3H, s, 1-CH3), 0.82 (3H,
d, J 6.9, 6-CH3), 0.86 [9H, s, SiC(CH3)3], 0.02 (6H, s, 2ꢂSiCH3); dC
(75 MHz, CDCl3) 174.9, 140.3, 128.9, 67.3, 64.4, 51.8, 48.2, 38.2, 37.2,
26.1, 21.4, 18.6, 17.0 and ꢀ5.3; m/z (CI) 346 (Mþþ18, 10%), 329 (3)
and 311 (100).
astereoisomers, Rf¼0.1 (30% ether in light petroleum) (Found:
MþþNH4, 230.1384. C11H20NO4 requires M, 230.1387); nmax/cmꢀ1
3437br, 2954, 2883, 1730, 1666, 1454, 1252, 1193, 1122 and 1070; dH
(300 MHz, CDCl3) major epimer 6.16 (1H, s, 3-H), 4.18 (2H, s, 2-CH2),
3.69 (3H, s, OCH3), 2.67 (1H, m, 6-H), 2.36 (1H, dd, J 15.5, 4.5, 5-H),
2.20 (1H, dd, J 15.5, 10.0, 5-H0), 1.27 (3H, s, 1-CH3) and 0.88 (3H, d, J
7.0, 6-CH3); minor epimer 3.66 (3H, s, OCH3), 1.38 (3H, s, 1-CH3) and
0.96 (3H, d, J 7.0, 6-CH3); dC (75 MHz, CDCl3) 199.6, 198.7, 175.0,
173.0, 165.7, 163.1, 125.7, 124.0, 63.1, 62.1, 52.9, 52.6, 50.4, 49.8, 42.4,
41.8, 39.0, 36.9, 20.9,16.9,16.3 and 16.0; m/z (CI) 230 (Mþþ18,100%)
and 213 (80).
4.2.5. Methyl
1,6-dimethyl-4-(2-trimethylsilylethoxy)methoxycyclohex-2-ene-1-
carboxylate (12). N,N-Di-isopropylethylamine (9.48 mL,
(1SR,4SR,6RS)-2-(tert-butyldimethylsilyloxymethyl)-
54.4 mmol) and (2-trimethylsilylethoxy)methyl chloride (4.82 mL,
27 mmol) were added to the alcohol 11 (5.96 g, 18 mmol) in DCM
(200 mL) at 0 ꢁC. The solution was allowed to warm to room
temperature and was stirred for 20 h. Water (100 mL) was added
and the aqueous phase extracted with EtOAc (4ꢂ200 mL). The or-
ganic extracts were washed with brine (100 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue on silica gel using 1e40% ether in light petroleum gave the
title compound 12 (6.7 g, 80%) as a clear oil, Rf¼0.66 (30% ether in
light petroleum) (Found: MþþNH4, 476.3228. C23H50O5Si2N re-
quires M, 476.3232); nmax/cmꢀ1 2944, 2867, 1735, 1462, 1249 and
1058; dH (300 MHz, CDCl3) 5.84 (1H, br s, 3-H), 4.78 and 4.75 (each
1H, d, J 7.1, OHCHO), 4.36 (1H, m, 4-H), 4.10 (1H, dt, J 14.0, 1.8, 2-CH),
3.95 (1H, ddd, J 14.0, 2.5, 1.8, 2-CH), 3.69 (3H, s, OCH3), 3.66 (2H, m,
OCH2), 2.27 (1H, m, 6-H), 1.90 (1H, m, 5-H), 1.42 (1H, td, J 13.0, 10.0,
5-H0), 1.23 (3H, s, 1-CH3), 0.97 (2H, m, CH2Si), 0.91 [9H, s, SiC(CH3)3],
0.86 (3H, d, J 7.0, 6-CH3), 0.05 (6H, s, 2ꢂSiCH3) and 0.03 (9H, s,
3ꢂSiCH3); dC (75 MHz, CDCl3) 176.5, 142.5, 124.1, 93.5, 72.5, 65.2,
63.3, 52.2, 49.7, 35.3, 33.6, 26.2, 18.7, 18.3, 17.0, 16.5, ꢀ1.2 and ꢀ5.2;
m/z (CI) 476 (Mþþ18, 8%), 459 (Mþþ1, 7%), 328 (10), 312 (22), 311
(100) and 90 (17).
4.2.3. Methyl 2-(tert-butyldimethylsilyloxymethyl)-1,6-dimethyl-4-
oxocyclohex-2-ene-1-carboxylate (10). Imidazole (6.3 g, 92 mmol)
followed by tert-butyldimethylsilyl chloride (10.4 g, 69 mmol) were
added to the alcohol 9 (9.77 g, 46 mmol) in DCM (340 mL) at 0 ꢁC
and the solution stirred at room temperature for 24 h. Saturated
aqueous ammonium chloride (340 mL) was added and the mixture
extracted into DCM (2ꢂ130 mL). The organic extracts were washed
with brine (200 mL), dried (MgSO4) and concentrated under re-
duced pressure. Chromatography of the residue on silica using
1e30 % ether in light petroleum as eluent gave the title compound
10 (13.81 g, 92%) as a colourless oil, a 75: 25 mixture of di-
astereoisomers, Rf¼0.46 (40% ether in light petroleum) (Found:
MþþH, 327.1989. C17H31O4Si requires M, 327.1986); nmax/cmꢀ1
2953, 2857, 1735, 1674, 1631, 1461, 1253, 1139, 1088, 838 and 780; dH
(300 MHz, CDCl3) major epimer 6.21 (1H, t, J 1.6, 3-H), 4.28 and 4.17
(each 1H, dd, J 17.0, 1.9, 2-CH), 3.74 (3H, s, OCH3), 2.72 (1H, m, 6-H),
2.44 (1H, dd, J 16.0, 4.0, 5-H), 2.29 (1H, dd, J 16.0, 10.0, 5-H0), 1.33
(3H, s, 1-CH3), 0.94 (3H, d, J 7.0, 6-CH3), 0.92 [9H, s, SiC(CH3)3], 0.07
(6H, s, 2ꢂSiCH3); minor epimer 6.24 (1H, m, 3-H), 4.33 and 4.22
(each 1H, dd, J 17.0, 1.6, 2-CH), 3.70 (3H, s, OCH3), 1.42 (3H, s, 1-CH3)
and 1.01 (3H, d, J 6.9, 6-CH3); dC (75 MHz, CDCl3) 199.3, 198.3, 174.8,
172.5, 165.3, 162.4, 125.5, 123.7, 63.4, 62.3, 52.6, 52.4, 50.2, 49.6,
42.6, 41.9, 39.1, 36.9, 26.0, 25.9, 21.0, 18.6, 16.9, 16.2, 16.0, ꢀ3.3 and
ꢀ5.3; m/z (ESþ) 327 (Mþþ1, 100).
4.2.6. (1SR,4SR,6RS)-1-Hydroxymethyl-2-(tert-butyldimethylsilylox-
ymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methoxycyclohex-
2-ene (14); general procedure for ester reduction. Lithium trie-
thylborohydride (1.0 M in THF, 45 mL, 45 mmol) was added to the
ester 12 (8.20 g, 18 mmol) in THF (140 mL) at 0 ꢁC and the solution
allowed to warm to room temperature and stirred for 4 h. Saturated
aqueous ammonium chloride (70 mL) was added and the mixture
diluted with EtOAc (50 mL). The aqueous phase was extracted with
ether (4ꢂ50 mL) and the organic extracts were washed with water
(70 mL) and brine (70 mL), then dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue on silica
with 10e50% ether in light petroleum as eluent gave the title
compound 14 (7.7 g, 82%), as a clear, viscous oil, Rf¼0.42 (30% ether
in light petroleum) (Found: MþþH, 431.3011. C22H47O4Si2 requires
M, 431.3015); nmax/cmꢀ1 3515br, 2944, 2866, 1659, 1464, 1382, 1250,
1054 and 836; dH (300 MHz, CDCl3) 5.85 (1H, s, 3-H), 4.82 and 4.77
(each 1H, d, J 7.0, OHCHO), 4.30 (1H, d, J 10.6, 2-CH), 4.28 (1H, m, 4-
H), 3.93 (1H, d, J 10.6, 2-CH0), 3.70e3.65 (2H, m, OCH2), 3.58 and
3.41 (each 1H, d, J 12.0, 1-CH), 3.27 (1H, br s, OH), 2.20 (1H, m, 6-H),
1.94 (1H, m, 5-H), 1.48 (1H, td, J 12.3, 10.5, 5-H0), 0.88e1.00 [14H, m,
CH2Si, 6-CH3 and SiC(CH3)3], 0.80 (3H, s, 1-CH3), 0.16 and 0.14 (each
3H, s, 2ꢂSiCH3) and 0.06 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 143.6,
126.0, 93.4, 72.6, 69.1, 65.2, 63.6, 41.5, 34.1, 26.3, 25.8,18.4,18.0,18.2,
15.8, ꢀ1.1 and ꢀ5.0.
4.2.4. Methyl (1SR,4SR,6RS)- and (1SR,4SR,6SR)-2-(tert-butyldime-
thylsilyloxymethyl)-4-hydroxy-1,6-dimethylcyclohex-2-ene-1-
carboxylates (11) and (13). Cerium(III) chloride heptahydrate
(14.63 g, 39 mmol) was added to the enone 10 (11.55 g, 35 mmol) in
methanol (345 mL) at room temperature and the suspension stirred
until the solid had dissolved. The solution was cooled to ꢀ78 ꢁC,
sodium borohydride (1.93 g, 51 mmol) was added portionwise and
the solution was stirred for 2 h. The reaction mixture was allowed
to warm to room temperature and concentrated under reduced
pressure. DCM (50 mL) and silica powder were added to the ge-
latinous residue until saturation of the solution occurred and the
mixture was concentrated under reduced pressure then loaded
directly onto silica gel. Chromatography using 40% ether in light
petroleum as eluent gave the title compound 11 (7.35 g, 63%) as
a colourless oil Rf¼0.26 (30% ether in light petroleum) (Found: Mþ,
328.2057. C17H32O4Si requires M, 328.2064); nmax/cmꢀ1 3415, 2952,
2859, 1731, 1464, 1383, 1253, 1140, 1109, 1033, 839 and 778; dH
(300 MHz, CDCl3) 5.84 (1H, s, 3-H), 4.34 (1H, m, 4-H), 4.05 and 3.96
(each 1H, dt, J 14.0, 1.0, 2-CH), 3.63 (3H, s, OCH3), 2.41 (1H, br s, OH),
2.22 (1H, m, 6-H), 1.86 (1H, ddd, J 12.9, 6.5, 2.6, 5-H), 1.40 (1H, td, J
12.9, 10.3, 5-H0), 1.18 (3H, s, 1-CH3), 0.86 [9H, s, SiC(CH3)3], 0.82 (3H,
d, J 6.9, 6-CH3), 0.02 (6H, s, 2ꢂSiCH3); dC (75 MHz, CDCl3) 176.6,
141.9, 126.2, 67.5, 63.1, 52.1, 49.6, 36.4, 35.4, 26.1, 18.6, 16.8, 16.5,
ꢀ5.2 and ꢀ5.3; m/z (CI) 329 (Mþþ1, 80%), 312 (10), 311 (42), 271
(18), 197 (100) and 90 (20). The second fraction was the title com-
pound 13 (2.1 g, 18%) as colourless oil, Rf¼0.19 (30% ether in light
petroleum) (Found: Mþ, 328.2058. C17H32O4Si requires M,
328.2064); nmax/cmꢀ1 3445, 2952, 2857,1730,1462,1375,1251,1141,
4.2.7. (1SR,4SR,6RS)-1-(Phenylsulfanylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methox-
ycyclohex-2-ene
(15);
general
procedure
for
thioether
synthesis. Triethylamine (3.62 mL, 26.0 mmol) and meth-
anesulfonyl chloride (1.45 mL, 14.86 mmol) were added to the al-
cohol 14 (3.2 g, 7.43 mmol) in DCM (130 mL) at 0 ꢁC and the solution
stirred at 0 ꢁC for 2 h. When complete consumption of the starting
material was observed by TLC, the solution was diluted with EtOAc
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8
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
(130 mL) and saturated aqueous sodium bicarbonate (70 mL). The
aqueous phase was extracted with EtOAc (4ꢂ40 mL) and the or-
ganic extracts were washed with saturated aqueous sodium bi-
carbonate (70 mL) and brine (70 mL), then dried (MgSO4) and
concentrated under reduced pressure to afford the mesylate as
a pale orange oil. Benzenethiol (3.50 mL, 34 mmol) was added to
sodium hydride (60% dispersion in mineral oil, 1.36 g, 34 mmol) in
DMF (120 mL), at 0 ꢁC. The solution was stirred for 20 min at 0 ꢁC
and the mesylate in DMF (100 mL) was added via a cannula. The
solution was heated under reflux for 20 h, allowed to cool to room
temperature, diluted with EtOAc (60 mL) and washed with aqueous
sodium hydroxide (60 mL). The aqueous phase was extracted with
EtOAc (3ꢂ50 mL) and the organic extracts were washed with water
(60 mL) and brine (60 mL), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue on silica using
1e20% ether in light petroleum as eluent gave the title compound 15
(2.84 g, 73%) as a pale yellow, viscous oil, Rf¼0.25 (15% ether in light
petroleum) (Found: Mþ, 522.3003. C28H50O3SSi2 requires M,
522.3003); nmax/cmꢀ1 2954, 2932, 2883, 2860, 1470, 1252, 1150,
1101,1035, 859, 838 and 776; dH (300 MHz, CDCl3) 7.16e7.40 (5H, m,
ArH), 5.92 (1H, s, 3-H), 4.82 (2H, s, 4-OCH2O), 4.20e4.38 (3H, m, 4-
H and 2-CH2), 3.70 (2H, m, OCH2), 3.14 and 3.08 (each 1H, d, J 12.2,
1-CH), 2.18 (1H, m, 6-H), 1.91 and 1.51 (each 1H, m, 5-H), 1.16 (3H, s,
1-CH3), 0.84e1.02 [14H, m, CH2Si, 6-CH3 and SiC(CH3)3] and 0.08
(15H, m, 5ꢂSiCH3); dC (75 MHz, CDCl3) 143.6, 137.94, 129.4, 129.1,
126.2, 126.0, 93.4, 72.6, 65.2, 63.6, 41.5, 41.2, 34.1, 33.3, 26.3, 21.4,
18.4, 15.8, ꢀ1.1 and ꢀ5.0; m/z (CI) 522 (Mþ, 2%) and 73 (100).
m, ArH), 5.95 (1H, s, 3-H), 4.81 and 4.78 (each 1H, d, J 7.0, OHCHO),
4.40 (1H, m, 4-H), 4.28 and 4.20 (each 1H, d, J 12.7, 2-CH), 3.75e3.60
(3H, m,1-CH and OCH2), 3.26 (1H, d, J 14.4,1-CH0), 2.74 (1H, m, 6-H),
1.96 (1H, m, 5-H), 1.48 (1H, td, J 12.7, 10.3, 5-H0), 1.05e0.95 (8H, m,
1-CH3, SiCH2 and 6-CH3) and 0.06 [9H, s, 3ꢂSiCH3); dC (75 MHz,
CDCl3) 143.3, 141.6, 133.9, 130.9, 129.6, 127.8, 93.6, 72.3, 65.3, 64.8,
60.9, 42.1, 34.2, 33.2, 21.7, 18.3, 16.2 and ꢀ1.1; m/z (CI) 458 (Mþþ18,
100%).
4.2.10. (1SR,4SR,6RS)-2-Bromomethyl-1,6-dimethyl-1-(phenyl-
sulfonylmethyl)-4-(2-trimethylsilylethoxy)methoxycyclohex-2-ene
(18). Triethylamine (0.25 mL, 1.82 mmol) and methanesulfonyl
chloride (0.1 mL, 1.1 mmol) were added to the alcohol 17 (400 mg,
0.91 mmol) in THF (5 mL) at 0 ꢁC and the solution was stirred at 0 ꢁC
for 45 min. Lithium bromide (325 mg, 3.7 mmol) in THF (3 mL) was
added and the mixture stirred at 0 ꢁC for 1 h. The mixture was
partitioned between pentane (15 mL) and ice-cold water (10 mL).
The organic phase was extracted with pentane (2ꢂ15 mL) and the
organic extracts washed with saturated aqueous sodium bi-
carbonate (5 mL) and brine (5 mL) then dried (Na2SO4) and con-
centrated under reduced pressure. Chromatography of the residue
on silica using 20% ether in light petroleum as eluent gave the title
compound 18 (392 mg, 86%) as a clear oil, Rf¼0.25 (20% ether in light
petroleum); nmax/cmꢀ1 2952, 2883, 1580, 1440, 1311, 1245, 1139,
1099, 1029, 838 and 749; dH (300 MHz, CDCl3) 7.93 (2H, d, J 7.0,
ArH), 7.69e7.61 (3H, m, ArH), 6.37 (1H, s, 3-H), 4.82 and 4.79 (each
1H, d, J 7.0, OHCHO), 4.37 (1H, br t, J 8.0, 4-H), 4.12 and 4.25 (each
1H, d, J 11.4, 2-CH), 3.70 (2H, m, OCH2), 3.43 and 3.30 (each 1H, d, J
14.9, 1-CH), 2.65 (1H, m, 6-H), 1.98 (1H, ddd, J 12.5, 7.0, 1.7, 5-H), 1.57
(1H, td, J 12.5, 9.3, 5-H0), 1.29 (3H, s, 1-CH3), 1.02 (5H, m, CH2Si and
6-CH3), 0.04 (9H, s, 3ꢂSi(CH3); m/z (CI) 520 (Mþþ18, 4%) and 90
(100).
4.2.8. (1SR,4SR,6RS)-1-(Phenylsulfonylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methox-
ycyclohex-2-ene
(16);
general
procedure
for
sulfide
oxidation. Hydrogen peroxide (30% in water, 14.25 mL) was added
to the sulfide 15 (2.50 g, 4.78 mmol) and ammonium molybdate
(8.86 g, 7.17 mmol) in ethanol (500 mL) at 0 ꢁC over a period of
5 min. The suspension was stirred for a further 5 min at 0 ꢁC and at
room temperature for 24 h. Water (100 mL) was added and the
aqueous phase extracted into ether (6ꢂ100 mL). The organic ex-
tracts were washed with aqueous FeSO4 (100 mL) and brine
(100 mL), dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on silica using 5e30% ether in light
petroleum as eluent gave the title compound 16 (1.88 g, 71%) as
4.2.11. (1SR,4SR,6RS)-2-[(2E)-3,7-Dimethylocta-2,6-dienyloxy]
me t hyl- 1, 6- di me t hyl -1-(p h e nyl sul fo nylme t hyl )- 4-(2 -
trimethylsilylethoxy)methoxycyclohex-2-ene (19). A suspension of
sodium hydride (60% dispersion in mineral oil, 13 mg, 0.32 mmol)
and tetra-n-butylammonium iodide (45 mg, 0.12 mmol) in THF
(0.15 mL) was cooled to 0 ꢁC and the alcohol 17 (130 mg, 0.29 mmol)
in THF (0.35 mL) was added. The suspension was stirred for 20 min
prior to the dropwise addition of 15-crown-5 (0.06 mL, 0.29 mmol)
and geranyl bromide (0.05 mL, 0.29 mmol) in THF (0.30 mL). The
brown suspension was allowed to warm to room temperature and
was stirred for 16 h. Saturated aqueous ammonium chloride (5 mL)
was added and the aqueous phase extracted with EtOAc (4ꢂ10 mL).
The organic extracts were washed with brine (10 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue using ether in light petroleum as eluent gave the
title compound 19 (150 mg, 80%) as a clear oil, Rf¼0.41 (30% ether in
light petroleum) (Found: MþþNH4, 594.3656. C32H56O5NSSi re-
quires M, 594.3648); nmax/cmꢀ1 2930, 2877, 1667, 1448, 1376, 1315,
1249, 1150, 1093, 980, 838 and 748; dH (300 MHz, CDCl3) 7.93 (2H,
m, ArH), 7.54e7.68 (3H, m, ArH), 5.85 (1H, s, 3-H), 5.31 (1H, td, J 6.7,
1.2, 20-H), 5.10 (1H, t, J 6.7, 60-H), 4.81 and 4.78 (each 1H, d, J 7.0,
OHCHO), 4.35 (1H, m, 4-H), 4.30 and 4.02 (each 1H, d, J 12.3, 2-CH),
3.97 (2H, m, 10-H2), 3.70 (2H, m, OCH2), 3.52 and 3.34 (each 1H, d, J
14.8, 1-CH), 2.68 (1H, m, 6-H), 1.94e2.13 (5H, m, 40-H2, 5-H and 50-
H2), 1.70 (3H, s, 30-CH3), 1.67 (3H, s, 70-CH3), 1.62 (3H, s, 80-H3), 1.58
(1H, m, 5-H0) 1.17 (3H, s, 1-CH3), 1.02 (3H, d, J 6.7, 6-CH3), 0.98 (2H,
m, CH2Si), 0.07 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 142.2, 140.5,
140.4, 133.7, 131.9, 130.3, 129.5, 127.7, 124.2, 121.0, 93.6, 72.9, 72.03,
66.7, 65.3, 60.9, 42.3, 39.9, 33.8, 33.4, 26.7, 25.9, 21.7, 18.3, 18.0, 16.8,
16.5 and ꢀ1.1; m/z (CI) 594 (Mþþ18, 10%) and 90 (100).
a clear, viscous oil, Rf¼0.25 (20% ether in light petroleum); nmax
/
cmꢀ1 2952, 2886, 2861, 1727, 1466, 1364, 1315, 1252, 1150, 1087,
1035, 838 and 776; dH (300 MHz, CDCl3) 7.93 (2H, m, ArH),
7.54e7.70 (3H, m, ArH), 5.79 (1H, s, 3-H), 4.82 and 4.78 (each 1H, d, J
7.0, OHCHO), 4.45 (1H, d, J 12.0, 2-CH), 4.33 (1H, m, 4-H), 4.29 (1H,
d, J 12.0, 2-CH0), 3.68 (2H, m, OCH2), 3.51 and 3.35 (each 1H, d, J 14.8,
1-CH), 2.67 (1H, m, 6-H), 1.99 and 1.61 (each 1H, m, 5-H), 1.20 (3H, s,
1-CH3), 0.98 (5H, m, CH2Si and 6-CH3), 0.88 [9H, s, SiC(CH3)3], 0.07
(15H, s, 5ꢂCH3); dC (75 MHz, CDCl3) 142.8, 142.2, 133.7, 129.5, 127.6,
126.6, 93.5, 71.9, 65.9, 65.2, 61.0, 42.1, 33.8, 33.5, 26.2, 22.2, 18.5,
18.3, 16.3, ꢀ1.1 and ꢀ5.1; m/z (CI) 572 (Mþþ18, 3%) and 90 (100).
4.2.9. (1SR,4SR,6RS)-1-(Phenylsulfonylmethyl)-2-hydroxymethyl-
1,6-dimethyl-4-(2-trimethylsilylethoxy)methoxycyclohex-2-ene (17);
general procedure for silyl ether deprotection using fluoride. Tetra-n-
butylammonium fluoride (1.0 M in THF, 1.59 mL, 1.59 mmol) was
added to the tert-butyldimethylsilyl ether 16 (200 mg, 0.36 mmol)
in THF (10.5 mL) at room temperature and the solution was stirred
for 16 h. The reaction mixture was concentrated under reduced
pressure and the residue added directly to silica. Elution with
20e80% ether in light petroleum gave the title compound 17
(135 mg, 85%), Rf¼0.10 (40% ether in light petroleum) (Found:
MþþNH4, 458.2402. C22H40O5NSSi requires M, 458.2396); nmax
/
cmꢀ1 3469, 2950, 2882, 1583, 1449, 1309, 1247, 1148, 1093, 1029,
4 . 2 .12 . M e t h y l ( Z ) - 5 - t e r t - b u t y l d i p h e n y l s i l y l o x y - 3 -
838 and 749; dH (300 MHz, CDCl3) 7.93 (2H, m, ArH), 7.54e7.69 (3H,
phenylsulfanylpent-2-enoate (21). Sodium methoxide (15 mg,
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
9
0.27 mmol) was added to the alkynyl ester 20 (2.0 g, 5.5 mmol) and
benzenethiol (720 mg, 6.5 mmol) in methanol (15 mL) at room
temperature. The solution was stirred for 16 h, filtered through
a silica pad and concentrated under reduced pressure. Chroma-
tography of the residue on silica using 20% ether in light petroleum
as eluent gave the title compound 21 (2.21 g, 85%) as a clear oil,
Rf¼0.32 (20% ether in light petroleum) (Found: MþþH, 477.1928.
(5 mL) and extracted with EtOAc (10 mL). The aqueous phase was
extracted with EtOAc (3ꢂ10 mL) and the organic extracts were
washed with brine (10 mL), dried (Na2SO4) and concentrated under
reduced pressure. IBX (310 mg, 1.1 mmol) was added to the residue
in DMSO (1 mL) and, after 3 h at room temperature, the reaction
mixture was diluted with water (5 mL), filtered through CeliteÒ and
extracted into ether (3ꢂ15 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. Chromatog-
raphy of the residue on silica using 20% ether in light petroleum as
eluent gave the title compound 24 (143 mg, 72%) as a clear oil,
Rf¼0.20 (15% ether in light petroleum) (Found: MþþH, 541.2515.
C
28H33O3SSi requires M, 477.1920); nmax/cmꢀ1 2951, 2858, 2253,
1697, 1711, 1581, 1474, 1216, 1110, 805 and 752; dH (300 MHz, CDCl3)
7.61 (4H, m, ArH), 7.40 (11H, m, ArH), 5.99 (1H, s, 2-H), 3.80 (3H, s,
OCH3), 3.60 (2H, t, J 6.5, 5-H2), 2.41 (2H, t, J 6.5, 4-H2) and 1.01 [9H, s,
SiC(CH3)3]; m/z (CI) 494 (Mþþ18, 31%), 477 (Mþþ1, 100%).
C34H41O2SSi requires M, 541.2518); dH (300 MHz, CDCl3) 7.79 (4H,
m, ArH), 7.37e7.50 (11H, m, ArH), 5.85 (1H, s, 2-H), 4.67 and 4.40
(each 1H, s, 20-CH), 4.00 (2H, t, J 6.6, 5-H2), 3.24 (2H, m, 4-H2), 2.92
(1H, t, J 4.7, 10-H), 2.01 (2H, m, 30-H2), 1.28e1.70 (6H, m, 40-H2, 50-H2
and 60-H2) and 1.12 [9H, s, SiC(CH3)3]; m/z (CI) 541 (Mþþ1, 40%), 448
(52) and 137 (100).
4.2.13. (Z)-5-tert-Butyldiphenylsilyloxy-3-phenylsulfanylpent-2-en-
1-ol (22). Di-isobutylaluminium hydride (1.0 M in THF, 10.5 mmol,
10.5 mL) was added dropwise to the ester 21 (2.0 g, 4.2 mmol) in
THF (40 mL) at ꢀ78 ꢁC. After 3 h at ꢀ78 ꢁC, saturated aqueous so-
dium potassium tartrate (40 mL) was added and the mixture
extracted into ether (3ꢂ50 mL). The organic extracts were washed
with water (30 mL) and brine (30 mL), dried (MgSO4) and con-
centrated under reduced pressure. Chromatography of the residue
on silica gel using 40% ether in light petroleum as eluent gave the
title compound 22 (2.54 g, 88%) as a clear oil, Rf¼0.30 (45% ether in
light petroleum); nmax/cmꢀ1 3425, 2951, 2858, 2253, 1637, 1473,
1383, 1217, 1110, 805 and 752; dH (300 MHz, CDCl3) 7.70 (4H, m,
ArH), 7.20e7.50 (11H, m, ArH), 6.20 (1H, t, J 6.3, 2-H), 4.43 (2H, d, J
6.3, 1-H2), 3.85 (2H, t, J 6.4, 5-H2), 2.49 (2H, t, J 6.4, 4-H2), 1.81 (1H,
br s, OH) and 1.10 [9H, s, SiC(CH3)3]; dC (75 MHz, CDCl3) 136.4, 135.9,
134.6, 134.1, 133.5, 130.3, 129.9, 129.3, 127.9, 126.8, 62.4, 61.0, 40.5,
27.1 and 19.5; m/z (CI) 466 (Mþþ18, 32%), 431 (44), 193 (68), 175
(100).
4.2.16. (1SR,4SR,6RS)-2-[(Z)-5-tert-Butyldiphenylsilyloxy-3-
phenylsulfanylpent-2-enyloxy]methyl-1,6-dimethyl-1-(phenyl-
sulfonylmethyl)-4-(2-trimethylsilylethoxy)methoxycyclohex-2-ene
(25). The alcohol 22 (265 mg, 0.59 mmol) in THF (0.50 mL) was
added to sodium hydride (60% dispersion in mineral oil, 24 mg,
0.59 mmol), tetra-n-butylammonium iodide (82 mg, 0.22 mmol)
and THF (0.4 mL) at 0 ꢁC and the suspension was stirred for 20 min.
15-Crown-5 (0.12 mL, 0.59 mmol) and the bromide 18 (245 mg,
0.49 mmol) in THF (0.40 mL) were added and the suspension was
allowed to warm to room temperature and was stirred for 16 h.
Saturated aqueous ammonium chloride (5 mL) and ethyl acetate
(5 mL) were added and the aqueous phase extracted with EtOAc
(4ꢂ5 mL). The organic extracts were washed with brine (10 mL),
dried (Na2SO4) and concentrated under reduced pressure. Chro-
matography of the residue using ether in light petroleum gave the
title compound 25 (301 mg, 0.35 mmol 71%) as a clear oil, Rf¼0.22
(25% ether in light petroleum) (Found: MþþNa, 893.3744.
4.2.14. Cyclohex-1-enylmethyl (Z)-5-tert-butyldiphenylsilyloxy-3-
phenylsulfanylpent-2-enyl ether (23). A suspension of sodium hy-
dride (60% dispersion in mineral oil, 110 mg, 2.6 mmol) and tetra-n-
butylammonium iodide (330 mg, 0.89 mmol) in THF (1 mL) was
cooled to 0 ꢁC. The alcohol 22 (1.00 g, 2.2 mmol) in THF (2 mL) was
added the suspension was stirred for 20 min prior to the dropwise
addition of 15-crown-5 (0.53 mL, 2.68 mmol) and 1-
bromomethylcyclohex-1-ene (585 mg, 3.3 mmol) in THF (1.5 mL).
The brown suspension was allowed to warm to room temperature
and was stirred for 24 h. Saturated aqueous ammonium chloride
(5 mL) was added and the aqueous phase extracted with EtOAc
(4ꢂ5 mL). The organic extracts were washed with water (5 mL) and
brine (5 mL), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue on silica with 10% ether in
light petroleum as eluent gave the title compound 23 (1.12 g,
9.1 mmol 93%) as a clear oil, Rf¼0.25 (10% ether in light petroleum)
(Found: MþþNH4, 560.3023. C34H46O2NSSi requires M, 560.3018);
nmax/cmꢀ1 2951, 2858, 2253, 1650, 1470, 1381, 1210, 1110, 1060, 804
and 750; dH (300 MHz, CDCl3) 7.65 (4H, m, ArH), 7.20e7.47 (11H, m,
ArH), 6.18 (1H, t, J 6.0, 20-H), 5.77 (1H, m, 2-H), 4.30 (2H, d, J 6.0, 10-
H2), 3.91 (2H, s, 1-CH2), 3.84 (2H, t, J 6.5, 50-H2), 2.49 (2H, t, J 6.5, 40-
H2), 2.08 (4H, m, 3-H2 and 6-H2), 1.63 (4H, m, 4-H2 and 5-H2) and
1.10 [9H, s, SiC(CH3)3]; dC (75 MHz, CDCl3) 138.1, 137.2, 135.1, 134.0,
132.5, 130.4, 129.4, 129.3, 128.8, 125.6, 122.0, 111.0, 79.1, 67.4, 59.5,
43.2, 27.1, 26.3, 26.1, 23.2 and 19.5; m/z (CI) 560 (Mþþ18, 51%), 431
(50) and 175 (100).
C
49H66O6NaS2Si2 requires M, 893.3732); nmax/cmꢀ1 3064, 2947,
2864, 1471, 1442, 1380, 1313, 1248, 1148, 1102, 1034, 934, 834 and
743; dH (300 MHz, CDCl3) 7.90 (2H, d, J 8.2, ArH), 7.20e7.72 (18H, m,
ArH), 6.09 (1H, t, J 6.0, 20-H), 5.88 (1H, s, 3-H), 4.82 and 4.75 (each
1H, d, J 7.0, OHCHO), 4.39 (1H, m, 4-H), 4.38 (1H, d, J 12.0, 2-CH),
4.27 (2H, d, J 6.0, 10-H2), 4.07 (1H, d, J 12.0, 2-CH0), 3.79 (2H, t, J 6.3,
50-H2), 3.69 (2H, m, OCH2), 3.50 and 3.32 (1H, d, J 14.7, 1-CH), 2.70
(1H, m, 6-H), 2.25 (2H, t, J 6.3, 40-H2), 2.00 and 1.62 (each 1H, m, 5-
H), 1.15 (3H, s, 1-CH3), 0.92e1.10 [14H, m, 6-CH3, CH2Si, SiC(CH3)3]
and 0.08 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 142.1, 140.4, 135.8,
134.3, 134.0, 133.8, 133.7, 130.4, 130.3, 129.9, 129.5, 129.3, 128.6,
127.9, 127.7, 126.8, 93.5, 73.4, 72.0, 68.1, 65.3, 62.4, 60.9, 42.3, 40.4,
33.9, 33.5, 27.1, 21.9, 19.5, 18.4, 16.5 and ꢀ1.1; m/z (ESþ) 893
(Mþþ23, 100%).
4.2.17. (1SR,4SR,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfonylmethyl)-4-(2-(trimethylsilylethoxy)me-
thoxycyclohex-2-ene (26); general procedure for stannane
synthesis. Sodium hydride (60% dispersion in mineral oil, 52 mg,
1.29 mmol) was added to the alcohol 17 (406 mg, 0.92 mmol) in THF
(7.5 mL) and the suspension stirred 5 min. Iodomethyl(tributyl)
stannane (0.38 mL, 1.29 mmol) was added and the mixture stirred
for 24 h. Water (10 mL) was added and the mixture extracted with
ether (4ꢂ10 mL). The organic extracts were washed with brine
(10 mL), dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on silica with 20% ether in light
petroleum as eluent gave the title compound 26 (534 mg,
0.72 mmol, 78%) as a clear oil, Rf¼0.32 (20% ether in light petro-
leum); nmax/cmꢀ1 2954, 2921, 2872, 1459, 1374, 1245, 1092, 1035,
855 and 834; dH (300 MHz, CDCl3) 7.95 (2H, d, J 6.9, ArH) 7.60 (3H,
m, ArH), 5.79 (1H, s, 3-H), 4.82 and 4.78 (1H, d, J 7.0, OHCHO), 4.35
4.2.15. (Z)-5-tert-Butyldiphenylsilyloxy-1-(2-methylenecyclohexyl)-
3-phenylsulfanylpent-2-en-1-one (24). n-Butyllithium (1.6
M in
THF, 0.56 mL, 0.92 mmol) was added to the diallyl ether 23 (200 mg,
0.37 mmol) in THF (2 mL) at ꢀ60 ꢁC dropwise over 10 min and the
yellow solution stirred at ꢀ60 ꢁC for 0.5 h. Saturated aqueous
ammonium chloride (1 mL) was added and, after being allowed to
warm to room temperature, the mixture was diluted with water
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

10
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
(1H, m, 4-H), 4.30 and 3.87 (each 1H, d, J 12.3, 2-CH), 3.71 (1H, J
10.2, OHCHSn), 3.70 (2H, m, OCH2), 3.58 (1H, d, J 10.2, OHCH0Sn),
3.51 and 3.29 (each 1H, d, J 14.8, 1-CH), 2.65 (1H, m, 6-H), 1.98 (1H,
ddd, J 12.9, 5.4, 2.2, 5-H), 1.60 (1H, m, 5-H0), 1.43 (6H, m,
3ꢂSnCH2CH2), 1.29 (6H, m, 3ꢂSnCH2CH2CH2), 1.17 (3H, s, 1-CH3),
1.00e1.80 (20H, m, CH2Si, 3ꢂSnCH2, 3ꢂCH3 and 6-CH3) and 0.05
(9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 142.2,140.7,133.6,129.4,129.3,
127.6, 93.5, 79.2, 71.9, 65.2, 61.7, 60.9, 42.3, 33.8, 33.4, 29.3, 27.5,
21.8, 18.3, 16.4, 13.9, 9.1 and ꢀ1.2.
oil, 60 mg, 1.47 mmol) and iodomethyl(tributyl)stannane (0.44 mL,
1.47 mmol), after chromatography on silica using 15% ether in light
petroleum, afforded the title compound 29 (525 mg, 0.74 mmol,
69%), as a clear oil, Rf¼0.28 (15% ether in light petroleum); nmax
/
cmꢀ1 2954, 2921, 2872, 1461, 1374, 1246, 1092, 1035, 859 and 836;
dH (300 MHz, CDCl3) 7.16e7.40 (5H, m, ArH), 5.93 (1H, s, 3-H), 4.82
(2H, s, OCH2O), 4.21e4.35 (3H, m, 4-H and 2-CH2), 3.71 (1H, d, J
10.0, OHCHSn), 3.70 (2H, m, OCH2), 3.57 (1H, d, J 10.0, OHCH0Sn),
3.13 and 3.08 (each 1H, d, J 12.1, 1-CH), 2.18 (1H, m, 6-H), 1.90 and
1.53 (each 1H, m, 5-H), 1.43 (6H, m, 3ꢂSnCH2CH2), 1.28 (6H, m,
3ꢂSnCH2CH2CH2), 1.16 (3H, s, 1-CH3), 0.90 (20H, m, 3ꢂCH2Sn,
CH2Si, 3ꢂCH3 and 6-CH3) and 0.05 (9H, s, 3ꢂSiCH3); dC (75 MHz,
CDCl3) 144.6, 138.4, 128.7, 128.6, 126.7, 125.5, 93.8, 77.9, 69.3, 65.2,
61.6, 41.7, 41.4, 33.2, 30.6, 29.6, 27.6, 20.3, 18.4, 15.6, 14.0, 9.3 and
ꢀ1.1.
4.2.18. (2RS,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-(2-trimethylsilylethoxy)me-
thoxycyclohexane (27); general procedure for sulfone re-
arrangement. n-Butyllithium (1.6 M in THF, 0.19 mL, 0.30 mmol)
was added to the sulfone 26 (107 mg, 0.14 mmol) in THF (2.0 mL) at
ꢀ78 ꢁC dropwise over 10 min and the solution allowed to warm to
ꢀ50 ꢁC and stirred at this temperature for 24 h. Saturated meth-
anolic ammonium chloride (0.5 mL) was added and, after being
allowed to warm to room temperature, the mixture was diluted
with water (10 mL) and EtOAc (10 mL). The aqueous layer was
extracted with EtOAc (4ꢂ10 mL) and the organic extracts were
washed with brine (10 mL), dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue on silica with 50%
ether in light petroleum as eluent gave the methyl ether 28 (39 mg,
60%), as a colourless oil, dH (300 MHz, CDCl3) 7.94 (2H, d, J 7.0, ArH),
7.72e7.54 (3H, m, ArH), 5.85 (1H, s, 3-H), 4.81 and 4.79 (each 1H, d, J
6.9, OHCHO), 4.37 (1H, m, 4-H), 4.25 and 3.97 (each 1H, d, J 12.0, 2-
CH), 3.68 (2H, m, OCH2), 3.49 and 3.35 (each 1H, d, J 15.0, 1-CH),
3.31 (3H, s, OCH3), 2.69 (1H, m, 6-H), 1.96 and 1.60 (each 1H, m, 5-
H), 1.14 (3H, s, 1-CH3), 1.05e0.90 (5H, m, CH2Si and 6-CH3) and 0.08
(9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 142.1, 140.1, 133.7, 130.5, 129.5,
127.7, 93.6, 75.3, 72.1, 65.3, 60.9, 58.1, 42.3, 33.9, 33.4, 21.7, 18.3, 16.4
and ꢀ1.1. The second fraction was the title compound 27 (23 mg,
35%) as a pale yellow oil, Rf¼0.14 (40% ether in light petroleum)
(Found: MþþNH4, 472.2545. C23H42O5NSSi requires M, 472.2547);
nmax/cmꢀ1 3512, 2951, 2890,1639,1447,1380,1313,1249,1150,1029,
935, 859, 837 and 749; dH (300 MHz, CDCl3) 7.95 (2H, d, J 7.0, ArH),
7.60e7.55 (3H, m, ArH), 5.33 and 5.11 (each 1H, s, 1-CH), 4.81 and
4.72 (each 1H, d, J 6.9, OHCHO), 4.01 (1H, dd, J 11.3, 4.3, 2-CH), 3.96
(1H, dd, J 11.3, 5.0, 2-CH0), 3.71e3.54 (3H, m, 3-H and OCH2), 3.54
and 3.45 (each 1H, d, J 15.0, 6-CH), 2.50 (1H, ddd, J 9.5, 5.0, 4.3, 2-H),
2.05e1.85 (2H, m, 4-H and 5-H), 1.51 (1H, q, J 11.7, 4-H0), 1.23 (3H, s,
6-CH3), 0.93 (5H, m, CH2Si and 5-CH3) and 0.06 (9H, s, 3ꢂSiCH3); dC
(75 MHz, CDCl3) 149.3, 142.8, 133.7, 129.6, 127.6, 110.3, 93.9, 78.9,
65.9, 63.5, 63.1, 47.2, 45.6, 36.5, 36.4, 19.7, 18.3, 16.9 and ꢀ1.2; m/z
(CI) 472 (Mþþ18, 22%), 354 (36), 337 (66) and 294 (100).
4.2.20. (2SR,3SR,5RS,6SR)- and (2RS,3SR,5RS,6SR)-5,6-dimethyl-2-
hydroxymethyl-1-methylene-6-(phenylsulfanylmethyl)-3-(2-
trimethylsilylethoxy)methoxycyclohexane (30) and (31); general
procedure for sulfide rearrangement. n-Butyllithium (1.6 M in THF,
0.39 mL, 0.62 mmol) was added to the sulphide 29 (400 mg,
0.56 mmol) in THF (8.0 mL) at ꢀ78 ꢁC dropwise over 10 min and the
solution allowed to warmed to ꢀ50 ꢁC and stirred at this temper-
ature for 24 h. Saturated methanolic ammonium chloride (0.5 mL)
was added and, after being allowed to warm to room temperature,
the mixture was diluted with water (10 mL) and EtOAc (10 mL). The
aqueous phase was extracted with EtOAc (4ꢂ10 mL) and the or-
ganic extracts washed with brine (10 mL), dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the
residue on silica using 30% ether in light petroleum as eluent gave
the title compound 31 (23 mg, 0.056 mmol, 10%) as a pale yellow oil,
Rf¼0.23 (30% ether in light petroleum); nmax/cmꢀ1 3482br, 3470,
2951, 2885, 1635, 1537, 1479, 1379, 1266, 1095, 1054, 1025, 940, 836
and 738; dH (300 MHz, CDCl3) 7.39 and 7.31 (each 2H, m, ArH), 7.21
(1H, t, J 7.4, ArH), 5.18 and 4.98 (each 1H, s, 1-CH), 4.85 and 4.74
(each 1H, d, J 6.7, OHCHO), 3.99 (2H, m, 2-CH and 3-H), 3.80e3.50
(3H, m, 2-CH0 and OCH2), 3.28 (1H, d, J 12.1, 6-CH), 3.19 (1H, br s,
OH), 3.10 (1H, d, J 12.1, 6-CH0), 2.49 (1H, m, 2-H), 2.10e1.85 (2H, m,
4-H, 5-H), 1.52 (1H, m, 4-H0), 1.12 (3H, s, 6-CH3), 0.95e0.80 (5H, m,
CH2Si and 5-CH3) and 0.06 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3)
150.7, 138.6, 129.6, 129.2, 126.1, 108.7, 93.8, 80.0, 66.0, 63.2, 46.7,
44.7, 43.4, 36.8, 35.4, 20.5, 18.3, 16.2 and ꢀ1.2; m/z (ES) 445
(Mþþ23, 100%). The second fraction was the title compound 30
(192 mg, 0.45 mmol, 81%) as a pale yellow oil, Rf¼0.22 (30% ether in
light petroleum); nmax/cmꢀ1 3483br, 3472, 2951, 2881, 1634, 1537,
1479, 1379, 1249, 1095, 1054, 1025, 936, 836 and 738; dH (300 MHz,
CDCl3) 7.39 (2H, m, ArH), 7.30 (3H, m, ArH), 5.09 and 5.00 (each 1H,
s, 1-CH), 4.74 and 4.68 (each 1H, d, J 6.7, OHCHO), 4.10 (1H, q, J 4.6,
3-H), 4.00 (1H, m, 2-CH), 3.69 (3H, m, 2-CH0 and OCH2), 3.29 and
3.12 (each 1H, d, J 12.1, 6-CH), 2.77 (1H, t, J 6.9, OH), 2.63 (1H, m, 2-
H), 1.97 (2H, m, 4-H, 5-H), 1.71 (1H, m, 4-H0), 1.19 (3H, s, 6-CH3), 0.93
(5H, m, CH2Si and 5-CH3) and 0.05 (9H, s, 3ꢂSiCH3); dC (75 MHz,
CDCl3) 148.4, 138.1, 130.0, 129.1, 126.2, 122.3, 93.9, 75.5, 66.0, 62.5,
46.4, 44.7, 44.3, 36.4, 32.6, 22.8, 18.4, 17.5 and ꢀ1.2; m/z (ES) 445
(Mþþ23, 100%).
Following the general procedure (4.2.8), the sulfide 31 (23 mg,
0.05 mmol), ammonium molybdate (11 mg, 0.008 mmol) and hy-
drogen peroxide (30% in water, 0.19 mL), after chromatography on
silica with 50% ether in light petroleum, gave the title compound 27
(21 mg, 0.046 mmol, 86%) as a colourless oil, with spectroscopic
data identical to those of the sample prepared from the stannane
26.
4.2.19. (1SR,4SR,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfanylmethyl)-4-(2-trimethylsilylethoxy)me-
thoxycyclohex-2-ene (29). Tetra-n-butylammonium fluoride (1.0 M
in THF, 4.71 mL, 4.71 mmol) was added to the silyl ether 15 (559 mg,
1.07 mmol) in THF (30.0 mL) at room temperature and the solution
stirred 16 h. Ethyl acetate (30 mL) and water (30 mL) were added
and the aqueous phase extracted with ethyl acetate (3ꢂ10 mL). The
organic extracts were washed with water (20 mL) and brine
(20 mL), dried (Na2SO4) and concentrated under reduced pressure
to give the corresponding alcohol as a pale yellow oil used without
further purification. Following the general procedure (4.2.7), this
alcohol in THF (8.5 mL), sodium hydride (60% dispersion in mineral
4.2.21. (2SR,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-(2-trimethylsilylethoxy)me-
thoxycyclohexane (32). Following the general procedure (4.2.8), the
sulfide 30 (43 mg, 0.10 mmol), ammonium molybdate (20 mg,
0.015 mmol) in ethanol (1.0 mL) and hydrogen peroxide (30% so-
lution in water, 0.35 mL), after chromatography on silica using 50%
ether in light petroleum as eluent, gave the title compound 32
(40 mg, 0.087 mmol, 86%) as a clear, viscous oil, Rf¼0.17 (40% ether
in light petroleum) (Found: MþþNH4, 472.2545. C23H42O5NSSi re-
quires M, 472.2547); dH (300 MHz, CDCl3) 7.92 (2H, d, J 7.0, ArH),
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
11
7.62 (3H, m, ArH), 5.17 and 4.98 (each 1H, s, 1-CH), 4.69 and 4.61
(each 1H, d, J 6.7, OHCHO), 4.09 (1H, q, J 3.7, 3-H), 3.82 (1H, dd, J 10.7,
8.1, 2-CH), 3.55e3.73 (3H, m, 2-CH0 and OCH2), 3.53 and 3.22 (each
1H, d, J 14.5, 6-CH), 2.77 (1H, br s, OH), 2.47 (1H, m, 2-H), 2.09 (1H,
m, 5-H), 1.92 and 1.72 (each 1H, dt, J 15.2, 3.7, 4-H), 1.42 (3H, s, 6-
CH3), 0.98 (5H, m, CH2Si and 5-CH3) and 0.06 (9H, s, 3ꢂSiCH3); dC
(75 MHz, CDCl3) 149.0, 141.9, 133.7, 130.2, 127.6, 109.7, 93.6, 79.3,
66.6, 63.8, 62.3, 47.6, 44.6, 36.4, 35.9, 20.5, 18.8, 17.8 and ꢀ1.2; m/z
(CI) 472 (Mþþ18, 2%), 354 (4), 337 (6), 294 (8) and 90 (100).
2.99 (1H, br s, OH), 2.27 (1H, m, 6-H), 1.78 (2H, m, 5-H2), 0.90 [14H,
m, CH2Si, 6-CH3 and SiC(CH3)3], 0.75 (3H, s, 1-CH3), 0.14 (6H, s,
2ꢂSiCH3) and 0.05 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 143.1, 127.1,
92.9, 72.6, 68.7, 65.1, 63.1, 42.4, 34.9, 26.5, 24.2, 18.4, 18.0, 18.2, 16.4,
ꢀ1.1 and ꢀ5.1; m/z (CI) 432 (Mþþ1, 2%), 300 (8), 283 (7), 168 (79)
and 151 (100).
4.2.24. (1SR,4RS,6RS)-1-(Phenylsulfanylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methox-
ycyclohex-2-ene (36). Following the general procedure (4.2.7), the
alcohol 35 (2.0 g, 4.64 mmol) in DCM (80 mL), triethylamine
(2.26 mL, 16.31 mmol) and methanesulfonyl chloride (0.91 mL,
9.29 mmol) gave the mesylate as a pale orange oil. This was con-
verted into the thioether 36 following the general procedure using
sodium hydride (850 mg, 21.25 mmol) in DMF (75 mL) and ben-
zenethiol (2.19 mL, 21.25 mmol) with the mesylate added in DMF
(60 mL). After heating the reaction mixture under reflux for 4 h,
chromatography on silica using 1e20% ether in light petroleum as
eluent gave the title compound 36 (1.82, g, 3.48 mmol, 75%) as a pale
yellow, viscous oil, Rf¼0.21 (15% ether in light petroleum) (Found:
4.2.22. Methyl (1SR,4RS,6RS)-2-(tert-butyldimethylsilyloxymethyl)-
4-hydroxy-1,6-dimethylcyclohex-2-ene-1-carboxylate (34). The al-
cohol 11 (2.32 g, 7.07 mmol) and triphenylphosphine (2.78 g,
10.60 mmol) in THF (10 mL) were added to a solution of DIAD
(2.09 mL, 10.6 mmol) and benzoic acid (1.29 g, 10.60 mmol) in THF
(10 mL) at 0 ꢁC and the mixture stirred for 4 h at 0 ꢁC. After con-
centration under reduced pressure, chromatography of the residue
on silica using 15% ether in light petroleum as eluent afforded
benzoate 33 as a colourless oil; dH (300 MHz, CDCl3) 8.10 (2H, d, J 7.1,
ArH), 7.58 (1H, t, J 7.1, ArH), 7.46 (2H, t, J 7.1, ArH), 6.05 (1H, d, m, 3-
H), 5.56 (1H, m, 4-H), 4.21 and 4.06 (each 1H, dt, J 15.0, 1.0, 2-CH),
3.76 (3H, s, OCH3), 2.60 (1H, m, 6-H), 1.87 (2H, m, 5-H2), 1.23 (3H, s,
1-CH3), 0.92 [12H, s, 6-CH3 and SiC(CH3)3] and 0.08 (6H, s,
2ꢂSiCH3). The benzoate was taken up into methanol containing
sodium hydroxide (5% NaOH, 8.0 mL) and the mixture stirred for
30 min. After concentration under reduced pressure, the residue
was dissolved in ether (100 mL) and the ethereal solution washed
with water (20 mL) and brine (20 mL) then dried (Na2SO4), and
concentrated under reduced pressure. Chromatography of the
residue on silica using 35% ether in light petroleum as eluent gave
the title compound 34 (2.18 g, 94%) as a clear oil, Rf¼0.25 (30% ether
in light petroleum) (Found: Mþ, 328.2058. C17H32O4Si requires M,
328.2064); nmax/cmꢀ1 3410, 2953, 2934, 2859, 1731, 1464, 1384,
1253, 1139, 1102, 1034, 839 and 779; dH (300 MHz, CDCl3) 5.96 (1H,
br d, J 5.4, 3-H), 4.20 (1H, m, 4-H), 4.12 and 3.95 (each 1H, d, J 14.4,
2-CH), 3.68 (3H, s, OCH3), 2.42 (1H, m, 6-H), 1.79 (1H, br s, OH), 1.68
(2H, m, 5-H2), 1.13 (3H, s, 1-CH3), 0.90 [9H, s, SiC(CH3)3], 0.86 (3H, d,
J 6.9, 6-CH3) and 0.05 (6H, s, 2ꢂSiCH3); dC (75 MHz, CDCl3) 174.2,
141.5, 128.5, 66.1, 64.4, 51.1, 46.1, 38.2, 36.3, 25.0, 21.2, 19.0, 17.0 and
ꢀ5.2; m/z (CI) 346 (Mþþ18, 10%) and 311 (100).
MþþNH4, 540.3355: C28H54O3NSSi2 requires M, 540.3357); nmax
/
cmꢀ1 2953, 2930, 2886, 2859, 1618, 1583, 1474, 1359, 1251, 1152,
1097, 1030, 932, 837, 776 and 738; dH (300 MHz, CDCl3) 7.52 (2H, d, J
7.0, ArH), 7.18e7.20 (3H, m, ArH), 5.98 (1H, br d, J 4.6, 3-H), 4.81 (2H,
s, OCH2O), 4.32 and 4.27 (each 1H, d, J 13.8, 2-CH), 4.17 (1H, m, 4-H),
3.75e3.65 (2H, m, OCH2), 3.20 and 3.12 (1H, d, J 12.0, 1-CH), 2.18
(1H, m, 6-H), 1.85-1.65 (2H, m, 5-H2), 1.10 (3H, s,1-CH3), 1.02 (2H, m,
CH2Si), 0.93 [9H, s, SiC(CH3)3], 0.91 (3H, d, J 6.3, 6-CH3), 0.09 (3H, s,
SiCH3) and 0.07 (12H, s, 4ꢂSiCH3); dC (75 MHz, CDCl3) 145.6, 138.2,
129.3, 129.1, 125.9, 123.3, 93.3, 68.8, 65.1, 63.8, 41.8, 41.2, 33.2, 30.7,
26.2, 20.3,18.6, 18.4, 15.4, ꢀ1.1, ꢀ5.0 and ꢀ5.2; m/z (CI) 540 (Mþþ18,
6%) and 375 (100).
4.2.25. (1SR,4RS,6RS)-1-(Phenylsulfonylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methox-
ycyclohex-2-ene (37). Following the general procedure (4.2.8), the
sulfide 36 (887 mg, 1.70 mmol), ammonium molybdate (3.14 mg,
2.54 mmol) in ethanol (175 mL) and hydrogen peroxide (30% so-
lution in water, 5.06 mL), after chromatography on silica using
5e30% ether in light petroleum as eluent, gave the title compound
37 (687 mg, 1.24 mmol, 73%) as a clear, viscous oil, Rf¼0.25 (20%
ether in light petroleum) (Found: MþþNH4, 572.3264.
4.2.23. (1SR,4RS,6RS)-1-Hydroxymethyl-2-(tert-butyldimethylsily-
loxymethyl)-1,6-dimethyl-4-(2-trimethylsilylethoxy)methox-
ycyclohex-2-ene (35). N,N-Di-isopropylethylamine (2.28 mL,
13.10 mmol) and SEM-chloride (1.27 mL, 7.18 mmol) were added to
the alcohol 34 (2.15 g, 6.54 mmol) in DCM (30 mL) at 0 ꢁC and the
reaction mixture was allowed to warm to room temperature then
stirred for 2 d. Water (50 mL) was added and the aqueous phase
was extracted with EtOAc (2ꢂ100 mL). The organic extracts were
washed with water (60 mL), brine (60 mL) and dried (MgSO4) then
concentrated under reduced pressure. Lithium triethylborohydride
(1.0 M in THF,19.62 mL,19.62 mmol) was added to the SEM-ether in
THF (20 mL) at 0 ꢁC and the solution allowed to warm to room
temperature then stirred for 4 h. Saturated aqueous ammonium
chloride (20 mL) was added, and the mixture was diluted with
EtOAc (40 mL) then stirred at room temperature for 1 h. The
aqueous phase was extracted into ether (440 mL) and the organic
extracts were washed with water (70 mL) and brine (70 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue on silica using 25% ether in light petroleum gave
the title compound 35 (2.09 g, 4.85 mmol, 74%) as a clear, viscous oil,
Rf¼0.40 (30% ether in light petroleum); nmax/cmꢀ1 3515br, 2943,
2866, 1464, 1382, 1249, 1096, 1052 and 834; dH (300 MHz, CDCl3)
5.89 (1H, br d, J 4.2, 3-H), 4.81 and 4.74 (each 1H, d, J 7.4, OHCHO),
4.30 (1H, d, J 10.9, 2-CH), 4.10 (1H, m, 4-H), 3.95 (1H, d, J 10.9, 2-
CH0), 3.68 (2H, m, OCH2), 3.58 and 3.35 (each 1H, d, J 13.2, 1-CH),
C
28H54O5NSSi2 requires M, 572.3256); nmax/cmꢀ1 2952, 2931, 2887,
2859, 1616, 1467, 1448, 1315, 1251, 1150, 1033, 837, 776 and 745; dH
(300 MHz, CDCl3) 7.91 (2H, d, J 7.0, ArH), 7.33-7.75 (3H, m, ArH), 5.74
(1H, br d, J 2.9, 3-H), 4.78 (2H, s, OCH2O), 4.26 (1H, d, J 12.7, 2-CH),
4.22 (1H, m, 4-H), 4.08 (1H, d, J 12.7, 2-CH0), 3.64 (2H, m, OCH2), 3.62
and 3.44 (each 1H, d, J 14.5, 1-CH), 2.92 (1H, m, 6-H), 1.91 (2H, m, 5-
H2), 1.39 (3H, s, 1-CH3), 0.98 (2H, t, J 8.5, CH2Si), 0.97 (3H, d, J 7.0, 6-
CH3), 0.82 [9H, s, SiC(CH3)3], 0.05 (12H, s, 4ꢂSiCH3) and 0.02 (3H, s,
SiCH3); dC (75 MHz, CDCl3) 142.4, 136.8, 133.5, 129.4, 127.7, 125.7,
93.6, 69.6, 65.7, 65.3, 63.5, 41.8, 33.4, 33.2, 26.1, 21.1, 18.4, 15.7, ꢀ1.1
and ꢀ5.2; m/z (CI) 572 (Mþþ18, 30%), 407 (68) and 268 (100).
4.2.26. (1SR,4RS,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfonylmethyl)-4-(2-trimethylsilylethoxy)me-
thoxycyclohex-2-ene (38). Following the general procedure (4.2.9),
desilylation of the silyl ether 37 (654 mg, 1.18 mmol) in THF (30 mL)
using tetra-n-butylammonium fluoride (1.0 M in THF, 5.16 mL,
5.16 mmol) gave the corresponding alcohol that was dissolved in
THF (10 mL). O-Alkylation was ahieved following the general pro-
cedure (4.2.17) using sodium hydride (66 mg, 1.65 mmol, 60% dis-
persion in mineral oil) and iodomethyl(tributyl)stannane (0.48 mL,
1.61 mmol) to give, after chromatography on silica using 15% ether
in light petroleum as eluent, the title compound 38 (669 mg,
0.90 mmol, 76%) as a clear oil, Rf¼0.20 (40% ether in light
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

12
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
petroleum); nmax/cmꢀ1 2955, 2918, 2872, 1460, 1374, 1241, 1096,
1035, 855 and 834; dH (300 MHz, CDCl3) 7.95 (2H, d, J 6.9, ArH),
7.65e7.52 (3H, m, ArH), 5.78 (1H, d, J 3.2, 3-H), 4.79 (2H, s, OCH2O),
4.21 (1H, m, 4-H), 3.90 (2H, s, 2-CH2), 3.68 (2H, t, J 8.5, OCH2), 3.65
and 3.59 (each 1H, d, J 10.2, OHCHSn), 3.46 and 3.44 (each 1H, d, J
15.0, 1-CH), 2.92 (1H, m, 6-H), 1.90 (2H, m, 5-H2), 1.60e1.35 (6H, m,
3ꢂSnCH2CH2), 1.40e1.20 (6H, m, 3ꢂSnCH2CH2CH2), 1.30 (3H, s, 1-
CH3), 0.81e1.05 (20H, m, 3ꢂCH2Sn, CH2Si, 3ꢂCH3 and 6-CH3) and
0.06 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 142.4, 141.3, 133.5, 129.4,
127.8, 127.5, 93.5, 78.8, 69.3, 63.0, 62.0, 42.0, 33.2, 32.8, 29.4, 29.1,
27.5, 21.1, 18.4, 14.0, 10.9, 9.1 and ꢀ1.1.
silica with 50% ether in light petroleum, gave the title compound 40
(21 mg, 0.046 mmol, 86%) as a colourless oil, with spectroscopic
data identical to those of the sample prepared from the stannane
38.
4.2.29. (2SR,3RS,5RS,6SR)- and (2RS,3RS,5RS,6SR)-5,6-dimethyl-2-
hydroxymethyl-1-methylene-6-(phenylsulfanylmethyl)-3-(2-
trimethylsilylethoxy)methoxycyclohexane (41) and (42). Following
the general procedure (4.2.20), the sulphide 39 (524 mg,
0.73 mmol) in THF (10 mL) and n-butyllithium (1.6 M in THF,
0.51 mL, 0.81 mmol), after chromatography on silica using 30%
ether in light petroleum as eluent gave the title compound 42
(23 mg, 0.051 mmol, 7%) as a pale yellow oil, Rf¼0.25 (30% ether in
light petroleum) (Found: MþþNa, 445.2203. C23H38O3NaSSi re-
quires M, 445.2203); nmax/cmꢀ1 3470, 2951, 2881, 1634, 1479, 1535,
1375,1249,1095,1054,1025, 936, 836 and 738; dH (300 MHz, CDCl3)
7.38 (2H, d, J 6.9, ArH), 7.28 (3H, m, ArH), 5.10 and 4.99 (each 1H, s,
1-CH), 4.85 and 4.69 (each 1H, d, J 6.9, OHCHO), 3.90e3.60 (5H, m,
2-CH2, 3-H and OCH2), 3.40 and 3.09 (each 1H, d, J 11.9, 6-CH), 2.80
(1H, br s, OH), 2.20 (1H, dt, J 10.3, 4.1, 2-H), 2.00 (3H, m, 4-H2 and 5-
H), 1.20 (3H, s, 6-CH3), 0.99 (2H, t, J 8.2, CH2Si), 0.80 (3H, d, J 7.2, 5-
CH3), 0.06 (9H, s, 3ꢂSiCH3); m/z (ES) 445 (Mþþ23, 100%). The
second fraction was the title compound 41 (281 mg, 0.62 mmol, 81%)
as a pale yellow oil, Rf¼0.22 (30% ether in light petroleum) (Found:
4.2.27. (1SR,4RS,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfanylmethyl)-4-(2-trimethylsilylethoxy)me-
thoxycyclohex-2-ene (39). Following the general procedure (4.2.9),
desilylation of the silyl ether 36 (900 mg, 1.72 mmol) in THF (50 mL)
using tetra-n-butylammonium fluoride (1.0 M in THF, 7.58 mL,
7.58 mmol) gave the corresponding alcohol as a pale yellow oil; dH
(300 MHz, CDCl3) 7.40e7.15 (5H, m, ArH), 6.04 (1H, d, J 4.7, 3-H),
4.81 (2H, s, OCH2O), 4.30 (1H, dd, J 13.6, 5.4, 2-CH), 4.22 (1H, d, J
13.6, 6.6, 2-CH0), 4.15 (1H, m, 4-H), 3.65 (2H, m, OCH2), 3.21 and 3.15
(each 1H, d, J 11.9, 1-CH), 2.58 (1H, br s, OH), 2.39 (1H, m, 6-H),
1.85e1.60 (2H, m, 5-H2), 1.10 (3H, s, 1-CH3), 0.98 (2H, m, CH2Si), 0.91
(3H, d, J 6.9, 6-CH3) and 0.06 (9H, s, 3ꢂSiCH3). This was dissolved in
THF (15 mL) and O-alkylation was achieved following the general
procedure (4.2.17) using sodium hydride (97 mg, 2.37 mmol, 60%
dispersion in mineral oil) and iodomethyl(tributyl)stannane
(0.71 mL, 2.37 mmol) to give, after chromatography on silica using
15% ether in light petroleum as eluent, the title compound 39
(905 mg, 1.27 mmol, 74%), as a clear oil, Rf¼0.26 (15% ether in light
petroleum) (Found: MþþNa, 735.3260. C35H64O3NaSSi120Sn re-
quires M, 735.3265); nmax/cmꢀ1 2954, 2921, 2872, 1461, 1374, 1247,
1035, 859 and 836; dH (300 MHz, CDCl3) 7.13e7.40 (5H, m, ArH),
5.91 (1H, d, J 4.4, 3-H), 4.80 (2H, s, OCH2O), 4.17 (1H, m, 4-H), 4.13
and 3.85 (each 1H, d, J 12.6, 2-CH), 3.61e3.79 (4H, m, OCH2Sn and
OCH2), 3.18 (2H, s, 1-CH2), 2.35 (1H, m, 6-H), 1.75 (2H, m, 5-H2), 1.50
(6H, m, 3ꢂSnCH2CH2), 1.31 (6H, m, 3ꢂSnCH2CH2CH2), 1.10 (3H, s, 1-
CH3), 0.81e1.05 (20H, m, 3ꢂCH2Sn, CH2Si, 3ꢂCH3 and 6-CH3) and
0.04 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 143.6, 138.3, 129.2, 129.0,
126.4, 125.8, 93.5, 77.7, 69.0, 65.2, 61.9, 41.7, 41.4, 33.2, 30.6, 29.4,
27.6, 20.3, 18.4, 15.6, 14.0, 9.3 and ꢀ1.1; m/e (ES) 735 (Mþþ23, 48%)
and 565 (100).
MþþNa, 445.2203. C23H38O3NaSSi requires M, 445.2203); nmax
/
cmꢀ1 3483br, 2951, 2882, 1635, 1584, 1480, 1438, 1380, 1249, 1095,
1054, 1025, 836 and 738; dH (300 MHz, CDCl3) 7.38 (2H, d, J 6.9,
ArH), 7.24 (3H, m, ArH), 5.15 and 5.04 (each 1H, s, 1-CH), 4.75 and
4.69 (each 1H, d, J 6.9, OHCHO), 3.99 (1H, dd, J 11.4, 4.3, 2-CH), 3.91
(1H, dd, J 11.4, 4.4, 2-CH0), 3.75e3.55 (3H, m, 3-H and OCH2), 3.43
and 3.09 (each 1H, d, J 11.9, 6-CH), 2.82 (1H, br s, OH), 2.39 (1H, dt, J
10.3, 4.1, 2-H), 2.04 (1H, m, 5-H), 1.95 (1H, m, 4-H), 1.84 (1H, ddd, J
13.2, 5.0, 3.0, 4-H0), 1.22 (3H, s, 6-CH3), 0.99 (1H, t, J 8.5, CH2Si), 0.92
(3H, d, J 7.2, 5-CH3) and 0.06 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3)
147.7, 137.8, 130.0, 129.0, 126.2, 111.9, 94.0, 76.4, 66.0, 62.3, 47.0,
44.8, 44.3, 37.1, 35.5, 22.9,18.5, 16.6 and ꢀ1.2; m/z (ES) 445 (Mþþ23,
100%).
4.2.30. (2SR,3RS,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-(2-trimethylsilylethoxy)me-
thoxycyclohexane (43). Following the standard procedure (4.2.8),
the sulfide 41 (214 mg, 0.50 mmol), ammonium molybdate
(100 mg, 0.075 mmol) in ethanol (5 mL) and hydrogen peroxide
(30% solution in water, 1.74 mL) after chromatography on silica
using 50% ether in light petroleum as eluent gave the title com-
pound 43 (208 mg, 0.46 mmol, 84%) as a clear, viscous oil, Rf¼0.20
(40% ether in light petroleum); dH (300 MHz, CDCl3) 7.87 (2H, d, J
7.5, ArH), 7.63 (1H, t, J 7.5, ArH), 7.52 (2H, t, J 7.5, ArH), 5.12 and 5.07
(each 1H, s, 1-CH), 4.70 and 4.62 (each 1H, d, J 6.9, OHCHO), 3.80
(2H, m, 2-CH2), 3.70e3.45 (3H, m, 3-H and OCH2), 3.57 and 3.28
(each 1H, d, J 14.4, 6-CH), 2.91 (1H, br t, J 5.9, OH), 2.25 (1H, m, 2-H),
2.10 (1H, m, 5-H), 1.82 (2H, m, 4-H2), 1.42 (3H, s, 6-CH3), 0.94 (1H, t, J
8.5, CH2Si), 0.86 (3H, d, J 7.2, 5-CH3) and 0.01 (9H, s, 3ꢂSiCH3); dC
(75 MHz, CDCl3) 145.9, 141.6, 133.8, 129.5, 128.1, 113.0, 94.1, 75.8,
66.0, 63.9, 61.5, 47.3, 44.0, 37.7, 35.7, 22.7, 18.3, 15.9 and ꢀ1.2.
4.2.28. (2RS,3RS,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-(2-trimethylsilylethoxy)me-
thoxycyclohexane (40). Following the general procedure (4.2.18),
the sulfone 38 (353 mg, 0.475 mmol) in THF (8 mL) and n-butyl-
lithium (1.6 M in THF, 0.64 mL, 1.02 mmol), after chromatography
on silica using 50% ether in light petroleum as eluent, gave the title
compound 40 (80 mg, 0.18 mmol, 37%) as a pale yellow oil, Rf¼0.17
(40% ether in light petroleum) (Found: MþþNH4, 472.2545.
C
23H42O5NSSi requires M, 472.2547); nmax/cmꢀ1 3512, 2951, 2890,
1639, 1447, 1380, 1313, 1249, 1150, 1029, 935, 859, 837 and 749; dH
(300 MHz, CDCl3) 7.97 (2H, d, J 6.9, ArH), 7.64 (3H, m, ArH), 5.31 and
5.01 (each 1H, s, 1-CH), 4.70 (2H, s, OCH2O), 4.09 (1H, m, 3-H), 3.94
(1H, dd, J 11.0, 8.1, 2-CH), 3.79 (1H, dd, J 11.0, 6.0, 2-CH0), 3.75-3.50
(2H, m, OCH2), 3.49 (2H, s, 6-CH2), 2.72 (1H, m, 2-H), 2.18 (1H, m, 5-
H), 1.89 (1H, ddd, J 14.4, 6.2, 4.4, 4-H), 1.62 (1H, ddd, J 14.4, 9.6, 3.6,
4-H0), 1.37 (3H, s, 6-CH3), 0.99 (2H, t, J 8.5, CH2Si), 0.93 (3H, d, J 6.7,
5-CH3), 0.05 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 149.0, 142.5,
133.3, 129.9, 127.9, 109.9, 93.6, 79.1, 66.0, 63.5, 62.9, 47.5, 45.0, 36.0,
35.9, 20.2, 18.5, 17.3 and ꢀ0.7; m/z (CI) 472 (Mþþ18, 2%), 354 (4),
337 (6), 294 (4) and 90 (100).
4.2.31. Methyl (1SR,4SR,6RS)-2-(tert-butyldimethylsilyloxymethyl)-
4-tert-butyldiphenylsilyloxy-1,6-dimethylcyclohex-2-ene-1-
carboxylate (44). Imidazole (15.62 g, 228 mmol), tert-butyldiphe-
nylsilyl chloride (47.46 mL, 182 mmol) and DMAP (7.21 g, 59 mmol)
were added to the alcohol 11 (30.00 g, 91 mmol) in DCM (600 mL) at
0 ꢁC and the solution stirred at room temperature for 24 h. Saturated
aqueous ammonium chloride (300 mL) was added and the mixture
extracted into DCM (2ꢂ150 mL). The organic extracts were washed
with water (200 mL) and brine (200 mL), then dried (MgSO4),
and concentrated under reduced pressure. Chromatography of the
Following the general procedure (4.2.8), the sulfide 42 (23 mg,
0.05 mmol), ammonium molybdate (11 mg, 0.008 mmol) and hy-
drogen peroxide (30% in water, 0.19 mL), after chromatography on
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T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
13
residue on silica using 10% ether in light petroleum as eluent gave
the title compound 44 (49.90 g, 88 mmol, 96%) as a colourless oil,
Rf¼0.65 (20% ether in light petroleum) (Found: MþþNa, 589.3136.
hydrogen carbonate (20 mL) and brine (20 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue on silica using 40% ether in light petroleum as eluent gave
the title compound 47 (771 mg, 1.49 mmol, 95%) as a clear oil,
Rf¼0.24 (40% ether in light petroleum) (Found: MþþNH4, 534.2841.
C
33H50O4Si2Na requires M, 589.3140); nmax/cmꢀ1 2937, 2857, 1732,
1665, 1590, 1465, 1431, 1251, 1106, 1057, 838 and 778; dH (300 MHz,
CDCl3) 7.74 (4H, m, ArH), 7.42 (6H, m, ArH), 5.87 (1H, br s, 3-H), 4.46
(1H, m, 4-H), 4.10 and 3.92 (each 1H, dt, J 14.1,1.8, 2-CH), 3.66 (3H, s,
OCH3), 2.10 (1H, m, 6-H),1.70e1.50 (2H, m, 5-H2),1.22 (3H, s,1-CH3),
1.12 and 0.96 [each 9H, s, SiC(CH3)3], 0.79 (3H, d, J 6.9, 6-CH3) and
0.04 (6H, s, SiCH3); dC (75 MHz, CDCl3) 176.7, 140.8, 136.1, 134.8,
129.8, 127.8, 126.8, 69.2, 63.0, 52.1, 49.6, 36.5, 35.3, 27.3, 26.2, 19.5,
18.7, 16.9, 16.5 and ꢀ5.2; m/z (ESþ) 589 (Mþþ23, 100%).
C32H44O2SSiN requires M, 534.2857); dH (300 MHz, CDCl3) 7.75 (4H,
m, ArH), 7.45 (6H, m, ArH), 7.28 (4H, m, ArH), 7.20 (1H, m, ArH), 5.88
(1H, br s, 3-H), 4.45 (1H, m, 4-H), 4.12 (2H, br s, 2-CH2), 3.12 and
3.07 (each 1H, d, J 11.9, 1-CH), 1.99 (1H, m, 6-H), 1.70e1.60 (3H, m,
OH and 5-H2), 1.12 [9H, s, SiC(CH3)3], 1.10 (3H, s, 1-CH3) and 0.85
(3H, d, J 6.9, 6-CH3); dC (75 MHz, CDCl3) 143.0, 137.1, 136.2, 136.1,
134.8, 134.7, 132.1, 129.9(2), 129.6, 129.2, 127.(2), 126.3, 69.3, 63.8,
41.5, 41.4, 37.0, 33.2, 27.3, 21.3, 19.5 and 15.8; m/z (CI) 534 (Mþþ18,
4%) and 261 (100).
4.2.32. (1SR,4SR,6RS)-1-Hydroxymethyl-2-(tert-butyldimethylsily-
loxymethyl)-4-tert-butyldiphenylsilyloxy-1,6-dimethylcyclohex-2-ene
(45). Following the general procedure (4.2.6), reduction of the es-
ter 44 (49.90 g, 88 mmol) in THF (600 mL) using lithium trie-
4.2.35. (1SR,4SR,6RS)-1-(Phenylsulfonylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-4-tert-butyldiphenylsilyloxy-1, 6-
dimethylcyclohex-2-ene (48). Following the general procedure
(4.2.8), the sulfide 46 (19.56 g, 31 mmol) was oxidised using am-
monium molybdate (57.46 g, 47 mmol) in ethanol (500 mL) and
hydrogen peroxide (30% solution in water, 14.25 mL) to give, after
chromatography on silica using 5e30% ether in light petroleum as
eluent, the title compound 48 (17.90 g, 27 mmol, 88%) as a clear,
viscous oil, Rf¼0.30 (20% ether in light petroleum) (Found: MþþNa,
685.3188. C38H54O4NaSSi2 requires M, 685.3174); nmax/cmꢀ1 3069,
2953, 2933, 2857, 1665, 1588, 1467, 1312, 1253, 1149, 1107, 837, 777
and 742; dH (300 MHz, CDCl3) 7.40e7.86 (15H, m, ArH), 5.72 (1H, br
s, 3-H), 4.20 (1H, m, 4-H), 4.29 and 4.22 (each 1H, d, J 13.1, 2-CH),
3.37 and 3.29 (each 1H, d, J 14.8, 1-CH), 2.48 (1H, m, 6-H), 1.65 (2H,
m, 5-H2), 1.21 (3H, s, 1-CH3), 1.11 [9H, s, SiC(CH3)3], 0.95 (3H, d, J 6.7,
6-CH3), 0.90 [9H, s, SiC(CH3)3] and 0.09 and 0.07 (each 3H, s,
OSiCH3); dC (75 MHz, CDCl3) 141.7, 140.7, 135.9, 134.5, 134.3, 133.4,
129.6, 129.2, 128.8, 127.6(2), 127.4, 67.9, 65.0, 61.0, 41.7, 36.3, 33.1,
27.0, 25.9, 21.8, 19.2, 18.2,16.1, ꢀ5.3 and ꢀ5.5; m/z (ES) 685 (Mþþ23,
100%).
thylborohydride (1.0
M in THF, 220 mL, 220 mmol), after
chromatography silica using 10e50% ether in light petroleum as
eluent gave the title compound 45 (41.57 g, 77 mmol, 88%) as a clear,
viscous oil, Rf¼0.51 (30% ether in light petroleum) (Found: MþþNa,
562.3261. C32H51O3Si2Na requires M, 562.3269); nmax/cmꢀ1 3464,
2955, 2931, 2857, 1467, 1254, 1108, 1051, 837 and 777; dH (300 MHz,
CDCl3) 7.67 (4H, m, ArH), 7.42 (6H, m, ArH), 5.78 (1H, br s, 3-H), 4.41
(1H, br dd, J 6.5, 6.3, 4-H), 4.26 and 3.86 (each 1H, d, J 10.8, 2-CH),
3.52 and 3.34 (each 1H, d, J 11.9, 1-CH), 2.00 (1H, m, 6-H), 1.70e1.45
(2H, m, 5-H2), 1.11 and 0.93 [each 9H, s, SiC(CH3)3], 0.93 (3H, d, J 7.0,
6-CH3), 0.81 (3H, s, 1-CH3) and 0.11 and 0.10 (each 3H, s, OSiCH3); dC
(75 MHz, CDCl3) 141.9, 137.3, 136.1, 134.7, 129.8, 127.8, 69.3, 65.5,
43.4, 37.0, 30.9, 27.3, 26.1, 19.5, 18.5, 16.6, 16.0 and ꢀ5.1; m/z (ESþ)
562 (Mþþ23, 60%) and 561 (100).
4.2.33. (1SR,4SR,6RS)-1-(Phenylsulfanylmethyl)-2-(tert-butyldime-
thylsilyloxymethyl)-4-tert-butyldiphenylsilyloxy-1, 6-
dimethylcyclohex-2-ene (46). Following the general procedure
(4.2.7), the alcohol 45 (20.79 g, 39 mmol) in DCM (400 mL), trie-
thylamine (18.74 mL, 135 mmol) and methanesulfonyl chloride
(7.50 mL, 77 mmol) gave the mesylate as a pale orange oil. This was
converted into the thioether following the general procedure using
sodium hydride (60% dispersion in mineral oil, 7.70 g, 193 mmol) in
DMF (500 mL), and benzenethiol (19.76 mL, 193 mmol) with the
mesylate added in DMF (300 mL). After heating the reaction mix-
ture under reflux, for 4 h, chromatography on silica using 1e20%
ether in light petroleum as eluent gave the title compound 46
(19.68 g, 31 mmol, 81%) as a pale yellow, viscous oil, Rf¼0.37 (15%
ether in light petroleum) (Found: MþþNH4, 648.3745. C38H58O2N-
SSi2 requires M, 648.3721); nmax/cmꢀ1 3069, 2955, 2932, 2857, 1584,
1470, 1431, 1254, 1107, 1057, 838, 776 and 739; dH (300 MHz, CDCl3)
7.77 (4H, m, ArH), 7.45 (6H, m, ArH), 7.30 (4H, m, ArH), 7.20 (1H, m,
ArH), 5.95 (1H, br s, 3-H), 4.45 (1H, m, 4-H), 4.30 and 4.23 (each 1H,
d, J 13.8, 2-CH), 3.10 and 3.02 (each 1H, d, J 12.0, 1-CH), 2.01 (1H, m,
6-H), 1.65 (2H, m, 5-H2), 1.19 (3H, s, 1-CH3), 1.17 and 0.99 [each 9H, s,
SiC(CH3)3], 0.85 (3H, d, J 7.0, 6-CH3) and 0.12 and 0.10 (each 3H, s,
OSiCH3); dC (75 MHz, CDCl3) 137.9, 136.1(2), 131.0, 129.7, 129.3(2),
129.1, 127.8, 127.7, 127.4, 125.9, 69.2, 63.2, 41.2, 37.0, 33.4, 27.3, 26.3,
22.9, 21.3, 19.5, 18.7, 15.7 and ꢀ5.0; m/z (ESþ) 653 (Mþþ23, 100%).
4.2.36. (1SR,4SR,6RS)-1-(Phenylsulfonylmethyl)-2-hydroxymethyl-
1,6-dimethyl-4-tert-butyldiphenylsilyloxycyclohex-2-ene
(49). Following the general procedure (4.2.34), the silyl ether 48
(11.60 g,17.4 mmol) in ethanol (290 mL) with concentrated aqueous
hydrogen chloride (12 M, 3.0 mL, 36.0 mmol), after chromatogra-
phy on silica using 45% ether in light petroleum, gave the title
compound 49 (9.17 g, 16.7 mmol, 95%) as a clear oil, Rf¼0.18 (40%
ether in light petroleum) (Found: MþþNa, 571.2316. C32H40O4NaSSi
requires M, 571.2309); nmax/cmꢀ1 3503, 3069, 2958, 2934, 2858,
1588, 1468, 1447, 1427, 1307, 1147, 1109, 1077, 822 and 743; dH
(300 MHz, CDCl3) 7.89 (2H, d, J 7.3, ArH), 7.72 (4H, d, J 7.6, ArH),
7.40e7.70 (9H, m, ArH), 5.92 (1H, br s, 3-H), 4.50 (1H, br t, J 7.2, 4-H),
4.21 and 4.12 (each 1H, d, J 12.5, 2-CH), 3.64 and 3.22 (each 1H, d, J
14.5, 1-CH), 2.53 (1H, br s, OH), 2.50 (1H, m, 6-H), 1.65e1.40 (2H, m,
5-H2),1.12 [9H, s, SiC(CH3)3],1.04 (3H, s,1-CH3) and 0.95 (3H, d, J 6.7,
6-CH3); dC (75 MHz, CDCl3) 141.7, 136.1, 134.7, 134.4, 133.8, 130.0,
129.9, 129.5, 127.9, 127.8, 68.9, 65.2, 61.1, 42.0, 37.0, 33.2, 27.3, 21.8,
19.5, and 16.2; m/z (ESþ) 571 (Mþþ23, 100%).
4.2.37. (1SR,4SR,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfonylmethyl)-4-tert-butyldiphenylsilylox-
ycyclohex-2-ene (50). Following the general procedure (4.2.17),
sodium hydride (60% dispersion in mineral oil, 515 mg,
12.88 mmol), the alcohol 49 (5.00 g, 9.11 mmol) in dry THF (75 mL)
and iodomethyl(tributyl)stannane (3.76 mL, 12.78 mmol), after
chromatography on silica using 25% ether in light petroleum as
eluent gave the title compound 50 (6.44 g, 7.56 mmol, 83%) as a clear
oil, Rf¼0.41 (20% ether in light petroleum) (Found: MþþNa,
875.3518. C45H68O4NaSSi120Sn requires M, 875.3527); nmax/cmꢀ1
3067, 2956, 2927, 2856, 1588, 1460, 1316, 1149, 1108, 1060, 821 and
4.2.34. (1SR,4SR,6RS)-1-(Phenylsulfanylmethyl)-2-hydroxymethyl-
1,6-dimethyl-4-tert-butyldiphenylsilyloxycyclohex-2-ene (47); gen-
eral procedure for silyl deprotection using acid. Concentrated
aqueous hydrogen chloride (12 M, 131 ml, 1.57 mmol) was added
dropwise to the silyl ether 46 (497 mg, 0.78 mmol) in ethanol
(12.5 mL) at room temperature and the solution was stirred for 1 h.
Saturated aqueous sodium hydrogen carbonate (15 mL) was added
and the aqueous phase extracted with EtOAc (5ꢂ15 mL). The or-
ganic extracts were washed with saturated aqueous sodium
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

14
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
742; dH (300 MHz, CDCl3) 7.89 (2H, d, J 7.2, ArH), 7.75 (4H, d, J 7.4,
ArH), 7.40e7.68 (9H, m, ArH), 5.70 (1H, br s, 3-H), 4.41 (1H, br t, J 7.3,
4-H), 4.19 and 3.79 (each 1H, d, J 12.0, 2-CH), 3.72 and 3.59 (each
1H, d, J 10.2, OHCHSn), 3.44 and 3.25 (each 1H, d, J 14.7, 1-CH), 2.49
(1H, m, 6-H), 1.63 (2H, m, 5-H2), 1.46 (6H, m, 3ꢂSnCH2CH2), 1.31
(6H, m, 3ꢂSnCH2CH2CH2), 1.18 (3H, s, 1-CH3), 1.12 [9H, s, SiC(CH3)3]
and 0.85e1.00 (18H, m, 3ꢂSnCH2, 3ꢂCH3 and 6-CH3); dC (75 MHz,
CDCl3) 142.1, 139.0, 136.1, 134.7, 134.6, 133.6, 132.2, 129.9, 129.4,
127.8, 79.2, 68.4, 61.7, 61.2, 42.3, 33.4, 29.4, 27.6, 27.3, 22.9, 21.9,
19.5, 16.5, 14.0 and 9.2; m/z (ESþ) 876 (100%).
d, J 12.4, 6-CH), 2.44 (1H, m, 2-H), 1.90 (1H, br s, OH), 1.60 (2H, m, 4-
H and 5-H), 1.39 (1H, m, 4-H0), 0.94 [9H, s, SiC(CH3)3], 0.90 (3H, s, 6-
CH3) and 0.59 (3H, d, J 6.9, 5-CH3); dC (75 MHz, CDCl3) 134.9, 134.4,
133.8, 132.1, 129.7, 129.4, 125.2, 124.5, 112.2, 71.0, 63.1, 48.4, 42.7,
40.8, 37.5, 34.9, 27.5, 20.3,18.2 and 17.5. The second fraction was the
title compound 53 (575 mg, 1.11 mmol, 92%) as a pale yellow oil,
Rf¼0.21 (30% ether in light petroleum); dH (300 MHz, CDCl3) 7.60
(4H, m, ArH), 7.32 (6H, m, ArH), 7.12 (4H, m, ArH), 7.02 (1H, m, ArH),
4.94 and 4.89 (each 1H, s, 1-CH), 4.04 (1H, td, J 8.7, 3.4, 3-H), 3.87
and 3.42 (each 1H, dd, J 10.6, 5.2, 2-CH), 3.20 and 2.92 (each 1H, d, J
12.5, 6-CH), 2.67 (1H, m, 2-H), 1.92 (1H, br s, OH), 1.60 (1H, m, 4-H
and 5-H), 1.39 (2H, m, 4-H0) 0.94 [9H, s, SiC(CH3)3], 0.92 (3H, s, 6-
CH3) and 0.68 (3H, d, J 6.4, 5-CH3); dC (75 MHz, CDCl3) 134.9,
134.7, 134.1, 133.8, 132.6, 130.0, 129.4, 125.0, 124.6, 112.2, 71.0, 63.1,
48.1, 43.1, 40.8, 37.5, 35.9, 27.1, 20.3, 18.2 and 17.5.
4.2.38. (1SR,4SR,6RS)-1,6-Dimethyl-2-(tributylstannylmethox-
ymethyl)-1-(phenylsulfanylmethyl)-4-tert-butyldiphenylsilylox-
ycyclohex-2-ene (51). Following the general procedure (4.2.17),
sodium hydride (60% dispersion in mineral oil, 515 mg,
12.88 mmol), the alcohol 47 (5.00 g, 9.11 mmol) in dry THF (75 mL)
and iodomethyl(tributyl)stannane (3.76 mL, 12.78 mmol), after
chromatography on silica using 25% ether in light petroleum as
eluent gave the title compound 51 (6.44 g, 7.56 mmol, 83%) as a clear
oil, Rf¼0.59 (20% ether in light petroleum); nmax/cmꢀ1 3099, 2950,
2925, 2855,1460,1374,1246,1092,1035, 859 and 836; dH (300 MHz,
CDCl3) 7.75 (4H, m, ArH), 7.45 (6H, m, ArH), 7.28 (4H, m, ArH), 7.20
(1H, m, ArH), 5.64 (1H, br s, 3-H), 4.36 (1H, m, 4-H), 4.15 and 3.76
(each 1H, d, J 12.0, 2-CH), 3.71 and 3.57 (each 1H, d, J 10.1, OHCHSn),
3.17 and 3.13 (each 1H, d, J 12.4, 1-CH), 2.04 (1H, m, 6-H), 1.58 (2H,
m, 5-H2),1.44 (6H, m, 3ꢂSnCH2CH2),1.29 (6H, m, 3ꢂSnCH2CH2CH2),
1.15 (3H, s, 1-CH3), 1.12 [9H, s, SiC(CH3)3] and 0.85e1.00 (18H, m,
3ꢂSnCH2, 3ꢂCH3 and 6-CH3); dC (75 MHz, CDCl3) 142.1, 137.2, 136.4,
133.6, 132.6, 130.1, 129.4, 129.0, 128.4, 126.8, 79.0, 68.0, 61.2, 40.8,
33.2, 29.0, 27.1, 27.0, 23.4, 22.9, 21.9, 18.0, 16.2, 13.6 and 9.0; m/z
(ESþ) 843 (Mþþ23, 100%).
4.2.41. (2SR,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-tert-butyldiphenylsilylcyclo-
hexane (55). Following the general procedure (4.2.8) using the
sulfide 53 (570 mg, 1.07 mmol), ammonium molybdate (214 mg,
0.16 mmol) in ethanol (11 mL) and hydrogen peroxide (30% solution
in water, 3.72 mL) after chromatography on silica using 50% ether in
light petroleum as eluent, gave the title compound 55 (518 mg,
0.92 mmol, 86%) as a clear, viscous oil, Rf¼0.19 (40% ether in light
petroleum) (Found: MþþNa, 585.2465. C33H42O4NaSSi requires M,
585.2465); nmax/cmꢀ1 3516, 3067,1469,1448,1428,1385,1312,1148,
1108, 1084, 1039 and 739; dH (300 MHz, CDCl3) 7.89 (2H, d, J 7.0,
ArH), 7.40e7.78 (13H, m, ArH), 5.25 and 5.02 (each 1H, s,1-CH), 4.29
(1H, m, 3-H), 3.60e3.40 (3H, m, 6-CH and 2-CH2), 3.21 (1H, d, J 14.4,
6-CH0), 2.48 (1H, m, 2-H), 2.01 (1H, m, 5-H), 1.78 (2H, m, 4-H2), 1.42
(3H, s, 6-CH3), 1.10 [9H, s, SiC(CH3)3], 1.08 (3H, d, J 7.2, 5-CH3); dC
(75 MHz, CDCl3) 136.4, 136.1, 134.1, 133.7, 130.2, 130.0, 129.4, 128.0,
127.6, 113.0, 71.0, 64.3, 62.1, 48.1, 44.4, 37.9, 36.1, 27.4, 22.6, 19.7 and
17.6; m/z (ES) 585 (Mþþ23, 100%).
4.2.39. (2RS,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)-3-tert-butyldiphenylsilylox-
ycyclohexane (52). Following the general procedure (4.2.18), the
sulfone 50 (6.40 g, 7.51 mmol) in THF (125 mL) and n-butyllithium
(1.6 M in THF, 10.12 mL, 16.13 mmol), after chromatography on silica
using 50% ether in light petroleum as eluent gave the title com-
pound 52 (2.75 g, 4.88 mmol, 65%) as a white solid, mp 143e144 ꢁC,
Rf¼0.18 (40% ether in light petroleum) (Found: MþþNa, 585.2465.
4.2.42. (2RS,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
m e t hyl e n e -6 - ( p h e nyl s u l fo nyl m e t hyl ) c yc l o h e x a n - 3 - o l
(56). Magnesium bromide (440 mg, 2.32 mmol) was dissolved in
ether (1.5 mL) and nitromethane (265 mL, 4.68 mmol) and added to
the SEM ether 27 (76 mg, 0.17 mmol) in ether (1.5 mL). The reaction
mixture was stirred at room temperature for 1 h and then diluted
with ether (50 mL), washed with water (10 mL) and brine (10 mL),
dried (Na2SO4) and concentrated under reduced pressure. Chro-
matography of the residue using ether as eluent gave the title
compound 56 (43 mg, 0.13 mmol, 76%) as a pale yellow oil, Rf¼0.18
(ether) (Found: MþþNH4, 342.1737. C17H28O4NS requires M,
342.1734); nmax/cmꢀ1 3430, 2928, 1637, 1447, 1409, 1306, 1144, 1085
and 742; dH (300 MHz, CDCl3) 7.98 (2H, d, J 7.0, ArH), 7.72e7.58 (3H,
m, ArH), 5.29 and 4.85 (each 1H, s, 1-CH), 4.15 (1H, dd, J 10.5, 3.7, 2-
CH), 4.02 (1H, dd, J 10.5, 7.8, 2-CH0), 3.69 (1H, td, J 10.5, 4.6, 3-H),
3.58 and 3.44 (each 1H, d, J 15.0, 6-CH), 3.45 (2H, br s, 2ꢂOH), 2.50
(1H, m, 2-H), 2.05e1.75 (2H, m, 4-H and 5-H), 1.59 (1H, q, J 10.5, 4-
H0), 1.24 (3H, s, 6-CH3) and 0.97 (3H, d, J 6.6, 5-CH3); dC (75 MHz,
CDCl3) 149.3, 142.8, 133.8, 129.7, 127.6, 109.2, 75.2, 65.5, 63.3, 46.7,
46.0, 39.7, 36.5, 19.5 and 16.8; m/z (CI) 342 (Mþþ18, 100%).
Following the general procedure (4.2.9) tetra-n-butylammo-
nium fluoride (1.0 M in THF, 0.25 mL, 0.25 mmol) was added to the
silyl ether 52 (90 mg, 0.16 mmol) in THF (0.80 mL) at room tem-
perature and the solution was stirred for 24 h then concentrated
under reduced pressure. Chromatography of the residue on silica
using ether as the eluent gave the title compound 56 (43 mg,
0.13 mmol, 83%) with spectroscopic data identical to those obtained
earlier.
C
33H42O4NaSSi requires M, 585.2465); nmax/cmꢀ1 3516, 3088, 2933,
2859, 1635, 1588, 1469, 1449, 1312, 1148, 1108, 739 and 703; dH
(300 MHz, CDCl3) 7.92 (2H, d, J 6.9, ArH), 7.77 (4H, d, J 7.2, ArH),
7.40e7.72 (9H, m, ArH), 5.35 and 5.08 (each 1H, s, 1-CH), 3.88 (2H,
m, 2-CH2), 3.75 (1H, m, 3-H), 3.44 and 3.37 (each 1H, d, J 14.8, 6-
CH), 2.66 (1H, m, 2-H), 2.62 (3H, br s, OH), 1.71 (1H, m, 5-H), 1.59
(2H, m, 4-H2), 1.30 (3H, s, 6-CH3), 1.13 [9H, s, SiC(CH3)3] and 0.80
(1H, d, J 6.6, 5-CH3); dC (75 MHz, CDCl3) 148.7, 142.6, 136.1(2), 134.4,
133.7, 133.6, 130.2, 130.0, 129.6, 128.0, 127.9, 127.6, 111.7, 74.4, 63.7,
63.2, 50.6, 45.0, 38.9, 36.2, 27.2, 20.5, 19.5 and 16.7; m/z (ESþ) 585
(Mþþ23, 100%).
Following the general procedure (4.2.8), the sulfide 54 was
oxidised to the title compound 52 with spectroscopic data identical
to those of the sample prepared from the stannane 50.
4.2.40. (2SR,3SR,5RS,6SR)- and (2RS,3SR,5RS,6SR)-5,6-Dimethyl-2-
hydroxymethyl-1-methylene-6-(phenylsulfanylmethyl)-3-tert-bu-
tyldiphenylsilyloxycyclohexane (53) and (54). Following the general
procedure (4.2.20), the sulphide 51 (989 mg, 1.21 mmol) in THF
(17 mL) and n-butyllithium (1.6 M in THF, 0.87 mL,1.33 mmol), after
chromatography on silica gel using 30% ether in light petroleum as
eluent, gave the title compound 54 (50 mg, 0.097 mmol, 8%) as a pale
yellow oil, Rf¼0.25 (30% ether in light petroleum); dH (300 MHz,
CDCl3) 7.60 (4H, m, ArH), 7.32 (6H, m, ArH), 7.10 (4H, m, ArH), 7.02
(1H, m, ArH), 5.00 and 4.75 (each 1H, s, 1-CH), 4.00 (2H, m, 2-CH
and 3-H), 3.55 (1H, dd, J 10.6, 5.2, 2-CH0), 3.05 and 2.85 (each 1H,
4.2.43. (2SR,3SR,5RS,6SR)-5,6-Dimethyl-2-hydroxymethyl-1-
methylene-6-(phenylsulfonylmethyl)cyclohexan-3-ol (57). Following
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
15
the general procedure (4.2.8) the sulfone 55 was prepared from the
sulfide 53 (80 mg, 0.15 mmol), ammonium molybdate (30 mg,
0.022 mmol) and hydrogen peroxide (30% in water, 0.52 mL).
Without purification it was dissolved in THF (0.5 mL) and following
the general procedure (4.2.9) tetra-n-butylammonium fluoride
(1 M in THF, 0.65 mL, 0.65 mmol) was added. The reaction mixture
was stirred for 24 h then concentrated under reduced presure.
Chromatography of the residue on silica gel using ether as eluent
gave the title compound 57 (57 mg, 0.10 mmol, 69%) as a pale yellow
oil, Rf¼0.20 (ether) (Found: MþþNH4, 342.1724. C17H28O4NS re-
quires M, 342.1734); nmax/cmꢀ1 3436, 2925, 1636, 1448, 1305, 1143,
1085, 1021, 903 and 744; dH (300 MHz, CDCl3) 7.90 (2H, d, J 8.5,
ArH), 7.52e7.71 (3H, m, ArH), 5.20 and 5.10 (each 1H, s, 1-CH), 4.25
(1H, m, 3-H), 3.91 (1H, dd, J 10.7, 6.8, 2-CH), 3.80 (1H, dd, J 10.7, 5.3,
2-CH0), 3.60 and 3.20 (each 1H, d, J 14.4, 6-CH), 3.98 (1H, br s, OH),
2.57 (2H, m, 2-H and OH), 2.02 (2H, m, 4-H and 5-H), 1.62 (1H, m, 4-
H0), 1.39 (3H, s, 6-CH3) and 1.02 (3H, d, J 7.0, 5-CH3); dC (75 MHz,
CDCl3) 145.4, 141.6, 133.9, 129.6, 128.0, 113.4, 69.7, 64.4, 62.3, 45.6,
44.5, 37.7, 36.3, 22.6 and 17.8; m/z (CI) 342 (Mþþ18, 50%), 307 (69)
and 147 (100).
7.95 (6H, m, ArH), 7.70e7.55 (5H, m, ArH), 7.50e7.40 (4H, m, Ar),
5.62 (1H, m, 3-H), 5.32 and 5.17 (each 1H, s, 1-CH), 4.51 (1H, dd, J
8.0, 5.4, 2-CH), 4.42 (1H, dd, J 8.0, 7.0, 2-CH0), 3.69 and 3.32 (each
1H, d, J 14.5, 6-CH), 2.99 (1H, m, 2-H), 2.30e2.10 (2H, m, 4-H and 5-
H), 2.04 (2H, dt, J 15.0, 1.0, 4-H0), 1.55 (3H, s, 6-CH3) and 1.02 (3H, d, J
7.5, 5-CH3); dC (75 MHz, CDCl3) 166.6, 165.8, 144.5, 141.7, 133.9,
133.4, 133.3, 130.4, 1303, 129.9, 129.8, 129.6, 128.7(2), 128.2, 113.3,
70.9, 64.3, 63.2, 44.4, 41.2, 37.6, 32.8, 23.0 and 17.5; m/z (ESþ) 555
(Mþþ23, 100%). This was taken up in methanol containing sodium
hydroxide (5%, 1.0 mL) and the solution stirred for 30 min. After
concentration under reduced pressure, the residue was dissolved in
ether (30 mL) and the solution washed with water (5 mL) and brine
(5 mL), then dried Na2SO4) and concentrated under reduced pres-
sure. Chromatography of the residue on silica eluting with 35%
ether in light petroleum gave the title compound 57 (17 mg,
0.055 mmol, 40%) with spectroscopic data identical to those ob-
tained earlier.
4.2.44. (2E,6E)-7-Iodo-2,6-dimethylhepta-2,6-dien-1-ol
(61). Trimethylaluminium (2.0 M in DCM, 63.3 mL, 126.6 mmol)
was added to a suspension of Cl2ZrCp2 (24.7 g, 84.4 mmol) in DCM
(40 mL) at room temperature and the reaction mixture stirred until
all the solids had dissolved. The alkyne 60 (5.24 g, 42.2 mmol) in
DCM (10 mL) was added and the reaction mixture stirred at room
temperature for 2 d. After cooling to 0 ꢁC, iodine (54.1 g, 211 mmol)
in THF (50 mL) was added, and the mixture was allowed to warm to
room temperature and was stirred until TLC indicated the complete
consumption of the starting material (5 h). The mixture was cooled
to 0 ꢁC and then water (75 mL) was added. The organic phase was
washed with saturated aqueous sodium sulfite (40 mL) and brine
(40 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue on silica using ether as
eluent gave the title compound 61 (6.96 g, 26.2 mmol, 62%) as a pale
yellow oil, Rf¼0.20 (40% ether in light petroleum) (Found;
MþþNH4, 284.0506; C9H19ONI requires M, 284.0506); nmax/cmꢀ1
3331br, 3057, 2914, 2856, 1619, 1443, 1376, 1268, 1141, 1000 and
768; dH (300 MHz, CDCl3) 5.92 (1H, s, 7-H), 5.39 (1H, td, J 6.8, 1.2, 3-
H), 4.02 (2H, s, 1-H2), 2.35e2.08 (4H, m, 4-H2 and 5-H2), 1.88 and
1.69 (each 3H, s, CH3); dC (75 MHz, CDCl3) 147.8, 136.0, 124.7, 75.3,
68.9, 39.4, 26.1, 24.2 and 14.0; m/z (CI) 284 (Mþþ18, 100%).
Following the general procedure (4.2.8), sulfide 41 (55 mg,
0.13 mmol), ammonium molybdate (26 mg, 0.019 mmol) in ethanol
(1.0 mL) and hydrogen peroxide (30% in water, 0.45 mL) gave the
sulfone 43. Without purification, this was dissolved in pyridine
(0.5 mL) and benzoyl chloride (0.49 mL, 4.2 mmol) and DMAP
(10 mg, cat.) were added. After 3 h, methanol (0.5 mL) was added
and the mixture stirred for 10 min before being concentrated under
reduced pressure. Chromatography of the residue on silica using
15% ether in light petroleum as eluent gave the benzoate 58 (70 mg,
0.14 mmol) as
C
a
colourless oil (Found: MþþNa, 581.2373.
30H42O6NaSSi requires M, 581.2364); nmax/cmꢀ1 2949, 2882, 1717,
1313, 1275, 1146, 1112, 1031 and 836; dH (300 MHz, CDCl3) 8.09 and
7.98 (each 2H, d, J 7.8, ArH), 7.70 (1H, t, J 7.3, ArH), 7.62 (3H, t, J 7.4,
ArH), 7.50 (2H, t, J 7.6, ArH), 5.28 and 5.22 (each 1H, s, 1-CH), 4.81
and 4.64 (each 1H, d, J 7.3, OHCHO), 4.60 (2H, m, 2-CH2), 3.85 (1H,
td, J 10.7, 5.4, 3-H), 3.75e3.50 (2H, m, OCH2), 3.61 and 3.45 (each
1H, d, J 14.4, 6-CH), 2.52 (1H, br d, J 10.7, 2-H), 2.30 (1H, m, 5-H),
2.10e1.90 (2H, m, 4-H2), 1.58 (3H, s, 6-CH3), 1.02 (3H, d, J 7.0, 5-CH3),
0.94 (2H, m, CH2Si) and 0.02 (9H, s, 3ꢂSiCH3); dC (75 MHz, CDCl3)
166.7, 145.6, 141.8, 133.9, 133.3, 130.5, 129.9, 129.5, 128.7, 128.2,
113.7, 94.2, 72.8, 65.8, 63.9, 62.1, 45.0, 44.1, 37.4, 35.6, 23.2, 18.2, 16.0
and ꢀ1.2; m/z (ESþ) 581 (Mþþ23, 95%). Magnesium bromide
4.2.45. (2E,6E)-1-tert-Butyldimethylsilyloxy-7-iodo-2,6-
dimethylhepta-2,6-diene (62). Imidazole (3.59 g, 54.4 mmol) and
tert-butyldimethylsilyl chloride (5.92 g, 39.3 mmol) were added to
the alcohol 61 (6.96 g, 26.2 mmol) in DCM (200 mL) at 0 ꢁC and the
solution stirred at room temperature for 24 h. Saturated aqueous
ammonium chloride (200 mL) was added and the mixture was
extracted with DCM (2ꢂ75 mL). The organic extracts were washed
with brine (100 mL), dried (MgSO4), and concentrated under re-
duced pressure. Chromatography of the residue on silica using 1%
ether in light petroleum as eluent gave the title compound 62
(9.56 g, 25.2 mmol, 96%) as a colourless oil, Rf¼0.20 (1% ether in
light petroleum) (Found: Mþ, 380.1023. C15H29OISi requires M,
380.1027); nmax/cmꢀ1 2953, 2927, 2855,1470, 1461, 1253,1110,1069,
836 and 774; dH (300 MHz, CDCl3) 5.91 (1H, s, 7-H), 5.39 (1H, td, J
6.8, 1.2, 3-H), 4.02 (2H, s, 1-H2), 2.35e2.20 (4H, m, 4-H2 and 5-H2),
1.88 and 1.62 (each 3H, s, CH3), 0.94 [9H, s, SiC(CH3)3] and 0.09 (6H,
s, 3ꢂSiCH3); dC (75 MHz, CDCl3) 147.9, 135.6, 123.0, 75.2, 68.6, 39.5,
26.2, 26.1, 24.2, 18.7, 13.7 and ꢀ5.0; m/z (CI) 398 (Mþþ18, 18%), 381
(Mþþ1, 9%) and 121 (100).
(24 mg, 1.75 mmol) in ether (0.5 mL) and nitromethane (50 mL) was
added to the benzoate in ether (0.5 mL) and the mixture stirred for
1 h. Ether (30 mL) was added and the solution washed with water
(5 mL) and brine (5 mL), then dried (Na2SO4), and concentrated
under reduced pressure to give the alcohol 59 as a colourless oil
(Found: MþþNa, 451.1559. C24H28O5NaS requires M, 451.1550);
nmax/cmꢀ1 3492br, 3055, 2928, 1715, 1584, 1476, 1434, 1277, 1145,
1088,1027 and 744; dH (300 MHz, CDCl3) 8.08 and 7.95 (each 2H, d, J
7.5, ArH), 7.70e7.40 (6H, m, ArH), 5.44 and 5.22 (each 1H, s, 1-CH),
5.02 (1H, dd, J 7.0, 3.0, 2-CH), 4.40 (1H, dd, J 7.0, 2.0, 2-CH0), 3.68 (1H,
d, J 13.0, 6-CH), 3.64 (1H, m, 3-H), 3.42 (1H, br s, OH), 3.30 (1H, d, J
13.0, 6-CH0), 2.40 (1H, br d, J 7.5, 2-H), 2.11 (1H, m, 5-H), 2.00e1.80
(2H, m, 4-H2), 1.52 (3H, s, 6-CH3) and 0.89 (3H, d, J 7.0, 5-CH3); dC
(75 MHz, CDCl3) 167.8, 145.6, 141.8, 133.9, 133.7, 130.0, 129.9, 129.5,
128.8, 128.2, 113.7, 66.5, 63.9, 63.1, 48.0, 44.1, 38.0, 37.2, 23.2 and
15.9; m/z (ESþ) 451 (Mþþ23, 50%). This was dissolved in THF
(0.5 mL) with triphenylphosphine (52 mg, 0.20 mmol) and the
solution added to DIAD (0.038 mL, 0.20 mmol) and benzoic acid
(12 mg, 0.20 mmol) in THF (0.5 mL) at 0 ꢁC. After 4 h at 0 ꢁC, the
mixture was concentrated under reduced pressure and chroma-
tography of the residue on silica using 15% ether in light petroleum
as eluent gave the inverted bis-benzoate as a colourless oil (Found:
MþþNa, 555.1812. C31H32O6NaS requires M, 555.1812); nmax/cmꢀ1
1715, 1450, 1276, 1146, 1112 and 1025; dH (300 MHz, CDCl3) 8.15 and
4.2.46. (1SR,3SR,4RS,6SR)-6-tert-Butyldiphenylsilyloxy-3,4-
dimethyl-2-methylene-3-(phenylsulfonylmethyl)cyclohexane-1-
carboxaldehyde (63). Di-isopropylethylamine (2.48 mL, 13.0 mmol)
was added to the alcohol 52 (1.66 g, 2.94 mmol) in DCM (12 mL) at
room temperature and the solution cooled to 0 ꢁC before the
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

16
T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
addition of py.SO3 (1.60 g, 8.85 mmol) in DMSO (13 mL). The re-
action mixture was stirred at 0 ꢁC for 15 min then poured into brine
(20 mL), and the aqueous phase extracted with ethyl acetate
(4ꢂ20 mL). The organic extracts were washed with saturated
aqueous copper(II) sulfate (30 mL), water (30 mL) and brine
(30 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue on silica using 40% ether
in light petroleum gave the title compound 63 (1.50 g, 91%) as
a colourless oil, Rf¼0.27 (40% ether in light petroleum) (Found:
to the alcohol 64 (700 mg, 0.85 mmol) in THF (1.5 mL) at room
temperature. The reaction mixture was stirred for 16 h, methanol
(0.4 mL) was added and the mixture stirred for 1 h. Ethyl acetate
(10 mL) and water (10 mL) were added the aqueous phase extracted
into ethyl acetate (4ꢂ5 mL). The organic extracts were washed with
aqueous sodium bisulfite (0.5 N, 15 mL), an aqueous pH 7 buffer
(15 mL) and brine (15 mL), then dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue on silica
using 30% ether in light petroleum as eluent gave the title compound
65 (652 mg, 82%) as a pale yellow oil, Rf¼0.35 (40% ether in light
petroleum) (Found: MþþNa, 957.4953. C56H78O6NaSSi2 requires M,
957.4950); nmax/cmꢀ1 3069, 2930, 2856, 1666, 1628, 1588, 1461,
1385, 1318, 1257, 1150, 1105, 1039, 837, 776, 742 and 703; dH
(300 MHz, CDCl3) 7.84 (2H, d, J 7.2, ArH), 7.75 (4H, d, J 8.8, ArH),
7.30e7.65 (12H, m, ArH), 7.15 (2H, m, ArH), 5.29 (1H, t, J 7.0, 60-H),
5.24 and 5.15 (each 1H, s, 2-CH), 4.89 (1H, d, J 8.8, 20-H), 4.46 (1H, d, J
7.0, OHCHO), 4.38 (1H, m,10-H), 4.28 (1H, d, J 7.0, OHCH0O), 4.12 (1H,
m, 6-H), 4.10 and 4.03 (each 1H, d, J 12.0, HCHPh), 4.04 (2H, s, 80-H2),
3.32 (1H, d, J 14.3, 3-CH), 2.70 (1H, br d, J 8.8,1-H), 2.65 (1H, d, J 14.3,
3-CH0), 2.59 (1H, m, 4-H), 1.80e2.00 (5H, m, 40-H2, 50-H2, 5-H), 1.63
(1H, m, 5-H0), 1.61 (3H, s, 70-CH3), 1.51 (3H, s, 30-CH3), 1.12 (3H, d, J
7.3, 4-CH3), 1.09 [9H, s, SiC(CH3)3], 1.05 (3H, s, 3-CH3), 0.98 [9H, s,
SiC(CH3)3] and 0.10 (6H, s, 2ꢂSiCH3); dC (125 MHz, CDCl3) 146.4,
141.3, 139.7, 137.1, 135.3, 135.2, 133.8, 133.3, 133.2, 132.3, 128.5(2),
128.2, 127.3, 126.5, 126.4, 126.3, 126.2, 122.8, 122.0, 117.0, 89.2, 70.0,
69.8, 68.3, 67.6, 62.7, 56.1, 42.7, 38.3, 32.6, 32.0, 28.7, 26.0, 25.0, 22.1,
18.1, 17.4, 14.7, 12.5 and ꢀ6.3; m/z (þES) 958 (40%) and 515 (100).
MþþNa, 583.2316. C33H40O4NaSSi requires M, 583.2309); nmax
/
cmꢀ1 3069, 2959, 2934, 2859, 1728, 1634, 1587, 1468, 1448, 1428,
1315, 1149, 1109, 1042, 911, 824 and 740; dH (300 MHz, CDCl3) 9.46
(1H, d, J 3.2, 1-CH), 7.88 (2H, d, J 7.9, ArH), 7.40e7.67 (13H, m, ArH),
5.37 and 4.93 (each 1H, s, 2-CH), 4.32 (1H, td, J 7.8, 4.4, 6-H), 3.32
and 3.22 (each 1H, d, J 14.8, 3-CH), 3.14 (1H, m, 1-H), 2.09 (1H, m, 4-
H), 1.79 (1H, dt, J 13.8, 4.4, 5-H), 1.60 (1H, m, 5-H0), 1.29 (3H, s, 3-
CH3), 1.08 [9H, s, SiC(CH3)3] and 0.96 (1H, d, J 6.9, 4-CH3); dC
(75 MHz, CDCl3) 202.7, 144.4, 142.4, 136.1(2), 134.2, 133.8, 133.6,
130.3, 130.1, 129.6, 128.1, 127.9, 127.6, 115.1, 69.6, 62.9, 62.6, 44.8,
36.9, 35.2, 27.2, 22.2, 19.4 and 17.1; m/z (ES) 583 (Mþþ23, 100%).
4.2.47. (1SR,3SR,4RS,6SR)-1-[(1RS,2E,6E)-8-tert-Butyldimethylsily-
loxy-1-hydroxy-3,7-dimethylocta-2,6-dien-1-yl]-6-tert-butyldiphe-
nylsilyloxy-3,4-dimethyl-2-methylene-3-(phenylsulfonylmethyl)cy-
clohexane (64). Ytterbium triflate (5.93 g, 9.57 mmol) was heated
to 140 ꢁC with stirring overnight under a high vacuum and then
allowed to cool to room temperature under an atmosphere of ni-
trogen. tert-Butyllithium (1.7 M in pentane, 5.63 mL, 9.57 mmol)
was added to the vinyl iodide 62 (3.63 g, 9.57 mmol) in THF (24 mL)
at ꢀ78 ꢁC. The solution was stirred for 1 h at ꢀ78 ꢁC and then added
to the ytterbium triflate in THF (210 mL). After being stirred at
ꢀ78 ꢁC for 30 min, a portion (81 mL) of the organoytterbium re-
agent was added to the aldehyde 63 (0.89 g, 1.6 mmol) in THF
(9.4 mL) at ꢀ78 ꢁC and the resulting solution stirred at ꢀ78 ꢁC for
3 h. More organo-ytterbium reagent (40 mL) was added and the
solution stirred at ꢀ78 ꢁC for a further 1.5 h. Saturated methanolic
ammonium chloride (48 mL) was added and the mixture allowed to
warm to ambient temperature before the addition of saturated
aqueous Rochelle’s salt (48 mL). The aqueous phase was extracted
with ethyl acetate (4ꢂ30 mL) and the organic extracts washed with
brine (100 mL), dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue on silica using 5e50%
ether in light petroleum as eluent gave the title compound 64 (1.10 g,
85%) as a white solid, mp 97e98 ꢁC, Rf¼0.25 (40% ether in light
petroleum) (Found: MþþNa, 837.4386; C48H70O5NaSSi2 requires M,
837.4375); nmax/cmꢀ1 3511br, 3071, 2956, 2931, 2857, 1629, 1588,
1447,1428,1387,1308,1254,1148,1108,1053, 837, 776, 741 and 704;
dH (300 MHz, CDCl3) 7.89 (2H, d, J 7.0, ArH), 7.76 (4H, m, ArH),
7.40e7.68 (9H, m, ArH), 5.35 (1H, br t, J 6.5, 60-H), 5.23 (1H, s, 2-CH),
5.12 (1H, d, J 8.6, 20-H), 4.95 (1H, s, 2-CH0), 4.42 (1H, m, 10-H), 4.12
(1H, m, 6-H), 4.05 (2H, s, 80-H2), 3.37 and 3.07 (each 1H, d, J 14.6, 3-
CH), 2.49 (2H, m, 1-H and OH), 2.10e1.90 (5H, m, 4-H, 40-H2, 50-H2),
1.66 (2H, m, 5-H2), 1.65 (3H, s, 70-CH3), 1.50 (3H, s, 30-CH3), 1.21 (3H,
s, 3-CH3), 1.10 and 0.98 [each 9H, s, SiC(CH3)3], 0.91 (3H, d, J 6.9, 4-
CH3), and 0.11 (6H, s, 2ꢂSiCH3); dC (75 MHz, CDCl3) 148.8, 142.8,
139.4, 136.3, 136.2, 135.0, 134.2, 133.9, 133.6, 130.1(2), 129.5,
127.9(2), 127.7, 126.7, 124.5, 115.2, 74.6, 69.6, 69.0, 63.7, 56.1, 44.8,
39.5, 37.2, 36.2, 27.2, 26.3, 21.1,19.4,18.7,17.5,16.5,13.8 and ꢀ4.9; m/
z (þES) 837 (Mþþ23, 48%), 798 (100), 667 (66) and 409 (54).
4.2.49. (1SR,3SR,4RS,6SR)-1-[(1RS,2E,6E)-1-(Benzyloxymethoxy)-8-
hydroxy-3,7-dimethylocta-2,6-dien-1-yl]-6-tert-butyldiphenylsily-
loxy-3,4-dimethyl-2-methylene-3-(phenylsulfonylmethyl)cyclohex-
ane (66). The silyl ether 65 (300 mg, 0.31 mmol) was dissolved in
acetic acid: water: THF (3:1:1, 2 mL) and the solution stirred at
room temperature for 2 d. Toluene (50 mL) was added and the
solution dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on silica using 50% ether in light
petroleum as eluent gave the title compound 66 (240 mg,
0.29 mmol, 91%) as a glassy white solid, Rf¼0.21 (50% ether in light
petroleum) (Found: MþþNa, 843.4074; C50H64O6NaSSi requires M,
843.4085); nmax/cmꢀ1 3523, 3068, 2929, 2856, 1447, 1383, 1307,
1158, 1103, 1038 and 702; dH (300 MHz, CDCl3) 7.80 (2H, d, J 8.1,
ArH), 7.71 (4H, d, J 8.0, ArH), 7.57 (1H, m, ArH), 7.30e7.50 (11H, m,
ArH), 7.11 (2H, m, ArH), 5.24 (1H, s, 2-CH), 5.24 (1H, t, J 6.6, 60-H),
5.14 (1H, s, 2-CH0), 4.88 (1H, d, J 9.9, 20-H), 4.42 (1H, d, J 7.0, OHCHO),
4.32 (1H, m,10-H), 4.25 (1H, d, J 7.0, OHCH0O), 4.02e4.20 (4H, m, OH,
6-H, OCH2Ph), 4.01 (2H, s, 80-H2), 3.28 (1H, d, J 14.1, 3-CH), 2.70 (1H,
br d, J 9.0, 1-H), 2.65 (1H, d, J 14.1, 3-CH0), 2.57 (1H, m, 4-H),
1.82e2.03 (5H, m, 40-H2, 50-H2 and 5-H), 1.80 (1H, m, 5-H0),1.68 (3H,
s, 70-CH3), 1.51 (3H, s, 30-CH3), 1.11 (3H, d, J 7.2, 4-CH3), 1.07 [9H, s,
SiC(CH3)3] and 0.98 (3H, s, 3-CH3); dC (125 MHz, CDCl3) 147.5, 142.3,
140.4, 138.1, 136.3, 136.2, 135.7, 134.3, 134.2, 133.5, 129.6, 129.4,
129.3, 128.4, 127.6, 127.5, 127.3, 127.2, 124.7, 123.5, 118.0, 90.2, 71.0,
69.4, 68.8, 63.5, 57.1, 43.7, 39.0, 33.6, 33.0, 27.0, 25.3, 23.0, 19.1, 18.5,
15.4 and 13.8; m/z (þES) 843 (Mþþ23, 100%).
4.2.50. (1SR,3SR,4RS,6SR)-1-[(1RS,2E,6E)-1-(Benzyloxymethoxy)-8-
bromo-3,7-dimethylocta-2,6-dien-1-yl]-6-tert-butyldiphenylsilyloxy-
3,4-dimethyl-2-methylene-3-(phenylsulfonylmethyl)cyclohexane
(67). Triethylamine (0.15 mL, 1.05 mmol) and methanesulfonyl
chloride (0.06 mL, 0.63 mmol) were added to the alcohol 66
(432 mg, 0.54 mmol) in THF (3 mL) at 0 ꢁC and the solution was
stirred at 0 ꢁC for 45 min. Lithium bromide (195 mg, 2.16 mmol) in
THF (1 mL) was added and, after 1 h at 0 ꢁC, pentane (15 mL) and ice-
cold water (10 mL) were added. The aqueous phase was extracted
with pentane (2ꢂ15 mL) and the organic extracts washed with
saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL),
4.2.48. (1SR,3SR,4RS,6SR)-1-[(1RS,2E,6E)-1-(Benzyloxymethoxy)-8-
tert-butyldimethylsilyloxy-3,7-dimethylocta-2,6-dien-1-yl]-6-tert-
butyldiphenylsilyloxy-3,4-dimethyl-2-methylene-3-(phenyl-
sulfonylmethyl)cyclohexane (65). Di-isopropylethylamine (1.05 mL,
36.2 mmol), benzyloxymethyl chloride (0.75 mL, 5.2 mmol) and
tetra-n-butylammonium iodide (35 mg, 0.085 mmol) were added
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005

T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17
17
dried (Na2SO4) and concentrated under reduced pressure. Chro-
References and notes
matography of the residue on silica using 20% ether in light petro-
leum as eluent gave the title compound 67 (411 mg, 86%) as a clear
oil, Rf¼0.32 (40% ether in light petroleum); nmax/cmꢀ1 3070, 2931,
2857,1663,1628,1588,1447,1428,1385,1318,1308,1149,1104,1038,
910, 742 and 702; dH (500 MHz, CDCl3) 7.65 (2H, d, J 7.8, ArH), 7.65
(4H, d, J 7.8, ArH), 7.46 (1H, m, ArH), 7.20e7.40 (11H, m, ArH), 7.09
(2H, d, J 8.2, ArH), 5.37 (1H, t, J 6.3, 60-H), 5.12 and 5.05 (each 1H, s, 2-
CH), 4.89 (1H, d, J 9.0, 20-H), 4.32 (1H, d, J 7.0, OHCHO), 4.25 (1H, m,
10-H), 4.19 (1H, d, J 7.0, OHCH0O), 4.03 (1H, d, J 12.0, OHCHPh), 4.01
(1H, m, 6-H), 3.92 (1H, d, J 12.0, OHCH0Ph), 3.87 (2H, s, 80-H2), 3.22
(1H, d, J 14.3, 3-CH), 2.60 (1H, br d, J 9.2, 1-H), 2.55 (1H, d, J 14.3, 3-
CH0), 2.43 (1H, m, 4-H), 1.67e1.92 (5H, m, 40-H2, 50-H2 and 5-H), 1.62
(3H, s, 70-CH3), 1.45 (1H, m, 5-H0), 1.39 (3H, s, 30-CH3), 1.01 (3H, d, J
7.0, 4-CH3), 0.96 [9H, s, SiC(CH3)3] and 0.95 (3H, s, 3-CH3); dC
(125 MHz, CDCl3) 148.0, 142.6, 140.3, 138.4, 136.5, 136.4, 134.5(2),
133.6, 132.7, 130.5, 129.8, 129.6, 129.5, 128.6, 127.7, 127.5(2), 123.8,
118.1, 90.6, 71.3, 69.7, 64.0, 57.2, 44.0, 41.7, 38.9, 33.9, 33.6, 30.6, 27.3,
26.7, 19.4, 18.6, 16.0 and 15.0; m/z (ESþ) 905 (Mþþ23, 100%).
1. (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.;
Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463; (b) Sugano, M.; Sato, A.; Iijima, Y.;
Furuya, K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 118.
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M.; Goldring, W. P. D.; Pattenden, G. Org. Biomol. Chem. 2003, 1, 3949; (d) Mohr,
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Hsung, R. P. J. Org. Chem. 2011, 76, 7027.
3. (a) Ryu, K.; Cho, Y.-S.; Jung, S.-I.; Cho, C.-G. Org. Lett. 2006, 8, 3343; (b) Teng, D.;
Wang, B.; Augatis, A. J.; Totah, N. I. Tetrahedron Lett. 2007, 48, 4605; (c) Huang,
J.; Wang, H.; Wu, C.; Wulff, W. D. Org. Lett. 2007, 9, 2799; (d) Goldring, W. P. D.;
Alexander, S. P. H.; Kendall, D. A.; Pattenden, G. Bioorg. Med. Chem. Lett. 2005, 15,
3263; (e) You, L.-F.; Hsung, R. P.; Bedermann, A. A.; Kurdyumov, A. V.; Tan, Y.;
Buchanan, G. S.; Cole, K. P. Adv. Synth. Catal. 2008, 350, 2885; (f) Schwartz, K. D.;
White, J. D. Org. Lett. 2011, 13, 248; (g) Huang, S.; Du, G.; Lee, C.-S. J. Org. Chem.
2011, 76, 6534; (h) Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y.; You, L.-F.; Hsung,
R. P. Tetrahedron 2011, 67, 10105; (i) Ciesielski, J.; Cariou, K.; Frontier, A. J. Org.
Lett. 2012, 14, 4082; (j) Ciesielski, J.; Gandon, V.; Frontier, A. J. J. Org. Chem. 2013,
78, 9541.
4. (a) Ciesielski, J.; Frontier, A. J. Org. Prep. Proced. Int. 2014, 46, 214; (b) Goldring,
W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354.
4.2.51. (1SR,2RS,10SR,11SR,12RS,14SR,3E,7E)-2-(Benzyloxymethoxy)-
14-tert-butyldiphenylsilyloxy-15-methylene-4,8,11,12-tetramethyl-
5. (a) Shapland, P. D. P.; Thomas, E. J. Tetrahedron 2009, 65, 4201; (b) McGowan, G.;
Thomas, E. J. Org. Biol. Chem. 2009, 7, 2576; (c) Blackburn, T. J.; Helliwell, M.;
Kilner, M. J.; Lee, A. T. L.; Thomas, E. J. Tetrahedron Lett. 2009, 50, 3550.
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Isobe, M. Org. Lett. 2012, 14, 5274; (c) Druais, V.; Hall, M. J.; Corsi, C.; Wende-
born, S. V.; Meyer, C.; Cossy, J. Tetrahedron 2010, 66, 6358.
10-phenylsulfonylbicyclo[9.3.1]pentadeca-3,7-diene
(68). Sodium
hexamethyldisilazide (1.0 M in THF, 0.98 mL, 0.98 mmol) was added
to the bromide 67 (288 mg, 0.32 mmol) in THF (6.4 mL) at 0 ꢁC via
syringe pump over 40 min and the yellow solution was stirred for
a further 30 min. Saturated aqueous ammonium chloride (5 mL)
and ethyl acetate (5 mL) were added. The aqueous phase was
extracted with ethyl acetate (4ꢂ5 mL) and the organic extracts were
washed with brine (5 mL), dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue on silica using
40% ether in light petroleum as eluent gave the title compound 68
(185 mg, 72%) as a white solid, mp 163e165 ꢁC, Rf¼0.21 (50% ether
in light petroleum) (Found: MþþNa, 825.3969. C50H62O5NaSSi re-
quires M, 825.3979); nmax/cmꢀ1 3066, 2933, 2885, 2856, 1588, 1446,
1428, 380, 1304, 1143, 1109, 1085, 1035, 910 and 823; dH (300 MHz,
CDCl3) 7.85 (4H, m, ArH), 7.27e7.58 (16H, m, ArH), 6.03 (1H, d, J 2.0,
15-CH), 5.24 (1H, d, J 10.2, 2-H), 5.12 (1H, d, J 2.2,15-CH0), 4.89 (1H, d,
J 10.2, 3-H), 4.80 (3H, m, OHCHPh, OCH2O), 4.66 (1H, d, J 12.4,
OHCH0Ph), 3.89 (2H, m, 7-H and 14-H), 3.27 (1H, br d, J 11.7, 1-H),
2.99 (1H, br s,10-H), 2.82 (1H, m,12-H), 2.60 (1H, m,13-H), 2.38 (2H,
br s, 9-H2), 1.70e1.93 (5H, m, 5-H2, 6-H2 and 13-H0), 1.50 (3H, s, 4-
CH3), 1.38 (3H, s, 8-CH3), 1.17 (3H, s, 11-CH3), 1.10 [9H, s, SiC(CH3)3]
and 1.00 (3H, d, J 7.1, 12-CH3); dC (75 MHz, CDCl3) 146.4, 141.0, 138.5,
137.6, 136.4, 136.3, 135.6, 134.7, 133.2, 129.8, 129.7, 129.4, 128.9,
128.7, 128.5, 128.0, 127.8, 127.7, 127.6, 125.1, 120.7, 119.2, 92.1, 73.2,
69.6, 68.6, 62.0, 52.7, 49.6, 39.0, 37.3, 35.0, 34.9, 27.5, 22.8, 22.0, 21.1,
19.5, 17.3, and 17.2; m/z (þES) 825 (Mþþ23, 100%) and 270 (99).
7. Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927.
8. Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
9. (a) Hardy, P. M.; Rydon, H. N.; Thompson, R. C. Tetrahedron Lett. 1968, 9, 2525;
ꢀ ꢀ
(b) Ferezou, J. P.; Julia, M. Tetrahedron 1990, 46, 475; (c) Parrott, M. J.; Davies, D.
I. J. Chem. Soc., Perkin Trans. 1 1973, 2205.
10. Nakai, T.; Mikami, K.; Taya, S.; Fujita, Y. J. Am. Chem. Soc. 1981, 103, 6492.
11. (a) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1974, 705; (b) Gardiner, J. M.; Giles,
P. E. Tetrahedron Lett. 1995, 36, 7519.
ꢁ
ꢁ
12. Crystallographic data for sulfone 52: SG Cc, a¼9.335(5) A, b¼38.229(5) A, c¼9.
ꢁ
125(5) A,
a
¼90.000(5)o,
b
¼107.509(5)o,
g
¼90.000(5)o, V¼3106(2) A^3,
T¼100(2)K, Z¼4. Crystallographic data for compound 52 (CCDC-1044748) can
be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_re-
quest/cif. Crystal data for sulfone 68: C50H62O5SSi, MW 803.15, monoclinic,
ꢁ
space group P21/c, a¼22.478(2), b¼10.2390(11), c¼21.361(2) A,
b
¼115.739(2) ꢁ
,
3
ꢁ
ꢀ3
, m
V¼4428.5(8) A , Z¼4, Dc¼1.205 g cm
(MoKa
)¼0.146 mm-1, F(000¼1728,
T¼100 K. Crystal dimensions were 0.4ꢂ0.07ꢂ0.02 mm 31,135 reflections
measured, 7817 independent reflections (Rint¼0.116), R1¼0.039 for the 3559
reflections with I>2
s
(I), wR(F2)¼0.112 (all data). CCDC 712103.
13. Marshall, J. A.; Nelson, D. A. Tetrahedron Lett. 1988, 29, 741.
14. Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985, 107, 6639.
15. (a) Imamoto, T.; Kusumoto, T.; Yokoyama, M. J. Chem. Soc., Chem. Commun. 1982,
1042 Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett., 1984, 25, 4233.
16. Marshall, J. A.; Eidam, P. Org. Lett. 2004, 6, 445.
17. (a) Molander, G. A.; Burkhardt, E. R.; Weinig, P. J. Org. Chem. 1990, 55, 4990; (b)
€
Molander, G. A.; Kollner, C. J. Org. Chem. 2000, 65, 8333; (c) Johnston, D.;
ꢀ
Couche, E.; Edmonds, D. ,J.; Muir, K. W.; Procter, D. J. Org. Biomol. Chem. 2003, 1,
328.
18. Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.;
Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52,
1017.
19. (a) Kibuchi, T.; Mineta, M.; Ohtaka, J.; Matsumoto, N.; Katoh, T. Eur. J. Org. Chem.
2011, 5020; (b) Oguchi, T.; Watanabe, K.; Ohkubo, K.; Abe, H.; Katoh, T. Chem.
dEur. J. 2009, 15, 2826.
Acknowledgements
20. Burnell, E. S.; Irshad, A.-R.; Raftery, J.; Thomas, E. J. Tetrahedron Lett. 2015, 56 in
press.
We thank the EPSRC for studentships (to M.J.K. and T.J.B.).
Please cite this article in press as: Blackburn, T. J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.005