An approach to aliphatic 1,8-stereocontrol: Diastereoselective syntheses of (±)-patulolide C and (±)-epipatulolide C

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An approach to aliphatic 1,8-stereocontrol: diastereoselective syntheses of

( )-patulolide C and ( )-epipatulolide C†

E. Kate Hoegenauer and Eric J. Thomas*

Received 22nd May 2012, Accepted 11th July 2012

DOI: 10.1039/c2ob25992c

The tin(IV) bromide promoted reaction of 7-hydroxy-7-phenylhept-2-enyl(tributyl)stannane 11 with

benzaldehyde gave a mixture of the epimeric 1,8-diphenyloct-3-ene-1,8-diols 12 and so indirect methods

were developed for aliphatic 1,8-stereocontrol to complete diastereoselective syntheses of ( )-patulolide

C 1 and ( )-epipatulolide C 40. (5Z)-3,7-syn-7-(2-Trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was

prepared from the tin(^IV) chloride promoted reaction of 4-(2-trimethylsilylethoxy)methoxypent-2-enyl

(tributyl)stannane 16 with acrolein (1,5-syn : 1,5-anti = 96 : 4). An Ireland–Claisen rearrangement of the

corresponding benzoyloxyacetate 21 with in situ esteriﬁcation of the resulting acid using

trimethylsilyldiazomethane gave methyl (4E,7Z)-2,9-anti-2-benzyloxy-9-(2-trimethylsilylethoxy)

methoxydeca-4,7-dienoate 22 together with 10–15% of its 2,9-syn-epimer 26, the 2,9-syn- : 2,9-anti-ratio

depending on the conditions used. An 88 : 12 mixture of esters was taken through to the tert-

butyldiphenylsilyl ether 38 of ( )-patulolide C 1 together with 6% of its epimer 39, by reduction, a Wittig

homologation and deprotection/macrocyclisation. Following separation of the epimeric silyl ethers,

deprotection of the major epimer 38 gave ( )-patulolide C 1. The success of 2,3-Wittig rearrangements of

allyl ethers prepared from (5Z)-3,7-syn-7-(2-trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was

dependent on the substituents on the allyl ether. Best results were obtained using the pentadienyl ether 56

and the cinnamyl ether 49 that rearranged with >90 : 10 stereoselectivity in favour of (1E,5E,8Z)-3,10-

syn-1-phenyl-10-(2-trimethylsilylethoxy)methoxyundeca-1,5,8-trien-3-ol 50. This product was taken

through to the separable silyl ethers 38 and 39, ratio 7 : 93 by regioselective epoxidation and alkene

reduction using diimide, followed by deoxygenation, ozonolysis, a Wittig homologation and selective

deprotection/macrocyclisation. Deprotection of the major epimer 39 gave ( )-epipatulolide C 40.

Tin(IV) halide promoted reactions of alkoxyalk-2-enylstan-

nanes with aldehydes have been found to proceed with useful

Introduction

Patulolide C 1¹is a naturally occurring 12-membered ring con-

taining macrolide with antifungal and antibiotic activity that has

been of considerable interest to synthetic chemists.²Its seco-acid

2 is characterised by the presence of stereogenic centres at the

4- and 11-positions, i.e. two stereogenic centres with a syn-1,8-

relationship.

levels of 1,5-, 1,6- and 1,7-stereocontrol.^3,4For example, 1,7-

stereocontrol in favour of the (Z)-1,7-syn-oct-3-ene-1,7-diols 4

was found for tin(^IV) bromide promoted reactions of the 6-hydro-

xyhept-2-enyl(tributyl)stannane 3 with aldehydes.³It was of

interest to see whether this chemistry could be applied to 1,8-

stereocontrol in aliphatic systems. In the event, direct 1,8-stereo-

control was found not to be viable using allylstannanes, but was

achieved by coupling 1,5-stereocontrol with a subsequent sigma-

tropic rearrangement. We here report details of this work together

with diastereoselective syntheses of ( )-patulolide C 3 and its

epimer using this chemistry.^5,6

The School of Chemistry, The University of Manchester, Manchester,

M13 9PL, UK. E-mail: e.j.thomas@manchester.ac.uk;

Fax: +00 44 (0)161 275 4639; Tel: +00 44 (0)161 275 4613

†Electronic supplementary information (ESI) available. See DOI:

10.1039/c2ob25992c

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Results and discussion

Studies of direct 1,8-stereocontrol

Following protection of 1-phenylbut-3-en-1-ol 5 as its tert-butyl-

dimethylsilyl ether 6,⁷hydroboration with an oxidative work-up

gave the butanol 7⁸that was converted into the corresponding

iodide 8, see Scheme 1. This was used to alkylate 3-methylimi-

dazol-2-yl prop-2-enylsulﬁde⁹to give the hept-1-en-3-yl sulﬁde

9, as a mixture of epimers. Treatment of this mixture with tri-

butyltin hydride under free radical conditions³gave the hept-2-

enylstannane 10 as a 67 : 33 mixture of (E)- and (Z)-isomers and

desilylation gave the 7-hydroxyhept-2-enylstannane 11. Tin(^IV)

bromide promoted reactions of stannane 11 with benzaldehyde

gave the (E)-1,8-diphenyloct-3-ene-1,8-diol 12, the trans-geome-

try of the double-bond being consistent with the vinylic coupling

constant of 15.8 Hz. Two isomers were apparent in the reverse

phase HPLC of the diol 12 and its bis-acetate 13, in a ratio of ca.

68 : 32. These were identiﬁed as the 1,8-syn- and 1,8-anti-(E)-

epimers of the diol 12 and bis-acetate 13 but which was which

was not investigated. Tin(^IV) halide promoted reactions of

7-hydroxyhept-2-enylstannanes with aldehydes would appear

not to proceed with useful levels of 1,8-stereocontrol.

Scheme 2 Synthesis of the 4-alkoxypent-2-enylstannane 16 and its

reaction with acrolein. Reagents and conditions i, Bu₃SnH, AIBN (cat.),

benzene, 65 °C, 1.5 h (89%); ii, SEMCl, ⁱPr₂NEt, DCM, 0 °C to r.t., 3 h

(83%); iii, SnCl₄, DCM, −78 °C, 10 min, then add acrolein, −78 °C,

10 min (77%; 1,5-syn-17 : 1,5-anti-20 = 96 : 4); iv, 4-NO₂C₆H₄COCl,

Et₃N, DMAP (cat.), DCM, r.t.,

2 h (78%); v, DEAD, Ph₃P,

4-NO₂C₆H₄CO₂H, benzene, r.t., 2 h (60%); vi, LiOH·H₂O, MeOH–H₂O,

r.t., 15 h (89%).

It was decided to see whether useful 1,8-stereocontrol could

be achieved combining the 1,5-syn-stereocontrol known for

4-alkoxypent-2-enylstannanes⁴with a subsequent sigmatropic

rearrangement, speciﬁcally with an Ireland–Claisen rearrange-

ment¹⁰or with a 2,3-Wittig rearrangement.¹¹If successful, this

chemistry could be used to complete a diastereoselective syn-

thesis of racemic patulolide C 1.

2-trimethylsilylethoxymethoxy (SEM) group was chosen with a

view to its selective removal at the end of the synthesis; only the

(E)-pent-2-enylstannane was isolated in this case.

The tin(^IV) chloride promoted reaction of the stannane 16 with

acrolein was carried out under the usual conditions at −78 °C

and gave the (5Z)-3,7-syn-7-(2-trimethylsilylethoxy)methoxy-

octa-1,5-dien-3-ol 17 with excellent 1,5-stereoselectivity, see

Scheme 2. The cis-geometry was assigned to the internal

double-bond of the product 17 on the basis of the vinylic coup-

ling constant of 11 Hz and its 1,5-syn-conﬁguration was assigned

by analogy with earlier work.^3,13The major product 17 was con-

verted into its epimer 20 by a Mitsunobu reaction using 4-nitro-

benzoic acid followed by saponiﬁcation of the resulting

1

4-nitrobenzoate 19. The H and ¹³C NMR spectra of the epi-

meric alcohols 17 and 20 were very similar but one of the dia-

stereotopic OCH₂O hydrogens had slightly different chemical

shifts for the two epimers, at δ 4.73 for 17 and at δ 4.69 for 20,

and this enabled the stereoselectivity of the reaction of acrolein

with the allylstannane 16 to be estimated as 96 : 4. The alcohol

17 was also converted into its 4-nitrobenzoate 18 with retention

of conﬁguration but the nitrobenzoates 18 and 19 could not be

distinguished by NMR.

The 3,7-syn- and anti-octadienols 17 and 20 were esteriﬁed

using benzyloxyacetyl chloride to give the esters 21 and 25.

Ireland–Claisen rearrangements^10,14,15involve the formation of

ketene silyl acetals from allylic esters, trimethylsilyl chloride

either being present during the deprotonation step¹⁶or added to

the preformed enolate. The silyl ketene acetals then undergo the

required [3,3]-sigmatropic shift and an aqueous work-up with

subsequent esteriﬁcation provides rearranged products. Both pro-

cedures were investigated using the esters 21 and 25.

Scheme 1 Attempted 1,8-stereocontrol using 7-hydroxy-7-phenylhept-

2-enylstannane 11. Reagents and conditions i, TBSCl, imid., DCM, r.t.,

15 h (95%); ii, 9-BBN, THF, r.t., 2.5 h, then NaOH, H₂O, EtOH, 30%

H₂O₂(86%); iii, Ph₃P, imid., I₂, THF, r.t., 1.5 h (90%); iv, 3-methylimi-

dazol-2-yl prop-2-enyl sulﬁde, BuLi, hexanes, THF, −78 °C, 30 min,

HMPA, −78 °C, 30 min, add 8, 1 h (74%); v, Bu₃SnH, AIBN (cat.),

benzene, heat under reﬂux, 1 h [89%, (E) : (Z) = 67 : 33]; vi, TBAF,

THF, r.t., 4 h (69%); vii, SnBr₄, DCM, −78 °C, 5 min, benzaldehyde,

−78 °C, 20 min (81%, 68 : 32 mixture of epimers); viii, Ac₂O, Et₃N,

DMAP (cat.), DCM, r.t., 3 h (82%).

1,8-Stereocontrol by combining (Z)-1,5-syn-stereoselectivity with

an Ireland–Claisen rearrangement

The (E)-4-(2-trimethylsilylethoxy)methoxypent-2-enylstannane

16 was prepared by treatment of the allylic sulfone 14¹²with

tributyltin hydride under free radical conditions followed by

protection of the resulting hydroxypentenylstannane 15 using

(2-trimethylsilylethoxy)methyl chloride, see Scheme 2. The

The Ireland–Claisen rearrangement of the 3,7-syn-ester 21

using lithium hexamethyldisilazide as the base and trimethylsilyl

chloride at −78 °C, after esteriﬁcation of the initially formed

acid using trimethylsilyl diazomethane, gave what appeared to

be a single ester, subsequently identiﬁed as predominantly the

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2,9-anti-dialkoxydeca-4,7-dienoate 22. Better yields, 89%, could

be obtained if the trimethylsilyl chloride was present during the

deprotonation, but the procedure whereby trimethylsilyl chloride

was added after the deprotonation was more reliable with yields

of ca. 78%. Rearrangement of the 3,7-anti-ester 25 using the

in situ trimethylsilyl chloride procedure, after esteriﬁcation using

trimethylsilyl diazomethane, gave the 2,9-syn-ester 26.

The Ireland–Claisen products 22 and 26 were indistinguish-

1

able by H or ¹³C NMR. Deprotection of ester 26 using butane-

thiol and magnesium bromide under buffered conditions¹⁷

gave alcohol 27 that was esteriﬁed directly using 4-nitrobenzoyl

chloride to give the 2,9-syn-ester 28 and with inversion of

conﬁguration using Mitsunobu conditions to give the inverted

2,9-anti-ester 24. The anti- and syn-esters 24 and 28 were found

1

to have slightly different H NMR spectra in benzene-d₆. For

Scheme 3 Ireland–Claisen rearrangements of the esters 21 and 25.

Reagents and conditions i, (a) TMSCl, THF, −78 °C, 5 min, add

LiHMDS, −78 °C, r.t., 20 min, (b) TMSCHN₂, hexanes, MeOH,

benzene, r.t., 1 h (89%; 22 : 26 = 67 : 33); ii, (a) LiHMDS, THF,

−78 °C, 1.5 min, TMSCl, −78 °C, 20 min, r.t., 20 min, (b)

Me₃SiCHN₂, hexanes, MeOH, benzene, r.t., 1 h (78%; 22 : 26 =

88 : 12); iii, 40% HF in H₂O, MeCN, r.t., 5 h (75%); iv, 4-NO₂C₆H₄-

COCl, Et₃N, DCM, r.t., 2 h (90%; 24 : 28 = 88 : 12); v, (a) TMSCl, THF,

−78 °C, 5 min, add LiHMDS, −78 °C, r.t., 20 min, (b) TMSCHN₂,

hexanes, MeOH, benzene, r.t., 1 h (76%; 26 : 22 = 89 : 11); vi, BuSH,

K₂CO₃, MgBr₂·Et₂O, ether, r.t., 7 h (53%); vii, 4-NO₂C₆H₄COCl, Et₃N,

example, the doublets assigned to 10-H₃were observed at δ 1.25

and at δ 1.26 for the 2,9-anti- and 2,9-syn-epimers 24 and 28,

respectively, and could be used to estimate the ratio of the two

epimers. The product ratios from the rearrangements of the 3,7-

syn- and 3,7-anti-esters 21 and 25 were then estimated by depro-

tection and conversion of the resulting alcohols into their 4-nitro-

benzoates. The rearrangement of the 3,7-anti-ester 25 when

trimethylsilyl chloride was present during the deprotonation step

took place with 89 : 11 stereoselectivity in favour of the 2,9-syn-

epimer 26. The stereoselectivity of the rearrangement of the 3,7-

syn-ester 21 was found to depend slightly on the conditions

used. Lower stereoselectivity was found if the trimethylsilyl

chloride was present during the deprotonation step, 2,9-anti-

22 : 2,9-syn-26 = 67 : 33, but better stereoselectivity, 2,9-anti-

22 : 2,9-syn-26 = 88 : 12, was observed if the trimethylsilyl

chloride was added after the base. Better yields were obtained

using lithium hexamethyldisilazide, 78–89%, rather than lithium

diisopropylamide, 50–55% or potassium hexamethyldisilazide

(Scheme 3).

DCM, r.t.,

2 h (79%; 28 : 24 = 89 : 11); viii, DEAD, Ph₃P,

4-NO₂C₆H₄CO₂H, benzene, r.t., 2 h (60%; 24 : 28 = 89 : 11).

The structures of the rearrangement products 22 and 26 were

consistent with their spectroscopic data. The conﬁgurations of

their double-bonds were conﬁrmed by their vinylic coupling

constants. The relative conﬁgurations of their stereogenic centres

were assigned on the basis of participation of (Z)-ketene acetals

generated from chelated lithium enolates of the esters 21 and 25

that rearrange through chair-like transition structures,^14,16e.g. the

ketene acetal 29 derived from the 3,7-syn-ester 21 gives the 2,9-

anti-epimer 22. These structures were conﬁrmed by the com-

pletion of a synthesis of patulolide C 1, vide infra. Of interest

was the fact that the 96 : 4 mixture of epimeric octa-1,5-dien-3-

ols 17 and 20 gave an 88 : 12 mixture of the epimeric 2,9-di-

alkoxydecadienoates 22 and 26 via the Ireland–Claisen

rearrangement of the 3,7-syn-ester 21, and an 89 : 11 mixture of

the 2,9-dialkoxydienoates 26 and 22 via rearrangement of the

3,7-anti-ester 25. It would appear that there had been about an

8% loss of stereochemical integrity during these [3,3]-sigmatropic

rearrangements (Fig. 1).

Fig. 1 Participation of the (Z)-ketene silyl acetal 29 in the Ireland–

Claisen rearrangement of ester 21.

hydrogen and 10% palladium on charcoal to give the alcohol 32,

see Scheme 4. Following protection of this alcohol as its tert-

butyldiphenylsilyl ether 33, reduction of the ester to the primary

alcohol 34 was achieved using lithium triethylborohydride. Oxi-

dation to the corresponding aldehyde was then carried out using

Swern conditions and the aldehyde was immediately converted

into the (E)-αβ-unsaturated ester 35 by a Wittig reaction with the

(E)-conﬁguration of the alkene being conﬁrmed by ¹H NMR.

Selective removal of the SEM-protecting group using butanethiol

and magnesium bromide diethyl etherate under buffered con-

ditions gave the alcohol 36 and saponiﬁcation gave the seco-acid

37. Macrolactonisation was carried out using the modiﬁed

Yamaguchi procedure and gave the epimers 38 and 39,^2hratio

94 : 6, that could be separated by chromatography. Desilylation

of the major macrolide 38 using tetrabutylammonium ﬂuoride

gave ( )-patulolide C 1.¹

Completion of a stereoselective synthesis of ( )-patulolide C

To avoid hydrogenolysis of the allylic carbon–oxygen bond, the

2,9-anti-dialkoxydecadienoate 22 was reduced using diimide to

give the 2,9-syn-ester 31. This was then hydrogenolysed using

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Scheme 4 Completion of a synthesis of ( )-patulolide C 1. Reagents and conditions i, TsNHNH₂, NaOAc, DME, heat under reﬂux, 5 h (93%); ii,

10% Pd/C, EtOH, r.t., 72 h (87%); iii, TBDPSCI, imid., DCM, r.t., 2 h (98%); iv, LiBHEt₃, THF, −10 °C, 30 min (89%); v, (a) DMSO, (COCl)₂,

DCM, −78 °C, 10 min, add 34, −78 °C, 5 h, Et₃N, r.t., (b) Ph₃PvCHCO₂Me, DCM, r.t., 15 h (72%); vi, BuSH, K₂CO₃, MgBr₂·Et₂O, ether, r.t., 2 h

(89%); vii, LiOH·H₂O, MeOH, H₂O, r.t., 15 h; viii, Et₃N, 2,6-Cl₂C₆H₃COCl, THF, r.t., 2 h, toluene, add to DMAP, toluene, heat under reﬂux, 5 h

(38, 47%; 39, 3%); ix, TBAF, THF, r.t., 3 h (76%).

The structures of the intermediates along this series were con-

sistent with their spectroscopic data. Both patulolide C 1, its

epimer 40 and the tert-butyldiphenylsilyl ethers 38 and 39 are

known compounds with distinctive ¹H NMR spectra.^1,2hThe for-

mation of macrolide 38, the precursor of patulolide C 1, as the

dominant product from the macrocyclisation, conﬁrmed the anti-

conﬁguration assigned to the ester 22 on the basis of the pro-

posed mechanism of the [3,3]-sigmatropic rearrangement. It is

likely that the 88 : 12 mixture of epimers 22 and 26 translated

into a 94 : 6 mixture of macrolides 38 and 39 during this syn-

thesis due to peak shaving during chromatography of the inter-

mediates. The selectivity of formation of 38 also indicated that

little epimerisation had taken place during the Swern oxidation

Scheme 5 Synthesis of precursors of Wittig rearrangements. Reagents

and conditions: i, N₂CHCO₂Et, Rh₂(OAc)₄, DCM, r.t., 30 min (61%); ii,

of alcohol 34 and the Wittig reaction of the resulting aldehyde.

DIBAL-H, DCM, −60 to −45 °C, 1 h (61%); iii, Ph₃PCHCO₂Me, DMF,

r.t., 15 h [(E)-isomer 70%; (Z)-isomer 4%); iv, 47, DBU, LiCl, MeCN,

1,8-Stereocontrol by combining (Z)-1,5-syn-stereoselectivity with

r.t., add 45, r.t., 48 h (60%).

a 2,3-Wittig rearrangement

It was decided to study 2,3-Wittig rearrangements of precur-

sors that would be just slightly more acidic than the propenyl

and propynyl ethers 41 and 42. Alkylation of the 3,7-syn-octa-

dienol 17 using (E)-cinnamyl bromide gave the ether 49. In this

case, treatment with butyllithium initiated a clean 2,3-Wittig

rearrangement to give the 3,10-syn-undeca-1,5,8-trien-3-ol 50,

see Scheme 6. The ¹H NMR spectrum of this 2,3-Wittig

rearrangement product conﬁrmed its gross structure and double-

bond geometry. To see whether the syn- and anti-3,10-epimers

could be distinguished, alcohol 50 was oxidised to the ketone 52

that was reduced using sodium borohydride to give a mixture of

the epimeric alcohols 50 and 53. This mixture was esteriﬁed to

give a mixture of esters 51 and 54, the former also having been

The prop-2-enyl and prop-2-ynyl ethers 41 and 42 were prepared

from the alcohol 17 but gave the linear triene 43¹⁷as a mixture

of geometrical isomers on treatment with butyllithium.

More acidic 2,3-rearrangement precursors were prepared by

alkylation of the octadienol 17 using ethyl diazoacetate.¹⁸

Reduction of the resulting alkoxyacetate 44 using diisobutyl-

aluminium hydride gave the aldehyde 45 and a Wittig condensation

provided the αβ-unsaturated ester 46. A condensation of the

aldehyde 45 with the phosphonate 47¹⁹gave the oxazoline 48,

see Scheme 5. However, attempted 2,3-Wittig rearrangements of

the esters 44 and 46, and the oxazoline 48, in our hands gave

complex mixtures of products.

1

prepared by direct acylation of the syn-alcohol 50. The H and

expanded ¹³C NMR spectra of the mixtures of epimeric alcohols

50 and 53 and esters 51 and 54 showed the presence of a

ca. 50 : 50 mixture of two isomers. Examination of the Wittig

rearrangement product 50 and its benzoate 51 indicated that the

rearrangement had given the 3,10-syn- and anti-products in a

ratio of ca. 90 : 10.

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Scheme 7 Further 2,3-Wittig rearrangements. Reagents and conditions

i, NaH, THF, (E)-CH₂vCH·CHvCH·CH₂Br, ⁿBu₄NI (cat.), r.t., 15 h

(76%); ii, ⁿBuLi, hexanes, THF, −78 °C, 3 h (70%); iii, NaH, THF,

30 min, ⁿBu₄NI (cat.), 1-bromo-3,3-diphenylprop-2-ene, r.t., 15 h

(83%); iv, (a) ⁿBuLi, hexanes, THF, −78 °C, 2.5 h, (b) BuPh₂SiCl,

t

Scheme 6 2,3-Wittig rearrangement of the (E)-cinnamyl ether 49.

Reagents and conditions i, NaH, THF, ⁿBu₄NI (cat.), (E)-

PhCHvCHCH₂Br, r.t., 15 h (70%); ii, ⁿBuLi, −78 °C, THF, 3 h (72%);

iii, PhCOCl, Et₃N, DMAP (cat.), r.t., 2 h (79%); iv, DMSO, (COCl)₂,

DCM, −78 °C, 10 min, add 50, −78 °C, 1 h, Et₃N, 15 min (38%); v,

NaBH₄, EtOH, 0 °C to r.t., 15 h (52%); vi, PhCOCl, Et₃N, DMAP

(cat.), r.t., 2 h (51%; 51 : 54 = 50 : 50).

imid., DMF, r.t., 5 h (35%).

as its tert-butyl dimethylsilyl ether 62 and the remaining double-

bonds reduced using diimide to give the saturated epoxide 64,

see Scheme 8.

However, epoxide 64 was found to be relatively inert to peri-

odic acid, perhaps because of solubility problems, and although

ring-opening was achieved using sodium acetate in glacial acetic

acid, this gave a mixture of regio- and stereo-isomeric hydroxy-

acetates. To see whether the double-bonds in the undecatrienol

could be differentiated before epoxidation, the tert-butyldiphe-

nylsilyl ether 66 was prepared but reduction of this hindered

silyl ether using diimide gave the dialkoxyundecane 67 with no

intermediate alkenes being isolated.

Reverting to the hydroxyepoxide 61, protection using tert-

butyldiphenylsilyl chloride gave the silyl ether 63 and this was

reduced using diimide to give the saturated epoxide 65. Treat-

ment with samarium iodide²¹then effected a deoxygenation to

give the undecene 68 albeit as a 66 : 34 mixture of (E)- and

(Z)-isomers. This mixture was not separated, instead ozonolysis

with a reductive work-up gave the corresponding aldehyde that

was taken through to the αβ-unsaturated ester 69 using a Wittig

condensation. Selective removal of the SEM-group, saponiﬁca-

tion and macrocylisation then gave the macrolide 39 together

with its epimer 38, ratio 39 : 38 = 93 : 7,^2hand desilylation of the

major silyl ether 39 completed a synthesis of epipatulolide C

40,¹see Scheme 8.

Fig. 2 Formation of the 3,10-syn-undecatrienol 50.

The 3,10-syn-conﬁguration of the two stereogenic centres in

the major Wittig rearrangement product 50 was assigned on the

basis that the rearrangement of the lithiated ether had proceeded

via an envelope conformation with the cinnamyl group in a

pseudo-equatorial position, see Fig. 2.²⁰This was conﬁrmed by

the completion of a synthesis of ( )-epipatulolide C 40.

2,3-Wittig rearrangements of other ethers were also brieﬂy

investigated. O-Alkylation of the 3,7-syn-octadienol 17 with (E)-

1-bromopenta-2,4-diene gave the ether 56. This underwent a

stereoselective 2,3-Wittig rearrangement on treatment with butyl-

1

lithium to give the trideca-1,3,7,10-tetraen-5-ol 57. By H NMR

this appeared to be essentially a single compound, the 5,12-syn-

conﬁguration being assigned by analogy to the stereoselectivity

of rearrangement of the cinnamyl ether 49. In contrast, rearrange-

ment of the 3,3-diphenylprop-2-enyl ether 58, also prepared by

O-alkylation of the syn-octadienol 17, gave a mixture of pro-

ducts. The expected alcohol 59 could not be separated from this

mixture, but silylation of the crude reaction mixture gave a

modest yield of a 2 : 1 mixture of epimeric silyl ethers 60, see

Scheme 7.

In this synthesis the structures of the intermediates were con-

sistent with spectroscopic data and the structures of the macro-

lides were conﬁrmed by comparison with samples prepared

earlier during the synthesis of patulolide C 1 outlined in

Scheme 4.

Summary and conclusions

Completion of a stereoselective synthesis of ( )-epipatulolide C

The synthesis of aliphatic compounds with remote stereogenic

centres is usually achieved by joining together two enantiomeri-

cally enriched starting materials to avoid the formation of diaster-

eoisomers. The work outlined in this paper has illustrated

an alternative approach whereby stereocentres that have a 1,8-

relationship can be introduced diastereoselectively using a single

chiral starting material. The stereogenic centre in a 4-alkoxyalk-

2-enylstannane is used to control the conﬁguration of a new

stereogenic centre ﬁve carbons down an aliphatic chain and the

To convert the syn-3,10-undecatrienol 50 into epipatulolide C

40, it was necessary to cleave oxidatively the 1,2-double-bond,

hydrogenolyse the remaining double-bonds, homologate and

effect macrocyclisation. Regioselective epoxidation of the un-

decatrienol 50 directed by the hydroxyl group using tert-butyl

hydroperoxide and vanadyl acetoacetate gave epoxide 61 as a

mixture of two diastereoisomers together with a small amount of

a bis-epoxide. The mixture of hydroxyepoxides 61 was protected

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t

Scheme 8 Synthesis of ( )-epipatulolide C 40. Reagents and conditions i, BuOOH, VO(acac)₂, benzene, r.t., 10 min (76%); ii, BuMe₂SiCI, imid.,

t

DMF, r.t., 15 h (77%); iii, BuPh₂SiCI, imid., DCM, r.t., 18 h (93%); iv, TsNHNH₂, NaOAc, H₂O, DME, heat under reﬂux, 4–4.5 h (64, 87%; 65,

85%; 67, 68%); v, BuPh₂SiCI, imid., DCM, r.t., 2.5 h (82%); vi, SmI₂, THF, r.t., 3 h [56%; (E) : (Z) = 75 : 25]; vii, (a) O₃, DCM, −78 °C, 1.5 h,

Me₂S, r.t., (b) Ph₃PCHCO₂Me, DCM, r.t., 15 h (61%); viii, BuSH, K₂CO₃, MgBr₂·Et₂O, ether, r.t., 2 h (79%); ix, (a) LiOH·H₂O, MeOH, H₂O, r.t.,

t

15 h, (b) Et₃N, 2,6-Cl₂C₆H₃COCI, THF, r.t., 2 h, toluene, add to DMAP, toluene, heat under reﬂux, 5 h (39, 56%); x, TBAF, THF, r.t., 3 h (61%).

chirality at this centre is then migrated down the chain to effect

overall 1,8-stereocontrol. The optical purity of the products

depends on the optical purity of the starting materials, but as the

original stereogenic centre in the stannane is used to control the

relative conﬁguration of the remote stereogenic centre, this

chemistry can also be used to effect diastereoselective syntheses

of racemic compounds with remote stereogenic centres as illus-

trated by the stereoselective syntheses of ( )-patulolide C 1 and

its epimer 40. This approach could be extended to include com-

pounds with even more widely dispersed stereocentres and has

been applied to effect 1,9-stereocontrol.²²It has also been used

to develop an approach to the total synthesis of epothilones^23,24

and should be useful for the stereoselective synthesis of other

aliphatic compounds with remote stereocentres.

petroleum ether distilled between 40–60 °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 2,2′-bipyridine as an indicator. Triethylamine and diisopro-

pylamine were dried over potassium hydroxide pellets. Brine

refers to saturated aqueous sodium chloride.

General procedure: Ireland–Claisen rearrangement with in situ

trimethylsilyl chloride

Trimethylsilyl chloride (4.2 equiv.) was added to the ester in

THF at −78 °C. After 5 min, the lithium hexamethyldisilazide

(4.0 equiv.) was added and the solution stirred for 20 min then

warmed to room temperature and stirred for a further 20 min.

Saturated aqueous ammonium chloride was added and aqueous

phase extracted with ethyl acetate. The organic extracts were

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure.

Experimental

General experimental procedures

¹H and ¹³C NMR spectra were recorded on Varian Unity 500,

Varian Unity Inova 400 and Varian Unity Inova 300 spectro-

meters. IR spectra were recorded on an ATI Mattson Genesis

FTIR, as thin ﬁlms, produced by evaporation of a chloroform

solution, or as liquid ﬁlms, on sodium chloride plates. Mass

spectra were recorded on Fisson VG Trio 2000 and Kratos

Concept spectrometers. Chemical ionisation (CI) was performed

using ammonia. Typical clusters of isotope peaks were observed

for tin containing compounds. Only those corresponding to

¹²⁰Sn are reported. Chromatography refers to ﬂash column

chromatography using silica gel 60 (230–400 mesh).

Tetrahydrofuran (THF) was dried and distilled from sodium

metal using benzophenone as an indicator under an atmosphere

of nitrogen. Dichloromethane (DCM) was dried and distilled

from calcium hydride under an atmosphere of nitrogen. Ether

refers to diethyl ether, which was dried and distilled from

sodium metal using benzophenone as an indicator under an

atmosphere of nitrogen. Light petroleum refers to the fraction of

General procedure: Ireland–Claisen rearrangement with

trimethylsilyl chloride added after the base

Lithium hexamethyldisilazide (1.3 equiv.) was added to the ester

in THF at −78 °C. After 90 s, trimethylsilyl chloride (1.6 equiv.)

was added and the solution stirred for 20 min then warmed to

room temperature and stirred for a further 20 min. Saturated

aqueous ammonium chloride was added and the aqueous phase

extracted with ethyl acetate. The organic extracts were washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure.

General procedure: methylation of acids with

trimethylsilyldiazomethane

Trimethylsilyldiazomethane (2.0 M in hexanes, 1.2 equiv.) was

added to the crude acid in methanol–benzene (1 : 4) and the

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solution stirred for 1 h. Concentration under reduced pressure

and chromatography gave the methyl ester.

0.18 (each 3 H, s, SiCH₃), 1.03 [9 H, s, SiC(CH₃)₃], 1.86–2.08

(4 H, m, 2-H₂and 3-H₂), 3.30 (2 H, m, 4-H₂), 4.83 (1 H, t,

J 6.3, 1-H) and 7.42 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) −5.1,

−4.7, 7.0, 18.1, 25.8, 29.5, 41.4, 73.9, 125.7, 127.0, 128.0 and

145.0; m/z (CI) 408 (M⁺+ 18, 2%), 391 (M⁺+ 1, 1), 350 (2),

276 (100), 259 (18) and 148 (22).

1-tert-Butyldimethylsilyloxy-1-phenylbut-3-ene 6.⁷Imidazole

(5.52 g, 81.0 mmol) and tert-butyldimethylsilyl chloride (5.88 g,

39.0 mmol) were added to the alcohol 5 (4.80 g, 32.0 mmol) in

DCM (40 mL) and the solution stirred overnight. Saturated

aqueous ammonium chloride was added and the aqueous phase

extracted with DCM. The organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(3%), gave the title compound 6⁷(7.98 g, 95%) as a colourless

oil (Found: M⁺+ H, 263.1829. C₁₆H₂₇SiO requires M,

263.1831); ν_max/cm⁻¹3077, 3029, 2954, 2931, 2857, 1641,

1467, 1362, 1254, 1089, 1069, 1005, 915, 836, 776 and 699; δ_H

(300 MHz, CDCl₃) 0.00 and 0.16 (each 3 H, s, SiCH₃), 1.01

[9 H, s, SiC(CH₃)₃], 2.56 (2 H, m, 2-H₂), 4.81 (1 H, dd, J 5.2,

7.1, 1-H), 5.14 (2 H, m, 4-H₂), 5.91 (1 H, m, 3-H) and 7.40

(5 H, m, ArH); δ_C(75 MHz, CDCl₃) −5.0, −4.7, 18.2, 25.8,

45.5, 74.9, 116.8, 125.8, 126.9, 127.9, 135.2 and 145.0; m/z (CI)

263 (M⁺+ 1, 1%), 188 (2), 171 (3) and 131 (100).

1-tert-Butyldimethylsilyloxy-5-[(1-methyl-1H-2-imidazolyl)-

sulfanyl]-1-phenylhept-6-ene 9. Butyllithium (4.7 mL, 1.63 M

in hexanes, 7.64 mmol) was added to 2-(prop-2-enylsulfanyl)-

1-methyl-1H-imidazole (0.98 g, 6.36 mmol) in THF (20 mL) at

−78 °C. After 30 min, HMPA (2.2 mL, 12.7 mmol) was added

and the solution stirred at −78 °C for 30 min. The iodide 8

(2.48 g, 6.36 mmol) in THF (5 mL) was added and the solution

stirred for 1 h. Saturated aqueous ammonium chloride was added

and the mixture allowed to warm to room temperature. The

aqueous phase was extracted with ether and the organic extracts

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (30%), gave the title compound 9 (1.94 g,

74%) as a clear, colourless oil, a mixture of epimers (¹³C NMR)

(Found: M⁺+ H, 417.2391. C₂₃H₃₇N₂SSiO requires M,

417.2396); ν_max/cm⁻¹3063, 3028, 2930, 2856, 1455, 1279,

1253, 1093, 1067, 837, 775 and 699; δ_H(300 MHz, CDCl₃)

0.00 and 0.17 (each 3 H, s, SiCH₃), 1.03 [9 H, s, SiC(CH₃)₃],

1.45–1.94 (6 H, m, 2-H₂, 3-H₂and 4-H₂), 3.81 (3 H, s, NCH₃),

3.93 (1 H, dt, J 5.8, 9.2, 5-H), 4.77 (1 H, m, 1-H), 5.03 (2 H, m,

7-H₂), 5.85 (1 H, dt, J 16.3, 9.2, 6-H), 7.09 (1 H, br. s, 9-H),

7.25 (1 H, t, J 1.1, 8-H) and 7.43 (5 H, m, ArH); δ_C(75 MHz,

CDCl₃) −5.0, −4.7, 18.1, 23.2, 23.4, 25.8, 33.6, 34.0, 34.1,

40.4, 40.5, 53.4, 74.7, 74.8, 116.1, 116.0, 122.4, 125.7, 126.7,

127.9, 129.6, 138.4 and 145.5; m/z (CI) 417 (M⁺+ 1, 100%)

and 115 (76).

4-tert-Butyldimethylsilyloxy-4-phenylbutan-1-ol 7.⁸The butene

6 (2.0 g, 7.63 mmol) in THF (15 mL) was added to 9-borabicyclo-

[3.3.1]nonane (16.8 mL, 0.5 M in THF, 8.40 mmol). The

solution was stirred for 2.5 h, after which time a mixture of

aqueous sodium hydroxide (6 mL, 0.5 M) and ethanol (5 mL)

was added, followed by aqueous hydrogen peroxide (3 mL,

30%). Saturated aqueous potassium carbonate was added and the

layers separated. The aqueous phase was extracted with ether

and the organic extracts washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (10%), gave the title

compound 7⁸(1.82 g, 86%) as a clear, colourless oil (Found:

M⁺+ H, 281.1943. C₁₈H₂₉SiO₂requires M, 281.1937);

ν_max/cm⁻¹3453, 2926, 2857, 1470, 1451, 1413, 1326, 1299,

1250, 1164, 1092, 1034, 837, 776 and 700; δ_H(300 MHz,

CDCl₃) −0.09 and 0.07 (each 3 H, s, SiCH₃), 0.93 [9 H, s,

SiC(CH₃)₃], 1.50–1.93 (4 H, m, 2-H₂and 3-H₂), 3.65 (2 H, m,

1-H₂), 4.76 (1 H, dd, J 4.0, 6.0, 4-H) and 7.33 (5 H, m, ArH);

δ_C(75 MHz, CDCl₃) −5.0, −4.6, 18.3, 25.9, 28.6, 37.2, 63.0,

74.8, 125.9, 126.9, 128.1 and 145.2; m/z (CI) 281 (M⁺+ 1, 4%),

172 (58) and 144 (100).

7-tert-Butyldimethylsilyloxy-7-phenylhept-2-en-1-yl(tributyl)-

stannane 10. Tributyltin hydride (1.43 mL, 5.51 mmol) and

AIBN (50 mg) were added to the sulﬁde 9 (1.91 g, 4.60 mmol)

in benzene (20 mL). The mixture was thoroughly degassed then

heated under reﬂux for 1 h. After concentration under reduced

pressure, chromatography of the residue, eluting with triethyl-

amine–petrol (1%), gave the title compound 10 (2.17 g, 89%) as

a clear, colourless oil, a 67 : 33 mixture of (E)- and (Z)-isomers

(¹H NMR) (Found: M⁺− C₄H₉, 537.2575. C₂₇H₄₉Si¹²⁰SnO

requires M, 537.2373); ν_max/cm⁻¹2955, 2927, 2855, 1460,

1361, 1253, 1092, 836, 775 and 699; δ_H(300 MHz, CDCl₃)

0.00 and 0.17 (each 3 H, s, SiCH₃), 1.01 (15 H, m, 3 ×

CH₃CH₂), 1.03 [9 H, s, SiC(CH₃)₃], 1.42 (6 H, m, 3 × CH₂),

1.60 (6 H, m, 3 × CH₂Sn), 1.69–1.85 (6 H, m, 1-H₂, 5-H₂and

6-H₂), 2.09 (2 H, m, 4-H₂), 4.76 (1 H, m, 7-H), 5.12 (0.33 H, m,

3-H), 5.32 (0.67 H, dt, J 16.6, 5.8, 3-H), 5.53 (0.33 H, m, 2-H),

5.64 (0.67 H, dt, J 16.6, 8.3, 2-H) and 7.42 (5 H, m, ArH); δ_C

(75 MHz, CDCl₃) major (E)-isomer −4.9, −4.6, 9.1, 9.3 13.8,

14.1, 18.3, 25.9, 27.4, 29.2, 32.7, 40.8, 75.2, 125.6, 125.9,

126.7, 128.0, 129.2 and 146.0; m/z (EI) 537 (M⁺− 57, 1%), 365

(2), 289 (21), 247 (100), 221 (51) and 75 (52).

1-tert-Butyldimethylsilyloxy-4-iodo-1-phenylbutane 8. Imida-

zole (0.24 g, 3.57 mmol), triphenylphosphine (0.47 g,

1.79 mmol) and iodine (0.46 g, 1.79 mmol) were added to the

alcohol 7 (500 mg, 1.79 mmol) in THF (25 mL) and the solution

stirred at room temperature for 1.5 h. Saturated aqueous sodium

hydrogen carbonate was added and the mixture stirred for

10 min. Iodine was added portionwise until the organic layer

turned purple. The excess iodine was removed with aqueous

sodium thiosulfate and the aqueous phase extracted with ether.

The organic extracts were washed with brine, dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (20%) gave the title

compound 8 (627 mg, 90%) as a clear, pale yellow oil (Found:

M⁺+ NH₄, 408.1229. C₁₆H₃₁NISiO requires M, 408.1221);

ν_max/cm⁻¹3063, 3027, 2952, 2929, 2855, 1467, 1362, 1254,

1092, 1067, 838, 776 and 700; δ_H(300 MHz, CDCl₃) 0.00 and

7-Hydroxy-7-phenylhept-2-en-1-yl(tributyl)stannene 11. Tetra-

butylammonium ﬂuoride (4.8 mL, 1.0 M in THF, 4.83 mmol)

was added to the stannane 10 (2.17 g, 4.03 mmol) in THF

(20 mL) and the solution stirred for 4 h. Saturated aqueous

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ammonium chloride was added and the aqueous phase extracted

with ether. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ethyl acetate–petrol (10%

with 1% TEA), gave the title compound 11 (1.33 g, 69%), as a

clear, colourless oil, a 67 : 33 mixture of (E)- and (Z)-isomers

(¹H NMR) (Found: M⁺− C₄H₉, 423.1709. C₂₁H₃₅¹²⁰SnO

requires M, 423.1709); ν_max/cm⁻¹3368, 2955, 2925, 2852,

1456, 1069, 1021, 961 and 699; δ_H(300 MHz, CDCl₃) 0.88

(15 H, m, 3 × CH₃CH₂), 1.30 (6 H, m, 3 × CH₂), 1.46 (6 H, m,

3 × CH₂Sn), 1.68 (2 H, d, J 8.0, 1-H₂), 1.70–1.86 (4 H, m, 5-H₂

and 6-H₂), 1.88 (1 H, br. s, OH), 2.00 (2 H, q, J 7.2, 4-H₂), 4.67

(1 H, t, J 5.4, 7-H), 5.02 (0.33 H, dt, J 10.8, 7.2, 3-H), 5.19

(0.67 H, dt, J 15.0, 7.2, 3-H), 5.53 (1 H, m, 2-H) and 7.35 (5 H,

m, ArH); m/z (EI) 479 (M⁺− 1, 2%), 423 (M⁺− 57, 12), 405

(23), 291 (53), 235 (72), 179 (54) and 107 (100).

δ_C(75 MHz, CDCl₃) 21.2, 25.1, 25.2, 32.1, 35.6, 39.5, 75.5,

75.9, 125.1, 126.4, 126.5, 127.8, 128.2, 128.3, 132.3, 133.4,

140.1, 140.6, 170.1 and 170.3; m/z (CI) 398 (M⁺+ 18, 100%)

and 261 (44). HPLC analysis (Perkin-Elmer LC0480 diode-array

system, ODS sphereclone 5u column, 4.6 mm × 25 cm silica)

eluting with acetonitrile–water (60 : 40) showed two diastereo-

mers in a 32 : 68 ratio.

(E)-4-Hydroxypent-2-eny(tributy)stannane 15. Tributyltin

hydride (0.15 mL, 0.55 mmol) and AIBN (5 mg) were added to

a thoroughly degassed solution of the sulfone 14 (104 mg,

0.46 mmol) in benzene (5 mL) and the solution heated to 65 °C

for 1.5 h. After concentration under reduced pressure, chromato-

graphy of the residue, eluting with ether–petrol (20% with 1%

triethylamine), gave the title compound 15 (153 mg, 89%) as a

clear, colourless oil, essentially just the (E)-isomer (¹H NMR)

(Found: M⁺− C₄H₉, 319.1093. C₁₃H₂₇O¹²⁰Sn requires M,

319.1083); ν_max/cm⁻¹3344, 2924, 2851, 1652, 1460, 1376,

1291, 1064, 962 and 867; δ_H(300 MHz, CDCl₃) 0.89 (15 H, m,

3 × CH₃CH₂), 1.32 (9 H, m, 3 × CH₂and 5-H₃), 1.53 (6 H, m, 3

× CH₂Sn), 1.75 (2 H, d, J 8.7, 1-H₂), 4.26 (1 H, m, 4-H), 5.35

(1 H, dd, J 7.3, 15.1, 3-H) and 5.80 (1H, dt, J 8.7, 15.1, 2-H);

δ_C(75 MHz, CDCl₃) 9.3, 13.8, 14.2, 23.6, 27.4, 29.1, 69.6,

129.5 and 131.3; m/z (CI) 308 (100%) and 244 (21).

(E)-1,8-Diphenyloct-3-ene-1,8-diol

12. Tin(IV)

bromide

(2.3 mL, 1.0 M in DCM, 2.34 mmol) was added to the stannane

11 (1.02 g, 2.13 mmol) in DCM (12 mL) at −78 °C. The solu-

tion was stirred for 5 min then benzaldehyde (0.65 mL,

6.39 mmol) was added. After 20 min, aqueous ammonium

chloride was added and the mixture was allowed to warm to

room temperature. The aqueous phase was extracted with DCM

and the organic extracts were washed with brine, dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (50% with 1% TEA),

gave the title compound 12 (515 mg, 81%) as a clear, colourless

oil (Found: M⁺+ NH₄, 314.2121. C₂₀H₂₈NO₂requires M,

314.2120); ν_max/cm⁻¹3374, 3028, 2932, 2859, 1603, 1493,

1452, 1201, 1046, 1027, 972, 760 and 701; δ_H(300 MHz,

CDCl₃) 1.29–1.59 (2 H, m, 6-H₂), 1.62–1.84 (2 H, m, 7-H₂),

2.06 (2 H, bq, J 6.7, 5-H₂), 2.30 (1 H, br. s, OH), 2.39 (1 H, br.

s, OH), 2.47 (2 H, m, 2-H₂), 4.67 (2 H, m, 1-H and 8-H), 5.42

(1 H, dt, J 15.8, 6.5, 4-H), 5.55 (1 H, dt, J 15.8, 6.3, 3-H) and

7.36 (10 H, m, ArH); δ_C(75 MHz, CDCl₃) 25.4, 32.3, 38.4,

42.6, 73.5, 74.4, 125.8(2), 127.3, 127.4, 128.3, 128.4, 132.9,

134.3, 144.0 and 144.8; m/z (CI) 314 (M⁺+ 18, 71%), 296 (M⁺,

53), 261 (100) and 157 (46). HPLC analysis (Perkin-Elmer

LC0480 diode-array system, ODS sphereclone 5u column,

4.6 mm × 25 cm silica) eluting with acetonitrile–water (40 : 60)

showed two diastereoisomers in a 33 : 67 ratio.

(E)-4-(2-Trimethylsilylethoxy)methoxypent-2-enyl(tributyl)-

stannane 16. Diisopropylethylamine (6.7 mL, 38.4 mmol) and

(2-trimethylsilylethoxy)methyl chloride (4.4 mL, 25.0 mmol)

were added to the stannane 15 (7.22 g, 19.2 mmol) in DCM

(40 mL) at 0 °C. The solution was allowed to warm to room

temperature and then stirred for 3 h. Saturated aqueous

ammonium chloride was added and the aqueous phase extracted

with ether. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with TEA–petrol (1%), gave the

title compound 16 (8.08 g, 83%) as a clear, colourless oil

(Found: M⁺− C₄H₉, 449.1897. C₁₉H₄₁O₂Si¹²⁰Sn requires M,

449.1897); ν_max/cm⁻¹(300 MHz, CDCl₃) 2956, 2925, 2853,

1651, 1461, 1376, 1248, 1100, 1023 and 836; δ_H0.05 (9 H, s,

3 × SiCH₃), 0.93 (17 H, m, 3 × CH₃CH₂and CH₂Si), 1.30 (9

H, m, 3 × CH₂and 5-H₃), 1.51 (6 H, m, 3 × CH₂Sn), 1.75 (2 H,

d, J 8.8, 1-H₂), 3.69 (2 H, m, OCH₂CH₂), 4.13 (1 H, m, 4-H),

4.61 and 4.73 (each 1 H, d, J 6.8, OHCHO), 5.54 (1 H, dd,

J 8.2, 15.1, 3-H) and 5.78 (1 H, dt, J 8.8, 15.1, 2-H); δ_C

(75 MHz, CDCl₃) −1.1, 9.2, 13.7, 14.2, 18.2, 22.0, 27.7, 29.0,

64.8, 65.0, 65.7, 65.9, 91.4, 91.6, 126.4 and 133.3; m/z (CI) 308

(100%) and 244 (41).

(E)-1,8-Diacetoxy-1,8-diphenyloct-3-ene 13. TEA (0.97 mL,

6.90 mmol), DMAP (10 mg, catalytic) and acetic anhydride

(261 μL, 2.77 mmol) were added to the diol 12 (205 mg,

0.69 mmol) in DCM (5 mL) and the solution was stirred for 3 h.

Saturated aqueous ammonium chloride was added and the

aqueous phase extracted with DCM. The organic extracts were

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (10%), gave the title compound (214 mg,

82%) as a clear, colourless oil (Found: M⁺+ NH₄, 398.2330.

C₂₄H₃₂NO₄requires M, 398.2331); ν_max/cm⁻¹3032, 2939,

2861, 1737, 1371, 1238, 1024, 760 and 700; δ_H(300 MHz,

CDCl₃) 1.18–1.46 (2 H, m, 6-H₂), 1.70–1.94 (2 H, m, 7-H₂),

2.01 (2 H, br. q, J 7.2, 5-H₂), 2.08 and 2.11 (each 3 H, s, CH₃),

2.46–2.73 (2 H, m, 2-H₂), 5.32 (1 H, m, 4-H), 5.43 (1 H, m,

3-H), 5.75 (2 H, m, 1-H and 8-H) and 7.33 (10 H, m, ArH);

(3SR,5Z,7RS)-3-Hydroxy-7-(2-trimethylsilylethoxy)methoxy-

octa-1,5-diene 17. Tin(IV) chloride (16.7 mL, 1.0 M in DCM,

16.7 mmol) was added to the stannane 16 (7.65 g, 15.2 mmol)

in DCM (60 mL) at −78 °C. After 10 min, acrolein (5 mL,

75 mmol) was added and the solution stirred for a further 10 min

at −78 °C. Water and saturated aqueous ammonium chloride

were added and the mixture allowed to warm to room tempera-

ture. The aqueous phase was extracted with DCM and the

organic extracts washed with brine, dried (MgSO₄) and concen-

trated under reduced pressure. Chromatography of the residue,

eluting with ether–petrol (10% with 1% TEA), gave the title

compound 17 (2.98 g, 77%) as a clear, colourless oil, a

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96 : 4 mixture of epimers (¹H NMR) (Found: M⁺+ NH₄

290.2148. C₁₄H₃₂NSiO₃requires M, 290.2151); ν_max/cm⁻¹

3433, 2954, 2893, 1646, 1375, 1249, 1101, 1024, 922, 860, 836

and 756; δ_H(300 MHz, CDCl₃) major epimer 17 0.00 (9 H, s,

3 × SiCH₃), 0.92 (2 H, m, CH₂Si), 1.22 (3 H, d, J 6.5, 8-H₃),

2.26 and 2.39 (each 1 H, m, 4-H), 2.65 (1 H, d, J 5.5, OH), 3.53

and 3.67 (each 1 H, dt, J 6.9, 9.8, OHCHCH₂), 4.41 (1 H, m,

3-H), 4.51 (1 H, dq, J 9.2, 6.5, 7-H), 4.60 and 4.73 (each 1 H, d,

J 7.1, OHCHO), 5.09 (1 H, dt, J 10.4, 1.5, 1-H), 5.25 (1 H, dt,

J 17.2, 1.5, 1-H), 5.41 (1 H, dt, J 10.0, 11.2, 6-H), 5.58 (1 H, m,

5-H) and 5.87 (1 H, ddd, J 5.5, 10.4, 17.2, 2-H); minor epimer

20 4.69 (1 H, d, J 7.1, OHCHO); δ_C(75 MHz, CDCl₃) −1.5,

18.0, 21.3, 35.6, 64.9, 67.0, 71.9, 91.7, 114.2, 128.2, 133.9 and

140.7; m/z (CI) 290 (M⁺+ 18, 100%), 197 (23), 142 (25), 107

(31) and 90 (93).

5.26 (1 H, dt, J 10.6, 1.0, 1-H), 5.35 (1 H, dt, J 17.2, 1.1, 1-H),

5.43 (1 H, dd, J 10.1, 8.2, 6-H), 5.54 (2 H, m, 3-H and 5-H),

5.90 (1 H, ddd, J 6.5, 10.6, 17.2, 2-H), 8.19 (2 H, m, ArH) and

8.27 (2 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.5, 18.0, 21.3,

32.5, 64.9, 66.5, 75.7, 91.6, 118.0, 123.5, 126.0, 130.6, 134.5,

135.1, 135.6, 150.5 and 163.7; m/z (CI) 439 (M⁺+ 18, 23%),

422 (4), 377 (51), 317 (100), 244 (53) and 90 (65).

(3RS,5Z,7RS)-3-Hydroxy-7-(2-trimethylsilylethoxy)methoxy-

octa-1,5-diene 20. Lithium hydroxide monohydrate (320 mg,

7.61 mmol) was added to an emulsion of the ester 19 (641 mg,

1.52 mmol) in methanol–water (10 mL, 3 : 1 v:v) and the

mixture stirred vigorously for 15 h. After concentration under

reduced pressure, the residue was dissolved in ether and water

and the aqueous phase extracted with ether. The organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (20%), gave the title compound 20 (367 mg,

89%) as a clear, colourless oil, a 96 : 4 mixture of epimers

(¹H NMR) (Found: M⁺+ H, 273.1890. C₁₄H₂₉SiO₃requires M,

273.1886); ν_max/cm⁻¹3443, 3013, 2953, 2892, 1422, 1375,

1249, 1101, 1052, 1024, 923, 859, 836 and 756; δ_H(300 MHz,

CDCl₃) major epimer 20 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H, m,

CH₂Si), 1.22 (3 H, d, J 6.5, 8-H₃), 2.30 (1 H, m, 4-H), 2.41

(1 H, d, J 4.1, OH), 2.44 (1 H, m, 4-H), 3.52 (1 H, dt, J 7.0, 9.6,

OHCHCH₂), 3.67 (1 H, dt, J 7.4, 9.8, OHCHCH₂), 4.19 (1 H,

m, 3-H), 4.53 (1 H, dq, J 9.1, 6.5, 7-H), 4.59 and 4.69 (each

1 H, d, J 7.0, OHCHO), 5.11 (1 H, dt, J 10.6, 1.4, 1-H), 5.24

(1 H, dt, J 16.9, 1.4, 1-H), 5.42 (1 H, dd, J 9.1, 10.9, 6-H), 5.56

(1 H, dt, J 10.9, 7.5, 5-H) and 5.87 (1 H, ddd, J 5.6, 10.6, 16.9,

2-H); minor epimer 17 4.73 (1 H, d, J 7.0, OHCHO) δ_C

(75 MHz, CDCl₃) −1.5, 18.0, 21.3, 35.0, 64.9, 67.0, 71.8, 91.7,

114.7, 127.2, 134.2 and 140.1; m/z (CI) 290 (M⁺+ 18, 4%), 273

(M⁺+ 1, 7), 123 (9), 107 (8) and 90 (100).

(3SR,5Z,7RS)-3-(4-Nitrobenzoyl)oxy-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 18. Triethylamine (58 μL, 0.42 mmol),

DMAP (5 mg) and 4-nitrobenzoyl chloride (55 mg, 0.30 mmol)

were added to the alcohol 17 (54 mg, 0.20 mmol) in DCM

(0.5 mL) at room temperature and the resulting solution stirred

for 2 h. Saturated aqueous ammonium chloride was added, the

aqueous phase extracted with DCM and the organic extracts

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (5%), gave the title compound 18 (66 mg,

78%) as a clear, colourless oil (Found: M⁺+ NH₄439.2263.

C₂₁H₃₅N₂SiO₆requires M, 439.2264); ν_max/cm⁻¹3017, 2953,

2889, 1727, 1607, 1530, 1346, 1272, 1102, 1025, 836 and 720;

δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, t,

J 8.2, CH₂Si), 1.20 (3 H, d, J 6.5, 8-H₃), 2.61 (2 H, m, 4-H₂),

3.50 (1 H, dt, J 7.4, 9.5, OHCHCH₂), 3.70 (1 H, dt, J 7.7, 9.6,

OHCHCH₂), 4.52 (1 H, m, 7-H), 4.54 and 4.62 (each 1 H, d,

J 7.0, OHCHO), 5.26 (1 H, d, J 10.6, 1-H), 5.35 (1 H, d, J 17.1,

1-H), 5.43 (1 H, dd J 10.2, 8.1, 6-H), 5.54 (2 H, m, 3-H and

5-H), 5.89 (1 H, ddd, J 6.3, 10.6, 17.2, 2-H), 8.20 (2 H, m, ArH)

and 8.27 (2 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.5, 18.1, 21.2,

32.4, 65.0, 66.6, 75.6, 91.7, 117.8, 123.4, 125.9, 130.7, 134.6,

135.1, 135.6, 150.5 and 163.7; m/z (CI) 439 (M⁺+ 18, 30%),

422 (M⁺+ 1, 3), 274 (53), 107 (39) and 90 (100).

(3SR,5Z,7RS)-3-(Benzyloxy)acetoxy-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 21. Benzyloxyacetyl chloride (1.59 mL,

10.1 mmol), TEA (1.96 mL, 14.1 mmol) and DMAP (50 mg)

were added to the alcohol 17 (1.83 g, 6.71 mmol) in DCM

(15 mL) at room temperature. The solution was heated under

reﬂux for 3 h then allowed to cool to room temperature. Satu-

rated aqueous ammonium chloride was added, the aqueous

phase was extracted with DCM and the organic extracts washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ethyl

acetate–petrol (7%), gave the title compound 21 (2.48 g, 88%) as

(3RS,5Z,7RS)-3-(4-Nitrobenzoyl)oxy-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 19. Diethyl azodicarboxylate (135 μL,

0.86 mmol) was added dropwise to the alcohol 17 (156 mg,

0.57 mmol), triphenylphosphine (226 mg, 0.86 mmol) and

4-nitrobenzoic acid (144 mg, 0.86 mmol) in benzene (1.5 mL) at

room temperature and the solution stirred for 2 h. Saturated

aqueous ammonium chloride was added, the aqueous phase was

extracted with ether and the organic extracts washed with brine,

dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(5%), gave the title compound 19 (143 mg, 60%) as a clear,

colourless oil (Found: M⁺+ NH₄, 439.2263. C₂₁H₃₅N₂SiO₆

requires M, 439.2264); ν_max/cm⁻¹2953, 2890, 1727, 1606,

1530, 1346, 1271, 1102, 1024, 836 and 719; δ_H(300 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, t, J 8.5, CH₂Si),

1.18 (3 H, d, J 6.3, 8-H₃), 2.61 (2 H, m, 4-H₂), 3.50 (1 H, dt,

J 7.3, 9.6, OHCHCH₂), 3.69 (1 H, dt, J 7.7, 9.5, OHCHCH₂),

4.54 (1 H, m, 7-H), 4.56 and 4.63 (each 1 H, d, J 7.0, OHCHO),

a

clear, colourless oil (Found: M⁺

+ NH₄, 438.2680.

C₂₃H₄₀NSiO₅requires M, 438.2677); ν_max/cm⁻¹2952, 2891,

1756, 1425, 1249, 1195, 1127, 1027, 836, 742 and 697; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.93 (2 H, m,

CH₂Si), 1.20 (3 H, d, J 6.4, 8-H₃), 2.47 (2 H, m, 4-H₂), 3.49

(1 H, dt, J 7.3, 8.0, OHCHCH₂), 3.78 (1 H, dt, J 7.7, 9.5,

OHCHCH₂), 4.08 (2 H, s, O₂CCH₂O), 4.48 (1 H, dq, J 8.1, 6.4,

7-H), 4.56 (1 H, d, J 7.0, OHCHO), 4.61 (3 H, m, CH₂Ph and

OHCHO), 5.19 (1 H, dd, J 1.1, 10.6, 1-H), 5.25 (1 H, d, J 1.0,

17.3, 1-H), 5.41 (3 H, m, 3-H, 5-H and 6-H), 5.78 (1 H, ddd,

J 6.5, 10.6, 17.2, 2-H) and 7.32 (5 H, m, ArH); δ_C(75 MHz,

CDCl₃) −1.4, 18.1, 21.3, 32.4, 65.0, 66.9, 67.2, 73.3, 74.5, 91.9,

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117.7, 126.0, 128.0, 128.1, 128.5, 134.5, 135.4, 137.1 and

0.13 mmol) was added to the alcohol 27 (31 mg, 0.10 mmol),

triphenylphosphine (35 mg, 0.13 mmol) and 4-nitrobenzoic acid

(22 mg, 0.13 mmol) in benzene (0.3 mL) at room temperature.

The solution was stirred for 2 h and then diluted with ether and

water. The aqueous phase was extracted with ether and the

organic extracts washed with brine, dried (MgSO₄) and concen-

trated under reduced pressure. Chromatography of the residue,

eluting with ethyl acetate–petrol (10%), gave the title compound

(30 mg, 60%) as a clear, pale yellow oil, a mixture of esters 24

and 28, ratio 24 : 28 = 89 : 11 (¹H NMR) (Found: M⁺+ NH₄,

471.2124. C₂₅H₃₁N₂O₇requires M, 471.2131); ν_max/cm⁻¹3027,

2950, 2872, 1748, 1723, 1605, 1528, 1342, 1273, 1105, 1036

and 720; δ_H(C₆D₆, 400 MHz) 1.25 (2.67 H, d, J 6.4, 10-H₃),

1.26 (0.33 H, d, J 6.4, 10-H₃), 2.55 (2 H, m, 3-H₂), 2.84 (2 H,

t, J 6.4, 6-H₂), 3.40 (2.67 H, s, OCH₃), 3.41 (0.33 H, s, OCH₃),

3.96 (1 H, t, J 6.0, 2-H), 4.29 (0.11 H, d, J 11.6, OHCHPh),

4.30 (0.89 H, d, J 12.0, OHCHPh), 4.70 (1 H, d, J 11.6,

OHCHPh), 5.40–5.52 (3 H, m, 5-H, 7-H and 8-H), 5.60 (1 H,

dtq, J 15.2, 6.8, 1.6, 4-H), 5.92 (1 H, dq, J 8.0, 6.4, 9-H), 7.13

(1 H, m, ArH), 7.21 (2 H, m, ArH), 7.37 (2 H, m, ArH), 7.73

(2 H, m, ArH) and 7.79 (2 H, m, ArH); δ_C(75 MHz, CDCl₃)

20.8, 30.9, 36.0, 51.8, 68.7, 72.2, 78.0, 123.4, 125.6, 127.8,

127.9, 128.3, 129.3, 130.6, 130.9, 131.2, 136.0, 137.4, 150.4,

163.8 and 172.5; m/z (CI) 471 (M⁺+ 18, 100%) and 304 (26).

A solution of the alcohol 23 (41 mg, 0.14 mmol), triethyl-

amine (47 μL, 0.34 mmol), 4-nitrobenzoyl chloride (38 mg,

0.20 mmol) and DMAP (2 mg) in DCM (0.3 mL) was stirred at

room temperature for 2 h. DCM and water were added and the

aqueous phase was extracted with DCM. The organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (10%), gave the title compound (57 mg,

90%) as a clear, pale yellow oil, a mixture of esters 24 and 28,

ratio 24 : 28 = 88 : 12 (¹H NMR).

169.6; m/z (CI) 438 (M⁺+ 18, 100%), 273 (54) and 107 (46).

Methyl (2SR,4E,7Z,9RS)-2-(benzyloxy)-9-(2-trimethylsilylethoxy)-

methoxydeca-4,7-dienoate 22. Using the general procedure with

the trimethylsilyl chloride in situ, the benzyloxyacetate 21

(1.23 g, 2.92 mmol) in THF (30 mL), trimethylsilyl chloride

(1.56 mL, 12.28 mmol) and lithium hexamethyldisilazide

(11.7 mL, 1.0 M in THF, 11.7 mmol) after reaction with tri-

methylsilyldiazomethane (1.75 mL, 2.0

M in hexanes,

3.51 mmol) and chromatography, eluting with ethyl acetate–

petrol (5%), gave the title compound 22 (1.13 g, 89%) as a clear,

colourless oil (Found: M⁺+ NH₄, 452.2832. C₂₄H₄₂NSiO₅

requires M, 452.2832); ν_max/cm⁻¹3009, 2952, 2889, 1752,

1451, 1438, 1249, 1202, 1104, 1025, 859, 836, 743 and 697; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, m, 3 × SiCH₃), 0.91 (2 H, t,

J 8.5, CH₂Si), 1.20 (3 H, d, J 6.4, 10-H₃), 2.45 (2 H, t, J 5.6,

3-H₂), 2.78 (2 H, m, 6-H₂), 3.50 (1 H, dt, J 7.1, 9.6,

OHCHCH₂), 3.69 (1 H, m, OHCHCH₂), 3.71 (3 H, s, OCH₃),

3.95 (1 H, t, J 6.4, 2-H), 4.41 (1 H, d, J 11.8, OHCHPh), 4.52

(1 H, dq, J 8.9, 6.5, 9-H), 4.55 and 4.62 (each 1 H, d, J 7.0,

OHCHO), 4.68 (1 H, d, J 11.8, OHCHPh), 5.30 (1 H, m, 8-H),

5.46 (3 H, m, 4-H, 5-H and 7-H) and 7.32 (5 H, m, ArH); δ_C

(75 MHz, CDCl₃) −1.5, 18.1, 21.4, 30.7, 36.1, 51.7, 64.9, 66.6,

72.2, 78.1, 91.7, 125.2, 127.8, 127.9, 128.3, 129.8, 131.6,

131.9, 137.4 and 172.6; m/z (CI) 452 (M⁺+ 18, 100%), 412

(13), 304 (22), 287 (26) and 90 (63).

The general procedure with addition of trimethylsilyl chloride

after the base, the benzyloxyacetate 21 (310 mg, 0.74 mmol) in

THF (3.6 mL), lithium hexamethyldisilazide (1.0 mL, 1.0 M in

THF, 0.96 mmol) and trimethylsilyl chloride (150 μL,

1.18 mmol) after reaction with trimethylsilyldiazomethane

(0.44 mL, 2.0 M in hexanes, 0.89 mmol) and chromatography,

eluting with ethyl acetate–petrol (5%), gave the title compound

22 (250 mg, 78%) as a clear, colourless oil.

Methyl

(2SR,4E,7Z,9RS)-2-benzyloxy-9-hydroxydeca-4,7-

(3RS,5Z,7RS)-3-(Benzyloxy)acetoxy-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 25. Triethylamine (81 μL, 0.58 mmol),

DMAP (5 mg) and benzyloxyacetyl chloride (74 μg, 0.47 mmol)

were added to the alcohol 20 (75 mg, 0.28 mmol) in DCM

(0.8 mL) at room temperature and the solution heated under

reﬂux for 3 h then allowed to cool to room temperature. Satu-

rated aqueous ammonium chloride was added and the aqueous

phase extracted with DCM. The organic extracts were washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ethyl

acetate–petrol (7%), gave the title compound 25 (101 mg, 86%)

as a clear, colourless oil (Found: M⁺+ NH₄, 438.2669.

C₂₃H₄₀NSiO₅requires M, 438.2677); ν_max/cm⁻¹3017, 2952,

2890, 1756, 1374, 1249, 1195, 1027, 859, 836, 743 and 697;

δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, m,

CH₂Si), 1.20 (3 H, d, J 6.3, 8-H₃), 2.45 (2 H, m, 4-H₂), 3.49 and

3.68 (each 1 H, dt, J 7.2, 9.6, OHCHCH₂), 4.08 (2 H, s,

O₂CCH₂O), 4.49 (1 H, dq, J 8.4, 6.3, 7-H), 4.56 (1 H, d, J 7.0,

OHCHO), 4.61 (2 H, s, CH₂Ph), 4.62 (1 H, d, J 7.0, OHCHO),

5.20 (1 H, dt, J 10.5, 0.9, 1-H), 5.26 (1 H, dt, J 17.1, 1.2, 1-H),

5.41 (3 H, m, 3-H, 5-H and 6-H), 5.78 (1 H, ddd, J 6.5, 10.5,

17.1, 2-H) and 7.32 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.5,

18.0, 21.3, 32.4, 64.9, 66.6, 67.1, 73.2, 74.5, 91.7, 117.7, 126.1,

dienoate 23. Hydroﬂuoric acid (0.5 mL, 40% in water,

10 mmol) was added to the ester 22 (78 mg, 0.18 mmol) in

acetonitrile (2 mL) and the solution was stirred for 5 h. Ether

and saturated aqueous sodium hydrogen carbonate were added

until no more effervescence was seen. The aqueous phase was

extracted with ether and the organic extracts washed with brine,

dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(30%), gave the title compound 23 (41 mg, 75%) as a clear, col-

ourless oil (Found: M⁺+ NH₄322.2017. C₁₈H₂₈NO₄requires

M, 322.2018); ν_max/cm⁻¹3422, 2966, 2921, 1746, 1438, 1276,

1206, 1112, 972, 741 and 698; δ_H(300 MHz, CDCl₃) 1.21 (3 H,

d, J 6.3, 10-H₃), 1.75 (1 H, br. s, OH), 2.45 (2 H, m, 3-H₂), 2.77

(2 H, m, 6-H₂), 3.71 (3 H, s, OCH₃), 3.95 (1 H, t, J 6.3, 2-H),

4.40 (1 H, d, J 12.0, OHCHPh), 4.59 (1 H, m, 9-H), 4.68 (1 H,

d, J 12.0, OHCHPh), 5.46 (4 H, m, 4-H, 5-H, 7-H and 8-H) and

7.31 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) 23.4, 30.5, 36.0, 51.8,

63.6, 72.2, 78.0, 125.0, 127.8, 127.9, 128.0, 128.3, 131.6,

134.8, 137.3 and 172.6; m/z (CI) 322 (M⁺+ 18, 60%), 287

(100) and 146 (50).

Methyl

(2SR,4E,7Z,9RS)-2-(benzyloxy)-9-(4-nitrobenzoyl)-

oxydeca-4,7-dienoate 24. Diethyl azodicarboxylate (21 μL,

7004 | Org. Biomol. Chem., 2012, 10, 6995–7014

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127.9, 128.0, 128.4, 134.3, 135.3, 137.0 and 169.5; m/z (CI)

oil, a mixture of esters 24 and 28, ratio 24 : 28 = 11 : 89

(¹H NMR) (Found: M⁺+ NH₄, 471.2138. C₂₅H₃₁N₂O₇requires

M, 471.2131); ν_max/cm⁻¹3026, 2950, 2873, 1748, 1723, 1605,

1528, 1343, 1273, 1106, 1037 and 721; δ_H(C₆D₆, 400 MHz)

1.25 (0.33 H, d, J 6.4, 10-H₃), 1.26 (2.67 H, d, J 6.4, 10-H₃),

2.55 (2 H, m, 3-H₂), 2.84 (2 H, t, J 6.8, 6-H₂), 3.39 (0.33 H,

s, OCH₃), 3.40 (2.67 H, s, OCH₃), 3.96 (1 H, t, J 6.0, 2-H), 4.29

and 4.71 (each 1 H, d, J 11.6, OHCHPh), 5.46 (3 H, m, 5-H,

7-H and 8-H), 5.60 (1 H, dtq, J 15.2, 6.8, 1.6, 4-H), 5.93 (1 H,

dq, J 8.0, 6.4, 9-H), 7.13 (1 H, m, ArH), 7.21 (2 H, m, ArH),

7.36 (2 H, m, ArH), 7.72 (2 H, m, ArH) and 7.79 (2 H, m,

ArH); δ_C(75 MHz, CDCl₃) 20.8, 30.9, 36.0, 51.8, 68.7, 72.2,

78.0, 123.4, 125.6, 127.8, 127.9, 128.3, 129.3, 130.6, 130.9,

131.2, 136.0, 137.4, 150.4, 163.8 and 172.5; m/z (CI) 471

(M⁺+ 18, 100%) and 304 (10).

438 (M⁺+ 18, 88%), 273 (38), 184 (33), 107 (100) and 90 (98).

Methyl

(2RS,4E,7Z,9RS)-2-(benzyloxy)-9-(2-trimethylsilyl-

ethoxy)methoxydeca-4,7-dienoate 26. Using the general pro-

cedure with in situ trimethylsilyl chloride, the benzyloxyacetate

25 (98 mg, 0.23 mmol) in THF (1.0 mL), trimethylsilyl chloride

(124 μL, 0.98 mmol) and lithium hexamethylsilazide (0.93 mL,

1.0 M in THF, 0.93 mmol), after treatment with trimethylsilyl-

diazomethane (140 μL, 2.0 M in hexanes, 0.28 mmol) and

chromatography, eluting with ethyl acetate–petrol (5%), gave the

title compound 26 (76 mg, 76%) as a clear, colourless oil

(Found: M⁺+ NH₄452.2837. C₂₄H₄₂NSiO₅requires M,

452.2832); ν_max/cm⁻¹3030, 2951, 2884, 1752, 1438, 1249,

1201, 1103, 1025, 836, 743 and 696; δ_H(300 MHz, CDCl₃)

0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, m, CH₂Si), 1.21 (3 H, d,

J 6.4, 10-H₃), 2.45 (2 H, br. t, J 6.4, 3-H₂), 2.79 (2 H, m, 6-H₂),

3.50 (1 H, dt, J 7.1, 9.5, OHCHCH₂), 3.69 (1 H, m,

OHCHCH₂), 3.71 (3 H, s, OCH₃), 3.94 (1 H, t, J 6.4, 2-H), 4.41

(1 H, d, J 11.8, OHCHPh), 4.53 (1 H, dq, J 9.0, 6.4, 9-H), 4.56

and 4.62 (each 1 H, d, J 7.0 OHCHO), 4.68 (1 H, d, J 11.8,

OHCHPh), 5.29 (1 H, dd, J 9.0, 10.9, 8-H), 5.45 (3 H, m, 4-H,

5-H and 7-H) and 7.31 (5 H, m, ArH); δ_C(75 MHz, CDCl₃)

−1.5, 18.1, 21.34, 30.6, 36.1, 51.7, 64.9, 66.6, 72.2, 78.0, 91.7,

125.2, 127.8, 127.9, 128.3, 129.8, 131.6, 131.9, 137.4 and

172.6; m/z (CI) 452 (M⁺+ 18, 100%), 287 (12) and 90 (13).

Methyl (2SR,9RS)-2-benzyloxy-9-(2-trimethylsilylethoxy)-

methoxydecanoate 31. A solution of the diene 22 (915 mg,

2.11 mmol) and toluene 4-sulfonylhydrazine (4.7 g, 25.3 mmol)

in DME (35 mL) was heated under reﬂux and a solution of

sodium acetate (5.7 g, 42.2 mmol) in water (7 mL) was added

dropwise over 2.5 h. The solution was stirred under reﬂux for a

further 2.5 h, and then allowed to cool to room temperature.

Water and ether were added and the aqueous phase extracted

with ether. The organic extracts were washed with water and

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(7%), gave the title compound 31 (862 mg, 93%) as a clear,

colourless oil (Found: M⁺+ NH₄456.3146. C₂₄H₄₆NSiO₅

requires M, 456.3145); ν_max/cm⁻¹3031, 2930, 2861, 1752,

1456, 1249, 1200, 1103, 1054, 1030, 859, 836, 739 and 697;

δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, m,

CH₂Si), 1.12 (3 H, d, J 6.2, 10-H₃), 1.21–1.55 (10 H, m, 4-H₂,

5-H₂, 6-H₂, 7-H₂and 8-H₂), 1.71 (2 H, m, 3-H₂), 3.60 (3 H, m,

OCH₂CH₂, 9-H), 3.71 (3 H, s, OCH₃), 3.91 (1 H, t, J 6.5, 2-H),

4.37 (1 H, d, J 11.7, OHCHPh), 4.66 (3 H, m, OHCHPh and

OCH₂O) and 7.32 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.5,

18.0, 20.2, 25.1, 25.5, 29.2, 29.4, 32.9, 36.9, 51.7, 64.7, 72.2,

72.8, 78.0, 92.9, 127.7, 127.9, 128.3, 137.5 and 173.3; m/z (CI)

456 (M⁺+ 18, 100%), 108 (12) and 90 (29).

Methyl

(2RS,4E,7Z,9RS)-2-benzyloxy-9-hydroxydeca-4,7-

dienoate 27. Butanethiol (0.36 mL, 3.35 mmol) was added to a

suspension of potassium carbonate (530 mg, 3.83 mmol), mag-

nesium bromide diethyl etherate (866 mg, 3.35 mmol) and ester

26 (208 mg, 0.48 mmol) in ether (2 mL) at room temperature

and the mixture stirred for 7 h. Dilute aqueous hydrogen chloride

was added and the aqueous phase extracted with ether. The

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (30%), gave the title

compound 27 (77 mg, 53%) as a clear, colourless oil (Found:

M⁺+ NH₄322.2019. C₁₈H₂₈NO₄requires M, 322.2018); ν_max

/

cm⁻¹3432, 3009, 2967, 2921, 1747, 1496, 1451, 1438, 1276,

1205, 1114, 1058, 972, 742 and 699; δ_H(300 MHz, CDCl₃)

1.28 (3 H, d, J 6.3, 10-H₃), 1.84 (1 H, br. s, OH), 2.52 (2 H, t,

J 5.9, 3-H₂), 2.83 (2 H, m, 6-H₂), 3.77 (3 H, s, OCH₃), 4.02

(1 H, t, J 6.3, 2-H), 4.47 (1 H, d, J 11.8, OHCHPh), 4.66 (1 H,

m, 9-H), 4.75 (1 H, d, J 11.8, OHCHPh), 5.51 (4 H, m, 4-H,

5-H, 7-H and 8-H) and 7.38 (5 H, m, ArH); δ_C(75 MHz,

CDCl₃) 23.4, 30.5, 36.0, 51.8, 63.6, 72.2, 78.0, 125.0, 127.8,

127.9, 128.0, 128.3, 131.6, 134.8, 137.3 and 172.6; m/z (CI) 322

(M⁺+ 18, 100%), 304 (M⁺, 47), 287 (76) and 164 (42).

Methyl

(2SR,9RS)-2-hydroxy-9-(2-trimethylsilylethoxy)-

methoxydecanoate 32. A suspension of palladium on carbon

(10%; 175 mg, 0.17 mmol) and the benzyl ether 31 (721 mg,

1.65 mmol) in ethanol (6 mL) was stirred under an atmosphere

of hydrogen for 72 h. The mixture was then ﬁltered through

celite and concentrated under reduced pressure. Chromatography

of the residue, eluting with ethyl acetate–petrol (15%), gave the

title compound 32 (499 mg, 87%) as a clear, colourless oil

(Found: M⁺+ NH₄366.2687. C₁₇H₄₀NSiO₅requires M,

366.2676); ν_max/cm⁻¹3442, 2930, 2859, 1742, 1459, 1442,

1377, 1249, 1207, 1098, 1055, 1029, 859 and 836; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.90 (2 H, m,

CH₂Si), 1.13 (3 H, d, J 6.2, 10-H₃), 1.20–1.82 (12 H, m, 3-H₂,

4-H₂, 5-H₂, 6-H₂, 7-H₂and 8-H₂), 2.78 (1 H, d, J 5.8, OH), 3.62

(3 H, m, OCH₂CH₂, 9-H), 3.77 (3 H, s, OCH₃), 4.16 (1 H, dt,

J 7.3, 5.4, 2-H) and 4.64 and 4.71 (each 1 H, d, J 7.2, OHCHO);

δ_C(75 MHz, CDCl₃) −1.5, 18.0, 20.2, 24.7, 25.4, 29.2, 29.4,

34.3, 36.9, 52.3, 64.8, 70.4, 72.8, 92.9 and 175.7; m/z (CI)

Methyl

(2RS,4E,7Z,9RS)-2-(benzyloxy)-9-(4-nitrobenzoyl)-

oxydeca-4,7-dienoate 28. A solution of the alcohol 27 (33 mg,

0.11 mmol), triethylamine (33 μL, 0.24 mmol), 4-nitrobenzoyl

chloride (32 mg, 0.17 mmol) and DMAP (2 mg) in DCM

(0.5 mL) was stirred for 2 h at room temperature. DCM and

water were added and the aqueous phase was extracted with

DCM. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ethyl acetate–petrol (10%),

gave the title compound 28 (38 mg, 79%) as a clear, pale yellow

This journal is © The Royal Society of Chemistry 2012

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366 (M⁺+ 18, 100%), 308 (27), 291 (72), 231 (52), 220 (41),

218 (41) and 90 (42).

the aqueous phase extracted with DCM. The organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure until ca. 1 mL of the solution remained.

Methoxycarbonylmethylene triphenylphosphorane (261 mg,

0.78 mmol) was added and the solution stirred for 15 h.

Saturated aqueous ammonium chloride was added and the

aqueous phase extracted with DCM. The organic extracts were

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (5%), gave the title compound 35 (172 mg,

72%) as a clear colourless oil (Found: M⁺+ NH₄630.4002.

C₃₅H₆₀NSi₂O₅requires M, 630.4010); ν_max/cm⁻¹3070, 2932,

2858, 1727, 1659, 1430, 1272, 1165, 1107, 1054, 859, 835 and

703; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.93 (2 H,

m, CH₂Si), 1.08 [9 H, s, SiC(CH₃)₃], 1.14 (3 H, d, J 6.3, 12-H₃),

1.10–1.54 (12 H, m, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂),

3.63 (3 H, m, OCH₂CH₂and 11-H), 3.72 (3 H, s, OCH₃), 4.34

(1 H, dq, J 1.2, 5.0, 4-H), 4.65 and 4.72 (each 1 H, d, J 6.9,

OHCHO), 5.93 (1 H, dd, J 1.5, 15.4, 2-H), 6.87 (1 H, dd, J 5.2,

15.4, 3-H), 7.38 (6 H, m, ArH) and 7.63 (4 H, m, ArH); δ_C

(75 MHz, CDCl₃) −1.5, 18.1, 19.3, 20.2, 23.9, 25.5, 27.0, 29.4,

29.5, 36.7, 37.0, 51.4, 66.8, 72.4, 72.9, 93.0, 119.7, 127.5(2),

129.6, 129.7, 133.4, 133.9, 135.7, 150.5 and 167.0; m/z (CI) 630

(M⁺+ 18, 37%), 274 (94), 196 (100) and 90 (89).

Methyl (2SR,9RS)-2-tert-butyldiphenylsilyloxy-9-(2-trimethyl-

silylethoxy)methoxydecanoate

33. Imidazole

(173

mg,

2.55 mmol) and tert-butyldiphenylchlorosilane (473 μL,

1.82 mmol) were added to the alcohol 32 (422 mg, 1.21 mmol)

in DCM (1.2 mL) and the solution stirred for 2 h at room temp-

erature. DCM and water were added and the aqueous phase

extracted with DCM. The organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(3%), gave the title compound 33 (695 mg, 98%) as a clear,

colourless oil (Found: M⁺+ NH₄, 604.3852. C₃₃H₅₈NSi₂O₅

requires M, 604.3853); ν_max/cm⁻¹3049, 2932, 2858, 1757,

1740, 1466, 1429, 1249, 1196, 1110, 1055, 1029, 858, 836 and

704; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × CH₃), 0.89 (2 H,

m, CH₂Si), 1.09 [9 H, s, SiC(CH₃)₃], 1.14 (3 H, d, J 6.2, 10-H₃),

1.17–1.73 (12 H, m, 3-H₂, 4-H₂, 5-H₂, 6-H₂, 7-H₂and 8-H₂),

3.46 (3 H, s, OCH₃), 3.62 (3 H, m, OCH₂CH₂and 9-H), 4.21

(1 H, t, J 5.5, 2-H), 4.65 and 4.72 (each 1 H, d, J 7.1, OHCHO),

7.36 (6 H, m, ArH) and 7.64 (4 H, m, ArH); δ_H(75 MHz,

CDCl₃) −1.5, 18.0, 19.3, 20.2, 24.4, 25.5, 26.8, 29.3, 29.4, 35.1,

36.9, 51.3, 64.8, 72.6, 72.8, 93.0, 127.4, 127.5, 129.6, 129.7,

133.2, 133.4, 135.7, 135.9 and 173.6; m/z (CI) 604 (M⁺+ 18,

100%) and 90 (89).

Methyl (2E,4RS,11SR)-4-tert-butyldiphenylsilyloxy-11-hydro-

xydodec-2-enoate 36. Butanethiol (0.26 mL, 2.46 mmol) was

added to a vigorously stirred suspension of potassium carbonate

(388 mg, 2.81 mmol), magnesium bromide diethyl etherate

(635 mg, 2.46 mmol) and the SEM-ether 35 (215 mg,

0.35 mmol) in ether (5 mL) at room temperature and the result-

ing mixture stirred for 2 h. Dilute aqueous hydrogen chloride

and water were added and the aqueous phase extracted with

ether. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ethyl acetate–petrol (20%),

gave the title compound 36 (150 mg, 89%) as a clear, colourless

oil (Found: M⁺, 482.2841. C₂₉H₄₂SiO₄requires M, 482.2852);

ν_max/cm⁻¹3431, 2931, 2857, 1725, 1658, 1464, 1431, 1276,

1166, 1108 and 704; δ_H(300 MHz, CDCl₃) 1.08 [9 H, s, SiC-

(CH₃)₃], 1.17 (3 H, d, J 6.2, 12-H₃), 1.03–1.48 (12 H, m, 5-H₂,

6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂), 3.73 (3 H, s, OCH₃), 3.75

(1 H, m, 11-H), 4.35 (1 H, q, J 5.1, 4-H), 5.93 (1 H, dd, J 1.4,

15.4, 2-H), 6.88 (1 H, dd, J 5.8, 15.4, 3-H), 7.31–7.46 (6 H, m,

ArH) and 7.58–7.69 (4 H, m, ArH); δ_C(75 MHz, CDCl₃) 19.2,

23.4, 23.8, 25.5, 27.0, 29.3(2), 36.6, 39.2, 51.4, 68.0, 72.3,

119.6, 127.5, 129.7, 129.7, 133.4, 133.9, 135.7, 150.5 and

167.0; m/z (CI) 500 (M⁺+ 18, 18%), 483 (M⁺+ 1, 20),

274 (20), 244 (100), 227 (30) and 196 (20).

(2SR,9RS)-2-tert-Butyldiphenylsilyloxy-9-(2-trimethylsilylethoxy)-

methoxydecan-1-ol 34. Lithium triethylborohydride (0.96 mL,

1.0 M in THF, 0.96 mmol) was added dropwise to the ester 33

(141 mg, 0.23 mmol) in THF (1 mL) at −10 °C and the solution

stirred for 30 min. Water and dilute aqueous hydrogen chloride

were added and the aqueous phase extracted with ether. The

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (15%), gave the title

compound 34 (114 mg, 89%), as a clear, colourless oil (Found:

M⁺+ NH₄576.3903. C₃₂H₅₈NSi₂O₄requires M, 576.3904);

ν_max/cm⁻¹3439, 3070, 3049, 2931, 2857, 1467, 1428, 1378,

1249, 1110, 1056, 1029, 859, 835 and 703; δ_H(300 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.90 (2 H, m, CH₂Si), 1.04

[9 H, s, SiC(CH₃)₃], 1.12 (3 H, d, J 6.2, 10-H₃), 1.06–1.52

(12 H, m, 3-H₂, 4-H₂, 5-H₂, 6-H₂, 7-H₂and 8-H₂), 1.81 (1 H, t,

J 6.3, OH), 3.49 (2 H, m, 1-H₂), 3.61 (3 H, m, OCH₂CH₂and

9-H), 3.75 (1 H, m, 2-H), 4.63 and 4.70 (each 1 H, d, J 7.0,

OHCHO), 7.37 (6 H, m, ArH) and 7.67 (4 H, m, ArH);

δ_C(75 MHz, CDCl₃) −1.5, 18.0, 19.3, 20.2, 25.0, 25.4, 26.5,

27.0, 29.5, 33.4, 36.9, 64.8, 65.9, 72.8, 74.0, 92.9, 127.5, 127.7,

129.5, 129.7, 133.9, 134.7, 135.6 and 135.8; m/z (CI) 576

(M⁺+ 18, 4%), 363 (10), 333 (12), 196 (18) and 90 (100).

Methyl (2E,4RS,11SR)-4-tert-butyldiphenylsilyloxy-11-(2-tri-

(4SR,11RS)- and (4RS,11RS)-4-tert-Butyldiphenylsilyloxy-11-

methylundec-2-en-11-olide 38 and 39.^2hLithium hydroxide

monohydrate (65 mg, 1.54 mmol) was added to the methyl ester

36 (150 mg, 0.31 mmol) in methanol–water (2.5 mL, 3 : 1) and

the solution stirred for 15 h. After concentration under reduced

pressure, the residue was taken up in water and ethyl acetate. The

aqueous phase was extracted with ethyl acetate and the organic

extracts washed with brine, dried (MgSO₄) and concentrated

under reduced pressure to leave the seco-acid 37 (123 mg, 85%)

methylsilylethoxy)methoxydodec-2-enoate

35. Dimethylsulf-

oxide (84 μL, 1.19 mmol) was added to oxalyl chloride (42 μL,

0.47 mmol) in DCM (3 mL) at −78 °C. The solution was stirred

for 10 min, then the alcohol 34 (217 mg, 0.39 mmol) in DCM

(1 mL) was added via a cannula and the resulting solution was

stirred for 5 h at −78 °C. Triethylamine (166 μL, 1.19 mmol)

was then added and the mixture allowed to warm to room temp-

erature. Saturated aqueous ammonium chloride was added and

7006 | Org. Biomol. Chem., 2012, 10, 6995–7014

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that was used without further puriﬁcation. Triethylamine (24 μL,

171 μmol) and 2,6-dichlorobenzoyl chloride (18 μL, 128 μmol)

were added to the seco-acid 37 (40 mg, 85 μmol) in THF

(0.5 mL) and the solution stirred for 2 h. The mixture was

ﬁltered and diluted with toluene (35 mL). This solution was then

added dropwise over 5 h to a solution of DMAP (63 mg,

0.51 mmol) in toluene (5 mL) heated under reﬂux. The solution

was then allowed to cool and water was added. The aqueous

phase was extracted with ether and the organic extracts washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ethyl

acetate–petrol (1%), gave the title compound 39^2h(1.2 mg, 3%)

as a clear, colourless oil (Found: M⁺+ NH₄, 468.2934.

C₂₈H₄₂NSiO₃requires M, 468.2934); ν_max/cm⁻¹2932, 2857,

1714, 1463, 1428, 1363, 1249, 1110, 822 and 703; δ_H

(300 MHz, CDCl₃) 0.84–1.74 (12 H, m, 5-H₂, 6-H₂, 7-H₂, 8-H₂,

9-H₂and 10-H₂), 1.09 [9 H, s, SiC(CH₃)₃], 1.28 (3 H, d, J 6.7,

11-CH₃), 4.50 (1 H, m, 4-H), 5.05 (1 H, dqn, J 3.0, 6.9, 11-H),

6.15 (1 H, dd, J 1.8, 15.6, 2-H), 7.00 (1 H, dd, J 3.6, 15.6, 3-H),

7.39 (6 H, m, ArH) and 7.66 (4 H, m, ArH); δ_C(75 MHz,

CDCl₃) 19.3, 19.9, 21.1, 23.0, 27.0, 27.7, 27.9, 33.6, 36.3, 72.4,

73.1, 120.2, 127.6, 127.6, 129.7, 133.4, 134.0, 135.7, 135.8,

135.9, 152.2 and 167.5; m/z (CI) 468 (M⁺+ 18, 80%), 451

(M⁺+ 1, 30), 274 (70) and 196 (100). The second fraction was

the title compound 38^2h(18.0 mg, 47%) as a clear, colourless oil

(Found: M⁺+ NH₄, 468.2936. C₂₈H₄₂NSiO₃requires M,

468.2934); ν_max/cm⁻¹3071, 2934, 2859, 1721, 1649, 1271,

1110 and 703; δ_H(300 MHz, CDCl₃) 0.86–1.78 (12 H, m, 5-H₂,

6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂), 1.10 [9 H, s, SiC(CH₃)₃],

1.32 (3 H, d, J 6.5, 11-CH₃), 4.47 (1 H, q, J 5.2, 4-H), 5.09

(1 H, dqn, J 3.2, 5.6, 11-H), 6.09 (1 H, d, J 15.8, 2-H), 6.79

(1 H, dd, J 5.2, 15.8, 3-H), 7.40 (6 H, m, ArH) and 7.65 (4 H,

m, ArH); δ_C(75 MHz, CDCl₃) 19.2(2), 20.5, 22.0, 26.9, 27.9,

28.5, 32.4, 35.9, 72.0, 72.8, 121.2, 127.5, 127.6, 129.7, 133.4,

133.9, 135.7, 149.8 and 168.5; m/z (CI) 468 (M⁺+ 18, 100%),

451 (M⁺+ 1, 58), 274 (39) and 196 (42).

After the evolution of gas had ceased, the mixture was cooled to

0 °C and tetrabutylammonium iodide (50 mg) and 1-bromoprop-

2-ene (0.62 mL, 7.23 mmol) were added. The mixture was

stirred overnight at room temperature then saturated aqueous

ammonium chloride was added. The aqueous phase was

extracted with ether and the organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ether–petrol (5%),

gave the title compound 41 (1.34 g, 77%) as a clear, colourless

oil (Found: M⁺+ NH₄330.2458, C₁₇H₃₆NSiO₃requires M,

330.2464); ν_max/cm⁻¹2953, 2888, 1644, 1421, 1249, 1100,

1027, 924, 836 and 656; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s,

3 × SiCH₃), 0.91 (2 H, m, CH₂Si), 1.20 (3 H, d, J 6.3, 8-H₃),

2.31 (1 H, dt, J 14.6, 7.0, 4-H), 2.42 (1 H, dt, J 14.4, 6.3, 4-H),

3.51 (1 H, q, J 9.6, 3-H), 3.70 (2 H, m, OCH₂CH₂), 3.82 (1 H,

dd, J 5.9, 12.8, 1′-H), 4.02 (1 H, dd, J 5.1, 12.9, 1′-H), 4.51

(1 H, dq, J 8.4, 6.5, 7-H), 4.57 and 4.64 (each 1 H, d, J 6.9,

OHCHO), 5.20 (4 H, m, 1-H₂and 3′-H₂), 5.35 (1 H, t, J 10.1,

6-H), 5.60 (2 H, m, 2-H, 5-H) and 5.87 (1 H, ddt, J 10.4, 16.4,

5.6, 2′-H); δ_C(75 MHz, CDCl₃) −1.5, 18.0, 21.3, 33.5, 64.8,

67.0, 69.1, 80.0, 91.8, 116.5, 117.3, 127.5, 133.1, 134.9 and

138.2; m/z (CI) 330 (M⁺+ 18, 94%), 283 (12), 165 (100) and

97 (88).

(3RS,5Z,7SR)-3-(Prop-2-ynyloxy)-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 42. The alcohol 17 (1.24 mg, 4.56 mmol)

in THF (2 mL) was added to a suspension of sodium hydride

(237 mg, 60% dispersion in oil, 5.92 mmol) in THF (5 mL).

After the evolution of gas had ceased, the mixture was cooled to

−78 °C and propargyl bromide (1.02 mL, 80% by wt in toluene,

5.92 mmol) was added. The mixture was stirred overnight at

room temperature then saturated aqueous ammonium chloride

was added. The aqueous phase was extracted with ether and the

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ether–petrol (5%), gave the title compound

42 (1.20 g, 85%) as a clear, pale yellow oil (Found: M⁺+ NH₄

328.2302. C₁₇H₃₄NSiO₃requires M, 328.2308); ν_max/cm⁻¹

3308, 2953, 2893, 2116, 1642, 1423, 1374, 1249, 1080, 1025,

931, 860, 836, 758 and 693; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s,

3 × SiCH₃), 0.91 (2 H, t, J 8.2, CH₂Si), 1.21 (3 H, d, J 6.3,

8-H₃), 2.33 (1 H, ddt, J 1.4, 14.7, 8.1, 4-H), 2.37 (1 H, t, J 2.3,

3′-H), 2.41 (1 H, ddt, J 1.4, 14.8, 7.7, 4-H), 3.50 and 3.68 (each

1 H, dt, J 7.1, 9.6, OHCHCH₂), 3.91 (1 H, q, J 6.6, 3-H), 4.01

and 4.17 (each 1 H, dd, J 2.3, 15.7, 1′-H), 4.50 (1 H, dq, J 2.6,

6.6, 7-H), 4.57 and 4.64 (each 1 H, d, J 6.9, OHCHO), 5.24

(1 H, d, J 11.5, 1-H), 5.24 (1 H, d, J 15.9, 1-H), 5.36 (1 H, ddt,

J 8.9, 10.7, 1.5, 6-H), 5.54 (1 H, dt, J 11.0, 7.3, 5-H) and 5.63

(1 H, ddd, J 8.0, 9.9, 17.7, 2-H); δ_C(75 MHz, CDCl₃) −1.5,

18.0, 21.2, 33.3, 55.2, 64.8, 67.0, 73.9, 79.5, 79.9, 91.8, 118.5,

127.1, 133.4 and 137.0; m/z (CI) 328 (M⁺+ 18, 95%), 281 (12),

163 (100) and 107 (71).

Patulolide C 1.¹Tetrabutylammonium ﬂuoride (120 μL, 1.0 M

in THF, 0.12 mmol) was added to the silyl ether 38 (36 mg,

80 μmol) in THF (0.3 mL) and the solution stirred for 3 h. Ether

and water were added and the aqueous phase extracted with

ether. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ethyl acetate–petrol (10%),

gave patulolide C 1^1,2(13 mg, 76%) as a clear, colourless oil

(Found: M⁺

+ NH₄230.1751. C₁₂H₂₄NO₃requires M,

230.1756); ν_max/cm⁻¹3413, 2934, 2859, 1717, 1645, 1461,

1263, 1161 and 992; δ_H(300 MHz, CDCl₃) 0.86–1.88 (12 H, m,

5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂), 1.33 (3 H, d, J 6.6,

11-CH₃), 4.54 (1 H, q, J 6.0, 4-H), 5.11 (1 H, dqn, J 3.3, 6.6,

11-H), 6.13 (1 H, dd, J 0.9, 15.7, 2-H) and 6.89 (1 H, dd, J 6.6,

15.7, 3-H); δ_C(75 MHz, CDCl₃) 19.3, 20.7, 22.1, 27.8, 28.2,

32.8, 35.9, 70.9, 73.1, 121.5, 149.5 and 168.0; m/z (CI) 230

(M⁺+ 18, 100%) and 213 (M⁺+ 1, 32).

Dodeca-2,4,6-triene 43.¹⁷Butyllithium (0.70 mL, 1.47 M in

hexanes, 0.97 mmol) was added to the ether 41 (252 mg,

0.81 mmol) in THF (2 mL) at −78 °C and the mixture stirred for

15 h. Saturated aqueous ammonium chloride was added, the

aqueous phase was extracted with ether and the organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

(3RS,5Z,7SR)-3-(Prop-2-enyloxy)-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 41. The alcohol 17 (1.51 mg, 5.56 mmol)

in DMF (2 mL) was added to a suspension of sodium hydride

(289 mg, 60% dispersion in oil, 7.23 mmol) in DMF (5 mL).

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reduced pressure. Chromatography of the residue, eluting with

petrol, gave the title compound 43¹⁷(83 mg, 64%), a mixture of

two isomers as a clear, colourless oil (Found: M⁺164.1565.

C₁₂H₂₀requires M, 164.1565); ν_max/cm⁻¹3013, 2957, 2927,

2857, 1649, 1459, 992 and 926; δ_H(300 MHz, CDCl₃) 0.93

(3 H, t, J 6.9, 12-H₃), 1.24–1.50 (6 H, m, 9-H₂, 10-H₂and

11-H₂), 1.81 (3 H, d, J 6.8, 1-H₃), 2.13 (2 H, q, J 7.0, 8-H₂),

5.71 (2 H, m, 2-H and 7-H) and 6.10 (4 H, m, 3-H, 4-H, 5-H

and 6-H); δ_C(75 MHz, CDCl₃) 13.3, 14.0, 18.2, 22.5, 28.9,

29.0, 31.4, 32.7, 125.6, 125.7, 128.6, 129.5, 130.3, 130.5,

130.6(2), 131.7, 132.6, 134.4 and 135.2; m/z (EI) 164 (M⁺,

100%), 107 (31), 93 (43), 91 (36), 79 (71) and 41 (28).

3.95 and 4.07 (each 1 H, d, J 18.0, 1′-H), 4.52 (1 H, dq, J 9.1,

6.4, 7-H), 4.57 and 4.64 (each 1 H, d, J 7.0, OHCHO), 5.21

(1 H, d, J 17.2, 1-H), 5.26 (1 H, d, J 9.6, 1-H), 5.38 (1 H, dd,

J 9.1, 11.0, 6-H), 5.55 (1 H, dt, J 11.0, 7.3, 5-H), 5.66 (1 H,

ddd, J 8.0, 9.6, 17.2, 2-H) and 9.69 (1 H, s, CHO); δ_C(75 MHz,

CDCl₃) −1.5, 18.0, 21.2, 33.3, 64.9, 66.8, 73.8, 82.0, 91.7,

118.9, 126.8, 133.7, 136.9 and 201.1; m/z (CI) 332 (M⁺+ 18,

34%), 184 (57), 107 (100) and 90 (42).

(3RS,5Z,7SR)-3-(3-Methoxycarbonylprop-2-enyl)oxy-7-(2-tri-

methylsilylethoxy)methoxyocta-1,5-diene 46. Methoxycarbonyl

triphenyl phosphorane (1.23 g, 3.68 mmol) was added to the

aldehyde 45 (577 mg, 1.83 mmol) in DMF (12 mL) at room

temperature and the solution stirred overnight. Water and DCM

were added and the aqueous phase extracted with DCM. The

organic extracts were washed with water then brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ether–petrol (4%), gave the

(2′Z)-isomer of the title compound (2′Z)-46 (30 mg, 4%) as a

clear, colourless oil (Found: M⁺+ NH₄388.2526. C₁₉H₃₈NSiO₅

requires M, 388.2519); ν_max/cm⁻¹2952, 2890, 1723, 1652,

1438, 1194, 1096, 1025, 926, 836, 757 and 694; δ_H(300 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.90 (2 H, m, CH₂Si), 1.21

(3 H, d, J 6.3, 8-H₃), 2.37 (2 H, m, 4-H₂), 3.50 (1 H, dt, J 7.1,

9.6, OHCHCH₂), 3.69 (3 H, s, OCH₃), 3.70 (2 H, m,

OHCHCH₂and 3-H), 4.47 (1 H, ddd, J 2.5, 5.9, 16.8, 1′-H),

4.50 (1 H, m, 7-H), 4.54 (1 H, ddd, J 2.5, 4.9, 16.8, 1′-H), 4.57

and 4.63 (each 1 H, d, J 6.9, OHCHO), 5.20 (2 H, m, 1-H₂),

5.35 (1 H, ddt, J 9.2, 11.0, 1.4, 6-H), 5.53 (1 H, dt, J 11.0, 7.8,

5-H), 5.66 (1 H, ddd, J 7.6, 9.9, 17.6, 2-H), 5.78 (1 H, dt,

J 11.7, 2.5, 3′-H) and 6.37 (1 H, dt, J 11.7, 4.9, 2′-H); δ_C

(75 MHz, CDCl₃) −1.5, 18.0, 21.3, 33.5, 51.2, 64.9, 66.6, 66.9,

80.8, 91.8, 117.7, 118.6, 127.4, 133.3, 137.8, 149.1 and 166.4;

m/z (CI) 388 (M⁺+ 18, 27%), 223 (38), 99 (100) and 56 (38).

The second fraction was the (2′E)-isomer of the title compound

(2′E)-46 (457 mg, 70%) as a colourless oil (Found: M⁺+ NH₄

388.2509. C₁₉H₃₈NSiO₅requires M, 388.2519); ν_max/cm⁻¹

2952, 2880, 1727, 1662, 1437, 1301, 1271, 1249, 1170, 1101,

1025, 928, 836, 758 and 693; δ_H(300 MHz, CDCl₃) 0.00 (9 H,

s, 3 × SiCH₃), 0.90 (2 H, m, CH₂Si), 1.21 (3 H, d, J 6.5, 8-H₃),

2.33 (1 H, ddt, J 1.6, 14.7, 6.3, 4-H), 2.43 (1 H, ddt, J 1.5, 14.7,

6.0, 4-H), 3.50 (1 H, dt, J 7.2, 9.5, OHCHCH₂), 3.71 (2 H, m,

OHCHCH₂and 3-H), 3.73 (3 H, s, OCH₃), 3.99 (1 H, ddd,

J 2.1, 4.4, 16.5, 1′-H), 4.17 (1 H, ddd, J 2.1, 3.8, 16.4, 1′-H),

4.51 (1 H, dq, J 9.1, 6.3, 7-H), 4.57 and 4.64 (1 H, d, J 6.9,

OHCHO), 5.19 (2 H, m, 1-H₂), 5.36 (1 H, ddt, J 9.1, 11.0, 1.4,

6-H), 5.54 (1 H, dt, J 11.0, 7.8, 5-H), 5.66 (1 H, ddd, J 7.7,

10.7, 16.9, 2-H), 6.07 (1 H, dt, J 15.7, 2.2, 3′-H) and 6.93 (1 H,

dt, J 15.7, 3.9, 2′-H); δ_C(75 MHz, CDCl₃) −1.5, 18.0, 21.2,

33.4, 51.5, 64.9, 66.7, 66.8, 80.9, 91.7, 117.8, 120.5, 127.2,

133.4, 137.7, 144.9 and 166.8; m/z (CI) 388 (M⁺+ 18, 53%),

240 (61), 155 (100) and 99 (82).

(3RS,5Z,7SR)-3-(Ethoxycarbonyl)methoxy-7-(2-trimethyl-

silylethoxy)methoxyocta-1,5-diene

44. Ethyl

diazoacetate

(0.47 mL, 4.43 mmol) was added dropwise to the alcohol 17

(241 mg, 0.89 mmol) and rhodium diacetate dimer (39 mg,

2 mol% wrt ethyl diazoacetate) in DCM (2.5 mL). After the

evolution of gas had ceased (30 min), saturated aqueous

ammonium chloride was added and the aqueous phase was

extracted with DCM. The organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ether–light petro-

leum (15%), gave the title compound 44 (193 mg, 61%) as a

clear, colourless oil (Found: M⁺+ NH₄376.2509. C₁₈H₃₈NSiO₅

requires M, 376.2519); ν_max/cm⁻¹2973, 2867, 1736, 1452,

1370, 1313, 1101, 931, 738 and 699; δ_H(300 MHz, CDCl₃)

0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, m, CH₂Si), 1.21 (3 H, d,

J 6.5, 8-H₃), 1.26 (3 H, t, J 7.1, CH₃CH₂), 2.37 (1 H, ddt, J 1.2,

14.7, 8.0, 4-H), 2.48 (1 H, ddt, J 1.5, 13.3, 7.0, 4-H), 3.60 (2 H,

m, OCH₂CH₂), 3.79 (1 H, q, J 6.6, 3-H), 3.97 and 4.08 (each

1 H, d, J 16.4, 1′-H), 4.18 (2 H, q, J 6.2, CH₃CH₂), 4.51 (1 H,

dq, J 6.5, 9.1, 7-H), 4.57 and 4.64 (each 1 H, d, J 6.9, OHCHO),

5.21 (2 H, m, 1-H₂), 5.36 (1 H, dd, J 10.7, 11.0, 6-H), 5.58

(1 H, dt, J 11.0, 7.4, 5-H) and 5.66 (1 H, ddd, J 8.0, 10.4, 17.0,

2-H); δ_C(75 MHz, CDCl₃) −1.5, 14.1, 18.0, 21.2, 33.3, 60.6,

64.8, 65.5, 67.0, 81.4, 91.8, 118.6, 127.0, 133.4, 137.1 and

170.5; m/z (CI) 376 (M⁺+ 18, 56%), 359 (M⁺+ 1, 7), 329 (8),

228 (22), 107 (100), 90 (53) and 56 (22).

(3RS,5Z,7SR)-3-(Formylmethoxy)-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 45. Diisobutylaluminium hydride (5.74 mL,

1.0 M in hexanes, 5.74 mmol) was added to the ester 44 (1.37 g,

3.82 mmol) in DCM (10 mL) at −78 °C. The solution was

stirred between −45 °C and −60 °C for 1 h then cooled to

−78 °C and triethanolamine (2 equiv.) in DCM was added. The

mixture was allowed to warm to 0 °C, then saturated aqueous

ammonium chloride and celite were added and the mixture

allowed to warm to room temperature. After ﬁltration through

celite, the ﬁltrate was concentrated under reduced pressure.

Chromatography of the residue, with ether–light petroleum

(20%) as the eluent, gave the starting material 44 (92 mg) and

the title compound 45 (733 mg, 61%) as a clear colourless oil

(Found: M⁺+ NH₄332.2257. C₁₆H₃₄NSiO₄requires M,

332.2257); ν_max/cm⁻¹2954, 2894, 1738, 1374, 1249, 1104,

1026, 933, 860, 836, 759 and 694; δ_H(300 MHz, CDCl₃) 0.00

(9 H, s, SiCH₃), 0.91 (2 H, m, CH₂Si), 1.22 (3 H, d, J 6.4,

8-H₃), 2.37 (1 H, ddt, J 1.4, 14.3, 6.5, 4-H), 2.51 (1 H, ddt,

J 1.2, 13.7, 6.2, 4-H), 3.50 (1 H, dt, J 7.3, 9.6, OHCHCH₂),

3.69 (1 H, dt, J 8.5, 10.7, OHCHCH₂), 3.75 (1 H, q, J 6.6, 3-H),

(3RS,5Z,7SR)-3-[3-(4,5-Dihydro-1,3-oxazol-2-l)prop-2-enyl]-

oxy-7-(2-trimethylsilylethoxy)methoxyocta-1,5-diene 48. Butyl-

lithium (26.9 mL, 1.6 M in hexanes, 44.9 mmol) was added to

diisopropylamine (6.43 mL, 46.0 mmol) in THF (20 mL) at 0 °C.

The solution was allowed to warm to room temperature, stirred for

20 min and then cooled to −78 °C. 2,4,4-Trimethyl-2-oxazoline

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(1.02 g, 8.98 mmol) in THF (3 mL) was added and the solution

stirred for 1 h. Diethyl chlorophosphate (1.6 mL, 10.8 mmol)

was added and the solution stirred for a further 1 h. Saturated

aqueous ammonium chloride was added and the aqueous phase

was extracted with ether. The organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure

to leave phosphonate 47 (1.24 g, 55%) as a clear yellow oil used

without further puriﬁcation.

5-H), 5.70 (1 H, m, 2-H), 6.25 (1 H, dt, J 15.9, 5.8, 2′-H), 6.57

(1 H, d, J 15.9, 3′-H), 7.22 (1 H, d, J 9.3, ArH), 7.29 (2 H, t,

J 7.6, ArH) and 7.36 (2 H, d, J 7.0, ArH); δ_C(75 MHz, CDCl₃)

−1.5, 18.1, 21.3, 33.5, 64.9, 67.0, 68.8, 80.1, 91.8, 117.4, 126.3,

126.4, 127.5, 128.4, 131.9, 133.2, 136.8 and 138.2; m/z (CI) 406

(M⁺+ 18, 41%), 241 (21), 134 (86), 117 (100) and 90 (33).

(10RS,3RS,1E,5E,8Z)-3-Hydroxy-1-phenyl-10-(2-trimethyl-

silylethoxy)methoxyundeca-1,5,8-triene 50. Butyllithium (1.76 mL,

1.54 M in hexanes, 2.71 mmol) was cooled to −78 °C and

added slowly to the ether 49 (525 mg, 1.35 mmol) in THF at

−78 °C. The solution was stirred at −78 °C for 3 h then saturated

aqueous ammonium chloride was added at −78 °C and the

mixture allowed to warm to room temperature. The aqueous

phase was extracted with ether and organic extracts were washed

with brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ether–

petrol (20%), gave the title compound 50 (377 mg, 72%) as a

clear, colourless oil, 90 : 10 mixture of epimers (¹³C NMR)

(Found: M⁺+ NH₄406.2775. C₂₃H₄₀NSiO₃requires M,

406.2777); ν_max/cm⁻¹3434, 3025, 2953, 2893, 1447, 1374,

1249, 1100, 1023, 967, 836, 749 and 693; δ_H(500 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.93 (2 H, m, CH₂Si), 1.20

(3 H, d, J 6.4, 11-H₃), 2.30 (2 H, m, 4-H and OH), 2.36 (1 H,

ddt, J 1.1, 14.1, 7.1, 4-H), 2.77 (1 H, ddt, J 1.3, 14.3, 5.8, 7-H),

2.85 (1 H, m, 7-H), 3.49 and 3.70 (each 1 H, dt, J 6.2, 9.8,

OHCHCH₂), 4.28 (1 H, q, J 6.0, 3-H), 4.54 (1 H, d, J 7.1,

OHCHO), 4.57 (1 H, m, 10-H), 4.64 (1 H, d, J 6.8, OHCHO),

5.29 (1 H, ddt, J 9.2, 10.7, 1.5, 9-H), 5.47 (1 H, ddt, J 0.6, 15.2,

7.3, 6-H), 5.54 (2 H, m, 5-H and 8-H), 6.20 (1 H, dd, J 6.0,

15.8, 2-H), 6.56 (1 H, d, J 15.8, 1-H), 7.21 (1 H, m, ArH), 7.29

(2 H, m, ArH) and 7.32 (2 H, m, ArH); δ_C(125 MHz, CDCl₃)

major epimer 50 −1.4, 18.1, 21.4, 30.8, 40.9, 64.9, 66.4, 71.8,

91.5, 126.0, 126.4, 127.5, 128.5, 129.9, 130.0, 131.8, 132.0,

132.1 and 136.8; minor epimer 53 71.9, 126.1, 130.0 and 131.7;

m/z (CI) 406 (M⁺+ 18, 3%), 371 (3), 313 (4), 253 (100), 223

(48) and 90 (48).

Lithium chloride (66 mg, 1.55 mmol) and 1,8-diazabicyclo

[5.4.0]undec-7-ene (0.21 mL, 1.42 mmol) were added to the

phosphonate 47 (387 mg, 1.55 mmol) in acetonitrile (6 mL) at

room temperature. The aldehyde 45 (409 mg, 1.29 mmol) in

acetonitrile (2 mL) was added and the solution stirred for 48 h.

Saturated aqueous ammonium chloride and DCM were added

and the aqueous phase extracted with DCM. The organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ether–petrol (25%), gave the title compound 48 (315 mg, 60%)

as a clear, colourless oil (Found: M⁺

+ H, 410.2632.

C₂₂H₄₀NSiO₄requires M, 410.2726); ν_max/cm⁻¹2965, 2890,

1678, 1646, 1615, 1459, 1355, 1307, 1248, 1102, 1025, 925,

836, 757 and 694; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 ×

SiCH₃), 0.86 (2 H, m, CH₂Si), 1.20 (3 H, d, J 6.4, 8-H₃), 1.28

(6 H, s, 2 × CH₃), 2.36 (2 H, m, 4-H₂), 3.50 and 3.68 (each 1 H,

dt, J 7.3, 9.6, OHCHCH₂), 3.72 (1 H, q, J 6.6, 3-H), 3.94 (2 H,

s, 5′-H₂), 3.96 (1 H, m, 1′-H), 4.15 (1 H, ddd, J 1.9, 4.4, 15.0,

1′-H), 4.50 (1 H, dq, J 8.7, 6.4, 7-H), 4.57 and 4.64 (1 H, d,

J 6.9, OHCHO), 5.19 (2 H, m, 1-H₂), 5.35 (1 H, ddt, J 9.1, 11.0,

1.5, 6-H), 5.55 (1 H, dt, J 11.0, 7.6, 5-H), 5.66 (1 H, m, 2-H),

6.17 (1 H, dt, J 15.7, 1.8, 3′-H) and 6.55 (1 H, dt, J 15.7, 4.7,

2′-H); δ_C(75 MHz, CDCl₃) major isomer −1.5, 18.0, 21.2, 22.5,

28.2, 33.4, 41.2, 64.8, 66.9, 67.1, 78.6, 80.5, 91.7, 117.7, 118.3,

127.2, 133.2, 137.8, 139.0 and 161.0; m/z (CI) 410 (M⁺+ 1,

100%), 256 (9), 194 (7), 140 (17) and 90 (23).

(3RS,7SR,5Z,2′E)-3-Cinnamyloxy-7-(2-trimethylsilylethoxy)-

methoxyocta-1,5-diene 49. The alcohol 17 (259 mg, 0.95 mmol)

in THF (1 mL) was added to a suspension of sodium hydride

(50 mg, 60% dispersion in oil, 1.24 mmol) in THF (2 mL).

After the evolution of gas had ceased, the mixture was cooled to

0 °C and tetrabutylammonium iodide (25 mg, catalytic) and

(E)-cinnamyl bromide (244 mg, 1.24 mmol) in THF (0.5 mL)

were added. The mixture was stirred overnight at room tempera-

ture then saturated aqueous ammonium chloride was added. The

aqueous phase was extracted with ether and the organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ether–petrol (5%), gave the title compound 49 (257 mg, 70%) as

a clear, pale yellow oil (Found: M⁺+ NH₄406.2773.

C₂₃H₄₀NSiO₃requires M, 406.2777); ν_max/cm⁻¹3021, 2951,

2886, 1448, 1374, 1248, 1100, 1026, 966, 926, 836, 744 and

692; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H,

t, J 8.5, CH₂Si), 1.21 (3 H, d, J 6.3, 8-H₃), 2.35 (1 H, ddt, J 1.4,

14.4, 6.4, 4-H), 2.46 (1 H, ddt, J 1.4, 14.7, 6.4, 4-H), 3.51 and

3.68 (each 1 H, dt, J 7.1, 9.6, OHCHCH₂), 3.78 (1H, q, J 6.7,

3-H), 4.00 and 4.19 (each 1 H, ddd, J 1.2, 5.8, 12.8, 1′-H), 4.53

(1 H, dq, J 8.7, 6.3, 7-H), 4.58 and 4.65 (each 1 H, d, J 6.9,

OHCHO), 5.20 (1 H, d, J 16.2, 1-H), 5.22 (1 H, d, J 12.1, 1-H),

5.36 (1 H, ddt, J 9.2, 11.0, 1.4, 6-H), 5.56 (1 H, dt, J 10.6, 7.4,

(3RS,10RS,1E,5E,8Z)-3-Benzoyloxy-1-phenyl-10-(2-trimethyl-

silylethoxy)methoxyundeca-1,5,8-triene 51. Benzoyl chloride

(7 μL, 0.06 mmol), triethylamine (22 μL, 0.15 mmol) and

DMAP (2 mg) were added to the alcohol 50 (20 mg,

0.05 mmol) in DCM (0.3 mL) and the solution stirred for 2 h.

Saturated aqueous ammonium chloride was added and the

aqueous phase extracted with DCM. The organic extracts were

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ether–petrol (5%), gave the title compound 51 (20 mg, 79%) as a

clear, colourless oil (Found: M⁺+ NH₄510.3046. C₃₀H₄₄NSiO₄

requires M, 510.3039); ν_max/cm⁻¹3027, 2952, 2894, 1791,

1720, 1601, 1451, 1268, 1109, 1025, 836 and 711; δ_H

(500 MHz) 0.00 (9 H, s, 3 × SiCH₃), 0.89 (2 H, m, CH₂Si), 1.16

(3 H, d, J 6.4, 11-H₃), 2.55 (2 H, m, 4-H₂), 2.77 (2 H, m, 7-H₂),

3.46 (1 H, m, OHCHCH₂), 3.66 (1 H, dt, J 7.0, 9.7,

OHCHCH₂), 4.50 (1 H, dq, J 9.0, 6.4, 10-H), 4.52 and 4.59

(each 1 H, d, J 7.1, OHCHO), 5.25 (1 H, dd, J 9.2, 10.7, 9-H),

5.48 (3 H, m, 5-H, 6-H and 8-H), 5.65 (1 H, q, J 7.1, 3-H), 6.22

(1 H dd, J 7.1, 16.0, 2-H), 6.67 (1 H, d, J 16.0, 1-H), 7.22 (1 H,

m, ArH), 7.29 (2 H, m, ArH), 7.36 (2 H, m, ArH), 7.43 (2 H, m,

Org. Biomol. Chem., 2012, 10, 6995–7014 | 7009

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ArH), 7.51 (1 H, m, ArH) and 8.05 (2 H, m, ArH); δ_C

(125 MHz) −1.4, 18.1, 21.4, 30.8, 38.1, 64.9, 66.5, 74.6, 91.7,

125.2, 126.6, 127.2, 127.9, 128.3, 128.5, 129.6, 129.9, 130.5,

131.9, 132.0 132.6, 132.9, 136.3 and 165.7; m/z (CI) 510

(M⁺+ 18, 1%), 253 (26), 223 (24), 105 (100) and 90 (41).

131.7, 132.1, 132.2, 132.2 and 136.8; m/z (CI) 406 (M⁺+ 18,

3%), 388 (M⁺, 2), 342 (12), 253 (100), 223 (48) and 90 (70).

Benzoyl chloride (8 μL, 66 μmol), triethylamine (16 μL,

0.12 mmol) and DMAP (2 mg) were added to a mixture of the

alcohols 50 and 53 (217 mg, 44 μmol) in DCM (0.3 mL)

and the solution stirred for 2 h. Saturated aqueous ammonium

chloride was added and the aqueous phase was extracted with

DCM. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue, eluting with ether–petrol (5%), gave a

mixture of the esters 51 and 54 (11 mg, 51%) as a clear, colour-

less oil, a 50 : 50 mixture of epimers (¹³C NMR) (Found: M⁺+

NH₄510.3043. C₃₀H₄₄NSiO₄requires M, 510.3039); ν_max/cm⁻¹

3029, 2953, 1720, 1449, 1268, 1106, 1025, 965, 836 and 711;

δ_H(500 MHz, CDCl₃) −0.01 (9 H, s, 3 × SiCH₃), 0.86 (2 H, m,

CH₂Si), 1.16 (1.5 H, d, J 6.4, 11-H₃), 1.16 (1.5 H, d, J 6.4,

11-H₃), 2.55 (2 H, m, 4-H₂), 2.78 (2 H, t, J 6.0, 7-H₂), 3.47 and

3.66 (each 1 H, m, OHCHCH₂), 4.49 (1 H, m, 10-H), 4.52 and

4.59 (each 1 H, d, J 6.8, OHCHO), 5.25 (1 H, m, 9-H),

5.41–5.57 (3 H, m, 5-H, 6-H and 8-H), 5.65 (1 H, q, J 6.8, 3-H),

6.23 (1 H dd, J 7.1, 16.0, 2-H), 6.67 (1 H, d, J 16.0, 1-H), 7.22

(1 H, m, ArH), 7.29 (2 H, m, ArH), 7.36 (2 H, m, ArH), 7.43

(2 H, m, ArH), 7.54 (1 H, m, ArH) and 8.05 (2 H, m, ArH); δ_C

(125 MHz, CDCl₃) −1.4, 18.1, 21.4, 30.8, 38.1, 64.9, 66.5, 74.7,

91.7, 125.2, 126.6, 127.2, 127.9, 128.3, 128.5, 129.6, 129.9(2),

130.5, 131.8, 131.9, 132.0, 132.6, 132.9, 136.3 and 165.7; m/z (CI)

510 (M⁺+ 18, 7%), 253 (92), 223 (53), 105 (37) and 90 (100).

(1E,5E,8Z)-1-Phenyl-10-(2-trimethylsilylethoxy)methoxyundeca-

1,5,8-trien-3-one 52. Dimethyl sulfoxide (0.35 mL, 4.89 mmol)

was added to a solution of oxalyl chloride (0.17 mL,

1.96 mmol) in DCM (9 mL) at −78 °C and the mixture stirred

for 10 min. A solution of the alcohol 50 (633 mg, 1.63 mmol) in

DCM (1 mL) was added and the solution stirred at −78 °C for

1 h. Triethylamine (0.68 mL, 4.98 mmol) was added and the

solution stirred for 15 min before being warmed to room temp-

erature. Saturated aqueous ammonium chloride was added and

the aqueous phase extracted with DCM. The organic extracts

were washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ether–petrol (10%), gave the title compound 52 (240 mg, 38%)

as a clear, colourless oil (Found: M⁺+ H, 387.2340. C₂₃H₃₅SiO₃

requires M, 387.2355); ν_max/cm⁻¹3015, 2953, 2885, 1691,

1665, 1611, 1449, 1249, 1100, 1025, 836, 753 and 693; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H, m,

CH₂Si), 1.22 (3 H, d, J 6.3, 11-H₃), 2.87 (2 H, t, J 6.2, 7-H₂),

3.37 (2 H, d, J 5.8, 4-H₂), 3.50 and 3.69 (each 1 H, dt, J 7.0,

9.6, OHCHCH₂), 4.56 (1 H, m, 10-H), 4.57 and 4.64 (each 1 H,

d, J 6.9, OHCHO), 5.33 (1 H, t, J 9.9, 9-H), 5.48–5.72 (3 H, m,

5-H, 6-H and 8-H), 6.74 (1 H, dd, J 0.7, 16.1, 1-H), 7.38 (3 H,

m, ArH) and 7.56 (3 H, m, ArH and 2-H); δ_C(75 MHz, CDCl₃)

−1.5, 18.1, 21.3, 30.7, 44.8, 64.9, 66.5, 91.7, 123.0, 125.4,

128.2, 128.9, 129.5, 130.4, 132.2, 132.5, 134.4, 142.9 and

198.0; m/z (CI) 404 (M⁺+ 18, 8%), 387 (M⁺+ 1, 4), 256 (29),

239 (100), 131 (31) and 90 (29).

Sodium borohydride (32 mg, 0.84 mmol) was added to a solu-

tion of the ketone 52 (215 mg, 0.56 mmol) in ethanol (1.5 mL)

at 0 °C and the solution allowed to warm to room temperature.

After 15 h, dilute aqueous hydrogen chloride was added and the

mixture concentrated under reduced pressure. The residue was

taken up in water and ethyl acetate. The aqueous phase was

extracted with ethyl acetate and the organic extracts washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ether–petrol (25%),

gave the alcohols 50 and 53 (114 mg, 52%) as a clear, colourless

oil, a 50 : 50 mixture (¹³C NMR) (Found: M⁺+ NH₄406.2782.

C₂₃H₄₀NSiO₃requires M, 406.2777); ν_max/cm⁻¹3438, 3025,

2952, 2893, 1447, 1249, 1100, 1023, 967, 836, 749 and 694; δ_H

(500 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.89 (2 H, m,

CH₂Si), 1.20 (3 H, m, 11-H₃), 2.19 (1 H, br. s, OH), 2.27 (1 H,

dt, J 14.5, 7.5, 4-H), 2.36 (1 H, dt, J 13.7, 7.1, 4-H), 2.78 (1 H,

dt, J 13.9, 6.8, 7-H), 2.86 (1 H, dt, J 15.4, 7.5, 7-H), 3.51 and

3.70 (each 1 H, dt, J 6.6, 9.8, OHCHCH₂), 4.28 (1 H, br. m,

3-H), 4.54 and 4.55 (each 0.5 H, d, J 6.8, OHCHO), 4.54 (1 H,

m, 10-H), 4.64 (1 H, d, J 6.8, OHCHO), 5.29 (1 H, m, 9-H),

5.48 (1 H, m, 6-H), 5.55 (2 H, m, 5-H and 8-H), 6.21 (1 H, dd,

J 6.2, 16.0, 2-H), 6.57 (1 H, d, J 16.0, 1-H), 7.21 (1 H, m, ArH),

7.29 (2 H, m, ArH) and 7.35 (2 H, m, ArH); δ_C(125 MHz,

CDCl₃) −1.4, 18.1, 21.4, 30.7, 40.9, 64.9, 66.4, 71.8, 71.9, 91.5,

126.0, 126.1, 126.4, 127.6, 128.5, 129.9, 130.0, 130.1, 131.7,

(3RS,7SR,5Z)-3-[(2E)-Penta-2,4-dienyloxy]-7-(2-trimethyl-

silylethoxy)methoxyocta-1,5-diene 56. The alcohol 17 (543 mg,

2.00 mmol) in THF (1 mL) was added to a stirred suspension of

sodium hydride (104 mg, 60% dispersion in oil, 2.60 mmol) in

THF (6 mL). After the evolution of gas had ceased, tetrabutyl-

ammonium iodide (100 mg) and (2E)-1-bromopenta-2,4-diene

(587 mg, 3.99 mmol) in THF (1 mL) were added. The mixture

was stirred overnight at room temperature and saturated aqueous

ammonium chloride was added. The aqueous phase was

extracted with ether and the organic extracts were washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ether–petrol (10%),

gave the title compound 56 (514 mg, 76%) as a clear, pale

yellow oil (Found: M⁺+ NH₄356.2624. C₁₉H₃₈NSiO₃requires

M, 356.2621); ν_max/cm⁻¹3085, 2953, 2882, 1656, 1605, 1422,

1374, 1249, 1102, 1026, 923, 836 and 693; δ_H(300 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.91 (2 H, m, CH₂Si), 1.20

(3 H, d, J 6.5, 8-H₃), 2.37 (2 H, m, 4-H₂), 3.50 (1 H, dt, J 7.1,

9.6, OHCHCH₂), 3.70 (2 H, m, 3-H and OHCHCH₂), 3.86 and

4.06 (each 1 H, dd, J 6.2, 13.1, 1′-H), 4.51 (1 H, dq, J 9.3, 6.5,

7-H), 4.57 and 4.64 (each 1 H, d, J 6.8, OHCHO), 5.04–5.22

(4 H, m, 1-H₂and 5′-H₂), 5.35 (1 H, ddt, J 9.3, 11.0, 1.5, 6-H),

5.54 (1 H, dt, J 11.0, 7.5, 5-H), 5.59–5.79 (2 H, m, 2-H and

2′-H), 6.21 (1 H, m, 3′-H) and 6.32 (1 H, dt, J 16.5, 10.2, 4′-H);

δ_C(75 MHz, CDCl₃) −1.5, 18.1, 21.3, 33.5, 64.9, 67.0, 68.2,

80.1, 91.8, 117.2, 117.4, 127.5, 130.3, 132.7, 133.2, 136.4 and

138.2; m/z (CI) 356 (M⁺+ 18, 100%), 339 (M⁺+ 1, 8), 309 (9),

191 (87), 123 (38), 90 (36).

(5RS,12RS,3E,7E,10Z)-5-Hydroxy-10-(2-trimethylsilylethoxy)-

methoxytrideca-1,3,7,10-tetraene 57. Butyllithium (3.10 mL,

7010 | Org. Biomol. Chem., 2012, 10, 6995–7014

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1.15 M in hexanes, 3.57 mmol) was cooled to −78 °C and

added to the ether 56 (514 mg, 1.78 mmol) in THF (3 mL) at

−78 °C. The solution was stirred for 3 h before saturated

aqueous ammonium chloride was added. After warming to room

temperature, the aqueous phase was extracted with ether. The

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ether–petrol (20%), gave the title compound

57 (360 mg, 70%) as a clear, colourless oil (Found: M⁺+ NH₄

356.2637. C₁₉H₃₈NSiO₃requires M, 356.2621); ν_max/cm⁻¹

3437, 2953, 2894, 1654, 1605, 1374, 1249, 1100, 1023, 836 and

693; δ_H(500 MHz, CDCl₃) 0.01 (9 H, s, 3 × SiCH₃), 0.90 (2 H,

m, CH₂Si), 1.20 (3 H, d, J 6.4, 13-H₃), 2.15 (1 H, br. s, OH),

2.19 (1 H, dt, J 14.5, 7.5, 6-H), 2.27 (1 H, dt, J 13.0, 5.3, 6-H),

2.76 (1 H, dt, J 15.8, 7.1, 9-H), 2.83 (1 H, dt, J 15.6, 7.3, 9-H),

3.48 (1 H, dt, J 6.2, 10.3, OHCHCH₂), 3.69 (1 H, dt, J 6.6,

10.0, OHCHCH₂), 4.15 (1 H, q, J 6.0, 5-H), 4.53 (1 H, m,

12-H), 4.54 and 4.62 (each 1 H, d, J 7.1, OHCHO), 5.05 (1 H,

dd, J 1.4, 10.0, 1-H), 5.17 (1 H, dd, J 1.4, 16.4, 1-H), 5.28 (1 H,

dd, J 9.2, 10.7, 11-H), 5.42 (1 H, dt, J 14.1, 6.8, 8-H), 5.53

(2 H, m, 7-H and 10-H), 5.69 (1 H, dd, J 6.0, 15.2, 4-H), 6.21

(1 H, dd, J 10.4, 15.2, 3-H) and 6.30 (1 H, dt, J 16.4, 10.4,

2-H); δ_C(125 MHz, CDCl₃) −1.4, 18.1, 21.4, 30.7, 40.7, 64.9,

66.4, 71.2, 91.5, 117.3, 126.0, 129.9, 130.8, 132.0, 132.1, 135.8

and 136.3; m/z (CI) 356 (M⁺+ 18, 2%), 203 (60), 173 (67), 122

(68) and 90 (100).

resulting solution stirred for 2.5 h. Saturated aqueous ammonium

chloride was added and the mixture allowed to warm to room

temperature. The aqueous phase was extracted with ether and the

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. The residue was dissolved

in DMF (3 mL) and imidazole (427 mg, 6.26 mmol) and tert-

butyldiphenylchlorosilane (0.98 mL, 3.76 mmol) were added.

After 5 h, the mixture was diluted with ether and water and the

aqueous phase was extracted with ether. The organic extracts

were washed with water and brine, dried (MgSO₄) and concen-

trated under reduced pressure. Chromatography of the residue,

eluting with ethyl acetate–petrol (2%), gave the title compound

60 (1.09 g, 35%) as a clear, colourless oil, a 2 : 1 mixture of

epimers (¹H NMR) (Found: M⁺+ NH₄720.4250. C₄₅H₆₂-

NSi₂O₃requires M, 720.4268); ν_max/cm⁻¹3070, 3017, 2953,

2857, 1427, 1249, 1106, 1055, 1027, 859, 835, 763 and 701; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H, m,

CH₂Si), 1.01 [9 H, s, SiC(CH₃)₃], 1.20 (3 H, d, J 6.0, 11-H₃),

2.52 (2 H, m, 4-H₂), 2.63 (1.33 H, t, J 6.6, 7-H₂), 2.74 (0.67 H,

m, 7-H₂), 3.51 and 3.69 (each 1 H, m, OHCHCH₂), 4.32 (1 H,

m, 3-H), 4.52 (1 H, m, 10-H), 4.57 and 4.63 (each 1 H, d, J 6.9,

OHCHO), 5.16–5.56 (4 H, m, 5-H, 6-H, 8-H and 9-H), 6.12

(1 H, d, J 9.3, 2-H), 6.66 (2 H, m, ArH) and 7.03–7.60 (18 H,

m, ArH); δ_C(75 MHz, CDCl₃) −1.5, 18.1, 19.7, 21.4, 25.9,

26.9, 36.4, 64.9, 66.8, 70.7, 91.8, 126.0, 126.8, 127.1, 127.2,

127.3, 127.8, 127.9, 129.2, 129.2, 129.3, 129.5, 130.4, 131.4,

131.6, 133.8, 134.3, 135.8, 135.9, 139.1, 141.0 and 142.0; m/z

(CI) 720 (M⁺+ 18, 4%), 329 (29) and 90 (100).

(3SR,7RS,5Z)-3-(3,3-Diphenylprop-2-enyloxy)-7-(2-trimethyl-

silylethoxy)methoxyocta-1,5-diene 58. The alcohol 17 (959 mg,

3.53 mmol) in THF (2 mL) was added slowly to a suspension of

sodium hydride (169 mg, 60% dispersion in oil, 4.23 mmol) in

THF (6 mL). After 30 min, tetrabutylammonium iodide (50 mg)

and 1-bromo-3,3-diphenylprop-2-ene (1.66 g, 6.08 mmol) in

THF (2 mL) were added and the mixture stirred overnight. Water

was added and the aqueous phase extracted with ether. The

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (2%), gave the title

compound 58 (1.36 g, 83%) as a clear, colourless oil (Found:

M⁺+ NH₄482.3103. C₂₉H₄₄NSiO₃requires M, 482.3090);

ν_max/cm⁻¹3022, 2952, 2889, 1669, 1444, 1374, 1248, 1099,

1026, 924, 836, 761 and 699; δ_H(300 MHz, CDCl₃) 0.00 (9 H,

s, 3 × SiCH₃), 0.89 (2 H, m, CH₂Si), 1.20 (3 H, d, J 6.6, 8-H₃),

2.35 (2 H, m, 4-H₂), 3.50 (1 H, dt, J 7.1, 9.6, OHCHCH₂), 3.65

(1 H, q, J 6.6, 3-H), 3.68 (1 H, dt, J 7.6, 9.8, OHCHCH₂), 3.89

and 4.08 (each 1 H, dd, J 6.3, 12.2, 1′-H), 4.50 (1 H, dq, J 9.1,

6.6, 7-H), 4.57 and 4.66 (each 1 H, d, J 6.9, OHCHO), 5.07

(2 H, m, 1-H₂), 5.37 (1 H, ddt, J 9.1, 11.0, 1.5, 6-H), 5.55 (1 H,

dt, J 11.0, 7.4, 5-H), 5.62 (1 H, ddd, J 7.7, 10.5, 17.2, 2-H), 6.19

(1 H, t, J 6.3, 2′-H) and 7.12–7.38 (10 H, m, ArH); δ_C(75 MHz,

CDCl₃) −1.5, 18.0, 21.3, 33.6, 64.9, 66.0, 67.0, 80.2, 91.8,

117.2, 125.7, 127.3, 127.5, 128.0(2), 128.3, 128.5, 129.7, 133.2,

138.2, 139.2, 141.9 and 144.4; m/z (CI) 482 (M⁺+ 18, 42%),

226 (16), 209 (48) and 193 (100).

(3RS,10RS,5E,8Z)-1,2-Epoxy-3-hydroxy-1-phenyl-10-(2-trimethyl-

silylethoxy)methoxyundeca-5,8-diene 61. tert-Butylhydroperoxide

(2.0 mL, 11.1 mmol) was added to the alcohol 50 (614 mg,

1.58 mmol) and vanadyl acetylacetonate (17 mg, 4 mol%) in

benzene (15 mL). After 10 min, the mixture was added to satu-

rated aqueous sodium thiosulfate. The aqueous phase was

extracted with ether and the organic extracts were washed with

saturated aqueous sodium thiosulfate and brine, dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of the

residue, eluting with ether–petrol (30%), gave the title compound

61 (482 mg, 76%) as a clear, colourless oil, a ca. 67 : 33 mixture

of diastereoisomers (¹H NMR) (Found: M⁺+ NH₄422.2725.

C₂₃H₄₀NSiO₄requires M, 422.2726); ν_max/cm⁻¹3436, 3009,

2953, 2927, 1439, 1374, 1249, 1100, 1024, 839, 836, 751 and

697; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.84 (1 H,

m, CH₂Si), 0.92 (1 H, m, CH₂Si), 1.21 (2 H, d, J 6.5, 11-H₃),

1.22 (1 H, d, J 6.5, 11-H₃), 2.34 (3 H, m, OH and 4-H₂), 2.81

(2 H, m, 7-H₂), 3.04 (1 H, m, 2-H), 3.49 and 3.69 (each 1 H, m,

OHCHCH₂), 3.84 (0.5 H, d, J 1.9, 1-H), 3.87 (1 H, q, J 4.2,

3-H), 3.92 (0.5 H, d, J 2.1, 1-H), 4.54 (2 H, m, 10-H and

OHCHO), 4.63 (1 H, m, OHCHO), 5.30 (1 H, m, 9-H), 5.52

(3 H, m, 5-H, 6-H and 8-H) and 7.28 (5 H, m, ArH); δ_C

(75 MHz, CDCl₃) major diastereoisomer −1.5, 18.1, 21.3, 30.6,

36.8, 55.2, 64.9, 66.5, 68.7, 91.6, 125.5, 125.6, 128.1, 128.4,

129.7, 131.9, 132.1 and 136.8; minor diastereoisomer 22.5,

37.9, 56.1, 64.3, 68.8, 70.1, 125.4 and 136.7; m/z (CI) 422

(M⁺+ 18, 1%), 329 (2), 274 (2), 239 (22), 137 (22), 107 (46),

91 (55), 90 (100) and 73 (68). The second fraction was

(3RS,8Z,10RS)-1,2-epoxy-5,6-epoxy-3-hydroxy-1-phenyl-10-

(2-trimethylsilylethoxy)methoxy-undec-8-ene (146 mg, 22%) as

(5E,8Z)-3-tert-Butyldiphenylsilyloxy-1,1-diphenyl-10-(2-trimethyl-

silylethoxy)methoxyundeca-1.5,8-triene 60. Butyllithium (14.7 mL,

1.50 M in hexanes, 22.1 mmol) at −78 °C was added to the

ether 58 (2.04 g, 4.41 mmol) in THF (10 mL) at −78 °C and the

Org. Biomol. Chem., 2012, 10, 6995–7014 | 7011

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a clear, colourless oil, a mixture of diastereoisomers (Found: M⁺+

NH₄438.2672. C₂₃H₄₀NSiO₅requires M, 438.2676); ν_max/cm⁻¹

3425, 2953, 2890, 1462, 1373, 1249, 1099, 1054, 1023, 836,

752 and 697; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃),

0.85–0.95 (2 H, m, CH₂Si), 1.21 (3 H, d, J 6.5, 11-H₃), 1.90

(2 H, m, 4-H₂), 2.35 (2 H, m, 7-H₂), 2.63 (1 H, m, OH), 2.80

and 2.98 (each 1 H, m), 3.05 (0.5 H, dd, J 2.2, 3.6, 2-H), 3.08

(0.5 H, dd, J 2.1, 3.3, 2-H), 3.48 (1 H, m, OHCHCH₂), 3.68

(1 H, dt, J 7.1, 9.9, OHCHCH₂), 3.92 (0.5 H, d, J 2.1, 1-H),

3.94 (0.5 H, d, J 2.1, 1-H), 4.04 (1 H, m, 3-H), 4.47 (1 H, dq,

J 8.7, 6.5, 10-H), 4.56 and 4.63 (each 1 H, d J 7.1, OHCHO),

5.39 (1 H, dd, J 8.7, 10.9, 9-H), 5.53 (1 H, m, 8-H) and 7.28

(5 H, m, ArH); m/z (CI) 438 (M⁺+ 18, 1%), 273 (5), 255 (8),

225 (7), 153 (38), 91 (56), 90 (100) and 73 (52).

1249, 1106, 1026, 834, 743 and 701; δ_H(300 MHz, CDCl₃)

0.00 (3 H, s, 3 × SiCH₃), 0.01 (6 H, s, 3 × SiCH₃), 0.91 (2 H,

m, CH₂Si), 1.04 [6 H, s, SiC(CH₃)₃], 1.10 [3 H, s, SiC(CH₃)₃],

1.19 (1 H, d, J 6.5, 11-H₃), 1.21 (2 H, d, J 6.3, 11-H₃),

2.13–2.38 (2 H, m, 4-H₂), 2.69 (0.67 H, m, 7-H₂), 2.78 (1.33 H,

m, 7-H₂), 3.01 (0.67 H, dd, J 2.1, 5.8, 2-H), 3.08 (0.33 H, dd,

J 2.1, 6.2, 2-H), 3.45 (0.67 H, d, J 2.1, 1-H), 3.51 (1 H, dt,

J 8.2, 10.7, OHCHCH₂), 3.66 (2.33 H, m, OHCHCH₂, 3-H and

1-H), 4.42–4.59 (1 H, m, 10-H), 4.58 and 4.64 (each 1 H, d,

J 7.0, OHCHO), 5.20–5.56 (4 H, m, 5-H, 6-H, 8-H and 9-H)

and 7.03–7.76 (15 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.4, 18.1,

19.3, 19.4, 21.4, 26.9, 27.0, 30.6, 30.8, 38.2, 38.2, 56.5, 57.3,

64.2, 64.9, 65.6, 66.5, 66.6, 72.6, 74.2, 91.7, 125.5, 125.7(2),

127.5(2), 127.6, 127.9, 128.0, 128.2, 128.3, 129.6, 129.8(2),

130.1, 131.3, 131.7, 131.8, 133.3, 133.7, 134.1, 135.8, 135.9(2),

137.0 and 137.1; m/z (CI) 660 (M⁺+ 18, 51%), 495 (24),

417 (64), 405 (51), 196 (51) and 90 (100).

(3RS,5E,8Z,10RS)-3-tert-Butyldimethylsilyloxy-1,2-epoxy-1-

phenyl-10-(2-trimethylsilylethoxy)methoxyundeca-5,8-diene 62.

Imidazole (532 mg, 7.81 mmol) and tert-butyldimethylsilyl

chloride (674 mg, 4.46 mmol) were added to the alcohol 61

(901 mg, 2.23 mmol) in DMF (8 mL) and the solution stirred

for 15 h. Ether and water were added and the aqueous phase

extracted with ether. The organic extracts were washed with

water and brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ether–

petrol (5%), gave the title compound 62 (895 mg, 77%) as a

clear, colourless oil, a 67 : 33 mixture of diastereoisomers

(¹H NMR) (Found: M⁺+ NH₄536.3594. C₂₉H₅₄NSi₂O₄requires

M, 536.3591); ν_max/cm⁻¹3010, 2954, 2857, 1463, 1371, 1250,

1101, 1026, 836, 778 and 697; δ_H(300 MHz, CDCl₃) 0.00 (9 H,

s, 3 × SiCH₃), 0.06 (4 H, s, 2 × SiCH₃), 0.08 and 0.14 (each

1 H, s, SiCH₃), 0.87 [6 H, s, SiC(CH₃)₃], 0.87 (2 H, m, SiCH₂),

0.91 [3 H, s, SiC(CH₃)₃], 1.21 (3 H, d, J 6.3, 11-H₃), 2.30 (2 H,

m, 4-H₂), 2.78 (2 H, m, 7-H₂), 2.92 (0.7 H, dd, J 2.1, 4.3, 2-H),

2.97 (0.3 H, dd, J 2.1, 6.3, 2-H), 3.50 (1 H, m, OHCHCH₂),

3.70 (2.3 H, m, 3-H, 1-H, OHCHCH₂), 3.79 (0.7 H, d, J 2.1,

1-H), 4.52 (1 H, m, 10-H), 4.56 (1 H, d J 6.9, OHCHO), 4.61

(0.7 H, d, J 6.9, OHCHO), 4.62 (0.3 H, d, J 6.9, OHCHO), 5.28

(1 H, dd, J 9.0, 10.8, 9-H), 5.46 (3 H, m, 5-H, 6-H and 8-H) and

7.27 (5 H, m, ArH); δ_C(75 MHz, CDCl₃) major diastereoisomer

−4.8, −4.5, −1.5, 18.1, 21.4, 25.7, 30.7, 38.4, 55.9, 56.6, 64.7,

64.9, 66.6, 71.0, 91.7, 125.5, 126.2, 127.9, 128.3, 130.0, 131.0,

131.8 and 137.4; minor diastereoisomer 18.1, 25.8, 65.8, 73.8,

128.0, 129.8 and 137.0; m/z (CI) 536 (M⁺+ 18, 2%), 401 (1),

263 (30), 239 (29), 221 (32), 107 (28), 91 (29), 90 (100) and

73 (76).

(3RS,10RS)-3-tert-Butyldimethylsilyloxy-1,2-epoxy-1-phenyl-

10-(2-trimethylsilylethoxy)methoxyundecane 64. Sodium acetate

(2.83 g, 34.6 mmol) in water (20 mL) was added dropwise over

2 h to the diene 62 (895 mg, 1.73 mmol) and toluene 4-sulfonyl-

hydrazine (3.86 g, 20.7 mmol) in DME (65 mL) heated under

reﬂux. The solution was heated under reﬂux for a further 2 h and

then allowed to cool to room temperature. The aqueous phase

was extracted with ether and the organic extracts washed with

water and brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ether–

petrol (5%), gave the title compound 64 (785 mg, 87%) as a

clear, colourless oil, a 67 : 33 mixture of diastereoisomers

(¹H NMR) (Found: M⁺+ NH₄540.3915. C₂₉H₅₈NSi₂O₄requires

M, 540.3904); ν_max/cm⁻¹2930, 2857, 1464, 1376, 1250, 1102,

1055, 1032, 836, 777, 753 and 697; δ_H(300 MHz, CDCl₃) 0.00

(9 H, s, 3 × SiCH₃), 0.06 and 0.07 (each 2 H, s, SiCH₃), 0.08

and 0.15 (each 1 H, s, SiCH₃), 0.87 [6 H, s, SiC(CH₃)₃], 0.87

(2 H, m, CH₂Si), 0.91 [3 H, s, SiC(CH₃)₃], 1.13 (3 H, d, J 6.2,

11-H₃), 1.20–1.58 (12 H, m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂and

9-H₂), 2.89 (0.7 H, dd, J 2.1, 4.4, 2-H), 2.96 (0.3 H, dd, J 2.2,

6.5, 2-H), 3.45 (1 H, m, OHCHCH₂), 3.65 (2.3 H, m,

OHCHCH₂, 1-H and 3-H), 3.79 (0.7 H, d, J 1.8, 1-H), 4.58

(1 H, m, 10-H), 4.64 and 4.71 (each 1 H, d, J 7.1, OHCHO) and

7.28 (5 H, m, ArH); m/z (CI) 540 (M⁺+ 18, 2%), 317 (4), 285

(13), 215 (14), 177 (13), 90 (100) and 73 (39).

(3RS,10RS)-3-tert-Butyldiphenylsilyloxy-1,2-epoxy-1-phenyl-10-

(2-trimethylsilylethoxy)methoxyundecane 65. Sodium acetate

(4.56 g, 33.0 mmol) in water (15 mL) was added dropwise over

2 h to the diene 63 (1.06 g, 1.65 mmol) and 4-sulfonylhydrazine

(3.69 g, 19.8 mmol) in DME (40 mL) heated under reﬂux. The

solution was heated under reﬂux for a further 2.5 h then allowed

to cool to room temperature. The aqueous phase was extracted

with ether and the organic extracts were washed with water and

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(3%), gave the title compound 65 (904 mg, 85%) as a clear,

colourless oil, a 67 : 33 mixture of two diastereoisomers

(¹H NMR) (Found: M⁺+ NH₄664.4219. C₃₉H₆₂NSi₂O₄requires

M, 664.4217); ν_max/cm⁻¹3048, 2932, 2858, 1465, 1428, 1248,

1107, 1055, 1031, 836, 742 and 702; δ_H(300 MHz, CDCl₃)

(3RS,10RS,5E,8Z)-3-tert-Butyldiphenylsilyloxy-1,2-epoxy-1-

phenyl-10-(2-trimethylsilylethoxy)methoxyundeca-5,8-diene 63.

Imidazole (681 mg, 10.0 mmol) and tert-butyldiphenylchloro-

silane (1.8 mL, 6.8 mmol) were added to the alcohol 61 (1.62 g,

4.0 mmol) in DCM (7 mL) at room temperature. The solution

was stirred for 18 h and water was added. The aqueous phase

was extracted with DCM and the organic extracts washed with

brine, dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue, eluting with ethyl acetate–petrol

(3%), gave the title compound 63 (2.38 g, 93%) as a clear, col-

ourless oil, a 67 : 33 mixture of two diastereoisomers (¹H NMR)

(Found: M⁺+ NH₄660.3903. C₃₉H₅₈NSi₂O₄required M,

660.3904); ν_max/cm⁻¹3013, 2953, 2859, 1467, 1428, 1368,

7012 | Org. Biomol. Chem., 2012, 10, 6995–7014

View Article Online

0.00 (3 H, s, 3 × SiCH₃), 0.01 (6 H, s, 3 × SiCH₃), 0.92 (2 H,

m, CH₂Si), 1.02 [6 H, s, SiC(CH₃)₃], 1.11 [3 H, s, SiC(CH₃)₃],

1.05–1.62 (12 H, m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂and 9-H₂),

1.14 (3 H, d, J 6.3, 11-H₃), 2.97 (0.67 H, dd, J 1.9, 5.9, 2-H),

3.05 (0.33 H, dd, J 2.1, 6.3, 2-H), 3.42 (0.67 H, d, J 1.9, 1-H),

3.62 (4.33 H, m, OCH₂CH₂, 10-H, 3-H and 1-H), 4.64 (0.33 H,

d J 6.5, OHCHO), 4.66 (0.67 H, d, J 6.5, OHCHO), 4.69

(0.33 H, d, J 6.5, OHCHO), 4.71 (0.67 H, d, J 6.5, OHCHO)

and 7.05–7.75 (15 H, m, ArH); m/z (CI) 664 (M⁺+ 18, 78%),

409 (42), 256 (26) and 90 (100).

δ_C(75 MHz, CDCl₃) −1.4, 18.1, 19.4, 20.2, 24.8, 25.5, 27.1,

29.6, 31.3, 36.3, 37.0, 38.1, 64.8, 72.8, 93.0, 125.5, 127.4(2),

128.2(2), 129.4, 134.6(2), 135.9 and 142.6; m/z (CI) 650

(M⁺+ 18, 27%), 447 (100) and 90 (86).

(3RS,10RS)-3-tert-Butyldiphenylsilyloxy-1-phenyl-10-(2-trimethyl-

silylethoxy)methoxyundec-1-ene 68. The epoxide 65 (904 mg,

1.40 mmol) in THF (2 mL) was added to samarium diiodide in

THF (28 mL, 0.1 M in THF, 2.8 mmol) and the mixture stirred

at room temperature for 3 h. Dilute aqueous hydrogen chloride

was added and the aqueous phase extracted with ether. The

organic extracts were washed with saturated aqueous sodium

hydrogen carbonate, water, saturated aqueous sodium thiosulfate,

water, then brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (3%), gave the title compound 68 (493 mg,

56%) as a clear, colourless oil, a 75 : 25 mixture of (E)- and

(3RS,10RS,1E,5E,8Z)-3-tert-Butyldiphenylsilyloxy-1-phenyl-10-

(2-trimethylsilylethoxy)methoxyundeca-1,5,8-triene 66. Imida-

zole (99 mg, 1.45 mmol) and tert-butyldiphenylchlorosilane

(189 μL, 0.73 mmol) were added to the alcohol 50 (141 mg,

0.36 mmol) in DCM (200 μL) at room temperature. The mixture

was stirred for 2.5 h then diluted with DCM and water. The

aqueous phase was extracted with DCM and the organic extracts

washed with brine, dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue, eluting with

ethyl acetate–petrol (5%), gave the title compound 66 (189 mg,

82%) as a clear, colourless oil (Found: M⁺+ NH₄644.3935.

C₃₉H₅₈NSi₂O₃requires M, 644.3955); ν_max/cm⁻¹3025, 2955,

2892, 1654, 1591, 1471, 1428, 1248, 1108, 1054, 1026, 966,

859, 835, 741 and 702; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 ×

SiCH₃), 0.91 (2 H, t, J 8.4, CH₂Si), 1.08 [9 H, s, SiC(CH₃)₃],

1.19 (3 H, d, J 6.6, 11-H₃), 2.25 (2 H, m, 4-H₂), 2.74 (2 H, m,

7-H₂), 3.50 (1 H, dt, J 7.3, 9.6, OHCHCH₂), 3.69 (1 H, dt, J 7.6,

9.5, OHCHCH₂), 4.31 (1 H, q, J 6.2, 3-H), 4.51 (1 H, dq, J 8.4,

6.6, 10-H), 4.54 and 4.61 (each 1 H, d, J 6.9, OHCHO),

5.22–5.50 (4 H, m, 5-H, 6-H, 8-H and 9-H), 6.10 (1 H, dd,

J 6.3, 15.9, 2-H), 6.22 (1 H, d, J 15.9, 1-H), 7.17–7.44 (11 H,

m, ArH) and 7.67 (4 H, m, ArH); δ_C(75 MHz, CDCl₃) −1.4,

18.1, 19.3, 21.4, 27.0, 30.8, 41.4, 64.9, 66.6, 74.3, 91.7, 126.4,

126.5, 127.2, 127.3, 127.4, 128.3, 129.4, 129.5, 129.8, 130.2,

130.7, 131.6, 132.1, 134.1, 134.3, 135.9, 136.0 and 137.1; m/z

(CI) 644 (M⁺+ 18, 2%), 371 (5), 274 (10), 253 (13), 196 (20),

90 (100) and 58 (63).

(Z)-isomers (¹H NMR) (Found: M⁺

+ NH₄648.4260.

C₃₉H₆₂NSi₂O₃requires M, 648.4268); ν_max/cm⁻¹3028, 2931,

2858, 1466, 1428, 1249, 1108, 1055, 836, 742 and 701; δ_H

(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H, m,

CH₂Si), 0.98–1.62 (12 H, m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂and

9-H₂), 1.01 [2.25 H, s, SiC(CH₃)₃], 1.07 [6.75 H, s, SiC(CH₃)₃],

1.12 (2.25 H, d, J 6.1, 11-H₃), 1.13 (0.75 H, d, J 6.0, 11-H₃),

3.63 (3 H, m, OCH₂CH₂and 10-H), 4.27 (1 H, q, J 5.9, 3-H),

4.64 (0.75 H, d, J 7.1, OHCHO), 4.65 (0.25 H, d, J 7.0,

OHCHO), 4.71 (0.75 H, d, J 7.0, OHCHO), 4.72 (0.25 H, d,

J 7.1, OHCHO), 5.71 (0.25 H, dd, J 9.2, 11.7, 2-H), 6.05–6.29

(1.75 H, m, 2-H and 1-H) and 6.80–7.72 (15 H, m, ArH); m/z

(CI) 648 (M⁺+ 18, 12%), 392 (16), 375 (13), 274 (68), 257 (86)

and 90 (100).

Methyl (4RS,11RS,2E)-4-tert-butyldiphenylsilyloxy-11-(2-tri-

methylsilylethoxy)methoxydodec-2-enoate 69. Oxygen was

bubbled through a solution of alkene 68 (697 mg, 1.11 mmol) in

DCM (40 mL) at −78 °C for 10 min followed by ozonolysed

oxygen for 1.5 h. After this time, the solution had turned pale

blue. Oxygen was bubbled through the solution for a further

10 min and then dimethyl sulﬁde (0.81 mL, 11.1 mmol) was

added. The mixture was allowed to warm to room temperature

and concentrated under reduced pressure to leave the corres-

ponding undecanal (183 mg, 69%) as a clear, colourless oil. This

was dissolved in DCM (5 mL) and methoxycarbonylmethylene

triphenyl phosphorane (1.11 g, 3.3 mmol) was added. After

15 h, water was added and the aqueous phase extracted with

DCM. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. Chromato-

graphy of the residue eluting with ethyl acetate–petrol (1%) gave

the title compound 69 (411 mg, 61%) as a clear colourless oil

(Found: M⁺+ NH₄630.3998. C₃₅H₆₀NSi₂O₅requires M,

630.4010); ν_max/cm⁻¹3048, 2932, 2859, 1727, 1660, 1431,

1273, 1166, 1107, 1054, 859, 835 and 704; δ_H(300 MHz,

CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.90 (2 H, m, CH₂Si), 1.04

[9 H, s, SiC(CH₃)₃], 1.12 (3 H, d, J 6.3, 12-H₃), 1.10–1.55 (12

H, m, 5-H₂, 6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂), 3.62 (3 H, m,

OCH₂CH₂and 11-H), 3.70 (3 H, s, OCH₃), 4.32 (1 H, dq, J 1.2,

5.0, 4-H), 4.68 and 4.70 (each 1 H, d, J 6.9, OHCHO), 5.92

(1 H, dd, J 1.5, 15.4, 2-H), 6.85 (1 H, dd, J 5.2, 15.4, 3-H), 7.36

(6 H, m, ArH) and 7.62 (4 H, m, ArH); δ_C(75 MHz, CDCl₃)

(3RS,10RS)-3-tert-Butyldiphenylsilyloxy-1-phenyl-10-(2-trimethyl-

silylethoxy)methoxyundecane 67. Sodium acetate (791 mg,

5.81 mmol) in water (2 mL) was added dropwise over 2 h to the

triene 66 (182 mg, 0.29 mmol) and toluene 4-sulfonylhydrazine

(650 mg, 3.49 mmol) in DME (8 mL) heated under reﬂux. The

solution was heated under reﬂux for a further 2.5 h and then

allowed to cool to room temperature. The aqueous phase was

extracted with ether and the organic extracts washed with water

and brine, dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue, eluting with ethyl

acetate–petrol (5%), gave the title compound 67 (125 mg, 68%)

as a clear, colourless oil (Found: M⁺+ NH₄650.4416.

C₃₉H₆₄NSi₂O₃requires M, 650.4425); ν_max/cm⁻¹3069, 3026,

2931, 2857, 1428, 1459, 1375, 1249, 1107, 1056, 858, 835 and

702; δ_H(300 MHz, CDCl₃) 0.00 (9 H, s, 3 × SiCH₃), 0.92 (2 H,

m, CH₂Si), 1.06 [9 H, s, SiC(CH₃)₃], 1.13 (3 H, d, J 6.2, 11-H₃),

1.04–1.52 (12 H, m, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H₂and 9-H₂),

1.72 (2 H, m, 2-H₂), 2.55 (2 H, m, 1-H₂), 3.63 (3 H, m, 10-H,

OCH₂CH₂), 3.78 (1 H, quin., J 5.5, 3-H), 4.65 and 4.71 (each

1 H, d, J 7.0, OHCHO), and 6.99–7.74 (15 H, m, ArH);

Org. Biomol. Chem., 2012, 10, 6995–7014 | 7013

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−1.5, 18.0, 19.3, 20.2, 23.9, 25.5, 27.0, 29.4(2), 36.6, 36.9,

51.4, 64.7, 72.3, 72.8, 92.9, 119.6, 127.5(2), 129.6, 129.7,

133.4, 133.9, 135.7, 150.5 and 167.0; m/z (CI) 630 (M⁺+ 18,

2%), 274 (35), 196 (32) and 90 (100).

with ethyl acetate–petrol (10%), gave the title compound 40^1,2h

(8 mg, 61%) as a clear, colourless oil (Found: M⁺+ H,

213.1494. C₁₂H₂₁O₃requires M, 213.1491); ν_max/cm⁻¹3433,

2934, 2860, 1711, 1644, 1459, 1356, 1249, 1100 and 1000; δ_H

(300 MHz, CDCl₃) 1.15–1.70 (10 H, m, 6-H₂, 7-H₂, 8-H₂, 9-H₂

and 10-H₂), 1.29 (3 H, d, J 6.5, 11-CH₃), 1.81 (1 H, d, J 4.0,

OH), 1.88 (2 H, m, 5-H₂), 4.50 (1 H, m, 4-H), 5.05 (1 H, dquin,

J 3.0, 6.5, 11-H), 6.05 (1 H, dd, J 2.0, 16.0, 2-H) and 7.02 (1 H,

dd, J 4.5, 16.0, 3-H); δ_C(75 MHz, CDCl₃) 19.7, 21.4, 22.8,

27.7, 28.0, 33.4, 36.4, 71.5, 73.2, 120.3, 151.2 and 167.3; m/z

(CI) 230 (M⁺+ 18, 48%), 213 (100) and 195 (12).

Methyl (2E,4RS,11RS)-4-tert-butyldiphenylsilyloxy-11-hydro-

xydodec-2-enoate 70. Butanethiol (0.50 mL, 4.7 mmol) was

added to a vigorously stirred suspension of potassium carbonate

(740 mg, 5.4 mmol), magnesium bromide diethyl etherate

(1.21 g, 4.7 mmol) and the SEM-ether 69 (411 mg, 0.67 mmol)

in ether (6 mL) at room temperature and the resulting mixture

stirred for 1.5 h. Dilute aqueous sodium bicarbonate and water

were added and the aqueous phase extracted with ether. The

organic extracts were washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue, eluting with ethyl acetate–petrol (20%), gave the title

compound 70 (254 mg, 79%) as a clear, colourless oil (Found:

M⁺+ NH₄, 500.3192. C₂₉H₄₆SiNO₄requires M, 500.3196);

ν_max/cm⁻¹3347, 2931, 2857, 1725, 1659, 1463, 1430, 1276,

1166, 1108 and 703; δ_H(300 MHz, CDCl₃) 1.08 [9 H, s, SiC

(CH₃)₃], 1.17 (3 H, d, J 6.2, 12-H₃), 1.00–1.50 (12 H, m, 5-H₂,

6-H₂, 7-H₂, 8-H₂, 9-H₂and 10-H₂), 3.72 (3 H, s, OCH₃), 3.74

(1 H, m, 11-H), 4.35 (1 H, q, J 5.1, 4-H), 5.94 (1 H, dd, J 1.4,

15.4, 2-H), 6.87 (1 H, dd, J 5.8, 15.4, 3-H), 7.31–7.46 (6 H, m,

ArH) and 7.58–7.69 (4 H, m, ArH); δ_C(75 MHz, CDCl₃) 19.3,

23.4, 23.8, 25.5, 27.0, 29.3(2), 36.6, 39.2, 51.4, 68.0, 72.3,

119.6, 127.5, 129.6, 129.7, 133.4, 133.9, 135.7, 150.5

and 167.0; m/z (CI) 500 (M⁺+ 18, 18%), 483 (M⁺+ 1, 20),

274 (80), 244 (85), 227 (100) and 196 (80).

Lithium hydroxide monohydrate (111 mg, 2.63 mmol) was

added to the methyl ester 70 (254 mg, 0.53 mmol) in methanol–

water (4 mL, 3 : 1) and the solution stirred for 15 h. After con-

centration under reduced pressure, the residue was taken up in

water and ethyl acetate. The aqueous phase was extracted with

ethyl acetate and the organic extracts washed with brine, dried

(MgSO₄) and concentrated under reduced pressure to leave the

seco-acid (204 mg, 82%) that was used without further

puriﬁcation.

Triethylamine (18 μL, 13 μmol) and 2,6-dichlorobenzoyl

chloride (17 μL, 12 μmol) were added to the seco-acid (55 mg,

12 μmol) in THF (1 mL) and the solution stirred for 6 h. The

mixture was ﬁltered and diluted with toluene (50 mL). This solu-

tion was then added dropwise over 3.5 h to a solution of DMAP

(85 mg, 0.69 mmol) in toluene (10 mL) heated under reﬂux. The

solution was then allowed to cool and water and ether were

added. The aqueous phase was extracted with ether and the

organic extracts washed with brine, dried (MgSO₄) and concen-

trated under reduced pressure. Chromatography of the residue,

eluting with ethyl acetate–petrol (1%), gave the macrolide 39^2h

(28 mg, 52%) as a clear, colourless oil (Found: M⁺, 451.2658.

C₂₈H₃₈SiO₃requires M, 451.2668). The second fraction was the

macrolide 38^2h(2 mg, 4%) as a clear, colourless oil.

Acknowledgements

We thank Astra Zeneca for a studentship (to E. K. D.).

Notes and references

1 D. Rodphaya, J. Sekiguchi and Y. Yamada, J. Antibiot., 1986, 39, 629.

2 previous total syntheses see: (a) R. M. Risi and S. D. Burke, Org. Lett.,

2012, 14, 1180; (b) G. Sabitha, G. Chandrashekhar, K. Yadagiri and

J. S. Yadav, Tetrahedron Lett., 2010, 51, 3824; (c) K. V. Babu and

G. V. M. Sharma, Tetrahedron: Asymmetry, 2008, 19, 577; (d) J. Tian,

N. Yamagiwa, S. Matsunaga and M. Shibasaki, Org. Lett., 2003, 5, 3021;

(e) L. Kaisalo, J. Koskimies and T. Hase, Synth. Commun., 1999, 29,

399; (f) S. Takano, T. Murakami, K. Samizu and K. Ogasawara, Hetero-

cycles, 1994, 39, 67; (g) F. M. C. Leemhuis, L. Thijs and

B. Zwanenburg, J. Org. Chem., 1993, 58, 7170; (h) H. Yang, H. Kuroda,

M. Miyashita and H. Irie, Chem. Pharm. Bull., 1992, 40, 1616.

3 J. S. Carey, S. MacCormick, S. J. Stanway, A. Teerawutgulrag and

E. J. Thomas, Org. Biomol. Chem., 2011, 9, 3896.

4 E. J. Thomas, Chem. Rec., 2007, 7, 115.

5 E. K. Dorling and E. J. Thomas, Tetrahedron Lett., 1999, 40, 471.

6 E. K. Dorling, A. P. Thomas and E. J. Thomas, Tetrahedron Lett., 1999,

40, 475.

7 M.-A. Hiebel, B. Pelotier and O. Piva, Tetrahedron, 2007, 63, 7874.

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7014 | Org. Biomol. Chem., 2012, 10, 6995–7014

Article Doi

An approach to aliphatic 1,8-stereocontrol: Diastereoselective syntheses of (±)-patulolide C and (±)-epipatulolide C

DOI: 10.1039/c2ob25992c

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Article abstract of DOI:10.1039/c2ob25992c

Full text of DOI:10.1039/c2ob25992c

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