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

Tetrahedron xxx (2015) 1e1 7

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Tetrahedron

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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.

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,⁷together 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.¹Several total syntheses,

including syntheses of phomactin A 1,²together with other novel

synthetic approaches,³have 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)dioxirane⁸generated 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,⁵a 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.^5bThis stereoselectivity had not been observed in

earlier analogous [2,3]-Wittig rearrangements.^5aThe 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.⁶However, 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 sulfur⁹gave the sulfone 16. Desilylation

* Corresponding author. Tel.: þ44 (0) 161 275 4613; e-mail address: e.j.thomas@

manchester.ac.uk (E.J. Thomas).

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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.^6,10Since the stereoselective

introduction of a vinylic methyl group by substitution of a phenyl-

thio substituent had proved useful in earlier studies,^5bthe control of

the regioselectivity of the Wittig rearrangement by a phenylthio

group was brieﬂy evaluated. The stereoselective addition¹¹of 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

process⁷since 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.⁶To 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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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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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 conditions¹⁴and 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) chloride¹⁵or anhy-

drous zinc(II) bromide¹⁶was added to the vinyllithium reagent

before addition to the aldehyde, but the best yield, 85%, was ach-

ieved using ytterbium(III) triﬂate,^17,18when 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. 4.¹²This 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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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.^5bIn 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 7^5aas 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, R_f¼0.7

þ

(10% ether in light petroleum) (Found:

C

M

Na, 333.1843.

₁₇H₃₀O₃NaSi requires M, 333.1856); n_max/cm^ꢀ12955, 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; d_H

(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); d_C

(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 (M^þþ123, 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.¹⁹In 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.^5cSolvent 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

oxone^Ò(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; d_H(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); d_C

(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 (M^þþ18, 10%), 329 (3)

and 311 (100).

astereoisomers, R_f¼0.1 (30% ether in light petroleum) (Found:

M^þþNH₄, 230.1384. C₁₁H₂₀NO₄requires M, 230.1387); n_max/cm^ꢀ1

3437br, 2954, 2883, 1730, 1666, 1454, 1252, 1193, 1122 and 1070; d_H

(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); d_C(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 (M^þþ18,100%)

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, R_f¼0.66 (30% ether in

light petroleum) (Found: M^þþNH₄, 476.3228. C₂₃H₅₀O₅Si₂N re-

quires M, 476.3232); n_max/cm^ꢀ12944, 2867, 1735, 1462, 1249 and

1058; d_H(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); d_C(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 (M^þþ18, 8%), 459 (M^þþ1, 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, R_f¼0.46 (40% ether in light petroleum) (Found:

M^þþH, 327.1989. C₁₇H₃₁O₄Si requires M, 327.1986); n_max/cm^ꢀ1

2953, 2857, 1735, 1674, 1631, 1461, 1253, 1139, 1088, 838 and 780; d_H

(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); d_C(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 (M^þþ1, 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, R_f¼0.42 (30% ether

in light petroleum) (Found: M^þþH, 431.3011. C₂₂H₄₇O₄Si₂requires

M, 431.3015); n_max/cm^ꢀ13515br, 2944, 2866, 1659, 1464, 1382, 1250,

1054 and 836; d_H(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-CH₃and SiC(CH₃)₃], 0.80 (3H, s, 1-CH₃), 0.16 and 0.14 (each

3H, s, 2ꢂSiCH₃) and 0.06 (9H, s, 3ꢂSiCH₃); d_C(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 R_f¼0.26 (30% ether in light petroleum) (Found: M^þ,

328.2057. C₁₇H₃₂O₄Si requires M, 328.2064); n_max/cm^ꢀ13415, 2952,

2859, 1731, 1464, 1383, 1253, 1140, 1109, 1033, 839 and 778; d_H

(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); d_C(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 (M^þþ1, 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, R_f¼0.19 (30% ether in light

petroleum) (Found: M^þ, 328.2058. C₁₇H₃₂O₄Si requires M,

328.2064); n_max/cm^ꢀ13445, 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, R_f¼0.25 (15% ether in light

petroleum) (Found: M^þ, 522.3003. C₂₈H₅₀O₃SSi₂requires M,

522.3003); n_max/cm^ꢀ12954, 2932, 2883, 2860, 1470, 1252, 1150,

1101,1035, 859, 838 and 776; d_H(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-CH₃and SiC(CH₃)₃] and 0.08

(15H, m, 5ꢂSiCH₃); d_C(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 (M^þ, 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, SiCH₂and 6-CH₃) and 0.06 [9H, s, 3ꢂSiCH₃); d_C(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 (M^þþ18,

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, R_f¼0.25 (20% ether in light

petroleum); n_max/cm^ꢀ12952, 2883, 1580, 1440, 1311, 1245, 1139,

1099, 1029, 838 and 749; d_H(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 (M^þþ18, 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, R_f¼0.41 (30% ether in

light petroleum) (Found: M^þþNH₄, 594.3656. C₃₂H₅₆O₅NSSi re-

quires M, 594.3648); n_max/cm^ꢀ12930, 2877, 1667, 1448, 1376, 1315,

1249, 1150, 1093, 980, 838 and 748; d_H(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); d_C(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 (M^þþ18, 10%) and 90 (100).

a clear, viscous oil, R_f¼0.25 (20% ether in light petroleum); n_max

/

cm^ꢀ12952, 2886, 2861, 1727, 1466, 1364, 1315, 1252, 1150, 1087,

1035, 838 and 776; d_H(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); d_C(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 (M^þþ18, 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%), R_f¼0.10 (40% ether in light petroleum) (Found:

M^þþNH₄, 458.2402. C₂₂H₄₀O₅NSSi requires M, 458.2396); n_max

/

cm^ꢀ13469, 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; d_H(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,

R_f¼0.32 (20% ether in light petroleum) (Found: M^þþH, 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 Celite^Òand

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,

R_f¼0.20 (15% ether in light petroleum) (Found: M^þþH, 541.2515.

C

₂₈H₃₃O₃SSi requires M, 477.1920); n_max/cm^ꢀ12951, 2858, 2253,

1697, 1711, 1581, 1474, 1216, 1110, 805 and 752; d_H(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 (M^þþ18, 31%), 477 (M^þþ1, 100%).

C₃₄H₄₁O₂SSi requires M, 541.2518); d_H(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 (M^þþ1, 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, R_f¼0.30 (45% ether in

light petroleum); n_max/cm^ꢀ13425, 2951, 2858, 2253, 1637, 1473,

1383, 1217, 1110, 805 and 752; d_H(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]; d_C(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 (M^þþ18, 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, R_f¼0.22

(25% ether in light petroleum) (Found: M^þþNa, 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, R_f¼0.25 (10% ether in light petroleum)

(Found: M^þþNH₄, 560.3023. C₃₄H₄₆O₂NSSi requires M, 560.3018);

n_max/cm^ꢀ12951, 2858, 2253, 1650, 1470, 1381, 1210, 1110, 1060, 804

and 750; d_H(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-H₂and 6-H₂), 1.63 (4H, m, 4-H₂and 5-H₂) and

1.10 [9H, s, SiC(CH₃)₃]; d_C(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 (M^þþ18, 51%), 431

(50) and 175 (100).

C

₄₉H₆₆O₆NaS₂Si₂requires M, 893.3732); n_max/cm^ꢀ13064, 2947,

2864, 1471, 1442, 1380, 1313, 1248, 1148, 1102, 1034, 934, 834 and

743; d_H(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); d_C(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

(M^þþ23, 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, R_f¼0.32 (20% ether in light petro-

leum); n_max/cm^ꢀ12954, 2921, 2872, 1459, 1374, 1245, 1092, 1035,

855 and 834; d_H(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, 3ꢂCH₃and 6-CH₃) and 0.05

(9H, s, 3ꢂSiCH₃); d_C(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, R_f¼0.28 (15% ether in light petroleum); n_max

/

cm^ꢀ12954, 2921, 2872, 1461, 1374, 1246, 1092, 1035, 859 and 836;

d_H(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, 3ꢂCH₃and 6-CH₃) and 0.05 (9H, s, 3ꢂSiCH₃); d_C(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, d_H(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); d_C(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, R_f¼0.14 (40% ether in light petroleum)

(Found: M^þþNH₄, 472.2545. C₂₃H₄₂O₅NSSi requires M, 472.2547);

n_max/cm^ꢀ13512, 2951, 2890,1639,1447,1380,1313,1249,1150,1029,

935, 859, 837 and 749; d_H(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); d_C

(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 (M^þþ18, 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,

R_f¼0.23 (30% ether in light petroleum); n_max/cm^ꢀ13482br, 3470,

2951, 2885, 1635, 1537, 1479, 1379, 1266, 1095, 1054, 1025, 940, 836

and 738; d_H(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-CH⁰and 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); d_C(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

(M^þþ23, 100%). The second fraction was the title compound 30

(192 mg, 0.45 mmol, 81%) as a pale yellow oil, R_f¼0.22 (30% ether in

light petroleum); n_max/cm^ꢀ13483br, 3472, 2951, 2881, 1634, 1537,

1479, 1379, 1249, 1095, 1054, 1025, 936, 836 and 738; d_H(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-CH⁰and 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); d_C(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

(M^þþ23, 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, R_f¼0.17 (40% ether

in light petroleum) (Found: M^þþNH₄, 472.2545. C₂₃H₄₂O₅NSSi re-

quires M, 472.2547); d_H(300 MHz, CDCl₃) 7.92 (2H, d, J 7.0, ArH),

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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-CH⁰and 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); d_C

(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 (M^þþ18, 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-CH₃and SiC(CH₃)₃], 0.75 (3H, s, 1-CH₃), 0.14 (6H, s,

2ꢂSiCH₃) and 0.05 (9H, s, 3ꢂSiCH₃); d_C(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 (M^þþ1, 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, R_f¼0.21 (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; d_H(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-CH₃and 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, R_f¼0.25 (30% ether

in light petroleum) (Found: M^þ, 328.2058. C₁₇H₃₂O₄Si requires M,

328.2064); n_max/cm^ꢀ13410, 2953, 2934, 2859, 1731, 1464, 1384,

1253, 1139, 1102, 1034, 839 and 779; d_H(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); d_C(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 (M^þþ18, 10%) and 311 (100).

M^þþNH₄, 540.3355: C₂₈H₅₄O₃NSSi₂requires M, 540.3357); n_max

/

cm^ꢀ12953, 2930, 2886, 2859, 1618, 1583, 1474, 1359, 1251, 1152,

1097, 1030, 932, 837, 776 and 738; d_H(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); d_C(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 (M^þþ18,

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, R_f¼0.25 (20%

ether in light petroleum) (Found: M^þþNH₄, 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,

R_f¼0.40 (30% ether in light petroleum); n_max/cm^ꢀ13515br, 2943,

2866, 1464, 1382, 1249, 1096, 1052 and 834; d_H(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

₂₈H₅₄O₅NSSi₂requires M, 572.3256); n_max/cm^ꢀ12952, 2931, 2887,

2859, 1616, 1467, 1448, 1315, 1251, 1150, 1033, 837, 776 and 745; d_H

(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); d_C(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 (M^þþ18, 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, R_f¼0.20 (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); n_max/cm^ꢀ12955, 2918, 2872, 1460, 1374, 1241, 1096,

1035, 855 and 834; d_H(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, 3ꢂCH₃and 6-CH₃) and

0.06 (9H, s, 3ꢂSiCH₃); d_C(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, R_f¼0.25 (30% ether in

light petroleum) (Found: M^þþNa, 445.2203. C₂₃H₃₈O₃NaSSi re-

quires M, 445.2203); n_max/cm^ꢀ13470, 2951, 2881, 1634, 1479, 1535,

1375,1249,1095,1054,1025, 936, 836 and 738; d_H(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-H₂and 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 (M^þþ23, 100%). The

second fraction was the title compound 41 (281 mg, 0.62 mmol, 81%)

as a pale yellow oil, R_f¼0.22 (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; d_H

(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, R_f¼0.26 (15% ether in light

petroleum) (Found: M^þþNa, 735.3260. C₃₅H₆₄O₃NaSSi¹²⁰Sn re-

quires M, 735.3265); n_max/cm^ꢀ12954, 2921, 2872, 1461, 1374, 1247,

1035, 859 and 836; d_H(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, 3ꢂCH₃and 6-CH₃) and

0.04 (9H, s, 3ꢂSiCH₃); d_C(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 (M^þþ23, 48%)

and 565 (100).

M^þþNa, 445.2203. C₂₃H₃₈O₃NaSSi requires M, 445.2203); n_max

/

cm^ꢀ13483br, 2951, 2882, 1635, 1584, 1480, 1438, 1380, 1249, 1095,

1054, 1025, 836 and 738; d_H(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); d_C(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 (M^þþ23,

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, R_f¼0.20

(40% ether in light petroleum); d_H(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); d_C

(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, R_f¼0.17

(40% ether in light petroleum) (Found: M^þþNH₄, 472.2545.

C

₂₃H₄₂O₅NSSi requires M, 472.2547); n_max/cm^ꢀ13512, 2951, 2890,

1639, 1447, 1380, 1313, 1249, 1150, 1029, 935, 859, 837 and 749; d_H

(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); d_C(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 (M^þþ18, 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,

R_f¼0.65 (20% ether in light petroleum) (Found: M^þþNa, 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,

R_f¼0.24 (40% ether in light petroleum) (Found: M^þþNH₄, 534.2841.

C

₃₃H₅₀O₄Si₂Na requires M, 589.3140); n_max/cm^ꢀ12937, 2857, 1732,

1665, 1590, 1465, 1431, 1251, 1106, 1057, 838 and 778; d_H(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); d_C(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 (M^þþ23, 100%).

C₃₂H₄₄O₂SSiN requires M, 534.2857); d_H(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); d_C(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 (M^þþ18,

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, R_f¼0.30 (20% ether in light petroleum) (Found: M^þþNa,

685.3188. C₃₈H₅₄O₄NaSSi₂requires M, 685.3174); n_max/cm^ꢀ13069,

2953, 2933, 2857, 1665, 1588, 1467, 1312, 1253, 1149, 1107, 837, 777

and 742; d_H(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); d_C(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 (M^þþ23,

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, R_f¼0.51 (30% ether in light petroleum) (Found: M^þþNa,

562.3261. C₃₂H₅₁O₃Si₂Na requires M, 562.3269); n_max/cm^ꢀ13464,

2955, 2931, 2857, 1467, 1254, 1108, 1051, 837 and 777; d_H(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); d_C

(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 (M^þþ23, 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, R_f¼0.37 (15%

ether in light petroleum) (Found: M^þþNH₄, 648.3745. C₃₈H₅₈O₂N-

SSi₂requires M, 648.3721); n_max/cm^ꢀ13069, 2955, 2932, 2857, 1584,

1470, 1431, 1254, 1107, 1057, 838, 776 and 739; d_H(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); d_C(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 (M^þþ23, 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, R_f¼0.18 (40%

ether in light petroleum) (Found: M^þþNa, 571.2316. C₃₂H₄₀O₄NaSSi

requires M, 571.2309); n_max/cm^ꢀ13503, 3069, 2958, 2934, 2858,

1588, 1468, 1447, 1427, 1307, 1147, 1109, 1077, 822 and 743; d_H

(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); d_C(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 (M^þþ23, 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, R_f¼0.41 (20% ether in light petroleum) (Found: M^þþNa,

875.3518. C₄₅H₆₈O₄NaSSi¹²⁰Sn requires M, 875.3527); n_max/cm^ꢀ1

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

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14

T.J. Blackburn et al. / Tetrahedron xxx (2015) 1e17

742; d_H(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, 3ꢂCH₃and 6-CH₃); d_C(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); d_C(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,

R_f¼0.21 (30% ether in light petroleum); d_H(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); d_C(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, R_f¼0.59 (20% ether in light petroleum); n_max/cm^ꢀ13099, 2950,

2925, 2855,1460,1374,1246,1092,1035, 859 and 836; d_H(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, 3ꢂCH₃and 6-CH₃); d_C(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 (M^þþ23, 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, R_f¼0.19 (40% ether in light

petroleum) (Found: M^þþNa, 585.2465. C₃₃H₄₂O₄NaSSi requires M,

585.2465); n_max/cm^ꢀ13516, 3067,1469,1448,1428,1385,1312,1148,

1108, 1084, 1039 and 739; d_H(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); d_C

(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 (M^þþ23, 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,

R_f¼0.18 (40% ether in light petroleum) (Found: M^þþNa, 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, R_f¼0.18

(ether) (Found: M^þþNH₄, 342.1737. C₁₇H₂₈O₄NS requires M,

342.1734); n_max/cm^ꢀ13430, 2928, 1637, 1447, 1409, 1306, 1144, 1085

and 742; d_H(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); d_C(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 (M^þþ18, 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); n_max/cm^ꢀ13516, 3088, 2933,

2859, 1635, 1588, 1469, 1449, 1312, 1148, 1108, 739 and 703; d_H

(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); d_C(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

(M^þþ23, 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, R_f¼0.25 (30% ether in light petroleum); d_H(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, R_f¼0.20 (ether) (Found: M^þþNH₄, 342.1724. C₁₇H₂₈O₄NS re-

quires M, 342.1734); n_max/cm^ꢀ13436, 2925, 1636, 1448, 1305, 1143,

1085, 1021, 903 and 744; d_H(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); d_C(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 (M^þþ18, 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); d_C(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

(M^þþ23, 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, R_f¼0.20 (40% ether in light petroleum) (Found;

M^þþNH₄, 284.0506; C₉H₁₉ONI requires M, 284.0506); n_max/cm^ꢀ1

3331br, 3057, 2914, 2856, 1619, 1443, 1376, 1268, 1141, 1000 and

768; d_H(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-H₂and 5-H₂), 1.88 and

1.69 (each 3H, s, CH₃); d_C(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 (M^þþ18, 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: M^þþNa, 581.2373.

₃₀H₄₂O₆NaSSi requires M, 581.2364); n_max/cm^ꢀ12949, 2882, 1717,

1313, 1275, 1146, 1112, 1031 and 836; d_H(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); d_C(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 (M^þþ23, 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, R_f¼0.20 (1% ether in

light petroleum) (Found: M^þ, 380.1023. C₁₅H₂₉OISi requires M,

380.1027); n_max/cm^ꢀ12953, 2927, 2855,1470, 1461, 1253,1110,1069,

836 and 774; d_H(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-H₂and 5-H₂),

1.88 and 1.62 (each 3H, s, CH₃), 0.94 [9H, s, SiC(CH₃)₃] and 0.09 (6H,

s, 3ꢂSiCH₃); d_C(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 (M^þþ18, 18%), 381

(M^þþ1, 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: M^þþNa, 451.1559. C₂₄H₂₈O₅NaS requires M, 451.1550);

n_max/cm^ꢀ13492br, 3055, 2928, 1715, 1584, 1476, 1434, 1277, 1145,

1088,1027 and 744; d_H(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); d_C

(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 (M^þþ23, 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:

M^þþNa, 555.1812. C₃₁H₃₂O₆NaS requires M, 555.1812); n_max/cm^ꢀ1

1715, 1450, 1276, 1146, 1112 and 1025; d_H(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, R_f¼0.27 (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, R_f¼0.35 (40% ether in light

petroleum) (Found: M^þþNa, 957.4953. C₅₆H₇₈O₆NaSSi₂requires M,

957.4950); n_max/cm^ꢀ13069, 2930, 2856, 1666, 1628, 1588, 1461,

1385, 1318, 1257, 1150, 1105, 1039, 837, 776, 742 and 703; d_H

(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); d_C(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).

M^þþNa, 583.2316. C₃₃H₄₀O₄NaSSi requires M, 583.2309); n_max

/

cm^ꢀ13069, 2959, 2934, 2859, 1728, 1634, 1587, 1468, 1448, 1428,

1315, 1149, 1109, 1042, 911, 824 and 740; d_H(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); d_C

(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 (M^þþ23, 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, R_f¼0.25 (40% ether in light

petroleum) (Found: M^þþNa, 837.4386; C₄₈H₇₀O₅NaSSi₂requires M,

837.4375); n_max/cm^ꢀ13511br, 3071, 2956, 2931, 2857, 1629, 1588,

1447,1428,1387,1308,1254,1148,1108,1053, 837, 776, 741 and 704;

d_H(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); d_C(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 (M^þþ23, 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, R_f¼0.21 (50% ether in light

petroleum) (Found: M^þþNa, 843.4074; C₅₀H₆₄O₆NaSSi requires M,

843.4085); n_max/cm^ꢀ13523, 3068, 2929, 2856, 1447, 1383, 1307,

1158, 1103, 1038 and 702; d_H(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-H₂and 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); d_C(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 (M^þþ23, 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, R_f¼0.32 (40% ether in light petroleum); n_max/cm^ꢀ13070, 2931,

2857,1663,1628,1588,1447,1428,1385,1318,1308,1149,1104,1038,

910, 742 and 702; d_H(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-H₂and 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); d_C

(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 (M^þþ23, 100%).

1. (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.;

Hanzawa, H. J. Am. Chem. Soc. 1991 , 1 13 , 5463; (b) Sugano, M.; Sato, A.; Iijima, Y.;

Furuya, K.; Kuwano, H.; Hata, T. J. Antibiot. 1995 , 48 , 1 18.

2. (a) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996 , 37 , 7107;

(b) Goldring, W. P. D.; Pattenden, G. Chem. Commun. 2002 , 1 736; (c) Diaper, C.

M.; Goldring, W. P. D.; Pattenden, G. Org. Biomol. Chem. 2003 , 1 , 3949; (d) Mohr,

P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003 , 125 , 1 712; (e) Goldring, W. P. D.;

Pattenden, G. Org. Biomol. Chem. 2004 , 2 , 466; (f) Huang, J.; Wu, C.; Wulff, W. D.

J. Am. Chem. Soc. 200 7 , 129 , 13366; (g) Tang, Y.; Cole, K. P.; Buchanan, G. S.; Li, G.;

Hsung, R. P. Org. Lett. 2009 , 1 1 , 1591; (h) Buchanan, G. S.; Cole, K. P.; Tang, Y.;

Hsung, R. P. J. Org. Chem. 20 1 1 , 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.

6. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986 , 86 , 885; (b) Tsao, K.-W.; Cheng, C.-Y.;

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: M^þþNa, 825.3969. C₅₀H₆₂O₅NaSSi re-

quires M, 825.3979); n_max/cm^ꢀ13066, 2933, 2885, 2856, 1588, 1446,

1428, 380, 1304, 1143, 1109, 1085, 1035, 910 and 823; d_H(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-H₂and 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); d_C(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 (M^þþ23, 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 (R_int¼0.116), R1¼0.039 for the 3559

reﬂections with I>2

s

(I), wR(F²)¼0.112 (all data). CCDC 712103.

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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

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

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